Dipeptide compound, chimeric molecule based on dipeptide compound and application of chimeric molecule

Abstract

The invention discloses a dipeptide compound, a chimera molecule based on the dipeptide compound and application of the chimera molecule, and relates to the technical field of targeted protein degradation. The invention provides a structural general formula of the dipeptide compound, also provides a structural general formula of a chimera molecule based on the dipeptide compound, and applies the chimera molecule to preparation of BRD4 wild type and mutant protein degradation agent drugs thereof and / or ALK wild type and mutant protein degradation agent drugs thereof. According to the present invention, the dipeptide compound is adopted as the ligands of the proteolysis targeting chimera (PROTAC) connecting E3 ubiquitin ligase to obtain the protein degradation drugs respectively targeting the BRD4 protein and the ALK protein, and can induce the degradation of the BRD4 or ALK protein, such that the good anti-tumor activity on various BRD4 or ALK dependent tumors can be provided, and the drug can be used for the related tumor treatment.

Description

Technical Field

[0001] The present invention relates to the technical field of targeted protein degradation, and in particular to a dipeptide compound and a chimeric molecule based on the dipeptide compound and applications thereof. Background Art

[0002] Proteolysis targeting chimera (PROTAC) is a heterobifunctional molecule, one end of the molecule is connected to the ligand that binds to the target protein, and the other end is connected to the ligand of the E3 ligase, and the middle is connected by a suitable linker. PROTAC degradation of target proteins is achieved through the ubiquitin protease system (UPS). The general process is that the PROTAC molecule binds to the target protein (POI) and the E3 ligase to form a ternary complex, and the target protein is labeled with ubiquitination. The ubiquitinated protein is then recognized and degraded by the proteasome 26S in the cell. In the use of PROTAC technology, it is particularly important to choose a suitable E3 ubiquitin ligase. Although there are more than 600 E3 ubiquitin enzymes in the human body, the most commonly used and most mature E3 ubiquitin ligases are CRBN and VHL. As early as 2010, Ito et al. deciphered the mechanism of action of thalidomide and finally confirmed that the target of thalidomide is CRBN. At present, many PROTAC molecules have been designed with thalidomide or thalidomide derivatives (lenalidomide and pomalidomide) as E3 ligase ligands. Although these molecules have been proven to have good protein degradation and anti-tumor effects, this kind of PROTAC with thalidomide and its derivatives as E3 ligase ligands has great safety risks: first, they may promote the degradation of lymphoid transcription factors such as IKZF1, IKZF3 and SALL4, and the last factor is the severe teratogenic effect caused by thalidomide analogs. In addition, typical IMID scaffolds are easily hydrolyzed and enzymatically degraded, which greatly limits their absorption in pharmacological applications. Summary of the invention

[0003] In order to solve the above technical problems, the purpose of the present invention is to provide a dipeptide compound and a chimeric molecule based on the dipeptide compound and its application, wherein the dipeptide compound is used as a ligand for connecting E3 ubiquitin ligase of protein hydrolysis targeting chimera (PROTAC) to obtain protein degradation drugs targeting BRD4 protein and ALK protein respectively, which can induce the degradation of BRD4 or ALK protein, thereby exerting good anti-tumor activity on a variety of BRD4 or ALK-dependent tumors, and can be used for the treatment of related tumors.

[0004] The technical solution of the present invention to solve the above technical problem is as follows: a dipeptide compound is provided, the general structural formula of which is:

[0005]

[0006] Among them, R1a is C1-C8 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl or

[0007] R 2a is H or C1-C3 alkyl;

[0008] or R 1a , R 2a and the carbon atoms to which they are commonly connected form a substituted or unsubstituted 3-8 membered saturated ring;

[0009] R 1b is H or C1-C3 alkyl;

[0010] R 2b is C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl or R3 is C3-C8 cycloalkyl, aryl or heteroaryl;

[0011] n1 and n2 are independently integers between 1 and 6.

[0012] Further, R 1a , R 2a and the carbon atoms they are connected to form

[0013] Among them, R 4a , R 4b R is independently hydrogen, methyl, cyclopropyl, cyclobutyl, vinyl or ethynyl.

[0014] Further, R 2b is C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl,

[0015]

[0016] Further, the dipeptide compound has the structural formula:

[0017]

[0018]

[0019] The present invention also provides a chimeric molecule based on the above dipeptide compound, the general structural formula of which is: MLN;

[0020] Wherein, M is a small molecule or peptide that can bind to the target protein;

[0021] L is a connecting unit, and both ends of L are connected to an atom of M and N respectively;

[0022] N is the dipeptide compound according to any one of claims 1 to 4.

[0023] Further, M is a BRD4 inhibitor or an ALK inhibitor;

[0024] M is

[0025] Further, L is -NH(CH2) n3 CO-, -NH(CH2CH2O) n4 -(CH2) n5 CO-, -CO(CH2) n3 CO-, -CO(CH2) n6 (CH2CH2O) n4 -(CH2) n5 CO-, -CO(CH2) n3 CH2-, -CO(CH2) n6 (CH2CH2O) n4 -(CH2) n5 CH2-;

[0026] Wherein, n3 is an integer between 1 and 20;

[0027] n4 is an integer between 1 and 10;

[0028] n5 is 1 or 2;

[0029] n6 is 0 or 1.

[0030] Further, when M is a BRD4 inhibitor, the chimera molecular structure is:

[0031]

[0032]

[0033] When M is an ALK inhibitor, the chimera molecular structure is:

[0034]

[0035]

[0036] The present invention also provides the use of the above-mentioned dipeptide compound-based chimeric molecules, their stereoisomers, their pharmaceutically acceptable salts, their physiologically acceptable salts or their solvates in the preparation of BRD4 wild-type and its mutant protein degrader drugs and / or ALK wild-type and its mutant protein degrader drugs.

[0037] Furthermore, the drug is a drug that inhibits BRD4-dependent tumors, diabetes, atherosclerosis, coronary artery disease, and a drug that inhibits ALK wild-type and mutant protein-dependent tumors.

[0038] The present invention has the following beneficial effects:

[0039] 1. The present invention uses a dipeptide compound as a ligand for connecting E3 ubiquitin ligase of a protein hydrolysis targeting chimera (PROTAC) to obtain a protein degradation drug that targets BRD4 protein and ALK protein respectively, which can induce the degradation of BRD4 or ALK protein, thereby exerting good anti-tumor activity against a variety of BRD4 or ALK-dependent tumors, and can be used for the treatment of related tumors.

[0040] 2. The present invention uses a dipeptide formed by a C-terminal cyclic imide and a non-natural amino acid instead of the traditional thalidomide and its derivatives as CRBN ligands to design PROTAC molecules, so as to avoid off-target effects and reduce the effects of hydrolysis and enzymatic hydrolysis, and uses non-natural amino acids as part of the dipeptide to reduce the drug metabolism rate. The chimeric molecule has good target protein degradation activity and selectivity, one type is used as a protein degradation drug for degrading BRD4 protein, and the other type is used as a degradation drug for degrading ALK protein. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 This is a schematic diagram of the results of the efficacy of the chimeric molecules obtained in Example 18-36 in inducing BRD4 protein degradation;

[0042] Figure 2 Schematic diagram of the results of the efficacy of the chimeric molecules obtained in Examples 37-47 in inducing ALK protein degradation. DETAILED DESCRIPTION

[0043] The principles and features of the present invention are described below, and the examples are only used to explain the present invention and are not used to limit the scope of the present invention. If no specific conditions are specified in the embodiments, they are carried out according to normal conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments is not specified, they are all conventional products that can be purchased commercially.

[0044] Example 1

[0045] A dipeptide compound, (2R)-2-amino-N-(2,6-piperidindione-3-yl)-2-phenylacetamide hydrochloride, has the structural formula:

[0046] The preparation method comprises the following steps:

[0047] (1) (R)-2-((tert-butyloxycarbonyl)amino)-2-phenylacetic acid (2.0 g, 7.96 mmol) was dissolved in N,N-dimethylformamide (40 mL) solution, and HATU (6.05 g, 15.92 mmol) and DIEA (3.08 g, 23.88 mmol) were added to the solution. After stirring at room temperature for 20 min, 3-amino-2,6-piperidindione (1.02 g, 7.96 mmol) was added to the solution, and stirred at room temperature for 12 h until the raw material was completely converted; the reaction mixture was quenched with 20 mL of water, extracted with 3×15 mL of EA, and the combined organic layer was washed with 30 mL of saturated NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product;

[0048] (2) The intermediate was dissolved in dioxane hydrochloride (20 mL) and stirred at room temperature for 1 h. The reaction was monitored by a plate. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a solid residue, which was washed with 3×20 mL DCM and filtered to obtain a yellow solid product (2R)-2-amino-N-(2,6-piperidindione-3-yl)-2-phenylacetamide hydrochloride (1.2 g, 4.52 mmol, yield 57%). 1 H NMR(400MHz, DMSO-d6)δ10.89(s,0.5H),10.83(s,0.5H),9.02(m,J=20.7,7.9Hz,1H),8.86–8.65(m,3H),7.69–7.33(m,5H),5.05(t,J =5.2Hz,1H),4.70–4.49(m,1H),3.66–3.43(m,1H),2.71(m,J=23.3,12.7,7.4Hz,1H),2.44(m,J=17.3,3.9Hz,1H),2.07–1.63(m,2H).

[0049] Example 2

[0050] (2R)-2-amino-N-(2,6-piperidindione-3-yl)-3-phenylpropanamide hydrochloride, the structural formula of which is:

[0051]

[0052] The preparation method is the same as that in Example 1. The raw material used is (tert-butyloxycarbonyl)-D-phenylalanine (2.1 g, 7.96 mmol), and the product is (1.19 g, 4.30 mmol, yield 54%). 1H NMR (400MHz, DMSO-d6) δ10.90(s,1H),9.05(d,J=8.1Hz,0.5H),8.89(d,J=7.9Hz,0.5 H),8.31(d,J=37.8Hz,3H),7.44–7.21(m,5H),4.61(m,J=20.1,11.7,8.0,5.8Hz,1H), 4.08(d,J=7.4Hz,2H),3.25–2.98(m,2H),2.84–2.61(m,1H),2.56(d,J=4.0Hz,0.5H) ,2.42(dt,J=17.4,4.1Hz,0.5H),1.97(m,J=12.6,5.9,3.7Hz,1H),1.88–1.56(m,1H).

