NSD protein degradation agent and use thereof

Abstract

The present invention provides an NSD protein degradation agent and a use thereof. Specifically, the present invention provides a compound having a structure as shown in formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer or prodrug molecule thereof. The compound can degrade proteins such as NSD2, NSD1, NSD3, c-MYC, KLK3 / PSA, AR, NKX3.1, and GSPT1 via target ubiquitination, and therefore can be used to treat indications related to abnormal expression of proteins such as NSD2, NSD1, NSD3, c-MYC, KLK3 / PSA, AR, NKX3.1, and GSPT1.

Description

A class of NSD protein degraders and their uses Technical Field

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

[0002] PROTACs refer to a class of small molecules that can specifically recognize and induce the degradation of target proteins. Their molecular structure consists of a target protein recognition ligand, a linker, and an E3 recognition ligand. PROTACs offer the advantages of not only effectively inhibiting target protein activity but also rapidly degrading and eliminating it. Theoretically, only a catalytic amount of drug is needed to degrade nearly all proteins in a cell (including membrane proteins), resulting in high safety, drug resistance, and broad application prospects. Degraders targeting target proteins such as ERRs, ABL, BET, and CDK4 / 6 have been successfully developed, demonstrating their potential to treat gene-driven tumor growth and overcome inhibitor resistance. In 2018, Pfizer announced an $830 million investment in the development of protein degraders based on PROTAC technology. In March 2019, WuXi AppTec's partner, Arvinas, announced that its androgen receptor-targeting protein degrader, ARV-110, had entered clinical trials; this was the world's first protein degrader to enter clinical trials. As of 2022, over 10 PROTAC molecules have entered clinical trials.

[0003] Histone lysine methyltransferases (HKMTases) are a class of epigenetic regulatory enzymes that catalyze the transfer of one to three methyl groups to specific lysine residues (K3, K9, K20, K27, K36, and K79) on histones H3 and H4. Histone lysine methyltransferases have important biological functions and are closely associated with a variety of diseases. The NSD protein family is a relatively newly identified family of histone methyltransferases and is often abnormally expressed in various diseases, particularly tumors. Overexpression of NSD2 can accelerate tumor cell proliferation, inhibit apoptosis, and promote tumor metastasis. In acute lymphoblastic leukemia (ALL) populations, the NSD2 E1099K point mutation is found in up to 14% of patients. Clinical and pathological 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 gastrointestinal tumors (colorectal cancer, gastric cancer, and anal canal cancer), bladder cancer, small cell lung cancer, female reproductive system tumors, and skin tumors. Its correlation with tumor grade and stage requires 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 tumor stage. It is associated with a poor prognosis in head and neck tumors, prostate cancer, and gliomas. Research on the NSD protein family not only helps further understand the pathogenesis of related tumors, but also helps discover new tumor markers and new targets for tumor treatment, with 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.

[0004] Summary of the Invention

[0005] The purpose of the present invention is to provide a compound and a pharmaceutical composition thereof that can target ubiquitination and degradation of proteins such as NSD2, NSD1, NSD3, c-MYC, KLK3 / PSA, AR, NKX3.1, and GSPT1.

[0006] 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 prodrug molecule thereof:

[0007] in:

[0008] A1, A2, A3, X, Z1, 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 includes a monocyclic, condensed ring, spirocyclic or heterocyclic structure;

[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, Y4 are each independently selected from the following group: chemical bond, 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 optionally be replaced by one or more R Z Substituted, the R Z Selected from the following groups: 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 Substituted, 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] wherein each R' is independently selected from the group consisting of H, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted C 1-6 alkoxy;

[0021] R2 is selected from the group consisting of:

[0022] 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, C3-8 Saturated or partially unsaturated carbocyclic group, C 3-8 Saturated or partially unsaturated heterocyclic group, C 6-10 Aryl, C 5-12 Heteroaryl,

[0023] R4 is selected from the group consisting of: substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted C 5-12 heteroaryl;

[0024] 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.

[0025] In some embodiments, the compound of formula I has a structure as shown in formula (II):

[0026] Among them, R1, K3, L, Y, and Q are defined as described above.

[0027] In some embodiments, R1 is H and K3 is cyclopropyl.

[0028] In some embodiments, Y has a structure selected from the group consisting of:

[0029] Among them, R, Z, R Z , and m are defined as described above.

[0030] In some embodiments, Q has a structure selected from the group consisting of:

[0031] In some embodiments, the compound is selected from the group consisting of:

[0032] In some embodiments, the compound is selected from the group consisting of:

[0033] In a second aspect of the present invention, there is provided a pharmaceutical composition comprising:

[0034] (1) the compound of formula I according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof; and

[0035] Optional (2) a pharmaceutically acceptable carrier.

[0036] 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 medicament 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, 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.

[0037] In some embodiments, the cancer is selected from the group consisting of hematologic malignancies, gastrointestinal stromal tumors, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, or nasopharyngeal carcinoma.

[0038] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] 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.

[0040] FIG2 shows the test results of the relationship between the degradation activity and concentration of some compounds of the present invention.

[0041] FIG3 shows the test results of the relationship between the degradation activity of some compounds of the present invention and time.

[0042] FIG4 shows the results of the cell proliferation inhibition test of compound LLC0424 on prostate cancer cells such as VCaP, LNCap or 22RV1 and normal cells. DETAILED DESCRIPTION

[0043] After extensive and in-depth research, the inventors have developed a class of compounds and pharmaceutical compositions capable of targeted ubiquitination degradation of proteins such as NSD2, NSD1, NSD3, c-MYC, KLK3 / PSA, AR, NKX3.1, and GSPT1. These compounds can efficiently and selectively degrade NSD2, NSD1, NSD3, c-MYC, KLK3 / PSA, AR, NKX3.1, and GSPT1 in cells, and therefore have potential uses in treating conditions associated with abnormal expression of NSD2, NSD1, NSD3, c-MYC, KLK3 / PSA, AR, NKX3.1, and GSPT1. Based on these findings, the inventors completed the present invention.

[0044] the term

[0045] In the compounds described herein, when any variable (e.g., R1, R2, etc.) occurs more than once in any component, its definition at each occurrence is independent of its definition at every other occurrence. Likewise, combinations of substituents and variables are permitted so long as such combinations result in a stable compound. A line drawn from a substituent into the ring system indicates that the indicated bond may be attached to any substitutable ring atom. If the ring system is polycyclic, this means that such bonds are attached only to any suitable carbon atom of the adjacent ring. It will be understood that one of ordinary skill in the art can select the substituents and substitution patterns of the compounds of the present invention to provide chemically stable compounds that can be readily synthesized from readily available raw materials using techniques in the art and the methods set forth below. If a substituent is itself substituted with more than one group, it will be understood that these groups may be on the same carbon atom or on different carbon atoms so long as the structure is stable.

[0046] 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.

[0047] The following terms are used to describe the present invention. Where a term is not specifically defined herein, it is given the art-recognized meaning by those of ordinary skill in the art in applying the term in the context of its use to describe the present invention.

[0048] As used herein, the term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to a specific substrate protein, thereby targeting the substrate protein for degradation. For example, Von Hippel-Lindau E3 ubiquitin ligase or CRBN E3 ubiquitin ligase is a protein that, alone or in combination with an E2 ubiquitin conjugating enzyme, results in the attachment of ubiquitin to a lysine on a target protein and subsequently targets the specific protein substrate for degradation by the proteasome. Thus, the E3 ubiquitin ligase, alone or in complex with an E2 ubiquitin conjugating enzyme, is responsible for the transfer of ubiquitin to the target protein. In general, the ubiquitin ligase participates in polyubiquitination, whereby a second ubiquitin is attached to a first ubiquitin; a third ubiquitin is attached to a second ubiquitin, and so on. Polyubiquitination marks proteins for degradation by the proteasome. However, there are some ubiquitination events that are limited to monoubiquitination, in which only a single ubiquitin is added to the substrate molecule by the ubiquitin ligase. Monoubiquitinated proteins are not targeted to the proteasome for degradation, but instead can be altered in their cellular location or function, for example, by binding to other proteins with domains capable of binding ubiquitin. Further complicating the situation is that different lysines on ubiquitin can be targeted by E3 to form chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to make polyubiquitin that is recognized by the proteasome.

[0049] As used herein, the term "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms. For example, the definition of "C1-C6 alkyl" includes groups having 1, 2, 3, 4, 5, or 6 carbon atoms in a straight or branched chain. For example, "C1-C6 alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, and hexyl.

[0050] The term "carbocyclyl" 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 bicyclic or polycyclic rings include spirocyclic, fused rings and bridged rings. For example, "carbocyclyl" includes but is not limited to the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wait.

[0051] 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.

[0052] 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) and the remaining ring atoms are carbon, and the bicyclic or polycyclic rings include spirocyclic, fused and bridged rings. For example: morpholinyl, piperidinyl, tetrahydropyrrolyl, pyrrolidinyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothiophenyl, dihydrotriazolyl, dihydroazetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, etc., and N-oxides thereof. Attachment of the heterocyclic substituents can be achieved via a carbon atom or via a heteroatom.

[0053] As used herein, the term alkylamino refers to a group having the specified number of carbon atoms and having the structure -alkyl-NH2, -NH-alkyl or -alkyl-NH-alkyl.

[0054] As will be understood by those skilled in the art, "halo" or "halo" as used herein refers to chlorine, fluorine, bromine and iodine.

[0055] Pharmaceutically acceptable salts

[0056] The present invention includes free forms of compounds of Formula I, as well as pharmaceutically acceptable salts and stereoisomers thereof. Certain 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 encompassed include not only the exemplary salts of the specific compounds described herein, but also all typical pharmaceutically acceptable salts of the free forms of 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 a suitable dilute aqueous base solution, such as dilute aqueous NaOH, dilute aqueous potassium carbonate, dilute aqueous ammonia, and dilute aqueous sodium bicarbonate. The free forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of the present invention, such acid and base salts are equivalent to their respective free forms in other pharmaceutical respects.

[0057] Pharmaceutically acceptable salts of the present invention can be synthesized from compounds of the present invention containing a basic or acidic moiety by conventional chemical methods. Typically, salts of basic compounds are prepared by ion exchange chromatography or by reacting a free base with a stoichiometric amount or an excess of an inorganic or organic acid in the desired salt form in a suitable solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reaction with a suitable inorganic or organic base.

[0058] Therefore, pharmaceutically acceptable salts of the compounds of this invention include conventional non-toxic salts of the compounds of this invention formed by reacting an alkaline compound of this invention with an inorganic or organic acid. For example, conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, and also include salts derived from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, and the like.

[0059] If the compound of the present invention is acidic, suitable "pharmaceutically acceptable salts" refer to salts prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, ferric salts, ferrous salts, lithium salts, magnesium salts, manganic salts, manganous salts, potassium salts, sodium salts, zinc salts, and the like. Ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic bases, including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxocobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, guaiac, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

[0060] Berg et al., "Pharmaceutical Salts," J. Pharm. Sci. '1977: 66: 1-19, describes in more detail the preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts.

[0061] Drug metabolites, prodrugs, isotopes, solvates, and polymorphs

[0062] The metabolites of the compounds involved in the present invention and their pharmaceutically acceptable salts, as well as prodrugs that can be converted into the structures of the compounds involved in the present application and their pharmaceutically acceptable salts in vivo, are also included in the claims of the present invention. As used herein, the term "prodrug" refers to a compound that, when metabolized (e.g., in vivo or in vitro), produces an active compound. In some embodiments, the prodrug can be inactive or have lower activity than the free drug, but can provide advantageous processing, administration or metabolic characteristics. The exemplary prodrug moiety of the present invention can be connected to the free drug through the hydroxyl, amino, phosphate or thiophosphate backbone of the nucleotide, and can include esters, carbamates, carbonyls, thioesters, amides, isocyanates, ureas, thioureas or other physiologically acceptable metabolically unstable parts. In some embodiments, the prodrug is activated by enzymatic hydrolysis.

[0063] The present disclosure also includes isotopically labeled compounds that are identical to those listed in formula (I) (including compounds of formulas (II)-(X)), except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually 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 the 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.

[0064] The compounds disclosed herein can exist in solvated and unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc., and the present invention is intended to encompass solvated and unsolvated 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.

[0065] Pharmaceutical composition and use thereof

[0066] The present invention also provides a pharmaceutical composition comprising an active ingredient within a safe and effective amount, and a pharmaceutically acceptable carrier or excipient. Since the active ingredient of the present application, the compound of Formula I 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, and GSPT1, the pharmaceutical composition can be used to treat tumors, cardiovascular diseases, diabetes, hypertension, muscular dystrophy, Parkinson's disease, Alzheimer's disease, and other diseases in humans or other mammals that are associated with abnormal expression of proteins such as NSD2, NSD1, NSD3, c-MYC, KLK3 / PSA, AR, NKX3.1, and GSPT1.

[0067] The present invention provides a class of protein kinase degraders and uses thereof. Specifically, the present invention provides a compound having a structure represented by formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer or prodrug molecule thereof. The compound can target ubiquitination degradation of proteins such as NSD2, NSD1, NSD3, c-MYC, KLK3 / PSA, AR, NKX3.1, and GSPT1, and widely inhibit the proliferation of tumor cells such as prostate cancer, non-small cell lung cancer, gastrointestinal stromal tumors, liver cancer, triple-negative breast cancer, and leukemia. It can be used to treat indications related to abnormal expression of proteins such as NSD2, NSD1, NSD3, c-MYC, KLK3 / PSA, AR, NKX3.1, and GSPT1, as well as the above-mentioned tumors.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] A "safe and effective amount" refers to an amount of the active ingredient sufficient to significantly improve the condition without causing serious side effects. Typically, a pharmaceutical composition contains 1-2000 mg of active ingredient per dose, more preferably 10-200 mg per dose. Preferably, "one dose" is one tablet.

[0072] "Pharmaceutically acceptable carrier or excipient" refers to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must be sufficiently pure and have sufficiently low toxicity.

[0073] "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.

[0074] 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, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0075] In another preferred embodiment, the compound of formula I of the present invention can form a complex with a macromolecular compound or polymer through non-bonding interaction. In another preferred embodiment, the compound of formula I of the present invention, as a small molecule, can also be linked to a macromolecular compound or polymer through a chemical bond. The macromolecular compound can be a biological macromolecule such as a polysaccharide, protein, nucleic acid, polypeptide, etc.

[0076] There is no particular limitation on the administration of the active ingredient or pharmaceutical composition of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and the like.

[0077] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.

[0078] 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:

[0079] (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid;

[0080] (b) binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic;

[0081] (c) humectants, for example, glycerin;

[0082] (d) disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate;

[0083] (e) buffering solvents, such as paraffin;

[0084] (f) absorption accelerators, for example, quaternary ammonium compounds;

[0085] (g) wetting agents, such as cetyl alcohol and glyceryl monostearate;

[0086] (h) adsorbents, for example, kaolin; and

[0087] (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.

[0088] The solid dosage forms can also be prepared using coatings and shells, such as enteric coatings and other materials known in the art. They can contain opacifying agents, and the release of the active ingredient in such compositions can be delayed in a certain portion of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes.

[0089] 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, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances. In addition to these inert diluents, the composition may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings and spices.

[0090] In addition to the active ingredients, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0091] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0092] The compounds of the present invention may be administered alone or in combination with other therapeutic agents.

[0093] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0094] Combination therapy

[0095] Compounds of Formula I may be used in combination with other drugs known to treat or ameliorate similar conditions. When administered in combination, the original drug's route of administration and dosage remain unchanged, while the compound of Formula I is administered simultaneously or subsequently. When a compound of Formula I is administered concurrently with one or more other drugs, a pharmaceutical composition containing both the one or more known drugs and the compound of Formula I is preferably used. Combination administration also includes administering a compound of Formula I and one or more other known drugs during overlapping time periods. When a compound of Formula I is administered in combination with one or more other drugs, the dosage of the compound of Formula I or the known drug may be lower than when administered alone.

[0096] The drugs or active ingredients that can be used in combination with the compounds of formula I include but are not limited to: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxins / cytostatics, antiproliferative agents, protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protein kinase inhibitors, reverse transcriptase inhibitors, angiogenesis inhibitors, cell proliferation and survival signal inhibitors, drugs that interfere with cell cycle checkpoints and apoptosis inducers, cytotoxic drugs, tyrosine protein inhibitors, EGFR inhibitors, VEGFR inhibitors, serine / threonine protein inhibitors, 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.

