A cyclic small molecule compound and a preparation method and application thereof

Abstract

The present application relates to the field of pharmacy, and specifically provides a cyclic small molecule compound, a preparation method and application thereof, wherein the structure of the compound is shown in formula (I): in formula (I), R 1 is selected from a hydrogen atom and a chlorine atom, the opposite positions of the amide bond and the oxymethyl connected with the A ring are ortho and meta, and n is selected from 1, 2 and 3. The cyclic small molecule compound is novel in structure, can selectively act on PD-1 / PD-L1, and shows good PD-1 / PD-L1 protein inhibition activity. The compound has high bioavailability, drug stability and low toxicity, and can be orally administered. In addition, the compound is convenient to prepare and low in production cost, and can be widely applied to preparation of a PD-L1 inhibitor and a drug for treating and / or preventing cancer.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmacy, and particularly relates to a compound, a preparation method and application thereof. BACKGROUND

[0002] In the past few decades, cancer has become the second leading cause of human death and a major obstacle to the extension of human life. Immune checkpoint blockade therapy (ICBT) is an effective strategy that has completely changed the treatment of various cancers in recent years. A large number of proteins have been found as potential targets and are being studied for ICBT. Among them, programmed cell death protein 1 (PD-1) / programmed cell death ligand 1 (PD-L1) is one of the most promising immune checkpoints in tumor immunology. PD-1 is expressed on the surface of various immune cells such as T lymphocytes and natural killer T cells. It regulates the function of effector T cells in various physiological processes such as cancer and autoimmunity, immune homeostasis. The binding between PD-1 and PD-L1 leads to the down-regulation of T cell effector function and T cell exhaustion, thereby promoting tumor cells to escape immune surveillance.

[0003] PD-1 / PD-L1 inhibitors can block the interaction between PD-1 and PD-L1, restore the function of T cells, and thus restore the immune response against cancer. Many anti-PD-1 / PD-L1 monoclonal antibodies (mAbs) have been approved by the US FDA, including Nivolumab (anti-PD-1), Pembrolizumab (anti-PD-1), Avelumab (anti-PD-L1), Duvalumab (anti-PD-L1) and Atezolizumab (anti-PD-L1). These monoclonal antibodies show effective anti-tumor activity in various types of tumors, but there are still limitations such as immune-related adverse reactions, long circulating half-life and lack of oral bioavailability. Therefore, the development of small molecule-based PD-1 / PD-L1 inhibitors can overcome the limitations of antibody-based therapy, or be combined with antibodies to achieve synergistic anti-tumor effect. SUMMARY

[0004] In order to overcome the problems existing in the prior art, one of the purposes of the present application is to provide a cyclic small molecule compound which can be used as a PD-1 / PD-L1 inhibitor; the second purpose of the present application is to provide a preparation method of the compound; the third purpose of the present application is to provide a pharmaceutical composition; and the fourth purpose of the present application is to provide the application of the compound.

[0005] In order to achieve the above-mentioned purposes, the technical scheme adopted by the present application is as follows:

[0006] The first aspect of the present application provides a compound, the structure of the compound is shown in formula (I);

[0007]

[0008] In formula (I), R 1 selected from hydrogen atom and chlorine atom, the amide bond and the oxygen methyl group connected with the A ring are in ortho and meta position, and n=1, 2, 3.

[0009] Preferably, R 1 selected from hydrogen atom and chlorine atom, the amide bond and the oxygen methyl group connected with the A ring are in ortho and meta position, and n=1, 2, 3.

[0010] Preferably, the compound comprises the structure shown in the following;

[0011]

[0012] Preferably, the compound is a PD-L1 inhibitor.

[0013] The second aspect of the present application provides a preparation method of the compound according to the first aspect of the present application, comprising the following steps:

[0014] 1) using 3-hydroxymethyl-2-methyl biphenyl as raw material, phosphorus tribromide is used for bromination to obtain a compound shown in formula (II), and the compound shown in formula (II) is mixed with a compound shown in formula (III) to obtain a compound shown in formula (IV);

[0015]

[0016] In formula (III), R 1 selected from hydrogen atom and chlorine atom;

[0017] 2) the compound shown in formula (IV) is mixed with a compound shown in formula (V) to obtain a compound shown in formula (VI);

[0018]

[0019] In formula (V), the two groups of substituents of the A ring are in ortho and meta position;

[0020] 3) the compound shown in formula (VI) is subjected to alkaline hydrolysis to obtain a compound shown in formula (VII);

[0021]

[0022] 4) the compound shown in formula (VII) is mixed with a compound shown in formula (VIII) to obtain a compound shown in formula (IX);

[0023]

[0024] In formula (VIII), n=1, 2, 3;

[0025] 5) deprotecting the compound shown as formula (IX) to obtain the compound shown as formula (X);

[0026]

[0027] 6) catalyzing the compound shown as formula (X) by sodium cyanoborohydride to obtain the compound.

[0028] The third aspect of the present application provides a pharmaceutical composition comprising the compound of the first aspect of the present application or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof.

[0029] The fourth aspect of the present application provides use of the compound of the first aspect of the present application or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof in the preparation of a medicament for treating and / or preventing and / or delaying and / or assisting in the treatment of cancer.

[0030] Preferably, the cancer comprises melanoma.

[0031] Preferably, the medicament for treating cancer comprises a PD-L1 inhibitor.

[0032] The beneficial effects of the present application are:

[0033] The compound disclosed in the present application is novel in structure, can selectively act on PD-1 / PD-L1, and exhibits good PD-1 / PD-L1 protein inhibitory activity; the compound has high bioavailability, stable drug, low toxicity, and can be orally administered; in addition, the compound is easy to prepare and has low production cost, and the compound can be widely used in the preparation of a PD-L1 inhibitor and a medicament for treating and / or preventing cancer. BRIEF DESCRIPTION OF DRAWINGS

[0034] Figure 1 The nuclear magnetic resonance hydrogen spectrum of the compound MP1 prepared in Example 1 is shown in Table 1.

[0035] Figure 2 The nuclear magnetic resonance carbon spectrum of the compound MP1 prepared in Example 1 is shown in Table 2.

[0036] Figure 3 The nuclear magnetic resonance hydrogen spectrum of the compound MP2 prepared in Example 2 is shown in Table 3.