[0053] Example 3

[0054] (2R)-2-amino-N-(2,6-piperidindione-3-yl)-4-phenylbutanamide hydrochloride, the structural formula of which is:

[0055]

[0056] The preparation method is the same as that in Example 1. The raw material used is (R)-2-((tert-butyloxycarbonyl)amino)-4-phenylbutyric acid (2.2 g, 7.96 mmol), and the product is (1.05 g, 3.62 mmol, yield 46%). 1 H NMR (400MHz, DMSO-d6) δ10.91(d,J=3.8Hz,1H),9.18(d,J=7.8Hz,0.5H),9.06(d,J=8.5Hz,0.5H),8.52(s,3H) ,7.46–7.03(m,5H),4.88–4.46(m,1H),3.95(s,1H),2.89–2.63(m,3H),2.61–2.53(m,1H),2.16–1.87(m,4H).

[0057] Example 4

[0058] (2R)-2-amino-3-cyclohexyl-N-(2,6-piperazinedione-3-yl)propionamide hydrochloride, the structural formula of which is:

[0059]

[0060] The preparation method is the same as that in Example 1. The raw material used is (R)-2-((tert-butoxycarbonyl)amino)-3-cyclohexylpropionic acid (2.2 g, 7.96 mmol), and the product is (1.47 g, 5.24 mmol, yield 66%). 1H NMR (400MHz, DMSO-d6) δ10.88(d,J=10.3Hz,1H),9.08(d,J=7.9Hz,0.5H),8.95(d,J =8.4Hz,0.5H),8.36(s,3H),4.78–4.49(m,1H),3.82(s,1H),2.74(m,J=21.0,13.0,8 .8,3.3Hz,1H),2.56(dt,J=9.2,4.0Hz,1H),1.97(m,J=14.5,7.1,4.2Hz,2H),1.85–1 .58(m,7H),1.54–1.34(m,1H),1.17(m,J=29.2,10.2,9.6Hz,3H),0.97–0.78(m,2H).

[0061] Example 5

[0062] (2R)-2-amino-4-cyclohexyl-N-(2,6-piperidindione-3-yl)butanamide hydrochloride, the structural formula of which is:

[0063]

[0064] The preparation method is the same as that in Example 1. The raw material used is (R)-2-((tert-butoxycarbonyl)amino)-4-cyclohexylbutanoic acid (2.3 g, 7.96 mmol), and the product is (1.49 g, 5.08 mmol, yield 65%). 1 H NMR(400MHz,DMSO-d6)δ10.88(d,J=13.1Hz,1H),8.99(d,J=7.9Hz,0.5H),8.8 7(d,J=8.4Hz,0.5H),8.30(s,3H),4.80–4.46(m,1H),3.87–3.75(m,1H),2.75( m,J=18.0,12.3,5.8Hz,1H),2.59–2.54(m,1H),2.09–1.90(m,2H),1.78(m,J=1 2.9, 6.6Hz, 2H), 1.70–1.55 (m, 5H), 1.39–1.10 (m, 6H), 0.87 (d, J = 12.9Hz, 2H).

[0065] Example 6

[0066] (2S)-2-amino-N-((2,6-piperidindione-3-yl)pent-4-enebutylamide hydrochloride, the structural formula of which is:

[0067] The preparation method is the same as that in Example 1. The raw material used is (S)-2-((tert-butoxycarbonyl)amino)pent-4-enoic acid (1.7 g, 7.96 mmol), and the product is (0.80 g, 3.58 mmol, yield 45%). 1 H NMR (400MHz, DMSO-d6) δ10.89(d,J=13.3Hz,1H),8.82(d,J=8.2Hz,0.5H),8.73(d,J=8.0Hz,0.5H),8.34(d,J=21.5Hz,3H),5.86– 5.65(m,1H),5.29–5.05(m,2H),4.24(m,J=8.2,5.0Hz,1H),3.94(s,1H),2.62–2.54(m,1H),2.41–2.27(m,2H),2.06–1.63(m,3H).

[0068] Example 7

[0069] (2S)-2-amino-N-((2,6-piperidindione-3-yl)pent-4-enebutylamide hydrochloride, the structural formula of which is:

[0070]

[0071] The preparation method is the same as that in Example 1. The raw material used is 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (1.6 g, 7.96 mmol), and the product is (0.78 g, 3.66 mmol, yield 46%). 1 H NMR (400MHz, DMSO-d6) δ10.87(s,1H),8.68(d,J=8.2Hz,1H),8.36(s,3H),4.60(m,J=13.1,8.2,5.3Hz,1H),2.78(m ,J=18.1,13.4,5.4Hz,1H),2.09(m,J=13.0,4.5Hz,1H),1.89(m,J=10.3,5.4,2.6Hz,0H),1.54(s,3H),1.51(s,3H).

[0072] Example 8

[0073] (2S)-2-amino-N-(2,6-piperidindione-3-yl)-2-phenylacetamide hydrochloride, the structural formula of which is:

[0074]

[0075] The preparation method is the same as that in Example 1. The raw material used is (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid (2.0 g, 7.96 mmol), and the product is (1.08 g, 4.10 mmol, yield 52%). 1 H NMR (400MHz, DMSO-d6) δ10.85(d,J=22.5Hz,1H),9.14(d,J=7.8Hz,0.5H),9.09(d,J=8.1Hz,0.5H),8.84(d,J=6.1Hz,3H ),7.70–7.37(m,5H),5.07(d,J=5.5Hz,1H),4.75–4.54(m,1H),2.88–2.63(m,1H),2.59–2.42(m,2H),2.07–1.72(m,2H).

[0076] Example 9

[0077] (2S)-2-amino-N-(2,6-piperidindione-3-yl)-3-phenylpropanamide hydrochloride, the structural formula of which is:

[0078]

[0079] The preparation method is the same as that in Example 1. The raw material used is (tert-butyloxycarbonyl)-D-phenylalanine (2.2 g, 7.96 mmol), and the product is (0.83 g, 2.90 mmol, yield 37%). 1 H NMR (400MHz, DMSO-d6) δ10.90(d,J=3.7Hz,1H),9.20(d,J=7.8Hz,0.5H),9.08(d,J=8.5Hz,0.5H),8. 53(s,3H),7.42–7.06(m,5H),4.82–4.45(m,1H),3.96(s,1H),2.90–2.54(m,4H),2.21–1.88(m,4H).

[0080] Example 10

[0081] (2S)-2-amino-3-cyclohexyl-N-(2,6-piperazinedione-3-yl)propionamide hydrochloride, the structural formula of which is:

[0082]

[0083] The preparation method is the same as that in Example 1. The raw material used is (S)-2-((tert-butyloxycarbonyl)amino)-3-cyclohexylpropionic acid (2.2 g, 7.96 mmol), and the product is (1.06 g, 3.78 mmol, yield 48%). 1H NMR (400MHz, DMSO-d6) δ10.88(d,J=10.3Hz,1H),9.08(d,J=7.9Hz,0.5H),8.95(d,J =8.4Hz,0.5H),8.36(s,3H),4.78–4.49(m,1H),3.82(s,1H),2.74(m,J=21.0,13.0,8 .8,3.3Hz,1H),2.56(dt,J=9.2,4.0Hz,1H),1.97(m,J=14.5,7.1,4.2Hz,2H),1.85–1 .58(m,7H),1.54–1.34(m,1H),1.17(m,J=29.2,10.2,9.6Hz,3H),0.97–0.78(m,2H).

[0084] Embodiment 11

[0085] (2S)-2-amino-4-cyclohexyl-N-(2,6-piperidindione-3-yl)butanamide hydrochloride, the structural formula of which is:

[0086]

[0087] The preparation method is the same as that in Example 1. The raw material used is (S)-2-((tert-butoxycarbonyl)amino)-4-cyclohexylbutanoic acid (2.3 g, 7.96 mmol), and the product is (1.05 g, 3.58 mmol, yield 45%). 1 H NMR(400MHz,DMSO-d6)δ10.88(d,J=13.1Hz,1H),8.99(d,J=7.9Hz,0.5H),8.8 7(d,J=8.4Hz,0.5H),8.30(s,3H),4.80–4.46(m,1H),3.87–3.75(m,1H),2.75( m,J=18.0,12.3,5.8Hz,1H),2.59–2.54(m,1H),2.09–1.90(m,2H),1.78(m,J=1 2.9, 6.6Hz, 2H), 1.70–1.55 (m, 5H), 1.39–1.10 (m, 6H), 0.87 (d, J = 12.9Hz, 2H).

[0088] Example 12

[0089] 1-amino-N-((2,6-piperidindione-3-yl)cyclopropyl-1-carboxamide hydrochloride, the structural formula of which is:

[0090] The preparation method is the same as that in Example 1. The raw material used is 1-((tert-butoxycarbonyl)amino)cyclopropane-1-carboxylic acid (1.6 g, 7.96 mmol), and the product is (0.90 g, 4.30 mmol, yield 54%). 1 H NMR (400MHz, DMSO-d6) δ10.86(s,1H),8.73(s,3H),8.08(d,J=8.2Hz,1H),4.60(m,J=13.0,8.2,5.3Hz,1H),2.76(m,J=18.4 ,13.5,5.5Hz,1H),2.54(d,J=3.9Hz,1H),2.04(m,J=13.0,4.5Hz,1H),1.85(m,J=13.3,5.5,2.8Hz,1H),1.50–1.33(m,4H).

