CN116987046A - Biphenyl oxadiazole ether derivative as PD-1/PD-L1 small molecule inhibitor and synthesis method and application thereof - Google Patents

Biphenyl oxadiazole ether derivative as PD-1/PD-L1 small molecule inhibitor and synthesis method and application thereof Download PDF

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CN116987046A
CN116987046A CN202310761086.9A CN202310761086A CN116987046A CN 116987046 A CN116987046 A CN 116987046A CN 202310761086 A CN202310761086 A CN 202310761086A CN 116987046 A CN116987046 A CN 116987046A
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陈建军
刘进
袁霖
刘婷
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Southern Medical University
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Abstract

The application discloses an immune checkpoint inhibitor biphenyl oxadiazole ether derivative capable of blocking a PD-1/PD-L1 signal path, a preparation method and application thereof, wherein the compound is shown in a formula I, can treat various related tumor diseases by regulating the PD-1/PD-L1 signal path and adopting tumor immunotherapy, and has potential patent medicine prospect. The biphenyl oxadiazole ether derivative or the pharmaceutically acceptable salt, the racemate and the optical rotation thereofAn isomer or a solvent compound.

Description

Biphenyl oxadiazole ether derivative as PD-1/PD-L1 small molecule inhibitor and synthesis method and application thereof
Technical Field
The application relates to a compound shown in a general formula I or a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, a preparation method thereof, and an effect of inhibiting a PD-1/PD-L1 pathway and an anti-tumor effect.
Background
Cancer, a problem currently not overcome by the world medical community, has become the second leading cause of death worldwide next to cardiovascular disease. China is the most populated country worldwide, and in 2020, cancer patients are newly added in 457 ten thousand, accounting for 23.7% of the total world; the number of Chinese cancer deaths is 300 ten thousand, and the number of Chinese cancer deaths is 30 percent, so that the number of Chinese cancer deaths is first in the world, huge social pressure and economic burden are caused for the China, and unprecedented challenges are brought to public health.
Immunotherapy has drastically altered cancer treatment and led to a paradigm shift in anti-cancer warfare. Key therapeutic strategies for cancer immunotherapy include cytokines (e.g., IL-2 and TNF- α), checkpoint inhibitors, chimeric Antigen Receptor (CAR) T cell therapies, adoptive cell metastasis, cancer vaccines, oncolytic virus therapies, immune receptor agonist antibodies, and bispecific T cell cements (BiTE). Cancer immunotherapy was rated as an annual scientific breakthrough in 2013 by the journal of science. In particular, immune checkpoint inhibitors have shown considerable promise, and since 2011, six immune checkpoint inhibitors have been approved by the U.S. food and drug administration (US FDA). Currently, these products are suitable for patients with specific types of skin, head and neck, lung, bladder, lymphoma and kidney cancers. Immunotherapy based on inhibition of immune checkpoints has been clinically used as a fifth anticancer therapy following surgery, chemotherapy, radiotherapy and targeted therapy. Immune checkpoint proteins PD-1/PD-L1 and CTLA-4 are the two proteins currently most studied clinically, especially the former. They have been successfully applied clinically, greatly promoting the progress of tumor immunotherapy.
Currently clinically available PD-1/PD-L1 drugs are monoclonal antibodies. However, monoclonal antibodies have some unavoidable disadvantages of biological drugs, such as poor oral bioavailability and difficult drug production. Meanwhile, due to the longer half-life of the PD-1/PD-L1 monoclonal antibody and the intracorporeal immune response which is difficult to control, various adverse reactions related to organism immunity appear in the clinical use of the PD-1/PD-L1 monoclonal antibody, and the damage to normal organ tissues is caused, which is mostly seen in skin, intestines and stomach, liver, lung and endocrine systems. These shortcomings have prompted pharmaceutical researchers to find small molecule PD1/PD-L1 inhibitors as alternatives to antibody drugs. To date, there are no small molecule inhibitors of the non-antibody class of the PD-1/PD-L1 signaling pathway on the market. Therefore, the development of a novel PD-1/PD-L1 small molecule inhibitor with good anti-tumor activity has important significance.
Disclosure of Invention
The application provides a series of biphenyl oxadiazole ether derivatives for treating various related tumor diseases by regulating and controlling PD-1/PD-L1 signal paths and tumor immunotherapy and a preparation method thereof.
