CN115477609B - PD-L1 protein degradation agent based on hydrophobic tag technology and application thereof - Google Patents

PD-L1 protein degradation agent based on hydrophobic tag technology and application thereof Download PDF

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CN115477609B
CN115477609B CN202211174922.5A CN202211174922A CN115477609B CN 115477609 B CN115477609 B CN 115477609B CN 202211174922 A CN202211174922 A CN 202211174922A CN 115477609 B CN115477609 B CN 115477609B
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CN115477609A (en
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周金明
高杰克
章建涛
韩小利
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Zhejiang Normal University CJNU
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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Abstract

The invention discloses a PD-L1 protein degradation agent based on a hydrophobic tag technology and application thereof, belonging to the field of pharmaceutical chemistry. The PD-L1 protein degradation agent comprises a compound shown in the following formula (I) or formula (II) or pharmaceutically acceptable salt thereof:wherein R is 1 is-OCH 2 ；R 2 Is a linker; r is R 3 Is a hydrophobic group. The invention designs a synthesized small molecule degradation agent with better targeting degradation of PD-L1 protein based on HyT technology, and provides a potential treatment means for treating tumors through PD-1/PD-L1 immune check points.

Description

PD-L1 protein degradation agent based on hydrophobic tag technology and application thereof
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a PD-L1 protein degradation agent based on a hydrophobic tag technology and application thereof.
Background
Currently, tumor immunotherapy has become one of the important means for advanced malignant tumor treatment. Blocking the interaction of PD-1/PD-L1, and can reactivate T cells to realize anti-tumor effect. Thus, blocking PD-1/PD-L1 interactions has become one of the strategies for tumor immunotherapy. There are a number of drugs currently approved by the U.S. food and drug administration (Food and Drug Administration, FDA) for targeting PD-1/PD-L1 monoclonal antibodies (Monoclonal antibody, MAb). However, antibody drugs have a number of disadvantages, mainly including lack of oral bioavailability, difficulty in production, high price, adverse reactions related to immunity, etc., thus limiting the clinical application of PD-L1/PD-1 mab. Therefore, the development of small molecule PD-1/PD-L1 blockers has become a hotspot in the development of tumor immunotherapeutic drugs.
In recent years, the advent of targeted protein degradation (Targeted protein degradation, TPD) technology has created a number of opportunities for drug discovery. Compared with the traditional medicine which needs a large number of medicine molecules by occupying binding sites, the protein-induced degradation small molecule can play a good role in inhibiting only by a catalytic amount, and the targeted protein degradation technology shows the unique advantages which are not possessed by the conventional small molecule inhibitor and provides a new therapeutic option for disease treatment. Among them, the hydrophobic tag technology (Hydrophobic tagging, hyT) is well known as a viable modular degradation target protein strategy for protein degradation targeting chimeras (Proteolysis Targeting Chimera, PROTAC). The concept is proposed by Crews et al at the earliest, and they hypothesize that adding a hydrophobic group on the surface of the protein simulates the partial denaturation state of the protein, thereby triggering a cell quality control mechanism and inducing the degradation thereof, overcoming the limitation of degrading the protein by an artificial HaloTag system by degrading pseudokinase Her3 in 2014, realizing the degradation of induced endogenous protein, and then successfully degrading various target proteins. At present, no report exists on the degradation of PD-L1 protein by using the technology.
Disclosure of Invention
The invention aims to provide a PD-L1 protein degradation agent based on a hydrophobic tag technology and application thereof, so as to solve the problems of the prior art, and the degradation agent can effectively degrade the expression level of PD-L1 in vitro, thereby providing a potential treatment means for treating tumors through PD-1/PD-L1 immune checkpoints.
In order to achieve the above object, the present invention provides the following solutions:
the invention provides a PD-L1 protein degradation agent based on a hydrophobic tag technology and application thereof, wherein the PD-L1 protein degradation agent comprises a compound shown in a structural formula (I) or a structural formula (II) or pharmaceutically acceptable salt thereof:
wherein R is 1 is-OCH 2 ；R 2 Is a linker; r is R 3 Is a hydrophobic group.
Preferably, the linker comprises a compound of the general structural formula:
preferably, the hydrophobic group comprises a compound having the following structural formula a to g:
the invention also provides a synthesis method of the PD-L1 protein degradation agent, which comprises the following synthesis routes:
synthesis of intermediate compound target proteins 1 and 2:
reagents and reaction conditions: (I) BH (BH) 3 -THF，THF，r.t.；(II)[(C 6 H 5 ) 3 P] 2 PdCl 2 Phenylboronic acid, naHCO 3 Toluene, etOH, H 2 0，80℃；(III)PBr 3 ，DCM，r.t.；(IV)C 3 H 9 ISi, DCM, r.t.; (V) 2-methyl-3-phenylbromomethylbenzene, K 2 CO 3 ，DMF，r.t.；
Reagents and reaction conditions: (I) [ (C) 6 H 5 ) 3 P] 2 PdCl 2 Phenylboronic acid, naHCO 3 Toluene, etOH, H 2 0,80 ℃; (II) Di-penta-diboron, pdCl 2 (dppf), KOAc,1, 4-dioxane, 100 ℃; (III) 2-bromo-5-aldehyde pyridine, pd [ P (C) 6 H 5 ) 3 ] 4 KOAc,1, 4-Dioxycyclohexylene, H 2 0，90℃；
Synthesis of intermediate compound linkers NLn, n=1-5, cln, n=1, 2 and GL:
reagents and reaction conditions: (I) triton b, meCN, r.t.; (II) CBr 4 DCM; (III) phthalimide, K 2 CO 3 ，DMF，r.t.；(IV)N 2 H 4 H 2 O, etOH,90 ℃; (V) N-t-butoxycarbonyl ethylenediamine, et3N, THF, r.t.; (VI) HATU, DIPEA, DMF; (VII) LiOH, THF/H 2 O；
Synthesis of hydrophobic groups of intermediate compounds:
reagents and reaction conditions: (I) NH (NH) 2 OH HCl, naOAc, etOH, refluxing; (II) AlLiH 4 ，THF；
Synthesis of target products LC1a, LC2a, L2a-L5i, Z2a-Z5 i:
reagents and reaction conditions: (1) HATU, DIPEA, DCM; (II) TFA, DCM, r.t.; (III) Compound7, naBH 4 ，MeOH，40℃；(IV)NaBH 4 ，MeOH，40℃；(V)TFA，DCM，r.t.；(VI)20a-20i，HATU，DIPEA，DCM，r.t.；(VII)TFA，DCM；(VIII)R 3 HATU, DIPEA, DCM; (IX) Compound 1/2, naBH 4 ,MeOH,r.t.。
The invention also provides a pharmaceutical composition comprising the PD-L1 protein degradation agent.
Preferably, a pharmaceutically acceptable carrier is also included.
Preferably, the pharmaceutical composition is in a pharmaceutically acceptable dosage form. More preferably, the injection, oral preparation or mucosal delivery preparation. More preferably, the combination of the pharmaceutical compositions is used sequentially.
The invention also provides an application of the PD-L1 protein degradation agent or the pharmaceutical composition in preparation of any one of the following medicaments:
(1) A drug that enhances the targeting effect of a therapeutic tumor drug;
(2) A drug for enhancing an antitumor effect;
(3) Enhancing the effect of blocking the PD-L1 site.
Preferably, the tumor comprises human fibrosarcoma, non-small cell lung cancer, lymphoma, chronic myelogenous leukemia, acute lymphoblastic leukemia, breast cancer or melanoma.
The invention discloses the following technical effects:
the invention designs a synthesized small molecule degradation agent with better targeting degradation of PD-L1 protein based on HyT technology; by utilizing a constructed PD-L1 protein degradation screening model and through synthesis optimization, the synthesized small molecule degradation agent HyTs can effectively degrade the expression level of PD-L1 in vitro, thereby providing a potential treatment means for treating tumors through PD-1/PD-L1 immune checkpoints.
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In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are needed in the embodiments will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 shows Western blot analysis of the small molecule degradants LC4a and LC5a prepared in examples 31-32, respectively, L2a, L3a, L4a and L5a prepared in examples 1-4, respectively, L2c and L3c prepared in examples 9-10, L4c prepared in examples 9-10, respectively, and the targeted PD-L1 protein HyTs of L5c prepared in example 12 incubated with H460 cells for 24 hours;
FIG. 2 shows Western blot analysis of targeted PD-L1 protein HyTs of small molecule degrading agents L2b, L3b, L4b and L5b prepared in examples 5-8 respectively and H460 cells prepared in examples 13-16 of small molecule degrading agents L2g, L3g, L4g and L5g prepared in examples of the invention incubated for 24 hours;
FIG. 3 shows Western blot analysis of the small molecule degradants L2b, L3b, L4b and L5b prepared in examples 5-8, respectively, and the targeted PD-L1 proteins HyTs prepared in examples 17-20, L2H, L3H, L4H and L5H, respectively, incubated with H460 cells for 24 hours;
FIG. 4 shows Western blot analysis of Z2e, Z3e and Z4e small molecule degradants Z2c, Z3e and Z4e prepared in examples 39-41, respectively, and Z2c targeting PD-L1 protein HyTs prepared in example 33 incubated with H460 cells for 24 hours;
FIG. 5 shows Western blot analysis of L2 d-targeted PD-L1 protein HyTs prepared in examples 34-35 and H460 cells incubated for 24 hours with small molecule degradants Z3c and Z4c prepared in examples 36-38, Z2d, Z3d and Z4d prepared in examples 36-38, Z2f, Z3f and Z4f prepared in examples 42-44, respectively;
FIG. 6 shows Western blot analysis of small molecule degradants L3d and L4d prepared in examples 22-23, respectively, L2f prepared in example 28, and targeted PD-L1 protein HyTs of L4f prepared in example 30 incubated with H460 cells for 24 hours.
Detailed Description
Various exemplary embodiments of the invention will now be described in detail, which should not be considered as limiting the invention, but rather as more detailed descriptions of certain aspects, features and embodiments of the invention.
