RU2813232C2 - Isoindoline compound, production method, pharmaceutical composition and their use - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a polysubstituted isoindoline compound of general formula (I), its enantiomer, racemate or a pharmaceutically acceptable salt thereof, as well as a production method, a pharmaceutical composition based on them and its use for the production of medicinal products for the treatment of diseases associated with the CRL4^CRBNE3 ligase. In general formula (I): X₁ represents -CH₂ - or -O-; X₂ represents -CH₂- or -CO-; R₁ represents hydrogen or a C₁ hydrocarbon group; R₂ and R₄ are each independently hydrogen; R₃ represents hydrogen or halogen; L represents a substituted or unsubstituted linear alkylene group containing 2–8 carbon atoms, wherein "substituted" means that one or more hydrogen atoms in the alkylene group are optionally substituted with the following substituents: -NHC(O)Ra₁, -NRa₃Ra₄, where Ra₁, Ra₃ and Ra₄ are each independently selected from hydrogen, C_1-6 alkyl, unsubstituted or hydroxyl substituted, and unsubstituted C_3-6 cycloalkyl; Y is absent or is -O-, -CO-, -CO-NH-, -NH-CO-, -NH-CO-NH-, -NH-CO-CH(NHRa₉)- or -CH(NHRa₉)-, the remaining values of the radicals are indicated in the claims.

EFFECT: obtaining of isoindoline compound, production method, a pharmaceutical composition and their use.

16 cl, 280 ex

Description

PRIORITY STATEMENT

This application claims the benefit of priority to Chinese Patent Application No. 201811156797.9, filed on September 30, 2018, entitled “Isoindoline Compound, Production Method, Pharmaceutical Composition and Use Thereof,” the entire contents of which are hereby incorporated herein for all purposes by reference.

1. FIELD OF TECHNICAL

The present invention relates to the class of a new polysubstituted compound isoindoline, its pharmaceutically acceptable salt, solvate, pharmaceutical composition and their use in the preparation of drugs for the treatment or prevention of various diseases.

2. BACKGROUND ART

Tight regulation of protein expression in cells plays an important role in cell function, survival and division. Many primary or acquired diseases are usually associated with protein dysfunction. The traditional way to regulate protein dysfunction mainly lies in the development of selective inhibitors or agonists. Such targeted drugs play an important role in the treatment of diseases. However, to obtain a satisfactory therapeutic effect, such inhibitors or agonists usually need to be maintained at a higher drug concentration to achieve a reliable therapeutic effect, which also leads to adverse drug reactions to a certain extent. Another way to regulate abnormal protein function is to change the dynamic balance of pathologically bound proteins, which entails protein synthesis and degradation, such as knockout or silencing of target protein genes using small interfering RNA (siRNA), antisense oligonucleotides, or gene editing technologies. These nucleic acid-based technologies alter protein synthesis by affecting the process of transcription and translation of the target protein. The main limitation of this type of technology is the low stability and bioavailability of the nucleic acid in vivo, which further limits its application to some extent. Another strategy for regulating the dynamic balance of proteins is to regulate the process of protein degradation so as to directly alter the expression of target proteins in cells by promoting or inhibiting protein degradation. The ubiquitin-proteasome system (UPS) plays an important role in protein degradation. By the action of a series of ubiquitin enzymes, the target protein can be tagged with ubiquitin, and proteins with specific ubiquitin tags can be transported to the proteasome for degradation.

There are various patterns of protein ubiquitination, including monoubiquitination (substrate proteins bind to only one ubiquitin), multi-monoubiquitination (substrate proteins have multiple ubiquitination sites, each of which is monoubiquitinated), or polyubiquitination (formation of a ubiquitin chain). In addition, the process of polyubiquitination can also occur on several amino groups of the lysine side chain or on the N-terminal amino groups of ubiquitin itself. Depending on different ubiquitination patterns, protein ubiquitination can influence protein processing in the cell, including subcellular localization, protein storage, protein-protein interactions, etc., and also influence protein function, including protein function activation, inhibition, or proteasomal/lysosomal degradation, etc.

The process of protein ubiquitination is a series of multistep reactions in which mainly three types of enzymes are involved: E1 - ubiquitin-activating enzyme, E2 - ubiquitin-conjugating enzyme and E3 - ubiquitin ligase. First, the C-terminus of ubiquitin is activated by ATP and forms an active thioester structure with the active site cysteine sulfhydryl of the E1 ubiquitin-activating enzyme. The active intermediate then covalently links ubiquitin to the E2 ubiquitin-conjugating enzyme through a new thioester structure through a transthioester reaction. Finally, E3 ubiquitin ligase recruits the substrate protein and simultaneously binds to the active intermediate of the E2 ubiquitin-conjugating enzyme and transfers ubiquitin to the substrate protein to complete ubiquitination of the substrate protein. E3 ubiquitin ligase plays an important role in the entire ubiquitination process, because it acts not only as a bridge to bring the two components of the reaction (the ubiquitin-conjugating enzyme E2 with the ubiquitin conjugate and the substrate protein) closer together in space, but also acts as an enzyme catalysis to accelerate the ubiquitination of the substrate protein. Because E3 ubiquitin ligases must specifically recognize substrates, the mammalian genome encodes more than 600 E3 ubiquitin ligases, while only two E1 ubiquitin-activating enzymes and about 40 E2 ubiquitin-conjugating enzymes have been discovered to date.

E3 ubiquitin ligases can be divided into three categories based on their conserved regions and mode of action. The HECT family and RBR family E3 ubiquitin ligase first transfers ubiquitin from the E2 ubiquitin-conjugating enzyme to itself, then transfers ubiquitin from the E3 ubiquitin ligase to the substrate protein during substrate ubiquitination. E3 ubiquitin ligases of the RING family occupy a relatively large proportion of the entire group of E3 ubiquitin ligases. This type of E3 ubiquitin ligase contains a RING domain or RING-like domains that can bind to the E2 ubiquitin-conjugating enzyme and facilitate the direct transfer of ubiquitin from the E2 ubiquitin-conjugating enzyme to the substrate protein.

E3 ubiquitin ligase CRL4 ^CRBN belongs to the RING family of E3 ubiquitin ligases, which is a protein complex assembled from several subunits. The complex consists of a substrate protein recognition module (CRBN), a recognition module of the ubiquitin-conjugating enzyme E2 (RING domain) and a linkage (cullin protein) between them. CRBN directly binds to the substrate of the entire protein complex and controls the substrate specificity of the entire ubiquitination process.

Small molecule modulators that act directly on CRBN can control the substrate selectivity of the CRL4 ^CRBN E3 ubiquitin ligase. New research has shown that cereblon (gene name: CRBN) is a direct target of the immunomodulator thalidomide and its analogues (Science, 2010, 327, 1345; Science, 2014, 343, 301; Science, 2014, 343, 305; Nature, 2015, 523, 183). It has been demonstrated that dosamine immunomodulators can selectively induce ubiquitination and degradation of the transcription factors IKZF1 and IKZF3 in multiple myeloma cell lines by regulating the activity of the CRBN-ubiquitin ligase complex. This process alters the functions of T cells and B cells, and at the same time has a toxic effect on multiple myeloma cells, thereby achieving a therapeutic effect for malignant myeloid systems, including multiple myeloma. Recent studies have shown that lenalidomide, a thalidomide analogue, can selectively induce ubiquitination and degradation of CK1α via the CRL4 ^CRBN E3 ubiquitin ligase, thereby achieving the treatment of 5q deletion myelodysplastic syndrome (MDS). However, another structural analogue of thalidomide (CC-885) can selectively induce and cleave GSPT1 by targeting the CRL4 ^CRBN E3 ligase, and exhibits potent cytotoxicity to numerous tumor cells.

Existing research results indicate that different dosamine drug molecules, after interacting with the target CRBN, have different specificities for substrate protein degradation. When lenalidomide is used to treat multiple myeloma, its therapeutic effect is achieved mainly through the selective degradation of IKZF1 and IKZF3; while in the treatment of 5q deletion myelodysplastic syndrome (del(5q) MDS) - mainly due to the degradation of CK1α. Lenalidomide is the main dosamine analogue developed to date that exhibits high CK1α degradation activity, therefore being the most important clinically effective agent in the treatment of del(5q) MDS with dosamine drugs. With the development of new dosamine drugs and as clinical trials progress, the indications for dosamine drug molecules are also expanding, such as the FDA-approved thalidomide for the treatment of erythema nodosum leprosum, lenalidomide for the treatment of prostate cancer in clinical trials, and pomalidomide for the treatment of myelofibrosis in clinical trials. tests.

The described compounds lenalidomide, pomalidomide, CC-122, CC-220, CC-885 are similar in structure to thalidomide. The characteristic of these types of compounds is that after structural changes and adjustments, these compounds have different pharmacological activities and completely different therapeutic effects, and can be used in clinical settings for the treatment of various indications.

Patents WO2008115516A2, US8153659B2, US9181216B2, US9920027B2 describe a compound represented by the general formula S1:

The main representative of R1 in the general formula S1 are aryl, arylalkyl, heterocyclylalkyl, etc.

WO2011100380 A1 and CN102822165B describe a class of compounds represented by the general formula S2:

In general formula S2, R1 represents a substituted aryl series, and a representative compound is CC-220:

WO2016065980A1, CN105566290A and US10017492B2

Representative compounds in general formula S3 are:

WO2007027527A2, CN101291924A and US8481568B2 describe a class of compounds represented by the general formula S3:

Representative compounds in general formula S4 and S5 are:

WO2008027542A2, US8877780B2 and US9447070B2 describe a class of compounds represented by the general formula S3:

Representative compounds in general formula S6 and S7 are:

The mechanism of action of lenalidomide and some of the above molecules is that compounds of different structures can bind to CRBN, thereby causing a conformational change in the CRBN binding moiety and recruiting various endogenous biological macromolecules to bind to CRBN; and the ubiquitination and degradation of potentially various endogenous substrate proteins, which may have different pharmacological actions and be used in clinical trials for treatment for various indications.

In summary, lenalidomide is primarily used to treat multiple myeloma and myelodysplastic syndrome, but its effect is not ideal for other indications; other aforementioned compounds such as CC-122, CC-885 and CC-220 are still in preclinical or clinical development stages. Thus, the development of new structural compounds such as CRL4 ^CRBN E3 ubiquitin ligase modulators may further improve therapeutic targeting of tumors and expand the clinical need for new indications for domid drug substances. Domid molecules of various structures have unknown pharmacological actions and pharmacological properties, and such properties and effects are in any respect uncertain. Based on the mechanism of action of the dosamine molecule, the development of a new structure of the dosamine molecule can realize the recruitment of new substrate proteins, providing improved therapeutic effect and expansion of new indications. Thus, further development of new structures of CRL4 ^CRBN E3 ubiquitin ligase modulators to expand new indications is of great research value and practical significance.

3. SUMMARY OF THE INVENTION

By analyzing the crystal structure of the complex between CRBN and small molecules (PDB ID: 4CI2, 5HXB), the inventors of the present invention obtained the following important information: CRBN has many binding pockets with small molecules. Therefore, to realize efficient binding between CRBN and small molecules, small molecules with complex structures and multiple binding sites can be designed. At the same time, to analyze the dynamics of the structure and binding site of the interface between the model molecule and the E3 ubiquitin ligase, molecular dynamics simulation methods combining molecular docking and complex pharmacophore comparison are used, and they also evaluate the binding mode and interaction of the active site of the junction on the E3 ubiquitin ligase by quantitatively assessing the function to obtain a new specific small molecule CRBN modulator. Based on this information, we designed and synthesized a series of small molecule CRBN modulators described in this application and tested the activity of these compounds. Test results show that the new small molecule regulator has very high cell growth inhibitory activity. Once the molecule is exposed to organisms, it can regulate the degradation of substrate proteins by regulating the ubiquitin-proteasomal protein degradation pathway in organisms so as to achieve effective disease treatment based on the CRBN target.

It is an object of the present invention to provide a compound represented by the following formula (I), its enantiomer, diastereomer, racemate, isotopic compound, metabolic precursor, metabolite, pharmaceutically acceptable salt, ester, prodrug or hydrate thereof.

Another object of the present invention is to provide important intermediates and methods for preparing the compound.

Another object of the present invention is to provide a pharmaceutical composition, wherein such pharmaceutical composition contains a therapeutically effective dose of a compound of formula (I), an enantiomer, a diastereomer, a racemate thereof, a pharmaceutically acceptable salt thereof, an ester, a prodrug or a hydrate thereof and at least , one pharmaceutically acceptable carrier.

It is yet another object of the present invention to provide a pharmaceutical composition, wherein the pharmaceutical composition contains a therapeutically effective dose of a compound of formula (I), an enantiomer, a diastereomer, a racemate thereof, a pharmaceutically acceptable salt, an ester, a prodrug or a hydrate thereof, and one or more other ingredients with pharmaceutical therapeutic activity. The compound of formula (I) of the present invention, its enantiomer, diastereomer, racemate, pharmaceutically acceptable salt, ester, prodrug, or hydrate thereof may be combined with one or more other ingredients having pharmaceutically therapeutic activity to obtain synergistic effects in preventing or treatment of specific diseases or dysfunctions. The compound of formula (I) of the present invention, its enantiomer, diastereomer, racemate, pharmaceutically acceptable salt, ester, prodrug or hydrate thereof may also reduce or eliminate the toxic and side effects of one or more other ingredients with pharmaceutically therapeutic activity in the course of preventing or treatment of specific diseases or dysfunctions, and vice versa.

It is yet another object of the present invention to provide another one or more ingredients with pharmaceutical therapeutic activity as described above, containing a macromolecular compound such as a protein, polysaccharide, nucleic acid, etc., and a low molecular compound such as an inorganic compound, an organometallic compound, synthetic or natural organic low molecular weight compound, etc.

Another object of the present invention is to provide the use of a compound of formula (I), its enantiomer, diastereomer, racemate, pharmaceutically acceptable salt, ester, prodrug or hydrate thereof for the production of a medicament for the treatment of diseases associated with CRL4 ^CRBN E3 ubiquitin ligase, preferably , such diseases include, but are not limited to, cancer, pain, neurological diseases and diseases of the immune system.

To solve the above object, the present invention provides a compound of formula (I) and its tautomer, enantiomer, diastereomer, racemate, metabolic precursor, metabolite, isotopic compound, pharmaceutically acceptable salt, ester, prodrug or hydrate thereof:

where X ₁ represents -CH ₂ - or -O-;

X ₂ represents -CH ₂ - or - CO-;

r ₁ represents hydrogen, deuterium, fluorine or a linear or branched C ₁ -C ₆ hydrocarbon group;

R ₂ and R ₄ are each independently hydrogen or deuterium;

R ₃ represents hydrogen, deuterium or halogen;

L represents a substituted or unsubstituted linear alkylene group containing 2-8 carbon atoms, wherein "substituted" means that one or more hydrogen atoms in the alkylene group are optionally substituted with the following substituents: deuterium, halogen, carbonyl, hydroxyl, amino group, cyano group, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₈ cycloalkyl, -NHC(O)Ra ₁ , -NHC(O)ORa ₂ , -NRa ₃ Ra ₄ , where Ra ₁ , Ra ₂ , Ra ₃ and Ra ₄ are each independently selected from hydrogen, C _1-6 alkyl, unsubstituted or substituted by halogen, hydroxyl, cyano or nitro, or C _3-6 cycloalkyl, unsubstituted or substituted by halogen, hydroxyl, cyano or nitro;

Y is absent or is -O-, -CO-, -CO-NH-, -NH-CO-, -NH-CO- NH-, -NH-CO-CH(NHRa ₉ )- or -CH(NHRa ₉ )-;

and when Y is -O- then A is 6-10 membered aryl, 5-10 membered heteroaryl, (6-10 membered aryl)-(CH ₂ ) _b1 - or (5-10 membered heteroaryl )-(CH ₂ ) _b1 , wherein aryl or heteroaryl is optionally substituted with one or more groups selected from: deuterium, halogen, cyano group, nitro group, amino group, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, hydroxyl substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ haloalkoxy, hydroxyl-substituted C ₁ -C ₆ alkoxy, cyano-substituted C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl , C ₃ -C ₆ cycloalkyloxy, phenyl, 5-6-membered heteroaryl, 3-6-membered heterocyclyl, -NHC(O)Ra ₅ , -NHC(O)ORa ₆ and -NRa ₇ Ra ₈ , where Ra ₅ , Ra ₆ , Ra ₇ and Ra ₈ are each independently hydrogen, C _1-6 alkyl, unsubstituted or substituted with halogen, hydroxyl, C ₁ -C ₆ alkoxy, cyano, or nitro, or C _3-6 cycloalkyl, unsubstituted or substituted with halogen , hydroxyl, C ₁ -C ₆ alkoxy, cyano group, or nitro group;

b ₁ represents 1 or 2;

and when Y is absent or is -CO- or -CO-NH-, (the corresponding arrangement of Y, A and L is A-L-, A-CO-L-, A-CO-NH-L-), then A is : i) heterocyclyl selected from the following:

X ₃ represents C, N or O;

n ₄ is 0, 1, 2 or 3;

n ₅ represents 0, 1, 2 or 3;

each Y ₁ and Y ₂ is independently selected from hydrogen, deuterium, halogen, cyano group, carboxyl group, nitro group, hydroxyl group, amino group, aminocarbonyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkylsulfonyl, C ₁ -C ₆ alkylaminocarbonyl, C ₃ -C ₆ cycloalkyl or heterocyclyl, C ₁ -C ₆ acylamino, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy , C ₁ -C ₃ alkenyl, C ₁ -C ₃ alkynyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, linear or branched C ₁ -C ₃ alkyl, substituted 6-10- membered aryl or 5-10 membered heteroaryl, wherein the substituted or unsubstituted 6-10 membered aryl or 5-10 membered heteroaryl is substituted with one or more substituents selected from: deuterium, halogen, cyano group, nitro group, hydroxyl group, amino group, aminocarbonyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxyl, C ₁ -C ₃ alkylcarbonyl, C ₁ -C ₃ alkoxycarbonyl, C ₁ -C ₃ alkylsulfonyl, C ₁ -C ₃ alkylaminocarbonyl, C ₃ -C ₆ cycloalkyl or heterocyclyl , C ₁ -C ₃ acylamino, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ haloalkoxy;

when each Y ₁ and Y ₂ are independently hydrogen, deuterium, C ₁ -C ₆ alkoxy, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, carboxyl, C ₁ -C ₆ alkylaminocarbonyl, C ₁ -C ₆ alkoxycarbonyl, nitro group, amino group, cyano group, C ₁ -C ₆ haloalkyl, hydroxyl group, C ₁ -C ₆ alkylsulfonyl, and when Y is absent, X ₁ is not -O-;

Y ₃ is absent or represents hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkylaminocarbonyl, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkylsulfonyl, C ₁ -C ₆ alkylcarbonyl, aminocarbonyl, C ₃ -C ₆ heterocyclyl, C ₁ -C ₆ acylamino, C ₁ -C ₆ haloalkoxy, C ₁ -C ₃ alkenyl, C ₁ -C ₃ alkynyl, substituted or unsubstituted 6-10 -membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, linear or branched C ₁ -C ₃ alkyl, substituted C ₅ -C ₁₀ aryl or heteroaryl, where substituted or unsubstituted 6-10 membered aryl or 5-10 membered heteroaryl is substituted with one or more substituents selected from: deuterium, halogen, cyano group, nitro group, hydroxyl group, amino group, aminocarbonyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxyl, C ₁ -C ₃ alkylcarbonyl, C ₁ -C ₃ alkoxycarbonyl, C ₁ -C ₃ alkylsulfonyl, C ₁ -C ₃ alkylaminocarbonyl, C ₃ -C ₆ cycloalkyl or heterocyclyl, C ₁ -C ₃ acylamino, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ haloalkoxy;

when Y ₃ is hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkylaminocarbonyl, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkylsulfonyl or Y ₃ is missing, and when Y is missing, X ₁ is not -O-;

Y ₄ and Y ₅ represent one or more substituents on a heterocyclic ring, each Y ₄ and Y ₅ independently representing deuterium, halogen, oxo, C ₁ -C ₃ alkyl, C ₁ -C ₃ cycloalkyl, C ₁ -C ₃ haloalkyl or phenyl;

ii) a fused heterocyclyl selected from:

X ₄ represents C, N or O;

n ₆ represents 0, 1, 2 or 3;

n ₇ represents 0, 1, 2 or 3;

n ₈ represents 0, 1, 2, 3 or 4;

is a 6-10 membered aryl ring or a 5-10 membered heteroaryl ring, preferably a ring -selected from a benzene ring, a pyridine ring, a thiophene ring, an indole ring, a benzothiophene ring, a benzimidazole ring, a naphthalene ring, a quinoline ring or an isoquinoline ring;

Each R ₈ is independently selected from hydrogen, deuterium, C ₁ -C ₃ alkoxyl, halogen, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, carboxyl, C ₁ -C ₃ alkylaminocarbonyl, C ₁ -C ₃ alkoxycarbonyl, nitro group , amino groups, cyano groups, C ₁ -C ₃ haloalkyl, hydroxyl group, C ₁ -C ₃ alkylsulfonyl, C ₁ -C ₃ alkylamino, C ₁ -C ₃ acylamino, aminocarbonyl, C ₃ -C ₆ heterocyclyl, C ₁ -C ₃ haloalkoxy, phenyl or 5-6 membered heteroaryl;

when each of R ₈ is independently selected from the following optional substituents: hydrogen, deuterium, C ₁ -C ₃ alkoxy, halogen, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, carboxyl, C ₁ -C ₃ alkylaminocarbonyl, C ₁ -C ₃ alkoxycarbonyl, nitro group, amino group, cyano group, C ₁ -C ₃ haloalkyl, hydroxyl group, C ₁ -C ₃ alkylsulfonyl, and when Y is absent, X ₁ is not -O-;

Y ₆ and Y ₇ represent one or more substituents on the heterocyclic ring, and each is independently selected from deuterium, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ cycloalkyl, C ₁ -C ₃ haloalkyl;

or iii) a spiroheterocyclic group selected from:

n _c1 is 0, 1, 2 or 3;

n _c2 is 0, 1, 2 or 3;

n _c3 represents 1, 2 or 3;

n ₉ represents 0, 1, 2, 3 or 4;

is a 6-10 membered aryl ring or a 5-10 membered heteroaryl ring;

R ₉ is independently selected from the following substituents: deuterium, halogen, cyano group, nitro group, hydroxyl group, amino group, C ₁ -C ₃ alkylamino, C ₁ -C ₃ acylamino, aminocarbonyl, linear or branched C ₁ -C ₆ alkyl, linear or branched C ₁ -C ₆ alkoxyl, C ₃ -C ₆ cycloalkyloxy, C ₃ -C ₆ cycloalkyl or heterocycloalkyl, C ₁ -C ₃ alkylaminocarbonyl, C _{1 -C 3} alkoxycarbonyl, C 1 -C ₃ alkylsulfonyl, C ₁ -C ₃ haloalkyl , C ₁ -C ₃ haloalkoxy, phenyl, 5-6 membered heteroaryl;

r ₁₀ and R ₁₁ are independently selected from hydrogen, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, the type of substituent being the same as in the ring substituent R ₉ mentioned above ;

Y ₈ is a substituent that optionally replaces a hydrogen atom in the non-aromatic portion of the spiro ring structure, and Y ₈ is optionally substituted with deuterium, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ cycloalkyl or C ₁ -C ₃ haloalkyl;

when Y is selected from -NH-CO-, -NH-CO-NH-, -NH-CO-CH(NHRa ₉ ) or -CH(NHRa ₉ )-, the corresponding arrangement of Y, A and L is A-NH-CO -L-, A-NH-CO-NH-L-, A-NH-CO-CH(NHRa ₉ )-L- or A-CH(NHRa ₉ )-L-, where A is:

6-10 membered aryl, 5-10 membered heteroaryl, (6-10 membered aryl) -CH ₂ - or (5-10 membered heteroaryl) -CH ₂ -, wherein the aryl or heteroaryl is optionally substituted by one or more substituents R ₅ ,

or A selected from the following groups:

n ₁ is 0, 1, 2, 3 or 4;

each R ₅ is independently selected from deuterium, halogen, hydroxyl, amino group, cyano group, nitro group, linear or branched C ₁ -C ₆ alkyl, linear or branched C ₁ -C ₆ alkoxyl, C ₁ -C ₃ acylamino, aminocarbonyl, phenyl, 5 -6-membered heteroaryl, 3-6-membered heterocyclyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkyloxy, C ₁ -C ₃ alkylaminocarbonyl, C ₁ -C ₃ alkylsulfonyl, phenyloxyl or 5-6 membered heteroaryloxy, when n ₁ >1, all R ₅ can be the same or different;

Ra ₉ is selected from hydrogen, substituted or unsubstituted C ₁ -C ₁₀ alkylcarbonyl, substituted or unsubstituted C ₃ -C ₈ cycloalkylcarbonyl, C ₁ -C ₈ heterocycloalkylcarbonyl, where "substituted" means that the end of the carbon chain is substituted with a hydroxyl or amino group.

Preferably, a compound of formula (I) wherein X ₁ is -CH ₂ - or -O-;

X ₂ represents -CH ₂ - or -CO-;

r ₁ represents hydrogen, deuterium, fluorine or a linear or branched C ₁ -C ₃ hydrocarbon group;

R ₂ and R ₄ are each independently hydrogen or deuterium;

R ₃ represents hydrogen, deuterium or halogen;

L represents a substituted or unsubstituted linear alkylene group containing 2-8 carbon atoms, wherein "substituted" means that one or more hydrogen atoms in the alkylene group are optionally substituted with the following substituents: deuterium, halogen, carbonyl, hydroxyl, amino group, cyano group, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, -NHC(O)Ra ₁ , -NHC(O)ORa ₂ , -NRa ₃ Ra ₄ , where Ra ₁ , Ra ₂ , Ra ₃ and Ra ₄ are each independently selected from hydrogen, C _1-6 alkyl substituted with halogen, hydroxyl, cyano or nitro, or C _3-6 cycloalkyl substituted with halogen, hydroxyl, cyano or nitro;

Y is absent or is -O-, -CO-, -CO-NH-, -NH-CO-, -NH-CO- NH-, -NH-CO-CH(NHRa ₉ )- or - CH(NHRa ₉ )-;

when Y is -O- then A is substituted or unsubstituted 9-10 membered aryl, 9-10 membered heteroaryl, (9-10 membered aryl)-(CH ₂ ) _b1 - or (9-10- member heteroaryl)-(CH ₂ ) _b1 -,

where b ₁ represents 1 or 2;

substituted or unsubstituted 9-10 membered aryl or 9-10 membered heteroaryl is selected from the following groups:

n ₂ is 0, 1, 2 or 3;

n ₃ represents 0, 1, 2 or 3;

each R ₆ and R ₇ is independently selected from the following groups: deuterium, halogen, cyano group, nitro group, amino group, hydroxyl group, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, hydroxyl-substituted C ₁ -C ₆ alkyl, C ₁ - C ₆ alkoxyl, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ haloalkoxyl, hydroxyl substituted C ₁ -C ₆ alkoxyl, cyanosubstituted C ₁ -C ₆ alkoxyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkyloxy, phenyl, C ₅ -C ₆ heteroaryl, C ₃ -C ₆ heterocyclyl, -NHC(O)Ra ₅ , -NHC(O)ORa ₆ , -NRa ₇ Ra ₈ ; where Ra ₅ , Ra ₆ , Ra ₇ and Ra ₈ are each independently hydrogen, C _1-6 alkyl, unsubstituted or substituted with halogen, hydroxyl, C ₁ -C ₆ alkoxy, cyano or nitro, or C _3-6 cycloalkyl, unsubstituted or substituted by halogen, hydroxyl group, C ₁ -C ₆ alkoxyl, cyano group or nitro group, where, when n ₂ >1 or n ₃ >1, R ₆ and R ₇ may be the same or different;

and when Y is absent or is -CO- or -CO-NH-, (the corresponding arrangement of Y, A and L is A-L-, A-CO-L-, A-CO-NH-L-), then A is :

i) heterocyclyl selected from the following:

where each Y ₁ and Y ₂ is independently selected from hydrogen, deuterium, halogen, cyano group, carboxyl group, nitro group, hydroxyl group, amino group, aminocarbonyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, C ₁ -C ₆ alkylcarbonyl , C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkylsulfonyl, C ₁ -C ₆ alkylaminocarbonyl, C ₃ -C ₆ cycloalkyl or heterocyclyl, C ₁ -C ₆ acylamino, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, C ₁ -C ₃ alkenyl, C ₁ -C ₃ alkynyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, linear or branched C ₁ -C ₃ alkyl, substituted 6-10 -membered aryl or 5-10 membered heteroaryl, where the substituted or unsubstituted 6-10 membered aryl or 5-10 membered heteroaryl is substituted with one or more substituents selected from: deuterium, halogen, cyano group, nitro group, hydroxyl group, amino group, aminocarbonyl , C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxyl, C ₁ -C ₃ alkylcarbonyl, C ₁ -C ₃ alkoxycarbonyl, C ₁ -C ₃ alkylsulfonyl, C ₁ -C ₃ alkylaminocarbonyl, C ₃ -C ₆ cycloalkyl or heterocyclyl, C ₁ -C ₃ acylamino, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ haloalkoxy;

when each Y ₁ and Y ₂ are independently hydrogen, deuterium, C ₁ -C ₆ alkoxy, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, carboxyl, C ₁ -C ₆ alkylaminocarbonyl, C ₁ -C ₆ alkoxycarbonyl, nitro group, amino group, cyano group, C ₁ -C ₆ haloalkyl, hydroxyl group, C ₁ -C ₆ alkylsulfonyl, and when Y is absent, X ₁ is not -O-;

Y ₃ is absent or represents C ₁ -C ₆ alkylcarbonyl, aminocarbonyl, C ₃ -C ₆ heterocyclyl, C ₁ -C ₆ acylamino, C ₁ -C ₆ haloalkoxy, C ₁ -C ₃ alkenyl, C ₁ -C ₃ alkynyl, substituted or unsubstituted 6-10-membered aryl, substituted or unsubstituted 5-10-membered heteroaryl, linear or branched C ₁ -C ₃ -alkyl, substituted C ₅ -C ₁₀ -aryl or heteroaryl, where substituted or unsubstituted 6-10- membered aryl or 5-10 membered heteroaryl is substituted with one or more of the following substituents: deuterium, halogen, cyano group, nitro group, hydroxyl group, amino group, aminocarbonyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxyl, C ₁ -C ₃ alkylcarbonyl, C ₁ -C ₃ alkoxycarbonyl, C ₁ -C ₃ alkylsulfonyl, C ₁ -C ₃ alkylaminocarbonyl, C ₃ -C ₆ cycloalkyl or heterocyclyl, C ₁ -C ₃ acylamino, C ₁ -C ₃ haloalkyl, C ₁ - C ₃ haloalkoxy; 6-10 membered aryl is preferably selected from phenyl, naphthyl, 5-10 membered heteroaryl is preferably selected from thienyl, pyridyl, benzothienyl, benzimidazolyl, indolyl, quinolinyl, isoquinolinyl;

when Y ₃ is hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkylaminocarbonyl, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkylsulfonyl or Y ₃ is missing, and when Y is missing, X ₁ is not -O-;

Y ₄ and Y ₅ represent one or more substituents on a heterocyclic ring, where Y ₄ and Y ₅ are each independently deuterium, halogen, oxo, C ₁ -C ₃ alkyl, C ₁ -C ₃ cycloalkyl or phenyl;

ii) a fused heterocyclyl selected from:

n ₈ represents 0, 1, 2, 3 or 4;

X ₄ represents C, N or O;

is a 6-10 membered aryl ring or a 5-10 membered heteroaryl ring, where selected from a benzene ring, a pyridine ring, a thiophene ring, an indole ring, a benzothiophene ring, a benzimidazole ring, a naphthalene ring, a quinoline ring or an isoquinoline ring;

each R ₈ is independently selected from hydrogen, deuterium, C ₁ -C ₃ alkoxyl, halogen, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, carboxyl, C ₁ -C ₃ alkylaminocarbonyl, C ₁ -C ₃ alkoxycarbonyl, nitro group , amino groups, cyano groups, C ₁ -C ₃ haloalkyl, hydroxyl group, C ₁ -C ₃ alkylsulfonyl, C ₁ -C ₃ alkylamino, C ₁ -C ₃ acylamino, aminocarbonyl, C ₃ -C ₆ heterocyclyl, C ₁ -C ₃ haloalkoxy, phenyl or 5-6 membered heteroaryl;

when each R ₈ is independently selected from the following substituents: hydrogen, deuterium, C ₁ -C ₃ alkoxy, halogen, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, carboxyl, C ₁ -C ₃ alkylaminocarbonyl, C ₁ -C ₃ alkoxycarbonyl, nitro group, amino group, cyano group, C ₁ -C ₃ haloalkyl, hydroxyl, C ₁ -C ₃ alkylsulfonyl, and when Y is absent, X ₁ is not -O-;

Y ₆ and Y ₇ represent one or more substituents on the heterocyclic ring, and each is independently selected from deuterium, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ cycloalkyl, C ₁ -C ₃ haloalkyl;

or iii) a spiroheterocyclic group selected from:

where n ₉ represents 0, 1, 2, 3 or 4;

is a 6-10 membered aryl ring or a 5-10 membered heteroaryl ring, preferably a thiophene ring, a pyrrole ring, a benzene ring, a pyridine ring, a benzothiophene ring, a benzimidazole ring, an indole ring, a quinoline ring and an isoquinoline ring;

R ₉ is independently selected from the following substituents: deuterium, halogen, cyano group, nitro group, hydroxyl group, amino group, C ₁ -C ₃ alkylamino, C ₁ -C ₃ acylamino, aminocarbonyl, linear or branched C ₁ -C ₆ alkyl, linear or branched C ₁ -C ₆ alkoxyl, C ₃ -C ₆ cycloalkyloxy, C ₃ -C ₆ cycloalkyl or heterocycloalkyl, C ₁ -C ₃ alkylaminocarbonyl, C _{1 -C 3} alkoxycarbonyl, C 1 -C ₃ alkylsulfonyl, C ₁ -C ₃ haloalkyl , C ₁ -C ₃ haloalkoxy, phenyl, 5-6-membered heteroaryl, while when n ₉ >1, all R ₉ can be the same or different;

Y ₈ is a substituent that optionally replaces a hydrogen atom in the non-aromatic portion of the spiro ring structure, and Y ₈ is optionally substituted with deuterium, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ cycloalkyl or C ₁ -C ₃ haloalkyl;

when Y is selected from -NH-CO-, -NH-CO-NH-, -NH-CO-CH(NHRa ₉ )- or -CH(NHRa ₉ )-, the corresponding arrangement of Y, A and L is A-NH- CO-L-, A-NH-CO-NH-L-, A-NH-CO-CH(NHRa ₉ )-L- or A-CH(NHRa ₉ )-L-, where A is:

6-10 membered aryl, 5-10 membered heteroaryl, (6-10 membered aryl)-CH ₂ -, (5-10 membered heteroaryl)-CH ₂ -, wherein the aryl or heteroaryl is optionally substituted by one or more the substituents R ₅ or A are selected from the following groups:

n ₁ is 0, 1, 2, 3 or 4;

each R ₅ is independently selected from deuterium, halogen, hydroxyl, amino group, cyano group, nitro group, linear or branched C ₁ -C ₆ alkyl, linear or branched C ₁ -C ₆ alkoxyl, C ₁ -C ₃ acylamino, aminocarbonyl, phenyl, 5 -6-membered heteroaryl, 3-6-membered heterocyclyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkyloxy, C ₁ -C ₃ alkylaminocarbonyl, C ₁ -C ₃ alkylsulfonyl, phenyloxyl or 5-6 membered heteroaryloxy, when n ₁ >1, all R ₅ can be the same or different;

Ra ₉ is independently selected from hydrogen, substituted or unsubstituted C ₁ -C ₁₀ alkylcarbonyl, substituted or unsubstituted C ₃ -C ₈ cycloalkylcarbonyl, C ₁ -C ₈ heterocycloalkylcarbonyl, where "substituted" means that the end of the carbon chain is substituted with a hydroxyl or amino group.

More preferably, a compound of formula (I) wherein X ₁ is -CH ₂ -or -O-;

X ₂ represents -CH ₂ - or -CO-;

r ₁ represents hydrogen, deuterium or fluorine;

R ₂ and R ₄ are each independently hydrogen or deuterium;

R ₃ represents hydrogen, deuterium or fluorine;

L represents a substituted or unsubstituted linear alkylene group containing 2-8 carbon atoms, wherein "substituted" means that one or more hydrogen atoms in the alkylene group are optionally substituted with the following substituents: deuterium, halogen, cyano, C ₁ -C ₃ alkyl , C ₁ -C ₃ haloalkyl, -NHC(O)Ra ₁ , -NHC(O)ORa ₂ , -NRa ₃ Ra ₄ , where Ra ₁ , Ra ₂ , Ra ₃ and Ra ₄ are each independently selected from hydrogen, C _{1 -6} alkyl, unsubstituted or substituted by one or more halogens or C _3-6 cycloalkyl, unsubstituted or substituted by one or more halogens;

Y is absent or is -O-, -CO-, -CO-NH-, -NH-CO-, -NH-CO- NH-, -NH-CO-CH(NHRa ₉ )- or - CH(NHRa ₉ )-;

when Y is -O-, A is selected from 9-10 membered aryl, 9-10 membered heteroaryl, (9-10 membered aryl)-(CH ₂ ) _b1 -, (9-10 membered heteroaryl)- (CH ₂ ) _b1 -, 9-10 membered aryl or 9-10 membered heteroaryl may be unsubstituted or substituted;

substituted or unsubstituted 9-10 membered aryl or 9-10 membered heteroaryl is selected from the following groups:

b ₁ represents 1 or 2;

n ₂ is 0, 1, 2 or 3;

n ₃ represents 0, 1, 2 or 3;

each R ₆ and R ₇ is independently selected from the following groups: deuterium, halogen, cyano group, nitro group, amino group, hydroxyl group, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, hydroxyl-substituted C ₁ -C ₆ alkyl, C ₁ - C ₆ alkoxyl, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ haloalkoxy, hydroxyl substituted C ₁ -C ₆ alkoxyl, cyanosubstituted C ₁ -C ₆ alkoxyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkyloxy, phenyl, C ₅ -C ₆ heteroaryl, C ₃ -C ₆ heterocyclyl, -NHC(O)Ra ₅ , -NHC(O)ORa ₆ , -NRa ₇ Ra ₈ ; where Ra ₅ , Ra ₆ , Ra ₇ and Ra ₈ are each independently hydrogen, C _1-6 alkyl, unsubstituted or substituted by halogen, hydroxyl or cyano, or C _3-6 cycloalkyl, unsubstituted or substituted by halogen, hydroxyl or cyano, where when n ₂ >1 or n ₃ >1, R ₆ and R ₇ may be the same or different;

Y is missing or is -CO- or -CO-NH-, (the corresponding arrangement of Y, A and L is -A-CO-L-, -A-CO-NH-L-, -A-L-), fragment A contains , at least one nitrogen atom and Y is attached to the nitrogen atom, then A is:

i) heterocyclyl selected from the following:

n ₁₀ is 0, 1, 2, 3, 4 or 5;

Y ₁ is selected from hydrogen, deuterium, halogen, cyano group, carboxyl group, nitro group, hydroxyl group, amino group, aminocarbonyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkylsulfonyl, C ₁ -C ₆ alkylaminocarbonyl, C ₃ -C ₆ cycloalkyl or heterocyclyl, C ₁ -C ₆ acylamino, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, C ₁ -C ₃ alkenyl, C ₁ -C ₃ alkynyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, linear or branched C ₁ -C ₃ alkyl, substituted 6-10 membered aryl or 5- 10-membered heteroaryl, where the substituted or unsubstituted 6-10-membered aryl or 5-10-membered heteroaryl is substituted with one or more substituents selected from: deuterium, halogen, cyano group, nitro group, hydroxyl group, amino group, aminocarbonyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxyl, C ₁ -C ₃ alkylcarbonyl, C ₁ -C _{3 alkoxycarbonyl, C 1 -C 3 alkylsulfonyl ,} C ₁ -C ₃ alkylaminocarbonyl, C ₃ -C ₆ cycloalkyl or heterocyclyl, C ₁ -C ₃ acylamino, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ haloalkoxy;

selected from substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, preferably 6-10 membered aryl or 5-10 membered heteroaryl selected from thienyl, pyridyl, phenyl, benzothienyl, benzimidazolyl, indolyl , naphthyl, quinolinyl, isoquinolinyl;

each r ₁₀ independently represents deuterium, halogen, cyano group, nitro group, hydroxyl group, amino group, aminocarbonyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxyl, C ₁ -C ₃ alkylcarbonyl, C ₁ -C ₃ alkoxycarbonyl, C ₁ -C ₃ alkylsulfonyl, C ₁ -C ₃ alkylaminocarbonyl, C ₃ -C ₆ cycloalkyl or heterocyclyl, C ₁ -C ₃ acylamino, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ haloalkoxy, when n ₁₀ >1, r ₁₀ may be the same or different;

Y ₄ and Y ₅ represent one or more substituents on the heterocyclic ring, wherein Y ₄ and Y ₅ are each independently deuterium, halogen, methyl, ethyl, cyclopropyl or phenyl;

ii) a fused heterocyclyl selected from:

n ₈ represents 0, 1, 2, 3 or 4;

X ₄ represents C, N or O;

each R ₈ is independently selected from hydrogen, deuterium, C ₁ -C ₃ alkoxyl, halogen, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, carboxyl, C ₁ -C ₃ alkylaminocarbonyl, C ₁ -C ₃ alkoxycarbonyl, nitro group , amino groups, cyano groups, C ₁ -C ₃ haloalkyl, hydroxyl group, C ₁ -C ₃ alkylsulfonyl, C ₁ -C ₃ alkylamino, C ₁ -C ₃ acylamino, aminocarbonyl, C ₃ -C ₆ heterocyclyl, C ₁ -C ₃ haloalkoxy, phenyl or 5-6-membered heteroaryl, and when n ₈ >1, all R ₈ can be the same or different;

when each R ₈ is independently selected from any of the following substituents:

deuterium, C ₁ -C ₃ alkoxy, halogen, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, carboxyl, C ₁ -C ₃ alkylaminocarbonyl, C ₁ -C ₃ alkoxycarbonyl, nitro group, amino group, cyano group, C ₁ - C ₃ haloalkyl, hydroxyl group, C ₁ -C ₃ alkylsulfonyl, and when Y is absent, X ₁ is not -O-;

Y ₆ and Y ₇ represent one or more substituents on the heterocyclic ring, each independently selected from deuterium, halogen, methyl, ethyl, cyclopropyl or trifluoromethyl;

or iii) a spiroheterocyclic group selected from:

where n ₉ represents 0, 1, 2, 3 or 4;

R ₉ is independently selected from the following substituents: deuterium, halogen, cyano group, nitro group, hydroxyl group, amino group, C ₁ -C ₃ alkylamino, C ₁ -C ₃ acylamino, aminocarbonyl, linear or branched C ₁ -C ₆ alkyl, linear or branched C ₁ -C ₆ alkoxyl, C ₃ -C ₆ cycloalkyloxy, C ₃ -C ₆ cycloalkyl or heterocycloalkyl, C ₁ -C ₃ alkylaminocarbonyl, C _{1 -C 3} alkoxycarbonyl, C 1 -C ₃ alkylsulfonyl, C ₁ -C ₃ haloalkyl , C ₁ -C ₃ haloalkoxy, phenyl, 5-6-membered heteroaryl, while when n ₉ >1, all R ₉ can be the same or different;

Y ₈ is a substituent that optionally replaces a hydrogen atom in a non-aromatic moiety of the spiro ring structure, wherein Y ₈ is optionally substituted with deuterium, halogen, methyl, ethyl, cyclopropyl or trifluoromethyl;

when Y is selected from -NH-CO-, -NH-CO-NH-, -NH-CO-CH(NHRa ₉ ) or CH(NHRa ₉ )-, the corresponding arrangement of Y, A and L is A-NH-CO- L-, A-NH-CO-NH-L-, A-NH-CO-CH(NHRa ₉ )-L- or A-CH(NHRa ₉ )-L-, where A is:

n ₁ is 0, 1, 2, 3 or 4;

each R ₅ is independently selected from deuterium, halogen, hydroxyl, amino group, cyano group, nitro group, linear or branched C ₁ -C ₆ alkyl, linear or branched C ₁ -C ₆ alkoxyl, C ₁ -C ₃ acylamino, aminocarbonyl, phenyl, 5 -6-membered heteroaryl, 3-6-membered heterocyclyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkyloxy, C ₁ -C ₃ alkylaminocarbonyl, C ₁ -C ₃ alkylsulfonyl, phenyloxyl or 5-6 membered heteroaryloxy, when n ₁ >1, all R ₅ can be the same or different;

Ra ₉ is selected from hydrogen, substituted or unsubstituted C ₁ -C ₁₀ alkylcarbonyl, substituted or unsubstituted C ₃ -C ₈ cycloalkylcarbonyl, C ₁ -C ₈ heterocycloalkylcarbonyl, where "substituted" means that the end of the carbon chain is substituted with a hydroxyl or amino group.

In a preferred embodiment, the compound of formula (I) is a compound of formula (I-1) to (I-8):

where X ₁ represents -CH ₂ - or -O-;

X ₂ represents -CH ₂ - or -CO-;

r ₁ represents hydrogen, deuterium or fluorine;

R ₂ and R ₄ are independently selected from hydrogen or deuterium;

r ₃ represents hydrogen, deuterium or fluorine;

L represents a substituted or unsubstituted linear alkylene group containing 2-8 carbon atoms, wherein "substituted" means that one or more hydrogen atoms in the alkylene group are optionally substituted with the following substituents: deuterium, halogen, cyano, C ₁ -C ₃ alkyl , C ₁ -C ₃ haloalkyl, -NHC(O)Ra ₁ , -NHC(O)ORa ₂ , -NRa ₃ Ra ₄ , where Ra ₁ , Ra ₂ , Ra ₃ and Ra ₄ are each independently selected from hydrogen, C _{1 -6} alkyl, unsubstituted or substituted by one or more halogens or C _3-6 cycloalkyl, unsubstituted or substituted by one or more halogens;

Y is absent or represents -CO- or -CO-NH-;

n ₉ represents 0, 1, 2, 3 or 4;

is a 6-10 membered aryl ring or a 5-10-membered heteroaryl ring, fused with the core of the spiro ring to form a spiroheterocyclic group, preferably is a thiophene ring, a pyrrole ring, a benzene ring, a pyridine ring, a benzothiophene ring, a benzimidazole ring, an indole ring, a quinoline ring and an isoquinoline ring;

Y ₈ is a substituent that optionally replaces a hydrogen atom in a non-aromatic moiety of the spiro ring structure, wherein Y ₈ is optionally substituted with deuterium, halogen, methyl, ethyl, cyclopropyl or trifluoromethyl;

R ₉ is independently selected from the following substituents: deuterium, halogen, cyano group, nitro group, hydroxyl group, amino group, C ₁ -C ₃ alkylamino, C ₁ -C ₃ acylamino, aminocarbonyl, linear or branched C ₁ -C ₆ alkyl, linear or branched C ₁ -C ₆ alkoxyl, C ₃ -C ₆ cycloalkyloxy, C ₃ -C ₆ cycloalkyl or heterocycloalkyl, C ₁ -C ₃ alkylaminocarbonyl, C _{1 -C 3} alkoxycarbonyl, C 1 -C ₃ alkylsulfonyl, C ₁ -C ₃ haloalkyl , C ₁ -C ₃ haloalkoxy, phenyl, 5-6-membered heteroaryl, while when n ₉ >1, all R ₉ can be the same or different;

In a preferred embodiment, the compound of formula (I) is a compound of formula (I-9) to (I-16):

where X ₁ represents -CH ₂ - or -O-;

X ₂ represents -CH ₂ - or -CO-;

r ₁ represents hydrogen, deuterium or fluorine;

R ₂ and R ₄ are each independently hydrogen or deuterium;

R ₃ represents hydrogen, deuterium or fluorine;

L represents a substituted or unsubstituted linear alkylene group containing 2-8 carbon atoms, wherein "substituted" means that one or more hydrogen atoms in the alkylene group are optionally substituted with the following substituents: deuterium, halogen, cyano, C ₁ -C ₃ alkyl , C ₁ -C ₃ haloalkyl, -NHC(O)Ra ₁ , -NHC(O)ORa ₂ , -NRa ₃ Ra ₄ , where Ra ₁ , Ra ₂ , Ra ₃ and Ra ₄ are each independently selected from hydrogen, C _{1 -6} alkyl, unsubstituted or substituted by one or more halogens or C _3-6 cycloalkyl, unsubstituted or substituted by one or more halogens;

Y is absent or represents -CO- or -CO-NH-;

n ₉ represents 0, 1, 2, 3 or 4;

R ₉ is independently selected from the following substituents: deuterium, halogen, cyano group, nitro group, hydroxyl group, amino group, C ₁ -C ₃ alkylamino, C ₁ -C ₃ acylamino, aminocarbonyl, linear or branched C ₁ -C ₆ alkyl, linear or branched C ₁ -C ₆ alkoxyl, C ₃ -C ₆ cycloalkyloxy, C ₃ -C ₆ cycloalkyl or heterocycloalkyl, C ₁ -C ₃ alkylaminocarbonyl, C _{1 -C 3} alkoxycarbonyl, C 1 -C ₃ alkylsulfonyl, C ₁ -C ₃ haloalkyl , C ₁ -C ₃ haloalkoxy, phenyl, 5-6-membered heteroaryl, while when n ₉ >1, all R ₉ can be the same or different;

Y ₈ is a substituent that optionally replaces a hydrogen atom in a non-aromatic moiety of the spiro ring structure, wherein Y ₈ is optionally substituted with deuterium, halogen, methyl, ethyl, cyclopropyl or trifluoromethyl;

In a preferred embodiment, the compound of formula (I) is a compound of formula (I-17) to (I-18):

where X ₁ represents -CH ₂ - or -O-;

X ₂ represents -CH ₂ - or -CO-;

r ₁ represents hydrogen, deuterium or fluorine;

R ₂ and R ₄ are each independently hydrogen or deuterium;

r ₃ is selected from hydrogen, deuterium or fluorine;

L represents a substituted or unsubstituted linear alkylene group containing 2-8 carbon atoms, wherein "substituted" means that one or more hydrogen atoms in the alkylene group are optionally substituted with the following substituents: deuterium, halogen, cyano, C ₁ -C ₃ alkyl , C ₁ -C ₃ haloalkyl, -NHC(O)Ra ₁ , -NHC(O)ORa ₂ , -NRa ₃ Ra ₄ , where Ra ₁ , Ra ₂ , Ra ₃ and Ra ₄ are each independently selected from hydrogen, C _{1 -6} alkyl, unsubstituted or substituted by one or more halogens or C _3-6 cycloalkyl, unsubstituted or substituted by one or more halogens;

Y is absent or represents -CO- or -CO-NH-;

n ₁₀ is 0, 1, 2, 3, 4 or 5;

each Y ₁ is independently selected from hydrogen, deuterium, halogen, cyano group, carboxyl group, nitro group, hydroxyl group, amino group, aminocarbonyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, C ₁ -C ₆ alkylcarbonyl, C ₁ - C ₆ alkoxycarbonyl, C ₁ -C ₆ alkylsulfonyl, C ₁ -C ₆ alkylaminocarbonyl, C ₃ -C ₆ cycloalkyl or heterocyclyl, C ₁ -C ₆ acylamino, C ₁ -C ₆ alkyl halo, C ₁ -C ₆ haloalkoxy, C ₁ -C ₃ alkenyl, C ₁ -C ₃ alkynyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, linear or branched C ₁ -C ₃ alkyl, substituted 6-10 membered aryl or 5-10 membered heteroaryl, wherein the substituted or unsubstituted 6-10 membered aryl or 5-10 membered heteroaryl is substituted with one or more substituents selected from: deuterium, halogen, cyano group, nitro group, hydroxyl group, amino group, aminocarbonyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxyl, C ₁ -C ₃ alkylcarbonyl, C ₁ -C ₃ alkoxycarbonyl, C ₁ -C ₃ alkylsulfonyl, C ₁ -C ₃ alkylaminocarbonyl, C ₃ -C ₆ cycloalkyl or heterocyclyl, C ₁ -C ₃ acylamino, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ haloalkoxy;

selected from substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, preferably 6-10 membered aryl or 5-10 membered heteroaryl selected from thienyl, pyridyl, phenyl, benzothienyl, benzimidazolyl, indolyl , naphthyl, quinolinyl, isoquinolinyl;

each r ₁₀ is independently selected from the following: deuterium, halogen, cyano group, nitro group, hydroxyl group, amino group, aminocarbonyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxyl, C ₁ -C ₃ alkylcarbonyl, C ₁ -C ₃ alkoxycarbonyl , C ₁ -C ₃ alkylsulfonyl, C ₁ -C ₃ alkylaminocarbonyl, C ₃ -C ₆ cycloalkyl or heterocyclyl, C 1 -C ₃ acylamino, C _{1 -C 3} haloalkyl, C ₁ -C ₃ haloalkoxy, when n ₁₀ >1 , r ₁₀ can be the same or different;

In a preferred embodiment, the compound of formula (I) is a compound of formula (I-19) to (I-23):

where X ₁ represents -CH ₂ - or -O-;

X ₂ represents -CH ₂ - or - CO-;

r ₁ represents hydrogen, deuterium or fluorine;

R ₂ and R ₄ are each independently hydrogen or deuterium;

R ₃ represents hydrogen, deuterium or fluorine;

L represents a substituted or unsubstituted linear alkylene group containing 2-8 carbon atoms, wherein "substituted" means that one or more hydrogen atoms in the alkylene group are optionally substituted with the following substituents: deuterium, halogen, cyano, C ₁ -C ₃ alkyl , C ₁ -C ₃ haloalkyl, -NHC(O)Ra ₁ , -NHC(O)ORa ₂ , -NRa ₃ Ra ₄ , where Ra ₁ , Ra ₂ , Ra ₃ and Ra ₄ are each independently selected from hydrogen, C _{1 -6} alkyl, unsubstituted or substituted by one or more halogens or C _3-6 cycloalkyl, unsubstituted or substituted by one or more halogens;

Y is absent or represents -CO- or -CO-NH-;

n ₈ represents 0, 1, 2, 3 or 4;

X ₄ represents C, N or O;

each R ₈ independently represents hydrogen, deuterium, C ₁ -C ₃ alkoxyl, halogen, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, carboxyl, C ₁ -C ₃ alkylaminocarbonyl, C ₁ -C ₃ alkoxycarbonyl, nitro group , amino group, cyano group, C ₁ -C ₃ haloalkyl, hydroxyl group, C ₁ -C ₃ alkylsulfonyl, C ₁ -C ₃ alkylamino, C ₁ -C ₃ acylamino, aminocarbonyl, C ₃ -C ₆ heterocyclyl, C ₁ -C ₃ haloalkoxy, phenyl or 5-6-membered heteroaryl, wherein when n ₈ >1, all R ₈ can be the same or different;

when R ₈ is selected from any of the following substituents: deuterium, C ₁ -C ₃ alkoxyl, halogen, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, carboxyl, C ₁ -C ₃ alkylaminocarbonyl, C ₁ -C ₃ alkoxycarbonyl , nitro group, amino group, cyano group, C ₁ -C ₃ haloalkyl, hydroxyl group, C ₁ -C ₃ alkylsulfonyl, and when Y is absent, X ₁ is not -O-;

Y ₆ and Y ₇ represent one or more substituents on the heterocyclic ring, each independently selected from deuterium, halogen, methyl, ethyl, cyclopropyl or trifluoromethyl;

In a preferred embodiment, the compound of formula (I) is a compound of formula (I-24) to (I-32):

where X ₂ represents -CH ₂ - or -CO-;

r ₁ represents hydrogen, deuterium or fluorine;

r ₂ and R ₄ are each independently hydrogen or deuterium;

R ₃ is selected from hydrogen, deuterium or fluorine;

L represents a substituted or unsubstituted linear alkylene group containing 2-8 carbon atoms, wherein "substituted" means that one or more hydrogen atoms in the alkylene group are optionally substituted with the following substituents: deuterium, halogen, cyano, C ₁ -C ₃ alkyl , C ₁ -C ₃ haloalkyl, -NHC(O)Ra ₁ , -NHC(O)ORa ₂ , -NRa ₃ Ra ₄ , where Ra ₁ , Ra ₂ , Ra ₃ and Ra ₄ are each independently selected from hydrogen, C _{1 -6} alkyl, unsubstituted or substituted by one or more halogens or C _3-6 cycloalkyl, unsubstituted or substituted by one or more halogens;

Y is absent or represents -CO- or -CO-NH-;

each n ₈ , n ₉ and n ₁₀ are independently selected from 0, 1, 2, 3 or 4;

X ₄ represents C, N or O;

R ₉ is selected from the following substituents: deuterium, halogen, cyano group, nitro group, hydroxyl group, amino group, C ₁ -C ₃ alkylamino, C ₁ -C ₃ acylamino, aminocarbonyl, linear or branched C ₁ -C ₆ alkyl, linear or branched C ₁ -C ₆ alkoxyl, C ₃ -C ₆ cycloalkyloxy, C ₃ -C ₆ cycloalkyl or heterocycloalkyl, C ₁ -C ₃ alkylaminocarbonyl, C _{1 -C 3} alkoxycarbonyl, C 1 -C ₃ alkylsulfonyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ haloalkoxy, phenyl, 5-6-membered heteroaryl, and when n ₉ >1, all R ₉ can be the same or different;

selected from substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, preferably 6-10 membered aryl or 5-10 membered heteroaryl selected from thienyl, pyridyl, phenyl, benzothienyl, benzimidazolyl, indolyl , naphthyl, quinolinyl, isoquinolinyl;

each r ₁₀ is independently selected from the following: deuterium, halogen, cyano group, nitro group, hydroxyl group, amino group, aminocarbonyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxyl, C ₁ -C ₃ alkylcarbonyl, C ₁ -C ₃ alkoxycarbonyl , C ₁ -C ₃ alkylsulfonyl, C ₁ -C ₃ alkylaminocarbonyl, C ₃ -C ₆ cycloalkyl or heterocyclyl, C 1 -C ₃ acylamino, C _{1 -C 3} haloalkyl, C ₁ -C ₃ haloalkoxy, when n ₁₀ >1 , r ₁₀ can be the same or different;

each R ₈ independently represents hydrogen, deuterium, C ₁ -C ₃ alkoxyl, halogen, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, carboxyl, C ₁ -C ₃ alkylaminocarbonyl, C ₁ -C ₃ alkoxycarbonyl, nitro group , amino group, cyano group, C ₁ -C ₃ haloalkyl, hydroxyl group, C ₁ -C ₃ alkylsulfonyl, C ₁ -C ₃ alkylamino, C ₁ -C ₃ acylamino, aminocarbonyl, C ₃ -C ₆ heterocyclyl, C ₁ -C ₃ haloalkoxy, phenyl or 5-6-membered heteroaryl, wherein when n ₈ >1, all R ₈ can be the same or different;

In a preferred embodiment, the compound of formula (I) is a compound of formula (I-33) to (I-40):

where X ₂ represents -CH ₂ - or -CO-;

r ₁ represents hydrogen, deuterium or fluorine;

R ₂ and R ₄ are each independently hydrogen or deuterium;

R ₃ represents hydrogen, deuterium or fluorine;

L represents a substituted or unsubstituted linear alkylene group containing 2-8 carbon atoms, wherein "substituted" means that one or more hydrogen atoms in the alkylene group are optionally substituted with the following substituents: deuterium, halogen, cyano, C ₁ -C ₃ alkyl , C ₁ -C ₃ haloalkyl, -NHC(O)Ra ₁ , -NHC(O)ORa ₂ , -NRa ₃ Ra ₄ , where Ra ₁ , Ra ₂ , Ra ₃ and Ra ₄ are each independently selected from hydrogen, C _{1 -6} alkyl, unsubstituted or substituted by one or more halogens or C _3-6 cycloalkyl, unsubstituted or substituted by one or more halogens;

Y is absent or represents -CO- or -CO-NH-;

each n ₈ , n ₉ and n ₁₀ are independently selected from 0, 1, 2, 3 or 4;

X ₄ is selected from C, N or O;

each R ₉ is independently selected from the following substituents: deuterium, halogen, cyano group, nitro group, hydroxyl group, amino group, C ₁ -C ₃ alkylamino, C ₁ -C ₃ acylamino, aminocarbonyl, linear or branched C ₁ -C ₆ alkyl, linear or branched C ₁ -C ₆ alkoxyl, C ₃ -C ₆ cycloalkyloxy, C ₃ -C ₆ cycloalkyl or heterocycloalkyl, C ₁ -C ₃ alkylaminocarbonyl, C ₁ -C ₃ alkoxycarbonyl, C ₁ -C ₃ alkylsulfonyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ haloalkoxy, phenyl, 5-6-membered heteroaryl, while when n ₉ >1, all R ₉ can be the same or different;

selected from substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, preferably 6-10 membered aryl or 5-10 membered heteroaryl selected from thienyl, pyridyl, phenyl, benzothienyl, benzimidazolyl, indolyl , naphthyl, quinolinyl, isoquinolinyl;

each r ₁₀ is independently selected from the following: deuterium, halogen, cyano group, nitro group, hydroxyl group, amino group, aminocarbonyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxyl, C ₁ -C ₃ alkylcarbonyl, C ₁ -C ₃ alkoxycarbonyl , C ₁ -C ₃ alkylsulfonyl, C ₁ -C ₃ alkylaminocarbonyl, C ₃ -C ₆ cycloalkyl or heterocyclyl, C 1 -C ₃ acylamino, C _{1 -C 3} haloalkyl, C ₁ -C ₃ haloalkoxy, when n ₁₀ >1 , r ₁₀ can be the same or different;

each R ₈ is independently selected from hydrogen, deuterium, C ₁ -C ₃ alkoxyl, halogen, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, carboxyl, C ₁ -C ₃ alkylaminocarbonyl, C ₁ -C ₃ alkoxycarbonyl, nitro group , amino groups, cyano groups, C ₁ -C ₃ haloalkyl, hydroxyl group, C ₁ -C ₃ alkylsulfonyl, C ₁ -C ₃ alkylamino, C ₁ -C ₃ acylamino, aminocarbonyl, C ₃ -C ₆ heterocyclyl, C ₁ -C ₃ haloalkoxy, phenyl or 5-6-membered heteroaryl, and when n ₈ >1, all R ₈ can be the same or different;

when R ₈ is selected from any of the following substituents: deuterium, C ₁ -C ₃ alkoxyl, halogen, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, carboxyl, C ₁ -C ₃ alkylaminocarbonyl, C ₁ -C ₃ alkoxycarbonyl , nitro group, amino group, cyano group, C ₁ -C ₃ haloalkyl, hydroxyl group, C ₁ -C ₃ alkylsulfonyl, and when Y is absent, X ₁ is not -O-;

In a preferred embodiment, the compound of formula (I) is a compound of formula (I-41) to (I-48):

where X ₁ represents -CH ₂ - or -O-;

X ₂ represents -CH ₂ - or - CO-;

r ₁ represents hydrogen, deuterium or fluorine;

r ₂ and R ₄ are each independently hydrogen or deuterium;

R ₃ represents hydrogen, deuterium or fluorine;

L represents a substituted or unsubstituted linear alkylene group containing 2-8 carbon atoms, wherein "substituted" means that one or more hydrogen atoms in the alkylene group are optionally substituted with the following substituents: deuterium, halogen, cyano, C ₁ -C ₃ alkyl , C ₁ -C ₃ haloalkyl, -NHC(O)Ra ₁ , -NHC(O)ORa ₂ , -NRa ₃ Ra ₄ , where Ra ₁ , Ra ₂ , Ra ₃ and Ra ₄ are each independently selected from hydrogen, C _{1 -6} alkyl, unsubstituted or substituted by one or more halogens or C _3-6 cycloalkyl, unsubstituted or substituted by one or more halogens;

n ₂ is 0, 1, 2 or 3;

n ₃ represents 0, 1, 2 or 3;

each R ₆ and R ₇ is independently selected from the following groups: deuterium, halogen, cyano group, nitro group, amino group, hydroxyl group, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, hydroxyl-substituted C ₁ -C ₆ alkyl, C ₁ - C ₆ alkoxyl, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ haloalkoxyl, hydroxyl substituted C ₁ -C ₆ alkoxyl, cyanosubstituted C ₁ -C ₆ alkoxyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkyloxy, phenyl, C ₅ -C ₆ heteroaryl, C ₃ -C ₆ heterocyclyl, -NHC(O)Ra ₅ , -NHC(O)ORa ₆ , -NRa ₇ Ra ₈ ; where Ra ₅ , Ra ₆ , Ra ₇ and Ra ₈ are each independently selected from the following: hydrogen, C _1-6 alkyl, unsubstituted or substituted with one or more substituents: halogen, hydroxyl group or cyano group, or C _3-6 cycloalkyl, unsubstituted or substituted with one or more substituents: halogen, hydroxyl group or cyano group, and when n ₂ >1 or n ₃ >1, R ₆ and R ₇ can be the same or different;

In a preferred embodiment, the compound of formula (I) is a compound of formula (I-49) to (I-53):

where X ₁ represents -CH ₂ - or -O-;

X ₂ represents -CH ₂ - or - CO-;

r ₁ represents hydrogen, deuterium or fluorine;

R ₂ and R ₄ are independently selected from hydrogen or deuterium;

r ₃ represents hydrogen, deuterium or fluorine;

L represents a substituted or unsubstituted linear alkylene group containing 2-8 carbon atoms, wherein "substituted" means that one or more hydrogen atoms in the alkylene group are optionally substituted with the following substituents: deuterium, halogen, cyano, C ₁ -C ₃ alkyl , C ₁ -C ₃ haloalkyl, -NHC(O)Ra ₁ , -NHC(O)ORa ₂ , -NRa ₃ Ra ₄ , where Ra ₁ , Ra ₂ , Ra ₃ and Ra ₄ are each independently selected from hydrogen, C _{1 -6} alkyl, unsubstituted or substituted by one or more halogens or C _3-6 cycloalkyl, unsubstituted or substituted by one or more halogens;

Y is selected from -NH-CO-, -NH-CO-NH-, -NH-CO-CH(NHRa ₉ )- or -CH(NHRa ₉ )-;

n ₁ is 0, 1, 2, 3 or 4;

each R ₅ is independently selected from deuterium, halogen, hydroxyl, amino group, cyano group, nitro group, linear or branched C ₁ -C ₆ alkyl, linear or branched C ₁ -C ₆ alkoxyl, C ₁ -C ₃ acylamino, aminocarbonyl, phenyl, 5 -6-membered heteroaryl, 3-6-membered heterocyclyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkyloxy, C ₁ -C ₃ alkylaminocarbonyl, C ₁ -C ₃ alkylsulfonyl, phenyloxyl or 5-6 membered heteroaryloxy, when n ₁ >1, all R ₅ can be the same or different;

Ra ₉ is selected from hydrogen, substituted or unsubstituted C ₁ -C ₁₀ alkylcarbonyl, substituted or unsubstituted C ₃ -C ₈ cycloalkylcarbonyl, C ₁ -C ₈ heterocycloalkylcarbonyl, where "substituted" means that the end of the carbon chain is substituted with a hydroxyl or amino group.