Some embodiments of the application relate to a compound of formula I, wherein:
r may be selected from
Further, the compound includes any one of the following compounds:
the synthetic route of the compound is as follows:
the specific synthesis steps are as follows:
(1) Compound L1 is diazotized and hydrolyzed to form compound L2;
(2) The compound L2 reacts with phenylboronic acid under the suzuki coupling condition to generate L3;
(3) Compound L3 is obtained by substituting phenolic hydroxyl groups with ethyl bromoacetate to give compound L4;
(4) Hydrazinolysis reaction is carried out on the compound L4 and hydrazine hydrate to generate a compound L5;
(5) The compound L5 and carbon disulfide react to form a ring to form a compound L6;
(6) Reacting compound L6 with the appropriate benzyl bromobenzaldehyde to form compounds L7a and L7b;
(7) Compounds L7a, b were subjected to sodium cyanoborohydride mediated reductive amination to give compounds PL1-27.
Wherein, the solvent used in the diazotization and hydrolysis reaction in the step (1) comprises, but is not limited to, concentrated sulfuric acid, water, cyclopentyl methyl ether, ethyl acetate or a mixed solvent optionally composed of the solvents; the base used includes, but is not limited to, sodium nitrite; the reaction temperature is 0 ℃ to 100 ℃.
Solvents used in the coupling reaction in step (2) include, but are not limited to, toluene, water, ethyl acetate or a mixed solvent optionally composed of these solvents; the catalyst is bis triphenylphosphine palladium dichloride; reagents used include, but are not limited to, sodium carbonate, phenylboronic acid; the reaction temperature is 85 ℃ to 95 ℃.
The solvent used in step (3) includes, but is not limited to, acetone, water, ethyl acetate, or a mixed solvent optionally composed of these solvents; the reagent is ethyl bromoacetate; the alkali used is anhydrous potassium carbonate; the reaction temperature is 55-65 DEG C
The solvent used in the hydrazine hydrate reaction in the step (4) comprises but is not limited to ethanol and water; the reaction temperature is 75 ℃ to 85 ℃.
The solvent used in the ring-synthesizing reaction in the step (5) includes, but is not limited to, ethanol, water, a dilute hydrochloric acid solution, or a mixed solvent optionally composed of these solvents; the reagent is carbon disulfide; the alkali is potassium hydroxide; the reaction temperature is 75 ℃ to 85 ℃.
The solvent used in step (6) includes, but is not limited to, acetone, water, ethyl acetate, or a mixed solvent optionally composed of these solvents; the alkali is potassium carbonate; the reagent is 3- (bromomethyl) benzaldehyde or 4- (bromomethyl) benzaldehyde; the reaction temperature is 55 ℃ to 65 ℃.
The solvent used in the sodium cyanoborohydride mediated reductive amination reaction in the step (7) is methylene dichloride, methanol or a mixed solvent optionally composed of the solvents; the acid is glacial acetic acid, and the reagent is corresponding amine; the reaction temperature is 20 ℃ to 30 ℃.
The application also discloses application of the biphenyl oxadiazole ether derivative or pharmaceutically acceptable salt, racemate, optical isomer or solvent compound thereof in preparation of inhibitors with PD-1/PD-L1 inhibitory activity.
The application also discloses application of the biphenyl oxadiazole ether derivative or pharmaceutically acceptable salt, racemate, optical isomer or solvent compound thereof in preparing antitumor drugs.
The application also discloses a pharmaceutical composition, which contains the biphenyl oxadiazole ether derivative or pharmaceutically acceptable salt, racemate, optical isomer or solvent compound thereof as an active ingredient, and a pharmaceutically acceptable carrier.
The pharmaceutical composition is a capsule, powder, tablet, granule, pill, injection, syrup, oral liquid, inhalant, ointment, suppository or patch.
The beneficial effects are that: the application provides a PD-1/PD-L1 small molecule immune checkpoint inhibitor which has novel structure, is simple to prepare as a small molecule inhibitor and is convenient for industrial production; can treat various related tumor diseases by tumor immunotherapy through regulating and controlling PD1/PD-L1 signal paths, and has potential patent medicine prospect.
Drawings
FIG. 1 shows PL17 nuclear magnetic resonance hydrogen spectrum.
FIG. 2 shows PL17 NMR spectra.
FIG. 3 is a PL17 high resolution mass spectrum.
FIG. 4 is a PL17 high performance liquid chromatogram.
FIG. 5 is a PL17/h/mPD-L1 binding assay.
FIG. 6 is a PL17/HepG2/Jukart cell co-culture model.
FIG. 7 is a PL17 in vivo tumor suppression assay.
Detailed Description
The application is further illustrated by the following examples.
Example 1: synthesis of PL1
The synthetic route is as follows:
synthesis of Compound L2
To a solution of L1 (10.0 g,53.76 mmol) in concentrated sulfuric acid (100 mL) was slowly added sodium nitrite (4.2 g,59.14 mmol) under ice-bath conditions. The thick suspension was warmed to room temperature and stirred for more than 1 hour until no caking was visible. The mixture was then slowly poured into a cyclopentyl methyl ether/water (300 mL:300 mL) solution and stirred at 100deg.C for an additional 2 hours. After completion of the reaction, ethyl acetate (3X 300 mL) was extracted. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude product was chromatographed on silica gel (petroleum ether: ethyl acetate=10:1) to give L2 as a yellow solid (7.3 g, 73%).
