Isoxazolidines as RIPK1 inhibitors and their uses

Abstract

Disclosed herein are isoxazolidine compounds and their use as receptor-interacting protein kinase 1 inhibitors, for example in the treatment of diseases and disorders mediated by RIP kinase 1.

Description

[Technical Field]

[0001] Related Applications This invention claims the benefit of European Patent Application No. 22315187.9, filed August 19, 2022, the contents of which are incorporated herein by reference in their entirety for all purposes. [Background technology]

[0002] Although inflammation can be a protective mechanism in response to harmful stimuli such as pathogen invasion and tissue damage, chronic inflammation is an important underlying factor in many human diseases, including neurodegeneration, rheumatoid arthritis, autoimmune and inflammatory diseases, and cancer. Similarly, activation of cell death pathways, such as necrosis and apoptosis, which are useful for eliminating infected or damaged cells, is also an important underlying mechanism of human diseases, including acute and chronic neurodegenerative diseases. Receptor-interacting protein kinase 1 (UniProtKB Q13546) is a key regulator of inflammation, apoptosis, and necroptosis. Receptor-interacting protein kinase 1 plays an important role in regulating the inflammatory response mediated by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). More recent studies have shown that its kinase activity regulates and uniquely characterizes necroptosis, a form of necrotic cell death traditionally considered passive and uncontrolled. Furthermore, receptor-interacting protein kinase 1 is part of a proapoptotic complex, which modulates apoptosis.

[0003] Receptor-interacting protein kinase 1 undergoes a complex and intricate regulatory mechanism, including ubiquitination, deubiquitination, and phosphorylation. These regulatory events collectively determine whether a cell survives, activates an inflammatory response, or dies by apoptosis or necroptosis. Dysregulation of receptor-interacting protein kinase 1 signaling can lead to excessive inflammation or cell death; conversely, studies have shown that inhibition of receptor-interacting protein kinase 1 can be an effective treatment for diseases involving inflammation or cell death.

[0004] RIPK1 inhibition has been identified as a promising principle for treating various diseases, such as rheumatoid arthritis (RA), psoriasis, multiple sclerosis, Alzheimer's disease, inflammatory bowel diseases such as Crohn's disease, amyotrophic lateral sclerosis (ALS), or ulcerative colitis (UC). While access to the central nervous system (CNS) is required to treat some of these diseases, such as multiple sclerosis (MS) and Alzheimer's disease, access to the CNS is not essential for other diseases, such as inflammatory bowel diseases (IBDs) such as rheumatoid arthritis, psoriasis, Crohn's disease, or UC.

[0005] Various RIPK1 inhibitors have already been described (e.g., WO2014125444, WO2016185423), WO2016027253 (GSK).

[0006] The most advanced RIPK1 inhibitor, GSK2982772 (an oxazepinone derivative disclosed in WO 2014 / 125444), has been evaluated in phase II clinical trials for RA, psoriasis, and UC.

[0007] Dihydropyrazole compounds with a phenyl substituent on the dihydropyrazole and a pyrimidine-piperidine element have been disclosed as RIPK1 inhibitors by GSK in WO2018092089.

[0008] Isoxazolidine compounds with a phenyl substituent on the isoxazolidine and a pyrimidine-piperidine element have been disclosed as RIPK1 inhibitors by GSK in WO 2019130230. Similar isoxazolidine compounds have been disclosed in KR2020087922 (Voronoi) and WO 2020043173.

[0009] Isoxazolidine compounds as RIPK1 inhibitors having a phenyl substituent on the isoxazolidine and a methoxy-substituted pyrimidine are disclosed in WO2021245070. Summary of the Invention [Means for solving the problem]

[0010] As used herein, Formula I: [ka] (In the formula, R1 is H or C1-C4 alkyl; R2 is CN or halogen; R3 is H or halogen; R4 is NH2 or OCH3, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof (However, compounds of Formula I in which R1 = H, R2 = F, R3 = H, and R4 = OCH3 are excluded.)

[0011] In another aspect, methods for preparing compounds and intermediates thereof are provided.

[0012] In a related aspect, provided herein is a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable excipient.

[0013] In another aspect, provided herein is a method of inhibiting receptor-interacting protein kinase 1. Further provided is a method of treating a receptor-interacting protein kinase 1-mediated disease or disorder, comprising administering a therapeutically effective amount of a compound or pharmaceutical composition described herein to a subject in need thereof. The present disclosure also provides for the use of a compound or composition thereof in the manufacture of a medicament for treating a disease, disorder, or condition mediated (or at least partially mediated) by receptor-interacting protein kinase 1. DETAILED DESCRIPTION OF THE INVENTION

[0014] definition As used herein, chemical nomenclature not otherwise defined has the meaning used in the art.

[0015] As used herein, the term "C1-C4-alkyl" refers to an alkyl group selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl.

[0016] As used herein, the term "halogen" refers to F, Cl, Br, or I.

[0017] The phrase "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio.

[0018] In this regard, the term "pharmaceutically acceptable salts" refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present disclosure, which can be prepared in situ during the administration excipient or dosage form manufacturing process, or by separately reacting a purified compound of the present disclosure in its free base form with a suitable organic or inorganic acid and then isolating the salt thus formed during purification.

[0019] As used herein, the term "pharmaceutically acceptable excipient" refers to a substance that aids in the administration of an active agent to a subject. "Pharmaceutically acceptable" means that the excipient is compatible with the other ingredients of the formulation and not harmful to the recipient thereof. Pharmaceutical excipients useful in the present disclosure include, but are not limited to, binders, fillers, disintegrants, lubricants, glidants, coatings, sweeteners, flavors, and colorants.

[0020] As used herein, the phrase "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or excipient, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, that is involved in carrying or transporting a compound of interest from one organ or part of the body to another.

[0021] "Treatment" or "treating" is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., reducing one or more symptoms caused by the disease or condition and / or reducing the severity of the disease or condition); b) delaying or halting the onset of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or slowing the worsening or progression of the disease or condition, and / or preventing or slowing the spread (e.g., metastasis) of the disease or condition); and / or c) palliation of the disease, i.e., causing regression of clinical symptoms (e.g., improving the disease state, providing partial or complete remission of the disease or condition, enhancing the effect of another drug, slowing the progression of the disease, improving quality of life, and / or prolonging survival).

[0022] "Prevention" or "preventing" means any treatment of a disease or condition that does not result in the development of clinical symptoms of the disease or condition. In some embodiments, the compounds may be administered to subjects (including humans) at risk for or who have a family history of the disease or condition.

[0023] "Subject" refers to an animal, e.g., a mammal (including a human), that has been or is the object of treatment, observation, or experiment. The methods described herein may be useful for human therapy and / or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.

[0024] The term "therapeutically effective amount" or "effective amount" of a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof means an amount sufficient to effect treatment when administered to a subject to provide a therapeutic benefit, such as amelioration of symptoms or delay of disease progression. For example, a therapeutically effective amount can be an amount sufficient to reduce the symptoms of a disease or condition described herein. The therapeutically effective amount can vary depending on the subject and the disease or condition being treated, the subject's weight and age, the severity of the disease or condition, and the method of administration, and can be readily determined by one of ordinary skill in the art.

[0025] As used herein, chemical nomenclature not otherwise defined has the meaning used in the art.

[0026] As used herein, Formula I: [ka] (In the formula, R1 is H or C1-C4 alkyl; R2 is CN or halogen; R3 is H or halogen; R4 is NH2 or OCH3, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof (However, compounds of Formula I in which R1 = H, R2 = F, R3 = H, and R4 = OCH3 are excluded.)

[0027] In one embodiment, R1 represents C1-C4 alkyl; Compounds of formula I, wherein R2 represents CN; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0028] In one embodiment, R1 represents H; Compounds of formula I, wherein R2 represents halogen; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0029] In one embodiment, R1 represents H; Compounds of formula I, wherein R2 represents Cl; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0030] In one embodiment, R1 represents CH3, Compounds of formula I, wherein R2 represents CN; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0031] In one embodiment, R1 represents H; Compounds of formula I, wherein R2 represents CN; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0032] In one embodiment, R1 represents H; Compounds of formula I, wherein R2 represents F; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0033] In one embodiment, Compounds of formula I, wherein R3 represents H; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0034] In one embodiment, Compounds of formula I, wherein R3 represents halogen; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0035] In one embodiment, Compounds of formula I, wherein R3 represents F; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0036] In one embodiment, Compounds of formula I, wherein R4 represents NH2; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0037] In one embodiment, Compounds of formula I, wherein R4 represents OCH3; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0038] In one embodiment, R1 represents H; R2 represents CN, R3 represents H or F; Compounds of formula I, wherein R4 represents NH2 or OCH3; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0039] In one embodiment, R1 represents H; R2 represents CN, R3 represents H; Compounds of formula I, wherein R4 represents NH2 or OCH3; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0040] In one embodiment, R1 represents H; R2 represents CN, R3 represents F, Compounds of formula I, wherein R4 represents NH2 or OCH3; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0041] In one embodiment, R1 represents H; R2 represents F, R3 represents F, Compounds of formula I, wherein R4 represents NH2 or OCH3; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0042] In one embodiment, Compounds of formula I, wherein when R2 is halogen, R4 is NH2; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0043] In one embodiment, Compounds of formula I, wherein R2 represents CN; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0044] Another embodiment is 3-[(3S)-2-[1-(6-aminopyrimidin-4-yl)piperidine-4-carbonyl]isoxazolidin-3-yl]-5-fluoro-benzonitrile [1-(6-aminopyrimidin-4-yl)-4-piperidyl]-[(3S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl]methanone, 5-[(3S)-2-[1-(6-aminopyrimidin-4-yl)piperidine-4-carbonyl]isoxazolidin-3-yl]-3-fluoro-2-methyl-benzonitrile, (S)-3-fluoro-5-[2-(1-(6-methoxypyrimidin-4-yl)piperidine-4-carbonyl)isoxazolidin-3-yl)benzonitrile, 3-fluoro-5-[(3S)-2-[1-(5-fluoro-6-methoxy-pyrimidin-4-yl)piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile, 3-fluoro-5-[(3S)-2-[1-(6-methoxypyrimidin-4-yl)piperidine-4-carbonyl]isoxazolidin-3-yl]-2-methyl-benzonitrile, and [(3S)-3-(3-chloro-5-fluoro-phenyl)isoxazolidin-2-yl]-[1-(6-methoxypyrimidin-4-yl)-4-piperidyl]methanone A compound of formula I selected from or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0045] Another embodiment is 3-[(3S)-2-[1-(6-aminopyrimidin-4-yl)piperidine-4-carbonyl]isoxazolidin-3-yl]-5-fluoro-benzonitrile [1-(6-aminopyrimidin-4-yl)-4-piperidyl]-[(3S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl]methanone, and 5-[(3S)-2-[1-(6-aminopyrimidin-4-yl)piperidine-4-carbonyl]isoxazolidin-3-yl]-3-fluoro-2-methyl-benzonitrile A compound of formula I selected from or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0046] Another embodiment is (S)-3-fluoro-5-[2-(1-(6-methoxypyrimidin-4-yl)piperidine-4-carbonyl)isoxazolidin-3-yl)benzonitrile, 3-fluoro-5-[(3S)-2-[1-(5-fluoro-6-methoxy-pyrimidin-4-yl)piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile, 3-fluoro-5-[(3S)-2-[1-(6-methoxypyrimidin-4-yl)piperidine-4-carbonyl]isoxazolidin-3-yl]-2-methyl-benzonitrile, and [(3S)-3-(3-chloro-5-fluoro-phenyl)isoxazolidin-2-yl]-[1-(6-methoxypyrimidin-4-yl)-4-piperidyl]methanone A compound of formula I selected from or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0047] Pharmaceutical Composition The compounds described herein are usually administered in the form of pharmaceutical compositions.Therefore, the present invention also provides pharmaceutical compositions containing one or more of the compounds described herein, or their pharmaceutically acceptable salts, tautomers, stereoisomers, stereoisomeric mixtures, prodrugs or deuterated analogs, and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients.