[0097] In one embodiment, the drugs or active ingredients that can be used in combination with the compound of formula I include but are not limited to: aldesleukin, alendronic acid, interferon, atrexin, allopurinol, allopurinol sodium, palonosetron hydrochloride, hexamethylmelamine, aminoglutethimide, amifostine, amrubicin, anacrine, anastrozole, dolasetron, aranesp, arglabin, arsenic trioxide, arnosine, 5-azacytidine, azathioprine, BCG or tice BCG, betadine, betamethasone acetate, betamethasone sodium phosphate preparation, bexarotene, bleomycin sulfate, bromourea, bortezomib, busulfan, calcitonin, alezotocin injection, capecitabine, carboplatin, casodex, cefone , cisplatin, cladribine, cladribine, clodronate, cyclophosphamide, cytarabine, dacarbazine, actinomycin D, liposomal daunorubicin, dexamethasone, dexamethasone phosphate, estradiol valerate, denileukin-2, depomet, deslorelin, delazoxane, diethylstilbestrol, diflucan, docetaxel, doxifluridine, doxorubicin, dronabinol, chin-166-chitosan complex, eligard, rasburicase, epirubicin hydrochloride, aprepitant, epirubicin, epoetin alfa, erythropoietin, epoetin, levamisole tablets, estradiol preparations, 17-beta-estradiol, estramustine sodium phosphate, ethinyl estradiol, amifostine, hydroxyphosphatase, fenbifostine, etoposide, fadrozoles, tamoxifen Oxifen preparations, filgrastim, finasteride, firaprestin, floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil, fluoxymesterone, flutamide, formestane, 1-β-D-arabinofuranosylcytosine-5'-stearoyl phosphate, fotemustine, fulvestrant, immunoglobulin (IgM), gemcitabine, gemtuzumab tuzumab, imatinib mesylate, carmustine rice paper capsules, goserelin, glaniciron hydrochloride, histrelin, holmesin, hydrocortisone, erythro-hydroxynonyl adenine, hydroxyurea, tentanamib, idarubicin, ifosfamide, interferon α, interferon-α2, interferon α-2A, interferon α-2B, interferon α-n1, interferon α-n3, interferon β , interferon gamma-1a, interleukin-2, intron A, Iressa, irinotecan, Kateri, lentinan sulfate, letrozole, leucovorin, leuprorelin acetate, levomizole, levofolinate calcium salt, levothyroxine sodium, levothyroxine sodium preparations, lomustine, lonidamine, dronabinol, nitrogen mustard, methylcobalamin, medroxyprogesterone acetate, megestrol acetate, melphalan, esterified estrogen, 6-mercaptopurine, mesna, methotrexate, methyl aminolevulinate, miltefosine, minocycline, mitomycin C, mitotane, mitoxantrone, trilostane, liposomal doxorubicin citrate, nedaplatin, pegfilgrastim, oprelleukin, neupogen, nilutamide, tamoxifen,NSC-631570, recombinant human interleukin-1-beta, octreotide, ondansetron hydrochloride, prednisone oral solution, oxaliplatin, paclitaxel, prednisone sodium phosphate, pegaspargase, PEGASYS, pentostatin, streptozotocin, pilocarpine hydrochloride, pirarubicin, plicamycin, porfimer sodium, prednimustine, stiprenisolone, prednisone, premarin, procarbazine, recombinant human erythropoietin, raltitrexed, rebifurcation, rhenium-186 etidronate, rituximab, dapoxetine-A, romostatide, pilocarpine hydrochloride tablets, octreotide, sarmustine, semustine, sizolan, sobuzosine, methylprednisolone sodium, paphos acid, stem cell therapy, streptozocin, strontium-89 chloride, levothyroxine sodium, tamoxifen Fen, tamsulosin, tasofenamin, tastolactone, taxotere, tesifuzine, temozolomide, teniposide, testosterone propionate, methyltestosterone, thioguanine, thiotepa, thyroid-stimulating hormone, tiludronic acid, topotecan, toremifene, tositumomab, trastuzumab, treosulfan, tretinoin, methotrexate tablets, trimethylmelamine, trimetrexate, triptorelin acetate, triptorelin pamoate, eufotaxime, uridine, valrubicin, veslanone, vinblastine, vincristine, vinsamide, vinorelbine, virulizine, dextromethorphan, statins, zofran, paclitaxel protein-stabilized formulation, acolbifene, interferon r-lb, affinitak, aminopterin, arzoxifene, as oprisnil, atamestane, atrasentan, BAY43-9006, Avastin, CCI-779, CDC-501, Celebrex, cetuximab, crisentan, cyproterone acetate, decitabine, DN-101, doxorubicin-MTC, dSLIM, dutasteride, edotecarin, eflornithine, exitecan, fenretinide, histamine dihydrochloride, histrelin hydrogel implant, holmium-166DOTMP, ibandronic acid, interferon gamma, intron-PEG, ixabepilone, keyhole limpet hemocyanin, L-651582, lanreotide, lasofoxifene, libra, lonafamib, miproxifene, minodecan, MS-2 09. Liposomal MTP-PE, MX-6, nafarelin, nemorubicin, nevastatin, noratriptide, oblimersen, onco-TCS, osidem, paclitaxel polyglutamate, sodium pyrimidine, PN-401, QS-21, quasitan, R-1549, raloxifene, ranpirnase, 13-cis retinoic acid, satraplatin, ciocalcitol, T-138067, tarceva, paclitaxel docosahexaenoic acid, thymosin alpha 1, gazofurin, tipifarnib, tirapazamine, TLK-286, toremifene, trans-MID-lo7R, valspodar, vapreotide, vatalanib, verteporfin, vinflunine, Z-100, and zoledronic acid, or a combination thereof.

[0098] The main benefits of the present invention are:

[0099] Provided is a structurally novel PROTAC compound that can efficiently and selectively degrade NSD2, NSD1, NSD3, c-MYC, KLK3 / PSA, AR, NKX3.1, GSPT1 and other proteins in cells, effectively inhibit the growth of various tumor cells, and can be used to prepare anti-tumor drugs.

[0100] The present invention will be further described below with reference to 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 procedures in the following examples, for which specific conditions are not specified, were generally performed under conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0101] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0102] 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.

[0103] The structures of the compounds were confirmed by nuclear magnetic resonance (1H-NMR) and / or mass spectrometry (MS). NMR measurements were performed using a Bruker AV-500 or AV-600 NMR instrument, using deuterated chloroform (CDCl3) or deuterated dimethyl sulfoxide (DMSO-D6) as the solvent, and TMS as the internal standard. MS measurements were performed using an LCQAD-40000 mass spectrometer. Column chromatography was performed using 200-300 mesh silica gel (produced by Qingdao Ocean Chemical Plant).

[0104] Example

[0105] 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)

[0106] Step 1: Preparation of methyl 4-((cyclopropylamino)methyl)benzoate trifluoroacetate (3)

[0107] Methyl p-formylbenzoate 2 (20.0 g, 121.8 mmol) was dissolved in methanol (200 mL), 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 portionwise, and after stirring at room temperature for 4 hours, most of the methanol was removed by vortexing, saturated sodium carbonate (200 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate three times (200 mL×3). The organic phases were combined, washed once with saturated sodium carbonate (300 mL), washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a crude product as 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 was precipitated, and the mixture was filtered, and the solid was washed with ether (50 mL) to collect 31.2 g (84%) of white solid. 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).

[0108] Step 2: Preparation of 4-((N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamido)methyl)benzoate (5)

[0109] 3-Oxo-3,4-dihydro-2H-1,4-benzoxazine-7-carboxylic acid 4 (10.0 g, 51.8 mmol) was dissolved in acetonitrile (100 mL), and 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, and ethyl acetate (200 mL) was added to dilute the mixture, washed twice with saturated sodium carbonate (200 mL), washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography with petroleum ether / ethyl acetate (1:1) 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]+.

[0110] Step 3: Preparation of 4-((N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamido)methyl)benzoic acid (6)

[0111] 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 lithium hydroxide solution (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 potassium hydrogen sulfate solution, and a large amount of white solid precipitated. The solution was filtered, washed with cold water, and dried to obtain 4.3 g (90%) of the product. 1 HNMR(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).

[0112] 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)

[0113] 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), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.09 g, 10.9 mmol) were weighed into a 50 mL eggplant flask, N,N-dimethylformamide (10 mL) was added to dissolve the mixture, and the mixture was reacted in an oil bath at 50 degrees for 10 hours; ethyl acetate (200 mL) was added to dilute the mixture, and the mixture was washed with saturated brine (200 mL) three times. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography with petroleum ether / ethyl acetate (1:1) 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]+.

[0114] 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)

[0115] 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) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 12 hours. The product was then dried to give 1.16 g (99%). 1HNMR (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]+.

[0116] 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)

[0117] 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), and trifluoroacetic acid (0.5 mL) was added. The mixture was stirred at room temperature for 5 hours. After thorough spin drying, the crude product was dissolved in N,N-dimethylformamide (2 mL), and triethylamine (29.2 mg, 0.288 mmol, 40 μg) was added in sequence. 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] + calcd for C 42 H 37 N7O9Na + 806.2545, found 806.2549.

[0118] 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)

[0119] The synthesis method is the same as in Example 1.

[0120] 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 for C 44 H 41 N7O9Na+834.2858, found 834.2853.

[0121] 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)

[0122] The synthesis method is the same as in Example 1.

[0123] 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.

[0124] 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)

[0125] The synthesis method is the same as in Example 1.

[0126] 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 for C 48 H 49 N7O9Na+890.3484, found 890.3480.

[0127] 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)

[0128] The synthesis method is the same as in Example 1.

[0129] 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,found 918.3796。

[0130] 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)

[0131] The synthesis method is the same as in Example 1.

[0132] 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.

[0133] 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)

[0134] The synthesis method is the same as in Example 1.

[0135] 1 H NMR (600MHz, DMSO-d6) δ 11.06 (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 39 N7O9Na+820.2701, found 820.2699.

[0136] 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)

[0137] The synthesis method is the same as in Example 1.

[0138] 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); 13 C 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.

[0139] 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)

[0140] The synthesis method is the same as in Example 1.

[0141] 1 H 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]+calcd for C45 H 43 N7O9Na+848.3014, found 848.3013.

[0142] 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)

[0143] The synthesis method is the same as in Example 1.

[0144] 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=8.2 Hz, 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, 1 H), 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=1 2.8, 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, 1H), 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); 13C NMR (151MHz, DMSO) δ172.82, 170.19, 167.71, 167.16, 165.57, 165.56, 164.85, 15 4.47, 142.49, 142.35, 141.66, 134.21, 133.44, 131.79, 129.56, 128.39, 128.06, 127.82, 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]+calcd for C 46 H 45 N7O9Na+862.3171, found 862.3165.

[0145] 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)

[0146] The synthesis method is the same as in Example 1.

[0147] 1H 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= 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 C 48 H 49 N7O9Na+890.3484, found 890.3482.

[0148] 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)

[0149] The synthesis method is the same as in Example 1.

[0150] 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); 13 C NMR (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 , 29.17, 29.00, 28.96, 28.79, 28.23, 26.54, 26.51, 22.23, 9.57; HRMS (m / z): [M+H]+calcd for C 50 H 54 N7O9+896.3978, found 896.3970.

[0151] 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)

[0152] The synthesis method is the same as in Example 1.

[0153] 1 H 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, found 806.2530.

[0154] 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)

[0155] The synthesis method is the same as in Example 1.

[0156] 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 41N7O9Na+834.2858, found834.2864.

[0157] 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)

[0158] The synthesis method is the same as in Example 1.

[0159] 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); 13C 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 for C 44 H 45 N7O9Na+862.3171, found 862.3176.

[0160] 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)

[0161] The synthesis method is the same as in Example 1.

[0162] 1H 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, 1 27.81, 127.21, 125.24, 121.87, 119.33, 118.96, 115.36, 115.15, 66.74, 51.52, 46.47, 40.0 6, 35.80, 31.20, 29.19, 28.66, 28.56, 26.44, 25.07, 22.64, 9.55; HRMS (m / z): [M+Na]+calcd for C 48 H 49 N7O9Na+890.3484, found 890.3491.

[0163] Example 17: N-cyclopropyl-N-(4-((4-((10-(2-(2,6-dioxopiperidin-3-yl)-1-isoindolin-4-yl)amino)-10-oxodecanyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0198)

[0164] The synthesis method is the same as in Example 1.

[0165] 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); 13 C 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.

[0166] 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)

[0167] The synthesis method is the same as in Example 1.

[0168] 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), 7.97-7.93 (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 52H 57 N7O9Na+946.4110, found 946.4119.

[0169] 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)

[0170] The synthesis method is the same as in Example 1.

[0171] 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); 13C 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, found 806.2539.

[0172] 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)

[0173] The synthesis method is the same as in Example 1.

[0174] 1H 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); 13 C 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.

[0175] 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)

[0176] The synthesis method is the same as in Example 1.

[0177] 1 H 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 C NMR (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, 1 26.10, 123.61, 121.87, 119.33, 118.66, 115.36, 115.16, 113.10, 66.74, 51.52, 47.13, 4 0.06, 39.03, 36.46, 31.21, 29.01, 26.16, 24.80, 22.52, 9.55; HRMS (m / z): [M+Na]+calcd for C 46 H 45 N7O9Na+862.3171, found 862.3163.

[0178] 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)

[0179] The synthesis method is the same as in Example 1.

[0180] 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), 8.1 0 (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, 1 H), 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, 5.1H z, 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 = 6.0Hz, 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); 13 C 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 H37 N7O9Na+806.2545, found 806.2538.

[0181] 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)

[0182] The synthesis method is the same as in Example 1.

[0183] 1 H 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, 2 H), 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); 13C 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, found 834.2852.

[0184] 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)

[0185] The synthesis method is the same as in Example 1.

[0186] 1H 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),7.87-7.81(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); 13 C NMR(151MHz,DMSO)δ172.89,171.50,171.04,168.06,165.57,164.86,142.49,142.34,141.65,139.27,136.29,133.44,132.11,131.79,129.57,128.39,128.06,127.82,127.22,123.74,122.62,121.87,119.34,115.36,115.16,112.97,66.74,51.68,46.95,40.06,36.41,31.22,29.03,26.20,24.84,22.47,9.52;HRMS(m / z):[M+Na]+calcd for C 46 H 45 N7O9Na+862.3171,found 862.3174.

[0187] 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)

[0188] The synthesis method is the same as in Example 1.

[0189] 1 H 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), 6.94 (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 H37 N7O9Na+806.2545, found 806.2547.

[0190] 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)

[0191] The synthesis method is the same as in Example 1.

[0192] 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); 13C 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.

[0193] 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)

[0194] The synthesis method is the same as in Example 1.

[0195] 1H 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=7.5Hz,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); 13 C NMR(151MHz,DMSO-d6)δ172.84,171.31,170.81,169.22,165.58,164.86,142.64,142.49,142.34,141.65,137.07,133.45,133.19,131.80,129.55,128.39,128.06,127.82,127.22,121.88,119.31,117.63,117.02,116.74,115.36,115.16,66.74,51.59,47.50,40.06,38.99,36.99,31.17,28.92,26.04,24.60,22.34,9.52;HRMS(m / z):[M+Na]+calcd for C 46 H 45 N7O9Na+862.3171,found 862.3164。

[0196] 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)

[0197] The synthesis method is the same as in Example 1.

[0198] 1 H 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), 7.5 6 (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, 5.2H z, 1H), 4.72 (s, 2H), 4.62 (s, 2H), 4.47 (d, J = 17.6Hz, 1H), 4.35 (d, J = 17.6 Hz, 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),1.5 5-1.49(m, 2H), 1.37-1.31(m, 6H), 0.58-0.52(m, 2H), 0.51-0.44(m, 2H); 13C 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.

[0199] 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)

[0200] 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 thorough spin drying, the crude product was dissolved in N,N-dimethylformamide (2 mL), and triethylamine (29.2 mg, 0.288 mmol) was added successively. , 40 μL), 4-((N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamido)methyl)benzoic acid 6 (38.7 mg, 0.106 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 54.2 mg (85%) of a yellow-green solid compound was obtained by column chromatography on a dichloromethane / methanol system. 1H NMR (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 32 N6O8Na+687.2174, found 687.2168.

[0201] 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)

[0202] The synthesis method is the same as Example 29.

[0203] 1H 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, found 715.2492.

[0204] 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)

[0205] The synthesis method is the same as Example 29.

[0206] 1H 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.

[0207] 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)

[0208] The synthesis method is the same as Example 29.

[0209] 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.

[0210] 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)

[0211] The synthesis method is the same as Example 29.

[0212] 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.

[0213] 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)

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

[0215] 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.

[0216] 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)

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

[0218] 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.

[0219] 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)

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

[0221] 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。

[0222] 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)

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

[0224] 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, 128.0 0, 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 .06, 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]+calcd for C 45 H 45 N7O9Na+850.3171, found 850.3166.

[0225] 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)

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

[0227] 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]+calcd for C 47 H 49 N7O9Na+878.3484,found 878.3477。

[0228] 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)

[0229] The synthesis method is the same as in Example 1.

[0230] 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); 13C NMR (151MHz, DMSO-d6) δ172.94, 172.90, 172.07, 172.01, 171.93, 171.63, 171.29, 170.44, 165.57, 165.52, 164.85 , 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.

[0231] Example 40: N-cyclopropyl-N-(4-((4-((10-((2R)-1-((2,6-dioxopiperidin-3-yl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-10-oxodecanyl)carbamoyl)phenyl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0446)

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

[0233] 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.

[0234] 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)

[0235] 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)

[0236] 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 a solid product was obtained by direct 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).

[0237] 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)

[0238] 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), and 5-((3-azidopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 14 (39.2 mg, 0.110 mmol) was added. Thiophene-2-carboxylic acid copper (I) (76.7 mg, 0.400 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The solvent was removed by vortexing, and 46.9 mg (57%) of a yellow-green solid was obtained by column chromatography. 1H 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.

[0239] 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)

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

[0241] 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.

[0242] 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)

[0243] 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)

[0244] 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), 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 24 hours; the solvent was removed by vortexing, and 444 mg (67%) of a 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).

[0245] 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)

[0246] 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) was dissolved in methanol (5 mL). 10% Pd / C (15 mg) was added and stirred under a hydrogen atmosphere for 12 hours. The mixture was filtered through Celite and dried to give 134 mg (95%) of the product. MS (ESI), m / z: 458.5 [M+H]+.

[0247] 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)

[0248] tert-Butyl 5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)pentanoate 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 thorough spin drying, the crude product was dissolved in N,N-dimethylformamide (2 mL), and triethylamine (30.4 mg, 0.300 mmol, 42 μL), 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 the product was purified by column chromatography in a dichloromethane / methanol system to give 35.0 mg (43%) of a yellow-green solid compound. 1 H 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, found 813.2994.

[0249] 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)

[0250] 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)

[0251] 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) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at room temperature for 3 hours; after being fully spin-dried, N,N-dimethylformamide (2 mL) was added for dissolution, N,N-diisopropylethylamine (138 mg, 1.06 mmol, 0.2 mL) was added, and 5-fluoro-2-nitropyridine 20 (31.8 mg, 0.234 mmol) was added, and the mixture was stirred in an oil bath at 110 degrees for 1 hour. Ethyl acetate was added for dilution (50 mL), and the mixture was washed once with saturated sodium bicarbonate (50 mL), washed twice with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 79.5 mg (76%) of a yellow-green solid. MS (ESI), m / z: 515.4[M+Na]+.