Synthesis of Compound L3
L2 (4.8 g,25.6 mmol), phenylboronic acid (3.7 g,30.7 mmol) and bis (triphenylphosphine) palladium dichloride (1.8 g,2.56 mmol) were suspended in toluene (80 mL) and aqueous sodium carbonate (8.2 g,16 mL). After 3 times air was replaced with nitrogen, the reaction mixture was heated at 90 ℃ for 10 hours. The residue was removed from the reaction mixture by suction filtration through celite under reduced pressure, followed by extraction with ethyl acetate (3X 80 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product obtained was purified by silica gel chromatography (oil ether: ethyl acetate=60:1 to 20:1) to give L3 as a colourless liquid (3.6 g, 75%).
Synthesis of Compound L4
L3 (2.2 g,11.8 mmol) was dissolved in acetone (20 mL) and anhydrous potassium carbonate (3.3 g,23.6 mmol) and ethyl bromoacetate (2.4 g,14.2 mmol) were added sequentially. The suspension was heated to 60 ℃ overnight under reflux and nitrogen blanket. The yellow suspension was cooled to room temperature and the solvent was removed in vacuo. The solid was dissolved in water and ethyl acetate and the layers were separated. The aqueous layer was extracted with additional ethyl acetate (3×20 mL) and the combined organic layers were washed with brine (2×20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give L4 (2.8 g, 88%) as a pale yellow solid.
Synthesis of Compound L5
A solution of L4 (2.0 g,7.8 mmol) and hydrazine hydrate (0.78 g,15.6 mmol) in ethanol (20 mL) was refluxed for 5 hours. The solvent was distilled off under reduced pressure, and then the residue was poured into crushed ice to give PL5 (1.6 g, 84%).
Synthesis of Compound L6
L5 (2.2 g,8.6 mmol), potassium hydroxide (0.53 g,9.4 mmol), carbon disulphide (2.0 g,15.7 mmol) were added to a solvent of ethanol (200 mL) with stirring, the reaction was degassed with nitrogen and heated to reflux overnight and monitored by TLC. After completion of the reaction, the solvent was distilled off under reduced pressure, followed by addition of water (200 mL). The aqueous phase was acidified to pH 2-3 with 1N dilute hydrochloric acid, filtered and dried to give L6 (1.7 g, 68%) as a white solid.
Synthesis of Compound L7a
L6 (2.0 g,6.70 mmol) was dissolved in acetone (20 mL) and anhydrous potassium carbonate (3.24 g,23.45 mmol) and 4-bromomethylbenzaldehyde (1.6 g,8.04 mmol) were added sequentially. The reaction was carried out overnight under reflux and under nitrogen. After completion of the reaction, the solvent was distilled off, and the solid was dissolved in water and ethyl acetate and the layers were separated. The aqueous layer was extracted with additional ethyl acetate (3×20 mL) and the combined organic layers were washed with brine (2×20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give L7a (2.06 g, 73.8%) as a pale yellow solid.
Synthesis of Compound PL1
Intermediate L7a (0.24 g,0.6 mmol) was dissolved in a mixed solution of dichloromethane (5 mL) and methanol (5 mL), morpholine (78.4 mg,0.9 mmol), glacial acetic acid (2 drops) and sodium cyanoborohydride (0.19 g,3 mmol) were added and the reaction was stirred at room temperature overnight and detected by TLC. The solvent was evaporated under reduced pressure and the crude product was purified by column on silica gel (DCM: meoh=100:1 to 5:1) to give PL1. Pale yellow oily liquid. 1 H NMR(400MHz,CDCl 3 -d)δ7.43(s,1H),7.41(s,1H),7.40(s,1H),7.37(d,J＝7.2Hz,1H),7.35(s,1H),7.32(s,2H),7.30(s,1H),7.28(s,1H),7.22(d,J＝7.9Hz,1H),7.02–6.95(m,2H),5.29(s,2H),4.50(s,2H),3.76(s,4H),3.56(s,2H),2.52(s,4H),2.16(s,3H).
Example 2
By the method of example 1, morpholine was replaced with N- (2-aminoethyl) acetamide to give compound PL2. 1 H NMR(400MHz,CDCl 3 -d)δ7.43(t,J＝7.6Hz,4H),7.37(t,J＝6.8Hz,3H),7.32(s,1H),7.29(d,J＝5.0Hz,1H),7.22(d,J＝8.0Hz,1H),7.02–6.95(m,2H),5.29(s,2H),4.48(s,2H),3.91(s,2H),3.44(d,J＝5.1Hz,2H),2.94–2.84(m,2H),2.16(s,3H),2.02(s,2H),1.98(s,3H).