[0048] Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical arts.

[0049] The pharmaceutical compositions of the present disclosure may be specially formulated for administration in solid or liquid form, including those adapted for oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., buccal, sublingual and those targeted for systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection, e.g., as a sterile solution or suspension or sustained release formulation; topical application, e.g., as a cream, ointment, or controlled release patch or spray applied to the skin; vaginal or rectal, e.g., as a pessary, cream, or foam; sublingually; ophthalmically; transdermally; or nasally to the lungs and other mucosal surfaces.

[0050] Some examples of materials which can serve as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; celluloses and their derivatives such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; surfactants such as polysorbate 80 (i.e., Tween 80); powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; pH buffers; polyesters, polycarbonates, and / or polyanhydrides; and other non-toxic, compatible substances used in pharmaceutical formulations. Examples of such formulations include, but are not limited to, DMSO, 10 mM DMSO, 8% hydroxypropyl-β-cyclodextrin in PBS, propylene glycol, etc. For example, in certain embodiments, compounds of the present disclosure can be used as a 4 mM solution in 8% hydroxypropyl-β-cyclodextrin in PBS for parenteral administration. In another specific embodiment, compounds of the present disclosure can be used as a suspension in 0.5% aqueous CMC containing 0.1% TWEEN 80.

[0051] Wetting agents, emulsifiers, and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening agents, flavorings and fragrances, preservatives, and antioxidants can also be present in the composition. Examples of pharmaceutically acceptable antioxidants include water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, and sodium sulfite; oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and alpha-tocopherol; and metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0052] Formulations of the present disclosure include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, and / or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any method well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host treated and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, this amount will range from about 1% to about 99% of the active ingredient, preferably from about 5% to about 70%, and most preferably from about 10% to about 30%. In certain embodiments, formulations of the present disclosure comprise one or more of cyclodextrins, liposomes, micelle-forming agents, such as bile acids, and polymeric carriers, such as polyesters and polyanhydrides; and a compound of the present disclosure. In certain embodiments, the formulations described above render the compounds of the present disclosure orally bioavailable.

[0053] Methods for preparing these formulations include bringing the compound of the present disclosure into association with the carrier and, optionally, one or more accessory ingredients. Generally, the formulations are prepared by uniformly and intimately bringing the compound of the present disclosure into association with a liquid carrier or a finely divided solid carrier, or both, and then, if necessary, shaping the product. Formulations of the present disclosure suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavor base, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as a lozenge (using an inert base such as gelatin and glycerin or sucrose and acacia), and / or as a mouthwash, each containing a predetermined amount of the compound of the present disclosure as an active ingredient. The compound of the present disclosure may also be administered as a bolus, electuary, or paste.

[0054] In solid dosage forms of the present disclosure for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, for example, fillers or extenders such as sodium citrate or dicalcium phosphate and / or starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; humectants such as glycerol; disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retardants such as paraffin; absorption accelerators such as quaternary ammonium compounds; wetting agents such as cetyl alcohol, glycerol monostearate, and nonionic surfactants; absorbents such as kaolin and bentonite clay; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and coloring agents. In the case of capsules, tablets, and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-shell gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

[0055] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersing agents. Molded tablets may be made in a suitable machine in which a mixture of powdered compounds is moistened with an inert liquid diluent.

[0056] Tablets and other solid dosage forms of the pharmaceutical compositions of the present disclosure, such as dragees, capsules, pills, and granules, can optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They can also be formulated to provide sustained or controlled release of the active ingredient therein, for example, using hydroxypropylmethylcellulose, other polymer matrices, liposomes, and / or microspheres in various proportions to provide the desired release profile. They can also be formulated for rapid release, for example, lyophilization. They can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions can also optionally contain opacifying agents and can be compositions that release the active ingredient only, or preferentially, in a certain part of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0057] Liquid dosage forms for oral administration of the compounds of the present disclosure include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.

[0058] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0059] Suspensions may contain, in addition to the active compound, suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0060] Formulations of pharmaceutical compositions of the present disclosure for rectal or vaginal administration may be provided as suppositories, which may be prepared by mixing one or more compounds of the present disclosure with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, a suppository wax or salicylate, which are solid at room temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release the active compound(s).

[0061] Formulations of the present disclosure which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

[0062] Dosage forms for topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants which may be required.

[0063] The ointments, pastes, creams and gels may contain, in addition to the active compounds of this disclosure, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.

[0064] Powders and sprays can contain, in addition to the compounds of this disclosure, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0065] Transdermal patches have the additional advantage of providing controlled delivery of the compounds of the present disclosure to the body.Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium.Absorption enhancers can also be used to increase the flux of the compound across the skin.The rate of such flux can be controlled by either providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0066] Ophthalmic formulations, eye ointments, powders, solutions, and the like are also contemplated as being within the scope of the present disclosure. Pharmaceutical compositions of the present disclosure suitable for parenteral administration comprise one or more compounds of the present disclosure in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately before use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0067] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0068] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms on the subject compounds can be ensured by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenylsorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like, in the compositions. Furthermore, prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.

[0069] In some cases, in order to prolong the effect of a drug, it is desirable to delay the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility. The absorption rate of the drug depends on its dissolution rate, which may depend on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form can be achieved by dissolving or suspending the drug in an oil vehicle.

[0070] Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the drug-to-polymer ratio and the nature of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0071] Treatment method In other embodiments, provided herein are methods for treating a receptor-interacting protein kinase 1-mediated disease or disorder. The method comprises administering a therapeutically effective amount of a compound or pharmaceutical composition described herein to a subject in need thereof. In some embodiments, the receptor-interacting protein kinase 1-mediated disease or disorder is trauma, ischemia, stroke, myocardial infarction, infection, Gaucher disease, Krabbe disease, sepsis, systemic inflammatory response syndrome (SIRS), Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Huntington's disease, HIV-associated dementia, retinal degenerative disease, glaucoma, age-related macular degeneration, rheumatoid arthritis, non-infectious inflammatory skin disease (ncISD) such as psoriasis or atopic dermatitis, psoriatic arthritis, or inflammatory bowel disease.

[0072] As used herein, the term "trauma" refers to any physical injury to the body caused by violence, accidents, fractures, etc. The term "ischemia" refers to a cardiovascular disorder characterized by a state of hypoxia, usually due to an obstruction of the arterial blood supply or insufficient blood flow resulting in hypoxia in tissues. The term "stroke" refers to a cardiovascular disorder caused by a blood clot or bleeding in the brain, most commonly caused by an interruption of blood flow in the brain, such as by a blood clot blocking a blood vessel; in certain embodiments of the present disclosure, the term stroke refers to an ischemic stroke or a hemorrhagic stroke. The term "myocardial infarction" refers to a cardiovascular disorder characterized by local necrosis due to an obstruction of the blood supply.

[0073] The methods described herein can be applied to cell populations in vivo or ex vivo. "In vivo" means within a living individual, such as within an animal or human. In this context, the methods described herein can be used therapeutically in an individual. "Ex vivo" means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including bodily fluid or tissue samples obtained from an individual.

[0074] Such samples can be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this regard, the compounds and compositions described herein can be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein can be used ex vivo to determine optimal schedules and / or dosages of administration of the disclosed compounds for a given indication, cell type, individual, and other parameters. Information gleaned from such use can be used experimentally or in the clinic to design protocols for in vivo treatment. Other ex vivo uses for which the compounds and compositions described herein may be suitable are described below or will become apparent to those skilled in the art. Selected compounds can be further characterized to determine safety or tolerability in human or non-human subjects. Such properties can be examined using methods commonly known to those skilled in the art.

[0075] Experiments using knockout animal models and the receptor-interacting protein kinase 1 inhibitor necrostatin 1 have demonstrated the efficacy of receptor-interacting protein kinase 1 inhibition in protecting tissues from inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), non-infectious inflammatory skin diseases (ncISDs) such as psoriasis or atopic dermatitis, retinal detachment-induced photoreceptor necrosis, retinitis pigmentosa, cerulein-induced acute pancreatitis, and sepsis / systemic inflammatory response syndrome (SIRS), as well as in alleviating ischemic brain injury, retinal ischemia / reperfusion injury, Huntington's disease, renal ischemia / reperfusion injury, cisplatin-induced kidney injury, traumatic brain injury, hematologic and solid organ malignancies, bacterial and viral infections (e.g., tuberculosis and influenza or SARS-coronavirus), and lysosomal storage diseases. Thus, the receptor-interacting protein kinase 1 inhibitors disclosed herein suggest that both RIPK1 kinase-driven inflammation and cell death are important contributors to systemic inflammatory response syndrome (SIRS). There is also theoretical evidence that vascular permeability and endothelial dysfunction contribute to SIRS / shock and mortality. Thus, the receptor-interacting protein kinase 1 inhibitors of the present disclosure are useful for treating diseases and conditions mediated by receptor-interacting protein kinase 1, including, but not limited to, inflammatory diseases or disorders, necrotic cell diseases, neurodegenerative diseases, central nervous system (CNS) diseases, ophthalmic diseases, infectious diseases, and malignancies. In certain embodiments, the receptor-interacting protein kinase 1 inhibitors described herein can inhibit inflammation, protect tissues or cells from damage or unwanted cell death (e.g., necrosis or apoptosis), ameliorate symptoms, and improve immune responses or neurological function in patients suffering from any of the specified diseases or conditions. Furthermore, the compounds may be suitable for treating immune-mediated diseases, such as, but not limited to, allergic diseases, autoimmune diseases, and the prevention of transplant rejection.

[0076] Provided herein are compounds and compositions for use in medicine. In certain embodiments, the compounds and compositions are for use in treating a receptor-interacting protein kinase 1-mediated disease or disorder. Also provided are methods for treating a receptor-interacting protein kinase 1-mediated disease or disorder, comprising administering a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein to a subject in need thereof. In certain embodiments, the disease or disorder is an inflammatory disease associated with the A20 SNP.

[0077] In some embodiments, the compounds and compositions are for use in the treatment of Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), and incontinentia pigmenti.