It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. In addition, for numerical ranges in this disclosure, it is understood that each intermediate value between the upper and lower limits of the ranges is also specifically disclosed. Every smaller range between any stated value or stated range, and any other stated value or intermediate value within the stated range, is also encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference for the purpose of disclosing and describing the methods and/or materials associated with the documents. In case of conflict with any incorporated document, the present specification will control.
It will be apparent to those skilled in the art that various modifications and variations can be made in the specific embodiments of the invention described herein without departing from the scope or spirit of the invention. Other embodiments will be apparent to those skilled in the art from consideration of the specification of the present invention. The specification and examples are exemplary only.
As used herein, the terms "comprising," "including," "having," "containing," and the like are intended to be inclusive and mean an inclusion, but not limited to.
The structural formula of the small molecule degrading agent HyTs for targeted degradation of PD-L1 protein prepared by the invention is shown as formula (I) or formula (II):
wherein R is 1 Independently selected from: -OCH 2 ；
R 2 The specific structure is as follows:
R 3 the specific structure is shown as the following a-i:
the small molecule degradation agent HyTs mainly comprises three parts, namely a target protein ligand, a linker and a hydrophobic group. Wherein the targeting protein ligand is shown as a formula (III), a formula (IV):
the synthetic route for formula (II) is shown below:
reagents and reaction conditions: (I) BH (BH) 3 -THF，THF，r.t.；(II)[(C 6 H 5 ) 3 P] 2 PdCl 2 Phenylboronic acid, naHCO 3 Toluene, etOH, H 2 0，80℃；(III)PBr 3 ，DCM，r.t.；(IV)C 3 H 9 ISi, DCM, r.t.; (V) 2-methyl-3-phenylbromomethylbenzene, K 2 CO 3 ，DMF，r.t.。
The synthetic route for formula (III) is shown below:
reagents and reaction conditions: (I) [ (C) 6 H 5 ) 3 P] 2 PdCl 2 Phenylboronic acid, naHCO 3 Toluene, etOH, H 2 0,80 ℃; (II) Di-penta-diboron, pdCl 2 (dppf), KOAc,1, 4-dioxane, 100 ℃; (III) 2-bromo-5-aldehyde pyridine, pd [ P (C) 6 H 5 ) 3 ] 4 KOAc,1, 4-dioxane, H 2 0，90℃。
The linker structure is shown as the formula (V), (VI) and (VII):
the synthetic routes of the above-mentioned linker formulas (V), (VI) and (VII) are as follows:
reagents and reaction conditions: (I) triton b, meCN, r.t.; (II) CBr 4 DCM; (III) phthalimide, K 2 CO 3 ，DMF，r.t.；(IV)N 2 H 4 H 2 O, etOH,90 ℃; (V) N-t-butoxycarbonyl ethylenediamine, et3N, THF, r.t.; (VI) HATU, DIPEA, DMF; (VII) LiOH, THF/H 2 O。
The synthetic route of the hydrophobic group is shown below:
R 4 and R is 5 The specific structure of (2) is as follows:
reagents and reaction conditions: (I) NH (NH) 2 OH HCl, naOAc, etOH, refluxing; (II) AlLiH 4 ,THF。
The synthetic route of the hydrophobic tag HyTs is as follows:
reagents and reaction conditions: (1) HATU, DIPEA, DCM; (II) TFA, DCM, r.t.; (III) Compound7, naBH 4 ，MeOH，40℃；(IV)NaBH 4 ，MeOH，40℃；(V)TFA，DCM，r.t.；(VI)20a-20i，HATU，DIPEA，DCM，r.t.；(VII)TFA，DCM；(VIII)R 3 ，HATU，DIPEA，DCM；(IX)Compound1/2,NaBH 4 ,MeOH,r.t.。
In order to further illustrate the preparation method and application of the small molecule degradation agent Hyts prepared by the present invention, specific examples will be described below.
Example 1 Compound N- ((3 s,5s,7 s) -adamantan-1-yl) -3- (2- (2- (((6- ((2-methyl- [1,1' -biphen yl ] -3-yl) methoxy) pyridin-3-yl) methyl) amino) method) prop-enamide (L2 a)
Compound 5 (n=2, 72mg,0.138 mmol), HATU (1.5 eq,78.7mg,0.207 mmol) and DIPEA (5.0 eq,89mg,0.69 mmol) were dissolved in DCM (5 ml), compound a (1.0 eq,19mg,0.138 mmol) dissolved in DCM (5 ml) was added dropwise, stirring was carried out at room temperature for 3h, the reaction solution was extracted with water, the organic phase extract was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the crude product was isolated by column chromatography to give a yellow solid hydrophobic tag compound L2a in 40% yield.
1 H NMR(400MHz,CDCl 3 )δ7.54(dd,J＝9.3,2.5Hz,1H),7.43–7.30(m,5H),7.24(d,J＝1.3Hz,1H),7.19(d,J＝2.3Hz,1H),7.18(s,1H),6.94(dd,J＝5.8,3.3Hz,1H),6.62(d,J＝9.3Hz,1H),5.95(s,1H),5.18(s,2H),3.68(dd,J＝10.7,5.1Hz,6H),3.58(s,4H),2.88(t,J＝4.9Hz,2H),2.33(t,J＝5.9Hz,2H),2.16(s,3H),2.02(s,3H),1.95(d,J＝2.9Hz,6H),1.63(s,6H).
Theoretical value: 598.3567[ M+H ]] + ；MS-ESI(m/z):598.3627[M+H] + 。
Example 2 Compound N- ((3 s,5s,7 s) -adamantan-1-yl) -1- (6- ((2-methyl- [1,1' -biphen-yl ] -3-yl) methoxy) pyridin-3-yl) -5,8,11-trioxa-2-azatetradecan-14-amide (L3 a)
The synthesis method is the same as (L2 a). Starting from compound 5 (n=3) and compound a, a yellow oily hydrophobic tag compound L3a was obtained in a yield of 38%.
1 H NMR(400MHz,CDCl 3 )δ7.44(dd,J＝9.3,2.5Hz,1H),7.38(dd,J＝8.1,6.4Hz,2H),7.34–7.29(m,1H),7.25(d,J＝1.7Hz,1H),7.24–7.20(m,2H),7.19–7.15(m,2H),6.91(dd,J＝5.9,3.2Hz,1H),6.62(d,J＝9.3Hz,1H),6.01(s,1H),5.17(s,2H),3.65(t,J＝5.9Hz,2H),3.57(q,J＝3.0,2.4Hz,12H),2.78(t,J＝5.0Hz,2H),2.33(t,J＝5.9Hz,2H),2.14(s,3H),2.01(d,J＝2.8Hz,3H),1.95(d,J＝3.2Hz,6H),1.64–1.61(m,6H).
Theoretical value: 642.3829[ M+H ]] + ；MS-ESI(m/z):642.3892[M+H] + 。
EXAMPLE 3 Compound N- (adamantan-1-yl) -1- (6- ((2-methyl- [1,1' -biphen yl ] -3-yl) methoxy) pyridin-3-yl) -5,8,11,14-tetraoxa-2-azaheptadecan-17-amide (L4 a)
The synthesis method is the same as (L2 a). Starting from compound 5 (n=4) and compound a, an oily hydrophobic tag compound L4a was obtained in a yield of 35%.
1 H NMR(400MHz,CDCl 3 )δ7.49(dd,J＝9.3,2.5Hz,1H),7.43(t,J＝7.3Hz,2H),7.39–7.34(m,1H),7.30(d,J＝1.7Hz,1H),7.26(m,1H),7.24–7.21(m,2H),6.96(dd,J＝5.9,3.2Hz,1H),6.67(d,J＝9.3Hz,1H),6.13(s,1H),5.21(s,2H),3.70(d,J＝5.9Hz,2H),3.65–3.60(m,16H),2.83(s,2H),2.39(t,J＝6.0Hz,2H),2.19(s,3H),2.06(s,3H),2.00(d,J＝2.9Hz,6H),1.67(d,J＝3.1Hz,6H).
Theoretical value: 686.4124[ M+H ]] + ；MS-ESI(m/z):686.4156[M+H] + 。
EXAMPLE 4 Compound N- (adamantan-1-yl) -1- (6- ((2-methyl- [1,1' -biphen yl ] -3-yl) methoxy) pyridin-3-yl) -5,8,11,14,17-pentaoxa-2-azaicosan-20-amide (L5 a)
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The synthesis method is the same as (L2 a). Starting from compound 5 (n=5) and compound a, a yellow oily hydrophobic tag compound L5a was obtained in a yield of 20%.
1 H NMR(400MHz,CDCl 3 )δ7.50(dd,J＝9.3,2.5Hz,1H),7.42(dd,J＝8.0,6.4Hz,2H),7.38–7.33(m,1H),7.29(d,J＝1.7Hz,1H),7.27(t,J＝1.5Hz,1H),7.24–7.19(m,2H),6.96(dd,J＝6.0,3.1Hz,1H),6.66(d,J＝9.3Hz,1H),6.11(s,1H),5.21(s,2H),3.70(t,J＝5.9Hz,2H),3.63(dd,J＝5.2,2.1Hz,20H),2.84(t,J＝5.0Hz,2H),2.39(t,J＝5.9Hz,2H),2.18(s,3H),2.06(d,J＝1.7Hz,3H),1.99(d,J＝2.9Hz,6H),1.67(d,J＝3.1Hz,6H).
Theoretical value: 730.4387[ M+H ]] + ；MS-ESI(m/z):730.4421[M+H] + 。
EXAMPLE 5 the compound N- (dicyclohexylmethyl) -3- (2- (2- (((6- ((2-methyl- [1,1' -biphen yl ] -3-yl) methoxy) pyridin-3-yl) methyl) amino) method) prop-enamide (L2 b)
The synthesis method is the same as (L2 a). Starting from compound 5 (n=2) and compound b, an oily hydrophobic tag compound L2b was obtained in a yield of 35%.
