Malonyl derivative compound and application thereof

Abstract

The invention discloses a malonyl compound as well as a pharmaceutical composition and application thereof. The malonyl 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 malonyl 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 found 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 common components such as DNA, RNA or tubulin, resulting in poor selectivity, large toxic and side effects. 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. At the same time, the drug resistance and toxic and side effects brought about 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 problems to be solved: The present invention provides a class of malonyl 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 malonyl-derived compounds shown in Formula I or a pharmaceutically acceptable salt, hydrate or solvate thereof,

[0007]

[0008] wherein,

[0009] R1 is selected from p-methoxyphenyl, p-trifluoromethoxyphenyl, trifluoroethyl, methylsulfonyl, C1-C3 alkyl or halogen-substituted phenyl;

[0010] R2 is selected from C1-C5 alkyl.

[0011] Preferably,

[0012] R1 is selected from p-methoxyphenyl, p-trifluoromethoxyphenyl, trifluoroethyl, methylsulfonyl, methyl, ethyl, cyclopropyl or p-fluorophenyl;

[0013] R2 is selected from C1-C5 alkyl.

[0014] More preferably,

[0015] R1 is selected from p-methoxyphenyl, p-trifluoromethoxyphenyl, trifluoroethyl, ethyl, cyclopropyl, p-fluorophenyl;

[0016] R2 is selected from methyl, n-propyl, n-pentyl.

[0017] Most preferably,

[0018] the compound is selected from:

[0019]

[0020] Compound 1 is as shown in S1 above;

[0021]

[0022] Compound 2 is as shown in S2 above;

[0023]

[0024] Compound 3 is as shown in S3 above;

[0025]

[0026] Compound 4 is as shown in S4 above;

[0027]

[0028] Compound 5 is as shown in S5 above;

[0029]

[0030] Compound 6 is as shown in S6 above;

[0031]

[0032] Compound 7 is as shown in S7 above;

[0033]

[0034] Compound 8 is as shown in S8 above.

[0035] The compounds provided by the present invention further include pharmaceutically acceptable equivalents of the compound or a mixture of two or more thereof.

[0036] Preferably, the compounds provided by the present invention may include one or a mixture of two or more of pharmaceutically acceptable salts, hydrates, solvates, metabolites, prodrugs.

[0037] Preferably, the compounds provided by the present invention include acid salts or base salts of the compounds provided by the present invention. The pharmaceutically acceptable salts have the pharmaceutical activity of the compound and meet the requirements both biologically and in practical applications.

[0038] The present invention provides a class of pyridohexacyclic compounds or pharmaceutically acceptable salts thereof for treating diseases such as cancer.

[0039] Beneficial effects:

[0040] A class of malonyl compounds described in the present application. The characteristics of this class of compounds are that they have PDK1 inhibitory activity, can be orally absorbed, and can be used to prepare drugs for treating malignant tumors. Detailed implementation manners

[0041] The present invention discloses a class of malonyl compounds and their uses. Those skilled in the art can draw on the content of this article and appropriately improve process parameters to achieve. The methods and applications of the present invention have been described through preferred embodiments. Relevant personnel can obviously make changes or appropriate alterations and combinations to the methods and applications described in this article without departing from the content, spirit and scope of the present invention to implement and apply the technology of the present invention.

[0042] In order to enable those skilled in the art to better understand the technical solutions of the present invention, the present invention will be further described in detail below in conjunction with specific embodiments.

[0043] Example 1: Synthesis of Compound S1

[0044]

[0045] Step 1: Synthesis of Intermediate B1

[0046] 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 p-methoxyaniline (0.68 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, 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: 323.66 [M+H]+.

[0047] Synthesis of Intermediate C1 in Step 2

[0048] Add B1 (0.8 g, 2.48 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 B1 (containing trifluoroacetic acid), calculate the yield as 100%, and directly use it for the next step. ESI-MS: 223.54 [M+H]+.

[0049] Step 3

[0050] Add D1 (1.00 g, 6.94 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 B (1.00 g, 4.50 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 800 mg of white solid, with a yield of 71%. ESI-MS: 349.62 [M+H]+.

