Amino acid derivative compound and application thereof

Abstract

The invention discloses an amino acid derivative compound as well as a preparation method and application thereof. The amino acid 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 amino acid-derived compounds, their preparation methods and pharmaceutical uses. Such compounds can inhibit the activity of PDK1 and have the application prospect of preparing anti-tumor drugs. Background Art

[0002] Malignant tumors are common and frequently-occurring diseases that seriously threaten human life, and their mortality rate ranks second only to cardiovascular diseases. According to the estimation of the World Health Organization, about more than 5 million people die from malignant tumors globally every year, and 10 million new cases of malignant tumor patients are discovered every year. In recent years, although remarkable progress has been made in tumor chemotherapy, the treatment of solid tumors, which are the most serious threats to human life and health and account for more than 90% of malignant tumors, has not achieved satisfactory results. Currently, the drug treatment of tumors mainly involves the combined use of chemotherapy drugs. However, chemotherapy drugs mainly act on vital cell components such as DNA, RNA or tubulin, resulting in poor selectivity, large toxic and side effects, and at the same time, long-term use will induce drug resistance and secondary mutations, seriously harming the physical and mental health of patients. Although the newly developed novel targeted anti-tumor drugs in recent years have certain therapeutic effects, their treatment of most solid tumors is also extremely limited, and the resulting drug resistance and toxic and side effects have also become important issues in cancer prevention and treatment. Therefore, in the face of the urgency of preventing and treating malignant tumors and the limitations of existing drug treatments, discovering potential targeted small molecule drugs with novel structures, significant activities and low toxic and side effects has become a research hotspot in 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 a research hotspot in current anti-tumor drugs. 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 anchoring 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 amino acid-derived compounds, which have the inhibitory activity of 3-phosphoinositide-dependent protein kinase-1 (PDK1) and can be used to prepare drugs for the treatment of malignant tumors.

[0006] Technical solution: A class of compounds represented by Formula I, Formula II and Formula III or pharmaceutically acceptable salts thereof,

[0007]

[0008]

[0009] wherein, R1 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, trifluoroethyl, nitrogen-methyl piperidyl, nitrogen-benzyl piperidyl, methylsulfonyl, ethylsulfonyl or halogenated benzenesulfonyl;

[0010] R2 is hydrogen or C1-C3 alkyl;

[0011] R3 and R4 are independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, methoxy, halogen, trifluoromethyl, trifluoromethoxy, phenyl, piperazinyl or nitrogen-methyl piperazinyl;

[0012] X is selected from a carbon atom or a nitrogen atom;

[0013] n is selected from the numbers 0, 1, 2 or 3.

[0014] Preferably, wherein the

[0015] R1 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, trifluoroethyl, nitrogen-benzyl piperidyl, methylsulfonyl or fluorobenzenesulfonyl;

[0016] R2 is hydrogen, methyl or ethyl;

[0017] R3 and R4 are independently selected from hydrogen, C1-C5 alkyl, C3-C6 cycloalkyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, phenyl or nitrogen-methyl piperazinyl;

[0018] X is selected from a carbon atom or a nitrogen atom;

[0019] n is selected from the numbers 0, 1 or 2.

[0020] Preferably, wherein the

[0021] R1 is hydrogen, C1-C3 alkyl, C3-C4 cycloalkyl, trifluoroethyl, nitrogen-benzyl piperidyl, methylsulfonyl or p-fluorobenzenesulfonyl;

[0022] R2 is hydrogen or methyl;

[0023] R3 and R4 are independently selected from hydrogen, C1-C5 alkyl, methoxy, fluorine, chlorine, trifluoromethyl, trifluoromethoxy, phenyl or nitrogen-methyl piperazinyl;

[0024] X is selected from a carbon atom;

[0025] n is selected from the numbers 0 or 1.

[0026] Preferably, the compound is selected from:

[0027]

[0028] Compound 1, as shown in S1:

[0029]

[0030] Compound 2, as shown in S2:

[0031]

[0032] Compound 3, as shown in S3:

[0033]

[0034] Compound 4, as shown in S4:

[0035]

[0036] Compound 5, as shown in S5:

[0037]

[0038] Compound 6, as shown in S6.

[0039] The present invention provides the use of the compounds represented by Formula I, Formula II and Formula III or their pharmaceutically acceptable salts in the preparation of drugs for treating cancer.