[0078] Various specific diseases and disorders are described below. In certain embodiments, the disease or disorder is necrotizing enterocolitis, tuberous sclerosis, Tangier disease, Wolman syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, non-contagious inflammatory skin diseases (ncISDs) such as psoriasis or atopic dermatitis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis (e.g., acute pancreatitis), interface dermatitis (e.g., cutaneous lupus erythematosus, lichen planus, lichen planus pilaris, toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, graft-versus-host disease (GvHD), alopecia areata, vitiligo), atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, SoJIA, systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, antiphospholipid syndrome, vasculitis, osteoarthritis, non-alcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune The following diseases are considered to be resistant to steroids: infectious hepatobiliary disease, primary sclerosing cholangitis, nephritis, celiac disease, autoimmune ITP, transplant rejection, ischemia-reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome (SIRS), cerebrovascular disease, myocardial infarction, Huntington's disease, Alzheimer's disease, Parkinson's disease, allergic disease, asthma, atopic dermatitis, multiple sclerosis, type 1 diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-1 converting enzyme-associated febrile syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-associated periodic syndrome, periodontitis, bacterial infection, staphylococcal infection, mycobacterial infection, retinitis pigmentosa, influenza, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), acute respiratory response syndrome (ARDS), transplant rejection, burns, or hypoxia. In certain embodiments, the disease or disorder is trauma, ischemia, stroke, myocardial infarction, infection, lysosomal storage disease, Niemann-Pick disease, Gaucher disease, Krabbe disease, sepsis, systemic inflammatory response syndrome (SIRS), Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, HIV-associated dementia, encephalopathy, retinal degenerative disease, glaucoma, age-related macular degeneration, rheumatoid arthritis, non-infectious inflammatory skin disease (ncISD) such as psoriasis or atopic dermatitis, psoriatic arthritis, or inflammatory bowel disease.In certain embodiments, the disease or disorder is Alzheimer's disease, ALS, Friedreich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, Huntington's disease, multiple sclerosis, diabetic neuropathy, polyglutamine (polyQ) disease, stroke, Fahr's disease, Menke's disease, Wilson's disease, cerebral ischemia, lysosomal storage disease, or prion disorder. In certain embodiments, the disease is ALS. In certain embodiments, the disease is Alzheimer's disease. In certain embodiments, the disease is a lysosomal storage disease. In certain embodiments, the disease is Parkinson's disease. In certain embodiments, the disorder is an ischemic disease of an organ, including, but not limited to, the brain, heart, kidney, and liver. In several different embodiments, the disorder is an ocular disorder, such as retinal degenerative disease, glaucoma, or age-related macular degeneration. In several different embodiments, the disorder is a central nervous system (CNS) disorder.

[0079] In certain embodiments, methods are provided for treating rheumatoid arthritis (see Lawlor KE, Nat Commun. 2015, 6282; Lee SH, Sci Rep. 7, 2017, 10133), systemic onset juvenile idiopathic arthritis (SoJIA), spondyloarthritis, osteoarthritis, non-contagious inflammatory skin diseases (ncISDs) such as psoriasis or atopic dermatitis, Crohn's disease, ulcerative colitis, or multiple sclerosis, comprising administering a therapeutically effective amount of a compound provided herein to a subject in need thereof. In certain embodiments, methods are provided for treating autoimmune hepatitis, atherosclerosis, neutrophilic skin diseases, or rare diseases caused by A20, NEMO, and / or LUBAC mutations, comprising administering a therapeutically effective amount of a compound provided herein to a subject in need thereof.

[0080] In certain embodiments, the compounds and compositions are useful for treating non-contagious inflammatory skin diseases (ncISDs), such as psoriasis or atopic dermatitis.

[0081] In certain embodiments, the disorder is an inflammatory disease of the intestine, such as Crohn's disease or ulcerative colitis (both commonly known as inflammatory bowel disease, IBD). In certain embodiments, the mammal is a primate, canine, or feline subject. In certain embodiments, the mammal is a human subject. Without wishing to be bound by theory, it is believed that inhibition of receptor-interacting protein kinase 1 by the disclosed compounds is at least partially responsible for their anti-inflammatory activity. Accordingly, embodiments of the present disclosure also include methods for inhibiting receptor-interacting protein kinase 1 in vitro or in a subject in need thereof, the methods comprising contacting receptor-interacting protein kinase 1 with a compound disclosed herein. In some of these embodiments, inhibiting receptor-interacting protein kinase 1 is effective in blocking (partially or completely) the release of inflammatory mediators, such as TNF and / or IL6.

[0082] Inflammatory diseases or disorders The receptor-interacting protein kinase 1 inhibitors described herein can be used to treat inflammatory diseases and disorders, which typically exhibit high levels of inflammation in connective tissues or degeneration of these tissues.

[0083] Non-limiting examples of inflammatory diseases and disorders include Alzheimer's disease, ankylosing spondylitis, arthritis including osteoarthritis, rheumatoid arthritis (RA), non-infectious inflammatory skin diseases (ncISDs) such as psoriasis or atopic dermatitis, asthma, atherosclerosis, Crohn's disease, colitis, dermatitis, diverticulitis, fibromyalgia, hepatitis, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), nephritis, Parkinson's disease, and ulcerative colitis. In certain embodiments, the compounds and compositions of the present disclosure are useful for treating autoimmune disorders such as rheumatoid arthritis, psoriasis, psoriatic arthritis, encephalitis, allograft rejection, autoimmune thyroid diseases (such as Graves' disease and Hashimoto's thyroiditis), autoimmune uveoretinitis, giant cell arteritis, inflammatory bowel disease (including Crohn's disease, ulcerative colitis, regional enteritis, granulomatous enteritis, distal ileitis, regional ileitis, and terminal ileitis), insulin-dependent diabetes mellitus, multiple sclerosis, pernicious anemia, sarcoidosis, scleroderma, and systemic lupus erythematosus. In one embodiment, the receptor-interacting protein kinase 1 inhibitors described herein are useful for treating autoimmune encephalitis. In certain embodiments, the compounds and compositions are useful for treating rheumatoid arthritis (RA). In certain embodiments, the compounds and compositions are useful for treating ulcerative colitis. In certain embodiments, the compounds and compositions are useful for treating non-contagious inflammatory skin diseases (ncISDs), such as psoriasis or atopic dermatitis.

[0084] In certain embodiments, the disorder is an inflammatory disease of the intestine, such as Crohn's disease or ulcerative colitis (both commonly known as inflammatory bowel disease). In certain embodiments, the mammal is a primate, canine, or feline subject. In certain embodiments, the mammal is a human subject. Without wishing to be bound by theory, it is believed that inhibition of receptor-interacting protein kinase 1 by the compounds of the present disclosure is, at least in part, responsible for their anti-inflammatory activity.

[0085] Accordingly, embodiments of the present disclosure also include methods for inhibiting receptor-interacting protein kinase 1 in vitro or in a subject in need thereof, the methods comprising contacting receptor-interacting protein kinase 1 with a compound disclosed herein. In some of these embodiments, inhibiting receptor-interacting protein kinase 1 is effective in blocking (partially or completely) the release of inflammatory mediators such as TNF and / or IL6.

[0086] In another embodiment, the receptor-interacting protein kinase 1 inhibitors described herein may be used to treat inflammatory diseases and disorders such as rheumatoid arthritis (RA), psoriasis, inflammatory bowel disease (IBD) such as Crohn's disease or ulcerative colitis.

[0087] In another embodiment, the receptor-interacting protein kinase 1 inhibitors described herein can be used to treat interface dermatitis such as cutaneous lupus erythematosus (CLE), lichen planus (LP), toxic epidermal necrolysis (TEN), or Stevens-Johnson syndrome (SJS).

[0088] In another embodiment, the receptor-interacting protein kinase 1 inhibitors described herein can be used to treat hyperinflammation during viral infections, such as coronavirus disease 19 (COVID-19), acute respiratory distress syndrome (ARDS), and systemic inflammatory response syndrome (SIRS).

[0089] In another embodiment, the receptor-interacting protein kinase 1 inhibitors described herein can be used to treat coronavirus disease 19 (COVID-19).

[0090] In another embodiment, the receptor-interacting protein kinase 1 inhibitors described herein can be used to treat respiratory diseases such as influenza (e.g., swine flu, H7N9), severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), or respiratory syncytial virus (RSV) or bronchiolitis.

[0091] Necrotizing cell disease The compounds described herein can be used to treat diseases / disorders that cause or are otherwise associated with cell necrosis. In particular, the present disclosure provides a method for preventing or treating a disorder associated with cell necrosis in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound or composition described herein. The term "necrotic cell disease" refers to a disease associated with or caused by cell necrosis, such as trauma, ischemia, stroke, myocardial infarction, infection, Gaucher disease, Krabbe disease, sepsis, systemic inflammatory response syndrome (SIRS), Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, HIV-associated dementia, retinal degenerative disease, glaucoma, age-related macular degeneration, rheumatoid arthritis, non-infectious inflammatory skin diseases (ncISDs) such as psoriasis or atopic dermatitis, psoriatic arthritis, or inflammatory bowel disease.

[0092] The necrotic cell disorder can be an acute condition such as trauma, ischemia, stroke, myocardial infarction, anthrax lethal toxin-induced septic shock, sepsis, systemic respiratory response syndrome (SIRS), LPS-induced cell death, and HIV-induced T-cell death leading to immune deficiency, hi certain embodiments, the disorder is an ischemic disease of an organ, including, but not limited to, the brain, heart, kidney, and liver.

[0093] Necrotic cell diseases also include chronic neurodegenerative diseases such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Alzheimer's disease, infectious encephalopathy, dementias such as HIV-associated dementia, etc. In some different embodiments, the disorder is an ocular disorder such as a retinal degenerative disease, glaucoma, or age-related macular degeneration. In some different embodiments, the disorder is a central nervous system (CNS) disorder.

[0094] Neurodegenerative and CNS diseases The receptor-interacting protein kinase 1 inhibitors described herein can also be used to treat neurodegenerative diseases. Neurodegenerative diseases can affect many of the body's activities, such as balance, movement, speech, breathing, and cardiac function. Neurodegenerative diseases can be hereditary or caused by medical conditions, such as alcoholism, tumors, stroke, toxins, chemicals, and viruses. Non-limiting examples of neurodegenerative diseases include Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Friedreich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, and spinal muscular atrophy. In certain embodiments, neurodegenerative diseases and CNS diseases include Niemann-Pick disease, type C1 (NPC1), Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Friedreich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, and spinal muscular atrophy.

[0095] In certain embodiments, the receptor-interacting protein kinase 1 inhibitors described herein can be used to treat NPC1 by inhibiting necroptosis, which leads to neuronal loss. In certain embodiments, the compounds and compositions of the present disclosure are useful for treating Alzheimer's disease. In certain embodiments, the compounds and compositions of the present disclosure are useful for treating Parkinson's disease. In certain embodiments, the compounds and compositions of the present disclosure are useful for treating amyotrophic lateral sclerosis (ALS).

[0096] More generally, the receptor-interacting protein kinase 1 inhibitors described herein can be used to preserve neuronal viability and promote axonal growth and neuronal function within the central nervous system (CNS). Thus, by maintaining neuronal viability and / or promoting axonal regeneration and / or neuronal function, the compounds can be used to reduce or even reverse the loss of cognitive, motor, and sensory function associated with diseases or disorders of the CNS.

[0097] The receptor-interacting protein kinase 1 inhibitors described herein can be used in methods for promoting axon regeneration in CNS neurons, such as CNS sensory neurons, motor neurons, cortical neurons, cerebellar neurons, hippocampal neurons, and midbrain neurons. The receptor-interacting protein kinase 1 inhibitors described herein can be used in methods for promoting neuronal function or preserving viability after injury to CNS neurons. In another embodiment, these compounds can be used to promote axon regeneration in CNS neurons that have degenerated in CNS diseases or disorders. The receptor-interacting protein kinase 1 inhibitors can be administered by any conventional means, for example, locally to neurons or applied ex vivo before retransplantation.

