Substituted amide derivative and application thereof

Abstract

The invention discloses a substituted amide compound as well as a pharmaceutical composition and application thereof. The amide derivative provided by the invention has PDK1 inhibitory activity, and the compound has a good application prospect in preparation of antitumor drugs.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceuticals, and provides a class of substituted amide compounds, their preparation methods and pharmaceutical uses. This class of compounds has PDK1 inhibitory activity and has application prospects for preparing anti-tumor drugs. Background Art

[0002] According to the 2019 statistical data of the World Health Organization, cancer is the first or second leading cause of death in 112 countries (CA CANCER J CLIN 2021; 71: 209–249). Moreover, in the next 20 years, the number of newly diagnosed cancer cases globally is expected to increase by approximately 50%. In recent years, with the in-depth understanding of the basic mechanisms of cancer, significant progress has been made in targeted therapy for some tumor indications. However, the huge unmet clinical needs still suggest that there is a continuous need to develop new anti-tumor drugs.

[0003] The PI3K / Akt / mTOR signaling pathway is abnormally expressed in tumor cells and plays an important role in tumor growth, survival and tumor angiogenesis. Kinase inhibitors of certain nodes (such as PDKl, Akt, mTOR) in this pathway have become the focus of current anti-tumor drug research. 3-Phosphoinositide-dependent protein kinase-1 (PDK1) can activate 23 downstream kinases, and at the same time can continuously phosphorylate substrates, causing conformational changes in the substrates, exposing the anchor sites, and enhancing the binding degree with PDK1. PDK1 has become an important target for anti-tumor drugs. Sodium dichloroacetate (DCA) is used as a specific PDK1 inhibitor for the treatment of malignant tumors. However, long-term application of this drug will cause clinical side effects such as peripheral neurotoxicity.

[0004] Therefore, novel small molecule PDK1 inhibitors have good application prospects in the treatment of malignant tumors. Summary of the Invention

[0005] Technical problem to be solved: The present invention provides a class of amide compounds, which have 3-phosphoinositide-dependent protein kinase-1 (PDK1) inhibitory activity and can be used to prepare drugs for the treatment of malignant tumors.

[0006] Technical solution: A class of amide compounds of formula I or their pharmaceutically acceptable salts, hydrates or solvates:

[0007]

[0008] wherein, R1 is selected from hydrogen, C1-C6 alkyl, aryl or substituted aryl; R2 is selected from hydrogen or C1-C6 alkyl; R3 is selected from hydrogen or C1-C6 alkyl; wherein, R2 and R3 are not both hydrogen at the same time.

[0009] Preferably, R1 is selected from C1-C3 alkyl, aryl or substituted aryl; R2 is selected from hydrogen or C1-C3 alkyl; R3 is selected from hydrogen or C1-C3 alkyl; wherein, R2 and R3 are not both hydrogen at the same time.

[0010] More preferably, R1 is selected from methyl, ethyl, aryl or substituted aryl; R2 is selected from hydrogen, methyl or isopropyl; R3 is selected from hydrogen or methyl;

[0011] wherein, R2 and R3 are not both hydrogen at the same time.

[0012] Most preferably, the compound is selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof:

[0013]

[0014] Compound 1: as shown in S1;

[0015]

[0016] Compound 2: as shown in S2;

[0017]

[0018] Compound 3: as shown in S3;

[0019]

[0020] Compound 4: as shown in S4;

[0021]

[0022] Compound 5: as shown in S5.

[0023] The compound provided by the present invention also includes a pharmaceutically acceptable equivalent of the compound or a mixture of two or more thereof.

[0024] Preferably, the compound provided by the present invention may include one or a mixture of two or more of a pharmaceutically acceptable salt, a hydrate, and a solvate.

[0025] Preferably, the compound provided by the present invention includes an acid salt or a base salt of the compound provided by the present invention. The pharmaceutically acceptable salt has the pharmaceutical activity of the compound and meets the requirements both biologically and in practical applications.

[0026] The present invention provides a class of amide compounds or a pharmaceutically acceptable salt thereof for treating tumors.