1 H NMR(400MHz,CDCl 3 )δ7.46(dt,J＝9.3,2.3Hz,1H),7.33(dt,J＝8.7,2.2Hz,3H),7.29–7.23(m,1H),7.18(ddd,J＝6.9,5.0,1.8Hz,2H),7.12(td,J＝5.6,2.5Hz,2H),6.83(dq,J＝13.1,5.0,4.2Hz,1H),6.58–6.50(m,1H),5.97–5.80(m,1H),5.12(s,2H),4.04(dt,J＝7.1,2.1Hz,4H),3.65(d,J＝9.7Hz,4H),3.07(dt,J＝7.3,3.8Hz,2H),2.85(d,J＝4.9Hz,2H),2.73–2.71(m,1H),2.38(td,J＝5.9,2.1Hz,2H),2.09(d,J＝3.2Hz,3H),1.57(t,J＝13.3Hz,10H),1.37–1.32(m,2H),1.12–1.02(m,6H),0.96–0.90(m,2H),0.80(td,J＝9.1,4.8Hz,2H).
Theoretical value: 642.4226[ M+H ]] + ；MS-ESI(m/z):642.4282[M+H] + 。
EXAMPLE 6 Compound N- (dicyclohexylmethyl) -1- (6- ((2-methyl- [1,1' -biphen yl ] -3-yl) methoxy) pyridin-3-yl) -5,8,11-trioxa-2-azatetradecan-14-amide (L3 b)
The synthesis method is the same as (L2 a). Starting from compound 5 (n=3) and compound b, an oily hydrophobic tag compound L3b was obtained in a yield of 30%.
1 H NMR(400MHz,CDCl 3 )δ7.56(dd,J＝9.4,2.6Hz,1H),7.50(d,J＝2.5Hz,1H),7.41(dd,J＝8.1,6.4Hz,2H),7.37–7.32(m,1H),7.28–7.25(m,2H),7.20(q,J＝4.5Hz,2H),6.96(dd,J＝5.9,3.2Hz,1H),6.63(d,J＝9.3Hz,1H),6.00(d,J＝10.3Hz,1H),5.19(s,2H),3.87(s,2H),3.71(dt,J＝11.5,5.2Hz,4H),3.59(d,J＝5.2Hz,8H),3.06(t,J＝4.9Hz,2H),2.46(t,J＝5.8Hz,2H),2.17(s,3H),1.75–1.58(m,10H),1.49–1.38(m,2H),1.22–0.86(m,10H).
Theoretical value: 686.4488[ M+H ]] + ；MS-ESI(m/z):686.4496[M+H] + 。
EXAMPLE 7 Compound N- (dicyclohexylmethyl) -1- (6- ((2-methyl- [1,1' -biphen yl ] -3-yl) methoxy) pyridin-3-yl) -5,8,11,14-tetraoxa-2-azaheptadecan-17-amide (L4 b)
The synthesis method is the same as (L2 a). Starting from compound 5 (n=4) and compound b, an oily hydrophobic tag compound L4b was obtained in 15% yield.
1 H NMR(400MHz,CDCl 3 )δ7.68(dd,J＝9.4,2.6Hz,1H),7.58(d,J＝2.5Hz,1H),7.43(t,J＝7.2Hz,2H),7.37(t,J＝7.2Hz,1H),7.30(d,J＝1.7Hz,1H),7.28(s,1H),7.26–7.19(m,2H),7.01(dd,J＝5.5,3.6Hz,1H),6.69(dd,J＝13.9,9.6Hz,2H),5.22(s,2H),3.92(s,2H),3.77(t,J＝6.6Hz,4H),3.67–3.58(m,12H),3.08(t,J＝4.6Hz,2H),2.52(t,J＝6.5Hz,2H),2.20(s,3H),1.76–1.58(m,10H),1.50(dq,J＝11.7,3.3Hz,2H),1.22–0.91(m,10H).
Theoretical value: 730.4750[ M+H ]] + ；MS-ESI(m/z):730.4723[M+H] + 。
EXAMPLE 8 Compound N- (dicyclohexylmethyl) -1- (6- ((2-methyl- [1,1' -biphen yl ] -3-yl) methoxy) pyridin-3-yl) -5,8,11,14,17-pentaoxa-2-azaicosan-20-amide (L5 b)
The synthesis method is the same as (L2 a). Starting from compound 5 (n=5) and compound b, a yellow oily hydrophobic tag compound L5b was obtained in a yield of 20%.
1 H NMR(400MHz,CDCl 3 )δ7.68–7.61(m,2H),7.43(ddd,J＝7.6,6.2,1.7Hz,3H),7.39–7.36(m,1H),7.30(d,J＝1.7Hz,1H),7.25–7.22(m,2H),7.01(dd,J＝5.9,3.2Hz,1H),6.69(d,J＝9.2Hz,1H),6.49(d,J＝10.3Hz,1H),5.23(s,2H),3.93(s,2H),3.81(t,J＝4.7Hz,2H),3.76(t,J＝6.3Hz,2H),3.65–3.61(m,16H),3.09(t,J＝4.6Hz,2H),2.56(t,J＝6.3Hz,2H),2.20(s,3H),2.07(s,1H),1.68(q,J＝12.5Hz,10H),1.43–1.39(m,2H),1.12–0.84(m,10H).
Theoretical value: 774.5019[ M+H ]] + ；MS-ESI(m/z):774.5024[M+H] + 。
Example 9 the Compound N-Benzhiyl-3- (2- (2- (((6- ((2-methyl- [1,1' -biphenyl ] -3-yl) methoxy) pyridin-3-yl) methyl) amino) method) propanomide (L2 c)
The synthesis method is the same as (L2 a). Starting from compound 5 (n=2) and compound c, an oily hydrophobic tag compound L2c was obtained in a yield of 25%.
1 H NMR(400MHz,CDCl 3 )δ7.46–7.38(m,3H),7.38–7.32(m,2H),7.29(t,J＝7.2Hz,8H),7.24–7.18(m,6H),6.91(t,J＝4.6Hz,1H),6.56(d,J＝9.3Hz,1H),6.20(d,J＝7.9Hz,1H),5.13(s,2H),3.73(t,J＝5.7Hz,2H),3.60–3.56(m,2H),3.52(dd,J＝10.0,5.0Hz,6H),2.71(t,J＝5.0Hz,2H),2.50(t,J＝5.7Hz,2H),2.16(s,3H).
Theoretical value: 630, 3287[ M+H ]] + ；MS-ESI(m/z):630.3325[M+H] + 。
EXAMPLE 10 Compound N-benzohydro-1- (6- ((2-methyl- [1,1' -biphen yl ] -3-yl) methoxy) pyridin-3-yl) -5,8,11-trioxa-2-azatetradecan-14-amide (L3 c)
The synthesis method is the same as (L2 a). Starting from compound 5 (n=3) and compound c, an oily hydrophobic tag compound L3c was obtained in a yield of 35%.
1 H NMR(400MHz,CDCl 3 )δ7.45–7.39(m,4H),7.38–7.35(m,1H),7.29(d,J＝6.8Hz,7H),7.22(dd,J＝12.0,3.7Hz,7H),6.93(t,J＝4.5Hz,1H),6.60(d,J＝9.2Hz,1H),6.23(d,J＝8.1Hz,1H),5.16(s,2H),3.73(t,J＝5.6Hz,2H),3.59–3.49(m,12H),2.75(t,J＝5.0Hz,2H),2.54(t,J＝5.7Hz,2H),2.17(s,3H).
Theoretical value: 674.3594[ M+H ]] + ；MS-ESI(m/z):674.3592[M+H] + 。
EXAMPLE 11 Compound N-benzohydro-1- (6- ((2-methyl- [1,1' -biphen yl ] -3-yl) methoxy) pyridin-3-yl) -5,8,11,14-tetraoxa-2-azaheptadecan-17-amide (L4 c)
The synthesis method is the same as (L2 a). Starting from compound 5 (n=4) and compound c, a yellow oily hydrophobic tag compound L4c was obtained in a yield of 38%.
1 H NMR(400MHz,CDCl 3 )δ7.51(d,J＝8.4Hz,1H),7.46–7.40(m,3H),7.39–7.34(m,1H),7.33–7.29(m,7H),7.28–7.19(m,7H),6.95(t,J＝4.5Hz,1H),6.63(d,J＝9.3Hz,1H),6.28(d,J＝8.3Hz,1H),5.18(s,2H),3.77(t,J＝5.8Hz,2H),3.62(dd,J＝6.2,3.0Hz,2H),3.60–3.50(m,14H),2.77(t,J＝5.0Hz,2H),2.57(t,J＝5.8Hz,2H),2.17(s,3H).
Theoretical value: 718.3811[ M+H ]] + ；MS-ESI(m/z):718.3856[M+H] + 。
EXAMPLE 12 Compound N-benzoyl-1- (6- ((2-methyl- [1,1' -biphen yl ] -3-yl) methoxy) pyridin-3-yl) -5,8,11,14,17-pentaoxa-2-azaicosan-20-amide (L5 c)
The synthesis method is the same as (L2 a). Starting from compound 5 (n=5) and compound c, a yellow oily hydrophobic tag compound L5c was obtained in a yield of 30%.
1 H NMR(400MHz,CDCl 3 )δ8.01(d,J＝8.4Hz,1H),7.53(dd,J＝9.4,2.6Hz,1H),7.48(d,J＝2.6Hz,1H),7.45–7.40(m,2H),7.40–7.34(m,1H),7.31–7.28(m,2H),7.28–7.20(m,7H),6.98(t,J＝8.7Hz,5H),6.62(d,J＝9.4Hz,1H),6.25(d,J＝8.3Hz,1H),5.17(s,2H),3.83(s,2H),3.76(t,J＝6.0Hz,2H),3.73–3.68(m,2H),3.61–3.52(m,16H),3.02(t,J＝4.8Hz,2H),2.60(t,J＝6.0Hz,2H),2.17(s,3H).
