Compound combining quinazoline derivative and pomalidomide as well as preparation method and application of compound

Abstract

The invention relates to a quinazoline derivative and pomalidomide combined compound as well as a preparation method, a pharmaceutical composition and an application of the quinazoline derivative and pomalidomide combined compound. Specifically disclosed is a compound represented by formula I or a pharmaceutically acceptable salt thereof. The compound provided by the invention has good tumor inhibition activity.

Description

TECHNICAL FIELD

[0001] The present application relates to a quinazoline derivative combined with pomalidomide compound, its preparation method, pharmaceutical composition and application. BACKGROUND

[0002] DCAF1 (DDB1-and CUL4-associated factor 1) is a key scaffold protein that plays an important role in the ubiquitin-proteasome system, which was first reported as a binding protein of human immunodeficiency virus type 1 (HIV-1) viral protein R. In 2012, Kyunghwan Kim et al. found that DCAF1 can inhibit the expression of p21 and Noxa activated by tumor suppressor p53, and p21 and Noxa are involved in cell cycle arrest and early apoptosis. Therefore, DCAF1 is a key to p53 inhibiting tumor development. DCAF1 can be considered as an oncogene, and inhibiting or degrading DCAF1 can inhibit the activity of tumors.

[0003]

[0004] In 2023, Anna Vulpetti et al. reported that compound 13 is a DCAF1 binder with good antitumor activity. SUMMARY

[0005] The first object of the present application is to provide a quinazoline derivative combined with pomalidomide compound; the second object of the present application is to provide a preparation method of the quinazoline derivative combined with pomalidomide compound; and the third object of the present application is to provide an application of the quinazoline derivative combined with pomalidomide compound.

[0006] Technical scheme: The quinazoline derivative combined with pomalidomide compound provided by the present application has the chemical structural formula:

[0007]

[0008] Wherein n is 2-6.

[0009] Preferably, the quinazoline derivative combined with pomalidomide compound has the structural formula:

[0010]

[0011] The preparation method of the quinazoline derivative combined with pomalidomide compound formula (I) provided by the present application has the following synthesis route:

[0012]

[0013] Preferably, the catalyst for the step 1 reaction is potassium iodide; the solvent is dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), dichloromethane or acetonitrile, preferably acetonitrile; and the reaction temperature is 70-80 °C.

[0014] Preferably, the catalyst for the step 2 reaction is palladium acetate, palladium chloride or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, preferably palladium acetate; the catalytic ligand is 1,1'-binaphthalene-2,2'-bisdiphenylphosphine (BINAP), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xanphos) or 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (Ruphos), preferably Ruphos; the base catalyst is potassium carbonate, cesium carbonate, triethylamine (TEA), N,N-diisopropylethylamine (DIEA) or N-methylimidazole (NMI), preferably potassium carbonate; the reaction temperature is 100-110 °C; and the organic solvent is dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), dichloromethane, acetonitrile, 1,4-dioxane or t-butanol (t-BuOH), preferably t-BuOH.

[0015] Preferably, the strong acid for the step 3 reaction is concentrated hydrochloric acid, trifluoroacetic acid or a hydrochloric acid / 1,4-dioxane mixture, preferably a hydrochloric acid / 1,4-dioxane mixture.

[0016] Preferably, the catalyst for the step 4 reaction is potassium carbonate, cesium carbonate, triethylamine (TEA), N,N-diisopropylethylamine (DIEA) or NMI, preferably potassium carbonate; the reaction temperature is 100-110 °C; and the solvent is dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), dichloromethane, acetonitrile or 1,4-dioxane, preferably DMF.

[0017] Preferably, the strong base reagent for the step 5 reaction is hydrazine hydrate, sodium hydroxide or sodium hydride, preferably hydrazine hydrate; the reaction temperature is 70-80 °C; and the solvent is dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), dichloromethane, acetonitrile or ethanol, preferably ethanol.

