CN116283929A - Compounds inducing EGFR degradation and uses thereof - Google Patents

Compounds inducing EGFR degradation and uses thereof Download PDF

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CN116283929A
CN116283929A CN202310036599.3A CN202310036599A CN116283929A CN 116283929 A CN116283929 A CN 116283929A CN 202310036599 A CN202310036599 A CN 202310036599A CN 116283929 A CN116283929 A CN 116283929A
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cancer
compound
egfr
pharmaceutically acceptable
hydrogen
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CN116283929B (en
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许芳
朱忠峰
夏娃·艾·福艾斯
李嘉颖
麻楠
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Jinan University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Abstract

The invention provides a compound with a structure shown in a formula I or pharmaceutically acceptable salt or hydrate thereof and application thereof. According to the invention, the modified EGFR small molecule inhibitor and ligand of key protein LC3 protein in the autophagy-lysosome pathway are connected by using a connecting chain to prepare an autophagy small molecule binding compound (ATTECTs) degradation agent, and EGFR and LC3 protein are promoted to be combined together, so that EGFR protein can be catalyzed and degraded by autophagy, and EGFR protein level can be selectively reduced, thereby having better anti-tumor activity.

Description

Compounds inducing EGFR degradation and uses thereof
Technical Field
The invention relates to the technical field of medicines, in particular to a compound for inducing EGFR degradation and application thereof.
Background
ATTEC (autophagosome binding compound) is a relatively direct method for degrading target protein by utilizing autophagosome pathway, and the principle is that drug molecules bind pathological proteins with key protein LC3 in autophagosome degradation pathway to promote rapid degradation of mutant protein. Atect has great potential to degrade different types of targets, including autophagy-recognized non-proteinaceous biomacromolecules, such as lipids, DNA/RNA molecules, damaged organelles, and the like.
EGFR (Epidermal GrowthFactor Receptor) is a receptor for Epithelial Growth Factor (EGF) cell proliferation and signaling. Studies have shown that there is high or abnormal expression of EGFR in many solid tumors. EGFR is involved in the inhibition of proliferation, angiogenesis, tumor invasion, metastasis and apoptosis of tumor cells. The possible mechanisms are as follows: high expression of EGFR leads to an enhancement of downstream signaling; increased expression of mutant EGFR receptors or ligands results in sustained activation of EGFR; the effect of the autocrine loop is enhanced; disruption of receptor down-regulation mechanisms; activation of abnormal signaling pathways, and the like. The overexpression of EGFR plays an important role in the evolution of malignant tumors, and EGFR is over-expressed in tissues such as glial cells, kidney cancer, lung cancer, prostate cancer, pancreatic cancer, breast cancer and the like.
However, small molecule inhibitors targeting EGFR cannot avoid secondary mutations again, which can easily lead to clinical resistance and thus affect the efficacy. Therefore, research on inhibitors with EGFR degrading function is of great clinical significance.
Disclosure of Invention
Aiming at the problems, the invention provides a compound capable of inducing EGFR degradation, which not only has excellent EGFR protein degradation effect and anti-tumor activity, but also can reduce toxic and side effects on human, and can be used for preparing anti-tumor drugs.
The method specifically comprises the following technical scheme.
A compound having the structure of formula i or a pharmaceutically acceptable salt or hydrate thereof:
Figure BDA0004048937120000021
wherein:
l is selected from:
Figure BDA0004048937120000022
Figure BDA0004048937120000023
Figure BDA0004048937120000024
wherein Z is selected from: oxy, methylene; n is an integer of 1 to 12;
ring a is selected from: c (C) 6 -C 10 Aryl, 5-10 heteroaryl;
ring B is selected from: c (C) 6 -C 10 Aryl, 5-10 heteroaryl;
d is selected from: c (C) 1 -C 3 Alkylene, -N (R) 8 )-；
R 0 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 Each independently selected from: hydrogen, halogen, cyano, C 1 -C 6 Alkyl, halogen substituted C 1 -C 6 Alkyl, C 6 -C 10 Aryl, 5-10 heteroaryl;
R 8 selected from: hydrogen, C 1 -C 8 An alkyl group.
In some embodiments, L is selected from:
Figure BDA0004048937120000031
n is selected from: 1. 2,3, 4, 5, 6.
In some embodiments, L is selected from:
Figure BDA0004048937120000032
n is selected from: 3. 4, 5, 6, 7, 8, 9, 10.
In some embodiments, D is selected from: methylene, -NH-.
In some of these embodiments, ring a is selected from: phenyl, 5-6 membered heteroaryl.
In some of these embodiments, ring B is selected from: phenyl, 5-6 membered heteroaryl.
In some of these embodiments, the compound has a structure according to formula II:
Figure BDA0004048937120000033
in some of these embodiments, R 0 、R 1 、R 2 、R 3 Each independently selected from: hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, trifluoromethyl, trifluoroethyl.
In some of these embodiments, R 4 、R 5 Each independently selected from: hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl.
In some of these embodiments, R 6 、R 7 Each independently selected from: hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, trifluoromethyl, trifluoroethyl.
In some of these embodiments, R 8 Selected from: hydrogen, methyl, ethyl, propyl.
In some of these embodiments, the compound is selected from the following:
Figure BDA0004048937120000041
Figure BDA0004048937120000051
the invention also provides application of the compound or pharmaceutically acceptable salt or hydrate thereof, which comprises the following technical scheme.
