A compound, preparation method thereof and medical use

Abstract

The present invention relates to the field of biomedicine, and more specifically to a compound, its preparation method, and its medical use. In the present invention, a novel compound is prepared using a simple and readily applicable method. This compound has the property of effectively inhibiting USP11 activity and can be used as a selective USP11 inhibitor. This compound can be used to prepare a drug for treating and / or preventing liver cancer, thereby enhancing the therapeutic effect of liver cancer.

Description

Technical Field

[0001] The present invention relates to the technical field of biomedicine, and in particular to a compound, a preparation method thereof, and medical applications thereof. Background Art

[0002] Liver cancer is a malignant tumor with high morbidity and mortality. Treatment options primarily include surgical resection, interventional therapy, targeted drugs, and immunotherapy. However, due to the heterogeneity and high recurrence rate of liver cancer, the efficacy of existing treatments remains significantly limited, especially for patients with advanced liver cancer, who often have a poor prognosis.

[0003] Studies have shown that ubiquitin-specific protease 11 (USP11) stabilizes cancer-promoting proteins through deubiquitination, playing a key role in the proliferation, invasion, metastasis and chemotherapy resistance of liver cancer. Its high expression is significantly correlated with the malignancy and poor prognosis of liver cancer, making it a potential therapeutic target.

[0004] However, due to the high homology among USP family members, existing USP11 inhibitors have poor selectivity, which can easily lead to off-target effects and potential toxicity. Furthermore, they suffer from defects such as poor metabolic stability and low bioavailability, which severely limit their clinical application. Therefore, the development of highly selective USP11 inhibitors with excellent pharmacokinetic properties is an important direction for the current research and development of liver cancer therapeutics. Summary of the Invention

[0005] In order to promote the therapeutic effect of liver cancer, the present invention provides a compound, a preparation method and medical use thereof.

[0006] The first aspect of the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound has a structure shown in Formula 6:

[0007] ;

[0008] Wherein, R is one of the following groups:

[0009] 、 、 ;

[0010] Wherein, R1 is selected from hydrogen, C1~C4 alkyl, and halogen atom.

[0011] The compound represented by Formula 6 or a pharmaceutically acceptable salt thereof has the property of selectively inhibiting the activity of USP11 and is a USP11 selective inhibitor. The pharmaceutically acceptable salt of the compound represented by Formula 6 can be easily prepared from the compound represented by Formula 6 as a raw material. For example, the hydrochloride salt of the compound represented by Formula 6 can be prepared by reacting the compound represented by Formula 6 with hydrochloric acid.

[0012] In some optional embodiments, the above R1 is selected from hydrogen, methyl, ethyl, fluorine atom, chlorine atom, bromine atom, and iodine atom.

[0013] In some optional embodiments, the compound has a structure shown in one of Formula 6a to Formula 6e:

[0014] 、

[0015] 、

[0016] 、

[0017] 、

[0018] .

[0019] The second aspect of the present invention provides a method for preparing the compound represented by Formula 6, which comprises the following steps:

[0020] The carboxylic acid compound represented by Formula 1 and the amine compound represented by Formula 2 undergo an amide condensation reaction to obtain a compound represented by Formula 3;

[0021] In the presence of a palladium catalyst, the compound represented by Formula 3 is subjected to a hydrogenation reaction with hydrogen to obtain an amine compound represented by Formula 4;

[0022] The amine compound represented by Formula 4 undergoes an amide condensation reaction with a carboxylic acid compound represented by one of Formulas 5a to 5c to obtain a compound represented by Formula 6;

[0023] 、 、

[0024] 、

[0025] 、

[0026] 、 、 、

[0027] ;

[0028] Wherein, R is one of the following groups:

[0029] 、 、 ;

[0030] Wherein, R1 is selected from hydrogen, C1~C4 alkyl, and halogen atom.

[0031] In some optional embodiments, the amide condensation reaction is carried out in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole.

[0032] In some optional embodiments, the amide condensation reaction is carried out in N,N-dimethylformamide solvent.

[0033] In some optional embodiments, the palladium catalyst is palladium carbon.

[0034] In some optional embodiments, the hydrogenation reaction is carried out in methanol solvent.

