Novel quinazoline, tetrahydronaphthyl ring protac compounds and methods of making and using the same

Abstract

The application belongs to the field of medicine, and particularly relates to a novel quinazoline ring and tetrahydronaphthalene ring PROTAC compound, a preparation method and application thereof. The quinazoline ring and tetrahydronaphthalene ring PROTAC compound has a structural formula shown in general formula (I), and has significant Bcr-Abl protein inhibitory activity as an antitumor drug. The application further provides a preparation method of the compound, a pharmaceutical composition containing the compound and use thereof. The PROTAC molecule obtained by the application has better antitumor activity and safety, and has great value as an antitumor agent in Bcr-Abl-mediated diseases.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, and particularly relates to a novel quinazoline ring, tetrahydronaphthalene ring PROTAC compound for inhibiting tumor cell growth and exerting an anti-tumor effect, and a pharmaceutically acceptable salt thereof, and a preparation method and medical use. BACKGROUND

[0002] Chronic myelogenous leukemia (CML) is a special type of white blood cell first discovered in 1840, accounting for about 15% of adult leukemia, and is characterized by abnormal proliferation of bone marrow cells and hematopoietic stem cell disorders. The root cause of the onset of 95% of CML patients is the translocation between the Abl gene on the long arm of chromosome 9 and the Bcr gene on chromosome 22, resulting in a short chromosome called Philadelphia (Ph) chromosome. The fusion gene encodes a chimeric Bcr-Abl protein and continuously activates Bcr-Abl. This will lead to uncontrolled over-proliferation of myeloid cells by downstream mediators such as PI3K, STAT5 and ERK. In fact, the Bcr-Abl gene has been proven to be the main cause of the onset of most CML. In other tumors, Bcr-Abl also causes malignant proliferation of tumor cells by silencing related tumor signaling pathways such as RAS, mTOR, etc. Therefore, Bcr-Abl has a very broad prospect as a molecular therapy target.

[0003] Imatinib, as the first artificially synthesized targeted anti-tumor drug against the mechanism of tumor occurrence, was approved for marketing in 2001 and has become a first-line drug for treating CML. With the widespread use of Imatinib, more and more patients have developed resistance to Imatinib. Subsequently, the second-generation tyrosine kinase inhibitors (TKIs) and the third-generation inhibitors targeting Bcr-Abl were developed, but both have obvious side effects limiting their clinical application. The medical problem of CML clinical resistance has not been solved, and therefore, it is necessary to continue to research and develop new inhibitors with high selectivity and low side effects. SUMMARY

[0004] The purpose of the present application is to provide a novel quinazoline ring, tetrahydronaphthalene ring PROTAC compound and its use in Bcr-Abl-mediated disease drugs. After in vitro activity screening, the compound has significant anti-tumor activity.

[0005] The present application relates to a quinazoline ring, tetrahydronaphthalene ring PROTAC compound represented by the general formula (I) and a pharmaceutically acceptable salt thereof:

[0006]

[0007] wherein,

[0008] A is selected from a quinazoline ring and a tetrahydronaphthalene ring;

[0009] B is selected from different length of connecting chains;

[0010] C is selected from CRBN class E3 ubiquitin ligase.

[0011] Preferably, the quinazoline ring, tetrahydronaphthalene ring PROTAC compound and pharmaceutically acceptable salts thereof described above,

[0012] A is selected from a quinazoline ring and a tetrahydronaphthalene ring;

[0013] B is selected from different length of carbon chain (n = 1, 2, 4, 5, 6, 7) and ether chain (n = 2, 4);

[0014] C is selected from pomalidomide and lenalidomide.

[0015] The present application preferably relates to quinazoline ring, tetrahydronaphthalene ring PROTAC compounds and pharmaceutically acceptable salts thereof represented by general formula (I), which are specifically as follows, but these compounds do not mean any limitation to the present application:

[0016]

[0017]

[0018]

[0019] The quinazoline ring, tetrahydronaphthalene ring PROTAC compound represented by general formula (I) in the present application can form a pharmaceutically acceptable salt with an acid, and the pharmaceutically acceptable addition salt includes inorganic acid and organic acid addition salt, and the addition salt with the following acids is particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid.

[0020] A pharmaceutical composition, the above-mentioned quinazoline ring, tetrahydronaphthalene ring PROTAC compound and pharmaceutically acceptable salt thereof as an active ingredient is combined with a pharmaceutically acceptable carrier to form.

[0021] Preferably, the above-mentioned pharmaceutical composition, the pharmaceutically acceptable carrier is selected from one or more of the filling agent, disintegrant, binder and lubricant.

[0022] Preferably, the above-mentioned pharmaceutical composition, the pharmaceutical composition is prepared into a dosage form of tablet, capsule, granule, spray or injection.

[0023] Use of the quinazoline ring, tetrahydronaphthalene ring PROTAC compound and pharmaceutically acceptable salt thereof according to any one of the above or the pharmaceutical composition according to any one of the above in the preparation of a drug for treating a Bcr-Abl-mediated disease.

[0024] Use of the quinazoline ring, tetrahydronaphthalene ring PROTAC compound and pharmaceutically acceptable salt thereof according to any one of the above or the pharmaceutical composition according to any one of the above in the preparation of a drug for treating a Bcr-Abl-mediated disease.

[0025] Use of the quinazoline ring, tetrahydronaphthalene ring PROTAC compound and pharmaceutically acceptable salt thereof according to any one of the above or the pharmaceutical composition according to any one of the above in the preparation of a drug for treating a Bcr-Abl-mediated disease.

[0026] Preferably, the tumor is: liver cancer, nasopharyngeal carcinoma, colorectal cancer, melanoma, bladder cancer, chronic myeloid leukemia, esophageal cancer, breast cancer, gastric cancer, prostate cancer, pancreatic cancer, lung cancer, ovarian cancer, epithelioid sarcoma, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma and follicular lymphoma.

[0027] The beneficial effects of the present application are: the novel quinazoline ring, tetrahydronaphthalene ring PROTAC compound and pharmaceutically acceptable salt thereof obtained by the present application have excellent anti-tumor activity and safety. It can be used for treating epithelioid sarcoma, lymphoma, prostate cancer and breast cancer and other tumor diseases and other autoimmune diseases. It has a high anti-cancer spectrum and a wide therapeutic window, and has great application value in the medical field. DETAILED DESCRIPTION

[0028] The examples and preparation examples provided below further illustrate and exemplify the compounds of the present application and methods for preparing them. It is to be understood that the scope of the examples and preparation examples described below is not intended to limit the scope of the present application in any way.

[0029] The following synthetic routes describe the preparation of the novel quinazoline ring, tetrahydronaphthalene ring PROTAC compounds of the general formula (I) of the present application.

[0030] All starting materials are prepared by methods well known to those skilled in the art of organic chemistry or are commercially available by the means described in the following synthetic routes. All final compounds of the present application are prepared by the methods described in the following synthetic routes or by methods analogous thereto, which are well known to those skilled in the art of organic chemistry. All variable factors used in the following synthetic routes are defined below.

[0031] The examples are intended to illustrate but not limit the scope of the present application. The nuclear magnetic resonance hydrogen spectrum of the compounds is determined by using a Bruker ARX-400 or ARX-600, and the mass spectrum is determined by using an Agilent 1100 LC / MSD; all the reagents used are of analytical or chemical purity.

[0032] The synthetic routes of the compounds 1-24 according to general formula (I) of the present application are as follows:

[0033]

[0034]

[0035] Example 1 N-(4-(4-(2-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-2- oxoethyl)piperazin-1-yl)quinazolin-7-yl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4- methylbenzamide (Compound 1)

[0036]

[0037] N-(4-(4-(2-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-2- oxoethyl)piperazin-1-yl)quinazolin-7-yl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4- methylbenzamide (Compound 1)

[0038] Step 1, synthesis of 7-nitroquinazolin-4-ol (intermediate 3)

[0039] The starting material 2-amino-4-nitrobenzoic acid (50 g, 1 eq) and formamidine acetate (57.2 g, 2 eq) were added to a 500 mL eggplant-shaped flask, about 350 mL of anhydrous ethanol was added, then a condenser tube was added, and the reaction was heated to reflux at 80°C for 48 h. After the reaction was completed, part of the solvent was removed by rotary evaporation, then 200 mL of water was added to the reaction system, and stirred on a magnetic stirrer for 10 min. Subsequently, the reaction liquid was transferred to a cold trap below 0°C and cooled for 1 h. Then, the filter cake was washed with cold ethanol, and then the filter cake was washed with water, and finally dried and weighed to obtain 43 g of product with a yield of 82.7%, which was intermediate 3.