[0252] 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)

[0253] 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), 10% Pd / C (4 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 12 hours; filtration was performed on celite, and the mixture was dried and dissolved in acetonitrile (2 mL), and 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), react in an oil bath at 50 degrees for 16 hours, concentrate, and obtain 27.0 mg (41%) of a solid by column chromatography. 1 HNMR (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, 1H), 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. 61 (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.

[0254] 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][1,41]oxazine-7-carboxamide (LLC0367)

[0255] The synthesis method is the same as Example 44.

[0256] 1 H 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 for C 44 H 43 N8O8+811.3198, found 811.3183.

[0257] 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)

[0258] The synthesis method is the same as Example 44.

[0259] 1 H 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.

[0260] 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][1,41]oxazine-7-carboxamide (LLC0333)

[0261] The synthesis method is the same as Example 44.

[0262] 1H NMR (600MHz, DMSO-d6) δ11.08 (s, 1H), 10.88 (s, 1H), 10.52 (s, 1H), 8.10 (d, J=3.0Hz, 1 H), 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, found 866.3624.

[0263] 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)

[0264] The synthesis method is the same as Example 44.

[0265] 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 for C 48 H 49 N9O8Na+902.3596, found 902.3591.

[0266] 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)

[0267] The synthesis method is the same as Example 44.

[0268] 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.

[0269] 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)

[0270] The synthesis method is the same as Example 44.

[0271] 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.

[0272] 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)

[0273] The synthesis method is the same as Example 44.

[0274] 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, 1 H), 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, 1 H), 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]+calcd for C 45 H 43 N9O8Na+860.3127, found 860.3115.

[0275] 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)

[0276] The synthesis method is the same as Example 44.

[0277] 1H NMR (600MHz, DMSO-d6) δ11.07 (s, 1H), 10.87 (s, 1H), 10.52 (s, 1H), 8.12-8.06 (m, 1 H), 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, found 852.3467.

[0278] 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][1,41]oxazine-7-carboxamide (LLC0377)

[0279] The synthesis method is the same as Example 44.

[0280] 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, found 874.3277.

[0281] 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)

[0282] The synthesis method is the same as Example 44.

[0283] 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.

[0284] 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)

[0285] The synthesis method is the same as in Example 1.

[0286] 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 C NMR(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,found 920.3411。

[0287] 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)

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

[0289] 1 H NMR (600MHz, DMSO-d6) δ 10.88 (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, found 977.3618.

[0290] 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)

[0291] The synthesis method is the same as in Example 1.

[0292] 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。

[0293] 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)

[0294] The synthesis method is the same as in Example 1.

[0295] 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 ,164.86,151.46,147.72,142.49,142.34,141.66,139.51,133.45,131.7 9, 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.

[0296] 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)

[0297] The synthesis method is the same as in Example 1.

[0298] 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]+calcd for C 57 H 66 N8O9SNa+1061.4566,found 1061.4555。

[0299] 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)

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

[0301] 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, 2 H), 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), 3.2 7-3.19(m, 2H), 2.86-2.76(m, 1H), 2.44(s, 3H), 2.28-2.22(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.

[0302] 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)

[0303] The synthesis method is the same as in Example 1.

[0304] 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 N8O95+1095.5372,found 1095.5368。

[0305] Example 62: N-cyclopropyl-N-(4-((4-((2-(((S)-4-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carbamoyl)-3,3-dimethylbutanoyl)-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)

[0306] The synthesis method is the same as in Example 1.

[0307] 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.

[0308] 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)

[0309] The synthesis method is the same as in Example 1.

[0310] 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 H 68 FN9O 10SNa+1148.4686, found 1148.4684.

[0311] 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)

[0312] The synthesis method is the same as in Example 1.

[0313] 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 FN9O 10SNa+1176.4999, found 1176.4983.

[0314] 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)

[0315] The synthesis method is the same as in Example 1.

[0316] 1 H 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 H76 FN9O 10 SNa+1204.5312, found 1204.5302.

[0317] Example 66: N-cyclopropyl-N-(4-((4-((10-(((S)-4-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carbamoyl)-3,3-dimethylbutanoyl)-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)

[0318] The synthesis method is the same as in Example 1.

[0319] 1H 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.

[0320] 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)

[0321] The synthesis method is the same as in Example 1.

[0322] 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 for C 58 H 64 FN9O8SNa+1120.4373, found 1120.4368.

[0323] 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)

[0324] 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)

[0325] 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). N-tert-Butyloxycarbonyl-1,2-ethylenediamine (72.6 mg, 0.453 mmol, 74 μL), triethylamine (125 mg, 1.24 mmol, 0.2 mL), and HATU (235 mg, 0.618 mmol) were added sequentially. The mixture was stirred at room temperature for 12 hours, concentrated, and purified by column chromatography to afford 228 mg (88%) of a white solid. MS (ESI), m / z: 650.1 [M+Na]+.

[0326] Step 2: Preparation of N-cyclopropyl-N-(4-((4-((2-(2-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carbamoyl)-3,3-dimethylbutanoyl)-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)

[0327] 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) 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, the mixture was dissolved 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 was added. Tert-butyl 2-(4-(4-(4-thiazol-5-yl)thiazol-2-yl)-4-oxathiol-2-carboxamide)methyl)-5-(4-methylthiazol-5-yl)phenoxy)acetate 23 (40.0 mg, 0.0618 mmol) was dissolved in dichloromethane (1.0 mL), trifluoroacetic acid (1.0 mL) was added, and the mixture was stirred for 2 hours. After thorough spin drying, the above-mentioned N,N-dimethylformamide solution of 22 was added, triethylamine (18.8 mg, 0.186 mmol, 26 μL) was added, and HATU (35.3 mg, 0.0928 mmol) was added. The mixture was stirred at room temperature for 12 hours, the solvent was removed by spin drying, and 34.7 mg (51%) of white solid was obtained by column chromatography. 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.

[0328] 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)

[0329] The synthesis method is the same as Example 68.

[0330] 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 C 59 H 66FN9O 11 SNa+1150.4479, found 1150.4463.

[0331] 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)

[0332] The synthesis method is the same as Example 68.

[0333] 1 H 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 FN9O11 SNa+1178.4792, found 1178.4788.

[0334] 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)

[0335] The synthesis method is the same as Example 68.

[0336] 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 74FN9O 11 SNa+1206.5105, found 1206.5107.

[0337] 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)

[0338] The synthesis method is the same as Example 68.

[0339] 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 78FN9O 11 SNa+1234.5418, found 1234.5424.

[0340] 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)

[0341] The synthesis method is the same as Example 68.

[0342] 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 10S2Na+1124.3781, found 1124.3776.

[0343] 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)

[0344] The synthesis method is the same as Example 68.

[0345] 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 10S2Na+1152.4094, found 1152.4097.

[0346] 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)

[0347] The synthesis method is the same as Example 68.

[0348] 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.

[0349] 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)

[0350] The synthesis method is the same as Example 68.

[0351] 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 for C 62 H 72 FN9O 10 S2Na+1208.4720, found 1208.4727.

[0352] 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)

[0353] The synthesis method is the same as Example 68.

[0354] 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, 2.6H z, 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, 1 H), 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), 2.44(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, 10 H), 1.29-1.18(m, 16H), 0.62-0.51(m, 2H), 0.51-0.40(m, 2H); HRMS(m / z): [M+Na]+calcd for C 64 H 76 FN9O 10 S2Na+1236.5033, found 1236.5018.

[0355] 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)

[0356] Synthesis route:

[0357] The synthesis method is the same as in Example 1.

[0358] 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); 13C 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, 127.83, 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.

[0359] 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)

[0360] The synthesis method is the same as in Example 1.

[0361] HRMS(m / z):[M+Na]+calcd for C 43 H 37 N7O 10 +834.2494, found 834.2498.

[0362] 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)

[0363] The synthesis method is the same as in Example 1.

[0364] HRMS(m / z):[M+Na]+calcd for C 45 H 41 N7O 10+862.2807, found 862.2812.

[0365] 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)

[0366] The synthesis method is the same as in Example 1.

[0367] HRMS(m / z):[M+Na]+calcd for C 47 H 45 N7O 10 +890.3120, found 890.3116.

[0368] 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)

[0369] The synthesis method is the same as in Example 1.

[0370] HRMS(m / z):[M+Na]+calcd for C 49 H 49 N7O 10 +918.3433, found 918.3439.

[0371] 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)

[0372] The synthesis method is the same as in Example 1.

[0373] HRMS(m / z):[M+Na]+calcd for C 53 H 57 N7O 10 Na+974.4059, found 974.4051.

[0374] 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)

[0375] The synthesis method is the same as in Example 1.

[0376] 1 H 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.

[0377] Example 85: N-cyclopropyl-N-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)piperidine-1-carbonyl)phenyl)carbamate)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (LLC0422)

[0378] The synthesis method is the same as in Example 1.

[0379] 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, found 846.2852.

[0380] 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)

[0381]

[0382] Synthesis route:

[0383] The synthesis method is the same as in Example 1.

[0384] 1H NMR (600MHz, DMSO-d6) δ 11.08 (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.

[0385] 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)

[0386] The synthesis method is the same as Example 43.

[0387] HRMS(m / z):[M+Na]+calcd for C 44 H 40 N8O9Na+847.2810, found 847.2814.

[0388] 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)

[0389] The synthesis method is the same as in Example 1.

[0390] 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, found 832.2700.

[0391] 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)

[0392] 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)

[0393] 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). Tert-butyl piperazine-1-carboxylate (84.4 mg, 0.453 mmol, 74 μL), triethylamine (125 mg, 1.24 mmol, 0.2 mL), and HATU (235 mg, 0.618 mmol) were added sequentially. The mixture was stirred at room temperature for 12 hours, concentrated, and purified by column chromatography to afford 213 mg (79%) of a white solid. MS (ESI), m / z: 654.7 [M+H]+.

[0394] 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)

[0395] 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 (40.0 mg, 0.0612 mmol) was dissolved in dichloromethane (1.0 mL), and trifluoroacetic acid (1.0 mL) was added. The mixture was stirred for 2 hours, and then completely dried by rotary evaporation. The mixture was dissolved in N,N-dimethylformamide (2 mL), and 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, and the solvent was removed by rotary evaporation. 28.6 mg (63%) of 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, found 764.2684.

[0396] 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)

[0397] Synthesis route:

[0398] The synthesis method is the same as in Example 1.

[0399] 1H NMR (600MHz, DMSO-d6) δ11.11 (s, 1H), 10.88 (s, 1H), 10.43 (s, 1H), 8.25 (d, J = 7.7Hz, 1H), 7.96 (d, J = 8.2Hz, 2H), 7.87 (s, 4H), 7.7 4 (d, J=11.4Hz, 1H), 7.50 (d, J=7.5Hz, 1H), 7.46 (d, J=7.7Hz, 2H), 7.19 (d, J=8.2Hz, 1H), 7.15 (s, 1H), 6.93 (d, J=8.1Hz, 1H), 5.11 ( dd, J=12.9, 5.4Hz, 1H), 4.72 (s, 2H), 4.62 (s, 2H), 4.09-4.00 (m, 1H), 3.73-3.62 (m, 2H), 3.11-3.01 (m, 2H), 2.93-2.85 (m, 1H), 2.8 4-2.76 (m, 1H), 2.63-2.54 (m, 2H), 2.08-2.00 (m, 1H), 1.98-1.91 (m, 2H), 1.80-1.68 (m, 2H), 0.62-0.52 (m, 2H), 0.51-0.43 (m, 2H). 13 C NMR (151MHz, DMSO-d6) δ172.76, 169.93, 166.71, 166.22, 165.57, 165.11, 164.85, 158 .12, 156.44, 145.56, 145.50, 142.48, 142.36, 141.79, 133.41, 131.79, 129.41, 128.7 8, 128.38, 128.06, 128.01, 127.21, 123.02, 121.87, 119.29, 115.36, 115.15, 113.99, 112.07, 111.89, 66.73, 49.14, 49.06, 46.18, 31.23, 30.95, 22.08, 9.55.HRMS(ESI)for C 45 H 41 FN7O9[M+H] + :calcd 842.2944, found 842.2940. HPLC purity: 95.10%.

[0400] 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)

[0401] Synthesis route:

[0402] The synthesis method is the same as in Example 1.

[0403] 1 H NMR (600MHz, DMSO-d6) δ11.09 (s, 1H), 10.88 (s, 1H), 10.44 (s, 1H), 9.48 (s, 1H), 7.96 (d, J = 8.2Hz, 2H), 7.87 (d, J = 8.7Hz, 2H ), 7.80 (d, J=8.7Hz, 2H), 7.71 (d, J=8.5Hz, 1H), 7.46 (d, J=7.7Hz, 2H), 7.40 (s, 1H), 7.34-7.28 (m, 1H), 7.19 (d, J=7.6Hz, 1H ), 7.15 (s, 1H), 6.93 (d, J = 8.1Hz, 1H), 5.08 (dd, J = 12.8, 5.4Hz, 1H), 4.72 (s, 2H), 4.62 (s, 2H), 3.68-3.53 (m, 4H), 3.09-2.9 8(m, 4H), 2.93-2.84(m, 1H), 2.84-2.76(m, 1H), 2.63-2.53(m, 2H), 2.07-1.99(m, 1H), 0.61-0.52(m, 2H), 0.50-0.40(m, 2H). 13 C NMR (151MHz, DMSO-d6) δ172.81, 170.08, 167.53, 166.98, 165.59, 164.85, 163 .83, 154.98, 142.48, 142.38, 141.93, 133.89, 133.38, 131.78, 128.66, 128.38 ,128.07,128.02,127.21,124.94,121.87,119.35,118.56,118.18,115.35,1 15.15, 108.31, 66.73, 53.21, 48.79, 46.92, 30.98, 22.17, 9.49.HRMS (ESI) for C 44 H 41 N8O9[M+H] + :calcd 825.2991, found 825.2979.HPLC purity: 93.11%.

[0404] 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)

[0405] The synthesis method is the same as in Example 1.

[0406] 1 H NMR (600MHz, DMSO-d6) δ11.07 (s, 1H), 10.88 (s, 1H), 10.43 (s, 1H), 8.44 (t, J=5.7Hz, 1H), 7.96 (d, J=8.2Hz, 2H), 7.87 (s, 4H), 7.65 (d, J=8.6H z, 1H), 7.46 (d, J=7.7Hz, 2H), 7.32 (d, J=1.9Hz, 1H), 7.24 (dd, J=8.7, 2.2Hz, 1H), 7.19 (d, J=7.9Hz, 1H), 7.15 (s, 1H), 6.93 (d, J=8.1Hz, 1H), 5. 06(dd, J=12.8, 5.5Hz, 1H), 4.72(s, 2H), 4.62(s, 2H), 4.14-3.99(m, 2H ), 3.21-3.16(m, 2H), 3.00-2.93(m, 2H), 2.92-2.84(m, 1H), 2.84-2.76 (m, 1H), 2.62-2.52 (m, 2H), 2.05-1.98 (m, 1H), 1.93-1.84 (m, 1H), 1.83 -1.74(m, 2H), 1.30-1.19(m, 2H), 0.62-0.52(m, 2H), 0.51-0.41(m, 2H). 13 C NMR (151MHz, DMSO-d6) δ172.81, 170.12, 167.63, 166.97, 165.82, 165.58, 164.85 ,154.98,142.49,142.36,141.73,134.05,133.42,131.79,129.45,128.39,128.0 6, 127.89, 127.22, 125.00, 121.87, 119.34, 117.66, 117.42, 115.36, 115.15, 107 .80, 66.74, 48.73, 47.19, 44.47, 35.76, 30.98, 28.94, 22.19, 9.54.HRMS (ESI) for C 46 H44 N7O9[M+H] + :calcd 838.3195, found 838.3192.HPLC purity: 95.95%.

[0407] 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)

[0408] The synthesis method is the same as in Example 1.

[0409] 1 H NMR (600MHz, DMSO-d6) δ11.06 (s, 1H), 10.88 (s, 1H), 10.43 (s, 1H), 8.61 (t, J=5.6Hz, 1H), 7.96 (d, J=8.2Hz, 2H), 7.86 (q, J=9.0Hz, 4H), 7 .63 (d, J=8.3Hz, 1H), 7.46 (d, J=7.6Hz, 2H), 7.19 (d, J=7.9Hz, 1H), 7.15 (s, 1H), 6.93 (d, J=8.1Hz, 1H), 6.77 (d, J=1.9Hz, 1H), 6.65 (dd, J= 8.4, 2.1Hz, 1H), 5.05 (dd, J=12.8, 5.4Hz, 1H), 4.72 (s, 2H), 4.62 (s, 2H), 4.16-4.08 (m, 2H), 3.82 (dd, J=8.3, 5.2Hz, 2H), 3.61-3.52 (m, 2 H), 3.07-2.98(m, 1H), 2.92-2.84(m, 1H), 2.83-2.76(m, 1H), 2.61-2.52(m, 2H), 2.05-1.95(m, 1H), 0.63-0.52(m, 2H), 0.51-0.37(m, 2H). 13C NMR (151MHz, DMSO-d6) δ172.81, 170.11, 167.48, 167.16, 166.12, 165.59, 164.85 ,155.23,142.48,142.37,141.88,133.83,133.40,131.79,129.15,128.39,128.0 6, 127.93, 127.22, 124.83, 121.87, 119.34, 116.71, 115.36, 115.15, 114.08, 104 .31, 66.74, 54.71, 48.69, 48.60, 42.27, 30.97, 29.43, 22.20, 9.50.HRMS(ESI)for C 44 H 40 N7O9[M+H] + :calcd 810.2882, found 810.2876.HPLC purity: 93.31%.

[0410] 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)

[0411] The synthesis method is the same as in Example 1.

