USP7 inhibitors

Abstract

The invention relates to a USP7 inhibitor as shown in a formula (I), a preparation method thereof and application of the USP7 inhibitor in treatment of tumor diseases. In the preparation process, the compound is obtained through a series of reactions such as substitution, coupling, SNAr, deprotection and the like. # imgabs0 #

Description

Technical Field

[0001] The present application relates to a USP7 inhibitor, a preparation method thereof and its therapeutic use in tumor diseases. Background Art

[0002] Ubiquitin-specific protease 7 (USP7), also known as herpesvirus-associated ubiquitin specific protease (HAUSP), is located at the key nodes of many signaling pathways and participates in cell and other life activities by regulating the biological activities of many proteins such as tumor suppressor genes, DNA repair proteins, immune responders, viral proteins and epigenetic modification proteins. Human USP7 is composed of 1102 amino acids with a molecular weight of about 135kDa. It includes four domains, of which the N-amino terminal TRAF region, the catalytic region and the 64kDa C-carboxyl terminal have been identified. The N-amino terminal TRAF region is responsible for directly binding to substrate proteins (such as p53, MDM2, etc.), mainly affecting the interaction between proteins. The catalytic region contains two highly conserved histidine boxes and cysteine ​​boxes, which are important features of the ubiquitin protease family. The ubiquitin binding pocket is located in the catalytic region, and the formation of the ubiquitin binding pocket can activate USP7, thereby promoting USP7 to bind to ubiquitin and play a role in deubiquitination. The C-carboxyl terminal region contains two ubiquitin ligases that can interact with ubiquitin, as well as five consecutive ubiquitin-like regions. The fourth domain can interact with the mouse double minute gene protein.

[0003] Abnormal USP7 activity can cause the occurrence of tumors and virus-related diseases. Studies have shown that USP7 protein is highly expressed in cancer tissues of various malignant tumors such as multiple myeloma, colon cancer, lung cancer and prostate cancer, and this high expression is positively correlated with the occurrence and development of tumors. In particular, USP7 is a key regulator of the p53 pathway, which can deubiquitinate MDM2, increase the level of MDM2 in cells, and then downregulate p53. As a tumor suppressor protein, p53 is one of the earliest discovered tumor suppressor genes, and p53 mutations occur in more than half of human cancers. In addition to losing its own tumor suppressor function, mutant p53 can also affect wild-type p53 protein and inhibit its function, further promoting tumor formation. Therefore, inhibiting the expression of USP7 protein can be used as a potential therapeutic strategy for p53 mutant cancers.

[0004] Unlike traditional small molecule inhibitors and antagonists, protein degradation agent technology (proteolysis-targeting chimeras, PROTAC) has developed rapidly in recent years because it can induce the degradation of pathogenic target proteins, providing a new idea for new drug development. PROTAC is a drug development technology that uses the ubiquitin-proteasome system (UPS) to degrade target proteins. The two ends of the molecule contain chemical molecules with different ligands, one end is a ligand that binds to E3 ligase, and the other end is a ligand that binds to intracellular proteins. These two ligands are connected by a linker, so that they can bind to both E3 ubiquitin ligase and intracellular proteins, and recruit the targeted protein to the vicinity of E3 ubiquitin ligase to achieve polyubiquitination of the targeted protein, which is finally degraded by the proteasome. In addition, PROTAC can be recycled and will not be degraded by the proteasome. With the entry of multiple PROTAC drugs into the clinic, this technology has also become a hot spot in drug development.

[0005] The compound of the present invention has high inhibitory activity on USP7 and can be used to effectively treat tumor patients with abnormal expression of USP7. Summary of the invention

[0006] In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof,

[0007]

[0008] in,

[0009] X is -CH2- or -(CO)-,

[0010] L is -(L1) n1 -(L2) n2 -(L3) n3 -(L4) n4 -(L5) n5 -,

[0011] L1 is connected to *carbon,

[0012] L1 is -NH-(CH2) 2-16 、-C≡C-(CH2) 0-6 , or -(3-12 membered heterocyclylene)-,

[0013] L2 is -(O-(CH2)2) 1-6- ,

[0014] L3 and L4 are each independently a 3-12 membered heterocyclylene group or -(CH2) 1-6 -,

[0015] L5 is a phenylene group or a 5-6-membered heteroarylene group,

[0016] n1, n2, n3, n4 and n5 are each independently 0 or 1.

[0017] In some embodiments, X is -(CO)-.

[0018] In some embodiments, L3 and L4 are each independently a 3-6 membered heterocyclylene or -(CH2) 1-6 -.

[0019] In some embodiments, the compound of formula (I) is the following compound or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof,

[0020]

[0021]

[0022] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, and optionally comprising a pharmaceutically acceptable carrier.

[0023] On the other hand, the present invention provides a method for treating a disease associated with USP7 activity, the method comprising administering to a subject an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, or a pharmaceutical composition of the present invention; in some embodiments, the disease associated with USP7 activity is ovarian cancer, breast cancer, lung cancer, pancreatic cancer, kidney cancer, melanoma, liver cancer, colon cancer, sarcoma, brain cancer, prostate cancer, leukemia, lymphoma, or multiple myeloma.

[0024] In some embodiments of the present invention, the subject involved in the present invention is a mammal including a human;

[0025] On the other hand, the present invention provides the use of a compound of the present invention or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, or a pharmaceutical composition of the present invention in the preparation of a medicament for treating a disease associated with USP7 activity; in some embodiments, the disease associated with USP7 activity is ovarian cancer, breast cancer, lung cancer, pancreatic cancer, kidney cancer, melanoma, liver cancer, colon cancer, sarcoma, brain cancer, prostate cancer, leukemia, lymphoma, or multiple myeloma. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 .Degradation activity of Examples 2 and 4 on USP7 protein.

[0028] Figure 2 .Example 8 Degradation activity on USP7 protein.

[0029] Figure 3 .Example 13 Degradation activity on USP7 protein. DETAILED DESCRIPTION OF THE INVENTION

[0031] Exemplary embodiments utilizing the principles of the invention are set forth in the following detailed description of the invention. The features and advantages of the invention may be better understood by reference to the following summary of the invention.

[0032] It should be understood that the scope of protection of various aspects of the present invention is determined by the claims, and methods and structures within the scope of these claims and their equivalent methods and structures are all within the scope of the claims.

[0033] Unless otherwise defined, all technical terms herein have the same meaning as commonly understood by those skilled in the art to which the subject matter of the claims belongs. Unless otherwise indicated, all patents, patent applications, and public materials cited in the entirety of this article are incorporated herein by reference in their entirety.

[0034] It should be understood that the above brief description and the following detailed description are exemplary and explanatory, rather than limiting to any subject matter of the present invention. Unless otherwise specifically stated, the use of singular forms also includes the plural. Unless otherwise stated, the use of "or" and "or" means "and / or". In addition, the use of the term "including" and other forms, such as "including", "containing" and "comprising" are not limiting.

[0035] Some chemical terms

[0036] Unless otherwise indicated, conventional methods within the technical scope of the art are adopted, such as mass spectrometry, nuclear magnetic resonance, high performance liquid chromatography, infrared and ultraviolet / visible spectroscopy and pharmacological methods. Unless specifically defined, the relevant terms and experimental steps and techniques of analytical chemistry, organic synthetic chemistry, and drugs and medicinal chemistry herein are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and in the treatment of patients. For example, the instructions for use of the kit can be utilized by the manufacturer, or the reaction and purification can be implemented in a manner well known in the art or the description of the present invention. The above-mentioned techniques and methods can usually be implemented according to the description in the multiple summaries and more specific documents cited and discussed in this specification, according to conventional methods well known in the art. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural parts and compounds.

[0037] When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents that would result if the formula were written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0038] As used herein, the terms "group" and "chemical group" refer to a specific part or functional group of a molecule. A chemical group is often considered to be a chemical entity embedded in or attached to a molecule.

[0039] Some chemical groups named herein may be represented by a shorthand notation to indicate the total number of carbon atoms. For example, C1-C6 alkyl describes an alkyl group, as defined below, having a total of 1 to 6 carbon atoms. The total number of carbon atoms shown in the shorthand notation does not include the carbon atoms on possible substituents.

[0040] The terms "aromatic", "aromatic ring", "aromatic", "aromatic", "aromatic ring" refer to a planar ring or ring moiety having a delocalized electron conjugated system containing 4n+2 electrons, where n is an integer. Aromatic rings may be formed by 5, 6, 7, 8, 9 or more atoms. Aromatic compounds may be optionally substituted and may be monocyclic or polycyclic with fused rings. The term aromatic compound includes all carbon rings (such as benzene rings) and rings containing one or more heteroatoms (such as pyridine).

[0041] The term "heteroatom" or "hetero" refers to atoms other than carbon and hydrogen. Heteroatoms are independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon, selenium and tin, but are not limited to these atoms. In embodiments where two or more heteroatoms are present, the two or more heteroatoms may be the same as each other, or some or all of the two or more heteroatoms may be different from each other.

[0042] The term "heteroaryl" or "heteroarylidene" refers to a monocyclic or fused ring of 5-12 ring atoms, having 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, wherein 1, 2, 3 or 4 ring atoms are selected from N, O, S, and the remaining ring atoms are C, and have a completely conjugated π-electron system. The heteroaryl group can be unsubstituted or substituted, and the substituents include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxyl, cyano, nitro, carbonyl and heteroalicyclic groups. Non-limiting examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazinyl.

[0043] The terms "heterocyclyl", "heterocyclylene", "heterocycloalkyl", "heterocycle" refer to stable 3-18 membered monovalent non-aromatic rings, including 2-12 carbon atoms, 1-6 heteroatoms selected from nitrogen, oxygen and sulfur. Unless otherwise specified, the heterocyclyl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may contain fused rings, spirocyclic or bridged ring systems, the nitrogen, carbon or sulfur on the heterocyclyl can be optionally oxidized, the nitrogen atom can be optionally quaternized, and the heterocyclyl can be partially or fully saturated. The heterocyclyl can be connected to the rest of the molecule through a single bond via a carbon atom or heteroatom on the ring. The heterocyclyl containing fused rings can contain one or more aromatic or heteroaromatic rings, as long as the atoms on the non-aromatic rings are connected to the rest of the molecule. For the purposes of the present application, the heterocyclic group is preferably a stable 4-11 membered monovalent non-aromatic monocyclic or bicyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, and more preferably a stable 4-8 membered monovalent non-aromatic monocyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heterocyclic groups include azepanyl, azetidinyl, decahydroisoquinolinyl, dihydrofuranyl, dihydroindolinyl, dioxolanyl, 1,1-dioxo-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazinyl, piperazinyl, piperidinyl, 4-piperidonyl, pyranyl, pyrazolidinyl, pyrrolidinyl, quinolizinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, and the like.