[0091] Embodiment 13

[0092] (1R, 2S)-1-amino-N-(2,6-piperidindione-3-yl)-2-vinylcyclopropanecarboxamide hydrochloride, the structural formula of which is:

[0093] The preparation method is the same as that in Example 1. The raw material used is (1R, 2S)-1-((tert-butoxycarbonyl)amino)-2-vinylcyclopropane-1-carboxylic acid (1.8 g, 7.96 mmol), and the product is (0.82 g, 3.46 mmol, yield 44%). 1 H NMR(400MHz,DMSO-d6)δ10.86(d,J=3.1Hz,1H),9.12–8.88(m,3H),8.65(d,J=8.2Hz,0.5H),8.5 8(d,J=8.2Hz,0.5H),5.69(m,J=83.4,17.1,10.3,8.9Hz,1H),5.30(m,J=17.0,5.2,1.7Hz,2H), 4.80–4.53(m,1H),2.75(m,J=18.5,13.1,5.6Hz,1H),2.60–2.53(m,1H),2.31(m,J=9.5,7.4,6. 6Hz,1H),2.15–1.96(m,2H),1.86(m,J=12.8,5.4,3.0Hz,1H),1.69(m,J=10.1,6.8,2.0Hz,1H).

[0094] Embodiment 14

[0095] (1S, 2R)-1-amino-N-(2,6-piperidindione-3-yl)-2-vinylcyclopropanecarboxamide hydrochloride, the structural formula of which is:

[0096]

[0097] The preparation method is the same as that in Example 1. The raw material used is (1R, 2R)-1-((tert-butoxycarbonyl)amino)-2-vinylcyclopropane-1-carboxylic acid (1.80 g, 7.96 mmol), and the product is (0.87 g, 3.66 mmol, yield 46%). 1 H NMR (400MHz, DMSO-d6) δ10.87(d,J=3.7Hz,1H),8.94(s,3H),8.60(d,J=8.2Hz,0.5 H),8.53(d,J=8.2Hz,0.5H),5.94–5.51(m,1H),5.39–5.07(m,2H),4.67(m,J=12.9 ,8.1,5.3Hz,1H),2.86–2.66(m,1H),2.55(d,J=4.4Hz,1H),2.30(m,J=15.8,9.0,5 .5Hz,1H),2.16–1.95(m,2H),1.94–1.77(m,1H),1.68(m,J=10.1,6.9,1.9Hz,1H).

[0098] Embodiment 15

[0099] 1-amino-N-((2,6-piperidindione-3-yl)cyclobutyl-1-carboxamide hydrochloride, the structural formula of which is:

[0100]

[0101] The preparation method is the same as that in Example 1. The raw material used is 1-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylic acid (1.7 g, 7.96 mmol), and the product is (1.72 g, 7.64 mmol, yield 96%). 1 H NMR (400MHz, DMSO-d6) δ10.91(s,1H),8.79(d,J=8.4Hz,1H),8.58(s,3H),4.67(m,J=13.0 ,8.2,5.3Hz,1H),2.80(m,J=18.2,13.5,5.5Hz,1H),2.68–2.55(m,3H),2.41–1.82(m,6H).

[0102] Example 16

[0103] 1-amino-N-((2,6-piperidindione-3-yl)cyclopentyl-1-carboxamide hydrochloride, the structural formula of which is:

[0104]

[0105] The preparation method is the same as that in Example 1. The raw material used is 1-((tert-butoxycarbonyl)amino)cyclopentane-1-carboxylic acid (1.7 g, 7.96 mmol), and the product is (1.60 g, 6.69 mmol, yield 84%). 1 H NMR (400MHz, DMSO-d6) δ10.86(s,1H),8.61(d,J=8.3Hz,1H),8.39(s,3H),4.62(m,J=13.1,8.3,5.3Hz ,1H),2.78(m,J=17.3,13.4,5.4Hz,1H),2.54(d,J=3.8Hz,1H),2.28–2.04(m,3H),2.00–1.75(m,7H).

[0106] Embodiment 17

[0107] 1-amino-N-((2,6-piperidindione-3-yl)cyclohexyl-1-carboxamide hydrochloride, the structural formula of which is:

[0108]

[0109] The preparation method is the same as that in Example 1. The raw material used is 1-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid (1.7 g, 7.96 mmol), and the product is (1.87 g, 7.40 mmol, yield 93%). 1 H NMR (400MHz, DMSO-d6) δ10.85(s,1H),8.83(d,J=8.2Hz,1H),8.36(s,3H),4.60(m,J=12.9,8.1,5.3Hz,1H),2.77(m,J=18.2,13.3,5.4Hz,1H),2. 55(m,J=3.7Hz,1H),2.09(m,J=16.3,10.6,4.6Hz,3H),1.88(m,J=13.3,5 .5,3.0Hz,1H),1.82–1.71(m,2H),1.70–1.48(m,5H),1.44–1.31(m,1H).

[0110] Embodiment 18

[0111] 9-(2-((S)-4-(4-chloromethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide)-N-((1S)-2-((2,6-piperidindione-3-yl)amino)-2-oxo-1-phenylethyl)nonanamide, the structural formula of which is:

[0112] The preparation method comprises the following steps:

[0113] (1) Dissolve (R)-2-(4-(4-chloromethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate (2 g, 4.38 mmol) in a hydrochloric acid dioxane solution (20 mL), and stir at room temperature for 10 h until the raw material is completely converted. After the reaction is completed, concentrate the reaction solution under reduced pressure to obtain a yellow solid crude product, which is directly used in the next step;

[0114] (2) The intermediate (1.8 g, 4.49 mmol) was dissolved in tetrahydrofuran (40 mL) solution, and HATU (6.05 g, 15.92 mmol) and DIEA (3.08 g, 23.88 mmol) were added to the solution. After stirring at room temperature for 20 min, tert-butyl 9-aminononanoate (1.02 g, 4.49 mmol) was added to the solution, and stirred at room temperature for 12 h until the raw material was completely converted. The reaction mixture was quenched with 20 mL of water and extracted with 3×15 mL of EA. The combined organic layer was washed with 30 mL of saturated NaCl and dried over anhydrous Na2SO4. After concentration under reduced pressure, the crude product was obtained, which was directly used for the next step;

[0115] (3) The crude product (2.0 g, 3.60 mmol) was dissolved in a hydrochloric acid dioxane solution (20 mL) and stirred at room temperature for 10 h until the raw material was completely converted. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a yellow solid crude product, which was directly used for the next step;

[0116] (4) The intermediate (100 mg, 0.18 mmol) was dissolved in tetrahydrofuran (2 mL) solution, and HATU (136.8 mg, 0.36 mmol) and DIEA (69.78 mg, 0.54 mmol) were added to the solution. After stirring at room temperature for 20 min, (2S)-2-amino-N-(2,6-piperidindione-3-yl)-2-phenylacetamide hydrochloride (53.47 mg, 0.18 mmol) was added to the solution, and stirred at room temperature for 12 h until the raw material was completely converted. The mixture was quenched with 2 mL of water and extracted with 3×2 mL of EA. The mixture was purified by column chromatography (DCM:MeOH 10:1), dried and concentrated to obtain a yellow solid. 1H NMR (601MHz, DMSO-d6) δ10.82 (d, J=28.8Hz, 1H), 8.67 (dd, J=39.4, 8.1Hz, 1H), 8.46 (dd, J= 19.8,8.3Hz,1H),8.18(t,J=5.7Hz,1H),7.50–7.39(m,6H),7.37–7.23(m,3H),5.55(dd,J= 11.0,8.3Hz,1H),4.58–4.46(m,2H),3.34–3.00(m,4H),2.69(m,1H),2.59(s,3H),2.40(s, 3H),2.29–2.10(m,J=7.4Hz,2H),2.01–1.74(m,2H),1.62(s,3H),1.44(m,4H),1.22(m,9H). 13 CNMR(151MHz,DMSO)δ173.43,172.57,169.93,163.52,155.59,150.34,139.11,137.17, 135.73,132.64,131.28,130.57,130.30,130.07,128.89,128.68,128.62,127.73,127.5 5,56.39,56.33,55.30,54.37,49.66,49.56,38.96,38.13,35.38,31.21,31.11,29.66,2 9.21,29.16,29.05,26.81,25.71,24.61,24.54,14.47,13.13,11.70.HRMS(ESI)+:calcd for C 41 H 47 ClN8O5S[M+H]+:799.3151,found:799.3324.

[0117] Embodiment 19

[0118] 9-(2-((S)-4-(4-chloromethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide)-N-((1R)-2-((2,6-piperidindione-3-yl)amino)-2-oxo-1-phenylethyl)nonanamide, the structural formula of which is: 1H NMR(601MHz,DMSO-d6)δ10.98–10.71(dd,1H),8.99–8.59(m,1H),8.58–8.39(m,1H),8.38–8.06(m,1H),7.87–7.06(m,9H),5.70–5.48(m,1H), 4.72–4.41(m,2H),3.17(m,4H),2.84–2.57(m,4H),2.40(s,3H),2.21( m,2H),2.11–1.76(m,2H),1.62(s,3H),1.57–1.38(m,4H),1.24(m,9H). 13 C NMR(151MHz,DMSO)δ173.40,173.34,172.40,172.33,172.30,172.19,170.37,169.78,163 .43,155.60,150.25,139.48,137.20,135.71,132.71,131.18,130.57,130.28,130.05,128 .90,128.64,128.58,127.74,127.55,56.34,54.41,49.65,49.55,35.39,31.25,29.72,29 .25,29.19,29.10,26.85,25.72,24.68,24.60,14.50,13.15,11.75.HRMS(ESI)+:calcdfor C 41 H 47 ClN8O5S[M+H]+:799.3151,found:799.3318.

[0119] The preparation methods of Examples 19-36 are the same as those of Example 18.

