Amide derivative compounds and uses thereof

Abstract

The application discloses an amide compound, a pharmaceutical composition of the amide compound and an application of the amide compound. The amide derivative in the application has PDK1 inhibiting activity, and the compound has a good application prospect in preparation of an anti-tumor drug.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmacy, and provides a class of amide compounds, a preparation method and pharmaceutical uses thereof. The compounds can inhibit PDK1 activity and have application prospects in the preparation of anti-tumor drugs. BACKGROUND

[0002] Malignant tumor is a common and frequently-occurring disease that seriously threatens human life, and its mortality rate is only second to cardiovascular disease. According to the World Health Organization, about 5 million people die of malignant tumors every year, and about 10 million new malignant tumor patients are found every year. In recent years, although tumor chemotherapy has made considerable progress, the treatment of solid tumors, which account for more than 90% of malignant tumors and are the most serious threat to human life and health, has not achieved satisfactory results. At present, the drug treatment of tumors mainly uses combined chemotherapy drugs. However, chemotherapy drugs mainly act on DNA, RNA or microtubule protein, etc., which are life and death shared components of cells, resulting in poor selectivity, large toxic and side effects, and long-term use can induce drug resistance and secondary mutations, seriously harming the body and mind of patients. Although the new type of targeted anti-tumor drugs developed in recent years have certain therapeutic effects, the treatment of most solid tumors is also extremely limited, and the drug resistance and toxic side effects brought about have become an important problem in the prevention and treatment of cancer. Therefore, in the face of the urgency of malignant tumor prevention and treatment and the limitations of existing drug treatment, discovering potential small molecule drugs with novel structure, significant activity and low toxicity has become a hot spot in the research of anti-tumor drugs.

[0003] PI3K / Akt / mTOR signaling pathway is abnormally expressed in tumor cells and plays an important role in tumor growth, survival and tumor angiogenesis. The kinase inhibitors of some nodes (such as PDKl, Akt, mTOR) in this pathway have become a hot spot in the research of anti-tumor drugs. 3-Phosphoinositide-dependent protein kinase-1 (PDK1) can activate 23 downstream kinases, and can continuously phosphorylate substrates, so that the substrates change in conformation, expose the anchor site, and enhance the binding degree with PDK1. PDK1 has become an important target for anti-tumor drugs. Sodium dichloroacetate (DCA) is used for the treatment of malignant tumors as a specific PDK1 inhibitor, but long-term use of this drug can cause clinical side effects such as peripheral nerve toxicity.

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

[0005] The technical problem solved by the present application is to provide a class of amide compounds, which have 3-phosphoinositide-dependent protein kinase-1 (PDK1) inhibitory activity and can be used for the preparation of drugs for treating malignant tumors.

[0006] Technical solution: a kind of compound as shown in formula I and formula II or its pharmaceutically acceptable salt,

[0007]

[0008] Formula I Formula II

[0009] Wherein, R1 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, trifluoroethyl, nitrogen methyl piperidyl, nitrogen benzyl piperidyl, methylsulfonyl, ethylsulfonyl, halogen benzene sulfonyl group;

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

[0011] R3 or R4 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, methoxy, halogen, trifluoromethyl, trifluoromethoxy, phenyl, piperazinyl, nitrogen methyl piperazinyl;

[0012] X is selected from carbon atom, nitrogen atom;

[0013] n is selected from the number 0, 1, 2, 3;

[0014] Preferably, wherein the

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

[0016] R2 is hydrogen, methyl, ethyl;

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

[0018] X is selected from carbon atom, nitrogen atom;

[0019] n is selected from the number 0, 1, 2;

[0020] More preferably, wherein the

[0021] R1 is hydrogen, C1-C6 alkyl, C3-C4 cycloalkyl, trifluoroethyl, nitrogen benzyl piperidyl, methylsulfonyl, p-fluorobenzenesulfonyl group;

[0022] R2 is hydrogen, methyl;

[0023] R3 or R4 is hydrogen, C1-C5 alkyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, phenyl, nitrogen methyl piperazinyl;

[0024] X is selected from carbon atom, nitrogen atom;

[0025] n is selected from the number 0, 1;

[0026] More preferably, the compound is selected from the group consisting of:

[0027]

[0028]

[0029] Advantages:

[0030] The patent describes a class of amide compounds, which have PDK1 inhibitory activity and can be used for the preparation of drugs for the treatment of malignant tumors. DETAILED DESCRIPTION

[0031] The following examples enable those skilled in the art to more fully understand the present application, but are not intended to limit the present application in any way.

[0032] Example 1: Synthesis of compound S1

[0033]

[0034] Synthesis of intermediate B1 in step 1

[0035] 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 the reaction bottle, stirred at room temperature for 1 h, then DIPEA (1.52 g, 11.5 mmol) and ethylamine hydrochloride (0.44 g, 5.55 mmol) were added in turn, stirred at room temperature for 12 h, TLC detection, the reaction was complete, 20 ml of water was added for washing, saturated NaCl was washed, anhydrous Na2SO4 was dried, filtered, rotary evaporated, the crude product was column chromatographed on silica gel (petroleum ether: ethyl acetate = 5:1), 800 mg of white solid was obtained, the yield was 71%. ESI-MS: 245.3 [M+H] + .

[0036] Synthesis of intermediate C1 in step 2

[0037] B (0.8 g, 3.27 mmol), 20 ml of dichloromethane, trifluoroacetic acid (5 ml, 65.4 mmol) were added to the reaction bottle, the temperature was raised to 30℃, stirred for 2 h, TLC detection, the reaction was complete, the reaction solution was directly rotary evaporated, 34 g of yellow oil B1 (containing trifluoroacetic acid) was obtained, the yield was calculated as 100%, which was directly used in the next step. ESI-MS: 259.24 [M+H] + .

[0038] Step 3

[0039] B (1.34 g, 3.27 mmol), dichloromethane 30 ml was added to the reaction bottle, cooling to 0-5 ℃, triethylamine (1.1 g, 11.4 mmol) was added, followed by the addition of divinyl ketone (0.32 g, 3.92 mmol), and then the temperature 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 448 mg of white solid with a yield of 60%. ESI-MS: 229.15 [M+H] +

[0040] 1H NMR (500 MHz, DMSO-d6) δ 8.11 (d, J = 8.9 Hz, 1H), 7.99 (t, J = 5.3Hz, 1H), 4.09 (dd, J = 8.9, 6.9 Hz, 1H), 3.46 – 3.36 (m, 2H), 3.18 – 2.97 (m,2H), 2.13 (s, 3H), 1.94 (dt, J = 13.6, 6.8 Hz, 1H), 1.01 (t, J = 7.2 Hz, 3H),0.84 (dd, J = 6.8, 4.0 Hz, 6H).

