Idebenone Derivatives and Their Use in Treating Plants - Patent application

Abstract

The present invention relates to compounds comprising a mitochondrial targeting group linked to a group capable of releasing hydrogen sulfide for use in the treatment of the human or animal body, or tissues and cells derived therefrom, as well as use in the treatment of plants and novel related compounds. TIFF2024535017000036.tif25170

Description

[Technical field]

[0001] The present invention relates to compounds comprising a mitochondrial targeting group linked to a group capable of releasing hydrogen sulfide for use in the treatment of the human or animal body, or tissues and cells derived therefrom, as well as use in the treatment of plants and novel related compounds. [Background technology]

[0002] Mitochondrially targeted H2S donor compounds In 2014, the first mitochondrially targeted H2S donor, AP39, was reported [Szczesny et al., 2014]. This compound is characterized by its lipophilicity and its affinity for decyl-TPP. + Due to its positive charge, it is taken up into mitochondria. AP39 also showed a concentration-dependent increase in intracellular levels of H2S, mainly inside mitochondria, an increase in ATP production in endothelial cells, and an increase in protein hypersulfuration inside mitochondria. However, AP39 is hygroscopic, has low water solubility, and has potential toxicity issues, and has not been developed as a drug.

[0003] Idebenone Coenzyme Q10 (CoQ10) or ubiquinone exerts redox and antioxidant effects due to the presence of a 1,4-benzoquinone ring. CoQ10 also has the ability to interact with other redox carriers in the mitochondrial electron transport chain [Escribano-Lopez et al., 2019]. To obtain an analogue with the same antioxidant properties but with better bioavailability, idebenone was developed by Takeda Pharmaceutical Co. (Osaka, Japan) and launched on the market in 1986 as a drug against age-related brain dysfunction [Sugiyama and Fujita, 1985]. No studies have been performed using the mitochondrial targeting properties of idebenone and derivatives to target H2S donors to mitochondria.

[0004] Several idebenone derivatives have been made as antioxidants. [Table 1]

[0005] Several idebenone derivatives have also been made as donors of the gaseous transmitter nitric oxide. [Table 2]

[0006] There remains an urgent unmet clinical need for H2S donor molecules with improved mitochondrial targeting properties.

[0007] “In Vitro Antioxidant Activity of Idebenone Derivative-Loaded Solid Lipid Nanoparticles” Lucia Montenegro et al., Molecules 2017, 22, 887 discloses idebenone derivatives for the treatment of neurodegenerative diseases involving mitochondrial dysfunction.

[0008] “Coenzyme Q Functionalized CdTe / ZnS Quantum Dots for Reactive Oxygen Species (ROS) Imaging”, Li-Xia Qin et al., Chem. Eur. J. 2011, 17, 5262-5271, discloses CoQ-derivatized QDs as probes for imaging redox coenzyme function in vitro and in vivo. [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] Szczesny B et al. (2014) Nitric Oxide 41:120-130 [Non-Patent Document 2] Escribano-Lopez I et al. (2019) Cell Physiol Biochem 52(2):186-197 [Non-Patent Document 3] Sugiyama Y and Fujita T (1985) FEBS Lett. 184(1):48-51 [Non-Patent Document 4] Lucia Montenegro et al., Molecules 2017, 22, 887 [Non-Patent Document 5] Li-Xia Qin et al., Chem.Eur.J. 2011, 17, 5262-5271 Summary of the Invention [Means for solving the problem]

[0010] The present invention provides active compounds, specifically mitochondrially targeted H2S donors as described herein.

[0011] The term "active" as used herein specifically includes both compounds (drugs) that have intrinsic activity and prodrugs of such compounds, which themselves may exhibit little or no intrinsic activity.

[0012] One aspect of the present invention relates to active H2S donor compounds described herein that are targeted to mitochondria.

[0013] According to a first aspect of the present invention there is provided a compound of formula (I) or a pharma- ceutically acceptable salt thereof: [ka] In the formula, R 1 and R 2 are independently 1~6 Alkyl group, C 1~6 alkoxy groups, or taken together form a cycloalkyl or aryl ring; R 3 is C 1~6 Alkyl group or C1~6 is an alkoxy group, L is a linker group; A is a group capable of releasing hydrogen sulfide.

[0014] The inventors have found that compounds of formula (I) may provide effective treatment for neuromuscular or muscular conditions, particularly those mediated by mitochondrial H2S donors (mtH2SDs), by targeting the mitochondria via the 1,4-benzoquinone ring and releasing hydrogen sulfide in the mitochondria to produce the desired physiological effect.

[0015] According to a second aspect of the invention there is provided a compound according to the first aspect for use as a medicament.

[0016] According to a third aspect of the invention there is provided a compound according to the first aspect for use in the treatment of a neuromuscular or muscular condition.

[0017] The neuromuscular or muscular condition may be mediated by mtH2SD. The neuromuscular or muscular condition may be selected from Duchenne muscular dystrophy, COPD, Leigh syndrome, primary mitochondrial disease, pancreatic islet transplantation, pre-eclampsia, heart transplantation, kidney transplantation, cardiovascular dysfunction, blunt chest trauma and hemorrhagic shock, necrotizing enterocolitis, myocardial reperfusion injury, burns, diabetic vascular disease, Alzheimer's disease, acute kidney injury, neurological injury following cardiac arrest, and hypertension.

[0018] Suitably the compound according to the first aspect is for use in the treatment of a disease associated with mitochondrial dysfunction, such as the diseases / conditions listed above.

[0019] According to a fourth aspect of the invention there is provided a pharmaceutical composition comprising a compound according to the first aspect, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, excipient or diluent, optionally for use in the treatment of a neuromuscular or muscular condition.

[0020] According to a fifth aspect of the present invention there is provided a method of prevention, management and / or treatment of a neuromuscular or muscular condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to the first aspect or a pharmaceutical composition according to the fourth aspect.

[0021] Another aspect of the present invention relates to active compounds described herein for treating neuromuscular or muscular conditions, such as muscular dystrophies.

[0022] Another aspect of the present invention pertains to active compounds described herein that treat conditions known to be mediated by mtH2SD or believed to be treatable by mtH2SD (eg, AP39, etc.).

[0023] Another aspect of the present invention pertains to compositions comprising a compound described herein and a pharma- ceutically acceptable carrier.

[0024] Another aspect of the present invention relates to a method of H2S donation in a cell, comprising the step of contacting said cell with an effective amount of an active compound described herein.

[0025] Another aspect of the present invention relates to a method of providing H2S, comprising contacting a cell in vitro or in vivo with an effective amount of an active compound described herein.

[0026] Another aspect of the present invention relates to a method for treating a condition in a patient, comprising administering to said patient a therapeutically effective amount of an active compound as described herein. In a preferred embodiment, the condition is muscular dystrophy. In a preferred embodiment, the condition is Duchenne muscular dystrophy.

[0027] Another aspect of the invention relates to a method of treating a condition in a patient known to be mediated by an mtH2SD or believed to be treatable by an mH2SD (e.g., AP39, etc.), comprising administering to the patient a therapeutically effective amount of an active compound described herein.

[0028] Another aspect of the present invention pertains to an active compound described herein for use in a method of treatment of the human or animal body.

[0029] Another aspect of the invention relates to the use of an active compound as described herein for the manufacture of a medicament for use in the treatment of a neuromuscular or muscular condition. In one preferred embodiment, the proliferative condition is a muscular dystrophy.

[0030] In one preferred embodiment, the proliferative condition is Duchenne muscular dystrophy.

[0031] In one preferred embodiment, the proliferative condition is COPD (chronic obstructive pulmonary disease).

[0032] Another aspect of the invention relates to the use of an active compound for the manufacture of a medicament for the treatment of a condition known to be mediated by mtH2SD or known to be treated by mtH2SD (e.g., AP39, etc.), e.g., as discussed herein. Such conditions include: Duchenne muscular dystrophy (Ellwood et al., 2021) COPD, airway inflammation (Karaman et al., 2020) Leigh syndrome, a primary mitochondrial disease (Fox et al., 2020) Islet transplantation (Nishime et al., 2020) Preeclampsia (Sanchez-Aranguren et al., 2020; Covarrubias et al., 2019) Heart transplantation (Zhu et al., 2019) Kidney transplantation (Juriasingani et al., 2018; Lobb et al., 2017) Cardiovascular dysfunction (Latorre et al., 2018) Blunt chest trauma and hemorrhagic shock (Wepler et al., 2019) Necrotizing enterocolitis (Drucker et al., 2018) Myocardial reperfusion injury (Karwi et al., 2017; Chatzianastasiou et al., 2016) Burn injury (Ahmad et al., 2016) Diabetic vascular disease (Gero et al., 2016) Alzheimer’s disease (Zhao et al., 2016) Acute kidney injury (Ahmad et al., 2016) Neurological damage after cardiac arrest (Ikeda et al., 2015) High blood pressure (Tomasova 2015) These include, but are not limited to:

[0033] Another aspect of the invention relates to a kit comprising: (a) an active compound, preferably provided as a pharmaceutical composition, in a suitable container and / or in suitable packaging; and (b) instructions for use, e.g., written instructions on how to administer the active compound.

[0034] Another aspect of the present invention pertains to compounds obtained by the synthetic methods described herein, or by a process comprising the synthetic methods described herein.

[0035] Another aspect of the present invention pertains to compounds obtained by the synthetic methods described herein, or by a process comprising the synthetic methods described herein.

[0036] Another aspect of the present invention pertains to novel intermediates, as described herein, that are suitable for use in the synthetic methods described herein.

[0037] Another aspect of the present invention pertains to the use of such novel intermediates described herein in the synthetic methods described herein.

[0038] The present invention also provides a method for producing H2S in the mitochondria of a cell, comprising contacting the cell with an effective amount of an active compound. Such a method may be performed in vitro or in vivo. In one embodiment, the method is performed in vitro. In one embodiment, the method is performed in vivo. Preferably, the active compound is provided in the form of a pharma- ceutically acceptable composition.

[0039] Those skilled in the art can easily determine whether a candidate compound counteracts mitochondrial dysfunction.For example, one assay that can be conveniently used to evaluate the level of mitochondrial dysfunction provided by a particular compound is described in the following examples.

[0040] For example, a sample of cells may be grown in vitro, an active compound may be contacted with the cells, and the effect of the compound on these cells may be observed. As an example of an "effect", the morphological state of the cells (e.g., alive or dead, etc.) may be determined. If an active compound is found to have an effect on the cells, this may be used as a prognostic or diagnostic marker of the effectiveness of the compound in methods of treating patients harboring cells of the same cell type. [Brief description of the drawings]

[0041] [Figure 1] Figure 2 shows aging-induced fragmentation of the mitochondrial network in C. elegans. [Diagram 2] Figure 2 shows the decline in networked mitochondria in C. elegans caused by aging. [Diagram 3] Figure 2 shows damage caused to the mitochondrial network in aging C. elegans. [Figure 4] The results of the test compound Example 17 are shown.

[0042] Treatment method The present invention further provides a method of treatment comprising the step of administering to a subject in need of treatment a therapeutically effective amount of an active compound, preferably in the form of a pharmaceutical composition.

[0043] The present invention further provides active compounds for use in a method of treatment of the human or animal body by therapy, e.g., in the treatment of a condition mediated by an H2S donor, a condition known to be treated by an H2S donor (e.g., AP39), or other condition described herein.

[0044] The invention further provides the use of the active compounds for the manufacture of a medicament for the treatment of a condition, e.g., a condition mediated by mitochondrial dysfunction or a condition known to be treated by a compound known to counteract mitochondrial dysfunction (e.g., AP39, etc.).

[0045] treatment The terms "treatment", "treating", when used herein in the context of treating a condition, generally relate to treatments and therapies, whether of humans or animals (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, such as inhibition of progression of the condition, including slowing the rate of progression, stopping the rate of progression, improving the condition, and curing the condition. Treatment as a preventative measure (i.e., prophylaxis) is also included.

[0046] The term "therapeutically effective amount," as used herein, refers to an amount of an active compound, or a material, composition, or dosage form containing an active compound, effective to produce some desired therapeutic effect, commensurate with a reasonable benefit / risk ratio.

[0047] The term "treatment" includes combination treatments and combination therapies, where two or more treatments (therapeutics) or therapies are combined, for example, sequentially or simultaneously. Examples of treatments (therapeutics) and therapies include, but are not limited to, small molecules, gene therapy, cell therapy, and antibody therapy.

[0048] The active compounds may also be used in combination therapy, ie in conjunction with other drugs, such as steroids, as described above.

[0049] The present invention also provides active compounds that combat mitochondrial dysfunction and treat conditions mediated by mitochondrial dysfunction.

[0050] The term "condition mediated by mitochondrial dysfunction", as used herein, relates to a condition in which mitochondrial dysfunction is important or necessary for, e.g., onset, progression, development, etc., or which is known to be treated by compounds that counteract mitochondrial dysfunction, such as, e.g., AP39.

[0051] One of skill in the art can readily determine whether a candidate compound treats a condition involving mitochondrial dysfunction in any particular cell type. For example, the Examples below describe assays that may be conveniently used to evaluate the activity offered by a particular compound.

[0052] The present invention also provides active compounds that are mitochondrial H2S donors and treat diseases associated with mitochondrial dysfunction, a non-limiting list of such indications is given above.

[0053] Route of administration The active compound or a pharmaceutical composition containing the active compound may be administered to a subject by any convenient route of administration, either systemically / peripherally or locally (ie, to the desired site of action).

[0054] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal (buccal); sublingual; transdermal (including, e.g., by patches, plasters, etc.); transmucosal (including, e.g., by patches, plasters, etc.); intranasal (e.g., by intranasal spray); ocular (e.g., by eye drops); pulmonary (e.g., via aerosol, e.g., through the mouth or nose, e.g., by inhalation or insufflation therapy); rectal (e.g., by suppository or enema); intravaginal (e.g., by pessary); parenteral, e.g., by injection, such as subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, subarachnoid, and intrasternal; e.g., by subcutaneous or intramuscular depot or reservoir placement.

[0055] subject The subject may be a prokaryote (eg, a bacterium) or a eukaryote (eg, a protist, a fungus, a plant, an animal).

[0056] The subject may be an animal, mammal, placental, marsupial, monotreme, rodent (e.g., guinea pig, hamster, rat, mouse), murine (e.g., mouse), lagomorph (e.g., rabbit), avian (e.g., bird), canine (e.g., dog), feline (e.g., cat), equine (e.g., horse), porcine (e.g., pig), ovine (e.g., sheep), bovine (e.g., cow), primate, simian (e.g., monkey or ape), monkey, ape, or human.

[0057] Furthermore, the subject may be any of its developmental forms, for example, a spore, seed, egg, larva, pupa, or fetus.

[0058] Preferably, the subject is a human.

[0059] formulation While it is possible for an active compound to be used (eg, administered) alone, it is often preferable to present the active compound as a formulation.

[0060] Accordingly, one aspect of the present invention pertains to a composition comprising a compound described herein and a carrier.

[0061] In one embodiment, the composition is a pharmaceutical composition (eg, formulation, preparation, medicament) comprising a compound described herein and a pharma- ceutically acceptable carrier.

[0062] In one embodiment, the composition is a pharmaceutical composition comprising at least one compound described herein in combination with one or more other pharma- ceutically acceptable ingredients known to those of skill in the art, including, but not limited to, pharma- ceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, antioxidants, lubricants, stabilizers, solubilizers, surfactants (e.g., wetting agents), masking agents, colorants, flavoring agents, and sweetening agents.

[0063] In one embodiment, the composition further comprises other active agents, eg, other therapeutic or prophylactic agents.

[0064] Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical texts, see, for example, Handbook of Pharmaceutical Additives, 2nd Edition (edited by M. Ash and I. Ash), 2001 (Synapse Information Resources, Inc., Endicott, NY, USA), Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton, PA, 1990; and Handbook of Pharmaceutical Excipients, 2nd edition, 1994.

[0065] Another aspect of the present invention relates to a process for the preparation of a pharmaceutical composition comprising mixing at least one active compound as defined above with one or more other pharma- ceutically acceptable ingredients well known to those skilled in the art, such as carriers, diluents, excipients, etc. When formulated as discrete units (e.g., tablets, etc.), each unit contains a given amount (dosage) of the active compound.

