CN115403510B - PD-L1/CXCL12 double-target inhibitor, preparation method and application - Google Patents
PD-L1/CXCL12 double-target inhibitor, preparation method and application Download PDFInfo
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
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Abstract
The invention relates to a PD-L1/CXCL12 double-target inhibitor. The chemical structure of the compound is shown as the following formula (I), wherein R 1 Represents Br, cl; r is R 2 Represents H,
R 3 Representative of
X represents H,
The PD-L1/CXCL12 double-target inhibitor can inhibit the mutual combination of PD-1/PD-L1 and the combination of CXCL12/CXCR4, and has good tumor inhibition effect in a mouse melanoma-bearing experiment.
Description
Technical Field
The invention relates to an organic compound, in particular to a PD-L1/CXCL12 double-target inhibitor, a preparation method and application.
Background
The receptor 1 for apoptosis/ligand 1 for apoptosis (PD-1/PD-L1) pathway is a very promising approach to anticancer therapy. Clinical studies have shown that the Overall Response Rate (ORR) of PD-L1 inhibitors is low (< 30%), and researchers have attempted to combine PD-L1 inhibitors with other anticancer drugs for the treatment of cancer.
The chemokine CXCL12 (C-X-C Motif Chemokine Ligand 12) is a ligand for CXCR4 (C-X-C Motif Chemokine Receptor 4) and plays a key role in tumor metastasis, immune escape and inflammation. Furthermore, CXCL12 exerts immunosuppressive effects and reduces T cell infiltration by modulating the tumor immune microenvironment, complementary to the PD-1/PD-L1 axis. Thus, the CXCL12/CXCR4 axis is considered an excellent target for anti-cancer and anti-inflammatory therapies. Recent studies indicate that anti-PD-1/L1 antibodies and CXCL12 inhibitors show better anti-tumor efficacy than monotherapy and are well tolerated and safe, indicating potential clinical application value for dual immunotherapy targeting the PD-L1 and CXCL12/CXCR4 axes as cancer treatment.
However, combination therapy has several drawbacks, including unpredictable PK/PD in combination with two or more drugs. One potential alternative to combination therapy is the use of a single molecule with dual or multi-targeting capability, as PK and PD for a single molecule are easily predicted. Therefore, a series of compounds which target PD-L1 and CXCL12 simultaneously are designed, and the compounds have very good application early stage as potential dual immunotherapy, and are helpful for improving the effect of tumor immunotherapy.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a PD-L1/CXCL12 double-target inhibitor, which can inhibit the mutual combination of a programmed cell death receptor 1/programmed cell death complex 1 (PD-1/PD-L1), has high affinity to CXCL12 and has remarkable effect.
The scheme for solving the technical problems is as follows:
a PD-L1/CXCL12 double-target inhibitor has a chemical structure shown in the following formula (I),
wherein R is 1 Represents Br, cl;
R 2 represents H,
R 3 Representative of
/>
X represents H,
The PD-L1/CXCL12 double-target inhibitor can inhibit the mutual combination of a programmed cell death receptor 1/a programmed cell death ligand 1 (PD-1/PD-L1), can be used for preparing PD-1/PD-L1 and CXCL12 inhibitors, and has remarkable effect.
The PD-L1/CXCL12 double-target inhibitor disclosed by the invention is preferably one of the following compounds:
the chemical structure of the PD-L1/CXCL12 double-target inhibitor CP1 is as follows:
the chemical structure of the PD-L1/CXCL12 double-target inhibitor CP2 is as follows:
the chemical structure of the PD-L1/CXCL12 double-target inhibitor CP3 is as follows:
the chemical structure of the PD-L1/CXCL12 double-target inhibitor P4 is as follows:
the chemical structure of the PD-L1/CXCL12 double-target inhibitor CP5 is as follows:
the chemical structure of the PD-L1/CXCL12 double-target inhibitor CP6 is as follows:
the chemical structure of the PD-L1/CXCL12 double-target inhibitor CP7 is as follows:
the chemical structure of the PD-L1/CXCL12 double-target inhibitor CP8 is as follows:
the chemical structure of the PD-L1/CXCL12 double-target inhibitor CP9 is as follows:
the chemical structure of the PD-L1/CXCL12 double-target inhibitor CP10 is as follows:
the chemical structure of the PD-L1/CXCL12 double-target inhibitor CP11 is as follows:
the chemical structure of the PD-L1/CXCL12 double-target inhibitor CP12 is as follows:
the chemical structure of the PD-L1/CXCL12 double-target inhibitor CP13 is as follows:
the chemical structure of the PD-L1/CXCL12 double-target inhibitor CP14 is as follows:
the chemical structure of the PD-L1/CXCL12 double-target inhibitor P15 is as follows:
the chemical structure of the PD-L1/CXCL12 double-target inhibitor CP16 is as follows:
the chemical structure of the PD-L1/CXCL12 double-target inhibitor CP17 is as follows:
the chemical structure of the PD-L1/CXCL12 double-target inhibitor CP18 is as follows:
the chemical structure of the PD-L1/CXCL12 double-target inhibitor CP19 is as follows:
the chemical structure of the PD-L1/CXCL12 double-target inhibitor CP20 is as follows:
the chemical structure of the PD-L1/CXCL12 double-target inhibitor CP21 is as follows:
the chemical structure of the PD-L1/CXCL12 double-target inhibitor CP22 is as follows:
the chemical structure of the PD-L1/CXCL12 double-target inhibitor CP23 is as follows:
the preparation method of the PD-L1/CXCL12 double-target inhibitor comprises the following steps of:
the invention relates to a preparation method of a PD-L1/CXCL12 double-target inhibitor, which is synthesized by four synthetic routes. Route one to three are the synthesis of the PD-L1 inhibitor moiety, and route four is the synthesis of the designed PD-L1& CXCL12 dual-target inhibitor.
Route one is as follows:
α Reagents and conditions:(a)DCM,0℃,0.5h,80％；(b)NaHCO 3 ,DMF,60℃,1h,45％；(c)NaCO 3 ,DMF,80 ℃,1h,65％；(d)AcOH,NaBH 3 CN,DMF,80℃,2hrs,15％～25％.
route two is shown below:
α Reagents and conditions:(a)DCM,0℃,0.5h,90％；(b)NaHCO 3 ,DMF,60℃,1h,40％；(c)AcOH,NaBH 3 CN, DMF,80℃,2hrs,15％～25％.
route three
α Reagents and conditions:(a)DCM,0℃,0.5h,90％；(b)NaHCO 3 ,DMF,60℃,1h,40％；(c)NaHCO 3 ,DMF,80 ℃,1h,40％～45％；(d)AcOH,NaBH 3 CN,DMF,80℃,2hrs,15％～25％.
Route four
Reagents and conditions:(a)NaOH,MeOH,25℃,12h，50％；(b)Na 2 CO3,DMF,80℃,1h，60％；(c)4M HCl/1,4-dioxane,DCM,0℃,1h,60％；(d)i,HATU,DIPEA,DMF,25℃,1h,60％～70％；ii,4M HCl/1,4-dioxane,DCM,0℃,2h；70～80％(e)HATU,DIPEA,DMF,25℃,1h，60％～70％.
In the above reaction formula, R 1 Represents Br, cl; r is R 2 Represents H,
R 3 Represents->
X represents H, & lt + & gt>
The PD-L1/CXCL12 double-target inhibitor can inhibit the mutual combination of a programmed cell death receptor 1/a programmed cell death ligand 1 (PD-1/PD-L1), has high binding affinity to CXCL12, can inhibit CXCL12 and CXCR4 axes, can be used for preparing the PD-L1 and CXCL12 double-inhibitor, and has remarkable anti-tumor effect.