[0098] Thus, in one aspect, the present disclosure provides a method for treating a CNS disorder in a subject in need of such treatment, wherein a symptom of the CNS disorder is axonal degeneration or injury within CNS neurons. The method includes administering to the subject an effective amount of a compound or composition disclosed herein to promote axonal regeneration in CNS neurons affected by the CNS disorder. After administration, neuronal function can be measured, for example, as an indicator of axonal regeneration. It is also contemplated that after administration of the compound or composition, the neuronal function of the CNS neurons is preserved or improved compared to the neuronal function before administration.

[0099] Non-limiting examples of CNS diseases or disorders include brain injury, spinal cord injury, dementia, stroke, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Huntington's disease, multiple sclerosis, diabetic neuropathy, polyglutamine (polyQ) disease, stroke, Fahr's disease, Menke's disease, Wilson's disease, cerebral ischemia, and prion disorders.

[0100] In an exemplary embodiment, the CNS disorder is a brain injury or a spinal cord injury.

[0101] Also provided herein are methods for promoting neuronal survival and axonal regeneration in the CNS. CNS disorders characterized by impaired or insufficient axonal growth or axonal degeneration can result from CNS neuron injury (e.g., trauma, surgery, nerve compression, nerve crush, nerve transection, neurotoxicity, or other physical injury to the brain or spinal cord) or neurodegenerative CNS diseases, where the symptoms of the disorder are axonal degeneration (e.g., Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, multiple sclerosis, diabetic neuropathy, polyglutamine (polyQ) disease, stroke, Fahr's disease, Menke's disease, Wilson's disease, cerebral ischemia, prion disorders (e.g., Creutzfeldt-Jakob disease, and others). In certain embodiments, the CNS disorder is a brain injury (e.g., a traumatic brain injury) or a spinal cord injury (e.g., a chronic, acute, or traumatic spinal cord injury). In certain embodiments, the CNS disorder affects a subject's basic life functions, such as breathing, heart rate, and blood pressure, e.g., brain stem injury or aneurysm. In certain embodiments, the CNS disease or disorder affects a subject's cognitive abilities. In certain embodiments, the CNS disease or disorder affects a subject's movement and / or strength. In certain embodiments, the CNS disease or disorder affects a subject's coordination.

[0102] In certain embodiments, the CNS disorder affects the cognitive abilities of a subject, such as brain damage to the cerebral cortex or a neurodegenerative CNS disorder, e.g., Alzheimer's disease, frontotemporal dementia, dementia with Lewy bodies, corticobasal degeneration, progressive supranuclear palsy, and prion disorders.

[0103] In certain embodiments, the CNS disorder affects movement and / or strength in a subject, such as brain or spinal cord injury or a neurodegenerative CNS disorder such as Parkinson's disease, frontotemporal dementia, dementia with Lewy bodies, corticobasal degeneration, progression of supranuclear palsy, Huntington's disease, multiple system atrophy, amyotrophic lateral sclerosis, and hereditary spastic paraparesis.

[0104] In certain embodiments, the CNS disorder affects coordination in a subject, such as brain damage to the cerebellum or neurodegenerative CNS disorders such as spinocerebellar atrophy, Friedreich's ataxia, and prion disorders.

[0105] In each of the foregoing methods, the CNS disorder includes, but is not limited to, brain injury, spinal cord injury, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, multiple sclerosis, diabetic neuropathy, polyglutamine (polyQ) disease, stroke, Fahr's disease, Menke's disease, Wilson's disease, cerebral ischemia, prion disorders (e.g., Creutzfeldt-Jakob disease), dementia (e.g., frontotemporal dementia, dementia with Lewy bodies), corticobasal degeneration, progressive supranuclear palsy, multiple system atrophy, hereditary spastic paresis, and spinocerebellar atrophy.

[0106] Non-limiting examples of neurodegenerative diseases include Alzheimer's disease, lysosomal storage diseases, amyotrophic lateral sclerosis (ALS), Friedreich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, and spinal muscular atrophy.

[0107] In certain embodiments, the compounds and compositions of the present disclosure are useful for treating Alzheimer's disease. In certain embodiments, the compounds and compositions of the present disclosure are useful for treating Parkinson's disease. In certain embodiments, the compounds and compositions of the present disclosure are useful for treating amyotrophic lateral sclerosis (ALS). In certain embodiments, the compounds and compositions of the present disclosure are useful for treating lysosomal storage diseases.

[0108] In certain embodiments, the disorder is a brain disorder such as, but not limited to, Alzheimer's disease, ALS, frontotemporal dementia, vascular dementia, Huntington's disease, Parkinson's disease, dementia with Lewy bodies, progressive supranuclear palsy, multiple sclerosis, neuromyelitis optica, ischemic brain injury (stroke), hypoxic brain injury, traumatic brain injury, spinal cord injury, sepsis-induced brain injury, CNS infection, CNS abscess, glioblastoma multiforme, epilepsy, neuropathic pain, major depression, bipolar depression, schizophrenia, autism, Niemann-Pick disease, and neuro-Behcet's disease.

[0109] In certain embodiments, provided is a method of treating a CNS disease or disorder, comprising administering a therapeutically effective amount of a compound provided herein to a subject in need thereof, hi certain embodiments, the disease or disorder is Alzheimer's disease or amyotrophic lateral sclerosis (ALS).

[0110] Eye conditions The receptor-interacting protein kinase 1 inhibitors described herein can also be used to treat ocular conditions, for example, to reduce or prevent loss of viability of photoreceptors and / or retinal pigment epithelial cells.

[0111] In certain embodiments, the present disclosure provides a method for maintaining visual function in an eye of a subject having an ocular condition, wherein a symptom of the ocular condition is loss of photoreceptor cell viability in the retina of the eye having the condition. The method includes administering to the eye of the subject an effective amount of a compound or composition described herein, thereby maintaining viability of photoreceptor cells located within the retina of the eye. After administration, the visual function (e.g., visual acuity) of the eye may be preserved or improved compared to the visual function of the eye before administration.

[0112] The ocular condition may be age-related macular degeneration (AMD), pigmentary retinopathy (RP), macular edema, diabetic retinopathy, central circular choroidal dystrophy, BEST disease, adult vitelliform disease, pattern dystrophy, myopic degeneration, central serous retinopathy, Stargardt disease, cone-rod dystrophy, North Carolina dystrophy, infectious retinitis, inflammatory retinitis, uveitis, toxic retinitis, or light-induced toxicity. The AMD may be neovascular or dry AMD. The retinal detachment may be keratogenic, serous, or tractional retinal detachment. In certain embodiments, the ocular condition may be geographic atrophy, glaucoma, or another ischemic ocular disease. In certain embodiments, the present disclosure provides a method of preserving the viability of retinal pigment epithelial (RPE) cells in the retina of a subject with an ocular condition by administering a compound of the present disclosure. The subject being treated may have a loss of retinal pigment epithelial cells in the retina of the eye with the condition, and the ocular condition may be age-related macular degeneration (AMD), BEST disease, myopic degeneration, Stargardt's disease, uveitis, adult foveomacular dystrophy, sickle-shaped fundus, multiple evanescent white dot syndrome, serpiginous choroidopathy, acute multifocal posterior plaque-like epitheliopathy (AMPPE), or another uveitis disorder. In certain embodiments, the method comprises administering to the eye of the subject an effective amount of a compound or composition described herein, thereby maintaining viability of retinal pigment epithelial cells. In another embodiment, a method is provided for preserving the viability of photoreceptor cells located within the retina of a subject suffering from age-related macular degeneration (AMD), pigmentary retinopathy (RP), macular edema, diabetic retinopathy, central circular choroidal dystrophy, BEST disease, adult vitelliform disease, pattern dystrophy, myopic degeneration, central serous retinopathy, Stargardt disease, cone-rod dystrophy, North Carolina dystrophy, infectious retinitis, inflammatory retinitis, uveitis, toxic retinitis, or light-induced toxicity. Thus, in certain embodiments, the method comprises administering to the eye an effective amount of a compound or composition described herein, thereby maintaining the viability of photoreceptor cells located within the retina of a subject suffering from the condition. In another embodiment, a method is provided for preserving the viability of photoreceptor cells located within the retina of a mammalian eye following retinal detachment. The retinal detachment may be rhegmatogenous retinal detachment, tractional retinal detachment, or serous retinal detachment.In other embodiments, retinal detachment can occur as a result of a retinal break, retinoblastoma, melanoma or other cancer, diabetic retinopathy, uveitis, choroidal neovascularization, retinal ischemia, pathological myopia, or trauma. In certain embodiments, the method comprises administering to an eye from which an area of ​​retina has detached a compound or composition described herein in an amount sufficient to preserve the viability of photoreceptor cells located within the area of ​​retina that has detached. In another embodiment, a method of preserving visual function in an eye of a subject with age-related macular degeneration (AMD), pigmentary retinopathy (RP), macular edema, central circular choroidal dystrophy, retinal detachment, diabetic retinopathy, BEST disease, adult vitreous disease, pattern dystrophy, myopic degeneration, central serous retinopathy, Stargardt disease, cone-rod dystrophy, North Carolina dystrophy, infectious retinitis, inflammatory retinitis, uveitis, toxic retinitis, or light-induced toxicity, wherein a symptom of the ocular condition is loss of photoreceptor cell viability in the retina of the eye, and the method comprises treating the subject with a compound or composition described herein. In another aspect, the disclosure provides a method of preserving visual function in an eye of a subject with an ocular condition, wherein a symptom of the ocular condition is loss of photoreceptor cell viability and / or RPE viability in the retina of the eye, and the method comprises treating the subject with a compound or composition described herein.

[0113] In certain embodiments, a method for maintaining visual function in an eye of a subject with an ocular condition is provided, wherein a symptom of the ocular condition is loss of retinal ganglion cell viability in the retina of the eye with the condition. The method comprises administering an effective amount of a compound or composition to the eye of the subject, thereby maintaining viability of retinal ganglion cells located within the retina of the eye. After administration of the compound or composition, the visual function of the eye may be preserved or improved compared to the visual function of the eye before administration. Furthermore, after administration, the preserved retinal ganglion cells may support axonal regeneration.

[0114] Non-limiting examples of symptoms associated with ophthalmic conditions include loss of retinal ganglion cell viability in the retina of the eye, glaucoma, optic nerve damage, optic neuritis, optic neuropathy, diabetic retinopathy, central retinal artery occlusion, and central retinal vein occlusion. The compounds described herein can also be used to treat optic neuropathies, such as ischemic optic neuropathies (e.g., arteritic or non-arteritic anterior ischemic neuropathy and posterior ischemic optic neuropathy), compressive optic neuropathy, infiltrative optic neuropathy, traumatic optic neuropathy, mitochondrial optic neuropathy (e.g., Leber's optic neuropathy), nutritional optic neuropathy, toxic optic neuropathy, and hereditary optic neuropathy (e.g., Leber's optic neuropathy, dominant optic atrophy, Beer's syndrome).

[0115] Also disclosed are methods for maintaining visual function in the eye of a subject having glaucoma, optic nerve damage, optic neuropathy, diabetic retinopathy, central retinal artery occlusion, or central retinal vein occlusion, comprising administering to the eye of the subject an effective amount of a compound or composition described herein, thereby maintaining viability of retinal ganglion cells located within the retina of the eye and visual function of the eye.