The application of the compound or the pharmaceutically acceptable salt or the hydrate thereof in preparing EGFR degradation agents and/or EGFR inhibitors.
The application of the compound or the pharmaceutically acceptable salt or the hydrate thereof in preparing medicaments for preventing and/or treating tumors.
In some of these embodiments, the tumor is multiple myeloma, gastric cancer, lung cancer, breast cancer, esophageal cancer, colon cancer, medulloblastoma, acute myelogenous leukemia, chronic leukemia, prostate cancer, hepatoma, renal cell carcinoma, cervical cancer, skin cancer, ovarian cancer, colon cancer, glioma, thyroid cancer, pancreatic cancer.
The invention also provides a medicinal composition for preventing and/or treating tumors, which comprises the following technical scheme.
A pharmaceutical composition for preventing and/or treating tumors is prepared from active ingredients and pharmaceutically acceptable auxiliary materials, wherein the active ingredients comprise the compound or pharmaceutically acceptable salts or hydrates thereof.
According to the invention, the modified EGFR small molecule inhibitor and ligand of key protein LC3 protein in the autophagy-lysosome pathway are connected by using a connecting chain to prepare an autophagy small molecule binding compound (ATTECTs) degradation agent, and EGFR and LC3 protein are promoted to be combined together, so that EGFR protein can be catalyzed and degraded by autophagy, and EGFR protein level can be selectively reduced, thereby having better anti-tumor activity. Thus, the compounds of the present invention have the following beneficial effects:
(1) The compound can promote EGFR to degrade through autophagy-lysosome, and can induce protein degradation with less dosage, and the process is similar to catalytic reaction, does not need equimolar amount of medicine, and can reduce toxic and side effects on human body.
(2) According to the invention, an in-vitro anti-tumor activity test and an in-vitro EGFR protein degradation activity test show that the compound (EGFR degradation agent) can enter a degradation system again after target protein degradation is completed, so that the compound can be recycled, has more obvious advantages than EGFR small molecule inhibitors, and can effectively overcome the defect that the EGFR small molecule inhibitors are easy to generate mutant drug resistance. Can be used for preventing or/and treating various cancers, and has great application prospect in the field of medicines.
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FIG. 1 is the effect of compounds on EGFR protein levels in PC-9 cell lines.
FIG. 2 shows the effect of compounds I3, I7 and I8 on EGFR protein levels.
FIG. 3 shows the effect of compound I4 on EGFR protein levels in the cell membrane and cytoplasm, respectively.
FIG. 4 shows the effect of compound I4 on PC-9 clone formation.
Detailed Description
The experimental methods of the present invention, in which specific conditions are not specified in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. The various chemicals commonly used in the examples are commercially available.
Unless defined otherwise, 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. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
The terms "comprising" and "having" and any variations thereof, are intended to cover a non-exclusive inclusion. For example, a process, method, apparatus, article, or device that comprises a list of steps is not limited to the elements or modules listed but may alternatively include additional steps not listed or inherent to such process, method, article, or device.
In the present invention, the term "plurality" means two or more. "and/or", describes an association relationship of an association object, and indicates that there may be three relationships, for example, a and/or B, and may indicate: a exists alone, A and B exist together, and B exists alone. The character "/" generally indicates that the context-dependent object is an "or" relationship.
In the compounds of the invention, when any variable occurs more than once in any component, the definition of each occurrence is independent of the definition of each other occurrence. Also, combinations of substituents and variables are permissible provided that such combinations stabilize the compounds. The lines drawn from the substituents into the ring system indicate that the bond referred to may be attached to any substitutable ring atom. If the ring system is polycyclic, it means that such bonds are only attached to any suitable carbon atom adjacent to the ring. It is to be understood that substituents and substitution patterns of the compounds of this invention may be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that may be readily synthesized from readily available starting materials by techniques in the art and methods set forth below. If the substituent itself is substituted with more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms, as long as the structure is stabilized.
The term "alkyl" as used herein is meant to include both branched and straight chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms. For example, "C 1 -C 6 Alkyl "medium" C 1 -C 6 The definition of "includes groups having 1, 2,3, 4, 5 or 6 carbon atoms arranged in a straight or branched chain. For example, "C 1 -C 6 The alkyl group includes, in particular, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl.
As used herein, the term "alkylene" refers to a group that has one less hydrogen on an "alkyl" basis, e.g., -CH 2 -、-CH 2 CH 2 -、-CH 2 CH 2 CH 2 -、-CH 2 CH 2 CH 2 CH 2 -and the like.
The term "heteroaryl" as used herein refers to an aromatic ring containing 1 or more heteroatoms selected from O, N or S, heteroaryl groups within the scope of the present invention include, but are not limited to: quinolinyl, pyrazolyl, pyrrolyl, thienyl, furyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, imidazolyl, oxazolyl, isoxazolyl, pyridazinyl, benzofuranyl, benzothienyl, benzoxazolyl, indolyl, and the like; "heteroaryl" is also understood to include any N-oxide derivative of a heteroaryl group containing nitrogen. The attachment of the heteroaryl group may be through a carbon atom or through a heteroatom.
The term "substituted" as used herein refers to the replacement of a hydrogen group in a particular structure with a group of the specified substituent.
