CN115536699B - Novel EGFR-TKIs, preparation method, pharmaceutical composition and application thereof - Google Patents

Novel EGFR-TKIs, preparation method, pharmaceutical composition and application thereof Download PDF

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CN115536699B
CN115536699B CN202211523776.2A CN202211523776A CN115536699B CN 115536699 B CN115536699 B CN 115536699B CN 202211523776 A CN202211523776 A CN 202211523776A CN 115536699 B CN115536699 B CN 115536699B
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compound
cancer
formula
substituted
synthesis
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CN115536699A (en
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王岩
蒋兴凯
范伏田
毕续海
杨洪伟
马明阳
张海鹏
苏小庭
戴信敏
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Beijing Xinkaiyuan Pharmaceuticals Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention relates to the technical field of medicines, and provides a novel EGFR-TKIs, a preparation method, a pharmaceutical composition and application thereof. The novel EGFR-TKIs are compounds having the structure of formula I:

Description

Novel EGFR-TKIs, preparation method, pharmaceutical composition and application thereof
Technical Field
The invention relates to the technical field of medicines, in particular to a novel EGFR-TKIs, a preparation method, a pharmaceutical composition and application thereof.
Background
The epidermal growth factor receptor (epidermal growth factor receptor, EGFR) is closely related to proliferation, angiogenesis, tumor invasion, metastasis and apoptosis of tumor cells, and is an important target for treating non-small cell lung cancer (non-small cell lung cancer, NSCLC). Epidermal growth factor receptor tyrosine kinase inhibitors (epidermal growth factor receptor tyrosine kinase inhibitors, EGFR-TKIs) can significantly improve the progression free survival and overall survival of patients with non-small cell lung cancer with EGFR (tyrosine kinase type receptor) positive mutations, but EGFR-TKIs can block EGFR-regulated pathways in the skin and gastrointestinal tract and cause associated adverse effects such as skin disease, diarrhea, hepatotoxicity, stomatitis, interstitial lung disease, and ocular toxicity. Although the first and second generation EGFR-TKIs have a certain therapeutic effect on early lung cancer and early mutation, the first and second generation EGFR-TKIs have to be clinically used to achieve the effective concentration of the drug effect by increasing the use amount due to poor selectivity and the like, and the use amount is increased while serious toxic and side effects are easily caused in human bodies, so that various serious skin reactions and other adverse reactions, such as diarrhea, hepatotoxicity and the like, are caused, and the adverse effects on the life quality and compliance of patients are inevitably caused.
Because the third generation EGFR-TKIs (used to treat non-small cell lung cancer positive for the metastatic EGFR T790M mutation) irreversibly bind to certain mutated EGFR, they require approximately nine times lower dosing concentrations than the first and second generation EGFR-TKIs, and are relatively mild in skin response and other side effects in humans. However, the currently marketed third generation EGFR-TKIs have C797S cis mutation, and have problems of adverse reaction and drug resistance in clinic. Therefore, research and development of novel EGFR-TKIs with good drug effect, high inhibitory activity and small toxic and side effects are needed.
Disclosure of Invention
In order to find novel compounds with better EGFR inhibition activity and low toxic and side effects, a series of novel EGFR-TKIs compounds with novel structure, high safety, high EGFR inhibition activity and small toxic and side effects are designed and synthesized through extensive and intensive research, and the drug resistance of the compounds is researched, so that cancers can be effectively treated, relieved and/or prevented through inhibiting EGFR activity, and the compounds have important significance in researching the development of cancer drugs.
In a first aspect of embodiments of the present invention, there is provided a compound having the structure of formula i, a stereoisomer or a pharmaceutically acceptable salt, an isotopic compound thereof:
Figure 148142DEST_PATH_IMAGE001
Wherein W, Q each independently represents carbon or nitrogen;
y, Z each independently represents carbon, nitrogen, oxygen or sulfur;
A 1 、A 2 、A 3 identical or different and each independently represents substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 1 -C 6 Alkylthio, substituted or unsubstituted C 1 -C 6 Alkylamino, substituted or unsubstituted phenyl, substituted or unsubstituted five-membered heteroaryl, substituted or unsubstituted six-membered heteroaryl, substituted or unsubstituted C 3- C 7 Cycloalkyl, substituted or unsubstituted C 3- C 7 Heterocyclyl, C 5 -C 12 Spiro, C 5 -C 12 Bridge ring, C 5 -C 12 Hetero-spiro or C 5 -C 12 A hetero-bridge ring; alternatively, A 1 、A 2 The linkage representing substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 1 -C 6 Alkylthio, substituted or unsubstituted C 1 -C 6 Alkylamino, substituted or unsubstituted phenyl, substituted or unsubstituted five-membered heteroaryl, substituted or unsubstituted six-membered heteroaryl, substituted or unsubstituted C 3 -C 7 Cycloalkyl, substituted or unsubstituted C 3 -C 7 Heterocyclyl, C 5 -C 12 Spiro, C 5 -C 12 Bridge ring, C 5 -C 12 Hetero-spiro or C 5 -C 12 A hetero-bridge ring;
R 1 、R 2 、R 3 、R 4 identical or different and each independently represents hydrogen, fluorine, chlorine, bromine,Iodine, acetyl, aldehyde, carboxyl, hydroxyl, amino, mercapto, cyano, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Alkoxy, substituted or unsubstituted C 1 -C 4 Alkylthio, substituted or unsubstituted C 1 -C 4 Alkylamino, substituted or unsubstituted phenyl, substituted or unsubstituted five-membered heteroaryl, substituted or unsubstituted six-membered heteroaryl, substituted or unsubstituted C 3 -C 7 Cycloalkyl, substituted or unsubstituted C 3 -C 7 A heterocyclic group.
The novel EGFR-TKIs compound provided by the invention has the advantages of novel structure, high safety, higher EGFR inhibition activity and smaller toxic and side effects, can effectively treat, relieve and/or prevent cancers by inhibiting EGFR activity, and has important significance for developing cancer medicaments.
In a second aspect of the embodiment of the present invention, there is provided a method for preparing a compound having the structure of formula i, a stereoisomer or a pharmaceutically acceptable salt thereof, or an isotopic compound as described in the first aspect, comprising the steps of:
Figure 57324DEST_PATH_IMAGE002
in W, Q, Y, Z, A 1 、A 2 、A 3 、R 1 、R 2 、R 3 、R 4 Is defined as pair W, Q, Y, Z, A in the first aspect 1 、A 2 、A 3 、R 1 、R 2 、R 3 、R 4 Is defined as follows;
synthesis of intermediate v:
reacting a compound II with a structure of formula II with a compound III with a structure of formula III in a first solvent in the presence of a first catalyst, a first base and a first ligand at a first reaction temperature to produce an intermediate V with a structure of formula V;
Synthesis of intermediate vii:
reacting the intermediate IV with the structure of the formula IV with a compound V with the formula V in a second solvent in the presence of a second catalyst, a second base and a second ligand at a second reaction temperature to generate an intermediate VII with the structure of the formula VII;
synthesis of Compound I:
intermediate VI having the structure of formula VI is reacted with compound VII having the structure of formula VII in a third solvent in the presence of a third base at a third reaction temperature to produce compound I having the structure of formula I.
The preparation method provided by the embodiment of the invention has the advantages of simplicity, mild condition, convenience in operation, low equipment condition requirement, easiness in realization, simplicity in post-treatment and high yield, and is suitable for industrial mass production.
In a third aspect of embodiments of the present invention there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group consisting of a compound having the structure of formula i as set forth in the first aspect, a stereoisomer or a pharmaceutically acceptable salt thereof, an isotopic compound, and a pharmaceutically acceptable carrier.
In the embodiment of the invention, the compound with the structure shown in the formula I, the stereoisomer or the pharmaceutically acceptable salt and the isotopic compound are used as active ingredients in the pharmaceutical composition.
In a fourth aspect of embodiments of the present invention, there is provided a novel EGFR-TKIs comprising a therapeutically effective amount of a compound selected from the group consisting of compounds having the structure of formula I as described in the first aspect, stereoisomers or pharmaceutically acceptable salts, isotopic compounds thereof, and a pharmaceutically acceptable carrier.
In an embodiment of the invention, the compound having the structure of formula I, stereoisomers or pharmaceutically acceptable salts, isotopic compounds thereof are used as active ingredients in EGFR-TKIs.
According to a fifth aspect of embodiments of the present invention, there is provided an application of the compound having the structure of formula I, the stereoisomer or the pharmaceutically acceptable salt, the isotopic compound thereof, or the pharmaceutical composition of the third aspect, or the EGFR-TKIs of the fourth aspect in preparing a medicament for preventing and/or treating cancer.
In terms of the use of the compounds and pharmaceutical compositions provided herein in the manufacture of a medicament for treating cancer, a therapeutically effective amount of a compound or pharmaceutical composition provided herein is administered to a patient in need of treatment for cancer to achieve a therapeutic effect. The compound or the pharmaceutical composition provided by the invention can be used alone as a treatment means for treating cancers, and can also be matched with other conventional treatment means for treating cancers such as surgery, radiotherapy, chemotherapy and the like.
