PIKfyve protein kinase degradation agent and application thereof

Abstract

The invention relates to a PIKfyve protein degradation agent and application thereof, and particularly provides a compound with a structure as shown in a formula (I) or pharmaceutically acceptable salt thereof, or a stereoisomer or a prodrug molecule thereof. The compound can degrade PIKfyve protein in a targeted manner through a ubiquitin-proteasome way, so that the compound can be used for treating indications mediated by abnormal expression of the PIKfyve protein.

Description

A type of PIKfyve protein kinase degrader and its use Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and in particular to a class of compounds targeting ubiquitination degradation of PIKfyve protein, as well as pharmaceutical compositions and applications thereof. Background Art

[0002] PIKfyve is a lipid kinase that catalyzes the phosphorylation of phosphatidylinositol-3-phosphate (PI(3)P) to generate phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2). PI(4,5)P2 plays a key role in the formation of endosomes and lysosomes. PIKfyve is one of the key enzymes in cell membrane homeostasis, intracellular trafficking, and the autophagy pathway. Studies have shown that inhibiting or silencing PIKfyve in a variety of tumor cells can effectively inhibit their autophagy pathway, leading to significant accumulation of the key autophagy protein LC3, causing cells to produce obvious vacuolar morphology, and thus inhibiting their proliferation. Currently, multiple PIKfyve inhibitors are widely used in the research of tumor treatment for leukemia, prostate cancer, lymphoma, and other tumors.

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

[0004] Targeted protein degradation technology is currently widely used in drug development and is considered a major breakthrough in the field of small molecule drugs. Among them, protein-targeted chimeric degradation (PROTAC) research is the most mature. The PROTAC molecular structure consists of three parts: a target protein recognition ligand, a linker, and a ubiquitination E3 ligase that recognizes the ligand. PROTAC can effectively induce ubiquitination of target proteins and effectively degrade them through the proteasome pathway. Compared with traditional small molecule inhibitors, PROTAC molecules have the advantages of small dosage, low resistance to drug resistance, and high safety. Currently, multiple PROTAC molecules have entered clinical research.

[0005] Summary of the Invention

[0006] The purpose of the present invention is to provide a compound capable of degrading PIKfyve protein through ubiquitin-proteasome pathway and a pharmaceutical composition thereof.

[0007] In the first aspect of the present invention, there is provided a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer or prodrug molecule thereof,

[0008] in,

[0009] R1 is selected from the group consisting of H, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy;

[0010] A is selected from the group consisting of: -NH-, 6-10 membered aryl, 5-10 membered heteroaryl; each of the A's is independently optionally substituted by 0-3 R2, wherein the R2 is selected from the following group: H, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy;

[0011] Linker has the following structure:

[0012] Wherein, W1, W2, W3, W4, and W5 are each independently selected from the following group: -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-, a 3-12 membered ring having 0-4 heteroatoms; n1, n2, n3, and n4 are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; wherein the 3-12 membered ring may be a monocyclic, spirocyclic, fused ring, or bridged ring structure;

[0013] E3Ligand is a ubiquitination E3 ligase ligand having a structure selected from the following group:

[0014] Among them, R3, R4, R5, R6, R7, R8, R9, R 11 Each is independently selected from the following group: H, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy;

[0015] R 10 Select from the following groups: Among them, each R 12 Each is independently selected from the following group: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy;

[0016] The substitution in the substituted or unsubstituted group refers to that one or more H atoms on the group are replaced by a substituent selected from the group consisting of halogen, deuterium atom, hydroxyl, cyano, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 aldehyde, C1-C3 carboxyl, and -SF5.

[0017] In some embodiments, the E3Ligand has a structure selected from the group consisting of:

[0018] Among them, R3, R4, R5, R6, R7, R8, R9, R 10 、R 11 The definition is as stated in claim 1.

[0019] In some embodiments, R1 is a C1-C6 alkyl group.

[0020] In some embodiments, R1 is methyl.

[0021] In some embodiments, A is

[0022] In some embodiments, the linker has a structure as shown below:

[0023] Wherein, W1, W2, W3, W4, and W5 are each independently selected from the following groups: -O-, -S-, -NH-, -CH2-, -CONH-, -NHCO-, -C(O)-, -C(O)O-, -OC(O)-, -NHCONH-, and a 3-10 membered ring with 0-4 heteroatoms; n1, n2, n3, and n4 are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0024] In some embodiments, the linker has a structure selected from the following group:

[0025] wherein each X and Y are independently selected from the group consisting of: -O-, -S-, -NH-, -CH2-, Each n and m is each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0026] In some embodiments, the linker is:

[0027] wherein 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.

[0028] In some embodiments, the A is selected from the following groups: -NH-, Each of the A's is independently optionally substituted by 0-2 R2's, and the definition of R2 is as described in claim 1.

[0029] In some embodiments, the compound is selected from the group consisting of:

[0030] In another preferred embodiment, the compound is selected from the following group:

[0031] In a second aspect of the present invention, a pharmaceutical composition for treating and / or preventing tumors is provided, comprising:

[0032] (1) The compound according to the first aspect of the present invention, its pharmaceutically acceptable salt, its stereoisomer or its prodrug molecule;

[0033] Optional (2) a pharmaceutically acceptable carrier.

[0034] In the third aspect of the present invention, a use of the compound as described in the first aspect of the present invention, its pharmaceutically acceptable salt, its stereoisomer or its prodrug molecule, or the pharmaceutical composition as described in the second aspect of the present invention is provided, characterized in that it is used to prepare a method for treating and / or preventing diseases or conditions related to abnormal PIKfyve expression.

[0035] In another preferred embodiment, the disease or condition is selected from the following group: tumor, autoimmune disease, viral infection, neurodegenerative disease.

[0036] In some embodiments, the disease or condition is selected from the group consisting of hematologic malignancies, gastrointestinal stromal tumors, histiocytic lymphoma, non-small cell lung cancer, small cell 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, or nasopharyngeal cancer.

[0037] In the fourth aspect of the present invention, a non-diagnostic and non-therapeutic method for degrading PIKfyve in a subject in need is provided, characterized in that the compound as described in the first aspect of the present invention, its pharmaceutically acceptable salt, its stereoisomer or its prodrug molecule, or the pharmaceutical composition as described in the second aspect of the present invention is administered to the subject.

[0038] In another preferred embodiment, the subject is a human.

[0039] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 shows the results of PIKfyve protein level detection in VCaP cells. DETAILED DESCRIPTION

[0041] After extensive and in-depth research, the inventors have developed a class of compounds capable of targeted ubiquitination and degradation of the PIKfyve protein, and pharmaceutical compositions thereof. These compounds can efficiently and selectively degrade PIKfyve protein in cells, and therefore have potential uses in treating conditions associated with abnormal PIKfyve protein expression. Based on these findings, the inventors completed the present invention.

[0042] the term

[0043] In the compounds described herein, when any variable (e.g., R1, R2, etc.) occurs more than once in any component, its definition at each occurrence is independent of its definition at every other occurrence. Likewise, combinations of substituents and variables are permitted so long as such combinations result in a stable compound. A line drawn from a substituent into the ring system indicates that the indicated bond may be attached to any substitutable ring atom. If the ring system is polycyclic, this means that such bonds are attached only to any suitable carbon atom of the adjacent ring. It will be understood that one of ordinary skill in the art can select the substituents and substitution patterns of the compounds of the present invention to provide chemically stable compounds that can be readily synthesized from readily available raw materials using techniques in the art and the methods set forth below. If a substituent is itself substituted with more than one group, it will be understood that these groups may be on the same carbon atom or on different carbon atoms so long as the structure is stable.

[0044] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. The terms used in the description are for the purpose of describing particular embodiments only and are not intended to limit the invention.

[0045] The following terms are used to describe the present invention. Where a term is not specifically defined herein, it is given the art-recognized meaning by those of ordinary skill in the art in applying the term in the context of its use to describe the present invention.

[0046] As used herein, the term "ubiquitin ligase" refers to a family of proteins that promote the transfer of ubiquitin to a specific substrate protein, thereby targeting the substrate protein for degradation. For example, Von Hippel-Lindau E3 ubiquitin ligase or CRBN E3 ubiquitin ligase is a protein that, alone or in combination with an E2 ubiquitin conjugating enzyme, results in the attachment of ubiquitin to a lysine on a target protein, and subsequently targets a specific protein substrate for degradation by the proteasome. Thus, an E3 ubiquitin ligase, alone or in combination with an E2 ubiquitin conjugating enzyme, is responsible for the transfer of ubiquitin to a target protein. In general, the ubiquitin ligase participates in polyubiquitination, whereby a second ubiquitin is attached to a first ubiquitin; a third ubiquitin is attached to a second ubiquitin, and so on. Polyubiquitination marks a protein for degradation by the proteasome. However, there are some ubiquitination events that are limited to monoubiquitination, in which only a single ubiquitin is added to a substrate molecule by a ubiquitin ligase. Monoubiquitinated proteins are not targeted to the proteasome for degradation, but instead can be altered in their cellular location or function, for example, by binding to other proteins with domains capable of binding ubiquitin. Further complicating the situation is that different lysines on ubiquitin can be targeted by E3 to form chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to make polyubiquitin that is recognized by the proteasome.

[0047] As used herein, the term "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms. For example, the definition of "C1-C6 alkyl" includes groups having 1, 2, 3, 4, 5, or 6 carbon atoms in a straight or branched chain. For example, "C1-C6 alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, and hexyl.

[0048] The term "cycloalkyl" as used herein refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic hydrocarbon group whose ring atoms are composed of carbon atoms, and the bicyclic or polycyclic rings include spirocyclic, fused rings and bridged rings. For example, "cycloalkyl" includes but is not limited to the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wait.

[0049] The term "alkoxy" used herein refers to a group having an -O-alkyl structure, such as -OCH3, -OCH2CH3, -OCH2CH2CH3, -O-CH2CH(CH3)2, -OCH2CH2CH2CH3, -O-CH(CH3)2, etc.

[0050] As used herein, the term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic cyclic substituent, wherein one or more ring atoms are selected from N, O or S(O)m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon, and the bicyclic or polycyclic rings include spirocyclic, fused and bridged rings. For example: morpholinyl, piperidinyl, tetrahydropyrrolyl, pyrrolidinyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothiophenyl, dihydrotriazolyl, dihydroazetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, etc., and N-oxides thereof. Attachment of the heterocyclic substituents can be achieved via a carbon atom or via a heteroatom.

[0051] In this application, unless otherwise specified, the term "ring" or "cyclic structure" is intended to include various forms of cyclic groups, including but not limited to: a saturated ring, a partially unsaturated but non-aromatic ring, or an aromatic ring (such as an aryl or heteroaryl group); in particular, the ring may be a monocyclic ring, or a polycyclic ring formed by multiple monocyclic rings, such as an aromatic or non-aromatic fused bicyclic ring, or a bridged or spirocyclic structure. Unless otherwise specified, the "ring" is intended to include (but not limited to) a cyclic structure selected from the following group: an aromatic ring (including a monocyclic or polycyclic ring such as a bicyclic ring), a heteroaromatic ring (including a monocyclic or polycyclic ring such as a bicyclic ring), a saturated or partially unsaturated carbocyclic ring (including a monocyclic or polycyclic ring such as a paracyclic, bridged or spirocyclic structure), and a saturated or partially unsaturated heterocyclic ring (including a monocyclic or polycyclic ring such as a paracyclic, bridged or spirocyclic structure).

[0052] As used herein, the term "aryl" refers to an aromatic ring group having a specific number of carbon atoms, such as C6-C 10 The aryl group represents an aromatic ring group having 6 to 10 carbon atoms, for example, a phenyl group, a naphthyl group or the like.

[0053] As used herein, the term "heteroaryl" refers to a cyclic aromatic group having a specific number of atoms, wherein 1-3 atoms are heteroatoms selected from N, S and O. For example, a 5-12 membered heteroaryl group represents an aromatic ring group having 5-12 carbon atoms. It can be a monocyclic ring or a condensed ring. Specific examples include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2,4)-triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, and the like.

[0054] Unless otherwise specified as "substituted or unsubstituted", the groups of the present invention may be substituted by substituents selected from the following groups: halogen, nitrile, nitro, hydroxyl, amino, C1-C6 alkyl-amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, halogenated C1-C6 alkoxy, allyl, benzyl, C6-C 12 Aryl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy-carbonyl, phenoxycarbonyl, C2-C6 alkynyl-carbonyl, C2-C6 alkenyl-carbonyl, C3-C6 carbocyclyl-carbonyl, C1-C6 alkyl-sulfonyl, etc.

[0055] As will be understood by those skilled in the art, "halogen" or "halo" as used herein refers to chlorine, fluorine, bromine and iodine.

[0056] As used herein, the term "subject" refers to a mammal. For example, mammals encompassed by the present invention include humans, primates, and domesticated animals, such as cattle, sheep, pigs, horses, mice, rats, and humans.

[0057] The present disclosure also includes isotopically labeled compounds, which are identical to the compounds described in formula (I), except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Suitable isotopes for inclusion in the compounds of the present disclosure include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, but not limited to, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 31 P, 35 S, 18 F and 36 Cl. Using heavier isotopes such as deuterium (i.e. 2 H) substitution may offer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some cases. Positron-emitting isotopes may be added to the compounds for use in medical imaging and positron emission tomography (PET) studies to determine receptor distribution. Suitable positron-emitting isotopes that may be added to the compounds of formula (I) include 11 C, 13 N, 15 O, and 18 F. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically labeled reagent in place of a non-isotopically labeled reagent.

[0058] The compounds disclosed herein may be present in a pharmaceutically acceptable solvent, such as water, ethanol, or the like, in dissolved or undissolved form. 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 another embodiment, the compound is a crystalline form.

[0059] Pharmaceutically acceptable salts

[0060] The present invention encompasses the free forms of the compounds of Formula I, as well as their pharmaceutically acceptable salts and stereoisomers. Certain specific exemplary compounds described herein are protonated salts of amine compounds. The term "free form" refers to the amine compounds in their non-salt form. Pharmaceutically acceptable salts encompassed include not only the exemplary salts of the specific compounds described herein, but also all typical pharmaceutically acceptable salts of the free forms of the compounds of Formula I. The free forms of specific salts of the compounds described can be isolated using techniques known in the art. For example, the free forms can be regenerated by treating the salts with a dilute aqueous base solution, such as dilute aqueous NaOH, dilute aqueous potassium carbonate, dilute aqueous ammonia, and dilute aqueous sodium bicarbonate. The free forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of the present invention, such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms.

[0061] Pharmaceutically acceptable salts of the present invention can be synthesized from compounds of the present invention containing a basic or acidic moiety by conventional chemical methods. Typically, salts of basic compounds are prepared by ion exchange chromatography or by reacting a free base with a stoichiometric amount or an excess of an inorganic or organic acid in the desired salt form in a suitable solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reaction with a suitable inorganic or organic base.

[0062] Therefore, pharmaceutically acceptable salts of the compounds of this invention include conventional non-toxic salts of the compounds of this invention formed by reacting an alkaline compound of this invention with an inorganic or organic acid. For example, conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, and also include salts derived 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, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, and the like.

[0063] If the compound of the present invention is acidic, suitable "pharmaceutically acceptable salts" refer to salts prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, ferric salts, ferrous salts, lithium salts, magnesium salts, manganic salts, manganous salts, potassium salts, sodium salts, zinc salts, and the like. Ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic bases, including salts of primary, secondary and tertiary amines, substituted amines including 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, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxocobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, guaiac, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0064] Berg et al., "Pharmaceutical Salts," J. Pharm. Sci. '1977: 66: 1-19, describes in more detail the preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts.

[0065] Drug metabolites and prodrugs

[0066] The metabolites of the compounds involved in the present invention and their pharmaceutically acceptable salts, as well as prodrugs that can be converted into the structures of the compounds involved in the present application and their pharmaceutically acceptable salts in vivo, are also included in the claims of the present invention. As used herein, the term "protodrug" refers to a compound that, when metabolized (such as in vivo or in vitro), produces an active compound. In certain embodiments, the protodrug may be inactive or less active than the free drug, but may provide advantageous handling, administration or metabolic properties. The exemplary protodrug molecules of the present invention may be connected to the free drug via the hydroxyl, amino, phosphate or thiophosphate backbone of the nucleotide, and may include esters, carbamates, carbonyls, thioesters, amides, isocyanates, ureas, thioureas or other physiologically acceptable metabolically variable molecules. In certain embodiments, the protodrug is activated by enzymatic hydrolysis.

[0067] Pharmaceutical composition and use thereof

[0068] The present invention also provides a pharmaceutical composition comprising an active ingredient in a safe and effective amount, and a pharmaceutically acceptable carrier or excipient. Because the active ingredient, the compound of Formula I and its pharmaceutically acceptable salts, exhibits a potent inhibitory effect on abnormal expression of the PIKfyve protein, the pharmaceutical composition can be used to treat cancers, autoimmune diseases, viral infections, neurodegenerative diseases, and other conditions associated with abnormal PIKfyve protein expression in humans or other mammals.

[0069] The present invention provides a class of protein kinase degraders and their uses. Specifically, the present invention provides a compound having the structure represented by Formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer or prodrug molecule thereof. The compound is capable of degrading the PIKfyve protein via ubiquitination and can be used to treat indications related to abnormal PIKfyve expression.

[0070] In one embodiment, the active ingredient of the present 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, leukemia, etc., or to prevent tumor recurrence after surgery.

[0071] The "active ingredient" described in the present invention refers to the compound of formula I described in the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof.

[0072] The "active ingredient" and pharmaceutical composition described in the present invention can be used as a PIKfyve protein degrader and can be used to prepare drugs for preventing and / or treating cancer, autoimmune diseases, viral infections, neurodegenerative diseases, etc.

[0073] A "safe and effective amount" refers to an amount of the active ingredient sufficient to significantly improve the condition without causing serious side effects. Typically, a pharmaceutical composition contains 1-2000 mg of active ingredient per dose, more preferably 10-200 mg per dose. Preferably, "one dose" is one tablet.

[0074] "Pharmaceutically acceptable carrier or excipient" refers to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must be sufficiently pure and have sufficiently low toxicity.

[0075] "Compatibility" herein means that the components of the composition can be mixed with the active ingredient of the present invention and with each other without significantly reducing the efficacy of the active ingredient.

[0076] Examples of pharmaceutically acceptable carriers or excipients include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0077] In another preferred embodiment, the compound of formula I of the present invention can form a complex with a macromolecular compound or polymer through non-bonding interaction. In another preferred embodiment, the compound of formula I of the present invention, as a small molecule, can also be linked to a macromolecular compound or polymer through a chemical bond. The macromolecular compound can be a biological macromolecule such as a polysaccharide, protein, nucleic acid, polypeptide, etc.

[0078] There is no particular limitation on the administration of the active ingredient or pharmaceutical composition of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and the like.

[0079] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.

[0080] In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with:

[0081] (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid;

[0082] (b) binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic;

[0083] (c) humectants, for example, glycerin;

[0084] (d) disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate;

[0085] (e) buffering solvents, such as paraffin;

[0086] (f) absorption accelerators, for example, quaternary ammonium compounds;

[0087] (g) wetting agents, such as cetyl alcohol and glyceryl monostearate;

[0088] (h) adsorbents, for example, kaolin; and

[0089] (i) Lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain a buffering agent.

[0090] The solid dosage forms can also be prepared using coatings and shells, such as enteric coatings and other materials known in the art. They can contain opacifying agents, and the release of the active ingredient in such compositions can be delayed in a certain portion of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes.

[0091] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. 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, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures thereof. In addition to these inert diluents, the composition may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0092] In addition to the active ingredients, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0093] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0094] The compounds of the present invention may be administered alone or in combination with other therapeutic agents.

[0095] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0096] Combination therapy

[0097] Compounds of Formula I may be used in combination with other drugs known to treat or ameliorate similar conditions. When administered in combination, the original drug's route of administration and dosage remain unchanged, while the compound of Formula I is administered simultaneously or subsequently. When a compound of Formula I is administered concurrently with one or more other drugs, a pharmaceutical composition containing one or more known drugs and a compound of Formula I is preferably used. Combination therapy also includes administering a compound of Formula I and one or more other known drugs during overlapping time periods. When a compound of Formula I is administered in combination with one or more other drugs, the dosage of the compound of Formula I or the known drug may be lower than when administered alone.

[0098] The drugs or active ingredients that can be used in combination with the compounds of formula I include, but are not limited to, estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxins / cytostatics, 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, Bc r-Abl inhibitors, 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, interferon-, interleukin-12, COX-2 inhibitors, p53, p53 activators, VEGF antibodies, EGF antibodies, JAK inhibitors, etc.

[0099] In one embodiment, the drugs or active ingredients that can be used in combination with the compound of formula I include but are not limited to: aldesleukin, alendronic acid, interferon, atrexin, allopurinol, allopurinol sodium, palonosetron hydrochloride, hexamethylmelamine, aminoglutethimide, amifostine, amrubicin, anacrine, anastrozole, dolasetron, aranesp, arglabin, arsenic trioxide, arnosine, 5-azacytidine, azathioprine, BCG or tice BCG, betadine, betamethasone acetate, betamethasone sodium phosphate preparation, bexarotene, bleomycin sulfate, bromourea, bortezomib, busulfan, calcitonin, alezotocin injection, capecitabine, carboplatin, casodex, cefone , cisplatin, cladribine, cladribine, clodronate, cyclophosphamide, cytarabine, dacarbazine, actinomycin D, liposomal daunorubicin, dexamethasone, dexamethasone phosphate, estradiol valerate, denileukin-2, depomet, deslorelin, delazoxane, diethylstilbestrol, diflucan, docetaxel, doxifluridine, doxorubicin, dronabinol, chin-166-chitosan complex, eligard, rasburicase, epirubicin hydrochloride, aprepitant, epirubicin, epoetin alfa, erythropoietin, epoetin, levamisole tablets, estradiol preparations, 17-beta-estradiol, estramustine sodium phosphate, ethinyl estradiol, amifostine, hydroxyphosphatase, fenbifostine, etoposide, fadrozoles, tamoxifen Oxifen preparations, filgrastim, finasteride, firaprestin, floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil, fluoxymesterone, flutamide, formestane, 1-β-D-arabinofuranosylcytosine-5'-stearoyl phosphate, fotemustine, fulvestrant, immunoglobulin G, gemcitabine, gemtuzumab tuzumab, imatinib mesylate, carmustine rice paper capsules, goserelin, granisetron hydrochloride, histrelin, holmesin, hydrocortisone, erythro-hydroxynonyl adenine, hydroxyurea, tentanamib, idarubicin, ifosfamide, interferon α, interferon-α2, interferon α-2A, interferon α-2B, interferon α-nl, interferon α-n3, interferon β , interferon gamma-la, interleukin-2, intron A, Iressa, irinotecan, Kateri, lentinan sulfate, letrozole, leucovorin, leuprorelin acetate, levomizole, levofolinate calcium salt, levothyroxine sodium, levothyroxine sodium preparations, lomustine, lonidamine, dronabinol, nitrogen mustard, methylcobalamin, medroxyprogesterone acetate, megestrol acetate, melphalan, esterified estrogen, 6-mercaptopurine, mesna, methotrexate, methyl aminolevulinate, miltefosine, minocycline, mitomycin C, mitotane, mitoxantrone, trilostane, liposomal doxorubicin citrate, nedaplatin, pegfilgrastim, oprelleukin, neupogen, nilutamide, tamoxifen,NSC-631570, recombinant human interleukin-1-beta, octreotide, ondansetron hydrochloride, prednisone oral solution, oxaliplatin, paclitaxel, prednisone sodium phosphate, pegaspargase, PEGASYS, pentostatin, streptozotocin, pilocarpine hydrochloride, pirarubicin, plicamycin, porfimer sodium, prednimustine, stiprenisolone, prednisone, premarin, procarbazine, recombinant human erythropoietin, raltitrexed, rebifurcation, rhenium-186 etidronate, rituximab, dapoxetine-A, romostatide, pilocarpine hydrochloride tablets, octreotide, sarmustine, semustine, sizolan, sobuzosine, methylprednisolone sodium, paphos acid, stem cell therapy, streptozocin, strontium-89 chloride, levothyroxine sodium, tamoxifen Fen, tamsulosin, tasofenamin, tastolactone, taxotere, tesifuzine, temozolomide, teniposide, testosterone propionate, methyltestosterone, thioguanine, thiotepa, thyroid-stimulating hormone, tiludronic acid, topotecan, toremifene, tositumomab, trastuzumab, treosulfan, tretinoin, methotrexate tablets, trimethylmelamine, trimetrexate, triptorelin acetate, triptorelin pamoate, eufotaxime, uridine, valrubicin, veslanone, vinblastine, vincristine, vinsamide, vinorelbine, virulizine, dextromethorphan, statins, zofran, paclitaxel protein-stabilized formulation, acolbifene, interferon r-lb, affinitak, aminopterin, arzoxifene, as oprisnil, atamestane, atrasentan, BAY43-9006, Avastin, CCI-779, CDC-501, Celebrex, cetuximab, crisentan, cyproterone acetate, decitabine, DN-101, doxorubicin-MTC, dSLIM, dutasteride, edotecarin, eflornithine, exitecan, fenretinide, histamine dihydrochloride, histrelin hydrogel implant, holmium-166DOTMP, ibandronic acid, interferon gamma, intron-PEG, ixabepilone, keyhole limpet hemocyanin, L-651582, lanreotide, lasofoxifene, libra, lonafamib, miproxifene, minodecan, MS-2 09. Liposomal MTP-PE, MX-6, nafarelin, nemorubicin, nevastatin, noratriptide, oblimersen, onco-TCS, osidem, paclitaxel polyglutamate, sodium pyrimidine, PN-401, QS-21, quasitan, R-1549, raloxifene, ranpirnase, 13-cis retinoic acid, satraplatin, ciocalcitol, T-138067, tarceva, paclitaxel docosahexaenoic acid, thymosin α1, gazofurin, tipifarnib, tirapazamine, TLK-286, toremifene, trans-MID-107R, valspodar, vapreotide, vatalanib, verteporfin, vinflunine, Z-100, and zoledronic acid, or a combination thereof.