[0027] Beneficial effects:

[0028] A class of amide compounds described in the present application. The characteristics of this class of compounds are that they have PDK1 inhibitory activity and can be used to prepare drugs for treating tumors. Detailed implementation manners

[0029] The present invention discloses a class of substituted amide compounds, their preparation methods and pharmaceutical uses. Those skilled in the art can draw on the content of this article and appropriately improve the process parameters to achieve. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art, and they are all regarded as included in the present invention. The methods and applications of the present invention have been described through preferred embodiments, and those skilled in the art can obviously make changes or appropriate modifications and combinations to the methods and applications described herein without departing from the content, spirit and scope of the present invention to implement and apply the technology of the present invention.

[0030] In order to enable those skilled in the art to better understand the technical solutions of the present invention, the present invention will be further described in detail below in conjunction with specific embodiments.

[0031] The general formula compounds of the present invention can be synthesized through the following route:

[0032]

[0033] Example 1: Synthesis of compound S1

[0034]

[0035]

[0036] Step 1: Synthesis of intermediate B1

[0037] Add A (1.00 g, 4.60 mmol), EDCI (1.32 g, 6.90 mmol), HOBT (0.93 g, 6.90 mmol) and 30 ml of dichloromethane into the reaction flask, stir at room temperature for 1 h, then add DIPEA (1.52 g, 11.50 mmol) and ethylamine (0.25 g, 5.55 mmol) in sequence, stir at room temperature for 12 h, detect by TLC, when the reaction is complete, add 20 ml of water for washing, saturated NaCl for washing, dry with anhydrous Na2SO4, filter, rotary evaporate, and purify the crude product by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 0.80 g of white solid, with a yield of 71%.

[0038] Step 2: Synthesis of intermediate C1

[0039] B1 (0.85 g, 3.48 mmol), 20 ml of dichloromethane, and trifluoroacetic acid (5.00 ml, 65.40 mmol) were added to a reaction flask. The temperature was raised to 30 °C and stirred for 2 h. TLC detection showed that the reaction was complete. The reaction solution was directly rotary evaporated to obtain 1.34 g of yellow oil C1 (containing trifluoroacetic acid). The yield was calculated as 100% and directly used for the next step.

[0040] Synthesis of Intermediate D1 in Step 3

[0041] C1 (1.34 g, 3.48 mmol) and 30 ml of dichloromethane were added to a reaction flask. The temperature was lowered to 0 - 5 °C, and triethylamine (1.10 g, 11.40 mmol) and diketene (0.32 g, 3.92 mmol) were added successively. The mixture was stirred at room temperature for 12 h. TLC detection showed that the reaction was complete. The reaction solution was rotary evaporated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain 0.48 g of white solid with a yield of 60%.

[0042] Synthesis of Final Product S1 in Step 4

[0043] D1 (1.06 g, 4.65 mmol), potassium carbonate (1.40 g, 10.22 mmol), and 30 ml of DMF were added to a reaction flask equipped with a U-shaped drying tube. The mixture was stirred at room temperature for 1 h, then iodomethane (2.62 g, 18.60 mmol) was added. TLC detection showed that the reaction was complete. 40 ml of water and 40 ml of ethyl acetate were added, and the mixture was stirred and separated. The ethyl acetate phase was retained, washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, rotary evaporated, and the crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 10:1) to obtain 0.73 g of yellow oil with a yield of 65%.

[0044] ESI-MS: 257.34 [M+H] +

[0045] 1 1H NMR (400 MHz, Chloroform-d) δ 6.39 (d, J = 8.5 Hz, 1H), 5.98 (s, 1H), 4.17 (dd, J = 8.5, 6.8 Hz, 1H), 3.32 (ddt, J = 13.0, 10.3, 7.4 Hz, 2H), 2.27–2.10 (m, 4H), 1.44 (d, J = 1.3 Hz, 6H), 1.16 (t, J = 7.3 Hz, 3H), 0.95 (dd, J = 11.9, 6.8 Hz, 6H).