The inhibition effect of the PD-L1/CXCL12 double-target inhibitor on PD-1/PD-L1 is measured by adopting an HTRF (homogeneous time resolved fluorescence) technical standard operation program, and the result shows that the compound has obvious inhibition effect on PD-1/PD-L1. The binding affinity of this compound to CXCL12 was determined using Surface Plasmon Resonance (SPR) and circular dichroism spectroscopy (CD for short) analysis. Of these, preferred compounds CP23 have been attached to their nuclear magnetic resonance hydrogen spectra (see FIG. 1) and nuclear magnetic resonance carbon spectra (see FIG. 2).
In addition, the PD-L1/CXCL12 double-target inhibitor disclosed by the invention can be used for treating a mouse melanoma model and shows better in-vivo anti-tumor activity (shown in figure 3).
Drawings
The invention is further described with reference to the accompanying drawings and examples, in which:
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a compound (E) -1- (1- (5-chloro-2- ((3-cyanobenzyl) oxy) -4- ((2-methyl- [1,1' -biphenyl ] -3-yl) methoxy) benzyl) piperidine-2-carbonyl) -N- (4- (2-methoxy-4- (3- (4-methoxyphenyl) -3-oxo-1-en-1-yl) phenoxy) methyl) benzylpiperidine-4-carboxamide (CP 23) according to formula (I) of the present invention.
FIG. 2 is a nuclear magnetic resonance carbon spectrum of the compound (E) -1- (1- (5-chloro-2- ((3-cyanobenzyl) oxy) -4- ((2-methyl- [1,1' -biphenyl ] -3-yl) methoxy) benzyl) piperidine-2-carbonyl) -N- (4- (2-methoxy-4- (3- (4-methoxyphenyl) -3-oxo-1-en-1-yl) phenoxy) methyl) benzylpiperidine-4-carboxamide (CP 23) according to formula (I) of the present invention.
FIG. 3 shows the therapeutic effect of the compound CP23 of formula (I) of the present invention on mice bearing B16-F10 melanoma tumors. (A) As tumor images, it can be seen that the tumor size significantly changed after drug administration treatment; (B) For mouse tumor weight, the treated group was significantly reduced and there was a significant difference compared to the non-treated group; (C) The tumor volume of the mice changes with time, and the volume of the treatment group increases slowly compared with that of the non-treatment group; (D) For the change in body weight of the mice during the treatment period, no significant change in body weight of the mice was seen. P <0.05, n=6.
Detailed Description
The invention is further described below in conjunction with the detailed description.
Example 1 (preparation of Compounds and identification)
The specific operation method of the PD-L1/CXCL12 double-target inhibitor route is as follows, and the target product is synthesized through routes 1-4:
dissolving the (1-1) in dichloromethanol, slowly dripping a boron tribromide solution, reacting for 30 minutes in an ice bath, quenching the reaction by using methanol after the reaction is finished, and passing the silica gel through a column to obtain a target product (1-2); adding 1.2 mol times of 5-chloro-2, 4-dihydroxybenzaldehyde and 2 mol times of sodium bicarbonate according to the mol weight of (1-2), reacting for 1 hour at 60 ℃ under the condition of DMF, adding ethyl acetate and water into the reaction solution for extraction, drying an organic phase with anhydrous sodium sulfate, removing a solvent, and separating and purifying by column chromatography to obtain an intermediate (1-3); (1-3) and (2 equivalent) sodium bicarbonate, respectively reacting with 3- (bromomethyl) benzonitrile, 1- (bromomethyl) -4- (trifluoromethoxy) benzene and ethyl 2-bromoacetate under the condition of 80 ℃ and DMF, pouring the reaction mixture into water after the reaction is finished, extracting the ethyl acetate, washing an organic phase with brine for 3 times, drying the organic phase with anhydrous sodium sulfate, and passing the organic phase through a silica gel column to obtain (1-4); the biphenyl compound (1-4) and (2 equivalent) piperidine formic acid are dissolved by DMF, added with (2 equivalent) cyano sodium borohydride, added with two drops of glacial acetic acid dropwise, heated to 80 ℃ for 2 hours of reaction, monitored by TLC, after the reaction is finished, the reaction mixture is poured into water, extracted by ethyl acetate, the organic phase is washed 3 times by brine and dried by anhydrous sodium sulfate, and the target product (1-5) can be obtained by passing silica gel through a column, namely BMS-1233, CH-1 and CH-11 respectively.
In the second route, boron tribromide is dropwise added into methylene dichloride solution of aryl benzyl alcohol in an ice bath. After the reaction is finished, the reaction is quenched by methanol, and silica gel is passed through a column to obtain (2-2); the intermediate is reacted with (1.2 equivalent) 3-bromo-4-hydroxybenzaldehyde and (2 equivalent) sodium bicarbonate for 1 hour under the condition of DMF at 60 ℃, ethyl acetate and water are added into the reaction solution for extraction, the organic phase is dried by anhydrous sodium sulfate, the solvent is removed, the intermediate (2-3) is obtained through column chromatography separation and purification, then the intermediate (2 equivalent) and (2 equivalent) piperidine formic acid are dissolved by DMF, the (2 equivalent) sodium cyanoborohydride is added, two drops of glacial acetic acid are dripped, the reaction is heated to 80 ℃ for 2 hours, TLC monitoring is carried out, after the reaction is finished, the reaction mixture is poured into water, ethyl acetate is extracted, the organic phase is washed 3 times by brine, and dried by anhydrous sodium sulfate, and the target product BMS-8 (2-4) can be obtained through a silica gel column.
Route III (3-1) to (3-4) are consistent with the process of route one, the intermediate (3-4) and (2 equivalent) 2-amino-2-methylpropanoic acid are dissolved by DMF, the (2 equivalent) sodium cyanoborohydride is added, two drops of glacial acetic acid are dripped, the reaction is heated to 80 ℃ for 2 hours, TLC monitoring is carried out, after the reaction is finished, the reaction mixture is poured into water, ethyl acetate is extracted, the organic phase is washed 3 times by brine and dried by anhydrous sodium sulfate, and the target product NP19 is obtained by passing silica gel through a column, namely (3-5).
In the fourth route, 4-methoxy acetophenone (4-1) is dissolved in methanol and stirred for 5-10min until the mixture is completely dissolved, KOH (2 equivalents) is added and stirred for 2h, the pH value of the reaction solution is regulated to 6.5-7, the reaction solution is filtered, the filtrate is dried by spin, vanillin (1.05 equivalents) is added into the reaction solution, and the temperature is raised to 80 ℃ for reaction for 20h. TLC monitoring, and directly passing the spin-dried solvent through a silica gel column after the reaction is finished to obtain an intermediate (4-2); then, (4-2) and benzyl bromide (1 equivalent) with Boc protecting group, (2 equivalents) sodium bicarbonate, under the condition of 80 ℃ and DMF (dimethyl formamide) react for 1h, after the reaction is finished, the reaction mixture is poured into water, ethyl acetate is extracted, an organic phase is washed 3 times by brine and dried by anhydrous sodium sulfate, silica gel is passed through a column to obtain (4-3), the (4-3) is dissolved into dichloromethane solution, 4M HCl/1,4-Dioxane (1 mL) is added to remove Boc protecting group, and after the reaction is finished, the product (4-4) is obtained by spin drying the solution; organic acid (1 equivalent), organic amine (1 equivalent), HATU (1.2 equivalent), DIPEA (1.8 equivalent) containing Boc protecting group were put in DMF and reacted at room temperature for 1 hour. After the amide condensation reaction is finished, pouring the reaction mixture into water, extracting by ethyl acetate, washing an organic phase with brine for 3 times, drying by anhydrous sodium sulfate, and passing silica gel through a column to obtain a target product. The reaction was dissolved in methylene chloride solution, 4M HCl/1,4-Dioxane (1 mL) was added to remove the Boc protecting group, and after the completion of the reaction, the solution was dried by spin-drying to obtain the product (4-5). (4-5) the product (1 equivalent) synthesized with the previous schemes one, two and three was condensed, HATU (1.2 equivalent) and DIPEA (1.8 equivalent) were put in DMF, reacted at room temperature for 1 hour, after the reaction was completed, the reaction mixture was poured into water, extracted with ethyl acetate, and the organic phase was washed 3 times with brine and dried over anhydrous sodium sulfate, and silica gel was passed through a column to obtain the final product, i.e., CP1-23.