[0018] Preferably, the condensing agent in step 6 is 2-(7-azabenzotriazolyl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (HATU), benzotriazolyl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), carbonyldiimidazole (CDI), (1-cyano-2-ethoxy-2- oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU) or butylphosphinic anhydride (T4P), preferably T4P; the base for the reaction is potassium carbonate, cesium carbonate, triethylamine (TEA), N,N-diisopropylethylamine (DIEA) or N-methylimidazole (NMI), preferably DIEA; the reaction solvent is dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), dichloromethane, acetonitrile or methanol, preferably dichloromethane, methanol.

[0019] Preferably, the catalyst in step 7 is 5-10% palladium-carbon (Pd / C), 10-20% palladium hydroxide-carbon (Pd / C), palladium-polyethyleneimine or palladium-polyethyleneimine / formic acid, preferably 5-10% Pd / C.

[0020] The salts of the compounds in the present application, preferably including pharmaceutically acceptable salts of the compounds, can be prepared by any suitable method available in the literature, for example, using inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; or using organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid and salicylic acid; pyranose acids such as glucuronic acid and galacturonic acid; α-hydroxy acids such as citric acid and tartaric acid; amino acids such as aspartic acid and glutamic acid; aromatic acids such as benzoic acid and cinnamic acid; sulfonic acids such as p-toluenesulfonic acid, ethanesulfonic acid.

[0021] In the present application, the pharmaceutically acceptable carrier is relatively non-toxic and harmless to patients at a concentration consistent with the effective activity of the active ingredient, so that any side effects caused by the carrier will not destroy the beneficial effects of the active ingredient. The pharmaceutically effective amount of the compound or its pharmaceutically acceptable salt is preferably the amount that produces results or has an impact on the specific condition being treated. The compounds of the present application can be administered orally, parenterally, topically, nasally, ophthalmically, sublingually, rectally, vaginally, etc. with pharmaceutically acceptable carriers well known in the art using any effective conventional dosage unit forms including immediate release, sustained release and timed release formulations.

[0022] The application of the quinazoline derivative combined with pomalidomide compound in the treatment of tumors, such as cervical cancer and breast cancer.

[0023] Beneficial effects: Compared with the prior art, the present application has the following remarkable advantages: (1) novel structure; (2) good inhibition effect on Hela and MDA-MB-231 tumor cells. DETAILED DESCRIPTION

[0024] The technical solutions of the present application are further described below in combination with examples.

[0025] Example 1

[0026] N-(2-(4-(4-((2-aminopropyl)amino)-2-(1-(4-chlorophenyl)cyclohexyl)quinazolin-7-yl)piperazin-1-yl)ethyl)-2-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino)acetamide, the structural formula is as follows:

[0027]

[0028] The preparation method comprises the following steps:

[0029] (1) Synthesis of benzyl (2-((7-bromo-2-(1-(4-chlorophenyl)cyclohexyl)quinazolin-4-yl)amino)ethyl)carbamate, the structural formula is as follows:

[0030]

[0031] Into the reaction bottle, 7-bromo-4-chloro-2-(1-(4-chlorophenyl)cyclohexane) quinazoline 8.0 g (18.34 mmol), N-benzyloxy carbonyl ethylenediamine hydrochloride 5.4 g (27.51 mmol), cesium carbonate 12.0 g (36.68 mmol) and acetonitrile 80 mL were sequentially added, and the reaction was carried out at 75°C for 12 hours. The reaction mixture was extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and the concentrate was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain 2.5 g of the target product, with a yield of 23.4%.