[0040] Step 2, preparation of 4-chloro-7-nitroquinazoline (intermediate 4)

[0041] Take intermediate 3 (20 g, 1 eq) in a 500 mL flask, then add dichloro sulfide as solvent, add a condenser tube for reflux, and finally add a drying tube to the condenser tube. Reflux at 80°C for about 48 h. After the reaction is completed, remove the dichloro sulfide by rotary evaporation to obtain the crude product. Then, use ethyl acetate to slurry the crude product, and obtain white solid product by suction filtration. Dry and weigh to obtain 15 g of product, with a yield of 70%, which is intermediate 4.

[0042] Step 3, Preparation of 4-(7-nitroquinazolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (intermediate 5)

[0043] Take intermediate 4 (10 g, 1 eq) in a 250 mL flask, then dissolve it in 30 mL of DMF, add (12.5 g, 2 eq) of K2CO3, dissolve N-Boc piperazine (12.5 g, 1.4 eq) in DMF, and then add it dropwise to the flask, and react at 55°C for 5 h. After the reaction is completed, add 20 mL of water to the reaction solution, stand at room temperature for 0.5 h, and yellow-green solid will precipitate, which is filtered by a Buchner funnel and washed with water. Dry and weigh to obtain 14.4 g of product, with a yield of 83.7%, which is intermediate 5.

[0044] Step 4, Preparation of 4-(7-aminoquinazolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (intermediate 6)

[0045] Take intermediate 5 (15 g, 1 eq) in a 250 mL flask, then add 250 mL of anhydrous ethanol as solvent. Then, add 0.83 g of palladium-carbon, and add 19 mL of hydrazine hydrate dropwise at 0°C. Then, react at 55°C for 4 h until the reaction is completed. Filter by diatomite to remove the palladium-carbon, then rotary evaporate the filtrate to remove the anhydrous ethanol. Add water and extract with DCM three times, wash the organic phase with water twice, and wash the organic phase with saturated brine once. Dry the organic phase with anhydrous Na2SO4, and rotary evaporate to obtain brown-yellow solid, which is dried and weighed to obtain 12.9 g of product, with a yield of 94.2%, which is intermediate 6.

[0046] Step 5, Preparation of 4-(7-(3-iodo-4-methylbenzamide)quinazolin-4-yl)piperazine-1-tert-butyl carboxylate (intermediate 7)

[0047] Intermediate 6 (13.7 g, 1 eq), DIPEA (18.3 g, 3.5 eq), DMAP (1.02 g, 0.2 eq) were dissolved in THF in a 250 mL flask, and triiodobenzoyl chloride (15.2 g, 1.3 eq) dissolved in THF was added dropwise at 0 °C, and the reaction was carried out at room temperature for 4 h. After the reaction was completed, the THF was removed by rotary evaporation, and water was added and extracted with DCM three times, and the organic phase was washed with water twice and saturated brine once, and the organic phase was dried over anhydrous Na2SO4 and rotary evaporated. Column chromatography was used for purification to obtain a white solid, and 16 g was dried and weighed, with a yield of 66.9% as intermediate 7.

[0048] Step 6, Preparation of 4-(7-(3-(imidazo[1,2-b]pyridazin-3-ethynyl)-4-tert-butylbenzamido)quinazolin-4-yl)piperazine-1-carboxylate (Intermediate 8)

[0049] Intermediate 7 (8.23 g, 1 eq), tetrakis triphenylphosphine palladium (0.498 g, 0.03 eq), cuprous iodide (0.205 g, 0.075 eq), and DIPEA (5.3 g, 3 eq) were placed in a 250 mL three-necked flask. DMF was used as the solvent for dissolution, and vacuum was applied and nitrogen was introduced to remove oxygen. Under nitrogen protection, when the temperature rose to 55 °C, a DMF solution of imidazo[1,2-b]pyridazin-3-ylacetylene (3.08 g, 1.6 eq) was slowly injected dropwise, and the temperature was maintained at 55 °C for 4 h. After the reaction was completed, celite was used for suction filtration to remove the insoluble matter. The filtrate was added with water and extracted with DCM, and the organic phases were combined. Subsequently, the organic phase was washed with water three times and saturated brine once. Finally, anhydrous Na2SO4 was added to the organic phase for drying, and rotary evaporation was performed. Column chromatography was used for purification to obtain a yellowish solid product. After drying and weighing, 7.5 g of product was obtained, with a yield of 89.3% as intermediate 8.

[0050] Step 7, Preparation of 3-(imidazo[1,2-b]pyridazin-3-ethynyl)-4-methyl-N-(4-(piperazin-1-yl)quinazolin-7-yl)benzamide (Intermediate 9)

[0051] Intermediate 8 (4 g, 1 eq) was dissolved in DCM, and 20 mL of TFA was added, and the reaction was carried out at room temperature for 5 h. After the reaction was completed, the reaction solution was added to a saturated Na2CO3 solution to adjust the pH to 8-9, and a solid was precipitated, which was suction filtered to obtain a white solid product, which was dried and weighed to obtain 3.1 g, with a yield of 93.9% as intermediate 9.

[0052] Step 8, Preparation of 2-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide (Intermediate 21a)

[0053] Step 1, Preparation of 2-bromoacetic acid (Intermediate 20a)

[0054] Step 9, Preparation of N-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)-2- iodoacetamide (Intermediate 22a)

[0055] Step 9, Preparation of N-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)-2- iodoacetamide (Intermediate 22a)

[0056] Step 10, N-(4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)-2- oxoethyl)piperazin-l-yl)quinazolin-7-yl)-3-(imidazo[l,2-b]pyridazin-3-ethynyl)-4- methylbenzamide (Compound 1)

[0057] Intermediate 9 (100 mg, 1 eq) and intermediate 22a (85.83 mg, 1.2 eq) were added to a 25 mL vial, followed by K2CO3 (56.5 mg, 2 eq), KI (170 mg, 5 eq), 5 mL DMSO as solvent, and reaction at 80 °C for 5 h. After the reaction was completed, immediately perform suction filtration, using diatomite as filter aid to remove the solid impurities that may be generated in the reaction. Subsequently, add an appropriate amount of water to the filtrate, and use DCM to extract to separate the organic components. Collect and combine these organic phases, then wash with water three times, and saturated brine once, to ensure the complete removal of inorganic salts and residual impurities. Next, add anhydrous Na2SO4 to the organic phase for drying treatment, spin dry the solvent, and concentrate the organic components. Column chromatography purification obtained white solid, successfully isolated the target product, 75 mg product. Yield 45.7%, compound 1.

[0058] MS (ESI) m / z (%): 802.3 [M+H] + . 1 H NMR (600 MHz, CDC13) δ 11.19 (s, 1H), 9.02 - 8.77 (m, 2H), 8.64 (s, 1H), 8.45 (d, J = 4.8 Hz, 1H), 8.00 (d, J = 46.8 Hz, 5H), 7.71 (d, J = 6.3 Hz, 3H), 7.52 (t, J = 4.6 Hz, 2H), 7.11 (s, 1H), 5.02 (s, 1H), 3.94 (s, 5H), 3.27 (s, 2H), 2.81 (s, 8H), 2.57 (s, 2H), 2.18 - 2.14 (m, 1H).

[0059] Example 2 N-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)-3- oxopropyl)piperazin-l-yl)quinazolin-7-yl)-3-(imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methylbenzamide (Compound 2)

[0060]

[0061] N-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)-3- oxopropyl)piperazin-l-yl)quinazolin-7-yl)-3-(imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methylbenzamide

[0062] MS (ESI) m / z (%): 816.3 [M+H] + .1 H NMR (600 MHz, CDC13) δ 10.76 (s, 1H), 9.10 (s, 1H), 8.79 (t, J = 10.8 Hz, 1H), 8.58 (d, J = 10.3 Hz, 1H), 8.44 (d, J = 26.2 Hz, 1H), 7.99 (t, J = 20.2 Hz, 5H), 7.77 (d, J = 8.5 Hz, 4H), 7.53 (d, J = 7.4 Hz, 1H), 7.09 (s, 1H), 4.96 (s, 1H), 4.13 (s, 1H), 3.86 (d, J = 69.8 Hz, 5H), 2.75 (d, J = 12.3 Hz, 10H), 2.55 (d, J = 17.0 Hz, 4H).