The identification result of the target product CP1 is as follows:
(E)-1-(3-bromo-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)-N-(5-((4-((2-methoxy-4-(3-(4-methoxyph enyl)-3-oxoprop-1-en-1-yl)phenoxy)methyl)benzyl)amino)-5-oxopentyl)piperidine-2-carboxamide(CP1). Yellow oil； 1 H NMR(400MHz,DMSO)δ8.27(t,J＝5.8Hz,1H),8.17(d,J＝8.8Hz,2H),7.84(dd,J＝16.2, 10.5Hz,2H),7.66(d,J＝15.5Hz,1H),7.60(s,1H),7.53(d,J＝8.8Hz,2H),7.46(t,J＝7.3Hz,2H),7.40– 7.36(m,3H),7.31(d,J＝7.1Hz,4H),7.22(dd,J＝15.7,7.2Hz,4H),7.09(dd,J＝8.5,5.0Hz,3H),5.21(s,2H), 5.12(s,2H),4.25(d,J＝5.7Hz,2H),3.87(d,J＝3.6Hz,6H),3.65(d,J＝13.5Hz,1H),3.17(d,J＝4.9Hz,1H), 3.12(d,J＝7.4Hz,1H),3.08(d,J＝7.3Hz,1H),3.03(s,1H),2.68(d,J＝7.7Hz,2H),2.22(s,3H),2.13(d,J＝ 7.1Hz,2H),1.99(d,J＝7.3Hz,1H),1.89(d,J＝9.9Hz,1H),1.69(dd,J＝23.1,13.2Hz,3H),1.53(dd,J＝10.7, 8.1Hz,3H),1.46–1.41(m,2H).MS：m/z＝978.6[M+1] + .HPLC:t R 21.875min,purity 100％.
the preparation method of the PD-L1/CXCL12 double-target inhibitor P2-17 is the same as that of the PD-L1/CXCL12 double-target inhibitor P1. The results of the identification of the target products P1-17 are respectively as follows:
(E)-1-(3-bromo-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)-N-(4-((2-methoxy-4-(3-(4-methoxyphenyl )-3-oxoprop-1-en-1-yl)phenoxy)methyl)benzyl)piperidine-2-carboxamide(CP2).Light yellow solid；mp: 124.8–125.9℃； 1 H NMR(400MHz,DMSO)δ8.42(t,J＝6.1Hz,1H),8.17(d,J＝8.9Hz,2H),7.82(d,J＝15.5 Hz,1H),7.65(d,J＝15.4Hz,1H),7.58(d,J＝1.6Hz,1H),7.54–7.50(m,2H),7.46(t,J＝7.3Hz,2H),7.38(s, 2H),7.31(dd,J＝14.1,7.1Hz,7H),7.27–7.12(m,3H),7.08(dd,J＝11.2,8.7Hz,3H),5.22(s,2H),5.10(s, 2H),4.33(dd,J＝21.8,5.9Hz,2H),4.14–4.07(m,2H),3.86(d,J＝9.0Hz,6H),3.65(s,1H),3.06(d,J＝13.2 Hz,1H),2.77(d,J＝12.2Hz,2H),2.22(s,3H),1.89(d,J＝13.6Hz,1H),1.77(d,J＝14.1Hz,1H),1.70–1.65 (m,1H),1.62(d,J＝12.4Hz,1H),1.53(s,1H),1.38(d,J＝8.4Hz,1H). 13 C NMR(101MHz,DMSO)δ187.72, 173.60,163.48,153.82,150.48,149.69,143.98,142.52,141.69,140.02,135.70,135.53,134.15,133.58,132.75, 131.22,131.08,129.99,129.83,129.57,128.65,128.28,127.91,127.70,127.37,125.92,123.91,120.11,114.36, 113.96,113.55,111.47,111.33,70.09,69.66,67.53,58.65,56.20,55.96,51.22,49.00,42.11,30.04,26.97,24.97, 23.53,21.16,16.21.MS：m/z＝879.4[M+1] + .HPLC:t R 22.734min,purity 98.834％.
(E)-1-(1-(3-bromo-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)piperidine-2-carbonyl)-N-(4-((2-metho xy-4-(3-(4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenoxy)methyl)benzyl)piperidine-4-carboxamide(CP3). Yellow oil；1H NMR(400MHz,DMSO)δ8.37(d,J＝5.9Hz,1H),8.17(d,J＝8.8Hz,2H),7.83(d,J＝15.5Hz, 1H),7.66(d,J＝15.5Hz,1H),7.53(d,J＝7.8Hz,3H),7.46(t,J＝7.4Hz,2H),7.40(d,J＝7.8Hz,2H),7.35(d, J＝10.2Hz,1H),7.31(d,J＝7.2Hz,3H),7.23(dd,J＝19.1,6.6Hz,5H),7.09(d,J＝8.7Hz,3H),5.23(s,2H), 5.13(s,2H),4.43(d,J＝15.4Hz,2H),4.27(d,J＝3.4Hz,2H),3.87(d,J＝2.9Hz,6H),3.71–3.54(m,2H), 3.17(d,J＝3.1Hz,2H),3.12(d,J＝7.5Hz,1H),3.04(d,J＝11.7Hz,2H),2.84(d,J＝4.7Hz,1H),2.69–2.56 (m,2H),1.99(d,J＝2.4Hz,1H),1.76(d,J＝13.0Hz,2H),1.64(d,J＝5.3Hz,2H),1.51–1.34(m,5H).MS： m/z＝990.64[M+1]+.HPLC:tR 21.682min,purity 95.907％.
(E)-1-(3-bromo-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)-N-(4-((4-((2-methoxy-4-(3-(4-methoxyph enyl)-3-oxoprop-1-en-1-yl)phenoxy)methyl)benzyl)amino)-4-oxobutyl)piperidine-2-carboxamide(CP4). Yellow oil； 1 H NMR(400MHz,DMSO)δ8.32(s,1H),8.17(d,J＝8.9Hz,2H),7.92(s,1H),7.82(d,J＝15.4 Hz,1H),7.72–7.59(m,3H),7.57–7.43(m,5H),7.39(d,J＝8.0Hz,3H),7.32(s,3H),7.28–7.19(m,4H), 7.12–7.06(m,2H),5.22(s,2H),5.12(s,2H),4.26(d,J＝6.0Hz,2H),3.86(d,J＝10.5Hz,6H),3.68–3.61(m, 2H),3.18(d,J＝5.8Hz,2H),3.12(s,2H),2.75(d,J＝4.2Hz,2H),2.68(d,J＝6.0Hz,2H),2.22(s,3H),2.17– 2.12(m,2H),1.99(d,J＝5.3Hz,2H),1.67(d,J＝7.7Hz,2H),1.48(d,J＝13.4Hz,2H).MS：m/z＝964.6 [M+1] + .HPLC:t R 21.662min,purity 100％.