[0100] In some embodiments, the compounds described herein are administered in combination with other treatment modalities, including surgery, radiotherapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), chemotherapy, immunotherapy, cryotherapy, and / or hyperthermia. Such combination therapy can reduce the dose of the drug and / or other agents, thereby avoiding toxicities or complications that may occur with various therapies.

[0101] Treatment

[0102] As described above, the compounds disclosed herein are PIKfyve protein degraders, and thus the compounds or compositions comprising the compounds herein can be used to treat, prevent, and alleviate diseases associated with PIKfyve activity or abnormal expression. In some embodiments, disclosed herein are uses of the compounds disclosed herein in the preparation of medicaments for preventing and / or treating diseases mediated by PIKfyve proteins. In some embodiments, the compounds disclosed herein are used to prevent and / or treat diseases mediated by PIKfyve proteins. In some embodiments, disclosed herein are methods for treating diseases mediated by PIKfyve proteins in subjects in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein (e.g., a compound of formula (I)) or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound of formula (I)). In some embodiments, the disease mediated by PIKfyve proteins is a tumor, an autoimmune disease, a viral infection, or a neurodegenerative disease. In some embodiments, the disease mediated by the PIKfyve protein is a tumor selected from the group consisting of hematological tumors, gastrointestinal stromal tumors, histiocytic lymphomas, 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 cancer, colorectal cancer, kidney cancer, gastric cancer, head and neck cancer or nasopharyngeal cancer, etc.

[0103] The main advantages of the present invention are:

[0104] Provided is a PROTAC compound with a novel structure, which can efficiently and selectively degrade PIKfyve protein in cells, effectively inhibit the growth of various tumor cells, and can be used to prepare anti-tumor drugs.

[0105] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. The experimental methods in the following examples, for which specific conditions are not specified, were generally performed under conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0106] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0107] The starting materials in the following examples can be obtained from commercial sources, or prepared by methods known in the art, or prepared according to the methods described herein.

[0108] The structures of the compounds were confirmed by nuclear magnetic resonance (1H-NMR) and / or mass spectrometry (MS). NMR measurements were performed using a Bruker AV-400 or AV-500 NMR instrument, using deuterated chloroform (CDCl3) or deuterated dimethyl sulfoxide (DMSO-D6) as the solvent, and TMS as the internal standard. MS measurements were performed using an LCQAD-40000 mass spectrometer. Column chromatography was performed using 200-300 mesh silica gel (produced by Qingdao Ocean Chemical Plant).

[0109] Example

[0110] Example 1: (E)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)acetamide (LCG-1)

[0111] Step 1: Preparation of 4-(2,6-dichloropyrimidin-4-yl)morpholine (2)

[0112] Morpholine (0.9 g, 10.9 mmol) was dissolved in 25 mL of 50% aqueous ethanol and stirred at -20°C. 2,4,6-trichloropyrimidine (1.0 g, 5.5 mmol) was dissolved in 10 mL of 50% aqueous ethanol and added dropwise to the morpholine-ethanol solution. The temperature was maintained at -20°C for 2 hours, then adjusted to 10°C and allowed to react for 1 hour. After completion of the reaction as monitored by TLC, 80 mL of water was added to precipitate a white solid, which was filtered and dried. Column chromatography yielded 0.8 g (62%) of a white solid. 1 H 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] + .

[0113] Step 2: Preparation of tert-butyl (4-(2-((4-chloro-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)carbamate (3)

[0114] NaH (0.15 g, 6.4 mmol) was added to 40 mL of DMF and stirred at -20°C. Subsequently, tert-butyl (4-(2-hydroxyethyl)phenyl)carbamate (1.0 g, 4.3 mmol) was dissolved in 5 mL of DMF and slowly added. After 10 minutes, a DMF solution of 4-(2,6-dichloropyrimidin-4-yl)morpholine (2) (1.0 g, 4.3 mmol) was added, and the temperature was maintained for 12 hours. After TLC monitoring, 100 mL of water was added to precipitate a distinct white solid, which was filtered, washed with water, dried, and recrystallized using PE / EA = 1:1 to obtain intermediate 3 (1.1 g, 60%). 1 H NMR (500MHz, CDCl3) δ7.28(d,J=8.2Hz,2H),7.19(d,J=8.2Hz,2H),6.43(s,1H),6.15(s,1H),4.42(t,J=7. 4Hz,2H),3.86–3.68(m,4H),3.59(brs,4H),3.03(t,J=7.4Hz,2H),1.51(s,9H).MS(ESI),m / z:435.3[M+H] + .

[0115] Step 3: Preparation of tert-butyl (4-(2-((4-hydrazino-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)carbamate (4)

[0116] 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 with stirring for 24 h. After TLC monitoring, the reaction was complete. A white solid was obtained by rotary evaporation under reduced pressure. The solid was washed with 50 mL of water and dried to obtain white intermediate 4 (1.8 g, 93%). 1 H NMR (400MHz, DMSO-d6) δ9.27(s,1H),7.67(s,1H),7.37(d,J=8.2Hz,2H),7.14(d,J=8.2Hz,2H),5.61(s,1H),4.63(brs,3H) ,4.25(t,J=7.1Hz,2H),3.68–3.59(m,4H),3.43–3.36(m,4H),2.86(t,J=7.1Hz,2H),1.46(s,9H).MS(ESI),m / z:431.4[M+H] + .

[0117] Step 4: Preparation of tert-butyl (E)-(4-(2-((4-(-2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)carbamate (5)

[0118] Intermediate 4 (1.7 g, 3.9 mmol) and 3-methylbenzaldehyde (0.7 g, 0.6 mmol) were dissolved in 30 mL of ethanol, and 10 drops of acetic acid were added. The mixture was refluxed for 4 h, and the reaction was complete after TLC monitoring. Rotary evaporation under reduced pressure afforded a white solid, which was resuspended in 50 mL of a 1:1 PE / DCM solution and filtered to afford white Intermediate 5 (1.7 g, 84%). 1 H NMR (400MHz, DMSO-d6) δ10.87(s,1H),9.26(s,1H),7.99(s,1H),7.50(d,J= 8.1Hz,2H),7.37(d,J=8.1Hz,2H),7.29(t,J=7.5Hz,1H),7.20–7.10(m,3H) ,6.06(s,1H),4.32(t,J=7.0Hz,2H),3.74–3.62(m,4H),3.57–3.50(m,4H), 2.90(t,J=7.0Hz,2H),2.34(s,3H),1.47(s,9H).MS(ESI),m / z:533.1[M+H] + .

[0119] Step 5: Preparation of (E)-4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)aniline (6)

[0120] Intermediate 5 (100 mg, 0.2 mmol) was added to 10 mL of a 25% TFA solution in DCM and stirred at room temperature for 4 h. The reaction was monitored for completion by TLC. The oil was evaporated under reduced pressure and dissolved in DCM. The product was backwashed twice with saturated NaHCO₃ solution and dried to afford Intermediate 6 (65 mg, 81%). 1 H NMR (500MHz, DMSO-d6) δ10.83(s,1H),7.97(s,1H),7.48(d,J=7.8Hz,1H),7.45(s ,1H),7.27(t,J=7.6Hz,1H),7.15(d,J=7.6Hz,1H),6.91(d,J=8.2Hz,2H),6.48(d, J=8.2Hz,2H),6.04(s,1H),4.86(s,2H),4.23(t,J=7.3Hz,2H),3.70–3.62(m,4H) ,3.55–3.48(m,4H),2.77(t,J=7.3Hz,2H),2.32(s,3H).MS(ESI),m / z:433.3[M+H] + .

[0121] Step 6: Preparation of (E)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-N-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)acetamide (LCG-1)

[0122] In a 25 mL eggplant flask, intermediate 5 (50 mg, 0.1 mmol) and 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid (7) (40 mg, 0.1 mmol) were dissolved in 10 mL of DMF. HATU (70 mg, 0.2 mmol) was added, followed by triethylamine (40 mg, 0.3 mmol). The mixture was stirred at room temperature for 5 h. After quenching the reaction with water, the mixture was extracted with EtOAc, backwashed with saturated brine, dried over Na2SO4, filtered, and then purified by flash column chromatography (DCM / MeOH) to give 42 mg (42%) of the product as a white solid. 1H NMR(600MHz,DMSO-d6)δ11.13(s,1H),10.85(s,1H),10.05(s,1H),7.99(s,1H),7.86–7.79( m,1H),7.55(d,J=8.4Hz,2H),7.53–7.45(m,4H),7.32–7.25(m,3H),7.17(d,J=7.5Hz,1H),6. 06(s,1H),5.14(dd,J=12.8,5.4Hz,1H),5.00(s,2H),4.35(t,J=7.0Hz,2H),3.71–3.63(m,4 H),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). 13 C NMR(150MHz,DMSO-d6)δ173.27,170.39,167.23,166.06,165.97,164.84,164.4 3,163.99,155.66,141.69,138.40,137.45,136.92,135.23,134.48,133.54,13 0.24,129.81,129.08,127.49,124.02,120.97,119.86,117.24,116.57,76.14, 68.10,66.94,66.38,49.32,44.69,34.75,31.43,22.47,21.41.HRMS(ESI)calcd for C 39 H 38 N8O8[M+H] + 747.2891, found 747.2870.

[0123] Example 2: (E)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)butanamide (LCG-2)

[0124] The synthesis method is the same as Example 1.

[0125] 1H NMR (600MHz, DMSO-d6) δ11.12(s,1H),10.86(s,1H),9.93(s,1H),8.00(s,1H),7.81(dd,J=8.3,7.5Hz,1H),7.54(t,J= 8.1Hz,3H),7.50(d,J=7.9Hz,1H),7.48(s,1H),7.46(d,J=7.2Hz,1H),7.29(t,J=7.6Hz,1H),7.21(d,J=8.5Hz,2H),7. 17(d,J=7.5Hz,1H),6.07(s,1H),5.09(dd,J=12.9,5.5Hz,1H),4.34(t,J=7.0Hz,2H),4.28(t,J=6.2Hz,2H),3.71–3.6 5(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(150MHz,DMSO-d6)δ173.28,170.82,170.44,167.32,165.83,164.85,164.44,1 63.99,156.35,141.69,138.39,137.98,137.55,135.24,133.72,133.52,130.23,1 29.56,129.07,127.48,124.02,120.28,119.66,116.76,115.75,76.13,68.70,67. 01,66.38,49.22,44.68,34.74,32.72,31.43,24.76,22.49,21.40.HRMS(ESI)calcd for C 41 H 42 N8O8[M+H] + 775.3204, found 775.3197.

[0126] Example 3: (E)-6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)hexanamide (LCG-3)

[0127] The synthesis method is the same as Example 1.

[0128] 1H NMR(600MHz,DMSO-d6)δ11.11(s,1H),10.87(brs,1H),9.84(s,1H),8.00(s,1H),7.80(dd,J=8.4,7.3Hz,1H),7.55–7.4 7(m,5H),7.44(d,J=7.2Hz,1H),7.29(t,J=7.5Hz,1H),7.20(d,J=8.5Hz,2H),7.17(d,J=7.5Hz,1H),6.06(s,1H),5.08(d d,J=12.9,5.5Hz,1H),4.35(t,J=7.0Hz,2H),4.21(t,J=6.4Hz,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(150MHz,DMSO-d6)δ173.27,171.46,170.44,167.32,165.79,156.46,13 8.39,138.07,137.49,135.21,133.71,133.42,130.26,129.54,129.07,127. 51,124.05,120.24,119.61,116.68,115.61,76.11,69.15,66.37,49.21,44. 70,36.82,34.73,31.44,28.72,25.51,25.34,22.48,21.41.HRMS(ESI)calcd for C 43 H 46 N8O8[M+H] + 803.3517, found 803.3509.

[0129] Example 4: (E)-8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)octanamide (LCG-4)

[0130] The synthesis method is the same as Example 1.

[0131] 1H NMR(600MHz,DMSO-d6)δ11.11(s,1H),10.85(s,1H),9.80(s,1H),7.99(s,1H),7.80(dd,J=8.4,7.4Hz,1H),7.53–7.47(m,5H),7 .43(d,J=7.2Hz,1H),7.29(t,J=7.6Hz,1H),7.20(d,J=8.5Hz,2H),7.17(d,J=7.6Hz,1H),6.07(s,1H),5.08(dd,J=12.8,5.5Hz,1 H),4.34(t,J=7.0Hz,2H),4.20(t,J=6.4Hz,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=7.4Hz,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). 13 C NMR(150MHz,DMSO-d6)δ170.95,169.25,168.13,165.02,163.48,162.53,162.12,161.67, 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)calcd for C 45 H 50 N8O8[M+H] + 831.3830, found 831.3828.

[0132] Example 5: (E)-10-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)decanamide (LCG-5)

[0133] The synthesis method is the same as Example 1.

[0134] 1 H NMR (600MHz, DMSO-d6) δ11.10(brs,1H),10.86(s,1H),9.80(s,1H),7.99(s,1H),7.79(dd,J=8.4,7.4Hz,1H),7.54–7.47( m,5H),7.43(d,J=7.2Hz,1H),7.29(t,J=7.6Hz,1H),7.20(d,J=8.5Hz,2H),7.17(d,J=7.5Hz,1H),6.07(s,1H),5.08(dd,J =12.9,5.5Hz,1H),4.34(t,J=7.0Hz,2H),4.18(t,J=6.4Hz,2H),3.70–3. 64(m,4H),3.56–3.51(m,4H),2.93(t,J=7.1Hz,2H),2.91–2.84(m,1H),2. 64–2.53(m,2H),2.34(s,3H),2.28(t,J=7.4Hz,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(150MHz,DMSO-d6)δ173.26,171.58,170.44,167.33,165.78,164.84,164.44,163.99,156 .49,141.67,138.39,138.09,137.48,135.24,133.72,133.42,130.22,129.54,129.07,127.4 8,124.01,120.22,119.57,116.68,115.58,76.13,69.25,67.01,66.38,49.20,44.68,36.86, 34.75,31.43,29.35,29.22,29.14,29.13,28.90,25.73,25.63,22.48,21.40.HRMS(ESI)calcd for C 47 H 54 N8O8[M+H] + 859.4143, found 859.4142.

[0135] Example 6: (E)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-N-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)acetamide (LCG-6)

[0136] The synthesis method is the same as Example 1.

[0137] 1 H NMR(600MHz,DMSO-d6)δ11.12(s,1H),10.99(brs,1H),10.14(s,1H),8.02(s,1H),7.88(d,J =8.3Hz,1H),7.64–7.48(m,5H),7.44(d,J=8.2Hz,1H),7.35–7.23(m,3H),7.19(d,J=7.3Hz, 1H),6.03(s,1H),5.13(dd,J=12.9,5.3Hz,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(150MHz,DMSO-d6)δ173.25,170.38,167.30,167.20,166.02,163.73, 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)calcd for C 39 H 38 N8O8[M+H] + 747.2891, found 747.2875.

[0138] Example 7: (E)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-N-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)butanamide (LCG-7)

[0139] The synthesis method is the same as Example 1.

[0140] 1 H NMR (600MHz, DMSO-d6) δ11.11(s,1H),10.85(s,1H),9.91(s,1H),7.99(s,1H),7.83(d,J=8.3Hz,1H),7.52(d,J=8.5Hz,2H), 7.50(d,J=7.9Hz,1H),7.47(s,1H),7.44(d,J=2.2Hz,1H),7.35(dd,J=8.3,2.3Hz,1H),7.29(t,J=7.6Hz,1H),7.21(d,J=8.5H z,2H),7.17(d,J=7.5Hz,1H),6.06(s,1H),5.12(dd,J=12.9,5.4Hz,1H),4.34(t,J=7.1Hz,2H),4.24(t,J=6.4Hz,2H),3.71– 3.62(m,4H),3.57–3.49(m,4H),2.93(t,J=7.0Hz,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(150MHz,DMSO-d6)δ172.17,169.74,169.33,166.27,166.20,163.77,163.36 ,162.91,140.60,137.32,136.90,134.16,133.35,132.46,129.16,128.50,128.0 0,126.42,124.73,122.94,122.37,120.10,118.56,108.34,75.05,67.69,65.92 ,65.30,48.36,43.61,33.67,31.92,30.35,23.74,21.47,20.33.HRMS(ESI)calcd for C 41 H 42 N8O8[M+H] + 775.3204,found 775.3204.

[0141] Example 8: (E)-6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-N-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)hexanamide (LCG-8)

[0142] The synthesis method is the same as Example 1.

[0143] 1 H NMR (600MHz, DMSO-d6) δ11.11(s,1H),10.85(s,1H),9.82(s,1H),7.99(s,1H),7.82(d,J=8.3Hz,1H),7.54–7.48(m,3H),7.47(s,1H) ,7.42(d,J=2.2Hz,1H),7.34(dd,J=8.3,2.3Hz,1H),7.29(t,J=7.6Hz,1H),7.20(d,J=8.5Hz,2H),7.17(d,J=7.5Hz,1H),6.06(s,1H), 5.12(dd,J=12.9,5.4Hz,1H),4.33(t,J=7.0Hz,2H),4.18(t,J=6.5Hz,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). 13 C NMR (150MHz, DMSO-d6) δ172.16,170.35,169.32,166.28,166.21,163.76,163.47,163. 35,162.90,140.59,137.31,136.97,134.15,133.34,132.37,129.14,128.47,127.99, 126.40,124.68,122.93,122.26,120.12,118.50,108.22,75.04,68.09,65.92,65.29, 48.34,43.60,35.66,33.66,30.34,27.56,24.45,24.23,21.46,20.32.HRMS(ESI)calcd for C 43 H 46 N8O8[M+H] + 803.3517, found 803.3517.

[0144] Example 9: (E)-8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-N-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)octanamide (LCG-9)

[0145] The synthesis method is the same as Example 1.

[0146] 1 H NMR (600MHz, DMSO-d6) δ11.12(s,1H),10.87(s,1H),9.81(s,1H),8.00(s,1H),7.82(d,J=8.3Hz,1H),7.54–7.47(m,4H),7.42(d,J=2.2Hz, 1H),7.33(dd,J=8.3,2.3Hz,1H),7.29(t,J=7.6Hz,1H),7.20(d,J=8.5Hz,2H),7.17(d,J=7.5Hz,1H),6.06(s,1H),5.12(dd,J=12.9,5.4Hz ,1H),4.34(t,J=7.0Hz,2H),4.16(t,J=6.5Hz,2H),3.68–3.63(m,4H),3.55–3.50(m,4H),2.93(t,J=7.1Hz,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(150MHz,DMSO-d6)δ171.24,169.55,168.41,165.37,165.29,162.56,136.38, 136.08,133.21,132.41,131.40,128.24,127.54,127.06,125.49,123.75,122.03 ,121.31,119.17,117.58,107.28,74.11,67.24,64.37,47.42,44.19,42.69,34.8 1,32.73,29.43,27.06,26.93,26.80,23.71,23.55,20.55,19.40.HRMS(ESI)calcd for C 45 H 50 N8O8[M+H]+ 831.3830, found 831.3818.

[0147] Example 10: (E)-10-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-N-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)decanamide (LCG-10)

[0148] The synthesis method is the same as Example 1.

[0149] 1 H NMR (600MHz, DMSO-d6) δ11.11(s,1H),10.85(s,1H),9.80(s,1H),7.99(s,1H),7.82(d,J=8.3Hz,1H),7.55–7.45(m,4H),7.41(d,J=2. 0Hz,1H),7.33(dd,J=8.3,2.2Hz,1H),7.29(t,J=7.6Hz,1H),7.20(d,J=8.4Hz,2H),7.17(d,J=7.5Hz,1H),6.06(s,1H),5.12(dd,J=12 .9,5.4Hz,1H),4.33(t,J=7.0Hz,2H),4.15(t,J=6.5Hz,2H),3.68–3.63(m,4H),3.56–3.49(m,4H),2.95–2.84(m,3H),2.63–2.51(m,2 H),2.34(s,3H),2.28(t,J=7.4Hz,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(150MHz,DMSO-d6)δ173.24,171.56,170.41,167.37,167.29,164.84,164.57,164.43,163 .99,141.67,138.39,138.08,135.24,134.42,133.42,130.22,129.54,129.07,127.48,125.7 6,124.01,123.32,121.18,119.57,109.28,76.13,69.27,67.01,66.38,49.43,44.68,36.84, 34.74,31.43,29.34,29.21,29.14,29.13,28.84,25.81,25.62,22.55,21.41.HRMS(ESI)calcd for C 47 H 54 N8O8[M+H] + 859.4143, found 859.4140.

[0150] Example 11: (E)-2-((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)acetamide (LCG-11)

[0151] The synthesis method is the same as Example 1.

[0152] 1H NMR (600MHz, DMSO-d6) δ11.11(s,1H),10.86(s,1H),10.15(s,1H),7.99(s,1H),7.61(dd,J=8.4,7.2Hz,1H),7.53(d,J=8.5Hz,2H) ,7.50(d,J=7.6Hz,1H),7.48(s,1H),7.29(t,J=7.6Hz,1H),7.24(d,J=8.5Hz,2H),7.17(d,J=7.5Hz,1H),7.09(d,J=7.0Hz,1H),7.0 2(t,J=5.7Hz,1H),6.96(d,J=8.6Hz,1H),6.06(s,1H),5.09(dd,J=12.7,5.5Hz,1H),4.35(t,J=7.0Hz,2H),4.18(d,J=5.6Hz,2H), 3.69–3.64(m,4H),3.55–3.49(m,4H),2.94(t,J=6.8Hz,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(150MHz,DMSO-d6)δ172.20,169.45,168.14,166.72,166.70,163.71,163.29 ,162.85,145.34,140.63,137.30,136.35,135.61,134.12,132.92,131.45,129.1 5,128.62,127.98,126.41,122.93,118.65,117.00,110.41,109.20,75.02,65.89 ,65.73,65.28,47.97,44.99,43.60,33.63,30.37,21.54,20.31.HRMS(ESI)calcd for C 39 H 39 N9O7[M+H] + 746.3050,found 746.3040.

[0153] Example 12: (E)-4-((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)butanamide (LCG-12)

[0154] The synthesis method is the same as Example 1.

[0155] 1 H NMR (600MHz, DMSO-d6) δ11.10(s,1H),10.86(s,1H),9.89(s,1H),7.99(s,1H),7.59(dd,J=8.5,7.2Hz,1H),7.53–7.46(m,4H),7.2 9(t,J=7.6Hz,1H),7.21(d,J=8.5Hz,2H),7.17(d,J=7.5Hz,1H),7.15(d,J=8.6Hz,1H),7.03(d,J=7.0Hz,1H),6.67(t,J=6.0Hz,1H ),6.06(s,1H),5.05(dd,J=12.9,5.5Hz,1H),4.34(t,J=7.0Hz,2H),3.70–3.64(m,4H),3.56–3.51(m,4H),3.39–3.36(m,2H),2.93 (t,J=6.9Hz,2H),2.91–2.85(m,1H),2.62–2.51(m,2H),2.40(t,J=7.3Hz,2H),2.34(s,3H),2.05–1.99(m,1H),1.93–1.85(m,2H). 13 C NMR(150MHz,DMSO-d6)δ172.20,169.93,169.49,168.22,166.68,163.71,163.30,16 2.85,145.73,140.63,137.30,136.87,135.65,134.12,132.41,131.62,129.15,128. 46,127.98,126.41,122.93,118.58,116.56,109.81,108.50,75.02,65.93,65.73,65 .28,47.90,43.60,40.85,33.64,32.77,30.36,23.90,21.54,20.31.HRMS(ESI)calcd for C 41 H 43 N9O7[M+H] + 774.3363, found 774.3349.

[0156] Example 13: (E)-6-((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)hexanamide (LCG-13)

[0157] The synthesis method is the same as Example 1.

[0158] 1 H NMR(600MHz,DMSO-d6)δ11.09(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 =7.6Hz,1H),7.20(d,J=8.5Hz,2H),7.17(d,J=7.6Hz,1H),7.10(d,J=8.6Hz,1H),7.01(d,J=7.0Hz,1H),6.55(t,J=5.8Hz,1H), 6.06(s,1H),5.05(dd,J=12.9,5.4Hz,1H),4.33(t,J=7.0Hz,2H),3.72–3.63(m,4H),3.57–3.45(m,4H),3.32–3.27(m,2H),2.9 4–2.85(m,3H),2.64–2.51(m,2H),2.34(s,3H),2.30(t,J=7.4Hz,2H),2.05–1.99(m,1H),1.66–1.57(m,4H),1.42–1.35(m,2H). 13 C NMR(150MHz,DMSO-d6)δ172.19,170.35,169.49,168.32,166.68,163.75,163.34,162.89,16 1.68,145.79,140.58,137.30,136.96,135.65,134.14,132.35,131.57,129.14,128.45,127 .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)calcd for C 43 H 47 N9O7[M+H] + 802.3676, found 802.3673.

