FLT3-ITD targeted proteolytic chimera and preparation method, pharmaceutical composition and application thereof

Abstract

The present invention belongs to the field of chemical medicine technology, and specifically relates to a FLT3-ITD targeted proteolytic chimera and a preparation method, a pharmaceutical composition and an application thereof. The structural formula of the FLT3-ITD targeted proteolytic chimera is shown in Formula I. The preparation process of the present invention is simple and easy, and the prepared proteolytic targeted chimera or its pharmaceutically acceptable salt has the effect of efficient targeted degradation of FLT-3, and has high in vitro and in vivo anti-tumor activity. In addition, the compound has good plasma stability and good drug potential.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical medicines, and specifically relates to a FLT3-ITD targeted protein hydrolysis chimera, a preparation method thereof, a pharmaceutical composition and application thereof. Background Art

[0002] Acute myeloid leukemia (AML) is a highly malignant blood disease in which FMS-like tyrosine receptor kinase 3 (FLT3) plays an important role. Clinical FLT3 mutations lead to poor treatment effects of existing FLT3 inhibitors, resulting in poor prognosis, high relapse rate, and low overall survival rate. FLT3 gene mutations are also the most common gene mutations in patients with acute myeloid leukemia (AML). There are two main types: internal tandem duplication mutations in the paramembrane domain (FLT3-ITD) and point mutations (FLT3-TKD) or deletions in the tyrosine kinase domain. FLT3-ITD (internal tandem duplication) and FLT3-TKD (tyrosine kinase domain) are the main mutation types. FLT3-ITD mutations exist in a portion of AML patients and are the most common mutated genes in AML patients, resulting in abnormal activation of multiple intracellular signaling pathways, mainly including STAT5, MAPK, and AKT. Since high-dose chemotherapy and allogeneic hematopoietic stem cell transplantation cannot fully improve prognosis, small molecule inhibitors are becoming a research hotspot for AML treatment. Although small molecule inhibitors show good effects in the early stages of treatment, resistance mutations will limit long-term administration and clinical benefits. The resistance mechanism of FLT3 inhibitors is relatively complex, and resistant cells are often heterogeneous, resulting in poor efficacy of existing FLT3 inhibitors and extremely poor prognosis. Therefore, further clinical research and treatment methods are urgently needed to develop the best treatment strategy for patients with FLT3-ITD mutant AML. Summary of the invention

[0003] The purpose of the present invention is to solve the deficiencies of the prior art and provide a FLT3-ITD targeted proteolytic chimera and a preparation method, a pharmaceutical composition and application thereof, specifically adopting the following technical solutions:

[0004] In the first aspect of the present invention, a FLT3-ITD targeted proteolytic chimera is provided, the structural formula of which is shown in Formula I:

[0005] Formula I;

[0006] Wherein, E3 in Formula I is , , , Any one of; X is H or F; Y is N or O;

[0007] In formula I, Linker is a saturated fatty chain, an unsaturated fatty chain or a fatty acid chain.

[0008] The present invention develops a series of small molecules that selectively degrade FLT3-ITD and C-Kit through PROTAC technology, and obtains a series of molecules that have exerted efficient anti-tumor activity both in vivo and in vitro, which are significantly better than single inhibitors. It not only provides a new strategy for the treatment of AML, but also provides a molecular probe for the study of FLT3 non-kinase functions. The linker is a saturated fatty chain, an unsaturated fatty chain or a fatty acid chain. By selecting ideal linkers of different types and lengths, the purpose of maintaining the binding of the two proteins without affecting their binding in space is achieved.

[0009] Preferably, the above-mentioned FLT3-ITD type targeted proteolytic chimera,

[0010] When E3 is When Linker is any of the following structures;

[0011] ;

[0012] When E3 is , , , When any of the structures in .

[0013] More preferably, the FLT3-ITD targeted proteolytic chimera is any one of the following structures:

[0014] ,

[0015] .

[0016] In a second aspect of the present invention, a method for preparing the above-mentioned FLT3-ITD targeted proteolytic chimera is provided, wherein the preparation route is as shown in route 1, route 2, route 3, route 4, route 5, route 6, route 7, route 8, route 9, route 10, route 11, route 12 or route 13:

[0017] Route 1:

[0018] ;

[0019] Route 2:

[0020] ;

[0021] Route 3:

[0022] ;

[0023] Route 4:

[0024] ;

[0025] Route 5:

[0026] ;

[0027] Route 6:

[0028] ;

[0029] Route 7:

[0030] ;

[0031] Route 8:

[0032] ;

[0033] Route Nine:

[0034] ;

[0035] Route 10:

[0036] ;

[0037] Route 11:

[0038] ;

[0039] Route 12:

[0040] ;

[0041] Route 13:

[0042] ;

[0043] Among them, X in route six is , , .

[0044] The third aspect of the present invention also provides the use of the above-mentioned FLT3-ITD targeted proteolysis chimera or a pharmaceutically acceptable salt thereof in the preparation of a FLT3 inhibitor.

[0045] The fourth aspect of the present invention provides the use of the above-mentioned FLT3-ITD targeted proteolytic chimera or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating and / or preventing cancer. Preferably, the above-mentioned cancer is leukemia.

[0046] The fifth aspect of the present invention provides a pharmaceutical composition, which comprises the above-mentioned FLT3-ITD-targeted proteolytic chimera or a pharmaceutically acceptable salt thereof.

[0047] Preferably, the above-mentioned pharmaceutical composition further comprises an excipient, a solvent, and a pharmaceutically acceptable carrier.

[0048] Preferably, the excipients include at least one of gum arabic, syrup, lanolin and starch.

[0049] The beneficial effects of the present invention are as follows: the preparation process of the present invention is simple and easy, the prepared protein hydrolysis targeted chimera or its pharmaceutically acceptable salt has the effect of highly efficient targeted degradation of FLT-3, and a FLT3-ITD and C-Kit dual degrader is obtained, and has high in vitro and in vivo anti-tumor activity; in addition, the compound has good plasma stability and good drug-making potential, and is suitable for the development of cancer drugs for the treatment of acute myeloid leukemia and the like. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] Figure 1 Shown are survival curves for compounds A1 and D11. DETAILED DESCRIPTION

[0051] The following will be combined with the embodiments and drawings to clearly and completely describe the concept, specific structure and technical effects of the present invention, so as to fully understand the purpose, scheme and effect of the present invention. It should be noted that the embodiments and features in the embodiments of this application can be combined with each other without conflict.

[0052] Example 1

[0053] The synthetic route of FLT3-ITD targeted proteolytic chimera (Compound A1) is as follows:

[0054]

[0055] (1) Preparation of compound 3 (5-(4-(2-bromoacetyl)piperazine-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione):

[0056] Compound 2 (3.00 g, 6.78 mmol) was dissolved in 4M hydrochloric acid-1,4-dioxane solution and reacted at room temperature for 3 hours. After the reaction was completed, the crude yellow solid was obtained by spin drying. The crude product was dissolved in 20 mL of acetonitrile, and triethylamine (1.75 g, 13.56 mmol) was added thereto. At 0 °C, bromoacetyl chloride (1.28 g, 8.14 mmol) was slowly added dropwise and stirred at room temperature for 3 hours. After the reaction was completed, 20 mL of saturated NaCl solution was added to the reaction solution and extracted with 40 mL of ethyl acetate. The organic phase was collected, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and column chromatography (dichloromethane: methanol = 80: 1) was performed to obtain compound 3 (2.5 g, 79.59%) as a yellow solid.

[0057] The test results of compound 3 are: 1 H NMR (400 MHz, Chloroform- d ) d 8.99 (s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.08 – 7.00 (m, 1H), 5.02 – 4.88 (m, 1H), 4.12 (s, 2H), 3.73 (d, J = 29.5 Hz, 4H), 3.54 – 3.40 (m, 4H), 2.88 – 2.68 (m, 3H), 2.15 –2.01 (m, 1H).

[0058] (2) Compound 5 (4-((4-(2-(4-amino-5-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)-1H-benzo [d] Preparation of tert-butyl imidazol-6-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate):

[0059] Compound 4 (1.00 g, 2.64 mmol) and N-Boc-4-piperidinecarboxaldehyde (732.69 mg, 2.64 mmol) were dissolved in a mixed solution of 20 mL of dichloroethane and 5 mL of methanol, and then 200 mg of 4A molecular sieves and sodium acetate borohydride (560.08 mg, 2.64 mmol) were added thereto, and the mixture was reacted at room temperature for 6 h under argon protection. After the reaction was completed, 20 mL of saturated sodium bicarbonate solution was added to the reaction solution to quench the reaction, and 50 mL of dichloromethane was used for extraction. The organic phase was dried, concentrated, and column chromatographed (dichloromethane: methanol = 50: 1-20: 1) to obtain the product compound 5 (1.00 g, 65.73%) as a yellow solid.