(E)-1-(3-bromo-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)-N-(3-((4-((2-methoxy-4-(3-(4-methoxyph enyl)-3-oxoprop-1-en-1-yl)phenoxy)methyl)benzyl)amino)-3-oxopropyl)piperidine-2-carboxamide(CP5). Yellow oil； 1 H NMR(400MHz,DMSO)δ8.38(t,J＝5.9Hz,1H),8.16(d,J＝8.7Hz,2H),7.89(s,1H),7.82(d, J＝15.5Hz,1H),7.66(d,J＝15.4Hz,1H),7.59(s,1H),7.52(d,J＝10.5Hz,2H),7.46(t,J＝7.2Hz,2H),7.36 (d,J＝8.2Hz,3H),7.31(dd,J＝12.3,5.5Hz,4H),7.24–7.20(m,3H),7.14–7.03(m,3H),5.21(s,2H),5.12(s, 2H),4.22(dt,J＝10.6,6.9Hz,2H),3.87(d,J＝5.9Hz,6H),3.67(s,1H),3.01(d,J＝13.6Hz,1H),2.73–2.66 (m,2H),2.37(t,J＝6.6Hz,2H),2.22(s,3H),2.04–1.98(m,1H),1.85(t,J＝9.7Hz,1H),1.70(s,1H),1.64(d, J＝9.0Hz,1H),1.51(d,J＝10.1Hz,3H),1.33(d,J＝10.1Hz,2H).MS：m/z＝950.7[M+1] + .HPLC:t R 21.997 min,purity 97.381％.
(E)-1-(5-chloro-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2-((4-(trifluoromethoxy)benzyl)oxy)benzyl)-N-(3 -((4-((2-methoxy-4-(3-(4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenoxy)methyl)benzyl)amino)-3-oxopropyl) piperidine-2-carboxamide(CP6).Yellowoil； 1 H NMR(400MHz,DMSO)δ8.36(t,J＝5.7Hz,1H),8.16(d,J ＝8.8Hz,2H),7.82(d,J＝15.4Hz,2H),7.65(d,J＝15.4Hz,1H),7.52(d,J＝13.2Hz,2H),7.46(dd,J＝10.6, 6.4Hz,4H),7.39(d,J＝7.3Hz,1H),7.36(d,J＝7.9Hz,2H),7.31(d,J＝8.1Hz,4H),7.28(d,J＝7.5Hz,1H), 7.21(t,J＝7.0Hz,3H),7.08(dd,J＝8.3,6.2Hz,3H),6.94(s,1H),5.22(s,2H),5.11(s,2H),4.91(s,2H),4.28– 4.19(m,2H),3.87(d,J＝6.1Hz,6H),2.76(d,J＝9.5Hz,2H),2.67(s,1H),2.34(s,2H),2.22(s,3H),2.01(dd, J＝15.8,6.4Hz,2H),1.90(t,J＝9.8Hz,2H),1.74(d,J＝9.6Hz,1H),1.62(d,J＝8.6Hz,2H),1.50(d,J＝7.2 Hz,4H).MS：m/z＝1096.6[M+1] + .HPLC:t R 21.684min,purity 96.268％.
(E)-1-(5-chloro-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2-((4-(trifluoromethoxy)benzyl)oxy)benzyl)-N-(4 -((2-methoxy-4-(3-(4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenoxy)methyl)benzyl)piperidine-2-carboxami de(CP7).Yellow oil； 1 H NMR(400MHz,DMSO)δ8.28(t,J＝6.4Hz,1H),8.16(d,J＝8.7Hz,2H),7.82(d,J ＝15.5Hz,1H),7.65(d,J＝15.4Hz,1H),7.60–7.55(m,2H),7.53(s,1H),7.47(dd,J＝15.2,7.2Hz,4H),7.39 (d,J＝8.5Hz,3H),7.31(d,J＝7.3Hz,5H),7.28(d,J＝7.6Hz,1H),7.21(d,J＝7.8Hz,3H),7.08(dd,J＝13.3, 10.3Hz,3H),5.23(d,J＝9.2Hz,4H),5.08(s,2H),4.25(dt,J＝15.1,9.0Hz,2H),3.86(d,J＝11.4Hz,6H), 3.48(s,1H),2.78(d,J＝15.6Hz,2H),2.24(s,3H),2.04–1.97(m,1H),1.93(t,J＝12.6Hz,1H),1.80–1.74(m, 1H),1.72–1.56(m,3H),1.54–1.49(m,1H),1.44(d,J＝4.1Hz,1H). 13 C NMR(101MHz,DMSO)δ187.70, 173.55,163.75,156.12,153.45,150.48,149.76,143.91,142.64,141.74,139.91,136.84,135.54,134.38,131.16, 129.80,129.56,128.66,128.26,127.47,125.96,123.90,121.49,120.66,120.12,114.35,113.51,111.48,100.91, 70.07,69.51,67.81,56.18,55.96,55.33,53.44,31.68,30.83,30.12,16.22.MS：m/z＝1025.4[M+1] + .HPLC:t R 24.243min,purity 99.488％.
(E)-1-(1-(5-chloro-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2-((4-(trifluoromethoxy)benzyl)oxy)benzyl)pi peridine-2-carbonyl)-N-(4-((2-methoxy-4-(3-(4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenoxy)methyl)benzy l)piperidine-4-carboxamide(CP8).Yellow oil； 1 H NMR(400MHz,DMSO)δ8.35(s,1H),8.17(d,J＝8.8Hz, 2H),7.82(d,J＝15.5Hz,1H),7.66(d,J＝15.5Hz,1H),7.60(d,J＝8.5Hz,2H),7.50(dd,J＝19.2,11.2Hz, 3H),7.37(ddd,J＝22.4,16.2,8.9Hz,7H),7.23(t,J＝13.4Hz,3H),7.13–7.02(m,3H),5.31–5.05(m,6H), 4.38(d,J＝10.9Hz,2H),4.26(d,J＝2.6Hz,2H),3.87(d,J＝9.7Hz,4H),3.54–3.45(m,2H),3.06–2.84(m, 5H),2.68(s,2H),2.23(s,3H),2.01(dd,J＝15.3,7.1Hz,4H),1.68(dd,J＝30.0,6.4Hz,5H),1.48–1.28(m, 6H).MS：m/z＝1136.7[M+1] + .HPLC:t R 22.679min,purity 99.012％.
(E)-1-(5-chloro-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2-((4-(trifluoromethoxy)benzyl)oxy)benzyl)-N-(4 -((4-((2-methoxy-4-(3-(4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenoxy)methyl)benzyl)amino)-4-oxobutyl)p iperidine-2-carboxamide(CP9).Yellow oil； 1 H NMR(400MHz,DMSO)δ8.29(d,J＝6.3Hz,1H),8.17(d,J＝ 8.8Hz,2H),7.80(t,J＝12.4Hz,2H),7.68(s,1H),7.60(d,J＝8.5Hz,2H),7.54(s,1H),7.47(dd,J＝13.6,7.4 Hz,4H),7.43–7.36(m,5H),7.35–7.28(m,4H),7.27–7.21(m,3H),7.08(t,J＝7.5Hz,3H),5.24(d,J＝5.4 Hz,4H),5.11(s,2H),4.25(d,J＝5.6Hz,2H),3.87(d,J＝5.5Hz,6H),2.73(dd,J＝10.0,6.4Hz,3H),2.23(s, 3H),2.11(t,J＝7.3Hz,2H),2.02–1.98(m,1H),1.94–1.83(m,2H),1.75(s,1H),1.68–1.61(m,3H),1.51(dd, J＝22.5,8.2Hz,3H),1.37(dd,J＝11.9,4.8Hz,2H).MS：m/z＝1110.6[M+1] + .HPLC:t R 23.384min,purity 97.701％.