As understood by those skilled in the art, "halo" or "halogen" as used herein means chlorine, fluorine, bromine and iodine.
The present invention includes the free forms of the compounds of formulas (I) - (II), as well as pharmaceutically acceptable salts and stereoisomers thereof. Included are pharmaceutically acceptable salts including not only the exemplary salts of the specific compounds described herein, but also all of the typical pharmaceutically acceptable salts of the compounds of formulas (I) - (II) in free form. The free form of the particular salt of the compound may be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a suitable dilute aqueous base solution, such as dilute aqueous NaOH, dilute aqueous potassium carbonate, dilute aqueous ammonia, and dilute aqueous sodium bicarbonate. The free forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of this invention such acid and base salts are otherwise pharmaceutically comparable to their respective free forms.
Pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of the present invention containing a basic moiety or an acidic moiety by conventional chemical methods. Typically, salts of basic compounds are prepared by ion exchange chromatography or by reacting the free base with a stoichiometric or excess of an inorganic or organic acid in the form of the desired salt in a suitable solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reaction with suitable inorganic or organic bases.
Thus, pharmaceutically acceptable salts of the compounds of the invention include the conventional non-toxic salts of the compounds of the invention formed by the reaction of a basic compound of the invention with an inorganic or organic acid. For example, conventional nontoxic salts include salts derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like, and also salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, trifluoroacetic and the like.
If the compounds of the present invention are acidic, suitable "pharmaceutically acceptable salts" refer to salts prepared with pharmaceutically acceptable non-toxic bases including inorganic and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Ammonium, calcium, magnesium, potassium and sodium salts are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic bases including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
Berg et al, "Pharmaceutical Salts," j.pharm.sci.'1977:66:1-19 describe in more detail the preparation of pharmaceutically acceptable salts as described above and other typical pharmaceutically acceptable salts.
In one embodiment, the present invention provides a method of treating neoplastic diseases in humans or other mammals using compounds having the structures of formulas (I) - (II) and pharmaceutically acceptable salts and hydrates thereof.
In one embodiment, the compounds of the present application and pharmaceutically acceptable salts and hydrates thereof can be used to treat or control multiple myeloma, gastric cancer, lung cancer, breast cancer, esophageal cancer, colon cancer, medulloblastoma, acute myelogenous leukemia, chronic leukemia, prostate cancer, hepatoma, renal cell carcinoma, cervical cancer, skin cancer, ovarian cancer, colon cancer, glioma, thyroid cancer, pancreatic cancer.
The invention also provides a pharmaceutical composition which comprises the active ingredients within a safe and effective amount range and pharmaceutically acceptable carriers or auxiliary materials.
The "active ingredient" as used herein refers to the compounds of formulae (I) - (II) or pharmaceutically acceptable salts thereof or stereoisomers and hydrates thereof as described herein.
The active ingredient and the pharmaceutical composition can be used as EGFR inhibitors and can be used for preparing medicines for preventing and/or treating tumors.
"safe and effective amount" means: the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects.
"pharmaceutically acceptable carrier or adjuvant" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity.
"compatible" as used herein means that the components of the composition are capable of blending with and between the active ingredients of the present invention without significantly reducing the efficacy of the active ingredients.
Examples of pharmaceutically acceptable carriers or excipients include cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as
Figure BDA0004048937120000101
) Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water and the like.
In another preferred embodiment, the compounds of formulae (I) - (II) according to the invention may form complexes with macromolecular compounds or macromolecules by non-bonding. In another preferred embodiment, the compounds of the formulae (I) to (II) according to the invention as small molecules can also be linked to macromolecular compounds or macromolecules by chemical bonds. The macromolecular compounds may be biological macromolecules such as polysaccharides, proteins, nucleic acids, polypeptides and the like.
The mode of administration of the active ingredient or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and the like.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
In these solid dosage forms, the active ingredient is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients:
(a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid;
(b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia;
(c) Humectants, for example, glycerin;
(d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate;
(e) Slow solvents such as paraffin;
(f) Absorption accelerators, for example quaternary amine compounds;
(g) Wetting agents, such as cetyl alcohol and glycerol monostearate;
(h) Adsorbents, such as kaolin; and
(i) Lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
The solid dosage forms may also be prepared using coatings and shells, such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active ingredient in such a composition may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like. In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active ingredient, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental procedure, which does not address the specific conditions in the examples below, is generally followed by routine conditions such as Sambrook et al, molecular cloning: conditions described in the laboratory Manual (New York: cold Spring Harbor Laboratory Press, 1989) or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described herein are presented for illustrative purposes only.
The structure of the compound is changed into a nuclear magnetic resonance structure 1 H-NMR) and High Resolution Mass Spectrometry (HRMS), the NMR measurement was performed by using a BRUKAVANCE III HD MHz nuclear magnetic resonance apparatus, and the measurement solvent was deuterated chloroform (CDCl) 3 ) Or deuterated dimethyl sulfoxide (DMSO-D) 6 ) Column chromatography adopts 200-300 mesh silica gel.