[0060] The test results of compound 5 are: 1 H NMR (400 MHz, DMSO- d 6) d 12.74 (d, J = 7.7 Hz, 1H),11.60 (s, 1H), 11.38 (d, J = 36.9 Hz, 1H), 7.73 (t, J = 12.7 Hz, 1H), 7.65 – 7.41(m, 2H), 7.30 – 6.85 (m, 4H), 3.92 (d, J = 12.8 Hz, 2H), 3.10 (s, 4H), 2.69 (s,2H), 2.31 – 2.03 (m, 2H), 1.68 (d, J = 12.6 Hz, 3H), 1.39 (s, 9H), 0.95 (q, J =12.3 Hz, 2H).

[0061] (3) Preparation of Compound A1 (5-(4-(2-(4-(4-(2-(4-amino-5-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)-1H-benzo[d]imidazol-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)acetyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione):

[0062] Compound 5 (0.20 g, 0.347 mmol) was dissolved in 5 mL of 4M hydrochloric acid-1,4-dioxane solution and reacted at room temperature for 3 h. After the reaction was completed, it was dried to obtain a yellow solid crude product for use. The obtained crude product was dissolved in 5 mL of N,N,-dimethylformamide, and N, N-diisopropylethylamine (89.80 mg, 694.82 μmol) was added thereto, and then compound 3 (177.05 mg, 0.38 mmol) was added thereto, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, 20 mL of saturated NaCl solution was added to the reaction solution, and extracted with 40 mL of ethyl acetate. The organic phase was collected, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and column chromatography (dichloromethane: methanol = 80:1) was performed to obtain the target compound A1 (168.02 mg, 56.37%) as a yellow solid.

[0063] The test results of compound A1 are: 1 H NMR (400 MHz, DMSO- d 6) d 12.73 (d, J = 7.1 Hz, 1H),11.58 (s, 1H), 11.31 (d, J = 31.8 Hz, 1H), 11.03 (s, 1H), 7.80 – 7.37 (m, 4H), 7.33 – 7.07 (m, 4H), 7.05 – 6.86 (m, 2H), 5.02 (dd, J = 12.8, 5.4 Hz, 1H), 3.78– 3.27 (m, 12H), 3.21 – 2.95 (m, 6H), 2.84 (ddd, J = 18.3, 13.7, 5.5 Hz, 2H), 2.60 – 2.50 (m, 2H), 2.42 (s, 3H), 2.27 – 2.06 (m, 2H), 1.96 (dt, J = 12.4, 6.3Hz, 1H), 1.87 – 1.49 (m, 3H), 1.42 – 1.11 (m, 3H).

[0064] Example 2

[0065] The synthetic route of FLT3-ITD targeted proteolytic chimera (Compound A2) is as follows:

[0066]

[0067] (1) Preparation of compound 6 (4-amino-3-(6-(4-(2-bromoacetyl)piperazin-1-yl)-1H-benzo[d]imidazol-2-yl)-5-fluoroquinolin-2(1H)-one):

[0068] Compound 4 (2 g, 5.28 mmol) was dissolved in 20 mL N,N-dimethylformamide, and N,N-diisopropylethylamine (1.37 g, 10.57 mmol) was added thereto, and then bromoacetyl chloride (1.07 g, 6.34 mmol) was added thereto, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, 20 mL of saturated NaCl solution was added to the reaction solution, and the mixture was extracted with 40 mL of ethyl acetate. The organic phase was collected, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and column chromatographed to obtain the target compound 6 (2.45 g, 93%).

[0069] The test results of compound 6 are: 1 H NMR (400 MHz, DMSO) d12.8 (d, J = 7.5 Hz, 1H), 11.6(s, 1H), 11.4 (d, J = 33.1 Hz, 1H), 7.8 (t, J = 12.4 Hz, 1H), 7.6 – 7.5 (m, 2H),7.3 – 7.1 (m, 2H), 7.1 – 6.9 (m, 2H), 4.5 (d, J = 2.6 Hz, 2H), 3.7 (s, 4H), 3.2– 2.9 (m, 4H). 19 F NMR (376 MHz, DMSO- d 6) δ -113.8 – -114.3 (m).

[0070] (2) Preparation of compound 9 (tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate):

[0071] Compound 8 (500 mg, 1.2 mmol) was dissolved in 5 mL of ethanol, palladium / carbon (12.7 mg, 0.12 mmol) was added thereto, hydrogen was introduced, and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, palladium / carbon was filtered off, 20 mL of saturated NaCl solution was added to the reaction solution, and the mixture was extracted with 40 mL of ethyl acetate. The organic phase was collected, dried over Na2SO4, filtered, and dried to obtain a white crude product for later use. The crude product was dissolved in 5 mL of dimethyl sulfoxide, and N,N-diisopropylethylamine (619 mg, 4.79 mmol) was added thereto, and compound 1 (794 mg, 2.87 mmol) was added thereto, and the mixture was heated and stirred at 90°C for 2 hours. After the reaction was completed, 20 mL of saturated NaCl solution was added to the reaction solution, and the mixture was extracted with 40 mL of ethyl acetate. The organic phase was collected, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and column chromatographed to obtain the target compound 9 (943 mg, 73%).

[0072] The test results of compound 9 are: 1 H NMR (400 MHz, Chloroform- d ) d 8.71 (s, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.02 (d, J = 8.6 Hz, 1H), 4.92 (dd, J= 12.0, 5.2 Hz, 1H), 4.08 (s, 2H), 3.39 (s, 4H), 2.91 – 2.62 (m, 6H), 2.54 (s, 4H), 2.21 (d, J = 6.8Hz, 2H), 2.13 – 2.04 (m, 1H), 1.72 (d, J = 13.6 Hz, 2H), 1.43 (s, 9H), 1.12 –1.01 (m, 2H).

[0073] (3) Preparation of Compound A2 (5-(4-((1-(2-(2-(2-(4-amino-5-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)-1h-benzo[d]imidazol-6-yl)piperazin-1-yl)-2-oxoethyl)piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione):

[0074] Compound 9 (1.00 g, 1.85 mmol) was dissolved in 5 mL of 4M hydrochloric acid-1,4-dioxane solution and reacted at room temperature for 3 h. After the reaction was completed, it was dried to obtain a yellow solid crude product for standby use (Compound 10). The obtained crude product was dissolved in 5 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (719 mg, 5.56 mmol) was added thereto, and then compound 6 (1.11 g, 2.23 mmol) was added thereto, and stirred at room temperature for 3 hours. After the reaction was completed, 20 mL of saturated NaCl solution was added to the reaction solution, and extracted with 40 mL of ethyl acetate. The organic phase was collected, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and column chromatographed to obtain the target compound A2 (1.243 g, 78.2%).

[0075] The test results of compound A2 are: 1 H NMR (400 MHz, DMSO- d 6) d 12.73 (d, J = 11.1 Hz,1H), 11.60 (s, 1H), 11.38 (d, J = 36.7 Hz, 1H), 11.08 (s, 1H), 7.84 – 7.62 (m,2H), 7.62 – 7.44 (m, 2H), 7.35 (d, J= 2.3 Hz, 1H), 7.32 – 7.11 (m, 3H), 7.09 –6.89 (m, 2H), 5.08 (dd, J = 13.0, 5.3 Hz, 1H), 4.36 (d, J = 12.7 Hz, 1H), 4.07(dt, J = 12.2, 3.4 Hz, 1H), 3.45 (t, J = 5.2 Hz, 4H), 3.29 (s, 4H), 3.22 – 3.08 (m, 5H), 3.07 – 2.78 (m, 3H), 2.66 – 2.52 (m, 9H), 2.20 (d, J = 6.9 Hz, 2H),2.08 – 1.99 (m, 1H), 1.77 (d, J = 13.5 Hz, 2H), 1.39 – 1.04 (m, 2H).

[0076] Example 3

[0077] The synthetic route of FLT3-ITD targeted proteolytic chimera (Compound A3) is as follows:

[0078]

[0079] (1) Preparation of Compound 11 (tert-butyl 2-(4-(2-(2,6-dioxopiperazin-3-yl)-1,3-dioxoisoindole-5-yl)piperazin-1-yl)acetate):

[0080] Compound 2 (500 mg, 1.13 mmol) was added to 4M hydrochloric acid-1,4-dioxane solution (10 mL) and reacted at room temperature for 2 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to obtain a yellow solid. Then, NN-dimethylformamide (5 mL), N,N-diisopropylethylamine (292.1 mg, 2.26 mmol) and tert-butyl bromoacetate (264.5 mg, 1.36 mmol) were added to the above yellow solid and reacted at room temperature for 1 h. When the reaction was completed as monitored by TLC, the reaction solution was extracted with ethyl acetate and washed with purified water. The obtained organic phase was concentrated under reduced pressure and subjected to silica gel column chromatography (dichloromethane: methanol = 40: 1) to obtain compound 11 (400 mg, 77.5%) as a yellow solid.