(E)-4-(2-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)amino)-2-met hylpropanamido)-N-(4-((2-methoxy-4-(3-(4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenoxy)methyl)benzyl)b utanamide(CP10).Yellow oil； 1 H NMR(400MHz,DMSO)δ8.31(d,J＝5.8Hz,1H),8.17(d,J＝8.6Hz,2H), 7.95(s,1H),7.86–7.73(m,4H),7.71–7.50(m,4H),7.46(dd,J＝13.2,5.8Hz,4H),7.37(t,J＝7.6Hz,3H), 7.31(d,J＝7.8Hz,3H),7.27(s,2H),7.21(s,1H),7.08(dd,J＝10.2,4.9Hz,3H),5.30(s,2H),5.23(s,2H),5.12 (s,2H),4.25(d,J＝5.6Hz,2H),3.87(d,J＝5.0Hz,6H),3.50(s,2H),3.03(d,J＝6.1Hz,2H),2.23(s,3H),2.12 (t,J＝7.4Hz,2H),2.04–1.95(m,2H),1.66–1.60(m,2H),1.20(s,6H).MS：m/z＝1025.6[M+1] + .HPLC:t R 20.848min,purity 95.976％.
(E)-2-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)amino)-N-(4-((2- methoxy-4-(3-(4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenoxy)methyl)benzyl)-2-methylpropanamide (CP11).Yellow oil； 1 H NMR(400MHz,DMSO)δ8.29(t,J＝6.2Hz,1H),8.17(d,J＝8.7Hz,2H),7.99–7.89 (m,2H),7.85–7.74(m,3H),7.65(d,J＝15.5Hz,1H),7.60–7.52(m,2H),7.46(dd,J＝12.9,5.6Hz,3H),7.39 (d,J＝9.0Hz,2H),7.36–7.31(m,3H),7.30–7.26(m,2H),7.22(dd,J＝12.7,7.8Hz,3H),7.08(t,J＝8.2Hz, 2H),7.04(s,1H),6.91(dd,J＝17.3,10.8Hz,1H),5.24(d,J＝13.1Hz,4H),5.10(s,2H),4.41–4.30(m,1H), 4.27(d,J＝6.1Hz,2H),3.87(d,J＝6.5Hz,6H),3.61(s,1H),3.52(s,2H),2.22(s,3H),1.25(s,6H).MS：m/z ＝940.4[M+1] + .HPLC:t R 21.515min,purity 98.528％.
(E)-2-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)amino)-N-(3-((4-( (2-methoxy-4-(3-(4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenoxy)methyl)benzyl)amino)-3-oxopropyl)-2-m ethylpropanamide(CP12).Yellow oil； 1 H NMR(400MHz,DMSO)δ8.37(s,1H),8.16(d,J＝8.8Hz,2H), 7.94(d,J＝12.8Hz,2H),7.89–7.75(m,3H),7.72–7.49(m,4H),7.46(s,3H),7.39(d,J＝7.5Hz,1H),7.36(d, J＝7.9Hz,2H),7.31(d,J＝8.2Hz,2H),7.27(s,1H),7.24–7.19(m,2H),7.18–6.93(m,4H),5.27(d,J＝29.4 Hz,4H),5.11(s,2H),4.23(d,J＝5.6Hz,2H),3.87(d,J＝6.7Hz,6H),3.47(d,J＝5.2Hz,2H),3.30(s,2H), 2.36–2.28(m,2H),2.22(s,3H),2.00(t,J＝10.1Hz,2H),1.51–1.41(m,1H),1.18(s,6H).MS：m/z＝1011.5 [M+1] + .HPLC:t R 20.879min,purity 95.343％.
(E)-5-(2-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)amino)-2-met hylpropanamido)-N-(4-((2-methoxy-4-(3-(4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenoxy)methyl)benzyl)p entanamide(CP13).Yellow oil； 1 H NMR(400MHz,DMSO)δ8.26(d,J＝5.7Hz,1H),8.16(d,J＝8.8Hz,2H), 7.95(s,2H),7.82(d,J＝15.2Hz,3H),7.74(s,1H),7.63(dd,J＝20.2,12.1Hz,2H),7.54(s,1H),7.46(dd,J＝ 14.9,7.5Hz,4H),7.38(d,J＝7.6Hz,3H),7.31(d,J＝7.1Hz,2H),7.28–7.18(m,4H),7.10–7.06(m,3H), 5.30(s,2H),5.23(s,2H),5.11(s,2H),4.25(d,J＝5.8Hz,2H),3.87(d,J＝4.9Hz,6H),3.49(s,2H),3.01(d,J＝ 6.3Hz,2H),2.23(s,3H),2.11(t,J＝7.2Hz,2H),2.02–1.93(m,2H),1.49–1.43(m,2H),1.38–1.33(m,2H), 1.19(s,6H). 13 C NMR(101MHz,DMSO)δ184.20,176.05,172.47,159.38,157.24,155.31,153.46,151.24, 141.44,139.58,135.71,134.07,132.57,132.11,131.45,131.27,130.35,130.22,130.18,130.03,129.56,128.67, 128.31,127.63,126.22,125.01,122.29,120.38,119.03,114.36,113.57,111.91,77.05,74.05,69.91,58.63,56.42, 55.89,55.72,49.71,42.27,35.12,29.24,27.98,27.18,25.89,20.82,16.17.MS：m/z＝1039.5[M+1] + .HPLC:t R 20.946min,purity 98.747％.
ethyl(E)-2-(4-chloro-2-((2-((3-((4-((2-methoxy-4-(3-(4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenoxy)methyl )benzyl)amino)-3-oxopropyl)carbamoyl)piperidin-1-yl)methyl)-5-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)p henoxy)acetate(CP14).Yellow oil； 1 H NMR(400MHz,DMSO)δ8.36(s,1H),8.16(d,J＝8.7Hz,2H),7.82(d, J＝15.4Hz,2H),7.67(s,1H),7.54(s,1H),7.50(s,1H),7.48(s,1H),7.46(d,J＝4.3Hz,3H),7.38(s,1H),7.37 (s,1H),7.35(s,1H),7.32(s,2H),7.31(s,1H),7.28(d,J＝7.1Hz,1H),7.23(s,1H),7.21(s,1H),7.11–7.06(m, 3H),6.94(s,1H),5.23(s,2H),5.11(s,2H),4.91(s,2H),4.24(d,J＝5.8Hz,2H),4.15(s,2H),3.87(d,J＝6.2 Hz,6H),2.70(s,1H),2.34(s,3H),2.22(s,3H),1.89(d,J＝6.7Hz,2H),1.75–1.71(m,2H),1.63(d,J＝9.7Hz, 2H),1.50–1.46(m,3H),1.20(s,1H),1.19(s,1H),1.17(s,1H).MS：m/z＝1008.6[M+1] + .HPLC:t R 21.563min, purity 95.959％.
ethyl(E)-2-(4-chloro-2-((2-((4-((2-methoxy-4-(3-(4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenoxy)methyl)be nzyl)carbamoyl)piperidin-1-yl)methyl)-5-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)acetate(CP15). Yellowoil； 1 H NMR(400MHz,DMSO)δ8.33(t,J＝6.0Hz,1H),8.17(d,J＝8.8Hz,2H),7.82(d,J＝15.5Hz, 1H),7.65(d,J＝15.4Hz,1H),7.54–7.43(m,5H),7.39(d,J＝7.4Hz,1H),7.32(d,J＝10.0Hz,5H),7.28– 7.17(m,4H),7.12–7.03(m,3H),6.93(s,1H),5.23(s,2H),5.10(s,2H),4.86(s,2H),4.31(dt,J＝15.0,9.2Hz, 2H),4.16–4.10(m,2H),3.87(d,J＝7.9Hz,6H),3.55(d,J＝13.9Hz,1H),3.18(d,J＝5.1Hz,1H),2.81(d,J＝ 9.3Hz,2H),2.23(s,3H),1.94(s,1H),1.79(d,J＝11.6Hz,1H),1.67(dd,J＝13.4,4.2Hz,2H),1.51(s,1H), 1.42–1.37(m,1H),1.31(s,1H),1.18(t,J＝7.1Hz,3H).MS：m/z＝937.5[M+1] + .HPLC:t R 22.296min,purity 95.312％.