[0120] Embodiment 20

[0121] 9-(2-((S)-4-(4-chloromethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide)-N-((2R)-1-((2,6-piperidindione-3-yl)amino)-1-oxo-3-phenylpropane-2-yl)nonanamide, the structural formula of which is: 1H NMR(400MHz, DMSO-d6)δ10.82(d,J=3.9Hz,1H),8.37(dd,J=14.9,7.8Hz,1H),8.27–7.93(m,2H),7.46(m,4H),7.36–7.11(m,5H),4.77–4.3 5(m,3H),3.35–2.97(m,6H),2.94–2.67(m,2H),2.59(s,3H),2.41(s, 3H),2.11–1.75(m,4H),1.62(s,3H),1.43(m,2H),1.33–1.09(m,10H). 13 C NMR(151MHz,DMSO)δ173.37,172.49,172.43,172.08,171.75,169.79,163.42,155.61,150.2 4,138.49,138.30,137.21,135.70,132.71,131.18,130.57,130.28,130.06,129.64,128.89 ,128.38,126.61,54.41,54.07,49.53,38.97,38.47,38.16,35.67,31.37,31.07,29.72,29. 25,29.12,28.93,26.87,25.61,24.68,24.61,22.94,14.49,13.14,11.74.HRMS(ESI)+:calcd for C 42 H 49 ClN8O5S[M+H]+:813.3307,found:813.3483.

[0122] Embodiment 21

[0123] 9-(2-((S)-4-(4-chloromethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide)-N-((2S)-1-((2,6-piperidindione-3-yl)amino)-1-oxo-4-phenylbutan-2-yl)nonanamide, the structural formula of which is: 1H NMR(400MHz, DMSO-d6)δ10.81(s,1H),8.39–7.95(m,3H),7.63–7.13(m,9H),4.69–4.46(m,2H),4.34(t,J=6.8Hz,1H),3.32–2.97(m,6H),2 .77–2.68(m,1H),2.60(s,3H),2.41(s,3H),2.17(dd,J=13.9,7.1Hz,2H),2.04–1.84(m,4H),1.63(s,3H),1.55–1.37(m,4H),1.26(m,9H). 13 C NMR(151MHz,DMSO)δ173.39,173.38,172.68,172.55,172.39,172.21,172.10,169.78,163.43, 155.61,150.25,142.10,137.21,135.71,132.71,131.18,130.57,130.28,130.06,128.90,128 .77,128.71,126.26,54.41,52.56,49.42,38.94,38.15,35.65,34.79,31.89,31.83,31.40,31 .25,29.72,29.28,29.21,29.12,26.87,25.74,24.59,14.50,13.14,11.75.HRMS(ESI)+:calcd for C 43 H 51 ClN8O5S[M+H]+:827.3464,found:827.3628.

[0124] Embodiment 22

[0125] 9-(2-((S)-4-(4-chloromethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide)-N-((2R)-1-((2,6-piperidindione-3-yl)amino)-1-oxo-4-phenylbutan-2-yl)nonanamide, the structural formula of which is: 1H NMR(400MHz, DMSO-d6)δ10.83(dd,J=17.5,9.1Hz,1H),8.39–7.99(m,3H),7.66–6.91(m,9H),4.77–4.22(m,3H),3.42–2.97(m,6H) ,2.74–2.64(m,1H),2.61(s,3H),2.41(s,3H),2.27–2.08(m,2H),2.02–1.75(m,4H),1.62(s,3H),1.53–1.38(m,4H),1.26(m,9H). 13 C NMR (151MHz, DMSO) δ173.37,172.72,172.67,172.54,172.38,172.21,172.10,169.73,163.54,155.55 ,150.36,142.10,137.10,135.77,132.64,131.33,130.61,130.32,130.10,128.90,128.76,128.70,1 26.24,54.34,52.58,49.70,49.43,38.95,38.07,35.66,34.79,34.67,31.90,31.83,31.40,31.25,29 .71,29.28,29.21,29.12,26.87,25.75,25.72,24.69,24.58,14.49,13.15,11.74.HRMS(ESI)+:calcd for C 43 H 51 ClN8O5S[M+H]+:827.3464,found:827.3629.

[0126] Embodiment 23

[0127] 9-(2-((S)-4-(4-chloromethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide)-N-((2S)-3-cyclohexyl-1-((2,6-piperidindione-3-yl)amino)-1-oxopropane-2-yl)nonanamide, the structural formula of which is: 1H NMR(601MHz,DMSO-d6)δ10.79(d,J=17.0Hz,1H),8.29–8.05(m,2H),7.92(dd,J=8.7,2.8Hz,1 H),7.59–7.36(m,4H),4.62–4.47(m,2H),4.39(m,J=18.8,9.2,5.0Hz,1H),3.16(m,4H),2.71( m,J=17.6,12.0,5.8Hz,1H),2.60(s,3H),2.46(m,1H),2.42(s,3H),2.11(m,J=33.3,7.0Hz,2 H),2.00–1.82(m,2H),1.64(m,8H),1.55–1.37(m,6H),1.36–1.04(m,12H),1.00–0.77(m,2H). 13 C NMR (151MHz, DMSO) δ173.38,172.93,172.78,172.47,172.38,169.77,163.43,155.60,150.25,137 .21,135.70,132.71,131.18,130.57,130.27,130.05,128.88,54.41,50.44,50.37,49.51,49.37, 38.95,38.15,35.65,34.02,33.92,33.76,33.69,32.26,32.20,31.36,31.17,29.74,29.29,29.25 ,28.99,26.88,26.55,26.34,26.15,25.77,24.75,24.62,14.50,13.15,11.75.HRMS(ESI)+:calcd for C 42 H 55 ClN8O5S[M+H]+:819.3777,found:819.3943.

[0128] Embodiment 24

[0129] 9-(2-((S)-4-(4-chloromethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide)-N-((2R)-3-cyclohexyl-1-((2,6-piperidindione-3-yl)amino)-1-oxopropane-2-yl)nonanamide, the structural formula of which is: 1H NMR(601MHz,DMSO-d6)δ10.79(d,J=16.4Hz,1H),8.30–8.12(m,2H),7.91(dd,J=8.6,2.4Hz,1H ),7.53–7.46(m,2H),7.45–7.41(m,2H),4.60–4.47(m,2H),4.39(m,1H),3.29–3.03(m,4H),2.7 7–2.67(m,1H),2.60(s,3H),2.50–2.45(m,1H),2.45–2.39(s,3H),2.11(m,14.0,7.0Hz,2H),2 .00–1.84(m,2H),1.75–1.56(m,8H),1.55–1.39(m,6H),1.34–1.10(m,12H),0.95–0.77(m,2H). 13 C NMR (151MHz, DMSO) δ173.39,173.37,172.93,172.78,172.48,172.46,172.38,169.78,163.43,155.60,1 50.25,137.21,135.71,132.71,131.19,130.57,130.27,130.05,128.89,54.40,50.44,50.37,49.51,49. 37,40.52,38.95,38.15,35.65,34.02,33.92,33.75,33.69,32.25,32.19,31.35,31.17,29.73,29.29,29 .24,28.99,26.87,26.55,26.34,26.15,25.78,24.75,24.61,14.50,13.15,11.75.HRMS(ESI)+:calcdfor C 42 H 55 ClN8O5S[M+H]+:819.3777,found:819.3936.

[0130] Embodiment 25

[0131] 9-(2-((S)-4-(4-chloromethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide)-N-((2S)-4-cyclohexyl-1-((2,6-piperidindione-3-yl)amino)-1-oxobutane-2-yl)nonanamide, the structural formula of which is: 1H NMR(601MHz,DMSO-d6)δ10.79(d,J=18.0Hz,1H),8.30–8.11(m,2H),7.88(d,J=8 .3Hz,1H),7.59–7.37(m,4H),4.63–4.44(m,2H),4.26(m,1H),3.29–3.03(m,4H), 2.71(m,1H),2.60(s,3H),2.47(m,1H),2.45–2.37(s,3H),2.12(m,2H),1.90(m,2 H),1.75–1.57(m,8H),1.56–1.36(m,5H),1.32–1.05(m,15H),0.89–0.78(m,2H). 13 C NMR (151MHz, DMSO) δ173.38,172.53,172.47,172.38,172.31,169.77,163.42,155.60,150.24,137. 20,135.70,132.71,131.18,130.56,130.27,130.05,128.88,54.40,52.86,52.76,49.54,49.37,38. 95,38.15,37.23,37.13,35.61,33.42,33.17,33.10,31.36,31.19,30.17,29.74,29.30,29.24,29. 06,26.88,26.66,26.63,26.24,26.21,25.78,24.78,24.62,14.50,13.15,11.75.HRMS(ESI)+:calcd for C 43 H 57 ClN8O5S[M+H]+:833.3933,found:833.4122.

[0132] Embodiment 26

[0133] 9-(2-((S)-4-(4-chloromethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide)-N-(1-cyclopropyl-2-((2,6-piperidin-3-yl)amino)-2-oxoethyl)nonanamide, the structural formula of which is: 1H NMR(400MHz, DMSO-d6)δ10.81(d,J=13.8Hz,1H),8.38–8.11(m,2H),8.02(t,J=9.0Hz,1H),7. 61–7.33(m,4H),4.64–4.41(m,2H),3.89(m,1H),3.28–3.18(m,2H),3.09(dt,J=16.5,6.8Hz, 2H),2.77–2.66(m,1H),2.59(s,3H),2.41(s,3H),2.18–2.06(m,2H),1.91(d,J=8.4Hz,2H),1 .63(s,3H),1.43(d,J=14.1Hz,4H),1.33–1.18(m,8H),1.10–0.89(m,2H),0.48–0.21(m,4H). 13 C NMR(151MHz,DMSO)δ173.38,173.35,172.40,172.32,171.54,171.51,169.78, 163.43,155.60,150.25,137.21,135.70,132.71,131.18,130.57,130.28,130 .05,128.90,55.75,54.40,49.45,35.51,31.28,29.71,29.26,29.19,29.08,2 6.85,25.73,14.51,14.28,13.15,11.75,3.23,3.12,2.97.HRMS(ESI)+:calcd for C 38 H 47 ClN8O5S[M+H]+:763.3151,found:763.3302.