[0041] Example 2: Synthesis of compound S2

[0042]

[0043] Synthesis of intermediate B2 in step 1

[0044] 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 the reaction bottle, stirred at room temperature for 1 h, then DIPEA (1.52 g, 11.5 mmol) and methylamine hydrochloride (0.37 g, 5.55 mol) were added in turn, 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 added for washing, anhydrous Na2SO4 was dried, filtered, rotary evaporated, and the crude product was purified 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: 231.16 [M+H] + .

[0045] Synthesis of intermediate C2 in step 2

[0046] B (0.73 g, 3.16 mmol), 20 ml dichloromethane, trifluoroacetic acid (5 ml, 65.4 mmol) were added into the reaction flask, warmed to 30 °C, stirred for 2 h, TLC detection, the reaction was complete, the reaction liquid was directly spin dry, to get yellow oil B1.16 g (containing trifluoroacetic acid), yield calculated as 100%, directly used in the next step. ESI-MS: 132.19 [M+H] + .

[0047] Step 3

[0048] B (1.16 g, 3.16 mmol), dichloromethane 30 ml were added into the reaction flask, cooled to 0-5 °C, triethylamine (1.1 g, 11.06 mmol), divinyl ketone (0.31 g, 3.79 mmol) were added in turn, warmed to room temperature and stirred for 12 h, TLC detection, the reaction was complete, the reaction liquid was spin dry, the residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain white solid 400 mg, yield 60%. ESI-MS: 215.153 [M+H] +

[0049] 1 H NMR (400 MHz, CDCl3) δ 6.40 (s, 1H), 4.30 – 4.14 (m, 1H), 3.46 (d, J = 12.8 Hz, 2H), 2.82 (d, J = 4.8 Hz, 3H), 2.28 (s, 3H), 2.25 – 2.15 (m, 1H),0.95 (dd, J = 6.7, 3.9 Hz, 6H).

[0050] Example 3: Synthesis of compound S3

[0051]

[0052] Synthesis of intermediate B3 in step 1

[0053] A (1.00 g, 4.60 mmol), EDCI (1.32 g, 6.90 mmol), HOBT (0.93 g, 6.90 mmol) and 30 ml dichloromethane were added into a reaction bottle, stirred at room temperature for 1 h, then DIPEA (1.52 g, 11.5 mmol) and cyclopropylamine (0.32 g, 5.55 mol) were added in turn, stirred at room temperature for 12 h, TLC detection, the reaction was complete, 20 ml water was added for washing, saturated NaCl was washed, anhydrous Na2SO4 was dried, filtered, rotary evaporated, the crude product was column chromatographed on silica gel (petroleum ether: ethyl acetate = 5:1), 782 mg of white solid was obtained, the yield was 66%. ESI-MS: 257.35 [M+H] + .

[0054] Synthesis of intermediate C3 in step 2

[0055] B (0.73 g, 3.05 mmol), 20 ml dichloromethane, trifluoroacetic acid (5 ml, 65.4 mmol) were added into a reaction bottle, the temperature was raised to 30 °C, stirred for 2 h, TLC detection, the reaction was complete, the reaction solution was directly rotary evaporated, 1.23 g of yellow oil B1 (containing trifluoroacetic acid) was obtained, the yield was calculated as 100%, which was directly used in the next step. ESI-MS: 157.23 [M+H] + .

[0056] Step 3

[0057] C (1.23 g, 3.05 mmol), dichloromethane 30 ml were added into a reaction bottle, the temperature was lowered to 0-5 °C, triethylamine (1.1 g, 11.06 mmol) and divinyl ketone (0.31 g, 3.66 mmol) were added in turn, the temperature was raised to room temperature and stirred for 12 h, TLC detection, the reaction was complete, the reaction solution was rotary evaporated, the residue was purified by column chromatography on silica gel (dichloromethane:methanol = 10:1) to obtain 350 mg of white solid, the yield was 60%. ESI-MS: 241.15 [M+H] +

[0058] 1H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 8.2 Hz, 1H), 6.60 (s, 1H), 4.20(dd, J = 8.5, 6.9 Hz, 1H), 3.49 (s, 2H), 2.83 – 2.65 (m, 1H), 2.37 – 2.12 (m,5H), 0.95 (dd, J= 6.7, 4.7 Hz, 6H), 0.82 – 0.75 (m, 2H), 0.58 – 0.50 (m, 2H).

[0059] Example 4: Synthesis of compound S4

[0060]

[0061] Synthesis of intermediate B4 in Step 1

[0062] A (1.00 g, 4.60 mmol), EDCI (1.32 g, 6.90 mmol), HOBT (0.93 g, 6.90 mmol) and 30 ml dichloromethane were added to the reaction bottle, 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 in turn, stirred at room temperature for 12 h, TLC detection, the reaction was complete, 20 ml water was added for washing, saturated NaCl was washed, anhydrous Na2SO4 was dried, filtered, rotary evaporated, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1), 800 mg of white solid was obtained, the yield was 67%. ESI-MS: 259.4 [M+H] + .

[0063] Synthesis of intermediate C4 in Step 2

[0064] B4 (0.8 g, 3.08 mmol), 20 ml dichloromethane, trifluoroacetic acid (5 ml, 65.4 mmol) were added to the reaction bottle, the temperature was raised to 30°C, stirred for 2 h, TLC detection, the reaction was complete, the reaction solution was directly rotary evaporated, yellow oil B1.34 g (containing trifluoroacetic acid) was obtained, the yield was calculated as 100%, which was directly used in the next step. ESI-MS: 159.25 [M+H] + .

[0065] Step 3

[0066] C4 (1.34 g, 3.08 mmol), dichloromethane 30 ml were added to the reaction bottle, the temperature was lowered to 0-5°C, triethylamine (1.1 g, 11.4 mmol) and divinyl ketone (0.32 g, 3.92 mmol) were added in turn, the temperature was raised to room temperature and stirred for 12 h, TLC detection, the reaction was complete, the reaction solution was rotary evaporated, the residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain 400 mg of white solid, the yield was 53%. ESI-MS: 243.32 [M+H] +

[0067] 1H NMR (400 MHz, CDCl3) δ 6.43 (s, 1H), 4.23 (dd,J = 8.5, 7.1 Hz, 1H),3.47 (s, 2H), 3.22 (dtd, J = 19.1, 13.2, 6.3 Hz, 2H), 2.27 (s, 3H), 2.21 (dt, J =13.5, 6.7 Hz, 1H), 1.89 (d, J = 13.6 Hz, 1H), 1.53 (dd, J = 14.6, 7.3 Hz, 2H),0.99 – 0.94 (m, 6H), 0.91 (d, J = 7.4 Hz, 3H).