ethyl(E)-2-(4-chloro-2-((2-(4-((4-((2-methoxy-4-(3-(4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenoxy)methyl) benzyl)carbamoyl)piperidine-1-carbonyl)piperidin-1-yl)methyl)-5-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy) phenoxy)acetate(CP16).Yellow oil； 1 H NMR(400MHz,DMSO)δ8.36(s,1H),8.17(d,J＝8.9Hz,2H),7.83 (d,J＝15.5Hz,1H),7.66(d,J＝15.4Hz,1H),7.55–7.44(m,4H),7.42–7.28(m,8H),7.24(dd,J＝21.6,8.7 Hz,4H),7.09(d,J＝8.8Hz,3H),6.94(s,1H),5.23(s,2H),5.13(s,2H),4.89(s,2H),4.40(d,J＝12.7Hz,1H), 4.26(s,2H),4.15(dd,J＝14.0,6.7Hz,2H),3.87(d,J＝2.8Hz,6H),3.56(dd,J＝40.1,36.0Hz,2H),3.03(d,J ＝12.0Hz,2H),2.92(d,J＝12.4Hz,2H),2.59(d,J＝5.4Hz,1H),2.44(s,2H),2.23(s,3H),2.05–1.96(m,2H), 1.76(s,2H),1.67(d,J＝10.1Hz,3H),1.46(d,J＝3.7Hz,2H),1.19(d,J＝7.1Hz,3H).MS:m/z＝1048.7 [M+1] + .HPLC:t R 21.009min,purity 99.412％.
ethyl(E)-2-(4-chloro-2-((2-((4-((4-((2-methoxy-4-(3-(4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenoxy)methyl )benzyl)amino)-4-oxobutyl)carbamoyl)piperidin-1-yl)methyl)-5-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)ph enoxy)acetate(CP17).Yellow oil； 1 H NMR(400MHz,DMSO)δ8.30(t,J＝6.1Hz,1H),8.17(d,J＝8.8Hz, 2H),7.82(d,J＝15.8Hz,2H),7.66(d,J＝15.4Hz,1H),7.55–7.44(m,5H),7.39(d,J＝8.1Hz,3H),7.33– 7.29(m,3H),7.26(d,J＝8.1Hz,2H),7.21(d,J＝7.3Hz,1H),7.09(dd,J＝8.4,4.6Hz,3H),6.94(s,1H),5.23 (s,2H),5.12(s,2H),4.90(s,2H),4.26(d,J＝5.6Hz,2H),4.15(q,J＝7.1Hz,2H),3.87(d,J＝4.4Hz,6H),3.10 (dd,J＝11.3,5.0Hz,3H),2.79(d,J＝13.6Hz,2H),2.71(d,J＝13.0Hz,2H),2.23(s,3H),2.12(d,J＝7.1Hz, 2H),2.02–1.89(m,3H),1.75(d,J＝11.5Hz,1H),1.68–1.64(m,2H),1.52(dd,J＝24.4,12.1Hz,2H),1.37(d, J＝9.0Hz,1H),1.19(t,J＝7.1Hz,3H).MS：m/z＝1022.6[M+1] + .HPLC:t R 21.776min,purity 95.685％.
ethyl(E)-2-(4-chloro-2-((2-((5-((4-((2-methoxy-4-(3-(4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenoxy)methyl )benzyl)amino)-5-oxopentyl)carbamoyl)piperidin-1-yl)methyl)-5-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)p henoxy)acetate(CP18).Yellow oil； 1 H NMR(400MHz,DMSO)δ8.26(t,J＝5.9Hz,1H),8.17(d,J＝8.8Hz, 2H),7.82(d,J＝15.5Hz,1H),7.70(d,J＝5.8Hz,1H),7.66(d,J＝15.4Hz,1H),7.60(d,J＝8.4Hz,2H),7.54 (s,1H),7.47(dd,J＝13.6,7.5Hz,4H),7.39(dd,J＝13.7,8.1Hz,4H),7.34–7.28(m,3H),7.22(t,J＝8.7Hz, 3H),7.08(t,J＝7.5Hz,3H),5.24(d,J＝3.3Hz,4H),5.11(s,2H),4.24(d,J＝5.6Hz,2H),3.87(d,J＝4.7Hz, 6H),3.55–3.46(m,2H),3.25(d,J＝13.6Hz,2H),3.07–2.90(m,3H),2.77–2.69(m,2H),2.23(s,3H),2.10 (d,J＝14.3Hz,2H),2.04–1.98(m,1H),1.89(t,J＝11.0Hz,1H),1.72(d,J＝9.7Hz,1H),1.65(d,J＝13.7Hz, 1H),1.53(d,J＝6.1Hz,1H),1.50–1.42(m,3H),1.41–1.32(m,3H).MS：m/z＝1036.7[M+1] + .HPLC:t R 23.358min,purity 97.054％.
(E)-1-(5-chloro-2-((3-cyanobenzyl)oxy)-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)-N-(4-((2-methoxy -4-(3-(4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenoxy)methyl)benzyl)piperidine-2-carboxamide(CP19). Yellow solid；mp:128.1–128.9℃； 1 H NMR(400MHz,DMSO)δ8.27(s,0H),8.17(d,J＝8.9Hz,0H),7.90(s, 0H),7.79(d,J＝4.9Hz,0H),7.69–7.56(m,1H),7.53(s,0H),7.47(dd,J＝11.6,4.5Hz,1H),7.39(d,J＝7.3 Hz,0H),7.31(d,J＝7.8Hz,1H),7.27(d,J＝7.5Hz,0H),7.21(d,J＝7.8Hz,1H),7.12–7.04(m,1H),5.24(d, J＝7.2Hz,1H),5.09(s,0H),4.25(dd,J＝11.7,7.8Hz,0H),3.87(d,J＝9.9Hz,6H),3.53(d,J＝12.9Hz,0H), 2.85–2.78(m,0H),2.23(s,1H),2.03–1.92(m,0H),1.78(d,J＝10.5Hz,0H),1.66(dd,J＝17.3,6.3Hz,0H), 1.53(d,J＝17.1Hz,0H),1.47–1.39(m,0H). 13 C NMR(101MHz,DMSO)δ187.70,173.61,163.49,155.83, 150.48,149.73,143.97,142.59,141.69,139.97,138.99,138.91,138.82,135.54,135.50,134.32,132.68,131.34, 131.22,131.12,131.10,131.05,131.03,130.22,130.19,130.16,129.57,128.66,128.21,127.55,127.39,125.99, 125.97,123.91,123.89,121.42,120.66,120.13,119.85,119.04,117.07,114.47,114.40,114.36,113.64,113.57, 113.54,111.90,111.50,100.86,70.03,70.00,62.16,56.25,55.96,42.02,29.48,28.98,27.05,16.32.MS：m/z ＝996.6[M+1] + .HPLC:t R 22.405min,purity 97.887％.