[0032] (2) Synthesis of tert-butyl 4-(4-((2-(((benzyloxy)carbonyl)amino)ethyl)amino)-2-(1-(4-chlorophenyl)cyclohexyl)quinazolin-7-yl)piperazin-1-carboxylate, the structural formula is as follows:

[0033]

[0034] To the reaction flask was added (2-((7-bromo-2-(l-(4-chlorophenyl)cyclohexyl)quinazolin-4-yl)amino)ethyl)benzylcarbamate 1.4 g (23.57 mmol), N-BOC piperazine hydrochloride 878 mg (47.14 mmol), potassium carbonate 652 mg (47.14 mmol), Ruphos 165 mg (3.54 mmol), palladium acetate 53 mg (2.36 mmol) and t-BuOH 20 mL, under nitrogen protection, and the reaction was carried out at 100 °C for 4 h. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrate was purified by column chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain the target product 420 mg, with a yield of 25.0%.

[0035] (3) Synthesis of (2-((2-(l-(4-chlorophenyl)cyclohexyl)-7-(piperazin-l- yl)quinazolin-4-yl)amino)ethyl)benzylcarbamate, with the following structure:

[0036]

[0037] To the reaction flask was added 4-(4-((2-(((benzyloxy)carbonyl)amino)ethyl)amino)-2-(l-(4-chlorophenyl)cyclohexyl)quinazolin-7-yl)piperazin-l-yl carboxylate tert-butyl 700 mg (1.01 mmol) and HCl / dioxane 10 mL, and the reaction was carried out at room temperature for 1 h, with TLC monitoring of the reaction until completion (dichloromethane:methanol = 10: 1). Concentration under reduced pressure gave the target product hydrochloride 598 mg, with a yield of 99.2%.

[0038] (4) Synthesis of (2-((2-(l-(4-chlorophenyl)cyclohexyl)-7-(4-(2-(l,3- diisopropylindolin-2-yl)ethyl)piperazin-l-yl)quinazolin-4-yl)amino)ethyl)benzylcarbamate, with the following structure:

[0039]

[0040] To a reaction flask was added (2-((2-(l-(4-chlorophenyl)cyclohexyl)-7-(4-(2-(l,3- diisopropylindolin-2-yl)ethyl)piperazin-l-yl)quinolin-4-yl)amino)ethyl)benzylcarbamate 140 mg (0.19 mmol), hydrazine hydrate 0.5 mL and ethanol 5 mL, 80 °C for 0.5 hours, the reaction was monitored by TLC until the reaction was completed (dichloromethane:methanol = 10:1). The reaction mixture was diluted with dilute hydrochloric acid, the aqueous phase was adjusted to pH 9-10 with 1 M sodium hydroxide, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the target product 80 mg in 69.2% yield.

[0041] (5) Synthesis of (2-((7-(4-(2-aminoethyl)piperazin-l-yl)-2-(l-(4- chlorophenyl)cyclohexyl)quinolin-4-yl)amino)ethyl)benzylcarbamate, the structure is as follows:

[0042]

[0043] To a reaction flask was added (2-((2-(l-(4-chlorophenyl)cyclohexyl)-7-(4-(2-(l,3- diisopropylindolin-2-yl)ethyl)piperazin-l-yl)quinolin-4-yl)amino)ethyl)benzylcarbamate 140 mg (0.19 mmol), hydrazine hydrate 0.5 mL and ethanol 5 mL, 80 °C for 0.5 hours, the reaction was monitored by TLC until the reaction was completed (dichloromethane:methanol = 10:1). The reaction mixture was diluted with dilute hydrochloric acid, the aqueous phase was adjusted to pH 9-10 with 1 M sodium hydroxide, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the target product 80 mg in 69.2% yield.

