NSD protein degradation agent and application thereof

Abstract

The invention provides an NSD 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 proteins such as NSD2, NSD1, NSD3, c-MYC, KLK3 / PSA, AR, NKX3.1, GSPT1 and the like in a targeted ubiquitination manner, so that the compound can be used for treating indications related to abnormal expression of the proteins such as NSD2, NSD1, NSD3, c-MYC, KLK3 / PSA, AR, NKX3.1, GSPT1 and the like. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and specifically to a class of compounds for targeting ubiquitination degradation of NSD2, NSD1, NSD3, c-MYC, KLK3 / PSA, AR, NKX3.1, GSPT1 and other proteins, as well as pharmaceutical compositions and applications thereof. Background Art

[0002] PROTAC refers to a class of small molecule compounds that can specifically recognize and induce the degradation of target proteins; the molecular structure consists of three parts: target protein recognition ligand, Linker and E3 recognition ligand. The advantage of PROTAC is that it not only effectively inhibits the activity of target proteins, but also can quickly degrade and remove target proteins. In theory, only a catalytic amount of drugs is needed to degrade almost all proteins in cells (including membrane proteins), so it has high safety, drug resistance and broad application prospects. At present, degraders for target proteins such as ERR, ABL, BET, CDK4 / 6 have been successfully developed. The results show that it can not only treat the proliferation of gene-driven tumors, but also overcome inhibitor resistance. In 2018, Pfizer announced an investment of US$830 million in the development of protein degrader drugs based on PROTAC technology. In March 2019, WuXi AppTec's partner Arvinas announced that its development of ARV-110, a protein degrader for androgen receptors, has entered clinical research; this is the world's first protein degrader to enter the clinical research stage. As of 2022, more than 10 PROTAC molecules have entered the clinical research stage.

[0003] Histone lysine methyltransferases (HKMTases) are a class of epigenetic regulatory enzymes that can catalyze the transfer of 1-3 methyl groups to specific lysine residues (K3, K9, K20, K27, K36 and K79) of histones H3 and H4. Histone lysine methyltransferases have very important biological functions and are closely related to a variety of diseases. The NSD protein family is a relatively newly identified family of histone methyltransferases, which are often abnormally expressed in a variety of diseases, especially in tumors. High expression of NSD2 can accelerate the proliferation of tumor cells, inhibit cell apoptosis and promote tumor metastasis. In the acute lymphoblastic leukemia (ALL) population, there is up to 14% of NSD2 E1099K point mutations. Clinical pathological correlation studies have shown that NSD2 protein levels are highly expressed in gliomas, neuroblastomas, ovarian cancer, endometrial cancer and liver cancer. NSD2 protein levels are highly expressed in digestive tract tumors (colorectal cancer, gastric cancer and anal canal cancer), bladder cancer, small cell lung cancer, female reproductive system tumors and skin tumors, and the correlation with tumor grade and stage needs further analysis. Genetic studies have shown that NSD2 mRNA is highly expressed in malignant gliomas, head and neck tumors, liver cancer, renal clear cell carcinoma, bladder cancer, prostate cancer, breast cancer and ovarian cancer, and is positively correlated with the stage of the tumor, and is associated with poor prognosis of head and neck tumors, prostate cancer and glioma. Research on the NSD protein family not only helps to further understand the pathogenesis of related tumors, but also helps to discover new tumor markers and new targets for tumor treatment, and has potential and important clinical application value. Therefore, designing NSD2 PROTAC degraders to achieve efficient degradation of NSD2 provides new opportunities for the development of anti-tumor drugs. Summary of the invention

[0004] The purpose of the present invention is to provide a compound capable of targeted ubiquitination degradation of NSD2, NSD1, NSD3, c-MYC, KLK3 / PSA, AR, NKX3.1, GSPT1 and other proteins and a pharmaceutical composition thereof.

[0005] In the first aspect of the present invention, there is provided a compound having a structure represented by formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer or a prodrug molecule thereof:

[0006]

[0007] in:

[0008] A1, A2, A3, X, Z, W, G are each independently N or C-R1;

[0009] Each R1 is independently selected from the group consisting of H, deuterium atom, halogen, CN, OH, NH2;

[0010] K3 is selected from the group consisting of H, D, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-8 Saturated or partially unsaturated carbocyclic group, substituted or unsubstituted C 3-8 Saturated or partially unsaturated heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted C 5-12 heteroaryl;

[0011] L is selected from the following group: chemical bond, C 1-16 Alkylene, Substituted or unsubstituted C 3-8 Saturated or partially unsaturated carbocyclic group, substituted or unsubstituted C 3-8 Saturated or partially unsaturated heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted C 5-12 Heteroaryl; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein the carbocyclic group, heterocyclic group, aryl group, heteroaryl group include monocyclic, condensed ring, spirocyclic or heterocyclic structures;

[0012] Y has the structure shown below:

[0013] wherein each m is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15;

[0014] Each Z is independently selected from the group consisting of a chemical bond, a C 3-8 Saturated or partially unsaturated carbon ring, C 3-8 Saturated or partially unsaturated heterocyclic ring, C 6-10 Aromatic ring, C 5-12 Heteroaromatic ring, -NH-, -O-, -C(O)-, -CONH-, -NHCO-, -S-, -CH2-, -C≡C-, -CH=CH-, -P=O-, -S(O)2-, -S(O)-, -P(O)2(OH)-, -NH-S(O)-NH-, -NH-CO-NH-, -C(O)O-, -OC(O)-;

[0015] Y1, Y2, Y3, and Y4 are each independently selected from the following groups: chemical bonds, C 3-8 Saturated or partially unsaturated carbocyclic group, C 3-8 Saturated or partially unsaturated heterocyclic group, C 6-10 Aryl, C 5-12Heteroaryl, -CH2-, -C≡C-, -CH=CH-, NH-, -O-, -C(O)-, -CONH-, -NHCO-, -S-, -P=O-, -S(O)2-, -S(O)-, -P(O)2(OH)-, -NH-S(O)-NH-, -NH-CO-NH-, -C(O)O-, -OC(O)-;

[0016] The Z may be optionally replaced by one or more R Z Substitute, the R Z Selected from the following group: deuterium atom, halogen, -OH, -CN, -CF3, -NH2, -COOH, oxygen atom (=O), C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C 3-8 saturated or partially unsaturated carbocyclic group;

[0017] The Y1, Y2, Y3, and Y4 may be optionally replaced by one or more R Y Substitute, the R Y Selected from the following group: halogen, -OH, -CN, -CF3, -NH2, -COOH, oxygen atom (=O), substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 alkoxy;

[0018] Or, 2 R Y The radicals and the atoms to which they are attached together form a structure selected from the group consisting of: substituted or unsubstituted C 3-8 Saturated or partially unsaturated carbocyclic group, substituted or unsubstituted C 3-8 Saturated or partially unsaturated heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted C 5-12 heteroaryl;

[0019] Q is an E3 ubiquitin ligase ligand having a structure selected from the group consisting of:

[0020]

[0021] wherein each R' is independently selected from the following group: H, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted C 1-6 Alkoxy;

[0022]

[0023] R3 is selected from the following group: substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C1-6 Alkylamino, C 3-8 Saturated or partially unsaturated carbocyclic group, C 3-8 Saturated or partially unsaturated heterocyclic group, C 6-10 Aryl, C 5-12 Heteroaryl,

[0024] R4 is selected from the group consisting of: substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted C 5-12 heteroaryl;

[0025] The substitution in the substituted or unsubstituted group refers to that one or more hydrogen atoms in the group are replaced by a substituent selected from the group consisting of a deuterium atom, a hydroxyl group, a cyano group, a halogen group, an amino group, an oxo group (=O), a C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Saturated or partially unsaturated carbocyclic group, C 3-6 Saturated or partially unsaturated heterocyclic group, C 6-10 Aryl, C 5-12 Heteroaryl.

[0026] In some embodiments, the compound of formula I has a structure as shown in formula (II):

[0027]

[0028]

[0029] Wherein, R1, K3, L, Y, and Q are defined as described in claim 1.

[0030] In some embodiments, R1 is H and K3 is cyclopropyl.

[0031] In some embodiments, Y has a structure selected from the group consisting of:

[0032]

[0033]

[0034]

[0035]

[0036] Among them, R, Z, R Z , m is defined as described in claim 1. In some embodiments, Q has a structure selected from the group consisting of:

[0037]

[0038]

[0039]

[0040] In some embodiments, the compound is selected from the group consisting of:

[0041]

[0042]

[0043]

[0044]

[0045]

[0046]

[0047]

[0048]

[0049]

[0050]

[0051]

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[0060]

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[0065]

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[0069]

[0070]

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[0073]

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[0075]

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[0079]

[0080]

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[0082]

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[0087]

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[0089]

[0090]

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[0092]

[0093]

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[0097]

[0098]

[0099]

[0100] In some embodiments, the compound is selected from the group consisting of:

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109] In a second aspect of the present invention, a pharmaceutical composition is provided, comprising:

[0110] (1) the compound of formula I or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof as described in the first aspect of the present invention; and

[0111] Optional (2) a pharmaceutically acceptable carrier.

[0112] In the third aspect of the present invention, there is provided a use of a compound of formula I or a pharmaceutically acceptable salt thereof, or a stereoisomer or a prodrug molecule thereof as described in the first aspect of the present invention, or a pharmaceutical composition as described in the second aspect of the present invention, characterized in that it is used in the preparation of a drug for treating or preventing a disease or condition related to the activity or expression of NSD2, NSD1, NSD3, c-MYC, KLK3 / PSA, AR, NKX3.1, GSPT1, specifically, the disease or condition is selected from the following group: cardiovascular disease, diabetes, hypertension, muscular dystrophy, Parkinson's disease, Alzheimer's disease, and cancer.

[0113] In some embodiments, the cancer is selected from the group consisting of hematological tumors, 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, or nasopharyngeal carcinoma.

[0114] 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 specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0115] FIG1 shows the test results of the degradation activity of some compounds of the present invention on NSD1, NSD2, NSD3 and other related proteins of VCaP, LNCap or 22RV1 prostate cancer cells.

[0116] Figure 2 The results of the test on the relationship between the degradation activity and concentration of some compounds of the present invention are shown.

[0117] Figure 3 The graph shows the test results of the relationship between the degradation activity of some compounds of the present invention and time.

[0118] Figure 4 The results of the test on the inhibition of cell proliferation of compound LLC0150 on prostate cancer cells such as VCaP, LNCap or 22RV1 and normal cells are shown. DETAILED DESCRIPTION

[0119] After long-term and in-depth research, the inventors have prepared a class of compounds and pharmaceutical compositions that can target ubiquitination degradation of NSD2, NSD1, NSD3, c-MYC, KLK3 / PSA, AR, NKX3.1, GSPT1 and other proteins. The compounds can efficiently and selectively degrade NSD2, NSD1, NSD3, c-MYC, KLK3 / PSA, AR, NKX3.1, GSPT1 and other proteins in cells, and therefore have potential uses for treating indications related to abnormal expression of NSD2, NSD1, NSD3, c-MYC, KLK3 / PSA, AR, NKX3.1, GSPT1 and other proteins. Based on the above findings, the inventors have completed the present invention.

[0120] the term

[0121] 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 the definition at every other occurrence. Likewise, combinations of substituents and variables are permitted as long as such combinations render the compound stable. Lines drawn from substituents into the ring system indicate that the indicated bond may be attached to any substitutable ring atom. If the ring system is polycyclic, it means that such bonds are attached only to any appropriate carbon atom of the adjacent ring. It is to be understood that one of ordinary skill in the art may select substituents and substitution patterns for the compounds of the invention to provide chemically stable compounds that can be readily synthesized from readily available raw materials by techniques in the art and the methods set forth below. If a substituent is itself substituted with more than one group, it is to be understood that these groups may be on the same carbon atom or on different carbon atoms as long as the structure is stable.

[0122] 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.

[0123] 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 one of ordinary skill in the art in which the term is applied in the context of its use to describe the present invention.

[0124] The term "ubiquitin ligase" as used herein refers to a protein family that promotes 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 such a protein: it alone or in combination with E2 ubiquitin conjugating enzymes causes the connection of ubiquitin to lysine on the target protein, and then targets a specific protein substrate for degradation by the proteasome. Thus, the E3 ubiquitin ligase that forms a complex alone or with the E2 ubiquitin conjugating enzyme is responsible for the transfer of ubiquitin to the target protein. In general, the ubiquitin ligase participates in polyubiquitination, so that the second ubiquitin is connected to the first ubiquitin; the third ubiquitin is connected to the second ubiquitin, and so on. Polyubiquitination marks proteins for degradation by the proteasome. However, there are some ubiquitination events limited to monoubiquitination, in which only a single ubiquitin is added to the substrate molecule by the ubiquitin ligase. Monoubiquitinated proteins are not targeted to the proteasome for degradation, but instead may 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 recognized by the proteasome.

[0125] As used herein, the term "alkyl" is intended to include branched and straight chain saturated aliphatic hydrocarbon groups having a specific number of carbon atoms. For example, the definition of "C1-C6" in "C1-C6 alkyl" includes groups having 1, 2, 3, 4, 5 or 6 carbon atoms in a straight or branched arrangement. For example, "C1-C6 alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, and hexyl.

[0126] The term "carbocyclic group" 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, "carbocyclic group" includes but is not limited to the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0127] 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.

[0128] As used herein, the term "heterocyclyl" 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) heteroatoms, 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, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, tetrahydrofuranyl, tetrahydrothienyl, etc., and N-oxides thereof. Attachment of the heterocyclic substituents may be via a carbon atom or via a heteroatom.

[0129] As used herein, the term alkylamino refers to a group having a specified number of carbon atoms and having the structure of -alkyl-NH2, -NH-alkyl or -alkyl-NH-alkyl.

[0130] As will be appreciated by those skilled in the art, "halo" or "halo" as used herein refers to chlorine, fluorine, bromine and iodine.

[0131] Pharmaceutically acceptable salts

[0132] The present invention includes free forms of compounds of formula I, as well as pharmaceutically acceptable salts and stereoisomers thereof. Some specific exemplary compounds herein are protonated salts of amine compounds. The term "free form" refers to amine compounds in non-salt form. Pharmaceutically acceptable salts included include not only the exemplary salts of specific compounds described herein, but also typical pharmaceutically acceptable salts of free forms of all compounds of formula I. The free form of a specific salt of the compound can be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with an appropriate dilute aqueous base solution, such as dilute aqueous NaOH, dilute aqueous potassium carbonate, dilute aqueous ammonia, and dilute aqueous sodium bicarbonate. The free form differs somewhat from its respective salt form in certain physical properties, such as solubility in polar solvents, but for the purposes of the invention, such acid and base salts are equivalent to their respective free forms in other pharmaceutical aspects.

[0133] 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 excess of an inorganic or organic acid in the desired salt form in an appropriate solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reacting with an appropriate inorganic or organic base.

[0134] Therefore, the pharmaceutically acceptable salts of the compounds of this invention include conventional non-toxic salts of the compounds of this invention formed by reacting alkaline compounds of this invention with inorganic or organic acids. 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, etc., 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, etc.

[0135] If the compound of the present invention is acidic, then 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, iron salts, ferrous salts, lithium salts, magnesium salts, manganic salts, manganous salts, potassium salts, sodium salts, zinc salts, etc. 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, methylglucosamine, morpholine, piperazine, piperidine, guazine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

[0136] Berg et al., "Pharmaceutical Salts," J. Pharm. Sci. '1977: 66: 1-19, describes in more detail the preparation of the above-mentioned pharmaceutically acceptable salts and other typical pharmaceutically acceptable salts.

[0137] Drug metabolites, prodrugs, isotopes, solvates and polymorphs

[0138] The metabolites of the compounds involved in the present invention and their pharmaceutically acceptable salts, as well as the 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 "prodrug" refers to a compound that, when metabolized (e.g., in vivo or in vitro), produces an active compound. In some embodiments, the prodrug may be inactive, or have lower activity than the free drug, but may provide favorable processing, administration or metabolic characteristics. The exemplary prodrug moiety of the present invention may be connected to the free drug through 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 unstable moieties. In some embodiments, the prodrug is activated by enzymatic hydrolysis.

[0139] The present disclosure also includes isotopically labeled compounds that are the same as those listed in formula (I) (including compounds of formula (II)-(X)), 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. Examples of isotopes suitable for inclusion in the compounds of the present disclosure are 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. With 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 may therefore be preferred in certain circumstances. The compounds may be combined with positron emitting isotopes for use in medical imaging and positron emission tomography (PET) studies to determine receptor distribution. Suitable positron emitting isotopes that may be incorporated into compounds of formula (I), (II) or (III) are 11 C. 13 N. 15 O and 18 F. Isotopically labeled compounds of formula (I), (II) or (III) 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.

[0140] The compounds disclosed in the present invention can exist in solvated and non-solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc., and the present invention is intended to cover solvated and non-solvated forms. 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 in crystalline form.

[0141] Pharmaceutical composition and use thereof

[0142] The present invention also provides a pharmaceutical composition, which comprises an active ingredient within a safe and effective amount, and a pharmaceutically acceptable carrier or excipient. Since the active ingredient compound of formula I of the present application and its pharmaceutically acceptable salt have a good inhibitory effect on the abnormal expression of proteins such as NSD2, NSD1, NSD3, c-MYC, KLK3 / PSA, AR, NKX3.1, GSPT1, etc., the pharmaceutical composition can be used to treat tumors, cardiovascular diseases, diabetes, hypertension, muscular dystrophy, Parkinson's disease, Alzheimer's disease and other diseases related to abnormal expression of proteins such as NSD2, NSD1, NSD3, c-MYC, KLK3 / PSA, AR, NKX3.1, GSPT1, etc. in humans or other mammals.

[0143] The present invention provides a class of protein kinase degraders and uses thereof. Specifically, the present invention provides a compound having a structure shown in formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer or a prodrug molecule thereof. The compound can target ubiquitination degradation of NSD2, NSD1, NSD3, c-MYC, KLK3 / PSA, AR, NKX3.1, GSPT1 and other proteins, and widely inhibit the proliferation of tumor cells such as prostate cancer, non-small cell lung cancer, gastrointestinal stromal tumor, liver cancer, triple-negative breast cancer, leukemia, etc., and can be used to treat indications related to abnormal expression of NSD2, NSD1, NSD3, c-MYC, KLK3 / PSA, AR, NKX3.1, GSPT1 and other proteins and the above-mentioned tumors.

[0144] 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 non-small cell lung cancer, malignant melanoma, prostate cancer, 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.

[0145] 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.

[0146] The "active ingredients" and pharmaceutical compositions described in the present invention can be used as protein degraders such as NSD2, NSD1, NSD3, c-MYC, KLK3 / PSA, AR, NKX3.1, GSPT1, etc., and can be used to prepare drugs for preventing and / or treating tumors, cardiovascular diseases, diabetes, hypertension, muscular dystrophy, Parkinson's disease, Alzheimer's disease, etc.

[0147] "Safe and effective amount" means: the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of active ingredient per dose, more preferably, 10-200 mg of active ingredient per dose. Preferably, the "one dose" is one tablet.

[0148] "Pharmaceutically acceptable carrier or excipient" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity.

[0149] "Compatibility" herein means that the components in the composition can be blended with the active ingredient of the present invention and with each other without significantly reducing the efficacy of the active ingredient.

[0150] 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 ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0151] In another preferred embodiment, the compound of formula I of the present invention can form a complex with a macromolecular compound or a polymer through a non-bonding reaction. In another preferred embodiment, the compound of formula I of the present invention as a small molecule can also be connected to a macromolecular compound or a polymer through a chemical bond. The macromolecular compound can be a biological macromolecule such as a high polysaccharide, protein, nucleic acid, polypeptide, etc.

[0152] 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), etc.

[0153] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.

[0154] 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 the following ingredients:

[0155] (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid;

[0156] (b) binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose and gum arabic;

[0157] (c) humectants, for example, glycerin;

[0158] (d) disintegrating agents, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate;

[0159] (e) a buffering solvent, such as paraffin;

[0160] (f) absorption accelerators, for example, quaternary ammonium compounds;

[0161] (g) wetting agents, such as cetyl alcohol and glyceryl monostearate;

[0162] (h) adsorbents, for example, kaolin; and

[0163] (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.

[0164] The solid dosage forms can also be prepared using coatings and shell materials, 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 part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes.

[0165] 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 conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances. In addition to these inert diluents, the composition may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and spices.

[0166] In addition to the active ingredients, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances.

[0167] Compositions for parenteral injection may include 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.

[0168] The compounds of the present invention may be administered alone or in combination with other therapeutic agents.

[0169] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

[0170] Combination medication

[0171] The compound of formula I can be used in combination with other drugs known to treat or improve similar conditions. When administered in combination, the administration method and dosage of the original drug remain unchanged, and the compound of formula I is taken simultaneously or subsequently. When the compound of formula I is taken simultaneously with one or more other drugs, it is preferred to use a pharmaceutical composition containing one or more known drugs and the compound of formula I. Drug combination also includes taking the compound of formula I and one or more other known drugs in overlapping time periods. When the compound of formula I is used 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 they are used alone.

[0172] 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, retinal 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, Bcr -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-α, interleukin-12, COX-2 inhibitors, p53, p53 activators, VEGF antibodies, EGF antibodies, JAK inhibitors, etc.

[0173] 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, atrenoin, allopurinol, allopurinol sodium, palonosetron hydrochloride, hexamethylmelamine, aminoglutethimide, amifostine, amrubicin, anacrine, anastrozole, dolasetron, aranesp, arglabin, arsenic trioxide, arnosin, 5-azacytidine, azathioprine, bacillus Calmette-Guérin or tice bacillus Calmette-Guérin, betadine, betamethasone acetate, betamethasone sodium phosphate preparation, bexarotene, bleomycin sulfate, bromourea, bortezomib, busulfan, calcitonin, alezosumab injection, capecitabine, carboplatin, casodex, cefone , cisplatin, cladribine, cladribine, clodrophosphamide, cytarabine, dacarbazine, actinomycin D, daunorubicin liposome, dexamethasone, dexamethasone phosphate, estradiol valerate, denileukin 2, depomet, deslorelin, delazosen, diethylstilbestrol, diflucan, docetaxel, doxorubicin, dronabinol, chin-166-chitosan complex, eligard, rasburicase, epirubicin hydrochloride, aprepitant, epirubicin, epoetin alfa, erythropoietin, epoetin, levamisole tablets, estradiol preparations, 17-β-estradiol, estramustine sodium phosphate, ethinyl estradiol, amifostine, hydroxyphosphoric acid, vanbifu, etoposide, fadrozole, tamoxifen Oxifen preparations, filgrastim, finasteride, firaprestin, floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine nucleoside monophosphate, 5-fluorouracil, fluoxymesterone, flutamide, formestan, 1-β-D-arabinofuranosylcytosine-5'-stearoyl phosphate, fotemustine, fulvestrant, gamma globulin, gemcitabine, gemtuzumab, imatinib mesylate, carmustine rice paper capsules, goserelin, granisiron hydrochloride, histrelin, and mexin, hydrocortisone, erythro-hydroxynonyl adenine, hydroxyurea, tentan isobetamin, 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, doxorubicin citrate liposome, nedaplatin, pegfilgrastim, oprelleukin, neupogen, nilutamide, tamoxifen,NSC-631570, recombinant human interleukin 1-β, octreotide, ondansetron hydrochloride, dehydrocortisone oral solution, oxaliplatin, paclitaxel, prednisone sodium phosphate preparation, pegaspargase, PEGASYS, pentostatin, lysin, pilocarpine hydrochloride, pilocarpine, plicamycin, porfimer sodium, prednimustine, stiprenisolone, prednisone, premarin, procarbazine, recombinant human erythropoietin, raltitrexed, libi, etidronate rhenium-186, rituximab, doxycycline-A, romotide, pilocarpine hydrochloride tablets, octreotide, sarmustine, semustine, sizoran, sobuzosine, sodium methylprednisolone, pafosic acid, stem cell therapy, streptozocin, strontium-89 chloride, levothyroxine sodium, tamoxifen Fen, tamsulosin, tasofenamin, tastolactone, taxotere, tesifazines, temozolomide, teniposide, testosterone propionate, methyltestosterone, thioguanine, thiotepa, thyroid stimulating hormone, tiludronic acid, topotecan, toremifene, tositumomab, trastuzumab, treosulfan, retinoic acid, methotrexate tablets, trimethylmelamine, trimetrexate, triptorelin acetate, triptorelin pamoate, eufodine, uridine, valrubicin, vesirinone, vinblastine, vincristine, vinamide, vinorelbine, virulizine, dexrazoxane, statins ester, zofran, paclitaxel protein stabilized preparation, acolbifene, interferon r-lb, affinitak, aminopterin, arzoxifene, as oprisnil, atamestane, atrasentan, BAY43-9006, Avastin, CCI-779, CDC-501, Celebrex, cetuximab, clenatol, 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, minocycline, MS-2 09. Liposomal MTP-PE, MX-6, nafarelin, nemorubicin, nevastatin, noratript, oblimersen, onco-TCS, osidem, paclitaxel polyglutamate, sodium bromoglutamate, PN-401, QS-21, quasi-sea, R-1549, raloxifene, ranpirnase, 13-cis retinoic acid, satraplatin, ciocalcitol, T-138067, tarceva, paclitaxel docosahexaenoic acid, thymosin αl, gazofurin, tipifarnib, tirapazamine, TLK-286, toremifene, trans-MID-lo7R, valspodar, vapreotide, vatalanib, verteporfin, vinflunine, Z-100 and zolelinic acid or a combination thereof.