[0068] Example 5: Synthesis of compound S5

[0069]

[0070] Synthesis of intermediate B5 in step 1

[0071] A (1.00 g, 4.60 mmol), EDCI (1.32 g, 6.90 mmol), HOBT (0.93 g, 6.90 mmol) and 30 ml dichloromethane were added to the reaction bottle, 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 in turn, stirred at room temperature for 12 h, TLC detection, the reaction was complete, 20 ml water was added for washing, saturated NaCl was washed, anhydrous Na2SO4 was dried, filtered, rotary evaporated, the crude product was column chromatographed on silica gel (petroleum ether: ethyl acetate = 5:1), 800 mg of white solid was obtained, the yield was 63%. ESI-MS: 273.39 [M+H] + .

[0072] Synthesis of intermediate C5 in step 2

[0073] B5 (0.8 g, 2.93 mmol), 20 ml dichloromethane, trifluoroacetic acid (5 ml, 65.4 mmol) were added to the reaction bottle, warmed to 30°C, stirred for 2 h, TLC detection, the reaction was complete, the reaction solution was directly rotary evaporated, yellow oil B1 was obtained, 1.41 g (containing trifluoroacetic acid), the yield was calculated as 100%, which was directly used in the next step. ESI-MS: 173.39 [M+H] + .

[0074] Step 3

[0075] C5 (1.41 g, 2.93 mmol), dichloromethane 30 ml were added into the reaction bottle, cooled to 0-5 °C, triethylamine (1.1 g, 11.4 mmol) was added, followed by the addition of divinyl ketone (0.32 g, 3.92 mmol), and stirred at room temperature for 12 h. TLC detection, 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 white solid, with a yield of 66%. ESI-MS: 257.35 [M+H] +

[0076] 1H NMR (400 MHz, CDCl3) δ 6.38 (s, 1H), 4.22 (dd, J = 8.5, 7.0 Hz, 1H),3.47 (s, 2H), 3.25 (dtd, J = 19.1, 13.2, 6.2 Hz, 2H), 2.27 (s, 3H), 2.20 (dd, J =13.5, 6.7 Hz, 1H), 1.89 (d, J = 13.5 Hz, 1H), 1.55 – 1.42 (m, 2H), 1.34 (dq, J =14.9, 7.5 Hz, 3H), 0.98 – 0.93 (m, 6H), 0.91 (d, J = 7.3 Hz, 3H).

[0077] Example 6: Synthesis of compound S6

[0078]

[0079] Synthesis of intermediate B6 in step 1

[0080] 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 into the reaction bottle, stirred at room temperature for 1 h, then DIPEA (1.52 g, 11.5 mmol) and trifluoroethylamine (0.5 g, 5.06 mmol) were added in turn, stirred at room temperature for 12 h. TLC detection, the reaction was complete, 20 ml of water was added for washing, saturated NaCl was added for washing, anhydrous Na2SO4 was dried, filtered, rotary evaporated, and the crude product was purified 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: 364.17 [M+H] + .

[0081] Synthesis of intermediate C6 in Step 2

[0082] B6 (1020 mg, 3.42 mmol), 20 ml dichloromethane, trifluoroacetic acid (5 ml, 65.4 mmol) were added into the reaction flask, warmed to 30 °C, stirred for 2 h, TLC detection, the reaction was complete, the reaction liquid was directly rotary dried to get yellow oil B1. 41 g (containing trifluoroacetic acid), the yield was calculated as 100%, which was directly used in the next step. ESI-MS: 199.19 [M+H] + .

[0083] Step 3

[0084] C6 (1.41 g, 3.42 mmol), dichloromethane 30 ml were added into the reaction flask, cooled to 0-5 °C, triethylamine (1.2 g, 11.4 mmol) and divinyl ketone (0.32 g, 3.76 mmol) were added in turn, warmed to room temperature and stirred for 12 h, TLC detection, the reaction was complete, the reaction liquid was rotary dried, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to get white solid 600 mg, yield 62%. ESI-MS: 283.26 [M+H] +

[0085] 1 H NMR (500 MHz, DMSO) δ 8.70 (d, J = 5.2 Hz, 1H), 8.21 (d, J = 8.4 Hz,1H), 4.23 (t, J = 6.9 Hz, 1H), 3.93 (ddd, J = 23.5, 16.3, 8.5 Hz, 2H), 3.42 (m,2H), 2.13 (s, 3H), 2.07 – 1.80(m, 1H), 1.08 – 0.72 (m, 6H).

[0086] Example 7: Synthesis of compound S7

[0087]

[0088] Synthesis of intermediate B7 in Step 1

[0089] A (1.00 g, 4.60 mmol), EDCI (1.32 g, 6.90 mmol), HOBT (0.93 g, 6.90 mmol) and 30 ml dichloromethane were added into a reaction bottle, stirred at room temperature for 1 h, then DIPEA (1.52 g, 11.5 mmol) and p-methoxyaniline (0.62 g, 5.06 mmol) were added in turn, stirred at room temperature for 12 h, TLC detection, the reaction was complete, 20 ml water was added for washing, saturated NaCl was washed, anhydrous Na2SO4 was dried, filtered, rotary evaporated, the crude product was column chromatographed on silica gel (petroleum ether: ethyl acetate = 5:1), 1071 mg of white solid was obtained, the yield was 71%. ESI-MS: 323.41 [M+H] + .

[0090] Synthesis of intermediate C7 in step 2

[0091] B7 (1071 mg, 3.26 mmol), 20 ml dichloromethane, trifluoroacetic acid (5 ml, 65.4 mmol) were added into a reaction bottle, the temperature was raised to 30 °C, stirred for 2 h, TLC detection, the reaction was complete, the reaction solution was directly rotary evaporated, 1.26 g of yellow oil (containing trifluoroacetic acid) was obtained, the yield was calculated as 100%, which was directly used in the next step. ESI-MS: 223.41 [M+H] + .

[0092] Step 3

[0093] C7 (1.26 g, 3.26 mmol), dichloromethane 30 ml were added into a reaction bottle, the temperature was lowered to 0-5 °C, triethylamine (1.2 g, 11.4 mmol) and divinyl ketone (0.32 g, 3.76 mmol) were added in turn, the temperature was raised to room temperature and stirred for 12 h, TLC detection, the reaction was complete, the reaction solution was rotary evaporated, the residue was purified by column chromatography on silica gel (dichloromethane:methanol = 10:1) to obtain 480 mg of white solid, the yield was 38%. ESI-MS: 303.36 [M+H] +

[0094] 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 7.44 (d, J = 9.0 Hz, 2H), 7.41– 7.34 (m, 1H), 6.82 (d, J = 9.0 Hz, 2H), 4.43 (dd, J = 8.4, 7.0 Hz, 1H), 3.77(s, 3H), 3.49 (s, 2H), 2.25 (s, 3H), 1.02 (dd, J= 9.2, 6.8 Hz, 6H).