[0134] Embodiment 27

[0135] 9-(2-((S)-4-(4-chloromethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide)-N-(1-cyclohexyl-2-((2,6-piperidindione-3-yl)amino)-2-oxoethyl)nonanamide, the structural formula of which is: 1H NMR(400MHz,DMSO-d6)δ10.76(s,1H),8.47–8.07(m,2H),7.88–7.73(m,1H),7. 54–7.19(m,4H),4.67–4.41(m,2H),4.22(q,J=7.6Hz,1H),3.29–3.01(m,4H),2. 70(m,1H),2.59(s,3H),2.41(s,3H),2.24–2.04(m,2H),1.94(s,3H),1.64(d,J =10.2Hz,8H),1.52–1.37(m,4H),1.24(t,J=5.9Hz,9H),0.81(d,J=35.0Hz,2H). 13 C NMR(151MHz,DMSO)δ173.40,173.36,172.52,172.31,171.57,171.44,169.78,163 .42,155.60,150.24,137.20,135.70,132.71,131.18,130.57,130.28,130.05,128 .89,57.33,54.40,49.48,38.15,35.58,31.13,29.72,29.57,29.49,29.23,29.09, 26.85,26.11,26.05,25.84,24.82,24.58,14.50,13.15,11.75.HRMS(ESI)+:calcd for C 41 H 53 ClN8O5S[M+H]+:805.3787,found:805.3620.

[0136] Embodiment 28

[0137] 9-(2-((S)-4-(4-chloromethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide)-N-((2S)-1-((2,6-piperidindione-3-yl)amino)-3,3-dimethyl-1-oxobutane-2-yl)nonanamide, the structural formula of which is: 1H NMR (400MHz, DMSO-d6) δ10.78 (d, J=20.3Hz, 1H), 8.55–8.03 (m, 2H), 7.84–7. 30(m,5H),4.55(m,2H),4.30(dd,J=23.1,9.8Hz,1H),3.28–3.05(m,4H),2.84 –2.68(m,1H),2.60(s,3H),2.41(s,3H),2.30–2.05(m,2H),1.93(d,J=18.6H z,2H),1.63(s,3H),1.55–1.37(m,4H),1.35–1.13(m,9H),1.03–0.85(m,9H). 13 C NMR(151MHz,DMSO)δ173.38,172.52,169.79,163.44,150.25,137.21,135 .71,132.71,131.19,130.57,130.28,130.07,128.90,60.08,54.40,49.33 ,38.94,38.14,35.57,34.81,34.71,31.30,29.70,29.19,29.09,27.17,2 7.10,26.84,25.94,24.85,24.56,14.50,13.14,11.74.HRMS(ESI)+:calcd forC 39 H 51 ClN8O5S[M+H]+:779.3636,found:779.3464.

[0138] Embodiment 29

[0139] 9-(2-((S)-4-(4-chloromethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide)-N-((2S)-1-((2,6-piperidin-3-yl)amino)-1-oxopent-4-en-2-yl)nonanamide, the structural formula of which is: 1H NMR(601MHz,DMSO-d6)δ10.81(d,J=15.4Hz,1H),8.22–8.13(m,1H),8.05–7.87(m,1H),7.54–7.38 (m,4H),7.32–7.09(m,1H),5.72(m,1H),5.13–4.89(m,2H),4.61–4.44(m,1H),4.35–4.07(m,2H),3 .58(m,2H),3.29–3.17(m,2H),3.09(m,2H),2.60(s,3H),2.44–2.40(s,3H),2.33–2.25(m,2H),2.1 1(m,2H),2.05–1.89(m,1H),1.83–1.68(m,1H),1.65–1.58(s,3H),1.44(m,4H),1.34–1.17(m,8H). 13 C NMR (151MHz, DMSO) δ173.46,173.25,173.23,173.08,172.92,171.71,171.58,169.79,163.44,155.60,150.25 ,137.20,135.70,134.89,134.63,132.70,131.19,130.57,130.28,130.06,128.89,117.83,117.74,54.40,53. 21,52.79,52.01,51.94,51.79,40.52,40.38,38.96,38.15,36.41,36.36,35.64,35.53,30.31,30.22,29.71, 29.28,29.26,29.17,29.08,29.06,27.65,27.27,26.86,25.75,25.73,14.50,13.14,11.74.HRMS(ESI)+:calcd for C 38 H 47 ClN8O5S[M+H]+:763.3151,found:763.2902.

[0140] Embodiment 30

[0141] 1-(9-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide)nonanamide)-N-(2,6-piperidindione-3-yl)cyclopropane-1-carboxamide, the structural formula of which is: 1H NMR(400MHz,DMSO-d6)δ10.79(s,1H),8.41–8.07(m,2H),7.83(d,J=7.9Hz,1H) ,7.51–7.39(m,4H),4.62–4.39(m,2H),3.72–3.52(m,1H),3.27–3.16(m,2H),3. 09(m,2H),2.70(m,1H),2.59(s,3H),2.41(s,3H),2.14–2.04(m,2H),2.01–1.80 (m,2H),1.63(s,3H),1.52–1.38(m,4H),1.27–1.22(m,10H),0.90–0.76(m,2H). 13 C NMR(151MHz,DMSO)δ173.88,173.43,172.68,172.66,172.02,172.00,169.79, 163.44,155.60,150.26,137.20,135.70,132.70,131.19,130.57,130.28,130. 05,128.90,54.40,53.90,50.06,35.82,34.41,31.30,29.69,29.27,29.16,29. 13,26.85,25.27,24.67,16.85,16.62,14.50,13.15,11.75.HRMS(ESI)+:calcd forC 37 H 45 ClN8O5S[M+H]+:749.2994,found:749.3162.

[0142] Embodiment 31

[0143] 1-(9-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide)nonanamide)-N-(2,6-piperidindione-3-yl)cyclobutane-1-carboxamide, the structural formula of which is: 1H NMR (400MHz, DMSO-d6) δ8.35(s,1H),8.19(t,J=5.6Hz,1H),7.68(d,J=8.0Hz,1H),7. 52–7.39(m,4H),4.60–4.24(m,2H),3.26–3.19(m,2H),3.09(dd,J=11.6,5.9Hz,2H), 2.68(m,1H),2.59(s,3H),2.43(d,J=4.1Hz,1H),2.42(s,3H),2.10(q,J=8.8,7.5Hz, 4H),1.98(q,J=9.7,9.1Hz,2H),1.83(m,4H),1.62(s,3H),1.44(m,4H),1.23(m,8H). 13 C NMR(151MHz,DMSO)δ173.72,173.53,173.51,172.81,172.73,169.93,169.93,16 3.52,155.59,150.34,135.72,131.28,130.57,130.30,130.30,130.07,128.89, 128.89,58.90,55.30,54.36,49.80,38.95,38.11,35.58,31.24,31.06,29.64,2 9.24,29.14,29.06,26.81,25.44,24.55,14.47,13.13,11.70.HRMS(ESI)+:calcd for C 38 H 47 ClN8O5S[M+H]+:763.3151,found:763.3318.

[0144] Embodiment 32

[0145] 1-(9-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide)nonanamide)-N-(2,6-piperidindione-3-yl)cyclopentane-1-carboxamide, the structural formula of which is: 1H NMR (400MHz, DMSO-d6) δ10.75 (s, 1H), 8.17 (t, J = 5.3Hz, 1H), 7.91 (s, 1H), 7.70 (d ,J=7.8Hz,1H),7.59–7.34(m,4H),4.69–4.31(m,2H),3.28–2.96(m,4H),2.70(dd ,J=12.4,5.6Hz,1H),2.60(s,3H),2.41(s,3H),2.23–2.08(m,2H),2.08–1.95(m, 2H),1.92–1.76(m,4H),1.73–1.57(m,6H),1.55–1.37(m,4H),1.36–0.88(m,10H). 13 C NMR(151MHz,DMSO)δ174.21,173.46,172.82,172.80,169.79,163.43,155.60, 150.25,137.21,135.70,132.71,131.19,130.57,130.28,130.05,128.89,66. 48,60.21,54.40,49.87,38.15,36.92,36.22,35.79,31.23,29.70,29.27,29. 19,29.11,26.85,25.52,24.60,24.48,14.50,13.15,11.75.HRMS(ESI)+:calcd forC 39 H 49 ClN8O5S[M+H]+:777.3307,found:777.3472.

[0146] Embodiment 33

[0147] 1-(9-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide)nonanamide)-N-(2,6-piperidindione-3-yl)cyclohexane-1-carboxamide, the structural formula of which is: 1H NMR(400MHz, DMSO-d6)δ10.77(d,J=7.0Hz,1H),8.31–8.05(m,1H),7.68–7.40(m,6H),4.65–4.35(m,2H),3.28–3.08(m,4H),2.7 2–2.55(m,4H),2.42(s,3H),2.23–2.11(m,2H),2.09–1.95(m,2H),1.87(m,2H),1.63(m,4H),1.48(m,10H),1.32–1.18(m,10H). 13 C NMR(151MHz,DMSO)δ174.81,173.45,172.79,169.78,163.43,155.60,150.25 ,137.21,135.70,132.71,131.19,130.57,130.28,130.05,128.89,59.27,54 .40,49.79,38.95,38.15,35.97,32.65,31.58,31.24,29.70,29.27,29.18,2 6.85,25.69,25.55,24.64,21.50,14.50,13.14,11.74.HRMS(ESI)+:calcdfor C 40 H 51 ClN8O5S[M+H]+:791.3464,found:791.3641.

[0148] Embodiment 34

[0149] 9-(2-((S)-4-(4-chloromethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide)-N-(1-((2,6-piperidindione-3-yl)amino)-2-methyl-1-oxopropane-2-yl)nonanamide, the structural formula of which is: 1 H NMR (400MHz, DMSO-d6) δ10.75(s,1H),8.16(m,1H),7.76(m,2H),7.46(m,4H),4.47(m,2H),3.17(m,4H),2.62(m,4H),2.41(s, 3H),2.07(q,J=7.4,6.7Hz,2H),1.96–1.79(m,2H),1.62(s,3H),1.52–1.39(m,4H),1.34(d,J=5.6Hz,6H),1.30–1.22(m,9H). 13C NMR (151MHz, DMSO) δ174.63,173.50,172.79,172.31,169.79,163.44,155.6 2,155.61,150.26,137.22,135.70,132.71,130.58,130.29,130.06,128.90, 56.15,54.40,49.75,38.95,38.15,35.92,31.20,29.70,29.29,29.17,29.13 ,26.85,26.08,25.46,25.15,24.58,14.50,13.14,11.74.HRMS(ESI)+:calcd for C 37 H 47 ClN8O5S[M+H]+:751.3151,found:751.3319.

