Bifunctional compounds, methods of making, pharmaceutical compositions, and uses thereof

Abstract

This application relates to bifunctional compounds, their preparation methods, pharmaceutical compositions, and uses. The compounds have the following general formula: The compounds designed in this application include a portion that binds to HIF-2α protein and a portion that binds to E3 ubiquitin ligase CRBN, which are coupled or linked by a linker L. The compounds of this application can recruit HIF-2α to the ubiquitin ligase using the ubiquitin-proteasome system in the body's cells, ubiquitinate HIF-2α, and then degrade it by the proteasome in the body's cells, thereby reducing the expression level of HIF-2α in tumor cells, and thus can be used to treat diseases related to high expression of HIF-2α.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and particularly relates to a bifunctional compound, a preparation method, a pharmaceutical composition and use thereof. BACKGROUND

[0002] Renal Cell Carcinoma (RCC) is the second largest cause of death in urological cancers, and metastasis and chemotherapy resistance are the main characteristics of renal cell carcinoma. 85% of renal cell carcinoma patients are clear cell renal cell carcinoma (ccRCC). Molecular biology studies have shown that 90% of clear cell renal cell carcinoma has inactivation of the VHL gene, and the inactivation of the VHL gene is considered to be the driving factor of clear cell renal cell carcinoma. VHL protein is a component of E3 ubiquitin ligase complex, which can recognize Hypoxia Inducible Factors 1 alpha (HIF-1 alpha) and Hypoxia Inducible Factors 2 alpha (HIF-2 alpha) and ubiquitinate them, and then be degraded by proteasome. Studies have shown that inactivation of the VHL gene increases the expression of HIF-2 alpha in clear cell renal cell carcinoma cells, and HIF-2 alpha is a transcription factor, and its increased expression will lead to increased expression of downstream regulated genes, such as increased expression and secretion of VEGFA, thereby promoting angiogenesis; increase the expression of cell cycle protein (CCDN1) to promote cell proliferation; increase the expression of glucose transporter, thereby enhancing the metabolism of cells, etc., which will promote the growth, metastasis, etc. of tumors. In addition to renal cell carcinoma, studies have shown that in liver cancer, breast cancer and colorectal cancer, the expression of HIF-2 alpha is up-regulated due to hypoxia in tumor tissues, which will also promote the occurrence and development of cancer.

[0003] Since HIF-2 alpha is a transcription factor, there is no endogenous small molecule ligand that binds to it, so HIF-2 alpha is considered to be a difficult-to-drug target. In 2009, scientists found that there is a certain size cavity in its protein that can bind small molecules, and through compound library screening, a compound with certain inhibitory activity was obtained, but due to insufficient affinity, it is difficult to be drugged. SUMMARY

[0004] In order to overcome the above-mentioned defects, the present application provides a bifunctional compound, a preparation method, a pharmaceutical composition and use thereof, which can solve the problem of difficult-to-drug hypoxia-inducible factor 2 alpha, thereby being used for treating diseases related to high expression of HIF-2 alpha.

[0005] In a first aspect, the embodiments of the present application provide a bifunctional compound, which has the following general formula:

[0006]

[0007] In the above formula: L is the connector;

[0008] R1 is selected from halogens, -NO2, -CN, and -S(O)2R. a -S(O)R a and -P(O)R b R c Any one of them, Ra, R b and R c Each is independently selected from any one of C1-C6 alkyl and C1-C6 haloalkyl;

[0009] R2 and R3 are each independently selected from any one of H, halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkyl;

[0010] X is selected from either -C(O)- or -CH2-;

[0011] The R4 is selected from any one of H, halogen, -CN, C1-C3 alkyl, C1-C3 haloalkyl and C1-C3 alkoxy.

[0012] In conjunction with the first aspect, the connector L has the following general formula (II):

[0013]

[0014] The L1 passes through The benzene ring connected to R1 is covalently linked, and L4 is through... The benzene ring connected to R4 is covalently bonded;

[0015] L1 does not exist or is selected from -NR d -, -O-, -S-, -NHCH2-, -NH(CH2) q Either C(O)- or -OC(O)-, wherein q is an integer from 0 to 6, and R d Selected from H, C1-C3 alkyl, and C1-C3 haloalkyl;

[0016] The L2 and / or L3 are either absent or selected from -(CH2). m -、-NR e -、-(CH2CH2O) n -、-(NH) o (CH2) p C(O)- and -C(O)(CH2) p (NH)o - any one of the foregoing, wherein m is an integer from 0 to 12, n is an integer from 0 to 6, o is 0 or 1, p is an integer from 0 to 6, R e is selected from any one of H, C1-C3 alkyl, and C1-C3 haloalkyl;

[0017] L4 is absent or selected from -O-, -S-, and -NR f - any one of the foregoing, wherein R f is selected from any one of H, halogen, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C3 haloalkoxy;

[0018] A, B, and C are each independently selected from any one of absent, C3-C7 cycloalkyl, 5-7 membered heterocyclyl comprising 1-3 atoms independently selected from O, N, and S, C5-C10 aryl, and 5-10 membered heteroaryl comprising 1-3 atoms independently selected from O, N, and S.

[0019] In a second aspect, the present application discloses a pharmaceutical composition comprising the bifunctional compound of the first aspect or a pharmaceutically acceptable salt, enantiomer, diastereomer, prodrug or solvate thereof, and at least one pharmaceutically acceptable carrier, additive, adjuvant or excipient.

[0020] In a third aspect, the present application discloses the use of the bifunctional compound of the first aspect or the second aspect in the preparation of a tumor or cancer drug.

[0021] Compared with the prior art, the present application has at least the following technical effects:

[0022] The compound of the present application comprises a moiety binding HIF-2α protein and a moiety binding E3 ubiquitin ligase CRBN through a linker L, wherein the left part of L is a small molecule moiety binding HIF-2α protein, and the right part of L is a small molecule ligand binding ubiquitin ligase. The bifunctional compound of the present application can recruit hypoxia-inducible factor HIF-2α to the ubiquitin ligase by utilizing the ubiquitin-proteasome system in the body cells. The compound can bind HIF-2α and ubiquitinate HIF-2α, and then HIF-2α is degraded by the proteasome in the body cells, thereby reducing the expression amount of HIF-2α in tumor cells, and further regulating the content of HIF-2α in the body cells. Therefore, the bifunctional compound of the present application can solve the problem of difficult drug development of HIF-2α, and the bifunctional compound of the present application can be used for treating diseases related to high expression of HIF-2α.

[0023] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the application, as claimed. DETAILED DESCRIPTION

[0024] For better understanding of the technical solutions of the present application, the embodiments of the present application are described in detail below in combination with specific implementation manners.

[0025] It should be clear that the described embodiments are only some of the embodiments of the present application, but not all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.

[0026] The terms used in the embodiments of the present application are only for the purpose of describing specific embodiments, and are not intended to limit the present application. The singular forms "a", "said" and "the" used in the embodiments of the present application and the appended claims are also intended to include the plural forms, unless the context clearly indicates otherwise.

[0027] It should be understood that the term "and / or" used herein only describes the association relationship of the associated objects, which means that there can be three relationships, for example, A and / or B can represent the three cases of A alone, A and B together, and B alone. In addition, the character " / " herein generally represents an "or" relationship between the front and rear associated objects.

[0028] It should be noted that "halogen" described in the embodiments of the present application refers to F, Cl, Br, I and At.

[0029] "C1-C6 alkyl" refers to an alkyl chain having 1-6 carbon atoms, which can be straight chain or branched chain, for example: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the like. The hydrogen atoms on the C1-6 alkyl carbon can be further substituted by the specified substituent.

[0030] "C1-C6 haloalkyl" refers to an alkyl chain having 1-6 carbon atoms, which can be straight chain or branched chain, for example: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the like, wherein the hydrogen atoms on the alkyl carbon are substituted by at least one halogen atom.

[0031] "C1-C6 alkoxy" refers to an alkyl chain having 1-6 carbon atoms, which can be straight chain or branched chain, connected to the position through an oxygen atom.

[0032] "C3-C7 cycloalkyl" refers to a cycloalkyl chain having 3-7 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. The hydrogen atoms on the carbon atoms in the cycloalkyl group can be substituted by the specified substituent.

[0033] "Heteroaryl" means an aromatic monocyclic or bicyclic ring having at least one heteroatom, such as quinolinyl, isoquinolinyl, pyridyl, furanyl, thienyl, pyrrolyl, and the like; the hydrogen atoms on the ring can be replaced by halogen, cyano, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, and the like;

[0034] "Aryl" means an aromatic monocyclic or bicyclic ring having all carbon atoms, such as phenyl, naphthyl, wherein the hydrogen atoms can be replaced by halogen, cyano, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, and the like;

[0035] "Heteroaryl" means an aromatic monocyclic or bicyclic ring having at least one heteroatom, such as quinolinyl, isoquinolinyl, pyridyl, furanyl, thienyl, pyrrolyl, and the like; the hydrogen atoms on the ring can be replaced by halogen, cyano, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, and the like;

[0036] "Haloalkoxy" means a haloalkyl chain having 1-3 carbon atoms, which can be straight-chained or branched, attached to the position of interest through an oxygen atom;

[0037] "C1-C3alkanoyl" means MeC(O)-, EtC(O)-, CH3CH2CH2C(O)-, (CH3)2CHC(O)-;

[0038] "C1-C3alkylsulfonyl" means MeS(O)2-, EtS(O)2-, CH3CH2CH2S(O)2-, (CH3)2CHS(O)2-;

[0039] The term "prodrug" means a derivative of a compound of the present application that is converted into the compound under physiological conditions, through the action of enzymes, such as oxidative, reductive, hydrolytic, and the like.

[0040] The term "isotopic derivative" means a compound of the present application that contains one or more isotopic atoms in a structure thereof in a non-natural proportion. For example, deuterium (2H or D), carbon-13 (13C), and nitrogen-15 (15N).

[0041] The term "solvate" means a physical association between a compound of the present application and solvent molecule(s), which can be formed through physical means, such as hydration. The physical association involves a hydrogen bond between the solvent molecule(s) and the compound of the present application. Suitable solvents include water, methanol, ethanol, acetic acid, tetrahydrofuran, ethyl acetate, acetonitrile, and the like. The compounds of the present application can be prepared in crystalline form and can be in the form of a hydrate, including a solvate.

[0042] The term "pharmaceutically acceptable salts" comprises one or more basic or acidic groups, in particular the pharmaceutically utilizable salts thereof. For example alkali metal salts, alkaline earth metal salts, ammonium salts. More precisely sodium salts, potassium salts, calcium salts, magnesium salts or organic amines such as ethylamine, ethanolamine, triethylamine or amino acid salts. The compounds of the present application can form protonated compounds of formula (I) with inorganic or organic acids, examples of which include hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, lactic acid, malic acid, maleic acid, tartaric acid and others known to the person skilled in the art.

[0043] HIF-2a is a transcription factor without endogenous small molecule ligand binding to it, therefore, HIF-2a is considered as a difficult-to-drug target. There is no drug on the market to construct a bifunctional compound to degrade HIF-2a protein.

[0044] Therefore, the present application provides a bifunctional compound, which has the following general formula (I):

[0045]

[0046] In the above formula: L is a linker.

[0047] R1is selected from any one of halogen, -NO2, -CN, -S(O)2R a , -S(O)R a and -P(O)R b R c , wherein R a , R b and R c are each independently selected from any one of C1-C6alkyl and C1-C6haloalkyl.

[0048] R2and R3are each independently selected from any one of H, halogen, -CN, C1-C6alkyl, C1-C6alkoxy and C1-C6haloalkyl.

[0049] X is selected from any one of -C(O)- and -CH2-.

[0050] R4is selected from any one of H, halogen, -CN, C1-C3alkyl, C1-C3haloalkyl and C1-C3alkoxy.

[0051] In the above technical solution, the compound of the application comprises a part binding to HIF-2α protein and a part binding to E3 ubiquitin ligase CRBN coupled or connected by a linker L, wherein the left part of L is a small molecule part binding to HIF-2α protein, and the right part of L is a small molecule ligand binding to ubiquitin ligase. The bifunctional compound of the application can recruit hypoxia-inducible factor HIF-2α to ubiquitin ligase by using the ubiquitin-proteasome system in the body cells. The compound can bind to HIF-2α and ubiquitinate HIF-2α, and then HIF-2α is degraded by the proteasome in the body cells, thereby reducing the expression amount of HIF-2α in the tumor cells of the body, and then the content of HIF-2α in the body cells can be adjusted. Therefore, the bifunctional compound of the application solves the problem of difficult drug development of HIF-2α, and can be used for treating diseases related to high expression of HIF-2α.

[0052] The ubiquitination process of the protein is carried out under the synergistic action of ubiquitin activating enzyme E1, ubiquitin conjugating enzyme E2 and E3 ubiquitin ligase. First, ubiquitin is connected to E1 in an activated state by forming a high-energy thioester bond between the carboxyl group on the C-terminal glycine of ubiquitin and the essential cysteine thiol on ubiquitin activating enzyme E1; second, the activated ubiquitin is transferred from ubiquitin activating enzyme E1 to ubiquitin conjugating enzyme E2; finally, under the action of E3 ubiquitin ligase, the ubiquitin molecule connected to ubiquitin conjugating enzyme E2 is connected to HIF-2α protein by covalent connection of isopeptide bond, and the HIF-2α protein is degraded in the proteasome after being ubiquitinated.

[0053] The right part of L in formula I is a part connected to E3 ubiquitin ligase CRBN. Specifically, the right part of L in formula I is a ligand that can bind to CRBN gene. CRBN is a part of E3 ubiquitin ligase, recognizes substrate protein as a substrate receptor (SRs), and thus initiates the degradation process. The right part of L in formula I has a six-membered piperidinedione structure, which can bind to E3 ubiquitin ligase, and the binding mode is usually non-covalent bond connection. Meanwhile, the left part of L contains a structural fragment of a HIF-2α small molecule inhibitor, which can recognize HIF-2α protein, and the part interacts with HIF-2α protein to make HIF-2α protein approach E3 ubiquitin ligase protein, thereby promoting the degradation of HIF-2α protein.

[0054] In some embodiments, preferably, R aAny of methyl and halomethyl. Halomethyl can be, for example, CH3F, CH3C1, CH3Br, CH3I, and CH3At, etc.

[0055] In some embodiments, preferably, R2and / or R3are each independently selected from any of H and halogen.

[0056] In some embodiments, the L linker has the following general formula II:

[0057]

[0058] wherein: L1is covalently attached to the benzene ring to which R1is attached in Formula I, L4is covalently attached to the benzene ring to which R4is attached in Formula I. Specifically, the linker L is covalently bound to the para position relative to L1, and the linker L is covalently bound to the ortho or meta position relative to the C atom to which X is attached.

[0059] L1is absent or selected from: -NR d -, -O-, -S-, -NHCH2-, -NH(CH2) q C(O)-, -OC(O)-, -C(O)O-, -OC(O)O-, -NR d is selected from any of H, C1-C3 alkyl, and C1-C3 haloalkyl.

[0060] L2and / or L3are absent or selected from any of -(CH2) m -, -NR e -, -(CH2CH2O) n -, -(NH) o (CH2) p C(O)-, and -C(O)(CH2) p (NH) o -; wherein m is an integer from 0 to 12, n is an integer from 0 to 6, o is 0 or 1, p is an integer from 0 to 6, and R e is selected from any of H, C1-C3 alkyl, and C1-C3 haloalkyl.

[0061] L4is absent or selected from any of -O-, -S-, and -NR f -; wherein R f is selected from any of H, halogen, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C3 haloalkoxy.

[0062] ​​​​A, B and C are each independently selected from the group consisting of absent, C3-C7 cycloalkyl, 5- to 7-membered heterocyclyl containing 1-3 atoms independently selected from O, N and S, C5-C10 aryl, and 5- to 10-membered heteroaryl containing 1-3 atoms independently selected from O, N and S. Preferably:

[0063] A is absent or selected from any one of the following groups:

[0064]

[0065] wherein Z is selected from any one of -N- and -CH2-, a represents the group attached to the left of the A group in formula (II), and β represents the group attached to the right of the A group in formula (II), and if both L1and L2are present, a represents the covalent bond to L1, and β represents the covalent bond to L2.

[0066] B is absent or selected from any one of the following groups:

[0067]

[0068] wherein γ represents the group attached to the left of the B group in formula (II), and δ represents the group attached to the right of the B group in formula (II), and if both L2and L3are present, γ represents the covalent bond to L2, and δ represents the covalent bond to L3.

[0069] C is absent or selected from any one of the following groups:

[0070]

[0071] wherein L5is absent or selected from any one of -CH2-, -O-, -NR g -, -C(O)- and -O(CH2) r C(O)-, wherein r is an integer from 0 to 6; R g is selected from any one of H, C1-C3 alkyl, C1-C3 alkanoyl and C1-C3 alkylsulfonyl.

[0072] R5is selected from any one of H, deuterium, halogen, -OH, C1-C3 alkyl, C1-C3 haloalkyl and C1-C3 alkoxy.

[0073] R6is selected from any one of H, -CN, halogen, -OH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy and -NR h -, wherein R h is selected from any one of H and C1-C3 alkyl.

[0074] p represents the connection of the group adjacent to the left of the C group in formula (II), and q represents the connection of the group adjacent to the right of the C group in formula (II), and specifically, if L3 and L4 are both present, p represents the connection of L3 through a covalent bond, and q represents the connection of L4 through a covalent bond.

[0075] The linker L connects the two parts of the bifunctional molecule, and can form a ternary complex of the HIF-2a protein, the small molecule and the E3 ubiquitin ligase. In addition, due to the flexibility of the linker L of the present application, the conformation of the ternary complex can be adjusted, so that the E3 ubiquitin ligase can catalyze the ubiquitination of the substrate protein. In addition, the linker L can affect the physicochemical properties of the whole molecule, so as to have better drugability. The linker L can shorten the distance between the HIF-2a protein and the E3 ubiquitin ligase, promote the ubiquitination of the protein, and has an irreplaceable role in degrading the target protein.

[0076] The present application also provides a preparation method of the above-mentioned bifunctional compound, which comprises any one of the following reaction routes:

[0077] Route A:

[0078]

[0079] Step 1: providing a reaction substrate A1, A-1 is reacted with the reaction substrate A1 under the action of sodium hydride in a solvent to obtain A-2.

[0080] Step 2: A-2 is reacted under the action of p-toluenesulfonic acid in a solvent to obtain an intermediate A-3.

[0081] Step 3: A-3 is reacted with a reaction substrate A2 in a solvent to obtain A-4.

[0082] Step 4: under the catalysis of monovalent copper, A-4 is reacted with a reaction substrate A3 in a solvent to obtain an intermediate A-5;

[0083] Step 5: A-5 is catalyzed by a chiral ruthenium catalyst, formic acid and triethylamine are added, wherein formic acid and triethylamine are used as a source of hydrogen, and the target product A-6 is obtained by reacting in a solvent under a protective atmosphere.

[0084] In the above preparation process, the solvent of the reaction is at least one selected from the group consisting of N,N-dimethylformamide, dichloromethane, ethyl acetate, dimethyl sulfoxide, 1,4-dioxane, methanol, ethanol, water, acetone and acetonitrile.

[0085] The monovalent copper is selected from any one of cuprous iodide, cuprous bromide, cuprous chloride and a compound generated in situ from copper sulfate and sodium ascorbate.

[0086] The chiral ruthenium reagent is selected from any one of [(R,R)-N-(2-amino-1,2-diphenylethyl)-p-toluenesulfonamide]chloride (p-cymene) ruthenium (II) and [(S,S)-N-(2-amino-1,2-diphenylethyl)-p-toluenesulfonamide]chloride (p-cymene) ruthenium (II).

[0087] The gas of the protective atmosphere includes at least one of argon and nitrogen.

[0088] The temperature of the above-mentioned warming reaction is 60-100°C. Exemplarily, the temperature of the warming reaction can be 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C and 100°C, and of course can also be other values within the above-mentioned range, which is not limited herein.

[0089] Route B:

[0090]

[0091] Step 1: providing a reaction substrate B1, B-1 reacts with the reaction substrate B1 under the action of sodium hydride in a solvent to obtain B-2.

[0092] Step 2: B-2 reacts under the action of p-toluenesulfonic acid in a solvent to obtain intermediate B-3 by warming reaction.

[0093] Step 3: B-3 reacts with a reaction substrate B2 in a solvent to obtain B-4 by warming reaction.

[0094] Step 4: B-4 reacts under the action of triphenylphosphine in a solvent to obtain intermediate B-5;

[0095] Step 5: B-5 reacts with a reaction substrate B3 under the action of a base in a solvent to obtain intermediate B-6 by warming reaction;

[0096] Step 6: B-6 is catalyzed by a chiral ruthenium catalyst, formic acid and triethylamine are added as a source of hydrogen, and the reaction is carried out in a solvent under a protective atmosphere to obtain the target product B-7.

[0097] In the above preparation process, the solvent of the reaction is selected from at least one of N,N-dimethylformamide, dichloromethane, ethyl acetate, dimethyl sulfoxide, 1,4-dioxane, methanol, ethanol, water, acetone and acetonitrile.

[0098] The base is selected from any one of sodium hydride, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, cesium carbonate, sodium carbonate, triethylamine and diisopropyl ethylamine.

[0099] The chiral ruthenium reagent is selected from any one of [(R,R)-N-(2-amino-1,2-diphenylethyl)-p-toluenesulfonamide] chloro(p-cymene)ruthenium(II) and [(S,S)-N-(2-amino-1,2-diphenylethyl)-p-toluenesulfonamide] chloro(p-cymene)ruthenium(II).

[0100] The gas of the protective atmosphere includes at least one of argon and nitrogen.

[0101] The temperature of the above-mentioned warming reaction is 60-100°C. Exemplarily, the temperature of the warming reaction can be 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C and 100°C, and of course can also be other values within the above-mentioned range, which is not limited herein.

[0102] Route C:

[0103]

[0104] Step 1: C-1 is reacted with cyanodiphenol in a solvent under the action of a base to obtain intermediate C-2;

[0105] Step 2: C-2 is reacted with reaction substrate C1 in a solvent under the action of a base to obtain intermediate C-3;

[0106] Step 3: C-3 is reacted in a solvent under the action of an acid to obtain intermediate C-4 through warming reaction;

[0107] Step 4: C-4 is reacted with reaction substrate C2 in a solvent to obtain C-5;

[0108] Step 5: C-5 is reacted with reaction substrate C3 in a solvent under the catalysis of monovalent copper to obtain intermediate C-6 through warming reaction;

[0109] Step 6: C-6 is reacted in a solvent under the catalysis of a chiral ruthenium catalyst, formic acid and triethylamine are added as a source of hydrogen, and the reaction is carried out under a protective atmosphere to obtain target product C-7.

[0110] In the above-mentioned preparation process, the solvent of the reaction is selected from at least one of N,N-dimethylformamide, dichloromethane, ethyl acetate, dimethyl sulfoxide, 1,4-dioxane, methanol, ethanol, water, acetone and acetonitrile.

[0111] The acid is selected from any one of hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, pyridine p-toluenesulfonate and trifluoroacetic acid.

[0112] The base is selected from any one of sodium hydride, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, cesium carbonate, sodium carbonate, triethylamine and diisopropylethylamine.

[0113] The chiral ruthenium reagent is selected from any one of [(R,R)-N-(2-amino-1,2-diphenylethyl)-p-toluenesulfonamide] chloro(p-cymene)ruthenium(II) and [(S,S)-N-(2-amino-1,2-diphenylethyl)-p-toluenesulfonamide] chloro(p-cymene)ruthenium(II).

[0114] The gas of the protective atmosphere includes at least one of argon and nitrogen.