[0095] Example 8: Synthesis of compound S8

[0096]

[0097] Synthesis of intermediate B8 in Step 1

[0098] A (1.00 g, 4.60 mmol), EDCI (1.32 g, 6.90 mmol), HOBT (0.93 g, 6.90 mmol) and 30 ml dichloromethane were added to the reaction bottle, stirred at room temperature for 1 h, then DIPEA (1.52 g, 11.5 mmol) and p-fluoroaniline (0.62 g, 5.06 mmol) were added in turn, stirred at room temperature for 12 h, TLC detection, the reaction was complete, 20 ml water was added for washing, saturated NaCl was washed, anhydrous Na2SO4 was dried, filtered, rotary evaporated, the crude product was column chromatographed on silica gel (petroleum ether: ethyl acetate = 5:1), and 1.14 g of white solid was obtained with a yield of 80%. ESI-MS: 311.37 [M+H] + .

[0099] Synthesis of intermediate C8 in Step 2

[0100] B8 (1.14 g, 3.68 mmol), 20 ml dichloromethane, trifluoroacetic acid (5 ml, 65.4 mmol) were added to the reaction bottle, and the temperature was raised to 30°C, stirred for 2 h, TLC detection, the reaction was complete, the reaction solution was directly rotary evaporated to obtain yellow oil B1.26 g (containing trifluoroacetic acid) with a yield of 100% calculated, which was directly used in the next step. ESI-MS: 111.37 [M+H] + .

[0101] Step 3

[0102] C8 (1.14 g, 3.68 mmol), dichloromethane 30 ml were added to the reaction bottle, the temperature was lowered to 0-5°C, triethylamine (1.2 g, 11.4 mmol) and divinyl ketone (0.32 g, 3.76 mmol) were added in turn, the temperature was raised to room temperature and stirred for 12 h, TLC detection, the reaction was complete, the reaction solution was rotary evaporated, and the residue was purified by column chromatography on silica gel (dichloromethane:methanol = 10:1) to obtain 700 mg of white solid with a yield of 64%. ESI-MS: 295.33 [M+H] +

[0103] 1H NMR (400 MHz, CDCl3) δ 8.81 (s, 1H), 7.55 – 7.46 (m, 2H), 7.43 (d, J= 8.6 Hz, 1H), 6.96 (t, J = 8.7 Hz, 2H), 4.45 (dd, J = 8.4, 7.0 Hz, 1H), 3.51(d, J = 1.7 Hz, 2H), 2.33 (dt, J = 13.7, 6.8 Hz, 1H), 2.26 (s, 3H), 1.02 (dd, J =8.9, 6.8 Hz, 6H).

[0104] Example 9: Synthesis of compound S9

[0105]

[0106] Synthesis of intermediate B9 in Step 1

[0107] A (1.00 g, 4.60 mmol), EDCI (1.32 g, 6.90 mmol), HOBT (0.93 g, 6.90 mmol) and 30 ml dichloromethane were added to the reaction bottle, stirred at room temperature for 1 h, then DIPEA (1.52 g, 11.5 mmol) and 4-chlorobenzylamine (0.66 g, 5.06 mmol) were added in turn, stirred at room temperature for 12 h, TLC detection, the reaction was complete, 20 ml water was added for washing, saturated NaCl was washed, anhydrous Na2SO4 was dried, filtered, rotary evaporated, the crude product was column chromatographed on silica gel (petroleum ether: ethyl acetate = 5:1), and 1.14 g of white solid was obtained with a yield of 73%. ESI-MS: 341.85 [M+H] + .

[0108] Synthesis of intermediate C9 in Step 2

[0109] B9 (1.14 g, 3.36 mmol), 20 ml dichloromethane, trifluoroacetic acid (5 ml, 65.4 mmol) were added to the reaction bottle, warmed to 30°C, stirred for 2 h, TLC detection, the reaction was complete, the reaction solution was directly rotary evaporated, and yellow oil B1.26 g (containing trifluoroacetic acid) was obtained with a yield of 100% calculated, which was directly used in the next step. ESI-MS: 241.85 [M+H] + .

[0110] Step 3

[0111] C9 (1.14 g, 3.36 mmol), dichloromethane 30 ml were added into the reaction bottle, cooled to 0-5 °C, triethylamine (1.2 g, 11.4 mmol) was added, followed by the addition of divinyl ketone (0.32 g, 3.76 mmol), and stirred at room temperature for 12 h. TLC detection, the reaction was complete, the reaction solution was dried, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain 711 mg of white solid, with a yield of 65%. ESI-MS: 325.81 [M+H] +

[0112] 1H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J = 5.3 Hz, 1H), 8.17 (d, J = 8.6Hz, 1H), 7.37 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 8.2 Hz, 2H), 4.27 (d, J = 5.7 Hz,2H), 4.22 – 4.12 (m, 1H), 3.33 (s, 2H), 2.13 (s, 3H), 2.00 (dd, J = 13.4, 6.7Hz, 1H), 0.85 (d, J = 6.7 Hz, 6H).

[0113] Example 10: Synthesis of compound S10

[0114]

[0115] Synthesis of intermediate B10 in step 1

[0116] 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 into the reaction bottle, stirred at room temperature for 1 h, then DIPEA (1.52 g, 11.5 mmol) and 2-fluorobenzylamine (0.63 g, 5.06 mmol) were added in turn, stirred at room temperature for 12 h. TLC detection, the reaction was complete, 20 ml of water was added for washing, saturated NaCl was washed, 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 988 mg of white solid, with a yield of 66%. ESI-MS: 325.40 [M+H] + .

[0117] Synthesis of intermediate C10 in step 2

[0118] B10 (988 mg, 3.03 mmol), 20 ml dichloromethane, trifluoroacetic acid (5 ml, 65.4 mmol) were added into the reaction flask, warmed to 30 °C, stirred for 2 h, TLC detection, the reaction was complete, the reaction solution was directly rotary dried to obtain yellow oil B1.26 g (containing trifluoroacetic acid), the yield was calculated as 100%, which was directly used in the next step. ESI-MS: 225.40 [M+H] + .

[0119] Step 3

[0120] C10 (1.26 g, 3.03 mmol), dichloromethane 30 ml were added into the reaction flask, cooled to 0-5 °C, triethylamine (1.2 g, 11.4 mmol) and divinyl ketone (0.32 g, 3.76 mmol) were added in turn, warmed to room temperature and stirred for 12 h, TLC detection, the reaction was complete, the reaction solution was rotary dried, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain 672 mg of white solid, with a yield of 72%. ESI-MS: 309.35 [M+H] +

[0121] 1H NMR (400 MHz, DMSO-d6) δ 8.51 (t, J = 5.7 Hz, 1H), 8.16 (d, J = 8.7Hz, 1H), 7.30 (dt, J = 7.8, 6.6 Hz, 2H), 7.16 (dd, J = 13.0, 6.4 Hz, 2H), 4.32(d, J = 3.0 Hz, 2H), 4.20 (dd, J = 8.6, 6.9 Hz, 1H), 3.33 (s, 2H), 2.12 (s, 3H),1.99 (dd, J = 13.6, 6.8 Hz, 1H), 0.84 (dd, J = 6.7, 1.5 Hz, 6H).

