Amino acid ester derivatives and uses thereof

Abstract

The application discloses an amino acid ester derivative compound, a pharmaceutical composition and application thereof. The amino acid ester derivative has PDK1 inhibiting activity, and the compound has a wide application prospect in preparation of anti-tumor drugs.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmacy, and provides a kind of amino acid ester compound and its preparation method and pharmaceutical use, the compound can inhibit PDK1 activity, with the application prospect of preparing 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 estimate of the World Health Organization, about 5 million people die of malignant tumor 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 tumor, which accounts for more than 90% of malignant tumors and is the most serious harm to human life and health, has not achieved satisfactory results. At present, the drug treatment of tumor mainly uses combined chemotherapy drugs, however, chemotherapy drugs mainly act on DNA, RNA or tubulin, etc., which are life and death related cell common components, resulting in poor selectivity, large toxic and side effects, and long-term use can induce drug resistance and secondary mutation, seriously harming the body and mind of patients. Although the new type of targeted anti-tumor drugs developed in recent years have certain therapeutic effect, the treatment of most solid tumors is also extremely limited, and the drug resistance and toxic side effects brought about also become an important problem in cancer prevention and treatment. 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) as a specific PDK1 inhibitor is used for the treatment of malignant tumor, however, long-term use of this drug can cause clinical side effects such as peripheral nerve toxicity.

[0004] Therefore, the new type of small molecule PDK1 inhibitor has very broad application prospect in the treatment of malignant tumor. SUMMARY

[0005] The technical problem solved by the present application is to provide a kind of amino acid ester compound, the compound has 3-phosphoinositide-dependent protein kinase-1 (PDK1) inhibitory activity, and can be used for preparing a drug for treating malignant tumor.

[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, R2, R3 are hydrogen, C1-C6 alkyl;

[0010] R2 and R3 are not hydrogen at the same time;

[0011] n is selected from the numbers 1,2,3,4,5,6,7,8,9.

[0012] Preferably, R1 is C1-C3 alkyl;

[0013] R2, R3 are hydrogen, C1-C6 alkyl, and R2 and R3 are not hydrogen at the same time;

[0014] n is selected from the numbers 1,2,3,4,5,6,7.

[0015] More preferably, R1 is C1-C3 alkyl;

[0016] R2, R3 are hydrogen, C1-C4 alkyl, and R2 and R3 are not hydrogen at the same time;

[0017] n is selected from the numbers 1,2,3,4,5.

[0018] More preferably, the compound is:

[0019]

[0020] Beneficial effects:

[0021] The amino acid ester compound described in the patent has the characteristics of PDK1 inhibitory activity, and can be used for preparing a drug for treating malignant tumors. DETAILED DESCRIPTION

[0022] The following examples can make the professional technical personnel more fully understand the present application, but do not limit the present application in any way.

[0023] Example 1: synthesis of compound P1

[0024]

[0025] SM1 (500 mg, 2.15 mmol), potassium carbonate (653 mg, 4.73 mmol), 30 ml DMF were added into a reaction flask with U-shaped drying tube, stirred at room temperature for 1 h, then added methyl iodide (1.5 g, 10.75 mmol), TLC detection, the reaction was complete, added 20 ml water and 20 ml ethyl acetate, stirred and separated, the ethyl acetate phase was retained, washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, rotary evaporated, the crude product was column chromatographed on silica gel (ethyl acetate: petroleum ether = 10:1) to give 220 mg of yellow oil, yield 42%. ESI-MS: 244.15 [M+H] + .

[0026] 1H NMR (400 MHz, DMSO-d6) δ 7.89 (d, J = 7.7 Hz, 1H), 4.11 (t, J =7.7 Hz, 1H), 3.63 (s, 3H), 2.08 (s, 4H), 1.27 (d, J = 5.0 Hz, 6H), 0.88 (dd,J = 8.1, 6.9 Hz, 6H).