The synthetic route for representative ligands targeting LC3 is as follows:
Figure BDA0004048937120000131
a representative synthetic route (I1-5) for degrading EGFR-targeted degradants is as follows:
Figure BDA0004048937120000132
example 1: preparation of [ (2, 6-dibromo-4- [ (5-iodo-2-oxo-2, 3-dihydro-1H-indol-3-ylidene) methyl ] phenyl) oxy ] acetic acid (a 4)
Figure BDA0004048937120000133
(1) Into a glass bottle equipped with a magnetic stirring bar was charged 3, 5-dibromo-4-hydroxybenzaldehyde (1.12 g,4.0 mmol) tert-butyl 2-bromoacetate (0.94 g,4.8 mmol), K 2 CO 3 (1.10 g,8.0 mmol) was reacted in DMF (10 ml) heated to 80℃overnight. After the completion of the reaction, the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, and concentrated under reduced pressure. And (3) performing silica gel column chromatography on the obtained crude product to obtain a pure product a2.
(2) To a solution of a2 (0.79 g,2.0 mmol) in ethanol (5.0 ml) was added 5-iodoindolin-2-one (0.45 g,2.6 mmol) and piperidine, which were mixed at room temperature. The reaction solution was then returned to 80 ℃ and refluxed for 2 hours. After the reaction is completed, suction filtration and purification are carried out. Washing the filter cake with ethanol gives a3. Compound a3 as a yellow solid (0.94 g,1.47 mmol) was dissolved in anhydrous dichloromethane (12 ml), and TFA (5 ml) was added to the reaction mixture to react at room temperature. And after the second step of complete reaction, carrying out negative pressure concentration on the reaction liquid. Finally purifying the product by silica gel column chromatography to obtain red solid a4.
1 H NMR(400MHz,DMSO)δ10.84(s,1H),8.78(s,2H),8.04(s,1H),7.86(s,1H),7.56(dd,J＝8.2,1.7Hz,1H),6.69(d,J＝8.1Hz,1H),4.60(s,2H).
Example 2: preparation of N- (2- { [2- ({ 4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxyquinazolin-6-yl } oxy) ethyl ] oxy } ethyl) -2- ({ 2, 6-dibromo-4- [ (5-iodo-2-oxon-ylidene-2, 3-dihydro-1H-indol-3-ylidene) methyl ] phenyl } oxy) acetamide (I2)
(1) In a 25ml double flask was added b1-2 (2.0 g,5.56 mmol), potassium carbonate (3.30 g, 16.8 mmol), 4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxyquinazolin-6-ol (2.07 g,5.56 mmol), DMF (15 ml), under nitrogen protection at 80℃for 8 hours, the reaction solution was poured into water, extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and separated by silica gel column chromatography to give a white solid (b 2-2)
(2) To a 25ml double flask was added b2-2 (0.8 g 0.82 mmol), methylene chloride (15 ml) and trifluoroacetic acid (7 ml), and after the reaction was completed, a triethylamine solution was slowly added dropwise to carry out spin-drying under low pressure without further purification. A4 (0.48 g 0.82 mmol), HATU (0.4 g1.02 mmol), DIPA, DMF was added and the reaction was carried out for about 2 hours. The reaction mixture was added to water, extracted with ethyl acetate, and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and separated by silica gel column chromatography to give yellow solid i 2.
The specific structure of the resulting N- (2- { [2- ({ 4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxyquinazolin-6-yl } oxy) ethyl ] oxy } ethyl) -2- ({ 2, 6-dibromo-4- [ (5-iodo-2-oxy-2, 3-dihydro-1H-indol-3-ylidene) methyl ] phenyl } oxy) acetamide (I2) is as follows:
Figure BDA0004048937120000151
1 H NMR(400MHz,DMSO)δ10.81(s,2/3H),10.77(s,2/3H),9.54(s,1/3H),9.52(s,2/3H),8.70(s,1H),8.47(s,1/3H),8.45(s,2/3H),8.15-8.04(m,2H),8.02(d,J＝1.6Hz,1H),7.95(s,1H),7.9–7.7(m,3H),7.6–7.5(m,1H),7.4(m,1H),7.18(s,1H),7.17(s,2/3H),6.73(d,J＝8.2Hz,1/3H),6.68(d,J＝8.1Hz,2/3H),4.47(s,2/3H),4.43(s,4/3H),4.30(t,J＝4.6Hz,2H).3.94(s,3H),3.91(t,J＝4.9Hz,2H),3.67(t,J＝5.4Hz,2H),3.44(t,J＝5.4Hz,2H).[M+H] + found 966.9208。