[0115] The temperature of the above-mentioned warming reaction is 60-100°C. Exemplarily, the temperature of the warming reaction can be 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C and 100°C, and of course can also be other values within the above-mentioned range, which is not limited herein.

[0116] Scheme D:

[0117]

[0118] Step 1: D-1, the reaction substrate D1 is reacted with sodium hydride in a solvent to obtain an intermediate D-2;

[0119] Step 2: D-2 is reacted in a solvent under acidic conditions to obtain an intermediate D-3 by warming;

[0120] Step 3: the intermediate D-3 is reacted with the reaction substrate D2 in a solvent to obtain D-4;

[0121] Step 4: D-5 is reacted with the reaction substrate D3 in a solvent under the catalysis of monovalent copper to obtain an intermediate D-6 by warming;

[0122] Step 5: the intermediate D-6 is dissolved in a solvent with D-4, and a base is added to perform a warming reaction to obtain an intermediate D-7;

[0123] Step 6: D-7 is reacted in a solvent under the catalysis of a chiral ruthenium catalyst, formic acid and triethylamine are added, formic acid and triethylamine are used as a source of hydrogen, and the reaction is performed in a solvent under a protective atmosphere to obtain a target product D-8.

[0124] In the above-mentioned preparation process, the solvent of the reaction is selected from at least one of N,N-dimethylformamide, dichloromethane, ethyl acetate, dimethyl sulfoxide, 1,4-dioxane, methanol, ethanol, water, acetone and acetonitrile.

[0125] The acid is selected from any one of hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, p-toluenesulfonic acid pyridine salt and trifluoroacetic acid.

[0126] The base is selected from any one of sodium hydride, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, cesium carbonate, sodium carbonate, triethylamine and diisopropylethylamine.

[0127] The chiral ruthenium reagent is selected from any one of [(R,R)-N-(2-amino-1,2-diphenylethyl)-p-toluenesulfonamide] chloro(p-cymene)ruthenium(II) and [(S,S)-N-(2-amino-1,2-diphenylethyl)-p-toluenesulfonamide] chloro(p-cymene)ruthenium(II).

[0128] The gas of the protective atmosphere includes at least one of argon and nitrogen.

[0129] The temperature of the above-mentioned warming reaction is 60-100°C. Exemplarily, the temperature of the warming reaction can be 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C and 100°C, and of course can also be other values within the above-mentioned range, which is not limited herein.

[0130] Scheme E:

[0131]

[0132] Step 1: E-1 is dissolved in a solvent, a base is added, and a warming reaction is carried out to obtain intermediate E-2;

[0133] Step 2: E-2 is subjected to a warming reaction in a solvent under acidic conditions to obtain intermediate E-3;

[0134] Step 3: E-3 is dissolved in a solvent, and trifluoroacetic acid is added to obtain intermediate E-4;

[0135] Step 4: Intermediate E-4 is dissolved in a solvent, a base is added, and a warming reaction is carried out to obtain intermediate E-5;

[0136] Step 5: E-5 is subjected to a reaction in a solvent under the catalysis of a chiral ruthenium catalyst, with formic acid and triethylamine as the source of hydrogen, under a protective atmosphere to obtain target product E-6.

[0137] In the above-mentioned preparation process, the solvent of the reaction is selected from at least one of N,N-dimethylformamide, dichloromethane, ethyl acetate, dimethyl sulfoxide, 1,4-dioxane, methanol, ethanol, water, acetone and acetonitrile.

[0138] The acid is selected from any one of hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, p-toluenesulfonic acid pyridine salt and trifluoroacetic acid.

[0139] The base is selected from any one of sodium hydride, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, cesium carbonate, sodium carbonate, triethylamine and diisopropylethylamine.

[0140] The chiral ruthenium reagent is selected from any one of [(R,R)-N-(2-amino-1,2-diphenylethyl)-p-toluenesulfonamide] chloro(p-cymene)ruthenium(II) and [(S,S)-N-(2-amino-1,2-diphenylethyl)-p-toluenesulfonamide] chloro(p-cymene)ruthenium(II).

[0141] The gas of the protective atmosphere includes at least one of argon and nitrogen.

[0142] The temperature of the above-mentioned warming reaction is 60-100°C, and exemplarily, the temperature of the warming reaction can be 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C and 100°C, and of course, other values within the above-mentioned range are also possible, which are not limited herein.

[0143] Route F:

[0144]

[0145] Step 1: F-1 is dissolved in a solvent with a reaction substrate F1, and a base is added to perform a warming reaction to obtain an intermediate F-2;

[0146] Step 2: The intermediate F-2 is dissolved in a solvent, and trifluoroacetic acid is added to perform a reaction to obtain an intermediate F-3;

[0147] Step 3: The intermediate F-3 is dissolved in a solvent with a reaction substrate F2, and a condensing agent and a base are added to perform a reaction to obtain an intermediate F-4;

[0148] Step 4: F-4 is catalyzed by a chiral ruthenium catalyst, formic acid and triethylamine are added, formic acid and triethylamine are used as a source of hydrogen, and a reaction is performed in a solvent under a protective atmosphere to obtain a target product F-5.

[0149] In the above-mentioned preparation process, the solvent of the reaction is selected from at least one of N,N-dimethylformamide, dichloromethane, ethyl acetate, dimethyl sulfoxide, 1,4-dioxane, methanol, ethanol, water, acetone and acetonitrile.

[0150] The acid is selected from any one of hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, p-toluenesulfonic acid pyridine salt and trifluoroacetic acid.

[0151] The base is selected from any one of sodium hydride, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, cesium carbonate, sodium carbonate, triethylamine and diisopropylethylamine.

[0152] The chiral ruthenium reagent is selected from any one of [(R,R)-N-(2-amino-1,2-diphenylethyl)-p-toluenesulfonamide] chloro(p-cymene)ruthenium(II) and [(S,S)-N-(2-amino-1,2-diphenylethyl)-p-toluenesulfonamide] chloro(p-cymene)ruthenium(II).

[0153] The gas of the protective atmosphere includes at least one of argon and nitrogen.

[0154] The temperature of the above-mentioned temperature rising reaction is 60-100℃, and exemplarily, the temperature of the temperature rising reaction can be 60℃, 65℃, 70℃, 75℃, 80℃, 85℃, 90℃, 95℃ and 100℃, and of course, other values within the above-mentioned range are also possible, which are not limited herein.

[0155] The condensing agent includes any one of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) or (1-propylphosphonic acid cyclic anhydride) T3P.

[0156] The present application also provides a pharmaceutical composition comprising an effective amount of the above-mentioned bifunctional compound or its pharmaceutically acceptable salt, enantiomer, diastereomer, prodrug, solvate and at least one pharmaceutically acceptable carrier, additive, adjuvant or excipient. The above-mentioned drug is a drug for regulating the content and function of HIF-2α, preferably a degrading agent of HIF-2α. It can be understood that based on the core skeleton of the bifunctional compound of the present application, those skilled in the art can make appropriate modifications to make it suitable for the above-mentioned various forms or types of target sites, so as to better play a therapeutic role, and it can also play a role in recruiting target proteins (HIF-2α), thereby promoting the degradation of target proteins.

[0157] The pharmaceutical composition of the present application, when used as a drug, refers to the compound of formula (I) of the present application and its salt, isotope derivative, prodrug, solvate and other compositions composed of other substances with or without biological activity, which can be used for the treatment or prevention of diseases related to HIF-2α.

[0158] In order to adapt to different administration methods, the pharmaceutical composition of the present application can be made into various dosage forms. Specifically, the preparation form of the pharmaceutical composition of the present application can be oral preparation or injection.

[0159] The bifunctional compounds or pharmaceutical compositions of the present application are used for treating cancer or tumor caused by proliferation of target protein (HIF-2a), wherein the cancer includes any one of renal cell carcinoma, lung cancer, skin cancer, head and neck cancer, and breast cancer. The tumor includes any one of blood tumor, glioma, digestive system tumor, reproductive system tumor, lymphoma, and nervous system tumor, wherein the blood tumor includes any one of acute lymphoblastic leukemia, chronic myelogenous leukemia, and mantle cell lymphoma, the digestive system tumor includes any one of esophageal cancer, gastric cancer, and colorectal cancer, the reproductive system tumor includes any one of ovarian cancer and endometrial cancer, and the nervous system tumor includes any one of brain glioma and retinoblastoma, and it is understood that the cancer and tumor mentioned above are caused by up-regulation of HIF-2a expression.

[0160] The embodiments of the present application are further described in the following examples. The embodiments of the present application are not limited to the following specific examples. Within the scope of the same rights, appropriate changes can be made.

[0161] Example 1

[0162] Compound 1-1: cis-2-(2,6-dioxopiperidin-3-yl)-4-((1-(2-(2-((1S)-2-fluoro-1-hydroxy-7- (methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl) amino)isoindoline-1,3-dione

[0163]

[0164] Compound 1-2: trans-2-(2,6-dioxopiperidin-3-yl)-4-((1-(2-(2-((1S)-2-fluoro-1-hydroxy-7- (methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl) amino)isoindoline-1,3-dione.

[0165]

[0166] Step A: Preparation of intermediate 1-A:

[0167] 2-(2-azidoxy)ethyl-1-ol (2 mmol) was dissolved in 5 mL of anhydrous DMF, sodium hydride (2.4 mmol) was added under ice water bath, and the mixture was stirred for 30 min under ice water bath. 4-fluoro-7-(methylsulfonyl)-2,3-dihydrospiro[indene-1,2'-[1,3]dioxolane] (2 mmol) was added, and the mixture was stirred at room temperature for 1 h. After the reaction was completed, the mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give intermediate 1-A.

[0168] Step B: Preparation of intermediate 1-B:

[0169] Intermediate 1-A was dissolved in a mixture of 8 mL of acetone and 2 mL of water, and pyridinium p-toluenesulfonate (PPTS, 1 mmol) was added. The mixture was refluxed for 1 h. After the reaction was completed, the mixture was cooled to room temperature, and the acetone was removed by rotary evaporation. The mixture was added with 20 mL of saturated sodium carbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give intermediate 1-B.

[0170] Step C: Preparation of intermediate 1-C:

[0171] Intermediate 1-B was dissolved in 10 mL of methanol, and SelectFluoro reagent (3 mmol) was added to a sealed bottle. The mixture was stirred at 70°C for 2 h. After the reaction was completed, the mixture was cooled to room temperature, and the methanol was removed by rotary evaporation. The solid residue was dissolved in dichloromethane, filtered, and the filtrate was concentrated. The residue was dissolved in 5 mL of acetonitrile, and 2 mL of dilute hydrochloric acid (2M) was added. The mixture was stirred at room temperature for 1 h. After the reaction was completed, the acetonitrile was removed by rotary evaporation. The mixture was added with 20 mL of saturated sodium carbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and column chromatographed to give intermediate 1-C (300 mg, total yield 42% over three steps).

[0172] Step D: Preparation of intermediate 1-D:

[0173] Intermediate 1-C (0.1 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-(prop-2-yn-1-ylamino)isoindoline-1,3-dione (0.1 mmol), anhydrous copper sulfate (0.05 mmol), and sodium ascorbate (0.2 mmol) were dissolved in a mixture of 4 mL of DMF and 0.5 mL of water, and the mixture was stirred at 70°C for 6 h under argon protection. After the reaction was completed, the mixture was cooled to room temperature, and 20 mL of saturated ammonium chloride solution was added. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and column chromatographed to give intermediate 1-D (40 mg, yield 59.8%).

[0174] Step E: Synthesis of 1-1 and 1-2:

[0175] Formic acid (20 μL) was dissolved in 1 mL of dichloromethane, and triethylamine (30 μL) was added under ice water bath, and stirred for 10 min. The above solution was added to the dichloromethane solution of 1-D, and catalyst [(R,R)-N-(2-amino-1,2-diphenylethyl)-p- methylbenzenesulfonamide] chloro(p-cymene) ruthenium(II) (5% mol) was added, and the reaction was carried out under argon protection at room temperature for 8 h. After the reaction was completed, 20 mL of dichloromethane was added, and saturated sodium bicarbonate was used for washing, and dried, and purified by high performance liquid chromatography, and freeze-dried to obtain the target products 1-1 (10 mg) and 1-2 (6 mg).

[0176] 1 H-NMR (1-1): (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.00 (s, 1H), 7.73 (d, J = 8.7 Hz, 1H), 7.56 (dd, J = 8.5, 7.1 Hz, 1H), 7.16 (d, J = 8.6 Hz, 1H), 7.10 (d, J = 8.7 Hz, 1H), 7.01-7.06 (m, 2H), 5.42 (dd, J = 7.0, 5.0 Hz, 1H), 5.22 (dq, J = 52.1, 5.6 Hz, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 4.49-4.58 (m, 4H), 4.13-4.18 (m, 2H), 3.88 (t, J = 5.2 Hz, 2H), 3.70-3.77 (m, 2H), 3.27 (s, 3H), 2.81-3.14 (m, 4H), 2.55-2.58 (m, 2H), 1.98-2.05 (m, 1H); MS: [M+1]: 671.2. + : 671.2.

[0177] 1H-NMR (1-2): (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.00 (s, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.55 (dd, J = 8.5, 7.1 Hz, 1H), 7.15 (dd, J = 10.6, 8.6 Hz, 2H), 7.00-7.06 (m, 2H), 5.50 (d, J = 16.5 Hz, 1H), 5.18 (dd, J = 50.5, 4.7 Hz, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 4.49-4.58 (m, 4H), 4.16-4.22 (m, 2H), 3.88 (t, J = 5.2 Hz, 2H), 3.72-3.79 (m, 2H), 3.23 (s, 3H), 2.80-2.95 (m, 2H), 2.52-2.62 (m, 2H), 1.96-2.05 (m, 1H); MS: [M+1] + : 671.2.

[0178] Example 2

[0179] Compound 2-1: cis-2-(2,6-dioxopiperidin-3-yl)-4-((1-(2-(2-(2-(2-((((1S)-2-fluoro-1- hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)ethoxy)ethoxy)ethyl)-1H- 1,2,3-triazol-4-yl)methyl)amino)isoindoline-1,3-dione.

[0180]

[0181] Compound 2-2: trans-2-(2,6-dioxopiperidin-3-yl)-4-((1-(2-(2-(2-(2-((((1S)-2-fluoro-1- hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)ethoxy)ethoxy)ethyl)-1H- 1,2,3-triazol-4-yl)methyl)amino)isoindoline-1,3-dione.

[0182]

[0183] Compounds 2-1 and 2-2 were synthesized in a similar manner to the synthesis of compound 1-1 as shown in Example 1-1.

[0184] 1H-NMR (2-1): (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.99 (s, 1H), 7.73 (d, J = 8.7 Hz, 1H), 7.56 (dd, J = 8.6, 7.1 Hz, 1H), 7.16 (d, J = 8.6 Hz, 1H), 7.12 (d, J = 8.8 Hz, 1H), 7.02 - 7.07 (m, 2H), 5.78 (d, J = 7.0 Hz, 1H), 5.42 (q, J = 6.3 Hz, 1H), 5.12 - 5.29 (m, 1H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 4.57 (d, J = 6.0 Hz, 2H), 4.48 (t, J = 5.2 Hz, 2H), 4.15 - 4.21 (m, 2H), 3.79 (t, J = 5.2 Hz, 2H), 3.70 (t, J = 4.5 Hz, 2H), 3.47 - 3.57 (m, 3H), 3.27 (s, 3H), 2.82 - 3.12 (m, 4H), 2.53 - 2.62 (m, 2H), 1.95 - 2.05 (m, 1H); MS: [M+1] + : 715.2.

[0185] 1 H-NMR (2-2): (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 7.98 (s, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.56 (dd, J = 8.6, 7.1 Hz, 1H), 7.12 - 7.22 (m, 2H), 7.02 - 7.08 (m, 2H), 6.02 (d, J = 6.3 Hz, 1H), 5.49 (dd, J = 16.6, 6.1 Hz, 1H), 5.18 (dd, J = 50.5, 4.6 Hz, 1H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 4.57 (d, J = 6.1 Hz, 2H), 4.48 (t, J = 5.2 Hz, 2H), 4.17 - 4.24 (m, 2H), 4.09 (q, J = 5.3 Hz, 2H), 3.79 (t, J = 5.2 Hz, 2H), 3.67 - 3.74 (m, 2H), 3.48 - 3.56 (m, 2H), 3.22 (s, 3H), 2.81 - 2.97 (m, 3H), 2.53 - 2.62 (m, 2H), 1.95 - 2.05 (m, 1H); MS: [M+1] + : 715.2.

[0186] Example 3

[0187] Compound 3-1: cis-2-(2,6-dioxopiperidin-3-yl)-4-(1-(2-(2-(2-(2-(2-((((1S)-2-fluoro-1- hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)ethoxy)ethoxy)ethoxy) ethyl)-1H-1,2,3-triazol-4-yl)methyl)amino)isoindoline-1,3-dione.

[0188]

[0189] Compound 3-2: trans-2-(2,6-dioxopiperidin-3-yl)-4-(1-(2-(2-(2-(2-(2-((((1S)-2-fluoro-1- hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)ethoxy)ethoxy)ethoxy) ethyl)-1H-1,2,3-triazol-4-yl)methyl)amino)isoindoline-1,3-dione.

[0190]

[0191] As shown in Example 1-1, compounds 3-1 and 3-2 were synthesized in a similar manner to the synthesis of compound 1-1.

[0192] 1 H-NMR (3-1): (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 7.99 (s, 1H), 7.73 (d, J = 8.6 Hz, 1H), 7.57 (dd, J = 8.6, 7.1 Hz, 1H), 7.02-7.18 (m, 2H), 7.03-7.07 (d, J = 7.0 Hz, 2H), 5.76-5.80 (m, 1H), 5.42 (td, J = 7.0, 5.0 Hz, 1H), 5.21 (dq, J = 52.1, 5.6 Hz, 1H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 4.58 (d, J = 6.0 Hz, 2H), 4.47 (t, J = 5.2 Hz, 2H), 4.18-4.24 (m, 2H), 3.72-3.80 (m, 4H), 3.52-3.58 (m, 2H), 3.43-3.50 (m, 5H), 3.27 (s, 3H), 2.82-3.14 (m, 4H), 2.52-2.62 (m, 2H), 1.97-2.05 (m, 1H); MS: [M+1]: 759.2. + : 759.2.

[0193] 1H-NMR (3-2): (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.98 (s, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.57 (dd, J = 8.5, 7.1 Hz, 1H), 7.15-7.20 (m 2H), 7.02-7.07 (m, 2H), 6.02 (d, J = 6.4 Hz, 1H), 5.49 (dd, J = 16.5, 6.4 Hz, 1H), 5.18 (dd, J = 50.6, 4.8 Hz, 1H), 5.02-5.09 (m, 1H), 4.59 (d, J = 6.0 Hz, 2H), 4.47 (t, J = 5.2 Hz, 2H), 4.24 (t, J = 4.6 Hz, 2H), 3.76 (q, J = 5.5 Hz, 4H), 3.52-3.57 (m, 2H), 3.42-3.48 (m, 5H), 3.23 (s, 3H), 2.81-2.95 (m, 3H), 2.54-2.69 (m, 3H), 1.97-2.06 (m, 1H); MS: [M+1] + 759.2.

[0194] Example 4

[0195] Compound 4-1: cis-2-(2,6-dioxo-cyclopenta-3-yl)-4-((2-(2-(2-((1S)-2-fluoro-1- hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)ethoxy)ethoxy)ethyl)amino) isoindole-1,3-dione.

[0196]

[0197] Compound 4-2: trans-2-(2,6-dioxo-cyclopenta-3-yl)-4-((2-(2-(2-((1S)-2-fluoro-1- hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)ethoxy)ethoxy)ethyl)amino) isoindole-1,3-dione.

[0198]

[0199] Step A: Preparation of Intermediate 4-A:

[0200] Intermediate 4-A (100 mg), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (74 mg), DIPEA (34 mg) were dissolved in 3 mL of DMF, and reacted at 90 °C for 2 h. After the reaction was completed, it was cooled to room temperature, 20 mL of saturated sodium chloride solution was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and column chromatography to obtain intermediate 4-B (45 mg, yield 27%).

[0201] Step B: Preparation of intermediate 4-B:

[0202] Intermediate 4-A (100 mg), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (74 mg), DIPEA (34 mg) were dissolved in 3 mL of DMF, and reacted at 90 °C for 2 h. After the reaction was completed, it was cooled to room temperature, 20 mL of saturated sodium chloride solution was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and column chromatography to obtain intermediate 4-B (45 mg, yield 27%).

[0203] Step C: Synthesis of 4-1 and 4-2:

[0204] Target compounds 4-1 and 4-2 were synthesized in a similar manner to Step E in the synthesis of 1-1.

[0205] 1 H NMR (4-1): (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.27 (t, J = 4.9 Hz, 1H), 7.73 (d, J = 9.3 Hz, 1H), 7.54 (dd, J = 7.9, 7.0 Hz, 1H), 7.39 (dd, J = 6.9, 1.2 Hz, 1H), 7.18 (dd, J = 7.9, 1.1 Hz, 1H), 6.87 (d, J = 9.3 Hz, 1H), 5.48 (m, 1H), 5.23 (dt, J = 25.3, 5.2 Hz, 1H), 5.00-5.15 (m, 1H), 4.30 (m, 1H), 4.16 (m, 3H), 3.75 (m, 3H), 3.59-3.69 (m, 8H), 3.20 (s, 3H), 3.16 (d, J = 5.4 Hz, 1H), 3.11 (d, J = 5.3 Hz, 1H), 2.51-2.66 (m, 2H), 2.10-2.20 (m, 1H), 1.73-1.81 (m, 1H). MS: [M+1] + : 634.5.

[0206] 1H NMR (4-2): (400 MHz, DMSO-d6) 11.09 (s, 1H), 8.29 (t, J = 4.9 Hz, 1H), 7.70 (d, J = 9.3 Hz, 1H), 7.52 (dd, J = 7.9, 7.0 Hz, 1H), 7.38 (dd, J = 6.9, 1.2 Hz, 1H), 7.13 (dd, J = 7.9, 1.1 Hz, 1H), 6.82 (d, J = 9.3 Hz, 1H), 5.40 (m, 1H), 5.17 - 5,27 (m), 4.87 - 5.02 (m, 1H), 4.46 (d, J = 5.5 Hz, 1H), 4.16 (t, J = 4.9 Hz, 2H), 3.72 - 3.78 (m, 2H), 3.45 - 3.65 (m, 8H), 3.16 - 3.26 (m, 4H), 3.00 - 3.10 (m, 1H), 2.51 - 2.66 (m, 2H), 2.14 - 2.22 (m, 1H), 1.75 - 1.80 (m, 1H). MS: [M+1] + : 634.5.

[0207] Example 5

[0208] Compound 5-1: cis-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoindolin-4-yl)amino)-N-(2-(2-(2-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)ethoxy)ethoxy)ethyl)acetamide.

[0209]

[0210] Compound 5-2: trans-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoindolin-4-yl)amino)-N-(2-(2-(2-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)ethoxy)ethoxy)ethyl)acetamide.

[0211]

[0212]

[0213] Step A: Preparation of Intermediate 5-A:

[0214] 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-l,3-dione (2 mmol), glycine tert-butyl ester (2.2 mmol), DIPEA (4 mmol) were dissolved in DMF, and reacted at 90 °C for 2 h. After the reaction was completed, it was cooled to room temperature, 20 mL of a saturated sodium chloride solution was added, and it was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and column chromatography was performed to obtain intermediate 5-A (600 mg, 77.5%).

[0215] Step B: Preparation of intermediate 5-B

[0216] Intermediate 5-A (600 mg) was dissolved in 10 mL of dichloromethane, 5 mL of trifluoroacetic acid was added, and it was reacted at room temperature for 4 h. After the reaction was completed, it was dried by evaporation, and intermediate 5-B was directly used for the subsequent synthesis.

