Platinum (II) compounds and their derivatives with targeting effects, preparation methods, pharmaceutical compositions and uses

Abstract

The present invention discloses a class of platinum(II) compounds with targeting effects, their derivatives, preparation methods, pharmaceutical compositions and applications. The structure of this class of platinum(II) compounds is as follows: The derivatives of this class of platinum(II) compounds refer to isomers of the platinum(II) compounds or mixtures thereof. This class of platinum(II) compounds and their derivatives have active targeting effects, can specifically inhibit related protein kinases and cancer cells. At the same time, the chemical structure contains a C=N double bond, which can passively target tumors using the acidic microenvironment of tumors and reduce tissue toxicity. They exhibit the characteristics of high efficiency and low toxicity in anti-tumor, and can overcome the drug resistance problems of existing platinum-based and targeted drugs. In addition, the synthesis method of this class of platinum(II) compounds is simple and easy to implement.

Description

Technical Field

[0001] The present invention relates to a class of platinum(II) compounds with targeting effects, their derivatives, preparation methods, pharmaceutical compositions and applications, and particularly to a class of platinum(II) compounds with targeting effects, their derivatives, preparation methods, pharmaceutical compositions and applications that can be prepared into anti-tumor drugs that effectively inhibit protein kinases and cancer cells and are adapted to the tumor microenvironment. Background Art

[0002] At present, the treatment methods for malignant tumors mainly include surgery, radiotherapy, chemotherapy, targeted and immunotherapy. Clinically, tumor treatment needs to be individualized according to the specificity of each individual. Especially in the middle and late stages of cancer, multiple treatment methods need to be combined to achieve better results. Generally, surgical treatment is suitable for the early stage of tumor occurrence, and other treatment means also need to be combined to achieve the purpose of clinically curing cancer. Radiotherapy usually uses high-energy rays to irradiate tumor tissues to achieve the effect of killing cancer cells. However, this treatment method has limitations, and tumors are prone to recurrence and cause side effects. Chemotherapy represented by cytotoxic drugs such as cisplatin, doxorubicin, camptothecin and paclitaxel is an important means of treating tumors, with the characteristic of strong anti-tumor activity. However, due to the lack of targeting and selectivity for tumors, it often causes serious side effects. In addition, after long-term use of these chemotherapy drugs, drug resistance will occur due to various factors, resulting in reduced efficacy.

[0003] Targeted therapy takes some overexpressed biomolecules on tumor tissues as targets to implement "precision strikes" on cancer cells. Compared with chemotherapy, targeted drugs are specific, generally only inhibit cancer cells, cause little harm to normal cells, and have relatively small side effects. Since the first molecular targeted drug, imatinib mesylate tablets (Gleevec), was approved for the treatment of chronic myeloid leukemia (CML) in 2001, targeted therapy has developed rapidly in clinical applications. Usually, targeted drugs are effective for the vast majority of patients with gene matching. However, after a period of treatment, most patients have developed drug resistance. This is because when the malignancy of the tumor is very high, after one biological target is inhibited, it will change to another target to drive, resulting in the weakening of the original targeted drug effect, that is, drug resistance is generated. Therefore, drug resistance is one of the huge obstacles in the clinical application of current targeted drugs.

[0004] Some existing literature has disclosed the introduction of small molecule groups with targeting functions at the axial positions of platinum(IV) to form stable platinum(IV) prodrugs. The design principle is based on the reduction of platinum(IV) to platinum(II) through in vivo biological reduction, releasing the axially linked functional small molecule groups, and then cooperating with the biologically active platinum(II) to exert anti-tumor effects. However, these platinum(IV) prodrugs usually have certain defects in aspects such as large-scale preparation, drug metabolism, and quality control, and it is difficult to prepare them into anti-tumor drugs. Summary of the Invention

[0005] Object of the Invention: Aiming at the deficiencies of existing targeted drugs and platinum anti-tumor drugs, the present invention aims to provide a class of anti-tumor platinum(II) compounds and their derivatives, preparation methods, pharmaceutical compositions, and applications with targeting effects that can effectively inhibit protein kinases and cancer cells and adapt to the tumor microenvironment.

[0006] Technical Solution: As the first aspect of the present invention, the platinum(II) compounds and their derivatives with targeting effects of the present invention have the following structures:

[0007]

[0008] The derivatives are isomers of the platinum(II) compounds or mixtures thereof;

[0009] Among them, TD is any of the following structures:

[0010]

[0011] n is 1 or 5.

[0012] In order to give full play to the advantages of high anti-tumor activity of platinum(II) chemotherapy drugs, solve their deficiencies of non-specificity and high toxicity, and at the same time utilize the advantages of high specificity and low toxicity of targeted drugs to overcome the drug resistance problem caused by gene mutations, the present invention designs some molecular targeted drug pharmacophores as "guidance units" and specific anti-tumor platinum(II) compounds as "bomb units", and combines the two through functional groups that can dissociate in the acidic microenvironment of tumors to provide an anti-tumor platinum(II) compound with both active and passive targeting effects.

[0013] The designed platinum(II) compounds can not only specifically target tumor tissues with the help of the targeted drug unit to precisely inhibit the growth of cancer cells, but also non-specifically kill cancer cells including gene mutations with the help of the specific platinum(II) drug unit. Combining the characteristics of both can not only reduce the toxicity caused by the drug but also overcome the related drug resistance.

[0014] The present invention specifically relates to a novel class of platinum(II) compounds obtained by bonding derivatives of known targeted drugs represented by EGFR inhibitors, HER2 inhibitors, PARP inhibitors, and BET inhibitors to a platinum(II) compound containing a ketone carbonyl group with antitumor activity through hydrazide groups.

[0015] Among them, representative known targeted drugs are any one of gefitinib and osimertinib (EGFR inhibitors), lapatinib (HER2 inhibitor), olaparib (PARP inhibitor), and (+)-JQ1 (BET inhibitor), and specific antitumor platinum(II) compounds are DN604 or DN603, and their structures are as follows:

[0016]

[0017] Among them, the epidermal growth factor receptor (EGFR) is a receptor for cell proliferation and signal transduction of epidermal growth factor (EGF). EGFR belongs to one of the ErbB receptor families, and this family includes subtypes such as EGFR (ErbB-1), HER2 (ErbB-2), HER3 (ErbB-3), and HER4 (ErbB-4). EGFR is also known as HER1 and ErbB1, and its mutation or overexpression generally triggers tumors. EGFR is a glycoprotein belonging to the tyrosine kinase type receptor, located on the cell membrane surface, and is related to the proliferation, angiogenesis, tumor invasion, metastasis, and inhibition of apoptosis of cancer cells.

[0018] Human epidermal growth factor receptor-2 (HER2) is one of the genes that have been relatively well studied in breast cancer so far. The overexpression of the HER2 gene is not only related to the occurrence and development of tumors, but also an important clinical treatment monitoring and prognostic indicator, and is an important target for the selection of tumor targeted drugs. The oncogenic mechanisms of the HER2 oncogene include inhibiting apoptosis, promoting proliferation, increasing the invasiveness of tumor cells, promoting tumor angiogenesis and lymphangiogenesis.

