WO2023109918A1 - 含氮杂环化合物、其制备方法及其用途 - Google Patents

含氮杂环化合物、其制备方法及其用途 Download PDF

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WO2023109918A1
WO2023109918A1 PCT/CN2022/139380 CN2022139380W WO2023109918A1 WO 2023109918 A1 WO2023109918 A1 WO 2023109918A1 CN 2022139380 W CN2022139380 W CN 2022139380W WO 2023109918 A1 WO2023109918 A1 WO 2023109918A1
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alkyl
aryl
membered
cycloalkyl
membered heteroaryl
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PCT/CN2022/139380
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English (en)
French (fr)
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段文虎
耿美玉
张贺峰
艾菁
兰垚瀚
彭霞
方晨
季寅淳
金泽宸
冯大智
丁健
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中国科学院上海药物研究所
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Publication of WO2023109918A1 publication Critical patent/WO2023109918A1/zh

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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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Definitions

  • the present invention relates to nitrogen-containing heterocyclic compounds, their preparation methods, pharmaceutical compositions containing the series of compounds and their use as therapeutic agents, especially for the treatment of inflammatory diseases, degenerative diseases, ischemic diseases, tumors, etc. and related diseases and disease use.
  • 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 natural protein kinases. Partyyl/glutamyl protein kinase.
  • 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 enzyme that can catalyze the transfer of adenosine triphosphate to protein tyrosine residues of proteases.
  • 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 for short, and RIPK3 are two types of serine/threonine kinases homologous, and they 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.
  • psoriasis retinitis pigmentosa
  • inflammatory bowel disease autoimmune disease
  • bombesin-induced Acute pancreatitis and sepsis/systemic inflammatory response syndrome have protective effects; can effectively alleviate ischemic brain injury, ischemic myocardial injury, retinal ischemia/reperfusion injury, retinal detachment-induced photoreceptor cell necrosis, glaucoma, renal Ischemia-reperfusion injury, cisplatin-induced renal injury, and traumatic brain injury: at least partial mitigation of other diseases associated with RIPK1-dependent apoptosis, necrosis, or cytokine production, including hematologic and solid organ malignancies, bacterial infections And viral infections (including tuberculosis, influenza, etc.) and lysosomal storage diseases (especially Gaucher disease).
  • kinase inhibitors especially RIPK1 kinase inhibitors
  • the existing inhibitors targeting necroptosis-related kinases have defects in varying degrees, such as poor selectivity, unsatisfactory in vivo inhibitory activity, poor pharmacokinetic properties, low oral bioavailability, etc., and some These shortcomings limit its further research and clinical application.
  • the present invention provides a compound represented by general formula (I), which can be used as a kinase inhibitor for detection, prevention and treatment of kinase-related diseases or disorders, especially RIPK1 kinase-related diseases or disorders; the present invention also provides general The preparation method of the compound represented by formula (I).
  • 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, isotope-labeled compounds thereof,
  • Ring A is a 6-membered heteroaromatic ring
  • Ring E is a benzene ring or a 6-membered heteroaromatic ring
  • Ring G is a 5-6-membered heteroaromatic ring or a 5-6-membered heteroaryl ring
  • Z is selected from CH 2 , CH 2 substituted by one or two halogens, CDH, CD 2 , O, S, NH, N(CH 3 ), N(CD 3 );
  • Y3 is N or CR 3a ; wherein, R 3a is selected from the group consisting of H, D, halogen, C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkyl, halogenated C1-C8 alkoxy Base, 5-14 membered heteroaryl, C3-C14 cycloalkyl, C6-C14 aryl, 3-14 membered heterocyclyl, NH 2 CO-, C2-C8 alkenyl, halogenated C2-C8 alkenyl , C2-C8 alkenyloxy, halogenated C2-C8 alkenyloxy, C2-C8 alkynyl, halogenated C2-C8 alkynyl, C2-C8 alkynyloxy, halogenated C2-C8 alkyne Oxygen, hydroxyl, hydroxyl substituted C1-C8 alkyl, mercapto, mercapto substituted C1
  • R 3a1 can form a 4-15 or 3-18 membered ring structure together with their respective connected atoms;
  • R 3a2 can form a 4-15 or 3-18 membered ring structure together with their respective atoms;
  • Y4 is N or CR 4a ;
  • R 2a , R 3a together with their respective carbons form a 3-18 membered ring structure substituted or unsubstituted by 0 to 5 (0, 1, 2, 3, 4 or 5) R b1 ;
  • R 4a , R 3a together with the carbons to which they are attached form a 3-18-membered ring structure substituted or unsubstituted by 0 to 5 (0, 1, 2, 3, 4 or 5) R b2 ,
  • Each R b1 , each R b2 is independently selected from each occurrence: H, D, halogen, oxo, thio, C1-C8 alkyl, hydroxy C1-C8 alkyl, C1-C8 alkoxy, C3 -C14 cycloalkyl, halogenated C1-C8 alkyl, halogenated hydroxy C1-C6 alkyl, halogenated C1-C8 alkoxy, halogenated C3-C14 cycloalkyl, 3-14 membered heterocyclic group, C6-C14 aryl, 5-14 membered heteroaryl, C2-C8 alkenyl, halogenated C2-C8 alkenyl, C2-C8 alkenyloxy, halogenated C2-C8 alkenyloxy, C2- C8 alkynyl, halogenated C2-C8 alkynyl, C2-C8 alkynyloxy, halogenated C2-C8 al
  • V1, V2, V3 are each independently selected from N, CR c ;
  • R c is selected from the following group: H, D, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C3-C6 cycloalkyl;
  • V4 and V5 are each independently C or N;
  • Each bond represented by a dotted line is independently selected from the group consisting of single bond, double bond;
  • n is independently selected from 1, 2, 3, 4 at each occurrence;
  • n each occurrence is independently selected from 0, 1, 2, 3;
  • U is the following groups substituted or unsubstituted by 1 to 5 R i : C5-C14 membered aryl, 5-14 membered heteroaryl, C3-C14 cycloalkyl, 3-14 membered heterocyclic group; R i at each occurrence is independently selected from: halogenated C1-C8 alkyl, C1-C8 alkyl, halogen, C6-C14 aryl, benzo 5-14 membered heteroaryl, halogenated C1-C8 alkane Oxygen, H, D, C2-C8 alkenyl, halogenated C2-C8 alkenyl, C2-C8 alkenyloxy, halogenated C2-C8 alkenyloxy, C2-C8 alkynyl, halogenated C2-C8 Alkynyl, C2-C8 alkynyloxy, halogenated C2-C8 alkynyloxy, C3-C14 cycloalkyl, 3-14
  • Each R i1 at each occurrence is independently selected from: 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 alkynyl, C2-C8 alkynyloxy, halogenated C2-C8 alkynyloxy, C3-C14 cycloalkyl, (C3-C14 cycloalkyl)-(C1-C8 alkane Base)-, (C3-C14cycloalkyl)oxy, (C3-C14cycloalkyl)-(C1-C8 al
  • R i1 can form a 3-18-membered ring structure together with their respective atoms
  • R 4b , R 4c , R 4d , R 4e , R 4f are at each occurrence independently selected from the group consisting of H, D, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkane Base, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C3-C6 cycloalkyl;
  • R d , R e are independently selected from the following group at each occurrence: H, D, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogenated C1-C6 alkyl , halogenated C1-C6 alkoxy, halogenated C3-C6 cycloalkyl;
  • R f , R g are independently selected from the following group at each occurrence: H, D, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkane Oxygen.
  • the compound is selected from compounds represented by formula (II), formula (III) or formula (IV):
  • R 1 , R 2 , R 2a , R 3a , R 4a , Y2, Y3, Y4, V1, V2, V3, L, U, and dashed lines are as defined above.
  • the compound is selected from compounds represented by formula (V) or formula (VI):
  • R 1b , R 1c at each occurrence are independently selected from: H, D, halogen, -NH(CH 3 ), C1-C6 alkyl CONH-, C1-C6 alkyl OC(O)NH-, -NH 2.
  • Ring Q is a five-membered ring;
  • R 4e and R 4f are as defined above.
  • Z is O; W does not exist and ring G is a five-membered heterocyclic ring or a five-membered heteroaromatic ring; L is "-(CH 2 )-" or -(CH 2 CH 2 )-; U It is selected from phenyl substituted or unsubstituted by 1-5 R i , 5-6 membered heteroaromatic ring, C3-C8 cycloalkyl; the definition of R i is as mentioned above.
  • U is the following groups substituted or unsubstituted by 1, 2 or 3 R i : phenyl, 5-10 membered heteroaryl, C3-C8 cycloalkyl; each R i Independently at each occurrence: halogenated C1-C4 alkyl, C1-C4 alkyl, halogen, phenyl, benzo 5-6 membered heteroaryl or halogenated C1-C4 alkoxy; Optionally substituted with 1-2 R i1 , each R i1 at each occurrence independently selected from: halogen, C1-C4 alkyl.
  • each R i is independently at each occurrence: trifluoromethyl, trifluoromethoxy, methyl, isopropyl, fluorine, benzo 5-6 membered heteroaryl or benzene
  • R i is optionally substituted by 1-2 R i1 , each R i1 at each occurrence is independently selected from: halogen, C1-C4 alkyl.
  • L is 1, 2 or 3 C1-C4 linear or branched chain alkylene groups substituted or unsubstituted by Rh, and each Rh is independently selected from each occurrence of: halogen, C1-C4 alkyl; or Rh and the attached carbon form a 3-6 membered saturated ring.
  • L is -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )-, or -CF 2 -.
  • V5 and X1 are linked by a single bond, and the bonds between X1 and X2 are single or double bonds, each independently being -CH 2 -, -CH-.
  • V4 and V5 are C.
  • V1, V2, V3 are each independently selected from N, CR c ; R c is selected from the following group: H, D, halogen, C1-C4 alkyl.
  • V1 is CR c ;
  • V2 is CR c ;
  • V3 is N or CR c , and R c is selected from the group consisting of H, D, halogen, and C1-C4 alkyl.
  • V1 is CR c ; V2 is CH; V3 is N or CH, and R c is selected from the group consisting of H, D, halogen, and C1-C4 alkyl.
  • ring E is a benzene ring or a pyridine ring, optionally substituted by 1, 2 or 3 substituents selected from the group consisting of halogen, C1-C4 alkyl.
  • Z is selected from CH 2 , O, S, NH.
  • ring A is a pyridine ring or a pyridazine ring; it is optionally substituted by R 1a , R 1b , R 1c , R 1d .
  • Y4 is N or CR 4a .
  • R 1a is selected from H, D, halogen, NR 1 R 2 ;
  • R 2a is H, D, halogen or C1-C4 alkyl.
  • Y4 is N or CR 4a ;
  • R 2a and R 3a form a 3-6 membered ring structure together with the carbons to which they are attached.
  • R 4a and R 3a form a 3-6 membered ring structure together with the carbons to which they are attached.
  • the compound has the following formula:
  • Cy 3 is selected from C5-C14 membered aryl and 5-14 membered heteroaryl.
  • Y1, Y2, Y3, Y4, R 1a , R 2a , R 3a , R 4a etc. are specific groups corresponding to specific compounds.
  • the compound is selected from the compounds in claim 5.
  • the second aspect of the present invention provides the preparation method of the compound shown in the formula (I) described in the first aspect, including at least one of Reaction Formula 1, Reaction Formula 2 or Reaction Formula 3:
  • reaction formula 1 reaction formula 1
  • reaction formula 2 reaction formula 3
  • R 6a is selected from -OR 6i , halogen, C1-C12 alkyl, -SO 3 H, -SO 3 Na, -OB(OH) 2 , -B(OH) 2 ;
  • R 6c is selected from -LU, -LX, -L-Mg-X, -L-OH, -LOR 6i , -LR 6i ;
  • R 6d is selected from -CN, halogen, -NO 2 , -CONR 6i R 6j , -COOR 6i ;
  • R 6g , R 6h are selected from halogen, -Mg-X, -Li, -Na, -K , -B(OH) 2 , 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl or other boron-containing substituents;
  • R 6i , R 6j in each The second occurrence is independently H, D, C1-C8 alkyl, C1-C8 alkoxy, C6-C14 aryl, C6-C14 aryloxy;
  • X is independently selected at each occurrence from the group consisting of F, Cl, Br, I;
  • the third aspect of the present invention provides the preparation method of the compound of general formula (I) described in the first aspect, selected from the following schemes one to six:
  • RX-1a is subjected to aromatic nucleophilic substitution reaction or coupling reaction with RX-1b to obtain RX-1c;
  • RX-1c is subjected to hydrogenation reduction to obtain RX-1d;
  • RX-2e was subjected to Hoffman degradation reaction to obtain RX-2f;
  • RX-1a and RX-2c undergo aromatic nucleophilic substitution reaction to obtain RX-3b, which is further hydrolyzed to RX-3d;
  • RX-1a with di-tert-butyl dicarbonate (Boc 2 O) to obtain RX-3a, then perform a substitution reaction with RX-2c to obtain RX-3c, and then hydrolyze RX-3c in the presence of sodium hydroxide for RX-3d;
  • RX-3d was obtained by Curtius rearrangement reaction to obtain RX-3e;
  • RX-4a is then coupled with boronic acid or boric acid pinacol ester of R 3a to obtain RX-4;
  • R is C1-C15 alkyl, C1-C15 alkoxy, C1-C15 alkyl-O-(C1-C8 alkylene)-, C1-C15 alkyl-O- or C6-C14 aryl;
  • RX-5b removes the protecting group to obtain RX-5c
  • RX-5c is reduced to obtain RX-5d
  • RX-6c was obtained by Curtius rearrangement reaction to obtain RX-6d;
  • RX-6d is reduced to obtain RX-6e
  • Y1, Y2, Y3, Y4, V1, V2, V3, V4, V5, W, X1, X2, L, U, R 3a , and dashed lines are as described above;
  • X is independently selected from the following at each occurrence Groups: F, Cl, Br, I.
  • a pharmaceutical composition comprising: a pharmaceutically acceptable carrier; and
  • 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 parts 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 oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (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 talc
  • solid lubricants such as stearic acid , magnesium stearate
  • calcium sulfate such
  • the pharmaceutical composition is injection, capsule, tablet, pill, powder or granule.
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration 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 admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea, or
  • 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, etc.
  • 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
  • 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 when administered, for a person with a body weight of 60kg, the daily
  • the 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.
  • the fifth aspect of the present invention provides a kinase inhibitor, comprising an effective amount of one or more compounds described in the first aspect of the present invention or its stereoisomers, enantiomers, diastereomers isomers, atropisomers, optical isomers, racemates, tautomers or pharmaceutically acceptable salts thereof, prodrugs thereof, hydrates or solvates thereof, isotope-labeled Compound or the pharmaceutical composition described in the fourth aspect.
  • the kinase inhibitor is an inhibitor of receptor-interacting protein kinase (RIPK).
  • RIPK receptor-interacting protein kinase
  • the kinase inhibitor is an inhibitor of receptor-interacting protein kinase 1 (RIPK1).
  • RIPK1 receptor-interacting protein kinase 1
  • the sixth aspect of the present invention provides a compound described in the first aspect of the present invention or its stereoisomers, enantiomers, diastereomers, atropisomers, optical isomers, Use of racemates, tautomers or pharmaceutically acceptable salts thereof, prodrugs thereof, hydrates or solvates thereof, isotope-labeled compounds thereof for the preparation of medicaments for 1) Detect and/or prevent and/or treat kinase-related diseases; 2) Detect and/or prevent and/or treat immune, inflammatory and/or infection-related diseases; 3) Detect and/or prevent and/or treat ischemia and/or reperfusion injury-related diseases; 4) detection and/or prevention and/or treatment of degenerative diseases; 5) detection and/or prevention and/or treatment of tumor-related diseases; 6) detection and/or prevention and/or treatment Cell necrosis-related diseases; 7) detection and/or prevention and/or treatment of metabolism-related diseases; 8) detection and/or prevention and/or treatment of eye diseases.
  • the kinase is preferably selected from the following group: RIPK1, RIPK3.
  • the immune, inflammatory and/or infectious diseases are preferably selected from the group consisting of colitis, Crohn's disease, ulcerative enteritis, rheumatoid arthritis, sepsis, hepatitis B, hepatitis C, Systemic lupus erythematosus, asthma, new coronary pneumonia.
  • the degenerative disease is preferably selected from the group consisting of Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, and amyotrophic lateral sclerosis.
  • the tumor-related diseases are preferably selected from the group consisting of leukemia, non-small cell lung cancer, small cell lung cancer, cervical cancer, uterine cancer, ovarian cancer, thyroid cancer, parathyroid cancer, glioblastoma , squamous cell carcinoma, kidney or ureter cancer, head and/or neck cancer, stomach cancer, prostate cancer, pancreatic cancer, rectal cancer, glioma.
  • the metabolic-related diseases are preferably selected from the group consisting of type I diabetes, non-alcoholic fatty liver, gout, chronic kidney disease, and the like.
  • the cell necrosis-related diseases are preferably selected from the group consisting of ischemic injury, hypoxic brain injury, and burn shock.
  • the eye disease is preferably selected from the group consisting of macular degeneration, glaucoma, ischemic optic neuropathy, ischemic retinal disease, diabetic retinopathy, retinal detachment, and retinal vascular disease.
  • the seventh aspect of the present invention provides the compound described in the first aspect or its stereoisomers, enantiomers, diastereomers, atropisomers, optical isomers, racemates, Use of tautomers or pharmaceutically acceptable salts thereof, prodrugs thereof, hydrates or solvates thereof, isotope-labeled compounds thereof, or the pharmaceutical composition according to the fourth aspect, for: 1) detection and/or prevention and/or treatment of kinase-related diseases; 2) detection and/or prevention and/or treatment of inflammation and/or infection-related diseases; 3) detection and/or prevention and/or treatment of ischemia and/or Reperfusion injury-related diseases; 4) detection and/or prevention and/or treatment of degenerative diseases; 5) detection and/or prevention and/or treatment of tumor-related diseases; 6) detection and/or prevention and/or treatment of cell necrosis diseases; 7) detection and/or prevention and/or treatment of metabolic diseases; 8) detection and/or prevention and/or treatment of eye diseases.