[0122] Example 11: Synthesis of compound S11

[0123]

[0124] Synthesis of intermediate B11 in step 1

[0125] A (1.00 g, 4.60 mmol), EDCI (1.32 g, 6.90 mmol), HOBT (0.93 g, 6.90 mmol) and 30 ml dichloromethane were added into a reaction bottle, stirred at room temperature for 1 h, then DIPEA (1.52 g, 11.5 mmol) and 2-fluorobenzylamine (0.85 g, 5.06 mmol) were added in turn, stirred at room temperature for 12 h, TLC detection, the reaction was complete, 20 ml water was added for washing, saturated NaCl was washed, anhydrous Na2SO4 was dried, filtered, rotary evaporated, the crude product was column chromatographed on silica gel (petroleum ether: ethyl acetate = 5:1), to obtain white solid 1.34 g, yield 80%. ESI-MS: 367.46 [M+H] + .

[0126] Synthesis of intermediate C11 in step 2

[0127] B11 (1.34 g, 3.68 mmol), 20 ml dichloromethane, trifluoroacetic acid (5 ml, 65.4 mmol) were added into a reaction bottle, warmed to 30 °C, stirred for 2 h, TLC detection, the reaction was complete, the reaction solution was directly rotary evaporated to obtain yellow oil B1.48 g (containing trifluoroacetic acid), calculated yield 100%, which was directly used in the next step. ESI-MS: 267.46 [M+H] + .

[0128] Step 3

[0129] C11 (1.48 g, 3.68 mmol), dichloromethane 30 ml were added into a reaction bottle, cooled to 0-5 °C, triethylamine (1.2 g, 11.4 mmol) and divinyl ketone (0.32 g, 3.76 mmol) were added in turn, warmed to room temperature and stirred for 12 h, TLC detection, the reaction was complete, the reaction solution was rotary evaporated, and the residue was purified by column chromatography on silica gel (dichloromethane:methanol = 10:1) to obtain white solid 980 mg, yield 76%. ESI-MS: 351.42 [M+H] +

[0130] 1H NMR (400 MHz, DMSO-d6) δ 8.51 (t, J = 5.7 Hz, 1H), 8.16 (d, J = 8.7Hz, 1H), 7.30 (dt, J = 7.8, 6.6 Hz, 2H), 7.16 (dd, J = 13.0, 6.4 Hz, 2H), 4.32(d, J = 3.0 Hz, 2H), 4.20 (dd, J= 8.6, 6.9 Hz, 1H), 3.33 (s, 2H), 2.12 (s, 3H),1.99 (dd, J = 13.6, 6.8 Hz, 1H), 0.84 (dd, J = 6.7, 1.5 Hz, 6H).

[0131] Example 12: Synthesis of compound S12

[0132]

[0133] Synthesis of intermediate B12 in Step 1

[0134] A (1.00 g, 4.60 mmol), EDCI (1.32 g, 6.90 mmol), HOBT (0.93 g, 6.90 mmol) and 30 ml dichloromethane were added to the reaction bottle, stirred at room temperature for 1 h, then DIPEA (1.52 g, 11.5 mmol) and benzidine (0.86 g, 5.06 mmol) were added in turn, stirred at room temperature for 12 h, TLC detection, the reaction was complete, 20 ml water was added for washing, saturated NaCl was washed, anhydrous Na2SO4 was dried, filtered, rotary evaporated, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1), to obtain 1.1 g of white solid, with a yield of 65%. ESI-MS: 369.48 [M+H] + .

[0135] Synthesis of intermediate C12 in Step 2

[0136] B12 (1.1 g, 2.99 mmol), 20 ml dichloromethane, trifluoroacetic acid (5 ml, 65.4 mmol) were added to the reaction bottle, and the temperature was raised to 30°C, stirred for 2 h, TLC detection, the reaction was complete, the reaction solution was directly rotary evaporated to obtain yellow oil B1.32 g (containing trifluoroacetic acid), with a yield of 100% calculated, which was directly used in the next step. ESI-MS: 169.48 [M+H] + .

[0137] Step 3

[0138] C12 (1.32 g, 2.99 mmol), dichloromethane 30 ml were added to the reaction bottle, the temperature was lowered to 0-5°C, triethylamine (1.2 g, 11.4 mmol) and divinyl ketone (0.32 g, 3.76 mmol) were added in turn, the temperature was raised to room temperature and stirred for 12 h, TLC detection, 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 845 mg of white solid, with a yield of 80%. ESI-MS: 353.43 [M+H] +

[0139] 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.34 (s, 1H), 7.73 (d, J = 8.2 Hz, 2H), 7.64 (d, J = 6.2 Hz, 4H), 7.45 (t, J = 7.4 Hz, 2H), 7.33 (s, 1H),4.37 (t, J = 7.7 Hz, 1H), 3.47 (s, 2H), 2.17 (s, 3H), 2.07 (dd, J = 13.3, 6.6 Hz,1H), 0.94 (d, J = 6.5 Hz, 6H).

[0140] Example 13: Synthesis of compound S13

[0141]

[0142] Synthesis of intermediate B13 in Step 1

[0143] A (1.00 g, 4.60 mmol), EDCI (1.32 g, 6.90 mmol), HOBT (0.93 g, 6.90 mmol) and 30 ml dichloromethane were added to the reaction bottle, stirred at room temperature for 1 h, then DIPEA (1.52 g, 11.5 mmol) and benzidine (0.86 g, 5.06 mmol) were added in turn, stirred at room temperature for 12 h, TLC detection, the reaction was complete, 20 ml water was added for washing, saturated NaCl was washed, anhydrous Na2SO4 was dried, filtered, rotary evaporated, the crude product was column chromatographed on silica gel (petroleum ether: ethyl acetate = 5:1), and 1.04 g of white solid was obtained with a yield of 60%. ESI-MS: 341.85 [M+H] + .

[0144] Synthesis of intermediate C13 in Step 2

[0145] B13 (1.04 g, 3.03 mmol), 20 ml dichloromethane, trifluoroacetic acid (5 ml, 65.4 mmol) were added to the reaction bottle, and the temperature was raised to 30°C, stirred for 2 h, TLC detection, the reaction was complete, the reaction solution was directly rotary evaporated to obtain yellow oil B1.38 g (containing trifluoroacetic acid), the yield was calculated as 100%, which was directly used in the next step. ESI-MS: 141.85 [M+H] + .