[0019] Poly ADP-ribose polymerase (PARP) is a DNA repair enzyme. PARP is a cleavage substrate of caspase, a core member of apoptosis. Therefore, it plays an important role in DNA damage repair and apoptosis. PARP inhibitors can enhance the efficacy of radiotherapy and chemotherapy with alkylating agents and platinum drugs by inhibiting DNA damage repair in cancer cells and promoting apoptosis of cancer cells.

[0020] The bromodomain and extraterminal domain (BET) family belongs to the bromodomain protein family, and its members include bromodomain-containing protein (BRD) BRD2, BRD3, BRD4, and bromodomain testis-specific protein (BRDT). Members of the BET family have a special double bromodomain and are widely involved in regulating gene expression related to transcription, DNA repair, immunity, metabolism, signal transduction, etc. by recognizing acetylated histones or transcription factors, and are anti-tumor targets that have received close attention. BET family proteins are upregulated in a variety of tumors, and are related to multiple biological processes such as cell growth, proliferation and differentiation, apoptosis and necrosis, and thus participate in regulating the process of tumorigenesis and development.

[0021] More specifically, the platinum(II) compound with a targeting effect is any one of the following compounds:

[0022]

[0023]

[0024]

[0025] As the second aspect of the present invention, the preparation method of the platinum(II) compound with a targeting effect and its derivatives of the present invention is as follows:

[0026]

[0027] Compound A6, B7, C3, D5 or E2 is respectively subjected to a condensation reaction with compound DN603 or DN604 to obtain the platinum(II) compound with a targeting effect;

[0028] Among them, the structures of compounds DN603, DN604, A6, B7, C3, D5 or E2 are as follows:

[0029]

[0030] Among them, the preparation method of the compound A6, B7, C3, D5 or E2 is as follows:

[0031] (1) Compound A6

[0032]

[0033] Compound A1 and A2 undergo a substitution reaction to obtain compound A3. Then, A3 is deprotected by Boc to obtain compound A4. A4 undergoes a substitution reaction to obtain compound A5. Finally, A5 undergoes a hydrazide transesterification reaction to obtain compound A6;

[0034] (2) Compound B7

[0035]

[0036] Compound B1 and B2 undergo a substitution reaction to obtain compound B3. Then, B3 undergoes a substitution reaction to obtain compound B4. B4 is deprotected by Boc to obtain compound B5. B5 undergoes a substitution reaction to obtain compound B6. Finally, B6 undergoes a hydrazide transesterification reaction to obtain compound B7;

[0037] (3) Compound C3

[0038]

[0039] Compound C1 undergoes an acylation reaction to obtain compound C2. Then, C2 undergoes a hydrazinolysis reaction and deprotection by Boc to obtain compound C3;

[0040] (4) Compound D5

[0041]

[0042] Compound D1 undergoes a condensation reaction to obtain compound D2. Then, D2 is deprotected by Boc to obtain compound D3. D3 undergoes a substitution reaction to obtain compound D4. Finally, D4 undergoes a hydrazide transesterification reaction to obtain compound D5;

[0043] (5) Compound E2

[0044]

[0045] Compound E1 undergoes a hydrazide transesterification reaction to obtain compound E2.

[0046] As the third aspect of the present invention, the pharmaceutical composition of the present invention comprises the platinum(II) compound and / or its derivative having a targeting effect and a pharmaceutically acceptable carrier.

[0047] The platinum(II) compound having a targeting effect and its derivative can be formulated into common pharmaceutical preparations by adding a pharmaceutically acceptable carrier, such as tablets, capsules, syrups, suspensions or injections. The preparations can be added with common pharmaceutical excipients such as flavors, sweeteners, liquid / solid fillers, diluents, etc.

[0048] As the fourth aspect of the present invention, the platinum(II) compounds with targeting effects, their derivatives, and pharmaceutical compositions of the present invention are applied to the preparation of anti-tumor drugs, specifically for the treatment of non-small cell lung cancer, breast cancer, ovarian cancer, leukemia, and related cancers resistant to gefitinib, osimertinib, lapatinib, olaparib, or cisplatin.

[0049] Beneficial effects: Compared with the prior art, the present invention has the following remarkable advantages:

[0050] (1) Such platinum(II) compounds with targeting effects can specifically inhibit mutant protein kinases and cancer cells. The anti-tumor activities of representative compounds are superior to those of existing platinum-based and targeted drugs, or have comparable activities;

[0051] (2) Such platinum(II) compounds with targeting effects contain a C=N double bond structure, can target tumors using the acidic microenvironment of tumors, and have lower toxicity to normal tissues than existing platinum-based drugs;

[0052] (3) The preparation method is simple and easy to implement. Description of the Drawings

[0053] Figure 1 Hydrolysis results of OS-2 within 24 h under neutral conditions (pH 7.4);

[0054] Figure 2 Hydrolysis results of OS-2 within 24 h under acidic conditions (pH 5.0);

[0055] Figure 3 Hydrolysis results of JD-1 within 24 h under neutral conditions (pH 7.4);

[0056] Figure 4 Hydrolysis results of JD-1 within 24 h under acidic conditions (pH 5.0). Detailed Embodiments

[0057] The technical solutions of the present invention will be further described below in conjunction with embodiments.

[0058] Example 1: Preparation of Gefitinib Derivative A6

[0059]

[0060] (i): Weigh 638 mg of compound A1, 828 mg of potassium carbonate, and 66 mg of potassium iodide into a flask. Add 10 mL of DMF, and then add 675 mg of compound A2 while stirring at room temperature. Heat to 70 °C and continue stirring for 4 h. Monitor the reaction using TLC. After the reaction is complete, concentrate under reduced pressure, extract with dichloromethane and saturated brine for 1 - 2 times, rotary evaporate the dichloromethane layer, and perform column chromatography to obtain compound A3 (750 mg), a pale yellow solid, with a yield of 68.8%.

[0061] (ii): Take 545 mg of compound A3 into a flask, add 10 mL of dichloromethane, and slowly add 1 mL of trifluoroacetic acid dropwise while stirring in an ice bath. Continue stirring for 3 h and then monitor the reaction using TLC. After the reaction is complete, rotary evaporate, redissolve with dichloromethane, adjust the pH to alkaline with saturated sodium bicarbonate solution, extract with dichloromethane, and rotary evaporate to obtain compound A4 (500 mg), a pale yellow solid, with a yield of 87.7%.

[0062] (iii): Weigh 445 mg of compound A4 and 414 mg of potassium carbonate into a flask. Add 8 mL of DMF, and then add 362 mg of ethyl 3 - bromopropionate while stirring at room temperature. Heat to 70 °C and continue stirring overnight. Monitor the reaction using TLC. After the reaction is complete, concentrate under reduced pressure, extract with dichloromethane and saturated brine for 1 - 2 times, rotary evaporate the dichloromethane layer, and perform column chromatography to obtain compound A5 (400 mg), a pale yellow solid, with a yield of 75.6%.

[0063] (iv): Take 350 mg of compound A5 into a flask, add 15 mL of methanol, and then add 250 mg of hydrazine hydrate. Heat to 80 °C for reflux and stir for 6 h. Monitor the reaction using TLC. After the reaction is complete, rotary evaporate, extract with dichloromethane and saturated brine for 1 - 2 times, and rotary evaporate again. Perform column chromatography to obtain compound A6 (300 mg), a pale yellow solid, with a yield of 85.5%. 1 H NMR(600MHz,DMSO - d6)δ9.54(s,1H),8.97(s,1H),8.49(s,1H),8.11(dd,J=6.8,2.6Hz,1H),7.80–7.77(m,2H),7.44(t,J=9.1Hz,1H),7.19(s,1H),4.17–4.11(m,4H),3.93(s,3H),3.17(d,J=4.5Hz,2H),2.48–2.27(m,10H),2.17(t,J=7.3Hz,2H),1.99–1.95(m,2H)ppm..