  • Systemic juvenile idiopathic arthritis, Behcet's disease, interleukin-1 converting enzyme-associated febrile syndrome, sepsis, alopecia areata, allergic disease, allergic disease, hepatitis B, hepatitis C, multiple Cirrhosis, pulmonary sarcoidosis, pulmonary fibrosis, pneumonia, mycobacterial infection, celiac disease, Sjogren's syndrome, osteoarthritis, hidradenitis suppurativa, necrotizing enterocolitis, acute pancreatitis, spondyloarthritis, colitis , Crohn's disease, Crohn's disease, ulcerative colitis, rheumatoid arthritis, bacterial infection, influenza, COPD, viral infection, sepsis, dermatitis, staphylococcal infection, autologous Immune disease, systemic lupus erythematosus, systemic inflammatory response syndrome, systemic scleroderma, prion disease, adrenal degeneration
  • 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.
  • C 1 -C 6 means having 1, 2, 3, 4, 5 or 6 carbon atoms
  • C 1 -C 8 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.
  • 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.
  • substituents contemplated by this invention are those that are stable or chemically feasible.
  • 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, tert-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, specifically 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 a sp triple bond, wherein the alkynyl group can be independently and optionally replaced by one or more substituents described in the present invention, specific examples Including, but not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl and the like. Alkynyl groups can be optionally substituted or unsubstituted.
  • Ring structure refers to a single or polycyclic structure. Generally, 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, aromatic hydrocarbon, heteroaromatic hydrocarbon, and ring, Structures such as bridged rings and spiro rings, 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 ,
  • 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 with 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", it means that the aryl ring connected to the parent structure has 6-14 carbon atoms, but the aryl group can be optionally combined with other
  • the ring structure is fused, and the other ring structure refers to a ring structure having 3-18 ring atoms, and the other ring structure may be optionally substituted or unsubstituted.
  • Heteroaryl refers to an aromatic ring structure containing one or more rings, which may contain one or more (eg 1, 2, 3 or 4) atoms selected from N, O or S. Alternatively, the heteroaryl 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 in the form of "5-14 membered heteroaryl", it means that the heteroaryl ring connecting the heteroaryl to the parent structure has 5-14 ring atoms, but the heteroaryl Aryl groups are optionally fused with other ring structures, referring to ring structures having 3-18 ring atoms, which 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 connected 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.
  • examples of polycyclic cycloalkyls (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.
  • Examples of fusions with other ring structures or formation of spirocycles (but not limited to the following examples):
  • the cycloalkyl group may be optionally substituted or unsubstituted.
  • cycloalkyl group When the description of the cycloalkyl group is "C3-C14 cycloalkyl", it means that the cycloalkyl ring connecting the cycloalkyl and the parent structure has 3-14 carbon atoms, but the A cycloalkyl group may optionally be fused or form a spiro ring with other ring structures having 3 to 18 ring atoms, which may be optionally substituted or unsubstituted.
  • Heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic ring structure in which at least one (such as 1, 2, 3 or 4) ring atoms is a heteroatom (such as O, N, S atoms, etc.) .
  • Examples include (but are not limited to) the following examples: tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, tetrahydrothienyl, piperidinyl, piperazinyl, azetidinyl, azepanyl, Morpholinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, etc.
  • 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 heteroalkyl group is described in the form of "3-14 membered heterocyclyl"
  • the other ring structures refer to ring structures having 3-18 ring atoms.
  • the other ring structures may be optionally substituted or unsubstituted.
  • 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.
  • Exemplary examples include but are not limited to the following examples: the structure of the glycine acyl group is to convert the carboxyl group of glycine (NH2-CH2-COOH) into an acyl group to obtain the glycine acyl group (NH2-CH2-CO-).
  • 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 Acid, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, histidine, selenocysteine , pyrrolysine, ⁇ -alanine, etc.
  • glycosyl refers to a substituent of a monosaccharide or oligosaccharide in the form of 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.
  • Tautomer means that structural isomers with different energies can be interconverted beyond a low energy barrier.
  • proton tautomers i.e., prototropism
  • prototropism include interconversions via proton migration, such as 1H-indazole and 2H-indazole, 1H-benzo[d]imidazole and 3H-benzo[d]imidazole
  • valence tautomers include interconversion by recombination of some of the bonding electrons.
  • 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.
  • 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
  • step 1
  • I-1c 278 mg was dissolved in 5 mL of glacial acetic acid, and 190 mg of sodium cyanoborohydride (NaBH 3 CN) was added under ice-cooling, followed by stirring at room temperature for 16 hours.
  • the reaction mixture was poured into saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain I-1d. Yield 209 mg, 75% yield.
  • Example 1 The I-1b in Step 1 of Example 1 is replaced by other different types of halogenated heterocycles, and the remaining required raw materials, reagents and preparation methods are the same as in Example 1 to obtain the following compounds:
  • Step 1 Dissolve 600 mg of 5-oxindole (I-1a) in 5 mL of acetic acid, add 340 mg of sodium cyanoborohydride (NaBH 3 CN) in three batches under argon protection, then stir at room temperature for 24 340 mg of NaBH 3 CN was added, and stirring was continued at room temperature for 24 hours.
  • the reaction mixture was poured into 1N aqueous sodium hydroxide solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain I-2a. Yield 199 mg, 33% yield.
  • Step 2 Mix 150 mg of I-2a, 227 mg of m-trifluoromethylphenylacetic acid (Acid-1) and 506 mg of N,N,N',N'-tetramethyl-O-(7-azabenzo Triazol-1-yl)urea hexafluorophosphate (HATU, CAS: 148893-10-1) was dissolved in 8 mL of N,N-dimethylformamide (DMF), and triethylamine (TEA) was added under stirring, It was then stirred at room temperature for 16 hours.
  • DMF N,N-dimethylformamide
  • TAA triethylamine
  • Step 3 Dissolve 200 mg of I-2b in 2 mL of DMF, add 28 mg of sodium hydrogen (NaH, 60%) at 0°C under argon protection, stir for 10 minutes, and then add 153 mg of 5-bromo-2 -Cyano-3-nitropyridine (I-2c), raised to room temperature and stirred for 30 minutes.
  • the reaction mixture was poured into water, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed once with saturated sodium chloride, and finally the organic phase was dried over anhydrous sodium sulfate and concentrated, and purified by column chromatography to obtain I-2d. Yield: 150 mg, Yield: 48%.
  • Step 4 Dissolve 25 mg of I-2d in 0.4 mL of concentrated sulfuric acid, and stir for 6 hours under the protection of argon. Pour the reaction mixture into ice water, adjust the pH to 3 with 1N aqueous sodium hydroxide solution, extract three times with ethyl acetate, combine the ethyl acetate layers, wash once with saturated water and once with saturated sodium chloride, and finally wash the organic phase with After drying over sodium sulfate, it was concentrated to obtain I-2e, yield: 26 mg, yield: 100%.
  • Step 5 Dissolve 30 mg of I-2e in 2 mL of methanol (MeOH), add 13 mg of N-bromosuccinimide (NBS), stir at room temperature for 5 minutes, and then slowly drop in 17 mg of hydroxide at 0°C Sodium 0.3mL aqueous solution was reacted at room temperature for 1 hour, then raised to 75°C for 4 hours.
  • MeOH methanol
  • NBS N-bromosuccinimide
  • reaction mixture was poured into a saturated aqueous solution of ammonium chloride (NH 4 Cl), extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed once with saturated sodium chloride, and finally the organic phase was dried over anhydrous sodium sulfate and concentrated , purified by column chromatography to obtain I-2f, yield: 2.7 mg, yield: 11%.
  • NH 4 Cl ammonium chloride
  • Step 6 Add 30 mg of I-2f, 15 mg of 1-methylpyrazole-4-boronic acid pinacol ester, 25 mg of potassium carbonate (K 2 CO 3 ) to 1 mL of 1,4-dioxane and 5 mg of Pd(dppf)Cl 2 (CAS: 72287-26-4) was added to the mixed solution of 0.1 mL of water, and finally reacted at 100° C. for 8 hours under the protection of argon.
  • K 2 CO 3 potassium carbonate
  • Pd(dppf)Cl 2 CAS: 72287-26-4
  • Step 1 Dissolve 5g of 5-oxindole (I-1a) in 150mL of acetonitrile, and add 460mg of 4-dimethylaminopyridine (4-DMAP) and 21.5mL of di-tert-butyldicarbonate successively under argon protection Ester (Boc 2 O), then reacted at room temperature for 3h. Then concentrated under reduced pressure to remove acetonitrile, then the residue was redissolved in 120mL of methanol, and then 15.6g of potassium carbonate (K 2 CO 3 ) was added, and the reaction was stirred at room temperature for 6h.
  • 4-DMAP 4-dimethylaminopyridine
  • Boc 2 O argon protection Ester
  • Step 2 Dissolve 2 g of I-3a in 30 mL of DMF, under the protection of argon, add 150 mg of sodium hydrogen (NaH, 60%) at 0 ° C, keep stirring at 0 ° C for 10 minutes, then warm up to room temperature for 0.5 h , and then 2.35 g of 5-bromo-2-cyano-3-nitropyridine was dissolved in 8 mL of DMF, and added dropwise to the above reaction solution at 0° C., and then raised to room temperature and stirred overnight.
  • sodium hydrogen NaH, 60%
  • Step 3 Disperse 2.5g of I-3b in 30mL of ethanol (EtOH), then add 30mL of 6N sodium hydroxide solution, set up a reflux device and fully replace the argon, then rise to 80°C for 3h. After the reaction, spin off the ethanol, adjust the pH to 1-2 with concentrated hydrochloric acid at 0°C, filter directly, rinse the filter cake with water, spin dry to obtain I-3c, yield: 2.1g, yield: 100%, The crude product is cast directly to the next step.
  • EtOH ethanol
  • Step 4 Take 1.9g of I-3c and disperse it in 25mL of toluene, add 1.6mL of triethylamine (TEA), 600 ⁇ L of water, 2.5mL of diphenylphosphoryl azide (DPPA) in order to set up a reflux device and fully replace the argon.
  • TAA triethylamine
  • DPPA diphenylphosphoryl azide
  • the reaction was reacted at 90°C for 3h.
  • the reaction mixture was poured into water, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed twice with saturated sodium chloride, and finally the organic phase was dried over anhydrous sodium sulfate and concentrated, and purified by column chromatography to obtain I-3d , yield: 911 mg, yield: 52.6%.
  • Step 5 Dissolve 1.05 g of I-3d in 15 mL of acetic acid, add 650 mg of sodium cyanoborohydride (NaBH 3 CN) in three batches under argon protection, and then stir overnight at room temperature. After the reaction was detected by TLC tracking, the acetic acid was directly spun off, and then concentrated and purified by column chromatography to obtain I-3e. Yield 854mg, yield 80.9%.
  • NaBH 3 CN sodium cyanoborohydride
  • Step 6 Mix 100 mg of I-3e, 60 mg of phenylacetic acid (Acid-2) and 186 mg of N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1- Base) urea hexafluorophosphate (HATU, CAS: 148893-10-1) was dissolved in 7 mL of N,N-dimethylformamide (DMF), and 165 ⁇ L of diisopropylethylamine (DIPEA) was added under stirring, It was then stirred at room temperature for 16 hours.
  • DMF N,N-dimethylformamide
  • DIPEA diisopropylethylamine
  • Step 7 Add 130 mg of I-3f, 83 mg of 1-methylpyrazole-4-boronic acid pinacol ester, 100 mg of sodium carbonate (Na 2 CO 3 ) to 7 mL of 1,4-dioxane and 106 mg of Pd(PPh 3 ) 4 was added to the mixed solution of 0.8 mL of water, and finally reacted overnight at 90° C. under the protection of argon.
  • reaction mixture was poured into water, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed once with saturated sodium chloride, and finally the organic phase was dried over anhydrous sodium sulfate and concentrated, and purified by column chromatography to obtain I -3, yield: 117.6 mg, yield: 90.5%.
  • Example 3 The phenylacetic acid in Step 6 of Example 3 is replaced by other different types of carboxylic acids, and all the other required raw materials, reagents and preparation methods are the same as in Example 3 to obtain the following compounds:
  • Step 1 Add 500 mg of 5-bromo-2-cyano-3-nitropyridine, 15 mL of 1,4-dioxane, and 350 mg of 1H-pyrrolo[2,3- B] Pyridin-5-ol (I-10a), 700mg of potassium phosphate (K 3 PO 4 ), fully replace the argon and react at 90°C for 4h. After the reaction, take it out and cool it to room temperature, extract it three times with ethyl acetate, combine the ethyl acetate layer, wash once with saturated sodium chloride, and finally the organic phase is dried over anhydrous sodium sulfate and concentrated, and purified by column chromatography to obtain I-10b. Yield: 680 mg, Yield: 100%.
  • Step 2 Disperse 770mg of I-10b in 15mL of ethanol (EtOH), then add 15mL of 6N sodium hydroxide solution, set up a reflux device and fully replace the argon, then rise to 80°C for 3h. After the reaction, spin off the ethanol, adjust the pH to 4-5 with concentrated hydrochloric acid at 0°C, filter directly, rinse the filter cake with water, spin dry to obtain I-10c, yield: 470mg, yield: 57.2%, crude product Go straight to the next step.
  • EtOH ethanol
  • 6N sodium hydroxide solution set up a reflux device and fully replace the argon
  • Step 3 Take 470 mg of I-10c and disperse it in 20 mL of toluene, add 400 ⁇ L of triethylamine (TEA), 150 ⁇ L of water, and 610 ⁇ L of diphenylphosphoryl azide (DPPA) in order to set up a reflux device, fully replace the argon, and react at 90 Reaction at °C for 3h.
  • TAA triethylamine
  • DPPA diphenylphosphoryl azide
  • Step 4 Dissolve 190 mg of I-10d in 10 mL of acetic acid, add 120 mg of sodium cyanoborohydride (NaBH 3 CN) under argon protection, and react at 80° C. overnight. After treatment, the acetic acid was directly spun off, and 135 mg of the raw material was recovered by column chromatography purification, and the target product I-10e was obtained after purification, with a yield of 46 mg and a yield of 81.8%, which was directly used for the next step.
  • sodium cyanoborohydride NaBH 3 CN
  • Step 5 Mix 46 mg of I-10e, 46 mg of m-trifluoromethylphenylacetic acid (Acid-1) and 114 mg of N,N,N′,N′-tetramethyl-O-(7-azabenzo Triazol-1-yl)urea hexafluorophosphate (HATU, CAS: 148893-10-1) was dissolved in 6 mL of N,N-dimethylformamide (DMF), and 74 ⁇ L of diisopropylethyl amine (DIPEA), then stirred at room temperature for 16 hours.
  • DMF N,N-dimethylformamide
  • DIPEA diisopropylethyl amine
  • Step 6 Add 32 mg of I-10f, 21 mg of 1-methylpyrazole-4-boronic acid pinacol ester, 21 mg of sodium carbonate (Na 2 CO 3 ) to 5 mL of 1,4-dioxane and 23 mg of Pd(PPh 3 ) 4 was added to the mixed solution of 0.6 mL of water, and finally reacted overnight at 90° C. under the protection of argon.
  • reaction mixture was poured into water, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed once with saturated sodium chloride, and finally the organic phase was dried over anhydrous sodium sulfate and concentrated, and purified by column chromatography to obtain I -10, yield: 10 mg, yield: 31.3%.
  • Step 1 Disperse 1 g of 5-oxindole (I-1a) in 10 mL of absolute ethanol, add 1.7 mL of 33% dimethylamino aqueous solution and 700 ⁇ L of 37% formaldehyde aqueous solution in sequence, and stir the reaction at room temperature for 8 h. After the reaction of the raw materials was detected by TLC, the solvent was spun off, and toluene was added to spin twice, and the crude product of I-11a was obtained by fully drying. Yield: 1.37g, yield: 96.5%, the crude product is directly put into the next step.
  • Step 2 Take 1.37g of I-11a and disperse it in 30mL of absolute ethanol, fully replace the argon and stir at 0°C for 20min, then add 1.43g of sodium borohydride (NaBH 4 ) in two batches. The reaction temperature was raised to 80°C for 12h. After the reaction, take out and cool to room temperature and stir again under ice bath for 20 min, then add 570 mg of sodium borohydride, and reflux again for 1 h. After the reaction was completed, it was stirred again under ice bath for 20 min, and 50 mL of water was added dropwise to quench the reaction.
  • NaBH 4 sodium borohydride
  • Step 3 Add 2.3g of 5-bromo-2-cyano-3-nitropyridine, 30mL of acetonitrile, 750mg of I-11b, and 1.76g of potassium phosphate (K 3 PO 4 ) in sequence in the sealed tube , and reacted at 80°C for 12h after fully replacing argon. After the reaction was completed, it was taken out and cooled to room temperature, extracted three times with ethyl acetate, combined with ethyl acetate layers, washed once with saturated sodium chloride, and finally the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain I-11c. Yield: 777.7 mg, Yield: 46.8%.
  • K 3 PO 4 potassium phosphate
  • Step 4 Disperse 770mg of I-11c in 10mL of ethanol (EtOH), then add 8mL of 6N sodium hydroxide solution, set up a reflux device and fully replace the argon, then rise to 80°C for 3h. After the reaction, spin off the ethanol, adjust the pH to 1-2 with concentrated hydrochloric acid at 0°C, filter directly, rinse the filter cake with water, spin dry to obtain I-11d, yield: 660mg, yield: 80.2%, crude product Go straight to the next step.
  • EtOH ethanol
  • Step 5 Take 470 mg of I-11d and disperse it in 20 mL of toluene, add 480 ⁇ L of triethylamine (TEA), 600 ⁇ L of water, and 740 ⁇ L of diphenylphosphoryl azide (DPPA) in order to set up a reflux device and fully replace the argon, and react at 90 °C overnight.