[0037] Figure 4 The nuclear magnetic resonance carbon spectrum of the compound MP2 prepared in Example 2 is shown in Table 4.

[0038] Figure 5 The nuclear magnetic resonance hydrogen spectrum of the compound MP3 prepared in Example 3 is shown in Table 5.

[0039] Figure 6The nuclear magnetic resonance hydrogen spectrum of compound MP4 was prepared for Example 4.

[0040] Figure 7 The nuclear magnetic resonance hydrogen spectrum of compound MP4 was prepared for Example 4.

[0041] Figure 8 The nuclear magnetic resonance hydrogen spectrum of compound MP4 was prepared for Example 4.

[0042] Figure 9 The nuclear magnetic resonance hydrogen spectrum of compound MP5 was prepared for Example 5.

[0043] Figure 10 The nuclear magnetic resonance hydrogen spectrum of compound MP5 was prepared for Example 5.

[0044] Figure 11 The nuclear magnetic resonance hydrogen spectrum of compound MP6 was prepared for Example 6.

[0045] Figure 12 The nuclear magnetic resonance hydrogen spectrum of compound MP6 was prepared for Example 6.

[0046] Figure 13 The cell survival rate of Example 2 (MP2) in different concentrations of HepG2 cell model and HepG2 / Jurkat T cell co-culture model.

[0047] Figure 14 The incubation time of Example 2 (MP2) in plasma and the corresponding compound residual amount.

[0048] Figure 15 The inhibitory effect of Example 2 (MP2) on the growth of melanoma subcutaneous tumor in C57BL / 6 mice. DETAILED DESCRIPTION

[0049] The following examples are provided to further illustrate the present application, but the practice and protection of the present application are not limited thereto. It should be noted that the following examples are not particularly detailed description of the process, which is understood by those skilled in the art can be achieved or reference to prior art. The reagents or instruments used are not specified manufacturer, is considered to be available through the purchase of conventional products.

[0050] The preparation reaction route of the compound of the present example is as follows,

[0051]

[0052] According to the above reaction route, the preparation of the compound comprises the following steps;

[0053] 1) 2-methyl-3-phenylbenzene methanol (A) was dissolved in dichloromethane, 2 moles of boron tribromide were added according to the molar amount of 2-methyl-3-phenylbenzene methanol, and the reaction was carried out at room temperature for 6 hours. After the reaction was completed by monitoring with a thin layer chromatography plate, ice water was added to the reaction solution, and the pH of the reaction solution was adjusted to 8 with potassium carbonate solid. The reaction solution was extracted with dichloromethane, and the organic phase was dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain intermediate 3-(bromomethyl)-2-methyl-1,1'-biphenyl (B). The specific reaction formula is as follows:

[0054]

[0055] 2) 3-(bromomethyl)-2-methyl-1,1'-biphenyl (B) obtained in step 1) was dissolved in DMF, 0.9 moles of 2,4-dihydroxybenzaldehyde compound were added according to the molar amount of 3-(bromomethyl)-2-methyl-1,1'-biphenyl, and 2 moles of sodium bicarbonate were added according to the molar amount of 3-(bromomethyl)-2-methyl-1,1'-biphenyl (B). The reaction was carried out at 60°C for 3 hours. After the reaction was completed by monitoring with a thin layer chromatography plate, the reaction solution was extracted with ethyl acetate, and the organic phase was dried with saturated brine and anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and intermediate D was obtained by column chromatography separation and purification. The specific reaction formula is as follows:

[0056]

[0057] 3) Intermediate D obtained in step 2) was added with an appropriate amount of DMF as a solvent, 1.2 moles of bromomethylbenzoic acid methyl ester compound (E) were added according to the molar amount of intermediate D, and 2 moles of potassium carbonate were added according to the molar amount of intermediate D. The reaction was carried out at 70°C for 7 hours. After the reaction was completed by monitoring with a thin layer chromatography plate, the reaction solution was extracted with ethyl acetate, and the organic phase was dried with saturated brine and anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and intermediate F was obtained by column chromatography separation and purification. The specific reaction formula is as follows:

[0058]

[0059] 4) Intermediate F obtained in step 3) was added with an appropriate amount of ethanol / dichloromethane (V / V = 4 / 1) as a solvent, and 10 moles of potassium hydroxide were added according to the molar amount of intermediate F. The reaction was carried out at 55°C for 4 hours. After the raw material was completely reacted by TLC detection, the solvent was removed by distillation under reduced pressure, and the yellow solid obtained was dispersed with an appropriate amount of water, and the pH was adjusted to 5 with dilute hydrochloric acid. Filtration, and the filter residue was dried to obtain yellow solid product G. The specific reaction formula is as follows:

[0060]

[0061] 5) Take the intermediate G obtained in step 4), add an appropriate amount of anhydrous DMF, then add 2 molar times of HATU and 4 molar times of DIPEA according to the molar amount of intermediate G, react at room temperature for about 30 minutes, then add 2 molar times of a single boc diamine compound (H) into the reaction system, react at room temperature for about 24 h, after the raw material is detected to be completely reacted by TLC, extract the reaction solution with ethyl acetate, dry the organic phase with saturated brine and anhydrous sodium sulfate, remove the solvent under reduced pressure, purify by column chromatography to obtain intermediate I. The specific reaction formula is as follows:

[0062]

[0063] 6) Take the intermediate I obtained in step 5), add an appropriate amount of DCM / TFA (V / V=5:1), react at room temperature for about 1 h, after the raw material is detected to be completely reacted by TLC, add an appropriate amount of saturated sodium bicarbonate aqueous solution into the reaction system for quenching, extract the reaction solution with DCM, dry the organic phase with saturated brine and anhydrous sodium sulfate, remove the solvent under reduced pressure to obtain intermediate J. The specific reaction formula is as follows:

[0064]

[0065] 7) Take the intermediate J obtained in step 6), add an appropriate amount of DCM / MeOH (V / V=1:1) solution as solvent, stir at room temperature for 30 minutes, then add NaBH3CN and 4 drops of glacial acetic acid into the reaction system, react at room temperature for about 24 h, after the raw material is detected to be completely reacted by TLC, remove the solvent under reduced pressure to obtain a white solid, extract the white solid with an appropriate amount of dichloromethane and water, dry the organic phase with saturated brine and anhydrous sodium sulfate, remove the solvent under reduced pressure, and purify by column chromatography to obtain white solid product K. The specific reaction formula is as follows:

[0066]

[0067] Example 1

[0068] The specific preparation steps of the compound of this example are as follows:

[0069] 1) Synthesis of intermediate 3-(bromomethyl)-2-methyl-1,1'-biphenyl: 1.0 g of 2-methyl-3-phenylbenzene methanol (A) (5.04 mmol) was dissolved in 20 mL of DCM, 971 μL of boron tribromide (10.08 mmol) was added dropwise in an ice bath, and the reaction was allowed to proceed at room temperature for 6 hours. After TLC monitoring showed that the reaction was complete, ice water was added to quench the reaction, and K2CO3 solid was added to adjust the pH to 8. The mixture was extracted with DCM (50 mL x 3), and the organic phase was separated and washed with saturated brine (5 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1.2 g of a white solid, with a yield of 91.1%. The white solid was identified by NMR, and the results showed that the white solid was 3-(bromomethyl)-2-methyl-1,1'-biphenyl (B), and its structural formula was as follows:

[0070]

[0071] 2) Synthesis of intermediate 2-hydroxy-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzaldehyde: 1.040 g of 3-(bromomethyl)-2-methyl-1,1'-biphenyl (B) (3.98 mmol) was taken in a reaction flask, and 0.500 g of 2,4-dihydroxybenzaldehyde (C) (3.62 mmol), 0.609 g of sodium bicarbonate (7.24 mmol), and 5 mL of DMF solution were added in sequence. The reaction was allowed to proceed at 60°C for 3 hours. After TLC monitoring showed that the reaction was complete, the reaction mixture was extracted with ethyl acetate (30 mL x 3), and the organic phase was separated and washed with water (50 mL x 3), saturated brine (50 mL x 2), and anhydrous sodium sulfate in sequence, and then filtered and concentrated under reduced pressure to obtain a solid. The solid was subjected to column chromatography using petroleum ether: ethyl acetate to obtain 0.437 g of a white solid, with a yield of 37.9%. The white solid obtained by column chromatography was identified by NMR, and the results showed that the white solid was 2-hydroxy-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzaldehyde (D), and its structural formula was as follows:

[0072]

[0073] 3) Synthesis of intermediate methyl 3-((2-formyl-5-((2-methyl-[l,l'-biphenyl]-3- yl)methoxy)phenoxy)methyl)benzoate: Take 0.160 g of 2-hydroxy-4-((2-methyl-[l,l'- biphenyl]-3-yl)methoxy)benzaldehyde (D) (0.503 mmol) and add 0.138 g of methyl 3- (bromomethyl)benzoate (E) (0.603 mmol), 0.139 g of potassium carbonate (1.006 mmol) and 5 mL of DMF solution, react at 70 degrees for 7 hours, monitor the reaction completion by TLC plate, then extract the reaction liquid with ethyl acetate (30 mL x 3), stand and separate, wash the organic phase with water (50 mL x 3) and saturated brine (50 mL x 2) in turn, then dry over anhydrous sodium sulfate, remove ethyl acetate under reduced pressure to obtain a solid, and perform column chromatography on the solid with petroleum ether: ethyl acetate to obtain 0.200 g of white solid, with a yield of 85.3%. Identify the white solid obtained by column chromatography by nuclear magnetic resonance method, and the results show that the white solid is methyl 3-((2-formyl-5-((2-methyl-[l,l'-biphenyl]-3-yl)methoxy)phenoxy)methyl)benzoate (F), and its structural formula is:

[0074]

[0075] 4) Synthesis of intermediate 3-((2-formyl-5-((2-methyl-[l,l'-biphenyl]-3-yl)methoxy)phenoxy)methyl)benzoic acid: Take 0.200 g of methyl 3-((2-formyl-5-((2-methyl-[l,l'-biphenyl]-3-yl)methoxy)phenoxy)methyl)benzoate (F) (0.399 mmol) and add 0.223 g of potassium hydroxide (3.992 mmol) and 5 mL of anhydrous ethanol / dichloromethane (V / V = 4: 1) solution, react at 55 degrees for 4 hours, monitor the reaction completion by TLC plate, then remove the solvent by distillation under reduced pressure, disperse the obtained yellow solid with an appropriate amount of water, adjust the pH to 5 with dilute hydrochloric acid, filter, and dry the filter residue to obtain 0.160 g of yellow solid product, with a yield of 82.3%. Identify the yellow solid obtained by filtration and drying by nuclear magnetic resonance method, and the results show that the yellow solid is 3-((2-formyl-5-((2-methyl-[l,l'-biphenyl]-3-yl)methoxy)phenoxy)methyl)benzoic acid (G), and its structural formula is:

[0076]

[0077] 5) Synthesis of intermediate tert-butyl (6-(3-(2-formyl-5-((2-methyl-[l,l'-biphenyl]-3- yl)methoxy)phenoxy)methyl)benzamido)hexyl)carbamate: Take 0.160 g of 3-((2-formyl-5-((2- methyl-[l,l'-biphenyl]-3-yl)methoxy)phenoxy)methyl)benzoic acid (G) (0.354 mmol) and add 0.269 g of HATU (0.708 mmol) and 5 mL of anhydrous DMF solution, then add 251 μL of DIPEA (1.416 mmol) dropwise, stir at room temperature for 30 minutes, then add 0.153 g of tert-butyl (6-aminohexyl)carbamate (H) (0.708 mmol), stir at room temperature for 24 hours. After monitoring the reaction completion by TLC, extract the reaction solution with ethyl acetate (30 mL x 3), separate and wash the organic phase with water (50 mL x 3), then wash with saturated brine (50 mL x 2), dry over anhydrous sodium sulfate, and remove the ethyl acetate under reduced pressure to obtain a solid. Column chromatography of the solid with petroleum ether: ethyl acetate gives a white-yellow solid 0.186 g with a yield of 80.8%. The white-yellow solid obtained by column chromatography is identified by nuclear magnetic resonance method, and the results show that the white-yellow solid is tert-butyl (6-(3-(2-formyl-5-((2-methyl-[l,l'-biphenyl]-3- yl)methoxy)phenoxy)methyl)benzamido)hexyl)carbamate (I), and its structural formula is:

