PIKfyve protein kinase degrading agent and its use

Abstract

The present invention provides PIKfyve proteolytic agents and their uses. Specifically, the present invention provides compounds having the structure represented by formula (I), or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or prodrug molecules thereof. Because the compounds can target and degrade the PIKfyve protein via the ubiquitin-proteasome pathway, they can be used to treat indications mediated by the abnormal expression of the PIKfyve protein. JPEG2026514100000234.jpg51164

Description

[Technical Field]

[0001] This invention relates to the field of medicinal chemistry, and more specifically to a class of compounds that target the ubiquitination and degradation of the PIKfyve protein, pharmaceutical compositions thereof, and their use. [Background technology]

[0002] PIKfyve is a class of lipid kinases that catalyze the phosphorylation of phosphatidylinositol-3-phosphate (PI(3)P) to produce phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2). PI(4,5)P2 plays a crucial role in the formation of cellular endosomes and lysosomes. PIKfyve is an important enzyme for cell membrane homeostasis, intracellular transport, and autophagy pathways. Studies have shown that inhibition or silencing of PIKfyve in various tumor cells can effectively suppress their autophagy pathways, thereby leading to a significant accumulation of the important autophagy protein LC3, resulting in cell vacuolation and inhibiting their proliferation. Currently, several PIKfyve inhibitors are widely used in research on the treatment of tumors such as leukemia, prostate cancer, and lymphoma.

[0003] Furthermore, PIKfyve plays a crucial role in the Toll-like receptor signaling pathway and is involved in the innate regulation of cellular immunity. Studies have shown that inhibiting PIKfyve can effectively suppress the production of IL-12 and IL-23 in immune cells such as B cells and macrophages. The PIKfyve inhibitor Apilimod exhibits specific inhibition of IL-12 and IL-23 both in vitro and in vivo, and is therefore used in research related to autoimmune and infectious diseases.

[0004] Currently, targeted protein degradation technologies are widely used in drug development and are considered a major breakthrough in the field of small molecule drugs. Among these, research on chimeric protein degradation (PROTAC) is the most mature. The molecular structure of a PROTAC consists of a target protein-recognizing ligand, a linker, and an E3 ubiquitin ligase-recognizing ligand. PROTACs can effectively induce ubiquitination and labeling of target proteins and degrade them effectively via the proteasome pathway. Compared to conventional small molecule inhibitors, PROTAC molecules offer advantages such as lower doses, a lower potential for developing drug resistance, and higher safety. Currently, several PROTAC molecules are entering clinical research. [Overview of the Initiative]

[0005] The object of the present invention is to provide compounds and pharmaceutical compositions that can degrade the PIKfyve protein via the ubiquitin-proteasome pathway.

[0006] A first aspect of the present invention is a compound represented by formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a prodrug molecule thereof, [ka] During the ceremony, R1 is selected from the group consisting of H, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, and substituted or unsubstituted C1-C6 alkoxy. A is -NH-, [ka] A is selected from the group consisting of 6-10 membered aryls and 5-10 membered heteroaryls, and A is independently and optionally substituted with 0-3 R2 molecules, where R2 is selected from the group consisting of H, halogens, substituted or unsubstituted C1-C6 alkyls, substituted or unsubstituted C3-C6 cycloalkyls, and substituted or unsubstituted C1-C6 alkoxys. The linker has a structure represented by the following formula, [ka] In the formula, W1, W2, W3, W4, and W5 are each independently selected from the group consisting of -O-, -S-, -NH-, -CH2-, -CONH-, -NHCO-, -C≡C-, -CH=CH-, -C(O)-, -P(=O)-, -S(O)2-, -S(O)-, -P(O)2(OH)-, -NH-S(O)-NH-, -C(O)O-, -OC(O)-, -NHCONH-, and 3- to 12-membered rings having 0 to 4 heteroatoms, n1, n2, n3, and n4 are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and the 3- to 12-membered ring can have the structure of a monocyclic ring, a spiroring, a fused ring, or a bridging ring. The E3 ligand is an E3 ubiquitin ligase ligand having a structure selected from the group consisting of the following: [ka] In the formula, R3, R4, R5, R6, R7, R8, R9, and R 11 However, each is independently selected from the group consisting of H, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, and substituted or unsubstituted C1-C6 alkoxy. R 10 but, [ka] Selected from the group consisting of each R 12 However, each is independently selected from the group consisting of H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, and substituted or unsubstituted C1-C6 alkoxy. The invention provides a compound, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a prodrug molecule thereof, in which "substituted" in "substituted or unsubstituted" means that one or more H atoms on the group are substituted with substituents selected from the group consisting of halogens, deuterium atoms, hydroxyl, cyano, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 aldehyde groups, C1-C3 carboxyl, and -SF5.

[0007] In some embodiments, the E3 ligand has a structure selected from the group consisting of the following: [ka] In the formula, R3, R4, R5, R6, R7, R8, R9, R 10 , and R 11 This is as defined in claim 1.

[0008] In some embodiments, R1 is a C1-C6 alkyl group.

[0009] In some embodiments, R1 is methyl.

[0010] In some embodiments, A is [ka] That is the case.

[0011] In some embodiments, the linker has a structure represented by the following formula: [ka] In the formula, W1, W2, W3, W4, and W5 are each independently selected from the group consisting of -O-, -S-, -NH-, -CH2-, -CONH-, -NHCO-, -C(O)-, -C(O)O-, -OC(O)-, -NHCONH-, and 3- to 10-membered rings having 0 to 4 heteroatoms, and n1, n2, n3, and n4 are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0012] In some embodiments, the linker has a structure selected from the group consisting of the following: [ka] [ka] [ka] [ka] [ka] [ka] In the formula, each of X and Y is independently -O-, -S-, -NH-, -CH2-, and [ka] Selected from the group consisting of, each of n and m is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0013] In some embodiments, the linking base linker is as follows: [ka] In the formula, X and Y are independently selected from -O- and -NH-, m is 0, 1, 2, 3, or 4, and n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0014] In some embodiments, A is -NH-, [ka] A is selected from the group consisting of the following, where each A is independently and optionally replaced by 0 to 2 R2s, where R2 is as defined in claim 1.

[0015] In some embodiments, the compound is selected from the group consisting of: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

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[0016] In another preferred embodiment, the compound is selected from the group consisting of:

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[0017] The second aspect of the present invention is a pharmaceutical composition for treating and / or preventing tumors, comprising: (1) a compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof; and optionally, (2) a pharmaceutically acceptable carrier.

[0018] The third aspect of the present invention provides the use of a compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer or a prodrug molecule thereof, or a pharmaceutical composition according to the second aspect of the present invention, for treating and / or preventing a disease or disorder associated with abnormal expression of PIKfyve.

[0019] In another preferred embodiment, the disease or disorder is selected from the group consisting of tumors, autoimmune diseases, viral infections, and neurodegenerative diseases.

[0020] In some embodiments, the disease or disorder is selected from the group consisting of hematological malignancies, gastrointestinal stromal tumors, histiocytic lymphomas, non-small cell lung cancers, small cell lung cancers, lung adenocarcinomas, lung squamous cell carcinomas, pancreatic cancers, breast cancers, prostate cancers, liver cancers, skin cancers, epithelial cell carcinomas, colorectal cancers, kidney cancers, gastric cancers, head and neck cancers, and nasopharyngeal cancers.

[0021] A fourth aspect of the present invention provides a non-diagnostic and non-therapeutic method for degrading PIKfyve in a subject requiring degradation of PIKfyve, comprising administering a compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof, or a pharmaceutical composition according to the second aspect of the present invention, to the subject.

[0022] In another preferred embodiment, the subject is a human being.

[0023] Within the scope of the present invention, the above-described technical features and the technical features specifically described below in the present invention (for example, in the examples) may be combined to form novel or preferred technical solutions, which are not repeated one by one due to space limitations. [Brief explanation of the drawing]

[0024] [Figure 1] The results of detecting PIKfyve protein levels in VCaP cells are shown. [Modes for carrying out the invention]

[0025] Following long-term and detailed research, the inventors have prepared a compound and a pharmaceutical composition thereof capable of targeting the ubiquitination and degradation of the PIKfyve protein. The compound can efficiently and selectively degrade the PIKfyve protein within cells and therefore has potential use for treating indications associated with the abnormal expression of the PIKfyve protein. Based on the above findings, the inventors have completed the present invention.

[0026] term In the compounds of the present invention, if any variable element (e.g., R1 or R2) appears multiple times in any component, the definition of the variable element in each appearance is independent of the definition of the variable element in each of the other appearances. Similarly, combinations of substituents and variable elements are permissible insofar as such combinations stabilize the compound. Lines drawn from substituents to the ring system indicate that the indicated bond can bond to any substituteable ring atom. If the ring system is polycyclic, it means that such bond can bond to any suitable carbon atom on the adjacent ring. Those skilled in the art will understand that substituents and substitution forms of the compounds of the present invention can be selected to provide compounds that are chemically stable and readily synthesized from readily available starting materials according to the art and the methods described below. If the substituent itself is substituted with multiple groups, these groups may be on the same carbon atom or on different carbon atoms, as long as the structure is stable.

[0027] Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art. Terms used in this description are for illustrative purposes only to illustrate specific embodiments and are not intended to limit the invention.

[0028] The following terms are used to describe the present invention. If a term is not specifically defined herein, a person with ordinary skill in using the term in the context in which it is used to describe the present invention will provide the meaning of the term as recognized in the art.

[0029] As used herein, the term “ubiquitin ligase” refers to a family of proteins that facilitate the transfer of ubiquitin to specific substrate proteins, thereby targeting those substrate proteins for degradation. For example, Von Hippel-Lindau E3 ubiquitin ligase or CRBN E3 ubiquitin ligase are such proteins that, alone or in combination with an E2 ubiquitin conjugate, bring about the attachment of ubiquitin to lysine on a target protein, and the subsequent targeting of a specific protein substrate for degradation by the proteasome. Thus, an E3 ubiquitin ligase, alone or in complex with an E2 ubiquitin conjugate, is involved in the transfer of ubiquitin to a target protein. Generally, ubiquitin ligases are involved in polyubiquitination, where a second ubiquitin attaches to a first ubiquitin, a third ubiquitin attaches to a second ubiquitin, and so on. Polyubiquitination labels proteins for degradation by the proteasome. However, some ubiquitination events are limited to monobiquitination, in which only a single ubiquitin is added to a substrate molecule by a ubiquitin ligase. Monobiquitinated proteins can alter their cellular location or function by binding to other proteins that have domains capable of binding to ubiquitin, rather than targeting the proteasome for degradation. Further complicating matters, different lysines on ubiquitin can be targeted by E3 for chain formation. The most common lysine is Lys48 on ubiquitin chains, which is used to prepare polyubiquitin recognized by the proteasome.

[0030] As used herein, the term “alkyl” is intended to include branched or linear saturated aliphatic hydrocarbon groups having a specific number of carbon atoms. For example, the definition of “C1-C6” in “C1-C6 alkyl” includes groups having 1, 2, 3, 4, 5, or 6 carbon atoms in a linear or branched configuration. For example, “C1-C6 alkyl” specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, pentyl, or hexyl.

[0031] As used herein, the term “cycloalkyl” refers to a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic hydrocarbon group having a ring atom composed of carbon atoms. Bicyclic or polycyclic rings include spiro rings, fused rings, and bridging rings. For example, “cycloalkyl” includes the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, [ka] This includes, but is not limited to, the following.

[0032] As used herein, the term "alkoxy" refers to a group having an -O-alkyl structure, such as -OCH3, -OCH2CH3, -OCH2CH2CH3, -O-CH2CH(CH3)2, -OCH2CH2CH2CH3, and -O-CH(CH3)2.

[0033] As used herein, the term “heterocycloalkyl” refers to a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic substituent having one or more ring atoms selected from a heteroatom of N, O, or S(O)m (where m is an integer between 0 and 2) and other ring atoms that are carbon atoms. Bicyclic or polycyclic rings include spiro rings, fused rings, and bridging rings, e.g., morpholinyl, piperidinyl, tetrahydropyrrolyl, pyrrolidinyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydroxazolyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothiophenyl, dihydrotriazolyl, dihydroazetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, [ka] These include, as well as their N-oxides. Heterocyclic substituents can be attached via carbon atoms or via heteroatoms.

[0034] In this application, unless otherwise specified, the terms “ring” or “cyclic structure” are intended to include various forms of cyclic groups, including but not limited to saturated rings, partially unsaturated but non-aromatic rings, or aromatic rings (such as aryl or heteroaryl rings), and in particular, a ring may be an aromatic or non-aromatic fused bicyclic ring, or a monocyclic or polycyclic ring formed by multiple monocyclic rings, such as a bridging or spirocyclic structure. Unless otherwise specified, “ring” includes, but is not limited to, cyclic structures selected from the group consisting of aromatic rings (including polycyclic rings such as monocyclic or bicyclic rings), heteroaromatic rings (including polycyclic rings such as monocyclic or bicyclic rings), saturated or partially unsaturated carbon rings (including polycyclic rings such as monocyclic or fused rings, bridging rings, or spirocyclic structures), and saturated or partially unsaturated heterocycles (including polycyclic rings such as monocyclic or fused rings, bridging rings, or spirocyclic structures).

[0035] As used herein, the term "aryl" refers to an aromatic ring group having a specific number of carbon atoms. For example, C6~C 10 The aryl group represents an aromatic ring group having 6 to 10 carbon atoms, such as phenyl or naphthyl.

[0036] As used herein, the term “heteroaryl” refers to an aromatic ring group having a specific number of atoms, where 1 to 3 atoms are heteroatoms selected from N, S, and O. For example, a 5- to 12-membered heteroaryl represents an aromatic ring group having 5 to 12 carbon atoms. It may be in the form of a monocyclic or fused ring. Specific examples may include pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2,4)-triazolyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, and the like.

[0037] Unless otherwise specified, the groups in this invention are "substituted or unsubstituted". 12 Substitutions may be made with substituents selected from the group consisting of aryl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy-carbonyl, phenoxycarbonyl, C2-C6 alkynyl-carbonyl, C2-C6 alkenyl-carbonyl, C3-C6 carbocykyl-carbonyl, C1-C6 alkyl-sulfonyl, etc.

[0038] As will be understood by those skilled in the art, the terms "halogen" or "halo" as used herein are intended to mean chlorine, fluorine, bromine, and iodine.

[0039] As used herein, the term "subject" refers to a mammal. For example, mammals included in the present invention include humans, primates, and domestic animals such as cows, sheep, pigs, horses, mice, rats, and humans.

[0040] The present disclosure further includes isotopically labeled compounds that are identical to the compounds represented by formula (I), but in which one or more atoms are replaced with atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Isotopes suitable for incorporation into the compounds of the present disclosure are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 31 P, 35 S, 18 F, and 36 Cl, but are not limited thereto. Replacement with heavier isotopes such as deuterium (i.e., 2 H) can result in several therapeutic advantages, such as increased in vivo half-life or decreased dose requirements, and may therefore be more preferred in some cases. Positron-emitting isotopes can be added to the compounds for medical imaging and positron emission tomography (PET) studies to determine receptor distribution. Suitable positron-emitting isotopes that can be added to the compounds of formula (I) are 11 C, 13 N, 15 O, and 18 F. Isotopically labeled compounds of formula (I) can generally be prepared by replacing non-isotopically labeled reagents with suitable isotopically labeled reagents according to conventional techniques known to those skilled in the art or processes similar to those described herein.

[0041] The compounds disclosed herein may exist in soluble or insoluble forms in pharmaceutically acceptable solvents such as water or ethanol. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In yet another embodiment, the compound is in crystalline form.

[0042] Medicinally acceptable salts The present invention includes not only the free forms of compounds of formula (I), but also their pharmaceutically acceptable salts and stereoisomers. Some specific exemplary compounds as used herein are protonated salts of amine compounds. The term "free form" refers to the unsalted form of amine compounds. The pharmaceutically acceptable salts included include not only exemplary salts of the specific compounds described herein, but also typical pharmaceutically acceptable salts of the free forms of all compounds of formula I. The free forms of specific salts of compounds can be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a suitable diluted aqueous solution of a base, such as a diluted aqueous solution of NaOH, a diluted aqueous solution of potassium carbonate, a diluted aqueous solution of ammonia, and a diluted aqueous solution of sodium bicarbonate. The free forms differ somewhat from their respective salt forms in some physical properties, such as solubility in polar solvents, but for the purposes of the present invention, such acidic and basic salts are otherwise pharmaceutically equivalent to their respective free forms.

[0043] The pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of the present invention, which include a basic or acidic moiety, according to conventional chemical methods. Generally, salts of alkaline compounds are prepared by ion-exchange chromatography or by reacting a free base with a stoichiometric or excess amount of an inorganic or organic acid in the desired salt form in a suitable solvent or a combination of solvents. Similarly, salts of acidic compounds are formed by reaction with a suitable inorganic or organic base.

[0044] Therefore, pharmaceutically acceptable salts of the compounds of the present invention include conventional non-toxic salts of the compounds of the present invention formed by reacting the alkali compounds of the present invention with inorganic or organic acids. For example, conventional non-toxic salts include not only salts prepared from inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, or nitric acid, but also salts prepared from organic acids, such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methylsulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, or trifluoroacetic acid.

[0045] When the compound of the present invention is acidic, a suitable "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable, non-toxic base, including inorganic and organic bases. Examples of salts obtained from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, ferric salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganese salts, potassium salts, sodium salts, and zinc salts, with ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts being particularly preferred. Examples of salts obtained from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, while examples of substituted amines include naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethyldiamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, aminoglucose, histidine, hydroxocobalamin, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, acridine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, and tromethamine.

[0046] Berg et al. “Pharmaceutical Salts,” J.Pharm.Sci. 1977:66:1-19 describes in further detail the preparations of the above-mentioned pharmaceutically acceptable salts and other typical pharmaceutically acceptable salts.

[0047] Drug metabolites and prodrugs Compounds involved in the present invention, metabolites of their pharmaceutically acceptable salts, and prodrugs that can be converted in vivo to the structures of the compounds involved in this application and their pharmaceutically acceptable salts are also included in the claims of the present invention. As used herein, the term “prodrug” refers to a compound that, when metabolized (e.g., in vivo or in vitro), produces an active compound. In some embodiments, the prodrug may be inactive or have lower activity than the free drug, but may provide advantageous therapeutic, administration, or metabolic properties. Exemplary prodrug molecules of the present invention may be linked to the free drug via a nucleotide hydroxyl, amino, phosphate, or thiophosphate skeleton, or may include an ester, carbamate, carbonyl, thioester, amide, isocyanate, urea, thiourea, or other physiologically acceptable metabolically unstable moiety. In some embodiments, the prodrug is activated by enzymatic hydrolysis.

[0048] Pharmaceutical compositions and their use The present invention further provides pharmaceutical compositions comprising an active ingredient in a safe and effective range and a pharmaceutically acceptable carrier or adjuvant. The active ingredient, the compound of formula I, and its pharmaceutically acceptable salts according to this application have potent inhibitory effects against the abnormal expression of PIKfyve protein, and thus the pharmaceutical compositions can be used to treat conditions associated with the abnormal expression of PIKfyve protein in humans or other mammals, such as cancer, autoimmune diseases, viral infections, or neurodegenerative diseases.

[0049] The present invention provides a protein kinase degrading agent and its use. Specifically, the present invention provides a compound having the structure represented by formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof. The compound can degrade the PIKfyve protein via the ubiquitination pathway and can be used to treat indications associated with the abnormal expression of PIKfyve.

[0050] In one embodiment, the active ingredient of this application or a pharmaceutical composition containing the active ingredient can be used to prevent and / or treat tumors such as prostate cancer, non-small cell lung cancer, malignant melanoma, kidney cancer, bladder cancer, ovarian cancer, colon cancer, rectal cancer, breast cancer, cervical cancer, lung cancer, laryngeal cancer, nasopharyngeal cancer, pancreatic cancer, multiple myeloma, B lymphoma, or leukemia, or to prevent postoperative recurrence of tumors.

[0051] The "active ingredient" according to the present invention refers to the compound of formula I or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof.

[0052] The "active ingredient" and pharmaceutical composition according to the present invention can be used as a PIKfyve protein degradation agent to prepare pharmaceuticals for the prevention and / or treatment of cancer, autoimmune diseases, viral infections, neurodegenerative diseases, and the like.

[0053] "A safe and effective amount" means that the amount of the active ingredient is sufficient to clearly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1 to 2,000 mg of the active ingredient / drug, and more preferably 10 to 200 mg of the active ingredient / drug. Preferably, the "single dose" is one tablet.

[0054] A "pharmaceutically acceptable carrier or adjuvant" refers to one or more compatible solid or liquid fillers or gels that are suitable for use in humans and must be of sufficient purity and sufficiently low toxicity.

[0055] In this specification, "compatibility" means that the components of a composition can be mixed with and with the active ingredient of the present invention without significantly reducing the effectiveness of the active ingredient.

[0056] Examples of pharmaceutically acceptable carriers or adjuvants include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, and cellulose acetate), gelatin, talc, solid lubricants (e.g., stearic acid and magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, and olive oil), polyols (e.g., propylene glycol, glycerin, mannitol, and sorbitol), emulsifiers (e.g., Tween®), humectants (e.g., sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, and pyrogen-free water.

[0057] In another preferred embodiment, the compound of formula I of the present invention can form a complex with a macromolecule compound or polymer through a non-binding effect. In another preferred embodiment, the compound of formula I of the present invention can also be bound to a macromolecule compound or polymer via chemical bonds as a low molecular weight. The polymer compound may be a biomolecule, such as a polysaccharide, protein, nucleic acid, or polypeptide.

[0058] The mode of administration of the active ingredient or pharmaceutical composition of the present invention is not particularly limited, and typical modes of administration (but are not limited to these) include oral, intratumor, rectal, or parenteral (intravenous, intramuscular, or subcutaneous) administration.

[0059] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.

[0060] In these solid dosage forms, the active ingredient is mixed with at least one conventional inactive excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) Fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, (b) Binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic. (c) Moisturizing agents such as glycerin, (d) Agar, calcium carbonate, potato starch or tapioca starch, alginic acid, several complex silicates, and disintegrants such as sodium carbonate. (e) Solution retarders such as paraffin, (f) Assimilation accelerators such as quaternary amine compounds, (g) Humectants such as cetyl alcohol and glyceryl monostearate, (h) Adsorbents such as kaolin, and (i) Lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may further contain a buffer.

[0061] Solid dosage forms can also be prepared from coating and shell materials, such as enteric coatings, as well as other materials well known in the art. They may contain opacifiers, and the active ingredients in such compositions may be released with a delay in part of the digestive tract. Examples of usable embedding components are polymers and waxes.

[0062] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, liquids, suspensions, syrups, or elixirs. In addition to the active ingredient, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propanediol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures thereof. Beyond these inert diluents, the composition may further contain auxiliary agents, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0063] In addition to the active ingredient, the suspension may contain suspending agents such as ethoxylated isooctadecanol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide, and agar, or mixtures thereof.

[0064] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or aqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for redissolution in sterile injection solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0065] The compounds of the present invention may be administered alone or in combination with other therapeutic agents.

[0066] When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (e.g., humans) in need of treatment, and the dose administered is considered to be a pharmaceutically effective dose. For a person weighing 60 kg, the daily dose is generally 1 to 2,000 mg, preferably 20 to 500 mg. Naturally, the specific dose should also be determined by comprehensively considering factors such as the route of administration and the patient's health condition, all within the scope of the skills of a skilled physician.

[0067] Concomitant administration Compounds of formula I may be administered in combination with other drugs known to treat or improve similar conditions. During concomitant administration, the original drug administration mode and dose remain unchanged, and compounds of formula I are administered simultaneously or subsequently. When compounds of formula I are administered concurrently with one or more additional drugs, it is preferable to use a pharmaceutical composition containing one or more known drugs and compounds of formula I. The drug combination further includes the administration of one or more known drugs and compounds of formula I during overlapping periods. When compounds of formula I are administered in combination with one or more additional drugs, compounds of formula I or known drugs may be administered at lower doses than when they are administered alone.

[0068] Drugs or active ingredients that can be administered in combination with compounds of formula I include estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxins / cell inhibitors, antiproliferative agents, protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protein kinase inhibitors, reverse transcriptase inhibitors, angiogenesis inhibitors, cell proliferation and survival signal inhibitors, drugs that interfere with cell cycle checkpoints and apoptosis inducers, cytotoxic drugs, tyrosine protein inhibitors, EGFR inhibitors, VEGFR inhibitors, serine / threonine protein inhibitors, and Bcr-Abl Examples of inhibitors include, but are not limited to, c-Kit inhibitors, Met inhibitors, Raf inhibitors, MEK inhibitors, MMP inhibitors, topoisomerase inhibitors, histidine deacetylase inhibitors, proteasome inhibitors, CDK inhibitors, Bcl-2 family protein inhibitors, MDM2 family protein inhibitors, IAP family protein inhibitors, STAT family protein inhibitors, PI3K inhibitors, AKT inhibitors, integrin blockers, interferons, interleukin-12, COX-2 inhibitors, p53, p53 activators, VEGF antibodies, EGF antibodies, and JAK inhibitors.

[0069] In one embodiment, drugs or active ingredients that can be administered in combination with a compound of formula I include aldresleukin, alendronate, interferon, alitretinoin, allopurinol, allopurinol sodium, palonosetron hydrochloride, hexamethylmelamine, aminoglutethimide, amifostin, amrubicin, amsacrin, anastrozole, drasetron, aranesp, algravin, arsenic trioxide, aromasin, 5-azacitidine, azathioprine, BCG vaccine, or TICE. BCG vaccine, bestatin, betamethasone acetate, betamethasone sodium phosphate preparation, bexarotene, bleomycin sulfate, proxlysine, bortezomib, busulfan, calcitonin, alemtuzumab injection, capecitabine, carboplatin, casodex, cephazone, cermoleukin, daunorubicin, chlorambucil, cisplatin, cladribine, cladribine, clodronate, cyclophosphamide, sita Rabin, dacarbazine, actinomycin D, daunorubicin liposome, dexamethasone, dexamethasone phosphate, estradiol valerate, denileukin-difutitox 2, methylprednisone, deslorerin, dexrazoxane, diethylstilbestrol, diflucan, docetaxel, doxifluridine, doxorubicin, dronabinol, holmium-166-chitosan complex, eliga rd), razubricase, epirubicin hydrochloride, aprepitant, epirubicin, epoetin alfa, erythrogenin, eptaplatin, levomizole tablets, estradiol preparation, 17-β-estradiol, estramustine sodium phosphate, ethinylestradiol, amifostine, hydroxyphosphate, etopophos, etoposide, fadrozol, tamoxifen preparation, filgrastim, finasteride Lido, Filgrastim, Floroxyuridine, Fluconazole, Fludarabine, 5-Fluorodeoxyuridine monophosphate, 5-Fluorouracil, Halotestin, Flutamide, Formestan, 1-β-D-Arabinofuranosylcytosine-5'-Stearoylphosphate, Fotemustine, Fulvestrant, Gammaglobulin, Gemcitabine, Gemtuzumab, Imatinib mesylate, Gliadel, Goserelin,Granisetron hydrochloride, histrelin, hicamtin, hydrocortisone, erythrohydroxynonyladenine, hydroxyurea, ibritumomab tiuxetan, idarubicin, ifosfamide, interferon α, interferon-α2, interferon α-2A, interferon α-2B, interferon α-nl, interferon α-n3, interferon β, interferon γ-LA, interleukin-2, intron A, gefitinib, irinotecan, granisetron hydrochloride Injectable solution, lentinan sulfate, letrozole, leucovorin, leuprolide, leuprolide acetate, levamisole, levofolinate calcium, levoid, levoid preparation, lomustine, lonidamine, dronabinol, mechloretamine, mecobalamin, medroxyprogesterone acetate, megestrol acetate, melphalan, esterified estrogen, 6-mercaptopurine, mesna, methotrexate, methyl aminolevulinate, miltefosine, minocycline, mitomycin C, mitotane, mitoxant Lon, trilostane, doxorubicin cintricate liposome, nedaplatin, pegfilgrastim, oprelvekin, neupogen, nilutamide, tamoxifen, NSC-631570, recombinant human interleukin 1-β, octreotide, ondansetron hydrochloride, oral solution of dehydrocortisone, oxaliplatin, paclitaxel, prednisone sodium phosphate preparation, pegaspargase, pegacis, pentostatin, picibanil, pilocarpine hydrochloride, pirarubicin, Mitramycin, porfimer sodium, prednimustine, prednisolone stearate, prednisone, premarin, procarbazine, recombinant human erythropoietin, larcitrexed, libby, rhenium-186 etidronate, rituximab, vitamin C effervescent tablets-A, romultide, pilocarpine hydrochloride tablets, octreotide, salglamostim, semustine, schizophyllan, sobuzoxane, solu-medrol, spar-fosic acid, stem cell therapy, streptozosin, strontium-89 chloride, levoid, tamoxifen, tamsulosin, tasonelmin, tastractone, taxotere, teseroykin, temozolomide,Teniposide, testosterone propionate, methyltestosterone, thioguanine, thiotepa, thyrotropin, chydronic acid, topotecan, toremifene, tocitumomab, trastuzumab, treosulfan, tretinoin, methotrexate tablets, trimethylmelamine, trimethrexate, triptorelin acetate, triptorelin pamoate, UFT, uridine, barrubicin, vesnarinone, vinblastine, vincristine, vindesine, vinorelbine, virulizin, dexrazoxin, dinostatin stimalamer, zofuran, stable paclitaxel Cell protein preparation, acorbifen, interferon r-lb, affinitak, aminopterin, arzoxifen, asoprisnil, atamestan, atrasentan, BAY43-9006, Avastin, CCI-779, CDC-501, Celebrex, cetuximab, cristatol, cyproterone acetate, decitabine, DN-101, doxorubicin-MTC, dSLIM, dutasteride, edotecarin, eflornithine, exatecan, fenretinide, histamine dihydrochloride, histreline hydrogel implant, holmium-166 DOTMP, ibandronate, interferon-γ, intron-PEG, ixabepyrone, keyhole limpet hemocyanin, L-651582, lanreotide, rasofoxifen, Libra, ronafamib, miproxyfen, minotauroate, MS-209, liposomal MTP-PE, MX-6, nafarelin, nemorubicin, neovastat, noratexed, oblimersen, onco-TCS, osidem, paclitaxel polyglutamate, disodium pamidronate, Examples include PN-401, QS-21, quazepam, R-1549, raloxifene, onconase, 13-cis-retinoic acid, satoraplatin, theocalcitol, T-138067, tarceva, docosahexaenoic acid-taxol, thymosin α-l, thiazophrine, tipifarnib, tirapazamin, TLK-286, toremifene, trans-MID-lo7R, valspodar, vapreotide, batalanib, verteporfin, vinflunin, Z-100, and zoledronic acid, or combinations thereof.This is not limited to these.

[0070] In some embodiments, the compounds described herein are administered in combination with other modes of treatment, including surgery, radiation, transplantation (e.g., stem cell transplantation or bone marrow transplantation), chemotherapy, immunotherapy, cryotherapy, and / or hyperthermia. This combination therapy can reduce the dosage of the drug and / or other drugs, thereby avoiding potential toxicity or complications arising from the various therapies.

[0071] Treatment method As described above, the compounds of this disclosure are PIKfyve proteolytic agents, and therefore, the compounds or compositions containing the compounds can be used to treat, prevent, and alleviate diseases associated with the activity or abnormal expression of PIKfyve. In some embodiments, the use of the compounds disclosed herein for the manufacture of pharmaceuticals for the prevention and / or treatment of diseases mediated by the PIKfyve protein is disclosed herein. In some embodiments, the compounds disclosed herein are used to prevent and / or treat diseases mediated by the PIKfyve protein. In some embodiments, disclosed herein is a method for treating a disease mediated by the PIKfyve protein in a subject requiring treatment of the disease mediated by the PIKfyve protein, the method comprising administering an effective amount of the compounds disclosed herein (e.g., the compound of formula (I)) or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition containing the compound of formula (I)) to the subject. In some embodiments, the disease mediated by the PIKfyve protein is a tumor, an autoimmune disease, a viral infection, or a neurodegenerative disease. In some embodiments, the diseases mediated by the PIKfyve protein are tumors selected from the group consisting of, for example, hematological malignancies, gastrointestinal stromal tumors, histological ring lymphoma, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, and lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, colorectal cancer, kidney cancer, gastric cancer, head and neck cancer, nasopharyngeal cancer, etc.