[0040] The present invention provides a pharmaceutical composition comprising the compounds represented by Formula I, Formula II and Formula III or their pharmaceutically acceptable salts and a pharmaceutically acceptable carrier.

[0041] Beneficial effects:

[0042] A class of amino acid-derived compounds described in the present application, which are characterized by having PDK1 inhibitory activity and can be used in the preparation of drugs for treating malignant tumors. Detailed implementation manners

[0043] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0044] Example 1: Synthesis of Compound S1

[0045]

[0046] Step 1: Synthesis of Intermediate B1

[0047] 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 a reaction flask, stir at room temperature for 1 h, then successively add DIPEA (1.52 g, 11.5 mmol) and ethylamine hydrochloride (0.44 g, 5.55 mmol), stir at room temperature for 12 h. Detect 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 800 mg of white solid with a yield of 71%. ESI-MS: 259.44 [M+H]+.

[0048] Step 2: Synthesis of Intermediate C1

[0049] Add B1 (0.8 g, 3.10 mmol), 20 ml of dichloromethane and trifluoroacetic acid (5 ml, 65.4 mmol) into a reaction flask, heat up to 30 °C, stir for 2 h. Detect by TLC. When the reaction is complete, directly rotary evaporate the reaction solution to obtain 1.34 g of yellow oil (containing trifluoroacetic acid), and calculate the yield as 100%. It is directly used for the next step. ESI-MS: 273.36 [M+H]+.

[0050] Step 3

[0051] Add C1 (1.34 g, 8.48 mmol) and 30 ml of dichloromethane into a reaction flask, cool down to 0 - 5 °C, successively add triethylamine (1.1 g, 11.4 mmol) and diketene (0.32 g, 3.92 mmol), warm up to room temperature and stir for 12 h. Detect 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 448 mg of white solid with a yield of 60%. ESI-MS: 243.52 [M+H]+

[0052] 1H NMR (400 MHz, DMSO-d6) δ 8.06 (d, J = 8.9 Hz, 2H), 4.18 (d, J = 9.5 Hz, 1H), 3.53–

[0053] 3.36 (m, 2H), 3.12 (dq, J = 13.3, 7.1, 6.6 Hz, 1H), 3.02 (dq, J = 13.1, 6.6, 6.0 Hz, 1H), 2.12 (s, 3H), 1.00 (t, J = 7.2 Hz, 3H), 0.91 (s, 9H).

[0054] Example 2: Synthesis of Compound S2

[0055]

[0056] Step 1: Synthesis of Intermediate B2

[0057] Add A (1.00 g, 4.32 mmol), EDCI (1.32 g, 6.90 mmol), HOBT (0.93 g, 6.90 mmol) and 30 ml of dichloromethane into a reaction flask, stir at room temperature for 1 h, then successively add DIPEA (1.52 g, 11.5 mmol) and methylamine hydrochloride (0.37 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 732 mg of white solid with a yield of 69%. ESI-MS: 291.51 [M+H]+.

[0058] Step 2: Synthesis of Intermediate C2

[0059] Add B2 (0.73 g, 1.87 mmol), 20 ml of dichloromethane and trifluoroacetic acid (5 ml, 65.4 mmol) into a reaction flask, heat up to 30 °C and stir for 2 h, monitor by TLC. When the reaction is complete, directly rotary evaporate the reaction solution to obtain 1.16 g of yellow oil B (containing trifluoroacetic acid), with a yield calculated as 100%, and directly use it for the next step. ESI-MS: 405.54 [M+H]+.

[0060] Step 3

[0061] Add C2 (1.16 g, 4.00 mmol) and 30 ml of dichloromethane into a reaction flask, cool down to 0 - 5 °C, successively add triethylamine (1.1 g, 11.06 mmol) and diketene (0.31 g, 3.79 mmol), warm up 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 400 mg of white solid with a yield of 60%. ESI-MS: 375.46 [M+H]+

[0062] 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.27 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 9.1 Hz, 2H), 7.32 (d, J = 8.5 Hz, 2H), 4.45 (d, J = 9.2 Hz, 1H), 3.62–3.39 (m, 2H), 2.14 (s, 3H), 0.98 (s, 9H).