[0078]

[0079] 6) Synthesis of intermediate N-(6-aminohexyl)-3-((2-formyl-5-((2-methyl-[l,l'-biphenyl]-3- yl)methoxy)phenoxy)methyl)benzamide: Take 0.186 g of tert-butyl (6-(3-(2-formyl-5-((2-methyl- [l,l'-biphenyl]-3-yl)methoxy)phenoxy)methyl)benzamido)hexyl)carbamate (I) (0.299 mmol) and add 6 mL of dichloromethane / trifluoroacetic acid (V / V = 5: 1) solution, stir at room temperature for 1 hour, add an appropriate amount of saturated aqueous sodium bicarbonate solution to quench the reaction after monitoring the reaction completion by TLC, extract the reaction solution with DCM (30 mL x 3), wash the organic phase with saturated brine (50 mL x 2), then dry over anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain a yellow oily product 0.150 g with a yield of 95.3%. The yellow oily product obtained is identified by nuclear magnetic resonance method, and the results show that the yellow oily product is N-(6-aminohexyl)-3-((2-formyl-5-((2-methyl-[l,l'-biphenyl]-3- yl)methoxy)phenoxy)methyl)benzamide (J), and its structural formula is

[0080]

[0081] 7) Synthesis 1 5 -((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2-oxo-6,13-diaza-1(1,2),4(1,3)- dibenzylcyclo tetradecan-5-one: Take 0.150 g of N-(6-aminohexyl)-3-((2- formyl-5-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)benzamide (J) (0.272 mmol) in a reaction bottle, add 4 mL of methanol / dichloromethane (V / V = 1:1) solution, stir at room temperature for 30 minutes. Then add 0.137 g of sodium cyanoborohydride (2.176 mmol) and 4 drops of glacial acetic acid to the reaction system, react at room temperature for about 24 h, after TLC detection of the completion of the reaction of raw materials, remove the solvent under reduced pressure, extract the obtained solid with dichloromethane (30 mL x 3), and separate the layers by standing. Wash the organic phase with water (50 mL x 3), saturated brine (50 mL x 2), then dry over anhydrous sodium sulfate, remove dichloromethane under reduced pressure to obtain a solid, and column chromatograph the solid with dichloromethane:methanol to obtain a white yellow solid 0.030 g with a yield of 20.6%. The obtained white yellow solid is identified by nuclear magnetic resonance method, and the results show that the white yellow solid is 1 5 -((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2-oxo-6,13-diaza-1(1,2),4(1,3)- dibenzylcyclo tetradecan-5-one, denoted as compound MP1, and its structural formula is

[0082]

[0083] The nuclear magnetic resonance hydrogen spectrum, nuclear magnetic resonance carbon spectrum and mass spectrum of compound MP1 are as follows: 1 H NMR (400 MHz, CDC13) δ 8.09 (s, 1H), 7.77 (d, J = 3.1 Hz, 1H), 7.49 - 7.41 (m, 5H), 7.38 (d, J = 6.5 Hz, 2H), 7.32 (d, J = 7.1 Hz, 2H), 7.28 (d, J = 1.4 Hz, 2H), 7.25 (s, 1H), 6.92 (s, 1H), 6.65 (s, 1H), 6.62 (s, 1H), 5.09 (s, 4H), 4.07 (s, 2H), 3.42 (s, 2H), 2.94 (s, 2H), 2.26 (s, 3H), 1.80 (s, 2H), 1.65 (s, 2H), 1.44 (s, 2H), 1.40 (s, 2H). 13C NMR (101 MHz, CDC13) δ 168.54, 161.83, 157.84, 143.00, 141.70, 136.44, 135.53, 134.56, 134.28, 132.85, 130.47, 130.34, 129.32, 129.21, 128.08, 127.99, 127.73, 126.90, 125.64, 125.50, 110.72, 106.07, 100.21, 69.55, 69.37, 48.06, 47.82, 39.86, 29.65, 26.99, 25.10, 24.75, 16.15, ESI-MS m / z: 535.40 [M+H] + . Figure 1 The compound MP1 was prepared according to the procedure described in Example 1. Figure 2 The compound MP1 was prepared according to the procedure described in Example 1.

[0084] Example 2

[0085] In the preparation of the compound of this example, compound (C) of step 2) was replaced by 5-chloro-2,4-dihydroxybenzaldehyde and compound (H) of step 5) was replaced by tert-butyl (5-aminopentyl)carbamate, and the remaining steps were identical to those of Example 1 to give the compound of this example 1 4 - chloro-1 5 -((2-methyl-[l,l'-biphenyl]-3-yl)methoxy)-2-oxa-6,12-diaza- 1(1,2),4(1,3)-dibenzylcyclo-tridecan-5-one, white solid product (0.038 g, 11% yield), designated as compound MP2, having the structural formula

[0086]

[0087] The compound MP2 was prepared according to the procedure described in Example 1. 1H NMR (400 MHz, DMSO) δ 8.42 (s, 1H), 8.00 (s, 1H), 7.63 (d, J = 6.7 Hz, 1H), 7.56 (d, J = 7.7 Hz, 1H), 7.52 (s, 2H), 7.50 (s, 1H), 7.47 (s, 1H), 7.45 (s, 1H), 7.40 (d, J = 7.3 Hz, 1H), 7.33 (s, 1H), 7.31 (s, 1H), 7.31 - 7.29 (m, 1H), 7.24 (d, J = 6.4 Hz, 2H), 5.36 (s, 4H), 4.14 (s, 2H), 2.94 (s, 2H), 2.49 - 2.47 (m, 2H), 2.26 (s, 3H), 1.85 (s, 2H), 1.61 (s, 2H), 1.49 (s, 2H). 13 C NMR (101 MHz, DMSO) δ 167.73, 156.63, 155.38, 142.70, 141.66, 137.07, 136.98, 135.35, 134.56, 132.86, 130.35, 129.58, 128.91, 128.70, 128.54, 127.43, 127.05, 126.04, 125.17, 113.11, 100.52, 70.21, 69.14, 47.52, 44.36, 27.51, 26.39, 25.18, 16.35, ESI-MS m / z: 555.36 [M+H] + . Figure 3 The compound MP2 was prepared according to the procedure described in Example 2. Figure 4 The compound MP2 was prepared according to the procedure described in Example 2.