[0072] The advantages of this invention mainly include the following: A novel PROTAC compound is provided. This class of compounds can be used to efficiently and selectively degrade intracellular PIKfyve protein, effectively inhibit the proliferation of various tumor cells, and prepare antitumor drugs.

[0073] The present invention will be further described below with reference to specific examples. It should be understood that these examples are used only to illustrate the present invention and not to limit its scope. Experimental methods in the following examples that do not explicitly specify particular conditions are typically subjected to conventional conditions, such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

[0074] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those well known to those skilled in the art. In addition, any methods and materials similar to or equivalent to those described herein may be applied to the methods of the present invention. Preferred embodiments and materials described herein are for illustrative purposes only.

[0075] The starting materials for the following examples can be commercially available, prepared using methods known in the art, or prepared according to the methods described herein.

[0076] The structure of the compound is determined by nuclear magnetic resonance (1H-NMR) and / or mass spectrometry (MS). A nuclear magnetic resonance spectrometer (Bruker AV-400 or AV-500) is used for NMR measurements using deuterated chloroform (CDCl3) or deuterated dimethyl sulfoxide (DMSO-D6) as a solvent and an internal standard for TMS. A mass spectrometer LCQAD-40000 is used for MS measurements. 200-300 mesh silica gel (manufactured by Qingdao Ocean Chemical Plant) is used for column chromatography. [Examples]

[0077] Example 1: (E)-2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)-N-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)acetamide (LCG-1) [ka] Step 1: Preparation of 4-(2,6-dichloropyrimidine-4-yl)morpholine (2) [ka] Morpholine (0.9 g, 10.9 mmol) was dissolved in 25 mL of 50% ethanol aqueous solution, and the mixture was stirred at a low temperature of -20°C. 2,4,6-trichloropyrimidine (1.0 g, 5.5 mmol) was dissolved in 10 mL of 50% ethanol aqueous solution, and the mixture was added dropwise to the morpholine-ethanol aqueous solution. The resulting mixture was kept at a low temperature of -20°C for 2 hours, then adjusted to 10°C and reacted for 1 hour. After the reaction was complete, it was monitored by TLC, 80 mL of water was added to precipitate a white solid, which was filtered, spin-dried, and subjected to column chromatography to obtain 0.8 g of white solid (62%). 1H NMR (500MHz, CDCl3) δ6.39 (s, 1H), 3.79~3.73 (m, 4H), 3.63 (brs, 4H). MS(ESI),m / z:234.2[M+H] + .

[0078] Step 2: Preparation of tert-butyl(4-(2-((4-chloro-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)carbamate (3) [ka] NaH (0.15 g, 6.4 mmol) was added to 40 mL of DMF, and the mixture was stirred at -20°C. Then, tert-butyl(4-(2-hydroxyethyl)phenyl)carbamate (1.0 g, 4.3 mmol) was dissolved in 5 mL of DMF solution and gradually added to the mixture. After 10 minutes, a solution of 4-(2,6-dichloropyrimidine-4-yl)morpholine (2) (1.0 g, 4.3 mmol) in DMF was added, and the mixture was reacted at this temperature for 12 hours. After monitoring the completion of the reaction by TLC, 100 mL of water was added to precipitate a clear white solid, which was filtered, washed with water, dried, and recrystallized at PE / EA = 1:1 to obtain intermediate 3 (1.1 g, 60%). 1 H NMR(500 MHz,CDCl3)δ 7.28(d,J=8.2 Hz,2H),7.19(d,J=8.2 Hz,2H),6.43(s,1H),6.15(s,1H),4.42(t,J=7.4 Hz,2H),3.86-3.68(m,4H),3.59(brs,4H),3.03(t,J=7.4 Hz,2H),1.51(s,9H).MS(ESI),m / z:435.3[M+H] + .

[0079] Step 3: Preparation of tert-butyl(4-(2-((4-hydrazino-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)carbamate (4) [ka] Intermediate 3 (2 g, 4.6 mmol) was dissolved in 50 mL of dioxane, and 10 mL of 50% hydrazine hydrate solution was added. The mixture was heated under reflux and stirred for 24 hours. After monitoring the completion of the reaction by TLC, the mixture was evaporated under reduced pressure to obtain a white solid, which was washed with 50 mL of water and dried to obtain white intermediate 4 (1.8 g, 93%). 1 H NMR(400 MHz,DMSO-d6)δ 9.27(s,1H),7.67(s,1H),7.37(d,J=8.2 Hz,2H),7.14(d,J=8.2 Hz,2H),5.61(s,1H),4.63(brs,3H),4.25(t,J=7.1 Hz,2H),3.68-3.59(m,4H),3.43-3.36(m,4H),2.86(t,J=7.1 Hz,2H),1.46(s,9H).MS(ESI),m / z:431.4[M+H] + .

[0080] Step 4: Preparation of tert-butyl(E)-(4-(2-((4-(-2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)carbamate(5) [ka] Intermediate 4 (1.7 g, 3.9 mmol) and 3-methylbenzaldehyde (0.7 g, 0.6 mmol) were dissolved in 30 mL of ethanol, 10 drops of acetic acid were added, and the mixture was refluxed and reacted for 4 hours. The completion of the reaction was monitored by TLC. The mixture was evaporated under reduced pressure to obtain a white solid, which was resuspended in 50 mL of PE / DCM = 1:1 solution and filtered to obtain white intermediate 5 (1.7 g, 84%). 1H NMR(400 MHz,DMSO-d6)δ 10.87(s,1H),9.26(s,1H),7.99(s,1H),7.50(d,J=8.1 Hz,2H),7.37(d,J=8.1 Hz,2H),7.29(t,J=7.5 Hz,1H),7.20-7.10(m,3H),6.06(s,1H),4.32(t,J=7.0 Hz,2H),3.74-3.62(m,4H),3.57-3.50(m,4H),2.90(t,J=7.0 Hz,2H),2.34(s,3H),1.47(s,9H).MS(ESI),m / z:533.1[M+H] + .

[0081] Step 5: Preparation of (E)-4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)aniline(6) [ka] Intermediate 5 (100 mg, 0.2 mmol) was added to 10 mL of DCM solution containing 25% TFA, and the mixture was stirred at room temperature for 4 hours. The completion of the reaction was monitored by TLC. The mixture was rotated under reduced pressure to obtain oil, which was dissolved in DCM, backwashed twice with saturated NaHCO3 solution, and spin-dried to obtain intermediate 6 (65 mg, 81%). 1 H NMR(500 MHz,DMSO-d6)δ 10.83(s,1H),7.97(s,1H),7.48(d,J=7.8 Hz,1H),7.45(s,1H),7.27(t,J=7.6 Hz,1H),7.15(d,J=7.6 Hz,1H),6.91(d,J=8.2 Hz,2H),6.48(d,J=8.2 Hz,2H),6.04(s,1H),4.86(s,2H),4.23(t,J=7.3 Hz,2H),3.70-3.62(m,4H),3.55-3.48(m,4H),2.77(t,J=7.3 Hz,2H),2.32(s,3H).MS(ESI),m / z:433.3[M+H] + .

[0082] Step 6: Preparation of (E)-2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)oxy)-N-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)acetamide (LCG-1) [ka] In a 25 mL round-bottom flask, intermediate 5 (50 mg, 0.1 mmol) and 2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)acetic acid (7) (40 mg, 0.1 mmol) were dissolved in 10 mL of DMF, and HATU (70 mg, 0.2 mmol) was added. Finally, triethylamine (40 mg, 0.3 mmol) was added, and the mixture was stirred at room temperature for 5 hours. After quenching the reaction with water, the mixture was extracted with ethyl acetate, backwashed with saturated brine, dried over Na2SO4, filtered, spin-dried, and then purified by flash column chromatography (DCM / MeOH) to obtain 42 mg of a white solid product (42%). 1 H NMR(600 MHz,DMSO-d6)δ 11.13(s,1H),10.85(s,1H),10.05(s,1H),7.99(s,1H),7.86-7.79(m,1H),7.55(d,J=8.4 Hz,2H),7.53-7.45(m,4H),7.32-7.25(m,3H),7.17(d,J=7.5 Hz,1H),6.06(s,1H),5.14(dd,J=12.8,5.4 Hz,1H),5.00(s,2H),4.35(t,J=7.0 Hz,2H),3.71-3.63(m,4H),3.58-3.50(m,4H),3.01-2.86(m,3H),2.66-2.52(m,2H),2.34(s,3H),2.09-2.02(m,1H). 13¹³C NMR (150 MHz, DMSO-d6)δ 173.27,170.39,167.23,166.06,165.97,164.84,164.43,163.99,155.6 6,141.69,138.40,137.45,136.92,135.23,134.48,133.54,130.24,129 .81,129.08,127.49,124.02,120.97,119.86,117.24,116.57,76.14,68 .10,66.94,66.38,49.32,44.69,34.75,31.43,22.47,21.41.HRMS(ESI)C 39 H 38 N8O8[M+H] + The calculated value is 747.2891, and the measured value is 747.2870.

[0083] Example 2: (E)-4-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)-N-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)butanamide (LCG-2) [ka] The synthesis method was as shown in Example 1. 1H NMR(600 MHz,DMSO-d6)δ 11.12(s,1H),10.86(s,1H),9.93(s,1H),8.00(s,1H),7.81(dd,J=8.3,7.5 Hz,1H),7.54(t,J=8.1 Hz,3H),7.50(d,J=7.9 Hz,1H),7.48(s,1H),7.46(d,J=7.2 Hz,1H),7.29(t,J=7.6 Hz,1H),7.21(d,J=8.5 Hz,2H),7.17(d,J=7.5 Hz,1H),6.07(s,1H),5.09(dd,J=12.9,5.5 Hz,1H),4.34(t,J=7.0 Hz,2H),4.28(t,J=6.2 Hz,2H),3.71-3.65(m,4H),3.58-3.51(m,4H),2.96-2.85(m,3H),2.66-2.52(m,4H),2.34(s,3H),2.14-2.06(m,2H),2.06-1.99(m,1H). 13 C NMR(150 MHz,DMSO-d6)δ 173.28,170.82,170.44,167.32,165.83,164.85,164.44,163.99,156.35,1 41.69,138.39,137.98,137.55,135.24,133.72,133.52,130.23,129.56,12 9.07,127.48,124.02,120.28,119.66,116.76,115.75,76.13,68.70,67.01 ,66.38,49.22,44.68,34.74,32.72,31.43,24.76,22.49,21.40.HRMS(ESI)C 41 H 42 N8O8[M+H] + The calculated value is 775.3204, and the measured value is 775.3197.

[0084] Example 3: (E)-6-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)-N-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)hexaneamide (LCG-3) [ka] The synthesis method and Example 1 are shown in the following. 1 H NMR(600 MHz, DMSO-d6)δ 11.11(s,1H),10.87(brs,1H),9.84(s,1H),8.00(s,1H),7.80(dd,J=8.4,7.3 Hz,1H),7.55-7.47(m,5H),7.44(d,J=7.2 Hz,1H),7.29(t,J=7.5 Hz,1H),7.20(d,J=8.5 Hz,2H),7.17(d,J=7.5 Hz,1H),6.06(s,1H),5.08(dd,J=12.9,5.5 Hz,1H),4.35(t,J=7.0 Hz,2H),4.21(t,J=6.4 Hz,2H),3.72-3.63(m,4H),3.59-3.49(m,4H),2.97-2.81(m,3H),2.63-2.51(m,2H),2.36 -2.30(m,5H),2.05-1.99(m,1H),1.83-1.77(m,2H),1.70-1.64(m,2H),1.54-1.47(m,2H). 13 C NMR (150 MHz, DMSO-d6)δ 173.27,171.46,170.44,167.32,165.79,156.46,138.39,138.07,13 7.49,135.21,133.71,133.42,130.26,129.54,129.07,127.51,124.0 5,120.24,119.61,116.68,115.61,76.11,69.15,66.37,49.21,44.70,36.82,34.73,31.44,28.72,25.51,25.34,22.48,21.41.HRMS(ESI)C 43 H 46 N8O8[M+H] + The calculated value is 803.3517 and the measured value is 803.3509.

[0085] Example 4: (E)-8-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)-N-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)octanamide (LCG-4) [ka] The synthesis method was as shown in Example 1. 1 H NMR(600 MHz,DMSO-d6)δ 11.11(s,1H),10.85(s,1H),9.80(s,1H),7.99(s,1H),7.80(dd,J=8.4,7.4 Hz,1H),7.53-7.47(m,5H),7.43(d,J=7.2 Hz,1H),7.29(t,J=7.6 Hz,1H),7.20(d,J=8.5 Hz,2H),7.17(d,J=7.6 Hz,1H),6.07(s,1H),5.08(dd,J=12.8,5.5 Hz,1H),4.34(t,J=7.0 Hz,2H),4.20(t,J=6.4 Hz,2H),3.69-3.63(m,4H),3.55-3.49(m,4H),2.95-2.83(m,3H),2.61-2.51(m,2H),2.34(s,3H),2.29(t,J=7.4 Hz,2H),2.06-1.99(m,1H),1.80-1.72(m,2H),1.63-1.56(m,2H),1.50-1.43(m,2H),1.41-1.30(m,4H). 13C NMR(150 MHz,DMSO-d6)δ 170.95,169.25,168.13,165.02,163.48,162.53,162.12,161.67,154.17,139.37, 136.08,135.77,135.17,132.92,131.41,131.11,127.92,127.24,126.76,125.18, 121.71,117.92,117.27,114.38,113.28,73.82,66.92,64.70,64.07,46.89,42.37 ,34.52,32.43,29.12,26.79,26.62,26.55,23.35,23.26,20.16,19.10.HRMS(ESI)C 45 H 50 N8O8[M+H] + The calculated value is 831.3830, and the measured value is 831.3828.

[0086] Example 5: (E)-10-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)-N-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)decanamide (LCG-5) [ka] The synthesis method was as shown in Example 1. 1H NMR(600 MHz, DMSO-d6)δ 11.10(brs,1H),10.86(s,1H),9.80(s,1H),7.99(s,1H),7.79(dd,J=8.4,7.4 Hz,1H),7.54-7.47(m,5H),7.43(d,J=7.2 Hz,1H),7.29(t,J=7.6 Hz,1H),7.20(d,J=8.5 Hz,2H),7.17(d,J=7.5 Hz,1H),6.07(s,1H),5.08(dd,J=12.9,5.5 Hz,1H),4.34(t,J=7.0 Hz,2H),4.18(t,J=6.4 Hz,2H),3.70-3.64(m,4H),3.56-3.51(m,4H),2.93(t,J=7.1 Hz,2H),2.91-2.84(m,1H),2.64-2.53(m,2H),2.34(s,3H),2.28(t,J=7.4 Hz,2H),2.06-2.00(m,1H),1.78-1.71(m,2H),1.62-1.55(m,2H),1.48-1.42(m,2H),1.35-1.28(m,8H). 13 C NMR(150 MHz,DMSO-d6)δ 173.26,171.58,170.44,167.33,165.78,164.84,164.44,163.99,156.49,141.67,138 .39,138.09,137.48,135.24,133.72,133.42,130.22,129.54,129.07,127.48,124.01 ,120.22,119.57,116.68,115.58,76.13,69.25,67.01,66.38,49.20,44.68,36.86,34 .75,31.43,29.35,29.22,29.14,29.13,28.90,25.73,25.63,22.48,21.40.HRMS(ESI)C 47 H 54 N8O8[M+H] + The calculated value is 859.4143 and the measured value is 859.4142.

[0087] Example 6: (E)-2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)oxy)-N-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)acetamide (LCG-6) [ka] The synthesis method was as shown in Example 1. 1 H NMR(600 MHz,DMSO-d6)δ 11.12(s,1H),10.99(brs,1H),10.14(s,1H),8.02(s,1H),7.88(d,J=8.3 Hz,1H),7.64-7.48(m,5H),7.44(d,J=8.2 Hz,1H),7.35-7.23(m,3H),7.19(d,J=7.3 Hz,1H),6.03(s,1H),5.13(dd,J=12.9,5.3 Hz,1H),4.96(s,2H),4.41(s,2H),3.67(s,4H),3.56(s,4H),2.98(s,2H) ),2.93-2.84(m,1H),2.65-2.52(m,2H),2.34(s,3H),2.12-1.99(m,1H). 13 C NMR(150 MHz,DMSO-d6)δ 173.25,170.38,167.30,167.20,166.02,163.73,151.62,138.41,137.02,134.98,134.23,130.50,129.74,129.35,129.07,127.72, 125.81,124.27,124.04,121.45,121.22,120.27,109.78,75.95,67.88,66.32,49.47,44.83,34.61,31.42,22.52,21.41.HRMS(ESI)C 39 H 38 N8O8[M+H] + The calculated value is 747.2891, and the measured value is 747.2875.

[0088] Example 7: (E)-4-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)oxy)-N-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)butanamide (LCG-7) [ka] The synthesis method was as shown in Example 1. 1 H NMR(600 MHz,DMSO-d6)δ 11.11(s,1H),10.85(s,1H),9.91(s,1H),7.99(s,1H),7.83(d,J=8.3 Hz,1H),7.52(d,J=8.5 Hz,2H),7.50(d,J=7.9 Hz,1H),7.47(s,1H),7.44(d,J=2.2 Hz,1H),7.35(dd,J=8.3,2.3 Hz,1H),7.29(t,J=7.6 Hz,1H),7.21(d,J=8.5 Hz,2H),7.17(d,J=7.5 Hz,1H),6.06(s,1H),5.12(dd,J=12.9,5.4 Hz,1H),4.34(t,J=7.1 Hz,2H),4.24(t,J=6.4 Hz,2H),3.71-3.62(m,4H),3.57-3.49(m,4H),2.93(t,J=7.0 Hz,2H),2.91-2.84(m,1H),2.63-2.52(m,2H),2.34(s,3H),2.10-2.02(m,3H). 13 C NMR(150 MHz,DMSO-d6)δ 172.17,169.74,169.33,166.27,166.20,163.77,163.36,162.91,140.60 ,137.32,136.90,134.16,133.35,132.46,129.16,128.50,128.00,126.42 ,124.73,122.94,122.37,120.10,118.56,108.34,75.05,67.69,65.92,6 5.30,48.36,43.61,33.67,31.92,30.35,23.74,21.47,20.33.HRMS(ESI)C 41 H 42N8O8[M+H] + The calculated value is 775.3204, and the measured value is 775.3204.

[0089] Example 8: (E)-6-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)oxy)-N-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)hexaneamide (LCG-8) [ka] The synthesis method was as shown in Example 1. 1 H NMR(600 MHz,DMSO-d6)δ 11.11(s,1H),10.85(s,1H),9.82(s,1H),7.99(s,1H),7.82(d,J=8.3 Hz,1H),7.54-7.48(m,3H),7.47(s,1H),7.42(d,J=2.2 Hz,1H),7.34(dd,J=8.3,2.3 Hz,1H),7.29(t,J=7.6 Hz,1H),7.20(d,J=8.5 Hz,2H),7.17(d,J=7.5 Hz,1H),6.06(s,1H),5.12(dd,J=12.9,5.4 Hz,1H),4.33(t,J=7.0 Hz,2H),4.18(t,J=6.5 Hz,2H),3.71-3.62(m,4H),3.57-3.48(m,4H),2.97-2.91(m,2H),2.90-2.83(m,1H),2.64-2.52(m, 2H),2.38-2.29(m,5H),2.09-2.00(m,1H),1.83-1.74(m,2H),1.70-1.63(m,2H),1.51-1.41(m,2H). 13C NMR(150 MHz,DMSO-d6)δ 172.16,170.35,169.32,166.28,166.21,163.76,163.47,163.35,162.90,140. 59,137.31,136.97,134.15,133.34,132.37,129.14,128.47,127.99,126.40,1 24.68,122.93,122.26,120.12,118.50,108.22,75.04,68.09,65.92,65.29,48 .34,43.60,35.66,33.66,30.34,27.56,24.45,24.23,21.46,20.32.HRMS(ESI)C 43 H 46 N8O8[M+H] + The calculated value is 803.3517, and the measured value is 803.3517.

[0090] Example 9: (E)-8-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)oxy)-N-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)octanamide (LCG-9) [ka] The synthesis method was as shown in Example 1. 1H NMR(600 MHz, DMSO-d6)δ 11.12(s,1H),10.87(s,1H),9.81(s,1H),8.00(s,1H),7.82(d,J=8.3 Hz,1H),7.54-7.47(m,4H),7.42(d,J=2.2 Hz,1H),7.33(dd,J=8.3,2.3 Hz,1H),7.29(t,J=7.6 Hz,1H),7.20(d,J=8.5 Hz,2H),7.17(d,J=7.5 Hz,1H),6.06(s,1H),5.12(dd,J=12.9,5.4 Hz,1H),4.34(t,J=7.0 Hz,2H),4.16(t,J=6.5 Hz,2H),3.68-3.63(m,4H),3.55-3.50(m,4H),2.93(t,J=7.1 Hz,2H),2.90-2.84(m,1H),2.63-2.51(m,2H),2.34(s,3H),2.31-2.27(m,2H),2.07-2. 02(m,1H),1.79-1.71(m,2H),1.64-1.56(m,2H),1.47-1.40(m,2H),1.40-1.30(m,4H). 13 C NMR(150 MHz,DMSO-d6)δ 171.24,169.55,168.41,165.37,165.29,162.56,136.38,136.08,133.21, 132.41,131.40,128.24,127.54,127.06,125.49,123.75,122.03,121.31, 119.17,117.58,107.28,74.11,67.24,64.37,47.42,44.19,42.69,34.81, 32.73,29.43,27.06,26.93,26.80,23.71,23.55,20.55,19.40.HRMS(ESI)C 45 H 50 N8O8[M+H] + The calculated value is 831.3830 and the measured value is 831.3818.

[0091] Example 10: (E)-10-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)oxy)-N-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)decanamide (LCG-10) [ka] The synthesis method was as shown in Example 1. 1 H NMR(600 MHz,DMSO-d6)δ 11.11(s,1H),10.85(s,1H),9.80(s,1H),7.99(s,1H),7.82(d,J=8.3 Hz,1H),7.55-7.45(m,4H),7.41(d,J=2.0 Hz,1H),7.33(dd,J=8.3,2.2 Hz,1H),7.29(t,J=7.6 Hz,1H),7.20(d,J=8.4 Hz,2H),7.17(d,J=7.5 Hz,1H),6.06(s,1H),5.12(dd,J=12.9,5.4 Hz,1H),4.33(t,J=7.0 Hz,2H),4.15(t,J=6.5 Hz,2H),3.68-3.63(m,4H),3.56-3.49(m,4H),2.95-2.84(m,3H),2.63-2.51(m,2H),2.34(s,3H),2.28(t,J=7.4 Hz,2H),2.09-2.00(m,1H),1.77-1.71(m,2H),1.62-1.54(m,2H),1.45-1.38(m,2H),1.32-1.24(m,8H). 13C NMR(150 MHz,DMSO-d6)δ 173.24,171.56,170.41,167.37,167.29,164.84,164.57,164.43,163.99,141.67,138 .39,138.08,135.24,134.42,133.42,130.22,129.54,129.07,127.48,125.76,124.01 ,123.32,121.18,119.57,109.28,76.13,69.27,67.01,66.38,49.43,44.68,36.84,34 .74,31.43,29.34,29.21,29.14,29.13,28.84,25.81,25.62,22.55,21.41.HRMS(ESI)C 47 H 54 N8O8[M+H] + The calculated value is 859.4143, and the measured value is 859.4140.

[0092] Example 11: (E)-2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)-N-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)acetamide (LCG-11) [ka] The synthesis method was as shown in Example 1. 1H NMR(600 MHz,DMSO-d6)δ 11.11(s,1H),10.86(s,1H),10.15(s,1H),7.99(s,1H),7.61(dd,J=8.4,7.2 Hz,1H),7.53(d,J=8.5 Hz,2H),7.50(d,J=7.6 Hz,1H),7.48(s,1H),7.29(t,J=7.6 Hz,1H),7.24(d,J=8.5 Hz,2H),7.17(d,J=7.5 Hz,1H),7.09(d,J=7.0 Hz,1H),7.02(t,J=5.7 Hz,1H),6.96(d,J=8.6 Hz,1H),6.06(s,1H),5.09(dd,J=12.7,5.5 Hz,1H),4.35(t,J=7.0 Hz,2H),4.18(d,J=5.6 Hz,2H),3.69-3.64(m,4H),3.55-3.49(m,4H),2.94(t,J=6.8 Hz,2H),2.93-2.86(m,1H),2.63-2.51(m,2H),2.34(s,3H),2.08-2.01(m,1H). 13 C NMR(150 MHz,DMSO-d6)δ 172.20,169.45,168.14,166.72,166.70,163.71,163.29,162.85,145.34 ,140.63,137.30,136.35,135.61,134.12,132.92,131.45,129.15,128.62 ,127.98,126.41,122.93,118.65,117.00,110.41,109.20,75.02,65.89,6 5.73,65.28,47.97,44.99,43.60,33.63,30.37,21.54,20.31.HRMS(ESI)C 39 H 39 N9O7[M+H] + The calculated value is 746.3050, and the measured value is 746.3040.

[0093] Example 12: (E)-4-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)-N-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)butanamide (LCG-12)

change

[0094] Example 13: (E)-6-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)-N-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)hexaneamide (LCG-13) [ka] The synthesis method was as shown in Example 1. 1 H NMR(600 MHz,DMSO-d6)δ 11.09(s,1H),10.85(s,1H),9.81(s,1H),7.99(s,1H),7.59-7.54(m,1H),7.52-7.45(m,4H),7.29(t,J=7.6 Hz,1H),7.20(d,J=8.5 Hz,2H),7.17(d,J=7.6 Hz,1H),7.10(d,J=8.6 Hz,1H),7.01(d,J=7.0 Hz,1H),6.55(t,J=5.8 Hz,1H),6.06(s,1H),5.05(dd,J=12.9,5.4 Hz,1H),4.33(t,J=7.0 Hz,2H),3.72-3.63(m,4H),3.57-3.45(m,4H),3.32-3.27(m,2H),2.94-2.85(m,3H),2.64-2.51(m,2H),2.34(s,3H),2.30(t,J=7.4 Hz,2H),2.05-1.99(m,1H),1.66-1.57(m,4H),1.42-1.35(m,2H). 1313C NMR (150 MHz, DMSO-d6) δ 172.19, 170.35, 169.49, 168.32, 166.68, 163.75, 163.34, 162.89, 161.68, 145.79, 140.58, 137.30, 136.96, 135.65, 134.14, 132.35, 131.57, 129.14, 128.45, 127.99, 126.40, 122.92, 118.49, 116.59, 109.76, 108.38, 75.03, 65.91, 65.28, 64.29, 47.91, 43.59, 41.11, 35.67, 33.64, 30.36, 27.91, 25.37, 24.28, 21.53, 20.32, 14.55. HRMS (ESI) C 43 H 47 N9O7 [M+H] + Calculated value 802.3676, measured value 802.3673.

[0095] Example 14: (E)-8-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-(4-(2-((4-(2-(3-Methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)octanamide (LCG-14)

Chemical Structure

[0096] Example 15: (E)-2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)amino)-N-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)acetamide (LCG-15)

change

[0097] Example 16: (E)-4-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)amino)-N-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)butanamide (LCG-16) [ka] The synthesis method was as shown in Example 1. 1 H NMR(600 MHz,DMSO-d6)δ 11.06(s,1H),10.87(s,1H),9.88(s,1H),7.99(s,1H),7.57(d,J=8.4 Hz,1H),7.54-7.46(m,4H),7.29(t,J=7.6 Hz,1H),7.23-7.15(m,4H),6.97(d,J=1.8 Hz,1H),6.87(dd,J=8.4,2.0 Hz,1H),6.06(s,1H),5.03(dd,J=12.8,5.5 Hz,1H),4.34(t,J=6.9 Hz,2H),3.69-3.63(m,4H),3.56-3.50(m,4H),3.25-3.19(m,2H),2.93(t,J=7.0 Hz,2H),2.91-2.83(m,1H),2.64-2.51(m,2H),2.43(t,J=7.4 Hz,2H),2.34(s,3H),2.03-1.96(m,1H),1.92-1.84(m,2H). 13 C NMR(150 MHz,DMSO-d6)δ 172.19,169.96,169.55,167.06,166.52,163.67,163.24,162.81,153.78 ,140.68,137.30,136.89,134.10,133.61,132.39,129.16,128.47,127.9 8,126.42,124.50,122.95,118.56,115.33,75.00,65.96,65.72,65.27,4 7.99,43.60,41.39,33.62,32.90,30.36,23.55,21.61,20.31.HRMS(ESI)C 41 H 43 N9O7[M+H] +The calculated value is 774.3363, and the measured value is 774.3354.

[0098] Example 17: (E)-6-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)amino)-N-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)hexaneamide (LCG-17) [ka] The synthesis method was as shown in Example 1. 1 H NMR(600 MHz,DMSO-d6)δ 11.05(s,1H),10.85(s,1H),9.81(s,1H),7.99(s,1H),7.55(d,J=8.4 Hz,1H),7.53-7.45(m,4H),7.29(t,J=7.6 Hz,1H),7.20(d,J=8.5 Hz,2H),7.17(d,J=7.5 Hz,1H),7.12(t,J=5.4 Hz,1H),6.94(s,1H),6.84(dd,J=8.4,1.9 Hz,1H),6.06(s,1H),5.02(dd,J=12.8,5.5 Hz,1H),4.33(t,J=7.1 Hz,2H),3.70-3.64(m,4H),3.55-3.49(m,4H),3.20-3.12(m,3H),2.94-2.9 0(m,2H),2.89-2.83(m,1H),2.63-2.52(m,2H),2.34(s,3H),2.30(t,J=7.3 Hz,2H),2.02-1.96(m,1H),1.66-1.57(m,4H),1.44-1.37(m,2H). 13C NMR(150 MHz,DMSO-d6)δ 172.19,170.36,169.56,167.08,166.53,163.75,163.34,162.89,153.83,14 0.58,137.30,136.96,134.13,133.59,132.36,129.14,128.45,127.99,126. 40,124.47,122.92,118.49,115.16,75.03,65.91,65.28,64.29,47.98,43.5 9,41.75,35.70,33.64,30.36,27.44,25.61,24.30,21.61,20.32.HRMS(ESI)C 43 H 47 N9O7[M+H] + The calculated value is 802.3676, and the measured value is 802.3679.

[0099] Example 18: (E)-8-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)amino)-N-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)octanamide (LCG-18) [ka] The synthesis method was as shown in Example 1. 1H NMR(600 MHz, DMSO-d6)δ 11.06(s,1H),10.85(s,1H),9.80(s,1H),7.99(s,1H),7.55(d,J=8.4 Hz,1H),7.53-7.46(m,4H),7.29(t,J=7.6 Hz,1H),7.20(d,J=8.5 Hz,2H),7.17(d,J=7.5 Hz,1H),7.09(t,J=5.3 Hz,1H),6.94(s,1H),6.84(dd,J=8.4,1.9 Hz,1H),6.06(s,1H),5.03(dd,J=12.8,5.5 Hz,1H),4.33(t,J=7.0 Hz,2H),3.69-3.63(m,4H),3.55-3.50(m,4H),3.18-3.12(m,2H),2.94-2.84(m,3H),2.62-2.51(m,2H),2.34(s,3H),2.28(t,J=7.4 Hz,2H),2.01-1.96(m,1H),1.62-1.54(m,4H),1.39-1.29(m,6H). 13 C NMR(150 MHz,DMSO-d6)δ 173.29,171.55,170.66,168.18,167.63,164.84,164.44,163.99,154.94,141.6 8,138.40,138.07,135.23,134.68,133.43,130.23,129.55,129.08,127.49,125 .57,124.01,119.57,116.24,76.13,67.00,66.38,65.39,49.08,44.68,42.93,3 6.82,34.74,31.46,29.13,29.05,28.69,26.91,25.59,22.71,21.41.HRMS(ESI)C 45 H 51 N9O7[M+H] + The calculated value is 830.3989 and the measured value is 830.3985.