[0081] The detection results of compound 11 are: 1 H NMR (400 MHz, CDCl3) d 8.9 (s, 1H), 7.7 (dd, J =8.9, 2.7 Hz, 1H), 7.0 (d, J = 8.4 Hz, 1H), 4.9 (dd, J = 11.6, 5.1 Hz, 1H), 3.6 –3.4 (m, 4H), 3.2 (d, J = 2.9 Hz, 2H), 2.9 – 2.6 (m, 7H), 2.1 – 2.1 (m, 1H), 1.5(d, J = 2.7 Hz, 9H).

[0082] (2) Preparation of Compound A3 (5-(4-(2-(4-(2-(4-amino-5-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)-1h-benzo[d]imidazol-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione):

[0083] Compound 11 (400 mg, 0.88 mmol) was added to 4M hydrochloric acid-1,4-dioxane solution (10 mL) and reacted at room temperature for 2 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to obtain a yellow solid (Compound 12); then NN-dimethylformamide (5 mL), compound 5 (400 mg, 0.69 mmol), N,N-diisopropylethylamine (226.5 mg, 1.75 mmol) and n-propylphosphoric anhydride 50% wt (472 mg, 1.75 mmol) were added to the above yellow solid and reacted at room temperature for 1 h. When the reaction was completed as monitored by TLC, the reaction solution was extracted with ethyl acetate and washed with purified water. The obtained organic phase was concentrated under reduced pressure and subjected to silica gel column chromatography (dichloromethane: methanol = 40: 1) to obtain Compound A3 (500 mg, 66.5%) as a yellow solid.

[0084] The test results of compound A3 are: 1 H NMR (400 MHz, DMSO- d 6) d 12.73 (d, J = 11.1 Hz, 1H),11.60 (s, 1H), 11.38 (d, J = 36.7 Hz, 1H), 11.08 (s, 1H), 7.84 – 7.62 (m, 2H), 7.62 – 7.44 (m, 2H), 7.35 (d,J = 2.3 Hz, 1H), 7.32 – 7.11 (m, 3H), 7.09 – 6.89(m, 2H), 5.08 (dd, J = 13.0, 5.3 Hz, 1H), 4.36 (d, J = 12.7 Hz, 1H), 4.07 (dt, J =12.2, 3.4 Hz, 1H), 3.45 (t, J = 5.2 Hz, 4H), 3.29 (s, 4H), 3.22 – 3.08 (m, 5H), 3.07 – 2.78 (m, 3H), 2.66 – 2.52 (m, 9H), 2.20 (d, J = 6.9 Hz, 2H), 2.08 – 1.99(m, 1H), 1.77 (d, J = 13.5 Hz, 2H), 1.39 – 1.04 (m, 2H). HRMS (ESI) calculated for C 45 H 49 FN 11 O6 + [M+H] + : 858.3846, found 858.3845.

[0085] Example 4

[0086] The synthetic route of FLT3-ITD targeted proteolytic chimera (Compound A4) is as follows:

[0087]

[0088] (1) Preparation of Compound 13 (tert-butyl 2-(4-(2-(4-amino-5-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)-1h-benzo[d]imidazol-6-yl)piperazin-1-yl)acetate):

[0089] Compound 4 (800 mg, 2.11 mmol) was dissolved in NN-dimethylformamide (10 mL), and N,N-diisopropylethylamine (546.5 mg, 4.23 mmol) and tert-butyl bromoacetate (824.7 mg, 1.36 mmol) were added to react at room temperature for 1 h. When the reaction was completed as monitored by TLC, the reaction solution was extracted with ethyl acetate and washed with purified water. The obtained organic phase was concentrated under reduced pressure and subjected to silica gel column chromatography (dichloromethane: methanol = 40: 1) to obtain compound 13 (900 mg, 86.4%) as a yellow solid.

[0090] The detection results of compound 13 are: 1 H NMR (400 MHz, DMSO- d 6) d 12.79 (d, J = 9.4 Hz,1H), 11.64 (s, 1H), 11.43 (d, J = 38.0 Hz, 1H), 7.77 (t, J = 12.6 Hz, 1H), 7.68 –7.47 (m, 2H), 7.35 – 6.95 (m, 4H), 3.18 (t, J = 4.8 Hz, 4H), 2.74 (t, J = 4.7 Hz,4H), 1.49 (s, 9H).

[0091] (2) Preparation of Compound A4 5-(4-(((1-(2-(4-(4-amino-5-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)-1H-benzo[d]imidazol-6-yl)piperazin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione:

[0092] Compound 13 (500 mg, 1.02 mmol) was added to 4M hydrochloric acid-1,4-dioxane solution (10 mL) and reacted at room temperature for 2 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to obtain a yellow solid (Compound 14). Then, NN-dimethylformamide (5 mL), N,N-diisopropylethylamine (262.4 mg, 2.03 mmol), compound 10 (448 mg, 1.02 mmol) and n-propylphosphoric anhydride 50% wt (1.1 g, 2.03 mmol) were added to the above yellow solid and reacted at room temperature for 1 h. When the reaction was completed as monitored by TLC, the reaction solution was extracted with ethyl acetate and washed with purified water. The obtained organic phase was concentrated under reduced pressure and subjected to silica gel column chromatography (dichloromethane: methanol = 40: 1) to obtain compound A4 (720 mg, 82.6 %) as a yellow solid.

[0093] The test results of compound A4 are: 1 H NMR (400 MHz, DMSO- d 6) d 12.74 (d, J = 9.4 Hz,1H), 11.58 (s, 1H), 11.38 (d, J = 37.2 Hz, 1H), 11.06 (s, 1H), 7.81 – 7.47 (m,4H), 7.36 – 7.11 (m, 4H), 7.08 – 6.90 (m, 2H), 5.07 (dd, J = 12.7, 5.3 Hz, 1H),4.22 (dd, J = 111.3, 12.5 Hz, 2H), 3.41 (s, 5H), 3.12 (d, J = 6.4 Hz, 6H), 3.01 –2.80 (m, 2H), 2.59 (d, J = 13.1 Hz, 6H), 2.46 (s, 4H), 2.16 (d, J = 7.4 Hz, 2H),2.02 (d, J = 13.0 Hz, 1H), 1.74 (d, J = 13.5 Hz, 3H), 1.16 – 0.90 (m, 2H).HRMS(ESI) calculated for C 45 H 49 FN 11 O6 + [M+H]+ : 858.3846, found 858.3842.

[0094] Example 5

[0095] The synthetic route of FLT3-ITD targeted proteolytic chimeras (compounds B1, B2) is as follows:

[0096]

[0097] (1) Preparation of Compound 19 (tert-butyl 2-(4-((4-(2-(4-amino-5-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)-1H-benzo[d]imidazol-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)acetate):

[0098] Compound 5 (1.00 g, 1.74 mmol) was dissolved in 5 mL of 4M hydrochloric acid-1,4-dioxane solution and reacted at room temperature for 2 h. After the reaction was completed, it was dried to obtain a yellow solid crude product for standby use. The obtained crude product was dissolved in 5 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (449 mg, 3.48 mmol) was added thereto, and then tert-butyl 2-bromoacetate (405 mg, 3.48 mmol) was added thereto, and the reaction was stirred at room temperature for 5 h. After the reaction was completed, 20 mL of saturated NaCl solution was added to the reaction solution, and extracted with 40 mL of ethyl acetate. The organic phase was collected, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and column chromatographed to obtain the target compound 19 (766 mg, 74.8%).

[0099] The detection results of compound 19 are: 1 H NMR (400 MHz, DMSO- d 6) d 12.74 (d, J = 7.7 Hz, 1H),11.60 (s, 1H), 11.38 (d, J = 36.9 Hz, 1H), 7.73 (t, J = 12.7 Hz, 1H), 7.65 – 7.41(m, 2H), 7.30 – 6.85 (m, 4H), 3.92 (d, J = 12.8 Hz, 2H), 3.10 (s, 4H), 2.69 (s,2H), 2.31 – 2.03 (m, 2H), 1.68 (d, J = 12.6 Hz, 3H), 1.39 (s, 9H), 0.95 (q,J =12.3 Hz, 2H).