[0088] Example 3

[0089] In the preparation of the compound of this example, step 2) compound (C) was prepared using 5-chloro-2,4-dihydroxybenzaldehyde and the remaining steps were identical to those described in Example 1 to obtain the compound of this example 1 4 - chloro-1 5 -((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2-oxa-6,13-diaza-1(1,2),4(1,3)- dibenzylcyclo tetradecan-5-one, white solid product (0.040 g, 10% yield), noted compound MP3, whose structural formula is

[0090]

[0091] The compound MP3 was prepared according to the procedure described in Example 2. 1H NMR (400 MHz, CDC13) δ 7.93 (d, J = 7.7 Hz, 1H), 7.89 (s, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.46 (s, 1H), 7.44 (d, J = 7.4 Hz, 2H), 7.42 (s, 1H), 7.39 (d, J = 7.2 Hz, 2H), 7.34 (s, 1H), 7.32 (s, 1H), 7.30 (s, 1H), 7.27 (s, 1H), 6.62 (s, 1H), 6.54 (s, 1H), 5.14 (s, 2H), 5.12 (s, 2H), 3.82 (s, 2H), 3.53 (dd, J = 9.2, 4.8 Hz, 2H), 2.74 (t, J = 6.5 Hz, 2H), 2.28 (s, 3H), 1.70 (d, J = 0.6 Hz, 2H), 1.68 - 1.63 (m, 2H), 1.50 (s, 4H). 13 C NMR (101 MHz, CDC13) δ 171.26, 167.38, 166.93, 155.78, 142.90, 141.72, 136.63, 136.09, 135.42, 134.55, 133.93, 132.01, 130.12, 129.33, 129.28, 129.09, 128.16, 128.07, 127.49, 126.88, 125.55, 114.77, 99.79, 70.48, 69.58, 69.56, 48.59, 39.84, 29.64, 29.27, 27.60, 26.26, 16.15, ESI-MS m / z: 569.36 [M+H] + . Figure 5 The compound MP3 was prepared according to the procedure described in Example 3. Figure 6 The compound MP3 was prepared according to the procedure described in Example 3.

[0092] Example 4

[0093] In the preparation of the compound of this example, step 3) compound (E) was prepared using methyl 2-(bromomethyl)benzoate and step 5) compound (H) was prepared using tert-butyl (4-aminobutyl)carbamate, and the remaining steps were the same as in Example 1 to obtain the compound 15-((2-methyl-[l,l'-biphenyl]-3-yl)methoxy)-7,8,9,10,12-hexahydro-6H-dibenzo[b,l][l]oxazacyclotetradecine-5(18H)-one, white solid product (0.031 g, yield 7%), which is denoted as compound MP4, and has the structural formula

[0094] In the preparation of the compound of this example, step 3) compound (E) was prepared using methyl 2-(bromomethyl)benzoate and step 5) compound (H) was prepared using tert-butyl (4-aminobutyl)carbamate, and the remaining steps were the same as in Example 1 to obtain the compound 15-((2-methyl-[l,l'-biphenyl]-3-yl)methoxy)-7,8,9,10,12-hexahydro-6H-dibenzo[b,l][l]oxazacyclotetradecine-5(18H)-one, white solid product (0.031 g, yield 7%), which is denoted as compound MP4, and has the structural formula

[0095] The nuclear magnetic resonance hydrogen spectrum, nuclear magnetic resonance carbon spectrum and mass spectrum of compound MP4 are as follows: 1 H NMR (400 MHz, CDC13) δ 7.56 (s, 1H), 7.46 (s, 2H), 7.44 (d, J = 7.8 Hz, 2H), 7.38 (s, 2H), 7.34 (d, J = 7.3 Hz, 2H), 7.31 (s, 1H), 7.29 (s, 2H), 7.28 - 7.23 (m, 1H), 6.74 (s, 1H), 6.65 (d, J = 7.7 Hz, 1H), 5.32 (s, 2H), 5.09 (s, 2H), 4.03 (s, 2H), 3.48 (s, 2H), 2.96 (s, 2H), 2.27 (s, 3H), 1.85 (s, 2H), 1.75 (s, 2H). 13 C NMR (101 MHz, CDC13) δ 170.61, 161.61, 158.08, 143.01, 141.74, 135.59, 134.60, 134.32, 133.68, 132.76, 131.31, 130.72, 130.34, 129.58, 129.34, 128.18, 128.09, 128.02, 126.89, 125.65, 110.10, 106.30, 100.33, 69.34, 45.49, 45.31, 45.23, 39.77, 25.79, 22.97, 16.18, ESI-MS m / z: 507.33 [M+H] + . Figure 7 The nuclear magnetic resonance hydrogen spectrum of compound MP4 prepared in Example 4 is as follows: Figure 8 The nuclear magnetic resonance carbon spectrum of compound MP4 prepared in Example 4 is as follows:

[0096] Example 5

[0097] In the preparation of the compound of this example, compound (C) in Step 2) is replaced by 5-chloro-2,4-dihydroxybenzaldehyde, compound (E) in Step 3) is replaced by methyl 2-(bromomethyl)benzoate, and compound (H) in Step 5) is replaced by tert-butyl (4-aminobutyl)carbamate, and the remaining steps are the same as in Example 1, to obtain the compound of this example, 14-chloro-15-((2-methyl-[l,l'-biphenyl]-3-yl)methoxy)-7,8,9,11,12-hexahydro-6H-dibenzo[b,l][l]oxazacyclotetradecin-5(18H)-one, white solid product (0.045 g, yield 11%), which is denoted as compound MP5, and has the structural formula of

[0098]