[0027] Example 2: Synthesis of compound P2

[0028]

[0029] SM1 (500 mg, 2.15 mmol), potassium carbonate (653 mg, 4.73 mmol), 30 ml DMF were added into a reaction flask with U-shaped drying tube, stirred at room temperature for 1 h, then added methyl iodide (305 mg, 3.15 mmol), TLC detection, the reaction was complete, added 20 ml water and 20 ml ethyl acetate, stirred and separated, the ethyl acetate phase was retained, washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, rotary evaporated, the crude product was column chromatographed on silica gel (ethyl acetate: petroleum ether = 10:1) to give 276 mg of yellow oil, yield 56%. ESI-MS: 230.28 [M+H] + .

[0030] 1H NMR (400 MHz, DMSO-d6) δ 8.56 (dd, J = 20.0, 7.9 Hz, 1H), 4.20(ddd, J = 15.7, 8.1, 6.2 Hz, 1H), 3.66 (d, J = 5.2 Hz, 3H), 3.33 – 3.28 (m,1H), 2.10 (dd, J = 10.5, 4.1 Hz, 4H), 1.10 (dd, J = 6.9, 3.9 Hz, 3H), 0.97 –0.82 (m, 6H).

[0031] Example 3: Synthesis of compound P3

[0032]

[0033] SM1 (500 mg, 2.32 mmol), potassium carbonate (652 mg, 4.73 mmol), 30 ml DMF were added into a reaction flask with U-shaped drying tube, stirred at room temperature for 1 h, then 1,2-dibromoethane (525 mg, 2.79 mmol) was added, TLC detection, the reaction was complete, 20 ml water and 20 ml ethyl acetate were added, stirred and separated into two layers, the ethyl acetate phase was reserved, washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, rotary evaporated, the crude product was column chromatographed on silica gel (ethyl acetate: petroleum ether = 10:1), 320 mg of yellow oil was obtained, the yield was 57%. ESI-MS: 242.29 [M+H] + .

[0034] 1H NMR (400 MHz, CDCl3) δ 9.36 (d, J = 6.8 Hz, 1H), 4.49 (dd, J =8.0, 5.0 Hz, 1H), 3.74(s, 3H), 2.23 (m,1H), 2.01 (s, 3H), 1.90 – 1.82 (m,2H), 1.59 – 1.51 (m, 2H), 0.99 (dd, J = 6.9, 1.9 Hz, 6H).

[0035] Example 4: Synthesis of compound P4

[0036]

[0037] SM1 (500 mg, 2.32 mmol), potassium carbonate (710 mg, 5.11 mmol), 30 ml DMF were added into a reaction flask with U-shaped drying tube, stirred at room temperature for 1 h, then 1,3-dibromopropane (840 mg, 2.79 mmol) was added, TLC detection, the reaction was complete, 20 ml water and 20 ml ethyl acetate were added, stirred and separated, the ethyl acetate phase was retained, washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, rotary evaporated, the crude product was column chromatographed on silica gel (ethyl acetate: petroleum ether = 10:1), 400 mg of yellow oil was obtained, the yield was 67%. ESI-MS: 256.31 [M+H] + .

[0038] 1H NMR (400 MHz, DMSO-d6) δ 11.27 (d, J = 8.0 Hz, 1H), 4.16 (dd, J =8.1, 5.1 Hz, 1H), 4.12 – 4.06 (m, 2H), 3.65 (s, 3H), 2.32 (t, J = 6.4 Hz,2H), 2.14 – 2.00 (m, 1H), 1.96 (s, 3H), 1.84 – 1.73 (m, 2H), 0.88 (t, J = 6.5Hz, 6H).

[0039] Example 5: Synthesis of compound P5

[0040]

[0041] SM1 (1000 mg, 4.65 mmol), potassium carbonate (1400 mg, 10.22 mmol), 30 ml DMF were added into a reaction flask with U-shaped drying tube, stirred at room temperature for 1 h, then 1,4-dibromobutane (2000 g, 2.97 mmol) was added, TLC detection, the reaction was complete, 40 ml water and 40 ml ethyl acetate were added, stirred and separated, the ethyl acetate phase was retained, washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, rotary evaporated, the crude product was column chromatographed on silica gel (ethyl acetate: petroleum ether = 10:1), 816 mg of yellow oil was obtained, the yield was 65%. ESI-MS: 270.34 [M+H] + .