[0217] Step C: Preparation of intermediate 5-C

[0218] Intermediate 5-B (100 mg), EDCI (116 mg), HOBT (82 mg), DIPEA (78 mg) were dissolved in DMF (5 mL), stirred at room temperature for 20 min, intermediate 4-A (113 mg) was added, and it was reacted at room temperature for 8 h. After the reaction was completed, 20 mL of a saturated sodium chloride solution was added, it was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and reverse phase column chromatography was performed to obtain intermediate 5-C (40 mg, yield 19%).

[0219] Step D: Synthesis of 5-1 and 5-2: Target compounds 5-1 and 5-2 were synthesized in a manner similar to Step E in the synthesis method of 1-1.

[0220] 1H-NMR (5-1): (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.16 (t, J = 5.6 Hz, 1H), 7.74 (d, J = 8.6 Hz, 1H), 7.54 - 7.62 (m, 1H), 7.15 (d, J = 8.7 Hz, 1H), 7.06 (d, J = 7.1 Hz, 1H), 6.94 (t, J = 5.6 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H), 5.78 (d, J = 6.9 Hz, 1H), 5.37 - 5.47 (m, 1H), 5.13 - 5.31 (m, 1H), 5.07 (dd, J = 13.0, 5.4 Hz, 1H), 4.21 - 4.26 (m, 2H), 3.93 (d, J = 5.6 Hz, 2H), 3.74 - 3.81 (m, 2H), 3.57 - 3.65 (m, 2H), 3.48 - 3.55 (m, 2H), 3.43 - 3.46 (m, 2H), 3.22 - 3.27 (m, 5H), 2.83 - 3.15 (m, 4H), 2.54 - 2.63 (m, 1H), 1.95 - 2.05 (m, 1H); MS: [M+1] + : 691.2.

[0221] 1 H-NMR (5-2): (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 8.19 (t, J = 5.6 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.50 - 7.58 (m, 1H), 7.09 (d, J = 8.7 Hz, 1H), 7.03 (d, J = 7.1 Hz, 1H), 6.94 (t, J = 5.6 Hz, 1H), 6.80 (d, J = 8.5 Hz, 1H), 5.68 (d, J = 6.9 Hz, 1H), 5.30 - 5.44 (m, 1H), 5.25 - 5.31 (m, 1H), 4.95 (dd, J = 13.0, 5.4 Hz, 1H), 4.18 - 4.27 (m, 2H), 3.89 (d, J = 5.6 Hz, 2H), 3.76 - 3.84 (m, 2H), 3.54 - 3.68 (m, 2H), 3.48 - 3.55 (m, 2H), 3.43 - 3.46 (m, 2H), 3.28 - 3.34 (m, 5H), 2.90 - 3.15 (m, 4H), 2.46 - 2.58 (m, 1H), 1.95 - 2.05 (m, 1H); MS: [M+1] + : 691.2.

[0222] Example 6

[0223] Compound 6-1 : cis-2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoindolin-4-yl)amino)-N-(2-(2-(2-(2-((lS)-2-fluoro-l-hydroxy-7-(methylsulfonyl)-2,3-dihydro-lH-inden-4-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)acetamide.

[0224]

[0225] Compound 6-2: trans-2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoindolin-4-yl)amino)-N-(2-(2-(2-(2-((lS)-2-fluoro-l-hydroxy-7-(methylsulfonyl)-2,3-dihydro-lH-inden-4-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)acetamide.

[0226]

[0227] Compounds 6-1 and 6-2 were synthesized in a similar manner to synthesis 5-1 as shown in Example 5-1.

[0228] 1 H-NMR (6-1): (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.16 (t, J = 5.6 Hz, 1H), 7.70-7.78 (m, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.15 (d, J = 8.7 Hz, 1H), 7.07 (d, J = 7.1 Hz, 1H), 6.94 (t, J = 5.7 Hz, 1H), 6.86 (d, J = 8.5 Hz, 1H), 5.78 (d, J = 6.9 Hz, 1H), 5.42 (q, J = 6.4 Hz, 1H), 5.22 (dq, J = 51.9, 5.7 Hz, 1H), 5.07 (dd, J = 12.9, 5.4 Hz, 1H), 4.18-4.28 (m, 2H), 3.93 (d, J = 5.6 Hz, 2H), 3.77 (t, J = 4.4 Hz, 2H), 3.56-3.65 (m, 2H), 3.47-3.56 (m, 6H), 3.42 (t, J = 5.8 Hz, 2H), 3.22-3.30 (m, 5H), 2.82-3.18 (m, 4H), 2.52-2.64 (m, 1H), 1.99-2.08 (m, 1H); MS: [M+1]: 735.2. + : 735.2.

[0229] 1H-NMR (6-2): (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.16 (t, J = 5.7 Hz, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.19 (d, J = 8.6 Hz, 1H), 7.07 (d, J = 7.1 Hz, 1H), 6.94 (t, J = 5.6 Hz, 1H), 6.86 (d, J = 8.6 Hz, 1H), 6.03 (d, J = 6.4 Hz, 1H), 5.50 (dd, J = 16.5, 6.4 Hz, 1H), 5.19 (dd, J = 50.4, 4.6 Hz, 1H), 5.07 (dd, J = 12.9, 5.4 Hz, 1H), 4.25 (t, J = 4.7 Hz, 2H), 3.93 (d, J = 5.6 Hz, 2H), 3.78 (t, J = 4.6 Hz, 2H), 3.56 - 3.63 (m, 2H), 3.45 - 3.55 (m, 6H), 3.42 (t, J = 5.7 Hz, 2H), 3.20 - 3.27 (m, 5H), 2.82 - 2.97 (m, 2H), 2.52 - 2.63 (m, 3H), 1.97 - 2.06 (m, 1H); MS: [M+1] + : 735.2.

[0230] Example 7

[0231] Compound 7-1: cis-4-((1-(2-(2-(2-(2-((1S)-7-((difluoromethyl)sulfonyl)-2-fluoro-1- hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4- yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

[0232]

[0233] Compound 7-2: trans-4-((1-(2-(2-(2-(2-((1S)-7-((difluoromethyl)sulfonyl)-2-fluoro-1- hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4- yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

[0234]

[0235]

[0236] Step A: Preparation of Intermediate 7-A:

[0237] Dissolve 4-fluoro-7-mercapto-2,3-dihydro-lH-inden-l-one (10 mmol) in 50 mL of acetone, add an aqueous solution of potassium hydroxide (200 mmol) (50 mL), cool to -78 °C, add bromodifluoromethylphosphonic acid diethyl ester (20 mmol), slowly raise to room temperature, and react at room temperature for 2 h. After the reaction is complete, add 100 mL of water, extract with ethyl acetate, dry over anhydrous sodium sulfate, and column chromatograph to obtain intermediate 7-A (8 mmol, 80% yield).

[0238] Step B: Preparation of intermediate 7-B

[0239] Dissolve 7-A (8 mmol), sodium periodate (20 mmol), and ruthenium trichloride (0.2 mmol) in a mixed solvent of acetonitrile (30 mL), carbon tetrachloride (30 mL), and water (30 mL), and react at room temperature for 5 h. After the reaction is complete, filter to remove the solid, spin to remove part of the solvent, add 100 mL of water, extract with dichloromethane, dry over anhydrous sodium sulfate, and spin dry to obtain intermediate 7-B (crude 7.2 mmol, 90% yield), which is directly used in subsequent synthesis.

[0240] Step C: Preparation of intermediate 7-C

[0241] Dissolve 7-B (1 mmol) in 5 mL of toluene, add 2 mL of ethylene glycol, and reflux react for 12 h. After the reaction is complete, cool to room temperature, spin to remove part of the solvent, add 20 mL of water, extract with ethyl acetate, dry over anhydrous sodium sulfate, and column chromatograph to obtain intermediate 7-C (0.4 mmol, 40% yield).

[0242] Step D-H are synthesized in a similar manner to 1-1 to obtain target compounds 7-1 and 7-2.

[0243] 1H-NMR (7-1): (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 7.99 (s, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.56 (dd, J = 8.6, 7.1 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 7.13-7.19 (m, 1H), 7.16 (t, J = 53.6 Hz, 1H), 7.02-7.07 (m, 2H), 5.15-5.39 (m, 2H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 4.57 (d, J = 6.0 Hz, 2H), 4.48 (t, J = 5.2 Hz, 2H), 4.18-4.27 (m, 2H), 3.79 (t, J = 5.2 Hz, 2H), 3.71 (dd, J = 5.7, 3.4 Hz, 2H), 3.47-3.55 (m, 4H), 2.81-3.16 (m, 4H), 2.52-2.62 (m, 2H), 1.97-2.05 (m, 1H); MS: [M+1] + : 751.2.

[0244] 1 H-NMR (7-2): (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 7.99 (s, 1H), 7.85 (d, J = 8.7 Hz, 1H), 7.52-7.60 (m, 1H), 7.28 (d, J = 8.8 Hz, 1H), 7.16 (d, J = 8.6 Hz, 1H), 7.07 (t, J = 53.1 Hz, 1H), 7.01-7.09 (m, 2H), 5.38 (d, J = 16.6 Hz, 1H), 5.20 (dd, J = 50.6, 4.8 Hz, 1H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 4.58 (d, J = 6.1 Hz, 2H), 4.48 (t, J = 5.2 Hz, 2H), 4.20-4.30 (m, 2H), 3.79 (t, J = 5.2 Hz, 2H), 3.72 (t, J = 4.5 Hz, 2H), 3.48-3.56 (m, 4H), 3.22-3.25 (m, 1H), 2.83-2.94 (m, 3H), 2.55-2.62 (m, 2H), 1.97-2.10 (m, 1H); MS: [M+1] + : 751.2.

[0245] Example 8

[0246] Compound 8-1: cis-2-(2,6-dioxopiperidin-3-yl)-5-((1-(2-(2-(2-(2-((((1S)-2-fluoro-1- hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)ethoxy)ethoxy)ethyl)-1H- 1,2,3-triazol-4-yl)methyl)amino)isoindoline-1,3-dione.

[0247]

[0248] Compound 8-2: trans-2-(2,6-dioxopiperidin-3-yl)-5-((1-(2-(2-(2-(2-((((1S)-2-fluoro-1- hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)ethoxy)ethoxy)ethyl)-1H- 1,2,3-triazol-4-yl)methyl)amino)isoindoline-1,3-dione.

[0249]

[0250] As shown in Example 1-1, compounds 8-1 and 8-2 were synthesized in a similar manner to the synthesis of compound 1-1.

[0251] 1 H-NMR (8-1): (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 7.99 (s, 1H), 7.73 (d, J = 8.7 Hz, 1H), 7.52-7.58 (m, 2H), 7.12 (d, J = 8.8 Hz, 1H), 7.05 (d, J = 2.1 Hz, 1H), 6.94 (dd, J = 8.4, 2.1 Hz, 1H), 5.38-5.45 (m, 1H), 5.21 (dq, J = 52.1, 5.6 Hz, 1H), 5.02 (dd, J = 12.9, 5.4 Hz, 1H), 4.42-4.53 (m, 4H), 4.12-4.22 (m, 2H), 3.79 (t, J = 5.2 Hz, 2H), 3.70 (t, J = 4.6 Hz, 2H), 3.48-3.57 (m, 4H), 3.27 (s, 3H), 2.80-3.16 (m, 4H), 2.52-2.61 (m, 2H), 1.94-2.01 (m, 1H); MS: [M+1]: 715.2. + : 715.2.

[0252] 1H-NMR (8-2): (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 7.99 (s, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.52-7.60 (m, 2H), 7.16 (d, J = 8.7 Hz, 1H), 7.06 (d, J = 2.1 Hz, 1H), 6.94 (dd, J = 8.4, 2.2 Hz, 1H), 5.49 (d, J = 16.5 Hz, 1H), 5.18 (dd, J = 50.4, 4.6 Hz, 1H), 5.03 (dd, J = 12.9, 5.4 Hz, 1H), 4.43-4.52 (m, 4H), 4.21 (t, J = 4.7 Hz, 2H), 3.79 (t, J = 5.2 Hz, 2H), 3.68-3.74 (m, 2H), 3.49-3.56 (m, 4H), 3.18-3.27 (m, 5H), 2.80-2.96 (m, 2H), 2.52-2.61 (m, 2H), 1.94-2.02 (m, 1H); MS: [M+1] + : 715.2.

[0253] Example 9

[0254] Compound 9-1: cis-2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-((1-(2-(2-(2-(((1S)-2-fluoro-1- hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)ethoxy)ethoxy)ethyl)-1H-1,2,3- triazol-4-yl)methyl)amino)isoindoline-1,3-dione.

[0255]

[0256] Compound 9-2: trans-2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-((1-(2-(2-(2-(((1S)-2-fluoro-1- hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)ethoxy)ethoxy)ethyl)-1H-1,2,3- triazol-4-yl)methyl)amino)isoindoline-1,3-dione.

[0257]

[0258] Compounds 9-1 and 9-2 were synthesized in a similar manner to the synthesis of compound 1-1 as shown in Example 1-1.

[0259] 1H-NMR (9-1): (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 7.96 (s, 1H), 7.73 (d, J = 8.6 Hz, 1H), 7.57 (d, J = 10.1 Hz, 1H), 7.42 (m, 1H), 7.22 (d, J = 7.2 Hz, 1H), 7.12 (d, J = 8.7 Hz, 1H), 5.78 (d, J = 6.9 Hz, 1H), 5.37-5.45 (m, 1H), 5.22 (dq, J = 52.1, 5.6 Hz, 1H), 5.04 (dd, J = 12.7, 5.4 Hz, 1H), 4.55 (d, J = 6.0 Hz, 2H), 4.48 (t, J = 5.2 Hz, 2H), 4.10-4.22 (m, 2H), 3.78 (t, J = 5.2 Hz, 2H), 3.69 (t, J = 4.6 Hz, 2H), 3.45-3.55 (m, 4H), 3.28 (s, 3H), 2.80-3.13 (m, 4H), 2.50-2.60 (m, 1H), 1.95-2.02 (m, 1H); MS: [M+1] + : 733.2.

[0260] 1 H-NMR (9-2): (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 7.95 (s, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.58 (d, J = 10.2 Hz, 1H), 7.37-7.45 (m, 1H), 7.22 (d, J = 7.2 Hz, 1H), 7.16 (d, J = 8.7 Hz, 1H), 6.03 (d, J = 6.2 Hz, 1H), 5.50 (dd, J = 16.6, 4.7 Hz, 1H), 5.18 (dd, J = 50.5, 4.6 Hz, 1H), 5.04 (dd, J = 12.7, 5.4 Hz, 1H), 4.56 (d, J = 6.1 Hz, 2H), 4.48 (t, J = 5.2 Hz, 3H), 4.21 (t, J = 4.6 Hz, 2H), 3.78 (t, J = 5.2 Hz, 2H), 3.70 (dd, J = 5.7, 3.5 Hz, 2H), 3.45-3.55 (m, 4H), 3.18-3.27 (m, 5H), 2.80-2.96 (m, 2H), 2.52-2.60 (m, 1H), 1.95-2.02 (m, 1H); MS: [M+1] + : 733.2.

[0261] Example 10

[0262] Compound 10-1: cis-3-(4-((1-(2-(2-(2-(2-(((1S)-2-fluoro-1-hydroxy-7- (methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)ethoxy)ethoxy)ethyl)-1H-1,2,3- triazol-4-yl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione.

[0263]

[0264] Compound 10-2: trans-3-(4-((1-(2-(2-(2-(2-(((1S)-2-fluoro-1-hydroxy-7- (methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)ethoxy)ethoxy)ethyl)-1H-1,2,3- triazol-4-yl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0265]

[0266] As shown in Example 1-1, compounds 10-1 and 10-2 were synthesized in a similar manner to the synthesis of compound 1-1.

[0267] 1 H-NMR (10-1): (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 7.93 (s, 1H), 7.74 (d, J = 8.6 Hz, 1H), 7.25 (t, J = 7.7 Hz, 1H), 7.12 (d, J = 8.7 Hz, 1H), 6.95 (d, J = 7.4 Hz, 1H), 6.82 (d, J = 8.1 Hz, 1H), 6.19 (t, J = 5.9 Hz, 1H), 5.79 (d, J = 7.0 Hz, 1H), 5.42 (q, J = 6.5 Hz, 1H), 5.05-5.30 (m, 2H), 4.46 (t, J = 5.2 Hz, 2H), 4.40 (d, J = 5.8 Hz, 2H), 4.10-4.27 (m, 4H), 3.78 (t, J = 5.2 Hz, 2H), 3.69 (t, J = 4.5 Hz, 2H), 3.50 (m, 4H), 3.28 (s, 3H), 2.85-3.16 (m, 3H), 2.54-2.67 (m, 1H), 2.20-2.35 (m, 1H), 1.95-2.05 (m, 1H); MS: [M+1]: 701.2. + : 701.2.

[0268] 1H-NMR (10"2): (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.93 (s, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.25 (t, J = 7.7 Hz, 1H), 7.15 (d, J = 8.7 Hz, 1H), 6.95 (d, J = 7.4 Hz, 1H), 6.82 (d, J = 8.1 Hz, 1H), 6.20 (t, J = 5.9 Hz, 1H), 6.00-6.08 (m, 1H), 5.45-5.55 (m, 1H), 5.06-5.26 (m, 2H), 4.46 (t, J = 5.2 Hz, 2H), 4.41 (d, J = 5.9 Hz, 2H), 4.10-4.30 (m, 4H), 3.78 (t, J = 5.2 Hz, 2H), 3.70 (t, J = 4.6 Hz, 2H), 3.51 (m, 4H), 3.24-3.28 (m, 1H), 3.23 (s, 3H), 2.81-2.97 (m, 2H), 2.52-2.65 (m, 1H), 2.22-2.33 (m, 1H), 2.01 (m, 1H); MS: [M+1] + 701.2.

[0269] Example 11

[0270] Compound 11-1: cis-3-(2-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoindolin-4- yl)amino)methyl)-lH-l,2,3-triazol-l-yl)ethoxy)ethoxy)-5-((lS)-2-fluoro-l-hydroxy-7- (methylsulfonyl)-2,3-dihydro-lH-inden-4-yl)oxy)benzonitrile.

[0271]

[0272] Compound 11-2: trans-3-(2-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoindolin-4- yl)amino)methyl)-lH-l,2,3-triazol-l-yl)ethoxy)ethoxy)-5-((lS)-2-fluoro-l-hydroxy-7- (methylsulfonyl)-2,3-dihydro-lH-inden-4-yl)oxy)benzonitrile.

[0273]

[0274] Step A: Preparation of Intermediate 11-A

[0275] Intermediate 11-A was prepared by dissolving 4-fluoro-7-(methylsulfonyl)-2,3- dihydrospiro[indene-l,2'-[l,3]dioxolane] (2 mmol), 3,5-dihydroxybenzonitrile (4 mmol) and potassium carbonate (4 mmol) in DMF (8 mL) and microwave reaction at 100 °C for 2 h. After the reaction was completed, it was cooled to room temperature, 50 mL saturated sodium chloride solution was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, rotary evaporated, and column chromatography to give intermediate 11-A (1.54 mmol, yield 77%).

[0276] Step B: Preparation of intermediate 11-B

[0277] Intermediate 11-B was prepared by dissolving 11-A (1.54 mmol) in anhydrous DMF (8 mL), adding sodium hydride (2 mmol) under ice water bath, stirring for 30 min under ice water bath, adding 2-(2-azidoethoxy)ethyl 4-methylbenzenesulfonate (1.54 mmol), and reacting at room temperature for 4 h. After the reaction was completed, 40 mL ice water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and rotary evaporated to give intermediate 11-B.

[0278] The synthesis method of Step C-F is similar to the reaction related in the synthesis method of 1-1 to give compounds 11-1 and 11-2.

[0279] 1 H-NMR (11-1): (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.78 (d, J = 8.6 Hz, 1H), 7.55 (dd, J = 8.8, 6.9 Hz, 1H), 7.28-7.33 (m, 1H), 7.13-7.19 (m, 2H), 7.00-7.08 (m, 4H), 5.45-5.52 (m, 1H), 5.17-5.36 (m, 1H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 4.47-4.59 (m, 4H), 4.10-4.15 (m, 2H), 3.84 (t, J = 5.2 Hz, 2H), 3.68-3.72 (m, 2H), 2.82-3.30 (m, 7H), 2.54-2.66 (m, 2H), 1.95-2.05 (m, 1H); MS: [M+1] 788.2. + : 788.2.

[0280] 1H-NMR (11-2): (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.55 (dd, J = 8.5, 7.1 Hz, 1H), 7.30-7.34 (m, 1H), 7.20-7.24 (m, 1H), 7.16 (d, J = 8.6 Hz, 2H), 7.00-7.10 (m, 4H), 5.56 (d, J = 16.3 Hz, 1H), 5.23 (dd, J = 50.4, 4.7 Hz, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 4.47-4.60 (m, 4H), 4.08-4.16 (m, 2H), 3.85 (t, J = 5.2 Hz, 2H), 3.67-3.73 (m, 2H), 3.40-3.50 (m, 2H), 3.29 (s, 3H), 2.82-3.06 (m, 2H), 2.54-2.66 (m, 2H), 1.97-2.10 (m, 1H); MS: [M+1] 788.2. + : 788.2.

[0281] Example 12

[0282] Compound 12-1: cis-3-(2-(2-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoindolin-4- yl)amino)methyl)-1H-1,2, 3-triazol-1-yl)ethoxy)ethoxy)ethoxy)-5-((1S)-2-fluoro-1- hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile.

[0283]

[0284] Compound 12-2: trans-3-(2-(2-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoindolin-4- yl)amino)methyl)-1H-1,2, 3-triazol-1-yl)ethoxy)ethoxy)ethoxy)-5-((1S)-2-fluoro-1- hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile.

[0285]

[0286] Compounds 12-1 and 12-2 were synthesized using similar procedures as 11-1 as described in the synthesis procedure of Example 11-1.

[0287] 1H-NMR (12-1): (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 7.99 (s, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.56 (dd, J = 8.6, 7.1 Hz, 1H), 7.31 (dd, J = 2.3, 1.3 Hz, 1H), 7.12 - 7.19 (m, 2H), 7.01 - 7.08 (m, 4H), 5.95 (d, J = 6.7 Hz, 1H), 5.49 (q, J = 6.8 Hz, 1H), 5.27 (dq, J = 52.1, 5.4 Hz, 1H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 4.57 (d, J = 6.1 Hz, 2H), 4.48 (t, J = 5.2 Hz, 2H), 4.12 (dd, J = 5.7, 3.3 Hz, 2H), 3.78 (t, J = 5.2 Hz, 2H), 3.65 (dd, J = 5.3, 3.3 Hz, 2H), 3.49 (s, 3H), 3.33 - 3.35 (m, 3H), 2.82 - 3.21 (m, 4H), 2.52 - 2.62 (m, 2H), 1.98 - 2.05 (m, 1H); MS: [M+1] 832.2. + :832.2.

[0288] 1 H-NMR (12-2): (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 7.99 (s, 1H), 7.78 (d, J = 8.6 Hz, 1H), 7.52 - 7.60 (m, 1H), 7.32 - 7.34 (m, 1H), 7.20 - 7.22 (m, 1H), 7.16 (d, J = 8.6 Hz, 1H), 7.01 - 7.10 (m, 3H), 6.18 (d, J = 5.7 Hz, 1H), 5.56 (dd, J = 16.3, 5.3 Hz, 1H), 5.23 (dd, J = 50.4, 4.7 Hz, 1H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 4.57 (d, J = 6.0 Hz, 2H), 4.48 (t, J = 5.2 Hz, 2H), 4.10 - 4.15 (m, 2H), 3.78 (t, J = 5.2 Hz, 2H), 3.63 - 3.69 (m, 2H), 3.49 (s, 3H), 3.34 - 3.46 (m, 2H), 3.29 (m, 3H), 2.81 - 3.05 (m, 2H), 2.54 - 2.65 (m, 2H), 1.95 - 2.05 (m, 1H); MS: [M+1] 832.2. + :832.2.