[0099] The nuclear magnetic resonance hydrogen spectrum, nuclear magnetic resonance carbon spectrum and mass spectrum of compound MP5 are as follows: 1 H NMR (400 MHz, CDC13) δ 7.83 (s, 1H), 7.61 (d, J = 7.1 Hz, 1H), 7.53 (d, J = 7.2 Hz, 1H), 7.51 - 7.46 (m, 2H), 7.45 (s, 1H), 7.43 (s, 1H), 7.41 - 7.37 (m, 2H), 7.36 (s, 1H), 7.34 (s, 1H), 7.33 (d, J = 3.7 Hz, 1H), 7.31 (s, 1H), 7.31 (s, 1H), 6.83 (s, 1H), 5.34 (s, 2H), 5.22 (s, 2H), 3.93 (s, 2H), 3.47 (s, 2H), 2.85 (s, 2H), 2.32 (s, 3H), 1.83 (d, J = 4.4 Hz, 2H), 1.72 (d, J = 7.9 Hz, 2H). 13 C NMR (101 MHz, CDC13) δ 170.32, 156.56, 156.10, 142.98, 141.68, 136.29, 135.14, 134.20, 134.15, 133.09, 132.39, 131.11, 130.52, 130.31, 129.67, 129.36, 128.40, 128.08, 127.64, 126.90, 125.63, 114.97, 98.94, 70.35, 69.57, 60.36, 45.97, 40.28, 26.41, 23.85, 16.24, ESI-MS m / z: 541.36 [M+H] + . Figure 9 The nuclear magnetic resonance hydrogen spectrum of compound MP5 prepared in Example 5 is shown in the following table. Figure 10 The nuclear magnetic resonance carbon spectrum of compound MP5 prepared in Example 5 is shown in the following table.

[0100] Example 6

[0101] In the preparation of the compound of this example, compound (C) in step 2) is replaced by 5-chloro-2,4-dihydroxybenzaldehyde, compound (E) in step 3) is replaced by methyl 2-(bromomethyl)benzoate, and compound (H) in step 5) is replaced by tert-butyl (6-aminohexyl)carbamate, and the remaining steps are the same as in Example 1, to obtain the compound of this example, 16-chloro-17-((2-methyl-[l,l'-biphenyl]-3-yl)methoxy)-7,8,9,10,12,13,14-octahydro-6H-dibenzo[b,n][l]oxa[5,12]diazocin-5(20H)-one, white solid product (0.052 g, yield 13%), which is denoted as compound MP6, and its structural formula is as follows:

[0102]

[0103] The nuclear magnetic resonance hydrogen spectrum, nuclear magnetic resonance carbon spectrum and mass spectrum of compound MP6 are as follows: 1 H NMR (400 MHz, CDC13) δ 7.71 (d, J = 6.5 Hz, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.54 (d, J = 6.7 Hz, 2H), 7.51 (s, 1H), 7.46 (s, 1H), 7.44 (d, J = 7.0 Hz, 2H), 7.39 (d, J = 6.9 Hz, 1H), 7.34 (d, J = 7.3 Hz, 2H), 7.30 (s, 1H), 7.30 (s, 1H), 7.29 (s, 1H), 7.14 - 7.04 (m, 1H), 6.87 (s, 1H), 5.23 (s, 2H), 5.12 (s, 2H), 4.01 (s, 2H), 3.48 (s, 2H), 2.91 (s, 2H), 2.31 (s, 3H), 2.06 (s, 2H), 1.87 (s, 2H), 1.68 (s, 2H), 1.56 (s, 2H). 13 C NMR (101 MHz, CDC13) δ 169.72, 156.94, 156.48, 142.95, 141.69, 135.25, 134.27, 134.16, 134.01, 133.29, 133.06, 131.65, 130.29, 129.87, 129.35, 128.08, 127.99, 127.65, 126.89, 125.63, 114.80, 112.71, 99.92, 70.46, 70.33, 47.20, 37.58, 31.45, 30.08, 29.64, 23.26, 22.61, 16.26, ESI-MS m / z: 569.29 [M+H] + . Figure 11 The nuclear magnetic resonance hydrogen spectrum of compound MP6 prepared in Example 8 is shown. Figure 12 The nuclear magnetic resonance carbon spectrum of compound MP6 prepared in Example 8 is shown.

[0104] Performance test

[0105] 1. In vitro anti-PD-1 / PD-L1 inhibitory activity test of the compound

[0106] The in vitro anti-PD-1 / PD-L1 activity test of the compound in this test part adopts homogeneous time-resolved fluorescence (HTRF), which is a technology for detecting the measured substance in a pure liquid phase system. The kit (Cat#64ICP01PEH) was purchased from Cisbio, and the 384-well flat bottom white plate (Cat#66PL96025) was purchased from Corning. The specific test method is as follows:

[0107] The experimental process is as follows:

[0108] 1) Dilution of compounds and preparation of test solution:

[0109] (1) Compound working solution: Each compound was diluted to 20 mmol / L of compound stock solution. The stock solution was diluted with the buffer solvent matched with the kit and mixed well for use.

[0110] (2) Preparation of PD-L1 protein working solution: Take 10 μL of PD-L1 protein (40x) in the kit, add 0.4 mL of buffer solvent and mix well for use.

[0111] (3) Preparation of PD-1 protein working solution: Take 10 μL of PD-1 protein (40x) in the kit, add 0.4 mL of buffer solvent and mix well for use.

[0112] (4) Preparation of detection working solution: Take 5 μL of Anti-Tag-Eu 3+ (50x) and 5 μL of Anti-Tag-XL665 (50x) in the kit, respectively, add 495 μL of buffer solvent, then mix the two for use.

[0113] 2) Test experimental steps:

[0114] (1) Add 2 μL of compound working solution to each well of the 384-well counting plate, 3 replicates for each concentration. Add 6 μL of buffer solvent to the negative control group, and add 2 μL of buffer solvent to the positive control group.

[0115] (3) Add 4 μL of PD-L1 protein working solution to each well, and incubate at room temperature for 15 minutes.

[0116] (5) Add 4 μL of PD-1 protein working solution to each well except the negative control group. Then add 10 μL of detection working solution to each well, and incubate at room temperature for 1 hour.

[0117] (10) Read the fluorescence value (set the excitation wavelength to 320 nm, and the detection wavelength to 665 nm and 620 nm) using a multifunctional microplate detector (TECAN M1000).

[0118] 3) Experimental data processing:

[0119] (1) Calculate the ratio of the signal value at the emission wavelength and the signal value at the absorption wavelength in each well. Ratio = (665 nm signal reading / 620 nm signal reading) * 10 4 ;

[0120] (2) Calculate the inhibition rate of each compound at each concentration. Inhibition rate = [1-((Ratio 实验孔 -Ratio 阴性孔 ) / (Ratio 阳性孔 -Ratio 阴性孔 ))] * 100%.