[0046] Example 2: Synthesis of Compound S2

[0047]

[0048] Synthesis of Intermediate B1 in Step 1

[0049] Add A (1.00 g, 4.60 mmol), EDCI (1.32 g, 6.90 mmol), HOBT (0.93 g, 6.90 mmol) and 30 ml of dichloromethane into the reaction flask, stir at room temperature for 1 h, then successively add DIPEA (1.52 g, 11.50 mmol) and ethylamine (0.25 g, 5.55 mmol), stir at room temperature for 12 h, detect by TLC, the reaction is complete, add 20 ml of water for washing, wash with saturated NaCl, dry with anhydrous Na2SO4, filter, rotary evaporate, purify the crude product by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 0.80 g of white solid with a yield of 71%.

[0050] Synthesis of Intermediate C1 in Step 2

[0051] Add B1 (0.85 g, 3.48 mmol), 20 ml of dichloromethane and trifluoroacetic acid (5.00 ml, 65.40 mmol) into the reaction flask, heat up to 30 °C, stir for 2 h, detect by TLC, the reaction is complete, directly rotary evaporate the reaction solution to obtain 1.34 g of yellow oily substance C1 (containing trifluoroacetic acid), calculate the yield as 100%, and directly use it for the next step.

[0052] Synthesis of Intermediate D1 in Step 3

[0053] Add C1 (1.34 g, 3.48 mmol) and 30 ml of dichloromethane into the reaction flask, cool down to 0 - 5 °C, successively add triethylamine (1.10 g, 11.40 mmol) and diketene (0.32 g, 3.92 mmol), warm up to room temperature and stir for 12 h, detect by TLC, the reaction is complete, rotary evaporate the reaction solution, purify the residue by silica gel column chromatography (dichloromethane: methanol = 10:1) to obtain 0.48 g of white solid with a yield of 60%.

[0054] Synthesis of Final Product S2 in Step 4

[0055] Add D1 (1.06 g, 4.65 mmol), potassium carbonate (1.40 g, 10.22 mmol) and 30 ml of DMF into the reaction flask equipped with a U-shaped drying tube, stir at room temperature for 1 h, then add 2-iodopropane (1.58 g, 9.30 mmol), detect by TLC, the reaction is complete, add 40 ml of water and 40 ml of ethyl acetate, stir and separate the layers, retain the ethyl acetate phase, wash with saturated NaCl aqueous solution, dry with anhydrous Na2SO4, filter, rotary evaporate, purify the crude product by silica gel column chromatography (ethyl acetate: petroleum ether = 10:1) to obtain 0.82 g of yellow oily substance with a yield of 65%.

[0056] ESI-MS: 271.37 [M+H] + 。

[0057] 1 H NMR (400 MHz, Chloroform-d) δ 6.84 (d, J = 7.2 Hz, 1H), 6.11 (s, 1H), 4.15 (dt, J = 16.0, 8.0 Hz, 1H), 3.40–3.23 (m, 2H), 3.21–3.11 (m, 1H), 2.27 (d, J = 4.7 Hz, 3H), 2.15 (dq, J = 14.2, 7.0 Hz, 1H), 1.14 (t, J = 7.3 Hz, 4H), 0.95 (dt, J = 14.3, 6.8 Hz, 13H).

[0058] Example 3: Synthesis of Compound S3

[0059]

[0060] Step 1: Synthesis of Intermediate B2

[0061] A (1.00 g, 4.60 mmol), EDCI (1.32 g, 6.90 mmol), HOBT (0.93 g, 6.90 mmol) and 30 ml of dichloromethane were added to a reaction flask and stirred at room temperature for 1 h. Then DIPEA (1.52 g, 11.50 mmol) and p-anisidine (0.68 g, 5.55 mmol) were added successively, and the mixture was stirred at room temperature for 12 h. TLC detection showed that the reaction was complete. 20 ml of water was added for washing, saturated NaCl was used for washing, and it was dried over anhydrous Na2SO4, filtered, rotary evaporated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 1.05 g of a white solid with a yield of 71%.