[0063] Example 3 N-(4-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)- 5-oxopentyl)piperazin-l-yl)quinolin-7-yl)-3-(imidazo[l,2-b]pyridazin-3-ethynyl)-4- methylbenzamide (Compound 3)

[0064]

[0065] N-(4-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)- 5-oxopentyl)piperazin-l-yl)quinolin-7-yl)-3-(imidazo[l,2-b]pyridazin-3-ethynyl)-4- methylbenzamide

[0066] MS (ESI) m / z (%): 844.3 [M+H] + . 1H NMR (600 MHz, DMSO) δ 11.14 (s, 1H), 10.70 (s, 1H), 9.70 (s, 1H), 8.73 (dd, J = 4.4, 1.6 Hz, 1H), 8.56 (s, 1H), 8.48 (d, J = 8.4 Hz, 1H), 8.36 (d, J = 2.1 Hz, 1H), 8.28 - 8.22 (m, 3H), 8.00 - 7.95 (m, 2H), 7.91 (dd, J = 9.1, 2.2 Hz, 1H), 7.85 - 7.80 (m, 1H), 7.61 (d, J = 7.3 Hz, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.39 (dd, J = 9.2, 4.4 Hz, 1H), 5.14 (dd, J = 12.9, 5.5 Hz, 1H), 3.71 (t, J = 4.8 Hz, 4H), 3.32 (s, 8H), 2.89 (ddd, J = 17.0, 13.9, 5.5 Hz, 1H), 2.62 (s, 3H), 2.39 (t, J = 7.3 Hz, 2H), 2.10 - 2.02 (m, 1H), 1.68 (p, J = 7.3 Hz, 2H), 1.55 (p, J = 7.3 Hz, 2H).

[0067] Example 4 N-(4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)-6- oxohexyl)piperazin-l-yl)quinolin-7-yl)-3-(imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methylbenzamide (Compound 4)

[0068]

[0069] N-(4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)-6- oxohexyl)piperazin-l-yl)quinolin-7-yl)-3-(imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methylbenzamide

[0070] MS (ESI) m / z (%): 858.3 [M+H] + . 1H NMR (600 MHz, DMSO) δ 11.15 (s, 1H), 10.71 (s, 1H), 9.70 (s, 1H), 8.73 (d, J = 4.4 Hz, 1H), 8.56 (s, 1H), 8.48 (d, J = 8.5 Hz, 1H), 8.36 (s, 1H), 8.28 - 8.22 (m, 3H), 8.02 - 7.88 (m, 3H), 7.82 (t, J = 7.9 Hz, 1H), 7.58 (dd, J = 26.9, 7.8 Hz, 2H), 7.39 (dd, J = 9.5, 4.4 Hz, 1H), 5.15 (dd, J = 12.9, 5.5 Hz, 1H), 3.70 (s, 4H), 3.33 (s, 8H), 2.94 - 2.85 (m, 1H), 2.36 (s, 2H), 2.07 (d, J = 13.1 Hz, 1H), 1.66 (t, J = 7.5 Hz, 3H), 1.51 (t, J = 7.8 Hz, 3H), 1.41 - 1.17 (m, 3H).

[0071] Example 5 N-(4-(4-(7-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)-7- oxoheptyl)piperazin-l-yl)quinazolin-7-yl)-3-(imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methylbenzamide (Compound 5)

[0072]

[0073] N-(4-(4-(7-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)-7- oxoheptyl)piperazin-l-yl)quinazolin-7-yl)-3-(imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methylbenzamide

[0074] MS (ESI) m / z (%): 872.4 [M+H] + . 1H NMR (400 MHz, DMSO) δ 11.18 (s, 1H), 10.72 (s, 1H), 9.71 (s, 1H), 8.73 (dd, J = 4.5, 1.7 Hz, 1H), 8.56 (s, 1H), 8.47 (d, J = 8.3 Hz, 1H), 8.36 (d, J = 2.3 Hz, 1H), 8.29 - 8.22 (m, 3H), 8.01 - 7.93 (m, 2H), 7.90 (dd, J = 9.2, 2.2 Hz, 1H), 7.82 (t, J = 7.9 Hz, 1H), 7.58 (dd, J = 16.8, 7.8 Hz, 2H), 7.40 (dd, J = 9.2, 4.5 Hz, 1H), 5.15 (dd, J = 12.8, 5.4 Hz, 1H), 3.69 (s, 4H), 3.37 (s, 4H), 2.96 - 2.83 (m, 1H), 2.61 (s, 5H), 2.33 (t, J = 7.3 Hz, 2H), 2.07 (dd, J = 9.0, 3.7 Hz, 1H), 1.63 (t, J = 7.1 Hz, 2H), 1.51 - 1.42 (m, 4H), 1.37 - 1.10 (m, 2H).

[0075] Example 6 N-(4-(4-(8-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)-8-oxooctyl)piperazin-l-yl)quinazolin-7-yl)-3-(imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methylbenzamide (Compound 6)

[0076]

[0077] N-(4-(4-(8-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)-8-oxooctyl)piperazin-l-yl)quinazolin-7-yl)-3-(imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methylbenzamide

[0078] MS (ESI) m / z (%): 886.4 [M+H] + . 1H NMR (400 MHz, DMSO) δ 11.20 (s, 1H), 10.72 (s, 1H), 9.69 (s, 1H), 8.73 (dd, J = 4.5, 1.7 Hz, 1H), 8.56 (s, 1H), 8.46 (d, J = 8.3 Hz, 1H), 8.36 (d, J = 2.2 Hz, 1H), 8.30 - 8.23 (m, 3H), 8.01 - 7.87 (m, 3H), 7.81 (t, J = 7.9 Hz, 1H), 7.58 (dd, J = 16.3, 7.8 Hz, 2H), 7.39 (dd, J = 9.2, 4.5 Hz, 1H), 5.15 (dd, J = 12.8, 5.4 Hz, 1H), 3.69 (s, 2H), 3.31 (s, 4H), 2.96 - 2.83 (m, 1H), 2.61 (s, 4H), 2.33 (t, J = 7.5 Hz, 2H), 2.12 - 2.02 (m, 1H), 1.62 (q, J = 6.9 Hz, 3H), 1.47 (s, 3H), 1.30 (s, 7H).

[0079] Example 7 N-(4-(4-(2-((2-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)amino)-2- oxoethyl)piperazin-l-yl)quinazolin-7-yl)-3-(imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methylbenzamide (Compound 7)

[0080]

[0081] N-(4-(4-(2-((2-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)amino)-2- oxoethyl)piperazin-l-yl)quinazolin-7-yl)-3-(imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methylbenzamide

[0082] MS (ESI) m / z (%): 788.3 [M+H] + . 1H NMR (600 MHz, DMSO) δ 10.16 (s, 1H), 9.88 (s, 1H), 8.99 (s, 1H), 7.89 (d, J = 6.0 Hz, 1H), 7.75 (s, 1H), 7.53 (s, 1H), 7.47 - 7.39 (m, 3H), 7.16 (dd, J = 14.4, 9.6 Hz, 2H), 7.09 (d, J = 9.1 Hz, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.90 - 6.78 (m, 1H), 6.75 - 6.65 (m, 3H), 6.56 (dd, J = 9.2, 4.5 Hz, 1H), 4.29 (dd, J = 13.3, 5.1 Hz, 1H), 3.59 (d, J = 13.6 Hz, 1H), 3.38 (t, J = 6.6 Hz, 1H), 2.99 (s, 4H), 2.12 - 2.03 (m, 1H), 1.95 (d, J = 5.0 Hz, 4H), 1.78 (s, 4H), 1.67 (s, 1H).

[0083] Example 8 N-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)amino)-3- oxopropyl)piperazin-l-yl)quinazolin-7-yl)-3-(imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methylbenzamide (Compound 8)

[0084]

[0085] N-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)amino)-3- oxopropyl)piperazin-l-yl)quinazolin-7-yl)-3-(imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methylbenzamide

[0086] MS (ESI) m / z (%): 802.3 [M+H] + . 1H NMR (600 MHz, DMSO) δ 11.02 (s, 1H), 10.72 (s, 1H), 9.99 (s, 1H), 8.73 (d, J = 4.4 Hz, 1H), 8.58 (s, 1H), 8.37 (s, 1H), 8.29 - 8.23 (m, 3H), 7.99 (dd, J = 8.7, 4.7 Hz, 2H), 7.93 (d, J = 9.1 Hz, 1H), 7.86 (d, J = 7.3 Hz, 1H), 7.74 - 7.63 (m, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.40 (dd, J = 9.4, 4.4 Hz, 1H), 5.16 (dd, J = 13.5, 5.1 Hz, 1H), 4.40 (d, J = 21.6 Hz, 2H), 4.22 (t, J = 6.7 Hz, 1H), 3.74 (s, 4H), 3.32 (s, 3H), 2.97 - 2.88 (m, 1H), 2.77 (t, J = 7.0 Hz, 2H), 2.69 (s, 3H), 2.62 (d, J = 9.1 Hz, 4H).