[0100] (2) Preparation of Compound B1 (5-(1-(2-(4-(2-(4-amino-5-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)-1h-benzo[d]imidazol-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)acetyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione):

[0101] Compound 19 (1.00 g, 1.69 mmol) was dissolved in 15 mL of a mixed solution of trifluoroacetic acid and dichloromethane and reacted at room temperature for 2 h. After the reaction was completed, the yellow solid crude product was obtained by spin drying for standby use. The obtained crude product was dissolved in 5 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (438 mg, 3.39 mmol) was added thereto, and then 1-propylphosphoric anhydride (1.08 g, 3.39 mmol) and compound 18 (690 mg, 2.04 mmol) were added thereto, and the reaction was stirred at room temperature for 6 hours. After the reaction was completed, 20 mL of saturated NaCl solution was added to the reaction solution, and extracted with 40 mL of ethyl acetate. The organic phase was collected, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and column chromatographed to obtain the target compound B1 (724.9 mg, 50%).

[0102] The test results of compound B1 are: 1 H NMR (400 MHz, DMSO- d 6) d 12.73 (d, J = 11.5 Hz, 1H),11.59 (s, 1H), 11.38 (d, J = 37.8 Hz, 1H), 11.12 (s, 1H), 8.00 – 7.88 (m, 3H), 7.69 (s, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.50 – 7.39 (m, 2H), 7.26 – 7.13 (m,2H), 7.10 – 6.98 (m, 1H), 6.94 (t, J = 9.4 Hz, 1H), 6.54 (s, 1H), 5.16 (dd, J =12.9, 5.3 Hz, 1H), 4.88 (s, 1H), 4.17 (d, J= 11.7 Hz, 2H), 3.74 – 3.58 (m,2H), 3.28 (s, 3H), 3.11 (s, 4H), 2.88 (d, J = 7.9 Hz, 2H), 2.71 – 2.52 (m, 6H), 2.25 – 1.96 (m, 5H), 1.69 (d, J = 12.5 Hz, 2H).HRMS (ESI) calculated forC 46 H 48 FN 10 O6 + [M+H] + : 855.3737, found 855.3735.

[0103] (3) Preparation of compound B2 (5-(1-(2-(4-(4-(2-(-4-amino-5-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)-1H-benzo[d]imidazol-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)acetyl)piperidin-4-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione):

[0104] Compound B1 (500 mg, 0.59 mmol) was dissolved in 5 mL of methanol, palladium / carbon (6.2 mg, 0.06 mmol) was added, hydrogen was introduced, and the mixture was stirred at room temperature for 5 hours. After the reaction was completed, palladium / carbon was filtered off, 20 mL of saturated NaCl solution was added to the reaction solution, and the mixture was extracted with 40 mL of ethyl acetate. The organic phase was collected, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and column chromatographed to obtain the target compound B2 (446 mg, 89%).

[0105] The test results of compound B2 are: 1 H NMR (400 MHz, DMSO- d 6) d 12.74 (d, J = 10.8 Hz, 1H),11.62 (s, 1H), 11.37 (d, J = 36.1 Hz, 1H), 11.13 (s, 1H), 7.98 – 7.67 (m, 4H), 7.63 – 7.44 (m, 2H), 7.32 – 7.17 (m, 2H), 7.17 – 6.91 (m, 2H), 5.15 (dd, J =12.9, 5.4 Hz, 1H), 4.54 (d,J = 12.7 Hz, 1H), 4.08 (s, 1H), 3.11 (q, J = 11.8,11.2 Hz, 8H), 2.90 (ddd, J = 17.4, 14.0, 5.5 Hz, 2H), 2.78 – 2.51 (m, 8H), 2.24(s, 2H), 2.12 – 2.03 (m, 1H), 1.93 – 1.61 (m, 6H), 1.54 (d, J = 11.0 Hz, 1H),1.25 (d, J = 20.2 Hz, 3H).HRMS (ESI) calculated for C 46 H 50 FN 10 O6 + [M+H] + : 857.3893, found 858.3896.

[0106] Example 6

[0107] The preparation process of FLT3-ITD targeted proteolytic chimeras (compounds C1-C3) is as follows:

[0108] (1) Preparation of Compound C1 (5-(6-(2-(4-(2-(4-amino-5-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)-1H-benzo[d]imidazol-6-yl)piperazin-1-yl)acetyl)-2,6-diazaspiro[3.3]heptane-2-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione):

[0109]

[0110] Compound 16a (1.00 g, 2.20 mmol) was dissolved in 5 mL of 4M hydrochloric acid-1,4-dioxane and reacted at room temperature for 2 h. After the reaction was completed, the yellow solid crude product was dried and used for standby. The obtained crude product was dissolved in 5 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (681 mg, 5.28 mmol) was added thereto, and then 1-propylphosphoric anhydride (1.68 g, 5.28 mmol) and compound 14 (1.15 g, 2.64 mmol) were added thereto, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, 20 mL of saturated NaCl solution was added to the reaction solution, and extracted with 40 mL of ethyl acetate. The organic phase was collected, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and column chromatographed to obtain the target compound C1 (1.31 g, 77.1%).

[0111] The test results of compound C1 are: 1 H NMR (400 MHz, DMSO- d 6) d 12.78 (d, J = 16.3 Hz, 1H),11.65 (d, J = 1.9 Hz, 1H), 11.43 (d, J = 36.9 Hz, 1H), 11.11 (s, 1H), 7.79 (dd, J =14.8, 5.9 Hz, 1H), 7.68 – 7.56 (m, 2H), 7.33 – 7.12 (m, 4H), 7.12 – 7.00 (m,2H), 6.95 (td, J = 9.1, 2.2 Hz, 1H), 5.08 (ddd, J = 13.7, 8.4, 5.4 Hz, 1H), 4.10(d, J = 38.7 Hz, 4H), 3.92 – 3.70 (m, 2H), 3.60 (d, J = 6.0 Hz, 2H), 3.23 – 3.01(m, 6H), 2.96 – 2.83 (m, 1H), 2.62 (d, J = 6.1 Hz, 6H), 1.95 (dt, J = 10.5, 4.5Hz, 1H).HRMS (ESI) calculated for C 40 H 38 FN 10O6 + [M+H] + : 773.2954, found 773.2955.

[0112] (2) Preparation of compound C2 (5-(2-(2-(4-(4-amino-5-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)-1H-benzo[d]imidazol-6-yl)piperazin-1-yl)acetyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione):

[0113]

[0114] Compound 16b (1.00 g, 2.07 mmol) was dissolved in 5 mL of 4M hydrochloric acid-1,4-dioxane and reacted at room temperature for 2 h. After the reaction was completed, the yellow solid crude product was dried by rotation and used for later use. The obtained crude product was dissolved in 5 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (536 mg, 4.15 mmol) was added thereto, and then 1-propylphosphoric anhydride (1.32 g, 4.15 mmol) and compound 14 (1.09 g, 2.49 mmol) were added thereto, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, 20 mL of saturated NaCl solution was added to the reaction solution, and extracted with 40 mL of ethyl acetate. The organic phase was collected, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and column chromatographed to obtain the target compound C2 (1.27 g, 76.6%).

[0115] The test results of compound C2 are: 1 H NMR (400 MHz, DMSO- d 6) d 12.75 (d, J = 10.1 Hz, 1H),11.68 – 11.51 (m, 1H), 11.38 (d, J = 37.8 Hz, 1H), 11.07 (s, 1H), 7.75 (t, J =13.0 Hz, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.56 (pd, J = 5.7, 5.3, 2.2 Hz, 2H), 7.48(d, J = 8.8 Hz, 1H), 7.29 – 7.10 (m, 2H), 7.09 – 6.99 (m, 1H), 6.95 (td,J = 8.9,2.3 Hz, 1H), 6.77 (d, J = 2.1 Hz, 1H), 6.65 (dd, J = 8.4, 2.1 Hz, 1H), 5.06 (dd, J = 12.9, 5.4 Hz, 1H), 3.82 (s, 4H), 3.52 (d, J = 28.5 Hz, 4H), 3.20 (d, J = 40.5Hz, 6H), 2.96 – 2.78 (m, 1H), 2.70 – 2.53 (m, 5H), 2.01 (d, J = 11.1 Hz, 1H),1.78 (d, J = 40.4 Hz, 4H).HRMS (ESI) calculated for C 42 H 42 FN 10 O6 + [M+H] + : 801.3267, found 801.3268.