[0044] The term "polymorph" or "polymorphism" used in the present invention refers to a compound of the present invention having multiple crystal lattice forms. Some compounds of the present invention may have more than one crystal form, and the present invention encompasses all polymorphic forms or mixtures thereof.

[0045] Intermediate compounds of the compounds of the present invention and polymorphs thereof are also within the scope of the present invention.

[0046] Unless otherwise specified, compounds of the present invention containing olefinic double bonds include both E and Z isomers.

[0047] It should be understood that the compounds of the present invention may contain asymmetric centers. These asymmetric centers may independently be in R or S configuration. Some of the compounds of the present invention may also exhibit cis-trans isomerism, which is obvious to those skilled in the art. It should be understood that the compounds of the present invention include their individual geometric isomers and stereoisomers and their mixtures, including racemic mixtures. These isomers can be separated from their mixtures by implementing or modifying known methods, such as chromatography techniques and recrystallization techniques, or they can be prepared separately from the appropriate isomers of their intermediates.

[0048] The term "pharmaceutically acceptable salt" as used herein includes both acid-added salts and base-added salts.

[0049] "Pharmaceutically acceptable salt addition" refers to salts formed with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, capric acid, caproic acid, carbonic acid, cinnamic acid, citric acid, etc. "Pharmaceutically acceptable base-added salt" refers to salts that retain the biological effectiveness and properties of the free acid of the compound and are not biologically or otherwise undesirable. These salts are prepared by reacting the free acid with an inorganic base or an organic base. Salts formed by reacting with an inorganic base include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, etc. Preferred inorganic salts are ammonium salts, sodium salts, potassium salts, calcium salts, and manganese salts.

[0050] Organic bases for forming salts include, but are not limited to, primary amines, secondary amines, tertiary amines, cyclic amines, and the like, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine, dicyclohexylamine, ethylenediamine, purine, piperazine, piperidine, choline, and caffeine. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0051] Crystallization often produces solvates of the compounds of the invention. The term "solvate" as used herein refers to a complex formed by the combination of one or more molecules of the compounds of the invention and one or more solvent molecules.

[0052] The term "pharmaceutical composition" as used herein refers to a preparation in which the compound of the present invention is mixed with a medium generally accepted in the art for delivering biologically active compounds to mammals (such as humans). Such a medium includes all pharmaceutically acceptable carriers.

[0053] Preparation of the compounds of the present invention

[0054] It should be understood that in the following description, combinations of substituent groups and / or variables of the formula are allowed only if stable compounds are formed.

[0055] Those skilled in the art will also appreciate that the functional groups of the intermediate compounds may need to be protected by suitable protecting groups. Protecting groups can be added or removed by standard techniques known to those skilled in the art.

[0056] Example 1: 4-((5-chloro-7-(2-(4-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)ethoxy)ethoxyoxy)methoxy)-3-ethyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-ylmethyl)piperidine-4-carbonitrile

[0057]

[0058]

[0059] Step 1: Synthesis of compound 2

[0060] 6-Chlorouracil (1, 10 g) was dissolved in 300 mL of dimethyl sulfoxide, potassium carbonate (4.72 g) was added and stirred evenly, and then iodoethane (32 g) was added in batches and reacted at room temperature for 5 h. Water was added to quench the reaction, and the extract was extracted with ethyl acetate. The extract was distilled under reduced pressure, and the residue was separated and purified by column chromatography (dichloromethane: methanol = 30: 1, V / V) to obtain a white solid 2 (10.3 g).

[0061] Step 2: Synthesis of compound 4

[0062] The synthesis of compound 3 refers to the patent USP7 inhibitor (International Publication No.: WO 2022 / 048498A1).

[0063] Compound 3 (2 g) and triethylamine (1.03 mL) were dissolved in 40 ml of dichloroethane. Methanesulfonic anhydride (0.97 g) was added under ice-cooling and the mixture was stirred for 0.5 h while maintaining ice-cooling. Water was added to quench the reaction. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to proceed directly to the next step.

[0064] Step 3: Synthesis of compound 5

[0065] Compound 4 (100 mg), compound 2 (34 mg) and cesium carbonate (106 mg) were dissolved in 5 mL of acetonitrile and heated to 50°C for 2 h. The solvent was removed by distillation under reduced pressure, and the residue was separated and purified by column chromatography (dichloromethane: methanol = 40: 1, V / V) to obtain a white solid 5 (64 mg).

[0066] Step 4: Synthesis of compound 7

[0067] Compound 6 (500 mg) and phthalic anhydride (501 mg) were dissolved in 10 mL of toluene and heated under reflux for 6 h. The solvent was then removed by distillation under reduced pressure to obtain an oily liquid compound 7 (1 g).

[0068] Step 5: Synthesis of compound 8

[0069] Compound 7 (35 mg), compound 5 (60 mg) and cesium fluoride (39 mg) were dissolved in 3 mL of dimethyl sulfoxide and heated to 60°C for 3 h. Water was added to quench the reaction, and a white solid precipitated. After filtration and washing, the solid was separated and purified by column chromatography (dichloromethane: methanol = 35:1, V / V) to obtain a white solid 8 (41 mg).

[0070] Step 6: Synthesis of compound 9

[0071] Compound 8 (41 mg) was dissolved in 2 mL of methanol, 2 drops of hydrazine hydrate were added, and the mixture was stirred at room temperature for 5 h. The mixture was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (dichloromethane: methanol = 15:1, V / V) to obtain an oily substance (20 ng).

[0072] Step 7: Synthesis of compound 10

[0073] Compound 9 (20 mg) and N, N-diisopropylethylamine (DIPEA, 9 μL) were dissolved in 1.5 ml of dimethyl sulfoxide, 2-(2,6-dioxapiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (7 mg) was added, and the mixture was heated to 100°C for overnight reaction. The mixture was cooled to room temperature, and water was added to quench the reaction. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by column chromatography (dichloromethane: methanol = 25:1, V / V) to obtain a light yellow solid 10 (18 mg).

[0074] Step 8: Synthesis of compound 11

[0075] Compound 10 (18 mg) was dissolved in 2 mL of dichloromethane, 0.5 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 h. The solvent was removed by concentration under reduced pressure, and the residue was separated and purified by column chromatography (dichloromethane: methanol = 10:1, V / V) to obtain a light yellow solid 11 (12.83 mg). 1H NMR (400MHz, CD3OD), 8.75-8.82 (m, 1H), 7.73-7.74 (m, 1H), 7.55-7.60 (m, 2H), 7.45-7.50 (m, 2H), 7.13 (d, J=2.0Hz, 1H), 6.96-7.02(m, 2H), 6.72-6.74(m, 1H), 5.24-5.33(m, 2H), 5.22(s, 1H), 4.94-5.01(m, 1H), 4.18-4.26(m, 2H), 4.0 2-4.06 (m, 1H), 3.80-3.91 (m, 4H), 3.60-3.72 (m, 7H), 3.41 (t, J=5.6Hz, 2H), 3.22-3.30 (m, 2H), 2.87-2.97 (m, 2H), 2 .74-2.86 (m, 1H), 2.58-2.72 (m, 2H), 1.98-2.07 (m, 1H), 1.76-1.85 (m, 1H), 1.22-1.39 (m, 3H), 1.13 (t, J=7.2Hz, 3H).

[0076] Example 2: 4-((5-chloro-7-(2-(4-((12-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)dodecyl)oxy)-3-ethyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)carbonitrile

[0077]

[0078] The synthesis method of compound 13 is as follows: Steps 4-8 of Example 1. 1H NMR (400MHz, CD3OD), 8.77-8.87 (m, 1H), 7.76 (d, J=2.0Hz, 1H), 7.64 (d, J=4.8Hz, 1H), 7.61 (s, 1H), 7.49-7.53 (m, 1H), 7.47 (d, J= 3.6Hz, 1H), 7.14 (d, J=2.0Hz, 1H), 7.01 (d, J=2.8Hz, 1H), 6.99 (s, 1H), 6.74 (d, J=3.6Hz, 1H), 5.35 (d, J=14.8Hz, 1H), 5.30 (d, J=1 4.8Hz, 1H), 5.18 (s, 1H), 5.02 (d, J=12.4Hz, 5.2Hz, 1H), 4.04-4.10 (m, 3H), 3.89-3.95 (m, 2H), 3.65 (d,.J=15.2Hz, 1H), 3.27-3.3 4(m, 4H), 2.64-2.96(m, 5H), 2.04-2.10(m, 1H), 1.75-1.82(m, 3H), 1.59-1.66(m, 2H), 1.23-1.47(m, 19H), 1.16(t, J=6.8Hz, 3H).

[0079] Example 3: 4-((5-chloro-7-(2-(4-((14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)-3,6,9,12-tetraoxotetradecyl)oxy)-3-ethyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)carbonitrile

[0080]

[0081] The synthesis method of compound 15 is as follows: Steps 4-8 of Example 1. 1H NMR (400MHz, CD3OD), 8.74-8.84 (m, 1H), 7.75 (d, J=2.0Hz, 1H), 7.58-7.60 (m, 2H), 7.46-7.50 (m, 2H), 7.13 (d, J=2.0Hz, 1H), 7.02 (d, J=8.8Hz, 1H), 6.98 (d, J=7.2Hz, 1H), 6.73 (d, J=3.2Hz, 1H), 5.34 (d, J=15.2Hz, 1H), 5.28 (d, J=15.2Hz, 1H), 5.19 (s, 1H), 5.00 (dd, J= 12.4Hz, 5.2Hz, 1H), 4.19-4.21(m, 2H), 4.04(d, J=15.2Hz, 1H), 3.92(q, J=7.2Hz, 2H), 3.79-3.81(m, 2H), 3.52-3.66(m, 15H), 3.43(t , J=5.6Hz, 2H), 3.24-3.30 (m, 2H), 2.60-2.96 (m, 5H), 2.00-2.08 (m, 1H), 1.76-1.84 (m, 1H), 1.22-1.39 (m, 3H), 1.15 (t, J=7.2Hz, 3H).