[0289] Example 13

[0290] Compound 13-1: cis-3-(2-(2-(2-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoindolin-4- yl)amino)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethoxy)ethoxy)ethoxy)-5-((1S)-2-fluoro-1- hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile.

[0291]

[0292] Compound 13-2: trans-3-(2-(2-(2-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoindolin-4- yl)amino)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethoxy)ethoxy)ethoxy)-5-((1S)-2-fluoro-1- hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile.

[0293]

[0294] 12-1 and 12-2 were synthesized using a similar method as 11-1 as described in the synthesis method of Example 11-1.

[0295] 1 H-NMR (13-1): (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.99 (s, 1H), 7.78 (d, J = 8.6 Hz, 1H), 7.52-7.60 (m, 1H), 7.30-7.34 (m, 1H), 7.13-7.20 (m, 2H), 7.01-7.08 (m, 4H), 5.90-6.00 (m, 1H), 5.45-5.55 (m, 1H), 5.27 (dq, J = 51.9, 5.4 Hz, 1H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 4.58 (d, J = 6.0 Hz, 2H), 4.47 (t, J = 5.2 Hz, 2H), 4.12-4.17 (m, 2H), 3.77 (t, J = 5.2 Hz, 2H), 3.65-370 (m, 2H), 3.41-3.55 (m, 7H), 3.30 (s, 3H), 2.81-3.23 (m, 4H), 2.52-2.62 (m, 2H), 1.96-2.06 (m, 1H); MS: [M+1] + : 876.2.

[0296] 1H-NMR (13-2): (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 7.99 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.56 (dd, J = 8.6, 7.1 Hz, 1H), 7.32-7.36 (m, 1H), 7.20-7.23 (m, 1H), 7.16 (d, J = 8.6 Hz, 1H), 7.01-7.11 (m, 4H), 6.15-6.25 (m, 1H), 5.56 (d, J = 15.9 Hz, 1H), 5.23 (dd, J = 50.3, 4.6 Hz, 1H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 4.58 (d, J = 6.1 Hz, 2H), 4.47 (t, J = 5.2 Hz, 2H), 4.10-4.17 (m, 2H), 3.77 (t, J = 5.2 Hz, 2H), 3.65-3.72 (m, 2H), 3.41-3.55 (m, 9H), 3.29 (s, 3H), 2.83.05 (m, 2H), 2.52-2.62 (m, 2H), 1.97-2.04 (m, 1H); MS: [M+1] 876.2. + : 876.2.

[0297] Example 14

[0298] Compound 14-1: cis 2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(3-fluoro-5-((1S)-2-fluoro-1- hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzoyl)piperazin-1-yl)piperidin- 1-yl)isoindole-1,3-dione.

[0299]

[0300] Compound 14-2: trans 2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(3-fluoro-5-((1S)-2-fluoro-1- hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzoyl)piperazin-1-yl)piperidin- 1-yl)isoindole-1,3-dione.

[0301]

[0302] Step A: Preparation of Intermediate 14-A

[0303] To a solution of 4-fluoro-7-(methylsulfonyl)-2,3-dihydrospiro[indene-l,2'- [l,3]dioxolane] (2 mmol), methyl 3-fluoro-5-hydroxybenzoate (2 mmol) and cesium carbonate (4 mmol) in DMF (8 mL) was heated at 100 °C for 2 h in a microwave reactor. After the reaction was completed, the mixture was cooled to room temperature. Intermediate 14-A (1 mmol, 50% yield) was obtained.

[0304] Step B: Preparation of Intermediate 14-B

[0305] To a solution of 14-A (1 mmol) in a mixture of 8 mL of acetone and 2 mL of water was added pyridinium p-toluenesulfonate (0.5 mmol) and the mixture was refluxed for 2 h. After the reaction was completed, the mixture was cooled to room temperature. The solvent was removed by rotary evaporation. The residue was dissolved in 20 mL of saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated by rotary evaporation to give Intermediate 14-B.

[0306] Step C: Preparation of Intermediate 14-C

[0307] To a solution of the crude product from Step B in 8 mL of anhydrous methanol was added SelectFluoro reagent (1.5 mmol) and the mixture was refluxed for 4 h. After the reaction was completed, the mixture was cooled to room temperature. The solvent was removed by rotary evaporation. The residue was dissolved in dichloromethane and filtered. The filtrate was concentrated by rotary evaporation. The residue was dissolved in 5 mL of acetonitrile. 1 mL of dilute hydrochloric acid (2 M) was added and the mixture was stirred at room temperature for 1 h. After the reaction was completed, the mixture was diluted with 20 mL of saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated by rotary evaporation. The residue was purified by column chromatography to give Intermediate 14-C (0.4 mmol, 40% yield over two steps).

[0308] Step D: Preparation of Intermediate 14-D

[0309] To a solution of 14-C (0.4 mmol) in a mixture of 4 mL of tetrahydrofuran and 1 mL of water was added lithium hydroxide (1 mmol) and the mixture was stirred at room temperature for 2 h. After the reaction was completed, the pH of the mixture was adjusted to 4-5 with dilute hydrochloric acid. The mixture was diluted with 10 mL of water. The mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated by rotary evaporation to give Intermediate 14-D.

[0310] Step E: Preparation of Intermediate 14-E

[0311] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-l,3-dione (2 mmol), tert-butyl 4-(piperidin-4-yl)piperazine-l-carboxylate (2 mmol) and DIPEA (3 mmol) in DMSO (8 mL) was heated at 90 °C for 2 h in a microwave reactor. After the reaction was completed, the mixture was cooled to room temperature. The mixture was diluted with 30 mL of saturated sodium chloride solution. The mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated by rotary evaporation to give Intermediate 14-F.

[0312] Step F: Synthesis of intermediate 14-F

[0313] The intermediate 14-E from Step E was dissolved in 10 mL of dichloromethane, 5 mL of trifluoroacetic acid was added, and the reaction was stirred at room temperature for 3 h. After the reaction was completed, the solvent was evaporated to give the intermediate 14-F.

[0314] Step G: Synthesis of intermediate 14-G

[0315] The intermediate 14-D (0.1 mmol), EDCI (0.2 mmol), HOBT (0.2 mmol), and triethylamine (0.2 mmol) were dissolved in DMF (4 mL), and the mixture was stirred at room temperature for 30 min. Then, 14-G (0.11 mmol) was added, and the reaction was stirred at room temperature for 8 h. After the reaction was completed, 20 mL of a saturated sodium chloride solution was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, evaporated, and purified by column chromatography to give the intermediate 14-G (0.05 mmol, 50% yield).

[0316] Step H: Synthesis of 14-1 and 14-2

[0317] Formic acid (20 μL) was dissolved in 1 mL of dichloromethane, and triethylamine (30 μL) was added under an ice water bath, and the mixture was stirred for 10 min. The above solution was added to a dichloromethane solution of 1-H (0.05 mmol), and a catalyst [(R,R)-N-(2-amino-1,2-diphenylethyl)-p-toluenesulfonamide] chloro(p-cymene) ruthenium(II) (5% mol) was added. The reaction was stirred at room temperature for 8 h under argon protection. After the reaction was completed, 20 mL of dichloromethane was added, and the mixture was washed with a saturated sodium bicarbonate solution, dried, and purified by high performance liquid chromatography to give the target products 1-1 (15 mg) and 1-2 (10 mg).

[0318] 1H-NMR (14-1): (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 7.80 (d, J = 8.6 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.32 (d, J = 2.2 Hz, 1H), 7.24 (dd, J = 8.7, 2.3 Hz, 1H), 7.07-7.18 (m, 3H), 6.91 (t, J = 1.8 Hz, 1H), 5.46-5.56 (m, 1H), 5.27 (dq, J = 52.2, 5.5 Hz, 1H), 5.06 (dd, J = 12.9, 5.4 Hz, 1H), 4.07 (d, J = 12.9 Hz, 2H), 3.56 (m, 2H), 3.33 (s, 3H), 2.82-3.22 (m, 8H), 2.54-2.68 (m, 7H), 1.95-2.05 (m, 1H), 1.82 (d, J = 12.4 Hz, 2H), 1.37-1.50 (m, 2H); MS: [M+1] 792.2. + : 792.2.

[0319] 1 H-NMR (14-2): (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.65 (d, J = 8.6 Hz, 1H), 7.32 (d, J = 2.3 Hz, 1H), 7.10-7.26 (m, 4H), 6.92-6.95 (m, 1H), 5.57 (d, J = 16.3 Hz, 1H), 5.23 (dd, J = 50.3, 4.6 Hz, 1H), 5.06 (dd, J = 12.9, 5.4 Hz, 1H), 4.07 (d, J = 13.0 Hz, 2H), 3.50-3.60 (m, 2H), 3.30 (s, 3H), 2.82-3.06 (m, 6H), 2.50-2.65 (m, 9H), 1.97-2.05 (m, 1H), 1.82 (d, J = 12.3 Hz, 2H), 1.45 (q, J = 11.3 Hz, 2H); MS: [M+1] 792.2. + : 792.2.

[0320] Example 15

[0321] Compound 15-1: cis 2-(2,6-dioxopiperidin-3-yl)-5-(6-(3-fluoro-5-((1S)-2-fluoro-1- hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzoyl)-2,6-diazaspiro[3.3]heptan- 2-yl)isoindole-1,3-dione.

[0322]

[0323] Compound 15-2: trans-2-(2,6-dioxopiperidin-3-yl)-5-(6-(3-fluoro-5-((1S)-2-fluoro-1- hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzoyl)-2,6-diazaspiro[3.3]heptan- 2-yl)isoindole-1,3-dione.

[0324]

[0325] As shown in Example 14-1, 15-1 and 15-2 were synthesized using a similar method as 14-1.

[0326] 1 H-NMR (15-1): (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.29 - 7.34 (m, 1H), 7.22 - 7.27 (m, 1H), 7.14 (s, 1H), 7.09 (d, J = 8.6 Hz, 1H), 6.81 (d, J = 2.1 Hz, 1H), 6.67 (dd, J = 8.3, 2.1 Hz, 1H), 5.45 - 5.55 (m, 1H), 5.28 (dq, J = 51.9, 5.5 Hz, 1H), 5.06 (dd, J = 12.9, 5.4 Hz, 1H), 4.54 (s, 2H), 4.13 - 4.30 (m, 6H), 3.33 (s, 3H), 2.80 - 3.25 (m, 4H), 2.53 - 2.63 (m, 2H), 1.95 - 2.05 (m, 1H); MS: [M+1]: 721.2. + : 721.2.

[0327] 1H-NMR (15-2): (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 7.82 (d, J = 8.6 Hz, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.27 - 7.35 (m, 2H), 7.16 (t, J = 1.7 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H), 6.80 (d, J = 2.1 Hz, 1H), 6.67 (dd, J = 8.3, 2.2 Hz, 1H), 5.57 (d, J = 16.3 Hz, 1H), 5.24 (dd, J = 50.3, 4.7 Hz, 1H), 5.06 (dd, J = 12.9, 5.4 Hz, 1H), 4.54 (s, 2H), 4.14 - 4.29 (m, 6H), 3.44 (dd, J = 18.4, 4.9 Hz, 2H), 3.30 (s, 3H), 2.82 - 3.07 (m, 2H), 2.52 - 2.62 (m, 2H), 1.95 - 2.05 (m, 1H); MS: [M+1] + : 721.2.

[0328] Example 16

[0329] Compound 16-1: cis-N-(2-(4-(l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)piperidin-4-yl)piperazin-l-yl)-2-oxoethyl)-3-fluoro-5-((lS)-2-fluoro-l-hydroxy-7- (methylsulfonyl)-2,3-dihydro-lH-inden-4-yl)oxy)benzamide;

[0330]

[0331] Compound 16-2: trans-N-(2-(4-(l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)piperidin-4-yl)piperazin-l-yl)-2-oxoethyl)-3-fluoro-5-((lS)-2-fluoro-l-hydroxy-7- (methylsulfonyl)-2,3-dihydro-lH-inden-4-yl)oxy)benzamide;

[0332]

[0333] Step A: Preparation of Intermediate 16-A

[0334] Step A: Preparation of intermediate 16-A

[0335] Step B: Preparation of intermediate 16-B

[0336] Step B: Preparation of intermediate 16-B

[0337] Step C and Step D: The target compounds 16-1 and 16-2 were synthesized using similar methods as described in Example 14-1.

[0338]

[0339] 1 H-NMR (16-1): (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.77 (t, J = 5.7 Hz, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.53-7.60 (m, 1H), 7.42-7.44 (m, 1H), 7.22-7.35 (m, 3H), 7.08 (d, J = 8.6 Hz, 1H), 5.45-5.55 (m, 1H), 5.29 (dq, J = 51.9, 5.4 Hz, 1H), 5.06 (dd, J = 12.9, 5.4 Hz, 1H), 4.00-4.15 (m, 4H), 2.82-3.50 (m, 14H), 2.46-2.62 (m, 6H), 1.97-2.05 (m, 1H), 1.83 (d, J = 12.4 Hz, 2H), 1.40-1.52 (m, 2H); MS: [M+1]: 849.2. + : 849.2.

[0340] 1H-NMR (16-2): (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.78 (t, J = 5.7 Hz, 1H), 7.80 (d, J = 8.6 Hz, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.55-7.60 (m, 1H), 7.45-7.49 (m, 1H), 7.32-7.37 (m, 2H), 7.25 (dd, J = 8.6, 2.3 Hz, 1H), 7.09 (d, J = 8.6 Hz, 1H), 5.57 (d, J = 16.3 Hz, 1H), 5.24 (dd, J = 50.4, 4.7 Hz, 1H), 5.06 (dd, J = 12.9, 5.4 Hz, 1H), 4.02-4.15 (m, 4H), 3.40-3.50 (m, 6H), 3.30 (s, 3H), 2.82-3.08 (m, 5H), 2.45-2.61 (m, 6H), 1.97-2.05 (m, 1H), 1.83 (d, J = 12.3 Hz, 2H), 1.40-1.52 (m, 2H); MS: [M+1] 849.2. + : 849.2.

[0341] Example 17

[0342] Compound 17-1: cis-2-(2,6-dioxopiperidin-3-yl)-4-(1-(2-(2-(3-((1S)-2-fluoro-1- hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)azetidin-1-yl)ethoxy)ethyl)- 1H-1,2,3-triazol-4-yl)methyl)amino)isoindoline-1,3-dione.

[0343]

[0344] Compound 17-2: trans-2-(2,6-dioxopiperidin-3-yl)-4-(1-(2-(2-(3-((1S)-2-fluoro-1- hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)azetidin-1-yl)ethoxy)ethyl)- 1H-1,2,3-triazol-4-yl)methyl)amino)isoindoline-1,3-dione.

[0345]

[0346] Step A: Preparation of Intermediate 17-A

[0347] Dissolve 3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (5 mmol) in anhydrous DMF (10 mL), and add sodium hydride (6 mmol) under ice water bath. After 30 min, add 4-fluoro-7-(methylsulfonyl)-2,3-dihydrospiro[indene-1,2'-[1,3]dioxolane] (5 mmol), and react at room temperature for 4 h. After the reaction is completed, add saturated ammonium chloride solution (50 mL), and then perform ethyl acetate extraction, anhydrous sodium sulfate drying, and rotary evaporation to obtain the intermediate 17-A.

[0348] Step B: Preparation of the intermediate 17-B

[0349] Dissolve the crude 17-A obtained in Step A in a mixed solvent of 15 mL of acetone and 3 mL of water, and add pyridine p-toluenesulfonic acid salt (PPTS, 2 mmol) to perform reflux reaction. After the reaction is completed, remove part of the solvent by rotary evaporation, add 40 mL of saturated sodium bicarbonate solution, and then perform ethyl acetate extraction, anhydrous sodium sulfate drying, and rotary evaporation to obtain the intermediate 17-B.

[0350] Step C: Preparation of the intermediate 17-C

[0351] Dissolve the crude 17-B obtained in Step B in 15 mL of methanol, and add SelectFluoro reagent (7.5 mmol) to perform reflux reaction for 4 h. After the reaction is completed, cool to room temperature, remove the solvent by rotary evaporation, dissolve the residue in dichloromethane, filter, rotary evaporate the filtrate, dissolve in 15 mL of acetonitrile, add 3 mL of dilute hydrochloric acid (2 M), and react at room temperature for 3 h. After the reaction is completed, rotary evaporation is performed. Dissolve the residue in 20 mL of dichloromethane, wash the organic phase with saturated sodium bicarbonate solution and saturated sodium chloride solution respectively, dry with anhydrous sodium sulfate, rotary evaporation, and perform column chromatography to obtain the intermediate 17-C (2.5 mmol, overall yield 50%).

[0352] Step D: Preparation of the intermediate 17-D

[0353] Dissolve 2-(2,6-dioxopiperidin-3-yl)-4-(prop-2-yn-1-ylamino)isoindoline-1,3-dione (0.5 mmol), 2-(2-azidoethoxy)ethyl 4-methylbenzenesulfonate (0.5 mmol), copper sulfate (0.25 mmol), and sodium ascorbate (1.5 mmol) in a mixed solvent of DMF (5 mL) and water (1 mL), and protect under argon gas. React at 70°C for 4 h. After the reaction is completed, cool to room temperature, add 30 mL of saturated sodium chloride solution, perform ethyl acetate extraction, dry with anhydrous sodium sulfate, rotary evaporation, and perform column chromatography to obtain the intermediate 17-D (0.3 mmol, yield 60%).

[0354] Step E: Preparation of the intermediate 17-E

[0355] Intermediate 17-C (0.05 mmol), intermediate 17-D (0.05 mmol) and N,N- diisopropylethylamine DIPEA (0.1 mmol) were dissolved in DMSO (3 mL) and reacted at 80 °C for 2 h. After the reaction was completed, a saturated sodium chloride solution (20 mL) was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and column chromatography to obtain intermediate 17-E (20 mg, yield 55%).

[0356] Step F: Preparation of 17-1 and 17-2

[0357] Formic acid (10 μL) was dissolved in 1 mL of dichloromethane, and triethylamine (15 μL) was added under ice water bath, and stirred for 10 min. The above solution was added to a dichloromethane solution of 17-E (20 mg), and a catalyst [(R,R)-N-(2-amino-1,2-diphenylethyl)-p- methylbenzenesulfonamide] chloro(p-cymene) ruthenium(II) (5% mol) was added, and argon was protected, and reacted at room temperature for 8 h. After the reaction was completed, 20 mL of dichloromethane was added, washed with saturated sodium bicarbonate, dried, purified by high performance liquid chromatography, and freeze-dried to obtain target products 17-1 (5 mg) and 17-2 (4 mg).

[0358] 1 H-NMR (17-1): (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.23 (s, 1H), 8.00 (s, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.56 (dd, J = 8.5, 7.1 Hz, 1H), 7.17 (d, J = 8.6 Hz, 1H), 7.00-7.10 (m, 2H), 6.86 (d, J = 8.7 Hz, 1H), 5.42 (dd, J = 7.3, 5.0 Hz, 1H), 5.22 (dq, J = 52.0, 5.6 Hz, 1H), 5.04 (ddd, J = 12.8, 5.4, 2.0 Hz, 1H), 4.77-4.87 (m, 1H), 4.58 (d, J = 6.1 Hz, 2H), 4.48 (t, J = 5.1 Hz, 2H), 3.74 (t, J = 5.1 Hz, 2H), 3.60-3.68 (m, 3H), 3.33-3.37 (m, 2H), 3.28 (s, 3H), 2.79-3.17 (m, 7H), 2.53-2.60 (m, 1H), 1.94-2.04 (m, 1H); MS: [M+1]: 726.2. + : 726.2.

[0359] 1H-NMR (17-2): (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.29 (s, 1H), 8.00 (s, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.56 (dd, J = 8.6, 7.1 Hz, 1H), 7.17 (d, J = 8.6 Hz, 1H), 7.00 - 7.10 (m, 2H), 6.89 (d, J = 8.6 Hz, 1H), 5.50 (d, J = 16.5 Hz, 1H), 5.19 (dd, J = 50.4, 4.7 Hz, 1H), 5.04 (dd, J = 12.8, 5.4 Hz, 1H), 4.82 - 4.87 (m, 1H), 4.58 (d, J = 6.0 Hz, 2H), 4.48 (t, J = 5.1 Hz, 2H), 3.74 (t, J = 5.2 Hz, 2H), 3.60 - 3.68 (m, 3H), 3.25 - 3.33 (m, 2H), 3.23 (s, 3H), 2.82 - 3.01 (m, 5H), 2.52 - 2.61 (m, 3H), 1.95 - 2.02 (m, 1H); MS: [M+1] + : 726.2.

[0360] Example 18

[0361] Compound 18-1: cis-2-(2,6-dioxopiperidin-3-yl)-4-((1-(2-(3-((1S)-2-fluoro-1-hydroxy-7- (methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)azetidin-1-yl)ethyl)-1H-1,2,3- triazol-4-yl)methyl)amino)isoindoline-1,3-dione.

[0362]

[0363] Compound 18-2: trans-2-(2,6-dioxopiperidin-3-yl)-4-((1-(2-(3-((1S)-2-fluoro-1-hydroxy-7- (methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)azetidin-1-yl)ethyl)-1H-1,2,3- triazol-4-yl)methyl)amino)isoindoline-1,3-dione.

[0364]

[0365] As shown in Example 17-1, the target compounds 18-1 and 18-2 were synthesized using a similar method as 17-1.

[0366] 1H-NMR (18-1): (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.50-7.58 (m, 1H), 7.16 (d, J = 8.6 Hz, 1H), 7.01-7.11 (m, 2H), 6.87 (d, J = 8.7 Hz, 1H), 5.81 (s, 1H), 5.42 (t, J = 6.0 Hz, 1H), 5.22 (dq, J = 52.1, 5.6 Hz, 1H), 5.06 (dd, J = 12.9, 5.4 Hz, 1H), 4.88 (p, J = 5.6 Hz, 1H), 4.60 (d, J = 6.0 Hz, 2H), 4.32 (t, J = 5.9 Hz, 2H), 3.65-3.72 (m, 2H), 3.28 (s, 3H), 2.97-3.18 (m, 5H), 2.85-2.95 (m, 3H), 2.52-2.57 (m, 1H), 1.97-2.06 (m, 1H); MS: [M+1] + : 682.2.

[0367] 1 H-NMR (18-2): (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H), 7.16 (d, J = 8.6 Hz, 1H), 7.01-7.11 (m, 2H), 6.91 (d, J = 8.6 Hz, 1H), 6.07 (s, 1H), 5.50 (d, J = 16.5 Hz, 1H), 5.19 (dd, J = 50.4, 4.6 Hz, 1H), 5.06 (dd, J = 12.9, 5.4 Hz, 1H), 4.90 (p, J = 5.6 Hz, 1H), 4.60 (d, J = 6.1 Hz, 2H), 4.33 (t, J = 5.9 Hz, 2H), 3.65-3.75 (m, 2H), 3.23 (s, 3H), 2.95-3.07 (m, 3H), 2.82-2.94 (m, 4H), 2.52-2.63 (m, 2H), 1.97-2.07 (m, 1H); MS: [M+1] + : 682.2.