[0066] The term "pharmaceutical acceptable" as used herein refers to compounds, ingredients, materials, compositions, dosage forms, etc., that are suitable for use in contact with the tissues of the subject of interest (e.g., humans) without undue toxicity, irritation, allergic response, or other problem or complication, within the scope of sound medical judgment, commensurate with a reasonable benefit-risk ratio. Each carrier, diluent, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

[0067] The formulation may be prepared by any method well known in the art of pharmacy. Such methods include the step of bringing active compound into association with carrier, which constitutes one or more accessory ingredients. In general, the formulation is prepared by uniformly and intimately bringing active compound into association with carrier (e.g., liquid carrier, finely divided solid carrier, etc.), and then, if necessary, shaping the product.

[0068] The formulations may be prepared to provide fast or slow release; immediate, delayed, timed, or sustained release; or combinations thereof.

[0069] The formulation may suitably be in the form of a liquid, solution (e.g., aqueous, non-aqueous), suspension (e.g., aqueous, non-aqueous), emulsion (e.g., oil-in-water, water-in-oil), elixir, syrup, electuary, mouthwash, drops, tablet (including, e.g., coated tablets), granules, powder, lozenges, troches, capsules (including, e.g., hard and soft gelatin capsules), cachets, pills, ampoules, boluses, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, mists, or aerosols.

[0070] The formulations may be suitably presented as a patch, adhesive plaster, bandage, dressing, etc. impregnated with one or more active compounds and optionally one or more other pharma- ceutically acceptable ingredients (including, for example, penetration enhancers, permeation enhancers, and absorption enhancers). The formulations may be suitably presented in the form of a depot or reservoir.

[0071] The active compound may be dissolved, suspended, or mixed with one or more other pharma- ceutically acceptable ingredients. The active compound may also be presented in liposomes or other microparticles designed to target the active compound, for example, to blood components or one or more organs.

[0072] Formulations suitable for oral administration (e.g., by ingestion) include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, lozenges, tablets, granules, powders, capsules, cachets, pills, ampoules, and boluses.

[0073] Formulations suitable for oral administration include mouthwash, lozenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.Lozenges typically contain the active compound in a flavored base, usually sucrose and gum arabic or tragacanth.Pastryches typically contain the active compound in an inert matrix such as gelatin and glycerin, or sucrose and gum arabic.Mouthwashes typically contain the active compound in a suitable liquid carrier.

[0074] Formulations suitable for sublingual administration include tablets, lozenges, troches, capsules, and pills.

[0075] Formulations suitable for oral transmucosal administration include solutions, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), mouthwashes, lozenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.

[0076] Formulations suitable for parenteral transmucosal administration include solutions, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), suppositories, pessaries, gels, pastes, ointments, creams, lotions, oils, as well as patches, adhesive plasters, depots and reservoirs.

[0077] Formulations suitable for transdermal administration include gels, pastes, ointments, creams, lotions, and oils, as well as patches, adhesive plasters, bandages, dressings, depots, and reservoirs.

[0078] Tablets may be made by conventional means, such as compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by mixing the active compound in a free-flowing form, such as powder or granules, with one or more binders (e.g., povidone, gelatin, gum arabic, sorbitol, tragacanth, hydroxypropylmethylcellulose); fillers or diluents (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, silica); disintegrants (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethylcellulose); surfactants or dispersants or wetting agents (e.g., sodium lauryl sulfate); preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid); flavors, flavor enhancers, and sweeteners, and compressing them in a suitable machine. Molded tablets (molded tablets) may be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine. The tablets may optionally be coated or scored and may be formulated to provide slow or controlled release of the active compound therein, for example using various percentages of hydroxypropyl methylcellulose to provide the desired release profile. The tablets may optionally be provided with a coating, for example to affect release, for example an enteric coating to provide release in parts of the digestive tract other than the stomach.

[0079] Ointments are typically prepared from the active compound and either a paraffinic or a water-miscible ointment base.

[0080] Creams are typically prepared from an active compound and an oil-in-water cream base. If desired, the aqueous phase of the cream base may contain, for example, at least about 30% w / w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups, such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol, and mixtures thereof. Topical formulations may desirably contain a compound that enhances the absorption or penetration of the active compound through the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogues.

[0081] Emulsions are typically prepared from active compounds and an oil phase, which may optionally contain only an emulsifier (also known as an emulgent) or a mixture of at least one emulsifier with a fat or oil, or both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier with or without a stabilizer constitutes the so-called emulsifying wax, which together with the oil and / or fat constitutes the so-called emulsifying ointment base that forms the oily dispersed phase of the cream formulation.

[0082] Suitable emulgents and emulsion stabilizers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate (glyceryl monostearate) and sodium lauryl sulfate. The choice of oil or fat suitable for the formulation is based on achieving the desired cosmetic properties. This is because the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations may be very low. Thus, creams should preferably be non-greasy, non-staining and washable products with suitable consistency to avoid leakage from tubes or other containers. Linear or branched alkyl esters of mono- or dibasic acids such as diisoadipate, isocetyl stearate, propylene glycol diesters of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched esters known as Crodamol CAP may be used, the last three being the preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils can be used.

[0083] Formulations suitable for intranasal administration, where the carrier is a liquid, include, for example, nasal spray, nasal drops, or aerosol administration by nebulizer, include aqueous or oily solutions of the active compound.

[0084] Formulations suitable for intranasal administration wherein the carrier is a solid include, for example, those presented as a coarse powder having a particle size in the range, for example, from about 20 to about 500 microns (about 20 to about 500 μm) and administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close to the nose.

[0085] Formulations suitable for pulmonary administration (e.g., by inhalation or insufflation therapy) include those presented as an aerosol spray from pressurized packs with the use of a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.

[0086] Formulations suitable for ocular administration include eye drops wherein the active compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active compound.

[0087] Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, such as cocoa butter or salicylates; or as solutions or suspensions for treatment by enema.

[0088] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active compound such carriers as are known in the art to be appropriate.

[0089] Formulations suitable for parenteral administration (e.g., by injection) include aqueous or non-aqueous, isotonic, pyrogen-free, sterile liquids (e.g., solutions, suspensions) in which the active compound is dissolved, suspended, or otherwise provided (e.g., in liposomes or other microparticles). Such liquids may further contain other pharma- ceutically acceptable components, such as antioxidants, buffers, preservatives, stabilizers, bacteriostats, suspending agents, thickening agents, and solutes that render the formulation isotonic with the blood (or other relevant bodily fluids) of the intended recipient. Examples of excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like. Examples of isotonic carriers suitable for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection.

[0090] Typically, the concentration of the active compound in the solution is about 1 ng / ml to about 10 μg / ml, for example, about 10 ng / ml to about 1 μg / ml. The preparations may be provided in unit-dose or multi-dose sealed containers, such as ampoules and vials, and may be stored in a freeze-dried (lyophilized) state, requiring only the addition of a sterile liquid carrier, such as water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

[0091] Dosage It will be understood by those skilled in the art that the appropriate dosage of the active compound and compositions containing the active compound may vary from patient to patient. Determining the optimal dosage generally involves balancing the level of therapeutic benefit against any risk or adverse side effects. The selected dosage level will depend on a variety of factors, including but not limited to the activity of the particular compound, the route of administration, the timing of administration, the rate of excretion of the compound, the duration of treatment, other drugs, compounds, and / or substances used in combination, the severity of the condition, and the patient's species, sex, age, weight, condition, general health, and previous medical history. The amount of the compound and the route of administration are ultimately at the discretion of the physician, veterinarian, or clinician, but generally, the dosage is selected to achieve a local concentration at the site of action that achieves the desired effect without causing substantial harm or adverse side effects.

[0092] Administration can be in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosages of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician, veterinarian, or clinician.

[0093] kit One aspect of the present invention relates to a kit comprising: (a) an active ingredient, preferably provided in a suitable container and / or in suitable packaging; and (b) instructions for use, such as written instructions on how to administer the active compound.

[0094] The written instructions may also include a list of indications for which the active ingredient is a suitable treatment.

[0095] As will be appreciated by those skilled in the art, features and preferred embodiments of one aspect of the invention also relate to other aspects of the invention.

[0096] active compound The compound of the first aspect has the formula (I) or a pharma- ceutically acceptable salt thereof: [ka] In the formula, R 1 and R 2 are independently 1~6 Alkyl group, C 1~6 alkoxy groups, or taken together form a cycloalkyl or aryl ring; R 3 is C 1~6 Alkyl group or C 1~6 is an alkoxy group, L is a linker group; A is a group capable of releasing hydrogen sulfide.

[0097] In some embodiments, R 1 and R 2 are both C 1~6 Alkoxy groups, preferably C 1~3 An alkoxy group, preferably -OMe.

[0098] Preferably, R 3 is C 1~6 Alkyl group, preferably C 1~3 It is an alkoxy group.

[0099] Preferably, R 1and R 2 are both -OMe and R 3 is C 1~3 It is an alkyl group.

[0100] R 1 and R 2 together form a cycloalkyl or aryl ring, the cycloalkyl or aryl ring is preferably a 5-, 6- or 7-membered cycloalkyl or aryl ring, preferably a 5-, 6- or 7-membered aryl ring. The cycloalkyl or aryl ring may be optionally substituted, preferably with one or more of the following groups: C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, C1-C4 alkylthio, hydroxy, amino, nitro, thiol, chloro, fluoro, bromo, CF3, CHF2 or CH2F.

[0101] In some embodiments, R 1 and R 2 forms a 5- or 6-membered aryl ring, preferably a 6-membered aryl ring. Thus, in such embodiments, the compound comprises a 1,4-naphthoquinone group.

[0102] Suitably, the group A capable of releasing hydrogen sulfide is [ka] wherein X is S, O or N-OH; R 4 , R 5 and R 6 are independently H or C 1~7 The C is selected from the group consisting of alkyl groups. 1~7 The alkyl group may be optionally substituted, suitably with one or more of the following groups: C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, C1-C4 alkylthio, hydroxy, amino, nitro, thiol, chloro, fluoro, bromo, CF3, CHF2 or CH2F.

[0103] Suitably, X is S or O.

[0104] Preferably, R 4 is H.

[0105] Preferably, R 5 and R 6 is methyl or H, preferably H.

[0106] Suitably, the group A is selected from a thiocarbamoyl group, a 5-thioxo-5H-1,2-dithiol-3-yl group, a 5-thioxo-5H-1,2-dithiol-4-yl group, a 5-oxo-5H-1,2-dithiol-3-yl group, a 5-oxo-5H-1,2-dithiol-4-yl group, a 5-hydroxyimino-5H-1,2-dithiol-3-yl group, a 5-hydroxyimino-5H-1,2-dithiol-4-yl group, a phosphinodithioate group or a phosphinodithioic acid group.

[0107] Preferably, A is the following group: [ka] is selected from.

[0108] Preferably, the linker group L comprises a group B which is an optionally substituted alkyl chain, an optionally substituted alkenyl chain, or an optionally substituted alkynyl chain. Preferably, B is an unsubstituted C 1~20 Alkyl chain, preferably C 6~14 Alkyl chain, preferably C 8~12 It is an alkyl chain.

[0109] Preferably, the linker group L comprises a group Z, Z being selected from a direct bond, -C(=O)NH-, -NHC(=O)-, -O-, -S-, -S(=O)2NH-, -NHS(=O)2-, -OC(=O)-, -OC(=O)CHO- and -C(=O)O-. Preferably, Z is -C(=O)O- or -OC(=O)CHO-, preferably -C(=O)O-. Additionally, Z may be a group -OCH2C(=O)O-.

[0110] Preferably, the linker group L comprises a group Y which is an optionally substituted 5- or 6-membered cycloalkyl or aryl ring. Preferably, Y is an optionally substituted phenyl group on which the groups Z and A are linked para to each other (i.e., in a 1,4 configuration). Preferably, Y is an unsubstituted phenyl group on which the groups Z and A are linked para to each other.

[0111] The Y group may be optionally substituted with one or more of the following groups: C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, C1-C4 alkylthio, hydroxy, amino, nitro, thiol, chloro, fluoro, bromo, CF3, CHF2, or CH2F.

[0112] Suitably, the compound according to the first aspect has the formula (II) or a pharma- ceutically acceptable salt thereof: [ka] In the formula, R 1 , R 2 and R 3 is as defined above, B is an optionally substituted alkyl chain, an optionally substituted alkenyl chain, or an optionally substituted alkynyl chain; Z is selected from a direct bond, -C(=O)NH-, -NHC(=O)-, -O-, -S-, -S(=O)2NH-, -NHS(=O)2-, -OC(=O)-, -OC(=O)CHO-, and -C(=O)O-; Y is an optionally substituted 5- or 6-membered cycloalkyl or aryl ring; A is a group capable of releasing hydrogen sulfide.

[0113] Suitably, B, Z, Y and A are as defined above.

[0114] When a group is described as being "optionally substituted," the group is preferably optionally substituted with one or more groups, defined below and referred to as "R" groups. Preferably, the group is substituted with one or more halogens, one or more aryl groups, one or more C 1~6 Alkyl group or one or more C 1~6 It may be substituted with an alkoxy group.

[0115] In some embodiments, the compound according to the first aspect has the formula (II) or a pharma- ceutically acceptable salt thereof: [ka] In the formula, R 1 and R 2 are both C 1~6 an alkoxy group or together form a 6-membered aryl ring; R 3 is C 1~6 is an alkyl group, B is an optionally substituted C 6~14 is an alkyl chain, Z is a group selected from -C(=O)NH-, -NHC(=O)-, -O-, -OC(=O)-, -OC(=O)CHO-, -OCHC(=O)O- and -C(=O)O-; Y is an optionally substituted phenyl group, the groups Z and A are linked to each other para on the phenyl group; A is, [ka] wherein X is S, O or N-OH; R 4 , R 5 and R 6 are independently H or C 1~7 The alkyl group is selected from the group consisting of aryl, ... and alkyl groups.

[0116] In some embodiments, the compound according to the first aspect has the formula (II) or a pharma- ceutically acceptable salt thereof: [ka] In the formula, R 1 and R 2 are both C 1~6 an alkoxy group or together form a 6-membered aryl ring; R 3 is C 1~6 is an alkyl group, B is a C group optionally substituted with one or more of C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, C1-C4 alkylthio, hydroxy, amino, nitro, thiol, chloro, fluoro, bromo, CF3, CHF2, or CH2F groups. 6~14 is an alkyl chain, Z is a group selected from -C(=O)NH-, -NHC(=O)-, -O-, -OC(=O)-, -OC(=O)CHO-, -OCHC(=O)O- and -C(=O)O-; Y is a phenyl group, the groups Z and A are linked para to each other on the phenyl group, the phenyl group being optionally substituted with one or more of the groups C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, C1-C4 alkylthio, hydroxy, amino, nitro, thiol, chloro, fluoro, bromo, CF3, CHF2 or CH2F; A is, [ka] wherein X is S, O or N-OH; R 4 , R 5 and R 6 are independently H or C 1~7 The alkyl group is selected from the group consisting of aryl, ... and alkyl groups.

[0117] In some embodiments, the compound according to the first aspect has the formula (II) or a pharma- ceutically acceptable salt thereof: [ka] In the formula, R 1 and R 2 are both C 1~6an alkoxy group or together form a 6-membered aryl ring; R 3 is C 1~6 is an alkyl group, B is an optionally substituted C 6~14 is an alkyl chain, Z is selected from -OC(=O)-, -OC(=O)CHO-, and -C(=O)O-; Y is an optionally substituted phenyl group, the groups Z and A are linked to each other para on the phenyl group; A is, [ka] wherein X is S, O or N-OH; R 4 , R 5 and R 6 are independently H or C 1~7 The alkyl group is selected from the group consisting of aryl, ... and alkyl groups.

[0118] In some embodiments, the compound according to the first aspect is selected from Examples 1-17 described below.

[0119] In some embodiments, the compound according to the first aspect comprises: [ka] is selected from.

[0120] chemical terms The terms "carbo", "carbyl", "hydrocarbo" and "hydrocarbyl", as used herein, refer to compounds and / or groups which contain only carbon and hydrogen atoms.

[0121] The term "hetero", as used herein, refers to compounds and / or groups having at least one heteroatom, e.g., polyvalent heteroatoms (also suitable as ring heteroatoms), such as boron, silicon, nitrogen, phosphorus, oxygen, and sulfur, and monovalent heteroatoms, such as fluorine, chlorine, bromine, and iodine.

[0122] The term "saturated," as used herein, pertains to compounds and / or groups that have no carbon-carbon double bonds or carbon-carbon triple bonds.

