CN113527215A

CN113527215A - Quinazoline compound, preparation method and application thereof

Info

Publication number: CN113527215A
Application number: CN202110395019.0A
Authority: CN
Inventors: 张强; 杨磊夫
Original assignee: Beijing Scitech MQ Pharmaceuticals Ltd
Current assignee: Beijing Scitech MQ Pharmaceuticals Ltd
Priority date: 2020-04-17
Filing date: 2021-04-13
Publication date: 2021-10-22
Anticipated expiration: 2041-04-13
Also published as: CN113527215B

Abstract

The invention provides a quinazoline compound, a preparation method and application thereof, and particularly relates to a compound shown in a formula (I), an isomer, a hydrate, a solvate, a pharmaceutically acceptable salt and a prodrug thereof, a preparation method and application thereof in preparation of a medicament serving as a tyrosine kinase inhibitor. The compound has good inhibitory activity to EGFR and HER2 kinase, and simultaneously shows excellent performance of penetrating blood brain barrier.

Description

Quinazoline compound, preparation method and application thereof

Technical Field

The invention belongs to the technical field of medicines, and relates to a quinazoline compound, a preparation method and application thereof.

Background

An Epidermal Growth Factor Receptor (EGFR) is a transmembrane glycoprotein, belongs to a tyrosine kinase receptor family, has very wide expression and plays an important role in growth and development and normal physiological function activities. In addition, EGFR and its mediated signaling pathways play an important role in the development and progression of tumors. However, EGFR expression is unstable, and gene amplification and rearrangement frequently occur, resulting in a change in the antigen phenotype on the surface of tumor cells, most commonly referred to as epidermal growth factor receptor type III mutant (EGFRvIII).

EGFRvIII is a recently discovered class of mutants of the Epidermal Growth Factor Receptor (EGFR) that are only expressed on the surface of tumor cells, but not normal tissue cells. Aberrant expression of EGFR has been associated with the development of numerous malignancies, including gliomas, small cell lung carcinoma, breast cancer, bladder cancer, ovarian cancer, and the like.

Compared with the complete structure of EGFR, the 2 nd-7 th exons for coding the EGFRvIII extracellular ligand binding region are deleted, so that 801 base pairs are deleted, exons 1 and 8 are connected, a new glycine is generated at the binding site, the 6 th-273 th amino acids of the new glycine are deleted, and the capability of binding with the EGF is lost. EGFRvIII enables the tyrosine kinase to be subjected to unregulated structural activation in a dimerization and autophosphorylation way under the condition of no ligand combination, induces downstream signal transduction and stimulates the proliferation of tumor cells.

Research has shown that: EGFRvIII can influence the generation and development of tumors by regulating various signal transmission pathways, including Ras/Raf/MEK/ERK, PI3/AKT/mTOR, JAK/STAT, PLC/PKC and the like. The tumor tumorigenicity of the EGFRvIII positive tumor cells is obviously improved, and the uncontrollable spontaneous proliferation and metastasis of the tumor cells are caused mainly by inhibiting apoptosis, promoting tumor angiogenesis, increasing invasiveness, migration and the like. In addition, EGFRvIII functions like escape during radiotherapy and chemotherapy of tumors.

Gliomas are a common malignant tumor with high invasiveness, and Glioblastoma (GBM) is the most malignant type. The effects of radiotherapy and chemotherapy are not ideal, and relapse often occurs after operation. The research at home and abroad finds that: 40% -60% of GBM remarkably expresses EGFR, and the mutant form of the GBM mainly takes EGFRvIII. EGFRvIII establishes a signal channel regulation network through receptor-independent autophosphorylation and tyrosine kinase activity, and plays an important role in regulating the growth, transfer and angiogenesis of GBM.

Recent studies find that the EGFRvIII molecular targeted therapeutic measures show good antitumor effect in vitro cell culture and in vivo animal model studies. Therefore, the development of new EGFRvIII molecule-targeted therapeutic drugs will provide more effective and economical treatment protocols for tumor patients, especially for glioma patients, and there is a great unmet clinical need.