[0150] Embodiment 35

[0151] (1R,2S)-1-(9-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide)nonanamide)-N-(2,6-piperidin-3-yl)-2-vinylcyclopropane-1-carboxamide, the structural formula of which is: 1 H NMR(601MHz,DMSO-d6)δ10.77(s,1H),8.51(d,J=13.7Hz,1H),8.18(m,1H),7.91(dd,1H),7.62 –7.30(m,4H),5.86–5.53(m,1H),5.18(m,1H),4.98(m,1H),4.65–4.33(m,2H),3.27–3.17(m,2 H),3.15–2.99(m,2H),2.76–2.65(m,1H),2.60(s,3H),2.47(m,1H),2.41(s,3H),2.12–2.01(m ,2H),1.98–1.85(m,2H),1.63(m,4H),1.53–1.38(m,4H),1.34–1.19(m,8H),1.19–1.08(m,2H). 13C NMR(151 MHz, DMSO) δ173.87,173.77,173.40,173.36,172.47,169.81,169.64,163.44,155.60,150.26 ,137.20,135.70,135.68,132.69,131.20,130.57,130.28,130.06,128.89,116.47,54.39,50 .24,50.05,41.01,40.97,40.51,38.95,38.14,35.68,32.84,32.58,31.31,31.17,29.69,29. 26,29.16,29.13,29.08,26.85,25.35,25.27,24.82,14.50,13.15,11.74.HRMS(ESI)+:calcd for C 39 H 47 ClN8O5S[M+H]+:775.3151,found:775.3316.

[0152] Embodiment 36

[0153] (1S,2R)-1-(9-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide)nonanamide)-N-(2,6-piperidindione-3-yl)-2-vinylcyclopropane-1-carboxamide, the structural formula of which is: 1 H NMR (601 MHz, DMSO-d6) δ10.80 (s, 1H), 8.48 (d, J = 10.0 Hz, 1H), 8.16 (m, 1H), 7.89 (dd, J = 27.6, 7.7 Hz,1H),7.64–7.21(m,4H),5.68(m,1H),5.19(m,1H),4.98(m,1H),4.57–4. 45(m,2H),3.31–3.17(m,2H),3.16–3.01(m,2H),2.73–2.65(m,1H),2.60(s, 3H),2.50–2.44(m,1H),2.44–2.37(s,3H),2.13–2.01(m,2H),1.98–1.85(m ,2H),1.67–1.58(m,4H),1.46(m,4H),1.28–1.20(m,8H),1.19–1.08(m,2H). 13C NMR(151 MHz, DMSO) δ173.83,173.74,173.39,173.35,172.52,172.48,169.80,169.63,163.44,155.60, 150.26,137.20,135.70,132.70,131.19,130.57,130.28,130.05,128.89,116.46,54.39,50.24 ,50.05,41.01,40.96,40.52,38.95,38.14,35.74,35.68,32.86,32.61,31.32,31.18,29.69,2 9.26,29.14,29.09,26.85,25.35,25.27,24.82,21.91,14.51,13.15,11.75.HRMS(ESI)+:calcd for C 39 H 47 ClN8O5S[M+H]+:775.3151,found:775.3307.

[0154] Embodiment 37

[0155] A chimeric molecule based on the above dipeptide compound, 8-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrazin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-N-((1S)-2-((2,6-piperidindione-3-yl)amino)-2-oxo-1-phenylethyl)octanamide, has the structural formula:

[0156] The preparation method comprises the following steps:

[0157] (1) 5-Chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (2 g, 3.58 mmol) was dissolved in DMF (20 mL), and 8-bromooctanoic acid tert-butyl ester (998 mg, 3.58 mmol) and K2CO3 (1.48 g, 10.74 mmol) were added. The mixture was stirred at 80°C for 5 h until the raw material was completely converted. The reaction mixture was quenched with 20 mL of water and extracted with 3×15 mL of EA. The combined organic layer was washed with 30 mL of saturated NaCl and dried over anhydrous Na2SO4. The crude product was concentrated under reduced pressure to obtain the crude product, which was directly used for the next step.

[0158] (2) The crude product (2.5 g, 3.30 mmol) was dissolved in a hydrochloric acid dioxane solution (20 mL) and stirred at room temperature for 2 h until the raw material was completely converted. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a yellow solid crude product;

[0159] (3) The crude product (100 mg, 0.142 mmol) was dissolved in tetrahydrofuran (2 mL) solution, and HATU (108.70 mg, 0.284 mmol) and DIEA (55.06 mg, 0.426 mmol) were added to the solution. After stirring at room temperature for 20 min, (2S)-2-amino-N-(2,6-piperidindione-3-yl)-2-phenylacetamide hydrochloride (42.39 mg, 0.142 mmol) was added to the solution, and stirred at room temperature for 12 h until the raw material was completely converted. The reaction mixture was quenched with 2 mL of water and extracted with 3×2 mL of EA. Purification was performed by column chromatography (DCM:MeOH 10:1), and the residue was dried and concentrated to obtain a yellow solid. 1 H NMR (601MHz, DMSO-d6) δ10.84(d,J=28.7Hz,1H),9.48(s,1H),8.69(dd,J=42.4,8.2Hz,1H),8.49(dd,J=25.4,8.4Hz,2H),8.2 6(s,1H),8.11(s,1H),7.85(d,J=8.0Hz,1H),7.63(t,J=7.9Hz,1H),7.55(s,1H),7.45(dd,J=19.5,7.6Hz,2H),7.35(dt,J=13. 4,7.2Hz,3H),7.28(q,J=7.0Hz,1H),6.79(s,1H),5.58(dd,J=14.3,8.4Hz,1H),4.56(m,2H),3.66–3.41(m,4H),3.19–2.82(m ,4H),2.71(m,2H),2.24(m,2H),2.15(s,3H),2.02–1.74(m,6H),1.69–1.45(m,4H),1.31–1.22(m,12H),1.17(d,J=6.8Hz,6H). 13C NMR(151MHz,DMSO)δ173.36,172.36,170.42,158.43,155.87,155.35,147.17,139.49,13 9.26,138.50,135.26,131.43,128.68,128.62,127.88,127.76,127.55,127.25,124.99,1 24.47,124.15,124.07,104.84,71.36,56.31,55.37,55.30,49.66,49.54,35.33,31.26, 31.14,28.91,28.85,25.59,24.68,24.58,22.37,19.02,18.83,15.32.HRMS(ESI)+:calcd for C 49 H 63 ClN8O7S[M+H]+:943.4301,found:943.4529.

[0160] Embodiment 38

[0161] 5-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrazin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-N-((1S)-2-((2,6-piperidindione-3-yl)amino)-2-oxo-1-phenylethyl)pentanamide, the structural formula of which is: 1 H NMR(400MHz,DMSO-d6)δ10.83(d,J=19.2Hz,1H),9.47(s,1H),8.80–8.42(m,3H),8.26(s,1H) ,8.10(s,1H),7.93–7.80(m,1H),7.63(t,J=7.8Hz,1H),7.53(s,1H),7.46(dd,J=12.2,7.5Hz, 2H),7.40–7.26(m,4H),6.80(s,1H),5.58(t,J=9.3Hz,1H),4.54(s,2H),2.91(s,5H),2.69(s ,2H),2.30(s,2H),2.14(s,3H),1.88(m,7H),1.57(m,4H),1.24(m,8H),1.17(d,J=6.8Hz,6H). 13C NMR(151MHz,DMSO)δ173.35,172.19,170.34,158.45,155.86,155.35,15 5.35,147.18,139.15,138.49,135.28,131.41,128.72,128.66,127.91, 127.82,127.62,124.97,124.15,71.36,56.40,55.32,49.69,49.56,40. 53,31.27,31.14,24.66,24.58,22.38,18.83,15.32.HRMS(ESI)+:calcd for C 46 H 57 ClN8O7S[M+H]+:901.3832,found:901.4032.

[0162] The preparation methods of Examples 38-47 are the same as those of Example 37.

[0163] Embodiment 39

[0164] 11-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrazin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-N-((1S)-2-((2,6-piperidindione-3-yl)amino)-2-oxo-1-phenylethyl)undecanoic acid amide, the structural formula of which is: 1 H NMR(400MHz, DMSO-d6)δ10.83(d,J=20.2Hz,1H),9.52–9.42(m,1H),8.75–8.60(m,1H),8.47( d,J=7.6Hz,2H),8.25(s,1H),8.07(s,1H),7.84(d,J=8.3Hz,1H),7.62(s,1H),7.52(s,1H),7. 44(t,J=9.9Hz,2H),7.35(d,J=8.5Hz,4H),6.83(s,1H),5.56(d,J=7.7Hz,1H),4.56(m,2H),2 .21(m,2H),2.13(s,3H),1.84(m,7H),1.50(m,4H),1.31–1.20(m,20H),1.16(d,J=6.7Hz,6H). 13CNMR(151MHz,DMSO)δ173.34,172.40,170.38,158.45,155.87,155.32,147.13,138.49,135.28,131.39,128.64,128.59,127.75,127.55,12 4.04,112.09,104.75,71.24,56.29,55.32,49.65,35.38,29.40,29.24,29.10,27.27,25.72,24.59,22.38,18.83,15.32.HRMS(ESI)+:calcd for C 52 H 69 ClN8O7S[M+H]+:985.4771,found:985.4994.