[0051] 1H NMR (500 MHz, Chloroform-d) δ 8.22 (s, 1H), 7.52–7.46 (m, 2H), 7.27 (s, 0H), 6.90–6.83 (m, 2H), 4.38 (dd, J=8.6, 6.5 Hz, 1H), 3.81 (s, 3H), 3.51 (s, 2H), 2.57 (t, J=7.4 Hz, 2H), 2.40 (h, J=6.8 Hz, 1H), 1.61 (p, J=7.4 Hz, 2H), 1.41–1.32 (m, 2H), 1.34–1.26 (m, 1H), 1.04 (dd, J=10.4, 6.8 Hz, 6H), 0.93 (t, J=7.3 Hz, 3H).

[0052] Example 2: Synthesis of Compound S2

[0053]

[0054] Step 1: Synthesis of Intermediate B2

[0055] 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 trifluoroethylamine (0.75 g, 5.55 mol), 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 782 mg of white solid, with a yield of 66%. ESI-MS: 299.42 [M+H]+.

[0056] Step 2: Synthesis of Intermediate C2

[0057] Add B2 (0.73 g, 2.45 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: 313.33 [M+H]+.

[0058] Step 3

[0059] D2 (1.00 g, 6.84 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 B (1.10 g, 5.55 mmol) were added successively, and the mixture was stirred at room temperature for 12 h. The reaction was monitored by TLC and found to be complete. Then 20 mL of water was added for washing, followed by saturated NaCl washing, and dried over anhydrous Na2SO4. 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 white solid with a yield of 71%. ESI-MS: 297.52 [M+H]+

[0060] 1H NMR (500 MHz, DMSO-d6) δ 8.70 (t, J = 6.3 Hz, 1H), 8.20 (d, J = 8.8 Hz, 1H), 4.23 (dd, J = 8.7, 6.7 Hz, 1H), 4.00 (ddd, J = 16.1, 9.8, 6.7 Hz, 1H), 3.84 (ddt, J = 14.0, 9.6, 4.8 Hz, 1H), 3.39 (d, J = 15.1 Hz, 2H), 2.49 (s, 1H), 1.96 (h, J = 6.8 Hz, 1H), 0.89 (s, 1H), 0.95–0.83 (m, 11H).

[0061] Example 3: Synthesis of compound S3

[0062]

[0063] Step 1: Synthesis of intermediate B3

[0064] A (1.00 g, 4.60 mmol), EDCI (1.32 g, 6.90 mmol), HOBT (0.93 g, 6.90 mmol) and 30 mL of dichloromethane were added to a reaction flask and stirred at room temperature for 1 h. Then DIPEA (1.52 g, 11.5 mmol) and p-methoxyaniline (0.68 g, 5.55 mmol) were added successively, and the mixture was stirred at room temperature for 12 h. The reaction was monitored by TLC and found to be complete. Then 20 mL of water was added for washing, followed by saturated NaCl washing, and dried over anhydrous Na2SO4. 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 white solid with a yield of 67%. ESI-MS: 323.66 [M+H]+.

[0065] Step 2: Synthesis of intermediate C3

[0066] Add B3 (0.8 g, 2.48 mmol), 20 ml of dichloromethane, and trifluoroacetic acid (5 ml, 65.4 mmol) to a reaction flask. Heat the temperature to 30 °C and stir for 2 h. Detect by TLC. After the reaction is complete, directly evaporate the reaction solution to dryness to obtain 1.34 g of a yellow oil B1 (containing trifluoroacetic acid). The yield is calculated as 100% and is directly used for the next step. ESI-MS: 223.54 [M+H]+.

[0067] Step 3

[0068] Add D3 (0.53 g, 4.60 mmol), EDCI (1.32 g, 6.90 mmol), HOBT (0.93 g, 6.90 mmol), and 30 ml of dichloromethane to a reaction flask. Stir at room temperature for 1 h, then sequentially add DIPEA (1.52 g, 11.5 mmol) and B (1.23 g, 5.55 mol). Stir at room temperature for 12 h. Detect by TLC. After the reaction is complete, add 20 ml of water for washing, wash with saturated NaCl, dry over anhydrous Na2SO4, filter, evaporate, and purify the crude product by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 800 mg of a white solid with a yield of 71%. ESI-MS: 307.61 [M+H]+

[0069] 1H NMR (500 MHz, Chloroform-d) δ 8.26 (s, 1H), 7.52–7.45 (m, 2H), 7.31 (d, J = 8.7 Hz, 1H), 6.90–6.83 (m, 2H), 4.40 (dd, J = 8.7, 6.6 Hz, 1H), 3.80 (s, 3H), 3.51 (s, 2H), 2.59 (q, J = 7.2 Hz, 2H), 2.39 (h, J = 6.8 Hz, 1H), 1.11 (t, J = 7.3 Hz, 3H), 1.04 (dd, J = 10.2, 6.8 Hz, 6H).