[0062] Step 2: Synthesis of Intermediate C2

[0063] B2 (1.12 g, 3.48 mmol), 20 ml of dichloromethane, and trifluoroacetic acid (5.00 ml, 65.40 mmol) were added to a reaction flask, and the temperature was raised to 30 °C and stirred for 2 h. TLC detection showed that the reaction was complete. The reaction solution was directly rotary evaporated to dryness to obtain 1.34 g of a yellow oil C2 (containing trifluoroacetic acid), and the yield was calculated as 100% and directly used for the next step.

[0064] Step 3: Synthesis of Intermediate D2

[0065] Add C2 (1.34 g, 3.48 mmol) and 30 ml of dichloromethane to a reaction flask, cool the temperature to 0 - 5 °C, successively add triethylamine (1.10 g, 11.40 mmol) and diketene (0.32 g, 3.92 mmol), raise the temperature to room temperature and stir for 12 h. Detect by TLC. After the reaction is complete, rotary evaporate the reaction solution. The residue is purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain 0.64 g of a white solid with a yield of 60%.

[0066] Synthesis of the final product S3 in Step 4

[0067] Add D2 (1.42 g, 4.65 mmol), potassium carbonate (1.40 g, 10.22 mmol) and 30 ml of DMF to a reaction flask equipped with a U-shaped drying tube, stir at room temperature for 1 h, then add methyl iodide (2.62 g, 18.60 mmol). Detect by TLC. After the reaction is complete, add 40 ml of water and 40 ml of ethyl acetate, stir and separate the layers. Retain the ethyl acetate layer, wash it with saturated NaCl aqueous solution, dry it over anhydrous Na2SO4, filter, rotary evaporate, and purify the crude product by silica gel column chromatography (ethyl acetate:petroleum ether = 10:1) to obtain 1.01 g of a yellow oil with a yield of 65%.

[0068] ESI-MS: 335.42 [M + H] + 。

[0069] 1 1H NMR (500 MHz, DMSO-d6) δ 9.89 (s, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 9.0 Hz, 2H), 6.89 (d, J = 9.0 Hz, 2H), 4.23 (t, J = 8.3 Hz, 1H), 3.72 (s, 3H), 2.10 (s, 4H), 1.29 (d, J = 14.4 Hz, 6H), 0.90 (dd, J = 6.6, 3.5 Hz, 6H).

[0070] Example 4: Synthesis of Compound S4

[0071]

[0072] Synthesis of Intermediate B3 in Step 1

[0073] Add A (1.00 g, 4.60 mmol), EDCI (1.32 g, 6.90 mmol), HOBT (0.93 g, 6.90 mmol) and 30 ml of dichloromethane to a reaction flask, stir at room temperature for 1 h, then successively add DIPEA (1.52 g, 11.50 mmol) and 4-fluoroaniline (0.62 g, 5.55 mmol), stir at room temperature for 12 h, monitor by TLC. When the reaction is complete, add 20 ml of water for washing, wash with saturated NaCl, dry over anhydrous Na2SO4, filter, rotary evaporate, and purify the crude product by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 1.01 g of a white solid with a yield of 71%.

[0074] Synthesis of Intermediate C3 in Step 2

[0075] Add B3 (1.08 g, 3.48 mmol), 20 ml of dichloromethane and trifluoroacetic acid (5.00 ml, 65.40 mmol) to a reaction flask, heat to 30 °C and stir for 2 h. Monitor by TLC. When the reaction is complete, directly rotary evaporate the reaction solution to obtain 1.34 g of a yellow oil C3 (containing trifluoroacetic acid), and calculate the yield as 100%. It is directly used for the next step.

[0076] Synthesis of Intermediate D3 in Step 3

[0077] Add C3 (1.34 g, 3.48 mmol) and 30 ml of dichloromethane to a reaction flask, cool to 0 - 5 °C, successively add triethylamine (1.10 g, 11.40 mmol) and diketene (0.32 g, 3.92 mmol), warm to room temperature and stir for 12 h. Monitor by TLC. When the reaction is complete, rotary evaporate the reaction solution, and purify the residue by silica gel column chromatography (dichloromethane: methanol = 10:1) to obtain 0.61 g of a white solid with a yield of 60%.