The therapeutically effective amount of a compound or pharmaceutical composition provided herein for treating cancer depends on a number of factors. May vary depending on the particular type of cancer that is desired to be treated, as may be determined by one of ordinary skill in the art without undue experimentation. The actual treatment may also take into account factors such as patient age and weight, severity of the condition, specific mode of administration, etc., ultimately depending on the discretion of the attendant physician or clinician.
Detailed Description
In order to make the technical problems, technical schemes and beneficial effects to be solved more clear, the invention is further described in detail below with reference to the embodiments. It should be understood that the specific examples described herein are for purposes of illustration only and that the embodiments of the invention are not limited thereto.
Unless defined otherwise, technical terms used in the following examples have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention pertains. The experimental reagents used in the following examples are all conventional biochemical reagents unless otherwise specified; the dosage of the experimental reagent is the dosage of the reagent in the conventional experimental operation if no special description exists; the experimental methods are conventional methods unless otherwise specified.
Some terms involved in the expression of the present invention are defined as follows:
the term "pharmaceutically acceptable salts" refers to those salts that retain the biological effectiveness and properties of the parent compound. The salt comprises: acid addition salts obtained by reaction of the free base of the parent compound with an inorganic acid or with an organic acid; the inorganic acid comprises hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, sulfuric acid, perchloric acid and the like; the organic acid comprises acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, fumaric acid, gluconic acid, glutamic acid, isethionic acid, lactic acid, mandelic acid, mucic acid, bis-toluenesulfonic acid, and citric acid
Hydroxy naphthoic acid, pantothenic acid, succinic acid or malonic acid, etc. Alternatively, salts formed when the acid protons present in the parent compound are replaced with metal ions or coordinated with an organic base; the metal ions comprise alkali metal ions, alkaline earth ions, aluminum ions and the like; the organic base includes ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.
The term "stereoisomers" refers to compounds having the same molecular formula but different in the spatial arrangement of the atoms in the molecule. Since the compounds provided herein may have one or more asymmetric centers, the compounds may be prepared as individual (R) -stereoisomers or as individual (S) -stereoisomers or as mixtures thereof. Unless otherwise indicated, descriptions or names of particular compounds in the present invention are intended to include individual enantiomers and racemic or other mixtures thereof. Methods for determining stereochemical configuration and isolating stereoisomers are routine in the art (see discussion in chapter 4 of Advanced Organic Chemistry, 4 th edition, J.March, john Wiley and Sons, new York, 1992). Thus, the invention also encompasses any stereoisomers, their corresponding enantiomers (D-and L-isomers or (+) and (-) isomers), and diastereomers and mixtures thereof, that have the ability to modulate EGFR kinase activity and are not limited to any one stereoisomer.
The carbon atom content of the various carbon-hydrogen containing moieties is represented by the prefix of the moiety, i.e. prefix C, which is marked with the smallest and largest number of carbon atoms i ~C j The number of carbon atoms representing the moiety is an integer from "i" to "j" (including i and j). Thus, for example, C 1~ C 4 Alkyl refers to an alkane of 1 to 4 carbon atomsRadicals (including 1 and 4).
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group containing from 1 to 12 carbon atoms, more preferably an alkyl group containing from 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, and various branched isomers thereof, and the like. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any useful point of attachment.
The term "substituted" refers to any available point of attachment that may be substituted with a substituent.
The term "alkoxy" refers to-O- (alkyl) wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment.
The term "alkylthio" refers to (alkyl) -S-, non-limiting examples of alkylthio groups include: methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, and the like.
The term "alkylamino" refers to an amine group having one or two alkyl substituents, such as "alkyl-NH-" or "(alkyl) 2 An N- "group, wherein alkyl is as defined above. Non-limiting examples of alkylamino groups include: dimethylamino, methylamino, and the like.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon group, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 7 carbon atoms. Non-limiting examples of cycloalkyl groups include cyclohexenyl, cyclopentenyl, and the like.
The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon group containing 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from silicon, phosphorus, nitrogen, oxygen or sulfur, the remaining ring atoms being carbon. Preferably containing 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably from 3 to 8 ring atoms, of which 1 to 3 are heteroatoms.
The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from silicon, phosphorus, oxygen, sulfur and nitrogen, having a fully conjugated pi-electron system. Heteroaryl groups are preferably 5 to 10 membered, containing 1 to 3 heteroatoms; more preferably 5 or 6 membered, containing 1 to 2 heteroatoms.
The term "pharmaceutical composition" refers to a mixture of one or more of the compounds described herein, or a physiologically acceptable salt thereof, with other chemical ingredients, such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration of the compound to the organism.
The term "pharmaceutically acceptable carrier" refers to a pharmaceutical carrier conventional in the pharmaceutical arts, a carrier that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound, e.g.: diluents such as water and the like; fillers such as starch, sucrose, etc.; binders, such as cellulose derivatives, alginates, gelatin, polyvinylpyrrolidone; humectants, such as glycerol; disintegrants such as agar-agar, calcium carbonate and sodium bicarbonate; absorption promoters, such as quaternary ammonium compounds; surfactants such as cetyl alcohol; adsorption carriers such as kaolin and soap clay; lubricants such as talc, calcium stearate and magnesium stearate, polyethylene glycol, and the like. In addition, other auxiliary materials such as flavoring agent and sweetener can be added into the pharmaceutical composition.
The term "therapeutically effective amount" refers to an amount of a compound of the invention sufficient to achieve the intended use. The therapeutically effective amount may vary depending on the following factors: the intended use (in vitro or in vivo), or the subject and disease condition being treated, such as the weight and age of the subject, the severity of the disease condition, the manner of administration, and the like, can be readily determined by one of ordinary skill in the art. The specific dosage will vary depending on the following factors: the particular compound selected, the regimen according to which it is administered, whether it is administered in combination with other compounds, the timing of administration, the tissue in which it is administered, and the physical delivery system carried.
The term "room temperature" as used herein has a meaning known in the art and generally refers to 24-28 ℃.
In a first aspect, embodiments of the present invention provide a compound having the structure of formula i, a stereoisomer, or a pharmaceutically acceptable salt, isotopic compound thereof:
Figure 768928DEST_PATH_IMAGE001
wherein W, Q each independently represents carbon or nitrogen;
y, Z each independently represents carbon, nitrogen, oxygen or sulfur;
A 1 、A 2 、A 3 identical or different and each independently represents substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 1 -C 6 Alkylthio, substituted or unsubstituted C 1 -C 6 Alkylamino, substituted or unsubstituted phenyl, substituted or unsubstituted five-membered heteroaryl, substituted or unsubstituted six-membered heteroaryl, substituted or unsubstituted C 3- C 7 Cycloalkyl, substituted or unsubstituted C 3- C 7 Heterocyclyl, C 5 -C 12 Spiro, C 5 -C 12 Bridge ring, C 5 -C 12 Hetero-spiro or C 5 -C 12 A hetero-bridge ring; alternatively, A 1 、A 2 The linkage representing substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 1 -C 6 Alkylthio, substituted or unsubstituted C 1 -C 6 Alkylamino, substituted or unsubstituted phenyl, substituted or unsubstituted five-membered heteroaryl, substituted or unsubstituted six-membered heteroaryl, substituted or unsubstituted C 3 -C 7 Cycloalkyl, substituted or unsubstituted C 3 -C 7 Heterocyclyl, C 5 -C 12 Spiro, C 5 -C 12 Bridge ring, C 5 -C 12 Screw with screw threadRing or C 5 -C 12 A hetero-bridge ring;
R 1 、R 2 、R 3 、R 4 identical or different and each independently of the others independently represents hydrogen, fluorine, chlorine, bromine, iodine, acetyl, aldehyde, carboxyl, hydroxyl, amino, mercapto, cyano, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Alkoxy, substituted or unsubstituted C 1 -C 4 Alkylthio, substituted or unsubstituted C 1 -C 4 Alkylamino, substituted or unsubstituted phenyl, substituted or unsubstituted five-membered heteroaryl, substituted or unsubstituted six-membered heteroaryl, substituted or unsubstituted C 3 -C 7 Cycloalkyl, substituted or unsubstituted C 3 -C 7 A heterocyclic group;
further, when A 1 、A 2 、A 3 Each independently represents substituted C 1 -C 6 Alkyl, substituted C 1 -C 6 Alkoxy, substituted C 1 -C 6 Alkylthio, substituted C 1 -C 6 Alkylamino, substituted phenyl, substituted five membered heteroaryl, substituted six membered heteroaryl, substituted C 3 -C 7 Cycloalkyl or substituted C 3 -C 7 When heterocyclic, the substituent is one or more of methyl, ethyl, hydroxyl, halogen, amino, methoxy, dimethylamino and diethylamino; when A is 1 、A 2 Connected and representing substituted C 1 -C 6 Alkyl, substituted C 1 -C 6 Alkoxy, substituted C 1 -C 6 Alkylthio, substituted C 1 -C 6 Alkylamino, substituted phenyl, substituted five membered heteroaryl, substituted six membered heteroaryl, substituted C 3 -C 7 Cycloalkyl or substituted C 3 -C 7 When heterocyclic, the substituent is one or more of methyl, ethyl, hydroxyl, halogen, amino, methoxy, dimethylamino and diethylamino; when R is 1 、R 2 、R 3 、R 4 Each independently represents substituted C 1 -C 4 Alkyl, substituted C 1 -C 4 Alkoxy, substituted C 1 -C 4 Alkylthio, substituted C 1 -C 4 Alkylamino, substituted phenyl, substituted five membered heteroaryl, substituted six membered heteroaryl, substituted C 3 -C 7 Cycloalkyl or substituted C 3 -C 7 When heterocyclic, the substituent is one or more of methyl, ethyl, hydroxyl, halogen, amino, methoxy, dimethylamino and diethylamino.
