WO2023138317A1 - 具有ripk1抑制活性的化合物、其制备方法及其用途 - Google Patents

具有ripk1抑制活性的化合物、其制备方法及其用途 Download PDF

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WO2023138317A1
WO2023138317A1 PCT/CN2022/142343 CN2022142343W WO2023138317A1 WO 2023138317 A1 WO2023138317 A1 WO 2023138317A1 CN 2022142343 W CN2022142343 W CN 2022142343W WO 2023138317 A1 WO2023138317 A1 WO 2023138317A1
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alkyl
aryl
membered heteroaryl
membered
disease
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French (fr)
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段文虎
耿美玉
张贺峰
艾菁
兰垚瀚
戴阳
金泽宸
彭霞
方晨
季寅淳
冯大智
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中国科学院上海药物研究所
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Definitions

  • the present invention relates to compounds with receptor-interacting protein kinase 1 inhibitory activity, their preparation methods and uses thereof, especially the use of the series of compounds or pharmaceutical compositions containing the series of compounds and therapeutic agents for treating inflammatory diseases, ischemic diseases, neurodegenerative diseases, tumors and other diseases and diseases related to receptor-interacting protein kinase 1.
  • Protein kinases are proteins (enzymes) that regulate various cellular functions by phosphorylating specific amino acids on proteins. Proteins regulate their activity and ability to bind to their chemical components through conformational changes.
  • the activity of a protein kinase refers to the rate at which a kinase binds a phosphate group to a substrate, which rate can be measured by measuring the amount of substrate converted to a product over a period of time. Phosphorylation of the substrate occurs at the activation site of the protein kinase.
  • protein kinases can be divided into five categories: serine/threonine protein kinases, tyrosine protein kinases, histidine protein kinases, tryptophan protein kinases and aspartyl/glutamyl protein kinases.
  • serine/threonine protein kinase is a class of enzymes that can catalyze the phosphorylation of serine/threonine residues on various substrate proteins
  • tyrosine kinase is a kind of protein enzyme that can catalyze the transfer of adenosine triphosphate to protein tyrosine residues.
  • Pathological conditions associated with protein kinases include inflammatory diseases, immune diseases, cardiovascular diseases, and tumors, among others.
  • Cell death mainly includes apoptosis, necroptosis, pyroptosis, ferroptosis, and cell death processes related to autophagy and unprogrammed necrosis.
  • Necroptosis also known as programmed cell death or programmed necrosis, is a new type of cell death discovered in recent years.
  • Necroptosis a highly inflammatory form of cell death that results in the release of danger-associated molecular patterns from cells, is considered an important pathological factor in a variety of degenerative and inflammatory diseases. These diseases include neurodegenerative diseases, stroke, coronary heart disease, myocardial infarction, retinal degenerative diseases, inflammatory bowel disease, kidney disease, liver disease, and various other related diseases.
  • Receptor-interacting protein kinase 1 (RIPK1) and RIPK3 are homologous serine/threonine kinases, which are key elements in mediating cell necroptosis.
  • RIPK1 kinase is recognized as a potential therapeutic target for necroptosis-related diseases.
  • the first RIPK1 inhibitor Necrostatin-1 (Nec-1) and its analogues have shown clear curative effects on a variety of degenerative diseases, inflammation, cancer and other diseases in preclinical studies.
  • Alzheimer's disease Parkinson's disease, Huntington's disease, age-related macular degeneration, etc.
  • it has a protective effect on psoriasis, retinitis pigmentosa, inflammatory bowel disease, autoimmune disease, acute pancreatitis and sepsis/systemic inflammatory response syndrome induced by bombesin
  • it can effectively relieve ischemic brain injury, ischemic myocardial injury, retinal ischemia/reperfusion injury, photoreceptor cell necrosis induced by retinal detachment, glaucoma, renal ischemia-reperfusion injury, and cisplatin-induced Renal injury and traumatic brain injury:
  • At least partial remission of other diseases associated with RIPK1-dependent apoptosis, necrosis or cytokine production including hematological and solid organ malignancies, bacterial and viral infections (including tuberculosis, influenza, etc.) and lysosomal storage disorders (
  • kinase inhibitors especially RIPK1 kinase inhibitors
  • the existing inhibitors targeting necroptosis-related kinases have defects of varying degrees, such as poor selectivity, unsatisfactory in vivo inhibitory activity, poor pharmacokinetic properties, low oral bioavailability, etc., and some cannot enter the central nervous system through the blood-brain barrier.
  • the object of the present invention is to provide RIPK1 kinase inhibitors.
  • the first aspect of the present invention provides a compound represented by general formula (I) or its stereoisomers, enantiomers, diastereomers, atropisomers, optical isomers, racemates, tautomers or pharmaceutically acceptable salts thereof, prodrugs thereof, hydrates or solvates thereof, and isotope-labeled compounds thereof,
  • Cy 1 is selected from the following group:
  • R at each occurrence is independently selected from: H, D, halogen, CD 3 , C1-C8 alkyl, halogenated C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkoxy, cyano, amino, C1-C8 alkyl substituted amino, hydroxyl, mercapto, C1-C8 alkylthio;
  • Cy 2 is selected from the following groups substituted by 0-5 R 8 : C3-C14 cycloalkyl, C6-C14 membered aryl, 6-14 membered heteroaryl, or 3-14 membered heterocyclic group;
  • R4 at each occurrence is independently selected from: H, D, CH3 , CD3 ;
  • Each dashed line independently represents a single bond or a double bond
  • Z 2 is selected from C(R z2 ) 2 , N, CR z2 ; each R z2 is independently H, halogen, hydroxyl, optionally substituted C1-C8 alkyl, or two R z2 form an optionally substituted C3-C6 carbocycle or 3-6 membered heterocycle together with the carbon atoms to which they are attached,
  • R z2 , R z1 together with the carbon atoms they are connected to form an optionally substituted C3-C6 carbocycle or 3-6 membered heterocycle;
  • Z 3 and Z 4 are selected from C, CH, N;
  • Ring A is a C6-C14 membered aromatic ring, a 5-membered heteroaromatic ring, a 6-14 membered heteroaromatic ring, a C3-C14 carbocyclic ring or a 3-14 membered heterocyclic ring;
  • n is selected from 1, 2, 3, 4;
  • R 1 is independently selected from H, D, "R 7 -C ⁇ C-", R 1a at each occurrence; preferably, at least one R 1 on ring A is a substituent of "R 7 -C ⁇ C-";
  • R 1a , R 7 are independently at each occurrence R 1a1 substituted by 0-5 R 1a2 ;
  • R 1a1 and R 1a2 can be optionally replaced by 0-5 R 1a3 ;
  • R 2 does not exist, or R 2 is in the ortho position of Z 4 , and forms an optionally substituted or unsubstituted 5-6 membered heterocyclic ring with R 3 and the atoms they are connected to;
  • R 3 is selected from: H, D, CH 3 , CD 3 ;
  • Y is O, S, NR y , wherein R y and R 3 form an optionally substituted 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring together with the atoms they are connected to;
  • R 6 is selected from: CD 3 , C1-C8 alkyl, halogenated C1-C8 alkyl, C6-C14 aryl;
  • R 1a1 , R 1a2 In each occurrence independently selected from the group consisting of: H, D, halogen, C1-C8 alkyl, halogenated C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkoxy, C1-C6 alkoxy substituted C1-C6 alkoxy, C2-C8 alkenyl, halogenated C2-C8 alkenyl, C2-C8 alkenyloxy, halogenated C2-C8 alkenyloxy, C2-C8 alkynyl, halogenated C2-C8 alkyne C2-C8 alkynyloxy, halogenated C2-C8 alkynyloxy, C3-C14 cycloalkyl, (C3-C14 cycloalkyl)-(C1-C8 alkyl)-, (C3-C14 cycloalkyl) oxy, (C3-C14 cycloalkyl
  • At least one R 1 is R 7 -C ⁇ C-". That is, m is 1, R 1 is R 7 -C ⁇ C-"; m is 2, 3 or 4, and one R 1 is R 7 -C ⁇ C-", and other R 1 are independently selected from H, D, "R 7 -C ⁇ C-", R 1a .
  • the compound represented by general formula (I) has the structure:
  • the compound shown in general formula (I) has the structure shown in formula (II):
  • the compound is selected from formulas (IV-1), (IV-2), (IV-4), (IV-5), (IV-6), (IV-7), (IV-9):
  • Cy 3 is selected from formulas (III-1) to (III-14):
  • Z 5 is selected from CR 1 or N; R 1 , m, Z 1 , R 3 are as defined above; preferably, Z 5 is selected from CH or N; when m is 1, R 1 is R 7 -C ⁇ C-; R 7 is as defined above.
  • the compound is selected from formulas (V-1), (V-2), (V-3), (V-4):
  • Z 5 is selected from CR 1 or N; R 1a1 , R 1 , R 3 , Z 1 , Cy 1 , Cy 2 and R 5 are as defined above.
  • the compound is selected from:
  • Z 5 is selected from CH or N; R 1 is a C1-C8 alkyl group; R 1a1 , R 3 , Z 1 , Cy 2 , and R 5 are as defined above.
  • R 1 is independently selected from the following group at each occurrence: H, D, methyl,
  • the compound is the compound listed in claim 5.
  • the second aspect of the present invention provides the preparation method of the compound shown in formula (I) described in the first aspect, and the synthesis step includes at least one of Reaction Formula 1 and Reaction Formula 2:
  • R 4 , R 1 , m, R 2 , R 3 , Y, Z 1 , Z 2 , Z 3 , Z 4 , dotted line, and Cy 1 are as defined above.
  • the third aspect of the present invention provides a pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and one or more compounds described in the first aspect or stereoisomers, enantiomers, diastereomers, atropisomers, optical isomers, racemates, tautomers or pharmaceutically acceptable salts thereof, prodrugs thereof, hydrates or solvates thereof, and isotope-labeled compounds thereof.
  • a fourth aspect of the present invention provides a receptor-interacting protein kinase 1 (RIPK1) inhibitor, comprising one or more compounds described in the first aspect or their stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts thereof, prodrugs thereof, hydrates or solvates thereof, or the pharmaceutical composition described in the third aspect.
  • RIPK1 receptor-interacting protein kinase 1
  • the fifth aspect of the present invention provides the use of the compound described in the first aspect or its stereoisomer, enantiomer, diastereoisomer, atropisomer, optical isomer, racemate, tautomer or pharmaceutically acceptable salt thereof, its prodrug, its hydrate or solvate, its isotope-labeled compound or the pharmaceutical composition described in the third aspect, characterized in that it is used for the preparation of medicines, and the medicines are used for: 1) detection and/or prevention and/or treatment of kinase-related diseases; 2) detection and/or 3) Detect and/or prevent and/or treat diseases related to ischemia and/or reperfusion injury; 4) Detect and/or prevent and/or treat degenerative diseases; 5) Detect and/or prevent and/or treat tumor-related diseases; 6) Detect and/or prevent and/or treat diseases related to cell necrosis; 7) Detect and/or prevent and/or treat diseases related to metabolism;
  • the sixth aspect of the present invention provides the use of the compound described in the first aspect or its stereoisomer, enantiomer, diastereomer, atropisomer, optical isomer, racemate, tautomer or pharmaceutically acceptable salt thereof, its prodrug, its hydrate or solvate, its isotope-labeled compound, or the pharmaceutical composition described in the third aspect, characterized in that it is used to prepare a drug for detection and/or prevention and/or treatment of a disease selected from the following group:
  • Systemic juvenile idiopathic arthritis, Behcet's disease, interleukin-1 converting enzyme-related febrile syndrome, sepsis, alopecia areata, allergic disease, allergic disease, hepatitis B, hepatitis C, multiple sclerosis, pulmonary sarcoidosis, pulmonary fibrosis, pneumonia, mycobacterial infection, celiac disease, Sjogren's syndrome, osteoarthritis, hidradenitis suppurativa, necrotizing enterocolitis, acute pancreatitis, spondyloarthritis, colitis, Crohn's disease, antiphosphorus Lipid syndrome, Crohn's disease, ulcerative colitis, rheumatoid arthritis, bacterial infection, influenza, chronic obstructive pulmonary disease, viral infection, sepsis, dermatitis, staphylococcal infection, autoimmune disease, systemic lupus erythematosus, systemic inflammatory response syndrome, systemic scleroderma
  • the kinase inhibitor has excellent RIPK1 inhibitory activity, so it can be used to prepare pharmaceutical compositions for detection and/or prevention and/or treatment of cell death and/or related diseases.
  • the inventors have completed the present invention.
  • C1 - C6 means having 1, 2, 3, 4, 5 or 6 carbon atoms
  • C1 - C8 means having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, and so on.
  • 5-8 membered means having 5-8 ring atoms, and so on.
  • Substituent refers to an atom or group that can replace a hydrogen atom in a substituent.
  • substitution means that one or more hydrogen atoms on a specified group are replaced by a specified substituent.
  • the specific substituents are the corresponding substituents described above, or the substituents appearing in each embodiment.
  • a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituents may be the same or different at each position.
  • Alkyl means a saturated aliphatic hydrocarbon group, which may be straight or branched.
  • the alkyl groups may be independently substituted with one or more substituents described herein. Further examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 3-methylpentyl.
  • Alkyl groups can be optionally substituted or unsubstituted.
  • Alkenyl straight-chain or branched hydrocarbon group, wherein at least one CC is a sp 2 double bond, wherein the alkenyl group can be independently and optionally replaced by one or more substituents described in the present invention, wherein specific examples include, but are not limited to vinyl, allyl, butyl, etc. Alkenyl groups can be optionally substituted or unsubstituted.
  • Alkynyl refers to a straight-chain or branched hydrocarbon group, wherein at least one C-C is an sp triple bond, wherein the alkynyl group can be independently and optionally substituted by one or more substituents described in the present invention, and specific examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, etc. Alkynyl groups can be optionally substituted or unsubstituted.
  • Ring structure refers to a single or polycyclic structure. Usually two or more fragments connected to one atom in the ring structure are connected to form a closed structure, including but not limited to cycloalkane, heterocycloalkane, cyclic lactam, arene, heteroarene, ring, bridged ring, spiro ring and other structures, examples are as follows (but not limited to the following examples): cyclopropane, cyclobutane, oxetane, cyclopentane, cyclohexane, adamantane, cyclohexene, cyclooctyne, pyrazole, benzene, pyridine, 3,4-dihydro-1,4- Benzoxazepine-5(2H)-one, naphthalene, anthracene, phenanthrene, quinoline, pyrrolopyridine, pyrazolopyridine, indole
  • the ring structures may be optionally substituted or unsubstituted. When it appears as a substituent, it means that one or more hydrogen atoms on a monocyclic or polycyclic ring are removed so that it can serve as a substituent for a substituted substance.