[0087] Example 9 N-(4-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)amino)-5- oxopentyl)piperazin-1-yl)quinolin-7-yl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4- methylbenzamide (Compound 9)

[0088]

[0089] N-(4-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)amino)-5- oxopentyl)piperazin-1-yl)quinolin-7-yl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4- methylbenzamide

[0090] MS (ESI) m / z (%): 830.3 [M+H] + . 1H NMR (600 MHz, DMSO) δ 11.02 (s, 1H), 10.73 (s, 1H), 9.85 (s, 1H), 8.73 (d, J = 4.5 Hz, 1H), 8.57 (s, 1H), 8.37 (d, J = 2.2 Hz, 1H), 8.29 - 8.23 (m, 3H), 8.00 (s, 1H), 7.92 (d, J = 9.1 Hz, 1H), 7.83 (d, J = 7.3 Hz, 1H), 7.56 (d, J = 8.3 Hz, 1H), 7.49 (q, J = 8.3 Hz, 2H), 7.40 (dd, J = 9.2, 4.4 Hz, 1H), 5.15 (dd, J = 13.4, 5.2 Hz, 1H), 4.46 - 4.32 (m, 2H), 3.72 (s, 4H), 3.34 (s, 6H), 2.38 (ddt, J = 25.7, 13.3, 6.0 Hz, 6H), 2.07 - 1.99 (m, 1H), 1.66 (p, J = 7.6 Hz, 2H), 1.54 (q, J = 8.1 Hz, 2H), 1.21 (s, 2H).

[0091] Example 10 N-(4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)amino)-6- oxohexyl)piperazin-l-yl)quinazolin-7-yl)-3-(imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methylbenzamide (Compound 10)

[0092]

[0093] N-(4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)amino)-6- oxohexyl)piperazin-l-yl)quinazolin-7-yl)-3-(imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methylbenzamide

[0094] MS (ESI) m / z (%): 843.4 [M+H] + . 1H NMR (400 MHz, DMSO) δ 11.06 (s, 1H), 10.78 (s, 1H), 9.89 (s, 1H), 8.74 (d, J = 4.3 Hz, 1H), 8.56 (s, 1H), 8.38 (s, 1H), 8.27 (d, J = 13.7 Hz, 3H), 8.03 - 7.88 (m, 3H), 7.83 (d, J = 6.8 Hz, 1H), 7.75 - 7.63 (m, 6H), 7.57 - 7.45 (m, 3H), 7.40 (dd, J = 9.2, 4.5 Hz, 1H), 5.15 (dd, J = 13.1, 5.1 Hz, 1H), 4.38 (d, J = 13.6 Hz, 2H), 4.21 (t, J = 6.5 Hz, 6H), 3.70 (s, 4H), 2.92 (t, J = 12.8 Hz, 1H), 2.62 (s, 4H), 2.36 (p, J = 7.4 Hz, 4H).

[0095] Example 11 N-(4-(4-(7-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)amino)-7- oxohexazin-1-yl)quinazolin-7-yl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4- methylbenzamide (Compound 11)

[0096]

[0097] N-(4-(4-(7-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)amino)-7- oxohexazin-1-yl)quinazolin-7-yl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4- methylbenzamide

[0098] MS (ESI) m / z (%): 858.4 [M+H] + . 1H NMR (400 MHz, DMSO) δ 11.06 (s, 1H), 10.73 (s, 1H), 9.81 (s, 1H), 8.74 (s, 1H), 8.57 (s, 1H), 8.37 (s, 1H), 8.26 (d, J = 13.6 Hz, 3H), 8.01 - 7.90 (m, 3H), 7.82 (d, J = 7.2 Hz, 1H), 7.56 (d, J = 8.6 Hz, 1H), 7.49 (d, J = 7.0 Hz, 2H), 7.39 (dd, J = 9.2, 4.5 Hz, 1H), 5.15 (dd, J = 12.9, 6.1 Hz, 1H), 4.46 - 4.31 (m, 2H), 3.71 (s, 4H), 3.37 (s, 4H), 2.92 (t, J = 14.9 Hz, 2H), 2.36 (s, 5H), 1.55 (d, J = 54.9 Hz, 6H), 1.27 (d, J = 54.5 Hz, 6H).

[0099] Example 12 N-(4-(4-(8-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)amino)-8- oxooctyl)piperazin-l-yl)quinazolin-7-yl)-3-(imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methylbenzamide (Compound 12)

[0100]

[0101] N-(4-(4-(8-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)amino)-8- oxooctyl)piperazin-l-yl)quinazolin-7-yl)-3-(imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methylbenzamide

[0102] MS (ESI) m / z (%): 872.4 [M+H] + . 1H NMR (400 MHz, DMSO) δ 11.18 (s, 1H), 10.81 (s, 1H), 9.78 (s, 1H), 8.73 (dd, J = 4.5, 1.6 Hz, 1H), 8.63 (s, 1H), 8.49 (d, J = 8.4 Hz, 1H), 8.42 (d, J = 2.1 Hz, 1H), 8.27 (dd, J = 9.2, 1.6 Hz, 2H), 8.12 - 8.04 (m, 1H), 7.96 (ddd, J = 19.8, 8.6, 2.2 Hz, 3H), 7.86 - 7.78 (m, 1H), 7.58 (dd, J = 14.7, 7.8 Hz, 2H), 7.40 (dd, J = 9.2, 4.5 Hz, 1H), 5.16 (dd, J = 12.9, 5.3 Hz, 1H), 4.01 - 3.59 (m, 6H), 2.97 - 2.68 (m, 4H), 2.61 (s, 7H), 2.54 (d, J = 5.5 Hz, 4H), 2.06 (d, J = 6.6 Hz, 2H), 1.17 (d, J = 30.7 Hz, 4H), 1.06 - 0.95 (m, 4H).

[0103] Example 13 N-(4-(4-(2-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)-2-oxoethoxy)ethyl)piperazin-l-yl)quinolin-7-yl)-3-(imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methylbenzamide (Compound 13)

[0104]

[0105] N-(4-(4-(2-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)-2-oxoethoxy)ethyl)piperazin-l-yl)quinolin-7-yl)-3-(imidazo[l,2-b]pyridazin-3- ylethynyl)-

[0106] 4-methylbenzamide

[0107] Step 1, 2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate (Intermediate 24a)

[0108] Into a 50 mL vial, 2,2'-oxybis(ethan-1-ol) (1 g, 1 eq) and Et3N were added with DCM as solvent. At 0 °C, TsCl in DCM was added dropwise slowly. After the addition of TsCl was completed, the sub-reaction was allowed to react at room temperature for 3 h. After sampling for testing, when the starting material was no longer present, the reaction was quenched by adding a certain amount of water to the reaction solution, and then the pH was adjusted to 7 with HC1. Subsequently, extraction was performed using DCM, and the extracted organic phase was combined. Then, the organic phase was washed with water three times and saturated brine once. After that, anhydrous Na2S04 was added to the organic phase for drying. Finally, the solvent was removed by rotary evaporation. Yield 40.2%, MS (ESI) m / z (%): 221.1 [M+H] + .

[0109] Step 2, tert-butyl 2-(2-(2-(methylthiophenylsulfonyloxy)ethoxy)ethoxy)acetate (intermediate 26a)

[0110] Into a 100 mL vial, intermediate 24a (1.2 g, 1 eq), TBAB, KOH, tert-butyl bromoacetate were added with toluene as solvent, and the reaction was allowed to proceed at room temperature for 12 h. After the reaction was completed, toluene was removed by rotary evaporation, and the solid obtained after removal of toluene was extracted with water and DCM. The extracted organic phase was combined, and then the organic phase was washed with water three times and saturated brine once. Anhydrous Na2S04 was added to the organic phase for drying, and the solvent was removed by rotary evaporation. Yield 42.2%, MS (ESI) m / z (%): 375.1 [M+H] + .

[0111] Step 3, tert-butyl 2-(2-(2-iodoethoxy)ethoxy)acetate (intermediate 27a)

[0112] Into a 50 mL three-necked flask, intermediate 26a (600 mg, 1 eq), NaI were added with acetone as solvent, N2 protection, and the reaction was allowed to proceed at 70 °C for 6 h. After the reaction was completed, acetone was removed by rotary evaporation, and the solid obtained after removal of acetone was extracted with water and ethyl acetate. The combined organic phase was washed with water three times and saturated brine once. Anhydrous Na2S04 was added to the organic phase for drying, and the solvent was removed by rotary evaporation. Yield 80.6%, MS (ESI) m / z (%): 331.0 [M+H] + .