Drugs targeting EGFRvIII for the treatment of gliomas need to be able to effectively penetrate the blood-brain barrier, while also being able to effectively inhibit EGFRvIII. At present, no report exists on the compound which can penetrate a blood brain barrier and inhibit EGFRvIII, so that the research on glioma driven by EGFRvIII has important clinical value. In addition, most of the EGFR and HER2 kinase inhibitors that are marketed do not penetrate the blood brain barrier, whereas EGFR-driven lung cancer and HER 2-driven breast cancer patients generally have a poor prognosis and a high risk of brain metastases. There is currently no approved effective drug for brain metastasis therapy, and therefore there is a strong need to develop an EGFR inhibitor and/or HER2 inhibitor that has blood brain barrier penetration.

Disclosure of Invention

The invention provides a compound shown in formula (I), an isomer, a hydrate, a solvate, a pharmaceutically acceptable salt and a prodrug thereof,

in the formula (I), m is 0, 1 or 2;

a is halogen, C₁-C₃An alkyl group; z is NH or O;

R₁is hydrogen, hydroxy, 4-7 membered heteroalicyclic or-NR^aR^b，

R^a、R^bEach independently is hydrogen, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, C substituted by hydroxy₁-C₆Alkyl radical, C_1-C₃Alkoxy-substituted C₁-C₆Alkyl, or by C_3-C₆Cycloalkyl-substituted C₁-C₆An alkyl group;

the 4-7-membered heteroalicyclic group is a heteroalicyclic group containing 1-2 heteroatoms selected from N, O or S, which is unsubstituted or C₁-C₃Alkyl radical, C₁-C₄Alkanoyl, hydroxy, cyano, aminoacyl, mono-or disubstituted C₁-C₃Aminoacyl, C_1-C₃Alkyl sulfone group, C_1-C₃Alkyl sulfoxide, oxo (═ o)O) or two of them;

R₂、R₃、R₄、R₅、R₆each independently of the others is hydrogen, halogen, C₁-C₆Alkyl, -O- (CH)₂)n-R₇，

R₇Is hydrogen, C₁-C₃Alkyl, substituted by 1 to 3 substituents selected from halogen, cyano, hydroxy, C₁-C₃Alkyl radical, C₁-C₃Alkoxy, halo C₁-C₃Alkyl radical, C₃-C₄Cycloalkyl radical, C₂-C₃Alkynyl, C₂-C₃Aryl or heteroaryl substituted or unsubstituted by a substituent in an alkenyl or-NR 'R', n is an integer of 0 to 3,

the aryl group is a monocyclic or bicyclic group having 6 to 12 carbon ring atoms and having at least one aromatic ring, the heteroaryl group is a monocyclic or bicyclic group having 1 to 3 heteroatoms selected from N, O, S as ring atoms and having 5 to 10 ring atoms,

r 'and R' are each independently H or C₁-C₃Alkyl group of (1).

Or, when m is 1, the compound of formula (I) has the following general formula (II),

in the formula (II), A is halogen and C₁-C₃An alkyl group; z is NH or O;

R₁is hydrogen, hydroxy, 4-7 membered heteroalicyclic or-NR^aR^b，

the 4-7 membered heteroalicyclic group isHeteroalicyclic comprising 1-2 heteroatoms selected from N, O or S, said heteroalicyclic being unsubstituted or substituted by C₁-C₃Alkyl radical, C₁-C₄Alkyl acyl, amino acyl, hydroxy, cyano, mono-or disubstituted C₁-C₃Aminoacyl, C_1-C₃Alkyl sulfone group, C_1-C₃One or two of alkyl sulfoxide group and oxo (═ O) are substituted;

r 'and R' are each independently H or C₁-C₃Alkyl group of (1).

According to a preferred embodiment, a is Cl, F or methyl; z is NH.

More preferably, a is Cl; z is NH.

According to a preferred embodiment, R₁Is a 4-7 membered heterocyclic group or-NR^aR^b，

R^a、R^bEach independently is hydrogen, C₁-C₃Alkyl, C substituted by hydroxy₁-C₃Alkyl radical, C₁-C₃Alkoxy-substituted C₁-C₃An alkyl group;

the 4-7-membered heteroalicyclic group is pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, tetrahydrofuryl, tetrahydropyranyl, thiomorpholinyl, and the above groups are unsubstituted or substituted by one or two of methyl, ethyl, propyl, isopropyl, aldehyde, acetyl, propionyl, hydroxyl, cyano, aminoacyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, methylsulfonyl, ethylsulfoxide, propylsulfoxide, isopropylsulfoxide, and oxo (═ O).