[0116] (3) Preparation of compound C3 (5-(5-(2-(4-(2-(4-amino-5-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)-1H-benzo[d]imidazol-6-yl)piperazin-1-yl)acetyl)pyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione):

[0117]

[0118] Compound 16c (1.00 g, 2.13 mmol) was dissolved in 5 mL of 4M hydrochloric acid-1,4-dioxane and reacted at room temperature for 2 h. After the reaction was completed, the yellow solid crude product was dried to obtain a crude product for use. The crude product was dissolved in 5 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (550 mg, 4.26 mmol) was added thereto, and then 1-propylphosphoric anhydride (1.35 g, 4.26 mmol) and compound 14 (1.11 g, 2.56 mmol) were added thereto, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, 20 mL of saturated NaCl solution was added to the reaction solution, and extracted with 40 mL of ethyl acetate. The organic phase was collected, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and column chromatographed to obtain the target compound C3 (1.26 g, 75.3%).

[0119] The test results of compound C3 are: 1 H NMR (400 MHz, DMSO- d 6) d 12.75 (d, J = 12.4 Hz, 1H),11.60 (d, J = 5.5 Hz, 1H), 11.38 (d, J = 36.0 Hz, 1H), 11.07 (s, 1H), 7.76 (d, J =9.3 Hz, 1H), 7.70 – 7.44 (m, 3H), 7.26 – 7.00 (m, 3H), 6.93 (d, J = 2.2 Hz,2H), 6.83 (dd, J = 8.6, 2.2 Hz, 1H), 5.06 (dt, J = 12.8, 4.9 Hz, 1H), 3.93 – 3.51(m, 6H), 3.37 (s, 2H), 3.06 (t, J = 7.0 Hz, 8H), 2.96 – 2.56 (m, 6H), 2.09 –1.91 (m, 1H).HRMS (ESI) calculated for C 41 H 40 FN 10 O6 + [M+H] + : 787.3111, found787.3114.

[0120] Example 7

[0121] The synthetic route of FLT3-ITD targeted proteolytic chimeras (compounds D1 and D2) is as follows:

[0122]

[0123] (1) Preparation of compound 20: Compound 19 (500 mg, 0.85 mmol) was dissolved in 10 mL of 30% trifluoroacetic acid / dichloromethane solution and stirred at room temperature for 1 hour. After the reaction was completed, 20 mL of saturated NaCl solution was added to the reaction solution and extracted with 40 mL of ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude yellow solid for standby use.

[0124] (2) Preparation of compound D1:

[0125]

[0126] Compound 22a (0.5 g, 1.28 mmol) was dissolved in 5 mL of 4M hydrochloric acid-1,4-dioxane solution and reacted at room temperature for 2 h. After the reaction was completed, it was dried to obtain a yellow solid crude product for standby use. The obtained crude product was dissolved in 5 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (725 mg, 5.61 mmol) was added thereto, and then 1-propylphosphoric anhydride (1.78 g, 5.61 mmol) and compound 20 (821.8 mg, 1.54 mmol) were added thereto, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, 20 mL of saturated NaCl solution was added to the reaction solution, and extracted with 40 mL of ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and column chromatographed to obtain the target compound D1 (1.12 g, 92%).

[0127] The test results of compound D1 are: 1 H NMR (400 MHz, DMSO- d 6) d 12.74 (d, J = 11.9 Hz, 1H),11.61 (s, 1H), 11.37 (d, J = 35.5 Hz, 1H), 10.90 (s, 1H), 7.79 – 7.68 (m, 1H), 7.61 – 7.43 (m, 2H), 7.29 – 7.12 (m, 2H), 7.11 – 7.00 (m, 1H), 6.99 – 6.86(m, 5H), 5.04 (dd, J = 10.5, 5.0 Hz, 1H), 3.56 (d, J = 44.0 Hz, 4H), 3.09 (dd, J =43.3, 17.1 Hz, 14H), 2.80 – 2.51 (m, 9H), 2.38 – 1.93 (m, 5H), 1.80 (s, 1H).HRMS (ESI) calculated for C 43 H 50 FN 10 O5 + [M+H]+: 805.3944, found 805.3946.

[0128] (3) Preparation of compound D2:

[0129]

[0130] Compound 22b (0.5 g, 1.28 mmol) was dissolved in 5 mL of 4M hydrochloric acid-1,4-dioxane solution and reacted at room temperature for 2 h. After the reaction was completed, it was dried to obtain a yellow solid crude product for standby use. The obtained crude product was dissolved in 5 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (725 mg, 5.61 mmol) was added thereto, and then 1-propylphosphoric anhydride (1.78 g, 5.61 mmol) and compound 20 (821.8 mg, 1.54 mmol) were added thereto, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, 20 mL of saturated NaCl solution was added to the reaction solution, and extracted with 40 mL of ethyl acetate. The organic phase was collected, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and column chromatographed to obtain the target compound D2 (950 mg, 90%).

[0131] The test results of compound D2 are: 1 H NMR (600 MHz, DMSO) d 12.7 (d, J = 15.7 Hz, 1H),11.6 (s, 1H), 11.4 (d, J = 53.7 Hz, 1H), 10.9 (s, 1H), 7.7 (t, J = 15.0 Hz, 1H),7.6 (d, J = 8.6 Hz, 1H), 7.4 (dd, J = 32.3, 8.2 Hz, 1H), 7.3 – 7.0 (m, 3H), 6.9(p, J = 10.0 Hz, 4H), 5.0 (dd, J = 10.7, 4.9 Hz, 1H), 3.8 – 3.5 (m, 6H), 3.2 –3.0 (m, 9H), 2.7 – 2.5 (m, 5H), 2.4 – 2.0 (m, 6H), 1.8 (d, J = 12.8 Hz, 2H).HRMS (ESI) calculated for C 43 H 50 FN 10 O5 + [M+H]+: 805.3944, found 805.3943.

[0132] Example 8

[0133] The synthetic routes of FLT3-ITD targeted proteolytic chimeras (compounds D3 and D4) are as follows:

[0134]

[0135] (1) Preparation of compound D3: Compound 24a (0.5 g, 1.28 mmol) was dissolved in 5 mL of 4M hydrochloric acid-1,4-dioxane solution and reacted at room temperature for 2 h. After the reaction was completed, the yellow solid crude product was obtained by rotary drying for standby use. The obtained crude product was dissolved in 5 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (725 mg, 5.61 mmol) was added thereto, and then 1-propylphosphoric anhydride (1.78 g, 5.61 mmol) and compound 20 (821.8 mg, 1.54 mmol) were added thereto, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, 20 mL of saturated NaCl solution was added to the reaction solution, and extracted with 40 mL of ethyl acetate. The organic phase was collected, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and column chromatographed to obtain the target compound D3 (931 mg, 90%).

[0136] The test results of compound D3 are: 1 H NMR (400 MHz, DMSO- d 6) d 12.74 (d, J = 11.3 Hz, 1H), 11.62 (s, 1H), 11.37 (d, J = 35.5 Hz, 1H), 10.76 (s, 1H), 7.74 (t, J = 13.0 Hz,1H), 7.61 – 7.42 (m, 2H), 7.28 – 7.15 (m, 2H), 7.13 – 6.87 (m, 3H), 6.79 (d, J = 8.6 Hz, 2H), 6.64 (dd, J = 9.3, 2.8 Hz, 2H), 5.52 – 5.33 (m, 1H), 4.21 (dt, J =11.6, 6.5 Hz, 1H), 3.60 (s, 4H), 3.14 (s, 6H), 2.93 (d, J = 28.2 Hz, 6H), 2.73(ddd, J= 17.1, 11.7, 5.3 Hz, 2H), 2.66 – 2.52 (m, 4H), 2.32 – 2.05 (m, 4H), 1.99 (dt, J = 14.3, 7.0 Hz, 2H), 1.86 (ddd, J = 25.3, 12.0, 7.2 Hz, 5H).HRMS(ESI) calculated for C 43 H 51 FN 11 O4 + [M+H]+: 804.4104, found 804.4105.

[0137] (2) Preparation of compound D4: Compound 24b (0.5 g, 1.28 mmol) was dissolved in 5 mL of 4M hydrochloric acid-1,4-dioxane solution and reacted at room temperature for 2 h. After the reaction was completed, the yellow solid crude product was obtained by rotary drying for standby use. The obtained crude product was dissolved in 5 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (725 mg, 5.61 mmol) was added thereto, and then 1-propylphosphoric anhydride (1.78 g, 5.61 mmol) and compound 20 (821.8 mg, 1.54 mmol) were added thereto, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, 20 mL of saturated NaCl solution was added to the reaction solution, and extracted with 40 mL of ethyl acetate. The organic phase was collected, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and column chromatographed to obtain the target compound D4 (909 mg, 90%).