Further, A 1 、A 2 Connection represents
Figure 634116DEST_PATH_IMAGE003
、
Figure 835290DEST_PATH_IMAGE004
、
Figure 418718DEST_PATH_IMAGE005
Or (b)
Figure 481483DEST_PATH_IMAGE006
。
In a preferred embodiment of the present invention, the compound having the structure of formula i may be, but is not limited to, compounds of the following formulas (1) to (20):
Figure 466757DEST_PATH_IMAGE007
Figure 776515DEST_PATH_IMAGE008
Figure 909556DEST_PATH_IMAGE009
Figure 962963DEST_PATH_IMAGE010
Figure 604073DEST_PATH_IMAGE011
。
in a second aspect, the embodiment of the invention also provides a preparation method of a compound with a structure shown in formula I, a stereoisomer or pharmaceutically acceptable salt and isotopic compound thereof, which comprises the following steps:
Figure 84733DEST_PATH_IMAGE002
in W, Q, Y, Z, A 1 、A 2 、A 3 、R 1 、R 2 、R 3 、R 4 Is defined as pair W, Q, Y, Z, A in the first aspect 1 、A 2 、A 3 、R 1 、R 2 、R 3 、R 4 Is defined as follows;
synthesis of intermediate v:
reacting a compound II with a structure of formula II with a compound III with a structure of formula III in a first solvent in the presence of a first catalyst, a first base and a first ligand at a first reaction temperature to produce an intermediate V with a structure of formula V;
synthesis of intermediate vii:
reacting the intermediate IV with the structure of the formula IV with a compound V with the formula V in a second solvent in the presence of a second catalyst, a second base and a second ligand at a second reaction temperature to generate an intermediate VII with the structure of the formula VII;
synthesis of Compound I:
intermediate VI having the structure of formula VI is reacted with compound VII having the structure of formula VII in a third solvent in the presence of a third base at a third reaction temperature to produce compound I having the structure of formula I.
The sequence numbers of the steps in the embodiment of the invention do not limit the sequence of the steps in the embodiment of the invention, and the preparation method provided by the embodiment of the invention has the advantages of simplicity, mild condition, convenient operation, low equipment condition requirement, easy realization, simple post-treatment and high yield, and is suitable for industrial mass production.
Further, in the step of synthesizing the intermediate V, the first reaction temperature is 50-120 ℃; for example, the first reaction temperature may be 50 ℃, 60 ℃, 70 ℃, 80 ℃, 90 ℃, 100 ℃, 110 ℃, 120 ℃, or the like. The first catalyst is dibenzylidene acetone dipalladium (Pd) 2 (dba) 3 ) Palladium acetate (Pd (OAc)) 2 ) [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (Pd (dppf) Cl) 2 ) Palladium tetraphenyl phosphine (Pd (PPh) 3 ) 4 ) At least one of them. The first alkali is at least one of sodium acetate, potassium acetate, sodium carbonate, potassium phosphate, cesium carbonate, sodium tert-butoxide and potassium tert-butoxide. The first ligand is at least one of 2,2 '-bis (diphenylphosphine) -1,1' -Binaphthyl (BINAP) and 4, 5-bis-diphenylphosphine-9, 9-dimethyl xanthene (Xantphos). The first solvent is at least one of N, N-dimethylformamide, 1, 4-dioxane and N-methylpyrrolidone.
Further preferably, the first catalyst is dibenzylidene acetone dipalladium; the first base is cesium carbonate; the first ligand is 2,2 '-bis (diphenylphosphine) -1,1' -Binaphthyl (BINAP); the first solvent is 1, 4-dioxane.
Further, in the step of synthesizing the intermediate VII, the second reaction temperature is 50-120 ℃; for example, the second reaction temperature may be 50 ℃, 60 ℃, 70 ℃, 80 ℃, 90 ℃, 100 ℃, 110 ℃, 120 ℃, or the like. The second catalyst is at least one of dibenzylidene acetone dipalladium, palladium acetate, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride and tetraphenylphosphine palladium. The second alkali is at least one of sodium acetate, potassium acetate, sodium carbonate, potassium phosphate, cesium carbonate, sodium tert-butoxide and potassium tert-butoxide. The second ligand is at least one of 2,2 '-bis (diphenylphosphine) -1,1' -binaphthyl and 4, 5-bis-diphenylphosphine-9, 9-dimethyl xanthene. The second solvent is at least one of N, N-dimethylformamide, 1, 4-dioxane and N-methylpyrrolidone.
Further preferably, the second catalyst is dibenzylidene acetone dipalladium; the second base is cesium carbonate; the second ligand is 2,2 '-bis (diphenylphosphine) -1,1' -binaphthyl; the second solvent is 1, 4-dioxane.
Further, in the step of synthesizing the compound I, the third reaction temperature is 135 ℃ to 145 ℃, for example, the third reaction temperature may be 135 ℃, 138 ℃, 140 ℃, 143 ℃, 145 ℃, or the like. The third base is at least one of N, N-diisopropylethylamine, triethylamine and 1, 8-diazabicyclo undec-7-ene (DBU). The third solvent is at least one of N-methyl pyrrolidone, 1, 4-dioxane, N-dimethylformamide, N-dimethylacetamide and dimethyl sulfoxide.
Further preferably, the third base is N, N-diisopropylethylamine; the third solvent is N-methyl pyrrolidone.
In a third aspect, embodiments of the present invention also provide a pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group consisting of a compound having the structure of formula i, a stereoisomer, or a pharmaceutically acceptable salt thereof, an isotopic compound as described in the first aspect, and a pharmaceutically acceptable carrier.
In the embodiment of the invention, the compound with the structure shown in the formula I, the stereoisomer or the pharmaceutically acceptable salt and the isotopic compound are used as active ingredients in the pharmaceutical composition.
In a fourth aspect, embodiments of the present invention also provide a novel EGFR-TKIs comprising a therapeutically effective amount of a compound selected from the group consisting of compounds having the structure of formula I as described in the first aspect, stereoisomers or pharmaceutically acceptable salts, isotopic compounds thereof, and a pharmaceutically acceptable carrier.
In a fifth aspect, the embodiment of the present invention further provides an application of the compound having the structure of formula I, the stereoisomer or the pharmaceutically acceptable salt thereof, the isotopic compound of the first aspect, or the pharmaceutical composition of the third aspect, or the EGFR-TKIs of the fourth aspect in preparing a medicament for preventing and/or treating cancer.
Further, the cancer is selected from the group consisting of skin cancer, bladder cancer, ovarian cancer, breast cancer, gastric cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, rectal cancer, esophageal cancer, tongue cancer, kidney cancer, cervical cancer, endometrial cancer, testicular cancer, urinary cancer, melanoma, astrocytoma, meningioma, hodgkin lymphoma, non-hodgkin lymphoma, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, adult T-cell leukemia lymphoma, hepatocellular carcinoma, bronchogenic carcinoma, multiple myeloma, basal cell tumor, seminoma, chondrosarcoma, myosarcoma, fibrosarcoma.
The invention has been tested several times in succession, and the invention will now be described in further detail with reference to a few test results, which are described in detail below in connection with specific examples.