  • Halogen refers to F, Cl, Br or I.
  • Halo means substituted with one or more halogens.
  • Aryl refers to a carbocyclic aromatic system containing one or more rings free of heteroatoms.
  • the aryl group may be fused to a heteroaryl, heterocyclyl, or other ring structure. Examples include (but are not limited to) the following examples: phenyl, naphthyl, tetrahydronaphthyl, wait.
  • the aryl group may be optionally substituted or unsubstituted.
  • aryl group is described as "C6-C14 aryl"
  • the aryl group can be optionally fused with other ring structures
  • the other ring structures refer to ring structures with 3-18 ring atoms, and the other ring structures may be optionally substituted or unsubstituted.
  • Heteroaryl refers to an aromatic ring structure containing one or more rings, which may contain one or more atoms selected from N, O or S. Alternatively, the aryl group may be fused to an aryl, heterocyclyl, cycloalkyl or other ring structure. Examples include (but are not limited to) the following examples: furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, wait.
  • the heteroaryl group can be optionally substituted or unsubstituted.
  • heteroaryl When the heteroaryl is described as "5-14 membered heteroaryl", it means that the heteroaryl ring connected to the parent structure has 5-14 ring atoms, but the heteroaryl may be fused with other ring structures, and the other ring structures refer to ring structures with 3-18 ring atoms, and the other ring structures may be optionally substituted or unsubstituted.
  • Cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • the first ring structure where the cycloalkyl is directly attached to the substituent is non-aromatic.
  • monocyclic cycloalkyl groups (but not limited to the following examples): cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, cyclooctynyl, etc.
  • multicyclic cycloalkyl groups (but not limited to the following examples): spiro, fused and bridged cycloalkyls.
  • the cycloalkyl may be fused or form a spiro with an aryl, heterocyclyl, cycloalkyl or other ring structures.
  • the cycloalkyl group may be optionally substituted or unsubstituted.
  • C3-C14 cycloalkyl it means that the cycloalkyl ring connected to the parent structure has 3-14 carbon atoms, but the cycloalkyl group can be fused with other ring structures or form a spiro ring.
  • the other ring structures refer to ring structures with 3-18 ring atoms, and the other ring structures can be optionally substituted or unsubstituted.
  • Heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic ring structure in which at least one ring atom is a heteroatom (eg, O, N, S atom, etc.). Examples include (but are not limited to) tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, tetrahydrothienyl, piperidinyl, piperazinyl, azetidinyl, azepanyl, morpholinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, and the like.
  • the heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring where the ring bonded to the parent structure is a heterocyclyl.
  • the heterocyclyl group may be optionally substituted or unsubstituted.
  • the description of the heteroalkyl group is "3-14 membered heterocyclic group” it means that the heterocyclic group connected to the parent structure has 3-14 ring atoms, but the heterocyclic group may be fused with other ring structures or form a spiro ring.
  • the other ring structures refer to ring structures with 3-18 ring atoms, and the other ring structures may be optionally substituted or unsubstituted.
  • Tautomer means that structural isomers with different energies can be interconverted beyond a low energy barrier.
  • proton tautomers i.e., proton shifts
  • proton migration such as 1H-indazole and 2H-indazole, 1H-benzo[d]imidazole and 3H-benzo[d]imidazole
  • valence tautomers include interconversions through some bonded electron recombination.
  • Stepoisomer refers to molecules that have atoms connected identically but arranged differently in space. For example, two compounds that contain a chiral center and have the same two-dimensional linkage, such as R-glyceraldehyde and S-glyceraldehyde, R-serine and S-serine.
  • Enantiomers means stereoisomers that are real and mirror images of each other and are not superimposable. Such as R-serine and S-serine.
  • Diastereoisomer means a stereoisomer whose molecules have two or more chiral centers and which are not mirror images of each other. Such as tartaric acid.
  • “Atropisomer” means a group of conformational isomers of a molecule resulting from hindered rotation about a single bond. For example, the individual stereoisomers of 6,6'-dinitro-2,2'-biphenyldicarboxylic acid.
  • Optical isomer refers to a compound in which two or more molecules have the same two-dimensional connection, but exhibit different optical rotation properties due to differences in configuration. Such as levamlodipine and dexamlodipine.
  • Racemate refers to compounds that have the same two-dimensional connection mode but are optical isomers of each other, and when mixed together, they finally appear as substances without optical activity. than racemic amlodipine.
  • amino acid acyl refers to a substituent in which the carboxyl group of an amino acid is converted into an acyl group and linked to a substituent through the acyl group.
  • the amino acids include, but are not limited to, ⁇ -amino acids, ⁇ -amino acids, ⁇ -amino acids, and ⁇ -amino acids.
  • Such amino acids include, but are not limited to, the following examples: glycine, alanine, valine, leucine, isoleucine, methionine (methionine), proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, histidine, selenocysteine, pyrrolysine, beta-alanine, and the like.
  • glycosyl refers to a substituent of a monosaccharide or an oligosaccharide in the form of providing a hemiacetal hydroxyl group.
  • the monosaccharides include aldoses and ketoses.
  • the monosaccharides include triose, tetose, pentose, hexose and heptose.
  • the oligosaccharide also known as oligosaccharide, refers to a compound containing 2-11 monosaccharides, and each monosaccharide is polymerized through glycosidic bonds.
  • Examples of the monosaccharide or polysaccharide are as follows (but not limited to the following examples): erythrose, thulose, arabinose, ribose, xylose, lyxose, glucose, mannose, fructose, galactose, lactose, sucrose, maltose, ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin.
  • the pharmaceutically acceptable salt of the present invention may be a salt formed by an anion and a positively charged group on the compound of formula (I).
  • Suitable anions are chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate, tosylate, tartrate, fumarate, glutamate, glucuronate, lactate, glutarate or maleate.
  • salts can be formed from cations with negatively charged groups on compounds of formula (I). Suitable cations include sodium, potassium, magnesium, calcium and ammonium, such as tetramethylammonium.
  • “pharmaceutically acceptable salt” refers to the salts formed by the compound of formula (I) with an acid selected from the following group: hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, nitric acid, methanesulfonic acid, sulfamic acid, salicylic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, citric acid, acetic acid, lactic acid, tartaric acid, succinic acid, oxalic acid, pyruvic acid, malic acid, glutamic acid, p-toluenesulfonic acid, naphthalenesulfonic acid acid, ethanesulfonic acid, naphthalenedisulfonic acid, malonic acid, fumaric acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid,
  • the present invention provides a pharmaceutical composition, comprising a pharmaceutically acceptable carrier and one or more therapeutically effective doses of the compound of the present invention or its stereoisomers, enantiomers, diastereomers, atropisomers, optical isomers, racemates, tautomers or pharmaceutically acceptable salts thereof, prodrugs thereof, hydrates or solvates thereof, and isotope-labeled compounds thereof.
  • the pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof within a safe and effective amount range and a pharmaceutically acceptable excipient or carrier.
  • safe and effective dose refers to: the amount of the compound is sufficient to obviously improve the condition without causing severe side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 50-200 mg of the compound of the present invention per dose.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and low enough toxicity. "Compatibility” herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound.
  • Examples of pharmaceutically acceptable carrier moieties include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyhydric alcohols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
  • cellulose and derivatives thereof such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • talc such as ste
  • the pharmaceutical composition is injection, capsule, tablet, pill, powder or granule.
  • administration methods of the compounds or pharmaceutical compositions of the present invention are not particularly limited, and representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia; Potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; In capsules, tablets and pills, the dosage form may also contain
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • coatings and shell materials such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • Examples of usable embedding components are polymeric substances and waxy substances.
  • the active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances and the like.
  • inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide and oils
  • compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for topical administration of a compound of this invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required, if necessary.
  • the compound of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as antineoplastic drugs).
  • other pharmaceutically acceptable compounds such as antineoplastic drugs.
  • the treatment method of the present invention can be used alone or in combination with other treatment methods or drugs.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage.
  • the daily dosage is usually 1-2000 mg, preferably 5-500 mg.
  • factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.
  • HATU N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate
  • DMF N,N-Dimethylformamide
  • TEA Triethylamine
  • DIPEA Diisopropylethylamine
  • DMAC N,N-dimethylacetamide
  • Pd(dppf)Cl 2 [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride
  • NBS N-bromosuccinimide
  • NMP N-methylpyrrolidone
  • Pd(PPh 3 ) 4 tetrakistriphenylphosphine palladium
  • DPPA diphenylphosphoryl azide
  • 4-DMAP 4-dimethylaminopyridine
  • NaBH 3 CN sodium cyanoborohydride
  • PTSA p-toluenesulfonic acid
  • MeOH methanol
  • EtOH ethanol
  • Boc 2 O di-tert-butyl dicarbonate
  • DMSO dimethyl sulfoxide
  • Pd(dppf)Cl 2 [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride
  • reaction mixture was poured into water, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed five times with saturated sodium chloride, and finally the organic phase was dried over anhydrous sodium sulfate and concentrated, and purified by preparative thin layer chromatography to obtain I-1, yield: 47 mg, yield: 92.1%.
  • + indicates that the IC 50 is less than ( ⁇ ) 0.1 ⁇ M. It can be seen from Table 1 that the compound of the present invention has obvious inhibitory effect on RIPK1 enzyme.
  • I2.1 cell line the FADD mutant of human acute T-cell leukemia Jurkat cells, the FADD protein in the cells is missing, and TNF ⁇ alone can induce programmed necrosis in cells. It was detected by CCK-8 cell counting kit (Dojindo).
  • I2.1 cells in the logarithmic growth phase were inoculated into 96-well culture plates at an appropriate density. After culturing overnight, compounds of different concentrations were added first, and 20 ng/mL of TNF ⁇ was added to stimulate one hour later. Control wells without compounds and stimulating factors (positive control) and control wells without compounds and stimulating factors (negative control) were set. After the compound acted on the cells for 24 hours, the effect of the compound on the cell proliferation was detected using the CCK-8 cell counting kit (Dojindo). Add 10 ⁇ L of CCK-8 reagent to each well, place it in a 37°C incubator for 2-4 hours, and read it with a full-wavelength microplate microplate reader SpectraMax190, with a wavelength of 450nm.
  • the recovery rate (%) of the compound to programmed cell necrosis was calculated by the following formula:
  • IC50 values were calculated using GraphPad Prism software.