More preferably, R₁Is pyrrolidin-1-yl, piperidin-1-yl, 1-methylpiperazin-4-yl, 1-ethylpiperazin-4-yl, morpholinyl, tetrahydrofuran 2-yl, tetrahydrofuran 3-yl, tetrahydropyran 2-yl, tetrahydropyran 3-yl, thiomorpholinyl, dimethylamino, diethylamino, dipropylamino, diisopropylamino, methylethylamino, methylpropylamino or ethylpropylamino.

Most preferably, R₁Is dimethylamino.

According to a preferred embodiment, m is 0 or 1,

R₁is 4-7 membered heteroalicyclic or-NR^aR^b，

R^a、R^bEach independently is hydrogen, C₁-C₃Alkyl radical, C₃-C₆A cycloalkyl group;

More preferably, m is 0 or 1,

R₁is 1-methyl-pyrrolidin-2-yl, 1-ethyl-pyrrolidin-2-yl, 1-isopropyl-pyrrolidin-2-yl, methylamino, ethylamino, propylamino, isopropylamino, cyclopropylamino, cyclobutylaminoMethyl isopropylamino, N-methyl-N-cyclopropylamino, N-methyl-N-cyclobutylamino, pyrrolidin-1-yl, piperidin-1-yl, 1-methylpiperazin-4-yl, 1-ethylpiperazin-4-yl, morpholinyl, tetrahydrofuran 2-yl, tetrahydrofuran 3-yl, tetrahydropyran 2-yl, tetrahydropyran 3-yl, thiomorpholinyl, dimethylamino, diethylamino, dipropylamino, diisopropylamino, methylethylamino, methylpropylamino or ethylpropylamino.

According to another preferred embodiment, R₂、R₃、R₄、R₅、R₆Each independently hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, -O- (CH)₂)n-R₇And R is₂、R₃、R₄、R₅、R₆At least 3 of which are hydrogen,

R₇is hydrogen, methyl, ethyl, propyl, isopropyl or an aryl or heteroaryl group substituted or unsubstituted by 1 to 3 substituents selected from fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, methoxy, ethoxy, fluoromethyl, fluoroethyl, trifluoromethyl, cyclopropyl, ethynyl, vinyl or-NR 'R', n is an integer from 0 to 3,

r 'and R' are respectively H or methyl,

the aryl is phenyl, and the heteroaryl is pyridyl, pyrimidyl, pyrrolyl, thienyl, furyl or imidazolyl.

More preferably, R₂、R₃、R₄、R₅、R₆Each independently of the others being hydrogen, fluorine, chlorine, -O- (CH)₂)n-R₇And R is₂、R₃、R₄、R₅、R₆At least 3 of which are hydrogen,

R₇is aryl or heteroaryl which is substituted or unsubstituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, methoxy, ethoxy, fluoromethyl, fluoroethyl, trifluoromethyl, n is an integer from 0 to 3,

the aryl group is phenyl and the heteroaryl group is pyridyl.

In othersIn a preferred embodiment, R₂、R₃、R₄、R₅、R₆Each independently is hydrogen, fluoro, chloro, phenoxy, 2-fluorophenoxy, 3-fluorophenoxy, 4-fluorophenoxy, pyridin-2-ylmethoxy, pyridin-3-ylmethoxy, pyridin-4-ylmethoxy, 3-fluorobenzyloxy, 2-fluorobenzyloxy, 4-fluorobenzyloxy, 3-chlorobenzyloxy, 2-chlorobenzyloxy, 4-chlorobenzyloxy, and R is₂、R₃、R₄、R₅、R₆At least 3 of which are hydrogen.