[0044] (6) Synthesis of N-(2-(4-(4-((2-benzyloxycarbonylaminoethyl)amino)-2-(l-(4- chlorophenyl)cyclohexyl)quinolin-7-yl)piperazin-l-yl)ethyl)-2-((2-(2-(2,6-dioxopiperidin-3- yl)-l,3-dioxoisoindolin-4-yl)amino)acetamide, the structure is as follows:

[0045]

[0046] To the reaction flask was added (2-((7-(4-(2-aminoethyl)piperazin-l-yl)-2-(l-(4- chlorophenyl)cyclohexyl)quinazolin-4-yl)amino)ethyl)benzylcarbamate 80 mg (0.12 mmol), (2-(2,6-dioxo-3-piperidyl)-l,3-dioxoisoindolin-4-yl)aminoacetic acid 45 mg (0.14 mmol), DIEA 47 mg (0.37 mmol), 1-butylphosphonic anhydride 132 mg (50% purity, 0.185 mmol) and dichloromethane 3 mL, and the reaction was allowed to proceed at room temperature for 1 hour, monitoring the reaction by TLC until completion (dichloromethane:methanol = 10:1). The reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and the concentrate was purified by column chromatography (dichloromethane:methanol = 20:1) to obtain the product 90 mg at a yield of 69.7%.

[0047] (7) Synthesis of N-(2-(4-(4-((2-aminoethyl)amino)-2-(l-(4-chlorophenyl)cyclohexyl)quinazolin-7-yl)piperazin-l-yl)ethyl)-2-((2-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)acetamide

[0048] To the reaction flask was added N-(2-(4-(4-((2-benzyloxycarbonylaminoethyl)amino)-2-(l-(4-chlorophenyl)cyclohexyl)quinazolin-7-yl)piperazin-l-yl)ethyl)-2-((2-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)acetamide 90 mg, methanol 5 mL, and the flask was purged with nitrogen. Pd / C 50 mg (10% purity, 0.33 mmol) was added under a nitrogen atmosphere, and the reaction was allowed to proceed at room temperature for 1 hour under a hydrogen atmosphere. The reaction mixture was suction filtered, washed with methanol, and concentrated under reduced pressure. The concentrate was purified by column chromatography (dichloromethane:methanol = 10:1) to obtain the target end product 51 mg at a yield of 56.7%.

[0049] The target compound was a yellow solid; 1H NMR (400 MHz, Methanol-d4) δ 8.07 (d, J = 9.3 Hz, 1H), 7.56 - 7.48 (m, 3H), 7.23 (dd, J = 9.4, 2.4 Hz, 1H), 7.16 (d, J = 2.4 Hz, 1H), 7.04 (d, J = 7.2 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H), 4.98 (d, J = 5.5 Hz, 1H), 4.02 (s, 2H), 3.97 (t, J = 6.0 Hz, 2H), 3.40 (t, J = 6.3 Hz, 2H), 3.35 (d, J = 0.8 Hz, 2H), 3.31 - 3.19 (m, 4H), 2.82 (d, J = 14.0 Hz, 2H), 2.72 (d, J = 4.9 Hz, 1H), 2.73 - 2.48 (m, 8H), 2.17 (t, J = 11.1 Hz, 2H), 1.95 (d, J = 6.1 Hz, 1H), 1.67 - 1.28 (m, 8H). 13 C NMR (101 MHz, Methanol-d4) δ 174.84, 172.45, 171.68, 170.53, 169.25, 168.96, 161.58, 156.57, 147.41, 144.74, 137.56, 134.15, 134.05, 130.06, 129.87, 126.34, 118.37, 118.14, 113.10, 112.46, 104.80, 102.99, 102.32, 59.20, 57.64, 56.06, 53.43, 50.99, 50.40, 47.58, 47.18, 40.57, 40.33, 38.96, 38.83, 36.85, 36.22, 32.39, 30.94, 26.86, 24.40, 23.96.