[0174] The main benefits of the present invention are:

[0175] Provided is a PROTAC compound with a novel structure, which can efficiently and highly selectively degrade NSD2, NSD1, NSD3, c-MYC, KLK3 / PSA, AR, NKX3.1, GSPT1 and other proteins in cells, can effectively inhibit the growth of various tumor cells, and can be used to prepare anti-tumor drugs.

[0176] 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 where specific conditions are not specified are 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 under conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0177] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0178] 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.

[0179] The structure of the compound was determined by nuclear magnetic resonance (1H-NMR) and / or mass spectrometry (MS). NMR determination was performed using a Bruker AV-500, AV-600 nuclear magnetic resonance instrument, the determination solvent was deuterated chloroform (CDCl3) or deuterated dimethyl sulfoxide (DMSO-D6), and TMS was used as an internal standard. MS determination was performed using a LCQAD-40000 mass spectrometer. Column chromatography used 200-300 mesh silica gel (produced by Qingdao Ocean Chemical Plant).

[0180] Example

[0181] Example 1: N-cyclopropyl-N-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-)amino)ethyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0139)

[0182]

[0183] Step 1: Preparation of methyl 4-((cyclopropylamino)methyl)benzoate trifluoroacetate (3)

[0184]

[0185] Methyl p-formylbenzoate 2 (20.0 g, 121.8 mmol) was dissolved in methanol (200 mL), and cyclopropylamine 1 (7.0 g, 121.8 mmol, 8.5 mL) was added, and the mixture was stirred at room temperature for 10 hours. NaBH4 (9.2 g, 243.6 mmol) was added in batches, and the mixture was stirred at room temperature for 4 hours. Most of the methanol was removed by vortexing, and saturated sodium carbonate (200 mL) was added to quench the mixture. The mixture was extracted with ethyl acetate three times (200 mL×3), and the organic phases were combined. The organic phases were washed once with saturated sodium carbonate (300 mL) and once with saturated brine, and dried over anhydrous sodium sulfate. The crude product was concentrated to obtain a light yellow oily liquid. The crude product was dissolved in ether (100 mL), and trifluoroacetic acid was added. A large amount of white solid precipitated. The solid was filtered, and 31.2 g (84%) of white solid was collected by washing the solid with ether (50 mL). 1 H NMR(500MHz,Methanol-d4)δ8.06(d,J=7.1Hz,1H),7.57(d,J=7.2Hz,1H),4.34 (s,1H),3.88(s,1H),2.78–2.72(m,1H),0.91–0.86(m,2H),0.85–0.80(m,2H).

[0186] Step 2: Preparation of 4-((N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamido)methyl)benzoate (5)

[0187]

[0188] 3-Oxo-3,4-dihydro-2H-1,4-benzoxazine-7-carboxylic acid 4 (10.0 g, 51.8 mmol) was dissolved in acetonitrile (100

[0189] mL), HATU (29.5 g, 77.6 mmol), triethylamine (15.7 g, 155.3 mmol, 22 mL) and methyl 4-((cyclopropylamino)methyl)benzoate trifluoroacetate 3 (17.3 g, 56.9 mmol) were added in sequence, and stirred at room temperature for 12 hours; most of the acetonitrile was removed by vortexing, ethyl acetate (200 mL) was added to dilute, and the mixture was washed twice with saturated sodium carbonate (200 mL), washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography with petroleum ether / ethyl acetate (1:1) system to obtain 16.9 g (86%) of a white solid. 1H NMR (500MHz, DMSO-d6) δ10.89(s,1H),7.95(d,J=8.2Hz,2H),7.44(d,J=7.9Hz,2H),7.18(d,J=8.2Hz,1H),7.14(s,1H),6.92(d,J=8.1 Hz,1H),4.71(s,2H),4.61(s,2H),3.85(s,3H),2.84–2.74(m,1H),0.57–0.49(m,2H),0.48–0.40(m,2H); MS(ESI),m / z:381.2[M+H]+.

[0190] Step 3: Preparation of 4-((N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamido)methyl)benzoic acid (6)

[0191]

[0192] 4-((N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamido)methyl)benzoate 5 (5.0 g, 13.2 mmol) was dissolved in tetrahydrofuran (100 mL), and an aqueous solution of lithium hydroxide (2.76 g dissolved in 25 mL of water) was added, and the mixture was stirred at room temperature for 12 hours; the pH was adjusted to 2 with a 1 M aqueous solution of potassium hydrogen sulfate, and a large amount of white solid precipitated. The solid was filtered, and the solid was washed with cold water. After the solid was collected, it was dried to obtain 4.3 g (90%) of the product. 1 H NMR(500MHz,DMSO-d6)δ12.90(br s,1H),10.88(s,1H),7.93(d,J=8.1Hz,2H),7.41(d,J=7.7Hz,1H),7.18(d,J=7.8Hz,1H),7.15(s,1H),6 .92(d,J=8.1Hz,1H),4.70(s,2H),4.61(s,2H),2.85–2.73(m,1H),0.56–0.50(m,2H),0.48–0.41(m,2H).

[0193] Step 4: Preparation of tert-butyl 4-(4-((N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxy)methyl)benzamide)benzoate (8)

[0194]

[0195] Weigh 4-((N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamido)methyl)benzoic acid 6 (2.0 g, 5.46 mmol), tert-butyl 4-aminobenzoate 7 (2.11 g, 10.9 mmol), 4-dimethylaminopyridine (1.34 g, 10.9 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.09 g, 10.9 mmol) in a 50 mL eggplant-shaped bottle, add N,N-dimethylformamide (10 mL) to dissolve, react in an oil bath at 50 degrees for 10 hours; add ethyl acetate (200 mL) to dilute, wash three times with saturated brine (200 mL), dry the organic phase with anhydrous sodium sulfate, concentrate, and perform column chromatography on a petroleum ether / ethyl acetate (1:1) system to obtain 2.66 g (90%) of a white solid product. 1 H NMR(500MHz,DMSO-d6)δ10.89(s,1H),10.54(s,1H),7.96(d,J=8.1Hz,2H), 7.94–7.88(m,4H),7.46(d,J=7.7Hz,2H),7.19(d,J=8.1Hz,1H),7.15(s,1H ),6.92(d,J=8.1Hz,1H),4.72(s,2H),4.62(s,2H),2.85–2.76(m,1H),1.55 (s,9H),0.57–0.52(m,2H),0.50–0.44(m,2H); MS(ESI),m / z:564.3[M+Na]+.

[0196] Step 5: Preparation of 4-(4-((N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamido)methyl)benzamido)benzoic acid (9)

[0197]

[0198] Dissolve tert-butyl 4-(4-((N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxy)methyl)benzamide)benzoate 8 (1.31 g, 2.42 mmol) in dichloromethane (2 mL), add trifluoroacetic acid (2 mL), stir at room temperature for 12 hours, and spin dry to obtain 1.16 g (99%) of the product. 1H NMR (500MHz, DMSO-d6) δ10.89(s,1H),10.53(s,1H),7.97–7.90(m,6H),7.47(d,J=8.2Hz,2H),7.19(d,J=7.7Hz,1H),7.15(s,1H),6. 92(d,J=8.1Hz,1H),4.72(s,2H),4.62(s,2H),2.84–2.76(m,1H),0.58–0.51(m,2H),0.50–0.43(m,2H); MS(ESI),m / z:486.1[M+H]+.

[0199] Step 6: Preparation of N-cyclopropyl-N-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0139)

[0200]

[0201] Tert-butyl (2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)carbamate 10 (40 mg, 0.0960 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at room temperature for 5 hours. The crude product was fully spin-dried and dissolved in N,N-dimethylformamide (2 mL). Triethylamine (29.2 mg, 0.288 mmol, 40 μmol) was added successively. L), 4-(4-((N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamido)methyl)benzamido)benzoic acid 9 (46.6 mg, 0.0960 mmol), HATU (54.8 mg, 0.144 mmol), stirred at room temperature for 12 hours, most of the N,N-dimethylformamide was removed by rotation, and 66.5 mg (88%) of a yellow-green solid compound was obtained by column chromatography using a dichloromethane / methanol system. 1H NMR (600MHz, DMSO-d6) δ11.09(s,1H),10.90(s,1H),10.47(s,1H),8.65(t,1H),7.97(d,J=8.1Hz,2H),7.90–7.83(m,4H),7. 61–7.57(m,1H),7.46(d,J=7.3Hz,2H),7.27(d,J=8.7Hz,1H),7.19(d,J=8.1Hz,1H),7.15(s,1H),7.03(d,J=7.0Hz,1H),6.94 (d,J=8.1Hz,1H),6.85(t,J=6.0Hz,1H),5.05(dd,J=12.8,5.4Hz,1H),4.72(s,2H),4.61(s,2H),3.55–3.50(m,2H),3.48–3. 43(m,2H),2.93–2.84(m,1H),2.83–2.77(m,1H),2.63–2.52(m,2H),2.05–1.99(m,1H),0.58–0.52(m,2H),0.51–0.44(m,2H); 13 C NMR(151MHz,DMSO-d6)δ172.8,170.1,168.7,167.3,166.3,165.6,164.8 ,146.4,142.5,142.4,141.9,136.2,133.4,132.2,131.8,129.1,128.4,1 28.1,127.9,127.2,121.9,119.4,117.3,115.4,115.2,110.5,109.3,66. 7,48.5,45.5,41.4,40.1,39.0,38.7,31.0,22.2,9.5; HRMS(m / z):[M+Na] + Calculate for C 42 H 37 N7O9Na + 806.2545, found 806.2549.

[0202] Example 2: N-cyclopropyl-N-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0144)

[0203]

[0204] The synthesis method is the same as in Example 1.

[0205] 1 H NMR (600MHz, DMSO-d6) δ11.09(s,1H),10.88(s,1H),10.42(s,1H),8.44–8.36(m,1H),7.96(d,J=7.9Hz,2H),7.88–7.82(m,4H) ),7.60–7.54(m,1H),7.46(d,J=7.2Hz,2H),7.19(d,J=7.9Hz,1H),7.15(s,1H),7.12(d,J=8.6Hz,1H),7.02(d,J=7.0Hz,1H), 6.93(d,J=8.1Hz,1H),6.61–6.55(m,1H),5.05(dd,J=12.8,5.4Hz,1H),4.72(s,2H),4.62(s,2H),3.37–3.29(m,4H),2.92–2. 84(m,1H),2.83–2.76(m,1H),2.62–2.52(m,2H),2.06–1.99(m,1H),1.67–1.56(m,4H),0.59–0.52(m,2H),0.50–0.44(m,2H); 13 C NMR(151MHz,DMSO-d6)δ172.82,170.11,168.93,167.31,165.63,165.58,164.86,146.4 2,142.49,142.35,141.70,136.27,133.44,132.22,131.79,129.48,128.39,128.06,12 7.84,127.22,121.87,119.34,117.25,115.36,115.16,110.39,109.02,66.74,48.53,4 5.71,41.57,40.06,38.78,30.98,26.61,26.28,22.16,9.54; HRMS(m / z):[M+Na]+calcd forC 44 H 41 N7O9Na+834.2858,found 834.2853.

[0206] Example 3: N-cyclopropyl-N-(4-((4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-)amino)hexyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0145)

[0207]

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

[0209] 1 H NMR (500MHz, DMSO-d6) δ11.08(s,1H),10.87(s,1H),10.41(s,1H),8.34(t,J=5.6Hz,1H),7.95(d,J=8.2Hz,2H),7.88–7.81(m,4H),7.60 –7.56(m,1H),7.46(d,J=7.9Hz,2H),7.19(d,J=8.0Hz,1H),7.15(s,1H),7.09(d,J=8.6Hz,1H),7.02(d,J=7.0Hz,1H),6.93(d,J=8.1Hz,1 H),6.54(t,J=6.0Hz,1H),5.05(dd,J=12.7,5.4Hz,1H),4.72(s,2H),4.62(s,2H),3.31–3.28(m,2H),3.27–3.23(m,2H),2.92–2.84(m,1 H),2.83–2.77(m,1H),2.65–2.52(m,2H),2.04–1.99(m,1H),1.62–1.51(m,4H),1.41–1.34(m,4H),0.58–0.52(m,2H),0.51–0.45(m,2H); 13 C NMR(151MHz,DMSO-d6)δ172.82,170.12,168.95,167.31,165.58,165.55,164.85,146.43 ,142.49,142.34,141.66,136.29,133.44,132.21,131.79,129.56,128.39,128.06,127.8 2,127.22,121.87,119.33,117.19,115.36,115.16,110.37,109.02,66.74,48.53,45.71 ,41.80,40.06,30.98,29.14,28.66,26.25,26.10,22.15,9.54; HRMS(m / z):[M+Na]+calcd for C 46 H 45 N7O9Na+862.3171, found 862.3177.

[0210] Example 4: N-cyclopropyl-N-(4-((4-((8-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0146)

[0211]

[0212] The synthesis method is the same as in Example 1.

[0213] 1 H NMR (500MHz, DMSO-d6) δ11.06(s,1H),10.87(s,1H),10.41(s,1H),8.33(t,J=5.6Hz,1H),7.95(d,J=8.2Hz,2H),7.87–7.81(m,4H),7.57(dd,J= 8.6,7.1Hz,1H),7.46(d,J=7.9Hz,2H),7.19(d,J=8.0Hz,1H),7.15(s,1H),7.09(d,J=8.6Hz,1H),7.01(d,J=7.0Hz,1H),6.93(d,J=8.0Hz,1H),6 .52(t,J=5.9Hz,1H),5.05(dd,J=12.7,5.4Hz,1H),4.72(s,2H),4.62(s ,2H),3.30–3.26(m,2H),3.26–3.21(m,2H),2.92–2.84(m,1H),2.82–2. 77(m,1H),2.64–2.52(m,2H),2.05–1.99(m,1H),1.60–1.55(m,2H),1.5 4–1.49(m,2H),1.37–1.29(m,8H),0.57–0.52(m,2H),0.50–0.45(m,2H); 13C NMR(151MHz,DMSO-d6)δ172.82,170.11,168.96,167.31,165.57,165.52,164.85,146.44,14 2.49,142.34,141.65,136.28,133.44,132.20,131.79,129.56,128.39,128.06,127.81,127. 21,121.87,119.33,117.19,115.36,115.15,110.36,109.00,66.74,48.53,45.73,41.83,40 .06,30.98,29.16,28.75,28.73,28.68,26.46,26.30,22.15,9.53; HRMS(m / z):[M+Na]+calcd forC 48 H 49 N7O9Na+890.3484, found 890.3480.

[0214] Example 5: N-cyclopropyl-N-(4-((4-((10-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)decyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0147)

[0215]

[0216] The synthesis method is the same as in Example 1.

[0217] 1H NMR(600MHz,DMSO-d6)δ11.09(s,1H),10.88(s,1H),10.41(s,1H),8.34(t,J=5.6Hz,1H),7.95(d,J=8.3Hz,2H),7.88–7.81(m,4H),7.57(dd,J=8.6,7.1Hz,1H),7.19(d,J=8.0Hz,2H),7.15(s,1H),7.08(d,J=8.6Hz,1H),7.01(d,J=7.0Hz,1H),6.93(d,J=8.1Hz,1H),6.52(t,J=5.9Hz,1H),5.05(dd,J=12.8,5.5Hz,1H),4.72(s,2H),4.62(s,2H),3.30–3.26(m,2H),3.25–3.21(m,2H),2.92–2.84(m,1H),2.83–2.76(m,1H),2.62–2.51(m,2H),2.05–1.99(m,1H),1.59–1.47(m,4H),1.36–1.23(m,12H),0.59–0.52(m,2H),0.50–0.43(m,2H); 13 C NMR(151MHz,DMSO-d6)δ172.82,170.10,168.95,167.31,165.57,165.52,164.85,146.44,142.49,142.34,141.65,136.28,133.43,132.19,131.79,129.57,128.39,128.06,127.81,127.21,121.87,119.32,117.19,115.36,115.15,110.36,109.00,66.74,48.53,45.74,41.83,40.06,39.15,30.98,29.16,28.95,28.94,28.77,28.75,28.67,26.50,26.32,22.15,9.53;HRMS(m / z):[M+Na]+calcd for C 50 H 53 N7O9Na+918.3797,found918.3796。

[0218] Example 6: N-cyclopropyl-N-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0149)

[0219]

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

[0221] 1 H NMR (600MHz, DMSO-d6) δ11.06(s,1H),10.88(s,1H),10.44(s,1H),8.57(t,J=5.5Hz,1H),7.96(d,J=8.2Hz,2H),7.90–7.8 3(m,4H),7.58(d,J=8.3Hz,1H),7.46(d,J=7.5Hz,2H),7.30(t,J=5.7Hz,1H),7.19(d,J=7.7Hz,1H),7.15(s,1H),7.05(d,J =1.8Hz,1H),6.93(d,J=8.1Hz,2H),5.04(dd,J=12.7,5.5Hz,1H),4.72(s,2H),4.62(s,2H),3.48–3.43(m,2H),3.41–3.37 (m,2H),2.91–2.84(m,1H),2.83–2.77(m,1H),2.62–2.51(m,2H),2.03–1.96(m,1H),0.60–0.52(m,2H),0.51–0.43(m,2H); 13 C NMR (151MHz, DMSO-d6) δ172.82,170.17,167.67,167.14,166.03,165.61,164. 85,154.38,142.49,142.37,141.88,134.28,133.41,131.79,129.15,128.39, 128.07,127.91,127.22,125.12,121.87,119.33,116.22,115.36,115.16,66. 74,48.63,41.83,40.06,38.27,30.98,22.24,9.55; HRMS(m / z):[M+Na]+calcd for C 42 H 37 N7O9Na+806.2545, found 806.2536.

[0222] Example 7: N-cyclopropyl-N-(4-((4-((3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)propyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0181)

[0223]

[0224] The synthesis method is the same as in Example 1.

[0225] 1 H NMR (600MHz, DMSO-d6) δ11.06(s,1H),10.88(s,1H),10.43(s,1H),8.44(t,J=5.6Hz,1H),7.96(d,J=8.2Hz,2H),7.88–7.83( m,4H),7.57(d,J=8.4Hz,1H),7.46(d,J=7.7Hz,2H),7.22–7.12(m,3H),6.97(d,J=1.6Hz,1H),6.93(d,J=8.1Hz,1H),6.87(d d,J=8.4,2.0Hz,1H),5.03(dd,J=12.8,5.5Hz,1H),4.72(s,2H),4.62(s,2H),3.40–3.36(m,2H),3.27–3.23(m,2H),2.91–2. 84(m,1H),2.83–2.75(m,1H),2.62–2.51(m,2H),2.02–1.96(m,1H),1.88–1.82(m,2H),0.58–0.52(m,2H),0.50–0.44(m,2H); 13 C NMR(151MHz,DMSO-d6)δ172.83,170.18,167.70,167.17,165.84,165.59,164.8 6,154.41,142.49,142.36,141.75,134.24,133.43,131.79,129.42,128.39,128 .07,127.88,127.22,125.10,121.87,119.35,115.98,115.36,115.16,66.74,4 8.63,40.35,40.06,37.10,30.99,28.35,22.24,9.54; HRMS(m / z):[M+Na]+calcd for C 43 H 39N7O9Na+820.2701, found 820.2699.

[0226] Example 8: N-cyclopropyl-N-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0150)

[0227]

[0228] The synthesis method is the same as in Example 1.

[0229] 1 H NMR (600MHz, DMSO-d6) δ11.05(s,1H),10.88(s,1H),10.43(s,1H),8.40(t,J=5.6Hz,1H),7.96(d,J=8.2Hz,2H),7.88–7.82( m,4H),7.55(d,J=8.4Hz,1H),7.46(d,J=7.7Hz,2H),7.22–7.13(m,3H),6.98–6.95(m,1H),6.93(d,J=8.1Hz,1H),6.86(dd,J =8.4,1.9Hz,1H),5.02(dd,J=12.8,5.5Hz,1H),4.72(s,2H),4.62(s,2H),3.30(d,J=6.2Hz,2H),3.23–3.19(m,2H),2.90–2. 84(m,1H),2.83–2.77(m,1H),2.62–2.51(m,2H),2.02–1.96(m,1H),1.67–1.59(m,4H),0.58–0.52(m,2H),0.50–0.45(m,2H); 13C NMR(151MHz,DMSO-d6)δ172.82,170.19,167.71,167.15,165.64,165.57,164.85, 154.46,142.49,142.35,141.70,134.22,133.42,131.79,129.49,128.39,128.06 ,127.83,127.21,125.10,121.87,119.34,115.81,115.36,115.16,66.74,48.61, 42.23,40.06,38.77,30.98,26.82,25.75,22.23,9.55; HRMS(m / z):[M+Na]+calcd for C 44 H 41 N7O9Na+834.2858, found 834.2861.

[0230] Example 9: N-cyclopropyl-N-(4-((4-((5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)pentanoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0183)

[0231]

[0232] The synthesis method is the same as in Example 1.

[0233] 1H NMR (600MHz, DMSO-d6) δ11.05(s,1H),10.88(s,1H),10.42(s,1H),8.37(t,J=5.6Hz,1H),7.96(d,J=8.2Hz,2H),7.88–7.82(m,4H),7.56 (d,J=8.4Hz,1H),7.46(d,J=7.7Hz,2H),7.19(d,J=7.9Hz,1H),7.15(s,1H),7.12(t,J=5.3Hz,1H),6.95(s,1H),6.93(d,J=8.1Hz,1H),6. 85(dd,J=8.4,1.9Hz,1H),5.02(dd,J=12.8,5.5Hz,1H),4.72(s,2H),4.62(s,2H),3.30–3.25(m,2H),3.19–3.14(m,2H),2.91–2.84(m,1 H),2.83–2.77(m,1H),2.61–2.51(m,2H),2.02–1.96(m,1H),1.66–1.55(m,4H),1.47–1.39(m,2H),0.58–0.52(m,2H),0.50–0.44(m,2H); 13 C NMR(151MHz,DMSO-d6)δ172.82,170.19,167.71,167.16,165.59,165.58,164.85, 154.47,142.49,142.35,141.67,134.22,133.43,131.79,129.54,128.39,128.06, 127.83,127.22,125.11,121.87,119.34,115.79,115.36,115.16,66.74,48.61,42 .47,40.06,39.04,30.98,28.97,27.98,22.24,9.56; HRMS(m / z):[M+Na]+calcdfor C 45 H 43 N7O9Na+848.3014,found 848.3013.

[0234] Example 10: N-cyclopropyl-N-(4-((4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0151)

[0235]

[0236] The synthesis method is the same as in Example 1.