[0113] Step 4, 2-(2-(2-iodoethoxy)ethoxy)acetic acid (intermediate 28a)

[0114] Intermediate 27a (500 mg, 1 eq) was added to a 50 mL vial, TFA was added dropwise at 0 °C, and the reaction was allowed to proceed at room temperature for 2 h. After the reaction was completed, water was added, and the pH was adjusted to 12 with a NaOH solution. The reaction was extracted with DCM three times, and the aqueous phase was collected. The aqueous phase was adjusted to pH 3 with HCl, and then extracted with ethyl acetate. The organic phase was combined, washed with water three times, and saturated brine once. The organic phase was dried over anhydrous Na2SO4, and the solvent was removed by rotary evaporation. The yield was 81.4%, and MS (ESI) m / z (%): 274.9 [M+H]+.

[0115] Step 5, N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-2-(2-(2- iodoethoxy)ethoxy)acetamide (Intermediate 29a)

[0116] 28a (500 mg, 1 eq) was placed in a 50 mL three-necked flask, and the operation was carried out under N2protection. Oxalyl chloride was added slowly dropwise at 0 °C, and the reaction was allowed to proceed at room temperature for 2 h after the addition was completed. After the reaction was completed, the excess solvent and unreacted reagents were removed by concentration under reduced pressure. Immediately after the concentration was completed, DMF and pomalidomide were added to the system, and the reaction was continued at room temperature for 1 h. After the reaction was completed, the reaction liquid was extracted with ethyl acetate, and the extracted organic phase was combined. Subsequently, the organic phase was washed with water three times and finally with saturated brine. Next, anhydrous Na2SO4was added to the organic phase for drying treatment. After the drying was completed, the solvent was removed by rotary evaporation. Finally, the product was purified by column chromatography to obtain a yellow solid product. The yield was 41.2%, and MS (ESI) m / z (%): 530.0 [M+H]+. + .

[0117] Step 6, N-(4-(4-(2-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)-2-oxoethoxy)ethyl)piperazin-1-yl)quinazolin-7-yl)-3-(imidazo[1,2-b]pyridazin- 3-ylethynyl)-4-methylbenzamide (Compound 13)

[0118] Intermediate 9 (100 mg, 1 eq) and intermediate 29a (130 mg, 1.2 eq) were added to a 25 mL vial, followed by K2CO3 (56.5 mg, 2 eq), KI (170 mg, 5 eq), 5 mL DMSO as solvent, and reaction at 80 °C for 5 h. After the reaction was completed, immediately perform suction filtration, using diatomite as filter aid to remove the solid impurities that may be generated in the reaction. Subsequently, add an appropriate amount of water to the filtrate, and use DCM to extract to separate the organic components. Collect and combine these organic phases, then wash with water three times, and saturated brine once, to ensure the complete removal of inorganic salts and residual impurities. Next, add anhydrous Na2SO4 to the organic phase for drying treatment, spin dry the solvent, and concentrate the organic components. Column chromatography purification obtained white solid, successfully isolated the target product, 17 mg product. Yield 9.2%, compound 13.

[0119] MS (ESI) m / z (%): 890.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.20 (s, 1H), 10.75 (s, 1H), 10.37 (s, 1H), 8.73 (s, 2H), 8.54 (s, 1H), 8.36 (s, 1H), 8.24 (s, 3H), 7.91 (t, J = 33.9 Hz, 4H), 7.49 (d, J = 63.0 Hz, 3H), 5.16 (s, 1H), 4.19 (d, J = 29.3 Hz, 4H), 3.78 (s, 6H), 2.90 (s, 2H), 2.61 (s, 9H), 2.07 (s, 2H), 1.20 (s, 2H).

[0120] Example 14 N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-14-(4-(7-(3- (imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamido)quinazolin-4-yl)piperazin-1- yl)-3,6,9,12-tetraoxatetradecanamide (Compound 14)

[0121]

[0122] N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-14-(4-(7-(3- (imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamido)quinazolin-4-yl)piperazin-1- yl)-3,6,9,12-tetraoxatetradecanamide

[0123] amine

[0124] MS (ESI) m / z (%): 978.4 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.19 (s, 1H), 10.72 (s, 1H), 10.34 (s, 1H), 8.76 - 8.67 (m, 2H), 8.55 (s, 1H), 8.35 (s, 1H), 8.30 - 8.21 (m, 3H), 8.05 - 7.78 (m, 4H), 7.58 (dd, J = 16.4, 7.7 Hz, 2H), 7.40 (dd, J = 9.3, 4.5 Hz, 1H), 5.16 (dd, J = 12.8, 5.3 Hz, 1H), 4.19 (s, 2H), 3.72 (d, J = 30.9 Hz, 8H), 3.59 - 3.46 (m, 10H), 2.62 (s, 6H), 2.11 - 1.87 (m, 2H),

[0125] 1.31 (d, J = 76.4 Hz, 5H).

[0126] Example 15 N-(4-(4-(2-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)-2-oxoethoxy)ethyl)piperazin-1-yl)quinazolin-7-yl)-3-(imidazo[1,2-b]pyridazin-3- ylethynyl)-4-methylbenzamide (Compound 15)

[0127]

[0128] N-(4-(4-(2-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)-2-oxoethoxy)ethyl)piperazin-1-yl)quinazolin-7-yl)-3-(imidazo[1,2-b]pyridazin-3- ylethynyl)-4-methylbenzamide (Compound 15)

[0129] N-(4-(4-(2-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)-2-oxoethoxy)ethyl)piperazin-1-yl)quinazolin-7-yl)-3-(imidazo[1,2-b]pyridazin-3- ylethynyl)-4-methylbenzamide (Compound 15)

[0130] MS (ESI) m / z (%): 978.4 [M+H] + . 1H NMR (400 MHz, DMSO) δ 11.04 (s, 1H), 10.74 (s, 1H), 9.75 (s, 1H), 8.74 (d, J = 6.1 Hz, 1H), 8.56 (s, 1H), 8.37 (s, 1H), 8.27 (d, J = 13.4 Hz, 3H), 7.96 (dd, J = 22.7, 9.0 Hz, 2H), 7.69 (d, J = 19.6 Hz, 2H), 7.54 (dd, J = 19.4, 8.9 Hz, 3H), 7.40 (dd, J = 9.2, 4.5 Hz, 1H), 5.20 - 5.11 (m, 1H), 4.51 - 4.29 (m, 2H), 4.21 (t, J = 6.6 Hz, 6H), 3.75 - 3.56 (m, 12H), 2.91 (t, J = 12.9 Hz, 1H), 2.62 (s, 3H), 2.43 - 2.33 (m, 1H), 2.01 (s, 2H).

[0131] Example 16 N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)-14-(4-(7-(3-(imidazo[l,2- b]pyridazin-3-ylethynyl)-4-methylbenzamido)quinazolin-4-yl)piperazin-l-yl)-3,6,9,12- tetraoxoestertetradecanamide (Compound 16)

[0132]

[0133] N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)-14-(4-(7-(3-(imidazo[l,2- b]pyridazin-3-ylethynyl)-4-methylbenzamido)quinazolin-4-yl)piperazin-l-yl)-3,6,9,12- tetraoxoestertetradecanamide

[0134] MS (ESI) m / z (%): 876.3 [M+H] + . 1H NMR (400 MHz, DMSO) δ 11.05 (s, 1H), 10.75 (s, 1H), 9.72 (s, 1H), 8.74 (dd, J = 4.4, 1.6 Hz, 1H), 8.57 (s, 1H), 8.38 (d, J = 2.2 Hz, 1H), 8.34 - 8.22 (m, 3H), 8.02 - 7.88 (m, 3H), 7.74 (d, J = 6.5 Hz, 1H), 7.54 (dd, J = 19.1, 8.4 Hz, 3H), 7.42 (s, 1H), 5.15 (dd, J = 13.3, 5.2 Hz, 1H), 4.49 - 4.27 (m, 2H), 4.14 (s, 2H), 3.74 - 3.66 (m, 8H), 3.53 (dq, J = 6.6, 3.4 Hz, 12H), 2.63 (d, J = 9.7 Hz, 7H), 2.37 (dd, J = 13.3, 4.8 Hz, 1H), 2.01 (t, J = 7.5 Hz, 1H), 1.22 (d, J = 3.9 Hz, 2H).

[0135] Example 17 5-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)-2- oxoethyl)piperazin-l-yl)-N-(3-(imidazo[l,2-b]pyridazine-3-ethynyl)-4-methylphenyl)- 5,6,7,8-tetrahydronaphthalene-2-carboxamide (Compound 17)

[0136]

[0137] 5-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)-2- oxoethyl)piperazin-l-yl)-N-(3-(imidazo[l,2-b]pyridazine-3-ethynyl)-4-methylphenyl)- 5,6,7,8-tetrahydronaphthalene-2-carboxamide

[0138] Step 1, 6-hydroxy-3,4-dihydronaphthalen-l(2H)-one (Intermediate 11)

[0139] The starting material 6-methoxy-3,4-dihydronaphthalen-l(2H)-one (50 g, 1 eq) was added to a 500 mL tomato flask, then 80 mL of HBr (40%) solution was added, and the reaction was carried out at 110°C for 12 h. After the reaction was completed, the reaction solution was suction filtered, the filter cake was washed, and the pH was adjusted to 7 to obtain a red product 45 g in a yield of 97.8%, which was Intermediate 11.