Example 3
By the method of example 1, morpholine was replaced with (R) -pyrrolidin-3-ol to give compound PL3. 1 H NMR(400MHz,CDCl 3 -d)δ7.44(t,J＝5.5Hz,3H),7.40(s,2H),7.38(s,1H),7.33–7.27(m,3H),7.22(d,J＝7.9Hz,1H),7.02–6.94(m,2H),5.29(s,2H),4.49(s,2H),4.44(s,1H),3.79(s,3H),3.24(dd,J＝16.2,8.0Hz,1H),3.04(d,J＝11.2Hz,1H),2.80(dd,J＝11.0,5.1Hz,1H),2.66(dd,J＝16.4,9.1Hz,1H),2.32–2.23(m,1H),2.16(s,3H),1.97(dd,J＝14.1,6.9Hz,1H).
Example 4
By the method of example 1, morpholine was replaced with D-serine to give compound PL4. 1 H NMR(400MHz,DMSO-d 6 )δ7.44(s,2H),7.42(s,1H),7.39(s,2H),7.36(s,2H),7.30(d,J＝7.2Hz,2H),7.28–7.21(m,1H),7.13(d,J＝8.1Hz,1H),6.89(d,J＝7.2Hz,1H),5.44(s,2H),4.52(s,2H),3.94(d,J＝13.3Hz,1H),3.85(d,J＝13.6Hz,1H),3.62(d,J＝6.5Hz,3H),3.10(s,1H),2.06(s,3H).
Example 5
Referring to the procedure of example 1, compound PL5 can be prepared by substituting glycine for morpholine. 1 H NMR(400MHz,CDCl 3 -d)δ7.42–7.36(m,4H),7.33(d,J＝7.2Hz,1H),7.28(d,J＝7.4Hz,4H),7.19(t,J＝7.9Hz,1H),6.98–6.91(m,2H),5.25(s,2H),4.45(s,2H),3.78(s,2H),3.28(s,1H),2.12(s,3H),1.27(d,J＝11.6Hz,2H).
Example 6
With reference to the procedure of example 1, morpholine was replaced with 2-aminoethan-1-ol to give compound PL6. 1 H NMR(400MHz,CDCl 3 -d)δ7.47–7.42(m,3H),7.41(s,2H),7.40–7.34(m,2H),7.32(s,1H),7.30(d,J＝5.0Hz,1H),7.22(d,J＝7.9Hz,1H),6.98(t,J＝8.7Hz,2H),5.28(s,2H),4.48(s,2H),3.99(s,2H),3.76(s,2H),2.92(s,2H),2.16(s,3H),1.98(s,2H).
Example 7
By the method of example 1, morpholine was replaced with 2-amino-2-methylpropanoic acid to give compound PL7. 1 H NMR(400MHz,DMSO-d 6 )δ7.39(m,7H),7.30(s,2H),7.25(s,1H),7.14(s,1H),6.90(s,1H),5.44(s,2H),4.52(s,2H),3.82(s,2H),2.06(s,3H),1.29(s,6H).
Example 8
Referring to the procedure of example 1, morpholine was replaced with azetidine-3-carboxylic acid to give compound PL8. 1 H NMR(400MHz,DMSO-d 6 )δ7.44(t,J＝7.1Hz,2H),7.37(d,J＝7.0Hz,1H),7.31(dd,J＝12.1,7.8Hz,4H),7.24(t,J＝7.9Hz,1H),7.17(d,J＝7.5Hz,2H),7.12(d,J＝8.1Hz,1H),6.89(d,J＝7.4Hz,1H),5.44(s,2H),4.48(s,2H),3.48(s,2H),3.34(s,2H),3.15(s,3H),2.05(s,3H).
Example 9
Referring to example 1, compound PL9 can be prepared by substituting morpholine with 3- (methylamino) propanol. 1 H NMR(400MHz,DMSO-d 6 )δ7.43(d,J＝6.6Hz,2H),7.36(d,J＝6.8Hz,3H),7.29(d,J＝6.4Hz,2H),7.23(s,3H),7.12(d,J＝7.6Hz,1H),6.89(d,J＝6.7Hz,1H),5.44(s,2H),4.50(s,2H),3.47(s,2H),3.42(s,3H),2.42(s,2H),2.10(s,3H),2.05(s,3H),1.60(s,2H).