[0237] 1 H NMR (600MHz, DMSO-d6) δ11.05(s,1H),10.88(s,1H),10.42(s,1H),8.36(t,J=5.6Hz,1H),7.96(d,J=8.2Hz,2H),7.88–7.81(m,4H),7.55 (d,J=8.4Hz,1H),7.46(d,J=7.7Hz,2H),7.19(d,J=8.0Hz,1H),7.15(s,1H),7.11(t,J=5.3Hz,1H),6.94(s,1H),6.93(d,J=8.1Hz,1H),6. 84(dd,J=8.5,1.8Hz,1H),5.02(dd,J=12.8,5.5Hz,1H),4.72(s,2H),4.62(s,2H),3.29–3.23(m,2H),3.19–3.12(m,2H),2.91–2.82(m,1 H),2.83–2.77(m,1H),2.63–2.50(m,2H),2.03–1.95(m,1H),1.63–1.50(m,4H),1.45–1.33(m,4H),0.58–0.52(m,2H),0.50–0.44(m,2H); 13 C NMR (151MHz, DMSO) δ172.82,170.19,167.71,167.16,165.57,165.56,164.85,154 .47,142.49,142.35,141.66,134.21,133.44,131.79,129.56,128.39,128.06,12 7.82,127.21,125.12,121.87,119.34,115.77,115.36,115.16,66.74,48.61,42. 44,40.06,30.98,29.18,28.21,26.30,22.23,9.55; HRMS(m / z):[M+Na]+calcdfor C 46 H 45 N7O9Na+862.3171, found 862.3165.

[0238] Example 11: N-cyclopropyl-N-(4-((4-((8-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0152)

[0239]

[0240] The synthesis method is the same as in Example 1.

[0241] 1 H NMR (600MHz, DMSO-d6) δ11.05(s,1H),10.88(s,1H),10.42(s,1H),8.34(t,J=5.6Hz,1H),7.98–7.93(m,2H),7.88–7.81(m,4H),7.5 5(d,J=8.4Hz,1H),7.46(d,J=7.7Hz,2H),7.19(d,J=8.0Hz,1H),7.15(s,1H),7.10(t,J=5.3Hz,1H),6.95–6.91(m,2H),6.84(dd,J= 8.4,1.9Hz,1H),5.02(dd,J=12.8,5.5Hz,1H),4.72(s,2H),4.62(s,2H),3.28–3.21(m,2H),3.18–3.12(m,2H),2.91–2.82(m,1H),2 .83–2.77(m,1H),2.63–2.50(m,2H),2.03–1.95(m,1H),1.61–1.47(m,4H),1.40–1.28(m,8H),0.59–0.52(m,2H),0.50–0.43(m,2H); 13 C NMR (151MHz, DMSO-d6) δ172.82,170.19,167.71,167.15,165.57,165.52,164.85,154. 47,142.48,142.34,141.65,134.21,133.44,131.79,129.56,128.39,128.06,127.81,1 27.21,125.11,121.87,119.33,115.76,115.36,115.15,66.74,48.60,42.48,40.06,3 0.98,29.18,28.79,28.77,28.24,26.52,26.48,22.23,9.58; HRMS(m / z):[M+Na]+calcd for C48 H 49 N7O9Na+890.3484, found 890.3482.

[0242] Example 12: N-cyclopropyl-N-(4-((4-((10-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)decyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0153)

[0243]

[0244] The synthesis method is the same as in Example 1.

[0245] 1 H NMR (600MHz, DMSO-d6) δ11.05(s,1H),10.88(s,1H),10.41(s,1H),8.34(t,J=5.6Hz,1H),7.95(d,J=8.2Hz,2H),7.88–7.81(m,4H ),7.55(d,J=8.4Hz,1H),7.48–7.41(m,2H),7.19(d,J=8.2Hz,1H),7.15(s,1H),7.09(t,J=5.3Hz,1H),6.95–6.91(m,2H),6.86–6. 81(m,1H),5.02(dd,J=12.8,5.5Hz,1H),4.72(s,2H),4.62(s,2H),3.27–3.20(m,2H),3.18–3.10(m,2H),2.91–2.82(m,1H),2.83 –2.76(m,1H),2.63–2.50(m,2H),2.02–1.95(m,1H),1.60–1.48(m,4H),1.38–1.26(m,12H),0.60–0.52(m,2H),0.50–0.42(m,2H); 13CNMR(151MHz,DMSO-d6)δ172.82,170.19,167.71,167.16,165.57,165.52,164.85,154.4 7,142.48,142.34,141.65,134.21,133.44,131.79,129.57,128.39,128.06,127.81,127. 21,125.10,121.87,119.33,115.75,115.36,115.15,66.74,48.60,42.47,40.05,30.98,2 9.17,29.00,28.96,28.79,28.23,26.54,26.51,22.23,9.57; HRMS(m / z):[M+H]+calcdfor C 50 H 54 N7O9+896.3978,found 896.3970.

[0246] Example 13: N-cyclopropyl-N-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1-isoindol-4-yl)amino)-2-oxoethyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0194)

[0247]

[0248] The synthesis method is the same as in Example 1.

[0249] 1H NMR (600MHz, DMSO-d6) δ11.03(s,1H),10.88(s,1H),10.46(s,1H),9.98(s,1H),8.79(t,J=5.8Hz,1H),7.96(d,J=8.3Hz,2H), 7.94–7.87(m,4H),7.85(dd,J=7.2,1.7Hz,1H),7.56–7.49(m,2H),7.47(d,J=7.9Hz,2H),7.19(d,J=8.1Hz,1H),7.15(s,1H), 6.93(d,J=8.1Hz,1H),5.16(dd,J=13.3,5.2Hz,1H),4.72(s,2H),4.62(s,2H),4.45–4.33(m,2H),4.18–4.08(m,2H),2.97–2. 88(m,1H),2.86–2.76(m,1H),2.65–2.59(m,1H),2.38–2.27(m,1H),2.08–2.02(m,1H),0.60–0.52(m,2H),0.51–0.43(m,2H); 13 C NMR(151MHz,DMSO-d6)δ172.86,171.09,168.21,167.80,166.13,165.65,164.85, 142.49,142.38,142.04,133.74,133.52,133.43,132.73,131.79,128.74,128.72, 128.39,128.12,128.08,127.22,125.23,121.87,119.37,119.19,115.36,115.15 ,66.74,51.55,46.44,43.01,40.06,31.21,22.70,9.57; HRMS(m / z):[M+Na]+calcd for C 42 H 37 N7O9Na+806.2545,found806.2530.

[0250] Example 14: N-cyclopropyl-N-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1-isoindol-4-yl)amino)-4-oxobutyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0195)

[0251]

[0252] The synthesis method is the same as in Example 1.

[0253] 1 H NMR (600MHz, DMSO-d6) δ11.01(s,1H),10.88(s,1H),10.42(s,1H),9.83(s,1H),8.43(t,J=5.6Hz,1H),7.96(d,J=8.3Hz,2H),7. 86(s,4H),7.81(dd,J=7.4,1.6Hz,1H),7.53–7.44(m,4H),7.19(d,J=8.1Hz,1H),7.15(s,1H),6.93(d,J=8.1Hz,1H),5.14(dd,J= 13.3,5.2Hz,1H),4.72(s,2H),4.62(s,2H),4.43–4.32(m,2H),3.37–3.33(m,2H),2.97–2.89(m,1H),2.85–2.77(m,1H),2.64–2. 58(m,1H),2.43(t,J=7.4Hz,2H),2.40–2.31(m,1H),2.05–1.99(m,1H),1.91–1.83(m,2H),0.59–0.52(m,2H),0.51–0.43(m,2H); 13 CNMR(151MHz,DMSO-d6)δ172.87,171.07,167.84,165.73,165.60,164.86,142.49,1 42.36,141.74,133.85,133.77,133.43,132.66,131.79,129.40,128.61,128.39,12 8.07,127.87,127.22,125.30,121.87,119.33,119.02,115.36,115.16,66.74,51.5 0,46.45,40.06,38.67,33.33,31.21,25.25,22.63,9.57; HRMS(m / z):[M+Na]+calcd for C 44 H 41 N7O9Na+834.2858,found834.2864.

[0254] Example 15: N-cyclopropyl-N-(4-((4-(6-((2-(2,6-dioxopiperidin-3-yl)-1-isoindol-4-yl)amino)-6-oxohexyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0196)

[0255]

[0256] The synthesis method is the same as in Example 1.

[0257] 1 H NMR (600MHz, DMSO-d6) δ11.01(s,1H),10.88(s,1H),10.41(s,1H),9.76(s,1H),8.37(t,J=5.6Hz,1H),7.96(d,J=8.3Hz,2H),7 .88–7.79(m,5H),7.52–7.42(m,4H),7.19(d,J=8.0Hz,1H),7.15(s,1H),6.93(d,J=8.1Hz,1H),5.14(dd,J=13.3,5.2Hz,1H),4 .72(s,2H),4.62(s,2H),4.42–4.31(m,2H),3.28–3.23(m,2H),2.96–2.87(m,1H),2.85–2.76(m,1H),2.63–2.57(m,1H),2.41– 2.32(m,3H),2.05–1.98(m,1H),1.69–1.61(m,2H),1.61–1.53(m,2H),1.41–1.33(m,2H),0.60–0.52(m,2H),0.51–0.43(m,2H); 13 C NMR(151MHz,DMSO-d6)δ172.87,171.34,171.09,167.83,165.58,165.57,164.85,142.4 9,142.35,141.67,133.80,133.69,133.44,132.66,131.79,129.54,128.61,128.39,12 8.06,127.81,127.22,125.24,121.87,119.33,118.96,115.36,115.15,66.74,51.52,4 6.46,40.06,35.77,31.21,29.02,26.18,24.89,22.62,9.55; HRMS(m / z):[M+Na]+calcd forC 44 H 45 N7O9Na+862.3171, found 862.3176.

[0258] Example 16: N-cyclopropyl-N-(4-((4-((8-(2-(2,6-dioxopiperidin-3-yl)-1-isoindol-4-yl)amino)-8-oxooctyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0197)

[0259]

[0260] The synthesis method is the same as in Example 1.

[0261] 1 H NMR (600MHz, DMSO-d6) δ11.02(s,1H),10.88(s,1H),10.41(s,1H),9.76(s,1H),8.35(t,J=5.6Hz,1H),7.95(d,J=8.3Hz,2H),7 .88–7.79(m,5H),7.52–7.44(m,4H),7.19(d,J=8.0Hz,1H),7.15(s,1H),6.93(d,J=8.1Hz,1H),5.14(dd,J=13.3,5.2Hz,1H),4 .72(s,2H),4.62(s,2H),4.42–4.30(m,2H),3.28–3.21(m,2H),2.96–2.87(m,1H),2.84–2.76(m,1H),2.63–2.57(m,1H),2.40– 2.30(m,3H),2.05–1.98(m,1H),1.64–1.58(m,2H),1.56–1.50(m,2H),1.37–1.28(m,6H),0.59–0.52(m,2H),0.51–0.43(m,2H); 13 C NMR(151MHz,DMSO-d6)δ172.87,171.38,171.09,167.83,165.58,165.54,164.85,142.49,1 42.35,141.66,133.81,133.69,133.44,132.66,131.79,129.56,128.62,128.39,128.06,12 7.81,127.21,125.24,121.87,119.33,118.96,115.36,115.15,66.74,51.52,46.47,40.06, 35.80,31.20,29.19,28.66,28.56,26.44,25.07,22.64,9.55; HRMS(m / z):[M+Na]+calcdfor C48 H 49 N7O9Na+890.3484,found 890.3491.

[0262] Example 17: N-cyclopropyl-N-(4-((4-((10-(2-(2,6-dioxopiperidin-3-yl)-1-isoindolin-4-yl)amino)-10-oxodecyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0198)

[0263]

[0264] The synthesis method is the same as in Example 1.

[0265] 1 H NMR (600MHz, DMSO-d6) δ11.02(s,1H),10.88(s,1H),10.41(s,1H),9.75(s,1H),8.34(t,J=5.6Hz,1H),7.95(d,J=8.2Hz,2H),7 .88–7.79(m,5H),7.52–7.43(m,4H),7.19(d,J=8.1Hz,1H),7.15(s,1H),6.93(d,J=8.1Hz,1H),5.14(dd,J=13.3,5.2Hz,1H),4. 72(s,2H),4.62(s,2H),4.41–4.30(m,2H),3.27–3.20(m,2H),2.96–2.87(m,1H),2.84–2.76(m,1H),2.64–2.58(m,1H),2.40–2 .29(m,3H),2.06–1.99(m,1H),1.64–1.57(m,2H),1.55–1.48(m,2H),1.36–1.26(m,10H),0.59–0.52(m,2H),0.51–0.43(m,2H); 13C NMR (151MHz, DMSO-d6) δ172.87,171.38,171.08,167.83,165.58,165.53,164.86,142.49,142. 34,141.65,133.81,133.69,133.44,132.66,131.79,129.56,128.62,128.39,128.06,127.81, 127.21,125.24,121.87,119.33,118.96,115.36,115.16,66.74,51.52,46.46,40.06,35.81,3 1.20,29.19,28.92,28.79,28.77,28.68,26.51,25.09,22.64,9.60; HRMS(m / z):[M+Na]+calcd for C 50 H 53 N7O9Na+918.3797, found 918.3799.

[0266] Example 18: N-cyclopropyl-N-(4-((4-((12-(2-(2,6-dioxopiperidin-3-yl)-1-isoindolin-4-yl)amino)-12-oxododecyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0199)

[0267]

[0268] The synthesis method is the same as in Example 1.

[0269] 1H NMR (600MHz, DMSO-d6) δ11.02(s,1H),10.88(s,1H),10.41(s,1H),9.75(s,1H),8.34(t,J=5.6Hz,1H),7.97–7.93(m,2H),7.8 8–7.78(m,5H),7.52–7.43(m,4H),7.19(d,J=8.1Hz,1H),7.15(s,1H),6.93(d,J=8.1Hz,1H),5.14(dd,J=13.3,5.2Hz,1H),4.7 2(s,2H),4.62(s,2H),4.41–4.30(m,2H),3.26–3.20(m,2H),2.96–2.87(m,1H),2.84–2.76(m,1H),2.63–2.57(m,1H),2.39–2. 29(m,3H),2.06–1.99(m,1H),1.64–1.56(m,2H),1.54–1.47(m,2H),1.33–1.25(m,14H),0.59–0.52(m,2H),0.51–0.43(m,2H); 13 C NMR(151MHz,DMSO-d6)δ172.87,171.39,171.08,167.84,165.58,165.53,164.86,142.49,142.3 4,141.65,133.81,133.69,133.44,132.66,131.80,129.57,128.62,128.39,128.06,127.81,127 .21,125.24,121.87,119.33,118.97,115.36,115.16,66.74,51.52,46.46,40.06,35.81,31.21 ,29.18,29.00,28.96,28.81,28.79,28.68,26.52,25.09,22.65,9.53; HRMS(m / z):[M+Na]+calcd for C 52 H 57 N7O9Na+946.4110, found 946.4119.

[0270] Example 19: N-cyclopropyl-N-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1-isoindol-5-yl)amino)-2-oxoethyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0209)

[0271]

[0272] The synthesis method is the same as in Example 1.

[0273] 1 H NMR (600MHz, DMSO-d6) δ10.97(s,1H),10.88(s,1H),10.46(s,1H),10.42(s,1H),8.81(t,J=5.9Hz,1H),8.00–7.94(m,3H),7.9 4–7.88(m,4H),7.70–7.61(m,2H),7.47(d,J=7.8Hz,2H),7.19(d,J=8.1Hz,1H),7.15(s,1H),6.93(d,J=8.1Hz,1H),5.09(dd,J= 13.3,5.1Hz,1H),4.76–4.69(m,2H),4.62(s,2H),4.44(d,J=17.2Hz,1H),4.30(d,J=17.3Hz,1H),4.11(d,J=5.8Hz,2H),2.95– 2.86(m,1H),2.85–2.76(m,1H),2.63–2.56(m,1H),2.43–2.32(m,1H),2.03–1.96(m,1H),0.60–0.52(m,2H),0.51–0.42(m,2H); 13 C NMR(151MHz,DMSO-d6)δ172.91,171.12,168.50,167.81,166.16,165.66,164.8 6,143.33,142.49,142.38,142.22,142.05,133.44,131.79,128.72,128.39,128 .10,127.23,126.37,123.72,121.87,119.39,118.78,115.36,115.16,113.25,6 6.74,51.53,47.15,43.43,40.06,31.22,22.52,9.50; HRMS(m / z):[M+Na]+calcd for C 42 H 37 N7O9Na+806.2545,found806.2539.

[0274] Example 20: N-cyclopropyl-N-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1-isoindol-5-yl)amino)-4-oxobutyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0210)

[0275]

[0276] The synthesis method is the same as in Example 1.

[0277] 1 H NMR (600MHz, DMSO-d6) δ10.97(s,1H),10.88(s,1H),10.42(s,1H),10.28(s,1H),8.43(t,J=5.6Hz,1H),8.00–7.93(m,3H),7.86(s,4H),7.65 (d,J=8.3Hz,1H),7.59(dd,J=8.4,1.8Hz,1H),7.46(d,J=7.8Hz,2H),7.19(d,J=8.1Hz,1H),7.15(s,1H),6.93(d,J=8.1Hz,1H),5.07(dd,J=13 .3,5.1Hz,1H),4.72(s,2H),4.62(s,2H),4.41(d,J=17.2Hz,1H),4.28 (d,J=17.2Hz,1H),3.36–3.31(m,2H),2.94–2.85(m,1H),2.85–2.76(m, 1H),2.61–2.55(m,1H),2.44(t,J=7.5Hz,2H),2.42–2.31(m,1H),2.01 –1.95(m,1H),1.91–1.84(m,2H),0.60–0.52(m,2H),0.51–0.43(m,2H); 13C NMR(151MHz,DMSO-d6)δ172.90,171.50,171.12,167.86,165.73,165.58,164.86,143 .27,142.54,142.49,142.36,141.73,133.42,131.79,129.41,128.39,128.07,127.88 ,127.22,126.11,123.61,121.87,119.32,118.67,115.36,115.16,113.11,66.74,51 .52,47.12,40.06,38.76,34.04,31.21,25.07,22.53,9.50; HRMS(m / z):[M+Na]+calcd for C 44 H 41 N7O9Na+834.2858, found 834.2852.

[0278] Example 21: N-cyclopropyl-N-(4-((4-(6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-5-yl)amino)-6-oxohexyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0211)

[0279]

[0280] The synthesis method is the same as in Example 1.

[0281] 1H NMR(600MHz,DMSO-d6)δ10.97(s,1H),10.88(s,1H),10.42(s,1H),10.23(s,1H),8.37(t,J=5.6Hz,1H),8.00–7.94(m,3H),7.88–7.81(m,4H),7.64(d,J=8.3Hz,1H),7.58(dd,J=8.3,1.8Hz,1H),7.46(d,J=7.9Hz,2H),7.19(d,J=8.1Hz,1H),7.15(d,J=1.7Hz,1H),6.93(d,J=8.1Hz,1H),5.07(dd,J=13.3,5.1Hz,1H),4.72(s,2H),4.62(s,2H),4.41(d,J=17.2Hz,1H),4.28(d,J=17.2Hz,1H),3.29–3.22(m,2H),2.94–2.85(m,1H),2.84–2.75(m,1H),2.61–2.55(m,1H),2.41–2.33(m,3H),2.02–1.94(m,1H),1.68–1.61(m,2H),1.59–1.50(m,2H),1.40–1.33(m,2H),0.60–0.52(m,2H),0.51–0.43(m,2H); 13 CNMR(151MHz,DMSO-d6)δ172.89,171.77,171.12,167.87,165.58,164.85,143.28,142.56,142.49,142.35,141.66,133.43,131.79,129.56,128.39,128.07,127.82,127.22,126.10,123.61,121.87,119.33,118.66,115.36,115.16,113.10,66.74,51.52,47.13,40.06,39.03,36.46,31.21,29.01,26.16,24.80,22.52,9.55;HRMS(m / z):[M+Na]+calcd forC 46 H 45 N7O9Na+862.3171,found 862.3163。

[0282] Example 22: N-cyclopropyl-N-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindol-5-yl)amino)-2-oxoethyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0204)

[0283]

[0284] The synthesis method is the same as in Example 1.

[0285] 1 H NMR (600MHz, DMSO-d6) δ10.99(s,1H),10.88(s,1H),10.47(s,1H),10.32(s,1H),8.81(t,J=5.9Hz,1H),8.10(d,J=2.1Hz,1H),7.97(d,J=8. 3Hz,2H),7.95–7.88(m,4H),7.77(dd,J=8.3,2.0Hz,1H),7.56(d,J=8.3Hz,1H),7.47(d,J=7.8Hz,2H),7.19(d,J=8.0Hz,1H),7.15(s,1H),6. 93(d,J=8.1Hz,1H),5.10(dd,J=13.3,5.1Hz,1H),4.72(s,2H),4.62(s,2H),4.41(d,J=17.1Hz,1H),4.29(d,J=17.0Hz,1H),4.10(d,J=6.0H z,2H),2.95–2.86(m,1H),2.85–2.75(m,1H),2.63–2.57(m,1H),2.44– 2.33(m,1H),2.04–1.98(m,1H),0.61–0.52(m,2H),0.51–0.43(m,2H); 13C NMR(151MHz,DMSO-d6)δ172.89,171.04,168.28,167.97,166.16,165.66,164.86, 142.49,142.37,142.04,138.93,136.58,133.45,132.21,131.80,128.75,128.39, 128.12,128.09,127.23,123.89,122.73,121.88,119.38,115.37,115.16,113.08 ,66.74,51.69,46.99,43.35,40.06,31.22,22.47,9.53; HRMS(m / z):[M+Na]+calcd for C 42 H 37 N7O9Na+806.2545, found 806.2538.

[0286] Example 23: N-cyclopropyl-N-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindol-5-yl)amino)-4-oxobutyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0205)

[0287]

[0288] The synthesis method is the same as in Example 1.

[0289] 1H NMR(600MHz,DMSO-d6)δ10.98(s,1H),10.88(s,1H),10.42(s,1H),10.18(s,1H),8.44(t,J=5.6Hz,1H),8.10(d,J=2.0Hz,1H),7.96(d,J=8.1Hz,2H),7.86(s,4H),7.71(dd,J=8.3,2.0Hz,1H),7.52(d,J=8.3Hz,1H),7.46(d,J=7.9Hz,2H),7.19(d,J=8.1Hz,1H),7.15(s,1H),6.93(d,J=8.1Hz,1H),5.09(dd,J=13.3,5.1Hz,1H),4.72(s,2H),4.62(s,2H),4.39(d,J=17.0Hz,1H),4.27(d,J=17.0Hz,1H),3.36–3.30(m,2H),2.93–2.86(m,1H),2.84–2.74(m,1H),2.62–2.56(m,1H),2.44–2.34(m,3H),2.03–1.98(m,1H),1.91–1.85(m,2H),0.60–0.52(m,2H),0.51–0.43(m,2H); 13 C NMR(151MHz,DMSO-d6)δ172.91,171.24,171.05,168.06,165.77,165.60,164.88,142.50,142.36,141.74,139.25,136.33,133.44,132.13,131.80,129.44,128.40,128.08,127.89,127.23,123.76,122.64,121.89,119.35,115.37,115.17,113.00,66.75,51.69,46.97,40.06,38.80,33.95,31.23,25.12,22.49,9.51;HRMS(m / z):[M+Na]+calcd for C 44 H 41 N7O9Na+834.2858,found834.2852。

[0290] Example 24: N-cyclopropyl-N-(4-((4-(6-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindol-5-yl)amino)-6-oxohexyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0206)

[0291]

[0292] The synthesis method is the same as in Example 1.

[0293] 1 H NMR(600MHz,DMSO-d6)δ10.98(s,1H),10.88(s,1H),10.41(s,1H),10.12(s, 1H),8.37(t,J=5.7Hz,1H),8.10(d,J=2.1Hz,1H),7.96(d,J=8.1Hz,2H),7.8 7–7.81(m,4H),7.71(dd,J=8.2,2.0Hz,1H),7.51(d,J=8.3Hz,1H),7.46(d,J =7.8Hz,2H),7.19(d,J=8.1Hz,1H),7.15(s,1H),6.93(d,J=8.1Hz,1H),5.09( dd,J=13.3,5.1Hz,1H),4.72(s,2H),4.62(s,2H),4.39(d,J=17.0Hz,1H),4. 27(d,J=17.0Hz,1H),3.28–3.24(m,2H),2.94–2.86(m,1H),2.85–2.76(m,1H) ,2.63–2.56(m,1H),2.42–2.33(m,3H),2.03–1.97(m,1H),1.69–1.62(m,2H) ,1.60–1.53(m,2H),1.42–1.33(m,2H),0.59–0.52(m,2H),0.51–0.44(m,2H); 13C NMR(151MHz,DMSO)δ172.89,171.50,171.04,168.06,165.57,164.86,142.49,142.3 4,141.65,139.27,136.29,133.44,132.11,131.79,129.57,128.39,128.06,127.82, 127.22,123.74,122.62,121.87,119.34,115.36,115.16,112.97,66.74,51.68,46. 95,40.06,36.41,31.22,29.03,26.20,24.84,22.47,9.52; HRMS(m / z):[M+Na]+calcd forC 46 H 45 N7O9Na+862.3171,found 862.3174.