[0050] Example 2

[0051] N-(3-(4-(4-((2-aminopropyl)amino)-2-(1-(4-chlorophenyl)cyclohexyl)quinazolin-7- yl)piperazin-1-yl)propyl)-2-((2-(2-(2-6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)acetyl)amide, having the structure:

[0052]

[0053] The preparation thereof comprises the following steps:

[0054] (1) Based on the procedure of Example 1, step (4) N-(2-bromethyl)phthalimide was replaced by N-(2-bromopropyl)phthalimide, and the rest of the conditions were the same as Example 1. Steps (1), (2), (3), (5) and (6) were the same as Example 1. The intermediate N-(2-(4-(4-((2-benzyloxycarbonylaminoethyl)amino)-2-(l-(4-chlorophenyl)cyclohexyl)quinazolin-7-yl)piperazin-l-yl)propyl)-2-((2-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)acetamide was obtained, and the structure is as follows:

[0055]

[0056] (7) N-(2-(4-(4-((2-benzyloxycarbonylaminoethyl)amino)-2-(l-(4-chlorophenyl)cyclohexyl)quinazolin-7-yl)piperazin-l-yl)propyl)-2-((2-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)acetamide 90 mg (0.09 mmol), methanol 5 mL, replace nitrogen, add Pd / C 50 mg (10% purity, 0.33 mmol) under nitrogen atmosphere, replace hydrogen, react at room temperature for 1 hour. Filter, wash with methanol, concentrate under reduced pressure, and the concentrate is purified by column chromatography (dichloromethane:methanol = 10:1) to obtain the target final product 57 mg, with a yield of 73.5%.

[0057] The target compound is a yellow solid; 1 H NMR (400 MHz, Methanol-d4) δ 8.02 (d, J = 9.3 Hz, 1H), 7.50 (dd, J = 17.2, 8.1 Hz, 3H), 7.32 - 7.21 (m, 3H), 7.12 (d, J = 2.1 Hz, 1H), 6.99 (d, J = 7.1 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H), 4.97 (dd, J = 12.3, 5.3 Hz, 1H), 4.01 (s, 2H), 3.92 (t, J = 5.8 Hz, 2H), 3.42 (s, 3H), 3.34 (t, J = 3.1 Hz, 2H), 3.28 - 3.22 (m, 2H), 2.76 (s, 5H), 2.69 - 2.61 (m, 5H), 2.44 (s, 1H), 2.23 - 1.89 (m, 4H), 1.85 - 1.74 (m, 2H), 1.60 (d, J = 12.3 Hz, 4H), 1.45 (d, J = 51.6 Hz, 4H). 13C NMR (101 MHz, Methanol-d4) δ 173.32, 171.00, 170.19, 169.04, 168.18, 167.75, 160.05, 154.41, 146.09, 144.57, 136.05, 135.91, 132.50, 132.14, 128.25, 124.27, 117.00, 116.51, 111.62, 111.49, 111.12, 104.38, 55.54, 52.08, 50.89, 49.62, 48.91, 45.98, 45.87, 39.11, 38.90, 37.31, 35.06, 33.00, 32.43, 30.88, 30.39, 29.41, 25.51, 24.86, 23.82, 23.01, 22.42.

[0058] Example 3

[0059] N-(4-(4-(4-((2-aminopropyl)amino)-2-(l-(4-chlorophenyl)cyclohexyl)quinazolin-7- yl)piperazin-l-yl)butyl)-2-((2-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)acetyl)amide, having the following structure:

[0060]

[0061] (1) Based on Example 1, replace step (4) N-(2-bromoethyl)phthalimide with N-(2- bromobutyl)phthalimide, and the remaining conditions are the same as Example 1. Steps (1), (2), (3), (5) and (6) are the same as Example 1. The intermediate N-(2-(4-(4-((2- benzyloxycarbonylaminoethyl)amino)-2-(l-(4-chlorophenyl)cyclohexyl)quinazolin-7- yl)piperazin-l-yl)butyl)-2-((2-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)acetyl)amide, having the following structure:

[0062]

[0063] (7) N-(2-(4-(4-((2-benzyloxycarbonylaminoethyl)amino)-2-(1-(4- chlorophenyl)cyclohexyl)quinazolin-7-yl)piperazin-1-yl)butyl)-2-((2-(2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetyl)amide 90 mg, methanol 5 mL, replace nitrogen, add Pd / C 50 mg (10% purity, 0.33 mmol) under nitrogen atmosphere, replace hydrogen, react at room temperature for 1 hour. Filter under suction, wash with methanol, concentrate under reduced pressure, purify the concentrate by column chromatography (dichloromethane:methanol = 10:1) to obtain the target final product 52 mg, yield 67.2%.