[0082] Example 4: 4-((5-chloro-7-(2-((4-((10-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)decyl)oxy)-3-ethyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)carbonitrile

[0083]

[0084] The synthesis method of compound 17 is as follows: Steps 4-8 of Example 1. 1H NMR (400MHz, CD3OD), 8.79 (d, J=4.8Hz, 1H), 7.76 (d, J=2.0Hz, 1H), 7.56-7.60 (m, 2H), 7.50-7.54 (m, 1H), 7.47 (d, J=3.6Hz, 1H) , 7.14 (d, J = 2.0Hz, 1H), 7.02 (d, J = 3.2Hz, 1H), 7.00 (s, 1H), 6.74 (d, J = 3.6Hz, 1H), 5.35 (d, J = 14.8Hz, 1H), 5.30 (d, J = 14.8Hz, 1 H), 5.19 (s, 1H), 5.03 (dd, J = 12.4Hz, 5.2Hz, 1H), 4.03-4.11 (m, 3H), 3.92 (q, J = 7.2Hz, 2H), 3.67 (d, J = 15.2Hz, 1H), 3.23-3.34 ( m, 4H), 2.64-2.98 (m, 5H), 2.03-2.11 (m, 1H), 1.75-1.86 (m, 3H), 1.60-1.67 (m, 2H), 1.21-1.50 (m, 15H), 1.16 (t, J=7.2Hz, 3H).

[0085] Example 5: 4-((5-chloro-7-(2-((4-((14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)tetradecyl)oxy)-3-ethyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0086]

[0087] The synthesis method of compound 19 refers to steps 4-8 of Example 1. 1H NMR (400MHz, CD3OD), 8.81 (d, J=3.6Hz, 1H), 7.77 (d, J=2.0Hz, 1H), 7.63 (d, J=4.8Hz, 1H), 7.61 (s, 1H), 7.50-7.54 (m, 1H), 7.48 (d, J= 3.6Hz, 1H), 7.16 (d, J=2.0Hz, 1H), 7.01 (d, J=3.6Hz, 1H), 7.00 (d, J=2.0Hz, 1H), 6.75 (d, J=3.6Hz, 1H), 5.37 (d, J=14.8Hz, 1H), 5.31 (d , J=14.8Hz, 1H), 5.19 (s, 1H), 5.03 (dd, J=12.8Hz, 5.2Hz, 1H), 4.04-4.11 (m, 3H), 3.93 (q, J=7.2Hz, 2H), 3.68 (d, J=15.2Hz, 1H), 3.26 -3.35 (m, 4H), 2.64-2.96 (m, 5H), 2.04-2.11 (m, 1H), 1.76-1.84 (m, 3H), 1.60-1.68 (m, 2H), 1.22-1.48 (m, 23H), 1.17 (t, J=7.2Hz, 3H).

[0088] Example 6: 4-((5-chloro-7-(2-((4-((8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)octyl)oxy)-3-ethyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)carbonitrile

[0089]

[0090] The synthesis method of compound 21 is as follows: Steps 4-8 of Example 1. 1H NMR (400MHz, CD3OD), 8.79-8.91 (m, 1H), 7.77 (d, J=2.0Hz, 1H), 7.69 (d, J=4.8Hz, 1H), 7.64 (s, 1H), 7.48-7.53 (m, 2H), 7.17 (d, J=2.0Hz, 1H), 7.01 (d, J=3.6Hz, 1H), 6.99 (d, J=2.0Hz, 1H), 6.75 (d, J=3.2Hz, 1H), 5.36 (d, J=15.2Hz, 1H), 5.32 (d, J=15 .2Hz, 1H), 5.19 (s, 1H), 4.99-5.04 (m, 1H), 4.054.18 (m, 3H), 3.91 (q, J=6.8Hz, 2H), 3.67 (d, J=15.2Hz, 1H), 3.24-3.32 (m, 4 H), 2.63-2.96 (m, 5H), 2.02-2.10 (m, 1H), 1.74-1.84 (m, 3H), 1.60-1.68 (m, 2H), 1.24-1.49 (m, 11H), 1.18 (t, J=6.8Hz, 3H).

[0091] Example 7: 4-((5-chloro-7-(2-(4-(2-(2-(-2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)ethoxy)ethoxy)ethoxyoxy)methoxy)-3-ethyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)carbonitrile

[0092]

[0093] The synthesis method of compound 23 is as follows: Steps 4-8 of Example 1. 1H NMR (400MHz, CD3OD), 8.76-8.86 (m, 1H), 7.75 (s, 1H), 7.58-7.64 (m, 2H), 7.46-7.50 (m, 2H), 7.14 (d, J=1.6Hz, 1H), 7.01 (d, J=8.8H z, 1H), 6.97 (dd, J=8.8Hz, 2.0Hz, 1H), 6.74 (d, J=3.2Hz, 1H), 5.33 (d, J=14.8Hz, 1H), 5.28 (d, J=14.8Hz, 1H), 5.19 (s, 1H), 4.98-5. 04 (m, 1H), 4.16-4.22 (m, 2H), 4.05 (d, J=14.8Hz, 1H), 3.91 (q, J=7.2Hz, 2H), 3.78-3.83 (m, 2H), 3.55-3.69 (m, 11H), 3.42 (t, J=4.8 Hz, 2H), 3.22-3.29 (m, 2H), 2.62-2.97 (m, 5H), 1.99-2.09 (m, 1H), 1.81 (d, J=15.2Hz, 1H), 1.22-1.40 (m, 3H), 1.15 (t, J=7.2Hz, 3H).

[0094] Example 8: 4-((5-chloro-7-(2-((4-(4-((11-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)undecyl)amino)methyl)phenyl)-3-ethyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)carbonitrile

[0095]

[0096] Step 1: Synthesis of compound 24

[0097] Under nitrogen protection, compound 2 (2 g), 4-formylphenylboronic acid (CAS: 87199-17-5, 2.58 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (CAS: 72287-26-4, 0.8 g) and sodium carbonate (3.65 g) were dissolved in 40 mL of 1,4-dioxane, 10 mL of water was added, and the mixture was heated to 100° C. and reacted overnight. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (dichloromethane: methanol = 30: 1, V / V) to obtain a white solid 24 (2.6 g).

[0098] Step 2: Synthesis of compound 25

[0099] Compound 4 (1 g), compound 24 (416 mg) and cesium carbonate (1.1 g) were dissolved in 20 mL of acetonitrile and heated to 50°C for 2 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified by column chromatography (dichloromethane: methanol = 50: 1, V / V) to obtain a white solid 25 (857 mg).

[0100] Step 3: Synthesis of compound 27

[0101] Compound 2-(2,6-dioxapiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (500 mg), compound 26 (623 mg) and N,N-diisopropylethylamine (632 mg) were dissolved in 5 mL of dimethyl sulfoxide and heated to 100°C for overnight reaction. Water was added to quench the reaction, and the extract was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was separated and purified by column chromatography (dichloromethane: methanol = 50: 1, V / V) to obtain a yellow solid 27 (887 mg).

[0102] Step 4: Synthesis of compound 28

[0103] Compound 27 (887 mg) was dissolved in 2 mL of dichloromethane, 5 mL of 1,4-dioxane hydrochloride solution (4 M) was added, and the mixture was stirred at room temperature for 1 h. The solvent was directly distilled off under reduced pressure to obtain a yellow solid 28 (723 mg).

[0104] Step 5: Synthesis of compound 29

[0105] Compound 28 (24 mg) and compound 25 (36 mg) were dissolved in 2 mL of 1,2-dichloroethane, and two drops of glacial acetic acid were added, and the mixture was stirred at room temperature for 2 h. Then sodium triacetyl borohydride (31 mg) was added, and the mixture was stirred overnight. The solvent was directly distilled off under reduced pressure, and the residue was separated and purified by column chromatography (dichloromethane: methanol = 25:1, V / V) to obtain a yellow solid 29 (37 mg).

[0106] Step 6: Synthesis of compound 30

[0107] Compound 29 (37 mg) was dissolved in 2 mL of dichloromethane, 0.5 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 h. The solvent was then removed by direct concentration under reduced pressure, and the residue was separated and purified by column chromatography (dichloromethane: methanol = 10:1, V / V) to obtain a light yellow solid 11 (23 mg). 1H NMR (400MHz, CD3OD), 8.74-8.90 (m, 1H), 7.75 (d, J = 1.6Hz, 1H), 7.58-7.68 (m, 4H), 7.47-7.52 (m, 4H), 7.12 (d, J = 1.6Hz, 1 H), 7.00 (s, 1H), 6.98 (s, 1H), 6.74 (d, J = 3.2Hz, 1H), 5.60 (s, 1H), 5.43 (d, J = 14.8Hz, 1H), 5.36 (d, J = 14.8Hz, 1H), 5.02 (d d, J=12.4Hz, 5.6Hz, 1H), 4.25 (s, 2H), 4.07 (d, J=15.2Hz, 1H), 3.62-3.70 (m, 3H), 3.26-3.33 (m, 2H), 3.01-.05 (m, 2H), 2. 62-2.98 (m, 6H), 2.02-2.11 (m, 1H), 1.82 (d, J=14.4Hz, 1H), 1.57-1.73 (m, 5H), 1.18-1.46 (m, 17H), 1.01 (t, J=7.2Hz, 3H).

[0108] Example 9: 4-((5-chloro-7-(2-(4-(4-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)ethoxy)ethoxy)ethyl)amino)methyl)phenyl)-3-ethyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)carbonitrile

[0109]

[0110] The synthesis method of compound 32 refers to steps 3-6 of Example 8. 1H NMR (400MHz, CD3OD), 8.74-8.89 (m, 1H), 7.75 (d, J=2.0Hz, 1H), 7.65 (s, 1H), 7.61 (d, J=4.4Hz, 1H), 7.57 (d, J=8.0Hz, 2H), 7.46-7.50 (m, 2 H), 7.43 (d, J = 8.0Hz, 2H), 7.14 (d, J = 2.0Hz, 1H), 7.03 (d, J = 8.8Hz, 1H), 6.97 (d, J = 7.2Hz, 1H), 6.74 (d, J = 3.2Hz, 1H), 5.55 (s, 1H), 5.43 (d , J=14.8Hz, 1H), 5.36 (d, J=14.8Hz, 1H), 5.01 (dd, J=12.4Hz, 5.6Hz, 1H), 4.28 (s, 2H), 4.08 (d, J=15.2Hz, 1H), 3.58-3.80 (m, 12H), 3.48 (t .