[0368] Example 19

[0369] Compound 19-1: 2-(2,6-dioxopiperidin-3-yl)-4-(1-(2-(2-(4-((1S)-2-fluoro-1- hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)piperidin-1-yl)ethoxy)ethyl)- 1H-1,2,3-triazol-4-yl)methyl)amino)isoindoline-1,3-dione.

[0370]

[0371]

[0372] Compound 19 was synthesized using a similar synthetic procedure as 17-1 as shown in Example 17-1.

[0373] 1 H NMR (19-1): (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 8.38 (t, J = 5.4 Hz, 1H), 7.74 (d, J = 9.7 Hz, 1H), 7.63 (s, 1H), 7.54 (dd, J = 7.9, 7.0 Hz, 1H), 7.39 (dd, J = 6.9, 1.2 Hz, 1H), 7.20 (dd, J = 7.9, 1.1 Hz, 1H), 6.94 (d, J = 9.7 Hz, 1H), 5.48 (t, J = 3.6 Hz, 1H), 5.18 - 5.28 (m, 1H), 5.00 - 5.15 (m, 1H), 4.62 (dd, J = 5.4, 1.9 Hz, 2H), 4.44 - 4.50 (m, 1H), 4.30 (d, J = 5.7 Hz, 1H), 4.21 (t, J = 4.2 Hz, 2H), 3.79 (m, 2H), 3.55 (m, 2H), 3.20 (s, 3H), 3.14 - 3.18 (m, 1H), 3.09 - 3.12 (m, 1H), 2.80 - 2.90 (m, 2H), 2.67 - 2.75 (m, 2H), 2.51 - 2.66 (m, 4H), 2.14 - 2.22 (m, 1H), 1.92 - 1.98 (m, 2H), 1.83 - 1.91 (m, 2H), 1.74 - 1.80 (m, 1H). MS: [M+1] + : 754.3.

[0374] Example 20

[0375] Compound 20-1: cis-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-7-((1-(2-(2-(3-((1S)-2-fluoro-1- hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)azetidin-1-yl)ethoxy)ethyl)- 1H-1,2,3-triazol-4-yl)methyl)amino)isoindoline-1,3-dione.

[0376]

[0377] Compound 20-2: trans-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-7-((1-(2-(2-(3-((1S)-2-fluoro-1- hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)azetidin-1-yl)ethoxy)ethyl)- 1H-1,2,3-triazol-4-yl)methyl)amino)isoindoline-1,3-dione.

[0378]

[0379]

[0380] Step A: Preparation of Intermediate 20-A

[0381] Dissolve 2-(2,6-dioxopiperidin-3-yl)-4,7-difluoroisoindoline-1,3-dione (3 mmol), propargylamine (1.5 mmol) and DIPEA (3 mmol) in DMSO (5 mL) and react at 90 °C for 2 h. After the reaction is completed, cool to room temperature, add 40 mL of saturated sodium chloride solution, then perform ethyl acetate extraction, anhydrous sodium sulfate drying and column chromatography in sequence to obtain Intermediate 20-A (1.3 mmol, yield 86.7%).

[0382] Step B-D: Synthesize target compounds 20-1 and 20-2 using a synthetic method similar to 17-1 as shown in Example 17-1.

[0383] 1H-NMR (20-1): (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.00 (s, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.47 (t, J = 9.0 Hz, 1H), 7.23 (dd, J = 9.4, 3.3 Hz, 1H), 7.03 (t, J = 6.1 Hz, 1H), 6.86 (d, J = 8.7 Hz, 1H), 5.42 (dd, J = 7.3, 5.0 Hz, 1H), 5.22 (dq, J = 52.2, 5.6 Hz, 1H), 5.05 (ddd, J = 12.8, 5.4, 1.9 Hz, 1H), 4.83 (p, J = 5.5 Hz, 1H), 4.57 (d, J = 6.0 Hz, 2H), 4.48 (t, J = 5.1 Hz, 2H), 3.74 (t, J = 5.2 Hz, 2H), 3.60 - 3.65 (m, 2H), 3.36 (t, J = 5.4 Hz, 2H), 3.28 (s, 3H), 3.12 (ddd, J = 16.1, 14.0, 6.4 Hz, 1H), 2.80 - 3.05 (m, 5H), 2.52 - 2.60 (m, 3H), 1.95 - 2.05 (m, 1H); MS: [M+1] 744.2. + :744.2.

[0384] 1 H-NMR (20-2): (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.00 (s, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.23 (dd, J = 9.3, 3.3 Hz, 1H), 7.03 (t, J = 6.1 Hz, 1H), 6.90 (d, J = 8.6 Hz, 1H), 5.49 (d, J = 16.6 Hz, 1H), 5.19 (dd, J = 50.5, 4.6 Hz, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 4.86 (p, J = 6.0 Hz, 1H), 4.57 (d, J = 6.1 Hz, 2H), 4.48 (t, J = 5.1 Hz, 2H), 3.74 (t, J = 5.2 Hz, 2H), 3.62 - 3.70 (m, 2H), 3.25 - 3.30 (m, 2H), 3.23 (s, 3H), 2.81 - 3.03 (m, 4H), 2.51 - 2.60 (m, 5H), 1.96 - 2.03 (m, 1H); MS: [M+1] 744.2. + :744.2.

[0385] Example 21

[0386] Compound 21-1: cis-2-(2,6-dioxopiperidin-3-yl)-4-(4-(1-(1S)-2-fluoro-1- hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)azetidin-3-yl)piperazin-1-yl)isoindoline- 1,3-dione.

[0387]

[0388] Compound 21-2: trans-2-(2,6-dioxopiperidin-3-yl)-4-(4-(1-(1S)-2-fluoro-1- hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)azetidin-3-yl)piperazin-1-yl)isoindoline- 1,3-dione.

[0389]

[0390] Step A: Preparation of Intermediate 21-A

[0391] Dissolve 2,4-difluoro-1,1-dimethoxy-7-(methylsulfonyl)-2,3-dihydro-1H-indene (1 mmol), 4-(azetidin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (1 mmol) and cesium bicarbonate (2 mmol) in DMSO (3 mL) and microwave at 90 °C for 2 h. After the reaction is completed, cool to room temperature, add saturated sodium chloride solution (30 mL), extract with ethyl acetate, dry over anhydrous sodium sulfate, and column chromatography to obtain intermediate 21-A (0.31 mmol, yield 31%).

[0392] Step B: Preparation of Intermediate 21-B

[0393] Dissolve intermediate 21-A (0.31 mmol) and pyridine p-toluenesulfonate (0.1 mmol) in a mixed solvent of acetone (5 mL) and water (1 mL) and reflux for 1 h. After the reaction is completed, cool to room temperature, spin dry the solvent, dissolve in dichloromethane (20 mL), wash the organic phase with saturated sodium bicarbonate solution and saturated sodium chloride solution, respectively, dry over anhydrous sodium sulfate, and spin dry to obtain intermediate 21-B, which is directly used in subsequent synthesis.

[0394] Step C: Preparation of Intermediate 21-C

[0395] To a solution of formic acid (40 μL) in 1 mL of dichloromethane, triethylamine (85 μL) was added under ice water bath and stirred for 10 min. The above solution was added to the solution of 21-B in dichloromethane and catalyst [(R,R)-N-(2-amino-l,2-diphenylethyl)-p- methylbenzenesulfonamide]chloride (p-cymene) ruthenium(II) (5% mol) was added. The reaction was stirred at room temperature for 8 h under argon atmosphere. After the reaction was completed, 20 mL of dichloromethane was added and washed with saturated sodium bicarbonate. The organic layer was dried and purified by preparative HPLC. The product was lyophilized to give intermediate 21-C (0.17 mmol, 55% overall yield).

[0396] Step D: Preparation of intermediate 21-D

[0397] Intermediate 21-C (0.17 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (2 mL) was added at room temperature. The reaction was stirred at room temperature for 1 h. The solvent was removed by rotary evaporation to give intermediate 21-D, which was used directly in the subsequent synthesis.

[0398] Step E: Preparation of 21-1 and 21-2

[0399] Intermediate 21-D was dissolved in DMF (3 mL) and 2-(2,6-dioxopiperidin-3-yl)-5- fluoroisoindoline-l,3-dione (0.17 mmol), DIPEA (0.34 mmol) were added. The reaction was stirred at 90 °C for 2 h. After the reaction was completed, the reaction was cooled to room temperature and saturated sodium chloride solution was added. The organic layer was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The product was purified by preparative HPLC to give 21-1 (11 mg) and 21-2 (7 mg).

[0400] 1 H-NMR (21-1): (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 7.71 (t, J = 7.8 Hz, 1H), 7.56 (d, J = 8.6 Hz, 1H), 7.32-7.40 (m, 2H), 6.42 (d, J = 8.7 Hz, 1H), 5.36 (t, J = 5.1 Hz, 1H), 5.04-5.24 (m, 2H), 4.19 (q, J = 7.5 Hz, 2H), 3.90-4.00 (m, 2H), 2.80-3.50 (m, 13H), 2.53-2.64 (m, 5H), 1.98-2.05 (m, 1H); MS: [M+l]+: 626.2.

[0401] 1H-NMR (21-2): (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 7.67-7.75 (m, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.32-7.38 (m, 2H), 6.44 (d, J = 8.6 Hz, 1H), 5.45 (d, J = 16.6 Hz, 1H), 5.04-5.20 (m, 2H), 4.20 (q, J = 8.1 Hz, 2H), 3.92-4.02 (m, 2H), 3.39-3.55 (m, 4H), 3.17 (s, 3H), 2.82-3.10 (m, 4H), 2.53-2.62 (m, 7H), 1.98-2.06 (m, 1H); MS: [M+1]+: 626.2.

[0402] Example 22

[0403] Compound 22-1: cis-2-(2,6-dioxopiperidin-3-yl)-5-(4-(1-(1S)-2-fluoro-1-hydroxy-7- (methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)piperidin-4-yl)piperazin-1-yl)isoindoline-1,3- dione.

[0404]

[0405] Compound 22-2: trans-2-(2,6-dioxopiperidin-3-yl)-5-(4-(1-(1S)-2-fluoro-1-hydroxy-7- (methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)piperidin-4-yl)piperazin-1-yl)isoindoline-1,3- dione.

[0406]

[0407] The target compounds 22-1 and 22-2 were synthesized using a similar method as described in Example 21-1.

[0408] 1H-NMR (22-1): (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.67 (t, J = 8.2 Hz, 1H), 7.35 (d, J = 2.3 Hz, 1H), 7.27 (dd, J = 8.6, 2.3 Hz, 1H), 7.01 (d, J = 8.7 Hz, 1H), 5.42 (t, J = 4.9 Hz, 1H), 5.03-5.23 (m, 2H), 3.42-3.57 (m, 6H), 3.25 (s, 3H), 3.02-3.15 (m, 2H), 2.79-2.95 (m, 2H), 2.64-2.71 (m, 5H), 2.53-2.63 (m, 3H), 1.98-2.05 (m, 1H), 1.85-1.95 (m, 2H), 1.52-1.70 (m, 2H); MS: [M+1] 654.2. + : 654.2.

[0409] 1 H-NMR (22-2): (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.68 (dd, J = 8.5, 2.5 Hz, 2H), 7.35 (d, J = 2.3 Hz, 1H), 7.24-7.30 (m, 1H), 7.05 (d, J = 8.6 Hz, 1H), 5.49 (d, J = 15.3 Hz, 1H), 5.04-5.25 (m, 2H), 3.42-3.59 (m, 7H), 3.22 (s, 3H), 2.82-2.93 (m, 3H), 2.51-2.73 (m, 8H), 1.85-2.05 (m, 3H), 1.49-1.69 (m, 2H); MS: [M+1] 654.2. + : 654.2.

[0410] Example 23

[0411] Compound 23-1: cis-2-(2,6-dioxopiperidin-3-yl)-4-(4-((1-((1S)-2-fluoro-1-hydroxy-7- (methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)azetidin-3-yl)methyl)piperazin-1-yl)isoindole- 1,3-dione.

[0412]

[0413] Compound 23-2: trans-2-(2,6-dioxopiperidin-3-yl)-4-(4-((1-((1S)-2-fluoro-1-hydroxy-7- (methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)azetidin-3-yl)methyl)piperazin-1-yl)isoindole- 1,3-dione.

[0414]

[0415] Step A: Preparation of Intermediate 23-A

[0416] Intermediate 23-A (400 mg) was dissolved in a mixture solvent of acetone (8 mL) and water (2 mL), and refluxed for 1 h. After the reaction was completed, the reaction mixture was cooled to room temperature, and part of the solvent was removed by rotary evaporation. Saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to give Intermediate 23-B, which was used directly in the subsequent synthesis.

[0417] Step B: Preparation of Intermediate 23-B

[0418] Intermediate 23-A (400 mg) was dissolved in a mixture solvent of acetone (8 mL) and water (2 mL), and refluxed for 1 h. After the reaction was completed, the reaction mixture was cooled to room temperature, and part of the solvent was removed by rotary evaporation. Saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to give Intermediate 23-B, which was used directly in the subsequent synthesis.

[0419] Step C: Preparation of Intermediate 23-C

[0420] Intermediate 23-B obtained in Step B was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (5 mL) was added. The mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was concentrated to give Intermediate 23-C, which was used directly in the subsequent synthesis.

[0421] Step D: Preparation of Intermediate 23-D

[0422] Intermediate 23-C (50 mg), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (37 mg), and DIPEA (34 mg) were dissolved in DMSO (2 mL), and the mixture was stirred at 90 °C for 2 h. After the reaction was completed, the reaction mixture was cooled to room temperature, and saturated sodium chloride solution (20 mL) was added. The mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The product was separated by preparative thin layer chromatography to give Intermediate 23-D (23 mg, yield 28%).

[0423] Step E: Preparation of 23-1 and 23-2

[0424] Formic acid (10 μL) was dissolved in 1 mL of dichloromethane, and triethylamine (15 μL) was added under ice water bath, and stirred for 10 min. The above solution was added to a dichloromethane solution of 23-D (23 mg), and catalyst [(R,R)-N-(2-amino-l,2-diphenylethyl)-p- methylbenzenesulfonamide]chloride (p-cymene) ruthenium(II) (5% mol) was added, and the reaction was carried out under argon protection at room temperature for 8 h. After the reaction was completed, 20 mL of dichloromethane was added, and saturated sodium bicarbonate was used for washing, and dried, and purified by high performance liquid chromatography, and freeze-dried to obtain target products 23-1 (7 mg) and 23-2 (5 mg).

[0425] 1 H-NMR (23-1): (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 7.67-7.75 (m, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.30-7.40 (m, 2H), 6.40 (d, J = 8.7 Hz, 1H), 5.35 (t, J = 5.0 Hz, 1H), 5.02-5.22 (m, 2H), 4.21 (q, J = 7.6 Hz, 2H), 3.77 (t, J = 6.7 Hz, 2H), 2.80-3.40 (m, 13H), 2.54-2.68 (m, 7H), 1.97-2.06 (m, 1H); MS: [M+1] + : 640.2.

[0426] 1 H-NMR (23-2): (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 7.71 (dd, J = 8.4, 7.2 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.35 (m, 2H), 6.41 (d, J = 8.6 Hz, 1H), 5.44 (d, J = 16.5 Hz, 1H), 5.02-5.20 (m, 2H), 4.23 (q, J = 8.1 Hz, 2H), 3.78 (m, 2H), 3.26-3.56 (m, 6H), 3.16 (s, 3H), 2.82-3.07 (m, 4H), 2.53-2.69 (m, 7H), 1.99-2.06 (m, 1H); MS: [M+1] + : 640.2.

[0427] Example 24

[0428] Compound 24-1 : cis-2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-((1S)-2-fluoro-1- hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)azetidin-3-yl)methyl)piperazin- 1-yl)isoindoline-1,3-dione.

[0429]

[0430] Compound 24-2: trans-2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-((1S)-2-fluoro-1- hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)azetidin-3-yl)methyl)piperazin- 1-yl)isoindoline-1,3-dione.

[0431]

[0432] The target compounds 24-1 and 24-2 were synthesized using a similar method as described in Example 23-1.

[0433] 1 H-NMR (24-1): (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.37 (m, 1H), 7.28 (d, J = 8.3 Hz, 1H), 6.39 (d, J = 8.6 Hz, 1H), 5.60 (d, J = 6.4 Hz, 1H), 5.35 (q, J = 5.3 Hz, 1H), 5.01-5.23 (m, 2H), 4.22 (q, J = 7.8 Hz, 2H), 3.72-3.82 (m, 2H), 3.40-3.52 (m, 4H), 3.07-3.23 (m, 6H), 2.82-2.92 (m, 2H), 2.55-2.70 (m, 7H), 1.97-2.05 (m, 1H); MS: [M+1] + : 640.2.

[0434] 1H-NMR (24-2): (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 2.3 Hz, 1H), 7.27 (dd, J = 8.7, 2.4 Hz, 1H), 6.41 (d, J = 8.6 Hz, 1H), 5.44 (d, J = 16.5 Hz, 1H), 5.02-5.20 (m, 2H), 4.22 (q, J = 7.8 Hz, 2H), 3.74-3.82 (m, 2H), 3.42-3.53 (m, 6H), 3.16 (s, 3H), 2.82-3.08 (m, 3H), 2.55-2.70 (m, 8H), 1.97-2.05 (m, 1H); MS: [M+1] + : 640.2.

[0435] Example 25

[0436] Compound 25-1: cis-2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-((1-((1S)-2-fluoro-1- hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)azetidin-3-yl)methyl)piperazin-1- yl)isoindoline-1,3-dione.

[0437]

[0438] Compound 25-2: trans-2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-((1-((1S)-2-fluoro-1- hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)azetidin-3-yl)methyl)piperazin-1- yl)isoindoline-1,3-dione.

[0439]

[0440] The target compounds 25-1 and 25-2 were synthesized as described in Example 23-1 using a similar method to 23-1.

[0441] 1H-NMR (25-1): (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 7.73 (d, J = 11.4 Hz, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.46 (d, J = 7.4 Hz, 1H), 6.39 (d, J = 8.7 Hz, 1H), 5.59 (d, J = 6.4 Hz, 1H), 5.31-5.37 (m, 1H), 5.02-5.22 (m, 2H), 4.21 (q, J = 7.7 Hz, 2H), 3.76 (t, J = 6.7 Hz, 2H), 3.22-3.27 (m, 4H), 3.05-3.21 (m, 5H), 2.82-3.00 (m, 2H), 2.52-2.68 (m, 8H), 1.98-2.05 (m, 1H); MS: [M+1] + 658.2.

[0442] 1 H-NMR (25-2): (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 7.73 (d, J = 11.4 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.46 (d, J = 7.4 Hz, 1H), 6.41 (d, J = 8.6 Hz, 1H), 5.85 (m, 1H), 5.44 (d, J = 16.5 Hz, 1H), 5.02-5.20 (m, 2H), 4.22 (q, J = 7.9 Hz, 2H), 3.75-3.82 (m, 2H), 3.38-3.52 (m, 1H), 3.25 (m, 4H), 3.16 (s, 3H), 2.82-3.07 (m, 3H), 2.52-2.69 (m, 8H), 1.97-2.06 (m, 1H); MS: [M+1] + 658.2.

[0443] Example 26

[0444] Compound 26-1: cis-2-(2,6-dioxopiperidin-3-yl)-4-(4-((1-((1S)-2-fluoro-1- hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)piperidin-4-yl)methyl)piperazin-1- yl)isoindoline-1,3-dione.

[0445]

[0446] Compound 26-2: trans-2-(2,6-dioxadiazin-3-yl)-4-(4-((1-((1S)-2-fluoro-1-hydroxy-7-(methanesulfonyl)-2,3-dihydro-1H-indene-4-yl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione.

[0447]

[0448] As described in Example 23-1, target compounds 26-1 and 26-2 were synthesized using a method similar to that in 23-1.

[0449] 1 H-NMR(26-1): (400MHz, DMSO-d6)δ11.09(s,1H),7.63-7.75(m,2H),7.30-7.40(m,2H),7.00(d,J=8.7 Hz,1H),5.63-5.75(m,1H),5.42(t,J=4.8Hz,1H),5.03-5.24(m,2H),3.45-3.52(m,2H),3.30-3.35(m,2H),3.25 (s,3H),3.02-3.19(m,2H),2.77-2.92(m,2H),2.52-2.71(m,8H),2.27(d,J=7.1Hz,2H),1.99-2.06(m,1H),1.70- 1.90(m,3H),1.16-1.37(m,3H);MS:[M+1] + :668.2.

[0450] 1 H-NMR(26-2): (400MHz, DMSO-d6)δ11.08(s,1H),7.64-7.75(m,2H),7.30-7.40(m,2H),7.03(d,J=8.6 Hz,1H),5.85-6.00(m,1H),5.49(d,J=15.4Hz,1H),5.05-5.25(m,2H),3.44-3.54(m,2H),3.30-3.40(m,3H),3.22 (s,3H),2.77-2.93(m,3H),2.52-2.69(m,8H),2.27(d,J=7.1Hz,2H),1.99-2.06(m,1H),1.71-1.92(m,3H),1.18- 1.40(m,3H);MS:[M+1] + :668.2.

[0451] Example 27

[0452] Compound 27-1: cis-2-(2,6-dioxadiazin-3-yl)-4-fluoro-7-(4-((1-((1S)-2-fluoro-1-hydroxy-7-(methanesulfonyl)-2,3-dihydro-1H-indene-4-yl)azacyclobut-3-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione.

[0453]

[0454] Compound 27-2: trans-2-(2,6-dioxadiazin-3-yl)-4-fluoro-7-(4-((1-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-indene-4-yl)azacyclobut-3-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione.

[0455]

[0456] As described in Example 23-1, target compounds 27-1 and 27-2 were synthesized using a method similar to that in Example 23-1.

[0457] 1 H-NMR(27-1): (400MHz, DMSO-d6)δ11.10(s,1H),7.60(t,J=8.8Hz,1H),7.54(d,J=8.6Hz,1H),7.40 (dd,J=9.2,3.6Hz,1H),6.39(d,J=8.6Hz,1H),5.36(m,1H),5.03-5.22(m,2H),4.21(q,J=7.6Hz,2H),3.76(t ,J=6.7Hz,2H),3.21-3.23(m,4H),3.20(s,3H),2.81-3.12(m,5H),2.53-2.69(m,7H),1.96-2.06(m,1H); MS: [M+1] + :658.2.

[0458] 1H-NMR(27-2): (400MHz, DMSO-d6)δ11.10(s,1H),7.60(t,J=8.9Hz,1H),7.55(d,J=8.5Hz,1H),7.40 (dd,J=9.3,3.7Hz,1H),6.41(d,J=8.6Hz,1H),5.44(d,J=16.6Hz,1H),5.12(dd,J=50.7,4.5Hz,1H),5.09(d d,J=12.8,5.5Hz,1H),4.23(q,J=8.1Hz,2H),3.75-3.83(m,2H),3.20-3.25(m,4H),3.16(s,3H),2.82-3.06 (m,5H),2.66(d,J=7.5Hz,2H),2.53-2.62(m,5H),1.98-2.07(m,1H);MS:[M+1] + :658.2.

[0459] Example 28

[0460] Compound 28-1: cis-2-(2,6-dioxadiazin-3-yl)-5-(4-((1-((1S)-2-fluoro-1-hydroxy-7-(methanesulfonyl)-2,3-dihydro-1H-indene-4-yl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione.

[0461]

[0462] Compound 28-2: trans-2-(2,6-dioxadiazin-3-yl)-5-(4-((1-((1S)-2-fluoro-1-hydroxy-7-(methanesulfonyl)-2,3-dihydro-1H-indene-4-yl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione.

[0463]

[0464]

[0465] As described in Example 23-1, target compounds 28-1 and 28-2 were synthesized using a method similar to that in 23-1.