[0100] Example 19: (E)-10-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)amino)-N-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)decanamide (LCG-19) [ka] The synthesis method was as shown in Example 1. 1 H NMR(600 MHz,DMSO-d6)δ 11.06(s,1H),10.85(s,1H),9.79(s,1H),7.99(s,1H),7.55(d,J=8.4 Hz,1H),7.53-7.46(m,4H),7.29(t,J=7.6 Hz,1H),7.20(d,J=8.5 Hz,2H),7.17(d,J=7.5 Hz,1H),7.09(t,J=5.3 Hz,1H),6.93(s,1H),6.83(dd,J=8.4,1.8 Hz,1H),6.06(s,1H),5.03(dd,J=12.8,5.5 Hz,1H),4.33(t,J=7.0 Hz,2H),3.71-3.62(m,4H),3.55-3.49(m,4H),3.19-3.10(m,2H),2.92(t,J=7.0 Hz,2H),2.90-2.83(m,1H),2.62-2.51(m,2H),2.34(s,3H),2.27(t,J=7.4 Hz,2H),2.03-1.95(m,1H),1.63-1.52(m,4H),1.40-1.22(m,10H). 13C NMR(150 MHz,DMSO-d6)δ 172.71,170.98,170.08,167.60,167.05,164.25,163.84,163.40,154.36,141.12,137 .81,137.50,134.65,134.10,132.85,129.73,129.05,128.89,128.57,128.41,126.87 ,124.99,123.40,118.97,115.65,75.55,66.43,66.25,65.80,48.50,44.10,42.37,36 .26,34.16,30.88,28.81,28.67,28.56,28.13,26.42,25.04,22.13,20.83.HRMS(ESI)C 47 H 55 N9O7[M+H] + The calculated value is 858.4302, and the measured value is 858.4284.

[0101] Example 20: (E)-N 1 -(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)-N 6 -(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)azipamide (LCG-20) [ka] The synthesis method was as shown in Example 1. 1H NMR(600 MHz,DMSO-d6)δ 11.02(s,1H),10.85(s,1H),9.84(s,1H),9.80(s,1H),7.99(s,1H),7.80(d,J=7.4 Hz,1H),7.54-7.46(m,6H),7.29(t,J=7.6 Hz,1H),7.21(d,J=8.4 Hz,2H),7.17(d,J=7.5 Hz,1H),6.06(s,1H),5.14(dd,J=13.3,5.1 Hz,1H),4.44-4.30(m,4H),3.72-3.64(m,4H),3.52(t,J=8.7 Hz,4H),2.96-2.87(m,3H),2.59(d,J=16.6 Hz,1H),2.42-2.31(m,8H),2.06-1.97(m,1H),1.71-1.59(m,4H). 13 C NMR(150 MHz,DMSO-d6)δ 173.33,171.66,171.55,171.38,168.31,164.84,164.44,163.99,141.69,13 8.40,138.04,135.23,134.30,134.23,133.47,133.15,130.24,129.57,129.0 9,127.49,125.82,124.02,119.58,119.52,76.13,67.00,66.38,51.99,46.9 5,44.69,36.67,36.15,34.74,31.69,25.32,25.30,23.09,21.41.HRMS(ESI)C 43 H 47 N9O7[M+H] + The calculated value is 802.3676, and the measured value is 802.3676.

[0102] Example 21: (E)-N 1 -(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)-N 8 -(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)octanediamide (LCG-21) [ka] The synthesis method was as shown in Example 1. 1 H NMR(600 MHz,DMSO-d6)δ 11.02(s,1H),10.85(s,1H),9.81(s,1H),9.77(s,1H),7.99(s,1H),7.83-7.79(m,1H),7.54-7.46(m,6H),7.29(t,J=7.6 Hz,1H),7.20(d,J=8.5 Hz,2H),7.17(d,J=7.5 Hz,1H),6.06(s,1H),5.14(dd,J=13.3,5.1 Hz,1H),4.44-4.30(m,4H),3.70-3.64(m,4H),3.55-3.49(m,4H),2.96-2.86(m,3H),2.63-2.58(m,1H),2.40-2.31(m,6H),2.29(t,J=7.4 Hz,2H),2.07-1.98(m,1H),1.65-1.57(m,4H),1.40-1.30(m,4H). 13 C NMR(150 MHz,DMSO-d6)δ 172.03,170.51,170.25,170.22,167.00,163.54,163.13,162.69,140.38,137.0 9,136.76,133.93,132.97,132.88,132.14,131.84,128.93,128.25,127.78,126. 19,124.43,122.71,118.28,118.14,74.83,65.70,65.07,50.70,45.66,43.38,3 5.50,34.95,33.43,30.37,27.67,27.64,24.24,24.18,21.80,20.10.HRMS(ESI)C 45 H 51 N9O7[M+H] + The calculated value is 830.3989, and the measured value is 830.3988.

[0103] Example 22: (E)-N 1 -(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)-N 10-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)decanediamide (LCG-22) [ka] The synthesis method was as shown in Example 1. 1 H NMR(600 MHz,DMSO-d6)δ 11.02(s,1H),10.85(s,1H),9.80(s,1H),9.76(s,1H),7.99(s,1H),7.81(d,J=6.8 Hz,1H),7.53-7.46(m,6H),7.29(t,J=7.6 Hz,1H),7.20(d,J=8.5 Hz,2H),7.17(d,J=7.5 Hz,1H),6.06(s,1H),5.15(dd,J=13.3,5.1 Hz,1H),4.41-4.31(m,4H),3.69-3.64(m,4H),3.55-3.50(m,4H),2.95-2.87(m,3H),2.64-2.57(m,1H),2.38-2.31(m,6H),2.28(t,J=7.4 Hz,2H),2.05-2.00(m,1H),1.64-1.55(m,4H),1.37-1.22(m,8H). 13 C NMR(150 MHz,DMSO-d6)δ 173.34,171.85,171.56,168.31,164.84,164.44,163.99,141.68,138.40,138.0 7,135.23,134.28,134.16,133.44,133.14,130.23,129.55,129.08,127.49,125 .71,124.02,119.58,119.44,76.13,67.00,66.38,51.99,46.95,44.68,36.84,3 6.28,34.74,31.68,29.21,29.16,29.14,25.61,25.55,23.12,21.41.HRMS(ESI)C 47 H 55 N9O7[M+H] + The calculated value is 858.4320, and the measured value is 858.4296.

[0104] Example 23: (E)-N 1 -(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)-N 12 -(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)dodecanediamide (LCG-23) [ka] The synthesis method was as shown in Example 1. 1 H NMR(600 MHz,DMSO-d6)δ 11.02(s,1H),10.85(s,1H),9.79(s,1H),9.75(s,1H),7.99(s,1H),7.81(dd,J=7.4,1.0 Hz,1H),7.52-7.46(m,6H),7.29(t,J=7.6 Hz,1H),7.20(d,J=8.5 Hz,2H),7.17(d,J=7.5 Hz,1H),6.06(s,1H),5.14(dd,J=13.3,5.1 Hz,1H),4.40-4.30(m,4H),3.73-3.64(m,4H),3.56-3.49(m,4H),2.95-2.88(m,3H),2.64-2.58(m,1H),2.38-2.31(m,6H),2.27(t,J=7.4 Hz,2H),2.06-1.99(m,1H),1.63-1.54(m,4H),1.34-1.19(m,12H). 13 C NMR(150 MHz,DMSO-d6)δ 173.33,171.85,171.57,171.55,168.30,164.84,164.43,163.99,141.68,138.40,138 .07,135.23,134.28,134.16,133.43,133.13,130.23,129.55,129.08,127.49,125.70 ,124.01,119.57,119.44,76.13,67.00,66.38,51.99,46.93,44.68,36.84,36.28,34. 74,31.68,29.41,29.39,29.28,29.25,29.16,25.63,25.56,23.12,21.41.HRMS(ESI)C 49H 59 N9O7[M+H] + The calculated value is 886.4615, and the measured value is 886.4605.

[0105] Example 24: (E)-N 1 -(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindole-5-yl)-N 4 -(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)succinimide(LCG-24) [ka] The synthesis method was as shown in Example 1. 1 H NMR(600 MHz,DMSO-d6)δ 10.97(s,1H),10.85(s,1H),10.35(s,1H),9.96(s,1H),7.98(d,J=2.4 Hz,2H),7.65(d,J=8.3 Hz,1H),7.60(d,J=8.3 Hz,1H),7.55-7.45(m,4H),7.29(t,J=7.6 Hz,1H),7.21(d,J=8.4 Hz,2H),7.17(d,J=7.5 Hz,1H),6.06(s,1H),5.08(dd,J=13.3,5.1 Hz,1H),4.41(d,J=17.2 Hz,1H),4.33(t,J=7.0 Hz,2H),4.28(d,J=17.2 Hz,1H),3.70-3.63(m,4H),3.55-3.47(m,4H),2.98-2.87(m,3H),2.75-2.64(m,4H),2.59(d,J=17.1 Hz,1H),2.41-2.35(m,1H),2.34(s,3H),2.02-1.95(m,1H). 13C NMR(150 MHz,DMSO-d6)δ 173.37,171.59,171.45,170.57,168.32,164.84,164.43,163.99,143.79,1 43.02,141.68,138.40,138.05,135.23,133.42,130.23,129.59,129.08,12 7.49,126.54,124.12,124.02,119.47,119.02,113.45,76.13,67.00,66.38 ,51.99,47.60,44.69,34.73,31.84,31.69,31.49,23.00,21.41.HRMS(ESI)C 41 H 43 N9O7[M+H] + The calculated value is 774.3363, and the measured value is 774.3342.

[0106] Example 25: (E)-N 1 -(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)-N 6 -(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)azipamide (LCG-25) [ka] The synthesis method was as shown in Example 1. 1H NMR(600 MHz, DMSO-d6)δ 10.97(s,1H),10.86(s,1H),10.33(d,J=8.4 Hz,1H),9.91(d,J=5.6 Hz,1H),8.00(d,J=3.2 Hz,2H),7.66-7.59(m,2H),7.53(d,J=8.4 Hz,2H),7.50(d,J=7.8 Hz,1H),7.47(s,1H),7.29(t,J=7.6 Hz,1H),7.20(d,J=8.5 Hz,2H),7.17(d,J=7.5 Hz,1H),6.06(s,1H),5.08(dd,J=13.3,5.1 Hz,1H),4.42(d,J=17.3 Hz,1H),4.33(t,J=7.1 Hz,2H),4.28(d,J=17.3 Hz,1H),3.70-3.63(m,4H),3.56-3.48(m,4H),2.96-2.86(m,3H),2.63 -2.56(m,1H),2.43-2.31(m,8H),2.02-1.95(m,1H),1.69-1.59(m,4H). 13 C NMR(150 MHz,DMSO-d6)δ 172.29,171.07,170.51,170.31,167.25,163.76,163.35,162.91,142.66,141. 97,140.60,137.32,136.99,134.16,132.36,129.15,128.47,128.00,126.41,1 25.49,122.99,122.94,118.52,118.05,112.49,75.05,65.93,65.30,50.91,46 .52,43.60,35.73,35.57,33.66,30.61,24.25,24.16,21.92,20.33.HRMS(ESI)C 43 H 47 N9O7[M+H] + The calculated value is 802.3676 and the measured value is 802.3667.

[0107] Example 26: (E)-N 1 -(2-(2,6-ジジキソピペリジン-3-イル)-1-オキソイソインドリン-5-イル)-N 8-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)octanediamide (LCG-26) [ka] The synthesis method was as shown in Example 1. 1 H NMR(600 MHz,DMSO-d6)δ 10.97(s,1H),10.85(s,1H),10.21(s,1H),9.80(s,1H),7.99(s,2H),7.64(d,J=8.3 Hz,1H),7.58(dd,J=8.3,1.5 Hz,1H),7.52-7.46(m,4H),7.29(t,J=7.6 Hz,1H),7.20(d,J=8.5 Hz,2H),7.17(d,J=7.5 Hz,1H),6.06(s,1H),5.08(dd,J=13.3,5.1 Hz,1H),4.42(d,J=17.2 Hz,1H),4.33(t,J=7.0 Hz,2H),4.28(d,J=17.3 Hz,1H),3.69-3.63(m,4H),3.55-3.49(m,4H),2.95-2.86(m,3H),2.63-2.56(m,1H),2.39-2.32(m,6H),2.29(t,J=7.4 Hz,2H),2.02-1.96(m,1H),1.65-1.56(m,4H),1.36-1.32(m,4H). 13 C NMR(150 MHz,DMSO-d6)δ 173.37,172.25,171.59,171.53,168.34,164.84,164.43,163.99,143.76,143.03, 141.68,138.40,138.07,135.23,133.44,130.24,129.55,129.08,127.49,126.57, 124.08,124.02,119.59,119.11,113.56,76.13,67.01,66.38,51.99,47.60,44.68 ,36.95,36.80,34.74,31.69,28.96,28.95,25.52,25.40,23.00,21.41.HRMS(ESI)C 45 H 51 N9O7[M+H]+ The calculated value is 830.3989, and the measured value is 830.3986.

[0108] Example 27: (E)-N 1 -(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)-N 10 -(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)decanediamide (LCG-27) [ka] The synthesis method was as shown in Example 1. 1 H NMR(600 MHz,DMSO-d6)δ 10.97(s,1H),10.85(s,1H),10.20(s,1H),9.79(s,1H),7.99(s,2H),7.64(d,J=8.3 Hz,1H),7.58(dd,J=8.3,1.5 Hz,1H),7.53-7.46(m,4H),7.29(t,J=7.6 Hz,1H),7.20(d,J=8.5 Hz,2H),7.17(d,J=7.5 Hz,1H),6.06(s,1H),5.08(dd,J=13.3,5.1 Hz,1H),4.42(d,J=17.3 Hz,1H),4.33(t,J=7.0 Hz,2H),4.28(d,J=17.3 Hz,1H),3.69-3.61(m,4H),3.56-3.48(m,4H),2.96-2.87(m,3H),2.59(d,J=17.1 Hz,1H),2.38-2.31(m,6H),2.27(t,J=7.4 Hz,2H),2.02-1.95(m,1H),1.63-1.54(m,4H),1.35-1.23(m,8H). 13C NMR(150 MHz,DMSO-d6)δ 172.29,171.20,170.51,170.48,167.25,163.76,163.35,162.91,142.68,141.96,1 40.60,137.32,137.00,134.15,132.35,129.15,128.47,128.00,126.41,125.49,123 .00,122.94,118.50,118.02,112.47,75.05,65.93,65.30,50.91,46.51,43.61,35.9 0,35.76,33.66,30.61,28.11,28.06,28.03,24.53,24.40,21.93,20.33.HRMS(ESI)C 47 H 55 N9O7[M+H] + The calculated value is 858.4302, and the measured value is 858.4298.

[0109] Example 28: (E)-N 1 -(2-(2,6-dioxopiperidine-3-yl)-3-oxoisoindorin-5-yl)-N 4 -(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)succinimide(LCG-28) [ka] The synthesis method was as shown in Example 1. 1H NMR(600 MHz,DMSO-d6)δ 10.98(s,1H),10.86(s,1H),10.25(s,1H),9.97(s,1H),8.10(d,J=1.4 Hz,1H),7.99(s,1H),7.72(dd,J=8.2,1.8 Hz,1H),7.56-7.44(m,5H),7.29(t,J=7.6 Hz,1H),7.21(d,J=8.5 Hz,2H),7.17(d,J=7.5 Hz,1H),6.06(s,1H),5.09(dd,J=13.3,5.1 Hz,1H),4.39(d,J=17.0 Hz,1H),4.33(t,J=7.1 Hz,2H),4.27(d,J=17.0 Hz,1H),3.70-3.61(m,4H),3.56-3.48(m,4H),2.96-2.86(m,3H),2.75-2.63(m,4H),2.60(d,J=18.0 Hz,1H),2.43-2.30(m,4H),2.05-1.97(m,1H). 13 C NMR(150 MHz,DMSO-d6)δ 172.26,170.41,170.06,169.52,167.41,163.75,163.33,162.89,140.58,1 38.64,137.30,136.95,135.63,134.14,132.31,131.52,129.14,128.49,12 7.99,126.40,123.15,122.92,121.87,118.40,112.19,75.03,65.91,65.28 ,51.04,46.32,43.59,33.64,30.67,30.59,30.48,21.85,20.32.HRMS(ESI)C 41 H 43 N9O7[M+H] + The calculated value is 774.3363, and the measured value is 774.3355.

[0110] Example 29: (E)-N 1 -(2-(2,6-dioxopiperidine-3-yl)-3-oxoisoindorin-5-yl)-N 6 -(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)azipamide (LCG-29) [ka] The synthesis method was as shown in Example 1. 1 H NMR(600 MHz,DMSO-d6)δ 10.98(brs,1H),10.85(s,1H),10.14(s,1H),9.84(s,1H),8.10(d,J=1.7 Hz,1H),7.99(s,1H),7.71(dd,J=8.2,1.9 Hz,1H),7.54-7.48(m,4H),7.47(s,1H),7.29(t,J=7.6 Hz,1H),7.20(d,J=8.5 Hz,2H),7.17(d,J=7.5 Hz,1H),6.06(s,1H),5.09(dd,J=13.3,5.1 Hz,1H),4.39(d,J=17.1 Hz,1H),4.33(t,J=7.1 Hz,2H),4.27(d,J=17.1 Hz,1H),3.70-3.61(m,4H),3.54-3.49(m,4H),2.96-2.86(m,3H),2.63 -2.57(m,1H),2.43-2.24(m,8H),2.02-1.98(m,1H),1.73-1.57(m,4H). 13 C NMR(150 MHz,DMSO-d6)δ 173.36,171.83,171.50,171.38,168.51,164.84,164.43,163.99,141.67,139. 71,138.40,138.04,136.78,135.23,133.46,132.59,130.23,129.56,129.08,1 27.49,124.22,124.02,123.09,119.61,113.45,76.12,67.01,66.38,52.14,47 .42,44.68,36.78,36.71,34.74,31.69,25.38,25.28,22.95,21.41.HRMS(ESI)C 43 H 47 N9O7[M+H] + The calculated value is 802.3676, and the measured value is 802.3675.

[0111] Example 30: (E)-N 1-(2-(2,6-dioxopiperidine-3-yl)-3-oxoisoindole-5-yl)-N 8 -(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)octanediamide (LCG-30) [ka] The synthesis method was as shown in Example 1. 1 H NMR(600 MHz,DMSO-d6)δ 10.98(s,1H),10.85(s,1H),10.10(s,1H),9.80(s,1H),8.10(d,J=1.5 Hz,1H),7.99(s,1H),7.70(dd,J=8.2,1.8 Hz,1H),7.54-7.46(m,5H),7.29(t,J=7.6 Hz,1H),7.20(d,J=8.5 Hz,2H),7.17(d,J=7.5 Hz,1H),6.06(s,1H),5.10(dd,J=13.3,5.1 Hz,1H),4.39(d,J=17.0 Hz,1H),4.33(t,J=7.0 Hz,2H),4.26(d,J=17.0 Hz,1H),3.70-3.62(m,4H),3.56-3.48(m,4H),2.95-2.86(m,3H),2.60(d,J=17.5 Hz,1H),2.43-2.31(m,6H),2.29(t,J=7.4 Hz,2H),2.04-1.97(m,1H),1.66-1.56(m,4H),1.39-1.30(m,4H). 13C NMR(150 MHz,DMSO-d6)δ 172.27,170.89,170.44,170.42,167.44,163.76,163.35,162.90,140.60,138.6 6,137.32,137.00,135.66,134.15,132.34,131.50,129.15,128.47,128.00,126. 41,123.12,122.94,121.99,118.51,112.34,75.05,65.93,65.30,51.06,46.34,4 3.60,35.80,35.73,33.66,30.61,27.88,24.45,24.35,21.87,20.33.HRMS(ESI)C 45 H 51 N9O7[M+H] + The calculated value is 830.3989, and the measured value is 830.3991.

[0112] Example 31: (E)-N 1 -(2-(2,6-dioxopiperidine-3-yl)-3-oxoisoindole-5-yl)-N 10 -(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)decanediamide (LCG-31) [ka] The synthesis method was as shown in Example 1. 1H NMR(600 MHz, DMSO-d6)δ 10.98(brs,1H),10.85(s,1H),10.11(s,1H),9.80(s,1H),8.10(t,J=3.4 Hz,1H),7.99(s,1H),7.70(dd,J=8.2,1.9 Hz,1H),7.53-7.46(m,5H),7.29(t,J=7.6 Hz,1H),7.20(d,J=8.5 Hz,2H),7.17(d,J=7.5 Hz,1H),6.06(s,1H),5.09(dd,J=13.3,5.1 Hz,1H),4.39(d,J=17.0 Hz,1H),4.33(t,J=7.1 Hz,2H),4.26(d,J=17.0 Hz,1H),3.70-3.62(m,4H),3.55-3.49(m,4H),2.96-2.86(m,3H),2.63-2.56(m,1H),2.43-2.30(m,6H),2.27(t,J=7.4 Hz,2H),2.03-1.97(m,1H),1.64-1.53(m,4H),1.34-1.26(m,8H). 13 C NMR(150 MHz,DMSO-d6)δ 172.28,170.94,170.50,170.43,167.46,163.77,163.36,162.92,140.61,138.67, 137.32,137.00,135.67,134.16,132.35,131.50,129.16,128.47,128.01,126.42, 123.13,122.94,122.00,118.51,112.35,75.05,65.93,65.31,51.07,46.35,43.61 ,35.83,35.77,33.66,30.62,28.11,28.06,24.54,24.43,21.87,20.34.HRMS(ESI)C 47 H 55 N9O7[M+H] + The calculated value is 858.4302 and the measured value is 858.4296.

[0113] Example 32: (E)-N 1 -(2-(2,6-ジジキソピペリジン-3-イル)-3-オキソイソインドリン-4-イル)-N 4-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)succinimide(LCG-32) [ka] The synthesis method was as shown in Example 1. 1 H NMR(600 MHz,DMSO-d6)δ 11.04(s,1H),10.85(s,1H),10.30(s,1H),9.98(s,1H),8.30(d,J=8.2 Hz,1H),7.98(s,1H),7.56(t,J=7.9 Hz,1H),7.54-7.45(m,4H),7.29(t,J=7.6 Hz,1H),7.25(d,J=7.5 Hz,1H),7.20(d,J=8.4 Hz,2H),7.17(d,J=7.5 Hz,1H),6.06(s,1H),5.08(dd,J=13.3,5.1 Hz,1H),4.48(d,J=17.6 Hz,1H),4.37(d,J=17.6 Hz,1H),4.33(t,J=7.0 Hz,2H),3.70-3.64(m,4H),3.56-3.49(m,4H),2.95-2.87(m,3H),2.76-2.66( m,4H),2.65-2.59(m,1H),2.47-2.39(m,1H),2.34(s,3H),2.07-2.02(m,1H). 13 C NMR(150 MHz,DMSO-d6)δ 172.22,170.17,170.03,169.19,168.56,163.74,163.32,162.88,142.04,1 40.59,137.30,136.90,136.43,134.14,132.56,132.33,129.14,128.49,12 7.98,126.40,122.92,118.39,117.00,116.35,116.09,75.02,65.91,65.28 ,51.00,46.90,43.59,33.63,31.16,30.55,30.29,21.72,20.31.HRMS(ESI)C 41 H 43 N9O7[M+H] +The calculated value is 774.3363, and the measured value is 774.3360.

[0114] Example 33: (E)-N 1 -(2-(2,6-dioxopiperidine-3-yl)-3-oxoisoindorin-4-yl)-N 6 -(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)azipamide (LCG-33) [ka] The synthesis method was as shown in Example 1. 1 H NMR(600 MHz,DMSO-d6)δ 11.04(s,1H),10.85(s,1H),10.27(s,1H),9.84(s,1H),8.32(d,J=8.2 Hz,1H),7.99(s,1H),7.57(t,J=7.9 Hz,1H),7.53-7.47(m,4H),7.29(t,J=7.6 Hz,1H),7.25(d,J=7.5 Hz,1H),7.20(d,J=8.5 Hz,2H),7.17(d,J=7.5 Hz,1H),6.06(s,1H),5.06(dd,J=13.3,5.1 Hz,1H),4.47(d,J=17.6 Hz,1H),4.39-4.32(m,3H),3.69-3.65(m,4H),3.55-3.50(m,4H),2.95-2.85(m,3H),2.62(d,J=16.8 Hz,1H),2.48-2.40(m,3H),2.36-2.32(m,5H),2.07-2.01(m,1H),1.70-1.63(m,4H). 13C NMR(150 MHz,DMSO-d6)δ 172.21,170.57,170.20,170.17,168.58,163.74,163.33,162.88,142.01,140. 60,137.30,136.93,136.43,134.14,132.57,132.37,129.14,128.46,127.99,1 26.40,122.93,118.53,117.03,116.41,116.14,75.03,65.92,65.29,51.00,46 .91,43.59,36.11,35.43,33.64,30.55,24.08,23.82,21.72,20.32.HRMS(ESI)C 43 H 47 N9O7[M+H] + The calculated value is 802.3676, and the measured value is 802.3670.

[0115] Example 34: (E)-N 1 -(2-(2,6-dioxopiperidine-3-yl)-3-oxoisoindorin-4-yl)-N 8 -(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)octanediamide (LCG-34) [ka] The synthesis method was as shown in Example 1. 1H NMR(600 MHz, DMSO-d6)δ 11.03(s,1H),10.85(s,1H),10.27(s,1H),9.80(s,1H),8.32(d,J=8.2 Hz,1H),7.99(s,1H),7.56(t,J=7.9 Hz,1H),7.53-7.46(m,4H),7.29(t,J=7.6 Hz,1H),7.25(d,J=7.5 Hz,1H),7.20(d,J=8.5 Hz,2H),7.17(d,J=7.5 Hz,1H),6.06(s,1H),5.07(dd,J=13.3,5.1 Hz,1H),4.47(d,J=17.6 Hz,1H),4.38-4.31(m,3H),3.68-3.63(m,4H),3.56-3.50(m,4H),2.95-2.8 5(m,3H),2.64-2.58(m,1H),2.45-2.37(m,3H),2.34(s,3H),2.28(t,J=7.4 Hz,2H),2.06-2.00(m,1H),1.67-1.62(m,2H),1.62-1.56(m,2H),1.39-1.30(m,4H). 13 C NMR(150 MHz,DMSO-d6)δ 173.30,171.78,171.52,171.28,169.69,164.84,164.43,163.99,143.10,141.68, 138.40,138.07,137.55,135.24,133.66,133.41,130.23,129.54,129.08,127.49, 124.02,119.59,118.09,117.48,117.21,76.13,67.01,66.38,52.06,47.97,44.68 ,37.50,36.78,34.74,31.64,28.89,28.80,25.48,25.19,22.81,21.41.HRMS(ESI)C 45 H 51 N9O7[M+H] + The calculated value is 830.3989 and the measured value is 830.3983.

[0116] Example 35: (E)-N 1 -(2-(2,6-ジジキソピペリジン-3-イル)-3-オキソイソインドリン-4-イル)-N 10-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)decanediamide (LCG-35) [ka] The synthesis method was as shown in Example 1. 1 H NMR(600 MHz,DMSO-d6)δ 11.03(s,1H),10.85(s,1H),10.26(s,1H),9.79(s,1H),8.32(d,J=8.2 Hz,1H),7.99(s,1H),7.56(t,J=7.9 Hz,1H),7.54-7.45(m,4H),7.29(t,J=7.6 Hz,1H),7.24(d,J=7.4 Hz,1H),7.20(d,J=8.5 Hz,2H),7.17(d,J=7.6 Hz,1H),6.06(s,1H),5.07(dd,J=13.3,5.1 Hz,1H),4.47(d,J=17.6 Hz,1H),4.40-4.28(m,3H),3.72-3.62(m,4H),3.57-3.49(m,4H),2.97-2.8 4(m,3H),2.64-2.57(m,1H),2.46-2.37(m,3H),2.34(s,3H),2.27(t,J=7.5 Hz,2H),2.07-2.00(m,1H),1.68-1.60(m,2H),1.60-1.54(m,2H),1.38-1.21(m,8H). 13 C NMR(150 MHz,DMSO-d6)δ 171.97,170.49,170.25,169.95,168.37,163.51,163.10,162.66,141.77,140.36, 137.07,136.76,136.23,133.91,132.34,132.08,128.91,128.22,127.75,126.17, 122.70,118.26,116.76,116.14,115.86,74.80,65.69,65.06,50.73,46.64,43.36 ,36.21,35.52,33.42,30.32,27.79,27.66,24.29,23.96,21.49,20.09.HRMS(ESI)C 47 H55 N9O7[M+H] + The calculated value is 858.4320, and the measured value is 858.4298.

[0117] Example 36: (E)-N 1 -(2-(2,6-dioxopiperidine-3-yl)-3-oxoisoindorin-4-yl)-N 12 -(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)dodecanediamide (LCG-36) [ka] The synthesis method was as shown in Example 1. 1 H NMR(600 MHz,DMSO-d6)δ 11.03(s,1H),10.85(s,1H),10.26(s,1H),9.78(s,1H),8.31(d,J=8.2 Hz,1H),7.99(s,1H),7.56(t,J=7.9 Hz,1H),7.52-7.44(m,4H),7.29(t,J=7.6 Hz,1H),7.24(d,J=7.5 Hz,1H),7.20(d,J=8.4 Hz,2H),7.17(d,J=7.6 Hz,1H),6.06(s,1H),5.07(dd,J=13.3,5.1 Hz,1H),4.47(d,J=17.6 Hz,1H),4.41-4.28(m,3H),3.72-3.64(m,4H),3.57-3.48(m,4H),2.96-2.85(m,3H),2.61(d,J=17.5 Hz,1H),2.45-2.37(m,3H),2.34(s,3H),2.26(t,J=7.4 Hz,2H),2.06-1.99(m,1H),1.66-1.59(m,2H),1.59-1.51(m,2H),1.34-1.24(m,12H). 13C NMR(150 MHz,DMSO-d6)δ 173.30,171.82,171.57,171.26,169.69,164.84,164.43,163.99,143.10,141.67,138.39 ,138.08,137.55,135.24,133.66,133.41,130.23,129.54,129.08,127.49,124.01,119.5 7,118.08,117.46,117.18,76.13,67.01,66.38,52.06,47.96,44.68,37.53,36.85,34.74 ,31.64,29.35,29.33,29.24,29.17,29.15,28.99,25.62,25.29,22.81,21.41.HRMS(ESI)C 49 H 59 N9O7[M+H] + The calculated value is 886.4615, and the measured value is 886.4608.

[0118] Example 37: N 1 -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazole-5-yl)benzyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 4 -(4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)succinimide(LCG-37) [ka] Step 1: Preparation of (E)-4-((4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinepyrimidine-2-yl)oxy)ethyl)phenyl)amino)-4-oxobutyric acid (8) [ka] Intermediate 6 (300 mg, 0.7 mmol) and 4-(tert-butoxy)-4-oxobutyric acid (126 mg, 0.7 mmol) were dissolved in 15 mL of DMF, then HATU (550 mg, 1.4 mmol) and triethylamine (220 mg, 2.1 mmol) were added, and the mixture was reacted at room temperature for 4 hours. 50 mL of water was added, and the mixture was extracted twice with EA. The organic phases were combined, washed once with saturated brine, dried over anhydrous Na2SO4, filtered, and spin-dried to obtain the oil, which was used directly in the next step without purification. The oil was dissolved in DCM containing 25% TFA, and the mixture was stirred at room temperature for 3 hours. The completion of the reaction was monitored by TLC. The mixture was rotated under reduced pressure and then subjected to column chromatography to obtain 250 mg of pale white solid (67%). 1 H NMR(500 MHz,DMSO-d6)δ 10.89(brs,1H),9.88(s,1H),7.98(s,1H),7.56-7.43(m,4H),7.27(t,J=7.5 Hz,1H),7.21-7.13(m,3H),6.03(s,1H),4.33(t,J=6.3 Hz,2H),3.69-3.62(m,6H),3.56-3.50(m,4H),2.91(t,J=6.9 Hz,2H),2.52(t,J=5.1 Hz,2H),2.32(s,3H).MS(ESI),m / z:533.3[M+H] + .