Theoretical value: 762.4040[ M+H ]] + ；MS-ESI(m/z):762.4038[M+H] + 。
EXAMPLE 13 Compound N- (1- (6- ((2-methyl- [1,1' -biphen-3-yl) methoxy) pyridin-3-yl) -11-oxo-5,8-dioxa-2, 12-diazatetradecan-14-yl) -9H-fluorne-9-carboxamide (L2 g)
The synthesis method is the same as (L2 a). Starting from compound 5 (n=2) and compound g, a yellow oily hydrophobic tag compound L2g was obtained in 36% yield.
1 H NMR(400MHz,CDCl 3 )δ7.78(d,J＝7.5Hz,2H),7.69–7.66(m,2H),7.50–7.39(m,6H),7.38–7.34(m,3H),7.30(d,J＝2.3Hz,1H),7.27(d,J＝1.0Hz,2H),7.21(d,J＝4.3Hz,2H),6.94(t,J＝4.6Hz,1H),6.91(s,1H),6.65(d,J＝9.3Hz,1H),6.23(s,1H),5.18(s,2H),4.78(s,1H),3.65(s,2H),3.62(t,J＝5.8Hz,2H),3.52(d,J＝1.2Hz,6H),3.28–3.22(m,4H),2.82(t,J＝5.1Hz,2H),2.32(t,J＝5.8Hz,2H),2.17(s,3H).
Theoretical value: 699.3468[ M+H ] +; MS-ESI (m/z): 699.3457[ M+H ] +.
EXAMPLE 14 Compound N- (2- (9H-fluorene-9-carboxamide) ethyl) -1- (6- ((2-methyl- [1,1' -biphen-yl ] -3-yl) methoxy) pyridin-3-yl) -5,8,11-trioxa-2-azatetradecan-14-amide (L3 g)
The synthesis method is the same as (L2 a). Starting from compound 5 (n=3) and compound g, a yellow oily hydrophobic tag compound L3g was obtained in 40% yield.
1 H NMR(600MHz,CDCl 3 )δ7.78(d,J＝7.4Hz,2H),7.68(dd,J＝7.5,1.0Hz,2H),7.47–7.39(m,6H),7.38–7.34(m,3H),7.27(d,J＝1.1Hz,2H),7.22(d,J＝2.2Hz,1H),7.21(s,1H),7.20(d,J＝2.3Hz,1H),6.94(dd,J＝5.6,3.4Hz,1H),6.88(d,J＝5.8Hz,1H),6.64(d,J＝9.3Hz,1H),6.16(s,1H),5.18(s,2H),4.79(s,1H),3.69(s,2H),3.58–3.55(m,4H),3.53(d,J＝3.8Hz,6H),3.51–3.48(m,2H),3.29–3.26(m,2H),3.26–3.23(m,2H),2.75(t,J＝5.1Hz,2H),2.31(t,J＝5.8Hz,2H),2.17(s,3H).
Theoretical value: 743.3764[ M+H ]] + ；MS-ESI(m/z):743.3748[M+H] + 。
EXAMPLE 15 Compound N- (2- (9H-fluorone-9-carboxamide) ethyl) -1- (6- ((2-methyl- [1,1' -biphen-yl ] -3-yl) methoxy) pyridin-3-yl) -5,8,11,14-tetraoxa-2-azaheptadecan-17-amide (L4 g)
The synthesis method is the same as (L2 a). Starting from compound 5 (n=4) and compound g, a yellow oily hydrophobic tag compound L4g was obtained in 40% yield.
1 H NMR(400MHz,CDCl 3 )δ7.78(d,J＝7.5Hz,2H),7.69(d,J＝7.5Hz,2H),7.48–7.39(m,6H),7.36(dd,J＝8.6,6.6Hz,3H),7.29(s,1H),7.28(s,1H),7.22(q,J＝4.6Hz,3H),6.95(dd,J＝5.5,3.6Hz,2H),6.65(d,J＝9.3Hz,1H),6.14(s,1H),5.19(s,2H),4.79(s,1H),3.59–3.53(m,14H),3.51(d,J＝3.5Hz,4H),3.28(td,J＝6.5,3.0Hz,4H),2.75(t,J＝5.0Hz,2H),2.33(t,J＝5.8Hz,2H),2.18(s,3H).
Theoretical value: 787.4026[ M+H ]] + ；MS-ESI(m/z):787.4018[M+H] + 。
EXAMPLE 16 Compound N- (2- (9H-fluoro-9-carboxamide) ethyl) -1- (6- ((2-methyl- [1,1' -biphen-yl ] -3-yl) methoxy) pyridin-3-yl) -5,8,11,14,17-pentaoxa-2-azaicosan-20-amide (L5 g)
The synthesis method is the same as (L2 a). Starting from compound 5 (n=5) and compound g, a yellow oily hydrophobic tag compound L5g was obtained in a yield of 35%.
1 H NMR(600MHz,CDCl 3 )δ7.72(d,J＝7.6Hz,2H),7.64(d,J＝7.5Hz,2H),7.45(dd,J＝9.4,2.5Hz,1H),7.38(t,J＝7.6Hz,4H),7.31(dd,J＝7.6,4.3Hz,4H),7.24(d,J＝7.5Hz,3H),7.15(m,2H),6.88(t,J＝4.6Hz,1H),6.59(d,J＝9.3Hz,1H),6.39(d,J＝5.4Hz,1H),5.12(s,2H),4.75(s,1H),3.68(s,2H),3.58(t,J＝5.0Hz,2H),3.55–3.49(m,14H),3.47(dd,J＝6.0,2.9Hz,2H),3.45–3.43(m,2H),3.26(dt,J＝11.2,5.8Hz,4H),2.86(t,J＝4.9Hz,2H),2.31(t,J＝5.8Hz,2H),2.12(s,3H).
Theoretical value: 831.4288[ M+H ]] + ；MS-ESI(m/z):831.4272[M+H] + 。
EXAMPLE 17 Compound 2- (4-isobutylphenyl) -N- (1- (6- ((2-methyl- [1,1' -biphenyl ] -3-yl) methoxy) pyridin-3-yl) -11-oxo-5,8-dioxa-2, 12-diazatetradecan-14-yl) pro-panamide (L2 h)
The synthesis method is the same as (L2 a). Starting from compound 5 (n=2) and compound h, a yellow oily hydrophobic tag compound L2h was obtained in a yield of 35%.
1 H NMR(600MHz,CDCl 3 )δ7.50(dd,J＝9.3,2.5Hz,1H),7.41(t,J＝7.5Hz,2H),7.37–7.32(m,2H),7.27(dd,J＝8.0,1.7Hz,2H),7.22–7.18(m,4H),7.08(d,J＝7.8Hz,3H),6.97–6.91(m,1H),6.70(d,J＝7.3Hz,1H),6.64(d,J＝9.3Hz,1H),5.20(s,2H),3.68–3.61(m,6H),3.55(s,4H),3.27(dt,J＝10.6,4.1Hz,4H),3.05(q,J＝7.3Hz,1H),2.85(t,J＝5.0Hz,2H),2.43(d,J＝7.2Hz,2H),2.36(t,J＝5.8Hz,2H),2.17(s,3H),1.99–1.94(m,2H),1.83(dq,J＝13.5,6.8Hz,1H),1.46(d,J＝7.1Hz,3H),0.89(d,J＝6.6Hz,6H).
Theoretical value: 695.4128[ M+H ]] + ；MS-ESI(m/z):695.4108[M+H] + 。
EXAMPLE 18 Compound N- (2- (4-isobutylphenyl) propanamidamido) ethyl) -1- (6- ((2-methyl- [1,1' -biphenyl ] -3-yl) methoxy) pyridin-3-yl) -5,8,11-trioxa-2-azatetradecan-14-amide (L3 h)
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The synthesis method is the same as (L2 a). Starting from compound 5 (n=3) and compound h, a yellow oily hydrophobic tag compound L3h was obtained in 25% yield.
1 H NMR(400MHz,CDCl 3 )δ7.50(dd,J＝9.4,2.5Hz,1H),7.41(dd,J＝8.0,6.4Hz,2H),7.38–7.32(m,1H),7.30–7.25(m,3H),7.21(dd,J＝6.0,2.4Hz,4H),7.08(d,J＝7.9Hz,3H),6.95(dd,J＝5.6,3.5Hz,1H),6.77(d,J＝5.1Hz,1H),6.64(d,J＝9.3Hz,1H),5.20(s,2H),3.63–3.55(m,13H),3.46(d,J＝8.4Hz,4H),3.28(dd,J＝5.6,2.7Hz,4H),2.82(t,J＝4.9Hz,2H),2.43(d,J＝7.1Hz,2H),2.36(t,J＝5.7Hz,2H),2.17(s,3H),1.83(d,J＝6.7Hz,1H),1.46(d,J＝7.1Hz,3H),0.89(d,J＝6.6Hz,6H).
Theoretical value: 739.4390[ M+H ]] + ；MS-ESI(m/z):739.4366[M+H] + 。
EXAMPLE 19 the compound N- (2- (4-isobutylphenyl) propanamidate) ethyl) -1- (6- ((2-methyl- [1,1' -biphenyl ] -3-yl) methoxy) pyridin-3-yl) -5,8,11,14-tetraoxa-2-azaheptadecan-17-amide (L4 h)
The synthesis method is the same as (L2 a). Starting from compound 5 (n=4) and compound h, the yield of yellow oily hydrophobic tag compound L4h was 35%.