More preferably, the compound of formula (I) is one of the following:

tautomer, enantiomer, diastereomer, racemate, metabolite, metabolic precursor, isotopic compound, pharmaceutically acceptable salt, ester, prodrug or hydrate thereof.

A compound of formula (I) may contain one or more asymmetric or chiral centers and, therefore, various stereoisomers may exist. The compound of the present invention includes all stereoisomeric forms, including, but not limited to, diastereomer, enantiomer, atropisomer, and mixtures thereof (such as racemates), which are all included within the scope of the present invention.

The term "substitution" refers to the replacement of one or more hydrogen atoms in a specific group with a specific substituent. Specific substituents are described in the previous paragraph or are present in each example. Unless otherwise specified, any substituent may have a substituent selected from a particular group at any substitutable position of that group, and at each position the substituent may be the same or different. Cyclic substituents, such as heterocycloalkyl, can be attached to another ring, such as cycloalkyl, to form a spirobicyclic ring system, for example, two rings sharing one carbon atom.

Those skilled in the art will appreciate that the combinations of substituents provided by the present invention are stable or chemically achievable. Substitution in the corresponding structure of the present invention includes substituted and unsubstituted, for example, "optionally" substituted with a particular substituent, which includes the meaning of substituted or unsubstituted with a particular substituent.

In the present invention, when the number of substituents is greater than 1, the R substituents may be the same or different substituents, which means when the number of substituents in a certain structure is more than one, the combination of R substituents can be selected from a variety of different types of substituents.

The term "substitution" can only apply to a site that can be replaced by a substituent, and does not include substitution that cannot be achieved based on existing knowledge in the field of chemistry.

The compound of formula (I) may also exist in various tautomeric forms, all of which are included within the scope of the invention.

The term "tautomer" refers to structural isomers with different energies that interconvert across a low energy barrier. This reaction usually results in the displacement of hydrogen atoms or protons accompanying the conversion of single bonds and adjacent double bonds.

The term "enantiomer" refers to stereoisomers that are mirror images of each other and do not match when superimposed on each other.

The term "diastereomers" refers to stereoisomers that have two or more chiral centers and are not mirror images.

"Racemate" refers to two stereoisomers that are mirror images of each other, whose opposing optical activity cancels out their optical activity.

"Pharmaceutically acceptable salt" refers to a drug molecule forming a corresponding salt with an appropriate organic acid, inorganic acid, or organic base, or inorganic base, such as hydrochloric acid, formic acid, trifluoroacetic acid, succinic acid, methylsulfonic acid, and the like. .

“Prodrug” refers to a class of compounds that are inactive or less active in vitro and release active drug substances through enzymatic or non-enzymatic transformation in vivo to exert their therapeutic effects.

"Hydrate" refers to a compound containing water.

The term "halogen" includes fluorine, chlorine, bromine or iodine.

The term "hydrocarbyl" refers to a substituent containing only carbon atoms and hydrogen atoms, and includes, but is not limited to, methyl, ethyl, isopropyl, propyl, cyclohexyl, phenyl, etc.

The term "C1-C6 alkyl" refers to straight or branched chain alkyl having from 1 to 6 carbon atoms, including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl , pentyl, hexyl, etc.

The term "C1-C6 alkoxy" refers to a straight or branched chain alkoxy having from 1 to 6 carbon atoms, including, but not limited to, methoxyl, ethoxyl, propoxyl, isopropoxyl, butoxyl, etc.

The term "C1-C6 alkoxycarbonyl" includes, but is not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl, pentoxycarbonyl and hexoxycarbonyl, etc.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. Monocyclic cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentenyl and cyclohexyl. Polycyclic cycloalkyl includes spiro-, fused and bridged cycloalkyl.

The term "heterocyclyl" refers to a cyclic substituent containing one or more saturated and/or partially saturated monocyclic or polycyclic rings, where one or more ring atoms are selected from nitrogen, oxygen, sulfur or S(O) _m (where m is an integer 0 to 2), and the remaining ring atoms are carbon; such as epoxypropane, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl; the heterocyclyl may be fused to an aryl, heteroaryl or cycloalkyl ring, with the ring attached to the core structure being a heterocyclyl.

The term "aryl" refers to a 6-14 membered all-carbon monocyclic or fused polycyclic group with a conjugated p-electron system, preferably a 6-10 membered ring, more preferably phenyl and naphthyl, most preferably phenyl. An aryl ring can be fused with a heteroaryl, heterocyclyl, or cycloalkyl ring, with the ring attached to the core structure being an aryl ring.

The term "heteroaryl" refers to a 5-14 membered aryl having 1 to 4 heteroatoms as ring atoms and the remaining ring atoms being carbon, the heteroatoms including oxygen, sulfur and nitrogen, preferably 5-10- member ring. Heteroaryl is preferably a 5- or 6-membered ring such as thienyl, pyridyl, pyrrolyl and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, with the ring attached to the core structure being a heteroaryl ring.

The term "spiroheterocyclic group" refers to a polycyclic heterocyclyl that has one common atom between the individual rings (called a spiroatom), in which one or more ring atoms are heteroatoms selected from nitrogen and oxygen, sulfur or S(O)m (where m represents is an integer from 0 to 2), and the remaining ring atoms represent carbon. The spiroheterocyclic ring may be fused to a 6-10 membered aryl or 5-10 membered heteroaryl ring, where the ring attached to the core structure is a spiroheterocyclic ring.

The term "haloalkyl" refers to linear, branched or cyclic alkyl substituted with one or more halogens, and includes, but is not limited to, 2-bromoethyl, 2-bromopropyl, etc.

The term "alkenyl" refers to alkenyl with 2-10 carbon atoms, such as vinyl, propenyl, butenyl, styryl, phenpropenyl.

The term "alkynyl" refers to an alkynyl with 2-10 carbon atoms, such as ethynyl, propynyl, butynyl, phenylethynyl, phenylpropynyl.

The term "C3-C8 cycloalkyl" refers to a cyclic alkyl having from 3 to 8 carbon atoms on the ring, and includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, etc.

The term "5-10 membered heterocyclyl" means containing one or more saturated and/or partially saturated rings that include from 5 to 10 ring atoms, of which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, sulfur or S(O)m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon; such as epoxypropane, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl.

The term "C3-C6 heterocyclyl" refers to containing one or more saturated and/or partially saturated rings that include from 3 to 6 ring atoms, of which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, sulfur or S(O)m (where m is an integer from 0 to 2) and the remaining ring atoms represent carbon; such as epoxypropyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl.

The term "hydroxyl-substituted alkyl" refers to a linear, branched or cyclic alkyl substituted with one or more hydroxyls, including, but not limited to, (S)-1-hydroxyisobutyl-2-yl and (R)-1-hydroxyisobutyl-2-yl etc.

In the present invention, unless otherwise indicated, the terms used have general meanings known to those skilled in the art.

The present invention also includes any new intermediates described herein.

In one aspect, the present invention provides a method for preparing a compound of formula (I), and such method is selected from one of the following methods:

For references to the synthesis of starting compounds 1A, 2A, 3D, 4A, 5A, 6A and 7A, see WO 2008115516 A2, WO 2011100380 A1, WO 2016065980 A1, WO 2007027527 A2 and WO 2008027542 A2.

Synthesis method 1:

in which the definitions of R ₁ , R ₂ , R ₃ , R ₄ and X ₂ are the same as in the above definitions;

m ₁ is an integer from 1 to 7;

has the same definition as i) heterocyclyl, ii) fused heterocyclyl and iii) spiroheterocyclic group in the definition of the above A;

Step 1-1: Compound 1C was prepared by Sonogashira coupling reaction of compounds 1A and 1B at room temperature or by heating in dipole organic solvents such as DMF or DMA, etc., in the presence of a Pd catalyst (such as Pd(PPh ₃ ) ₄ or Pd(PPh ₃ ) ₂ Cl ₂ etc.), a cuprous catalyst (copper(I) iodide) and a base (such as triethylamine or diisopropylethylamine, etc.);

Step 1-2: Compound 1C is reduced to compound 1D with hydrogen under Pd/C, Raney nickel or other metal catalyst (such as Wilkinson catalyst) catalyst conditions.

Step 1-3: compound 1F was prepared by reacting compound 1D with hydroxyquinoline 1E (or substituted or unsubstituted hydroxyquinoline and its analogs, substituted or unsubstituted naphthol and its analogs, etc.) under the conditions of triphenylphosphine and diisopropyl azodiformate;

Step 1-4: Compound 1D is reacted to produce compound 1G in the presence of triphenylphosphine and carbon tetrabromide;

Step 1-5: Compound 1G and nitrogen-containing heterocyclic compound 1H (compound 1H is a series of amino compounds containing group A as defined above) react to produce compound 1I, in the presence of sodium iodide;

Synthesis method 2:

in which the definitions of R ₁ , R ₂ , R ₃ , R ₄ and X ₂ are the same as in the above definitions;

m ₁ is an integer from 1 to 7;

has the same definition as i) heterocyclyl, ii) fused heterocyclyl and iii) spiroheterocyclic group in the definition of the above A;

G2 is a protecting group selected from TBS (Tris-buffered saline), Trit, benzyl;

Step 2-1: Multi-substituted olefin derivative 2C was prepared by reacting compounds 2A and 2B under heating conditions in the presence of a protonless solvent (such as acetonitrile or DMF, etc.), Pd catalyst (palladium(II) acetate or Pd (PPh ₃ ) ₄ etc.), phosphine ligand (such as triphenylphosphine, s-Phos, etc.), organic base (triethylamine or diisopropylethylamine, etc.) (Heck coupling reaction);

Step 2-2: Compound 2C is reduced to compound 2D with hydrogen under Pd/C, Raney nickel or other metal catalyst (such as Wilkinson catalyst) catalyst conditions.

Step 2-3: piperidone derivative 2E was prepared by ring closure in the presence of potassium tert-butoxide in anhydrous tetrahydrofuran;

Step 2-4: compound 2F was prepared by deprotecting compound 2E in an acidic environment or in the presence of TBAF (tetrabutylammonium fluoride);

Step 2-5: Compound 2F is reacted to produce compound 2G in the presence of triphenylphosphine and carbon tetrabromide;

Step 2-6: compound 2G and nitrogen-containing heterocyclic compound 2H (compound 2H is a series of amino compounds containing group A, as defined above) react to obtain compound 21, in the presence of sodium iodide; Synthesis method 3:

in which the definitions of R ₁ , R ₂ , R ₃ , R ₄ and X ₂ are the same as in the above definitions;

m ₂ is an integer from 1 to 7;

has the same definition as i) heterocyclyl, ii) fused heterocyclyl and iii) spiroheterocyclic group in the definition of the above A;

G ₃ -NH2 are various aromatic amine or aliphatic amine compounds used in the examples of the present invention;

Step 3-1: Compounds 3A and 3B were reacted in the presence of trifluoroacetic anhydride and tert-butanol to obtain compound 3C;

Step 3-2: Compounds 3C and 3D were reacted in the presence of potassium carbonate to obtain compound 3E;

Step 3-3: piperidone derivative 3F was prepared by ring closure of compound 3E in the presence of potassium tert-butoxide;

Step 3-4: Compound 3G was prepared by deprotecting Compound 3F under hydrochloric acid conditions;

Step 3-5: Compound 3I was prepared by the condensation reaction of compound 3G and a nitrogen-containing heterocyclic compound 3H (compound 3H is a series of amino compounds containing group A in the above definition) in the presence of a condensing agent (HATU or HOBt) and a base (triethylamine);

Step 3-6: Compound 3G and compound 3J are condensed in the presence of a condensing agent (HATU or HOBt) and a base (triethylamine) to obtain compound 3K;

Synthesis method 4:

in which the definitions of R ₁ , R ₂ , R ₃ , R ₄ , X ₂ , Ra ₉ , R ₁₁ and n ₁₁ are the same as in the above definitions;

G ₄ and G ₅ are protecting groups selected from tert-butoxycarbonyl or benzyl;

G ₆ -NH ₂ is an aromatic amine or aliphatic amine compound;

Step 4-1: Compound 4C was prepared by Sonogashira coupling reaction of compounds 4A and 4B at room temperature or under heating conditions in the presence of a Pd catalyst (such as Pd(PPh ₃ ) ₄ or Pd(PPh ₃ ) ₂ Cl ₂ etc. etc.), a cuprous catalyst (copper(I) iodide) and a base (such as triethylamine or diisopropylethylamine, etc.);

Step 4-2: Compound 4C is reduced to compound 4D with hydrogen under Pd/C, Raney nickel or other metal catalyst (such as Wilkinson catalyst) catalyst conditions.

Step 4-3: Compound 4D is condensed under the conditions of amine derivative 4E and condensing agent HATU and HOBt to obtain compound 4F;

Step 4-4: The protecting group of compound 4F is removed under hydrochloric acid conditions and after the reaction, it is dried by centrifugation and reacted with the corresponding acyl chloride or carboxylic acid to obtain compound 4G;

Step 4-5: Compound 4D and o-phenylenediamine derivative 4H are reacted under condensing agent conditions of HATU and HOBt, and then heated under acidic conditions to obtain compound 4I;

Step 4-6: The protecting group of compound 41 is removed under hydrochloric acid conditions and after the reaction, it is dried by centrifugation and reacted with the corresponding acyl chloride or carboxylic acid to obtain compound 4J;

Synthesis method 5:

in which the definitions of R ₁ , R ₂ , R ₃ , R ₄ and X ₂ are the same as in the above definitions;

m ₃ is an integer from 1 to 7;

has the same definition as heterocyclyl, fused heterocyclyl and spiroheterocyclic group in the definition of the above A;

Ar represents 6-10 membered aryl, 5-10 membered heteroaryl, such aryl or heteroaryl being optionally substituted with one or more R ₅ substituents, and the definition of R ₅ is similar to the above definition;

Step 5-1: Compounds 5A and 5B were reacted under conditions of triphenylphosphine and diisopropyl azodicarboxylate to obtain compound 5C;

Step 5-2: Compounds 5C were reacted in the presence of potassium carbonate to obtain compound 5D;

Step 5-3: Compound 5E was prepared by deprotecting Compound 5D under hydrochloric acid conditions;

Step 5-4: Compound 5E and compound 5F were reacted in the presence of a base (such as triethylamine or diisopropylethylamine, etc.) to obtain compound 5G;

Step 5-5: compound 5E and nitrogen-containing heterocyclic compound 5H (compound 5H is a series of amino compounds containing group A as defined above) were reacted in the presence of N,N-carbonyldiimidazolyl and a base to obtain compound 51;

Synthesis method 6:

in which the definitions of R ₁ , R ₂ , R ₃ , R ₄ and X ₂ are the same as in the above definitions;

m ₄ is an integer from 1 to 7;

has the same definition as heterocyclyl, fused heterocyclyl and spiroheterocyclic group in the definition of the above A;

Step 6-1: Compounds 6A and 6B were reacted in the presence of potassium carbonate to obtain compound 6C;

Step 6-2: Compounds 6C were reacted in the presence of potassium tert-butoxide to obtain compound 6D;

Step 6-3: Compound 6D and nitrogen-containing heterocyclic compound 6E (compound 6E is a series of amino compounds containing group A as defined above) were reacted in the presence of a base to produce compound 6F. Synthesis method 7

in which the definitions of R ₁ , R ₂ , R ₃ and R ₄ are the same as in the above definitions;

m ₄ is an integer from 1 to 7;

has the same definition as heterocyclyl, fused heterocyclyl and spiroheterocyclic group in the definition of the above A;

Step 7-1: Compounds 7A and chloromethyl methyl ether 7B were reacted in the presence of sodium hydride to obtain compound 7C;

Step 7-2: compound 7C was reacted in the presence of 7D and azodiisobutyronitrile to obtain compound 7E;

Step 7-3: Compound 7E and compound 7F were reacted in the presence of a base (such as triethylamine or diisopropylethylamine, etc.) to obtain compound 7G;

Step 7-4: Compounds 7G were reacted under acidic conditions (hydrochloric acid and dioxane) to produce compound 7H;

Step 7-5: Compound 71 and compound 7F were reacted in the presence of a base (such as triethylamine or diisopropylethylamine, etc.) to obtain compound 7H;

Step 7-6: Compounds 7H and 6B were reacted in the presence of potassium carbonate to obtain compound 7J;

Step 7-7: Compound 7J and nitrogen-containing heterocyclic compound 7K (compound 7K is a series of amino compounds containing group A as defined above) were reacted in the presence of a base to produce compound 7L.

It is yet another object of the present invention to provide a compound of formula (I), a tautomer, a diastereomer, a racemate, a metabolic precursor, a metabolite, an isotopic compound, a pharmaceutically acceptable salt thereof, an ester, a prodrug or a hydrate thereof for use in regulating the activity of the CRL4 ^CRBN E3 ubiquitin ligase .

Another object of the present invention is to provide a pharmaceutical composition, wherein such pharmaceutical composition contains a therapeutically effective dose of a compound of formula (I), a tautomer, a diastereomer, diastereomers, a racemate, a metabolic precursor, a metabolite, an isotopic compound, a pharmaceutically acceptable salt, an ester thereof, a prodrug or a hydrate thereof and at least one pharmaceutically acceptable carrier.

Another object of the present invention is to provide a pharmaceutical composition, wherein such pharmaceutical composition contains a therapeutically effective dose of a compound of formula (I), a tautomer, a diastereomer, a racemate, a metabolic precursor, a metabolite, an isotopic compound, a pharmaceutically acceptable salt, an ester, a prodrug thereof or a hydrate thereof, and one or more other ingredients with pharmaceutically therapeutic activity. The compound of formula (I) described in claim 1 of the present invention, its enantiomer, diastereomer, racemate, pharmaceutically acceptable salt, ester, prodrug or hydrate thereof may be combined with one or more other ingredients having pharmaceutical therapeutic activity to obtaining synergistic effects in the prevention or treatment of specific diseases or dysfunctions. The compound of formula (I) described in claim 1 of the present invention, its enantiomer, diastereomer, racemate, pharmaceutically acceptable salt, ester, prodrug or hydrate thereof may also reduce or eliminate the toxic and side effects of one or more other ingredients with pharmaceutically therapeutic activity in the prevention or treatment of specific diseases or dysfunctions, and vice versa.

It is yet another object of the present invention to provide another one or more ingredients with pharmaceutical therapeutic activity as described above, containing a macromolecular compound such as a protein, polysaccharide, nucleic acid, etc., and a low molecular compound such as an inorganic compound, an organometallic compound, synthetic or natural organic low molecular weight compound, etc.

Another object of the present invention is to provide the use of a compound of formula (I), its enantiomer, diastereomer, racemate, metabolic precursor, metabolite, isotopic compound, pharmaceutically acceptable salt, ester, prodrug or hydrate thereof for the preparation of a medicament for the treatment of diseases, associated with the CRL4 ^CRBN E3 ubiquitin ligase, preferably such diseases include, but are not limited to, cancer, inflammatory diseases, pain, neurological diseases and diseases of the immune system.

The compound of the present invention can be prepared into pharmaceutically acceptable salts if it contains basic groups, which include inorganic acid salts and organic acid salts. Acids suitable for salt formation include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, toluenesulfonic acid and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.

Another object of the present invention is to provide a pharmaceutical composition that includes one or more therapeutically effective doses of a compound of formula (I), a tautomer, a diastereomer, diastereomers, a racemate, a metabolic precursor, a metabolite, an isotopic compound, a pharmaceutically acceptable salt, an ester thereof , prodrugs and their solvates, hydrates or crystalline forms and at least one excipient, diluent or carrier.

A typical formulation is prepared by mixing a compound of formula (I) of the present invention with a carrier, diluent or excipient. Suitable carriers, diluents or excipients are well known to those skilled in the art, including carbohydrates, waxes, water-soluble and/or swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, water and other substances. The particular carrier, diluent or excipient used will depend on the use and purpose of the compound of the present invention. The solvent is typically selected to be one that is considered safe and effective when administered to a mammal by those skilled in the art. In general, safe solvents are non-toxic aqueous solvents such as pharmaceutical water, as well as other non-toxic solvents that are soluble in or miscible with water. Suitable aqueous solvents include one or more of the following: water, ethanol, propylene glycol, polyethylene glycol (eg, PEG400 or PEG300), and the like. The composition may also include one or more of the following: buffer, stabilizer, surfactant, wetting agent, lubricant, emulsifier, suspending agent, preservative, antioxidant, opalizer, glidant, processing aid, color, sweetening agent, spices, flavoring or other known additives capable of producing or using the compound of formula (I) in an acceptable form.

When a compound of formula (I) of the present invention is used in combination with at least one other drug, the two or more drugs may be used alone or in combination, and are preferably administered in the form of a pharmaceutical composition. The compound or pharmaceutical composition of formula (I) of the present invention can be administered separately in any known form of oral, intravenous, rectal, vaginal, transdermal administration or other form of local or systemic administration, administered alone or together to a patient.

These pharmaceutical compositions may also contain one or more of the following: buffer, stabilizer, surfactant, wetting agent, lubricant, emulsifier, suspending agent, preservative, antioxidant, opalizer, glidant, processing aid, colorant, sweetening agent, spices, flavoring or other known additives allowing the pharmaceutical composition to be manufactured or used in an acceptable form.

The drug of the present invention is preferably administered orally. Solid dosage forms for oral administration may include capsules, tablets, powders or pellets. A solid dosage form of a compound or pharmaceutical composition of the present invention is mixed with at least one excipient, diluent or carrier. Suitable fillers, diluents or carriers include substances such as sodium citrate or dicalcium phosphate, or starch, lactose, sucrose, mannose alcohol, silicic acid, etc.; binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, gum arabic, etc.; wetting agents such as glycerin, etc.; disintegration agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, specific complexing silicate, sodium carbonate, etc.; solution blockers such as paraffin, etc.; absorption promoters such as quaternary ammonium compounds, etc.; adsorbents such as kaolin, bentonite, etc.; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, etc. In the case of capsules and tablets, the composition may also include a buffer. These types of solid compositions can also be used as fillers for soft and hard filled gelatin capsules where lactose and high molecular weight polyethylene glycol are used as fillers.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and infusions. In addition to the compound of the present invention or composition thereof, liquid dosage forms may contain an inert diluent commonly used in the art, such as water or other solvents; solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide; oils (such as cottonseed oil, peanut oil, olive oil, castor oil, sesame oil, etc.); glycerol; tetrahydrofurfuryl alcohol; fatty acid esters of polyethylene glycol and sorbitan; or a mixture of several of these substances, etc.

In addition to these inert diluents, the composition may also contain one or more excipients such as a wetting agent, an emulsifier, a suspending agent, a sweetening agent, a flavoring agent and spices.

As for the suspension, in addition to the compound or composition of the present invention, it may further contain a carrier such as a suspending agent such as ethoxylated stearyl alcohol, polyoxyethylene sorbitol, sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, or a mixture of several of these substances.

The composition for rectal or vaginal administration is preferably a suppository, which can be prepared by mixing the compound or composition of the present invention with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or suppository wax. The excipient or carrier is solid at normal room temperature and liquid at body temperature, and is capable of melting in the rectum or vagina to release the active compound.

The compound or pharmaceutical composition of the present invention can be administered in other topical formulations, including ointment, powder, spray and inhalant. The compound may be mixed under sterile conditions with a pharmaceutically acceptable excipient, diluent or carrier, as well as any preservative, buffer or propellant, if desired. The present invention also includes an ophthalmic composition, ophthalmic ointment, powder and solution.

Another object of the present invention is to provide a compound of formula (I), tautomer, diastereomer, racemate, metabolic precursor, metabolite, isotopic compound, pharmaceutically acceptable salt, ester, prodrug thereof, or a hydrate or crystalline form thereof for use in monotherapy or combination therapy. therapy. When used in combination therapy, the treatment includes a therapeutically effective dose of the compound of formula (I) described in claim 1, its enantiomer, diastereomer, racemate and mixture thereof, as well as pharmaceutically acceptable salts, crystalline hydrate and solvate, and one or more ingredients with pharmaceutical therapeutic activity. These other one or more ingredients with pharmaceutical therapeutic activity contain a high molecular weight compound such as a protein (antibody or polypeptide), polysaccharide, nucleic acid (DNA or RNA), etc., and a low molecular weight compound such as an inorganic compound, an organometallic compound, synthetic or natural organic low-molecular compound, etc. In addition, treatment also includes radiation, surgery, cell therapy, hormonal therapy or cytokine therapy, etc. The compound of formula (I) described in claim 1 of the present invention, its prodrug, enantiomer, diastereomer, racemate and mixture thereof, as well as a pharmaceutically acceptable salt, crystalline hydrate and solvate may be combined with one or more other ingredients having pharmaceutical properties therapeutic activity to produce synergistic effects in the prevention or treatment of specific diseases or dysfunctions. The compound of formula (I) described in claim 1 of the present invention, its prodrug, enantiomer, diastereomer, racemate and mixture thereof, as well as a pharmaceutically acceptable salt, crystalline hydrate and solvate may also reduce or eliminate the toxic and side effects of one or more other ingredients with pharmaceutically therapeutic activity in the prevention or treatment of specific diseases or dysfunctions, and vice versa.

Another object of the present invention is to provide the use of a compound of formula (I), a tautomer, a diastereomer, a racemate, a metabolic precursor, a metabolite, an isotopic compound, a pharmaceutically acceptable salt thereof, an ester, a prodrug or a hydrate thereof, for the manufacture of a medicament for the treatment of diseases. , associated with the ubiquitin ligase CRL4CRBNE3. Such related diseases described in the present invention that are associated with the CRL4CRBNE3 ubiquitin ligase include, but are not limited to, tumors, central nervous system diseases and immune diseases.

In a preferred embodiment, such disease or dysfunction includes, but is not limited to, cancer, angiogenesis-related diseases or dysfunction, pain (including, but not limited to, complex local pain syndrome), macular degeneration and related dysfunction, skin diseases, pulmonary dysfunction, diseases associated with immunodeficiency, damage and dysfunction of the central nervous system, diseases or dysfunctions associated with TNFa.

In another preferred embodiment, cancer includes, but is not limited to, skin cancer (such as melanoma), lymphatic cancer, breast cancer, cervical cancer, uterine cancer, alimentary canal cancer, lung cancer, ovarian cancer, prostate cancer, colon cancer, rectal cancer, oral cancer, brain tumor, head and neck cancer, throat cancer, testicular cancer, kidney cancer, pancreatic cancer, spleen cancer, liver cancer, bladder cancer, laryngeal cancer and related cancers with AIDS. The compound of the present invention is also effective in hematological tumors and myelomas, and is useful in the treatment of multiple myeloma, lymphoma, and acute and chronic leukemia. The compounds of the present invention can also be used to prevent or treat primary tumors and tumor metastases.

The term "deuterium (D)" as used in the present invention is a stable, non-radioactive isotope of hydrogen with an atomic mass of 2.0144. Natural hydrogen exists as a mixture of isotopes H (hydrogen or protium), D (2H or deuterium), and T (3H or tritium), in which the abundance of deuterium is 0.0156. According to general technical knowledge in the field, all compounds in the structural formulas of all compounds containing natural hydrogen atoms are actually a mixture of H, D, and T. Therefore, when the abundance of deuterium at any site of a compound is higher than its natural abundance of 0, 0156%, such compounds should be considered to be of non-natural origin or enriched in deuterium.

The term “isotopic compound” as used in the present invention refers to a compound of formula (I) of the present invention, a pharmaceutically acceptable salt, solvate, stereoisomer, metabolite or prodrug thereof containing one or more naturally occurring or non-naturally occurring isotopes of an atom. The present invention also covers the isotopically labeled compounds of the present invention, except that one or more atoms are replaced by an atom with an atomic mass or mass number different from the atomic mass or mass number found in nature. It is similar to the atoms mentioned in this document. Examples of isotopes that may be included in the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as: ² hydrogen, ³ hydrogen, ¹¹ carbon, ¹³ carbon, ¹⁴ carbon, ¹³ nitrogen, 15 nitrogen, ¹⁵ oxygen, ¹⁷ oxygen, ¹⁸ oxygen, ³¹ phosphorus ^{, 32} phosphorus, ³⁵ sulfur, ¹⁸ fluorine, ¹²³ iodine, ¹²⁵ iodine and ³⁶ chlorine.

Certain isotopically labeled compounds of the present invention (such as 3H and 14C labeled compounds) are used in compound and/or substrate tissue distribution tests. Isotopes of tritium (3H) and carbon-14 (14C) are particularly preferred because they are easy to obtain and detect. Moreover, substitution of heavier isotopes such as deuterium (e.g., 2H) may provide some therapeutic benefits (e.g., increased in vivo half-life or reduced dosage requirements) while providing greater metabolic stability, so may be preferable in some cases . Positron emission isotopes such as 15O, 13N, 11C and 18F are used in positron emission tomography (PET) to study the occupancy of substrate receptors. The isotope-labeled compound of the present invention can generally be prepared by the following methods, similar to those disclosed in the diagram and/or in the examples below, by replacing isotope-labeled reagents with reagents that are not isotope-labeled. All isotopic variants of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention will be further described below along with specific examples, but these examples do not limit the scope of the present invention.

I. Examples of receipt

In all examples, ¹ H NMR was recorded using a Bruker Avance III-300 or Avance III-400 nuclear magnetic resonance instrument and the chemical shift was expressed as 5 (ppm); mass spectrum was measured using UPLC-MS mass spectrometry (ESI); where the Ultra Performance Liquid Chromatography (UPLC) instrument is a Waters HPLC H-CLASS and the Electric Spray Ionization (MS(ESI) mass spectrometry instrument is a Waters SQ Detector 2. Anhydrous tetrahydrofuran was prepared by refluxing reflux benzophenone/sodium metal to dry and remove oxygen. Anhydrous toluene and anhydrous dichloromethane were prepared by refluxing with calcium chloride for drying. Petroleum ether, ethyl acetate, dichloromethane and other solvents used in the mobile phase of column chromatography were purchased from Sinopharm Chemical Reagent Co., Ltd. The thin layer chromatography silica gel plate (HSGF254) used for reaction detection was purchased from Sinopharm Chemical Reagent Co., Ltd. Silica gel 200-300 mesh for separating the compound was purchased from Sinopharm Chemical Reagent Co., Ltd. The raw materials of the present invention can be purchased commercially, for example, the basic reagents were purchased from Sinopharm Chemical Reagent Co., Ltd., or prepared by methods known in the art, or prepared by the methods described in the present invention.

1. Synthesis of intermediates

The intermediates were synthesized using the synthetic methods described in Methods 1-7 above.

Methyl 3-bromo-2-bromomethyl benzoate:

3-Bromo-2-methylbenzoic acid (4.0 g, 17.46 mmol) was dissolved in 40 ml benzene, NBS (3.73 g, 20.95 mmol) and BPO (424 mg, 1.75 mmol) were added. the reaction mixture was heated to 95°C overnight. After completion of the reaction, the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 5.3 g of a colorless oily liquid of methyl 3-bromo-2-bromomethyl benzoate, yield 98%; ^1H NMR (400 MHz, CDCl ₃ ) δ 7.88 (dd, J=7.8, 1.3 Hz, 1H), 7.76 (dd, J=8.0, 1.3 Hz, 1H) , 7.22 (t, J=7.9 Hz, 1H), 5.12 (s, 2H), 3.95 (s, 3H).

3-(4-bromo-1-oxoisoindoline-2-)piperidine-2,6-dione:

Methyl 3-bromo-2-bromomethyl benzoate (5.3 g, 17.2 mmol) was dissolved in 50 ml of acetonitrile, then 3-aminopiperidine-2,6-dione hydrochloride (3.45 g, 21.0 mmol) was successfully added and triethylamine (3.18 ml, 22.88 mmol), and the reaction mixture was reacted at 80°C for 18 hours. After completion of the reaction, the solvent was removed under reduced pressure and the product was dispersed in a mixed solution of water-ethyl acetate-petroleum ether (volume ratio 2:1:1), and the resulting precipitate was filtered and dried to obtain 3-(4-bromo) under reduced pressure -1-oxoisoindoline-2-)piperidine-2,6-dione (3.35 g, 60%). ^1H NMR (400 MHz, DMSO) δ 11.03 (s, 1H), 7.87 (dd, J=7.9, 0.7 Hz, 1H), 7.79-7.75 (m, 1H ), 7.51 (t, J=7.7 Hz, 1H), 5.15 (dd, J=13.3, 5.1 Hz, 1H), 4.42 (d, J=17.6 Hz , 1H), 4.26 (d, J=17.6 Hz, 1H), 2.92 (ddd, J=17.5, 13.7, 5.4 Hz, 1H), 2.64-2, 55 (m, 1H), 2.55-2.39 (m, 1H), 2.02 (dtd, J=12.5, 5.2, 2.0 Hz, 1H). 3-(4-(5-hydroxypentyl-1-yne-1-)-1-oxoisoindoline-2-)piperidine-2,6-dione:

3-(4-bromo-1-oxoisoindolin-2-)piperidine-2,6-dione (1.0 g, 3.09 mmol), 4-pentin-1-ol (521 mg, 6.19 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (218 mg, 0.31 mmol) and CuI (118 mg, 0.62 mmol) were dissolved in 10 ml of anhydrous DM FA. The reaction solution was replaced with high-purity nitrogen 3 times, then 10 ml of triethylamine was added, and the reaction solution was replaced with high-purity nitrogen again. The reaction solution was heated to 60°C overnight. After completion of the reaction, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 1.03 g of the product 3-(4-(5-hydroxypentyl-1-yne-1-)-1-oxoisoindoline-2-)piperidine-2,6-dione, as a solid white substances, yield 100%; ¹ H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 7.71 (d, J=7.6 Hz, 0.8 Hz, 1H), 7.64 (dd, J=7, 6, 0.8 Hz, 1H), 7.53 (t, J=7.6 Hz, 1H), 5.15 (dd, J=13.3, 5.1 Hz, 1H), 4.57 ( t, J=5.1 Hz, 1H), 4.46 (d, J=17.8 Hz, 1H), 4.31 (d, J=17.8 Hz, 1H), 3.54 (dd, J=11.4, 6.1 Hz, 2H), 2.99-2.86 (m, 1H), 2.65-2.57 (m, 1H), 2.56-2.39 (m, 3H), 2.06-1.97 (m, 1H), 1.77-1.67 (m, 2H). 3-(4-(6-hydroxyhexyl-1-yne-1-)-1-oxoisoindoline-2-) piperidine-2,6-dione:

The raw materials used were 3-(4-bromo-1-oxoisoindoline-2-)piperidine-2,6-dione and 5-hexin-1-ol, and the preparation method was the same as for 3-(4-( 5-hydroxypenthyl-1-yne-1-)-1-oxoisoindoline-2-) piperidine-2,6-dione, yielding 665 mg of 3-(4-(6-hydroxyhexyl-1-yne-1-)- 1-oxoisoindoline-2-) piperidine-2,6-dione in the form of a light yellow solid, yield 84%; ^1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.70 (d, J=7.0 Hz, 1H), 7.63 (d, J=7.6 Hz, 1H) , 7.51 (t, J=7.6 Hz, 1H), 5.14 (dd, J=13.3, 5.1 Hz, 1H), 4.50-4.40 (m, 2H) , 4.30 (d, J=17.7 Hz, 1H), 3.44 (q, J=5.9 Hz, 2H), 2.91 (ddd, J=17.5, 13.7, 5.4 Hz, 1H), 2.64-2.55 (m, 1H), 2.50-2.40 (m, 3H), 2.01 (ddd, J=10.2, 5.0, 3.2 Hz, 1H), 1.58 (ddd, J=11.3, 6.4, 2.6 Hz, 4H).

3-(4-(5-hydroxypentyl)-1-oxoisoindoline-2-)piperidine-2,6-dione:

3-(4-(5-hydroxypentyl-1-yne-1-)-1-oxoisoindoline-2-)piperidine-2,6-dione (1.0 g, 3.09 mmol) was dissolved in 30 ml of tetrahydrofuran, to 10% Pd/C (200 mg) was added to the reaction solution and heated to 40° C. under hydrogen atmosphere (260 psi) for 7 hours. After completion of the reaction, the catalyst was removed by filtration. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1.02 g of 3-(4-(5-hydroxypentyl)-1-oxoisoindoline-2-)piperidine-2,6-dione as a white solid, yield 100%; ¹ H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.58-7.53 (m, 1H), 7.48-7.43 (m, 2H), 5.13 (dd , J=13.2, 5.2 Hz, 1H), 4.46 (d, J=17.1 Hz, 1H), 4.35 (t, J=5.1 Hz, 1H), 4.30 (d, J=17.1 Hz, 1H), 3.38 (dd, J=11.6, 6.4 Hz, 2H), 2.92 (ddd, J=17.4, 13.8, 5 ,6 Hz, 1H), 2.68-2.56 (m, 3H), 2.48-2.37 (m, 1H), 2.06-1.96 (m, 1H), 1.66- 1.54 (m, 2H), 1.45 (td, J=13.4, 6.5 Hz, 2H), 1.33 (dt, J=9.4, 7.5 Hz, 2H).

3-(4-(5-bromopentyl)-1-oxoisoindoline-2-)piperidine-2,6-dione:

3-(4-(5-hydroxypentyl)-1-oxoisoindoline-2-)piperidine-2,6-dione (500 mg, 1.513 mmol) and triphenylphosphine (794 mg, 3.036 mmol) were dissolved in 40 ml of anhydrous tetrahydrofuran. Carbon tetrabromide (1.506 g, 4.54 mmol) was added to the reaction solution, and the resulting mixture was reacted at room temperature for 1 hour. After completion of the reaction, the solvent was removed under reduced pressure and the resulting residue was purified by silica gel column chromatography to obtain 588 mg of 3-(4-(5-bromopentyl)-1-oxoisoindoline-2-)piperidine-2,6-dione as a white solid colors, yield 99%; ^1H NMR (500 MHz, DMSO) δ 11.01 (s, 1H), 7.62 (dd, J=11.8, 7.3 Hz, 1H), 7.56 (dd, J=6.5 , 4.0 Hz, 1H), 7.48-7.43 (m, 1H), 5.14 (dd, J=13.4, 5.2 Hz, 1H), 4.47 (d, J= 17.1 Hz, 1H), 4.31 (d, J=17.1 Hz, 1H), 3.54 (t, J=6.6 Hz, 2H), 2.98-2.87 (m, 1H), 2.63 (dd, J=22.8, 14.8 Hz, 3H), 2.43 (ddd, J=26.4, 13.4, 4.3 Hz, 1H), 2.06 -1.97 (m, 1H), 1.94-1.76 (m, 2H), 1.63 (dt, J=15.3, 7.6 Hz, 2H), 1.44 (dt, J =14.8, 7.5 Hz, 2H).

3-(4-(4-hydroxybutyl)-1-oxoisoindoline-2-)piperidine-2,6-dione:

3-(4-(4-hydroxybutyl-1-yne-)-1-oxoisoindoline-2-)piperidine-2,6-dione (0.74 g, 2.37 mmol) was added to a mixed solution of 30 ml of tetrahydrofuran and 10 ml of methanol, and Raney nickel was also added. The resulting mixture was reacted for 30 hours under a hydrogen atmosphere at 260 psi. inch. After completion of the reaction, the reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 0.75 g of 3-(4-(4-hydroxybutyl)-1-oxoisoindoline-2-)piperidine-2 ,6-dione, yield 100%; ^1H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 7.58-7.54 (m, 1H), 7.46 (d, J=4.3 Hz, 2H), 5, 14 (dd, J=13.3, 5.0 Hz, 1H), 4.46 (d, J=17.2 Hz, 1H), 4.41 (t, J=5.2 Hz, 1H), 4.30 (d, J=17.1 Hz, 1H), 3.42 (dd, J=11.7, 6.3 Hz, 2H), 3.14-3.04 (m, 1H), 2 .98-2.87 (m, 1H), 2.69-2.60 (m, 3H), 2.05-1.96 (m, 1H), 1.68-1.57 (m, 2H) , 1.50 1.42 (m, 2H), 1.17 (t, J=7.4 Hz, 1H). Electric sputter ionization mass spectroscopy (ESI-MS) [M+H] ⁺ m/z = 317.24.

3-(4-(3-hydroxypropyl-1-oxoisoindoline-2-)piperidine-2,6-dione:

The preparation method was the same as for 3-(4-(4-hydroxybutyl)-1-oxoisoindoline-2-)piperidine-2,6-dione; ¹ H NMR (400 MHz, DMSO) δ 10.96 (s, 1H), 7.56 (p, J=3.8 Hz, 1H), 7.46 (s, 2H), 5.13 (dd, J=13.3, 5.1 Hz, 1H), 4.46 (d, J=17.2 Hz, 1H), 4.39 (t, J=5.2 Hz, 1H), 4.30 ( d, J=17.2 Hz, 1H), 3.42 (dd, J=11.6, 6.3 Hz, 2H), 2.92 (ddd, J=17.5, 13.7, 4, 7 Hz, 1H), 2.69-2.56 (m, 3H), 2.48-2.36 (m, 1H), 2.01 (ddd, J=9.8, 4.9, 2, 9 Hz, 1H), 1.70-1.56 (m, 2H), 1.51-1.40 (m, 2H).

3-(4-(2-bromoethoxy)-1-oxoisoindoline-2-)piperidine-2,6-dione:

Step 1: Methyl 5-amino-4-(4-hydroxy-1-oxoisoindoline-2-)-5-oxopentanoate (200 mg, 0.68 mmol, 1.0 eq.) was dissolved in 10 ml anhydrous acetonitrile, 1 ,2-dibromoethane (643 mg, 3.42 mmol, 5.0 eq.) and anhydrous potassium carbonate (96 mg, 0.68 mmol, 1.0 eq.) was added, followed by vigorous stirring for 24 hours at 50 °C. After completion of the reaction, acetonitrile was separated by centrifugation and purified by column chromatography to obtain 100 mg of a white solid with a yield of 37%; ^1H NMR (400 MHz, DMSO) δ 7.61 (s, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.32 (d, J=7.3 Hz, 1H) , 7.25 (d, J=8.0 Hz, 1H), 7.20 (d, J=9.8 Hz, 1H), 4.74 (dd, J=10.4, 5.0 Hz, 1H), 4.55 (d, J=17.6 Hz, 1H), 4.51-4.43 (m, 2H), 4.39 (d, J=17.6 Hz, 1H), 3, 91-3.81 (m, 2H), 3.53 (d, J=14.0 Hz, 3H), 2.33-2.14 (m, 3H), 2.12-2.03 (m, 1H).

Step 2: Methyl 5-amino-4-(4-(2-bromoethoxy)-1-oxoisoindoline-2-)-5-oxopentanoate (100 mg, 0.25 mmol, 1.0 eq.) was dissolved in 20 ml anhydrous tetrahydrofuran and stirred at -78°C for 15 minutes. Potassium tert-butoxide (31 mg, 0.28 mmol, 1.1 eq) was added and the reaction was continued for 90 minutes. After completion of the reaction, 1 ml of 1N hydrochloric acid was added to stop the reaction at -78°C. The reaction system was gradually warmed to room temperature, the solvent was separated, and 90 mg of a white solid was obtained by column chromatography with a yield of 98%; ¹ H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 7.49 (t, J=7.8 Hz, 1H), 7.35 (d, J=7.4 Hz, 1H) , 7.27 (d, J=8.1 Hz, 1H), 5.12 (dd, J=13.3, 5.1 Hz, 1H), 4.47 (dt, J=8.1, 4 .9 Hz, 2H), 4.43-4.34 (m, 1H), 4.26 (d, J=17.4 Hz, 1H), 3.83 (t, J=5.3 Hz, 2H ), 2.90 (ddd, J=13.6, 12.4, 5.4 Hz, 1H), 2.58 (d, J=18.1 Hz, 1H), 2.49-2.40 ( m, 1H), 1.99 (s, 1H).

3-(4-(3-bromopropoxyl)-1-oxoisoindoline-2-)piperidine-2,6-dione:

1,2-dibromoethane was replaced by 1,3-dibromopropane, while the synthesis method was the same as for 3-(4-(2-bromoethoxy)-1-oxoisoindoline-2-)piperidine-2,6- dione to give 634 mg of 3-(4-(3-bromopromoxy)-1-oxoisoindoline-2-)piperidine-2,6-dione as a white solid, 95% yield; ^1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.49 (t, J=7.8 Hz, 1H), 7.32 (d, J=7.4 Hz, 1H) , 7.27 (d, J=8.0 Hz, 1H), 5.12 (dd, J=13.3, 5.0 Hz, 1H), 4.41 (d, J=17.5 Hz, 1H), 4.23 (dd, J=14.3, 8.4 Hz, 3H), 3.71 (t, J=6.6 Hz, 2H), 2.96-2.86 (m, 1H ), 2.58 (d, J=17.2 Hz, 1H), 2.47-2.38 (m, 2H), 2.32-2.22 (m, 2H), 2.03-1, 94 (m, 1H).

3-(4-(5-bromopentyloxy)-1-oxoisoindoline-2-)piperidine-2,6-dione:

1,2-dibromoethane was replaced by 1,5-dibromopentane, while the synthesis method was the same as for 3-(4-(2-bromoethoxy)-1-oxoisoindoline-2-)piperidine-2,6-dione to obtain 322 mg of 3-(4-(5-bromopentyloxy)-1-oxoisoindoline-2-)piperidine-2,6-dione as a white solid, 97% yield; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.00 (s, 1H), 7.48 (dd, J=7.6, 0.9 Hz, 1H), 7.43 (t, J=7, 7 Hz, 1H), 7.04-6.99 (m, 1H), 5.23 (dd, J=13.3, 5.1 Hz, 1H), 4.43 (d, J=16.5 Hz, 1H), 4.30 (d, J=16.5 Hz, 1H), 4.08 (t, J=6.2 Hz, 2H), 3.45 (t, J=6.7 Hz, 2H), 2.86 (ddd, J=23.2, 15.9, 4.1 Hz, 2H), 2.44-2.32 (m, 1H), 2.22 (dtd, J=10, 3, 5.2, 2.6 Hz, 1H), 1.99-1.90 (m, 2H), 1.89-1.79 (m, 2H), 1.71-1.60 (m, 2H).

3-(4-(6-bromohexyloxy)-1-oxoisoindoline-2-)piperidine-2,6-dione:

1,2-dibromoethane was replaced by 1,6-dibromohexane, while the synthesis method was the same as for 3-(4-(2-bromoethoxy)-1-oxoisoindoline-2-)piperidine-2,6- dione to give 474 mg of 3-(4-(6-bromohexyloxy)-1-oxoisoindoline-2-)piperidine-2,6-dione as a white solid, 95% yield; ¹ H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.30 (d, J=7.4 Hz, 1H) , 7.23 (d, J=8.1 Hz, 1H), 5.10 (dd, J=13.3, 5.1 Hz, 1H), 4.37 (d, J=17.4 Hz, 1H), 4.22 (d, J=17.4 Hz, 1H), 4.11 (t, J=6.3 Hz, 2H), 3.54 (t, J=6.7 Hz, 2H) , 2.99-2.84 (m, 1H), 2.58 (d, J=18.0 Hz, 1H), 2.45 (dd, J=13.1, 4.4 Hz, 1H), 1.99 (t, J=5.1 Hz, 1H), 1.89 1.68 (m, 4H), 1.46 (dd, J=7.1, 3.5 Hz, 4H).

Benzyl (S)-2-((tert-butoxycarbonyl) amino)-4-pentinoate:

L-propargylalanine protected with tert-butoxycarbonyl (3.0 g, 14.07 mmol), DMAP (172 mg, 1.41 mmol) and DIPEA (4.88 ml, 29.55 mmol) was dissolved in 150 ml anhydrous dichloromethane . The reaction solution was cooled to 0°C, and benzyl chloroformate (2.08 mL, 14.77 mmol) was added dropwise to the reaction solution. The resulting reaction solution was reacted at 0°C for 4 hours. After completion of the reaction, the reaction solution was washed with 1N aqueous potassium hydrogen sulfate, in turn, the organic phase was dried over anhydrous sodium sulfate, and then the reaction solution was filtered and concentrated under reduced pressure. The resulting residue was passed through silica gel column chromatography to obtain 3.321 g of the desired product as a colorless oily liquid, yield 78%.

Benzyl (2R)-2-tert-butoxycarbonylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)

-4-pentinoate:

Benzyl (S)-2 ((tert-butoxycarbonyl)amino)-4-pentinoate (3.18 g, 10.47 mmol), 3-(4-bromo-1-oxoisoindoline-2-) was added to a 100 mL reaction flask. )piperidine-2,6-dione (2.26 g, 6.98 mmol), bistriphenylphosphine palladium dichloride (491 mg, 0.70 mmol) and CuI (267 mg, 1.40 mmol), then the reaction system was replaced with nitrogen, under With nitrogen protection, anhydrous DMF (20 ml) and anhydrous triethylamine (20 ml) were added and the solution was heated to 60° C. to react overnight. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 3.64 g of benzyl (2R)-2-tert-butoxycarbonylamino-5-(2-(2,6-dioxopiperidine-3-)-1 -oxoisoindoline-4-)-4-pentinoate in the form of a whitish solid with a yield of 95%.

(2R)-2-tert-butoxycarbonylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)pentanoic acid:

Benzyl (2R)-2-tert-butoxycarbonylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-4-pentinoate (127 mg, 0.23 mmol) was dissolved in 50 ml of tetrahydrofuran, 10% Pd/C (50 mg) was added and the solution was reacted overnight under hydrogen conditions (at a pressure of 8 bar). After completion of the reaction, the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to obtain 107 mg of (27?)-2-tert-butoxycarbonylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4 -)pentanoic acid, yield 100%; ^1H NMR (400 MHz, DMSO) δ 12.43 (s, 1H), 10.99 (s, 1H), 7.57 (dd, J=6.5, 2.0 Hz, 1H), 7, 49-7.41 (m, 2H), 7.09 (d, J=7.8 Hz, 1H), 5.75 (s, 1H), 5.14 (ddd, J=13.3, 4, 9, 2.0 Hz, 1H), 4.46 (d, J=17.1 Hz, 1H), 4.30 (dd, J=17.2, 1.3 Hz, 1H), 3.97- 3.86 (m, 1H), 3.00-2.87 (m, 1H), 2.71-2.57 (m, 3H), 2.41 (ddd, J=26.4, 13.3 , 4.2 Hz, 1H), 2.09-1.91 (m, 1H), 1.78-1.56 (m, 4H), 1.37 (s, 9H).

2. Examples of synthesis:

The compounds were synthesized by the above methods 1-7.

Example 1: 3-(1-oxo-4-(5-(quinoline-4-oxy)pentyl)isoindoline-2-)piperidine-2,6-dione (1)

3-(4-(5-hydroxypentyl)-1-oxoisoindoline-2-)piperidine-2,6-dione (100 mg, 0.303 mmol, 1 eq.), 4-hydroxyquinoline (132 mg, 0.909 mmol, 3 eq. ) and triphenylphosphine (159 mg, 0.605 mmol, 2 eq.) were dissolved in 20 ml of anhydrous THF and diisopropyl azodicarboxylate (120 μl, 0.605 mmol, 2 eq.) was added under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was removed under reduced pressure. The resulting residue was separated by silica gel column chromatography and then purified by HPLC to obtain 52 mg of 3-(1-oxo-4-(5-(quinoline-4-oxy)pentyl)isoindoline-2-)piperidine-2,6- dione in the form of a white solid, yield 38%; ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 8.71 (d,J=5.2 Hz, 1H), 8.12-8.07 (m, 1H), 7, 93 (dd, J=8.4, 0.5 Hz, 1H), 7.73 (ddd, J=8.4, 6.9, 1.5 Hz, 1H), 7.57 (dd, J= 7.3, 1.3 Hz, 1H), 7.55-7.51 (m, 1H), 7.48 (dd, J=7.5, 1.4 Hz, 1H), 7.47-7 .42 (m, 1H), 7.01 (d, J=5.3 Hz, 1H), 5.13 (dd, J=13.3, 5.1 Hz, 1H), 4.47 (d, J=17.1 Hz, 1H), 4.32 (d, J=17.1 Hz, 1H), 4.26 (t, J=6.3 Hz, 2H), 2.91 (ddd, J= 17.6, 13.8, 5.3 Hz, 1H), 2.74-2.67 (m, 2H), 2.63-2.55 (m, 1H), 2.39 (ddd, J= 17.4, 13.1, 4.8 Hz, 1H), 2.01-1.88 (m, 3H), 1.79-1.68 (m, 2H), 1.63-1.52 ( m, 2H).

Example 2: 3-(1-oxo-4-(3-(quinoline-4-oxy)propyl)isoindoline-2-)piperidine-2,6-dione (2)

3-(4-(3-hydroxypropyl)-1-oxoisoindoline-2-)piperidine-2,6-dione (48 mg, 0.16 mmol), 4-hydroxyquinoline (70 mg, 0.48 mmol) and triphenylphosphine ( 84 mg, 0.32 mmol) was added to a 100 ml round bottom flask under a nitrogen atmosphere, 20 ml of tetrahydrofuran was added, and the mixture was vigorously stirred. Diisopropyl azodicarboxylate (65 mg, 0.32 mmol) was then added. After completion of the reaction, the solvent was separated by centrifugation and purified by HPLC to obtain 17.6 mg of product, 26% yield; ^1H NMR (400 MHz, DMSO) δ 10.96 (s, 1H), 9.10 (d, J=6.4 Hz, 1H), 8.26 (d, J=7.7 Hz, 1H) , 8.13 (d, J=8.4 Hz, 1H), 8.08-8.01 (m, 1H), 7.79 (t, J=11.3 Hz, 1H), 7.56 ( t, J=6.4 Hz, 2H), 7.46 (dd, J=10.5, 4.4 Hz, 2H), 5.11 (dd, J=13.3, 5.1 Hz, 1H ), 4.52 (t, J=5.9 Hz, 2H), 4.47 (d, J=17.1 Hz, 1H), 4.31 (d, J=17.1 Hz, 1H), 3.00-2.84 (m, 3H), 2.6 (m, 1H), 2.36-2.14 (m, 3H), 1.97-1.86 (m, 1H).

Example 3: 3-(1-oxo-4-(6-(quinoline-4-oxy)hexyl)isoindoline--2-)piperidine-2,6-dione (3)

3-(4-(5-hydroxypentyl)-1-oxoisoindoline-2-)piperidine-2,6-dione was replaced by 3-(4-(6-hydroxyhexyl)-1-oxoisoindoline-2-)piperidine-2, 6-dione, preparation method was the same as for 3-(1-oxo-4-(5-(quinoline-4-oxy)pentyl)isoindoline-2-)piperidine-2,6-dione, 47.2 mg , yield 50%; ^1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 8.72 (d, J=5.3 Hz, 1H), 8.14 (dd, J=8.3, 0.9 Hz, 1H), 7.97 7.91 (m, 1H), 7.74 (ddd, J=8.4, 6.9, 1.5 Hz, 1H), 7.56 (tdd, J=4 ,7, 3.9, 1.2 Hz, 2H), 7.48-7.40 (m, 2H), 7.02 (d, J=5.3 Hz, 1H), 5.13 (dd, J=13.2, 5.2 Hz, 1H), 4.46 (d, J=17.2 Hz, 1H), 4.30 (d, J=17.1 Hz, 1H), 4.25 ( t, J=6.3 Hz, 2H), 2.92 (ddd, J=17.5, 13.5, 5.5 Hz, 1H), 2.70-2.63 (m, 2H), 2 .59 (dd, J=16.3, 2.0 Hz, 1H), 2.41 (ddd, J=26.5, 13.4, 4.6 Hz, 1H), 2.05-1.95 (m, 1H), 1.92-1.83 (m, 2H), 1.71 1.62 (m, 2H), 1.61 1.51 (m, 2H), 1.44 (dt, J =15.9, 8.0 Hz, 2H).

Example 4: 3-(1-oxo-4-(3-(quinoline-4-oxy)propoxy)isoindoline-2-)piperidine-2,6-dione (4)

Step 1: 1,3-propanediol (5.0 g, 6.57 mmol) was dissolved in 60 ml of anhydrous tetrahydrofuran, sodium hydride (2.39 g, 5.97 mmol) was added in an ice bath and stirred for 30 minutes. Tert-butyldimethylchlorosilane (9.0 g, 5.97 mmol) was then added and the reaction was continued for 1 hour. After completion of the reaction, saturated ammonium chloride was added to stop the reaction, extracted with ethyl acetate, washed with saturated sodium chloride, dried, concentrated and purified by column chromatography to give a colorless oily liquid (10.06 g, 90%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.87-3.76 (m, 4H), 2.65 (t, J=5.2 Hz, 1H), 1.83-1.73 (m, 2H), 0.89 (s, 9H), 0.07 (s, 6H).

Step 2: Compound methyl 5-amino-4-(4-hydroxy-1-oxoisoindoline-2-)-5-oxopentanoate (100 mg, 0.34 mmol, 1.0 eq.) was added to a 100 mL round bottom flask and 3-tert-butyldimethylsiloxy-1-propanol (174 mg, 0.85 mmol, 2.5 eq.) and triphenylphosphine (178 mg, 0.68 mmol, 2 eq.) were added. The reaction system was replaced with nitrogen and 20 ml of anhydrous tetrahydrofuran was added. Diisopropyl azodicarboxylate (134 μL, 0.68 mmol, 2 eq) was added to the reaction system to allow the reaction to proceed at room temperature for 1 hour. After completion of the reaction, the solvent was separated by centrifugation, and the target product was obtained using column chromatography. Electric sputter ionization mass spectroscopy (ESI-MS) [M+H] ⁺ m/z = 465.60.

Step 3: The product obtained in the previous step was added to a 50 mL round bottom flask, 20 mL of tetrahydrofuran was added, and tetrabutylammonium fluoride (0.64 mL, 0.64 mmol) was added to react at room temperature overnight. After completion of the reaction, the solvent was separated under reduced pressure and the product was purified by column chromatography to obtain 211 mg of a white solid with a yield of 78%; ¹ H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.49 (t, J=7.8 Hz, 1H), 7.31 (d, J=7.2 Hz, 1H) , 7.25 (d, J=8.0 Hz, 1H), 5.12 (dd, J=13.3, 5.1 Hz, 1H), 4.59 (t, J=6.0 Hz, 1H), 4.38 (d, J=17.4 Hz, 1H), 4.22 (d, J=17.3 Hz, 1H), 4.19 (t, J=6.2 Hz, 2H) , 3.58 (dd, J=11.4, 6.1 Hz, 2H), 2.97-2.85 (m, 1H), 2.63-2.54 (m, 1H), 2.48 -2.38 (m, 1H), 2.05-1.93 (m, 1H), 1.89 (p, J=6.1 Hz, 2H). Electric sputter ionization mass spectroscopy (ESI-MS) [M+H] ⁺ m/z = 319.26

Step 4: Add 3-(4-(3-hydroxypropoxy)-1-oxoisoindoline-2-)piperidine-2,6-dione (50 mg, 0.16 mmol, 1.0 eq.) to a 100 mL round bottom flask. ), 4-hydroxyquinoline (68 mg, 0.47 mmol, 3 eq.) and triphenylphosphine (82 mg, 0.31 mmol, 2 eq.). This system was replaced with nitrogen and tetrahydrofuran (20 ml) was added. Diisopropyl azodicarboxylate (62 μL, 0.31 mmol, 2 eq.) was added to react at room temperature for 1 hour. After completion of the reaction, the solvent was removed under reduced pressure and purified by HPLC to give 27.6 mg of product in 39% yield; ¹ H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 9.13 (d, J=6.2 Hz, 1H), 8.37 (d, J=8.4 Hz, 1H) , 8.12 (d, J=8.4 Hz, 1H), 8.05 (t, J=7.7 Hz, 1H), 7.81 (t, J=7.7 Hz, 1H), 7 .54 (d, J=6.3 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.36-7.28 (m, 2H), 5.10 (dd, J=13.3, 5.0 Hz, 1H), 4.71 (t, J=5.8 Hz, 2H), 4.41 (t, J=5.8 Hz, 2H), 4.32 ( d, J=17.4 Hz, 1H), 4.17 (d, J=17.4 Hz, 1H), 2.99-2.84 (m, 1H), 2.62-2.53 (m , 1H), 2.48-2.39 (m, 2H), 2.29 (qd, J=13.4, 4.4 Hz, 1H), 1.99-1.89 (m, 1H). Electric sputter ionization mass spectroscopy (ESI-MS) [M+H] ⁺ m/z = 446.33.

Example 5: 3-(4-(5-(isoindoline-5-oxy)pentyl)-1-oxoisoindoline-2-)piperidine-2,6-dione (5)

4-Hydroxyquinoline was replaced by 5-hydroxyisoquinoline, and the preparation method was the same as for 3-(1-oxo-4-(5-(quinoline-4-oxy)pentyl)isoindoline-2-)piperidine-2. 6-dione, 26 mg, yield 38%; ^1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 9.30 (s, 1H), 8.49 (d, J=5.9 Hz, 1H), 7.92 (d, J=5.9 Hz, 1H), 7.67 (d, J=8.2 Hz, 1H), 7.63 -7.54 (m, 2H), 7.46 (dt, J=14.5 , 7.2 Hz, 2H), 7.24 (d, J=7.6 Hz, 1H), 5.13 (dd, J=13.3, 5.1 Hz, 1H), 4.47 (d , J=17.2 Hz, 1H), 4.32 (d, J=17.1 Hz, 1H), 4.20 (t, J=6.3 Hz, 2H), 2.92 (ddd, J =17.5, 13.8, 5.5 Hz, 1H), 2.71 (t, J=7.6 Hz, 2H), 2.64-2.55 (m, 1H), 2.40 ( qd, J=13.5, 4.5 Hz, 1H), 1.98 (ddd, J=10.5, 5.0, 2.4 Hz, 1H), 1.91 (dd, J=14, 5, 7.0 Hz, 2H), 1.78 1.68 (m, 2H), 1.63 1.53 (m, 2H).

Example 6: 3-(1-oxo-4-(4-(quinoline-4-oxy)butoxy)isoindoline-2-)piperidine-2,6-dione (6)

Step 1: 1,4-butanediol (1.0 g, 11.10 mmol, 1.1 eq.) was dissolved in 20 ml tetrahydrofuran, sodium hydride (0.40 g, 10.09 mmol, 1 eq.) was added to ice bath and stirred for 30 minutes. Tert-butyldimethylchlorosilane (1.52 g, 10.09 mmol, 1 eq) was then added and the reaction continued for 1 hour. After completion of the reaction, saturated ammonium chloride was added to stop the reaction, extracted with ethyl acetate, washed with saturated sodium chloride, dried, concentrated and purified by column chromatography to give 1.75 g of a colorless oily liquid, 78% yield. ^1H NMR (400 MHz, CDCl ₃ ) δ 9.71-3.60 (m, 4H), 2.59 (t, J=5.5 Hz, 1H), 1.70-1.58 (m, 4H), 0.90 (s, 9H), 0.07 (s, 6H).