[0078] Synthesis of Final Product S4 in Step 4

[0079] Add D3 (1.37 g, 4.65 mmol), potassium carbonate (1.40 g, 10.22 mmol) and 30 ml of DMF to a reaction flask equipped with a U-shaped drying tube, stir at room temperature for 1 h, then add methyl iodide (2.62 g, 18.60 mmol). Monitor by TLC. When the reaction is complete, add 40 ml of water and 40 ml of ethyl acetate, stir and separate the layers. Retain the ethyl acetate layer, wash with saturated NaCl aqueous solution, dry over anhydrous Na2SO4, filter, rotary evaporate, and purify the crude product by silica gel column chromatography (ethyl acetate: petroleum ether = 10:1) to obtain 0.97 g of a yellow oil with a yield of 65%.

[0080] ESI-MS: 333.38 [M + H] + 。

[0081] 1 1H NMR (500 MHz, DMSO-d6) δ 10.11 (s, 1H), 7.68 (d, J = 8.3 Hz, 1H), 7.65–7.59 (m, 2H), 7.15 (t, J = 8.9 Hz, 2H), 4.23 (t, J = 8.3 Hz, 1H), 2.10 (s, 4H), 1.29 (d, J = 14.0 Hz, 6H), 0.91 (d, J = 6.7 Hz, 6H).

[0082] Example 5: Synthesis of Compound S5

[0083]

[0084] Step 1: Synthesis of Intermediate B4

[0085] A (1.00 g, 4.60 mmol), EDCI (1.32 g, 6.90 mmol), HOBT (0.93 g, 6.90 mmol) and 30 ml of dichloromethane were added to a reaction flask, stirred at room temperature for 1 h, then DIPEA (1.52 g, 11.50 mmol) and 5-amino-2-methoxypyridine (0.69 g, 5.55 mmol) were added successively, stirred at room temperature for 12 h, monitored by TLC. After the reaction was complete, 20 ml of water was added for washing, saturated NaCl solution for washing, dried over anhydrous Na2SO4, filtered, rotary evaporated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 1.05 g of a white solid with a yield of 71%.

[0086] Step 2: Synthesis of Intermediate C4

[0087] B4 (1.12 g, 3.48 mmol), 20 ml of dichloromethane and trifluoroacetic acid (5.00 ml, 65.40 mmol) were added to a reaction flask, heated to 30 °C and stirred for 2 h. Monitored by TLC, after the reaction was complete, the reaction solution was directly rotary evaporated to dryness to obtain 1.34 g of a yellow oil C4 (containing trifluoroacetic acid), and the yield was calculated as 100%, which was directly used for the next step.

[0088] Step 3: Synthesis of Intermediate D4

[0089] C4 (1.34 g, 3.48 mmol) and 30 ml of dichloromethane were added to a reaction flask, cooled to 0 - 5 °C, triethylamine (1.10 g, 11.40 mmol) and diketene (0.32 g, 3.92 mmol) were added successively, and the mixture was stirred at room temperature for 12 h. Monitored by TLC, after the reaction was complete, the reaction solution was rotary evaporated to dryness, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain 0.64 g of a white solid with a yield of 60%.

[0090] Step 4: Synthesis of the Final Product S5

[0091] D4 (1.43 g, 4.65 mmol), potassium carbonate (1.40 g, 10.22 mmol), and 30 ml of DMF were added to a reaction flask equipped with a U-shaped drying tube. The mixture was stirred at room temperature for 1 h, then methyl iodide (2.62 g, 18.60 mmol) was added. After TLC detection showed that the reaction was complete, 40 ml of water and 40 ml of ethyl acetate were added. The mixture was stirred and separated, and the ethyl acetate phase was retained. It was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, rotary evaporated, and the crude product was subjected to silica gel column chromatography (ethyl acetate: petroleum ether = 10:1) to obtain 0.93 g of a yellow oil with a yield of 65%.