(E)-1-(5-chloro-2-((3-cyanobenzyl)oxy)-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)-N-(4-((4-((2-meth oxy-4-(3-(4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenoxy)methyl)benzyl)amino)-4-oxobutyl)piperidine-2-c arboxamide(CP20).Yellow solid；mp:120.1–120.9℃； 1 H NMR(400MHz,DMSO)δ8.29(t,J＝6.0Hz,1H), 8.17(d,J＝8.8Hz,2H),7.94(s,1H),7.81(dd,J＝17.3,9.0Hz,4H),7.63(dd,J＝19.1,11.5Hz,2H),7.54(s, 1H),7.47(t,J＝8.2Hz,4H),7.38(dd,J＝14.3,6.4Hz,3H),7.34–7.28(m,3H),7.25(d,J＝8.2Hz,2H),7.21 (d,J＝7.3Hz,1H),7.13–7.05(m,3H),5.26(d,J＝24.1Hz,4H),5.12(s,2H),4.25(d,J＝5.8Hz,2H),3.87(d, J＝5.2Hz,6H),3.53(d,J＝13.7Hz,2H),3.29–3.21(m,2H),3.02(dd,J＝17.6,8.6Hz,2H),2.74(dd,J＝21.6, 8.1Hz,2H),2.20(s,3H),2.11(t,J＝7.2Hz,2H),2.03–1.96(m,1H),1.91(t,J＝11.3Hz,1H),1.74(d,J＝12.3 Hz,1H),1.63(dd,J＝13.9,7.0Hz,2H),1.52(d,J＝17.5Hz,2H),1.39(d,J＝12.8Hz,1H). 13 C NMR(101MHz, DMSO)δ178.51,173.48,172.04,163.44,155.92,153.66,150.40,149.74,142.59,142.33,141.64,138.96, 135.49,134.33,132.73,132.13,131.43,131.25,131.23,131.08,130.22,130.18,129.61,129.57,128.67,128.33, 128.30,128.22,127.66,127.63,127.39,125.97,123.89,120.64,114.42,114.32,113.61,113.54,111.85,111.49, 70.14,69.39,67.76,67.69,56.17,55.79,33.14,31.67,31.16,30.45,29.47,29.41,26.03,16.26.MS：m/z＝1051.6 [M+1] + .HPLC:t R 21.591min,purity 100％.
(E)-1-(5-chloro-2-((3-cyanobenzyl)oxy)-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)-N-(5-((4-((2-meth oxy-4-(3-(4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenoxy)methyl)benzyl)amino)-5-oxopentyl)piperidine-2- carboxamide(CP21).Yellow oil； 1 H NMR(400MHz,DMSO)δ8.25(s,1H),8.16(d,J＝8.7Hz,2H),7.82(d,J ＝15.6Hz,1H),7.67(t,J＝13.8Hz,2H),7.60(d,J＝8.5Hz,2H),7.54(s,1H),7.47(dd,J＝13.3,7.5Hz,4H), 7.39(dd,J＝13.8,8.4Hz,5H),7.32(d,J＝7.2Hz,2H),7.28(d,J＝7.4Hz,1H),7.22(t,J＝8.6Hz,3H),7.08(t, J＝7.5Hz,3H),5.24(d,J＝3.3Hz,4H),5.11(s,2H),4.24(d,J＝5.4Hz,2H),3.87(d,J＝5.0Hz,6H),3.60– 3.47(m,2H),3.06–2.89(m,4H),2.73(dd,J＝22.8,11.8Hz,3H),2.23(s,3H),2.10(t,J＝7.2Hz,2H),2.04– 1.94(m,2H),1.90(d,J＝7.9Hz,1H),1.71(d,J＝7.2Hz,1H),1.64(d,J＝6.5Hz,1H),1.53(s,1H),1.47(d,J＝ 6.4Hz,2H),1.37–1.32(m,2H).MS：m/z＝1065.5[M+1] + .HPLC:t R 21.753min,purity 100％.
(E)-1-(5-chloro-2-((3-cyanobenzyl)oxy)-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)-N-(3-((4-((2-meth oxy-4-(3-(4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenoxy)methyl)benzyl)amino)-3-oxopropyl)piperidine-2- carboxamide(CP22).Yellow oil； 1 H NMR(400MHz,DMSO)δ8.35(s,1H),8.16(d,J＝8.8Hz,2H),7.93(s, 1H),7.84–7.77(m,4H),7.63(dd,J＝22.7,11.7Hz,3H),7.53(s,1H),7.45(s,4H),7.40(s,1H),7.36(s,2H), 7.30(s,2H),7.26(s,1H),7.21(d,J＝7.6Hz,3H),7.10(s,2H),7.05(s,2H),5.31(s,2H),5.22(s,2H),5.11(s, 2H),4.23–4.16(m,2H),3.87(d,J＝6.9Hz,6H),2.32(d,J＝6.8Hz,3H),2.22(s,3H),2.00(d,J＝5.1Hz,2H), 1.91–1.85(m,2H),1.73(d,J＝11.5Hz,2H),1.64(d,J＝6.3Hz,2H),1.53–1.45(m,4H). 13 C NMR(101MHz, DMSO)δ173.35,172.30,172.11,163.53,149.78,143.92,138.83,137.56,134.37,134.09,132.83,131.50, 131.23,131.14,131.09,130.19,129.63,129.56,129.48,128.66,128.42,128.36,128.29,127.39,125.98,123.87, 121.58,120.24,119.09,114.41,113.54,111.92,111.59,66.76,56.24,56.00,51.81,42.24,36.50,35.21,34.67, 34.50,31.88,28.61,16.23.MS：m/z＝1037.6[M+1] + .HPLC:t R 21.219min,purity 97.625％.
(E)-1-(1-(5-chloro-2-((3-cyanobenzyl)oxy)-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)piperidine-2-ca rbonyl)-N-(4-((2-methoxy-4-(3-(4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenoxy)methyl)benzyl)piperidine- 4-carboxamide(CP23).Yellow solid；mp:125.3–126.3℃；1H NMR(400MHz,DMSO)δ8.35(s,1H),8.17(d, J＝8.3Hz,2H),7.95(s,2H),7.81(s,3H),7.71–7.59(m,2H),7.55(s,1H),7.47(dd,J＝16.0,7.4Hz,3H),7.42 –7.36(m,3H),7.31(d,J＝7.4Hz,2H),7.24(d,J＝14.3Hz,4H),7.07(t,J＝11.0Hz,2H),6.86(d,J＝42.4Hz, 1H),5.26(d,J＝12.6Hz,3H),5.08(d,J＝38.5Hz,1H),4.38(s,2H),4.26(s,2H),3.87(s,3H),3.77(s,1H), 3.63–3.50(m,2H),2.94(d,J＝20.0Hz,2H),2.42(s,2H),2.24(s,3H),2.03(d,J＝27.0Hz,2H),1.68(d,J＝ 24.3Hz,5H),1.46(s,3H),1.33(d,J＝18.8Hz,2H). 13 C NMR(101MHz,DMSO)δ170.78,163.56,162.62, 153.38,150.31,149.81,143.77,142.46,135.68,135.46,134.88,131.58,131.22,131.10,130.20,129.57,128.67, 128.34,127.55,127.39,125.98,124.49,122.66,121.56,120.73,120.16,114.36,113.96,113.58,113.51,111.92, 111.74,111.55,70.00,60.24,56.23,56.01,53.48,51.98,36.17,33.29,31.22,28.21,28.12,27.07,24.54,16.22. MS：m/z＝1077.6[M+1] + .HPLC:t R 21.651min,purity 97.154％.
example 2 study of the inhibition Effect of a PD-L1/CXCL12 double-target inhibitor on PD-1/PD-L1
The inhibitory effect of the compounds of the present invention on PD-1/PD-L1 was demonstrated using the following method test.