[0116] In another aspect, disclosed herein are methods for preserving the viability of retinal ganglion cells located within the retina of a mammalian eye afflicted with, for example, glaucoma, optic nerve injury, optic neuritis, optic neuropathy, diabetic retinopathy, central retinal artery occlusion, and central retinal vein occlusion. The method comprises administering a compound or composition described herein to an eye with an affected area of ​​the retina in an amount sufficient to preserve the viability of retinal ganglion cells located within the affected area of ​​the retina. The preserved retinal ganglion cells can support axonal regeneration, linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome, hematologic and solid organ malignancies, bacterial and viral infections (e.g., tuberculosis and influenza or SARS-coronavirus), and lysosomal storage diseases.

[0117] Non-limiting examples of lysosomal storage diseases include Gaucher disease, GM2 gangliosidosis, alpha-mannosidosis, aspartylglucosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidase disease, GM1 gangliosidosis, mucolipidosis, infantile free sialic acid storage disease, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidosis, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinosis, Pompe disease, pycnodysostat disease, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay-Sachs disease, and Wolman disease. In certain embodiments, compounds and compositions for use in medicine are provided. In certain embodiments, the compounds and compositions are for use in treating receptor-interacting protein kinase 1-mediated diseases or disorders. Also provided are methods for treating receptor-interacting protein kinase 1-mediated diseases or disorders, comprising administering a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein to a subject in need thereof. In another embodiment, the present disclosure provides a method for inhibiting receptor-interacting protein kinase 1. The method comprises contacting receptor-interacting protein kinase 1 with an effective amount of a compound described herein. Inhibiting receptor-interacting protein kinase 1 generally involves contacting receptor-interacting protein kinase 1 with an amount of the compound sufficient to reduce receptor-interacting protein kinase 1 activity compared to receptor-interacting protein kinase 1 activity in the absence of the compound. For example, contacting receptor-interacting protein kinase 1 with the compound can result in about 1% to about 99% inhibition of receptor-interacting protein kinase 1 (i.e., the activity of the inhibited enzyme is in the range of 99% to 1% of the enzyme activity in the absence of the compound).The level of receptor-interacting protein kinase 1 inhibition can be in the range of about 1% to about 10%, or about 10% to about 20%, or about 20% to about 30%, or about 30% to about 40%, or about 40% to about 50%, or about 50% to about 60%, or about 60% to about 70%, or about 70% to about 80%, or about 80% to about 90%, or about 90% to about 99%. The level of receptor-interacting protein kinase 1 inhibition can be in the range of about 5% to about 95%, or about 10% to about 90%, or about 20% to about 80%, or about 30% to about 70%, or about 40% to about 60%. In some embodiments, contacting receptor-interacting protein kinase 1 with a compound described herein will result in complete (i.e., 100%) inhibition.

[0118] Combination therapy In certain embodiments, the compounds described herein may be administered in combination with at least one other therapeutically active agent, and the two or more agents may be co-administered, co-formulated, or administered separately.

[0119] In certain embodiments, the other therapeutically active agent is a thrombolytic agent, a tissue plasminogen activator, an anticoagulant, a platelet aggregation inhibitor, an antibacterial agent (antibiotic, broad-spectrum antibiotic, lactam, antimicrobial, bactericidal antibiotic, anti-MRSA therapy), a long-acting beta agonist, a combination of an inhaled corticosteroid and a long-acting beta agonist, a short-acting beta agonist, a leukotriene modifier, an anti-IgE, a methylxanthine bronchodilator, a mast cell inhibitor, a protein tyrosine kinase inhibitor, a CRTH2 / D prostanoid receptor antagonist, an epinephrine inhalation aerosol, a phosphodiesterase inhibitor, a combination of a phosphodiesterase-3 inhibitor and a phosphodiesterase-4 inhibitor, a long-acting inhaled anticholinergic, a muscarinic antagonist, a long-acting muscarinic antagonist, a low-dose steroid, an inhaled corticosteroid, an oral corticosteroid, a topical corticosteroid, an antithymocyte globulin, thalidomide, a clopidogrel ... The therapeutic agent is selected from lorambucil, calcium channel blockers, topical emollients, ACE inhibitors, serotonin reuptake inhibitors, endothelin I receptor inhibitors, antifibrotic agents, proton pump inhibitors, cystic fibrosis transmembrane conductance regulator enhancers, mucolytic agents, pancreatic enzymes, bronchodilators, ophthalmic intravitreal injections, anti-vascular endothelial growth factor inhibitors, ciliary neurotrophic growth factor agents, trivalent (IIV3) inactivated influenza vaccine, tetravalent (IIV4) inactivated influenza vaccine, trivalent recombinant influenza vaccine, tetravalent live attenuated influenza vaccine, antiviral agent, inactivated influenza vaccine, ciliary neurotrophic growth factor, gene transfer agent, topical immunomodulator, calcineurin inhibitor, interferon gamma, antihistamine, monoclonal antibody, polyclonal anti-T cell antibody, anti-thymocyte gamma globulin-horse antibody, anti-thymocyte globulin-rabbit antibody, anti-CD40 antagonist, JAK inhibitor, and anti-TCR mouse mAb.

[0120] The compounds described herein may be administered in combination with other anti-inflammatory agents for any of the above indications, including oral or topical corticosteroids, anti-TNF agents, 5-aminoalicyclic acid and mesalamine preparations, hydroxychloroquine, thiopurines, methotrexate, cyclophosphamide, cyclosporine, calcineurin inhibitors, mycophenolic acid, mTOR inhibitors, JAK inhibitors, Syk inhibitors, anti-inflammatory biologics (including anti-IL6 biologics, anti-IL1 agents, anti-IL17 biologics, anti-CD22, anti-integrins, anti-IFNa, anti-CD20 or CD4 biologics, and other cytokine inhibitors or biologics), T cell or B cell receptor or interleukin inhibitors.

[0121] In certain embodiments, the at least one other therapeutically active agent is selected from a broad spectrum antibiotic, an anti-MRSA treatment, and a low-dose steroid.

[0122] In certain embodiments, the at least one other therapeutically active agent is an antimicrobial agent or antibiotic.

[0123] In certain embodiments, the at least one other therapeutically active agent is selected from an inhaled corticosteroid, a long-acting beta-agonist, a combination of an inhaled corticosteroid and a long-acting beta-agonist, a short-acting beta-agonist, a leukotriene modifier, an anti-IgE, a methylxanthine bronchodilator, a mast cell inhibitor, and a long-acting muscarinic antagonist.

[0124] In certain embodiments, the at least one other therapeutically active agent is selected from a protein tyrosine kinase inhibitor, a CRTH2 / D-prostanoid receptor antagonist, epinephrine inhalation aerosol, and a combination of a phosphodiesterase-3 inhibitor and a phosphodiesterase-4 inhibitor.

[0125] In certain embodiments, the at least one other therapeutically active agent is selected from a combination of a long-acting beta agonist, a long-acting inhaled anticholinergic or muscarinic antagonist, a phosphodiesterase inhibitor, an inhaled corticosteroid long-acting beta agonist, a short-acting beta agonist, and an inhaled corticosteroid.

[0126] In certain embodiments, the at least one other therapeutically active agent is an antimycobacterial agent or a bactericidal antibiotic.

[0127] In certain embodiments, the at least one other therapeutically active agent is selected from oral corticosteroids, antithymocyte globulin, thalidomide, chlorambucil, calcium channel blockers, topical emollients, ACE inhibitors, serotonin reuptake inhibitors, endothelin-I receptor inhibitors, antifibrotic agents, and proton pumps.

[0128] In certain embodiments, the at least one other therapeutically active agent is selected from a cystic fibrosis transmembrane conductance regulator enhancer, a mucolytic agent, a pancreatic enzyme, a bronchodilator, an antibiotic, or ivacaftor / lumacaftor, ataluren, and thiopropium bromide.

[0129] In certain embodiments, the at least one other therapeutically active agent is a ciliary neurotrophic growth factor or a gene transfer agent.

[0130] In certain embodiments, the at least one other therapeutically active agent is selected from an ophthalmic intravitreal injection, an anti-vascular endothelial growth factor inhibitor, and a ciliary neurotrophic growth factor agent.

[0131] In certain embodiments, the at least one other therapeutically active agent is selected from a trivalent (IIV3) inactivated influenza vaccine, a tetravalent (IIV4) inactivated influenza vaccine, a trivalent recombinant influenza vaccine, a tetravalent live attenuated influenza vaccine, an antiviral agent, or an inactivated influenza vaccine.

[0132] In certain embodiments, the at least one other therapeutically active agent is selected from a monoclonal antibody, a polyclonal anti-T cell antibody, an anti-thymocyte gamma globulin-horse antibody, an anti-thymocyte globulin-rabbit antibody, an anti-CD40 antagonist, a JAK inhibitor, and an anti-TCR mouse mAb.

[0133] In certain embodiments, the at least one other therapeutically active agent is selected from a topical immunomodulator or calcineurin inhibitor, a topical corticosteroid, an oral corticosteroid, interferon gamma, an antihistamine, or an antibiotic.

[0134] Administration As used herein, the phrases "parenteral administration" and "administered parenterally" refer to modes of administration other than enteral and topical administration, usually by injection, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0135] As used herein, the phrases "systemic administration," "administered systemically," "peripheral administration," and "peripherally administered" refer to administration of a compound, drug, or other substance other than directly into the central nervous system, e.g., subcutaneous administration, so that the compound, drug, or other substance enters the patient's system and is therefore subjected to metabolism and other similar processes. These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, for example, by spray, rectally, intravaginally, parenterally, intracisternally, and topically, by powder, ointment, or drops (including buccal and sublingual).

[0136] Regardless of the route of administration selected, the compounds of the present disclosure and / or pharmaceutical compositions of the present disclosure, which may be used in a suitable hydrated form, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.

[0137] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present disclosure may be varied to obtain an amount of the active ingredient that is not toxic to the patient and is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration.

[0138] The selected dosage level will depend upon a variety of factors, including the activity of the particular compound of the present disclosure or its salt or solvate being used, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being used, the duration of treatment, other drugs, compounds and / or substances being used in combination with the particular compound being used, the age, sex, weight, condition, general health and previous medical history of the patient being treated, and similar factors well known in the medical arts. Daily, weekly or monthly dosages (or other time intervals) can be used.

[0139] A person skilled in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, a physician or veterinarian can start a patient on a dose of a compound of the present disclosure used in a pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect, and then gradually increase the dose until the desired effect is achieved.

[0140] Generally, a suitable daily dose of a compound of the present disclosure will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect (e.g., inhibit necrosis). Such an effective dose will generally depend upon the factors described above.

[0141] Generally, patient doses of the compounds of the present disclosure, when used for the indicated effects, range from about 0.0001 to about 100 mg / kg body weight / day. Preferably, the daily dosage ranges from 0.001 to 50 mg of compound per kg body weight, and even more preferably from 0.01 to 10 mg of compound per kg body weight.

[0142] If desired, the effective daily dose of the active compound can be administered as two, three, four, five, six, or more subdoses administered separately at appropriate intervals throughout the day, optionally in unit dosage form. In certain embodiments, the present disclosure relates to a compound for inhibiting cell death, wherein the compound is represented by Formula (I). In certain embodiments, the compounds of the present disclosure are inhibitors of cell death. In any case, the compounds of the present disclosure preferably exert their effect on inhibiting cell death at concentrations of less than about 50 micromolar, more preferably less than about 10 micromolar, and most preferably less than 1 micromolar. The compounds of the present disclosure can be tested using standard animal models of stroke and standard protocols such as those described by Hara, H., et al. Proc. Natl. Acad. Sci. USA, 1997. 94(5):2007-12.