1 H NMR(600MHz,CDCl 3 )δ7.51(dd,J＝9.4,2.6Hz,1H),7.41(t,J＝7.6Hz,2H),7.38–7.33(m,2H),7.32(d,J＝2.5Hz,1H),7.30–7.27(m,2H),7.24–7.19(m,4H),7.07(d,J＝8.1Hz,2H),6.95(dd,J＝5.7,3.4Hz,1H),6.80(t,J＝5.1Hz,1H),6.65(d,J＝9.3Hz,1H),5.20(s,2H),3.68–3.57(m,20H),3.54(d,J＝7.1Hz,1H),3.33(td,J＝5.9,1.8Hz,2H),3.31–3.27(m,2H),2.85(t,J＝4.9Hz,2H),2.42(d,J＝7.1Hz,2H),2.37(t,J＝6.0Hz,2H),2.17(s,3H),1.83(dq,J＝13.5,6.7Hz,1H),1.46(d,J＝7.0Hz,3H),0.89(d,J＝6.6Hz,6H).
Theoretical value: 783.4652[ M+H ]] + ；MS-ESI(m/z):783.4666[M+H] + 。
EXAMPLE 20 Compound N- (2- (4-isobutylphenyl) propanamidate) ethyl) -1- (6- ((2-methyl- [1,1' -biphenyl ] -3-yl) methoxy) pyridin-3-yl) -5,8,11,14,17-pentaoxa-2-azaicosan-20-amide (L5 h)
The synthesis method is the same as (L2 a). Starting from compound 5 (n=5) and compound h, a yellow oily hydrophobic tag compound L5h was obtained in 15% yield.
1 H NMR(600MHz,CDCl 3 )δ7.55(dd,J＝9.3,2.5Hz,1H),7.47(t,J＝5.6Hz,1H),7.43–7.39(m,3H),7.37–7.34(m,1H),7.28–7.26(m,2H),7.23–7.19(m,4H),7.07(d,J＝7.8Hz,2H),6.94(dd,J＝5.6,3.6Hz,1H),6.86(s,1H),6.66(d,J＝9.4Hz,1H),5.20(s,2H),3.77(s,2H),3.66(ddd,J＝7.6,3.0Hz,4H),3.62–3.51(m,18H),3.37–3.31(m,2H),3.30–3.24(m,2H),3.08(q,J＝7.3Hz,1H),2.97–2.89(m,2H),2.44–2.39(m,4H),2.18(s,3H),1.83(dq,J＝13.5,6.8Hz,1H),1.46(d,J＝7.1Hz,3H),0.89(d,J＝6.6Hz,6H).
Theoretical value: 827.4914[ M+H ]] + ；MS-ESI(m/z):827.4930[M+H] + 。
EXAMPLE 21 the Compound 1- (4- (bis (4-fluoro) methyl) piperazin-1-yl) -3- (2- (2- (((6- ((2-methyl- [1,1' -biphen yl ] -3-yl) method) pyridin-3-yl) methyl) amino) method-1-one (L2 d)
The synthesis method is the same as (L2 a). Starting from compound 5 (n=2) and compound d, a yellow oily hydrophobic tag compound L2d was obtained in 40% yield.
1 H NMR(400MHz,CDCl 3 )δ7.52(dd,J＝9.4,2.5Hz,1H),7.43(t,J＝7.3Hz,2H),7.35(dd,J＝8.3,5.4Hz,6H),7.31–7.27(m,3H),7.22(d,J＝4.5Hz,2H),7.00(t,J＝8.5Hz,5H),6.65(d,J＝9.3Hz,1H),5.20(s,2H),4.24(s,1H),3.76(t,J＝6.3Hz,2H),3.70(s,2H),3.66(d,J＝4.9Hz,2H),3.60(d,J＝6.9Hz,6H),3.46(t,J＝5.0Hz,2H),2.87(t,J＝5.0Hz,2H),2.57(t,J＝6.3Hz,2H),2.34(q,J＝4.2Hz,4H),2.18(s,3H).
Theoretical value: 735.3677[ M+H ]] + ；MS-ESI(m/z):735.3624[M+H] + 。
EXAMPLE 22 Compound 14- (4- (bis (4-fluoro) methyl) piperazin-1-yl) -1- (6- ((2-methyl- [1,1' -biphen yl ] -3-yl) methoxy) pyridin-3-yl) -5,8,11-trioxa-2-azatetradecan-14-one (L3 d)
The synthesis method is the same as (L2 a). Starting from compound 5 (n=3) and compound d, a yellow oily hydrophobic tag compound L3d was obtained in 25% yield.
1 H NMR(400MHz,CDCl 3 )δ7.51(dd,J＝9.3,2.5Hz,1H),7.41(dd,J＝8.1,6.5Hz,3H),7.34(td,J＝5.4,2.5Hz,6H),7.29–7.26(m,2H),7.20(d,J＝3.7Hz,2H),6.98(t,J＝8.6Hz,5H),6.62(d,J＝9.3Hz,1H),5.18(s,2H),4.22(s,1H),3.73(t,J＝6.3Hz,2H),3.65–3.56(m,14H),3.45(t,J＝5.0Hz,2H),2.85(t,J＝4.9Hz,2H),2.57(t,J＝6.3Hz,2H),2.37–2.30(m,4H),2.16(s,3H).
Theoretical value: 779.3939[ M+H ]] + ；MS-ESI(m/z):779.3847[M+H] + 。
EXAMPLE 23 Compound 17- (4- (bis (4-fluorophenyl) methyl) piperazin-1-yl) -1- (6- ((2-methyl- [1,1' -biphen yl ] -3-yl) methoxy) pyridin-3-yl) -5,8,11, 14-tetraoxa-2-azahepadecan-17-one (L4 d)
The synthesis method is the same as (L2 a). Starting from compound 5 (n=4) and compound d, a yellow oily hydrophobic tag compound L4d was obtained in a yield of 30%.
1 H NMR(400MHz,CDCl 3 )δ7.56(dd,J＝9.4,2.5Hz,1H),7.49–7.39(m,4H),7.35(dt,J＝8.5,5.3Hz,5H),7.28(t,J＝4.3Hz,2H),7.21(d,J＝5.8Hz,2H),6.98(t,J＝8.7Hz,5H),6.64(d,J＝9.3Hz,1H),5.20(s,2H),4.23(s,1H),3.75(t,J＝6.6Hz,2H),3.72(s,2H),3.69(t,J＝4.9Hz,2H),3.65–3.55(m,14H),3.46(t,J＝5.0Hz,2H),2.90(t,J＝4.8Hz,2H),2.58(t,J＝6.6Hz,2H),2.38–2.27(m,4H),2.18(s,3H).
Theoretical value: 823.4201[ M+H ]] + ；MS-ESI(m/z):823.4126[M+H] + 。
EXAMPLE 24 the compound N- (bis (4-fluorophenyl) methyl) -3- (2- (2- (((6- ((2-methyl- [1,1' -biphen yl ] -3-yl) methoxy) pyridin-3-yl) methyl) amino) method) prop-enamide (L2 e)
The synthesis method is the same as (L2 a). Starting from compound 5 (n=2) and compound e, a yellow oily hydrophobic tag compound L2e was obtained in a yield of 35%.
1 H NMR(400MHz,CDCl 3 )δ7.68(d,J＝8.0Hz,1H),7.50(d,J＝2.5Hz,1H),7.45(dd,J＝9.4,2.5Hz,1H),7.39(dd,J＝8.1,6.4Hz,2H),7.36–7.31(m,1H),7.25–7.22(m,2H),7.22–7.16(m,6H),6.97–6.92(m,4H),6.90(dd,J＝5.6,3.6Hz,1H),6.50(d,J＝9.3Hz,1H),6.14(d,J＝7.9Hz,1H),5.12(s,2H),3.82(s,2H),3.69(t,J＝5.8Hz,2H),3.63(d,J＝5.0Hz,2H),3.55–3.47(m,4H),2.97(t,J＝4.9Hz,2H),2.48(t,J＝5.8Hz,2H),2.13(s,3H).
Theoretical value: 666.3099[ M+H ]] + ；MS-ESI(m/z):666.3110[M+H] + 。
EXAMPLE 25 Compound N- (bis (4-fluorophenyl) methyl) -1- (6- ((2-methyl- [1,1' -biphen yl ] -3-yl) methoxy) pyridin-3-yl) -5,8,11-trioxa-2-azatetradecan-14-amide (L3 e)
The synthesis method is the same as (L2 a). Starting from compound 5 (n=3) and compound e, a yellow oily hydrophobic tag compound L3e was obtained in a yield of 35%.
1H NMR(400MHz,CDCl 3 )δ7.43(dt,J＝14.4,2.1Hz,5H),7.39–7.33(m,1H),7.28–7.25(m,2H),7.24–7.18(m,6H),7.04–6.96(m,4H),6.94(t,J＝4.6Hz,1H),6.57(d,J＝9.2Hz,1H),6.16(d,J＝7.9Hz,1H),5.17(s,2H),3.74(s,2H),3.70(t,J＝5.7Hz,2H),3.64–3.59(m,2H),3.54(d,J＝5.4Hz,8H),2.93(t,J＝5.0Hz,2H),2.55(t,J＝5.7Hz,2H),2.17(s,3H).
Theoretical value: 710.3361[ M+H ]] + ；MS-ESI(m/z):710.3371[M+H] + 。
EXAMPLE 26 Compound N- (bis (4-fluorophenyl) methyl) -1- (6- ((2-methyl- [1,1' -biphen yl ] -3-yl) methoxy) pyridin-3-yl) -5,8,11,14-tetraoxa-2-azaheptadecan-17-amide (L4 e)
The synthesis method is the same as (L2 a). Starting from compound 5 (n=4) and compound e, a yellow oily hydrophobic tag compound L4e was obtained in a yield of 35%.
1 H NMR(400MHz,CDCl 3 )δ8.15(d,J＝8.4Hz,1H),7.50(dd,J＝9.4,2.6Hz,1H),7.42(td,J＝6.3,2.7Hz,3H),7.39–7.34(m,1H),7.29–7.21(m,8H),7.04–6.91(m,5H),6.59(d,J＝9.4Hz,1H),6.24(d,J＝8.4Hz,1H),5.16(s,2H),3.80–3.71(m,4H),3.67(dd,J＝5.9,3.8Hz,2H),3.64–3.60(m,2H),3.60–3.50(m,10H),2.99(t,J＝4.7Hz,2H),2.52(t,J＝6.2Hz,2H),2.16(s,3H).