[0111] Example 10: 4-((5-chloro-7-(2-(4-(4-(13-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)-5,8,11-trioxa-2-azatridecyl)phenyl)-3-ethyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)carbonitrile

[0112]

[0113] The synthesis method of compound 34 is as follows: Steps 3-6 of Example 8. 1H NMR (400MHz, CD3OD), 8.78-8.88 (m, 1H), 7.76 (d, J=2.0Hz, 1H), 7.67 (s, 1H), 7.63 (d, J=4.8Hz, 1H), 7.60 (d, J=8.4Hz, 2H), 7.45-7.50 (m, 4H), 7.15 (d, J=1.6Hz, 1H), 7.02 (d, J=8.4Hz, 1H), 6.99 (d, J=7.2Hz, 1H), 6.75 (d, J=3.6Hz, 1H), 5.55 (s, 2H), 5.44 (d, J=14.8Hz, 1H), 5.37 (dd, J=14.8Hz, 1H), 5.02 (dd, J=12.4Hz, 5.6Hz, 1H), 4.29 (s, 2H), 4.09 (d, J=15.2Hz, 1H), 3.74-3.76 (m, 2H), 3.59-3.72 (m, 14H), 3.44 (t, J=5.2Hz, 1H), 3.24-3.36 (m, 3H), 2.61-2.98 (m, 5H), 2.01-2.10 (m, 1H), 1.83 (d, J=14.4Hz, 1H), 1.24-1.46 (m, 3H), 0.99 (t, J=7.2Hz, 3H).

[0114] Example 11: 4-((5-chloro-7-(2-(4-(4-(16-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)-5,8,11,14-tetraoxo-2-azahexadecyl)phenyl)-3-ethyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)carbonitrile

[0115]

[0116] The synthesis method of compound 36 refers to steps 3-6 of Example 8. 1H NMR (400MHz, CD3OD), 8.72-8.96 (m, 1H), 7.75 (d, J=2.0Hz, 1H), 7.58-7.70 (m, 4H), 7.45-7.50 (m, 4H), 7.13 (d, J=2.0Hz, 1H), 7.0 0 (d, J=3.2Hz, 1H), 6.98 (d, J=2.4Hz, 1H), 6.74 (d, J=3.2Hz, 1H), 5.57 (s, 1H), 5.43 (d, J=14.8Hz, 1H), 5.35 (d, J=14.8Hz, 1H), 5. 01 (dd, J=12.4Hz, 5.6Hz, 1H), 4.30 (s, 2H), 4.08 (d, J=15.2Hz, 1H), 3.74 (t, J=4.8Hz, 2H), 3.56-3.70 (m, 18H), 3.41 (t, J=4.8Hz, 2H), 3.23-3.33 (m, 3H), 2.60-2.97 (m, 5H), 1.99-2.09 (m, 1H), 1.82 (d, J=13.2Hz, 1H), 1.24-1.46 (m, 3H), 0.99 (t, J=7.2Hz, 3H).

[0117] Example 12: 4-((5-chloro-7-(2-((4-(4-((7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptyl))amino)methyl)phenyl)-3-ethyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-ylmethyl)piperidine-4-carbonitrile

[0118]

[0119] The synthesis method of compound 38 is as follows: Steps 3-6 of Example 8. 1H NMR (400MHz, CD3OD), 8.82 (s, 1H), 7.76 (s, 1H), 7.65 (s, 1H), 7.59-7.64 (m, 3H), 7.50-7.56 (m, 3H), 7.48 (d, J=3.2Hz, 1H), 7.14 (s, 1H), 7.01-7.03 (m, 2H), 6.75 (d, J=3.6Hz, 1H), 5.61 (s, 1H), 5.44 (d, J=14.8Hz, 1H), 5.37 (d, J=14.8Hz, 1H), 5.03 ( dd, J=12.4Hz, 5.6Hz, 1H), 4.25 (s, 2H), 4.09 (d, J=14.8Hz, 1H), 3.63-3.71 (m, 3H), 3.26-3.34 (m, 4H), 3.03-3.07 (m, 2H), 2 .66-2.98 (m, 5H), 2.04-2.12 (m, 1H), 1.84 (d, J=14.4Hz, 1H), 1.62-1.75 (m, 4H), 1.24-1.50 (m, 9H), 1.01 (t, J=7.2Hz, 3H).

[0120] Example 13: 4-((5-chloro-7-(2-((4-(4-((13-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)tridecyl)amino)methyl)phenyl)-3-ethyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)carbonitrile

[0121]

[0122] The synthesis method of compound 40 is shown in step 3-6 of Example 8. 1H NMR (400MHz, CD3OD), 8.74-8.92 (m, 1H), 7.76 (d, J=2.0Hz, 1H), 7.67 (s, 1H), 7.60-7.65 (m, 3H), 7.49-7.54 (m, 3H), 7.48 (d, J=3.6 Hz, 1H), 7.14 (d, J=1.6Hz, 1H), 7.01 (s, 1H), 6.99 (s, 1H), 6.75 (d, J=3.2Hz, 1H), 5.61 (s, 1H), 5.44 (d, J=14.8Hz, 1H), 5.37 (d, J=1 4.8Hz, 1H), 5.03 (dd, J=12.4Hz, 5.6Hz, 1H), 4.26 (s, 2H), 4.08 (d, J=15.2Hz, 1H), 3.63-3.72 (m, 3H), 3.27-3.34 (m, 4H), 3.02-3.0 6 (m, 2H), 2.66-2.98 (m, 5H), 2.03-2.12 (m, 1H), 1.79-1.86 (m, 1H), 1.60-1.74 (m, 4H), 1.24-1.46 (m, 21H), 1.01 (t, J=6.8Hz, 3H).

[0123] Example 14: 4-((5-chloro-7-(2-((4-(4-(((9-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)nonyl))amino)methyl)phenyl)-3-ethyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-ylmethyl)piperidine-4-carbonitrile

[0124]

[0125] The synthesis method of compound 42 is shown in step 3-6 of Example 8. 1H NMR (400MHz, CD3OD), 8.79-8.91 (m, 1H), 7.77 (d, J=2.0Hz, 1H), 7.69 (s, 1H), 7.67 (d, J=5.2Hz, 1H), 7.62 (d, J=8.4Hz, 2H), 7.49-7 .54 (m, 4H), 7.16 (d, J = 2.0Hz, 1H), 7.02 (s, 1H), 7.00 (s, 1H), 6.76 (d, J = 3.2Hz, 1H), 5.61 (s, 1H), 5.45 (d, J = 14.8Hz, 1H), 5.38 (d, J =14.8Hz, 1H), 5.03 (dd, J = 12.4Hz, 5.2Hz, 1H), 4.25 (s, 2H), 4.09 (d, J = 15.2Hz, 1H), 3.64-3.71 (m, 3H), 3.28-3.34 (m, 4H), 3.02-3. 06 (m, 2H), 2.64-2.98 (m, 5H), 2.04-2.12 (m, 1H), 1.78-1.86 (m, 1H), 1.60-1.74 (m, 4H), 1.26-1.48 (m, 13H), 1.01 (t, J=6.8Hz, 3H).

[0126] Example 15: 4-(5-chloro-7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)-2,6-dioxopiperazin-1-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0127]

[0128] Step 1: Synthesis of compound 44

[0129] Compound 43 (500 mg) was dissolved in 10 mL of N,N-dimethylformamide, and sodium hydride (60% purity, 80 mg) was added in batches under ice-cooling. 2-(Trimethylsilyl)ethoxymethyl chloride (302 mg) was added after 10 minutes, and the mixture was removed and stirred at room temperature for 2 h. Saturated aqueous ammonium chloride was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was separated and purified by column chromatography (dichloromethane:methanol=50:1, V / V) to give 44 (366 mg) as an off-white solid.

[0130] Step 2: Synthesis of Compound 46 Reference Example 8 Step 4.

[0131] Step 3: Synthesis of compound 47

[0132] Compound 46 (200 mg) was dissolved in 5 mL of dichloromethane, and Dess-Martin periodinane (239 mg) was added under ice-bath cooling, and then stirred at room temperature for 2 h. Saturated sodium bicarbonate solution and sodium thiosulfate solution were added to the reaction solution to quench the reaction, the organic phase was separated, the aqueous phase was extracted with dichloromethane, the extract was washed with water, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was separated and purified by column chromatography (dichloromethane: methanol = 50: 1, V / V) to obtain yellow solid 57 (153 mg).

[0133] Step 4: Synthesis of Compound 48 Refer to Step 5 in Example 8.

[0134] Step 5: Synthesis of Compound 49 Refer to Step 3 in Example 1.

[0135] Step 6: Synthesis of compound 50

[0136] Compound 49 (50 mg) was dissolved in 2 mL of dichloromethane, and 0.5 mL of trifluoroacetic acid was added and stirred at room temperature for 2 h. The trifluoroacetic acid was distilled off under reduced pressure, and the residue was dissolved in 2 mL of methanol, and sodium bicarbonate (11 mg) was added and stirred at room temperature for 0.5 h. Then the solvent was distilled off under reduced pressure, and the residue was separated and purified by column chromatography (dichloromethane: methanol = 10: 1, V / V) to obtain a light yellow solid 50 (21 mg). 1 H NMR (400MHz, CD3OD), 8.78 (d, J=4.4Hz, 1H), 7.76 (d, J=1.6Hz, 1H), 7.57 (d, J=4.8Hz, 1H), 7.50-7.54 (m, 2H), 7.47 (d, J =3.2Hz, 1H), 7.14 (d, J = 2.0Hz, 1H), 7.02 (s, 1H), 7.00 (d, J = 2.8Hz, 1H), 6.74 (d, J = 3.2Hz, 1H), 5.22 (d, J = 15.2Hz, 1H), 5.14 (d, J=15.2Hz, 1H), 5.03 (dd, J=12.4Hz, 5.2Hz, 1H), 4.07 (d, J=14.8Hz, 1H), 3.63 (d, J=14.8Hz, 1H), 3.47 (s, 4H), 3 .24-3.33(m, 4H), 2.65-2.97(m, 5H), 2.45(t, J=7.2Hz, 2H), 1.99-2.11(m, 1H), 1.80-1.86(m, 1H), 1.20-1.75(m, 15H).

[0137] Example 16: 4-(5-chloro-7-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)dodecyl)-2,6-dioxopiperazin-1-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0138]

[0139] The synthesis method of compound 52 is based on the steps of Example 15. 1 H NMR (400MHz, CD3OD), 8.76-8.88 (m, 1H), 7.77 (d, J=2.0Hz, 1H), 7.64 (d, J=4.8Hz, 1H), 7.58 (s, 1H), 7.50-7.54 (m, 1H), 7.48 (d , J=3.2Hz, 1H), 7.15 (d, J=2.0Hz, 1H), 7.02 (d, J=2.8Hz, 1H), 7.00 (s, 1H), 6.75 (d, J=3.2Hz, 1H), 5.23 (d, J=15.2Hz, 1H), 5.16 (d, J=15.2Hz, 1H), 5.03 (dd, J=12.4Hz, 5.2Hz, 1H), 4.07 (d, J=15.2Hz, 1H), 3.65 (d, J=15.2Hz, 1H), 3.55 (s, 4H), 3.22-3.34 (m , 4H), 2.64-2.98(m, 5H), 2.50-2.54(m, 2H), 2.03-2.11(m, 1H), 1.81(d, J=13.6Hz, 1H), 1.60-1.67(m, 2H), 1.14-1.50(m, 21H).