[0466] 1H-NMR(28-1): (400MHz, DMSO-d6)δ11.08(s,1H),7.67(t,J=8.6Hz,2H),7.35(d,J=2.3Hz,1H),7.26 (dd,J=8.7,2.3Hz,1H),7.00(d,J=8.7Hz,1H),5.71(d,J=6.5Hz,1H),5.42(dt,J=6.6,4.8Hz,1H),5.03-5.23( m,2H),3.42-3.53(m,6H),3.25(s,3H),2.99-3.18(m,2H),2.78-2.95(m,2H),2.53-2.71(m,6H),2.26(d,J=7.1 Hz,2H),1.98-2.05(m,1H),1.72-1.90(m,3H),1.17-1.37(m,3H);MS:[M+1] + :668.2.

[0467] 1 H-NMR(28-2): (400MHz, DMSO-d6)δ11.07(s,1H),7.68(dd,J=8.5,2.7Hz,2H),7.35(d,J=2.2Hz,1H), 7.26(dd,J=8.6,2.3Hz,1H),7.03(d,J=8.6Hz,1H),5.94(s,1H),5.49(d,J=15.3Hz,1H),5.03-5.26(m,2H),3. 42-3.53(m,6H),3.22(s,3H),2.77-2.94(m,4H),2.53-2.68(m,6H),2.26(d,J=7.1Hz,2H),1.98-2.03(m,1H), 1.70-1.90(m,3H),1.18-1.40(m,3H); MS:[M+1] + :668.2.

[0468] Example 29

[0469] Compound 29-1: cis-2-(2,6-dioxadiazin-3-yl)-5-fluoro-6-(4-((1-((1S)-2-fluoro-1-hydroxy-7-(methanesulfonyl)-2,3-dihydro-1H-indene-4-yl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione.

[0470]

[0471] Compound 29-2: trans-2-(2,6-dioxadiazin-3-yl)-5-fluoro-6-(4-((1-((1S)-2-fluoro-1-hydroxy-7-(methanesulfonyl)-2,3-dihydro-1H-indene-4-yl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione.

[0472]

[0473]

[0474] As described in Example 23-1, target compounds 29-1 and 29-2 were synthesized using a method similar to that in 23-1.

[0475] 1 H-NMR(29-1): (400MHz, DMSO-d6)δ11.11(s,1H),7.73(d,J=11.4Hz,1H),7.66(d,J=8.5Hz,1H), 7.46(d,J=7.4Hz,1H),7.00(d,J=8.7Hz,1H),5.71(s,1H),5.37-5.46(m,1H),5.04-5.24(m,2H),3.18-3.30(m, 8H),3.00-3.14(m,2H),2.77-2.95(m,2H),2.53-2.73(m,8H),2.27(d,J=7. 1Hz,2H),2.00-2.07(m,1H),1.7-1.90(m,3H),1.15-1.35(m,2H);MS:[M+1] + :686.2.

[0476] 1 H-NMR(29-2): (400MHz, DMSO-d6)δ11.11(s,1H),7.73(d,J=11.4Hz,1H),7.68(d,J=8.5Hz,1H), 7.46(d,J=7.4Hz,1H),7.03(d,J=8.6Hz,1H),5.94(d,J=6.2Hz,1H),5.49(dd,J=15.2,4.6Hz,1H),5.04-5.26( m,2H),3.44-3.54(m,2H),3.25-3.30(m,5H),3.22(s,3H),2.77-2.96(m,3H),2.53-2.67(m,8H),2.28(d,J=7.1 Hz,2H),2.00-2.08(m,1H),1.70-1.90(m,3H),1.18-1.41(m,2H);MS:[M+1] +:686.2.

[0477] Example 30

[0478] Compound 30-1: cis-2-(2,6-dioxadiazin-3-yl)-4-(4-(2-(1-(2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-indole-4-yl)piperidin-4-yl)ethyl)piperazin-1-yl)isoindoline-1,3-dione.

[0479]

[0480] Compound 30-2: trans-2-(2,6-dioxadiazin-3-yl)-4-(4-(2-(1-(2-fluoro-1-hydroxy-7-(methanesulfonyl)-2,3-dihydro-1H-indole-4-yl)piperidin-4-yl)ethyl)piperazin-1-yl)isoindoline-1,3-dione.

[0481]

[0482]

[0483] As described in Example 23-1, target compounds 30-1 and 30-2 were synthesized using a method similar to that in Example 23-1.

[0484] 1 H-NMR(30-1): (400MHz, DMSO-d6)δ11.09(s,1H),7.63-7.75(m,2H),7.30-7.40(m,2H),7.00(d,J=8.6 Hz,1H),5.42(t,J=4.8Hz,1H),5.02-5.22(m,2H),3.26-3.35(m,4H),3.25(s,3H),3.00-3.16(m,3H),2.75-2.92 (m,3H),2.53-2.69(m,7H),2.42(t,J=6.9Hz,2H),1.98-2.07(m,1H),1.75-1.85(m,2H),1.20-1.55(m,6H); MS: [M+1] + :682.2.

[0485] 1H-NMR(30-2): (400MHz, DMSO-d6)δ11.09(s,1H),7.64-7.75(m,2H),7.30-7.37(m,2H),7.03(d,J=8.6 Hz,1H),5.49(d,J=15.4Hz,1H),5.06-5.25(m,2H),3.26-3.35(m,4H),3.22(s,3H),2.77-2.94(m,4H),2.5 2-2.67(m,7H),2.39-2.45(m,2H),1.97-2.07(m,1H),1.81(t,J=13.6Hz,2H),1.21-1.59(m,6H);MS:[M+1] + :682.2.

[0486] Example 31

[0487] Compound 31-1: cis-2-(2,6-dioxadiazin-3-yl)-5-fluoro-6-(4-(2-(1-(2-fluoro-1-hydroxy-7-(methanesulfonyl)-2,3-dihydro-1H-indene-4-yl)piperidin-4-yl)ethyl)piperazin-1-yl)isoindoline-1,3-dione.

[0488]

[0489] Compound 31-2: trans-2-(2,6-dioxadiazin-3-yl)-5-fluoro-6-(4-(2-(1-(2-fluoro-1-hydroxy-7-(methanesulfonyl)-2,3-dihydro-1H-indene-4-yl)piperidin-4-yl)ethyl)piperazin-1-yl)isoindoline-1,3-dione.

[0490]

[0491]

[0492] As described in Example 23-1, target compounds 31-1 and 31-2 were synthesized using a method similar to that in Example 23-1.

[0493] 1H-NMR(31-1): (400MHz, DMSO-d6)δ11.11(s,1H),7.73(d,J=11.4Hz,1H),7.66(d,J=8.5Hz,1H), 7.46(d,J=7.4Hz,1H),7.00(d,J=8.6Hz,1H),5.42(t,J=4.8Hz,1H),5.03-5.22(m,2H),3.47(d,J=12.3Hz, 2H),3.34(d,J=11.8Hz,2H),3.25(s,3H),2.98-3.18(m,3H),2.74-2.95(m,3H),2.53-2.68(m, 7H),2.37-2.45(m,2H),2.00-2.08(m,1H),1.81(d,J=12.4Hz,2H),1.20-1.53(m,6H); MS:[M+1] + :700.2.

[0494] 1 H-NMR(31-2): (400MHz, DMSO-d6)δ11.11(s,1H),7.73(d,J=11.4Hz,1H),7.67(d,J=8.5Hz,1H), 7.46(d,J=7.4Hz,1H),7.03(d,J=8.6Hz,1H),5.49(d,J=15.4Hz,1H),5.06-5.26(m,2H),3.33-3.51(m,7H),3. 22(s,3H),2.77-2.95(m,3H),2.53-2.67(m,7H),2.41(t,J=7.2Hz,2H),2.00-2.07(m,1H),1.81(t,J=12.9Hz, 2H),1.21-1.58(m,6H);MS:[M+1] + :700.2.

[0495] Example 32

[0496] Compound 32-1: cis-5-(4-((1-((1S)-7-(difluoromethyl)sulfonyl)-2-fluoro-1-hydroxy-2,3-dihydro-1H-inden-4-yl)azacyclobut-3-yl)methyl)piperazin-1-yl)-2-(2,6-dioxadiazin-3-yl)-6-fluoroisoindoline-1,3-dione.

[0497]

[0498] Compound 32-2: trans-5-(4-((1-((1S)-7-(difluoromethyl)sulfonyl)-2-fluoro-1-hydroxy-2,3-dihydro-1H-inden-4-yl)azacyclobut-3-yl)methyl)piperazin-1-yl)-2-(2,6-dioxadiazin-3-yl)-6-fluoroisoindoline-1,3-dione).

[0499]

[0500]

[0501] Step A: Preparation of intermediate 32-A

[0502] 7-(difluoromethyl)sulfonyl)-4-fluoro-2,3-dihydro-1H-inden-1-one (1 mmol) and SelectFluoro reagent (1.5 mmol) were dissolved in methanol (10 mL) and refluxed for 6 h. After the reaction was complete, the mixture was cooled to room temperature, the solvent was removed by rotary evaporation, the residue was dissolved in dichloromethane, filtered, and the filtrate was evaporated to dryness to give intermediate 32-A, which was used directly for subsequent synthesis (0.89 mmol, yield 89%).

[0503] Step B: Preparation of intermediate 32-B

[0504] Intermediate 32-A (100 mg), 4-(azacyclobutane-3-ylmethyl)piperazine-1-carboxylic acid tert-butyl ester (90 mg), and triethylamine (72 mg) were dissolved in DMSO (3 mL) and reacted at 90 °C. After the reaction was completed, the mixture was cooled to room temperature, and saturated sodium chloride solution (20 mL) was added. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and subjected to column chromatography to give intermediate 32-B (120 mg, yield 65.6%).

[0505] Step C: Preparation of intermediate 32-C

[0506] Intermediate 32-B (120 mg) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2 mL) was added. The reaction was carried out at room temperature. After the reaction was completed, the solution was evaporated to dryness to obtain intermediate 32-C, which was used directly for subsequent synthesis.

[0507] Step D: Preparation of intermediate 32-D

[0508] Intermediate 32-C (80 mg), 2-(2,6-dioxadiazin-3-yl)-5,6-difluoroisoindoline-1,3-dione (113 mg), and DIPEA (50 mg) were dissolved in DMSO (3 mL) and reacted at 90 °C for 2 h. After the reaction was completed, saturated sodium chloride solution (20 mL) was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and subjected to column chromatography to obtain intermediate 32-D (25 mg, yield 18.8%).

[0509] Step E: Preparation of compounds 32-1 and 32-2

[0510] Formic acid (10 μL) was dissolved in 1 mL of dichloromethane. Triethylamine (15 μL) was added under ice-water bath conditions, and the mixture was stirred for 10 min. This solution was then added to a dichloromethane solution of 32-D (25 mg), and the catalyst [(R,R)-N-(2-amino-1,2-diphenylethyl)-p-methylbenzenesulfonamide] ruthenium(II) chloride (5% mol) was added. The mixture was reacted under argon protection at room temperature for 8 h. After the reaction was complete, 20 mL of dichloromethane was added, followed by washing with saturated sodium bicarbonate, drying, and purification by preparative high-performance liquid chromatography (HPLC). The purified products were then freeze-dried to obtain the target products 32-1 (7 mg) and 32-2 (5 mg).

[0511] 1 H-NMR(32-1): (400MHz, DMSO-d6)δ11.11(s,1H),7.73(d,J=11.3Hz,1H),7.57(d,J=8.7Hz,1H), 7.46(d,J=7.4Hz,1H),7.03(t,J=53.9Hz,1H),6.42(d,J=8.8Hz,1H),5.07-5.28(m,3H),4.30(t,J=8.1Hz, 2H),3.87(t,J=6.8Hz,2H),3.22-3.30(m,5H),2.83-3.19(m,4H),2.53-2.70(m,8H),1.98-2.08(m,1H); MS: [M+1] + :694.2.

[0512] 1 H-NMR(32-2): (400MHz, DMSO-d6)δ11.11(s,1H),7.73(d,J=11.4Hz,1H),7.57(d,J=8.6Hz,1H), 7.46(d,J=7.4Hz,1H),6.94(t,J=53.7Hz,1H),6.44(d,J=8.8Hz,1H),5.29(d,J=16.9Hz,1H),5.03-5.20(m,2H) ,4.25-4.39(m,2H),3.85-3.93(m,2H),3.50-3.60(m,1H),3.20-3.30(m,4H),2.81-3.14(m,4H),2.52-2.75(m, 8H),1.98-2.08(m,1H); MS:[M+1] + :694.2.

[0513] Example 33

[0514] Compound 33-1: cis-2-(2,6-dioxadiazin-3-yl)-4-(4-(1-(1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-indene-4-yl)azacyclobutane-3-carbonyl)piperazin-1-yl)isoindoline-1,3-dione.

[0515]

[0516] Compound 33-2: trans-2-(2,6-dioxadiazin-3-yl)-4-(4-(1-(1S)-2-fluoro-1-hydroxy-7-(methanesulfonyl)-2,3-dihydro-1H-indene-4-yl)azacyclobutane-3-carbonyl)piperazin-1-yl)isoindoline-1,3-dione.

[0517]

[0518] As described in Example 23-1, compounds 33-1 and 33-2 were synthesized using a method similar to that in Example 23-1.

[0519] 1 H-NMR(33-1): (400MHz, DMSO-d6)δ11.09(s,1H),7.74(dd,J=8.4,7.2Hz,1H),7.56(d,J=8.6Hz,1H), 7.41(d,J=7.1Hz,1H),7.36(d,J=8.4Hz,1H),6.45(d,J=8.6Hz,1H),5.61(d,J=6.5Hz,1H),5.35(q,J=5.4Hz ,1H),5.04-5.23(m,2H),4.31(q,J=8.1Hz,2H),4.21(t,J=6.9Hz,2H),3.85-3.95(m,1H),3.65-3.73(m,2H), 3.50-3.58(m,2H),3.25-3.28(m,2H),3.05-3.24(m,5H),2.82-2.96(m,1H),2.53-2.65(m,3H),2.00-2.07(m,1H); MS:[M+1] + :654.2.

[0520] 1H-NMR(33-2): (400MHz, DMSO-d6)δ11.10(s,1H),7.74(dd,J=8.4,7.2Hz,1H),7.57(d,J=8.5Hz,1H), 7.41(d,J=7.1Hz,1H),7.37(d,J=8.4Hz,1H),6.47(d,J=8.6Hz,1H),5.85-5.91(m,1H),5.44(dd,J=16.5,4.4 Hz,1H),5.04-5.21(m,2H),4.33(dt,J=15.4,8.1Hz,2H),4.23(q,J=7.5Hz,2H),3.85-3.95(m,1H),3.65-3.75( m,2H),3.52-3.58(m,2H),3.42-3.51(m,2H),3.17(s,3H),2.83-3.08(m,3H),2.52-2.65(m,3H),2.00-2.07(m, 1H);MS:[M+1] + :654.2.

[0521] Example 34

[0522] Compound 34-1: cis-2-(2,6-dioxadiazin-3-yl)-5-fluoro-6-(4-(1-((1S)-2-fluoro-1-hydroxy-7-(methanesulfonyl)-2,3-dihydro-1H-inden-4-yl)azacyclobutane-3-carbonyl)piperazin-1-yl)isoindoline-1,3-dione.

[0523]

[0524] Compound 34-2: trans-2-(2,6-dioxadiazin-3-yl)-5-fluoro-6-(4-(1-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-indene-4-yl)azacyclobutane-3-carbonyl)piperazin-1-yl)isoindoline-1,3-dione.

[0525]

[0526] As described in Example 23-1, compounds 34-1 and 34-2 were synthesized using a method similar to that in Example 23-1.

[0527] 1H-NMR(34-1): (400MHz, DMSO-d6)δ11.11(s,1H),7.78(d,J=11.2Hz,1H),7.56(d,J=8.6Hz,1H), 7.50(d,J=7.3Hz,1H),6.46(d,J=8.6Hz,1H),5.62(d,J=6.6Hz,1H),5.36(q,J=5.4Hz,1H),5.05-5.24(m,2 H),4.31(q,J=8.1Hz,2H),4.21(t,J=6.9Hz,2H),3.84-3.96(m,1H),3.65-3.70(m,2H),3.50-3.56(m,2H), 3.18-3.28(m,5H),2.82-3.13(m,3H),2.52-2.65(m,3H),2.00-2.10(m,1H); MS:[M+1] + :672.2.

[0528] 1 H-NMR(34-2): (400MHz, DMSO-d6)δ11.11(s,1H),7.78(d,J=11.2Hz,1H),7.57(d,J=8.5Hz,1H), 7.50(d,J=7.3Hz,1H),6.47(d,J=8.6Hz,1H),5.83-5.90(m,1H),5.44(d,J=16.4Hz,1H),5.05-5.21(m,2H),4 .33(dt,J=13.8,8.1Hz,2H),4.23(q,J=7.6Hz,2H),3.88-3.97(m,1H),3.63-3.70(m,2H),3.49-3.59(m,2H), 2.82-3.21(m,8H),2.53-2.62(m,2H),2.00-2.08(m,1H); MS:[M+1] + :672.2.

[0529] Example 35

[0530] Compound 35-1: cis-2-(2,6-dioxadiazin-3-yl)-5-(4-(2-(3-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-indene-4-yl)oxy)azacyclobut-1-yl)-2-oxoethyl)piperazin-1-yl)isoindoline-1,3-dione.

[0531]

[0532] Compound 35-2: trans-2-(2,6-dioxadiazin-3-yl)-5-(4-(2-(3-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-indene-4-yl)oxy)azacyclobut-1-yl)-2-oxoethyl)piperazin-1-yl)isoindoline-1,3-dione.

[0533]

[0534] Step A: Preparation of intermediate 35-A

[0535] 2-(2,6-dioxadiazin-3-yl)-5-fluoroisoindoline-1,3-dione (1 mmol), 2-(piperazin-1-yl) tert-butyl acetate (1 mmol) and DIPEA (2 mmol) were dissolved in DMSO (6 mL) and reacted at 90 °C for 2 h. After the reaction was completed, the mixture was cooled to room temperature, and saturated sodium chloride solution (40 mL) was added. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain intermediate 35-A, which was used directly in subsequent synthesis.

[0536] Step B: Preparation of intermediate 35-B

[0537] The product obtained in Step A was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (5 mL) was added. The reaction was carried out at room temperature. After the reaction was completed, the solvent was evaporated to obtain intermediate 35-B, which was used directly in subsequent synthesis.

[0538] Step C: Preparation of intermediate 35-C

[0539] Intermediate 35-B (30 mg), intermediate 17-C (22.5 mg), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (29 mg), and 1-hydroxybenzotriazole (HOBT) (20 mg) were dissolved in DMF (3 mL) and reacted at room temperature. After the reaction was completed, saturated sodium chloride solution (20 mL) was added, followed by extraction with ethyl acetate, drying with anhydrous sodium sulfate, and column chromatography to obtain intermediate 35-C (37 mg, yield 71%).

[0540] Step D: Preparation of compounds 35-1 and 35-2

[0541] Formic acid (20 μL) was dissolved in 1 mL of dichloromethane. Triethylamine (30 μL) was added and stirred for 10 min under ice-water bath conditions. This solution was then added to a 35°C (37 mg) dichloromethane solution, and the catalyst [(R,R)-N-(2-amino-1,2-diphenylethyl)-p-methylbenzenesulfonamide] ruthenium(II) chloride (5% mol) was added. The reaction was carried out at room temperature for 8 h under argon protection. After the reaction was complete, 20 mL of dichloromethane was added, followed by washing with saturated sodium bicarbonate, drying, preparative high-performance liquid chromatography (HPLC) purification, and freeze-drying to obtain the target products 35-1 (13 mg) and 35-2 (8 mg).

[0542] 1 H-NMR(35-1): (400MHz, DMSO-d6)δ11.08(s,1H),7.74(d,J=8.6Hz,1H),7.68(d,J=8.4Hz,1H),7.35 (d,J=2.3Hz,1H),7.25(dd,J=8.8,2.3Hz,1H),6.92(d,J=8.6Hz,1H),5.85(d,J=6.9Hz,1H),5.40-5.48(m,1H ),5.14-5.35(m,2H),5.07(dd,J=12.9,5.4Hz,1H),4.68-4.76(m,1H),4.35-4.44(m,1H),4.18-4.25(m,1H), 3.80-3.90(m,1H),3.40-3.50(m,4H),3.29(s,3H),2.82-3.20(m,6H),2.54-2.65(m,5H),1.96-2.06(m,1H); MS: [M+1] + :684.2.

[0543] 1H-NMR(35-2): (400MHz, DMSO-d6)δ11.08(s,1H),7.76(d,J=8.6Hz,1H),7.68(d,J=8.5Hz,1H),7.35 (d,J=2.3Hz,1H),7.25(d,J=8.7Hz,1H),6.92-6.99(m,1H),6.09(t,J=5.5Hz,1H),5.51(dd,J=16.5,5.7Hz,1 H),5.14-5.29(m,2H),5.07(dd,J=12.9,5.4Hz,1H),4.70-4.78(m,1H),4.36-4.43(m,1H),4.20-4.30(m,1H), 3.88(d,J=10.9Hz,1H),3.40-3.50(m,4H),3.25(s,3H),2.81-3.12(m,6H),2.52-2.68(m,5H),1.97-2.05(m,1H); MS:[M+1] + :684.2.

[0544] Example 36

[0545] Compound 36-1: cis-2-(2,6-dioxadiazin-3-yl)-4-(4-(2-(3-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-indene-4-yl)oxy)azacyclobut-1-yl)ethyl)piperidin-1-yl)isoindoline-1,3-dione.

[0546]

[0547] Compound 36-2: trans-2-(2,6-dioxadiazin-3-yl)-4-(4-(2-(3-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-indene-4-yl)oxy)azacyclobut-1-yl)ethyl)piperidin-1-yl)isoindoline-1,3-dione.

[0548]

[0549] As described in Example 23-1, compounds 36-1 and 36-2 were synthesized using a method similar to that in Example 23-1.

[0550] 11H-NMR(36-1): (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 7.74 (d, J = 8.6 Hz, 1H), 7.70 (d, J = 11.4 Hz, 1H), 7.43 (d, J = 7.4 Hz, 1H), 6.92 (d, J = 8.7 Hz, 1H), 5.79 - 5.90 (m, 1H), 5.40 - 5.48 (m, 1H), 5.04 - 5.36 (m, 3H), 4.63 (m, 1H), 4.35 (m, 1H), 4.15 (m, 1H), 3.76 - 3.85 (m, 1H), 3.59 (d, J = 12.0 Hz, 2H), 3.30 (s, 3H), 2.79 - 3.21 (m, 4H), 2.50 - 2.63 (m, 2H), 2.14 (m, 2H), 1.99 - 2.07 (m, 1H), 1.78 (d, J = 12.6 Hz, 2H), 1.49 (m, 3H), 1.20 - 1.35 (m, 3H); MS: [M+1] + : 669.2。

[0551] 1 1H-NMR(36-2): (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 7.76 (d, J = 8.6 Hz, 1H), 7.70 (d, J = 11.4 Hz, 1H), 7.43 (d, J = 7.4 Hz, 1H), 6.95 (d, J = 8.6 Hz, 1H), 6.05 - 6.14 (m, 1H), 5.52 (d, J = 16.5 Hz, 1H), 5.05 - 5.31 (m, 3H), 4.58 - 4.58 (m, 1H), 4.30 - 4.40 (m, 1H), 4.12 - 4.20 (m, 1H), 3.83 (d, J = 10.7 Hz, 1H), 3.59 (d, J = 12.0 Hz, 2H), 3.25 (s, 3H), 2.80 - 3.05 (m, 4H), 2.�3 - 2.67 (m, 2H), 2.15 (t, J = 7.4 Hz, 2H), 1.99 - 2.06 (m, 1H), 1.78 (d, J = 12.6 Hz, 2H), 1.40 - 1.53 (m, 3H), 1.20 - 1.35 (m, 3H); MS: [M+1] + : 669.2。

[0552] Example 37

[0553] Compound 37-1: cis-N-(2-(4-(2-(2,6-dioxadipiperidin-3-yl)-6-fluoro-1,3-dioxadiindololin-5-yl)piperazin-1-yl)-2-oxoethyl)-1-((1S)-2-fluoro-1-hydroxy-7-(methanesulfonyl)-2,3-dihydro-1H-inden-4-yl)azacyclobutane-3-carboxamide;

[0554]

[0555] Step A: Preparation of intermediate 37-A

[0556] 1-((benzyloxy)carbonyl)azacyclobutane-3-carboxylic acid (100 mg), glycine tert-butyl ester (56 mg), EDCI (163 mg), HOBT (115 mg), and triethylamine (85 mg) were dissolved in DMF (3 mL) and reacted at room temperature. After the reaction was complete, saturated sodium chloride solution (30 mL) was added, followed by extraction with ethyl acetate, drying with anhydrous sodium sulfate, and rotary evaporation to obtain intermediate 37-A, which was directly used for subsequent synthesis.