[0165] Embodiment 40

[0166] 1-(8-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrazin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)octanamido)-N-(2,6-piperidindione-3-yl)cyclobutane-1-carboxamide, the structural formula of which is: 1 H NMR (601MHz, DMSO-d6) δ10.80(s,1H),9.47(s,1H),8.47(d,J=8.4Hz,1H),8.36(s,1H),8.25(s,1H),8.08(s,1H),7.8 4(dd,J=8.0,1.7Hz,1H),7.68(d,J=7.9Hz,1H),7.66–7.60(m,1H),7.53(s,1H),7.36(t,J=7.7Hz,1H),6.84(s,1H),4. 62–4.41(m,2H),3.44(m,1H),2.86–2.64(m,4H),2.60–2.54(m,1H),2.48–2.38(m,2H),2.13(d,J=5.6Hz,6H),2.04–1 .98(m,1H),1.97–1.65(m,9H),1.64–1.37(m,5H),1.29(d,J=7.9Hz,6H),1.23(d,J=6.0Hz,7H),1.16(d,J=6.8Hz,7H). 13CNMR(151MHz,DMSO)δ173.63,173.45,172.75,172.65,158.44,155.85,155.33, 147.14,138.49,135.28,131.40,127.49,127.11,124.93,124.32,124.11,124. 05,112.06,104.79,71.31,58.93,55.32,49.80,35.54,31.28,31.14,31.11,29 .00,28.94,26.92,25.36,24.62,22.38,18.83,15.69,15.32.HRMS(ESI)+:calcd for C 46 H 63 ClN8O7S[M+H]+:907.4301,found:907.4513.

[0167] Embodiment 41

[0168] 1-(8-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrazin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)octanamido)-N-(2,6-piperidindione-3-yl)cyclopentane-1-carboxamide, the structural formula of which is: 1 H NMR (601MHz, DMSO-d6) δ10.85–10.73(s,1H),9.47(s,1H),8.47(d,J=8.5Hz,1H),8.25(s,1H),8.08(s,1H),7.94(s ,1H),7.84(dd,J=8.0,1.7Hz,1H),7.72(d,J=7.9Hz,1H),7.68–7.60(m,1H),7.53(s,1H),7.42–7.33(m,1H),6.84( s,1H),4.59–4.41(m,2H),3.44(m,1H),3.04–2.58(m,6H),2.46(t,J=3.8Hz,1H),2.19–2.07(m,6H),2.00(m,1H),1 .96–1.71(m,8H),1.69–1.56(m,6H),1.50(m,2H),1.36–1.25(m,6H),1.23(d,J=6.0Hz,7H),1.16(d,J=6.7Hz,7H). 13C NMR(151MHz,DMSO)δ174.21,173.50,172.85,172.79,158.43,155.85,155.33,147 .14,138.49,135.27,131.40,127.52,127.13,124.93,124.33,124.11,124.05,104 .80,71.32,66.49,55.32,49.86,40.52,36.93,36.24,35.71,32.00,31.24,28.99, 28.95,26.89,25.41,24.61,24.51,24.49,22.38,18.83,15.32.HRMS(ESI)+:calcd for C 47 H 65 ClN8O7S[M+H]+:921.4458,found:921.4669.

[0169] Embodiment 42

[0170] 8-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrazin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidine-1-carboxamide-N-(1-cyclohexyl-2-((2,6-piperidindione-3-yl)amino)-2-oxoethyl)octanamide, the structural formula of which is: 1 H NMR (601MHz, DMSO-d6) δ10.79(d,J=21.9Hz,1H),9.47(s,1H),8.47(d,J=8.4Hz,1H),8.39(d,J=8.0Hz,1H),8.26(d,J=9.3H z,1H),8.07(s,1H),7.90–7.78(m,2H),7.67–7.59(m,1H),7.53(s,1H),7.42–7.33(m,1H),6.83(s,1H),4.59–4.49(m,2H), 4.33–4.14(m,1H),3.44(m,1H),3.24(m,2H),2.72(m,4H),2.54(m,1H),2.48(dd,J=9.2,5.5Hz,1H),2.28–2.18(m,1H),2.1 3(m,4H),2.02–1.80(m,4H),1.79–1.64(m,6H),1.63–1.40(m,7H),1.26(m,12H),1.16(d,J=6.7Hz,7H),1.12–0.98(m,4H). 13C NMR (151MHz, DMSO) δ173.41,173.37,172.56,172.53,172.32,171.56,171.43,158.44,155.85,15 5.32,147.12,138.49,135.27,131.40,127.09,124.93,124.31,124.11,124.05,112.06,104.78,7 1.29,57.35,57.28,55.32,49.50,49.40,40.53,35.54,31.31,31.14,29.58,29.49,28.97,28.65 ,28.46,27.02,26.33,26.12,26.06,25.76,24.83,24.58,22.38,18.82,15.31.HRMS(ESI)+:calcd for C 49 H 69 ClN8O7S[M+H]+:949.4771,found:949.4985.

[0171] Embodiment 43

[0172] 8-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrazin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidine-1-carboxamide-N-(1-(2,6-piperidindione-3-yl)amino)-2-methyl-1-oxopropyl)octanamide, the structural formula of which is: 1 H NMR (601MHz, DMSO-d6) δ10.77(s,1H),9.47(s,1H),8.46(d,J=8.1Hz,1H),8.25(s,1H),8.08(s,1H),7.89–7.81(m, 2H),7.74(d,J=8.0Hz,1H),7.67–7.60(m,1H),7.53(s,1H),7.36(m,1H),6.84(s,1H),4.61–4.41(m,2H),3.29-3.2 2(m,1H),2.94–2.61(m,6H),2.49–2.44(m,1H),2.14(s,3H),2.10(m,2H),2.00–1.83(m,4H),1.78(d,J=13.1Hz,2H ),1.61(m,2H),1.49(m,2H),1.35(d,J=2.4Hz,6H),1.33–1.25(m,7H),1.23(d,J=6.0Hz,7H),1.16(d,J=6.8Hz,6H). 13C NMR(151MHz,DMSO)δ174.65,173.53,172.80,172.32,158.44,155.85,155.33,1 47.16,138.48,135.28,131.40,127.52,127.13,124.93,124.35,124.12,124.0 7,112.07,104.79,71.33,56.17,55.32,49.74,40.51,35.84,31.20,29.00,28. 97,26.85,26.08,25.35,25.17,24.58,22.38,18.83,15.31.HRMS(ESI)+:calcd for C 45 H 63 ClN8O7S[M+H]+:895.4301,found:895.4498.

[0173] Embodiment 44

[0174] 8-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrazin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidine-1-carboxamide-N-[(2S)-1-((2,6-piperidindione-3-yl)amino)-1-oxo-4-phenylbutyl]octanamide, the structural formula of which is: 1 H NMR (601MHz, DMSO-d6) δ10.82(s,1H),9.47(s,1H),8.47(d,J=8.4Hz,1H),8.30(d,J=8.0Hz,1H),8.25(d,J=5.3Hz,1H),8.07(q ,J=4.7,4.1Hz,2H),7.84(dd,J=8.0,1.6Hz,1H),7.67–7.59(m,1H),7.53(s,1H),7.39–7.33(m,1H),7.31–7.26(m,2H),7.24–7. 13(m,3H),6.83(s,1H),4.64–4.45(m,2H),4.34(m,1H),3.49–3.44(m,1H),3.18(m,2H),2.80–2.54(m,6H),2.49–2.42(m,1H),2 .24–2.15(m,2H),2.13(s,3H),2.03–1.65(m,8H),1.54(m,4H),1.36–1.26(m,6H),1.22(d,J=6.0Hz,7H),1.16(d,J=6.8Hz,7H). 13C NMR(151MHz,DMSO)δ173.40,172.75,172.70,172.54,172.40,172.23,172.12,158.44,155.85,155.32,1 47.10,142.10,141.96,138.49,135.28,131.40,128.78,128.72,127.37,127.04,126.27,124.91,124.26 ,124.10,124.05,112.07,104.77,71.26,55.33,52.60,49.70,49.43,40.52,35.63,34.81,34.70,31.92 ,31.86,31.41,31.26,29.07,29.01,27.12,25.68,24.69,24.58,22.38,18.83,15.31.HRMS(ESI)+:calcd for C 51 H 67 ClN8O7S[M+H]+:971.4614,found:971.4836.

[0175] Embodiment 45

[0176] 8-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrazin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidine-1-carboxamide-N-[(1R)-2-((2,6-piperidindione-3-yl)amino)-2-oxo-1-phenylethyl]octanamide, the structural formula of which is: 11H NMR (601 MHz, DMSO-d6) δ 10.83 (d, J = 27.5 Hz, 1H), 9.47 (s, 1H), 8.75 (d, J = 8.2 Hz, 1H), 8.68 (d, J = 8.0 Hz, 1H), 8.49 (m, 2H), 8.25 (s, 1H), 8.07 (s, 1H), 7.84 (dd, J = 8.0, 1.6 Hz, 1H), 7.69–7.59 (m, 1H), 7.52 (s, 1H), 7.50–7.41 (m, 2H), 7.39–7.31 (m, 3H), 7.28 (m, 1H), 6.85 (s, 1H), 5.58 (dd, J = 11.4, 8.3 Hz, 1H), 4.61–4.48 (m, 2H), 3.47 (m, 1H), 3.17 (m, 2H), 2.83–2.66 (m, 2H), 2.64–2.51 (m, 2H), 2.47–2.38 (m, 1H), 2.30–2.17 (m, J = 7.4 Hz, 2H), 2.13 (s, 3H), 2.03–1.78 (m, 4H), 1.72 (m, 2H), 1.51 (m, 4H), 1.36–1.24 (m, 6H), 1.22 (d, J = 6.0 Hz, 7H), 1.16 (d, J = 6.8 Hz, 7H). 13 13C NMR (151 MHz, DMSO) δ 173.36, 172.41, 172.30, 172.19, 170.43, 170.37, 158.46, 155.85, 155.32, 147.14, 139.48, 139.26, 138.49, 135.29, 131.39, 128.66, 128.60, 127.83, 127.75, 127.56, 127.02, 124.90, 124.29, 124.10, 112.12, 104.74, 71.25, 56.38, 56.33, 55.32, 49.65, 49.54, 35.37, 31.25, 31.14, 29.05, 29.00, 27.13, 25.66, 24.66, 24.58, 22.38, 18.83, 15.32. HRMS (ESI)+: calcd for C 49 H 63 ClN8O7S [M + H]+: 943.4301, found: 943.4248.