Abstract

本发明公开了一种具有RIPK1抑制活性的化合物、其制备方法及其用途，该化合物结构如通式I所示，各取代基的定义如说明书和权利要求书所述。本发明的化合物，能够用于治疗与受体相互作用蛋白激酶1相关的炎症性疾病、缺血性疾病、神经退行性疾病、肿瘤等病症和疾病。

Description

具有RIPK1抑制活性的化合物、其制备方法及其用途 技术领域
本发明涉及具有受体相互作用蛋白激酶1抑制活性的化合物、其制备方法及其用途，特别是该系列化合物或含有该系列化合物的药物组合物以及治疗剂用于治疗与受体相互作用蛋白激酶1相关的炎症性疾病、缺血性疾病、神经退行性疾病、肿瘤等病症和疾病的用途。
背景技术
蛋白激酶是一种通过对蛋白质上特定氨基酸的磷酸化来调节各种细胞功能的蛋白质(酶)。蛋白质通过构象的改变来调节活性以及与其化组分结合能力。蛋白质激酶的活性指的是，激酶将磷酸基团结合到底物上的速率，该速率可以通过检测一定时间内转化为产物的底物的量来进行测定。底物的磷酸化发生在蛋白质激酶的活化位点上。根据蛋白激酶底物蛋白被磷酸化的氨基酸残基种类，可将蛋白激酶分五类：丝氨酸/苏氨酸蛋白激酶、酪氨酸蛋白激酶、组氨酸蛋白激酶、色氨酸蛋白激酶和天冬氨酰基/谷氨酰基蛋白激酶。其中，丝氨酸/苏氨酸蛋白激酶是一类能够催化多种底物蛋白质上的丝氨酸/苏氨酸残基磷酸化的酶；酪氨酸激酶是一种可以催化将三磷酸腺苷转移到蛋白质酪氨酸残基的蛋白质酶。与蛋白激酶有关的病理状况包括炎症疾病、免疫疾病、心血管疾病和肿瘤等等。
细胞死亡主要包括凋亡、坏死性凋亡、细胞焦亡、铁死亡以及与自噬和非程序性坏死相关的细胞死亡过程。坏死性凋亡，也称为程序性细胞死亡或程序性坏死，是近年研究发现的一种新型细胞死亡方式。程序性坏死是一种高度炎症形式的细胞死亡，程序性坏死导致从细胞释放危险相关分子模式，被认为是多种退行性及炎症疾病的一个重要病理学因素。上述疾病包括神经退行性疾病、中风、冠心病、心肌梗死、视网膜退行性疾病、炎症性肠道病、肾病、肝病，和其他多种相关疾病。受体相互作用蛋白激酶1(RIPK1)与RIPK3是同源的两类丝氨酸/苏氨酸激酶，它们是介导细胞坏死性凋亡的关键元件。
RIPK1激酶被公认是细胞程序性坏死相关疾病的潜在治疗靶标。首创型RIPK1抑制剂Necrostatin-1(Nec-1)及其类似物在临床前研究中，已经对多种退行性疾病、炎症、癌症等疾病展示出明确的疗效。例如，对阿尔茨海默病、帕金森氏症、亨廷顿症、老年性黄斑变性等具有缓解作用；对银屑病、色素性视网膜炎、炎症性肠病、自身免疫性疾病、蛙皮素诱导的急性胰腺炎和败血症/全身炎症反应综合症具有保护作用；能有效缓解缺血性脑损伤、缺血性心肌损伤、视网膜缺血/再灌注损伤、视网膜脱离诱导的感光细胞坏死、青光眼、肾缺血再灌注损伤、顺铂诱导的肾损伤和创伤性脑损伤：至少部分缓解由RIPK1依赖性细胞凋亡、坏死或细胞因子生成所相关的其他疾病，包括血液和实体器官恶性肿瘤、细菌感染和病毒感染(包括结核病、流感等)和溶酶体贮积症(尤其是戈谢病)。另一类RIPK1抑制剂GSK2982772也正处于治疗多种自身免疫性疾病的临床试验当中。
对于用作药剂的激酶抑制剂，尤其是RIPK1激酶抑制剂，存在着需求。然而，现有的靶向程序性坏死相关激酶的抑制剂均存在着不同程度的缺陷，如选择性差、活体抑制活性 仍不够理想、药代性质不佳、口服生物利用度低等，还有一些无法透过血脑屏障进入中枢神经***，这些缺点均限制了其进一步的研究与临床应用。本领域中仍然需要更多化学结构更新颖、理化性质更佳、药效、药代性质更突出的新型激酶抑制剂，以作为检测、预防和治疗涉及坏死性凋亡相关激酶(例如RIPK1)的疾病的候选药物。
发明内容
本发明的目的在于提供RIPK1激酶抑制剂。
本发明的第一方面，提供一种通式(I)所示的化合物或其立体异构体、对映异构体、非对映异构体、阻转异构体、光学异构体、外消旋体、互变异构体或其药学上可接受的盐、其前药、其水合物或溶剂合物、其经同位素标记之化合物，
Figure PCTCN2022142343-appb-000001
其中，Cy 1选自下组：
Figure PCTCN2022142343-appb-000002
R 5在每次出现时独立地选自：H、D、卤素、CD 3、C1-C8烷基、卤代C1-C8烷基、C1-C8烷氧基、卤代C1-C8烷氧基、氰基、氨基、C1-C8烷基取代的氨基、羟基、巯基、C1-C8烷基硫基；
Cy 2选自被0-5个R 8取代的以下基团：C3-C14环烷基、C6-C14元芳基、6-14元杂芳基、或3-14元杂环基；
R 4在每次出现时独立地选自：H、D、CH 3、CD 3；
各虚线独立地表示单键或双键；
Z 1选自：O、S、N、CR z1、C＝O、SO、SO 2、NH；
Z 2选自C(R z2) 2、N、CR z2；各R z2独立地为H、卤素、羟基、任选取代的C1-C8烷基，或者两个R z2与它们所连接的碳原子一起形成任选取代的C3-C6碳环或3-6元杂环，
或者R z2、R z1与它们所连接的碳原子一起形成任选取代的C3-C6碳环或3-6元杂环；
Z 3、Z 4选自C、CH、N；
环A为C6-C14元芳环、5元杂芳环、6-14元杂芳环、C3-C14碳环或3-14元杂环；
m选自1、2、3、4；
R 1在每次出现时独立地选自H、D、“R 7-C≡C-”、R 1a；较佳地环A上至少有一个R 1为“R 7-C≡C-”的取代基；
R 1a、R 7在每次出现时独立地为由0-5个R 1a2取代的R 1a1；
R 1a1、R 1a2可选被0-5个R 1a3取代；
R 1a3为“-Linker2-R 1a4”；Linker2不存在，或者Linker2选自：键、O、NH、NR 1a4、-C(＝O)O-、-C(＝O)NH-、-C(＝O)NR 1a4-、3-14元环烷基、3-14元杂环基、C6-C14芳基、5-14元杂芳基；
R 2不存在，或者R 2在Z 4的邻位，且与R 3及它们所连接的原子一起形成任选取代或未取代的的5-6元杂环；
R 3选自：H、D、CH 3、CD 3；
Y为O、S、NR y，其中R y和R 3与它们所连接的原子一起形成任选取代的5-6元杂环或5-6元杂芳环；
R 6选自：CD 3、C1-C8烷基、卤代C1-C8烷基、C6-C14芳基；
R 8在每次出现时独立地选自：H、D、卤素、CD 3、C1-C8烷基、卤代C1-C8烷基、C1-C8烷氧基、卤代C1-C8烷氧基、氰基、氨基、C1-C8烷基取代的氨基、羟基、巯基、C1-C8烷基硫基、卤代C1-C8烷基硫基、-C(＝O)NH2、-C(＝O)NH(C1-C8烷基)、-C(＝O)-(C1-C8烷基)、氧代、硫代；
R 1a1、R 1a2在每次出现独立地选自下组：H、D、卤素、C1-C8烷基、卤代C1-C8烷基、C1-C8烷氧基、卤代的C1-C8烷氧基、C1-C6烷氧基取代的C1-C6烷氧基、C2-C8烯基、卤代C2-C8烯基、C2-C8烯基氧基、卤代C2-C8烯基氧基、C2-C8炔基、卤代C2-C8炔基、C2-C8炔基氧基、卤代C2-C8炔基氧基、C3-C14环烷基、(C3-C14环烷基)-(C1-C8烷基)-、(C3-C14环烷基)氧基、(C3-C14环烷基)-(C1-C8烷基)氧基、(C3-C14环烷基)氧基(C1-C8烷基)-、(C3-C14环烷基)硫基、(C3-C14环烷基)-(C1-C8烷基)硫基、(C3-C14环烷基)硫基(C1-C8烷基)-、(C3-C14环烷基)NH-、(C3-C14环烷基)-(C1-C8烷基)-NH-、(C3-C14环烷基)-NH-(C1-C8烷基)-、(C3-C14环烷基)-C(＝O)-、(C3-C14环烷基)-(C1-C8烷基)-C(＝O)-、(C3-C14环烷基)C(＝O)-(C1-C8烷基)-、(C3-C14环烷基)-C(＝O)O-、(C3-C14环烷基)-(C1-C8烷基)-C(＝O)O-、(C3-C14环烷基)-C(＝O)O-(C1-C8烷基)-、(C3-C14环烷基)-OC(＝O)-、(C3-C14环烷基)-(C1-C8烷基)-OC(＝O)-、(C3-C14环烷基)-OC(＝O)-(C1-C8烷基)-、(C3-C14环烷基)-C(＝O)NH-、(C3-C14环烷基)-(C1-C8烷基)-C(＝O)NH-、(C3-C14环烷基)-C(＝O)NH-(C1-C8烷基)-、(C3-C14环烷基)-NHC(＝O)-、(C3-C14环烷基)-(C1-C8烷基)-NHC(＝O)-、(C3-C14环烷 基)-(C1-C8烷基)-NHC(＝O)-、(C1-C8烷基)-(C3-C14环烷基)-、羟基(C3-C14环烷基)-、(C1-C8烷氧基)-(C3-C14环烷基)-、羟基(C1-C8烷基)-(C3-C14环烷基)-、巯基(C3-C14环烷基)、(C1-C8烷硫基)-(C3-C14环烷基)-、巯基(C1-C8烷基)-(C3-C14环烷基)-、氨基(C3-C14环烷基)、(C1-C8烷基)NH-(C3-C14环烷基)-、氨基(C1-C8烷基)-(C3-C14环烷基)-、HC(＝O)-(C3-C14环烷基)-、(C1-C8烷基)-C(＝O)-(C3-C14环烷基)-、HC(＝O)-(C1-C8烷基)-(C3-C14环烷基)-、HC(＝O)O-(C3-C14环烷基)-、(C1-C8烷基)-C(＝O)O-(C3-C14环烷基)-、HC(＝O)O-(C1-C8烷基)-(C3-C14环烷基)-、HOC(＝O)-(C3-C14环烷基)-、(C1-C8烷基)-O-C(＝O)-(C3-C14环烷基)-、HO-C(＝O)-(C1-C8烷基)-(C3-C14环烷基)-、HC(＝O)NH-(C3-C14环烷基)-、(C1-C8烷基)C(＝O)NH-(C3-C14环烷基)-、HC(＝O)NH-(C1-C8烷基)-(C3-C14环烷基)-、NH 2C(＝O)-(C3-C14环烷基)-、(C1-C8烷基)NHC(＝O)-(C3-C14环烷基)-、NH 2C(＝O)-(C1-C8烷基)-(C3-C14环烷基)-、(C1-C8烷基)-(C3-C14环烷基)-(C1-C8烷基)-、3-14元杂环基、(3-14元杂环基)-(C1-C8烷基)-、(3-14元杂环基)氧基、(3-14元杂环基)-(C1-C8烷基)-氧基、(3-14元杂环基)氧基-(C1-C8烷基)-、(3-14元杂环基)硫基、(3-14元杂环基)-(C1-C8烷基)-硫基、(3-14元杂环基)硫基-(C1-C8烷基)-、(3-14元杂环基)NH-、(3-14元杂环基)(C1-C8烷基)NH-、(3-14元杂环基)-NH-(C1-C8烷基)-、(3-14元杂环基)-C(＝O)-、(3-14元杂环基)-(C1-C8烷基)-C(＝O)-、(3-14元杂环基)-C(＝O)-(C1-C8烷基)-、(3-14元杂环基)-C(＝O)O-、(3-14元杂环基)-(C1-C8烷基)-C(＝O)O-、(3-14元杂环基)-C(＝O)O-(C1-C8烷基)-、(3-14元杂环基)-OC(＝O)-、(3-14元杂环基)-(C1-C8烷基)-OC(＝O)-、(3-14元杂环基)-OC(＝O)-(C1-C8烷基)-、(3-14元杂环基)-C(＝O)NH-、(3-14元杂环基)-(C1-C8烷基)-C(＝O)NH-、(3-14元杂环基)-C(＝O)NH-(C1-C8烷基)-、(3-14元杂环基)-NHC(＝O)-、(3-14元杂环基)-(C1-C8烷基)-NHC(＝O)-、(3-14元杂环基)-NHC(＝O)-(C1-C8烷基)-、(C1-C8烷基)-(3-14元杂环基)-、羟基(3-14元杂环基)-、(C1-C8烷氧基)-(3-14元杂环基)-、羟基(C1-C8烷基)-(3-14元杂环基)-、巯基(C3-C14环烷基)、(C1-C8烷硫基)-(3-14元杂环基)-、巯基(C1-C8烷基)-(3-14元杂环基)-、氨基(3-14元杂环基)、(C1-C8烷基)NH-(3-14元杂环基)-、氨基(C1-C8烷基)-(3-14元杂环基)-、HC(＝O)-(3-14元杂环基)-、(C1-C8烷基)-C(＝O)-(3-14元杂环基)-、HC(＝O)-(C1-C8烷基)-(3-14元杂环基)-、HC(＝O)O-(3-14元杂环基)-、(C1-C8烷基)-C(＝O)O-(3-14元杂环基)-、HC(＝O)O-(C1-C8烷基)-(3-14元杂环基)-、HOC(＝O)-(3-14元杂环基)-、(C1-C8烷基)-O-C(＝O)-(3-14元杂环基)-、HO-C(＝O)-(C1-C8烷基)-(3-14元杂环基)-、HC(＝O)NH-(3-14元杂环基)-、(C1-C8烷基)C(＝O)NH-(3-14元杂环基)-、HC(＝O)NH-(C1-C8烷基)-(3-14元杂环基)-、NH 2C(＝O)-(3-14元杂环基)-、(C1-C8烷基)NHC(＝O)-(3-14元杂环基)-、NH 2C(＝O)-(C1-C8烷基)-(3-14元杂环基)-、(C1-C8烷基)-(3-14元杂环基)-(C1-C8烷基)-、C6-C14芳基、(C6-C14芳基)-(C1-C8烷基)-、(C6-C14芳基)氧基、(C6-C14芳基)-(C1-C8烷基)氧基、(C6-C14芳基)氧基(C1-C8烷基)-、(C6-C14芳基)硫基、(C6-C14芳基)-(C1-C8烷基)硫基、(C6-C14芳基)硫基(C1-C8烷基)-、(C6-C14芳基)NH-、(C6-C14芳基)-(C1-C8烷基)-NH-、(C6-C14芳基)-NH-(C1-C8烷基)-、(C6-C14芳基)-C(＝O)-、(C6-C14芳基)-(C1-C8烷基)-C(＝O)-、(C6-C14芳基)C(＝O)-(C1-C8烷基)-、(C6-C14芳基)-C(＝O)O-、(C6-C14芳基)-(C1-C8烷基)-C(＝O)O-、(C6-C14芳基)-C(＝O)O-(C1-C8烷基)-、(C6-C14芳基)-OC(＝O)-、(C6-C14芳 