Step 2: Compound methyl 5-amino-4-(4-hydroxy-1-oxoisoindoline-2-)-5-oxopentanoate (100 mg, 0.34 mmol, 1.0 eq.) was added to a 100 mL round bottom flask and 4-tert-butyldimethylsiloxy-1-butanol (174 mg, 0.85 mmol, 2.5 eq.) and triphenylphosphine (178 mg, 0.68 mmol, 2 eq.) were added. The reaction system was protected with nitrogen and tetrahydrofuran (20 ml) was added. Diisopropyl azodicarboxylate (134 μL, 0.68 mmol, 2 eq) was added to the reaction system to allow the reaction to proceed at room temperature for 1 hour. After completion of the reaction, the solvent was separated by centrifugation, and a mixture of product and triphenylphosphine oxide was obtained by purification by column chromatography;

Electric sputter ionization mass spectroscopy (ESI-MS) [M+H] ⁺ m/z = 479.42.

Step 3: The mixture obtained in the previous step was added to a 50 mL round bottom flask, 20 mL of tetrahydrofuran was added, and tetrabutylammonium fluoride (0.34 mL, 0.34 mmol, 1 eq.) was added to react at room temperature overnight . After completion of the reaction, the solvent was separated by centrifugation and purified by column chromatography to obtain 96 mg of product as a white solid, 85% yield; ¹ H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.30 (d, J=7.4 Hz, 1H) , 7.23 (d, J=8.1 Hz, 1H), 5.11 (dd, J=13.3, 5.1 Hz, 1H), 4.47 (t, J=5.1 Hz, 1H), 4.37 (d, J=17.4 Hz, 1H), 4.21 (d, J=17.4 Hz, 1H), 4.12 (t, J=6.4 Hz, 2H) , 3.45 (dd, J=11.6, 6.3 Hz, 2H), 2.96-2.86 (m, 1H), 2.62-2.54 (m, 1H), 2.48 -2.39 (m, 1H), 2.03-1.94 (m, 1H), 1.82-1.73 (m, 2H), 1.63-1.53 (m, 2H). Electric sputter ionization mass spectroscopy (ESI-MS) [M+H] ⁺ m/z = 333.27.

Step 4: Compound-(4-(4-hydroxybutoxy)-1-oxoisoindoline-2)piperidine-2,6-dione (50 mg, 0.15 mmol, 1.0 eq.) was added to a 100 ml round bottom flask. 4-hydroxyquinoline (65 mg, 0.45 mmol, 3 eq.) and triphenylphosphine (79 mg, 0.30 mmol, 2 eq.). This system was replaced with nitrogen and tetrahydrofuran (20 ml) was added. Diisopropyl azodicarboxylate (59 μL, 0.30 mmol, 2 equiv) was added to the reaction system and the reaction was carried out at room temperature for 1 hour. After completion of the reaction, the solvent was removed under reduced pressure. The residue was purified by HPLC to give 9.9 mg of product, 14% yield; ^1H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 9.16 (d, J=6.4 Hz, 1H), 8.32 (d, J=8.3 Hz, 1H) , 8.15-8.06 (m, 2H), 7.82 (t, J=7.6 Hz, 1H), 7.55 (d, J=6.6 Hz, 1H), 7.46 ( t, J=7.8 Hz, 1H), 7.27 (dd, J=14.2, 7.8 Hz, 2H), 5.10 (dd, J=13.5, 5.1 Hz, 1H ), 4.63 (t, J=5.9 Hz, 2H), 4.33 (d, J=17.4 Hz, 1H), 4.27 (t, J=5.9 Hz, 2H), 4.19 (d, J=17.4 Hz, 1H), 2.97-2.85 (m, 1H), 2.63-2.54 (m, 1H), 2.36 (dt, J= 13.4, 8.7 Hz, 1H), 2.18-2.09 (m, 2H), 2.09-1.92 (m, 3H). Electric sputter ionization mass spectroscopy (ESI-MS) [M+H] ⁺ m/z = 460.34.

Example 7: 3-(4-(5-((6-methyl-2-(trifluoromethyl)quinoline-4-)oxy)pentyl)-1-oxoisoindoline-2-)piperidine-2,6-dione (7)

4-hydroxyquinoline was replaced by 6-methyl-2-trifluoromethyl-4-hydroxyquinoline, and the preparation method was the same as for 3-(1-oxo-4-(5-(quinoline-4-oxy)pentyl)isoindoline -2-)piperidine-2,6-dione, 71 mg, yield 87%; ¹ H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.98 (d, J=8.6 Hz, 1H), 7.94 (s, 1H), 7.72 (dd, J=8.7, 2.0 Hz, 1H), 7.57 (dd, J=7.2, 1.2 Hz, 1H), 7.46 (dt, J=14.7, 6.8 Hz , 2H), 7.35 (s, 1H), 5.12 (dd, J=13.1, 5.1 Hz, 1H), 4.47 (d,J=17.1 Hz, 1H), 4 .38 (t, J=6.4 Hz, 2H), 4.32 (d, J=17.2 Hz, 1H), 2.91 (ddd, J=17.8, 13.6, 5.2 Hz, 1H), 2.75-2.68 (m, 2H), 2.62-2.55 (m, 1H), 2.52 (s, 3H), 2.39 (ddd, J=17, 4, 12.9, 4.0 Hz, 1H), 1.96 (ddd, J=18.1, 8.7, 4.9 Hz, 3H), 1.81-1.71 (m, 2H) , 1.64-1.54 (m, 2H).

Example 8: 3-(4-(4-((2-cyclopropylquinoline-4-)oxy)butoxy)-1-oxoisoindoline-2-)piperidine-2,6-dione (8)

Step 1: 2-cyclopropyl-4-hydroxyquinoline (120 mg, 0.65 mmol, 1 eq.), 1,4-butanediol (0.87 g, 9.72 mmol, 15 eq.), triphenylphosphine (2.56 g, 9.72 mmol, 15 eq.) was added under nitrogen protection, then 60 ml of tetrahydrofuran was added and mixed thoroughly. Diisopropyl azodicarboxylate (1.91 mL, 9.72 mmol, 15 eq.) was then added. The mixture was reacted at room temperature for 1 hour. After completion of the reaction, the solvent was removed under reduced pressure, and triphenylphosphine oxide and 1,4-butanediol were removed by purification using column chromatography. The resulting mixture was directly used in the next step without further purification. Electric sputter ionization mass spectroscopy (ESI-MS) [M+H] ⁺ m/z = 258.57.

Step 2: Under the protection of nitrogen, the mixture of methyl 5-amino-4-(4-hydroxy-1-oxoisoindoline-2-)-5-oxopentanoate (50 mg, 0.7 mmol, 1 eq.) and triphenylphosphine obtained in the previous step (89 mg, 0.34 mmol, 2 eq.) was added to a 100 mL round bottom flask, then 20 mL of tetrahydrofuran was added and mixed thoroughly. Diisopropyl azodicarboxylate (67 μL, 0.34 mmol, 2 eq.) was then added to allow the reaction to proceed at room temperature for one hour. After completion of the reaction, the solvent was separated by centrifugation and purified by column chromatography to obtain 77 mg of product as a light yellow oily liquid with a yield of 85%;

Electric sputter ionization mass spectroscopy (ESI-MS) [M+H] ⁺ m/z = 532.31.

Step 3: Methyl 5-amino-4-(4-(4-((2-cyclopropylquinoline-4-)oxy)butoxy)-1-oxoisoindoline-2-)-5-oxopentanoate (40 mg, 0.075 mmol, 1 eq. .) dissolved in 10 ml of anhydrous tetrahydrofuran, potassium tert-butoxide (8.5 mg, 0.075 mmol, 1 eq.) was added under ice bath conditions, and the reaction was recorded after 10 min. After completion of the reaction, 5 μl of formic acid was added to stop the reaction, the solvent was separated by centrifugation and purified by HPLC to obtain 21.5 mg of product as a white solid in 57% yield. ^1H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 8.20 (d, J=8.1 Hz, 1H), 8.08-7.97 (m, 2H), 7, 72 (t, J=6.9 Hz, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.30 (d, J=7.4 Hz, 1H), 7.25 ( d, J=8.2 Hz, 1H), 6.94 (s, 1H), 5.10 (dd, J=13.3, 5.1 Hz, 1H), 4.57 (t, J=6 ,0 Hz, 2H), 4.33 (d, J=17.4 Hz, 2H), 4.26 (t, J=6.0 Hz, 2H), 4.17 (s, 1H), 2, 99-2.84 (m, 1H), 2.63-2.53 (m, 1H), 2.48-2.42 (m, 1H), 2.41-2.28 (m, 1H), 2.15-2.07 (m, 2H), 2.05-1.94 (m, 3H), 1.48-1.40 (m, 4H). Electric sputter ionization mass spectroscopy (ESI-MS) [M+H] ⁺ m/z = 500.47.

Example 9: 3-(1-oxo-4-(5-(thieno[3,2-b]pyridine-7-oxy)pentyl)isoindoline-2-)piperidine-2,6-dione (9)

4-hydroxyquinoline was replaced by thieno[3,2-b]pyridine-7-phenol, the preparation method was the same as for 3-(1-oxo-4-(5-(quinoline-4-oxy)pentyl)isoindoline -2-)piperidine-2,6-dione, 31 mg, yield 44%; *H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 8.52 (d, J=5.4 Hz, 1H), 8.04 (d, J=5.4 Hz, 1H) , 7.56 (dd, J=6.9, 1.7 Hz, 1H), 7.51 (d, J=5.4 Hz, 1H), 7.49-7.40 (m, 2H), 7.00 (d, J=5.4 Hz, 1H), 5.13 (dd, J=13.4, 5.1 Hz, 1H), 4.47 (d, J=17.1 Hz, 1H ), 4.30 (dd, J=15.0, 8.5 Hz, 3H), 2.92 (ddd, J=17.0, 13.4, 5.3 Hz, 1H), 2.72- 2.65 (m, 2H), 2.63-2.56 (m, 1H), 2.40 (ddd, J=26.4, 13.5, 4.7 Hz, 1H), 1.98 ( ddd, J=8.7, 7.3, 4.8 Hz, 1H), 1.92-1.81 (m, 2H), 1.71 (dt, J=15.5, 7.9 Hz, 2H), 1.58-1.46 (m, 2H).

Example 10: 3-(4-(4-((2-ethylquinoline-4-)oxy)butoxy)-1-oxoisoindoline-2-)piperidine-2,6-dione (10)

Step 1: 1,4-Butanediol (10.0 g, 110.96 mmol, 5 eq.) was dissolved in 50 mL dichloromethane and TEA (4.63 mL, 33.29 mmol, 1.5 eq.) was added under conditions ice bath. Methyl methyl ether (1.69 mL, 1.79 mmol, 1 eq.) was then added dropwise and reacted at room temperature for 5 hours. After completion of the reaction, saturated ammonium chloride was added to stop it, and the mixture was extracted with dichloromethane, dried, concentrated and purified by column chromatography to obtain 1.10 g (37%) of a colorless liquid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.63 (s, 1H), 3.67 (s, 1H), 3.57 (t, J=5.9 Hz, 1H), 3.36 (s , 1H), 1.93 (s, 1H), 1.70-1.64 (m, 2H).

Step 2: 2-ethylquinoline-1-phenol (100 mg, 0.57 mmol, 1 eq.), 4-methoxymethoxy-1-butanol (1.16 g, 8.66 mmol, 15 eq.), triphenylphosphine (2 .27 g, 8.66 mmol, 15 eq.) was dissolved in 40 ml of tetrahydrofuran. diisopropyl azodicarboxylate (1.75 g, 8.66 mmol, 15 eq.) was added at room temperature and reacted at room temperature for 2 hours. After completion of the reaction, the solvent was separated by centrifugation and 147 mg of product was obtained by purification by thin layer chromatography (TLC) as a light yellow oily liquid, 90% yield; J=8.2 Hz, 1H), 7.65 (t, J=6.9 Hz, 1H), 7.45-7.40 (m, 1H), 6.63 (s, 1H), 4, 66 (s, 2H), 4.22 (t, J=6.3 Hz, 2H), 3.65 (t, J=6.3 Hz, 2H), 3.39 (s, 3H), 2, 94 (q, J=7.6 Hz, 2H), 2.05 (d, J=27.7 Hz, 2H), 1.92-1.86 (m, 2H), 1.38 (t, J =7.6 Hz, 3H). Electric sputter ionization mass spectroscopy (ESI-MS) [M+H] ⁺ m/z = 290.61.

Step 3: The compound 2-ethyl-4-(4-(methoxymethoxy)butoxy)quinoline (147 mg, 0.51 mmol) was transferred to a 100 ml round bottom flask, 10 ml of dioxane hydrochloride and 1 ml of methanol were added. The resulting mixed system was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was separated by centrifugation, a small amount of aminomethanol was added, and the solvent was separated by centrifugation. 75 mg of white solid was obtained by purification by column chromatography, yield 100%; Electric sputter ionization mass spectroscopy (ESI-MS) [M+H] ⁺ m/z = 246.65.

Step 4: Compound methyl 5-amino-4-(4-hydroxy-1-oxoisoindoline-2-)-5-oxopentanoate (50 mg, 0.17 mmol, 1 eq.), 2-ethyl-4-(4- hydroxybutoxy)quinoline (100 mg, 0.34 mmol, 2 equiv.), triphenylphosphine (90 mg, 0.34 mmol, 2 equiv.) were added to a 50 ml round bottom flask, 20 ml of tetrahydrofuran was added, and then diisopropyl azodicarboxylate (67) was added µl, 0.34 mmol, 2 eq.) to allow the reaction to proceed at room temperature for 2 hours. After completion of the reaction, the solvent was separated by centrifugation and the product was purified by TLC to obtain 72 mg of a white solid in 81% yield; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.14 (d, J=7.3 Hz, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.68 (t, J =8.4 Hz, 1H), 7.49-7.41 (m, 1H), 7.06 (dd, J=6.8, 2.1 Hz, 1H), 6.68 (s, 1H) , 6.29 (s, 1H), 5.32 (s, 1H), 4.92 (dd, J=8.8, 6.2 Hz, 1H), 4.44 (q, J=17.5 Hz, 1H), 4.32 (t, J=5.5 Hz, 1H), 4.23 (d, J=5.8 Hz, 1H), 3.67 (s, 1H), 2.98 ( q, J=7.6 Hz, 1H), 2.50-2.39 (m, 1H), 2.24-2.14 (m, 2H), 1.42 (t, J=7.6 Hz , 1H). Electric sputter ionization mass spectroscopy (ESI-MS) [M+H] ⁺ m/z = 520.35.

Step 5: Methyl 5-amino-4-(4-(4-((2-ethylquinoline-4-)oxy)butoxy)-1-oxoisoquinoline-2-)-5-oxopentanoate (72 mg, 0.14 mmol , 1.0 eq.) was dissolved in 10 ml of anhydrous tetrahydrofuran, potassium tert-butoxide (16 mg, 0.14 mmol, 1 eq.) was added under ice bath conditions, and the reaction was recorded after 10 min. After completion of the reaction, 5 μl of formic acid was added to stop the reaction, the solvent was separated by centrifugation and purified by HPLC to obtain 54 mg of product as a white solid in 79% yield. ^1H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 8.27 (d, J=8.2 Hz, 1H), 8.08 (dt, J=8.5, 7.6 Hz, 2H), 7.82-7.75 (m, 1H), 7.52 (s, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.28 (dd, J =17.6, 7.8 Hz, 2H), 5.11 (dd, J=13.3, 5.1 Hz, 1H), 4.62 (t, J=6.0 Hz, 2H), 4 .33 (d, J=17.4 Hz, 1H), 4.26 (t, J=6.0 Hz, 2H), 4.19 (d, J=17.4 Hz, 1H), 3.11 (q, J=7.6 Hz, 2H), 2.98-2.84 (m, 1H), 2.62-2.53 (m, 1H), 2.35 (qd, J=13.3 , 4.4 Hz, 1H), 2.19-2.09 (m, 2H), 2.08-1.92 (m, 4H), 1.40 (t,J=7.6 Hz, 3H) . Electric sputter ionization mass spectroscopy (ESI-MS) [M+H] ⁺ m/z = 488.43.

Example 11: 3-(1-oxo-4-(5-(quinoline-3-oxy)pentyl)isoindoline--2-)piperidine-2,6-dione (11)

4-hydroxyquinoline was replaced by 3-hydroxyquinoline, and the preparation method was the same as for 3-(1-oxo-4-(5-(quinoline-4-oxy)pentyl)isoindoline-2-)piperidine-2. 6-dione, 51 mg, yield 74%; ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 8.61 (d, J=2.9 Hz, 1H), 7.96-7.91 (m, 1H), 7, 89-7.84 (m, 1H), 7.76 (d, J=2.9 Hz, 1H), 7.60-7.52 (m, 3H), 7.51-7.43 (m, 2H), 5.13 (dd, J=13.3, 5.2 Hz, 1H), 4.48 (d, J=17.2 Hz, 1H), 4.33 (d, J=17.1 Hz, 1H), 4.15 (t, J=6.5 Hz, 2H), 2.92 (ddd, J=17.6, 13.9, 5.5 Hz, 1H), 2.73-2 .65 (m, 2Н), 2.58 (ddd, J=16.7, 4.2, 2.1 Hz, 1Н), 2.42 (ddd, J=18.3, 13.1, 4, 4 Hz, 1H), 2.03-1.95 (m, 1H), 1.91-1.81 (m, 2H), 1.76-1.66 (m, 2H), 1.53 (dt , J=15.3, 7.8 Hz, 2H).

Example 12: 3-(1-oxo-4-((5-(quinoline-4-oxy)pentyl)oxy)isoindoline-2-)piperidine-2,6-dione (12)

Step 1: 1,5-pentanediol (5.00 g, 48.00 mmol, 5 eq.) was dissolved in 20 mL dichloromethane and TEA (2.0 mL, 14.40 mmol, 1.5 eq.) was added under conditions ice bath. Bromomethyl methyl ether (0.75 mL, 9.6 mmol, 1 eq.) was then added dropwise and reacted at room temperature for 5 hours. After completion of the reaction, saturated ammonium chloride was added to stop it, extracted with dichloromethane, dried, concentrated and purified by column chromatography to obtain 0.57 g of a colorless liquid, 40% yield. ^1H NMR (400 MHz, CDCl ₃ ) δ 4.61 (s, 1H), 3.64 (t, J=6.5 Hz, 1H), 3.53 (t, J=6.5 Hz, 1H ), 3.35 (s, 1H), 1.64-1.58 (m, 1H), 1.54 (s, 1H), 1.47-1.41 (m, 1H).

Step 2: 5-(methoxymethoxy)-1-pentanol (296 mg, 2.04 mmol, 3.0 eq) was added to a 100 mL round bottom flask, 4-hydroxyquinoline (110 mg, 0.68 mmol, 1 eq) was added .) and triphenylphosphine (357 mg, 1.36 mmol, 2 eq.). This system was replaced with nitrogen and tetrahydrofuran (20 ml) was added. Diisopropyl azodicarboxylate (268 μL, 1.36 mmol, 2 eq.) was added to the reaction system. The reaction was carried out at room temperature for 1 hour. After completion of the reaction, the solvent was separated by centrifugation and purified by column chromatography to obtain 147 mg of product as a colorless oily liquid, 79% yield; ^1H NMR (400 MHz, CDCl ₃ ) δ 8.73 (d, J=5.2 Hz, 1H), 8.21 (dd, J=8.3, 1.0 Hz, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.69 (ddd, J=8.4, 6.9, 1.4 Hz, 1H), 7.49 (t, J=8.3 Hz, 1H), 6.71 (d, J=5.2 Hz, 1H), 4.63 (s, 2H), 4.20 (t, J=6.3 Hz, 2H), 3.58 (t, J=6.2 Hz, 2H), 3.37 (s, 3H), 2.01-1.96 (m, 2H), 1.76-1.63 (m, 4H).

Step 3: Compound 4-(5-(methoxymethoxy)pentoxy)quinoline (147 mg, 0.53 mmol) was transferred to a 100 ml round bottom flask, 10 ml of dioxane hydrochloride and 1 ml of methanol were added. The resulting mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was separated by centrifugation, a small amount of aminomethanol was added, and the solvent was separated by centrifugation. Column chromatography provided 124 mg (100%) of a white solid. Electric sputter ionization mass spectroscopy (ESI-MS) [M+H] ⁺ m/z=276.57.

Step 4: Compound Methyl 5-amino-4-(4-hydroxy-1-oxoisoindoline-2-)-5-oxopentanoate (50 mg, 0.17 mmol, 1 eq.), 5-(quinoline-4-oxo) -1-pentanol (100 mg, 0.34 mmol, 2 eq.), triphenylphosphine (90 mg, 0.34 mmol, 2 eq.) was added to a 50 mL round bottom flask, 20 mL of tetrahydrofuran was added, and then diisopropyl azodicarboxylate was added ( 67 µl, 0.34 mmol, 2 eq.) to allow the reaction to proceed at room temperature for 2 hours. After completion of the reaction, the solvent was separated by centrifugation and the product was purified by TLC to obtain 65 mg of white solid, 76% yield; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.74 (d, J=5.2 Hz, 1H), 8.23-8.18 (m, 1H), 8.02 (d, J=8, 4 Hz, 1H), 7.69 (t, J=8.4 Hz, 1H), 7.49 (dd, J=11.2, 4.0 Hz, 1H), 7.44-7.39 ( m, 2H), 7.01 (dq, J=7.9, 4.1 Hz, 1H), 6.75 (d, J=5.2 Hz, 1H), 6.40 (s, 1H), 5.43 (s, 1H), 4.91 (dd, J=8.8, 6.2 Hz, 1H), 4.41 (q, J=17.6 Hz, 2H), 4.25 (t , J=6.3 Hz, 2H), 4.11 (t, J=10.9, 2H), 3.63 (s, 3H), 2.42-1.81 (m, 10H). Electric sputter ionization mass spectroscopy (ESI-MS) [M+H] ⁺ m/z=506.83.

Step 5: Methyl 5-amino-4-(5-(4-((2-quinoline-4-)oxy)pentoxy)-1-oxoisoindoline-2-)-5-oxopentanoate (85 mg, 0.17 mmol, 1 eq.) was dissolved in 10 ml of anhydrous tetrahydrofuran, potassium tert-butoxide (17 mg, 0.17 mmol, 1 eq.) was added under ice bath conditions, and the reaction was recorded after 10 min. After completion of the reaction, 5 μl of formic acid was added to stop the reaction, the solvent was separated by centrifugation and purified by HPLC to obtain 29.6 mg of product as a white solid in 34% yield. ¹ H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 9.14 (d, J=6.5 Hz, 1H), 8.33 (d, J=8.4 Hz, 1H) , 8.14 (d, J=8.6 Hz, 1H), 8.07 (t, J=8.6 Hz, 1H), 7.82 (t, J=7.7 Hz, 1H), 7 .53 (d, J=6.5 Hz, 1H), 7.46 (t, J=7.8 Hz, 1H), 7.30 (d, J=7.3 Hz, 1H), 7.24 (d, J=8.1 Hz, 1H), 5.10 (dd, J=13.3, 5.1 Hz, 1H), 4.56 (t, J=6.3 Hz, 2H), 4 .35 (d, J=17.4 Hz, 1H), 4.25-4.14 (m, 3H), 3.00-2.84 (m, 1H), 2.56 (m, 1H), 2.38 (qd, J=13.1, 4.3 Hz, 1H), 2.06-1.80 (m, 5H), 1.78-1.67 (m, 2H). Electric sputter ionization mass spectroscopy (ESI-MS) [M+H] ⁺ m/z=506.31.

Example 13: 3-(1-oxo-4-(5-((2-(trifluoromethyl)quinoline-4-)oxy)pentyl)isoindoline-2-)piperidine-2,6-dione (13)

4-hydroxyquinoline was replaced by 2-trifluoromethyl-4-hydroxyquinoline, and the preparation method was the same as for 3-(1-oxo-4-(5-(quinoline-4-oxy)pentyl)isoindoline-2-)piperidine -2,6-dione, 37 mg with a yield of 47%; ^1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 8.19 (dd, J=8.3, 0.7 Hz, 1H), 8.08 (d, J=8.4 Hz, 1H), 7.89 (ddd, J=8.4, 6.9, 1.4 Hz, 1H), 7.75-7.69 (m, 1H), 7.57 (dd, J= 7.2, 1.1 Hz, 1H), 7.50-7.42 (m, 2H), 7.40 (s, 1H), 5.13 (dd, J=13.3, 5.1 Hz , 1H), 4.47 (d, "J=17.4 Hz, 1H), 4.40 (t, J=6.3 Hz, 2H), 4.32 (d, J=17.2 Hz, 1Н), 2.92 (ddd, J=17.4, 13.9, 5.9 Hz, 1Н), 2.76-2.67 (m, 2Н), 2.58 (ddd, J=6, 0, 3.3, 1.7 Hz, 1H), 2.39 (ddd, J=26.7, 13.7, 5.0 Hz, 1H), 2.02-1.89 (m, 3H) , 1.81-1.70 (m, 2H), 1.65-1.53 (m, 2H).

Example 14: 3-(1-oxo-4-((6-(quinoline-4-oxy)hexyl)oxyisoindoline-2-)piperidine-2,6-dione (14)

Step 1: 1,6-hexanediol (10.00 g, 84.62 mmol, 5 eq.) was dissolved in 20 mL dichloromethane and TEA (3.53 mL, 25.38 mmol, 1.5 eq.) was added in ice cold bath. Bromomethyl methyl ether (1.33 mL, 16.92 mmol, 1 eq.) was then added dropwise and reacted at room temperature for 5 hours. After completion of the reaction, saturated ammonium chloride was added to stop it, extracted with dichloromethane, dried, concentrated and purified by column chromatography to obtain 1.11 g of a colorless liquid, 41% yield. ^1H NMR (400 MHz, CDCl ₃ ) δ 4.61 (s, 2H), 3.63 (t,J=6.6 Hz, 1H), 3.51 (t,J=6.6 Hz, 1H ), 3.35 (s, 1H), 1.63-1.53 (m, 2H), 1.51 (s, 1H), 1.43-1.34 (m, 2H).

Step 2: 6-(methoxymethoxy)-1-hexanol (180 mg, 1.24 mmol, 2.0 eq.) was added to a 100 mL round bottom flask, then 4-hydroxyquinoline (100 mg, 0.62 mmol, 1 eq.), and triphenylphosphine (330 mg, 1.24 mmol, 2 eq.). This system was replaced with nitrogen and tetrahydrofuran (20 ml) was added. Diisopropyl azodicarboxylate (207 μL, 1.24 mmol, 2 eq.) was added to the reaction system to allow the reaction to proceed at room temperature for 1 hour. After completion of the reaction, the solvent was separated by centrifugation and purified by column chromatography to obtain 140 mg of product as a colorless oily liquid, 78% yield; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.75 (d, J=5.2 Hz, 1H), 8.23 (d, J=8.3 Hz, 1H), 8.04 (d, J =8.5 Hz, 1H), 7.72 (d, J=8.1 Hz, 1H), 7.51 (t, J=8.3 Hz 1H), 6.73 (d, J=5, 2 Hz, 1H), 4.65 (s, 2H), 4.21 (t, J=6.3 Hz, 2H), 3.57(t, J=8.1 Hz 2H), 3.39 ( s, 3H), 2.02-1.93 (m, 3H), 1.71-1.49 (m, 6H). [M+H] ⁺ m/z=290.39.

Step 3: Compound 4-(6-(methoxymethoxy)hexyloxy)quinoline (140 mg, 0.48 mmol) was transferred to a 100 ml round bottom flask and 10 ml of dioxane hydrochloride and 1 ml of methanol were added. The resulting mixed system was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was separated by centrifugation, a small amount of aminomethanol was added, and the solvent was separated by centrifugation. 118 mg (100%) of a white solid was obtained by purification by column chromatography, yield 100%; ^1H NMR (400 MHz, CDCl ₃ ) δ 8.72 (d, J=5.2 Hz, 1H), 8.21 (dd, J=8.3, 0.8 Hz, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.72-7.66 (m, 1H), 7.53-7.47 (m, 1H), 6.71 (d, J=5.2 Hz, 1H), 4.18 (t, J=6.4 Hz, 2H), 3.69 (t, J=6.5 Hz, 2H), 1.95 (dd, J=14.5, 6 .7 Hz, 2H), 1.62 (qd, J=14.5, 7.0 Hz, 4H), 1.54-1.45 (m, 2H). [M+H] ⁺ m/z=246.72.

Step 4: Compound Methyl 5-amino-4-(4-hydroxy-1-oxoisoindoline-2-)-5-oxopentanoate (50 mg, 0.17 mmol, 1 eq.), 5-(quinoline-4-oxy) -1-hexanol (83 mg, 0.34 mmol, 2 equiv.), triphenylphosphine (90 mg, 0.34 mmol, 2 equiv.) was added to a 50 ml round bottom flask, 20 ml of tetrahydrofuran was added, diisopropyl azodicarboxylate (67 µl, 0.34 mmol, 2 eq.) to allow the reaction to proceed at room temperature for 2 hours. After completion of the reaction, the solvent was separated by centrifugation and the product was purified by TLC to obtain 63 mg of white solid, 71% yield; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.73 (d, J=5.2 Hz, 1H), 8.20 (d, J=8.3 Hz, 1H), 8.01 (d, J =8.4 Hz, 1H), 7.68 (t, J=7.0 Hz, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.39 (d, J=1 ,1 Hz, 1H), 6.98 (p, J=4.0 Hz, 1H), 6.73 (d, J=5.2 Hz, 1H), 6.54 (s, 1H), 5, 61 (s, 1H), 4.92 (dd, J=8.8, 6.1 Hz, 1H), 4.40 (dd, J=38.8, 17.6 Hz, 1H), 4.22 (t, J=6.3 Hz, 1H), 4.11-4.02 (m, 1H), 3.62 (s, 1H), 2.46-2.27 (m, 1H), 2, 22-2.12 (m, 1H), 2.05-1.96 (m, 1H), 1.93-1.82 (m, 1H), 1.70-1.66 (m, 2H). [M+H] ⁺ m/z=520.35.

Step 5: Methyl 5-amino-5-oxo-4-(1-oxo-4-((6-(quinoline-4-oxy)hexyl)oxy)isoindoline-2-)oxopentanoate (63 mg, 0.19 mmol , 1.0 eq.) was dissolved in 10 ml of anhydrous tetrahydrofuran, potassium tert-butoxide (22 mg, 0.19 mmol, 1 eq.) was added under ice bath conditions, and the reaction was recorded after 10 min. After completion of the reaction, 5 μl of formic acid was added to stop the reaction, the solvent was separated by centrifugation and purified by HPLC to obtain 42 mg of product as a white solid in 45% yield. ^1H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 9.15 (d, J=6.5 Hz, 1H), 8.34 (d, J=8.4 Hz, 1H) , 8.15 (d, J=8.6 Hz, 1H), 8.09 (t, J=8.4 Hz, 1H), 7.83 (t, J=8.4 Hz, 1H), 7 .54 (d, J=6.6 Hz, 1H), 7.45 (t, J=7.8 Hz, 1H), 7.28 (d, J=7.3 Hz, 1H), 7.22 (d, J=8.1 Hz, 1H), 5.10 (dd, J=13.2, 5.1 Hz, 1H), 4.55 (t, J=6.3 Hz, 2H), 4 .34 (d, J=17.4 Hz, 1H), 4.21 (d, J=17.4 Hz, 1H), 4.14 (t, J=6.3 Hz, 2H), 2.97 -2.84 (m, 1H), 2.61-2.53 (m, 1H), 2.41 (qd, J=13.3, 4.5 Hz, 1H), 2.03-1.91 (m, 3H), 1.86-1.72 (m, 2H), 1.67-1.52 (m, 4H). Electric sputter ionization mass spectroscopy (ESI-MS) [M+H] ⁺ m/z=488.76.

Example 15: 3-(1-oxo-4-(4-(quinoline-4-oxy)butyl)isoindoline-2-)piperidine-2,6-dione (15)

3-(4-(4-hydroxybutyl)-1-oxoisoindoline-2-)piperidine-2,6-dione (50 mg, 0.16 mmol), 4-hydroxyquinoline (70 mg, 0.48 mmol) and triphenylphosphine ( 84 mg, 0.32 mmol) was added to a 100 ml round bottom flask, 20 ml of anhydrous tetrahydrofuran was added under nitrogen, the reaction system was stirred until it became homogeneous, and then diisopropyl azodicarboxylate (65 mg, 0.32 mmol) was added ) and stirred at room temperature for 30 minutes. After completion of the reaction, the solvent was removed under reduced pressure and the residue was separated by HPLC to obtain 21.7 mg of product, 31% yield; ^1H NMR (400 MHz, DMSO) δ 11.04 (s, 1H), 9.19 (d, J=6.4 Hz, 1H), 8.36 (d, J=8.4 Hz, 1H) , 8.21-8.06 (m, 2H), 7.88 (t, J=7.4 Hz, 1H), 7.60-7.44 (m„ 4H), 5.15 (dd, J =13.3, 4.9 Hz, 1H), 4.59 (t, J=5.8 Hz, 2H), 4.48 (d, J=17.2 Hz, 1H), 4.32 (d , J=17.1 Hz, 1H), 3.00-2.87 (m, 1H), 2.86-2.71 (m, 2H), 2.54 (s, 2H), 2.38- 2.26 (m, 1H), 2.05-1.82 (m, 5H).

Example 16: 3-(4-(5-morpholinepentyl)-1-oxoisoindoline-2-)piperidine-2,6-dione (16)

Compound 3-(4-(5-bromopentyl)-1-oxoisoindoline-2-)piperidine-2,6-dione (78 mg, 0.198 mmol, 1 eq.) and morpholine (34 mg, 0.396 mmol, 2 eq.) dissolved in 5 ml of anhydrous DMF, potassium iodide (50 mg, 0.297 mmol, 2 eq.) was added with stirring at room temperature, and the resulting reaction solution was stirred overnight at room temperature. After completion of the reaction, the resulting reaction solution was directly separated by HPLC to obtain 13.4 mg of 3-(4-(5-morpholinepentyl)-1-oxoisoindoline-2-)piperidine-2,6-dione as a white solid, yield 17%; ^1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.59-7.53 (m, 1H)5 7.45 (dd, J=6.2, 2.5 Hz, 2H ), 5.13 (dd, J=13.3, 5.1 Hz, 1H), 4.46 (d, J=17.1 Hz, 1H), 4.30 (d, J=17.1 Hz , 1H), 3.59-3.50 (m, 4H), 2.98-2.86 (m, 1H), 2.67-2.56 (m, 3H), 2.42 (ddd, J =12.6, 9.7, 6.9 Hz, 1H), 2.31 (s, 4H), 2.28-2.21 (m, 2H), 2.06-1.96 (m, 1H ), 1.61 (dt, J=15.3, 7.5 Hz, 2H), 1.51-1.39 (m, 2H), 1.32 (dt, J=14.9, 7.3 Hz, 2H).

Example 17: 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione (17)

The compound 3-(4-(5-bromopentyl)-1-oxoisoindoline-2-)piperidine-2,6-dione (50 mg, 0.127 mmol) was dissolved in 3 ml of anhydrous dimethyl sulfoxide, 2-phenylpyrroline (28 mg, 0.193 mmol) and triethylamine (10 μL, 0.386 mmol) with stirring at room temperature and stirred at room temperature for 24 hours. The reaction was monitored to completion using LC-MS. The product was directly separated by HPLC to obtain 30.5 mg of a white solid, 52% yield; ^1H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 7.55 (d, J=7.3 Hz, 1H), 7.44 (t, J=7.4 Hz, 1H) , 7.38 (d, J=7.4 Hz, 1H), 7.35-7.26 (m, 4H), 7.22 (t, J=6.5 Hz, 1H), 5.13 ( dd, J=13.3, 5.1 Hz, 1H), 4.42 (dd, J=17.2, 3.9 Hz, 1H), 4.26 (d,J=17.1 Hz, 1H ), 3.31-3.19 (m, 2H), 2.98-2.87 (m, 1H), 2.69-2.31 (m, 15H), 2.24-1.94 (m , 4H), 1.79 (ddd, J=19.8, 16.0, 8.8 Hz, 2H), 1.61-1.36 (m, 5H), 1.35-1.14 (m , 2H).

Example 18: 3-(1-oxo-4-(5-(4-phenylpiperazine-1-)pentyl)indoline-2-)piperidine-2,6-dione (18)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 22.4 mg, yield 37%; ^1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.60-7.54 (m, 1H), 7.50-7.41 (m, 2H), 7.20 (dd , J=8.5, 7.4 Hz, 2H), 6.91 (d,J=8.0 Hz, 2H), 6.76 (t, J=7.2 Hz, 1H), 5.14 (dd, J=13.3, 5.1 Hz, 1H), 4.47 (d, J=17.2 Hz, 1H), 4.31 (d, J=17.1 Hz, 1H), 3 ,15-3.05 (m, 4H), 2.92 (ddd, J=17.6, 13.7, 5.4 Hz, 1H), 2.69-2.57 (m, 3H), 2 .57-2.51 (m, 4H), 2.43 (dd, J=13.1, 4.3 Hz, 1H), 2.38-2.30 (m, 2H), 2.06-1 .95 (m, 1H), 1.64 (dt, J=15.2, 7.6 Hz, 2H), 1.52 (dt, J=14.8, 7.6 Hz, 2H), 1, 41-1.28 (m, 2H).

Example 19: 3-(4-(5-(4-(2-methoxyphenyl)piperazine-1-)pentyl)-1-oxoindoline-2-)piperidine-2,6-dione (19)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 26.3 mg, yield 41%; ¹ H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 7.56 (dt, J=7.8, 3.9 Hz, 1H), 7.50-7.42 (m, 2H ), 6.97-6.90 (m, 2H), 6.87 (d, J=3.8 Hz, 2H), 5.14 (dd, J=13.3, 5.1 Hz, 1H) , 4.47 (d, J=17.2 Hz, 1H), 4.31 (d, J=17.2 Hz, 1H), 3.76 (s, 3H), 3.03-2.85 ( m, 5H), 2.70-2.52 (m, 5H), 2.48-2.24 (m, 4H), 2.05-1.96 (m, 1H), 1.68-1, 58 (m, 2H), 1.56-1.46 (m, 2H), 1.40-1.18 (m, 3H).

Example 20: 3-(1-oxo-4-(5-(4-phenylpiperidine-1-)pentyl)indoline-2-)piperidine-2,6-dione (20)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 15.6 mg, yield 26%; ^1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 8.25 (s, 1H), 7.61-7.54 (m, 1H), 7.51-7.42 (m , 2H), 7.33-7.16 (m, 5H), 5.14 (dd, J=13.3, 5.1 Hz, 1H), 4.47 (d, J=17.2 Hz, 1H), 4.31 (d, J=17.1 Hz, 1H), 3.09 (d, J=11.3 Hz, 2H), 2.99-2.86 (m, 1H), 2, 71-2.56 (m, 3H), 2.53-2.36 (m, 4H), 2.22 (dd, J=11.5, 9.7 Hz, 2H), 2.01 (ddd, J=10.2, 5.0, 3.0 Hz, 1H), 1.83-1.48 (m, 8H), 1.41-1.26 (m, 2H).

Example 21: 3-(4-(4-(4-(2,3-dichlorophenyl)piperazine-1-)butyl)-1-oxoisoin oline-2-)piperidine-2,6-dione (21)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 30.9 mg, yield 33%; ^1H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 8.15 (s, 1H), 7.61-7.55 (m, 1H), 7.50-7.45 (m , 2H), 7.34-7.27 (m, 2H), 7.17-7.10 (m, 1H), 5.15 (dd, J=13.3, 5.2 Hz, 1H), 4.48 (d, J=17.2 Hz, 1H), 4.33 (d, J=17.2 Hz, 1H), 3.04-2.86 (m, 5H), 2.68 (t , J=7.6 Hz, 2H), 2.65-2.53 (m, 5H), 2.47-2.35 (m, 3H), 2.07-1.98 (m, 1H), 1.71-1.59 (m, 2H), 1.52 (dt, J=14.2, 7.1 Hz, 2H).

Example 22: 3-(4-(5-(4-(6-fluorobenzo[d]isoxazole-3-)piperidine-1-)pentyl)-l-oxoisoindoline-2-)piperidine-2,6-dione (22 )

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 20.4 mg, yield thirty%; *H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 8.17 (s, 1H), 8.00 (dd, J=8.7, 5.3 Hz, 1H), 7, 69 (dd, J=9.1, 2.1 Hz, 1H), 7.56 (dt, J=7.7, 3.9 Hz, 1H), 7.51-7.43 (m, 2H) , 7.28 (td, J=9.1, 2.1 Hz, 1H), 5.14 (dd, J=13.3, 5.1 Hz, 1H), 4.47 (d, J=17 ,2 Hz, 1H), 4.31 (d,J=17.1 Hz, 1H), 3.23-3.12 (m, 1H), 3.05 (d, J=11.6 Hz, 2H ), 2.93 (ddd, J=17.7, 13.8, 5.3 Hz, 1H), 2.71-2.55 (m, 3H), 2.47-2.35 (m, 3H ), 2.23 (t, J=11.0 Hz, 2H), 2.09-1.97 (m, 3H), 1.93-1.78 (m, 2H), 1.70-1, 59 (m, 2H), 1.58-1.48 (m, 2H), 1.41-1.30 (m, 2H).

Example 23: 3-(1-oxo-4-(5-(4-(3-trifluoromethylphenyl)piperazine-1-)pentyl)isoindoline-2-)piperidine-2,6-dione (23)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 25.5 mg, yield thirty%; ^1H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 7.57 (dd, J=5.0, 2.0 Hz, 1H), 7.49-7.44 (m, 2H ), 7.41 (t, J=8.1 Hz, 1H), 7.21 (dd, J=8.6, 2.1 Hz, 1H), 7.15 (s, 1H), 7.06 (d, J=7.4 Hz, 1H), 5.14 (dd, J=13.2, 5.3 Hz, 1H), 4.47 (d, J=17.2 Hz, 1H), 4 .31 (d, J=17.0 Hz, 1H), 3.28 (d, J=48.8 Hz, 7H), 2.98-2.87 (m, 1H), 2.63 (dt, J=22.0, 15.0 Hz, 4H), 2.46-2.30 (m, 3H), 2.05-1.95 (m, 1H), 1.70-1.58 (m, 2H), 1.52 (dt, J=9.8, 6.2 Hz, 2H), 1.41-1.28 (m, 2H).

Example 24: 3-(1-oxo-4-(5-(4-(quinoline-4-)piperazine-1-)pentyl)isoindoline-2-)piperidine-2,6-dione (24)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 16.2 mg, yield 24%; ^1H NMR (400 MHz, DMSO) δ 11.03 (s, 1H), 8.69 (d, J=4.9 Hz, 1H), 8.16 (s, 2H), 8.01 (d, J=8.1 Hz, 1H), 7.95 (d, J=8.3 Hz, 1H), 7.73-7.66 (m, 1H), 7.60-7.52 (m, 2H ), 7.51-7.44 (m, 2H), 6.98 (d, J=5.0 Hz, 1H), 5.15 (dd, J=13.3, 5.0 Hz, 1H) , 4.49 (d, J=17.2 Hz, 1H), 4.32 (d, J=17.2 Hz, 1H), 3.24-3.09 (m, 4H), 3.00- 2.88 (m, 1H), 2.73-2.57 (m, 6H), 2.48-2.38 (m, 3H), 2.06-1.97 (m, 1H), 1, 66 (dt, J=15.3, 7.7 Hz, 2H), 1.60-1.49 (m, 2H), 1.44-1.32 (m, 2H).

Example 25: (S)-3-(4-(3-(4-(2,3-dichlorophenyl)piperazine-1-)propoxy)-1-oxoisoindoline-2-)-3-methylpiperidine-2,6-dione (25)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, and 15 mg of the final product was obtained as a white solid, yield 27%; ^1H NMR (400 MHz, DMSO) δ 10.87 (s, 1H), 7.46 (t, J=7.8 Hz, 1H), 7.34-7.11 (m, 5H), 4, 65 (d, J=17.5 Hz, 1H), 4.54 (d, J=17.7 Hz, 1H), 4.19 (t, J=5.9 Hz, 2H), 3.00 ( s, 3H), 2.67 (ddd, J=51.9, 30.3, 22.3 Hz, 7H), 2.00-1.83 (m, 3H), 1.70 (s, 3H) .

Example 26: 3-(4-(5-(4-(2,3-dichlorophenyl)piperazine-1-)pentyl)-1-oxoisoindoline-2-)piperidine-2,6-dione (26)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 29.0 mg, yield 42%; ^1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 8.16 (s, 1H), 7.60-7.53 (m, 1H), 7.49-7.42 (m , 2H), 7.33-7.26 (m, 2H), 7.16-7.10 (m, 1H), 5.75 (s, 1H), 5.14 (dd, J=13.3 , 5.1 Hz, 1H), 4.47 (d, J=17.2 Hz, 1H), 4.31 (d, J=17.2 Hz, 1H), 3.01-2.86 (m , 5H), 2.69-2.63 (m, 2H), 2.58 (s, 1H), 2.53 (d, J=6.6 Hz, 4H), 2.47-2.38 ( m, 1H), 2.37-2.29 (m, 2H), 2.06-1.96 (m, 1H), 1.63 (dt, J=15.3, 7.8 Hz, 2H) , 1.57-1.43 (m, 2H), 1.40-1.29 (m, 2H).

Example 27: (S)-4-(3-(4-(2,3-dichlorophenyl)piperazine-1-)propoxy)-2-(3-methyl-2,6-dioxopiperidin-3-)isoindoline-1, 3-dione (27)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, and 25 mg of the final product was obtained as a white solid, yield 45%; ^1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.78 (t, J=7.9 Hz, 1H), 7.50 (d, J=8.5 Hz, 1H) , 7.37 (d, J=7.2 Hz, 1H), 7.33-7.27 (m, 2H), 7.14 (dd, J=5.8, 3.6 Hz, 1H), 4.24 (t, J=6.0 Hz, 2H), 2.98 (s, 4H), 2.75-2.51 (m, 9H), 2.08 1.91 (m, 3H), 1.86 (d, J=6.1 Hz, 3H).

Example 28: 3-(1-oxo-4-(4-oxo-4-(4-phenylpiperazine-1-)butoxy)isoindoline-2-)piperidine-2,6-dione (28)

The synthesis method was the same as for N-(3-chloro-4-methylphenyl)-4-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-oxy)butanamide, and 26 mg of final product was obtained as a white solid, yield 56%; ^1H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.30 (d, J=7.5 Hz, 1H) , 7.23 (dd, J=15.1, 7.6 Hz, 3H), 6.93 (d, J=8.0 Hz, 2H), 6.80 (t, J=7.2 Hz, 1H), 5.11 (dd, J=13.3, 5.1 Hz, 1H), 4.40 (d, J=17.4 Hz, 1H), 4.24 (d, J=17.4 Hz, 1H), 4.16 (t, J=6.3 Hz, 2H), 3.60 (d, J=4.6 Hz, 4H), 3.10 (dd, J=9.7, 4 ,7 Hz, 4H), 2.99-2.85 (m, 1H), 2.56 (dd, J=16.8, 9.9 Hz, 3H), 2.47-2.37 (m, 1H), 2.06-1.93 (m, 3H).

Example 29: 3-(4-(4-(4-(2,3-dichlorophenyl)piperazine-1-)-4-oxobutoxy)-1-oxoisoindoline-2-)piperidine-2,6-dione (29)

The synthesis method was the same as for N-(3-chloro-4-methylphenyl)-4-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-oxy)butanamide, and 21 mg of final product was obtained as a white solid, yield 26%; ^1H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.37-7.28 (m, 3H), 7, 25 (d, J=8.1 Hz, 1H), 7.13-7.07 (m, 1H), 5.11 (dd, J=13.3, 5.1 Hz, 1H), 4.40 (d, J=17.4 Hz, 1H), 4.25 (d, J=17.4 Hz, 1H), 4.16 (t, J=6.3 Hz, 2H), 3.62 (d , J=3.6 Hz, 4H), 2.91 (td, J=14.2, 7.7 Hz, 5H), 2.64-2.53 (m, 3H), 2.48-2, 35 (m, 1H), 2.06-1.94 (m, 3H).

Example 30: 3-(1-oxo-4-((5-oxo-5-(4-phenylpiperazine-1-)pentyloxy)isoindoline-2-)piperidine-2,6-dione (30)

The synthesis method was the same as for N-(3-chloro-4-methylphenyl)-4-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-oxy)butanamide, and 26 mg of final product was obtained as a white solid, yield 37%; ¹ H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.31 (d, J=7.4 Hz, 1H) , 7.27-7.16 (m, 3H), 6.95 (d, J=7.9 Hz, 2H), 6.81 (t, J=7.3 Hz, 1H), 5.10 ( dd, J=13.3, 5.1 Hz, 1H), 4.38 (d, J=17.4 Hz, 1H), 4.23 (d, J=17.4 Hz, 1H), 4, 15 (t, J=6.2 Hz, 2H), 3.65-3.56 (m, 4H), 3.19-3.04 (m, 4H), 2.98-2.85 (m, 1H), 2.57 (d, J=18.5 Hz, 1H), 2.50-2.37 (m, 4H), 2.04-1.93 (m, 1H), 1.74 (ddd , J=21.7, 14.2, 6.9 Hz, 4H).

Example 31: 3-(4-((5-(4-(2,3-dichlorophenyl)piperazine-1-)-5-oxopentyl)oxy)-1-oxopentyl-2-)piperidine-2,6-dione ( 31)

The synthesis method was the same as for N-(3-chloro-4-methylphenyl)-4-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)butanamide, 20 mg of the final product was obtained as a white solid, yield 25%; ¹ H NMR (400 MHz, DMSO) δ 10.96 (s, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.37-7.27 (m, 3H), 7, 25 (d, J=8.1 Hz, 1H), 7.12 (dd, J=6.3, 3.3 Hz, 1H), 5.10 (dd, J=13.3, 5.1 Hz , 1H), 4.37 (d, J=17.4 Hz, 1H), 4.23 (d, J=17.3 Hz, 1H), 4.15 (t, J=6.2 Hz, 2H ), 3.60 (d, J=4.6 Hz, 4H), 3.00-2.81 (m, 5H), 2.56 (d, J=18.6 Hz, 1H), 2.49 -2.36 (m, 4H), 2.02-1.92 (m, 1H), 1.74 (ddd, J=21.8, 14.3, 7.0 Hz, 4H).

Example 32: 4-(2,3-dichlorophenyl)-N-(2-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)ethyl)piperazine-1-carboxamide ( 32)

3-(4-(2-Aminoethoxy)-1-oxoisoindoline-2-)piperidine-2,6-dione hydrochloride (50 mg, 0.147 mmol) was dissolved in 3 ml anhydrous DMSO, triethylamine (61 µl, 0.147 mmol) was added with stirring. 44 mmol) and carbonyldiimidazole (36 mg 0.22 mmol) at room temperature. The resulting reaction solution was stirred and the reaction was carried out at 40°C for 0.5 hour. After complete conversion to the active intermediate, 4-(2,3-dichlorophenyl)piperazine hydrochloride (59 mg, 0.22 mmol) was added to the reaction solution. The resulting reaction solution was stirred and reacted at 40°C for 2 hours. After completion of the reaction, the reaction solution was separated by HPLC to obtain 39.6 mg of the target product, a yield of 48%; ^1H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.35-7.26 (m, 3H), 7, 16-7.09 (m, 1H), 6.81 (t, J=5.3 Hz, 1H), 5.11 (dd, J=13.3, 5.1 Hz, 1H), 4.39 (d,J=17.4 Hz, 1H), 4.25 (d, J=17.3 Hz, 1H), 4.17 (t, J=5.9 Hz, 2H), 3.58-3 .37 (m, 6H), 3.01-2.80 (m, 5H), 2.63-2.55 (m, 1H), 2.41 (ddd, J=26.1, 13.1, 4.4 Hz, 1H), 2.04-1.94 (m, 1H).

Example 33: 4-(2,3-dichlorophenyl)-N-(4-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)butyl)piperazine-1-carboxamide ( 33)

The preparation method was the same as for 4-(2,3-dichlorophenyl)-N-(2-((2-(2,6-dioxopiperidin-3-)-1-oxoisoindoline-4-oxy)ethyl) piperazine-1-carboxamide to give the compound as a white solid, 44.6 mg, 56% yield; ^1H NMR (400 MHz, DMSO) δ 10.96 (s, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.31 (t, J=5.8 Hz, 3H) , 7.24 (d, J=8.1 Hz, 1H), 7.16-7.12 (m, 1H), 6.60 (t, J=5.4 Hz, 1H), 5.11 ( dd, J=13.2, 5.0 Hz, 1H), 4.39 (d, J=17.4 Hz, 1H), 4.23 (d, J=17.4 Hz, 1H), 4, 13 (t, J=6.3 Hz, 2H), 3.46-3.39 (m, 4H), 3.12 (dd, J=12.7, 6.8 Hz, 2H), 2.97 -2.85 (m, 5H), 2.58 (d, J=18.6 Hz, 1H), 2.50-2.40 (m, 1H), 2.03-1.95 (m, 1H ), 1.79-1.72 (m, 2H), 1.64-1.54 (m, 2H).

Example 34: 4-(2,3-dichlorophenyl)-N-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindole-4-)oxy)propyl)piperidine-1-carboxamide ( 34)

The preparation method was the same as for 4-(2,3-dichlorophenyl)-N-(2-((2-(2,6-dioxopiperidin-3-)-1-oxoisoindoline-4-oxy)ethyl) piperazine-1-carboxamide to obtain 20.3 mg of a white solid, 29% yield; ¹ H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 7.48 (t, J=8.0 Hz, 1H), 7.34-7.29 (m, 3H), 7, 24 (d, J=8.1 Hz, 1H), 7.15-7.11 (m, 1H), 6.68 (t, J=5.4 Hz, 1H), 5.11 (dd, J =13.0, 5.0 Hz, 1H), 4.39 (d, J=17.5 Hz, 1H), 4.24 (d, J=17.5 Hz, 1H), 4.15 (t , J=6.0 Hz, 2H), 3.44 (t, 4H), 3.26-3.19 (m, 2H), 2.90 (t, 4H), 2.63-2.55 ( m, 1H), 2.45-2.32 (t,1H), 2.04-1.86 (m, 3H).

Example 35: 3-(4-(6-(4-(2,3-dichlorophenyl)piperazine-1-)hexyl)-1-oxoisoindoline-2-)piperidine-2,6-dione (35)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 30.5 mg, yield thirty%; 1I NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.56 (dd, J=8.2, 4.5 Hz, 1H), 7.46 (d, J=3.5 Hz , 2H), 7.30 (dd, J=9.1, 5.3 Hz, 2H), 7.13 (dd, J=6.3, 3.1 Hz, 1H), 5.13 (dd, J=13.3, 5.1 Hz, 1H), 4.46 (d, J=17.1 Hz, 1H), 4.31 (d, J=17.2 Hz, 1H), 3.32 ( s, 4H), 3.0-2.88 (m, 5H), 2.68-2.56 (m, 3H), 2.47-2.37 (t, 1H), 2.32 (s, 2H), 2.04-1.96 (m, 1H), 1.66-1.56 (m, 2H), 1.50-1.40 (m, 2H), 1.38-1.27( m, 4H).

Example 36: 4-(4-(4-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)butyl)piperazine-1-)benzonitrile (36)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 12.5 mg solid white, yield 20%; ^1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.60-7.53 (m, 3H), 7.49-7.44 (m, 2H), 7.00 (d , J=9.0 Hz, 2H), 5.13 (dd, J=13.3, 5.2 Hz, 1H), 4.47 (d, J=17.2 Hz, 1H), 4.31 (d, J=17.2 Hz, 1H), 3.32-3.28 (m, 4H), 2.97-2.86 (m, 1H), 2.67 (t, J=7.6 Hz, 2H), 2.58 (d, J=16.3 Hz, 1H), 2.47-2.43 (m, 4H), 2.42-2.32 (m, 3H), 2.05 -1.96 (m, 1H), 1.69-1.60 (m, 2H), 1.54-1.46 (m, 2H).

Example 37: 3-(4-(4-(4-(3-chlorophenyl)piperazine-1-)butyl)-1-oxoisoindoline-2-)piperidine-2,6-dione (37)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 21 mg white solid , yield 32.6%; ^1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.57 (dt, J=7.7, 3.9 Hz, 1H), 7.49-7.43 (m, 2H ), 7.19 (t, J=8.1 Hz, 1H), 6.94-6.84 (m, 2H), 6.77 (dd, J=7.8, 1.4 Hz, 1H) , 5.13 (dd, J=13.3, 5.1 Hz, 1H), 4.47 (d, J=17.2 Hz, 1H), 4.32 (d, J=17.1 Hz, 1H) , 3.20-3.10 (m, 4H), 2.98-2.86 (m, 1H), 2.67 (t, J=7.5 Hz, 2H), 2.59 (d, J =17.0 Hz, 1H), 2.49-2.46 (m, 4H), 2.45-2.35 (m, 3H), 2.05-1.96 (m, 1H), 1.69- 1.59 (m, 2H), 1.56-1.46 (m, 2H).

Example 38: 2-(4-(4-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)butyl)piperazine-1-)benzonitrile (38)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 20 mg yellow solid , yield 31.7%; ^1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.69 (dd, J=7.7, 1.5 Hz, 1H), 7.62-7.55 (m, 2H ), 7.49-7.45 (m, 2H), 7.14 (d, J=8.2 Hz, 1H), 7.08 (t, J=7.6 Hz, 1H), 5.14 (dd , J=13.2, 5.1 Hz, 1H), 4.48 (d, J=17.1 Hz, 1H), 4.32 (d, J=17.1 Hz, 1H), 3.17 -3.10 (m, 4H), 2.97-2.87 (t,1H), 2.72-2.65 (m, 2H), 2.60 (d, J=17.2 HzDN), 2.54 (t, 4H), 2.47-2.36 (m, 3H), 2.06-1.98 (m, 1H), 1.65 (dt, J=15.6, 6.3 Hz, 2H), 1.52 (dt, J=14.8, 7.5 Hz, 2H).

Example 39: 3-(4-(4-(4-(4-fluorophenyl)piperazine-1-)butyl)-1-oxoisoindoline-2-)piperidine-2,6-dione (39)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 41.4 mg solid white, yield 66.5%; ^1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.57 (dd, J=5.2, 3.4 Hz, 1H), 7.49-7.44 (m, 2H ), 7.03 (t, J=8.9 Hz, 2H), 6.96-6.89 (m, 2H), 5.13 (dd, J=13.2, 5.0 Hz, 1H) , 4.47 (d, J=17.2 Hz, 1H), 4.32 (d, J=17.1 Hz, 1H), 3.08-3.01 (m, 4H), 2.97- 2.86 (m, 1H), 2.68 (t, J=7.6 Hz, 2H), 2.58 (d, J=17.6 Hz, 1H), 2.49-2.46 (m , 4H), 2.44-2.34 (m, 3H), 2.01 (dt, J=10.4, 5.0 Hz, 1H), 1.69-1.59 (m, 2H), 1.51 (dt, J=14.2, 7.1 Hz, 2H).

Example 40: 3-(1-oxo-4-(4-(4-(3-methylphenyl)piperazine-1-)butyl)isoindoline-2-)piperidine-2,6-dione (40)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 45.2 mg solid white, yield 73.3%; ¹ H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.57 (dd, J=5.4, 3.2 Hz, 1H), 7.50-7.44 (m, 2H ), 7.07 (t, J=7.8 Hz, 1H), 6.76-6.66 (m, 2H), 6.58 (d, J=7.3 Hz, 1H), 5.13 (dd, J=13.3, 5.1 Hz, 1H), 4.47 (d, J=17.2 Hz, 1H), 4.32 (d, J=17.2 Hz, 1H), 3 ,12-3.07 (m, 4H), 2.97-2.86 (m, 1H), 2.68 (t, J=7.5 Hz, 2H), 2.58 (d, J=17 ,4 Hz, 1H), 2.44-2.34 (m, 3H), 2.23 (s, 3H), 2.05-1.96 (m, 1H), 1.69-1.59 ( m, 2H), 1.51 (dt, J=14.7, 7.5 Hz, 2H).

Example 41: 3-(4-(4-(4-(4-chlorophenyl)piperazine-1-)butyl)-1-oxoisoindoline-2-)piperidine-2,6-dione (41)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 42.8 mg solid white, yield 66.5%; ^1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.57 (dd, J=5.4, 3.2 Hz, 1H), 7.49-7.45 (m, 2H ), 7.22 (d, J=9.0 Hz, 2H), 6.93 (d, J=9.0 Hz, 2H), 5.14 (dd, J=13.2, 5.1 Hz , 1H), 4.47 (d,J=17.1 Hz, 1H), 4.32 (d,J=17.2 Hz, 1H), 3.14 (s, 4H), 2.98-2 .86 (m, 1H), 2.68 (t, J=7.5 Hz, 2H), 2.62-2.53 (m, 5H), 2.48-2.35 (m, 3H), 2.05-1.95 (m, 1H), 1.65 (dt, J=15.5, 6.9 Hz, 2H), 1.53 (dt, J=15.2, 7.6 Hz, 2H).

Example 42: 3-(4-(4-(4-(4-nitrophenyl)piperazine-1-)butyl)-1-oxoisoindoline-2-)piperidine-2,6-dione (42)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 34.9 mg solid yellow, yield 53%; ^1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 8.05 (d, J=9.4 Hz, 2H), 7.57 (dd, J=5.4, 3.2 Hz, 1H), 7.50-7.45 (m, 2H), 7.01 (d, J=9.5 Hz, 2H), 5.14 (dd, J=13.3, 5.0 Hz , 1H), 4.47 (d, J=17.2 Hz, 1H), 4.32 (d, J=17.2 Hz, 1H), 3.45-3.41 (m, 4H), 2 ,97-2.87 (m, 1H), 2.68 (t, J=7.6 Hz, 2H), 2.59 (d, J=17.2 Hz, 1H), 2.49-2, 44 (m, 4H), 2.44-2.33 (m, 3H), 2.06-1.96 (m, 1H), 1.70-1.59 (m, 2H), 1.51 ( dt, J=15.2, 7.7 Hz, 2H).

Example 43: 3-(4-(4-(4-(2,4-difluorophenyl)piperazine-1-)butyl)-1-oxoisoindoline-2-)piperidine-2,6-dione (43)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 13.3 mg solid white, yield 20.6%; ¹ H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.56 (dt, J=7.7, 3.9 Hz, 1H), 7.49-7.44 (m, 2H ), 7.22-7.14 (m, 1H), 7.08-6.94 (m, 2H), 5.14 (dd, J=13.2, 4.9 Hz, 1H), 4, 47 (d,J=17.1 Hz, 1H), 4.32 (d, J=17.2 Hz, 1H), 2.98-2.87 (m, 5H), 2.67 (t, J =7.6 Hz, 2H), 2.59 (d, J=17.6 Hz, 1H), 2.46-2.30 (m, 7H), 2.06-1.97 (m, 1H) , 1.68-1.57 (m, 2H), 1.55-1.45 (m, 2H).

Example 44: 3-(4-(4-(4-(3,4-dichlorophenyl)piperazine-1-)butyl)-1-oxoisoindoline-2-)piperidine-2,6-dione (44)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 45.8 mg solid white, yield 66.5%; ^1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.56 (dd, J=8.1, 4.8 Hz, 1H), 7.49-7.45 (m, 2H ), 7.38 (d, J=9.0 Hz, 1H), 7.10 (d, J=2.8 Hz, 1H), 6.91 (dd, J=9.1, 2.9 Hz , 1H), 5.13 (dd, J=13.3, 5.0 Hz, 1H), 4.47 (d, J=17.2 Hz, 1H), 4.31 (d, J=17, 2 Hz, 1H), 3.16 (m, 4H), 2.98-2.86 (m, 1H), 2.67 (t, J=7.6 Hz, 2H), 2.59 (d, J=16.4 Hz, 1H), 2.48-2.31 (m, 7H), 2.05-1.96 (m, 1H), 1.64 (dt, J=15.1, 7, 2 Hz, 2H), 1.56-1.45 (m, 2H).

Example 45: 3-(1-oxo-4-(4-(4-(4-trifluoromethylphenyl)piperazine-1-)butyl)isoindoline-2-)piperidine-2,6-dione (45)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 27.6 mg solid white, yield 40.6%; ^1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.58 (dd, J=5.5, 3.0 Hz, 1H), 7.55-7.46 (m, 4H ), 7.07 (d, J=7.9 Hz, 2H), 5.14 (dd, J=13.4, 5.3 Hz, 1H), 4.48 (d, J=17.2 Hz , 1H), 4.32 (d, J=17.1 Hz, 1H), 3.20-3.10(t,4H), 2.99-2.87 (m, 1H), 2.72- 2.65 (t, 2H), 2.60 (d, J=16.5 Hz, 1H), 2.46-2.30 (m, 7H), 2.05-1.96 (m, 1H) , 1.67-1.54 (m, 4H).