[0123] The term "unsaturated," as used herein, pertains to compounds and / or groups that have at least one carbon-carbon double bond or carbon-carbon triple bond.

[0124] The term "aliphatic," as used herein, refers to compounds and / or groups that are straight-chained or branched, but not cyclic (also known as "acyclic" or "open-chain" groups).

[0125] The term "cyclic," as used herein, pertains to compounds and / or groups having one ring, or two or more rings (eg, spiro, fused, bridged).

[0126] The term "ring" as used herein refers to a closed ring of 3 to 10 covalently bonded atoms, more preferably 3 to 8 covalently bonded atoms.

[0127] The term "aromatic ring", as used herein, relates to a closed ring of 3 to 10 covalently bonded atoms, more preferably 5 to 8 covalently bonded atoms, which ring is aromatic.

[0128] The term "heterocyclic ring", as used herein, refers to a closed ring of 3 to 10 covalently bonded atoms, more preferably 3 to 8 covalently bonded atoms, in which at least one of the ring atoms is a polyvalent ring heteroatom, such as nitrogen, phosphorus, silicon, oxygen, and sulfur, but more commonly nitrogen, oxygen, and sulfur.

[0129] The term "alicyclic," as used herein, pertains to compounds and / or groups that have one ring, or two or more rings (e.g., spiro, fused, bridged), but which ring(s) are not aromatic.

[0130] The term "aromatic," as used herein, pertains to compounds and / or groups having one ring, or two or more rings (e.g., fused), at least one of which is aromatic.

[0131] The term "heterocyclic," as used herein, pertains to cyclic compounds and / or groups having one heterocyclic ring, or two or more heterocyclic rings (e.g., spiro, fused, bridged), which ring(s) may be alicyclic or aromatic.

[0132] The term "heteroaromatic," as used herein, pertains to cyclic compounds and / or groups having one heterocyclic ring, or two or more heterocyclic rings (e.g., fused), which ring(s) are aromatic.

[0133] substituent The phrase "optionally substituted," as used herein, pertains to a parent group which may be unsubstituted or substituted.

[0134] Unless otherwise indicated, the term "substituted" as used herein refers to a parent group that bears one or more substituents. The term "substituent" is used herein in its conventional sense to refer to a chemical moiety that is covalently bonded to, appended to, or, where appropriate, fused to a parent group. A wide variety of substituents are well known, as are methods for their formation and introduction onto a variety of parent groups.

[0135] In a preferred embodiment, the substituents, often referred to herein as R, are independently halo; hydroxy; ether (e.g., C 1~7 alkoxy; formyl; acyl (e.g., C 1~7 Alkyl acyl, C 5~20 aryl acyls;acyl halides;carboxy;esters;acyloxy;amides;acyl amides;thioamides;tetrazolyl;amino;nitro;nitroso;azides;cyano;isocyano;cyanato;isocyanato;thiocyano;isothiocyano;sulfhydryls;thioethers (e.g., C 1~7Alkylthio;sulfonic acid;sulfonate;sulfone;sulfonyloxy;sulfinyloxy;sulfamino;sulfonamino;sulfinamino;sulfamyl;sulfonamide;C 1~7 Alkyl (e.g., C 1~7 Haloalkyl, C 1~7 Hydroxyalkyl, C 1~7 Carboxyalkyl, C 1~7 Aminoalkyl, C 5~20 Aryl-C 1~7 Alkyl, etc.);C 3~20 Heterocyclyl; or C 5~20 Aryl (e.g., C 5~20 Carboaryl, C 5~20 Heteroaryl, C 1~7 Alkyl-C 5~20 Aryl and C 5~20 haloaryl, etc.).

[0136] In one preferred embodiment, the substituents, sometimes referred to herein as R, are independently: -F, -Cl, -Br, and -I; -OH; -OMe, -OEt, -O(tBu), and -OCH2Ph; -SH; -SMe, -SEt, -S(tBu), and -SCH2Ph; -C(=O)H; -C(=O)Me, -C(=O)Et, -C(=O)(tBu), and -C(=O)Ph; -C(=O)OH; -C(=O)OMe, -C(=O)OEt, and -C(=O)O(tBu); -C(=O)NH2, -C(=O)NHMe, -C(=O)NMe2, and -C(=O)NHEt; -NHC(=O)Me, -NHC(=O)Et, -NHC(=O)Ph, succinimidyl, and maleimidyl; -NH2, -NHMe, -NHEt, -NH(iPr), -NH(nPr), -NMe2, -NEt2, -N(iPr)2, -N(nPr)2, -N(nBu)2, and -N(tBu)2; -CN; -NO2; -Me, -Et, -nPr, -iPr, -nBu, -tBu; -CF3, -CHF2, -CH2F, -CCl3, -CBr3, -CH2CH2F, -CH2CHF2, and -CH2CF3; -OCF3, -OCHF2, -OCH2F, -OCCl3, -OCBr3, -OCH2CH2F, -OCH2CHF2 and -OCH2CF3; -CH2OH, -CH2CH2OH, and -CH(OH)CH2OH; -CH2NH2, -CH2CH2NH2, and -CH2CH2NMe2; and Optionally substituted phenyl is selected from.

[0137] In a preferred embodiment, the substituents, sometimes referred to herein as R, are independently selected from -F, -Cl, -Br, -I, -OH, -OMe, -OEt, -SH, -SMe, -SEt, -C(=O)Me, -C(=O)OH, -C(=O)OMe, -CONH, -CONHMe, -NH, -NMe, -NEt, -N(nPr), -N(iPr), -CN, -NO, -Me, -Et, -CF, -OCF, -CHOH, -CHCHOH, -CHNH, -CHCHNH, and -Ph.

[0138] In a preferred embodiment, the substituents, sometimes referred to herein as R, are independently hydroxy; ether (e.g., C 1~7 Alkoxy; ester; amide; amino; and C 1~7 Alkyl (e.g., C 1~7 Haloalkyl, C 1~7 Hydroxyalkyl, C 1~7 Carboxyalkyl, C 1~7 Aminoalkyl, C 5~20 Aryl-C 1~7 alkyl, etc.

[0139] In one preferred embodiment, the substituents, sometimes referred to herein as R, are independently: -OH; -OMe, -OEt, -O(tBu), and -OCH2Ph; -C(=O)OMe, -C(=O)OEt, and -C(=O)O(tBu); -C(=O)NH2, -C(=O)NHMe, -C(=O)NMe2, and -C(=O)NHEt; -NH2, -NHMe, -NHEt, -NH(iPr), -NH(nPr), -NMe2, -NEt2, -N(iPr)2, -N(nPr)2, -N(nBu)2, and -N(tBu)2; -Me, -Et, -nPr, -iPr, -nBu, -tBu; -CF3, -CHF2, -CH2F, -CCl3, -CBr3, -CH2CH2F, -CH2CHF2, and -CH2CF3; -CHOH, -CHCHOH, and -CH(OH)CHOH; and -CH2NH2, -CH2CH2NH2, and -CH2CH2NMe2 is selected from.

[0140] The substituents are described in more detail below.

[0141] C 1~20 Alkyl: The term "C 1~20 "Alkyl" as used herein refers to a C alkyl group having 1 to 20 carbon atoms. 1~7 Regarding monovalent moieties obtained by removing hydrogen atoms from hydrocarbon compounds, this C 1~7 The hydrocarbon compounds may be aliphatic or alicyclic, or combinations thereof, and may be saturated, partially unsaturated, or fully unsaturated.

[0142] (Unsubstituted) Saturated Linear C 1~20 Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl (amyl), n-octyl, n-nonyl, and n-decyl.

[0143] (unsubstituted) saturated branched C 1~7Examples of alkyl groups include, but are not limited to, iso-propyl, iso-butyl, sec-butyl, tert-butyl, and neopentyl.

[0144] Saturated alicyclic (also carbocyclic) C 1~7 Alkyl group ("C 3~7 Examples of cycloalkyl groups (also referred to as "cycloalkyl" groups) include, but are not limited to, unsubstituted groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornane, and substituted groups (e.g., groups that contain such groups) such as methylcyclopropyl, dimethylcyclopropyl, methylcyclobutyl, dimethylcyclobutyl, methylcyclopentyl, dimethylcyclopentyl, methylcyclohexyl, dimethylcyclohexyl, cyclopropylmethyl, and cyclohexylmethyl.

[0145] (Unsubstituted) unsaturated C with one or more carbon-carbon double bonds 1~20 Alkyl group ("C 2~7 Examples of alkyl groups (also referred to as "alkenyl" groups) include, but are not limited to, ethenyl (vinyl, -CH=CH2), 2-propenyl (allyl, -CH-CH=CH2), isopropenyl (-C(CH3)=CH2), butenyl, pentenyl, and hexenyl.

[0146] (Unsubstituted) unsaturated C with one or more carbon-carbon triple bonds 1~20 Alkyl group ("C 2~20 Examples of "alkylynyl" groups (also referred to as "alkylynyl" groups) include, but are not limited to, ethynyl and 2-propynyl (propargyl).

[0147] Unsaturated alicyclic (also carbocyclic) rings with one or more carbon-carbon double bonds 1~7 Alkyl group ("C 3~20Examples of cycloalkenyl groups (also referred to as "cycloalkenyl" groups) include, but are not limited to, unsubstituted groups such as cyclopropenyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl, as well as substituted groups (e.g., groups that contain such groups), such as cyclopropenylmethyl and cyclohexenylmethyl.

[0148] Replaced C 3~20 Further examples of -cycloalkyl groups are those having one or more other rings fused to the group, such as indene (C9), indane (2,3-dihydro-1H-indene) (C9), tetralin (1,2,3,4-tetrahydronaphthalene (C 10 ), Adamantane (C 10 ), Decalin (Decahydronaphthalene) (C 12 ), fluorene (C 13 ), Phenalene (C 13 ) For example, 2H-inden-2-yl is a C5 cycloalkyl group fused to a substituent (phenyl).

[0149] C 3~20 Heterocyclyl: The term "C 3~20 Heterocyclyl, as used herein, is 3~20 Regarding the monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, this C 3~20 Heterocyclic compounds have one ring, or two or more rings (e.g., spiro, fused, bridged) with 3 to 20 ring atoms, of which 1 to 10 are ring heteroatoms, and at least one of the rings is a heterocyclic ring. Preferably, each ring has 3 to 7 ring atoms, of which 1 to 4 are ring heteroatoms.

[0150] In this context, prefixes (e.g., C 3~20 , C 3~7 , C 5~6 etc.) represents the number of ring atoms, or range of numbers of ring atoms, whether carbon atoms or heteroatoms. For example, the term "C 5~6"Heterocyclyl" as used herein refers to a heterocyclyl group having 5 or 6 ring atoms. Exemplary groups of heterocyclyl groups include C 3~20 Heterocyclyl, C 3~7 Heterocyclyl, C 5~7 Examples include heterocyclyl.

[0151] Examples of (non-aromatic) monocyclic heterocyclyl groups are: Ni: aziridine (C3), azetidine (C4), pyrrolidine (tetrahydropyrrole) (C5), pyrroline (e.g., 3-pyrroline, 2,5-dihydropyrrole) (C5), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole) (C5), piperidine (C6), dihydropyridine (C6), tetrahydropyridine (C6), azepine (C7); O1: oxirane (C3), oxidine (C8), Cetane (C4), oxolane (tetrahydrofuran) (C5), oxole (dihydrofuran) (C5), oxane (tetrahydropyran) (C6), dihydropyran (C6), pyran (C6), oxepine (C7); Si: thiirane (C3), thietane (C4), thiolane (tetrahydrothiophene) (C5), thiane (tetrahydrothiopyran) (C6), thiepane (C7); O2: dioxo orane (C5), dioxane (C6), and dioxepane (C7); O3: trioxane (C6); N2: imidazolidine (C5), pyrazolidine (diazolidine) (C5), imidazoline (C5), pyrazoline (dihydropyrazole) (C5), piperazine (C6); N1O1: tetrahydrooxazole (C5), dihydrooxazole (C5), tetrahydroisoxazole (C5), di Hydroisoxazoles (C5), morpholines (C6), tetrahydrooxazines (C6), dihydrooxazines (C6), oxazines (C6); N1S1: thiazolines (C5), thiazolidines (C5), thiomorpholines (C6); N2O1: oxadiazines (C6); O1S1: oxathioles (C5) and oxathianes (thioxanes) (C6); and N1O1S1: oxathiazines (C6). These include, but are not limited to, those derived from

[0152] Examples of substituted (non-aromatic) monocyclic heterocyclyl groups include the cyclic forms of sugars, for example furanoses (C5), such as arabinofuranose, lyxofuranose, ribofuranose, and xylofuranose, and pyranoses (C6), such as allopyranose, altropyranose, glucopyranose, mannopyranose, globyranose, idopyranose, galactopyranose, and talopyranose.

[0153] Examples of heterocyclyl groups that are also heteroaryl groups are listed below together with aryl groups. C 5~20 Aryl: The term "C 5~20 "Aryl," as used herein, refers to any of the groups represented by C 5~20 With respect to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound, the compound has one ring, or two or more rings (e.g. fused) having 5 to 20 ring atoms, at least one of the rings being aromatic. Preferably, each ring has 5 to 7 ring atoms. In this context, the prefixes (e.g. C 3~20 , C 5~7 , C 5~6 etc.) represents the number of ring atoms, or range of numbers of ring atoms, whether carbon atoms or heteroatoms. For example, the term "C 5~6 "Aryl" as used herein refers to an aryl group having 5 or 6 ring atoms. Exemplary groups of aryl groups include C 3~20 Aryl, C 5~7 Aryl, C 5~6 Examples of such radicals include aryl radicals.

[0154] The ring atoms are "carboaryl groups" (e.g., C 5~20 Examples of carboaryl groups include benzene (i.e., the derivative is phenyl) (C6), naphthalene (C 10 ), Azur Lane (C 10 ), anthracene (C 14 ), phenanthrene (C 14 ), naphthacene (C 18 ), and pyrene (C16 ) are included, but are not limited to.

[0155] Examples of aryl groups containing fused rings in which at least one of the rings is aromatic include indene (C9), isoindene (C9), and fluorene (C 13 ) are included, but are not limited to.

[0156] Alternatively, the ring atoms may contain one or more heteroatoms, including, but not limited to, oxygen, nitrogen, and sulfur, as in "heteroaryl groups." In this case, the group is conveniently referred to as "C 5~20 Heteroaryl groups may also be referred to as "C 5~20 " represents a ring atom, whether a carbon atom or a heteroatom. Preferably, each ring has 5 to 7 ring atoms, of which 0 to 4 are ring heteroatoms.

[0157] Examples of monocyclic heteroaryl groups include: N1: pyrrole (azole) (C5), pyridine (azine) (C6); O1: furan (oxole) (C5); S1: thiophene (thiol) (C5); N1O1: oxazole (C5), isoxazole (C5), isoxazine (C6); N2O1: oxadiazole (furazan) (C5); N3O1: oxatriazole (C5); N1S1: thiazole (C5), isothiazole (C5); N2: imidazole (1,3-diazole) (C5), pyrazole (1,2-diazole) (C5), pyridazine (1,2-diazine) (C6), pyrimidine (1,3-diazine) (C6) (e.g., cytosine, thymine, uracil), pyrazine (1,4-diazine) (C6); N3: triazole (C5), triazine (C6); and N4: tetrazole (C5). These include, but are not limited to, those derived from

[0158] Examples of heterocyclic groups containing fused rings (some of which are also heteroaryl groups) include benzofuran (O1), isobenzofuran (O1), indole (N1), isoindole (N1), purine (N4) (e.g., adenine, guanine), benzimidazole (N2), benzoxazole (N1O1), benzisoxazole (N1O1), benzodioxole (O2), benzofurazan (N2O1). C9 heterocyclic groups (having two condensed rings) derived from benzotriazole (N3), benzothiofuran (S1), benzothiazole (N1S1), and benzothiadiazole (N2S); C derived from benzodioxane (O2), quinoline (N1), isoquinoline (N1), benzoxazine (N1O1), benzodiazine (N2), pyridopyridine (N2), quinoxaline (N2), and quinazoline (N2). 10 Heterocyclic groups (having two fused rings); C derived from carbazole (N1), dibenzofuran (O1), dibenzothiophene (S1) 13 Heterocyclic groups (having three fused rings); and C derived from acridine (N1), xanthene (O1), phenoxathiin (O1S1), phenazine (N2), phenoxazine (N1O1), phenothiazine (N1S1), thianthrene (S2), phenanthridine (N1), phenanthroline (N2), phenazine (N2). 14 Heterocyclic groups (having three fused rings) include, but are not limited to, heterocyclic groups (having three fused rings). Heterocyclic groups (including heteroaryl groups) having a nitrogen ring atom in the form of an -NH- group may be N-substituted, i.e., substituted as -NR-. For example, pyrrole may be N-methyl substituted to give N-methylpyrrole. Examples of N-substituents include C 1~7 Alkyl, C 3~20 Heterocyclyl, C 5~20 These include, but are not limited to, aryl and acyl groups.