[0070] Example 4: Synthesis of Compound S4

[0071]

[0072] Step 1 Synthesis of Intermediate B4

[0073] Add A (1.00 g, 4.60 mmol), EDCI (1.32 g, 6.90 mmol), HOBT (0.93 g, 6.90 mmol) and 30 ml of dichloromethane into a reaction flask, stir at room temperature for 1 h, then successively add DIPEA (1.52 g, 11.5 mmol) and cyclopropylamine (0.31 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 800 mg of white solid, with a yield of 71%. ESI-MS: 257.53 [M+H]+.

[0074] Synthesis of Intermediate C4 in Step 2

[0075] Add B4 (0.8 g, 3.12 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, detect by TLC, when the reaction is complete, directly rotary evaporate the reaction solution to obtain 1.34 g of yellow oil B (containing trifluoroacetic acid), with a yield calculated as 100%, and directly use it for the next step. ESI-MS: 157.32 [M+H]+.

[0076] Step 3

[0077] Add D4 (0.53 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 B (0.86 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 800 mg of white solid, with a yield of 71%. ESI-MS: 255.43 [M+H]+.

[0078] 1H NMR (500 MHz, Chloroform-d) δ 7.12 (d, J = 8.6 Hz, 1H), 6.44–6.40 (m, 1H), 4.18 (dd, J = 8.6, 6.4 Hz, 1H), 3.46 (s, 2H), 2.74 (tq, J = 7.2, 3.7 Hz, 1H), 2.59 (q, J = 7.3 Hz, 2H), 2.24 (dp, J = 12.9, 6.5 Hz, 1H), 1.11 (t, J = 7.2 Hz, 3H), 0.96 (t, J = 6.4 Hz, 6H), 0.79 (tdd, J = 5.7, 4.4, 1.2 Hz, 2H), 0.58–0.49 (m, 2H).

[0079] Example 5: Synthesis of Compound S5

[0080]

[0081] Step 1: Synthesis of Intermediate B5

[0082] A (1.00 g, 4.60 mmol), EDCI (1.32 g, 6.90 mmol), HOBT (0.93 g, 6.90 mmol) and 30 ml of dichloromethane were added to a reaction flask and stirred at room temperature for 1 h. Then DIPEA (1.52 g, 11.5 mmol) and ethylamine (0.25 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 white solid with a yield of 71%. ESI-MS: 245.43 [M+H]+.

[0083] Step 2: Synthesis of Intermediate C5

[0084] B5 (0.8 g, 3.27 mmol), 20 ml of dichloromethane and trifluoroacetic acid (5 ml, 65.4 mmol) were added to a reaction flask, and the temperature was raised to 30 °C and stirred for 2 h. TLC detection showed that the reaction was complete. The reaction solution was directly rotary evaporated to obtain 1.34 g of yellow oil B (containing trifluoroacetic acid) with a yield calculated as 100% and was directly used for the next step. ESI-MS: 145.36 [M+H]+.

[0085] Step 3

[0086] D5 (0.80 g, 4.60 mmol), EDCI (1.32 g, 6.90 mmol), HOBT (0.93 g, 6.90 mmol) and 30 mL of dichloromethane were added to a reaction flask and stirred at room temperature for 1 h. Then, DIPEA (1.52 g, 11.5 mmol) and B (0.80 g, 5.55 mmol) were added successively, and the mixture was stirred at room temperature for 12 h. The reaction was monitored by TLC and found to be complete. Then, 20 mL of water was added for washing, followed by saturated NaCl washing, and dried over anhydrous Na2SO4. 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 71%. ESI-MS: 299.52 [M+H]+

[0087] 1H NMR (500 MHz, DMSO-d6) δ 8.09 (d, J = 8.9 Hz, 1H), 7.98 (t, J = 5.3 Hz, 1H), 4.09 (dd, J = 8.8, 7.0 Hz, 1H), 3.45–3.34 (m, 2H), 3.15–3.01 (m, 2H), 2.47 (t, J = 7.3 Hz, 2H), 1.93 (dq, J = 14.1, 7.0 Hz, 1H), 1.49–1.40 (m, 2H), 1.26–1.18 (m, 6H), 1.01 (t, J = 7.2 Hz, 3H), 0.86–0.82 (m, 9H).