According to another preferred embodiment, R₂、R₃、R₅、R₆Each independently hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, R₄Is hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, -O- (CH)₂)n-R₇And R is₂、R₃、R₄、R₅、R₆At least 2 of which are hydrogen,

r 'and R' are respectively H or methyl,

the aryl is phenyl, and the heteroaryl is pyridyl, pyrimidyl, pyrrolyl, thienyl, furyl or imidazolyl;

alternatively, more preferably, R₂、R₃、R₅、R₆Each independently of the others being hydrogen, fluorine, chlorine, R₄Is hydrogen, fluorine, chlorine, phenoxy, 2-fluorophenoxy, 3-fluorophenoxy, 4-fluorophenoxy, pyridin-2-ylmethoxy, pyridin-3-ylmethoxy, pyridin-4-ylmethoxy, 3-fluorobenzyloxy, 2-fluorobenzyloxy, 4-fluorobenzyloxy, 3-chlorobenzyloxy, 2-chlorobenzyloxy, 4-chlorobenzyloxy, and R is₂、R₃、R₄、R₅、R₆At least 2 of which are hydrogen.

Typical compounds to which the present application relates are as follows:

another aspect of the present invention provides a pharmaceutical composition comprising a compound described herein, a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof, and one or more pharmaceutically acceptable carriers or excipients.

The pharmaceutical compositions of the present application may also comprise one or more other therapeutic agents.

The present invention also relates to a method of treating EGFR, HER2, etc. kinase-mediated diseases or disorders, including those mentioned above, comprising administering to a patient (human or other mammal, especially human) in need thereof a therapeutically effective amount of a compound described herein, or a salt thereof.

Detailed Description

Unless otherwise indicated, the following terms used in the present application (including the specification and claims) have the definitions given below. In this application, the use of "or" and "means" and/or "unless stated otherwise. Furthermore, the use of the terms "including" and other forms, such as "including", "comprising", and "having", are not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

Unless otherwise specified, alkyl represents a saturated straight-chain, branched-chain hydrocarbon radical having the indicated number of carbon atoms, the term C₁-C₁₀Alkyl represents an alkyl moiety containing from 1 to 10 carbon atoms, as with C₁-C₃Alkyl represents an alkyl moiety containing 1 to 3 carbon atoms, e.g. C₁-C₆Alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, and 2-methylpentyl groups and the like.

When substituent terms such as "alkyl" are used in combination with other substituent terms, for example, in the term "C₁-C₃Alkoxy radical C₁-C₆Alkylthio "or" hydroxy-substituted C₁-C₁₀In alkyl, "the linking substituent term (e.g., alkyl or alkylthio) is intended to encompass divalent moieties wherein the point of attachment is through the linking substituent. "C₁-C₃Alkoxy radical C₁-C₆Examples of alkylthio "include, but are not limited to, methoxymethylthio, methoxyethylthio, ethoxypropylthio, and the like. "hydroxy substituted C₁-C₁₀Examples of alkyl include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxyisopropyl, and the like.

Alkoxy is an alkyl-O-group formed from a straight or branched chain alkyl group previously described with-O-, for example, methoxy, ethoxy, and the like. Similarly, an alkylthio group is an alkyl-S-group formed from a straight or branched chain alkyl group previously described with-S-, for example, methylthio, ethylthio, and the like.

Alkenyl and alkynyl groups include straight-chain, branched alkenyl or alkynyl groups, the term C₂-C₆Alkenyl or C₂-C₆Alkynyl represents a straight or branched hydrocarbon group having at least one alkenyl or alkynyl group.

The term "haloalkyl", e.g. "halo C₁-C₁₀Alkyl "denotes a group having one or more halogen atoms which may be the same or different on one or more carbon atoms of the alkyl moiety including 1 to 10 carbon atoms. "halo C₁-C₁₀Examples of alkyl groups "may include, but are not limited to, -CF₃(trifluoromethyl), -CCl₃(trichloromethyl), 1-difluoroethyl, 2,2, 2-trifluoroethyl, hexafluoroisopropyl, and the like. Similarly, the term "halo C₁-C₁₀Alkoxy "denotes a group consisting of said halo C₁-C₁₀Of alkyl groups with-O-formationhaloalkyl-O-groups, which may be, for example, trifluoromethoxy, trichloromethoxy, and the like.