[0140] Example 17: 4-(5-chloro-7-(2-(4-(14-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)tetradecyl)-2,6-dioxopiperazin-1-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0141]

[0142] The synthesis method of compound 54 refers to the steps of Example 15. 1H NMR (400MHz, CD3OD), 8.75-8.85 (m, 1H), 7.76 (d, J=2.0Hz, 1H), 7.58 (d, J=4.4Hz, 1H), 7.50-7.54 (m, 2H), 7.48 (d, J=3. 2Hz, 1H), 7.14 (d, J=2.0Hz, 1H), 6.99-7.04 (m, 2H), 6.75 (d, J=3.2Hz, 1H), 5.22 (d, J=15.2Hz, 1H), 5.15 (d, J=15.2Hz, 1H ), 5.03 (dd, J=12.4Hz, 5.2Hz, 1H), 4.07 (d, J=15.2Hz, 1H), 3.64 (d, J=15.2Hz, 1H), 3.48 (s, 4H), 3.22-3.38 (m, 4H), 2.66 -2.98 (m, 5H), 2.46 (t, J=7.2Hz, 2H), 2.03-2.13 (m, 1H), 1.83 (d, J=14.4Hz, 1H), 1.58-1.68 (m, 2H), 1.14-1.48 (m, 25H).

[0143] Example 18: 4-(5-chloro-7-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)piperazin-1-yl)-3-ethyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)methylthieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0144]

[0145] Step 1: Synthesis of compound 56

[0146] Compound 43 (500 mg), 4-hydroxypiperidine (274 mg) and N,N-diisopropylethylamine were dissolved in 5 mL of dimethyl sulfoxide and heated to 100°C for overnight reaction. After cooling to room temperature, a large amount of water was added to the reaction solution, and a light yellow flocculent precipitate was precipitated. The filter cake was washed with water and dried to obtain compound 56 (579 mg).

[0147] Step 2: Synthesis of compound 57

[0148] Compound 56 (200 mg) was dissolved in 5 mL of dichloromethane, and Dess-Martin periodinane (356 mg) was added under ice-bath cooling, followed by stirring at room temperature for 2 h. Saturated sodium bicarbonate solution and sodium thiosulfate solution were added to the reaction solution to quench the reaction, the organic phase was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was separated and purified by column chromatography (dichloromethane: methanol = 50: 1, V / V) to obtain yellow solid 57 (183 mg).

[0149] Step 3: Synthesis of compound 58

[0150] Piperazine (74 mg), compound 5 (200 mg) and cesium fluoride (39 mg) were dissolved in 5 mL of dimethyl sulfoxide and heated to 60°C for 3 h. Water was added to quench the reaction, and a white solid precipitated. The solid was filtered and washed with water, and then separated and purified by column chromatography (dichloromethane: methanol = 35: 1, V / V) to obtain a white solid 58 (192 mg).

[0151] Step 4: Synthesis of compound 59

[0152] Compound 57 (19 mg) and compound 58 (40 mg) were dissolved in 2 mL of 1,2-dichloroethane, two drops of glacial acetic acid were added, and the mixture was stirred at room temperature for 2 h. Then sodium triacetylborohydride (34 mg) was added, and stirring was continued overnight. The solvent was removed by distillation under reduced pressure, and the residue was separated and purified by column chromatography (dichloromethane: methanol = 25: 1, V / V) to obtain a yellow solid 59 (45 mg).

[0153] Step 5: Synthesis of compound 60

[0154] Compound 59 (45 mg) was dissolved in 2 mL of dichloromethane, 0.5 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 h. The solvent was removed by distillation under reduced pressure, and the residue was separated and purified by column chromatography (dichloromethane: methanol = 10: 1, V / V) to give a light yellow solid 60 (32 mg). 1H NMR (400MHz, CD3OD), 8.82 (d, J=4.4Hz, 1H), 7.78 (d, J=2.0Hz, 1H), 7.69 (t, J=8.0Hz, 1H), 7.60-7.62 (m, 2H), 7.48 (d, J=3.6H z, 1H), 7.42 (d, J = 7.2Hz, 1H), 7.34 (d, J = 8.0Hz, 1H), 7.14 (d, J = 2.0Hz, 1H), 6.76 (d, J = 3.2Hz, 1H), 5.38-5.42 (m, 2H), 5.30 (d , J=14.8Hz, 1H), 5.09 (dd, J=12.4Hz, 5.6Hz, 1H), 4.08 (d, J=15.2Hz, 1H), 3.90-3.98 (m, 4H), 3.60-3.83 (m, 3H), 3.24-3.59 (m , 7H), 2.64-3.17(m, 9H), 2.24-2.34(m, 2H), 1.97-2.15(m, 3H), 1.80-1.88(m, 1H), 1.26-1.42(m, 3H), 1.22(t, J=7.2Hz, 3H).

[0155] Example 19: 4-(5-chloro-7-(2-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)piperazin-1-yl)-3-ethyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)methylthieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0156]

[0157] The synthesis method of compounds 62-65 is based on the steps of Example 18. 1H NMR (400MHz, CD3OD), 8.83-8.87 (m, 1H), 7.79-7.80 (m, 1H), 7.62-7.74 (m, 3H), 7.49-7.50 (m, 1H), 7.37 (dd, J=7.2Hz, 2.0H z, 1H), 7.31 (d, J=8.8Hz, 1H), 7.15-7.17 (m, 1H), 6.77 (d, J=3.2Hz, 1H), 5.38-5.42 (m, 2H), 5.29-5.34 (m, 1H), 5.08 (dd, J= 12.4Hz, 5.6Hz, 1H), 4.08 (d, J=15.2Hz, 1H), 3.93 (q, J=6.8Hz, 2H), 3.61-3.84 (m, 5H), 3.04-3.51 (m, 10H), 2.65-2.99 (m, 7 H), 2.06-2.16 (m, 2H), 1.88-1.96 (m, 2H), 1.76-1.86 (m, 1H), 1.57-1.69 (m, 2H), 1.26-1.43 (m, 3H), 1.21 (t, J=6.8Hz, 3H).

[0158] Example 20: 4-(5-chloro-7-(2-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-3-ethyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)methylthieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0159]

[0160] Step 1: Synthesis of compound 67

[0161] Under nitrogen protection, compound 5 (100 mg), 4-piperazinephenylboronic acid pinacol ester (CAS: 912369-50-7, 62 mg), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (CAS: 72287-26-4, 10 mg) and sodium carbonate (46 mg) were dissolved in 2 mL of 1,4-dioxane, 0.5 mL of water was added, and the mixture was heated to 100° C. and reacted overnight. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (dichloromethane: methanol = 30: 1, V / V) to obtain 67 (116 mg) as a white solid.

[0162] The synthesis of compound 69 was carried out according to step 4 and step 5 in Example 18. 1H NMR (400MHz, CD3OD), 8.80-8.88 (m, 1H), 7.78 (d, J=2.0Hz, 1H), 7.64-7.67 (m, 3H), 7.49 (d, J=3.2Hz, 1H), 7.31-7.37 (m, 4 H), 7.16 (d, J=2.0Hz, 1H), 7.12 (d, J=8.8Hz, 2H), 6.76 (d, J=3.2Hz, 1H), 5.59 (s, 1H), 5.44 (d, J=15.2Hz, 1H), 5.38 (d, J=15 .2Hz, 1H), 5.09 (dd, J=12.4Hz, 5.6Hz, 1H), 4.09 (d, J=15.2Hz, 1H), 3.62-4.04 (m, 9H), 3.15-3.40 (m, 7H), 2.65-2.99 (m, 8 H), 2.06-2.21(m, 2H), 1.91-2.04(m, 3H), 1.78-1.86(m, 1H), 1.56-1.70(m, 2H), 1.30-1.45(m, 2H), 1.04(t, J=7.2Hz, 3H).

[0163] Example 21: 4-(5-chloro-7-(2-(4-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)piperazin-1-yl)phenyl)-3-ethyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)methylthieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0164]

[0165] The synthesis of compound 71 was carried out according to step 4 and step 5 in Example 18. 1H NMR (400MHz, CD3OD), 8.76-8.88 (m, 1H), 7.77 (d, J=1.6Hz, 1H), 7.66-7.70 (m, 1H), 7.65 (s, 1H), 7.61 (d, J=4.4Hz, 1H), 7.48 (d, J= 3.6Hz, 1H), 7.41 (d, J=7.2Hz, 1H), 7.33-7.36 (m, 3H), 7.15 (d, J=2.0Hz, 1H), 7.12 (d, J=8.8Hz, 2H), 6.75 (d, J=3.2Hz, 1H), 5.59 (s, 1H), 5.43 (d, J=14.8Hz, 1H), 5.37 (d, J=14.8Hz, 1H), 5.09 (dd, J=12.4Hz, 5.6Hz, 1H), 3.87-4.20 (m, 5H), 3.58-3.84 (m, 5H), 3.07-3 .56 (m, 7H), 2.64-3.02 (m, 7H), 2.26-2.36 (m, 2H), 1.98-2.16 (m, 3H), 1.79-1.88 (m, 1H), 1.30-1.43 (m, 2H), 1.04 (t, J=7.2Hz, 3H).

[0166] Example 22: 4-(5-chloro-7-(2-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)piperazin-1-ylmethyl)phenyl)-3-ethyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)methylthieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0167]

[0168] Step 1: Synthesis of Compound 73 Refer to Step 4 of Example 18.

[0169] Step 2: Synthesis of Compound 74 Refer to Step 4 of Example 8.

[0170] Step 3: Synthesis of Compound 75 Refer to Step 4 of Example 18.

[0171] Step 4: Synthesis of Compound 76 Refer to Step 5 of Example 18. 1H NMR (400MHz, CD3OD), 8.82 (d, J=4.0Hz, 1H), 7.77 (d, J=2.0Hz, 1H), 7.65-7.70 (m, 1H), 7.65 (s, 1H), 7.60 (d, J=4.8Hz, 1H), 7.53 (d, J=8.0Hz, 2H), 7. 49 (d, J=3.6Hz, 1H), 7.40-7.44 (m, 3H), 7.33 (d, J=8.8Hz, 1H), 7.15 (d, J= 2.0Hz, 1H), 6.76 (d, J=3.2Hz, 1H), 5.60 (s, 1H), 5.45 (d, J=14.8Hz, 1H), 5. 37 (d, J=14.8Hz, 1H), 5.09 (d, J=12.4Hz, 5.6Hz, 1H), 4.09 (d, J=15.2Hz, 1 H), 3.91 (d, J=12.8Hz, 2H), 3.42-3.78 (m, 7H), 3.02-3.41 (m, 7H), 2.65-3. 00(m,7H),2.40-2.63(m,2H),2.20-2.28(m,2H),2.06-2.15(m,1H),1.92- 2.04 (m, 2H), 1.82-1.89 (m, 1H), 1.26-1.39 (m, 3H), 1.04 (t, J=7.2Hz, 3H).