[0088] Example 6: Synthesis of Compound S6

[0089]

[0090] Step 1: Synthesis of Intermediate B6

[0091] A (1.00 g, 4.60 mmol), EDCI (1.32 g, 6.90 mmol), HOBT (0.93 g, 6.90 mmol) and 30 mL of dichloromethane were added to a reaction flask and stirred at room temperature for 1 h. Then, DIPEA (1.52 g, 11.5 mmol) and ethylamine (0.25 g, 5.55 mmol) were added successively, and the mixture was stirred at room temperature for 12 h. The reaction was monitored by TLC and found to be complete. Then, 20 mL of water was added for washing, followed by saturated NaCl washing, and dried over anhydrous Na2SO4. After filtration and rotary evaporation, the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 732 mg of a white solid with a yield of 69%. ESI-MS: 245.43 [M+H]+.

[0092] Step 2: Synthesis of Intermediate C6

[0093] Add B6 (0.73 g, 3.00 mmol), 20 ml of dichloromethane, and trifluoroacetic acid (5 ml, 65.4 mmol) to a reaction flask, heat to 30°C, and stir for 2 h. TLC confirms the reaction is complete. The reaction solution is then directly spin-dried to give 1.16 g of a yellow oil (containing trifluoroacetic acid). The yield is calculated as 100%, and the product is used directly in the next step. ESI-MS: 145.36 [M+H]+.

[0094] Step 3

[0095] D6 (0.53 g, 4.60 mmol), EDCI (1.32 g, 6.90 mmol), HOBT (0.93 g, 6.90 mmol), and 30 ml of dichloromethane were added to a reaction flask and stirred at room temperature for 1 h. DIPEA (1.52 g, 11.5 mmol) and B (0.80 g, 5.55 mol) were then added in sequence. The mixture was stirred at room temperature for 12 h. TLC indicated that the reaction was complete. The mixture was washed with 20 ml of water, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, and rotary evaporated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give 800 mg of a white solid, with a yield of 71%. ESI-MS: 243.53 [M+H]+

[0096] 1H NMR (500MHz, DMSO-d6) δ8.09 (d, J=9.0Hz, 1H), 7.98 (q, J=5.6Hz, 1H), 4.09 (dd, J=8.9, 6.8Hz, 1H), 3.47–3.36 (m, 2H), 3.18–2. 99(m,2H),2.54–2.46(m,1H),1.94(h,J=6.7Hz,1H),1.01(t,J=7.2Hz,3H),0.92(t,J=7.3Hz,3H),0.84(dd,J=6.8,3.4Hz,6H).

[0097] Example 7: Synthesis of Compound S7

[0098]

[0099] Step 1 Synthesis of Intermediate B7

[0100] A (1.00 g, 4.60 mmol), EDCI (1.32 g, 6.90 mmol), HOBT (0.93 g, 6.90 mmol) and 30 ml of dichloromethane were added to a reaction flask and stirred at room temperature for 1 h. Then DIPEA (1.52 g, 11.5 mmol) and p-fluoroaniline (0.62 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, followed by saturated NaCl washing, and then 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 732 mg of white solid with a yield of 69%. ESI-MS: 311.42 [M+H]+.

[0101] Synthesis of Intermediate C7 in Step 2

[0102] B7 (0.73 g, 2.35 mmol), 20 ml of dichloromethane and trifluoroacetic acid (5 ml, 65.4 mmol) were added to a reaction flask, and the temperature was raised to 30 °C and stirred for 2 h. TLC detection showed that the reaction was complete. The reaction solution was directly rotary evaporated to obtain 1.16 g of yellow oil B (containing trifluoroacetic acid), and the yield was calculated as 100% and directly used for the next step. ESI-MS: 211.39 [M+H]+.