example 3: specific preparation method referring to example 2, N- [8- ({ 4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxyquinazolin-6-yl } oxy) -3, 6-dioxaoct-1-yl ] -2- ({ 2, 6-dibromo-4- [ (5-iodo-2-oxon-2, 3-dihydro-1H-indol-3-ylidene) methyl ] phenyl } oxy) acetamide (I3) was prepared
Figure BDA0004048937120000161
1 H NMR(400MHz,DMSO)δ10.78(s,1/3H),10.76(s,2/3H),9.52(s,1/3H),9.52(s,2/3H),8.68(s,1H),8.49(s,1/3H),8.46(s,2/3H),8.10(d,J＝6.7Hz,1H),8.00(d,J＝7.5Hz,1H),7.93(s,1H),7.78(d,J＝10.0Hz,2H),7.56(d,J＝8.2Hz,1H),7.41(q,J＝9.3Hz,1H),7.18(s,1H),6.72(d,J＝8.3Hz,1/3H),6.68(d,J＝8.1Hz,2/3H),4.48(s,2/3H),4.45(s,4/3H),4.26(t,J＝5.2Hz,2H),3.94(s,3H),3.91(d,J＝4.7Hz,2H),3.73–3.52(m,6H),3.40(t,J＝6.0Hz,2H).[M+H] + found:1009.9424。
Example 4 specific preparation method referring to example 2N- [11- ({ 4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxyquinazolin-6-yl } oxy) -3,6, 9-trioxaundec-1-yl ] -2- ({ 2, 6-dibromo-4- [ (5-iodo-2-oxon-ylidene-2, 3-dihydro-1H-indol-3-ylidene) methyl ] phenyl } oxy) acetamide (I4) was prepared
Figure BDA0004048937120000162
1 H NMR(400MHz,DMSO)δ10.81(s,2/3H),10.76(s,1/3H),9.51(s,1/3H),9.48(s,2/3H),8.7(s,1H),8.49(s,1/3H),8.48(s,2/3H),8.11(dt,J＝6.9,2.2Hz,1H),8.05(t,J＝5.7Hz,1H),8.00–7.99(m,1H),7.81–7.7(m,3H),7.57–7.53(m,1H),7.43(td,J＝9.1,5.4Hz,1H),7.19(s,1/3H),7.18(s,2/3H),6.72(d,J＝8.2Hz,1/3H),6.67(d,J＝8.1Hz,2/3H),4.47(s,1/3H),4.45(s,2/3H),4.26(t,J＝4.8Hz,2H),3.94(s,3H),3.87(t,J＝4.8Hz,2H),3.67–3.64(m,2H),3.6–3.5(m,8H),3.37(2H,overlapped with H 2 O),3.32(2H,overlapped with H 2 O).[M+H] + found:1054.9764。
Example 5: specific preparation method referring to example 2, N- [14- ({ 4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxyquinazolin-6-yl } oxy) -3,6,9, 12-tetraoxatetradecan-1-yl ] -2- ({ 2, 6-dibromo-4- [ (5-iodo-2-oxon-ylidene-2, 3-dihydro-1H-indol-3-ylidene) methyl ] phenyl } oxy) acetamide (I5) was prepared
Figure BDA0004048937120000171
1 H NMR(400MHz,DMSO)δ10.83(s,1/3H),10.78(s,2/3H),9.65(s,1H),8.76(s,1H),8.50(s,1/3H),8.49(s 2/3H),8.17–8.09(m,1H),8.05(d,J＝6.5Hz,1H),8.00(s,1H),7.88(d,J＝5.7Hz,1H),7.82(d,J＝9.1Hz,1H),7.60–7.49(m,1H),7.42(t,J＝8.8Hz,1H),7.19(d,J＝3.4Hz,1H),6.72(d,J＝8.4Hz,1/3H),6.67(d,J＝8.3Hz,2/3H),4.47(s,2/3H),4.47(s,4/3H),4.28(t,J＝5.3Hz,2H),3.93(s,3H),3.86(d,J＝5.2Hz,2H),3.67–3.60(m,2H),3.56(d,J＝4.8Hz,2H),3.52(s,6H),3.39(s,2H),3.37(s,2H)。[M+H] + found:1097.9956。
Example 6: specific preparation method referring to example 2, N- [8- ({ 4- [ (3-chlorophenyl) amino ] -7-methoxyquinazolin-6-yl } oxy) octyl ] - -2- ({ 2, 6-dibromo-4- [ (5-iodo-2-oxy subunit-2, 3-dihydro-1H-indol-3-ylidene) methyl ] phenyl } oxy) acetamide (I6) was prepared
Figure BDA0004048937120000181
1 H NMR(400MHz,DMSO)δ10.82(s,1H),9.53(s,1H),8.74(s,2H),8.48(s,1H),8.11(t,J＝6.5Hz,2H),8.00(d,J＝13.9Hz,1H),7.78(d,J＝5.3Hz,2H),7.55(d,J＝7.9Hz,1H),7.42(t,J＝9.1Hz,1H),7.18(s,1H),6.68(d,J＝8.1Hz,1H),4.43(s,2H),4.13(t,J＝6.5Hz,2H),3.94(s,3H),3.20(q,J＝6.7Hz,2H),1.84(p,J＝6.8Hz,2H),1.49(p,J＝7.1Hz,4H),1.34(d,J＝6.6Hz,6H).[M+H] + found:1055.9867。
EXAMPLE 7 specific preparation methods referring to example 1 and example 2N- [8- ({ 4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxyquinazolin-6-yl } oxy) -3, 6-dioxaoct-1-yl ] -2- ({ 2, 6-dibromo-4- [ (5-methyl-2-oxo-2, 3-dihydro-1H-indol-3-ylidene) methyl ] phenyl } oxy) acetamide (I7) was prepared
Figure BDA0004048937120000182
1 H NMR(400MHz,DMSO)δ10.57(s,2/3H),10.53(s,1/3H),9.51(s,,1/3H),9.50(s,,2/3H),8.69(s,1H),8.49(s,,1/3H),8.47(s,2/3H),8.15–7.96(m,2H),7.80(d,J＝10.4Hz,2H),7.45–7.38(m,2H),7.20(d,J＝9.6Hz,1H),7.05(d,J＝7.9Hz,1H),6.76(d,J＝7.9Hz,1/3H),6.72(d,J＝7.8Hz,2/3H),4.48(s,2/3H),4.44(s,4/3H),4.27(t,J＝5.5Hz,2H),3.94(s,3H),3.90(s,2H),3.73–3.66(m,2H),3.62(d,J＝4.7Hz,2H),3.56(t,J＝6.2Hz,2H),3.39(q,J＝5.9Hz,2H),2.30(s,3H).[M+H] + found:898.0479。