[0121] (3) According to the average inhibition rate of each compound at different concentrations, draw a standard S-shaped curve, and then obtain the half-inhibitory concentration (IC 50 ) of each compound.

[0122] Table 2 shows the results of the PD-1 / PD-L1 interaction competitive inhibition activity test of compounds MP1-MP5.

[0123] Table 2 shows the results of the PD-1 / PD-L1 interaction competitive inhibition activity test of compounds MP1-MP5.

[0124]

[0125] The in vitro experimental results of Table 2 show that the biphenyl ether-containing cyclic compounds (MP1-6) have good inhibitory effect on PD-1 / PD-L1.

[0126] 2. In vitro immune regulation function test of compounds

[0127] The in vitro immune regulation function test of the compounds described in this test part uses a HepG2 / Jurkat T cell co-culture model to evaluate the ability of the compounds to re-activate the immune function inhibited by the PD-1 / PD-L1 interaction.

[0128] The experimental process is as follows:

[0129] 1) Cell survival rate test of the compound-treated HepG2 single cell model group:

[0130] (1) Take the logarithmic growth phase of HepG2 cells, inoculate 5000 cells / well into a 96-well plate, and after the cells adhere, remove the culture medium and replace it with a culture medium containing the corresponding compound concentration (2.5 μM, 1.25 μM, 0.625 μM, 0.3125 μM), add a culture medium containing DMSO to the positive control group, and a culture medium containing no cells and no drugs to the blank group, and incubate all groups at 37°C for 48 hours.

[0131] (2) Add 10 μL CCK8 to each well of each group, and incubate at 37°C for 2 hours. Then measure the absorbance (OD) at 450 nm wavelength, and calculate the survival rate of HepG2 cells. Survival rate = (OD value 实验组 - OD value 空白组 ) / (OD value 对照组 - OD value 空白组 ) x 100%

[0132] 2) Compound treatment of HepG2 / Jurkat T cell model group cell survival rate test:

[0133] (1) Take the HepG2 cells in the logarithmic growth phase, and inoculate 5000 cells per well into a 96-well plate. After the cells adhere, add IFN-γ (10 ng / mL per well) to each well to stimulate for 48 hours.

[0134] (2) Seed Jurkat cells into a T25 culture dish, and add PHA-P (2 μg / mL per well) to stimulate for 48 hours.

[0135] (3) Remove the culture medium containing IFN-γ from the HepG2 cells, and seed the PHA-P pretreated Jurkat cells into the IFN-γ pretreated HepG2 cells at a density of 10000 cells per well.

[0136] (4) Add culture medium containing various concentrations of drugs to the drug group, add culture medium containing DMSO to the positive control group, and add culture medium containing no cells and no drugs to the blank group. Incubate all groups at 37°C for 48 hours.

[0137] (5) Remove the Jurkat cells, wash each well with 100 μL PBS, add 100 μL PBS containing CCK8, and incubate at 37°C.

[0138] (6) After 2 hours, measure the absorbance (OD) at 450 nm wavelength, and calculate the survival rate of HepG2 cells. Survival rate = (OD value 实验组 - OD value 空白组 ) / (OD value 对照组 - OD value 空白组 ) x 100%;

[0139] Figure 13The experimental results show that MP2 itself has low toxicity to HepG2 cells, and the cell viability is 93.5% at a concentration of 2.5 μM. In the HepG2 / Jurkat co-culture model, MP2 promotes the death of HepG2 cells in a dose-dependent manner. In the HepG2 / Jurkat co-culture model treated with 2.5 μM of compound MP2, the cell death rate (about 40%) is more than 6 times higher than that of the HepG2 cell model treated alone (about 6.5%). This shows that MP2 can reactivate the immune-suppressed T cells to kill tumor cells in vitro.

[0140] 3. In vitro plasma stability test of the compound

[0141] The in vitro plasma stability test of the compound described in this test part uses the method of co-incubation of drugs with rat plasma to preliminarily evaluate the stability of the compound in plasma.

[0142] The experimental process is as follows:

[0143] (1) Compound MP2 was prepared into a 5 mmol / L stock solution with DMSO.

[0144] (2) Fresh rat whole blood was taken and centrifuged at 4000 rpm for 10 min at 4°C, and the upper plasma was aspirated.

[0145] (3) The samples were divided into groups according to different time points (time points were set at 0 h, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h, and 24 h), and 3 sample tubes were prepared for each group. Then 200 μL of plasma and 2 μL of compound stock solution were added to obtain a plasma mixture containing 50 μM of compound.

[0146] (4) The plasma mixture was vortexed for 1 min, and then incubated in a 37°C incubator. The corresponding samples were taken out at the specified time. Then 3 times the volume of methanol was added to quench the reaction, and the mixture was vortexed for 2 min and centrifuged at 12000 rpm for 15 min at 26°C.

[0147] (5) The supernatant obtained by centrifugation was taken for LC-MS detection.

[0148] Figure 14 The results of the plasma stability of compound MP2 are shown in the table. The results show that after 24 hours of in vitro plasma incubation, the residual amount of compound MP2 is 89.4%, and about 10.6% of MP2 is metabolized by plasma. The in vitro plasma half-life is more than 24 hours, indicating that compound MP2 is stable in plasma.

[0149] 4. Test of pharmacokinetic properties of the compound

[0150] The pharmacokinetic properties described in this test section were investigated by determining the concentration of the test substance in the plasma of SD rats after a single intravenous injection and gavage of the compound MP2 in the present application to SD rats, and calculating the relevant parameters, to investigate the pharmacokinetic characteristics of the test substance in vivo.

[0151] The experimental process was as follows:

[0152] (1) Compound MP2 was configured into a 4 mg / ml solution (solvent ratio DMSO: polyoxyethylene castor oil: normal saline = 5:25:75, volume ratio).

[0153] (2) 12 male SD rats (200-250 g) were selected and divided into two groups (for intravenous administration and gavage administration), and were fasted for about 12 hours before administration, and were fed for about 4 hours after administration.

[0154] (3) The gavage group (20 mg / kg) and the intravenous group (2 mg / kg) were administered according to the actual body weight of the rats.