[0146] Step 3

[0147] C13 (1.38 g, 3.03 mmol), dichloromethane 30 ml were added into the reaction bottle, and cooled to 0-5 °C, triethylamine (1.2 g, 11.4 mmol), divinyl ketone (0.32 g, 3.76 mmol) were added in turn, and stirred at room temperature for 12 h, TLC detection, 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 845 mg of white solid, with a yield of 80%. ESI-MS: 325.81 [M+H] +

[0148] 1H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.32 (d, J = 8.4 Hz, 1H),7.82 (d, J = 1.4 Hz, 1H), 7.44 – 7.35 (m, 1H), 7.28 (d, J = 8.3 Hz, 1H), 4.29 (t, J = 7.8 Hz, 1H), 3.45 (s, 2H), 2.27 (s, 3H), 2.15 (s, 3H), 2.08 – 1.97 (m,1H), 0.91 (d, J = 6.6 Hz, 6H).

[0149] Example 14: Synthesis of compound S14

[0150]

[0151] Synthesis of intermediate B14 in step 1

[0152] 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 into the reaction bottle, and stirred at room temperature for 1 h, then DIPEA (1.52 g, 11.5 mmol) and benzidine (0.86 g, 5.06 mmol) were added in turn, and stirred at room temperature for 12 h, TLC detection, the reaction was complete, 20 ml of water was added for washing, saturated NaCl was added for washing, anhydrous Na2SO4 was added for drying, filtered, rotary evaporated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 1.2 g of white solid, with a yield of 72%. ESI-MS: 362.26 [M+H] + .

[0153] Synthesis of intermediate C14 in step 2

[0154] B14 (1.2 g, 3.31 mmol), 20 ml dichloromethane, trifluoroacetic acid (5 ml, 65.4 mmol) were added into a reaction flask, warmed to 30 °C, stirred for 2 h, TLC detection, the reaction was complete, the reaction solution was directly rotary dried to get yellow oil B1.46 g (containing trifluoroacetic acid), yield calculated as 100%, directly used in the next step. ESI-MS: 162.26 [M+H] + .

[0155] Step 3

[0156] C14 (1.46 g, 3.31 mmol), dichloromethane 30 ml were added into a reaction flask, cooled to 0-5 °C, triethylamine (1.2 g, 11.4 mmol), divinyl ketone (0.32 g, 3.76 mmol) were added in turn, warmed to room temperature and stirred for 12 h, TLC detection, the reaction was complete, the reaction solution was rotary dried, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to get white solid 848 mg, yield 74%. ESI-MS: 346.22 [M+H] +

[0157] 1H NMR (500 MHz, DMSO-d6) δ 8.25 (s, 1H), 8.12 (d, J = 9.0 Hz, 1H),7.49 (d, J = 8.0 Hz, 2H), 7.37 (t, J = 8.0 Hz, 1H), 4.57 (dd, J = 13.7, 4.9 Hz,1H), 4.44 (dd, J = 13.7, 3.8 Hz, 1H), 4.28 – 4.18 (m, 1H),3.46 – 3.34 (m, 2H),2.12 (s, 3H), 1.93 (dd, J = 13.4, 6.7 Hz, 1H), 0.82 (t, J = 6.2 Hz, 6H).

[0158] Example 15: Synthesis of compound S15

[0159]

[0160] Synthesis of intermediate B15 in step 1

[0161] A (1.00 g, 4.60 mmol), EDCI (1.32 g, 6.90 mmol), HOBT (0.93 g, 6.90 mmol) and 30 ml dichloromethane were added into a reaction flask, stirred at room temperature for 1 h, then DIPEA (1.52 g, 11.5 mmol) and benzidine (0.86 g, 5.06 mmol) were added in turn, stirred at room temperature for 12 h, TLC detection, the reaction was complete, 20 ml water was added for washing, saturated NaCl was washed, anhydrous Na2SO4 was dried, filtered, rotary evaporated, the crude product was column chromatographed on silica gel (petroleum ether: ethyl acetate = 5:1), to obtain 1.2 g of white solid, yield 72%. ESI-MS: 349.49 [M+H] + .

[0162] Synthesis of intermediate C15 in step 2

[0163] B15 (1.15 g, 3.31 mmol), 20 ml dichloromethane, trifluoroacetic acid (5 ml, 65.4 mmol) were added into a reaction flask, warmed to 30 °C, stirred for 2 h, TLC detection, the reaction was complete, the reaction solution was directly rotary evaporated to obtain yellow oil B1.46 g (containing trifluoroacetic acid), yield calculated as 100%, which was directly used in the next step. ESI-MS: 162.26 [M+H] + .

[0164] Step 3

[0165] C15 (1.46 g, 3.31 mmol), dichloromethane 30 ml were added into a reaction flask, cooled to 0-5 °C, triethylamine (1.2 g, 11.4 mmol) and divinyl ketone (0.32 g, 3.76 mmol) were added in turn, warmed to room temperature and stirred for 12 h, TLC detection, the reaction was complete, the reaction solution was rotary evaporated, and the residue was purified by column chromatography on silica gel (dichloromethane:methanol = 10:1) to obtain 849 mg of white solid, yield 77%. ESI-MS: 333.21 [M+H] +

[0166] 1H NMR (500 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.29 (d, J = 8.6 Hz, 1H),7.50 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H), 4.39 – 4.24 (m, 1H), 3.45 (s,2H), 2.15 (s, 3H), 2.03 (td, J = 13.5, 6.7 Hz, 1H), 1.52 (dt,J = 15.1, 7.5 Hz,2H), 1.30 (d, J = 4.4 Hz, 2H), 1.25 (d, J = 11.5 Hz, 2H), 0.94 – 0.85 (m, 9H).

[0167] Example 16: Synthesis of compound S16

[0168]

[0169] Synthesis of intermediate B16 in step 1

[0170] A (1.00 g, 4.60 mmol), EDCI (1.32 g, 6.90 mmol), HOBT (0.93 g, 6.90 mmol) and 30 ml dichloromethane were added to the reaction bottle, stirred at room temperature for 1 h, then DIPEA (1.52 g, 11.5 mmol) and benzidine (0.86 g, 5.06 mmol) were added in turn, stirred at room temperature for 12 h, TLC detection, the reaction was complete, 20 ml water was added for washing, saturated NaCl was washed, anhydrous Na2SO4 was dried, filtered, rotary evaporated, the crude product was column chromatographed on silica gel (petroleum ether: ethyl acetate = 5:1), and 1.38 g of white solid was obtained with a yield of 72%. ESI-MS: 376.29 [M+H] + .

[0171] Synthesis of intermediate C16 in step 2

[0172] B16 (1.38 g, 3.68 mmol), 20 ml dichloromethane, trifluoroacetic acid (5 ml, 65.4 mmol) were added to the reaction bottle, and the temperature was raised to 30°C, stirred for 2 h, TLC detection, the reaction was complete, the reaction solution was directly rotary evaporated to obtain yellow oil B1.52 g (containing trifluoroacetic acid), calculated with a yield of 100%, which was directly used in the next step. ESI-MS: 176.29 [M+H] + .