基)-(C1-C8烷基)-OC(＝O)-、(C6-C14芳基)-OC(＝O)-(C1-C8烷基)-、(C6-C14芳基)-C(＝O)NH-、(C6-C14芳基)-(C1-C8烷基)-C(＝O)NH-、(C6-C14芳基)-C(＝O)NH-(C1-C8烷基)-、(C6-C14芳基)-NHC(＝O)-、(C6-C14芳基)-(C1-C8烷基)-NHC(＝O)-、(C6-C14芳基)-(C1-C8烷基)-NHC(＝O)-、(C1-C8烷基)-(C6-C14芳基)-、羟基(C6-C14芳基)-、(C1-C8烷氧基)-(C6-C14芳基)-、羟基(C1-C8烷基)-(C6-C14芳基)-、巯基(C3-C14环烷基)、(C1-C8烷硫基)-(C6-C14芳基)-、巯基(C1-C8烷基)-(C6-C14芳基)-、氨基(C6-C14芳基)、(C1-C8烷基)NH-(C6-C14芳基)-、氨基(C1-C8烷基)-(C6-C14芳基)-、HC(＝O)-(C6-C14芳基)-、(C1-C8烷基)-C(＝O)-(C6-C14芳基)-、HC(＝O)-(C1-C8烷基)-(C6-C14芳基)-、HC(＝O)O-(C6-C14芳基)-、(C1-C8烷基)-C(＝O)O-(C6-C14芳基)-、HC(＝O)O-(C1-C8烷基)-(C6-C14芳基)-、HOC(＝O)-(C6-C14芳基)-、(C1-C8烷基)-O-C(＝O)-(C6-C14芳基)-、HO-C(＝O)-(C1-C8烷基)-(C6-C14芳基)-、HC(＝O)NH-(C6-C14芳基)-、(C1-C8烷基)C(＝O)NH-(C6-C14芳基)-、HC(＝O)NH-(C1-C8烷基)-(C6-C14芳基)-、NH 2C(＝O)-(C6-C14芳基)-、(C1-C8烷基)NHC(＝O)-(C6-C14芳基)-、NH 2C(＝O)-(C1-C8烷基)-(C6-C14芳基)-、(C1-C8烷基)-(C6-C14芳基)-(C1-C8烷基)-、5-14元杂芳基、(5-14元杂芳基)-(C1-C8烷基)-、(5-14元杂芳基)氧基、(5-14元杂芳基)-(C1-C8烷基)氧基、(5-14元杂芳基)氧基(C1-C8烷基)-、(5-14元杂芳基)硫基、(5-14元杂芳基)-(C1-C8烷基)硫基、(5-14元杂芳基)硫基(C1-C8烷基)-、(5-14元杂芳基)NH-、(5-14元杂芳基)-(C1-C8烷基)-NH-、(5-14元杂芳基)-NH-(C1-C8烷基)-、(5-14元杂芳基)-C(＝O)-、(5-14元杂芳基)-(C1-C8烷基)-C(＝O)-、(5-14元杂芳基)C(＝O)-(C1-C8烷基)-、(5-14元杂芳基)-C(＝O)O-、(5-14元杂芳基)-(C1-C8烷基)-C(＝O)O-、(5-14元杂芳基)-C(＝O)O-(C1-C8烷基)-、(5-14元杂芳基)-OC(＝O)-、(5-14元杂芳基)-(C1-C8烷基)-OC(＝O)-、(5-14元杂芳基)-OC(＝O)-(C1-C8烷基)-、(5-14元杂芳基)-C(＝O)NH-、(5-14元杂芳基)-(C1-C8烷基)-C(＝O)NH-、(5-14元杂芳基)-C(＝O)NH-(C1-C8烷基)-、(5-14元杂芳基)-NHC(＝O)-、(5-14元杂芳基)-(C1-C8烷基)-NHC(＝O)-、(5-14元杂芳基)-(C1-C8烷基)-NHC(＝O)-、(C1-C8烷基)-(5-14元杂芳基)-、羟基(5-14元杂芳基)-、(C1-C8烷氧基)-(5-14元杂芳基)-、羟基(C1-C8烷基)-(5-14元杂芳基)-、巯基(C3-C14环烷基)、(C1-C8烷硫基)-(5-14元杂芳基)-、巯基(C1-C8烷基)-(5-14元杂芳基)-、氨基(5-14元杂芳基)、(C1-C8烷基)NH-(5-14元杂芳基)-、氨基(C1-C8烷基)-(5-14元杂芳基)-、HC(＝O)-(5-14元杂芳基)-、(C1-C8烷基)-C(＝O)-(5-14元杂芳基)-、HC(＝O)-(C1-C8烷基)-(5-14元杂芳基)-、HC(＝O)O-(5-14元杂芳基)-、(C1-C8烷基)-C(＝O)O-(5-14元杂芳基)-、HC(＝O)O-(C1-C8烷基)-(5-14元杂芳基)-、HOC(＝O)-(5-14元杂芳基)-、(C1-C8烷基)-O-C(＝O)-(5-14元杂芳基)-、HO-C(＝O)-(C1-C8烷基)-(5-14元杂芳基)-、HC(＝O)NH-(5-14元杂芳基)-、(C1-C8烷基)C(＝O)NH-(5-14元杂芳基)-、HC(＝O)NH-(C1-C8烷基)-(5-14元杂芳基)-、NH 2C(＝O)-(5-14元杂芳基)-、(C1-C8烷基)NHC(＝O)-(5-14元杂芳基)-、NH 2C(＝O)-(C1-C8烷基)-(5-14元杂芳基)-、(C1-C8烷基)-(5-14元杂芳基)-(C1-C8烷基)-、羟基、羟基取代的C1-C8烷基、巯基、巯基取代的C1-C8烷基、氨基、氨基取代的C1-C8烷基、-NH(C1-C8烷基)、-N(C1-C8烷基)(C1-C8烷基)、氰基、氰基取代的C1-C8烷基、-COOH、-(C1-C8烷基)-COOH、-C(＝O)O-(C1-C8烷基)、-(C1-C8烷基)-C(＝O)O-(C1-C8烷基)、-OC(＝O)H、-(C1-C8烷基)-OC(＝O)H、-OC(＝O)-(C1-C8烷基)、-(C1-C8烷基)-OC(＝O)-(C1-C8 烷基)、-C(O)H、-(C1-C8烷基)-C(＝O)H、-C(＝O)-(C1-C8烷基)、-(C1-C8烷基)-C(＝O)-(C1-C8烷基)、NH 2C(＝O)-、一个或二个C1-C8烷基取代的NH 2C(O)-、一个或二个C1-C8环烷基取代的NH 2C(O)-、一个或二个C6-C14芳基取代的NH 2C(O)-、一个或二个5-14元杂芳基取代的NH 2C(O)-、一个或二个4-10元杂环基取代的NH 2C(O)-、NH 2C(＝O)-(C1-C8烷基)-、一个或二个C1-C8烷基取代的NH 2C(O)-(C1-C8烷基)-、一个或二个C1-C8环烷基取代的NH 2C(O)-(C1-C8烷基)-、一个或二个C6-C14芳基取代的NH 2C(O)-(C1-C8烷基)-、一个或二个5-14元杂芳基取代的NH 2C(O)-(C1-C8烷基)-、一个或二个4-10元杂环基取代的NH 2C(O)-(C1-C8烷基)-、氧代(＝O)、硫代(＝S)；
R 1a4在每次出现时独立地选自下组：H、D、卤素、羟基、C1-C8烷基、卤代C1-C8烷基、C2-C8烯基、卤代C2-C8烯基、C2-C8炔基、卤代C2-C8炔基、(C1-C15烷基)-OC(＝O)-、(C6-C14芳基)-OC(＝O)-、(4-12元杂环基)-OC(＝O)-、(5-14元杂芳基)-OC(＝O)-、(C1-C15烷基)-C(＝O)-、(C6-C14芳基)-C(＝O)-、(4-12元杂环基)-C(＝O)-、(5-14元杂芳基)-C(＝O)-、(C1-C15烷基)-C(＝O)O-、(C6-C14芳基)-C(＝O)O-、(4-12元杂环基)-C(＝O)O-、(5-14元杂芳基)-C(＝O)O-、(卤代C1-C15烷基)-OC(＝O)-、(卤代C6-C14芳基)-OC(＝O)-、(卤代4-12元杂环基)-OC(＝O)-、(卤代5-14元杂芳基)-OC(＝O)-、(卤代C1-C15烷基)-C(＝O)-、(卤代C6-C14芳基)-C(＝O)-、(卤代4-12元杂环基)-C(＝O)-、(卤代5-14元杂芳基)-C(＝O)-、(卤代C1-C15烷基)-C(＝O)O-、(卤代C6-C14芳基)-C(＝O)O-、(卤代4-12元杂环基)-C(＝O)O-、(卤代5-14元杂芳基)-C(＝O)O-、C1-C8烷基取代的(C1-C15烷基)-OC(＝O)-、C1-C8烷基取代的(C6-C14芳基)-OC(＝O)-、C1-C8烷基取代的(4-12元杂环基)-OC(＝O)-、C1-C8烷基取代的(5-14元杂芳基)-OC(＝O)-、C1-C8烷基取代的(C1-C15烷基)-C(＝O)-、C1-C8烷基取代的(C6-C14芳基)-C(＝O)-、C1-C8烷基取代的(4-12元杂环基)-C(＝O)-、C1-C8烷基取代的(5-14元杂芳基)-C(＝O)-、C1-C8烷基取代的(C1-C15烷基)-C(＝O)O-、C1-C8烷基取代的(C6-C14芳基)-C(＝O)O-、C1-C8烷基取代的(4-12元杂环基)-C(＝O)O-、C1-C8烷基取代的(5-14元杂芳基)-C(＝O)O-、(C1-C8烷基) 3-Si-(C1-C8烷基)-O-(C1-C8亚烷基)-、被卤素取代或未取代的(C1-C8烷基)-OC(＝O)-(C1-C8烷基)C(＝O)O-、被卤素取代或未取代的(C1-C8烷基)-OC(＝O)-(C3-C14环烷基)C(＝O)O-、糖基、-O-P(＝O)(O-卤代或未卤代的C6-C14芳基)(NH-(C1-C8烷基)C(＝O)O(C1-C8烷基))、-O-P(＝O)(O-卤代或未卤代的C6-C14芳基)(O-(C1-C8烷基)C(＝O)O(C1-C8烷基))、-O-P(＝O)(O-卤代或未卤代的C6-C14芳基)(NH-(C1-C8烷基)OC(＝O)(C1-C8烷基))、-O-P(＝O)(O-卤代或未卤代的C6-C14芳基)(O-(C1-C8烷基)OC(＝O)(C1-C8烷基))、-O-P(＝O)(O-卤代或未卤代的C6-C14芳基)(NH-(C1-C8烷基)-S-C(＝O)(C1-C8烷基))、-O-P(＝O)(O-卤代或未卤代的C6-C14芳基)(O-(C1-C8烷基)-S-C(＝O)(C1-C8烷基))、-O-P(＝O)(ONa) 2、-O-P(＝O)(OK) 2、-O-P(＝O)(OLi) 2、-O-(卤代或未卤代的C1-C8烷基)-P(＝O)(O-C1-C8烷基) 2、(C1-C8烷基)-C(＝O)-CH＝CH-、氨基酸酰基、C1-C16烷基、卤代C1-C16烷基、C6-C14芳基、卤代C6-C14芳基。
在另一优选例中，至少一个R 1为R 7-C≡C-”。即m为1，R 1为R 7-C≡C-”；m为2、3或4，其中一个R 1为R 7-C≡C-”，其他R 1独立地选自H、D、“R 7-C≡C-”、R 1a。
在另一优选例中，通式(I)所示的化合物具有结构：
Figure PCTCN2022142343-appb-000003
在另一优选例中，通式(I)所示的化合物具有式(II)所示的结构：
Figure PCTCN2022142343-appb-000004
在另一优选例中，所述化合物选自式(IV-1)、(IV-2)、(IV-4)、(IV-5)、(IV-6)、(IV-7)、(IV-9)：
Figure PCTCN2022142343-appb-000005
其中，Cy 3选自式(III-1)至(III-14)：
Figure PCTCN2022142343-appb-000006
Figure PCTCN2022142343-appb-000007
Z 5选自C-R 1或N；R 1、m、Z 1、R 3的定义同前；较佳地，Z 5选自CH或N；m为1时，R 1为R 7-C≡C-；R 7的定义同前。
在另一优选例中，所述化合物选自式(V-1)、(V-2)、(V-3)、(V-4)：
Figure PCTCN2022142343-appb-000008
其中，Z 5选自C-R 1或N；R 1a1、R 1、R 3、Z 1、Cy 1、Cy 2、R 5的定义同前。
在另一优选例中，所述化合物选自：
Figure PCTCN2022142343-appb-000009
式中，Z 5选自CH或N；R 1为C1-C8烷基；R 1a1、R 3、Z 1、Cy 2、R 5的定义同前。
在另一优选例中，R 1在每次出现时独立选自下组：H、D、甲基、
Figure PCTCN2022142343-appb-000010
Figure PCTCN2022142343-appb-000011
在另一优选例中，所述化合物为权利要求5中列出的化合物。
本发明的第二方面，提供第一方面所述式(I)所示化合物的制备方法，合成步骤至少包括反应式1、反应式2之一所述反应式：
[反应式1]
Figure PCTCN2022142343-appb-000012
[反应式2]
Figure PCTCN2022142343-appb-000013
其中,
G 2选自：-OH，卤素，C1-C8烷氧基，C6-C14芳基氧基，-OC(＝O)-(C1-C8烷氧基)，-OS(＝O)-(C1-C8烷氧基)，-OS(＝O) 2-(C1-C8烷氧基)，-OC(＝O)-(C6-C14芳基氧基)，-OS(＝O)-(C6-C14芳基氧基)，-OS(＝O) 2-(C6-C14芳基氧基)；
R 4、R 1、m、R 2、R 3、Y、Z 1、Z 2、Z 3、Z 4、虚线、Cy 1的定义同前。
本发明的第三方面，提供药物组合物，包含：药学上可接受的载体和一种或多种第一方面所述的化合物或其立体异构体、对映异构体、非对映异构体、阻转异构体、光学异构体、外消旋体、互变异构体或其药学上可接受的盐、其前药、其水合物或溶剂合物、其经同位素标记之化合物。
本发明的第四方面，提供一种受体相互作用蛋白激酶1(RIPK1)抑制剂，包含一种或多种第一方面所述的化合物或其立体异构体、几何异构体、互变异构体、其药学上可接受的盐、其前药、其水合物或溶剂合物，或第三方面所述的药物组合物。