[0557] Step B: Preparation of intermediate 37-B

[0558] Intermediate 37-A obtained in Step A was dissolved in methanol (8 mL), and palladium hydroxide (50 mg) was added. The mixture was then reacted overnight under hydrogen atmosphere. After the reaction was complete, the mixture was filtered, and the filtrate was evaporated to dryness to obtain intermediate 37-B, which was used directly in subsequent synthesis.

[0559] Step C: Preparation of intermediate 37-C

[0560] Intermediate 37-B (40 mg) obtained in Step B, 2,4-difluoro-7-(methanesulfonyl)-2,3-dihydro-1H-inden-1-one (46 mg) and potassium carbonate (53 mg) were dissolved in DMF (2 mL) and reacted at 80 °C. After the reaction was completed, the mixture was cooled to room temperature, and saturated sodium chloride solution (20 mL) was added. The mixture was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and subjected to column chromatography to obtain intermediate 37-C (15 mg, yield 18.2%).

[0561] Step D: Preparation of intermediate 37-D

[0562] Intermediate 37-C (15 mg) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2 mL) was added. The reaction was carried out at room temperature. After the reaction was completed, the solvent was evaporated to obtain intermediate 37-D, which was used directly for subsequent synthesis.

[0563] Step E: Synthesis of intermediate 37-E

[0564] 2-(2,6-dioxadiazin-3-yl)-5,6-difluoroisoindoline-1,3-dione (50 mg), tert-butylpiperazine-1-carboxylic acid ester (22 mg), and DIPEA (22 mg) were dissolved in DMSO (2 mL) and reacted at 90 °C for 1 h. After the reaction was completed, the mixture was cooled to room temperature, and saturated sodium chloride solution (20 mL) was added. The mixture was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain intermediate 37-E, which was used directly in subsequent synthesis.

[0565] Step F: Synthesis of intermediate 37-F

[0566] The 37-E obtained in Step E was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The reaction was carried out at room temperature. After the reaction was completed, the intermediate 37-F was obtained by rotary evaporation and used directly for subsequent synthesis.

[0567] Step G: Synthesis of intermediate 37-G

[0568] Intermediate 37-D obtained in Step D, intermediate 37-G obtained in Step G, EDCI (15 mg) and HOBT (10 mg) were dissolved in DMF (2 mL) and reacted at room temperature. After the reaction was completed, saturated sodium chloride solution was added and the mixture was extracted with ethyl acetate, dried with anhydrous sodium sulfate, and subjected to column chromatography to obtain intermediate 37-G (15 mg).

[0569] Step H: Synthesis of Compound 37-1

[0570] Formic acid (10 μL) was dissolved in 1 mL of dichloromethane. Triethylamine (15 μL) was added under ice-water bath conditions, and the mixture was stirred for 10 min. This solution was then added to a 15 mg solution of 37-G in dichloromethane, along with the catalyst [(R,R)-N-(2-amino-1,2-diphenylethyl)-p-methylbenzenesulfonamide] ruthenium(II) chloride (5% mol). The reaction was carried out under argon protection at room temperature for 8 h. After the reaction was complete, 20 mL of dichloromethane was added, followed by washing with saturated sodium bicarbonate, drying, preparative high-performance liquid chromatography (HPLC) purification, and freeze-drying to obtain the target product 37-1 (3 mg).

[0571]

[0572] 1H-NMR(37-1): (400MHz, DMSO-d6)δ11.10(s,1H),8.24(t,J=5.3Hz,1H),7.77(d,J=11.3Hz,1H),7.56 (d,J=8.5Hz,1H),7.50(d,J=7.3Hz,1H),6.43(d,J=8.6Hz,1H),5.61(d,J=6.8Hz,1H),5.31-5.39(m,1H),5.03 -5.23(m,2H),4.18-4.30(m,2H),4.03-4.14(m,3H),3.58-3.67(m,4H),3.03-3.26(m,7H),2.83-2.94(m,2H), 2.56-2.69(m,4H),2.32-2.37(m,1H),1.95-2.05(m,1H); MS:[M+1] + :729.2.

[0573] Example 38

[0574] Compound 38-1: cis-2-(2,6-dioxadiazin-3-yl)-5-fluoro-6-(4-(4-(3-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-indene-4-yl)oxy)azacyclobut-1-yl)-4-oxobutyl)piperazin-1-yl)isoindoline-1,3-dione.

[0575]

[0576] Compound 38-2: trans-2-(2,6-dioxadiazin-3-yl)-5-fluoro-6-(4-(4-(3-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-indene-4-yl)oxy)azacyclobut-1-yl)-4-oxobutyl)piperazin-1-yl)isoindoline-1,3-dione.

[0577]

[0578] 1H-NMR(38-1): (400MHz, DMSO-d6)δ11.11(s,1H),8.32(s,1H),7.68-7.77(m,2H),7.44(d,J=7.4Hz, 1H),6.92(d,J=8.7Hz,1H),5.40-5.44(m,1H),5.05-5.31(m,3H),4.55-4.65(m,1H),4.30-4.40(m,1H),4.10-4.2 0(m,1H),3.78-3.84(m,1H),3.20-3.30(m,7H),2.81-3.15(m,5H),2.55-2.64(m,3H),2.29-2.35(m,2H),2.12(t,J =7.2Hz,2H),2.00-2.07(m,1H),1.63-1.75(m,2H); MS:[M+1] + :730.2.

[0579] 1 H-NMR(38-2): (400MHz, DMSO-d6)δ11.10(s,1H),8.41(s,2H),7.67-7.78(m,2H),7.44(dd,J=7.5,1.9 Hz,1H),6.95(d,J=8.6Hz,1H),5.45-5.55(m,1H),5.06-5.28(m,3H),4.63(t,J=8.0Hz,1H),4.30-4.40(m,1H), 4.18(dt,J=10.7,5.5Hz,1H),3.84(dd,J=10.5,3.8Hz,1H),3.20-3.25(m,7H),2.82-3.03(m,5H),2.67(m,1 H),2.54-2.63(m,3H),2.28-2.36(m,2H),2.08-2.15(m,2H),2.00-2.07(m,1H),1.65-1.73(m,2H); MS:[M+1] + :730.2.

[0580] Example 39

[0581] Compound 39-1: cis-5-(4-(4-(4-((1-((1S)-7-(((difluoromethyl)sulfonyl)-2-fluoro-1-hydroxy-2,3-dihydro-1H-inden-4-yl)azacyclobut-3-yl)methyl)piperazin-1-yl)-4-oxobutyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione.

[0582]

[0583]

[0584] 1 H-NMR(39-1): (400MHz, DMSO-d6)δ11.11(s,1H),7.72(d,J=11.5Hz,1H),7.57(d,J=8.8Hz,1H), 7.45(d,J=7.4Hz,1H),7.03(t,J=54.0Hz,1H),6.41(d,J=8.8Hz,1H),5.06-5.26(m,3H),4.28(t,J=7.8Hz,2H ),3.84(t,J=7.0Hz,2H),3.10-3.60(m,10H),2.83-2.97(m,3H),2.52-2.63(m,8H),2.25-2.40(m,8H),1.98- 2.04(m,1H),1.62-1.76(m,2H);MS:[M+1] + :849.3.

[0585] Example 40

[0586] Compound 40-1: cis-2-(2,6-dioxadiazin-3-yl)-4-((2-((1-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)azacyclobut-3-yl)(methyl)amino)ethyl)(methyl)amino)isoindoline-1,3-dione.

[0587]

[0588] Compound 40-2: trans-2-(2,6-dioxadiazin-3-yl)-4-((2-((1-((1S)-2-fluoro-1-hydroxy-7-(methanesulfonyl)-2,3-dihydro-1H-indene-4-yl)azacyclobut-3-yl)(methyl)amino)ethyl)(methyl)amino)isoindoline-1,3-dione.

[0589]

[0590] Step A: Preparation of intermediate 40-A

[0591] 1 g of tert-butylmethyl (2-(methylamino)ethyl)carbamate and 1.09 g of benzyl 3-oxozycyclobutane-1-carboxylate were dissolved in 20 mL of dichloromethane. After stirring at room temperature for 1 h, 1.13 g of sodium acetoxyborohydride was added, and the mixture was stirred overnight at room temperature. After the reaction was complete, 40 mL of saturated sodium bicarbonate solution and 20 mL of dichloromethane were added. The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain intermediate 40-A, which was used directly in subsequent synthesis.

[0592] Step B: Preparation of intermediate 40-B

[0593] Intermediate 40-A was dissolved in methanol (20 mL), and palladium hydroxide (200 mg) was added. The reaction was carried out at room temperature under hydrogen atmosphere. After the reaction was completed, the mixture was filtered and evaporated to dryness to obtain intermediate 40-B, which was used directly in subsequent synthesis.

[0594] Step CG:

[0595] As described in Example 23-1, target compounds 40-1 and 40-2 were synthesized using a method similar to that in Example 23-1.

[0596]

[0597] 1 H-NMR(40-1): (400MHz, DMSO-d6)δ11.07(s,1H),7.51-7.61(m,2H),7.28(d,J=8.7Hz,1H),7.21(d, J=7.0Hz,1H),6.34(d,J=8.6Hz,1H),5.60(d,J=6.3Hz,1H),5.30-5.38(m,1H),5.02-5.22(m,2H),4.02-4.15(m, 2H),3.60-3.75(m,4H),3.21(s,3H),3.08-3.18(m,2H),3.05(s,3H),2.80-2.92(m,2H),2.53-2.69(m,4H),2.10 (s,3H),1.94-2.04(m,1H);MS:[M+1] + :628.2.

[0598] 1H-NMR(40-2): (400MHz, DMSO-d6)δ11.07(s,1H),7.51-7.61(m,2H),7.28(d,J=8.6Hz,1H),7.21(d, J=7.0Hz,1H),6.34(d,J=8.6Hz,1H),5.60(d,J=6.5Hz,1H),5.35(q,J=5.2Hz,1H),5.02-5.23(m,2H),4.04-4.1 5(m,2H),3.62-3.75(m,4H),3.21(s,3H),3.05-3.18(m,2H),3.05(s,3H),2.82-2.92(m,2H),2.52-2.68(m,4H), 2.10(s,3H),1.96-2.03(m,1H);MS:[M+1] + :628.2.

[0599] Example 41

[0600] Compound 41-1: cis-2-(2,6-dioxadiazin-3-yl)-5-fluoro-6-((2-((1-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-indene-4-yl)azacyclobut-3-yl)(methyl)amino)ethyl)(methyl)amino)isoindoline-1,3-dione.

[0601]

[0602] Compound 41-2: trans-2-(2,6-dioxadiazin-3-yl)-5-fluoro-6-((2-((1-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-indene-4-yl)azacyclobut-3-yl)(methyl)amino)ethyl)(methyl)amino)isoindoline-1,3-dione.

[0603]

[0604]

[0605] As described in Example 40-1, compounds 41-1 and 41-2 were synthesized using a method similar to that in 40-1.

[0606] 1H-NMR(41-1): (400MHz, DMSO-d6)δ11.09(s,1H),7.65(d,J=12.6Hz,1H),7.52(d,J=8.5Hz,1H), 7.29(d,J=7.8Hz,1H),6.34(d,J=8.6Hz,1H),5.59(m,1H),5.34(t,J=5.0Hz,1H),5.00-5.22(m,2H),4.07-4. 16(m,2H),3.69-3.76(m,2H),3.52(t,J=6.9Hz,2H),3.35-3.45(m,2H),3.01-3.24(m,9H),2.82-2.92(m,1H), 2.54-2.65(m,2H),2.17(s,3H),1.97-2.05(m,1H); MS:[M+1] + :646.2.

[0607] 1 H-NMR(41-2): (400MHz, DMSO-d6)δ11.09(s,1H),7.65(d,J=12.7Hz,1H),7.54(d,J=8.5Hz,1H), 7.30(d,J=7.7Hz,1H),6.36(d,J=8.6Hz,1H),5.85(m,1H),5.43(d,J=16.6Hz,1H),4.98-5.18(m,2H),4.05- 4.18(m,2H),3.68-3.83(m,2H),3.38-3.56(m,5H),3.17(s,3H),3.08(s,3H),2 .82-3.02(m,3H),2.52-2.63(m,2H),2.18(s,3H),1.96-2.05(m,1H);MS:[M+1] + :646.2.

[0608] Example 42

[0609] Compound 42-1: cis-2-(2,6-dioxadiazin-3-yl)-5-fluoro-6-(4-(6-(3-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-indene-4-yl)oxy)azacyclobut-1-yl)-6-oxohexyl)piperazin-1-yl)isoindoline-1,3-dione.

[0610]

[0611] Compound 42-2: trans-2-(2,6-dioxadiazin-3-yl)-5-fluoro-6-(4-(6-(3-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-indene-4-yl)oxy)azacyclobut-1-yl)-6-oxohexyl)piperazin-1-yl)isoindoline-1,3-dione.

[0612]

[0613] As described in Example 38-1, compounds 42-1 and 42-2 were synthesized using a method similar to that in 38-1.

[0614] 1 H-NMR(42-1): (400MHz, DMSO-d6)δ11.10(s,1H),7.67-7.76(m,2H),7.45(d,J=7.4Hz,1H),6.91(d,J=8 .7Hz,1H),5.44(dd,J=7.6,5.0Hz,1H),5.07-5.34(m,3H),4.60(m,1H),4.34(m,1H),4.12(m,1H),3.80 (m,1H),3.29(s,3H),3.20-3.28(m,5H),2.82-3.18(m,5H),2.52-2.68(m,4H),2.31 (t,J=7.5Hz,2H),2.00-2.13(m,3H),1.40-1.55(m,4H),1.20-1.35(m,2H); MS:[M+1] + :758.2.

[0615] 1 H-NMR(42-2): (400MHz, DMSO-d6)δ11.10(s,1H),7.68-7.77(m,2H),7.45(d,J=7.4Hz,1H),6.95(d, J=8.6Hz,1H),5.51(d,J=16.5Hz,1H),5.06-5.29(m,3H),4.59-4.63(m,1H),4.30-4.38(m,1H),4.10-4.18(m, 1H),3.78-3.86(m,1H),3.18-3.31(m,10H),2.82-3.04(m,3H),2.52-2.68(m,4H),2.31(t,J=7.1Hz,2H),1.97- 2.13(m,3H),1.40-1.55(m,4H),1.22-1.35(m,2H); MS:[M+1] + :758.2.

[0616] Example 43

[0617] Compound 43: 5-(4-((1-((S)-2,2-difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-indene-4-yl)azacyclobut-3-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperazin-3-yl)-6-fluoroisoindoline-1,3-dione.

[0618]

[0619] Step A: Preparation of intermediate 43-A

[0620] 2,2,4-trifluoro-7-(methanesulfonyl)-2,3-dihydro-1H-inden-1-one (100 mg), 4-(azacyclobutane-3-ylmethyl)piperazine-1-carboxylic acid tert-butyl ester (997 mg), and triethylamine (57 mg) were dissolved in DMSO (3 mL) and reacted at 90 °C. After the reaction was completed, the mixture was cooled to room temperature, and saturated sodium chloride solution (30 mL) was added. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and subjected to column chromatography to obtain the target compound (130 mg, yield 69%).

[0621] Step BD:

[0622] As described in Example 23-1, compound 43 was synthesized using a method similar to that in 23-1.

[0623] 1 H-NMR(43): (400MHz, DMSO-d6)δ11.10(s,1H),7.73(d,J=11.4Hz,1H),7.58(d,J=8.6Hz,1H),7.46 (d,J=7.4Hz,1H),6.43(d,J=8.7Hz,1H),5.25(d,J=13.4Hz,1H),5.11(dd,J=12.8,5.4Hz,1H),4.23(q,J=7.8Hz,2H),3. 79(t,J=6.4Hz,2H),3.32-3.62(m,6H),3.17(s,3H),2.82-3.01(m,2H),2.52-2.70(m,8H),1.98-2.08(m,1H); MS:[M+1] + :676.2.

[0624] Example 44

[0625] Compound 44-1: cis-5-(4-(1-((1S)-7-(difluoromethyl)sulfonyl)-2-fluoro-1-hydroxy-2,3-dihydro-1H-inden-4-yl)-3-fluoroazacyclobutane-3-carbonyl)piperazin-1-yl)-2-(2,6-dioxadiazin-3-yl)-6-fluoroisoindoline-1,3-dione.

[0626]

[0627] Compound 44-2: trans-5-(4-(1-((1S)-7-(difluoromethyl)sulfonyl)-2-fluoro-1-hydroxy-2,3-dihydro-1H-inden-4-yl)-3-fluoroazacyclobutane-3-carbonyl)piperazin-1-yl)-2-(2,6-dioxadiazin-3-yl)-6-fluoroisoindoline-1,3-dione.

[0628]

[0629] Step A: Preparation of intermediate 44-A

[0630] 1-((benzyloxy)carbonyl)-3-hydroxyazacyclobutane-3-carboxylic acid (200 mg), tert-butylpiperazine-1-carboxylic acid ester (148 mg), EDCI (300 mg), HOBT (215 mg), and triethylamine (160 mg) were dissolved in DMF (5 mL) and reacted at room temperature. After the reaction was completed, saturated sodium chloride solution (35 mL) was added, followed by extraction with ethyl acetate, drying with anhydrous sodium sulfate, and column chromatography to obtain intermediate 44-A (180 mg, yield 54%).

[0631] Step B: Preparation of intermediate 44-B

[0632] Intermediate 44-A (180 mg) was dissolved in ultradry dichloromethane, and diethylaminosulfur trifluoride (DAST) (103 mg) was added and reacted at room temperature. After the reaction was complete, dichloromethane (20 mL) was added, followed by washing with saturated sodium bicarbonate solution and saturated sodium chloride solution, drying with anhydrous sodium sulfate, and column chromatography to obtain intermediate 44-B (130 mg, yield 72%).

[0633] Step CF:

[0634] As described in Example 32-1, compounds 44-1 and 44-2 were synthesized using a method similar to that in 32-1.

[0635] 1H-NMR(44-1): (400MHz, DMSO-d6)δ11.11(s,1H),7.79(d,J=11.2Hz,1H),7.65(d,J=8.7Hz,1H), 7.52(d,J=7.3Hz,1H),7.08(t,J=53.9Hz,1H),6.60(d,J=8.8Hz,1H),5.88(m,1H),5.24-5.30(m,1H),5.07- 5.15(m,1H),4.79-4.89(m,2H),4.49-4.63(m,2H),3.71(m,2H),3.58(m,2H),3.1 3-3.26(m,5H),2.82-2.95(m,1H),2.53-2.64(m,4H),2.01-2.10(m,1H);MS:[M+1] + 726.2.

[0636] 1 H-NMR(44-2): (400MHz, DMSO-d6)δ11.10(s,1H),7.90(d,J=11.2Hz,1H),7.68(d,J=8.7Hz,1H), 7.47(d,J=7.3Hz,1H),6.90(d,J=8.8Hz,1H),6.65(t,J=53.9Hz,1H),5.92(m,1H),5.20-5.30(m,1H),4.90-5 .10(m,1H),4.60(m,1H),4.10-4.25(m,4H),3.76(m,2H),3.65(m,2H),3.45-3.55(m,4H),3.00-3.18(m,2H), 2.15-2.20(m,1H),2.50-2.65(m,2H),1.75-1.80(m,1H); MS:[M+1] + 726.2.

[0637] Performance testing:

[0638] (I) Determination of HIF-2α degradation rate

[0639] The degradation rate of HIF-2α was determined by Western blotting, including the following steps:

[0640] 1) Seed 768-O cells into T25 culture flasks, approximately 6 mL of culture medium per flask, with a cell count of approximately 1.2 x 10⁻⁶ cells. 6 On the day of medication administration, a confluence rate of approximately 80%-90% is guaranteed.

[0641] 2) Incubate overnight in a 37°C, 5% CO2 incubator.

[0642] 3) Dissolve the compounds prepared in Examples 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 16, 17, 19, 20, 21, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 and 44 in DMSO to obtain compound solutions.

[0643] 4) Take 6 μL of the compound solution (or DMSO) from step 3) and add it to the culture flask. Incubate at 37°C and 5% CO2 for 6 hours.

[0644] 5) Collect cells 6 hours after drug administration (refer to the RIPA instruction manual provided by ThermoFisher for lysis method).

[0645] 6) Prepare cell lysis buffer. Add one protease inhibitor tablet and one phosphatase inhibitor tablet to each 10 mL RIPA buffer, mix well and set aside.

[0646] 7) Discard the supernatant in the culture flask and wash twice with PBS.

[0647] 8) Add 100 μL of pre-chilled RIPA to each flask, rotate the culture flask to spread the cells evenly, and place the culture flask on ice for 15 minutes to lyse.

[0648] 9) Collect the protein lysate with a cell scraper and transfer it to a 1.5 ml centrifuge tube. Centrifuge at 14,000 r / min for 15 minutes.

[0649] 10) Transfer the supernatant to a clean, pre-cooled 1.5ml centrifuge tube for later use.

[0650] 11) Refer to the BCA protein quantification kit instructions for the experimental procedure.

[0651] 12) Sample loading: 30ug / well (pre-formed adhesive, Bio-rad, 26 wells, 4-15%).

[0652] 13) Electrophoresis: Electrophoresis is performed at 70 volts until the bromophenol blue dye reaches the bottom of the gel. The electrophoresis time is approximately 2.5 hours.

[0653] 14) Transfer: First, pre-activate the PVDF membrane with methanol and assemble it into a "sandwich" structure, from bottom to top: filter paper-gel-membrane-filter paper. Wet transfer, 60 minutes, 280mA.

[0654] 15) Blocking: 5% skim milk / TBS / 0.1% T solution, incubate at room temperature for 1 hour.

[0655] 16) Wash the membrane: TBS / 0.1% T solution, 5 minutes, 3 times.

[0656] 17) Primary antibody: Dilute the primary antibody with 5% skim milk / TBS / 0.1% T solution and incubate overnight at 4°C.

[0657] 18) Wash the membrane: TBS / 0.1% T solution, 5 minutes, 3 times.

[0658] 19) Secondary antibody: Dilute the corresponding secondary antibody with 5% skim milk / TBS / 0.1% T solution at a ratio of 1:250, incubate at room temperature for 1 hour, and protect from light.

[0659] 20) Wash the membrane: TBS / 0.1% T solution, 5 minutes, 3 times.

[0660] 21) Detection: Odyssey scanning detection was performed at wavelengths of 700 nm or 800 nm, or Tanon 5200 imaging was used. The detection results are shown in Table 1.