[0119] Step 2: N 1 -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazole-5-yl)benzyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 4 Preparation of -(4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)succinimide (LCG-37) [ka] Intermediate 8 (40 mg, 0.07 mmol) and the reported intermediate 9 (30 mg, 0.7 mmol) of the VHL ligand for E3 ubiquitin ligase were dissolved in 10 mL of DMF. Then, HATU (70 mg, 0.2 mmol) and triethylamine (40 mg, 0.4 mmol) were added, and the mixture was reacted at room temperature for 4 hours. 20 mL of water was added, and the mixture was extracted twice with EA. The organic phases were combined, washed once with saturated brine, dried over anhydrous Na2SO4, filtered, spin-dried, and then subjected to column chromatography to obtain 29 mg of white solid (44%). 1 H NMR(600 MHz,DMSO-d6)δ 10.86(s,1H),9.88(s,1H),8.98(s,1H),8.57(t,J=6.0 Hz,1H),7.99(s,1H),7.96(d,J=9.3 Hz,1H),7.53-7.46(m,4H),7.42(d,J=8.3 Hz,2H),7.39(d,J=8.3 Hz,2H),7.29(t,J=7.6 Hz,1H),7.20(d,J=8.5 Hz,2H),7.17(d,J=7.5 Hz,1H),6.06(s,1H),5.12(d,J=3.5 Hz,1H),4.55(d,J=9.4 Hz,1H),4.47-4.40(m,2H),4.33(t,J=7.1 Hz,3H),4.22(dd,J=15.8,5.4 Hz,1H),3.72-3.60(m,6H),3.55-3.49(m,4H),2.92(t,J=7.0 Hz,2H),2.63-2.56(m,1H),2.56-2.52(m,2H),2.49-2.42(m,4H),2.34(s,3H),2.06-2.01(m,1H),1.93-1.87(m,1H),0.94(s,9H). 13C NMR(150 MHz,DMSO-d6)δ 172.41,171.65,170.78,170.05,164.85,164.43,163.99,151.93,148.19,141.67,1 39.98,138.40,138.07,135.23,133.37,131.64,130.23,130.11,129.56,129.12,129 .08,127.90,127.49,124.01,119.48,76.13,69.36,67.01,66.38,59.19,56.93,56.8 2,44.69,42.12,38.40,35.86,34.73,32.32,30.59,26.84,21.41,16.42.HRMS(ESI)C 50 H 60 N 10 O7S[M+H] + The calculated value is 945.4445, and the measured value is 945.4438.

[0120] Example 38: N 1 -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazole-5-yl)benzyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 6 -(4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)azipamide (LCG-38) [ka] The synthesis method was as shown in Example 37. 1H NMR(600 MHz, DMSO-d6)δ 10.86(s,1H),9.81(s,1H),8.98(s,1H),8.57(t,J=6.1 Hz,1H),7.99(s,1H),7.88(d,J=9.3 Hz,1H),7.53-7.47(m,4H),7.42(d,J=8.3 Hz,2H),7.40-7.36(m,2H),7.29(t,J=7.6 Hz,1H),7.20(d,J=8.5 Hz,2H),7.17(d,J=7.5 Hz,1H),6.07(s,1H),5.13(d,J=3.6 Hz,1H),4.55(d,J=9.4 Hz,1H),4.47-4.41(m,2H),4.33(t,J=7.1 Hz,3H),4.22(dd,J=15.9,5.5 Hz,1H),3.71-3.62(m,6H),3.56-3.50(m,4H),2.92(t,J=7.0 Hz,2H),2.45(s,3H),2.34(s,3H),2.32-2.24(m,3H),2.20-2.13(m,1H) ,2.06-2.00(m,1H),1.94-1.87(m,1H),1.61-1.48(m,4H),0.94(s,9H). 13 C NMR(150 MHz,DMSO-d6)δ 172.42,172.41,171.45,170.19,164.85,164.44,163.99,151.92,148.19,141.68,139.98 ,138.39,138.04,135.24,133.46,131.64,130.23,130.11,129.55,129.11,129.08,127.8 9,127.49,124.02,119.60,76.14,69.35,67.01,66.38,59.17,56.85,56.81,44.69,42.12 ,38.42,36.69,35.69,35.21,34.74,26.93,26.87,25.67,25.44,21.41,16.42.HRMS(ESI)C 52 H 64 N 10 O7S[M+H] + The calculated value is 973.4758 and the measured value is 973.4757.

[0121] Example 39:N 1-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazole-5-yl)benzyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 8 -(4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)octanediamide (LCG-39) [ka] The synthesis method was as shown in Example 37. 1 H NMR(600 MHz,DMSO-d6)δ 10.85(s,1H),9.80(s,1H),8.98(s,1H),8.56(t,J=6.1 Hz,1H),7.99(s,1H),7.85(d,J=9.4 Hz,1H),7.53-7.46(m,4H),7.42(d,J=8.2 Hz,2H),7.40-7.36(m,2H),7.29(t,J=7.6 Hz,1H),7.20(d,J=8.5 Hz,2H),7.17(d,J=7.5 Hz,1H),6.06(s,1H),5.13(d,J=3.6 Hz,1H),4.55(d,J=9.4 Hz,1H),4.46-4.40(m,2H),4.37-4.31(m,3H),4.22(dd,J=15.9,5.5 Hz,1H),3.70-3.63(m,6H),3.55-3.50(m,4H),2.92(t,J=7.0 Hz,2H),2.44(s,3H),2.34(s,3H),2.29-2.22(m,3H),2.15-2.10(m,1H),2.06-2. 01(m,1H),1.93-1.88(m,1H),1.60-1.42(m,4H),1.32-1.24(m,4H),0.94(s,9H). 13C NMR(150 MHz,DMSO-d6)δ 172.56,172.43,171.55,170.20,164.84,164.43,163.99,151.92,148.19,141.68,139.98, 138.39,138.07,135.23,133.43,131.64,130.23,130.11,129.54,129.11,129.08,127.89,1 27.49,124.02,119.59,76.13,69.34,67.01,66.38,59.16,56.84,56.76,44.68,42.12,38.4 2,36.84,35.68,35.34,34.74,28.98,28.94,26.86,25.83,25.56,21.41,16.42.HRMS(ESI)C 54 H 68 N 10 O7S[M+H] + The calculated value is 1001.5071, and the measured value is 1001.5063.

[0122] Example 40: N 1 -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazole-5-yl)benzyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 10 -(4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)decanediamide (LCG-40) [ka] The synthesis method was as shown in Example 37. 1H NMR(600 MHz, DMSO-d6)δ 10.85(s,1H),9.79(s,1H),8.98(s,1H),8.56(t,J=6.0 Hz,1H),7.99(s,1H),7.84(d,J=9.4 Hz,1H),7.54-7.46(m,4H),7.42(d,J=8.3 Hz,2H),7.38(d,J=8.3 Hz,2H),7.29(t,J=7.6 Hz,1H),7.20(d,J=8.5 Hz,2H),7.17(d,J=7.5 Hz,1H),6.06(s,1H),5.12(d,J=3.6 Hz,1H),4.54(d,J=9.4 Hz,1H),4.46-4.40(m,2H),4.37-4.31(m,3H),4.22(dd,J=15.8,5.4 Hz,1H),3.70-3.62(m,6H),3.56-3.50(m,4H),2.92(t,J=7.0 Hz,2H),2.44(s,3H),2.34(s,3H),2.29-2.23(m,3H),2.14-2.08(m,1H),2.05-1. 99(m,1H),1.94-1.87(m,1H),1.60-1.42(m,4H),1.32-1.17(m,8H),0.93(s,9H). 13 C NMR(150 MHz,DMSO-d6)δ 172.56,172.42,171.56,170.19,164.84,164.43,163.99,151.92,148.19,141.67,139.98,13 8.39,138.08,135.24,133.41,131.64,130.23,130.11,129.54,129.11,129.08,127.89,127. 49,124.01,119.57,76.13,69.33,67.01,66.38,59.16,56.82,56.74,44.68,42.11,38.43,36 .86,35.68,35.32,34.74,29.24,29.15,29.13,26.85,25.89,25.63,21.41,16.42.HRMS(ESI)C 56 H 72 N 10 O7S[M+H] + The calculated value is 1029.5384 and the measured value is 1029.5378.

[0123] Example 41: N 1 -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazole-5-yl)benzyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 5 -(4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)glutaramide (LCG-41) [ka] The synthesis method was as shown in Example 37. 1 H NMR(600 MHz,DMSO-d6)δ 10.85(s,1H),9.81(s,1H),8.98(s,1H),8.56(t,J=6.0 Hz,1H),7.99(s,1H),7.92(d,J=9.2 Hz,1H),7.54-7.45(m,4H),7.42(d,J=8.3 Hz,2H),7.40-7.36(m,2H),7.29(t,J=7.6 Hz,1H),7.20(d,J=8.5 Hz,2H),7.17(d,J=7.5 Hz,1H),6.06(s,1H),5.14(d,J=3.3 Hz,1H),4.55(d,J=9.3 Hz,1H),4.46-4.40(m,2H),4.38-4.32(m,3H),4.22(dd,J=15.8,5.4 Hz,1H),3.70-3.62(m,6H),3.55-3.50(m,4H),2.92(t,J=6.9 Hz,2H),2.44(s,3H),2.34(s,3H),2.32-2.25(m,3H),2.24-2.18(m,1H) ,2.07-2.00(m,1H),1.95-1.87(m,1H),1.84-1.75(m,2H),0.95(s,9H). 13C NMR(150 MHz,DMSO-d6)δ 172.41,172.18,171.20,170.20,164.84,164.43,163.99,151.92,148.19,141.68,139 .98,138.39,138.05,135.23,133.45,131.64,130.23,130.11,129.53,129.11,129.08 ,127.89,127.49,124.02,119.63,76.13,69.37,67.01,66.38,59.18,56.91,56.84,44 .68,42.12,38.42,36.32,35.66,34.74,34.68,26.88,21.99,21.41,16.42.HRMS(ESI)C 51 H 62 N 10 O7S[M+H] + The calculated value is 959.4602, and the measured value is 959.4584.

[0124] Example 42: N 1 -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazole-5-yl)benzyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 7 -(4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)heptanediamide (LCG-42) [ka] The synthesis method was as shown in Example 37. 1H NMR(600 MHz, DMSO-d6)δ 10.85(s,1H),9.79(s,1H),8.98(d,J=5.4 Hz,1H),8.56(t,J=6.1 Hz,1H),7.99(s,1H),7.86(d,J=9.3 Hz,1H),7.53-7.46(m,4H),7.42(d,J=8.3 Hz,2H),7.38(d,J=8.3 Hz,2H),7.29(t,J=7.6 Hz,1H),7.20(d,J=8.5 Hz,2H),7.17(d,J=7.5 Hz,1H),6.06(s,1H),5.13(d,J=3.6 Hz,1H),4.54(d,J=9.4 Hz,1H),4.45-4.40(m,2H),4.37-4.30(m,3H),4.22(dd,J=15.8,5.5 Hz,1H),3.70-3.62(m,6H),3.55-3.50(m,4H),2.92(t,J=7.0 Hz,2H),2.44(s,3H),2.34(s,3H),2.30-2.22(m,3H),2.16-2.10(m,1H),2.07-2. 00(m,1H),1.95-1.86(m,1H),1.62-1.43(m,4H),1.32-1.23(m,2H),0.93(s,9H). 13 C NMR(150 MHz,DMSO-d6)δ 172.51,172.42,171.51,170.19,164.84,164.43,163.99,151.93,148.19,141.68,139.98 ,138.39,138.08,135.23,133.41,131.64,130.23,130.11,129.54,129.11,129.08,127.8 9,127.49,124.01,119.58,76.13,69.34,67.01,66.38,59.16,56.84,56.76,44.68,42.12 ,38.43,36.75,35.68,35.26,34.74,28.84,26.86,25.73,25.41,21.41,16.42.HRMS(ESI)C 53 H 66 N 10 O7S[M+H] + The calculated value is 987.4915 and the measured value is 987.4912.

[0125] Example 43:N1 -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazole-5-yl)benzyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 9 -(4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)nonhesamide (LCG-43) [ka] The synthesis method was as shown in Example 37. 1 H NMR(600 MHz,DMSO-d6)δ 10.85(s,1H),9.79(s,1H),8.98(s,1H),8.56(t,J=6.1 Hz,1H),7.99(s,1H),7.84(d,J=9.4 Hz,1H),7.53-7.46(m,4H),7.42(d,J=8.3 Hz,2H),7.40-7.36(m,2H),7.29(t,J=7.6 Hz,1H),7.20(d,J=8.5 Hz,2H),7.17(d,J=7.5 Hz,1H),6.06(s,1H),5.12(d,J=3.6 Hz,1H),4.54(d,J=9.4 Hz,1H),4.46-4.39(m,2H),4.33(t,J=7.1 Hz,3H),4.21(dd,J=15.8,5.5 Hz,1H),3.72-3.61(m,6H),3.56-3.48(m,4H),2.92(t,J=7.0 Hz,2H),2.44(s,3H),2.34(s,3H),2.30-2.20(m,3H),2.15-2.08(m,1H),2.05-1. 98(m,1H),1.95-1.85(m,1H),1.62-1.40(m,4H),1.30-1.20(m,6H),0.93(s,9H). 13C NMR(150 MHz,DMSO-d6)δ 170.70,170.56,169.71,168.32,162.98,162.57,162.13,150.06,146.33,139.81,138.12, 136.53,136.21,133.37,131.56,129.77,128.37,128.24,127.68,127.25,127.22,126.03,1 25.63,122.15,117.72,74.27,67.47,65.14,64.52,57.29,54.96,54.87,42.82,38.67,36.5 6,34.99,33.81,33.46,32.87,27.21,27.16,24.98,24.03,23.76,19.55,14.56.HRMS(ESI)C 55 H 70 N 10 O7S[M+H] + The calculated value is 1015.5228, and the measured value is 1015.5218.

[0126] Example 44: N 1 -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazole-5-yl)benzyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 11 -(4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)undecanediamide (LCG-44) [ka] The synthesis method was as shown in Example 37. 1H NMR(600 MHz, DMSO-d6)δ 10.85(s,1H),9.79(s,1H),8.98(s,1H),8.55(t,J=6.1 Hz,1H),7.99(s,1H),7.84(d,J=9.4 Hz,1H),7.52-7.47(m,4H),7.42(d,J=8.3 Hz,2H),7.39-7.37(m,2H),7.29(t,J=7.6 Hz,1H),7.20(d,J=8.5 Hz,2H),7.17(d,J=7.5 Hz,1H),6.06(s,1H),5.11(d,J=3.2 Hz,1H),4.54(d,J=9.4 Hz,1H),4.45-4.40(m,2H),4.33(t,J=7.1 Hz,3H),4.21(dd,J=15.9,5.4 Hz,1H),3.68-3.62(m,6H),3.54-3.50(m,4H),2.92(t,J=7.0 Hz,2H),2.44(s,3H),2.34(s,3H),2.29-2.22(m,3H),2.14-2.07(m,1H),2.05-1.97(m,1H) ,1.93-1.86(m,1H),1.62-1.52(m,2H),1.53-1.42(m,2H),1.30-1.20(m,12H),0.93(s,9H). 13 C NMR(150 MHz,DMSO-d6)δ 172.56,172.42,171.56,170.18,164.84,164.43,163.99,151.93,148.19,141.67,139.98,138.3 9,138.08,135.23,133.42,131.64,130.23,130.11,129.54,129.11,129.08,127.89,127.49,124 .01,119.58,76.13,69.33,67.01,66.38,59.15,56.82,56.73,44.68,42.11,38.43,36.86,35.68 ,35.33,34.74,29.34,29.27,29.22,29.16,29.13,26.85,25.91,25.64,21.41,16.42.HRMS(ESI)C 57 H 74 N 10 O7S[M+H] + The calculated value is 1043.5541 and the measured value is 1043.5527.

[0127] Example 45: N 1 -((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-4-(4-methylthiazole-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 5 -(4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)glutaramide (LCG-45) [ka] The synthesis method was as shown in Example 37. 1 H NMR(600 MHz,DMSO-d6)δ 10.86(s,1H),9.82(s,1H),8.98(s,1H),8.38(d,J=7.8 Hz,1H),7.99(s,1H),7.86(d,J=9.2 Hz,1H),7.54-7.46(m,4H),7.45-7.41(m,2H),7.39-7.36(m,2H),7.29(t,J=7.6 Hz,1H),7.21(d,J=8.5 Hz,2H),7.17(d,J=7.4 Hz,1H),6.06(s,1H),5.12(s,1H),4.95-4.88(m,1H),4.52(d,J=9.3 Hz,1H),4.43(t,J=8.0 Hz,1H),4.33(t,J=7.0 Hz,2H),4.29(s,1H),3.69-3.64(m,4H),3.65-3.60(m,2H),3.56-3.50(m,4H),2.93(t,J=7.0 Hz,2H),2.45(s,3H),2.34(s,3H),2.32-2.25(m,3H),2.24-2.18(m,1H),2.04-1.99(m,1H),1.83-1.75(m,3H),1.37(d,J=7.0 Hz,3H),0.94(d,J=9.5 Hz,9H). 13C NMR(150 MHz,DMSO-d6)δ 171.06,170.12,170.01,169.02,163.76,163.35,162.90,150.87,147.14,144.05,140. 60,137.31,136.98,134.15,132.38,130.50,129.15,129.08,128.45,128.21,128.00,12 6.41,125.77,122.93,118.54,75.05,68.18,65.94,65.30,57.96,55.91,55.65,47.08,4 3.60,37.11,35.23,34.55,33.66,33.61,25.86,21.83,20.91,20.33,15.38.HRMS(ESI)C 52 H 64 N 10 O7S[M+Na] + The calculated value is 995.4578, and the measured value is 995.4565.

[0128] Example 46: N 1 -((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-4-(4-methylthiazole-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 6 -(4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)azipamide (LCG-46) [ka] The synthesis method was as shown in Example 37. 1H NMR(600 MHz, DMSO-d6)δ 10.86(s,1H),9.81(s,1H),8.98(s,1H),8.37(d,J=7.8 Hz,1H),7.99(s,1H),7.81(d,J=9.2 Hz,1H),7.53-7.46(m,4H),7.43(d,J=8.2 Hz,2H),7.37(d,J=8.2 Hz,2H),7.29(t,J=7.6 Hz,1H),7.20(d,J=8.5 Hz,2H),7.17(d,J=8.0 Hz,1H),6.06(s,1H),5.10(s,1H),4.96-4.88(m,1H),4.51(d,J=9.3 Hz,1H),4.43(t,J=8.0 Hz,1H),4.33(t,J=7.0 Hz,2H),4.28(s,1H),3.69-3.64(m,4H),3.64-3.58(m,2H),3.56-3.49(m,4H),2.93(t,J=7.0 Hz,2H),2.45(s,3H),2.34(s,3H),2.31-2.25(m,3H),2.19-2.12(m,1H) ,2.04-1.97(m,1H),1.83-1.75(m,1H),1.60-1.48(m,4H),1.37(d,J=7.0 Hz,3H),0.94(s,9H). 13 C NMR(150 MHz,DMSO-d6)δ 171.26,170.35,169.99,168.98,163.73,163.31,162.87,150.85,147.12,144.03,140.59,1 37.29,136.94,134.13,132.35,130.48,129.13,129.06,128.46,128.19,127.98,126.40,12 5.74,125.61,122.92,118.50,75.02,68.14,65.92,65.28,57.92,55.78,55.64,47.06,43.5 9,37.08,35.59,34.56,34.13,33.64,25.83,24.55,24.32,21.81,20.31,15.36.HRMS(ESI)C 53 H 66 N 10 O7S[M+Na] + The calculated value is 1009.4735 and the measured value is 1009.4711.

[0129] Example 47: N 1 -((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-4-(4-methylthiazole-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 7 -(4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)heptanediamide (LCG-47) [ka] The synthesis method was as shown in Example 37. 1 H NMR(600 MHz,DMSO-d6)δ 10.85(s,1H),9.80(s,1H),8.98(s,1H),8.37(d,J=7.8 Hz,1H),7.99(s,1H),7.80(d,J=9.3 Hz,1H),7.53-7.46(m,4H),7.45-7.41(m,2H),7.37(d,J=8.2 Hz,2H),7.29(t,J=7.6 Hz,1H),7.20(d,J=8.5 Hz,2H),7.17(d,J=7.5 Hz,1H),6.06(s,1H),5.10(d,J=3.4 Hz,1H),4.96-4.88(m,1H),4.51(d,J=9.3 Hz,1H),4.42(t,J=8.0 Hz,1H),4.33(t,J=7.0 Hz,2H),4.28(s,1H),3.70-3.64(m,4H),3.63-3.57(m,2H),3.55-3.49(m,4H),2.92(t,J=7.0 Hz,2H),2.45(s,3H),2.34(s,3H),2.30-2.22(m,3H),2.17-2.10(m,1H) ,2.05-1.98(m,1H),1.82-1.76(m,1H),1.62-1.45(m,4H),1.37(d,J=7.0 Hz,3H),1.31-1.23(m,2H),0.93(s,9H). 13C NMR(150 MHz,DMSO-d6)δ 171.31,170.36,169.94,168.93,163.70,163.29,162.84,150.81,147.08,143.99,140.53, 137.25,136.94,134.09,132.27,130.44,129.08,129.01,128.39,128.15,127.93,126.35,1 25.70,122.87,118.42,74.98,68.09,65.87,65.23,57.87,55.68,55.59,47.01,43.54,37.0 5,35.62,34.50,34.12,33.59,27.68,25.77,24.57,24.26,21.75,20.26,15.31.HRMS(ESI)C 54 H 68 N 10 O7S[M+H] + The calculated value is 1001.5071, and the measured value is 1001.5070.

[0130] Example 48: N 1 -((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-4-(4-methylthiazole-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 10 -(4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)decanediamide (LCG-48) [ka] The synthesis method was as shown in Example 37. 1H NMR(600 MHz,DMSO-d6)δ 10.85(s,1H),9.79(s,1H),8.98(s,1H),8.37(d,J=7.8 Hz,1H),7.99(s,1H),7.78(d,J=9.3 Hz,1H),7.53-7.46(m,4H),7.44-7.42(m,2H),7.37(d,J=8.2 Hz,2H),7.29(t,J=7.6 Hz,1H),7.20(d,J=8.5 Hz,2H),7.17(d,J=7.5 Hz,1H),6.06(s,1H),5.09(d,J=2.2 Hz,1H),4.94-4.89(m,1H),4.51(d,J=9.4 Hz,1H),4.42(t,J=8.0 Hz,1H),4.33(t,J=7.1 Hz,2H),4.28(s,1H),3.69-3.64(m,4H),3.63-3.57(m,2H),3.55-3.50(m,4H),2.92(t,J=7.0 Hz,2H),2.45(d,J=2.5 Hz,3H),2.34(s,3H),2.29-2.20(m,3H),2.14-2.07(m,1H),2.04-1.96(m,1H),1.82-1.76(m,1H),1.62-1.54(m,2H),1.54-1.41(m,2H),1.37(d,J=7.0 Hz,3H),1.32-1.16(m,8H),0.93(s,9H). 13 C NMR(150 MHz,DMSO-d6)δ 171.41,170.46,169.99,168.98,163.74,163.33,162.88,150.85,147.13,144.04,140.58,137.29,136.98,134.13,132.31,130.48,129.13,129.06,128.45,128.19,127.98,126.40,125.75,122.92,118.48,75.03,68.12,65.91,65.28,57.90,55.69,55.62,47.06,43.59,37.10,35.76,34.56,34.24,33.64,28.14,28.05,28.02,25.81,24.78,24.54,21.81,20.32,15.36.HRMS(ESI)C 57 H 74 N 10 O7S[M+Na]+ The calculated value is 1065.5361, and the measured value is 1065.5359.

[0131] Example 49: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-4-((4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)amino)-1-(4-(4-methylthiazole-5-yl)phenyl)4-oxobutyl)pyrrolidine-2-carboxamide (LCG-49) [ka] Intermediate 6 (40 mg, 0.09 mmol) and the reported intermediate 10 (55 mg, 0.09 mmol) of the VHL ligand for E3 ubiquitin ligase were dissolved in 10 mL of DMF. Then, HATU (70 mg, 0.18 mmol) and triethylamine (30 mg, 0.3 mmol) were added, and the mixture was reacted at room temperature for 4 hours. 20 mL of water was added, and the mixture was extracted twice with EA. The organic phases were combined, washed once with saturated brine, dried over anhydrous Na2SO4, filtered, spin-dried, and then subjected to column chromatography to obtain 45 mg of white solid (49%). 1H NMR(600 MHz, DMSO-d6)δ 10.85(s,1H),9.79(s,1H),8.99(s,1H),8.59(d,J=8.2 Hz,1H),7.99(s,1H),7.50(dd,J=8.0,3.0 Hz,3H),7.48-7.44(m,3H),7.40(d,J=8.3 Hz,2H),7.31-7.25(m,2H),7.19(d,J=8.5 Hz,2H),7.17(d,J=7.5 Hz,1H),6.06(s,1H),5.16(d,J=3.6 Hz,1H),4.90-4.83(m,1H),4.58(d,J=9.3 Hz,1H),4.50(t,J=8.3 Hz,1H),4.33(t,J=7.0 Hz,2H),4.28(s,1H),3.72-3.63(m,4H),3.64-3.57(m,2H),3.56-3.48(m,4H),2.92(t,J=7.0 Hz,2H),2.46(s,3H),2.45-2.41(m,1H),2.40-2.35(m,1H),2.34(s,3H),2. 11-1.93(m,3H),1.78-1.72(m,1H),1.42-1.30(m,2H),1.22(dd,J=8.2,2.1 Hz,2H),0.96(s,9H). 13 C NMR(150 MHz,DMSO-d6)δ 170.22,169.99,168.22,167.48,167.35,163.75,163.34,162.89,150.91,147.19,142.59,140.57, 137.30,136.89,134.14,132.37,130.45,129.31,129.13,128.43,128.25,127.98,126.39,126.27, 122.92,118.55,78.27,76.73,75.03,68.18,65.91,65.28,58.16,56.06,55.98,51.35,43.59,37.1 4,35.42,33.64,32.61,31.47,25.68,25.60,20.31,15.41,12.38,12.32,12.11,12.04.HRMS(ESI)C 53 H 63 FN 10 O7S[M+H] + The calculated value is 1003.4664 and the measured value is 1003.4646.

[0132] Example 50: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-4-((2-((4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)amino)-2-oxoethyl)amino)-1-(4-(4-methylthiazole-5-yl)phenyl)4-oxobutyl)pyrrolidine-2-carboxamide (LCG-50) [ka] Step 1: Preparation of tert-butyl(E)-(2-((4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinepyrimidine-2-yl)oxy)ethyl)phenyl)amino)-2-oxoethyl)carbamate(11) Intermediate 6 (300 mg, 0.7 mmol) and (tert-butoxycarbonyl)glycine (122 mg, 0.7 mmol) were dissolved in 15 mL of DMF, and then HATU (550 mg, 1.4 mmol) and triethylamine (220 mg, 2.1 mmol) were added. The mixture was reacted at room temperature for 4 hours. 50 mL of water was added, and the mixture was extracted twice with EA. The organic phases were combined, washed once with saturated brine, dried over anhydrous Na2SO4, filtered, spin-dried, and then subjected to column chromatography to obtain 288 mg of solid (70%). 1H NMR(500 MHz,DMSO-d6)δ 10.84(s,1H),9.84(s,1H),7.96(s,1H),7.51-7.43(m,4H),7.27(t,J=7.6 Hz,1H),7.20(d,J=8.4 Hz,2H),7.15(d,J=7.6 Hz,1H),7.01(t,J=6.0 Hz,1H),6.04(s,1H),4.32(t,J=7.0 Hz,2H),3.68(d,J=6.0 Hz,2H),3.66-3.61(m,4H),3.53-3.48(m,4H),2.91(t,J=7.0 Hz,2H),2.32(s,3H),1.37(s,9H).MS(ESI),m / z:560.4[M+H] + .

[0133] Step 2: Preparation of (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-4-((2-((4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)amino)-2-oxoethyl)amino)-1-(4-(4-methylthiazole-5-yl)phenyl)4-oxobutyl)pyrrolidine-2-carboxamide (LCG-50) Intermediate 11 (40 mg, 0.07 mmol) was dissolved in 10 mL of DCM containing 25% TFA, and the mixture was stirred at room temperature for 3 hours, after which the completion of the reaction was monitored by TLC. The reaction mixture was spin-dried to obtain oil, which was used in the next step without purification. The oil was dissolved in 10 mL of DMF, and the reported intermediate 10 (50 mg, 0.08 mmol), HATU (65 mg, 0.14 mmol), and triethylamine (30 mg, 0.3 mmol) of the VHL ligand for E3 ubiquitin ligase were added, and the mixture was reacted at room temperature for 4 hours. The completion of the reaction was monitored by TLC, 20 mL of water was added, and the mixture was extracted twice with EA. The organic phases were combined, washed once with saturated brine, dried over anhydrous Na2SO4, filtered, spin-dried, and then subjected to column chromatography to obtain 30 mg of white solid (40%). 1H NMR(600 MHz,DMSO-d6)δ 10.86(s,1H),9.89(s,1H),8.99(s,1H),8.58(d,J=8.3 Hz,1H),8.03(t,J=5.8 Hz,1H),7.99(s,1H),7.54-7.48(m,3H),7.48-7.44(m,3H),7.39(d,J=8.3 Hz,2H),7.35(dd,J=9.4,2.5 Hz,1H),7.29(t,J=7.6 Hz,1H),7.22(d,J=8.5 Hz,2H),7.17(d,J=7.5 Hz,1H),6.06(s,1H),5.16(d,J=3.6 Hz,1H),4.84(dd,J=15.2,7.7 Hz,1H),4.61(d,J=9.3 Hz,1H),4.50(t,J=8.4 Hz,1H),4.34(t,J=7.1 Hz,2H),4.29(s,1H),3.86(d,J=5.8 Hz,2H),3.71-3.64(m,4H),3.64-3.56(m,2H),3.56-3.49(m,4H),2.93(t,J=7.0 Hz,2H),2.47(s,3H),2.37-2.31(m,4H),2.28-2.22(m,1H),2.10-2.04(m,1H),2.00-1.92(m,2H),1.79-1.72(m,1H),1.41-1.31(m,2H),1.26-1.18(m,2H),0.97(s,9H). 13 C NMR(150 MHz,DMSO-d6)δ 171.72,170.20,168.28,167.55,167.41,167.00,163.76,163.34,162.90,150.90,147.20,142.66,140.59,137.31,136.51,134.15,132.67,130.47,129.29,129.14,128.54,128.25,127.99,126.40,126.22,122.93,118.60,78.18,76.64,75.05,68.18,65.88,65.29,58.21,56.12,55.99,51.26,43.60,42.12,37.16,35.43,33.64,31.88,31.55,25.64,20.32,15.42,12.41,12.34,12.12,12.06.HRMS(ESI)C 55 H 66FN 11 O8S[M+H] + The calculated value is 1060.4879, and the measured value is 1060.4879.