[0140] Step 2, 5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (Intermediate 12)

[0141] Intermediate 11 (40 g, 1 eq) was added to a 500 mL three-neck flask and dissolved in DCM. Pyridine (39 g, 4.4 eq) was added, and the temperature was controlled at -10 °C. Trifluoromethanesulfonic anhydride was added slowly dropwise. The reaction was allowed to react at room temperature for 24 h. The DCM was removed from the reaction by rotary evaporation, and the pH was adjusted to 7 with 1 N HCl. Extraction was performed with ethyl acetate, and the organic phases were combined. The combined organic phases were washed with water three times and saturated brine once. The organic phase was dried over anhydrous Na2SO4. The product was obtained as a red oil (37 g) as intermediate 12.

[0142] Step 3, Methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (Intermediate 13)

[0143] Intermediate 12 (10 g, 1 eq), triethylamine (6.87 g, 2 eq), 1,3-bis(diphenylphosphino)propane palladium dichloride (0.421 g, 0.03 eq), and palladium acetate (0.229 g, 0.03 eq) were mixed in a 500 mL three-neck flask and dissolved in anhydrous methanol (27.77 g, 20 eq) and an appropriate amount of DMF as a solvent. Next, the reaction system was degassed and purged with carbon monoxide. The reaction was allowed to react at room temperature for 12 h. After the reaction was completed, the pH of the reaction solution was adjusted to 6 with 2 N HCl solution. Extraction was performed with ethyl acetate, and the organic phases were combined. The organic phase was then washed with water three times and saturated brine once. Finally, the organic phase was dried over anhydrous Na2SO4. The solvent was removed by rotary evaporation, and the organic components were concentrated. Column chromatography was used to purify the product, which was obtained as intermediate 13 (5.73 g).

[0144] Step 4, Methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (Intermediate 14)

[0145] Intermediate 13 (10 g, 1 eq) was added to a 250 mL flask and dissolved in anhydrous methanol. The temperature was reduced to -10 °C, and sodium borohydride was added in five portions. The reaction was allowed to react at room temperature for 1 h. After the reaction was completed, the anhydrous methanol was removed from the reaction by rotary evaporation. Extraction was performed with ethyl acetate, and the organic phases were combined. To ensure the purity of the product, the combined organic phase was washed with water three times and saturated brine once. Next, the organic phase was dried over anhydrous Na2SO4. The solvent was removed by rotary evaporation, and the organic components were concentrated. Column chromatography was used to purify the product, which was obtained as intermediate 14 (9.5 g).

[0146] Step 5, Methyl 5-chloro-5,6,7,8-tetrahydronaphthalene-2-carboxylate (Intermediate 15)

[0147] Intermediate 14 (9 g, 1 eq) was added to a 250 mL flask, which was then dissolved in 100 mL of toluene, and a solution of thionyl chloride in toluene was added dropwise at 0 °C. After 3 h of reaction at room temperature, we first removed the toluene and thionyl chloride from the reaction solution by rotary evaporation. Then, it was extracted with ethyl acetate, and the obtained organic phase was combined. It was washed with water three times and then with saturated brine once. Then, anhydrous Na2SO4 was added to the organic phase for drying to remove trace amounts of water. Finally, rotary evaporation was performed to obtain a yellowish oil product. After drying and weighing, 9.11 g of product was obtained as intermediate 15.

[0148] Step 6, tert-butyl 4-(6-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)piperazine-1- carboxylate (intermediate 16)

[0149] Intermediate 15 (2.41 g, 1 eq) was added to a 100 mL flask, which was then dissolved in 20 mL of DMF, and potassium carbonate (2.78 g, 1.8 eq), potassium iodide (1.79 g, 1 eq), and N-Boc piperazine (2 g, 1 eq) were added. The reaction was carried out at 70 °C for 5 h. After the reaction was completed, ethyl acetate was added to the reaction solution for extraction, and then the obtained organic phase was combined. In order to remove impurities from the organic phase, it was washed with water three times and with saturated brine once. Then, anhydrous Na2SO4 was added to the organic phase for drying treatment. The solvent was rotary evaporated, and column chromatography was performed to obtain 2.03 g of product as intermediate 16.

[0150] Step 7, tert-butyl 4-(6-((3-iodo-4-methylphenyl)carbamoyl)-1,2,3,4-tetrahydronaphthalen-1- yl)piperazine-1-carboxylate (intermediate 17)

[0151] Intermediate 16 (1 g, 1 eq) and 3-iodo-4-methyl-phenylamine (0.809 g, 1.3 eq) were added to a 250 mL three-necked flask, which was vacuumed, purged with N2, stirred at room temperature, and 2.1 mL of trimethylaluminum was slowly added dropwise. The reaction was carried out at 100 °C for 6 h. After the reaction was completed, the reaction solution was cooled to room temperature, and then DCM was added for extraction. After the obtained organic phase was combined, it was first washed with 5% potassium sodium tartrate aqueous solution twice to remove specific impurities. Then, it was washed with water three times to further ensure the purity of the organic phase. Subsequently, it was washed with saturated brine solution once. Then, anhydrous Na2SO4 was added to the organic phase for drying treatment. The solvent was rotary evaporated, and column chromatography was performed to obtain 0.99 g of product as intermediate 17.

[0152] Step 8, tert-butyl 4-(6-((3-(imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methylphenyl)carbamoyl)-l,2,3,4-tetrahydronaphthalen-l-yl)piperazine-l-carboxylate (Intermediate 18)

[0153] Intermediate 17 (1.78 g, 1 eq), tetrakis triphenylphosphine palladium (0.107 g, 0.03 eq), cuprous iodide (0.044 g, 0.075 eq), DIPEA (0.798 g, 3 eq) were added into a 250 mL three-necked flask, then dissolved with DMF, vacuumed and purged with N2, and then the temperature was raised to 55 °C. An injection of imidazo[l,2-b]pyridazin-3-ylethynyl DMF solution (0.575 g, 1.6 eq) was added dropwise under N2 protection. The reaction was carried out at 55 °C for 5 h. After the reaction was completed, the reaction solution was filtered with celite to remove insoluble impurities. Then, water was added to the filtrate, and DCM was used for extraction to separate the organic phase. The combined organic phase was washed with water three times and saturated brine once to remove residual impurities. Then, Na2S04 was added to the organic phase for drying treatment, the solvent was rotary evaporated, and column chromatography was used for purification to obtain 1.8 g of product as Intermediate 18.

[0154] Step 9, N-(3-(imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methylphenyl)-5-(piperazin-l-yl)- 5,6,7,8-tetrahydronaphthalene-2-carboxamide (Intermediate 19)

[0155] Intermediate 18 (1.8 g, 1 eq) was dissolved with DCM, and then 20 mL of TFA was added. The reaction was carried out at room temperature for 5 h. After the reaction was completed, saturated NaHCO3 solution was first added to the reaction solution to adjust the pH value of the solution to 8-9. Then, DCM was used for extraction to separate the organic phase. The combined organic phase was washed with water three times and saturated brine once to remove residual impurities and water. Then, Na2S04 was added to the organic phase for drying treatment, the solvent was rotary evaporated, and brown solid product was obtained. After drying and weighing, 1.1 g of Intermediate 19 was obtained.

[0156] Step 10, 5-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)-2- oxoethyl)piperazin-l-yl)-N-(3-(imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methylphenyl)- 5,6,7,8-tetrahydronaphthalene-2-carboxamide (Compound 17)

[0157] Intermediate 19 (100 mg, 1 eq) and intermediate 22a (96.2 mg, 1.2 eq) were added to a 25 mL vial, followed by K2CO3 (56.5 mg, 2 eq), KI (170 mg, 5 eq), 5 mL DMSO as solvent, and reaction at 80 °C for 5 h. After the reaction was completed, immediately perform suction filtration, using diatomite as filter aid to remove the solid impurities that may be generated in the reaction. Subsequently, add an appropriate amount of water to the filtrate, and use DCM to extract to separate the organic components. Collect and combine these organic phases, then wash with water three times, and saturated brine once to ensure the complete removal of inorganic salts and residual impurities. Next, add anhydrous Na2SO4 to the organic phase for drying treatment, spin dry the solvent to concentrate the organic components. Column chromatography purification obtained white solid, successfully isolated the target product, 67 mg product. Yield 40.2%, compound 17.