本发明的第五方面，提供第一方面所述化合物或其立体异构体、对映异构体、非对映异构体、阻转异构体、光学异构体、外消旋体、互变异构体或其药学上可接受的盐、其前药、其水合物或溶剂合物、其经同位素标记之化合物或第三方面所述的药物组合物的用途，其特征在于，用于制备药物，所述药物用于：1)检测和/或预防和/或治疗激酶相关疾病；2)检测和/或预防和/或治疗免疫、炎症和/或感染相关疾病；3)检测和/或预防和/或治疗缺血和/或再灌注损伤相关疾病；4)检测和/或预防和/或治疗退行性疾病；5)检测和/或预防和/或***相关疾病；6)检测和/或预防和/或治疗细胞坏死相关疾病；7)检测和/或预防和/或治疗代谢相关疾病；或者8)检测和/或预防和/或治疗眼部疾病。
本发明的第六方面，提供第一方面所述化合物或其立体异构体、对映异构体、非对映异构体、阻转异构体、光学异构体、外消旋体、互变异构体或其药学上可接受的盐、其前药、其水合物或溶剂合物、其经同位素标记之化合物或第三方面所述的药物组合物的用途，其特征在于，用于制备检测和/或预防和/或治疗选自下组的疾病的药物：
全身型幼年特发性关节炎，***，白细胞介素‐1转化酶相关性发热综合征，败血症，斑秃，变应性疾病，过敏性疾病，乙型肝炎，丙型肝炎，多发性硬化，肺结节病，肺纤维化，肺炎，分枝杆菌感染，腹腔疾病，干燥综合征，骨关节炎，化脓性汗腺炎，坏死性小肠结肠炎，急性胰腺炎，脊柱关节炎，结肠炎，局限性回肠炎，抗磷脂综合征，克罗恩病，溃疡性肠炎，类风湿性关节炎，细菌感染，流感，慢性阻塞性肺病，病毒感染，脓毒症，皮炎，葡萄球菌感染，自身免疫疾病，全身性红斑狼疮，全身性炎症反应综合征，全身性硬皮病，朊病毒症，肾上腺皮质变性，肾炎，史‐约综合征，手术感染，特应性皮炎，韦格纳肉芽肿，***性红斑狼疮，哮喘，新冠肺炎，血管炎，牙周炎，炎性肠病，胰腺炎，移植器官排除，银屑病，原发性硬化性胆管炎，肿瘤坏死因子受体相关周期性发热综合征，白细胞介素‐1转换酶相关的发热综合征，自身免疫特发性血小板减少性紫癜，Fahr病，GM1神经节苷脂贮积病，GM2神经节苷脂贮积病，艾滋病相关痴呆综合征，Tau蛋白病，阿尔茨海默病，帕金森病，路易体痴呆，多***萎缩症，多重硬化，额颞叶痴呆，法伯病，弗里德赖希共济失调症，格林巴利综合征，亨廷顿病，原发性侧索硬化，肌萎缩性侧索硬化，脊髓性肌萎缩，假性延髓麻痹，进行性延髓麻痹，结节状硬化症，进行性核上性麻痹，进行性肌萎缩，精神***症，脱髓鞘病，慢性炎症性脱髓鞘性多发性神经病，尼曼匹克病，皮质基底节变性，溶酶体贮积病，桑德霍夫病，神经节细胞病，神经元蜡样脂褐质沉积症，术后认知障碍，双相障碍，糖尿病性神经病，疼痛(神经疼痛)，谵妄，抑郁症，周围神经病变，自闭症，创伤，创伤性脑损伤，局部缺血，创伤性视网膜损伤，脑血管意外，脑卒中，地理性萎缩，对乙酰胺基酚中毒，急性肝衰竭，急性肾损伤，急性呼吸窘迫综合征，颅内出血，脑出血，脑缺血，缺血，缺血性损伤，缺氧性脑损伤，缺氧，烧伤，烧伤性休克，实体器官的缺血再灌注损伤，顺铂诱导的肾损伤，吸烟诱导的损伤，心肌梗塞，心力衰竭，中毒性表皮坏死松解症，急性肾小管坏死，心脏衰竭，NF‐κB关键调节基因突变，白血病，髓细胞白血病，淋巴细胞白血病，T细胞白血病，淋巴瘤，T细胞淋巴瘤，鼻咽癌，表皮样癌，垂体腺瘤，胆道癌肉瘤，胆管癌，多发性骨髓瘤，儿童实体瘤，霍奇金病，非霍奇金淋巴瘤，非小细胞肺癌，小细胞肺癌，***区域癌，睾丸癌，***，子宫癌，子宫内膜癌，卵巢癌，骨癌，骨肉瘤，黑色素瘤，环境诱发的癌症，脊柱肿瘤，甲状腺癌，甲状旁腺癌，胶质母细胞瘤，结肠直肠癌，卡波西氏肉瘤，鳞状上皮细胞癌，脑胶质瘤，内分泌***癌症，尿道癌，膀胱癌，皮肤癌，皮肤或眼内恶性黑色素瘤，***癌，三阴性乳腺癌，神经胶质瘤，肾或输尿管癌，肾盂癌，肾上腺癌，实体器官恶性肿瘤，食道癌，输卵管癌，头和/或颈癌，外阴癌，胃癌，胃肠间质瘤，小肠癌，血液恶性肿瘤，胰腺癌，遗传性大动脉瘤，***癌，***癌，直肠癌，肿瘤血管生成，黄斑病变，黄斑裂孔，黄斑毛细管扩张，干眼症，进行性视网膜萎缩，莱伯氏先天性黑蒙，囊性黄斑水肿，年龄相关性黄斑变性，青光眼，视网膜神经变性，缺血性视神经病变，缺血性视网膜疾病，糖尿病性视网膜病变，色素性视网膜炎，视网膜感光器疾病，视网膜退行性疾病，视神经疾病，视网膜脱离，医源性视网膜损伤，视网膜血管疾病，视锥视杆营养不良，无脉络膜症，眼底疾病，眼血管疾病，尤塞氏综合症，I型糖尿病，非酒精性脂肪肝，白癜风，唾液酸苷贮积症，肠易激综合征，达农病，胆固醇酯贮积症，沃尔曼病， 低脂血症，动脉粥样硬化，多种硫酸酯酶缺乏症，法布里病，戈谢病，骨髓纤维化，骨质疏松症，胱氨酸贮积症，肌营养不良，多聚谷氨酰胺疾病，克拉伯病，慢性肾病，门克斯病，囊性纤维化病，庞皮病，泰伊‐萨克斯二氏病，溶酶体酸脂酶缺乏，天冬氨酰葡萄糖胺尿症，痛风，威尔逊氏病，线粒体病症，岩藻糖苷贮积症，异染性脑白质营养不良，浴酶体酸脂酶缺乏，粘多糖累积病，粘脂质累积，致密性成骨不全症，血色病，Niemann‐Pick病，Heme‐氧化的IRP2泛素连接酶‐1缺乏，骨坏死，链状泛素链组装复合物缺乏综合征，纤毛病等。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。说明书中所揭示的各个特征，可以被任何提供相同、均等或相似目的的替代性特征取代。限于篇幅，在此不再一一累述。
具体实施方法
本发明人经过长期而深入的研究，意外地研发出一种结构新颖、激酶抑制作用显著的通式(I)和/或通式(II)所示化合物。所述的激酶抑制剂具有优异的RIPK1抑制活性，因此可用于制备检测和/或预防和/或治疗涉及细胞死亡和/或相关的疾病的药物组合物。在此基础上，发明人完成了本发明。
术语
除非明确另外指出，根据本发明和本文所用的术语具有以下含义：
术语“C 1-C 6”是指具有1、2、3、4、5或6个碳原子，“C 1-C 8”是指具有1、2、3、4、5、6、7或8个碳原子，依此类推。“5-8元”是指具有5-8个环原子，依此类推。
“取代基”指可以取代被取代基物中的氢原子的原子或基团。示例如下(但并不限于下列示例)：氘代、烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、异氰酸基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氨基、卤代烷基、羟烷基、羧基、羧酸酯基、氧代、硫代、-C(＝O)R n、-C(＝O)OR n、-C(＝O)NR nR o、-NR nR o、-NR nC(＝O)R o、-NR nC(＝O)OR o、NR nC(＝O)NR oR p、-NR nS(＝O)R o、NR nS(＝O)NR oR p、-NR nS(＝O) 2R o、NR nS(＝O) 2NR oR p、-OR n、-SR n、-OC(＝O)R n、-OC(＝O)NR nR o、-OC(＝O)OR n、-S(＝O)NR nR o、-S(＝O) 2NR nR o、-BR nR o、B(OR n)(OR o)、-SiR nR oR p、-OP(＝O)R nR o、-P(＝O)R nR o、-OP(＝O) 2R n、-P(＝O) 2R n、-NP(＝O)R nR o、-NP(＝O)R nR o、-NP(＝O) 2R n、-NP(＝O) 2R n等，其中R n、R o、R p在每次出现时独立地选自下组：H、D、C1-C12烷基、卤代的C1-C12烷基、C1-C12杂烷基、卤代的C1-C12杂烷基、C3-C12环烷基、卤代的C3-C12环烷基、C3-C12芳基、卤代的C3-C12芳基、C3-C12芳基、卤代的C3-C12芳基、C3-C12杂芳基、卤代的C3-C12杂芳基；可选的，R n、R o及它们所连的原子一起可以形成环结构。本领域技术人员应理解，本发明所预期的取代基与被取代物的组合是那些稳定的或化学上可实现的组合。
“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于)：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、疏基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氨基、卤代烷基、羟烷基、羧基、羧酸酯基、氧代、硫代、-C(＝O)R n、-C(＝O)OR n、-C(＝O)NR nR o、-NR nR o、-NR nC(＝O)R o、-NR nC(＝O)OR o、NR nC(＝O)NR oR p、-NR nS(＝O)R o、NR nS(＝O)NR oR p、-NR nS(＝O) 2R o、NR nS(＝O) 2NR oR p、-OR n、-SR n、-OC(＝O)R n、-OC(＝O)NR nR o、-OC(＝O)OR n、-S(＝O)NR nR o、-S(＝O) 2NR nR o、-BR nR o、B(OR n)(OR o)、-SiR nR oR p、-OP(＝O)R nR o、-P(＝O)R nR o、-OP(＝O) 2R n、-P(＝O) 2R n、-NP(＝O)R nR o、-NP(＝O)R nR o、-NP(＝O) 2R n、-NP(＝O) 2R n等，其中R n、R o、R p的定义同前述。
“烷基”指饱和的脂肪族烃基，可以是直链或支链的。所述烷基可以独立地被一个或多个本发明所描述地取代基所取代。烷基基团更近一步地实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、3-甲基戊基。烷基可以是任选取代或未取代的。
“烯基”直链或支链的烃基，其中至少一个C-C为sp 2双键，其中烯基的基团可以独立任选地被一个或多个本发明所描述的取代基所取代，其中具体的实例包括，但并不限于乙烯基、烯丙基、烯丁基、
Figure PCTCN2022142343-appb-000014
等等。烯基可以是任选取代或未取代的。
“炔基”指直链或支链的烃基，其中至少一个C-C为sp三键，其中炔基基团可以独立任选地被一个或多个本发明所描述的取代基所取代，具体的实例包括，但并不限于乙炔基、1-丙炔基、2-丙炔基、1-、2-或3-丁炔基等。炔基可以是任选取代或未取代的。
“环结构”指单环或多环结构。通常为环状结构中的某一个原子上相连的两个或多个片段相连进而形成了闭合的结构，包括但不限于环烷烃、杂环烷烃、环内酰胺、芳烃、杂芳烃、并环、桥环、螺环等结构，示例如下(但并不限于下列示例)：环丙烷、环丁烷、氧杂环丁烷、环戊烷、环己烷、金刚烷、环己烯、环辛炔、吡唑、苯、吡啶、3,4-二氢-1,4-苯并氧氮杂卓-5(2H)-酮、萘、蒽、菲、喹啉、吡咯并吡啶、吡唑并吡啶、吲哚、二氢吲哚、甾环、卟啉环等。所述环结构可以是任选取代或未取代的。当其作为取代基出现时，指单环或多环上的一个或多个氢原子被移除，从而可以作为被取代物的取代基。
“卤素”指F、Cl、Br或I。
“卤代”指被一个或多个卤素取代。
“芳基”指含有一个或多个环的碳环芳香***，所述环上不含杂原子。可选地，所述芳基可以与杂芳基、杂环基或其它环结构稠合。示例如下(但并不限于下列示例)：苯基、 萘基、四氢萘基、
Figure PCTCN2022142343-appb-000015
Figure PCTCN2022142343-appb-000016
Figure PCTCN2022142343-appb-000017
等。所述芳基可以是任选取代的或未取代的。当所述芳基描述形式为“C6-C14芳基”时，指的是所述芳基与母体结构连接在一起的芳环具有6-14个碳原子，但所述芳基可选与其它环结构稠合，所述其它环结构指具有3-18个环原子的环结构，所述其它环结构可以是任选取代或未取代的。
“杂芳基”指含有一个或多个环的芳香族环结构，其可以包含一个或多个选自N、O或S原子。可选地，所述芳基可以与芳基、杂环基、环烷基或其它环结构稠合。示例如下(但并不限于下列示例)：呋喃基、噻吩基、吡啶基、吡唑基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基、
Figure PCTCN2022142343-appb-000018
Figure PCTCN2022142343-appb-000019
等。所述杂芳基可以是任选取代的或未取代的。当所述杂芳基描述形式为“5-14元杂芳基”时，指的是所述杂芳基与母体结构连接在一起的杂芳环具有5-14个环原子，但所述杂芳基可选与其它环结构稠合，所述其它环结构指具有3-18个环原子环结构，所述其它环结构可以是任选取代或未取代的。
“环烷基”指饱和或部分不饱和单环或多环环状烃取代基。所述环烷基与被取代物直接相连的第一个环结构是非芳香性的。单环环烷基的示例(但并不限于下列示例)：环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基、环辛炔基等；多环环烷基的示例(但并不限于下列示例)：螺环、稠环和桥环的环烷基。可选地，所述环烷基可以与芳基、杂环基、环烷基或其它环结构稠合或形成螺环。与其它环结构稠合或形成螺环的示例(但并不限于下列示例)：
Figure PCTCN2022142343-appb-000020
Figure PCTCN2022142343-appb-000021
Figure PCTCN2022142343-appb-000022
所述环烷基可以是任选取代的或未取代的。当所述环烷基基描述形式为“C3-C14环烷基”时，指的是所述环烷基与母体结构连接在一起的环烷基环具有3-14个碳原子，但所述环烷基可选与其它环结构稠合或形成螺环，所述其它环结构指具有3-18个环原子环结构，所述其它环结构可以是任选取代或未取代的。
“杂环基”指至少一个环原子原子是杂原子(例如O、N、S原子等)的饱和或部分不饱和的单环或多环环状结构。示例如下(但并不限于下列示例)：四氢呋喃基、四氢吡喃基、四氢吡咯基、四氢噻吩基、哌啶基、哌嗪基、氮杂环丁基、氮杂环庚基、吗啉基、2-氧代-吡咯烷基、哌嗪-2-酮、8-氧杂-3-氮杂-双环[3.2.1]辛基等。所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基。所述杂环基可以是任选取代的或未取代的。当所述杂烷基基描述形式为“3-14元杂环基”时，指的是所述杂环基与母体结构连接在一起的杂环基环具有3-14个环原子，但所述杂环基可选与其它环结构稠合或形成螺环，所述其它环结构指具有3-18个环原子环结构，所述其它环结构可以是任选取代或未取代的。