[0063] Example 3: Synthesis of Compound S3

[0064]

[0065] Step 1: Synthesis of Intermediate B3

[0066] Add A (1.00 g, 4.32 mmol), EDCI (1.32 g, 6.90 mmol), HOBT (0.93 g, 6.90 mmol) and 30 ml of dichloromethane into a reaction flask, stir at room temperature for 1 h, then successively add DIPEA (1.52 g, 11.5 mmol) and cyclopropylamine (0.32 g, 5.55 mmol), stir at room temperature for 12 h, detect by TLC, when 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 782 mg of white solid, with a yield of 66%. ESI-MS: 405.56 [M+H]+.

[0067] Step 2: Synthesis of Intermediate C3

[0068] Add B3 (0.73 g, 1.80 mmol), 20 ml of dichloromethane and trifluoroacetic acid (5 ml, 65.4 mmol) into a reaction flask, heat up to 30 °C, stir for 2 h, detect by TLC, when the reaction is complete, directly rotary evaporate the reaction solution to obtain 1.23 g of yellow oil B (containing trifluoroacetic acid), with a yield calculated as 100%, and directly use it for the next step. ESI-MS: 419.55 [M+H]+.

[0069] Step 3

[0070] Add C3 (1.23 g, 4.04 mmol) and 30 ml of dichloromethane into a reaction flask, cool down to 0 - 5 °C, successively add triethylamine (1.1 g, 11.06 mmol) and diketene (0.31 g, 3.66 mmol), raise the temperature to room temperature and stir for 12 h, detect by TLC, when the reaction is complete, rotary evaporate the reaction solution, purify the residue by silica gel column chromatography (dichloromethane: methanol = 10:1) to obtain 350 mg of white solid, with a yield of 60%. ESI-MS: 389.63 [M+H]+

[0071] 1H NMR (400 MHz, Chloroform-d) δ 8.10 (d, J = 10.4 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.44–7.35 (m, 2H), 6.91–6.83 (m, 2H), 4.46 (dd, J = 9.1, 2.5 Hz, 1H), 3.53–3.46 (m, 2H), 3.21–3.14 (m, 4H), 2.61 (t, J = 5.0 Hz, 4H), 2.38 (s, 3H), 2.27 (s, 3H), 1.91 (s, 5H), 1.27 (s, 0H), 1.11 (s, 9H).

[0072] Example 4: Synthesis of Compound S4

[0073]

[0074] Step 1: Synthesis of Intermediate B4

[0075] A (1.00 g, 4.32 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, 11.5 mmol) and n-propylamine (0.32 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 anhydrous Na2SO4 was used for drying. After filtration and rotary evaporation, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 800 mg of a white solid with a yield of 67%. ESI-MS: 445.53 [M+H]+.

[0076] Step 2: Synthesis of Intermediate C4

[0077] B4 (0.8 g, 1.80 mmol), 20 ml of dichloromethane and trifluoroacetic acid (5 ml, 65.4 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 a yellow oil B (containing trifluoroacetic acid) with a yield calculated as 100%, which was directly used for the next step. ESI-MS: 459.36 [M+H]+.

[0078] Step 3

[0079] C4 (1.34 g, 3.89 mmol) and 30 mL of dichloromethane were added to a reaction flask. The temperature was lowered to 0 - 5 °C, and triethylamine (1.1 g, 11.4 mmol) and diketene (0.32 g, 3.92 mmol) were added successively. The mixture was warmed to room temperature and stirred for 12 h. TLC detection showed that 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 400 mg of a white solid with a yield of 53%. ESI-MS: 429.45 [M + H]+

[0080] 1H NMR (400 MHz, Chloroform-d) δ 7.42 (d, J = 9.1 Hz, 1H), 7.20 (dd, J = 8.0, 1.7 Hz, 1H), 7.15 (t, J = 7.9 Hz, 1H), 6.91 (dd, J = 7.9, 1.8 Hz, 1H), 4.95 (d, J = 9.2 Hz, 1H), 4.05 (d, J = 13.1 Hz, 1H), 3.97–3.89 (m, 1H), 3.74 (ddd, J = 13.0, 7.9, 3.1 Hz, 1H), 3.51–3.36 (m, 2H), 3.09 (s, 1H), 3.10–2.91 (m, 2H), 2.27 (s, 3H), 1.31–1.22 (m, 1H), 1.04 (s, 9H), 1.02 (d, J = 2.0 Hz, 1H).