Example 46: 3-(4-(4-(4-(4-methoxyphenyl)piperazine-1-)butyl)-1-oxoisoindoline-2-)piperidine-2,6-dione (46)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 43.3 mg solid white, yield 68%; ^1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.58 (dd, J=5.5, 3.2 Hz, 1H), 7.51-7.46 (m, 2H ), 6.89 (d, J=9.2 Hz, 2H), 6.82 (d, J=9.1 Hz, 2H), 5.14 (dd, J=13.2, 5.1 Hz , 1H), 4.48 (d, J=17.2 Hz, 1H), 4.33 (d, J=17.2 Hz, 1H), 3.69 (s, 3H), 3.08-2 .87 (m, 5H), 2.73 -2.66 (m, 2H), 2.60 (d, J=17.9 Hz, 1H), 2.48-2.31 (m, 7H), 2.06-1.97 (m, 1H), 1.70-1.50 (m, 4H).

Example 47: 2-(2,6-dioxopiperidine-3-)-4-(4-(quinoline-4-oxy)butoxy)isoindoline-1,3-dione (47)

Step 1: Add 4-hydroxyquinoline (100 mg, 0.69 mmol, 1.0 eq.) to a 50 mL round bottom flask, add 4-methoxymethoxy-1-butanol (278 mg, 2.07 mmol, 2 eq.) and triphenylphosphine (543 mg, 2.07 mmol, 2 eq.). The reaction system was replaced with nitrogen and 15 ml of anhydrous tetrahydrofuran was added. Diisopropyl azodicarboxylate (408 μL, 2.07 mmol, 2 eq.) was added to the reaction system to allow the reaction to proceed at room temperature for 1 hour. The completion of the reaction was monitored by TLC, concentrated under reduced pressure to obtain 173 mg of the desired product by column chromatography, 96% yield.

Step 2: 4-(4-methoxymethoxybutoxy)quinoline was added to a 50 ml round bottom flask, and 10 ml of 4M dioxane hydrochloride and 1 ml of methanol were added to react at room temperature for 1 hour. Completion of the reaction was monitored by LC-MS and the product was then concentrated under reduced pressure. Saturated sodium bicarbonate solution was added, extracted with ethyl acetate and separated. The organic layer was washed with saturated sodium chloride, dried to obtain 140 mg of a white solid by column chromatography, 100% yield.

Step 3: Add 2-(2,6-dioxopiperidine-3-)-4-hydroxyisoindoline-1,3-dione (35 mg, 0.128 mmol) to a 50 mL round bottom flask, add 4-(quinoline-4-oxy) -1-butanol (56 mg, 0.256 mmol, 2 eq.) and triphenylphosphine (67 mg, 0.256 mmol, 2 eq.). The reaction system was replaced with nitrogen and 5 ml of anhydrous tetrahydrofuran was added. Diisopropyl azodicarboxylate (51 μL, 0.256 mmol, 2 eq.) was added to the reaction system to allow the reaction to proceed at room temperature for 1 hour. The completion of the reaction was monitored by TLC, concentrated under reduced pressure, 20.3 mg of a white solid was obtained by HPLC, yield 33.4%; ^1H NMR (400 MHz, DMSO) δ 11.11 (s, 1H), 8.75 (d, J=5.3 Hz, 1H), 8.16-8.11 (m, 1H), 7, 94 (d, J=8.4 Hz, 1H), 7.83-7.72 (m, 2H), 7.54 (t, J=7.7 Hz, 2H), 7.43 (d, J =7.2 Hz, 1H), 7.08 (d, J=5.4 Hz, 1H), 5.08 (dd, J=12.7, 5.4 Hz, 1H), 4.41 (t , J=6.1 Hz, 2H), 4.35 (t, J=5.8 Hz, 2H), 2.87 (dd, J=8.5, 5.3 Hz, 1H), 2.70 -2.55 (m, 1H), 2.18-1.95 (m, 6H).

Example 48: 3-(4-(4-(4-(2,6-dichlorophenyl)piperazine-1-)butyl)-1-oxoisoindoline-2-)piperidine-2,6-dione (48)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 39.3 mg solid white, yield 43%; ^1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.58 (dd, J=5.8, 2.7 Hz, 1H), 7.50-7.46 (m, 2H ), 7.41 (d, J=8.1 Hz, 2H), 7.17-7.12 (m, 1H), 5.14 (dd, J=13.5, 5.1 Hz, 1H) , 4.48 (d, J=17.1 Hz, 1H), 4.33 (d, J=17.1 Hz, 1H), 3.13 (s, 4H), 2.99-2.87 ( m, 2H), 2.72-2.66 (t,2H), 2.61 (d, J=19.2 Hz, 1H), 2.48-2.45 (m, 4H), 2.42 -2.33 (dd, J=14.2, 6.7 Hz, 3H), 2.07-1.99 (m, 1H), 1.70-1.61 (m, 1H), 1.56 -1.47 (m, 1H).

Example 49: 4-(4-chlorophenyl)-1-(5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)pentyl)piperidine-4-carbonitrile (49)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 19.9 mg, yield 26%; ^1H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 7.60-7.54 (m, 2H), 7.54-7.49 (m, 2H), 7.49-7 .45 (m, 2H), 5.15 (dd, J=13.3, 5.4 Hz, 1H), 4.47 (d, J=17.0 Hz, 1H), 4.31 (d, J=17.2 Hz, 1H), 2.99-2.88 (m, 1H), 2.72-2.56 (m, 3H), 2.48-2.20 (m, 5H), 2 .12 (d, J=14.0 Hz, 2H), 2.06-1.88 (m, 3H), 1.70-1.59 (m, 2H), 1.52 (dt, J=13 ,4, 6.7 Hz, 2H), 1.36 (dd, J=14.7, 5.1 Hz, 2H).

Example 50: (S)-4-(2-chlorophenyl)-1-(3-((2-(3-methyl-2,6-dioxopiperidine-3-)-1,3-dioxoisoindoline-4-)oxy) propyl) piperidine-4-carbonitrile (50)

Step 1: Add 4-hydroxyisobenzofuran-1,3-dione (200 mg, 1.22 mmol, 1.0 eq), (8)-3-amino-3-methylpiperidine-2,6-dione hydrobromic acid monohydrate ( 294 mg, 1.22 mmol, 1.0 eq.) and dissolved in 20 ml of toluene. Triethylamine (136 mg, 1.34 mmol, 1.1 eq.) was added at reflux at 120°C for 24 hours. After completion of the reaction, toluene was separated by centrifugation and purified by column chromatography to obtain 200 mg of a white solid with a yield of 57%. ^1H NMR (400 MHz, DMSO) δ 11.07 (s, 1H), 10.97 (s, 1H), 7.62 (dd, J=8.3, 7.3 Hz, 1H), 7, 22 (dd, J=15.6, 7.7 Hz, 2H), 2.75-2.62 (m, 1H), 2.57-2.52 (m, 1H), 2.06-1, 97 (m, 1H), 1.86 (s, 3H), 1.29-1.18 (m, 1H).

Step 2: (S)-4-hydroxyl-2-(3-methyl-2,6-dioxopiperidine-3-)isoindoline-1,3-dione (200 mg, 0.69 mmol, 1.0 eq.) was dissolved in 20 ml of acetonitrile and 1,3-dibromopropane (681 mg, 3.54 mmol, 3.0 eq.) and anhydrous potassium carbonate (96 mg, 0.69 mmol, 1.0 eq.) were added. The reaction system was reacted at 50°C for 24 hours. After completion of the reaction, the solvent was separated by centrifugation, diluted with ethyl acetate, washed with saturated sodium chloride, and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure and purified by column chromatography to obtain 243 mg of a white solid in 86% yield. ^1H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 7.83-7.78 (m, 1H), 7.52 (d, J=8.5 Hz, 1H), 7, 40 (d, J=7.1 Hz, 1H), 4.29 (t, J=5.8 Hz, 2H), 3.72 (t, J=6.5 Hz, 1H), 2.68 ( s, 1H), 2.31 (dd, J=13.8, 7.7 Hz, 1H), 2.03 (d, J=18.2 Hz, 1H), 1.88 (s, 1H).

Step 3: (S)-4-(3-bromopropyl)-2-(3-methyl-2,6-dioxopiperidine-3-)isoindoline-1,3-dione (40 mg, 0.098 mmol, 1.0 eq. ) was dissolved in 3 ml DMSO, and 4-(2-chlorophenyl)piperidine-4-carbonitrile hydrochloride (38 mg, 0.147 mmol, 1.5 eq) and triethylamine (9.89 mg, 0.980 mmol, 10.0 eq) were added .), and the reaction was carried out at 40°C overnight. After completion of the reaction, the solution was diluted with 20 ml of ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, purified by thin layer chromatography and high performance liquid chromatography to obtain 23 mg of product as a white solid, 43% yield; ^1H NMR (400 MHz, DMSO) δ 10.99 (d, J=5.1 Hz, 1H), 7.81-7.75 (m, 1H), 7.59-7.51 (m, 2H ), 7.49 (d, J=8.6 Hz, 1H), 7.47-7.40 (m, 2H), 7.37 (d, J=7.2 Hz, 1H), 4.23 (t, J=6.0 Hz, 2H), 3.05 (d, J=9.4 Hz, 2H), 2.76-2.62 (m, 1H), 2.55 (dd, J= 12.7, 5.3 Hz, 3H), 2.38 (dd, J=29.5, 18.0 Hz, 5H), 2.00 (dd, J=16.1, 10.9 Hz, 5H ), 1.87 (s, 3H).

Example 51: 4-(3-chlorophenyl)-1-(5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)pentyl)piperidine-4-carbonitrile (51)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 21.6 mg, yield 28%; ^1H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 7.60-7.49 (m, 3H), 7.49-7.43 (m, 3H), 5.15 (dd , J=13.6, 5.2 Hz, 1H), 4.48 (d, J=17.1 Hz, 1H), 4.31 (d, J=17.2 Hz, 1H), 2.99 (d, J=12.2 Hz, 2H), 2.95-2.87 (m, 1H), 2.69-2.64 (m, 2H), 2.64-2.57 (m, 1H ), 2.49-2.41 (m, 1H), 2.40-2.32 (m, 2H), 2.24 (td, J=11.9, 1.3 Hz, 2H), 2, 14 (dd, J=12.7, 1.5 Hz, 2H), 2.06-1.93 (m, 3H), 1.64 (dt, J=15.3, 7.7 Hz, 2H) , 1.56-1.46 (m, 2H), 1.35 (dd, J=15.1, 7.2 Hz, 2H).

Example 52: (S)-4-(3-chlorophenyl)-1-(3-((2-(3-methyl-2,6-dioxopiperidine-3-)-1-oxoisoindole-4-)oxy)propyl) piperidine-4-carbonitrile (52)

The preparation method was the same as for (S)-4-(2-chlorophenyl)-1-(3-((2-(3-methyl-2,6-dioxopiperidin-3-)-1-oxoisoindoline-4 -)hydroxy)propyl)piperidine-4-carbonitrile to obtain 14 mg of the final product as a white solid, 26% yield; ¹ H NMR (400 MHz, DMSO) δ 10.88 (s, 1H), 7.60 (s, 1H), 7.50 (dt, J=17.6, 7.7 Hz, 4H), 7, 24 (dd, J=12.5, 7.8 Hz, 2H), 4.66 (d, J=17.6 Hz, 1H), 4.54 (d, J=17.6 Hz, 1H), 4.20 (t, J=6.0 Hz, 2H), 3.05 (d, J=10.6 Hz, 2H), 2.80-2.52 (m, 5H), 2.35-2 ,24 (m, 2H), 2.16 (d, J=12.4 Hz, 2H), 1.94 (ddd, J=23.3, 12.4, 8.2 Hz, 5H), 1, 70 (s, 3H).

Example 53: 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-4-phenylpiperidine-4-carboxonitrile (53)

3-(4-(3-bromopropoxy)-1-oxoisoindoline-2-)piperidine-2,6-dione (40 mg, 0.11 mmol) was dissolved in 3 ml of anhydrous DMSO, 4-phenylpiperidine-4-carbonitrile hydrochloride was added (0.16 mmol, 1.5 eq.) itriethylamine (110 mg, 1.1 mmol, 10.0 eq.) to react at 40°C overnight. After completion of the reaction, the reaction solution was diluted with 20 ml of ethyl acetate. The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated and purified by thin layer chromatography and high performance liquid chromatography to obtain 26.3 mg of the final product as a white solid, 41% yield; ^1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.53 (dt, J=3.1, 2.1 Hz, 2H), 7.46 (ddd, J=13.1 , 11.8, 7.1 Hz, 3H), 7.36 (ddd, J=8.3, 4.3, 1.7 Hz, 1H), 7.31 (d, J=7.4 Hz, 1H), 7.25 (d, J=8.1 Hz, 1H), 5.11 (dd, J=13.3, 5.1 Hz, 1H), 4.39 (d, J=17.4 Hz, 1H), 4.24 (d, J=17.4 Hz, 1H), 4.18 (t, J=6.2 Hz, 2H), 3.03 (d, J=12.2 Hz, 2H), 2.91 (ddd, J=17.4, 13.7, 5.4 Hz, 1H), 2.58 (dd, J=12.2, 4.8 Hz, 3H), 2.48 -2.38 (m, 1H), 2.30 (dd, J=12.0, 11.3 Hz, 2H), 2.11 (d, J=13.0 Hz, 2H), 2.05- 1.89 (m, 5H). Electric sputter ionization mass spectroscopy (ESI-MS) [M+H] ⁺ m/z=487.65.

Example 54: (S)-4-(3-chlorophenyl)-1-(3-((2-(3-methyl-2,6-dioxopiperidine-3-)-1,3-dioxoisoindoline-4-)oxy) propyl) piperidine-4-carbonitrile (54)

The preparation method was the same as for (S)-4-(2-chlorophenyl)-1-(3-((2-(3-methyl-2,6-dioxopiperidin-3-)-1,3-dioxoisoindoline -4-)hydroxy)propyl)piperidine-4-carbonitrile to give 18 mg of the final product as a white solid, 34% yield; ^1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.81-7.75 (m, 1H), 7.58 (s, 1H), 7.55-7.41 (m , 4H), 7.37 (d, J=7.2 Hz, 1H), 4.24 (t, J=6.0 Hz, 2H), 3.02 (d, J=11.3 Hz, 2H ), 2.74-2.63 (m, 1H), 2.62-2.51 (m, 4H), 2.28 (t, J=11.4 Hz, 2H), 2.14 (d, J=12.2 Hz, 2H), 2.08-1.93 (m, 5H), 1.87 (s, 3H).

Example 55: 4-(2-chlorophenyl)-1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)piperidine-4-carbonitrile (55)

The preparation method was the same as for 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-4-phenylpiperidine-4-carbonitrile, 21 .0 mg, yield 31%; ^1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.61-7.52 (m, 2H), 7.51-7.39 (m, 3H), 7.31 (d , J=7.0 Hz, 1H), 7.25 (d, J=8.2 Hz, 1H), 5.12 (dd, J=13.1, 6.1 Hz, 1H), 4.39 (d, J=17.4 Hz, 1H), 4.24 (d, J=17.2 Hz, 1H), 4.20-4.13 (m, 2H), 3.12-3.00 ( m, 2H), 2.97-2.85 (m, 1H), 2.68-2.53 (m, 3H), 2.38 (ddd, J=16.4, 14.0, 6.7 Hz, 5H), 1.98 (ddd, J=21.0, 12.0, 4.6 Hz, 5H). Electric sputter ionization mass spectroscopy (ESI-MS) [M+H] ⁺ m/z=522.28.

Example 56: (S)-1-(3-((2-(3-methyl-2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-4-(2-(trifluoromethoxy ) phenyl)piperidine-4-carbonitrile (56)

The preparation method was the same as for (S)-4-(2-chlorophenyl)-1-(3-((2-(3-methyl-2,6-dioxopiperidin-3-)-1-oxoisoindoline-4 -)oxy)propyl)piperidine-4-carbonitrile to obtain 16 mg of the final product as a white solid, 30% yield; 1H NMR (400 MHz, DMSO) δ 10.87 (s, 1H), 7.57 (dd, J=18.0, 7.6 Hz, 2H), 7.44 (dd, J=15.4, 7.6 Hz, 3H), 7.22 (dd, J=10.7, 7.9 Hz, 2H), 4.65 (d, J=17.5 Hz, 1H), 4.53 (d, J=17.6 Hz, 1H), 4.18 (t, J=5.9 Hz, 2H), 3.06 (d, J=11.1 Hz, 2H), 2.82-2.52 ( m, 5H), 2.41-2.22 (m, 4H), 2.11-1.84 (m, 5H), 1.69 (s, 3H).

Example 57: 4-(3-chlorophenyl)-1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)piperidine-4-carbonitrile (57)

The preparation method was the same as for 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-4-phenylpiperidine-4-carbonitrile, 25 .7 mg, yield 38%; ^1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.62-7.58 (m, 1H), 7.56-7.44 (m, 4H), 7.32 (d , J=7.2 Hz, 1H), 7.26 (d, J=7.9 Hz, 1H), 5.12 (dd, J=13.4, 5.1 Hz, 1H), 4.39 (d, J=17.5 Hz, 1H), 4.24 (d, J=17.4 Hz, 1H), 4.18 (t, J=6.2 Hz, 2H), 3.05 (dd , J=10.8, 2.7 Hz, 2H), 2.92 (ddd, J=17.4, 13.3, 5.0 Hz, 1H), 2.62-2.55 (m, 3H ), 2.49-2.40 (m, 1H), 2.38-2.25 (m, 2H), 2.17 (d, J=12.0 Hz, 2H), 1.99 (ddd, J=21.0, 15.7, 9.3 Hz, 5H).

Example 58: (S)-1-(3-((2-(3-methyl-2,6-dioxopiperidine-3-)-1,3-dioxoisoindoline-4-oxy)propyl)-4-(2- (trifluoromethoxy)phenyl)piperidine-4-carbonitrile (58)

The preparation method was the same as for (S)-4-(2-chlorophenyl)-1-(3-((2-(3-methyl-2,6-dioxopiperidin-3-)-1,3-dioxoisoindoline -4-)hydroxy)propyl)piperidine-4-carbonitrile to give 21 mg of the final product as a white solid, 36% yield; ^1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.81-7.74 (m, 1H), 7.56 (dd, J=15.7, 7.6 Hz, 2H ), 7.51-7.40 (m, 3H), 7.37 (d, J=7.2 Hz, 1H), 4.23 (t, J=6.0 Hz, 2H), 3.04 (d, J=11.9 Hz, 2H), 2.68 (dd, J=12.5, 6.4 Hz, 1H), 2.60-2.51 (m, 4H), 2.43- 2.18 (m, 4H), 2.10-1.92 (m, 5H), 1.87 (s, 3H).

Example 59: 4-(4-chlorophenyl)-1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)piperidine-4-carbonitrile (59)

The preparation method was the same as for 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-4-phenylpiperidine-4-carbonitrile, 24 .6 mg, yield 36%; ^1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.60-7.55 (m, 2H), 7.54-7.50 (m, 2H), 7.48 (d ,J=7.8 Hz, 1H), 7.32 (d, J=7.5 Hz, 1H), 7.26 (d, J=8.1 Hz, 1H), 5.12 (dd, J =13.1, 5.0 Hz, 1H), 4.40 (d, J=17.4 Hz, 1H), 4.25 (d, J=17.4 Hz, 1H), 4.19 (t , J=6.0 Hz, 2H), 3.18-3.00 (m, 2H), 2.92 (ddd, J=18.5, 13.0, 4.4 Hz, 1H), 2, 59 (ddd, J=16.3, 3.5, 1.3 Hz, 3H), 2.49-2.39 (m, 2H), 2.38-2.32 (m, 1H), 2, 16 (d, J=15.1 Hz, 2H), 2.09-1.92 (m, 5H). Electric sputter ionization mass spectroscopy (ESI-MS) [M+H] ⁺ m/z=522.28.

Example 60: (S)-1-(3-((2-(3-methyl-2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-4-(3-(trifluoromethoxy ) phenyl)piperidine-4-carbonitrile (60)

The preparation method was the same as for (S)-4-(2-chlorophenyl)-1-(3-((2-(3-methyl-2,6-dioxopiperidin-3-)-1-oxoisoindoline-4 -)oxy)propyl)piperidine-4-carbonitrile to obtain 18 mg of the final product as a white solid, 34% yield; ¹ H NMR (400 MHz, DMSO) δ 10.87 (s, 1H), 7.61 (d, J=7.0 Hz, 2H), 7.54-7.37 (m, 3H), 7, 23 (dd, J=12.8, 7.8 Hz, 2H), 4.65 (d, J=17.6 Hz, 1H), 4.54 (d, J=17.6 Hz, 1H), 4.19 (t, J=5.9 Hz, 2H), 3.05 (d, J=10.4 Hz, 2H), 2.82-2.51 (m, 5H), 2.37-2 .24 (m, 2H), 2.17 (d, J=12.3 Hz, 2H), 2.11-1.85 (m, 5H).

Example 61: 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-4-(2-fluorophenyl)piperidine-4-carbonitrile (61)

The preparation method was the same as for 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-4-phenylpiperidine-4-carbonitrile, 23 .6 mg, yield 36%; ^1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.50 (dd, J=15.4, 7.3 Hz, 3H), 7.37-7.22 (m, 4H ), 5.12 (dd, J=13.4, 5.2 Hz, 1H), 4.40 (d, J=17.4 Hz, 1H), 4.24 (d, J=17.8 Hz , 1H), 4.18 (t, J=5.8 Hz, 2H), 3.05 (ddd, J=12.6, 7.5, 3.9 Hz, 2H), 2.98-2, 86 (m, 1H), 2.65-2.55 (m, 3H), 2.49-2.43 (m, 1H), 2.40-2.20 (m, 4H), 2.10- 1.89 (m, 5H). Electric sputter ionization mass spectroscopy (ESI-MS) [M+H] ⁺ m/z=505.66.

Example 62: (S)-1-(3-((2-(3-methyl-2,6-dioxopiperidin-3-)-1,3-dioxoisoindoline-4-oxy)propyl)-4-(3- (trifluoromethoxy)phenyl)piperidine-4-carbonitrile (62)

The preparation method was the same as for (S)-4-(2-chlorophenyl)-1-(3-((2-(3-methyl-2,6-dioxopiperidin-3-)-1,3-dioxoisoindoline -4-)hydroxy)propyl)piperidine-4-carbonitrile to give 21 mg of the final product as a white solid, 36% yield; ^1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.78 (t, J=7.9 Hz, 1H), 7.65-7.56 (m, 2H), 7, 49 (d, J=8.8 Hz, 2H), 7.38 (t, J=9.1 Hz, 2H), 4.24 (t, J=5.8 Hz, 2H), 3.02 ( d, J=10.4 Hz, 2H), 2.68 (dd, J=12.4, 6.5 Hz, 1H), 2.55 (dd, J=12.8, 4.6 Hz, 4H ), 2.29 (t, J=11.6 Hz, 2H), 2.16 (d, J=12.9 Hz, 2H), 2.08-1.91 (m, 5H), 1.87 (s, 3H).

Example 63: 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-4-(3-fluorophenyl)piperidine-4-carbonitrile (63)

The preparation method was the same as for 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-4-phenylpiperidine-4-carbonitrile, 23 .6 mg, yield 36%; ^1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.54-7.46 (m, 2H), 7.44-7.37 (m, 2H), 7.32 (d , J=7.3 Hz, 1H), 7.28-7.19 (m, 2H), 5.12 (dd, J=13.3, 5.1 Hz, 1H), 4.39 (d, J=17.5 Hz, 1H), 4.24 (d, J=17.5 Hz, 1H), 4.18 (t, J=6.2 Hz, 2H), 3.03 (d, J= 12.4 Hz, 2H), 2.97-2.86 (m, 1H), 2.63-2.55 (m, 3H), 2.49-2.41 (m, 1H), 2.30 (t, J=12.2 Hz, 2H), 2.15 (d, J=12.4 Hz, 2H), 2.08 1.89 (m, 5H). Electric sputter ionization mass spectroscopy (ESI-MS) [M+H] ⁺ m/z=505.66.

Example 64: 4-(2-chlorophenyl)-1-(2-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)ethyl)piperidine-4-carbonitrile (64)

The preparation method was the same as for 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-oxy)propyl)-4-phenylpiperidine-4-carbonitrile, and 16 mg of final product was obtained as a white solid, yield 29%; ^1H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 7.59-7.40 (m, 5H), 7.30 (dd, J=11.8, 7.8 Hz, 2H ), 5.11 (dd, J=13.3, 5.0 Hz, 1H), 4.39 (d, J=17.4 Hz, 1H), 4.26 (t, J=12.6 Hz , 3H), 3.13 (d, J=12.2 Hz, 2H), 3.00-2.79 (m, 3H), 2.57 (d, J=22.0 Hz, 3H), 2 .46 (d, J=13.6 Hz, 3H), 1.98 (t, J=9.0 Hz, 3H), 1.23 (s, 3H).

Example 65: 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-4-(4-fluorophenyl)piperidine-4-carbonitrile (65)

The preparation method was the same as for 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-4-phenylpiperidine-4-carbonitrile, 22 .3 mg, yield 34%; ^1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.58 (ddd, J=8.7, 5.5, 2.8 Hz, 2H), 7.48 (t, J =7.8 Hz, 1H), 7.33-7.22 (m, 4H), 5.11 (dd, J=13.3, 5.2 Hz, 1H), 4.39 (d, J= 17.5 Hz, 1H), 4.23 (d, J=17.5 Hz, 1H), 4.17 (t, J=6.2 Hz, 2H), 3.09-2.98 (m, 2H), 2.91 (ddd, J=17.7, 13.8, 5.5 Hz, 1H), 2.64-2.54 (m, 3H), 2.48-2.38 (m, 1H), 2.35-2.23 (m, 2H), 2.18-2.08 (m, 2H), 2.05 1.89 (m, 5H). Electric sputter ionization mass spectroscopy (ESI-MS) [M+H] ⁺ m/z=505.61.

Example 66: 1-(2-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)ethyl)-4-(3-(trifluoromethoxy)phenyl)piperidine-4-carbonitrile (66)

The preparation method was the same as for 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-oxy)propyl)-4-phenylpiperidine-4-carbonitrile, and 12 mg of final product was obtained as a white solid, yield 20%; ^1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.64-7.56 (m, 2H), 7.53-7.46 (m, 2H), 7.40 (d , J=6.2 Hz, 1H), 7.31 (dd, J=12.8, 7.8 Hz, 2H), 5.11 (dd, J=13.3, 5.0 Hz, 1H) , 4.39 (d, J=17.5 Hz, 1H), 4.25 (t, J=10.6 Hz, 3H), 3.11 (d, J=11.8 Hz, 2H), 2 ,98-2.80 (m, 3H), 2.61-2.52 (m, 1H), 2.49-2.37 (m, 3H), 2.16 (d, J=12.6 Hz , 2H), 2.10-1.91 (m, 3H).

Example 67: 4-(3-cyanophenyl)-1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-piperidine-4-carbonitrile (67 )

The preparation method was the same as for 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-4-phenylpiperidine-4-carbonitrile, 16 .9 mg, yield 25%; ^1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 8.03 (t, J=1.5 Hz, 1H), 7.93 (ddd, J=8.0, 2.1 , 1.1 Hz, 1H), 7.90-7.85 (m, 1H), 7.67 (t, J=7.8 Hz, 1H), 7.49 (t, J=7.9 Hz , 1H), 7.32 (d, J=7.6 Hz, 1H), 7.26 (d, J=7.9 Hz, 1H), 5.16-5.08 (m, 1H), 4 .40 (d, J=17.5 Hz, 1H), 4.24 (d, J=17.6 Hz, 1H), 4.18 (t, J=6.6 Hz, 2H), 3.04 (dt, J=8.5, 3.7 Hz, 2H), 2.98-2.86 (m, 1H), 2.63-2.55 (m, 3H), 2.48-2.40 (m, 1H), 2.30 (t, J=11.3 Hz, 2H), 2.19 (d, J=12.1 Hz, 2H), 2.09-1.90 (m, 5H) . Electric sputter ionization mass spectroscopy (ESI-MS) [M+H] ⁺ m/z=512.63.

Example 68: 4-(2-chloro-6-fluorophenyl)-1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl) piperidine-4- carbonitrile (68)

The preparation method was the same as for 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-4-phenylpiperidine-4-carbonitrile, 30 mg, as a white solid, yield 37%; ¹ H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 7.52-7.41 (m, 3H), 7.35-7.22 (m, 3H), 5.11 (dd , J=13.3, 5.0 Hz, 1H), 4.39 (d, J=17.4 Hz, 1H), 4.27-4.11 (m, 3H), 3.03 (d, J=10.9 Hz, 2H), 2.91 (s, 2H), 2.57 (d, J=24.3 Hz, 4H), 2.48-2.22 (m, 6H), 2, 03-1.89 (m, 3H).

Example 69: 4-(4-cyanophenyl)-1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)piperidine-4-carbonitrile (69)

The preparation method was the same as for 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-4-phenylpiperidine-4-carbonitrile, 20 .0 mg, yield 30%; ^1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.93 (d, J=8.5 Hz, 2H), 7.76 (d, J=8.6 Hz, 2H) , 7.48 (t, J=7.8 Hz, 1H), 7.31 (d, J=7.3 Hz, 1H), 7.25 (d, J=8.1 Hz, 1H), 5 .11 (dd, J=13.3, 5.2 Hz, 1H), 4.39 (d, J=17.5 Hz, 1H), 4.24 (d, J=17.4 Hz, 1H) , 4.18 (t, J=6.1 Hz, 2H), 3.15-2.99 (m, 2H), 2.97-2.85 (m, 1H), 2.64-2.55 (m, 3H), 2.48-2.39 (m, 1H), 2.38-2.25 (m, 2H), 2.23-2.11 (m, 2H), 2.09-1 .89 (m, 5H). Electric sputter ionization mass spectroscopy (ESI-MS) [M+H] ⁺ m/z=512.68.

Example 70: 4-(2,4-chlorophenyl)-1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)piperidine-4-carbonitrile ( 70)

The preparation method was the same as for 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-4-phenylpiperidine-4-carbonitrile, 38 mg, as a white solid, yield 46%; ^1H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 7.75 (d, J=1.9 Hz, 1H), 7.58-7.44 (m, 3H), 7, 30 (d, J=7.4 Hz, 1H), 7.24 (d, J=8.1 Hz, 1H), 5.11 (dd, J=13.3, 5.1 Hz, 1H), 4.39 (d, J=17.5 Hz, 1H), 4.23 (d, J=17.5 Hz, 1H), 4.17 (t, J=6.1 Hz, 2H), 3, 05 (d, J=10.6 Hz, 2H), 2.97-2.86 (m, 1H), 2.58 (d, J=17.1 Hz, 3H), 2.49-2.26 (m, 5H), 2.04-1.88 (m, 5H).

Example 71: 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-4-(3-trifluoromethoxyphenyl)piperidine-4-carbonitrile (71)

The preparation method was the same as for 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-4-phenylpiperidine-4-carbonitrile, 27 .4 mg, yield 47%; ^1H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 7.63-7.56 (m, 2H), 7.51 (d, J=2.4 Hz, 1H), 7, 47 (d, J=7.8 Hz, 1H), 7.42-7.37 (m, 1H), 7.31 (d, J=7.4 Hz, 1H), 7.25 (d, J =8.1 Hz, 1H), 5.11 (dd, J=13.3, 5.1 Hz, 1H), 4.39 (d, J=17.5 Hz, 1H), 4.24 (d , J=17.4 Hz, 1H), 4.18 (t,J=6.l Hz, 2H), 3.05 (d, J=9.8 Hz, 2H), 2.91 (ddd, J =18.7, 13.7, 5.4 Hz, 1H), 2.58 (dd, J=13.5, 2.3 Hz, 3H), 2.49-2.39 (m, 1H), 2.32 (t, J=11.7 Hz, 2H), 2.18 (d, J=12.8 Hz, 2H), 2.10-1.87 (m, 5H). Electric sputter ionization mass spectroscopy (ESI-MS) [M+H] ⁺ m/z=571.66.

Example 72: 4-(4-chloro-2-fluorophenyl)-1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl) piperidine-4- carbonitrile (72)

The preparation method was the same as for 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-oxy)propyl)-4-phenylpiperidine-4-carbonitrile, and 27 mg of final product was obtained as a white solid, yield 33%; ^1H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 7.59 (d, J=11.8 Hz, 1H), 7.56-7.45 (m, 2H), 7, 39 (d, J=8.6 Hz, 1H), 7.31 (d, J=7.4 Hz, 1H), 7.25 (d, J=8.1 Hz, 1H), 5.11 ( dd, J=13.2, 5.0 Hz, 1H), 4.39 (d, J=17.4 Hz, 1H), 4.24 (d, J=17.4 Hz, 1H), 4, 17 (t, J=6.0 Hz, 2H), 3.20-2.82 (m, 4H), 2.58 (d, J=18.6 Hz, 2H), 2.48-2.18 (m, 5H), 2.09-1.89 (m, 5H).

Example 73: 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-4-(4-trifluoromethoxyphenyl)piperidine-4-carbonitrile (73)

The preparation method was the same as for 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-4-phenylpiperidine-4-carbonitrile, 26 .9 mg, yield 36%; ^1H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 7.68 (d, J=8.8 Hz, 2H), 7.52-7.41 (m, 3H), 7, 31 (d, J=7.4 Hz, 1H), 7.25 (d, J=8.2 Hz, 1H), 5.11 (dd, J=13.5, 5.0 Hz, 1H), 4.39 (d, J=17.4 Hz, 1H), 4.24 (d, J=17.5 Hz, 1H), 4.18 (t, J=6.0 Hz, 2H), 3, 03 (ddd, J=7.4, 4.6, 1.9 Hz, 2H), 2.98-2.85 (m, 1H), 2.69-2.52 (m, 3H), 2, 48-2.39 (m, 1H), 2.36-2.23 (m, 2H), 2.14 (dd, J=13.2, 5.0 Hz, 2H), 2.08-1, 86 (m, 5H). Electric sputter ionization mass spectroscopy (ESI-MS) [M+H] ⁺ m/z=571.66.

Example 74: 4-(2-chloro-4-fluorophenyl)-1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl) piperidine-4- carbonitrile (74)

The preparation method was the same as for 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-4-phenylpiperidine-4-carbonitrile, 28 mg white solid, yield 47%; ^1H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 7.63-7.54 (m, 2H), 7.48 (t, J=7.8 Hz, 1H), 7, 32 (dd, J=15.2, 5.0 Hz, 2H), 7.24 (d, J=8.1 Hz, 1H), 5.11 (dd, J=13.3, 5.1 Hz , 1H), 4.39 (d, J=17.4 Hz, 1H), 4.24 (d, J=17.4 Hz, 1H), 4.17 (t, J=5.9 Hz, 2H ), 3.05 (d, J=11.7 Hz, 2H), 2.97-2.85 (m, 1H), 2.56 (t, J=13.0 Hz, 3H), 2.45 (d, J=13.1 Hz, 3H), 2.35 (t, J=11.6 Hz, 2H), 2.03-1.88 (m, 5H).

Example 75: 4-(3-chlorophenyl)-1-(4-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)butyl)piperidine-4-carbonitrile (75)

The preparation method was the same as for 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-4-phenylpiperidine-4-carbonitrile, 18 .5 mg, yield 27%; ^1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.57 (s, 1H), 7.55-7.40 (m, 4H), 7.30 (d, J=7 .5 Hz, 1H), 7.23 (d, J=8.2 Hz, 1H), 5.14 (dd, J=13.3, 5.0 Hz, 1H), 4.40 (d, J =17.2 Hz, 1H), 4.24 (d, J=17.5 Hz, 1H), 4.17 (t, J=5.7 Hz, 2H), 3.02 (d, J=12 ,0 Hz, 2H), 2.98-2.86 (m, 1H), 2.60 (dt, J=10.3, 5.1 Hz, 1H), 2.45 (t, J=6, 4 Hz, 3H), 2.27 (t, J=12.0 Hz, 2H), 2.12 (d, J=12.7 Hz, 2H), 2.02-1.88 (m, 3H) , 1.80 (dt, J=13.3, 6.8 Hz, 2H), 1.70-1.59 (m, 2H).

Example 75: 4-(2,6-chlorophenyl)-1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-oxy)propyl)piperidine-4-carbonitrile ( 76)

The preparation method was the same as for 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-oxy)propyl)-4-phenylpiperidine-4-carbonitrile, and 33 mg of final product was obtained as a white solid, yield 40%; ^1H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 7.56 (d, J=8.0 Hz, 2H), 7.48 (t, J=7.8 Hz, 1H) , 7.40 (t, J=8.0 Hz, 1H), 7.31 (d, J=7.5 Hz, 1H), 7.25 (d, J=8.2 Hz, 1H), 5 .11 (dd, J=13.3, 5.1 Hz, 1H), 4.39 (d, J=17.5 Hz, 1H), 4.24 (d, J=17.4 Hz, 1H) , 4.17 (t, J=5.9 Hz, 2H), 3.07 (d, J=11.3 Hz, 2H), 2.96-2.86 (m, 1H), 2.56 ( t, J=12.2 Hz, 6H), 2.39 (d, J=11.7 Hz, 4H), 2.04-1.87 (m, 3H).

Example 77: 4-(4-chlorophenyl)-1-(4-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)butyl)piperidine-4-carbonitrile (77)

The preparation method was the same as for 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-4-phenylpiperidine-4-carbonitrile, 18 .5 mg, yield 27%; ^1H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 7.50 (dt, J=11.2, 8.4 Hz, 5H), 7.30 (d, J=7.5 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 5.11 (dd, J=13.3, 5.0 Hz, 1H), 4.38 (d, J=17 .2 Hz, 1H), 4.22 (d, J=17.5 Hz, 1H), 4.15 (t, J=5.7 Hz, 2H), 3.00 (d, J=12.0 Hz, 2H), 2.96-2.85 (m, 1H), 2.59 (dt, J=10.3, 5.1 Hz, 1H), 2.43 (t, J=6.4 Hz , 3H), 2.24 (t, J=12.0 Hz, 2H), 2.10 (d, J=12.7 Hz, 2H), 2.02-1.87 (m, 3H), 1 .78 (dt, J=13.3, 6.8 Hz, 2H), 1.69-1.57 (m, 2H).

Example 78: 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-4-(2-trifluoromethoxyphenyl)piperidine-4-carbonitrile (78)

The preparation method was the same as for Example 59, and 17 mg of the final product was obtained as a white solid, yield 28%; ^1H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 7.61-7.52 (m, 2H), 7.51-7.38 (m, 3H), 7.30 (d , J=7.4 Hz, 1H), 7.24 (d, J=8.1 Hz, 1H), 5.11 (dd, J=13.3, 5.1 Hz, 1H), 4.39 (d, J=17.4 Hz, 1H), 4.24 (d, J=17.4 Hz, 1H), 4.17 (t, J=6.1 Hz, 2H), 3.04 (d , J=12.3 Hz, 2H), 2.96-2.85 (m, 1H), 2.56 (t, J=12.2 Hz, 3H), 2.48-2.41 (m, 1H), 2.35 (t, J=11.9 Hz, 2H), 2.26 (d, J=13.2 Hz, 2H), 2.05-1.88 (m, 5H).

Example 79: 4-(3-chlorophenyl)-1-(5-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)piperidine-4-carbonitrile (79)

The preparation method was the same as for 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-4-phenylpiperidine-4-carbonitrile, and obtained 25 mg of 4-(3-chlorophenyl)-1-(5-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindole-4-)oxy)pentyl)piperidine-4-carbonitrile as a solid white substances, yield 37%; ^1H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 7.58 (s, 1H), 7.54-7.41 (m, 4H), 7.30 (d, J=7 .5 Hz, 1H), 7.24 (d, J=8.2 Hz, 1H), 5.10 (dd, J=13.3, 5.1 Hz, 1H), 4.37 (d, J =17.4 Hz, 1H), 4.22 (d, J=17.4 Hz, 1H), 4.12 (t, J=6.3 Hz, 2H), 2.99 (d, J=12 ,2 Hz, 2H), 2.96-2.84 (m, 1H), 2.56 (d, J=18.3 Hz, 2H), 2.48-2.35 (m, 3H), 2 .25 (t, J=11.5 Hz, 2H), 2.13 (d, J=12.4 Hz, 1H), 1.98 (t, J=11.2 Hz, 3H), 1.82 -1.72 (m, 2H), 1.50 (dt, J=16.5, 10.5 Hz, 4H).

Example 80: (S)-4-(2-chlorophenyl)-1-(3-((2-(3-methyl-2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-oxy)propyl) piperidine-4-carbonitrile (80)

Step 1: Methyl 3-hydroxy-2-methylbenzoate (20.54 g, 123.56 mmol, 1.0 eq.) was dissolved in 200 ml DMF in an ice bath for 15 minutes, sodium hydride (5.93 g, 148.27 mmol, 1.2 eq.), then MOMCl (11.94 g, 148.27 mmol, 1.2 eq.), and reacted at room temperature for 1 hour. After completion of the reaction, saturated ammonium chloride was added to stop the reaction, extracted three times with ethyl acetate, washed three times with saturated ammonium chloride, dried, concentrated under reduced pressure and purified by column chromatography to obtain 25.98 g of a yellow oily liquid, 100% yield. ^1H NMR (400 MHz, CDCl ₃ ) δ 7.47 (dd, J=7.5, 1.4 Hz, 1H), 7.24-7.14 (m, 2H), 5.21 (s, 2H), 3.89 (s, 3H), 3.49 (s, 3H), 2.49-2.41 (m, 3H).

Step 2: Methyl 3-methoxymethoxy-2-methylbenzoate (25.98 g, 123.56 mmol, 1.0 eq.) was dissolved in 200 ml carbon tetrachloride, n-bromosuccinimide (NBS) (23.09 mmol, 129. 24 mmol, 1.05 mmol) and AIBN (2.03 g, 12.36 mmol, 0.1 eq.) and refluxed at 88°C for 6 hours. After completion of the reaction, the solvent was separated by centrifugation under reduced pressure and purified by column chromatography to obtain 35.73 g of a brown solid. Yield 100%. ^1H NMR (400 MHz, CDCl ₃ ) δ 7.58 (dd, J=6.5, 2.5 Hz, 1H), 7.35-7.27 (m, 1H), 5.30 (s, 1H), 5.10-5.05 (m, 1H), 3.94 (s, 1H), 3.53 (s, 1H).

Step 3: Methyl 2-bromomethyl-3-methoxymethoxybenzoate (353 mg, 1.22 mmol, 1.0 eq.) and (8)-3-amino(o-3-methylpiperidine)-2,6-dione hydrochloride monohydrate ( 294 mg, 1.22 mmol, 1.0 eq.) was dissolved in 20 ml of toluene. Triethylamine (136 mg, 1.34 mmol, 1.1 eq) was added and refluxed at 120°C for 24 hours. After completion of the reaction, the toluene was separated and purified by column chromatography to obtain 232 mg of a white solid with a yield of 61%.

Step 4: (S)-3-(4-methoxymethoxy-1-oxoisoindoline-2-)-3-methylpiperidine-2,6-dione (232 mg, 0.73 mmol, 1.0 eq.) was added to the round bottom flask capacity of 50 ml and added 20 ml of dioxane-hydrochloric acid and 200 μl of methanol. The mixture was reacted at room temperature for 1 hour. After completion of the reaction, the solvent was separated by centrifugation and used directly in the next step without further purification.

Step 5: (S)-3-(4-hydroxy-1-oxoisoindoline-2-)-3-methylpiperidine-2,6-dione (200 mg, 0.73 mmol, 1.0 eq.) was dissolved in 20 ml acetonitrile. 1,2-Dibromopropane (736 mg, 3.65 mmol, 5.0 eq) and anhydrous potassium carbonate (101 mg, 0.73 mmol, 1.0 eq) were added and reacted at 50°C for 24 hours. After completion of the reaction, the solvent was separated by centrifugation, diluted with ethyl acetate, washed with saturated sodium chloride and purified by column chromatography to obtain 200 mg of a white solid with a yield of 69%.

Step 6: (S)-3-(4-(3-bromopropoxy)-1-oxoisoindoline-2-)-3-methylpiperidine-2,6-dione (40 mg, 0.10 mmol, 1.0 eq.) dissolved in 3 ml of DMSO, 4-(2-chlorophenyl)piperidine-4-carbonitrile (39 mg, 0.15 mmol, 1.5 eq.) and triethylamine (102 mg, 1.01 mmol, 10.0 eq.) were added. ) and reacted at 40°C overnight. After completion of the reaction, diluted with 20 ml of ethyl acetate, washed with saturated sodium chloride and purified by thin layer chromatography and high performance liquid chromatography to obtain 15 mg of product as a white solid, 28% yield; ^1H NMR (400 MHz, DMSO) δ 10.87 (s, 1H), 7.61-7.51 (m, 2H), 7.45 (dd, J=12.1, 6.3 Hz, 3H ), 7.22 (dd, J=11.7, 7.8 Hz, 2H), 4.65 (d, J=17.5 Hz, 1H), 4.54 (d, J=17.6 Hz , 1H), 4.18 (t, J=6.1 Hz, 2H), 3.07 (d, J=11.7 Hz, 2H), 2.80-2.51 (m, 7H), 2 .37 (t, J=12.3 Hz, 2H), 2.08 1.84 (m, 5H), 1.69 (s, 3H).

Example 81: 4-(4-chlorophenyl)-1-(5-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)pentyl)piperidine-4-carbonitrile (81)

The preparation method was the same as for 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-4-phenylpiperidine-4-carbonitrile, and in the end 21 mg of 4-(4-chlorophenyl)-1-(5-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindole-4-)oxy)pentyl)piperidine-4-carbonitrile were obtained in as a white solid, yield 22%; ^1H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 7.55 (d, J=8.5 Hz, 2H), 7.52-7.43 (m, 3H), 7, 30 (d, J=7.5 Hz, 1H), 7.24 (d, J=8.1 Hz, 1H), 5.11 (dd, J=13.3, 5.0 Hz, 1H), 4.37 (d, J=17.4 Hz, 1H), 4.22 (d, J=17.4 Hz, 1H), 4.12 (t, J=6.2 Hz, 2H), 2, 98 (d, J=11.9 Hz, 2H), 2.94-2.84 (m, 1H), 2.56 (d, J=17.6 Hz, 1H), 2.48-2.34 (m, 3H), 2.24 (t, J=11.7 Hz, 2H), 2.09 (d, J=12.8 Hz, 2H), 1.95 (dd, J=17.2, 8.5 Hz, 3H), 1.77 (dd, J=13.4, 6.6 Hz, 2H), 1.58-1.38 (m, 4H).

Example 82: 4-(2-chlorophenyl)-1-(4-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)butyryl)piperidine-4-carbonitrile (82)

The synthesis method was the same as for N-(3-chloro-4-methylphenyl)-4-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-oxy)butanamide, and 52 mg of final product was obtained as a white solid, yield 66%; ^1H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 7.60-7.54 (m, 1H), 7.51-7.40 (m, 4H), 7.30 (d , J=7.5 Hz, 1H), 7.24 (d, J=8.2 Hz, 1H), 5.11 (dd, J=13.2, 5.0 Hz, 1H), 4.64 (d, J=13.4 Hz, 1H), 4.39 (d, J=17.5 Hz, 1H), 4.25 (d, J=17.4 Hz, 1H), 4.13 (d , J=16.2 Hz, 3H), 3.37 (d,J=12.8 Hz, 1H), 2.89 (q, J=13.3 Hz, 2H), 2.64-2.53 (m, 3H), 2.44 (dd, J=16.8, 8.0 Hz, 4H), 2.05-1.92 (m, 4H), 1.84 (d, J=12.5 Hz, 1H).

Example 83: 4-(3-chlorophenyl)-1-(4-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)butyryl)piperidine-4-carbonitrile (83)

The synthesis method was the same as for N-(3-chloro-4-methylphenyl)-4-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-oxy)butanamide, and 39 mg of final product was obtained as a white solid, yield 49%; ¹ H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 7.61 (s, 1H), 7.56-7.43 (m, 4H), 7.30 (d, J=7 .4 Hz, 1H), 7.25 (d, J=8.1 Hz, 1H), 5.11 (dd, J=13.3, 5.0 Hz, 1H), 4.62 (d, J =14.0 Hz, 1H), 4.39 (d, J=17.4 Hz, 1H), 4.24 (d, J=17.4 Hz, 1H), 4.16 (t, J=6 ,2 Hz, 2H), 4.09 (d, J=14.4 Hz, 1H), 3.27 (d, J=13.2 Hz, 1H), 2.98-2.74 (m, 2H ), 2.56 (dd, J=13.3, 6.2 Hz, 3H), 2.43 (dd, J=13.2, 4.4 Hz, 1H), 2.24-1.79 ( m, 7H).

Example 84: 4-(4-chlorophenyl)-1-(4-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)butyryl)piperidine-4-carbonitrile (84)

The synthesis method was the same as for N-(3-chloro-4-methylphenyl)-4-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-oxy)butanamide, and 38 mg of final product was obtained as a white solid, yield 47%; ^1H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 7.60-7.43 (m, 5H), 7.27 (dd, J=21.4, 7.8 Hz, 2H ), 5.11 (dd, J=13.3, 5.1 Hz, 1H), 4.62 (d, J=13.5 Hz, 1H), 4.39 (d, J=17.5 Hz , 1H), 4.24 (d, J=17.4 Hz, 1H), 4.16 (t, J=6.2 Hz, 2H), 4.09 (d, J=13.6 Hz, 1H ), 3.27 (d, J=12.6 Hz, 1H), 2.99-2.75 (m, 2H), 2.56 (dd, J=13.2, 7.1 Hz, 3H) , 2.43 (dd, J=13.0, 4.4 Hz, 3H), 2.13 (d, J=13.3 Hz, 2H), 2.05-1.92 (m, 4H), 1.86 (d, J=12.6 Hz, 1H).

Example 85: 4-(2-chlorophenyl)-1-(5-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)valeryl)piperidine-4-carbonitrile (85)

The synthesis method was the same as for N-(3-chloro-4-methylphenyl)-4-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-oxy)butanamide, and 26 mg of final product was obtained as a white solid, yield 33%; ^1H NMR (400 MHz, DMSO) δ 10.96 (s, 1H), 7.57 (dt, J=7.3, 3.7 Hz, 1H), 7.54-7.41 (m, 4H ), 7.30 (d, J=7.4 Hz, 1H), 7.24 (d, J=8.1 Hz, 1H), 5.10 (dd, J=13.3, 5.1 Hz , 1H), 4.63 (d, J=14.1 Hz, 1H), 4.37 (d, J=17.4 Hz, 1H), 4.22 (d, J=17.4 Hz, 1H ), 4.13 (dd, J=14.7, 8.6 Hz, 3H), 3.37 (d, J=12.7 Hz, 1H), 2.89 (ddd, J=25.1, 15.0, 8.7 Hz, 2H), 2.59 (s, 1H), 2.51-2.37 (m, 9H), 1.99 (dd, J=16.4, 8.8 Hz , 2H), 1.91-1.62 (m, 5H).

Example 86: 1-(4-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-oxy-)butyryl)-4-(4-trifluoromethoxyphenyl)piperidine-4-carbonitrile ( 86)

The synthesis method was the same as for N-(3-chloro-4-methylphenyl)-4-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-oxy)butanamide, and 32 mg of final product was obtained as a white solid, yield 35%; ^1H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 7.67 (d, J=8.5 Hz, 2H), 7.47 (dd, J=15.0, 7.9 Hz, 3H), 7.27 (dd, J=19.9, 7.8 Hz, 2H), 5.11 (dd, J=13.4, 5.0 Hz, 1H), 4.63 (d , J=13.7 Hz, 1H), 4.40 (d, J=17.4 Hz, 1H), 4.25 (d, J=17.3 Hz, 1H), 4.20-4.06 (m, 3H), 3.28 (d, J=13.4 Hz, 1H), 2.99-2.77 (m, 2H), 2.65-2.54 (m, 3H), 2, 43 (dd, J=13.3, 4.4 Hz, 1H), 2.16 (d, J=13.0 Hz, 2H), 2.01 (dd, J=13.1, 6.8 Hz , 4H), 1.92-1.80(m, 1H).

Example 87: 4-(3-chlorophenyl)-1-(5-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)valeryl)piperidine-4-carbonitrile (87)

The synthesis method was the same as for N-(3-chloro-4-methylphenyl)-4-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-oxy)butanamide, and 32 mg of final product was obtained as a white solid, yield 42%; ^1H NMR (400 MHz, DMSO) δ 10.96 (s, 1H), 7.62 (s, 1H), 7.56-7.43 (m, 4H), 7.30 (d, J=7 .4 Hz, 1H), 7.24 (d, J=8.1 Hz, 1H), 5.10 (dd, J=13.3, 5.1 Hz, 1H), 4.61 (d, J =13.6 Hz, 1H), 4.37 (d, J=17.4 Hz, 1H), 4.22 (d, J=17.4 Hz, 1H), 4.15 (t, J=6 ,2 Hz, 2H), 4.09 (d, J=14.2 Hz, 1H), 3.27 (t, J=9.6 Hz, 1H), 2.97-2.84 (m, 1H ), 2.79 (t, J=12.6 Hz, 1H), 2.56 (d, J=17.9 Hz, 1H), 2.50-2.34 (m, 6H), 2.23 -1.60 (m, 10N).

Example 88: 1-(4-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-oxy-)butyryl)-4-(3-trifluoromethoxyphenyl)piperidine-4-carbonitrile ( 88)

The synthesis method was the same as for N-(3-chloro-4-methylphenyl)-4-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-oxy)butanamide, and 32 mg of final product was obtained as a white solid, 56% yield; ¹ H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 7.67 (d, J=8.5 Hz, 2H), 7.47 (dd, J=15.0, 7.9 Hz, 3H), 7.27 (dd, J=19.9, 7.8 Hz, 2H), 5.11 (dd, J=13.4, 5.0 Hz, 1H), 4.63 (d , J=13.7 Hz, 1H), 4.40 (d, J=17.4 Hz, 1H), 4.25 (d, J=17.3 Hz, 1H), 4.20-4.06 (m, 3H), 3.28 (d, J=13.4 Hz, 1H), 2.99-2.77 (m, 2H), 2.65-2.54 (m, 3H), 2, 43 (dd, J=13.3, 4.4 Hz, 1H), 2.16 (d, J=13.0 Hz, 2H), 2.01 (dd, J=13.1, 6.8 Hz , 4H), 1.92-1.80(m, 1H).

Example 89: 4-(3-chlorophenyl)-1-(5-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)valeryl)piperidine-4-carbonitrile (89)

The synthesis method was the same as for N-(3-chloro-4-methylphenyl)-4-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-oxy)butanamide, and 64 mg of final product was obtained as a white solid, yield 82%; ¹ H NMR (400 MHz, DMSO) δ 10.96 (s, 1H), 7.57 (d, J=8.8 Hz, 2H), 7.51 (d, J=8.8 Hz, 2H) , 7.47 (d, J=7.8 Hz, 1H), 7.30 (d, J=7.5 Hz, 1H), 7.24 (d, J=8.1 Hz, 1H), 5 .10 (dd, J=13.3, 5.1 Hz, 1H), 4.61 (d, J=12.4 Hz, 1H), 4.37 (d, J=17.4 Hz, 1H) , 4.22 (d, J=17.4 Hz, 1H), 4.15 (t, J=6.1 Hz, 2H), 4.08 (d, J=14.9 Hz, 1H), 3 .28 (s, 1H), 2.88 (d, J=12.1 Hz, 1H), 2.79 (s, 1H), 2.56 (d, J=18.5 Hz, 1H), 2 .45 (t, J=7.4 Hz, 6H), 2.14 (d, J=12.5 Hz, 2H), 2.10-1.92 (m, 2H), 1.92-1, 60 (m, 6H).

Example 90: 1-(4-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-oxy-)butyryl)-4-(2-trifluoromethoxyphenyl)piperidine-4-carbonitrile ( 90)

The synthesis method was the same as for N-(3-chloro-4-methylphenyl)-4-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)butanamide, obtained 47 mg of final product as a white solid, 88% yield; ¹ H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 7.60-7.40 (m, 5H), 7.30 (d, J=7.5 Hz, 1H), 7, 24 (d, J=8.1 Hz, 1H), 5.11 (dd, J=13.3, 5.0 Hz, 1H), 4.63 (d, J=13.8 Hz, 1H), 4.39 (d, J=17.4 Hz, 1H), 4.25 (d, J=17.3 Hz, 1H), 4.15 (t, J=6.0 Hz, 3H), 3, 35 (s, 1H), 2.97-2.82 (m, 2H), 2.56 (t, J=10.2 Hz, 3H), 2.45 (s, 1H), 2.28 (d , J=13.1 Hz, 2H), 2.07-1.93 (m, 4H), 1.91-1.77 (m, 1H).

Example 91: 4-(2-chlorophenyl)-1-(4-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)butyl)piperidine-4-carbonitrile (91)

The preparation method was the same as for 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-4-phenylpiperidine-4-carbonitrile, 17 .4 mg, yield 17%. ^1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.55 (ddd, J=11.7, 5.3, 2.8 Hz, 3H), 7.44 (ddd, J =7.1, 5.1, 2.8 Hz, 4H), 5.13 (dd, J=13.2, 5.1 Hz, 1H), 4.47 (d, J=17.2 Hz, 1H), 4.32 (d, J=17.2 Hz, 1H), 2.99 (d, J=12.3 Hz, 2H), 2.96-2.85 (m, 1H), 2, 67 (t, J=7.6 Hz, 2H), 2.58 (d, J=17.6 Hz, 1H), 2.48-2.36 (m, 5H), 2.30 (t, J =11.9 Hz, 2H), 2.04-1.89 (m, 3H), 1.63 (dt, J=15.3, 7.7 Hz, 2H), 1.56-1.45 ( m, 2H).

Example 92: 4-(2-chlorophenyl)-1-(5-(2-(2,6-oxopiperidine-3-)-1-oxoisoindoline-4-)pentyl)piperidine-4-carbonitrile (92)

The preparation method was the same as for 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-oxy)propyl)-4-phenylpiperidine-4-carbonitrile, 10 .5 mg, yield 10%; ^1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.59-7.51 (m, 3H), 7.44 (dt, J=4.4, 3.4 Hz, 4H ), 5.13 (dd,J=13.3, 5.1 Hz, 1H), 4.46 (d, J=17.2 Hz, 1H), 4.31 (d, J=17.2 Hz , 1H), 3.00 (d, J=12.0 Hz, 2H), 2.96-2.86 (m, 1H), 2.67-2.56 (m, 3H), 2.44 ( d, J=12.9 Hz, 3H), 2.39-2.25 (m, 4H), 2.05-1.88 (m, 3H), 1.63 (dt, J=15.6, 7.9 Hz, 2H), 1.55-1.44 (m, 2H), 1.34 (dt,J=14.8, 7.5 Hz, 2H).

Example 93: 4-(3-chlorophenyl)-1-(5-(2-(2,6-oxopiperidine-3-)-1-oxoisoindoline-4-)pentyl)piperidine-4-carbonitrile (93)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 27 mg, 26% yield ; ^1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.61-7.41 (m, 7H), 5.13 (dd, J=13.3, 5.1 Hz, 1H ), 4.47 (d, J=17.2 Hz, 1H), 4.32 (d, J=17.2 Hz, 1H), 3.02-2.84 (m, 3H), 2.67 (t, J=7.6 Hz, 2H), 2.59 (d, J=16.8 Hz, 1H), 2.46-2.35 (m, 3H), 2.23 (t, J= 11.3 Hz, 2H), 2.13 (d, J=12.6 Hz, 2H), 2.05-1.93 (m, 3H), 1.65 (dt, J=16.6, 6 .8 Hz, 2H), 1.51 (dt, J=15.2, 7.5 Hz, 2H).

Example 94: 1-(5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)pentyl)-4-(3-trifluoromethoxyphenyl)piperidine-4-carbonitrile (94)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 9 mg, 8% yield ; ^1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.62-7.58 (m, 2H), 7.56 (dd, J=5.9, 2.7 Hz, 1H ), 7.50 (s, 1H), 7.48-7.45 (m, 2H), 7.40 (d, J=4.1 Hz, 1H), 5.14 (dd, J=13, 3, 5.1 Hz, 1H), 4.47 (d, J=17.2 Hz, 1H), 4.31 (d, J=17.1 Hz, 1H), 2.98 (d, J= 11.5 Hz, 2H), 2.94-2.87 (m, 1H), 2.67-2.56(m, 3H), 2.45-2.38 (m, 1H), 2.39 -2.31 (m, 2H), 2.23 (t, J=11.4 Hz, 2H), 2.14 (d, J=12.3 Hz, 2H), 2.06-1.93 ( m, 3H), 1.63 (dt, J=15.1, 7.6 Hz, 2H), 1.50 (dt, J=14.8, 7.6 Hz, 2H), 1.39-1 .29 (m, 2H).

Example 95: 4-(4-chlorophenyl)-1-(4-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)butyl)piperidine-4-carbonitrile (95)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 32.8 mg, yield 31.6%; ^1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 5.13 (dd, J=13.3, 5.0 Hz, 1H), 4.47 (d, J=17.2 Hz, 1H), 4.32 (d, J=17.2 Hz, 1H), 3.00-2.86 (m, 3H), 2.67 (t, J=7.5 Hz, 2H), 2.62-2.55 (m, 1H), 2.47-2.36 (m, 3H), 2.24 (t, J=11.9 Hz, 2H), 2.09 (d, J= 12.9 Hz, 2H), 2.04-1.90 (m, 3H), 1.69-1.58 (m, 2H), 1.51 (dt, J=14.1, 7.1 Hz , 2H), 1.23-1.23 (m, 1H).

Example 96: 1-(5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)pentyl)-4-(4-trifluoromethoxyphenyl)piperidine-4-carbonitrile (96)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 19.9 mg, yield 18%; ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.66 (dd, J=7.0, 4.9 Hz, 2H), 7.56 (dt, J=7.7 , 3.8 Hz, 1H), 7.45 (dd, J=8.8, 5.8 Hz, 4H), 5.14 (dd, J=13.3, 5.1 Hz, 1H), 4 .47 (d, J=17.2 Hz, 1H), 4.31 (d, J=17.1 Hz, 1H), 2.98 (d, J=11.3 Hz, 2H), 2.94 -2.86 (m, 1H), 2.67-2.56(m, 3H), 2.43 (dt, J=13.5, 9.1 Hz, 1H), 2.38-2.33 (m, 2H), 2.24 (t, J=11.4 Hz, 2H), 2.12 (d, J=12.3 Hz, 2H), 2.05-1.90 (m, 3H), 1 .63 (dt, J=15.2, 7.7 Hz, 2H), 1.55-1.45 (m, 2H), 1.34 (dt, J=14.9, 7.6 Hz, 2H).

Example 97: 1-(4-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)butyl)-4-(3-trifluoromethoxyphenyl)piperidine-4-carbonitrile (97)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 13 mg, 11% yield ; ^1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.63-7.54 (m, 3H), 7.52-7.44 (m, 3H), 7.39 (d , J=6.6 Hz, 1H), 5.13 (dd, J=13.3, 5.1 Hz, 1H), 4.47 (d, J=17.2 Hz, 1H), 4.32 (d, J=17.2 Hz, 1H), 3.02-2.86 (m, 3H), 2.67 (t, J=7.6 Hz, 2H), 2.59 (d, J= 17.1 Hz, 1H), 2.47-2.36 (m, 3H), 2.24 (t, J=11.6 Hz, 2H), 2.14 (d, J=12.2 Hz, 2H), 2.06-1.94 (m, 3H), 1.64 (dt, J=15.7, 6.5 Hz, 2H), 1.51 (dt, J=14.5, 7, 2 Hz, 2H).

Example 98: 4-(2-chlorophenyl)-1-(6-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)hexyl)piperidine-4-carbonitrile (98)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 11.9 mg, yield 11.7%; ¹ H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.55 (dd, J=10.3, 6.6 Hz, 3H), 7.48-7.40 (m, 4H ), 5.13 (dd, J=13.3, 5.0 Hz, 1H), 4.46 (d, J=17.2 Hz, 1H), 4.30 (d, J=17.1 Hz , 1H), 3.01 (d, J=12.2 Hz, 2H), 2.98-2.86 (m, 1H), 2.68-2.56(m, 3H), 2.47- 2.41 (m, 3H), 2.40-2.27 (t,4H), 2.05-1.90 (m, 3H), 1.65-1.57 (m, 2H), 1, 50-1.40 (m, 2H), 1.38-1.27 (m, 4H).