[0138] The test results of compound D4 are: 1 H NMR (400 MHz, DMSO) d 12.74 (d, J = 10.8 Hz, 1H),11.62 (d, J = 5.3 Hz, 1H), 11.36 (d, J = 35.9 Hz, 1H), 10.78 (s, 1H), 7.74 (dd, J =15.9, 10.0 Hz, 1H), 7.66 – 7.40 (m, 2H), 7.32 – 7.19 (m, 2H), 7.11 – 6.79 (m,3H), 6.58 – 6.40 (m, 2H), 5.91 (d, J = 7.5 Hz, 1H), 4.27 (ddd,J = 12.0, 7.6, 4.8Hz, 1H), 4.09 (t, J = 6.1 Hz, 1H), 3.60 (d, J = 12.7 Hz, 4H), 2.91 – 2.68 (m,6H), 2.57 (dt, J = 17.5, 4.4 Hz, 3H), 2.23 (s, 2H), 2.14 – 1.95 (m, 2H), 1.93 –1.78 (m, 3H). HRMS (ESI) calculated for C 43 H 50 F2N 11 O4 + [M+H]+: 822.4010, found822.4012.

[0139] Example 9

[0140] The synthetic route of FLT3-ITD targeted proteolytic chimera (compound D5) is as follows:

[0141]

[0142] Compound 26 (0.5 g, 1.28 mmol) was dissolved in 5 mL of 4M hydrochloric acid-1,4-dioxane solution and reacted at room temperature for 3 h. After the reaction was completed, it was dried to obtain a yellow solid crude product for standby use. The obtained crude product was dissolved in 5 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (725 mg, 5.61 mmol) was added thereto, and then 1-propylphosphoric anhydride (1.78 g, 5.61 mmol) and compound 20 (821.8 mg, 1.54 mmol) were added thereto, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, 20 mL of saturated NaCl solution was added to the reaction solution, and extracted with 40 mL of ethyl acetate. The organic phase was collected, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and column chromatographed to obtain the target compound D5 (879 mg, 85%).

[0143] The test results of compound D5 are: 1 H NMR (400 MHz, DMSO- d 6) d 12.73 (d, J = 11.2 Hz, 1H),11.60 (s, 1H), 11.38 (d, J= 36.4 Hz, 1H), 10.77 (s, 1H), 7.72 (d, J = 14.0 Hz,1H), 7.62 – 7.42 (m, 2H), 7.28 – 7.09 (m, 2H), 7.08 – 6.89 (m, 3H), 6.36 –6.14 (m, 3H), 5.68 (d, J = 7.6 Hz, 1H), 4.33 (ddd, J = 11.9, 7.6, 4.9 Hz, 1H), 3.77 – 3.55 (m, 4H), 3.07 (d, J = 33.6 Hz, 10H), 2.58 (dt, J = 23.1, 4.7 Hz, 4H), 2.34 – 2.02 (m, 5H), 1.93 – 1.61 (m, 4H), 1.59 (s, 1H), 1.24 (d, J = 7.6 Hz,2H). HRMS (ESI) calculated for C 43 H 51 FN 11 O4 + [M+H]+: 804.4104, found 804.4105.

[0144] Example 10

[0145] The synthetic route of FLT3-ITD targeted proteolytic chimera (compound D6) is as follows:

[0146]

[0147] Compound 28 (500 mg, 1.09 mmol) was dissolved in 5 mL of 4M hydrochloric acid-1,4-dioxane solution and reacted at room temperature for 1 h. After the reaction was completed, it was dried to obtain a yellow solid crude product for standby use. The obtained crude product was dissolved in 5 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (617.58 mg, 4.78 mmol) was added thereto, and then 1-propylphosphoric anhydride (1.52 g, 4.78 mmol) and compound 20 (698.0 mg, 1.30 mmol) were added thereto, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, 20 mL of saturated NaCl solution was added to the reaction solution, and extracted with 40 mL of ethyl acetate. The organic phase was collected, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and column chromatographed to obtain the target compound D6 (729.44 mg, 76.4%).

[0148] The test results of compound D6 are: 1 H NMR (600 MHz, DMSO- d 6) d 12.73 (d, J = 16.7 Hz, 1H),11.61 (s, 1H), 11.37 (d, J = 54.0 Hz, 1H), 11.12 (s, 1H), 7.74 (dd, J = 26.0,13.2 Hz, 2H), 7.61 – 7.33 (m, 3H), 7.31 – 7.07 (m, 2H), 6.98 (ddd, J = 62.1,15.2, 8.4 Hz, 2H), 5.11 (dd, J = 12.9, 5.5 Hz, 1H), 3.85 – 3.58 (m, 4H), 3.33 –2.94 (m, 10H), 2.89 (td, J = 13.2, 7.0 Hz, 2H), 2.64 – 2.48 (m, 8H), 2.32 –1.94 (m, 4H), 1.74 (d, J = 12.5 Hz, 2H), 1.57 (s, 1H), 1.33 – 1.08 (m, 2H).HRMS (ESI) calculated for C 45 H 48 F2N 11 O6 + [M+H] +: 876.3752, found 876.3754.

[0149] Embodiment 11

[0150] The synthetic routes of FLT3-ITD targeted proteolytic chimeras (compounds D7 and D8) are as follows:

[0151]

[0152] (1) Preparation of compound 32a:

[0153]

[0154] Compound 31a (500 mg, 0.91 mmol) was dissolved in 10 mL of tetrahydrofuran, palladium / carbon (9.6 mg, 0.09 mmol) was added, hydrogen was introduced, and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, the palladium / carbon was filtered off, 20 mL of saturated NaCl solution was added to the reaction solution, and the mixture was extracted with 40 mL of ethyl acetate. The organic phase was collected, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and column chromatographed to obtain the target compound 32a (305.9 mg, 90%).

[0155] The detection results of compound 32a are: 1 H NMR (400 MHz, DMSO- d 6) d 10.76 (s, 1H), 6.99 (dd, J = 63.0, 8.2 Hz, 4H), 3.73 (dd, J = 11.3, 5.0 Hz, 1H), 3.45 (t, J = 5.0 Hz, 4H),3.07 (t, J = 5.2 Hz, 4H), 2.63 (ddd, J = 16.9, 11.3, 5.3 Hz, 1H), 2.49 – 2.37 (m,2H), 2.19 – 1.97 (m, 2H), 1.42 (d, J = 1.5 Hz, 9H).

[0156] (2) Preparation of compound D7:

[0157]

[0158] Compound 32a (500 mg, 1.34 mmol) was dissolved in 5 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (346 mg, 2.67 mmol) was added thereto, and then 1-propylphosphoric anhydride (852 mg, 2.67 mmol) and compound 20 (859.11 mg, 1.61 mmol) were added thereto, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, 20 mL of saturated NaCl solution was added to the reaction solution, and the mixture was extracted with 40 mL of ethyl acetate. The organic phase was collected, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and column chromatographed to obtain the target compound D7 (824 mg, 78%).

[0159] The test results of compound D7 are: 1 H NMR (400 MHz, DMSO- d 6) d 12.73 (d, J = 11.5 Hz, 1H),11.59 (s, 1H), 11.38 (d, J = 36.6 Hz, 1H), 10.76 (s, 1H), 7.72 (t, J = 12.5 Hz,1H), 7.62 – 7.39 (m, 2H), 7.33 – 7.14 (m, 2H), 7.04 (dd, J = 23.0, 8.2 Hz, 3H),6.94 (t, J = 7.4 Hz, 2H), 3.72 (dd, J = 12.1, 6.6 Hz, 3H), 3.58 (d, J = 6.5 Hz, 2H), 3.20 (s, 4H), 3.13 (d, J = 17.4 Hz, 8H), 2.84 (d, J = 10.8 Hz, 2H), 2.63(td, J = 11.6, 5.8 Hz, 2H), 2.41 (d, J = 24.9 Hz, 2H), 2.28 – 1.93 (m, 6H), 1.71(d, J = 12.4 Hz, 2H), 1.53 (s, 1H), 1.24 – 1.05 (m, 2H). HRMS (ESI) calculated for C 43 H 50 FN10 O4 + [M+H] + : 788.3922, found788.3923.

[0160] (3) Preparation of compound 32b:

[0161]

[0162] Compound 31b (500 mg, 0.9 mmol) was dissolved in 10 mL of tetrahydrofuran, palladium / carbon (9.5 mg, 0.09 mmol) was added, hydrogen was introduced, and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, the palladium / carbon was filtered off, 20 mL of saturated NaCl solution was added to the reaction solution, and the mixture was extracted with 40 mL of ethyl acetate. The organic phase was collected, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and column chromatographed to obtain the target compound 32b (301 mg, 89%).

[0163] The detection results of compound 32b are: 1 H NMR (400 MHz, Chloroform- d ) d 8.18 (s, 1H), 7.17– 7.04 (m, 2H), 7.01 – 6.85 (m, 2H), 3.72 (dd, J = 9.3, 5.3 Hz, 1H), 3.57 (t, J =5.2 Hz, 4H), 3.25 – 3.08 (m, 4H), 2.79 – 2.57 (m, 2H), 2.24 (tdd, J = 13.9,8.9, 5.2 Hz, 2H), 1.48 (s, 9H).