“互变异构体”表示具有不同能量的结构同分异构体可以超过低能垒，从而互相转化。比如，质子互变异构体(即质子移变)包括通过质子迁移进行互变，如1H-吲唑与2H-吲唑、1H-苯并[d]咪唑与3H-苯并[d]咪唑，化合价互变异构体包括通过一些成键电子重组而进行互变。
“立体异构体”表示具有相同连接而不同空间排列方式原子的分子。比如，含有一个手性中心、具有相同二维连接方式的两个化合物，如R-甘油醛与S-甘油醛、R-丝氨酸与S-丝氨酸。
“对映异构体”表示互为实物与镜像关系，且不可重叠的立体异构体。比如R-丝氨酸与S-丝氨酸。
“非对映异构体”表示分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。比如酒石酸。
“阻转异构体”表示表示分子因为围绕单键的旋转受阻碍而产生的一组构象异构体。比如6,6'-二硝基-2,2'-联苯二甲酸的各个立体异构体。
“光学异构体”表示两个或多个分子具有相同二维连接方式，但由于构型上的差异而表现出不同旋光性能的化合物。比如左旋氨氯地平与右旋氨氯地平。
“外消旋体”表示具有相同二维连接方式但互为光学异构体的化合物，混合在一起最终表现为无旋光性能的物质。比消旋氨氯地平。
术语“氨基酸酰基”指氨基酸的羧基转化为酰基，并通过该酰基连接到被取代物的取代基。示范性实例包换但不限于下述例子：甘氨酸酰基的结构，是把甘氨酸(NH 2-CH 2-COOH)的羧基转化为酰基，获得甘氨酸酰基(NH 2-CH 2-C(＝O)-)。所述氨基酸包括但不限于α-氨基酸、β-氨基酸、γ-氨基酸、ω-氨基酸。所述氨基酸包括但不限于下述示例：甘氨酸、 丙氨酸、缬氨酸、亮氨酸、异亮氨酸、甲硫氨酸(蛋氨酸)、脯氨酸、色氨酸、丝氨酸、酪氨酸、半胱氨酸、苯丙氨酸、天冬酰胺、谷氨酰胺、苏氨酸、天门冬氨酸、谷氨酸、赖氨酸、精氨酸、组氨酸、硒半胱氨酸、吡咯赖氨酸、β-丙氨酸等。
术语“糖基”指单糖或低聚糖通过提供半缩醛羟基的形式形成的取代基。所述单糖包括醛糖和酮糖。所述单糖包括丙糖、丁糖、戊糖、己糖、庚糖。所述低聚糖又名寡糖，指含有2-11个单糖，且各单糖通过糖苷键聚合而成的化合物。所述单糖或多糖的示例如下(但并不限于下列示例)：赤藓糖、苏力糖、***糖、核糖、木糖、来苏糖、葡萄糖、甘露糖、果糖、半乳糖、乳糖、蔗糖、麦芽糖、α-环糊精、β-环糊精、γ-环糊精。
本发明所述药学上可接受的盐可以是阴离子与式(I)化合物上带正电荷的基团形成的盐。合适的阴离子为氯离子、溴离子、碘离子、硫酸根、硝酸根、磷酸根、柠檬酸根、甲基磺酸根、三氟乙酸根、乙酸根、苹果酸根、甲苯磺酸根、酒石酸根、富马酸根、谷氨酸根、葡糖醛酸根、乳酸根、戊二酸根或马来酸根。类似地，可以由阳离子与式(I)化合物上的带负电荷的基团形成盐。合适的阳离子包括钠离子、钾离子、镁离子、钙离子和铵离子，例如四甲基铵离子。
在另一优选例中，“药学上可接受的盐”是指式(I)化合物同选自下组的酸形成的盐类：氢氟酸、盐酸、氢溴酸、磷酸、乙酸、草酸、硫酸、硝酸、甲磺酸、胺基磺酸、水杨酸、三氟甲磺酸、萘磺酸、马来酸、柠檬酸、醋酸、乳酸、酒石酸、琥珀酸、酢浆草酸、丙酮酸、苹果酸、谷氨酸、对甲苯磺酸、萘磺酸、乙磺酸、萘二磺酸、丙二酸、富马酸、丙酸、草酸、三氟乙酸、硬酯酸、扑酸、羟基马来酸、苯乙酸、苯甲酸、谷氨酸、抗坏血酸、对胺基苯磺酸、2-乙酰氧基苯甲酸和羟乙磺酸等；或者式(I)化合物与无机碱形成的钠盐、钾盐、钙盐、铝盐或铵盐；或者通式I化合物与有机碱形成的甲胺盐、乙胺盐或乙醇胺盐。
药物组合物
本发明提供了一种药物组合物，包含药学上可接受的载体和一种或多种治疗有效量的本发明的化合物或其立体异构体、对映异构体、非对映异构体、阻转异构体、光学异构体、外消旋体、互变异构体或其药学上可接受的盐、其前药、其水合物或溶剂合物、其经同位素标记之化合物。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有50-200mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化 剂(如
Figure PCTCN2022142343-appb-000023
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
所述的药物组合物为注射剂、囊剂、片剂、丸剂、散剂或颗粒剂。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的其他化合物(如抗肿瘤药物)联合给药。
本发明治疗方法可以单独施用，或者与其它治疗手段或者治疗药物联用。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选5～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件(如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press，1989)中所述的条件)或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
缩写定义
HATU：N,N,N′,N′-四甲基-O-(7-氮杂苯并***-1-基)六氟磷酸脲
DMF：N,N-二甲基甲酰胺；TEA：三乙胺；DIPEA：二异丙基乙基胺
DMAC：N,N-二甲基乙酰胺；Pd(dppf)Cl 2：[1,1'-双(二苯基膦基)二茂铁]二氯化钯
NBS：N-溴代丁二酰亚胺；NMP：N-甲基吡咯烷酮；Pd(PPh 3) 4：四三苯基膦钯
DPPA：叠氮磷酸二苯酯；4-DMAP：4-二甲氨基吡啶；NaBH 3CN：氰基硼氢化钠
PTSA：对甲基苯磺酸；MeOH：甲醇；EtOH：乙醇；Boc 2O：二叔丁基二碳酸酯
DMSO：二甲基亚砜；Pd(dppf)Cl 2：[1,1'-双(二苯基膦基)二茂铁]二氯化钯
实施例1：
Figure PCTCN2022142343-appb-000024
将30mg的(IM-1)、35mg的(Acid-1)和78mg的N,N,N′,N′-四甲基-O-(7-氮杂苯并***-1-基)六氟磷酸脲(HATU，CAS：148893-10-1)溶于3mL的N,N-二甲基甲酰胺(DMF)中，搅拌下加入50μL二异丙基乙基胺(DIPEA)，而后于室温搅拌12小时。将反应混合物倾入到水中，乙酸乙酯萃取三次，合并乙酸乙酯层，用饱和氯化钠洗涤五次，最后有机相经无水硫酸钠干燥后浓缩，经制备薄层层析纯化得I-1，产量：47mg，产率：92.1％。 1H NMR(400MHz,Chloroform-d)δ11.02(d,J＝7.3Hz,1H),8.80–8.74(m,1H),8.56(dd,J＝4.9,1.7Hz,1H),8.34(s,1H),7.82(dt,J＝7.9,2.0Hz,1H),7.53(dt,J＝5.2,1.9Hz,3H),7.41(d,J＝2.0Hz,1H),7.37(dd,J＝8.2,1.9Hz,1H),7.33–7.28(m,1H),7.27(s,1H),7.25(d,J＝3.3Hz,1H),7.17(d,J＝8.2Hz,1H),6.54(d,J＝0.9Hz,1H),5.14(dt,J＝11.3,7.2Hz,1H), 4.68(dd,J＝9.7,7.3Hz,1H),4.40(dd,J＝11.4,9.7Hz,1H),3.45(s,3H),2.05(s,3H).LC-MS:505.3.[M+H] +
使用相同的合成方法，以不同的氨基化合物和羧基化合物为起始原料，获得以下化合物：
Figure PCTCN2022142343-appb-000025
Figure PCTCN2022142343-appb-000026
Figure PCTCN2022142343-appb-000027
Figure PCTCN2022142343-appb-000028
Figure PCTCN2022142343-appb-000029
Figure PCTCN2022142343-appb-000030
Figure PCTCN2022142343-appb-000031
Figure PCTCN2022142343-appb-000032
Figure PCTCN2022142343-appb-000033
实验例2：化合物分子水平对RIPK1激酶活性的影响
384孔板中，加入2μL酶和1μL不同浓度化合物，同时设置不加激酶和化合物的0％激酶活性对照孔和不加化合物的100％激酶活性对照孔，室温孵育10min。继续加入2μL ATP+底物肽段的混合液(底物终浓度100μg/mL，ATP终浓度10μM)，37℃孵育1h。每孔加入5μL ADP-Glo TMReagent,室温孵育40分钟，去除未反应ATP。每孔加入10μL Kinase Detection Reagent，室温孵育30-60分钟，使反应中生成的ADP转化为ATP。检测荧光信号(luminescence：integration time 0.5s)。通过平均RLU值表示0％激酶活性(无酶和化合物)和100％激酶活性(无化合物)来计算每个孔的抑制率，IC 50值采用GraphPad Prism软件计算求得。
表1：化合物对RIPK1酶抑制活性
编号 IC 50 编号 IC 50
I-1 + II-4 +
II-1 + II-5 +
I-2 + II-6 +
I-5 + II-11 +
I-6 + II-12 +
I-11 + II-13 +
I-12 + II-14 +
II-2 + II-15 +
II-3 + II-16 +
其中，+表示IC 50小于(≤)0.1μM，从表1可以看出，本发明化合物对RIPK1酶具有明显的抑制作用。
实验例3：化合物对I2.1细胞程序性坏死回复作用
测试I2.1细胞株(人源急性T细胞白血病Jurkat细胞的FADD突变体，细胞中FADD蛋白缺失，单独TNFα即可诱导细胞发生程序性坏死)。以CCK-8细胞计数试剂盒(Dojindo)检测。
处于对数生长期的I2.1细胞按合适密度接种至96孔培养板中，培养过夜后，先加入不同浓度的化合物，一小时之后加入20ng/mL的TNFα刺激，并设定不加化合物不加刺激因 子对照孔(阳性对照)和不加化合物加刺激因子对照孔(阴性对照)。待化合物作用细胞24h后，化合物对细胞增殖的影响采用CCK-8细胞计数试剂盒(Dojindo)检测，每孔加入10μL CCK-8试剂，置于37℃培养箱中放置2-4小时后，用全波长式微孔板酶标仪SpectraMax190读数，测定波长为450nm。
采用以下列公式计算化合物对细胞程序性坏死的回复率(％)：
回复率(％)＝(OD给药孔-OD阴性对照孔)/(OD阳性对照孔-OD阴性对照孔)×100％
IC 50值采用GraphPad Prism软件计算求得。
表2：化合物对I2.1细胞死亡的回复率
Figure PCTCN2022142343-appb-000034
其中，“+”表示IC 50小于(≤)1μM；“-”表示IC 50大于(＞)1μM
从上述试验结果可以看出，相对于“对比化合物1”，本发明化合物对于TNFα诱导的Hepa1-6细胞死亡具有明显回复作用。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种通式(I)所示的化合物或其立体异构体、对映异构体、非对映异构体、阻转异构体、光学异构体、外消旋体、互变异构体或其药学上可接受的盐、其前药、其水合物或溶剂合物、其经同位素标记之化合物，
    Figure PCTCN2022142343-appb-100001
    其中，Cy 1选自下组：
    Figure PCTCN2022142343-appb-100002
    R 5在每次出现时独立地选自：H、D、卤素、CD 3、C1-C8烷基、卤代C1-C8烷基、C1-C8烷氧基、卤代C1-C8烷氧基、氰基、氨基、C1-C8烷基取代的氨基、羟基、巯基、C1-C8烷基硫基；
    Cy 2选自被0-5个R 8取代的以下基团：C3-C14环烷基、C6-C14元芳基、6-14元杂芳基、或3-14元杂环基；
    R 4在每次出现时独立地选自：H、D、CH 3、CD 3；
    各虚线独立地表示单键或双键；
    Z 1选自：O、S、N、C＝O、SO、SO 2、NH；
    Z 2选自C(R z2) 2、N、CR z2；
    各R z2独立地为H、卤素、羟基、任选取代的C1-C8烷基，或者两个R z2与它们所连接的碳原子一起形成任选取代的C3-C6碳环或3-6元杂环；
    Z 3、Z 4选自C、CH、N；
    环A为C6-C14元芳环、5元杂芳环、6-14元杂芳环、C3-C14碳环或3-14元杂环；
    m选自1、2、3、4；
    R 1在每次出现时独立地选自H、D、“R 7-C≡C-”、R 1a；较佳地环A上至少有一个R 1为“R 7-C≡C-”的取代基；
    R 1a、R 7在每次出现时独立地为由0-5个R 1a2取代的R 1a1；
    R 1a1、R 1a2可选被0-5个R 1a3取代；
    R 1a3为“-Linker2-R 1a4”；Linker2不存在，或者Linker2选自：键、O、NH、NR 1a4、-C(＝O)O-、-C(＝O)NH-、-C(＝O)NR 1a4-、3-14元环烷基、3-14元杂环基、C6-C14芳基、5-14元杂芳基；