[0159] 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)

[0160] The synthesis method is the same as Example 1.

[0161] 1 H NMR (600MHz, DMSO-d6) δ11.09(s,1H),10.85(s,1H),9.80(s,1H),7.99(s,1H),7.57(t,J=7.7Hz,1H),7.54–7.44(m,4H ),7.29(t,J=7.5Hz,1H),7.24–7.14(m,3H),7.08(d,J=8.5Hz,1H),7.01(d,J=6.9Hz,1H),6.53(s,1H),6.06(s,1H),5.0 5(dd,J=12.7,5.2Hz,1H),4.33(t,J=6.7Hz,2H),3.68–3.63(m,4H),3.55–3.50(m,4H),3.31–3.24(m,2H),2.97–2.82( m,3H),2.64–2.52(m,2H),2.34(s,3H),2.28(t,J=7.0Hz,2H),2.06–1.99(m,1H),1.59–1.56(m,4H),1.42–1.26(m,6H). 13 C NMR(150MHz,DMSO-d6)δ173.28,171.55,170.58,169.43,167.78,164.84,164.44,163.99, 146.90,141.68,138.40,138.07,136.75,135.23,133.43,132.67,130.23,129.55,129.08 ,127.49,124.01,119.57,117.65,110.84,109.48,76.13,67.01,66.38,49.01,44.68,42. 28,36.81,34.74,31.45,29.13,29.11,29.00,26.69,25.56,22.62,21.41.HRMS(ESI)calcd for C 45 H 51 N9O7[M+H] + 830.3989,found 830.3979.

[0162] Example 15: (E)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-N-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)acetamide (LCG-15)

[0163] The synthesis method is the same as Example 1.

[0164] 1 H NMR (600MHz, DMSO-d6) δ11.06(s,1H),10.86(s,1H),10.11(s,1H),7.99(s,1H),7.61(d,J=8.3Hz,1H),7.53(d,J=8.5Hz,2H),7 .50(d,J=7.8Hz,1H),7.48(s,1H),7.43(t,J=5.6Hz,1H),7.29(t,J=7.6Hz,1H),7.24(d,J=8.5Hz,2H),7.17(d,J=7.5Hz,1H),7. 02(s,1H),6.92(d,J=7.9Hz,1H),6.06(s,1H),5.04(dd,J=12.8,5.4Hz,1H),4.34(t,J=7.0Hz,2H),4.09(d,J=5.3Hz,2H),3.70 –3.64(m,4H),3.55–3.50(m,4H),2.94(t,J=7.0Hz,2H),2.91–2.82(m,1H),2.62–2.51(m,2H),-2.34(s,3H),2.03–1.97(m,1H). 13 C NMR(150MHz,DMSO-d6)δ172.20,169.52,167.04,166.53,163.74,163.31,1 62.89,153.70,140.64,137.32,136.39,134.14,133.41,132.94,129.17,12 8.64,128.00,126.42,124.38,122.95,118.69,116.33,75.04,65.90,65.7 4,65.30,48.05,45.63,43.61,33.65,30.37,21.60,20.33.HRMS(ESI)calcd for C 39 H 39 N9O7[M+H] + 746.3050, found 746.3032.

[0165] Example 16: (E)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-N-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)butanamide (LCG-16)

[0166] The synthesis method is the same as Example 1.

[0167] 1 H NMR (600MHz, DMSO-d6) δ11.06(s,1H),10.87(s,1H),9.88(s,1H),7.99(s,1H),7.57(d,J=8.4Hz,1H),7.54–7.46(m,4 H),7.29(t,J=7.6Hz,1H),7.23–7.15(m,4H),6.97(d,J=1.8Hz,1H),6.87(dd,J=8.4,2.0Hz,1H),6.06(s,1H),5.03(dd ,J=12.8,5.5Hz,1H),4.34(t,J=6.9Hz,2H),3.69–3.63(m,4H),3.56–3.50(m,4H),3.25–3.19(m,2H),2.93(t,J=7.0Hz ,2H),2.91–2.83(m,1H),2.64–2.51(m,2H),2.43(t,J=7.4Hz,2H),2.34(s,3H),2.03–1.96(m,1H),1.92–1.84(m,2H). 13 C NMR(150MHz,DMSO-d6)δ172.19,169.96,169.55,167.06,166.52,163.67,163.24 ,162.81,153.78,140.68,137.30,136.89,134.10,133.61,132.39,129.16,128. 47,127.98,126.42,124.50,122.95,118.56,115.33,75.00,65.96,65.72,65.27 ,47.99,43.60,41.39,33.62,32.90,30.36,23.55,21.61,20.31.HRMS(ESI)calcd for C 41 H 43 N9O7[M+H] + 774.3363, found 774.3354.

[0168] Example 17: (E)-6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-N-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)hexanamide (LCG-17)

[0169] The synthesis method is the same as Example 1.

[0170] 1 H NMR (600MHz, DMSO-d6) δ11.05(s,1H),10.85(s,1H),9.81(s,1H),7.99(s,1H),7.55(d,J=8.4Hz,1H),7.53–7.45(m,4H),7.29(t,J= 7.6Hz,1H),7.20(d,J=8.5Hz,2H),7.17(d,J=7.5Hz,1H),7.12(t,J=5.4Hz,1H),6.94(s,1H),6.84(dd,J=8.4,1.9Hz,1H),6.06(s,1 H),5.02(dd,J=12.8,5.5Hz,1H),4.33(t,J=7.1Hz,2H),3.70–3.64(m,4H),3.55–3.49(m,4H),3.20–3.12(m,3H),2.94–2.90(m,2H) ,2.89–2.83(m,1H),2.63–2.52(m,2H),2.34(s,3H),2.30(t,J=7.3Hz,2H),2.02–1.96(m,1H),1.66–1.57(m,4H),1.44–1.37(m,2H). 13 C NMR(150MHz,DMSO-d6)δ172.19,170.36,169.56,167.08,166.53,163.75,163.34,16 2.89,153.83,140.58,137.30,136.96,134.13,133.59,132.36,129.14,128.45,127 .99,126.40,124.47,122.92,118.49,115.16,75.03,65.91,65.28,64.29,47.98,43 .59,41.75,35.70,33.64,30.36,27.44,25.61,24.30,21.61,20.32.HRMS(ESI)calcd for C 43 H 47 N9O7[M+H]+ 802.3676, found 802.3679.

[0171] Example 18: (E)-8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-N-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)octanamide (LCG-18)

[0172] The synthesis method is the same as Example 1.

[0173] 1 H NMR (600MHz, DMSO-d6) δ11.06(s,1H),10.85(s,1H),9.80(s,1H),7.99(s,1H),7.55(d,J=8.4Hz,1H),7.53–7.46(m,4H),7.29( t,J=7.6Hz,1H),7.20(d,J=8.5Hz,2H),7.17(d,J=7.5Hz,1H),7.09(t,J=5.3Hz,1H),6.94(s,1H),6.84(dd,J=8.4,1.9Hz,1H), 6.06(s,1H),5.03(dd,J=12.8,5.5Hz,1H),4.33(t,J=7.0Hz,2H),3.69–3.63(m,4H),3.55–3.50(m,4H),3.18–3.12(m,2H),2.9 4–2.84(m,3H),2.62–2.51(m,2H),2.34(s,3H),2.28(t,J=7.4Hz,2H),2.01–1.96(m,1H),1.62–1.54(m,4H),1.39–1.29(m,6H). 13C NMR(150MHz,DMSO-d6)δ173.29,171.55,170.66,168.18,167.63,164.84,164.44,163.9 9,154.94,141.68,138.40,138.07,135.23,134.68,133.43,130.23,129.55,129.08,12 7.49,125.57,124.01,119.57,116.24,76.13,67.00,66.38,65.39,49.08,44.68,42.93 ,36.82,34.74,31.46,29.13,29.05,28.69,26.91,25.59,22.71,21.41.HRMS(ESI)calcd for C 45 H 51 N9O7[M+H] + 830.3989,found 830.3985.

[0174] Example 19: (E)-10-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-N-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)decanamide (LCG-19)

[0175] The synthesis method is the same as Example 1.

[0176] 1H NMR (600MHz, DMSO-d6) δ11.06(s,1H),10.85(s,1H),9.79(s,1H),7.99(s,1H),7.55(d,J=8.4Hz,1H),7.53–7.46(m,4H),7.29(t,J=7 .6Hz,1H),7.20(d,J=8.5Hz,2H),7.17(d,J=7.5Hz,1H),7.09(t,J=5.3Hz,1H),6.93(s,1H),6.83(dd,J=8.4,1.8Hz,1H),6.06(s,1H) ,5.03(dd,J=12.8,5.5Hz,1H),4.33(t,J=7.0Hz,2H),3.71–3.62(m,4H),3.55–3.49(m,4H),3.19–3.10(m,2H),2.92(t,J=7.0Hz,2H) ,2.90–2.83(m,1H),2.62–2.51(m,2H),2.34(s,3H),2.27(t,J=7.4Hz,2H),2.03–1.95(m,1H),1.63–1.52(m,4H),1.40–1.22(m,10H). 13 C NMR(150MHz,DMSO-d6)δ172.71,170.98,170.08,167.60,167.05,164.25,163.84,163.40,154 .36,141.12,137.81,137.50,134.65,134.10,132.85,129.73,129.05,128.89,128.57,128.4 1,126.87,124.99,123.40,118.97,115.65,75.55,66.43,66.25,65.80,48.50,44.10,42.37, 36.26,34.16,30.88,28.81,28.67,28.56,28.13,26.42,25.04,22.13,20.83.HRMS(ESI)calcd for:C 47 H 55 N9O7[M+H] + 858.4302, found 858.4284.

[0177] Example 20: (E)-N 1 -(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-N 6-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)adipamide (LCG-20)

[0178] The synthesis method is the same as Example 1.

[0179] 1 H NMR(600MHz,DMSO-d6)δ11.02(s,1H),10.85(s,1H),9.84(s,1H),9.80(s,1H) ,7.99(s,1H),7.80(d,J=7.4Hz,1H),7.54–7.46(m,6H),7.29(t,J=7.6Hz,1H), 7.21(d,J=8.4Hz,2H),7.17(d,J=7.5Hz,1H),6.06(s,1H),5.14(dd,J=13.3,5.1Hz,1H),4.44–4.30(m,4H),3.72–3.64(m,4H ),3.52(t,J=8.7Hz,4H),2.96–2.87(m,3H),2.59(d,J=16.6Hz,1H),2.42–2.31(m,8H),2.06–1.97(m,1H),1.71–1.59(m,4H). 13 C NMR(150MHz,DMSO-d6)δ173.33,171.66,171.55,171.38,168.31,164.84,164.44,16 3.99,141.69,138.40,138.04,135.23,134.30,134.23,133.47,133.15,130.24,129. 57,129.09,127.49,125.82,124.02,119.58,119.52,76.13,67.00,66.38,51.99,46 .95,44.69,36.67,36.15,34.74,31.69,25.32,25.30,23.09,21.41.HRMS(ESI)calcd for C 43 H 47 N9O7[M+H] + 802.3676, found 802.3676.

[0180] Example 21: (E)-N 1 -(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-N 8-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)octanediamide (LCG-21)

[0181] The synthesis method is the same as Example 1.

[0182] 1 H NMR(600MHz,DMSO-d6)δ11.02(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=7.6Hz,1H),7.20(d,J=8.5Hz,2H),7.17(d,J=7.5Hz,1H),6.06(s,1H),5.14( dd,J=13.3,5.1Hz,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=7.4Hz,2H),2.07–1.98(m,1H),1.65–1.57(m,4H),1.40–1.30(m,4H). 13 C NMR(150MHz,DMSO-d6)δ172.03,170.51,170.25,170.22,167.00,163.54,163.13,162.6 9,140.38,137.09,136.76,133.93,132.97,132.88,132.14,131.84,128.93,128.25,127 .78,126.19,124.43,122.71,118.28,118.14,74.83,65.70,65.07,50.70,45.66,43.38 ,35.50,34.95,33.43,30.37,27.67,27.64,24.24,24.18,21.80,20.10.HRMS(ESI)calcd for C 45 H 51 N9O7[M+H] + 830.3989,found 830.3988.

[0183] Example 22: (E)-N 1 -(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-N10 -(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)sebacate (LCG-22)

[0184] The synthesis method is the same as Example 1.

[0185] 1 H NMR (600MHz, DMSO-d6) δ11.02(s,1H),10.85(s,1H),9.80(s,1H),9.76(s,1H),7.99(s,1H),7.81(d,J=6.8Hz, 1H),7.53–7.46(m,6H),7.29(t,J=7.6Hz,1H),7.20(d,J=8.5Hz,2H),7.17(d,J=7.5Hz,1H),6.06(s,1H),5.15 (dd,J=13.3,5.1Hz,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=7.4Hz,2H),2.05–2.00(m,1H),1.64–1.55(m,4H),1.37–1.22(m,8H). 13 C NMR(150MHz,DMSO-d6)δ173.34,171.85, 171.56,168.31,164.84,164.44,163.99,141.68,138.40,138.07,135.23,13 4.28,134.16,133.44,133.14,130.23,129.55,129.08,127.49,125.71,124.0 2,119.58,119.44,76.13,67.00,66.38,51.99,46.95,44.68,36.84,36.28,34 .74,31.68,29.21,29.16,29.14,25.61,25.55,23.12,21.41.HRMS(ESI)calcd for C 47 H 55 N9O7[M+H] + 858.4320, found 858.4296.

[0186] Example 23: (E)-N 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-N 12 -(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)dodecanediamide (LCG-23)

[0187] The synthesis method is the same as Example 1.

[0188] 1 H NMR (600MHz, DMSO-d6) δ11.02(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. 0Hz,1H),7.52–7.46(m,6H),7.29(t,J=7.6Hz,1H),7.20(d,J=8.5Hz,2H),7.17(d,J=7.5Hz,1H),6.06(s,1H),5. 14(dd,J=13.3,5.1Hz,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=7.4Hz,2H),2.06–1.99(m,1H),1.63–1.54(m,4H),1.34–1.19(m,12H). 13 C NMR(150MHz,DMSO-d6)δ173.33,171.85,171.57,171.55,168.30,164.84,164.43,163.99,141 .68,138.40,138.07,135.23,134.28,134.16,133.43,133.13,130.23,129.55,129.08,127.4 9,125.70,124.01,119.57,119.44,76.13,67.00,66.38,51.99,46.93,44.68,36.84,36.28,3 4.74,31.68,29.41,29.39,29.28,29.25,29.16,25.63,25.56,23.12,21.41.HRMS(ESI)calcd for C 49 H 59 N9O7[M+H] + 886.4615, found 886.4605.

[0189] Example 24: (E)-N 1 -(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-5-yl)-N 4 -(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)succinimide (LCG-24)

[0190] The synthesis method is the same as Example 1.

[0191] 1 H NMR (600MHz, DMSO-d6) δ10.97(s,1H),10.85(s,1H),10.35(s,1H),9.96(s,1H),7.98(d,J=2.4Hz,2H),7.65(d,J=8.3Hz,1H) ,7.60(d,J=8.3Hz,1H),7.55–7.45(m,4H),7.29(t,J=7.6Hz,1H),7.21(d,J=8.4Hz,2H),7.17(d,J=7.5Hz,1H),6.06(s,1H),5 .08(dd,J=13.3,5.1Hz,1H),4.41(d,J=17.2Hz,1H),4.33(t,J=7.0Hz,2H),4.28(d,J=17.2Hz,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=17.1Hz,1H),2.41–2.35(m,1H),2.34(s,3H),2.02–1.95(m,1H). 13 C NMR(150MHz,DMSO-d6)δ173.37,171.59,171.45,170.57,168.32,164.84,164.43,1 63.99,143.79,143.02,141.68,138.40,138.05,135.23,133.42,130.23,129.59,1 29.08,127.49,126.54,124.12,124.02,119.47,119.02,113.45,76.13,67.00,66. 38,51.99,47.60,44.69,34.73,31.84,31.69,31.49,23.00,21.41.HRMS(ESI)calcd for C 41 H 43 N9O7[M+H]+ 774.3363, found 774.3342.

[0192] Example 25: (E)-N 1 -(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-N 6 -(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)adipamide (LCG-25)

[0193] The synthesis method is the same as Example 1.

[0194] 1 H NMR (600MHz, DMSO-d6) δ10.97(s,1H),10.86(s,1H),10.33(d,J=8.4Hz,1H),9.91(d,J=5.6Hz,1H),8.00(d,J=3.2Hz,2H),7.66– 7.59(m,2H),7.53(d,J=8.4Hz,2H),7.50(d,J=7.8Hz,1H),7.47(s,1H),7.29(t,J=7.6Hz,1H),7.20(d,J=8.5Hz,2H),7.17(d,J=7 .5Hz,1H),6.06(s,1H),5.08(dd,J=13.3,5.1Hz,1H),4.42(d,J=17.3Hz,1H),4.33(t,J=7.1Hz,2H),4.28(d,J=17.3Hz,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). 13C NMR (150MHz, DMSO-d6) δ172.29,171.07,170.51,170.31,167.25,163.76,163.35,162. 91,142.66,141.97,140.60,137.32,136.99,134.16,132.36,129.15,128.47,128.00, 126.41,125.49,122.99,122.94,118.52,118.05,112.49,75.05,65.93,65.30,50.91, 46.52,43.60,35.73,35.57,33.66,30.61,24.25,24.16,21.92,20.33.HRMS(ESI)calcd for C 43 H 47 N9O7[M+H] + 802.3676, found 802.3667.

[0195] Example 26: (E)-N 1 -(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-N 8 -(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)octanediamide (LCG-26)

[0196] The synthesis method is the same as Example 1.

[0197] 1H NMR (600MHz, DMSO-d6) δ10.97(s,1H),10.85(s,1H),10.21(s,1H),9.80(s,1H),7.99(s,2H),7.64(d,J=8.3Hz,1H),7.58(dd,J=8. 3,1.5Hz,1H),7.52–7.46(m,4H),7.29(t,J=7.6Hz,1H),7.20(d,J=8.5Hz,2H),7.17(d,J=7.5Hz,1H),6.06(s,1H),5.08(dd,J=13. 3,5.1Hz,1H),4.42(d,J=17.2Hz,1H),4.33(t,J=7.0Hz,2H),4.28(d,J=17.3Hz,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=7.4Hz,2H),2.02–1.96(m,1H),1.65–1.56(m,4H),1.36–1.32(m,4H). 13 C NMR(150MHz,DMSO-d6)δ173.37,172.25,171.59,171.53,168.34,164.84,164.43,163.99, 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)calcd for C 45 H 51 N9O7[M+H] + 830.3989,found 830.3986.

[0198] Example 27: (E)-N 1 -(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-N 10 -(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)sebacate (LCG-27)

[0199] The synthesis method is the same as Example 1.

[0200] 1 H NMR (600MHz, DMSO-d6) δ10.97(s,1H),10.85(s,1H),10.20(s,1H),9.79(s,1H),7.99(s,2H),7.64(d,J=8.3Hz,1H),7.58(dd,J=8.3 ,1.5Hz,1H),7.53–7.46(m,4H),7.29(t,J=7.6Hz,1H),7.20(d,J=8.5Hz,2H),7.17(d,J=7.5Hz,1H),6.06(s,1H),5.08(dd,J=13.3, 5.1Hz,1H),4.42(d,J=17.3Hz,1H),4.33(t,J=7.0Hz,2H),4.28(d,J=17.3Hz,1H),3.69–3.61(m,4H),3.56–3.48(m,4H),2.96–2.87 (m,3H),2.59(d,J=17.1Hz,1H),2.38–2.31(m,6H),2.27(t,J=7.4Hz,2H),2.02–1.95(m,1H),1.63–1.54(m,4H),1.35–1.23(m,8H). 13 C NMR(150MHz,DMSO-d6)δ172.29,171.20,170.51,170.48,167.25,163.76,163.35,162.91,1 42.68,141.96,140.60,137.32,137.00,134.15,132.35,129.15,128.47,128.00,126.41,12 5.49,123.00,122.94,118.50,118.02,112.47,75.05,65.93,65.30,50.91,46.51,43.61,35 .90,35.76,33.66,30.61,28.11,28.06,28.03,24.53,24.40,21.93,20.33.HRMS(ESI)calcd for C 47 H 55 N9O7[M+H] + 858.4302, found 858.4298.

[0201] Example 28: (E)-N 1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-N 4 -(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)succinimide (LCG-28)

[0202] The synthesis method is the same as Example 1.

[0203] 1 H NMR (600MHz, DMSO-d6) δ10.98(s,1H),10.86(s,1H),10.25(s,1H),9.97(s,1H),8.10(d,J=1.4Hz,1H),7.99(s,1H),7.72 (dd,J=8.2,1.8Hz,1H),7.56–7.44(m,5H),7.29(t,J=7.6Hz,1H),7.21(d,J=8.5Hz,2H),7.17(d,J=7.5Hz,1H),6.06(s,1 H),5.09(dd,J=13.3,5.1Hz,1H),4.39(d,J=17.0Hz,1H),4.33(t,J=7.1Hz,2H),4.27(d,J=17.0Hz,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=18.0Hz,1H),2.43–2.30(m,4H),2.05–1.97(m,1H). 13 C NMR(150MHz,DMSO-d6)δ172.26,170.41,170.06,169.52,167.41,163.75,163.33,1 62.89,140.58,138.64,137.30,136.95,135.63,134.14,132.31,131.52,129.14,1 28.49,127.99,126.40,123.15,122.92,121.87,118.40,112.19,75.03,65.91,65. 28,51.04,46.32,43.59,33.64,30.67,30.59,30.48,21.85,20.32.HRMS(ESI)calcd for C 41 H 43 N9O7[M+H] + 774.3363, found 774.3355.

[0204] Example 29: (E)-N 1 -(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-N 6 -(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)adipamide (LCG-29)

[0205] The synthesis method is the same as in Example 1.

[0206] 1 H NMR (600MHz, DMSO-d6) δ10.98(brs,1H),10.85(s,1H),10.14(s,1H),9.84(s,1H),8.10(d,J=1.7Hz,1H),7.99(s,1H),7.71 (dd,J=8.2,1.9Hz,1H),7.54–7.48(m,4H),7.47(s,1H),7.29(t,J=7.6Hz,1H),7.20(d,J=8.5Hz,2H),7.17(d,J=7.5Hz,1H), 6.06(s,1H),5.09(dd,J=13.3,5.1Hz,1H),4.39(d,J=17.1Hz,1H),4.33(t,J=7.1Hz,2H),4.27(d,J=17.1Hz,1H),3.70–3.6 1(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 (150MHz, DMSO-d6) δ173.36,171.83,171.50,171.38,168.51,164.84,164.43,163. 99,141.67,139.71,138.40,138.04,136.78,135.23,133.46,132.59,130.23,129.56, 129.08,127.49,124.22,124.02,123.09,119.61,113.45,76.12,67.01,66.38,52.14, 47.42,44.68,36.78,36.71,34.74,31.69,25.38,25.28,22.95,21.41.HRMS(ESI)calcd for C 43 H 47 N9O7[M+H]+ 802.3676, found 802.3675.

[0207] Example 30: (E)-N 1 -(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindol-5-yl)-N 8 -(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)octanediamide (LCG-30)

[0208] The synthesis method is the same as in Example 1.

[0209] 1 H NMR (600MHz, DMSO-d6) δ10.98(s,1H),10.85(s,1H),10.10(s,1H),9.80(s,1H),8.10(d,J=1.5Hz,1H),7.99(s,1H),7.70(dd,J=8.2 ,1.8Hz,1H),7.54–7.46(m,5H),7.29(t,J=7.6Hz,1H),7.20(d,J=8.5Hz,2H),7.17(d,J=7.5Hz,1H),6.06(s,1H),5.10(dd,J=13.3, 5.1Hz,1H),4.39(d,J=17.0Hz,1H),4.33(t,J=7.0Hz,2H),4.26(d,J=17.0Hz,1H),3.70–3.62(m,4H),3.56–3.48(m,4H),2.95–2.86 (m,3H),2.60(d,J=17.5Hz,1H),2.43–2.31(m,6H),2.29(t,J=7.4Hz,2H),2.04–1.97(m,1H),1.66–1.56(m,4H),1.39–1.30(m,4H). 13C NMR(150MHz,DMSO-d6)δ172.27,170.89,170.44,170.42,167.44,163.76,163.35,162.9 0,140.60,138.66,137.32,137.00,135.66,134.15,132.34,131.50,129.15,128.47,128 .00,126.41,123.12,122.94,121.99,118.51,112.34,75.05,65.93,65.30,51.06,46.34 ,43.60,35.80,35.73,33.66,30.61,27.88,24.45,24.35,21.87,20.33.HRMS(ESI)calcd for C 45 H 51 N9O7[M+H] + 830.3989,found 830.3991.

[0210] Example 31: (E)-N 1 -(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindol-5-yl)-N 10 -(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)sebacate (LCG-31)

[0211] The synthesis method is the same as in Example 1.