[0134] Example 51: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-4-((4-((4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)amino)-4-oxobutyl)amino)-1-(4-(4-methylthiazole-5-yl)phenyl)4-oxobutyl)pyrrolidine-2-carboxamide (LCG-51) [ka] The synthesis method was as shown in Example 50. 1H NMR(600 MHz,DMSO-d6)δ 10.85(s,1H),9.83(s,1H),8.98(s,1H),8.56(d,J=8.2 Hz,1H),7.99(s,1H),7.73(t,J=5.6 Hz,1H),7.51-7.47(m,4H),7.44(d,J=8.2 Hz,2H),7.37(d,J=8.2 Hz,2H),7.31-7.27(m,2H),7.20(d,J=8.5 Hz,2H),7.17(d,J=7.5 Hz,1H),6.06(s,1H),5.15(d,J=3.3 Hz,1H),4.82-4.76(m,1H),4.59(d,J=9.3 Hz,1H),4.48(t,J=8.3 Hz,1H),4.33(t,J=7.1 Hz,2H),4.28(s,1H),3.68-3.65(m,4H),3.64-3.56(m,2H),3.55-3.51(m,4H),3.12-3.05(m,2H),2.92(t,J=7.0 Hz,2H),2.46(s,3H),2.34(s,3H),2.28(t,J=7.4 Hz,2H),2.26-2.18(m,1H),2.17-2.10(m,1H),2.08-2.02(m,1H),1.98-1.87(m,2H),1.79-1.66(m,3H),1.42-1.29(m,2H),1.25-1.17(m,2H),0.97(s,9H). 13 C NMR(150 MHz,DMSO-d6)δ 171.09,170.17,170.06,168.23,167.50,167.37,163.76,163.35,162.91,150.90,147.18,142.67,140.59,137.31,136.95,134.15,132.36,130.47,129.27,129.15,128.46,128.23,128.00,126.41,126.24,122.93,118.49,78.27,76.73,75.05,68.18,65.93,65.30,58.17,56.08,55.97,54.31,51.35,43.60,37.52,37.16,35.42,33.66,33.24,31.81,31.75,25.68,25.61,24.71,20.33,15.42,12.40,12.33,12.12,12.06.HRMS(ESI)C57 H 70 FN 11 O8S[M+H] + The calculated value is 1088.5192, and the measured value is 1088.5190.

[0135] Example 52: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-4-((6-((4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)amino)-6-oxohexyl)amino)-1-(4-(4-methylthiazole-5-yl)phenyl)4-oxobutyl)pyrrolidine-2-carboxamide (LCG-52) [ka] The synthesis method was as shown in Example 50. 1H NMR(600 MHz,DMSO-d6)δ 10.85(s,1H),9.79(s,1H),8.98(s,1H),8.55(d,J=8.2 Hz,1H),7.99(s,1H),7.65(t,J=5.6 Hz,1H),7.53-7.46(m,4H),7.44(d,J=8.2 Hz,2H),7.36(d,J=8.2 Hz,2H),7.31-7.25(m,2H),7.19(d,J=8.5 Hz,2H),7.17(d,J=7.5 Hz,1H),6.06(s,1H),5.15(s,1H),4.82-4.75(m,1H),4.59(d,J=9.2 Hz,1H),4.48(t,J=8.3 Hz,1H),4.33(t,J=7.1 Hz,2H),4.28(s,1H),3.72-3.64(m,4H),3.63-3.56(m,2H),3.56-3.49(m,4H),3.07-2.99(m,2H),2.92(t,J=7.0 Hz,2H),2.46(s,3H),2.34(s,3H),2.27(t,J=7.4 Hz,2H),2.23-2.16(m,1H),2.14-2.08(m,1H),2.05(dd,J=12.7,7.8 Hz,1H),1.98-1.87(m,2H),1.78-1.69(m,1H),1.61-1.53(m,2H),1.44-1.32(m,4H),1.32-1.25(m,2H),1.25-1.18(m,2H),0.97(s,9H). 13C NMR(150 MHz,DMSO-d6)δ 170.90,170.38,170.13,168.22,167.49,167.36,163.76,163.34,162.90,150.90,147.18,142.69,140.60, 137.31,136.99,134.15,132.33,130.47,129.26,129.15,128.46,128.23,128.00,126.41,126.22,122.94,1 18.50,78.28,76.74,75.05,68.18,65.93,65.30,58.16,56.09,55.96,51.35,43.60,37.81,37.15,35.70,35 .44,33.66,31.86,31.75,28.41,25.61,25.53,24.28,20.33,15.42,12.40,12.33,12.12,12.06.HRMS(ESI)C 59 H 74 FN 11 O8S[M+H] + The calculated value is 1116.5505, and the measured value is 1116.5507.

[0136] Example 53: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-(2-(2-((4-(2-((4-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)amino)-2-oxoethoxy)-4-(4-methylthiazole-5-yl)benzyl)pyrrolidine-2-carboxamide (LCG-53) [ka] Intermediate 6 (40 mg, 0.09 mmol) and the reported intermediate 12 (53 mg, 0.09 mmol) of the VHL ligand for E3 ubiquitin ligase were dissolved in 10 mL of DMF. Then, HATU (70 mg, 0.18 mmol) and triethylamine (30 mg, 0.3 mmol) were added, and the mixture was reacted at room temperature for 4 hours. 20 mL of water was added, and the mixture was extracted twice with EA. The organic phases were combined, washed once with saturated brine, dried over anhydrous Na2SO4, filtered, spin-dried, and then subjected to column chromatography to obtain 35 mg of white solid (39%). 1 H NMR(600 MHz,DMSO-d6)δ 10.85(s,1H),10.03(s,1H),8.98(s,1H),8.58(t,J=6.0 Hz,1H),7.99(s,1H),7.61(d,J=8.5 Hz,2H),7.50(d,J=7.8 Hz,1H),7.47(s,1H),7.45(d,J=8.1 Hz,1H),7.31-7.26(m,2H),7.25(d,J=8.5 Hz,2H),7.17(d,J=7.5 Hz,1H),7.03(dd,J=3.9,2.5 Hz,2H),6.06(s,1H),5.16(brs,1H),4.83-4.76(m,2H),4.58(d,J=9.4 Hz,1H),4.50(t,J=8.2 Hz,1H),4.48-4.30(m,5H),3.69-3.64(m,4H),3.64-3.56(m,2H),3.56-3.51(m,4H),2.95(t,J=6.9 Hz,2H),2.42(s,3H),2.34(s,3H),2.10-2.03(m,1H),1.94-1.88(m,1H),1.41-1.30(m,2H),1.21(dd,J=8.4,2.7 Hz, 2H), 0.94(s, 9H). 13C NMR(150 MHz,DMSO-d6)δ 171.16,168.27,167.49,167.36,165.63,163.73,163.30,162.86,154.60,151.01,147.35,140.60,13 7.30,135.90,134.13,133.28,130.55,130.45,129.14,128.52,128.28,127.98,126.55,126.41,122. 93,120.94,119.34,111.58,78.25,76.71,75.04,68.25,66.82,65.86,65.28,58.27,56.04,55.92,43 .60,37.25,36.80,35.38,33.65,25.58,25.52,20.32,15.37,12.38,12.32,12.12,12.05.HRMS(ESI)C 52 H 61 FN 10 O8S[M+Na] + The calculated value is 1027.4277, and the measured value is 1027.4269.

[0137] Example 54: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-(2-(2-((2-((4-(2-((4-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)amino)-2-oxoethyl)amino)-2-oxoethoxy)-4-(4-methylthiazole-5-yl)benzyl)pyrrolidine-2-carboxamide (LCG-54) [ka] The synthesis method was as shown in Example 53. 1H NMR(600 MHz,DMSO-d6)δ 10.86(s,1H),9.95(s,1H),8.99(s,1H),8.58(t,J=6.0 Hz,1H),8.39(t,J=5.9 Hz,1H),7.99(s,1H),7.49(t,J=9.8 Hz,4H),7.45(d,J=7.7 Hz,1H),7.32-7.26(m,2H),7.23(d,J=8.5 Hz,2H),7.17(d,J=7.5 Hz,1H),7.05-7.00(m,2H),6.06(s,1H),5.15(brs,1H),4.68(dd,J=28.1,14.9 Hz,2H),4.58(d,J=9.3 Hz,1H),4.50(t,J=8.3 Hz,1H),4.45(dd,J=16.0,6.0 Hz,1H),4.39-4.31(m,4H),4.03-3.92(m,2H),3.68-3.65(m,4H),3.65-3.57(m,2H),3.56-3.50(m,4H),2.94(t,J=7.0 Hz,2H),2.46(s,3H),2.34(s,3H),2.10-2.04(m,1H),1.97-1.90(m,1H),1.40-1.30(m,2H),1.21(dd,J=8.4,3.1 Hz,2H),0.95(s,9H). 13 C NMR(150 MHz,DMSO-d6)δ 171.25,168.26,167.50,167.42,167.36,166.47,163.73,163.30,162.88,154.39,150.94,147.42,140.63,137.30,136.47,134.13,132.70,130.55,130.46,129.15,128.57,127.98,126.53,126.41,122.93,120.98,118.58,111.69,78.25,76.71,75.03,68.32,66.54,65.89,65.28,58.23,56.09,55.92,43.60,41.70,37.21,36.85,35.42,33.63,25.53,20.31,15.37,12.39,12.32,12.12,12.05.HRMS(ESI)C 54 H 64 FN 11 O9S[M+Na] +The calculated value is 1084.4491, and the measured value is 1084.4491.

[0138] Example 55: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-(2-(2-((4-((4-((2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)amino)-4-oxobutyl)amino)-2-oxoethoxy)-4-(4-methylthiazole-5-yl)benzyl)pyrrolidine-2-carboxamide (LCG-55) [ka] The synthesis method was as shown in Example 53. 1 H NMR(600 MHz,DMSO-d6)δ 10.86(s,1H),9.84(s,1H),8.97(s,1H),8.56(t,J=6.0 Hz,1H),8.18(t,J=5.8 Hz,1H),7.99(s,1H),7.53-7.46(m,4H),7.43(d,J=7.8 Hz,1H),7.32-7.25(m,2H),7.21-7.16(m,3H),7.02(dd,J=7.7,1.3 Hz,1H),6.96(d,J=1.2 Hz,1H),6.06(s,1H),5.16(brs,1H),4.61-4.52(m,3H),4.52-4.42(m,2H),4.37-4.29 (m,4H),3.68-3.65(m,4H),3.65-3.57(m,2H),3.55-3.51(m,4H),3.21(dd,J=13.2,6.7 Hz,2H),2.92(t,J=7.0 Hz,2H),2.45(s,3H),2.34(s,3H),2.31(t,J=7.5 Hz,2H),2.09-2.02(m,1H),1.92-1.86(m,1H),1.82-1.75(m,2H),1.41-1.30(m,2H),1.25-1.19(m,2H),0.95(s,9H). 13C NMR(150 MHz,DMSO-d6)δ 171.13,170.01,168.26,167.50,167.36,166.78,163.70,163.26,162.84,154.47,150.95,147.36,140.66,1 37.30,136.92,134.12,132.32,130.58,130.46,129.16,128.45,128.29,127.98,126.51,126.42,122.94,12 0.89,118.50,111.54,78.26,76.72,75.01,68.26,66.58,65.95,65.28,58.24,56.09,55.92,43.60,37.45,3 7.23,36.83,35.39,33.63,33.23,25.58,25.50,24.62,20.31,15.35,12.39,12.32,12.12,12.05.HRMS(ESI)C 56 H 68 FN 11 O9S[M+H] + The calculated value is 1090.4984, and the measured value is 1090.4983.

[0139] Example 56: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-(2-(2-((6-((4-(2-((4-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)amino)-6-oxohexyl)amino)-2-oxoethoxy)-4-(4-methylthiazole-5-yl)benzyl)pyrrolidine-2-carboxamide (LCG-56) [ka] The synthesis method was as shown in Example 53. 1H NMR(600 MHz,DMSO-d6)δ 10.86(s,1H),9.79(s,1H),8.98(s,1H),8.55(t,J=6.0 Hz,1H),8.12(t,J=5.8 Hz,1H),7.99(s,1H),7.54-7.46(m,4H),7.42(d,J=7.8 Hz,1H),7.32-7.25(m,2H),7.22-7.15(m,3H),7.02(dd,J=7.7,1.4 Hz,1H),6.95(d,J=1.3 Hz,1H),6.06(s,1H),5.17(brs,1H),4.62-4.51(m,3H),4.49(t,J=8.2 Hz,1H),4.45(dd,J=15.7,6.3 Hz,1H),4.37-4.28(m,4H),3.70-3.65(m,4H),3.65-3.58(m,2H),3.56-3.49(m,4H),3.17-3.12(m,2H),2.92(t,J=7.0 Hz,2H),2.45(s,3H),2.34(s,3H),2.26(t,J=7.4 Hz,2H),2.09-2.00(m,1H),1.92-1.82(m,1H),1.61-1.53(m,2H),1.51-1.44(m,2H),1.42-1.33(m,2H),1.32-1.25(m,2H),1.25-1.19(m,2H),0.95(s,9H). 13 C NMR(150 MHz,DMSO-d6)δ 171.09,170.34,168.26,167.49,167.35,166.59,163.70,163.29,162.87,154.49,150.96,147.35,140.62,137.29,136.97,134.12,132.30,130.58,130.45,129.14,128.44,128.30,127.98,126.48,126.41,122.93,120.85,118.49,111.54,78.26,76.72,75.02,68.25,66.59,65.94,65.28,58.23,56.08,55.91,43.59,37.66,37.22,36.79,35.63,35.40,33.63,28.36,25.57,25.50,25.44,24.24,20.31,15.36,12.38,12.31,12.12,12.05.HRMS(ESI)C58 H 72 FN 11 O9S[M+Na] + The calculated value is 1140.5117, and the measured value is 1140.5113.

[0140] Example 57: (2S,4R)-1-((R)-2-(1-fluorocyclopropane-1-carboxamide)-3-methyl-3-((2-((4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)amino)-2-oxoethyl)thio)butanoyl)-4-hydroxy-N-(4-(4-methylthiazole-5-yl)benzyl)pyrrolidine-2-carboxamide (LCG-57) [ka] Intermediate 6 (40 mg, 0.09 mmol) and the reported intermediate 13 (54 mg, 0.09 mmol) of the VHL ligand for E3 ubiquitin ligase were dissolved in 10 mL of DMF. Then, HATU (70 mg, 0.18 mmol) and triethylamine (30 mg, 0.3 mmol) were added, and the mixture was reacted at room temperature for 4 hours. 20 mL of water was added, and the mixture was extracted twice with EA. The organic phases were combined, washed once with saturated brine, dried over anhydrous Na2SO4, filtered, spin-dried, and then subjected to column chromatography to obtain 38 mg of white solid (42%). 1H NMR(600 MHz, DMSO-d6)δ 10.86(s,1H),9.95(s,1H),8.96(s,1H),8.74(t,J=6.0 Hz,1H),7.99(s,1H),7.56(dd,J=8.9,2.3 Hz,1H),7.51-7.44(m,4H),7.40-7.35(m,4H),7.29(t,J=7.6 Hz,1H),7.21-7.15(m,3H),6.05(s,1H),5.22(brs,1H),4.85(d,J=8.9 Hz,1H),4.50(t,J=8.3 Hz,1H),4.41(dd,J=15.7,6.4 Hz,1H),4.37(s,1H),4.33(t,J=7.0 Hz,2H),4.26(dd,J=15.7,5.6 Hz,1H),3.77-3.68(m,2H),3.68-3.64(m,4H),3.55-3.50(m,4H),3.40-3.38(m,2H),2.92(t,J=6.9 Hz,2H),2.42(s,3H),2.34(s,3H),2.14-2.08(m,1H),1.97-1.89(m,1H),1.41(d,J=3.1 Hz,6H),1.39-1.34(m,2H),1.24-1.19(m,2H). 13 C NMR(150 MHz,DMSO-d6)δ 171.24,167.76,167.62,167.28,167.22,163.70,163.26,162.84,150.81,147.14,140.63,138.51,137 .30,136.61,134.12,132.78,130.47,129.19,129.15,128.54,128.24,128.15,127.98,127.43,126.81, 126.41,122.94,118.46,78.21,76.68,75.02,68.21,65.90,65.28,58.49,56.00,54.38,49.28,45.13, 43.60,41.18,37.40,33.63,33.13,26.00,23.68,20.31,15.29,12.47,12.40,12.32,12.25.HRMS(ESI)C 51 H 59 FN 10 O7S2[M+Na] + The calculated value is 1029.3892 and the measured value is 1029.3884.

[0141] Example 58: (2S,4R)-1-((R)-2-(1-fluorocyclopropane-1-carboxamide)-3-methyl-3-((2-((2-((4-(2-((4-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)amino)-2-oxoethyl)amino)-2-oxoethyl)thio)butanoyl)-4-hydroxy-N-(4-(4-methylthiazole-5-yl)benzyl)pyrrolidine-2-carboxamide (LCG-58) [ka] The synthesis method was as shown in Example 57. 1 H NMR(600 MHz,DMSO-d6)δ 10.86(s,1H),9.91(s,1H),8.97(s,1H),8.65(t,J=6.0 Hz,1H),8.25(t,J=5.6 Hz,1H),7.99(s,1H),7.54(dd,J=9.0,2.1 Hz,1H),7.51-7.46(m,4H),7.42-7.37(m,4H),7.29(t,J=7.6 Hz,1H),7.22(d,J=8.5 Hz,2H),7.17(d,J=7.5 Hz,1H),6.06(s,1H),5.20(brs,1H),4.84(d,J=9.0 Hz,1H),4.47(t,J=8.2 Hz,1H),4.42-4.26(m,5H),3.89(t,J=7.2 Hz,2H),3.76(dd,J=10.7,3.9 Hz,1H),3.69-3.62(m,5H),3.55-3.49(m,4H),3.40-3.34(m,2H),2.93(t,J=7.0 Hz,2H),2.44(s,3H),2.34(s,3H),2.12-2.05(m,1H),1.95-1.87(m,1H),1.43(s,3H),1.40-1.33(m,5H),1.28-1.19(m,2H). 13C NMR(150 MHz,DMSO-d6)δ 171.02,168.80,167.77,167.64,167.12,166.60,163.74,163.32,162.88,150.82,147.15,140.59, 138.67,137.30,136.43,134.13,132.70,130.50,129.16,128.56,128.27,128.13,127.98,126.92, 126.40,122.92,118.56,78.18,76.64,75.03,68.22,65.87,65.28,58.43,55.93,49.08,43.59,42. 29,41.10,37.37,33.63,31.72,25.49,23.55,20.31,15.32,12.49,12.42,12.32,12.25.HRMS(ESI)C 53 H 62 FN 11 O8S2[M+H] + The calculated value is 1064.4286, and the measured value is 1064.4274.

[0142] Example 59: (2S,4R)-1-((R)-2-(1-fluorocyclopropane-1-carboxamide)-3-methyl-3-((2-((4-((4-(2-((4-((E)-3-methylbenzylidene)hydrazino-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)amino)-4-oxobutyl)amino)-2-oxoethyl)thio)butanoyl)-4-hydroxy-N-(4-(4-methylthiazole-5-yl)benzyl)pyrrolidine-2-carboxamide (LCG-59) [ka] The synthesis method was as shown in Example 57. 1H NMR(600 MHz,DMSO-d6)δ 10.86(s,1H),9.84(s,1H),8.97(d,J=2.4 Hz,1H),8.68(t,J=6.0 Hz,1H),7.99(s,1H),7.97(d,J=5.6 Hz,1H),7.53(dd,J=9.0,2.2 Hz,1H),7.52-7.46(m,4H),7.43-7.36(m,4H),7.29(t,J=7.6 Hz,1H),7.20(d,J=8.5 Hz,2H),7.17(d,J=7.6 Hz,1H),6.06(s,1H),5.20(s,1H),4.82(d,J=9.0 Hz,1H),4.47(t,J=8.2 Hz,1H),4.43-4.35(m,2H),4.33(t,J=7.0 Hz,2H),4.27(dd,J=15.7,5.7 Hz,1H),3.74(dd,J=10.7,3.9 Hz,1H),3.69-3.61(m,5H),3.55-3.50(m,4H),3.23-3.18(m,2H),3.07-3.03(m,2H),2.92(t,J=7.0 Hz,2H),2.43(s,3H),2.34(s,3H),2.27(t,J=7.5 Hz,2H),2.12-2.06(m,1H),1.96-1.86(m,1H),1.73-1.62(m,2H),1.42-1.31(m,8H),1.24-1.20(m,2H). 13 C NMR(150 MHz,DMSO-d6)δ 171.11,169.97,168.36,167.73,167.60,167.14,163.70,163.28,162.82,150.82,147.15,140.63,138.60,137.30,136.91,134.12,132.34,130.50,129.15,128.45,128.14,127.98,126.84,126.41,122.93,118.50,78.18,76.64,75.02,68.20,65.94,65.28,58.43,55.92,54.31,49.01,43.60,41.12,37.87,37.37,33.63,33.11,31.98,25.60,24.45,23.62,20.32,15.31,12.46,12.39,12.32,12.25.HRMS(ESI)C 55 H 66FN 11 O8S2[M+H] + The calculated value is 1114.4419, and the measured value is 1114.4379.

[0143] Example 60: (2S,4R)-1-((R)-2-(1-fluorocyclopropane-1-carboxamide)-3-methyl-3-((2-((6-((4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)amino)-6-oxohexyl)amino)-2-oxoethyl)thio)butanoyl)-4-hydroxy-N-(4-(4-methylthiazole-5-yl)benzyl)pyrrolidine-2-carboxamide (LCG-60) [ka] The synthesis method was as shown in Example 57. 1H NMR(600 MHz,DMSO-d6)δ 10.85(s,1H),9.79(s,1H),8.97(s,1H),8.68(t,J=6.0 Hz,1H),7.99(s,1H),7.88(t,J=5.6 Hz,1H),7.53(dd,J=9.0,2.3 Hz,1H),7.52-7.46(m,4H),7.42-7.36(m,4H),7.29(t,J=7.6 Hz,1H),7.19(d,J=8.5 Hz,2H),7.17(d,J=7.5 Hz,1H),6.06(s,1H),5.20(s,1H),4.81(d,J=9.0 Hz,1H),4.47(t,J=8.2 Hz,1H),4.40(dd,J=15.7,6.3 Hz,1H),4.37(s,1H),4.33(t,J=7.1 Hz,2H),4.26(dd,J=15.8,5.7 Hz,1H),3.73(dd,J=10.7,4.0 Hz,1H),3.69-3.61(m,5H),3.56-3.50(m,4H),3.20-3.15(m,2H),3.04-2.96(m,2H),2.92(t,J=7.0 Hz,2H),2.44(s,3H),2.34(s,3H),2.25(t,J=7.5 Hz,2H),2.13-2.06(m,1H),1.95-1.87(m,1H),1.58-1.51(m,2H),1.42-1.31(m,10H),1.28-1.20(m,4H). 13C NMR(150 MHz,DMSO-d6)δ 171.13,170.34,168.16,167.73,167.59,167.16,163.74,163.32,162.88,150.82,147.16,140.60,138.59,13 7.30,136.96,134.13,132.32,130.49,129.16,128.44,128.25,128.15,127.99,127.37,126.82,126.40,122.9 2,118.50,78.18,76.64,75.03,68.20,65.92,65.28,58.44,55.92,54.33,48.99,43.59,41.11,38.11,37.38, 35.65,33.64,31.98,28.12,25.64,25.45,24.21,23.66,20.31,15.31,12.46,12.39,12.31,12.25.HRMS(ESI)C 57 H 70 FN 11 O8S2[M+H] + The calculated value is 1142.4732, and the measured value is 1142.4719.

[0144] Example 61: N 1 -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazole-5-yl)benzyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 4 -(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)succinimide(LCG-61) [ka] The synthesis method was as shown in Examples 1 and 37. 1H NMR(600 MHz, DMSO-d6)δ 10.84(s,1H),8.98(s,1H),8.57(t,J=6.0 Hz,1H),8.07(t,J=5.5 Hz,1H),8.02(s,1H),7.91(d,J=9.3 Hz,1H),7.50(d,J=7.8 Hz,1H),7.48(s,1H),7.42(d,J=8.4 Hz,2H),7.38(d,J=8.3 Hz,2H),7.29(t,J=7.6 Hz,1H),7.17(d,J=7.5 Hz,1H),6.07(s,1H),5.13(brs,1H),4.52(d,J=9.4 Hz,1H),4.45-4.39(m,2H),4.35(s,1H),4.22(dd,J=15.9,5.5 Hz,1H),4.17(t,J=5.8 Hz,2H),3.69-3.60(m,6H),3.57-3.50(m,4H),3.41-3.35(m,3H),2.44(s, 3H),2.40-2.28(m,6H),2.07-2.01(m,1H),1.93-1.86(m,1H),0.93(s,9H). 13 C NMR(150 MHz,DMSO-d6)δ 171.31,171.04,170.64,168.96,163.71,163.31,162.82,150.83,147.09,1 40.72,138.88,137.30,134.13,130.54,129.16,129.01,128.02,127.99,126 .80,126.42,122.94,75.11,68.26,65.30,63.93,58.08,55.80,55.69,43.60 ,41.02,37.60,37.31,34.71,30.24,29.87,25.73,20.31,15.32.HRMS(ESI)C 44 H 56 N 10 O7S[M+Na] + The calculated value is 891.3952 and the measured value is 891.3949.

[0145] Example 62:N 1-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazole-5-yl)benzyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 6 -(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)phenyl)azipamide (LCG-62) [ka] The synthesis method was as shown in Examples 1 and 37. 1 H NMR(600 MHz,DMSO-d6)δ 10.85(s,1H),8.98(s,1H),8.57(t,J=6.1 Hz,1H),8.04-7.98(m,2H),7.88(d,J=9.3 Hz,1H),7.51(d,J=7.8 Hz,1H),7.48(s,1H),7.41(d,J=8.3 Hz,2H),7.38(d,J=8.3 Hz,2H),7.29(t,J=7.6 Hz,1H),7.17(d,J=7.5 Hz,1H),6.07(s,1H),5.14(brs,1H),4.54(d,J=9.4 Hz,1H),4.46-4.39(m,2H),4.35(s,1H),4.24-4.13(m,3H),3.70-3.63(m,6H),3.57-3.51(m,4H),3.44-3.32(m ,2H),2.44(s,3H),2.34(s,3H),2.29-2.23(m,1H),2.13-2.01(m,4H),1.94-1.87(m,1H),1.45(dt,J=11.7,5.3 Hz,4H),0.93(s,9H). 13C NMR(150 MHz,DMSO-d6)δ 171.67,171.33,169.13,163.66,163.23,162.76,150.83,147.09,140.79,138 .87,137.29,134.11,130.54,129.17,129.01,128.01,127.98,126.79,126.44 ,122.96,75.09,68.25,65.30,64.03,58.08,55.75,55.71,43.61,41.02,37.4 6,37.32,34.57,34.45,34.02,25.76,24.53,24.30,20.31,15.32.HRMS(ESI)C 46 H 60 N 10 O7S[M+Na] + The calculated value is 919.4265, and the measured value is 919.4255.

[0146] Example 63: N 1 -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazole-5-yl)benzyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 8 -(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)octanediamide(LCG-63) [ka] The synthesis method was as shown in Examples 1 and 37. 1H NMR(600 MHz, DMSO-d6)δ 10.82(s,1H),8.98(s,1H),8.56(t,J=6.1 Hz,1H),8.01(s,1H),7.99(t,J=5.5 Hz,1H),7.85(d,J=9.4 Hz,1H),7.53-7.45(m,2H),7.42(d,J=8.3 Hz,2H),7.39-7.36(m,2H),7.29(t,J=7.6 Hz,1H),7.17(d,J=7.5 Hz,1H),6.07(s,1H),5.12(brs,1H),4.54(d,J=9.4 Hz,1H),4.46-4.39(m,2H),4.35(s,1H),4.22(dd,J=15.9,5.5 Hz,1H),4.18(t,J=5.7 Hz,2H),3.70-3.62(m,6H),3.56-3.49(m,4H),3.38-3.35(m,2H),2.44(s,3H),2.34(s,3H),2.27-2.20(m,1H),2.13-2. 08(m,1H),2.08-2.05(m,2H),2.05-2.00(m,1H),1.94-1.86(m,1H),1.51-1.41(m,4H),1.25-1.20(m,4H),0.93(s,9H). 13 C NMR(150 MHz,DMSO-d6)δ 171.77,171.47,171.33,169.11,163.71,163.33,162.82,150.83,147.09,140.71,13 8.88,137.30,134.13,130.54,129.15,129.01,128.01,127.98,126.79,126.42,122. 93,75.11,68.24,65.30,64.29,63.94,58.07,55.73,55.66,43.59,41.02,37.51,37. 32,34.67,34.57,34.23,27.86,27.84,25.76,24.71,24.57,20.31,15.32.HRMS(ESI)C 48 H 64 N 10 O7S[M+Na] + The calculated value is 947.4578 and the measured value is 947.4577.

[0147] Example 64:N 1-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazole-5-yl)benzyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 10 -(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidine-2-yl)oxy)ethyl)octanediamide(LCG-64) [ka] The synthesis method was as shown in Examples 1 and 37. 1 H NMR(600 MHz,DMSO-d6)δ 10.82(s,1H),8.98(s,1H),8.56(t,J=6.1 Hz,1H),8.01(s,1H),8.00(t,J=5.6 Hz,1H),7.83(d,J=9.4 Hz,1H),7.50(d,J=7.7 Hz,1H),7.48(s,1H),7.42(d,J=8.2 Hz,2H),7.38(d,J=8.3 Hz,2H),7.29(t,J=7.6 Hz,1H),7.17(d,J=7.5 Hz,1H),6.07(s,1H),5.12(brs,1H),4.54(d,J=9.4 Hz,1H),4.46-4.40(m,2H),4.35(s,1H),4.21(dd,J=15.9,5.5 Hz,1H),4.18(t,J=5.7 Hz,2H),3.69-3.62(m,6H),3.56-3.50(m,4H),3.37-3.34(m,2H),2.44(s,3H),2.34(s,3H),2.28-2. 20(m,1H),2.13-2.00(m,4H),1.93-1.86(m,1H),1.52-1.40(m,4H),1.27-1.17(m,8H),0.93(s,9H). 13C NMR(150 MHz,DMSO-d6)δ 171.77,171.45,171.32,169.08,163.70,163.34,162.80,150.82,147.08,140.69,13 8.88,137.29,134.12,130.53,129.15,129.00,128.00,127.98,126.79,126.41,122. 92,75.10,68.23,65.29,64.29,63.93,58.05,55.71,55.63,43.59,41.01,37.52,37. 32,34.68,34.57,34.23,28.13,28.04,25.74,24.79,24.64,20.31,15.31.HRMS(ESI)C 50 H 68 N 10 O7S[M+Na] + The calculated value is 975.4891, and the measured value is 975.4878.

[0148] Example 65: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)-4-((2-((4-(2-((4-morpholino-6-(3-(m-tolyl)-1H-pyrazole-1-yl)pyrimidine-2-yl)oxy)ethyl)phenyl)amino)-2-oxoethyl)amino)-4-oxobutyl)pyrrolidine-2-carboxamide (LCG-II-1) [ka] Step 1: Preparation of intermediate ii-2 Dissolve ii-1 (150 mg, 0.95 mmol) in 10 mL of ultra-dry DMF, add NaH (80 mg, 2.85 mmol) under ice bath conditions, stir the mixture at room temperature for 2 hours, add the solution of 4,6-dichloro-2-methylsulfanylpyrimidine (276 mg, 1.42 mmol) in DMF dropwise, and react the mixture at room temperature for 3 hours. Then add morpholine (330 mg, 3.8 mmol) and continue reacting the mixture at room temperature for 3 hours. Add 50 mL of water and extract the mixture twice with EA. Combine the organic phases, wash once with saturated saline, and add anhydrous Na 2SO The mixture was dried in 4, filtered, spin-dried, and separated by column chromatography to obtain 167 mg of white solid (48%). 1 H NMR(500 MHz,chloroform-d)δ 8.56(d,J=2.7 Hz,1H),7.75(s,1H),7.69(d,J=7.7 Hz,1H),7.33(t,J=7.6 Hz,1H),7.19(d,J=7.5 Hz,1H),6.91(s,1H),6.74(d,J=2.7 Hz,1H),3.84-3.78(m,4H),3.78-3.72(m,4H),2.56(s,3H),2.43(s,3H).LC-MS:C 19 H 21 N5OS[M+H] + The calculated value is 368.1, and the measured value is 368.2.