  • TAA triethylamine
  • DPPA diphenylphosphoryl azide
  • Step 6 Dissolve 180 mg of I-11e in 10 mL of acetic acid, add 107 mg of sodium cyanoborohydride (NaBH 3 CN) under argon protection, and react overnight at room temperature. After treatment, the acetic acid was directly spinned off, and the target product I-11f was obtained by column chromatography purification. Yield: 128.4 mg, 70.9% yield.
  • NaBH 3 CN sodium cyanoborohydride
  • Step 7 Mix 120 mg of I-11f, 115 mg of m-trifluoromethylphenylacetic acid (Acid-1) and 286 mg of N,N,N',N'-tetramethyl-O-(7-azabenzo Triazol-1-yl)urea hexafluorophosphate (HATU, CAS: 148893-10-1) was dissolved in 10 mL of N,N-dimethylformamide (DMF), and 186 ⁇ L of diisopropylethyl amine (DIPEA), then stirred at room temperature for 16 hours.
  • DMF N,N-dimethylformamide
  • DIPEA diisopropylethyl amine
  • Step 8 Add 180 mg of I-11g, 111 mg of 1-methylpyrazole-4-boronic acid pinacol ester, 114 mg of sodium carbonate (Na 2 CO 3 ) to 10 mL of 1,4-dioxane and 111 mg of Pd(PPh 3 ) 4 was added to the mixed solution of 1 mL of water, and finally reacted overnight at 90° C. under the protection of argon.
  • reaction mixture was poured into water, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed once with saturated sodium chloride, and finally the organic phase was dried over anhydrous sodium sulfate and concentrated, and purified by column chromatography to obtain I -11, yield: 71.6 mg, yield: 39.7%.
  • Embodiment 6 is a diagrammatic representation of Embodiment 6
  • Step 1 Take 150 mg of I-2f in 6 mL of anhydrous dichloromethane, fully replace the argon, then add 151 ⁇ L of diisopropylethylamine (DIPEA), and stir for 20 min under ice-bath conditions. Then 49 ⁇ L of pivaloyl chloride was added dropwise, kept at 0°C for 30 min, and then warmed to room temperature for overnight reaction.
  • DIPEA diisopropylethylamine
  • reaction mixture was poured into water, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed once with saturated sodium chloride, and finally the organic phase was dried over anhydrous sodium sulfate and concentrated, and purified by column chromatography to obtain I -12a, yield: 143.1 mg, yield: 81.7%.
  • Step 2 Add 100 mg of I-12a, 55 mg of 1-methylpyrazole-4-boronic acid pinacol ester, 55 mg of sodium carbonate (Na 2 CO 3 ) to 8 mL of 1,4-dioxane and 60 mg of Pd(PPh 3 ) 4 was added to the mixed solution of 1 mL of water, and finally reacted overnight at 90° C. under the protection of argon.
  • reaction mixture was poured into water, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed once with saturated sodium chloride, and finally the organic phase was dried over anhydrous sodium sulfate and concentrated, and purified by column chromatography to obtain I -12, yield: 69 mg, yield: 69%.
  • Embodiment 7 is a diagrammatic representation of Embodiment 7:
  • Step 1 Take 88 mg of I-2f in 3 mL of anhydrous tetrahydrofuran, fully replace the argon, and stir for 20 min in an ice bath. Then add 8 mg of sodium hydride (60%, NaH), keep the ice bath for 30 min, then warm up to room temperature, and react for 1 h. After that, 12 ⁇ L iodomethane (MeI) was added dropwise, and the reaction was carried out overnight after the addition was completed.
  • sodium hydride 50%, NaH
  • reaction mixture was poured into water, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed once with saturated sodium chloride, and finally the organic phase was dried over anhydrous sodium sulfate and concentrated, and purified by preparative thin layer to obtain I -13a, yield: 23 mg, yield: 25.5%.
  • Step 2 Add 23 mg of I-13a, 15 mg of 1-methylpyrazole-4-boronic acid pinacol ester, 55 mg of sodium carbonate (Na 2 CO 3 ) to 5 mL of 1,4-dioxane and 16 mg of Pd(PPh 3 ) 4 was added to the mixed solution of 0.5 mL of water, and finally reacted at 90° C. for 6 h under the protection of argon.
  • reaction mixture was poured into water, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed once with saturated sodium chloride, and finally the organic phase was dried over anhydrous sodium sulfate and concentrated, and purified by column chromatography to obtain I -13, yield: 11.5 mg, yield: 50%.
  • Embodiment 8 is a diagrammatic representation of Embodiment 8
  • reaction mixture was poured into water, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed once with saturated sodium chloride, and finally the organic phase was dried over anhydrous sodium sulfate and concentrated, and purified by column chromatography to obtain I -14, yield: 37 mg, yield: 44%.
  • Example 8 The 3,4-dimethoxyphenylboronic acid in Example 8 was replaced with other different kinds of aromatic rings, heterocyclic boronic acids or boronic acid esters, and the remaining required raw materials, reagents and preparation methods remained unchanged, and the following compounds were obtained:
  • Embodiment 9 is a diagrammatic representation of Embodiment 9:
  • Step 1 Add 300 mg of 4-pyrazoleboronic acid pinacol ester (I-15a), 7 mL of N,N-dimethylformamide (DMF) and 600 mg of cesium carbonate in sequence in a sealed tube, and stir the reaction at room temperature After 20 min, 280 ⁇ L of 2-(2-bromoethoxy)tetrahydro-2H-pyran was added dropwise, and the reaction was carried out at 70° C. for 18 h after fully replacing the argon.
  • DMF N,N-dimethylformamide
  • reaction mixture was poured into water, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed once with saturated sodium chloride, and finally the organic phase was dried over anhydrous sodium sulfate and concentrated, and purified by column chromatography to obtain I -15b, yield: 237.6 mg, yield: 47.6%. Go straight to the next step.
  • Step 2 Replace 3,4-dimethoxyphenylboronic acid with I-15b, and the remaining raw materials, reagents and preparation methods are the same as those in Example 7 to obtain product I-15c, yield: 62 mg, yield: 43%. Go straight to the next step.
  • Step 3 Dissolve 40 mg of I-15c in 7 mL of anhydrous methanol, fully replace the argon, add 3 mg of p-toluenesulfonic acid (PTSA), and keep the reaction at room temperature overnight. After TLC detection, the reaction was directly concentrated and purified by thin layer separation to obtain I-15, yield: 32 mg, yield: 92.7%.
  • PTSA p-toluenesulfonic acid
  • Step 1 Add 300mg of 2-amino-3,5-dibromopyrazine (I-16a) and 15mL of N-methylpyrrolidone (NMP) in sequence in the sealed tube, then add 331mg of I-3a, 330mg of Potassium carbonate (K 2 CO 3 ), fully replaced with argon, reacted at 100°C for 6h.
  • NMP N-methylpyrrolidone
  • Step 2 Dissolve 300 mg of I-16b in 15 mL of acetic acid, add 190 mg of sodium cyanoborohydride (NaBH 3 CN) in three batches under argon protection, and then stir overnight at room temperature. After the reaction was detected by TLC, the acetic acid was directly spun off, then concentrated and purified by column chromatography to obtain I-16c. Yield: 130 mg, 43.3% yield.
  • NaBH 3 CN sodium cyanoborohydride
  • Step 3 Mix 110 mg of I-16c, 81 mg of m-trifluoromethylphenylacetic acid (Acid-1) and 205 mg of N,N,N',N'-tetramethyl-O-(7-azabenzo Triazol-1-yl)urea hexafluorophosphate (HATU, CAS: 148893-10-1) was dissolved in 10 mL of N,N-dimethylformamide (DMF), and 180 ⁇ L of diisopropylethyl amine (DIPEA), then stirred at room temperature for 16 hours.
  • DMF N,N-dimethylformamide
  • DIPEA diisopropylethyl amine
  • Step 4 Add 120 mg of I-16d, 76 mg of 1-methylpyrazole-4-boronic acid pinacol ester, 78 mg of sodium carbonate (Na 2 CO 3 ) to 10 mL of 1,4-dioxane and 85 mg of Pd(PPh 3 ) 4 was added to the mixed solution of 1 mL of water, and finally reacted at 90° C. for 12 h under the protection of argon.
  • Step 1 Add 200mg of 2-nitro-3-fluoropyridine (I-17a), 15mL of acetonitrile (MeCN) to the sealed tube, then add 400mg of I-3a, 290mg of potassium carbonate (K 2 CO 3 ), fully replaced with argon and reacted at 80°C for 16h. After the reaction, take it out and cool it to room temperature, pour the reaction solution into water and extract it three times with ethyl acetate, combine the ethyl acetate layer, wash it three times with saturated sodium chloride, and finally dry the organic phase over anhydrous sodium sulfate and concentrate it, and then go through column chromatography Purified to obtain I-17b, yield: 501 mg, yield: 100%.
  • Step 2 Disperse 800mg of I-17b in 20mL of ethanol, then add 10mL of saturated ammonium chloride solution, fully replace the argon, and react overnight at 80°C. After the reaction, take it out and cool to room temperature, spin off the ethanol and then extract with ethyl acetate three times, combine the ethyl acetate layers, wash with saturated sodium chloride three times, and finally the organic phase is dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography I-17c was obtained, yield: 380 mg, yield: 76%.
  • Step 3 Dissolve 200 mg of I-17c in 8 mL of acetic acid, add 116 mg of sodium cyanoborohydride (NaBH 3 CN) in three batches under argon protection, and then stir overnight at room temperature. After the reaction was detected by TLC, the acetic acid was directly spun off, then concentrated and purified by column chromatography to obtain I-17d. Yield: 213 mg, 100% yield.
  • NaBH 3 CN sodium cyanoborohydride
  • Step 4 Mix 115 mg of I-17d, 115 mg of m-trifluoromethylphenylacetic acid (Acid-1) and 285 mg of N,N,N',N'-tetramethyl-O-(7-azabenzo Triazol-1-yl)urea hexafluorophosphate (HATU, CAS: 148893-10-1) was dissolved in 8 mL of N,N-dimethylformamide (DMF), and 245 ⁇ L of diisopropylethyl amine (DIPEA), then stirred at room temperature for 16 hours.
  • DMF N,N-dimethylformamide
  • DIPEA diisopropylethyl amine
  • Step 1 Take 3g of 2-bromo-3-fluoro-4-methylpyridine (I-18a), 1.85g of zinc cyanide and 3.6g of tetrakis (triphenylphosphine) palladium and disperse them in 30mL of N,N- In dimethylformamide, fully replace the argon and react at 90°C for 18h.
  • Step 2 Add 900 mg of I-18b, 6 mL of N,N-dimethylformamide, 2 g of I-3a, and 4.3 g of cesium carbonate (Cs 2 CO 3 ) in sequence in the sealed tube to fully replace the argon After airing, react at 80°C for 3h. After the reaction, take it out and cool it to room temperature, pour the reaction solution into water and extract it three times with ethyl acetate, combine the ethyl acetate layer, wash it three times with saturated sodium chloride, and finally dry the organic phase over anhydrous sodium sulfate and concentrate it, and then go through column chromatography Purified to obtain I-18c, yield: 1.89g, yield: 74.3%.
  • Cs 2 CO 3 cesium carbonate
  • Step 3 Disperse 1.89g of I-18c in 20mL of ethanol (EtOH), then add 18mL of 6N sodium hydroxide solution, set up a reflux device and fully replace the argon, then rise to 80°C for 3h. After the reaction, spin off the ethanol, adjust the pH to 1-2 with concentrated hydrochloric acid at 0°C, filter directly, rinse the filter cake with water, spin dry to obtain I-18d, yield: 877mg, yield: 60.4%, crude product Go straight to the next step.
  • EtOH ethanol
  • Step 4 Take 777 mg of I-18d and disperse it in 20 mL of toluene, add 0.8 mL of triethylamine (TEA), 500 ⁇ L of water, and 1.3 mL of diphenylphosphoryl azide (DPPA) in order to set up a reflux device, fully replace the argon, and react React overnight at 90°C.
  • TAA triethylamine
  • DPPA diphenylphosphoryl azide
  • the reaction mixture was poured into water, extracted three times with ethyl acetate, the combined ethyl acetate layers were washed twice with saturated sodium chloride, and finally the organic phase was dried over anhydrous sodium sulfate and concentrated, and purified by column chromatography to obtain I-18e , yield: 211 mg, yield: 30.4%. Go straight to the next step.
  • Step 5 Dissolve 211 mg of I-18e in 10 mL of acetic acid, add 190 mg of sodium cyanoborohydride (NaBH 3 CN) in three batches under argon protection, and then stir overnight at room temperature. After the reaction was detected by TLC, the acetic acid was directly spun off, then concentrated and purified by column chromatography to obtain I-18f. Yield: 227 mg, 100% yield. Go straight to the next step.
  • sodium cyanoborohydride NaBH 3 CN
  • Step 6 Mix 80 mg of I-18f, 68 mg of m-trifluoromethylphenylacetic acid (Acid-1) and 164 mg of N,N,N',N'-tetramethyl-O-(7-azabenzo Triazol-1-yl)urea hexafluorophosphate (HATU, CAS: 148893-10-1) was dissolved in 8 mL of N,N-dimethylformamide (DMF), and 170 ⁇ L of diisopropylethyl amine (DIPEA), then stirred at room temperature for 16 hours.
  • DMF N,N-dimethylformamide
  • DIPEA diisopropylethyl amine
  • Step 1 Mix 60 mg of I-3e, 80 mg of Acid-3 and 164 mg of N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluoro Urea phosphate was dissolved in 8 mL of N,N-dimethylformamide (DMF), and 210 ⁇ L of diisopropylethylamine (DIPEA) was added with stirring, followed by stirring at room temperature for 16 hours.
  • DMF N,N-dimethylformamide
  • DIPEA diisopropylethylamine
  • 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 spin-dried to obtain a crude product that was directly used in the next step.
  • Step 2 Add 163 mg of I-20a, 100 mg of I-19b, and 110 mg of sodium carbonate to a mixed solution of 5 mL of 1,4-dioxane and 0.5 mL of water, and then add 40 mg of Pd(PPh 3 ) 4 , and finally reacted at 90°C for 12h under the protection of argon. After the reaction, the reaction mixture was poured into water, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed once with saturated sodium chloride, and finally the organic phase was dried over anhydrous sodium sulfate and concentrated, and purified by column chromatography to obtain I -20, yield: 98 mg, yield: 66.7%.
  • Step 3 Dissolve 50 mg of I-20b in 7 mL of anhydrous methanol, fully replace the argon, add 5 mg of p-toluenesulfonic acid (PTSA), and keep the reaction at room temperature overnight. After TLC detection, the reaction was directly concentrated and purified by thin layer separation to obtain I-20, yield: 40 mg, yield: 93%.
  • PTSA p-toluenesulfonic acid
  • Acid-3 in Example 14 is replaced by other different kinds of carboxylic acids, and all the other required raw materials, reagents and preparation methods are unchanged to obtain the following compounds:
  • A indicates that IC 50 is less than ( ⁇ ) 0.1 ⁇ M; B indicates that IC 50 is less than ( ⁇ ) 1 ⁇ M and greater than (>) 0.1 ⁇ M
  • C means IC 50 is greater than (>) 1 ⁇ M
  • Example 16 The recovery effect of the compound on the programmed necrosis of I2.1 cells
  • 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, different concentrations of compounds were added first, and after one hour, different concentrations of TNF ⁇ were added for stimulation, and no compound or compound was added. Stimulating factor control wells (positive control) and no compound plus stimulating factor control wells (negative control). After the compound acted on the cells for 24 hours, the effect of the compound on cell proliferation was detected with a 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 use The full-wavelength microplate microplate reader SpectraMax 190 reads, and the measurement wavelength is 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.