EXAMPLE 1 preparation of Compound I-1
Figure 377174DEST_PATH_IMAGE012
Figure 296589DEST_PATH_IMAGE013
S1: synthesis of Compound c1
In a 100mL single port flask, compound a1 (3.42 g,20 mmol) was weighed and dissolved in 30mL of N, N-Dimethylformamide (DMF), then compound b1 (2.2 g,22 mmol) and potassium carbonate (4.15 g,30 mmol) were added, the reaction was allowed to react at room temperature for 15h, TLC was monitored, after completion of the reaction, 300mL of purified water was added, extraction was performed three times with methylene chloride, the volume of methylene chloride used for each extraction was 50mL, the organic phases were combined, and the organic phases were washed with 100mL of saturated brine, and then dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to give 3.5g of compound c1 in a yield of 69.6%, compound c1 was a yellow solid, ESI (+) m/z=252.3 [ M+H ]] + 。
S2: synthesis of Compound d1
In a 100mL single-necked flask, compound C1 (3.5 g,13.9 mmol) was weighed and dissolved in 35mL of methanol, 10% Pd/C350mg was added, the hydrogen was replaced three times, and reacted under a hydrogen atmosphere at room temperature for 3h, TLCAfter the reaction was monitored, the mixture was filtered and concentrated under reduced pressure to give 3.0g of compound d1 in 97.5% yield, compound d1 as a yellow solid, ESI (+) m/z=222.3 [ M+H ] ] + 。
S3: synthesis of Compound f1
In a 100mL single port flask, compound e1 (2.97 g,10 mmol) was weighed and dissolved in 30mL DMF, then potassium carbonate (2.76 g,20 mmol), potassium iodide (0.83 g,5 mmol) and phosphorus dimethyl oxide (1.54 g,20 mmol) were sequentially added, the reaction mixture was placed in an oil bath at 80℃for reaction for 12 hours, the reaction was monitored by iodine-jar chromogenic method by TLC, after the reaction was completed, 300mL of purified water was added, extraction was performed three times with methylene chloride, the methylene chloride volume used for each extraction was 50mL, the organic phases were combined, the organic phases were washed with 100mL of saturated saline, then dried with anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 2.1g of compound f1 in a yield of 84.9% and compound f1 as a yellow solid, ESI (+) m/z=248.2 [ M+H ]] + 。
S4: synthesis of Compound g1
In a 100mL single port flask, compound f1 (2.1 g,8.49 mmol) was weighed and dissolved in 10mL of methylene chloride, 3mL of trifluoroacetic acid (TFA) was added to react at room temperature for 3h, TLC was monitored, after completion of the reaction, the solvent and the excess trifluoroacetic acid were removed by concentration under reduced pressure, 50mL of purified water and 50mL of saturated sodium bicarbonate were added, extraction was performed three times with methylene chloride, the methylene chloride volume used for each extraction was 50mL, the organic phases were combined, the organic phases were washed with 100mL of saturated brine, and then dried with anhydrous sodium sulfate and concentrated under reduced pressure to give 1.2g of compound g1 in 96% yield, compound g1 was a white solid, ESI (+) m/z=148.1 [ M+H ] ] + 。
S5: synthesis of Compound j1
Compound h1 (1.98 g,8.15 mmol) and compound g1 (1.2 g,8.15 mmol) were dissolved in 20mL 1, 4-dioxane, and tris dibenzylideneacetone dipalladium (732 mg,0.8 mmol), 2 '-bis (diphenylphosphine) -1,1' -binaphthyl (995 mg,1.6 mmol) and cesium carbonate (5.21 g,16 mmol) were added at room temperature, and the mixture was heated to reflux under nitrogen protection to stir for 4h, TLC was monitored, and after the reaction was completed, the solvent was removed by concentration under reduced pressure,then 200mL of purified water was added and extraction was performed three times with ethyl acetate, the volume of ethyl acetate used for each extraction was 50mL, the organic phases were combined, the organic phases were washed with 50mL of purified water, 50mL of saturated saline, then dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to give 1.8g of compound j1 in 71.5% yield, compound j1 as a pale yellow solid, ESI (+) m/z=309.7 [ M+H ]] + 。
S6: synthesis of Compound k1
In a 100mL single-port flask, compound j1 (1.8 g,5.83 mmol) was weighed and dissolved in 10mL acetic acid solution, N-iodosuccinimide (NIS, 1.57g,7.0 mmol) was added, the reaction was carried out at room temperature for 5 hours, TLC monitoring was carried out, after the reaction was completed, poured into 100mL ice water, a pale yellow solid was precipitated, and after filtration, column chromatography was carried out to obtain 1.76g of compound k1, the yield was 69.5%, compound k1 was a pale yellow solid, ESI (+) m/z=435.6 [ M+H ] ] + 。
S7: synthesis of Compound m1
Compound k1 (1.76 g,4 mmol) was dissolved in 16mL of 1, 4-dioxane, pinacol isopropenylborate (806 mg,4.8 mmol), palladium tetraphenylphosphine (460 mg,0.4 mmol), potassium phosphate (1.7 g,8 mmol) and 4mL of purified water were added at room temperature, the reaction was stirred under nitrogen at elevated temperature to reflux for 4 hours, the reaction was monitored by TLC, after completion of the reaction, concentrated under reduced pressure to remove the solvent, 200mL of purified water was added, extracted three times with ethyl acetate, the ethyl acetate used for each extraction had a volume of 50mL, the organic phases were combined, the organic phases were washed successively with 50mL of purified water and 50mL of saturated brine, then dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to give 1.05g of compound m1 in 75.0% yield, compound m1 was a yellow solid, ESI (+) m/z=349.8 M+H [ H ]] + 。
S8: synthesis of Compound n1
In a 50mL one-necked flask, 8mL of Ethyl Acetate (EA) was added, and the mixture was stirred at room temperature, followed by addition of Compound m1 (1.05 g,3 mmol) and platinum dioxide (PtO 2 100mg,0.1 w/w), air was pumped out of the system, hydrogen was displaced three times, the reaction was carried out for 3h at room temperature under hydrogen atmosphere, and TLC monitoring was performed for the reactionAfter the reaction, the mixture was filtered, the filtrate was collected and concentrated under reduced pressure to give 900mg of compound n1 in a yield of 85.5%, compound n1 as a yellow solid, ESI (+) m/z=351.8 [ m+h ] ] + 。
S9: synthesis of Compound q1
Compound n1 (900 mg,2.56 mmol) and compound p1 (362 mg,2.56 mmol) were dissolved in 10mL of 1, 4-dioxane, dibenzylideneacetone dipalladium (229 mg,0.25 mmol), 2 '-bis (diphenylphosphine) -1,1' -binaphthyl (311 mg,0.5 mmol) and cesium carbonate (1.63 g,5 mmol) were added at room temperature, the reaction was monitored by heating to reflux under nitrogen protection with stirring for 4h, after completion of the reaction, the reaction was concentrated under reduced pressure to remove the solvent, 200mL of purified water was then added, extraction was performed three times with ethyl acetate, the volume of ethyl acetate used for each extraction was 50mL, the organic phases were combined, washed with 50mL of purified water and 50mL of saturated brine, then dried with anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to give 720mg of compound q1, the yield was 61.7%, compound q1 was pale yellow solid, ESI (+) m/z=456.5 M+H, the organic phase was obtained] + 。
S10: synthesis of Compound I-1
Compound q1 (100 mg,0.22 mmol) was dissolved in 3mL of N-methylpyrrolidone, N-diisopropylethylamine (DIEA, 57mg,0.44 mmol) and compound d1 (49 mg,0.22 mmol) were added at room temperature, the reaction solution was reacted at 140℃for 3 hours, TLC was monitored, after completion of the reaction, 30mL of purified water was added, extraction was performed three times with methylene chloride, the volume of methylene chloride used for each extraction was 10mL, the organic phases were combined, the organic phase was washed successively with 30mL of purified water and 30mL of saturated brine, and then dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to give 41.7mg of compound I-1 in a yield of 30.1% as a pale yellow solid, ESI (+) m/z=629.7 [ M+H ] ] + 。
EXAMPLE 2 preparation of Compound I-2
Figure 990875DEST_PATH_IMAGE014
S1: synthesis of Compound p2
In a 100mL single port flask, 4-amino-2-chloro-5-fluoropyrimidine (2.95 g,20 mmol) was weighed and dissolved in 30mL of anhydrous ethanol solution, sodium methyl mercaptide (1.68 g,24 mmol) was added to reflux for 3h, TLC was monitored, after completion of the reaction, the reaction was concentrated under reduced pressure to remove the solvent, 200mL of purified water was added, extraction was performed three times with ethyl acetate, the volume of ethyl acetate used for each extraction was 50mL, the organic phases were combined, the organic phases were washed with 50mL of purified water, then with 50mL of saturated brine, and then dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 3.0g of compound p2 in 94.2% yield as a pale yellow solid, ESI (+) m/z=160.1 M+H [ H ]] + 。
S2: synthesis of Compound q2
According to the synthetic route provided in this example, compound q2 was synthesized with reference to step S9 in example 1 to yield 800mg of compound q2 in 66.0% yield, compound q2 was a pale yellow solid, ESI (+) m/z=474.5 [ m+h ]] + 。