Theoretical value: 754.3632[ M+H ]] + ；MS-ESI(m/z):754.3634[M+H] + 。
EXAMPLE 27 Compound N- (bis (4-fluorophenyl) methyl) -1- (6- ((2-methyl- [1,1' -biphen yl ] -3-yl) methoxy) pyridin-3-yl) -5,8,11,14,17-pentaoxa-2-azaicosan-20-amide (L5 e)
The synthesis method is the same as (L2 a). Starting from compound 5 (n=5) and compound e, a yellow oily hydrophobic tag compound L5e was obtained in 25% yield.
1 H NMR(400MHz,CDCl 3 )δ8.01(d,J＝8.4Hz,1H),7.53(dd,J＝9.4,2.6Hz,1H),7.48(d,J＝2.6Hz,1H),7.45–7.40(m,2H),7.40–7.34(m,1H),7.30–7.28(m,2H),7.28–7.25(m,3H),7.25(d,J＝2.1Hz,1H),7.23–7.20(m,2H),7.02–6.93(m,5H),6.62(d,J＝9.4Hz,1H),6.25(d,J＝8.3Hz,1H),5.17(s,2H),3.83(s,2H),3.76(t,J＝6.0Hz,2H),3.73–3.68(m,2H),3.61–3.52(m,16H),3.02(t,J＝4.8Hz,2H),2.60(t,J＝6.0Hz,2H),2.17(s,3H).
Theoretical value: 798.3385[ M+H ]] + ；MS-ESI(m/z):798.3856[M+H] + 。
Example 28 Compound 3- (2- (2- (((6- ((2-methyl- [1,1' -biphenyl ] -3-yl) methoxy) pyridin-3-yl) methyl) amino) method-N- (phenyl (4- (trifluoromethyl) phenyl) methyl) propenamide (L2 f)
The synthesis method is the same as (L2 a). Starting from compound 5 (n=2) and compound f, a yellow oily hydrophobic tag compound L2f was obtained in a yield of 20%.
1 H NMR(400MHz,CDCl 3 )δ7.56(d,J＝8.1Hz,2H),7.45–7.37(m,6H),7.37–7.29(m,3H),7.29–7.21(m,6H),7.21(d,J＝4.0Hz,2H),6.91(t,J＝4.5Hz,1H),6.59(d,J＝9.3Hz,1H),6.27(d,J＝8.0Hz,1H),5.16(s,2H),3.75(td,J＝5.9,2.0Hz,2H),3.60(q,J＝2.6Hz,2H),3.55–3.44(m,6H),2.70(t,J＝5.1Hz,2H),2.54(t,J＝5.7Hz,2H),2.17(s,3H).
Theoretical value: 698.3168[ M+H ]] + ；MS-ESI(m/z):698.3161[M+H] + 。
EXAMPLE 29 Compound 1- (6- ((2-methyl- [1,1' -biphen-3-yl) methoxy) pyridin-3-yl) -N- (phenyl (4- (trifluoromethyl) phenyl) methyl) -5,8,11-trioxa-2-azatetradecan-14-amide (L3 f)
The synthesis method is the same as (L2 a). Starting from compound 5 (n=3) and compound f, a yellow oily hydrophobic tag compound L3f was obtained in 28% yield.
1 H NMR(400MHz,CDCl 3 )δ7.69(s,1H),7.54(d,J＝8.0Hz,2H),7.46–7.38(m,5H),7.36(d,J＝7.1Hz,2H),7.30(s,2H),7.28–7.22(m,5H),7.20(d,J＝4.5Hz,2H),6.94(t,J＝4.6Hz,1H),6.58(d,J＝9.3Hz,1H),6.26(d,J＝8.0Hz,1H),5.16(s,2H),3.76–3.72(m,2H),3.68–3.50(m,12H),2.87(s,2H),2.59(s,2H),2.16(s,3H).
Theoretical value: 742.3423[ M+H ]] + ；MS-ESI(m/z):742.3438[[M+H] + 。
EXAMPLE 30 Compound 1- (6- ((2-methyl- [1,1' -biphen-3-yl) methoxy) pyridin-3-yl) -N- (phenyl (4- (trifluoromethyl) phenyl) methyl) -5,8,11, 14-tetraoxa-2-azahepadecan-17-amide (L4 f)
The synthesis method is the same as (L2 a). Starting from compound 5 (n=4) and compound f, a yellow oily hydrophobic tag compound L4f was obtained in a yield of 30%.
1 H NMR(400MHz,CDCl 3 )δ7.57–7.49(m,4H),7.45–7.39(m,3H),7.39–7.33(m,3H),7.29(d,J＝6.8Hz,5H),7.28–7.20(m,4H),6.97(dd,J＝5.4,3.7Hz,1H),6.60(d,J＝9.4Hz,1H),6.34(d,J＝8.5Hz,1H),5.17(s,2H),3.80–3.74(m,2H),3.70(s,2H),3.68–3.61(m,4H),3.58(d,J＝7.9Hz,10H),2.94(q,J＝3.7Hz,2H),2.63–2.56(m,2H),2.16(s,3H).
Theoretical value: 786.3685[ M+H ]] + ；MS-ESI(m/z):786.3676[M+H] + 。
Example 31 Compound N1- (adamantan-1-yl) -N4- (2- (((6- ((2-methyl- [1,1' -biphen yl ] -3-yl) methoxy) pyridin-3-yl) methyl) amino) ethyl) succinimide (LC 4 a)
Compound 4 (n=1), compound 1 (1.0 eq) were dissolved in methanol under nitrogen atmosphere and reacted overnight at 40 ℃. Adding NaBH again 4 (3.0 eq) the solvent was evaporated under reduced pressure and the crude product was separated by column chromatography to give compound CL1a as a yellow solid.
1 H NMR(400MHz,CDCl 3 )δ7.47–7.40(m,3H),7.40–7.34(m,1H),7.30(d,J＝1.6Hz,1H),7.25–7.21(m,2H),7.18(d,J＝2.5Hz,1H),6.96(dd,J＝5.9,3.1Hz,1H),6.67(d,J＝9.3Hz,1H),6.55(s,1H),5.47(s,1H),5.21(s,2H),3.54(s,2H),3.35(q,J＝5.8Hz,2H),2.74(t,J＝5.8Hz,2H),2.45(s,4H),2.19(s,3H),2.06(s,3H),1.96(d,J＝3.2Hz,6H),1.67(d,J＝3.1Hz,6H).
Theoretical value: 581.3472[ M+H ]] + ；MS-ESI(m/z):581.3447[M+H] + 。
EXAMPLE 32 Compound N1- (adamantan-1-yl) -N5- (2- (((6- ((2-methyl- [1,1' -biphen yl ] -3-yl) methoxy) pyridin-3-yl) methyl) amino) ethyl) glut-to-amamide (LC 5 a)
The synthesis method is the same as CL1a, and compound 4 (n=2), compound 1 (1.0 eq) and NaBH are used 4 As a starting material, yellow solid compound CL2a was obtained.
1 H NMR(400MHz,CDCl 3 )δ7.47–7.41(m,3H),7.39–7.34(m,1H),7.30(d,J＝1.7Hz,1H),7.26–7.21(m,2H),7.16(d,J＝2.5Hz,1H),6.95(dd,J＝6.0,3.1Hz,1H),6.67(d,J＝9.3Hz,1H),6.41(t,J＝5.6Hz,1H),5.44(s,1H),5.21(s,2H),3.53(s,2H),3.36(q,J＝5.7Hz,2H),2.74(t,J＝5.8Hz,2H),2.25(t,J＝7.1Hz,2H),2.19(s,3H),2.15(t,J＝6.9Hz,2H),2.08(s,3H),1.99(d,J＝2.9Hz,6H),1.91(t,J＝7.0Hz,5H),1.68(t,J＝3.1Hz,6H).
Theoretical value: 595.3603[ M+H ]] + ；MS-ESI(m/z):595.3628[M+H] + 。
EXAMPLE 33 Compound N-benzoyl-3- (2- (2- (6- (2-methyl- [1,1' -biphen yl ] -3-yl) pyridin-3-yl) methyl) amino) method) propanoy-l-propanomide (Z2 c)
The synthesis method is the same as (L2 a). Starting from compound 6 (n=2) and compound c, a yellow oily hydrophobic tag compound Z2c was obtained in a yield of 25%.
1 H NMR(400MHz,CDCl 3 )δ8.64(d,J＝2.2Hz,1H),7.82(dd,J＝8.1,2.3Hz,1H),7.62(d,J＝8.3Hz,1H),7.46–7.40(m,3H),7.38–7.27(m,10H),7.27–7.19(m,6H),6.28(d,J＝8.3Hz,1H),3.92(s,2H),3.78(t,J＝5.7Hz,2H),3.65–3.55(m,6H),2.86(t,J＝5.0Hz,2H),2.54(t,J＝5.7Hz,2H),2.16(s,3H).
Theoretical value: 600.3199[ M+H ]] + ；MS-ESI(m/z):600.3181[M+H] + 。
Example 34N-Benzhiyl-1- (6- (2-methyl- [1,1' -biphenyl ] -3-yl) pyridin-3-yl) -5,8,11-trioxa-2-azatetradecan-14-amide (Z3 c)
The synthesis method is the same as (L2 a). Starting from compound 6 (n=3) and compound c, a yellow oily hydrophobic tag compound Z3c was obtained in 25% yield.
1 H NMR(400MHz,CDCl 3 )δ8.60(d,J＝2.2Hz,1H),7.76(dd,J＝7.9,2.3Hz,1H),7.44–7.40(m,2H),7.38–7.27(m,12H),7.26–7.19(m,6H),6.27(d,J＝8.3Hz,1H),3.83(s,2H),3.75(t,J＝5.7Hz,2H),3.63–3.56(m,6H),3.52(d,J＝2.6Hz,4H),2.82(t,J＝5.1Hz,2H),2.54(t,J＝5.6Hz,2H),2.15(s,3H).