  • A indicates that IC 50 is less than ( ⁇ ) 0.1 ⁇ M; B indicates that IC 50 is less than ( ⁇ ) 1 ⁇ M and greater than (>) 0.1 ⁇ M; C indicates that IC 50 is greater than (>) 1 ⁇ M

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Abstract

本发明涉及含氮杂环化合物、其制备方法及其用途，含氮杂环化合物结构如通式I所示，各取代基的定义如说明书和权利要求书所述。本发明的含氮杂环化合物，作为治疗剂用于治疗炎症性疾病、缺血性疾病、退行性疾病、肿瘤等相关病症和疾病。

Description

含氮杂环化合物、其制备方法及其用途 技术领域
本发明涉及含氮杂环化合物、其制备方法、含有该系列化合物的药物组合物以及其作为治疗剂特别是用于治疗炎症性疾病、退行性疾病、缺血性疾病、肿瘤等和相关病症和疾病的用途。
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，简称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系统，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、 药代药效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
本发明提供一种通式(I)所示化合物，其可作为激酶抑制剂用于检测、预防和治疗涉及激酶相关疾病或病症，尤其是RIPK1激酶相关的疾病或病症；本发明还提供了通式(I)所示化合物的制备方法。
本发明的第一方面提供了一种通式(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 PCTCN2022139380-appb-000001
式中，环A为6元杂芳环；环E为苯环或6元杂芳环；环G为5-6元杂芳环或5-6元杂环；
Z选自CH 2、一个或二个卤素取代的CH 2、CDH、CD 2、O、S、NH、N(CH 3)、N(CD 3)；
Y1为N或C-R 1a；其中，R 1a选自H、D、卤素、NR 1R 2；R 1、R 2独立地选自：H、D、C1-C8烷基、C1-C15烷基C(＝O)-、C1-C15烷基OC(＝O)-、C1-C15烷基-O-(C1-C8亚烷基)-、C1-C15烷基(O＝)CO-、C2-C8烯基、C2-C8炔基、C6-C14芳基C(＝O)-、氨基酸酰基、C1-C8烷基-C(＝O)-CH＝CH-；上述R 1、R 2基团可选地被选自下组的1-5个基团取代：C6-C14芳基、(C1-C8烷基) 3Si-、氨基、羟基、卤素、一个或二个C1-C8烷基取代基的氨基、氧代(＝O)、C1-C8烷基；
Y2为N或C-R 2a；其中，R 2a选自下组：H、D、卤素、C1-C8烷基、C1-C8烷氧基、卤代C1-C8烷基、卤代C1-C8烷氧基、3-14元环烷基、3-14元杂环基、C2-C8烯基、C2-C8炔基；上述R 2a基团可选地被选自下组的1-5(1、2、3、4或5)个基团取代：D、卤素、羟基、氨基、一个或二个C1-C8烷基取代基的氨基、氰基、NH 2C(＝O)-、C1-C8烷基；
Y3为N或C-R 3a；其中，R 3a选自下组：H、D、卤素、C1-C8烷基、C1-C8烷氧基、卤代C1-C8烷基、卤代C1-C8烷氧基、5-14元杂芳基、C3-C14环烷基、C6-C14芳基、3-14元杂环基、NH 2CO-、C2-C8烯基、卤代的C2-C8烯基、C2-C8烯基氧基、卤代的C2-C8烯基氧基、C2-C8炔基、卤代的C2-C8炔基、C2-C8炔基氧基、卤代的C2-C8炔基氧基、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)(C1-C8烷基)-、(C1-C8烷基)-NHC(＝O)-、(C1-C8烷基)(C1-C8烷基)N-C(＝O)-、(C1-C8烷基)-NHC(＝O)-(C1-C8烷基)-、(C1-C8烷基)(C1-C8烷基)N-C(＝O)-(C1-C8烷基)-、HC(＝O)NH-、HC(＝O)N(C1-C8烷基)-、(C1-C8烷基)-C(＝O)NH-、(C1-C8烷基)-C(＝O)N(C1-C8烷基)-、(5-14元杂芳基)-NHC(＝O)-；其中，R 3a可选地被0-5(0、1、2、3、4或5)个R 3a1取代；
各R 3a1在每次出现时独立地选自：C1-C8烷基、氧代(＝O)、C2-C8烯基、C2-C8炔基、C1-C8烷氧基、3-14元杂环基、3-14元杂环基-C(＝O)-、C3-C14环烷基、5-14元杂芳基、H、D、卤素、卤代C1-C8烷基、卤代的C1-C8烷氧基、卤代C2-C8烯基、C2-C8烯基氧基、卤代C2-C8烯基氧基、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)-(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)-(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)-(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)-、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)-(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)-、(C1-C8烷基)-NHC(＝O)-、(C1-C8烷基)(C1-C8烷基)N-C(＝O)-、(C1-C8烷基)-NHC(＝O)-(C1-C8烷基)-、(C1-C8烷基)(C1-C8烷基)N-C(＝O)-(C1-C8烷基)-、HC(＝O)NH-、HC(＝O)N(C1-C8烷基)-、(C1-C8烷基)-C(＝O)NH-、(C1-C8烷基)-C(＝O)N(C1-C8烷基)-、硫代(＝S)；其中，R 3a1可选地被0-5(0、1、2、3、4或5)个R 3a2取代(限制条件为：当R 3a选自被1-5个R 3a1取代的5-14元杂芳基、C3-C14环烷基、C6-C14芳基、3-14元杂环基时)；
各R 3a2在每次出现时独立地选自：-CN、(C6-C14芳基)-(C1-C8烷基)氧基、氨基、羟基、卤代C1-C8烷基、C1-C8烷氧基、-N(C1-C8烷基)(C1-C8烷基)、C1-C8烷基、氧代(＝O)、-NH(C1-C8烷基)、NH 2CO-、C1-C8烷氧基取代的C1-C8烷氧基、C1-C14烷基OC(＝O)-、C1-C14烷基C(＝O)O-、C3-C14环烷基氧基、C1-C8烷基取代的3-14元杂环基、H、D、卤素、卤代的C1-C8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)-(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)-、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)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)-、羟基取代的C1-C8烷基、巯基、巯基取代的C1-C8烷基、氨基取代的C1-C8烷基、氰基取代的C1-C8烷基、-COOH、-(C1-C8烷基)-COOH、-(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)、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)-、硫代(＝S)；上述R 3a1、R 3a2可选被0-5(0、1、2、3、4或5)个R 3a3取代；
R 3a3为“-Linker-R 3a4”；上述Linker选自：键、O、NH、NR 3a4、-C(＝O)O-、-OC(＝O)-、-C(＝O)NH-、-C(＝O)NR 3a4-、3-14元环烷基、3-14元杂环基、C6-C14芳基、5-14元杂芳基；
R 3a4选自：H、D、卤素、C1-C8烷基、羟基、羟基取代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；
其中，可选地两个R 3a1可以与它们各自所连的原子一起形成4-15或3-18元环结构；
其中，可选地两个R 3a2可以与它们各自所连的原子一起形成4-15或3-18元环结构；
Y4为N或C-R 4a；R 4a选自H、D、C1-C6烷基、氨基、卤素、-C(R 4b)＝C(R 4c)-R 4d、-C(R 4b)＝N-R 4d、-N＝C(R 4c)-R 4d、-N＝N-R 4d、-C(R 4e)(R 4f)-R 4d、-C(＝O)-R 4d、-C(＝S)-R 4d、NR 4eR 4f、NR 4bC(＝O)R 4d；其中，R 4a可选地被0-5(0、1、2、3、4或5)个R 4a1取代，各R 4a1在每次出现时独立地选自：卤素、C3-C6环烷基、C1-C6烷基C(＝O)-；
可选地，R 2a、R 3a与它们各自所连接的碳一起形成由0至5(0、1、2、3、4或5)个R b1取代或未取代的3-18元环结构；
可选地，R 4a、R 3a与它们各自所连接的碳一起形成由0至5(0、1、2、3、4或5)个R b2取代或未取代的3-18元环结构，
各R b1、各R b2在每次出现时独立地选自：H、D、卤素、氧代、硫代、C1-C8烷基、羟基C1-C8烷基、C1-C8烷氧基、C3-C14环烷基、卤代C1-C8烷基、卤代的羟基C1-C6烷基、卤代C1-C8烷氧基、卤代C3-C14环烷基、3-14元杂环基、C6-C14芳基、5-14元杂芳基、C2-C8烯基、卤代的C2-C8烯基、C2-C8烯基氧基、卤代的C2-C8烯基氧基、C2-C8炔基、卤代的C2-C8炔基、C2-C8炔基氧基、卤代的C2-C8炔基氧基、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；可选地，R b1、R b2可以被0-5个R b3取代；R b3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C1-C8烷氧基、C2-C8烯基、卤代的C2-C8烯基、C2-C8烯基氧基、卤代的C2-C8烯基氧基、C2-C8炔基、卤代的C2-C8炔基、C2-C8炔基氧基、卤代的C2-C8炔基氧基、羟基C1-C8烷基、卤代的羟基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、氧代、硫代、(C1-C6烷基)3-Si-(C1-C6烷基)-O-(C1-C6亚烷基)-、C1-C15烷基OC(O)-、(C1-C8烷基)-OC(O)-(C1-C8烷基)COO-、C1-C8烷基-C(O)-CH＝CH-；
V1、V2、V3各自独立地选自N、C-R c；R c选自下组：H、D、卤素、C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、卤代C1-C6烷基、卤代C1-C6烷氧基、卤代C3-C6环烷基；
V4、V5各自独立地为C或N；
虚线表示的每个键独立地选自下组：单键、双键；
W不存在且V5与X1直接相连，或者，W为C(＝O)、C(＝S)、C(R d)(R e)、N(R d)、C、N、O、S；
X1、X2独立地选自C(＝O)、C(＝S)、C(R f)、C(R f)(R g)、N、N(R f)；
L选自被1至5个R h所取代或未取代的下组基团：C1-C12直链或支链亚烷基、-(CH2) m-NH-(CH2) n-、-(CH2) m-O-(CH2) n-、-(CH2) m-S-(CH2) n-、-(CH2) m-(S＝O)-(CH2) n-、-(CH2) m-(S＝O)2-(CH2) n-；各R h在每次出现时独立地选自：卤素、C1-C6烷基；可选地，R h与连接的碳形成3-6元饱和环；
m每次出现时独立地选自1、2、3、4；
n每次出现时独立地选自0、1、2、3；
U为由1至5个R i取代或未取代的下组基团：C5-C14元芳基、5-14元杂芳基、C3-C14环烷基、3-14元杂环基；各R i在每次出现时独立地选自：卤代C1-C8烷基、C1-C8烷基、卤素、C6-C14芳基、苯并5-14元杂芳基、卤代C1-C8烷氧基、H、D、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、3-14元杂环基、5-14元杂芳基、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)-、NH 2C(＝O)(C1-C8烷基)-、(C1-C8烷基)-NHC(＝O)-、(C1-C8烷基)(C1-C8烷基)N-C(＝O)-、(C1-C8烷基)-NHC(＝O)-(C1-C8烷基)-、(C1-C8烷基)(C1-C8烷基)N-C(＝O)-(C1-C8烷基)-、HC(＝O)NH-、HC(＝O)N(C1-C8烷基)-、(C1-C8烷基)-C(＝O)NH-、(C1-C8烷基)-C(＝O)N(C1-C8烷基)-、氧代(＝O)、硫代(＝S)；其中，R i可选地被0-5(0、1、2、3、4或5)个R i1取代；
各R i1在每次出现时独立地选自：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)-、-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)、(C1-C6烷基)3-Si-(C1-C6烷基)-O-(C1-C6亚烷基)-、C1-C15烷基OC(O)-、(C1-C8烷基)-OC(O)-(C1-C8烷基)COO-、C1-C8烷基-C(O)-CH＝CH-；
其中，可选地两个R i1可以与它们各自所连的原子一起形成3-18元环结构；
R 4b、R 4c、R 4d、R 4e、R 4f在每次出现时独立地选自下组：H、D、卤素、C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、卤代C1-C6烷基、卤代C1-C6烷氧基、卤代C3-C6环烷基；
R d、R e在每次出现时独立地选自下组：H、D、卤素、C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、卤代C1-C6烷基、卤代C1-C6烷氧基、卤代C3-C6环烷基；
R f、R g在每次出现时独立地选自下组：H、D、卤素、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基。
在另一优选例中，所述化合物选自式(II)、式(III)或式(IV)所示化合物：
Figure PCTCN2022139380-appb-000002
其中，R 1、R 2、R 2a、R 3a、R 4a、Y2、Y3、Y4、V1、V2、V3、L、U、虚线的定义如前所述。
在另一优选例中，所述化合物选自式(V)或式(VI)所示化合物：
Figure PCTCN2022139380-appb-000003
其中，Y2、Y3、V1、V2、V3、L、U、R 4a、虚线的定义如前所述；
R 1b、R 1c在每次出现时独立地选自：H、D、卤素、-NH(CH 3)、C1-C6烷基CONH-、C1-C6烷基OC(O)NH-、-NH 2、(C1-C8烷基) 3Si-(C1-C8烷基)O(C1-C8烷基)NH-、C6-C14芳基(C1-C8烷基)OC(O)NH-、C6-C14芳基C(O)NH-、-NH(C2-C8烯基)，上述基团可选地被选自下组的1-5个基团取代：氨基、羟基、C1-C8烷基、氧代；
环Q为五元环；Q1、Q2、Q3独立地选自：C(＝O)、C(＝S)、C(R 4e)、C(R 4e)(R 4f)、N、N(R 4e)；
R 4e、R 4f的定义如前所述。
在另一优选例中，Z为O；W不存在且环G为五元杂环或五元杂芳环；L为“-(CH 2)-”或-(CH 2CH 2)-；U选自被1-5个R i取代或未取代的苯基、5-6元杂芳环、C3-C8环烷基；R i的定义如前所述。
在另一优选例中，U为由1、2或3个R i取代或未取代的下组基团：苯基、5-10元杂芳基、C3-C8环烷基、；各R i在每次出现时独立地为：卤代C1-C4烷基、C1-C4烷基、卤素、苯基、苯并5-6元杂芳基或卤代C1-C4烷氧基；R i任选地被1-2个R i1取代，各R i1在每次出现时独立地选自：卤素、C1-C4烷基。在另一优选例中，各R i在每次出现时独立地为：三氟甲基、三氟甲氧基、甲基、异丙基、氟、苯并5-6元杂芳基或苯基；R i任选地被1-2个R i1取代，各R i1在每次出现时独立地选自：卤素、C1-C4烷基。
在另一优选例中，L为1、2或3个R h所取代或未取代的C1-C4直链或支链亚烷基，各R h在每次出现时独立地选自：卤素、C1-C4烷基；或者R h与连接的碳形成3-6元饱和环。在另一优选例中，L为-CH 2-、-CH 2CH 2-、-CH(CH 3)-、
Figure PCTCN2022139380-appb-000004
或-CF 2-。
在另一优选例中，W不存在，V5与X1通过单键连接，X1、X2之间的键为单键或双键，各自独立地为-CH 2-、-CH-。在另一优选例中，V4、V5为C。在另一优选例中，V1、V2、V3各自独立地选自N、C-R c；R c选自下组：H、D、卤素、C1-C4烷基。在另一优选例中，V1为C-R c；V2为C-R c；V3为N或C-R c，R c选自下组：H、D、卤素、C1-C4烷基。在另一优选例中，V1为C-R c；V2为CH；V3为N或CH，R c选自下组：H、D、卤素、C1-C4烷基。
在另一优选例中，环E为苯环或吡啶环，任选被选自下组的1、2或3个取代基取代；卤素、C1-C4烷基。
在另一优选例中，
Figure PCTCN2022139380-appb-000005
为
Figure PCTCN2022139380-appb-000006
在另一优选例中，Z选自CH 2、O、S、NH。
在另一优选例中，环A为吡啶环或哒嗪环；任选被R 1a、R 1b、R 1c、R 1d取代。
在另一优选例中，
Figure PCTCN2022139380-appb-000007
为
Figure PCTCN2022139380-appb-000008
Y4为N或CR 4a。
在另一优选例中，R 1a选自H、D、卤素、NR 1R 2；R 1、R 2独立地选自：H、D、C1-C4烷基、C1-C4烷基C(＝O)-、C1-C4烷基OC(＝O)-、C1-C4烷基-O-(C1-C4亚烷基)-、C1-C4烷基(O)CO-、C2-C6烯基、C2-C4炔基、苯基C(O)-；上述R 1、R 2基团可选地被选自下组的1、2或3个基团取代：苯基、(C1-C4烷基) 3Si-、氨基、羟基、卤素、氧代(＝O)、C1-C4烷基；
在另一优选例中，R 2a为H、D、卤素或C1-C4烷基。
在另一优选例中，R 3a为H、5-6元杂芳基、C3-C6环烷基、苯基、5-6元杂环基、(5-6元杂芳基)-NHC(＝O)-；其中，R 3a任选地被1、2或3个R 3a1取代；各R 3a1在每次出现时独立地选自：C1-C8烷基、氧代(＝O)、C2-C8烯基、C2-C8炔基、C1-C8烷氧基、3-14元杂环基、3-14元杂环基-C(＝O)-、C3-C14环烷基、NH 2C(＝O)-(C1-C8烷基)-；R 3a1任选地被1-5个R 3a2取代；各R 3a2在每次出现时独立地选自：CN、氨基、羟基、卤代C1-C8烷基、C1-C8烷氧基、-N(C1-C8烷基)(C1-C8烷基)、C1-C8烷基、氧代(＝O)、-NH(C1-C8烷基)、NH 2CO-、C1-C8烷氧基取代的C1-C8烷氧基、C1-C14烷基OC(＝O)-、C1-C14烷基C(＝O)O-、C3-C14环烷基氧基、3-14元杂环基、(3-14元杂环基)-(C1-C8烷基)-、(3-14元杂环基)氧基、(C6-C14芳基)-(C1-C8烷基)-O-、(C6-C14芳基)-C(＝O)O-、上述R 3a1、R 3a2可选被1-5个R 3a3取代；R 3a3为“-Linker-R 3a4”；上述Linker选自：键、O、-C(＝O)O-、-OC(＝O)-；R 3a4选自：H、D、卤素、C1-C8烷基、羟基、羟基取代C1-C8烷基、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)-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。
在另一优选例中，Y4为N或C-R 4a；R 4a选自H、D、C1-C6烷基、氨基、卤素、NR 4bC(＝O)R 4d；其中，R 4a任选地被1-5个R 4a1取代，各R 4a1在每次出现时独立地选自：卤素、C3-C6环烷基、C1-C6烷基C(＝O)-。
在另一优选例中，R 2a、R 3a与它们各自所连接的碳一起形成3-6元环结构。
在另一优选例中，R 4a、R 3a与它们各自所连接的碳一起形成3-6元环结构。
在另一优选例中，所述化合物具有下式：
Figure PCTCN2022139380-appb-000009
各取代基的定义如前所述，Cy 3选自C5-C14元芳基、5-14元杂芳基。
在另一优选例中，本发明中，Y1、Y2、Y3、Y4、R 1a、R 2a、R 3a、R 4a等为具体化合物中对应的具体基团。
在另一优选例中，所述化合物选自权利要求5中的化合物。
本发明的第二方面，提供第一方面所述的式(I)所示化合物的制备方法，包括反应式1、反应式2或反应式3中的至少一个：
[反应式1]
Figure PCTCN2022139380-appb-000010
[反应式2]
Figure PCTCN2022139380-appb-000011
[反应式3]
Figure PCTCN2022139380-appb-000012
在反应式1、反应式2、反应式3中，
R 6a选自
Figure PCTCN2022139380-appb-000013
-O-R 6i，卤素，C1-C12烷基，-SO 3H，-SO 3Na，-OB(OH) 2，-B(OH) 2；R 6b选自-OH，卤素，-OC(＝O)-R 6i，-OS(＝O)-R 6i，-OS(＝O)2-R 6i；R 6c选自-L-U，-L-X，-L-Mg-X，-L-OH，-L-O-R 6i，-L-R 6i；R 6d选自-CN，卤素，-NO 2，-CONR 6iR 6j，-COOR 6i；