[0143] When the compounds of the present disclosure are administered to humans and animals as pharmaceuticals, they can be given as they are or as pharmaceutical compositions containing, for example, 0.1% to 99.5% (more preferably 0.5% to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

[0144] The compounds of the present disclosure or compositions thereof may be administered once, twice, three times, or four times daily using any suitable method described above. Administration or treatment with the compounds may also continue for several days; for example, treatment will generally continue for at least 7, 14, or 28 days during one treatment cycle. Treatment cycles are well known and frequently alternate with rest periods of about 1 to 28 days, typically about 7 days or about 14 days, between cycles. In certain embodiments, treatment cycles may be continuous.

[0145] When administered orally, the total daily dosage for a human subject can be 1 mg to 1,000 mg, about 1,000 to 2,000 mg / day, about 10 to 500 mg / day, about 50 to 300 mg / day, about 75 to 200 mg / day, or about 100 to 150 mg / day.

[0146] The daily dosage may also be described as the total amount of a compound described herein administered per dose or per day. The daily dosage of the compound may be about 1 mg to 4,000 mg, about 2,000 to 4,000 mg / day, about 1 to 2,000 mg / day, about 1 to 1,000 mg / day, about 10 to 500 mg / day, about 20 to 500 mg / day, about 50 to 300 mg / day, about 75 to 200 mg / day, or about 15 to 150 mg / day. In certain embodiments, the method includes administering to the subject an initial daily dose of about 1 to 800 mg of a compound described herein, and incrementally increasing the dose until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dosage can be increased daily, every other day, twice a week, or once a week.

[0147] In certain embodiments, the compound or pharmaceutical formulation is administered orally. In certain embodiments, the compound or pharmaceutical formulation is administered intravenously. Alternative routes of administration include sublingual, intramuscular, and transdermal administration.

[0148] The preparations of the present disclosure can be administered orally, parenterally, topically, or rectally. They are naturally provided in a form suitable for each administration route. For example, they are administered in the form of tablets or capsules, by injection, inhalation, eye drops, ointments, suppositories, etc., by injection, infusion, or inhalation; topically by lotion or ointment; and rectally by suppositories. In certain embodiments, administration is oral. [Example]

[0149] Abbreviation: [Table 1]

[0150] NMR 400 MHz: NMR spectra were recorded on a Bruker AVANCE II 400 spectrometer operating at a proton frequency of 400.23 MHz. The instrument was equipped with a 5 mm BBI room temperature probehead. Alternatively, a Bruker AVANCE III HD 400 MHz or a Bruker AVANCE NEO 400 MHz was used.

[0151] Analytical LC / MS instrument for Method A For retention time and mass detection, an LC / MS system manufactured by Agilent (LC1200 series / MS6120 quadrupole LC / MS, LC1260 infinity / MS6120 quadrupole LC / MS, or LC1260 Infinity II / MSD Infinity Lab) was used. Molecular weights are given in grams per mole [g / mol], and detected masses are given in mass / charge [m / z].

[0152] Analytical LC / MS equipment for Method B Retention time and mass detection was performed on a Waters Acquity UHPLC system coupled with a Waters SQD mass detector. The injection volume was 1.0 μl. Molecular weights are given in grams per mole [g / mol], and detected masses are given in mass / charge [m / z].

[0153] LC / MS-Method A Gradient: 98% HO (0.05% formic acid) / 2% acetonitrile (0.035% formic acid) for 0.2 min, then 98% HO (0.05% formic acid) to 98% acetonitrile (0.035% formic acid) for 3.6 min, then 98% acetonitrile (0.035% formic acid) for 0.5 min. Flow rate: 1.0 ml / min. Column: 2.1 x 50 mm Waters ACQUITY UPLC BEH C18, 1.7 μm, 55 °C. UV data: retention time ad λ = 220 nm (given in minutes) MS data: ES+ ionization, [M+H] unless otherwise stated + m / z given as

[0154] LC / MS-Method B Gradient: 95% H2O (0.0375% TFA) / 5% acetonitrile (0.01875% TFA) to 5% H2O (0.0375% TFA) / 95% acetonitrile (0.01875% TFA) in 0.8 min. Flow rate: 1.5 ml / min. Column: Kinetex EVO C18 2.1 x 30 mm, 5 μm, 50 °C. UV data: Retention times ad λ220 nm given in minutes MS data: ES+ ionization, [M+H] unless otherwise stated + m / z given as

[0155] Analytical Chiral HPLC SFC: Shimadzu LC-30AD sf system LC: Agilent 1100 series system

[0156] salt For compounds described as HCl-, TFA-, or other salts, the exact amount of each salt is not usually determined, and therefore the amount of salt can range from as low as 0.01 equivalents to as high as 5.0 equivalents, depending on the chemical structure (e.g., number of basic centers).

[0157] Chiral Purity If the enantiomeric ratio is greater than 90:10, the compound is isolated and named as a single enantiomer. If the enantiomeric ratio is less than 90:10, the racemate is used.

[0158] Synthetic Route A: [ka]

[0159] Synthetic Route B: [ka]

[0160] Example according to synthetic route A: Example 1 [1-(6-aminopyrimidin-4-yl)-4-piperidyl]-[(3S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl]methanone [ka] Step 1: Methyl 1-(6-aminopyrimidin-4-yl)piperidine-4-carboxylate [ka] To a solution of 6-chloropyrimidin-4-amine (2 g, 15.44 mmol, 1 equiv.) and methylpiperidine-4-carboxylate (3.32 g, 23.16 mmol, 1.5 equiv.) in DMSO (20 mL) was added DIPEA (9.98 g, 77.20 mmol, 13.45 mL, 5 equiv.). The mixture was stirred at 80° C. for 12 h. Another amount of methylpiperidine-4-carboxylate (2.21 g, 15.44 mmol, 1 equiv.) and KCO (4.27 g, 30.88 mmol, 2 equiv.) was added, and the mixture was again stirred at 80° C. for 12 h. The reaction mixture was filtered, diluted with water (100 mL), and extracted with EtOAc (80 mL×3). The combined organic layer was washed with brine (200 ml), dried over NaSO, filtered, and concentrated. The crude product was triturated with PE / EtOAc (2:1, 45 mL) at 25° C. for 30 min to give the title compound (3.05 g, 12.39 mmol, 80.3% yield) as a yellow solid. LC / MS: m / z=237.1 [M+H] + ;tR: 0.32 min (LC / MS method A). 1 H NMR:(400MHz,CDCl3):δ ppm 8.18(d,J=0.6Hz,1H),5.60(d,J=0.9Hz,1H),4.57(br s,2H),4.20(td,J=3.6,13.5Hz,2H),3.70(s,3H),2.99(ddd,J=2.9,11.1,13 .6Hz,2H),2.58(tt,J=4.2,11.0Hz,1H),2.00-1.94(m,2H),1.77-1.67(m,2H)

[0161] Step 2: 1-(6-aminopyrimidin-4-yl)piperidine-4-carboxylic acid [ka] To a solution of methyl 1-(6-aminopyrimidin-4-yl)piperidine-4-carboxylate (500 mg, 2.12 mmol, 1 equiv.) in THF (5 ml) was added LiOH·HO (1 M, 4.23 ml, 2 equiv.). The mixture was stirred at 25 °C for 1 h. The reaction mixture was adjusted to pH = 5 with 1 N aqueous HCl, then filtered, and the filter cake was dried to give the title compound (353 mg, crude) as an off-white solid. 1 H NMR:(400MHz,DMSO-d6):δ ppm 13.06-11.40(m,1H),7.94(s,1H),6.16(s,2H),5.61(s,1H),4.06(br d,J=13.2Hz,2H),3.00-2.83(m,2H),2.49-2.44(m,1H),1.82(br dd,J=2.9,13.2Hz,2H),1.51-1.40(m,2H)

[0162] Step 3: [1-(6-aminopyrimidin-4-yl)-4-piperidyl]-[(3S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl]methanone [ka] To a solution of 1-(6-aminopyrimidin-4-yl)piperidine-4-carboxylic acid (46.7 mg, 0.210 mmol, 1.05 equiv) in DMF (1 mL) was added HATU (114 mg, 0.300 mmol, 1.5 equiv), DIPEA (64.6 mg, 0.500 mmol, 87 uL, 2.5 equiv), and (3S)-3-(3,5-difluorophenyl)isoxazolidine (37.0 mg, 0.200 mmol, 1.00 equiv)) and the mixture was stirred at 25° C. for 4.5 h. The reaction mixture was purified by prep-HPLC (column: Agilent Prep-C18 5 μm 30 × 100 mm; eluent: water and acetonitrile; flow rate: 50 ml / min; gradient: 1 min 10% acetonitrile, 12 min 10 to 100% acetonitrile, 2 min 100% acetonitrile) to give 29 mg (74.0 μmol, yield 37.0%) of the title compound. LC / MS: m / z=390.2 [M+H] + ;tR: 1.32 min (LC / MS method A). 1 H NMR:(400MHz,DMSO-d6):δ ppm 7.94(s,1H),7.13(tt,J=9.34,9.34,2.28,2.28Hz,1H),6.99(m,2H),6. 14(s,2H),5.62(s,1H),5.35(m,1H),4.22(m,3H),3.90(m,1H),3.02(br s,1H),2.89(m,3H),2.20(m,1H),1.88(br d,J=11.49Hz,1H),1.68(br d,J=12.72Hz,1H),1.47(m,2H)

[0163] Example 2 5-[(3S)-2-[1-(6-aminopyrimidin-4-yl)piperidine-4-carbonyl]isoxazolidin-3-yl]-3-fluoro-2-methyl-benzonitrile [ka] This compound was synthesized as described in Example 1 to give a yield of 49 mg (60%). LC / MS: m / z=411.2 [M+H] +;tR: 1.34 min (LC / MS method A). 1 H NMR:(400MHz,DMSO-d6):δ ppm 7.94(s,1H),7.55(s,1H),7.43(d,J=10.39Hz,1H),6.13(s,2H),5.61(s,1H),5.34(m,1H),4.28(m,1H),4.18(br t,J=11.49,11.49Hz,2H),3.92(m,1H),3.00(m,1H),2.88(m,3H),2.37(d,J=1.71Hz,3H),2.23(m,1H),1.87(br d,J=11.62Hz,1H),1.69(br d,J=12.72Hz,1H),1.47(m,2H)

[0164] Example 3 3-[(3S)-2-[1-(6-aminopyrimidin-4-yl)piperidine-4-carbonyl]isoxazolidin-3-yl]-5-fluoro-benzonitrile [ka] This compound was synthesized as described in Example 1 to yield 200 mg (37%) of the title compound. LC / MS: m / z=397.2 [M+H] + ;tR: 0.77 min (LC / MS method B). 1 H NMR:(400MHz,DMSO-d6):δ ppm 7.94(s,1H),7.81-7.72(m,1H),7.61(s,1H),7.48(br d,J=9.5Hz,1H),6.16(s,2H),5.61(s,1H),5.38(br dd,J=6.7,8.2Hz,1H),4.28(dt,J=2.9,7.7Hz,1H),4.18(br dd,J=10.1,12.2Hz,2H),3.96-3.88(m,1H),3.02(br t,J=10.9Hz,1H),2.94-2.82(m,3H),2.29-2.18(m,1H),1.88(br d,J=11.5Hz,1H),1.69(br d,J=12.6Hz,1H),1.54-1.40(m,2H) SFC: Column: Chiralpak OJ-3 50 x 4.6mm ID, 3μm, Eluent: MeOH (0.05%DEA) and CO2; Gradient: 5-40% MeOH in CO2, Flow rate: 3mL / min, Column temperature: 35℃, 100bar): tR: 1.71 min (100%)