[0042] 1H NMR (400 MHz, DMSO-d6) δ 7.93 (d, J = 7.6 Hz, 1H), 4.13 – 4.08 (m,1H), 3.62 (s, 3H), 2.14 – 1.86 (m, 8H), 1.50 (m, 4H), 0.87 (m, 6H).

[0043] Example 6: Synthesis of compound P6

[0044]

[0045] SM1 (1000 mg, 4.65 mmol), potassium carbonate (1400 mg, 10.22 mmol), 30 ml DMF were added into a reaction flask with U-shaped drying tube, stirred at room temperature for 1 h, then 1,5-dibromopentane (2100 g, 1.97 mmol) was added, TLC detection, the reaction was complete, 40 ml water and 40 ml ethyl acetate were added, stirred and separated into two layers, the ethyl acetate phase was retained, washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, rotary evaporated, the crude product was subjected to silica gel column chromatography (ethyl acetate: petroleum ether = 10:1), and 920 mg of yellow oil was obtained in a yield of 70%. ESI-MS: 284.37 [M+H] + .

[0046] 1H NMR (400 MHz, DMSO-D6) δ 8.59 (m, 1H), 4.23 (dd, J = 8.0, 6.1 Hz,1H), 3.65 (s, 3H), 3.60 (m, 1H), 3.50 (t, J = 6.6 Hz, 2H), 2.11 (s, 3H), 1.82– 1.70 (m, 2H), 1.65-1.59 (m, 2H), 1.47 – 1.28 (m, 2H), 1.29 – 1.13 (m, 2H),0.97 – 0.83 (m, 6H).

[0047] Example 7: Synthesis of compound P7

[0048] Synthesis of SM2

[0049]

[0050] Synthesis of intermediate Int-1 in Step 1

[0051] Into a 250 ml three necked flask was placed ethanol 150 ml, cooled to -5 °C, started to add thionyl chloride 15 ml drop wise, after the drop wise addition was completed, D-Valine (10.0 g, 0.085 mol) was added, stirred at room temperature for 1 h, then heated to reflux for 5 h, TLC was used to check the completion of the reaction, the ethanol was removed by rotary evaporation, added water 100 ml, adjusted the pH to 7-8 with saturated NaHC03, extracted with dichloromethane 100 ml for 3 times, dried over anhydrous Na2S04overnight, filtered, rotary evaporated to get a yellow oil 8.0 g, yield 64.5 %. ESI-MS: 146.2 [M+H] + .

[0052] Step 2

[0053] Into a 250 ml three necked flask was placed ethanol 150 ml, cooled to -5 °C, started to add thionyl chloride 15 ml drop wise, after the drop wise addition was completed, D-Valine (10.0 g, 0.085 mol) was added, stirred at room temperature for 1 h, then heated to reflux for 5 h, TLC was used to check the completion of the reaction, the ethanol was removed by rotary evaporation, added water 100 ml, adjusted the pH to 7-8 with saturated NaHC03, extracted with dichloromethane 100 ml for 3 times, dried over anhydrous Na2S04overnight, filtered, rotary evaporated to get a yellow oil 8.0 g, yield 64.5 %. ESI-MS: 146.2 [M+H] + .

[0054] 1H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 8.1 Hz, 1H), 4.15 (ddd, J = 15.8, 8.4, 6.6 Hz, 3H), 3.41 (s, 2H), 2.14 (s, 3H), 2.04 (dt, J = 13.5, 6.7 Hz, 1H), 1.20 (t, J = 7.1 Hz, 3H), 0.89 (dd, J = 6.8, 2.2 Hz, 6H).