[0212] 1H NMR (600MHz, DMSO-d6) δ10.98(brs,1H),10.85(s,1H),10.11(s,1H),9.80(s,1H),8.10(t,J=3.4Hz,1H),7.99(s,1H),7.70(dd,J= 8.2,1.9Hz,1H),7.53–7.46(m,5H),7.29(t,J=7.6Hz,1H),7.20(d,J=8.5Hz,2H),7.17(d,J=7.5Hz,1H),6.06(s,1H),5.09(dd,J=13 .3,5.1Hz,1H),4.39(d,J=17.0Hz,1H),4.33(t,J=7.1Hz,2H),4.26(d,J=17.0Hz,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=7.4Hz,2H),2.03–1.97(m,1H),1.64–1.53(m,4H),1.34–1.26(m,8H). 13 C NMR(150MHz,DMSO-d6)δ172.28,170.94,170.50,170.43,167.46,163.77,163.36,162.92, 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)calcd for C 47 H 55 N9O7[M+H] + 858.4302, found 858.4296.

[0213] Example 32: (E)-N 1 -(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)-N 4 -(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)succinimide (LCG-32)

[0214] The synthesis method is the same as in Example 1.

[0215] 1 H NMR (600MHz, DMSO-d6) δ11.04(s,1H),10.85(s,1H),10.30(s,1H),9.98(s,1H),8.30(d,J=8.2Hz,1H),7.98(s,1H),7.56(t,J= 7.9Hz,1H),7.54–7.45(m,4H),7.29(t,J=7.6Hz,1H),7.25(d,J=7.5Hz,1H),7.20(d,J=8.4Hz,2H),7.17(d,J=7.5Hz,1H),6.06( s,1H),5.08(dd,J=13.3,5.1Hz,1H),4.48(d,J=17.6Hz,1H),4.37(d,J=17.6Hz,1H),4.33(t,J=7.0Hz,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(150MHz,DMSO-d6)δ172.22,170.17,170.03,169.19,168.56,163.74,163.32,1 62.88,142.04,140.59,137.30,136.90,136.43,134.14,132.56,132.33,129.14,1 28.49,127.98,126.40,122.92,118.39,117.00,116.35,116.09,75.02,65.91,65. 28,51.00,46.90,43.59,33.63,31.16,30.55,30.29,21.72,20.31.HRMS(ESI)calcd for C 41 H 43 N9O7[M+H] + 774.3363,found 774.3360.

[0216] Example 33: (E)-N 1 -(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)-N 6-(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)adipamide (LCG-33)

[0217] The synthesis method is the same as in Example 1.

[0218] 1 H NMR(600MHz,DMSO-d6)δ11.04(s,1H),10.85(s,1H),10.27(s,1H),9.84(s, 1H),8.32(d,J=8.2Hz,1H),7.99(s,1H),7.57(t,J=7.9Hz,1H),7.53–7.47(m,4H),7.29(t,J=7.6Hz,1H) ,7.25(d,J=7.5Hz,1H),7.20(d,J=8.5Hz,2H),7.17(d,J=7.5Hz,1H),6.06(s,1H),5.06(dd,J=13.3,5.1 Hz,1H),4.47(d,J=17.6Hz,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=16.8Hz,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). 13 C NMR (150MHz, DMSO-d6) δ172.21,170.57,170.20,170.17,168.58,163.74,163.33,162. 88,142.01,140.60,137.30,136.93,136.43,134.14,132.57,132.37,129.14,128.46, 127.99,126.40,122.93,118.53,117.03,116.41,116.14,75.03,65.92,65.29,51.00, 46.91,43.59,36.11,35.43,33.64,30.55,24.08,23.82,21.72,20.32.HRMS(ESI)calcd for C 43 H 47 N9O7[M+H] + 802.3676, found 802.3670.

[0219] Example 34: (E)-N 1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)-N 8 -(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)octanediamide (LCG-34)

[0220] The synthesis method is the same as in Example 1.

[0221] 1 H NMR (600MHz, DMSO-d6) δ11.03(s,1H),10.85(s,1H),10.27(s,1H),9.80(s,1H),8.32(d,J=8.2Hz,1H),7.99(s,1H),7.56(t,J=7.9Hz,1 H),7.53–7.46(m,4H),7.29(t,J=7.6Hz,1H),7.25(d,J=7.5Hz,1H),7.20(d,J=8.5Hz,2H),7.17(d,J=7.5Hz,1H),6.06(s,1H),5.07(dd, J=13.3,5.1Hz,1H),4.47(d,J=17.6Hz,1H),4.38–4.31(m,3H),3.68–3.63(m,4H),3.56–3.50(m,4H),2.95–2.85(m,3H),2.64–2.58(m, 1H),2.45–2.37(m,3H),2.34(s,3H),2.28(t,J=7.4Hz,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(150MHz,DMSO-d6)δ173.30,171.78,171.52,171.28,169.69,164.84,164.43,163.99, 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)calcd for C 45 H51 N9O7[M+H] + 830.3989,found 830.3983.

[0222] Example 35: (E)-N 1 -(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)-N 10 -(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)sebacate (LCG-35)

[0223] The synthesis method is the same as in Example 1.

[0224] 1 H NMR (600MHz, DMSO-d6) δ11.03(s,1H),10.85(s,1H),10.26(s,1H),9.79(s,1H),8.32(d,J=8.2Hz,1H),7.99(s,1H),7.5 6(t,J=7.9Hz,1H),7.54–7.45(m,4H),7.29(t,J=7.6Hz,1H),7.24(d,J=7.4Hz,1H),7.20(d,J=8.5Hz,2H),7.17(d,J=7.6 Hz,1H),6.06(s,1H),5.07(dd,J=13.3,5.1Hz,1H),4.47(d,J=17.6Hz,1H), 4.40–4.28(m,3H),3.72–3.62(m,4H),3.57–3.49(m,4H),2.97–2.84(m,3H) ,2.64–2.57(m,1H),2.46–2.37(m,3H),2.34(s,3H),2.27(t,J=7.5Hz,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). 13C NMR(150MHz,DMSO-d6)δ171.97,170.49,170.25,169.95,168.37,163.51,163.10,162.66, 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)calcd for C 47 H 55 N9O7[M+H] + 858.4320, found 858.4298.

[0225] Example 36: (E)-N 1 -(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)-N 12 -(4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)dodecanediamide (LCG-36)

[0226] The synthesis method is the same as in Example 1.

[0227] 11H 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). 13 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, 119.57, 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) calcd for C 49 H 59 N9O7 [M + H] + 886.4615, found 886.4608.

[0228] Example 37: N 1-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 4 -(4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)succinimide (LCG-37)

[0229] Step 1: Preparation of (E)-4-((4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)amino)-4-oxobutanoic acid (8)

[0230] Intermediate 6 (300 mg, 0.7 mmol) and 4-(tert-butoxy)-4-oxobutanoic acid (126 mg, 0.7 mmol) were dissolved in 15 mL of DMF, followed by the addition of HATU (550 mg, 1.4 mmol) and triethylamine (220 mg, 2.1 mmol) and allowed to react at room temperature for 4 h. 50 mL of water was added, and the mixture was extracted twice with EA. The combined organic phases were washed once with saturated brine, dried over anhydrous Na2SO4, and filtered to dryness to afford an oil. This oil was used directly in the next step without purification. The oil was dissolved in DCM containing 25% TFA and stirred at room temperature for 3 h. The reaction was monitored for completion by TLC. Vacuum evaporation and column chromatography afforded 250 mg (67%) of a pale white solid. 1 H NMR (500MHz, DMSO-d6) δ10.89(brs,1H),9.88(s,1H),7.98(s,1H),7.56–7.43(m,4H),7.27(t,J=7.5Hz,1H),7.21–7.13(m,3H),6.03(s,1H),4. 33(t,J=6.3Hz,2H),3.69–3.62(m,6H),3.56–3.50(m,4H),2.91(t,J=6.9Hz,2H),2.52(t,J=5.1Hz,2H),2.32(s,3H).MS(ESI),m / z:533.3[M+H] + .

[0231] Step 2: Preparation of N 1 -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 4-(4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)succinimide (LCG-37)

[0232] Intermediate 8 (40 mg, 0.07 mmol) and the reported E3 ubiquitin ligase VHL ligand intermediate 9 (30 mg, 0.7 mmol) were dissolved in 10 mL of DMF. HATU (70 mg, 0.2 mmol) and triethylamine (40 mg, 0.4 mmol) were then added and reacted at room temperature for 4 hours. 20 mL of water was added, and the mixture was extracted twice with EA. The combined organic phases were washed once with saturated brine, dried over anhydrous NaSO, filtered, and then purified by column chromatography to yield 29 mg (44%) of a white solid. 1 H NMR(600 MHz, DMSO-d6)δ10.86(s,1H),9.88(s,1H),8.98(s,1H),8.57(t,J=6.0Hz,1H),7.99(s,1H),7.96(d,J=9.3Hz,1H),7.53–7.46(m,4H),7.42( d,J=8.3Hz,2H),7.39(d,J=8.3Hz,2H),7.29(t,J=7.6Hz,1H),7.20(d,J=8.5Hz,2H),7.17(d,J=7.5Hz,1H),6.06(s,1H),5.12(d,J=3.5Hz,1 H),4.55(d,J=9.4Hz,1H),4.47–4.40(m,2H),4.33(t,J=7.1Hz,3H),4.22(dd,J=15.8,5.4Hz,1H),3.72–3.60(m,6H),3.55–3.49(m,4H),2.9 2(t,J=7.0Hz,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(150MHz,DMSO-d6)δ172.41,171.65,170.78,170.05,164.85,164.43,163.99,151.93,1 48.19,141.67,139.98,138.40,138.07,135.23,133.37,131.64,130.23,130.11,129.56,12 9.12,129.08,127.90,127.49,124.01,119.48,76.13,69.36,67.01,66.38,59.19,56.93,56 .82,44.69,42.12,38.40,35.86,34.73,32.32,30.59,26.84,21.41,16.42.HRMS(ESI)calcd for C 50 H 60 N 10 O7S[M+H] + 945.4445, found 945.4438.

[0233] Example 38: N 1 -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 6 -(4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)adipamide (LCG-38)

[0234] The synthesis method is the same as Example 37.

[0235] 11H 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 13C NMR (150 MHz, DMSO-d6) δ 172.42, 172.41,​​​​​​​​​​​​-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 8 -(4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)octanediamide (LCG-39)

[0237] The synthesis method is the same as Example 37.

[0238] 1 H NMR (600MHz, DMSO-d6) δ10.85(s,1H),9.80(s,1H),8.98(s,1H),8.56(t,J=6.1Hz ,1H),7.99(s,1H),7.85(d,J=9.4Hz,1H),7.53–7.46(m,4H),7.42(d,J=8.2Hz,2H ),7.40–7.36(m,2H),7.29(t,J=7.6Hz,1H),7.20(d,J=8.5Hz,2H),7.17(d,J=7.5 Hz,1H),6.06(s,1H),5.13(d,J=3.6Hz,1H),4.55(d,J=9.4Hz,1H),4.46–4.40(m, 2H),4.37–4.31(m,3H),4.22(dd,J=15.9,5.5Hz,1H),3.70–3.63(m,6H),3.55–3.50(m,4H),2.92(t,J=7.0Hz,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(150MHz,DMSO-d6)δ172.56,172.43,171.55,170.20,164.84,164.43,163.99,151.92,148.19, 141.68,139.98,138.39,138.07,135.23,133.43,131.64,130.23,130.11,129.54,129.11,129.08, 127.89,127.49,124.02,119.59,76.13,69.34,67.01,66.38,59.16,56.84,56.76,44.68,42.12,38 .42,36.84,35.68,35.34,34.74,28.98,28.94,26.86,25.83,25.56,21.41,16.42.HRMS(ESI)calcd for C 54 H 68 N 10 O7S[M+H] + 1001.5071,found 1001.5063.

[0239] Example 40: N 1 -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 10 -(4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)sebacate (LCG-40)

[0240] The synthesis method is the same as Example 37.

[0241] 11H 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 13C 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, 138.39, 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) calcd for C 56 H 72 N 10 O7S [M + H] + 1029.5384, found 1029.5378.

[0242] Example 41: N 1-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 5 -(4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)glutaramide (LCG-41)

[0243] The synthesis method is the same as Example 37.

[0244] 1 H NMR (600MHz, DMSO-d6) δ10.85(s,1H),9.81(s,1H),8.98(s,1H),8.56(t,J=6.0Hz,1H),7.99(s,1H),7.92(d,J=9.2Hz,1H) ,7.54–7.45(m,4H),7.42(d,J=8.3Hz,2H),7.40–7.36(m,2H),7.29(t,J=7.6Hz,1H),7.20(d,J=8.5Hz,2H),7.17(d,J=7.5H z,1H),6.06(s,1H),5.14(d,J=3.3Hz,1H),4.55(d,J=9.3Hz,1H),4.46–4.40(m,2H),4.38–4.32(m,3H),4.22(dd,J=15.8,5 .4Hz,1H),3.70–3.62(m,6H),3.55–3.50(m,4H),2.92(t,J=6.9Hz,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(150MHz,DMSO-d6)δ172.41,172.18,171.20,170.20,164.84,164.43,163.99,151.92,148 .19,141.68,139.98,138.39,138.05,135.23,133.45,131.64,130.23,130.11,129.53,129.1 1,129.08,127.89,127.49,124.02,119.63,76.13,69.37,67.01,66.38,59.18,56.91,56.84, 44.68,42.12,38.42,36.32,35.66,34.74,34.68,26.88,21.99,21.41,16.42.HRMS(ESI)calcd for C 51 H 62 N 10 O7S[M+H] + 959.4602, found 959.4584.

[0245] Example 42: N 1 -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 7 -(4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)pimelanediamide (LCG-42)

[0246] The synthesis method is the same as Example 37.

[0247] 11H 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 13C 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, thirteen eighty point zero eight, 135.23, 133.41, 131.64, 130.23, 130.11, 129.54, 129.11, 129.08, 127.89, 127.49, 124.01, thirteen eighty point zero eight, 135.23, 133.41, 131.64, 130.23, 130.11, 129.54, 129.11, 129.08, 127.89, 127.49, 124.01, 119.58, 76.13, 6; sixty-nine point three four, 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) calcd for C 53 H 66 N 10 O7S [M + H] + 987.4915, found 987.4912.

[0248] Example 43: N 1-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 9 -(4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)azepanamide (LCG-43)

[0249] The synthesis method is the same as Example 37.

[0250] 1 H NMR(600MHz,DMSO-d6)δ10.85(s,1H),9.79(s,1H),8.98(s,1H),8.56(t,J =6.1Hz,1H),7.99(s,1H),7.84(d,J=9.4Hz,1H),7.53–7.46(m,4H),7.42(d ,J=8.3Hz,2H),7.40–7.36(m,2H),7.29(t,J=7.6Hz,1H),7.20(d,J=8.5Hz ,2H),7.17(d,J=7.5Hz,1H),6.06(s,1H),5.12(d,J=3.6Hz,1H),4.54(d,J= 9.4Hz,1H),4.46–4.39(m,2H),4.33(t,J=7.1Hz,3H),4.21(dd,J=15.8,5. 5Hz,1H),3.72–3.61(m,6H),3.56–3.48(m,4H),2.92(t,J=7.0Hz,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 (150MHz, DMSO-d6) δ170.70,170.56,169.71,168.32,162.98,162.57,162.13,150.06,146.33,139.81,138.12,136 .53,136.21,133.37,131.56,129.77,128.37,128.24,127.68,127.25,127.22,126.03,125.63,122.15,117.72,74.27, 67.47,65.14,64.52,57.29,54.96,54.87,42.82,38.67,36.56,34.99,33.81,3 3.46,32.87,27.21,27.16,24.98,24.03,23.76,19.55,14.56.HRMS(ESI)calcd for C 55 H 70 N 10 O7S[M+H] + 1015.5228,found 1015.5218.

[0251] Example 44: N 1 -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 11 -(4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)undecanediamide (LCG-44)

[0252] The synthesis method is the same as Example 37.

[0253] 1H NMR(600MHz,DMSO-d6)δ10.85(s,1H),9.79(s,1H),8.98(s,1H),8.55(t,J=6.1Hz,1H),7.99(s,1H),7.84(d,J=9.4Hz,1H),7.52–7.47(m,4H),7.42(d,J=8.3Hz,2H),7.39–7.37(m,2H),7.29(t,J=7.6Hz,1H),7.20(d,J=8.5Hz,2H),7.17(d,J=7.5Hz,1H),6.06(s,1H),5.11(d,J=3.2Hz,1H),4.54(d,J=9.4Hz,1H),4.45–4.40(m,2H),4.33(t,J=7.1Hz,3H),4.21(dd,J=15.9,5.4Hz,1H),3.68–3.62(m,6H),3.54–3.50(m,4H),2.92(t,J=7.0Hz,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(150MHz,DMSO-d6)δ172.56,172.42,171.56,170.18,164.84,164.43,163.99,151.93,148.19,141.67,139.98,138.39,138.08,135.23,133.42,131.64,130.23,130.11,129.54,129.11,129.08,127.89,127.49,124.01,119.58,76.13,69.33,67.01,66.38,59.15,56.82,56.73,44.68,42.11,38.43,36.86,35.68,35.33,34.74,29.34,29.27,29.22,29.16,29.13,26.85,25.91,25.64,21.41,16.42.HRMS(ESI)calcd for C 57 H 74 N 10 O7S[M+H] + 1043.5541,found 1043.5527.

[0254] Example 45: N 1 -((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 5 -(4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)glutaramide (LCG-45)

[0255] The synthesis method is the same as Example 37.

[0256] 1 H NMR(600MHz,DMSO-d6)δ10.86(s,1H),9.82(s,1H),8.98(s,1H),8.38(d,J= 7.8Hz,1H),7.99(s,1H),7.86(d,J=9.2Hz,1H),7.54–7.46(m,4H),7.45–7. 41(m,2H),7.39–7.36(m,2H),7.29(t,J=7.6Hz,1H),7.21(d,J=8.5Hz,2H), 7.17(d,J=7.4Hz,1H),6.06(s,1H),5.12(s,1H),4.95–4.88(m,1H),4.52(d ,J=9.3Hz,1H),4.43(t,J=8.0Hz,1H),4.33(t,J=7.0Hz,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=7.0Hz,2 H),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=7.0Hz,3H),0.94(d,J=9.5Hz,9H). 13C NMR(150MHz,DMSO-d6)δ171.06,170.12,170.01,169.02,163.76,163.35,162.90 ,150.87,147.14,144.05,140.60,137.31,136.98,134.15,132.38,130.50,129. 15,129.08,128.45,128.21,128.00,126.41,125.77,122.93,118.54,75.05,68. 18,65.94,65.30,57.96,55.91,55.65,47.08,43.60,37.11,35.23,34.55,33.66, 33.61,25.86,21.83,20.91,20.33,15.38.HRMS(ESI)calcd for C 52 H 64 N 10 O7S[M+Na] + 995.4578, found 995.4565.

[0257] Example 46: N 1 -((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 6 -(4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)adipamide (LCG-46)

[0258] The synthesis method is the same as Example 37.

[0259] 11H 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 13C 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, 137.29, 136.94, 134.13, 132.35, 130.48, 129.13, 129.06, 128.46, 128.19, 127.98, 126.40, 125.74, 125.61, 122.92, 118.50, 75.02, 68.14, 65.92, 65.28, 57.92, 55.78, 55.64, 47.06, 43.59, 37.08, 35.59, 34.56, 34.13, 33.64, 25.83, 24.55, 24.32, 21.81, 20.31, 15.36. HRMS (ESI) calcd for C 53 H 66 N 10 O7S [M+Na] + 1009.4735, found 【1009.4711】.

[0260] Example 47: N1 -((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 7 -(4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)pimelanediamide (LCG-47)

[0261] The synthesis method is the same as Example 37.

[0262] 1 H NMR (600MHz, DMSO-d6) δ10.85(s,1H),9.80(s,1H),8.98(s,1H),8.37(d,J=7.8H z,1H),7.99(s,1H),7.80(d,J=9.3Hz,1H),7.53–7.46(m,4H),7.45–7.41(m,2H), 7.37(d,J=8.2Hz,2H),7.29(t,J=7.6Hz,1H),7.20(d,J=8.5Hz,2H),7.17(d,J=7 .5Hz,1H),6.06(s,1H),5.10(d,J=3.4Hz,1H),4.96–4.88(m,1H),4.51(d,J=9.3H z,1H),4.42(t,J=8.0Hz,1H),4.33(t,J=7.0Hz,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=7.0Hz,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=7.0Hz,3H),1.31–1.23(m,2H),0.93(s,9H). 13C NMR(150MHz,DMSO-d6)δ171.31,170.36,169.94,168.93,163.70,163.29,162.84,150.81,147.08, 143.99,140.53,137.25,136.94,134.09,132.27,130.44,129.08,129.01,128.39,128.15,127.93, 126.35,125.70,122.87,118.42,74.98,68.09,65.87,65.23,57.87,55.68,55.59,47.01,43.54,37 .05,35.62,34.50,34.12,33.59,27.68,25.77,24.57,24.26,21.75,20.26,15.31.HRMS(ESI)calcd for C 54 H 68 N 10 O7S[M+H] + 1001.5071,found 1001.5070.

[0263] Example 48: N 1 -((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 10 -(4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)sebacate (LCG-48)

[0264] The synthesis method is the same as Example 37.

[0265] 1H NMR(600MHz,DMSO-d6)δ10.85(s,1H),9.79(s,1H),8.98(s,1H),8.37(d,J=7.8Hz,1H),7.99(s,1H),7.78(d,J=9.3Hz,1H),7.53–7.46(m,4H),7.44–7.42(m,2H),7.37(d,J=8.2Hz,2H),7.29(t,J=7.6Hz,1H),7.20(d,J=8.5Hz,2H),7.17(d,J=7.5Hz,1H),6.06(s,1H),5.09(d,J=2.2Hz,1H),4.94–4.89(m,1H),4.51(d,J=9.4Hz,1H),4.42(t,J=8.0Hz,1H),4.33(t,J=7.1Hz,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=7.0Hz,2H),2.45(d,J=2.5Hz,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=7.0Hz,3H),1.32–1.16(m,8H),0.93(s,9H). 13 C NMR(150MHz,DMSO-d6)δ171.41,170.46,169.99,168.98,163.74,163.33,162.88,150.85,147.13,144.04,140.58,137.29,136.98,134.13,132.31,130.48,129.13,129.06,128.45,128.19,127.98,126.40,125.75,122.92,118.48,75.03,68.12,65.91,65.28,57.90,55.69,55.62,47.06,43.59,37.10,35.76,34.56,34.24,33.64,28.14,28.05,28.02,25.81,24.78,24.54,21.81,20.32,15.36.HRMS(ESI)calcd for C 57 H 74 N 10 O7S[M+Na] +1065.5361, found 1065.5359.

[0266] Example 49: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-4-((4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)amino)-1-(4-(4-methylthiazol-5-yl)phenyl)4-oxobutyl)pyrrolidine-2-carboxamide (LCG-49)

[0267] Intermediate 6 (40 mg, 0.09 mmol) and the reported E3 ubiquitin ligase VHL ligand intermediate 10 (55 mg, 0.09 mmol) were dissolved in 10 mL of DMF. HATU (70 mg, 0.18 mmol) and triethylamine (30 mg, 0.3 mmol) were then added and reacted at room temperature for 4 hours. 20 mL of water was added, and the mixture was extracted twice with EA. The combined organic phases were washed once with saturated brine, dried over anhydrous NaSO, filtered, and purified by column chromatography to yield 45 mg (49%) of a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.85(s,1H),9.79(s,1H),8.99(s,1H),8.59(d,J=8.2Hz,1H),7.99(s,1H),7.50(dd,J=8.0,3.0Hz,3H),7.48–7.44(m,3H), 7.40(d,J=8.3Hz,2H),7.31–7.25(m,2H),7.19(d,J=8.5Hz,2H),7.17(d,J =7.5Hz,1H),6.06(s,1H),5.16(d,J=3.6Hz,1H),4.90–4.83(m,1H),4.58( d,J=9.3Hz,1H),4.50(t,J=8.3Hz,1H),4.33(t,J=7.0Hz,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=7.0H z,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). 13C NMR(150MHz,DMSO-d6)δ170.22,169.99,168.22,167.48,167.35,163.75,163.34,162.89,150.91,147.19, 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 .14,35.42,33.64,32.61,31.47,25.68,25.60,20.31,15.41,12.38,12.32,12.11,12.04.HRMS(ESI)calcd for C 53 H 63 FN 10 O7S[M+H] + 1003.4664,found 1003.4646.