These effects indicate that the compounds of the present invention have a remarkable inhibitory effect on PD-1/PD-L1, and are useful for the treatment of cancer, particularly for the treatment of melanoma. The specific test method is as follows:
1. purpose and principle of experiment
The detection method of the PD-1/PD-L1 protein-protein interaction inhibition activity is a biochemical level-based homogeneous time-resolved fluorescence method (HTRF) technology, and the detection method simply and rapidly characterizes the compound and the antibody blocking agent in a high-throughput form. The interaction between PD-L1 and PD1 (HTRF donor) and anti-Tag 2 labeled with XL665 (HTRF acceptor) were detected using europium-labeled anti-Tag 1. When the donor and acceptor antibodies are in close proximity due to PD-L1 and PD1 binding, excitation of the donor antibody triggers Fluorescence Resonance Energy Transfer (FRET) to the acceptor antibody, which in turn emits specifically at 665 nm. This specific signal is proportional to the extent of PD1/PD-L1 interaction. Thus, blocking the PD1/PD-L1 interaction by a compound or antibody results in a decrease in HTRF signal. The intensity of the generated fluorescence was measured by a microplate reader and the magnitude of the compound blocking PD-1/PD-L1 activity was reflected in a ratio of 665nm/620 nm.
2. Basic information of reagents
Table 1: reagent brand goods number
3. Preparation of Experimental reagents
Table 2: experimental reagent preparation method
4. Experimental procedure
(1) Mu.l of the compound dilution was added to each well of the 96-well plate, and centrifuged at 1000rpm for 1min.
(2) Mu.l (2.5X) of PD-L1 mix was added to each well and centrifuged at 1000rpm for 1min.
(3) To each well 4ul (2.5X) of PD-1 mix was added and centrifuged at 1000rpm for 1min and incubated at room temperature for 15min.
(4) Mu.l (2X) of the test mixture was added to each well and centrifuged at 1000rpm for 1min.
( 5) Incubation was performed at room temperature for 120min, and fluorescence values were read using a Tecan microplate reader (Ex: 320nM; em 620and 665nM ).
(6) The inhibition ratio (inhibition)% = (1- (signal value 665nm/620nm per well-low control group average)/(high control group average-low control group average)) 100 was calculated as follows. Wherein the high control group is treated without adding compound, and is added into the reaction system group by using the DMSO solution with the same concentration; the low control group was no PD-1 mixture, and only the equivalent amount of the test mixture was added. In this assay system, the final DMSO concentration was 0.5%.
(7) Fitting dose-response curve: the log values of the concentrations were used as the X-axis, the percent inhibition was on the Y-axis, and the analytical software GraphPad Prism 5 log (inhibitor) vs. response-Variable slope fitted-in-dose-response curves were used to obtain the IC50 values (+representing IC50=1 to 10. Mu.M and++ representing IC50=0.001 to 1. Mu.M) of the respective compounds for enzyme activities.
Table 3: inhibitory Effect of Compounds CP 1-CP 23 on PD-1/PD-L1
According to the above in vitro experimental results, we can obtain that a PD-L1/CXCL12 dual-target inhibitor of the invention can inhibit the mutual binding of the apoptosis receptor 1/the apoptosis ligand 1 (PD-1/PD-L1).
EXAMPLE 3 inhibition effect study of a PD-L1/CXCL12 double-target inhibitor of the invention on CXCL12
1. Purpose and principle of experiment
Since CP23 showed the strongest inhibition of PD-1/PD-L1 in the HTRF results, we chose CP23 for further validation. To further verify whether CP23 can cross-react with CXCL12, we determined its binding affinity to human CXCL12 and murine CXCL12 by Surface Plasmon Resonance (SPR) and Circular Dichroism (CD) analysis.
Surface Plasmon Resonance (SPR) is an optical phenomenon that can be used to track interactions between biomolecules in their natural state in real time. This method does not have any damage to the biomolecules and does not require any markers. One biomolecule (target molecule) is first bound to the biosensor surface and then a solution containing another biomolecule (analyte) capable of interacting with the target molecule is injected into and flows over the biosensor surface. The binding between biomolecules causes an increase in the surface quality of the biosensor, resulting in an increase in the refractive index in the same proportion, and a change in the reaction between biomolecules is observed. When the analyte is injected, analyte-target molecule complexes form at the biosensor surface, resulting in an enhanced reaction. And when the analyte is injected, the analyte-target molecule complex dissociates, resulting in a reduced reaction. By fitting this reaction curve to the binding interaction model, the kinetic constants can be determined. Whereas the effects of nonspecific binding and total refractive index shift equality can be driven off by the reference curve subtraction function.
2. Experimental procedure
(1) Preparing a regeneration liquid: 500ml of glycine hydrochloride 50mM, ph=2.0;
(2) Buffer preparation: 500ml of 1XPBS phosphate buffer;
(3) PD-L1 protein spotting: spotting with concentration of 0.5-1mg/ml, volume of 10-20 μl, and dissolving with H2O or PBS;
(4) The inhibition effect of each compound on CXCL12/CXCR4 can be obtained according to the SPR test fitting curve, as shown in the following table (+represents ic50=1 to 10 μm and++represents ic50=0.001 to 1 μm).
Table 4: inhibition effect of Compounds CP 1-CP 23 on CXCL12/CXCR4
According to the in vitro experimental results, we can obtain that the PD-L1/CXCL12 double-target inhibitor can inhibit the mutual combination of CXCL12/CXCR 4.
EXAMPLE 4 study of the therapeutic Effect of the Compounds of the invention on the murine melanoma model
1. Experimental materials
Cell line: murine melanoma cells (B16F 10).
Experimental animals: seven week old C57BL/6 male mice were purchased from Liaoning long Biotechnology Co., ltd.
2. Experimental method
Mouse tumor model establishment, grouping and dosing: B16F 10 cells were injected into the mice forelimb axilla, 2x 10 per injection 5 Individual cells, tumor volume up to 100mm 3 At the beginning of the administration, the experimental mice were divided into 3 groups of 6 mice each, and a blank group (5% dimethyl sulfoxide, 30% polyethylene glycol 200,65% physiological saline), compound CP23 (75 mg/kg/day) and compound CP23 (125 mg/kg/day) were orally administered, respectively, for 14 days. The weight and tumor volume changes of the mice are monitored in the treatment process, and the tumor volume calculation formula is as follows: (width) 2 X length)/2.
3. Experimental results
Preferred in vivo tumor model treatment of compound as shown in fig. 3, compound CP23 exhibits superior in vivo antitumor activity. Oral administration of 125mg/kg of CP23 reduced tumor weight and tumor volume by 60.5% and 85.5%, respectively, compared to the control group. And CP23 with the dosage of 75mg/kg reduces the tumor weight and tumor volume by 55 percent and 85.1 percent respectively, and has obvious effect.
FIG. 3 shows the therapeutic effect of CP23 on B16-F10 melanoma tumor-bearing mice. (A) As tumor images, it can be seen that the tumor size significantly changed after drug administration treatment; (B) For mouse tumor weight, the treated group was significantly reduced and there was a significant difference compared to the non-treated group; (C) The tumor volume of the mice changes with time, and the volume of the treatment group increases slowly compared with that of the non-treatment group; (D) For the change in body weight of the mice during the treatment period, no significant change in body weight of the mice was seen. P <0.05, n=6.
Claims (5)
1. A PD-L1/CXCL12 double-target inhibitor has a chemical structure shown in the following formula (I),
wherein R is 1 Represents Br, cl;
R 2 represents H,
R 3 Represents->
X represents
2. A PD-L1/CXCL12 dual target inhibitor comprising one of the following compounds:
3. use of a PD-L1/CXCL12 dual target inhibitor according to claim 1 or 2 for the preparation of a PD-1/PD-L1 inhibitor.
4. Use of a PD-L1/CXCL12 dual target inhibitor according to claim 1 or 2 for the preparation of a CXCL12 inhibitor.
5. The use according to claims 3 and 4, wherein the PD-L1/CXCL12 dual target inhibitor is for the treatment of a neoplastic disease associated with the PD-L1 and/or CXCL12 target.
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