[0155] (4) Blood was taken at 0.083, 0.167, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, and 36 hours after administration, and was centrifuged at 4000 rpm for 10 min at 4°C, and the supernatant was aspirated and stored in a -80°C refrigerator.

[0156] (5) The UPLC-MS / MS method was used to detect the drug concentration in the plasma. The chromatographic column was CORTECS UPLC C18 Column (2.1 mm x 100 mm, 1.6 μm), the mobile phase was acetonitrile / 0.1% formic acid aqueous solution, the flow rate was set to 0.4 mL / min, the internal standard method was used for quantification, and the internal standard was Midazolam. The mass spectrometry was performed by positive ion mode electrospray ESI source, and the ion fragments generated by multiple reaction monitoring (MRM) were tuned and optimized. The mass spectrometry parameters after optimization are shown in the following table:

[0157]

[0158] (5) The plasma drug concentration-time curve was drawn, and the pharmacokinetic parameters (MRT, C max , T max , T 1 / 2 , CL, V z , and AUC) were analyzed by DAS software, and the drug bioavailability was calculated.

[0159] The pharmacokinetic property related parameters are shown in Table 2

[0160] Table 2. Pharmacokinetic properties of compound MP2 in SD rats (n=6, Mean ± SD)

[0161]

[0162] Under the conditions of this experiment, the average Cmax of SD rats after intravenous administration of 2 mg / kg of compound MP2 was 385.3 ug / L, the average half-life t1 / 2 was 6.8 h, the average residence time MRT was 8.5 h, and the average AUC was 835.5 ug / L*h. max 1 / 2 (0-∞) (0-∞)

[0163] Under the conditions of this experiment, the average Tmax of SD rats after oral administration of 20 mg / kg of compound MP2 was 10.7 h, the average Cmax was 95.9 ug / L, the half-life t1 / 2 was 8.5 h, the average residence time MRT was 18.4 h, and the average AUC was 1800.5 ug / L*h. max max 1 / 2 (0-∞) (0-∞) The average bioavailability of compound MP2 in rats was 21.5%.

[0164] The pharmacokinetic study results show that the compound of the present application exhibits good pharmacokinetic characteristics, high oral bioavailability (F=21.5%), good stability, and a reasonable half-life, thereby providing an important basis for further preclinical research.

[0165] 5. In vivo anti-tumor activity test of the compound

[0166] The in vivo anti-tumor activity test of the compound described in this test part uses a mouse melanoma subcutaneous tumor transplantation model to preliminarily evaluate the therapeutic effect of compound MP2 on melanoma.

[0167] The experimental process is as follows:

[0168] (1) Take 15 C57BL / 6 mice (male, 20-25 g) and divide them into three groups (blank group, 20 mg / kg dose group, and 40 mg / kg dose group), with 5 mice in each group.

[0169] (2) Take mouse melanoma B16-F10 cells in the logarithmic growth phase, digest them, centrifuge them (800 rpm for 5 minutes), resuspend them in PBS, and obtain a cell suspension (1.25 x 10 6 / mL).

[0170] (3) Inject the cell suspension into the left axillary subcutaneous part of the C57 mice (2.5 x 10​​​​​​​​5 one).

[0171] (4) Compound MP2 was configured into a 4mg / mL solution (20mg / kg dose group) and an 8mg / mL solution (40mg / kg dose group) with a solvent ratio of DMSO: polyoxyethylene castor oil: normal saline = 5:25:75 (volume ratio).

[0172] (5) After the tumors of the mice were visible, the body weight of the mice was weighed and the dosing amount was converted for administration once a day. The changes in the body weight of the mice and the changes in the tumors were recorded.

[0173] (6) After 14 days of administration, the mice were euthanized, and the tumors were removed for weighing and photographing.

[0174] (7) The drug-induced tumor growth inhibition rate of the mice was analyzed.

[0175] In vivo anti-tumor effect Figure 15 The experimental results show that no significant weight loss and adverse reactions were observed during the treatment. In addition, compound MP2 showed significant anti-tumor activity in a dose-dependent manner. At a dose of 40mg / kg, MP2 reduced the tumor weight and tumor volume by 64.5% and 74.6%, respectively, which was significantly better than the blank control group. At 20mg / kg, the tumor weight and volume of the MP2 group were reduced by 35.5% and 43.1%, respectively.

[0176] The application discloses a compound and a preparation method and application thereof, and the structure of the compound is The compound disclosed by the application is novel in structure, has better inhibition on PD-1 / PD-L1 activity, high bioavailability, stable medicine and can be orally administered. The preparation method of the compound is mature in process, safe and pollution-free, and has the advantages of industrial popularization. The compound can be widely applied to preparation of a PD-L1 inhibitor and a medicine for treating and / or preventing cancer.

Claims

1. A compound, characterized in that: The compound is selected from the structures shown below:

2. A process for the preparation of a compound according to claim 1, characterized in that: The method comprises the following steps: 1) using 3-hydroxymethyl-2-methyl diphenyl as raw material, obtaining the compound shown in formula (II) through phosphorus tribromide bromination, mixing the compound shown in formula (II) with the compound shown in formula (III), and reacting to obtain the compound shown in formula (IV); In formula (III), R 1 is selected from a chlorine atom; 2) mixing the compound shown in formula (IV) with the compound shown in formula (V), and reacting to obtain the compound shown in formula (VI); In formula (V), the two groups of substituent positions of ring A are meta positions; 3) obtaining the compound shown in formula (VII) through base hydrolysis of the compound shown in formula (VI); 4) mixing the compound shown in formula (VII) with the compound shown in formula (VIII), and reacting to obtain the compound shown in formula (IX); In formula (VIII), n=2; 5) obtaining the compound shown in formula (X) through deprotection of the compound shown in formula (IX); 6) obtaining the compound through sodium cyanoborocyanide catalytic reaction of the compound shown in formula (X).

3. A pharmaceutical composition, characterized by: The pharmaceutical composition comprises the compound or stereoisomer, pharmaceutically acceptable salt thereof according to claim 1.

4. Use of the compound or stereoisomer, pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a medicament for treating and / or adjuvant treating cancer.

5. The use of a cancer drug according to claim 4, characterized in that: The cancer is selected from colon cancer, lung cancer, leukemia and melanoma.

6. Use according to claim 5, characterized in that: The cancer medicament is selected from a PD-L1 inhibitor.

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