[0268] Example 50: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-4-((2-((4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)amino)-2-oxoethyl)amino)-1-(4-(4-methylthiazol-5-yl)phenyl)4-oxobutyl)pyrrolidine-2-carboxamide (LCG-50)

[0269] Step 1: Preparation of tert-butyl (E)-(2-((4-(2-((4-(2-(3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)amino)-2-oxoethyl)carbamate (11)

[0270] Intermediate 6 (300 mg, 0.7 mmol) and (tert-butyloxycarbonyl)glycine (122 mg, 0.7 mmol) were dissolved in 15 mL of DMF, followed by the addition of HATU (550 mg, 1.4 mmol) and triethylamine (220 mg, 2.1 mmol) and allowed to react at room temperature for 4 h. 50 mL of water was added, and the mixture was extracted twice with EA. The combined organic phases were washed once with saturated brine, dried over anhydrous NaSO, filtered, and then purified by column chromatography to yield 288 mg (70%) of a solid. 1H NMR(500MHz,DMSO-d6)δ10.84(s,1H),9.84(s,1H),7.96(s,1H),7.51–7.43(m,4H),7. 27(t,J=7.6Hz,1H),7.20(d,J=8.4Hz,2H),7.15(d,J=7.6Hz,1H),7.01(t,J=6.0Hz,1H) ,6.04(s,1H),4.32(t,J=7.0Hz,2H),3.68(d,J=6.0Hz,2H),3.66–3.61(m,4H),3.53–3 .48(m,4H),2.91(t,J=7.0Hz,2H),2.32(s,3H),1.37(s,9H).MS(ESI),m / z:560.4[M+H] + .

[0271] Step 2: Preparation of (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-4-((2-((4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)amino)-2-oxoethyl)amino)-1-(4-(4-methylthiazol-5-yl)phenyl)4-oxobutyl)pyrrolidine-2-carboxamide (LCG-50)

[0272] Intermediate 11 (40 mg, 0.07 mmol) was dissolved in 10 mL of DCM containing 25% TFA and stirred at room temperature for 3 h. The reaction was complete as monitored by TLC. The oily product was then dried and used in the next step without purification. It was dissolved in 10 mL of DMF and reacted with the reported E3 ubiquitin ligase VHL ligand intermediate 10 (50 mg, 0.08 mmol), HATU (65 mg, 0.14 mmol), and triethylamine (30 mg, 0.3 mmol) for 4 h at room temperature. The reaction was complete as monitored by TLC. 20 mL of water was added, and the product was extracted twice with EA. The combined organic phases were washed once with saturated brine, dried over anhydrous Na2SO4, filtered, dried, and purified by column chromatography to yield 30 mg (40%) of a white solid. 1H NMR(600MHz,DMSO-d6)δ10.86(s,1H),9.89(s, 1H),8.99(s,1H),8.58(d,J=8.3Hz,1H),8.03(t,J=5.8Hz,1H),7.99(s,1H),7.54–7.48(m,3H),7.48–7.44(m,3H),7.39(d,J=8.3Hz,2H),7.35(dd,J=9.4,2.5Hz,1H),7.29(t,J=7.6Hz,1H),7.22(d,J=8.5Hz,2H),7.17(d,J=7.5Hz,1H),6.06(s,1H),5.16(d,J=3.6Hz,1H),4.84(dd,J=15.2,7.7Hz,1H),4.61(d,J=9.3Hz,1H),4.50(t,J=8.4Hz,1H),4.34(t,J=7.1Hz,2H),4.29(s,1H),3.86(d,J=5.8Hz,2H),3.71–3.64(m,4H),3.64–3.56(m,2H),3.56–3.49(m,4H),2.93(t,J=7.0Hz,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(150MHz,DMSO-d6)δ171.72,170.20,168.28,167.55,167.41,167.00,163.76,163.34,162.90,150.90,147.20,142.66,140.59,137.31,136.51,134.15,132.67,130.47,129.29,129.14,128.54,128.25,127.99,126.40,126.22,122.93,118.60,78.18,76.64,75.05,68.18,65.88,65.29,58.21,56.12,55.99,51.26,43.60,42.12,37.16,35.43,33.64,31.88,31.55,25.64,20.32,15.42,12.41,12.34,12.12,12.06.HRMS(ESI)calcd for C 55 H 66 FN11 O8S[M+H] + 1060.4879,found 1060.4879.

[0273] Example 51: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-4-((4-((4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)amino)-4-oxobutyl)amino)-1-(4-(4-methylthiazol-5-yl)phenyl)4-oxobutyl)pyrrolidine-2-carboxamide (LCG-51)

[0274] The synthesis method is the same as Example 50.

[0275] 1 H NMR(600MHz,DMSO-d6)δ10.85(s,1H),9.83(s,1H),8.98(s,1H),8.56(d,J=8.2Hz,1H ),7.99(s,1H),7.73(t,J=5.6Hz,1H),7.51–7.47(m,4H),7.44(d,J=8.2Hz,2H),7.37( d,J=8.2Hz,2H),7.31–7.27(m,2H),7.20(d,J=8.5Hz,2H),7.17(d,J=7.5Hz,1H),6.0 6(s,1H),5.15(d,J=3.3Hz,1H),4.82–4.76(m,1H),4.59(d,J=9.3Hz,1H),4.48(t,J=8 .3Hz,1H),4.33(t,J=7.1Hz,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=7.0Hz,2H),2.46(s,3H),2.34(s,3H) ,2.28(t,J=7.4Hz,2H),2.26–2.18(m,1H),2.17–2.10(m,1H),2.08–2.02(m,1H),1.9 8–1.87(m,2H),1.79–1.66(m,3H),1.42–1.29(m,2H),1.25–1.17(m,2H),0.97(s,9H). 13C NMR(150MHz,DMSO-d6)δ171.09,170.17,170.06,168.23,167.50,167.37,163.76,163.35,162.91,150.90,147.18, 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)calcd for C 57 H 70 FN 11 O8S[M+H] + 1088.5192,found 1088.5190.

[0276] Example 52: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-4-((6-((4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)amino)-6-oxohexyl)amino)-1-(4-(4-methylthiazol-5-yl)phenyl)4-oxobutyl)pyrrolidine-2-carboxamide (LCG-52)

[0277] The synthesis method is the same as Example 50.

[0278] 1H NMR(600MHz,DMSO-d6)δ10.85(s,1H),9.79(s,1H),8.98(s,1H),8.55(d,J=8.2Hz,1H),7.99(s,1H),7.65(t,J=5.6Hz,1H),7.53–7.46(m,4H),7.44(d,J=8.2Hz,2H),7.36(d,J=8.2Hz,2H),7.31–7.25(m,2H),7.19(d,J=8.5Hz,2H),7.17(d,J=7.5Hz,1H),6.06(s,1H),5.15(s,1H),4.82–4.75(m,1H),4.59(d,J=9.2Hz,1H),4.48(t,J=8.3Hz,1H),4.33(t,J=7.1Hz,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=7.0Hz,2H),2.46(s,3H),2.34(s,3H),2.27(t,J=7.4Hz,2H),2.23–2.16(m,1H),2.14–2.08(m,1H),2.05(dd,J=12.7,7.8Hz,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(150MHz,DMSO-d6)δ170.90,170.38,170.13,168.22,167.49,167.36,163.76,163.34,162.90,150.90,147.18, 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, 122.94,118.50,78.28,76.74,75.05,68.18,65.93,65.30,58.16,56.09,55.96,51.35,43.60,37.81,37.15,35.70, 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)calcd for C 59 H 74 FN 11 O8S[M+H] + 1116.5505, found 1116.5507.

[0279] Example 53: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(2-(2-((4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)amino)-2-oxoethoxy)-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (LCG-53)

[0280] Intermediate 6 (40 mg, 0.09 mmol) and the reported E3 ubiquitin ligase VHL ligand intermediate 12 (53 mg, 0.09 mmol) were dissolved in 10 mL of DMF. HATU (70 mg, 0.18 mmol) and triethylamine (30 mg, 0.3 mmol) were then added and reacted at room temperature for 4 hours. 20 mL of water was added, and the mixture was extracted twice with EA. The combined organic phases were washed once with saturated brine, dried over anhydrous NaSO, filtered, and then purified by column chromatography to yield 35 mg (39%) of a white solid. 1H NMR(600 MHz,DMSO-d6)δ10.85(s,1H),10.03(s,1H),8.98(s,1H),8.58(t,J=6.0Hz,1H),7.99(s,1H),7.61(d,J=8.5Hz,2H),7.50(d,J=7.8Hz,1H),7.47(s,1H),7.45(d,J=8.1Hz,1H),7.31–7.26(m,2H),7.25(d,J=8.5Hz,2H),7.17(d,J=7.5Hz,1H),7.03(dd,J=3.9,2.5Hz,2H),6.06(s,1H),5.16(brs,1H),4.83–4.76(m,2H),4.58(d,J=9.4Hz,1H),4.50(t,J=8.2Hz,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=6.9Hz,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=8.4,2.7Hz,2H),0.94(s,9H). 13 C NMR(150MHz,DMSO-d6)δ171.16,168.27,167.49,167.36,165.63,163.73,163.30,162.86,154.60,151.01,147.35,140.60,137.30,135.90,134.13,133.28,130.55,130.45,129.14,128.52,128.28,127.98,126.55,126.41,122.93,120.94,119.34,111.58,78.25,76.71,75.04,68.25,66.82,65.86,65.28,58.27,56.04,55.92,43.60,37.25,36.80,35.38,33.65,25.58,25.52,20.32,15.37,12.38,12.32,12.12,12.05.HRMS(ESI)calcd for C 52 H 61 FN 10 O8S[M+Na] + 1027.4277,found 1027.4269.

[0281] Example 54: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(2-(2-((2-((4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)amino)-2-oxoethyl)amino)-2-oxoethoxy)-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (LCG-54)

[0282] The synthesis method is the same as Example 53.

[0283] 1 H NMR(600MHz,DMSO-d6)δ10.86(s,1H),9.95(s,1H),8.99(s,1H),8.58(t,J=6.0 Hz,1H),8.39(t,J=5.9Hz,1H),7.99(s,1H),7.49(t,J=9.8Hz,4H),7.45(d,J=7 .7Hz,1H),7.32–7.26(m,2H),7.23(d,J=8.5Hz,2H),7.17(d,J=7.5Hz,1H),7.0 5–7.00(m,2H),6.06(s,1H),5.15(brs,1H),4.68(dd,J=28.1,14.9Hz,2H),4.5 8(d,J=9.3Hz,1H),4.50(t,J=8.3Hz,1H),4.45(dd,J=16.0,6.0Hz,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),3.56–3.5 0(m,4H),2.94(t,J=7.0Hz,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=8.4,3.1Hz,2H),0.95(s,9H). 13C NMR (150MHz, DMSO-d6) δ171.25,168.26,167.50,167.42,167.36,166.47,163.73,163.30,162.88,154.39,15 0.94,147.42,140.63,137.30,136.47,134.13,132.70,130.55,130.46,129.15,128.57,127.98,126.53,126 .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)calcd for C 54 H 64 FN 11 O9S[M+Na] + 1084.4491,found 1084.4491.

[0284] Example 55: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(2-(2-((4-((4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)amino)-4-oxobutyl)amino)-2-oxoethoxy)-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (LCG-55)

[0285] The synthesis method is the same as Example 53.

[0286] 1H NMR(600MHz,DMSO-d6)δ10.86(s,1H),9.84(s,1H),8.97(s,1H),8.56(t,J=6.0Hz,1H),8.18(t,J=5.8Hz,1H),7.99(s,1H),7.53–7.46(m,4H),7.43(d,J=7.8Hz,1H),7.32–7.25(m,2H),7.21–7.16(m,3H),7.02(dd,J=7.7,1.3Hz,1H),6.96(d,J=1.2Hz,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=13.2,6.7Hz,2H),2.92(t,J=7.0Hz,2H),2.45(s,3H),2.34(s,3H),2.31(t,J=7.5Hz,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). 13 C NMR(150MHz,DMSO-d6)δ171.13,170.01,168.26,167.50,167.36,166.78,163.70,163.26,162.84,154.47,150.95,147.36,140.66,137.30,136.92,134.12,132.32,130.58,130.46,129.16,128.45,128.29,127.98,126.51,126.42,122.94,120.89,118.50,111.54,78.26,76.72,75.01,68.26,66.58,65.95,65.28,58.24,56.09,55.92,43.60,37.45,37.23,36.83,35.39,33.63,33.23,25.58,25.50,24.62,20.31,15.35,12.39,12.32,12.12,12.05.HRMS(ESI)calcd for C 56 H 68 FN 11 O9S[M+H] +1090.4984,found 1090.4983.

[0287] Example 56: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(2-(2-((6-((4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)amino)-6-oxohexyl)amino)-2-oxoethoxy)-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (LCG-56)

[0288] The synthesis method is the same as Example 53.

[0289] 1 H NMR(600MHz,DMSO-d6)δ10.86(s,1H),9.79(s,1H),8.98(s,1H),8.55(t,J=6.0Hz,1 H),8.12(t,J=5.8Hz,1H),7.99(s,1H),7.54–7.46(m,4H),7.42(d,J=7.8Hz,1H),7. 32–7.25(m,2H),7.22–7.15(m,3H),7.02(dd,J=7.7,1.4Hz,1H),6.95(d,J=1.3Hz,1 H),6.06(s,1H),5.17(brs,1H),4.62–4.51(m,3H),4.49(t,J=8.2Hz,1H),4.45(dd, J=15.7,6.3Hz,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=7.0Hz,2H),2.45(s,3H),2.34(s,3H),2. 26(t,J=7.4Hz,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). 13C NMR(150MHz,DMSO-d6)δ171.09,170.34,168.26,167.49,167.35,166.59, 163.70,163.29,162.87,154.49,150.96,147.35,140.62,137.29,136.97,134.12,132.30,130.58,1 30.45,129.14,128.44,128.30,127.98,126.48,126.41,122.93,120.85,118.49,111.54,78.26,76.7 2,75.02,68.25,66.59,65.94,65.28,58.23,56.08,55.91,43.59,37.66,37.22,36.79,35.63,35.40, 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)calcd for C 58 H 72 FN 11 O9S[M+Na] + 1140.5117,found1140.5113.

[0290] Example 57: (2S,4R)-1-((R)-2-(1-fluorocyclopropane-1-carboxamido)-3-methyl-3-((2-((4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)amino)-2-oxoethyl)thio)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (LCG-57)

[0291] Intermediate 6 (40 mg, 0.09 mmol) and the reported E3 ubiquitin ligase VHL ligand intermediate 13 (54 mg, 0.09 mmol) were dissolved in 10 mL of DMF. HATU (70 mg, 0.18 mmol) and triethylamine (30 mg, 0.3 mmol) were then added and reacted at room temperature for 4 hours. 20 mL of water was added, and the mixture was extracted twice with EA. The combined organic phases were washed once with saturated brine, dried over anhydrous NaSO, filtered, and then purified by column chromatography to yield 38 mg (42%) of a white solid. 1H NMR(600MHz,DMSO-d6)δ10.86(s,1H),9.95(s,1H),8.96(s,1H),8.74(t,J=6.0Hz,1H),7.99(s,1H),7.56(dd,J=8.9,2.3Hz,1H),7.51–7.44(m,4H),7.40–7.35(m,4H),7.29(t,J=7.6Hz,1H),7.21–7.15(m,3H),6.05(s,1H),5.22(brs,1H),4.85(d,J=8.9Hz,1H),4.50(t,J=8.3Hz,1H),4.41(dd,J=15.7,6.4Hz,1H),4.37(s,1H),4.33(t,J=7.0Hz,2H),4.26(dd,J=15.7,5.6Hz,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=6.9Hz,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=3.1Hz,6H),1.39–1.34(m,2H),1.24–1.19(m,2H). 13 C NMR(150MHz,DMSO-d6)δ171.24,167.76,167.62,167.28,167.22,163.70,163.26,162.84,150.81,147.14,140.63,138.51,137.30,136.61,134.12,132.78,130.47,129.19,129.15,128.54,128.24,128.15,127.98,127.43,126.81,126.41,122.94,118.46,78.21,76.68,75.02,68.21,65.90,65.28,58.49,56.00,54.38,49.28,45.13,43.60,41.18,37.40,33.63,33.13,26.00,23.68,20.31,15.29,12.47,12.40,12.32,12.25.HRMS(ESI)calcd for C 51 H 59 FN 10 O7S2[M+Na] + 1029.3892,found 1029.3884.

[0292] Example 58: (2S,4R)-1-((R)-2-(1-fluorocyclopropane-1-carboxamido)-3-methyl-3-((2-((2-((4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)amino)-2-oxoethyl)amino)-2-oxoethyl)thio)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (LCG-58)

[0293] The synthesis method is the same as Example 57.

[0294] 1 H NMR (600MHz, DMSO-d6) δ10.86(s,1H),9.91(s,1H),8.97(s,1H),8.65(t,J=6.0Hz,1H),8.25(t,J=5.6Hz,1H),7.99(s,1H),7.54(dd,J=9.0,2.1Hz,1H ),7.51–7.46(m,4H),7.42–7.37(m,4H),7.29(t,J=7.6Hz,1H),7.22(d,J=8 .5Hz,2H),7.17(d,J=7.5Hz,1H),6.06(s,1H),5.20(brs,1H),4.84(d,J=9. 0Hz,1H),4.47(t,J=8.2Hz,1H),4.42–4.26(m,5H),3.89(t,J=7.2Hz,2H), 3.76(dd,J=10.7,3.9Hz,1H),3.69–3.62(m,5H),3.55–3.49(m,4H),3.40–3 .34(m,2H),2.93(t,J=7.0Hz,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(150MHz,DMSO-d6)δ171.02,168.80,167.77,167.64,167.12,166.60,163.74,163.32,162.88,150.82, 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 ,126.92,126.40,122.92,118.56,78.18,76.64,75.03,68.22,65.87,65.28,58.43,55.93,49.08,43.59,4 2.29,41.10,37.37,33.63,31.72,25.49,23.55,20.31,15.32,12.49,12.42,12.32,12.25.HRMS(ESI)calcd for C 53 H 62 FN 11 O8S2[M+H] + 1064.4286, found 1064.4274.

[0295] Example 59: (2S,4R)-1-((R)-2-(1-fluorocyclopropane-1-carboxamido)-3-methyl-3-((2-((4-((4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)amino)-4-oxobutyl)amino)-2-oxoethyl)thio)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (LCG-59)

[0296] The synthesis method is the same as Example 57.

[0297] 1H NMR(600MHz,DMSO-d6)δ10.86(s,1H),9.84(s,1H),8.97(d,J=2.4Hz,1H),8.68(t,J=6.0Hz,1H),7.99(s,1H),7.97(d,J=5.6Hz,1H),7.53(dd,J=9.0,2.2Hz,1H),7.52–7.46(m,4H),7.43–7.36(m,4H),7.29(t,J=7.6Hz,1H),7.20(d,J=8.5Hz,2H),7.17(d,J=7.6Hz,1H),6.06(s,1H),5.20(s,1H),4.82(d,J=9.0Hz,1H),4.47(t,J=8.2Hz,1H),4.43–4.35(m,2H),4.33(t,J=7.0Hz,2H),4.27(dd,J=15.7,5.7Hz,1H),3.74(dd,J=10.7,3.9Hz,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=7.0Hz,2H),2.43(s,3H),2.34(s,3H),2.27(t,J=7.5Hz,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(150MHz,DMSO-d6)δ171.11,169.97,168.36,167.73,167.60,167.14,163.70,163.28,162.82,150.82,147.15,140.63,138.60,137.30,136.91,134.12,132.34,130.50,129.15,128.45,128.14,127.98,126.84,126.41,122.93,118.50,78.18,76.64,75.02,68.20,65.94,65.28,58.43,55.92,54.31,49.01,43.60,41.12,37.87,37.37,33.63,33.11,31.98,25.60,24.45,23.62,20.32,15.31,12.46,12.39,12.32,12.25.HRMS(ESI)calcd for C 55 H 66 FN11 O8S2[M+H] + 1114.4419, found 1114.4379.

[0298] Example 60: (2S,4R)-1-((R)-2-(1-fluorocyclopropane-1-carboxamido)-3-methyl-3-((2-((6-((4-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)phenyl)amino)-6-oxohexyl)amino)-2-oxoethyl)thio)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (LCG-60)

[0299] The synthesis method is the same as Example 57.

[0300] 1 H NMR(600MHz,DMSO-d6)δ10.85(s,1H),9.79(s,1H),8.97(s,1H),8.68(t,J=6.0Hz,1H), 7.99(s,1H),7.88(t,J=5.6Hz,1H),7.53(dd,J=9.0,2.3Hz,1H),7.52–7.46(m,4H),7.4 2–7.36(m,4H),7.29(t,J=7.6Hz,1H),7.19(d,J=8.5Hz,2H),7.17(d,J=7.5Hz,1H),6.0 6(s,1H),5.20(s,1H),4.81(d,J=9.0Hz,1H),4.47(t,J=8.2Hz,1H),4.40(dd,J=15.7,6. 3Hz,1H),4.37(s,1H),4.33(t,J=7.1Hz,2H),4.26(dd,J=15.8,5.7Hz,1H),3.73(dd,J= 10.7,4.0Hz,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=7.0Hz,2H),2.44(s,3H),2.34(s,3H),2.25(t,J=7.5Hz,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(150MHz,DMSO-d6)δ171.13,170.34,168.16,167.73,167.59,167.16,163.74,163.32,162.88,150.82,147.16,14 0.60,138.59,137.30,136.96,134.13,132.32,130.49,129.16,128.44,128.25,128.15,127.99,127.37,126.82,126. 40,122.92,118.50,78.18,76.64,75.03,68.20,65.92,65.28,58.44,55.92,54.33,48.99,43.59,41.11,38.11,37.3 8,35.65,33.64,31.98,28.12,25.64,25.45,24.21,23.66,20.31,15.31,12.46,12.39,12.31,12.25.HRMS(ESI)calcd for C 57 H 70 FN 11 O8S2[M+H] + 1142.4732,found 1142.4719.

[0301] Example 61: N 1 -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 4 -(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)succinimide (LCG-61)

[0302] The synthesis method is the same as Examples 1 and 37.

[0303] 1H NMR (600MHz, DMSO-d6) δ10.84(s,1H),8.98(s,1H),8.57(t,J=6.0Hz,1H),8.07(t,J=5.5Hz,1H),8.02(s,1H),7.91(d,J=9.3Hz,1H),7 .50(d,J=7.8Hz,1H),7.48(s,1H),7.42(d,J=8.4Hz,2H),7.38(d,J=8.3Hz,2H),7.29(t,J=7.6Hz,1H),7.17(d,J=7.5Hz,1H),6.07(s, 1H),5.13(brs,1H),4.52(d,J=9.4Hz,1H),4.45–4.39(m,2H),4.35(s,1H),4.22(dd,J=15.9,5.5Hz,1H),4.17(t,J=5.8Hz,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(150MHz,DMSO-d6)δ171.31,171.04,170.64,168.96,163.71,163.31,162.82,1 50.83,147.09,140.72,138.88,137.30,134.13,130.54,129.16,129.01,128.02,12 7.99,126.80,126.42,122.94,75.11,68.26,65.30,63.93,58.08,55.80,55.69,43. 60,41.02,37.60,37.31,34.71,30.24,29.87,25.73,20.31,15.32.HRMS(ESI)calcd for C 44 H 56 N 10 O7S[M+Na] + 891.3952, found 891.3949.

[0304] Example 62: N 1 -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 6-(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)adipamide (LCG-62)

[0305] The synthesis method is the same as Examples 1 and 37.

[0306] 1 H NMR (600MHz, DMSO-d6) δ10.85(s,1H),8.98(s,1H),8.57(t,J=6.1Hz,1H),8.04–7.98(m,2H),7.88(d,J=9.3Hz,1H),7.51(d,J=7.8H z,1H),7.48(s,1H),7.41(d,J=8.3Hz,2H),7.38(d,J=8.3Hz,2H),7.29(t,J=7.6Hz,1H),7.17(d,J=7.5Hz,1H),6.07(s,1H),5.14(br s,1H),4.54(d,J=9.4Hz,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=11.7,5.3Hz,4H),0.93(s,9H). 13 C NMR(150MHz,DMSO-d6)δ171.67,171.33,169.13,163.66,163.23,162.76,150.83,147 .09,140.79,138.87,137.29,134.11,130.54,129.17,129.01,128.01,127.98,126.7 9,126.44,122.96,75.09,68.25,65.30,64.03,58.08,55.75,55.71,43.61,41.02,37 .46,37.32,34.57,34.45,34.02,25.76,24.53,24.30,20.31,15.32.HRMS(ESI)calcd for C 46 H 60 N 10 O7S[M+Na] + 919.4265, found 919.4255.

[0307] Example 63: N 1 -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 8 -(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)octanediamide (LCG-63)

[0308] The synthesis method is the same as Examples 1 and 37.

[0309] 1 H NMR(600MHz,DMSO-d6)δ10.82(s,1H),8.98(s,1H),8.56(t,J=6.1Hz,1H),8 .01(s,1H),7.99(t,J=5.5Hz,1H),7.85(d,J=9.4Hz,1H),7.53–7.45(m,2H) ,7.42(d,J=8.3Hz,2H),7.39–7.36(m,2H),7.29(t,J=7.6Hz,1H),7.17(d,J =7.5Hz,1H),6.07(s,1H),5.12(brs,1H),4.54(d,J=9.4Hz,1H),4.46–4.39( m,2H),4.35(s,1H),4.22(dd,J=15.9,5.5Hz,1H),4.18(t,J=5.7Hz,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). 13C NMR(150MHz,DMSO-d6)δ171.77,171.47,171.33,169.11,163.71,163.33,162.82,150.83,14 7.09,140.71,138.88,137.30,134.13,130.54,129.15,129.01,128.01,127.98,126.79,126 .42,122.93,75.11,68.24,65.30,64.29,63.94,58.07,55.73,55.66,43.59,41.02,37.51,3 7.32,34.67,34.57,34.23,27.86,27.84,25.76,24.71,24.57,20.31,15.32.HRMS(ESI)calcd for C 48 H 64 N 10 O7S[M+Na] + 947.4578,found 947.4577.