[0177] Example 46

[0178] 8-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrazin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidine-1-carboxamide-N-[(2R)-1-((2,6-piperidindione-3-yl)amino)-1-oxo-3-phenylpropyl]octanamide, the structural formula of which is: 1 H NMR (601MHz, DMSO-d6) δ10.92–10.81(s,1H),9.47(s,1H),8.47(d,J=8.4Hz,1H) ,8.38(dd,J=22.6,8.1Hz,1H),8.25(s,1H),8.11–8.05(m,1H),8.02(d,J=8.6Hz ,1H),7.84(dd,J=8.0,1.6Hz,1H),7.65–7.60(m,1H),7.53(s,1H),7.36(m,1H), 7.31–7.23(m,4H),7.23–7.16(m,1H),6.83(s,1H),4.65–4.49(m,3H),3.46–3.4 3(m,1H),3.27–3.17(m,2H),3.10(dd,J=13.9,4.0Hz,1H),2.99(dd,J=13.6,5.1 Hz,1H),2.82–2.72(m,2H),2.72–2.59(m,2H),2.47–2.41(m,1H),2.13(s,3H),2 .05(m,2H),2.00–1.90(m,1H),1.89–1.79(m,3H),1.75(t,J=7.3Hz,2H),1.53(m ,2H),1.41–1.30(m,2H),1.22(m,10H),1.16(d,J=6.8Hz,6H),1.14–1.07(m,2H). 13CNMR(151MHz,DMSO)δ173.39,173.35,172.49,172.41,172.36,172.08,171.75,158.45,155.85,155.32,14 7.13,138.49,138.32,135.27,131.40,129.67,128.41,127.38,127.05,126.64,124.92,124.31,124.10,1 24.04,112.05,104.77,71.25,55.32,54.10,54.07,49.54,49.52,40.53,38.50,38.23,35.63,32.00,31.3 9,31.08,29.90,29.05,28.84,28.80,27.01,25.55,24.68,24.62,22.38,18.83,15.32.HRMS(ESI)+:calcd forC 50 H 65 ClN8O7S[M+H]+:957.4458,found:957.4396.

[0179] Embodiment 47

[0180] 8-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrazin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-N-(1-cyclopropyl-2-((2,6-piperidindione-3-yl)amino)-2-oxoethyl)octanamide, the structural formula of which is: 1H NMR (601MHz, DMSO-d6) δ10.82(d,J=18.6Hz,1H),9.47(s,1H),8.47(d,J=8.3Hz,1H),8.31–8.24(m,1H),8.20(d,J=8.2Hz,1H), 8.12–8.00(m,2H),7.84(dd,J=8.0,1.6Hz,1H),7.67–7.59(m,1H),7.53(s,1H),7.41–7.32(m,1H),6.82(s,1H),4.63–4.47(m,2 H),3.90(m,1H),3.46(d,J=6.7Hz,1H),3.29-3.22(m,2H),2.89–2.64(m,4H),2.48(d,J=4.0Hz,1H),2.20–2.08(m,5H),1.97–1 .72(m,6H),1.65–1.44(m,4H),1.40–1.25(m,7H),1.23(d,J=6.1Hz,7H),1.16(d,J=6.8Hz,6H),1.05(m,1H),0.48–0.25(m,4H). 13 C NMR (151MHz, DMSO) δ173.39,173.37,172.40,172.33,171.52,158.44,155.85,155.33,147.1 3,138.49,135.27,131.41,127.50,127.13,124.94,124.34,124.13,124.06,112.03,104.79 ,71.30,55.75,55.32,49.45,40.52,35.47,32.00,31.29,31.13,29.90,28.95,26.91,25.64 ,24.92,24.77,22.38,18.83,15.32,14.61,14.30,3.30,3.26,3.13,2.97.HRMS(ESI)+:calcd for C 46 H 63 ClN8O7S[M+H]+:907.4301,found:907.4252.

[0181] Test example

[0182] 1. The chimeric molecule obtained in Example 18-36 was used to induce BRD4 protein degradation, and the process was as follows:

[0183] (1) Cell culture and drug treatment: MDA-MB-468 and SU-DHL-4 cells in the logarithmic growth phase were cultured at 5 × 10 cells per dish. 5The cells were inoculated in a 60 mm dish and cultured in a 37° C., 5% CO 2 incubator. When the cells were almost completely attached to the wall and reached the logarithmic growth phase, the culture medium was removed and the cells were treated with different concentrations of compounds for 4 h.

[0184] (2) Protein extraction and quantification: The cells treated with the compound were digested with trypsin, and the culture medium was centrifuged to collect the precipitate in an ep tube after terminating the digestion. The cells were washed 2-3 times with pre-cooled PBS on ice, and a certain cell lysis solution was added to lyse for about 30 minutes. The samples were ultrasonically broken on ice until the solution was clear, and then the lysis was continued on ice for about 30 minutes and centrifuged on ice for 15 minutes, and the supernatant was collected into a new ep tube. The protein supernatant collected in the above process was quantified for total protein using a BCA protein quantification kit, and the sample was diluted with RIPA to the same protein concentration in each tube. Then, 1 / 4 of the protein loading buffer (5×) was added, vortexed to mix, and placed in a metal bath to denature the protein, then cooled naturally, and then stored at -20°C.

[0185] (3) Protein immunoblotting analysis: Select sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) gel of appropriate concentration according to the molecular weight of the target protein, and prepare the required number of gels according to the instructions. After checking the solidified gel plate for leaks, add the protein pre-stained marker and the protein sample prepared above into the gel wells according to the loading order and volume. After running the sample out of the concentrated gel area with an 80V voltage, adjust the voltage to 120V and continue running the gel. When the sample runs to the bottom of the gel, end the electrophoresis and transfer the membrane to a methanol-activated PVDF membrane. Then, load the prepared transfer clamp into the electrophoresis tank, place it in an ice box, select the appropriate transfer voltage and time for transfer, and remove the PVDF membrane after the end. After the blocking is completed, incubate the primary antibody overnight. After the primary antibody incubation is completed, wash (3 times, 10 minutes each time), then incubate the secondary antibody, incubate at room temperature for 1 hour, and then wash (3 times, 10 minutes each time). After cleaning, the PDVF membrane was immersed in the ultrasensitive ECL chemiluminescent substrate for a few seconds, and then placed in an exposure machine for exposure to obtain a WB image, which was then analyzed in grayscale using Image J.

[0186] The efficacy of inducing BRD4 protein degradation was tested 4 h after administration, and the results are as follows: Figure 1 As shown. Among them, Figure 1In,*SAKIICHIKAWA,HOPE A.FLAXMAN,WENQING XU,et al.The E3 ligase adapter cereblontargets the C-terminal cyclic imide degron[J].Nature,2022,610(Oct.27TN.7933):775-782.DOI:10.1038 / s41586-022-05333-5.

[0187] Depend on Figure 1 It can be seen that the chimeric molecules obtained in Examples 18-36 can induce BRD4 protein degradation to varying degrees.

[0188] 2. The chimeric molecules obtained in Examples 37-47 were used to induce ALK protein degradation, and the detection process was the same as that in Experimental Example 1.

[0189] The efficacy of inducing ALK protein degradation was tested 24 hours after administration, and the results were as follows Figure 2 shown.

[0190] Depend on Figure 2 It can be seen that the chimeric molecules obtained in Examples 37-47 can induce ALK protein degradation to varying degrees.

[0191] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A dipeptide compound, characterized in that: Its general structural formula is: Among them, R 1a is C1-C8 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl or R 2a is H or C1-C3 alkyl; or R 1a , R 2a and the carbon atoms to which they are connected together form a substituted or unsubstituted 3-8 membered saturated ring; R 1b is H or C1-C3 alkyl; R 2b is C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl or R3 is C3-C8 cycloalkyl, aryl or heteroaryl; n1 and n2 are independently integers between 1 and 6.

2. The dipeptide compound according to claim 1, characterized in that R 1a , R 2a and the carbon atoms they are connected to form Among them, R 4a , R 4b R is independently hydrogen, methyl, cyclopropyl, cyclobutyl, vinyl or ethynyl.

3. The dipeptide compound according to claim 1, characterized in that R 2b is C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, 4. The dipeptide compound according to claim 1, characterized in that Its structural formula is:

5. A chimeric molecule based on the dipeptide compound according to any one of claims 1 to 4, characterized in that: Its general structural formula is: MLN; Wherein, M is a small molecule or peptide that can bind to the target protein; L is a connecting unit, and both ends of L are connected to an atom of M and N respectively; N is the dipeptide compound according to any one of claims 1 to 4.

6. The dipeptide compound-based chimeric molecule according to claim 5, characterized in that M is a BRD4 inhibitor or an ALK inhibitor; M is 7. The dipeptide compound-based chimeric molecule according to claim 5, characterized in that L is -NH(CH2) n3 CO-, -NH(CH2CH2O) n4 -(CH2) n5 CO-, -CO(CH2) n3 CO-, -CO(CH2) n6 (CH2CH2O) n4 -(CH2) n5 CO-, -CO(CH2) n3 CH2-, -CO(CH2) n6 (CH2CH2O) n4 -(CH2) n5 CH2-; Wherein, n3 is an integer between 1 and 20; n4 is an integer between 1 and 10; n5 is 1 or 2; n6 is 0 or 1.

8. The dipeptide compound-based chimeric molecule according to claim 5, characterized in that When M is a BRD4 inhibitor, the chimera molecular structure is: When M is an ALK inhibitor, the chimera molecular structure is:

9. Use of the dipeptide compound-based chimeric molecule according to any one of claims 5 to 8, its stereoisomers, its pharmaceutically acceptable salts, its physiologically acceptable salts or its solvates in the preparation of BRD4 wild-type and its mutant protein degrader drugs and / or ALK wild-type and its mutant protein degrader drugs.

10. The use according to claim 9, characterized in that The drug is a drug for inhibiting BRD4-dependent tumors, diabetes, atherosclerosis, and coronary artery disease, as well as a drug for inhibiting ALK wild-type and mutant protein-dependent tumors.

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