[0081] Example 5: Synthesis of Compound S5

[0082]

[0083] Step 1: Synthesis of Intermediate B5

[0084] A (1.00 g, 4.32 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, 11.5 mmol) and n-butylamine (0.41 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 anhydrous Na2SO4 was used for drying. After filtration and rotary evaporation, the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 800 mg of a white solid with a yield of 63%. ESI-MS: 271.54 [M + H]+.

[0085] Step 2: Synthesis of Intermediate C5

[0086] B5 (0.8 g, 2.96 mmol), 20 ml of dichloromethane, and trifluoroacetic acid (5 ml, 65.4 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 1.41 g of a yellow oil (containing trifluoroacetic acid). The yield was calculated as 100% and directly used for the next step. ESI-MS: 171.52 [M+H]+.

[0087] Step 3

[0088] C5 (1.41 g, 8.29 mmol) and 30 ml of dichloromethane were added to a reaction flask. The temperature was lowered to 0 - 5 °C, and triethylamine (1.1 g, 11.4 mmol) and diketene (0.32 g, 3.92 mmol) were added successively. The mixture was raised to room temperature and stirred 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 500 mg of a white solid with a yield of 66%. ESI-MS: 255.66 [M+H]+

[0089] 1H NMR (500 MHz, Chloroform-d) δ 7.42–7.37 (m, 1H), 6.24 (s, 1H), 4.20–4.13 (m, 1H), 3.52–3.41 (m, 2H), 2.72 (tq, J = 7.3, 3.7 Hz, 1H), 2.29 (s, 3H), 1.75–1.67 (m, 2H), 1.04 (s, 2H), 1.02 (s, 9H), 1.00 (s, 1H), 0.84–0.74 (m, 2H), 0.52 (dtt, J = 5.8, 3.5, 1.6 Hz, 2H).

[0090] Example 6: Synthesis of Compound S6

[0091]

[0092] Step 1: Synthesis of Intermediate B6

[0093] Add A (1.00 g, 4.32 mmol), EDCI (1.32 g, 6.90 mmol), HOBT (0.93 g, 6.90 mmol) and 30 ml of dichloromethane into a reaction flask, stir at room temperature for 1 h, then successively add DIPEA (1.52 g, 11.5 mmol) and trifluoroethylamine (0.5 g, 5.06 mmol), stir at room temperature for 12 h, detect 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, purify the crude product by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 1020 mg of white solid, with a yield of 74%. ESI-MS: 313.66 [M+H]+.

[0094] Synthesis of Intermediate C6 in Step 2

[0095] Add B6 (1.02 g, 3.26 mmol), 20 ml of dichloromethane and trifluoroacetic acid (5 ml, 65.4 mmol) into a reaction flask, heat up to 30 °C, stir for 2 h, detect by TLC, when the reaction is complete, directly rotary evaporate the reaction solution to obtain 1.41 g of yellow oil B (containing trifluoroacetic acid), with a yield calculated as 100%, and directly use it for the next step. ESI-MS: 213.43 [M+H]+.

[0096] Step 3

[0097] Add C6 (1.41 g, 6.65 mmol) and 30 ml of dichloromethane into a reaction flask, cool down to 0 - 5 °C, successively add triethylamine (1.2 g, 11.4 mmol) and diketene (0.32 g, 3.76 mmol), warm up to room temperature and stir for 12 h, detect by TLC, when the reaction is complete, rotary evaporate the reaction solution, purify the residue by silica gel column chromatography (dichloromethane: methanol = 10:1) to obtain 600 mg of white solid, with a yield of 62%. ESI-MS: 297.60 [M+H]+

[0098] 1H NMR (500 MHz, Chloroform-d) δ 7.54 (d, J = 8.9 Hz, 1H), 7.11–7.05 (m, 1H), 4.41 (d, J = 8.9 Hz, 1H), 4.21–4.07 (m, 1H), 3.82 (s, 1H), 3.69 (dqd, J = 14.7, 9.1, 5.5 Hz, 1H), 3.48 (d, J = 1.9 Hz, 2H), 2.29 (s, 3H), 1.68 (s, 1H), 1.07 (s, 2H), 1.06 (s, 9H), 1.03 (d, J = 2.4 Hz, 1H).