[0310] Example 64: N 1 -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 10 -(2-((4-(2-((E)-3-methylbenzylidene)hydrazino)-6-morpholinopyrimidin-2-yl)oxy)ethyl)sebacate (LCG-64)

[0311] The synthesis method is the same as Examples 1 and 37.

[0312] 1H NMR(600MHz,DMSO-d6)δ10.82(s,1H),8.98(s,1H),8.56(t,J=6.1Hz,1H),8.01(s,1H),8.00(t,J=5.6Hz,1H),7.83(d,J=9.4Hz,1H),7.50(d,J=7.7Hz,1H),7.48(s,1H),7.42(d,J=8.2Hz,2H),7.38(d,J=8.3Hz,2H),7.29(t,J=7.6Hz,1H),7.17(d,J=7.5Hz,1H),6.07(s,1H),5.12(brs,1H),4.54(d,J=9.4Hz,1H),4.46–4.40(m,2H),4.35(s,1H),4.21(dd,J=15.9,5.5Hz,1H),4.18(t,J=5.7Hz,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). 13 C NMR(150MHz,DMSO-d6)δ171.77,171.45,171.32,169.08,163.70,163.34,162.80,150.82,147.08,140.69,138.88,137.29,134.12,130.53,129.15,129.00,128.00,127.98,126.79,126.41,122.92,75.10,68.23,65.29,64.29,63.93,58.05,55.71,55.63,43.59,41.01,37.52,37.32,34.68,34.57,34.23,28.13,28.04,25.74,24.79,24.64,20.31,15.31.HRMS(ESI)calcd for C 50 H 68 N 10 O7S[M+Na] + 975.4891,found 975.4878.

[0313] Example 65: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-4-((2-((4-(2- ((4-morpholino-6-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrimidin-2-yl)oxy)ethyl)phenyl)amino)-2-oxoethyl)amino)-4-oxobutyl)pyrrolidine-2-carboxamide(LCG-Ⅱ-1)

[0314] Step 1: Preparation of intermediate II-2

[0315] ⅱ-1 (150 mg, 0.95 mmol) was dissolved in 10 mL of ultra-dry DMF. NaH (80 mg, 2.85 mmol) was added in an ice bath and stirred at room temperature for 2 h. A solution of 4,6-dichloro-2-methylsulfanylpyrimidine (276 mg, 1.42 mmol) in DMF was added dropwise and allowed to react at room temperature for 3 h. Morpholine (330 mg, 3.8 mmol) was then added and the reaction continued at room temperature for 3 h. 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 dried by spin drying. 167 mg (48%) of a white solid was obtained by column chromatography. 1 H NMR(500MHz,Chloroform-d)δ8.56(d,J=2.7Hz,1H),7.75(s,1H),7.69(d,J=7.7Hz,1H),7.33(t,J=7.6Hz,1H),7.19(d,J=7 .5Hz,1H),6.91(s,1H),6.74(d,J=2.7Hz,1H),3.84–3.78(m,4H),3.78–3.72(m,4H),2.56(s,3H),2.43(s,3H).LC-MS:calcd for C 19 H 21 N5OS[M+H] + 368.1,found 368.2.

[0316] Step 2: Preparation of intermediate II-3

[0317] The 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 and stirred at room temperature for 12 h. After the reaction was completed by TLC, 10 mL of saturated sodium thiosulfate solution was added and stirred at room temperature for 2 h. 50 mL of water was added and extracted twice with dichloromethane. The organic phases were combined, washed once with saturated brine, dried over anhydrous Na2SO4, filtered, and slurried with methanol to obtain 455 mg (83%) of a white solid. 1 H NMR (600MHz, DMSO-d6) δ8.69(d,J=2.7Hz,1H),7.86(s,1H),7.82(d,J=7.9Hz,1H),7.37(t,J=7.6Hz,1H),7.30( s,1H),7.23(d,J=7.5Hz,1H),7.15(d,J=2.7Hz,1H),3.83–3.70(m,8H),3.43(s,3H),2.39(s,3H).LC-MS:calcd for C 19 H 21 N5O3S[M+H] + 400.1,found 400.0.

[0318] Step 3: Preparation of intermediate II-4

[0319] N-BOC-2-(4-aminophenyl)ethanol (355 mg, 1.5 mmol) was dissolved in 10 mL of ultra-dry DMF. NaH (54 mg, 2.25 mmol) was added in an ice bath and stirred at room temperature for 2 h. A DMF solution of intermediate ii-3 (300 mg, 0.75 mmol) was then added and the mixture was allowed to react at room temperature for 3 h. After completion of the reaction as monitored by TLC, 50 mL of water was added and the mixture was extracted twice with EA. The combined organic phases were washed once with saturated brine, dried over anhydrous Na2SO4, filtered, and separated by column chromatography to yield 312 mg (75%) of a white solid. 1 H NMR (600MHz, DMSO-d6) δ9.26 (s, 1H), 8.57 (d, J = 2.7Hz, 1H), 7.81 (s, 1H), 7.77 (d, J = 7.7Hz, 1H), 7.39 (d, J = 8.1Hz, 2H), 7.35 (t, J = 7.6Hz, 1H), 7.23–7. 17(m,3H),7.05(d,J=2.7Hz,1H),6.89(s,1H),4.47(t,J=7.1Hz,2H),3.76– 3.64(m,8H),2.97(t,J=7.0Hz,2H),2.38(s,3H),1.47(s,9H).LC-MS:calcd for C31 H 36 N6O4[M+H] + 557.3,found 557.3.

[0320] Step 4: Preparation of Intermediate II-5

[0321] Preparation of Intermediate ii-5 Refer to the preparation method of Intermediate 11 in Example 50. 1 H NMR(600MHz,DMSO-d6)δ9.87(s,1H),8.58(d,J=2.7Hz,1H),7.95(s,1H),7.81(s,1H),7.77 (d,J=7.7Hz,1H),7.52(d,J=8.5Hz,2H),7.35(t,J=7.6Hz,1H),7.26(d,J=8.5Hz,2H),7.21 (d,J=7.5Hz,1H),7.05(d,J=2.7Hz,1H),7.02(t,J=6.1Hz,1H),6.89(s,1H),4.49(t,J=7.0 Hz,2H),3.76–3.64(m,10H),3.00(t,J=7.0Hz,2H),2.38(s,3H),1.39(s,9H).LC-MS:calcd for C 33 H 39 N7O5[M+H] + 614.3,found 614.3.

[0322] Step 5: Preparation of LCG-II-1

[0323] Based on intermediate ii-5, the preparation method of LCG-50 in reference example 50 was used for synthesis. 1H NMR(600MHz,DMSO-d6)δ9.90(s,1H),8.98(s,1H),8.57(q,J=2.8Hz,2H),8.03(t,J=5.8Hz,1H),7.81(d,J=1.8Hz,1H),7.77(d,J=7.8Hz,1H),7.53(d,J=8.5Hz,2H),7.48–7.43(m,2H),7.41–7.36(m,2H),7.38–7.32(m,2H),7.25(d,J=8.5Hz,2H),7.21(m,1H),7.04(d,J=2.7Hz,1H),6.89(s,1H),5.16(d,J=3.6Hz,1H),4.84(q,J=7.7Hz,1H),4.64–4.57(m,1H),4.49(m,3H),4.29(s,1H),3.86(d,J=5.8Hz,2H),3.74–3.58(m,8H),3.65–3.53(m,2H),3.00(t,J=7.0Hz,2H),2.46(s,3H),2.38(s,3H),2.33(m,1H),2.24(m,1H),2.06(dd,J=12.7,7.7Hz,1H),1.95(q,J=7.7Hz,2H),1.75(m,1H),1.35(m,2H),1.26–1.18(m,2H),0.97(s,9H). 13 C NMR(150MHz,DMSO-d6)δ171.70,170.19,168.26,167.53,167.40,167.00,164.08,163.43,157.50,152.96,150.89,147.18,142.64,137.33,136.58,132.37,131.32,130.45,129.27,128.72,128.70,128.52,128.23,128.03,126.21,125.68,122.47,118.63,105.31,81.54,78.16,76.62,68.16,66.54,65.18,58.19,56.11,55.97,51.25,43.66,42.11,37.15,35.42,33.46,31.87,31.53,25.68,25.62,20.43,15.40,12.39,12.32,12.11,12.04.HRMS(ESI)calcd for C 57 H 66 FN 11 O8S[M+H] +1084.4879,found 1084.4877.

[0324] Example 66: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-((6-((4-(2-((4-morpho lino-6-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrimidin-2-yl)oxy)ethyl)phenyl)amino)-6-oxohexyl)amino)-2-oxoethoxy)benzyl)pyrrolidine-2-carboxamide(LCG-Ⅱ-2)

[0325] Based on intermediate ii-4, the preparation method of LCG-53 in reference example 53 was used for synthesis. 1H NMR(600MHz,DMSO-d6)δ9.80(s,1H),8.98(s,1H),8.57(d,J=2.7Hz,1H),8.56(t,J=6.2Hz,1H),8.13(t,J=5.9Hz,1H),7.81(d,J=1.8Hz,1H),7.77(d,J=7.7Hz,1H),7.53(d,J=8.4Hz,2H),7.43(d,J=7.8Hz,1H),7.35(t,J=7.6Hz,1H),7.27(dd,J=9.2,2.7Hz,1H),7.22(m,3H),7.04(d,J=2.7Hz,1H),7.02(dd,J=7.7,1.6Hz,1H),6.96(d,J=1.7Hz,1H),6.89(s,1H),5.17(d,J=3.6Hz,1H),4.61–4.42(m,7H),4.35(s,1H),4.30(dd,J=15.8,5.7Hz,1H),3.73–3.58(m,10H),3.15(m,2H),2.99(t,J=7.1Hz,2H),2.45(s,3H),2.38(s,3H),2.26(t,J=7.4Hz,2H),2.09–2.02(m,1H),1.91–1.85(m,1H),1.57(p,J=7.5Hz,2H),1.48(p,J=7.2Hz,2H),1.40–1.32(m,2H),1.32–1.25(m,2H),1.21(dd,J=8.5,3.2Hz,2H),0.95(s,9H). 1313C NMR(150MHz,DMSO-d6)δ171.10,170.37,168.27,167.50,167.36,166.60,164.09,163.44,157.51,154.51,152.97,150.96,147.37,137.34,137.06,132.02,131.33,130.60,130.46,128.72,128.69,128.45,128.32,128.03,126.49,125.69,122.48,120.86,118.55,111.55,105.31,81.54,78.27,76.73,68.27,66.60,65.19,64.30,58.24,56.10,55.93,43.67,37.68,37.23,36.81,35.65,35.63,35.41,33.48,28.37,25.59,25.51,25.45,24.26,20.44,15.40,15.37,14.55,12.39,12.32,12.13,12.06.HRMS(ESI)calcd for C 60 H 72 FN 11 O9S[M+H] + 1142.5297,found 1142.5284.

[0326] Example 67: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-((4-(4-((4-morpholino-6-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrimidin-2-yl)oxy)piperidin-1-yl)phenyl)amino)-3-oxopropyl)pyrrolidine-2-carboxamide (LCG-II-3)

[0327] Step 1: Preparation of intermediate ii-6

[0328] 4-Hydroxypiperidine (500 mg, 5.0 mmol) was dissolved in 10 mL of acetonitrile, and 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 h, filtered and dried to obtain a yellow solid, which was not further purified. LC-MS: calculated for C 11 H 14 N2O3[M+H] + 222.1,found 222.3.

[0329] Step 2: Preparation of intermediate II-7

[0330] Based on intermediates ii-3 and ii-6, the nitro-containing intermediate was obtained by referring to the synthesis method of ii-4 above, and then a conventional nitro hydrogenation reduction reaction was used to obtain intermediate ii-7. 1 H NMR (600MHz, DMSO-d6) δ8.59(d,J=2.7Hz,1H),7.82(s,1H),7.78(d,J=8.0Hz,1H),7.35(t,J =7.6Hz,1H),7.21(dt,J=7.5,0.9Hz,1H),7.06(d,J=2.7Hz,1H),6.89(s,1H),6.74(d,J=8.8 Hz,2H),6.50(d,J=8.7Hz,2H),5.12–5.04(m,1H),4.59(s,2H),3.74–3.63(m,8H),3.29–3.2 2(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:calcd for C 29 H 33 N7O2[M+H] + 512.3,found 512.3.

[0331] Step 3: Preparation of LCG-II-3

[0332] Based on intermediate ii-7, the preparation method of LCG-50 in reference example 50 was used for synthesis. 1H NMR(600MHz,DMSO-d6)δ9.69(s,1H),8.98(s,1H),8.61(d,J=7.9Hz,1H),8.60(d,J=2.7Hz,1H),7.82(s,1H),7.78(d,J=7.7Hz,1H),7.46–7.40(m,4H),7.40–7.32(m,3H),7.26(dd,J=9.2,2.9Hz,1H),7.24–7.17(m,1H),7.06(d,J=2.7Hz,1H),6.91(s,1H),6.90(s,2H),5.27(q,J=7.7Hz,1H),5.18–5.10(m,2H),4.58(d,J=9.2Hz,1H),4.48(t,J=8.3Hz,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=9.2Hz,2H),2.87–2.77(m,2H),2.44(s,3H),2.39(s,3H),2.11(d,J=11.7Hz,2H),2.05(dd,J=12.8,7.9Hz,1H),1.85–1.72(m,3H),1.43–1.29(m,2H),1.22(dd,J=8.6,3.0Hz,2H),0.98(s,9H). 13 C NMR(150MHz,DMSO-d6)δ169.92,168.24,167.48,167.34,166.83,164.21,162.88,157.55,152.99,150.93,147.21,141.63,137.36,131.35,130.43,129.41,128.75,128.10,128.05,126.51,125.71,122.50,119.94,115.66,105.34,81.48,78.31,76.77,71.38,68.19,65.23,64.32,58.21,56.01,55.98,49.28,46.25,45.14,43.70,41.98,37.07,35.48,29.69,25.69,25.65,20.46,15.42,14.57,12.41,12.34,12.13,12.06,8.03.HRMS(ESI)calcd for C 57 H 66 FN 11 O7S[M+H] +1068.4929,found 1068.4927.

[0333] Example 68: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-4-((4-( 4-((4-morpholino-6-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrimidin-2-yl)oxy)piperidin-1-yl)phenyl)amino)-4-oxobutyl)pyrrolidine-2-carboxamide(LCG-Ⅱ-4)

[0334] Synthesized according to the preparation method of LCG-Ⅱ-3 in Reference Example 67. 1 H NMR (600MHz, DMSO-d6) δ9.60 (s, 1H), 8.99 (s, 1H), 8.60 (d, J = 2.7Hz, 1H), 8.57 (d ,J=8.2Hz,1H),7.82(s,1H),7.78(d,J=7.7Hz,1H),7.46(d,J=8.3Hz,2H),7.41( dd,J=13.7,8.4Hz,4H),7.35(t,J=7.6Hz,1H),7.28(dd,J=9.2,2.8Hz,1H),7.21 (d,J=7.6Hz,1H),7.06(d,J=2.7Hz,1H),6.92(d,J=8.5Hz,2H),6.90(s,1H),5.17 –5.10(m,2H),4.86(q,J=8.1Hz,1H),4.59(d,J=9.2Hz,1H),4.50(t,J=8.3Hz,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=10.1Hz,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=8.4,2.5Hz,2H),0.97(s,9H). 13C NMR (150MHz, DMSO-d6) δ170.23,169.51,168.24,167.50,167.37,164.21,162.88,157.55,152.99,150.92,147.20,146 .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 .16,35.45,32.56,31.59,29.73,25.70,25.63,20.45,15.43,14.57,12.41,12.34,12.14,12.07,8.03.HRMS(ESI)calcd for C 58 H 68 FN 11 O7S[M+H] + 1082.5086,found 1082.5076.

[0335] Example 69: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-6-((4-( 4-((4-morpholino-6-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrimidin-2-yl)oxy)piperidin-1-yl)phenyl)amino)-6-oxohexyl)pyrrolidine-2-carboxamide(LCG-Ⅱ-5)

[0336] Synthesized according to the preparation method of LCG-Ⅱ-3 in Reference Example 67. 1H NMR(600MHz,DMSO-d6)δ9.61(s,1H),8.99(s,1H),8.60(d,J=2.7Hz,1H),8.46(d,J=8.2Hz,1H),7.82(s,1H),7.78(d,J=7.7Hz,1H),7.42(d,J=8.3Hz,4H),7.36(m,3H),7.27(dd,J=9.3,2.8Hz,1H),7.21(d,J=7.5Hz,1H),7.06(d,J=2.7Hz,1H),6.91(d,J=8.3Hz,3H),5.17–5.10(m,2H),4.80(q,J=7.7Hz,1H),4.58(d,J=9.2Hz,1H),4.50(t,J=8.2Hz,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=9.4Hz,2H),2.45(s,3H),2.39(s,3H),2.24(t,J=7.4Hz,2H),2.16–2.09(m,2H),2.04(dd,J=12.9,7.9Hz,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=8.4,2.9Hz,2H),0.97(s,9H). 13 C NMR(150MHz,DMSO-d6)δ170.05,169.91,168.11,167.47,167.34,164.21,162.89,157.55,152.99,150.86,147.14,146.33,143.23,137.35,131.34,130.81,130.51,129.10,128.75,128.16,128.05,126.22,125.70,122.49,119.61,115.73,105.34,81.48,78.30,76.75,71.40,68.21,65.23,64.31,58.04,56.03,55.96,51.44,46.32,45.13,43.69,37.12,35.59,35.48,35.46,29.73,25.73,25.62,24.78,24.35,20.45,15.43,14.57,12.41,12.34,12.12,12.06,8.03.HRMS(ESI)calcd for C60 H 72 FN 11 O7S[M+H] + 1110.5399,found 1110.5399.

[0337] Example 70: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-(4-((4-(2-( (4-morpholino-6-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrimidin-2-yl)oxy)ethyl)phenyl)ethynyl)piperidin-1-yl)-3-oxopropyl)pyrrolidine-2-carboxamide(LCG-Ⅱ-6)

[0338] Step 1: Preparation of intermediate II-8

[0339] 4-Bromophenethyl alcohol (200 mg, 1.0 mmol), 1-Boc-4-ethynylpiperidine (630 mg, 3.0 mmol), cuprous iodide (400 mg, 0.2 mmol), bistriphenylphosphine palladium dichloride (70 mg, 0.1 mmol), and triethylamine (304 mg, 3.0 mmol) were dissolved in 10 mL of ultra-dry DMF, replaced with nitrogen twice, and reacted at 60 ° C for 8 h. After the reaction was completed as monitored 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, and separated by spin drying and column chromatography to obtain 200 mg (61%) of a yellow oil. 1 H NMR (600MHz, DMSO-d6) δ7.29(d,J=8.2Hz,2H),7.19(d,J=8.2Hz,2H),4.64(s,1H),3.69–3.61(m,2H),3.59(t,J=7.0Hz,2H) ,3.12(brs,2H),2.89–2.80(m,1H),2.71(t,J=6.9Hz,2H),1.83–1.76(m,2H),1.55–1.45(m,2H),1.40(s,9H).LC-MS:calcd for C 20 H 27 NO3[M+H] + 330.2,found 330.2.

[0340] Step 2: Preparation of Intermediate II-9

[0341] Based on intermediate ii-8, intermediate ii-9 was obtained by referring to the synthesis method of ii-4 above. 1 H NMR(500MHz,Chloroform-d)δ8.52(t,J=2.4Hz,1H),7.74(s,1H),7.69(d,J=7.4Hz,1H),7. 37–7.30(m,3H),7.23(d,J=8.0Hz,2H),7.20–7.16(m,1H),6.89(d,J=1.9Hz,1H),6.74(t,J =2.4Hz,1H),4.52(t,J=7.5Hz,2H),3.83–3.64(m,10H),3.33–3.17(m,2H),3.13(t,J=7.4Hz,2H),2 .78(d,J=7.5Hz,1H),2.43(s,3H),1.84(brs,2H),1.66(d,J=10.5Hz,2H),1.47(s,9H).LC-MS:calcd for C 38 H 44 N6O4[M+H] + 649.3,found 649.4.

[0342] Step 3: Preparation of LCG-II-6

[0343] Based on intermediate ii-9, the synthesis was carried out according to the preparation method of LCG-50 in reference example 50. 1H NMR(600MHz,DMSO-d6)δ8.95(d,J=24.6Hz,1H),8.57(t,J=2.8Hz,1H),8.51(dd,J=11.6,8.0Hz,1H),7.81(s,1H),7.77(d,J=7.8Hz,1H),7.46–7.37(m,4H),7.35(t,J=7.6Hz,1H),7.33–7.24(m,4H),7.22(dd,J=12.2,7.9Hz,2H),7.05(d,J=2.7Hz,1H),6.89(s,1H),5.24–5.10(m,2H),4.57(d,J=9.2Hz,1H),4.52(t,J=6.8Hz,2H),4.45(t,J=8.2Hz,1H),4.28(s,1H),3.92–3.50(m,13H),3.27–3.16(m,1H),3.05(t,J=6.7Hz,2H),2.94–2.78(m,3H),2.44(d,J=7.2Hz,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(150MHz,DMSO-d6)δ169.92,169.87,168.26,168.22,167.48,167.35,167.05,166.96,164.09,163.41,157.51,153.00,150.92,150.84,147.17,141.76,137.96,137.87,137.35,131.33,130.72,130.66,130.47,130.45,129.48,129.38,128.75,128.72,128.54,128.49,128.11,128.05,126.66,125.70,122.49,120.21,105.34,81.60,78.29,76.75,68.19,66.19,65.21,64.32,58.18,55.95,49.61,49.21,45.14,37.01,35.46,33.84,31.01,30.47,26.32,26.17,25.66,25.63,20.46,15.41,15.37,14.57,12.40,12.33,12.12,12.05,8.04.HRMS(ESI)calcd for C 61 H 69 FN10 O7S[M+H] + 1105.5133, found 1105.5138.

[0344] Example 71: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-4-(4-((4-(2- ((4-morpholino-6-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrimidin-2-yl)oxy)ethyl)phenyl)ethynyl)piperidin-1-yl)-4-oxobutyl)pyrrolidine-2-carboxamide(LCG-Ⅱ-7)

[0345] Synthesized according to the preparation method of LCG-Ⅱ-6 in Reference Example 70. 1H NMR(600MHz,DMSO-d6)δ8.99(s,1H),8.57(d,J=2.7Hz,1H),8.53(dd,J=12.7,8.7Hz,1H),7.81(s,1H),7.77(d,J=7.7Hz,1H),7.46(d,J=8.3Hz,2H),7.40(d,J=8.2Hz,2H),7.38–7.28(m,5H),7.21(d,J=7.6Hz,1H),7.18(d,J=9.0Hz,1H),7.05(d,J=2.7Hz,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=6.4Hz,2H),4.49–4.44(m,1H),4.31(s,1H),3.83–3.54(m,12H),3.06(t,J=6.9Hz,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=12.9,7.6Hz,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=18.9Hz,9H). 13C NMR (150MHz, DMSO-d6) δ170.26,170.22,169.54,169.45,168.18,168.14,167.41,167.38,167.28,167.26,164.08,163.40,157.50,152. 99,150.90,147.21,143.13,143.08,137.92,137.35,131.32,130.71 ,130.68,130.47,129.22,129.21,128.74,128.69,128.51,128.48,1 28.29,128.04,126.10,126.06,125.70,122.49,120.28,105.33,81.58,68.28,66.21,65.20,64.31,58.38,56.16,55.98,43.68,42.61, 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)calcd for C 62 H 71 FN 10 O7S[M+H] + 1119.5290,found 1119.5293.

[0346] Example 72: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-( 4-(4-methylthiazol-5-yl)phenyl)-6-(4-((4-(2-((4-morpholino-6-(3-(m-tolyl))-1H-pyrazol-1-yl)pyrimidin-2- yl)oxy)ethyl)phenyl)ethynyl)piperidin-1-yl)-6-oxohexyl)pyrrolidine-2-carboxamide(LCG-Ⅱ-8)

[0347] Synthesized according to the preparation method of LCG-II-6 in Reference Example 70. 1H NMR(600MHz,DMSO-d6)δ8.98(s,1H),8.56(d,J=2.7Hz,1H),8.45(d,J=6.9Hz,1H),7.81(s,1H),7.77(d,J=7.7Hz,1H),7.43(d,J=8.3Hz,2H),7.38(d,J=8.2Hz,2H),7.38–7.31(m,3H),7.30(d,J=7.8Hz,2H),7.28–7.22(m,1H),7.21(d,J=7.6Hz,1H),7.04(d,J=2.2Hz,1H),6.89(s,1H),5.13(brs,1H),4.82(q,J=5.7,5.2Hz,1H),4.57(d,J=9.2Hz,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=6.8Hz,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=12.9,7.8Hz,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=4.3Hz,9H). 1313C NMR(150MHz, 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, 131.33, 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, 105.33, 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, 33.85, 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) calcd for C 64 H 75 FN 10 O7S [M + H] + 1147.5603, found 1147.5604.