Example 8 specific preparation methods referring to example 1 and example 2N- [8- ({ 4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxyquinazolin-6-yl } oxy) -3, 6-dioxaoct-1-yl ] -2- ({ 2, 6-dibromo-4- [ (5-bromo-2-oxo-2, 3-dihydro-1H-indol-3-ylidene) methyl ] phenyl } oxy) acetamide (I8) was prepared
Figure BDA0004048937120000191
1 H NMR(400MHz,DMSO)δ10.80(s,1H),9.51(s,1H),8.66(s,1H),8.48(s,1/3H),8.45(s,2/3H),8.07(dd,J＝34.8,6.7Hz,2H),7.93(s,1H),7.85–7.78(m,2H),7.70(s,1H),7.43–7.39(m,1H),7.17(s,1H),6.83(d,J＝8.3Hz,1/3H),6.78(d,J＝8.2Hz,2/3H),4.48(s,2/3H),4.45(s,4/3H),4.27(dt,J＝10.7,4.9Hz,2H),3.94(s,3H),3.90(t,J＝4.9Hz,2H),3.73–3.65(m,2H),3.61–3.53(m,4H),3.40(d,J＝6.2Hz,2H).[M+H] + found:961.9576。
Example 9: specific preparation method referring to example 2, N- [8- ({ 4- [ (3-chlorophenyl) amino ] -7-methoxyquinazolin-6-yl } oxy) butyl ] - -2- ({ 2, 6-dibromo-4- [ (5-iodo-2-oxy subunit-2, 3-dihydro-1H-indol-3-ylidene) methyl ] phenyl } oxy) acetamide (I21) was prepared
Figure BDA0004048937120000201
/>
1 H NMR(400MHz,DMSO)δ10.83(s,2/3H),10.77(s,1/3H),9.57(s,1H),8.77(s,1H),8.50(s,1H),8.27(q,J＝7.7,6.2Hz,1H),8.12(d,J＝6.8Hz,1H),8.02(d,J＝9.3Hz,1H),7.81(t,J＝9.0Hz,3H),7.55(d,J＝8.1Hz,1H),7.44(t,J＝9.0Hz,1H),7.20(s,1H),6.73(d,J＝8.2Hz,1/3H),6.70–6.57(m,2/3H),4.48(s,2/3H),4.45(s,4/3H),4.20(t,J＝6.4Hz,2H),3.95(s,3H),2.03–1.82(m,3H),1.75(q,J＝8.0,7.1Hz,3H).
Example 10: specific preparation method referring to example 2, N- [8- ({ 4- [ (3-chlorophenyl) amino ] -7-methoxyquinazolin-6-yl } oxy) hexyl ] - -2- ({ 2, 6-dibromo-4- [ (5-iodo-2-oxy subunit-2, 3-dihydro-1H-indol-3-ylidene) methyl ] phenyl } oxy) acetamide (I22) was prepared
Figure BDA0004048937120000202
1 H NMR(400MHz,DMSO)δ10.84(s,2/3H),10.78(s,1/3H),9.53(s,1H),8.76(s,1H),8.49(s,1H),8.26–8.07(m,2H),8.02(d,J＝18.0Hz,1H),7.82(d,J＝7.9Hz,2H),7.56(d,J＝6.5Hz,1H),7.43(t,J＝9.0Hz,1H),7.20(s,1H),6.74(d,J＝7.9Hz,1/3H),6.69(d,J＝8.2Hz,2/3H),4.46(s,2/3H),4.43(s,4/3H),4.16(d,J＝6.4Hz,3H),3.95(s,3H),3.23(d,J＝6.7Hz,2H),1.85(d,J＝8.2Hz,2H),1.64–1.38(m,6H).[M+H] + found:977.9539
Example 11: specific preparation method referring to example 2, N- [8- ({ 4- [ (3-chlorophenyl) amino ] -7-methoxyquinazolin-6-yl } oxy) decyl ] - -2- ({ 2, 6-dibromo-4- [ (5-iodo-2-oxy subunit-2, 3-dihydro-1H-indol-3-ylidene) methyl ] phenyl } oxy) acetamide (I23) was prepared
Figure BDA0004048937120000211
1 H NMR(400MHz,DMSO)δ10.82(s,1H),9.62(s,1H),8.77(s,2H),8.52(d,J＝5.2Hz,1H),8.16–8.06(m,2H),8.01(s,1H),7.80(d,J＝7.0Hz,3H),7.55(d,J＝7.6Hz,1H),7.45(q,J＝8.9,8.2Hz,1H),7.20(d,J＝10.3Hz,1H),6.68(d,J＝8.2Hz,1H),4.43(s,2H),4.13(d,J＝6.5Hz,2H),3.94(s,3H),3.18(d,J＝6.7Hz,2H),2.89(s,4H),1.83(t,J＝7.2Hz,2H),1.57–1.43(m,6H),1.30(s,4H).[M+H] + found:1034.0166
Example 12: influence of Compounds of the series on EGFR protein levels in non-Small cell Lung cancer PC-9 cells
The experiment was performed in non-small cell lung cancer PC9, EGFR was expressed as EGFR in PC-9 cells del19 Deletion type mutation and abnormally high expression. Protein levels were detected using western blot (western immunoblotting technique) as follows: a certain number of PC9 cells were inoculated into a 6-well plate, placed in an incubator, and subjected to wall-attached culture overnight, and treated with a certain concentration of the compound for 16 hours. Cells were lysed with SDS lysate containing 1 x protease and phosphatase inhibitor, sonicated, and boiled at 95 ℃ for 10min. Run through SDS-PAGE and transfer to 0.45. Mu.M PVDF membrane. Then, the mixture was taken out and put into 5% skim milk/TBST to be blocked for 1 hour. EGFR and the internal GAPDH were then incubated overnight, respectively. The secondary antibody was incubated for 2 hours after 3 washes with TBST. Protein development was performed using ECLWestern Blotting Detection Kit (Thermo Scientific, waltham, MA) and imaged using the Amersham Imager 600 system (GE, america) scanning.