[0035] A third aspect of the present invention provides use of the compound represented by Formula 6 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing liver cancer.

[0036] A fourth aspect of the present invention provides a drug for treating and / or preventing liver cancer, comprising a compound represented by Formula 6 or a pharmaceutically acceptable salt thereof. The compound represented by Formula 6 or a pharmaceutically acceptable salt thereof is the main active ingredient (primary agent) in the drug for treating and / or preventing liver cancer.

[0037] In some optional embodiments, the drug for treating and / or preventing liver cancer further comprises an excipient. The dosage form of the drug for treating and / or preventing liver cancer is any pharmaceutically acceptable dosage form. The excipient is stable, has no incompatibility with the main drug, does not produce side effects, does not affect the efficacy, is not easily deformed, cracked, or moldy at room temperature, and is harmless to the human body.

[0038] In some optional embodiments, the excipient is at least one of gum arabic, syrup, lanolin, and starch.

[0039] The technical solution of the embodiment of the present invention has the following beneficial effects:

[0040] A new compound was prepared by a simple and easy method. The compound has the property of effectively inhibiting the activity of USP11 and can be used as a selective inhibitor of USP11. The compound can be used to prepare drugs for treating and / or preventing liver cancer to promote the therapeutic effect of liver cancer. DETAILED DESCRIPTION

[0041] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0042] Example 1

[0043] The compound represented by formula 6a was synthesized according to the following route:

[0044]

[0045] Step 1: In a 250 mL round-bottom flask, 4-nitro-1H-pyrazole-3-carboxylic acid (2.0 g, 12.73 mmol, 1.0 eq) of Formula 1 was dissolved in 100 mL of N,N-dimethylformamide. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.93 g, 15.28 mmol, 1.2 eq) and 1-hydroxybenzotriazole (2.06 g, 15.28 mmol, 1.2 eq) were added. Finally, 4-((2-(4-methylpiperazin-1-yl)ethyl)oxy)aniline (3.0 g, 12.73 mmol, 1.0 eq) of Formula 2 was added. The reaction progress was monitored by thin layer chromatography (TLC). After completion of the reaction, the mixture was filtered to obtain the compound of Formula 3 (yellow solid, 3.72 g, 78%).

[0046] The characterization results of the compound shown in Formula 3 are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 8.88 (s, 1H), 7.61 (d, J = 9.0 Hz, 2H), 6.96 (d, J = 9.0 Hz, 2H), 4.09 (t, J= 5.5 Hz, 2H), 2.68-2.82 (m, 10H), 2.51 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ158.5, 155.3, 132.8, 132.3, 131.7, 121.6, 116.0, 115.2, 65.9, 56.1, 52.8,50.3, 42.7. (ESI) calculated for C 17 H 23 N6O4 + [M+H] + : 375.4010, found: 375.4011.

[0047] Step 2: In a 150 mL three-necked flask, the compound represented by Formula 3 (3.0 g, 8.01 mmol, 1.0 eq) was dissolved in 80 mL of methanol, and palladium on carbon (10% w / w, 400 mg) was added. The reaction apparatus was replaced with argon three times and with hydrogen three times, and hydrogen was injected. The reaction was allowed to react at room temperature for 8 hours. The reaction progress was monitored by thin layer chromatography (TLC). After the reaction was complete, the reaction solution was filtered through diatomaceous earth and concentrated to obtain the amine compound represented by Formula 4 (brown solid, 2.62 g, 95%).

[0048] The characterization results of the amine compound shown in Formula 4 are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 12.75 (s,1H), 9.65 (s, 1H), 7.66 (d, J = 8.5 Hz, 2H), 7.17 (s, 1H), 6.88 (d, J = 8.5Hz, 2H), 4.71 (s, 2H), 4.04 (d, J = 5.7 Hz, 2H), 2.68 (d, J = 5.7 Hz, 2H), 2.43 (s, 8H), 2.22 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 162.9, 154.8, 134.1,132.5, 132.2, 122.0, 115.7, 114.8, 66.1, 57.0, 54.9, 53.1, 45.8. (ESI)calculated for C 17 H 25 N6O2 + [M+H] + : 345.4190, found: 345.4192.