[0149] Step 2: Preparation of intermediate ii-3 Intermediate ii-2 (500 mg, 1.36 mmol) was dissolved in 30 mL of dichloromethane, and m-chloroperbenzoic acid (582 mg, 3.4 mmol) was added under ice bath conditions. The mixture was stirred at room temperature for 12 hours. After monitoring the completion of the reaction by TLC, 10 mL of saturated sodium thiosulfate solution was added, and the mixture was stirred at room temperature for 2 hours. 50 mL of water was added, and the mixture was extracted twice with dichloromethane. The organic phases were combined, washed once with saturated brine, dried over anhydrous Na2SO4, filtered, spin-dried, and then slurryed with methanol to obtain 455 mg of white solid (83%). 1H NMR(600 MHz,DMSO-d6)δ 8.69(d,J=2.7 Hz,1H),7.86(s,1H),7.82(d,J=7.9 Hz,1H),7.37(t,J=7.6 Hz,1H),7.30(s,1H),7.23(d,J=7.5 Hz,1H),7.15(d,J=2.7 Hz,1H),3.83-3.70(m,8H),3.43(s,3H),2.39(s,3H).LC-MS:C 19 H 21 N5O3S[M+H] + The calculated value is 400.1, and the measured value is 400.0.

[0150] Step 3: Preparation of intermediates ii-4 N-BOC-2-(4-aminophenyl)ethanol (355 mg, 1.5 mmol) was dissolved in 10 mL of ultra-dry DMF, and NaH (54 mg, 2.25 mmol) was added under ice bath conditions. The mixture was stirred at room temperature for 2 hours, then the solution of intermediate ii-3 (300 mg, 0.75 mmol) in DMF was added, and the mixture was reacted at room temperature for 3 hours. After monitoring the completion of the reaction by TLC, 50 mL of water was added, and the mixture was extracted twice with EA. The organic phases were combined, washed once with saturated brine, dried over anhydrous Na2SO4, filtered, spin-dried, and then separated by column chromatography to obtain 312 mg of white solid (75%). 1 H NMR(600 MHz,DMSO-d6)δ 9.26(s,1H),8.57(d,J=2.7 Hz,1H),7.81(s,1H),7.77(d,J=7.7 Hz,1H),7.39(d,J=8.1 Hz,2H),7.35(t,J=7.6 Hz,1H),7.23-7.17(m,3H),7.05(d,J=2.7 Hz,1H),6.89(s,1H),4.47(t,J=7.1 Hz,2H),3.76-3.64(m,8H),2.97(t,J=7.0 Hz,2H),2.38(s,3H),1.47(s,9H).LC-MS:C 31 H 36 N6O4[M+H] + The calculated value is 557.3, and the measured value is 557.3.

[0151] Step 4: Preparation of intermediates ii-5 The method for preparing intermediate 11 in Example 50 was used as a reference for preparing intermediate ii-5. 1 H NMR(600 MHz,DMSO-d6)δ 9.87(s,1H),8.58(d,J=2.7 Hz,1H),7.95(s,1H),7.81(s,1H),7.77(d,J=7.7 Hz,1H),7.52(d,J=8.5 Hz,2H),7.35(t,J=7.6 Hz,1H),7.26(d,J=8.5 Hz,2H),7.21(d,J=7.5 Hz,1H),7.05(d,J=2.7 Hz,1H),7.02(t,J=6.1 Hz,1H),6.89(s,1H),4.49(t,J=7.0 Hz,2H),3.76-3.64(m,10H),3.00(t,J=7.0 Hz,2H),2.38(s,3H),1.39(s,9H).LC-MS:C 33 H 39 N7O5[M+H] + The calculated value is 614.3, and the measured value is 614.3.

[0152] Step 5: Preparation of LCG-II-1 Based on intermediate ii-5, the preparation method of LCG-50 in Example 50 was referenced for synthesis. 1H NMR(600 MHz,DMSO-d6)δ 9.90(s,1H),8.98(s,1H),8.57(q,J=2.8 Hz,2H),8.03(t,J=5.8 Hz,1H),7.81(d,J=1.8 Hz,1H),7.77(d,J=7.8 Hz,1H),7.53(d,J=8.5 Hz,2H),7.48-7.43(m,2H),7.41-7.36(m,2H),7.38-7.32(m,2H),7.25(d,J=8.5 Hz,2H),7.21(m,1H),7.04(d,J=2.7 Hz,1H),6.89(s,1H),5.16(d,J=3.6 Hz,1H),4.84(q,J=7.7 Hz,1H),4.64-4.57(m,1H),4.49(m,3H),4.29(s,1H),3.86(d,J=5.8 Hz,2H),3.74-3.58(m,8H),3.65-3.53(m,2H),3.00(t,J=7.0 Hz,2H),2.46(s,3H),2.38(s,3H),2.33(m,1H),2.24(m,1H),2.06(dd,J=12.7,7.7 Hz,1H),1.95(q,J=7.7 Hz,2H),1.75(m,1H),1.35(m,2H),1.26-1.18(m,2H),0.97(s,9H). 13 C NMR(150 MHz,DMSO-d6)δ 171.70,170.19,168.26,167.53,167.40,167.00,164.08,163.43,157.50,152.96,150.89,147.18,142.64,137.33,136.58,132.37,131.32,130.45,129.27,128.72,128.70,128.52,128.23,128.03,126.21,125.68,122.47,118.63,105.31,81.54,78.16,76.62,68.16,66.54,65.18,58.19,56.11,55.97,51.25,43.66,42.11,37.15,35.42,33.46,31.87,31.53,25.68,25.62,20.43,15.40,12.39,12.32,12.11,12.04.HRMS(ESI)C 57 H 66 FN 11 O8S[M+H]+ The calculated value is 1084.4879, and the measured value is 1084.4877.

[0153] Example 66: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazole-5-yl)-2-(2-((6-((4-(2-((4-morpholino-6-(3-(m-tolyl)-1H-pyrazole-1-yl)pyrimidine-2-yl)oxy)ethyl)phenyl)amino)-6-oxohexyl)amino)-2-oxoethoxy)benzyl)pyrrolidine-2-carboxamide (LCG-II-2) [ka] Based on intermediate ii-4, the method for preparing LCG-53 in Example 53 was referenced for synthesis. 1H NMR(600 MHz,DMSO-d6)δ 9.80(s,1H),8.98(s,1H),8.57(d,J=2.7 Hz,1H),8.56(t,J=6.2 Hz,1H),8.13(t,J=5.9 Hz,1H),7.81(d,J=1.8 Hz,1H),7.77(d,J=7.7 Hz,1H),7.53(d,J=8.4 Hz,2H),7.43(d,J=7.8 Hz,1H),7.35(t,J=7.6 Hz,1H),7.27(dd,J=9.2,2.7 Hz,1H),7.22(m,3H),7.04(d,J=2.7 Hz,1H),7.02(dd,J=7.7,1.6 Hz,1H),6.96(d,J=1.7 Hz,1H),6.89(s,1H),5.17(d,J=3.6 Hz,1H),4.61-4.42(m,7H),4.35(s,1H),4.30(dd,J=15.8,5.7 Hz,1H),3.73-3.58(m,10H),3.15(m,2H),2.99(t,J=7.1 Hz,2H),2.45(s,3H),2.38(s,3H),2.26(t,J=7.4 Hz,2H),2.09-2.02(m,1H),1.91-1.85(m,1H),1.57(p,J=7.5 Hz,2H),1.48(p,J=7.2 Hz,2H),1.40-1.32(m,2H),1.32-1.25(m,2H),1.21(dd,J=8.5,3.2 Hz,2H),0.95(s,9H). 13C NMR(150 MHz,DMSO-d6)δ 171.10,170.37,168.27,167.50,167.36,166.60,164.09,163.44,157.51,154.51,152.97,150.96,147.37,137.34,137.0 6,132.02,131.33,130.60,130.46,128.72,128.69,128.45,128.32,128.03,126.49,125.69,122.48,120.86,118.55,111 .55,105.31,81.54,78.27,76.73,68.27,66.60,65.19,64.30,58.24,56.10,55.93,43.67,37.68,37.23,36.81,35.65,35 .63,35.41,33.48,28.37,25.59,25.51,25.45,24.26,20.44,15.40,15.37,14.55,12.39,12.32,12.13,12.06.HRMS(ESI)C 60 H 72 FN 11 O9S[M+H] + The calculated value is 1142.5297, and the measured value is 1142.5284.

[0154] Example 67: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)-3-((4-(4-((4-morpholino-6-(3-(m-tolyl)-1H-pyrazole-1-yl)pyrimidine-2-yl)oxy)piperidine-1-yl)phenyl)amino)-3-oxopropyl)pyrrolidine-2-carboxamide (LCG-II-3) [ka] Step 1: Preparation of intermediate ii-6 4-hydroxypiperidine (500 mg, 5.0 mmol) was dissolved in 10 mL of acetonitrile. K2CO3 (2 g, 15.0 mmol) and 4-fluoronitrobenzene (700 mg, 5.0 mmol) were added. The mixture was stirred at room temperature for 5 hours, filtered, and spin-dried to obtain a yellow solid, which was not further purified. LC-MS:C 11 H 14 N2O3[M+H] + The calculated value is 222.1, and the measured value is 222.3.

[0155] Step 2: Preparation of intermediate ii-7 Based on intermediates ii-3 and ii-6, a nitro-containing intermediate was obtained by referring to the above synthesis method for ii-4, and then intermediate ii-7 was obtained by a conventional nitrohydrogenation reduction reaction. 1 H NMR(600 MHz,DMSO-d6)δ 8.59(d,J=2.7 Hz,1H),7.82(s,1H),7.78(d,J=8.0 Hz,1H),7.35(t,J=7.6 Hz,1H),7.21(dt,J=7.5,0.9 Hz,1H),7.06(d,J=2.7 Hz,1H),6.89(s,1H),6.74(d,J=8.8 Hz,2H),6.50(d,J=8.7 Hz,2H),5.12-5.04(m,1H),4.59(s,2H),3.74-3.63(m,8H),3.29-3.22(m,2H), 2.87-2.80(m,2H),2.39(s,3H),2.15-2.08(m,2H),1.87-1.75(m,2H).LC-MS:C 29 H 33 N7O2[M+H] + The calculated value is 512.3, and the measured value is 512.3.

[0156] Step 3: Preparation of LCG-II-3 Based on intermediate ii-7, the preparation method of LCG-50 in Example 50 was referenced for synthesis. 1H NMR(600 MHz,DMSO-d6)δ 9.69(s,1H),8.98(s,1H),8.61(d,J=7.9 Hz,1H),8.60(d,J=2.7 Hz,1H),7.82(s,1H),7.78(d,J=7.7 Hz,1H),7.46-7.40(m,4H),7.40-7.32(m,3H),7.26(dd,J=9.2,2.9 Hz,1H),7.24-7.17(m,1H),7.06(d,J=2.7 Hz,1H),6.91(s,1H),6.90(s,2H),5.27(q,J=7.7 Hz,1H),5.18-5.10(m,2H),4.58(d,J=9.2 Hz,1H),4.48(t,J=8.3 Hz,1H),4.28(s,1H),3.74-3.65(m,8H),3.64-3.54(m,2H),3.50-3.42(m,2H),3.00(t,J=9.2 Hz,2H),2.87-2.77(m,2H),2.44(s,3H),2.39(s,3H),2.11(d,J=11.7 Hz,2H),2.05(dd,J=12.8,7.9 Hz,1H),1.85-1.72(m,3H),1.43-1.29(m,2H),1.22(dd,J=8.6,3.0 Hz,2H),0.98(s,9H). 13 C NMR(150 MHz,DMSO-d6)δ 169.92,168.24,167.48,167.34,166.83,164.21,162.88,157.55,152.99,150.93,147.21,141.63,137.36,131.35,130.43,129.41,128.75,128.10,128.05,126.51,125.71,122.50,119.94,115.66,105.34,81.48,78.31,76.77,71.38,68.19,65.23,64.32,58.21,56.01,55.98,49.28,46.25,45.14,43.70,41.98,37.07,35.48,29.69,25.69,25.65,20.46,15.42,14.57,12.41,12.34,12.13,12.06,8.03.HRMS(ESI)C 57 H 66 FN 11 O7S[M+H] +The calculated value is 1068.4929, and the measured value is 1068.4927.

[0157] Example 68: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)-4-((4-(4-((4-morpholino-6-(3-(m-tolyl)-1H-pyrazole-1-yl)pyrimidine-2-yl)oxy)piperidine-1-yl)phenyl)amino)-4-oxobutyl)pyrrolidine-2-carboxamide (LCG-II-4) [ka] The method for preparing LCG-II-3 in Example 67 was referenced for synthesis. 1 H NMR(600 MHz,DMSO-d6)δ 9.60(s,1H),8.99(s,1H),8.60(d,J=2.7 Hz,1H),8.57(d,J=8.2 Hz,1H),7.82(s,1H),7.78(d,J=7.7 Hz,1H),7.46(d,J=8.3 Hz,2H),7.41(dd,J=13.7,8.4 Hz,4H),7.35(t,J=7.6 Hz,1H),7.28(dd,J=9.2,2.8 Hz,1H),7.21(d,J=7.6 Hz,1H),7.06(d,J=2.7 Hz,1H),6.92(d,J=8.5 Hz,2H),6.90(s,1H),5.17-5.10(m,2H),4.86(q,J=8.1 Hz,1H),4.59(d,J=9.2 Hz,1H),4.50(t,J=8.3 Hz,1H),4.28(s,1H),3.75-3.66(m,8H),3.65-3.55(m,2H),3.52-3.43(m,2H),3.00(t,J=10.1 Hz,2H),2.47(s,3H),2.39(s,3H),2.37-2.30(m,1H),2.16-1.95(m,5H),1.86-1.71(m,3H),1.45-1.29(m,2H),1.22(dd,J=8.4,2.5 Hz,2H),0.97(s,9H). 13C NMR(150 MHz,DMSO-d6)δ 170.23,169.51,168.24,167.50,167.37,164.21,162.88,157.55,152.99,150.92,147.20,146.37,142.62,137 .35,131.34,130.72,130.47,129.31,128.75,128.26,128.05,126.29,126.20,125.70,122.49,119.63,115.73, 105.34,81.48,78.29,76.75,71.40,68.20,65.23,64.31,58.19,56.09,56.00,51.41,46.33,45.14,43.70,37.1 6,35.45,32.56,31.59,29.73,25.70,25.63,20.45,15.43,14.57,12.41,12.34,12.14,12.07,8.03.HRMS(ESI)C 58 H 68 FN 11 O7S[M+H] + The calculated value is 1082.5086, and the measured value is 1082.5076.

[0158] Example 69: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)-6-((4-(4-((4-morpholino-6-(3-(m-tolyl)-1H-pyrazole-1-yl)pyrimidine-2-yl)oxy)piperidine-1-yl)phenyl)amino)-6-oxohexyl)pyrrolidine-2-carboxamide (LCG-II-5) [ka] The method for preparing LCG-II-3 in Example 67 was referenced for synthesis. 1H NMR(600 MHz,DMSO-d6)δ 9.61(s,1H),8.99(s,1H),8.60(d,J=2.7 Hz,1H),8.46(d,J=8.2 Hz,1H),7.82(s,1H),7.78(d,J=7.7 Hz,1H),7.42(d,J=8.3 Hz,4H),7.36(m,3H),7.27(dd,J=9.3,2.8 Hz,1H),7.21(d,J=7.5 Hz,1H),7.06(d,J=2.7 Hz,1H),6.91(d,J=8.3 Hz,3H),5.17-5.10(m,2H),4.80(q,J=7.7 Hz,1H),4.58(d,J=9.2 Hz,1H),4.50(t,J=8.2 Hz,1H),4.28(s,1H),3.75-3.64(m,8H),3.63-3.53(m,2H),3.50-3.43(m,2H),2.99(t,J=9.4 Hz,2H),2.45(s,3H),2.39(s,3H),2.24(t,J=7.4 Hz,2H),2.16-2.09(m,2H),2.04(dd,J=12.9,7.9 Hz,1H),1.84-1.77(m,2H),1.77-1.67(m,3H),1.65-1.55(m,2H),1.49-1.40(m,1H),1.40-1.28(m,3H),1.22(dd,J=8.4,2.9 Hz,2H),0.97(s,9H). 13C NMR(150 MHz,DMSO-d6)δ 170.05,169.91,168.11,167.47,167.34,164.21,162.89,157.55,152.99,150.86,147.14,146.33,143.23,137.3 5,131.34,130.81,130.51,129.10,128.75,128.16,128.05,126.22,125.70,122.49,119.61,115.73,105.34,81. 48,78.30,76.75,71.40,68.21,65.23,64.31,58.04,56.03,55.96,51.44,46.32,45.13,43.69,37.12,35.59,35. 48,35.46,29.73,25.73,25.62,24.78,24.35,20.45,15.43,14.57,12.41,12.34,12.12,12.06,8.03.HRMS(ESI)C 60 H 72 FN 11 O7S[M+H] + The calculated value is 1110.5399, and the measured value is 1110.5399.

[0159] Example 70: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)-3-(4-((4-(2-((4-morpholino-6-(3-(m-tolyl)-1H-pyrazole-1-yl)pyrimidine-2-yl)oxy)ethyl)ethynyl)piperidine-1-yl)-3-oxopropyl)pyrrolidine-2-carboxamide (LCG-II-6) [ka] Step 1: Preparation of intermediate ii-8 4-bromophenethyl alcohol (200 mg, 1.0 mmol), 1-Boc-4-ethynylpiperidine (630 mg, 3.0 mmol), copper iodide (400 mg, 0.2 mmol), bis(triphenylphosphine)palladium dichloride (70 mg, 0.1 mmol), and triethylamine (304 mg, 3.0 mmol) were dissolved in 10 mL of ultra-dry DMF. After two nitrogen purgings, the mixture was reacted at 60°C for 8 hours. After monitoring the completion of the reaction by TLC, 50 mL of water was added, and the mixture was extracted twice with EA. The organic phases were combined, washed once with saturated brine, dried over anhydrous Na2SO4, filtered, spin-dried, and then separated by column chromatography to obtain 200 mg of yellow oil (61%). 1 H NMR(600 MHz,DMSO-d6)δ 7.29(d,J=8.2 Hz,2H),7.19(d,J=8.2 Hz,2H),4.64(s,1H),3.69-3.61(m,2H),3.59(t,J=7.0 Hz,2H),3.12(brs,2H),2.89-2.80(m,1H),2.71(t,J=6.9 Hz,2H),1.83-1.76(m,2H),1.55-1.45(m,2H),1.40(s,9H).LC-MS:C 20 H 27 NO3 [M+H] + The calculated value is 330.2, and the measured value is 330.2.

[0160] Step 2: Preparation of intermediates ii-9 Intermediate ii-9 was obtained by referring to the synthesis method of ii-4 above, based on intermediate ii-8. 1H NMR(500 MHz,chloroform-d)δ 8.52(t,J=2.4 Hz,1H),7.74(s,1H),7.69(d,J=7.4 Hz,1H),7.37-7.30(m,3H),7.23(d,J=8.0 Hz,2H),7.20-7.16(m,1H),6.89(d,J=1.9 Hz,1H),6.74(t,J=2.4 Hz,1H),4.52(t,J=7.5 Hz,2H),3.83-3.64(m,10H),3.33-3.17(m,2H),3.13(t,J=7.4 Hz,2H),2.78(d,J=7.5 Hz,1H),2.43(s,3H),1.84(brs,2H),1.66(d,J=10.5 Hz,2H),1.47(s,9H).LC-MS:C 38 H 44 N6O4[M+H] + The calculated value is 649.3, and the measured value is 649.4.

[0161] Step 3: Preparation of LCG-II-6 Based on intermediate ii-9, the preparation method of LCG-50 in Example 50 was referenced for synthesis. 1H NMR(600 MHz,DMSO-d6)δ 8.95(d,J=24.6 Hz,1H),8.57(t,J=2.8 Hz,1H),8.51(dd,J=11.6,8.0 Hz,1H),7.81(s,1H),7.77(d,J=7.8 Hz,1H),7.46-7.37(m,4H),7.35(t,J=7.6 Hz,1H),7.33-7.24(m,4H),7.22(dd,J=12.2,7.9 Hz,2H),7.05(d,J=2.7 Hz,1H),6.89(s,1H),5.24-5.10(m,2H),4.57(d,J=9.2 Hz,1H),4.52(t,J=6.8 Hz,2H),4.45(t,J=8.2 Hz,1H),4.28(s,1H),3.92-3.50(m,13H),3.27-3.16(m,1H),3.05(t,J=6.7 Hz,2H),2.94-2.78(m,3H),2.44(d,J=7.2 Hz,3H),2.38(s,3H),2.09-2.00(m,1H),1.82-1.70(m,3H),1.52-1.29(m,4H),1.25-1.19(m,2H),0.97(s,9H). 13 C NMR(150 MHz,DMSO-d6)δ 169.92,169.87,168.26,168.22,167.48,167.35,167.05,166.96,164.09,163.41,157.51,153.00,150.92,150.84,147.17,141.76,137.96,137.87,137.35,131.33,130.72,130.66,130.47,130.45,129.48,129.38,128.75,128.72,128.54,128.49,128.11,128.05,126.66,125.70,122.49,120.21,105.34,81.60,78.29,76.75,68.19,66.19,65.21,64.32,58.18,55.95,49.61,49.21,45.14,37.01,35.46,33.84,31.01,30.47,26.32,26.17,25.66,25.63,20.46,15.41,15.37,14.57,12.40,12.33,12.12,12.05,8.04.HRMS(ESI)C 61 H69 FN 10 O7S[M+H] + The calculated value is 1105.5133, and the measured value is 1105.5138.

[0162] Example 71: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)-4-(4-((4-(2-((4-morpholino-6-(3-(m-tolyl)-1H-pyrazole-1-yl)pyrimidine-2-yl)oxy)ethyl)ethynyl)piperidine-1-yl)-4-oxobutyl)pyrrolidine-2-carboxamide (LCG-II-7) [ka] The preparation method for LCG-II-6 in Example 70 was referenced for synthesis. 1H NMR(600 MHz,DMSO-d6)δ 8.99(s,1H),8.57(d,J=2.7 Hz,1H),8.53(dd,J=12.7,8.7 Hz,1H),7.81(s,1H),7.77(d,J=7.7 Hz,1H),7.46(d,J=8.3 Hz,2H),7.40(d,J=8.2 Hz,2H),7.38-7.28(m,5H),7.21(d,J=7.6 Hz,1H),7.18(d,J=9.0 Hz,1H),7.05(d,J=2.7 Hz,1H),6.89(s,1H),5.18-5.11(m,1H),4.93(m,2H),4.59-4.53(m,1H),4.51(q,J=6.4 Hz,2H),4.49-4.44(m,1H),4.31(s,1H),3.83-3.54(m,12H),3.06(t,J=6.9 Hz,2H),2.96-2.84(m,1H),2.77-2.60(m,1H),2.46(s,3H),2.45-2.39(m,1H),2.38(s,3H),2.36-2.28(m,1H),2.03(dd,J=12.9,7.6 Hz,1H),1.92-1.72(m,5H),1.69-1.54(m,1H),1.50-1.41(m,1H),1.37-1.28(m,1H),1.27-1.15(m,3H),0.97(d,J=18.9 Hz,9H). 13C NMR(150 MHz,DMSO-d6)δ 170.26,170.22,169.54,169.45,168.18,168.14,167.41,167.38,167.28,167.26,164.08,163.40,157.50,152.99,150.90,147. 21,143.13,143.08,137.92,137.35,131.32,130.71,130.68,130.47,129.22,129.21,128.74,128.69,128.51,128.48,128.29,12 8.04,126.10,126.06,125.70,122.49,120.28,105.33,81.58,68.28,66.21,65.20,64.31,58.38,56.16,55.98,43.68,42.61,37 .15,37.12,35.62,33.83,31.82,31.66,31.12,28.83,26.45,26.24,25.64,25.54,20.45,15.41,14.56,12.31,12.03.HRMS(ESI)C 62 H 71 FN 10 O7S[M+H] + The calculated value is 1119.5290, and the measured value is 1119.5293.

[0163] Example 72: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)-6-(4-((4-(2-((4-morpholino-6-(3-(m-tolyl)-1H-pyrazole-1-yl)pyrimidine-2-yl)oxy)ethyl)phenyl)ethynyl)piperidine-1-yl)-6-oxohexyl)pyrrolidine-2-carboxamide (LCG-II-8) [ka] The preparation method for LCG-II-6 in Example 70 was referenced for synthesis. 1H NMR(600 MHz,DMSO-d6)δ 8.98(s,1H),8.56(d,J=2.7 Hz,1H),8.45(d,J=6.9 Hz,1H),7.81(s,1H),7.77(d,J=7.7 Hz,1H),7.43(d,J=8.3 Hz,2H),7.38(d,J=8.2 Hz,2H),7.38-7.31(m,3H),7.30(d,J=7.8 Hz,2H),7.28-7.22(m,1H),7.21(d,J=7.6 Hz,1H),7.04(d,J=2.2 Hz,1H),6.89(s,1H),5.13(brs,1H),4.82(q,J=5.7,5.2 Hz,1H),4.57(d,J=9.2 Hz,1H),4.54-4.46(m,3H),4.28(s,1H),3.89-3.80(m,1H),3.71-3.65(m,10H),3.62-3.52(m,2H),3.31-3.24(m,1H),3.20-3.11(m,1H),3.05(t,J=6.8 Hz,2H),2.94-2.84(m,1H),2.45(s,3H),2.38(s,3H),2.33-2.25(m,2H),2.03(dd,J=12.9,7.8 Hz,1H),1.88-1.65(m,5H),1.59-1.40(m,5H),1.39-1.29(m,3H),1.23-1.16(m,2H),0.96(d,J=4.3 Hz,9H). 13C NMR(150 MHz,DMSO-d6)δ 170.09,169.72,168.09,167.45,167.31,164.09,163.41,157.50,153.00,150.88,147.15,143.27,143.22,137.96,137.35,13 1.33,130.72,130.51,129.12,128.75,128.71,128.55,128.20,128.05,126.25,126.22,126.19,125.70,122.49,120.25,105.3 3,81.59,80.81,78.31,76.77,68.23,66.19,65.20,64.32,58.08,56.04,55.94,51.32,51.22,43.68,43.02,37.13,35.52,33.8 5,31.73,31.67,31.28,30.53,26.34,25.72,25.60,24.87,23.95,20.45,15.41,14.57,12.39,12.32,12.11,12.05.HRMS(ESI)C 64 H 75 FN 10 O7S[M+H] + The calculated value is 1147.5603, and the measured value is 1147.5604.

[0164] Example 73: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)-3-(3-(3-(4-(2-((4-morpholino-6-(3-(m-tolyl)-1H-pyrazole-1-yl)pyrimidine-2-yl)oxy)ethyl)phenyl)ureido)azetidine-1-yl)-3-oxopropyl)pyrrolidine-2-carboxamide (LCG-II-9) [ka] Step 1: Preparation of intermediate ii-10 Intermediate ii-4 (300 mg, 0.44 mmol) was dissolved in 10 mL of dichloromethane, and 4 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 3 hours, spin-dried, and then redissolved in isopropanol / water (10 mL / 8 mL). Phenylchloroformate (86 mg, 0.6 mmol) and Na2HPO4 (93 mg, 0.7 mmol) were added. The mixture was reacted at room temperature for 12 hours. After monitoring the completion of the reaction by TLC, 10 mL of water was added, and the mixture was extracted twice with EA. The organic phases were combined, washed once with saturated brine, dried over anhydrous Na2SO4, filtered, spin-dried, and then slurryed with PE / EA to obtain 200 mg of white solid (79%). 1 H NMR(600 MHz,DMSO-d6)δ 10.18(s,1H),8.58(d,J=2.7 Hz,1H),7.82(s,1H),7.77(d,J=7.7 Hz,1H),7.48-7.40(m,4H),7.35(t,J=7.6 Hz,1H),7.31-7.23(m,3H),7.24-7.19(m,3H),7.05(d,J=2.7 Hz,1H),6.89(s,1H),4.50(t,J=7.1 Hz,2H),3.74-3.59(m,8H),3.01(t,J=7.0 Hz,2H),2.38(s,3H).LC-MS:C 33 H 32 N6O4[M+H] + The calculated value is 577.3, and the measured value is 577.2.

[0165] Step 2: Preparation of intermediate ii-11 Intermediate ii-11 (200 mg, 0.34 mmol) was dissolved in 10 mL of toluene, and 1-Boc-3-aminocyclobutylamine (120 mg, 0.70 mmol) and DMAP (4.2 mg, 0.03 mmol) were added. The mixture was then heated to 90°C and reacted for 24 hours. The completion of the reaction was monitored by TLC, and the mixture was cooled to precipitate a white solid. The mixture was filtered to obtain 139 mg of the target product (61%). LC-MS:C 35 H 42 N8O5[M+H] + The calculated value is 655.3, and the measured value is 655.3.

[0166] Step 3: Preparation of LCG-II-9 Based on intermediate ii-11, the preparation method of LCG-50 in Example 50 was referenced for synthesis. 1 H NMR(600 MHz,DMSO-d6)δ 8.98(d,J=10.7 Hz,1H),8.57(d,J=2.7 Hz,1H),8.56-8.45(m,2H),7.81(s,1H),7.77(d,J=7.7 Hz,1H),7.48-7.42(m,2H),7.40(d,J=8.2 Hz,2H),7.38-7.25(m,4H),7.21(d,J=7.5 Hz,1H),7.18(dd,J=8.7,2.3 Hz,2H),7.05(d,J=2.7 Hz,1H),6.89(s,1H),6.73(dd,J=17.3,6.6 Hz,1H),5.19-5.11(m,1H),4.58(d,J=9.2 Hz,1H),4.51-4.42(m,3H),4.42-4.25(m,3H),4.19-4.07(m,1H),4.06-3.91(m,1H),3.82-3.52(m,12H),2.97(t,J=6.9 Hz,2H),2.70-2.60(m,1H),2.59-2.52(m,1H),2.46(d,J=8.4 Hz,3H),2.38(s,3H),2.09-1.99(m,1H),1.81-1.74(m,1H),1.42-1.30(m,2H),1.25-1.19(m,2H),0.98(s,9H). 13¹³C NMR (150 MHz, DMSO-d6)δ 169.88, 168.68, 168.63, 168.24, 167.54, 167.50, 167.40, 167.37, 164.10, 163.47, 157.52, 154.03, 152.98, 150.96, 150.91, 147.25, 147.22, 141.84, 141.70, 137.80, 137.35, 131.34, 130.44, 129.48, 129.43, 128.74, 128.70, 128.48, 128.15, 128.05, 126.49, 126.44, 125.70, 122.49, 117. 56,117.52,105.34,81.54,78.28,78.25,76.74,76.71,68.18,66.70,6 6.32,65.21,64.32,58.18,58.16,56.93,56.76,55.97,54.10,53.96,48 .80,48.77,45.09,43.69,37.09,37.07,37.02,35.47,35.44,33.40,25 .64,20.46,15.40,14.57,12.40,12.33,12.13,12.06,8.01.HRMS(ESI)C 58 H 67 FN 12 O8S[M+H] + The calculated value is 1111.4988, and the measured value is 1111.4989.