[0159] Heterocyclic groups (including heteroaryl groups) having a nitrogen ring atom in the form of a -N= group may be used in the form of an N-oxide, i.e. -N(→O)=(-N +(→O-)=). For example, quinoline may be substituted to give quinoline N-oxide, pyridine to give pyridine N-oxide, and benzofurazan to give benzofurazan N-oxide (also known as benzofuroxan). The cyclic group may further bear one or more oxo (=O) groups on the ring carbon atoms. Monocyclic examples of such groups include: C5: cyclopentanone, cyclopentenone, cyclopentadienone; C6: cyclohexanone, cyclohexenone, cyclohexadienone; O1: furanone (C5), pyrone (C6); N1: pyrrolidone (pyrrolidinone) (C5), piperidinone (piperidone) (C6), piperidinedione (C6); N2: imidazolidone (imidazolidinone) (C5), pyrazolone (pyrazolinone) (C5), piperazinone (C6), piperazinedione (C6), pyridazinone (C6), pyrimidinone (C6) (e.g., cytosine), pyrimidinedione (C6) (e.g., thymine, uracil), barbituric acid (C6); N1S1: thiazolone (C5), isothiazolone (C5); N1O1: oxazolinone (C5) These include, but are not limited to, those derived from

[0160] Polycyclic examples of such groups include: C9: indenediones; N1: oxindoles (C9); O1: benzopyrones (e.g., coumarins, isocoumarins, chromones) (C 10 );N1O1: Benzoxazolinone (C9), Benzoxazolinone (C 10 );N2: Quinazolinedione (C 10 ); N4: Purinone (C9) (e.g., guanine) These include, but are not limited to, those derived from

[0161] Further examples of cyclic groups having one or more oxo (=O) groups on a ring carbon atom include: Cyclic anhydrides (-C(=O)-OC(=O)- in the ring), including, but not limited to, maleic anhydride (C5), succinic anhydride (C5), and glutaric anhydride (C6); cyclic carbonates (-OC(=O)-O- in the ring), such as ethylene carbonate (C5) and 1,2-propylene carbonate (C5); imides (-C(=O)-NR-C(=O)- in the ring), including, but not limited to, succinimide (C5), maleimide (C5), phthalimide, and glutarimide (C6); β-propiolactone, γ-butyrolactone, δ-valerolactone (2-piperidone), and ε-caproic anhydride (C6). lactones (cyclic esters, -OC(=O)- in the ring), including but not limited to prolactone; lactams (cyclic amides, -NR-C(=O)- in the ring), including but not limited to β-propiolactam (C4), γ-butyrolactam (2-pyrrolidone) (C5), δ-valerolactam (C6), and ε-caprolactam (C7); cyclic carbamates (-OC(=O)-NR- in the ring), such as 2-oxazolidones (C5); cyclic ureas (-NR-C(=O)-NR- in the ring), such as 2-imidazolidones (C5) and pyrimidine-2,4-diones (e.g., thymine, uracil) (C6). These include, but are not limited to, those derived from

[0162] C above 1~20 Alkyl, C 3~20 Heterocyclyl, and C 5~20 Aryl groups, whether alone or as part of another substituent, may themselves be optionally substituted with one or more groups selected from themselves and the further substituents listed below.

[0163] Hydrogen: -H. Note that when the substituent at a particular position is hydrogen, it is sometimes convenient to refer to the compound as being "unsubstituted" at that position.

[0164] Halo: -F, -Cl, -Br, and -I.

[0165] Hydroxy: -OH.

[0166] Ether: -OR, where R is an ether substituent, e.g., C 1~7 Alkyl groups (C discussed below) 1~7 (Also called alkoxy group), C 3~20 Heterocyclyl group (C 3~20 (also called heterocyclyloxy group), or C 5~20 Aryl group (C 5~20 (also called aryloxy group), preferably C 1~7 It is an alkyl group.

[0167] C 1~7 Alkoxy: -OR, where R is C 1~7 It is an alkyl group. 1~7 Examples of alkoxy groups include, but are not limited to, -OCH3 (methoxy), -OCH2CH3 (ethoxy), and -OC(CH3)3 (tert-butoxy).

[0168] Oxo (keto, -one): =O. Examples of cyclic compounds and / or groups having an oxo group (=O) as a substituent include, but are not limited to, carbocyclic groups such as cyclopentanone and cyclohexanone; heterocyclic groups such as pyrrone, pyrrolidone, pyrazolone, pyrazolinone, piperidone, piperidinedione, piperazinedione, and imidazolidone; cyclic anhydrides, including but not limited to maleic anhydride and succinic anhydride; cyclic carbonates, such as propylene carbonate; imides, including but not limited to succinimides and maleimides; lactones (cyclic esters, -OC(=O)- in the ring), including but not limited to β-propiolactone, γ-butyrolactone, δ-valerolactone, and ε-caprolactone; and lactams (cyclic amides, -NH-C(=O)- in the ring), including but not limited to β-propiolactam, γ-butyrolactam, δ-valerolactam, and ε-caprolactam.

[0169] Imino (imine): =NR, where R is an imino substituent, e.g., hydrogen, C 1~7 Alkyl group, C 3~20Heterocyclyl group, or C 5~20 Aryl group, preferably hydrogen or C 1~7 Examples of imino groups include, but are not limited to, =NH, =NMe, =NEt, and =NPh.

[0170] Formyl (carbaldehyde, carboxaldehyde): -C(=O)H.

[0171] Acyl (keto): -C(=O)R, where R is an acyl substituent, e.g., C 1~20 Alkyl group (C 1~20 Alkyl acyl or C 1~20 (Also called alkanoyl), C 3~20 Heterocyclyl group (C 3~20 Heterocyclyl acyl), or C 5~20 Aryl group (C 5~20 (also called aryl acyls), preferably C 1~20 Examples of acyl groups include, but are not limited to, -C(=O)CH3 (acetyl), -C(=O)CH2CH3 (propionyl), -C(=O)C(CH3)3 (butyryl), and -C(=O)Ph (benzoyl, phenone).

[0172] Acyl halide (haloformyl, halocarbonyl): -C(=O)X, where X is -F, -Cl, -Br or -I, preferably -Cl, -Br or -I. Carboxy (carboxylic acid): -COOH.

[0173] Ester (carboxylate, carboxylic acid ester, oxycarbonyl): -C(=O)OR, where R is an ester substituent, e.g., C 1~7 Alkyl group, C 3~20 Heterocyclyl group, or C 5~20 Aryl groups, preferably C 1~7 Examples of ester groups include, but are not limited to, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)OC(CH3)3, and -C(=O)OPh.

[0174] Acyloxy (reverse ester): -OC(=O)R, where R is an acyloxy substituent, e.g., C 1~7 Alkyl group, C 3~20 Heterocyclyl group, or C 5~20 Aryl groups, preferably C 1~7 It is an alkyl group. Examples of acyloxy groups are -OC(=O)CH3 (acetoxy), -OC(=O)CH2CH 3、 -OC(=O)C(CH3) 3、 These include, but are not limited to, -OC(=O)Ph and -OC(=O)CH2Ph.

[0175] Amide (carbamoyl, carbamyl, aminocarbonyl, carboxamide): -C(=O)NR 1 R 2 . In the formula, R 1 and R 2 are independently amino substituents as defined for amino groups. Examples of amido groups include -C(=O)NH, -C(=O)NHCH, -C(=O)NH(CH), -C(=O)NHCHCH, and -C(=O)N(CHCH), and R 1 and R 2 and amide groups which, together with the nitrogen atom to which they are attached, form a heterocyclic structure, such as in piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, and piperazinocarbonyl.

[0176] Acylamide (acylamino): -NR 1 C(=O)R 2 . In the formula, R 1 is an amide substituent, e.g., C 1~7 Alkyl group, C 3~20 Heterocyclyl group, or C 5~20 Aryl groups, preferably C 1~7 is an alkyl group, R 2 is an acyl substituent, e.g., C 1~7 Alkyl group, C 3~20 Heterocyclyl group, or C 5~20Aryl groups, preferably C 1~7 It is an alkyl group.

[0177] Amino: -NR 1 R 2 . In the formula, R 1 and R 2 are independently an amino substituent, e.g., hydrogen, C 1~7 Alkyl group (C 1~7 Alkylamino or di-C 1~7 (Also called alkylamino), C 3~20 Heterocyclyl group or C 5~20 Aryl group, preferably H or C 1~7 R is an alkyl group or, in the case of a "cyclic" amino group, 1 and R 2 together with the nitrogen atom to which they are attached form a heterocyclic ring having 4 to 8 ring atoms. Examples of amino groups include, but are not limited to, -NH2, -NHCH3, -NHCH(CH3)2, -N(CH3)2, -N(CH2CH3)2, and -NHPh. Examples of cyclic amino groups include, but are not limited to, aziridino, azetidino, piperidino, piperazino, morpholino, and thiomorpholino.

[0178] Nitro: -NO2. Nitroso: -NO. Azide: -N3. Cyano (nitrile, carbonitrile): -CN. Isocyano: -NC. Cyanato: -OCN. Isocyanato: -NCO. Thiocyano (thiocyanato): -SCN. Isothiocyano (isothiocyanato): -NCS. Sulfhydryl (thiol, mercapto): -SH.

[0179] Thioether (sulfide): -SR, where R is a thioether substituent, e.g., C 1~7 Alkyl group (C 1~7 (Also called alkylthio group), C 3~20 Heterocyclyl group, or C 5~20 Aryl groups, preferably C 1~7 It is an alkyl group. 1~7Examples of alkylthio groups include, but are not limited to, -SCH3 and -SCH2CH3. Sulfonic acid (sulfo): -S(=O)2OH.

[0180] Sulfonate (sulfonic acid ester): -S(=O)2OR, where R is a sulfonate substituent, e.g., C 1~7 Alkyl group, C 3~20 Heterocyclyl group, or C 5~20 Aryl groups, preferably C 1~7 It is an alkyl group. Examples of sulfonate groups include, but are not limited to, -S(=O)2OCH3 and -S(=O)2OCH2CH3.

[0181] Sulfone (sulfonyl): -S(=O)R, where R is a sulfone substituent, e.g., C 1~7 Alkyl group, C 3~20 Heterocyclyl group, or C 5~20 Aryl groups, preferably C 1~7 Examples of sulfone groups include, but are not limited to, -S(=O)2CH3 (methanesulfonyl, mesyl), -S(=O)2CF3, -S(=O)2CH2CH3, and 4-methylphenylsulfonyl (tosyl).

[0182] Sulfonyloxy: -OS(=O)R, where R is a sulfonyloxy substituent, e.g., C 1~7 Alkyl group, C 3~20 Heterocyclyl group, or C 5~20 Aryl groups, preferably C 1~7 It is an alkyl group. Examples of sulfonyloxy groups include, but are not limited to, -OS(=O)2CH3 and -OS(=O)2CH2CH3.

[0183] Sulfinyloxy: -OS(=O)R, where R is a sulfinyloxy substituent, e.g., C 1~7 Alkyl group, C 3~20 Heterocyclyl group, or C 5~20 Aryl groups, preferably C 1~7It is an alkyl group. Examples of sulfinyloxy groups include, but are not limited to, -OS(=O)CH3 and -OS(=O)CH2CH3.

[0184] Sulfamino: -NR 1 S(=O)2OH. In the formula, R 1 is an amino substituent as defined for an amino group. Examples of sulfamino groups include, but are not limited to, -NHS(=O)2OH and -N(CH3)S(=O)2OH.

[0185] Sulfonamino: -NR 1 S(=O)2R. In the formula, R 1 is an amino substituent as defined for an amino group, and R is a sulfoneamino substituent, e.g., C 1~7 Alkyl group, C 3~20 Heterocyclyl group, or C 5~20 Aryl groups, preferably C 1~7 It is an alkyl group.

[0186] Examples of sulfonamino groups include, but are not limited to, -NHS(=O)2CH3 and -N(CH3)S(=O)2C6H5.

[0187] Sulfinamino: -NR 1 S(=O)R. In the formula, R 1 is an amino substituent as defined for an amino group, and R is a sulfinamino substituent, e.g., C 1~7 Alkyl group, C 3~20 Heterocyclyl group, or C 5~20 Aryl groups, preferably C 1~7 It is an alkyl group.

[0188] Examples of sulfinamino groups include, but are not limited to, -NHS(=O)CH3 and -N(CH3)S(=O)C6H5.

[0189] Sulfamyl: -S(=O)NR 1 R 2 . In the formula, R 1and R 2 are independently amino substituents as defined for amino groups. Examples of sulfamyl groups include, but are not limited to, -S(=O)NH2, -S(=O)NH(CH3), -S(=O)N(CH3), -S(=O)NH(CH2CH3), -S(=O)N(CH2CH3), and -S(=O)NHPh.

[0190] Sulfonamide: -S(=O)2NR 1 R 2 . In the formula, R 1 and R 2 are independently amino substituents as defined for amino groups. Examples of sulfonamide groups include, but are not limited to, -S(=O)2NH2, -S(=O)2NH(CH3), -S(=O)2N(CH3), -S(=O)2NH(CH2CH3), -S(=O)2N(CH2CH3), and -S(=O)2NHPh.

[0191] As mentioned above, C 1~20 The alkyl group is, for example, hydroxy (C 1~20 (also called hydroxyalkyl group), C 1~20 Alkoxy(C 1~7 (Also called alkoxyalkyl groups), amino (C 1~20 (also called aminoalkyl groups), halo (C 1~20 Also called haloalkyl groups, carboxy (C 1~20 (also called carboxyalkyl group) and C 5~20 Aryl (C 5~20 Aryl-C 1~7 It may be substituted with an alkyl group.

[0192] Similarly, C 5~20 The aryl group is, for example, hydroxy (C 5~20 (also called hydroxyaryl groups), halo (C 5~20 haloaryl groups), amino (e.g., as in aniline, 5~20 (also called aminoaryl group), C 1~7 Alkyl (e.g., C as in toluene)1~7 Alkyl-C 5~20 (also called aryl group) and C 1~7 Alkoxy (e.g., C as in anisole) 1~7 Alkoxy-C 5~20 The aryl group may be substituted with an aryl group.

[0193] These and other examples of such substituted groups are discussed below.

[0194] C 1~20 Haloalkyl group: The term "C 1~20 "Haloalkyl group," as used herein, refers to a C alkyl group in which at least one hydrogen atom (e.g., 1, 2, 3) has been replaced with a halogen atom (e.g., F, Cl, Br, I). 1~20 In the case where multiple hydrogen atoms are replaced by halogen atoms, the halogen atoms may be independently the same or different. All hydrogen atoms may be replaced by halogen atoms, in which case the group is conveniently referred to as "C 1~20 They may also be called "perhaloalkyl groups". 1~7 Examples of haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CH2F, -CCl3, -CBr3, -CH2CH2F, -CH2CHF2, and -CH2CF3.

[0195] C 1~20 Hydroxyalkyl: The term "C 1~7 "Hydroxyalkyl group," as used herein, refers to a C 11 alkyl group in which at least one hydrogen atom is replaced with a hydroxy group. 1~20 It relates to alkyl groups. 1~7 Examples of hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, and -CH(OH)CH2OH.

[0196] C 1~20 Carboxyalkyl: The term "C 1~20"Carboxyalkyl group," as used herein, refers to a C 1 -alkyl group in which at least one hydrogen atom is replaced with a carboxy group. 1~20 It relates to alkyl groups. 1~20 Examples of carboxyalkyl groups include, but are not limited to, -CH2COOH and -CH2CH2COOH.

[0197] C 1~20 Aminoalkyl: The term "C 1~20 "Aminoalkyl group," as used herein, refers to a C alkyl group in which at least one hydrogen atom is replaced with an amino group. 1~20 It relates to alkyl groups. 1~20 Examples of aminoalkyl groups include, but are not limited to, -CH2NH2, -CH2CH2NH2, and -CH2CH2N(CH3)2.