[0049] Step 3: In a 50 mL round-bottom flask, pyridine-3-carboxylic acid (200 mg, 1.62 mmol, 1.0 eq) of Formula 5ba was dissolved in 10 mL of N,N-dimethylformamide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (265 mg, 1.38 mmol, 1.2 eq) and 1-hydroxybenzotriazole (186 mg, 1.38 mmol, 1.2 eq) were added, and finally the amine compound (271 mg, 1.15 mmol, 1.0 eq) of Formula 4 was added. The reaction progress was monitored by thin layer chromatography (TLC). After the reaction was complete, saturated sodium chloride solution (20 mL) was added and the mixture was extracted with ethyl acetate (2×20 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (CH2Cl2:CH3OH = 5:1) to obtain the compound of Formula 6a (white solid, 445 mg, 61%).

[0050] The characterization results of the compound represented by Formula 6a are as follows: Mp 196.3-197.5 °C; IR (KBr): 3689, 3280, 2968, 2190, 1915, 1682, 1420, 1089, 920 cm -1 . 1 H NMR (400 MHz, DMSO-d6)δ 13.60 (s, 1H), 10.66 (s, 1H), 10.32 (s, 1H), 9.08 (s, 1H), 8.81 (d, J = 3.5Hz, 1H), 8.39 (s, 1H), 8.25 (d, J = 6.9 Hz, 1H), 7.74 (d, J = 8.5 Hz, 2H), 7.63 (dd, J = 7.8, 4.9 Hz, 1H), 6.93 (d, J = 8.5 Hz, 2H), 4.07 (t, J = 6.0Hz, 2H), 2.72 (s, 2H), 2.59 (s, 8H), 2.34 (s, 3H). 13 C NMR (100 MHz, DMSO-d6)δ 162.0, 155.3, 153.0, 152.4, 150.9, 148.6, 137.2, 135.2, 131.8, 129.5,124.5, 123.9, 122.8, 114.9, 66.0, 56.5, 53.6, 51.4, 44.0. (ESI) calculated for C 23 H28 N7O3 + [M+H] + : 450.5150, found: 450.5153.

[0051] Example 2

[0052] The compound shown in formula 6b was synthesized according to the following route:

[0053]

[0054] Step 1: Same as step 1 in Example 1.

[0055] Step 2: Same as step 2 in Example 1.

[0056] Step 3: In a 50 mL round-bottom flask, pyridine-2-carboxylic acid (200 mg, 1.62 mmol, 1.0 eq) of Formula 5aa was dissolved in 10 mL of N,N-dimethylformamide. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (265 mg, 1.38 mmol, 1.2 eq) and 1-hydroxybenzotriazole (186 mg, 1.38 mmol, 1.2 eq) were added, and finally, the amine compound (271 mg, 1.15 mmol, 1.0 eq) of Formula 4 was added. The reaction progress was monitored by thin layer chromatography (TLC). After the reaction was complete, saturated sodium chloride solution (20 mL) was added, and the mixture was extracted with ethyl acetate (2 × 20 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by silica gel column chromatography (CH2Cl2: CH3OH = 5: 1), to obtain the compound represented by formula 6b (white solid, 414 mg, 57%).

[0057] The characterization results of the compound represented by Formula 6b are as follows: Mp 197.1-198.2 °C; IR (KBr): 3687, 3279, 2972, 2200, 1914, 1698, 1426, 1092, 922 cm -1 . 1H NMR (400 MHz, CDCl3) δ11.70 (s, 1H), 8.73 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 8.57 (s, 1H), 8.52 (s,1H), 8.24 (d, J = 7.8 Hz, 1H), 7.88 (td, J = 7.7, 1.7 Hz, 1H), 7.55 (d, J =9.0 Hz, 2H), 7.46 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 6.91 (d, J = 9.0 Hz, 2H), 4.17 (t, J = 5.6 Hz, 2H), 2.88 (t, J = 5.6 Hz, 2H), 2.75 (s, 4H), 2.60 (s, 4H), 2.37 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 162.4, 161.4, 155.7, 149.4,148.9, 137.3, 134.1, 130.6, 126.4, 123.1, 122.2, 122.1, 121.2, 115.0, 66.0,57.2, 54.8, 53.3, 45.8. (ESI) calculated for C 23 H 28 N7O3 + [M+H] + : 450.5150,found: 450.5151.