[0064] Example 2: Preparation of compound GE - 1

[0065]

[0066] Weigh 265 mg of compound A6 and 192 mg of DN604 into a flask, add 50 mL of methanol, heat in an oil bath to 60 °C, add 2 drops of acetic acid, stir for 24 h, and monitor the reaction by TLC. After the reaction is complete, filter, and wash the product with methanol and distilled water respectively to obtain 375 mg of a pale yellow solid with a yield of 83.5%.

[0067] 1 H NMR(600MHz,DMSO-d6)δ10.53(s,1H),9.56(s,1H),8.49(s,1H),8.12(d,J=4.8Hz,1H),7.80(s,2H),7.44(t,J=9.0Hz,1H),7.20(s,1H),4.26–4.16(m,8H),3.93(s,3H),3.69–3.65(m,2H),3.47–3.44(m,2H),2.60–2.52(m,4H),2.47–2.35(m,10H),2.03–1.98(m,2H)ppm. 13 C NMR(150MHz,DMSO-d6)δ175.88,175.83,167.17,156.02,154.53,153.60,152.61,153.15(d,J=241.5Hz),148.37,146.97,136.82,123.52,122.37(d,J=6.0Hz),118.76(d,J=18.0Hz),116.52(d,J=21.0Hz),108.78,107.30,102.52,67.19,55.88,54.49,53.75,52.89,52.85,52.66,52.42,48.96,43.60,41.63,31.45,26.24ppm.HRMS(m / z)(ESI):calcd for C 31 H 40 ClFN9O7Pt[M+H] + :899.2293;found:899.2227.

[0068] Example 3: Preparation of compound GE-2

[0069]

[0070] 228 mg of compound A6 and 200 mg of DN603 were separately taken in a flask, 50 mL of methanol was added, and the mixture was heated to 60 °C in an oil bath. 2 drops of acetic acid were added dropwise, and after stirring for 24 h, the reaction was monitored by TLC. After the reaction was completed, it was concentrated, dissolved in dichloromethane, and ether was added dropwise continuously. It was filtered, and the insoluble matter was rinsed with distilled water to obtain 210 mg of a pale yellow solid with a yield of 79.9%.

[0071] 1 H NMR(600MHz,DMSO-d6)δ10.52–10.28(m,1H),9.69–9.61(m,1H),8.48(s,1H),8.12(s,1H),7.87–7.74(m,2H),7.43(s,1H),7.18(s,1H),6.27–5.99(m,2H),5.74(s,1H),5.34–5.24(m,1H),4.15–4.04(m,3H),3.93(s,3H),3.73–3.65(m,1H),3.60–3.55(m,1H),3.47–3.41(m,1H),3.34–3.29(m,1H),3.17–3.06(m,3H),2.61–2.39(m,10H),2.07–1.81(m,6H),1.47(s,2H),1.23(s,2H),1.02(s,2H)ppm. 13 C NMR(150MHz,DMSO-d6)δ176.34,175.81,167.21,156.03,154.52,153.13(d,J=241.5Hz),152.59,148.36,146.94,136.86,123.49,122.33(d,J=6.0Hz),118.75(d,J=19.5Hz),116.47(d,J=21.0Hz),108.81,107.25,102.58,67.19,62.15,55.86,54.51,52.86,52.65,52.48,48.60,43.30,42.49,40.06,31.58,31.47,26.23,24.05ppm.HRMS(m / z)(ESI):calcd for C 37 H 48 ClFN9O7Pt[M+H] + :979.2919;found:979.2385.

[0072] Example 4: Preparation of osimertinib derivative B7

[0073]

[0074] (i): Weigh 1.22 g of compound B1 and 930 mg of compound B2 into a flask, add 20 mL of sec-amyl alcohol, and add 1.14 g of p-toluenesulfonic acid portionwise under stirring at room temperature. Heat to 105 °C and continue stirring for 3 h, and monitor the reaction using TLC. After the reaction is completed, filter, wash the filter cake twice with ethyl acetate, and dry to obtain compound B3 (1.8 g), a yellow solid, with a yield of 91.8%.

[0075] (ii): Take 1.7 g of compound B3 and 894 mg of potassium carbonate into a flask, add 10 mL of DMSO, and continue to add a DMSO solution of 965 mg of 1-(tert-butoxycarbonyl)piperazine under stirring. Heat to 90 °C and stir overnight, and monitor the reaction using TLC. After the reaction is completed, extract with dichloromethane, evaporate to dryness, and perform column chromatography to obtain compound B4 (1.8 g), a pale yellow solid, with a yield of 74.7%.

[0076] (iii): Take 1.7 g of compound B4 into a flask, add 30 mL of dichloromethane, and dropwise add 2 mL of trifluoroacetic acid under stirring in an ice bath. Continue stirring for 3 h, and then monitor the reaction using TLC. After the reaction is completed, evaporate to dryness, redissolve with dichloromethane, adjust the pH to alkaline with saturated sodium bicarbonate solution, extract with dichloromethane, and evaporate to dryness to obtain compound B5 (1.2 g), a pale yellow solid, with a yield of 85.7%.

[0077] (iv): Take 918 mg of compound B5 and 828 mg of potassium carbonate into a flask, add 15 mL of DMF, and continue to add 724 mg of ethyl 3-bromopropionate under stirring at room temperature. Heat to 70 °C and continue stirring overnight, and monitor the reaction using TLC. After the reaction is completed, concentrate under reduced pressure, extract 1 - 2 times with dichloromethane and saturated brine, evaporate the dichloromethane layer to dryness, and perform column chromatography to obtain compound B6 (800 mg), a pale yellow solid, with a yield of 71.4%.

[0078] (v): Take 559 mg of compound B6 into a flask, add 15 mL of methanol, and continue to add 500 mg of hydrazine hydrate. Heat to 80 °C and reflux, stir for 6 h, and then monitor the reaction using TLC. After the reaction is completed, evaporate to dryness, extract 1 - 2 times with dichloromethane and saturated brine, evaporate to dryness, and perform column chromatography to obtain compound B7 (410 mg), a pale yellow solid, with a yield of 75.2%. 11H NMR (600 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.81 (s, 1H), 8.36 (d, J = 7.9 Hz, 1H), 8.34–8.32 (m, 2H), 8.14 (s, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.27–7.23 (m, 2H), 7.12 (t, J = 7.4 Hz, 1H), 6.86 (s, 1H), 4.21 (s, 2H), 3.98 (s, 3H), 3.87 (s, 3H), 3.10–3.03 (m, 4H), 2.61 (t, J = 7.2 Hz, 2H), 2.56–2.53 (m, 4H), 2.25 (t, J = 7.2 Hz, 2H) ppm.

[0079] Example 5: Preparation of Compound OS-1

[0080]

[0081] The preparation method was the same as that in Example 2, an orange-red solid, with a yield of 82.9%.