[0164] (4) Preparation of compound D8:

[0165]

[0166] Compound 32b (500 mg, 1.34 mmol) was dissolved in 5 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (346 mg, 2.67 mmol) was added thereto, and then 1-propylphosphoric anhydride (852 mg, 2.67 mmol) and compound 20 (859.11 mg, 1.61 mmol) were added thereto, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, 20 mL of saturated NaCl solution was added to the reaction solution, and the mixture was extracted with 40 mL of ethyl acetate. The organic phase was collected, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and column chromatographed to obtain the target compound D8 (824 mg, 78%).

[0167] The test results of compound D8 are: 1 H NMR (400 MHz, DMSO- d 6) d 12.75 (d, J = 9.3 Hz, 1H),11.65 (s, 1H), 11.39 (d, J = 37.3 Hz, 1H), 10.83 (s, 1H), 7.75 (t, J = 12.4 Hz,1H), 7.51 (dd, J = 39.0, 8.6 Hz, 2H), 7.30 – 7.03 (m, 4H), 6.95 – 6.78 (m, 3H), 6.66 (d, J = 7.5 Hz, 1H), 3.91 – 3.47 (m, 6H), 3.13 (d, J = 25.8 Hz, 10H), 2.97 –2.59 (m, 4H), 2.46 (s, 2H), 2.28 – 1.96 (m, 6H), 1.72 (d, J = 12.3 Hz, 2H), 1.54 (s, 1H), 1.19 (d, J = 24.6 Hz, 3H). HRMS (ESI) calculated for C 43 H 50 FN 10 O4 + [M+H] + : 789.3955, found789.3956.

[0168] Example 12

[0169] The synthetic routes of FLT3-ITD targeted proteolytic chimeras (compounds D9 and D10) are as follows:

[0170]

[0171] (1) Preparation of compound 35a:

[0172]

[0173] Compound 34a (500 mg, 1.34 mmol) was dissolved in 15 mL of 6M hydrochloric acid / water, stirred at 100°C for 12 h, 20 mL of saturated NaCl solution was added to the reaction solution, and extracted with 40 mL of ethyl acetate. The organic phase was collected, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and column chromatographed to obtain the target compound 35a (428 mg, 90%).

[0174] The detection results of compound 35a are: 1 H NMR (400 MHz, DMSO) d 9.75 (s, 2H), 7.98 (d, J = 9.8 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.32 – 7.09 (m, 2H), 7.08 (d, J = 8.5Hz, 1H), 6.94 (d, J = 9.8 Hz, 1H), 3.51 (t, J = 4.9 Hz, 4H), 3.19 (t, J = 5.1 Hz,4H).

[0175] (3) Preparation of compound D9:

[0176]

[0177] Compound 35a (0.5 g, 1.40 mmol) was dissolved in 5 mL of 4M hydrochloric acid-1,4-dioxane solution and reacted at room temperature for 1 h. After the reaction was completed, it was dried to obtain a yellow solid crude product for standby use. The crude product was dissolved in 5 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (346 mg, 2.67 mmol) was added thereto, and then 1-propylphosphoric anhydride (852 mg, 2.67 mmol) and compound 20 (896.46 mg, 1.68 mmol) were added thereto, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, 20 mL of saturated NaCl solution was added to the reaction solution, and extracted with 40 mL of ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and column chromatographed to obtain the target compound D9 (824 mg, 78%).

[0178] The detection process of compound D9 is as follows: 1 H NMR (400 MHz, DMSO- d 6) d 13.01 (s, 1H), 12.74 (d, J = 10.9 Hz, 1H), 11.63 (s, 1H), 11.38 (d, J = 37.2 Hz, 1H), 7.97 (d, J = 9.8 Hz,2H), 7.73 (d, J = 8.5 Hz, 3H), 7.63 – 7.41 (m, 2H), 7.24 – 7.18 (m, 1H), 7.14 –7.00 (m, 4H), 6.93 (td, J = 9.5, 3.4 Hz, 2H), 3.79 – 3.46 (m, 8H), 3.31 – 3.09(m, 10H), 2.82 (d, J = 10.8 Hz, 2H), 2.17 (d, J = 7.2 Hz, 2H), 2.06 – 1.92 (m,2H), 1.79 – 1.61 (m, 2H), 1.50 (s, 1H), 1.22 – 1.02 (m, 2H). HRMS (ESI)calculated for C 42 H 47 FN 11 O3 + [M+H] + : 772.3842, found: 772.3845.

[0179] (4) Preparation of compound 34b:

[0180]

[0181] Compound 30b (1 g, 2.57 mmol) was dissolved in 25 mL of dioxane, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (218 mg, 0.29 mmol) was added thereto, and then sodium carbonate (405 mg, 3.86 mmol) and compound 33 (565 mg, 3.85 mmol) were added thereto, and the mixture was stirred at 90°C for 8 hours. After the reaction was completed, 20 mL of saturated NaCl solution was added to the reaction solution, and the mixture was extracted with 40 mL of ethyl acetate. The organic phase was collected, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and subjected to column chromatography to obtain the target compound 34b (626 mg, 65%).

[0182] The detection results of compound 34b are: 1 H NMR (400 MHz, CDCl3) d 7.8 (d, J = 9.0 Hz, 1H), 7.7(d, J = 2.6 Hz, 1H), 7.5 (d, J = 9.0 Hz, 1H), 7.4 (d, J = 6.7 Hz, 2H), 7.1 (m, 1H), 3.6 (t, J = 5.2 Hz, 4H), 3.2 (t, J = 5.2 Hz, 4H), 1.5 (s, 9H).

[0183] (5) Preparation of compound 35b:

[0184]

[0185] Compound 34b (500 mg, 1.34 mmol) was dissolved in 15 mL of 6M hydrochloric acid / water, stirred at 100°C for 12 h, 20 mL of saturated NaCl solution was added to the reaction solution, and extracted with 40 mL of ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and column chromatography was performed to obtain the target compound 35b (428 mg, 90%).

[0186] The detection results of compound 35b are: 1 H NMR (400 MHz, DMSO- d 6) d 13.20 (s, 1H), 9.48 (s, 2H), 8.07 (d, J = 9.9 Hz, 1H), 7.52 – 7.30 (m, 3H), 7.09 (dt, J = 7.3, 2.3 Hz,1H), 6.99 (d, J = 9.9 Hz, 1H), 3.47 (t, J = 5.1 Hz, 4H), 3.22 (t, J = 5.3 Hz, 4H).

[0187] (6) Preparation of compound D10:

[0188]

[0189] Compound 35b (1.00 g, 2.80 mmol) was dissolved in 5 mL of 4M hydrochloric acid-1,4-dioxane and reacted at room temperature for 3 h. After the reaction was completed, it was dried to obtain a yellow solid crude product for standby use. The obtained crude product was dissolved in 5 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (725 mg, 5.61 mmol) was added thereto, and then 1-propylphosphoric anhydride (1.78 g, 5.61 mmol) and compound 20 (1.79 g, 3.36 mmol) were added thereto, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, 20 mL of saturated NaCl solution was added to the reaction solution, and extracted with 40 mL of ethyl acetate. The organic phase was collected, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and column chromatographed to obtain the target compound D10 (1.65 g, 76.4%).

[0190] The detection results of compound D10 are: 1 H NMR (400 MHz, DMSO-d6) d13.18 (s, 1H), 12.73(d, J = 11.0 Hz, 1H), 11.65 (s, 1H), 11.36 (d, J = 36.5 Hz, 1H), 8.06 (d, J =9.6 Hz, 1H), 7.71 (d, J = 13.7 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.50 – 7.11 (m, 6H), 7.09 – 6.89 (m, 4H), 3.61 (t, J = 39.5 Hz, 4H), 3.34 – 2.99 (m,12H), 2.87 (s, 2H), 2.13 (d, J = 45.0 Hz, 3H), 1.80 – 1.33 (m, 4H), 1.19 (d,J = 23.4 Hz, 4H). HRMS (ESI) calculated for C 42 H 47 FN 11 O3 + [M+H] + : 772.3842, found: 772.3843.