[0348] Example 73: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-(3-(3-(4-(2-((4-morpholino-6-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrimidin-2-yl)oxy)ethyl)phenyl)ureido)azetidin-1-yl)-3-oxopropyl)pyrrolidine-2-carboxamide (LCG-II-9)

[0349] Step 1: Preparation of Intermediate ii-10

[0350] Intermediate ⅱ-4 (300 mg, 0.44 mmol) was dissolved in 10 mL of dichloromethane, 4 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 3 h. After being spun off, it was redissolved in isopropanol / water (10 mL / 8 mL), and phenyl chloroformate (86 mg, 0.6 mmol) and Na2HPO4 (93 mg, 0.7 mmol) were added. The mixture was reacted at room temperature for 12 h. After the reaction was completed as monitored 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, spun off, and slurried with PE / EA to obtain 200 mg (79%) of a white solid. 1 H NMR(600MHz,DMSO-d6) δ10.18(s,1H),8.58(d,J=2.7Hz,1H),7.82(s,1H),7.77(d,J=7.7Hz,1H),7.48–7.40(m,4H),7.35(t,J=7.6Hz,1H),7.31–7.23(m,3H),7.24 LC-MS for C 33 H 32 N6O4[M+H] + 577.3,found 577.2.

[0351] Step 2: Preparation of intermediate II-11

[0352] 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 for 24 h. After completion of the reaction as monitored by TLC, a white solid precipitated after cooling. The target product (139 mg, 61%) was obtained by filtration. LC-MS: calculated for C 35 H 42 N8O5[M+H] + 655.3,found 655.3.

[0353] Step 3: Preparation of LCG-II-9

[0354] Based on intermediate ii-11, the preparation method of LCG-50 in reference example 50 was used to synthesize it. 1H NMR(600MHz,DMSO-d6)δ8.98(d,J=10.7Hz,1H),8.57(d,J=2.7Hz,1H),8.56–8.45(m,2H),7.81(s,1H),7.77(d,J=7.7Hz,1H),7.48–7.42(m,2H),7.40(d,J=8.2Hz,2H),7.38–7.25(m,4H),7.21(d,J=7.5Hz,1H),7.18(dd,J=8.7,2.3Hz,2H),7.05(d,J=2.7Hz,1H),6.89(s,1H),6.73(dd,J=17.3,6.6Hz,1H),5.19–5.11(m,1H),4.58(d,J=9.2Hz,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=6.9Hz,2H),2.70–2.60(m,1H),2.59–2.52(m,1H),2.46(d,J=8.4Hz,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). 13C NMR(150MHz,DMSO-d6)δ169.88,168.68,168.63,168.24,167.54,167.50,1 67.40,167.37,164.10,163.47,157.52,154.03,152.98,150.96,150.91,14 7.25,147.22,141.84,141.70,137.80,137.35,131.34,130.44,129.48,129.43,128.74,128.70,128.48,128.15,128.05,126.49,126.44,125.70,122 .49,117.56,117.52,105.34,81.54,78.28,78.25,76.74,76.71,68.18,66.70,66.32,65.21,64.32,58.18,58.16,56.93,56.76,55.97,54.10,53.96, 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)calcd for C 58 H 67 FN 12 O8S[M+H] + 1111.4988,found 1111.4989.

[0355] Example 74: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-4-(3-(3-(4-(2) -((4-morpholino-6-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrimidin-2-yl)oxy)ethyl)phenyl)ureido)azetidin-1-yl)-4-oxobutyl)pyrrolidine-2-carboxamide(LCG-Ⅱ-10)

[0356] Synthesized according to the preparation method of LCG-II-9 in Reference Example 73. 1H NMR(600MHz,DMSO-d6)δ8.98(d,J=1.9Hz,1H),8.57(d,J=2.7Hz,1H),8.52(d,J=8.5Hz,1H),8.50(d,J=5.3Hz,1H),7.82(s,1H),7.77(d,J=7.8Hz,1H),7.46(d,J=8.1Hz,2H),7.41–7.36(m,2H),7.37–7.32(m,3H),7.31–7.23(m,1H),7.21(d,J=7.6Hz,1H),7.18(d,J=8.4Hz,2H),7.05(d,J=2.7Hz,1H),6.89(s,1H),6.77(dd,J=10.0,7.0Hz,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=7.1Hz,2H),2.46(d,J=2.1Hz,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=7.5Hz,9H). 1313C NMR(150MHz, 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, 122.48, 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) calcd for C 59 H 69 FN 12 O8S [M+H] + 1125.5144, found 1125.5143. <00015​​​​​​​4-Bromophenethanol (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-dry 1,4-dioxane, replaced with nitrogen twice, and reacted at 90°C for 12 h. After the reaction was completed as 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, and separated by spin-drying and column chromatography to obtain 540 mg (64%) of a yellow oil. 1 H NMR(600MHz,DMSO-d6)δ7.38(d,J=3.9Hz,4H),7.35–7.30(m,1H),7.07(d,J=8.6Hz,2H),6.86(d,J=8.6Hz,2H) ,5.10(s,2H),4.57(t,J=5.2Hz,1H),3.63–3.46(m,6H),3.09–2.99(m,3H),2.62(t,J=7.2Hz,2H).LC-MS:calcd for C 20 H 24 N2O3[M+H] + 341.2,found 341.2.

[0360] Step 2: Preparation of intermediate II-13

[0361] Based on intermediates ii-3 and ii-12, the synthetic method of ii-4 was referred to obtain an intermediate containing a Cbz protective group, and then a conventional hydrogenation reduction reaction was used to obtain intermediate ii-13. 1 H NMR(600MHz,DMSO-d6)δ8.57(d,J=2.7Hz,1H),7.81(s,1H),7.77(d,J=7.7Hz, 1H),7.35(t,J=7.6Hz,1H),7.25–7.18(m,3H),7.05(d,J=2.7Hz,1H),6.94(d, J=8.7Hz,1H),6.89(s,1H),4.47(t,J=7.0Hz,2H),3.75–3.63(m,8H),3.41–3. 26(m,8H),3.22–3.13(m,4H),2.97(t,J=7.0Hz,2H),2.38(s,3H).LC-MS:calcd for C 30 H 35 N7O2[M+H] + 526.3,found 526.2.

[0362] Step 3: Preparation of LCG-II-11

[0363] Based on intermediate ii-13, the preparation method of LCG-50 in reference example 50 was used to synthesize it. 1 H NMR (600MHz, DMSO-d6) δ8.96(s,1H),8.57(d,J=2.7Hz,1H),8.53(d,J=7.9Hz,1H),7.81(s,1H),7.77(d,J=7.7Hz,1H),7.44–7.39(m,4H),7.35(t,J= 7.6Hz,1H),7.26(dd,J=9.2,2.8Hz,1H),7.21(d,J=7.1Hz,1H),7.15(d,J= 8.5Hz,2H),7.05(d,J=2.7Hz,1H),6.89(s,1H),6.85(d,J=8.7Hz,2H),5.21 (q,J=7.2Hz,1H),5.14(s,1H),4.57(d,J=9.8Hz,1H),4.46(q,J=7.7,6.9H z,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=8.5,3.3Hz,2H),0.96(s,9H). 13C NMR(150MHz,DMSO-d6)δ169.89,168.22,167.47,167.34,167.17,164.10,163.46,157.52,152.98,150.91,15 0.88,148.73,147.19,147.18,141.65,137.34,131.33,130.40,129.43,128.82,128.79,128.73,128.68,128. 34,128.12,128.04,126.92,126.66,125.69,122.48,115.47,115.44,105.32,81.52,78.27,76.73,68.16,66.79,65.19,64.30,58.16,55.94,55.89,49.39,48.26,47.90,45.14,44.47,43.68,40.33,37.91,37.02,35.43, 33.18,25.65,25.61,20.44,15.32,14.56,12.39,12.32,12.11,12.05,8.02.HRMS(ESI)calcd for C 58 H 68 FN 11 O7S[M+H] + 1082.5086,found 1082.5083.

[0364] Example 76: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-4-(4-(4- (2-((4-morpholino-6-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrimidin-2-yl)oxy)ethyl)phenyl)piperazin-1-yl)-4-oxobutyl)pyrrolidine-2-carboxamide(LCG-Ⅱ-12)

[0365] Synthesized according to the preparation method of LCG-II-11 in Reference Example 75. 1H NMR(600MHz,DMSO-d6)δ8.99(s,1H),8.57(d,J=2.7Hz,1H),8.55(d,J=8.8Hz,1H),7.82(s,1H),7.77(d,J=7.8Hz,1H),7.46(d,J=8.3Hz,2H),7.40(d,J=8.3Hz,2H),7.35(t,J=7.6Hz,1H),7.25–7.13(m,4H),7.05(d,J=2.7Hz,1H),6.90(d,J=8.1Hz,3H),5.16(brs,1H),4.98–4.90(m,1H),4.57(d,J=9.2Hz,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=7.0Hz,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(150MHz,DMSO-d6)δ170.25,169.79,168.23,167.43,167.30,164.11,163.48,157.53,152.99,150.91,148.79,147.22,142.99,137.36,131.34,130.48,129.26,128.84,128.75,128.67,128.45,128.30,128.05,126.12,125.70,122.49,115.50,105.33,81.53,78.41,76.87,68.27,66.81,65.21,58.35,56.15,56.04,50.76,48.37,48.17,43.91,43.69,40.30,37.17,35.59,33.19,31.67,28.76,25.66,25.59,20.46,15.42,12.41,12.34,12.09,12.02,10.66.HRMS(ESI)calcd for C 59 H 70 FN 11 O7S[M+H] + 1096.5242,found 1096.5243.

[0366] Example 77: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-6-(4-(4- (2-((4-morpholino-6-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrimidin-2-yl)oxy)ethyl)phenyl)piperazin-1-yl)-6-oxohexyl)pyrrolidine-2-carboxamide(LCG-Ⅱ-13)

[0367] Synthesized according to the preparation method of LCG-II-11 in Reference Example 75. 1 H NMR (600MHz, DMSO-d6) δ8.98(s,1H),8.57(d,J=2.7Hz,1H),8.46(d,J=8.4Hz,1H),7.81(s,1H),7.77(d,J=7.9Hz,1H),7.43(d,J=8.2 Hz,2H),7.38(d,J=8.3Hz,2H),7.35(t,J=7.6Hz,1H),7.26(dd,J=9.2,2.8Hz,1H),7.21(d,J=7.5Hz,1H),7.18(d,J=8.5Hz,2H),7.04 (d,J=2.7Hz,1H),6.92–6.86(m,3H),5.13(brs,1H),4.81(td,J=8.4,6.1Hz,1H),4.58(dd,J=9.3,1.2Hz,1H),4.50(t,J=8.2Hz,1H), 4.46(t,J=7.1Hz,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=7.1Hz,2H),2.45(s,3H),2.38 (s,3H),2.33(t,J=7.5Hz,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=8.5,3.1Hz,2H),0.96(s,9H). 13C NMR (150MHz, DMSO-d6) δ170.08,169.96,168.10,167.45,167.32,164.10,163.48,157.52,152.99,150.87,148.81,147.15,143. 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)calcd for C 61 H 74 FN 11 O7S[M+H] + 1124.5555,found 1124.5555.

[0368] Example 78: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-(4-(3-(4-(2- ((4-morpholino-6-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrimidin-2-yl)oxy)ethyl)phenyl)ureido)piperidin-1-yl)-3-oxopropyl)pyrrolidine-2-carboxamide(LCG-Ⅱ-14)

[0369] Synthesized according to the preparation method of LCG-II-9 in Reference Example 73. 1H NMR(600MHz,DMSO-d6)δ8.98(d,J=8.5Hz,1H),8.57(d,J=2.7Hz,1H),8.48(dd,J=14.9,8.0Hz,1H),8.27(d,J=20.7Hz,1H),7.81(s,1H),7.77(d,J=7.7Hz,1H),7.46–7.37(m,4H),7.35(t,J=7.6Hz,1H),7.34–7.25(m,3H),7.21(d,J=7.5Hz,1H),7.17(d,J=8.5Hz,2H),7.05(d,J=2.7Hz,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=9.2Hz,1H),4.46(q,J=8.7,7.9Hz,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=7.1Hz,2H),2.93–2.75(m,3H),2.46(d,J=3.3Hz,3H),2.38(s,3H),2.04(dd,J=12.9,7.9Hz,1H),1.85–1.67(m,3H),1.47–1.15(m,6H),0.98(s,9H). 13C NMR(150MHz,DMSO-d6)δ169.92,169.90,168.23,167.51,167.38,166.97, 164.09,163.46,157.51,153.90,153.88,152.97,150.93,150.90,147.19 ,141.79,141.74,138.10,137.34,131.33,130.46,130.03,129.41,129.3 8,128.73,128.69,128.49,128.12,128.08,128.04,126.91,126.73,126. 67,125.69,122.48,117.17,105.32,81.53,78.26,76.72,68.18,68.16,6 6.72,66.30,65.19,64.30,58.18,55.94,49.37,49.16,45.48,45.38,43. 67,43.22,43.13,37.96,37.02,35.71,35.42,33.39,31.87,31.02,25.62 ,20.44,15.37,15.34,14.55,12.39,12.32,12.13,12.06.HRMS(ESI)calcd for C 60 H 71 FN 12 O8S[M+H] + 1139.5301, found 1139.5303.

[0370] Example 79: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-4-(4-(3-(4-(2) -((4-morpholino-6-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrimidin-2-yl)oxy)ethyl)phenyl)ureido)piperidin-1-yl)-4-oxobutyl)pyrrolidine-2-carboxamide(LCG-Ⅱ-15)

[0371] Synthesized according to the preparation method of LCG-II-9 in Reference Example 73. 1H NMR(600MHz,DMSO-d6)δ8.99(s,1H),8.57(d,J=2.7Hz,1H),8.55(dd,J=8.9,4.9Hz,1H),8.28(d,J=13.3Hz,1H),7.82(s,1H),7.77(d,J=7.7Hz,1H),7.47(d,J=8.2Hz,2H),7.41(d,J=7.9Hz,2H),7.35(t,J=7.6Hz,1H),7.32(d,J=8.3Hz,2H),7.19(dd,J=20.2,7.8Hz,4H),7.05(d,J=2.7Hz,1H),6.89(s,1H),6.14(dd,J=35.1,7.6Hz,1H),5.17(s,1H),4.93(td,J=10.1,4.4Hz,2H),4.58(dd,J=9.5,3.2Hz,1H),4.52–4.44(m,3H),4.32(s,1H),4.19(dd,J=58.7,12.8Hz,1H),3.88(s,1H),3.74–3.55(m,11H),3.23–3.07(m,1H),2.97(t,J=7.1Hz,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=12.8,7.6Hz,1H),1.99–1.73(m,5H),1.43–1.12(m,6H),0.98(s,9H). 13C NMR(150MHz,DMSO-d6)δ170.26,170.22,169.61,169.53,168.22,168.19,167.49,167.46,167.36,167.32,164.10,163.47,157.53,153.91,153.89,152.99,150.91,147.22,143.09,143.02,138.20,138.15,137.36,131.35,130.48,130.04,130.01,129.25,128.74,128.69,128.49,128.30,128.05,126.12,125.71,122.49,117.21,117.17,117.12,105.33,81.54,78.36,78.23,76.82,76.69,68.28,66.75,65.21,64.32,58.40,58.35,56.17,56.13,55.96,50.87,50.69,45.59,45.45,43.68,42.76,37.16,35.66,35.58,33.40,32.22,32.00,31.79,31.26,31.19,29.00,28.77,25.64,25.58,25.55,20.46,15.44,15.41,14.57,12.38,12.31,12.23,12.11,12.04,11.97.HRMS(ESI)calcd for C 61 H 73 FN 12 O8S[M+H] + 1153.5458,found 1153.5457.

[0372] Example 80: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-(3-(3-(4-(4-((4- morpholino-6-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrimidin-2-yl)oxy)piperidin-1-yl)phenyl)ureido)azetidin-1-yl)-3-oxopropyl)pyrrolidine-2-carboxamide(LCG-Ⅱ-16)

[0373] The preparation methods of LCG-Ⅱ-3 in Reference Example 67 and LCG-Ⅱ-9 in Example 73 were used for synthesis. 1 H NMR(600MHz,DMSO-d6)δ8.99(d,J=7.2Hz,1H),8.60(d,J=2.6Hz,1H),8.53(dd,J=1 1.8,8.1Hz,1H),8.27(d,J=23.1Hz,1H),7.82(s,1H),7.78(d,J=7.7Hz,1H),7.48–7 .42(m,2H),7.40(dd,J=8.3,1.7Hz,2H),7.35(t,J=7.7Hz,1H),7.30(ddd,J=24.0, 9.3,2.8Hz,1H),7.25–7.19(m,3H),7.06(d,J=2.7Hz,1H),6.90(s,3H),6.67–6.58( m,1H),5.20–5.06(m,3H),4.59(d,J=9.2Hz,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=7.1Hz,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). 13C NMR(150MHz,DMSO-d6)δ170.37,169.18,169.13,168.74,168.73,168.04 ,168.00,167.90,167.87,164.71,163.38,158.05,154.70,153.49,151. 46,151.42,147.74,147.73,142.34,142.20,137.85,131.84,130.94,12 9.97,129.92,129.24,128.65,128.55,126.98,126.94,126.20,122.99, 119.31,116.71,105.84,81.98,78.78,78.75,77.24,77.20,71.90,68.6 8,66.82,65.73,64.81,58.67,58.66,57.47,57.31,56.47,54.65,54.51 ,49.29,49.27,47.17,44.19,37.59,37.57,37.49,35.96,35.94,30.31, 26.14,20.95,15.90,15.07,12.90,12.83,12.63,12.57.HRMS(ESI)calcd for C 61 H 72 FN 13 O8S[M+H] + 1166.5410, found 1166.5414.

[0374] Example 81: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-4-(3-(3-(4-(4-((4 -morpholino-6-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrimidin-2-yl)oxy)piperidin-1-yl)phenyl)ureido)azetidin-1-yl)-4-oxobutyl)pyrrolidine-2-carboxamide(LCG-Ⅱ-17)

[0375] The preparation methods of LCG-Ⅱ-3 in Reference Example 67 and LCG-Ⅱ-9 in Example 73 were used for synthesis.1 H NMR(600MHz,DMSO-d6)δ8.99(d,J=1.0Hz,1H),8.60(d,J=2.6Hz,1H),8.52(d,J=8.5Hz,1H),8.26(brs,1H),7.82(s,1H),7.78(d,J=7.8Hz,1H),7.46(d,J=8.1Hz,2H),7.38(dd,J=8.2,3.4Hz,2H),7.35(t,J=7.6Hz,1H),7.30–7.19(m,4H),7.06(d,J=2.7Hz,1H),6.90(s,3H),6.67(brs,1H),5.14(d,J=12.7Hz,2H),4.88–4.79(m,1H),4.59(d,J=9.2Hz,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=9.9Hz,9H),3.62(dd,J=10.8,3.7Hz,1H),3.57(d,J=10.9Hz,1H),3.48–3.40(m,2H),2.97(brs,2H),2.46(d,J=2.2Hz,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=6.0Hz,9H). 13C NMR (150MHz, DMSO-d6) δ171.81,171.68,170.73,168.70,168.66,168.02,167.98,167.89,167.85,164.71,163.38,158.05,154.69,153.49,151 .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 ,78.73,78.71,77.19,71.91,68.71,65.72,64.81,58.72,58.68,57.32 ,57.25,56.56,56.47,56.44,54.70,51.51,51.33,47.18,44.19,37.68, 36.00,35.95,31.48,31.34,30.31,27.67,27.42,26.21,26.19,26.11,2 6.08,20.95,15.92,15.06,12.88,12.81,12.60,12.53.HRMS(ESI)calcd for C 62 H 74 FN 13 O8S[M+H] + 1180.5566,found 1180.5566.

[0376] Example 82: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-(4-(3-(4-(4-((4- morpholino-6-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrimidin-2-yl)oxy)piperidin-1-yl)phenyl)ureido)piperidin-1-yl)-3-oxopropyl)pyrrolidine-2-carboxamide(LCG-Ⅱ-18)

[0377] The preparation methods of LCG-Ⅱ-3 in Reference Example 67 and LCG-Ⅱ-9 in Example 73 were used for synthesis. 1H NMR(600MHz,DMSO-d6)δ8.98(d,J=6.4Hz,1H),8.60(d,J=2.7Hz,1H),8.48(dd,J=15.2,8.0Hz,1H),8.05(d,J=18.0Hz,1H),7.82(s,1H),7.78(d,J=7.7Hz,1H),7.47–7.40(m,4H),7.35(t,J=7.6Hz,1H),7.33–7.28(m,1H),7.22(t,J=7.8Hz,3H),7.06(d,J=2.7Hz,1H),6.89(d,J=12.7Hz,3H),6.01(dd,J=46.4,6.7Hz,1H),5.27–5.09(m,3H),4.59(d,J=9.2Hz,1H),4.46(t,J=8.2Hz,1H),4.29(s,1H),4.11(dd,J=25.5,12.9Hz,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=2.0Hz,3H),2.39(s,3H),2.12(brs,2H),2.05(dd,J=12.9,8.0Hz,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(150MHz,DMSO-d6)δ170.43,170.40,168.74,168.02,167.89,167.47,164.71,163.39,158.05,154.59,153.49,151.43,147.70,145.80,14 2.30,142.24,137.85,132.55,131.84,130.97,129.88,129.24,128.63 ,128.59,128.55,127.42,127.24,127.18,126.20,122.99,118.88,116 .83,105.84,81.97,78.77,77.22,71.93,68.69,68.67,66.81,65.73,6 4.81,58.69,56.45,56.41,49.88,49.67,47.25,45.99,45.89,44.19,4 3.76,43.66,38.47,37.53,36.23,35.93,32.46,31.61,30.35,26.13,20.95,15.88,15.85,15.07,12.90,12.83,12.64,12.57.HRMS(ESI)calcd for C 63 H 76 FN 13 O8S[M+H] + 1194.5723, found 1194.5726.

[0378] Example 83: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-4-(4-(3-(4-(4-((4- morpholino-6-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrimidin-2-yl)oxy)piperidin-1-yl)phenyl)ureido)piperidin-1-yl)-4-oxobutyl)pyrrolidine-2-carboxamide(LCG-Ⅱ-19)

[0379] The preparation methods of LCG-Ⅱ-3 in Reference Example 67 and LCG-Ⅱ-9 in Example 73 were used for synthesis. 1H NMR(600MHz,DMSO-d6)δ8.99(s,1H),8.60(d,J=2.7Hz,1H),8.57–8.51(m,1H),8.05(d,J=12.6Hz,1H),7.82(s,1H),7.78(d,J=7.7Hz,1H),7.47(d,J=8.3Hz,2H),7.41(d,J=7.9Hz,2H),7.35(t,J=7.6Hz,1H),7.26–7.16(m,4H),7.06(d,J=2.7Hz,1H),6.89(d,J=10.8Hz,3H),6.02(dd,J=36.2,7.7Hz,1H),5.16(d,J=3.4Hz,1H),5.13–5.08(m,1H),4.97–4.88(m,1H),4.58(d,J=8.9Hz,1H),4.49–4.44(m,1H),4.31(s,1H),4.19(dd,J=57.6,12.9Hz,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=9.4Hz,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=12.8,7.6Hz,1H),1.99–1.72(m,7H),1.41–1.14(m,6H),0.99(s,9H). 1313C 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) calcd for C 64 H 78 FN 13 O8S [M+H] + 1208.5879, found 1208.5874.

[0380] Example 84: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-(4-(4-(4-((4-morpholino-6-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrimidin-2-yl)oxy)piperidin-1-yl)phenyl)piperazin-1-yl)-3-oxopropyl)pyrrolidine-2-carboxamide (LCG-II-20)

[0381] The preparation method of LCG-II-3 in Reference Example 67 was used for synthesis. 1 H NMR(600MHz, DMSO-d6)δ8.98(s,1H),8.60(d,J=2.7Hz,1H),8.53(d,J=7.9Hz,1H),7.82(s,1H),7.78(d,J=7.8Hz,1H),7.45–7.38(m,4H), 7.35(t,J=7.6Hz,1H),7.27(dd,J=9.3,2.8Hz,1H),7.21(dt,J=7.5,1.0Hz,1H),7.06(d,J=2.7Hz,1H),6.92–6.75(m,5H),5.21(q,J=7.2Hz ,1H),5.17–5.09(m,2H),4.58(d,J=9.3Hz,1H),4.46(t,J=8.2Hz,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=12.3,8.4Hz,1H),1.86–1.73(m,2H),1.41–1.31(m,2H),1.22(dd,J=8.4,3.3Hz,2H),0.97(s,9H). 13 C NMR(150MHz,DMSO-d6)δ170.40,168.73,167.98,167.85,164.71,163.39,158.05,153.49,151.41,147 .70,142.15,137.85,131.84,130.91,129.94,129.24,128.63,128.55,127.18,126.20,122.99,117.3 5,105.84,81.98,78.79,77.25,68.67,65.72,58.67,56.44,49.92,47.39,45.62,44.19,38.40,37.53 ,36.24,35.95,26.16,26.12,20.95,15.88,15.85,12.90,12.83,12.62,12.55,8.52.HRMS(ESI)calcd for C 61 H 73 FN 12 O7S[M+H] + 1137.5508,found 1137.5508.