[0294] Example 25: N-cyclopropyl-N-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindol-4-yl)amino)-2-oxoethyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC1100)

[0295]

[0296] The synthesis method is the same as in Example 1.

[0297] 1H NMR (600MHz, DMSO-d6) δ10.98(s,1H),10.89(s,1H),10.72(s,1H),10.48(s,1H),9.17(t,J=5.8Hz,1H),8.42(d,J=8.3Hz,1H),7.99–7.93 (m,4H),7.90(d,J=8.8Hz,2H),7.60(t,J=7.9Hz,1H),7.47(d,J=7.9Hz,2H),7.27(d,J=7.8Hz,1H),7.19(d,J=8.0Hz,1H),7.15(s,1H),6.9 4(d,J=8.1Hz,1H),4.98(dd,J=13.3,5.2Hz,1H),4.72(s,2H),4.62(s,2H),4.46(d,J=17.6Hz,1H),4.31(d,J=17.6Hz,1H),4.12–4.02(m, 2H),2.91–2.84(m,1H),2.84–2.76(m,1H),2.59–2.53(m,1H),2.40–2 .31(m,1H),2.02–1.95(m,1H),0.60–0.52(m,2H),0.51–0.43(m,2H); 13 C NMR(151MHz,DMSO-d6)δ172.81,170.82,169.06,168.76,166.88,165.69,164.86, 142.66,142.50,142.40,142.18,136.55,133.43,133.24,131.80,128.52,128.40, 128.30,128.10,127.24,121.88,119.48,117.99,117.30,116.61,115.37,115.17 ,66.74,51.41,47.38,44.42,40.06,31.07,22.30,9.55; HRMS(m / z):[M+Na]+calcd for C 42 H 37 N7O9Na+806.2545, found 806.2547.

[0298] Example 26: N-cyclopropyl-N-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindol-4-yl)amino)-4-oxobutyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC1101)

[0299]

[0300] The synthesis method is the same as in Example 1.

[0301] 1 H NMR (600MHz, DMSO-d6) δ11.02(s,1H),10.88(s,1H),10.42(s,1H),10.27(s,1H),8.44(t,J=5.6Hz,1H),8.31(d,J=8.3Hz,1H),7.98–7.93(m ,2H),7.85(s,4H),7.57(t,J=7.9Hz,1H),7.46(d,J=7.8Hz,2H),7.25(d,J=7.5Hz,1H),7.19(d,J=8.0Hz,1H),7.15(s,1H),6.93(d,J=8.1Hz, 1H),5.06(dd,J=13.3,5.2Hz,1H),4.72(s,2H),4.62(s,2H),4.48(d,J=17.5Hz,1H),4.36(d,J=17.6Hz,1H),3.37–3.33(m,2H),2.94–2.85( m,1H),2.84–2.76(m,1H),2.64–2.58(m,1H),2.47–2.37(m,1H),2.06– 1.99(m,1H),1.94–1.86(m,2H),0.61–0.52(m,2H),0.51–0.43(m,2H); 13 C NMR(151MHz,DMSO-d6)δ172.84,171.08,170.80,169.17,165.75,165.59,164.86,142.6 4,142.49,142.34,141.72,137.06,133.45,133.17,131.80,129.41,128.39,128.07,12 7.88,127.22,121.87,119.30,117.65,117.08,116.83,115.36,115.16,66.74,51.61,4 7.52,45.73,40.06,38.62,34.45,31.17,24.85,22.35,9.56; HRMS(m / z):[M+Na]+calcd for C 44 H 41 N7O9Na+834.2858, found 834.2861.

[0302] Example 27: N-cyclopropyl-N-(4-((4-(6-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)amino)-6-oxohexyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0201)

[0303]

[0304] The synthesis method is the same as in Example 1.

[0305] 1 H NMR(600MHz,DMSO-d6)δ11.03(s,1H),10.88(s,1H),10.41(s,1H),10.27(s ,1H),8.36(t,J=5.6Hz,1H),8.32(d,J=8.3Hz,1H),7.96(d,J=8.3Hz,2H),7. 87–7.80(m,4H),7.57(t,J=7.9Hz,1H),7.46(d,J=7.8Hz,2H),7.25(d,J=7.5 Hz,1H),7.19(d,J=8.1Hz,1H),7.15(s,1H),6.93(d,J=8.0Hz,1H),5.07(dd, J=13.3,5.2Hz,1H),4.72(s,2H),4.62(s,2H),4.47(d,J=17.6Hz,1H),4.36 (d,J=17.6Hz,1H),3.28–3.23(m,2H),2.93–2.86(m,1H),2.84–2.75(m,1H), 2.64–2.58(m,1H),2.46–2.37(m,3H),2.06–2.01(m,1H),1.71–1.64(m,2H), 1.60–1.53(m,2H),1.42–1.35(m,2H),0.60–0.53(m,2H),0.51–0.43(m,2H); 13C NMR (151MHz, DMSO-d6) δ172.84,171.31,170.81,169.22,165.58,164.86,142.64,142. 49,142.34,141.65,137.07,133.45,133.19,131.80,129.55,128.39,128.06,127.82,1 27.22,121.88,119.31,117.63,117.02,116.74,115.36,115.16,66.74,51.59,47.50,4 0.06,38.99,36.99,31.17,28.92,26.04,24.60,22.34,9.52; HRMS(m / z):[M+Na]+calcd for C 46 H 45 N7O9Na+862.3171, found 862.3164.

[0306] Example 28: N-cyclopropyl-N-(4-((4-((8-(2-(2,6-dioxopiperidin-3-yl)-3-isoindol-4-yl)amino)-8-oxooctyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0202)

[0307]

[0308] The synthesis method is the same as in Example 1.

[0309] 1H NMR(600MHz,DMSO-d6)δ11.03(s,1H),10.88(s,1H),10.41(s,1H),10.27(s,1H),8.36–8.29(m,2H),7.95(d,J=8.2Hz,2H),7.87–7.81(m,4H),7.56(t,J=7.9Hz,1H),7.46(d,J=7.6Hz,2H),7.24(d,J=7.5Hz,1H),7.19(d,J=8.1Hz,1H),7.15(s,1H),6.93(d,J=8.1Hz,1H),5.08(dd,J=13.3,5.2Hz,1H),4.72(s,2H),4.62(s,2H),4.47(d,J=17.6Hz,1H),4.35(d,J=17.6Hz,1H),3.26–3.21(m,2H),2.94–2.85(m,1H),2.84–2.75(m,1H),2.64–2.58(m,1H),2.44–2.36(m,3H),2.06–2.01(m,1H),1.67–1.61(m,2H),1.55–1.49(m,2H),1.37–1.31(m,6H),0.58–0.52(m,2H),0.51–0.44(m,2H); 13 C NMR(151MHz,DMSO-d6)δ172.84,171.35,170.81,169.22,165.57,165.53,164.85,142.63,142.49,142.34,141.64,137.07,133.45,133.19,131.80,129.65,129.57,128.39,128.06,127.81,127.21,121.87,119.32,117.62,117.00,116.72,115.36,115.15,66.74,51.58,47.49,45.75,40.06,37.04,31.17,29.13,28.50,26.39,24.80,22.34,9.53,8.65;HRMS(m / z):[M+Na]+calcd for C 48 H 49 N7O9Na+890.3484,found 890.3470。

[0310] Example 29: N-cyclopropyl-N-(4-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0451)

[0311]

[0312] Tert-butyl (2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethyl)carbamate 11 (40 mg, 0.0961 mmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 3 hours. After being fully spin-dried, the crude product was dissolved in N,N-dimethylformamide (2 mL), and triethylamine (29.2 mg, 0.288 mmol) was added in turn. , 40μL), 4-((N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamido)methyl)benzoic acid 6 (38.7mg, 0.106mmol), HATU (54.8mg, 0.144mmol), stirred at room temperature for 12 hours, most of the N,N-dimethylformamide was removed by rotation, and 54.2mg (85%) of yellow-green solid compound was obtained by column chromatography on a dichloromethane / methanol system. 1 HNMR(600MHz,DMSO-d6)δ11.08(s,1H),10.87(s,1H),8.67(t,J=5.4Hz,1H),7.86–7.79(m,2H),7.59(dd,J=8.6,7.1Hz,1H),7.38 (d,J=7.8Hz,2H),7.25(d,J=8.6Hz,1H),7.17(d,J=8.0Hz,1H),7.13(d,J=1.8Hz,1H),7.02(d,J=7.0Hz,1H),6.92(d,J=8.1Hz,1H) ,6.84(t,J=6.1Hz,1H),5.05(dd,J=12.8,5.5Hz,1H),4.67(s,2H),4.61(s,2H),3.54–3.49(m,2H),3.48–3.44(m,2H),2.92–2.84 (m,1H),2.81–2.72(m,1H),2.62–2.47(m,2H),2.05–1.98(m,1H),0.59–0.50(m,2H),0.48–0.40(m,2H); HRMS(m / z):[M+Na]+calcd for C 35 H 32N6O8Na+687.2174, found 687.2168.

[0313] Example 30: N-cyclopropyl-N-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0248)

[0314]

[0315] The synthesis method is the same as Example 29.

[0316] 1 H NMR (600MHz, DMSO-d6) δ11.05(s,1H),10.87(s,1H),8.46(t,J=5.7Hz,1H),7.84–7.79(m,2H),7.55(d,J=8.4Hz,1H),7.37 (d,J=7.8Hz,2H),7.19–7.10(m,3H),6.95(d,J=2.1Hz,1H),6.91(d,J=8.1Hz,1H),6.85(dd,J=8.4,2.1Hz,1H),5.02(dd,J =12.8,5.5Hz,1H),4.67(s,2H),4.61(s,2H),3.33–3.28(m,2H),3.23–3.18(m,2H),2.91–2.83(m,1H),2.80–2.71(m,1H), 2.60–2.47(m,2H),2.02–1.96(m,1H),1.67–1.57(m,4H),0.59–0.50(m,2H),0.49–0.39(m,2H); HRMS(m / z):[M+Na]+calcd for C 37 H 36 N6O8Na+715.2487,found715.2492.

[0317] Example 31: N-cyclopropyl-N-(4-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0452)

[0318]

[0319] The synthesis method is the same as Example 29.

[0320] 1 H NMR (600MHz, DMSO-d6) δ11.05(s,1H),10.87(s,1H),8.42(t,J=5.6Hz,1H),7.81(d,J=8.3Hz,2H),7.55(d,J=8.3Hz,1H),7.16(d,J= 8.0Hz,1H),7.12(s,1H),7.10(t,J=5.4Hz,1H),6.94(d,J=2.1Hz,1H),6.91(d,J=8.0Hz,1H),6.84(dd,J=8.4,2.1Hz,1H),5.02(dd, J=12.8,5.5Hz,1H),4.67(s,2H),4.61(s,2H),3.28–3.23(m,2H),3.19–3.12(m,2H),2.91–2.83(m,1H),2.80–2.70(m,1H),2.60–2. 48(m,2H),2.02–1.95(m,1H),1.62–1.50(m,4H),1.44–1.32(m,4H),0.59–0.49(m,2H),0.48–0.41(m,2H); HRMS(m / z):[M+Na]+calcd for C 39 H 40 N6O8Na+743.2800, found 743.2804.

[0321] Example 32: N-cyclopropyl-N-(4-((8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0453)

[0322]

[0323] The synthesis method is the same as Example 29.

[0324] 1H NMR (600MHz, DMSO-d6) δ11.05(s,1H),10.87(s,1H),8.40(t,J=5.6Hz,1H),7.84–7.78(m,2H),7.55(d,J=8.3Hz,1H),7.36(d,J=7.9Hz,2 H),7.16(d,J=8.0Hz,1H),7.12(d,J=1.7Hz,1H),7.09(t,J=5.4Hz,1H),6.93(d,J=2.1Hz,1H),6.92(s,1H),6.83(dd,J=8.4,2.1Hz,1H), 5.02(dd,J=12.8,5.5Hz,1H),4.67(s,2H),4.61(s,2H),3.27–3.21(m,2H),3.17–3.11(m,2H),2.91–2.82(m,1H),2.81–2.70(m,1H),2.6 0–2.50(m,2H),2.03–1.95(m,1H),1.60–1.49(m,4H),1.40–1.28(m,8H),0.58–0.49(m,2H),0.48–0.38(m,2H); HRMS(m / z):[M+Na]+calcd for C 41 H 44 N6O8Na+771.3113, found 771.3121.

[0325] Example 33: N-cyclopropyl-N-(4-((10-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)decyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0232)

[0326]

[0327] The synthesis method is the same as Example 29.

[0328] 1H NMR (600MHz, DMSO-d6) δ11.05(s,1H),10.87(s,1H),8.40(t,J=5.7Hz,1H),7.81(d,J=8.3Hz,2H),7.55(d,J=8.3Hz,1H),7.36(d,J=7.8 Hz,2H),7.16(d,J=8.1Hz,1H),7.12(s,1H),7.09(t,J=5.4Hz,1H),6.93(s,1H),6.91(d,J=8.0Hz,1H),6.83(dd,J=8.5,2.1Hz,1H),5.0 2(dd,J=12.8,5.5Hz,1H),4.67(s,2H),4.61(s,2H),3.27–3.20(m,2H),3.17–3.10(m,2H),2.91–2.82(m,1H),2.80–2.71(m,1H),2.60– 2.45(m,2H),2.03–1.95(m,1H),1.60–1.46(m,4H),1.40–1.25(m,12H),0.59–0.49(m,2H),0.48–0.39(m,2H); HRMS(m / z):[M+Na]+calcd for C 43 H 48 N6O8Na+799.3426, found 799.3421.

[0329] Example 34: N-cyclopropyl-N-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1-isoindol-5-yl)amino)butyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0384)

[0330]

[0331] The synthesis method is the same as in Example 1.

[0332] 1H NMR (600MHz, DMSO-d6) δ10.91(s,1H),10.88(s,1H),10.42(s,1H),8.39(t,J= 5.7Hz,1H),7.96(d,J=8.2Hz,2H),7.86(d,J=2.0Hz,4H),7.46(d,J=7.8Hz,2H ),7.37(d,J=8.4Hz,1H),7.19(d,J=8.1Hz,1H),7.15(s,1H),6.93(d,J=8.1Hz ,1H),6.66(dd,J=8.4,2.0Hz,1H),6.62(s,1H),6.39(t,J=5.5Hz,1H),5.00(dd ,J=13.3,5.1Hz,1H),4.72(s,2H),4.62(s,2H),4.23(d,J=16.7Hz,1H),4.12( d,J=16.6Hz,1H),3.32–3.28(m,2H),3.15–3.09(m,2H),2.93–2.84(m,1H),2.8 4–2.76(m,1H),2.60–2.53(m,1H),2.37–2.27(m,1H),1.97–1.89(m,1H),1.68 –1.58(m,4H),0.60–0.52(m,2H),0.51–0.43(m,2H); HRMS(m / z):[M+Na]+calcd for C 44 H 43 N7O8Na+820.3065, found 820.3052.

[0333] Example 35: N-cyclopropyl-N-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindol-5-yl)amino)butyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0396)

[0334]

[0335] The synthesis method is the same as in Example 1.

[0336] 1H NMR(600MHz,DMSO-d6)δ10.95(s,1H),10.88(s,1H),10.42(s,1H),8.39(t,J=5 .7Hz,1H),7.96(d,J=8.3Hz,2H),7.88–7.82(m,4H),7.46(d,J=7.9Hz,2H),7.2 5(d,J=8.3Hz,1H),7.19(d,J=7.8Hz,1H),7.15(s,1H),6.93(d,J=8.1Hz,1H),6 .86(dd,J=8.3,2.2Hz,1H),6.81(d,J=2.1Hz,1H),5.91(t,J=5.5Hz,1H),5.06( dd,J=13.3,5.1Hz,1H),4.72(s,2H),4.62(s,2H),4.26(d,J=16.3Hz,1H),4.14 (d,J=16.3Hz,1H),3.32–3.27(m,2H),3.12–3.06(m,2H),2.94–2.86(m,1H),2. 84–2.76(m,1H),2.60–2.55(m,1H),2.41–2.31(m,1H),2.01–1.94(m,1H),1.68 –1.58(m,4H),0.62–0.52(m,2H),0.51–0.41(m,2H); HRMS(m / z):[M+Na]+calcd for C 44 H 43 N7O8Na+820.3065, found 820.3063.

[0337] Example 36: N-cyclopropyl-N-(4-((4-(2-((2R)-1-((2,6-dioxopiperidin-3-yl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0444)

[0338]

[0339] The synthesis method is the same as in Example 1.

[0340] 1H NMR(600MHz,DMSO-d6)δ10.88(s,1H),10.86(s,0.50H),10.84(s,0.50H),10.45(s,1H),8.66(t,J=5.8Hz,0.50H),8.63(t,J=5.8Hz,0.50H),8.47–8.40(m,1H),8.23(d,J=8.4Hz,0.50H),8.13(d,J=8.4Hz,0.50H),7.96(d,J=8.2Hz,2H),7.90–7.84(m,4H),7.46(d,J=7.6Hz,2H),7.29–7.13(m,7H),6.93(d,J=8.1Hz,1H),4.72(s,2H),4.62(s,2H),4.61–4.52(m,2H),3.94–3.87(m,2H),3.83–3.72(m,1H),3.09(dd,J=13.8,3.9Hz,0.50H),3.01(dd,J=13.6,5.2Hz,0.55H),2.88–2.64(m,3H),2.55–2.51(m,0.50H),2.47–2.41(m,0.50H),2.03–1.88(m,1H),1.84–1.77(m,1H),0.62–0.52(m,2H),0.51–0.40(m,2H); 13 C NMR(151MHz,DMSO-d6)δ172.95,172.91,171.96,171.85,171.08,170.78,170.62,168.90,168.88,165.98,165.96,165.63,164.85,142.48,142.36,142.01,141.99,137.71,137.59,133.43,131.79,129.29,129.24,128.72,128.67,128.38,128.08,128.06,128.04,127.22,126.31,126.27,121.87,119.33,115.36,115.15,66.74,53.90,53.72,49.06,49.01,42.60,42.54,40.06,37.98,37.71,30.89,30.57,24.24,24.16,9.55;HRMS(m / z):[M+Na]+calcd for C 43 H 41 N7O9Na+822.2858,found 822.2846。

[0341] Example 37: N-cyclopropyl-N-(4-((4-(((2R)-1-((2,6-dioxopiperidin-3-yl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-4-oxobutyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0398)

[0342]

[0343] The synthesis method is the same as in Example 1.

[0344] 1 H NMR(600MHz,DMSO-d6)δ10.88(s,1H),10.84(s,0.50H),10.81(s,0.50H), 10.43(s,1H),8.42(d,J=8.1Hz,0.50H),8.39(d,J=8.3Hz,0.50H),8.37–8 .31(m,1H),8.18(d,J=8.6Hz,0.50H),8.12(d,J=8.6Hz,0.50H),7.96(d,J =8.1Hz,2H),7.89–7.81(m,4H),7.46(d,J=7.8Hz,2H),7.30–7.22(m,4H), 7.21–7.13(m,3H),6.93(d,J=8.1Hz,1H),4.72(s,2H),4.62(s,2H),4.61– 4.51(m,2H),3.23–3.06(m,2.50H),3.00(dd,J=13.6,5.1Hz,0.50H),2.82 –2.63(m,3H),2.49–2.40(m,1H),2.20–2.04(m,2H),2.03–1.88(m,1H),1. 86–1.78(m,1H),1.70–1.59(m,2H),0.61–0.52(m,2H),0.51–0.42(m,2H); 13C NMR(151MHz,DMSO-d6)δ172.95,172.92,172.04,171.95,171.82,171.74,171.55,171.21,170.53,165.65,165.58, 164.85,142.48,142.34,141.70,138.04,137.88,133.43,131.78,129.47,129.45,129.17,128.39,128.06,128.00, 127.86,127.84,127.21,126.22,126.20,121.87,119.33,115.35,115.15,66.74,53.76,49.05,49.01,45.63,40.0 6,38.68,38.64,37.96,37.70,32.79,32.68,30.93,30.61,25.36,24.21,24.15,9.54; HRMS(m / z):[M+Na]+calcdfor C 45 H 45 N7O9Na+850.3171, found 850.3166.

[0345] Example 38: N-cyclopropyl-N-(4-((4-(6-(((2R)-1-((2,6-dioxopiperidin-3-yl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-6-oxohexyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0399)

[0346]

[0347] The synthesis method is the same as in Example 1.

[0348] 1H NMR(600MHz,DMSO-d6)δ10.88(s,1H),10.83(s,0.50H),10.82(s,0.50H),10.42(s,1H),8.40–8.29(m,2H),8.07(d,J=8.7Hz,0.50H),8.01(d,J=8.6Hz,0.50H),7.96(d,J=8.2Hz,2H),7.89–7.81(m,4H),7.46(d,J=7.9Hz,2H),7.29–7.21(m,4H),7.21–7.13(m,3H),6.93(d,J=8.1Hz,1H),4.72(s,2H),4.62(s,2H),4.61–4.47(m,2H),3.22–3.15(m,2H),3.09–3.05(m,0.50H),2.97(dd,J=13.6,5.2Hz,0.50H),2.84–2.63(m,3H),2.54–2.50(m,0.50H),2.47–2.39(m,0.50H),2.10–2.01(m,2H),2.02–1.88(m,1H),1.85–1.77(m,1H),1.49–1.34(m,4H),1.16–1.11(m,2H),0.61–0.52(m,2H),0.51–0.43(m,2H); 13 C NMR(151MHz,DMSO-d6)δ172.96,172.91,172.07,171.99,171.94,171.91,171.61,171.26,170.63,165.58,165.52,164.85,142.49,142.34,141.65,138.03,137.83,133.44,131.79,129.56,129.20,128.39,128.06,127.97,127.82,127.21,126.21,126.18,121.87,119.33,115.36,115.16,66.74,53.63,53.59,49.04,49.02,40.05,38.06,37.77,35.19,35.16,30.92,30.60,28.99,26.06,26.03,24.97,24.21,24.14,9.56;HRMS(m / z):[M+Na]+calcdfor C 47 H 49 N7O9Na+878.3484,found 878.3477。

[0349] Example 39: N-cyclopropyl-N-(4-((4-((8-((2R)-1-((2,6-dioxopiperidin-3-yl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-8-oxooctyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0445)

[0350]

[0351] The synthesis method is the same as in Example 1.

[0352] 1 H NMR(600MHz,DMSO-d6)δ10.88(s,1H),10.83(s,0.50H),10.82(s,0.50H),10 .42(s,1H),8.39–8.30(m,2H),8.05(d,J=8.7Hz,0.50H),8.00(d,J=8.6Hz,0. 50H),7.96(d,J=8.3Hz,2H),7.88–7.82(m,4H),7.46(d,J=7.8Hz,2H),7.28– 7.21(m,4H),7.20–7.13(m,3H),6.93(d,J=8.0Hz,1H),4.72(s,2H),4.62(s,2 H),4.60–4.49(m,2H),3.26–3.21(m,2H),3.08–3.06(m,0.50H),2.97(dd,J= 13.6,5.1Hz,0.50H),2.84–2.63(m,3H),2.47–2.41(m,1H),2.06–1.99(m,2H) ,1.98–1.89(m,1H),1.85–1.78(m,1H),1.52–1.44(m,2H),1.39–1.31(m,2H) ,1.28–1.19(m,4H),1.12–1.02(m,2H),0.61–0.52(m,2H),0.51–0.41(m,2H); 13CNMR(151MHz,DMSO-d6)δ172.94,172.90,172.07,172.01,171.93,171.63,171.29,170.44,165.57,165.52,164.8 5,142.48,142.33,141.65,138.03,137.84,133.44,131.79,129.57,129.19,129.17,128.38,128.06,127.94,127. 81,127.21,126.18,126.15,121.87,119.33,115.35,115.15,66.73,53.60,53.56,49.03,40.06,38.02,37.74,35 .19,35.16,30.92,30.60,29.21,28.60,28.45,28.42,26.41,25.12,24.21,24.14,9.51; HRMS(m / z):[M+Na]+calcd for C 49 H 53 N7O9Na+906.3797, found 906.3791.