The experimental results are shown in fig. 1: from the WB experimental results, it can be found that the compounds prepared by the invention can obviously degrade EGFR protein in PC-9 cells.
Example 13 Effect of Compounds I7, I8 and I3 on EGFR protein levels in non-Small cell lung cancer PC-9 cells
The experimental procedure is as in example 12.
The experimental results are shown in fig. 2: i7 and I8 are based on I3, and the iodine substitution at the para position of the ligand aromatic ring is replaced by methyl and bromine atom substitution. The result shows that: compared with I3, I7 and I8, the activity and selectivity of degrading EGFR protein are improved, and the effect of the I8 molecule is better.
Example 14 influence of representative Compound I4 on EGFR protein levels in cell membranes and cytoplasm, respectively
One of the non-small cell lung cancer drug resistance mechanisms is also associated with the transfer of the transmembrane protein EGFR from the original localized cell membrane to the cytosol. Representative compound i 4 at different concentrations was treated with non-small cell lung cancer PC9 and cytoplasmic and envelope proteins (cell membrane and cytoplasmic protein extraction kit (P0033), bi yun day) were extracted, respectively. EGFR protein levels were analyzed using the Western blot described in example 12.
The results are shown in FIG. 3, which shows that compound I4 can degrade EGFR protein in cell membranes and cytoplasm, indicating that it can effectively overcome drug resistance.
Example 15: effect of Compound I4 on the formation of PC-9 clones
The PC-9 of the non-small cell lung cancer cells is respectively incubated with I4 with different concentrations for 14 days, and the specific implementation method is as follows: PC-9 cells were centrifuged by digestion, 1500 wells per well were counted, inoculated in 6-well plates, added with different concentrations of I4, and allowed to stand for 14 days. The medium was discarded and washed with PBS. The excess crystal violet was washed off by staining with 1% crystal violet for 30 minutes, photographed, imageJ counted for clones and plotted with graphpad 7.0.
The results are shown in FIG. 4, and the results show that the representative compound I4 can significantly inhibit the clone formation of the non-small cell lung cancer and inhibit the proliferation of tumors.
Example 16: proliferation inhibition activity research of series of compounds on various tumor cell lines
The specific experimental method comprises the following steps: tumor cells were seeded in a number of 96 empty plates (4000-6000/well). After overnight incubation, the cells were treated separately with different concentrations (maximum concentration 20. Mu.M, 10 concentrations diluted 1:3 ratio)72 hours. Cell proliferation was assessed using the CCK-8 (Cell Counting Kit 8,Dojindo Laboratories,Kumamoto,Japan) assay. Half maximal Inhibitory Concentration (IC) was calculated by concentration response curve fitting using GraphPad Prism 5.0 software (GraphPad Software, la Jolla, CA) 50 ) Values. Each IC 50 Values are all expressed as mean ± SD.
The results are shown in Table 1, which shows: the compounds have good antiproliferative activity on various tumor cells and have good antiproliferative activity on cell lines comprising EGFR abnormally high expression and mutation thereof.
Table 1 antiproliferative activity of Compounds against various tumor cells
Figure BDA0004048937120000231
Figure BDA0004048937120000241
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the following embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The foregoing examples illustrate only a few embodiments of the invention and are described in detail herein without thereby limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.

Claims (14)

1. A compound having the structure of formula i or a pharmaceutically acceptable salt or hydrate thereof:
Figure FDA0004048937110000011
wherein:
l is selected from:
Figure FDA0004048937110000012
Figure FDA0004048937110000013
Figure FDA0004048937110000014
wherein Z is selected from: oxy, methylene; n is an integer of 1 to 12;
ring a is selected from: c (C) 6 -C 10 Aryl, 5-10 heteroaryl;
ring B is selected from: c (C) 6 -C 10 Aryl, 5-10 heteroaryl;
d is selected from: c (C) 1 -C 3 Alkylene, -N (R) 8 )-；
R 0 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 Each independently selected from: hydrogen, halogen, cyano, C 1 -C 6 Alkyl, halogen substituted C 1 -C 6 Alkyl, C 6 -C 10 Aryl, 5-10 heteroaryl;
R 8 selected from: hydrogen, C 1 -C 8 An alkyl group.