[0055]

[0056] SM2 (1.0 g, 4.36 mmol), potassium carbonate (2.4 g, 17.35 mmol), 25 ml DMF were added into a reaction flask with U-shaped drying tube, stirred at room temperature for 1 h, then added iodomethane (2.5 g, 17.45 mmol), TLC detection, the reaction was complete, added 20 ml water and 20 ml ethyl acetate, stirred and separated, the ethyl acetate phase was retained, washed with saturated NaCl aqueous solution, dried over anhydrous Na2S04, filtered, rotary evaporated, the crude product was column chromatographed on silica gel (ethyl acetate: petroleum ether = 10:1) to give 900 mg of yellow oil, yield 80%. ESI-MS: 258.33 [M+H] + .

[0057] 1H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J = 7.8 Hz, 1H), 4.17 – 4.02 (m,3H), 2.09 (s, 4H), 1.26 (d, J = 4.9 Hz, 6H), 1.19 (t, J = 7 Hz, 3H), 0.89 (m,6H).

[0058] Example 8: Synthesis of compound P8

[0059]

[0060] SM2 (1.0 g, 4.36 mmol), potassium carbonate (2.4 g, 17.45 mmol), 25 ml DMF were added into a reaction flask with U-shaped drying tube, stirred at room temperature for 1 h, then added 1,3-dibromopropane (2.2 g, 10.9 mmol), TLC detection, the reaction was complete, added 20 ml water and 20 ml ethyl acetate, stirred and separated, the ethyl acetate phase was retained, washed with saturated NaCl aqueous solution, dried over anhydrous Na2S04, filtered, rotary evaporated, the crude product was column chromatographed on silica gel (ethyl acetate: petroleum ether = 10:1) to give 700 mg of yellow oil, yield 60%. ESI-MS: 270.34 [M+H] + .

[0061] 1H NMR (400 MHz, DMSO-d6) δ 11.26 (d, J = 7.9 Hz, 1H), 4.15 – 4.10 (m, 3H), 2.54 – 2.46 (m, 2H), 2.33 (s, 2H), 2.08 (qd, J = 12.1, 6.8 Hz, 1H), 1.97 (s, 3H), 1.85 – 1.73 (m, 2H), 1.18 (t, J = 7.1 Hz, 3H), 0.90 (t, J = 6.6 Hz, 6H).

[0062] Example 9: Synthesis of compound P9

[0063]

[0064] SM2 (1.0 g, 4.36 mmol), potassium carbonate (2.4 g, 17.45 mmol), 25 ml DMF were added into a reaction flask with U-shaped drying tube, stirred at room temperature for 1 h, then 1,4-dibromobutane (2.4 g, 10.9 mmol) was added, TLC detection, the reaction was complete, 40 ml water and 40 ml ethyl acetate were added, stirred and separated into two liquid phases, the ethyl acetate phase was reserved, washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, rotary evaporated, the crude product was subjected to silica gel column chromatography (ethyl acetate: petroleum ether = 10:1), 800 mg of yellow oil was obtained, the yield was 64%. ESI-MS: 284.37 [M+H] + .

[0065] 1H NMR (400 MHz, DMSO-d6) δ 7.90 (d, J = 7.7 Hz, 1H), 4.16 – 4.01 (m, 3H), 2.18 – 2.00 (m, 7H), 1.90 (d, J = 13.0 Hz, 1H), 1.51 (t, J = 5.9 Hz, 4H), 1.18 (t, J = 7.1 Hz, 3H), 0.88 (dd, J = 6.7, 3.3 Hz, 6H).

[0066] Example 10: Synthesis of compound P10

[0067]

[0068] SM2 (1.0 g, 4.36 mmol), potassium carbonate (2.0 g, 10.9 mmol), 30 ml DMF were added into a reaction flask with U-shaped drying tube, stirred at room temperature for 1 h, then 1,2-dibromoethane (525 mg, 2.79 mmol) was added, TLC detection, the reaction was complete, 20 ml water and 20 ml ethyl acetate were added, stirred and separated, the ethyl acetate phase was retained, washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, rotary evaporated, the crude product was column chromatographed on silica gel (ethyl acetate: petroleum ether = 10:1) to give yellow oil 1.0 g, yield 89%. ESI-MS: 256.14 [M+H] + .