[0167] Example 74: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)-4-(3-(3-(4-(2-((4-morpholino-6-(3-(m-tolyl)-1H-pyrazole-1-yl)pyrimidine-2-yl)oxy)ethyl)phenyl)ureido)azetidine-1-yl)-4-oxobutyl)pyrrolidine-2-carboxamide (LCG-II-10) [ka] The preparation method for LCG-II-9 in Example 73 was referenced for synthesis. 1H NMR(600 MHz,DMSO-d6)δ 8.98(d,J=1.9 Hz,1H),8.57(d,J=2.7 Hz,1H),8.52(d,J=8.5 Hz,1H),8.50(d,J=5.3 Hz,1H),7.82(s,1H),7.77(d,J=7.8 Hz,1H),7.46(d,J=8.1 Hz,2H),7.41-7.36(m,2H),7.37-7.32(m,3H),7.31-7.23(m,1H),7.21(d,J=7.6 Hz,1H),7.18(d,J=8.4 Hz,2H),7.05(d,J=2.7 Hz,1H),6.89(s,1H),6.77(dd,J=10.0,7.0 Hz,2H),5.15(brs,1H),4.90-4.79(m,1H),4.62-4.54(m,1H),4.51-4.32(m,5H),4.31-4.27(s,1H),4.13-4.03(m,1H),3.97-3.87(m,1H),3.74-3.63(m,9H),3.64-3.53(m,2H),2.97(t,J=7.1 Hz,2H),2.46(d,J=2.1 Hz,3H),2.38(s,3H),2.35-2.01(m,3H),1.97-1.82(m,2H),1.80-1.71(m,1H),1.40-1.25(m,2H),1.25-1.17(m,2H),0.97(d,J=7.5 Hz,9H). 13¹³C NMR (150 MHz, DMSO-d6)δ 171.31,171.18,170.23,168.19,168.16,167.51,167.47,167.38,167.34,164.09,163.45,157.51,154.02,152.97,150.90,147.19,142.87,142.83,137.85,137.34,131.33,130.46,130.43,130.37,129.25,128.73,128.68,128.48,128.45,128.25,128.04,126.14,126.12,125.69,1 22.48,117.55,117.52,105.32,81.53,78.20,76.66,68.21,66.71,65. 19,64.30,58.23,58.18,56.81,56.73,56.05,55.97,55.93,54.10,51. 00,50.80,43.67,37.17,35.50,35.44,33.39,30.97,30.84,25.59,25. 56,20.44,15.40,14.56,12.36,12.30,12.08,12.01,7.99.HRMS(ESI)C 59 H 69 FN 12 O8S[M+H] + The calculated value is 1125.5144, and the measured value is 1125.5143.

[0168] Example 75: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)-3-(4-(4-(2-((4-morpholino-6-(3-(m-tolyl)-1H-pyrazole-1-yl)pyrimidine-2-yl)oxy)ethyl)phenyl)piperazine-1-yl)-3-oxopropyl)pyrrolidine-2-carboxamide (LCG-II-11) [ka] Step 1: Preparation of intermediate ii-12 4-Bromophenethyl alcohol (500 mg, 2.5 mmol), 1-Cbz-piperazine (700 mg, 3.8 mmol), Tris(dibenzylideneacetone)dipalladium (230 mg, 0.25 mmol), K3PO4 (1.1 g, 5.0 mmol), and BrettPhos (270 mg, 0.50 mmol) were dissolved in 20 mL of ultra-dried 1,4-dioxane. After two nitrogen purgings, the mixture was reacted at 90°C for 12 hours. After the completion of the reaction, it was monitored by TLC, 20 mL of water was added, and the mixture was extracted twice with EA. The organic phases were combined, washed once with saturated brine, dried over anhydrous Na2SO4, filtered, spin-dried, and then separated by column chromatography to obtain 540 mg of yellow oil (64%). 1 H NMR(600 MHz,DMSO-d6)δ 7.38(d,J=3.9 Hz,4H),7.35-7.30(m,1H),7.07(d,J=8.6 Hz,2H),6.86(d,J=8.6 Hz,2H),5.10(s,2H),4.57(t,J=5.2 Hz,1H),3.63-3.46(m,6H),3.09-2.99(m,3H),2.62(t,J=7.2 Hz,2H).LC-MS:C 20 H 24 N2O3[M+H] + The calculated value is 341.2, and the measured value is 341.2.

[0169] Step 2: Preparation of intermediate ii-13 Based on intermediates ii-3 and ii-12, an intermediate containing a Cbz protecting group was obtained by referring to the synthesis method of ii-4 above, and then intermediate ii-13 was obtained by a conventional hydrogenation-reduction reaction. 1H NMR(600 MHz,DMSO-d6)δ 8.57(d,J=2.7 Hz,1H),7.81(s,1H),7.77(d,J=7.7 Hz,1H),7.35(t,J=7.6 Hz,1H),7.25-7.18(m,3H),7.05(d,J=2.7 Hz,1H),6.94(d,J=8.7 Hz,1H),6.89(s,1H),4.47(t,J=7.0 Hz,2H),3.75-3.63(m,8H),3.41-3.26(m,8H),3.22-3.13(m,4H),2.97(t,J=7.0 Hz,2H),2.38(s,3H).LC-MS:C 30 H 35 N7O2[M+H] + The calculated value is 526.3, and the measured value is 526.2.

[0170] Step 3: Preparation of LCG-II-11 Based on intermediate ii-13, the preparation method of LCG-50 in Example 50 was referenced for synthesis. 1 H NMR(600 MHz,DMSO-d6)δ 8.96(s,1H),8.57(d,J=2.7 Hz,1H),8.53(d,J=7.9 Hz,1H),7.81(s,1H),7.77(d,J=7.7 Hz,1H),7.44-7.39(m,4H),7.35(t,J=7.6 Hz,1H),7.26(dd,J=9.2,2.8 Hz,1H),7.21(d,J=7.1 Hz,1H),7.15(d,J=8.5 Hz,2H),7.05(d,J=2.7 Hz,1H),6.89(s,1H),6.85(d,J=8.7 Hz,2H),5.21(q,J=7.2 Hz,1H),5.14(s,1H),4.57(d,J=9.8 Hz,1H),4.46(q,J=7.7,6.9 Hz,3H),4.28(s,1H),3.72-3.44(m,15H),3.08-3.00(m,2H),3.00-2.85(m,5H),2.82-2.72(m,1H),2. 39(s,3H),2.38(s,3H),2.10-2.01(m,1H),1.82-1.71(m,1H),1.42-1.30(m,2H),1.21(dd,J=8.5,3.3 Hz,2H),0.96(s,9H). 13C NMR(150 MHz,DMSO-d6)δ 169.89,168.22,167.47,167.34,167.17,164.10,163.46,157.52,152.98,150.91,150.88,148.73,147.19,147.18,141.65,1 37.34,131.33,130.40,129.43,128.82,128.79,128.73,128.68,128.34,128.12,128.04,126.92,126.66,125.69,122.48,115 .47,115.44,105.32,81.52,78.27,76.73,68.16,66.79,65.19,64.30,58.16,55.94,55.89,49.39,48.26,47.90,45.14,44.4 7,43.68,40.33,37.91,37.02,35.43,33.18,25.65,25.61,20.44,15.32,14.56,12.39,12.32,12.11,12.05,8.02.HRMS(ESI)C 58 H 68 FN 11 O7S[M+H] + The calculated value is 1082.5086, and the measured value is 1082.5083.

[0171] Example 76: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)-4-(4-(4-(2-((4-morpholino-6-(3-(m-tolyl)-1H-pyrazole-1-yl)pyrimidine-2-yl)oxy)ethyl)phenyl)piperazine-1-yl)-4-oxobutyl)pyrrolidine-2-carboxamide (LCG-II-12) [ka] The preparation method for LCG-II-11 in Example 75 was referenced for synthesis. 1H NMR(600 MHz, DMSO-d6)δ 8.99(s,1H),8.57(d,J=2.7 Hz,1H),8.55(d,J=8.8 Hz,1H),7.82(s,1H),7.77(d,J=7.8 Hz,1H),7.46(d,J=8.3 Hz,2H),7.40(d,J=8.3 Hz,2H),7.35(t,J=7.6 Hz,1H),7.25-7.13(m,4H),7.05(d,J=2.7 Hz,1H),6.90(d,J=8.1 Hz,3H),5.16(brs,1H),4.98-4.90(m,1H),4.57(d,J=9.2 Hz,1H),4.51-4.43(m,3H),4.31(s,1H),3.75-3.49(m,14H),3.20-2.98(m,4H),2.96(t,J=7.0 Hz,2H),2.75-2.70(m,1H),2.46(s,3H),2.40-2.35(m,4H),2.06-1.96(m,2H),1.94 -1.84(m,1H),1.81-2.35(m,1H),1.41-1.28(m,2H),1.24-1.19(m,2H),0.98(s,9H). 13 C NMR(150 MHz,DMSO-d6)δ 170.25,169.79,168.23,167.43,167.30,164.11,163.48,157.53,152.99,150.91,148.79,147.22,142.99,137. 36,131.34,130.48,129.26,128.84,128.75,128.67,128.45,128.30,128.05,126.12,125.70,122.49,115.50,1 05.33,81.53,78.41,76.87,68.27,66.81,65.21,58.35,56.15,56.04,50.76,48.37,48.17,43.91,43.69,40.30 ,37.17,35.59,33.19,31.67,28.76,25.66,25.59,20.46,15.42,12.41,12.34,12.09,12.02,10.66.HRMS(ESI)C 59 H 70 FN 11 O7S[M+H] + The calculated value is 1096.5242 and the measured value is 1096.5243.

[0172] Example 77: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)-6-(4-(4-(2-((4-morpholino-6-(3-(m-tolyl)-1H-pyrazole-1-yl)pyrimidine-2-yl)oxy)ethyl)phenyl)piperazine-1-yl)-6-oxohexyl)pyrrolidine-2-carboxamide (LCG-II-13) [ka] The preparation method for LCG-II-11 in Example 75 was referenced for synthesis. 1 H NMR(600 MHz,DMSO-d6)δ 8.98(s,1H),8.57(d,J=2.7 Hz,1H),8.46(d,J=8.4 Hz,1H),7.81(s,1H),7.77(d,J=7.9 Hz,1H),7.43(d,J=8.2 Hz,2H),7.38(d,J=8.3 Hz,2H),7.35(t,J=7.6 Hz,1H),7.26(dd,J=9.2,2.8 Hz,1H),7.21(d,J=7.5 Hz,1H),7.18(d,J=8.5 Hz,2H),7.04(d,J=2.7 Hz,1H),6.92-6.86(m,3H),5.13(brs,1H),4.81(td,J=8.4,6.1 Hz,1H),4.58(dd,J=9.3,1.2 Hz,1H),4.50(t,J=8.2 Hz,1H),4.46(t,J=7.1 Hz,2H),4.29(s,1H),3.72-3.64(m,8H),3.63-3.51(m,6H),3.12-2.98(m,4H),2.95(t,J=7.1 Hz,2H),2.45(s,3H),2.38(s,3H),2.33(t,J=7.5 Hz,2H),2.07-2.00(m,1H),1.77-1.65(m,3H),1.57-1.48(m,2H),1.49-1.41(m,1H),1.40-1.28(m,3H),1.21(dd,J=8.5,3.1 Hz,2H),0.96(s,9H). 13C NMR(150 MHz,DMSO-d6)δ 170.08,169.96,168.10,167.45,167.32,164.10,163.48,157.52,152.99,150.87,148.81,147.15,143.24,137.35,131. 34,130.51,129.12,128.85,128.74,128.67,128.42,128.19,128.05,126.24,125.70,122.49,115.51,105.32,81.53,78 .33,76.79,68.23,66.80,65.20,64.32,58.09,56.05,55.96,51.34,48.49,48.08,45.13,44.15,43.68,40.20,37.13,35 .61,35.53,33.21,31.62,25.73,25.62,24.88,23.91,20.46,15.42,14.57,12.40,12.33,12.11,12.04,8.03.HRMS(ESI)C 61 H 74 FN 11 O7S[M+H] + The calculated value is 1124.5555, and the measured value is 1124.5555.

[0173] Example 78: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)-3-(4-(3-(4-(2-((4-morpholino-6-(3-(m-tolyl)-1H-pyrazole-1-yl)pyrimidine-2-yl)oxy)ethyl)phenyl)ureido)piperidine-1-yl)-3-oxopropyl)pyrrolidine-2-carboxamide (LCG-II-14) [ka] The preparation method for LCG-II-9 in Example 73 was referenced for synthesis. 1H NMR(600 MHz,DMSO-d6)δ 8.98(d,J=8.5 Hz,1H),8.57(d,J=2.7 Hz,1H),8.48(dd,J=14.9,8.0 Hz,1H),8.27(d,J=20.7 Hz,1H),7.81(s,1H),7.77(d,J=7.7 Hz,1H),7.46-7.37(m,4H),7.35(t,J=7.6 Hz,1H),7.34-7.25(m,3H),7.21(d,J=7.5 Hz,1H),7.17(d,J=8.5 Hz,2H),7.05(d,J=2.7 Hz,1H),6.89(s,1H),6.21-6.04(m,1H),5.25-5.16(m,1H),5.15(s,1H),4.58(d,J=9.2 Hz,1H),4.46(q,J=8.7,7.9 Hz,3H),4.29(s,1H),4.18-4.05(m,1H),3.80-3.52(m,12H),3.22-3.04(m,1H),2.96(t,J=7.1 Hz,2H),2.93-2.75(m,3H),2.46(d,J=3.3 Hz,3H),2.38(s,3H),2.04(dd,J=12.9,7.9 Hz,1H),1.85-1.67(m,3H),1.47-1.15(m,6H),0.98(s,9H). 13¹³C NMR (150 MHz, DMSO-d6)δ 169.92, 169.90, 168.23, 167.51, 167.38, 166.97, 164.09, 163.46, 157.51, 153.90, 153.88, 152.97, 150.93, 150.90, 147.19, 141.79, 141.74, 138.10, 137.34, 131.33, 130.46, 130.03, 129.41, 129.38, 128.73, 128.69, 128.49, 128.12, 128.08, 128.04, 126.91, 126.73, 126.67, 125.6 9,122.48,117.17,105.32,81.53,78.26,76.72,68.18,68.16,66.72, 66.30,65.19,64.30,58.18,55.94,49.37,49.16,45.48,45.38,43.67 ,43.22,43.13,37.96,37.02,35.71,35.42,33.39,31.87,31.02,25.6 2,20.44,15.37,15.34,14.55,12.39,12.32,12.13,12.06.HRMS(ESI)C 60 H 71 FN 12 O8S[M+H] + The calculated value is 1139.5301, and the measured value is 1139.5303.

[0174] Example 79: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)-4-(4-(3-(4-(2-((4-morpholino-6-(3-(m-tolyl)-1H-pyrazole-1-yl)pyrimidine-2-yl)oxy)ethyl)phenyl)ureido)piperidine-1-yl)-4-oxobutyl)pyrrolidine-2-carboxamide (LCG-II-15) [ka] The preparation method for LCG-II-9 in Example 73 was referenced for synthesis. 1H NMR(600 MHz,DMSO-d6)δ 8.99(s,1H),8.57(d,J=2.7 Hz,1H),8.55(dd,J=8.9,4.9 Hz,1H),8.28(d,J=13.3 Hz,1H),7.82(s,1H),7.77(d,J=7.7 Hz,1H),7.47(d,J=8.2 Hz,2H),7.41(d,J=7.9 Hz,2H),7.35(t,J=7.6 Hz,1H),7.32(d,J=8.3 Hz,2H),7.19(dd,J=20.2,7.8 Hz,4H),7.05(d,J=2.7 Hz,1H),6.89(s,1H),6.14(dd,J=35.1,7.6 Hz,1H),5.17(s,1H),4.93(td,J=10.1,4.4 Hz,2H),4.58(dd,J=9.5,3.2 Hz,1H),4.52-4.44(m,3H),4.32(s,1H),4.19(dd,J=58.7,12.8 Hz,1H),3.88(s,1H),3.74-3.55(m,11H),3.23-3.07(m,1H),2.97(t,J=7.1 Hz,2H),2.91-2.66(m,2H),2.47(s,3H),2.38(s,3H),2.37-2.27(m,1H),2.04(dd,J=12.8,7.6 Hz,1H),1.99-1.73(m,5H),1.43-1.12(m,6H),0.98(s,9H). 13C NMR(150 MHz,DMSO-d6)δ 170.26,170.22,169.61,169.53,168.22,168.19,167.49,167.46,167.36,167.32 ,164.10,163.47,157.53,153.91,153.89,152.99,150.91,147.22,143.09,143.0 2,138.20,138.15,137.36,131.35,130.48,130.04,130.01,129.25,128.74,128.69,128.49,128.30,128.05,126.12,125.71,122.49,117.21,117.17,117.12,105. 33, 81, 54, 78, 36, 78, 23, 76, 82, 76, 69, 68, 28, 66, 75, 65, 21, 64, 32, 58, 40, 58, 35, 56, 17, 56, 13, 55, 96, 50, 87, 50, 69, 45, 59, 45, 45, 43, 68, 42, 76, 37, 16, 35, 66, 35. 58,33.40,32.22,32.00,31.79,31.26,31.19,29.00,28.77,25.64,25.58,25.55, 20.46,15.44,15.41,14.57,12.38,12.31,12.23,12.11,12.04,11.97.HRMS(ESI)C 61 H 73 FN 12 O8S[M+H] + The calculated value is 1153.5458, and the measured value is 1153.5457.

[0175] Example 80: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-(4-methylthiazole-5-yl)phenyl)-3-(3-(3-(4-(4-((4-morpholino-6-(3-(m-tolyl)-1H-pyrazole-1-yl)pyrimidine-2-yl)oxy)piperidine-1-yl)phenyl)ureido)azetidine-1-yl)-3-oxopropyl)pyrrolidine-2-carboxamide (LCG-II-16) [ka] For the preparation method of LCG-II-3 in Example 67 and the preparation method of LCG-II-9 in Example 73, please refer to the synthesis method. 1 H NMR(600 MHz, DMSO-d6)δ 8.99(d,J=7.2 Hz,1H),8.60(d,J=2.6 Hz,1H),8.53(dd,J=11.8,8.1 Hz,1H),8.27(d,J=23.1 Hz,1H),7.82(s,1H),7.78(d,J=7.7 Hz,1H),7.48-7.42(m,2H),7.40(dd,J=8.3,1.7 Hz,2H),7.35(t,J=7.7 Hz,1H),7.30(ddd,J=24.0,9.3,2.8 Hz,1H),7.25-7.19(m,3H),7.06(d,J=2.7 Hz,1H),6.90(s,3H),6.67-6.58(m,1H),5.20-5.06(m,3H),4.59(d,J=9.2 Hz,1H),4.49-4.43(m,1H),4.41-4.35(m,1H),4.34-3.73(m,4H),3.72-3.66(m,8H),3.65-3.54 (m,3H),3.48-3.41(m,2H),2.97(brs,2H),2.70-2.59(m,1H),2.57-2.52(m,1H),2.46(d,J=7.1 Hz,3H),2.39(s,3H),2.12(brs,2H),2.09-2.01(m,1H),1.92-1.73(m,3H),1.41-1.29(m,2H),1.24-1.19(m,2H),0.98(s,9H). 13¹³C NMR (150 MHz, DMSO-d6)δ 170.37,169.18,169.13,168.74,168.73,168.04,168.00,167.90,167.87,164.71,163.38,158.05,154.70,153.49,151.46,151.42,147.74,147.73,142.34,142.20,137.85,131.84,130.94,129.97,129.92,129.24,128.65,128.55,126.98,126.94,126.20,122.99,119.31,1 16.71,105.84,81.98,78.78,78.75,77.24,77.20,71.90,68.68,66. 82,65.73,64.81,58.67,58.66,57.47,57.31,56.47,54.65,54.51,4 9.29,49.27,47.17,44.19,37.59,37.57,37.49,35.96,35.94,30.31,26.14,20.95,15.90,15.07,12.90,12.83,12.63,12.57.HRMS(ESI)C 61 H 72 FN 13 O8S[M+H] + The calculated value is 1166.5410, and the measured value is 1166.5414.

[0176] Example 81: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-(4-methylthiazole-5-yl)phenyl)-4-(3-(3-(4-(4-((4-morpholino-6-(3-(m-tolyl)-1H-pyrazole-1-yl)pyrimidine-2-yl)oxy)piperidine-1-yl)phenyl)ureido)azetidine-1-yl)-4-oxobutyl)pyrrolidine-2-carboxamide (LCG-II-17) [ka] The preparation methods for LCG-II-3 in Example 67 and LCG-II-9 in Example 73 were referenced for synthesis. 1H NMR(600 MHz,DMSO-d6)δ 8.99(d,J=1.0 Hz,1H),8.60(d,J=2.6 Hz,1H),8.52(d,J=8.5 Hz,1H),8.26(brs,1H),7.82(s,1H),7.78(d,J=7.8 Hz,1H),7.46(d,J=8.1 Hz,2H),7.38(dd,J=8.2,3.4 Hz,2H),7.35(t,J=7.6 Hz,1H),7.30-7.19(m,4H),7.06(d,J=2.7 Hz,1H),6.90(s,3H),6.67(brs,1H),5.14(d,J=12.7 Hz,2H),4.88-4.79(m,1H),4.59(d,J=9.2 Hz,1H),4.50-4.44(m,1H),4.44-4.31(m,2H),4.29(s,1H),4.13-4.00(m,1H),3.95-3.84(m,1H),3.69(d,J=9.9 Hz,9H),3.62(dd,J=10.8,3.7 Hz,1H),3.57(d,J=10.9 Hz,1H),3.48-3.40(m,2H),2.97(brs,2H),2.46(d,J=2.2 Hz,3H),2.39(s,3H),2.33-2.00(m,5H),1.95-1.73(m,5H),1.45-1.28(m,2H),1.26-1.16(m,2H),0.98(d,J=6.0 Hz,9H). 13¹³C NMR (150 MHz, DMSO-d6)δ 171.81,171.68,170.73,168.70,168.66,168.02,167.98,167.89,167.85,164.71,163.38,158.05,154.69,153.49,151.40,147.71,143.37,143.34,137.85,131.84,130.96,129.76,129.24,128.76,128.54,126.64,126.20,122.99,119.32,116.70,105.84,81.98,78.73,7 8.71,77.19,71.91,68.71,65.72,64.81,58.72,58.68,57.32,57.25,56.56,56.47,56.44,54.70,51.51,51.33,47.18,44.19,37.68,36 .00,35.95,31.48,31.34,30.31,27.67,27.42,26.21,26.19,26.11,26.08,20.95,15.92,15.06,12.88,12.81,12.60,12.53.HRMS(ESI)C 62 H 74 FN 13 O8S[M+H] + The calculated value is 1180.5566, and the measured value is 1180.5566.

[0177] Example 82: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-(4-methylthiazole-5-yl)phenyl)-3-(4-(3-(4-(4-((4-morpholino-6-(3-(m-tolyl)-1H-pyrazole-1-yl)pyrimidine-2-yl)oxy)piperidine-1-yl)phenyl)ureido)piperidine-1-yl)-3-oxopropyl)pyrrolidine-2-carboxamide (LCG-II-18) [ka] The preparation methods for LCG-II-3 in Example 67 and LCG-II-9 in Example 73 were referenced for synthesis. 1H NMR(600 MHz,DMSO-d6)δ 8.98(d,J=6.4 Hz,1H),8.60(d,J=2.7 Hz,1H),8.48(dd,J=15.2,8.0 Hz,1H),8.05(d,J=18.0 Hz,1H),7.82(s,1H),7.78(d,J=7.7 Hz,1H),7.47-7.40(m,4H),7.35(t,J=7.6 Hz,1H),7.33-7.28(m,1H),7.22(t,J=7.8 Hz,3H),7.06(d,J=2.7 Hz,1H),6.89(d,J=12.7 Hz,3H),6.01(dd,J=46.4,6.7 Hz,1H),5.27-5.09(m,3H),4.59(d,J=9.2 Hz,1H),4.46(t,J=8.2 Hz,1H),4.29(s,1H),4.11(dd,J=25.5,12.9 Hz,1H),3.81-3.53(m,12H),3.47-3.40(m,2H),3.22-3.06(m,1H),3.02-2.74(m,5H),2.46(d,J=2.0 Hz,3H),2.39(s,3H),2.12(brs,2H),2.05(dd,J=12.9,8.0 Hz,1H),1.88-1.67(m,5H),1.44-1.30(m,2H),1.26-1.17(m,2H),0.98(s,9H). 13C NMR(150 MHz,DMSO-d6)δ 170.43,170.40,168.74,168.02,167.89,167.47,164.71,163.39,158.05,154.59,153.49,151.43,147.70,145.80,142.30,142.24,13 7.85,132.55,131.84,130.97,129.88,129.24,128.63,128.59,128.55,127.42,127.24,127.18,126.20,122.99,118.88,116.83,105. 84,81.97,78.77,77.22,71.93,68.69,68.67,66.81,65.73,64.81,58.69,56.45,56.41,49.88,49.67,47.25,45.99,45.89,44.19,43. 76,43.66,38.47,37.53,36.23,35.93,32.46,31.61,30.35,26.13,20.95,15.88,15.85,15.07,12.90,12.83,12.64,12.57.HRMS(ESI)C 63 H 76 FN 13 O8S[M+H] + The calculated value is 1194.5723, and the measured value is 1194.5726.

[0178] Example 83: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-(4-methylthiazole-5-yl)phenyl)-4-(4-(3-(4-(4-((4-morpholino-6-(3-(m-tolyl)-1H-pyrazole-1-yl)pyrimidine-2-yl)oxy)piperidine-1-yl)phenyl)ureido)piperidine-1-yl)-4-oxobutyl)pyrrolidine-2-carboxamide (LCG-II-19) [ka] The preparation methods for LCG-II-3 in Example 67 and LCG-II-9 in Example 73 were referenced for synthesis. 1H NMR(600 MHz,DMSO-d6)δ 8.99(s,1H),8.60(d,J=2.7 Hz,1H),8.57-8.51(m,1H),8.05(d,J=12.6 Hz,1H),7.82(s,1H),7.78(d,J=7.7 Hz,1H),7.47(d,J=8.3 Hz,2H),7.41(d,J=7.9 Hz,2H),7.35(t,J=7.6 Hz,1H),7.26-7.16(m,4H),7.06(d,J=2.7 Hz,1H),6.89(d,J=10.8 Hz,3H),6.02(dd,J=36.2,7.7 Hz,1H),5.16(d,J=3.4 Hz,1H),5.13-5.08(m,1H),4.97-4.88(m,1H),4.58(d,J=8.9 Hz,1H),4.49-4.44(m,1H),4.31(s,1H),4.19(dd,J=57.6,12.9 Hz,1H),3.87(brs,1H),3.75-3.55(m,12H),3.51-3.40(m,2H),3.22-3.07(m,1H),2.96(t,J=9.4 Hz,2H),2.89-2.64(m,2H),2.47(s,3H),2.39(s,3H),2.37-2.26(m,1H),2.12(brs,2H),2.04(dd,J=12.8,7.6 Hz,1H),1.99-1.72(m,7H),1.41-1.14(m,6H),0.99(s,9H). 13C NMR(150 MHz,DMSO-d6)δ 170.75,170.71,170.09,170.01,168.70,168.68,167.98,167.83,164.71, 163.39,158.05,154.58,153.49,151.41,147.72,145.79,143.58,143.52, 137.85, 132.64, 132.58, 131.85, 130.97, 129.75, 129.24, 128.79, 128.75, 128.55, 126.61, 126.20, 122.99, 118.86, 118.79, 116.83, 105.84, 81.97, 78 .87,78.74,77.32,77.20,71.93,68.77,65.73,64.81,58.88,58.83,56.66,56.46,51.36,51.20,47.26,46.09,45.94,44.19,43.28,37.65,36.14,36. 07,32.77,32.56,32.49,32.29,31.85,31.77,30.35,29.49,29.25,26.16, 26.07,26.05,20.95,15.93,15.91,15.07,12.89,12.82,12.55.HRMS(ESI)C 64 H 78 FN 13 O8S[M+H] + The calculated value is 1208.5879, and the measured value is 1208.5874.

[0179] Example 84: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)-3-(4-(4-(4-((4-morpholino-6-(3-(m-tolyl)-1H-pyrazole-1-yl)pyrimidine-2-yl)oxy)piperidine-1-yl)phenyl)piperazine-1-yl)-3-oxopropyl)pyrrolidine-2-carboxamide (LCG-II-20) [ka] The preparation method for LCG-II-3 in Example 67 was used as a reference for the synthesis.1 H NMR(600 MHz, DMSO-d6)δ 8.98(s,1H),8.60(d,J=2.7 Hz,1H),8.53(d,J=7.9 Hz,1H),7.82(s,1H),7.78(d,J=7.8 Hz,1H),7.45-7.38(m,4H),7.35(t,J=7.6 Hz,1H),7.27(dd,J=9.3,2.8 Hz,1H),7.21(dt,J=7.5,1.0 Hz,1H),7.06(d,J=2.7 Hz,1H),6.92-6.75(m,5H),5.21(q,J=7.2 Hz,1H),5.17-5.09(m,2H),4.58(d,J=9.3 Hz,1H),4.46(t,J=8.2 Hz,1H),4.28(brs,1H),3.73-3.36(m,17H),3.01-2.62(m,8H),2.40(s,3H),2.39(s,3H),2.12(brs,2H),2.05(dd,J=12.3,8.4 Hz,1H),1.86-1.73(m,2H),1.41-1.31(m,2H),1.22(dd,J=8.4,3.3 Hz,2H),0.97(s,9H). 13 C NMR(150 MHz,DMSO-d6)δ 170.40,168.73,167.98,167.85,164.71,163.39,158.05,153.49,151.41,147.70,142.15,137 .85,131.84,130.91,129.94,129.24,128.63,128.55,127.18,126.20,122.99,117.35,105.84 ,81.98,78.79,77.25,68.67,65.72,58.67,56.44,49.92,47.39,45.62,44.19,38.40,37.53,3 6.24,35.95,26.16,26.12,20.95,15.88,15.85,12.90,12.83,12.62,12.55,8.52.HRMS(ESI)C 61 H 73 FN 12 O7S[M+H] + The calculated value is 1137.5508 and the measured value is 1137.5508.

[0180] Example 85: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-(4-methylthiazole-5-yl)phenyl)-4-(4-(4-((4-morpholino-6-(3-(m-tolyl)-1H-pyrazole-1-yl)pyrimidine-2-yl)oxy)piperidine-1-yl)phenyl)piperazine-1-yl)-4-oxobutyl)pyrrolidine-2-carboxamide (LCG-II-21) [ka] The preparation method for LCG-II-3 in Example 67 was used as a reference for the synthesis. 1 H NMR(600 MHz,DMSO-d6)δ 8.99(s,1H),8.60(d,J=2.7 Hz,1H),8.55(d,J=8.7 Hz,1H),7.82(s,1H),7.78(d,J=7.8 Hz,1H),7.47(d,J=8.2 Hz,2H),7.41(d,J=8.3 Hz,2H),7.35(t,J=7.6 Hz,1H),7.26-7.18(m,2H),7.06(d,J=2.7 Hz,1H),6.93-6.79(m,5H),5.16(d,J=3.2 Hz,1H),5.12(brs,1H),4.96-4.91(m,1H),4.58(d,J=9.2 Hz,1H),4.51-4.45(m,1H),4.31(brs,1H),3.76-3.49(m,15H),3.40(brs,2H),3.05-2.87(m,5H),2.78-2.66(m,1H), 2.47(s,3H),2.40-2.35(m,4H),2.12(brs,2H),2.07-1.73(m,6H),1.42-1.29(m,2H),1.26-1.21(m,2H),0.98(s,9H). 13C NMR(150 MHz,DMSO-d6)δ 170.74,170.26,168.71,167.94,167.80,164.71,163.40,158.05,153.49,151.41,147.72,143.50,137 .85,131.84,130.97,129.75,129.23,128.79,128.55,126.62,126.20,122.99,117.37,105.84,81.98,7 8.92,77.38,71.92,68.77,65.72,64.81,58.84,56.65,56.52,51.27,47.41,45.60,44.19,37.67,36.08 ,32.18,30.39,29.26,26.16,26.09,20.95,15.92,15.07,12.93,12.86,12.61,12.55,8.51.HRMS(ESI)C 62 H 75 FN 12 O7S[M+H] + The calculated value is 1151.5664, and the measured value is 1151.5664.