[0082] 1 1H NMR (600 MHz, DMSO-d6) δ 10.49 (s, 1H), 8.82 (d, J = 12.7 Hz, 1H), 8.42–8.33 (m, 3H), 8.12 (s, 1H), 7.51 (s, 1H), 7.24 (s, 2H), 7.13 (s, 1H), 6.88 (s, 1H), 4.21 (s, 6H), 3.98 (s, 3H), 3.87 (s, 3H), 3.68 (s, 2H), 3.53–3.47 (m, 2H), 3.10–3.07 (m, 4H), 2.67–2.59 (m, 8H) ppm. 13 13C NMR (150 MHz, DMSO-d6) δ 175.93, 167.20, 162.12, 159.79, 157.19, 154.38, 153.87, 150.45, 143.47, 137.64, 134.56, 133.13, 125.42, 122.27, 121.94, 120.93, 118.37, 112.30, 110.44, 107.72, 103.27, 56.53, 53.73, 52.64, 52.47, 51.63, 49.02, 43.64, 41.76, 33.08, 31.48, 29.83 ppm. HRMS (m / z) (ESI): calcd for C 33 H 40 N 11 O8Pt [M+H] +: 913.2631; found: 913.2597.

[0083] Example 6: Preparation of Compound OS-2

[0084]

[0085] The preparation method was the same as that in Example 3, orange-red solid, yield 78.3%.

[0086] 1 H NMR (600 MHz, DMSO-d6) δ 10.52–10.35 (m, 1H), 8.83 (d, J = 14.7 Hz, 1H), 8.48–8.33 (m, 3H), 8.11 (s, 1H), 7.51 (s, 1H), 7.30–7.24 (m, 2H), 7.13 (s, 1H), 6.88 (s, 1H), 6.06–5.94 (m, 1H), 5.33–5.23 (m, 1H), 3.98 (s, 3H), 3.87 (s, 3H), 3.75–3.66 (m, 2H), 3.54–3.46 (m, 2H), 3.21–3.10 (m, 2H), 2.67–2.52 (m, 8H), 2.50–2.36 (m, 4H), 2.06 (s, 2H), 1.81 (s, 2H), 1.45 (s, 2H), 1.21 (s, 2H), 1.00 (s, 2H) ppm. 13 C NMR (150 MHz, DMSO-d6) δ 176.35, 175.76, 172.93, 167.16, 162.12, 159.78, 157.18, 154.39, 143.43, 137.63, 134.52, 133.13, 125.41, 123.48, 122.25, 121.94, 120.91, 118.37, 112.29, 110.42, 107.70, 103.28, 62.13, 56.53, 53.70, 52.47, 51.61, 48.87, 43.75, 41.45, 33.07, 31.54, 29.80, 24.06 ppm. HRMS (m / z) (ESI): calcd for C 39 H 48 N 11 O8Pt [M+H] + : 993.3257; found: 993.3216.

[0087] Example 7: Preparation of Lapatinib Derivative C3

[0088]

[0089] (i): Weigh 1.45 g of compound C1 and 300 mg of succinic anhydride into a flask, add 20 mL of dichloromethane, and continue to add 379 mg of triethylamine under stirring at room temperature. Stir for another 4 h and monitor the reaction using TLC. After the reaction is completed, concentrate under reduced pressure and perform column chromatography to obtain compound C2 (1.0 g), a yellow solid, with a yield of 58.8%.

[0090] (ii): Take 680 mg of compound C2 and 418 mg of HATU into a flask, add 8 mL of DMF, and stir at room temperature for 10 min. Then continue to add 151 mg of triethylamine and 146 mg of NH2NHBoc, and heat to 50 °C to react overnight. Monitor the reaction using TLC. After the reaction is completed, evaporate to dryness, extract with dichloromethane and saturated brine for 1 - 2 times, evaporate to dryness, perform column chromatography, and obtain a pale yellow solid. Dissolve the obtained pale yellow solid in dichloromethane, add 1 mL of trifluoroacetic acid dropwise under an ice bath, and continue to stir for 3 h. Monitor the reaction using TLC. After the reaction is completed, evaporate to dryness, redissolve in dichloromethane, adjust the pH to alkaline with saturated sodium bicarbonate solution, extract with saturated brine for 1 - 2 times, evaporate the organic layer to dryness, and recrystallize from methanol to obtain compound C3 (300 mg), a yellow solid, with a yield of 43.2%. 1 H NMR (600 MHz, DMSO-d6) δ 9.90 (s, 1H), 9.08–9.01 (m, 1H), 8.77–8.73 (m, 1H), 8.56 (s, 1H), 8.20–8.14 (m, 1H), 8.02–8.00 (m, 1H), 7.81 (d, J = 7.7 Hz, 1H), 7.74–7.70 (m, 1H), 7.49–7.46 (m, 1H), 7.34–7.28 (m, 3H), 7.18 (t, J = 7.7 Hz, 1H), 7.11–7.06 (m, 1H), 6.64 (s, 1H), 5.26 (s, 2H), 4.74–4.67 (m, 2H), 4.18 (s, 2H), 3.72–3.60 (m, 3H), 3.05–3.02 (m, 3H), 2.86 (s, 2H), 2.46–2.36 (m, 3H) ppm.

[0091] Example 8: Preparation of Compound LA-1

[0092]

[0093] The preparation method is the same as that in Example 2, a pale yellow solid, with a yield of 84.0%.

[0094] 11H NMR(600MHz,DMSO-d6)δ10.42–10.35(m,1H),9.92–9.83(m,1H),8.76–8.71(m,1H),8.55(s,1H),8.20–8.13(m,1H),8.01–7.97(m,1H),7.81(s,1H),7.72–7.69(m,1H),7.48–7.45(m,1H),7.34–7.25(m,3H),7.18(t,J=7.8Hz,1H),7.10–7.05(m,1H),6.66(s,1H),5.26(s,2H),4.78–4.68(m,2H),4.21(s,6H),3.78–3.62(m,5H),3.53–3.47(m,2H),3.06–3.02(m,3H),2.86–2.73(m,3H),2.59–2.50(m,2H)ppm. 13 13C NMR(150MHz,DMSO-d6)δ175.94,171.94,168.35,162.22(d,J=241.5Hz),157.62,154.42,153.82,152.56,151.23,150.33,149.88,149.10,139.70,132.97,130.55,128.57,124.58,124.37,123.37,122.55,121.02,116.59,115.34,114.71(d,J=21.0Hz),114.29,114.15,111.09,110.43,107.95(d,J=16.5Hz),69.40,51.27,49.13,48.95,44.32,43.54,41.61,40.63,28.67,27.30ppm.HRMS(m / z)(ESI):calcd for C 39 H 41 ClFN8O 10 PtS[M+H] + :1062.1908;found:1062.1876.

[0095] Example 9: Preparation of Compound LA-2

[0096]

[0097] The preparation method was the same as that in Example 3, and a pale yellow solid was obtained with a yield of 80.5%.