[0173] Step 3

[0174] C16 (1.52 g, 3.68 mmol), dichloromethane 30 ml were added to the reaction bottle, the temperature was lowered to 0-5°C, triethylamine (1.2 g, 11.4 mmol) and divinyl ketone (0.32 g, 3.76 mmol) were added in turn, the temperature was raised to room temperature and stirred for 12 h, TLC detection, the reaction was complete, the reaction solution was rotary evaporated, and the residue was purified by column chromatography on silica gel (dichloromethane:methanol = 10:1) to obtain 938 mg of white solid with a yield of 71%. ESI-MS: 360.25 [M+H] +

[0175] 1H NMR (500 MHz, DMSO-d6) δ 8.25 (s, 1H), 8.12 (d, J = 9.0 Hz, 1H),7.49 (d, J = 8.0 Hz, 2H), 7.37 (t, J = 8.0 Hz, 1H), 4.57 (dd, J = 13.7, 4.9 Hz,1H), 4.44 (dd, J = 13.7, 3.8 Hz, 1H), 4.28 – 4.18 (m, 1H),3.46 – 3.34 (m, 2H),2.12 (s, 3H), 1.93 (dd, J = 13.4, 6.7 Hz, 1H), 0.82 (t, J = 6.2 Hz, 6H).

[0176] Example 17: Synthesis of compound S17

[0177]

[0178] Synthesis of intermediate B17 in Step 1

[0179] A (1.00 g, 4.60 mmol), EDCI (1.32 g, 6.90 mmol), HOBT (0.93 g, 6.90 mmol) and 30 ml dichloromethane were added to the reaction bottle, stirred at room temperature for 1 h, then DIPEA (1.52 g, 11.5 mmol) and benzidine (0.86 g, 5.06 mmol) were added in turn, stirred at room temperature for 12 h, TLC detection, the reaction was complete, 20 ml water was added for washing, saturated NaCl was washed, anhydrous Na2SO4 was dried, filtered, rotary evaporated, the crude product was column chromatographed on silica gel (petroleum ether: ethyl acetate = 5:1), to obtain 1.47 g of white solid, with a yield of 85%. ESI-MS: 377.38 [M+H] + .

[0180] Synthesis of intermediate C16 in Step 2

[0181] B17 (1.47 g, 3.91 mmol), 20 ml dichloromethane, trifluoroacetic acid (5 ml, 65.4 mmol) were added to the reaction bottle, and the temperature was raised to 30°C, stirred for 2 h, TLC detection, the reaction was complete, the reaction solution was directly rotary evaporated to obtain yellow oil B1.71 g (containing trifluoroacetic acid), with a yield of 100% calculated, which was directly used in the next step. ESI-MS: 177.38 [M+H]+ .

[0182] Step 3

[0183] C17 (1.71 g, 3.91 mmol), dichloromethane 30 ml were added into the reaction bottle, and cooled to 0-5 ℃, triethylamine (1.2 g, 11.4 mmol), divinyl ketone (0.39 g, 4.69 mmol) were added in turn, and stirred at room temperature for 12 h. TLC detection, the reaction was complete, the reaction solution was dried, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain 938 mg of white solid, yield 80%. ESI-MS: 361.33 [M+H] +

[0184] 1H NMR (500 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.36 (d, J = 8.5 Hz, 1H),7.73 (d, J = 8.9 Hz, 2H), 7.34 (d, J = 8.8 Hz, 2H), 4.32 (t, J = 7.8 Hz, 1H), 3.45(s, 2H), 2.15 (s, 3H), 2.04 (dd, J = 13.5, 6.7 Hz, 1H), 0.92 (d, J = 6.7 Hz, 6H).

[0185] Example 18: Synthesis of compound S18

[0186]

[0187] Synthesis of reference examples 1 to 17 according to the route, using the corresponding amino fragment as starting material, by the same experimental procedure as example 1, to obtain compound S18.

[0188] ESI-MS: 345.2 [M+H] +

[0189] 1 HNMR (400MHz, CDCl3)δ8.84(s, 1H), 7.92(s, 1H), 7.79-7.77(d, J =8.12Hz,1H), 7.43-7.39(m, 1H), 7.35-7.26(m, 2H), 4.45-4.42(dd, J= 8.48 Hz, 6.68 Hz, 1H), 3.50 (s, 2H), 3.18-3.15 (t, J = 4.88 Hz, 4H), 2.60-2.58 (t,

[0190] Example 19: Synthesis of compound S19

[0191]

[0192] The route of synthesis of Reference Examples 1 to 17 was followed using the corresponding amino fragment as starting material, and the target product was obtained by the same experimental procedure as Example 1.

[0193] ESI-MS: 375.3 [M+H] +

[0194] 1 HNMR (400MHz, CDCl3) δ 8.07 (s, 1H), 7.45-7.42 (d, J = 8.92 Hz, 2H), 7.21-7.19 (d, J = 8.64 Hz, 1H), 6.89-6.86 (d, J = 8.96 Hz, 2H), 4.36-4.33 (dd, J = 8.48 Hz, 6.68 Hz, 1H), 3.50 (s, 2H), 3.18-3.15 (t, J = 4.88 Hz, 4H), 2.60-2.58 (t, J = 4.88 Hz, 4H), 2.39-2.33 (m, 4H), 2.28 (s, 3H), 1.03-0.99 (m, 6H)

[0195] Example 20: Synthesis of compound S20

[0196]

[0197] The route of synthesis of Reference Examples 1 to 17 was followed using the corresponding amino fragment as starting material, and the target product was obtained by the same experimental procedure as Example 1.

[0198] ESI-MS: 414.2 [M+H] +

[0199] 1 HNMR (400MHz, CDCl3) δ 7.28-7.24 (m, 3H), 7.15-7.11 (m, 2H), 4.49-4.45 (dd, J= 8.88Hz, 6.88Hz, 1H), 3.43(s, 2H), 3.26(s, 3H), 2.26(s, 3H), 1.93-1.83(m, 1H),0.85-0.76(m, 6H)

[0200] Example 21: Synthesis of compound S21

[0201]

[0202] The routes in Reference Examples 1 to 17 were synthesized by using the corresponding amino fragment as a starting material, and by the same experimental procedure as in Example 1 to give the target product.

[0203] ESI-MS: 308.2 [M+H] +

[0204] 1 HNMR (400MHz, CDCl3)δ8.39(s, 1H), 8.26(d, J =2.64Hz, 1H), 7.95(dd, J =8.88Hz, 2.68Hz, 1H), 7.11(d, J = 8.64Hz, 1H), 6.72(d, J =8.92Hz, 1H), 4.42(dd, J =8.44Hz, 6.28Hz, 1H), 3.90(s, 3H), 3.54-3.53(d, J =1.64Hz, 2H), 2.45-2.37(m,1H), 2.30(s, 3H), 1.04-0.99(m, 6H)

[0205] Example 22: Synthesis of compound S22

[0206]

[0207] The routes in Reference Examples 1 to 17 were synthesized by using the corresponding amino fragment as a starting material, and by the same experimental procedure as in Example 1 to give the target product.