Example 99: 1-(4-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)butyl)-4-(4-trifluoromethoxyphenyl)piperidine-4-carbonitrile (99)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 18.5 mg, yield 16%; ^1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.67 (d, J=8.9 Hz, 2H), 7.56 (dt, J=7.6, 3.8 Hz, 1H), 7.46 (dt, J=13.1, 6.3 Hz, 4H), 5.14 (dd, J=13.3, 5.1 Hz, 1H), 4.47 (d , J=17.2 Hz, 1H), 4.32 (d, J=17.1 Hz, 1H), 2.97 (d, J=12.0 Hz, 2H), 2.94-2.86 (m, 1H), 2.67 (t, J=7.6 Hz, 2H), 2.59 (d, J=16.8 Hz, 1H), 2.42 (dd, J=14.1, 7.5 Hz, 3H), 2.25 (t, J=11.9 Hz, 2H), 2.12 (d, J=12.5 Hz, 2H), 2.01-l.95(m, 3H), 1.63 (dd, J=14.1, 6.6 Hz, 2H), 1.52 (dd, J=13.9, 7.1 Hz, 2H).

Example 100: 4-(3-chlorophenyl)-1-(6-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)hexyl)piperidine-4-carbonitrile (100)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 13.2 mg, yield 13%; ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.60-7.42 (m, 7H), 5.14 (dd, J=13.3, 5.1 Hz, 1H ), 4.46 (d, J=17.2 Hz, 1H), 4.30 (d, J=17.1 Hz, 1H), 3.04-2.86 (m, 3H), 2.68 -2.56(m, 3H), 2.47-2.33 (m, 3H), 2.26 (t,J=11.5 Hz, 2H), 2.14 (d, J=12.3 Hz, 2H), 2.05-1.95 (m, 3H), 1.66-1.56 (m, 2H), 1.51-1.41 (m, 2H), 1.38-1, 27(m, 4H).

Example 101: 4-(2,4-chlorophenyl)-1-(4-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)butyl)piperidine-4-carbonitrile (101)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 31 mg, 29% yield ^1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.74 (d, J=2.0 Hz, 1H), 7.54 (qd, J=8.7, 3.7 Hz, 3H), 7.48-7.44 (m, 2H), 5.13 (dd, J=13.3, 5.1 Hz, 1H), 4.47 (d, J=17.2 Hz , 1H), 4.31 (d, J=17.1 Hz, 1H), 2.99 (d, J=11.9 Hz, 2H), 2.95-2.86 (m, 1H), 2 .67 (t, J=7.6 Hz, 2H), 2.62-2.54 (m, 1H), 2.47-2.36 (m, 5H), 2.30 (t, J=12 .0 Hz, 2H), 2.04-1.91 (m, 3H), 1.69-1.57 (m, 2H), 1.54-1.47 (m, 2H).

Example 102: 4-(4-chlorophenyl)-1-(6-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)hexyl)piperidine-4-carbonitrile (102)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 32.9 mg, yield 32.5%; ^1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.58-7.53 (m, 3H), 7.53-7.48 (m, 2H), 7.47-7 .44 (m, 2H), 5.13 (dd, J=13.3, 5.1 Hz, 1H), 4.46 (d, J=17.2 Hz, 1H), 4.30 (d, J=17.1 Hz, 1H), 3.02-2.87 (m, 3H), 2.68-2.56(m, 3H), 2.46-2.31 (m, 3H), 2 .24 (t, J=11.5 Hz, 2H), 2.10 (d, J=12.0 Hz, 2H), 2.05-1.90 (m, 4H), 1.66-1, 56 (m, 2H), 1.50-1.40 (m, 2H), 1.38-1.27 (m, 4H).

Example 103: 3-(4-(5-(3,4-dihydroquinoline-1(2H))pentyl)-1-oxoisoindoline-2-)piperidine-2,6-dione (103)

Compound 3-(4-(5-bromopentyl)-1-oxoisoindoline-2-)piperidine-2,6-dione (77 mg, 0.196 mmol, 1 eq.) and 1,2,3,4-tetrahydroquinoline (78 mg , 0.587 mmol, 3 eq.) was dissolved in 5 ml of anhydrous DMF, sodium iodide (44 mg, 0.294 mmol, 1.5 eq.) was added with stirring at room temperature, and the resulting reaction solution was reacted overnight at 80° WITH. After completion of the reaction, the resulting reaction solution was directly separated by HPLC to obtain 8.5 mg of 3-(4-(5-(3,4-dihydroquinoline-1(2H))pentyl)-1-oxoisoindoline-2-)piperidine-2 ,6-dione as a white solid, yield 10%; ^1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.56 (p, J=3.9 Hz, 1H), 7.46 (dd, J=7.6, 4.0 Hz, 2H), 6.95-6.89 (m, 1H), 6.83 (dd, J=7.2, 1.3 Hz, 1H), 6.54-6.48 (m, 1H) , 6.42 (td, J=7.2, 0.7 Hz, 1H), 5.13 (dd, J=13.4, 5.2 Hz, 1H), 4.46 (d, J=17 ,1 Hz, 1H), 4.30 (d, J=17.1 Hz, 1H), 3.20 (dd, J=9.8, 4.9 Hz, 4H), 2.92 (ddd, J =17.6, 13.4, 5.2 Hz, 1H), 2.61 (ddd, J=8.7, 6.6, 4.9 Hz, 5H), 2.45-2.31 (m , 1H), 2.04-1.94 (m, 1H), 1.87-1.77 (m, 2H), 1.65 (dt, J=8.8, 7.0 Hz, 2H), 1.54 (dt, J=14.8, 7.3 Hz, 2H), 1.36 (dd, J=14.4, 7.6 Hz, 2H).

Example 104: 3-(4-(5-(6-fluoro-2-methyl-3,4-dihydroquinoline-1(2H))pentyl)-1-oxoisoindoline-2-)piperidine-2,6-dione (104 )

Tetrahydroquinoline was replaced by 2-methyl-6-fluorotetrahydroquinoline. The preparation method was the same as for 3-(4-(5-(3,4-dihydroquinoline-1(2H))pentyl)-1-oxoisoindoline-2-)piperidine-2,6-dione, 17 mg, yield 28%; ^1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.60-7.53 (m, 1H), 7.45 (d, J=4.3 Hz, 2H), 6, 76 (ddt, J=12.2, 5.8, 3.0 Hz, 2H), 6.42 (dd, J=8.8, 4.8 Hz, 1H), 5.13 (dd,J= 13.3, 5.1 Hz, 1H), 4.46 (dd, J=17.2, 1.9 Hz, 1H), 4.30 (dd, J=17.2, 1.7 Hz, 1H ), 3.45-3.37 (m, 1H), 3.31-3.20 (m, 1H), 3.12-3.02 (m, 1H), 2.92 (ddd, J=17 ,1, 13.6, 5.4 Hz, 1H), 2.75-2.55 (m, 5H), 2.42 (ddd, J=26.0, 13.1, 4.3 Hz, 1H ), 2.04-1.94 (m, 1H), 1.66 (ddd, J=9.5, 8.0, 4.6 Hz, 4H), 1.59-1.43 (m, 2H ), 1.40-1.28 (m, 2H), 1.03 (d, J=6.4 Hz, 3H).

Example 105: 3-(4-(5-(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-)pentyl)-1-oxoisoindoline-2-)piperidine-2,6- dione (105)

1,2,3,4-Tetrahydroquinoline was replaced by benzomorpholine. The preparation method was the same as for 3-(4-(5-(3,4-dihydroquinoline-1(2H))pentyl)-1-oxoisoindoline-2-)piperidine-2,6-dione, 23 mg, yield 25%; ¹ H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.56 (dd, J=8.2, 4.5 Hz, 1H), 7.49-7.43 (m, 2H ), 6.77-6.70 (m, 1H), 6.68-6.61 (m, 2H), 6.47 (td, J=7.8, 1.4 Hz, 1H), 5, 13 (dd, J=13.3, 5.1 Hz, 1H), 4.46 (d, J=17.1 Hz, 1H), 4.30 (d, J=17.1 Hz, 1H), 4.15-4.07 (m, 2H), 3.29-3.25 (m, 2H), 3.24-3.18 (m, 2H), 2.92 (ddd, J=17.7 , 13.7, 5.4 Hz, 1H), 2.63 (dd, J=22.5, 14.7 Hz, 3H), 2.42 (ddd, J=26.3, 13.2, 4 .4 Hz, 1H), 2.07-1.94 (m, 1H), 1.71-1.61 (m, 2H), 1.60-1.49 (m, 2H), 1.36 ( dt, J=15.2, 7.7 Hz, 2H).

Example 106: 3-(4-(5-(6-bromo-3,4-dihydroquinoline-1(2H))pentyl)-1-oxoisoindoline-2-)piperidine-2,6-dione (106)

Tetrahydroquinoline was replaced by 6-bromotetrahydroquinoline. The preparation method was the same as for 3-(4-(5-(3,4-dihydroquinoline-1(2H))pentyl)-1-oxoisoindoline-2-)piperidine-2,6-dione, 10.3 mg, yield 10%; ^1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.56 (p, J=3.9 Hz, 1H), 7.47-7.42 (m, 2H), 7. 05 (dd, J=8.8, 2.5 Hz, 1H), 6.99 (d, J=2.5 Hz, 1H), 6.46 (d, J=8.9 Hz, 1H), 5.13 (dd, J=13.2, 5.1 Hz, 1H), 4.46 (d, J=17.0 Hz, 1H), 4.30 (d, J=17.3 Hz, 1H ), 3.26-3.12 (m, 4H), 2.92 (ddd, J=17.3, 13.3, 5.3 Hz, 1H), 2.64 (dd, J=9.6 , 5.9 Hz, 5H), 2.47-2.31 (m, 2H), 2.05-1.95 (m, 1H), 1.83-1.74 (m, 2H), 1, 68-1.58 (m, 2H), 1.52 (dt, J=14.5, 7.4 Hz, 2H), 1.40-1.28 (m, 2H).

Example 107: 3-(4-(5-(indoline-1-)pentyl)-1-oxoisoindoline-2-)piperidine-2,6-dione (107)

1,2,3,4-Tetrahydroquinoline was replaced by hydrogenated indole. The preparation method was the same as for 3-(4-(5-(3,4-dihydroquinoline-1(2H))pentyl)-1-oxoisoindoline-2-)piperidine-2,6-dione, 46.3 mg, yield 45%; ^1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.56 (dd, J=6.1, 2.4 Hz, 1H), 7.49-7.43 (m, 2H ), 7.03-6.90 (m, 2H), 6.53 (t, J=7.2 Hz, 1H), 6.45 (d, J=7.8 Hz, 1H), 5.13 (dd, J=13.3, 5.1 Hz, 1H), 4.46 (d, J=17.2 Hz, 1H), 4.31 (d, J=17.1 Hz, 1H), 3 .26 (t, J=8.4 Hz, 2H), 3.01 (t, J=7.2 Hz, 2H), 2.97-2.89 (m, 1H)5 2.85 (t, J=8.3 Hz, 2H), 2.69-2.64 (m, 2H), 2.63-2.56 (m, 1H), 2.41 (ddd, J=17.6, 13, 5, 4.7 Hz, 1H), 2.00 (ddd, J=10.5, 6.9, 3.3 Hz, 1H), 1.73-1.53 (m, 4H), 1.47 -1.35 (m, 2H).

Example 108: 2-(2,6-dioxopiperidine-3-)-4-(4-((2-methylquinoline-4-)oxy)butoxy)isoindoline-1,3-dione (108)

The preparation method was the same as for 2-(2,6-dioxopiperidine-3-)-4-(4-(quinoline-4-oxo)butoxy) isoindoline-1,3-dione, and 12.5 mg was obtained white solid, yield 20%; ^1H NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 8.15 (d, J=9.0 Hz, 1H), 7.92 (d, J=8.1 Hz, 1H) , 7.88-7.78 (m, 2H), 7.55 (t, J=11.0 Hz, 2H), 7.44 (d, J=7.2 Hz, 1H), 7.20 ( s, 1H), 5.07 (dd, J=12.8, 5.4 Hz, 1H), 4.49 (s, 2H), 4.35 (t, J=5.9 Hz, 2H), 2.88 (ddd, J=16.8, 14.0, 5.4 Hz, 1H), 2.69 (s, 3H), 2.63-2.55 (m, 1H), 2.18- 1.95 (m, 6H).

Example 109: 3-(4-(5-(7-chloro-3,4-dihydroquinoline-1(2H))pentyl)-1-oxoisoindoline-2-)piperidine-2,6-dione (109)

Tetrahydroquinoline was replaced by 7-chloro-1,2,3,4-tetrahydroquinoline, the preparation method was the same as for 3-(4-(5-(3,4-dihydroquinoline-1(2H))pentyl)-1- oxoisoindoline-2-)piperidine-2,6-dione, 4.5 mg, yield 5%; ^1H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 7.56 (dt, J=7.7, 3.9 Hz, 1H), 7.47-7.43 (m, 2H ), 6.83 (d, J=7.9 Hz, 1H), 6.48 (d, J=1.9 Hz, 1H), 6.42 (dd, J=7.9, 1.9 Hz , 1H), 5.13 (dd, J=13.3, 5.1 Hz, 1H), 4.46 (d, J=17.2 Hz, 1H), 4.31 (d, J=17, 1 Hz, 1H), 3.21 (dd, J=9.3, 5.6 Hz, 4H), 2.98-2.86 (m, 1H), 2.72-2.56 (m, 5H ), 2.47-2.35 (m, 1H), 2.01 (ddd, J=10.7, 5.0, 2.7 Hz, 1H), 1.83-1.73 (m, 2H ), 1.71-1.60 (m, 2H), 1.59-1.49 (m, 2H), 1.35 (dt, J=15.4, 7.7 Hz, 2H).

Example 110: 3-(4-(5-(7-bromo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-)pentyl)-1-oxoisoindoline-2-)piperidine- 2,6-dione (110)

Tetrahydroquinoline was replaced by 6-bromobenzomorpholine, and the preparation method was the same as for 3-(4-(5-(3,4-dihydroquinoline-1(2H))pentyl)-1-oxoisoindoline-2-)piperidine-2, 6-dione, 14.9 mg, yield 28%; ¹ H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.56 (t, J=4.3 Hz, 1H), 7.45 (d, J=4.3 Hz, 2H) , 6.87 (dd, J=8.6, 2.3 Hz, 1H), 6.80 (d, J=2.3 Hz, 1H), 6.61 (d, J=8.7 Hz, 1H), 5.13 (dd, J=13.3, 5.1 Hz, 1H), 4.46 (d, J=17.1 Hz, 1H), 4.30 (d, J=17.1 Hz, 1H), 4.20-4.05 (m, 2H), 3.30-3.25 (m, 2H), 3.24-3.17 (m, 2H), 2.99-2, 85 (m, 1H), 2.63 (dd, J=20.5, 12.8 Hz, 3H), 2.47-2.35 (m, 1H), 2.07-1.93 (m, 1H), 1.64 (dt, J=15.1, 7.7 Hz, 2H), 1.54 (dt, J=14.9, 7.6 Hz, 2H), 1.41-1.27 (m, 2H).

Example 111: 3-(1-oxo-4-(5-(2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-)pentyl)isoindoline-2-)piperidine-2,6- dione (111)

-1,2,3,4-Tetrahydroquinoline was replaced by benzazepine, and the preparation method was the same as for 3-(4-(5-(3,4-dihydroquinoline-1(2H)-)pentyl)-1-oxoisoindoline -2-)piperidine-2,6-dione, 14.8 mg, yield 25%; ¹ H NMR (400 MHz, DMSO) δ 10.98 (d, J=5.3 Hz, 1H), 7.55 (dd, J=8.2, 4.2 Hz, 1H), 7.43 ( dd, J=11.7, 8.0 Hz, 2H), 7.11-6.98 (m, 2H), 6.88 (t, J=6.9 Hz, 1H), 6.77 (dd , J=13.5, 6.7 Hz, 1H), 5.17-5.04 (m, 1H), 4.43 (dd, J=16.7, 6.2 Hz, 1H), 4, 28 (dd, J=17.0, 6.2 Hz, 1H), 3.07 (dd, J=12.5, 6.2 Hz, 2H), 2.98-2.76 (m, 3H) , 2.60 (d, J=18.9 Hz, 4H), 2.45-2.34 (m, 1H), 1.99 (dd, J=12.1, 4.6 Hz, 1H), 1.68-1.44 (m, 7H), 1.43-1.32 (m, 2H).

Example 112: 3-(4-(5-(indoline-1-)pentyl)-1-oxoisoindoline-2-)piperidine-2,6-dione (112)

Tetrahydroquinoline was replaced by 5-bromohydroindole, and the preparation method was the same as for 3-(4-(5-(3,4-dihydroquinoline-1(2H)-)pentyl)-1-oxoisoindoline-2-)piperidine-2 ,6-dione, 29.7 mg, yield 46%; ¹ H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.56 (dt, J=7.7, 3.8 Hz, 1H), 7.49-7.44 (m, 2H ), 7.12 (d, J=1.7 Hz, 1H), 7.08 (dd, J=8.3, 2.0 Hz, 1H), 6.39 (d, J=8.3 Hz , 1H), 5.75 (s, 1H), 5.13 (dd, J=13.3, 5.1 Hz, 1H), 4.46 (d, J=17.1 Hz, 1H), 4 .30 (d, J=17.1 Hz, 1H), 3.30 (t, J=8.5 Hz, 2H), 3.01 (t, J=7.3 Hz, 2H), 2.98 -2.91 (m, 1H), 2.87 (t, J=8.2 Hz, 2H), 2.70-2.56 (m, 3H), 2.42 (ddd, J=26.6 , 13.4, 4.5 Hz, 1H), 2.00 (dtd, J=6.8, 4.9, 1.8 Hz, 1H), 1.65 (dt, J=15.5, 7 .8 Hz, 2H), 1.56 (dt, J=14.8, 7.5 Hz, 2H), 1.38 (dt, J=15.0, 7.7 Hz, 2H).

Example 113: 3-(4-(5-(3,4-dihydroisoquinoline-2(1H))pentyl)-1-oxoisoindoline-2-)piperidine-2,6-dione (113)

-1,2,3,4-Tetrahydroquinoline was replaced by 1,2,3,4-tetrahydroisoquinoline, and the preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrrolidine-1- )pentyl)indoline-2-)piperidine-2,6-dione, 20 mg, yield 35%; ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.50 (dt, J=20.8, 6.9 Hz, 3H), 7.23-7.03 (m, 4H ), 5.14 (dd, J=13.1, 4.7 Hz, 1H), 4.49 (d, J=17.3 Hz, 1H), 4.32 (d, J=17.1 Hz , 1H), 3.46-3.16 (m, 6H), 3.07-2.76 (m, 5H), 2.74-2.65 (m, 2H), 2.60 (dd, J =18.5, 1.8 Hz, 1H), 2.48-2.37 (m, 1H), 2.09-1.96 (m, 1H), 1.79-1.58 (m, 4H ), 1.39 (dd, J=14.9, 7.9 Hz, 2H).

Example 114: 3-(4-(5-(5-bromoindoline-1-)pentyl)-1-oxoisoindoline-2-)piperidine-2,6-dione (114)

Tetrahydroquinoline was replaced by 6-bromohydroindole, and the preparation method was the same as for 3-(4-(5-(3,4-dihydroquinoline-1(2H)-)pentyl)-1-oxoisoindoline-2-)piperidine-2 ,6-dione, 25.3 mg, yield 39%; ^1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.60-7.53 (m, 1H), 7.48-7.41 (m, 2H), 6.90 (d , J=7.6 Hz, 1H), 6.63 (dd, J=7.6, 1.7 Hz, 1H), 6.59 (d, J=1.6 Hz, 1H), 5.13 (dd, J=13.3, 5.1 Hz, 1H), 4.46 (d, J=17.2 Hz, 1H), 4.31 (d, J=17.1 Hz, 1H), 3 ,37-3.31 (m, 2H), 3.04 (t, J=7.2 Hz, 2H), 2.92 (ddd, J=17.6, 13.7, 5.4 Hz, 1H), 2.83 (t, J=8.4 Hz, 2H), 2.71-2.57 (m, 3H), 2.42 (ddd, J=26.5, 13.3, 4.5 Hz, 1H), 2.01 (ddd, J=12.3, 6.2, 4.0 Hz, 1H), 1.66 (dt, J=15.5, 7.7 Hz, 2H), 1.56 (dt, J=14.8, 7.5 Hz, 2H), 1.38 (dt, J=14.8, 7.6 Hz, 2H).

Example 115: 3-(4-(5-(6-chloro-3,4-dihydroisoquinoline-1(2H))pentyl)-1-oxoisoindoline-2-)piperidine-2,6-dione (115)

Tetrahydroquinoline was replaced by 6-chlorotetrahydroquinoline, and the preparation method was the same as for 3-(4-(5-(3,4-dihydroquinoline-1(2H)-)pentyl)-1-oxoisoindoline-2-)piperidine-2 ,6-dione, 19 mg, yield 31%; ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.56 (p, J=3.8 Hz, 1H), 7.45 (d, J=4.4 Hz, 2H) , 6.93 (dd, J=8.8, 2.7 Hz, 1H), 6.88 (d, J=2.6 Hz, 1H), 6.50 (d, J=8.9 Hz, 1H) , 5.13 (dd, J=13.4, 5.1 Hz, 1H), 4.46 (d, J=17.2 Hz, 1H), 4.30 (d, J=17.2 Hz, 1H), 3.19 (dd, J=9.8, 5.4 Hz, 4H), 2.92 (ddd, J=17.2, 12.9, 5.5 Hz, 1H), 2.69 -2.56 (m, 5H), 2.48-2.32 (m, 1H), 2.05-1.96 (m, 1H), 1.84-1.74 (m, 2H), 1 .64 (dt, J=16.2, 8.0 Hz, 2H), 1.53 (dt, J=14.3, 7.3 Hz, 2H), 1.34 (dt, J=14.2 , 7.0 Hz, 2H).

Example 116: 3-(4-(4-(indoline-1-)-4-oxobutoxy)-1-oxoisoindoline-2-)piperidine-2,6-dione (116)

The synthesis method was the same as for N-(3-chloro-4-methylphenyl)-4-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-oxy)butanamide, and 41 mg of final product was obtained as a white solid, yield 64%; ^1H NMR (400 MHz, DMSO) δ 10.96 (s, 1H), 8.10 (d, J=8.0 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H) , 7.34-7.16 (m, 3H), 7.13 (t, J=7.6 Hz, 1H), 6.96 (t, J=7.4 Hz, 1H), 5.07 ( dd, J=13.4, 5.0 Hz, 1H), 4.31 (d, J=17.3 Hz, 1H), 4.18 (dd, J=15.4, 11.7 Hz, 3H ), 4.09 (t, J=8.5 Hz, 2H), 3.13 (t, J=8.4 Hz, 2H), 2.95-2.82 (m, 1H), 2.64 (t, J=6.7 Hz, 2H), 2.55 (d, J=10.6 Hz, 1H), 2.30-2.04 (m, 3H), 1.97-1.87 ( m, 1H).

Example 117: 3-(4-(4-(3,4-dihydroquinoline-1(2H)-)-4-oxobutoxy)-1-oxoisoindoline-2-)piperidine-2,6-dione (117)

The synthesis method was the same as for N-(3-chloro-4-methylphenyl)-4-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-oxy)butanamide, and in the end 47 mg of white solid were obtained, yield 71%; ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.46 (t, J=7.8 Hz, 2H), 7.29 (d, J=7.5 Hz, 1H) , 7.21 (d, J=8.1 Hz, 1H), 7.18 7.10 (m, 2H), 7.06 (t, J=7.3 Hz, 1H), 5.09 (dd , J=13.3, 5.1 Hz, 1H), 4.25-4.02 (m, 4H), 3.68 (td, J=12.6, 6.2 Hz, 2H), 3, 29 (s, 1H), 2.99-2.86 (m, 1H), 2.77-2.55 (m, 5H), 2.34 (dd, J=13.1, 4.2 Hz, 1H), 2.09-1.94 (m, 3H), 1.86-1.77 (m, 2H).

Example 118: 3-(4-((5-(indoline-1-)-5-oxopentyl)oxy)-1-oxoisoindoline-2-)piperidine-2,6-dione (118)

The synthesis method was the same as for N-(3-chloro-4-methylphenyl)-4-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-oxy)butanamide, and at the end 29 mg of product were obtained as a white solid, yield 39%; ^1H NMR (400 MHz, DMSO) δ 10.96 (s, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H) , 7.30 (d, J=7.4 Hz, 1H), 7.25 (d, J=8.1 Hz, 1H), 7.21 (d, J=7.3 Hz, 1H), 7 .13 (t, J=7.7 Hz, 1H), 6.96 (t, J=7.4 Hz, 1H), 5.10 (dd, J=13.3, 5.1 Hz, 1H) , 4.37 (d, J=17.4 Hz, 1H), 4.27-4.13 (m, 3H), 4.08 (t, J=8.5 Hz, 2H), 3.12 ( t, J=8.4 Hz, 2H), 2.96-2.84 (m, 1H), 2.55 (dd, J=12.5, 7.6 Hz, 3H), 2.44-2.31 (m, 1H), 2.02-1.92 (m, 1H), 1.90-1.71 (m, 4H).

Example 119: 3-(4-((5-(3,4-dihydroquinoline-1(2H)-)-5-oxopentyl)oxy)-1-oxoisoindoline-2-)piperidine-2,6-dione (119)

The synthesis method was the same as for N-(3-chloro-4-methylphenyl)-4-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-oxy)butanamide, and at the end 19 mg of a white solid were obtained, yield 39%; ¹ H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 7.45 (d, J=7.7 Hz, 2H), 7.30 (d, J=7.5 Hz, 1H), 7 ,23-7.01 (m, 4H), 5.10 (dd, J=13.3, 5.1 Hz, 1H), 4.31 (s, 1H), 4.21 (s, 1H), 4.08 (s, 2H), 3.67 (t, J=6.4 Hz, 2H), 2.96-2.84 (m, 1H), 2.66 (d, J=6.5 Hz , 2H), 2.55 (d, J=7.0 Hz, 3H), 2.40 (ddd, J=35.4, 17.8, 9.0 Hz, 1H), 2.05-1, 93 (m, 1H), 1.89-1.80 (m, 2H), 1.72 (s, 4H).

Example 120: 3-(4-(6-(6-chloro-3H-spiro[isobenzofuran-1,4'-piperidine]-1'-)hexyl)-1-oxoisoindoline-2-)piperidine-2,6- dione (120)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 34 mg, yield 33, 4%; ¹ H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.56 (dd, J=8.2, 4.5 Hz, 1H), 7.46 (d, J=3.7 Hz, 2H), 7.36 (s, 1H), 7.34-7.27 (m, 2H), 5.13 (dd, J=13.3, 5.1 Hz, 1H), 4.94 (s, 2H), 4.47 (d, J=17.1 Hz, 1H), 4.31 (d, J=17.1 Hz, 1H), 2.99-2.86 (m, 2H) , 2.79 (d, J=10.0 Hz, 2H), 2.68-2.56(m, 3H), 2.46-2.23 (m, 5H), 2.05-1.97 (m, 1H), 1.92 (dd, J=12.7, 9.1 Hz, 2H), 1.61 (d, J=11.7 Hz, 4H), 1.46 (s, 2H) , 1.38-1.27(m, 4H).

Example 121: 3-(1-oxo-4-(5-(2-oxospiro[indoline-3,4'-piperidine]-1')pentyl)indoline-2-)piperidine-2,6-dione (121)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 24.6 mg, yield 38%; ¹ H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 10.40 (s, 1H), 8.19 (s, 1H), 7.58 (dd, J=6.2, 2 ,4 Hz, 1H), 7.52-7.42 (m, 3H), 7.19 (t, J=7.5 Hz, 1H), 6.96 (t, J=7.5 Hz, 1H ), 6.85 (d, J=7.7 Hz, 1H), 5.15 (dd, J=13.3, 5.1 Hz, 1H), 4.49 (d, J=17.2 Hz , 1H), 4.32 (d, J=17.2 Hz, 1H), 2.99-2.85 (m, 3H), 2.73-2.57 (m, 5H), 2.48- 2.37 (m, 1H), 2.07-1.97 (m, 1H), 1.88-1.76 (m, 2H), 1.73-1.49 (m, 6H), 1. 37 (dt, J=14.4, 7.4 Hz, 2H).

Example 122: 3-(4-(4-(2H-spiro[benzofuran-3,4-piperidine]-1-)butyl)-1-oxoisoindoline-2-)piperidine-2,6-dione (122)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 29.0 mg, yield 33%; ^1H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 8.17 (s, 1H), 7.61-7.54 (m, 1H), 7.50-7.44 (m , 2H), 7.19 (dd, J=7.4, 0.9 Hz, 1H), 7.10 (td, J=7.9, 1.3 Hz, 1H), 6.84 (dd, J=7.8, 7.0 Hz, 1H), 6.75 (d, J=7.9 Hz, 1H), 5.14 (dd, J=13.2, 5.1 Hz, 1H), 4.47 (d, J=17.2 Hz, 1H), 4.32 (d, J=16.4 Hz, 3H), 2.93 (ddd, J=17.5, 14.0, 5, 5 Hz, 1H), 2.84 (d, J=11.8 Hz, 2H), 2.67 (t, J=7.5 Hz, 2H), 2.65-2.57 (m, 1H) , 2.48-2.30 (m, 3H), 2.01 (dd, J=17.2, 6.7 Hz, 3H), 1.84 (td, J=12.8, 3.7 Hz , 2H), 1.69-1.57 (m, 4H), 1.57-1.45 (m, 2H).

Example 123: 3-(4-(5-(3H-spiro[isobenzofuran-1,4'-piperidine]-1'-)pentyl)-1-oxoisoindoline-2-)piperidine-2,6-dione (114)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 11.2 mg, yield 17%; ^1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 8.19 (s, 1H), 7.60-7.55 (m, 1H), 7.49-7.44 (m , 2H), 7.30-7.20 (m, 3H), 5.14 (dd, J=13.3, 5.1 Hz, 1H), 4.97 (s, 2H), 4.47 ( d, J=17.2 Hz, 1H), 4.32 (d, J=17.2 Hz, 1H), 2.92 (ddd, J=17.9, 11.8, 4.6 Hz, 3H ), 2.71-2.56 (m, 3H), 2.43 (dd, J=21.2, 8.6 Hz, 5H), 1.98 (dddd, J=26.0, 16.8 , 8.7, 2.8 Hz, 3H), 1.65 (t, J=12.0 Hz, 4H), 1.54 (dd, J=14.6, 7.7 Hz, 2H), 1 .40-1.29 (m, 2H).

Example 124: 3-(4-(4-(6-chloro-3H-spiro[isobenzofuran-1,4'-piperidine]-1'-)butoxy)-1-oxoisoindoline-2-)piperidine-2,6- dione (124)

The preparation method was the same as for 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-4-phenylpiperidine-4-carbonitrile, 25 .9 mg, yield 38%; ^1H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 7.49 (t, J=7.8 Hz, 1H), 7.35-7.23 (m, 5H), 5, 11 (dd, J=13.3, 5.1 Hz, 1H), 4.93 (s, 2H), 4.38 (d, J=17.4 Hz, 1H), 4.23 (d, J =17.4 Hz, 1H), 4.16 (t, J=6.3 Hz, 2H), 2.97-2.85 (m, 1H), 2.79 (d, J=10.7 Hz , 2H), 2.58 (d, J=18.2 Hz, 1H), 2.48-2.36 (m, 3H), 2.26 (t, J=10.9 Hz, 2H), 2 .03-1.94 (m, 1H), 1.88 (dd, J=17.6, 7.6 Hz, 2H), 1.83-1.72 (m, 2H), 1.63 (dd , J=21.1, 9.9 Hz, 4H).

Example 125: 3-(1-oxo-4-(5-(2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,4'-piperidine]-1')pentyl) isoindoline-2-)piperidine-2,6-dione (125)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 14.4 mg, yield 21%; ^1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 10.18 (s, 1H), 8.18 (s, 1H), 7.59-7.54 (m, 1H), 7.50-7.43 (m, 2H), 7.30-7.19 (m, 2H), 7.05-6.98 (m, 1H), 6.91-6.85 (m, 1H ), 5.13 (dd, J=13.2, 5.1 Hz, 1H), 4.47 (d, J=17.2 Hz, 1H), 4.31 (d, J=17.2 Hz , 1H), 2.98-2.86 (m, 1H), 2.75 (d, J=10.6 Hz, 2H), 2.70-2.56 (m, 3H), 2.40 ( ddd, J=24.4, 15.6, 7.6 Hz, 5H), 1.98 (ddd, J=39.2, 21.1, 8.9 Hz, 5H), 1.64 (dt, J=15.3, 7.6 Hz, 2H), 1.57-1.45 (m, 2H), 1.35 (dt, J=14.8, 7.5 Hz, 2H).

Example 126: 3-(4-(4-(2H-spiro[benzofuran-3,4'-piperidine]-1')butoxy)-1-oxoisoindoline-2-)piperidine-2,6-dione (116)

The preparation method was the same as for 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-4-phenylpiperidine-4-carbonitrile, 28 .0 mg, yield 44%; ^1H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 7.49 (t, J=7.8 Hz, 1H), 7.31 (d, J=7.4 Hz, 1H) , 7.25 (d, J=8.1 Hz, 1H), 7.18 (d, J=7.1 Hz, 1H), 7.14-7.05 (m, 1H), 6.84 ( t, J=7.4 Hz, 1H), 6.75 (d, J=7.9 Hz, 1H), 5.11 (dd, J=13.3, 5.1 Hz, 1H), 4, 38 (d, J=17.4 Hz, 1H), 4.34 (s, 2H), 4.23 (d, J=17.4 Hz, 1H), 4.15 (t, J=6.2 Hz, 2H), 2.92 (dd, J=22.7, 8.6 Hz, 3H), 2.60 (s, 1H), 2.48-2.39 (m, 3H), 2.00 (ddd, J=13.9, 10.4, 7.6 Hz, 3H), 1.89-1.73 (m, 4H), 1.65 (t, J=11.5 Hz, 4H).

Example 127: 3-(4-(5-(6-chloro-3H-spiro[isobenzofuran-1,4'-piperidine]-1'-)pentyl-1-oxoisoindoline--2-)piperidine-2,6- dione (127)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 24.4 mg, yield 36%; ^1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.56 (dt, J=7.6, 3.9 Hz, 1H), 7.49-7.43 (m, 2H ), 7.39-7.25 (m, 3H), 5.14 (dd, J=13.3, 5.1 Hz, 1H), 4.93 (s, 2H), 4.47 (d, J=17.2 Hz, 1H), 4.31 (d, J=17.1 Hz, 1H), 2.99-2.86 (m, 1H), 2.82-2.53 (m, 5H ), 2.48-2.37 (m, 1H), 2.35-2.27 (m, 2H), 2.26-2.15 (m, 2H), 2.02 (ddd, J=9 ,9, 4.9, 2.9 Hz, 1H), 1.94-1.81 (m, 2H), 1.69-1.55 (m, 4H), 1.54-1.43 (m , 2H), 1.34 (dt, J=14.8, 7.3 Hz, 2H).

Example 128: 3-(4-(4-(6-fluoro-3H-spiro[isobenzofuran-1,4'-piperidine]-1'-)butoxy)-1-oxoisoindoline-2-)piperidine-2,6- dione (128)

The preparation method was the same as for 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-4-phenylpiperidine-4-carbonitrile, 22 .9 mg, yield 35%; ^1H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.33-7.22 (m, 3H), 7, 14 (dd, J=8.9, 2.2 Hz, 1H), 7.12-7.05 (m, 1H), 5.11 (dd, J=13.3, 5.0 Hz, 1H) , 4.93 (s, 2H), 4.38 (d, J=17.4 Hz, 1H), 4.23 (d, J=17.4 Hz, 1H), 4.15 (t, J= 6.2 Hz, 2H), 2.97-2.85 (m, 1H), 2.81 (d, J=11.0 Hz, 2H), 2.57 (d, J=18.0 Hz, 1H), 2.47-2.38 (m, 3H), 2.29 (t, J=11.5 Hz, 2H), 2.02-1.95 (m, 1H), 1.95-1 .85 (m, 2H), 1.83-1.73 (m, 2H), 1.64 (dd, J=19.0, 10.7 Hz, 4H).

Example 129: 3-(4-(5-(5-chloro-3-oxo-3H-spiro[isobenzofuran-1,4'-piperidine]-1'-)pentyl)-1-oxoisoindoline-2-)piperidine- 2,6-dione (129)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 23.2 mg, yield 48%; ¹ H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 8.15 (s, 1H), 7.87 (d, J=1.4 Hz, 1H), 7.82 (dt, J=13.8, 5.0 Hz, 2H), 7.57 (dt, J=7.7, 3.8 Hz, 1H), 7.51-7.41 (m, 2H), 5.75 (s, 1H), 5.14 (dd, J=13.3, 5.1 Hz, 1H), 4.48 (d, J=17.2 Hz, 1H), 4.32 (d, J= 17.1 Hz, 1H), 2.99-2.85 (m, 3H), 2.71-2.56 (m, 3H), 2.47-2.37 (m, 3H), 2.36 -2.27 (m, 2H), 2.21 (t, J=12.1 Hz, 2H), 2.07-1.95 (m, 1H), 1.64 (dd, J=13.9 , 8.5 Hz, 4H), 1.58-1.48 (m, 2H), 1.36 (dt, J=14.8, 7.5 Hz, 2H).

Example 130: 3-(4-(4-(6-methyl-3H-spiro[isobenzofuran-1,4'-piperidine]-1'-)butoxy)-1-oxoisoindoline-2-)piperidine-2,6- dione (130)

The preparation method was the same as for 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-4-phenylpiperidine-4-carbonitrile, 16 .2 mg white solid, yield 29%; ^1H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 7.49 (t, J=7.8 Hz, 1H), 7.31 (d, J=7.5 Hz, 1H) , 7.25 (d, J=8.1 Hz, 1H), 7.13 (d, J=7.6 Hz, 1H), 7.07 (d, J=7.7 Hz, 1H), 7 .00 (s, 1H), 5.11 (dd, J=13.3, 5.1 Hz, 1H), 4.90 (s, 2H), 4.38 (d, J=17.4 Hz, 1H), 4.23 (d, J=17.4 Hz, 1H), 4.16 (t, J=6.3 Hz, 2H), 2.98-2.85 (m, 1H), 2, 80 (d, J=11.0 Hz, 2H), 2.57 (d, J=18.4 Hz, 1H), 2.48-2.38 (m, 3H), 2.35-2.23 (m, 5H), 2.03-1.93 (m, 1H), 1.90-1.73 (m, 4H), 1.63 (dt, J=20.6, 10.0 Hz, 4H ).

Example 131: 3-(1-oxo-4-(5-(2'-oxo-1',2'-dihydrospiro[piperidine-4,4'-pyrido[2,3-d][1,3)oxazine )-1]-)pentyl) isoindoline-2-)piperidine-2,6-dione (131)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 18.0 mg, yield 27%; ¹ H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 10.74 (s, 1H), 8.19 (dd, J=4.9, 1.3 Hz, 1H), 8, 16 (s, 1H), 7.72 (dd, J=7.6, 1.1 Hz, 1H), 7.59-7.54 (m, 1H), 7.50-7.43 (m, 2H), 7.07 (dd, J=7.6, 5.0 Hz, 1H), 5.75 (s, 1H), 5.13 (dd, J=13.2, 5.1 Hz, 1H ), 4.47 (d, J=17.2 Hz, 1H), 4.31 (d, J=17.1 Hz, 1H), 2.99-2.86 (m, 1H), 2.78 (d, J=10.6 Hz, 2H), 2.64 (dd, J=22.3, 14.4 Hz, 3H), 2.47-2.29 (m, 5H), 2.09- 1.88 (m, 5H), 1.64 (dt, J=15.4, 7.7 Hz, 2H), 1.56-1.44 (m, 2H), 1.41-1.29 ( m, 2H).

Example 132: 3-(4-((5-(6-chloro-3H-spiro[isobenzofuran-1,4-piperidine]-1-)pentyl)oxy)-1-oxoisoindoline-2-)piperidine-2,6 -dione (132)

The preparation method was the same as for 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-oxy)propyl)-4-phenylpiperidine-4-carbonitrile, and in the end 32 mg of white solid were obtained, yield 48%; ¹ H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.36 (s, 1H), 7.33-7, 27 (m, 3H), 7.24 (d, J=8.1 Hz, 1H), 5.11 (dd, J=13.3, 5.1 Hz, 1H), 4.93 (s, 2H ), 4.37 (d, J=17.4 Hz, 1H), 4.23 (d, J=17.4 Hz, 1H), 4.13 (t, J=6.3 Hz, 2H), 2.97-2.84 (m, 1H), 2.78 (d, J=10.5 Hz, 2H), 2.56 (d, J=18.0 Hz, 1H), 2.45 (dd , J=13.1, 4.4 Hz, 1H), 2.37 (t, J=7.0 Hz, 2H), 2.27 (t, J=11.5 Hz, 2H), 2.02 -1.85 (m, 3H), 1.82-1.71 (m, 2H), 1.61 (d, J=12.4 Hz, 2H), 1.48 (ddd, J=22.2 , 14.8, 9.1 Hz, 4H).

Example 133: 3-(4-(5-(5-chloro-2-oxospiro[indoline-3,4'-piperidine]-1'-)pentyl)-1-oxoisoindoline--2-)piperidine-2,6 -dione (133)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 36.2 mg, yield 55%; ¹ H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 10.51 (s, 1H), 8.18 (s, 1H), 7.57 (dd, J=6.0, 2 ,6 Hz, 1H), 7.53-7.43 (m, 3H), 7.24 (dd, J=8.3, 2.1 Hz, 1H), 6.85 (d, J=8, 3 Hz, 1H), 5.14 (dd, J=13.3, 5.1 Hz, 1H), 4.48 (d, J=17.2 Hz, 1H), 4.32 (d, J= 17.1 Hz, 1H), 3.01-2.84 (m, 3H), 2.63 (ddd, J=21.4, 16.7, 4.4 Hz, 5H), 2.53 (d , J=6.9 Hz, 2H), 2.48-2.36 (m, 1H), 2.02 (ddd, J=10.2, 5.0, 3.1 Hz, 1H), 1, 86-1.70 (m, 4H), 1.69-1.61 (m, 2H), 1.60-1.50 (m, 2H), 1.37 (dt, J=14.7, 7 .5 Hz, 2H).

Example 134: 3-(4-((5-(3H-spiro[isobenzofuran-1,4'-piperidin]-1'-yl)pentyl)oxy)-1-oxoisoindolin-2-yl)piperidin-2,6 -dion (134)

The preparation method was the same as for 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-4-phenylpiperidine-4-carbonitrile, and at the end 35 mg of 3-(4-((5-(2H-spiro[benzofuran-3,4'-piperidine]-1'-)pentyl)oxy)-1-oxoisoindole-2-)piperidine-2,6 were obtained -dione in the form of a white solid, yield 37%; ¹ H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 7.49 (t, J=7.8 Hz, 1H), 7.31 (d, J=7.5 Hz, 1H) , 7.25 (d, J=8.1 Hz, 1H), 7.19 (d, J=7.3 Hz, 1H), 7.11 (td, J=7.8, 1.2 Hz, 1H), 6.85 (t, J=7.4 Hz, 1H), 6.76 (d, J=7.9 Hz, 1H), 5.12 (dd, J=13.3, 5.1 Hz, 1H), 4.42-4.31 (m, 3H), 4.24 (d, J=17.4 Hz, 1H), 4.14 (t, J=6.3 Hz, 2H), 2.91 (ddd, J=13.4, 11.9, 5.7 Hz, 3H), 2.59 (s, 1H), 2.45 (dd, J=13.1, 4.3 Hz, 1H), 2.38 (t, J=6.8 Hz, 2H), 2.10-1.94 (m, 3H), 1.91-1.72 (m, 4H), 1.63 (d , J=13.0 Hz, 2H), 1.59-1.39 (m, 4H).

Example 135: 3-(4-(5-(5-methoxy-2-oxospiro[indoline-3,4'-piperidine]-1'-)pentyl)-1-oxoisoindoline-2-)piperidine-2,6- dione (135)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 32.1 mg, yield 46%; ¹ H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 10.19 (s, 1H), 8.18 (s, 1H), 7.56 (dt, J=7.9, 3 .9 Hz, 1H), 7.51-7.43 (m, 2H), 7.02 (s, 1H), 6.75 (s, 2H), 5.75 (s, 2H), 5.14 (dd, J=13.2, 5.1 Hz, 1H), 4.48 (d, J=17.2 Hz, 1H), 4.32 (d, J=17.1 Hz, 1H), 3 .71 (s, 3H), 2.92 (ddd, J=13.0, 12.2, 5.1 Hz, 3H), 2.71-2.57 (m, 5H), 2.54 (s , 2H), 2.47-2.37 (m, 1H), 2.02 (ddd, J=10.4, 5.0, 3.6 Hz, 1H), 1.90-1.47 (m , 8H), 1.44-1.28 (m, 2H).

Example 136: 3-(4-(3-(2H-spiro[isobenzofuran-1,4'-piperidine]-1'-)propoxy)-1-oxoisoindoline-2-)piperidine-2,6-dione (136)

The preparation method was the same as for 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-4-phenylpiperidine-4-carbonitrile, 26 .9 mg, yield 42%; ^1H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 7.49 (t, J=7.8 Hz, 1H), 7.32 (d, J=7.5 Hz, 1H) , 7.26 (d, J=8.1 Hz, 1H), 7.20 (d, J=6.9 Hz, 1H), 7.11 (t, J=7.7 Hz, 1H), 6 .86 (t, J=7.4 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 5.12 (dd, J=13.3, 5.1 Hz, 1H) , 4.39 (d, J=14.5 Hz, 3H), 4.29-4.13 (m, 3H), 3.57-3.12 (m, 4H), 3.07-2.83 (m, 3H), 2.63-2.55 (m, 1H), 2.47-2.37 (m, 1H), 2.09-1.81 (m, 5H), 1.69 (d , J=12.4 Hz, 2H).

Example 137: 3-(1-oxo-4-(5-(spiro[isochroman-1,4'-piperidine]-1'-)pentyl)isoindoline-2-)piperidine-2,6-dione (137)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 20.6 mg, yield 33%; ^1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.57 (dt, J=7.5, 3.8 Hz, 1H), 7.51-7.40 (m, 2H ), 7.21-7.05 (m, 4H), 5.14 (dd, J=13.2, 5.0 Hz, 1H), 4.47 (d, J=17.2 Hz, 1H) , 4.32 (d, J=17.1 Hz, 1H), 3.81 (t, J=5.4 Hz, 2H), 2.99-2.86 (m, 1H), 2.74 ( dd, J=14.1, 8.6 Hz, 4H), 2.69-2.57 (m, 3H), 2.46-2.31 (m, 5H), 2.06-1.87 ( m, 3H), 1.78 (d, J=13.1 Hz, 2H), 1.70-1.59 (m, 2H), 1.53 (dd, J=12.4, 6.0 Hz , 2H), 1.36 (dd, J=13.7, 7.5 Hz, 2H).

Example 138: 3-(4-(3-(6-chloro-3H-spiro[isobenzofuran-1,4'-piperidine]-1'-)propoxy)-1-oxoisoindoline-2-)piperidine-2,6- dione (138)

The preparation method was the same as for 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-4-phenylpiperidine-4-carbonitrile, 42 mg, yield 61%; ^1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.50 (t, J=7.8 Hz, 1H), 7.40-7.30 (m, 3H), 7, 27 (t, J=7.0 Hz, 2H), 5.12 (dd, J=13.3, 5.1 Hz, 1H), 4.99 (s, 2H), 4.41 (d, J =17.4 Hz, 1H), 4.24 (dd, J=17.8, 11.6 Hz, 3H), 3.47-3.16 (m, 6H), 2.97-2.87 ( m, 1H), 2.59 (dd, J=17.2, 1.0 Hz, 1H), 2.47-2.37 (m, 1H), 2.36-2.05 (m, 4H) , 2.04-1.97 (m, 1H), 1.85-1.67 (m, 2H).

Example 139: 3-(1-oxo-4-(5-(2-oxospiro[indoline-3,3'-pyrroline]-1'-)pentyl)isoindoline-2-)piperidine-2,6-dione (139 )

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 39.5 mg, yield 65%; ¹ H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 10.35 (s, 1H), 8.15 (s, 1H), 7.56 (dt, J=7.8, 3 ,9 Hz, 1H), 7.49-7.40 (m, 2H), 7.27 (dd, J=7.1, 4.0 Hz, 1H), 7.15 (td, J=7, 6, 0.6 Hz, 1H), 6.94 (tdd, J=7.6, 2.6, 0.8 Hz, 1H), 6.81 (d, J=7.7 Hz, 1H), 5.75 (s, 2H), 5.13 (dd, J=13.3, 5.1 Hz, 1H), 4.46 (dd, J=17.2, 2.9 Hz, 1H), 4 .30 (d, J=17.1 Hz, 1H), 3.09 (td, J=8.1, 4.7 Hz, 1H), 2.98-2.85 (m, 1H), 2, 81 (dd, J=9.0, 2.0 Hz, 1H), 2.70-2.52 (m, 6H), 2.39 (ddd, J=25.6, 12.8, 4.3 Hz, 1H), 2.16 (ddd, J=12.1, 7.9, 4.1 Hz, 1H), 1.99 (dd, J=11.5, 5.5 Hz, 1H), 1 .88 (dt, J=12.5, 7.6 Hz, 1H), 1.64 (dt, J=14.9, 7.4 Hz, 2H), 1.57-1.46 (m, 2H ), 1.45-1.33 (m, 2H).

Example 140: 3-(4-(3-(6-methyl-3H-spiro[isobenzofuran-1,4'-piperidine]-1'-)propoxy)-1-oxoisoindoline-2-)piperidine-2,6- dione (140)

The preparation method was the same as for 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-4-phenylpiperidine-4-carbonitrile, 34 .7 mg, yield 52%; ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.50 (t, J=7.8 Hz, 1H), 7.33 (d, J=7.5 Hz, 1H) , 7.27 (d, J=8.1 Hz, 1H), 7.18 (d, J=7.6 Hz, 1H), 7.12 (d, J=7.6 Hz, 1H), 6 .98 (s, 1H), 5.13 (dd, J=13.3, 5.0 Hz, 1H), 4.96 (s, 2H), 4.41 (d, J=17.4 Hz, 1H), 4.31-4.17 (m, 3H), 3.37 (dd, J=17.2, 16.7 Hz, 6H), 2.97-2.88 (m, 1H), 2 .59 (d, J=17.2 Hz, 1H), 2.46-2.37 (m, 1H), 2.33 (s, 3H), 2.17 (dt, J=36.9, 32 .7 Hz, 4H), 2.01 (dd, J=8.9, 3.3 Hz, 1H), 1.83-1.63 (m, 2H).

Example 141: 3-(1-oxo-4-(5-(spiro[indene-1,4'-piperidine]-1'-)pentyl)isoindoline-2-)piperidine-2,6-dione (141)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 18.8 mg, yield thirty%; ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 8.19 (s, 1H), 7.58 (dd, J=5.9, 2.6 Hz, 1H), 7, 52-7.44 (m, 2H), 7.39 (d, J=7.0 Hz, 1H), 7.33 (d, J=7.0 Hz, 1H), 7.26-7.15 (m, 2H), 6.97 (d, J=5.6 Hz, 1H), 6.80 (d, J=5.6 Hz, 1H), 5.75 (s, 2H), 5.14 (dd, J=13.3, 5.0 Hz, 1H), 4.47 (dd, J=17.1, 8.0 Hz, 1H), 4.31 (dd, J=17.1, 7 .9 Hz, 1H), 3.06 (d, J=11.6 Hz, 2H), 2.99-2.87 (m, 1H), 2.72-2.53 (m, 5H), 2 .46-2.35 (m, 2H), 2.19-2.07 (m, 2H), 2.06-1.94 (m, 1H), 1.63 (qd, J=14.8, 8.1 Hz, 4H), 1.43 1.31 (m, 2H), 1.23 (d, J=12.9 Hz, 2H).

Example 142: 3-(4-(3-(6-fluoro-3H-spiro[isobenzofuran-1,4'-piperidine]-1'-)propoxy)-1-oxoisoindoline-2-)piperidine-2,6- dione (142)

The preparation method was the same as for 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-4-phenylpiperidine-4-carbonitrile, 37 .3 mg, yield 56%; ¹ H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.49 (t, J=7.8 Hz, 1H), 7.34-7.22 (m, 3H), 7, 17 (dd, J=8.9, 2.2 Hz, 1H), 7.08 (td, J=9.4, 2.3 Hz, 1H), 5.11 (dd, J=13.3, 5.1 Hz, 1H), 4.93 (s, 2H), 4.38 (d, J=17.4 Hz, 1H), 4.23 (d, J=17.4 Hz, 1H), 4 ,18 (t, J=6.1 Hz, 2H), 2.97-2.86 (m, 1H), 2.82 (d, J=10.2 Hz, 2H), 2.63-2, 52 (m, 3H), 2.48-2.39 (m, 1H), 2.31 (t, J=11.1 Hz, 2H), 2.04-1.86 (m, 5H), 1 .62 (d, J=12.5 Hz, 2H).

Example 143: 3-(4-(5-(2,3-dihydrospiro[indene-1,4'-piperidine]-1'-)pentyl)-1-oxoisoindoline-2-)piperidine-2,6-dione ( 143)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 31.1 mg, yield 49%; ^1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.57 (dt, J=7.7, 3.9 Hz, 1H), 7.50-7.43 (m, 2H ), 7.23-7.09 (m, 4H), 5.75 (s, 1H), 5.14 (dd, J=13.2, 5.0 Hz, 1H), 4.48 (d, J=17.2 Hz, 1H), 4.32 (d, J=17.2 Hz, 1H), 3.03-2.88 (m, 3H), 2.84 (t, J=7.3 Hz, 2H), 2.71-2.57 (m, 4H), 2.47-2.37 (m, 2H), 2.35-2.20 (m, 2H), 2.06-1, 92 (m, 3H), 1.90-1.78 (m, 2H), 1.69-1.60 (m, 2H), 1.55 (dd, J=13.9, 7.3 Hz, 2H), 1.47 (d, J=12.6 Hz, 2H), 1.39-1.30 (m, 2H).

Example 144: 3-(4-((5-(6-fluoro-3H-spiro[isobenzofuran-1,4-piperidine]-1-)pentyl)oxy)-1-oxoisoindoline-2-)piperidine-2,6 -dion (144)

The preparation method was the same as for 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-4-phenylpiperidine-4-carbonitrile, and at the end 26 mg of a white solid were obtained, yield 40%; ¹ H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 7.48 (t, J=7.7 Hz, 1H), 7.35-7.21 (m, 3H), 7, 19-7.13 (m, 1H), 7.09 (dd, J=12.5, 5.1 Hz, 1H), 5.11 (dd, J=13.2, 5.0 Hz, 1H) , 4.93 (s, 2H), 4.37 (d, J=17.4 Hz, 1H), 4.22 (d, J=17.4 Hz, 1H), 4.12 (t, J= 6.1 Hz, 2H), 2.98-2.85 (m, 1H), 2.80 (d, J=9.9 Hz, 2H), 2.58 (s, 1H), 2.48- 2.35 (m, 3H), 2.29 (t, J=11.4 Hz, 2H), 2.04-1.85 (m, 3H), 1.82-1.71 (m, 2H) , 1.61 (d, J=12.7 Hz, 2H), 1.57-1.39 (m, 4H).

Example 145: 3-(4-(5-(2H-spiro[benzofuran-3,4'-piperidine]-1'-)pentyl-1-oxoisoindoline-2-)piperidine-2,6-dione (145)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 15.5 mg, yield 50%; ^1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.63-7.53 (m, 1H), 7.45 (dd, J=7.1, 5.7 Hz, 2H ), 7.19 (d, J=7.1 Hz, 1H), 7.11 (dd, J=11.2, 4.2 Hz, 1H), 6.85 (t, J=7.3 Hz , 1H), 6.75 (d, J=7.9 Hz, 1H), 5.14 (dd, J=13.2, 5.1 Hz, 1H), 4.47 (d, J=17, 2 Hz, 1H), 4.36-4.28 (m, 3H), 3.00-2.82 (m, 3H), 2.73-2.57 (m, 3H), 2.49-2 .30 (m, 3H), 2.12-1.96 (m, 3H), 1.86 (td, J=12.8, 3.1 Hz, 2H), 1.63 (d, J=13 ,2 Hz, 4H), 1.57-1.44 (m, 2H), 1.41-1.28 (m, 2H).

Example 146: 3-(4-((5-(6-methyl-3H-spiro[isobenzofuran-1,4'-piperidine]-1'-)pentyl)oxy)-1-oxoisoindoline-2-)piperidine-2 ,6-dione (146)

The preparation method was the same as for 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-4-phenylpiperidine-4-carbonitrile, and at the end 19 mg of a white solid were obtained, yield 20%; ¹ H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.31 (d, J=7.5 Hz, 1H) , 7.25 (d, J=8.2 Hz, 1H), 7.14 (d, J=7.6 Hz, 1H), 7.07 (d, J=7.8 Hz, 1H), 7 .02 (s, 1H), 5.11 (dd, J=13.3, 5.1 Hz, 1H), 4.91 (s, 2H), 4.38 (d, J=17.4 Hz, 1H), 4.23 (d, J=17.4 Hz, 1H), 4.13 (t, J=6.2 Hz, 2H), 2.97-2.74 (m, 3H), 2, 56 (d, J=16.4 Hz, 1H), 2.47-2.25 (m, 8H), 2.03-1.94 (m, 1H), 1.93-1.83 (m, 2H), 1.77 (dd, J=13.5, 6.5 Hz, 2H), 1.64-1.40 (m, 6H).

Example 147: 3-(1-oxo-4-(5-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-)pentyl)isoindoline-2-)piperidine-2, 6-dion (147)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 33.8 mg, yield 52%; ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 8.73 (s, 1H), 8.28 (s, 1H), 7.57 (dd, J=6.3, 2 ,2 Hz, 1H), 7.52-7.42 (m, 2H), 7.22 (t, J=7.9 Hz, 2H), 6.87 (d, J=8.2 Hz, 2H ), 6.75 (t, J=7.3 Hz, 1H), 5.13 (dd, J=13.3, 5.1 Hz, 1H), 4.58 (s, 2H), 4.47 (d, J=17.2 Hz, 1H), 4.31 (d, J=17.1 Hz, 1H), 3.20-2.73 (m, 5H), 2.71-2.52 ( m, 7H), 2.40 (ddd, J=26.3, 13.2, 4.3 Hz, 1H), 2.07-1.95 (m, 1H), 1.75-1.60 ( m, 4H), 1.56 (dd, J=14.2, 7.6 Hz, 2H), 1.42-1.28 (m, 2H).

Example 148: 3-(4-((6-(2H-spiro[benzofuran-3,4'-piperidine]-G-)hexyl)oxy)-1-oxoisoindoline-2-)piperidine-2,6-dione ( 148)

The preparation method was the same as for 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-4-phenylpiperidine-4-carbonitrile, and at the end 21 mg of a white solid were obtained, yield 22%; ¹ H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.30 (d, J=7.4 Hz, 1H) , 7.24 (d, J=8.1 Hz, 1H), 7.18 (d, J=7.2 Hz, 1H), 7.10 (td, J=7.9, 1.2 Hz, 1H), 6.84 (t, J=7.4 Hz, 1H), 6.75 (d, J=7.9 Hz, 1H), 5.11 (dd, J=13.3, 5.1 Hz, 1H), 4.37 (d, J=17.4 Hz, 1H), 4.33 (s, 2H), 4.22 (d, J=17.4 Hz, 1H), 4.12 ( t, J=6.3 Hz, 2H), 2.97-2.87 (m, 1H), 2.83 (d, J=11.7 Hz, 2H), 2.57 (d, J=17 ,9 Hz, 1H), 2.48-2.38 (m, 1H), 2.36-2.25 (m, 2H), 1.97 (t, J=10.8 Hz, 3H), 1 .83 (td, J=12.8, 3.6 Hz, 2H), 1.79 1.68 (m, 2H), 1.61 (d, J=12.4 Hz, 2H), 1.53 1.40 (m, 4H), 1.39 1.30 (m, 2H).

Example 149: 3-(4-(4-(3H-spiro[isobenzofuran-1,4'-piperidine]-1'-)butyl)-1-oxoisoindoline-2-)piperidine-2,6-dione (149)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 36.9 mg, yield 42%; ^1H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 7.62-7.56 (m, 1H), 7.51-7.45 (m, 2H), 7.31-7 .21 (m, 4H), 5.15 (dd, J=13.3, 5.1 Hz, 1H), 4.96 (s, 2H), 4.49 (d, J=17.2 Hz, 1H), 4.33 (d, J=17.1 Hz, 1H), 2.94 (ddd, J=17.6, 13.9, 5.5 Hz, 1H), 2.84-2.75 (m, 2H), 2.69 (t, J=7.5 Hz, 2H), 2.65-2.57 (m, 1H), 2.47-2.37 (m, 3H), 2, 31 (t, J=10.9 Hz, 2H), 2.03 (dtd, J=12.6, 5.1, 2.0 Hz, 1H), 1.90 (td, J=13.1, 4.3 Hz, 2H), 1.65 (ddd, J=21.1, 10.2, 4.5 Hz, 4H), 1.53 (dt, J=14.9, 7.6 Hz, 2H ).

Example 150: 3-(4-((6-(6-chloro-3H-spiro[isobenzofuran-1,4'-piperidine]-1'-)hexyl)oxy)-1-oxoisoindoline-2-)piperidine-2 ,6-dione (150)

The preparation method was the same as for 1-(3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)-4-phenylpiperidine-4-carbonitrile, and in the end 27 mg of a white solid were obtained, yield 26%; ¹ H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.35 (s, 1H), 7.33-7, 27 (m, 3H), 7.24 (d, J=8.1 Hz, 1H), 5.11 (dd, J=13.3, 5.1 Hz, 1H), 4.93 (s, 2H ), 4.37 (d, J=17.4 Hz, 1H), 4.22 (d, J=17.4 Hz, 1H), 4.12 (t, J=6.3 Hz, 2H), 3.00-2.85 (m, 1H), 2.78 (d, J=10.6 Hz, 2H), 2.63-2.54 (m, 1H), 2.48-2.39 ( m, 1H), 2.38-2.31 (m, 2H), 2.27 (t, J=11.3 Hz, 2H), 2.04-1.83 (m, 3H), 1.80 -1.68 (m, 2H), 1.60 (d, J=12.6 Hz, 2H), 1.47 (q, J=16.3 Hz, 4H), 1.35 (dd, J= 13.0, 6.3 Hz, 2H).

Example 151: 3-(4-(4-(6-chloro-3H-spiro[isobenzofuran-1,4-piperidine]-1-)butyl)-1-oxoisoindoline-2-)piperidine-2,6-dione ( 151)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 34.7 mg, yield 37%; ^1H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 8.18 (s, 1H), 7.60-7.54 (m, 1H), 7.50-7.44 (m , 2H), 7.37 (d, J=1.4 Hz, 1H), 7.35-7.27 (m, 2H), 5.14 (dd, J=13.3, 5.1 Hz, 1H), 4.94 (s, 2H), 4.48 (d, J=17.2 Hz, 1H), 4.32 (d, J=17.2 Hz, 1H), 2.99-2, 88 (m, 1H), 2.82 (d, J=11.0 Hz, 2H), 2.68 (t, J=7.5 Hz, 2H), 2.60 (dd, J=17.0 , 2.8 Hz, 1H), 2.48-2.41 (m, 3H), 2.34 (t, J=10.8 Hz, 2H), 2.02 (ddd, J=9.6, 5.5, 2.0 Hz, 1H), 1.94 (ddd, J=14.4, 10.7, 3.8 Hz, 2H), 1.70-1.59 (m, 4H), 1 .57-1.47 (m, 2H).

Example 152: 3-(4-((5-(6-chloro-3H-spiro[isobenzofuran-1,4'-piperidine]-1'-)-5-oxopentyl)oxy)-1-oxoisoindoline-2-) piperidine-2,6-dione (152)

The synthesis method was the same as for N-(3-chloro-4-methylphenyl)-4-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-oxy)butanamide, and 31 mg of final product was obtained as a white solid, yield 39%; ¹ H NMR (400 MHz, DMSO) δ 10.96 (s, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.42 (s, 1H), 7.32 (q, J=8.1 Hz, 3H), 7.25 (d, J=8.1 Hz, 1H), 5.10 (dd, J=13.0, 4.7 Hz, 1H), 4.47- 4.34 (m, 2H), 4.22 (d, J=17.4 Hz, 1H), 4.15 (t, J=6.1 Hz, 2H), 3.87 (d, J=12 ,3 Hz, 1H), 3.27 (s, 1H), 2.87 (ddd, J=31.9, 19.7, 9.4 Hz, 2H), 2.62-2.53 (m, 1H), 2.45 (d, J=6.8 Hz, 5H), 1.94 (dd, J=23.7, 11.7 Hz, 2H), 1.87-1.57 (m, 7H ).