[0103] Step 3

[0104] D7 (0.79 g, 4.60 mmol), EDCI (1.32 g, 6.90 mmol), HOBT (0.93 g, 6.90 mmol) and 30 ml of dichloromethane were added to a reaction flask and stirred at room temperature for 1 h. Then DIPEA (1.52 g, 11.5 mmol) and B (1.16 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, followed by saturated NaCl washing, and then 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 800 mg of white solid with a yield of 71%. ESI-MS: 365.58 [M+H]+

[0105] 1H NMR (500MHz, DMSO-d6) δ10.16(s,1H),8.33(d,J=8.6Hz,1H),7.64(dd,J=8.7,5.0Hz,2H),7.15(t,J=8.8Hz,2H),4.31(t,J=7.9Hz,1H),3.48 –3.37(m,2H),2.48(d,J=7.3Hz,2H),2.08–1.96(m,1H),1.49–1.40(m,2H),1.27–1.17(m,7H),0.91(d,J=6.7Hz,6H),0.84(t,J=6.8Hz,3H).

[0106] Example 8: Synthesis of Compound S8

[0107]

[0108] Step 1 Synthesis of Intermediate B8

[0109] A (1.00 g, 4.60 mmol), EDCI (1.32 g, 6.90 mmol), HOBT (0.93 g, 6.90 mmol), and 30 ml of dichloromethane were added to a reaction flask and stirred at room temperature for 1 h. DIPEA (1.52 g, 11.5 mmol) and p-fluoroaniline (0.62 g, 5.55 mmol) were then added sequentially. The mixture was stirred at room temperature for 12 h. TLC confirmed the reaction was complete. The mixture was washed with 20 ml of water, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, and rotary evaporated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give 800 mg of a white solid, in a 67% yield. ESI-MS: 311.42 [M+H]+.

[0110] Step 2 Synthesis of intermediate C8

[0111] Add B8 (0.8 g, 2.58 mmol), 20 ml of dichloromethane, and trifluoroacetic acid (5 ml, 65.4 mmol) to a reaction flask, heat to 30°C, and stir for 2 h. TLC confirms the reaction is complete. The reaction solution is then directly spin-dried to give 1.34 g of a yellow oil (containing trifluoroacetic acid). The yield is calculated as 100%, and the product is used directly in the next step. ESI-MS: 211.39 [M+H]+.

[0112] Step 3

[0113] D8 (0.53 g, 4.60 mmol), EDCI (1.32 g, 6.90 mmol), HOBT (0.93 g, 6.90 mmol) and 30 ml of dichloromethane were added to a reaction flask and stirred at room temperature for 1 h. Then, DIPEA (1.52 g, 11.5 mmol) and B (1.16 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. Then, 20 ml of water was added for washing, followed by saturated NaCl washing, and drying over anhydrous Na2SO4. 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 white solid with a yield of 71%. ESI-MS: 309.42 [M+H]+

[0114] 1H NMR (500 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.31 (d, J = 8.6 Hz, 1H), 7.67–7.60 (m, 2H), 7.20–7.12 (m, 2H), 4.31 (dd, J = 8.6, 7.1 Hz, 1H), 3.50–3.39 (m, 2H), 2.56–2.48 (m, 1H), 2.03 (h, J = 6.9 Hz, 1H), 0.92 (t, J = 7.1 Hz, 9H).

[0115] Example 9 Testing of the IC50 Value of Compound PDK1

[0116] Add 100 μl of 10 mM ATP to each 1.25 ml tube of 6 μM substrate peptide to make a 2X ATP / substrate mixture. Add 1 ml of 10X kinase buffer to 1.5 ml of double-distilled water to make 2.5 ml of 4X reaction buffer. Transfer 1.2 ml of 4X reaction buffer to each enzyme tube for a 4X reaction. Add 12.5 μl of 4X reaction mixture to the target compound at 12.5 μl / well and incubate at room temperature for 5 minutes. Add 25 μl of 2X ATP / substrate mixture to the pre-incubated reaction mixture / compound at 25 μl / well, and incubate the reaction plate at room temperature for 30 minutes. Add 50 μl / well of termination buffer (50 mM EDTA, pH 8) to terminate the reaction. Transfer 25 μl of each reaction to a 96-well streptavidin-coated plate containing 75 μl of dH2O / well and incubate at room temperature for 60 minutes. Wash three times with 200 μl / well of PBS / T. Dilute the primary antibody Phospho-PKAC (Thr197) antibody with PBS / T containing 1% BSA, and add 100 μl / well of the primary antibody at a dilution of 1:1000. Incubate at room temperature for 120 minutes, wash three times with 200 μl / well of PBS / T, and prepare an appropriate dilution of the Eu-labeled secondary antibody in PBS / T containing 1% BSA (dilution of anti-mouse IgG is 1:500, dilution of anti-rabbit IgG is 1:1000). Add 100 μl / well of the secondary antibody solution and incubate at room temperature for 30 minutes. Wash five times with 200 μl / well of PBS / T, add 100 μl / well of DELFIA enhancement, and incubate at room temperature for 5 minutes. Read the plate using a time-resolved fluorescence plate reader.