[0058] Example 3

[0059] The compound represented by formula 6c was synthesized according to the following route:

[0060]

[0061] Step 1: Same as step 1 in Example 1.

[0062] Step 2: Same as step 2 in Example 1.

[0063] Step 3: In a 50 mL round-bottom flask, 6-methylpyridine-3-carboxylic acid (200 mg, 1.46 mmol, 1.0 eq) represented by Formula 5bb was dissolved in 10 mL of N,N-dimethylformamide. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (265 mg, 1.38 mmol, 1.2 eq) and 1-hydroxybenzotriazole (186 mg, 1.38 mmol, 1.2 eq) were added, and finally, the amine compound represented by Formula 4 (271 mg, 1.15 mmol, 1.0 eq) was added. The reaction progress was monitored by thin layer chromatography (TLC). After the reaction was complete, saturated sodium chloride solution (20 mL) was added, and the mixture was extracted with ethyl acetate (2 × 20 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by silica gel column chromatography (CH2Cl2: CH3OH = 5: 1), to obtain the compound represented by formula 6c (white solid, 422 mg, 62%).

[0064] The characterization results of the compound represented by Formula 6c are as follows: Mp 200.1-201.3 °C; IR (KBr): 3688, 3277, 2972, 2109, 1913, 1679, 1419, 1101, 925 cm -1 . 1 H NMR (400 MHz, DMSO-d6)δ 13.68 (s, 1H), 10.61 (s, 1H), 10.34 (s, 1H), 8.96 (s, 1H), 8.36 (s, 1H),8.13 (d, J = 7.9 Hz, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 7.9 Hz, 1H), 6.94 (d, J = 8.0 Hz, 2H), 4.08 (t, J = 5.8 Hz, 2H), 2.75 (t, J = 5.8 Hz, 2H), 2.67 (s, 8H), 2.57 (s, 3H), 2.43 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 162.2,162.0, 155.3, 148.1, 135.3, 131.8, 126.8, 123.7, 123.2, 123.1, 122.8, 120.6,114.9, 66.0, 56.6, 53.9, 51.8, 44.3, 24.6. (ESI) calculated for C 24 H30 N7O3 + [M+H] + : 464.5420, found: 464.5423.

[0065] Example 4

[0066] The compound represented by formula 6d was synthesized according to the following route:

[0067]

[0068] Step 1: Same as step 1 in Example 1.

[0069] Step 2: Same as step 2 in Example 1.

[0070] Step 3: In a 50 mL round-bottom flask, 3,5-dichloropyridine-4-carboxylic acid (200 mg, 1.04 mmol, 1.0 eq) of Formula 5ca was dissolved in 10 mL of N,N-dimethylformamide. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (265 mg, 1.38 mmol, 1.2 eq) and 1-hydroxybenzotriazole (186 mg, 1.38 mmol, 1.2 eq) were added, and finally, the amine compound (271 mg, 1.15 mmol, 1.0 eq) of Formula 4 was added. The reaction progress was monitored by thin layer chromatography (TLC). After the reaction was complete, saturated sodium chloride solution (20 mL) was added, and the mixture was extracted with ethyl acetate (2 × 20 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by silica gel column chromatography (CH2Cl2: CH3OH = 5: 1), to obtain the compound represented by formula 6d (white solid, 342 mg, 63%).

[0071] The characterization results of the compound represented by Formula 6d are as follows: Mp 207.1-208.2 °C; IR (KBr): 3689, 3279, 2972, 2109, 1912, 1688, 1418, 1123, 921 cm -1 . 1H NMR (400 MHz, DMSO-d6)δ 13.76 (s, 1H), 10.55 (s, 1H), 10.25 (s, 1H), 8.74 (s, 2H), 8.43 (s, 1H),7.70 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 4.05 (s, 2H), 2.73 (s, 2H), 2.66 (s, 8H), 2.42 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 161.3, 159.6,159.5, 155.2, 148.0, 147.3, 142.9, 142.8, 131.9, 131.9, 128.9, 122.4, 122.3,121.4, 114.8, 66.0, 56.6, 53.9, 51.7, 44.3. (ESI) calculated for C 23 H 26 Cl2N7O3 + [M+H] + : 519.3990, found: 519.3994.