[0158] MS (ESI) m / z (%): 804.3 [M+H] + . 1 H NMR (600 MHz, CDC13) δ 11.21 (d, J = 7.0 Hz, 1H), 8.88 (d, J = 8.5 Hz, 1H), 8.45 (t, J = 5.5 Hz, 1H), 8.20 - 7.94 (m, 3H), 7.81 (dd, J = 23.3, 4.8 Hz, 2H), 7.69 (t, J = 7.8 Hz, 1H), 7.64 (t, J = 8.8 Hz, 2H), 7.56 (dd, J = 16.9, 10.5 Hz, 2H), 7.26 (s, 1H), 7.25 - 7.20 (m, 1H), 7.10 (dt, J = 9.5, 4.7 Hz, 1H), 5.00 - 4.94 (m, 1H), 3.86 (d, J = 7.0 Hz, 1H), 3.20 (s, 2H), 2.92 (d, J = 14.9 Hz, 1H), 2.87 - 2.72 (m, 6H), 2.67 (d, J = 6.2 Hz, 5H), 2.54 (d, J = 4.5 Hz, 3H), 2.18 (d, J = 3.8 Hz, 1H), 2.04 (d, J = 18.3 Hz, 2H), 1.80 - 1.68 (m, 3H).

[0159] Example 18 5-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)-3- oxopropyl)piperazin-l-yl)-N-(3-(imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methylphenyl)- 5,6,7,8-tetrahydronaphthalene-2-carboxamide (Compound 18)

[0160]

[0161] 5-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3- oxopropyl)piperazin-1-yl)-N-(3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4- methylphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide

[0162] MS (ESI) m / z (%): 818.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.20 (s, 1H), 10.55 (s, 1H), 10.23 (s, 1H), 8.71 (d, J = 6.2 Hz, 1H), 8.58 (d, J = 8.4 Hz, 1H), 8.36 - 8.21 (m, 2H), 8.07 (s, 1H), 7.83 (d, J = 7.3 Hz, 1H), 7.77 - 7.66 (m, 4H), 7.60 (d, J = 7.2 Hz, 1H), 7.41 - 7.28 (m, 2H), 5.16 (dd, J = 12.7, 5.3 Hz, 1H), 3.84 (s, 1H), 3.37 (s, 2H), 2.77 (s, 2H), 2.60 (d, J = 27.1 Hz, 10H), 2.48 (s, 3H), 2.10 (s, 1H), 1.90 (s, 3H), 1.69 - 1.59 (m, 2H), 1.21 (s, 1H), 0.90 (d, J = 14.8 Hz, 1H).

[0163] Example 19 5-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-5- oxopentyl)piperazin-1-yl)-N-(3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4- methylphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (Compound 19)

[0164]

[0165] 5-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-5- oxopentyl)piperazin-1-yl)-N-(3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4- methylphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide

[0166] MS (ESI) m / z (%): 846.4 [M+H] + . 1H NMR (400 MHz, DMSO) δ 11.18 (s, 1H), 10.23 (s, 1H), 9.69 (s, 1H), 8.72 (s, 1H), 8.47 (d, J = 8.4 Hz, 1H), 8.29 - 8.21 (m, 2H), 8.07 (s, 1H), 7.82 (t, J = 7.9 Hz, 1H), 7.69 (d, J = 19.3 Hz, 4H), 7.61 (d, J = 7.3 Hz, 1H), 7.42 - 7.29 (m, 2H), 5.15 (dd, J = 13.0, 5.5 Hz, 1H), 3.81 (s, 1H), 3.37 (s, 2H), 2.97 - 2.83 (m, 2H), 2.77 (s, 3H), 2.46 (s, 8H), 2.31 (s, 4H), 1.99 (dd, J = 60.8, 10.0 Hz, 4H), 1.56 (dd, J = 51.2, 7.5 Hz, 6H).

[0167] Example 20 5-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)-6- oxohexyl)piperazin-l-yl)-N-(3-(imidazo[l,2-b]pyridazin-3-ethynyl)-4-methylphenyl)- 5,6,7,8-tetrahydronaphthalene-2-carboxamide (Compound 20)

[0168]

[0169] 5-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)-6- oxohexyl)piperazin-l-yl)-N-(3-(imidazo[l,2-b]pyridazin-3-ethynyl)-4-methylphenyl)- 5,6,7,8-tetrahydronaphthalene-2-carboxamide

[0170] MS (ESI) m / z (%): 818.3 [M+H] +1H NMR (400 MHz, DMSO) δ 11.18 (s, 1H), 10.23 (s, 1H), 9.70 (s, 1H), 8.71 (d, J = 4.5 Hz, 1H), 8.47 (d, J = 8.4 Hz, 1H), 8.31 - 8.18 (m, 2H), 8.07 (d, J = 2.4 Hz, 1H), 7.82 (t, J = 7.9 Hz, 1H), 7.69 (d, J = 17.1 Hz, 4H), 7.61 (d, J = 7.2 Hz, 1H), 7.42 - 7.29 (m, 2H), 5.15 (dd, J = 12.8, 5.4 Hz, 1H), 4.21 (t, J = 6.5 Hz, 1H), 2.96 - 2.73 (m, 4H), 2.47 (d, J = 8.6 Hz, 8H), 2.33 (s, 3H), 2.10 - 1.82 (m, 4H), 1.63 (p, J = 6.7 Hz, 5H), 1.46 (s, 2H), 1.41 - 1.28 (m, 3H), 1.21 (s, 1H), 0.90 (t, J = 7.4 Hz, 1H).

[0171] Example 21 5-(4-(8-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)-8-oxooctyl)piperazin-l-yl)-N-(3-(imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methylphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (Compound 21)

[0172]

[0173] 5-(4-(8-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)-8-oxooctyl)piperazin-l-yl)-N-(3-(imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methylphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide

[0174] MS (ESI) m / z (%): 888.4 [M+H] + . 1H NMR (400 MHz, DMSO) δ 11.19 (s, 1H), 10.24 (s, 1H), 9.70 (s, 1H), 8.71 (d, J = 4.4 Hz, 1H), 8.46 (d, J = 8.4 Hz, 1H), 8.29 - 8.19 (m, 2H), 8.07 (s, 1H), 7.82 (t, J = 7.9 Hz, 1H), 7.72 (s, 3H), 7.67 (s, 1H), 7.61 (d, J = 7.2 Hz, 1H), 7.40 - 7.30 (m, 2H), 5.15 (dd, J = 12.7, 5.5 Hz, 1H), 4.21 (t, J = 6.5 Hz, 1H), 2.96 - 2.82 (m, 2H), 2.78 (s, 2H), 2.60 (d, J = 19.9 Hz, 8H), 2.14 - 1.88 (m, 3H), 1.62 (q, J = 6.7 Hz, 6H), 1.45 (s, 4H), 1.26 (d, J = 32.2 Hz, 8H), 0.90 (t, J = 7.4 Hz, 2H).

[0175] Example 22 5-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)amino)-2- oxoethyl)piperazin-l-yl)-N-(3-(imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methylphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (Compound 22)

[0176]

[0177] 5-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)amino)-2- oxoethyl)piperazin-l-yl)-N-(3-(imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methylphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide

[0178] MS (ESI) m / z (%): 790.4 [M+H] + . 1H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 10.20 (s, 1H), 9.76 (s, 1H), 8.67 (dd, J = 4.4, 1.6 Hz, 1H), 8.29 - 8.14 (m, 2H), 8.03 (d, J = 2.3 Hz, 1H), 7.80 (dq, J = 4.6, 2.4 Hz, 1H), 7.75 - 7.62 (m, 4H), 7.54 - 7.43 (m, 2H), 7.34 (dd, J = 9.2, 4.5 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 5.12 (dd, J = 13.3, 5.3 Hz, 1H), 4.49 - 4.15 (m, 2H), 3.84 (s, 1H), 3.46 (s, 2H), 3.22 - 3.08 (m, 2H), 2.96 - 2.83 (m, 1H), 2.75 (s, 2H), 2.57 (d, J = 15.4 Hz, 8H), 2.31 (d, J = 13.8 Hz, 1H), 1.92 (s, 3H), 1.62 (d, J = 6.7 Hz, 2H), 1.18 (s, 2H).