[0172] Example 23: 4-((5-chloro-7-(2-(4-(4-((4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)piperidin-4-yl)methyl)piperazin-1-yl))methyl)phenyl)-3-ethyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)methylmethyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)carbonitrile

[0173]

[0174] Step 1: Synthesis of Compound 77 Reference Example 18 Step 4.

[0175] Step 2: Synthesis of Compound 78 Refer to Step 4 of Example 8.

[0176] Step 3: Synthesis of Compound 79 Refer to Step 4 of Example 18.

[0177] Step 4: Synthesis of Compound 80 Reference Example 18 Step 5. 1H NMR (400MHz, CD3OD), 8.83 (d, J=5.2Hz, 1H), 7.78 (d, J=2.0Hz, 1H), 7.63-7.67 (m, 3H), 7.54 (d, J=7.6Hz, 2H), 7.50 (d, J=3.2Hz, 1H), 7.45 (d, J=7.6Hz, 2 H), 7.37 (d, J=7.6Hz, 1H), 7.31 (d, J=8.0Hz, 1H), 7.17 (d, J=2.0Hz, 1H), 6.7 7 (d, J=3.6Hz, 1H), 5.60 (s, 1H), 5.47 (d, J=14.8Hz, 1H), 5.37 (d, J=14.8Hz, 1H), 5.08 (dd, J=12.4Hz, 5.6Hz, 1H), 4.10 (d, J=15.2Hz, 1H), 3.84 (s, 2H), 3 .75-3.82(m, 2H), 3.71(q, J=7.2Hz, 2H), 3.67(d, J=15.2Hz, 1H), 3.22-3.44 (m, 6H), 3.04 (d, J=7.2Hz, 2H), 2.68-3.00 (m, 11H), 1.98-2.15 (m, 2H), 1.82 -1.94(m, 3H), 1.53-1.65(m, 2H), 1.28-1.42(m, 3H), 1.04(t, J=7.2Hz, 3H).

[0178] Example 24: 4-((5-chloro-7-(2-((4-((1′-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)-[1,4′-dipiperidin-4-yl)methyl)piperazin-1-yl)-3-ethyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)methylmethyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)carbonitrile

[0179]

[0180]

[0181] Step 1: Synthesis of Compound 73 Reference Example 18 Step 4.

[0182] Step 2: Synthesis of Compound 74 Reference Example 18 Step 2.

[0183] Step 3: Synthesis of Compound 75 Refer to Step 4 of Example 18.

[0184] Step 4: Synthesis of Compound 76 Reference Example 18 Step 5. 1H NMR (400MHz, CD3OD), 8.80 (d, J=5.2Hz, 1H), 7.77 (d, J=2.0Hz, 1H), 7.67-7.71 (m, 1H), 7.58-7.59 (m, 2H), 7.48 (d, J=3.6Hz, 1H), 7.42 (d, J=6.8Hz, 1H), 7.33 (d, J=8.0Hz, 1H), 7.13 (d, J=2.0Hz, 1H), 6.76 (d, J=3.2Hz, 1H), 5.36-5.40 (m, 2H), 5.29 (d, J =15.2Hz, 1H), 5.09 (dd, J = 12.4Hz, 5.6Hz, 1H), 4.07 (d, J = 15.2Hz, 1H), 3.88-3.96 (m, 4H), 3.63-3.70 (m, 3H), 3.08-3.46 (m, 12H), 2.66-3.00(m, 9H), 1.98-2.26(m, 7H), 1.81-1.88(m, 1H), 1.51-1.65(m, 2H), 1.24-1.40(m, 5H), 1.20(t, J=7.2Hz, 3H).

[0185] Example 25: 4-((5-chloro-7-(2-(4-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)-2,7-diazaspiro[3.5]non-7-yl)methyl)phenyl)-3-ethyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl))methyl)thieno[3,2-b]pyridin-7-yl]-1H-indol-1-yl)carbonitrile

[0186]

[0187] Steps 3-6 of Synthesis Example 8 of Compounds 87-90. 1H NMR (400MHz, CD3OD), 8.82 (d, J=3.6Hz, 1H), 7.77 (d, J=2.0Hz, 1H), 7.58-7.68 (m, 7H), 7.49 (d, J=3.6Hz, 1H), 7.15 (d, J=2.0Hz, 1H), 6.84 ( d, J=2.0Hz, 1H), 6.76 (d, J=3.6Hz, 1H), 6.68 (dd, J=8.0Hz, 2.0Hz, 1H), 5.63 (s, 1H), 5.46 (d, J=14.8Hz, 1H), 5.37 (d, J=14.8Hz, 1H), 5.05 (d d, J=12.0Hz, 5.6Hz, 1H), 4.41 (s, 2H), 4.40 (d, J=15.2Hz, 1H), 3.80-3.99 (m, 4H), 3.64-3.73 (m, 3H), 3.45-3.58 (m, 2H), 3.24-3.36 (m, 2H) , 3.08-3.22(m, 2H), 2.64-3.00(m, 5H), 2.20-2.31(m, 1H), 1.96-2.14(m, 3H), 1.82-1.90(m, 1H), 1.25-1.43(m, 4H), 1.05(t, J=7.2Hz, 3H).

[0188] Example 26: 4-(5-chloro-7-(2-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-ethyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methylmethyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl))methyl)pyridine-4-carbonitrile

[0189]

[0190] The synthesis of compounds 91 and 92 was carried out according to Step 1-2 of Example 8.

[0191] The synthesis of compounds 93-96 was carried out according to the steps of Example 18. 1H NMR (400MHz, CD3OD), 8.80 (d, J=5.2Hz, 1H), 7.76-7.78 (m, 2H), 7.58-7.59 (m, 2H), 7.48-7.49 (m, 2H), 7.35 (dd, J= 8.8Hz, 2.4Hz, 1H), 7.14 (d, J=2.0Hz, 1H), 6.76 (d, J=3.2Hz, 1H), 5.38 (d, J=14.8Hz, 1H), 5.30 (s, 1H), 5.28 (d, J=14 .8Hz, 1H), 5.09 (dd, J=12.8Hz, 6.0Hz, 1H), 4.08 (d, J=15.2Hz, 1H), 3.91 (q, J=6.8Hz, 2H), 3.08-3.74 (m, 11H), 2.6 6-2.98 (m, 7H), 1.98-2.19 (m, 3H), 1.81-1.97 (m, 3H), 1.44-1.56 (m, 2H), 1.22-1.39 (m, 6H), 1.19 (t, J=6.8Hz, 3H).

[0192] Example 27: 4-((5-chloro-7-(2-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)piperidin-1-yl)methyl)piperidin-4-yl)-3-ethyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methylmethyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl))methyl)pyridine-4-carbonitrile

[0193]

[0194] Step 1: Synthesis of Compound 98 Reference Example 20 Step 1.

[0195] Step 2: Synthesis of compound 99

[0196] Compound 98 (2 g) was dissolved in 50 mL of methanol, 10% Pd / C (100 mg) was added, and the hydrogen atmosphere was replaced three times, and the hydrogen atmosphere was maintained overnight. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to remove the solvent, and the next step was directly carried out.

[0197] The synthesis of compounds 100-102 was carried out according to the steps of Example 8. 1H NMR (400MHz, CD3OD), 8.72-8.88 (m, 1H), 7.87 (d, J = 7.6Hz, 1H), 7.82 (s, 1H), 7.74-7.77 (m, 2H), 7.54-7.64 (m, 2H), 7.48 (d, J = 3.6Hz, 1 H), 7.14 (d, J=2.0Hz, 1H), 6.75 (d, J=3.6Hz, 1H), 5.37 (d, J=14.8Hz, 1H), 5.30 (s, 1H), 5.29 (d, J=14.8Hz, 1H), 5.13 (dd, J=12.8Hz, 5.6H z, 1H), 4.06 (d, J = 15.2Hz, 1H), 3.91 (q, J = 7.2Hz, 2H), 3.72-3.80 (m, 2H), 3.65 (d, J = 15.2Hz, 1H), 3.24-3.30 (m, 2H), 3.10-3.21 (m, 4H) , 2.82-2.98(m, 3H), 2.67-2.80(m, 4H), 2.02-2.24(m, 6H), 1.90-1.98(m, 2H), 1.80-1.88(m, 1H), 1.43-1.56(m, 2H), 1.16-1.40(m, 9H).

[0198] Example 28: 4-((5-chloro-7-(2-((4-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)prop-2-yn-1-yl)piperazin-1-yl)phenyl)-3-ethyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-ylmethyl)piperidine-4-carbonitrile

[0199]

[0200] Step 1: Synthesis of compound 105

[0201] Under nitrogen protection, compound 103 (1 g), 3,3-diethoxy-1-propyne (645 μL), cuprous iodide (114 mg) and bistriphenylphosphine palladium dichloride (211 mg) were dissolved in 20 mL of tetrahydrofuran and heated under reflux for 12 h. The mixture was evaporated under reduced pressure and the residue was separated and purified by column chromatography (dichloromethane: methanol = 50: 1) to obtain an off-white solid 104 (956 mg).

[0202] Compound 104 was dissolved in 10 mL of tetrahydrofuran, and 9 mL of deionized water and 1 mL of concentrated sulfuric acid were added, and stirred at room temperature for 5 h. The reaction solution was poured into ice water and extracted with ethyl acetate. The extracts were combined, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was directly used for the next step.

[0203] The synthesis of compounds 106-107 is described in Example 8. 1 H NMR (400MHz, CD3OD), 8.82 (d, J=4.4Hz, 1H), 7.96 (dd, J=7.6Hz, 2.8Hz, 0.5H), 7.83 (d, J=8.0Hz, 0.5H), 7.75-7.79 (m, 2H), 7.62-7.71 (m, 3H), 7 .48-7.50 (m, 1H), 7.36 (d, = 8.8Hz, 1H), 7.32 (d, J = 8.8Hz, 1H), 7.13-7. 17(m, 2H), 7.07(d, J=8.8Hz, 1H), 6.76-6.77(m, 1H), 5.59(s, 0.5H), 5.5 7(s, 0.5H), 5.33-5.47(m, 2H), 5.13-5.21(m, 1H), 4.44-4.60(m, 4H), 4 .07-4.11(m, 1H), 3.54-3.78(m, 7H), 3.25-3.34(m, 2H), 2.86-2.99(m, 4 H), 2.74-2.82(m, 1.5H), 2.34-2.57(m, 2H), 2.12-2.28(m, 2H), 1.98-2 .04(m, 0.5H), 1.80-1.88(m, 1H), 1.24-1.43(m, 3H), 1.00-1.05(m, 3H).