[0208] ESI-MS: 372.4 [M-H] - 374.2 [M+H] +

[0209] 1 HNMR (500MHz, CDCl3)δ7.47-7.25(m, 5H), 7.11-7.09(d,J =10.0Hz, 1H), 6.16-6.14(d, J =10.0Hz, 1H), 4.23-4.20(m, 1H), 3.81-3.80(m, 1H), 3.50-3.48(d, J =10Hz, 4H), 2.83-2.81(d, J =10Hz, 2H), 2.29(s, 3H), 2.22-2.21(m, 1H), 2.15-2.13(m, 1H),1.93-1.88(m, 1H), 1.54-1.49(m, 2H),0.97-0.94(m, 6H)

[0210] Example 23: Synthesis of compound S23

[0211]

[0212] Compound A1 (200 mg, 1.31 mmol) and 10 mL of dichloromethane were added to a reaction flask. The mixture was cooled to 0 °C, and triethylamine (278 mg, 2.75 mmol) and diketene (121 mg, 1.44 mmol) dissolved in 2 mL of acetone were added. The mixture was stirred for 5 h, and the reaction was monitored by TLC until complete. 10 mL of water and 20 mL of ethyl acetate were added, and the mixture was extracted. The organic phase was washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, and purified by silica gel column chromatography to give 220 mg of a white solid, with a yield of 83%.

[0213] ESI-MS: 201.12 [M+H] +

[0214] 1 H NMR (400 MHz, CDCl3) δ4.33 – 4.29 (m, 1H), 3.49 (s, 2H), 2.29-2.22(m, 4H), 2.28 (s, 3H), 0.98 (m, 6H).

[0215] Example 24: Synthesis of compound S24

[0216]

[0217] The target product was obtained by following the synthetic route of Examples 1 to 17, using methanesulfonamide as the starting material and following the same experimental steps as in Example 1.

[0218] ESI-MS: 277.1 [MH] -

[0219] 1 HNMR (400MHz, CDCl3)δ7.54-7.52(d, J =8.0Hz, 1H), 4.42-4.38 (m, 1H),3.56(s, 2H), 3.24(s, 3H), 2.35-2.30(m, 4H), 1.03-0.99(m, 6H)

[0220] Example 25: Synthesis of compound S25

[0221]

[0222] Synthesis of Reference Examples 1 to 17 was carried out by the same experimental procedure as Example 1 using p-fluorobenzenesulfonamide as starting material to give the target product.

[0223] ESI-MS: 357.2 [M-H] - 359.2 [M+H] +

[0224] 1 HNMR (500MHz, DMSO-d6)δ12.38(s, 1H), 8.22-8.20(m, 1H), 8.00-7.97(m,2H), 7.50-7.46(m, 2H), 4.19-4.16(m, 1H), 3.36-3.32(m, 2H), 2.07(s, 3H), 1.93-1.83(m,1H), 0.76-0.70(m, 6H)

[0225] Example 26: Testing of compound PDK1 IC50values

[0226] To each 1.25 ml 6 µM substrate peptide tube, add 100 µl of 10 mM ATP to make a 2X ATP / substrate mix. Add 1 ml of 10X kinase buffer to 1.5 ml of double distilled water to make a 2.5 ml 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 mix to 12.5 µl / well of test compound and incubate at room temperature for 5 minutes. Add 25 µl of 2X ATP / substrate mix to 25 µl / well of pre-incubated reaction mix / compound and incubate the reaction plate at room temperature for 30 minutes. Add 50 µl / well of stop buffer (50 mM EDTA, pH 8) to stop 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 3 times with 200 µl / well PBS / T, dilute primary antibody Phospho-PKA C (Thr197) antibody 1 : 1000 in PBS / T with 1% BSA and add 100 µl / well of primary antibody. Incubate at room temperature for 120 minutes, wash 3 times with 200 µl / well PBS / T, prepare appropriate dilution of Eu labeled secondary antibody in PBS / T with 1% BSA (dilution of 1 : 500 for anti-mouse IgG and 1 : 1000 for anti-rabbit IgG). Add 100 µl / well of secondary antibody solution and incubate at room temperature for 30 minutes. Wash 5 times with 200 µl / well PBS / T, add 100 µl / well DELFIA Enhancement and incubate at room temperature for 5 minutes. Read the plate using a time resolved fluorescence plate reader.

[0227] The IC50values for the test compounds were calculated using the statistical software GraphPad Prism 7.

[0228] Results: The PDK1 in vitro activity results for the compounds are shown in the table below:

[0229] No. Compound No. PDK1 IC50 (μM) 1 2 3 4 5 6 7 8 9 10 11 1 S1 50.2 2 S2 66.7 3 S3 42.9 4 S4 38.3 5 S5 41.2 6 S6 37.5 7 S7 21.7 8 S8 21.4 9 S9 25.2 10 S10 11.7 11 S11 33.2 12 S12 16.8 13 S13 21.5 14 S14 6.2 15 S15 81.7 16 S16 12.6 17 S17 5.3 18 S18 20.6 19 S19 2.7 20 S20 22.7 21 S21 16.4 22 S22 6.8 23 S23 72.5 24 S24 30.6 25 S25 10.3

Claims

1. A class of compounds as shown in Formula I and Formula II, or pharmaceutically acceptable salts thereof, in, R1 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, trifluoroethyl, N-methylpiperidinyl, N-benzylpiperidinyl, methanesulfonyl, ethanesulfonyl, or halobenzenesulfonyl. R2 is hydrogen or a C1-C3 alkyl group; R3 or R4 is hydrogen, C1-C6 alkyl, methoxy, halogen, trifluoromethyl, trifluoromethoxy, phenyl, piperazine, or N-methylpiperazine. X is selected from carbon atoms and nitrogen atoms; n is selected from the numbers 0 and 1.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The above R1 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, trifluoroethyl, nitrobenzylpiperidinyl, methanesulfonyl, or fluorobenzenesulfonyl. R2 is hydrogen, methyl, or ethyl; R3 or R4 is hydrogen, C1-C5 alkyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, phenyl, or N-methylpiperazinyl. X is selected from carbon atoms and nitrogen atoms; n is selected from the numbers 0 and 1.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The above R1 is hydrogen, C1-C6 alkyl, C3-C4 cycloalkyl, trifluoroethyl, nitrobenzylpiperidinyl, methanesulfonyl, or p-fluorobenzenesulfonyl. R2 is hydrogen or methyl; R3 or R4 is hydrogen, C1-C5 alkyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, phenyl, or N-methylpiperazinyl. X is selected from carbon atoms and nitrogen atoms; n is selected from the numbers 0 and 1.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The compound is selected from:

5. The use of the compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 4 in the preparation of a drug for treating PDK1-mediated cancer.

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

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