Example 153: 3-(4-(4-(6-chloro-3H-spiro[isobenzofuran-1,4'-piperidine]-1'-)-4-oxobutyl)-1-oxoisoindoline-2-)piperidine-2 ,6-dione (153)

The synthesis method was the same as for N-(3-chloro-4-methylphenyl)-4-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-oxy)butanamide, and 18 mg of final product was obtained as a white solid, yield 23%; ^1H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 7.49 (t, J=7.8 Hz, 1H), 7.39 (s, 1H), 7.35-7, 24 (m, 4H), 5.11 (dd, J=13.3, 5.1 Hz, 1H), 4.99 (s, 2H), 4.48-4.36 (m, 2H), 4 .24 (d, J=17.4 Hz, 1H), 4.17 (t, J=6.3 Hz, 2H), 3.87 (d, J=11.9 Hz, 1H), 3.27 (s, 1H), 2.99-2.79 (m, 2H), 2.65-2.52 (m, 3H), 2.48-2.35 (m, 1H), 2.01 (dt , J=14.6, 7.3 Hz, 3H), 1.82 (ddd, J=19.2, 17.3, 8.8 Hz, 2H), 1.63 (d, J=13.0 Hz, 2H).

Example 154: 6-chloro-N-(4-((2-(2,6-dioxopiperidin-3-)-1-oxoisoindoline-4-)-oxy-)butyl)-3H-spiro[isobenzofuran-1,4 -piperidine]-1-carboxamide (154)

The preparation method was the same as for 1-(3-chloro-4-methylphenyl)-3-(2-((2-(2,6-dioxopiperidin-3-)-1-oxoisoindoline-4-)oxy) ethyl)urea, compound as a white solid, 50.6 mg, yield 65%; ¹ H NMR (400 MHz, DMSO) δ 10.96 (s, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.38 (s, 1H), 7.35-7, 28 (m, 3H), 7.24 (d, J=8.1 Hz, 1H), 6.54 (t, J=5.2 Hz, 1H), 5.11 (dd, J=13.3 , 5.1 Hz, 1H), 4.97 (s, 2H), 4.39 (d, J=17.5 Hz, 1H), 4.23 (d, J=17.4 Hz, 1H), 4.14 (t, J=6.3 Hz, 2H), 3.95 (d, J=11.5 Hz, 2H), 3.12 (dd, J=12.4, 6.7 Hz, 2H ), 2.99-2.85 (m, 3H), 2.60-2.52 (m, 1H), 2.44 (dd, J=17.5, 8.9 Hz, 1H), 2, 04-1.92 (m, 1H), 1.83-1.72 (m, 4H), 1.62-1.55 (m, 4H).

Example 155: 6-chloro-N-(2-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)ethyl)-3H-spiro[isobenzofuran-1,4-piperidine ]-1-carboxamide (155)

The preparation method was the same as for 1-(3-chloro-4-methylphenyl)-3-(2-((2-(2,6-dioxopiperidin-3-)-1-oxoisoindoline-4-)oxy) ethyl)urea, compound as a white solid, 49 mg, yield 60%; ¹ H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 7.49 (t, J=7.8 Hz, 1H), 7.37 (s, 1H), 7.34-7, 28 (m, 4H), 6.76 (t, J=5.3 Hz, 1H), 5.11 (dd, J=13.2, 5.0 Hz, 1H), 4.97 (s, 2H ), 4.39 (d, J=17.4 Hz, 1H), 4.25 (d, J=17.4 Hz, 1H), 4.17 (t, J=6.1 Hz, 2H), 3.96 (d, J=12.7 Hz, 2H), 3.43 (dd, J=11.5, 5.8 Hz, 2H), 3.02-2.95 (m, 2H), 2 .94-2.86 (m, 1H), 2.58 (d, J=18.0 Hz, 1H), 2.46-2.34 (m, 1H), 2.04-1.94 (m , 1H), 1.79 (td, J=13.0, 4.5 Hz, 2H), 1.58 (d, J=12.8 Hz, 2H).

Example 156: 3-(4-(5-(6-fluoro-3H-spiro[isobenzofuran-1,4'-piperidine]-1'-)pentyl)-1-oxoisoindoline-2-)piperidine-2,6- dione (156)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 37 mg, 37% yield ; ^1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.60-7.54 (m, 1H), 7.49-7.44 (m, 2H), 7.29 (dd , J=8.0, 4.9 Hz, 1H), 7.18-7.06 (m, 2H), 5.14 (dd, J=13.2, 5.2 Hz, 1H), 4, 93 (s, 2H), 4.47 (d, J=17.4 Hz, 1H), 4.31 (d, J=17.2 Hz, 1H), 3.00-2.79 (m, 3H ), 2.68-2.56 (m, 3H), 2.38 (dt, J=26.6, 15.4 Hz, 5H), 2.05-1.91 (m, 3H), 1, 63 (d, J=11.3 Hz, 4H), 1.58-1.48 (m, 2H), 1.35 (dd, J=15.8, 6.9 Hz, 2H).

Example 157: 3-(4-5-(6-methyl-3H-spiro[isobenzofuran-1,4'-piperidine]-1-)pentyl)-1-oxoisoindoline-2-)piperidine-2,6-dione ( 157)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 27.5 mg, yield 28%; ^1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.57 (dd, J=5.4, 3.1 Hz, 1H), 7.51-7.41 (m, 2H ), 7.13 (d, J=7.6 Hz, 1H), 7.07 (d, J=7.7 Hz, 1H), 7.02 (s, 1H), 5.14 (dd, J =13.3, 5.1 Hz, 1H), 4.91 (s, 2H), 4.47 (d, J=17.2 Hz, 1H), 4.31 (d, J=17.1 Hz , 1H), 2.98-2.87 (m, 1H), 2.80 (d, J=10.8 Hz, 2H), 2.70-2.56 (m, 3H), 2.47- 2.27 (m, 8H), 2.03-1.98 (m, 1H), 1.92-1.81 (m, 2H), 1.69-1.47 (m, 6H), 1, 40-1.30 (m, 2H).

Example 158: N-(3-chloro-4-methylphenyl)-4-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)butanamide (158)

Step 1: 4-bromobutyric acid (3.0 g, 16.57 mmol, 1.0 eq.) was dissolved in 20 ml of anhydrous tetrahydrofuran, cooled to -40°C, trifluoroacetic anhydride (6.96 g, 33 .14 mmol, 2.0 eq.), stirred at -40°C for 30 minutes. Tert-butanol (9.83 g, 132.56 mmol, 8.0 eq.) was then added and the temperature was gradually raised to room temperature and allowed to react overnight. After completion of the reaction, the reaction system was poured into saturated sodium bicarbonate solution, extracted with ethyl acetate, washed with saturated sodium chloride and concentrated under reduced pressure to obtain 3.75 g of a light yellow oily liquid with a yield of 95%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.41 (t, J=6.7 Hz, 2H), 2.25 (t, J=7.3 Hz, 2H), 1.94-1.85 (m, 2H), 1.79-1.68 (m, 2H), 1.44 (s, 9H).

Step 2: Methyl 5-amino-4-(4-hydroxy-1-oxoisoindoline-2-)-5-oxopentanoate (400 mg, 1.37 mmol, 1.0 eq.) and tert-butyl 4-bromobutyrate (1 .62 g, 6.85 mmol, 5.0 eq.) was dissolved in 20 ml DMSO, anhydrous potassium carbonate (379 mg, 2.74 mmol, 2.0 eq.) was added and reacted at 50°C for 24 hours. After completion of the reaction, the solution was diluted with ethyl acetate, washed with saturated sodium chloride, dried, concentrated under reduced pressure and purified by column chromatography to obtain 530 mg of a colorless oily liquid with a yield of 86%. ^1H NMR (400 MHz, DMSO) δ 7.61 (s, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.27 (d, J=7.4 Hz, 1H) , 7.20 (d, J=8.3 Hz, 1H), 4.72 (dd, J=10.4, 4.8 Hz, 1H), 4.50 (d, J=17.6 Hz, 1H), 4.35 (d, J=17.6 Hz, 1H), 4.11 (t, J=6.0 Hz, 1H), 3.50 (s, 1H), 2.31-2, 14 (m, 2H), 2.06 (ddd, J=13.7, 10.3, 6.5 Hz, 1H), 1.79-1.62 (m, 2H), 1.38 (s, 3H).

Step 3: Methyl 5-amino-4-(4-(4-(tert-butoxy)-4-oxobutoxy)-1-oxoisoindoline-2-)-5-oxopentanoate (530 mg, 1.18 mmol, 1.0 eq.) was dissolved in 20 mg of anhydrous tetrahydrofuran in an ice bath for 15 min. Potassium tert-butoxide (146 mg, 1.30 mmol, 1.1 eq) was added and the reaction was continued for 90 min in an ice bath. After completion of the reaction, 50 μL of formic acid was added to stop the reaction. The solvent was separated by centrifugation under reduced pressure and purified by column chromatography to obtain 463 mg of a yellow solid with a yield of 94%; ¹ H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 7.46 (d, J=7.8 Hz, 1H), 7.30 (d, J=7.4 Hz, 1H) , 7.23 (d, J=8.1 Hz, 1H), 5.11 (dd, J=13.3, 5.0 Hz, 1H), 4.37 (d, J=17.3 Hz, 1H), 4.21 (d, J=17.2 Hz, 1H), 4.12 (t, J=5.9 Hz, 2H), 2.98-2.83 (m, 1H), 2, 58 (d, J=18.0 Hz, 1H), 2.44 (dd, J=17.9, 8.8 Hz, 2H), 2.27 (t, J=7.1 Hz, 3H), 2.03-1.92 (m, 1H), 1.85-1.54 (m, 6H), 1.40-1.36 (m, 13H).

Step 4: tert-butyl 4-((2-(2,6-dioxopiperidin-3-)-1-oxoisoindoline-4-)oxy)butyrate (463 mg, 1.11 mmol) was added to the 100 mL round bottom flask , added 20 ml of a solution of hydrochloric acid in dioxane and carried out the reaction at room temperature for 30 minutes. After completion of the reaction, the solvent was separated by centrifugation and used directly in the next step without further purification. ^1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.30 (d, J=7.4 Hz, 1H) , 7.23 (d, J=8.1 Hz, 1H), 5.11 (dd, J=13.3, 5.1 Hz, 1H), 4.41-4.32 (m, 1H), 4.23 (t, J=12.9 Hz, 1H), 4.12 (t, J=6.0 Hz, 2H), 3.59-3.54 (m, 1H), 2.90 (ddd , J=13.6, 11.9, 5.4 Hz, 1H), 2.57 (d, J=17.8 Hz, 1H), 2.47-2.35 (m, 1H), 2, 33-2.25 (m, 2H), 2.02-1.92 (m, 1H), 1.71 (ddd, J=19.0, 13.1, 5.6 Hz, 4H).

Step 5: 4-((2-(2,6-dioxopiperidin-3-)-1-oxoisoindoline-4-)oxy)butanoic acid (50 mg, 0.139 mmol, 1.0 eq.) was dissolved in 3 ml dimethyl sulfoxide, added 3-chloro-4-methylaniline (0.208 mmol, 1.5 eq.), 0-(7-nitrobenzotriazole)-N,N,N,N-hexafluorophosphate tetramethylurea (79 mg, 0.208 mmol, 1.5 eq.) , 1-hydroxybenzotriazole (28 mg, 0.208 mmol, 1.5 eq.) and triethylamine (141 mg, 1.39 mmol, 10 eq.), and reacted at room temperature for one hour. After completion of the reaction, the solution was diluted with ethyl acetate, washed with saturated sodium chloride and purified by thin layer chromatography and high performance liquid chromatography to obtain 18 mg of product as a white solid, 26% yield; ¹ H NMR (400 MHz, DMSO) δ 10.96 (s, 1H), 10.03 (s, 1H), 7.83 (d, J=1.8 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.35-7.28 (m, 2H), 7.24 (dd, J=8.2, 3.6 Hz, 2H), 5.07 (dd, J =13.4, 5.0 Hz, 1H), 4.27 (d, J=17.4 Hz, 1H), 4.14 (d, J=17.1 Hz, 3H), 2.96-2 .84 (m, 1H), 2.59-2.52 (m, 1H), 2.25 (s, 3H), 2.21-1.87 (m, 4H), 1.24 (s, 2H ).

Example 159: N-(3-chloro-4-methylphenyl)-5-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)valeramide (159)

The synthesis method was the same as for N-(3-chloro-4-methylphenyl)-4-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-oxy)butanamide, and at the end 14 mg of a white solid were obtained with a yield of 21%; ¹ H NMR (400 MHz, DMSO) δ 10.96 (s, 1H), 10.00 (s, 1H), 7.80 (d, J=1.9 Hz, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.36-7.28 (m, 2H), 7.24 (d, J=8.4 Hz, 2H), 5.10 (dd, J=13.3 ,5.1 Hz, 1H), 4.37 (d, J=17.4 Hz, 1H), 4.22 (d, J=17.4 Hz, 1H), 4.14 (d, J=5 ,4 Hz, 2H), 2.98-2.85 (m, 1H), 2.56 (d, J=19.3 Hz, 1H), 2.46-2.32 (m, 3H), 2 .25 (s, 3H), 2.03-1.93 (m, 1H), 1.78 (d, J=3.5 Hz, 4H).

Example 160: 1-(3-chloro-4-methylphenyl)-3-(-2-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)ethyl)urea (160 )

Step 1: Methyl 5-amino-4-(4-hydroxy-1-oxoisoindoline-2-)-5-oxopentanoate (500 mg, 1.71 mmol), N-BoC-2-aminoethanol (413 mg, 2.56 mmol) and triphenylphosphine (672 mg 2.56 mmol) were dissolved in anhydrous tetrahydrofuran (30 ml), DIAD (504 μL, 2.56 mmol) was added with stirring at room temperature, the resulting reaction solution was stirred to carry out the reaction at room temperature for 30 min. After completion of the reaction, the solvent was removed under reduced pressure and the resulting residue was purified by silica gel column chromatography to obtain 468 mg of methyl-5-amino-4-(4-(2-(tert-butoxycarbonylamino)ethoxy)-1-oxoisoindoline-2-)- 5-oxopentanoate, 63%.

Step 2: Methyl 5-amino-4-(4-(2-(tert-butoxycarbonylamino)ethoxy)-1-oxoisoindoline-2-)-5-oxopentanoate (468 mg, 1.07 mmol) was dissolved in anhydrous tetrahydrofuran (40 ml), the reaction solution was cooled to 0°C, potassium tert-butoxide (133 mg, 1.18 mmol) was added with stirring, and stirring was continued in an ice bath for 10 minutes. Once complete, the solution was quenched with 60 μL of formic acid, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 350 mg of the desired product, 81% yield.

Step 3: The product obtained in Step 2 was dissolved in 20 ml of hydrogen chloride in 1,4-dioxane and reacted with stirring at room temperature for 2 hours. After completion of the reaction, the solvent was removed under reduced pressure to obtain the desired product as a white solid powder.

Step 4: 3-(4-(2-Aminoethoxy)-1-oxoisoindoline-2-)piperidine-2,6-dione hydrochloride (50 mg, 0.147 mmol) was dissolved in 3 ml of anhydrous DMSO, triethylamine ( 61 µl, 0.44 mmol) and 3-chloro-4-methylphenyl isocyanate (37 mg, 0.22 mmol). The resulting reaction solution was heated at 40°C to allow the reaction to proceed for 3 hours. After completion of the reaction, the resulting reaction solution was separated by HPLC to obtain 48 mg of the target product 1-(3-chloro-4-methylphenyl)-3-(2-((2-(2,6-dioxopiperidine)-3-)-1 -oxoisoindoline-4-)oxy)ethyl)urea, yield 69%; ^1H NMR (400 MHz, DMSO) δ 10.96 (s, 1H), 8.78 (s, 1H), 7.66 (d, J=2.0 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.32 (d, J=7.4 Hz, 1H), 7.27 (d, J=8.1 Hz, 1H), 7.21-7.00 ( m, 4H), 6.46 (t, J=5.6 Hz, 1H), 5.11 (dd, J=13.3, 5.1 Hz, 1H), 4.39 (d, J=17 .4 Hz, 1H), 4.24 (d, J=17.3 Hz, 1H), 4.17 (t, J=5.5 Hz, 2H), 3.49 (dd, J=5.4 , 1.9 Hz, 2H), 2.91 (ddd, J=17.6, 13.7, 5.4 Hz, 1H), 2.58 (dt, J=6.8, 3.3 Hz, 1H), 2.33 (ddd, J=26.6, 13.4, 4.5 Hz, 1H), 2.22 (s, 3H), 2.03-1.91 (m, 1H).

Example 161: 1-(4-chloro-3-methylphenyl)-3-(-3-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)propyl)urea (161 )

The preparation method was the same as for 1-(3-chloro-4-methylphenyl)-3-(2-((2-(2,6-dioxopiperidin-3-)-1-oxoisoindoline-4-)oxy) ethyl)urea, 13.2 mg of white solid was obtained, yield 31%; ¹ H NMR (400 MHz, DMSO) δ 10.96 (s, 1H), 8.64-8.55 (m, 1H), 7.64 (d, J=2.1 Hz, 1H), 7, 48 (t, J=7.8 Hz, 1H), 7.31 (d, J=7.4 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 7.15 ( d, J=8.5 Hz, 1H), 7.08 (dd, J=8.3, 2.1 Hz, 1H), 6.32 (s, 1H), 5.09 (dd, J=13 ,3, 5.2 Hz, 1H), 4.39 (d, J=17.4 Hz, 1H), 4.24 (d, J=17.4 Hz, 1H), 4.17 (t, J =5.9 Hz, 2H), 3.33-3.24 (m, 2H), 2.95-2.85 (m, 1H), 2.63-2.55 (m, 1H), 2, 45-2.32 (m, 1H), 2.22 (s, 3H), 2.01-1.88 (m, 3H).

Example 162: 1-(3-chloro-4-methylphenyl)-3-(4-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)oxy)butyl)urea (162)

The preparation method was the same as for 1-(3-chloro-4-methylphenyl)-3-(2-((2-(2,6-dioxopiperidin-3-)-1-oxoisoindoline-4-)oxy) ethyl)urea, white solid, 44.2 mg, yield 65%; ^1H NMR (400 MHz, DMSO) δ 10.96 (s, 1H), 8.52 (s, 1H), 7.63 (d, J=2.0 Hz, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.30 (d, J=7.4 Hz, 1H), 7.24 (d, J=8.1 Hz, 1H), 7.16 (d, J= 8.4 Hz, 1H), 7.09 (dd, J=8.3, 2.1 Hz, 1H), 6.22 (t, J=5.8 Hz, 1H), 5.10 (dd, J=13.3, 5.0 Hz, 1H), 4.38 (d, J=17.4 Hz, 1H), 4.22 (d, J=17.3 Hz, 1H), 4.15 ( t, J=6.2 Hz, 2H), 3.15 (dd, J=12.8, 6.6 Hz, 2H), 2.96-2.85 (m, 1H), 2.56 (d , J=17.6 Hz, 1H), 2.47-2.36 (m, 1H), 2.22 (s, 3H), 2.03-1.94 (m, 1H), 1.76 ( dd, J=14.3, 6.4 Hz, 2H), 1.61 (dd, J=14.4, 6.9 Hz, 2H).

Example 163: 1-(3,4-dichlorophenyl)-3-(2-((2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-oxoethyl)urea (163)

The preparation method was the same as for 1-(3-chloro-4-methylphenyl)-3-(2-((2-(2,6-dioxopiperidin-3-)-1-oxoisoindoline-4-)oxy) ethyl)urea, white solid, 50 mg, yield 69%; ^1H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 8.96 (s, 1H), 7.85 (d, J=2.5 Hz, 1H), 7.65-7, 54 (m, H), 7.59-7.52 (m, 1H), 7.52-7.42 (m, 2H), 7.27 (ddd, J=13.5, 11.3, 5 .0 Hz, 3H), 6.56 (t, J=5.7 Hz, 1H), 5.11 (dd, J=13.3, 5.1 Hz, 1H), 4.38 (d, J =17.4 Hz, 1H), 4.25 (d, J=17.3 Hz, 1H), 4.18 (t, J=5.5 Hz, 2H), 3.55-3.47 (m , 1H), 2.91 (ddd, J=18.6, 13.6, 5.2 Hz, 1H), 2.57 (d, J=17.0 Hz, 2H), 2.41-2, 28 (m, 2H), 2.02-1.93 (m, 1H).

Example 164: (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-phenylpentanamide (164)

Step 1: Aniline (15 µl, 0.163 mmol) and compound (2H)-2-tert-butoxycarbonylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)pentanoic acid (50 mg, 0.109 mmol) was dissolved in 10 mL of dichloromethane and triethylamine (46 μL, 0.326 mmol), HOBt (mg, mmol) and HATU (62 mg, 0.163 mmol) were added sequentially with stirring at room temperature. The reaction solution was stirred at room temperature for 2 hours. The reaction was monitored to completion using LC-MS. The reaction solution was diluted with ethyl acetate, washed with saturated sodium chloride solution, and the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, the solvent was removed under reduced pressure, and the crude product was used directly in the next step.

Step 2: The crude reaction product obtained in Step 1 was dissolved in 10 ml of a saturated solution of hydrogen chloride in 1,4-dioxane. The reaction in solution was carried out at room temperature for 2 hours. Completion of the reaction was monitored using LC-MS. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate, washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and dried under reduced pressure to obtain a crude product and used directly in the next reaction.

Step 3: The crude product of Step 2 was dissolved in 10 mL of anhydrous dichloromethane and triethylamine (152 μL, 1.09 mmol) and acetyl chloride (16 μL, 0.218 mmol) were added sequentially with stirring at room temperature. The reaction solution was stirred overnight at room temperature. The completion of the reaction was monitored by LC-MS, the solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate and washed successively with saturated sodium bicarbonate and saturated sodium chloride solution. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under reduced pressure. The resulting crude product was separated by reverse phase HPLC to obtain 10.2 mg

(2S)-2-acetamido-5-(2-(2,6-dioxopiperidin-3-)-1-oxoisoindoline-4-)-N-phenylpentanamide, yield 19%;

^1H NMR (400 MHz, DMSO) δ 10.95 (s, 1H), 10.08 (d, J=5.3 Hz, 1H), 8.18 (d, J=7.8 Hz, 1H) , 7.63-7.51 (m, 3H), 7.48-7.40 (m, 2H), 7.29 (t, J=7.8 Hz, 2H), 7.04 (t, J =7.3 Hz, 1H), 5.12 (dd, J=13.3, 5.0 Hz, 1H), 4.47 (dd, J=12.1, 6.8 Hz, 1H), 4 .39 (d, J=17.3 Hz, 1H), 4.26 (dd, J=17.1, 6.3 Hz, 1H), 2.99-2.85 (m, 1H), 2, 73-2.56 (m, 3H), 2.30 (dtd, J=16.3, 12.3, 3.0 Hz, 1H), 2.05-1.92 (m, 1H), 1, 86 (s, 3H), 1.80-1.50 (m, 4H).

Example 165: N-((2S)-1-(benzylamino)-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-1-oxopentyl-2-)cyclopropylformamide (165 )

The synthesis method was the same as for (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidin-3-)-1-oxoisoindoline-4-)-N-phenylpentanamide, 20.1 mg, yield 60%; ^1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 8.48 (dd, J=9.2, 5.9 Hz, 1H), 8.26 (d, J=8.2 Hz, 1H), 7.57 (d, J=7.3 Hz, 1H), 7.46 (t, J=7.5 Hz, 1H), 7.40 (d, J=7.2 Hz, 1H), 7.29 (dd, J=10.4, 4.2 Hz, 2H), 7.24-7.18 (m, 3H), 5.75 (s, 2H), 5.14 (ddd , J=8.5, 4.9, 4.1 Hz, 1H), 4.48-4.34 (m, 2H), 4.33-4.20 (m, 3H), 2.99-2 .86 (m, 1H), 2.63 (dd, J=19.4, 12.7 Hz, 3H), 2.46-2.29 (m, 1H), 2.06-1.95 (m , 1H), 1.79-1.49 (m, 5H), 0.73-0.57 (m, 4H).

Example 166: (2S)-2-acetylamino-N-benzyl-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)pentanamide (166)

The synthesis method was the same as for (2S)-2-acetylamino-5-(2-(2.,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-phenylpentanamide, 10.2 mg , yield 18%; ^1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 8.46 (td, J=5.7, 2.6 Hz, 1H), 8.04 (d, J=7.9 Hz, 1H), 7.57 (d, J=7.1 Hz, 1H), 7.49-7.37 (m, 2H), 7.33-7.17 (m, 3H), 5.14 (ddd, J=13.0, 5.7, 1.1 Hz, 1H), 4.43 (dd, J=17.4, 7.0 Hz, 1H), 4.36-4.23 (m , 3H), 2.99-2.87 (m, 1H), 2.69-2.57 (m, 3H), 2.37 (ddd, J=18.1, 10.9, 5.9 Hz , 1H), 2.05-1.94 (m, 1H), 1.85 (s, 3H), 1.63 (ddd, J=35.4, 18.8, 7.9 Hz, 4H).

Example 167: (2S)-N-Benzyl-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-2-isobutyramidopentanamide (167)

The synthesis method was the same as for (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-phenylpentanamide, 12.3 mg, yield 36%; ^1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 8.42 (dd, J=9.5, 5.9 Hz, 1H), 7.89 (d, J=8.2 Hz, 1H), 7.57 (d, J=7.4 Hz, 1H), 7.46 (t, J=7.5 Hz, 1H), 7.40 (d, J=7.0 Hz, 1H), 7.29 (dd, J=10.2, 4.3 Hz, 2H), 7.22 (dd, J=6.9, 3.5 Hz, 3H), 5.14 (ddd, J =13.2, 5.0,3.1 Hz, 1H), 4.43 (dd, J=17.1, 6.0 Hz, 1H), 4.38-4.31 (m, 1H), 4.31-4.20 (m, 3H), 2.99-2.87 (m, 1H), 2.69-2.56 (m, 3H), 2.49-2.43 (m, 1H ), 2.37 (ddd, J=17.8, 11.3, 4.4 Hz, 1H), 2.05-1.95 (m, 1H), 1.72 (dt, J=8.9 , 5.6 Hz, 1H), 1.66-1.45 (m, 3H), 0.98 (dd, J=6.8, 3.2 Hz, 6H).

Example 168: (2S)-2-acetylamino-N-tert-butyl-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)pentanamide (168)

The synthesis method was the same as for (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-phenylpentanamide, 6.3 mg, yield 13%; ¹ H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.59-7.51 (m, 2H), 7, 45 (dt, J=7.4, 6.9 Hz, 2H), 5.15 (dd, J=13.2, 5.1 Hz, 1H), 4.44 (dd, J=17.1, 7.2 Hz, 1H), 4.28 (dd, J=18.7, 8.9 Hz, 2H), 3.00-2.86 (m, 1H), 2.70-2.56 (m , 3H), 2.40 (ddd, J=28.4, 14.4, 5.0 Hz, 1H), 2.02 (dt, J=12.1, 4.9 Hz, 1H), 1, 82 (s, 3H), 1.66-1.43 (m, 4H), 1.23 (d, J=0.8 Hz, 9H).

Example 169: (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-(R)-1-phenethyl)pentanoamide (169)

The synthesis method was the same as for (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-phenylpentanamide, 17.3 mg, yield 53%; ^1H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 8.37 (dd, J=8.0, 5.0 Hz, 1H), 7.97 (d, J=8.3 Hz, 1H), 7.58 (dd, J=6.9, 1.6 Hz, 1H), 7.50-7.42 (m, 2H), 7.30 (d, J=4.3 Hz , 4H), 7.26-7.18 (m, 1H), 5.15 (dd, J=13.3, 5.1 Hz, 1H), 4.95-4.85 (m, 1H), 4.45 (dd, J=17.2, 6.5 Hz, 1H), 4.36 (dd, J=14.4, 6.6 Hz, 1H), 4.29 (d, J=17, 0 Hz, 1H), 2.94 (ddd, J=17.5, 13.8, 5.4 Hz, 1H), 2.74-2.58 (m, 3H), 2.41 (ddd, J =16.8, 13.5, 4.2 Hz, 1H), 2.02 (ddd, J=9.6, 4.7, 2.2 Hz, 1H), 1.81 (s, 3H), 1.75-1.51 (m, 4H), 1.32 (d, J=7.0 Hz, 3H).

Example 170: (2S)-2-amino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-(2-(pyridin-2-)phenyl)pentanamide ( 170)

The synthesis method was the same as for (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidin-3-)-1-oxoisoindoline-4-)-N-phenylpentanamide, deprotected with trifluoroacetic acid and separated directly by HPLC, 37 mg, 66% yield; ¹ H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 8.63 (t, J=6.1 Hz, 1H), 8.29 (dd, J=8.2, 1.3 Hz, 1H), 7.90 (tt, J=7.8, 1.9 Hz, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.73 (dt, J=7 ,8, 1.6 Hz, 1H), 7.56 (d, J=7.4 Hz, 1H), 7.48-7.40 (m, 2H), 7.39-7.32 (m, 2H), 7.23 (td, J=7.7, 1.1 Hz, 1H), 5.12 (dd, J=13.2, 4.8 Hz, 1H), 4.40 (d, J =17.0 Hz, 1H), 4.25 (d, J=17.1 Hz, 1H), 3.66 (d, J=4.6 Hz, 1H), 2.99-2.84 (m , 1H), 2.69-2.55 (m, 3H), 2.39-2.22 (m, 1H), 1.98 (dd, J=11.4, 6.1 Hz, 1H), 1, 87-1.72 (m, 1H), 1.63 (s, 3H).

Example 171: (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-((S)-1-phenethyl)pentanamide (171)

The synthesis method was the same as for (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidin-3-)-1-oxoisoindoline-4-)-N-phenylpentanamide, the preparation method was the same , as in Example 127, 16.0 mg, yield 49%; ^1H NMR (400 MHz, DMSO) δ 11.00 (d, J=2.7 Hz, 1H), 8.46 (d, J=8.0 Hz, 1H), 7.97 (d, J= 8.3 Hz, 1H), 7.57 (dd, J=7.5, 1.0 Hz, 1H), 7.44 (td, J=7.5, 1.6 Hz, 1H), 7, 33 (d, J=7.5 Hz, 1H), 7.31-7.15 (m, 5H), 5.13 (ddd, J=13.2, 5.0, 2.4 Hz, 1H) , 4.96-4.85 (m, 1H), 4.44-4.33 (m, 2H), 4.23 (dd, J=17.1, 9.9 Hz, 1H), 2.99 -2.86 (m, 1H), 2.64 (ddd, J=13.5, 7.7, 4.6 Hz, 3H), 2.45-2.31 (m, 1H), 1.99 (ddd , J=6.8, 5.2, 2.2 Hz, 1H), 1.84 (d, J=1.8 Hz, 3H), 1.69-1.41 (m, 4H), 1, 34 (dd, J=7.0, 2.7 Hz, 3H).

Example 172: (2S)-2-amino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-(2-(pyridin-3-)phenyl)pentanamide ( 172)

The synthesis method was the same as for (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-phenylpentanamide. After deprotection with trifluoroacetic acid, the product was directly separated by HPLC, 38 mg, 68% yield; ^1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 8.58 (s, 1H), 8.54 (dd, J=4.8, 1.5 Hz, 1H), 8, 23 (s, 1H), 7.85 (d, J=7.9 Hz, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.58 (dd, J=7.0 , 1.2 Hz, 1H), 7.51-7.38 (m, 4H), 7.34 (dd, J=7.5, 1.4 Hz, 1H), 7.28 (t, J= 7.4 Hz, 1H), 5.14 (dd, J=13.2, 5.1 Hz, 1H), 4.45 (d, J=17.1 Hz, 1H), 4.30 (d, J=17.1 Hz, 1H), 3.41 (dd, J=6.8, 5.2 Hz, 1H), 2.99-2.85 (m, 1H), 2.66-2.54 (m, 3H), 2.45-2.31 (m, 1H), 2.05-1.95 (m, 1H), 1.73-1.62 (m, 1H), 1.57 (dt , J=14.8, 7.4 Hz, 2H), 1.51-1.40 (m, 1H).

Example 173: N-((2S)-1-(benzylamine)-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-1-oxopentyl-2-)cyclobutylcarboxamide (173 )

The synthesis method was the same as for (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-phenylpentanamide, 12.8 mg, yield 37%; ^1H NMR (400 MHz, DMSO) δ 10.96 (s, 1H), 8.43 (dd, J=9.3, 5.8 Hz, 1H), 7.79 (d, J=8.2 Hz, 1H), 7.57 (d, J=7.3 Hz, 1H), 7.45 (t, J=7.5 Hz, 1H), 7.39 (d, J=7.3 Hz, 1H), 7.28 (dd, J=10.3, 4.3 Hz, 2H), 7.24-7.17 (m, 3H), 5.75 (s, 2H), 5.18-5 ,10 (m, 1H), 4.43 (dd, J=17.2, 6.3 Hz, 1H), 4.35 (dd, J=13.7, 7.9 Hz, 1H), 4, 30-4.20 (m, 3H), 3.09 (p, J=8.2 Hz, 1H), 3.00-2.85 (m, 1H), 2.71-2.56 (m, 3H), 2.39 (tdd, J=16.9, 8.3, 3.8 Hz, 1H), 2.18-1.93 (m, 5H), 1.87 (dt, J=17, 6, 8.7 Hz, 1H), 1.74 (ddd, J=14.4, 9.0, 3.5 Hz, 2H), 1.63-1.49 (m, 3H).

Example 174: (2S)-N-((3R,5R,7R)-adamantane-1-)-2-amino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4- )pentanamide (174)

The synthesis method was the same as for (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-phenylpentanamide. After deprotection with trifluoroacetic acid, the product was directly separated by HPLC, 51 mg, 94% yield; ^1H NMR (400 MHz, DMSO) δ 11.04 (s, 1H), 8.10 (d, J=7.5 Hz, 1H), 7.58 (d, J=7.1 Hz, 1H) , 7.50-7.40 (m, 2H), 5.75 (s, 1H), 5.15 (dd, J=13.2, 5.0 Hz, 1H), 4.45 (d, J =17.1 Hz, 1H), 4.29 (dd, J=17.0, 4.2 Hz, 1H), 3.85 (d, J=6.5 Hz, 1H), 3.71-3 .64 (m, 1H), 3.00-2.87 (m, 1H), 2.71-2.56 (m, 3H), 2.39 (ddd, J=26.3, 13.2, 4.3 Hz, 1H), 2.06-1.90 (m, 2H), 1.63 (ddd, J=68.6, 36.4, 13.9 Hz, 17H).

Example 175: (2S)-2-acetylamino-N-((S)-2,3-dihydro-1H-indene-1-)-5-(2-(2,6-dioxopiperidine-3-)-1- oxoisoindoline-4-) pentanamide (175)

The synthesis method was the same as for (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-phenylpentanamide, 16.8 mg, yield 50%; ¹ H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 8.32 (d, J=8.3 Hz, 1H), 8.01 (dd, J=8.2, 3.7 Hz, 1H), 7.57 (d, J=6.9 Hz, 1H), 7.44 (dt, J=7.4, 6.9 Hz, 2H), 7.26-7.09 (m , 3H), 7.05 (d, J=6.9 Hz, 1H), 5.27 (q, J=8.1 Hz, 1H), 5.13 (ddd, J=13.3, 4, 8, 3.8 Hz, 1H), 4.36 (ddd, J=32.6, 31.1, 17.1 Hz, 3H), 2.99-2.85 (m, 2H), 2.84 -2.73 (m, 1H), 2.72-2.55 (m, 3H), 2.45-2.29 (m, 2H), 1.98 (dddd, J=15.4, 9, 8, 4.8, 2.6 Hz, 1H), 1.84 (s, 3H), 1.82-1.68 (m, 2H), 1.63 (dd, J=18.5, 6, 0 Hz, 3H).

Example 176: (2S)-N-((1S,3S,5S,7S)-adamantane-2-)-2-amino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindolin- 4-)pentanamide (176)

The synthesis method was the same as for (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-phenylpentanamide. After deprotection with trifluoroacetic acid, the product was directly separated by HPLC, 47 mg, 87% yield; ¹ H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 7.72 (s, 1H), 7.59 (d, J=7.1 Hz, 1H), 7.51-7, 42 (m, 2H), 5.75 (s, 1H), 5.15 (dd, J=13.3, 4.9 Hz, 1H), 4.45 (d, J=17.1 Hz, 1H ), 4.30 (dd, J=17.1, 3.2 Hz, 1H), 3.51 (s, 1H), 3.02-2.87 (m, 1H), 2.70-2, 57 (m, 3H), 2.46-2.31 (m, 1H), 2.01 (s, 4H), 1.89 (s, 6H), 1.73-1.48 (m, 10H) .

Example 177: (2S)-2-acetylamino-N-((R)-2,3-dihydro-1H-indene-1-)-5-(2-(2,6-dioxopiperidine-3-)-1- Oxoisoindoline-4-)pentanamide (177)

The synthesis method was the same as for (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-phenylpentanamide, 24.3 mg, yield 72%; ^1H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 8.33 (d, J=8.0 Hz, 1H), 8.01 (d, J=7.8 Hz, 1H) , 7.58 (d, J=6.6 Hz, 1H), 7.51-7.41 (m, 2H), 7.29-7.12 (m, 4H), 5.33-5.21 (m, 1H), 5.15 (dd, J=13.0, 4.4 Hz, 1H), 4.45 (dd, J=17.4, 6.7 Hz, 1H), 4.30 ( t, J=11.8 Hz, 2H), 2.92 (ddd, J=13.1, 10.9, 3.5 Hz, 2H), 2.83-2.73 (m, 1H), 2 .72-2.57 (m, 3H), 2.46-2.29 (m, 2H), 2.02 (dd, J=8.8, 4.7 Hz, 1H), 1.85 (s , 3H), 1.79-1.68 (m, 2H), 1.68-1.51 (m, 3H).

Example 178: (2S)-2-acetylamino-N-(2,4-difluorobenzyl)-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)pentanamide (178)

The synthesis method was the same as for (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-phenylpentanamide, 37 mg, yield 65 %; ¹ H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 8.48 (td, J=5.7, 1.8 Hz, 1H), 8.06 (dd, J=7.9 , 1.4 Hz, 1H), 7.57 (d, J=7.2 Hz, 1H), 7.45 (t, J=7.5 Hz, 1H), 7.39 (d, J=7 ,2 Hz, 1H), 7.32 (td, J=8.6, 6.8 Hz, 1H), 7.23-7.15 (m, 1H), 7.02 (td, J=8, 6, 2.5 Hz, 1H), 5.14 (dd, J=13.4, 5.2 Hz, 1H), 4.43 (dd, J=17.0, 4.8 Hz, 1H), 4.34-4.23 (m, 4H), 2.99-2.87 (m, 1H), 2.68-2.55 (m, 3H), 2.40 (ddd, J=16.7 , 13.2, 5.1 Hz, 1H), 2.06-1.96 (m, 1H), 1.84 (s, 3H), 1.73-1.64 (m, 1H), 1, 62-1.48 (m, 3H).

Example 179: (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-((S)-1,2,3,4- tetrahydronaphthyl-1-)pentanamide (179)

The synthesis method was the same as for (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-phenylpentanamide, 22.4 mg, yield 67%; ¹ H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 8.26 (dd, J=8.6, 1.2 Hz, 1H), 7.97 (dd, J=8.1 , 2.6 Hz, 1H), 7.57 (d, J=6.2 Hz, 1H), 7.44 (dt, J=7.5, 6.9 Hz, 2H), 7.17-7 .10 (m, 1H), 7.06 (dt, J=12.5, 5.3 Hz, 3H), 5.13 (ddd, J=13.2, 4.9, 3.3 Hz, 1H ), 4.95 (t, J=7.5 Hz, 1H), 4.36 (ddd, J=37.5, 31.1, 17.1 Hz, 3H), 2.92 (tdd, J= 17.3, 5.1, 1.6 Hz, 1H), 2.80-2.55 (m, 5H), 2.46-2.30 (m, 1H), 2.04-1.94 ( m, 1H), 1.91-1.80 (m, 5H), 1.77-1.55 (m, 6H).

Example 180: (2S)-2-acetylamino-N-(2,4-dimethoxybenzyl)-5-(2-(2,6-dipiperidine-3-)-1-oxoisoindoline-4-)pentanamide (180)

The synthesis method was the same as for (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-phenylpentanamide, 39.3 mg, yield 65%; ¹ H NMR (400 MHz, DMSO) δ 11.03 (s, 1H), 8.20 (td, J=5.9, 1.9 Hz, 1H), 8.04 (dd, J=8.2 , 2.0 Hz, 1H), 7.58 (d, J=7.3 Hz, 1H), 7.46 (t, J=7.4 Hz, 1H), 7.41 (d, J=7 .5 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.52 (d, J=2.4 Hz, 1H), 6.42 (dd, J=8.3 , 2.4 Hz, 1H), 5.15 (dd, J=12.9, 4.9 Hz, 1H), 4.44 (dd, J=17.0, 6.9 Hz, 1H), 4.38 -4.32 (m, 1H), 4.28 (dd, J=17.1, 3.9 Hz, 1H), 4.17 (dd, J=15.2, 5.8 Hz, 1H), 4.10 (ddd, J=15.4, 5.7, 1.6 Hz, 1H), 3.74 (s, 3H), 3.73 (s, 3H), 3.01-2.87 ( m, 1H), 2.72-2.56 (m, 3H), 2.47-2.31 (m, 1H), 2.06-1.94 (m, 1H), 1.84 (s, 3H), 1.75-1.47 (m, 4H).

Example 181: (2S)-2-acetylamino-N-benzhydryl-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)pentanamide (181)

The synthesis method was the same as for (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-phenylpentanamide, 21.5 mg, yield 58%; ¹ H NMR (400 MHz, DMSO) δ 11.00 (d, J=3.3 Hz, 1H), 8.92 (dd, J=8.5, 5.9 Hz, 1H), 8.03 ( d, J=8.2 Hz, 1H), 7.57 (d, J=7.5 Hz, 1H), 7.44 (t, J=7.5 Hz, 1H), 7.38-7, 18 (m, 10H), 6.10 (d, J=8.7 Hz, 1H), 5.13 (dd, J=12.9, 5.2 Hz, 1H), 4.49 (dt, J=7 ,8, 5.2 Hz, 1H), 4.39 (dd, J=17.1, 2.3 Hz, 1H), 4.24 (dd, J=17.1, 7.2 Hz, 1H) , 3.00-2.86 (m, 1H), 2.69-2.56 (m, 3H), 2.45-2.29 (m, 1H), 2.07-1.94 (m, 1H), 1.83 (d, J=1.5 Hz, 3H), 1.74-1.44 (m, 4H).

Example 182: (2S)-2-acetylamino-N-(3-bromobenzyl)-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)pentanamide (182)

The synthesis method was the same as for (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-phenylpentanamide, 38.8 mg, yield 63%; ^1H NMR (400 MHz, DMSO) δ 11.03 (s, 1H), 8.54 (td, J=6.1, 2.3 Hz, 1H), 8.10 (dd, J=8.0 , 1.0 Hz, 1H), 7.57 (d, J=7.2 Hz, 1H), 7.49-7.38 (m, 4H), 7.29-7.19 (m, 2H) , 5.14 (ddd, J=13.3, 4.9, 1.2 Hz, 1H), 4.43 (dd, J=17.2, 7.6 Hz, 1H), 4.30 (ddd , J=17.4, 11.1, 4.4 Hz, 4H), 3.00-2.87 (m, 1H), 2.72-2.56 (m, 3H), 2.47-2 .31 (m, 1H), 2.05-1.95 (m, 1H), 1.85 (s, 3H), 1.71 (dt, J=11.5,7.0 Hz, 1H), 1.64-1.51 (m, 3H).

Example 183: (2S)-N-(3-chloro-4-methylphenyl)-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-2-isobutyrylaminopentanamide (183)

The synthesis method was the same as for (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-phenylpentanamide, 26.5 mg, yield 44%; ^1H NMR (400 MHz, DMSO) δ 11.00 (d, J=4.2 Hz, 1H), 10.17 (d, J=2.4 Hz, 1H), 8.03 (d, J= 7.7 Hz, 1H), 7.83-7.77 (m, 1H), 7.57 (dd, J=6.6, 1.8 Hz, 1H), 7.50-7.40 (m , 2H), 7.36 (dd, J=8.3, 2.1 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 5.13 (dd, J=13, 7, 5.7 Hz, 1H), 4.42 (dd, J=17.0, 11.7 Hz, 2H), 4.28 (dd, J=17.1, 5.4 Hz, 1H), 2.99-2.87 (m, 1H), 2.68 (t, J=1.1 Hz, 2H), 2.65-2.55 (m, 2H), 2.34 (ddd, J= 15.4, 13.2, 5.0 Hz, 1H), 2.26 (s, 3H), 2.05-1.94 (m, 1H), 1.82-1.53 (m, 4H) , 1.05-0.93 (m, 6H).

Example 184: (2S)-2-acetylamino-N-(3-chlorobenzyl)-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)pentanamide (184)

The synthesis method was the same as for (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-phenylpentanamide, 34 mg, yield 60 %; ^1H NMR (400 MHz, DMSO) δ 11.03 (s, 1H), 8.54 (td, J=5.9, 2.4 Hz, 1H), 8.10 (dd, J=7.9 , 8.1 Hz, 1H), 7.57 (d, J=7.2 Hz, 1H), 7.45 (t, J=1.4 Hz, 1H), 7.40 (d, J=7 ,2 Hz, 1H), 7.35 (td, J=8.6, 6.8 Hz, 1H), 7.18-7.15 (m, 1H), 5.14 (td, J=13, 5, 1.0 Hz, 1H), 4.43 (dd, J=17.2, 7.3 Hz, 1H), 4.35 (dd, J=17.0, 4.8 Hz, 1H), 3.00-2.86 (m, 1H), 2.72-2.56 (m, 1H), 2.47-2.31 (m, 3H), 2.00 (ddd, J=10.4 , 13.2, 5.7 Hz, 1H), 1.85-1.96 (m, 1H), 1.84 (s, 3H), 1.77-1.65 (m, 1H), 1, 65-1.49 (m, 3H).

Example 185: N-((2S)-1-((3-chloro-4-methylphenyl)amino)-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-1 -oxopentyl-2-) cyclopropylformamide (185)

The synthesis method was the same as for (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-phenylpentanamide, 21.9 mg, yield 36%; ^1H NMR (400 MHz, DMSO) δ 11.00 (d, J=3.7 Hz, 1H), 10.22 (d, J=4.1 Hz, 1H), 8.43 (d, J= 7.9 Hz, 1H), 7.82 (dd, J=3.5, 2.2 Hz, 1H), 7.58 (dd, J=5.9, 2.6 Hz, 1H), 7, 49-7.42 (m, 2H), 7.36 (dd, J=8.3, 2.0 Hz, 1H), 7.27 (d, J=8.3 Hz, 1H), 5.13 (dd, J=14.0, 4.9 Hz, 1H), 4.50-4.37 (m, 2H), 4.28 (dd, J=17.1, 7.1 Hz, 1H), 3.00-2.87 (m, 1H), 2.69 (t, J=7.1 Hz, 2H), 2.65-2.56 (m, 1H), 2.44-2.29 ( m, 1H), 2.27 (s, 3H), 2.00 (tdd, J=9.9, 6.2, 3.9 Hz, 1H), 1.83-1.55 (m, 5H) , 0.65 (dd, J=6.1, 2.6 Hz, 4H).

Example 186: (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-(4-(pyrrolidine-1-)benzyl)pentanamide ( 186)

The synthesis method was the same as for (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-phenylpentanamide, 32 mg, yield 52 %; ¹ H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 8.31 (td, J=5.8, 1.6 Hz, 1H), 8.01 (dd, J=8.3 , 2.0 Hz, 1H), 7.56 (d, J=7.3 Hz, 1H), 7.44 (t, J=7.5 Hz, 1H), 7.38 (d, J=7 .3 Hz, 1H), 7.01 (d, J=8.3 Hz, 2H), 6.43 (dd, J=8.7, 2.4 Hz, 2H), 5.14 (dd, J =13.5, 5.2 Hz, 1H), 4.42 (dd, J=17.1, 10.4 Hz, 1H), 4.29 (ddd, J=22.5, 11.9, 4 ,6 Hz, 2H), 4.20-4.04 (m, 2H), 3.16 (td, J=6.4, 2.2 Hz, 4H), 2.99-2.87 (m, 1H), 2.60 (dt, J=5.9, 4.6 Hz, 3H), 2.46-2.31 (m, 1H), 2.04-1.96 (m, 1H), 1 .96-1.90 (m, 4H), 1.83 (s, 3H), 1.73-1.64 (m, 1H), 1.61-1.49 (m, 3H).

Example 187: N-((2S)-1-((3-chloro-4-methylphenyl)amino)-5-(2-(2,6-dioxopiperidin-3-)-1-oxoisoindoline-4-)-1 -oxopentyl-2-) cyclobutylcarboxamide (187)

The synthesis method was the same as for (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-phenylpentanamide, 24.2 mg, yield 39%; ¹ H NMR (400 MHz, DMSO) δ 11.00 (d, J=3.7 Hz, 1H), 10.18 (d, J=3.3 Hz, 1H), 7.95 (d, J= 7.9 Hz, 1H), 7.80 (dd, J=3.2, 2.3 Hz, 1H), 7.57 (dd, J=6.6, 1.7 Hz, 1H), 7, 49-7.40 (m, 2H), 7.36 (dd, J=8.3, 2.1 Hz, 1H), 7.26 (d, J=8.3 Hz, 1H), 5.12 (ddd, J=13.3, 5.0, 1.5 Hz, 1H), 4.47-4.35 (m, 2H), 4.27 (dd, J=17.1, 5.2 Hz , 1H), 3.11 (p, J=8.3 Hz, 1H), 3.01-2.87 (m, 1H), 2.67 (t, J=7.2 Hz, 2H), 2 ,64-2.56 (m, 1H), 2.42-2.29 (m, 1H), 2.26 (s, 3H), 2.17-2.05 (m, 2H), 2.04 -1.95 (m, 3H), 1.87 (dt, J=17.7, 8.7 Hz, 1H), 1.79-1.71 (m, 2H), 1.70-1.53 (m, ZN).

Example 188: (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-(2-phenylpropyl-2-)pentanamide (188)

The synthesis method was the same as for (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-phenylpentanamide, 36.5 mg, yield 65%; ¹ H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 8.16 (d, J=3.4 Hz, 1H), 7.89 (d, J=8.1 Hz, 1H) , 7.60-7.56 (m, 1H), 7.47 (ddd, J=13.4, 9.8, 4.2 Hz, 2H), 7.29 (dd, J=5.7, 4.2 Hz, 2H), 7.23 (td, J=7.6, 1.8 Hz, 2H), 7.18-7.11 (m, 1H), 5.15 (ddd, J=13 ,1, 5.1, 1.3 Hz, 1H), 4.49-4.36 (m, 2H), 4.28 (dd, J=17.3, 6.2 Hz, 1H), 3, 00-2.88 (m, 1H), 2.71-2.57 (m, 3H), 2.45-2.31 (m, 1H), 2.06-1.96 (m, 1H), 1.83 (s, 3H), 1.72-1.45 (m, 10H).

Example 189: 6-amino-N-((2S)-1-((3-chloro-4-methylphenyl)amino)-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4 -)-1-oxopentyl-2-)hexanamide (189)

The synthesis method was the same as for (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-phenylpentanamide, 23.9 mg, yield 37%; ¹ H NMR (400 MHz, DMSO) δ 11.00 (d, J=3.2 Hz, 1H), 10.29 (s, 1H), 8.20 (d, J=6.9 Hz, 1H) , 7.83 (dd, J=8.8, 6.4 Hz, 4H), 7.57 (dd, J=6.6, 1.9 Hz, 1H), 7.42 (ddd, J=11 ,3, 10.3, 4.7 Hz, 3H), 7.26 (d, J=8.4 Hz, 1H), 5.13 (dd, J=13.3, 5.0 Hz, 1H) , 4.43 (dd, J=17.1, 11.9 Hz, 2H), 4.28 (dd, J=17.1, 4.6 Hz, 1H), 2.93 (ddd, J=17 ,6, 11.8, 4.9 Hz, 1H), 2.70 (dt, J=19.6, 6.6 Hz, 4H), 2.60 (d, J=17.0 Hz, 1H) , 2.43-2.30 (m, 1H), 2.26 (s, 3H), 2.15 (t, J=7.4 Hz, 2H), 1.99 (dd, J=10.8 , 5.2 Hz, 1H), 1.84 1.57 (m, 4H), 1.51 (tt, J=15.6, 7.7 Hz, 4H), 1.26 (dt, J=13 ,7, 6.9 Hz, 2H).

Example 190: (2S)-2-acetylamino-N-(4-(2-(dimethylamino)ethoxy)benzyl)-5-(2-(2,6-dioxopiperidine)-3-)-1-oxoisoindoline-4- )pentanamide (190)

The synthesis method was the same as for (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-phenylpentanamide, 35.4 mg, yield 56%; ^1H NMR (400 MHz, DMSO) δ 11.03 (s, 1H), 8.42 (t, J=5.2 Hz, 1H), 8.16 (s, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.57 (d, J=7.3 Hz, 1H), 7.45 (t, J=7.5 Hz, 1H), 7.39 (d, J= 7.3 Hz, 1H), 7.13 (d, J=8.4 Hz, 2H), 6.85 (d, J=8.3 Hz, 2H), 5.14 (dd, J=13, 6, 4.8 Hz, 1H), 4.43 (dd, J=16.8, 7.5 Hz, 1H), 4.34-4.23 (m, 2H), 4.22-4.14 (m, 2H), 4.04 (t, J=5.5 Hz, 2H), 3.00-2.87 (m, 1H), 2.76 (t, J=5.4 Hz, 2H) , 2.61 (dd, J=25.9, 7.7 Hz, 3H), 2.43-2.36 (m, 1H), 2.32 (s, 6H), 2.05-1.95 (m, 1H), 1.84 (s, 3H), 1.73-1.64 (m, 1H), 1.63-1.49 (m, 3H).

Example 191: N-((2S)-1-((3-chloro-4-methylphenyl)amino)-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-1 -oxopentyl-2-)piperidine-4-carboxamide (191)

The synthesis method was the same as for (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-phenylpentanamide, 33.8 mg, yield 52%; ^1H NMR (400 MHz, DMSO) δ 11.00 (d, J=4.8 Hz, 1H), 10.31 (s, 1H), 8.97 (d, J=9.3 Hz, 1H) , 8.67-8.49 (m, 1H), 8.31 (d, J=7.8 Hz, 1H), 7.82 (t, J=2.3 Hz, 1H), 7.57 ( dd, J=6.6, 1.8 Hz, 1H), 7.48-7.41 (m, 2H), 7.38 (dd, J=8.3, 2.0 Hz, 1H), 7 .26 (d, J=8.4 Hz, 1H), 5.13 (dd, J=13.2, 4.9 Hz, 1H), 4.49-4.38 (m, 2H), 4, 28 (dt, J=5.9, 3.5 Hz, 1H), 3.30-3.17 (m, 2H), 3.01-2.76 (m, 3H), 2.68 (t, J=6.9 Hz, 2H), 2.65-2.52 (m, 2H), 2.37 (ddd, J=26.3, 13.1, 4.2 Hz, 1H), 2.26 (s , 3H), 2.00 (td, J=10.3, 5.1 Hz, 1H), 1.91-1.53 (m, 8H).

Example 192: (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-(4-phenoxybenzyl)pentanamide (192)

The synthesis method was the same as for (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-phenylpentanamide, 39 mg, yield 61 %; ¹ H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 8.49 (td, J=5.9, 2.1 Hz, 1H), 8.06 (dd, J=8.0 , 1.2 Hz, 1H), 7.56 (dd, J=7.0, 1.5 Hz, 1H), 7.45-7.34 (m, 4H), 7.24 (d, J= 8.6 Hz, 2H), 7.13 (td, J=7.4, 0.5 Hz, 1H), 6.99-6.91 (m, 4H), 5.14 (dd, J=13 ,2, 5.0 Hz, 1H), 4.43 (dd, J=17.2, 7.4 Hz, 1H), 4.32 (ddd, J=13.6, 8.5, 3.6 Hz, 2H), 4.25 (d, J=6.1 Hz, 2H), 2.99-2.86 (m, 1H), 2.71-2.55 (m, 3H), 2.40 (ddd , J=17.5, 13.8, 5.6 Hz, 1H), 2.00 (ddd, J=8.4, 5.8, 3.2 Hz, 1H), 1.84 (s, 3H ), 1.75-1.66 (m, 1H), 1.65-1.47 (m, 3H).

Example 193: N-((2S)-1-(3-chloro-4-methylaniline)-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-1-oxopentyl- 2-)-6-hydroxyhexanamide (193)

The synthesis method was the same as for (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidin-3-)-1-oxoisoindoline-4-)-N-phenylpentanamide, white solid, 48 mg, yield 69%; ¹ H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 10.16 (d, J=3.4 Hz, 1H), 8.11 (d, J=7.8 Hz, 1H) , 7.83-7.76 (m, 1H), 7.57 (dd, J=6.4, 2.0 Hz, 1H), 7.49-7.41 (m, 2H), 7.36 (dd, J=8.3, 2.0 Hz, 1H), 7.26 (d, J=8.3 Hz, 1H), 5.12 (dd, J=13.3, 3.5 Hz, 1H), 4.47-4.37 (m, 2H), 4.29 (dt, J=17.1, 5.6 Hz, 2H), 3.37-3.33 (m, 2H), 2 .93 (t, J=13.9 Hz, 1H), 2.68 (t, J=7.0 Hz, 2H), 2.59 (d, J=17.3 Hz, 1H), 2.43 -2.29 (m, 1H), 2.26 (s, 3H), 2.13 (t, J=7.2 Hz, 2H), 1.99 (dd, J=12.0, 5.2 Hz, 1H), 1.78-1.56 (m, 4H), 1.48 (dt, J=15.1, 7.5 Hz, 2H), 1.43-1.34 (m, 2H) , 1.30-1.19 (m, 2H).

Example 194: (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-(2-(pyridin-2-)phenyl)pentanamide ( 194)

The synthesis method was the same as for (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-phenylpentanamide, 19.5 mg, yield 67%; ^1H NMR (400 MHz, DMSO) δ 12.17 (s, 1H), 11.01 (s, 1H), 8.72-8.68 (m, 1H), 8.43 (dd, J=7 ,2, 1.9 Hz, 1H), 8.37 (dd, J=8.2, 0.6 Hz, 1H), 7.99-7.93 (m, 1H), 7.89 (d, J=8.3 Hz, 1H), 7.78 (dd, J=8.0, 1.3 Hz, 1H), 7.56 (dd, J=7.2, 1.2 Hz, 1H), 7.42 (ddd, J=12.4, 9.6, 4.5 Hz, 3H), 7.21 (td, J=7.9, 1.3 Hz, 1H), 5.13 (dd, J=13.3, 5.2 Hz, 1H), 4.43 (d, J=17.2 Hz, 1H), 4.33-4.22 (m, 2H), 3.00-2.86 (m, 1H), 2.71-2.56 (m, 3H), 2.44-2.27 (m, 1H), 1.99 (dtd, J=12.5, 5.1, 2, 4 Hz, 1H), 1.95-1.76 (m, 4H), 1.75-1.55 (m, 3H).

Example 195: 3-(4-((S)-4-amino-4-(7-bromo-1H-benzo[d]imidazole-2-)butyl)-1-oxoisoindoline-2-)piperidine-2,6 -dion (195)

3-bromo-o-phenylenediamine (75 mg, 0.4 mmol), (2R)-2-tert-butoxycarbonylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-) pentanoic acid (92 mg, 0.2 mmol) and HOBt (54 mg, 0.4 mmol) were dissolved in 10 ml of dichloromethane, triethylamine (84 μl, 0.6 mmol) and HATU (152 mg, 0.4 mmol) were added with stirring at room temperature. The reaction in the resulting solution proceeded with stirring at room temperature for 4 hours. Completion of the condensation reaction was monitored using LC-MS. The solvent was removed under reduced pressure, 5 ml of acetic acid was added to the resulting residue, and the reaction solution was heated to 110°C under reflux for 2 hours. Completion of the reaction was monitored using LC-MS. The solvent was removed under reduced pressure and the residue was separated by HPLC to obtain 84 mg of the desired product: 3-(4-((S)-4-amino-4-(7-bromo-1H-benzo[d]imidazole-2- )butyl)-1-oxoisoindoline-2-) piperidine-2,6-dione, as a white solid, yield 82%; ¹ H NMR (400 MHz, DMSO) δ 7.56 (dd, J=8.2, 3.0 Hz, 2H), 7.43 (q, J=7.6 Hz, 3H), 7.14 ( t, J=7.9 Hz, 1H), 5.12 (dd, J=13.2, 4.9 Hz, 1H), 4.50 (t, J=6.5 Hz, 1H), 4, 31 (ddd, J=24.0, 19.8, 12.0 Hz, 3H), 3.00-2.86 (m, 1H), 2.64 (dd, J=19.6, 12.5 Hz, 3H), 2.54 (s, 2H), 2.41-2.22 (m, 1H), 2.01 (dd, J=14.6, 8.4 Hz, 3H), 1.75 -1.54 (m, 2H).

Example 196: (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-(2-(pyridin-3-)phenyl)pentanamide ( 196)

The synthesis method was the same as for (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-phenylpentanamide, 21.4 mg, yield 70%; ¹ H NMR (400 MHz, DMSO) δ 11.02 (d, J=3.0 Hz, 1H), 9.53 (d, J=3.8 Hz, 1H), 8.55-8.52 ( m, 1H), 8.49 (dt, J=4.8, 1.6 Hz, 1H), 8.04 (dd, J=7.7, 1.7 Hz, 1H), 7.74 (ddd , J=7.7, 3.8, 1.8 Hz, 1H), 7.58 (d, J=7.4 Hz, 1H), 7.52-7.40 (m, 4H), 7, 40-7.30 (m, 3H), 5.14 (dd, J=12.5, 5.2 Hz, 1H), 4.43 (dd, J=17.3, 9.0 Hz, 1H) , 4.30 (ddd, J=18.9, 13.1, 3.5 Hz, 2H), 2.93 (t, J=14.7 Hz, 1H), 2.60 (t, J=7 ,1 Hz, 3H), 2.38 (ddd, J=20.5, 14.9, 4.7 Hz, 1H), 2.05-1.93 (m, 1H), 1.81 (s, 3H), 1.66-1.40 (m, 4H).

Example 197: N-((1S)-1-(7-bromo-1H-benzo[d]imidazole-2-)-4-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4 -)butyl) acetamide (197)

3-(4-((S)-4-amino-4-(7-bromo-1H-benzo[d]imidazol-2-)butyl)-1-oxoisoindoline-2-)piperidine-2,6-dione ( 31 mg, 0.061 mmol) was dissolved in 10 ml of dry dichloromethane. Triethylamine (85 μL, 0.61 mmol) and acetyl chloride (5 μL, 0.072 mmol) were sequentially added with stirring at room temperature, and stirring was continued to allow the reaction to proceed at room temperature for 2 hours. After completion of the reaction, the solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and dried under reduced pressure. The resulting crude product was separated by HPLC to obtain 15.5 mg of product in 46% yield; ¹ H NMR (400 MHz, DMSO) δ 12.63 (d, J=14.9 Hz, 1H), 11.00 (s, 1H), 8.51 (d, J=8.0 Hz, 1H) , 7.56 (dd, J=5.3, 3.2 Hz, 1H), 7.45 (dd, J=8.1, 5.2 Hz, 3H), 7.36 (dd, J=7 ,6, 4.4 Hz, 1H), 7.09 (td, J=7.5, 3.0 Hz, 1H), 5.26-5.07 (m, 2H), 4.50-4, 18 (m, 2H), 3.00-2.87 (m, 1H), 2.71 (dd, J=16.9, 8.1 Hz, 2H), 2.65-2.56 (m, 1H), 2.35 (ddd, J=12.5, 10.5, 4.4 Hz, 1H), 2.13-1.96 (m, 2H), 1.95-1.82 (m, 4H), 1.76-1.52 (m, 2H).

Example 198: (2S)-2-acetylamino-N-((3R,5R,7R)-adamantane-1-)-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4- )pentanamide (198)

The synthesis method was the same as for (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidin-3-)-1-oxoisoindoline-4-)-N-phenylpentanamide, 15 mg, yield 49 %; ¹ H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 7.85 (d, J=8.3 Hz, 1H), 7.57 (dd, J=7.1, 1.1 Hz, 1H), 7.44 (ddd, J=13.0, 10.7, 6.4 Hz, 3H), 5.15 (dd, J=13.4, 5.3 Hz, 1H), 4 .43 (dd, J=16.9, 6.6 Hz, 1H), 4.33-4.23 (m, 2H), 3.00-2.87 (m, 1H), 2.62 (ddd , J=19.9, 7.6, 3.5 Hz, 3H), 2.46-2.32 (m, 1H), 2.07-1.94 (m, 4H), 1.81 (d , J=2.1 Hz, 9H), 1.67-1.43 (m, 10H).