R 6e，R 6f在每次出现时独立地选自H，-C(＝O)-L-U，-C(＝O)-L-X，-C(＝O)-L-Mg-X，-C(＝O)-L-OH，-C(＝O)-L-O-R 6i，-C(＝O)-L-R 6i；R 6g、R 6h选自卤素、-Mg-X、-Li、-Na、-K、-B(OH) 2、4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基或其它含硼的取代基；R 6i、R 6j在每次出现时独立地为H、D、C1-C8烷基、C1-C8烷氧基、C6-C14芳基、C6-C14芳基氧基；
X在每次出现时独立地选自下组：F、Cl、Br、I；
Y1、Y2、Y3、Y4、V1、V2、V3、V4、V5、W、X1、X2、Z、R 3a、虚线的定义如前所述。
本发明的第三方面，提供第一方面所述的通式(I)化合物的制备方法，选自下述方案一至方案六：
方案一：
Figure PCTCN2022139380-appb-000014
将RX-1a与RX-1b进行芳香亲核取代反应或偶联反应得到RX-1c；
将RX-1c进行加氢还原得到RX-1d；
将RX-1d与羧酸RX-1e进行缩合反应得到RX-1所示化合物；
方案二：
Figure PCTCN2022139380-appb-000015
将RX-2a与RX-1e进行缩合反应得到RX-2b；
将RX-2b与RX-2c进行芳香亲核取代反应得到RX-2d；
将RX-2d的氰基进行水解得到RX-2e；
将RX-2e进行Hoffman降解反应得到RX-2f；
将RX-2f与R 3a的硼酸或硼酸频哪醇酯进行偶联反应得到RX-2；
方案三：
Figure PCTCN2022139380-appb-000016
将RX-1a与RX-2c进行芳香亲核取代反应得到RX-3b，再进一步水解为RX-3d；
或者将RX-1a与二碳酸二叔丁酯(Boc 2O)反应得到RX-3a，再与RX-2c进行取代反应得到RX-3c，接下来在氢氧化钠存在下，将RX-3c水解为RX-3d；
将RX-3d通过Curtius重排反应得到RX-3e；
将RX-3e进行还原反应得到RX-3f；
把RX-3f与相应羧酸进行酰胺缩合得到RX-3g；
将RX-3g与R 3a的硼酸或硼酸频哪醇酯进行偶联反应得到RX-3；
方案四：
Figure PCTCN2022139380-appb-000017
将RX-2d的氨基引入取代基得到RX-4a；
RX-4a再与R 3a的硼酸或硼酸频哪醇酯进行偶联反应得到RX-4；
其中，R为C1-C15烷基、C1-C15烷氧基、C1-C15烷基-O-(C1-C8亚烷基)-、C1-C15烷基-O-或C6-C14芳基；
方案五：
Figure PCTCN2022139380-appb-000018
将RX-5a与RX-3c进行取代反应得到RX-5b；
RX-5b脱去保护基得到RX-5c；
将RX-5c进行还原得到RX-5d；
将RX-5d与相应羧酸进行酰胺缩合得到RX-5；
方案六：
Figure PCTCN2022139380-appb-000019
将RX-6a与RX-3c进行取代反应得到RX-6b；
将RX-6b的氰基水解得到RX-6c；
将RX-6c通过Curtius重排反应得到RX-6d；
将RX-6d进行还原得到RX-6e；
将RX-6e与相应羧酸进行酰胺缩合得到RX-6；
Y1、Y2、Y3、Y4、V1、V2、V3、V4、V5、W、X1、X2、L、U、R 3a、虚线的定义同前所述；X在每次出现时独立地选自下组：F、Cl、Br、I。
本发明的第四方面，提供一种药物组合物，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 PCTCN2022139380-appb-000020
)、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、蔗糖和阿拉伯胶；(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。
本发明的第五方面，提供一种激酶抑制剂，包含抑制有效量的一种或多种本发明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或第四方面所述的药物组合物。
在另一优选例中，该激酶抑制剂为受体相互作用蛋白激酶(RIPK)的抑制剂。
在另一优选例中，该激酶抑制剂为受体相互作用蛋白激酶1(RIPK1)的抑制剂。
本发明的第六方面，提供一种本发明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的用途，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/或治疗肿瘤相关疾病；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；8)检测和/或预防和/或治疗眼部疾病。
在另一优选例中，所述激酶优选自下组：RIPK1、RIPK3。
在另一优选例中，所述免疫、炎症和/或感染疾病优选自下组：结肠炎、克罗恩病、溃疡性肠炎、类风湿性关节炎、败血症、乙型肝炎、丙型肝炎、系统性红斑狼疮、哮喘、新冠肺炎。
在另一优选例中，所述退行性疾病优选自下组：阿尔茨海默病、帕金森病、路易体痴呆、肌萎缩性侧索硬化。
在另一优选例中，所述肿瘤相关疾病优选自下组：白血病、非小细胞肺癌、小细胞肺癌、宫颈癌、子宫癌、卵巢癌、甲状腺癌、甲状旁腺癌、胶质母细胞瘤、鳞状上皮细胞癌、肾或输尿管癌、头和/或颈癌、胃癌、前列腺癌、胰腺癌、直肠癌、脑胶质瘤。
在另一优选例中，所述代谢相关疾病优选自下组：I型糖尿病、非酒精性脂肪肝、痛风、慢性肾病等。
在另一优选例中，所述细胞坏死相关疾病优选自下组：缺血性损伤、缺氧性脑损伤、烧伤性休克。
在另一优选例中，所述眼部疾病优选自下组：黄斑病变、青光眼、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、视网膜脱离、视网膜血管疾病。
本发明的第七方面，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，或根据第四方面所述的药物组合物的用途，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/或治疗肿瘤相关疾病；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/或治疗代谢类疾病；8)检测和/或预防和/或治疗眼部疾病。
在另一优选例中，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，或根据第四方面所述的药物组合物的用途，用于制备治疗包括但不限于下列疾病的药物：
全身型幼年特发性关节炎，白塞氏病，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，系统性红斑狼疮，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，多系统萎缩症，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，精神分裂症，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，肛门区域癌，睾丸癌，宫颈癌，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，内分泌系统癌症，尿道癌，膀胱癌，皮肤癌，皮肤或眼内恶性黑色素瘤，前列腺癌，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，阴道癌，阴茎癌，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。
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)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 PCTCN2022139380-appb-000021
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系统，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 PCTCN2022139380-appb-000022
Figure PCTCN2022139380-appb-000023
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(如1、2、3或4个)选自N、O或S原子。可选地，所述杂芳基可以与芳基、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 PCTCN2022139380-appb-000024
Figure PCTCN2022139380-appb-000025
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 PCTCN2022139380-appb-000026
Figure PCTCN2022139380-appb-000027
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(如1、2、3或4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。
“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(NH2-CH2-COOH)的羧基转化为酰基，获得甘氨酸酰基(NH2-CH2-CO-)。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。
“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、阿拉伯糖、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。
“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。
如下将参照以示例性的方式示出结构和式的本申请的某些实施方案来详细描述本申请。尽管结合列举的实施方案对本申请进行了描述，但应了解其不旨在将本申请限定为所描述的那些实施方案。相反，本申请旨在涵盖落入权利要求书所限定的范围内的所有替代方式、修改方式和等同方式。本领域技术人员将会认识到可用于实施本申请的与本文描述的方法和材料类似或等同的其他方法和材料，本申请不以任何方式局限于所描述的方法和材料。
还应理解在不同实施方案中描述的某些特征也可在单个实施方案中组合提供。反之，在单个实施方案中描述的多种特征也可以单独提供或以任何适当的亚组合提供。
实施例
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，否则百分比和份数按重量计算。
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。
HATU：N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-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
实施例1：
Figure PCTCN2022139380-appb-000028
步骤1：
将898mg的叔丁醇钾、532mg的5-羟基吲哚(I-1a)溶于2mL的二甲基亚砜(DMSO)，加入904mg的2-三氟甲基-5-溴吡啶(I-1b)，而后100℃反应2小时。将所得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，经柱层析纯化得I-1c，产量：390mg，产率：35％。 1H NMR(400MHz,CDCl 3) δ8.47(d,J＝2.8Hz,1H),8.30(s,1H),7.56(d,J＝8.7Hz,1H),7.48–7.40(m,1H),7.36(d,J＝2.3Hz,1H),7.31(t,J＝2.8Hz,1H),7.29–7.22(m,1H),6.95(dd,J＝8.7,2.3Hz,1H),6.58–6.55(m,1H).
步骤2：
将278mg的I-1c溶于5mL的冰醋酸，于冰浴下加入190mg的氰基硼氢化钠(NaBH 3CN)，而后于室温搅拌16小时。将反应混合物倾入到饱和碳酸氢钠水溶液中，乙酸乙酯萃取，无水硫酸钠干燥，再经柱层析纯化得I-1d。产量209mg，产率75％。 1H NMR(400MHz,CDCl 3)δ8.42(d,J＝2.8Hz,1H),7.56(d,J＝8.8Hz,1H),7.28–7.22(m,2H),6.85(dd,J＝2.3,1.1Hz,1H),6.80–6.72(m,1H),6.63(d,J＝8.3Hz,1H),3.62(t,J＝8.4Hz,2H),3.04(t,J＝8.5Hz,2H).
步骤3：
将40mg的I-1d，44mg的间三氟甲基苯乙酸(Acid-1)和109mg的N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-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75μL的二异丙基乙基胺(DIPEA)，而后于室温搅拌16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，经柱层析纯化得I-1-1，产量：52mg，产率：78％。LC-MS:467.3([M+H] +).
将实施例1步骤1中的I-1b替换为其他不同种类的卤代杂环，其余所需原料、试剂及制备方法同实施例1，得以下化合物：
Figure PCTCN2022139380-appb-000029
实施例2：
Figure PCTCN2022139380-appb-000030
步骤1：将600mg的5-羟基吲哚(I-1a)溶于5mL的醋酸中，在氩气保护下分三批加入340mg的氰基硼氢化钠(NaBH 3CN)，而后于室温搅拌24小时，补加340mg的NaBH 3CN，继续于室温搅拌24小时。将反应混合物倾入到1N氢氧化钠水溶液中，乙酸乙酯萃取，无水硫酸 钠干燥，再经柱层析纯化得I-2a。产量199mg，产率33％。 1H NMR(400MHz,CDCl 3)δ6.70–6.43(m,3H),3.53(t,J＝8.3Hz,2H),2.98(t,J＝8.2Hz,2H).
步骤2：将150mg的I-2a、227mg的间三氟甲基苯乙酸(Acid-1)和506mg的N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(HATU，CAS：148893-10-1)溶于8mL的N,N-二甲基甲酰胺(DMF)中，搅拌下加入三乙胺(TEA)，而后于室温搅拌16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，经柱层析纯化得I-2b，产量：217mg，产率：61％。 1H NMR(400MHz,DMSO-d 6)δ9.17(s,1H),7.83(d,J＝8.6Hz,1H),7.70–7.53(m,4H),6.64(d,J＝2.4Hz,1H),6.50(dd,J＝8.6,2.5Hz,1H),4.15(t,J＝8.4Hz,2H),3.93(s,2H),3.10(t,J＝8.4Hz,2H).
步骤3：将200mg的I-2b溶于2mL的DMF中，在氩气保护下，于0℃加入28mg的钠氢(NaH，60％)，搅拌10分钟，再加入153mg的5-溴-2-氰基-3-硝基吡啶(I-2c)，升至室温搅拌30分钟。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，用饱和氯化钠洗涤一次，最后有机相经无水硫酸钠干燥后浓缩，经柱层析纯化得I-2d，产量：150mg，产率：48％。 1H NMR(400MHz,CDCl 3)δ8.41(d,J＝1.8Hz,1H),8.32(d,J＝8.4Hz,1H),7.62–7.44(m,4H),7.29(d,J＝1.8Hz,1H),6.99–6.88(m,2H),4.21(t,J＝8.5Hz,2H),3.27(t,J＝8.4Hz,2H).
步骤4：将25mg的I-2d溶解于0.4mL的浓硫酸，氩气保护下搅拌6小时。将反应混合物倾入到冰水中，用1N氢氧化钠水溶液调节pH至3，乙酸乙酯萃取三次，合并乙酸乙酯层，用饱水洗涤一次、饱和氯化钠洗涤一次，最后有机相经无水硫酸钠干燥后浓缩得I-2e，产量：26mg，产率：100％。 1H NMR(400MHz,CDCl 3)δ8.37(d,J＝1.8Hz,1H),8.27(d,J＝8.7Hz,1H),7.61–7.45(m,5H),7.35(d,J＝1.8Hz,1H),6.94(d,J＝2.4Hz,1H),6.89(dd,J＝8.7,2.6Hz,1H),5.69(s,1H),4.18(t,J＝8.5Hz,2H),3.87(s,2H),3.24(t,J＝8.4Hz,2H).
步骤5：将30mg的I-2e溶于2mL甲醇(MeOH)中，加入13mg的N-溴代丁二酰亚胺(NBS)，于室温搅拌5分钟，而后于0℃缓慢滴入17mg氢氧化钠的0.3mL水溶液，于室温反应1小时，再升至75℃反应4小时。将反应混合物倾入到氯化铵(NH 4Cl)的饱和水溶液中，乙酸乙酯萃取三次，合并乙酸乙酯层，用饱和氯化钠洗涤一次，最后有机相经无水硫酸钠干燥后浓缩，经柱层析纯化得I-2f，产量：2.7mg，产率：11％。 1H NMR(400MHz,CDCl 3)δ8.35–8.25(m,1H),7.63–7.43(m,5H),7.11–6.87(m,3H),4.21(t,J＝8.2Hz,2H),3.90(s,2H),3.84(s,2H),3.26(q,J＝8.1Hz,2H).
步骤6：将30mg的I-2f、15mg的1-甲基吡唑-4-硼酸频哪醇酯、25mg的碳酸钾(K 2CO 3)加入到1mL的1,4-二氧六环和0.1mL水的混合溶液中，再加入5mg的Pd(dppf)Cl 2(CAS：72287-26-4)，最后在氩气保护下于100℃反应8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，用饱和氯化钠洗涤一次，最后有机相经无水硫酸钠干燥后浓缩，经柱层析纯化得I-2，产量：13mg，产率：43％。 1H NMR(400MHz,CD 3OD)δ8.11(d,J＝8.8Hz,1H),7.91(d,J＝2.0Hz,1H),7.76(s,1H),7.68–7.50(m,5H),7.15(d,J＝2.0Hz,1H),6.94(d,J＝2.6Hz,1H),6.86(dd,J＝8.8,2.6Hz,1H),4.22(t,J＝8.4Hz,2H),3.97(s,2H),3.85(s,3H),3.20(t,J＝8.4Hz,2H).LC MS:494.3([M+H] +).
实施例3：
Figure PCTCN2022139380-appb-000031
步骤1：取5g的5-羟基吲哚(I-1a)溶于150mL乙腈中，在氩气保护下依次加入460mg 4-二甲氨基吡啶(4-DMAP)和21.5mL二叔丁基二碳酸酯(Boc 2O)，然后在室温下反应3h。然后减压浓缩除去乙腈，然后将残余物复溶于120mL甲醇中，再加入15.6g碳酸钾(K 2CO 3)，反应于室温下搅拌6h。TLC监测反应结束后直接硅藻土过滤，滤液旋干后加入适量水稀释，再用醋酸调pH至中性，乙酸乙酯萃取三次，合并乙酸乙酯层，用饱和氯化钠洗涤一次，最后有机相经无水硫酸钠干燥后浓缩，经柱层析纯化得I-3a，产量：8.71g，产率：99.5％。 1H NMR(400MHz,CDCl 3)δ7.98(d,J＝8.2Hz,1H),7.56(d,J＝3.7Hz,1H),6.98(d,J＝2.5Hz,1H),6.84(dd,J＝8.8,2.5Hz,1H),6.46(d,J＝3.7Hz,1H),4.94(s,1H),1.66(s,9H).
步骤2：将2g的I-3a溶于30mL的DMF中，在氩气保护下，于0℃加入150mg的钠氢(NaH，60％)，保持0℃搅拌10分钟后升温至室温反应0.5h，再将2.35g的5-溴-2-氰基-3-硝基吡啶溶于8mL DMF中，于0℃下逐滴加入上反应液中，后再次升至室温搅拌过夜。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，用饱和氯化钠洗涤两次，最后有机相经无水硫酸钠干燥后浓缩，经柱层析纯化得I-3b，产量：3.116g，产率：88％。 1H NMR(400MHz,CDCl 3)δ8.39(d,J＝1.8Hz,1H),8.25(d,J＝9.0Hz,1H),7.70(d,J＝3.7Hz,1H),7.31(d,J＝2.4Hz,1H),7.26(s,1H),7.06(dd,J＝8.9,2.5Hz,1H),6.59(d,J＝3.7Hz,1H),1.69(s,9H).
步骤3：将2.5g的I-3b分散于30mL的乙醇(EtOH)中，再加入30mL 6N氢氧化钠溶液，搭建回流装置后充分置换氩气，再升至80℃反应3h。反应结束后，旋去乙醇，于0℃下用浓盐酸调pH至1-2，直接过滤，滤饼用水充分淋洗、旋干得I-3c，产量：2.1g，产率：100％，粗品直接投下一步。
步骤4：取1.9g的I-3c分散于25mL甲苯中，依次加入1.6mL三乙胺(TEA)、600μL水、2.5mL叠氮磷酸二苯酯(DPPA)搭建回流装置后充分置换氩气，反应于90℃下反应3h。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，用饱和氯化钠洗涤两次，最后有机相经无水硫酸钠干燥后浓缩，经柱层析纯化得I-3d，产量：911mg，产率：52.6％。 1H NMR(400MHz,CDCl 3)δ8.37(s,1H),7.80(d,J＝1.9Hz,1H),7.41(d,J＝8.7Hz,1H),7.33–7.27(m,2H),6.93(dd,J＝8.7,2.3Hz,1H),6.91(d,J＝2.0Hz,1H),6.55(t,J＝2.6Hz,1H),4.85(s,2H).