[0204] Example 29: 4-((5-chloro-7-(2-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)piperazin-1-yl)-3-ethyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)carbonitrile

[0205]

[0206] The synthesis of compounds 108-109 was carried out according to the steps of Example 8. 1H NMR (400MHz, CD3OD), 8.80 (d, J=5.2Hz, 1H), 7.77 (d, J=2.0Hz, 1H), 7.68-7.72 (m, 1H), 7.59-7.60 (m, 2H), 7.48 (d, J=3.2Hz, 1H), 7.43 (d, J=6.8Hz, 1H), 7.35 (d, =8.4Hz, 1H), 7.16 (d, J=2.0Hz, 1H), 6.76 (d, J=3.2Hz, 1H), 5.30-5.4 0 (m, 3H), 5.09 (dd, J = 12.4Hz, 5.6Hz, 1H), 4.06 (d, J = 15.2Hz, 1H), 3.99 (q, J = 7.2Hz, 2H), 3.68 (d, J = 15.2Hz, 1H), 3 .43-3.52(m, 4H), 3.16-3.23(m, 4H), 2.68-2.98(m, 6H), 2.06-2.14(m, 1H), 1.78-1.86(m, 1H), 1.20-1.38(m, 7H).

[0207] Example 30: 4-((5-chloro-7-(2-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)piperazin-1-yl)-3-ethyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)carbonitrile

[0208]

[0209] The synthesis of compounds 110-111 was carried out according to the steps of Example 8. 1H NMR (400MHz, CD3OD), 8.83 (d, J=5.2Hz, 1H), 7.78 (d, J=2.0Hz, 1H), 7.71 (d, J=8.8Hz, 1H), 7.65 (d, J=4.4Hz, 1H), 7.63 (s, 1H), 7.49 (d, J=3.6Hz, 1H), 7. 40 (d, J=2.0Hz, 1H), 7.28 (dd, J=8.8Hz, 2.0Hz, 1H), 7.16 (d, J=2.4Hz, 1H), 6 .76 (d, J=3.6Hz, 1H), 5.39 (d, J=15.2Hz, 1H), 5.37 (s, 1H), 5.32 (d, J=15.2Hz , 1H), 5.07 (dd, J=12.8Hz, 5.2Hz, 1H), 4.07 (d, J=15.2Hz, 1H), 3.99 (q, J=6. 8Hz, 2H), 3.68 (d, J=15.2Hz, 1H), 3.54-3.61 (m, 4H), 3.24-3.34 (m, 2H), 3.11 -3.17(m, 4H), 2.88-2.97(m, 2H), 2.81-2.86(m, 1H), 2.65-2.77(m, 2H), 2.0 6-2.13(m, 1H), 1.78-1.84(m, 1H), 1.26-1.38(m, 3H), 1.23(t, J=6.8Hz, 3H).

[0210] Example 31: 4-((5-chloro-7-(2-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)piperazin-1-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl))methyl)piperidine-4-carbonitrile

[0211]

[0212] The synthesis of compound 112 was carried out in step 3 of reference example 1.

[0213] The synthesis of compounds 113-114 was carried out according to steps 7-8 of Example 1. 1H NMR (400MHz, CD3OD), 8.92 (d, J=4.8Hz, 1H), 7.89 (s, 1H), 7.80-7.81 (m, 1H), 7.69-7.73 (m, 2H), 7.46-7.52 (m, 2H), 7.33 (d, J=8.4Hz, 1H), 7.22 (d, J=1.6Hz, 1H), 6.78 (t, J=3.6 Hz, 1H), 5.07-5.13 (m, 1H), 4.72 (s, 2H), 4.15-4.23 (m, 1H), 3.40-3.66 (m, 9H), 3.24-3. 32(m, 2H), 2.64-2.98(m, 5H), 2.06-2.15(m, 1H), 1.78-1.88(m, 1H), 1.26-1.48(m, 3H).

[0214] Example 32: 4-((5-chloro-7-(2-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)piperazin-1-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl))methyl)piperidine-4-carbonitrile

[0215]

[0216] The synthesis of compounds 115-116 was carried out according to step 7 to step 8 of reference example 1. 1 H NMR (400MHz, CD3OD), 8.88 (d, J=4.8Hz, 1H), 7.79 (d, J=2.0Hz, 1H), 7.76 (s, 1H), 7.68-7.71 (m, 2H), 7.49 (d, J=3 .6Hz, 1H), 7.38 (d, J=2.4Hz, 1H), 7.26 (dd, J=8.4Hz, 2.4Hz, 1H), 7.20 (d, J=2.0Hz, 1H), 6.77 (d, J=3.6Hz, 1H), 5. 06 (dd, J=12.8Hz, 5.2Hz, 1H), 4.41 (s, 2H), 4.15 (d, J=15.2Hz, 1H), 3.65 (d, J=15.2Hz, 1H), 3.55-3.62 (m, 4H), 3. 26-3.36 (m, 2H), 3.08-3.18 (m, 4H), 2.64-2.99 (m, 5H), 2.05-2.12 (m, 1H), 1.81-1.88 (m, 1H), 1.27-1.48 (m, 3H).

[0217] Example 33: (2R,4S)-1-((R)-2-(12-((4-(1-(7-(5-chloro-1-((4-cyanopiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl]-3-ethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)benzyl)amino)dodecanoyl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0218]

[0219]

[0220] Step 1: Synthesis of compound 118

[0221] Under ice-bath cooling, 12-(BOC-amino)dodecanoic acid (162 mg), HATU (326 mg), HOAt (117 mg) and DIPEA (373 μL) were dissolved in DMF (3 mL), stirred under ice-bath cooling for 30 minutes, compound 117 (200 mg) was added, and then reacted at room temperature overnight. After concentration under reduced pressure, the residue was separated and purified by column chromatography (dichloromethane: methanol = 25: 1) to obtain white solid 118 (259 mg).

[0222] The synthesis of compounds 119-121 was carried out according to the steps of Example 8. 1H NMR (400MHz, CD3OD), 8.88 (s, 1H), 8.82 (d, J=5.2Hz, 1H), 8.64-8.67 (m, 1H), 7.81 (d, J= 8.8Hz, 1H), 7.78 (d, J=2.0Hz, 1H), 7.66 (s, 1H), 7.61-7.63 (m, 3H), 7.55 (d, J=8.4Hz, 2H) , 7.49 (d, J = 3.2Hz, 1H), 7.46 (d, J = 8.0Hz, 2H), 7.40 (d, J = 8.4Hz, 2H), 7.15 (d, J = 2.0Hz, 1 H), 6.76 (d, J = 3.2Hz, 1H), 5.61 (s, 1H), 5.47 (d, J = 14.8Hz, 1H), 5.36 (d, J = 14.8Hz, 1H), 4 .63 (d, J=8.8Hz, 1H), 4.46-4.57 (m, 3H), 4.32.4.37 (m, 1H), 4.26 (s, 2H), 4.11 (d, J=15. 2Hz, 1H), 3.89 (d, J=10.8Hz, 1H), 3.79 (dd, J=10.8Hz, 4.0Hz, 1H), 3.64-3.71 (m, 3H), 3.2 5-3.35(m, 2H), 3.04-3.08(m, 2H), 2.90-2.98(m, 2H), 2.46(s, 3H), 2.18-2.27(m, 3H), 2. 02-2.11(m, 1H), 1.83-1.90(m, 1H), 1.53-1.74(m, 3H), 1.24-1.42(m, 21H), 1.02(s, 9H).

[0223] Example 34: (2R,4S)-1-((R)-15-(tert-butyl)-1-(4-(1-(7-(5-chloro-1-((4-cyanopiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl]-3-ethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)phenyl)-13-oxo-5,8,11-trioxo-2,14-diazahexadecane-16-yl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0224]

[0225] The synthesis of compound 123 was carried out by referring to step 1 of Example 33 and the step of Example 8. 1H NMR (400MHz, CD3OD), 8.86 (s, 1H), 8.82 (d, J=3.6Hz, 1H), 8.63 (t, J=6.0Hz, 1H), 7.76 (d, J=2.0Hz, 1H), 7.70 (d, J=9.2Hz, 1H), 7.66 (s, 1H), 7. 58-7.63(m, 3H), 7.47-7.54(m, 3H), 7.38-7.44(m, 4H), 7.14(d, J=1.6H z, 1H), 6.75 (d, J = 3.2Hz, 1H), 5.61 (s, 1H), 5.46 (d, J = 14.8Hz, 1H), 5.35 (d, J=14.8Hz, 1H), 4.66 (d, J=9.2Hz, 1H), 4.44-4.56 (m, 3H), 4.28-4.39 (m, 3H), 4.10 (d, J=15.2Hz, 1H), 3.87-3.93 (m, 3H), 3.62-3.82 (m, 16H) , 3.24-3.36(m, 2H), 2.88-2.98(m, 2H), 2.45(s, 3H), 2.20-2.25(m, 1H) , 2.01-2.10(m, 1H), 1.82-1.89(m, 1H), 1.23-1.43(m, 6H), 1.02(s, 9H).

[0226] Example 35: (2R,4S)-1-((R)-2-(11-((1-((7-(5-chloro-1-((4-cyanopiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl]-3-ethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)oxy)undecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0227]

[0228] The synthesis of compound 125 was carried out according to step 5 of Example 1.

[0229] Step 1: Synthesis of compound 126

[0230] Compound 126 (60 mg) was dissolved in 2 mL of solvent (tetrahydrofuran: methanol: water = 3: 1: 1), lithium hydroxide monohydrate (7 mg) was added, and the mixture was reacted at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (dichloromethane: methanol = 30: 1) to obtain 126 (37 mg) as a white solid.

[0231] The synthesis of compounds 127-128 was carried out by referring to step 1 of reference example 33 and the step of example 8.1 H 7 .40 (d, J=8.4Hz, 2H), 7.15 (s, 1H), 6.76 (d, J=3.2Hz, 1H), 5.36 (d, J=15.2 Hz, 1H), 5.30 (d, J=15.2Hz, 1H), 5.20 (s, 1H), 4.46-4.64 (m, 4H), 4.34 (d, J =15.6Hz, 1H), 4.04-4.11(m, 3H), 3.88-3.96(m, 3H), 3.79(dd, J=11.2Hz, 4.0Hz, 1H), 3.67 (d, J=14.8Hz, 1H), 3.24-3.32 (m, 2H), 2.89-2.97 (m, 2H) ,2.46(s,3H),2.16-2.32(m,3H),2.03-2.10(m,1H),1.74-1.86(m,3H),1 .51-1.65(m, 2H), 1.22-1.49(m, 15H), 1.17(t, J=7.2Hz, 3H), 1.02(s, 9H).