S3: synthesis of Compound I-2
According to the synthetic route provided in this example, compound I-2 was synthesized with reference to step S10 in example 1 to give 45mg of compound I-2 in a yield of 31.6%, compound I-2 as a pale yellow solid, ESI (+) m/z=647.7 [ M+H ] ] + 。
EXAMPLE 3 preparation of Compound I-3
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S1: synthesis of Compound c3
According to the synthetic route provided in this example, compound c3 was synthesized with reference to step S1 in example 1 to give 3.3g of compound c3 in a yield of 49.4%, compound c3 was a yellow solid, ESI (+) m/z=335.4 [ m+h ]] + 。
S2: synthesis of Compound d3
Compound c3 (3.3 g,9.87 mmol) was weighed out and compound d3 was synthesized according to the synthetic route provided in this example with reference to step S2 of example 1 to give 2.6g of compound d3 in 86.5% yield, compoundProduct d3 was a yellow solid, ESI (+) m/z=305.4 [ M+H ]] + 。
S3: synthesis of Compound I-3
According to the synthetic route provided in this example, compound I-3 was synthesized by referring to step S10 in example 1 to give 47mg of compound I-3 in a yield of 30.0%, compound I-3 was a pale yellow solid, ESI (+) m/z=712.9 [ M+H ]] + 。
EXAMPLE 4 preparation of Compound I-4
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S1: synthesis of Compound I-4
According to the synthetic route provided in this example, compound I-4 was synthesized by referring to step S10 in example 1 to give 44mg of compound I-4 in a yield of 27.3%, compound I-4 as a pale yellow solid, ESI (+) m/z=730.8 [ M+H ]] + 。
EXAMPLE 5 preparation of Compound I-5
Figure 896012DEST_PATH_IMAGE017
S1: synthesis of Compound f5
According to the synthetic route provided in this example, compound f5 was synthesized with reference to step S3 in example 1 to give 2.17g of compound f5 in a yield of 83.0%, compound f5 as a yellow solid, ESI (+) m/z=262.3 [ m+h ] ] + 。
S2: synthesis of Compound g5
Compound f5 (2.17 g,8.30 mmol) was weighed out and compound g5 was synthesized according to the synthetic route provided in this example by reference to step S4 in example 1 to give 1.31g of compound g5 in 98.0% yield, compound g5 as a white solid, ESI (+) m/z=162.1 [ m+h ]] + 。
S3: synthesis of Compound j5
According to the synthetic route provided in this example, compound j5 was synthesized with reference to step S5 in example 1 to give 1.88g of compound j5 in a yield of 71.5%, compound j5 as pale yellow solid, ESI (+) m/z=323.7 [ m+h ]] + 。
S4: synthesis of Compound k5
According to the synthetic route provided in this example, compound k5 was synthesized with reference to step S6 in example 1 to yield 1.79g of compound k5 in a yield of 68.4%, compound k5 was a pale yellow solid, ESI (+) m/z=449.6 [ m+h ]] + 。
S5: synthesis of Compound m5
According to the synthetic route provided in this example, compound m5 was synthesized with reference to step S7 in example 1 to yield 1.2g of compound m5 in 82.7% yield, compound m5 was a yellow solid, ESI (+) m/z=363.8 [ m+h ]] + 。
S6: synthesis of Compound n5
According to the synthetic route provided in this example, compound n5 was synthesized with reference to step S8 in example 1, yielding 1.1g of compound n5 in a yield of 91.3%, compound n5 being a yellow solid, ESI (+) m/z=365.8 [ m+h ] +.
S7: synthesis of Compound q5
N5 (1.1 g,3.0 mmol) and compound p1 (424.2 mg,3.0 mmol) were weighed out and compound q5 was synthesized according to the synthetic route provided in this example by reference to step S9 of example 1 to give 800mg of compound q5 in a yield of 56.8% and compound q5 as a pale yellow solid, ESI (+) m/z=470.5 [ M+H ]] + 。
S8: synthesis of Compound I-5
According to the synthetic route provided in this example, compound I-5 was synthesized by referring to step S10 in example 1 to yield 36.6mg of compound I-5 in a yield of 22.9%, compound I-5 was a pale yellow solid, ESI (+) m/z=726.9 [ M+H ]] + 。
EXAMPLE 6 preparation of Compound I-6
Figure 507122DEST_PATH_IMAGE018
S1: synthesis of Compound q6
According to the synthetic route provided in this example, compound q6 was synthesized with reference to step S9 in example 1 to give760mg of compound q6 in 60.9% yield, compound q6 as a pale yellow solid, ESI (+) m/z=488 [ M+H ]] + 。
S2: synthesis of Compound I-6
According to the synthetic route provided in this example, compound I-6 was synthesized by referring to step S10 in example 1 to give 50mg of compound I-6 in a yield of 30.6%, compound I-6 was a pale yellow solid, ESI (+) m/z=744.9 [ M+H ]] + 。
EXAMPLE 7 preparation of Compound I-7
Figure 595163DEST_PATH_IMAGE019
S1: synthesis of Compound f7
According to the synthetic route provided in this example, compound f7 was synthesized with reference to step S3 in example 1 to yield 2.36g of compound f7 in a yield of 85.7%, compound f7 was a yellow solid, ESI (+) m/z=276.3 [ m+h ]] + 。
S2: synthesis of Compound g7
Compound f7 (2.36 g,8.57 mmol) was weighed out and compound g7 was synthesized according to the synthetic route provided in this example with reference to step S4 of example 1 to give 1.43g of compound g7 in 95.2% yield, compound g7 as a white solid, ESI (+) m/z=176.2 [ m+h ]] + 。
S3: synthesis of Compound j7
According to the synthetic route provided in this example, compound j7 was synthesized with reference to step S5 in example 1 to yield 1.96g of compound j7 in a yield of 71.4%, compound j7 was a pale yellow solid, ESI (+) m/z=337.8 [ m+h ]] + 。
S4: synthesis of Compound k7
According to the synthetic route provided in this example, compound k7 was synthesized with reference to step S6 in example 1 to yield 1.85g of compound k7 in a yield of 68.6%, compound k7 was a pale yellow solid, ESI (+) m/z=463.7 [ m+h] + 。
S5: synthesis of Compound m7
According to the synthetic route provided in this example, reference is made to example 1Step S7 synthesis of compound m7 gives 1.2g of compound m7 in 80.0% yield, compound m7 as a yellow solid, ESI (+) m/z=377.8 [ m+h ] ] + 。
S6: synthesis of Compound n7
Compound m7 (1.2 g,3.2 mmol) was weighed out and compound n7 was synthesized according to the synthetic route provided in this example with reference to step S8 in example 1 to give 1.14g of compound n7 in 94.0% yield, compound n7 as a yellow solid, ESI (+) m/z=379.8 [ m+h] + 。
S7: synthesis of Compound q7
Compound n7 (1.14 g,3.0 mmol) and compound p1 (424.2 mg,3.0 mmol) were weighed out and compound q7 was synthesized according to the synthetic route provided in this example with reference to step S9 of example 1 to yield 920mg of compound q7 in 63.4% yield, compound q7 was a pale yellow solid, ESI (+) m/z=484.6 [ m+h ]] + 。
S8: synthesis of Compound I-7
According to the synthetic route provided in this example, compound I-7 was synthesized by referring to step S10 of example 1 to give 40mg of compound I-7 in 24.5% yield, compound I-7 as a pale yellow solid, ESI (+) m/z=740.9 [ M+H ]] + 。
EXAMPLE 8 preparation of Compound I-8
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S1: synthesis of Compound f8
According to the synthetic route provided in this example, compound f8 was synthesized with reference to step S3 in example 1 to yield 2.36g of compound f8 in a yield of 85.7%, compound f8 was a yellow solid, ESI (+) m/z=276.3 [ m+h ]] + 。
S2: synthesis of Compound g8
Compound f8 (2.36 g,8.57 mmol) was weighed out and compound g8 was synthesized according to the synthetic route provided in this example by reference to step S4 of example 1 to give 1.43g of compound g8 in 95.3% yield, compound g8 as a white solid, ESI (+) m/z=176.1 [ m+h ]] + 。
S3: synthesis of Compound j8
According to the synthetic route provided in this example, compound j8 was synthesized with reference to step S5 in example 1 to yield 1.96g of compound j8 in a yield of 71.4%, compound j8 was a pale yellow solid, ESI (+) m/z=337.8 [ m+h ]] + 。
S4: synthesis of Compound k8
According to the synthetic route provided in this example, compound k8 was synthesized with reference to step S6 in example 1 to yield 1.85g of compound k8 in a yield of 68.6%, compound k8 was a pale yellow solid, ESI (+) m/z=463.7 [ m+h ]] + 。
S5: synthesis of Compound m8
According to the synthetic route provided in this example, compound m8 was synthesized with reference to step S7 in example 1 to yield 1.2g of compound m8 in 79.6% yield, compound m8 was a yellow solid, ESI (+) m/z=377.8 [ m+h ]] + 。
S6: synthesis of Compound n8
Compound m8 (1.2 g,3.2 mmol) was weighed out and compound n8 was synthesized according to the synthetic route provided in this example with reference to step S8 in example 1 to give 1.14g of compound n8 in 94.0% yield, compound n8 as a yellow solid, ESI (+) m/z=379.8 [ m+h ] + 。
S7: synthesis of Compound q8
Compound n8 (1.14 g,3.0 mmol) and compound p1 (424.2 mg,3.0 mmol) were weighed out and compound q8 was synthesized according to the synthetic route provided in this example by reference to step S9 of example 1 to yield 920mg of compound q8 in 63.4% yield, compound q8 was a pale yellow solid, ESI (+) m/z=484.6 [ m+h ]] + 。
S8: synthesis of Compound I-8
According to the synthetic route provided in this example, compound I-8 was synthesized by referring to step S10 in example 1 to give 40mg of compound I-8 in 24.5% yield, compound I-8 as a pale yellow solid, ESI (+) m/z=740.9 [ M+H ]] + 。