Example 10
By the method of example 1, morpholine was replaced with piperidine-2-carboxylic acid to give compound PL10. 1 H NMR(400MHz,DMSO-d 6 )δ7.44(t,J＝7.1Hz,2H),7.36(d,J＝6.8Hz,3H),7.31(s,1H),7.25(dd,J＝15.0,8.2Hz,4H),7.13(d,J＝8.1Hz,1H),6.89(d,J＝7.4Hz,1H),5.44(s,2H),4.50(s,2H),3.84(d,J＝13.5Hz,1H),3.46(d,J＝13.4Hz,1H),3.04(s,1H),2.81(s,1H),2.17(s,1H),2.05(s,3H),1.91(s,1H),1.79(d,J＝19.6Hz,1H),1.70(s,1H),1.44(s,3H).
Example 11
By the method of example 1, morpholine was replaced with 3-aminopropane-1-ol to give compound PL11. 1 H NMR(400MHz,DMSO-d 6 )δ7.44(t,J＝7.3Hz,2H),7.39–7.33(m,3H),7.32–7.25(m,4H),7.23(d,J＝7.9Hz,1H),7.12(d,J＝8.2Hz,1H),6.89(d,J＝7.5Hz,1H),5.44(s,2H),4.50(s,2H),3.70(s,2H),3.44(t,J＝6.1Hz,2H),3.17(s,1H),2.58(t,J＝6.9Hz,2H),2.05(s,3H),1.62–1.54(m,2H).
Example 12
Referring to example 1, morpholine was replaced with 2- (methylamino) ethane-1-ol to give compound PL12. 1 H NMR(400MHz,DMSO-d 6 )δ9.43(s,1H),7.51(d,J＝8.0Hz,2H),7.47–7.41(m,4H),7.37(d,J＝7.2Hz,1H),7.29(d,J＝7.1Hz,2H),7.25(t,J＝7.9Hz,1H),7.13(d,J＝8.2Hz,1H),6.89(d,J＝7.5Hz,1H),5.44(s,2H),4.55(s,2H),4.18(s,2H),3.69(s,2H),3.00(s,2H),2.64(s,3H),2.05(s,3H).
Example 13
By the method of example 1, morpholine was replaced with 3-aminopropionic acid to give compound PL13. 1 H NMR(400MHz,DMSO-d 6 )δ7.44(t,J＝7.3Hz,2H),7.38(d,J＝7.7Hz,3H),7.29(t,J＝8.0Hz,4H),7.23(d,J＝7.9Hz,1H),7.12(d,J＝8.2Hz,1H),6.89(d,J＝7.5Hz,1H),5.44(s,2H),4.51(s,2H),3.74(s,2H),2.73(t,J＝6.5Hz,2H),2.29(t,J＝6.5Hz,2H),2.05(s,3H),1.90(s,1H).
Example 14
Referring to the procedure of example 1, 4-bromomethylbenzaldehyde was replaced with 3-bromomethylbenzaldehyde to prepare compound PL14. 1 H NMR(400MHz,DMSO-d 6 )δ7.43(d,J＝7.3Hz,2H),7.36(t,J＝7.2Hz,2H),7.29(d,J＝7.8Hz,3H),7.25–7.18(m,3H),7.12(d,J＝8.2Hz,1H),6.88(d,J＝7.6Hz,1H),5.42(s,2H),4.51(s,2H),3.54(s,4H),3.41(s,2H),2.30(s,4H),1.91(s,3H).
Example 15
Referring to the procedure of example 2, 4-bromomethylbenzaldehyde was replaced with 3-bromomethylbenzaldehyde to prepare compound PL15. 1 H NMR(400MHz,DMSO-d 6 )δ7.83(s,1H),7.47–7.41(m,3H),7.38(d,J＝7.3Hz,1H),7.32–7.26(m,5H),7.23(d,J＝7.7Hz,1H),7.13(d,J＝8.2Hz,1H),6.89(d,J＝7.5Hz,1H),5.44(s,2H),4.52(s,2H),3.73(s,2H),3.16(dd,J＝12.0,6.0Hz,2H),2.59(t,J＝6.3Hz,2H),2.05(s,3H),1.91(s,1H),1.79(s,3H).
Example 16
Referring to the procedure of example 3, 4-bromomethylbenzaldehyde was replaced with 3-bromomethylbenzaldehyde to prepare compound PL16. 1 H NMR(400MHz,DMSO-d 6 )δ7.43(d,J＝5.4Hz,2H),7.38(s,2H),7.28(s,3H),7.23(d,J＝6.9Hz,3H),7.13(d,J＝6.6Hz,1H),6.89(d,J＝6.0Hz,1H),5.43(s,2H),4.51(s,2H),4.19(s,1H),3.56(s,2H),2.63(d,J＝48.9Hz,2H),2.46–2.29(m,2H),2.05(s,3H),1.98(s,1H),1.91(s,1H),1.54(s,1H).