步骤5：将1.05g的I-3d溶于15mL的醋酸中，在氩气保护下分三批加入650mg的氰基硼氢化钠(NaBH 3CN)，而后于室温搅拌过夜。TLC跟踪检测反应结束后，直接旋去乙酸，再浓缩经柱层析纯化得I-3e。产量854mg，产率80.9％。 1H NMR(400MHz,CDCl 3)δ7.76(d,J＝2.1Hz,1H),6.89(d,J＝2.1Hz,1H),6.82(d,J＝2.4Hz,1H),6.72(dd,J＝8.3,2.4Hz,1H),6.63(d,J＝8.3Hz,1H),4.93(s,2H),3.62(t,J＝8.4Hz,2H),3.05(t,J＝8.4Hz,2H).
步骤6：将100mg的I-3e、60mg的苯乙酸(Acid-2)和186mg的N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(HATU，CAS：148893-10-1)溶于7mL的N,N-二甲基甲酰胺(DMF)中，搅拌下加入165μL二异丙基乙基胺(DIPEA)，而后于室温搅拌16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，经柱层析纯化得I-3f，产量：138mg，产率：100％。 1H NMR(400MHz,CDCl 3)δ8.28(d,J＝8.7Hz,1H),7.43–7.21(m,6H),6.94(s,1H),6.89–6.79(m,2H),4.96(s,2H),4.12(t,J＝8.5Hz,2H),3.82(s,2H),3.17(t,J＝8.4Hz,2H).
步骤7：将130mg的I-3f、83mg的1-甲基吡唑-4-硼酸频哪醇酯、100mg的碳酸钠(Na 2CO 3)加入到7mL的1,4-二氧六环和0.8mL水的混合溶液中，再加入106mg的Pd(PPh 3) 4，最后在氩气保护下于90℃反应过夜。反应结束后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，用饱和氯化钠洗涤一次，最后有机相经无水硫酸钠干燥后浓缩，经柱层析纯化得I-3，产量：117.6mg，产率：90.5％。 1H NMR(400MHz,CDCl 3)δ8.26(d,J＝8.8Hz,1H),7.96(d,J＝2.0Hz,1H),7.57(d,J＝0.9Hz,1H),7.44(d,J＝0.8Hz,1H),7.36(dt,J＝6.8,1.2Hz,1H),7.34–7.27(m,4H),7.00(d,J＝2.0Hz,1H),6.89(dd,J＝8.8,2.6Hz,1H),6.83(d,J＝2.5Hz,1H),4.69(s,2H),4.11(t,J＝8.5Hz,2H),3.89(s,3H),3.82(s,2H),3.15(t,J＝8.4Hz,2H).
将实施例3步骤6中的苯乙酸替换为其他不同种类的羧酸，其余所需原料、试剂及制备方法同实施例3，得以下化合物：
Figure PCTCN2022139380-appb-000032
Figure PCTCN2022139380-appb-000033
将实施例3步骤1中的5-羟基吲哚(I-1a)替换为4-氟-5-羟基吲哚，其余所需原料、试剂及制备方法同实施例3，得以下化合物：
Figure PCTCN2022139380-appb-000034
实施例4：
Figure PCTCN2022139380-appb-000035
步骤1：在封管中依次加入500mg的5-溴-2-氰基-3-硝基吡啶、15mL的1,4-二氧六环，再加入350mg的1H-吡咯并[2,3-B]吡啶-5-醇(I-10a)、700mg磷酸钾(K 3PO 4),充分置换氩气后于90℃下反应4h。反应结束后取出冷至室温，乙酸乙酯萃取三次，合并乙酸乙酯层，用饱和氯化钠洗涤一次，最后有机相经无水硫酸钠干燥后浓缩，经柱层析纯化得I-10b，产量：680mg，产率：100％。 1H NMR(400MHz,CDCl 3)δ9.15(s,1H),8.44(d,J＝1.8Hz,1H),8.20(d,J＝2.6Hz,1H),7.73(dd,J＝2.6,0.8Hz,1H),7.47(dd,J＝3.6,2.5Hz,1H),7.28(d,J＝1.8Hz,1H),6.58(dd,J＝3.5,2.0Hz,1H).
步骤2：将770mg的I-10b分散于15mL的乙醇(EtOH)中，再加入15mL 6N氢氧化钠溶液，搭建回流装置后充分置换氩气，再升至80℃反应3h。反应结束后，旋去乙醇，于0℃下用浓盐酸调pH至4-5，直接过滤，滤饼用水充分淋洗、旋干得I-10c，产量：470mg，产率：57.2％，粗品直接投下一步。
步骤3：取470mg的I-10c分散于20mL甲苯，依次加入400μL三乙胺(TEA)、150μL的水、610μL叠氮磷酸二苯酯(DPPA)搭建回流装置后充分置换氩气，反应于90℃下反应3h。反应结束后取出冷至室温，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，用饱和氯化钠洗涤两次，最后有机相经无水硫酸钠干燥后浓缩，经柱层析纯化得I-10d，产量：191mg，产率：44.4％。 1H NMR(400MHz,DMSO-d 6)δ11.78(s,1H),8.10(d,J＝2.7Hz,1H),7.75(d,J＝2.1Hz,1H),7.71(dd,J＝2.6,0.6Hz,1H),7.58–7.50(m,1H),6.90(d,J＝2.1Hz,1H),6.45(dd,J＝3.4,1.9Hz,1H),6.35(s,2H).
步骤4：将190mg的I-10d溶于10mL的醋酸中，在氩气保护下加入120mg的氰基硼氢化钠(NaBH 3CN)，而后于80℃下反应过夜。后处理直接旋去乙酸，经柱层析纯化回收原料135mg，纯化得目标产物I-10e，产量：46mg，产率：81.8％，直接投下一步。
步骤5：将46mg的I-10e、46mg的间三氟甲基苯乙酸(Acid-1)和114mg的N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(HATU，CAS：148893-10-1)溶于6mL的N,N-二甲基甲酰胺(DMF)中，搅拌下加入74μL二异丙基乙基胺(DIPEA)，而后于室温搅拌16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，经柱层析纯化得I-10f，产量：32mg，产率：43.2％。 1H NMR(400MHz,CDCl 3)δ7.97(d,J＝2.6Hz,1H),7.50(d,J＝2.4Hz,2H),7.43(dd,J＝14.1,7.1Hz,3H),7.21(dt,J＝2.8,1.3Hz,1H),6.97(d,J＝1.8Hz,1H),4.58(s,2H),4.27–4.16(t,J＝8.5Hz,2H),3.10(t,J＝8.5Hz,2H).
步骤6：将32mg的I-10f、21mg的1-甲基吡唑-4-硼酸频哪醇酯、21mg的碳酸钠(Na 2CO 3)加入到5mL的1,4-二氧六环和0.6mL水的混合溶液中，再加入23mg的Pd(PPh 3) 4，最后在氩气保护下于90℃反应过夜。反应结束后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，用饱和氯化钠洗涤一次，最后有机相经无水硫酸钠干燥后浓缩，经柱层析纯化得I-10，产量：10mg，产率：31.3％。 1H NMR(400MHz,CDCl 3)δ8.00(d,J＝2.6Hz,2H),7.66(s,1H),7.58(d,J＝6.9Hz,2H),7.52–7.46(m,2H),7.42(t,J＝7.7Hz,1H),7.22(dt,J＝2.6,1.3Hz,1H),7.05(d,J＝1.7Hz,1H),5.20(s,2H),4.58(s,2H),4.19(t,J＝8.5Hz,2H),3.91(s,3H),3.09(t,J＝8.5Hz,2H).
实施例5：
Figure PCTCN2022139380-appb-000036
步骤1：取1g的5-羟基吲哚(I-1a)分散于10mL无水乙醇中，依次加入1.7mL的33％二甲氨基水溶液、700μL的37％甲醛水溶液，反应于室温下搅拌8h。TLC检测原料反应完毕后，旋去溶剂后加甲苯带旋两次，充分抽干得I-11a粗品。产量：1.37g，产率：96.5％，粗品直接投下一步。
步骤2：取1.37g的I-11a分散于30mL无水乙醇中，充分置换氩气后于0℃下搅拌20min，后分两批加入1.43g的硼氢化钠(NaBH 4),加毕后将反应升温至80℃反应12h。反应结束后，取出冷至室温再次于冰浴下搅拌20min，再加入570mg的硼氢化钠，再次回流1h。反应完毕后再次于冰浴下搅拌20min，逐滴加入50mL的水淬灭反应。淬灭完毕后乙酸乙酯萃取三次，合并乙酸乙酯层，用饱和氯化钠洗涤一次，最后有机相经无水硫酸钠干燥后浓缩，经柱层析纯化得I-11b，产量：795mg，产率：72.3％。 1H NMR(400MHz,CDCl 3)δ8.06(s,1H),7.18(t,J＝2.9Hz,1H),7.11(d,J＝8.5Hz,1H),6.77(d,J＝8.6Hz,1H),6.55–6.46(m,1H),4.57(s,1H),2.45(s,3H).
步骤3：在封管中依次加入2.3g的5-溴-2-氰基-3-硝基吡啶、30mL的乙腈，再加入750mg的I-11b、1.76g的磷酸钾(K 3PO 4),充分置换氩气后于80℃下反应12h。反应结束后取出冷至室温，乙酸乙酯萃取三次，合并乙酸乙酯层，用饱和氯化钠洗涤一次，最后有机相经无水硫酸钠干燥后浓缩，经柱层析纯化得I-11c，产量：777.7mg，产率：46.8％。 1H NMR(400MHz,CDCl 3)δ8.43(s,1H),8.36(d,J＝1.8Hz,1H),7.36–7.30(m,2H),7.12(d,J＝1.8Hz,1H),6.87(d,J＝8.7Hz,1H),6.63(ddd,J＝3.2,2.1,0.9Hz,1H),2.37(s,3H).
步骤4：将770mg的I-11c分散于10mL的乙醇(EtOH)中，再加入8mL的6N氢氧化钠溶液，搭建回流装置后充分置换氩气，再升至80℃反应3h。反应结束后，旋去乙醇，于0℃下用浓盐酸调pH至1-2，直接过滤，滤饼用水充分淋洗、旋干得I-11d，产量：660mg，产率：80.2％，粗品直接投下一步。
步骤5：取470mg的I-11d分散于20mL甲苯，依次加入480μL三乙胺(TEA)、600μL的水、740μL叠氮磷酸二苯酯(DPPA)搭建回流装置后充分置换氩气，反应于90℃下反应过夜。反应结束后取出冷至室温，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，用饱和氯化钠洗涤两次，最后有机相经无水硫酸钠干燥后浓缩，经柱层析纯化得I-11e，产量：180.2mg，产率：33.4％。 1H NMR(400MHz,CDCl 3)δ8.39(s,1H),7.75(d,J＝2.0Hz,1H),7.32–7.28(m,1H),7.26(d,J＝1.7Hz,1H),6.88(d,J＝8.7Hz,1H),6.70–6.58(m,2H),4.95(s,2H),2.36(s,3H).
步骤6：将180mg的I-11e溶于10mL的醋酸中，在氩气保护下加入107mg的氰基硼氢化钠(NaBH 3CN)，而后于室温下反应过夜。后处理直接旋去乙酸，经柱层析纯化得目标产物I-11f。产量：128.4mg，产率70.9％。 1H NMR(400MHz,CDCl3)δ7.73(dd,J＝2.0,1.0Hz,1H),6.86–6.62(m,2H),6.49(d,J＝8.2Hz,1H),4.89(s,2H),3.64(t,J＝8.4Hz,2H),3.00(t,J＝8.4Hz,2H),2.01(s,3H).
步骤7：将120mg的I-11f、115mg的间三氟甲基苯乙酸(Acid-1)和286mg的N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(HATU，CAS：148893-10-1)溶于10mL的N,N-二甲基甲酰胺(DMF)中，搅拌下加入186μL二异丙基乙基胺(DIPEA)，而后于室温搅拌16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，经柱层析纯化得I-11g，产量：190mg，产率：100％。 1H NMR(400MHz,CDCl 3)δ8.11(d,J＝8.7Hz,1H),7.76(t,J＝1.8Hz,1H),7.53(dq,J＝25.3,7.8Hz,5H),6.85(d,J＝8.7Hz,1H),4.96(s,2H),4.24–4.16(m,2H),3.87(s,2H),3.17(t,J＝8.4Hz,2H),2.06(s,3H).
步骤8：将180mg的I-11g、111mg的1-甲基吡唑-4-硼酸频哪醇酯、114mg的碳酸钠(Na 2CO 3)加入到10mL的1,4-二氧六环和1mL水的混合溶液中，再加入111mg的Pd(PPh 3) 4，最后在氩气保护下于90℃反应过夜。反应结束后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，用饱和氯化钠洗涤一次，最后有机相经无水硫酸钠干燥后浓缩，经柱层析纯化得I-11，产量：71.6mg，产率：39.7％。 1H NMR(400MHz,CDCl 3)δ8.09(d,J＝8.7Hz,1H),7.90(d,J＝1.9Hz,1H),7.60–7.47(m,5H),7.42–7.35(m,1H),6.85(d,J＝8.7Hz,1H),6.74(d,J＝1.9Hz,1H),4.79(s,2H),4.20(t,J＝8.4Hz,2H),3.88(d,J＝2.1Hz,5H),3.17(t,J＝8.4Hz,2H),2.10(s,3H).
实施例6：
Figure PCTCN2022139380-appb-000037
步骤1：取150mg的I-2f于6mL无水二氯甲烷中，充分置换氩气，再加入151μL二异丙基乙基胺(DIPEA)，冰浴条件下搅拌20min。再逐滴加入49μL特戊酰氯，保持0℃反应30min后升温至室温反应过夜。反应结束后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，用饱和氯化钠洗涤一次，最后有机相经无水硫酸钠干燥后浓缩，经柱层析纯化得I-12a，产量：143.1mg，产率：81.7％。 1H NMR(400MHz,CDCl 3)δ8.26(dd,J＝9.9,8.6Hz,1H),7.58–7.44(m,4H),7.16(s,1H),7.03–6.77(m,3H),4.82(s,1H),4.17(t,J＝8.4,3.9Hz,2H),3.87(s,J＝2.3Hz,2H),3.22(t,J＝8.5,3.1Hz,2H),1.26(s,9H).
步骤2：将100mg的I-12a、55mg的1-甲基吡唑-4-硼酸频哪醇酯、55mg的碳酸钠(Na 2CO 3)加入到8mL的1,4-二氧六环和1mL水的混合溶液中，再加入60mg的Pd(PPh 3) 4，最后在氩气保护下于90℃反应过夜。反应结束后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，用饱和氯化钠洗涤一次，最后有机相经无水硫酸钠干燥后浓缩，经柱层析纯化得I-12，产量：69mg，产率：69％。 1H NMR(400MHz,CDCl 3)δ8.33(d,J＝2.0Hz,1H),8.25(d,J＝8.7Hz,1H),7.91(s,1H),7.62(s,1H),7.58–7.47(m,5H),7.17(d,J＝2.0Hz,1H),6.95–6.81(m,2H),4.16(t,J＝8.4Hz,2H),3.92(s,3H),3.87(s,2H),3.21(t,J＝8.4Hz,2H),1.27(s,9H).
实施例7：
Figure PCTCN2022139380-appb-000038
步骤1：取88mg的I-2f于3mL无水四氢呋喃中，充分置换氩气，冰浴条件下搅拌20min。再加入8mg氢化钠(60％，NaH)，保持冰浴30min后升温至室温，反应1h。后逐滴加入12μL碘甲烷(MeI),滴加完毕后反应过夜。反应结束后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，用饱和氯化钠洗涤一次，最后有机相经无水硫酸钠干燥后浓缩，经制备薄层纯化得I-13a，产量：23mg，产率：25.5％。 1H NMR(400MHz,CDCl 3)δ8.32(d,J＝8.8Hz,1H),7.81(s,1H),7.65–7.50(m,3H),7.47(t,J＝7.7Hz,1H),6.94(d,J＝1.9Hz,1H),6.89(dd,J＝8.7,2.6Hz,1H),6.82(d,J＝2.5Hz,1H),4.94(s,1H),4.20(td,J＝10.3,6.5Hz,1H), 3.95(q,J＝6.9Hz,1H),3.84(td,J＝10.3,6.4Hz,1H),3.17(ddd,J＝16.8,10.4,6.5Hz,1H),3.06(ddd,J＝16.6,10.5,6.5Hz,1H),1.56(d,J＝6.8Hz,3H).
步骤2：将23mg的I-13a、15mg的1-甲基吡唑-4-硼酸频哪醇酯、55mg的碳酸钠(Na 2CO 3)加入到5mL的1,4-二氧六环和0.5mL水的混合溶液中，再加入16mg的Pd(PPh 3) 4，最后在氩气保护下于90℃反应6h。反应结束后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，用饱和氯化钠洗涤一次，最后有机相经无水硫酸钠干燥后浓缩，经柱层析纯化得I-13，产量：11.5mg，产率：50％。 1H NMR(400MHz,CDCl 3)δ8.31(d,J＝8.8Hz,1H),7.94(d,J＝1.8Hz,1H),7.62–7.52(m,4H),7.50–7.41(m,2H),7.01(d,J＝1.9Hz,1H),6.91(dd,J＝8.7,2.5Hz,1H),6.82(d,J＝2.6Hz,1H),4.88(s,1H),4.19(td,J＝10.3,6.6Hz,1H),3.95(q,J＝6.7Hz,1H),3.89(s,3H),3.83(dt,J＝10.2,5.1Hz,1H),3.16(ddd,J＝16.7,10.5,6.7Hz,1H),3.05(ddd,J＝16.6,10.4,6.5Hz,1H),1.56(d,J＝6.8Hz,3H).