[0098] 11H NMR (600 MHz, DMSO-d6) δ 10.48–10.33 (m, 1H), 9.96–9.87 (m, 1H), 8.78–8.73 (m, 1H), 8.55 (s, 1H), 8.19–8.13 (m, 1H), 8.02–7.97 (m, 1H), 7.80–7.69 (m, 2H), 7.46 (s, 1H), 7.33–7.29 (m, 2H), 7.18–7.06 (m, 2H), 6.61–6.51 (m, 2H), 5.98 (s, 2H), 5.21 (s, 2H), 4.75–4.68 (m, 2H), 3.77–3.68 (m, 3H), 3.60–3.58 (m, 2H), 3.50–3.46 (m, 1H), 3.34–3.30 (m, 2H), 3.17–3.14 (m, 2H), 3.06–2.95 (m, 5H), 2.85–2.79 (m, 2H), 2.06 (s, 2H), 1.81 (s, 2H), 1.45 (s, 2H), 1.22 (s, 2H), 1.01 (s, 2H) ppm. 13 13C NMR (150 MHz, DMSO-d6) δ 176.41, 175.83, 175.75, 175.59, 162.23 (d, J = 241.5 Hz), 157.61, 154.42, 152.72, 152.47, 151.95, 151.26, 149.80, 149.00, 139.69, 133.11, 130.55, 128.56, 124.29, 123.35, 122.53, 121.07, 115.38, 114.72 (d, J = 21.0 Hz), 114.30, 114.15, 114.00, 107.96 (d, J = 15.0 Hz), 69.41, 62.13, 56.95, 55.91, 51.26, 48.62, 46.41, 40.79, 40.64, 40.06, 31.51, 24.06 ppm. HRMS (m / z) (ESI): calcd for C 45 H 49 ClFN8O 10 PtS [M+H] + : 1142.2534; found: 1142.2503.

[0099] Example 10: Preparation of Olaparib Derivative D5-1

[0100]

[0101] (i): Take 5.96 g of compound D1 and 9.12 g of HATU in a flask, add 60 mL of DMF, stir at room temperature for 10 min, and then add 3.03 g of triethylamine and 4.09 g of compound 2. Heat to 50 °C and continue stirring overnight. Monitor the reaction using TLC. After the reaction is complete, concentrate under reduced pressure, extract with dichloromethane and saturated brine, dry the dichloromethane layer with anhydrous sodium sulfate, concentrate under reduced pressure, and perform silica gel column chromatography to obtain compound D2 (7.2 g), a pale yellow solid, with a yield of 77.2%.

[0102] (ii): Take 7 g of compound D2 in a flask, add 60 mL of dichloromethane, and dropwise add 10 mL of trifluoroacetic acid under ice-bath stirring. Continue stirring for 3 h and then monitor the reaction using TLC. After the reaction is complete, evaporate to dryness, redissolve with dichloromethane, adjust the pH to alkaline with saturated sodium bicarbonate solution, extract with dichloromethane, and evaporate to dryness to obtain compound D3 (4.8 g), a pale yellow solid, with a yield of 87.4%.

[0103] (iii): Take 366 mg of compound D3 and 414 mg of potassium carbonate in a flask, add 10 mL of DMF, continue to add 334 mg of ethyl bromoacetate under stirring at room temperature, heat to 70 °C and continue stirring overnight. Monitor the reaction using TLC. After the reaction is complete, concentrate under reduced pressure, extract with dichloromethane and saturated brine 1 - 2 times, evaporate the dichloromethane layer to dryness, and perform column chromatography to obtain compound D4-1 (360 mg), a pale yellow solid, with a yield of 79.6%.

[0104] (iv): Take 300 mg of compound D4-1 in a flask, add 15 mL of methanol, then add 330 mg of hydrazine hydrate, heat to 80 °C for reflux, stir for 6 h, and monitor the reaction using TLC. After the reaction is complete, evaporate to dryness, extract with dichloromethane and saturated brine 1 - 2 times, evaporate to dryness, and perform column chromatography to obtain compound D5-1 (260 mg), a pale yellow solid, with a yield of 89.6%. 1 H NMR (600 MHz, DMSO-d6) δ 12.60 (s, 1H), 8.98 (s, 1H), 8.26 (dd, J = 7.9, 0.9 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.89 (t, J = 7.7 Hz, 1H), 7.82 (t, J = 7.5 Hz, 1H), 7.43–7.40 (m, 1H), 7.32 (dd, J = 6.4, 2.2 Hz, 1H), 7.21 (t, J = 9.0 Hz, 1H), 4.32 (s, 2H), 4.24 (s, 2H), 3.63 (s, 2H), 3.17 (s, 2H), 2.95 (s, 2H), 2.48–2.46 (m, 2H), 2.33 (s, 2H) ppm.

[0105] Example 11: Preparation of Olaparib Derivative D5-2

[0106]

[0107] The preparation method was the same as that of Example 10, a pale yellow solid, with a yield of 86.8%. 1 H NMR(600MHz,DMSO-d6)δ12.60(s,1H),8.92(s,1H),8.26(dd,J=7.9,1.0Hz,1H),7.96(d,J=8.0Hz,1H),7.88(t,J=7.6Hz,1H),7.83(t,J=7.5Hz,1H),7.43–7.40(m,1H),7.30(dd,J=6.4,2.2Hz,1H),7.21(t,J=9.0Hz,1H),4.32(s,2H),4.14(s,2H),3.59(s,2H),3.12(s,2H),2.35(s,2H),2.24–2.22(m,2H),2.20(s,2H),1.99(t,J=7.4Hz,2H),1.51–1.46(m,2H),1.41–1.36(m,2H),1.24–1.19(m,2H)ppm.

[0108] Example 12: Preparation of Compound OL-1

[0109]

[0110] The preparation method was the same as that of Example 2, a pale yellow solid, with a yield of 83.5%.

[0111] 1 H NMR(600MHz,DMSO-d6)δ12.60(s,1H),10.22(s,1H),8.26(s,1H),7.97–7.82(m,3H),7.41–7.21(m,3H),4.32–4.22(m,8H),3.66–3.57(m,4H),3.50–3.43(m,2H),3.23–3.09(m,4H),2.50–2.40(m,4H)ppm. 1313C NMR(150MHz,DMSO-d6)δ175.83,170.25,164.71,163.79,159.41,156.34(d,J=243.0Hz),150.91,144.96,134.83,133.55,131.62,129.09,128.83,127.90,126.11,125.52,123.83(d,J=18.0Hz),115.93(d,J=22.5Hz),64.96,59.24,52.68,52.25,49.02,46.62,43.50,41.38,36.42ppm.HRMS(m / z)(ESI):calcd for C 28 H 32 FN8O7Pt[M+H] + :806.1947;found:806.1908.

[0112] Example 13: Preparation of Compound OL-2

[0113]

[0114] The preparation method was the same as that in Example 2, and a pale yellow solid was obtained with a yield of 79.2%.

[0115] 1 1H NMR(600MHz,DMSO-d6)δ12.60(s,1H),10.25(s,1H),8.26(d,J=7.3Hz,1H),7.97–7.80(m,3H),7.41–7.16(m,3H),4.32–4.22(m,6H),3.72(s,2H),3.64–3.48(m,4H),3.16–3.03(m,4H),2.36–2.10(m,8H),1.56–1.48(m,2H),1.41–1.35(m,2H),1.26–1.18(m,2H)ppm. 1313C NMR (150 MHz, DMSO-d6) δ 175.98, 175.79, 168.38, 163.71, 159.44, 156.36 (d, J = 243.0 Hz), 153.77, 144.98, 134.85, 133.57, 131.63, 129.10, 128.76, 127.92, 126.12, 125.54, 123.89 (d, J = 16.5 Hz), 115.94 (d, J = 21.0 Hz), 57.57, 55.97, 52.89, 52.41, 46.62, 46.52, 41.39, 36.43, 33.61, 26.72, 26.62, 25.97, 25.15 ppm. HRMS (m / z) (ESI): calcd for C 32 H 40 FN8O7Pt [M+H] + : 862.2573; found: 862.2536.