[0412] 1H NMR (600MHz, DMSO-d6) δ11.08 (s, 1H), 10.88 (s, 1H), 10.45 (s, 1H), 9.03 (d, J=7.0Hz, 1H), 7.96 (d, J=8.3Hz, 2H), 7.93-7.86 (m, 4 H), 7.67 (d, J=8.3Hz, 1H), 7.46 (d, J=7.7Hz, 2H), 7.19 (d, J=7.9Hz, 1H), 7.15 (s, 1H), 6.93 (d, J=8.1Hz, 1H), 6.87 (d, J=1.9Hz, 1H) , 6.72 (dd, J=8.4, 2.0Hz, 1H), 5.07 (dd, J=12.8, 5.4Hz, 1H), 4.95-4.88 (m, 1H), 4.72 (s, 2H), 4.62 (s, 2H), 4.44-4.38 (m, 2H), 4.08 -4.00(m, 2H), 2.93-2.84(m, 1H), 2.84-2.74(m, 1H), 2.62-2.51(m, 2H), 2.05-1.99(m, 1H), 0.60-0.52(m, 2H), 0.51-0.41(m, 2H). 13 C NMR (151MHz, DMSO-d6) δ172.81, 170.12, 167.49, 167.18, 165.63, 164.85, 1 54.98, 142.48, 142.39, 142.13, 133.86, 133.38, 131.79, 128.61, 128.39, 12 8.11, 128.07, 127.22, 124.86, 121.87, 119.36, 117.07, 115.36, 115.15, 114 .49, 104.75, 66.74, 58.41, 48.73, 48.60, 30.99, 22.21, 9.55.HRMS(ESI)for C 43 H 38 N7O9[M+H] + :calcd 796.2726, found 796.2722.HPLC purity: 96.92%.

[0413] 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)

[0414] The synthesis method is the same as in Example 1.

[0415] 1 H NMR (600MHz, DMSO-d6) δ11.07 (s, 1H), 10.88 (s, 1H), 7.79 (d, J=7.6Hz, 1H), 7.66 (d, J=8.6Hz, 1H), 7.38-7.33 (m, 5H), 7.25 (dd, J=8.7, 2. 3Hz, 1H), 7.18 (d, J=7.9Hz, 1H), 7.13 (s, 1H), 6.92 (d, J=8.1Hz, 1H), 5.06 (dd, J=12.8, 5.4Hz, 1H), 4.66 (s, 2H), 4.61 (s, 2H), 4.53-4.33 (m , 1H), 4.01-3.92(m, 2H), 3.88-3.81(m, 1H), 3.70-3.54(m, 1H), 3.15-3.07(m, 4H), 2.92-2.85(m, 1H), 2.82-2.76(m, 1H), 2.62-2.52(m, 2 H), 2.40-2.33(m, 1H), 2.05-1.97(m, 1H), 1.83-1.60(m, 4H), 1.56-1.46(m, 2H), 1.45-1.36(m, 2H), 0.59-0.50(m, 2H), 0.49-0.38(m, 2H). 13 C NMR (151MHz, DMSO-d6) δ173.10, 172.81, 170.11, 168.87, 167.60, 166.95, 1 64.85, 154.74, 142.47, 139.65, 134.85, 134.06, 131.80, 128.37, 127.12, 1 27.03, 125.03, 121.89, 117.78, 117.64, 115.38, 115.13, 107.93, 66.73, 48 .75, 46.15, 45.60, 45.44, 41.80, 30.98, 30.45, 22.18, 9.56.HRMS(ESI)for C 44 H 45 N7NaO9[M+Na] + :calcd 838.3171, found 838.3166.HPLC purity: 96.06%.

[0416] 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)

[0417] The synthesis method is the same as in Example 1.

[0418] 1 H NMR (600MHz, DMSO-d6) δ11.08 (s, 1H), 10.88 (s, 1H), 10.40 (s, 1H), 7.95 (d, J = 8.2Hz, 2H), 7.86 (d, J = 8.3Hz, 2H), 7.67 (d, J = 8.5Hz, 1H) , 7.46 (d, J=7.7Hz, 2H), 7.42 (d, J=8.5Hz, 2H), 7.35 (s, 1H), 7.31-7.24 (m, 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), 4.72 (s, 2H), 4.62 (s, 2H), 4.27-4.06 (m, 2H), 3.35-3.28 (m, 2H), 3.14-3.06 (m, 1H), 2.93-2.85 (m, 1H) , 2.84-2.74(m, 4H), 2.62-2.52(m, 2H), 2.06-1.98(m, 1H), 1.90-1.79(m, 2H), 1.79-1.70(m, 2H), 0.61-0.52(m, 2H), 0.51-0.42(m, 2H). 13 C NMR (151MHz, DMSO-d6) δ172.81, 170.11, 167.59, 166.94, 165.61, 164.85, 1 42.48, 142.28, 140.18, 134.07, 133.55, 131.84, 131.79, 128.38, 128.04, 1 27.22, 125.03, 121.87, 119.66, 117.82, 115.36, 115.15, 107.97, 66.74, 64 .92, 54.92, 48.74, 48.60, 46.73, 30.98, 22.18, 15.17, 9.55.HRMS(ESI)for C 46 H 44 N7O9[M+H] +:calcd 838.3195, found 838.3181. HPLC purity: 96.06%.

[0419] 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)

[0420] The synthesis method is the same as in Example 1.

[0421] 1 H NMR (600MHz, DMSO-d6) δ11.07 (s, 1H), 10.88 (s, 1H), 10.43 (s, 1H), 8.56 (d, J = 6.6Hz, 1H), 7.96 (d, J = 8.2Hz, 2H), 7.88 (s, 4H), 7.66 (d, J = 8.4Hz, 1H) ), 7.46 (d, J=7.6Hz, 2H), 7.19 (d, J=7.9Hz, 1H), 7.15 (s, 1H), 6.95 (d, J=1.8Hz, 1H), 6.93 (d, J=8.1Hz, 1H), 6.86 (dd, J=8.6, 2.1Hz, 1H), 5.06 (dd, J= 12.8, 5.4Hz, 1H), 4.72 (s, 2H), 4.70-4.64 (m, 1H), 4.61 (s, 2H), 3.81-3.7 4(m, 1H), 3.66-3.59(m, 1H), 3.56-3.48(m, 1H), 3.45-3.40(m, 1H), 2.94- 2.84(m, 1H), 2.83-2.75(m, 1H), 2.62-2.52(m, 2H), 2.36-2.28(m, 1H), 2. 19-2.11(m, 1H), 2.05-1.97(m, 1H), 0.61-0.52(m, 2H), 0.51-0.41(m, 2H). 13C NMR (151MHz, DMSO-d6) δ172.83, 170.15, 167.71, 167.25, 165.96, 165.59, 164.86, 163.04 , 151.91, 142.49, 142.38, 141.95, 134.00, 133.39, 131.79, 129.03, 128.39, 128.15, 128. 09, 128.06, 127.21, 124.96, 121.87, 119.27, 115.77, 115.44, 115.36, 115.15, 105.62, 66 .74, 54.92, 53.05, 49.27, 48.71, 48.60, 46.28, 31.00, 30.72, 22.26, 9.54.HRMS(ESI)for C 44 H 40 N7O9[M+H] + :calcd 810.2882, found 810.2879.HPLC purity: 97.22%.

[0422] 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)

[0423] The synthesis method is the same as in Example 1.

[0424] 1H NMR(600MHz,DMSO-d6)δ11.06(s,1H),10.88(s,1H),10.44(s,1H),8.55(t,J=5.7Hz,1H),7.96(d,J=8.2Hz,2H),7.88(s,4H),7.65(d,J=8.4Hz,1H),7.46(d,J=7.7Hz,2H),7.19(d,J=7.9Hz,1H),7.15(s,1H),6.93(d,J=8.1Hz,1H),6.91(d,J=1.9Hz,1H),6.82(dd,J=8.6,2.1Hz,1H),5.05(dd,J=12.8,5.4Hz,1H),4.72(s,2H),4.62(s,2H),3.60-3.50(m,2H),3.46-3.38(m,3H),3.27(dd,J=10.1,6.2Hz,1H),2.93-2.84(m,1H),2.84-2.74(m,1H),2.70-2.63(m,1H),2.62-2.51(m,2H),2.18-2.10(m,1H),2.04-1.97(m,1H),1.90-1.82(m,1H),0.61-0.52(m,2H),0.51-0.41(m,2H). 13 C NMR(151MHz,DMSO-d6)δ172.82,170.16,167.72,167.24,166.01,165.58,164.85,151.90,142.48,142.36,141.83,134.00,133.41,131.79,129.32,128.39,128.07,127.96,127.92,127.22,124.96,121.87,119.35,115.53,115.36,115.30,115.15,105.52,66.74,51.37,48.68,47.16,41.62,38.36,30.99,28.52,22.25,9.50.HRMS(ESI)for C 45 H 42 N7O9[M+H] + :calcd 824.3039,found 824.3043.HPLC purity:95.51%.

[0425] 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)

[0426] The synthesis method is the same as in Example 1.

[0427] HRMS (m / z): [M+H]+calcd for C 44 H 41 N8O9+825.2991, found 825.2985.

[0428] 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)

[0429] The synthesis method is the same as in Example 1.

[0430] HRMS (m / z): [M+H]+calcd for C 43 H 40 N7O 10 +814.2831, found 814.2830.

[0431] 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)

[0432] The synthesis method is the same as in Example 1.

[0433] 1H NMR (600MHz, DMSO-d6) δ11.08 (s, 1H), 10.87 (s, 1H), 7.72 (br s, 1H), 7.66 (d, J=8.5Hz, 1H), 7.42-7.32 (m, 5H), 7.26 (dd, J=8.7, 2.2Hz, 1H), 7.18 (d, J=7.6Hz, 1H ), 7.13 (s, 1H), 6.92 (d, J = 8.1Hz, 1H), 5.07 (dd, J = 12.8, 5.5Hz, 1H), 4.66 (s, 2H), 4.61 (s, 2H), 4.01 (d, J=13.3Hz, 2H), 3.97-3.87(m, 1H), 3.77-3.51(m, 2H), 3.45-3.34(m, 6H), 3.15-3.08(m, 2H), 3.02-2.93(m, 2H), 2.93-2.84(m, 1H), 2.83-2.75(m, 1H), 2.62-2.53(m, 2H), 2.08-1.96(m, 1H), 1.84-1.70(m, 2H), 1.59-1.44(m, 2H), 0.60-0.50(m, 2H), 0.50-0.40(m, 2H). 13 C NMR (151MHz, DMSO-d6) δ172.81, 170.11, 168.82, 167.61, 166.96, 164.85, 154.69, 142.47, 139.83, 134.42, 134.09, 131.79, 128.37, 127.28, 127.13, 125.05, 121.89, 117.78, 117.61, 115.38, 115.13, 107.91, 66.73, 60.83, 52 .42, 48.75, 46.31, 45.69, 45.59, 30.98, 30.43, 22.19, 9.54.HRMS(ESI)for C 44 H 47 N8O9[M+H] + :calcd 831.3461, found 831.3462. HPLC purity: 97.58%.

[0434] 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)

[0435] Synthesis route:

[0436] The synthesis method is the same as in Example 1.

[0437] 1 H NMR (600MHz, DMSO-d6) δ11.08 (s, 1H), 10.87 (s, 1H), 8.18 (d, J = 8.0Hz, 1H), 7.82 (d, J = 8.2Hz, 2H), 7.70 (d, J = 7.7Hz, 1H), 7.66 (d, J = 8.5Hz, 1 H), 7.38-7.32 (m, 3H), 7.26 (dd, J=8.7, 2.2Hz, 1H), 7.16 (d, J=8.0Hz, 1H), 7.11 (s, 1H), 6.91 (d, J=8.1Hz, 1H), 5.11-5.03 (m, 1H), 4.67 (s, 2H) , 4.61 (s, 2H), 4.02-3.92 (m, 2H), 3.88-3.79 (m, 1H), 3.77-3.68 (m, 1H) , 3.17-3.07(m, 2H), 2.94-2.83(m, 1H), 2.79-2.68(m, 1H), 2.62-2.53( m, 2H), 2.10-1.97 (m, 2H), 1.92-1.83 (m, 2H), 1.84-1.71 (m, 4H), 1.51- 1.38(m, 4H), 1.38-1.29(m, 2H), 0.60-0.48(m, 2H), 0.48-0.38(m, 2H). 13 C NMR (151MHz, DMSO-d6) δ174.19, 172.82, 170.11, 167.61, 166.96, 165.19, 164.8 4, 154.77, 142.48, 141.35, 134.06, 133.58, 131.83, 128.35, 127.54, 127.03, 125 .03, 121.82, 117.77, 117.63, 115.31, 115.14, 107.93, 66.73, 48.75, 47.84, 46. 15, 45.69, 45.30, 43.27, 31.50, 30.98, 30.53, 28.37, 22.19, 9.50.HRMS(ESI)for C 45 H 47 N7NaO9[M+Na] + :calcd 852.3327, found 852.3320.HPLC purity: 98.42%.

[0438] 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)

[0439] Synthesis route:

[0440] The synthesis method is the same as in Example 1.

[0441] 1 H NMR (600MHz, DMSO-d6) δ11.07 (s, 1H), 10.87 (s, 1H), 8.13 (d, J = 7.0Hz, 1H), 7.83 (d, J = 8.2Hz, 2H), 7.66 (d, J = 8.5Hz, 1H), 7.62 (d, J = 7.7Hz, 1H), 7.40-7.32 (m, 3H), 7.26 (dd, J=8.7, 2.2Hz, 1H), 7.16 (d, J=7.9Hz, 1H), 7.12 (s, 1H), 6.92 (d, J=8.1Hz, 1H), 5.07 (dd, J=12.8, 5.5Hz, 1H ), 4.67(s, 2H), 4.61(s, 2H), 4.05-3.96(m, 2H), 3.94-3.84(m, 2H), 3.15-3.08(m, 2H), 2.92-2.84(m, 1H), 2.80-2.69(m, 1H), 2.63-2.53(m, 2H), 2.27-2.20(m, 1H), 2.05-1.98(m, 1H), 1.94-1.85(m, 2H), 1.83-1 .72(m, 4H), 1.60-1.40(m, 6H), 0.58-0.50(m, 2H), 0.49-0.40(m, 2H). 13C NMR (151MHz, DMSO-d6) δ173.86, 172.81, 170.11, 167.61, 166.96, 165.77, 164. 85, 154.75, 142.48, 141.24, 134.07, 133.74, 131.84, 128.35, 127.76, 126.90, 125.04, 121.82, 117.78, 117.61, 115.31, 115.14, 107.91, 66.73, 48.75, 46.27 ,46.22,45.70,45.45,30.98,30.54,28.74,25.29,22.18,9.46.HRMS(ESI)for C 45 H 48 N7O9[M+H] + :calcd 830.3508, found 830.3507. HPLC purity: 97.63%.

[0442] 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)

[0443] Synthesis route:

[0444] The amide condensation method is the same as that in Example 43, and the reductive amination method is the same as the reductive amination operation of the same type in this patent.

[0445] 1H NMR(600MHz,DMSO-d6)δ11.08(s,1H),10.93(s,1H),10.41(s,1H),9.51(s,1H),7.97(d,J=8.1Hz,2H),7.84(d,J=8.6Hz,2H),7.69(d,J=8.5Hz,1H),7.59(d,J=8.3Hz,2H),7.45(d,J=7.6Hz,2H),7.39(d,J=1.8Hz,1H),7.30(dd,J=8.7,2.1Hz,1H),7.18(d,J=8.1Hz,1H),7.14(s,1H),6.95(d,J=8.1Hz,1H),5.07(dd,J=12.8,5.4Hz,1H),4.71(s,2H),4.61(s,2H),4.21-4.15(m,3H),3.37-3.29(m,2H),3.04-2.96(m,2H),2.92-2.85(m,1H),2.83-2.76(m,1H),2.63-2.52(m,2H),2.24-2.17(m,2H),2.06-1.98(m,1H),1.79-1.69(m,2H),0.58-0.52(m,2H),0.50-0.43(m,2H). 13 C NMR(151MHz,DMSO-d6)δ172.81,170.08,167.55,166.93,165.45,164.81,154.51,142.47,142.25,139.74,134.00,133.44,131.76,130.56,128.40,128.05,127.18,127.00,125.02,121.84,120.18,118.24,118.13,115.32,115.18,108.25,66.73,53.83,48.77,46.53,45.62,30.98,26.99,22.16,9.50.HRMS(ESI)for C 45 H 44 N7O8[M+H] + :calcd 810.3246,found 810.3243.HPLC purity:99.59%.

[0446] 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

[0447] The synthesis method is the same as in Example 1.

[0448] Molecular Weight: 824.9

[0449] 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

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

[0451] LRMS (m / z): [M+H]+826.1.

[0452] 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

[0453] The synthesis method is the same as in Example 1.

[0454] Molecular Weight: 810.9

[0455] 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

[0456] The synthesis method is the same as in Example 1.

[0457] Molecular Weight: 811.9

[0458] 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

[0459] The synthesis method is the same as in Example 1.

[0460] Molecular Weight: 810.9

[0461] 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 (LLC05102)

[0462] Synthesis route:

[0463] The synthesis method is the same as in Example 1.

[0464] 1 H NMR (600MHz, DMSO-d6) δ11.08 (s, 1H), 10.87 (s, 1H), 7.74 (d, J = 8.2Hz, 2H), 7.67 (d, J = 8.5Hz, 1H), 7.62 (s, 1H), 7.36-7.30 (m , 3H), 7.26 (dd, J=8.7, 2.2Hz, 1H), 7.18-7.13 (m, 2H), 7.11 (s, 1H), 6.91 (d, J=8.1Hz, 1H), 5.07 (dd, J=12.8, 5.4Hz, 1H), 4.65 ( s, 2H), 4.61 (s, 2H), 4.08-3.98 (m, 2H), 3.91-3.82 (m, 1H), 3.11-3.01 (m, 2H), 2.93-2.84 (m, 1H), 2.77-2.69 (m, 1H), 2.62-2. 52(m, 2H), 2.05-1.99(m, 1H), 1.96-1.90(m, 6H), 1.79-1.68(m, 8H), 1.53-1.41(m, 2H), 0.56-0.48(m, 2H), 0.47-0.39(m, 2H). 13C NMR (151MHz, DMSO-d6) δ175.81, 172.81, 170.11, 167.63, 166.97, 166.22, 164.8 4, 154.75, 142.47, 141.13, 134.51, 134.07, 131.82, 128.35, 127.63, 126.89, 125 .03, 121.80, 117.83, 117.56, 115.29, 115.14, 107.94, 66.72, 64.91, 50.79, 48. 76, 46.53, 45.82, 37.53, 30.98, 30.27, 29.41, 28.41, 22.19, 9.47.HRMS (ESI) for C 47 H 50 N7O9[M+H] + :calcd 856.3665, found 856.3657.HPLC purity: 98.19%.