[0165] Example according to synthesis route B: Example 4 (S)-3-Fluoro-5-(2-(1-(6-methoxypyrimidin-4-yl)piperidine-4-carbonyl)isoxazolidin-3-yl)benzonitrile [ka] Step 1: tert-Butyl 4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazolidine-2-carbonyl]piperidine-1-carboxylate [ka] A solution of (S)-3-fluoro-5-(isoxazolidin-3-yl)benzonitrile 2,2-trifluoroacetate (500 mg, 1.63 mmol), 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (411.8 mg, 1.80 mmol), HATU (1.24 g, 3.27 mmol), and DIPEA (627 μL, 3.59 mmol) in DMF (5 mL) was stirred for 16 h. The reaction mixture was diluted with saturated NaHCO solution and water and extracted with ethyl acetate (3 times). The combined organic layers were dried over NaSO, filtered, and evaporated. The crude product was purified by prep HPLC (column: Agilent Prep-C18 10 μm 30 × 100 mm; eluent: water and acetonitrile; flow rate: 50 ml / min; gradient: 1 min 10% acetonitrile, 12 min 10–100% acetonitrile, 2 min 100% acetonitrile) to give 410 mg (62%) of the title compound. LC / MS: m / z=348.34[M+H] + ;tR: 2.28 min (LC / MS method A). 1H NMR:(400MHz,DMSO-d6):δ ppm 7.78(m,1H),7.61(s,1H),7.48(br d,J=9.54Hz,1H),5.38(m,1H),4.27(m,1H),3.91(m,3H),2.89(m,4H),2.22(m,1H),1.84(br d,J=11.49Hz,1H),1.65(br d,J=12.10Hz,1H),1.39(m,9H)

[0166] Step 2: 3-Fluoro-5-[(3S)-2-(piperidine-4-carbonyl)isoxazolidin-3-yl]benzonitrile [ka] A solution of tert-butyl (S)-4-(3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)piperidine-1-carboxylate (1.5 g, 3.72 mmol) and trifluoroacetic acid (3 mL, 38.94 mmol) in dichloromethane (30 mL) was stirred at room temperature for 16 hours. The reaction mixture was evaporated and lyophilized twice to give 1.65 g (98%) of the title compound as the trifluoroacetic acid salt, which was used in the next step without further purification. LC / MS: m / z=304.2 [M+H] + ;tR: 0.92 min (LC / MS method A).

[0167] Step 3: (S)-3-Fluoro-5-(2-(1-(6-methoxypyrimidin-4-yl)piperidine-4-carbonyl)isoxazolidin-3-yl)benzonitrile [ka] To a suspension of (S)-3-fluoro-5-(2-(piperidine-4-carbonyl)isoxazolidin-3-yl)benzonitrile 2,2-trifluoroacetate (50 mg, 110.73 μmol) and 4-chloro-6-methoxypyrimidine (24.0 mg, 166.1 μmol) in acetonitrile (1.5 mL) was added DIPEA (96.7 μL, 553.6 μmol). The reaction mixture was heated to 120 °C under microwave conditions for 1 h. The reaction mixture was purified by reverse-phase chromatography (Agilent Prep-C18 10 μm 30 × 100 mm column; eluent: HO and acetonitrile; flow rate: 50 mL / min; gradient: 10% acetonitrile for 1 min, 10–100% acetonitrile for 12 min, 100% acetonitrile for 2 min) to give 22 mg (48%) of the title compound. LC / MS: m / z=412.3 [M+H] + ;tR: 1.73 min (LC / MS method A). 1 H NMR:(400MHz,DMSO-d6):δ ppm 8.23(s,1H),7.77(m,1H),7.61(s,1H),7.48(br d,J=9.54Hz,1H),6.08(s,1H),5.39(m,1H),4.30(m,3H),3.93(m,1H),3.81(s,3H),3.07(br s,1H),3.03(br d,J=2.93Hz,1H),2.93(m,2H),2.25(m,1H),1.91(br d,J=11.74Hz,1H),1.72(br d,J=12.96Hz,1H),1.48(m,2H)

[0168] Example 5 3-Fluoro-5-[(3S)-2-[1-(5-fluoro-6-methoxy-pyrimidin-4-yl)piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile [ka] One method for synthesizing Example 5 is similar to that described for Example 4.

[0169] Example 5 was synthesized as a by-product of another synthesis as described below.

[0170] Step 1: Ethyl 1-(6-chloro-5-fluoro-pyrimidin-4-yl)piperidine-4-carboxylate [ka] To a mixture of 4,6-dichloro-5-fluoro-pyrimidine (1.06 g, 6.36 mmol, 1 equiv.) and ethyl piperidine-4-carboxylate (1.00 g, 0.98 mL, 6.36 mmol, 1 equiv.) in acetonitrile (20 mL) was added DIPEA (3.288 g, 4.43 mL, 25.44 mmol, 4 equiv.). The reaction mixture was stirred at room temperature for 16 hours, diluted with ethyl acetate, and extracted twice with 0.1 N HCl. The organic layer was washed with water, dried over Na2SO4, and lyophilized to give 1.65 g (90%) of the title compound, which was used in the next step without further purification. LC / MS: m / z=288.1 [M+H] + ;tR: 2.14 min (LC / MS method A).

[0171] Step 2: Ethyl 1-[5-fluoro-6-(4-methylpyrazol-1-yl)pyrimidin-4-yl]piperidine-4-carboxylate [ka] A mixture of ethyl 1-(6-chloro-5-fluoro-pyrimidin-4-yl)piperidine-4-carboxylate (300 mg, 1.04 mmol, 1 equiv.), 4-methyl-1H-pyrazole (171 mg, 0.168 mL, 2.08 mmol, 2 equiv.), potassium carbonate (576 mg, 4.17 mmol, 4 equiv.), and copper(I) iodide (99 mg, 0.52 mmol, 0.5 equiv.) in DMSO (1.5 mL) was stirred at 120° C. for 4 hours under microwave irradiation. The reaction mixture was diluted with ethyl acetate, filtered, and extracted with water. The organic layer was dried over NaSO and evaporated to give 294 mg (72%) of the title compound, which was used in the next step without further purification.

[0172] Step 3: 1-(5-fluoro-6-methoxy-pyrimidin-4-yl)piperidine-4-carboxylic acid [ka] A solution of ethyl 1-[5-fluoro-6-(4-methylpyrazol-1-yl)pyrimidin-4-yl]piperidine-4-carboxylate (294 mg, 0.75 mmol, 1 equiv) in NaOH (2N in THF / MeOH 1:1:1) (5.7 mL, 3.75 mmol, 5 equiv) was stirred for 16 h at 25° C. The reaction mixture was acidified with 1N HSO, extracted three times with ethyl acetate, dried over NaSO, filtered and evaporated. The residue was purified by reverse-phase chromatography (column: YMC-Actus Triart prep. C18-S 10 μm, 250 × 30 mm, eluent: acetonitrile and water (0.05% TFA), flow rate 70 ml / min; gradient: 2 min 5% acetonitrile, 24 min 5 to 100% acetonitrile, 4 min 100% acetonitrile) to give 156 mg (68%) of the expected product 1-[5-fluoro-6-(4-methylpyrazol-1-yl)pyrimidin-4-yl]piperidine-4-carboxylic acid and 32 mg (13%) of the title compound as a by-product. LC / MS: m / z=256.1 [M+H] + ;tR: 1.48 min (LC / MS method A). 1 H NMR:(400MHz,DMSO-d6):δ ppm 12.25(br s,1H),8.07(s,1H),4.20(m,2H),3.91(s,3H),3.13(m,2H),2.58(m,1H),1.88(m,2H),1.56(m,2H)

[0173] Step 4: 3-Fluoro-5-[(3S)-2-[1-(5-fluoro-6-methoxy-pyrimidin-4-yl)piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile [ka] This compound was synthesized as described in Example 1, Step 3 to give 11 mg (26%). LC / MS: m / z=430.2 [M+H] + ;tR: 2.23 min (LC / MS method A). 1 H NMR:(400MHz,DMSO-d6):δ ppm 8.07(s,1H),7.77(br d,J=7.46Hz,1H),7.61(s,1H),7.48(br d,J=9.66Hz,1H),5.38(m,1H),4.29(m,2H),3.91(s,3H),3.13(q,J=11. 62,11.62,11.62Hz,3H),2.90(m,1H),2.33(m,1H),2.23(m,1H),1.94(br d,J=13.94Hz,1H),1.73(br s,1H),1.58(br d,J=12.59Hz,2H),1.24(s,2H)

[0174] Example 6 3-Fluoro-5-[(3S)-2-[1-(6-methoxypyrimidin-4-yl)piperidine-4-carbonyl]isoxazolidin-3-yl]-2-methyl-benzonitrile [ka] This compound was synthesized as described in Example 1 to give 42 mg (50% yield). LC / MS: m / z=426.2 [M+H] + ;tR: 1.89 min (LC / MS method A). 1 H NMR:(400MHz,DMSO-d6):δ ppm 8.23(s,1H),7.55(s,1H),7.44(s,1H),7.41(m,1H),6.09(s,1H),5.34(m,1H),4.29(m,2H),3. 92(m,1H),3.82(s,3H),3.01(m,3H),2.88(m,1H),2.37(d,J=1.83Hz,3H),2.22(m,1H),1.90(br d,J=11.25Hz,1H),1.71(br d,J=11.86Hz,1H),1.47(m,2H)

[0175] Example 7 [(3S)-3-(3-chloro-5-fluoro-phenyl)isoxazolidin-2-yl]-[1-(6-methoxypyrimidin-4-yl]-4-piperidyl]methanone [ka] This compound was synthesized as described in Example 1 to give 30 mg (36% yield). LC / MS: m / z=421.1 [M+H] + ;tR: 2.04 min (LC / MS method A). 1 H NMR:(400MHz,DMSO-d6):δ ppm 8.23(d,J=0.61Hz,1H),7.33(dt,J=8.68,2.14,2.14Hz,1H),7.19(s,1H),7.10(br d,J=9.54Hz,1H),6.08(s,1H),5.34(m,1H),4.29(m,3H),3.90(m,1H),3.81(s,3H),3.01(m,3H),2.89(m,1H),2.21(m,1H),1.90(br d,J=12.84Hz,1H),1.71(br d,J=11.25Hz,1H),1.48(m,2H)

[0176] Evaluation of receptor-interacting protein kinase 1 inhibition. The catalytic activity of RIPK1 was measured by monitoring the conversion of adenosine triphosphate (ATP) to adenosine diphosphate (ADP) by autophosphorylation using the ADP-Glo ​​kinase kit (Promega, catalog no. V9104).