[0198] C 1~20 Alkyl-C 5~20 Aryl: The term "C 1~20 Alkyl-C 5~20 "Aryl," as used herein, refers to any of the groups represented by C 1~20 Certain C substituted with alkyl groups 5~20 Represents an aryl group. Examples of such groups include, but are not limited to, tolyl (as in toluene), xylyl (as in xylene), mesityl (as in mesitylene), styryl (as in styrene), and cumenyl (as in cumene).

[0199] C 5~20 Aryl-C 1~20 Alkyl: The term "C 5~20 Aryl-C 1~20 "Alkyl," as used herein, is defined as any one of the following: 5~20 Certain C substituted with aryl groups 1~20 Represents an alkyl group.

[0200] Examples of such groups include, but are not limited to, benzyl (phenylmethyl), tolylmethyl, phenylethyl, and triphenylmethyl (trityl).

[0201] C 5~20 Haloaryl: The term "C 5~20 "Haloaryl," as used herein, refers to a specific C aryl group that is substituted with one or more halo groups. 5~20 represents an aryl group. Examples of such groups include, but are not limited to, halophenyl (e.g., fluorophenyl, chlorophenyl, bromophenyl, or iodophenyl, which may be ortho-, meta-, or para-substituted), dihalophenyl, trihalophenyl, tetrahalophenyl, and pentahalophenyl.

[0202] Bidentate Substituents. Some substituents are bidentate, i.e., have two points for covalent attachment. For example, a bidentate group may be covalently attached to two different atoms on two different groups, thereby acting as a linker between them. Alternatively, a bidentate group may be covalently attached to two different atoms on the same group, thereby forming a cyclic or ring structure with the two atoms to which the bidentate group is attached (and any intervening atoms, if present). In this way, a bidentate group may result in a heterocyclic and / or aromatic group / compound. Typically, the ring has 3-8 ring atoms, which are carbon or divalent heteroatoms (e.g., boron, silicon, nitrogen, phosphorus, oxygen, and sulfur, typically nitrogen, oxygen, and sulfur), and the bonds between the ring atoms are single or double bonds as permitted by the valence of the ring atoms. Typically, a bidentate group is covalently attached to vicinal atoms, i.e., adjacent atoms, in the parent group.

[0203] C 1~20 Alkylene: The term "C 1~20 "Alkylene," as used herein, refers to a C alkylene group having 1 to 20 carbon atoms, which may be aliphatic, alicyclic, or a combination thereof, and which may be saturated, partially unsaturated, or fully unsaturated. 1~20 It refers to a bidentate moiety obtained by removing two hydrogen atoms, either from the same carbon atom or from each of two different carbon atoms, of a hydrocarbon compound.

[0204] Linear saturated C 1~20 Examples of alkylene groups include -(CH2) where n is an integer from 1 to 20. n -, for example, but not limited to, -CH2- (methylene), -CH2CH2- (ethylene), -CH2CH2CH2- (propylene), and -CH2CH2CH2CH2- (butylene).

[0205] branched saturated C 1~20 Examples of alkylene groups include, but are not limited to, -CH(CH3)-, -CH(CH3)CH2-, -CH(CH3)CH2CH2-, -CH(CH3)CH2CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH(CH3)CH2CH2-, -CH2CH(CH3)CH2CH2-, -CH(CH2CH3)-, -CH(CH2CH3)CH2-, and -CH2CH(CH2CH3)CH2-.

[0206] Linear partially unsaturated C 1~20 Examples of alkylene groups include, but are not limited to, -CH=CH-(vinylene), -CH=CH-CH2-, -CH=CH-CH2-CH2-, -CH=CH-CH2-CH2-CH2-, -CH=CH-CH=CH-, -CH=CH-CH=CH-CH2-, -CH=CH-CH=CH-CH2-CH2-, -CH=CH-CH=CH-CH2-CH2-, -CH=CH-CH2-CH=CH-, and -CH=CH-CH2-CH2-CH2-CH=CH-.

[0207] Branched partially unsaturated C 1~20 Examples of alkylene groups include, but are not limited to, -C(CH3)=CH-, -C(CH3)=CH-CH2-, and -CH=CH-CH(CH3)-.

[0208] Alicyclic saturated C 1~20 Examples of alkylene groups include, but are not limited to, cyclopentylene (eg, cyclopent-1,3-ylene) and cyclohexylene (eg, cyclohex-1,4-ylene).

[0209] Alicyclic partially unsaturated C1~20 Examples of alkylene groups include, but are not limited to, cyclopentenylene (eg, 4-cyclopenten-1,3-ylene), cyclohexenylene (eg, 2-cyclohexen-1,4-ylene, 3-cyclohexen-1,2-ylene, 2,5-cyclohexadiene-1,4-ylene).

[0210] C 5~20 Arylene: The term "C 5~20 As used herein, "arylene" refers to any of the following: 5~20 For a bidentate moiety obtained by removing two hydrogen atoms, one from each of two different ring atoms of an aromatic compound, this C 5~20 An aromatic compound has one ring or two or more rings (e.g., fused) having 5 to 20 ring atoms, at least one of which is aromatic, and preferably each ring has 5 to 7 ring atoms.

[0211] The ring atoms may be all carbon atoms, as in a "carbarylene group", in which case the group is conveniently referred to as "C 5~20 They may also be referred to as "carbarylene" groups.

[0212] Alternatively, the ring atoms may contain one or more heteroatoms, including, but not limited to, oxygen, nitrogen, and sulfur, as in "heteroarylene groups." In this case, the group is conveniently referred to as "C 5~20 Heteroarylene groups may also be referred to as "C 5~20 " represents a ring atom, whether a carbon atom or a heteroatom.

[0213] Preferably, each ring has from 5 to 7 ring atoms, of which from 0 to 4 are ring heteroatoms.

[0214] C with no ring heteroatoms 5~20 Arylene groups (i.e., C 5~20 Examples of carboarylene groups include benzene (i.e., the derivative is phenyl) (C6), naphthalene (C 10), anthracene (Cu), phenanthrene (C 14 ), and pyrene (C 16 ) are included, but are not limited to.

[0215] C 5~20 Examples of heteroarylene groups include, but are not limited to, C5 heteroarylene groups derived from furan (oxole), thiophene (thiol), pyrrole (azole), imidazole (1,3-diazole), pyrazole (1,2-diazole), triazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, and oxatriazole; and C6 heteroarylene groups derived from isoxazine, pyridine (azine), pyridazine (1,2-diazine), pyrimidine (1,3-diazine; e.g., cytosine, thymine, uracil), pyrazine (1,4-diazine), triazine, tetrazole, and oxadiazole (furazan).

[0216] C 5~20 Arylene-C 1~20 Alkylene: The term "C 5~20 Arylene-C 1~20 As used herein, "alkylene" refers to 1~20 C linked to an alkylene moiety, -alkylene- 5~20 The arylene moiety relates to a bidentate moiety containing -arylene-, ie -arylene-alkylene-.

[0217] C 5~20 Arylene-C 1~20 Examples of alkylene groups include, but are not limited to, phenylene-methylene, phenylene-ethylene, phenylene-propylene, and phenylene-ethenylene (also known as phenylene-vinylene).

[0218] C 5~20 Alkylene-C 1~20 Arylene: The term "C 5~20 Alkylene-C 1~20 As used herein, "arylene" refers to any of the following:1~20 C linked to an arylene moiety, -arylene- 5~20 It relates to a bidentate moiety containing an alkylene moiety, -alkylene-, ie -alkylene-arylene-.

[0219] C 5~20 Alkylene-C 1~20 Examples of arylene groups include, but are not limited to, methylene-phenylene, ethylene-phenylene, propylene-phenylene, and ethenylene-phenylene (also known as vinylene-phenylene).

[0220] The above includes well-known ionic, salt, solvate (e.g., hydrate) and protected forms of these substituents. For example, a reference to a carboxylic acid (-COOH) also includes the carboxylate (-COO-). Similarly, a reference to an amino group includes the salts of the amino group, such as the hydrochloride salt. A reference to a hydroxyl group also includes conventional protected forms of the hydroxyl group.

[0221] Similarly, a reference to an amino group also includes conventional protected forms of an amino group.

[0222] acronym For convenience, many chemical moieties are represented herein using well-known abbreviations, examples of which include, but are not limited to, methyl (Me), ethyl (Et), n-propyl (nPr), iso-propyl (iPr), n-butyl (nBu), tert-butyl (tBu), n-hexyl (nHex), cyclohexyl (cHex), phenyl (Ph), biphenyl (biPh), benzyl (Bn), naphthyl (naph), methoxy (MeO), ethoxy (EtO), benzoyl (Bz), and acetyl (Ac).

[0223] For convenience, many compounds are referred to herein using well-known abbreviations, including, but not limited to, methanol (MeOH), ethanol (EtOH), iso-propanol (i-PrOH), methyl ethyl ketone (MEK), acetic acid (AcOH), dichloromethane (methylene chloride, DCM), trifluoroacetic acid (TFA), dimethylformamide (DMF), and tetrahydrofuran (THF).

[0224] Isomers, salts, solvates, protected forms, and prodrugs. Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diastereomeric, epimeric, stereoisomeric, tautomeric, conformational, or anomeric forms, including, but not limited to, cis and trans forms; E and Z forms; c, t, and r forms; endo and exo forms; R, S, and meso forms; D and L forms; (+) and (-) forms; keto, enol, and enolate forms; syn and anti forms; synclinal and anticlinal forms; α and β forms; axial and equatorial forms; boat, chair, twisted, envelope, and half-chair forms; and combinations thereof, hereinafter collectively referred to as "isomers" (or "isomeric forms").

[0225] It should be noted that, except as tautomeric forms are discussed below, structural isomers (or constitutional isomers) (i.e., isomers that differ not simply by the position of the atoms in space but by the connections between the atoms) are specifically excluded from the term "isomer" as used herein. For example, a reference to a methoxy group, -OCH3, should not be construed as a reference to its structural isomer, a hydroxymethyl group, -CH2OH. Similarly, a reference to ortho-chlorophenyl should not be construed as a reference to its structural isomer, meta-chlorophenyl.

[0226] However, reference to a class of structures may also include structurally isomeric forms that fall within that class (e.g., C1~20 Alkyl includes n-propyl and iso-propyl, butyl includes n-, iso-, sec- and tert-butyl, methoxyphenyl includes ortho-, meta- and para-methoxyphenyl).

[0227] The above exclusion does not pertain to tautomers, such as keto, enol, and enolate, for example, as in the following tautomeric pairs: keto / enol (shown below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, N-nitroso / hydroxyazo, and nitro / aci-nitro.

[0228] Unless otherwise specified, a reference to a particular compound includes all such isomeric forms, including racemic and other mixtures thereof. Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallization and chromatographic means) of such isomeric forms are either known in the art or readily obtained by adapting in a known manner the methods taught herein.

[0229] Unless otherwise specified, a reference to a particular compound also includes ionic forms, salt forms, solvate (eg, hydrate) forms, protected forms, and prodrugs thereof, for example, as discussed below.

[0230] It may be convenient or desirable to prepare, purify, and / or handle corresponding salts of the active compounds, e.g., pharma- ceutically acceptable salts. Examples of pharma-ceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci., vol. 66, pp. 1-19.

[0231] For example, if the compound is anionic, or has a functional group which may be anionic (e.g., -COOH may be -COO-), then a salt may be formed with a suitable cation. Examples of suitable inorganic cations include Na + and K+ Alkali metal ions such as Ca 2+ and Mg 2+ Alkaline earth cations such as Al 3+ Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH + ) and substituted ammonium ions (e.g., NHR + , NH2R2 + , NHR3 + , NR4 + ) are included, but are not limited to. Some suitable examples of substituted ammonium ions are those derived from ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine. An example of a common quaternary ammonium ion is N(CH3)4 + The compound is cationic or has a functional group which may be cationic (e.g., -NH2 is -NH3 + In the case of a carboxylic acid having an acid salt, salts may be formed with suitable anions. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfurous acid, nitric acid, nitrous acid, phosphoric acid, and phosphorous acid. Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetyloxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, and valeric acid.

[0232] It may be convenient or desirable to prepare, purify, and / or handle the corresponding solvate of the active compound.The term "solvate" is used herein in the conventional sense to refer to a complex of solute (e.g., active compound, salt of active compound) and solvent.When the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a monohydrate, a dihydrate, a trihydrate, etc.

[0233] It may be convenient or desirable to prepare, purify, and / or handle active compounds in a chemically protected form. The term "chemically protected form" as used herein refers to a compound in which one or more reactive functional groups are protected from undesired chemical reactions, i.e., in the form of a protected or protective group (also known as a masked or masking group). By protecting a reactive functional group, reactions involving other unprotected reactive functional groups can be carried out without affecting the protected group, and the protective group can usually be removed in a subsequent step without substantially affecting other parts of the molecule. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts, Wiley, 1991) and Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999).

[0234] For example, a hydroxy group may be protected as an ether (-OR) or ester (-OC(=O)R), e.g., as a t-butyl ether; benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (-OC(=O)CH, -OAc).

[0235] For example, aldehyde or ketone groups may be protected as acetals or ketals, respectively, where the carbonyl group (>C=O) is converted to a diether (>C(OR)2), for example, by reaction with a primary alcohol. The aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.

[0236] For example, amine groups may be represented as, for example, amides (-NRCO-R) or urethanes (-NRCO-OR), for example, as methylamides (-NHCO-CH3); as benzyloxyamides (-NHCO-OCH2C6H5, -NH-Cbz); as t-butoxyamides (-NHCO-OC(CH3)3, -NH-Boc); as 2-biphenyl-2-propoxyamides (-NHCO-OC(CH3)2C6H4C6H5, -NH-Bpoc), as 9-fluorenylmethoxyamides (- NH-Fmoc), as 6-nitroveratryloxyamide (-NH-Nvoc), as 2-trimethylsilylethyloxyamide (-NH-Teoc), as 2,2,2-trichloroethyloxyamide (-NH-Troc), as allyloxyamide (-NH-Alloc), as 2(-phenylsulfonyl)ethyloxyamide (-NH-Psec); or, in appropriate cases (e.g., cyclic amines), as a nitroxide radical (>NO·).

[0237] For example, a carboxylic acid group may be protected as an ester or amide, for example, as a benzyl ester; a t-butyl ester; a methyl ester; or a methyl amide.

[0238] For example, a thiol group may be protected as a thioether (-SR), e.g., as a benzylthioether; an acetamidomethyl ether (-S-CH2NHC(=O)CH3).

[0239] It may be convenient or desirable to prepare, purify, and / or handle active compounds in the form of prodrugs. The term "prodrug" as used herein refers to a compound that, when metabolized, produces the desired active compound. Typically, prodrugs are inactive or less active than the active compound, but may offer advantageous handling, administration, or metabolic properties. For example, some prodrugs are esters of the active compound, and during metabolism, the ester group is cleaved to produce the active drug. Also, some prodrugs are enzymatically activated to produce the active compound, or a compound that produces the active compound upon further chemical reaction. For example, the prodrug may be a sugar derivative or other glycoside conjugate, or an amino acid ester derivative.

[0240] It should be noted that the term "isomer" specifically includes compounds with one or more isotopic substitutions. For example, H is 1 H, 2 H(D), and 3 H(T) may be in any isotopic form, and C may be 12 C. 13 C, and 14 It may be in any isotopic form, including C, and O is 16 O and 18 It may be any isotopic form including O, etc.

[0241] Unless otherwise specified, a reference to a particular compound includes all such isomeric forms, including racemic and other mixtures thereof. Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallization and chromatographic means) of such isomeric forms are either known in the art or readily obtained by adapting in a known manner the methods taught herein.

[0242] Unless otherwise specified, a reference to a particular compound also includes ionic forms, salt forms, solvate (eg, hydrate) forms, protected forms, and prodrugs thereof, for example, as discussed below.

[0243] It may be convenient or desirable to prepare, purify, and / or handle corresponding salts of the active compounds, e.g., pharma- ceutically acceptable salts. Examples of pharma-ceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci., vol. 66, pp. 1-19.