[0465] Molecular Weight: 855.9

[0466] 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 (LLC05103)

[0467] Synthesis route;

[0468] The synthesis method is the same as in Example 1.

[0469] 1H NMR (600MHz, DMSO-d6) δ11.08 (s, 1H), 10.87 (s, 1H), 8.97 (s, 1H), 7.81 (d, J = 8.3Hz, 2H), 7.67 (d, J = 8.5Hz, 1H), 7.63 (d, J = 8.0Hz, 1H), 7.39-7.32 (m, 3H), 7.26 (dd, J=8.7, 2.2Hz, 1H), 7.16 (d, J=8.0Hz, 1H), 7.12 (s, 1H), 6.91 (d, J=8.1Hz, 1H), 5.07 (dd, J=12.8, 5 .5Hz, 1H), 4.67(s, 2H), 4.61(s, 2H), 4.10-3.99(m, 2H), 3.93-3.84(m, 1H), 3.11-3.05(m, 2H), 2.93-2.84(m, 1H), 2.81-2.71(m, 1H) ), 2.63-2.51(m, 2H), 2.22(s, 6H), 2.05-1.98(m, 1H), 1.80-1.72(m, 2H), 1.53-1.44(m, 2H), 0.57-0.48(m, 2H), 0.47-0.38(m, 2H). 13 C NMR (151MHz, DMSO-d6) δ172.81, 170.11, 167.90, 167.62, 166.97, 166.41, 164.8 4, 154.70, 142.47, 141.76, 134.09, 132.99, 131.79, 128.36, 127.50, 127.05, 125 .05, 121.84, 117.84, 117.60, 115.33, 115.13, 107.97, 66.73, 53.43, 48.76, 48. 60, 46.53, 45.84, 45.70, 45.23, 37.56, 30.99, 30.29, 22.19, 9.48.HRMS (ESI) for C 44 H 44 N7O9[M+H] + :calcd 814.3195, found 814.3202.HPLC purity: 97.69%.

[0470] 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

[0471] The synthesis method is the same as in Example 1.

[0472] Molecular Weight: 910.9

[0473] 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

[0474] The synthesis method is the same as in Example 1.

[0475] Molecular Weight: 938.0

[0476] 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

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

[0478] Molecular Weight: 933.9

[0479] 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

[0480] The synthesis method is the same as Example 88.

[0481] Molecular Weight: 741.8

[0482] 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

[0483] The synthesis method is the same as Example 88.

[0484] Molecular Weight: 729.8

[0485] 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

[0486] The synthesis method is the same as Example 88.

[0487] Molecular Weight: 729.8

[0488] 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

[0489] The synthesis method is the same as Example 88.

[0490] Molecular Weight: 725.8

[0491] 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

[0492] The synthesis method is the same as Example 88.

[0493] Molecular Weight: 725.8

[0494] 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)

[0495] The synthesis method is the same as in Example 1.

[0496] HRMS(m / z):[M+Na]+calcd for C 56 H 61 N7O 13Na+1062.4220, found 1062.4212.

[0497] 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)

[0498] The synthesis method is the same as in Example 1.

[0499] HRMS(m / z):[M+Na]+calcd for C 50 H 51 N7O 11 Na+948.3539, found 948.3529.

[0500] 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)

[0501] The synthesis method is the same as in Example 1.

[0502] HRMS(m / z):[M+Na]+calcd for C 50 H 51 N7O 11 Na+948.3539, found 948.3528.

[0503] 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)

[0504] The synthesis method is the same as in Example 1.

[0505] Molecular Weight: 898.9

[0506] 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)

[0507] The synthesis method is the same as in Example 1.

[0508] Molecular Weight: 921.9

[0509] 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 (LLC0636)

[0510] Synthesis route:

[0511] The synthesis method is the same as in Example 1.

[0512] 1 H NMR (600MHz, DMSO-d6) δ11.06 (s, 1H), 10.87 (s, 1H), 8.60 (t, J=5.6Hz, 1H), 7.83 (d, J=8.3Hz, 2H), 7.58 (d, J=8.4 Hz, 1H), 7.38 (d, J=7.7Hz, 2H), 7.30-7.22 (m, 1H), 7.17 (d, J=8.0Hz, 1H), 7.13 (s, 1H), 7.05 (d, J=2.0Hz, 1H), 6.92 (d, J=8.0Hz, 2H), 5.04 (dd, J=12.8, 5.5Hz, 1H), 4.68 (s, 2H), 4.61 (s, 2H), 3.48-3.43 (m, 2H), 3.41-3.36 (m, 2H), 2 .92-2.83(m, 1H), 2.81-2.69(m, 1H), 2.62-2.51(m, 2H), 2.04-1.96(m, 1H), 0.60-0.49(m, 2H), 0.49-0.37(m, 2H). 13C NMR (151MHz, DMSO-d6) δ172.83, 170.16, 167.67, 167.14, 166.36, 164.85, 154.36, 142.48, 141.66, 134.28, 133.14, 131.81, 128.37, 127.49, 127.14,125.12,121.85,116.25,115.35,115.14,66.74,64.92,54.92,48.64,48.60,41.74,38.28,30.99,22.24,15.17,9.51.HRMS(ESI)for C 35 H 33 N6O8[M+H] + :calcd 665.2354, found 665.2362.HPLC purity: 98.45%.

[0513] 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 (LLC0637)

[0514] The synthetic route is the same as that of Example 124

[0515] The synthesis method is the same as in Example 1.

[0516] 1 H NMR (600MHz, DMSO-d6) δ11.09 (s, 1H), 10.87 (s, 1H), 8.46 (t, J=5.7Hz, 1H), 7.82 (d, J=8.3Hz, 2H), 7.56 (dd, J=8.5, 7 .1Hz, 1H), 7.37 (d, J=7.7Hz, 2H), 7.17 (d, J=8.0Hz, 1H), 7.13-7.08 (m, 2H), 7.01 (d, J=7.0Hz, 1H), 6.92 (d, J=8.1Hz, 1H), 6.62-6.54(m, 1H), 5.04(dd, J=12.9, 5.4Hz, 1H), 4.67(s, 2H), 4.61(s, 2H), 3.36-3.27(m, 4H), 2.92-2.83(m, 1H ), 2.80-2.71(m, 1H), 2.63-2.51(m, 2H), 2.06-1.98(m, 1H), 1.65-1.56(m, 4H), 0.58-0.49(m, 2H), 0.48-0.40(m, 2H).13 C NMR (151MHz, DMSO-d6) δ172.82, 170.10, 168.92, 167.30, 165.94, 164.85 , 146.40, 142.47, 141.41, 136.25, 133.41, 132.21, 131.81, 128.36, 127. 43, 127.08, 121.84, 117.23, 115.34, 115.13, 110.37, 109.02, 66.73, 48. 53, 45.75, 41.55, 38.77, 30.97, 26.54, 26.24, 22.15, 9.49.HRMS(ESI)for C 37 H 37 N6O8[M+H] + :calcd 693.2667, found 693.2670.HPLC purity: 98.64%.

[0517] 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 (LLC0638)

[0518] The synthetic route is the same as that of Example 124

[0519] The synthesis method is the same as in Example 1.

[0520] 1H NMR (600MHz, DMSO-d6) δ11.09 (s, 1H), 10.87 (s, 1H), 8.41 (t, J = 5.6Hz, 1H), 7.81 (d, J = 8.2Hz, 2H), 7.57 (dd, J = 8.4, 7.2Hz, 1H) , 7.36 (d, J = 7.6Hz, 2H), 7.16 (d, J = 8.0Hz, 1H), 7.12 (s, 1H), 7.09 (d, J = 8.6Hz, 1H), 7.01 (d, J = 7.0Hz, 1H), 6.92 (d, J = 8.1Hz, 1H) , 6.54 (t, J=5.8Hz, 1H), 5.05 (dd, J=12.9, 5.4Hz, 1H), 4.67 (s, 2H), 4.61 (s, 2H), 3.31-3.21 (m, 4H), 2.91-2.84 (m, 1H), 2.80-2 .70(m, 1H), 2.62-2.51(m, 2H), 2.06-1.97(m, 1H), 1.63-1.49(m, 4H), 1.42-1.32(m, 4H), 0.58-0.49(m, 2H), 0.49-0.40(m, 2H). 13 C NMR (151MHz, DMSO-d6) δ172.81, 170.11, 168.95, 167.30, 165.87, 164.84, 146.42, 142.47, 141.36, 136.28, 133.49, 132.20, 131.81, 128.35, 127.42, 127.06, 121.84, 117.18, 115.34, 115.13, 110.36, 109.01, 66.73, 54.91, 48 .53, 41.79, 30.97, 29.08, 28.65, 26.21, 26.08, 22.15, 9.51.HRMS(ESI)for C 39 H 41 N6O8[M+H] + :calcd 721.2980, found 721.2986.HPLC purity: 98.22%.

[0521] 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 (LLC0639)

[0522] The synthetic route is the same as that of Example 124

[0523] The synthesis method is the same as in Example 1.

[0524] 1 H NMR (600MHz, DMSO-d6) δ11.09 (s, 1H), 10.87 (s, 1H), 8.40 (t, J=5.6Hz, 1H), 7.81 (d, J=8.2Hz, 2H), 7.57 (dd, J=8.5, 7.2Hz, 1H) , 7.36 (d, J=7.6Hz, 2H), 7.16 (d, J=8.0Hz, 1H), 7.12 (s, 1H), 7.08 (d, J=8.6Hz, 1H), 7.01 (d, J=7.0Hz, 1H), 6.91 (d, J=8.1Hz, 1H) , 6.52 (t, J=5.8Hz, 1H), 5.05 (dd, J=12.9, 5.4Hz, 1H), 4.67 (s, 2H), 4.61 (s, 2H), 3.30-3.21 (m, 4H), 2.92-2.84 (m, 1H), 2.80-2 .69(m, 1H), 2.63-2.52(m, 2H), 2.06-1.98(m, 1H), 1.61-1.46(m, 4H), 1.39-1.26(m, 8H), 0.58-0.49(m, 2H), 0.48-0.39(m, 2H). 13 C NMR (151MHz, DMSO-d6) δ172.81, 170.11, 168.95, 167.31, 165.84, 164.84, 14 6.43, 142.47, 141.35, 136.28, 133.50, 132.19, 131.81, 128.35, 127.41, 127 .06, 121.84, 117.18, 115.34, 115.13, 110.36, 109.00, 66.73, 54.92, 48.53, 41.83, 30.98, 29.10, 28.73, 28.67, 26.43, 26.29, 22.15, 9.50.HRMS(ESI)for C 41 H 45 N6O8[M+H] + :calcd 749.3293, found 749.3297.HPLC purity: 98.83%.

[0525] 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 (LLC0640)

[0526] The synthetic route is the same as that of Example 124

[0527] The synthesis method is the same as in Example 1.

[0528] 1 H NMR (600MHz, DMSO-d6) δ11.09 (s, 1H), 10.87 (s, 1H), 8.40 (t, J=5.6Hz, 1H), 7.81 (d, J=8.3Hz, 2H), 7.57 (dd, J=8.4, 7.2Hz, 1H) , 7.36 (d, J=7.6Hz, 2H), 7.16 (d, J=7.9Hz, 1H), 7.12 (s, 1H), 7.08 (d, J=8.6Hz, 1H), 7.01 (d, J=7.0Hz, 1H), 6.94-6.88 (m, 1H), 6 .51 (t, J=5.9Hz, 1H), 5.05 (dd, J=12.9, 5.4Hz, 1H), 4.67 (s, 2H), 4.61 (s, 2H), 3.30-3.21 (m, 4H), 2.92-2.84 (m, 1H), 2.80-2.7 1(m, 1H), 2.62-2.51(m, 2H), 2.06-1.99(m, 1H), 1.60-1.47(m, 4H), 1.37-1.21(m, 12H), 0.58-0.49(m, 2H), 0.49-0.40(m, 2H). 13 C NMR (151MHz, DMSO) δ172.81, 170.10, 168.95, 167.31, 165.84, 164.84, 146.43, 142.48, 141.35, 136.27, 133.50, 132.19, 131.81, 128.36, 127.41, 127.06, 121. 84, 117.18, 115.34, 115.13, 110.36, 109.00, 66.73, 54.91, 48.54, 41.83, 30.9 8, 29.12, 28.95, 28.76, 28.74, 28.67, 26.48, 26.31, 22.15, 9.51.HRMS (ESI) for C 43 H 49 N6O8[M+H] + :calcd 777.3606, found 777.3604.HPLC purity: 98.47%.

[0529] Example 129: Compound LLC0635

[0530] The synthesis method is the same as in Example 1.

[0531] 1 H NMR (600MHz, DMSO-d6) δ11.07 (s, 1H), 10.88 (s, 1H), 10.41 (s, 1H), 7.96 (d, J = 8.3Hz, 2H), 7.85 (s, 4H), 7.73 (s, 1H), 7.66 (d, J = 8.6Hz , 1H), 7.46 (d, J=7.7Hz, 2H), 7.37 (d, J=2.0Hz, 1H), 7.27 (dd, J=8.7, 2.2Hz, 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, 5.5Hz, 1H), 4.72 (s, 2H), 4.62 (s, 2H), 3.81-3.73 (m, 2H), 3.32-3.28 (m, 2H), 2.92-2.84 (m, 1H), 2.84-2.74 (m , 1H), 2.62-2.51(m, 2H), 2.46-2.40(m, 2H), 2.05-1.98(m, 1H), 1.66-1.58(m, 2H), 1.42(s, 3H), 0.59-0.51(m, 2H), 0.51-0.43(m, 2H). 13 C NMR (151MHz, DMSO-d6) δ172.82, 170.12, 167.66, 166.99, 166.40, 165.54, 164.85 ,154.89,142.49,142.34,141.63,134.02,133.42,131.79,130.61,128.39,128.1 5, 128.07, 127.21, 124.98, 121.87, 119.20, 117.50, 117.44, 115.36, 115.16, 107 .77, 66.74, 51.39, 48.74, 43.62, 34.51, 30.99, 25.81, 22.20, 9.49.HRMS (ESI) for C 46 H 44 N7O9[M+H] + :calcd 838.3195, found 838.3197. HPLC purity: 96.69%.

[0532] Example 130: Compound LLC0889

[0533] The synthetic route is the same as that of Example 124

[0534] The synthesis method is the same as in Example 1.

[0535] 1 H NMR (600MHz, DMSO-d6) δ11.08 (s, 1H), 10.86 (s, 1H), 8.26 (d, J = 7.8Hz, 1H), 7.83 (d, J = 8.3Hz, 2H), 7.68 (d, J = 8.5Hz, 1H ), 7.40-7.33 (m, 3H), 7.29 (dd, J=8.7, 2.3Hz, 1H), 7.15 (d, J=7.9Hz, 1H), 7.11 (s, 1H), 6.91 (d, J=8.1Hz, 1H), 5.07 (dd, J=12.8, 5.4Hz, 1H), 4.67 (s, 2H), 4.61 (s, 2H), 4.16-4.05 (m, 3H), 3.17-3.11 (m, 2H), 2.93-2.84 (m, 1H), 2.78-2.69 (m, 2H), 2.62-2.52(m, 2H), 2.06-1.98(m, 1H), 1.93-1.84(m, 2H), 1.67-1.56(m, 2H), 0.58-0.49(m, 2H), 0.48-0.39(m, 2H). 13 C NMR (151MHz, DMSO-d6) δ172.82, 170.12, 167.63, 166.97, 165.38, 164.84, 154.75, 142.47, 141.51, 134.09, 133.36, 131.82, 128.35, 127.5 8, 127.07, 125.06, 121.82, 117.84, 117.62, 115.31, 115.13, 107.98, 66.72, 64.92, 48.76, 46.52, 45.76, 30.99, 30.41, 22.19, 15.17, 9.53.

[0536] Example 131: Compound LLC0669

[0537] Synthesis route:

[0538] The synthesis method is the same as in Example 1.

[0539] 1H NMR (600MHz, DMSO-d6) δ11.07 (s, 1H), 10.88 (s, 1H), 10.45 (s, 1H), 7.95 (d, J = 8.2Hz, 2H), 7.88 (d, J = 8.7Hz, 2H), 7.70-7.64 (m, 3H), 7.46 (d, J = 7.6Hz, 2H), 7.19 (d, J = 7.9Hz, 1H), 7.15 (s, 1H), 6.93 (d, J = 8.1Hz, 1H), 6.81 (d, J = 1.7Hz, 1H), 6.68 (dd, J =8.4, 1.9Hz, 1H), 5.06 (dd, J = 12.8, 5.4Hz, 1H), 4.72 (s, 2H), 4.62 (s, 2H), 4.60-4.54 (m, 2H), 4.32-4.26 (m, 2H), 4.26-4.17 (m, 4H), 2.92-2.84 (m, 1H), 2.83-2.75 (m, 1H), 2.62-2.52 (m, 2H), 2.05-1.97 (m, 1H), 0.62-0.52 (m, 2H), 0.51-0.40 (m, 2H). 13 C NMR (151MHz, DMSO-d6) δ172.81, 170.10, 168.47, 167.45, 167.16, 165.67, 164.85, 154.86, 142.48, 142.38, 141.71, 133.78, 133. 43,131.79,129.65,128.62,128.39,128.08,127.79,127.23,124.84,121.87,119.47,117.26,115.36,115.16,114.62,104.79, 66.74, 61.33, 48.73, 33.41, 30.98, 22.20, 9.53.

[0540] Example 132: Compound LLC0670

[0541] The synthetic route is the same as that of Example 131;

[0542] The synthesis method is the same as in Example 1.