[0069] 1H NMR (400 MHz, CDCl3) δ 9.34 (d, J = 7.1 Hz, 1H), 4.48 (dd, J =8.0, 4.9 Hz, 1H), 4.29 – 4.09 (m, 2H), 2.29 – 2.16 (m, 1H), 2.01 (s, 3H),1.91 – 1.80 (m, 2H), 1.60 – 1.48 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H), 1.00 (d,J = 6.9 Hz, 6H).

[0070] Example 11: Synthesis of compound P11

[0071]

[0072] SM1 (800 mg, 4.36 mmol), potassium carbonate (2.4 g, 17.45 mmol), 30 ml DMF were added into a reaction flask with U-shaped drying tube, stirred at room temperature for 1 h, then 1,5-dibromopentane (2.5 g, 10.9 mmol) was added, TLC detection, the reaction was complete, 40 ml water and 40 ml ethyl acetate were added, stirred and separated, the ethyl acetate phase was retained, washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, rotary evaporated, the crude product was column chromatographed on silica gel (ethyl acetate: petroleum ether = 10:1) to give yellow oil 250 mg, yield 20%. ESI-MS: 298.4 [M+H] + .

[0073] 1H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J = 7.7 Hz, 1H), 4.10 (m, 3H),2.21 – 2.01 (m, 6H), 1.75 – 1.63 (m, 1H), 1.63 – 1.53 (m, 1H), 1.44 (m, 4H),1.39 – 1.21 (m, 2H), 1.18 (t, J = 7.1 Hz, 3H), 0.88 (dd, J = 6.8, 1.6 Hz,6H).

[0074] Example 12: Synthesis of compound P12

[0075]

[0076] SM2 (1.0 g, 4.36 mmol), potassium carbonate (2.5 g, 17.45 mmol), 30 ml DMF were added into a reaction flask with U-shaped drying tube, stirred at room temperature for 1 h, then iodine isopropyl (1.9 g, 10.9 mmol) was added, TLC detection, the reaction was complete, 40 ml water and 40 ml ethyl acetate were added, stirred and separated into two layers, the ethyl acetate phase was reserved, washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, rotary evaporated, the crude product was column chromatographed on silica gel (ethyl acetate: petroleum ether = 10:1), 100 mg of yellow oil was obtained, the yield was 0.8%. ESI-MS: 272.36 [M+H]+.

[0077] 1H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J = 7.8 Hz, 1H), 4.12 (m, 3H),3.33 (d, J = 6.0 Hz, 1H), 2.23 (dd, J = 6.6, 3.2 Hz, 1H), 2.09 (dd, J = 12.6,5.1 Hz, 4H), 1.18 (m, 3H), 0.90 (dd, J = 11.9, 6.1 Hz, 6H), 0.86 – 0.78 (m,6H).

[0078] Example 13: Synthesis of compound P13

[0079]

[0080] SM2 (0.5 g, 2.18 mmol), potassium carbonate (1.5 g, 10.90 mmol), 30 ml DMF were added into a reaction flask with U-shaped drying tube, stirred at room temperature (1 h, then iodide isobutane 1.6 g, 8.72 mmol) was added, TLC detection, the reaction was complete, 40 ml water and 40 ml ethyl acetate were added, stirred and separated into two layers, the ethyl acetate phase was retained, washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, rotary evaporated, and column chromatography (ethyl acetate: petroleum ether = 10:1) was performed on the crude product to obtain 400 mg of yellow oil, with a yield of 53%. ESI-MS: 342.49 [M+H]+.

[0081] 1H NMR (400 MHz, CDCl3) δ 8.74 (d, J = 7.4 Hz, 1H), 4.42 (m, 1H),4.16 (q, J = 7.1 Hz, 2H), 2.25 (s, 3H), 2.22 – 2.16 (m, 1H), 2.08 (m, 2H),1.66 (m, 2H), 1.48 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H), 0.96 (dd, J = 6.9, 3.8Hz, 6H), 0.85 – 0.78 (m, 12H).