[0179] Example 23 5-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)amino)-3- oxopropyl)piperazin-l-yl)-N-(3-(imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methylphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (Compound 23)

[0180]

[0181] 5-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)amino)-3- oxopropyl)piperazin-l-yl)-N-(3-(imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methylphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide

[0182] MS (ESI) m / z (%): 803.4 [M+H] + . 1H NMR (400 MHz, DMSO) δ 11.07 (s, 1H), 10.26 (s, 1H), 10.15 (s, 1H), 8.72 (s, 1H), 8.29 - 8.18 (m, 2H), 8.10 - 8.05 (m, 1H), 7.87 (d, J = 6.7 Hz, 1H), 7.72 (d, J = 15.3 Hz, 4H), 7.51 (d, J = 7.3 Hz, 2H), 7.35 (dd, J = 15.9, 6.6 Hz, 2H), 5.17 (d, J = 13.2 Hz, 1H), 4.36 (t, J = 19.2 Hz, 2H), 3.92 - 3.46 (m, 3H), 3.32 (s, 2H), 3.01 - 2.59 (m, 8H), 2.54 (s, 3H), 2.31 (d, J = 12.8 Hz, 2H), 2.02 (d, J = 47.7 Hz, 4H), 1.63 (s, 2H), 1.22 (s, 2H).

[0183] Example 24 N-(4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)-4- oxobutyryl)piperazin-l-yl)quinazolin-7-yl)-3-(imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methylbenzamide (Compound 24)

[0184]

[0185] N-(4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)-4- oxobutyryl)piperazin-l-yl)quinazolin-7-yl)-3-(imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methylbenzamide (Compound 24)

[0186]

[0187] Step 1, 4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)-4- oxobutanoic acid (Intermediate 31)

[0188] ​succinic anhydride (549.35 mg, 5 eq), pomalidomide (300 mg, 1 eq) and AcOK were added into a 50 mL tomato bottle, with acetic acid as the solvent. Next, the mixture was placed in a 100 °C environment to allow the reaction to proceed, and the reaction was allowed to proceed for 5 h. After the reaction was completed, an appropriate amount of water was added to the reaction solution, and extraction was performed with ethyl acetate to effectively separate the organic components. Next, the organic phases were collected and combined, then washed with water three times and saturated brine once, and anhydrous Na2SO4 was added to the organic phase for drying treatment. After drying was complete, the solvent was removed by rotary evaporation. Column chromatography purification yielded 257 mg of solid product with a yield of 62.6%.

[0189] Step 2, N-(4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)-4- oxobutanoyl)piperazin-l-yl)quinazolin-7-yl)-3-(imidazo[l,2-b]pyridazin-3-yl ethynyl)-4- methylbenzamide (Compound 24)

[0190] Intermediate 9 (100 mg, 1 eq), intermediate 31 (91.7 mg, 1.2 eq), triethylamine, HATU were added to a 25 mL tomato bottle, and then DMSO (5 mL) was added as the solvent, and the reaction was allowed to proceed at room temperature for 4 h. After the reaction was completed, the reaction solution was extracted with water and DCM, and the organic phases were combined, washed with water three times, washed with saturated brine three times, and the organic phase was dried with anhydrous Na2SO4, and the solvent was removed by rotary evaporation. Column chromatography purification yielded 14 mg of yellow solid product with a yield of 8.2%.

[0191] MS (ESI) m / z (%): 844.3 [M+H] + . 1H NMR (400 MHz, DMSO) δ 11.06 (s, 1H), 10.73 (s, 1H), 9.79 (s, 1H), 8.73 (dd, J = 4.4, 1.6 Hz, 1H), 8.56 (s, 1H), 8.37 (d, J = 2.2 Hz, 1H), 8.25 (t, J = 2.4 Hz, 2H), 7.98 (dd, J = 8.7, 2.8 Hz, 2H), 7.91 (dd, J = 9.2, 2.2 Hz, 1H), 7.81 (dd, J = 7.1, 2.0 Hz, 1H), 7.74 - 7.69 (m, 1H), 7.67 (s, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 1.8 Hz, 1H), 7.39 (dd, J = 9.2, 4.5 Hz, 1H), 5.15 (dd, J = 13.4, 5.1 Hz, 1H), 4.44 - 4.28 (m, 2H), 4.21 (t, J = 6.5 Hz, 2H), 3.70 (s, 4H), 2.61 (s, 4H), 2.35 (q, J = 6.4 Hz, 5H), 2.10 - 1.96 (m, 2H).

[0192] Example 25 In vitro anti-tumor activity

[0193] The quinazoline, tetrahydronaphthalene ring PROTAC compound was subjected to in vitro inhibition of human chronic myeloid leukemia cell (K562) activity screening.

[0194] (1) Plating:

[0195] Take the test cells in logarithmic growth phase, centrifuge, discard the supernatant, add 1 mL of medium. Take 100 μL of cells and dilute 10 times with 900 μL of medium, count with a counting plate, inoculate 100 μL of cells (1 x 10 4 / well) in a 96-well plate, and incubate in an incubator for 24 h.

[0196] (2) Sample preparation:

[0197] Accurately weigh the test compound. First, add 100 μL of DMSO to dissolve it completely, then add 50 μL of Tween 80, and finally add RPMI-1640 basic medium to make up to 2 mL. Shake well until the solution is clear and transparent, and the mother liquor concentration is 1000 μmol / L.

[0198] (3) Drug addition:

[0199] The drug was diluted to 5 concentrations according to 10 times gradient of 100 μmol / L, 10 μmol / L, 1 μmol / L, 0.1 μmol / L, 0.01 μmol / L, 100 μL of the drug solution was added to each well, which was diluted twice to the final concentration of 50 μmol / L, 5 μmol / L, 0.5 μmol / L, 0.05 μmol / L, 0.005 μmol / L, and cultured for 48 h before detection.

[0200] (4) Detection:

[0201] 20 μL of 0.5% MTT solution was taken by a pipette and added to the 96-well plate in the dark, and incubated in a 37°C incubator for 4 h, centrifuged at 1500 rpm for 5 min, and the supernatant was discarded. 150 μL of DMSO was added to the 96-well plate, and the enzyme marker was shaken for 30 s, so that the blue-purple crystals were completely dissolved, and the optical density value (OD) was detected at 490 nm. According to the data, the cell inhibition rate and the half-inhibition concentration IC50 value of each administration group were calculated (see Table 1).

[0202] Table 1 Results of in vitro anti-tumor cell activity of compounds

[0203] Comp. <![CDATA[K562 IC 50 (μmol / L)]]> Compound 1 4.014 Compound 2 0.232 Compound 3 40.945 Compound 4 1.326 Compound 5 1.795 Compound 6 0.369 Compound 7 0.906 Compound 8 2.545 Compound 9 4.101 Compound 10 11.195 Compound 11 23.620 Compound 12 1.749 Compound 13 5.118 Compound 14 4.616 Compound 15 3.089 Compound 16 2.846 Compound 17 14.025 Compound 18 0.088 Compound 19 26.675 Compound 20 1.326 Compound 21 0.292 Compound 22 23.980 Compound 23 1.904 Compound 24 2.184

Claims

1. Quinazoline ring, tetrahydronaphthalene ring PROTAC compounds and their pharmaceutically acceptable salts, characterized in that, The quinazoline ring, tetrahydronaphthalene ring PROTAC compound has the following structural formula:

2. A pharmaceutical composition, characterized in that, It is prepared by combining the quinazoline ring, tetrahydronaphthyl ring PROTAC compound as described in claim 1 and its pharmaceutically acceptable salt as active ingredients with a pharmaceutically acceptable carrier.

3. The pharmaceutical composition according to claim 2, characterized in that, The pharmaceutically acceptable carrier is selected from one or more of fillers, disintegrants, binders, and lubricants.

4. The pharmaceutical composition according to claim 2, characterized in that, The formulation of a pharmaceutical composition into tablets, capsules, granules, sprays or injections.

5. The use of the quinazolin ring, tetrahydronaphthyl ring PROTAC compound of claim 1 and its pharmaceutically acceptable salt, or the pharmaceutical composition of any one of claims 2-4, in the preparation of a medicament for treating Bcr-Abl mediated diseases.

6. The use of the quinazolin ring, tetrahydronaphthyl ring PROTAC compound of claim 1 and its pharmaceutically acceptable salt, or the pharmaceutical composition of any one of claims 2-4, in the preparation of Bcr-Abl as a molecular therapeutic target drug.

7. The use of the quinazolin ring, tetrahydronaphthyl ring PROTAC compound of claim 1 and its pharmaceutically acceptable salt, or the pharmaceutical composition of any one of claims 2-3, in the preparation of an antitumor drug.

8. The application according to claim 7, characterized in that, The tumors mentioned are: liver cancer, nasopharyngeal carcinoma, colorectal cancer, melanoma, bladder cancer, chronic myeloid leukemia, esophageal cancer, breast cancer, gastric cancer, prostate cancer, pancreatic cancer, lung cancer, ovarian cancer, epithelioid sarcoma, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, and follicular lymphoma.

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