[0543] 1H NMR (600MHz, DMSO-d6) δ11.07 (s, 1H), 10.88 (s, 1H), 10.40 (s, 1H), 7.95 (d, J = 8.1Hz, 2H), 7.84 (d, J = 8.6Hz, 2H), 7.66 (d, J = 8.4Hz, 1H), 7. 55 (d, J=8.6Hz, 2H), 7.46 (d, J=7.5Hz, 2H), 7.19 (d, J=7.9Hz, 1H), 7.15 (s, 1H), 6.95-6.91 (m, 2H), 6.83 (dd, J=8.5, 1.8Hz, 1H), 5.06 (dd, J =12.7, 5.4Hz, 1H), 4.72(s, 2H), 4.62(s, 2H), 3.87-3.75(m, 2H), 3.75-3.67(m, 1H), 3.67-3.57(m, 1H), 3.54-3.41(m, 3H), 3.38-3.34(m, 1 H), 3.16-3.04(m, 2H), 2.93-2.84(m, 1H), 2.84-2.74(m, 1H), 2.62-2.51(m, 2H), 2.05-1.97(m, 1H), 0.61-0.52(m, 2H), 0.51-0.42(m, 2H). 13 C NMR (151MHz, DMSO-d6) δ172.82, 170.13, 168.18, 167.68, 167.25, 165.59, 164.85, 1 51.93, 142.48, 142.31, 140.65, 133.92, 133.49, 131.79, 131.59, 128.38, 128.09, 1 28.05, 127.22, 124.92, 121.87, 119.39, 116.00, 115.70, 115.35, 115.15, 105.93, 6 6.74, 52.64, 52.05, 51.39, 50.14, 48.71, 42.09, 30.99, 22.25, 9.53.HRMS(ESI)for C 46 H 42 N7O9[M+H] + :calcd 836.3039, found 836.3031.HPLC purity: 98.88%.

[0544] Example 133: Compound LLC0674

[0545] The synthetic route is the same as that of Example 131;

[0546] The synthesis method is the same as in Example 1.

[0547] 1 H NMR (600MHz, DMSO-d6) δ11.07 (s, 1H), 10.89 (s, 1H), 10.42 (s, 1H), 8.22 (d, J = 7.8Hz, 1H), 7.95 (d, J = 8.2Hz, 2H), 7.87-7.78 (m, 4H), 7.66 (d, J = 8 .6Hz, 1H), 7.45 (d, J=7.7Hz, 2H), 7.19 (d, J=7.9Hz, 1H), 7.16-7.12 (m, 2H), 7.06 (dd, J=8.7, 2.2Hz, 1H), 6.93 (d, J=8.1Hz, 1H), 5.06 (dd, J=12.8 , 5.4Hz, 1H), 4.71(s, 2H), 4.61(s, 2H), 3.97-3.89(m, 1H), 3.81-3.74(m , 1H), 3.71-3.65(m, 1H), 3.64-3.53(m, 2H), 2.93-2.85(m, 1H), 2.83-2. 74(m,1H),2.63-2.52(m,2H),2.14-2.06(m,1H),2.05-1.93(m,2H),1.8 9-1.75(m, 3H), 1.61-1.49(m, 1H), 0.59-0.52(m, 2H), 0.50-0.41(m, 2H). 13 C NMR (151MHz, DMSO-d6) δ172.84, 170.18, 167.76, 167.08, 165.55, 164.85, 164.65, 153.41, 142.49, 142.34, 141.70, 134.31, 133 .40, 131.78, 129.49, 128.39, 128.06, 127.94, 127.20, 125.22, 121.87, 119.27, 115.73, 115.36, 115.16, 114.99, 105.24, 66.74, 64.92, 49.39, 49.24, 48.70, 45.63, 45.57, 33.07, 32.36, 31.00, 23.52, 22.23, 15.18, 9.55.

[0548] Example 134: Compound LLC0678

[0549] Synthesis route:

[0550] The synthesis method is the same as in Example 1.

[0551] 1H NMR (600MHz, DMSO-d6) δ11.07 (s, 1H), 10.88 (s, 1H), 8.28 (d, J=7.7Hz, 1H), 7.83 ( d, J=8.2Hz, 2H), 7.66 (d, J=8.5Hz, 1H), 7.38 (d, J=7.6Hz, 2H), 7.33 (d, J=2.0Hz, 1 H), 7.25 (dd, J=8.7, 2.2Hz, 1H), 7.16 (d, J=8.0Hz, 1H), 7.12 (s, 1H), 6.92 (d, J=8. 1Hz, 1H), 5.07 (dd, J=12.8, 5.4Hz, 1H), 4.67 (s, 2H), 4.61 (s, 2H), 4.40-4.31 (m, 1 H), 4.12-4.00(m, 4H), 3.22-3.15(m, 1H), 3.13-3.06(m, 2H), 3.05-2.98(m, 1H), 2 .92-2.84(m, 1H), 2.78-2.67(m, 2H), 2.62-2.52(m, 2H), 2.04-1.95(m, 1H), 1.94- 1.86 (m, 1H), 1.85-1.77 (m, 1H), 1.71 (d, J = 11.1Hz, 2H), 1.62 (dq, J = 24.9, 11.7Hz , 2H), 1.52-1.43(m, 1H), 1.42-1.33(m, 1H), 0.57-0.49(m, 2H), 0.48-0.41(m, 2H). 13 C NMR (151MHz, DMSO-d6) δ172.83, 172.10, 170.11, 167.61, 166.97, 165.40, 164.85, 154 .84, 142.48, 141.54, 134.06, 133.36, 131.82, 128.36, 127.60, 127.08, 125.03, 121.8 3, 117.63, 117.59, 115.32, 115.15, 107.83, 66.73, 64.92, 48.74, 46.73, 46.60, 45.65, 43.83, 36.82, 32.45, 31.26, 30.98, 28.58, 27.59, 27.49, 22.19, 22.10, 15.18, 9.53.

[0552] Example 135: Compound LLC0679

[0553] The synthetic route is the same as that of Example 134;

[0554] The synthesis method is the same as in Example 1:

[0555] 1 H NMR (600MHz, DMSO-d6) δ11.07 (s, 1H), 10.89 (s, 1H), 9.03 (d, J = 6.8Hz, 1H), 7.87 (d, J = 8.3Hz, 2H), 7.66 (d, J = 8.5Hz, 1H), 7.40 (d, J = 7.6Hz, 2H), 7.33 (d, J=2.0Hz, 1H), 7.24 (dd, J=8.7, 2.2Hz, 1H), 7.17 (d, J=7.9Hz, 1H), 7.13 (s, 1H), 6.93 (d, J=8.1Hz, 1H), 5.06 (dd, J=12.8, 5.5Hz, 1H), 4.7 4-4.65(m, 3H), 4.61(s, 2H), 4.56-4.50(m, 1H), 4.19-4.11(m, 2H), 4.10 -4.03 (m, 2H), 3.88 (dd, J=9.8, 5.4Hz, 1H), 3.07-3.02 (m, 2H), 2.92-2.8 3(m, 1H), 2.80-2.72(m, 1H), 2.63-2.51(m, 3H), 2.04-1.97(m, 1H), 1.76 -1.68(m, 2H), 1.62-1.51(m, 2H), 0.60-0.50(m, 2H), 0.49-0.38(m, 2H). 13 C NMR (151MHz, DMSO-d6) δ173.65, 172.82, 170.10, 167.61, 166.96, 166.00, 164 .84, 154.76, 142.48, 141.98, 134.07, 132.60, 131.80, 128.38, 127.64, 127.1 6, 125.04, 121.84, 118.32, 117.64, 117.60, 116.33, 115.33, 115.15, 107.85, 66.74, 56.95, 54.18, 48.73, 46.69, 36.61, 30.98, 26.70, 26.65, 22.19, 9.52.

[0556] Example 135: Compound LLC0681

[0557] Synthesis route:

[0558] The synthesis operation method is similar to the same type of reaction operation in this patent.

[0559] 1H NMR (600MHz, DMSO-d6) δ11.07 (s, 1H), 10.87 (s, 1H), 8.89 (s, 1H), 7.81 (d, J = 8.2Hz, 2H), 7.65 (d, J = 8.5Hz, 1H), 7.40-7.33 (m , 2H), 7.31 (d, J=1.9Hz, 1H), 7.23 (dd, J=8.7, 2.1Hz, 1H), 7.16 (d, J=7.7Hz, 1H), 7.12 (s, 1H), 6.92 (d, J=8.1Hz, 1H), 5.06 (dd, J=12.8, 5.5Hz, 1H), 4.67 (s, 2H), 4.61 (s, 2H), 3.97-3.88 (m, 2H), 3.14-3.05 (m, 2H), 2.93-2.83 (m, 1H), 2.82-2.73 (m, 2H), 2. 62-2.52(m, 2H), 2.06(s, 6H), 2.04-1.96(m, 1H), 1.90-1.82(m, 2H), 1.36-1.27(m, 2H), 0.59-0.49(m, 2H), 0.49-0.38(m, 2H). 13 C NMR (151MHz, DMSO-d6) δ172.82, 170.12, 167.64, 166.97, 166.26, 164.85, 154.84, 142.48, 134.07, 133.24, 131.80, 129.65, 128.36, 127.50, 1 27.02, 125.01, 121.85, 117.53, 117.32, 115.34, 115.14, 107.66, 66.73 , 54.14, 51.63, 51.40, 48.73, 45.91, 44.20, 32.08, 30.98, 22.19, 9.51.

[0560] Example 136: Compound LLC0686

[0561] The synthetic route is the same as that of Example 134;

[0562] The synthesis method is the same as in Example 1:

[0563] 1H NMR (600MHz, DMSO-d6) δ11.07 (s, 1H), 10.88 (s, 1H), 8.55 (dd, J=32.8, 6.5Hz, 1H), 7.84 (dd, J=8.3, 2.4Hz, 2H), 7.66 (dd, J=8.5, 5.1Hz, 1H), 7.4 4-7.35(m, 2H), 7.33(dd, J=6.9, 2.1Hz, 1H), 7.28-7.21(m, 1H), 7.16(d, J=8.0Hz, 1H), 7.12 (s, 1H), 6.96-6.89 (m, 1H), 5.10-5.02 (m, 1H), 4.68 ( s, 2H), 4.61 (s, 2H), 4.56-4.40 (m, 1H), 4.14-4.03 (m, 2H), 3.92-3.69 (m , 1H), 3.67-3.56(m, 1H), 3.53-3.46(m, 1H), 3.07-3.02(m, 2H), 2.93-2. 84(m,1H),2.82-2.71(m,2H),2.62-2.52(m,2H),2.24-1.89(m,3H),1.8 2-1.68(m, 2H), 1.67-1.54(m, 2H), 0.59-0.50(m, 2H), 0.49-0.38(m, 2H). 13 C NMR (151MHz, DMSO-d6) δ172.21, 171.65, 171.60, 169.49, 166.99, 166.34, 165.80, 165.75, 164.23, 157.33 , 157.12, 154.21, 154.17, 141.87, 133.45, 132.48, 132.44, 131.19, 127.75, 127.11, 126.43, 124.41, 121. 21,117.67,117.02,116.97,116.91,115.68,114.70,114.54,107.21,66.12,64.30,54.30,50.34,49.78,49.20,48.12,47.55,46.19,46.15,43.62,43.20,30.71,30.36,28.67,26.35,26.31,21.57,14.55,8.86.

[0564] Example 137: Compound LLC0687

[0565] The synthetic route is the same as that of Example 134;

[0566] The synthesis method is the same as in Example 1:

[0567] 1H NMR (600MHz, DMSO-d6) δ11.08 (s, 1H), 10.88 (s, 1H), 8.97 (s, 1H), 8.46 (s, 1H), 7.81 (d, J = 8.3Hz, 2H), 7.66 (d, J = 8.5Hz, 1H), 7.36 (d, J =7.7Hz, 2H), 7.33 (d, J = 2.0Hz, 1H), 7.24 (dd, J = 8.7, 2.2Hz, 1H), 7.16 (d, J = 7.9Hz, 1H), 7.12 (s, 1H), 6.92 (d, J = 8.1Hz, 1H), 5.07 (dd, J =12.8, 5.4Hz, 1H), 4.67(s, 2H), 4.61(s, 2H), 4.08-4.02(m, 2H), 3.02-2.94(m, 2H), 2.92-2.84(m, 1H), 2.81-2.71(m, 1H), 2.62-2.52( m, 2H), 2.42-2.34 (m, 1H), 2.27 (s, 6H), 2.05-1.98 (m, 1H), 1.81-1.72 (m, 2H), 1.63-1.53 ​​(m, 2H), 0.59-0.49 (m, 2H), 0.48-0.38 (m, 2H). 13 C NMR (151MHz, DMSO-d6) δ174.33, 172.83, 170.11, 167.62, 166.98, 166.32, 164.8 6, 154.87, 142.48, 141.71, 134.04, 133.05, 131.80, 128.38, 127.52, 127.05, 125 .01, 121.86, 117.75, 117.66, 115.35, 115.15, 107.92, 66.74, 64.93, 54.92, 54.58, 48.75, 48.60, 46.87, 45.05, 44.72, 41.54, 30.99, 27.42, 22.20, 15.18, 9.52.

[0568] Example 138: Compound LLC0688

[0569] Synthesis route:

[0570] The synthesis operation method is similar to the same type of reaction operation in this patent.

[0571] 1H NMR (600MHz, DMSO-d6) δ11.07 (s, 1H), 10.87 (s, 1H), 8.23 ​​(d, J = 7.8Hz, 1H), 7.82 (d, J = 8.2Hz, 2H), 7.66 (d, J = 8.6Hz, 1H), 7.36 (d, J = 7.5Hz, 2H), 7.3 4(d, J=2.0Hz, 1H), 7.26 (dd, J=8.7, 2.2Hz, 1H), 7.16 (d, J=7.8Hz, 1H), 7.1 1 (s, 1H), 6.91 (d, J = 8.1Hz, 1H), 6.27 (d, J = 7.6Hz, 1H), 5.06 (dd, J = 12.8, 5 .5Hz, 1H), 4.67 (s, 2H), 4.61 (s, 2H), 4.04 (d, J=13.2Hz, 2H), 3.96 (d, J=1 3.6Hz, 3H), 3.81-3.71(m, 1H), 3.11-3.02(m, 2H), 2.92-2.83(m, 1H), 2.79 -2.69(m, 3H), 2.63-2.51(m, 2H), 2.06-1.96(m, 1H), 1.87-1.77(m, 2H), 1. 76-1.68(m, 2H), 1.52-1.33(m, 4H), 0.59-0.49(m, 2H), 0.49-0.38(m, 2H). 13 C NMR (151MHz, DMSO-d6) δ172.83, 170.13, 167.65, 166.99, 165.33, 164.86, 15 6.66, 154.76, 142.49, 141.48, 134.11, 133.42, 131.83, 128.36, 127.59, 127. 07, 125.07, 121.83, 117.77, 117.48, 115.32, 115.16, 107.89, 66.74, 64.93, 48.77, 47.50, 46.79, 46.70, 42.78, 31.34, 31.10, 31.00, 22.20, 15.18, 9.51.

[0572] Example 139: Compound LLC0689

[0573] The synthetic route is the same as that of Example 138.

[0574] 1HNMR (600MHz, DMSO-d6) δ11.07 (s, 1H), 10.87 (s, 1H), 8.93 (d, J = 6.9Hz, 1H), 7.86 (d, J = 8.3Hz, 2H), 7.66 (d, J = 8.6Hz, 1H), 7.38 (d, J = 7.7Hz, 2H), 7.33 (d, J=2.0Hz, 1H), 7.25 (dd, J=8.7, 2.2Hz, 1H), 7.17 (d, J=7.8Hz, 1H), 7.12 (s, 1H), 6.92 (d, J=8.1Hz, 1H), 6.21 (d, J=8.0Hz, 1H), 5.06 (dd, J= 12.8, 5.5Hz, 1H), 4.68 (s, 2H), 4.65-4.59 (m, 3H), 4.10-3.99 (m, 4H), 3. 79(dd, J=8.4, 5.7Hz, 2H), 3.75-3.68(m, 1H), 3.12-3.03(m, 2H), 2.93-2. 83(m, 1H), 2.82-2.70(m, 1H), 2.63-2.51(m, 2H), 2.06-1.96(m, 1H), 1.8 4-1.73(m, 2H), 1.49-1.39(m, 2H), 0.60-0.49(m, 2H), 0.49-0.38(m, 2H). 13 C NMR (151MHz, DMSO-d6) δ172.83, 170.13, 167.64, 166.97, 165.84, 164.86 ,158.89,154.72,142.49,141.88,134.10,132.64,131.81,128.37,127.6 3, 127.12, 125.07, 121.85, 117.77, 117.51, 115.34, 115.15, 107.90, 66. 74, 64.93, 55.94, 48.77, 46.80, 46.61, 31.13, 30.99, 22.20, 15.18, 9.52.

[0575] Example 140: Compound LLC0708

[0576] The synthetic route is the same as that of Example 131;

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

[0578] 1H NMR (600MHz, DMSO-d6) δ 11.08 (s, 1H), 10.88 (s, 1H), 10.44 (s, 1H), 8.31 (d, J = 7.2Hz, 1H), 7.96 (d, J = 8.2Hz, 2H), 7.91-7.83 (m, 4H), 7.68 (d, J = 8. 5Hz, 1H), 7.46 (d, J=7.5Hz, 2H), 7.37 (d, J=2.1Hz, 1H), 7.32-7.27 (m, 1H) , 7.19 (d, J=7.9Hz, 1H), 7.15 (s, 1H), 6.93 (d, J=8.1Hz, 1H), 5.07 (dd, J=1 2.8, 5.4Hz, 1H), 4.72 (s, 2H), 4.62 (s, 2H), 4.14-4.07 (m, 1H), 4.06-3.99 (m, 1H), 3.96-3.87 (m, 1H), 3.09-2.97 (m, 2H), 2.93-2.84 (m, 1H), 2.84-2 .76(m, 1H), 2.62-2.51(m, 2H), 2.05-1.94(m, 2H), 1.89-1.83(m, 1H), 1.7 7-1.69(m, 1H), 1.63-1.54(m, 1H), 0.60-0.52(m, 2H), 0.51-0.43(m, 2H). 13 C NMR (151MHz, DMSO-d6) δ174.08, 173.27, 172.82, 170.11, 167.57, 166.93, 165.7 0, 165.60, 164.86, 154.58, 142.49, 141.90, 134.14, 133.41, 131.79, 129.14, 12 8.39, 128.14, 128.07, 127.22, 125.14, 121.87, 119.25, 117.61, 115.36, 115.16 ,107.82,91.00,83.35,66.74,52.33,28.29,26.22,23.28,9.51.HRMS(ESI)for C 45 H 42 N7O9[M+H] + :calcd 824.3039, found 824.3020.HPLC purity: 96.45%.