[0232] Example 36: 4-((5-chloro-7-(2-(4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)amino)ethoxy)butoxy)-3-ethyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)carbonitrile

[0233]

[0234] Step 1: Synthesis of compound 130

[0235] Under ice-bath cooling, 1,4-butanediol (2 g) was dissolved in DMF (40 mL), and sodium hydride (666 mg) was added in batches. After 1 h, benzyl 2-bromoethyl ether (dissolved in 10 mL DMF, 2.39 g) was added dropwise. After the addition was complete, the mixture was stirred at room temperature overnight. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain colorless liquid 130 (1.3 g).

[0236] Step 2: Synthesis of compound 131

[0237] Compound 130 (1.3 g) was dissolved in 20 mL of dichloromethane, triethylamine (1.6 mL) was added, acetyl chloride (640 μL) was added dropwise under ice-cooling, and the reaction was allowed to react at room temperature for 2 h. Water was then added to quench the reaction, the organic phase was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain colorless liquid 131 (1.7 g).

[0238] Step 3: Synthesis of compound 132

[0239] Compound 131 (1 g) was dissolved in 20 mL of ethanol, 10% P / C (100 mg) was added, and the hydrogen atmosphere was replaced three times, and then the hydrogen atmosphere was maintained for 24 h. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to remove the solvent to obtain a colorless liquid 132 (570 mg).

[0240] Steps of Synthesis Example 8 of Compounds 133-137. 1 H NMR (400MHz, CD3OD), 8.78 (d, J=4.8Hz, 1H), 7.75 (d, J=2.0Hz, 1H), 7.55-7.57 (m, 2H), 7.40-7.44 (m, 1H), 7.20-7.26 (m, 1H), 7.12 (d, J=2.0Hz, 1H), 6.99 (dd, J=9.6Hz, 7.6Hz, 1H), 6.71-6.76 (m, 2H), 5.24-5.34 (m, 3H), 5.09-5.16 (m, 1H), 4.19-4.30 (m, 3H), 3.9 9 (dd, J=15.2Hz, 11.2Hz, 1H), 3.89 (q, .J=6.8Hz, 2H), 3.76-3.78 (m, 2H), 3.65 (dd, J=15.2Hz, 2.4Hz, 1H), 3.53-3.58 (m, 2H), 3.15 -3.34(m, 4H), 2.73-2.96(m, 4H), 2.41-2.47(m, 1H), 2.12-2.20(m, 1H), 1.65-1.83(m, 4H), 1.24-1.37(m, 4H), 1.10-1.14(m, 3H).

[0241] Example 37: 4-((5-chloro-7-(2-(4-(1-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)amino)ethoxy)ethoxyethyl)-1H-1,2,3-triazol-4-yl)-3-ethyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)carbonitrile

[0242]

[0243] Step 1: Synthesis of Compound 138 Refer to Step 1 of Example 28.

[0244] Step 2: Synthesis of compound 139

[0245] Compound 138 (211 mg) was dissolved in 5 mL of solvent (tetrahydrofuran: methanol = 1: 1), anhydrous potassium carbonate (247 mg) was added, and the mixture was reacted at room temperature for 2 h. The mixture was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (dichloromethane: methanol = 50: 1) to obtain white solid 139 (71 mg).

[0246] Step 3: Synthesis of Compound 140 Refer to Step 3 of Example 1.

[0247] Step 4: Synthesis of compound 143

[0248] Dissolve azide-triethylene glycol (500 mg) in 10 mL of dichloromethane, add triethylamine (791 μL), add methylsulfonyl chloride under ice-cooling, and react at room temperature for 1 h. Add water to quench the reaction, wash the organic phase with saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is directly used for the next step.

[0249] The compound obtained in the previous step was dissolved in 10 mL of DMF, and lenalidomide (738 mg) and DIPEA (1.5 mL) were added. The mixture was heated to 110°C and reacted overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified by column chromatography (dichloromethane:methanol=30:1) to obtain 143 (75 mg), a white solid.

[0250] Step 4: Synthesis of compound 144

[0251] Compounds 140 (20 mg) and 143 (12 mg) were dissolved in 1.5 mL of solvent (tetrahydrofuran: water = 2: 1), anhydrous copper sulfate (19 mg) and sodium ascorbate (12 mg) were added, and the mixture was reacted at room temperature for 5 h. The reaction solution was diluted with water and extracted with dichloromethane. The extract was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by column chromatography (dichloromethane: methanol = 25: 1) to obtain 144 (21 mg) as a white solid.

[0252] Step 4: Synthesis of Compound 145 Refer to Step 8 of Example 1. 1 H NMR (400MHz, CD3OD+CDCl3), 8.74-8.83 (m, 1H), 8.33 (s, 1H), 7.72 (d, J=2.0Hz, 1H), 7.66 (s, 1H), 7.55 (d, J=4.8Hz, 1H) , 7.38-7.41(m, 1H), 7.11-7.18(m, 2H), 6.97-7.00(m, 1H), 6.68-6.72(m, 2H), 5.83(s, 1H), 5.30-5.39(m, 2H), 5.07-5. 17 (m, 1H), 4.59-4.62 (m, 2H), 4.23 (s, 2H), 3.94-4.01 (m, 3H), 3.88 (t, J=4.8Hz, 2H), 3.56-3.67 (m, 7H), 3.21-3.33 (m, 3H), 2.73-2.96(m, 4H), 2.38-2.50(m, 2H), 2.12-2.19(m, 1H), 1.76-1.83(m, 1H), 1.20-1.36(m, 3H), 1.12-1.16(m, 3H).

[0253] Biological activity test:

[0254] 1. Determination of compound inhibition of USP7 in vitro enzymatic activity

[0255] In this patent, the enzymatic activity of USP7 is detected by rapid fluorescence method, using Ubiquitin-Rhodamine110 as an alternative substrate for reaction and optimizing a high-throughput screening platform. The inhibitory activity of compounds on USP7 is detected on this platform. The specific method is as follows: the compound is diluted 5 times with 100% DMSO starting from 1mM (7 concentrations in total), and 2μL of the compound is added to 48μL of reaction buffer (20mMTris, pH 8.0, 2mM CaCl2, 1mM reduced glutathione, 0.01% (v / v) Triton X-100, 0.01% (w / v) BSA) for dilution and mixing. Take 5μL of the final diluted compound and add it to a black 384-well plate (OptiPlate-384, item number 6007270, purchased from PerkinElmer), and then add 10μL of His-USP7 (final concentration is 0.05nM). After the 384-well plate was placed in an incubator at 23°C for 30 minutes, 5 μL of the alternative substrate Ubiquitin-Rhodamine 110 (Cat. No. U-555, purchased from Boston Biochem, final concentration 10 nM) was added to each well and the reaction was continued in an incubator at 23°C for 1.5 hours. 5 μL of citric acid (Cat. No. 77-92-9, purchased from Sinopharm Group, final concentration 10 mM) was added to each well to terminate the reaction, and the fluorescence value was read using a BMG Clariostar Microplate Reader (excitation 485 nm / emission 535 nm). The IC value of the compound for inhibition of USP7 enzymatic activity was calculated using GraphPad Ptism software. 50 value.

[0256] Table 1. Inhibitory effects of example compounds on USP7

[0257]

[0258] 2. Western blotting assay to detect the degradation activity of compounds on USP7 protein

[0259] The human acute lymphoblastic leukemia cell line RS4;11 was cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum (purchased from Gibco) and 1% Penicillin-Streptomycin (purchased from Thermo Fisher Scientific) at 37°C and 5% CO2. The cells were counted and expressed as 1×10 6 / 2mL culture medium density was plated in 6-well cell culture plates and cultured overnight at 37℃. The next day, different concentrations of the test compound were added for 24h, and the cells were collected by centrifugation, the culture medium was discarded and washed once with PBS, and the cells were collected by centrifugation again. 30μL 1× cell lysis buffer (purchased from Cell Signaling Teehnology) was added to each sample and lysed on ice for 30min. Centrifuged at 12000rpm at 4℃ for 10min, and the supernatant was taken. Protein quantification was performed using the BCA method (purchased from Thermo Fisher Scientific), and an equal amount of total protein was added to 5× electrophoresis loading buffer and denatured at 105℃ for 5min. Proteins were separated by polyacrylamide gel electrophoresis, and the proteins were transferred to PVDF membranes by wet transfer, and then blocked with 5% skim milk at room temperature for 1h. Anti-USP7 antibody (purchased from Abcam) and anti-Actin antibody (purchased from Cell Signaling Technology) were diluted with TBST in proportion and incubated overnight at 4℃. The next day, anti-Rabbit IgG antibody was diluted with TBST in proportion and incubated at room temperature for 1 h. The expression level of the target protein was detected by ECL method. The results are shown in Figure 1-3 .

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, in, X is -CH2- or -(CO)-, L is -(L1) n1 -(L2) n2 -(L3) n3 -(L4) n4 -(L5) n5 -, L1 is connected to the carbon. L1 is -NH-(CH2) 2-16 、-C≡C-(CH2) 0-6 , or -(3-12 membered heterocyclylene)-, L2 is -(O-(CH2)2) 1-6 -, L3 and L4 are each independently a 3-12 membered heterocyclylene group or -(CH2) 1-6 -, L5 is a phenylene group or a 5-6-membered heteroarylene group, n1, n2, n3, n4 and n5 are each independently 0 or 1.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, wherein X is -(CO)-.

3. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, wherein L3 and L4 are each independently a 3-6 membered heterocyclylene group or -(CH2) 1-6 -.

4. The following compounds or their pharmaceutically acceptable salts, solvates, polymorphs, or isomers, 5. A pharmaceutical composition comprising the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, and optionally comprising a pharmaceutically acceptable carrier.

6. Use of the compound according to any one of claims 1 to 4 or its pharmaceutically acceptable salt, solvate, polymorph, or isomer, or the pharmaceutical composition according to claim 5 in the preparation of a medicament for treating a disease associated with USP7 activity.

7. The use according to claim 6, wherein the disease associated with USP7 activity is ovarian cancer, breast cancer, lung cancer, pancreatic cancer, kidney cancer, melanoma, liver cancer, colon cancer, sarcoma, brain cancer, prostate cancer, leukemia, lymphoma, or multiple myeloma.

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