[0099] Example 7: Activity Test of the Compound

[0100] To each 1.25 ml tube of 6 μM substrate peptide, 100 μl of 10 mM ATP was added to make a 2X ATP / substrate mixture. 1 ml of 10X kinase buffer was added to 1.5 ml of double-distilled water to make 2.5 ml of 4X reaction buffer. 1.2 ml of the 4X reaction buffer was transferred to each enzyme tube for a 4X reaction. 12.5 μl of the 4X reaction mixture was added to the target compound at 12.5 μl / well and incubated at room temperature for 5 minutes. 25 μl of the 2X ATP / substrate mixture was added to the pre-incubated reaction mixture / compound at 25 μl / well, and the reaction plate was incubated at room temperature for 30 minutes. 50 μl / well of the termination buffer (50 mM EDTA, pH 8) was added to terminate the reaction, and 25 μl of each reaction was transferred to a 96-well streptavidin-coated plate containing 75 μl of dH2O / well and incubated at room temperature for 60 minutes. It was washed 3 times with 200 μl / well of PBS / T. The primary antibody, Phospho-PKAC (Thr197) antibody, was diluted with PBS / T containing 1% BSA at 1:1000, and 100 μl / well of the primary antibody was added. It was incubated at room temperature for 120 minutes, washed 3 times with 200 μl / well of PBS / T, and an appropriate dilution of the Eu-labeled secondary antibody was prepared in PBS / T containing 1% BSA (dilution of anti-mouse IgG was 1:500, and dilution of anti-rabbit IgG was 1:1000). 100 μl / well of the secondary antibody solution was added and incubated at room temperature for 30 minutes. It was washed five times with 200 μl / well of PBS / T, 100 μl / well of DELFIA enhancement was added, and incubated at room temperature for 5 minutes. The plate was read using a time-resolved fluorescence plate reader.

[0101] The IC50 values of the test compounds were calculated using the statistical software GraphPad Prism 7.

[0102] Results: The PDK1 activity results of the compounds are shown in the following table:

[0103] Serial number Compound number PDK1 IC50 (μM) 1 S1 ++ 2 S2 ++ 3 S3 +++ 4 S4 +++ 5 S5 ++ 6 S6 ++

[0104] ++ represents an IC50 of 10 - 50 μM; +++ represents an IC50 of 1 - 10 μM.

[0105] For those skilled in the art, it is obvious that the present invention is not limited to the details of the above exemplary embodiments, and the present invention can be implemented in other specific forms without departing from the spirit or basic characteristics of the present invention. Therefore, from any point of view, the embodiments should be regarded as exemplary and non-limiting. The scope of the present invention is defined by the appended claims rather than the above description. Therefore, all changes falling within the meaning and scope of the equivalent elements of the claims are intended to be encompassed within the present invention. Any reference signs in the claims should not be regarded as limiting the claims involved.

Claims

1. A compound of formula I, formula II or formula III, or a pharmaceutically acceptable salt thereof, characterized in that, wherein, R1 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, trifluoroethyl, nitrogen-methyl piperidinyl, nitrogen-benzyl piperidinyl, methylsulfonyl, ethylsulfonyl or halogenated benzenesulfonyl; R2 is hydrogen or C1-C3 alkyl; R3 and R4 are independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, methoxy, halogen, trifluoromethyl, trifluoromethoxy, phenyl, piperazinyl or nitrogen-methyl piperazinyl; X is selected from a carbon atom or a nitrogen atom; n is selected from the numbers 0, 1, 2 or 3.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein Wherein the R1 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, trifluoroethyl, nitrogen-benzyl piperidinyl, methylsulfonyl or fluorobenzenesulfonyl; R2 is hydrogen, methyl or ethyl; R3 and R4 are independently selected from hydrogen, C1-C5 alkyl, C3-C6 cycloalkyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, phenyl or nitrogen-methyl piperazinyl; X is selected from a carbon atom or a nitrogen atom; n is selected from the numbers 0, 1 or 2.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, Wherein the R1 is hydrogen, C1-C3 alkyl, C3-C4 cycloalkyl, trifluoroethyl, nitrogen-benzyl piperidinyl, methylsulfonyl or p-fluorobenzenesulfonyl; R2 is hydrogen or methyl; R3 and R4 are independently selected from hydrogen, C1-C5 alkyl, methoxy, fluorine, chlorine, trifluoromethyl, trifluoromethoxy, phenyl or nitrogen-methyl piperazinyl; X is selected from a carbon atom; n is selected from the numbers 0 or 1.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The compounds are selected from: 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: Compound 6, as shown in S6.

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

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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