[0353] Example 40: N-cyclopropyl-N-(4-((4-((10-((2R)-1-((2,6-dioxopiperidin-3-yl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-10-oxodecyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0446)

[0354]

[0355] The synthesis method is the same as in Example 1.

[0356] 1H NMR (600MHz, DMSO-d6) δ10.88(s,1H),10.83(s,0H),10.82(s,1H),10.42(s,1H),8.40–8.30(m,2H),8.04(d,J=8.7Hz,0H),7.99(d,J=8.7Hz,1H), 7.96(d,J=8.2Hz,2H),7.88–7.80(m,4H),7.46(d,J=7.5Hz,2H),7.28–7. 21(m,4H),7.21–7.13(m,3H),6.93(d,J=8.1Hz,1H),4.72(s,2H),4.62(s ,2H),4.61–4.48(m,1H),3.27–3.21(m,2H),3.09–3.05(m,0H),2.97(dd, J=13.6,5.1Hz,0H),2.85–2.64(m,3H),2.48–2.39(m,0H),2.06–1.98(m, 2H),1.85–1.76(m,1H),1.56–1.48(m,2H),1.39–1.15(m,6H),1.12–1.00 (m,2H),0.59–0.52(m,2H),0.51–0.43(m,2H); HRMS(m / z):[M+Na]+calcd for C 51 H 57 N7O9Na+934.4110, found 934.4102.

[0357] Example 41: N-cyclopropyl-N-(4-((5-(1-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)propyl)-1H-1,2,3-triazol-4-yl)pyridin-2-yl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0244)

[0358]

[0359] Step 1: Preparation of N-cyclopropyl-N-(4-((5-ethynylpyridin-2-yl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (13)

[0360]

[0361] 4-((N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamido)methyl)benzoic acid 6 (500 mg, 1.365 mmol) was dissolved in acetonitrile (5 mL), and 5-ethynyl-2-amine 12 (177 mg, 1.50 mmol), N-methylimidazole (392 mg, 4.78 mmol, 380 μL), and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (498 mg, 1.77 mmol) were added in sequence. The mixture was stirred in an oil bath at 40 degrees for 16 hours; the solvent was removed by vortexing, and 204 mg (32%) of solid product was obtained directly by column chromatography. 1 H NMR(500MHz,DMSO-d6)δ10.99(s,1H),10.88(s,1H),8.51(dd,J=2.3,0.8Hz,1H),8.2 3(dd,J=8.6,0.9Hz,1H),8.02(d,J=8.3Hz,2H),7.95(dd,J=8.7,2.4Hz,1H),7.43(d, J=7.9Hz,2H),7.19(d,J=8.0Hz,1H),7.15(s,1H),6.93(d,J=8.1Hz,1H),4.71(s,2H) ,4.62(s,2H),3.17(s,1H),2.85–2.77(m,1H),0.59–0.52(m,2H),0.50–0.42(m,2H).

[0362] Step 2: Preparation of N-cyclopropyl-N-(4-((5-(1-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)propyl)-1H-1,2,3-triazol-4-yl)pyridin-2-yl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0244)

[0363]

[0364] N-cyclopropyl-N-(4-((5-ethynylpyridin-2-yl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide 13 (46.6 mg, 0.100 mmol) was dissolved in N,N-dimethylformamide (2 mL), 5-((3-azidopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 14 (39.2 mg, 0.110 mmol) was added, and thiophene-2-carboxylic acid copper (I) (76.7 mg, 0.400 mmol) was added. The mixture was stirred at room temperature for 3 hours, the solvent was removed by vortexing, and 46.9 mg (57%) of yellow-green solid was obtained by column chromatography.1 H NMR (600MHz, DMSO-d6) δ11.06(s,1H),10.90(s,1H),10.88(s,1H),8.86(dd,J=2.3,1.0Hz,1H),8.69(s,1H),8.33–8.23(m,2H),8.05(d,J=8.3Hz, 2H),7.58(d,J=8.3Hz,1H),7.44(d,J=7.9Hz,2H),7.23(t,J=5.5Hz,1H), 7.20(d,J=7.9Hz,1H),7.16(s,1H),6.98(d,J=2.1Hz,1H),6.93(d,J=8.1H z,1H),6.88(dd,J=8.4,2.1Hz,1H),5.03(dd,J=12.8,5.5Hz,1H),4.72(s ,2H),4.62(s,2H),4.56(t,J=7.0Hz,2H),3.29–3.24(m,2H),2.91–2.84(m ,1H),2.84–2.77(m,1H),2.59–2.51(m,1H),2.24–2.17(m,2H),2.03–1.9 6(m,1H),0.59–0.52(m,2H),0.51–0.44(m,2H); HRMS(m / z):[M+Na]+calcd for C 43 H 38 N 10 O8Na+845.2766, found 845.2762.

[0365] Example 42: N-cyclopropyl-N-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0256)

[0366]

[0367] The synthesis method is the same as in Example 1.

[0368] 1H NMR (600MHz, DMSO-d6) δ11.11(s,1H),10.88(s,1H),10.42(s,1H),8.42(t,J=5.6Hz,1H),7.96(d,J=8.3Hz,2H),7.88–7.81(m,5H),7.4 6(d,J=7.8Hz,2H),7.44(d,J=2.3Hz,1H),7.36(dd,J=8.4,2.3Hz,1H),7.19(d,J=8.1Hz,1H),7.15(s,1H),6.93(d,J=8.1Hz,1H),5.12( dd,J=12.9,5.5Hz,1H),4.72(s,2H),4.62(s,2H),4.23(t,J=6.4Hz,2H),3.36–3.33(m,2H),2.92–2.85(m,1H),2.84–2.77(m,1H),2.62 –2.53(m,2H),2.07–2.01(m,1H),1.85–1.79(m,2H),1.74–1.66(m,2H),0.60–0.53(m,2H),0.51–0.44(m,2H); HRMS(m / z):[M+H]+calcd for C 44 H 41 N6O 10 +813.2879, found 813.2867.

[0369] Example 43: N-cyclopropyl-N-(4-((5-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)pentanamide)pyridin-2-yl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0265)

[0370]

[0371] Step 1: Preparation of N-cyclopropyl-N-(4-((5-nitropyridin-2-yl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (16)

[0372]

[0373] 4-((N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamido)methyl)benzoic acid 6 (500 mg, 1.365 mmol) was dissolved in acetonitrile (5 mL), and 2-amino-5-nitropyridine 15 (209 mg, 1.50 mmol), N-methylimidazole (392 mg, 4.78 mmol, 380 μL), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (498 mg, 1.77 mmol) were added in sequence, and stirred in an oil bath at 40 degrees for 24 hours; the solvent was removed by vortexing, and 444 mg (67%) of solid product was obtained directly by column chromatography. 1 H NMR(500MHz,DMSO-d6)δ11.52(s,1H),10.88(s,1H),9.23(d,J=3.1Hz,1H),8.67 (dd,J=9.3,2.8Hz,1H),8.44(d,J=9.3Hz,1H),8.05(d,J=8.3Hz,2H),7.46(d,J=7 .9Hz,2H),7.20(d,J=8.1Hz,1H),7.16(d,J=1.7Hz,1H),6.93(d,J=8.0Hz,1H),4. 72(s,2H),4.62(s,2H),2.89–2.75(m,1H),0.60–0.52(m,2H),0.50–0.43(m,2H).

[0374] Step 2: Preparation of N-(4-((5-aminopyridin-2-yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (17)

[0375]

[0376] Dissolve N-cyclopropyl-N-(4-((5-nitropyridin-2-yl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide 16 (150 mg, 0.3078 mmol) in methanol (5 mL), add 10% Pd / C (15 mg), stir for 12 hours under hydrogen atmosphere; filter through celite, spin dry to obtain 134 mg (95%) of the product. MS (ESI), m / z: 458.5 [M+H] +.

[0377] Step 3: Preparation of N-cyclopropyl-N-(4-((5-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)pentanamide)pyridin-2-yl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0265)

[0378]

[0379] 5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)pentanoic acid tert-butyl ester 18 (42.9 mg, 0.100 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at room temperature for 5 hours. After being fully spin-dried, the crude product was dissolved in N,N-dimethylformamide (2 mL), and triethylamine (30.4 mg, 0.300 mmol, 42 μL) and N-( 4-((5-aminopyridin-2-yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide 17 (50.3 mg, 0.110 mmol), HATU (57.0 mg, 0.15 mmol), stirred at room temperature for 12 hours, most of the N,N-dimethylformamide was removed by rotation, and 35.0 mg (43%) of a yellow-green solid compound was obtained by column chromatography using a dichloromethane / methanol system. 1H NMR (600MHz, DMSO-d6) δ11.05(s,1H),10.87(s,1H),10.69(s,1H),10.10(s,1H),8.63(dd,J=2.6,0.8Hz,1H),8.13(d,J=9.0Hz,1H),8.03– 7.97(m,3H),7.56(d,J=8.4Hz,1H),7.42(d,J=7.8Hz,2H),7.19(d,J=8.0Hz,1H),7.16–7.13(m,2H),6.96(s,1H),6.93(d,J=8.1Hz,1H),6.8 6(dd,J=8.5,2.1Hz,1H),5.03(dd,J=12.8,5.4Hz,1H),4.71(s,2H),4.62(s,2H),3.23–3.19(m,2H),2.91–2.77(m,2H),2.60–2.51(m,2H), 2.42–2.37(m,2H),2.02–1.96(m,1H),1.75–1.69(m,2H),1.67–1.59(m,2H),0.60–0.51(m,2H),0.50–0.43(m,2H); HRMS(m / z):[M+H]+calcd for C 43 H 41 N8O9+813.2991,found813.2994.

[0380] Example 44: N-cyclopropyl-N-(4-((5-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)amino)pyridin-2-yl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0334)

[0381]

[0382] Step 1: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(4-(((6-nitropyridin-3-yl)amino)methyl)piperidin-1-yl)isoindoline-1,3-dione (21)

[0383]

[0384] Dissolve tert-butyl ((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)carbamate 19 (100 mg, 0.213 mmol) in dichloromethane (1 mL), add trifluoroacetic acid (0.5 mL), and stir at room temperature for 3 hours; after being fully spin-dried, add N,N-dimethylformamide (2 mL) to dissolve, add N,N-diisopropylethylamine (138 mg, 1.06 mmol, 0.2 mL), add 5-fluoro-2-nitropyridine 20 (31.8 mg, 0.234 mmol), stir in an oil bath at 110 degrees for 1 hour, add ethyl acetate to dilute (50 mL), wash once with saturated sodium bicarbonate (50 mL), wash twice with saturated brine (50 mL), dry over anhydrous sodium sulfate, concentrate, and obtain 79.5 mg (76%) of yellow-green solid by column chromatography. MS (ESI), m / z: 515.4 [M+Na]+.

[0385] Step 2: Preparation of N-cyclopropyl-N-(4-((5-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)amino)pyridin-2-yl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0334)

[0386]

[0387] 2-(2,6-dioxopiperidin-3-yl)-5-(4-(((6-nitropyridin-3-yl)amino)methyl)piperidin-1-yl)isoindoline-1,3-dione 21 (40 mg, 0.0812 mmol) was dissolved in methanol (2 mL) and 10% Pd / C (4 mg), stirred for 12 hours under hydrogen atmosphere; filtered through diatomaceous earth, dried by rotation, added with acetonitrile (2 mL) to dissolve, and then added with 4-((N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamido)methyl)benzoic acid 6 (32.7 mg, 0.0893 mmol), N-methylimidazole (20.0 mg, 0.244 mmol, 20 μL), N,N',N'-tetramethylchloroformamidine hexafluorophosphate (34.2 mg, 0.122 mmol), reacted in an oil bath at 50 degrees for 16 hours, concentrated, and obtained 27.0 mg (41%) of solid by column chromatography. 1H NMR(600MHz,DMSO-d6)δ11.07(s,1H),10.87(s,1H),10.32(s,1H),7.99(d,J =8.3Hz,2H),7.85(d,J=8.9Hz,1H),7.78(d,J=2.9Hz,1H),7.65(d,J=8.5Hz,1 H),7.40(d,J=7.9Hz,2H),7.33(d,J=2.3Hz,1H),7.25(dd,J=8.7,2.3Hz,1H) ,7.19(d,J=8.1Hz,1H),7.14(s,1H),7.07(dd,J=9.0,2.9Hz,1H),6.92(d,J=8 .1Hz,1H),5.88–5.80(m,1H),5.06(dd,J=12.8,5.4Hz,1H),4.70(s,2H),4.6 1(s,2H),4.10(d,J=12.9Hz,2H),3.00–2.93(m,4H),2.93–2.84(m,1H),2.83– 2.76(m,1H),2.61–2.51(m,2H),2.04–1.97(m,1H),1.90–1.83(m,3H),1.31– 1.25(m,2H),0.61–0.51(m,2H),0.50–0.42(m,2H); HRMS(m / z):[M+Na]+calcd for C 44 H 42 N8O8Na+833.3018, found 833.3021.

[0388] Example 45: N-cyclopropyl-N-(4-((5-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)methyl)piperidin-1-yl)pyridin-2-yl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0367)

[0389]

[0390] The synthesis method is the same as Example 44.

[0391] 1H NMR(600MHz,DMSO-d6)δ11.06(s,1H),10.87(s,1H),10.50(s,1H),8.08(d, J=3.0Hz,1H),8.02–7.98(m,2H),7.57(d,J=8.3Hz,1H),7.46(dd,J=9.2,3. 1Hz,1H),7.41(d,J=7.8Hz,2H),7.36(s,1H),7.23(t,J=5.7Hz,1H),7.19(d ,J=8.0Hz,1H),7.15(s,1H),7.01(s,1H),6.94–6.89(m,2H),5.03(dd,J=12 .8,5.4Hz,1H),4.70(s,2H),4.61(s,2H),3.74(d,J=11.8Hz,2H),3.17–3.1 2(m,2H),2.91–2.84(m,1H),2.83–2.76(m,1H),2.72–2.65(m,2H),2.60–2. 52(m,2H),2.03–1.96(m,1H),1.90–1.83(m,2H),1.80–1.72(m,1H),1.41–1 .33(m,2H),0.58–0.51(m,2H),0.50–0.41(m,2H); HRMS(m / z):[M+H]+calcd forC 44 H 43 N8O8+811.3198,found 811.3183.

[0392] Example 46: N-cyclopropyl-N-(4-((5-(4-(1-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazin-1-yl)pyridin-2-yl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0331)

[0393]

[0394] The synthesis method is the same as Example 44.

[0395] 1H NMR (600MHz, DMSO-d6) δ11.08(s,1H),10.88(s,1H),10.57(s,1H),8.13(d,J=3.0Hz,1H),8.05(d,J=9.0Hz,1H),8.00(d,J=8.3Hz,2H),7.70(d,J=8 .5Hz,1H),7.52(dd,J=9.1,3.0Hz,1H),7.43–7.38(m,3H),7.32(dd,J=8. 7,2.3Hz,1H),7.19(d,J=8.1Hz,1H),7.15(s,1H),6.93(d,J=8.1Hz,1H),5 .08(dd,J=12.8,5.5Hz,1H),4.70(s,2H),4.61(s,2H),4.22(d,J=12.9Hz ,2H),3.39–3.09(m,9H),3.05–2.97(m,2H),2.94–2.84(m,1H),2.84–2.76 (m,1H),2.63–2.52(m,2H),2.16–2.06(m,2H),2.06–1.98(m,1H),1.69–1. 58(m,2H),0.63–0.50(m,2H),0.50–0.39(m,2H); HRMS(m / z):[M+H]+calcd for C 47 H 48 N9O8+866.3620,found 866.3622.

[0396] Example 47: N-cyclopropyl-N-(4-((5-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)piperidin-2-yl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0333)

[0397]

[0398] The synthesis method is the same as Example 44.

[0399] 1H NMR (600MHz, DMSO-d6) δ11.08(s,1H),10.88(s,1H),10.52(s,1H),8.10(d,J=3.0Hz,1H),8.01(dd,J=8.6,5.8Hz,3H),7.71(d,J=8.5Hz,1H) ,7.48(dd,J=9.2,3.0Hz,1H),7.43–7.37(m,3H),7.30(d,J=8.9Hz,1H),7.19(d,J=8.0Hz,1H),7.15(s,1H),6.93(d,J=8.1Hz,1H),5.08(dd,J =12.8,5.4Hz,1H),4.70(s,2H),4.62(s,2H),3.87–3.78(m,2H),3.64 –3.38(m,4H),3.04–2.67(m,3H),2.93–2.85(m,3H),2.83–2.79(m,1H) ,2.76–2.71(m,2H),2.62–2.52(m,2H),2.07–1.93(m,3H),1.70–1.55(m,2H),0.59–0.52(m,2H),0.50–0.39(m,2H); HRMS(m / z):[M+H]+calcd for C 47 H 48 N9O8+866.3620,found866.3624.

[0400] Example 48: N-cyclopropyl-N-(4-((5-(4-((1-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0329)

[0401]

[0402] The synthesis method is the same as Example 44.

[0403] 1H NMR(600MHz,DMSO-d6)δ11.08(s,1H),10.88(s,1H),10.57(s,1H),8.14(d, J=3.0Hz,1H),8.05(d,J=9.0Hz,1H),8.01(d,J=8.2Hz,2H),7.68(d,J=8.5H z,1H),7.52(dd,J=9.2,3.2Hz,1H),7.42(d,J=7.9Hz,2H),7.35(s,1H),7.2 7(dd,J=8.8,2.3Hz,1H),7.19(d,J=8.0Hz,1H),7.15(s,1H),6.93(d,J=8.1 Hz,1H),5.07(dd,J=12.8,5.5Hz,1H),4.70(s,2H),4.62(s,2H),4.14–4.06 (m,2H),3.33–3.06(m,10H),3.04–2.98(m,2H),2.92–2.86(m,1H),2.83–2. 78(m,1H),2.62–2.52(m,2H),2.14–1.97(m,2H),1.89–1.79(m,2H),1.32–1 .23(m,2H),0.62–0.51(m,2H),0.51–0.40(m,2H); HRMS(m / z):[M+Na]+calcd forC 48 H 49 N9O8Na+902.3596, found 902.3591.

[0404] Example 49: N-cyclopropyl-N-(4-((5-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0330)

[0405]

[0406] The synthesis method is the same as Example 44.

[0407] 1H NMR (600MHz, DMSO-d6) δ11.08(s,1H),10.87(s,1H),10.50(s,1H),8.07(d,J=3.0Hz,1H),8.00(d,J=7.9Hz,3H),7.69(d,J=8.4Hz,1H),7.45(dd,J=9 .2,3.0Hz,1H),7.41(d,J=7.7Hz,2H),7.36(s,1H),7.27(d,J=8.6Hz,1H), 7.19(d,J=8.0Hz,1H),7.15(s,1H),6.93(d,J=8.1Hz,1H),5.07(dd,J=12. 8,5.4Hz,1H),4.70(s,2H),4.62(s,2H),3.75–3.66(m,2H),3.61–3.38(m, 4H),2.93–2.86(m,1H),2.84–2.76(m,1H),2.75–2.68(m,2H),2.65–2.51( m,6H),2.08–1.97(m,1H),1.88–1.81(m,2H),1.80–1.67(m,1H),1.33–1.2 2(m,2H),0.62–0.51(m,2H),0.50–0.38(m,2H); HRMS(m / z):[M+Na]+calcd for C 48 H 49 N9O8Na+902.3596,found 902.3601.

[0408] Example 50: N-cyclopropyl-N-(4-((5-(4-(1-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazin-1-yl)pyridin-2-yl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0354)

[0409]

[0410] The synthesis method is the same as Example 44.

[0411] 1H NMR (600MHz, DMSO-d6) δ11.07(s,1H),10.87(s,1H),10.54(s,1H),8.12–8.08(m,1H),8.05–7.98(m,3H),7.67(d,J=8.2Hz,1H),7.52 –7.46(m,1H),7.41(d,J=7.9Hz,2H),7.19(d,J=8.0Hz,1H),7.15(s,1H),6.92(d,J=8.1Hz,1H),6.82(s,1H),6.72–6.65(m,1H),5.06( dd,J=12.7,5.3Hz,1H),4.70(s,2H),4.61(s,2H),4.20–4.10(m,2H),3.99–3.87(m,2H),3.44–3.38(m,1H),3.26–3.16(m,4H),2.94–2 .85(m,3H),2.83–2.74(m,1H),2.61–2.52(m,4H),2.05–1.96(m,1H),0.59–0.52(m,2H),0.50–0.41(m,2H); HRMS(m / z):[M+Na]+calcd for C 45 H 43 N9O8Na+860.3127,found 860.3119.

[0412] Example 51: N-cyclopropyl-N-(4-((5-(3-(4-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)azetidin-2-yl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0347)

[0413]

[0414] The synthesis method is the same as Example 44.

[0415] 1H NMR (600MHz, DMSO-d6) δ11.08(s,1H),10.87(s,1H),10.47(s,1H),8.04–7.96(m,3H),7.70(d,J=8.4Hz,1H),7.66(d,J=2.9Hz,1H ),7.43–7.36(m,3H),7.29(d,J=7.3Hz,1H),7.19(d,J=8.1Hz,1H),7.15(s,1H),6.99(dd,J=8.9,2.9Hz,1H),6.92(d,J=8.1Hz,1H) ,5.08(dd,J=12.8,5.4Hz,1H),4.70(s,2H),4.61(s,2H),4.13–3.94(m,2H),3.81–3.65(m,2H),3.60–3.37(m,4H),2.93–2.84(m, 1H),2.83–2.75(m,1H),2.64–2.52(m,4H),2.05–1.98(m,1H),0.62–0.51(m,2H),0.50–0.39(m,2H); HRMS(m / z):[M+Na]+calcdfor C 45 H 43 N9O8Na+860.3127, found 860.3115.

[0416] Example 52: N-cyclopropyl-N-(4-((5-(4-((1-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazin-1-yl)pyridin-2-yl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0332)

[0417]

[0418] The synthesis method is the same as Example 44.

[0419] 1H NMR (600MHz, DMSO-d6) δ11.07(s,1H),10.87(s,1H),10.52(s,1H),8.12–8.06(m,1H),8.05–7.95(m,3H),7.64(d,J=8.1Hz,1H),7.50–7.44( m,1H),7.41(d,J=7.8Hz,2H),7.19(d,J=8.1Hz,1H),7.15(s,1H),6.93(d,J=8.1Hz,1H),6.83–6.76(m,1H),6.66(d,J=8.4Hz,1H),5.05(dd,J =12.8,5.4Hz,1H),4.70(s,2H),4.62(s,2H),4.22–4.10(m,2H),3.77 –3.68(m,2H),3.24–3.13(m,4H),3.10–3.01(m,1H),2.92–2.84(m,1H) ,2.83–2.76(m,1H),2.71–2.65(m,2H),2.61–2.53(m,6H),2.05–1.95(m,1H),0.61–0.51(m,2H),0.50–0.38(m,2H); HRMS(m / z):[M+H]+calcd for C 46 H 46 N9O8+852.3464,found852.3467.

[0420] Example 53: N-cyclopropyl-N-(4-((5-(3-((4-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)azetidin-1-yl)pyridin-2-yl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0377)

[0421]

[0422] The synthesis method is the same as Example 44.

[0423] 1H NMR (600MHz, DMSO-d6) δ11.09(s,1H),10.88(s,1H),10.46(s,1H),8.02–7.95(m,3H),7.76–7.69(m,1H),7.64(d,J=2.9Hz ,1H),7.48–7.38(m,3H),7.36–7.29(m,1H),7.19(d,J=8.1Hz,1H),7.14(s,1H),6.97(dd,J=8.7,2.9Hz,1H),6.93(d,J=8. 1Hz,1H),5.09(dd,J=12.8,5.4Hz,1H),4.70(s,2H),4.61(s,2H),4.11–3.97(m,2H),3.67–3.56(m,2H),3.51–3.34(m,4H) ,2.99–2.73(m,6H),2.64–2.51(m,4H),2.09–1.96(m,2H),0.60–0.51(m,2H),0.50–0.40(m,2H); HRMS(m / z):[M+Na]+calcd for C 46 H 45 N9O8Na+874.3283,found874.3277.