[0191] Embodiment 13

[0192] The synthetic route of FLT3-ITD targeted proteolytic chimera (compound D11) is as follows:

[0193]

[0194] (1) Preparation of compound D11: Compound 37 (1.00 g, 2.4 mmol) was dissolved in 5 mL of 4M hydrochloric acid / dioxane and reacted at room temperature for 3 h. After the reaction was completed, the yellow solid crude product was obtained by rotary drying for standby use. The obtained crude product was dissolved in 5 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (621 mg, 4.8 mmol) was added thereto, and then 1-propylphosphoric acid cyclic anhydride (1.52 g, 4.8 mmol) and compound 20 (1.24 g, 2.49 mmol) were added thereto, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, 20 mL of saturated NaCl solution was added to the reaction solution, and extracted with 40 mL of ethyl acetate. The organic phase was collected, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and column chromatographed to obtain the target compound D11 (1.57 g, 79%).

[0195] The detection results of compound D11 are: 1H NMR (400 MHz, DMSO- d 6) d 12.73 (d, J = 11.7 Hz,1H), 11.60 (s, 1H), 11.38 (d, J = 36.7 Hz, 1H), 10.83 (s, 1H), 8.50 (d, J = 8.3Hz, 1H), 7.77 (q, J = 14.0, 10.8 Hz, 3H), 7.67 – 7.41 (m, 2H), 7.38 – 7.17 (m,2H), 7.11 – 6.86 (m, 4H), 4.75 (dt, J = 12.5, 7.1 Hz, 1H), 3.66 (d, J = 49.2 Hz,4H), 3.15 – 2.96 (m, 4H), 2.81 (ddd, J = 36.3, 15.5, 7.1 Hz, 3H), 2.56 (s, 4H), 2.24 – 1.87 (m, 6H), 1.79 – 1.65 (m, 2H), 1.63 – 1.50 (m, 1H), 1.23 – 1.10(m, 2H).HRMS (ESI) calculated for C 44 H 51 FN 11 O5 + [M+H] + : 832.4053, found: 832.4055.

[0196] Embodiment 14

[0197] The compounds (A1-A4, B1-B2, C1-C3, D1-D11) prepared in Examples 1 to 13 were subjected to performance tests, and the specific process is as follows:

[0198] (1) The in vitro proliferation inhibitory activity of the above PROTACs compounds on cancer cells was detected. The present invention selected leukemia cells MV-4-11 and used the CCK-8 detection method to test the anti-proliferation activity of the synthesized compounds. The experimental results are shown in Table 1. As can be seen from Table 1, A1, A2, A3, and D11 have strong cytotoxicity to MV-4-11.

[0199] Table 1 Cytotoxicity test of PROTAC molecules on AML cells and SCLC cells

[0200]

[0201] +++: <10 nM; ++: 10-100 nM; +: >100 nM.

[0202] (2) The degradation effect of the above PROTAC molecules on FLT3 protein in MV-4-11 cells was evaluated by Western Blot experiment. The expression of FLT3 protein in cells was detected by Western Blot experiment and quantified by ImageJ software. The results are shown in Table 2. It can be seen that A1, A2, and D11 have stronger degradation ability and their linker structure is more reasonable.

[0203] Table 2. Compound structures and degradation ability evaluation

[0204]

[0205] DC50: +++: <5 nM; ++: 5-20nM; +: >20nM.

[0206] (3) Plasma and buffer stability tests of compounds

[0207] Plasma stability is one of the important factors in evaluating whether a drug can be made into a drug. Take a buffer solution and mouse whole blood plasma under physiological conditions, add a certain concentration of the test compound solution, and take samples after incubation at 37°C for different times. Use LC-MS / MS to determine the remaining amount of the compound in the buffer solution and mouse whole blood plasma, and calculate the half-life of the compound in the buffer solution and plasma respectively; the test results show that compounds A1 and D11 have good stability.

[0208] Table 3 Plasma and buffer stability tests of compounds

[0209]

[0210] Plasma stability: +++: >3; ++: 1-3; +: <1; Physiological buffer stability: +++: >48; ++: 24-48; +: <24.

[0211] (4) Plasma and buffer stability tests of compounds

[0212] Compounds A1 and D11, which are more effective in degrading FLT3 and C-Kit and have good stability in plasma and buffer, were selected for in vivo liver microsome stability tests in humans and mice. The stability of the candidate compounds was tested, and it can be seen that the candidate molecules have good stability.

[0213] Table 4 Liver microsome stability test of PROTAC molecules

[0214]

[0215] Final remaining amount: ++++: >60%; +++: 40-60%; ++: 20-40%; +: 0-20%;

[0216] Half-life: +++: >120 min; ++: 60-120 min; +: <60 min.

[0217] (5) hERG cardiotoxicity test of compounds

[0218] In order to understand the cardiotoxicity of active compounds, we cooperated with Aisiyipu Biotechnology Co., Ltd. to conduct hERG inhibition experiments. The results are shown in Table 5. The IC50 of compounds A1 and D11 is greater than 30 μM, which has low cardiotoxicity, indicating that the drugs have good cardiac safety. This provides support for the safety of subsequent animal experiments.

[0219] Table 5 hERG cardiotoxicity test of PROTAC molecules

[0220]

[0221] (6) Compound survival curve analysis

[0222] Survival rate curves are commonly used in clinical or life science fields to describe the survival status of patients or the survival status of each group of experimental animals. Figure 1 As shown, the experimental results showed that the D11-administered group more effectively prolonged the survival period and improved the survival rate compared with the inhibitor group.

[0223] (7) Animal tumor inhibition experiments of compounds

[0224] In order to evaluate the anti-tumor ability of active molecules A1 and D11 in vivo, we conducted animal experiments on two xenograft tumor models in mice (MV-4-11, MOLM-13). The mice were divided into 4 groups, 5 in each group, respectively, the control group and the drug group (25 mg / kg) were orally administered once a day for 14 days, and the weight of the mice was recorded every day. As shown in Table 6, A1 and D11 both showed anti-tumor activity, and had a more obvious inhibitory effect on the MV-4-11 model. This shows that compounds A1 and D11 can show relatively good tumor inhibition effects in four animal models.

[0225] Table 6 Animal experiments of compounds A1 and D11

[0226]

[0227] (8) Animal in situ model experiments

[0228] In order to evaluate the active molecules A1 and D11 in mice, we conducted an orthotopic tumor-bearing animal experiment in mice (MV-4-11-luci). MV-4-11 cells with green fluorescence were injected into the mice through the tail vein, and the mice were divided into four groups, 5 in each group, a control group and a drug-treated group (25 mg / kg). Oral administration began on the seventh day after transplantation, once a day, for 14 days, and bioluminescence imaging was used to continuously evaluate the progression of leukemia and record the weight of mice. As shown in Table 7, A1 and D11 can effectively inhibit the proliferation and metastasis of tumor cells in mice. This shows that compounds A1 and D11 can effectively inhibit the progression of the disease in four animal models.

[0229] Table 7 Animal experiments of compounds A1 and D11

[0230]

[0231] (9) Animal tumor xenograft (PDX) model experiments

[0232] We transplanted tumor samples from patients into mice, collected the transplanted tumors when the mice showed obvious disease, and then performed a second transplant. The mice were divided into four groups, 5 in each group, a control group, and a drug-treated group (25 mg / kg). Oral administration began on the seventh day after transplantation, once a day, for 14 days, and the weight of the mice was recorded. As shown in Table 8, A1 and D11 can effectively inhibit the growth of tumors in mice. This shows that compounds A1 and D11 can show relatively good tumor inhibition effects in four animal models.

[0233] Table 8 Animal experiments of compounds A1 and D11

[0234]

[0235] The above is only a preferred embodiment of the present invention. The present invention is not limited to the above implementation. As long as the technical effect of the present invention is achieved by the same means, it should belong to the protection scope of the present invention. Within the protection scope of the present invention, its technical scheme and / or implementation method can have various modifications and changes.

Claims

1. A FLT3-ITD targeted proteolytic chimera, characterized in that: The FLT3-ITD targeted proteolytic chimera is any one of the following structures: 、 、 、 。 2. A method for preparing the FLT3-ITD targeted proteolytic chimera according to claim 1, characterized in that: The preparation route is shown in route 1, route 2, route 7 or route 13: Route 1: ； Route 2: ； Route 7: ； Route 13: 。 3. Use of the FLT3-ITD targeted proteolysis chimera or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a FLT3 inhibitor.

4. A use of the FLT3-ITD targeted proteolytic chimera or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a drug for treating and / or preventing cancer, characterized in that: The cancer is leukemia.

5. A pharmaceutical composition, characterized in that It comprises the FLT3-ITD targeted proteolytic chimera as claimed in claim 1 or a pharmaceutically acceptable salt thereof.

6. The pharmaceutical composition according to claim 5, characterized in that The pharmaceutical composition further comprises an excipient, a solvent and a pharmaceutically acceptable carrier.

7. The pharmaceutical composition according to claim 6, characterized in that The excipient comprises at least one of gum arabic, syrup, lanolin and starch.

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