[0579] Example 141: Compound LLC0791

[0580] Synthesis route:

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

[0582] 1 H NMR (600MHz, DMSO-d6) δ11.08 (s, 1H), 10.88 (s, 1H), 10.56 (s, 1H), 8.17-8.08 (m, 1H), 7.95 (d, J=8.2Hz, 2H), 7.85-7.79 (m, 1H), 7.67 (d, J =8.6Hz, 1H), 7.63-7.58 (m, 2H), 7.47 (d, J = 7.7Hz, 2H), 7.36 (d, J = 2.0Hz, 1H), 7.28 (dd, J = 8.7, 2.2Hz, 1H), 7.19 (d, J = 7.9Hz, 1H), 7.14 (s, 1H), 6.93 (d, J=8.1Hz, 1H), 5.07 (dd, J=12.8, 5.4Hz, 1H), 4.72 (s, 2H), 4.61 (s, 2H), 4.13-4.01 (m, 3H), 3.20-3.13 (m, 2H), 2.93-2.84 (m, 1 H), 2.83-2.76(m, 1H), 2.63-2.51(m, 2H), 2.05-1.98(m, 1H), 1.95-1.86(m, 2H), 1.65-1.53(m, 2H), 0.60-0.51(m, 2H), 0.51-0.42(m, 2H). 13 C NMR (151MHz, DMSO-d6) δ172.84, 170.13, 167.64, 166.99, 165.81, 164.87, 162.77, 160.06, 158.42, 1 54.79, 142.67, 142.64, 142.60, 142.50, 134.09, 133.07, 131.79, 130.49, 130.46, 128.40, 128.12, 1 27.28, 125.06, 121.89, 118.86, 118.77, 117.84, 117.68, 115.44, 115.42, 115.37, 115.17, 107.98, 106.99, 106.81, 66.75, 64.93, 54.92, 48.77, 48.61, 46.46, 46.30, 31.00, 30.34, 22.21, 15.18, 9.51.

[0583] Example 142: Compound LLC0793

[0584] The synthetic route is the same as that of Example 141;

[0585] The synthesis method is the same as that of Example 1

[0586] 1 H NMR (600MHz, DMSO-d6) δ11.08 (s, 1H), 10.88 (s, 1H), 10.23 (s, 1H), 8.34 (d, J = 7.7Hz, 1H), 7.97 (d, J = 8.2Hz, 2H), 7.80-7.71 (m, 3H) , 7.69 (d, J=8.5Hz, 1H), 7.46 (d, J=7.6Hz, 2H), 7.38 (d, J=2.0Hz, 1H), 7.30 (dd, J=8.7, 2.2Hz, 1H), 7.19 (d, J=7.9Hz, 1H), 7.15 (s, 1H ), 6.93 (d, J=8.1Hz, 1H), 5.12-5.03 (m, 1H), 4.72 (s, 2H), 4.61 (s, 2H), 4.17-4.06 (m, 3H), 3.20-3.11 (m, 2H), 2.95-2.85 (m, 1H), 2. 84-2.76 (m, 1H), 2.63-2.52 (m, 2H), 2.07-1.98 (m, 1H), 1.96-1.83 (m, 2H), 1.69-1.53 ​​(m, 2H), 0.62-0.51 (m, 2H), 0.51-0.40 (m, 2H). 13 C NMR (151MHz, DMSO-d6) δ172.84, 170.14, 167.64, 166.99, 165.27, 164.87, 163.93, 155.49, 154.75, 153.85, 142.62, 142.50, 134.11, 132.56, 132.52, 132.46, 131.79, 128.63, 128.55 , 128.40, 128.21, 127.29, 125.79, 125.09, 123.44, 123.42, 121.89, 117.88, 117.67, 115.38, 115.16, 114.77, 114.63, 108.02, 66.75, 48.79, 46.72, 46.51, 31.00, 30.35, 22.21, 9.57.

[0587] Example 143: Compound LLC0789

[0588] Synthesis route:

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

[0590] 1H NMR (600MHz, DMSO-d6) δ11.12 (s, 1H), 10.88 (s, 1H), 10.44 (s, 1H), 9.50 (s, 1H), 7.96 (d, J = 8.2Hz, 2H), 7.88 (d, J = 8.7Hz, 2H), 7.81 (d, J=8.7Hz, 2H), 7.75 (d, J=11.3Hz, 1H), 7.53 (d, J=7.3Hz, 1H), 7.46 (d, J=7.5Hz, 2H), 7.19 (d, J=8.0Hz, 1H), 7.15 (s, 1H) , 6.93 (d, J=8.1Hz, 1H), 5.12 (dd, J=12.9, 5.4Hz, 2H), 4.72 (s, 2H), 4.62 (s, 2H), 3.40-3.37 (m, 4H), 3.10-3.04 (m, 4H), 2.97-2 .93(m, 1H), 2.93-2.85(m, 1H), 2.84-2.77(m, 1H), 2.64-2.52(m, 2H), 2.10-2.00(m, 1H), 0.62-0.52(m, 2H), 0.51-0.42(m, 2H). 13 C NMR (151MHz, DMSO-d6) δ172.81, 169.94, 169.92, 166.68, 166.23, 165.64, 164.89, 163.9 1, 158.25, 156.58, 145.14, 145.08, 142.51, 142.41, 141.96, 133.41, 131.82, 128.76, 128 .70, 128.41, 128.10, 128.06, 127.24, 123.71, 123.64, 121.90, 119.40, 115.38, 115.19, 114.14, 114.11, 112.11, 111.94, 66.76, 53.49, 49.43, 49.40, 49.11, 30.98, 22.10, 9.54.

[0591] Example 144: Compound LLC0802

[0592] The synthetic route and method are the same as in Example 143 and Example 1.

[0593] 1H NMR (600MHz, DMSO-d6) δ 11.08 (s, 1H), 10.88 (s, 1H), 10.45 (s, 1H), 7.95 (d, J = 8.2Hz, 2H), 7.88 (d, J = 8.8Hz, 2H), 7.6 6 (d, J=8.7Hz, 2H), 7.62 (d, J=11.1Hz, 1H), 7.46 (d, J=7.6Hz, 2H), 7.19 (d, J=7.9Hz, 1H), 7.15 (s, 1H), 6.96-6.90 (m, 2H), 5.07 (dd, J=12.9, 5.4Hz, 1H), 4.72 (s, 2H), 4.62 (s, 2H), 4.60-4.51 (m, 2H), 4.41-4.32 (m, 4H), 4.31-4.21 (m, 2H) ), 2.92-2.84(m, 1H), 2.83-2.73(m, 1H), 2.63-2.53(m, 2H), 2.06-1.98(m, 1H), 0.62-0.52(m, 2H), 0.51-0.42(m, 2H). 13 C NMR (151MHz, DMSO-d6) δ172.77, 169.99, 168.44, 166.79, 166.40, 166.38, 165.67, 164.86, 154 .67, 153.03, 143.82, 143.74, 142.49, 142.38, 141.70, 133.43, 131.79, 129.28, 128.61, 128.3 9, 128.08, 128.03, 127.80, 127.23, 121.87, 119.47, 118.92, 118.86, 115.36, 115.16, 111.39, 111.24, 108.33, 108.29, 66.74, 64.92, 63.12, 62.64, 58.45, 48.95, 34.02, 34.01, 30.96, 9.56.

[0594] Example 145: Compound LLC0821

[0595] Synthesis route:

[0596] The synthesis method is the same as in Example 1:

[0597] 1H NMR (600MHz, DMSO-d6) δ 11.08 (s, 1H), 10.88 (s, 1H), 10.45 (s, 1H), 7.95 (d, J = 8.2Hz, 2H), 7.88 (d, J = 8.7Hz, 2H), 7.71-7.65 (m, 3H), 7.46 (d, J=7.6Hz, 2H), 7.36 (s, 1H), 7.30-7.25 (m, 1H), 7.19 (d, J=7.9Hz, 1H), 7.15 (s, 1H), 6.93 (d, J=8.1Hz, 1H), 5.07 (dd, J=12.8, 5.4Hz, 1H) , 4.72(s, 2H), 4.62(s, 2H), 4.43-4.33(m, 1H), 4.28-4.19(m, 1H), 4.15-4.07(m, 1H), 3.97-3.88(m, 1H), 3.54-3.41(m, 4H), 3.35-3.29(m, 4H), 3.25-3.18(m, 1H), 2.93-2.84(m, 1H), 2.83-2.75(m, 1H), 2.63-2 .50(m, 2H), 2.05-1.97(m, 1H), 0.61-0.51(m, 2H), 0.51-0.41(m, 2H). 13 C NMR (151MHz, DMSO-d6) δ172.81, 170.08, 168.59, 167.55, 166.99, 165.68, 164.86, 155.22, 142. 49, 142.38, 141.67, 133.84, 133.45, 131.79, 128.66, 128.39, 128.09, 127.79, 127.24, 124.90, 121.87, 119.47, 118.46, 117.90, 115.36, 115.16, 108.03, 66.74, 56.81, 53.74, 52.28, 48.78, 48.65, 46.62, 30.98, 22.18, 9.59.

[0598] Example 146: Compound LLC0822

[0599] The synthetic route and method are the same as those in Example 146:

[0600] 1H NMR (600MHz, DMSO-d6) δ 11.08 (s, 1H), 10.88 (s, 1H), 10.44 (s, 1H), 7.95 (d, J = 8.2Hz, 2H), 7.87 (d, J = 8.7Hz, 2H), 7.72-7.62 (m, 3 H), 7.46 (d, J=7.6Hz, 2H), 7.34 (s, 1H), 7.25 (d, J=8.4Hz, 1H), 7.19 (d, J=7.8Hz, 1H), 7.15 (s, 1H), 6.93 (d, J=8.1Hz, 1H), 5.07 (dd , J=12.8, 5.4Hz, 1H), 4.72 (s, 2H), 4.62 (s, 2H), 4.49-4.38 (m, 1H), 4.19-4.08 (m, 1H), 4.07-3.97 (m, 1H), 3.79-3.66 (m, 1H), 3.51 -3.36(m, 6H), 2.98-2.84(m, 2H), 2.84-2.75(m, 1H), 2.69-2.53(m, 6H), 2.08-1.96(m, 1H), 0.65-0.52(m, 2H), 0.51-0.40(m, 2H). 13 C NMR (151MHz, DMSO-d6) δ172.82, 170.09, 168.42, 167.55, 166.98, 165.67, 16 4.86, 142.49, 142.38, 141.58, 133.86, 133.44, 131.80, 128.61, 128.39, 128. 09, 127.90, 127.23, 124.91, 121.87, 119.48, 115.36, 115.17, 66.75, 61.43, 57.39, 54.92, 52.63, 52.22, 48.78, 48.61, 46.84, 30.98, 26.47, 22.18, 9.55.

[0601] Example 147: Compound LLC0840

[0602] The synthetic route and synthetic method are the same as those in Example 144:

[0603] 1H NMR (600MHz, DMSO-d6) δ11.08 (s, 1H), 10.88 (s, 1H), 10.44 (s, 1H), 7.95 (d, J = 8.2Hz, 2H), 7.87 (d, J = 8.7Hz, 2H), 7.68 (d, J = 8.7Hz, 2H), 7.62 (d, J=12.5Hz, 1H), 7.46 (d, J=7.7Hz, 2H), 7.19 (d, J=8.0Hz, 1H), 7.14 (s, 1H), 7.06 (d, J=7.5Hz, 1H), 6.92 (d, J=8.1Hz, 1H), 5.06 (d d, J=12.9, 5.4Hz, 1H), 4.72 (s, 2H), 4.61 (s, 2H), 4.36 (dd, J=53.5, 8.4Hz, 2H), 4.14-3.95 (m, 2H), 3.88-3.74 (m, 2H), 3.69-3.54 (m, 2H) , 2.93-2.84(m, 1H), 2.83-2.74(m, 1H), 2.63-2.52(m, 2H), 2.27-2.16(m, 2H), 2.06-1.98(m, 1H), 0.62-0.51(m, 2H), 0.51-0.40(m, 2H). 13 C NMR (151MHz, DMSO-d6) δ172.79, 170.02, 168.50, 166.96, 166.41, 165.64, 164.86, 153.97, 15 2.33, 142.48, 142.38, 141.75, 141.69, 141.65, 133.41, 131.79, 129.52, 128.66, 128.38, 128. 08, 127.88, 127.23, 121.87, 119.43, 117.58, 117.52, 115.35, 115.16, 111.87, 111.70, 109.29, 109.24, 66.74, 62.21, 58.83, 58.79, 57.08, 48.93, 48.79, 48.76, 34.92, 30.97, 22.17, 9.54.

[0604] Example 148: Compound LLC0841

[0605] The synthetic route and method are the same as those in Example 144:

[0606] 1H NMR (600MHz, DMSO-d6) δ11.08 (d, J=10.9Hz, 1H), 10.88 (s, 1H), 10.40 (s, 1H), 8.00-7.91 (m, 2H), 7.86 (d, J=8.3Hz, 2H), 7.66-7.54(m, 3H), 7.52-7.43(m, 2H), 7.23-7.11(m, 2H), 6.98-6.87(m, 2H), 5.12-5.01(m, 1H), 4.72(s, 2H), 4. 61 (s, 2H), 4.20 (dd, J=50.3, 7.4Hz, 2H), 4.13-4.04 (m, 2H), 3.79-3.67 (m, 2H), 3.62-3.53 (m, 2H), 2.92-2.83 (m, 1H) , 2.83-2.73(m, 1H), 2.63-2.53(m, 2H), 2.26-2.11(m, 2H), 2.07-1.95(m, 1H), 0.62-0.51(m, 2H), 0.51-0.40(m, 2H). 13 C NMR (151MHz, DMSO-d6) δ172.78, 169.99, 168.01, 166.80, 166.41, 165.61, 164.86, 152.97, 144.06, 143.98, 142.49 , 142.32, 140.73, 133.49, 131.80, 131.49, 131.27, 129.30, 129.23, 128.39, 128.15, 128.11, 128.06, 127.80, 127.2 3, 121.87, 119.42, 119.33, 118.75, 118.67, 115.36, 115.16, 111.40, 111.32, 111.25, 111.17, 108.30, 108.26, 66.74, 64.93, 62.36, 61.81, 57.53, 55.02, 54.92, 48.95, 48.60, 47.81, 44.76, 41.54, 36.07, 33.82, 30.97, 22.15, 9.55.

[0607] Example 149: Compound LLC0842

[0608] The synthetic route and method are the same as those in Example 144:

[0609] 1H NMR (600MHz, DMSO-d6) δ11.15-11.01 (m, 1H), 10.88 (s, 1H), 10.44-10.35 (m, 1H), 7.94 (dd, J=12.5, 8.1Hz, 2 H), 7.90-7.81 (m, 2H), 7.65-7.52 (m, 3H), 7.46 (s, 2H), 7.19 (d, J=7.5Hz, 1H), 7.14 (s, 1H), 7.07 (dd, J=36.8 , 7.4Hz, 1H), 6.93 (d, J=8.0Hz, 1H), 5.11-5.00 (m, 1H), 4.72 (s, 2H), 4.61 (s, 2H), 3.78-3.46 (m, 8H), 2.93-2 .83(m, 1H), 2.83-2.74(m, 1H), 2.63-2.52(m, 2H), 2.11-1.86(m, 5H), 0.65-0.51(m, 2H), 0.51-0.39(m, 2H). 13 C NMR (151MHz, DMSO-d6) δ172.79, 170.03, 168.16, 167.98, 167.01, 166.95, 166.42, 166.39, 165.61, 164.86, 153.91, 152.28, 142.49 , 142.31, 141.85, 141.78, 141.70, 140.69, 133.51, 131.80, 131.56, 131.47, 129.57, 129.51, 128.39, 128.12, 128.06, 127.23, 121.8 7, 119.43, 119.39, 119.33, 117.47, 117.42, 115.36, 115.16, 111.87, 111.71, 109.38, 109.31, 66.74, 64.93, 58.56, 58.12, 57.34, 54.92, 54.71, 49.26, 49.15, 48.93, 48.60, 48.56, 48.15, 46.60, 45.78, 45.26, 34.84, 33.97, 33.46, 32.96, 30.98, 22.18, 15.18, 9.56.

[0610] Example 150: Compound LLC0848

[0611] The amide condensation method was the same as in Example 43. Sonogashira reaction procedure: The bromide (0.2 mmol) and the alkynyl compound (0.22 mmol) were weighed into a 25 ml eggplant-shaped flask. Palladium catalyst Pd(PPh3)2Cl2 (0.02%), cuprous iodide (0.04 mmol), triethylamine (0.6 mmol), and 5 ml of acetonitrile solvent were added. The argon atmosphere was switched three times, and the mixture was stirred in an oil bath at 60°C for 8 hours. After cooling to room temperature, the mixture was directly concentrated, and the corresponding fractions were analyzed by column chromatography and NMR to obtain the desired product (85%).