Example 199: 3-(4-((S)-4-amino-4-(1H-benzo(d)imidazol-2-)butyl)-1-oxoisoindoline-2-)piperidine-2,6-dione (199 )

The preparation method was the same as for 3-(4-((S)-4-amino-4-(7-bromo-1H-benzo[d]imidazol-2-)butyl)-1-oxoisoindoline--2 -)piperidine-2,6-dione, 37 mg, yield 43%; ^1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 8.24 (s, 1H), 7.55 (dd, J=5.6, 2.9 Hz, 1H), 7. 53-7.47 (m, 2H), 7.46-7.40 (m, 2H), 7.17-7.09 (m, 2H), 5.11 (dd, J=13.3, 5 ,1 Hz, 1H), 4.37 (dd, J=21.6, 17.2 Hz, 1H), 4.23 (dd, J=14.5, 7.8 Hz, 2H), 2.98 -2.85 (m, 1H), 2.70-2.56 (m, 3H), 2.30 (tdd, J=26.1, 13.0, 4.4 Hz, 2H), 1.96 (ddd, J=17.0, 12.2, 6.0 Hz, 2H), 1.89-1.78 (m, 1H), 1.73-1.55 (m, 2H).

Example 200: (2S)-2-acetylamino-N-((1S,3S,5S,7S)-adamantane-2-)-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline- 4-) pentanamide (200)

The synthesis method was the same as for (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-phenylpentanamide, 15.3 mg, yield 47%; ¹ H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.76 (dd, J=7.3, 2.7 Hz, 1H), 7.57 (dd, J=6.9, 1.4 Hz, 1H), 7.49-7.39 (m, 2H), 5.14 (dd, J=13.2, 5.1 Hz, 1H), 4.46 (ddd, J=19.3, 15.4, 4.6 Hz, 2H), 4.27 (d, J=17.1 Hz, 1H), 3, 80 (d, J=6.8 Hz, 1H), 3.01-2.85 (m, 1H), 2.73-2.57 (m, 3H), 2.40 (ddd, J=22, 7, 13.5, 4.5 Hz, 1H), 2.11-1.92 (m, 2H), 1.91-1.38 (m, 20H).

Example 201: 3-(4-((8)-4-amino-4-(3H-imidazole[4,5-c]pyridin-2-)butyl)-1-oxoisoindoline-2-)piperidine-2,6 -dion (201)

The preparation method was the same as for 3-(4-((8)-4-amino-4-(7-bromo-1H-benzo[d]imidazol-2-)butyl)-1-oxoisoindoline--2 -)piperidine-2,6-dione, 47 mg, yield 54%; ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 9.50 (s, 1H), 9.04 (d, J=53.3 Hz, 2H), 8.58 (dd, J=29.1, 6.2 Hz, 1H), 8.13 (dd, J=51.3, 6.3 Hz, 1H), 7.63-7.51 (m, 1H), 7.43 (d, J=4.0 Hz, 2H), 5.12 (d,J=11.0 Hz, 1H), 4.88 (s, 1H), 4.55-4.39 (m, 1H) , 4.34-4.21 (m, 1H), 3.00-2.85 (m, 1H), 2.76-2.58 (m, 3H), 2.44-2.30 (m, 1H), 2.18 (d, J=6.0 Hz, 2H), 2.05-1.87 (m, 1H), 1.78-1.61 (m, 2H).

Example 202: (2S)-2-acetylamino-N-(3-chloro-4-methylphenyl)-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)pentanamide (202)

The synthesis method was the same as for (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-phenylpentanamide, 34 mg, yield 60 %; ¹ H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 10.17 (d, J=3.8 Hz, 1H), 8.20 (d, J=7.8 Hz, 1H) , 7.81 (dd, J=3.3, 2.2 Hz, 1H), 7.57 (dd, J=5.9, 2.6 Hz, 1H), 7.49-7.41 (m , 2H), 7.37 (dd, J=8.3, 2.0 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 5.13 (dd, J=13, 3, 5.1 Hz, 1H), 4.42 (dd, J=16.9, 13.3 Hz, 2H), 4.27 (dd, J=17.1, 4.5 Hz, 1H), 3.00 2.86 (m, 1H), 2.68 (t, J=6.8 Hz, 2H), 2.59 (ddd, J=7.4, 6.7, 2.4 Hz, 1H ), 2.42-2.29 (m, 1H), 2.26 (s, 3H), 1.99 (dd, J=12.4, 5.2 Hz, 1H), 1.86 (s, 3H), 1.80-1.53 (m, 4H).

Example 203: N-((1S)-1-(-1H-benzo[d]imidazole-2-)-4-(2-(2,6-dioxopiperidin-3-)-1-oxoisoindoline-4-)butyl )amide (203)

The preparation method was the same as for N-((1S)-1-(7-bromo-1H-benzo[d]imidazol-2-)-4-(2-(2,6-dioxopiperidine-3-) -1-oxoisoindoline-4-)butyl)acetamide, 18.5 mg, yield 74%; ¹ H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 8.24 (s, 1H), 7.55 (dd, J=5.6, 2.9 Hz, 1H), 7, 53-7.47 (m, 2H), 7.46-7.40 (m, 2H), 7.17-7.09 (m, 2H), 5.11 (dd, J=13.3, 5 ,1 Hz, 1H), 4.37 (dd, J=21.6, 17.2 Hz, 1H), 4.23 (dd, J=14.5, 7.8 Hz, 2H), 2.98 -2.85 (m, 1H), 2.70-2.56 (m, 3H), 2.30 (tdd, J=26.1, 13.0, 4.4 Hz, 2H), 1.96 (ddd, J=17.0, 12.2, 6.0 Hz, 2H), 1.91 (s, 3H), 1.89-1.78 (m, 1H), 1.73-1.55 (m, 2H).

Example 204: (2S)-2-acetylamino-N-benzyl-5-(2-(2,6-oxopiperidine-3-)-1-oxoisoindoline-4-)-N-methylpentanamide (204)

The synthesis method was the same as for (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-phenylpentanamide, 17 mg, yield 52 %; ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 8.20 (ddd, J=9.9, 9.0, 1.7 Hz, 1H), 7.56 (t, J =6.4 Hz, 1H), 7.49-7.40 (m, 2H), 7.39-7.29 (m, 2H), 7.28-7.20 (m, 2H), 7. 18 (d, J=7.2 Hz, 1H), 5.17-5.09 (m, 1H), 4.79 (s, 1H), 4.64-4.18 (m, 4H), 2 ,99-2.75 (m, 4Н), 2.64 (ddd, J=20.4, 15.7, 4.6 Hz, 3Н), 2.39 (ddd, J=22.0, 16, 2, 7.2 Hz, 1H), 2.01 (dd, J=10.9, 5.0 Hz, 1H), 1.80 (d, J=34.8 Hz, 3H), 1.73- 1.40 (m, 4H).

Example 205: N-((1S)-4-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-1-(3H-imidazole[4,5-c]pyridine-2 -)butyl) acetamide (205)

The preparation method was the same as for N-((1S)-1-(7-bromo-1H-benzo[d]imidazol-2-)-4-(2-(2,6-dioxopiperidine-3-) -1-oxoisoindoline-4-)butyl)acetamide, 9.2 mg, yield 29%; ¹ H NMR (400 MHz, DMSO) δ 11.04 (s, 1H), 8.84 (s, 1H), 8.52 (d, J=8.0 Hz, 1H), 8.26 (d, J=5.5 Hz, 1H), 8.17 (s, 1H), 7.60-7.54 (m, 1H), 7.52-7.48 (m, 1H), 7.47-7 .42 (m, 2H), 5.21-5.09 (m, 2H), 4.43 (t, J=16.5 Hz, 1H), 4.28 (d, J=17.1 Hz, 1H), 3.01-2.88 (m, 1H), 2.76-2.57 (m, 3H), 2.45-2.29 (m, 1H), 2.13-1.96 ( m, 2H), 1.91 (s, 3H), 1.76-1.59 (m, 2H).

Example 206: (2S)-N-Benzyl-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-2-propionamidopentanamide (206)

The synthesis method was the same as for (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-phenylpentanamide, 32 mg, yield 58 %; ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 8.44 (d, J=1.9 Hz, 1H), 7.94 (d, J=7.8 Hz, 1H) , 7.57 (d, J=7.2 Hz, 1H), 7.46 (t, J=7.3 Hz, 1H), 7.40 (d, J=7.4 Hz, 1H), 7 ,32-7.25 (m, 2H), 7.22 (d, J=7.1 Hz, 3H), 5.75 (d, J=2.3 Hz, 1H), 5.14 (dd, J=11.8, 3.1 Hz, 1H), 4.43 (dd, J=17.0, 6.9 Hz, 1H), 4.38-4.20 (m, 4H), 3.01 -2.85 (m, 1H), 2.61 (d, J=19.4 Hz, 3H), 2.39 (dd, J=27.6, 13.5 Hz, 1H), 2.14 ( dd, J=14.8, 7.2 Hz, 2H), 2.05-1.94 (m, 1H), 1.77-1.46 (m, 4H), 0.98 (t, J= 7.5 Hz, 3H).

Example 207: N-((2S)-5-(2-(2,6-dioxopiperidin-3-)-1-oxoisoindoline-4-)-1-oxo-1-(3H-spiro[isobenzofuran-1,4 '-piperidine]-1'-)pentyl-2-)acetamide (207)

The synthesis method was the same as for (2S)-2-acetylamino-5-(2-(2,6-dioxopiperidine-3-)-1-oxoisoindoline-4-)-N-phenylpentanamide, 32.3 mg, yield 51%; ¹ H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 8.17 (dd, J=18.4, 7.4 Hz, 1H), 7.64-7.54 (m, 1H ), 7.47 (dd, J=6.9, 3.2 Hz, 2H), 7.29 (d, J=8.5 Hz, 3H), 7.24-7.06 (m, 1H) , 5.15 (dd, J=13.2, 4.3 Hz, 1H), 5.01 (d, J=3.8 Hz, 2H), 4.81 (dd, J=7.5, 4 ,3 Hz, 1H), 4.55-4.23 (m, 3H), 3.88 (d, J=9.4 Hz, 1H), 3.32-3.24 (m, 1H), 3 .04-2.82 (m, 2H), 2.80-2.55 (m, 3H), 2.41 (ddd, J=22.3, 15.0, 9.5 Hz, 1H), 2 .02 (dd, J=14.8, 5.4 Hz, 1H), 1.85 (d, J=5.0 Hz, 3H), 1.78-1.48 (m, 7H).

Example 208: 3-(1-oxo-4-(4-(4-(phenyl-d5)piperazine-1-)butyl)isoindoline-2-)piperidine-2,6-dione (208)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 9.8 mg, yield 14%; ¹ H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.57 (dd, J=5.5, 3.1 Hz, 1H), 7.48-7.44 (m, 2H ), 5.13 (dd,J=13.3, 5.1 Hz, 1H), 4.47 (d, J=17.1 Hz, 1H), 4.32 (d, J=17.1 Hz , 1H), 3.14-3.06 (m, 4H), 2.97-2.85 (m, 1H), 2.68 (t, J=7.6 Hz, 2H), 2.59- 2.53 (m, 1H), 2.49-2.38 (m, 5H), 2.35 (t, J=7.1 Hz, 2H), 2.05-1.96 (m, 1H) , 1.64 (dt, J=15.1, 7.5 Hz, 2H), 1.51 (dt, J=14.3, 7.3 Hz, 2H).

Example 209: 3-(1-oxo-4-(6-(4-(phenyl-d5)piperazine-l-)hexyl)isoindoline-2-)piperidine-2,6-dione (209)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 51.1 mg, yield 68%; ¹ H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.56 (dd, J=8.1, 4.6 Hz, 1H), 7.48-7.42 (m, 2H ), 5.13 (dd, J=13.3, 5.1 Hz, 1H), 4.46 (d, J=17.2 Hz, 1H), 4.30 (d, J=17.1 Hz , 1H), 3.32 (s, 4H), 3.14-3.06 (m, 4H), 2.98-2.85 (m, 1H), 2.69-2.56 (m, 3H ), 2.46-2.37 (m, 1H), 2.32 (t, J=7.2 Hz, 2H), 2.05-1.98 (m, 1H), 1.66-1, 58 (m, 2H), 1.52-1.41 (m, 2H), 1.38-1.32 (m, 4H).

Example 210: 3-(1-oxo-4-(5-(4-(phenyl-d5)piperazine-1-)pentyl)isoindoline-2-)piperazine-2,6-dione (210)

The preparation method was the same as for 3-(1-oxo-4-(5-(2-phenylpyrroline-1-)pentyl)indoline-2-)piperidine-2,6-dione, 24 mg, yield 32, 7%; ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.56 (dd, J=5.9, 2.7 Hz, 1H), 7.49-7.43 (m, 2H ), 5.14 (dd, J=13.2, 5.1 Hz, 1H), 4.47 (d, J=17.2 Hz, 1H), 4.31 (d, J=17.1 Hz , 1H), 3.32 (s, 4H), 3.10 (s, 4H), 2.99-2.86 (m, 1H), 2.69-2.55 (m, 3H), 2, 46-2.27 (m, 3H), 2.05-1.95 (m, 1H), 1.63 (dd, J=15.1, 7.7 Hz, 2H), 1.56-1, 46 (m, 2H), 1.36 (dd, J=13.8, 6.9 Hz, 2H).

Example 211: 3-(6-fluoro-1-oxo-4-(4-(quinoline-4-oxo)butoxy)-1-oxoisoindoline-

2-)piperidine-2,6-dione (211)

The preparation method was the same as for 3-(6-fluoro-4-(4-((2-methylquinoline-4-)oxy)butoxy)-1-oxoisoindoline-2-)piperidine-2,6-dione ( Example 212) to obtain 19.0 mg of a white solid, yield 43.2%; ¹ H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 8.73 (d, J=5.2 Hz, 1H), 8.12 (d, J=7.2 Hz, 1H) , 7.93 (d, J=8.5 Hz, 1H), 7.74 (t, J=7.0 Hz, 1H), 7.53 (t, J=7.5 Hz, 1H), 7 .20 (dd, J=11.5, 2.0 Hz, 1H), 7.11-7.02 (m, 2H), 5.08 (dd, J=13.4, 5.1 Hz, 1H ), 4.35 (t, J=5.8 Hz, 2H), 4.27 (dd, J=11.5, 5.3 Hz, 3H), 4.14 (d, J=17.4 Hz , 1H), 2.95-2.85 (m, 1H), 2.63-2.55 (m, 1H), 2.45-2.32 (m, 1H), 2.11-1.91 (m, 5H).

Example 212: 3-(6-fluoro-4-(4-((2-methylquinoline-4-)oxy)butoxy)-1-oxoisoindoline-2-)piperidine-2,6-dione (212)

Step 1: 5-fluoro-2-methyl-3-nitrobenzoic acid was dissolved in 20 mL methanol, thionyl chloride (728 μL, 10.04 mmol) was added under ice bath conditions, refluxing for 3 hours. After completion of the reaction, the reaction was dried by centrifugation, diluted with ethyl acetate, washed with saturated sodium bicarbonate and saturated sodium chloride and dried to obtain 1.025 g of the desired product with a yield of 96%.

Step 2: Methyl 5-fluoro-2-methyl-3-nitrobenzoate (1.02 g, 4.8 mmol) was dissolved in 20 ml methanol, added 10% Pd/C (110 mg) and reacted with hydrogen at room temperature temperature and normal pressure overnight. After completion of the reaction as monitored by TLC, the reaction solution was filtered with suction and the solid was washed with methanol (20 ml x 1); and the filtrate was concentrated to obtain 918 mg of colorless liquid methyl 3-amino-5-fluoro-2-methylbenzene formate, which was directly used in the next step.

Step 3: Add methyl 3-amino-5-fluoro-2-methylbenzoate (918 mg, crude product) and ₁₀ % _H2SO4 (1.54 mL, 28.71 mmol), aqueous sodium nitrite (505 mg, 7.32) (5 ml) at 0°C and reacted at the same temperature for 1 hour, then added 50% H ₂ SO ₄ (7.65 ml, 143.55 mmol) and heated to 100 °C to complete the reaction within 1 hour. After completion of the reaction as monitored by TLC, the reaction solution was concentrated and 20 ml water and 100 ml ethyl acetate were added, shaken until homogeneous and separated, the aqueous phase was extracted with ethyl acetate (50 ml × 2) and the combined organic phase was dried with anhydrous sodium sulfate , concentrated under reduced pressure and purified by column chromatography to obtain 415 mg of product with a two-step yield of 47%.

Step 4: Methyl 5-fluoro-3-hydroxy-2-methylbenzoate (410 mg, 2.23 mmol) was dissolved in 20 ml DMF, 60% sodium hydride (107 mg, 2.67 mmol) was added at 0°C and carried out reaction within 1 hour. Chloromethyl methyl ether (203 μL, 2.67 mmol) was added dropwise at the same temperature, then warmed to room temperature and allowed to react for 2 hours. The reaction was monitored to completion by TLC, stopped with water, extracted with ethyl acetate, separated, and the organic phase was washed successively with water and saturated sodium chloride solution, dried and purified by column chromatography to obtain 430 mg of product in 84% yield.

Step 5: Methyl 5-fluoro-3-methoxymethoxy-2-methylbenzoate (425 mg, 1.86 mmol) and NBS (398 mg, 2.23 mmol) were dissolved in 15 ml carbon tetrachloride, then 70% benzoyl peroxide (65) was added mg, 0.186 mmol), refluxed for 3 hours, concentrated under reduced pressure and separated by flash column chromatography to give 545 mg of a yellow solid, 95.4% yield.

Step 6: N,N-Diisopropylethylamine (873 μL, 5.28 mmol) was added to a suspension of methyl 2-bromomethyl-5-fluoro-3-methoxymethoxybenzoate (540 mg, 1.76 mmol) and methyl 4,5-diamino hydrochloride -5-oxopentanoate (413 mg, 2.11 mmol) in acetonitrile (20 ml) and reacted at 40° C. overnight. After completion of the reaction, the solution was concentrated under reduced pressure, diluted with ethyl acetate, washed successively with water and saturated sodium chloride, dried, concentrated and directly used in the next step.

Step 7: The crude product from the previous step was added to a 50 ml round bottom flask, 10 ml of 4M hydrochloric acid in dioxane and 1 ml of methanol were added, reacted at room temperature for 1 hour, then dried by centrifugation and purified by column chromatography to obtain 300 mg of the target product, yield (two stages) 55%.

Step 8: Methyl 5-amino-4-(6-fluoro-4-hydroxy-1-oxoisoindoline-2-)-5-oxopentanoate (35 mg, 0.11 mmol) was added to a 50 mL round bottom flask, then 4 -((2-methylquinoline-4-)oxy)-1-butanol (51 mg, 0.22 mmol, 2 eq.) and triphenylphosphine (58 mg, 0.22 mmol, 2 eq.). The reaction system was replaced with nitrogen and 5 ml of anhydrous tetrahydrofuran was added. Diisopropyl azodicarboxylate (43 μL, 0.22 mmol, 2 eq.) was added to the reaction system to allow the reaction to proceed at room temperature for 1 hour. The completion of the reaction was monitored by TLC, concentrated under reduced pressure to obtain 56.8 mg of product by purification by column chromatography with a yield of 98%.

Step 9: The product obtained in the previous step (56.8 mg, 0.108 mmol) was dissolved in anhydrous THF, potassium tert-butoxide (13 mg, 0.12 mmol) was added at 0°C and the reaction proceeded at the same temperature within 30 min. To stop the reaction, add 1N HCl, dilute with ethyl acetate, wash with saturated sodium chloride, dry and purify by HPLC to give 20.1 mg of white solid, 37.9% yield; ¹ H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 8.04 (d, J=8.3 Hz, 1H), 7.82 (d, J=8.5 Hz, 1H) , 7.67 (t, J=7.0 Hz, 1H), 7.43 (t, J=7.6 Hz, 1H), 7.20 (d, J=11.6 Hz, 1H), 7 .08 (dd, J=7.4, 1.8 Hz, 1H), 6.93 (s, 1H), 5.08 (dd, J=13.5, 4.9 Hz, 1H), 4, 36-4.23 (m, 5H), 4.14 (d, J=17.3 Hz, 1H), 2.95-2.85 (m, 1H), 2.62-2.54 (m, 4H), 2.36-2.25 (m, 1H), 2.10-1.91 (m, 5H).

Example 213: 3-(4-(4-((2-methylquinoline-4-)methoxy)butoxy)-1-oxoisoindoline-2-)piperidine-2,6-dione (213)

Step 1: Add indoline-2,3-dione (1 g, 6.87 mmol) to a 100 mL round bottom flask, add KOH (3.6 g, 54.4 mmol) in water (7.2 mL) and stir for 5 minutes, add 12 ml of acetone and reflux overnight. After completion of the reaction, the pH was adjusted to 5-6 with 1N HCl, a solid precipitated and 666 mg of product was obtained by filtration in a yield of 52%.

Step 2: Quinoline-4-carboxylic acid (665 mg, 3.55 mmol) was dissolved in 25 ml anhydrous THF, triethylamine (598 µl, 4.62 mmol) was added and isopropyl chloroformate (635 µl, 4.62 mmol) was added dropwise. in an ice bath. After 0.5 hour, sodium boron hydride (403 mg, 10.65 mmol) in water (5 ml) was added and the reaction proceeded at the same temperature for 2 hours. After completion of the reaction, the solution was dried by centrifugation, diluted with ethyl acetate, washed with saturated sodium chloride, dried and purified by column chromatography to obtain 390 mg of product, 63% yield.

Step 3: Quinoline-4-methanol (100 mg, 0.577 mmol) was dissolved in 6 ml anhydrous THF, and completely cooled to 0°C. Add 60% sodium hydride (35 mg, 0.87 mmol) and react at the same temperature for 0.5 h, then add 1,4-dibromobutane (206 μl, 0.866 mmol) and reflux overnight . After completion of the reaction, it was quenched with water, extracted with ethyl acetate, the organic layer was washed with saturated sodium chloride, dried and purified by column chromatography, 83 mg, 47% yield.

Step 4: 4-((4-bromobutoxy) methyl)-2-methylquinoline (44.7 mg, 0.145 mmol) and methyl 5-amino-4-(4-hydroxy-1-oxoisoindoline-2-)-5-oxopentanoate (42 mg, 0.145 mmol) was dissolved in 6 ml of acetonitrile, anhydrous potassium carbonate (20 mg, 0.145 mmol) was added and heated to 80°C to react for 48 hours. After completion of the reaction, the solution was filtered and dried by centrifugation, purified by column chromatography to obtain 38.3 mg of product, yield 51%.

Step 5: The product obtained in the previous step (38.3 mg, 0.074 mmol) was dissolved in 6 ml THF, potassium tert-butoxide (9 mg, 0.081 mmol) was added at 0°C and reacted for 0.5 h at the same temperature, IN HCl was added to stop the reaction and the solution was diluted with ethyl acetate, washed with saturated sodium chloride, dried, centrifuged, purified by HPLC to obtain 17.7 mg of a white solid, 49% yield.

¹ H NMR (400 MHz, DMSO) δ 10.96 (s, 1H), 8.00 (d, J=8.2 Hz, 1H), 7.93 (d, J=8.3 Hz, 1H) , 7.70 (t, J=7.3 Hz, 1H), 7.53 (t, J=7.4 Hz, 1H), 7.46 (t, J=7.8 Hz, 1H), 7 .40 (s, 1H), 7.30 (d, J=7.4 Hz, 1H), 7.20 (d, J=8.1 Hz, 1H), 5.09 (dd, J=13, 3, 5.0 Hz, 1H), 4.96 (s, 2H), 4.36 (d, J=17.4 Hz, 1H), 4.21 (d, J=17.4 Hz, 1H) , 4.14 (t, J=5.9 Hz, 2H), 3.65 (t, J=5.9 Hz, 2H), 2.96-2.83 (m, 1H), 2.63 ( s, 3H), 2.56 (d, J=17.5 Hz, 1H), 2.45-2.32 (m, 1H), 2.02-1.92 (m, 1H), 1.89 -1.74 (m, 4H).

Example 214: 3-(4-(4-((2-ethylquinoline-4-)methoxy)butoxy)-1-oxoisoindoline-2-)piperidine-2,6-dione (214)

The preparation method was the same as for 3-(4-(4-((2-methylquinoline-4-)methoxy)butoxy)-1-oxoisoindoline-2-)piperidine-2,6-dione, 16.5 was obtained mg white solid, yield 35.1%; ¹ H NMR (400 MHz, DMSO) δ 10.96 (s, 1H), 8.01 (d, J=8.4 Hz, 1H), 7.95 (d, J=8.3 Hz, 1H) , 7.70 (t, J=7.7 Hz, 1H), 7.53 (t, J=7.6 Hz, 1H), 7.45 (dd, J=13.6, 5.7 Hz, 2H), 7.30 (d, J=7.4 Hz, 1H), 7.20 (d, J=8.2 Hz, 1H), 5.09 (dd, J=13.3, 5.1 Hz, 1H), 4.97 (s, 2H), 4.35 (d, J=17.4 Hz, 1H), 4.21 (d, J=17.4 Hz, 1H), 4.14 ( t, J=5.9 Hz, 2H), 3.66 (t, J=5.9 Hz, 2H), 2.91 (q, J=7.5 Hz, 2H), 2.56 (d, J=18.5 Hz, 1H), 2.44-2.31 (m, 1H), 2.01-1.91 (m, 1H), 1.89-1.74 (m, 4H), 1 .29 (t, J=7.6 Hz, 3H).

Example 215: 3-(4-(4-(4-(2-chlorophenyl)piperazin-1-yl)butyl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (215)

For the method of preparation, see synthesis method 1 and Example 21. ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.57 (dd, J=5.5, 3.1 Hz, 1H) , 7.50-7.45 (m, 2H), 7.39 (dd, J=7.9, 1.4 Hz, 1H), 7.32-7.26 (m, 1H), 7.14 (dd, J=8.1, 1.3 Hz, 1H), 7.03 (td, J=7.7, 1.4 Hz, 1H), 5.14 (dd, J=13.3, 5 ,1 Hz, 1H), 4.48 (d, J=17.1 Hz, 1H), 4.32 (d, J=17.1 Hz, 1H), 3.02-2.84 (m, 5H ), 2.68 (t, J=7.6 Hz, 2H), 2.59 (d, J=20.8 Hz, 5H), 2.48-2.36 (m, 3H), 2.06 -1.97 (m, 1H). 1.70 1.60 (m, 2H), 1.57-1.47 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₂₇ H ₃₁ ClN ₄ O ₃ [M+H] ⁺ : 495.21, obtained value 495.52.

Example 216: 3-(4-(4-(4-(2-nitrophenyl)piperazin-1-yl)butyl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (216)

For the method of preparation, see synthesis method 1 and Example 21. ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.78 (dd, J=8.1, 1.5 Hz, 1H) , 7.57 (ddd, J=7.4, 4.3, 1.6 Hz, 2H), 7.50-7.44 (m, 2H), 7.30 (d, J=7.7 Hz , 1H), 7.11 (t,J=7.2 Hz, 1H), 5.14 (dd, J=13.2, 5.0 Hz, 1H), 4.47 (d, J=17, 2 Hz, 1H), 4.32 (d, J=17.2 Hz, 1H), 3.00-2.87 (m, 5H), 2.67 (t, J=7.6 Hz, 2H) , 2.62-2.53 (m, 1H), 2.48-2.43 (m, 4H), 2.43-2.34 (m, 3H), 2.02 (ddd, J=12, 1, 7.1, 5.1 Hz, 1H), 1.63 (dt, J=14.7, 7.5 Hz, 2H), 1.55-1.45 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₂₇ H ₃₁ N ₅ O ₅ [M+H] ⁺ : 506.23, obtained value 506.44.

Example 217: 3-(1-oxo-4-(4-(4-(o-tolyl)piperazin-1-yl)butyl)isoindolin-2-yl)piperidin-2,6-dione (217)

For the method of preparation, see synthesis method 1 and Example 21. ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.57 (dd, J=5.6, 3.0 Hz, 1H) , 7.50-7.45 (m, 2H), 7.13 (t, J=7.7 Hz, 2H), 6.99 (d, J=7.7 Hz, 1H), 6.94 ( t, J=7.3 Hz, 1H), 5.14 (dd, J=13.3, 5.1 Hz, 1H), 4.48 (d, J=17.2 Hz, 1H), 4, 32 (d, J=17.1 Hz, 1H), 2.93 (ddd, J=17.3, 13.7, 5.4 Hz, 1H), 2.83 (t, 4H), 2.68 (t, J=7.5 Hz, 2H), 2.64-2.53 (m, 5H), 2.48-2.38 (m, 3H), 2.22 (s, 3H), 2, 06-1.96 (m, 1H), 1.70-1.59 (m, 2H), 1.52 (dt, J=15.5, 7.8 Hz, 2H). UPLC-MS (ESI) peak value calculated for C ₂₈ H ₃₄ N ₄ O ₃ [M+H] ⁺ : 475.26, obtained value 475.49.

Example 218: 3-(4-(4-(4-(2-fluorophenyl)piperazin-1-yl)butyl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (218)

For the method of preparation, see synthesis method 1 and Example 21. ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.57 (dd, J=5.5, 3.2 Hz, 1H) , 7.49-7.45 (m, 2H), 7.15-7.06 (m, 2H), 7.05-6.92 (m, 2H), 5.14 (dd, J=13, 4, 5.1 Hz, 1H), 4.48 (d, J=17.2 Hz, 1H), 4.32 (d, J=17.2 Hz, 1H), 3.05-2.98 ( m, 4H), 2.92 (ddd, J=17.6, 13.7, 5.5 HzDN), 2.68 (t, J=7.5 Hz, 2H), 2.67-2.52 (m, 5H), 2.46-2.35 (m, 3H), 2.06-1.97 (m, 1H), 1.70-1.58 (m, 2H), 1.57-1 .47 (m, 2H). UPLC MS (ESI) peak value calculated for C ₂₇ H ₃₁ FN ₄ O ₃ [M+H] ⁺ : 479.24, obtained value 479.47.

Example 219: 3-(1-oxo-4-(4-(4-(2-(trifluoromethyl)phenyl)piperazin-1-yl)butyl)isoindolin-2-yl)piperidin-2,6-dione (219)

For the preparation method, see synthesis method 1 and Example 21. ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.65 (t, J=7.4 Hz, 2H), 7.60 -7.52 (m, 2H), 7.50-7.45 (m, 2H), 7.33 (t, J=7.6 Hz, 1H), 5.15 (dd, J=13.3, 5 ,1 Hz, 1H), 4.48 (d, J=17.2 Hz, 1H), 4.32 (d, J=17.2 Hz, 1H), 3.00-2.85 (m, 5H ), 2.68 (t, J=7.6 Hz, 2H), 2.65-2.53 (m, 5H), 2.48-2.36 (m, 3H), 2.07-1.98 ( m, 1H), 1.70-1.58 (m, 2H), 1.58-1.48 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₂₈ H ₃₁ F ₃ N ₄ O ₃ [M+H] ⁺ : 529.23, obtained value 529.39.

Example 220: 3-(1-oxo-4-(4-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)butyl)isoindolin-2-yl)piperidin-2,6-dione (220)

For the method of preparation, see synthesis method 1 and Example 21. ¹ H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.57 (dt, J=7.6, 3.8 Hz, 1H) , 7.49-7.45 (m, 2H), 7.42 (dd, J=14.7, 6.4 Hz, 1H), 7.21 (dd, J=8.4, 1.8 Hz , 1H), 7.15 (s, 1H), 7.06 (d, J=7.7 Hz, 1H), 5.14 (dd, J=13.3, 4.9 Hz, 1H), 4 .47 (d, J=17.2 Hz, 1H), 4.32 (d, J=17.2 Hz, 1H), 3.22 (t, 4H), 2.97-2.86 (m, 1H), 2.68 (t, J=7.5 Hz, 2H), 2.65-2.53 (m, 5H), 2.45-2.35 (m, 3H), 2.06-1 .96 (m, 1H), 1.70-1.58 (m, 2H), 1.57-1.48 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₂₈ H ₃₁ F ₃ N ₄ O ₃ [M+H] ⁺ : 529.23, obtained value 529.41.

Example 221: 3-(4-(4-(4-(benzothiophen-7-yl)piperazin-1-yl)butyl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (221)

For the method of preparation, see synthesis method 1 and Example 21. ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.69 (d, J=5.5 Hz, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.57 (dd, J=6.1, 2.5 Hz, 1H), 7.51-7.44 (m, 2H), 7.39 ( d, J=5.5 Hz, 1H), 7.27 (t, J=7.8 Hz, 1H), 6.88 (d, J=7.5 Hz, 1H), 5.14 (dd, J=13.2, 5.0 Hz, 1H), 4.49 (d, J=17.2 Hz, 1H), 4.33 (d, J=17.2 Hz, 1H), 3.06 ( s, 4H), 2.98-2.87 (m, 1H), 2.69(t, J=7.5 Hz, 2H), 2.64-2.54 (m, 5H), 2.47 -2.38 (m, 3H), 2.06 1.98 (m, 1H), 1.72-1.62 (m, 2H), 1.58-1.48 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₂₉ H ₃₂ N ₄ O ₃ S [M+H] ⁺ : 519.22, obtained value 517.47.

Example 222: 3-(4-(4-(4-(2,4-dichlorophenyl)piperazin-1-yl)butyl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (222)

For the method of preparation, see synthesis method 1 and Example 21. ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.57 (dd, J=5.2, 3.4 Hz, 1H) , 7.52 (d, J=2.4 Hz, 1H), 7.48-7.45 (m, 2H), 7.35 (dd, J=8.6, 2.5 Hz, 1H), 7.14 (d, J=8.7 Hz, 1H), 5.14 (dd, J=13.2, 5.1 Hz, 1H), 4.47 (d, J=17.1 Hz, 1H ), 4.32 (d, J=17.1 Hz, 1H), 2.99-2.87 (m, 5H), 2.67 (t, J=7.5 Hz, 2H), 2.64 -2.56 (m, 1H), 2.46-2.34 (m, 3H), 2.08-1.95 (m, 1H), 1.70-1.58 (m, 2H), 1 .56-1.44 (m, 2H). UPLC MS (ESI) peak value calculated for C ₂₇ H ₃₀ Cl ₂ N ₄ O ₃ [M+H] ⁺ : 529.17, obtained value 529.35.

Example 223: 3-(4-(4-(4-(3,5-dichlorophenyl)piperazin-1-yl)butyl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (223)

For the preparation method, see synthesis method 1 and Example 21. ¹ H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.59-7.54 (m, 1H), 7.50-7, 42 (m, 2H), 6.91 (d, J=1.6 Hz, 2H), 6.84 (t, J=1.5 Hz, 1H), 5.13 (dd, J=13.3 , 5.1 Hz, 1H), 4.47 (d, J=17.2 Hz, 1H), 4.31 (d, J=17.2 Hz, 1H), 3.22-3.15 (m , 4H), 2.98-2.86 (m,1H), 2.67 (t, J=7.5 Hz, 2H), 2.63-2.56 (m, 1H), 2.47- 2.38 (m, 5H), 2.33 (t, J=7.0 Hz, 2H), 2.08-1.95 (m, 1H), 1.69-1.57 (m, 2H) , 1.55-1.42 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₂₇ H ₃₀ Cl ₂ N ₄ O ₃ [M+H] ⁺ : 529.17, obtained value 529.53.

Example 224: 3-(4-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-1-isoindolin-2-yl)piperidin-2,6-dione (224)

For the method of preparation, see synthesis method 1 and Example 21. ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.57 (dt, J=7.7, 3.9 Hz, 1H) , 7.49-7.45 (m, 2H), 6.95-6.89 (m, 2H), 6.86 (d, J=2.6 Hz, 2H), 5.14 (dd, J =13.3, 5.1 Hz, 1H), 4.47 (d, J=17.2 Hz, 1H), 4.32 (d, J=17.2 Hz, 1H), 2.98-2 .87 (m, 5H), 2.68 (t, J=7.5 Hz, 2H), 2.64-2.55 (m, 1H), 2.48-2.42 (m, 2H), 2.39-2.34 (m, 2H), 2.06-1.97 (m, 1H), 1.69-1.58 (m, 2H), 1.55-1.44 (m, 2H ). UPLC-MS (ESI) peak value calculated for C ₂₈ H ₃₄ N ₄ O ₄ [M+H] ⁺ : 491.26, obtained value 491.53.

Example 225: 3-(4-(5-(4-(benzothiophen-7-yl)piperazin-1-yl)pentyl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (225)

For the method of preparation, see synthesis method 1 and Example 21. ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.69 (d, J=5.5 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.57 (dd, J=6.2, 2.3 Hz, 1H), 7.51-7.42 (m, 2H), 7.39 ( d, J=5.5 Hz, 1H), 7.27 (t, J=7.9 Hz, 1H), 6.89 (d, J=7.6 Hz, 1H), 5.14 (dd, J=13.3, 5.0 Hz, 1H), 4.48 (d, J=17.1 Hz, 1H), 4.32 (d, J=17.2 Hz, 1H), 3.10- 3.01(m, 4H), 2.98-2.87 (m, 1H), 2.73-2.56 (m, 5H), 2.44 (dd, J=13.3, 4.4 Hz, 3H), 2.06-1.96 (m, 1H), 1.72-1.59 (m, 2H), 1.59-1.47 (m, 2H), 1.36 (dt, J=8.6, 5.6 Hz, 2H), 1.28-1.18 (m, 2H). UPLC-MS (ESI) peak value calculated for C30H34N4O3S [M+H] ⁺ : 531.24, obtained value 531.47.

Example 226: 3-(4-(5-(4-(6-fluorobenzisoxazol-3-yl)piperidin-1-yl)pentyl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (226)

For the method of preparation, see synthesis method 1 and Example 21. ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 8.00 (dd, J=8.7, 5.3 Hz, 1H) , 7.69 (dd, J=9.1, 2.0 Hz, 1H), 7.57 (dd, J=5.9, 2.6 Hz, 1H), 7.50-7.42 (m , 2H), 7.28 (td, J=9.2, 2.0 Hz, 1H), 5.14 (dd, J=13.2, 5.1 Hz, 1H), 4.47 (d, J=17.2 Hz, 1H), 4.31 (d, J=17.2 Hz, 1H), 3.20-3.08 (m, 1H), 3.04-2.87 (m, 3H ), 2.70-2.64 (m, 2H), 2.60 (d, J=17.8 Hz, 1H), 2.47-2.30 (m, 3H), 2.17-1, 95 (m, 5H), 1.83 (dd, J=22.7, 12.1 Hz, 2H), 1.64 (dt, J=15.2, 7.6 Hz, 2H), 1.51 (dd, J=13.1, 6.9 Hz, 2H), 1.36 (dd, J=13.4, 6.3 Hz, 2H). UPLC-MS (ESI) peak value calculated for C ₃₀ H ₃₃ FN ₄ O ₄ [M+H] ⁺ : 533.25, obtained value 533.51.

Example 227: 3-(4-(4-(4-(6-fluorobenzisoxazol-3-yl)piperidin-1-yl)butyl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (227)

For the preparation method, see synthesis method 1 and Example 21. ¹ H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 8.00 (dd, J=8.8, 5.3 Hz, 1H) , 7.69 (dd, J=9.1, 2.1 Hz, 1H), 7.57 (dd, J=5.9, 2.7 Hz, 1H), 7.51-7.43 (m , 2H), 7.28 (td, J=9.2, 2.2 Hz, 1H), 5.14 (dd, J=13.3, 5.1 Hz, 1H), 4.48 (d, J=17.2 Hz, 1H), 4.32 (d, J=17.2 Hz, 1H), 3.20-3.08 (m, 1H), 3.04-2.96 (m, 2H ), 2.96-2.86 (m, 1H), 2.68 (t, J=7.5 Hz, 2H), 2.60 (d, J=16.8 Hz, 1H), 2.47 -2.38 (m, 3H), 2.17 (t, J=10.2 Hz, 2H), 2.04 (dd, J=13.4, 9.5 Hz, 3H), 1.84 ( dd, J=24.4, 11.9 Hz, 2H), 1.64 (dt, J=15.3, 7.8 Hz, 2H), 1.53 (dt, J=14.7, 7, 5 Hz, 2H). UPLC-MS (ESI) peak value calculated for C ₂₉ H ₃₁ FN ₄ O ₄ [M+H] ⁺ : 519.23, obtained value 519.53.

Example 228: 3-(4-(4-(4-(benzisoxazol-3-yl)piperazin-1-yl)butyl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (228)

For the preparation method, see synthesis method 1 and Example 21. ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.61 -7.54 (m, 3H), 7.50-7.43 (m, 2H), 7.29 (dt, J=8.0, 4.0 Hz, 1H), 5.14 (dd, J =13.3, 5.1 Hz, 1H), 4.48 (d, J=17.2 Hz, 1H), 4.32 (d, J=17.2 Hz, 1H), 3.46 (t , J=4.1 Hz, 4H), 2.97-2.87 (m, 1H), 2.68 (t, J=7.5 Hz, 2H), 2.62-2.56 (m, 1H), 2.54 (t, J=4.1 Hz, 4H), 2.47-2.41 (m, 1H), 2.38 (t, J=6.8 Hz, 2H), 2, 05-1.97 (m, 1H), 1.68-1.61 (m, 2H), 1.56-1.47 (m, 2H). UPLC-MS (ESI) peak value calculated for C28H31 N5O4 [M+H] ⁺ : 502.24, the value obtained was 502.53.

Example 229: 3-(4-(4-(4-(2,5-dichlorophenyl)piperazin-1-yl)butyl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (229)

For the preparation method, see synthesis method 1 and Example 21. ¹ H NMR (400 MHz, DMSO-d ₆ ) 11.00 (s, 1H), 7.59-7.55 (m, 1H), 7.48- 7.44 (m, 2H), 7.42 (d, J=8.5 Hz, 1H), 7.14 (d, J=2.4 Hz, 1H), 7.09 (dd, J=8 .5, 2.4 Hz, 1H), 5.14 (dd, J=13.3, 5.1 Hz, 1H), 4.47 (d, J=17.2 Hz, 1H), 4.32 (d, J=17.2 Hz, 1H), 2.97 (t, J=5.6 Hz,4H), 2.94-2.87 (m, 1H), 2.67 (t, J= 7.5 Hz, 2H), 2.64-2.56 (m, 1H), 2.48 (t, J=5.6 Hz, 4H), 2.46-2.41 (m, 1H), 2.36 (t, J=7.5 Hz, 2H), 2.05-1.98 (m, 1H), 1.69-1.58 (m, 2H), 1.46-1.53 ( m, 2H). UPLC-MS (ESI) peak value calculated for C ₂₇ H ₃₀ ClN ₄ O ₃ [M+H] ⁺ : 529.17, obtained value 529.45.

Example 230: 3-(4-(4-(4-(benzisothiazol-3-yl)piperazin-1-yl)butyl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (230)

For the method of preparation, see synthesis method 1 and Example 21. ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 8.08-8.02 (m, 2H), 7.61-7, 52 (m, 2H), 7.51-7.40 (m, 3H), 5.14 (dd, J=13.3, 5.1 Hz, 1H), 4.48 (d, J=17.2 Hz , 1H), 4.33 (d, J=17.1 Hz, 1H), 3.48-3.38 (m, 4H)5 2.99-2.86 (m, 1H), 2.69 ( t, J=7.6 Hz, 2H), 2.65-2.54 (m, 5H), 2.47-2.35 (m, 3H), 2.07-1.96 (m, 1H), 1 .71-1.60 (m, 2H), 1.60-1.48 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₂₈ H ₃₁ N ₅ O ₃ S [M+H] ⁺ : 518.21, obtained value 518.45.

Example 231: 3-(4-(5-(4-(benzisoxazol-3-yl)piperazin-1-yl)pentyl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (231)

For the method of preparation, see synthesis method 1 and Example 22. ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.97 (d, J=8.1 Hz, 1H), 7.62 -7.52 (m, 3H), 7.51-7.41 (m, 2H), 7.33-7.24 (m, 1H), 5.14 (dd, J=13.3, 5, 1 Hz, 1H), 4.47 (d, J=17.2 Hz, 1H), 4.31 (d, J=17.2 Hz, 1H), 3.53-3.39 (m, 4H) , 2.92 (ddd, J=18.4, 13.6, 5.2 Hz, 1H), 2.66 (t, J=7.7 Hz, 2H), 2.59 (dd, J=11 ,2, 8.5 Hz, 1H), 2.55-2.51 (m, 4H), 2.46-2.38 (m, 1H), 2.33 (t, J=7.0 Hz, 2H), 2.04-1.97 (m, 1H), 1.64 (dt, J=15.3, 7.8 Hz, 2H), 1.57-1.44 (m, 2H), 1 .41-1.30 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₂₉ H ₃₃ N ₅ O ₄ [M+H] ⁺ : 516.25, obtained value 516.51.

Example 232: 3-(4-(5-(4-(benzisothiazol-3-yl)piperazin-1-yl)pentyl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (232)

For the preparation method, see synthesis method 1 and Example 22. ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 8.04 (t, J=7.3 Hz, 2H), 7.59 -7.52 (m, 2H), 7.49-7.42 (m, 3H), 5.14 (dd, J=13.4, 5.3 Hz, 1H), 4.47 (d, J=17 ,2 Hz, 1H), 4.32 (d, J=17.3 Hz, 1H), 3.47-3.37 (m, 4H), 2.92-2.86 (m, 1H), 2 ,70-2.54 (m, 7H), 2.48-2.40 (m, 1H), 2.34 (d, J=8.1 Hz, 2H), 2.06-1.97 (m, 1H ), 1.70-1.60 (m, 2H), 1.53 (dt, J=10.4, 5.1 Hz, 2H), 1.41-1.30 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₂₉ H ₃₃ N ₅ O ₃ S [M+H] ⁺ : 532.23, obtained value 532.53.

Example 233: 3-(4-(5-(4-(2,5-dichlorophenyl)piperazin-1-yl)pentyl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (233)

For the method of preparation, see synthesis method 1 and Example 22. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.00 (s, 1H), 7.58-7.54 (m, 1H), 7.44 -7.48 (m, 2H), 7.42 (d, J=8.5 Hz, 1H), 7.14 (d, J=2.4 Hz, 1H), 7.09 (dd, J= 8.5, 2.4 Hz, 1H), 5.14 (dd, J=13.4, 5.0 Hz, 1H), 4.47 (d, J=17.2 Hz, 1H), 4, 31 (d, J=17.2 Hz, 1H), 2.99-2.95 (m, 4H), 2.94-2.87 (m, 1H), 2.70-2.63 (m, 2H), 2.61-2.57 (m, 1H), 2.49-2.47 (m, 4H), 2.45-2.38 (m, 1H), 2.49-2.47 ( m, 2H), 2.01-1.98 (m, 1H), 1.67-1.59 (m, 2H), 1.54-1.46 (m, 2H), 1.39-1, 31 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₂₈ H ₃₂ Cl ₂ N ₄ O ₃ [M+H] ⁺ : 543.19, obtained value 543.47.

Example 234: 3-(4-(5-(4-(3,4-dichlorophenyl)piperazin-1-yl)pentyl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (234)

For the method of preparation, see synthesis method 1 and Example 22. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.00 (s, 1H), 7.58-7.54 (m, 1H), 7.47 -7.43 (m, 2H), 7.37 (d, J=8.8 Hz, 1H), 7.10 (d, J=2.4 Hz, 1H), 6.91 (dd, J= 8.8, 2.4 Hz, 1H), 5.13 (dd, J=13.2, 5.2 Hz, 1H), 4.47 (d, J=17.1 Hz, 1H), 4, 30 (d, J=17.1 Hz, 1H), 3.14 (t, J=2.4 Hz, 4H), 2.97-2.88 (m, 1H), 2.65 (t, J =8.0 Hz, 2H), 2.62-2.57 (m, 1H), 2.45 (t, J=8.0 Hz, 4H), 2.42-2.37 (m, 1H) , 2.29 (t, J=8.0 Hz, 2H), 2.04-1.96 (m, 1H), 1.66-1.58 (m, 2H), 1.53-1.45 (m, 2H), 1.37-1.29 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₂₈ H ₃₂ Cl ₂ N ₄ O ₃ [M+H] ⁺ : 543.19, obtained value 543.42.

Example 235: 3-(4-(5-(4-(2,6-dichlorophenyl)piperazin-1-yl)pentyl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (235)

For the method of preparation, see synthesis method 1 and Example 22. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.00 (s, 1H), 7.57 (dd, J=6.1, 2.3 Hz , 1H), 7.49-7.44 (m, 1H), 7.41 (d, J=8.0 Hz, 2H), 7.15 (t, J=8.0 Hz, 1H), 5 .14 (dd, J=13.3, 5.2 Hz, 1H), 4.47 (d, J=17.2 Hz, 1H), 4.31 (d, J=17.2 Hz, 1H) , 3.12 (t, J=3.2 Hz,4H), 2.98-2.88 (m, 1H), 2.71-2.63 (m, 2H), 2.62-2.56 (m, 1H), 2.49-2.43 (m, 4H), 2.42-2.37 (m, 1H), 2.35-2.27 (m, 2H), 2.05-1 .98 (m, 1H), 1.69-1.59 (m, 2H), 1.54-1.45 (m, 2H), 1.39-1.32 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₂₈ H ₃₂ Cl ₂ N ₄ O ₃ [M+H] ⁺ : 543.19, obtained value 543.51.

Example 236: 3-(4-(5-(4-(2,4-dichlorophenyl)piperazin-1-yl)pentyl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (236)

For the method of preparation, see synthesis method 1 and Example 22. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.00 (s, 1H), 7.57-7.54 (m, 1H), 7.53 (d, J=2.4 Hz, 1H), 7.49-7.43 (m, 2H), 7.36 (dd, J=8.7, 2.4 Hz, 1H), 7.15 ( d, J=8.7 Hz, 1H), 5.14 (dd, J=13.2, 5.1 Hz, 1H), 4.47 (d, J=17.1 Hz, 1H), 4, 31 (d, J=17.1 Hz, 1H), 2.97-2.92 (m, 4H), 2.90-2.88 (m, 1H), 2.65 (t, J=4, 0 Hz, 2H), 2.62-2.56 (m, 1H), 2.48-2.47 (m, 4H), 2.45-2.38 (m, 1H), 2.32 (t , J=5.6 Hz, 2H), 2.06-1.97 (m, 1H), 1.67-1.59 (m, 2H), 1.54-1.44 (m, 2H), 1.38-1.30 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₂₈ H ₃₂ Cl ₂ N ₄ O ₃ [M+H] ⁺ : 543.19, obtained value 543.42.

Example 237: 3-(4-(5-(4-(3,5-dichlorophenyl)piperazin-1-yl)pentyl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (237)

For the method of preparation, see synthesis method 1 and Example 22. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.00 (s, 1H), 7.58-7.54 (m, 1H), 7.47 -7.43 (m, 2H), 6.92 (d, J=1.6 Hz 2H), 6.85 (t, J=1.6 Hz, 1H), 5.14 (dd, J=13 ,3, 5.1 Hz, 1H), 4.47 (d, J=17.2 Hz, 1H), 4.31 (d, J=17.2 Hz, 1H), 3.19 (t, J =4.0 Hz, 4H), 2.97-2.88 (m, 1H), 2.65 (t, J=8 Hz, 2H), 2.62-2.57 (m, 1H), 2 .43(t, J=4.0 Hz, 4H), 2.40-2.36 (m, 1H), 2.29 (t, J=6.6 Hz, 2H), 2.04-1, 97 (m, 1H), 1.67-1.59 (m, 2H), 1.53-1.46 (m, 2H), 1.38-1.30 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₂₈ H ₃₂ Cl ₂ N ₄ O ₃ [M+H] ⁺ : 543.19, obtained value 543.43.

Example 238: 3-(4-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propoxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (238)

For the method of preparation, see synthesis method 6 and Example 21. ¹ H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.33 -7.28 (m, 3H), 7.25 (d, J=8.1 Hz, 1H), 7.14 (dd, J=6.4, 3.2 Hz, 1H), 5.11 ( dd, J=13.3, 5.1 Hz, 1H), 4.39 (d, J=17.5 Hz, 1H), 4.24 (d, J=17.4 Hz, 1H), 4, 18 (t, J=6.2 Hz, 2H), 3.02-2.86 (m, 5H), 2.63-2.52 (m, 7H), 2.48-2.38 (m, 1H), 2.03 1.90 (m, 3H). UPLC-MS (ESI) peak value calculated for C ₂₆ H ₂₈ Cl ₂ N ₄ O ₄ [M+H] ⁺ : 531.15, obtained value 531.35.

Example 239: 3-(4-(4-(4-(benzothiophen-7-yl)piperazin-1-yl)butoxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (239)

For the method of preparation, see synthesis method 6 and Example 21. ¹ H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 7.69 (d, J=5.5 Hz, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.39 (d, J=5.5 Hz, 1H), 7.31-7 .25 (m, 3H), 6.89 (d, J=7.5 Hz, 1H), 5.10 (dd, J=13.4, 5.1 Hz, 1H), 4.39 (d, J=17.4 Hz, 1H), 4.24 (d, J=17.4 Hz, 1H), 4.17 (t, J=6.2 Hz, 2H), 3.11-2.99 ( m, 4H), 2.96-2.84(m, 1H), 2.69-2.53 (m, 5H), 2.46-2.42 (m, 3H), 2.03-1, 95 (m, 1H), 1.86-1.73 (m, 2H), 1.72-1.59 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₂₉ H ₃₂ N ₄ O ₄ S [M+H] ⁺ : 533.21, obtained value 533.51.

Example 240: 3-(4-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (240)

For the method of preparation, see synthesis method 6 and Example 21. ¹ H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 7.49 (t, J=7.8 Hz, 1H), 7.35 -7.28 (m, 3H), 7.26 (d, J=8.1 Hz, 1H), 7.14 (dd, J=6.2, 3.3 Hz, 1H), 5.12 ( dd, J=13.3, 5.1 Hz, 1H), 4.39 (d, J=17.5 Hz, 1H), 4.24 (d, J=17.5 Hz, 1H), 4, 16 (t, J=6.3 Hz, 2H), 3.06-2.85 (m, 5H), 2.71-2.52 (m, 5H), 2.49-2.38 (m, 3H), 1.99 (td, J=5.5, 2.7 Hz, 1H), 1.85-1.74 (m, 2H), 1.69-1.59 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₂₇ H ₃₀ Cl ₂ N ₄ O ₄ [M+H] ⁺ : 545.16, obtained value 545.37.

Example 241: 3-(4-(4-(4-(6-fluorobenzisoxazol-3-yl)piperidin-1-yl)butoxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (241)

For the method of preparation, see synthesis method 6 and Example 21. ¹ H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 7.99 (dd, J=8.7, 5.3 Hz, 1H) , 7.69 (dd, J=9.1, 2.1 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.35-7.20 (m, 3H), 5.11 (dd, J=13.3, 5.0 Hz, 1H), 4.38 (d, J=17.4 Hz, 1H), 4.23 (d, J=17.4 Hz, 1H ), 4.16 (t, J=6.2 Hz, 2H), 3.23-3.12 (m, 2H), 3.05 (d, J=11.0 Hz, 2H), 2.95 -2.86 (m, 1H), 2.62-2.50 (m, 2H), 2.47-2.40 (m, 1H), 2.30-2.14 (m, 2H), 2 ,10-2.01 (m, 2H), 1.98 (ddd, J=12.3, 5.4, 2.1 Hz, 1H), 1.92-1.82 (m, 2H), 1 .78 (dd, J=13.9, 6.3 Hz, 2H), 1.72 1.60 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₂₉ H ₃₁ FN ₄ O ₅ [M+H] ⁺ : 535.23, obtained value 535.49.

Example 242: 3-(4-(4-(4-(benzisoxazol-3-yl)piperazin-1-yl)butoxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (242)

For the method of preparation, see synthesis method 6 and Example 21. ¹ H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 7.97 (d, J=8.1 Hz, 1H), 7.58 (d, J=3.8 Hz, 2H), 7.48 (t, J=7.8 Hz, 1H), 7.35-7.19 (m, 3H), 5.11 (dd, J= 13.3, 5.1 Hz, 1H), 4.39 (d, J=17.4 Hz, 1H), 4.23 (d, J=17.4 Hz, 1H), 4.16 (t, J=6.3 Hz, 2H), 3.56-3.38 (m, 4H), 2.96-2.84 (m, 1H), 2.58 (d, J=13.0 Hz, 5H ), 2.47-2.34 (m, 3H), 2.03-1.94 (m, 1H), 1.85-1.73 (m, 2H), 1.70-1.60 (m , 2H). UPLC-MS (ESI) peak value calculated for C ₂₈ H ₃₁ N ₅ O ₅ [M+H] ⁺ : 518.23, obtained value 518.47.

Example 243: 3-(4-(4-(4-(3,4-dichlorophenyl)piperazin-1-yl)butoxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (243)

For the method of preparation, see synthesis method 6 and Example 21. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.98 (s, 1H), 7.47 (t, J=7.9 Hz, 1H), 7.38 (d, J=9.0 Hz, 1H), 7.30 (d, J=7.9 Hz, 1H), 7.24 (d, J=7.9 Hz, 1H), 7, 11 (d, J=2.8 Hz, 1H), 6.92 (dd, J=9.0, 2.8 Hz, 1H), 5.11 (dd, J=13.3, 5.1 Hz , 1H), 4.38 (d,J=17.4 Hz, 1H), 4.23 (d, J=17.4 Hz, 1H), 4.15 (t, J=6.3 Hz, 2H ), 3.15 (t, J=4.0 Hz, 4H), 2.96-2.87 (m, 1H), 2.61-2.55 (m, 1H), 2.47 (t, J=4.0 Hz, 4H), 2.40-2.44 (m, 1H), 2.37 (t, J=6.4 Hz, 2H), 2.03-1.95 (m, 1H ), 1.82-1.73 (m, 2H), 1.67-1.58 (m, 2H). UPLC-MS (ESI) peak value calculated for C ²⁷ H ³⁰ Cl ² N ⁴ O ⁴ [M+H] ⁺ : 545.16, obtained value 545.49.

Example 244: 4-(3,5-dichlorophenyl)-1-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butyl)piperidine-4-carbonitrile (244 )

For the method of preparation, see synthesis method 1 and Example 51. ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.68 (s, 1H), 7.60 (s, 2H), 7 .57 (dt, J=7.7, 3.9 Hz, 1H), 7.52-7.41 (m, 2H), 5.14 (dd, J=13.2, 5.0 Hz, 1H ), 4.47 (d, J=17.2 Hz, 1H), 4.32 (d, J=17.2 Hz, 1H), 3.14-2.86 (m, 3H), 2.68 (t, J=7.0 Hz, 2H), 2.60 (dd, J=17.2, 1.6 Hz, 1H), 2.47-2.36 (m, 3H), 2.30- 2.10 (m, 4H), 2.10-1.87 (m, 3H), 1.74-1.42 (m, 4H). UPLC-MS (ESI) peak value calculated for C ₂₉ H ₃₀ Cl ₂ N ₄ O ₃ [M+H] ⁺ : 553.17, obtained value 553.49.

Example 245: 4-(2-chloro-4-methoxyphenyl)-1-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butyl)piperidine-4-carbonitrile (245)

For the method of preparation, see synthesis method 1 and Example 51. ¹ H NMR (500 MHz, DMSO) δ 10.99 (s, 1H), 7.57 (dd, J=5.7, 2.9 Hz, 1H) , 7.48-7.45 (m, 2H), 7.42 (d, J=9.0 Hz, 1H), 7.13 (d, J=2.7 Hz, 1H), 6.98 ( dd, J=8.9, 2.7 Hz, 1H), 5.13 (dd, J=13.3, 5.1 Hz, 1H), 4.47 (d, J=17.1 Hz, 1H ), 4.32 (d, J=17.1 Hz, 1H), 3.79 (s, 3H), 2.98 (d, J=11.1 Hz, 2H), 2.94-2.86 (m, 1H), 2.67 (t, J=7.7 Hz, 2H), 2.58 (d, J=17.0 Hz, 1H), 2.44-2.37 (m, 5H) , 2.30 (t, J=11.9 Hz, 2H), 2.03-1.97 (m, 1H), 1.91 (t, J=14.0 Hz, 2H), 1.63 ( d, J=7.9 Hz, 2H), 1.56-1.46 (m, 2H). UPLC-MS (ESI) peak value calculated for C30H33CIN4O4 [M+H] ⁺ : 549.22, obtained value 549.43.

Example 246: 4-(2,5-dimethoxyphenyl)-1-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butyl)piperidine-4-carbonitrile (246 )

For the method of preparation, see synthesis method 1 and Example 51. ¹ H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 7.56 (dt, J=7.7, 3.9 Hz, 1H) , 7.49-7.44 (m, 2H), 7.06 (d, J=9.0 Hz, 1H), 6.95-6.90 (m, 1H), 6.84 (d, J =2.9 Hz, 1H), 5.13 (dd, J=13.3, 5.1 Hz, 1H), 4.47 (d, J=17.2 Hz, 1H), 4.31 (d , J=17.1 Hz, 1H), 3.80 (s, 3H), 3.72 (s, 3H), 2.90 (dd, J=22.3, 8.8 Hz, 3H), 2 .67 (t, J=7.6 Hz, 2H), 2.58 (d, J=17.6 Hz, 1H), 2.41 (dd, J=17.8, 4.7 Hz, 3H) , 2.27 (d, J=11.5 Hz, 4H), 2.04-1.96 (m, 1H), 1.90 (d, J=13.3 Hz, 2H), 1.62 ( dd, J=13.9, 6.7 Hz, 2H), 1.55-1.45 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₃₁ H ₃₆ N ₄ O ₅ [M+H] ⁺ : 545.27, obtained value 545.56.

Example 247: 4-(2,5-dimethoxyphenyl)-1-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pentyl)piperidine-4-carbonitrile (247 )

For the method of preparation, see synthesis method 1 and Example 51. ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.56 (dt, J=7.7, 3.9 Hz, 1H) , 7.51-7.39 (m, 2H), 7.06 (d, J=8.9 Hz, 1H), 6.93 (dd, J=8.9, 2.9 Hz, 1H), 6.84 (d, J=2.9 Hz, 1H), 5.13 (dd, J=13.2, 5.0 Hz, 1H), 4.46 (d, J=17.2 Hz, 1H ), 4.31 (d, J=17.2 Hz, 1H), 3.80 (s, 3H), 3.73 (s, 3H), 3.04-2.82 (m, 3H), 2 ,72-2.55 (m, 3H), 2.45-2.40 (m, 1H), 2.39-2.30 (m, 2H), 2.25 (t, J=3.6 Hz , 4H), 2.04-1.97 (m, 1H), 1.88 (t, J=12.2, 10.8 Hz, 2H), 1.68-1.59 (m, 2H), 1.53-1.45 (m, 2H), 1.39-1.28 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₃₂ H ₃₈ N ₄ O ₅ [M+H] ⁺ : 559.28, obtained value 559.51.

Example 248: 4-(2,5-dichlorophenyl)-1-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pentyl)piperidine-4-carbonitrile (248 )

For the preparation method, see synthesis method 1 and Example 51. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.00 (s, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.58-7.50 (m, 3H), 7.47-7.43 (m, 2H), 5.13 (dd, J=13.2, 5.1 Hz, 1H), 4.46 ( d,J=17.2 Hz, 1H), 4.30 (d, J=17.2 Hz, 1H), 3.00 (d, J=12.5 Hz, 2H), 2.95-2, 87 (m, 1H), 2.69-2.62 (m, 2H), 2.60-2.56 (m, 1H), 2.45-2.41 (m, 3H), 2.39- 2.32 (m, 2H), 2.32-2.20 (m, 2H), 2.05-1.89 (m, 3H), 1.66-1.59 (m, 2H), 1, 56-1.44 (m, 2H), 1.41-1.28 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₃₀ H ₃₂ Cl ₂ N ₄ O ₃ [M+H] ⁺ : 567.19, obtained value 567.48.

Example 249: 4-(3,4-dimethoxyphenyl)-1-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pentyl)piperidine-4-carbonitrile (249 )

For the method of preparation, see synthesis method 1 and Example 51. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.00 (s, 1H), 7.56 (dd, J=5.8, 2.8 Hz , 1H), 7.48-7.31 (m, 2H), 7.04-7.03 (m, 2H), 6.97 (d, J=9.1 Hz, 1H), 5.13 ( dd, J=13.3, 5.1 Hz, 1H), 4.47 (d, J=17.2 Hz, 1H), 4.31 (d, J=17.2 Hz, 1H), 3, 78 (s, 3H), 3.75 (s, 3H), 3.00-2.93 (m, 2H), 2.92-2.88 (m, 1H), 2.65 (t, J= 7.2 Hz, 2H), 2.61-2.56 (m, 1H), 2.45-2.41 (m, 1H), 2.34 (t, J=7.2 Hz, 2H), 2.22 (t, J=11.4 Hz, 2H), 2.09 (d, J=13.4 Hz, 2H), 2.05-1.89 (m, 3H), 1.67-1 .59 (m, 2H), 1.53-1.46 (m, 2H), 1.37-1.30 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₃₂ H ₃₈ N ₄ O ₅ [M+H] ⁺ : 559.28, obtained value 559.59.