    R 2不存在，或者R 2在Z 4的邻位，且与R 3及它们所连接的原子一起形成任选取代或未取代的的5-6元杂环；
    R 3选自：H、D、CH 3、CD 3；
    Y为O、S、NR y，其中R y和R 3与它们所连接的原子一起形成任选取代的5-6元杂环或5-6元杂芳环；
    R 6选自：CD 3、C1-C8烷基、卤代C1-C8烷基、C6-C14芳基；
    R 8在每次出现时独立地选自：H、D、卤素、CD 3、C1-C8烷基、卤代C1-C8烷基、C1-C8烷氧基、卤代C1-C8烷氧基、氰基、氨基、C1-C8烷基取代的氨基、羟基、巯基、C1-C8烷基硫基、卤代C1-C8烷基硫基、-C(＝O)NH2、-C(＝O)NH(C1-C8烷基)、-C(＝O)-(C1-C8烷基)、氧代、硫代；
    R 1a1、R 1a2在每次出现独立地选自下组：H、D、卤素、C1-C8烷基、卤代C1-C8烷基、C1-C8烷氧基、卤代的C1-C8烷氧基、C1-C6烷氧基取代的C1-C6烷氧基、C2-C8烯基、卤代C2-C8烯基、C2-C8烯基氧基、卤代C2-C8烯基氧基、C2-C8炔基、卤代C2-C8炔基、C2-C8炔基氧基、卤代C2-C8炔基氧基、C3-C14环烷基、(C3-C14环烷基)-(C1-C8烷基)-、(C3-C14环烷基)氧基、(C3-C14环烷基)-(C1-C8烷基)氧基、(C3-C14环烷基)氧基(C1-C8烷基)-、(C3-C14环烷基)硫基、(C3-C14环烷基)-(C1-C8烷基)硫基、(C3-C14环烷基)硫基(C1-C8烷基)-、(C3-C14环烷基)NH-、(C3-C14环烷基)-(C1-C8烷基)-NH-、(C3-C14环烷基)-NH-(C1-C8烷基)-、(C3-C14环烷基)-C(＝O)-、(C3-C14环烷基)-(C1-C8烷基)-C(＝O)-、(C3-C14环烷基)C(＝O)-(C1-C8烷基)-、(C3-C14环烷基)-C(＝O)O-、(C3-C14环烷基)-(C1-C8烷基)-C(＝O)O-、(C3-C14环烷基)-C(＝O)O-(C1-C8烷基)-、(C3-C14环烷基)-OC(＝O)-、(C3-C14环烷基)-(C1-C8烷基)-OC(＝O)-、(C3-C14环烷基)-OC(＝O)-(C1-C8烷基)-、(C3-C14环烷基)-C(＝O)NH-、(C3-C14环烷基)-(C1-C8烷基)-C(＝O)NH-、(C3-C14环烷基)-C(＝O)NH-(C1-C8烷基)-、(C3-C14环烷基)-NHC(＝O)-、(C3-C14环烷基)-(C1-C8烷基)-NHC(＝O)-、(C3-C14环烷基)-(C1-C8烷基)-NHC(＝O)-、(C1-C8烷基)-(C3-C14环烷基)-、羟基(C3-C14环烷基)-、(C1-C8烷氧基)-(C3-C14环烷基)-、羟基(C1-C8烷基)-(C3-C14环烷基)-、巯基(C3-C14环烷基)、(C1-C8烷硫基)-(C3-C14环烷基)-、巯基(C1-C8烷基)-(C3-C14环烷基)-、氨基(C3-C14环烷基)、(C1-C8烷基)NH-(C3-C14环烷基)-、氨基(C1-C8烷基)-(C3-C14环烷基)-、HC(＝O)-(C3-C14环烷基)-、(C1-C8烷基)-C(＝O)-(C3-C14环烷基)-、HC(＝O)-(C1-C8烷基)-(C3-C14环烷基)-、 HC(＝O)O-(C3-C14环烷基)-、(C1-C8烷基)-C(＝O)O-(C3-C14环烷基)-、HC(＝O)O-(C1-C8烷基)-(C3-C14环烷基)-、HOC(＝O)-(C3-C14环烷基)-、(C1-C8烷基)-O-C(＝O)-(C3-C14环烷基)-、HO-C(＝O)-(C1-C8烷基)-(C3-C14环烷基)-、HC(＝O)NH-(C3-C14环烷基)-、(C1-C8烷基)C(＝O)NH-(C3-C14环烷基)-、HC(＝O)NH-(C1-C8烷基)-(C3-C14环烷基)-、NH 2C(＝O)-(C3-C14环烷基)-、(C1-C8烷基)NHC(＝O)-(C3-C14环烷基)-、NH 2C(＝O)-(C1-C8烷基)-(C3-C14环烷基)-、(C1-C8烷基)-(C3-C14环烷基)-(C1-C8烷基)-、3-14元杂环基、(3-14元杂环基)-(C1-C8烷基)-、(3-14元杂环基)氧基、(3-14元杂环基)-(C1-C8烷基)-氧基、(3-14元杂环基)氧基-(C1-C8烷基)-、(3-14元杂环基)硫基、(3-14元杂环基)-(C1-C8烷基)-硫基、(3-14元杂环基)硫基-(C1-C8烷基)-、(3-14元杂环基)NH-、(3-14元杂环基)(C1-C8烷基)NH-、(3-14元杂环基)-NH-(C1-C8烷基)-、(3-14元杂环基)-C(＝O)-、(3-14元杂环基)-(C1-C8烷基)-C(＝O)-、(3-14元杂环基)-C(＝O)-(C1-C8烷基)-、(3-14元杂环基)-C(＝O)O-、(3-14元杂环基)-(C1-C8烷基)-C(＝O)O-、(3-14元杂环基)-C(＝O)O-(C1-C8烷基)-、(3-14元杂环基)-OC(＝O)-、(3-14元杂环基)-(C1-C8烷基)-OC(＝O)-、(3-14元杂环基)-OC(＝O)-(C1-C8烷基)-、(3-14元杂环基)-C(＝O)NH-、(3-14元杂环基)-(C1-C8烷基)-C(＝O)NH-、(3-14元杂环基)-C(＝O)NH-(C1-C8烷基)-、(3-14元杂环基)-NHC(＝O)-、(3-14元杂环基)-(C1-C8烷基)-NHC(＝O)-、(3-14元杂环基)-NHC(＝O)-(C1-C8烷基)-、(C1-C8烷基)-(3-14元杂环基)-、羟基(3-14元杂环基)-、(C1-C8烷氧基)-(3-14元杂环基)-、羟基(C1-C8烷基)-(3-14元杂环基)-、巯基(C3-C14环烷基)、(C1-C8烷硫基)-(3-14元杂环基)-、巯基(C1-C8烷基)-(3-14元杂环基)-、氨基(3-14元杂环基)、(C1-C8烷基)NH-(3-14元杂环基)-、氨基(C1-C8烷基)-(3-14元杂环基)-、HC(＝O)-(3-14元杂环基)-、(C1-C8烷基)-C(＝O)-(3-14元杂环基)-、HC(＝O)-(C1-C8烷基)-(3-14元杂环基)-、HC(＝O)O-(3-14元杂环基)-、(C1-C8烷基)-C(＝O)O-(3-14元杂环基)-、HC(＝O)O-(C1-C8烷基)-(3-14元杂环基)-、HOC(＝O)-(3-14元杂环基)-、(C1-C8烷基)-O-C(＝O)-(3-14元杂环基)-、HO-C(＝O)-(C1-C8烷基)-(3-14元杂环基)-、HC(＝O)NH-(3-14元杂环基)-、(C1-C8烷基)C(＝O)NH-(3-14元杂环基)-、HC(＝O)NH-(C1-C8烷基)-(3-14元杂环基)-、NH 2C(＝O)-(3-14元杂环基)-、(C1-C8烷基)NHC(＝O)-(3-14元杂环基)-、NH 2C(＝O)-(C1-C8烷基)-(3-14元杂环基)-、(C1-C8烷基)-(3-14元杂环基)-(C1-C8烷基)-、C6-C14芳基、(C6-C14芳基)-(C1-C8烷基)-、(C6-C14芳基)氧基、(C6-C14芳基)-(C1-C8烷基)氧基、(C6-C14芳基)氧基(C1-C8烷基)-、(C6-C14芳基)硫基、(C6-C14芳基)-(C1-C8烷基)硫基、(C6-C14芳基)硫基(C1-C8烷基)-、(C6-C14芳基)NH-、(C6-C14芳基)-(C1-C8烷基)-NH-、(C6-C14芳基)-NH-(C1-C8烷基)-、(C6-C14芳基)-C(＝O)-、(C6-C14芳基)-(C1-C8烷基)-C(＝O)-、(C6-C14芳基)C(＝O)-(C1-C8烷基)-、(C6-C14芳基)-C(＝O)O-、(C6-C14芳基)-(C1-C8烷基)-C(＝O)O-、(C6-C14芳基)-C(＝O)O-(C1-C8烷基)-、(C6-C14芳基)-OC(＝O)-、(C6-C14芳基)-(C1-C8烷基)-OC(＝O)-、(C6-C14芳基)-OC(＝O)-(C1-C8烷基)-、(C6-C14芳基)-C(＝O)NH-、(C6-C14芳基)-(C1-C8烷基)-C(＝O)NH-、(C6-C14芳基)-C(＝O)NH-(C1-C8烷基)-、(C6-C14芳基)-NHC(＝O)-、(C6-C14芳基)-(C1-C8烷基)-NHC(＝O)-、(C6-C14芳基)-(C1-C8烷基)-NHC(＝O)-、(C1-C8烷基)-(C6-C14芳基)-、羟基(C6-C14芳基)-、(C1-C8烷氧基)-(C6-C14芳基)-、羟基(C1-C8烷基)-(C6-C14芳基)-、巯基(C3-C14环烷基)、(C1-C8烷硫基)-(C6-C14 芳基)-、巯基(C1-C8烷基)-(C6-C14芳基)-、氨基(C6-C14芳基)、(C1-C8烷基)NH-(C6-C14芳基)-、氨基(C1-C8烷基)-(C6-C14芳基)-、HC(＝O)-(C6-C14芳基)-、(C1-C8烷基)-C(＝O)-(C6-C14芳基)-、HC(＝O)-(C1-C8烷基)-(C6-C14芳基)-、HC(＝O)O-(C6-C14芳基)-、(C1-C8烷基)-C(＝O)O-(C6-C14芳基)-、HC(＝O)O-(C1-C8烷基)-(C6-C14芳基)-、HOC(＝O)-(C6-C14芳基)-、(C1-C8烷基)-O-C(＝O)-(C6-C14芳基)-、HO-C(＝O)-(C1-C8烷基)-(C6-C14芳基)-、HC(＝O)NH-(C6-C14芳基)-、(C1-C8烷基)C(＝O)NH-(C6-C14芳基)-、HC(＝O)NH-(C1-C8烷基)-(C6-C14芳基)-、NH 2C(＝O)-(C6-C14芳基)-、(C1-C8烷基)NHC(＝O)-(C6-C14芳基)-、NH 2C(＝O)-(C1-C8烷基)-(C6-C14芳基)-、(C1-C8烷基)-(C6-C14芳基)-(C1-C8烷基)-、5-14元杂芳基、(5-14元杂芳基)-(C1-C8烷基)-、(5-14元杂芳基)氧基、(5-14元杂芳基)-(C1-C8烷基)氧基、(5-14元杂芳基)氧基(C1-C8烷基)-、(5-14元杂芳基)硫基、(5-14元杂芳基)-(C1-C8烷基)硫基、(5-14元杂芳基)硫基(C1-C8烷基)-、(5-14元杂芳基)NH-、(5-14元杂芳基)-(C1-C8烷基)-NH-、(5-14元杂芳基)-NH-(C1-C8烷基)-、(5-14元杂芳基)-C(＝O)-、(5-14元杂芳基)-(C1-C8烷基)-C(＝O)-、(5-14元杂芳基)C(＝O)-(C1-C8烷基)-、(5-14元杂芳基)-C(＝O)O-、(5-14元杂芳基)-(C1-C8烷基)-C(＝O)O-、(5-14元杂芳基)-C(＝O)O-(C1-C8烷基)-、(5-14元杂芳基)-OC(＝O)-、(5-14元杂芳基)-(C1-C8烷基)-OC(＝O)-、(5-14元杂芳基)-OC(＝O)-(C1-C8烷基)-、(5-14元杂芳基)-C(＝O)NH-、(5-14元杂芳基)-(C1-C8烷基)-C(＝O)NH-、(5-14元杂芳基)-C(＝O)NH-(C1-C8烷基)-、(5-14元杂芳基)-NHC(＝O)-、(5-14元杂芳基)-(C1-C8烷基)-NHC(＝O)-、(5-14元杂芳基)-(C1-C8烷基)-NHC(＝O)-、(C1-C8烷基)-(5-14元杂芳基)-、羟基(5-14元杂芳基)-、(C1-C8烷氧基)-(5-14元杂芳基)-、羟基(C1-C8烷基)-(5-14元杂芳基)-、巯基(C3-C14环烷基)、(C1-C8烷硫基)-(5-14元杂芳基)-、巯基(C1-C8烷基)-(5-14元杂芳基)-、氨基(5-14元杂芳基)、(C1-C8烷基)NH-(5-14元杂芳基)-、氨基(C1-C8烷基)-(5-14元杂芳基)-、HC(＝O)-(5-14元杂芳基)-、(C1-C8烷基)-C(＝O)-(5-14元杂芳基)-、HC(＝O)-(C1-C8烷基)-(5-14元杂芳基)-、HC(＝O)O-(5-14元杂芳基)-、(C1-C8烷基)-C(＝O)O-(5-14元杂芳基)-、HC(＝O)O-(C1-C8烷基)-(5-14元杂芳基)-、HOC(＝O)-(5-14元杂芳基)-、(C1-C8烷基)-O-C(＝O)-(5-14元杂芳基)-、HO-C(＝O)-(C1-C8烷基)-(5-14元杂芳基)-、HC(＝O)NH-(5-14元杂芳基)-、(C1-C8烷基)C(＝O)NH-(5-14元杂芳基)-、HC(＝O)NH-(C1-C8烷基)-(5-14元杂芳基)-、NH 2C(＝O)-(5-14元杂芳基)-、(C1-C8烷基)NHC(＝O)-(5-14元杂芳基)-、NH 2C(＝O)-(C1-C8烷基)-(5-14元杂芳基)-、(C1-C8烷基)-(5-14元杂芳基)-(C1-C8烷基)-、羟基、羟基取代的C1-C8烷基、巯基、巯基取代的C1-C8烷基、氨基、氨基取代的C1-C8烷基、-NH(C1-C8烷基)、-N(C1-C8烷基)(C1-C8烷基)、氰基、氰基取代的C1-C8烷基、-COOH、-(C1-C8烷基)-COOH、-C(＝O)O-(C1-C8烷基)、-(C1-C8烷基)-C(＝O)O-(C1-C8烷基)、-OC(＝O)H、-(C1-C8烷基)-OC(＝O)H、-OC(＝O)-(C1-C8烷基)、-(C1-C8烷基)-OC(＝O)-(C1-C8烷基)、-C(O)H、-(C1-C8烷基)-C(＝O)H、-C(＝O)-(C1-C8烷基)、-(C1-C8烷基)-C(＝O)-(C1-C8烷基)、NH 2C(＝O)-、一个或二个C1-C8烷基取代的NH 2C(O)-、一个或二个C1-C8环烷基取代的NH 2C(O)-、一个或二个C6-C14芳基取代的NH 2C(O)-、一个或二个5-14元杂芳基取代的NH 2C(O)-、一个或二个4-10元杂环基取代的NH 2C(O)-、NH 2C(＝O)-(C1-C8烷基)-、一个或二个C1-C8烷基取代的NH 2C(O)-(C1-C8烷基)-、一个或二 个C1-C8环烷基取代的NH 2C(O)-(C1-C8烷基)-、一个或二个C6-C14芳基取代的NH 2C(O)-(C1-C8烷基)-、一个或二个5-14元杂芳基取代的NH 2C(O)-(C1-C8烷基)-、一个或二个4-10元杂环基取代的NH 2C(O)-(C1-C8烷基)-、氧代(＝O)、硫代(＝S)；