[0082] Example 14: Synthesis of compound P14

[0083] Synthesis of compound SM3

[0084]

[0085] Synthesis of intermediate Int-2 in Step 1

[0086] Into a 250 ml three-necked flask, isopropyl alcohol 150 ml was added and cooled to -5 °C, thionyl chloride 15 ml was started to be added dropwise, after the dropwise addition was completed, D-Valine (10.0 g, 0.085 mol) was added, stirred at room temperature for 1 h, then warmed to reflux for 5 h, TLC judged that the reaction was completed, rotary evaporation to remove isopropyl alcohol, added 100 ml water, saturated NaHCO3 to adjust pH to 7-8, extracted with 100 ml dichloromethane for 3 times, dried over anhydrous sodium sulfate overnight, filtered, rotary evaporated to obtain 7.8 g of yellow oil, with a yield of 57%. ESI-MS: 160.23 [M+H] + .

[0087] Step 2

[0088] Int-2 (1.76 g, 11.1 mmol), 150 ml dichloromethane was added to the reaction flask, cooled to 0 °C, triethylamine (1.17 g, 11.6 mmol) was added, divinyl ketone (0.98 g, 11.6 mmol), stirred at room temperature for 12 h, TLC detection, the reaction was complete, the reaction solution was dried, 150 ml of ethyl acetate was added, washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, rotary evaporated, the crude product was purified by silica gel column chromatography to give yellow oil 1.54 g, yield 57%. ESI-MS: 244.30 [M+H] + .

[0089] 1H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J = 8.2 Hz, 1H), 5.08 – 4.71 (m,1H), 4.14 (dd, J = 8.2, 5.9 Hz, 1H), 3.40 (s, 2H), 2.14 (s, 3H), 2.02 (dd, J= 14.3, 7.5 Hz, 1H), 1.19 (t, J = 5.9 Hz, 6H), 0.89 (dd, J = 6.8, 1.3 Hz,6H).

[0090]

[0091] SM2 (800 mg, 3.3 mmol), potassium carbonate (2.27 g, 16.4 mmol), 25 ml DMF was added to the reaction flask with a U-shaped drying tube, stirred at room temperature for 1 h, then iodomethane (1.87 g, 13.2 mmol) was added, TLC detection, the reaction was complete, 20 ml water and 20 ml ethyl acetate were added, stirred and separated, the ethyl acetate phase was retained, washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, rotary evaporated, the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 10:1) to give yellow oil 200 mg, yield 30%. ESI-MS: 272.18 [M+H] + .

[0092] 1H NMR (400 MHz, DMSO-d6) δ 7.80 (d, J = 7.8 Hz, 1H), 4.99 – 4.82 (m,1H), 4.05 (t, J = 7.5 Hz, 1H), 2.17 – 1.99 (m, 4H), 1.26 (d, J = 4.3 Hz, 6H),1.18 (dd, J = 6.2, 4.0 Hz, 6H), 0.88 (dd, J = 6.8, 4.2 Hz, 6H).

[0093] Example 15: Synthesis of compound P15

[0094]

[0095] SM1 (1.0 g, 4.36 mmol), potassium carbonate (2.0 g, 10.9 mmol), 25 ml DMF were added into a reaction flask with U-shaped drying tube, stirred at room temperature for 1 h, then 1,2-dibromoethane (1.54 g, 8.2 mmol) was added, TLC detection, the reaction was complete, 20 ml water and 20 ml ethyl acetate were added, stirred and separated into two layers, the ethyl acetate phase was retained, washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, rotary evaporated, the crude product was column chromatographed on silica gel (ethyl acetate: petroleum ether = 10:1), 300 mg of yellow oil was obtained, the yield was 33%. ESI-MS: 270.16 [M+H] + .

[0096] 1H NMR (400 MHz, DMSO-d6) δ 8.92 (d, J = 7.8 Hz, 1H), 4.93 (m, 1H),4.17 (m, 1H), 2.13 (s, 3H), 2.07 (dd, J = 13.2, 6.5 Hz, 1H), 1.50 – 1.41 (m,2H), 1.39 – 1.29 (m, 2H), 1.19 (q, J = 6.3 Hz, 6H), 0.91 (dd, J = 6.8, 4.2Hz, 6H).