[0116] Example 14: Preparation of Compound OL-3

[0117]

[0118] The preparation method was the same as that in Example 3, a pale yellow solid, with a yield of 78.8%.

[0119] 1 1H NMR (600 MHz, DMSO-d6) δ 12.60 (s, 1H), 10.37–10.20 (m, 1H), 8.25 (d, J = 7.8 Hz, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.90–7.87 (m, 1H), 7.83–7.81 (m, 1H), 7.42–7.40 (m, 1H), 7.33–7.30 (m, 1H), 7.23–7.20 (m, 1H), 6.12–5.98 (m, 2H), 5.38–5.26 (m, 2H), 4.32 (s, 2H), 3.75–3.69 (m, 1H), 3.66–3.59 (m, 3H), 3.51 (d, J = 4.6 Hz, 1H), 3.41 (d, J = 5.1 Hz, 1H), 3.18–3.15 (m, 2H), 3.12–3.08 (m, 2H), 2.59–2.50 (m, 2H), 2.45–2.35 (m, 2H), 2.06 (s, 2H), 1.85 (s, 2H), 1.44 (s, 2H), 1.22 (s, 2H), 1.00 (s, 2H) ppm. 1313C NMR (150 MHz, DMSO-d6) δ 175.65, 175.56, 170.26, 164.61, 163.76, 159.39, 156.32 (d, J=243.0 Hz), 144.92, 134.81, 133.51, 131.58, 129.07, 128.80, 127.89, 126.08, 125.48, 123.82 (d, J=18.0 Hz), 115.89 (d, J=21.0 Hz), 62.12, 59.30, 56.94, 55.89, 52.66, 52.24, 48.93, 46.62, 43.46, 41.40, 36.41, 31.53, 24.05 ppm. HRMS (m / z) (ESI): calcd for C 34 H 40 FN8O7Pt [M+H] + : 886.2573; found: 886.2529.

[0120] Example 15: Preparation of Compound OL-4

[0121]

[0122] The preparation method was the same as that in Example 3, a pale yellow solid, with a yield of 77.5%.

[0123] 1 1H NMR (600 MHz, DMSO-d6) δ 12.59 (s, 1H), 10.24–10.15 (m, 1H), 8.26 (d, J=7.5 Hz, 1H), 7.96 (d, J=7.6 Hz, 1H), 7.88 (t, J=7.1 Hz, 1H), 7.82 (t, J=7.0 Hz, 1H), 7.41 (s, 1H), 7.30 (s, 1H), 7.21 (t, J=8.5 Hz, 1H), 6.04–5.98 (m, 2H), 5.34–5.26 (m, 2H), 4.32 (s, 2H), 3.75–3.67 (m, 2H), 3.63–3.59 (m, 2H), 3.45–3.43 (m, 1H), 3.32–3.29 (m, 1H), 3.17–3.12 (m, 2H), 2.50–2.44 (m, 2H), 2.36–2.32 (m, 2H), 2.25–2.16 (m, 4H), 2.06 (s, 2H), 1.85–1.80 (m, 2H), 1.52–1.40 (m, 6H), 1.32–1.24 (m, 4H), 1.07–1.00 (m, 2H) ppm. 1313C NMR(150MHz,DMSO-d6)δ175.71,175.53,168.24,163.66,159.37,156.31(d,J=243.0Hz),153.93,150.12,144.89,134.80,133.49,131.56,129.06,128.71,127.89,126.06,125.47,123.86(d,J=19.0Hz),115.88(d,J=21.0Hz),62.10,57.52,55.88,52.85,52.35,48.84,46.57,43.64,41.34,36.38,33.59,31.48,26.69,26.57,25.92,25.10,24.03ppm.HRMS(m / z)(ESI):calcd for C 38 H 48 FN8O7Pt[M+H] + :942.3199;found:942.3158.

[0124] Example 16: Preparation of (+)-JQ1 derivative E2

[0125]

[0126] (i): Dissolve 0.68 g of (+)-JQ1 in 30 mL of methanol. Slowly add 0.6 g of hydrazine hydrate dropwise with stirring, and reflux the reaction for 48 h, monitored by TLC. After the reaction is completed, cool to room temperature, rotary evaporate the solvent, add 20 mL of water and stir for 30 min. Filter, wash the filter cake with water (10 mL×3), and dry in vacuo to obtain compound E2 (0.47 g), a white solid, with a yield of 94%. 1 1H NMR(600MHz,DMSO-d6)δ9.33(s,1H),7.49(d,J=8.8Hz,2H),7.44(d,J=8.5Hz,2H),4.52(dd,J=8.4,5.8Hz,1H),4.26(dd,J=13.5,6.7Hz,2H),3.22(dd,J=14.9,8.4Hz,1H),3.14(dd,J=14.9,5.7Hz,1H),2.59(s,3H),2.40(s,3H),1.61(s,3H)ppm.

[0127] Example 17: Preparation of compound JD-1

[0128]

[0129] The preparation method is the same as that of Example 2, a pale yellow solid, with a yield of 89.0%.

[0130] 1 1H NMR (600 MHz, DMSO-d6) δ 10.68 (s, 1H), 7.55 - 7.39 (m, 4H), 4.69 (s, 6H), 4.20 (dd, J = 5.6, 3.9 Hz, 1H), 3.72 - 3.60 (m, 2H), 3.23 - 3.14 (m, 2H), 2.94 (s, 2H), 2.41 (s, 3H), 2.31 (s, 3H), 1.83 (s, 3H) ppm. 13 13C NMR (150 MHz, DMSO-d6) δ 177.03, 176.84, 176.43, 173.35, 155.57, 150.30, 150.20, 137.14, 135.75, 132.75, 131.07, 130.64, 130.33, 128.95, 100.00, 57.38, 54.31, 54.23, 42.98, 22.67, 14.52, 13.16, 11.75 ppm. HRMS (m / z) (ESI): calcd for C 25 H 27 ClN8O5PtS [M + H] + : 782.1161; found: 782.1125.

[0131] Example 18: Test for the inhibitory activity of platinum (II) compounds against related kinases

[0132] According to the kit instructions, blank wells (no samples and enzyme-labeled reagents are added to the blank control wells), standard wells, and wells for samples to be tested are set up respectively. Accurately add 50 μL of the standard product to the standard wells on the enzyme-labeled coated plate. First, add 40 μL of the sample dilution solution to the wells for samples to be tested, and then add 10 μL of the sample to be tested (the final dilution factor of the sample is 5 times). Add the sample to the bottom of the enzyme-labeled plate wells, try not to touch the well walls, and gently shake to mix evenly. Seal the plate with a sealing film and incubate at 37 °C for 30 min. Dilute the 30-fold concentrated washing solution 30-fold with distilled water for later use. Carefully remove the sealing film, discard the liquid, shake dry, fill each well with the washing solution, let it stand for 30 seconds and then discard, repeat this 5 times, and pat dry. Add 50 μL of the enzyme-labeled reagent to each well, except for the blank wells. Incubate and wash again. First, add 50 μL of chromogenic reagent A to each well, then add 50 μL of chromogenic reagent B, gently shake to mix evenly, and develop color at 37 °C in the dark for 10 min. Add 50 μL of the stop solution to each well to terminate the reaction. Zero with the blank well, and measure the absorbance (OD value) of each well in sequence at a wavelength of 450 nm. Calculate the cell growth inhibition rate, and combine with SPSS (Statistical Product and Service Solutions) software to calculate the IC 50The value, and the test result is the average value of the three test values. The results are shown in Table 1.