[0117] The IC50 values of the test compounds were calculated using the statistical software GraphPad Prism 7.

[0118] Results: The in vitro activity results of the compounds against PDK1 are shown in Table 1.

[0119] Table 1 Results of Compound PDK1 Activity

[0120] Serial number Compound number PDK1 IC50 (μM) 1 S1 ++ 2 S2 ++ 3 S3 +++ 4 S4 ++ 5 S5 ++ 6 S6 ++ 7 S7 +++ 8 S8 ++

[0121] ++ represents an IC50 of 10 - 50 μM; +++ represents an IC50 of 1 - 10 μM.

[0122] Example 10 PK Study after Intravenous and Oral Administration of the Compound to SD Rats

[0123] 1 Materials and Methods

[0124] 1.1 Experimental Animals

[0125] Sprague-Dawley (SD) rats, male, SPF grade, weighing about 220 g,

[0126] Source: Zhejiang Vital River Laboratory Animal Technology Co., Ltd. (SPF level).

[0127] 1.2 Test drug

[0128] Compound S3

[0129] 1.3 Dose design

[0130] Group A: 3 rats, i.v. administered 2.00 mg / kg S3

[0131] Group B: 3 rats, i.g. administered 10.0 mg / kg S3

[0132] 1.4 Administration prescription

[0133] i.v.: 5% DMA + 5% Solutol in saline

[0134] i.g.: 0.5% CMC-Na

[0135] 1.5 Administration method

[0136] Animals were fasted (about 12 h) one day before the experiment and allowed free access to food 4 h after administration; water was not restricted.

[0137] Rats in each group were accurately drawn with the corresponding amount of the administration preparation and administered via the tail vein or oral gavage. The dosage for each animal was calculated based on the body weight on the day of the experiment.

[0138] 1.6 Blood sample collection

[0139] After the rats were administered, the blood sampling time points were 5, 15, 30 min, 45 min, 1, 2, 4, 6, 8, 10, 24 h after administration. The above samples were placed in an EP tube anticoagulated with EDTA-K2 and ice-bathed after collection, centrifuged at 8000 rpm for 5 minutes at 4°C, and the plasma was transferred to -20°C for storage and waiting for measurement as soon as possible.

[0140] 1.7 Blood drug concentration detection

[0141] The LC-MS / MS analysis method was used to determine the concentration of each corresponding compound in rat plasma.

[0142] 1.8 Data analysis

[0143] Winnonlin 6.0 software was used to calculate the relevant pharmacokinetic parameters.

[0144] 2 Results

[0145] Table 2. Pharmacokinetic parameters of S3 in SD rats after i.v. and i.g.

[0146]

Claims

1. A class of malonyl compounds represented by formula I or pharmaceutically acceptable salts, hydrates or solvates thereof, Among them, R1 is selected from p-methoxyphenyl, p-trifluoromethoxyphenyl, trifluoroethyl, methylsulfonyl, C1-C3 alkyl or halogen-substituted phenyl; R2 is selected from C1-C5 alkyl.

2. Any compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, Wherein the R1 is selected from p-methoxyphenyl, p-trifluoromethoxyphenyl, trifluoroethyl, methylsulfonyl, methyl, ethyl, cyclopropyl or p-fluorophenyl; R2 is selected from C1-C5 alkyl.

3. Any compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, Wherein the R1 is selected from p-methoxyphenyl, p-trifluoromethoxyphenyl, trifluoroethyl, ethyl, cyclopropyl or p-fluorophenyl; R2 is selected from methyl, n-propyl or n-pentyl.

4. Any compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that The compounds are selected from: Compound 1 is as shown in S1 above; Compound 2 is as shown in S2 above; Compound 3 is as shown in S3 above; Compound 4 is as shown in S4 above; Compound 5 is as shown in S5 above; Compound 6 is as shown in S6 above; Compound 7 is as shown in S7 above; Compound 8 is as shown in S8 above.

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