Example 250: 4-(2,6-dichlorophenyl)-1-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pentyl)piperidine-4-carbonitrile (250 )

For the method of preparation, see synthesis method 1 and Example 51. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.00 (s, 1H), 7.61-7.52 (m, 3H), 7.48 -7.43(m, 2H), 7.40 (dd, J=8.5, 7.6 Hz, 1H), 5.13 (dd, J=13.3, 5.1 Hz, 1H), 4.47 (d, J=17.2 Hz, 1H), 4.31 (d, J=17.2 Hz, 1H), 3.11-3.03 (m, 2H), 2.97-2 .88 (m, 1H), 2.70-2.63 (m, 2H), 2.61-2.57 (m, 1H), 2.55-2.52 (m, 4H), 2.47 -2.43 (m, 1H), 2.42-2.31 (m, 4H), 2.04-1.98 (m, 1H), 1.67-1.59 (m, 2H), 1 .55-1.47 (m, 2H), 1.37-1.30 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₃₀ H ₃₂ Cl ₂ N ₄ O ₃ [M+H] ⁺ : 567.19, obtained value 567.48.

Example 251: 4-(3,5-dichlorophenyl)-1-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pentyl)piperidine-4-carbonitrile (251 )

For the preparation method, see synthesis method 1 and Example 51. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.00 (s, 1H), 7.67 (d, J=1.6 Hz, 1H), 7.60 (d, J=1.6 Hz, 2H), 7.56 (dd, J=7.7, 4.0 Hz, 1H), 7.48-7.43 (m, 2H), 5 .14 (dd, J=13.3, 5.0 Hz, 1H), 4.47 (d, J=17.2 Hz, 1H), 4.31 (d, J=17.2 Hz, 1H) , 3.04-2.87 (m, 3H), 2.70-2.63 (m, 2H), 2.60-2.56 (m, 1H), 2.45-2.41 (m, 1H), 2.40-2.29 (m, 2H), 2.29-2.09 (m, 4H), 2.06-1.91 (m, 3H), 1.69-1.58 ( m, 2H), 1.57-1.43 (m, 2H), 1.37-1.29 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₃₀ H ₃₂ Cl ₂ N ₄ O ₃ [M+H] ⁺ : 567.19, obtained value 567.52.

Example 252: 1-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pentyl)-4-(-4-(((8)-tetrahydrofuran-3- yl)oxy)phenyl)piperidine-4-carbonitrile (252)

For the method of preparation, see synthesis method 1 and Example 51. ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.58-7.53 (m, 1H), 7.49-7, 39 (m,4H), 6.96 (d, J=8.8 Hz, 2H), 5.14 (dd, J=13.2, 5.1 Hz, 1H), 5.05-5.00 (m, 1H), 4.47 (d, J=17.2 Hz, 1H), 4.31 (d, J=17.2 Hz, 1H), 3.92-3.71 (m, 4H) , 3.00-2.86 (m, 3H), 2.71-2.54 (m, 3H), 2.47-2.30 (m, 3H), 2.27-2.16 (m, 3H), 2.11-1.84 (m, 6H), 1.65-1.57 (m, 2H), 1.55-1.44 (m, 2H), 1.38-1.29 ( m, 2H). UPLC-MS (ESI) peak value calculated for C ₃₄ H ₄₀ N ₄ O ₅ [M+H] ⁺ : 585.30, obtained value 585.56.

Example 253: 1-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butyl)-4-(2,3,4-trimethoxyphenyl)piperidine-4-carbonitrile (253)

For the method of preparation, see synthesis method 1 and Example 51. ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.64-7.53 (m, 1H), 7.53-7, 40 (m, 2H), 6.87 (dd, J=76.8, 8.9 Hz, 2H), 5.13 (dd, J=13.2, 5.0 Hz, 1H), 4.47 (d, J=17.2 Hz, 1H), 4.32 (d, J=17.1 Hz, 1H), 3.92 (s, 3H), 3.80 (s, 3H), 3.76 (s, 3H), 3.03-2.84 (m, 3H), 2.67 (t, J=7.4 Hz, 2H), 2.62-2.53 (m, 1H), 2, 48-2.12 (m, 7H), 2.06-1.95 (m, 1H), 1.91-1.74 (m, 2H), 1.70-1.56 (m, 2H), 1.56-1.44 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₃₂ H ₃₈ N ₄ O ₆ [M+H] ⁺ : 575.28, obtained value 575.57.

Example 254: 1-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pentyl)-4-(2,3,4-trimethoxyphenyl)piperidine-4-carbonitrile (254)

For the method of preparation, see synthesis method 1 and Example 51. ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.61-7.52 (m, J=2.9 Hz, 1H) , 7.50-7.41 (m, 2H), 6.88 (dd, J=74.6, 8.9 Hz, 2H), 5.18-5.08 (m, 1H), 4.46 (d,J=17.2 Hz, 1H), 4.31 (d,J=17.2 Hz, 1H), 3.92 (s, 3H), 3.80 (s, 3H), 3.76 (s, 3H), 3.06-2.85 (m, 3H), 2.71-2.54 (m, 3H), 2.46-2.12 (m, 7H), 2.05-1 .96 (m, 1H), 1.91-1.73 (m, 2H), 1.70-1.57 (m, 2H), 1.56-1.41 (m, 3H), 1.38 -1.27 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₃₃ H ₄₀ N ₄ O ₆ [M+H] ⁺ : 589.30, obtained value 589.58.

Example 255: 4-(2,4-dimethoxyphenyl)-1-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pentyl)piperidine-4-carbonitrile (255 )

For the method of preparation, see synthesis method 1 and Example 51. ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.60-7.52 (m, 1H), 7.49-7, 41 (m, 2H), 7.19 (d, J=8.7 Hz, 1H), 6.70-6.41 (m, 1H), 6.59-6.51 (m, 1H), 5 .14 (dd, J=13.2, 5.1 Hz, 1H), 4.46 (d, J=17.2 Hz, 1H), 4.31 (d, J=17.2 Hz, 1H) , 3.84 (s, 3H), 3.77 (s, 3H), 3.05-2.82 (m, 3H), 2.70-2.54 (m, 3H), 2.46-2 .13 (m, 7H), 2.06-1.95 (m, 1H), 1.92-1.76 (m, 2H), 1.68-1.57 (m, 2H), 1.56 -1.42 (m, 2H), 1.38-1.26 (m, 2H). UPLC-MS (ESI) peak _magnitude calculated for _{C32H38N4O ;} [M+H] ⁺ : 559.28, the resulting value is 559.54.

Example 256: 4-(2,4-dimethoxyphenyl)-1-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butyl)piperidine-4-carbonitrile (256 )

For the method of preparation, see synthesis method 1 and Example 51. ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.60-7.53 (m, 1H), 7.49-7, 43 (m, 2H), 7.19 (d, J=8.7 Hz, 1H), 6.69-6.30 (m, 1H), 6.57-6.51 (m, 1H), 5 .13 (dd, J=13.2, 5.0 Hz, 1H), 4.47 (d, J=17.1 Hz, 1H), 4.31 (d, J=17.1 Hz, 1H) , 3.84 (s, 3H), 3.77 (s, 3H), 2.99-2.82 (m, 3H), 2.67 (t, J=7.3 Hz, 2H), 2, 62-2.53 (m, 1H), 2.46-2.11 (m, 8H), 2.05-1.94 (m, 1H), 1.89-1.77 (m, 2H), 1.69-1.56 (m, 2H), 2.46-2.11 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₃₁ H ₃₆ N ₄ O ₅ [M+H] ⁺ : 545.27, obtained value 545.53.

Example 257: 4-(2-chloro-4-(trifluoromethoxy)phenyl)-1-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butyl)piperidin- 4-carbonitrile (257)

For the preparation method, see synthesis method 1 and Example 51. ¹ H NMR (400 MHz, DMSO) δ 11.00(s, 1H), 7.72-7.64 (m, 2H), 7.59-7, 54 (m, 1H), 7.51-7.44 (m, 3H), 5.13 (dd, J=13.3, 5.1 Hz, 1H), 4.47 (d, J=17, 1 Hz, 1H), 4.31 (d, J=17.1 Hz, 1H), 3.06-2.84 (m, 3H), 2.73-2.54 (m, 3H), 2, 47-2.23 (m, 7H), 2.04-1.90 (m, 3H), 1.67-1.58 (m, 2H), 1.56-1.44 (m, 2H). UPLC MS (ESI) peak value calculated for C ₃₀ H ₃₀ ClF ₃ N ₄ O ₄ [M+H] ⁺ : 603.19, obtained value 603.51.

Example 258: 4-(2-chloro-4-(trifluoromethoxy)phenyl)-1-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pentyl)piperidin- 4-carbonitrile (258)

For the preparation method, see synthesis method 1 and Example 51. ¹ H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.23-7.64 (m, 2H), 7.58-7, 63 (m,1H), 7.52-7.41 (m, 3H), 5.14 (dd, J=13.3, 5.0 Hz, 1H), 4.46 (d, J=17, 2 Hz, 1H), 4.31 (d, J=17.1 Hz, 1H), 3.05-2.87 (m, 3H), 2.69-2.56 (m, 3H), 2, 47-2.22 (m, 7H), 2.06-1.89 (m, 3H), 1.69-1.57 (m, 2H), 1.55-1.43 (m, 2H), 1.41 1.29 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₃₁ H ₃₂ ClF ₃ N ₄ O ₄ [M+H] ⁺ : 617.21, obtained value 617.58.

Example 259: 4-(2,3-dimethoxyphenyl)-1-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butyl)piperidine-4-carbonitrile (259 )

For method of preparation, see synthesis method 1 and Example 51. ¹ H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.56 (dt, J=7.7, 3.8 Hz, 1H) , 7.49-7.42 (m, 2H), 7.13-7.04 (m, 2H), 6.90 (dd, J=7.4, 1.9 Hz, 1H), 5.13 (dd, J=13.3, 5.1 Hz, 1H), 4.46 (d, J=17.2 Hz, 1H), 4.31 (d, J=17.2 Hz, 1H), 3 .87 (s, 3H), 3.83 (s, 3H), 2.98-2.85 (m, 3H), 2.67 (t, J=7.6 Hz, 2H), 2.62- 2.55 (m, 1H), 2.47-2.33 (m, 3H), 2.33-2.16 (m, 4H), 2.04-1.95 (m, 1H), 1, 84 (t, J=12.3 Hz, 2H), 1.68-1.56 (m, 2H), 1.55-1.45 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₃₁ H ₃₆ N ₄ O ₅ [M+H] ⁺ : 545.27, obtained value 545.49.

Example 260: 4-(2,3-dimethoxyphenyl)-1-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pentyl)piperidine-4-carbonitrile (260 )

For the method of preparation, see synthesis method 1 and Example 51. ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.57 (dd, J=7.1, 4.0 Hz, 1H) , 7.51-7.42 (m, 2H), 7.14-7.12 (m, 2H), 6.90 (d, J=7.l Hz, 1H), 5.14 (dd, J =13.2, 5.2 Hz, 1H), 4.47 (d, J=17.1 Hz, 1H), 4.31 (d, J=17.0 Hz, 1H), 3.89 (s , 3H), 3.84 (s, 3H), 3.14-3.05 (m, 2H), 2.99-2.89 (m, 1H), 2.68-2.57 (m, 3H ), 2.49-2.36 (m, 3H), 2.36-2.07 (m, 4H), 2.04-1.98 (m, 1H), 1.88-1.84 (m , 2H), 1.68-1.58 (m, 2H), 1.53-1.46 (m, 2H), 1.27-1.20 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₃₂ H ₃₈ N ₄ O ₅ [M+H] ⁺ : 559.28, obtained value 559.56.

Example 261: 1-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butyl)-4-sym-trimethylphenylpiperidine-4-carbonitrile (261)

For the method of preparation, see synthesis method 1 and Example 51. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.99 (s, 1H), 7.57 (dd, J=5.6, 2.7 Hz , 1H), 7.51-7.42 (m, 2H), 6.86 (s, 2H), 5.13 (dd, J=13.1, 4.9 Hz, 1H), 4.47 ( d, J=17.0 Hz, 1H), 4.32 (d, J=17.1 Hz, 1H), 3.01-2.86 (m, 3H), 2.73-2.64 (m , 2H), 2.63-2.56 (m, 1H), 2.51 (s, 6H), 2.49-2.39 (m, 3H), 2.39-2.21 (m, 6H ), 2.17 (s, 3H), 2.09-2.03 (m, 1H), 1.69-1.58 (m, 2H), 1.56-1.43 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₃₂ H ₃₈ N ₄ O ₃ [M+H] ⁺ : 527.29, obtained value 527.56.

Example 262: 1-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pentyl)-4-sym-trimethylphenylpiperidine-4-carbonitrile (262)

For the method of preparation, see synthesis method 1 and Example 51. (q, J=4.0, 3.5 Hz, 2H), 6.86 (s, 2H), 5.14 (dd, J=13.4, 5.0 Hz, 1H), 4.47 (d, J=17.2 Hz, 1H), 4.31 (d, J=17.3 Hz, 1H), 3.00-2.86 (m, 3H), 2.69-2.56 (m, 3H), 2.51 (s, 6H), 2.49-2.36 (m , 3H), 2.36-2.20 (m, 6H), 2.18 (s, 3H), 2.05-1.97 (m, 1H), 1.70-1.58 (m, 2H), 1.56-1.44 (m, 2H), 1.41-1.29 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₃₃ H ₄₀ N ₄ O ₃ [M+H] ⁺ : 541.31, obtained value 541.45.

Example 263: 1-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pentyl)-4-(-4-(((8)-tetrahydrofuran-3- yl)oxy)phenyl)piperidine-4-carbonitrile (263)

For the preparation method, see synthesis method 1 and Example 51. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.00 (s, 1H), 7.56 (dd, J=5.7, 2.8 Hz , 1H), 7.46 (q, J=4.1, 3.4 Hz, 2H), 7.42 (d, J=8.9 Hz, 2H), 6.96 (d, J=8, 8 Hz, 2H), 5.14 (dd, J=13.4, 5.1 Hz, 1H), 5.08-4.97 (m, 1H), 4.47 (d, J=17.2 Hz, 1H), 4.31 (d, J=17.2 Hz, 1H), 3.89 (dd, J=10.1, 4.6 Hz, 1H), 3.86-3.80 (m , 1H), 3.76 (ddd, J=16.5, 8.7, 4.9 Hz, 2H), 3.07-2.84 (m, 3H), 2.68-2.56 (m , 3H), 2.43-2.36 (m, 3H), 2.29-2.15 (m, 3H), 2.14-1.80 (m, 6H), 1.70-1.56 (m, 2H), 1.56-1.42 (m, 2H), 1.33 (p, J=8.7, 8.3 Hz, 2H). UPLC-MS (ESI) peak value calculated for C ₃₄ H ₄₀ N ₄ O ₅ [M+H]+: 585.30, obtained value 585.53.

Example 264: 1-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pentyl)-4-(4-(2-methoxyethoxy)phenyl)piperidin-4- carbonitrile (264)

For the method of preparation, see synthesis method 1 and Example 51. ¹ H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 7.57 (dd, J=5.4, 3.2 Hz, 1H), 7 .45 (dt, J=18.7, 6.6 Hz, 4H), 7.00 (d, J=8.8 Hz, 2H), 5.14 (dd, J=13.3, 5.1 Hz, 1H), 4.47 (d, J=17.2 Hz, 1H), 4.31 (d, J=17.1 Hz, 1H), 4.12-4.07 (m, 2H), 3.68-3.61 (m, 2H), 3.47-3.35 (m, 3H), 3.30 (s, 3H), 3.23-3.04 (m, 2H), 2, 99-2.87 (m, 1H), 2.70-2.56 (m, 3H), 2.46-2.35 (m, 2H), 2.27-2.12 (m, 2H), 2.09-1.94 (m, 3H), 1.69-1.52 (m, 4H), 1.41-1.29 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₃₃ H ₄₀ N ₄ O ₅ [M+H] ⁺ : 573.30, obtained value 573.53.

Example 265: 1-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pentyl)-4-(4-methoxyphenyl)piperidine-4-carbonitrile (265)

For the preparation method, see synthesis method 1 and Example 51. ¹ H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 7.61-7.55 (m, 1H), 7.50-7.41 ( m, 4H), 7.01 (d, J=8.6 Hz, 2H), 5.15 (dd, J=13.3, 5.0 Hz, 1H), 4.48 (d, J=17 ,2 Hz, 1H), 4.32 (d, J=17.0 Hz, 1H), 3.77 (s, 3H), 3.44-3.23(m, 6H), 3.01-2 .87 (m, 1H), 2.70-2.56 (m, 3H), 2.46-2.35 (m, 1H), 2.29-2.14 (m, 2H), 2.07 -1.94 (m, 3H), 1.70-1.50 (m, 4H), 1.40-1.27 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₃₁ H ₃₆ N ₄ O ₄ [M+H] ⁺ : 529.27, obtained value 529.58.

Example 266: 4-(2,6-dichlorophenyl)-1-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butyl)piperidine-4-carbonitrile (266 )

For the method of preparation, see synthesis method 1 and Example 51. ¹ H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 7.62-7.56 (m, 3H), 7.51-7, 47 (m, 2H), 7.43 (dd, J=13.8, 6.0 Hz, 1H), 5.15 (dd, J=13.3, 5.0 Hz, 1H), 4.48 (d, J=17.1 Hz, 1H), 4.33 (d, J=17.1 Hz, 1H), 3.52-3.17(m, 4H), 2.99-2.88 ( m, 1H), 2.80-2.58 (m, 9H), 2.46-2.35 (m, 1H), 2.08-1.98 (m, 1H), 1.72-1, 50 (m, 4H). UPLC-MS (ESI) peak value calculated for C ₂₉ H ₃₀ Cl ₂ N ₄ O ₃ [M+H] ⁺ : 553.17, obtained value 553.50.

Example 267: 4-(2-chloro-4-methoxyphenyl)-1-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pentyl)piperidine-4-carbonitrile (267)

For the method of preparation, see synthesis method 1 and Example 51. ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.58-7.53 (m, 1H), 7.49-7, 39 (m, 3H), 7.13 (d, J=2.7 Hz, 1H), 6.98 (dd, J=8.9, 2.7 Hz, 1H), 5.14 (dd, J =13.3, 5.1 Hz, 1H), 4.46 (d, J=17.2 Hz, 1H), 4.31 (d, J=17.1 Hz, 1H), 3.79 (s , 3H), 3.07-2.86 (m, 3H), 2.68-2.56 (m, 3H), 2.46-2.36 (m, 3H), 2.37-2.32 (m, 2H), 2.28 (t, J=11.7 Hz, 2H), 2.05-1.95 (m, 1H), 1.89 (t, J=11.1 Hz, 2H) , 1.68-1.56 (m, 2H), 1.50 (dt, J=14.8, 7.6 Hz, 2H), 1.34 (dd, J=14.1, 7.2 Hz , 2H). UPLC-MS (ESI) peak value calculated for C ₃₁ H ₃₅ ClN ₄ O ₄ [M+H] ⁺ : 563.23, obtained value 563.52.

Example 268: 4-(4-cyanophenyl)-1-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pentyl)piperidine-4-carbonitrile (268)

For the method of preparation, see synthesis method 1 and Example 51. ^NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.93 (d, J=8.4 Hz, 2H), 7.75 ( d, J=8.5 Hz, 2H), 7.56 (dd, J=5.5, 3.0 Hz, 1H), 7.49-7.41 (m, 2H), 5.14 (dd , J=13.2, 5.1 Hz, 1H), 4.47 (d, J=17.2 Hz, 1H), 4.31 (d, J=17.1 Hz, 1H), 3.12 -2.86 (m, 3H), 2.70-2.56 (m, 3H), 2.46-2.38 (m, 3H), 2.35-2.20 (m, 2H), 2 .19-2.09 (m, 2H), 2.08-1.94 (m, 3H), 1.63 (dt, J=15.5, 7.7 Hz, 2H), 1.53 (dd , J=12.5, 7.1 Hz, 2H), 1.40-1.29 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₃₁ H ₃₃ N ₅ O ₃ [M+H] ⁺ : 524.26, obtained value 524.55.

Example 269: 4-(2,5-dichlorophenyl)-1-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butyl)piperidine-4-carbonitrile (269 )

For the method of preparation, see synthesis method 1 and Example 51. ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.61 (d, J=8.3 Hz, 1H), 7.59 -7.51 (m, 3H), 7.49-7.43 (m, 2H), 5.13 (dd, J=13.3, 5.1 Hz, 1H), 4.47 (d, J =17.1 Hz, 1H), 4.31 (d, J=17.2 Hz, 1H), 3.08-2.86 (m, 3H), 2.66 (t, J=7.6 Hz ,2H), 2.59 (d, J=17.1 Hz, 1H), 2.47-2.23 (m, 7H), 2.05-1.93 (m, 3H), 1.63 ( dd, J=15.5, 7.8 Hz, 2H), 1.58-1.45 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₂₉ H ₃₀ Cl ₂ N ₄ O ₃ [M+H] ⁺ : 553.17, obtained value 553.52.

Example 270: 1-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pentyl)-4-(4-(oxetan-3-yloxy)phenyl)piperidin- 4-carbonitrile (270)

For the method of preparation, see synthesis method 1 and Example 51. ¹ H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 7.57 (dt, J=7.7, 3.9 Hz, 1H) ,7.49-7.42 (m, 4H), 6.86 (d, J=8.5 Hz, 2H), 5.34-5.25 (m, 1H), 5.14 (dd, J =13.3, 5.0 Hz, 1H), 4.93 (t, J=6.7 Hz, 2H), 4.54 (dd, J=7.4, 5.1 Hz, 2H), 4 .47 (d, J=17.2 Hz, 1H), 4.31 (d, J=17.2 Hz, 1H), 3.24-3.05 (m, 2H), 3.04-2, 83 (m, 3H), 2.72-2.64 (m, 2H), 2.60-2.56 (m, 1H), 2.48-2.31 (m, 3H), 2.23- 2.09 (m, 2H), 2.04-1.98 (m, 3H), 1.70-1.47 (m, 4H), 1.40-1.29 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₃₃ H ₃₈ N ₄ O ₅ [M+H] ⁺ : 571.28, obtained value 571.53.

Example 271: 1-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pentyl)-4-(4-(trifluoromethyl)phenyl)piperidine-4-carbonitrile ( 271)

For the preparation method, see synthesis method 1 and Example 51. ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.80 (q, J=8.6 Hz, 4H), 7.56 (dd, J=5.7, 2.8 Hz, 1H), 7.49-7.44 (m, 2H), 5.14 (dd, J=13.2, 5.1 Hz, 1H), 4.47 (d, J=17.2 Hz, 1H), 4.31 (d, J=17.2 Hz, 1H), 3.03-2.95 (m, 2H), 2.94-2 .86 (m, 1H), 2.69-2.54 (m,ZN), 2.43 (dd, J=13.2, 4.5 Hz, 1H), 2.39-2.33 (m , 2H), 2.24 (t, J=11.4 Hz, 2H), 2.12 (d, J=12.3 Hz, 2H), 2.06-1.95 (m, 3H), 1 .68-1.58 (m, 2H), 1.55-1.46 (m, 2H), 1.40-1.29 (m, 2H). UPLC-MS (ESI) peak value calculated for C31H33F3N4O3 [M+H] ⁺ : 567.25, obtained value 567.53.

Example 272: 4-(3,4-dichlorophenyl)-1-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butyl)piperidine-4-carbonitrile (272 )

For the preparation method, see synthesis method 1 and Example 51: ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.79 (d, J=1.8 Hz, 1H), 7, 73 (d, J=8.5 Hz, 1H), 7.59-7.53 (m, 2H), 7.50-7.45 (m, 2H), 5.14 (dd, J=13, 2, 5.0 Hz, 1H), 4.47 (d, J=17.1 Hz, 1H), 4.32 (d, J=17.1 Hz, 1H), 3.40-3.28( m, 4H), 3.10-2.86 (m, 3H), 2.68 (t, J=7.0 Hz, 2H), 2.59 (d, J=16.6 Hz, 1H), 2.42 (dd, J=13.2, 4.3 Hz, 1H), 2.29-2.10 (m, 3H), 2.05-1.94 (m, 2H), 1.69- 1.40 (m, 4H). UPLC-MS (ESI) peak value calculated for C ₂₉ H ₃₀ Cl ₂ N ₄ O ₃ [M+H] ⁺ : 553.17, obtained value 553.52.

Example 273: 3-(4-(5-(5-fluoro-3H-spiro[isobenzofuran-1,4'-piperidine]-1'-)pentyl)-1-oxoisoindolin-2-yl)piperidin-2,6 -dione (273)

For method of preparation, see synthesis method 1 and Example 120. ¹ H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 7.58 (dd, J=5.3, 3.1 Hz, 1H) , 7.47 (dd, J=7.8, 5.4 Hz, 2H), 7.17 (dd, J=16.5, 8.1 Hz, 3H), 5.15 (dd, J=13 ,3, 5.0 Hz, 1H), 5.02 (s, 2H), 4.48 (d,J=17.2 Hz, 1H), 4.31 (d, J=17.2 Hz, 1H ), 3.50 (d, J=6.9 Hz, 2H), 3.20-3.06 (m, 2H), 3.00-2.88 (m, 1H), 2.68 (t, J=7.4 Hz, 2H), 2.64-2.56 (m, 1H), 2.44-2.34 (m, 3H), 2.19 (t, J=13.5 Hz, 2H ), 2.06-1.97 (m, 1H), 1.86 (d, J=13.6 Hz, 2H), 1.78-1.62 (m, 4H), 1.41-1, 33 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₃₀ H ₃₄ FN ₃ O ₄ [M+H] ⁺ : 520.25, obtained value 520.53.

Example 274: 3-(4-(5-(5-chloro-3H-spiro[isobenzofuran-1,4'-piperidin]-1-yl)pentyl)-1-oxoisoindolin-2-yl)piperidin-2,6 -dione (274)

For the method of preparation, see synthesis method 1 and Example 120. ¹ H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 7.62-7.55 (m, 1H), 7.48 (d, J=3.5 Hz, 2H), 7.45-7.37 (m, 2H), 7.20 (d, J=8.1 Hz, 1H), 5.15 (dd, J=13.3 , 5.1 Hz, 1H), 5.03 (s, 2H), 4.48 (d, J=17.1 Hz, 1H), 4.31 (d, J=17.1 Hz, 1H), 3.51 (d, J=12.2 Hz, 2H), 3.20-3.08 (m, 2H), 3.00-2.87(m, 1H), 2.72-2.57 ( m, 3H), 2.41 (dd, J=17.7, 8.7 Hz, 1H), 2.14 (t, J=12.0 Hz, 2H), 2.07-1.95 (m , 2H), 1.88 (d, J=13.2 Hz, 2H), 1.80-1.60 (m, 5H), 1.42-1.32 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₃₀ H ₃₄ ClN ₃ O ₄ [M+H] ⁺ : 536.22, obtained value 536.52.

Example 275: 3-(4-(5-(6-chloro-2-oxospiro[dihydroindole-3,4-piperidin]-1-yl)pentyl)-1-oxoisoindolin-2-yl)piperidin-2,6- dione (275)

For the method of preparation, see synthesis method 1 and Example 120. ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 10.56 (s, 1H), 7.57 (dd, J=5, 9, 2.6 Hz, 1H), 7.49-7.43(m, 3H), 7.00 (dd, J=8.0, 1.9 Hz, 1H), 6.86 (d,J =1.9 Hz, 1H), 5.14 (dd, J=13.3, 5.1 Hz, 1H), 4.48 (d, J=17.1 Hz, 1H), 4.31 (d , J=17.1 Hz, 1H), 2.99-2.85 (m, 3H), 2.70-2.60 (m, 4H), 2.59-2.52 (m, 3H), 2.47-2.37 (m, 1H), 2.06-1.97 (m, 1H), 1.87-1.77 (m, 2H), 1.72-1.61 (m, 4H ), 1.55 (dd, J=14.3, 7.0 Hz, 2H), 1.43-1.29 (m, 2H). UPLC MS (ESI) peak value calculated for C ₃₀ H ₃₃ ClN ₄ O ₄ [M+H] ⁺ : 549.22, obtained value 549.53.

Example 276: 3-(4-(5-(4-chloro-2-oxospiro[dihydroindole-3,4-piperidin]-1-yl)pentyl)-1-oxoisoindolin-2-yl)piperidin-2,6- dione (276)

For the method of preparation, see synthesis method 1 and Example 120. ¹ H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 10.66 (s, 1H), 7.58 (dd, J=6, 1, 2.5 Hz, 1H), 7.51-7.46 (m, 2H), 7.22 (t, J=

8.0 Hz, 1H), 6.97 (d, J=8.2 Hz, 1H), 6.82 (A, J=1.6 Hz, 1H), 5.15 (dd, J=13.3, 5.1 Hz, 1H), 4.49 (d, J=17.2 Hz, 1H), 4.32 (d, J=17.2 Hz, 1H), 3.15-2.88 (m, 5H), 2.75-2.57 (m, 6H), 2.47-2.38 (m, 2H), 2.07-1.98 (m, 3H), 1.76-1.58 ( m, 6H), 1.42-1.32 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₃₀ H ₃₃ ClN ₄ O ₄ [M+H] ⁺ : 549.22, obtained value 549.49.

Example 277: 3-(4-(5-(6-chloro-2-oxo-1,2-dihydrospiro[benzo[1,3]oxazin-4,4'-piperidin]-1'-yl)pentyl)- 1-oxoisoindolin-2-yl) piperidin-2,6-dione (277)

For the method of preparation, see synthesis method 1 and Example 120. ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 10.35 (s, 1H), 7.57 (dd, J=5, 6, 3.0 Hz, 1H), 7.49-7.45 (m, 2H), 7.38 (d, J=

2.1 Hz, 1H), 7.31 (dd, J=8.5, 2.2 Hz, 1H), 6.89 (d, J=8.5 Hz, 1H), 5.14 (dd, J= 13.3, 5.1 Hz, 1H), 4.47 (d, J=17.2 Hz, 1H), 4.31 (d, J=17.2 Hz, 1H), 2.98-2, 87 (m, 1H), 2.75 (d, J=10.3 Hz, 2H), 2.68-2.54 (m, 3H), 2.43 (dd, J=13.1, 4, 4 Hz, 1H), 2.39-2.28 (m, 4H), 2.07-1.98 (m, 3H), 1.90 (d, J=13.0 Hz, 2H), 1, 68-1.58 (m, 2H), 1.56-1.45 (m, 2H), 1.39-1.32 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₃₀ H ₃₃ ClN ₄ O ₅ [M+H] ⁺ : 565.21, obtained value 565.53.

Example 278: 3-(4-(5-(5-fluoro-2-oxospiro[dihydroindole-3,4-piperidin]-1-yl)pentyl)-1-oxoisoindolin-2-yl)piperidin-2,6- dione (278)

For the method of preparation, see synthesis method 1 and Example 120. ¹ H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 10.39 (s, 1H), 7.57 (dd, J=6.0, 2.6 Hz, 1H), 7.52-7.41 (m, 2H), 7.34 (dd, J=8.6, 2.4 Hz, 1H), 7.01 (td, J=9 ,5, 2.4 Hz, 1H), 6.82 (dd, J=8.6, 4.6 Hz, 1H), 5.14 (dd, J=13.3, 5.2 Hz, 1H) , 4.48 (d, J=17.2 Hz, 1H), 4.32 (d, J=17.2 Hz, 1H), 2.99-2.81 (m, 3H), 2.67 ( t, J=7.8 Hz, 2H), 2.65-2.55 (m, 3H), 2.46-2.40 (m, 3H), 2.06-1.98 (m, 1H) , 1.86-1.75 (m, 2H), 1.74-1.59 (m, 4H), 1.59-1.50 (m, 2H), 1.42-1.32 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₃₀ H ₃₃ FN ₄ O ₄ [M+H] ⁺ : 533.25, obtained value 533.52.

Example 279: 3-(4-(5-(7-chloro-2-oxospiro[dihydroindole-3,4-piperidin]-1-yl)pentyl)-1-oxoisoindolin-2-yl)piperidin-2,6- dione (279)

For the method of preparation, see synthesis method 1 and Example 120. ¹ H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 10.92 (s, 1H), 7.58 (dd, J=5.8, 2.6 Hz, 1H), 7.48 (d, J=5.9 Hz, 2H), 7.44-7.35 (m, 1H), 7.29 (d, J=8.1 Hz, 1H), 7.02 (t, J=7.8 Hz, 1H), 5.14 (dd, J=13.3, 5.1 Hz, 1H), 4.48 (d, J=17.0 Hz, 1H), 4.32 (d, J=17.1 Hz, 1H), 3.22-3.14 (m, 2H), 3.05-2.88 (m, 3H), 2.87 -2.76 (m, 2H), 2.72-2.64 (m, 2H), 2.64-2.57 (m, 1H), 2.46-2.36 (m, 1H), 2 .06-1.98 (m, 1H), 1.97-1.84 (m, 4H), 1.73-1.58 (m, 4H), 1.44-1.33 (m, 2H) . UPLC MS (ESI) peak value calculated for C ₃₀ H ₃₃ ClN ₄ O ₄ [M+H] ⁺ : 549.22, obtained value 549.48.

Example 280: 3-(4-(5-(4-chloro-3H-spiro[isobenzofuran-1,4'-piperidin]-1-yl)pentyl)-1-oxoisoindolin-2-yl)piperidin-2,6 -dion (280)

For the method of preparation, see synthesis method 1 and Example 120. ¹ H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 7.61-7.56 (m, 1H), 7.48 (d, J=3.5 Hz, 2H), 7.44-7.40 (m, 2H), 7.20-7.15 (m, 1H), 5.15 (dd, J=13.4, 5, 1 Hz, 1H), 5.08 (s, 2H), 4.48 (d, J=17.2 Hz, 1H), 4.31 (d, J=

17.2 Hz, 1H), 3.53 (d, J=11.8 Hz, 2H), 3.23-3.10 (m, 4H), 3.01-2.85 (m, 1H), 2, 73-2.65 (m, 2H), 2.61 (d, J=18.7 HzDN), 2.44-2.36 (m, 1H), 2.20-2.08 (m, 2H) , 2.07-1.99 (m, 2H), 1.98-1.91 (m, 1H), 1.77-1.63 (m, 4H), 1.42-1.30 (m, 2H). UPLC-MS (ESI) peak value calculated for C ₃₀ H ₃₄ ClN ₃ O ₄ [M+H] ⁺ : 536.22, obtained value 536.53.

2. Test cases:

Method for testing inhibition of tumor cell proliferation: The inventors tested all examples of compounds on hematological tumor cells of the multiple myeloma cell line MM1s and the acute leukemia cell line MV-4-11 in some examples. The activity testing method and its results are as follows:

1. Inhibitory effect of the compound on MM.1S cell proliferation, MTS cell viability test:

1). Experimental method:

MM.1S cells were cultured and harvested in 1640 medium plus 10% fetal bovine serum. The cell concentration was diluted according to 7 days, and 180 μl of cell suspension was added to each well of a 96-well plate, up to 20 000 cells. 20 μl of DMSO was added to control wells at a final concentration of 0.2%. The compound from the 10 mmol/L stock solution was diluted 5-fold and 20 μL was also added to each well of cells and compound (final DMSO concentration was 0.2%). The cells were placed in an incubator with 5% CO ₂ at 37°C and incubated for 7 days. After preparing the reaction solution according to the instructions of the MTS kit (Promega, G5430), 20 μl was added to each well and incubated in a 5% CO ₂ incubator at 37°C for 3-4 hours. The absorbance value at 490 nm was read using a microtiter plate, and the absorbance value at 690 nm was used as the background value. The optical density values of OD490 OD690 were used as the final initial data. Formula for calculating the degree of inhibition of a compound: Degree of inhibition=(OD _DMSO -OD _compound )/(OD _DMSO -OD _blank )×100%. The IC50 inhibition of proliferation by the compound was calculated using Graph Pad Prism 5.0. This experiment was repeated three times, and the mean and standard deviation were calculated according to three parallel experiments.

Cell viability test results: **** represents cell viability at IC ₅₀ >20 µmol/L, *** represents cell viability at 1 µmol/L < IC ₅₀ <20 µmol/L, ** represents cell viability at 100 nmol/ l <IC ₅₀ <1 µmol/L, * represents cell viability at IC ₅₀ <100 nmol/L.

2). Experimental results:

Based on the results of testing the above compounds for cell growth inhibitory activity, the compounds of some embodiments of the present invention have good growth inhibitory activity against multiple myeloma MM1s cells, and the activity of some compounds is equivalent to or superior to that of the positive compounds. On the other hand, the development of these structurally diverse compounds provides an alternative source for obtaining more active drug molecules and molecules with better pharmaceutical properties. Therefore, the compounds of the present invention can be used for the prevention and treatment of diseases associated with the regulation of CRBN ( ^CRBN E3 ubiquitin ligase) activity, such as multiple myeloma, or including, but not limited to, other potential neoplastic diseases, pain, diseases of the nervous system and diseases of the immune system.

2. Inhibitory effect of the compound on MV-4-11 cell proliferation, MTS cell viability test:

1). Experimental method:

MV-4-11 cells were cultured and harvested in IMDM plus 10% fetal bovine serum. The cell concentration was diluted according to 7 days, and 180 μl of cell suspension was added to each well of a 96-well plate up to 2000 cells. 20 μl of DMSO was added to control wells at a final concentration of 0.2%. The compound from the 10 mmol/L stock solution was diluted 5-fold and 20 μL was also added to the wells containing cells and compound (final DMSO concentration was 0.2%). The cells were placed in an incubator with 5% CO ₂ at 37°C and incubated for 7 days. After preparing the reaction solution according to the instructions of the MTS kit (Promega, G5430), 20 μl was added to each well and incubated in a 5% CO ₂ incubator at 37°C for 3-4 hours. The absorbance value at 490 nm was read using a microtiter plate, and the absorbance value at 690 nm was used as the background value. Optical densities OD490-OD690 were used as the final initial data. Formula for calculating the degree of inhibition of a compound: Degree of inhibition=(OD _DMCO -OD _compound )/(OD _DMCO -OD _blank )×100%. The IC50 inhibition of proliferation by the compound was calculated using Graph Pad Prism 5.0. This experiment was repeated three times, and the mean and standard deviation were calculated each time according to three parallel experiments.

2). Experimental results:

Based on the results of testing the cell growth inhibitory activity of the above compounds, it can be concluded that the compounds of some examples of the present invention have very good inhibitory activity against acute leukemia cells MV-4-11. The IC50 value of several compounds is in the nanomolar level, and the best activity of the tested compounds in the table can reach 17 nmol/L. Cytostatic activity (IC50) of positive compounds (either lenalidomide or pomalidomide) already commercially available and those compounds (CC-122 or CC-220) currently used in clinical practice on acute leukemia MV cells -4-11 more than 20 µmol/l. According to the test results shown in the table above, it was found that the inhibitory activity of some compounds of the present invention on the proliferation of acute leukemia cells-MV-4-11 cells is better than that of the related positive compounds, and the best compound has 1000 times higher activity. than that of a positive connection. Thus, the compound of the present invention expands the scope of dosamine drugs in the treatment of hematological diseases and can be used to expand other indications for use on hematological tumors, such as an inhibitor of acute leukemia, and as a drug for the treatment of such diseases. The compound of the present invention can be used as a potent new type of CRBN modulator for the prevention and treatment of diseases associated with the regulation of CRBN ( ^CRBN E3 ubiquitin ligase) activity, such as multiple myeloma or including, but not limited to, other potential neoplastic diseases, pain, diseases of the nervous system and diseases of the immune system.

In general, the present invention provides a class of substituted isoindoline compounds with novel structures, in which certain representative compounds exhibit very potent inhibitory activity against the proliferation of hematological cells tested. In addition, some of the exemplary compounds of the present invention are capable of effectively overcoming limitations in the use of existing doxamine preparations, which not only effectively compensates for the shortcomings of existing doxamine preparations, but also expands their indications for use in new areas. Consequently, these compounds have very great research potential and application prospects.

Claims (253)

1. The compound represented by formula (I), or an enantiomer, racemate or pharmaceutically acceptable salt thereof (I), where X ₁ represents -CH ₂ - or -O-; X ₂ represents -CH ₂ - or - CO-; R ₁ represents hydrogen or a C ₁ hydrocarbon group; R ₂ and R ₄ are each independently hydrogen; R ₃ represents hydrogen or halogen; L represents a substituted or unsubstituted linear alkylene group containing 2-8 carbon atoms, wherein "substituted" means that one or more hydrogen atoms in the alkylene group are optionally substituted with the following substituents: -NHC(O)Ra ₁ , -NRa ₃ Ra ₄ , where Ra ₁ , Ra ₃ and Ra ₄ are each independently selected from hydrogen, C _1-6 alkyl, unsubstituted or hydroxyl substituted, and unsubstituted C _3-6 cycloalkyl; Y is absent or is -O-, -CO-, -CO-NH-, -NH-CO-, -NH-CO-NH-, -NH-CO-CH(NHRa ₉ )- or -CH(NHRa ₉ )-; and when Y is -O-, then A is 9-10 membered heteroaryl or (9-10 membered heteroaryl)-(CH ₂ ) _b1 , wherein the heteroaryl is optionally substituted with one or more groups selected from C ₁ - C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl; b ₁ represents 1; and when Y is absent or is -CO- or -CO-NH-, the corresponding arrangement of Y, A and L is A-L-, A-CO-L- and A-CO-NH-L-, then A is: i) heterocyclyl selected from the following: , X ₃ represents N or O; n ₄ represents 0 or 1; n ₅ represents 1, each Y ₁ and Y ₂ independently represents hydrogen, cyano, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, where substituted or unsubstituted 6-10 membered aryl or 5-10 membered heteroaryl substituted with one or more substituents selected from halogen, cyano, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ haloalkoxy; with the proviso that when Y ₁ and Y ₂ are each independently hydrogen, cyano and when Y is absent, X ₁ is not -O-; Y ₃ is absent or represents hydrogen, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the substituted or unsubstituted 6-10 membered aryl or 5-10 membered heteroaryl is substituted with one or more substituents selected from deuterium, halogen, cyano group, nitro group, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ haloalkoxy; with the proviso that when Y ₃ is hydrogen or absent and when Y is absent, X ₁ is not -O-; Y ₄ and Y ₅ are absent or represent one or more substituents on the heterocyclic ring, each Y ₄ and Y ₅ independently representing phenyl; ii) a fused heterocyclyl selected from: , X ₄ represents C or O; n ₆ represents 1; n ₇ represents 0, 1, 2; n ₈ represents 0 or 1; ring selected from the benzene ring; each R ₈ is independently selected from hydrogen or halogen; with the proviso that when R ₈ is selected from hydrogen, halogen and Y is absent, X ₁ is not -O-; Y ₆ and Y ₇ are absent or represent one or more substituents on the heterocyclic ring and are independently selected from C ₁ -C ₃ alkyl; or iii) a spiroheterocyclic group selected from: n _c1 is 0 or 1; n _c2 represents 1; n _c3 represents 1 or 2; n ₉ represents 0 or 1; is a 6-membered aryl ring or a 6-membered heteroaryl ring; R ₉ is independently selected from the following substituents: halogen, linear C ₁ -C ₆ alkyl, linear C ₁ -C ₆ alkoxy; Y ₈ represents a substituent that does not replace a hydrogen atom in the non-aromatic part of the spiro ring structure; and when Y is selected from -NH-CO-, -NH-CO-NH-, -NH-CO-CH(NHR _a9 )- or -CH(NHR _a9 )-, the corresponding arrangement of Y, A and L is A-NH -CO-L-, A-NH-CO-NH-L-, A-NH-CO-CH(NHR _a9 )-L- or A-CH(NHR _a9 )-L-, then A is: 6-10 membered aryl, 5-10 membered heteroaryl, (6-10 membered aryl)-CH ₂ - and such aryl or heteroaryl is optionally substituted with one or more R ₅ substituents, or A is selected from the following group: n ₁ is 0, 1 or 2; each R ₅ is independently selected from halogen, linear C ₁ -C ₆ alkyl, linear C ₁ -C ₆ alkoxyl, 5-6 membered heteroaryl, 3-6 membered heterocyclyl or phenyloxyl, when n ₁ > 1, all R ₅ may be the same or different; R _a9 is selected from hydrogen, substituted or unsubstituted C ₁ -C ₁₀ alkylcarbonyl, substituted or unsubstituted C ₃ -C ₈ cycloalkylcarbonyl, C ₃ -C ₈ heterocycloalkylcarbonyl, where "substituted" means that the end of the carbon chain is substituted with a hydroxyl or amino group; heterocyclyl refers to a cyclic substituent containing one or more saturated and/or partially saturated monocycles or polycycles, where one or more ring atoms are selected from nitrogen, oxygen, sulfur or S(O) _m , where m is an integer from 0 to 2 , and the remaining atoms of the ring are carbon; heteroaryl has 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen as ring atoms, and the remaining ring atoms are carbon. 2. The compound according to claim 1 or its enantiomer, racemate or pharmaceutically acceptable salt, where when Y is -O-, then A is substituted or unsubstituted 9-10 membered heteroaryl or (substituted or unsubstituted 9-10 membered heteroaryl)-(CH ₂ ) _b1 -, where b ₁ represents 1; substituted or unsubstituted 9-10 membered heteroaryl is selected from the following groups: n ₂ represents 0 or 1; n ₃ represents 0 or 1; each R ₆ and R ₇ is independently selected from the following: C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or C ₃ -C ₆ cycloalkyl; when Y is absent or is -CO- or -CO-NH-, the corresponding arrangement of Y, A and L is A-L-, A-CO-L- or A-CO-NH-L-, then A is: i) heterocyclyl selected from the following: , where each Y ₁ and Y ₂ independently represents hydrogen, cyano, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, where substituted or unsubstituted 6-10 membered aryl or 5-10 membered heteroaryl is substituted with one or more of the following substituents: halogen, cyano, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ haloalkoxy; with the proviso that when Y ₁ and Y ₂ are independently each hydrogen, cyano and when Y is absent, X ₁ is not -O-; Y ₃ is absent, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the substituted or unsubstituted 6-10 membered aryl or 5-10 membered heteroaryl is substituted with one or more of the following substituents: deuterium , halogen, cyano group, nitro group, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ haloalkoxy; and 6-10 membered aryl is selected from phenyl, naphthyl, 5-10 membered heteroaryl is selected from thienyl, pyridyl, benzothienyl, benzimidazolyl, indolyl, quinolinyl, isoquinolinyl; with the proviso that when Y ₃ is hydrogen or Y ₃ is absent and when Y is absent, X ₁ is not -O-; Y ₄ and Y ₅ are absent or represent one or more substituents on the heterocyclic ring, wherein Y ₄ and Y ₅ are each independently phenyl; ii) a fused heterocyclyl selected from: , n ₈ represents 0 or 1; X ₄ represents C or O; is a benzene ring; each R ₈ is independently selected from hydrogen or halogen; with the proviso that, when each R ₈ mentioned above is independently selected from hydrogen or halogen and when Y is absent, X ₁ is not -O-; Y ₆ and Y ₇ are absent or represent one or more substituents on the heterocyclic ring and are each independently selected from C ₁ -C ₃ alkyl; or iii) a spiroheterocyclic group selected from: , where n ₉ represents 0 or 1; is a benzene ring or a pyridine ring; R ₉ is independently selected from the following substituents: halogen, linear C ₁ -C ₆ alkyl, linear C ₁ -C ₆ alkoxy; Y ₈ is a substituent that does not replace a hydrogen atom in the non-aromatic portion of the spiro ring structure; when Y is selected from -NH-CO-, -NH-CO-NH-, -NH-CO-CH(NHR _a9 )- or -CH(NHR _a9 )-, the corresponding arrangement of Y, A and L is A-NH- CO-L-, A-NH-CO-NH-L-, A-NH-CO-CH(NHR _a9 )-L- or A-CH(NHR _a9 )-L-, then A is: 6-10 membered aryl, 5-10 membered heteroaryl, (6-10 membered aryl)-CH ₂ - and aryl or heteroaryl is optionally substituted with one or more R ₅ or A substituents selected from the following groups: , n ₁ is 0, 1 or 2; each R ₅ is independently selected from halogen, linear C ₁ -C ₆ alkyl, linear C ₁ -C ₆ alkoxyl, 5-6 membered heteroaryl, 3-6 membered heterocyclyl, phenyloxyl, when n ₁ > 1, all R ₅ may be the same or different; R _a9 is independently selected from hydrogen, substituted or unsubstituted C ₁ -C ₁₀ alkylcarbonyl, substituted or unsubstituted C ₃ -C ₈ cycloalkylcarbonyl, C ₃ -C ₈ heterocycloalkylcarbonyl, where "substituted" means that the end of the carbon chain is substituted with a hydroxyl or amino group. 3. The compound according to claim 2 or its enantiomer, racemate or pharmaceutically acceptable salt, where R ₁ represents hydrogen; R ₃ represents hydrogen or fluorine; L represents a substituted or unsubstituted linear alkylene group containing 2-8 carbon atoms, wherein "substituted" means that one or more hydrogen atoms in the alkylene group are optionally substituted with the following substituents: -NHC(O)Ra ₁ , -NRa ₃ Ra ₄ , where Ra ₁ , Ra ₃ and Ra ₄ are each independently selected from hydrogen or unsubstituted C _3-6 cycloalkyl; when Y is -O-, A is selected from 9-10 membered heteroaryl or (9-10 membered heteroaryl)-(CH ₂ ) _b1 -, 9-10 membered heteroaryl may be unsubstituted or substituted; substituted or unsubstituted 9-10 membered heteroaryl is selected from the following groups: , b ₁ represents 1; n ₂ represents 0 or 1; n ₃ represents 0 or 1; R ₆ and R ₇ are each independently selected from the following: C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₃ -C ₆ cycloalkyl Y is absent or is -CO- or -CO-NH-, the corresponding arrangement of Y, A and L is -A-CO-L-, -A-CO-NH-L-, -A-L-, fragment A contains at least at least one nitrogen atom and Y is attached to the nitrogen atom, A is: i) heterocyclyl selected from the following: , n ₁₀ is 0, 1, 2, 3, 4 or 5; Y ₁ is selected from hydrogen, cyano group, selected from substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl and 6-10 membered aryl or 5-10 membered heteroaryl selected from thienyl, pyridyl, phenyl, benzothienyl, benzimidazolyl, indolyl, naphthyl , quinolinyl, isoquinolinyl; each R ₁₀ independently represents: halogen, cyano group, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ haloalkoxy, when n ₁₀ > 1, R ₁₀ may be the same or different; Y ₄ and Y ₅ are absent or represent one or more substituents on the heterocyclic ring, with Y ₄ and Y ₅ each independently representing phenyl; ii) a fused heterocyclyl selected from: , n ₈ represents 0 or 1; X ₄ represents C or O; each R ₈ is independently selected from hydrogen or halogen; with the proviso that, when each R ₈ mentioned above is independently selected from hydrogen or halogen and when Y is absent, X ₁ is not -O-; Y ₆ and Y ₇ are absent or represent one or more substituents on the heterocyclic ring, each independently selected from methyl, ethyl; or iii) a spiroheterocyclic group selected from: where n ₉ represents 0 or 1; R ₉ is independently selected from the following substituents: halogen, linear C ₁ -C ₆ alkyl, linear C ₁ -C ₆ alkoxy; Y ₈ is a substituent that does not replace a hydrogen atom in the non-aromatic portion of the spiro ring structure; and when Y is selected from -NH-CO-, -NH-CO-NH-, -NH-CO-CH(NHR _a9 )- or -CH(NHR _a9 )-, the corresponding arrangement of Y, A and L is A-NH -CO-L-, A-NH-CO-NH-L-, A-NH-CO-CH(NHR _a9 )-L- or A-CH(NHR _a9 )-L-, then A is: n ₁ is 0, 1 or 2; each R ₅ is independently selected from halogen, linear C ₁ -C ₆ alkyl, linear C ₁ -C ₆ alkoxyl, 5-6 membered heteroaryl, 3-6 membered heterocyclyl, phenyloxyl, when n ₁ > 1, all R ₅ may be the same or different; R _a9 is selected from hydrogen, substituted or unsubstituted C ₁ -C ₁₀ alkylcarbonyl, substituted or unsubstituted C ₃ -C ₈ cycloalkylcarbonyl, C ₃ -C ₈ heterocycloalkylcarbonyl, where "substituted" means that the end of the carbon chain is substituted with a hydroxyl or amino group. 4. A compound according to claim 1 or an enantiomer, racemate or pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of any of formulas (I-1) to (I-5) and (I-7): where X ₁ represents -CH ₂ - or -O-; X ₂ represents -CH ₂ - or -CO-; R ₁ represents hydrogen; R ₂ and R ₄ are independently selected from hydrogen; R ₃ represents hydrogen or fluorine; L represents a substituted or unsubstituted linear alkylene group containing 2-8 carbon atoms, wherein "substituted" means that one or more hydrogen atoms in the alkylene group are optionally substituted with the following substituents: -NHC(O)Ra ₁ , -NRa ₃ Ra ₄ , where Ra ₁ , Ra ₃ and Ra ₄ are each independently selected from hydrogen or unsubstituted C _3-6 cycloalkyl; Y is absent or represents -CO- or -CO-NH-; n ₉ represents 0 or 1; benzene ring or pyridine ring; Y ₈ is a substituent that does not replace a hydrogen atom in the non-aromatic portion of the spiro ring structure; R ₉ is independently selected from the following substituents: halogen, linear C ₁ -C ₆ alkyl, linear C ₁ -C ₆ alkoxy. 5. A compound according to claim 1 or an enantiomer, racemate or pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of any of formulas (I-9) to (I-13) and (I-15): , where X ₁ represents -CH ₂ - or -O-; X ₂ represents -CH ₂ - or -CO-; R ₁ represents hydrogen; R ₂ and R ₄ are each independently hydrogen; R ₃ represents hydrogen or fluorine; L represents a substituted or unsubstituted linear alkylene group containing 2-8 carbon atoms, wherein "substituted" means that one or more hydrogen atoms in the alkylene group are optionally substituted with the following substituents: -NHC(O)Ra ₁ , -NRa ₃ Ra ₄ , where Ra ₁ , Ra ₃ and Ra ₄ are each independently selected from hydrogen or unsubstituted C _3-6 cycloalkyl; Y is absent or represents -CO- or -CO-NH-; n ₉ represents 0 or 1; R ₉ is independently selected from the following substituents: halogen, linear C ₁ -C ₆ alkyl, linear C ₁ -C ₆ alkoxy; Y ₈ is a substituent that does not replace a hydrogen atom in the non-aromatic portion of the spiro ring structure. 6. A compound according to claim 1 or an enantiomer, racemate or pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formulas (I-17) or (I-18): , where X ₁ represents -CH ₂ - or -O-; X ₂ represents -CH ₂ - or -CO-; R ₁ represents hydrogen; R ₂ and R ₄ are each independently hydrogen; R ₃ is selected from hydrogen or fluorine; L represents a substituted or unsubstituted linear alkylene group containing 2-8 carbon atoms, wherein "substituted" means that one or more hydrogen atoms in the alkylene group are optionally substituted with the following substituents: -NHC(O)Ra ₁ , -NRa ₃ Ra ₄ , where Ra ₁ , Ra ₃ and Ra ₄ are each independently selected from hydrogen or unsubstituted C _3-6 cycloalkyl; Y is absent or represents -CO- or -CO-NH-; n ₁₀ is 0, 1, 2, 3, 4 or 5; each Y ₁ is independently selected from hydrogen, cyano; selected from substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl and 6-10 membered aryl or 5-10 membered heteroaryl selected from thienyl, pyridyl, phenyl, benzothienyl, benzimidazolyl, indolyl, naphthyl , quinolinyl, isoquinolinyl; each R ₁₀ is independently selected from the following: halogen, cyano, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ haloalkoxy, when n ₁₀ > 1, R ₁₀ may be same or different. 7. The compound according to claim 1 or its enantiomer, racemate, pharmaceutically acceptable salt, wherein the compound of formula (I) is a compound of any of formulas (I-19) - (I-23): where X ₁ represents -CH ₂ - or -O-; X ₂ represents -CH ₂ - or -CO-; R ₁ represents hydrogen; R ₂ and R ₄ are each independently hydrogen; R ₃ represents hydrogen or fluorine; L represents a substituted or unsubstituted linear alkylene group containing 2-8 carbon atoms, wherein "substituted" means that one or more hydrogen atoms in the alkylene group are optionally substituted with the following substituents: -NHC(O)Ra ₁ , -NRa ₃ Ra ₄ , where Ra ₁ , Ra ₃ and Ra ₄ are each independently selected from hydrogen or unsubstituted C _3-6 cycloalkyl; Y is absent or represents -CO- or -CO-NH-; n ₈ represents 0 or 1; X ₄ represents C or O; each R ₈ independently represents hydrogen or halogen; when R ₈ is selected from hydrogen or halogen and when Y is absent, X ₁ is not -O-; Y ₆ and Y ₇ are absent or represent one or more substituents on the heterocyclic ring, each independently selected from methyl, ethyl. 8. A compound according to claim 1 or an enantiomer, racemate or pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of any of formulas (I-24) to (I-32): where X ₂ represents -CH ₂ - or -CO-; R ₁ represents hydrogen; R ₂ and R ₄ are each independently hydrogen; R ₃ is selected from hydrogen or fluorine; L represents a substituted or unsubstituted linear alkylene group containing 2-8 carbon atoms, wherein "substituted" means that one or more hydrogen atoms in the alkylene group are optionally substituted with the following substituents: -NHC(O)Ra ₁ , -NRa ₃ Ra ₄ , where Ra ₁ , Ra ₃ and Ra ₄ are each independently selected from hydrogen or unsubstituted C _3-6 cycloalkyl; Y is absent or represents -CO- or -CO-NH-; n ₈ selected from 0 or 1; n ₉ represents 0 or 1; n ₁₀ is 0, 1, 2, 3, 4 or 5; X ₄ represents C or O; R ₉ is selected from the following substituents: halogen, linear C ₁ -C ₆ alkyl, linear C ₁ -C ₆ alkoxy; selected from substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl and 6-10 membered aryl or 5-10 membered heteroaryl selected from thienyl, pyridyl, phenyl, benzothienyl, benzimidazolyl, indolyl, naphthyl , quinolinyl, isoquinolinyl; each R ₁₀ is independently selected from the following: halogen, cyano, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ haloalkoxy, when n ₁₀ > 1, R ₁₀ may be same or different; each R ₈ is independently selected from hydrogen or halogen; with the proviso that when R ₈ is selected from hydrogen or halogen and Y is absent, X ₁ is other than -O-. 9. The compound according to claim 1 or its enantiomer, racemate, pharmaceutically acceptable salt, wherein the compound of formula (I) is a compound of any of formulas (I-33) - (I-40): where X ₂ represents -CH ₂ - or -CO-; R ₁ represents hydrogen; R ₂ and R ₄ are each independently hydrogen; R ₃ represents hydrogen or fluorine; L represents a substituted or unsubstituted linear alkylene group containing 2-8 carbon atoms, wherein "substituted" means that one or more hydrogen atoms in the alkylene group are optionally substituted with the following substituents: -NHC(O)Ra ₁ , -NRa ₃ Ra ₄ , where Ra ₁ , Ra ₃ and Ra ₄ are each independently selected from hydrogen or unsubstituted C _3-6 cycloalkyl; Y is absent or represents -CO- or -CO-NH-; n ₈ represents 0; n ₉ represents 0 or 1; n ₁₀ is 0, 1, 2, 3, 4 or 5; X ₄ selected from C or O; each R ₉ is independently selected from the following substituents: halogen, linear C ₁ -C ₆ alkyl, linear C ₁ -C ₆ alkoxy; selected from substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl and 6-10 membered aryl or 5-10 membered heteroaryl selected from thienyl, pyridyl, phenyl, benzothienyl, benzimidazolyl, indolyl, naphthyl , quinolinyl, isoquinolinyl; each R ₁₀ is independently selected from the following: halogen, cyano, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ haloalkoxy, when n ₁₀ > 1, R ₁₀ may be same or different; each R ₈ is independently selected from hydrogen or halogen; with the proviso that when R ₈ is selected as any of the following substituents: hydrogen or halogen and when Y is absent, X ₁ is not -O-. 10. A compound according to claim 1 or an enantiomer, racemate or pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of any of formulas (I-41) - (I-44) and (I-47) - (I -48): , where X ₁ represents -CH ₂ - or -O-; X ₂ represents -CH ₂ - or -CO-; R ₁ represents hydrogen; R ₂ and R ₄ are each independently hydrogen; R ₃ represents hydrogen or fluorine; L represents a substituted or unsubstituted linear alkylene group containing 2-8 carbon atoms, wherein "substituted" means that one or more hydrogen atoms in the alkylene group are optionally substituted with the following substituents: -NHC(O)Ra ₁ , -NRa ₃ Ra ₄ , where Ra ₁ , Ra ₃ and Ra ₄ are each independently selected from hydrogen or unsubstituted C _3-6 cycloalkyl; n ₁₁ is the same as b ₁ in paragraph 1; n ₂ represents 0 or 1; n ₃ represents 0 or 1; each R ₆ and R ₇ is independently selected from the following groups: C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or C ₃ -C ₆ cycloalkyl. 11. A compound according to claim 1 or an enantiomer, racemate or pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of any of formulas (I-49) to (I-51): where X ₁ represents -CH ₂ - or -O-; X ₂ represents -CH ₂ - or -CO-; R ₁ represents hydrogen; R ₂ and R ₄ are independently selected from hydrogen; R ₃ represents hydrogen or fluorine; L represents a substituted or unsubstituted linear alkylene group containing 2-8 carbon atoms, wherein "substituted" means that one or more hydrogen atoms in the alkylene group are optionally substituted with the following substituents: -NHC(O)Ra ₁ , -NRa ₃ Ra ₄ , where Ra ₁ , Ra ₃ and Ra ₄ are each independently selected from hydrogen or unsubstituted C _3-6 cycloalkyl; Y is selected from -NH-CO-, -NH-CO-NH-, -NH-CO-CH(NHR _a9 )- or -CH(NHR _a9 )-; n ₁ is 0, 1 or 2; each R ₅ is independently selected from halogen, linear C ₁ -C ₆ alkyl, linear C ₁ -C ₆ alkoxyl, 5-6 membered heteroaryl, 3-6 membered heterocyclyl, phenyloxyl, when n ₁ > 1, all R ₅ may be the same or different; R _a9 is selected from hydrogen, substituted or unsubstituted C ₁ -C ₁₀ alkylcarbonyl, substituted or unsubstituted C ₃ -C ₈ cycloalkylcarbonyl, C ₃ -C ₈ heterocycloalkylcarbonyl, where "substituted" means that the end of the carbon chain is substituted with a hydroxyl or amino group. 12. A compound and its enantiomer, racemate or pharmaceutically acceptable salt, wherein the compound is one of the following: Serial number Compound, Serial number Compound, 1 2 3 4 5 6 7 8 9 10 eleven 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 thirty 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 13. A method for producing compounds according to claim 1, in which the method includes the stages: in which the definitions of R ₁ , R ₂ , R ₃ , R ₄ and X ₂ are the same as in paragraph 1; m ₁ is an integer from 1 to 7; has the same definition as i) heterocyclyl, ii) fused heterocyclyl and iii) spiroheterocyclic group in definition A according to claim 1; Step 1-1: Compound 1C is prepared by Sonogashira coupling reaction of compounds 1A and 1B at room temperature or heating in the presence of a dipole organic solvent, a Pd catalyst, a cuprous catalyst and a base, where the dipole organic solvent is DMF or DMA, the Pd catalyst is Pd(PPh ₃ ) ₄ or Pd(PPh ₃ ) ₂ Cl ₂ , the cuprous catalyst is copper(I) iodide and the base is triethylamine or diisopropylethylamine; Step 1-2: compound 1C is reduced to compound 1D with hydrogen under Pd/C, Raney nickel or Wilkinson catalyst conditions; Step 1-3: compound 1F is prepared by reacting compound 1D with hydroxyquinoline 1E under the conditions of triphenylphosphine and diisopropyl azodiformate; Step 1-4: Compound 1D is reacted to produce compound 1G in the presence of triphenylphosphine and carbon tetrabromide; And Step 1-5: Compound 1I is prepared by reacting compound 1G with a nitrogen-containing heterocyclic compound 1H in the presence of sodium iodide, wherein compound 1H is an amino compound containing group A according to claim 1. 14. A pharmaceutical composition for the manufacture of a medicinal product for the treatment of diseases associated with the CRL4 ^CRBN E3 ubiquitin ligase, in which such pharmaceutical composition contains a therapeutically effective dose of a compound of formula (I) according to any one of claims. 1-12 or its enantiomer, racemate or pharmaceutically acceptable salt and at least one pharmaceutically acceptable carrier. 15. Use of a compound of formula (I), its enantiomer, racemate, pharmaceutically acceptable salt thereof according to claim 1 for the manufacture of a medicament for the treatment of diseases associated with the CRL4 ^CRBN E3 ubiquitin ligase. 16. Use according to claim 15, wherein the diseases are selected from the group consisting of cancer and diseases of the immune system.