Example 17
Referring to the procedure of example 4, 4-bromomethylbenzaldehyde was replaced with 3-bromomethylbenzaldehyde to prepare compound PL17. 1 H NMR(400MHz,DMSO-d 6 )δ12.43(s,1H),7.47–7.40(m,3H),7.37(d,J＝6.9Hz,1H),7.28(d,J＝7.2Hz,3H),7.25–7.20(m,3H),7.10(d,J＝8.2Hz,1H),6.87(d,J＝7.4Hz,1H),5.40(s,2H),4.51(s,2H),3.77(d,J＝14.2Hz,2H),3.60(d,J＝14.4Hz,2H),3.23(t,J＝5.9Hz,1H),2.03(s,3H).
Example 18
Referring to the procedure of example 5, 4-bromomethylbenzaldehyde was replaced with 3-bromomethylbenzaldehyde to prepare compound PL18. 1 H NMR(400MHz,DMSO-d 6 )δ7.42(s,5H),7.26(s,5H),7.10(s,1H),6.87(s,1H),5.40(s,2H),4.51(s,2H),3.68(s,2H),3.13(s,2H),2.02(s,3H).
Example 19
Referring to the procedure of example 6, 4-bromomethylbenzaldehyde was replaced with 3-bromomethylbenzaldehyde to prepare compound PL19. 1 H NMR(400MHz,DMSO-d 6 )δ7.45(s,2H),7.43(s,1H),7.40–7.35(m,1H),7.30(d,J＝7.5Hz,4H),7.28–7.21(m,2H),7.13(d,J＝8.2Hz,1H),6.89(d,J＝7.5Hz,1H),5.44(s,2H),4.53(s,2H),3.80(s,2H),3.51(t,J＝5.5Hz,2H),2.66(t,J＝5.5Hz,2H),2.05(s,3H).
Example 20
Referring to the procedure of example 1, compound PL20 can be prepared by replacing 4-bromomethylbenzaldehyde with 3-bromomethylbenzaldehyde and simultaneously replacing morpholine with (2 r,4 r) -4-hydroxypyrrolidine-2-carboxylic acid. 1 H NMR(400MHz,DMSO-d 6 )δ7.43(dd,J＝13.9,6.6Hz,3H),7.37(d,J＝7.2Hz,1H),7.30(s,2H),7.28(d,J＝7.4Hz,3H),7.23(d,J＝7.9Hz,1H),7.13(d,J＝8.3Hz,1H),6.89(d,J＝7.5Hz,1H),5.44(s,2H),4.52(s,2H),4.16(s,2H),3.25–3.19(m,1H),3.18(s,3H),2.81(d,J＝9.9Hz,1H),2.30(s,1H),2.05(s,2H),1.76(d,J＝11.1Hz,1H).
Example 21
Referring to the procedure of example 7, 4-bromomethylbenzaldehyde was replaced with 3-bromomethylbenzaldehyde to prepare compound PL21. 1 H NMR(400MHz,DMSO-d 6 )δ7.53(s,1H),7.43(s,2H),7.36(s,3H),7.30(s,3H),
7.24(s,1H),7.14(s,1H),6.89(s,1H),5.44(s,2H),4.53(s,2H),3.84(s,2H),2.04(s,3H),
1.89(s,1H),1.31(s,6H).
Example 22
By the method of example 8, a compound can be produced by substituting 3-bromomethylbenzaldehyde for 4-bromomethylbenzaldehyde
PL22。 1 H NMR(400MHz,DMSO-d 6 )δ7.43(d,J＝7.0Hz,2H),7.37(d,J＝6.9Hz,1H),
7.35–7.20(m,6H),7.19–7.09(m,2H),6.89(d,J＝7.2Hz,1H),5.43(s,2H),4.50(s,2H),
3.49(s,2H),3.34(s,2H),3.15(s,2H),2.04(s,3H),1.90(s,1H).
Example 23
Referring to the procedure of example 9, 4-bromomethylbenzaldehyde was replaced with 3-bromomethylbenzaldehyde to prepare compound PL23. 1 H NMR(400MHz,CDCl 3 -d)δ7.46(s,1H),7.43(s,1H),7.41(s,1H),7.39–7.35
(m,2H),7.33(d,J＝5.3Hz,2H),7.30(d,J＝6.0Hz,2H),7.22(d,J＝7.9Hz,1H),6.98(t,J
＝8.5Hz,2H),5.29(s,2H),4.50(s,2H),3.80(t,J＝5.2Hz,2H),3.77(s,2H),2.83(t,J＝
6.1Hz,2H),2.40(s,3H),2.16(s,3H),1.91–1.82(m,2H).