[0661] Table 1. Degradation rate of HIF-2α at 1 μM compound concentration in each example.

[0662]

[0663]

[0664] In the table above: A, B, and C represent degradation rates, where A ≥ 50%, 30% ≤ B < 50%, and 10% ≤ C < 30%.

[0665] As shown in Table 1, the bifunctional compound of this application has a high HIF-2α degradation rate, indicating that the bifunctional compound of this application can effectively reduce the expression level of HIF-2α in tumor cells and can be used to treat tumors or cancers related to high expression of HIF-2α, showing good application prospects.

[0666] The above are merely preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A bifunctional compound or a pharmaceutically acceptable salt, enantiomer, diastereomer thereof, wherein, The bifunctional compound has the following general formula (I): In the above formula (I): the L is a linker; said R1is selected from the group consisting of halogen, -CN, -S(O)2R a wherein R a is selected from any one of C1-C6alkyl and C1-C6haloalkyl; each of R2 and R3 is independently selected from any one of H, halogen, -CN, C1-C6 alkyl and C1-C6 haloalkyl; X is selected from any one of -C(O)- and -CH2-; R4 is selected from any one of H, halogen, -CN, C1-C3 alkyl and C1-C3 haloalkyl; the linker L has the following general formula (II): In the above formula (II): said L1is covalently attached to the phenyl ring to which R1is attached, said L4is covalently attached to the phenyl ring to which R4is attached; In the above formula (II): said L1is covalently attached to the phenyl ring to which R1is attached, said L4is covalently attached to the phenyl ring to which R4is attached; In the above formula (II): said L1 said L1is absent or selected from the group consisting of -NR d -0-, -S-, -NHCH2-, -NH(CH2) q -0-, -S-, -NHCH2-, -NH(CH2) d -0-, -S-, -NHCH2-, -NH(CH2) L2and / or L3are absent or selected from the group consisting of -(CH2) m -, -NR e -, -(CH2CH2O) n -, -(NH) o (CH2) p C(O)- and -C(O)(CH2) p (NH) o -, wherein m is an integer from 0 to 12, n is an integer from 0 to 6, o is 0 or 1, p is an integer from 0 to 6, R e is selected from the group consisting of H, C1-C3 alkyl and C1-C3 haloalkyl; said L4is absent or selected from the group consisting of -0-, -S-, and -NR f - any one of H, halogen, -CN, C1-C3 alkyl, C1-C3 haloalkyl; and f - any one of H, halogen, -CN, C1-C3 alkyl, C1-C3 haloalkyl; and each of A, B and C is independently selected from none; or, A is selected from any one of the following groups: wherein Z is selected from any one of -N- and -CH2-, and α represents the connection of the group adjacent to the left of the A group in formula (II), and β represents the connection of the group adjacent to the right of the A group in formula (II); B is selected from at least one of the following groups: wherein γ represents the connection of the group adjacent to the left of the B group in formula (II), and δ represents the connection of the group adjacent to the right of the B group in formula (II); C is selected from any one of the following groups: a 5-membered heteroaryl containing 3 N atoms; wherein said L5is absent or selected from -CH2-, -O-, -NR g - -C(O)-, -O(CH2) r - -C(O)-, -O(CH2) g selected from H, C1-C3alkyl, C1-C3alkanoyl and C1-C3alkylsulfonyl; R5 is selected from any one of H, deuterium, halogen, -OH, C1-C3 alkyl and C1-C3 haloalkyl; R6 is selected from any one of H, -CN, halogen, -OH, C1-C3 alkyl and C1-C3 haloalkyl; π represents the connection of the group adjacent to the left of the C group in formula (II), and θ represents the connection of the group adjacent to the right of the C group in formula (II).

2. The bifunctional compound or pharmaceutically acceptable salt, enantiomer, diastereomer thereof of claim 1, wherein, The bifunctional compound has the following general formula (I): said R1is selected from the group consisting of halogen, -S(O)2R a wherein R a is selected from the group consisting of Ci-C6-alkyl and Ci-C6-haloalkyl; each of R2 and R3 is independently selected from H and halogen; X is selected from any one of -C(O)- and -CH2-; R4 is selected from any one of H and halogen; the linker L has the following general formula (II): In the above formula (II): said L1is covalently attached to the phenyl ring to which R1is attached, said L4is covalently attached to the phenyl ring to which R4is attached; In the above formula (II): said L1is covalently attached to the phenyl ring to which R1is attached, said L4is covalently attached to the phenyl ring to which R4is attached; In the above formula (II): said L1 said L1is absent or selected from the group consisting of -NR d -0-, -S-, -NHCH2-, -NH(CH2) q C(O)- and -OC(O)-, wherein said q is an integer from 0 to 6, said R d is selected from the group consisting of H and C1-C3alkyl; L2and / or L3are absent or selected from the group consisting of -(CH2) m -, -NR e -, -(CH2CH2O) n -, -(NH) o (CH2) p C(O)- and -C(O)(CH2) p (NH) o -, wherein m is an integer from 0 to 12, n is an integer from 0 to 6, o is 0 or 1, p is an integer from 0 to 6, R e is selected from the group consisting of H and C1-C3 alkyl; said L4is absent or selected from the group consisting of -O-, -S- and -NR f - any one of R f is selected from the group consisting of H and C1-C3alkyl; each of A, B and C is independently selected from none; or, A is selected from any one of the following groups: wherein Z is selected from any one of -N- and -CH2-, and α represents the connection of the group adjacent to the left of the A group in formula (II), and β represents the connection of the group adjacent to the right of the A group in formula (II); B is selected from at least one of the following groups: wherein γ represents the connection of the group adjacent to the left of the B group in formula (II), and δ represents the connection of the group adjacent to the right of the B group in formula (II); C is selected from any one of the following groups: a 5-membered heteroaryl containing 3 N atoms; wherein said L5is absent or selected from -CH2-, -0-, -NR g -, -C(O)-, -0(CH2) r -, -C(O)-, -0(CH2) g r is an integer from 0 to 6, and R R5 is selected from any one of H and halogen; R6 is selected from any one of H, -CN, halogen and C1-C3 alkyl; π represents the connection of the group adjacent to the left of the C group in formula (II), and θ represents the connection of the group adjacent to the right of the C group in formula (II).

3. The bifunctional compound or pharmaceutically acceptable salt, enantiomer, diastereomer thereof of claim 1, wherein, the C1-C6 alkyl is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl; said C1-C6 haloalkyl is a methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl group in which a hydrogen atom bound to a carbon atom is replaced by at least one halogen atom; halogen is selected from F, Cl, Br, I, At.

4. The bifunctional compound or pharmaceutically acceptable salt, enantiomer, diastereomer thereof of claim 1, wherein, said R2and R3are each independently selected from H, F, Cl, Br, I, At.

5. The bifunctional compound or pharmaceutically acceptable salt, enantiomer, diastereomer thereof of claim 1, wherein, said R4is selected from H, F, Cl, Br, I, At.

6. A bifunctional compound or a pharmaceutically acceptable salt, enantiomer, diastereomer thereof as shown below: cis-2-(2,6-dioxopiperidin-3-yl)-4-((1-(2-(2-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)amino)isoindoline-1,3-dione; trans-2-(2,6-dioxopiperidin-3-yl)-4-((1-(2-(2-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)amino)isoindoline-1,3-dione; cis-2-(2,6-dioxopiperidin-3-yl)-4-((1-(2-(2-(2-(2-((((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)amino)isoindoline-1,3-dione; trans-2-(2,6-dioxopiperidin-3-yl)-4-((1-(2-(2-(2-(2-((((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)amino)isoindoline-1,3-dione; cis-2-(2,6-dioxopiperidin-3-yl)-4-(1-(2-(2-(2-(2-(2-((((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)amino)isoindoline-1,3-dione; trans-2-(2,6-dioxopiperidin-3-yl)-4-(1-(2-(2-(2-(2-(2-((((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)amino)isoindoline-1,3-dione; Cis-2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(2-((1S)-2-fluoro-1-hydroxy-7- (methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)ethoxy)ethoxy)ethyl)amino)isoindoline- 1,3-dione; Trans-2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(2-((1S)-2-fluoro-1-hydroxy-7- (methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)ethoxy)ethoxy)ethyl)amino)isoindoline- 1,3-dione; Cis-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-(2-(2-(2-((1S)- 2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)ethoxy)ethoxy) ethyl)acetamide; Trans-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-(2-(2-(2-((1S)- 2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)ethoxy)ethoxy) ethyl)acetamide; Cis-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-(2-(2-(2-((1S)- 2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)ethoxy)ethoxy) ethyl)acetamide; Trans-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-(2-(2-(2-((1S)- 2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)ethoxy)ethoxy) ethyl)acetamide; Cis-4-((1-(2-(2-(2-(2-((1S)-7-((difluoromethyl)sulfonyl)-2-fluoro-1-hydroxy-2,3-dihydro- 1H-inden-4-yl)oxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione; Trans-4-((1-(2-(2-(2-(2-((1S)-7-((difluoromethyl)sulfonyl)-2-fluoro-1-hydroxy-2,3-dihydro- 1H-inden-4-yl)oxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione; Cis-2-(2,6-dioxopiperidin-3-yl)-5-((1-(2-(2-(2-(2-((((1S)-2-fluoro-1-hydroxy-7- (methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)ethoxy)ethoxy)ethyl)-1H-1,2,3- triazol-4-yl)methyl)amino)isoindoline-1,3-dione; Trans-2-(2,6-dioxopiperidin-3-yl)-5-((1-(2-(2-(2-(2-((((1S)-2-fluoro-1-hydroxy-7- (methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)ethoxy)ethoxy)ethyl)-1H-1,2,3- triazol-4-yl)methyl)amino)isoindoline-1,3-dione; Cis-2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-((1-(2-(2-(2-(((1S)-2-fluoro-1-hydroxy-7- (methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)ethoxy)ethoxy)ethyl)-1H-1,2,3- triazol-4-yl)methyl)amino)isoindoline-1,3-dione; Trans-2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-((1-(2-(2-(2-(((1S)-2-fluoro-1-hydroxy-7- (methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)ethoxy)ethoxy)ethyl)-1H-1,2,3- triazol-4-yl)methyl)amino)isoindoline-1,3-dione; Cis-3-(4-((1-(2-(2-(2-(2-(((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H- inden-4-yl)oxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione; Trans-3-(4-((1-(2-(2-(2-(2-(((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H- inden-4-yl)oxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione; Cis-3-(2-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)methyl)-1H- 1,2,3-triazol-1-yl)ethoxy)ethoxy)-5-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3- dihydro-1H-inden-4-yl)oxy)benzonitrile; Trans-3-(2-(2-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethoxy)ethoxy)-5-((1S)-2-fluoro-1- hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile; Cis-3-(2-(2-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethoxy)ethoxy)-5-((1S)-2-fluoro-1- hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile; Trans-3-(2-(2-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethoxy)ethoxy)-5-((1S)-2-fluoro-1- hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile; Cis-3-(2-(2-(2-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethoxy)ethoxy)ethoxy)-5-((1S)-2-fluoro-1- hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile; Trans-3-(2-(2-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethoxy)ethoxy)-5-((1S)-2-fluoro-1- hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile; Cis 2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(3-fluoro-5-((1S)-2-fluoro-1-hydroxy-7- (methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzoyl)piperazin-1-yl)piperidin-1- yl)isoindoline-1,3-dione; Trans 2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(3-fluoro-5-((1S)-2-fluoro-1-hydroxy-7- (methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzoyl)piperazin-1-yl)piperidin-1- yl)isoindoline-1,3-dione; Cis-2-(2,6-dioxopiperidin-3-yl)-5-(6-(3-fluoro-5-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzoyl)-2,6-diazaspiro[3.3]oct-2-yl)isoindole-1,3-dione; Trans-2-(2,6-dioxopiperidin-3-yl)-5-(6-(3-fluoro-5-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzoyl)-2,6-diazaspiro[3.3]oct-2-yl)isoindole-1,3-dione; Cis-N-(2-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazin-1-yl)-2-oxoethyl)-3-fluoro-5-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzamide; Trans-N-(2-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazin-1-yl)-2-oxoethyl)-3-fluoro-5-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzamide; Cis-2-(2,6-dioxopiperidin-3-yl)-4-(1-(2-(2-(3-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)azetidin-1-yl)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)amino)isoindole-1,3-dione; Trans-2-(2,6-dioxopiperidin-3-yl)-4-(1-(2-(2-(3-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)azetidin-1-yl)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)amino)isoindole-1,3-dione; Cis-2-(2,6-dioxopiperidin-3-yl)-4-((1-(2-(3-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)azetidin-1-yl)ethyl)-1H-1,2,3-triazol-4-yl)methyl)amino)isoindole-1,3-dione; Trans-2-(2,6-dioxopiperidin-3-yl)-4-((1-(2-(3-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)azetidin-1-yl)ethyl)-1H-1,2,3-triazol-4-yl)methyl)amino)isoindole-1,3-dione; Cis-2-(2,6-dioxopiperidin-3-yl)-4-(1-(2-(2-(3-((1S)-2-fluoro-1-hydroxy-7- (methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)piperidin-1-yl)ethoxy)ethyl)-1H- 1,2,3-triazol-4-yl)methyl)amino)isoindoline-1,3-dione; Cis-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-7-((1-(2-(2-(3-((1S)-2-fluoro-1-hydroxy-7- (methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)azetidin-1-yl)ethoxy)ethyl)-1H- 1,2,3-triazol-4-yl)methyl)amino)isoindoline-1,3-dione; Cis-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-7-((1-(2-(2-(3-((1S)-2-fluoro-1-hydroxy-7- (methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)azetidin-1-yl)ethoxy)ethyl)-1H- 1,2,3-triazol-4-yl)methyl)amino)isoindoline-1,3-dione; Cis-2-(2,6-dioxopiperidin-3-yl)-4-(4-(1-(1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)- 2,3-dihydro-1H-inden-4-yl)azetidin-3-yl)piperazin-1-yl)isoindoline-1,3-dione; Cis-2-(2,6-dioxopiperidin-3-yl)-4-(4-(1-(1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)- 2,3-dihydro-1H-inden-4-yl)azetidin-3-yl)piperazin-1-yl)isoindoline-1,3-dione; Cis-2-(2,6-dioxopiperidin-3-yl)-5-(4-(1-(1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)- 2,3-dihydro-1H-inden-4-yl)piperidin-4-yl)piperazin-1-yl)isoindoline-1,3-dione; Cis-2-(2,6-dioxopiperidin-3-yl)-5-(4-(1-(1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)- 2,3-dihydro-1H-inden-4-yl)piperidin-4-yl)piperazin-1-yl)isoindoline-1,3-dione; Cis-2-(2,6-dioxopiperidin-3-yl)-4-(4-((1-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)- 2,3-dihydro-1H-inden-4-yl)azetidin-3-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione; Cis-2-(2,6-dioxopiperidin-3-yl)-4-(4-((1-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)- 2,3-dihydro-1H-inden-4-yl)azetidin-3-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione; Cis-2-(2,6-dioxopiperidin-3-yl)-4-(4-((1-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)- 2,3-dihydro-1H-inden-4-yl)azetidin-3-yl)methyl)piperazin-1-yl)isoindole-1,3-dione; Trans-2-(2,6-dioxopiperidin-3-yl)-4-(4-((1-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)- 2,3-dihydro-1H-inden-4-yl)azetidin-3-yl)methyl)piperazin-1-yl)isoindole-1,3-dione; Cis-2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)- 2,3-dihydro-1H-inden-4-yl)azetidin-3-yl)methyl)piperazin-1-yl)isoindole-1,3-dione; Trans-2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)- 2,3-dihydro-1H-inden-4-yl)azetidin-3-yl)methyl)piperazin-1-yl)isoindole-1,3-dione; Cis-2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-((1-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)- 2,3-dihydro-1H-inden-4-yl)azetidin-3-yl)methyl)piperazin-1-yl)isoindole-1,3-dione; Trans-2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-((1-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)- 2,3-dihydro-1H-inden-4-yl)azetidin-3-yl)methyl)piperazin-1-yl)isoindole-1,3-dione; Cis-2-(2,6-dioxopiperidin-3-yl)-4-(4-((1-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)- 2,3-dihydro-1H-inden-4-yl)piperidin-4-yl)methyl)piperazin-1-yl)isoindole-1,3-dione; Trans-2-(2,6-dioxopiperidin-3-yl)-4-(4-((1-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)- 2,3-dihydro-1H-inden-4-yl)piperidin-4-yl)methyl)piperazin-1-yl)isoindole-1,3-dione; Cis-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-7-(4-((1-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)- 2,3-dihydro-1H-inden-4-yl)azetidin-3-yl)methyl)piperazin-1-yl)isoindole-1,3-dione; Trans-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-7-(4-((1-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)azetidin-3-yl)methyl)piperazin-1-yl)isoindole-1,3-dione; Cis-2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)piperidin-4-yl)methyl)piperazin-1-yl)isoindole-1,3-dione; Trans-2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)piperidin-4-yl)methyl)piperazin-1-yl)isoindole-1,3-dione; Cis-2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-((1-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)piperidin-4-yl)methyl)piperazin-1-yl)isoindole-1,3-dione; Trans-2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-((1-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)piperidin-4-yl)methyl)piperazin-1-yl)isoindole-1,3-dione; Cis-2-(2,6-dioxopiperidin-3-yl)-4-(4-(2-(1-(2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)piperidin-4-yl)ethyl)piperazin-1-yl)isoindole-1,3-dione; Trans-2-(2,6-dioxopiperidin-3-yl)-4-(4-(2-(1-(2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)piperidin-4-yl)ethyl)piperazin-1-yl)isoindole-1,3-dione; Cis-2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-(2-(1-(2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)piperidin-4-yl)ethyl)piperazin-1-yl)isoindole-1,3-dione; Trans-2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-(2-(1-(2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)piperidin-4-yl)ethyl)piperazin-1-yl)isoindole-1,3-dione; Cis-5-(4-((1-((1S)-7-(difluoromethyl)sulfonyl)-2-fluoro-1-hydroxy-2,3-dihydro-1H-inden-4-yl)azetidin-3-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindole-1,3-dione; Trans-5-(4-((1-((1S)-7-(difluoromethyl)sulfonyl)-2-fluoro-1-hydroxy-2,3-dihydro-1H-inden-4-yl)azetidin-3-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindole-1,3-dione; Cis-2-(2,6-dioxopiperidin-3-yl)-4-(4-(1-(1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)azetidin-3-ylcarbonyl)piperazin-1-yl)isoindole-1,3-dione; Trans-2-(2,6-dioxopiperidin-3-yl)-4-(4-(1-(1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)azetidin-3-ylcarbonyl)piperazin-1-yl)isoindole-1,3-dione; Cis-2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-(1-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)azetidin-3-ylcarbonyl)piperazin-1-yl)isoindole-1,3-dione; Trans-2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-(1-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)azetidin-3-ylcarbonyl)piperazin-1-yl)isoindole-1,3-dione; Cis-2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(3-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)azetidin-1-yl)-2-oxoethyl)piperazin-1-yl)isoindole-1,3-dione; Trans-2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(3-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)azetidin-1-yl)-2-oxoethyl)piperazin-1-yl)isoindole-1,3-dione; Cis-2-(2,6-dioxopiperidin-3-yl)-4-(4-(2-(3-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)azetidin-1-yl)ethyl)piperidin-1-yl)isoindole-1,3-dione; Cis-2-(2,6-dioxopiperidin-3-yl)-4-(4-(2-(3-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)azetidin-1-yl)ethyl)piperazin-1-yl)isoindoline-1,3-dione; N-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)-2- oxoethyl)-1-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)azetidine-3- carboxamide; Cis-2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-(4-(3-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3- dihydro-1H-inden-4-yl)oxy)azetidin-1-yl)-4-oxobutyl)piperazin-1-yl)isoindoline-1,3-dione; Trans-2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-(4-(3-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3- dihydro-1H-inden-4-yl)oxy)azetidin-1-yl)-4-oxobutyl)piperazin-1-yl)isoindoline-1,3-dione; 5-(4-(4-(4-((1-((1S)-7-((difluoromethyl)sulfonyl)-2-fluoro-1-hydroxy-2,3-dihydro-1H-inden-4-yl)azetidin-3- yl)methyl)piperazin-1-yl)-4-oxobutyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3- dione; Cis-2-(2,6-dioxopiperidin-3-yl)-4-((2-((1-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4- yl)azetidin-3-yl)(methyl)amino)ethyl)(methyl)amino)isoindoline-1,3-dione; Trans-2-(2,6-dioxopiperidin-3-yl)-4-((2-((1-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4- yl)azetidin-3-yl)(methyl)amino)ethyl)(methyl)amino)isoindoline-1,3-dione; Cis-2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-((2-((1-((1S)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4- yl)azetidin-3-yl)(methyl)amino)ethyl)(methyl)amino)isoindoline-1,3-dione; Trans-2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-((2-((1-((1S)-2-fluoro-1-hydroxy-7- (methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)azetidin-3-yl)(methyl)amino)ethyl)(methyl) amino)isoindoline-1,3-dione; Cis-2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-(6-(3-((1S)-2-fluoro-1-hydroxy-7- (methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)azetidin-1-yl)-6-oxohexyl)piperazin- 1-yl)isoindoline-1,3-dione; Trans-2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-(6-(3-((1S)-2-fluoro-1-hydroxy-7- (methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)azetidin-1-yl)-6-oxohexyl)piperazin- 1-yl)isoindoline-1,3-dione; 5-(4-((1-((S)-2,2-difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl) azetidin-3-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperazin-3-yl)-6-fluoroisoindoline- 1,3-dione; Cis-5-(4-(1-((1S)-7-(difluoromethyl)sulfonyl)-2-fluoro-1-hydroxy-2,3-dihydro-1H-inden- 4-yl)-3-fluoroazetidine-3-carbonyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6- fluoroisoindoline-1,3-dione; Trans-5-(4-(1-((1S)-7-(difluoromethyl)sulfonyl)-2-fluoro-1-hydroxy-2,3-dihydro-1H- inden-4-yl)-3-fluoroazetidine-3-carbonyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)- 6-fluoroisoindoline-1,3-dione.

7. A pharmaceutical composition, wherein, The pharmaceutical composition comprises the bifunctional compound or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof according to any one of claims 1 to 6, and at least one pharmaceutically acceptable additive.

8. The pharmaceutical composition of claim 7, wherein, The additive is a carrier or an excipient.

9. The pharmaceutical composition of claim 7, wherein, The additive is an auxiliary agent.

10. Use of the pharmaceutical composition according to any one of claims 7 to 9 for the manufacture of a medicament for treating a tumor.

11. Use according to claim 10, wherein, The tumor is selected from at least one of a hematological tumor, a glioma, a digestive system tumor, a reproductive system tumor, a lymphoma and a nervous system tumor.

12. Use according to claim 11, wherein, The hematological tumor is selected from any one of acute lymphoblastic leukemia, chronic myelocytic leukemia and mantle cell lymphoma.

13. The use according to claim 11, wherein, The digestive system tumor is selected from any one of esophageal cancer, gastric cancer and colorectal cancer.

14. The use according to claim 11, wherein, The reproductive system tumor is selected from any one of ovarian cancer and endometrial cancer.

15. The use of claim 11, wherein, The nervous system tumor is selected from any one of brain glioma and retinoblastoma.

16. Use according to any one of claims 10 to 15, wherein, The tumor is selected from a cancer.

17. The use according to claim 16, wherein, The cancer is selected from at least one of renal cell carcinoma, skin cancer, lung cancer, and breast cancer. The cancer is selected from at least one of renal cell carcinoma, skin cancer, lung cancer, and breast cancer.

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