[0133] Table 1. Inhibitory activities of compounds against related kinases

[0134]

[0135] α The experimental results are all the average values of the three experimental values.

[0136] To evaluate whether the anti-tumor platinum(II) compounds of the present invention have the ability to target specific targets, their inhibitory activities against related kinases were determined. In the experiment, the inhibitory activities of compounds GE-1, GE-2, OS-1, and OS-2 against EGFR WT (EGFR wild kinase) and EGFR T790M (EGFR mutant kinase) IC 50 values, the IC 50 values of compounds LA-1 and LA-2 against HER2, the IC 50 values of compounds OL-1, OL-2, OL-3, and OL-4 against PARP, and the IC 50 value of compound JD-1 against BRD4 were measured. The positive controls were gefitinib, osimertinib, lapatinib, olaparib, and (+)-JQ1, respectively. The specific data results are shown in Table 1.

[0137] As shown in Table 1, compounds GE-1 and GE-2 with the gefitinib pharmacophore as the parent can significantly inhibit the activity of wild EGFR WT . Although their inhibitory ability is slightly weaker than that of gefitinib, their inhibitory ability against mutant EGFR T790M is slightly stronger than that of gefitinib, retaining the targeting characteristics of gefitinib. Compounds OS-1 and OS-2 with the osimertinib pharmacophore as the parent have significantly lower inhibitory effects on EGFR WT than their activity against EGFR T790M , which is similar to the inhibitory difference of osimertinib against these two kinases. Importantly, OS-1 and OS-2 also have a significant inhibitory effect on EGFR T790M , indicating that OS-1 and OS-2 have good selectivity for mutant EGFR T790M ; considering that their IC 50 values are not much different from those of osimertinib and are in the same order of magnitude, it shows that these two compounds retain the targeting characteristics of osimertinib.

[0138] As shown in Table 1, compounds LA-1 and LA-2 with the pharmacophore of lapatinib as the parent can effectively inhibit HER2. Their inhibitory activities are slightly lower than that of lapatinib, but they also retain the targeting characteristics of lapatinib for HER2. In the experiment of PARP inhibition, it was found that compounds OL-1, OL-2, OL-3, and OL-4 with the pharmacophore of olaparib as the parent all showed a certain degree of PARP inhibitory activity. Among them, the compound combined with DN604 was higher than the compound combined with DN603, and the IC 50 was between 0.058 - 0.105 μM. Although their inhibitory ability was slightly lower than that of olaparib, they also retained the targeting characteristics of olaparib for PARP. Moreover, JD-1 also retained the targeting characteristics of the BET inhibitor (+)-JQ1 for BRD4, and its IC 50 value was almost equivalent to that of (+)-JQ1.

[0139] In summary, the platinum(II) compounds of the present invention can all effectively inhibit the activities of related kinases, retain the targeting characteristics of the parent compounds of the targeting drugs, and can target cancer cells with overexpression of related kinases, thus endowing them with targeting ability.

[0140] Example 19: Cytotoxic Activity Test of Platinum(II) Compounds

[0141] Experimental method: The MTT method was used to evaluate the in vitro cytotoxicity of the synthesized target compounds. Cells in the logarithmic phase with good state were digested with trypsin and then inoculated into 96-well plates, with about 1×10 4 cells in each well. After adding the culture medium, they were placed in a constant temperature incubator overnight. After the cells adhered to the wall, drug administration tests were carried out. Prepared platinum(II) compound solutions and cisplatin solutions with different concentrations were respectively added to the 96-well plates. Three replicates were set for each concentration, and the same volume of the prepared solution was added to the blank group. After adding, they were placed in the incubator and incubated for another 72 h. After the incubation ended, 10 μL of MTT solution with a concentration of 5 mg / mL was added respectively, and after incubating in the incubator for another 4 h, the supernatant was removed, and 150 μL of dimethyl sulfoxide was added and shaken well to fully dissolve the formazan. Finally, the absorbance value (OD value) of each well under the condition of 490 nm was measured using an enzyme-linked immunosorbent assay (ELISA) reader, the cell growth inhibition rate was calculated, and combined with SPSS software, the IC 50 value was calculated. The test results were the average values of three trials. The results are shown in Tables 2 - 4.

[0142] Table 2. Cytotoxic Activities of Compounds GE-1, GE-2, OS-1, and OS-2

[0143]

[0144]

[0145] α The experimental results are all the average values of the three experimental values.

[0146] Table 3. Cytotoxic activities of compounds LA-1, LA-2, OL-1, OL-2, OL-3 and OL-4

[0147]

[0148] α The experimental results are all the average values of the three experimental values.

[0149] Table 4. Cytotoxic activity of compound JD-1

[0150]

[0151] α The experimental results are all the average values of the three experimental values

[0152] Gefitinib and osimertinib belong to the first-generation and third-generation EGFR inhibitors respectively, and are mainly used clinically to treat patients with non-small cell lung cancer with EGFR activating mutations. However, the mutation of cancer cells T790M will cause gefitinib resistance. Although osimertinib can overcome gefitinib resistance and has a strong inhibitory effect on non-small cell lung cancer with T790M mutation, long-term drug use will cause C797S mutation, resulting in osimertinib resistance. In the present invention, the MTT method was used to test the inhibitory activities of compounds GE-1, GE-2, OS-1 and OS-2 against human epidermoid carcinoma (A431), human non-small cell lung cancer A549 and T790M mutant H1975 and EGFR triple mutant BaF3 (Del19 / T790M / C797S) cancer cells, and gefitinib, osimertinib, cisplatin and DN604 were used as positive controls. As shown in Table 2, all compounds showed stronger inhibitory activities against double mutant H1975 cells and triple mutant BaF3 (Del19 / T790M / C797S) cells than gefitinib. In particular, the cell activity of OS-2 against H1975 was almost equivalent to that of osimertinib. Importantly, the inhibitory activities of these platinum(II) compounds against BaF3 (Del19 / T790M / C797S) were all stronger than that of osimertinib, and the activity of OS-2 (IC 50(0.26 μM) is 5.9 times that of osimertinib, indicating that the strategy of combining derivatives of EGFR inhibitors with active platinum(II) compounds has the ability to overcome EGFR mutant drug resistance. In addition, the activities of these platinum(II) compounds against wild-type EGFR A549 and A431 cells are lower than that of osimertinib, meaning that the compounds have a lower off-target risk. Moreover, the activities of GE-1, GE-2, OS-1, and OS-2 against normal human umbilical vein endothelial cells HUVEC are lower than those of positive controls including cisplatin. The experimental results show that the platinum(II) compounds containing gefitinib or osimertinib pharmacophores of the present invention can not only improve the inhibitory activity against EGFR mutant cancer cells, but also reduce the toxicity of platinum drugs to normal cells, indicating that they are specific and can inhibit cancer cells with high efficiency and low toxicity.