EXAMPLE 9 preparation of Compound I-9
Figure 874146DEST_PATH_IMAGE021
S1: synthesis of Compound c9
According to the synthetic route provided in this example, compound c9 was synthesized with reference to step S1 in example 1 to yield 3.0g of compound c9 in a yield of 57.0%, compound c9 was a yellow solid, ESI (+) m/z=264.3 [ m+h ]] + 。
S2: synthesis of Compound d9
Compound c9 (3.0 g,11.4 mmol) was weighed out and compound d9 was synthesized according to the synthetic route provided in this example with reference to step S2 in example 1 to give 2.5g of compound d9 in 94% yield, compound d9 as a yellow solid, ESI (+) m/z=234.3 [ m+h ]] + 。
S3: synthesis of Compound I-9
According to the synthetic route provided in this example, compound I-9 was synthesized by referring to step S10 in example 1 to yield 39mg of compound I-9 in 27.7% yield, compound I-9 was a pale yellow solid, ESI (+) m/z=641.7 [ M+H ]] + 。
EXAMPLE 10 preparation of Compound I-10
Figure 277445DEST_PATH_IMAGE022
S1: synthesis of Compound I-10
According to the synthetic route provided in this example, compound I-10 was synthesized by referring to step S10 in example 1 to give 40.5mg of compound I-10 in a yield of 27.9%, compound I-10 as a pale yellow solid, ESI (+) m/z=659.7 [ M+H ]] + 。
EXAMPLE 11 preparation of Compound I-11
Figure 598705DEST_PATH_IMAGE023
S1: synthesis of Compound c11
According to the synthetic route provided in this example, compound c11 was synthesized with reference to step S1 in example 1 to obtain2.8g of compound c11 in a yield of 48.1% and compound c11 as a yellow solid, ESI (+) m/z=292.3 [ M+H ]] + 。
S2: synthesis of Compound d11
Compound c11 (2.8 g,9.6 mmol) was weighed out and compound d11 was synthesized according to the synthetic route provided in this example with reference to step S2 in example 1 to give 2.4g of compound d11 in 95.7% yield, compound d11 as a yellow solid, ESI (+) m/z=262.3 [ m+h ]] + 。
S3: synthesis of Compound I-11
According to the synthetic route provided in this example, compound I-11 was synthesized by referring to step S10 in example 1 to yield 42mg of compound I-11 in 28.5% yield, compound I-11 was a pale yellow solid, ESI (+) m/z=669.8 [ M+H ] ] + 。
EXAMPLE 12 preparation of Compound I-12
Figure 353035DEST_PATH_IMAGE024
S1: synthesis of Compound I-12
According to the synthetic route provided in this example, compound I-12 was synthesized by referring to step S10 in example 1 to yield 38.5mg of compound I-12 in 25.5% yield, compound I-12 was a pale yellow solid, ESI (+) m/z=687.8 [ M+H ]] + 。
EXAMPLE 13 preparation of Compound I-13
Figure 903096DEST_PATH_IMAGE025
S1: synthesis of Compound c13
According to the synthetic route provided in this example, compound c13 was synthesized with reference to step S1 in example 1 to yield 3.25g of compound c13 in a yield of 50.9%, compound c13 was a yellow solid, ESI (+) m/z=320.4 [ m+h] + 。
S2: synthesis of Compound d13
Compound c13 (3.25 g,10.2 mmol) was weighed out and the synthesis provided according to this exampleCompound d13 was synthesized according to step S2 of example 1 to yield 2.66g of compound d13 in 90.1% yield, compound d13 being a yellow solid, ESI (+) m/z=290.4 [ m+h] + 。
S3: synthesis of Compound I-13
According to the synthetic route provided in this example, compound I-13 was synthesized by referring to step S10 in example 1 to yield 44.6mg of compound I-13 in 29.1% yield, compound I-13 was a pale yellow solid, ESI (+) m/z=697.8 [ M+H ]] + 。
EXAMPLE 14 preparation of Compound I-14
Figure 426481DEST_PATH_IMAGE026
S1: synthesis of Compound I-14
According to the synthetic route provided in this example, compound I-14 was synthesized by referring to step S10 of example 1 to yield 40.2mg of compound I-14 in 25.6% yield, compound I-14 was a pale yellow solid, ESI (+) m/z=715.8 [ M+H ]] + 。
EXAMPLE 15 preparation of Compound I-15
Figure 918642DEST_PATH_IMAGE027
Figure 894689DEST_PATH_IMAGE028
S1: synthesis of Compound h15-2
50 mLN, N-Dimethylformamide (DMF), compound h15-1 (5 g,21.2 mmol) and N, N-diisopropylethylamine (DIEA, 8.21g,63.5 mmol) were added to a 100mL three-necked flask under nitrogen protection, 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (HATU, 17.69g,46.5 mmol) was added at a controlled temperature of 0 to 10℃and stirred at room temperature for 12h, TLC was monitored to react, 50mL of purified water was added after the reaction was completed, and extraction was performed three times with ethyl acetate with a volume of 75mL ethyl acetate for each extraction, andand the organic phase was washed with 50mL of saturated sodium chloride, then dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (column chromatography eluting with Petroleum Ether (PE): ethyl Acetate (EA) =2:1) to give 4.3g of compound h15-2 in 69.5% yield as a white solid, ESI (+) m/z=292.5 [ m+h ] ] + 。
S2: synthesis of Compound h15-4
To a 250mL single-necked flask, 64mL of 1, 4-dioxane and 19mL of purified water were added, and stirred at room temperature, followed by sequential addition of Compound h15-2 (4.3 g,14.7 mmol), compound h15-3 (3.2 g,16.2 mmol), cesium carbonate (Cs) 2 CO 3 9.61g,29.5 mmol) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (Pd (dppf) Cl) 2 1.07g,1.47 mmol) in the reaction system, air was pumped out under nitrogen protection, nitrogen was replaced three times, the reaction flask was moved to an oil bath under nitrogen atmosphere, reacted at 80 ℃ for 2 hours, removed from the oil bath, cooled to room temperature, TLC monitored the reaction, after completion of the reaction, 40mL of purified water was added to the reaction system to quench the reaction, extraction was performed three times with ethyl acetate, the volume of ethyl acetate used for each extraction was 100mL, the organic phases were combined, the organic phases were washed with 40mL of saturated sodium chloride, and then dried over anhydrous sodium sulfate, concentrated under reduced pressure, column chromatography (column chromatography elution polarity: PE: ea=2:1) to give 2.6g of compound h15-4 in 62.6% yield, compound h15-4 as a white solid, ESI (+) m/z=283.7 [ m+h ]] + 。
S3: synthesis of Compound h15-5
Adding a compound h15-4 (2.5 g,8.84 mmol) into a 50mL single-port bottle, then adding 25mL trifluoroacetic acid, transferring the reaction bottle into an oil bath kettle, reacting at 100 ℃ for 12h, removing the oil bath kettle, cooling to room temperature, monitoring the reaction by TLC, concentrating under reduced pressure, adding saturated sodium bicarbonate into concentrated solution until the pH value is 7-8, extracting three times by ethyl acetate, wherein the volume of ethyl acetate used for each extraction is 100mL, merging organic phases, drying by anhydrous sodium sulfate, concentrating under reduced pressure, separating by column chromatography (column chromatography elution polarity: PE: EA=3:1), and obtaining 1.3g of a compound h15-5, wherein the yield is 81.5%, and the compound h15-5 is White solid, ESI (+) m/z=181.5 [ m+h ]] + 。
S4: synthesis of Compound h15-6
To a 50mL single flask under nitrogen protection were added 20mL of Dichloromethane (DCM), compound h15-5 (1.23 g,6.81 mmol) and N-bromosuccinimide (NBS, 1.45g,8.17 mmol), the reaction was stirred at room temperature for 1h, TLC was monitored, after completion of the reaction, the solid was filtered and collected to give 1.2g of compound h15-6 in 67.9% yield as a pale yellow solid, ESI (+) m/z=260.4 [ M+H ]] + 。
S5: synthesis of Compound h15-7
To a 50mL three-necked flask under nitrogen atmosphere were added 25mL of methylene chloride, compound h15-6 (1.5 g,5.78 mmol) and triethylamine (TEA, 1.17g,11.6 mmol), the flask was transferred to a low temperature reactor, and trifluoromethanesulfonic anhydride (Tf) was added dropwise at-78deg.C 2 O,6.52g,23.1 mmol), stirring the reaction flask at-78deg.C for 30min, then moving to room temperature, continuing stirring for 1h, TLC monitoring reaction, adding 15mL ice water into the reaction flask, quenching reaction, extracting three times with dichloromethane, each time with dichloromethane volume of 30mL, combining organic phases, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and column chromatography (column chromatography eluting polarity: PE: ea=20:1) to give 2.2g of compound h15-7 in 97.2% yield, compound h15-7 as a white solid, ESI (+) m/z=392.5 [ m+h ] ] + 。
S6: synthesis of Compound h15-8
To a 50mL three-necked flask under nitrogen, 21mL of acetonitrile, compound h15-7 (1.2 g,3.07 mmol) and sodium iodide (NaI, 2.30g,15.3 mmol) were added. The reaction flask was transferred to a low temperature reactor, the temperature was controlled at 0℃and trifluoromethanesulfonic acid (CF) was added dropwise to the reaction system 3 SO 3 H,0.92g,6.13 mmol) in acetonitrile (3 mL) and the reaction was moved to room temperature and stirred for 2H. TLC monitoring the reaction, after the reaction, adding 15mL of ice water to the reaction flask to quench the reaction, extracting three times with ethyl acetate, each with a volume of 30mL, combining the organic phases, drying over anhydrous sodium sulfate, concentrating under reduced pressure, and column chromatography (columnChromatographic elution polarity: PE: ea=20:1) to yield 730mg of compound h15-8 in 64.4% yield, compound h15-8 as a earthy yellow solid, ESI (+) m/z=370.3 [ m+h ]] + 。