The term "C₁-C₃Acyl includes formyl (-CHO), acetyl (CH)₃CO-), acetyl (C)₂H₅CO-)。

"cycloalkyl" means a non-aromatic, saturated, cyclic hydrocarbon group containing the specified number of carbon atoms. For example, the term "(C)₃-C₆) Cycloalkyl "refers to a non-aromatic cyclic hydrocarbon ring having from 3 to 6 ring carbon atoms. Exemplary "(C)₃-C₆) Cycloalkyl "includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "aryl" denotes a group or moiety comprising an aromatic monocyclic or bicyclic hydrocarbon radical containing from 6 to 12 carbon ring atoms and having at least one aromatic ring. Examples of "aryl" are phenyl, naphthyl, indenyl and indanyl (indanyl). Typically, in the compounds of the present invention, aryl is phenyl.

The term "heteroalicyclic", as used herein, unless otherwise specified, represents an unsubstituted or substituted stable 4-to 8-membered non-aromatic monocyclic saturated ring system consisting of carbon atoms and 1 to 3 heteroatoms selected from N, O, S, wherein the N, S heteroatoms may be optionally oxidized and the N heteroatoms may be optionally quaternized. Examples of such heterocycles include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, 1, 3-dioxolanyl, piperidinyl, piperazinyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, 1, 3-dioxanyl, 1, 4-dioxanyl, 1, 3-oxathiolanyl, 1, 3-oxathianyl, 1, 3-dithianyl, 1, 4-oxathianyl, 1, 4-dithianyl, morpholinyl, thiomorpholinyl.

The term "heteroaryl" as used herein denotes a group or moiety comprising an aromatic monocyclic or bicyclic radical containing 5 to 10 ring atoms, which includes 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. The term also includes bicyclic heterocyclic aryl groups containing an aryl ring moiety fused to a heterocycloalkyl ring moiety, or a heteroaryl ring moiety fused to a cycloalkyl ring moiety. Unless otherwise specified, represents an unsubstituted or substituted stable 5-or 6-membered monocyclic aromatic ring system, and may also represent an unsubstituted or substituted 9-or 10-ring atom fused-benzene heteroaromatic ring system or bicyclic heteroaromatic ring system consisting of carbon atoms and from 1 to 3 heteroatoms selected from N, O, S, where the N, S heteroatom may be oxidized and the N heteroatom may also be quaternized. The heteroaryl group may be attached to any heteroatom or carbon atom to form a stable structure. Illustrative examples of heteroaryl groups include, but are not limited to, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridyl, oxo-pyridyl (pyridyl-N-oxide), pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, benzofuranyl, isobenzofuranyl, 2, 3-dihydrobenzofuranyl, 1, 3-benzodioxolyl, dihydrobenzodioxinyl, benzothienyl, indolizinyl, indolyl, isoindolyl, dihydroindolyl, benzimidazolyl, dihydrobenzimidazolyl, benzoxazolyl, dihydrobenzoxazolyl, benzothiazolyl, benzisothiazolyl, dihydrobenzisothiazolyl, indazolyl, imidazopyridinyl, pyrazolopyridyl, and the like, Benzotriazolyl, triazolopyridinyl, purinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, 1, 5-naphthyridinyl, 1, 6-naphthyridinyl, 1, 7-naphthyridinyl, 1, 8-naphthyridinyl, and pteridinyl.

The term "carbonyl" refers to the group-C (O) -. The terms "halogen" and "halo" represent a chloro, fluoro, bromo, or iodo substituent. "oxo" represents the oxygen moiety of a double bond; for example, if directly attached to a carbon atom, a carbonyl moiety (C ═ O) is formed. "hydroxyl" is intended to mean the radical-OH. The term "cyano" as used herein refers to the group-CN.

The term "each independently" means that when more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.

It is clear that the compounds of formula I, isomers, crystalline forms or prodrugs, and pharmaceutically acceptable salts thereof, may exist in solvated as well as unsolvated forms. For example, the solvated form may be water soluble. The present invention includes all such solvated and unsolvated forms.

The term "isomer" in this application is a different compound having the same molecular formula and may include various isomeric forms such as stereoisomers, tautomers and the like. "stereoisomers" are isomers that differ only in the arrangement of the atoms in space. Certain compounds described herein contain one or more asymmetric centers and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms which can be defined as (R) -or (S) -in terms of absolute stereochemistry. The chemical entities, pharmaceutical compositions and methods of the present invention are intended to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R) -and (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical activity of the compounds can be analyzed by any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other can be determined.