[0097] Example 16: Synthesis of compound P16

[0098]

[0099] SM2 (0.8 g, 3.3 mmol), potassium carbonate (2.27 g, 16.44 mmol), 25 ml DMF were added into a reaction flask with U-shaped drying tube, stirred at room temperature for 1 h, then 1,3-dibromopropane (1.66 g, 8.22 mmol) was added, TLC detection, the reaction was complete, 20 ml water and 20 ml ethyl acetate were added, stirred and separated, the ethyl acetate phase was retained, washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, rotary evaporated, the crude product was column chromatographed on silica gel (ethyl acetate: petroleum ether = 10:1) to give 200 mg of yellow oil, yield 21%. ESI-MS: 284.37 [M+H] + .

[0100] 1H NMR (400 MHz, DMSO-d6) δ 11.23 (d, J = 7.7 Hz, 1H), 5.00 – 4.89(m, 1H), 4.15 – 4.01 (m, 3H), 2.33 (t, J = 6.4 Hz, 2H), 2.06 (d, J = 5.2 Hz,1H), 1.97 (s, 3H), 1.86 – 1.75 (m, 2H), 1.20 (m, 6H), 0.91 (m, 6H).

[0101] Example 17: Synthesis of compound P17

[0102]

[0103] SM3 (0.8 g, 3.29 mmol), potassium carbonate (2.27 g, 16.44 mmol), 25 ml DMF were added into a reaction flask with U-shaped drying tube, stirred at room temperature for 1 h, then 1,4-dibromobutane (1.77 g, 8.22 mmol) was added, TLC detection, the reaction was complete, 40 ml water and 40 ml ethyl acetate were added, stirred and separated, the ethyl acetate phase was retained, washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, rotary evaporated, the crude product was column chromatographed on silica gel (ethyl acetate: petroleum ether = 10:1) to give 280 mg of yellow oil, yield 28%. ESI-MS: 298.4 [M+H] + .

[0104] 1H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 7.7 Hz, 1H), 4.91 (m, 1H),4.06 (t, J = 7.5 Hz, 1H), 2.20 – 1.97 (m, 7H), 1.92 (dd, J = 13.8, 7.2 Hz,1H), 1.52 (d, J = 6.6 Hz, 4H), 1.18 (m, 6H), 0.88 (dd, J = 6.8, 2.2 Hz, 6H).

[0105] Example 18: Synthesis of compound P18

[0106]

[0107] SM3 (1.0 g, 4.11 mmol), potassium carbonate (2.8 g, 20.56 mmol), 30 ml DMF were added into a reaction flask with U-shaped drying tube, stirred at room temperature for 1 h, then 1,5-dibromopentane (2.4 g, 10.28 mmol) was added, TLC detection, the reaction was complete, 40 ml water and 40 ml ethyl acetate were added, stirred and separated into two liquid phases, the ethyl acetate phase was reserved, washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, rotary evaporated, the crude product was column chromatographed on silica gel (ethyl acetate: petroleum ether = 10:1) to obtain 300 mg of yellow oil, with a yield of 23%. ESI-MS: 312.42 [M+H] + .

[0108] 1H NMR (400 MHz, DMSO-d6) δ 7.74 (d, J = 7.7 Hz, 1H), 4.99 – 4.82 (m,1H), 4.06 (m, 1H), 2.20 – 1.96 (m, 6H), 1.67 (dd, J = 16.8, 6.7 Hz, 1H), 1.58(dd, J = 13.0, 6.0 Hz, 1H), 1.44 (d, J = 2.7 Hz, 4H), 1.35 (dd, J = 9.7, 3.0Hz, 1H), 1.29 – 1.21 (m, 1H), 1.18 (dd, J = 6.2, 3.7 Hz, 6H), 0.88 (d, J =6.7 Hz, 6H).