[0064] The target compound is a yellow solid; 1 H NMR (400 MHz, Methanol-d4) δ 8.13 (d, J = 9.2 Hz, 1H), 7.63 - 7.46 (m, 3H), 7.35 - 7.27 (m, 4H), 7.07 (d, J = 7.0 Hz, 1H), 6.91 (d, J = 8.5 Hz, 1H), 5.04 (dd, J = 12.5, 5.4 Hz, 1H), 4.03 (s, 2H), 3.98 (t, J = 5.9 Hz, 2H), 3.65 (q, J = 5.0 Hz, 4H), 3.28 (d, J = 5.9 Hz, 4H), 3.15 (t, J = 5.1 Hz, 4H), 2.96 (m, 2H), 2.86 - 2.80 (m, 2H), 2.80 - 2-77 (m, 1H), 2-74 - 2.62 (m, 2H), 2.18 (dd, J = 10.0, 9.2, 5.2 Hz, 2H), 2.12 - 2.06 (m, 1H), 1.75 - 1.64 (m, 4H), 1.63 - 1.46 (m, 6H), 1.28 (s, 2H). 13 C NMR (101 MHz, Methanol-d4) δ 174.45, 171.95, 171.38, 170.19, 169.00, 161.26, 155.28, 147.17, 145.88, 144.89, 137.14, 133.65, 133.50, 129.49, 129.39, 125.91, 118.03, 117.89, 112.55, 112.11, 110.60, 105.49, 58.74, 57.53, 52.47, 50.68, 50.04, 46.66, 46.01, 40.10, 40.00, 39.12, 38.41, 35.97, 32.83, 32.00, 31.44, 30.50, 29.42, 27.37, 26.52, 24.03, 23.54, 22.37.

[0065] Example 4

[0066] N-(5-(4-(4-((2-aminoethyl)amino)-2-(1-(4-chlorophenyl)cyclohexyl)quinazolin-7- yl)piperazin-1-yl)pentyl)-2-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)acetamide, the structure of which is as follows:

[0067]

[0068] (1) On the basis of Example 1, replace N-(2-bromoethyl)phthalimide in step (4) with N-(2-bromopentyl)phthalimide, and the remaining conditions are unchanged. Steps (1), (2), (3), (5), and (6) are the same as in Example 1. The intermediate N-(2-(4-(4-((2-benzyloxycarbonylaminoethyl)amino)-2-(1-(4-chlorophenyl)cyclohexyl)quinazolin-7-yl)piperazin-1-yl)pentyl)-2-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamide, the structure of which is as follows, is obtained:

[0069]

[0070] (7) N-(2-(4-(4-((2-benzyloxycarbonylaminoethyl)amino)-2-(1-(4-chlorophenyl)cyclohexyl)quinazolin-7-yl)piperazin-1-yl)pentyl)-2-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamide 90 mg, methanol 5 mL, replace nitrogen, add Pd / C 50 mg (10% purity, 0.33 mmol) under nitrogen atmosphere, replace hydrogen, and react at room temperature for 1 hour. Filter under suction, wash with methanol, concentrate under reduced pressure, and purify the concentrate by column chromatography (dichloromethane:methanol = 10:1) to obtain the target final product 55 mg with a yield of 70.5%.