Example 24
Referring to the procedure of example 10, 4-bromomethylbenzaldehyde was replaced with 3-bromomethylbenzaldehyde to prepare compound PL24. 1 H NMR(400MHz,DMSO-d 6 )δ7.43(t,J＝7.3Hz,2H),7.40–7.34(m,2H),7.29(d,J＝6.9Hz,3H),7.24(t,J＝8.0Hz,3H),7.12(d,J＝8.1Hz,1H),6.88(d,J＝7.5Hz,1H),5.43(s,2H),4.51(s,2H),3.83(d,J＝13.4Hz,1H),3.44(d,J＝13.4Hz,1H),3.05(d,J＝3.8Hz,1H),2.85–2.76(m,1H),2.20–2.09(m,1H),2.04(s,3H),1.77(s,1H),1.69(d,J＝9.1Hz,1H),1.44(s,3H),1.33(s,1H).
Example 25
Referring to the procedure of example 11, 4-bromomethylbenzaldehyde was replaced with 3-bromomethylbenzaldehyde to prepare compound PL25. 1 H NMR(400MHz,CDCl 3 -d)δ7.41(d,J＝7.3Hz,3H),7.36(d,J＝7.2Hz,1H),7.31(d,J＝5.6Hz,3H),7.28(d,J＝5.0Hz,2H),7.21(t,J＝7.9Hz,1H),6.96(t,J＝7.9Hz,2H),5.25(s,2H),4.50(s,2H),3.64(t,J＝5.1Hz,1H),3.59(s,2H),2.64(s,1H),2.14(s,3H),1.84–1.71(m,2H),1.65(s,2H).
Example 26
Referring to the procedure of example 12, 4-bromomethylbenzaldehyde was replaced with 3-bromomethylbenzaldehyde to prepare compound PL26. 1 H NMR(400MHz,CDCl 3 -d)δ7.48(s,1H),7.45–7.40(m,3H),7.36–7.33(m,2H),7.33–7.27(m,3H),7.22(t,J＝7.9Hz,1H),6.98(t,J＝8.3Hz,2H),5.28(s,2H),4.49(s,2H),3.84(s,2H),3.80–3.76(m,2H),3.50(s,1H),2.79(t,J＝5.0Hz,2H),2.45(s,3H),2.15(s,3H).
Example 27
Referring to the procedure of example 13, 4-bromomethylbenzaldehyde was replaced with 3-bromomethylbenzaldehyde to prepare compound PL27. 1 H NMR(400MHz,DMSO-d 6 )δ7.46–7.40(m,3H),7.37(d,J＝7.2Hz,1H),7.30(s,2H),7.29–7.25(m,3H),7.23(d,J＝7.9Hz,1H),7.12(d,J＝8.1Hz,1H),6.88(d,J＝7.5Hz,1H),5.43(s,2H),4.51(s,2H),3.75(s,2H),2.73(t,J＝6.4Hz,2H),2.29(t,J＝6.4Hz,2H),2.04(s,3H).
In vivo and in vitro pharmacological experiments prove that the PD-1/PD-L1 inhibitory activity of the application can be used for preparing antitumor drugs. The following are the results of pharmacological experiments with the compounds of the present application:
test example 1: HTRF (homogeneous time resolved fluorescence) experiment
(1) Reagents and apparatus
PD-1/PD-L1 kit 10,000tests (64 PD1 PEH);
multifunctional 96 Kong Baiban (you Ning Wei);
multifunctional microplate detector (Tecan, infinite M1000 Pro);
precision pipette gun head (Eppendorf, J90066J)
Manual pipette (Eppendorf, M39970J)
Biological grade dimethyl sulfoxide (Shanghai Michlin Biochemical technologies Co., ltd.).
(2) Experimental procedure
(3) And (3) data processing:
(a) Calculating the Ratio of acceptor and donor emission signals per well: ratio=od 665 /OD 620 x10 4
(b) Calculated CV%: CV (%) = standard deviation/average ratio x100
(c) The half Inhibition Concentration (IC) of each test sample was converted by plotting an S-pattern on the average inhibition ratio from high to low concentration for each compound 50 )。
(4) Experimental results
The following table shows the activity ranges or ICs of the compounds on PD-1/PD-L1 interaction inhibitory activity 50 . The range is as follows:
from the above results, it can be seen that most of the compounds in the examples of the present application showed good PD1/PD-L1 inhibitory activity, and the best in example 17, the inhibitory activity reached 16.7nM, which is significantly better than that of positive reference BMS202. The biphenyl oxadiazole ether derivatives of the application are shown to be useful as immune checkpoint PD-1/PD-L1 inhibitors.