S7: synthesis of Compound h15-9
To a 50mL single port flask were added 12mL of 1, 4-dioxane and 1.2mL of purified water, stirred at room temperature, then compound h15-8 (0.6 g,1.62 mmol), pinacol isopropenylborate (279 mg,1.62 mmol), potassium carbonate (450 mg,3.25 mmol) and Pd (dppf) Cl were added sequentially 2 (117 mg,0.16 mmol). Under the protection of nitrogen, air in the system is pumped out by a pump, nitrogen is replaced for three times, the reaction bottle is moved to an oil bath pot under the nitrogen environment, the reaction is carried out for 2 hours at 80 ℃, the oil bath pot is moved out, the temperature is reduced to room temperature, TLC monitors the reaction, after the reaction is finished, 6mL of purified water is added to the reaction system for quenching reaction, the ethyl acetate is extracted for three times, the volume of ethyl acetate used for each extraction is 15mL, organic phases are combined, 10mL of saturated sodium chloride is used for washing the organic phases, then anhydrous sodium sulfate is used for drying, reduced pressure concentration is carried out, column chromatography (elution polarity of the column chromatography: PE: EA=2:1) is separated, 0.35g of compound h15-9 is obtained, the yield is 76.2%, the compound h15-9 is white solid, ESI (+) m/z=284.5 [ M+H ] ] + 。
S8: synthesis of Compound h15
To a 50mL single port flask, 8mL of ethyl acetate was added and stirred at room temperature, and Compound h15-9 (400 mg,1.41 mmol) and PtO were added 2 (40 mg,0.1 w/w), air was removed from the system by pumping, hydrogen was replaced three times, the reaction was carried out at room temperature under a hydrogen atmosphere for 3 hours, TLC was monitored, after the completion of the reaction, the filtrate was filtered, collected, and concentrated under reduced pressure to give 320mg of Compound h15, yield 79.5%, compound h15 was a yellow solid, ESI (+) m/z=286.5 [ M+H ]] + 。
S9: synthesis of Compound j15
Compound h15 (233 mg,0.82 mmol) and compound g1 (120 mg,0.82 mmol) were dissolved in 20mL of 1, 4-dioxane, and tris dibenzylideneacetone dipalladium (73 mg,0.08 mmol), 2 '-bis (diphenylphosphine) -1,1' -binaphthyl (100 mg,0.16 mmol) and cesium carbonate (730 mg,1.6 mm) were added at room temperatureMol) under nitrogen protection, heating to reflux and stirring for 4 hours, TLC monitoring the reaction, concentrating under reduced pressure to remove the solvent after the reaction is finished, adding 20mL of purified water, extracting three times with ethyl acetate, wherein the volume of ethyl acetate used for each extraction is 10mL, combining organic phases, washing the organic phases with 10mL of purified water and 20mL of saturated saline water successively, drying with anhydrous sodium sulfate, concentrating under reduced pressure, separating by column chromatography to obtain 184mg of compound j15, the yield is 63.8%, the compound j15 is light yellow solid, ESI (+) m/z=352.8 [ M+H ] ] + 。
S10: synthesis of Compound q15
Compound j15 (184 mg,0.52 mmol) was dissolved in 3mL of 1, 4-dioxane (73.5 mg,0.52 mmol), and tris dibenzylideneacetone dipalladium (46 mg,0.05 mmol), 2 '-bis (diphenylphosphine) -1,1' -binaphthyl (62 mg,0.1 mmol) and cesium carbonate (326 mg,1 mmol) were added at room temperature, the reaction was monitored by heating to reflux under nitrogen protection with stirring for 4h, TLC, after the completion of the reaction, concentrated under reduced pressure to remove the solvent, 20mL of purified water was added, extracted three times with ethyl acetate, the volume of ethyl acetate used for each extraction was 10mL, the organic phases were combined, washed with 20mL of purified water and 20mL of saturated saline, then dried with anhydrous sodium sulfate, concentrated under reduced pressure, separated by column chromatography to give 150mg of compound q15, the yield was 63.2%, compound q15 was a pale yellow solid, ESI (+) m/z=457.5 M+H] + 。
S11: synthesis of Compound I-15
According to the synthetic route provided in this example, compound I-15 was synthesized with reference to step S10 in example 1 to give 48mg of compound I-15 in a yield of 30.6%, compound I-15 as a pale yellow solid, ESI (+) m/z=713.8 [ m+h ]] + 。
EXAMPLE 16 preparation of Compound I-16
Figure 435391DEST_PATH_IMAGE029
S1: synthesis of Compound q16
Weighing Compound j15 (184 mg,0.52 mmol) and Compoundp2 (83 mg,0.52 mmol) was dissolved in 3mL of 1, 4-dioxane and compound q16 was synthesized according to the synthetic route provided in this example and with reference to step S9 of example 1 to give 166mg of compound q16 in 67.3% yield, compound q16 as a pale yellow solid, ESI (+) m/z=475.5 [ M+H ]] + 。
S2: synthesis of Compound I-16
According to the synthetic route provided in this example, compound I-16 was synthesized by referring to step S10 in example 1 to yield 50.2mg of compound I-16 in a yield of 31.2%, compound I-16 was a pale yellow solid, ESI (+) m/z=731.8 [ M+H ]] + 。
EXAMPLE 17 preparation of Compound I-17
Figure 891912DEST_PATH_IMAGE030
S1: synthesis of Compound I-17
According to the synthetic route provided in this example, compound I-17 was synthesized by referring to step S10 in example 1 to yield 39mg of compound I-17 in 27.6% yield, compound I-17 was a pale yellow solid, ESI (+) m/z=642.7 [ M+H ]] + 。
EXAMPLE 18 preparation of Compound I-18
Figure 227078DEST_PATH_IMAGE031
S1: synthesis of Compound I-18
According to the synthetic route provided in this example, compound I-18 was synthesized by referring to step S10 of example 1 to give 45mg of compound I-18 in a yield of 31.0%, compound I-18 was a pale yellow solid, ESI (+) m/z=660.7 [ M+H ] ] + 。
EXAMPLE 19 preparation of Compound I-19
Figure 18317DEST_PATH_IMAGE032
S1: synthesis of Compound q19
Compound j15 (184 mg,0.52 mmol) and compound p19 (81 mg,0.52 mmol) were dissolved in 3mL of 1, 4-dioxane, and compound q19 was synthesized according to the synthetic route provided in this example with reference to step S9 of example 1 to give 135mg of compound q19 in 55.2% yield as a pale yellow solid, ESI (+) m/z=471.5 [ M+H ]] + 。
S2: synthesis of Compound I-19
According to the synthetic route provided in this example, compound I-19 was synthesized by referring to step S10 in example 1 to give 24mg of compound I-19 in 15.0% yield, compound I-19 as a pale yellow solid, ESI (+) m/z=727.9 [ M+H ]] + 。
EXAMPLE 20 preparation of Compound I-20
Figure 97131DEST_PATH_IMAGE033
S1: synthesis of Compound q20
Compound j15 (184 mg,0.52 mmol) and compound p20 (86.4 mg,0.52 mmol) were weighed and dissolved in 3ml 1, 4-dioxane, and compound q20 was synthesized according to the synthetic route provided in this example with reference to step S9 in example 1 to give 150mg of compound q20 in 60.0% yield, compound q20 as a pale yellow solid, ESI (+) m/z=482.5 [ m+h ]] + 。
S2: synthesis of Compound I-20
According to the synthetic route provided in this example, compound I-20 was synthesized by referring to step S10 in example 1 to give 40mg of compound I-20 in a yield of 24.6%, compound I-20 was a pale yellow solid, ESI (+) m/z=738.8 [ M+H ] ] + 。
Experimental examples, EGFR kinase in vitro Activity test
Fourth generation EGFR-TKIs Brigatinib (Bugatinib) and the compounds I-1 to I-20 prepared in examples 1 to 20 above were each diluted 4-fold in a gradient starting at 10000nM with 100% DMSO (dimethyl sulfoxide) (total 9 concentrations). Brigatinib and compounds I-1 to I-20 were each 50-fold diluted into 1X kinase reaction buffer and shaken on a shaker for 20 minutes. By usingPreparation of kinase response buffer of 1X 2 XEGFR Wt 、EGFR （d746-750 T790M C797S） 、EGFR （T790M L858R C797S） Kinase and 4x atp&And (5) a mixed solution. 2. Mu.L of EGFR kinase prepared as described above and 1. Mu.L of the compound diluted in buffer were added to each well of 384 reaction plates, the plates were sealed with a sealing plate membrane, centrifuged at 1000g for 30 seconds, and left at room temperature for 10 minutes. To 384 reaction plates, 1. Mu.L of the 4 Xsubstrate mixture prepared above was added, the plates were sealed with a seal plate membrane, centrifuged at 1000g for 30 seconds, and reacted at room temperature for 60 minutes. Transfer 4. Mu.L ADP-Glo to 384 reaction plates, centrifuge 1min at 1000rpm/min and incubate at 25℃for 40min. Transfer 8. Mu.L of the detection solution to 384 reaction plates, centrifuge for 1min at 1000rpm/min, and incubate for 40min at 25 ℃. RLU (Relative luminescence unit) signals were read using a Biotek multifunctional plate reader, and signal intensity was used to characterize the extent of kinase activity. Data IC of this compound was calculated using grafit6.0 software (Erithacus Software) 50 Value, IC 50 The specific results of the values are shown in Table 1. The activity results are indicated by letter A in the 0.1-10nM range, the activity results are indicated by letter B in the 10nM-100nM range, the activity results are indicated by letter C in the 100nM-1uM range, and greater than 1uM is indicated by letter D.