[0153] Given that HER2 inhibitor lapatinib and PARP inhibitor olaparib are mainly used in the clinic for the treatment of breast cancer and ovarian cancer, the present invention tested the inhibitory activities of the platinum(II) compounds LA-1, LA-2, OL-1, OL-2, OL-3, and OL-4 of the present invention against human breast cancer (MCF-7, MDA-MB-231, and BT474) and ovarian cancer (A2780 and SKOV3) cells, with lapatinib, olaparib, and cisplatin as positive controls. As shown in Table 3, the in vitro anti-tumor activities of these compounds against the selected breast cancer and ovarian cancer cell lines are weaker than those of the positive controls, and the activities are 1 / 3 to 1 / 7 of the positive drugs, but the toxicities to normal liver cancer cells LO2 are lower than those of the positive controls.

[0154] JQ-1 is the first BET-targeted inhibitor, which can inhibit the function of the BET family by specifically inhibiting the binding of BRD4 to the bromodomain. The present invention tested the inhibitory activities of the platinum(II) compound JD-1 of the present invention against human non-small cell lung cancer A549 and its cisplatin-resistant cell line A549 / CDDP, human ovarian cancer A2780 and its cisplatin-resistant cell line A2780 / CDDP, human leukemia cell lines MV4-11 and RS4;11. As shown in Table 4, the activities of JD-1 against A549 and A2780 and their cisplatin-resistant strains are lower than those of the positive controls JQ-1 and cisplatin, but higher than those of DN604. In the tests against leukemia cells, it was found that the inhibitory activities of JD-1 against MV4-11 and RS4;11 cells (IC 50 0.99 and 1.48 μM) are stronger than those of cisplatin and DN604, and even comparable to those of (+)-JQ1, indicating that JD-1 has great potential in the treatment of leukemia.

[0155] Example 20: Hydrolysis of OS-2 and JD-1

[0156] Experimental method: Weigh a certain amount of compounds OS-2 and JD-1, dissolve them in a little DMSO, add PBS solution with pH 5.0 or 7.4, dilute to a concentration of 5.0 μM, and after filtering through an organic filter head, use HPLC for injection detection at 1, 4, 12, and 24 h respectively. The mobile phase is acetonitrile and water (acetonitrile: water = 20:80 - 100:0), the flow rate is 1.0 mL / min, and the detection wavelength is 254 nm. The results are shown in Figures 1-4 .

[0157] Due to the presence of C=N double bonds in the structure of the platinum(II) compounds of the present invention, they can dissociate under acidic conditions. The inventors selected representative platinum(II) compounds OS-2 and JD-1 and investigated their hydrolysis behavior by HPLC under neutral (pH = 7.4) and weakly acidic (pH = 5.0) conditions respectively. As Figure 1 and 3 shown, the peaks of OS-2 and JD-1 did not change within 24 h in the neutral medium. However, in the weakly acidic medium, as Figure 2 and 4 shown, with the increase of time, the peaks of OS-2 and JD-1 gradually decreased, indicating that hydrolysis occurred, and the released products were derivatives B7 and E2 respectively. Although the hydrolysis of the compounds would release DN604 or DN603 simultaneously, due to their weak ultraviolet absorption, they were not observed in HPLC. The above results indicate that the platinum(II) compounds of the present invention have high stability under neutral conditions but can dissociate in an acidic environment. Because the tumor microenvironment is acidic, these platinum(II) compounds containing C=N double bonds can selectively release anti-tumor active groups slowly around the tumor to play an anti-tumor role, thereby reducing tissue toxicity.

[0158] In summary, the anti-tumor platinum(II) compounds containing targeted drug pharmacophores of the present invention not only have the ability to actively target related protein kinases, but also have the property of passive targeting tumor tissues in the acidic tumor microenvironment. The in vitro experimental results show that they not only have an effective inhibitory effect on related protein kinases, showing good in vitro anti-tumor activity, but also the inhibitory activities on related protein kinases and cancer cells are comparable to the corresponding targeted drug parent compounds, with the characteristics of high efficiency and low toxicity.

Claims

1. A platinum(II) compound with a targeting effect, characterized in that, It has the following structure: wherein, TD is any one of the following structures: n is 1 or 5.

2. The platinum (II) compound with a targeting effect according to claim 1, characterized in that, The platinum(II) compound is any one of the following compounds:

3. A method for preparing a platinum(II) compound with a targeting effect according to any one of claims 1 to 2, characterized in that, The preparation method is as follows: Compound A6, B7, C3, D5 or E2 respectively undergoes a condensation reaction with compound DN603 or DN604 to obtain the platinum(II) compound with a targeting effect; wherein, the structures of compounds DN603, DN604, A6, B7, C3, D5 or E2 are respectively as follows:

4. The preparation method according to claim 3, characterized in that, The preparation method of the said compound A6, B7, C3, D5 or E2 is as follows: (1) Compound A6 Compound A1 and A2 undergo a substitution reaction to obtain compound A3, then A3 is deprotected from Boc to obtain compound A4, A4 undergoes a substitution reaction to obtain compound A5, and finally A5 undergoes a hydrazide transesterification reaction to obtain compound A6; (2) Compound B7 Compound B1 and B2 undergo a substitution reaction to obtain compound B3, then B3 undergoes a substitution reaction to obtain compound B4, B4 is deprotected from Boc to obtain compound B5, B5 undergoes a substitution reaction to obtain compound B6, and finally B6 undergoes a hydrazide transesterification reaction to obtain compound B7; (3) Compound C3 Compound C1 undergoes an acylation reaction to obtain compound C2, then C2 undergoes a hydrazinolysis reaction and Boc deprotection to obtain compound C3; (4) Compound D5 Compound D1 undergoes a condensation reaction to obtain compound D2, then D2 is deprotected from Boc to obtain compound D3, D3 undergoes a substitution reaction to obtain compound D4, and finally D4 undergoes a hydrazide transesterification reaction to obtain compound D5; (5) Compound E2 Compound E1 undergoes a hydrazide transesterification reaction to obtain compound E2.

5. A pharmaceutical composition, characterized in that, It contains the platinum(II) compound with a targeting effect as described in any one of claims 1 to 2 and a pharmaceutically acceptable carrier.

6. The pharmaceutical composition according to claim 5, wherein Its pharmaceutical preparation is tablets, capsules, syrups, suspensions or injections.

7. Use of the platinum(II) compound with a targeting effect as described in any one of claims 1 to 2 in the preparation of an anti-tumor drug, wherein the tumor is non-small cell lung cancer, breast cancer, ovarian cancer or leukemia.

8. Use of the platinum(II) compound with a targeting effect as described in any one of claims 1 to 2 in the preparation of an anti-tumor drug, wherein the tumor is a related cancer resistant to gefitinib, osimertinib, lapatinib, olaparib or cisplatin.

9. Use of the pharmaceutical composition as described in claim 5 in the preparation of an anti-tumor drug, wherein the tumor is non-small cell lung cancer, breast cancer, ovarian cancer or leukemia.

10. Use of the pharmaceutical composition as described in claim 5 in the preparation of an anti-tumor drug, wherein the tumor is a related cancer resistant to gefitinib, osimertinib, lapatinib, olaparib or cisplatin.

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