[0244] For example, if the compound is anionic, or has a functional group which may be anionic (e.g., -COOH may be -COO-), then a salt may be formed with a suitable cation. Examples of suitable inorganic cations include Na + and K + Alkali metal ions such as Ca 2+ and Mg 2+ Alkaline earth cations such as Al 3+ Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH + ) and substituted ammonium ions (e.g., NHR + , NH2R2 + , NHR3 + , NR4 + ) are included, but are not limited to. Some suitable examples of substituted ammonium ions are those derived from ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine. An example of a common quaternary ammonium ion is N(CH3)4 + It is.

[0245] The compound is cationic or has a functional group which may be cationic (e.g., -NH2 is -NH3 +In the case of a carboxylic acid having an acid salt, salts may be formed with suitable anions. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfurous acid, nitric acid, nitrous acid, phosphoric acid, and phosphorous acid. Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetyloxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, and valeric acid.

[0246] It may be convenient or desirable to prepare, purify, and / or handle the corresponding solvate of the active compound.The term "solvate" is used herein in the conventional sense to refer to a complex of solute (e.g., active compound, salt of active compound) and solvent.When the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a monohydrate, a dihydrate, a trihydrate, etc.

[0247] It may be convenient or desirable to prepare, purify, and / or handle active compounds in a chemically protected form. The term "chemically protected form" as used herein refers to a compound in which one or more reactive functional groups are protected from undesired chemical reactions, i.e., in the form of a protected or protective group (also known as a masked or masking group). By protecting a reactive functional group, reactions involving other unprotected reactive functional groups can be carried out without affecting the protected group, and the protective group can usually be removed in a subsequent step without substantially affecting other parts of the molecule. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts, Wiley, 1991) and Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999).

[0248] For example, a hydroxy group may be protected as an ether (-OR) or ester (-OC(=O)R), e.g., as a t-butyl ether; benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (-OC(=O)CH, -OAc).

[0249] For example, aldehyde or ketone groups may be protected as acetals or ketals, respectively, where the carbonyl group (>C=O) is converted to a diether (>C(OR)2), for example, by reaction with a primary alcohol. The aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.

[0250] For example, amine groups may be represented as, for example, amides (-NRCO-R) or urethanes (-NRCO-OR), for example, as methylamides (-NHCO-CH3); as benzyloxyamides (-NHCO-OCH2C6H5, -NH-Cbz); as t-butoxyamides (-NHCO-OC(CH3)3, -NH-Boc); as 2-biphenyl-2-propoxyamides (-NHCO-OC(CH3)2C6H4C6H5, -NH-Bpoc), as 9-fluorenylmethoxyamides (- NH-Fmoc), as 6-nitroveratryloxyamide (-NH-Nvoc), as 2-trimethylsilylethyloxyamide (-NH-Teoc), as 2,2,2-trichloroethyloxyamide (-NH-Troc), as allyloxyamide (-NH-Alloc), as 2(-phenylsulfonyl)ethyloxyamide (-NH-Psec); or, in appropriate cases (e.g., cyclic amines), as a nitroxide radical (>NO·).

[0251] For example, a carboxylic acid group may be protected as an ester or amide, for example, as a benzyl ester; a t-butyl ester; a methyl ester; or a methyl amide.

[0252] For example, a thiol group may be protected as a thioether (-SR), e.g., as a benzylthioether; an acetamidomethyl ether (-S-CH2NHC(=O)CH3).

[0253] It may be convenient or desirable to prepare, purify, and / or handle active compounds in the form of prodrugs. The term "prodrug" as used herein refers to a compound that, when metabolized, produces the desired active compound. Typically, prodrugs are inactive or less active than the active compound, but may offer advantageous handling, administration, or metabolic properties. For example, some prodrugs are esters of the active compound, and during metabolism, the ester group is cleaved to produce the active drug. Also, some prodrugs are enzymatically activated to produce the active compound, or a compound that produces the active compound upon further chemical reaction. For example, the prodrug may be a sugar derivative or other glycoside conjugate, or an amino acid ester derivative. EXAMPLES

[0254] Synthesis of Example 1 Example 1 was prepared in 3 steps in 25% overall yield (from ADTOH) using the following reaction scheme. [ka] Scheme 1. Synthesis route of Example 1. First, 2 (90%) was prepared by reaction of ADTOH (5-(4-hydroxyphenyl)-3H-1,2-dithiol-3-thione) and tert-butyl bromoacetate (1.5 eq.) with cesium carbonate (2 eq.) in acetone. The ester protecting group was then removed with trifluoroacetic acid (10 eq.) (46% yield). Coupling reaction with idebenone (1 eq.) was carried out using EDCI (1.5 eq.) and DMAP (0.1 eq.), thus obtaining Example 1 (60% yield).

[0255] Synthesis of Examples 2, 3, and 4 An alternative, more efficient synthetic approach to attach ADTOH to idebenone was also carried out. The alcohol functionality in idebenone was oxidized to a carboxylic acid using Jones reagent (chromic acid made by chromium trioxide or dichromate and sulfuric acid) as previously reported [patent document U.S. Pat. No. 8,263,094], and a coupling reaction was carried out between ADTOH and idebenone carboxylic acid to produce Example 2. [ka] Scheme 2: Synthesis route of Example 2. The idebenone alcohol functional group was oxidized to a carboxylic acid using Jones reagent (16 equivalents) made by sodium dichromate dihydrate and sulfuric acid (94% yield). The resulting product was coupled to ADTOH (1 equivalent) using EDCI (1.5 equivalents) and DMAP (0.1 equivalents) to give Example 2 (45% yield).

[0256] In a similar manner, coupling reactions between idebenone carboxylic acid and both HTB (4-hydroxythiobenzamide) and intermediate RT02 were carried out. Examples 3 and 4 (Scheme 3) were obtained in 45% and 66% overall yields (from idebenone), respectively. [ka] Scheme 3. Synthetic route for Example 3 and Example 4. Idebenone carboxylic acid (1 eq.) was coupled to HTB or RT02 (5-(4-hydroxyphenyl)-3H-1,2-dithiol-3-one) using DCCI (N,N'-dicyclohexylcarbodiimide) (1.5 eq.) and DMAP (4-dimethylaminopyridine) (0.1 eq.) to produce Example 3 (48% yield) and Example 4 (70% yield).

[0257] Example 1 (10-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dien-1-yl)decyl (4-(3-thioxo-3H-1,2-dithiol-5yl)phenoxy)acetate). In the synthesis of Example 1, silica gel flash chromatography was performed using a solvent mixture of petroleum ether / ethyl acetate 1 / 1, which gave RT154 as a red oil (363 mg, 60%, 0.60 mmol) (cLogP=6.23). IR spectrum v max / cm -1 = 2851(m),1760(C=O)(m),1607(C=O)(s),1523(s),1588(w),1487(m),1436( m),1412(w),1203(w),1184(m),1166(m),1024(m),945(w),835(w),743(w). 1 H-NMR δ H (400 MHz, CDCl3) = 7.55 (2H, d, part of AA'BB', J = 8 Hz, aryl CH), 7.31 (1H, s, alkene CH), 6.92 (2H, d, part of AA'BB', J = 12 Hz, aryl CH), 4.63 (2H, s, OCCH2O), 4.14 (2H, t, J = 8 Hz, CH2O), 3.92 (6H, s, 2 × CH3O), 2.37 (2H, t, J = 8 Hz, CH2), 1.94 (3H, s, CH3), 1.58 (2H, t, J = 8 Hz, CH2), 1.27-1.19 (14H, m, 7 × CH2). 13 C-NMR δ C(100MHz,CDCl3) = 215.20(C=S), 184.72(C=O), 184.17(C=O), 172.57(COO), 168.19(SC=CH), 160.99(arylCO), 144.30(C=C), 143.03(C=C), 138.70(C=C), 134.94(alkeneCH), 128.64(arylCH), 125.15(arylCC), 11 5.59 (arylCH), 65.80 (OCCH2), 65.23 (CH2O), 61.17 (CH3O), 29.81 (CH2), 29.46 (CH2), 29.40 (CH2), 29.33 (CH2), 29.14 (CH2), 28.72 (CH2), 28.50 (CH2), 26.39 (CH2), 25.77 (CH2), 11.95 (CH3).

[0258] Example 2 ((4-(3-thioxo-3H-1,2-dithiol-5yl)phenoxy) 10-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dien-1-yl)decanoate). In the synthesis of Example 2, silica gel flash chromatography was performed using a solvent mixture of petroleum ether / ethyl acetate 2 / 1, which gave the product as a red oil (252 mg, 45%, 0.45 mmol) (cLogP=6.10). HRMS (ES) + Measured value m / z (relative intensity) 561.1445 (MH + ;30), C 28 H 33 O6S3 requirement 561.1439, 226.9663 (MH-Idebenone + ;100). IR spectrum ν max / cm -1 = 1762(C=O)(w),1705(C=O)(m),1642(s),1605(s),1546(w),1436(m),1379(w),1263(m),1204(m),1172(m),1094(w),1025(w),836(w). 1 H-NMR δ H(400 MHz, CDCl3) = 7.70 (2H, d, part of AA'BB', J = 8 Hz, aryl CH), 7.42 (1H, s, alkene CH), 7.25 (2H, d, part of AA'BB', J = 8 Hz, aryl CH), 4.01 (6H, s, 2 × CH3O), 2.60 (2H, t, J = 8 Hz, CH2), 2.47 (2H, t, J = 8 Hz, CH2), 2.03 (3H, s, CH3), 1.77 (2H, m, CH2), 1.42-1.34 (12H, m, 6 × CH2). 13 C-NMR δ C (100MHz, CDCl3) = 215.51(C=S), 184.72(C=O), 184.18(C=O), 171.78(COO), 171.72(SC=CH), 153.71(arylCO), 144.30(C=C), 143.02(C=C), 138.71(C=C), 136.01(alkeneCH), 129.10(arylCC), 128.21(arylCH), 122.96(arylCH), 61.19(CH3O), 34.36(CH2), 29.79(CH2), 29.28(CH2), 29.19(CH2), 28.72(CH2), 26.40(CH2), 24.79(CH2), 11.95(CH3).

[0259] Example 3 ((4-Carbamothioylphenoxy) 10-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dien-1-yl)decanoate). In the synthesis of Example 3, silica gel flash chromatography was performed using a solvent mixture of ether / ethyl acetate 1 / 1 to give RTI64 as an orange solid (234 mg, 48%, 0.48 mmol) (cLogP=5.59). HRMS (ES) + Measured value m / z (relative intensity) 488.2095 (MH + ;100), C 26 H 34 NO6S required value 488.2107. 1 H-NMR δ H(400MHz, CDCl3) = 7.90 (2H, d, part of AA'BB', J = 8Hz, aryl CH), 7.84 (1H, br s, NH), 7.55 (1H, br s, NH), 7.10 (2H, d, part of AA'BB', J = 8Hz, aryl CH), 3.98 (6H, s, 2 x CH3O), 2.57 (2H, t, J = 8Hz, CH2), 2.44 (2H, t, J = 8Hz, CH2), 2.01 (3H, s, CH3), 1.75 (2H, m, CH2), 1.40-1.32 (12H, m, 6 x CH2). 13 C-NMR δ C (100MHz,CDCl3) = 201.45(C=S), 184.76(C=O), 184.23(C=O), 171.99(COO), 153.58(arylCO), 144.29(C=C), 144.26(C=C), 143.05(C=C), 138.76(C=C), 136.60(arylCC), 128.53(arylCH), 121.54(arylCH), 61.18(CH3O), 34.36(CH2), 29.78(CH2), 29.24(CH2), 29.12(CH2), 28.97(CH2), 28.72(CH2), 26.40(CH2), 24.79(CH2), 11.95(CH3).

[0260] Example 4 ((4-(3-oxo-3H-1,2-dithiol-5-yl)phenoxy) 10-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dien-1-yl)decanoate). In the synthesis of Example 4, silica gel flash chromatography was performed using a solvent mixture of petroleum ether / ethyl acetate 2 / 1. Example 4 was obtained as an orange solid (381 mg, 70%, 0.70 mmol) (cLogP=5.40). HRMS (ES) + Measured value m / z (relative intensity) 545.1663 (MH + ;20), C 28 H 33 O7S2 requirement 545.1662, 210.9913 (MH-idebenone + ;100). IR spectrum ν max / cm -1= 3295(m),1760(C=O)(w),1734(C=O)(w),1706(C=O)(w),1641(C=O)(s),1604(s),1585 (s),1457(m),1436(m),1373(w),1263(m),1126(m),1073(m),828(w),800(w),742(w). 1 H-NMR δ H (400 MHz, CDCl3) = 7.58 (2H, d, part of AA'BB', J = 8 Hz, aryl CH), 7.16 (2H, d, part of AA'BB', J = 12 Hz, aryl CH), 6.75 (1H, s, alkene CH), 3.92 (6H, s, 2 x CH3O), 2.52 (2H, t, J = 8 Hz, CH2), 2.38 (2H, t, J = 8 Hz, CH2), 1.94 (3H, s, CH3), 1.69 (2H, m, CH2), 1.33-1.25 (12H, m, 6 x CH2). 13 C-NMR δ C (100MHz,CDCl3) = 194.02(SC=O), 184.73(C=O), 184.19(C=O), 171.80(COO), 169.25(SC=CH), 153.41(arylCO), 144.30(C=C), 143.03(C=C), 138.72(C=C), 130.03(arylCC), 127.82(arylCH), 122.76(arylCH), 118.03(1H,s,alkeneCH), 61.18(CH3O), 34.35(CH2), 29.80(CH2), 29.29(CH2), 29.19(CH2), 29.04(CH2), 28.72(CH2), 26.40(CH2), 24.80(CH2), 11.95(CH3).

[0261] General procedure for the synthesis of Examples 5, 6 and 7. These syntheses were carried out by modifying a reported literature protocol [Gero et al., 2016]. 10-(3-methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)decanoic acid (292 mg; 0.853 mmol) was dissolved in dichloromethane (8 ml). The mixture was stirred at room temperature and ADTOH (193 mg; 0.853 mmol) or HTB (131 mg; 0.853 mmol) or 5-(4-hydroxyphenyl)-3H-1,2-dithiol-3-one (179 mg; 0.853 mmol) was added to it. 4-Dimethylaminopyridine (10 mg; 0.085 mmol) and N,N'-dicyclohexylcarbodiimide (264 mg; 1.28 mmol) (for examples 5 and 7) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (164 mg; 0.853 mmol) (for example 6) were added to this initial solution, which was stirred at room temperature for 18 hours. The solution was filtered to remove the precipitate formed and the solvent was evaporated in vacuum (for examples 5 and 7). Alternatively, the reaction mixture was washed with deionized water (6 x 15 ml), the organic phase was dried over MgSO4 and the solvent was removed under reduced pressure (for example 6). The crude product obtained was loaded onto a silica gel flash chromatography column.

[0262] Synthesis of 10-(3-methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)decanoic acid (2-methyl-1,4-naphthoquinonic acid derivative). The acid derivative synthesis was carried out by slightly modifying the reported literature protocol [Salmon-Chemin et al., 2001]. To a stirred solution containing 2-methyl-1,4-naphthoquinone (300 mg; 1.74 mmol) and undecanedioic acid (1.129 g; 5.22 mmol) in 50 ml of degassed 30% aqueous acetonitrile was added silver nitrate (88 mg; 0.522 mmol). A solution of ammonium peroxodisulfate (516 mg; 2.26 mmol) in 12 ml of degassed 30% aqueous acetonitrile was added dropwise to the stirred solution over 15 min. The resulting solution was stirred at 70° C. for 3 h under nitrogen atmosphere. After the solution was cooled to room temperature, the residue was extracted with dichloromethane (3 x 50 ml) and the organic phases were combined and washed with deionized water (3 x 50 ml). The organic solution was dried over MgSO4 and the solvent was removed under reduced pressure. The crude product was loaded onto a silica gel flash chromatography column, which was eluted with an initial solvent mixture of 3 / 1 petroleum ether (bp 40-60 °C) / ethyl acetate followed by a solvent mixture of 2 / 1 petroleum ether (bp 40-60 °C) / ethyl acetate to give the title product as a yellow solid (292 mg; 49%; 0.853 mmol). 10-(3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)decanoic acid. 1 H-NMR δ H (400MHz,CDCl3) = 8.01-7.99(2H,m,Aryl CH),7.63-7.60(2H,m,Aryl CH),2.55(2H,t,J=8.0Hz,CH2C(O)),2.27( 2H,t,J=8.0Hz,CH2C=C),2.12(3H,s,CH3),1.58-1.53(2H,m,CH2),1.40-1.23(12H,m,6×CH2). 13 C-NMR δ C(100MHz,CDCl3) = 185.42(C=O), 184.75(C=O), 179.86(COOH), 147.55(aryl CC), 143.12(aryl CC), 133.33(aryl CH), 133.30(aryl CH), 132.20(aryl CC), 126.28(aryl CH), 126.18(aryl CH), 34.00(CH2), 29.94(CH2), 29.33(CH2), 29.29(CH2), 29.18(CH2), 29.01(CH2), 28.73(CH2), 27.10(CH2), 24.64(CH2), 12.66(CH3).