[0424] Example 54: N-cyclopropyl-N-(4-((5-((2-(4-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)amino)pyridin-2-yl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0356)

[0425]

[0426] The synthesis method is the same as Example 44.

[0427] 1H NMR (600MHz, DMSO-d6) δ11.08(s,1H),10.87(s,1H),10.33(s,1H),7.99(d,J=8.2Hz,2H),7.91–7.86(m,1H),7.84–7.79(m,1H), 7.73–7.66(m,1H),7.40(d,J=7.9Hz,2H),7.37–7.33(m,1H),7.30–7.25(m,1H),7.22–7.17(m,1H),7.16–7.13(m,1H),7.12–7.0 8(m,1H),6.92(d,J=8.1Hz,1H),5.10–5.05(m,1H),4.70(s,2H),4.61(s,2H),3.52–3.43(m,4H),3.25–3.16(m,2H),2.92–2.85( m,3H),2.84–2.77(m,1H),2.61–2.52(m,6H),2.03–1.95(m,1H),0.58–0.52(m,2H),0.50–0.42(m,2H); HRMS(m / z):[M+H]+calcd for C 44 H 44 N9O8+826.3307, found 826.3303.

[0428] Example 55: N-cyclopropyl-N-(4-((4-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0185)

[0429]

[0430] The synthesis method is the same as in Example 1.

[0431] 1H NMR(600MHz,DMSO-d6)δ10.88(s,1H),10.45(s,1H),8.99(s,1H),8.60(t,J=6.1Hz,1H),7.97(d,J=8.1Hz,2H),7.93–7.83(m,5H),7.46(d,J=7.8Hz,2H),7.45–7.38(m,4H),7.19(d,J=8.0Hz,1H),7.15(s,1H),6.93(d,J=8.1Hz,1H),5.16(d,J=3.6Hz,1H),4.80–4.76(m,1H),4.72(s,2H),4.62(s,2H),4.49–4.39(m,2H),4.41–4.35(m,1H),4.25(dd,J=15.7,5.1Hz,1H),3.78–3.68(m,2H),2.86–2.75(m,1H),2.45(s,3H),2.09–2.02(m,1H),1.96–1.89(m,1H),1.04(s,9H),0.58–0.52(m,2H),0.50–0.42(m,2H); 13 CNMR(151MHz,DMSO-d6)δ171.91,171.83,170.64,169.55,169.53,165.83,165.76,165.61,164.85,151.47,147.74,142.49,142.36,142.03,139.49,139.47,133.41,131.79,131.17,129.67,128.77,128.73,128.70,128.39,128.09,127.46,127.21,121.87,119.29,115.36,115.16,68.92,66.74,58.82,58.77,57.20,57.11,56.45,41.68,40.06,37.95,35.59,26.53,15.96,9.54;HRMS(m / z):[M+Na]+calcd for C 49 H 51 N7O8SNa+920.3412,found920.3411。

[0432] Example 56: N-cyclopropyl-N-(4-((2-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0186)

[0433]

[0434] The synthesis method is the same as in Example 1.

[0435] 1 H NMR (600MHz, DMSO-d6) δ10.88(s,1H),10.46(s,1H),8.97(s,1H),8.70(t,J=6.0Hz,1H),8.59(t,J=6.1Hz,1H),7.96(d,J=8.2Hz,2H),7. 88(s,5H),7.47(d,J=7.5Hz,2H),7.43–7.36(m,4H),7.19(d,J=7.9Hz,1H),7.15(s,1H),6.93(d,J=8.1Hz,1H),5.15(d,J=3.6Hz,1H),4.7 2(s,2H),4.62(s,2H),4.56(d,J=9.4Hz,1H),4.47–4.38(m,2H),4.37–4.33(m,1H),4.23(dd,J=15.8,5.5Hz,1H),4.01–3.94(m,2H),3.7 1–3.61(m,2H),2.87–2.75(m,1H),2.44(s,3H),2.08–2.01(m,1H),1.93–1.87(m,1H),0.94(s,9H),0.60–0.51(m,2H),0.51–0.41(m,2H); 13C NMR(151MHz,DMSO-d6)δ171.88,170.65,169.34,168.71,165.96,165.64,164.85,151.44,14 7.72,142.49,142.36,142.01,139.48,133.44,131.79,131.16,129.66,128.82,128.65,128. 39,128.08,127.98,127.44,127.23,121.87,119.40,115.36,115.16,68.89,66.74,58.75,56 .45,56.39,42.39,41.66,40.06,37.93,35.61,26.27,15.94,9.53; HRMS(m / z):[M+Na]+calcd for C 51 H 54 N8O9SNa+977.3627,found977.3618.

[0436] Example 57: N-cyclopropyl-N-(4-((4-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-4-oxobutyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0187)

[0437]

[0438] The synthesis method is the same as in Example 1.

[0439] 1H NMR(600MHz,DMSO-d6)δ10.88(s,1H),10.42(s,1H),8.98(s,1H),8.56(t,J=6.1Hz,1H),8.38(t,J=5.6Hz,1H),7.96(d,J=8.4Hz,3H),7.88–7.82(m,4H),7.46(d,J=7.8Hz,2H),7.44–7.36(m,4H),7.19(d,J=8.1Hz,1H),7.15(s,1H),6.93(d,J=8.1Hz,1H),5.13(d,J=3.6Hz,1H),4.72(s,2H),4.62(s,2H),4.56(d,J=9.4Hz,1H),4.47–4.40(m,2H),4.38–4.33(m,1H),4.22(dd,J=15.8,5.4Hz,1H),3.72–3.61(m,2H),3.28–3.21(m,2H),2.88–2.73(m,1H),2.44(s,3H),2.35–2.29(m,1H),2.24–2.18(m,1H),2.06–2.01(m,1H),1.94–1.87(m,1H),1.80–1.69(m,J=6.6,6.0Hz,2H),0.95(s,9H),0.61–0.52(m,2H),0.51–0.41(m,2H); 13 C NMR(151MHz,DMSO-d6)δ171.95,171.86,170.62,169.68,165.65,165.58,164.85,151.46,147.72,142.49,142.35,141.70,139.51,133.44,131.78,131.16,129.64,129.49,128.64,128.39,128.06,127.86,127.42,127.22,121.87,119.32,115.36,115.15,68.88,66.73,58.70,56.42,56.38,41.64,37.96,35.25,32.65,26.40,15.94,9.51;HRMS(m / z):[M+Na]+calcd for C 53 H 58 N8O9SNa+1005.3940,found 1005.3940。

[0440] Example 58: N-cyclopropyl-N-(4-((4-((6-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-6-oxohexyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0188)

[0441]

[0442] The synthesis method is the same as in Example 1.

[0443] 1 H NMR(600MHz,DMSO-d6)δ10.88(s,1H),10.42(s,1H),8.98(s,1H),8.56(t,J =6.1Hz,1H),8.34(t,J=5.6Hz,1H),7.95(d,J=8.0Hz,2H),7.89–7.80(m,5H ),7.46(d,J=7.4Hz,2H),7.44–7.35(m,4H),7.19(d,J=7.9Hz,1H),7.15(s, 1H),6.93(d,J=8.0Hz,1H),5.22–5.06(m,1H),4.72(s,2H),4.62(s,2H),4. 54(d,J=9.4Hz,1H),4.47–4.39(m,2H),4.38–4.31(m,1H),4.26–4.17(m,1H ),3.71–3.61(m,2H),3.27–3.18(m,2H),2.87–2.76(m,1H),2.44(s,3H),2. 32–2.23(m,1H),2.18–2.10(m,1H),2.06–2.01(m,1H),1.95–1.88(m,1H),1 .62–1.45(m,4H),1.35–1.26(m,2H),0.60–0.51(m,2H),0.50–0.44(m,2H); 13C NMR(151MHz,DMSO-d6)δ172.08,171.96,170.66,169.72,165.58,165.53,164.86,151.46,147.72, 142.49,142.34,141.66,139.51,133.45,131.79,131.17,129.64,129.55,128.64,128.39,128.06 ,127.82,127.42,127.22,121.87,119.32,115.36,115.16,68.88,66.74,58.69,56.37,56.29,41. 64,40.06,37.95,35.21,34.89,28.99,26.39,26.24,25.26,15.95,9.55; HRMS(m / z):[M+Na]+calcd for C 55 H 62 N8O9SNa+1033.4253, found 1033.4247.

[0444] Example 59: N-cyclopropyl-N-(4-((4-((8-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-8-oxooctyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0189)

[0445]

[0446] The synthesis method is the same as in Example 1.

[0447] 1H NMR(600MHz,DMSO-d6)δ10.88(s,1H),10.42(s,1H),8.98(s,1H),8.56(t,J=6.1Hz,1H),8.34(t,J=5.6Hz,1H),7.95(d,J=8.2Hz,2H),7.88–7.81(m,5H),7.46(d,J=7.6Hz,2H),7.43–7.36(m,4H),7.19(d,J=7.7Hz,1H),7.15(s,1H),6.93(d,J=8.1Hz,1H),5.14–5.09(m,1H),4.72(s,2H),4.62(s,2H),4.54(d,J=9.4Hz,1H),4.46–4.40(m,2H),4.37–4.33(m,1H),4.22(dd,J=15.9,5.5Hz,1H),3.70–3.61(m,2H),3.27–3.20(m,2H),2.86–2.75(m,1H),2.44(s,3H),2.30–2.22(m,1H),2.15–2.08(m,1H),2.05–1.99(m,1H),1.94–1.87(m,1H),1.58–1.42(m,4H),1.33–1.27(m,4H),0.93(s,9H),0.62–0.52(m,2H),0.51–0.41(m,2H); 13 C NMR(151MHz,DMSO-d6)δ172.10,171.96,170.68,169.72,165.57,165.54,164.85,151.46,147.72,142.49,142.34,141.65,139.51,133.44,131.79,131.16,129.66,129.63,129.57,128.64,128.39,128.06,127.81,127.42,127.21,121.87,119.32,115.36,115.15,68.86,66.74,58.68,56.35,56.26,41.64,40.06,37.95,35.20,34.84,29.20,28.65,28.55,26.48,26.45,26.38,25.41,15.94,9.51;HRMS(m / z):[M+Na]+calcdfor C 57 H 66 N8O9SNa+1061.4566,found 1061.4555。

[0448] Example 60: N-cyclopropyl-N-(4-((4-((10-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-10-oxodecanyl)carbamate)phenyl)carbamate)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0192)

[0449]

[0450] The synthesis method is the same as in Example 1.

[0451] 1 H NMR (600MHz, DMSO-d6) δ10.88(s,1H),10.42(s,1H),8.98(s,1H),8.56(t,J=6. 1Hz,1H),8.34(t,J=5.6Hz,1H),7.96(d,J=8.2Hz,2H),7.88–7.81(m,5H),7.46 (d,J=7.8Hz,2H),7.43–7.37(m,4H),7.19(d,J=8.0Hz,1H),7.15(s,1H),6.93( d,J=8.1Hz,1H),5.12(d,J=3.6Hz,1H),4.72(s,2H),4.62(s,2H),4.54(d,J=9. 4Hz,1H),4.46–4.39(m,2H),4.37–4.32(m,1H),4.21(dd,J=15.8,5.4Hz,1H),3 .70–3.62(m,2H),3.27–3.19(m,2H),2.86–2.76(m,1H),2.44(s,3H),2.28–2.2 2(m,1H),2.14–2.08(m,1H),2.05–2.00(m,1H),1.93–1.87(m,1H),1.55–1.41( m,4H),1.32–1.22(m,10H),0.93(s,9H),0.58–0.52(m,2H),0.50–0.43(m,2H); 13C NMR(151MHz,DMSO-d6)δ172.09,171.95,170.64,169.71,165.57,165.52,164.85,151.45,147.72,142.48, 142.33,141.65,139.51,133.44,131.79,131.16,129.63,129.57,128.63,128.39,128.06,127.81,127.42, 127.21,121.87,119.33,115.36,115.15,68.86,66.74,58.68,56.34,56.26,41.64,40.06,39.91,37.95,3 5.21,34.86,29.20,28.94,28.79,28.74,28.67,26.53,26.37,25.44,15.94,9.54; HRMS(m / z):[M+H]+calcd for C 59 H 71 N8O9S+1067.5059, found 1067.5046.

[0452] Example 61: N-cyclopropyl-N-(4-((4-((12-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-12-oxododecyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0193)

[0453]

[0454] The synthesis method is the same as in Example 1.

[0455] 1H NMR(600MHz,DMSO-d6)δ10.94(s,1H),10.47(s,1H),9.04(s,1H),8.62(t,J=6.1Hz,1H),8.40(t,J=5.7Hz,1H),8.01(d,J=8.2Hz,2H),7.94–7.86(m,5H),7.52(d,J=7.7Hz,2H),7.50–7.42(m,4H),7.25(d,J=8.0Hz,1H),7.21(s,1H),6.99(d,J=8.1Hz,1H),5.18(d,J=3.6Hz,1H),4.78(s,2H),4.68(s,2H),4.60(d,J=9.4Hz,1H),4.52–4.45(m,2H),4.43–4.39(m,1H),4.27(dd,J=15.8,5.4Hz,1H),3.75–3.66(m,2H),3.32–3.26(m,2H),2.92–2.81(m,1H),2.50(s,3H),2.36–2.27(m,1H),2.20–2.12(m,1H),2.12–2.05(m,1H),1.99–1.92(m,1H),1.61–1.47(m,4H),1.39–1.25(m,14H),0.99(s,9H),0.65–0.58(m,2H),0.57–0.49(m,2H); 13 C NMR(151MHz,DMSO-d6)δ172.10,171.95,170.62,169.71,165.57,165.52,164.85,151.45,147.71,142.49,142.33,141.65,139.51,133.44,131.79,131.16,129.64,129.57,128.64,128.39,128.06,128.03,127.81,127.42,127.21,121.87,119.32,115.36,115.15,68.86,66.74,58.68,56.34,56.26,41.64,40.06,37.95,35.21,34.86,29.19,29.01,29.00,28.98,28.83,28.77,28.67,26.53,26.37,25.44,15.94,9.53;HRMS(m / z):[M+H]+calcd for C 61 H 75 N8O9S+1095.5372,found 1095.5368。

[0456] Example 62: N-cyclopropyl-N-(4-((4-((2-(((S)-4-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carbamoyl)-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxamide)-4-(4-(4-methylthiazol-5-yl)phenyl)butyl)amino)-2-oxoethyl)carbamate)phenyl)carbamate)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC022)

[0457]

[0458] The synthesis method is the same as in Example 1.

[0459] 1 H NMR(600MHz,DMSO-d6)δ10.89(s,1H),10.45(s,1H),8.96(s,1H),8.64(t,J=6.0Hz,1H), 8.48(d,J=8.4Hz,1H),7.96(d,J=8.2Hz,2H),7.93–7.86(m,5H),7.46(d,J=7.7Hz,2H),7. 41–7.36(m,4H),7.27(dd,J=9.2,2.5Hz,1H),7.19(d,J=7.8Hz,1H),7.15(s,1H),6.93(d, J=8.1Hz,1H),5.14(d,J=3.6Hz,1H),4.90–4.83(m,1H),4.72(s,2H),4.62(s,2H),4.58(d ,J=9.3Hz,1H),4.50(t,J=8.2Hz,1H),4.31–4.26(m,1H),3.88–3.79(m,2H),3.62–3.54( m,2H),3.21–3.13(m,1H),3.12–3.02(m,1H),2.85–2.76(m,1H),2.45(s,3H),2.08–2.02( m,1H),1.77–1.68(m,2H),1.67–1.54(m,2H),1.52–1.46(m,1H),1.40–1.32(m,2H),1.24– 1.20(m,2H),0.97(s,9H),0.60–0.52(m,2H),0.52–0.42(m,2H); HRMS(m / z):[M+H]+calcd for C 58 H 65 FN9O 10 S+1098.4554, found 1098.4536.

[0460] Example 63: N-cyclopropyl-N-(4-((4-((4-(((S)-4-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carbamoyl)-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxamide)-4-(4-(4-methylthiazol-5-yl)phenyl)butyl)amino)-4-oxobutyl)carbonyl)phenyl)carbonyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0227)

[0461]

[0462] The synthesis method is the same as in Example 1.

[0463] 1 H NMR (600MHz, DMSO-d6) δ10.88(s,1H),10.42(s,1H),8.97(s,1H),8.48(d,J=8.4Hz,1H),8.38(t,J= 5.5Hz,1H),7.95(d,J=8.2Hz,2H),7.88–7.79(m,5H),7.46(d,J=7.4Hz,2H),7.42(d,J=8.2Hz,2H),7 .37(d,J=8.2Hz,2H),7.26(dd,J=9.2,2.3Hz,1H),7.19(d,J=7.8Hz,1H),7.15(s,1H),6.93(d,J=8. 1Hz,1H),5.13(d,J=3.5Hz,1H),4.87–4.80(m,1H),4.72(s,2H),4.62(s,2H),4.57(d,J=9.2Hz,1H), 4.49(t,J=8.2Hz,1H),4.31–4.25(m,1H),3.62–3.54(m,2H),3.27–3.20(m,2H),3.14–3.07(m,1H), 3.07–2.98(m,1H),2.86–2.75(m,1H),2.44(s,3H),2.12(t,J=7.5Hz,2H),2.07–2.00(m,1H),1.78–1 .72(m,3H),1.70–1.61(m,J=5.8,5.0Hz,2H),1.59–1.51(m,1H),1.50–1.42(m,1H),1.40–1.30(m,2 H),1.23–1.19(m,2H),0.96(s,9H),0.60–0.52(m,2H),0.51–0.40(m,2H); HRMS(m / z):[M+Na]+calcd for C 60 H68 FN9O 10 SNa+1148.4686, found 1148.4684.

[0464] Example 64: N-cyclopropyl-N-(4-((4-((6-(((S)-4-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carbamoyl)-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxamide)-4-(4-(4-methylthiazol-5-yl)phenyl)butyl)amino)-6-oxohexyl)carbonyl)phenyl)carbonyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0228)

[0465] The synthesis method is the same as in Example 1.

[0466] 1 H NMR(600MHz,DMSO-d6)δ10.89(s,1H),10.43(s,1H),8.97(s,1H),8.50(d,J=8.3Hz,1H),8.3 5(t,J=5.6Hz,1H),7.96(d,J=8.2Hz,2H),7.87–7.81(m,4H),7.74(t,J=5.6Hz,1H),7.49–7. 41(m,4H),7.37(d,J=8.2Hz,2H),7.25(dd,J=9.2,2.5Hz,1H),7.19(d,J=7.9Hz,1H),7.15(s ,1H),6.93(d,J=8.1Hz,1H),5.14(d,J=3.6Hz,1H),4.87–4.81(m,1H),4.72(s,2H),4.62(s,2 H),4.57(d,J=9.1Hz,1H),4.49(t,J=8.3Hz,1H),4.32–4.26(m,1H),3.62–3.52(m,2H),3.25 –3.19(m,2H),3.13–3.07(m,1H),3.05–2.99(m,1H),2.86–2.75(m,1H),2.45(s,3H),2.08–2 .01(m,3H),1.76–1.71(m,1H),1.70–1.61(m,2H),1.57–1.42(m,7H),1.40–1.32(m,2H),1.3 0–1.19(m,5H),0.96(s,9H),0.59–0.51(m,2H),0.51–0.43(m,2H); HRMS(m / z):[M+Na]+calcd for C 62 H 72 FN9O10 SNa+1176.4999,found1176.4983.

[0467] Example 65: N-cyclopropyl-N-(4-((4-((8-(((S)-4-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carbamoyl)-3,3-dimethylbutyryl)-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxamide)-4-(4-(4-methylthiazol-5-yl)phenyl)butyl)amino)-8-oxooctyl)carbonyl)phenyl)carbonyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0229)

[0468]

[0469] The synthesis method is the same as in Example 1.

[0470] 1H NMR (600MHz, DMSO-d6) δ10.89(s,1H),10.43(s,1H),8.97(s,1H),8.49(d,J=8.3Hz,1H),8.34( t,J=5.6Hz,1H),7.96(d,J=8.2Hz,2H),7.87–7.81(m,4H),7.73(t,J=5.6Hz,1H),7.46(d,J=7.6 Hz,2H),7.43(d,J=8.2Hz,2H),7.37(d,J=8.2Hz,2H),7.25(dd,J=9.2,2.4Hz,1H),7.19(d,J=8 .0Hz,1H),7.15(s,1H),6.93(d,J=8.1Hz,1H),5.14(d,J=3.6Hz,1H),4.87–4.80(m,1H),4.72(s ,2H),4.62(s,2H),4.57(d,J=9.3Hz,1H),4.52–4.47(m,1H),4.31–4.26(m,1H),3.62–3.54(m, 2H),3.25–3.20(m,2H),3.11–3.05(m,1H),3.03–2.96(m,1H),2.86–2.76(m,1H),2.45(s,3H),2 .08–1.96(m,3H),1.77–1.71(m,1H),1.70–1.60(m,2H),1.57–1.41(m,7H),1.40–1.31(m,2H),1 .30–1.16(m,9H),0.96(s,9H),0.61–0.52(m,2H),0.51–0.43(m,2H); HRMS(m / z):[M+Na]+calcd for C 64 H 76 FN9O 10 SNa+1204.5312, found 1204.5302.

[0471] Example 66: N-cyclopropyl-N-(4-((4-((10-(((S)-4-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carbamoyl)-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxamide)-4-(4-(4-methylthiazol-5-yl)phenyl)butyl)amino)-10-oxodecanoyl)phenyl)carbamate)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0230)

[0472]

[0473] The synthesis method is the same as in Example 1.

[0474] 1 H NMR (600MHz, DMSO-d6) δ10.88(s,1H),10.42(s,1H),8.97(s,1H),8.49(d,J=8.3Hz,1H),8.33( t,J=5.5Hz,1H),7.96(d,J=8.2Hz,2H),7.88–7.81(m,4H),7.72(t,J=5.6Hz,1H),7.46(d,J=7.4 Hz,2H),7.43(d,J=8.3Hz,2H),7.37(d,J=8.2Hz,2H),7.25(dd,J=9.2,2.4Hz,1H),7.19(d,J=8. 5Hz,1H),7.15(s,1H),6.93(d,J=8.1Hz,1H),5.14(d,J=3.5Hz,1H),4.87–4.81(m,1H),4.72(s, 2H),4.62(s,2H),4.57(d,J=9.4Hz,1H),4.52–4.46(m,1H),4.30–4.26(m,1H),3.62–3.53(m,2 H),3.25–3.19(m,2H),3.14–3.05(m,1H),3.04–2.94(m,1H),2.85–2.76(m,1H),2.45(s,3H),2. 07–1.95(m,3H),1.76–1.71(m,1H),1.69–1.61(m,2H),1.56–1.44(m,7H),1.40–1.32(m,2H),1. 29–1.18(m,13H),0.96(s,9H),0.60–0.52(m,2H),0.51–0.43(m,2H); HRMS(m / z):[M+Na]+calcd for C 66 H 80 FN9O 10 SNa+1232.5625, found 1232.5610.

[0475] Example 67: N-cyclopropyl-N-(4-((4-((3-((S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carbamoyl)-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxamide)-3-(4-(4-methylthiazol-5-yl)phenyl)propionamide)propyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0389)

[0476]

[0477] The synthesis method is the same as in Example 1.

[0478] 1 H NMR (600MHz, DMSO-d6) δ10.88(s,1H),10.43(s,1H),8.95(s,1H),8.57(d,J=8.0Hz,1H),8.28(t ,J=5.6Hz,1H),7.96(d,J=8.2Hz,2H),7.92(t,J=5.7Hz,1H),7.86(d,J=8.8Hz,2H),7.81(d,J=8 .8Hz,2H),7.46(d,J=7.8Hz,2H),7.41(d,J=8.4Hz,2H),7.37(d,J=8.3Hz,2H),7.25(dd,J=9.2, 2.7Hz,1H),7.19(d,J=8.0Hz,1H),7.15(s,1H),6.93(d,J=8.1Hz,1H),5.22–5.16(m,1H),5.14(d ,J=3.7Hz,1H),4.72(s,2H),4.62(s,2H),4.57(d,J=9.4Hz,1H),4.48–4.43(m,1H),4.30–4.26( m,1H),3.63–3.52(m,2H),3.17–3.06(m,3H),3.04–2.97(m,1H),2.86–2.75(m,1H),2.66–2.57(m ,2H),2.42(s,2H),2.08–2.00(m,1H),1.79–1.69(m,1H),1.57–1.48(m,2H),1.41–1.30(m,2H), 1.26–1.20(m,2H),0.97(s,9H),0.61–0.52(m,2H),0.51–0.41(m,2H); HRMS(m / z):[M+Na]+calcd forC 58 H 64 FN9O8SNa+1120.4373, found 1120.4368.