The individual isomers (or isomer-enriched mixtures) of the present invention can be resolved using methods known to those skilled in the art. For example, the splitting can be performed as follows: (1) by forming diastereomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer-specific reagent, for example by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support (e.g., silica gel with bound chiral ligand) or in the presence of a chiral solvent. One skilled in the art will appreciate that when the desired stereoisomer is converted to another chemical entity by one of the separation methods described above, additional steps are required to release the desired form. Alternatively, specific stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or one enantiomer may be converted to the other by asymmetric transformation.

When a compound described herein contains an olefinic double bond, it is meant that the compound includes various cis-trans isomers, unless otherwise specified.

"tautomers" are structurally different isomers that can be interconverted by tautomerization. "tautomerization" is a form of isomerization and includes proton shift or proton shift tautomerization, which can be considered a subset of acid-base chemistry. "proton shift tautomerization" or "proton shift tautomerization" involves the migration of protons with a shift in the bond order, often an interchange of a single bond with an adjacent double bond. When tautomerization is possible (e.g., in solution), chemical equilibrium of the tautomers can be reached. One example of tautomerization is keto-enol tautomerization.

The compounds of the present invention as active ingredients, as well as methods for preparing the compounds, are the subject of the present invention. Furthermore, some crystalline forms of the compounds may exist as polymorphs and as such may be included in the present invention. In addition, some compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also included within the scope of this invention.

The compounds of the invention may be used in therapy in free form or, where appropriate, in the form of pharmaceutically acceptable salts or other derivatives. As used herein, the term "pharmaceutically acceptable salts" refers to organic and inorganic salts of the compounds of the present invention which are suitable for use in humans and lower animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates, and other types of compounds are well known in the art. The salts may be formed by reacting a compound of the invention with a suitable free base or acid. Including, but not limited to, salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, or by using methods well known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, caproates, hydroiodides, 2-hydroxyethanesulfonates, lactobionates, lactates, laurates, laurylsulfates, malates, maleates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoate, pectinates, persulfates, per3-phenylpropionates, phosphates, picrates, propionates, stearates, sulfates, thiocyanates, P-toluenesulfonate, undecanoate, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include the appropriate non-toxic ammonium, quaternary ammonium, and amine-based cations formed using such salts as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

In addition, the term "prodrug" as used herein means that a compound can be converted in vivo to a compound described herein. This conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent compound in the blood or tissue.

The pharmaceutical compositions of the invention comprise a compound described herein, or a pharmaceutically acceptable salt thereof, a kinase inhibitor (small molecule, polypeptide, antibody, etc.), an immunosuppressive agent, an anti-cancer agent, an antiviral agent, an anti-inflammatory agent, an antifungal agent, an antibiotic, or an additional active agent that is an anti-vascular hyperproliferative compound; and any pharmaceutically acceptable carrier, adjuvant or vehicle.

The compounds of the present invention may be used alone or in combination with one or more other compounds of the present invention or with one or more other agents. When administered in combination, the therapeutic agents may be formulated for simultaneous administration or for sequential administration at different times, or the therapeutic agents may be administered as a single composition. By "combination therapy" is meant the use of a compound of the invention in combination with another agent, either by co-administration of each agent simultaneously or by sequential administration of each agent, in either case, for the purpose of achieving optimal effect of the drug. Co-administration includes simultaneous delivery dosage forms, as well as separate dosage forms for each compound. Thus, administration of the compounds of the invention may be used concurrently with other therapies known in the art, for example, radiation therapy or adjunctive therapies such as cytostatic agents, cytotoxic agents, other anti-cancer agents, etc. in the treatment of cancer to ameliorate the symptoms of the cancer. The present invention is not limited to the order of administration; the compounds of the invention may be administered previously, concurrently, or after other anti-cancer or cytotoxic agents.