[0263] Example 5 (4-(3-thioxo-3H-1,2-dithiol-5yl)phenoxy) 10-(1,4-dihydronaphthalen-2-yl)decanoate). In the synthesis of Example 5, silica gel flash chromatography was performed using a solvent mixture of petroleum ether (bp 40-60°C) / ethyl acetate 3 / 1 to give RTK-46 as an orange waxy solid (179 mg; 38%; 0.324 mmol) (cLogP=7.23). 1 H-NMR δ H (400 MHz, CDCl3) = 8.02-7.99 (2H,m, aryl CH), 7.63-7.60 (4H,m, aryl CH), 7.33 (1H,s, alkene CH), 7.16 (2H,d, part of AA'BB', J = 8.0 Hz, aryl CH), 2.58-2.50 (4H,m, CH2C(O) and CH2C=C), 2.12 (3H,s, CH3), 1.69-1.67 (2H,m, CH2), 1.40-1.27 (12H,m, 6×CH2). 13 C-NMR δ C(100MHz,CDCl3) = 215.52(C=S), 185.40(C=O), 184.77(C=O), 171.76(COO), 171.71(aryl CC), 153.71(aryl CC), 147.51(aryl CC), 143.14(aryl CC), 136.00(alkene CH), 133.36(aryl CH), 133.34(aryl CH), 132.20(aryl CC), 132.17(aryl CC), 1 29.09 (aryl CC), 128.20 (aryl CH), 126.28 (aryl CH), 126.21 (aryl CH), 122.95 (aryl CH), 34.36 (CH2), 29.95 (CH2), 29.33 (CH2), 29.30 (CH2), 29.18 (CH2), 29.02 (CH2), 28.74 (CH2), 27.10 (CH2), 24.79 (CH2), 12.68 (CH3).

[0264] Example 6 (4-Carbamothioylphenoxy) 10-(1,4-dihydronaphthalen-2-yl)decanoate) In the synthesis of Example 6, silica gel flash chromatography was performed starting with a solvent mixture of petroleum ether (bp 40-60° C.) / ethyl acetate 2 / 1, followed by a solvent mixture of petroleum ether (bp 40-60° C.) / ethyl acetate 1 / 1 to give Example 6 as a yellow solid (98 mg; 24%; 0.205 mmol) (cLogP=6.35). 1 H-NMR δ H (400MHz, CDCl3) = 8.00-7.96 (2H,m, aryl CH), 7.81 (2H,d, part of AA'BB', J = 8.0Hz, aryl CH), 7.75 (1H,br s, NH), 7.61-7.60 (2H,m, aryl CH), 7.41 (1H,br s, NH), 7.02 (2H,d, part of AA'BB', J = 8.0Hz, aryl CH), 2.56-2.47 (4H,m, CH2C(O) and CH2C=C), 2.10 (3H,s, CH3), 1.69-1.65 (2H,m, CH2), 1.40-1.26 (12H,m, 6×CH2). 13 C-NMR δ C(100MHz,CDCl3) = 201.49(C=S), 184.76(C=O), 184.78(C=O), 171.98(COO), 171.26(aryl CC), 153.59(aryl CC), 147.53(aryl CC), 143.15 aryl(CC), 136.61(aryl CC), 133.67(aryl CH), 133.38(aryl CC), 128.49(aryl CH), 126.27(aryl CH), 126.19(aryl CH) 121.56 (aryl CH), 34.36 (CH2), 29.93 (CH2), 29.31 (CH2), 29.28 (CH2), 29.15 (CH2), 29.01 (CH2), 28.74 (CH2), 27.09 (CH2), 24.79 (CH2), 12.67 (CH3).

[0265] Example 7 (4-(3-oxo-3H-1,2-dithiol-5-yl)phenoxy) 10-(1,4-dihydronaphthalen-2-yl)decanoate). In the synthesis of Example 7, silica gel flash chromatography was performed using a solvent mixture of petroleum ether (bp 40-60°C) / ethyl acetate 4 / 1 to give RTK-48 as a yellow solid (128 mg; 28%; 0.239 mmol) (cLogP=6.75). 1 H-NMR δ H (400 MHz, CDCl3) = 8.00-7.99 (2H,m, aryl CH), 7.63-7.56 (4H,m, aryl CH), 7.15 (2H,d, part of AA'BB', J = 8.0 Hz, aryl CH), 6.74 (1H,s, alkene CH), 2.56-2.50 (4H,m, CH2C(O) and CH2C=C), 2.12 (3H,s, CH3), 1.69-1.57 (2H,m, CH2), 1.34-1.27 (12H,m, 6×CH2). 13 C-NMR δ C(100MHz,CDCl3) = 193.99(SC=O), 185.39(C=O), 184.76(C=O), 171.79(COO), 169.23(aryl CC), 153.41(aryl CC), 147.51(aryl CC), 143.13(aryl CC), 133.36(aryl CH), 133.33(aryl CH), 132.20(aryl CC), 132.16(aryl CC), 130.02(aryl CC), 127.81 (aryl CH), 126.27 (aryl CH), 126.20 (aryl CH), 122.76 (aryl CH), 118.02 (alkene CH), 34.36 (CH2), 29.95 (CH2), 29.33 (CH2), 29.30 (CH2), 29.18 (CH2), 29.02 (CH2), 28.74 (CH2), 27.10 (CH2), 24.80 (CH2), 12.68 (CH3).

[0266] Synthesis of 2,3-dimethoxy-5-methyl-6-{10-[4-(3-sulfanylidene-3H-1,2-dithiol-5-yl)phenoxy]decyl}cyclohexa-2,5-diene-1,4-dione (Example 8). [ka] 2-(10-hydroxydecyl)-5,6-dimethoxy-3-methyl-1,4-benzoquinone (1.00 g, 0.00295 mol) and TPP (triphenyl phosphate) (0.775 g, 0.00295 mol) were dissolved in dry THF (12 mL) under nitrogen. DEAD (diethyl azodicarboxylate) (2.2 M in toluene) (2.20 mol / L, 1.34 mL, 0.00295 mol) was added dropwise (slight exotherm was observed) and stirred at room temperature for 5 min. 5-(4-hydroxyphenyl)dithiol-3-thione (0.669 g, 0.00295 mol) was added and stirred at room temperature overnight. The reaction mixture was evaporated to dryness and purified by column chromatography eluting with DCM. Most of the impurities were removed. Column again with 0-30% EtOAc in hexane gave the product of Example 8 in 18% yield. 1H NMR(400MHz,CDCl3) δ 7.64-7.56(m,2H),7.39(s,1H),7.00-6.92(m,2H),4.02(t,J=6.5Hz,2H),3.99(d,J=1.2Hz,6H),2.49-2. 39(m,2H),2.01(d,J=0.7Hz,3H),1.81(dt,J=14.6,6.7Hz,2H),1.46(p,J=6.8Hz,2H),1.42-1.24(m,13H). 13 C NMR(101MHz,CDCl3) δ 215.12(C),184.71(C),184.17(C),173.17(C),162.61(C),144.34(C),144.32 (C),143.05(C),138.69(C),134.55(CH),128.58(CH),123.94(C),115.47(CH) ,68.48(CH2),61.15(CH),29.81(CH2),29.48(CH2),29.40(CH2),29.33(CH2), 29.29(CH2), 29.04(CH2), 28.72(CH2), 26.40(CH2), 25.94(CH2), 11.91(CH3). LCMS 80.5%, @ 225nm (±50), MH+ 547.0.

[0267] Synthesis of Example 9 [ka] Step 1: Synthesis of 4-{[10-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dien-1-yl)decyl]oxy}benzonitrile. Idebenone (1 g, 2.9 mol) and 4-hydroxybenzonitrile (352 mg, 2.9 mol, 1 equiv.) were dissolved in THF (20 ml). After dissolution, TPP (852 mg, 3.3 mmol, 1.1 equiv.) was added, followed by dropwise addition of DEAD (2.2 molar solution in toluene, 1.48 ml, 0.00325 mol, 1.1 equiv.) and the reaction mixture was stirred overnight. The solution was concentrated and then purified with ethyl acetate:hexane system to give the product as a red viscous oil. This oil solidified on standing to give intermediate product 3 as an orange solid. 0.831 g, 64% yield. Rf = 0.22 (20% ethyl acetate:hexane).1 H NMR(400MHz,CDCl3) δ 7.61-7.51(m,2H),6.97-6.89(m,2H),3.99(d,J=1.2Hz,9H),2.49-2.41(m,2H),2.009(s,3H),1.84-1.74(m,2H),1.42-1.23(m,14H). LCMS 75% @ 225nm (±50), MH+ 440, 441.

[0268] Step 2: Synthesis of 4-{[10-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dien-1-yl)decyl]oxy}benzene-1-carbothioamide (compound 9). Magnesium chloride hexahydrate (189 mg, 1.8 mmol, 1 eq) and sodium hydrogen sulfide (173 mg, 1.8 mmol, 2 eq) were stirred in THF (5 ml) to which was added intermediate 3 (408 mg, 0.93 mmol, 1 eq, in 5 ml THF). This was heated to 30° C. and after 1 h TLC showed the reaction was complete and the reaction was concentrated to an oil. The organic phase was then dissolved in DCM and eluted through a silica plug and the relevant spot was concentrated. This was then eluted on a Biotage system using 0-25% ethyl acetate:hexane to give the product after concentration as an orange solid, Example 9. 235 mg, 53% yield. Rf = 0.75 (10% ethyl acetate:DCM), 0.13 (20% ethyl acetate:hexane). 1 H NMR(400MHz,CDCl3) δ 7.63-7.48(m,2H),7.02-6.85(m,2H),5.28(d,J=22.5Hz,2H),3.99(t,J=6.5Hz,2H),3.89(d,J=1 .1Hz,6H),2.64-2.49(m,2H),2.15(s,3H),1.79(dt,J=14.6,6.6Hz,2H),1.38(d,J=53.7Hz,14H). 13C NMR(CDCl3,101MHz) δ 162.49(C),140.03(C),129.83(C),136.64(C),136.62(C),133.96(CH),123.21(C),119.33(C),117.63(C),115.20(CH),103.64(C),68.4 5(CH2),60.79(CH3),60.73(CH3),29.88(CH2),29.51(CH2),29.48(CH2),29.29(CH2),28.97(CH2),26.34(CH2),25.91(CH2),11.15(CH3). LCMS 95% @ 225nm(±50), MH - 472.

[0269] Example compounds 10-17 were prepared using procedures similar to those described above for compounds 1-9.

[0270] The structures of Example Compounds 1 to 15 are shown below. [Table 3(1)] [Table 3(2)]

[0271] Biological Screening Methods and Results cell culture b.End3 cells were split by trypsinization (usually twice a week) when they reached or slightly exceeded 90% confluence. The following procedure was followed: First, the old cell medium was removed and the cells were washed with about 10 ml of PBS without calcium and magnesium salts. 1 ml of trypsin-EDTA was added to the cells, the cells were rinsed twice with trypsin-EDTA, and then the trypsin solution was removed from the cell flask. The cells were incubated at 37°C for 2-3 min until the cells detached from the flask surface, and finally fresh supplemented DMEM (4 or 5 ml) was added to the cell flask. The resulting cell-containing mixture was removed from the original flask and divided into different flasks in a ratio of 1 / 4 or 1 / 5 of the volume. To each flask, additional DMEM was added to bring the volume to 12-13 ml. Cell growth and eventual evidence of contamination were checked daily or every 2 days under an inverted microscope.

[0272] To store the cells for longer periods and to avoid the need to culture the cells when they are not needed immediately, the cells were kept frozen in liquid nitrogen, but the cells were not frozen after passage 27. To freeze the cells, the old cell medium was removed and, after trypsinization, the cells were resuspended in a solution of cold (4°C) supplemented DMEM containing 5% DMSO (cell culture grade) before transferring them into cryogenic vials (1.5 ml per vial) (approximately 10 -6 cells / ml), which were placed in a freezing container (Mr. Frosty) filled with isopropyl alcohol to achieve a cooling rate of -1°C / min. The freezing container was placed in a -80°C freezer where the cells were kept overnight and the next morning they were transferred to a liquid nitrogen tank. When necessary, the frozen cells were thawed by warming in a water bath at 37°C for 1-2 min, after which the cells were gently transferred to a pre-incubated (5 min) T75 flask containing 12 ml of supplemented DMEM. They were incubated overnight to allow the cells to attach to the flask surface, after which the old cell medium was removed and fresh DMEM was added to the flask.

[0273] Hyperglycemia (HG)-induced mitochondrial dysfunction The b.End3 cell line was used as a model of oxidative stress since in vivo the vascular endothelium was found to be the primary target of oxidative stress. Furthermore, loss of endothelial function and cell death was observed in cardiovascular diseases such as hypertension and diabetes [Poredos et al., 2021]. Diabetic microvascular complications (i.e. neuropathy, nephropathy, retinopathy) are also mainly caused by long-term exposure of tissues to excessive glucose concentrations, such exposure leads to increased mitochondrial ROS production, alterations in mitochondrial membrane potential and loss of ATP synthesis [Vincent et al., 2002; Kiritoshi et al., 2003; Manea et al., 2004].

[0274] b.To induce hyperglycemia in End3 cells, protocols reported in the literature [Lorenzi et al., 1985; Qu et al., 2014] were followed. After trypsinization, cells were diluted with supplemented DMEM (approximately 2 ml / flask), so that cells from three or four different flasks were transferred to a 15 ml sterile conical centrifuge tube and centrifuged for 5 min to separate the cells from the medium. Afterwards, the supernatant medium was removed and the cells were gently resuspended and mixed with approximately 4 ml of fresh supplemented DMEM. 20 μl of this solution were added to 40 μl of trypan blue and 10 μl of the final solution was loaded into a cell counting slide dual chamber. Trypan blue allows to distinguish between live and dead cells. Indeed, trypan blue is impermeable in live cells but absorbed by dead cells. An automated cell counter was used to measure the number of cells per ml. Usually, the values ​​found were around 10 -6The cell solution was diluted to obtain a concentration of 20,000 cells / ml and thus 20,000 cells / well in the minimum volume required to fill a 96-well plate (200 μl / well, approximately 13 ml for one plate. The two outer columns and rows were loaded with cell-free medium as they are susceptible to evaporation, therefore the cell medium in these wells prevented evaporation of the outer cell-containing wells). The cells were cultured overnight in a humidified incubator to allow the cells to attach to the plate surface. The medium was then removed (a part of the plate was kept with normal glucose DMEM as a positive control) and supplemented high glucose DMEM was added. The cells were cultured for 8 days. This was because previous studies determined that 8 days was the minimum amount of time required to induce widespread mitochondrial dysfunction such as excessive oxidant production and mitochondrial membrane hyperpolarization [Lorenzi et al., 1985; Qu et al., 2014].

[0275] On day 8, cells were dosed with 10 μl / well (1 / 20 dilution factor) of H2S donor or control compound solution or PBS vehicle solution (containing calcium and magnesium salts and 10% DMSO). The final concentration of DMSO in the cells was 0.5%. Higher DMSO doses may be toxic to the cells. Cells were incubated for another 2 days in the presence of compounds to determine the amount of mitochondrial oxidants and mitochondrial membrane hyperpolarization after 10 days of hyperglycemic exposure. Note that in this procedure, drugs were added only after mitochondrial dysfunction had already occurred in the cells in order to evaluate the cytoprotective activity of new compounds. The described protocol is summarized in the following scheme.

[0276] [Table 4]

[0277] On day 0, cells (20,000 cells / ml) were seeded in 96-well plates. Cells were cultured overnight at 37°C. On day 1, supplemented DMEM was removed and high glucose supplemented DMEM was added. On day 8, H2S donor compounds (Examples 1-7), control compounds or vehicle solutions were added to the cells. On day 10, mitochondrial dysfunction was determined [Lorenzi et al., 1985; Qu et al., 2014].