[0479] Example 68: N-cyclopropyl-N-(4-((4-((2-(2-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carbamoyl)-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxamide)methyl)-5-(4-methylthiazol-5-yl)phenoxy)acetamide)ethyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0401)

[0480]

[0481] Step 1: Preparation of tert-butyl (2-(4-(4-((N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide)methyl)benzamide)ethyl)carbamate (22)

[0482]

[0483] 4-(4-((N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamido)methyl)benzamido)benzoic acid 9 (200 mg, 0.412 mmol) was dissolved in dichloromethane (2 mL), and N-tert-butyloxycarbonyl-1,2-ethylenediamine (72.6 mg, 0.453 mmol, 74 μL), triethylamine (125 mg, 1.24 mmol, 0.2 mL), HATU (235 mg, 0.618 mmol) were added in sequence. The mixture was stirred at room temperature for 12 hours, concentrated, and column chromatography was performed to obtain 228 mg (88%) of a white solid. MS (ESI), m / z: 650.1 [M+Na]+.

[0484] Step 2: Preparation of N-cyclopropyl-N-(4-((4-((2-(2-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carbamoyl)-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxamide)methyl)-5-(4-methylthiazol-5-yl)phenoxy)acetamide)ethyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0401)

[0485]

[0486] Dissolve tert-butyl (2-(4-(4-((N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide)methyl)benzamide)ethyl)carbamate 22 (38.8 mg, 0.0618 mmol) in dichloromethane (1.0 mL), add trifluoroacetic acid (1.0 mL), stir for 2 hours, spin dry thoroughly and dissolve in N,N-dimethylformamide (2 mL) for later use; 2-(2-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutyryl)-4-hydroxypyrrole Tert-butyl 2-(4-(4-(4-((4-(((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((( 1 H NMR (600MHz, DMSO-d6) δ10.88(s,1H),10.43(s,1H),8.98(s,1H),8.57(t,J=6.1H z,1H),8.49–8.44(m,1H),8.31–8.25(m,1H),7.96(d,J=8.1Hz,2H),7.88–7.81(m, 4H),7.50–7.42(m,3H),7.28(dd,J=9.3,2.8Hz,1H),7.19(d,J=8.0Hz,1H),7.15(s ,1H),7.03–7.00(m,1H),6.98(s,1H),6.93(d,J=8.1Hz,1H),5.17(d,J=3.7Hz,1H) ,4.72(s,2H),4.62(s,2H),4.61–4.56(m,3H),4.54–4.48(m,1H),4.46–4.38(m,1 H),4.37–4.30(m,1H),3.70–3.58(m,2H),3.31–3.24(m,2H),3.20–3.14(m,2H),2. 86–2.75(m,1H),2.45(s,3H),2.11–2.04(m,1H),1.95–1.88(m,1H),1.51–1.26(m, 4H),0.95(s,9H),0.60–0.52(m,2H),0.52–0.43(m,2H); HRMS(m / z):[M+Na]+calcd for C 57 H62 FN9O 11 SNa+1122.4166, found 1122.4164.

[0487] Example 69: N-cyclopropyl-N-(4-((4-((4-(2-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carbamoyl)-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxamide)methyl)-5-(4-methylthiazol-5-yl)phenoxy)acetamide)butyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0402)

[0488]

[0489] The synthesis method is the same as Example 68.

[0490] 1 H NMR (600MHz, DMSO-d6) δ10.89(s,1H),10.42(s,1H),8.97(s,1H),8.56(t,J=6.1Hz,1H),8. 37(t,J=5.7Hz,1H),8.15(t,J=5.9Hz,1H),7.96(d,J=8.2Hz,2H),7.88–7.82(m,4H),7.46( d,J=7.9Hz,2H),7.43(d,J=7.8Hz,1H),7.27(dd,J=9.3,2.7Hz,1H),7.19(d,J=8.0Hz,1H), 7.15(s,1H),7.02(dd,J=7.7,1.6Hz,1H),6.96(d,J=1.7Hz,1H),6.93(d,J=8.1Hz,1H),5.17 (d,J=3.6Hz,1H),4.72(s,2H),4.62(s,2H),4.62–4.52(m,3H),4.51–4.42(m,2H),4.37–4. 29(m,2H),3.67–3.57(m,2H),3.29–3.22(m,2H),3.21–3.16(m,2H),2.87–2.74(m,1H),2.4 5(s,3H),2.08–2.03(m,1H),1.91–1.85(m,1H),1.55–1.47(m,4H),1.40–1.33(m,2H),1.23 –1.19(m,2H),0.95(s,9H),0.59–0.53(m,2H),0.52–0.45(m,2H); HRMS(m / z):[M+Na]+calcd for C59 H 66 FN9O 11 SNa+1150.4479,found1150.4463.

[0491] Example 70: N-cyclopropyl-N-(4-((4-((6-(2-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carbamoyl)-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxamide)methyl)-5-(4-methylthiazol-5-yl)phenoxy)acetamide)hexyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0403)

[0492]

[0493] The synthesis method is the same as Example 68.

[0494] 1H NMR(600MHz,DMSO-d6)δ10.88(s,1H),10.42(s,1H),8.98(s,1H),8.55(t,J=6.0Hz,1H),8 .34(t,J=5.6Hz,1H),8.11(t,J=5.9Hz,1H),8.00–7.93(m,2H),7.88–7.81(m,4H),7.46(d, J=7.9Hz,2H),7.42(d,J=7.8Hz,1H),7.27(dd,J=9.2,2.9Hz,1H),7.19(d,J=8.2Hz,1H),7. 15(s,1H),7.02(dd,J=7.7,1.6Hz,1H),6.95(d,J=1.7Hz,1H),6.93(d,J=8.1Hz,1H),5.17( d,J=3.2Hz,1H),4.72(s,2H),4.62(s,2H),4.60–4.54(m,3H),4.51–4.41(m,2H),4.36–4.2 8(m,2H),3.67–3.58(m,2H),3.26–3.20(m,2H),3.18–3.12(m,2H),2.87–2.75(m,1H),2.45 (s,3H),2.09–2.03(m,1H),1.91–1.85(m,1H),1.53–1.41(m,4H),1.40–1.33(m,2H),1.31– 1.20(m,6H),0.95(s,9H),0.59–0.52(m,2H),0.51–0.42(m,2H); HRMS(m / z):[M+Na]+calcd for C 61 H 70 FN9O 11 SNa+1178.4792,found1178.4788.

[0495] Example 71: N-cyclopropyl-N-(4-((4-((8-(2-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carbamoyl)-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxamide)methyl)-5-(4-methylthiazol-5-yl)phenoxy)acetamide)octyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0404)

[0496]

[0497] The synthesis method is the same as Example 68.

[0498] 1 H NMR (600MHz, DMSO-d6) δ10.88(s,1H),10.42(s,1H),8.98(s,1H),8.55(t,J=6.1Hz,1H),8.34 (t,J=5.6Hz,1H),8.10(t,J=5.9Hz,1H),7.96(d,J=8.3Hz,2H),7.88–7.81(m,4H),7.46(d,J= 7.8Hz,2H),7.42(d,J=7.8Hz,1H),7.27(dd,J=9.3,2.8Hz,1H),7.19(d,J=8.1Hz,1H),7.15(s ,1H),7.02(dd,J=7.7,1.6Hz,1H),6.94(d,J=1.7Hz,1H),6.93(d,J=8.1Hz,1H),5.17(d,J=3.6 Hz,1H),4.72(s,2H),4.62(s,2H),4.61–4.53(m,3H),4.52–4.40(m,2H),4.36–4.27(m,2H),3 .67–3.58(m,2H),3.26–3.20(m,2H),3.16–3.09(m,2H),2.85–2.77(m,1H),2.45(s,3H),2.09– 2.03(m,1H),1.92–1.84(m,1H),1.53–1.46(m,2H),1.46–1.39(m,2H),1.40–1.32(m,2H),1.3 3–1.22(m,10H),0.95(s,9H),0.59–0.52(m,2H),0.51–0.44(m,2H); HRMS(m / z):[M+Na]+calcd for C 63 H 74 FN9O 11 SNa+1206.5105, found 1206.5107.

[0499] Example 72: N-cyclopropyl-N-(4-((4-((10-(2-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carbamoyl)-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxamide)methyl)-5-(4-methylthiazol-5-yl)phenoxy)acetamide)decyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0405)

[0500]

[0501] The synthesis method is the same as Example 68.

[0502] 1 H NMR (600MHz, DMSO) δ10.90(s,1H),10.45(d,J=2.2Hz,1H),8.98(s,1H),8.57(t,J=6.0Hz,1H ),8.36(t,J=4.8Hz,1H),8.11(t,J=5.9Hz,1H),7.97(dd,J=8.2,1.5Hz,2H),7.89–7.82(m,4H ),7.46(d,J=7.9Hz,2H),7.42(d,J=7.8Hz,1H),7.27(dd,J=9.3,2.8Hz,1H),7.19(d,J=8.1H z,1H),7.15(s,1H),7.01(dd,J=7.8,1.6Hz,1H),6.96–6.93(m,2H),5.19(d,J=3.7Hz,1H),4. 76–4.69(m,2H),4.62(s,2H),4.60–4.54(m,3H),4.51–4.41(m,2H),4.37–4.27(m,2H),3.67 –3.58(m,2H),3.26–3.21(m,2H),3.15–3.10(m,2H),2.86–2.74(m,1H),2.45(s,3H),2.09–2. 03(m,1H),1.91–1.84(m,1H),1.55–1.47(m,2H),1.46–1.39(m,2H),1.39–1.33(m,2H),1.32 –1.22(m,14H),0.95(s,9H),0.60–0.52(m,2H),0.51–0.43(m,2H); HRMS(m / z):[M+Na]+calcd for C 65 H 78 FN9O 11 SNa+1234.5418, found1234.5424.

[0503] Example 73: N-cyclopropyl-N-(4-((2-((R)-3-(1-fluorocyclopropane-1-carboxamido)-4-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-2-methyl-4-oxobutan-2-yl)thio)acetylamino)ethyl)carbamoyl)phenyl)carbamoyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0436)

[0504]

[0505] The synthesis method is the same as Example 68.

[0506] 1 H NMR (600MHz, DMSO-d6) δ10.88(s,1H),10.43(s,1H),8.97(s,1H),8.67(t,J=6.0Hz,1H),8 .37(t,J=5.5Hz,1H),8.08(t,J=5.6Hz,1H),7.95(d,J=8.2Hz,2H),7.89–7.80(m,4H),7.5 4(dd,J=9.0,2.5Hz,1H),7.46(d,J=7.4Hz,2H),7.41(d,J=8.2Hz,2H),7.37(d,J=8.3Hz,2 H),7.19(d,J=8.2Hz,1H),7.15(s,1H),6.93(d,J=8.1Hz,1H),5.20(d,J=3.7Hz,1H),4.81( d,J=9.0Hz,1H),4.72(s,2H),4.62(s,2H),4.49–4.43(m,1H),4.42–4.33(m,2H),4.26(dd ,J=15.7,5.8Hz,2H),3.74–3.62(m,2H),3.32–3.27(m,2H),3.25–3.18(m,4H),2.86–2.75( m,1H),2.43(s,3H),2.11–2.05(m,1H),1.93–1.85(m,1H),1.42–1.38(m,4H),1.36–1.33( m,4H),1.30–1.24(m,2H),0.62–0.51(m,2H),0.51–0.38(m,2H); HRMS(m / z):[M+Na]+calcd for C 56 H 60 FN9O 10 S2Na+1124.3781, found 1124.3776.

[0507] Example 74: N-cyclopropyl-N-(4-((4-(2-((R)-3-(1-fluorocyclopropane-1-carboxamido)-4-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-2-methyl-4-oxobutan-2-yl)thio)acetylamino)butyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0437)

[0508]

[0509] The synthesis method is the same as Example 68.

[0510] 1 H NMR (600MHz, DMSO-d6) δ10.88(s,1H),10.42(s,1H),8.97(s,1H),8.68(t,J=6.1Hz,1H),8.3 5(t,J=5.6Hz,1H),7.98–7.94(m,2H),7.91(t,J=5.6Hz,1H),7.87–7.81(m,4H),7.53(dd,J= 9.0,2.3Hz,1H),7.46(d,J=7.8Hz,2H),7.42–7.36(m,4H),7.19(d,J=8.2Hz,1H),7.16–7.14 (m,1H),7.13(d,J=2.5Hz,1H),6.93(d,J=8.1Hz,1H),5.20(d,J=3.7Hz,1H),4.81(d,J=9.0Hz ,1H),4.72(s,2H),4.62(s,2H),4.49–4.45(m,1H),4.42–4.34(m,2H),4.26(dd,J=15.7,5.6 Hz,1H),3.75–3.64(m,2H),3.25–3.20(m,2H),3.19–3.16(m,2H),3.06–3.00(m,2H),2.85–2 .76(m,1H),2.43(s,3H),2.11–2.05(m,1H),1.94–1.88(m,1H),1.53–1.45(m,4H),1.41–1.3 8(m,4H),1.37–1.33(m,8H),0.58–0.52(m,2H),0.50–0.45(m,2H); HRMS(m / z):[M+Na]+calcd for C 58 H 64 FN9O 10 S2Na+1152.4094,found1152.4097.

[0511] Example 75: N-cyclopropyl-N-(4-((6-(2-((R)-3-(1-fluorocyclopropane-1-carboxamido)-4-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-2-methyl-4-oxobutan-2-yl)thio)acetamido)hexyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0438)

[0512]

[0513] The synthesis method is the same as Example 68.

[0514] 1 H NMR(600MHz,DMSO-d6)δ10.88(s,1H),10.41(s,1H),8.97(s,1H),8.69(t,J=6.1Hz,1 H),8.33(t,J=5.6Hz,1H),7.98–7.93(m,2H),7.89–7.82(m,5H),7.53(dd,J=9.0,2.6 Hz,1H),7.46(d,J=7.9Hz,2H),7.42–7.35(m,4H),7.19(d,J=8.0Hz,1H),7.17–7.13( m,1H),6.93(d,J=8.1Hz,1H),5.25–5.17(m,1H),4.80(d,J=9.0Hz,1H),4.72(s,2H), 4.62(s,2H),4.49–4.44(m,1H),4.43–4.34(m,2H),4.27–4.23(m,1H),3.75–3.64(m, 2H),3.24–3.20(m,2H),3.19–3.16(m,2H),3.02–2.97(m,1H),2.84–2.76(m,1H),2.4 4(s,3H),2.12–2.06(m,1H),1.94–1.88(m,1H),1.52–1.42(m,4H),1.41–1.32(m,10H ),1.30–1.23(m,6H),0.59–0.52(m,2H),0.51–0.43(m,2H); HRMS(m / z):[M+H]+calcd for C 60 H 69 FN9O 10 S2+1158.4587, found 1158.4584.

[0515] Example 76: N-cyclopropyl-N-(4-((8-(2-((R)-3-(1-fluorocyclopropane-1-carboxamide)-4-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-2-methyl-4-oxobutan-2-yl)thio)acetylamino)octyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0439)

[0516]

[0517] The synthesis method is the same as Example 68.

[0518] 1 H NMR (600MHz, DMSO-d6) δ10.88(s,1H),10.42(s,1H),8.97(s,1H),8.69(t,J=6.0Hz,1H ),8.33(t,J=5.6Hz,1H),7.96(d,J=8.3Hz,2H),7.88–7.81(m,5H),7.53(dd,J=9.0,2. 6Hz,1H),7.46(d,J=7.8Hz,2H),7.43–7.35(m,4H),7.19(d,J=8.1Hz,1H),7.15(d,J=1 .8Hz,1H),6.93(d,J=8.1Hz,1H),5.21(s,1H),4.83–4.79(m,1H),4.72(s,2H),4.62(s ,2H),4.50–4.45(m,1H),4.43–4.34(m,2H),4.25(dd,J=15.8,5.6Hz,1H),3.77–3.60( m,2H),3.24–3.20(m,2H),3.20–3.14(m,2H),3.02–2.93(m,2H),2.86–2.76(m,1H),2. 44(s,3H),2.13–2.06(m,1H),1.95–1.87(m,1H),1.54–1.45(m,2H),1.42–1.31(m,10H ),1.29–1.20(m,12H),0.59–0.51(m,2H),0.51–0.42(m,2H); HRMS(m / z):[M+Na]+calcd forC 62 H 72 FN9O 10 S2Na+1208.4720, found 1208.4727.

[0519] Example 77: N-cyclopropyl-N-(4-((4-((10-(2-(((R)-3-(1-fluorocyclopropane-1-carboxamide)-4-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-2-methyl-4-oxobutan-2-yl)thio)acetylamino)decyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0440)

[0520]

[0521] The synthesis method is the same as Example 68.

[0522] 1 H NMR (600MHz, DMSO-d6) δ10.89(s,1H),10.43(s,1H),8.97(s,1H),8.70(t,J=6.1Hz,1H) ,8.34(t,J=5.6Hz,1H),7.96(d,J=8.2Hz,2H),7.89–7.81(m,5H),7.53(dd,J=9.0,2.6Hz ,1H),7.46(d,J=7.8Hz,2H),7.43–7.35(m,4H),7.19(d,J=8.1Hz,1H),7.16–7.12(m,1H ),6.93(d,J=8.1Hz,1H),5.22(d,J=3.8Hz,1H),4.81(d,J=9.0Hz,1H),4.72(s,2H),4.62 (s,2H),4.50–4.45(m,1H),4.43–4.34(m,2H),4.25(dd,J=15.8,5.6Hz,1H),3.77–3.64 (m,2H),3.26–3.20(m,2H),3.19–3.15(m,2H),3.01–2.95(m,2H),2.85–2.75(m,1H),2.4 4(s,3H),2.13–2.06(m,1H),1.94–1.87(m,1H),1.54–1.44(m,2H),1.41–1.31(m,10H), 1.29–1.18(m,16H),0.62–0.51(m,2H),0.51–0.40(m,2H); HRMS(m / z):[M+Na]+calcdfor C 64 H 76 FN9O 10 S2Na+1236.5033,found 1236.5018.

[0523] Example 78: N-cyclopropyl-N-(4-((4-((2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)amino)butyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0174)

[0524]

[0525] The synthesis method is the same as in Example 1.

[0526] 1 H NMR (600MHz, DMSO-d6) δ10.88(s,1H),10.42(s,1H),8.40(t,J=5.6Hz,1H),7.95(d,J=8.2Hz,2H),7.89–7.81(m,4H),7.56(d,J=8.4Hz ,1H),7.46(d,J=7.8Hz,2H),7.19(d,J=8.0Hz,1H),7.16–7.12(m,2H),6.96(d,J=2.1Hz,1H),6.93(d,J=8.1Hz,1H),6.86(dd,J=8.4,2. 1Hz,1H),5.10(dd,J=13.0,5.4Hz,1H),4.72(s,2H),4.62(s,2H),3.32–3.29(m,2H),3.24–3.19(m,2H),3.00(s,3H),2.97–2.89(m,1H) ,2.85–2.77(m,1H),2.77–2.69(m,1H),2.58–2.51(m,1H),2.05–1.97(m,1H),1.69–1.57(m,4H),0.62–0.51(m,2H),0.51–0.39(m,2H); 13 C NMR(151MHz,DMSO-d6)δ171.81,170.62,169.93,167.70,167.13,165.65,165.57,164.85 ,154.48,142.48,142.35,141.69,134.21,133.43,131.79,129.49,128.38,128.06,127.8 3,127.79,127.22,125.12,121.87,119.34,115.79,115.36,115.15,66.74,54.92,49.19 ,42.23,40.06,38.77,31.14,26.82,26.58,25.74,21.43,9.52; HRMS(m / z):[M+Na]+calcd for C 45 H 43 N7O9+848.3014,found 848.3021.

[0527] Example 79: N-cyclopropyl-N-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-carboxamide)ethyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0154)

[0528]

[0529] The synthesis method is the same as in Example 1.

[0530] HRMS(m / z):[M+Na]+calcd for C 43 H 37 N7O 10 +834.2494, found 834.2498.

[0531] Example 80: N-cyclopropyl-N-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-carboxamide)butyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0160)

[0532]

[0533] The synthesis method is the same as in Example 1.

[0534] HRMS(m / z):[M+Na]+calcd for C 45 H 41 N7O 10 +862.2807, found 862.2812.

[0535] Example 81: N-cyclopropyl-N-(4-((4-((6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-carboxamide)hexyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0161)

[0536]

[0537] The synthesis method is the same as in Example 1.

[0538] HRMS(m / z):[M+Na]+calcd for C 47 H 45 N7O 10 +890.3120, found 890.3116.

[0539] Example 82: N-cyclopropyl-N-(4-((4-((8-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-4-carboxamide)octyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0167)

[0540]

[0541] The synthesis method is the same as in Example 1.

[0542] HRMS(m / z):[M+Na]+calcd for C 49 H 49 N7O 10 +918.3433, found 918.3439.

[0543] Example 83: N-cyclopropyl-N-(4-((4-((12-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-carboxamide)dodecyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0169)

[0544]

[0545] The synthesis method is the same as in Example 1.

[0546] HRMS(m / z):[M+Na]+calcd for C 53 H 57 N7O 10 Na+974.4059, found 974.4051.

[0547] Example 84: N-cyclopropyl-N-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)ethynyl)piperidine-1-carbonyl)phenyl)carbamoyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0421)

[0548]

[0549] The synthesis method is the same as in Example 1.

[0550] 1H NMR (600MHz, DMSO-d6) δ10.99(s,1H),10.88(s,1H),10.40(s,1H),7.95(d,J=8.3Hz,2H),7.85(d,J=8.6Hz,2H),7.69(d,J=7.9Hz,1H),7.65(s ,1H),7.52(d,J=7.8Hz,1H),7.46(d,J=7.8Hz,2H),7.41–7.37(m,2H),7.19(s,1H),7.15(s,1H),6.93(d,J=8.1Hz,1H),5.11(dd,J=13.3,5.1Hz ,1H),4.72(s,2H),4.62(s,2H),4.55–4.41(m,1H),4.32(d,J=17.5Hz, 1H),3.86–3.60(m,1H),3.11–2.98(m,1H),2.95–2.86(m,1H),2.84–2.7 3(m,2H),2.63–2.51(m,2H),2.44–2.33(m,1H),2.04–1.96(m,1H),1.94 –1.73(m,3H),1.33–1.26(m,2H),0.60–0.52(m,2H),0.51–0.41(m,2H); 13 C NMR(151MHz,DMSO-d6)δ172.86,170.95,168.78,167.42,165.58,164.85,142 .48,142.40,142.28,140.23,133.51,131.79,131.20,131.15,130.95,128.3 8,128.04,127.58,127.22,126.41,126.36,123.15,121.86,119.69,115.35,115.15,91.31,81.52,66.74,51.65,47.02,35.17,31.19,25.39,22.42,9.51.

[0551] Example 85: N-cyclopropyl-N-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)piperidine-1-carboxyl)phenyl)carbamate)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0422)

[0552]

[0553] The synthesis method is the same as in Example 1.

[0554] 1H NMR (600MHz, DMSO-d6) δ11.06(s,1H),10.88(s,1H),10.40(s,1H),7.95(d,J=8.2Hz,2H),7.86(d,J=8.5Hz,2H),7.57(d,J=8.4Hz,1H ),7.46(d,J=7.9Hz,2H),7.43–7.39(m,2H),7.19(d,J=8.2Hz,1H),7.15(s,1H),7.07(d,J=7.9Hz,1H),7.04(d,J=2.1Hz,1H),6.95–6 .90(m,2H),5.03(dd,J=12.8,5.5Hz,1H),4.72(s,2H),4.62(s,2H),3.89–3.75(m,1H),3.29–2.97(m,4H),2.92–2.83(m,1H),2.83–2 .75(m,1H),2.63–2.52(m,2H),2.03–1.93(m,3H),1.49–1.33(m,2H),0.61–0.51(m,2H),0.51–0.41(m,2H); HRMS(m / z):[M+Na]+calcd for C 45 H 41 N7O9Na+846.2858,found846.2852.

[0555] Example 86: N-cyclopropyl-N-(4-((4-((1-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0424)

[0556]

[0557] The synthesis method is the same as in Example 1.