[0072] Example 5

[0073] The compound represented by formula 6e was synthesized according to the following route:

[0074]

[0075] Step 1: Same as step 1 in Example 1.

[0076] Step 2: Same as step 2 in Example 1.

[0077] Step 3: In a 50 mL round-bottom flask, 2,4-dichloronicotinic acid (200 mg, 1.04 mmol, 1.0 eq) of Formula 5ab was dissolved in 10 mL of N,N-dimethylformamide. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (265 mg, 1.38 mmol, 1.2 eq) and 1-hydroxybenzotriazole (186 mg, 1.38 mmol, 1.2 eq) were added, and finally, the amine compound (271 mg, 1.15 mmol, 1.0 eq) of Formula 4 was added. The reaction progress was monitored by thin layer chromatography (TLC). After the reaction was complete, saturated sodium chloride solution (20 mL) was added, and the mixture was extracted with ethyl acetate (2 × 20 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by silica gel column chromatography (CH2Cl2: CH3OH = 5: 1), to obtain the compound represented by formula 6e (white solid, 306 mg, 57%).

[0078] The characterization results of the compound represented by Formula 6e are as follows: Mp 206.3-207.5 °C; IR (KBr): 3685, 3282, 2973, 2108, 1913, 1710, 1399, 1092, 922 cm -1 . 1 H NMR (400 MHz, DMSO-d6)δ 13.67 (s, 1H), 10.48 (s, 1H), 10.22 (s, 1H), 8.47 (d, J = 5.5 Hz, 1H), 8.44(s, 1H), 7.72 (d, J = 6.2 Hz, 1H), 7.69 (d, J = 8.5 Hz, 2H), 6.89 (d, J = 8.3Hz, 2H), 4.05 (t, J = 5.4 Hz, 2H), 2.71 (t, J = 5.4 Hz, 3H), 2.58 (s, 8H), 2.32 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 161.5, 160.3, 155.2, 155.1, 150.1,148.2, 142.8, 132.7, 131.9, 124.6, 122.5, 121.7, 114.8, 66.0, 56.8, 54.4,52.4, 45.0. (ESI) calculated for C 23 H 26 Cl2N7O3 + [M+H]+ : 519.3990, found:519.3992.

[0079] Example 6

[0080] The compounds of Formula 6a to Formula 6e prepared by the methods of Examples 1 to 5 were tested for USPs kinase inhibition rate according to the following fluorescence assay:

[0081] The compound was first diluted to 10 μM, and then the optimal concentration of deubiquitinase (DUB) was added. After brief mixing, the mixture was placed in a 200 μL reaction system and incubated at room temperature for 1 hour. After adding 200 nM ubiquitin rhodamine 110 (Ub-Rho110, Catalog # M3022, UBPBio), the final fluorescence signal (excitation wavelength: 485 nm, emission wavelength: 535 nm) was obtained using a TECAN SPARK multi-function microplate reader to calculate the inhibition rate of the compound on enzyme activity.

[0082] The reaction system used contained 50 mM HEPES (pH 8.0), 150 mM NaCl, 0.5 mM EDTA, 1 mM DTT, and 0.1 mg / mL bovine serum albumin (BSA).

[0083] The test results are shown in Table 1. The compounds represented by Formula 6a to Formula 6e can selectively inhibit the kinase activity of USP11 at the protein level, and the inhibition rate is greater than 80%.

[0084] Table 1 Results of the determination of the inhibitory activity of compounds against USPs

[0085]

[0086] In Table 1, +++ represents an inhibition rate greater than 80%, ++ represents an inhibition rate between 50% and 80%, and + represents an inhibition rate less than 50%.

[0087] Example 7

[0088] The in vitro anti-proliferative activity of the compounds of Formula 6a to Formula 6e prepared by the methods of Examples 1 to 5 against liver cancer cell lines HEPG2 and HUH7 was evaluated by CCK-8 assay, as follows:

[0089] The highest concentration was set to 10 μM, and the dilution was performed in a 3-fold gradient, with the lowest concentration set to 0 μM. A total of 10 concentration gradients were used, and HEPG2 and HUH7 cells were incubated for 72 h. Cell activity was detected by CCK-8, and data were processed using GraphPad Prism 9 to calculate the IC 50 value.