TABLE 1
Figure 595108DEST_PATH_IMAGE034
Generally, EGFR Wt The larger the activity result of the compound is, the worse the inhibition effect of the compound on wild EGFR is, the better the selectivity of the predicted compound is, and the smaller the toxic and side effects possibly occur clinically; EGFR (epidermal growth factor receptor) （d746-750 T790M C797S） And EGFR (epidermal growth factor receptor) （T790M L858R C797S） The smaller the activity results, the more active the compound is shown to be effective against both triple mutant resistances.
As can be seen from Table 1, the EGFR of the compounds I-1 to I-20 provided in the examples of the present invention Wt The activity results of (C) or (D), i.e., 100nM-1uM, or greater than 1uM, in particular EGFR of compounds I-9 to I-20 Wt The activity result of (a) can reach D, phaseEGFR compared to comparative example (Bugetinib) Wt (the activity result is C), the selectivity is better, the possible toxic and side effects in clinic are smaller, and the problems of serious toxic and side effects, such as rash, and the like, of patients caused by strong inhibition of wild EGFR can be well reduced in the aspect of medicine application. In addition, the EGFR of the compounds I-1 to I-20 provided by the embodiment of the invention （d746-750 T790M C797S） And EGFR (epidermal growth factor receptor) （T790M L858R C797S） The smaller the activity results, the compounds provided by the examples of the present invention are effective against both these three mutations. On the premise of achieving the same therapeutic effect, the dosage can be greatly reduced, thereby greatly reducing other toxic and side effects caused by the medicine. Wherein the EGFR of the compounds I-14, I-16, I-20 provided in the examples of the present invention （d746-750 T790M C797S） And EGFR (epidermal growth factor receptor) （T790M L858R C797S） The activity results of the three-mutation-resistant drug are 0.1-10nM, and the three-mutation-resistant drug is effective for the two three-mutation-resistant drugs and has higher inhibition activity.
The above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present invention, and are intended to be included in the scope of the present invention.

Claims (7)

1. A compound having the structure of formula i:
Figure QLYQS_1
wherein W represents carbon or nitrogen, Q represents carbon, Y represents nitrogen, Z represents oxygen;
R 1 Represents methyl, R 2 Represents hydrogen, fluorine, cyano or methyl;
R 3 represents substituted or unsubstituted C 1 -C 4 An alkyl group;
R 4 represents substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 3 -C 7 A heterocyclic group;
A 1 、A 2 the linkage representing substituted or unsubstituted C 3 -C 7 Heterocyclyl or C 5 -C 12 A heterospiro ring;
A 3 represents substituted or unsubstituted C 3 -C 7 A heterocyclic group;
the compound with the structure shown in the formula I is selected from the following compounds:
Figure QLYQS_2
/>
Figure QLYQS_3
Figure QLYQS_4
/>
Figure QLYQS_5
Figure QLYQS_6
。
2. the process for the preparation of a compound having the structure of formula i or a pharmaceutically acceptable salt thereof according to claim 1, comprising the steps of:
Figure QLYQS_7
in W, Q, Y, Z, A 1 、A 2 、A 3 、R 1 、R 2 、R 3 、R 4 Is defined as pair W, Q, Y, Z, A in claim 1 1 、A 2 、A 3 、R 1 、R 2 、R 3 、R 4 Is defined as follows;
synthesis of intermediate v:
reacting a compound II with a structure of formula II with a compound III with a structure of formula III in a first solvent in the presence of a first catalyst, a first base and a first ligand at a first reaction temperature to produce an intermediate V with a structure of formula V;
synthesis of intermediate vii:
reacting the intermediate IV with the structure of the formula IV with a compound V with the formula V in a second solvent in the presence of a second catalyst, a second base and a second ligand at a second reaction temperature to generate an intermediate VII with the structure of the formula VII;
Synthesis of Compound I:
intermediate VI having the structure of formula VI is reacted with compound VII having the structure of formula VII in a third solvent in the presence of a third base at a third reaction temperature to produce compound I having the structure of formula I.
3. The method for preparing a compound having the structure of formula i or a pharmaceutically acceptable salt thereof according to claim 2, wherein in the step of synthesizing intermediate v, the first reaction temperature is 50 ℃ to 120 ℃;
the first catalyst is at least one of dibenzylidene acetone dipalladium, palladium acetate, and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride and tetraphenylphosphine palladium;
the first alkali is at least one of sodium acetate, potassium acetate, sodium carbonate, potassium phosphate, cesium carbonate, sodium tert-butoxide and potassium tert-butoxide;
the first ligand is at least one of 2,2 '-bis (diphenylphosphine) -1,1' -binaphthyl and 4, 5-bis-diphenylphosphine-9, 9-dimethyl xanthene;
the first solvent is at least one of N, N-dimethylformamide, 1, 4-dioxane and N-methylpyrrolidone;
in the step of synthesizing the intermediate VII, the second reaction temperature is 50-120 ℃;
The second catalyst is at least one of dibenzylidene acetone dipalladium, palladium acetate, and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride and tetraphenylphosphine palladium;
the second alkali is at least one of sodium acetate, potassium acetate, sodium carbonate, potassium phosphate, cesium carbonate, sodium tert-butoxide and potassium tert-butoxide;
the second ligand is at least one of 2,2 '-bis (diphenylphosphine) -1,1' -binaphthyl and 4, 5-bis-diphenylphosphine-9, 9-dimethyl xanthene;
the second solvent is at least one of N, N-dimethylformamide, 1, 4-dioxane and N-methylpyrrolidone;
in the synthesis step of the compound I, the third reaction temperature is 135-145 ℃;
the third base is N, N-diisopropylethylamine, triethylamine, 1, 8-diazabicyclo undec-7-ene;
the third solvent is at least one of N-methyl pyrrolidone, 1, 4-dioxane, N-dimethylformamide, N-dimethylacetamide and dimethyl sulfoxide.
4. A pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group consisting of compounds having the structure of formula i according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
5. A novel EGFR-TKIs comprising a therapeutically effective amount of a compound selected from the group consisting of compounds having the structure of formula i as defined in claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
6. Use of a compound having the structure of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 4, or a novel EGFR-TKIs according to claim 5, for the manufacture of a medicament for the prevention and/or treatment of cancer.
7. The use according to claim 6, wherein the cancer is selected from skin cancer, bladder cancer, ovarian cancer, breast cancer, gastric cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, rectal cancer, esophageal cancer, tongue cancer, kidney cancer, cervical cancer, uterine body cancer, endometrial cancer, testicular cancer, urinary cancer, melanoma, astrocytoma, meningioma, hodgkin's lymphoma, non-hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, adult T-cell leukemia lymphoma, hepatocellular carcinoma, bronchogenic cancer, multiple myeloma, basal cell tumor, seminoma, chondrosarcoma, myosarcoma, fibrosarcoma.
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