[0278] Mitochondrial superoxide production The determination of mitochondrial superoxide production was performed using Mitosox Red, as previously described in the literature [Mukhopadhyay, 2007]. Mitosox Red is selectively and rapidly taken up by mitochondria due to its positive delocalized charge and its polarity. Inside the organelle, this dye can be easily oxidized by superoxide and exhibits a highly red fluorescence. The dye is selective for superoxide and is not oxidized by nitric oxide species

[0300] .

[0279] Oxidation of Mitosox Red by superoxide. The oxidized form of Mitosox Red binds to DNA and produces fluorescence [Mukhopadhyay, 2007]. [ka]

[0280] The Mitosox Red protocol was carried out as follows: After 10 days of hyperglycemic exposure and 2 days with test compounds, the medium was removed and the endothelial cells were washed twice with 100 μl / well of PBS (containing calcium and magnesium salts). The endothelial cells were incubated with 50 μl / well of 5 μM Mitosox Red solution (5 μl from a 5 mM stock solution in DMSO was added to 5 ml of calcium / magnesium-containing PBS) for 25 min at 37°C. Afterwards, the cells were washed three times with 100 μl / well of PBS (containing calcium / magnesium salts) and loaded with 100 μl / well of reading medium (PBS containing 10% FBS supplemented with calcium / magnesium). The oxidation of Mitosox Red (Ex / Em: 510 / 580 nm) was then recorded kinetically for 60 min at 37°C on a Pherastar microplate reader using an ROX filter (Ex / Em: 575 / 610 nm). Mitochondrial ROS production was measured using the fluorescent probe oxidation V max value.

[0281] result Table 1 shows the results of this mitochondrial dysfunction screen for Comparative Example AP39 and Examples 1-4.

[0282] [Table 5]

[0283] Table 1 shows that the compounds of the present invention are as potent as AP39, and sometimes more potent, with the advantage of being less toxic. The compounds of the present invention have a lower clogP, which is a predictor of increased aqueous solubility, and because of increased aqueous solubility, the compounds of the present invention can be more easily formulated into pharmaceuticals. In contrast, AP39 has the problem of high hygroscopicity, which makes it much more difficult to formulate than the compounds of the present invention.

[0284] Screening using C. elegans Strains and culture conditions C. elegans strains were cultured at 20°C on Petri dishes containing nematode growth medium (NGM) agar and a lawn of Escherichia coli OP50 unless otherwise stated. Animals for the study were age-synchronized by gravity synchronization from the L1 stage and grown to the desired day of adulthood. The C. elegans strain used in this study was Bristol strain N2 (WT), provided by the Caenorhabditis Genetics Center.

[0285] Imaging mitochondria and cell death Mitochondrial imaging was used in day 1 adults with or without treatment to examine the mitochondrial network. Worms were cultured with test compounds as described. Approximately 20 day 1 adults were harvested in 20 μL of M9 buffer on a cover slipped microscope slide. Worms were photographed at 40x magnification using a Nikon Eclipse 50i microscope. The protocol used was as described by Oh and Kim. Briefly, animals were evaluated at days 4 and 8 of adulthood, and the number of dead myocytes was determined by quantifying the number of myocytes that had lost their distinct circular nuclear GFP signal. Approximately 30 animals were harvested in 20 μL of M9 buffer on a cover slipped microscope slide. Worms were photographed at 10x magnification using a Nikon Eclipse 50i microscope.

[0286] result Figures 1-3 show the results obtained from the nematode screening of test compounds.

[0287] Figure 1 shows the fragmentation of the mitochondrial network in C. elegans caused by aging, which is inhibited by Example 2 but not by the components of this molecule, idebenone and ADTOH.

[0288] Figure 2 shows the decrease in networked mitochondria in C. elegans caused by aging. This network is preserved by Example 2, but not by idebenone and ADTOH, which are components of this molecule.

[0289] FIG. 3 shows the damage caused to the mitochondrial network in aging C. elegans, which can be inhibited by Example 2, but not by its constituent parts idebenone and ADTOH.

[0290] These results clearly demonstrate the therapeutic efficacy of the compounds of the present invention in the C. elegans model of mitochondrial aging. Thus, the compounds may find utility in indications where maintaining mitochondrial health is therapeutic. In particular, C. elegans muscle aging is a well-validated animal model of human sarcopenia (reviewed in [Christian and Benian, 2020]).

[0291] Improved cellular bioenergetics in senescent primary human lung fibroblasts Human primary lung fibroblasts were isolated from healthy volunteers and cultured in DMEM supplemented with 10% fetal bovine serum and 1% pen / strep and 2 nM L-glutamine at 37 °C, 5% CO2. To induce senescence, cells were seeded on Seahorse V7 plates at a density of 50,000 cells / well in 250 μl cell culture medium and treated daily with fresh cell culture medium containing 100 nM H2O2 for 5 days, and then the cells were cultured in normal medium for an additional 9 days. Senescence was confirmed by microscopy and staining for the senescence marker senescence-associated-β-galactosidase (SA-βgal; Cell Signalling kit no. 9860). Cells were then treated with compounds (0-300 nM) for an additional 24 h (control was without compound). * SIP cells), after this time cellular bioenergetics was determined using a Seahorse XFe24 extracellular flux analyzer as described below. *SIP (senescence-induced phenotype) - Senescence-induced phenotype.

[0292] Assessment of Cellular Metabolism (Seahorse) – Lung Fibroblasts For mitochondrial and glycolytic stress tests (Agilent, UK), Seahorse XFe24 sensor cartridges were hydrated with Seahorse XF calibrant solution and kept overnight at 37°C in a non-CO2 incubator. After confirming cell senescence, the medium was diluted with test example compound ( * The medium was replaced with low-buffered Seahorse XF medium supplemented with 0–300 nM of 50 mM glycerol (0–300 nM) and the cells were incubated for 1 h at 37 °C in a non-CO2 incubator. After incubation, the plate was loaded onto a Seahorse XF Analyser and the basal oxygen consumption rate (OCR) was measured for three cycles. After the basal measurement, the cells were injected every three cycles with the following: oligomycin (final concentration 1 μM), FCCP (final concentration 1 μM) and rotenone / antimycin A (1:1 ratio, final concentration 0.5 μM). Measurements were performed every 8 min with a 3 min mix, 2 min wait, 3 min measurement cycle. Extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) were measured for three baseline cycles and the injection strategy was initiated. After completion of all assays, the medium was removed and the cells were lysed with sodium hydroxide (100 μL of 50 mM NaOH per well). Protein concentration was quantified using the Bradford method. OCR and ECAR readings were normalized to the total protein concentration in each well.

[0293] Figure 4 shows the results of test compound Example 17. The reduced loss of OCR caused by the test compound compared to the control indicates that mitochondrial dysfunction in these senescent cells is reversed by Example 17. This demonstrates that compounds of the present invention may provide benefits in senescent cells, particularly senescent airway muscle cells, and therefore may provide benefits in the treatment of COPD.

[0294] C2C12 cell culture and differentiation cell culture C2C12 myoblast medium requirements and seeding densities are shown in Tables 2 and 3, respectively. Cells were maintained in culture in proliferation medium at subconfluence (60-70%). For differentiation, cells were seeded according to the seeding density and volume in Table 3 in seeding medium and incubated for 48 h at 37 °C and 5% CO2. After 48 h (100% confluence), the medium was replaced with differentiation medium. Medium was replaced daily for 6 consecutive days. Overnight treatments were performed in serum-deficient amino acid-poor medium (Table 2). All experiments were performed in serum-deficient medium.

[0295] [Table 6]

[0296] [Table 7]

[0297] Assessment of Cell Metabolism (Seahorse) – Mouse C2C12 Skeletal Myotubes For mitochondrial stress testing (Agilent, UK), C2C12 myoblasts were cultured at 3 × 10 3 Cells / well were differentiated in Seahorse XFe96 microplates as described above. Seahorse XFe96 sensor cartridges were hydrated with Seahorse XF calibrant solution and kept overnight at 37° C. in a non-CO2 incubator. On day 7, the medium was diluted with test example compounds ( *The medium was replaced with low-buffered Seahorse XF medium (Table 3) supplemented with 0–300 nM of riboflavin and the cells were incubated for 1 h at 37 °C in a non-CO2 incubator. After incubation, the plate was loaded into a Seahorse XFe96 Analyser and the basal oxygen consumption rate (OCR) was measured for 4 cycles. After the basal measurement, the cells were injected every 4 cycles with the following: oligomycin (final concentration 2 μM), FCCP (final concentration 1 μM) and rotenone / antimycin A (1:1 ratio, final concentration 1 μM). Measurements were performed every 6 min with a 3 min mix, 3 min measurement cycle. The extracellular acidification rate (ECAR) was measured for 4 baseline cycles and the injection strategy was initiated. After completion of all assays, the medium was removed and the cells were lysed with sodium hydroxide (100 μL of 50 mM NaOH per well). Protein concentration was quantified using the Bradford method. OCR and ECAR readings were normalized to the total protein concentration in each well.

[0298] References Ahmad A and Szabo C (2016) Pharmacol Res 113(Pt.A):348-355 Ahmad A et al. (2016) Shock 45(1):88-97 Berge SM et al. (1977) J Pharm Sci 66(1):1-19 Chatzianastasiou A et al. (2016) J Pharmacol Exp Ther 358(3):431-440 Christian, CJ and Benian GM (2020) Aging Cell 19(10):e13223 Covarrubias AE et al. (2019) Am J Pathol 189(1):104-114 Drucker NA et al. (2018) J Pediatr Surg. 53(9):1692-1698 Ellwod RA et al. (2021) Proc Natl Acad Sci USA 118(9):e2018342118 Cell Physiol Biochem 52(2):186-197 Fox BCら(2020) J Inherited Metab Dis 44(2):367-375 Gero D (2016) Pharmacol Res 113(pt.A):186-198 Ikeda Kら(2015) Nitric Oxide 49:90–96 Juriasingani Sら(2018) Nitric Oxide 81:57-66 Karaman Yら(2021) Basic Clin Pharmacol Toxicol 128(5):652-660 Cardio QGら(2017) Br J Pharmacol 174(4):287-301 Latorre E (2018) Aging 10(7):1666-1681 Lobb Iら(2017) Am J Transplant 17(2):341-352 Nishime Kら(2020) Am J Transplant doi:10.1111 / ajt.16401 Oh KH and Kim H. Proc.Natl.Acad.Sci.USA2013, 110, 19024-19029). Poredos P (2021) Angiology doi:10.1177 / 0003319720987752 Salmon-Chemin L (2001) J Med Chem 44(4):548-565 Sanchez-Aranguren LC(2020) Sci Rep 10:15810 Sugiyama Y and Fujita T (1985) FEBS Lett. 184(1):48-51 Szczesny B (2014) Nitric Oxide 41:120–130 Tomasova L (2015) Nitric Oxide 46:131–144 Wepler Mら(2019) Shock 52(2):230-239 Zhao FLら(2016) Oxid Med Cell Longev 2016:8360738 Zhu C (2019) Am J Transplant 19(11):3139-3148

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 In the formula, R １ and R ２ are independently １～６ Alkyl group, C １～６ alkoxy groups, or together form a cycloalkyl or aryl ring; R ３ is C １～６ Alkyl group or C １～６ is an alkoxy group, L is a linker group; A is a group capable of releasing hydrogen sulfide compound.

2. Group A is 【Chemistry 2】 wherein X is S, O, or N—OH; and R ４ , R ５ and R ６ are independently H or C １～７ The compound of claim 1, wherein the alkyl group is selected from the group consisting of:

3. The compound according to claim 1, wherein A is selected from a thiocarbamoyl group, a 5-thioxo-5H-1,2-dithiol-3-yl group, a 5-thioxo-5H-1,2-dithiol-4-yl group, a 5-oxo-5H-1,2-dithiol-3-yl group, a 5-oxo-5H-1,2-dithiol-4-yl group, a 5-hydroxyimino-5H-1,2-dithiol-3-yl group, a 5-hydroxyimino-5H-1,2-dithiol-4-yl group, a phosphinodithioate group, or a phosphinodithioic acid group.

4. 2. The compound of claim 1, wherein L comprises a group B that is an optionally substituted alkyl chain, an optionally substituted alkenyl chain, or an optionally substituted alkynyl chain.

5. L is a direct bond, -C(=O)NH-, -NHC(=O)-, -O-, -S-, -S(=O) ２ NH-, -NHS (=O) ２ -, -OC(=O)-, -OC(=O)CH ２ 2. The compound of claim 1, comprising a group Z selected from -O- and -C(=O)O-.

6. 2. The compound of claim 1, wherein L contains a group Y which is an optionally substituted 5- or 6-membered cycloalkyl or aryl ring.

7. or a pharmaceutically acceptable salt thereof, 【Transformation 3】 In the formula, R １ , R ２ and R ３ is as defined in claim 1, B is an optionally substituted alkyl chain, an optionally substituted alkenyl chain, or an optionally substituted alkynyl chain; Z is a direct bond, —C(═O)NH—, —NHC(═O)—, —O—, —S—, or —S(═O) ２ NH-, -NHS (=O) ２ -, -OC(=O)-, -OC(=O)CH ２ selected from —O— and —C(═O)O—; Y is an optionally substituted 5- or 6-membered cycloalkyl or aryl ring; A is a group capable of releasing hydrogen sulfide The compound of claim 1.

8. or a pharmaceutically acceptable salt thereof, 【Chemistry 4】 In the formula, R １ and R ２ are both C １～６ are alkoxy groups or together form a 6-membered aryl ring; R ３ is C １～６ is an alkyl group, B is optionally substituted C ６～１４ is an alkyl chain, Z is -C(=O)NH-, -NHC(=O)-, -O-, -OC(=O)-, -OC(=O)CH ２ O-, -OCH ２ a group selected from —C(═O)O— and —C(═O)O—, Y is an optionally substituted phenyl group, and the groups Z and A are linked to each other para on the phenyl group; A is, 【Transformation 5】 wherein X is S, O, or N—OH; and R ４ , R ５ and R ６ are independently H or C １～７ alkyl groups The compound of claim 1.

9. The compound according to claim 7, wherein A is selected from thiocarbamoyl, 5-thioxo-5H-1,2-dithiol-3-yl, 5-thioxo-5H-1,2-dithiol-4-yl, 5-oxo-5H-1,2-dithiol-3-yl, 5-oxo-5H-1,2-dithiol-4-yl, 5-hydroxyimino-5H-1,2-dithiol-3-yl, 5-hydroxyimino-5H-1,2-dithiol-4-yl, phosphinodithioate, and phosphinodithioic acid.

10. R １ and R ２ are both -OMe, and R ３ is C １～３ The compound of claim 1 which is an alkyl group.

11. R １ and R ２ The compound according to claim 1 , wherein:

12. B is unsubstituted C １～２０ The compound of claim 7, which is an alkyl group.

13. Z is -C(=O)O- or -OC(=O)CH ２ The compound according to claim 7, wherein O-.

14. 8. The compound of claim 7, wherein Y is an optionally substituted phenyl group, and the groups Z and A are linked to each other para on said phenyl group. 【Request Item 15】 【Chemistry 6】 2. The compound of claim 1 selected from: 【Request Item 16】 【Chemistry 7】 【Transformation 8】 2. The compound of claim 1 selected from:

17. 17. A compound according to any one of claims 1 to 16 for use as a pharmaceutical.

18. 17. A compound according to any one of claims 1 to 16 for use in the treatment of a neuromuscular or muscular condition.

19. The neuromuscular or muscular state is mitochondrial H ２ 19. The compound for use according to claim 18, mediated by an S donor.

20. 19. The compound for use according to claim 18, wherein the neuromuscular or muscle condition is selected from Duchenne muscular dystrophy, COPD, Leigh's syndrome, primary mitochondrial diseases, pancreatic islet transplantation, pre-eclampsia, heart transplant, kidney transplant, cardiovascular dysfunction, blunt chest trauma and hemorrhagic shock, necrotizing enterocolitis, myocardial reperfusion injury, burns, diabetic vascular disease, Alzheimer's disease, acute kidney injury, neurological injury after cardiac arrest and hypertension.

21. 17. A pharmaceutical composition comprising a compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

22. 22. A pharmaceutical composition according to claim 21 for use in the treatment of a neuromuscular or muscular condition.

23. 17. A method for the prevention, management and / or treatment of a neuromuscular or muscular condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 16.

Images