实施例8：
Figure PCTCN2022139380-appb-000039
将76mg的I-2f、42mg的3,4-二甲氧基苯硼酸、50mg的碳酸钠(Na 2CO 3)加入到8mL的1,4-二氧六环和1mL水的混合溶液中，再加入42mg的Pd(PPh 3) 4，最后在氩气保护下于90℃反应6h。反应结束后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，用饱和氯化钠洗涤一次，最后有机相经无水硫酸钠干燥后浓缩，经柱层析纯化得I-14，产量：37mg，产率：44％。 1H NMR(400MHz,CDCl 3)δ8.23(d,J＝8.8Hz,1H),8.04(d,J＝2.1Hz,1H),7.68–7.63(m,2H),7.55–7.53(m,2H),7.48–7.44(m,3H),7.16(d,J＝2.0Hz,1H),6.93(d,J＝1.7Hz,2H),4.81(s,2H),4.14(t,J＝8.4Hz,2H),3.89(d,J＝6.0Hz,6H),3.86(s,2H),3.19(t,J＝8.4Hz,2H).
将实施例8中的3,4-二甲氧基苯硼酸替换为其他不同种类的芳环、杂环的硼酸或硼酸酯，其余所需原料、试剂及制备方法不变，得以下化合物：
Figure PCTCN2022139380-appb-000040
Figure PCTCN2022139380-appb-000041
Figure PCTCN2022139380-appb-000042
Figure PCTCN2022139380-appb-000043
实施例9：
Figure PCTCN2022139380-appb-000044
步骤1：在封管内依次加入300mg的4-吡唑硼酸频哪醇酯(I-15a)、7mL的N,N-二甲基甲酰胺(DMF)和600mg的碳酸铯，反应于室温下搅拌20min，再逐滴加入280μL的2-(2-溴乙氧基)四氢-2H-吡喃，充分置换氩气后于70℃下反应18h。反应结束后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，用饱和氯化钠洗涤一次，最后有机相经无水硫酸钠干燥后浓缩，经柱层析纯化得I-15b，产量：237.6mg，产率：47.6％。直接投下一步。
步骤2：用I-15b替换3,4-二甲氧基苯硼酸，其余所需原料、试剂及制备方法同实施例7中的步骤相同，得产品I-15c，产量：62mg，产率：43％。直接投下一步。
步骤3：将40mg的I-15c溶解于7mL无水甲醇中，充分置换氩气后加入3mg的对甲苯磺酸(PTSA)，反应保持室温过夜。TLC检测反应结束后直接浓缩制备薄层分离纯化，得I-15，产量：32mg，产率：92.7％。 1H NMR(400MHz,CDCl 3)δ8.24(d,J＝8.7Hz,1H),7.92(s,1H),7.61(s,1H),7.52(td,J＝15.8,15.2,7.1Hz,6H),7.01(d,J＝1.9Hz,1H),6.94–6.88(m,1H),6.87(s,1H),5.02(s,2H),4.25–4.21(m,2H),4.17(t,J＝8.4Hz,2H),4.01(dd,J＝5.5,4.1Hz,2H),3.87(s,2H),3.22(t,J＝8.4Hz,2H).
实施例10：
Figure PCTCN2022139380-appb-000045
步骤1：在封管中依次加入300mg的2-氨基-3,5-二溴吡嗪(I-16a)、15mL的N-甲基吡咯烷酮(NMP)，再加入331mg的I-3a、330mg的碳酸钾(K 2CO 3),充分置换氩气后于100℃下反应6h。反应结束后取出冷至室温，将反应液倒入水中乙酸乙酯萃取三次，合并乙酸乙酯层，用饱和氯化钠洗涤三次，最后有机相经无水硫酸钠干燥后浓缩，经柱层析纯化得I-16b，产量：310mg，产率：64.5％。 1H NMR(400MHz,DMSO-d 6)δ11.25(s,1H),7.68(s,1H),7.45–7.38(m,2H),7.34(d,J＝2.3Hz,1H),6.91(dd,J＝8.7,2.3Hz,1H),6.88–6.70(s,2H),6.44(t,J＝2.6Hz,1H).
步骤2：将300mg的I-16b溶于15mL的醋酸中，在氩气保护下分三批加入190mg的氰基硼氢化钠(NaBH 3CN)，而后于室温搅拌过夜。TLC检测反应结束后，直接旋去乙酸，再浓缩经柱层析纯化得I-16c。产量：130mg，产率43.3％。 1H NMR(400MHz,CDCl 3)δ7.66(d,J＝1.4Hz,1H),6.95–6.88(m,1H),6.78(dt,J＝8.3,2.0Hz,1H),6.62(dd,J＝8.4,1.4Hz,1H),5.23(s,2H),3.58(t,J＝8.4Hz,2H),3.04(t,J＝8.4Hz,2H),2.69(d,J＝1.4Hz,1H).
步骤3：将110mg的I-16c、81mg的间三氟甲基苯乙酸(Acid-1)和205mg的N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(HATU，CAS：148893-10-1)溶于10mL的N,N-二甲基甲酰胺(DMF)中，搅拌下加入180μL二异丙基乙基胺(DIPEA)，而后于室温搅拌 16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，经柱层析纯化得I-16d，产量：123mg，产率：70％。 1H NMR(400MHz,CDCl 3)δ8.26(dd,J＝8.8,2.5Hz,1H),7.75(d,J＝2.4Hz,1H),7.64–7.42(m,4H),7.09–6.86(m,2H),4.95(s,2H),4.16(td,J＝8.5,2.5Hz,2H),3.86(d,J＝2.6Hz,2H),3.24(t,J＝8.5Hz,2H).
步骤4：将120mg的I-16d、76mg的1-甲基吡唑-4-硼酸频哪醇酯、78mg的碳酸钠(Na 2CO 3)加入到10mL的1,4-二氧六环和1mL水的混合溶液中，再加入85mg的Pd(PPh 3) 4，最后在氩气保护下于90℃反应12h。反应结束后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，用饱和氯化钠洗涤一次，最后有机相经无水硫酸钠干燥后浓缩，经柱层析纯化得I-16，产量：92.7mg，产率：77％。 1H NMR(400MHz,CDCl 3)δ8.30–8.24(m,1H),7.87(s,1H),7.70–7.66(m,1H),7.60–7.52(m,3H),7.50(d,J＝6.5Hz,2H),7.08–7.02(m,2H),4.89(s,2H),4.18(t,J＝8.4Hz,2H),3.87(d,J＝8.6Hz,5H),3.24(t,J＝8.4Hz,2H).
实施例11：
Figure PCTCN2022139380-appb-000046
步骤1：在封管中依次加入200mg的2-硝基-3-氟吡啶(I-17a)、15mL的乙腈(MeCN)，再加入400mg的I-3a、290mg的碳酸钾(K 2CO 3),充分置换氩气后于80℃下反应16h。反应结束后取出冷至室温，将反应液倒入水中乙酸乙酯萃取三次，合并乙酸乙酯层，用饱和氯化钠洗涤三次，最后有机相经无水硫酸钠干燥后浓缩，经柱层析纯化得I-17b，产量：501mg，产率：100％。 1H NMR(400MHz,CDCl 3)δ8.24–8.07(m,2H),7.65(d,J＝4.1Hz,1H),7.42(ddt,J＝8.8,4.5,2.2Hz,1H),7.33(dt,J＝8.5,2.0Hz,1H),7.04(dt,J＝9.0,2.3Hz,1H),6.98–6.76(m,1H),6.53(dt,J＝4.3,2.3Hz,1H),1.66(s,9H).
步骤2：取800mg的I-17b分散于20mL乙醇，再加入饱和氯化铵溶液10mL，充分置换氩气后于80℃下反应过夜。反应结束后取出冷至室温，旋去乙醇后再乙酸乙酯萃取三次，合并乙酸乙酯层，用饱和氯化钠洗涤三次，最后有机相经无水硫酸钠干燥后浓缩，经柱层析纯化得I-17c，产量：380mg，产率：76％。 1H NMR(400MHz,CDCl 3)δ8.35(s,1H),7.78(dd,J＝5.0,1.5Hz,1H),7.38(dt,J＝8.7,0.7Hz,1H),7.27(t,J＝2.3Hz,2H),6.94(dd,J＝8.7,2.3Hz,1H),6.89(dd,J＝7.8,1.5Hz,1H),6.55(dd,J＝7.8,5.0Hz,1H),6.51(ddd,J＝3.1,2.1,1.0Hz,1H),4.79(s,2H).
步骤3：将200mg的I-17c溶于8mL的醋酸中，在氩气保护下分三批加入116mg的氰基硼氢化钠(NaBH 3CN)，而后于室温搅拌过夜。TLC检测反应结束后，直接旋去乙酸，再浓缩经柱层析纯化得I-17d。产量：213mg，产率100％。 1H NMR(400MHz,CDCl 3)δ7.58(dd,J＝5.5,1.4Hz,1H),6.89(dd,J＝7.9,1.4Hz,1H),6.82(dt,J＝2.5,1.2Hz,1H),6.71(dd,J＝8.3,2.4Hz,1H),6.62(d,J＝8.3Hz,1H),6.53(dd,J＝7.8,5.5Hz,1H),5.34(s,2H),3.60(t,J＝8.4Hz,2H),3.03(t,J＝8.4Hz,2H).
步骤4：将115mg的I-17d、115mg的间三氟甲基苯乙酸(Acid-1)和285mg的N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(HATU，CAS：148893-10-1)溶于8mL的N,N- 二甲基甲酰胺(DMF)中，搅拌下加入245μL二异丙基乙基胺(DIPEA)，而后于室温搅拌16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，经柱层析纯化得I-17，产量：70mg，产率：34％。 1H NMR(400MHz,CDCl 3)δ8.20(d,J＝8.7Hz,1H),7.81(dd,J＝5.0,1.5Hz,1H),7.57–7.43(m,4H),6.95(dd,J＝7.8,1.5Hz,1H),6.87–6.80(m,2H),6.58(dd,J＝7.8,5.0Hz,1H),4.82(s,2H),4.13(t,J＝8.4Hz,2H),3.85(s,2H),3.18(t,J＝8.4Hz,2H).
实施例12：
Figure PCTCN2022139380-appb-000047
步骤1：取3g的2-溴-3-氟-4-甲基吡啶(I-18a)、1.85g的氰化锌和3.6g四(三苯基膦)钯分散于30mL的N,N-二甲基甲酰胺中，充分置换氩气后于90℃下反应18h。反应完毕后取出冷至室温，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，经柱层析纯化得I-18b，产量：1.056g，产率：49.3％。 1H NMR(400MHz,CDCl 3)δ8.36(d,J＝4.8Hz,1H),7.42(t,J＝5.4Hz,1H),2.39(s,3H).
步骤2：在封管中依次加入900mg的I-18b、6mL的N,N-二甲基甲酰胺，再加入2g的I-3a、4.3g的碳酸铯(Cs 2CO 3),充分置换氩气后于80℃下反应3h。反应结束后取出冷至室温，将反应液倒入水中乙酸乙酯萃取三次，合并乙酸乙酯层，用饱和氯化钠洗涤三次，最后有机相经无水硫酸钠干燥后浓缩，经柱层析纯化得I-18c，产量：1.89g，产率：74.3％。 1H NMR(400MHz,CDCl 3)δ8.45(d,J＝4.7Hz,1H),8.09(d,J＝8.9Hz,1H),7.61(d,J＝3.7Hz,1H),7.50–7.39(m,1H),6.92(dd,J＝9.0,2.6Hz,1H),6.88(d,J＝2.6Hz,1H),6.46(d,J＝3.7Hz,1H),2.22(s,3H),1.66(s,9H).
步骤3：将1.89g的I-18c分散于20mL的乙醇(EtOH)中，再加入18mL 6N氢氧化钠溶液，搭建回流装置后充分置换氩气，再升至80℃反应3h。反应结束后，旋去乙醇，于0℃下用浓盐酸调pH至1-2，直接过滤，滤饼用水充分淋洗、旋干得I-18d，产量：877mg，产率：60.4％，粗品直接投下一步。
步骤4：取777mg的I-18d分散于20mL甲苯中，依次加入0.8mL三乙胺(TEA)、500μL水、1.3mL叠氮磷酸二苯酯(DPPA)搭建回流装置后充分置换氩气，反应于90℃下反应过夜。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，用饱和氯化钠洗涤两次，最后有机相经无水硫酸钠干燥后浓缩，经柱层析纯化得I-18e，产量：211mg，产率：30.4％。直接投下一步。
步骤5：将211mg的I-18e溶于10mL的醋酸中，在氩气保护下分三批加入190mg的氰基硼氢化钠(NaBH 3CN)，而后于室温搅拌过夜。TLC检测反应结束后，直接旋去乙酸，再浓缩经柱层析纯化得I-18f。产量：227mg，产率100％。直接投下一步。
步骤6：将80mg的I-18f、68mg的间三氟甲基苯乙酸(Acid-1)和164mg的N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(HATU，CAS：148893-10-1)溶于8mL的N,N-二甲基甲酰胺(DMF)中，搅拌下加入170μL二异丙基乙基胺(DIPEA)，而后于室温搅拌16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，经柱层析纯化得I-18，产量：60mg，产率：42.8％。 1H NMR(400MHz,CDCl 3)δ8.15(d,J＝8.8Hz,1H),7.82(d,J＝5.1Hz,1H),7.57–7.43(m,4H),6.70(dd,J＝8.8,2.7Hz,1H),6.66–6.61(m,1H),6.56(d,J＝5.2Hz,1H),4.57(s,2H),4.10(t,J＝8.4Hz,2H),3.84(s,2H),3.15(t,J＝8.4Hz,2H),2.07(s,3H).
实施例13：
Figure PCTCN2022139380-appb-000048
用3,5-二甲基吡唑-4-硼酸频那醇酯替换I-15a，其余所需原料、试剂及制备方法同实施例9中的步骤相同，得产品I-19。 1H NMR(400MHz,Methanol-d 4)δ8.11(d,J＝8.8Hz,1H),7.64(s,1H),7.54(dd,J＝14.4,7.3Hz,6H),6.99(s,1H),4.23(q,J＝7.9,7.4Hz,3H),4.10(t,J＝5.4Hz,2H),3.98(s,2H),3.83(t,J＝5.4Hz,2H),3.31(s,7H),3.22(t,J＝8.5Hz,2H),2.20(s,3H),2.10(s,3H).
实施例14：
Figure PCTCN2022139380-appb-000049
步骤1：将60mg的I-3e、80mg的Acid-3和164mg的N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲溶于8mL的N,N-二甲基甲酰胺(DMF)中，搅拌下加入210μL二异丙基乙基胺(DIPEA)，而后于室温搅拌16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，旋干得粗品直接投下一步。
步骤2：将163mg的I-20a、100mg的I-19b、110mg的碳酸钠加入到5mL的1,4-二氧六环和0.5mL水的混合溶液中，再加入40mg的Pd(PPh 3) 4，最后在氩气保护下于90℃反应12h。反应结束后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，用饱和氯化钠洗涤一次，最后有机相经无水硫酸钠干燥后浓缩，经柱层析纯化得I-20，产量：98mg，产率：66.7％。1H NMR(400MHz,Chloroform-d)δ8.19(d,J＝8.5Hz,1H),7.73–7.62(m,2H),7.53(t,J＝7.5Hz,1H),7.45–7.35(m,2H),6.91–6.78(m,3H),4.89(s,2H),4.49(t,J＝3.4Hz,1H),4.18(t,J＝5.6Hz,2H),4.12(t,J＝8.4Hz,2H),4.04–3.93(m,3H),3.78–3.52(m,3H),3.49–3.37(m,4H),3.18(t,J＝8.4Hz,2H),2.19(s,3H),2.12(s,3H),1.75–1.34(m,9H).
步骤3：将50mg的I-20b溶解于7mL无水甲醇中，充分置换氩气后加入5mg的对甲苯磺酸(PTSA)，反应保持室温过夜。TLC检测反应结束后直接浓缩制备薄层分离纯化，得I-20，产量：40mg，产率：93％。1H NMR(400MHz,Chloroform-d)δ8.16(d,J＝8.6Hz,1H),7.86(t,J＝7.8Hz,1H),7.68–7.62(m,2H),7.59(d,J＝7.7Hz,1H),6.90–6.83(m,2H),6.81(d,J＝1.9 Hz,1H),4.91(s,2H),4.32(t,J＝8.4Hz,2H),4.06(d,J＝6.0Hz,4H),3.97(dd,J＝5.6,3.9Hz,2H),3.19(t,J＝8.3Hz,2H),2.13(d,J＝14.7Hz,6H).