Theoretical value: 644.3460[ M+H ]] + ；MS-ESI(m/z):644.3444[M+H] + 。
Example 35N-Benzhydryl-1- (6- (2-methyl- [1,1' -biphenyl ] -3-yl) pyridin-3-yl) -5,8,11,14-tetraoxa-2-azaheptadecan-17-amide (Z4 c)
The synthesis method is the same as (L2 a). Starting from compound 6 (n=4) and compound c, a yellow oily hydrophobic tag compound Z4c was obtained in a yield of 30%.
1 H NMR(400MHz,CDCl 3 )δ8.63(d,J＝2.3Hz,1H),7.97–7.88(m,2H),7.44–7.39(m,3H),7.37–7.33(m,3H),7.33–7.29(m,3H),7.26(d,J＝4.7Hz,8H),7.22–7.16(m,2H),6.25(d,J＝8.3Hz,1H),4.06(s,2H),3.74(t,J＝6.0Hz,2H),3.69(t,J＝4.8Hz,2H),3.57(d,J＝12.5Hz,12H),3.06(d,J＝4.9Hz,2H),2.52(t,J＝6.0Hz,2H),2.14(s,3H).
Theoretical value: 688.3723[ M+H ]] + ；MS-ESI(m/z):688.3706[M+H] + 。
Example 36 Compound 1- (4- (bis (4-fluoro) methyl) piperazin-1-yl) -3- (2- (2- (((6- (2-methyl- [1,1' -biphen yl ] -3-yl) methyl) amino) method) prop an-1-one (Z2 d)
The synthesis method is the same as (L2 a). Starting from compound 6 (n=2) and compound d, a yellow oily hydrophobic tag compound Z2d was obtained in a yield of 30%.
1 H NMR(400MHz,CDCl 3 )δ8.68(d,J＝2.2Hz,1H),7.95(dd,J＝8.1,2.3Hz,1H),7.44(dd,J＝7.7,5.6Hz,3H),7.40–7.30(m,10H),6.98(t,J＝8.6Hz,4H),4.23(s,1H),4.04(s,2H),3.79(t,J＝6.4Hz,2H),3.73(t,J＝5.0Hz,2H),3.64(s,4H),3.59(t,J＝5.1Hz,2H),3.47(t,J＝5.0Hz,2H),2.98(t,J＝5.0Hz,2H),2.60(t,J＝6.4Hz,2H),2.34(q,J＝6.0Hz,4H),2.17(s,3H).
Theoretical value: 705.3564[ M+H ]] + ；MS-ESI(m/z):705.3572[M+H] + 。
EXAMPLE 37 Compound 14- (4- (bis (4-fluoro) methyl) piperazin-1-yl) -1- (6- (2-methyl- [1,1' -biphen yl ] -3-yl) pyridin-3-yl) -5,8,11-trioxa-2-azatetradecan-14-one (Z3 d)
The synthesis method is the same as (L2 a). Starting from compound 6 (n=3) and compound d, a yellow oily hydrophobic tag compound Z3d was obtained in a yield of 30%.
1 H NMR(400MHz,CDCl 3 )δ8.75(d,J＝2.3Hz,1H),8.13(dd,J＝8.1,2.3Hz,1H),7.46(dd,J＝15.6,7.7Hz,3H),7.40–7.29(m,10H),6.97(t,J＝8.5Hz,4H),4.28(s,2H),4.21(s,1H),3.87–3.81(m,2H),3.71(t,J＝5.8Hz,2H),3.62(m,10H),3.47–3.41(m,2H),3.23(d,J＝4.7Hz,2H),2.56(t,J＝5.8Hz,2H),2.32(dt,J＝14.1,4.8Hz,4H),2.15(s,3H).
Theoretical value: 749.3834[ M+H ]] + ；MS-ESI(m/z):749.3835[M+H] + 。
EXAMPLE 38 Compound 17- (4- (bis (4-fluorophenyl) methyl) piperazin-1-yl) -1- (6- (2-methyl- [1,1' -biphen yl ] -3-yl) pyridin-3-yl) -5,8,11, 14-tetraoxa-2-azahepadecan-17-one (Z4 d)
The synthesis method is the same as (L2 a). Starting from compound 6 (n=4) and compound d, a yellow oily hydrophobic tag compound Z4d was obtained in a yield of 30%.
1 H NMR(400MHz,CDCl 3 )δ8.68(d,J＝2.3Hz,1H),7.99–7.94(m,1H),7.47–7.41(m,3H),7.36(ddd,J＝13.9,3.1Hz,9H),7.31–7.29(m,1H),6.99(dd,J＝9.9,7.4Hz,4H),4.23(s,1H),4.00(s,2H),3.75(dt,J＝14.4,5.8Hz,4H),3.68–3.58(m,14H),3.47(t,J＝5.1Hz,2H),2.97(t,J＝5.1Hz,2H),2.60(t,J＝6.7Hz,2H),2.34(q,J＝5.5Hz,4H),2.18(s,3H).
Theoretical value: 793.4096[ M+H ]] + ；MS-ESI(m/z):793.4094[M+H] + 。
Example 39 Compound N- (bis (4-fluorophenyl) methyl) -3- (2- (2- (((6- (2-methyl- [1,1' -biphen yl ] -3-yl) pyridin-3-yl) methyl) amino) method) prop-enamide (Z2 e)
The synthesis method is the same as (L2 a). Starting from compound 6 (n=2) and compound e, a yellow oily hydrophobic tag compound Z2e was obtained in 25% yield.
1 H NMR(400MHz,CDCl 3 )δ8.62(d,J＝2.2Hz,1H),7.74(dd,J＝8.0,2.3Hz,1H),7.54(d,J＝8.2Hz,1H),7.47–7.40(m,3H),7.38–7.35(m,3H),7.31(q,J＝4.9Hz,3H),7.21–7.16(m,4H),7.01–6.94(m,4H),6.23(d,J＝8.1Hz,1H),3.83(s,2H),3.77(t,J＝5.7Hz,2H),3.65–3.62(m,2H),3.58(dt,J＝8.1,4.0Hz,4H),2.80(t,J＝5.1Hz,2H),2.53(t,J＝5.7Hz,2H),2.16(s,3H).
Theoretical value: 636.3002[ M+H ]] + ；MS-ESI(m/z):636.2993[M+H] + 。
EXAMPLE 40 Compound N- (bis (4-fluorophenyl) methyl) -1- (6- (2-methyl- [1,1' -biphen yl ] -3-yl) pyridin-3-yl) -5,8,11-trioxa-2-azatetradecan-14-amide (Z3 e)
The synthesis method is the same as (L2 a). Starting from compound 6 (n=3) and compound e, a yellow oily hydrophobic tag compound Z3e was obtained in 25% yield.
1 H NMR(400MHz,CDCl 3 )δ8.62(d,J＝2.2Hz,1H),7.77(dd,J＝8.0,2.3Hz,1H),7.48–7.39(m,4H),7.37(dt,J＝6.8,1.5Hz,3H),7.35–7.32(m,2H),7.30(d,J＝3.2Hz,1H),7.25–7.18(m,4H),7.04–6.97(m,4H),6.25(d,J＝8.2Hz,1H),3.86(s,2H),3.76(t,J＝5.6Hz,2H),3.65–3.52(m,10H),2.85(dd,J＝6.8,3.4Hz,2H),2.55(t,J＝5.6Hz,2H),2.17(s,3H).
Theoretical value: 680.3261[ M+H ]] + ；MS-ESI(m/z):680.3225[M+H] + 。
EXAMPLE 41 Compound N- (bis (4-fluorophenyl) methyl) -1- (6- (2-methyl- [1,1' -biphen yl ] -3-yl) pyridin-3-yl) -5,8,11,14-tetraoxa-2-azaheptadecan-17-amide (Z4 e)
The synthesis method is the same as (L2 a). Starting from compound 6 (n=4) and compound e, a yellow oily hydrophobic tag compound Z4e was obtained in a yield of 30%.
1 H NMR(400MHz,CDCl 3 )δ8.64(d,J＝2.3Hz,1H),7.84(dd,J＝7.9,2.3Hz,1H),7.68(s,1H),7.47–7.35(m,6H),7.35–7.32(m,2H),7.32–7.29(m,1H),7.26–7.21(m,4H),7.00(t,J＝8.7Hz,4H),6.25(d,J＝8.3Hz,1H),3.92(s,2H),3.76(t,J＝5.8Hz,2H),3.66(t,J＝4.9Hz,2H),3.63–3.55(m,12H),2.92(t,J＝5.0Hz,2H),2.54(t,J＝5.9Hz,2H),2.17(s,3H).
Theoretical value: 724.3523[ M+H ]] + ；MS-ESI(m/z):742.3517[M+H] + 。
Example 42 Compound 3- (2- (2- (((6- (2-methyl- [1,1' -biphenyl ] -3-yl) pyridin-3-yl) methyl) amino) method) -N- (phenyl (4- (trifluoromethyl) phenyl) methyl) propenamide (Z2 f)
The synthesis method is the same as (L2 a). Starting from compound 6 (n=2) and compound f, a yellow oily hydrophobic tag compound Z2f was obtained in 25% yield.
1 H NMR(400MHz,CDCl 3 )δ8.62(d,J＝2.3Hz,1H),7.72(dd,J＝7.9,2.3Hz,1H),7.57(d,J＝8.1Hz,2H),7.50(d,J＝8.1Hz,1H),7.47–7.42(m,2H),7.39(td,J＝8.0,4.5Hz,6H),7.35–7.28(m,6H),7.23–7.18(m,2H),6.32(d,J＝8.0Hz,1H),3.81(s,4H),3.69–3.63(m,2H),3.62–3.55(m,4H),2.78(t,J＝5.1Hz,2H),2.57(t,J＝5.6Hz,2H),2.17(s,3H).