[0382] Example 85: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-4-(4-(4-(4-((( 4-morpholino-6-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrimidin-2-yl)oxy)piperidin-1-yl)phenyl)piperazin-1-yl)-4-oxobutyl)pyrrolidine-2-carboxamide(LCG-Ⅱ-21)

[0383] The preparation method of LCG-II-3 in Reference Example 67 was used for synthesis. 1 H NMR(600MHz,DMSO-d6)δ8.99 (s,1H),8.60(d,J=2.7Hz,1H),8.55(d,J=8.7Hz,1H),7.82(s,1H),7.78(d,J=7.8Hz,1H),7.47(d,J=8.2Hz,2H),7.41(d,J=8.3Hz,2 H),7.35(t,J=7.6Hz,1H),7.26–7.18(m,2H),7.06(d,J=2.7Hz,1H),6.93–6.79(m,5H),5.16(d,J=3.2Hz,1H),5.12(brs,1H),4.96– 4.91(m,1H),4.58(d,J=9.2Hz,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(150MHz,DMSO-d6)δ170.74,170.26,168.71,167.94,167.80,164.71,163.40,158.05,153.49,151.41,147 .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 ,81.98,78.92,77.38,71.92,68.77,65.72,64.81,58.84,56.65,56.52,51.27,47.41,45.60,44.19,37.67,36. 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)calcd for C 62 H 75 FN 12 O7S[M+H] + 1151.5664,found 1151.5664.

[0384] Example 86: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-6-(4-(4-(4-((( 4-morpholino-6-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrimidin-2-yl)oxy)piperidin-1-yl)phenyl)piperazin-1-yl)-6-oxohexyl)pyrrolidine-2-carboxamide(LCG-Ⅱ-22)

[0385] The preparation method of LCG-II-3 in Reference Example 67 was used for synthesis. 1H NMR(600MHz,DMSO-d6)δ8.99(s,1H),8.60(d,J=2.6Hz,1H),8.46(d,J=8.3Hz,1H),7.82(s,1H),7.78(d,J=7.8Hz,1H),7.43(d,J=8.2Hz,2H),7.39–7.34(m,3H),7.26(dd,J=9.2,2.5Hz,1H),7.21(d,J=7.5Hz,1H),7.06(d,J=2.7Hz,1H),6.88(d,J=23.2Hz,5H),5.22–5.08(m,2H),4.81(q,J=8.2Hz,1H),4.58(d,J=9.3Hz,1H),4.50(t,J=8.2Hz,1H),4.29(s,1H),3.78–3.62(m,8H),3.58(dd,J=17.4,6.8Hz,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=7.5Hz,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=8.3,2.5Hz,2H),0.97(s,9H). 13 C NMR(150MHz,DMSO-d6)δ170.58,170.43,168.60,167.95,167.82,164.71,163.39,158.05,153.49,151.37,147.65,143.73,137.85,131.84,131.00,129.62,129.24,128.69,128.55,126.74,126.20,122.99,117.37,105.84,81.98,78.83,77.28,71.92,68.72,65.72,64.81,58.58,56.54,56.45,51.83,49.99,49.54,47.41,45.64,44.19,40.85,37.62,36.11,36.02,32.13,30.39,26.22,26.12,25.37,24.42,20.95,15.95,15.92,15.07,12.90,12.84,12.62,12.55,8.53.HRMS(ESI)calcd for C 64 H 79 FN 12O7S[M+H] + 1179.5977, found 1179.5983.

[0386] Example 87: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-((4'-(2-( (4-morpholino-6-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrimidin-2-yl)oxy)ethyl)-[1,1'-biphenyl]-4-yl)amino)-3-oxopropyl)pyrrolidine-2-carboxamide(LCG-Ⅱ-23)

[0387] Synthesized according to the preparation method of LCG-II-6 in Reference Example 70. 1 H NMR(600MHz,DMSO-d6)δ10.01(s,1H),8.98(s,1H),8.64(d,J=7.9Hz,1H),8.58(d ,J=2.7Hz,1H),7.82(s,1H),7.77(d,J=7.7Hz,1H),7.62(d,J=8.7Hz,2H),7.57(d, J=8.3Hz,4H),7.44(s,4H),7.39(d,J=8.1Hz,2H),7.35(t,J=7.6Hz,1H),7.26(dd ,J=9.3,2.8Hz,1H),7.21(d,J=7.5Hz,1H),7.05(d,J=2.7Hz,1H),6.90(s,1H),5.3 6–5.23(m,1H),5.15(d,J=3.6Hz,1H),4.59(d,J=9.3Hz,1H),4.55(t,J=6.9Hz,2H ),4.49(t,J=8.3Hz,1H),4.29(brs,1H),3.73–3.65(m,8H),3.64–3.54(m,2H),3.0 8(t,J=6.8Hz,2H),2.98–2.77(m,2H),2.44(s,3H),2.38(s,3H),2.05(dd,J=12.2, 7.9Hz,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(150MHz,DMSO-d6)δ170.47,168.74,168.01,167.98,167.84,164.60,163.96,158.02,153.49,151.43,147.72, 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)calcd for C 60 H 65 FN 10 O7S[M+H] + 1089.4820,found 1089.4816.

[0388] Example 88: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-4-((4'-(2-( (4-morpholino-6-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrimidin-2-yl)oxy)ethyl)-[1,1'-biphenyl]-4-yl)amino)-4-oxobutyl)pyrrolidine-2-carboxamide(LCG-Ⅱ-24)

[0389] Synthesized according to the preparation method of LCG-II-6 in Reference Example 70. 1H NMR(600MHz,DMSO-d6)δ9.93(s,1H),8.99(s,1H),8.63–8.57(m,2H),7.82(s,1H),7.77(d,J=7.7Hz,1H),7.67(d,J=8.5Hz,2H),7.58(d,J=8.2Hz,4H),7.47(d,J=8.3Hz,2H),7.44–7.37(m,4H),7.35(t,J=7.6Hz,1H),7.28(dd,J=9.2,2.8Hz,1H),7.21(d,J=7.5Hz,1H),7.05(d,J=2.7Hz,1H),6.90(s,1H),5.16(d,J=3.5Hz,1H),4.89(q,J=8.1Hz,1H),4.59(d,J=9.2Hz,1H),4.55(t,J=6.9Hz,2H),4.51(t,J=8.3Hz,1H),4.29(brs,1H),3.74–3.66(m,8H),3.64–3.56(m,2H),3.09(t,J=6.8Hz,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). 13 C NMR(150MHz,DMSO-d6)δ170.76,170.71,168.75,168.01,167.87,164.60,163.96,158.03,153.50,151.42,147.71,143.09,138.49,137.85,137.76,136.96, 134.38,131.84,130.97,129.85,129.36,129.24,129.22,128.78,128.54,126.81,126.55,126.20,126.12,122.99,119.31,119.27,105.84,82.08,78.80,77.26,68.71,67.00,65.70,64.81,58.69,56.59,56.57,56.52,51.87,45.64,44.19,37.66,35.95,34.16,33.19,31.93,26.21,26.12,20.95,15.92,15.07,12.91,12.84,12.64,12.57.HRMS(ESI)calcd for C 61 H67 FN 10 O7S[M+H] + 1103.4977,found 1103.4977.

[0390] Example 89: 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-(4-(4-((4-morpholino-6-(3-(m-tolyl))-1H-pyrazo l-1-yl)pyrimidin-2-yl)oxy)piperidin-1-yl)phenyl)piperazin-1-yl)isoindoline-1,3-dione(LCG-Ⅱ-25)

[0391] 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, 4 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 h. After being spun down to dryness, the mixture was redissolved in 10 mL of DMF, 2-(2,6-dioxo-piperidin-3-yl)-5,6-difluoro-isoindole-1,3-dione (60 mg, 0.2 mmol) and DIPEA (129 mg, 1.0 mmol) were added, and the mixture was reacted at 100°C for 4 h. After TLC monitoring, 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, spun down to dryness, and separated by column chromatography to obtain 30 mg (35%) of a yellow solid. 1 H NMR (600MHz, DMSO-d6) δ11.12(s,1H),8.60(d,J=2.7Hz,1H),7.82(s,1H),7.77(t,J=10.0Hz,2H),7.52(d,J=7. 4Hz,1H),7.35(t,J=7.6Hz,1H),7.21(d,J=7.5Hz,2H),7.06(d,J=2.7Hz,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=9.5Hz,2H),2.91–2.85(m,1 H),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(150MHz,DMSO-d6)δ172.14,169.28,166.02,165.56,164.20,162.89,161.68,157.66,157.54,155 .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 ,49.01,48.99,48.79,48.45,46.94,43.68,35.16,30.33,29.90,21.45,20.44,14.55.HRMS(ESI)calcd for C 46 H 47 FN 10 O6[M+H] + 855.3742, found 855.3737.

[0392] Example 90: 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-((4-(2-((4-morpholino-6-(3-(m-tolyl))-1H-pyraz ol-1-yl)pyrimidin-2-yl)oxy)ethyl)phenyl)ethynyl)piperidin-1-yl)isoindoline-1,3-dione(LCG-Ⅱ-26)

[0393] Synthesized according to the preparation method of LCG-II-25 in Reference Example 89. 1H NMR(600MHz,DMSO-d6)δ11.11(s,1H),8.57(d,J=2.7Hz,1H),7.81(s,1H),7.77(d,J=7.7Hz,1H),7.72(d,J=11.3Hz,1H),7.49(d,J=7.4Hz,1H),7.37(d,J=8.2Hz,2H),7.34(d,J=7.6Hz,1H),7.31(d,J=8.3Hz,2H),7.21(d,J=7.5Hz,1H),7.05(d,J=2.7Hz,1H),6.89(s,1H),5.11(dd,J=12.9,5.4Hz,1H),4.52(t,J=6.8Hz,2H),3.72–3.63(m,8H),3.52–3.46(m,2H),3.15(t,J=9.4Hz,2H),3.06(t,J=6.8Hz,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(150MHz,DMSO-d6)δ172.13,169.28,166.03,165.58,164.06,163.39,157.53,157.48,155.86,152.97,145.07,145.01,137.95,137.33,131.31,130.75,128.72,128.69,128.54,128.16,128.15,128.03,125.68,122.61,122.54,122.47,120.26,113.28,111.41,111.24,105.32,91.56,81.57,80.95,66.17,65.18,64.29,48.42,47.90,47.88,43.66,33.84, 30.59,30.33,25.84,21.45,20.43,14.55.HRMS(ESI)calcd for C 46 H 43 FN8O6[M+H] + 823.3368,found 823.3368.

[0394] Example 91: 2-(2,6-Dioxopiperidin-3-yl)-5-fluoro-6-(4-((4-(4-(2-((4-morpholino-6-(3-(m-tolyl))-1H-pyrazol-1-y l)pyrimidin-2-yl)oxy)ethyl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione(LCG-Ⅱ-27)

[0395] Synthesized according to the preparation method of LCG-II-25 in Reference Example 89. 1 H NMR (600MHz, DMSO-d6) δ11.11(s,1H),8.57(d,J=2.7Hz,1H),7.81(s,1H),7.77(d,J=7.7Hz,1H),7.70(d,J=11.4Hz,1H),7.43(d,J=7.3Hz,1H ),7.35(t,J=7.6Hz,1H),7.21(d,J=7.5Hz,1H),7.16(d,J=8.3Hz,2H),7.05(d,J=2.7Hz,1H),6.89(t,J=4.3Hz,3H),5.10(dd,J=12.9,5.4Hz,1 H),4.45(t,J=7.1Hz,2H),3.74–3.64(m,8H),3.61(d,J=12.1Hz,2H),3.09(s,4H),2.95(t,J=7.1Hz,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=7.2Hz,2H),2.05–2.01(m, 1H),1.84(d,J=12.0Hz,2H),1.79–1.72(m,1H),1.27(q,J=11.3Hz,2H). 13C NMR(150MHz,DMSO-d6)δ172.14,169.30,166.09,165.60,164.08,163.46,161.68,157.50,157.46,155.79,152 .96,149.07,145.30,145.24,137.33,131.32,128.77,128.72,128.66,128.18,128.03,127.69,125.68,122.4 7,122.20,122.14,114.92,113.06,113.03,111.35,111.18,105.31,81.50,66.83,65.19,64.29,63.17,52.58 ,49.34,49.31,48.41,47.92,43.67,35.16,33.18,31.63,30.33,29.65,21.46,20.44,14.55.HRMS(ESI)calcd for C 49 H 53 FN 10 O6[M+H] + 897.4212, found 897.4210.

[0396] Example 92: 1-(1-(2-(2,6-Dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)-3-(4-(4-( (4-morpholino-6-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrimidin-2-yl)oxy)piperidin-1-yl)phenyl)urea(LCG-Ⅱ-28)

[0397] Synthesized according to the preparation method of LCG-II-25 in Reference Example 89. 1H NMR(600MHz,DMSO-d6)δ11.11(s,1H),8.60(d,J=2.7Hz,1H),8.10(s,1H),7.82(s,1H),7.78(d,J=7.7Hz,1H),7.72(d,J=11.3Hz,1H),7.48(d,J=7.4Hz,1H),7.35(t,J=7.6Hz,1H),7.25(d,J=8.5Hz,2H),7.21(d,J=7.6Hz,1H),7.06(d,J=2.7Hz,1H),6.90(s,2H),6.88(s,1H),6.11(d,J=7.6Hz,1H),5.16–5.05(m,2H),3.75–3.67(m,9H),3.55(d,J=12.9Hz,2H),3.48–3.41(m,2H),3.07–3.00(m,2H),2.97(t,J=10.3Hz,2H),2.89(ddd,J=17.0,13.9,5.5Hz,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(150MHz,DMSO-d6)δ172.14,169.30,166.06,165.59,165.57,164.19,162.88,157.53,155.85,154.16,152.97,145.30,145.02,144.97,137.34,132.08,131.33,128.72,128.16,128.14,128.03,125.69,122.54,122.48,118.41,116.32,113.29,113.26,111.39,111.22,105.32,81.46,71.43,65.21,64.30,48.43,48.19,48.16,46.74,45.13,43.68,31.40,30.34,29.85,21.46,20.44,14.55.HRMS(ESI)calcd for C 48 H 50 FN 11 O7[M+H] + 912.3957,found 912.3955.

[0398] Example 93: 1-(1-(2-(2,6-Dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)azetidin-3-yl)-3-(4-(4-((4-morpholino-6-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrimidin-2-yl)oxy)piperidin-1-yl)phenyl)urea(LCG-Ⅱ-29)

[0399] Synthesized according to the preparation method of LCG-II-25 in Reference Example 89. 1 H NMR (600MHz, DMSO-d6) δ11.09(s,1H),8.60(d,J=2.7Hz,1H),8.32(s,1H),7.82(s,1H),7.78(d,J=7.7Hz,1H),7.62(d,J=11.1Hz,1H),7.35(t,J=7. 6Hz,1H),7.25(d,J=8.5Hz,2H),7.21(d,J=7.5Hz,1H),7.06(d,J=2.7Hz,1 H),6.97(d,J=7.6Hz,1H),6.92–6.86(m,3H),6.74(d,J=7.4Hz,1H),5.16– 5.09(m,1H),5.08(dd,J=12.9,5.4Hz,1H),4.68–4.57(m,1H),4.44(t,J= 7.1Hz,2H),4.01(t,J=7.1Hz,2H),3.78–3.64(m,8H),3.49–3.41(m,2H),2 .97(t,J=9.7Hz,2H),2.88(ddd,J=17.1,13.9,5.5Hz,1H),2.65–2.51(m,2 H),2.39(s,3H),2.19–2.08(m,2H),2.07–1.97(m,1H),1.89–1.75(m,2H). 13C NMR(150MHz,DMSO-d6)δ172.15,169.37,166.19,165.79,165.78,164.19,162.87,157.53,154.1 8,153.92,152.97,152.28,145.57,143.38,143.29,137.33,131.58,131.33,128.72,128.69,12 8.03,125.69,122.47,118.91,118.15,118.09,116.20,110.74,110.60,107.83,107.78,105.32 ,81.45,71.41,65.21,60.19,48.32,46.64,43.67,30.34,29.82,21.53,20.44.HRMS(ESI)calcd for C 46 H 46 FN 11 O7[M+H] + 884.3644, found 884.3643.

[0400] Example 94: 2-(2,6-Dioxopiperidin-3-yl)-5-fluoro-6-(4-(1-(4-((4-morpholino-6-(3-(m-tolyl))-1H-pyrazo l-1-yl)pyrimidin-2-yl)oxy)phenyl)piperidin-4-yl)piperazin-1-yl)isoindoline-1,3-dione(LCG-Ⅱ-30)

[0401] Synthesized according to the preparation method of LCG-II-25 in Reference Example 89. 1H NMR(600MHz,DMSO-d6)δ11.11(s,1H),8.33(d,J=2.7Hz,1H),7.81(s,1H),7.77(s,1H),7.73(d,J=11.3Hz,1H),7.45(d,J=7.3Hz,1H),7.35(t,J=7.6Hz,1H),7.21(d,J=7.5Hz,1H),7.12–7.06(m,2H),7.04(d,J=2.7Hz,1H),6.98(d,J=9.2Hz,2H),6.95(s,1H),5.11(dd,J=12.9,5.4Hz,1H),3.72(d,J=11.6Hz,2H),3.66(t,J=4.8Hz,4H),3.59(t,J=4.8Hz,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=11.9Hz,2H),1.65–1.51(m,2H). 13 C NMR(150MHz,DMSO-d6)δ172.14,169.28,166.04,165.58,164.11,163.69,157.55,157.50,155.87,153.11,147.68,144.79,144.74,144.34,137.35,131.22,128.79,128.44,128.16,128.04,125.68,122.73,122.67,122.49,121.26,115.75,112.97,111.39,111.22,105.45,82.31,65.10,60.11,49.30,48.44,48.00,47.90,43.64,30.33,27.09,21.45,20.43.HRMS(ESI)calcd for C 46 H 47 FN 10 O6[M+H] + 885.3722,found 885.3736.

[0402] Example 95: 2-(2,6-Dioxopiperidin-3-yl)-5-fluoro-6-(4-(4-(4-((4-morpholino-6-(3-(m-tolyl))-1H-pyrazo l-1-yl)pyrimidin-2-yl)oxy)piperidin-1-yl)benzyl)piperazin-1-yl)isoindoline-1,3-dione(LCG-Ⅱ-31)

[0403] Synthesized according to the preparation method of LCG-II-25 in Reference Example 89. 1 H NMR (600MHz, DMSO-d6) δ11.11(s,1H),8.60(d,J=2.7Hz,1H),7.82(d,J=1.8Hz,1H),7.78(d,J=7.8Hz,1H),7.71(d,J=11.3Hz,1H), 7.44(d,J=7.3Hz,1H),7.35(t,J=7.6Hz,1H),7.21(d,J=7.6Hz,1H),7.17(d,J=8.2Hz,2H),7.06(d,J=2.7Hz,1H),6.95(d,J=8.2Hz ,2H),6.90(s,1H),5.17–5.13(m,1H),5.11(dd,J=12.9,5.4Hz,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(150MHz,DMSO-d6)δ172.14,169.28,166.04,165.57,164.20,162.87,161.68,157.54,155.85,152.98,1 49.39,144.79,144.74,137.34,131.33,129.22,128.73,128.71,128.13,128.03,127.08,125.69,122.74,1 22.68,122.48,115.06,113.06,113.03,111.38,111.21,105.32,81.48,71.42,65.22,64.30,60.89,51.54, 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)calcd for C 47 H 49 FN 10 O6[M+H] + 869.3899, found 869.3886.

[0404] Example 96: 2-(2,6-Dioxopiperidin-3-yl)-5-fluoro-6-(4-((4-(4-((4-morpholino-6-(3-(m-tolyl))-1H-pyrazol-1 -yl)pyrimidin-2-yl)oxy)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione(LCG-Ⅱ-32)

[0405] Synthesized according to the preparation method of LCG-II-25 in Reference Example 89. 1H NMR (600MHz, DMSO-d6) δ11.11(s,1H),8.33(d,J=2.7Hz,1H),7.81(s,1H),7.77(d,J=7.7Hz,1H),7.70(d,J=11.3Hz,1H),7. 44(d,J=7.3Hz,1H),7.35(t,J=7.6Hz,1H),7.24–7.19(m,1H),7.09(d,J=8.9Hz,2H),7.04(d,J=2.7Hz,1H),6.97(d,J=9.1H z,2H),6.95(s,1H),5.11(dd,J=12.9,5.4Hz,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=7.1Hz,2H),2.08–1.99(m,1H),1.85(d,J=11.8Hz,2H),1.79(d,J=3.8Hz,1H),1.29(q,J=11.0Hz,2H). 13 C NMR(150MHz,DMSO-d6)δ172.14,169.30,166.09,165.60,164.11,163.67,157.50,157.47,155.79,153.1 1,147.68,145.30,145.24,144.51,137.35,131.22,128.79,128.45,128.19,128.17,128.04,125.69,122 .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)calcd for C 47 H 49 FN 10 O6[M+H] + 869.3899, found 869.3887. Example 97: Degradation of PIKfyve protein in VCaP and DU145 tumor cells by compounds

[0406] Method: 200 μL density is 5×10 6Cells were seeded at a concentration of 100 / ml in a 6-well plate, and then different concentrations of drugs were added; treated at 37°C for 24 hours, the supernatant was collected, and washed twice with PBS; then 100-200μl of 1×SDS lysis buffer was added, the cell lysate was collected into a centrifuge tube, the cells were broken by ultrasonication for 10-20s, and boiled for 10 minutes. The protein samples were subjected to SDS-PAGE electrophoresis at 90V, transferred to a PVDF membrane at 110V, blocked with 5% BSA for 4 hours, incubated with primary antibodies (PIKfyve, GAPDH) at 4°C overnight, and incubated with secondary antibodies (anti-Rabbit IgG or anti-Mouse IgG) at room temperature. The membrane was washed with TBST buffer, ECL developer was added, and then imaged to obtain protein band signals. The single-concentration WB results are shown in Figure 1. The concentration that achieved 50% degradation activity compared to the DMSO control group was defined as DC 50 .

[0407] Table 1 Degradation activity of compounds on PIKfyve protein in VCaP and DU145 cells

[0408] The results showed that the compounds of the present invention could achieve good PIKfyve protein degradation activity against VCaP and DU145 cells.

[0409] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound as represented by formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer or prodrug molecule thereof, in, R1 is selected from the group consisting of H, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy; A is selected from the following group: -NH-, 6-10 membered aryl, 5-10 membered heteroaryl; each of the A's is independently optionally substituted by 0-3 R2, wherein the R2 is selected from the following group: H, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy; Linker has the following structure: Wherein, W1, W2, W3, W4, and W5 are each independently selected from the following group: -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 a 3-12 membered ring having 0-4 heteroatoms; n1, n2, n3, and n4 are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; wherein the 3-12 membered ring may be a monocyclic, spirocyclic, fused, or bridged ring structure; E3 Ligand is a ubiquitination E3 ligase ligand having a structure selected from the following group: Among them, R3, R4, R5, R6, R7, R8, R9, R 11 Each is independently selected from the following group: H, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy; R 10 Select from the following group: Among them, each R 12 Each is independently selected from the following group: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy; The substitution in the substituted or unsubstituted group refers to that one or more H atoms on the group are replaced by a substituent selected from the following group: halogen, deuterium atom, hydroxyl, cyano, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 aldehyde, C1-C3 carboxyl, -SF5.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, characterized in that: The E3 Ligand has a structure selected from the group consisting of: Among them, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 The definition is as stated in claim 1.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, characterized in that: The Linker has a structure as shown below: Wherein, W1, W2, W3, W4, and W5 are each independently selected from the following groups: -O-, -S-, -NH-, -CH2-, -CONH-, -NHCO-, -C(O)-, -C(O)O-, -OC(O)-, -NHCONH-, and a 3-10 membered ring with 0-4 heteroatoms; n1, n2, n3, and n4 are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, characterized in that: The linker has a structure selected from the following group: Wherein each X and Y are independently selected from the following groups: -O-, -S-, -NH-, -CH2-, Each n and m is each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, characterized in that: The A is selected from the following groups: -NH-, Each of the A's is independently optionally substituted by 0-2 R2's, and the definition of R2 is as described 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, characterized in that: The compound is selected from the following group:

7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, characterized in that: The compound is selected from the following group:

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

9. Use of the compound according to any one of claims 1 to 7, its pharmaceutically acceptable salt, its stereoisomer or its prodrug molecule, or the pharmaceutical composition according to claim 8, characterized in that: Used for preparing a method for treating and / or preventing diseases or conditions related to abnormal PIKfyve expression; preferably, the disease or condition is selected from the following group: tumors, autoimmune diseases, viral infections, and neurodegenerative diseases.

10. The use according to claim 9, characterized in that The disease or condition is selected from the group consisting of hematologic malignancies, gastrointestinal stromal tumors, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, colorectal cancer, kidney cancer, gastric cancer, head and neck cancer, or nasopharyngeal cancer.

11. A non-diagnostic, non-therapeutic method for degrading PIKfyve in a subject in need thereof, characterized in that: The compound according to any one of claims 1 to 7, its pharmaceutically acceptable salt, its stereoisomer or its prodrug molecule, or the pharmaceutical composition according to claim 7 is administered to a subject.

12. The method according to claim 11, characterized in that The subject is a human.

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