[0177] Two microliters of recombinantly produced hRIPK1 (aa1-375) fusion protein (final concentration 3.6 μg / ml) and 2 μl of compound (final concentration 33300-1.69 nM; final DMSO concentration 1%) were incubated at room temperature for 30 minutes, followed by the addition of 2 μl of ATP (ADP Glo kit, final concentration 50 μM). After a further 240 minutes of incubation at room temperature, 5 μl of Promega ADP-Glo ​​Reagent I was added to quench the reaction and deplete any unconsumed ATP. After a 30-minute incubation period, 10 μl of Promega ADP-Glo ​​Detection Reagent II was added, converting ADP to ATP and generating a light-emitting reaction between luciferase and luciferin. After 30 minutes, luminescence was quantified using a Pherastar FS (BMG LABTECH, Ortenberg).

[0178] For dose-response experiments, IC with 95% confidence interval 50 Values ​​were calculated using a four-parameter logistic model according to Ratkowsky and Reedy, with constraints for lower and upper asymptotic values ​​of 0% and 100%. Adjustments were obtained by nonlinear regression using the Levenberg-Marquardt algorithm.

[0179] Cellular assay in U937 cells to measure the activity of RIPK1 inhibitors on cell death (necroptosis). Upon TNF-receptor I ligation, the Ser / Thr kinase RIPK1 is recruited to transient receptor complex I. Upon modification of RIPK1 that promotes its activation, complex IIb can form, which is involved in the recruitment of RIPK3 and MLKL (mixed lineage kinase domain-like protein), which then translocates from the cytosol to the plasma membrane to execute cell death (Cai, Z. et al., Nat. Cell Biol. (2014) 16:55-65).

[0180] Cell death was quantified in 96-well plates by determining the amount of viable cells using CellTiter 96 AQueous reagent (Promega), a calorimetric method that measures the amount of viable cells by reducing the tetrazolium compound [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt; MTS] to formazan. The absorbance of the formazan was read at 490 nm. The inhibitory activity of test compounds was quantified in concentration-response curve (CRC) experiments.

[0181] Compounds were obtained as 10 mM stock solutions and diluted 1 to 10 volumes with DMSO to obtain a 1 mM solution. From this solution, 2 μl was diluted in 998 μl of growth medium. 100 μl of the 2 μM compound solution was further diluted serially by a dilution factor of 2.5 by adding 150 μl of growth medium. A total of 10 concentrations were tested, ranging from 10 μM to 0.26 nM or 1 μM to 0.07 nM.

[0182] U937 cells were cultured in RPMI 1640 Glutamax and 10% heat-inactivated FBS. 50 μl of cell suspension containing 1 x 10 cells / ml supplemented with 50 μM zVAD.fmk (benzyloxycarbonyl-Val-Ala-Asp(OMe) fluoromethylketone) and 100 ng / ml recombinant human TNFα was dispensed into each well of a 96-well plate. 50 μl of compound dilution solution (see above) was added, and the cell suspension was incubated overnight (18–24 h) at 37°C and 5% CO2 in a humidified atmosphere (95% rH2O). High controls (no compound) and low controls (no TNFα, no zVAD.fmk) were tested in seven replicates, and all compound concentrations were tested in duplicate on each experimental plate.

[0183] The CellTiter96 aqueous reagent was mixed (100 μl of PMS (phenazine methosulfate) solution / 2 ml of MTS (3-(4,5-dimethyldiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt) solution) and 20 μl was added per well. After 4 hours of incubation at 37°C (5% CO2, 95% rH2), the optical density was measured at 490 nm using a Tecan Infinite M1000 microplate reader.

[0184] % Inhibition is expressed as a percentage of the maximum inhibition value obtained in the absence of TNFα / zVAD.fmc. For each dose-response experiment, IC with 95% confidence intervals is 50 Values ​​were calculated using a four-parameter logistic model according to Ratkowsky and Reedy without constraints using an internal application (Biost@t-Speed ​​LTS V2.3).

[0185] [Table 2]

Claims

1. Formula I: [Chemical 1] (In the formula, R1 is H or C １ ~C ４ is alkyl, R2 is CN or halogen; R3 is H or halogen; R4 is NH ２ or OCH ３ a compound of formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof (wherein R1 = H, R2 = F, R3 = H and R4 = OCH ３ (Excluding compounds of formula I where:

2. R4 is NH ２ That is, 10. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

3. R4 is OCH ３ That is, 10. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

4. R3 represents F; A compound of formula I according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

5. When R2 is halogen, R4 is NH ２ That is, 3. A compound of formula I according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

6. R2 represents CN; A compound of formula I according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

7. R1 represents H, R2 represents CN; R3 represents H; R4 is NH ２ or OCH ３ Represents, A compound of formula I according to any one of claims 1 to 3 or 6, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

8. 3-[(3S)-2-[1-(6-aminopyrimidin-4-yl)piperidine-4-carbonyl]isoxazolidin-3-yl]-5-fluoro-benzonitrile, [1-(6-aminopyrimidin-4-yl)-4-piperidyl]-[(3S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl]methanone, 5-[(3S)-2-[1-(6-aminopyrimidin-4-yl)piperidine-4-carbonyl]isoxazolidin-3-yl]-3-fluoro-2-methyl-benzonitrile, (S)-3-fluoro-5-(2-(1-(6-methoxypyrimidin-4-yl)piperidine-4-carbonyl)isoxazolidin-3-yl)benzonitrile, 3-fluoro-5-[(3S)-2-[1-(5-fluoro-6-methoxy-pyrimidin-4-yl)piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile, 3-fluoro-5-[(3S)-2-[1-(6-methoxypyrimidin-4-yl)piperidine-4-carbonyl]isoxazolidin-3-yl]-2-methyl-benzonitrile, and [(3S)-3-(3-chloro-5-fluoro-phenyl)isoxazolidin-2-yl]-[1-(6-methoxypyrimidin-4-yl)-4-piperidyl]methanone The compound of formula I according to claim 1, selected from or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

9. 3-[(3S)-2-[1-(6-aminopyrimidin-4-yl)piperidine-4-carbonyl]isoxazolidin-3-yl]-5-fluoro-benzonitrile, [1-(6-aminopyrimidin-4-yl)-4-piperidyl]-[(3S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl]methanone, and 5-[(3S)-2-[1-(6-aminopyrimidin-4-yl)piperidine-4-carbonyl]isoxazolidin-3-yl]-3-fluoro-2-methyl-benzonitrile The compound of formula I according to claim 1 selected from or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

10. (S)-3-fluoro-5-(2-(1-(6-methoxypyrimidin-4-yl)piperidine-4-carbonyl)isoxazolidin-3-yl)benzonitrile, 3-fluoro-5-[(3S)-2-[1-(5-fluoro-6-methoxy-pyrimidin-4-yl)piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile, 3-fluoro-5-[(3S)-2-[1-(6-methoxypyrimidin-4-yl)piperidine-4-carbonyl]isoxazolidin-3-yl]-2-methyl-benzonitrile, and [(3S)-3-(3-chloro-5-fluoro-phenyl)isoxazolidin-2-yl]-[1-(6-methoxypyrimidin-4-yl)-4-piperidyl]methanone Compounds of formula I according to claim 1 selected from: or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 and at least one pharmaceutically acceptable carrier.

12. A compound according to any one of claims 1 to 10, together with at least one pharmaceutically acceptable carrier and / or a thrombolytic agent, tissue plasminogen activator, anticoagulant, platelet aggregation inhibitor, antibacterial agent (antibiotic, broad-spectrum antibiotic, lactam, antibacterial, bactericidal antibiotic, anti-MRSA therapy), long-acting beta agonist, combination of inhaled corticosteroid and long-acting beta agonist, short-acting beta agonist, leukotriene modifier, anti-IgE, methylxanthine bronchodilator. , mast cell inhibitors, protein tyrosine kinase inhibitors, CRTH2 / D prostanoid receptor antagonists, epinephrine inhalation aerosol, phosphodiesterase inhibitors, combination phosphodiesterase-3 inhibitors and phosphodiesterase-4 inhibitors, long-acting inhaled anticholinergics, muscarinic antagonists, long-acting muscarinic antagonists, low-dose steroids, inhaled corticosteroids, oral corticosteroids, topical corticosteroids, antithymocyte globulin, thalidomide , chlorambucil, calcium channel blockers, topical emollients, ACE inhibitors, serotonin reuptake inhibitors, endothelin I receptor inhibitors, antifibrotic agents, proton pump inhibitors, cystic fibrosis transmembrane conductance regulator enhancers, mucolytic agents, pancreatic enzymes, bronchodilators, intravitreal ophthalmic injections, anti-vascular endothelial growth factor inhibitors, ciliary neurotrophic growth factor agents, trivalent (IIV3) inactivated influenza vaccine, quadrivalent (IIV4) inactivated influenza vaccine, trivalent recombinant influenza vaccine and one or more additional active agents selected from a steroid, a tetravalent live attenuated influenza vaccine, an antiviral agent, an inactivated influenza vaccine, a ciliary neurotrophic growth factor, a gene transfer agent, a local immunomodulator, a calcineurin inhibitor, interferon gamma, an antihistamine, a monoclonal antibody, a polyclonal anti-T cell antibody, an anti-thymocyte gamma globulin-horse antibody, an anti-thymocyte globulin-rabbit antibody, an anti-CD40 antagonist, a JAK inhibitor, and an anti-TCR mouse mAb.

13. A compound according to any one of claims 1 to 10 or a pharmaceutical composition according to claim 11 or 12 for use in therapy.

14. A compound according to any one of claims 1 to 10 or a pharmaceutical composition according to claim 11 or 12 for use in the treatment of a RIP kinase 1 mediated disease or disorder.

15. Necrotizing enterocolitis, tuberous sclerosis, Tangier disease, Wolman syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis (e.g., acute pancreatitis), atopic dermatitis, rheumatoid arthritis, psoriatic arthritis, spondyloarthritis, gout, SoJIA, systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, antiphospholipid syndrome, vasculitis, osteoarthritis, nonalcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune diseases, and inflammatory bowel disease. Immune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis, nephritis, celiac disease, autoimmune ITP, transplant rejection, ischemia, ischemia-reperfusion injury of solid organs, cerebral ischemia, sepsis, systemic inflammatory response syndrome, cerebrovascular disease, myocardial infarction, Huntington's disease, Alzheimer's disease, Parkinson's disease, allergic diseases, asthma, atopic dermatitis, multiple sclerosis, type 1 diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-1 converting enzyme Antibody-associated fever syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-associated periodic syndrome, periodontitis, infection, bacterial infection, staphylococcal infection, mycobacterial infection, influenza, transplant rejection, burns, hypoxia, trauma, stroke, myocardial infarction, lysosomal storage diseases, Niemann-Pick disease, Gaucher disease, Krabbe disease, amyotrophic lateral sclerosis (ALS), HIV-associated dementia, encephalopathy, retinal degenerative diseases, glaucoma, age-related macular degeneration, Friedreich's ataxia, Levitra 13. A compound according to any one of claims 1 to 10 or a pharmaceutical composition according to claim 11 or 12 for use in the treatment of inflammatory bowel disease, diabetic neuropathy, polyglutamine (polyQ) disease, Fahr's disease, Menke's disease, Wilson's disease, prion disorders, atherosclerosis, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, major depressive disorder, bipolar disorder, confusion, post-operative cognitive impairment, autism, schizophrenia, purpura or incontinentia pigmenti.

16. A compound according to any one of claims 1 to 10 or a pharmaceutical composition according to claim 11 or 12 for use in the treatment of Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS) and incontinentia pigmenti.

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