To prepare the pharmaceutical compositions of this invention, one or more compounds or salts of formula (I) as the active ingredient may be intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation designed for administration by any convenient route, e.g. oral or parenteral. Suitable pharmaceutically acceptable carriers are well known in the art. A description of some of these pharmaceutically acceptable carriers can be found in the handbook of pharmaceutical excipients, which is published by the United states society of pharmacy and British pharmaceutical society.

The pharmaceutical compositions of the invention may be in a form, for example, suitable for oral administration, for example, as tablets, capsules, pills, powders, sustained release forms, solutions or suspensions; for parenteral injection such as clear solutions, suspensions, emulsions; or for topical application such as creams; or as suppositories for rectal administration. The pharmaceutical compositions may also be in unit dosage form suitable for single use administration of the precise dosage. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and the compound as an active ingredient prepared in accordance with the present invention, and may also include other medicinal or pharmaceutical agents, carriers, adjuvants, and the like.

Therapeutic compounds may also be administered to mammals other than humans. The dosage of the drug administered to a mammal will depend on the species of the animal and its disease state or disorder in which it is suffering. The therapeutic compound may be administered to the animal in the form of a capsule, bolus, tablet or solution. Therapeutic compounds may also be administered into the animal by injection or infusion. We prepared these pharmaceutical forms according to conventional means which meet the criteria of veterinary practice. Alternatively, the pharmaceutical composition may be mixed with animal feed for feeding to the animal, and thus, the concentrated feed supplement or premix may be prepared for mixing with conventional animal feed.

It is a further object of the present invention to provide a method for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a composition comprising a compound of the present invention.

The invention also includes the use of a compound of the invention, or a pharmaceutically acceptable derivative thereof, for the manufacture of a medicament for the treatment of cancer and autoimmune diseases associated with the tyrosine kinases EGFR, HER 2. Such cancers (including non-solid tumors, primary or metastatic cancers, as noted elsewhere herein and including one or more other treatments for which the cancer is resistant or refractory) as well as other diseases (including but not limited to ocular fundus disease, psoriasis, atheroma, pulmonary fibrosis, liver fibrosis, bone marrow fibrosis, etc.). Such cancers include, but are not limited to: non-small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumors, thyroid cancer, chronic myelogenous leukemia, acute myelogenous leukemia, non-hodgkin lymphoma, nasopharyngeal cancer, esophageal cancer, brain tumors, B-cell and T-cell lymphomas, lymphoma, multiple myeloma, biliary sarcoma, bile duct cancer.

Detailed Description

The present invention also provides methods for preparing the corresponding compounds, and the compounds described herein can be prepared using a variety of synthetic methods, including the methods described below, and the compounds of the present invention, or pharmaceutically acceptable salts, isomers, or hydrates thereof, can be synthesized using the methods described below, and synthetic methods known in the art of organic chemical synthesis, or by variations on these methods as understood by those skilled in the art, with preferred methods including, but not limited to, the methods described below.

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items. The examples provided below are intended to better illustrate the invention, all temperatures being in degrees Celsius unless otherwise indicated. The nomenclature of some of the compounds of the present application is translated according to the chemdraw nomenclature.

Synthesis of intermediates

Synthesis of acid intermediate: (E) synthesis of (E) -4- (diethylamino) but-2-enoic acid and (E) -4- (piperidin-1-yl) but-2-enoic acid

Take (E) -4- (diethylamino) but-2-enoic acid as an example. Under an argon atmosphere, 2g (27.34mM) of diethylamine and 20ml of THF were added to the flask, and 5g (27.93mM) of methyl bromate and 9g (69.63mM) of diisopropylethylamine were added under ice bath. Reacting for 3 hours, and extracting by using ethyl acetate and water; the solvent was removed by rotary evaporation and a liquid base (2g NaOH and 2ml H) was added to 20ml ethanol₂O), stirring for 3h, dropwise adding concentrated hydrochloric acid to adjust the pH value to 1-2, and concentrating under reduced pressure. Acetone (2) is added0ml) was recrystallized to yield a white solid.