Test example 2: surface Plasmon Resonance (SPR) experiments
To further verify whether PL17 cross-reacted with h/m PD-L1, we determined the binding affinities of PL17 to h/m PD-L1, respectively, using Surface Plasmon Resonance (SPR) experiments.As shown in FIG. 5, PL17 has similar binding affinity to h/mPD-L1 and mPD-L1, K D The values were 11.4nM and 73.1nM, respectively, indicating that PL17 was able to cross react with h/mPD-L1 and had a strong affinity.
Test example 3: hepG2/Jurkat T cell co-culture experiment
To evaluate the efficacy of the preferred compound PL17 in inducing anti-tumor immunity, we monitored the effect of compound PL17 on Jurkat T cell killing HepG2 cells by cell co-culture assays. As shown in FIG. 6A/B, compound PL17 showed no toxicity to either Jurkat T cells or HepG2 cells over the corresponding concentration range. Meanwhile, jurkat T cells alone failed to exhibit antitumor activity against HepG2 cells. When HepG2, PL17 and Jurkat T cells are co-cultured, the dead tumor cells increase in a concentration-dependent manner, with their IC 50 The value was 4.32. Mu.M (FIG. 6C/D). These results indicate that PL17 is effective in increasing the killing capacity of Jurkat T cells against HepG2 cells in cell co-culture models.
Test example 4: in vivo pharmacodynamics study of compound PL17 on B16-F10 mouse tumor model
To evaluate the in vivo efficacy of PL17, we selected a B16-F10 mouse tumor model for study. C57 Male mice (18-20 g) were randomly divided into four groups: control group, low dose (8 mg/kg), medium dose (15 mg/kg), high dose (30 mg/kg). As shown in fig. 7A/C, compound PL17 showed a highly potent tumor inhibitory effect, with a 53.2%,75.9%,88.6% decrease in tumor mass after different doses of PL17 administration, respectively, relative to the solvent control group. Correspondingly, the tumor volumes were reduced by 74.4%,84.3% and 95.4%, respectively. Meanwhile, the body weight of the mice was analyzed in summary, and the body weight of the mice was maintained relatively stable during the PL17 administration treatment period, and no symptoms of weight loss occurred, indicating that PL17 did not affect the quality of life of the mice while exerting the antitumor effect (fig. 7D).

Claims (8)

1. A biphenyl oxadiazole ether compound represented by the following formula I:
r may be selected from
2. The biphenyl oxadiazole ether compound of claim 1, wherein the compound comprises any one of the following structures:
3. a method for preparing the biphenyl oxadiazole ether compound according to any one of claims 1-2, wherein the synthetic route of the compound is shown in the following formula II:
(1) Compound L1 is diazotized and hydrolyzed to form compound L2;
(2) The compound L2 reacts with phenylboronic acid under the suzuki coupling condition to generate L3;
(3) Compound L3 is obtained by substituting phenolic hydroxyl groups with ethyl bromoacetate to give compound L4;
(4) Hydrazinolysis reaction is carried out on the compound L4 and hydrazine hydrate to generate a compound L5;
(5) The compound L5 and carbon disulfide react to form a ring to form a compound L6;
(6) Reacting the compound L6 with corresponding benzyl bromobenzaldehyde to generate compounds L7a and L7b;
(7) Compounds L7a, b were subjected to sodium cyanoborohydride mediated reductive amination to give compounds PL1-27.
4. Use of the biphenyl oxadiazole ether compound according to any one of claims 1-2, characterized in that: the application is the application of the biphenyl oxadiazole ether compound in preparation of an immune checkpoint inhibitor.
5. Use of the biphenyl oxadiazole ether compound according to any one of claims 1-2, characterized in that: the application is the application of the phenyl-substituted five-membered heterocyclic compound in preparing an inhibitor with PD-1/PD-L1 inhibition activity.
6. Use of the biphenyl oxadiazole ether compound according to any one of claims 1-2, characterized in that: the application is the application of the biphenyl oxadiazole ether compound in preparing antitumor drugs.
7. A pharmaceutical composition comprising the biphenyl oxadiazole ether compound of any one of claims 1 to 2, characterized in that: the pharmaceutical composition takes the biphenyl oxadiazole ether compound as an active ingredient and a pharmaceutically acceptable carrier.
8. The pharmaceutical composition of the biphenyl oxadiazole ether compound according to claim 7, wherein: the pharmaceutical composition is in the form of capsule, powder, tablet, granule, pill, injection, syrup, oral liquid, inhalant, ointment, suppository or patch.
CN202310761086.9A 2023-06-25 2023-06-25 Biphenyl oxadiazole ether derivative as PD-1/PD-L1 small molecule inhibitor and synthesis method and application thereof Pending CN116987046A (en)

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