[0090] The results are shown in Table 2. The compounds represented by Formula 6a to Formula 6e all have excellent in vitro anti-proliferative activity.

[0091] Table 2 Results of screening for antiproliferative activity of compounds on cells

[0092]

[0093] In Table 2, + represents greater than 1000 nM; ++ represents 1000-100 nM; and +++ represents less than 100 nM.

[0094] Example 8

[0095] Animal experiments were conducted using two hepatocellular carcinoma cell xenograft models (HEPG2 and HUH7) in BALB / c mice to evaluate the anti-tumor activity of the compounds in vivo. A subcutaneous tumor-bearing mouse model was constructed to evaluate the anti-tumor effects of the compounds represented by Formula 6a to Formula 6e, prepared by the methods of Examples 1 to 5, in BALB / c mice. The following procedures were used:

[0096] HEPG2 and HUH7 were cultured in a 37°C, 5% carbon dioxide incubator. All mice were housed under standard specific pathogen-free (SPF) conditions. BALB / c female mice aged 6 to 8 weeks were subcutaneously injected with HEPG2 and HUH7 cells. The mice were examined daily for tumor formation to determine tumor progression. When the tumors grew to a certain size, the mice were randomly divided into a control group and a treatment group, with 5 mice in each group. The treatment group received an intraperitoneal injection of 50 mpk of the compound. Tumor diameters were measured daily with a vernier caliper, and mouse weights were recorded. Tumor tissue was removed 21 days later, and the compound's anti-tumor effect was evaluated by changes in tumor volume.

[0097] The results are shown in Table 3. The compounds represented by Formula 6a to Formula 6e all have excellent in vivo anti-proliferative activity.

[0098] Table 3 Animal experiment results

[0099]

[0100] In Table 3, + represents a tumor inhibition rate of less than 50%, ++ represents a tumor inhibition rate of 50% to 80%, and +++ represents a tumor inhibition rate of more than 80%.

[0101] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any form or substance. It should be pointed out that ordinary technicians in this technical field can make several improvements and supplements without departing from the method of the present invention. These improvements and supplements should also be regarded as the scope of protection of the present invention. Any equivalent changes, modifications and evolutions made by technicians familiar with this profession without departing from the spirit and scope of the present invention by using the technical content disclosed above are all equivalent embodiments of the present invention; at the same time, any equivalent changes, modifications and evolutions made to the above embodiments based on the essential technology of the present invention are still within the scope of the technical solution of the present invention.

Claims

1. Use of a compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing diseases related to inhibition of USP11 activity, characterized in that: The compound has a structure shown in Formula 6, Formula 6d or Formula 6e: 、 、 ； Wherein, R is one of the following groups: 、 、 ； Wherein, R1 is selected from hydrogen, C1~C4 alkyl, and halogen atom.

2. The use according to claim 1, characterized in that The related disease is liver cancer.

3. The use according to claim 1, characterized in that The R1 is selected from hydrogen, methyl, ethyl, fluorine, chlorine, bromine and iodine.

4. The use according to claim 1, characterized in that The compound has a structure shown in one of Formula 6a to Formula 6c: 、 、 。 5. A drug for treating and / or preventing diseases related to inhibition of USP11 activity, characterized in that: Including compounds represented by Formula 6, Formula 6d or Formula 6e or pharmaceutically acceptable salts thereof; 、 、 ； Wherein, R is one of the following groups: 、 、 ； Wherein, R1 is selected from hydrogen, C1~C4 alkyl, and halogen atom.

6. The drug for treating and / or preventing diseases related to inhibition of USP11 activity according to claim 5, characterized in that The related disease is liver cancer.

7. The drug for treating and / or preventing diseases related to inhibition of USP11 activity according to claim 5, characterized in that The R1 is selected from hydrogen, methyl, ethyl, fluorine, chlorine, bromine and iodine.

8. The drug for treating and / or preventing diseases related to inhibition of USP11 activity according to claim 5, characterized in that The compound has a structure shown in one of Formula 6a to Formula 6c: 、 、 。

Images