将实施例14中的Acid-3替换为其他不同种类的羧酸，其余所需原料、试剂及制备方法不变，得以下化合物：
Figure PCTCN2022139380-appb-000050
Figure PCTCN2022139380-appb-000051
Figure PCTCN2022139380-appb-000052
Figure PCTCN2022139380-appb-000053
实施例15：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 TM Reagent,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
化合物 IC 50 化合物 IC 50
I-2 A I-14-40 A
I-5 B I-15 A
I-6 B I-17 A
I-7 B I-18 A
I-8 B I-19 A
I-9 B I-20 A
I-9-2 A I-20-2 B
I-11 B I-20-3 B
I-14 B I-20-4 B
I-14-37 B I-20-31 A
I-14-38 A I-20-33 A
I-14-39 A I-20-34 A
其中，A表示IC 50小于(≤)0.1μM；B表示IC 50小于(≤)1μM且大于(＞)0.1μM
C表示IC 50大于(＞)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。
实施例16：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，一小时之后加入不同浓度的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SpectraMax 190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
化合物 IC 50 化合物 IC 50
I-2 A I-20 A
I-5 A I-20-2 B
I-6 B I-20-3 B
I-7 B I-20-4 B
I-11 B I-20-5 A
I-14 A I-20-6 A
I-15 A I-20-8 A
I-17 B I-20-9 A
I-18 B I-20-10 B
I-14-12 A I-20-15 A
I-14-15 B I-20-16 A
I-14-17 B I-20-17 A
I-19 A I-20-18 A
其中，A表示IC 50小于(≤)0.1μM；B表示IC 50小于(≤)1μM且大于(＞)0.1μM；C表示IC 50大于(＞)1μM
从上述试验结果可以看出本发明化合物对于TNFα诱导的I2.1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 PCTCN2022139380-appb-100001
    式中，环A为6元杂芳环；环E为苯环或6元杂芳环；环G为5-6元杂芳环或5-6元杂环；
    Z选自CH 2、一个或二个卤素取代的CH 2、CDH、CD 2、O、S、NH、N(CH 3)、N(CD 3)；
    Y1为N或C-R 1a；其中，R 1a选自H、D、卤素、NR 1R 2；R 1、R 2独立地选自：H、D、C1-C8烷基、C1-C15烷基C(＝O)-、C1-C15烷基OC(＝O)-、C1-C15烷基-O-(C1-C8亚烷基)-、C1-C15烷基(O＝)CO-、C2-C8烯基、C2-C8炔基、C6-C14芳基C(＝O)-、氨基酸酰基、C1-C8烷基-C(＝O)-CH＝CH-；上述R 1、R 2基团可选地被选自下组的1-5个基团取代：C6-C14芳基、(C1-C8烷基) 3Si-、氨基、羟基、卤素、一个或二个C1-C8烷基取代基的氨基、氧代(＝O)、C1-C8烷基；
    Y2为N或C-R 2a；其中，R 2a选自下组：H、D、卤素、C1-C8烷基、C1-C8烷氧基、卤代C1-C8烷基、卤代C1-C8烷氧基、3-14元环烷基、3-14元杂环基、C2-C8烯基、C2-C8炔基；上述R 2a基团可选地被选自下组的1-5个基团取代：D、卤素、羟基、氨基、一个或二个C1-C8烷基取代基的氨基、氰基、NH 2C(＝O)-、C1-C8烷基；
    Y3为N或C-R 3a；其中，R 3a选自下组：H、D、卤素、C1-C8烷基、C1-C8烷氧基、卤代C1-C8烷基、卤代C1-C8烷氧基、5-14元杂芳基、C3-C14环烷基、C6-C14芳基、3-14元杂环基、NH 2CO-、C2-C8烯基、卤代的C2-C8烯基、C2-C8烯基氧基、卤代的C2-C8烯基氧基、C2-C8炔基、卤代的C2-C8炔基、C2-C8炔基氧基、卤代的C2-C8炔基氧基、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)(C1-C8烷基)-、(C1-C8烷基)-NHC(＝O)-、(C1-C8烷基)(C1-C8烷基)N-C(＝O)-、(C1-C8烷基)-NHC(＝O)-(C1-C8烷基)-、(C1-C8烷基)(C1-C8烷基)N-C(＝O)-(C1-C8烷基)-、HC(＝O)NH-、HC(＝O)N(C1-C8烷基)-、(C1-C8烷基)-C(＝O)NH-、(C1-C8烷基)-C(＝O)N(C1-C8烷基)-、(5-14元杂芳基)-NHC(＝O)-；其中，R 3a可选地被0-5个R 3a1取代；
    各R 3a1在每次出现时独立地选自：C1-C8烷基、氧代(＝O)、C2-C8烯基、C2-C8炔基、C1-C8烷氧基、3-14元杂环基、3-14元杂环基-C(＝O)-、C3-C14环烷基、5-14元杂芳基、H、D、卤素、卤代C1-C8烷基、卤代的C1-C8烷氧基、卤代C2-C8烯基、C2-C8烯基氧基、卤代C2-C8烯基氧基、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)-(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)-(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)-(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)-、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)-(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)-、(C1-C8烷基)-NHC(＝O)-、(C1-C8烷基)(C1-C8烷基)N-C(＝O)-、(C1-C8烷基)-NHC(＝O)-(C1-C8烷基)-、(C1-C8烷基)(C1-C8烷基)N-C(＝O)-(C1-C8烷基)-、HC(＝O)NH-、HC(＝O)N(C1-C8烷基)-、(C1-C8烷基)-C(＝O)NH-、(C1-C8烷基)-C(＝O)N(C1-C8烷基)-、硫代(＝S)；其中，R 3a1可选地被0-5个R 3a2取代；
    各R 3a2在每次出现时独立地选自：-CN、(C6-C14芳基)-(C1-C8烷基)氧基、氨基、羟基、卤代C1-C8烷基、C1-C8烷氧基、-N(C1-C8烷基)(C1-C8烷基)、C1-C8烷基、氧代(＝O)、-NH(C1-C8烷基)、NH 2CO-、C1-C8烷氧基取代的C1-C8烷氧基、C1-C14烷基OC(＝O)-、C1-C14烷基C(＝O)O-、C3-C14环烷基氧基、C1-C8烷基取代的3-14元杂环基、H、D、卤素、卤代的C1-C8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)-(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)-、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)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)-、羟基取代的C1-C8烷基、巯基、巯基取代的C1-C8烷基、氨基取代的C1-C8烷基、氰基取代的C1-C8烷基、-COOH、-(C1-C8烷基)-COOH、-(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)、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)-、硫代(＝S)；上述R 3a1、R 3a2可选被0-5个R 3a3取代；
    R 3a3为“-Linker-R 3a4”；上述Linker选自：键、O、NH、NR 3a4、-C(＝O)O-、-OC(＝O)-、-C(＝O)NH-、-C(＝O)NR 3a4-、3-14元环烷基、3-14元杂环基、C6-C14芳基、5-14元杂芳基；
    R 3a4选自：H、D、卤素、C1-C8烷基、羟基、羟基取代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；
    其中，可选地两个R 3a1可以与它们各自所连的原子一起形成3-18元环结构；
    其中，可选地两个R 3a2可以与它们各自所连的原子一起形成3-18元环结构；
    Y4为N或C-R 4a；R 4a选自H、D、C1-C6烷基、氨基、卤素、-C(R 4b)＝C(R 4c)-R 4d、-C(R 4b)＝N-R 4d、-N＝C(R 4c)-R 4d、-N＝N-R 4d、-C(R 4e)(R 4f)-R 4d、-C(＝O)-R 4d、-C(＝S)-R 4d、NR 4eR 4f、NR 4bC(＝O)R 4d；其中，R 4a可选地被0-5个R 4a1取代，各R 4a1在每次出现时独立地选自：卤素、C3-C6环烷基、C1-C6烷基C(＝O)-；
    可选地，R 2a、R 3a与它们各自所连接的碳一起形成由0至5个R b1取代或未取代的3-18元环结构；
    可选地，R 4a、R 3a与它们各自所连接的碳一起形成由0至5个R b2取代或未取代的3-18元环结构，
    各R b1、各R b2在每次出现时独立地选自：H、D、卤素、氧代、硫代、C1-C8烷基、羟基C1-C8烷基、C1-C8烷氧基、C3-C14环烷基、卤代C1-C8烷基、卤代的羟基C1-C6烷基、卤代C1-C8烷氧基、卤代C3-C14环烷基、3-14元杂环基、C6-C14芳基、5-14元杂芳基、C2-C8烯基、卤代的C2-C8烯基、C2-C8烯基氧基、卤代的C2-C8烯基氧基、C2-C8炔基、卤代的C2-C8炔基、C2-C8炔基氧基、卤代的C2-C8炔基氧基、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；可选地，R b1、R b2可以被0-5个R b3取代；R b3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C1-C8烷氧基、C2-C8烯基、卤代的C2-C8烯基、C2-C8烯基氧基、卤代的C2-C8烯基氧基、C2-C8炔基、卤代的C2-C8炔基、C2-C8炔基氧基、卤代的C2-C8炔基氧基、羟基C1-C8烷基、卤代的羟基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、氧代、硫代、(C1-C6烷基)3-Si-(C1-C6烷基)-O-(C1-C6亚烷基)-、C1-C15烷基OC(O)-、(C1-C8烷基)-OC(O)-(C1-C8烷基)COO-、C1-C8烷基-C(O)-CH＝CH-；
    V1、V2、V3各自独立地选自N、C-R c；R c选自下组：H、D、卤素、C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、卤代C1-C6烷基、卤代C1-C6烷氧基、卤代C3-C6环烷基；
    V4、V5各自独立地为C或N；
    虚线表示的每个键独立地选自下组：单键、双键；
    W不存在且V5与X1直接相连，或者，W为C(＝O)、C(＝S)、C(R d)(R e)、N(R d)、C、N、O、S；
    X1、X2独立地选自C(＝O)、C(＝S)、C(R f)、C(R f)(R g)、N、N(R f)；
    L选自被1至5个R h所取代或未取代的下组基团：C1-C12直链或支链亚烷基、-(CH2) m-NH-(CH2) n-、-(CH2) m-O-(CH2) n-、-(CH2) m-S-(CH2) n-、-(CH2) m-(S＝O)-(CH2) n-、-(CH2) m-(S＝O)2-(CH2) n-；各R h在每次出现时独立地选自：卤素、C1-C6烷基；可选地，R h与连接的碳形成3-6元饱和环；
    m每次出现时独立地选自1、2、3、4；
    n每次出现时独立地选自0、1、2、3；
    U为由1至5个R i取代或未取代的下组基团：C5-C14元芳基、5-14元杂芳基、C3-C14环烷基、3-14元杂环基；各R i在每次出现时独立地选自：卤代C1-C8烷基、C1-C8烷基、卤素、C6-C14芳基、苯并5-14元杂芳基、卤代C1-C8烷氧基、H、D、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、3-14元杂环基、5-14元杂芳基、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)-、NH 2C(＝O)(C1-C8烷基)-、(C1-C8烷基)-NHC(＝O)-、(C1-C8烷基)(C1-C8烷基)N-C(＝O)-、(C1-C8烷基)-NHC(＝O)-(C1-C8烷基)-、(C1-C8烷基)(C1-C8烷基)N-C(＝O)-(C1-C8烷基)-、HC(＝O)NH-、HC(＝O)N(C1-C8烷基)-、(C1-C8烷基)-C(＝O)NH-、(C1-C8烷基)-C(＝O)N(C1-C8烷基)-、氧代(＝O)、硫代(＝S)；其中，R i可选地被0-5个R i1取代；
    各R i1在每次出现时独立地选自：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)-、-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)、(C1-C6烷基)3-Si-(C1-C6烷基)-O-(C1-C6亚烷基)-、C1-C15烷基OC(O)-、(C1-C8烷基)-OC(O)-(C1-C8烷基)COO-、C1-C8烷基-C(O)-CH＝CH-；
    其中，可选地两个R i1可以与它们各自所连的原子一起形成3-18元环结构；
    R 4b、R 4c、R 4d、R 4e、R 4f在每次出现时独立地选自下组：H、D、卤素、C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、卤代C1-C6烷基、卤代C1-C6烷氧基、卤代C3-C6环烷基；
    R d、R e在每次出现时独立地选自下组：H、D、卤素、C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、卤代C1-C6烷基、卤代C1-C6烷氧基、卤代C3-C6环烷基；
    R f、R g在每次出现时独立地选自下组：H、D、卤素、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基。
  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、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，其特征在于，所述化合物选自式(II)、式(III)或式(IV)所示化合物：
    Figure PCTCN2022139380-appb-100002
    其中，R 1、R 2、R 2a、R 3a、R 4a、Y2、Y3、Y4、V1、V2、V3、L、U、虚线的定义如权利要求1所述。
  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、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，其特征在于，所述化合物选自式(V)或式(VI)所示化合物：
    Figure PCTCN2022139380-appb-100003
    其中，Y2、Y3、V1、V2、V3、L、U、R 4a、虚线的定义如权利要求1所述；
    R 1b、R 1c在每次出现时独立地选自：H、D、卤素、-NH(CH 3)、C1-C6烷基CONH-、C1-C6烷基OC(O)NH-、-NH 2、(C1-C8烷基) 3Si-(C1-C8烷基)O(C1-C8烷基)NH-、C6-C14芳基(C1-C8烷基)OC(O)NH-、C6-C14芳基C(O)NH-、-NH(C2-C8烯基)、，上述基团可选地被选自下组的1-5个基团取代：氨基、羟基、C1-C8烷基、氧代；
    环Q为五元环；Q1、Q2、Q3独立地选自：C(＝O)、C(＝S)、C(R 4e)、C(R 4e)(R 4f)、N、N(R 4e)；
    R 4e、R 4f的定义如权利要求1所述。
  4. 根据权利要求1-3任一项中所述的式(I)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，其特征在于：Z为O；W不存在且环G为五元杂环或五元杂芳环；L为“-(CH 2)-”或-(CH 2CH 2)-；U选自被1-5个R i取代或未取代的苯基、5-6元杂芳环、C3-C8环烷基；R i的定义如权利要求1所述。
  5. 根据权利要求1-4任一项中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，其特征在于，所述化合物选自下组：
    Figure PCTCN2022139380-appb-100004
    Figure PCTCN2022139380-appb-100005
    Figure PCTCN2022139380-appb-100006
    Figure PCTCN2022139380-appb-100007
    Figure PCTCN2022139380-appb-100008
    Figure PCTCN2022139380-appb-100009
    Figure PCTCN2022139380-appb-100010
  6. 一种制备权利要求1所述化合物的方法，其特征在于，所述方法包括反应式1、反应式2或反应式3中的至少一个：
    Figure PCTCN2022139380-appb-100011
    在反应式1、反应式2、反应式3中，
    R 6a选自
    Figure PCTCN2022139380-appb-100012
    -O-R 6i，卤素，C1-C12烷基，-SO 3H，-SO 3Na，-OB(OH) 2，-B(OH) 2；
    R 6b选自-OH，卤素，-OC(＝O)-R 6i，-OS(＝O)-R 6i，-OS(＝O)2-R 6i；
    R 6c选自-L-U，-L-X，-L-Mg-X，-L-OH，-L-O-R 6i，-L-R 6i；
    R 6d选自-CN，卤素，-NO 2，-CONR 6iR 6j，-COOR 6i；
    R 6e，R 6f在每次出现时独立地选自H，-C(＝O)-L-U，-C(＝O)-L-X，-C(＝O)-L-Mg-X，-C(＝O)-L-OH，-C(＝O)-L-O-R 6i，-C(＝O)-L-R 6i；
    R 6g、R 6h选自卤素、-Mg-X、-Li、-Na、-K、-B(OH) 2、4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基或其它含硼的取代基；
    R 6i、R 6j在每次出现时独立地为H、D、C1-C8烷基、C1-C8烷氧基、C6-C14芳基、C6-C14芳基氧基；
    X在每次出现时独立地选自下组：F、Cl、Br、I；
    Y1、Y2、Y3、Y4、V1、V2、V3、V4、V5、W、X1、X2、Z、R 3a、虚线的定义如权利要求1所述。
  7. 根据权利要求1所述的化合物的制备方法，其特征在于，所述制备方法选自下述方案一至方案六：
    方案一：
    Figure PCTCN2022139380-appb-100013
    将RX-1a与RX-1b进行芳香亲核取代反应或偶联反应得到RX-1c；
    将RX-1c进行加氢还原得到RX-1d；
    将RX-1d与羧酸RX-1e进行缩合反应得到RX-1所示化合物；
    方案二：
    Figure PCTCN2022139380-appb-100014
    将RX-2a与RX-1e进行缩合反应得到RX-2b；
    将RX-2b与RX-2c进行芳香亲核取代反应得到RX-2d；
    将RX-2d的氰基进行水解得到RX-2e；
    将RX-2e进行Hoffman降解反应得到RX-2f；
    将RX-2f与R 3a的硼酸或硼酸频哪醇酯进行偶联反应得到RX-2；
    方案三：
    Figure PCTCN2022139380-appb-100015
    将RX-1a与RX-2c进行芳香亲核取代反应得到RX-3b，再进一步水解为RX-3d；
    或者将RX-1a与二碳酸二叔丁酯(Boc 2O)反应得到RX-3a，再与RX-2c进行取代反应得到RX-3c，接下来在氢氧化钠存在下，将RX-3c水解为RX-3d；
    将RX-3d通过Curtius重排反应得到RX-3e；
    将RX-3e进行还原反应得到RX-3f；
    把RX-3f与相应羧酸进行酰胺缩合得到RX-3g；
    将RX-3g与R 3a的硼酸或硼酸频哪醇酯进行偶联反应得到RX-3；
    方案四：
    Figure PCTCN2022139380-appb-100016
    将RX-2d的氨基引入取代基得到RX-4a；
    RX-4a再与R 3a的硼酸或硼酸频哪醇酯进行偶联反应得到RX-4；
    其中，R为C1-C15烷基、C1-C15烷氧基、C1-C15烷基-O-(C1-C8亚烷基)-、C1-C15烷基-O-或C6-C14芳基；
    方案五：
    Figure PCTCN2022139380-appb-100017
    将RX-5a与RX-3c进行取代反应得到RX-5b；
    RX-5b脱去保护基得到RX-5c；
    将RX-5c进行还原得到RX-5d；
    将RX-5d与相应羧酸进行酰胺缩合得到RX-5；
    方案六：
    Figure PCTCN2022139380-appb-100018
    将RX-6a与RX-3c进行取代反应得到RX-6b；
    将RX-6b的氰基水解得到RX-6c；
    将RX-6c通过Curtius重排反应得到RX-6d；
    将RX-6d进行还原得到RX-6e；
    将RX-6e与相应羧酸进行酰胺缩合得到RX-6；
    Y1、Y2、Y3、Y4、V1、V2、V3、V4、V5、W、X1、X2、L、U、R 3a、虚线的定义同权利要求1所述；X在每次出现时独立地选自下组：F、Cl、Br、I。
  8. 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。
  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8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/或治疗肿瘤相关疾病；
    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
    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8所述的药物组合物的用途，其特征在于，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/或治疗肿瘤相关疾病；
    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/或治疗代谢类疾病；
    8)检测和/或预防和/或治疗眼部疾病；
    所述疾病包括但不限于下列：
    全身型幼年特发性关节炎，白塞氏病，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，系统性红斑狼疮，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，多系统萎缩症，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，精神分裂症，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，肛门区域癌，睾丸癌，宫颈癌，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，内分泌系统癌症，尿道癌，膀胱癌，皮肤癌，皮肤或眼内恶性黑色素瘤，前列腺癌，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，阴道癌，阴茎癌，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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