[0181] Example 86: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)-6-(4-(4-(4-((4-morpholino-6-(3-(m-tolyl)-1H-pyrazole-1-yl)pyrimidine-2-yl)oxy)piperidine-1-yl)phenyl)piperazine-1-yl)-6-oxohexyl)pyrrolidine-2-carboxamide (LCG-II-22) [ka] The preparation method for LCG-II-3 in Example 67 was referenced for synthesis. 1H NMR(600 MHz,DMSO-d6)δ 8.99(s,1H),8.60(d,J=2.6 Hz,1H),8.46(d,J=8.3 Hz,1H),7.82(s,1H),7.78(d,J=7.8 Hz,1H),7.43(d,J=8.2 Hz,2H),7.39-7.34(m,3H),7.26(dd,J=9.2,2.5 Hz,1H),7.21(d,J=7.5 Hz,1H),7.06(d,J=2.7 Hz,1H),6.88(d,J=23.2 Hz,5H),5.22-5.08(m,2H),4.81(q,J=8.2 Hz,1H),4.58(d,J=9.3 Hz,1H),4.50(t,J=8.2 Hz,1H),4.29(s,1H),3.78-3.62(m,8H),3.58(dd,J=17.4,6.8 Hz,6H),3.44-3.37(m,2H),2.99-2.85(m,5H),2.46(s,3H),2.39(s,3H),2.33(t,J=7.5 Hz,2H),2.12(s,2H),2.09-2.00(m,1H),1.87-1.64(m,5H),1.57-1.42(m,3H),1.41-1.31(m,3H),1.22(dd,J=8.3,2.5 Hz,2H),0.97(s,9H). 13 C NMR(150 MHz,DMSO-d6)δ 170.58,170.43,168.60,167.95,167.82,164.71,163.39,158.05,153.49,151.37,147.65,143.73,137.85,131.84,131.00,129.62,129.24,128.69,128.55,126.74,126.20,122.99,117.37,105.84,81.98,78.83,77.28,71.92,68.72,65.72,64.81,58.58,56.54,56.45,51.83,49.99,49.54,47.41,45.64,44.19,40.85,37.62,36.11,36.02,32.13,30.39,26.22,26.12,25.37,24.42,20.95,15.95,15.92,15.07,12.90,12.84,12.62,12.55,8.53.HRMS(ESI)C 64 H 79 FN12 O7S[M+H] + The calculated value is 1179.5977, and the measured value is 1179.5983.

[0182] Example 87: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)-3-((4'-(2-((4-morpholino-6-(3-(m-tolyl)-1H-pyrazole-1-yl)pyrimidine-2-yl)oxy)ethyl)-[1,1'-biphenyl]-4-yl)amino)-3-oxopropyl)pyrrolidine-2-carboxamide (LCG-II-23) [ka] The preparation method for LCG-II-6 in Example 70 was referenced for synthesis. 1H NMR(600 MHz,DMSO-d6)δ 10.01(s,1H),8.98(s,1H),8.64(d,J=7.9 Hz,1H),8.58(d,J=2.7 Hz,1H),7.82(s,1H),7.77(d,J=7.7 Hz,1H),7.62(d,J=8.7 Hz,2H),7.57(d,J=8.3 Hz,4H),7.44(s,4H),7.39(d,J=8.1 Hz,2H),7.35(t,J=7.6 Hz,1H),7.26(dd,J=9.3,2.8 Hz,1H),7.21(d,J=7.5 Hz,1H),7.05(d,J=2.7 Hz,1H),6.90(s,1H),5.36-5.23(m,1H),5.15(d,J=3.6 Hz,1H),4.59(d,J=9.3 Hz,1H),4.55(t,J=6.9 Hz,2H),4.49(t,J=8.3 Hz,1H),4.29(brs,1H),3.73-3.65(m,8H),3.64-3.54(m,2H),3.08(t,J=6.8 Hz,2H),2.98-2.77(m,2H),2.44(s,3H),2.38(s,3H),2.05(dd,J=12.2,7.9 Hz,1H),1.81-1.73(m,1H),1.42-1.30(m,2H),1.25-1.18(m,2H),0.98(s,9H). 13 C NMR(150 MHz,DMSO-d6)δ 170.47,168.74,168.01,167.98,167.84,164.60,163.96,158.02,153.49,151.43,147.72,142.01,138.17,137.85,137.72,137.01,134.67,131.84,130.91,129.95,129.36,129.23,128.63,128.54,127.02,126.56,126.20,126.14,122.99,119.58,105.84,82.07,78.80,77.26,68.69,66.98,65.70,58.70,56.51,56.47,49.73,44.19,42.64,37.56,35.97,34.16,26.18,26.13,20.95,15.91,12.91,12.84,12.62,12.55.HRMS(ESI)C 60 H 65 FN10 O7S[M+H] + The calculated value is 1089.4820, and the measured value is 1089.4816.

[0183] Example 88: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)-4-((4'-(2-((4-morpholino-6-(3-(m-tolyl)-1H-pyrazole-1-yl)pyrimidine-2-yl)oxy)ethyl)-[1,1'-biphenyl]-4-yl)amino)-4-oxobutyl)pyrrolidine-2-carboxamide (LCG-II-24) [ka] The preparation method for LCG-II-6 in Example 70 was referenced for synthesis. 1 H NMR(600 MHz,DMSO-d6)δ 9.93(s,1H),8.99(s,1H),8.63-8.57(m,2H),7.82(s,1H),7.77(d,J=7.7 Hz,1H),7.67(d,J=8.5 Hz,2H),7.58(d,J=8.2 Hz,4H),7.47(d,J=8.3 Hz,2H),7.44-7.37(m,4H),7.35(t,J=7.6 Hz,1H),7.28(dd,J=9.2,2.8 Hz,1H),7.21(d,J=7.5 Hz,1H),7.05(d,J=2.7 Hz,1H),6.90(s,1H),5.16(d,J=3.5 Hz,1H),4.89(q,J=8.1 Hz,1H),4.59(d,J=9.2 Hz,1H),4.55(t,J=6.9 Hz,2H),4.51(t,J=8.3 Hz,1H),4.29(brs,1H),3.74-3.66(m,8H),3.64-3.56(m,2H),3.09(t,J=6.8 Hz,2H),2.47(s,3H),2.45-2.40(m,1H),2.38(s,3H),2.09-2.01(m,3H) ,1.82-1.73(m,1H),1.41-1.32(m,2H),1.27-1.18(m,2H),0.97(s,9H). 13C NMR(150 MHz,DMSO-d6)δ 170.76,170.71,168.75,168.01,167.87,164.60,163.96,158.03,153.50,151.42,147.71,143.09,138.49,137.85,137. 76,136.96,134.38,131.84,130.97,129.85,129.36,129.24,129.22,128.78,128.54,126.81,126.55,126.20,126.12,1 22.99,119.31,119.27,105.84,82.08,78.80,77.26,68.71,67.00,65.70,64.81,58.69,56.59,56.57,56.52,51.87,45. 64,44.19,37.66,35.95,34.16,33.19,31.93,26.21,26.12,20.95,15.92,15.07,12.91,12.84,12.64,12.57.HRMS(ESI)C 61 H 67 FN 10 O7S[M+H] + The calculated value is 1103.4977, and the measured value is 1103.4977.

[0184] Example 89: 2-(2,6-dioxopiperidine-3-yl)-5-fluoro-6-(4-(4-((4-morpholino-6-(3-(m-tolyl)-1H-pyrazole-1-yl)pyrimidine-2-yl)oxy)piperidine-1-yl)phenyl)piperazine-1-yl)isoindoline-1,3-dione (LCG-II-25) [ka] Intermediate ii-14 was obtained by referring to the preparation method of ii-4 above. ii-14 (68 mg, 0.1 mmol) was dissolved in 10 mL of dichloromethane, and 4 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 2 hours, spin-dried, and then redissolved in 10 mL of DMF. 2-(2,6-dioxo-piperidine-3-yl)-5,6-difluoro-isoindole-1,3-dione (60 mg, 0.2 mmol) and DIPEA (129 mg, 1.0 mmol) were added. The mixture was reacted at 100°C for 4 hours. After monitoring the completion of the reaction by TLC, 20 mL of water was added, and the mixture was extracted twice with EA. The organic phases were combined, washed once with saturated brine, dried over anhydrous Na2SO4, filtered, spin-dried, and then separated by column chromatography to obtain 30 mg of yellow solid (35%). 1 H NMR(600 MHz,DMSO-d6)δ 11.12(s,1H),8.60(d,J=2.7 Hz,1H),7.82(s,1H),7.77(t,J=10.0 Hz,2H),7.52(d,J=7.4 Hz,1H),7.35(t,J=7.6 Hz,1H),7.21(d,J=7.5 Hz,2H),7.06(d,J=2.7 Hz,1H),6.94-6.91(m,4H),6.90(s,1H),5.16-5.07(m,2H),3.74-3.64(m,8H),3.45-3.36(m,6H),3.22-3.13(m,3H),2.96(t,J=9.5 Hz,2H),2.91-2.85(m,1H),2.64-2.57(m,1H),2.58-2.51(m,1H),2.39(s,3H),2.14-2.12(m,2H),2.08-2.01(m,1H),1.88-1.78(m,2H). 13C NMR(150 MHz,DMSO-d6)δ 172.14,169.28,166.02,165.56,164.20,162.89,161.68,157.66,157.54,155.98,152.97,144 .72,144.66,144.44,143.65,137.34,131.33,128.72,128.15,128.13,128.03,125.68,123.06, 122.99,122.47,116.95,116.61,113.24,111.45,111.28,105.33,81.46,71.43,65.21,64.29,4 9.01,48.99,48.79,48.45,46.94,43.68,35.16,30.33,29.90,21.45,20.44,14.55.HRMS(ESI)C 46 H 47 FN 10 O6[M+H] + The calculated value is 855.3742, and the measured value is 855.3737.

[0185] Example 90: 2-(2,6-dioxopiperidine-3-yl)-5-fluoro-6-(4-((4-(2-((4-morpholino-6-(3-(m-tolyl)-1H-pyrazole-1-yl)pyrimidine-2-yl)oxy)ethyl)phenyl)ethynyl)piperidine-1-yl)isoindoline-1,3-dione (LCG-II-26) [ka] The preparation method for LCG-II-25 in Example 89 was referenced for synthesis. 1H NMR(600 MHz, DMSO-d6)δ 11.11(s,1H),8.57(d,J=2.7 Hz,1H),7.81(s,1H),7.77(d,J=7.7 Hz,1H),7.72(d,J=11.3 Hz,1H),7.49(d,J=7.4 Hz,1H),7.37(d,J=8.2 Hz,2H),7.34(d,J=7.6 Hz,1H),7.31(d,J=8.3 Hz,2H),7.21(d,J=7.5 Hz,1H),7.05(d,J=2.7 Hz,1H),6.89(s,1H),5.11(dd,J=12.9,5.4 Hz,1H),4.52(t,J=6.8 Hz,2H),3.72-3.63(m,8H),3.52-3.46(m,2H),3.15(t,J=9.4 Hz,2H),3.06(t,J=6.8 Hz,2H),2.95-2.84(m,2H),2.63-2.57(m,1H),2.56-2.51(m,1H),2.38(s,3H),2.09-1.93(m,3H),1.82-1.70(m,2H). 13 C NMR(150 MHz,DMSO-d6)δ 172.13,169.28,166.03,165.58,164.06,163.39,157.53,157.48,155.86,152.97,145.07,145.0 1,137.95,137.33,131.31,130.75,128.72,128.69,128.54,128.16,128.15,128.03,125.68,122 .61,122.54,122.47,120.26,113.28,111.41,111.24,105.32,91.56,81.57,80.95,66.17,65.18 ,64.29,48.42,47.90,47.88,43.66,33.84,30.59,30.33,25.84,21.45,20.43,14.55.HRMS(ESI)C 46 H 43 FN8O6[M+H] + The calculated value is 823.3368 and the measured value is 823.3368.

[0186] Example 91: 2-(2,6-dioxopiperidine-3-yl)-5-fluoro-6-(4-((4-(4-(2-((4-morpholino-6-(3-(m-tolyl)-1H-pyrazole-1-yl)pyrimidine-2-yl)oxy)ethyl)phenyl)piperazine-1-yl)methyl)piperidine-1-yl)isoindoline-1,3-dione (LCG-II-27) [ka] The preparation method for LCG-II-25 in Example 89 was referenced for synthesis. 1 H NMR(600 MHz,DMSO-d6)δ 11.11(s,1H),8.57(d,J=2.7 Hz,1H),7.81(s,1H),7.77(d,J=7.7 Hz,1H),7.70(d,J=11.4 Hz,1H),7.43(d,J=7.3 Hz,1H),7.35(t,J=7.6 Hz,1H),7.21(d,J=7.5 Hz,1H),7.16(d,J=8.3 Hz,2H),7.05(d,J=2.7 Hz,1H),6.89(t,J=4.3 Hz,3H),5.10(dd,J=12.9,5.4 Hz,1H),4.45(t,J=7.1 Hz,2H),3.74-3.64(m,8H),3.61(d,J=12.1 Hz,2H),3.09(s,4H),2.95(t,J=7.1 Hz,2H),2.92-2.85(m,3H),2.62-2.52(m,3H),2.48-2.45(m,1H),2.38(s,3H),2.23(d,J=7.2 Hz,2H),2.05-2.01(m,1H),1.84(d,J=12.0 Hz,2H),1.79-1.72(m,1H),1.27(q,J=11.3 Hz,2H). 13C NMR(150 MHz,DMSO-d6)δ 172.14,169.30,166.09,165.60,164.08,163.46,161.68,157.50,157.46,155.79,152.96,149.07,145 .30,145.24,137.33,131.32,128.77,128.72,128.66,128.18,128.03,127.69,125.68,122.47,122.20 ,122.14,114.92,113.06,113.03,111.35,111.18,105.31,81.50,66.83,65.19,64.29,63.17,52.58,4 9.34,49.31,48.41,47.92,43.67,35.16,33.18,31.63,30.33,29.65,21.46,20.44,14.55.HRMS(ESI)C 49 H 53 FN 10 O6[M+H] + The calculated value is 897.4212, and the measured value is 897.4210.

[0187] Example 92: 1-(1-(2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxoisoindorin-5-yl)piperidine-4-yl)-3-(4-(4-((4-morpholino-6-(3-(m-tolyl)-1H-pyrazole-1-yl)pyrimidine-2-yl)oxy)piperidine-1-yl)phenyl)urea (LCG-II-28) [ka] The preparation method for LCG-II-25 in Example 89 was referenced for synthesis. 1H NMR(600 MHz, DMSO-d6)δ 11.11(s,1H),8.60(d,J=2.7 Hz,1H),8.10(s,1H),7.82(s,1H),7.78(d,J=7.7 Hz,1H),7.72(d,J=11.3 Hz,1H),7.48(d,J=7.4 Hz,1H),7.35(t,J=7.6 Hz,1H),7.25(d,J=8.5 Hz,2H),7.21(d,J=7.6 Hz,1H),7.06(d,J=2.7 Hz,1H),6.90(s,2H),6.88(s,1H),6.11(d,J=7.6 Hz,1H),5.16-5.05(m,2H),3.75-3.67(m,9H),3.55(d,J=12.9 Hz,2H),3.48-3.41(m,2H),3.07-3.00(m,2H),2.97(t,J=10.3 Hz,2H),2.89(ddd,J=17.0,13.9,5.5 Hz,1H),2.63-2.58(m,1H),2.57-2.51(m,1H),2.39(s,3H),2.16-2.09(m,2H) ,2.07-2.00(m,1H),2.01-1.93(m,2H),1.87-1.78(m,2H),1.61-1.50(m,2H). 13 C NMR(150 MHz,DMSO-d6)δ 172.14,169.30,166.06,165.59,165.57,164.19,162.88,157.53,155.85,154.16,152.97,145 .30,145.02,144.97,137.34,132.08,131.33,128.72,128.16,128.14,128.03,125.69,122.54, 122.48,118.41,116.32,113.29,113.26,111.39,111.22,105.32,81.46,71.43,65.21,64.30,4 8.43,48.19,48.16,46.74,45.13,43.68,31.40,30.34,29.85,21.46,20.44,14.55.HRMS(ESI)C 48 H 50 FN 11 O7[M+H] + The calculated value is 912.3957 and the measured value is 912.3955.

[0188] Example 93: 1-(1-(2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)azetidine-3-yl)-3-(4-(4-((4-morpholino-6-(3-(m-tolyl)-1H-pyrazole-1-yl)pyrimidine-2-yl)oxy)piperidine-1-yl)phenyl)urea (LCG-II-29) [ka] The preparation method for LCG-II-25 in Example 89 was referenced for synthesis. 1 H NMR(600 MHz,DMSO-d6)δ 11.09(s,1H),8.60(d,J=2.7 Hz,1H),8.32(s,1H),7.82(s,1H),7.78(d,J=7.7 Hz,1H),7.62(d,J=11.1 Hz,1H),7.35(t,J=7.6 Hz,1H),7.25(d,J=8.5 Hz,2H),7.21(d,J=7.5 Hz,1H),7.06(d,J=2.7 Hz,1H),6.97(d,J=7.6 Hz,1H),6.92-6.86(m,3H),6.74(d,J=7.4 Hz,1H),5.16-5.09(m,1H),5.08(dd,J=12.9,5.4 Hz,1H),4.68-4.57(m,1H),4.44(t,J=7.1 Hz,2H),4.01(t,J=7.1 Hz,2H),3.78-3.64(m,8H),3.49-3.41(m,2H),2.97(t,J=9.7 Hz,2H),2.88(ddd,J=17.1,13.9,5.5 Hz,1H),2.65-2.51(m,2H),2.39(s,3H),2.19-2.08(m,2H),2.07-1.97(m,1H),1.89-1.75(m,2H). 13C NMR(150 MHz,DMSO-d6)δ 172.15,169.37,166.19,165.79,165.78,164.19,162.87,157.53,154.18,153.92,152.9 7,152.28,145.57,143.38,143.29,137.33,131.58,131.33,128.72,128.69,128.03,125 .69,122.47,118.91,118.15,118.09,116.20,110.74,110.60,107.83,107.78,105.32,8 1.45,71.41,65.21,60.19,48.32,46.64,43.67,30.34,29.82,21.53,20.44.HRMS(ESI)C 46 H 46 FN 11 O7[M+H] + The calculated value is 884.3644, and the measured value is 884.3643.

[0189] Example 94: 2-(2,6-dioxopiperidine-3-yl)-5-fluoro-6-(4-(1-(4-((4-morpholino-6-(3-(m-tolyl)-1H-pyrazole-1-yl)pyrimidine-2-yl)oxy)phenyl)piperidine-4-yl)piperazine-1-yl)isoindoline-1,3-dione (LCG-II-30) [ka] The preparation method for LCG-II-25 in Example 89 was referenced for synthesis. 1H NMR(600 MHz, DMSO-d6)δ 11.11(s,1H),8.33(d,J=2.7 Hz,1H),7.81(s,1H),7.77(s,1H),7.73(d,J=11.3 Hz,1H),7.45(d,J=7.3 Hz,1H),7.35(t,J=7.6 Hz,1H),7.21(d,J=7.5 Hz,1H),7.12-7.06(m,2H),7.04(d,J=2.7 Hz,1H),6.98(d,J=9.2 Hz,2H),6.95(s,1H),5.11(dd,J=12.9,5.4 Hz,1H),3.72(d,J=11.6 Hz,2H),3.66(t,J=4.8 Hz,4H),3.59(t,J=4.8 Hz,4H),3.26(s,4H),2.93-2.83(m,1H),2.74-2.52(m,8H),2.49-2.39(m,1H),2.38(s,3H),2.12-2.01(m,1H),1.90(d,J=11.9 Hz,2H),1.65-1.51(m,2H). 13 C NMR(150 MHz,DMSO-d6)δ 172.14,169.28,166.04,165.58,164.11,163.69,157.55,157.50,155.87,153.11,147 .68,144.79,144.74,144.34,137.35,131.22,128.79,128.44,128.16,128.04,125.68 ,122.73,122.67,122.49,121.26,115.75,112.97,111.39,111.22,105.45,82.31,65. 10,60.11,49.30,48.44,48.00,47.90,43.64,30.33,27.09,21.45,20.43.HRMS(ESI)C 46 H 47 FN 10 O6[M+H] + The calculated value is 885.3722 and the measured value is 885.3736.

[0190] Example 95: 2-(2,6-dioxopiperidine-3-yl)-5-fluoro-6-(4-(4-((4-morpholino-6-(3-(m-tolyl)-1H-pyrazole-1-yl)pyrimidine-2-yl)oxy)piperidine-1-yl)benzyl)piperazine-1-yl)isoindoline-1,3-dione (LCG-II-31) [ka] The preparation method for LCG-II-25 in Example 89 was referenced for synthesis. 1 H NMR(600 MHz,DMSO-d6)δ 11.11(s,1H),8.60(d,J=2.7 Hz,1H),7.82(d,J=1.8 Hz,1H),7.78(d,J=7.8 Hz,1H),7.71(d,J=11.3 Hz,1H),7.44(d,J=7.3 Hz,1H),7.35(t,J=7.6 Hz,1H),7.21(d,J=7.6 Hz,1H),7.17(d,J=8.2 Hz,2H),7.06(d,J=2.7 Hz,1H),6.95(d,J=8.2 Hz,2H),6.90(s,1H),5.17-5.13(m,1H),5.11(dd,J=12.9,5.4 Hz,1H),3.74-3.62(m,8H),3.57-3.49(m,2H),3.43(s,2H),3.23(s,4H),3.10-2.99(m,2H),2.94-2. 83(m,1H),2.65-2.53(m,4H),2.39(s,3H),2.24-2.08(m,2H),2.08-1.98(m,1H),1.86-1.75(m,2H). 13C NMR(150 MHz,DMSO-d6)δ 172.14,169.28,166.04,165.57,164.20,162.87,161.68,157.54,155.85,152.98,149.39,144.79,1 44.74,137.34,131.33,129.22,128.73,128.71,128.13,128.03,127.08,125.69,122.74,122.68,12 2.48,115.06,113.06,113.03,111.38,111.21,105.32,81.48,71.42,65.22,64.30,60.89,51.54,48 .96,48.92,48.44,45.79,43.68,30.34,29.66,27.87,21.87,21.45,20.44,14.56,10.64.HRMS(ESI)C 47 H 49 FN 10 O6[M+H] + The calculated value is 869.3899, and the measured value is 869.3886.

[0191] Example 96: 2-(2,6-dioxopiperidine-3-yl)-5-fluoro-6-(4-((4-((4-morpholino-6-(3-(m-tolyl)-1H-pyrazole-1-yl)pyrimidine-2-yl)oxy)phenyl)piperazine-1-yl)methyl)piperidine-1-yl)isoindoline-1,3-dione (LCG-II-32) [ka] The preparation method for LCG-II-25 in Example 89 was referenced for synthesis. 1H NMR(600 MHz, DMSO-d6)δ 11.11(s,1H),8.33(d,J=2.7 Hz,1H),7.81(s,1H),7.77(d,J=7.7 Hz,1H),7.70(d,J=11.3 Hz,1H),7.44(d,J=7.3 Hz,1H),7.35(t,J=7.6 Hz,1H),7.24-7.19(m,1H),7.09(d,J=8.9 Hz,2H),7.04(d,J=2.7 Hz,1H),6.97(d,J=9.1 Hz,2H),6.95(s,1H),5.11(dd,J=12.9,5.4 Hz,1H),3.72-3.52(m,10H),3.14(s,4H),2.97-2.82(m,3H),2.65-2.52(m,5H),2.38(s,3H),2.25(d,J=7.1 Hz,2H),2.08-1.99(m,1H),1.85(d,J=11.8 Hz,2H),1.79(d,J=3.8 Hz,1H),1.29(q,J=11.0 Hz,2H). 13 C NMR(150 MHz,DMSO-d6)δ 172.14,169.30,166.09,165.60,164.11,163.67,157.50,157.47,155.79,153.11,147.68,145.3 0,145.24,144.51,137.35,131.22,128.79,128.45,128.19,128.17,128.04,125.69,122.49,122. 21,122.15,121.27,115.25,113.08,113.05,111.35,111.19,105.45,82.31,65.10,64.29,63.16 ,52.58,49.35,49.31,48.41,48.09,43.64,31.65,30.33,29.65,21.46,20.43,14.55.HRMS(ESI)C 47 H 49 FN 10 O6[M+H] + The calculated value is 869.3899 and the measured value is 869.3887.

[0192] Example 97: Decomposition of compound によるVCaP and びDU145 tumor cell PIKfyve タンパクsubstance Method: 5×10 6200 μL of cells at a density of cells / ml were inoculated into a 6-well plate, and then different concentrations of drugs were added. The cells were treated at 37°C for 24 hours. The supernatant was collected and washed twice with PBS. Then, 100-200 μL of 1×SDS lysate was added, and the cell lysates were collected in a centrifuge tube. The cells were sonicated for 10-20 seconds and boiled for 10 minutes. Protein samples were subjected to SDS-PAGE electrophoresis at 90 V, transferred to a PVDF membrane at 110 V, blocked with 5% BSA for 4 hours, incubated overnight with primary antibody (PIKfyve, GAPDH) at 4°C, and incubated with secondary antibody (anti-rabbit IgG or anti-mouse IgG) at room temperature. The membrane was washed with TBST buffer, developed with ECL developer, and imaged to obtain protein band signals, and single-concentration WB results were obtained as shown in Figure 1. The concentration that achieved 50% degradation activity was DC compared to the DMSO control group. 50 Defined as follows. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16]

[0193] The results demonstrate that each compound of the present invention can achieve good PIKfyve proteolytic activity against VCaP and DU145 cells.

[0194] All documents described herein are incorporated by reference to this application, as are each of the documents incorporated by reference individually. Furthermore, after reading the above teachings of the present invention, it should be understood that various changes or modifications can be made to the invention, and these equivalent forms also fall within the scope defined by the claims appended to this application.

Claims

1. A compound represented by formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a prodrug molecule thereof, 【Chemistry 1】 During the ceremony, R 1 However, H, halogen, cyano, substituted or unsubstituted C 1 ~C 6 Alkyl, substituted, or unsubstituted C 3 ~C 6 Cycloalkyl and substituted or unsubstituted C 1 ~C 6 Selected from the group consisting of alkoxys, A is -NH-, 【Chemistry 2】 Selected from the group consisting of 6- to 10-membered aryl and 5- to 10-membered heteroaryl, wherein each A is independently, optionally, substituted with 0 to 3 R 2 and the R 2 is selected from the group consisting of H, halogen, substituted or unsubstituted C 1 to C 6 alkyl, substituted or unsubstituted C 3 to C 6 cycloalkyl, and substituted or unsubstituted C 1 to C 6 alkoxy The linker has a structure represented by the following formula, 【Transformation 3】 During the ceremony, W 1 , W 2 , W 3 , W 4 , and W 5 However, each is independent of -O-, -S-, -NH-, and -CH 2 -, -CONH-, -NHCO-, -C≡C-, -CH=CH-, -C(O)-, -P(=O)-, -S(O) 2 -, -S(O)-, -P(O) 2 Selected from the group consisting of (OH)-, -NH-S(O)-NH-, -C(O)O-, -OC(O)-, -NHCONH-, and 3- to 12-membered rings having 0 to 4 heteroatoms, n 1 , n 2 , n 3 , and n 4 However, each is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and the 3-12 membered rings can have the structure of a monocyclic ring, a spiroring, a fused ring, or a bridging ring. The E3 ligand is an E3 ubiquitin ligase ligand having a structure selected from the group consisting of the following: 【Chemistry 4】 In the formula, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 11 However, each is independent of H, halogen, cyano, substituted or unsubstituted C. 1 ~C 6 Alkyl, substituted, or unsubstituted C 3 ~C 6 Cycloalkyl, or substituted or unsubstituted C 1 ~C 6 Selected from the group consisting of alkoxys, R 10 but, 【Transformation 5】 Selected from the group consisting of each R 12 However, each independently, H, substituted or unsubstituted C 1 ~C 6 Alkyl, substituted, or unsubstituted C 3 ~C 6 Cycloalkyl and substituted or unsubstituted C 1 ~C 6 Selected from the group consisting of alkoxys, In the aforementioned "substituted or unsubstituted," "substituted" means that one or more H atoms on the group are halogen, deuterium, hydroxyl, cyano, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 aldehyde group, C1-C3 carboxyl, and -SF 5 The compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, meaning that it is substituted with a substituent selected from the group consisting of the above.

2. The E3 ligand has a structure selected from the group consisting of the following: 【Transformation 6】 In the formula, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 However, the compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, as defined in claim 1.

3. The linker has a structure represented by the following formula, 【Transformation 7】 During the ceremony, W 1 , W 2 , W 3 , W 4 , and W 5 However, each is independent of -O-, -S-, -NH-, and -CH 2 -, -CONH-, -NHCO-, -C(O)-, -C(O)O-, -OC(O)-, -NHCONH-, and a group consisting of 3 to 10 membered rings having 0 to 4 heteroatoms, n 1 , n 2 , n 3 , and n 4 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, wherein each is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

4. The linker has a structure selected from the group consisting of the following: 【Chemistry 8-1】 【Chemistry 8-2】 【Chemistry 8-3】 【Chemistry 8-4】 【Chemistry 8-5】 【Chemistry 8-6】 In the formula, X and Y are each independently -O-, -S-, -NH-, and -CH 2 -, and 【Chemistry 9】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, selected from the group consisting of the following, wherein each of n and m is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

5. The aforementioned A is -NH-, 【Chemistry 10】 A is selected from the group consisting of, and each A is independently and arbitrarily selected to have 0 to 2 R 2 It is replaced by the R 2 However, the compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, as defined in claim 1.

6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, selected from the group consisting of the following. 【Chemistry 11-1】 【Chemistry 11-2】 【Chemistry 11-3】 【Chemistry 11-4】 【Chemistry 11-5】 【Chemistry 11-6】 【Chemistry 11-7】 【Chemistry 11-8】 【Chemistry 11-9】 【Chemistry 11-10】 【Chemistry 11-11】 [Chemistry 11-12] [Chemistry 11-13] [Chemistry 11-14] [Chemistry 11-15] 【Chemistry 11-16】 [Chemistry 11-17] [Chemistry 11-18] [Chemistry 11-19] [Chemistry 11-20] 【Chemistry 11-21】 [Chemistry 11-22] [Chemistry 11-23] [Chemistry 11-24] [Chemistry 11-25] [Chemistry 11-26] [Chemistry 11-27] [Chemistry 11-28]

7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, selected from the group consisting of the following. 【Chemistry 12-1】 【Chemistry 12-2】 【Chemistry 12-3】 【Chemistry 12-4】 【Chemistry 12-5】 【Chemistry 12-6】 【Chemistry 12-7】 【Chemistry 12-8】 【Chemistry 12-9】 【Chemistry 12-10】 【Chemistry 12-11】 【Chemistry 12-12】

8. A pharmaceutical composition for treating and / or preventing tumors, (1) A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof The pharmaceutical composition comprising, optionally, (2) a pharmaceutically acceptable carrier.

9. Use of a compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a prodrug molecule thereof, or a pharmaceutical composition according to claim 8, for the treatment and / or prevention of a disease or disorder associated with the abnormal expression of PIKfyve, wherein the disease or disorder is preferably selected from the group consisting of tumors, autoimmune diseases, viral infections, and neurodegenerative diseases.

10. The use according to claim 9, wherein the disease or disorder is selected from the group consisting of hematological malignancies, gastrointestinal stromal tumors, histiocytic lymphomas, non-small cell lung cancers, small cell lung cancers, lung adenocarcinomas, lung squamous cell carcinomas, pancreatic cancers, breast cancers, prostate cancers, liver cancers, skin cancers, epithelial cell carcinomas, colorectal cancers, kidney cancers, gastric cancers, head and neck cancers, and nasopharyngeal cancers.

11. A non-diagnostic and non-therapeutic method for degrading PIKfyve in a subject requiring degradation of PIKfyve, comprising administering to the subject a compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a prodrug molecule thereof, or a pharmaceutical composition according to claim 7.

12. The method according to claim 11, wherein the subject is a human being.

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