Theoretical value: 668.3007[ M+H ]] + ；MS-ESI(m/z):668.3055[M+H] + 。
EXAMPLE 43 Compound 1- (6- (2-methyl- [1,1' -biphen-3-yl) pyridin-3-yl) -N- (phenyl (4- (trifluoromethyl) phenyl) methyl) -5,8,11-trioxa-2-azatetradecan-14-amide (Z3 f)
The synthesis method is the same as (L2 a). Starting from compound 6 (n=3) and compound f, a yellow oily hydrophobic tag compound Z3f was obtained in 25% yield.
1 H NMR(400MHz,CDCl 3 )δ8.62(d,J＝2.3Hz,1H),7.78(dd,J＝8.0,2.3Hz,1H),7.61–7.54(m,3H),7.47–7.39(m,5H),7.39–7.34(m,4H),7.33–7.28(m,5H),7.26–7.21(m,2H),6.30(d,J＝8.0Hz,1H),3.90(s,2H),3.74(td,J＝5.7,2.5Hz,2H),3.60(s,10H),2.86(t,J＝5.1Hz,2H),2.60–2.49(m,2H),2.16(s,3H).
Theoretical value: 712.3281[ M+H ]] + ；MS-ESI(m/z):712.3317[M+H] + 。
EXAMPLE 44 Compound 1- (6- (2-methyl- [1,1' -biphenyl ] -3-yl) pyridin-3-yl) -N- (phenyl (4- (trifluoromethyl) phenyl) methyl) -5,8,11,14-tetraoxa-2-azaheptadecan-17-amide (Z4 f)
The synthesis method is the same as (L2 a). Starting from compound 6 (n=4) and compound f, a yellow oily hydrophobic tag compound Z4f was obtained in 25% yield.
1 H NMR(400MHz,CDCl 3 )δ8.65(d,J＝2.2Hz,1H),7.81(dd,J＝8.0,2.3Hz,1H),7.56(t,J＝9.2Hz,3H),7.46–7.41(m,5H),7.39–7.30(m,8H),7.26(dd,J＝8.8,6.8Hz,4H),6.26(d,J＝7.9Hz,1H),3.99(s,2H),3.75(t,J＝5.8Hz,2H),3.63(d,J＝5.0Hz,2H),3.59(d,J＝4.2Hz,6H),3.53(dd,J＝7.7,3.2Hz,6H),2.97(t,J＝5.1Hz,2H),2.58(dd,J＝5.8,3.4Hz,2H),2.16(s,3H).
Theoretical value: 756.3553[ M+H ]] + ；MS-ESI(m/z):756.3580[M+H] + 。
EXAMPLE 45 cell culture and transfection
H-460 cells were cultured in RPMI1640 medium containing 10% FBS. When the cells grew to 90% or more in a flask or dish, the cells were washed with PBS 1 time, 1mL of 0.25% pancreatin was allowed to pass over the cell surface, and the excess pancreatin was aspirated off and the cells were placed in an incubator for digestion. Cells were digested for 2min. The flask was gently tapped to disperse the cells evenly. Adding proper amount of culture medium, blowing and sucking for several times to make the cells in single suspension state. H-460 cells are passaged at a ratio of 1:4-1:5-the passaged cells are placed at 37 ℃ and 5% CO 2 The incubator is used for static culture, and the density of the incubator can be increased to 90% or more 2-3 days after inoculation. The number of cells seeded per well of the 6-well plate was 3×10 5 After 24 hours of incubation, the cells were transfected with serum-free medium, with Lipofectamine 2000 as DNA transfection reagent and Lipofectamine RNAiMAX as siRNA transfection reagent, and the transfection procedure was performed according to the instructions.
Example 46 immunoblotting experiments
Will be 1.0X10 6 H460, H-1975, 1.0X10/mL 8 Each mL of H-1650 cell suspension was seeded in 6-well plates at 2mL per well. The cells were incubated at 37℃with 5% CO 2 Is cultured in a constant temperature incubator. After 24 hours of culture, 2. Mu.L of the corresponding drug is added to each well, the culture is continued for 24 hours after shaking, when the cells grow to 90% or more, the culture medium is sucked out, and 80. Mu.L of RIPA lysate containing protease inhibitor is added to each well. The lysates were transferred to 1.5ml EP tubes and lysed on ice for 30mins, 20. Mu.L of 5 Xprotein loading buffer (loading buffer) was added to each tube and boiled in a metal bath at 100℃for 30mins. Protein samples were separated by 10% SDS-PAGE gel electrophoresis, wet-transferred at a constant pressure of 70V for 1.5h, and blocked with 5% skim milk at room temperature for 1h. Incubation with the primary antibody and the secondary antibody is carried out sequentially, and the Protein Smiple instrument detects the Protein expression quantity. Protein expression was quantified using grayscale software Image J.
Antibody use concentration: PD-L1 (1:1000), beta-actin (1:5000), goat anti-rabbit (1:6000), goat anti-mouse (1:6000).
The results are shown in figures 1-6, and Western blot analysis results of partially targeting PD-L1 protein HyTs and H460 cells incubated for 24 hours show that the HyTs prepared by the method can better target and degrade the PD-L1 protein, and provide a new medicine direction for inhibiting tumors.
The above embodiments are only illustrative of the preferred embodiments of the present invention and are not intended to limit the scope of the present invention, and various modifications and improvements made by those skilled in the art to the technical solutions of the present invention should fall within the protection scope defined by the claims of the present invention without departing from the design spirit of the present invention.

Claims (7)

1. The PD-L1 protein degradation agent based on the hydrophobic tag technology is characterized by being a compound shown in the following formula (I) or formula (II) or pharmaceutically acceptable salt thereof:
wherein R is 1 is-OCH 2 ；R 2 Is a linker; r is R 3 Is a hydrophobic group;
the linker is a compound with a structural general formula shown as follows:
；
the hydrophobic group is a compound with a structural general formula shown as follows:
。
2. the method of synthesizing the PD-L1 protein degradation agent according to claim 1, wherein the synthetic route is as follows:
synthesis of intermediate compound target proteins 1 and 2:
reagents and reaction conditions: (I) Borane-tetrahydrofuran adducts, tetrahydrofuran, room temperature; (II) bis (triphenylphosphine) palladium (II) chloride, phenylboronic acid, sodium bicarbonate, toluene, ethanol, water, 80 ℃; (III) phosphorus tribromide, dichloromethane, room temperature; (IV) iodotrimethylsilane, dichloromethane, room temperature; (V) 2-methyl-3-phenylbromomethylbenzene, potassium carbonate, N-dimethylformamide, at room temperature;
reagents and reaction conditions: (I) Bis (triphenylphosphine) palladium (II) chloride, phenylboronic acid, sodium bicarbonate, toluene, ethanol, water, 80 ℃; (II) Di-penta-diboron, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, potassium acetate, 1, 4-dioxane, 100deg.C; (III) 2-bromo-5-aldehyde pyridine, palladium tetraphenylphosphine, potassium acetate, 1, 4-dioxane, water, 90 ℃;
synthesis of intermediate compound linkers NLn, n=1-5, cln, n=1, 2:
reagents and reaction conditions: trimethyl benzyl ammonium hydroxide, acetonitrile, room temperature; (II) tetrabromomethane, methylene chloride; (III) phthalimide, potassium carbonate, N-dimethylformamide, room temperature; (IV) hydrazine hydrate, ethanol, 90 ℃; (V) N-Boc ethylenediamine, triethylamine, tetrahydrofuran, room temperature;
synthesis of hydrophobic groups of intermediate compounds:
R 4 and R is 5 The specific structure of (2) is as follows:
reagents and reaction conditions: hydroxylamine hydrochloride, sodium peroxyacetate, ethanol, reflux; (II) lithium aluminum hydride, tetrahydrofuran;
synthesis of target products LC1a, LC2a, L2a-L5i, Z2a-Z5 i:
reagents and reaction conditions: (I) 2- (7-aza-benzotriazol) -N, N' -tetramethyl urea hexafluorophosphate, N-diisopropylethylamine, dichloromethane; (II) trifluoroacetic acid, dichloromethane, room temperature; (III) compound7, sodium borohydride, methanol, 40 ℃; (IV) sodium borohydride, methanol, 40 ℃; (V) trifluoroacetic acid, dichloromethane, room temperature; (VI) 20a-20i,2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate, N, N-diisopropylethylamine, dichloromethane, at room temperature.
3. A pharmaceutical composition comprising the PD-L1 protein degradation agent of claim 1.
4. The pharmaceutical composition of claim 3, further comprising a pharmaceutically acceptable carrier.
5. A pharmaceutical composition according to claim 3, wherein the pharmaceutical composition is in a pharmaceutically acceptable dosage form.
6. The use of a PD-L1 protein degradation agent according to claim 1 or a pharmaceutical composition according to any one of claims 3-5, for the preparation of any one of the following:
(1) A drug that enhances the targeting effect of a therapeutic tumor drug;
(2) A drug for enhancing an antitumor effect;
(3) Drugs that enhance the blocking effect on the PD-L1 site.
7. The use of claim 6, wherein the tumor is human fibrosarcoma, non-small cell lung cancer, lymphoma, chronic myelogenous leukemia, acute lymphoblastic leukemia, breast cancer, or melanoma.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105705489A (en) * 2013-09-04 2016-06-22 百时美施贵宝公司 Compounds useful as immunomodulators
CN112479988A (en) * 2020-12-09 2021-03-12 中国药科大学 Substituted biphenyl compound, preparation method, application and pharmaceutical composition thereof
CN115010658A (en) * 2022-05-11 2022-09-06 南方医科大学 Compound and preparation method and application thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105705489A (en) * 2013-09-04 2016-06-22 百时美施贵宝公司 Compounds useful as immunomodulators
CN112479988A (en) * 2020-12-09 2021-03-12 中国药科大学 Substituted biphenyl compound, preparation method, application and pharmaceutical composition thereof
CN115010658A (en) * 2022-05-11 2022-09-06 南方医科大学 Compound and preparation method and application thereof

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