2. The compound of claim 1, wherein L is selected from:
Figure FDA0004048937110000015
n is selected from: 1. 2,3, 4, 5, 6.
3. The compound of claim 1, wherein L is selected from:
Figure FDA0004048937110000021
n is selected from: 3. 4, 5, 6, 7, 8, 9, 10.
4. A compound according to claim 1, wherein D is selected from: methylene, -NH-.
5. The compound of claim 1, wherein ring a is selected from the group consisting of: phenyl, 5-6 membered heteroaryl.
6. The compound of claim 1, wherein ring B is selected from: phenyl, 5-6 membered heteroaryl.
7. The compound of claim 1, having the structure of formula II:
Figure FDA0004048937110000022
8. a compound according to any one of claims 1 to 7, wherein R 0 、R 1 、R 2 、R 3 Each independently selected from: hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, trifluoromethyl, trifluoroethyl; and/or the number of the groups of groups,
R 4 、R 5 each independently selected from: hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl; and/or the number of the groups of groups,
R 6 、R 7 each independently selected from: hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, trifluoromethyl, trifluoroethyl.
9. A compound according to any one of claims 1 to 7, wherein R 8 Selected from: hydrogen, methyl, ethyl, propyl.
10. A compound according to claim 1, selected from the group consisting of:
Figure FDA0004048937110000031
Figure FDA0004048937110000041
11. use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or hydrate thereof, for the preparation of an EGFR degrading agent and/or an EGFR inhibitor.
12. Use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or hydrate thereof, for the manufacture of a medicament for the prevention and/or treatment of a tumour.
13. The use according to claim 12, wherein the tumour is multiple myeloma, gastric cancer, lung cancer, breast cancer, oesophageal cancer, colon cancer, medulloblastoma, acute myeloid leukaemia, chronic leukaemia, prostate cancer, hepatoma, renal cell tumour, cervical cancer, skin cancer, ovarian cancer, colon cancer, glioma, thyroid cancer, pancreatic cancer.
14. A pharmaceutical composition for the prevention and/or treatment of tumors, characterized in that it is prepared from an active ingredient comprising a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt or hydrate thereof and pharmaceutically acceptable excipients.
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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190262458A1 (en) * 2016-11-22 2019-08-29 Dana-Farber Cancer Institute, Inc. Degradation of bruton's tyrosine kinase (btk) by conjugation of btk inhibitors with e3 ligase ligand and methods of use
CN110372669A (en) * 2019-06-19 2019-10-25 浙江省医学科学院 A kind of compound and preparation method thereof, pharmaceutical composition and application based on the induction EGFR degradation of CRBN ligand
CN112321566A (en) * 2019-08-05 2021-02-05 上海科技大学 EGFR protein degradation agent and anti-tumor application thereof
CN112939965A (en) * 2021-02-08 2021-06-11 沈阳药科大学 Compound for simultaneously inducing degradation of EGFR (epidermal growth factor receptor) and PARP (para-amyloid peptide) proteins as well as preparation method and application thereof
CN113004251A (en) * 2021-03-05 2021-06-22 郑州大学第一附属医院 Quinazoline derivative containing 2-nitroimidazole and application thereof
WO2022140246A1 (en) * 2020-12-21 2022-06-30 Hangzhou Jijing Pharmaceutical Technology Limited Methods and compounds for targeted autophagy
CN114890990A (en) * 2022-04-13 2022-08-12 中国人民解放军海军军医大学 Compound and application thereof in preparation of NAMPT protein autophagy degradation agent

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190262458A1 (en) * 2016-11-22 2019-08-29 Dana-Farber Cancer Institute, Inc. Degradation of bruton's tyrosine kinase (btk) by conjugation of btk inhibitors with e3 ligase ligand and methods of use
CN110372669A (en) * 2019-06-19 2019-10-25 浙江省医学科学院 A kind of compound and preparation method thereof, pharmaceutical composition and application based on the induction EGFR degradation of CRBN ligand
CN112321566A (en) * 2019-08-05 2021-02-05 上海科技大学 EGFR protein degradation agent and anti-tumor application thereof
WO2022140246A1 (en) * 2020-12-21 2022-06-30 Hangzhou Jijing Pharmaceutical Technology Limited Methods and compounds for targeted autophagy
CN112939965A (en) * 2021-02-08 2021-06-11 沈阳药科大学 Compound for simultaneously inducing degradation of EGFR (epidermal growth factor receptor) and PARP (para-amyloid peptide) proteins as well as preparation method and application thereof
CN113004251A (en) * 2021-03-05 2021-06-22 郑州大学第一附属医院 Quinazoline derivative containing 2-nitroimidazole and application thereof
CN114890990A (en) * 2022-04-13 2022-08-12 中国人民解放军海军军医大学 Compound and application thereof in preparation of NAMPT protein autophagy degradation agent

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
XIN ZHANG等: "Design and synthesis of selective degraders of EGFRL858R/T790M mutant", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 192, pages 112199 *
XUFEN YU等: "Exploring Degradation of Mutant and Wild-Type Epidermal Growth Factor Receptors Induced by Proteolysis-Targeting Chimeras", J. MED. CHEM., vol. 65, pages 8416, XP093060981, DOI: 10.1021/acs.jmedchem.2c00345 *

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