[0071] The target compound is a yellow solid; 1H NMR (400 MHz, Methanol-d4) δ 8.00 (d, J = 9.2 Hz, 1H), 7.58 - 7.53 (m, 1H), 7.49 - 7.44 (m, 2H), 7.28 - 7.25 (m, 3H), 7.22 (d, J = 2.5 Hz, 1H), 7.07 (d, J = 7.0 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H), 5.07 - 5.02 (m, 1H), 4.01 (s, 2H), 3.88 (t, J = 5.8 Hz, 2H), 3.54 (m, 4H), 3.29 - 3.18 (m, 4H), 2.96 (t, J = 5.1 Hz, 4H), 2.88 - 2.69 (m, 6H), 2.67 (t, J = 2.0 Hz, 1H), 2.14 - 2.08 (m, 2H), 2.08 - 2.04 (m, 1H), 1.71 - 1.63 (m, 4H), 1.59 - 1.34 (m, 8H), 1.28 (s, 2H). 13 C NMR (101 MHz, Methanol-d4) δ 174.66, 171.91, 171.59, 170.40, 169.84, 169.20, 161.40, 155.25, 147.33, 146.40, 137.29, 133.84, 133.26, 129.53, 129.46, 125.48, 118.47, 118.24, 117.85, 112.75, 112.28, 106.39, 59.32, 58.45, 53.04, 51.02, 50.23, 46.86, 46.83, 46.80, 45.36, 40.51, 40.16, 39.80, 36.52, 33.09, 32.19, 30.72, 29.84, 26.90, 25.24, 24.99, 24.37, 23.74.

[0072] Example 5

[0073] N-(6-(4-(4-((2-aminoethyl)amino)-2-(1-(4-chlorophenyl)cyclohexyl)quinazolin-7- yl)piperazin-1-yl)hexyl)-2-((2-(2-(2-6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)acetamide, having the structure:

[0074]

[0075] (1) Based on the example 1, step (4) N-(2-bromoethyl)phthalimide is replaced by N-(2-bromohexyl)phthalimide, and the rest of the conditions are the same as example 1. Steps (1), (2), (3), (5) and (6) are the same as example 1. The intermediate N-(2-(4-(4-((2-benzyloxycarbonylaminoethyl)amino)-2-(1-(4-chlorophenyl)cyclohexyl)quinazolin-7-yl)piperazin-1-yl)hexyl)-2-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamide is obtained, and the structural formula is as follows:

[0076]

[0077] (7) N-(2-(4-(4-((2-benzyloxycarbonylaminoethyl)amino)-2-(1-(4-chlorophenyl)cyclohexyl)quinazolin-7-yl)piperazin-1-yl)hexyl)-2-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamide 90 mg, methanol 5 mL, replace nitrogen, add Pd / C 50 mg (10% purity, 0.33 mmol) under nitrogen atmosphere, replace hydrogen, react at room temperature for 1 hour. Filter, wash with methanol, concentrate under reduced pressure, and purify the concentrate by column chromatography (dichloromethane:methanol=10:1) to obtain the target final product 53 mg, with a yield of 67.9%.

[0078] The target compound is a yellow solid; 1 H NMR (400 MHz, Methanol-d4) δ 8.05 (d, J = 9.2 Hz, 1H), 7.59-7.51 (m, 1H), 7.47 (d, J = 8.5 Hz, 2H), 7.28 (d, J = 8.7 Hz, 3H), 7.21 (s, 1H), 7.08 (d, J = 7.1 Hz, 1H), 6.88 (d, J = 8.5 Hz, 1H), 5.05 (d, J = 12.0 Hz, 1H), 4.00 (s, 2H), 3.91 (t, J = 5.8 Hz, 2H), 3.62 (s, 4H), 3.54 (s, 1H), 3.35 (s, 1H), 3.28-3.19 (m, 4H), 3.13 (s, 4H), 2.91-2.65 (m, 6H), 2.55-2.26 (m, 2H), 2.12 (s, 3H), 1.65 (s, 4H), 1.53 (d, J = 7.9 Hz, 4H), 1.38-1.26 (m, 5H). 13C NMR (101 MHz, Methanol-d4) δ 173.24, 170.47, 170.25, 169.58, 169.02, 168.42, 167.85, 160.04, 153.79, 145.92, 135.92, 135.78, 132.56, 132.47, 131.94, 128.15, 128.11, 124.18, 116.84, 116.68, 116.52, 111.39, 111.30, 111.08, 110.90, 104.99, 56.92, 54.47, 51.51, 49.63, 48.88, 45.50, 45.26, 39.09, 38.81, 38.61, 35.10, 30.82, 30.35, 28.71, 25.88, 25.83, 25.50, 24.14, 23.76, 22.98, 22.36.