[0092] ESI-MS: 336.18 [M+H] + 。

[0093] 1 H NMR (500 MHz, Chloroform-d) δ 8.44 (s, 1H), 8.25 (d, J = 2.7 Hz, 1H), 7.89 (dd, J = 8.9, 2.7 Hz, 1H), 6.72 (d, J = 8.8 Hz, 1H), 6.49 (d, J = 8.5 Hz, 1H), 4.41 (dd, J = 8.5, 6.8 Hz, 1H), 3.92 (s, 3H), 2.34 (dq, J = 13.5, 6.7 Hz, 1H), 2.24 (s, 3H), 1.48 (d, J = 2.8 Hz, 6H), 1.29 (d, J = 14.2 Hz, 1H), 1.02 (dd, J = 22.0, 6.8 Hz, 6H).

[0094] Example 6: Activity Test of Compound PDK1

[0095] Add 100 μl of 10 mM ATP to each 1.25 ml tube of 6 μM substrate peptide to make a 2X ATP / substrate mixture. Add 1 ml of 10X kinase buffer to 1.5 ml of double-distilled water to make 2.5 ml of 4X reaction buffer. Transfer 1.2 ml of 4X reaction buffer to each enzyme tube for a 4X reaction. Add 12.5 μl of 4X reaction mixture to the target compound at 12.5 μl / well and incubate at room temperature for 5 minutes. Add 25 μl of 2X ATP / substrate mixture to the pre-incubated reaction mixture / compound at 25 μl / well and incubate the reaction plate at room temperature for 30 minutes. Add 50 μl / well of stop buffer (50 mM EDTA, pH 8) to terminate the reaction. Transfer 25 μl of each reaction to a 96-well streptavidin-coated plate containing 75 μl of dH2O / well and incubate at room temperature for 60 minutes. Wash three times with 200 μl / well of PBS / T. Dilute the primary antibody Phospho-PKAC (Thr197) antibody in PBS / T containing 1% BSA, and add 100 μl / well of the primary antibody at a dilution of 1:1000. Incubate at room temperature for 120 minutes, wash three times with 200 μl / well of PBS / T. Prepare an appropriate dilution of the Eu-labeled secondary antibody in PBS / T containing 1% BSA (dilution of anti-mouse IgG is 1:500, dilution of anti-rabbit IgG is 1:1000). Add 100 μl / well of the secondary antibody solution and incubate at room temperature for 30 minutes. Wash five times with 200 μl / well of PBS / T, add 100 μl / well of DELFIA enhancement, and incubate at room temperature for 5 minutes. Read the plate using a time-resolved fluorescence plate reader.

[0096] The IC50 values of the test compounds were calculated using the statistical software GraphPad Prism 7.

[0097] Results: The PDK1 activity results of the compounds are shown in the following table:

[0098] Serial number Compound number PDK1 IC50 (μM) 1 S1 ++ 2 S2 ++ 3 S3 ++ 4 S4 ++ 5 S5 +++

[0099] ++ represents an IC50 of 10 - 50 μM; +++ represents an IC50 of 1 - 10 μM.

Claims

1. A class of amide compounds represented by formula I or a pharmaceutically acceptable salt, hydrate or solvate thereof: Among them, R1 is selected from hydrogen, C1-C6 alkyl, aryl or substituted aryl; R2 is selected from hydrogen or C1-C6 alkyl; R3 is selected from hydrogen or C1-C6 alkyl; wherein R2 and R3 are not both hydrogen at the same time.

2. Any of the compounds according to claim 1, characterized in that: R1 is selected from C1-C3 alkyl, aryl or substituted aryl; R2 is selected from hydrogen or C1-C3 alkyl; R3 is selected from hydrogen or C1-C3 alkyl; wherein R2 and R3 are not both hydrogen at the same time.

3. Any of the compounds according to claim 1, characterized in that: R1 is selected from methyl, ethyl, aryl or substituted aryl; R2 is selected from hydrogen, methyl or isopropyl; R3 is selected from hydrogen or methyl; wherein R2 and R3 are not both hydrogen at the same time.

4. The compound according to claim 1, wherein The compound is a compound selected from the following group or a pharmaceutically acceptable salt thereof: Compound 1: as shown in S1; Compound 2: as shown in S2; Compound 3: as shown in S3; Compound 4: as shown in S4; Compound 5: as shown in S5.

5. Use of the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating tumors.

6. A pharmaceutical composition, characterized in that, Comprising the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

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