[0612] 1 H NMR (600MHz, DMSO-d6) δ11.08 (s, 1H), 10.92 (s, 1H), 10.87 (s, 1H), 8.44 (s, 1H), 8.20 (d, J = 8.4Hz, 1H), 8.01 (d, J = 8.2Hz, 2H), 7.91-7.84 (m, 1H), 7.68 (d, J=8.5Hz, 1H), 7.42 (d, J=7.6Hz, 2H), 7.37 (d, J=1.9Hz, 1H), 7.28 (dd, J=8.7, 2.2Hz, 1H), 7.19 (d, J=7.9Hz, 1H), 7.15 (s, 1 H), 6.92 (d, J=8.1Hz, 1H), 5.07 (dd, J=12.8, 5.5Hz, 1H), 4.71 (s, 2H), 4.61 (s, 2H), 3.89-3.80 (m, 2H), 3.42-3.38 (m, 2H), 3.06-2.98 (m, 1 H), 2.93-2.85(m, 1H), 2.84-2.75(m, 1H), 2.63-2.53(m, 2H), 2.05-1.93(m, 3H), 1.75-1.67(m, 2H), 0.61-0.51(m, 2H), 0.51-0.38(m, 2H). 13 C NMR (151MHz, DMSO-d6) δ172.82, 170.11, 167.60, 166.96, 165.78, 164.86 ,154.84,151.24,150.24,142.70,142.48,140.57,134.04,131.75,128.3 9, 127.12, 125.04, 121.90, 117.82, 115.39, 115.14, 114.02, 108.02, 94. 81, 78.40, 66.73, 48.75, 48.59, 46.02, 30.98, 30.38, 26.89, 22.19, 9.58.

[0613] Example 151: Compound LLC0851

[0614] Synthesis route:

[0615] The synthesis operation method is similar to the same type of reaction operation in this patent.

[0616] 1 H NMR (600MHz, DMSO-d6) δ11.08 (s, 1H), 10.88 (s, 1H), 9.99 (s, 1H), 8.27 (d, J = 2.4Hz, 1H), 7.93 (d, J = 8.1Hz, 2H), 7.73-7.64 (m, 2 H), 7.43 (d, J=7.5Hz, 1H), 7.39-7.34 (m, 1H), 7.31-7.25 (m, 1H), 7.21-7.11 (m, 2H), 6.93 (d, J=8.1Hz, 1H), 6.49 (d, J=8.9Hz, 1H ), 6.40 (d, J = 7.7Hz, 1H), 5.07 (dd, J = 12.8, 5.4Hz, 1H), 4.71 (s, 2H), 4.61 (s, 2H), 4.08-3.94 (m, 3H), 3.23-3.15 (m, 2H), 2.94-2 .84(m, 1H), 2.82-2.73(m, 1H), 2.64-2.54(m, 2H), 2.07-1.94(m, 3H), 1.52-1.41(m, 2H), 0.60-0.51(m, 2H), 0.50-0.41(m, 2H). 13 C NMR (151MHz, DMSO-d6) δ172.83, 170.13, 167.64, 166.98, 164.88, 164.86, 15 5.11, 154.83, 142.49, 141.87, 140.65, 134.10, 133.49, 131.81, 131.45, 128 .38, 127.80, 127.18, 125.10, 125.06, 121.86, 117.67, 117.48, 115.35, 115.16, 107.90, 107.86, 66.74, 48.75, 47.15, 46.31, 30.99, 30.90, 22.20, 9.55.

[0617] Example 152: Compound LLC0859

[0618] Synthesis route:

[0619] The synthesis method is the same as Example 44.

[0620] 1 H NMR (600MHz, DMSO-d6) δ11.11 (s, 1H), 10.88 (s, 1H), 10.27 (s, 1H), 8.50 (d, J=2.7Hz, 1H), 8.05 (dd, J=8.9, 2.7Hz, 1H), 7.95 (d , J=8.2Hz, 2H), 7.71 (d, J=11.4Hz, 1H), 7.52-7.41 (m, 3H), 7.21-7.10 (m, 2H), 6.93 (d, J=8.1Hz, 1H), 6.86 (d, J=8.9Hz, 1H), 5.1 0 (dd, J=12.9, 5.4Hz, 1H), 4.71 (s, 2H), 4.62 (s, 2H), 4.17 (d, J=6.4Hz, 2H), 3.65 (d, J=11.9Hz, 2H), 2.98-2.84 (m, 3H), 2.83-2 .75(m, 1H), 2.64-2.52(m, 2H), 2.06-1.96(m, 2H), 1.93-1.84(m, 2H), 1.54-1.42(m, 2H), 0.61-0.51(m, 2H), 0.50-0.38(m, 2H). 13 C NMR (151MHz, DMSO-d6) δ172.78, 169.93, 166.71, 166.23, 165.26, 164.86, 159.71, 158.17, 15 6.49, 145.90, 145.84, 142.49, 142.24, 138.86, 133.18, 132.64, 131.80, 130.00, 128.81, 128. 39, 127.94, 127.25, 123.04, 122.97, 121.87, 115.36, 115.16, 113.85, 113.82, 112.00, 111.83, 110.13, 69.66, 66.74, 64.93, 49.74, 49.70, 49.05, 34.81, 30.96, 28.43, 22.09, 15.18, 9.54.

[0621] Example 153: Compound LLC0864

[0622] The synthesis method is the same as Example 44.

[0623] 1H NMR (600MHz, DMSO-d6) δ9.96 (s, 1H), 8.23 ​​(d, J = 2.5Hz, 1H), 7.92 (d, J = 8.2Hz, 2H), 7.68 (dd, J = 8.9, 2.6Hz, 1H), 7.65 (d, J = 8.6Hz, 1H), 7.43 (d, J=7.8Hz, 2H), 7.32 (d, J=2.0Hz, 1H), 7.24 (dd, J=8.7, 2.2Hz, 1H), 7.18 (d, J=8.1Hz, 1H), 7.14 (s, 1H), 6.92 (d, J=8.1Hz, 1H), 6.56-6.47 ( m, 2H), 5.05 (dd, J=12.7, 5.3Hz, 1H), 4.70 (s, 2H), 4.61 (s, 2H), 4.07 (d, J=13.0Hz, 2H), 3.19-3.11 (m, 2H), 3.00-2.92 (m, 2H), 2.91-2.83 (m , 1H), 2.82-2.73(m, 1H), 2.63-2.53(m, 2H), 2.04-1.96(m, 1H), 1.91- 1.79 (m, 3H), 1.26-1.20 (m, 2H), 0.60-0.51 (m, 2H), 0.50-0.42 (m, 2H). 13 C NMR (151MHz, DMSO-d6) δ172.93, 170.21, 167.66, 166.99, 164.89, 164.86, 1 56.07, 154.98, 142.50, 141.85, 140.71, 134.08, 133.51, 131.76, 131.42, 12 7.80, 127.18, 125.00, 124.85, 121.86, 117.62, 117.35, 115.34, 115.19, 107.74, 107.34, 66.74, 48.75, 47.28, 46.37, 35.49, 31.02, 29.05, 22.22, 9.51.

[0624] Example 154: Compound LLC0877

[0625] Synthesis route:

[0626] The synthetic operation method is the same as in Example 1:

[0627] 1H NMR (600MHz, DMSO-d6) δ11.08 (s, 1H), 10.86 (s, 1H), 10.40 (s, 1H), 8.19 (d, J = 7.8Hz, 1H), 7.91 (d, J = 8.3Hz, 2H), 7.8 8-7.82 (m, 4H), 7.68 (d, J=8.5Hz, 1H), 7.51-7.42 (m, 2H), 7.38 (d, J=1.9Hz, 1H), 7.29 (dd, J=8.7, 2.2Hz, 1H), 7.10-7 .00 (m, 2H), 7.00-6.91 (m, 1H), 5.08 (dd, J=12.8, 5.4Hz, 1H), 4.73-4.52 (m, 4H), 4.22-4.00 (m, 4H), 3.20-3.09 (m, 2H ), 2.94-2.83(m, 1H), 2.63-2.53(m, 2H), 2.07-1.98(m, 1H), 1.94-1.83(m, 2H), 1.67-1.55(m, 2H), 1.17-1.04(m, 6H). 13 C NMR (151MHz, DMSO-d6) δ172.82, 170.17, 170.13, 167.63, 166.98, 165.04, 164.74, 154.77, 141.82, 134.10, 129.33, 128.13, 127.99, 127.76, 1 26.56, 125.07, 120.50, 119.25, 117.85, 117.62, 114.22, 107.99, 66.7 3, 48.77, 46.57, 46.49, 30.99, 30.47, 22.19, 20.78.HRMS (m / z): [M+Na] + calcd for C 45 H 43 N7O9Na + 848.3014, found 848.3011.HPLC purity: 96.19%.

[0628] Example 155: Compound LLC0971

[0629] Synthesis route:

[0630] The synthetic operation method is the same as in Example 1:

[0631] HRMS (m / z): [M+Na] + calcd for C 44 H 39 N7O9Na+ 832.2701, found 832.2704.

[0632] Example 156: Compound LLC0972

[0633] The synthesis method is the same as that of Example 155:

[0634] HRMS (m / z): [M+Na] + calcd for C 44 H 39 N7O9Na + 832.2701, found 832.2696.

[0635] Example 157: Compound LLC0985

[0636] Synthesis route:

[0637] The synthesis operation method is similar to the same type of reaction operation in this patent.

[0638] HRMS (m / z): [M+H] + calcd for C 48 H 49 FN7O9 + 886.3570, found 886.3561.

[0639] General method: The reductive amination steps involved in the patent of this invention are:

[0640] Take the following reaction formula as an example:

[0641] Compound 1 (119 mg, 0.2 mmol) was weighed and dissolved in 2 mL of dichloromethane. 1 mL of trifluoroacetic acid was added and stirred at room temperature for 1 hour. The mixture was concentrated to obtain the crude product. The crude product was then dissolved in 2 mL of dichloromethane, and the carbonyl compound compound 2 (60.0 mg, 0.3 mmol) and 0.1 mL of acetic acid were added. The mixture was stirred at room temperature for 2 hours. Sodium acetate borohydride (75.7 mg, 2.0 mmol) was then added and stirred at room temperature for 12 hours. The mixture was quenched with 20 mL of saturated sodium bicarbonate solution and extracted three times with a mixed solvent of dichloromethane:methanol (v:v = 10:1) (20 mL each time). The organic phases were combined, concentrated, and purified by column chromatography using a dichloromethane / methanol (0-10%) eluent. The corresponding fractions were concentrated and identified by NMR.

[0642] The patent of this invention involves similar reduction amination operation to this operation.

[0643] General method: The operating steps of the nucleophilic substitution reaction involved in the patent of this invention are:

[0644] Take the following reaction formula as an example:

[0645] Amino compound 4 (0.5 mmol) and aryl fluoride compound 5 (0.6 mmol) were weighed into a 25 ml eggplant flask and dissolved in 10 ml of dimethyl sulfoxide. The mixture was stirred in an oil bath at 110°C for 1 hour. Heating was stopped, the mixture was cooled to room temperature, and diluted with 100 ml of ethyl acetate. The mixture was washed three times with saturated sodium bicarbonate solution (50 ml each time). The organic phase was dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography using a dichloromethane / methanol (0-10%) eluent. The corresponding fractions were concentrated and characterized by NMR. The desired product was obtained.

[0646] The experimental operation method involving similar amino groups or alcoholic hydroxyl groups attacking aromatic fluorides in the patent of this invention is the same as the operation steps.

[0647] Biological test example 1: Degradation activity test of compounds on NSD1, NSD2, NSD3 and other related proteins in VCaP, LNCap or 22RV1 prostate cancer cells

[0648] Western blotting. After treatment, the cultured cells were collected and washed with phosphate-buffered saline (PBS) at room temperature. The cells were treated with RIPA buffer (ThermoFisher Scientific) supplemented with HaltTM protease and phosphatase inhibitor cocktail (ThermoFisher Scientific). After sonication and centrifugation, the cells were lysed using Pierce TMThe total amount of protein in the cell lysate was determined using the Bovine Serum Albumin Standard Pre-Diluted Set (ThermoFisher Scientific). After mixing with LDS sample buffer (Invitrogen) supplemented with a sample reducing agent (Invitrogen) and heating at 70°C for 10 minutes, equal amounts of protein were loaded onto NuPAGE 4 to 12% Bis-Tris protein gels (ThermoFisher Scientific) or NuPAGE 3 to 8% Tris-Acetate protein gels (ThermoFisher Scientific) and blotted with primary antibodies. After incubation with an HRP-conjugated secondary antibody, the proteins were developed using ECL Prime Western Blotting Detection Reagent (Cytiva) and imaged on an Odyssey Fc Imager (LiCOR Biosciences).

[0649] Compound screening. After compound synthesis, dilute the compound in dimethyl sulfoxide (DMSO). Plate 1.5 million VCaP cells, 800,000 LNCaP cells, or 1 million 22RV1 cells per well in a 6-well plate. Each well was then treated with 1 μM or 2 μM of the compound for 24 hours. Western blotting was then performed as previously described to assess the degradation of proteins such as NSD2 and GSPT1.

[0650] The activity results are shown in Figures 1a-1p and Tables 1-5. The NSD2 degradation rates are as follows:

[0651] Table 1:

[0652] Table 2:

[0653] Table 3:

[0654] Table 4:

[0655] GSPT1 degradation rate:

[0656] Table 5

[0657] (2) Proliferation inhibition activity of compounds LLC0424 and LLC0877

[0658] Assay: Cells were cultured in 50 μL of the corresponding culture medium in a 96-well plate. A two-fold dilution series was prepared with 2x concentrations of LLC0424 in the culture medium with a maximum concentration of 60 μM. 50 μL of a mixture containing 2× compound was added to each well, and each concentration was repeated 6 times to reach a 1× concentration with a maximum concentration of 30 μM. Culture was carried out in 96-well plates for 7 days. Finally, the CellTiter-Glo assay (Promega) was performed according to the manufacturer's instructions to determine cell proliferation. The luminescence signal intensity of each well was collected on an Infinite M1000Pro microplate reader, and the data were analyzed using GraphPad Prism software (GraphPad Software).

[0659] Results: LLC0424 and LLC0877 compounds were tested for IC using SEM cells 50 The IC50 values ​​of LLC0424 and LLC0877 compounds tested in RPMI8402 cells were less than 1 μM and equal to 0.135 μM, respectively; the results are shown in Figure 2.

[0660] Biological Test Example 2: Inhibitory Effect of Compound LLC0150 on Cell Proliferation of Prostate Cancer Cells such as VCaP and LNCap and Normal Cells

[0661] Assay Method: Different cells and their respective culture media were plated onto 96-well plates and incubated at 37°C, 5% CO2. After overnight incubation, a series of dilutions of the compound LLC0150 were added to the 96-well plates. Cells were cultured for a further 5 days, and then the CellTiter-Glo assay was performed according to the manufacturer's instructions to determine cell proliferation. Luminescence signals were acquired from each well using a microplate reader, and data were analyzed using GraphPad Prism software.

[0662] Results: The IC50 values ​​of compound LLC0150 against HEK293FT cells, RWPE2-W99 cells, MCF10A cells and PC3 cells were all greater than 10 μM, respectively; the IC50 values ​​of compound LLC0150 against VCaP and LNCap cells were all less than 1 μM, as shown in Figure 3.

[0663] Biological Test Example 3: Study on the anti-tumor effect of compound LLC0424 in mice bearing xenograft tumors.

[0664] How to do it:

[0665] Male CB17 severe combined immunodeficiency (SCID) mice, 6-8 weeks old, were purchased from the University of Michigan breeding facility. Subcutaneous tumors were established on both sides of the dorsal flank of the mice. Tumors were measured at least every two weeks using a digital caliper using the formula (π / 6)(L×W2), where L is the length of the tumor and W is the width. At the end of the study, the mice were sacrificed and the tumors were extracted. A portion of each tumor was paraffin-fixed and then embedded in paraffin to make tissue blocks. The blocks were sliced ​​into 4 μM sections for immunohistochemical analysis. Another portion was prepared as a tissue lysate for Western blot analysis. All in vivo studies were approved by the University of Michigan Institutional Animal Care and Use Committee (IACUC).

[0666] In the SEM tumor model, mice were subcutaneously injected with 10 × 10 6 SEM cells were grown in serum-free medium containing 50% Matrigel (BD Biosciences). When tumors reached the palpable stage (approximately 200 cubic millimeters), mice were intravenously injected with 60 mg / kg of LLC0424 or a control group for five consecutive days. NSD2 protein expression in tumors was assessed by Western blotting.

[0667] For the 22RV1 tumor model, 2×10 6 22RV1 cells were injected subcutaneously into the dorsal flanks of mice in serum-free medium supplemented with 50% Matrigel (BD Biosciences). 3 ), mice received 60 mg / kg LLC0424 or vehicle via intravenous or intraperitoneal injection for five consecutive days. Tumors in all treatment groups did not exceed 2.0 cm in any dimension, in accordance with IACUC guidelines. NSD2 protein expression in tumors was assessed by western blotting.

[0668] Immunohistochemistry. Immunohistochemistry was performed on 4 μm sections of formalin-fixed, paraffin-embedded mouse or xenograft tissue. Slides with tissue sections were degraphitized in xylene and then treated in ethanol (100%, 70%) and water for 5 minutes consecutively. Endogenous tissue peroxidase activity was blocked by placing the slides in 3% H2O2-methanol solution for 1 hour at room temperature. Antigen retrieval was performed by microwave-blocking the slides in citrate buffer (pH 6) for 15 minutes and then blocking them in 2.5% normal horse serum (Vector Laboratories, product number S-2012-50) for 2 hours. The slides were then incubated overnight at 4°C in the following primary antibody: NSD2 (Abcam cat.). The next day, the slides were rinsed with PBST and incubated with the secondary antibody (ImmPRESS TMIncubate with HRP universal anti-mouse IgG / anti-rabbit IgG (Vector Laboratories, catalog number MP-7500-50) at room temperature for 1 hour. Staining was performed using a DAB substrate kit (Vector Laboratories, catalog number SK-4100) according to the manufacturer's protocol. After DAB staining, slides were dehydrated in ethanol and xylene (5 minutes each) and mounted using EcoMount (Thermo Fisher Scientific, catalog number EM897L).

[0669] The experimental results are shown in Figures 4a and 4b, which show that compared with the control group, compound LLC0424 can effectively degrade NSD2 in two cell line xenograft mouse models.

[0670] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound 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, Z1, 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 or isopropyl.

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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