[0109] Example 19: Synthesis of compound P19

[0110]

[0111] SM3 (1.0 g, 4.11 mmol), potassium carbonate (2.8 g, 20.56 mmol), 30 ml DMF were added into a reaction flask with U-shaped drying tube, stirred at room temperature for 1 h, then iodoisopropane (2.4 g, 14.39 mmol) was added, TLC detection, the reaction was complete, 40 ml water and 40 ml ethyl acetate were added, stirred and separated, the ethyl acetate phase was reserved, washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, rotary evaporated, the crude product was column chromatographed on silica gel (ethyl acetate: petroleum ether = 10:1), 500 mg of yellow oil was obtained, the yield was 42%. ESI-MS: 286.38 [M+H]+.

[0112] 1H NMR (400 MHz, DMSO-d6) δ 8.48 (t, J = 7.3 Hz, 1H), 4.92 (m, 1H),4.19 – 4.09 (m, 1H), 2.28 – 2.18 (m, 1H), 2.15 – 2.02 (m, 5H), 1.22 – 1.14(m, 6H), 0.90 (dd, J = 11.6, 6.1 Hz, 6H), 0.86 – 0.78 (m, 6H).

[0113] Example 20: Synthesis of compound P20

[0114]

[0115] SM3 (0.5 g, 2.06 mmol), potassium carbonate (1.4 g, 10.22 mmol), 30 ml DMF were added into a reaction flask with U-shaped drying tube, stirred at room temperature for 1 h, then iodoisobutane 1.5 g, 8.22 mmol) was added, TLC detection, the reaction was complete, 40 ml water and 40 ml ethyl acetate were added, stirred and separated, the ethyl acetate phase was reserved, washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, rotary evaporated, the crude product was column chromatographed on silica gel (ethyl acetate: petroleum ether = 10:1), 200 mg of yellow oil was obtained, the yield was 53%. ESI-MS: 356.52 [M+H] + .

[0116] 1H NMR (400 MHz, CDCl3) δ 8.70 (d, J = 7.4 Hz, 1H), 5.03 (m, 1H),4.41 (m, 1H), 2.25 (s, 3H), 2.22 – 2.13 (m, 1H), 2.08 (dt, J = 14.2, 6.3 Hz,2H), 1.71 – 1.63 (m, 2H), 1.49 (m, 2H), 1.23 (dd, J = 6.2, 4.6 Hz, 6H), 0.96(dd, J = 6.9, 2.2 Hz, 6H), 0.82 (m, 12H).

[0117] Example 21: Compound PDK1 IC50 value testing

[0118] To each 1.25 ml 6 µM substrate peptide tube, add 100 µl 10 mM ATP to make a 2X ATP / substrate mix. Add 1 ml 10X kinase buffer to 1.5 ml double distilled water to make a 2.5 ml 4X reaction buffer. Transfer 1.2 ml 4X reaction buffer to each enzyme tube for a 4X reaction. Add 12.5 µl 4X reaction mix to 12.5 µl / well of test compound and incubate at room temperature for 5 minutes. Add 25 µl 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 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 with 1% BSA in PBS / T, 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 1% BSA in PBS / T (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 microliters / well DELFIA Enhancement and incubate at room temperature for 5 minutes. Read the plate using a time resolved fluorescence plate reader.

[0119] The IC50values of the test compounds were calculated using the statistical software GraphPad Prism 7.

[0120] Results: The PDK1 in vitro activity results of the compounds are shown in the following table:

[0121]

Claims

1. A class of compounds as shown in Formula I and Formula II, or pharmaceutically acceptable salts thereof, in, R1, R2, and R3 are hydrogen or C1-C6 alkyl groups; R2 and R3 are not both hydrogen; n is taken from the numbers 1, 2, 3, 4, 5, 6, 7, 8, 9.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The above R1 is a C1-C3 alkyl group; R2 and R3 are hydrogen and C1-C6 alkyl groups, and R2 and R3 are not both hydrogen; n is taken from the numbers 1, 2, 3, 4, 5, 6, 7.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The above R1 is a C1-C3 alkyl group; R2 and R3 are hydrogen and C1-C4 alkyl groups, and R2 and R3 are not both hydrogen; n is taken from the numbers 1, 2, 3, 4, and 5.

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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