[0558] 1H NMR (600MHz, DMSO-d6) δ11.08(s,1H),10.88(s,1H),10.42(s,1H),8.19(d,J=7.7Hz,1H),7.95(d,J=8.2Hz,2H),7.86(s,4H),7.68(d,J=8. 5Hz,1H),7.46(d,J=7.8Hz,2H),7.38(d,J=2.3Hz,1H),7.30(dd,J=8.7,2.3Hz,1H),7.19(d,J=8.1Hz,1H),7.15(s,1H),6.93(d,J=8.1Hz,1 H),5.08(dd,J=12.8,5.4Hz,1H),4.72(s,2H),4.61(s,2H),4.14–4.11(m,1H),3.19–3.08(m,4H),2.93–2.85(m,1H),2.84–2.75(m,1H),2. 63–2.53(m,2H),2.07–1.97(m,1H),1.96–1.84(m,2H),1.67–1.57(m,2H),0.61–0.52(m,2H),0.52–0.43(m,2H); HRMS(m / z):[M+Na]+calcd for C 45 H 41 N7O9Na+846.2858,found 846.2860.

[0559] Example 87: N-cyclopropyl-N-(4-((5-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carboxamide)pyridin-2-yl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0425)

[0560]

[0561] The synthesis method is the same as Example 43.

[0562] HRMS(m / z):[M+Na]+calcd for C 44 H 40 N8O9Na+847.2810,found 847.2814.

[0563] Example 92: N-cyclopropyl-N-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-carboxyl)phenyl)carbamoyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0426)

[0564]

[0565] The synthesis method is the same as in Example 1.

[0566] 1H NMR (600MHz, DMSO-d6) δ11.08(s,1H),10.88(s,1H),10.43(s,1H),7.96(d,J=8.2Hz,2H),7.91–7.86(m,2H),7.71(d,J =8.5Hz,1H),7.50–7.45(m,4H),7.37(d,J=2.3Hz,1H),7.27(dd,J=8.7,2.3Hz,1H),7.19(d,J=8.0Hz,1H),7.15(s,1H), 6.93(d,J=8.1Hz,1H),5.08(dd,J=12.8,5.5Hz,1H),4.72(s,2H),4.62(s,2H),3.82–3.46(m,8H),2.92–2.85(m,1H),2. 84–2.74(m,1H),2.62–2.53(m,2H),2.07–1.98(m,1H),0.61–0.52(m,2H),0.52–0.42(m,2H); HRMS(m / z):[M+Na]+calcd for C 44 H 39 N7O9Na+832.2701,found832.2700.

[0567] Example 88: (E)-N-cyclopropyl-N-(4-((4-(4-(4-methoxyphenyl)-4-oxobut-2-enoyl)piperazine-1-carboxyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0435)

[0568]

[0569] Step 1 Preparation of tert-butyl 4-(4-(4-((N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamido)methyl)benzamido)piperazine-1-carboxylate (24)

[0570]

[0571] Dissolve 4-(4-((N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamido)methyl)benzamido)benzoic acid 9 (200 mg, 0.412 mmol) in dichloromethane (2 mL), add tert-butyl piperazine-1-carboxylate (84.4 mg, 0.453 mmol, 74 μL), triethylamine (125 mg, 1.24 mmol, 0.2 mL), HATU (235 mg, 0.618 mmol) in sequence, stir at room temperature for 12 hours, concentrate, and obtain 213 mg (79%) of white solid by column chromatography. MS (ESI), m / z: 654.7 [M+H] +.

[0572] Step 2 Preparation of (E)-N-cyclopropyl-N-(4-((4-(4-(4-methoxyphenyl)-4-oxobut-2-enoyl)piperazine-1-carboxyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0435)

[0573]

[0574] 4-(4-(4-((N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamido)methyl)benzamido)piperazine-1-carboxylic acid tert-butyl ester 24 (40.0 mg, 0.0612 mmol) was dissolved in dichloromethane (1.0 mL), trifluoroacetic acid (1.0 mL) was added, and the mixture was stirred for 2 hours. After being fully spin-dried, it was dissolved in N,N-dimethylformamide (2 mL), triethylamine (20.4 mg, 0.202 mmol, 28 μL) was added, 3-(4-methoxybenzoyl)acrylic acid 25 (13.9 mg, 0.0673 mmol) was added, and HATU (38.4 mg, 0.101 mmol) was added. The mixture was stirred at room temperature for 12 hours, the solvent was spin-dried off, and 28.6 mg (63%) of a white solid was obtained by column chromatography. 1H NMR (600MHz, DMSO-d6) δ10.88(s,1H),10.42(s,1H),8.05(d,J=8.7Hz,2H),7.95(d,J=8.2Hz,2H) ,7.87(d,J=8.6Hz,2H),7.80(d,J=15.1Hz,1H),7.49–7.41(m,4H),7.19(d,J=8.0Hz,1H),7.15(s ,1H),7.09(d,J=8.9Hz,1H),6.93(d,J=8.1Hz,1H),4.72(s,2H),4.62(s,2H),3.87(s,3H),3.77– 3.46(m,4H),2.86–2.75(m,1H),0.60–0.52(m,2H),0.52–0.43(m,2H); HRMS(m / z):[M+Na]+calcd for C 42 H 39 N5O8Na+764.2691,found764.2684.

[0575] Example 89: N-cyclopropyl-N-(4-((4-((1-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0548)

[0576]

[0577] The synthesis method is the same as in Example 1.

[0578] HRMS(m / z):[M+H]+calcd for C 45 H 41 FN7O9+842.2944,found 842.2940.

[0579] Example 90: N-cyclopropyl-N-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0549)

[0580]

[0581] The synthesis method is the same as in Example 1.

[0582] HRMS(m / z):[M+H]+calcd for C 44 H 41 N8O9+825.2991, found 825.2979.

[0583] Example 91: N-cyclopropyl-N-(4-((4-((1-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0551)

[0584]

[0585] The synthesis method is the same as in Example 1.

[0586] HRMS(m / z):[M+H]+calcd for C 46 H 44 N7O9+838.3195,found 838.3192.

[0587] Example 92: N-cyclopropyl-N-(4-((4-((1-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0552)

[0588]

[0589] The synthesis method is the same as in Example 1.

[0590] HRMS(m / z):[M+H]+calcd for C 44 H 40 N7O9+810.2882,found 810.2876.

[0591] Example 93: N-cyclopropyl-N-(4-((4-((1-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0553)

[0592]

[0593] The synthesis method is the same as in Example 1.

[0594] HRMS(m / z):[M+H]+calcd for C 43 H 38 N7O9+796.2726, found 796.2722.

[0595] Example 94: N-cyclopropyl-N-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)carbamoyl)piperidine-1-carbonyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0562)

[0596]

[0597] The synthesis method is the same as in Example 1.

[0598] HRMS(m / z):[M+Na]+calcd for C 44 H 45 N7O9Na+838.3171,found 838.3166.

[0599] Example 95: N-cyclopropyl-N-(4-((4-((1-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)(methyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0563)

[0600]

[0601] The synthesis method is the same as in Example 1.

[0602] HRMS(m / z):[M+Na]+calcd for C 46 H 43 N7O9Na+860.3014,found 860.3006.

[0603] Example 96: N-cyclopropyl-N-(4-((4-((1-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0564)

[0604]

[0605] The synthesis method is the same as in Example 1.

[0606] HRMS(m / z):[M+H]+calcd for C 44 H 40 N7O9+810.2882,found 810.2879.

[0607] Example 97: N-cyclopropyl-N-(4-((4-((1-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0565)

[0608]

[0609] The synthesis method is the same as in Example 1.

[0610] HRMS(m / z):[M+H]+calcd for C 45 H 42 N7O9+824.3039, found 824.3043.

[0611] Example 98: N-cyclopropyl-N-(4-((6-((1-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)carbamoyl)pyridin-3-yl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0567)

[0612]

[0613] The synthesis method is the same as in Example 1.

[0614] HRMS(m / z):[M+H]+calcd for C 44 H 41 N8O9+825.2991,found 825.2985.

[0615] Example 99: N-cyclopropyl-N-(4-((5-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butyl)carbamoyl)pyridin-2-yl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0568)

[0616]

[0617] The synthesis method is the same as in Example 1.

[0618] HRMS(m / z):[M+H]+calcd for C 43 H 40 N7O 10 +814.2831, found 814.2830.

[0619] Example 100: N-cyclopropyl-N-(4-(4-(2-((1-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)amino)-2-oxoethyl)piperazine-1-carbonyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0570)

[0620]

[0621] The synthesis method is the same as in Example 1.

[0622] HRMS(m / z):[M+H]+calcd for C 44 H 47 N8O9+831.3461,found 831.3452.

[0623] Example 101: N-cyclopropyl-N-(4-(((1r,4r)-4-((1-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)carbamoyl)cyclohexyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0571)

[0624]

[0625] The synthesis method is the same as in Example 1.

[0626] HRMS(m / z):[M+Na]+calcd for C 45 H 47 N7O9Na+852.3327, found 852.3320.

[0627] Example 102: N-cyclopropyl-N-(4-(((1s,4s)-4-((1-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)carbamoyl)cyclohexyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0572)

[0628]

[0629] The synthesis method is the same as in Example 1.

[0630] HRMS(m / z):[M+Na]+calcd for C 45 H 47 N7O9Na+852.3327, found 852.3321.

[0631] Example 103: N-cyclopropyl-N-(4-((4-((1-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)amino)methyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0576)

[0632]

[0633] The synthesis method is the same as in Example 1.

[0634] LRMS (m / z): [M+H]+810.3.

[0635] Example 104: N-cyclopropyl-N-(4-((5-((1-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)carbamoyl)pyridin-2-yl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide

[0636]

[0637] The synthesis method is the same as in Example 1.

[0638] Molecular Weight:824.9

[0639] Example 105: N-cyclopropyl-N-(4-((5-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)carbamoyl)pyrazin-2-yl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide

[0640]

[0641] The synthesis method is the same as in Example 1.

[0642] LRMS (m / z): [M+H]+826.1.

[0643] Example 106: N-cyclopropyl-N-(4-((5-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)amino)methyl)pyridin-2-yl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide

[0644]

[0645] The synthesis method is the same as in Example 1.

[0646] Molecular Weight:810.9

[0647] Example 107: N-cyclopropyl-N-(4-((5-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)amino)methyl)pyrazin-2-yl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide

[0648]

[0649] The synthesis method is the same as in Example 1.

[0650] Molecular Weight:811.9

[0651] Example 108: N-cyclopropyl-N-(4-((6-((1-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)amino)methyl)pyridin-3-yl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide

[0652]

[0653] The synthesis method is the same as in Example 1.

[0654] Molecular Weight:810.9

[0655] Example 109: N-cyclopropyl-N-(4-((4-((1-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)carbamoyl)bicyclo[2.2.2]octan-1-yl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide

[0656]

[0657] The synthesis method is the same as in Example 1.

[0658] Molecular Weight:855.9

[0659] Example 110: N-cyclopropyl-N-(4-((3-((1-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)carbamoyl)bicyclo[1.1.1]pentan-1-yl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide

[0660]

[0661] The synthesis method is the same as in Example 1.

[0662] Molecular Weight:813.9

[0663] Example 111: (3-(5-(4-(4-((N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide)methyl)benzamide)piperidin-1-yl)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methylglycine

[0664]

[0665] The synthesis method is the same as in Example 1.

[0666] Molecular Weight:910.9

[0667] Example 112: (3-(5-(4-(4-((N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide)methyl)benzamide)piperidin-1-yl)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl pivalate

[0668]

[0669] The synthesis method is the same as in Example 1.

[0670] Molecular Weight:938.0

[0671] Example 113: (3-(5-(4-(4-((N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide)methyl)benzamide)piperidin-1-yl)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl dihydrogen phosphate

[0672]

[0673] The synthesis method is the same as in Example 1.

[0674] Molecular Weight:933.9

[0675] Example 114: (E)-N-cyclopropyl-N-(4-((4-(4-(2-methoxyphenyl)-4-oxobut-2-enoyl)piperazine-1-carbonyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide

[0676]

[0677] The synthesis method is the same as in Example 1.

[0678] Molecular Weight:741.8

[0679] Example 115: (E)-N-cyclopropyl-N-(4-((4-(4-(2-fluorophenyl)-4-oxobut-2-enoyl)piperazine-1-carboxyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide

[0680]

[0681] The synthesis method is the same as in Example 1.

[0682] Molecular Weight:729.8

[0683] Example 116: (E)-N-cyclopropyl-N-(4-((4-(4-(4-fluorophenyl)-4-oxobut-2-enoyl)piperazine-1-carbonyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide

[0684]

[0685] The synthesis method is the same as in Example 1.

[0686] Molecular Weight:729.8

[0687] Example 117: (E)-N-cyclopropyl-3-oxo-N-(4-((4-oxo-4-(p-tolyl)but-2-enoyl)piperazine-1-carbonyl)phenyl)carbamoyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide

[0688]

[0689] The synthesis method is the same as in Example 1.

[0690] Molecular Weight:725.8

[0691] Example 118: (E)-N-cyclopropyl-3-oxo-N-(4-((4-oxo-4-(o-tolyl)but-2-enoyl)piperazine-1-carboxyl)phenyl)carbamoyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide

[0692]

[0693] The synthesis method is the same as in Example 1.

[0694] Molecular Weight:725.8

[0695] Example 119: Methyl (7-(cyclopropyl(4-((4-((2-(2,6-dioxo-1-((pivaloyloxy)methyl)piperidin-3-yl)-1,3-dioxoindole-5-yl)amino)butyl)carbamoyl)phenyl)carbamoyl)benzyl)carbamoyl)-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)pivalate (LLC03281)

[0696]

[0697] The synthesis method is the same as in Example 1.

[0698] HRMS(m / z):[M+Na]+calcd for C 56 H 61 N7O 13 Na+1062.4220, found 1062.4212.

[0699] Example 120: (7-(Cyclopropyl(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butyl)carbamoyl)phenyl)carbamoyl)benzyl)carbamoyl)-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl pivalate (LLC03282)

[0700]

[0701] The synthesis method is the same as in Example 1.

[0702] HRMS(m / z):[M+Na]+calcd for C 50 H 51 N7O 11 Na+948.3539, found 948.3529.

[0703] Example 121: (3-(5-((4-(4-((N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamido)methyl)benzamido)butyl)amino)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidinyl)methyl pivalate (LLC03283)

[0704]

[0705] The synthesis method is the same as in Example 1.

[0706] HRMS(m / z):[M+Na]+calcd for C 50 H 51 N7O 11 Na+948.3539, found 948.3528.

[0707] Example 122: (3-(5-((4-(4-((N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamido)methyl)benzamido)butyl)amino)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidinyl)methylglycinate (LLC03284)

[0708]

[0709] The synthesis method is the same as in Example 1.

[0710] Molecular Weight:898.9

[0711] Example 123: (3-(5-((4-(4-((N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide)methyl)benzamide)butyl)amino)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl dihydrogen phosphate (LLC03285)

[0712]

[0713] The synthesis method is the same as in Example 1.

[0714] Molecular Weight:921.9

[0715] Example 124: N-cyclopropyl-N-(4-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide

[0716]

[0717] The synthesis method is the same as in Example 1.

[0718] Molecular Weight:664.7

[0719] Example 125: N-cyclopropyl-N-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide

[0720]

[0721] The synthesis method is the same as in Example 1.

[0722] Molecular Weight:692.7

[0723] Example 126: N-cyclopropyl-N-(4-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoindolin-4-yl)amino)hexyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide

[0724]

[0725] The synthesis method is the same as in Example 1.

[0726] Molecular Weight:720.8

[0727] Example 127: N-cyclopropyl-N-(4-((8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoindolin-4-yl)amino)octyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide

[0728]

[0729] The synthesis method is the same as in Example 1.

[0730] Molecular Weight:748.8

[0731] Example 128: N-cyclopropyl-N-(4-((10-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)decyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide

[0732]

[0733] The synthesis method is the same as in Example 1.

[0734] Molecular Weight:776.9

[0735] Embodiment 129:

[0736]

[0737]

[0738]

[0739]

[0740]

[0741]

[0742]

[0743]

[0744]

[0745]

[0746]

[0747]

[0748]

[0749]

[0750]

[0751]

[0752]

[0753]

[0754]

[0755]

[0756]

[0757]

[0758]

[0759]

[0760]

[0761]

[0762]

[0763] Embodiment 130:

[0764] 1. (1) Degradation activity of compounds on NSD1, NSD2, NSD3 and other related proteins in VCaP, LNCap or 22RV1 prostate cancer cells

[0765] Method 1: After the above compounds were synthesized, they were diluted in DMSO. One million VCaP cells, 800,000 LNCaP cells, or 1 million 22RV1 cells were seeded into 6-well plates per well, and each well was treated with 1 μM or 2 μM of each compound for 24 hours. After treatment, the cultured cells were collected and rinsed with phosphate-buffered saline (PBS) at room temperature. After drug treatment, the cultured cells were collected and rinsed with phosphate-buffered saline (PBS) at room temperature. The cells were treated with lysis buffer containing protease and phosphatase inhibitors. After sonication and centrifugation, the total amount of protein in the cell lysate was measured. After the cell lysate was mixed with sample buffer and sample reducing agent, it was heated at 70°C for 10 minutes, and equal amounts of protein were loaded onto the protein gel and incubated with primary antibodies. After incubation with HRP-labeled secondary antibodies, the protein band signals were obtained by developing with chemiluminescent colorimetric reagents and imaging on an imager. The activity results are shown in Figure 1 and Table 1.

[0766]

[0767]

[0768]

[0769] (2) Relationship between the degradation activity of a series of compounds and their concentration and time.

[0770] Method 2: Set different concentration gradients and different time gradients respectively. Other operations are the same as method 1. The results are shown in Figure 2 and Figure 3 .

[0771] (3) Degradation of various proteins in tumor cells by the compounds described in the examples

[0772] Method 3: The operation method is the same as Method 1. The result is shown in Figure 1.

[0773] 2. Compound LLC0150 inhibits the proliferation of prostate cancer cells such as VCaP, LNCap or 22RV1 and normal cells.

[0774] Method 4: Different cells and their respective culture media were added to a 96-well plate and cultured at 37°C and 5% CO2. After overnight culture, a series of dilutions of compound LLC0150 were added to the 96-well plate. The cells were further cultured for 5 days and then the CellTiter-Glo assay was performed according to the manufacturer's instructions to determine cell proliferation. The luminescence signal of each well was obtained using a microplate reader and the data was analyzed using GraphPad Prism software. The results are shown in Figure 4 .

[0775] 3. Study on the anti-tumor effect of compound LLC0150 in mice with xenograft tumors.

[0776] Method 5: The in vivo antitumor efficacy of compound LLC0150 was evaluated in a nude mouse model of VCaP xenograft tumors by oral administration and intraperitoneal injection. VCaP cells were implanted into mice to construct a xenograft model. When the tumor volume grew to 200-300mm 3 The mice were randomly divided into groups and started to be treated with drugs. Each group had 10 mice. The negative control group was Vehicle, and the experimental group was LLC0150 (60 mg / kg). The drugs were given once every 2 days. The animal body weight and tumor volume were measured on the 0th, 2nd, 4th, 8th, and 16th day of treatment, and the expression level of NSD2 protein in the tumor was detected by protein immunoblotting. The clinical symptoms of the animals were observed and recorded once a day during the period.

[0777] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A compound having a structure represented by formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer or prodrug molecule thereof: in: A1, A2, A3, X, Z, W, G are each independently N or C-R1; Each R1 is independently selected from the group consisting of H, deuterium atom, halogen, CN, OH, NH2; K3 is selected from the group consisting of H, D, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-8 Saturated or partially unsaturated carbocyclic group, substituted or unsubstituted C 3-8 Saturated or partially unsaturated heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted C 5-12 heteroaryl; L is selected from the following group: chemical bond, C 1-16 Alkylene, Substituted or unsubstituted C 3-8 Saturated or partially unsaturated carbocyclic group, substituted or unsubstituted C 3-8 Saturated or partially unsaturated heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted C 5-12 Heteroaryl; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; wherein the carbocyclic group, heterocyclic group, aryl group, heteroaryl group include monocyclic, condensed ring, spirocyclic or heterocyclic structures; Y has the structure shown below: wherein each m is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15; Each Z is independently selected from the group consisting of a chemical bond, a C 3-8 Saturated or partially unsaturated carbon ring, C 3-8 Saturated or partially unsaturated heterocyclic ring, C 6-10 Aromatic ring, C 5-12 Heteroaromatic ring, -NH-, -O-, -C(O)-, -CONH-, -NHCO-, -S-, -CH2-, -C≡C-, -CH=CH-, -P=O-, -S(O)2-, -S(O)-, -P(O)2(OH)-, -NH-S(O)-NH-, -NH-CO-NH-, -C(O)O-, -OC(O)-; Y1, Y2, Y3, and Y4 are each independently selected from the following groups: chemical bonds, C 3-8 Saturated or partially unsaturated carbocyclic group, C 3-8 Saturated or partially unsaturated heterocyclic group, C 6-10 Aryl, C 5-12 Heteroaryl, -CH2-, -C≡C-, -CH=CH-, NH-, -O-, -C(O)-, -CONH-, -NHCO-, -S-, -P=O-, -S(O)2-, -S(O)-, -P(O)2(OH)-, -NH-S(O)-NH-, -NH-CO-NH-, -C(O)O-, -OC(O)-; The Z may be optionally replaced by one or more R Z Substitute, the R Z Selected from the following group: deuterium atom, halogen, -OH, -CN, -CF3, -NH2, -COOH, oxygen atom (=O), C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C 3-8 saturated or partially unsaturated carbocyclic group; The Y1, Y2, Y3, and Y4 may be optionally replaced by one or more R Y Substitute, the R Y Selected from the following group: halogen, -OH, -CN, -CF3, -NH2, -COOH, oxygen atom (=O), substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 alkoxy; Or, 2 R Y The radicals and the atoms to which they are attached together form a structure selected from the group consisting of: substituted or unsubstituted C 3-8 Saturated or partially unsaturated carbocyclic group, substituted or unsubstituted C 3-8 Saturated or partially unsaturated heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted C 5-12 heteroaryl; Q is an E3 ubiquitin ligase ligand having a structure selected from the group consisting of: wherein each R' is independently selected from the following group: H, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted C 1-6 Alkoxy; R2 is selected from the following group: R3 is selected from the following group: substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkylamino, C 3-8 Saturated or partially unsaturated carbocyclic group, C 3-8 Saturated or partially unsaturated heterocyclic group, C 6-10 Aryl, C 5-12 Heteroaryl, R4 is selected from the group consisting of: substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted C 5-12 heteroaryl; The substitution in the substituted or unsubstituted group refers to that one or more hydrogen atoms in the group are replaced by a substituent selected from the group consisting of a deuterium atom, a hydroxyl group, a cyano group, a halogen group, an amino group, an oxo group, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Saturated or partially unsaturated carbocyclic group, C 3-6 Saturated or partially unsaturated heterocyclic group, C 6-10 Aryl, C 5-12 Heteroaryl.

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 compound of formula I has a structure as shown in formula (II): Wherein, R1, K3, L, Y, and Q are defined as described in claim 1.

3. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, characterized in that: R1 is H and K3 is cyclopropyl.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer or a prodrug molecule thereof, characterized in that: Y has a structure selected from the group consisting of: Among them, R, Z, R Z , m is defined as in claim 1.

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: Q has a structure selected from the group consisting of:

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 comprising: (1) A compound of formula I according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof; and Optional (2) a pharmaceutically acceptable carrier.

9. Use of the compound of formula I or a pharmaceutically acceptable salt thereof, or a stereoisomer or a prodrug molecule thereof according to any one of claims 1 to 7, or the pharmaceutical composition according to claim 8, characterized in that: Used in the preparation of a drug for treating or preventing a disease or condition related to the activity or expression level of NSD2, NSD1, NSD3, c-MYC, KLK3 / PSA, AR, NKX3.1, or GSPT1, specifically, the disease or condition is selected from the group consisting of cardiovascular disease, diabetes, hypertension, muscular dystrophy, Parkinson's disease, Alzheimer's disease, and cancer.

10. The use according to claim 9, characterized in that The cancer is selected from the group consisting of hematologic tumors, 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, or nasopharyngeal carcinoma.

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