    R 1a4在每次出现时独立地选自下组：H、D、卤素、羟基、C1-C8烷基、卤代C1-C8烷基、C2-C8烯基、卤代C2-C8烯基、C2-C8炔基、卤代C2-C8炔基、(C1-C15烷基)-OC(＝O)-、(C6-C14芳基)-OC(＝O)-、(4-12元杂环基)-OC(＝O)-、(5-14元杂芳基)-OC(＝O)-、(C1-C15烷基)-C(＝O)-、(C6-C14芳基)-C(＝O)-、(4-12元杂环基)-C(＝O)-、(5-14元杂芳基)-C(＝O)-、(C1-C15烷基)-C(＝O)O-、(C6-C14芳基)-C(＝O)O-、(4-12元杂环基)-C(＝O)O-、(5-14元杂芳基)-C(＝O)O-、(卤代C1-C15烷基)-OC(＝O)-、(卤代C6-C14芳基)-OC(＝O)-、(卤代4-12元杂环基)-OC(＝O)-、(卤代5-14元杂芳基)-OC(＝O)-、(卤代C1-C15烷基)-C(＝O)-、(卤代C6-C14芳基)-C(＝O)-、(卤代4-12元杂环基)-C(＝O)-、(卤代5-14元杂芳基)-C(＝O)-、(卤代C1-C15烷基)-C(＝O)O-、(卤代C6-C14芳基)-C(＝O)O-、(卤代4-12元杂环基)-C(＝O)O-、(卤代5-14元杂芳基)-C(＝O)O-、C1-C8烷基取代的(C1-C15烷基)-OC(＝O)-、C1-C8烷基取代的(C6-C14芳基)-OC(＝O)-、C1-C8烷基取代的(4-12元杂环基)-OC(＝O)-、C1-C8烷基取代的(5-14元杂芳基)-OC(＝O)-、C1-C8烷基取代的(C1-C15烷基)-C(＝O)-、C1-C8烷基取代的(C6-C14芳基)-C(＝O)-、C1-C8烷基取代的(4-12元杂环基)-C(＝O)-、C1-C8烷基取代的(5-14元杂芳基)-C(＝O)-、C1-C8烷基取代的(C1-C15烷基)-C(＝O)O-、C1-C8烷基取代的(C6-C14芳基)-C(＝O)O-、C1-C8烷基取代的(4-12元杂环基)-C(＝O)O-、C1-C8烷基取代的(5-14元杂芳基)-C(＝O)O-、(C1-C8烷基) 3-Si-(C1-C8烷基)-O-(C1-C8亚烷基)-、被卤素取代或未取代的(C1-C8烷基)-OC(＝O)-(C1-C8烷基)C(＝O)O-、被卤素取代或未取代的(C1-C8烷基)-OC(＝O)-(C3-C14环烷基)C(＝O)O-、糖基、-O-P(＝O)(O-卤代或未卤代的C6-C14芳基)(NH-(C1-C8烷基)C(＝O)O(C1-C8烷基))、-O-P(＝O)(O-卤代或未卤代的C6-C14芳基)(O-(C1-C8烷基)C(＝O)O(C1-C8烷基))、-O-P(＝O)(O-卤代或未卤代的C6-C14芳基)(NH-(C1-C8烷基)OC(＝O)(C1-C8烷基))、-O-P(＝O)(O-卤代或未卤代的C6-C14芳基)(O-(C1-C8烷基)OC(＝O)(C1-C8烷基))、-O-P(＝O)(O-卤代或未卤代的C6-C14芳基)(NH-(C1-C8烷基)-S-C(＝O)(C1-C8烷基))、-O-P(＝O)(O-卤代或未卤代的C6-C14芳基)(O-(C1-C8烷基)-S-C(＝O)(C1-C8烷基))、-O-P(＝O)(ONa) 2、-O-P(＝O)(OK) 2、-O-P(＝O)(OLi) 2、-O-(卤代或未卤代的C1-C8烷基)-P(＝O)(O-C1-C8烷基) 2、(C1-C8烷基)-C(＝O)-CH＝CH-、氨基酸酰基、C1-C16烷基、卤代C1-C16烷基、C6-C14芳基、卤代C6-C14芳基。
  2. 根据权利要求1所述的化合物或其立体异构体、对映异构体、非对映异构体、阻转异构体、光学异构体、外消旋体、多晶型物、互变异构体或其可药用的盐、其前药、其水合物或溶剂合物、其经同位素标记之化合物，其特征在于，所述化合物选自式(IV-1)、(IV-2)、(IV-4)、(IV-5)、(IV-6)、(IV-7)、(IV-9)：
    Figure PCTCN2022142343-appb-100003
    其中，Cy 3选自式(III-1)至(III-14)：
    Figure PCTCN2022142343-appb-100004
    Z 5选自C-R 1或N；R 1、m、Z 1、R 3、Cy 2、R 5、R 6的定义同权利要求1；
    较佳地，Z 5选自CH或N；m为1时，R 1为R 7-C≡C-；R 7的定义同权利要求1。
  3. 根据权利要求1所述的化合物或其立体异构体、对映异构体、非对映异构体、阻转异构体、光学异构体、外消旋体、多晶型物、互变异构体或其可药用的盐、其前药、其水合物或溶剂合物、其经同位素标记之化合物，其特征在于，所述化合物选自式(V-1)、(V-2)、(V-3)、(V-4)：
    Figure PCTCN2022142343-appb-100005
    其中，Z 5选自C-R 1或N；R 1a1、R 1、R 3、Z 1、Cy 1、Cy 2、R 5的定义同权利要求1；
    较佳地，所述化合物选自：
    Figure PCTCN2022142343-appb-100006
    式中，Z 5选自CH或N；R 1为C1-C8烷基；R 1a1、R 3、Z 1、Cy 2、R 5的定义同权利要求1。
  4. 根据权利要求1所述的化合物或其立体异构体、对映异构体、非对映异构体、阻转异构体、光学异构体、外消旋体、多晶型物、互变异构体或其可药用的盐、其前药、其水合物或溶剂合物、其经同位素标记之化合物，其特征在于，R 1在每次出现时独立选自下组：H、D、甲基、
    Figure PCTCN2022142343-appb-100007
    Figure PCTCN2022142343-appb-100008
  5. 根据权利要求1所述的化合物或其立体异构体、对映异构体、非对映异构体、阻转异构体、光学异构体、外消旋体、多晶型物、互变异构体或其可药用的盐、其前药、其水合物或溶剂合物、其经同位素标记之化合物，其特征在于，所述化合物为：
    Figure PCTCN2022142343-appb-100009
    Figure PCTCN2022142343-appb-100010
    Figure PCTCN2022142343-appb-100011
  6. 一种制备权利要求1所述式(I)所示化合物的方法，其特征在于，化合物的合成步骤至少包括反应式1、反应式2之一所述反应式：
    Figure PCTCN2022142343-appb-100012
    其中,
    G 2选自：-OH，卤素，C1-C8烷氧基，C6-C14芳基氧基，-OC(＝O)-(C1-C8烷氧基)，-OS(＝O)-(C1-C8烷氧基)，-OS(＝O) 2-(C1-C8烷氧基)，-OC(＝O)-(C6-C14芳基氧基)，-OS(＝O)-(C6-C14芳基氧基)，-OS(＝O) 2-(C6-C14芳基氧基)；
    R 4、R 1、m、R 2、R 3、Y、Z 1、Z 2、Z 3、Z 4、虚线、Cy 1的定义同权利要求1。
  7. 一种药物组合物，其特征在于，包含：药学上可接受的载体和一种或多种权利要求1-5中任意一项所述的化合物或其立体异构体、对映异构体、非对映异构体、阻转异构体、光学异构体、外消旋体、互变异构体或其药学上可接受的盐、其前药、其水合物或溶剂合物、其经同位素标记之化合物。
  8. 一种受体相互作用蛋白激酶1(RIPK1)抑制剂，其特征在于，包含一种或多种权利要求1-5中任意一项所述的化合物或其立体异构体、几何异构体、互变异构体、其药学上可接受的盐、其前药、其水合物或溶剂合物，或根据权利要求7所述的药物组合物。
  9. 一种权利要求1-5中任一项所述化合物或其立体异构体、对映异构体、非对映异构体、阻转异构体、光学异构体、外消旋体、互变异构体或其药学上可接受的盐、其前药、其水合物或溶剂合物、其经同位素标记之化合物或根据权利要求7所述的药物组合物的用途，其特征在于，用于制备药物，所述药物用于：
    1)检测和/或预防和/或治疗激酶相关疾病；
    2)检测和/或预防和/或治疗免疫、炎症和/或感染相关疾病；
    3)检测和/或预防和/或治疗缺血和/或再灌注损伤相关疾病；
    4)检测和/或预防和/或治疗退行性疾病；
    5)检测和/或预防和/或***相关疾病；
    6)检测和/或预防和/或治疗细胞坏死相关疾病；
    7)检测和/或预防和/或治疗代谢相关疾病；或者
    8)检测和/或预防和/或治疗眼部疾病。
  10. 一种权利要求1-5中任一项所述化合物或其立体异构体、对映异构体、非对映异构体、阻转异构体、光学异构体、外消旋体、互变异构体或其药学上可接受的盐、其前药、其水合物或溶剂合物、其经同位素标记之化合物或根据权利要求7所述的药物组合物的用途，其特征在于，用于制备检测和/或预防和/或治疗选自下组的疾病的药物：
    全身型幼年特发性关节炎，***，白细胞介素-1转化酶相关性发热综合征，败血症，斑秃，变应性疾病，过敏性疾病，乙型肝炎，丙型肝炎，多发性硬化，肺结节病，肺纤维化，肺炎，分枝杆菌感染，腹腔疾病，干燥综合征，骨关节炎，化脓性汗腺炎，坏死性小肠结肠炎，急性胰腺炎，脊柱关节炎，结肠炎，局限性回肠炎，抗磷脂综合征，克罗恩病，溃疡性肠炎，类风湿性关节炎，细菌感染，流感，慢性阻塞性肺病，病毒感染，脓毒症，皮炎，葡萄球菌感染，自身免疫疾病，全身性红斑狼疮，全身性炎症反应综合征，全身性硬皮病，朊病毒症，肾上腺皮质变性，肾炎，史-约综合征，手术感染，特应性皮炎，韦格纳肉芽肿，***性红斑狼疮，哮喘，新冠肺炎，血管炎，牙周炎，炎性肠病，胰腺炎，移植器官排除，银屑病，原发性硬化性胆管炎，肿瘤坏死因子受体相关周期性发热综合征，白细胞介素-1转换酶相关的发热综合征，自身免疫特发性血小板减少性紫癜，Fahr病，GM1神经节苷脂贮积病，GM2神经节苷脂贮积病，艾滋病相关痴呆综合征，Tau蛋白病，阿尔茨海默病，帕金森病，路易体痴呆，多***萎缩症，多重硬化，额颞叶痴呆，法伯病，弗里德赖希共济失调症，格林巴利综合征，亨廷顿病，原发性侧索硬化，肌萎缩性侧索硬化，脊髓性肌萎缩，假性延髓麻痹，进行性延髓麻痹，结节状硬化症，进行性核上性麻痹，进行性肌萎缩，精神***症，脱髓鞘病，慢性炎症性脱髓鞘性多发性神经病，尼曼匹克病，皮质基底节变性，溶酶体贮积病，桑德霍夫病，神经节细胞病，神经元蜡样脂褐质沉积症，术后认知障碍，双相障碍，糖尿病性神经病，疼痛(神经疼痛)，谵妄，抑郁症，周围神经病变，自闭症，创伤，创伤性脑损伤，局部缺血，创伤性视网膜损伤，脑血管意外，脑卒中，地理性萎缩，对乙酰胺基酚中毒，急性肝衰竭，急性肾损伤，急性呼吸窘迫综合征，颅内出血，脑出血，脑缺血，缺血，缺血性损伤，缺氧性脑损伤，缺氧，烧伤，烧伤性休克，实体器官的缺血再灌注损伤，顺铂诱导的肾损伤，吸烟诱导的损伤，心肌梗塞，心力衰竭，中毒性表皮坏死松解症，急性肾小管坏死，心脏衰竭，NF-κB关键调节基因突变，白血病，髓细胞白血病，淋巴细胞白血病，T细胞白血病，淋巴瘤，T细胞淋巴瘤，鼻咽癌，表皮样癌，垂体腺瘤，胆道癌肉瘤，胆管癌，多发性骨髓瘤，儿童实体瘤，霍奇金病，非霍奇金淋巴瘤，非小细胞肺癌，小细胞肺癌，***区域癌，睾丸癌，***，子宫癌，子宫内膜癌，卵巢癌，骨癌，骨肉瘤，黑色素瘤，环境诱发的癌症，脊柱肿瘤，甲状腺癌，甲状旁腺癌，胶质母细胞瘤，结肠直肠癌，卡波西氏肉瘤，鳞状上皮细胞癌，脑胶质瘤，内分泌***癌症，尿道癌，膀胱癌，皮肤癌，皮肤或眼内恶性黑色素瘤，***癌，三阴性乳腺癌，神经胶质瘤，肾或输尿管癌，肾盂癌，肾上腺癌，实体器官恶性肿瘤，食道癌，输卵管癌，头和/或颈癌，外阴癌，胃癌，胃肠间质瘤，小肠癌，血液恶性肿瘤，胰腺癌，遗传性大动脉瘤，***癌，***癌，直肠癌，肿瘤血管生成，黄斑病 变，黄斑裂孔，黄斑毛细管扩张，干眼症，进行性视网膜萎缩，莱伯氏先天性黑蒙，囊性黄斑水肿，年龄相关性黄斑变性，青光眼，视网膜神经变性，缺血性视神经病变，缺血性视网膜疾病，糖尿病性视网膜病变，色素性视网膜炎，视网膜感光器疾病，视网膜退行性疾病，视神经疾病，视网膜脱离，医源性视网膜损伤，视网膜血管疾病，视锥视杆营养不良，无脉络膜症，眼底疾病，眼血管疾病，尤塞氏综合症，I型糖尿病，非酒精性脂肪肝，白癜风，唾液酸苷贮积症，肠易激综合征，达农病，胆固醇酯贮积症，沃尔曼病，低脂血症，动脉粥样硬化，多种硫酸酯酶缺乏症，法布里病，戈谢病，骨髓纤维化，骨质疏松症，胱氨酸贮积症，肌营养不良，多聚谷氨酰胺疾病，克拉伯病，慢性肾病，门克斯病，囊性纤维化病，庞皮病，泰伊-萨克斯二氏病，溶酶体酸脂酶缺乏，天冬氨酰葡萄糖胺尿症，痛风，威尔逊氏病，线粒体病症，岩藻糖苷贮积症，异染性脑白质营养不良，浴酶体酸脂酶缺乏，粘多糖累积病，粘脂质累积，致密性成骨不全症，血色病，Niemann-Pick病，Heme-氧化的IRP2泛素连接酶-1缺乏，骨坏死，链状泛素链组装复合物缺乏综合征，纤毛病等。
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