[0079] Effect test example

[0080] MTT method for determining anti-tumor activity

[0081] Cell culture: Human cancer cell lines MDA-MB-231 and Hela cells were purchased from Beijing National Biomedical Laboratory, and were cultured in DMEM (KGM12800-500) or MEM medium (KGM41500-500) containing 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin, and were cultured in a 37°C constant temperature incubator (Thermo Fisher Scientific, BB150) containing 5% CO2. When the cell confluence reached 70%-80%, 0.25% trypsin was added for digestion, resuspension, and culture. Cells in the logarithmic growth phase and in good growth condition were selected for study.

[0082] Methyl thiazolyl tetrazolium (MTT) was used for cell activity determination. The blood cell counting plate method was used for cell counting, and the cell viability was greater than 95% in all experiments. MDA-MB231 and Hela cells were seeded at 1 x 10 4Cells were seeded in 96-well plates. 100 μL of medium (containing 1% FBS) dissolved in different concentrations of drugs (0-50 μM) were added to each well, and incubated for 24 h, respectively. The supernatant was discarded using a plate centrifuge (5 min, 2000 rpm), 10 μL of MTT (5 mg / mL) solution was added to each well, and incubated at 37°C for 4 h. The supernatant was discarded by plate centrifugation, 100 μL of DMSO was added to each well, and placed on a shaker for 10 min to fully dissolve the Formazan crystals. The absorbance was measured at 570 nm wavelength using a microplate reader (BioTek, USA). The cytotoxicity was determined compared with the control group (DMSO). The concentration of 50% cell growth inhibition induced by drugs (IC 50 ) was determined by non-linear regression using the curve fitting algorithm of GraphPad Prism 9 (GraphPad software, La Jolla, CA, USA).

[0083] To explore the effect of the compound on the activity of tumor cells, MTT method was used to detect cell toxicity. As shown in Table 1, the effect of the compound on the activity of different tumor cells, the half inhibitory concentration IC 50 (24h) of the drug on each cell line was calculated.

[0084] Table 1 Inhibitory activity of compounds on different tumor cells (IC 50 )

[0085] Examples MDA-MB-231 (μM) Hela (μM) Example 1 14.85±0.16 / Example 2 / / Example 3 11.37±0.35 8.38±0.32 Example 4 7.03±0.05 6.90±0.08 Example 5 3.04±0.13 3.68±0.09 Compound 13 17.13+0.23 8.68±0.13

[0086] “ / ” means not tested.

[0087] As shown by the results in Table 1, the inhibitory effect of the compound on Hela and MDA-MB-231 tumor cells was significant, and had good research value.

Claims

1. A compound of Formula I: ###0001### or a pharmaceutically acceptable salt thereof. wherein n is 2-6.

2. The quinazoline derivative compound of claim 1, wherein The compound has the following structure:

3. A process for preparing the benzodioxolane-conjugated pomalidomide compound of claim 1, comprising: The compound 10 is deprotected by removing the CBZ (benzyloxycarbonyl) group to obtain the compound I. n is 2-6.

4. A compound 11: ###0003### n is 2-6, preferably, the compound 11 is: ###0004### 5. A pharmaceutical composition comprising: (1) the compound I or a pharmaceutically acceptable salt thereof according to any one of claims 1-2; and (2) a pharmaceutically acceptable excipient.

6. Use of the compound I or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, or a pharmaceutical composition in the manufacture of a medicament for treating a tumor, preferably cervical cancer and breast cancer.

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