Preparation of (R, E) -3- (1-methylpyrrolidin-2-yl) acryloyl chloride

Adding (R, E) -3- (1-methylpyrrolidin-2-yl) acrylic acid (160mg,1mmol) into dried dichloromethane (3ml), respectively adding oxalyl chloride (130mg,1mmol) and DMF (1 drop, catalytic amount), stirring at room temperature for 3 hours, and obtaining a white-like solid after the reaction system is turbid and becomes clear and is concentrated;

synthesis of amine intermediate B1-B5:

synthesis of 4- ((1H-benzo [ d ] [1,2,3] triazole-1-yl) oxy) -5-chloroquinazoline-6-amine

Conditions and reagents (a) EtOH, formamidine acetate, 80 ℃,8 h; (b) h₂SO₄,HNO₃-5 ℃ overnight; (c) CH (CH)₃OH,Fe,NH₄Cl,80 ℃, reflux/Ni, H₂,rt；(d)CH₃CN,BOP,DBU,rt

Cyclizing with formamidine acetate at 80 ℃ using 2-amino-6-chlorobenzoic acid as a starting material to give the compound 5-chloroquinazolin-4 (3H) -one, dissolving the compound in concentrated sulfuric acid solution, adding nitric acid at-10 ℃ and subjecting the resulting solution to column chromatography to give the compound 5-chloro-6-nitroquinazolin-4 (3H) -one. Then reducing the nitration product by iron powder to obtain the compound 5-chloro-6-aminoquinazolin-4 (3H) -one in an acid environment (or reducing the nitration product in a hydrogen environment by using Raney nickel). Then, by using BOP, 4- ((1H-benzo [ d ] [1,2,3] triazol-1-yl) oxy) -5-chloroquinazolin-6-amine is obtained.

The compound 4- ((1H-benzo [ d ] [1,2,3] triazol-1-yl) oxy) -5-chloroquinazolin-6-amine (100mg, 0.32mM) and a series of amine compounds (71-90mg, 0.38mM) were dissolved in a solution of i-PrOH (20ml), stirred at 90 ℃ for 10 minutes, and TsOH (7mg, 0.03mM) was added to the mixture and reacted for 5 hours. And the progress of the reaction was monitored by TLC, at the end of the reaction water was added and filtered to obtain a solid. Purification by column chromatography (EA: PE ═ 5: 1) afforded intermediates B1-B5 (brown or green solids), whose structures and characterizations are shown in table 1 below.

TABLE 1 Structure, nomenclature, and characterization of intermediates B1-B5

Examples

The first synthesis method comprises the following steps:

series 2-enoic acid (120mg, 0.9mM) was dissolved in anhydrous DCM (5ml) and oxalyl chloride (80. mu.L, 0.9mM) was added to react for 3h under ice bath. The solvent was then evaporated to give an orange solid. The orange solid dissolved in DCM (1ml) was then added to a solution of B1-B5(100mg, 0.3mM) in NMP (2ml) under ice bath for 4 h. And the progress of the reaction was monitored by TLC. Then potassium carbonate solution was added to adjust the pH to 8-9, and then the crude product was extracted with DCM. By column chromatography (DCM: CH)₃OH ═ 30: 1-10: 1) and (5) purifying. Examples 1-7 were synthesized using this method one.

And a second synthesis method comprises the following steps:

(E) -4-bromobut-2-enoic acid (150mg, 0.9mM) was dissolved in anhydrous DCM (5ml) and oxalyl chloride (80. mu.L, 0.9mM) was added to react for 3h under ice bath. The solvent was then evaporated to give an orange solid. The orange solid dissolved in DCM (1ml) was then added to a solution of B1-B5(100mg, 0.3mM) in NMP (2ml) under ice bath for 4 h. And the progress of the reaction was monitored by TLC. The pH was then adjusted to 8-9 by addition of potassium carbonate solution and the crude product was extracted with DCM. The pure product was isolated by column chromatography (EA: PE ═ 5: 1-3: 1). Then, pyrrolidine (100-150mg, 1.5mM) was added to the DMA solution of the product, and stirred at 0 ℃ for 4 hours. And the progress of the reaction was monitored by TLC. Then potassium carbonate solution was added to adjust the pH to 8-9, and then the crude product was extracted with DCM. The pure product was isolated by column chromatography (DCM: CH3OH ═ 30: 1-10: 1). Examples 8-10 were synthesized using this method two.

EXAMPLE 1 (E) -N- (5-chloro-4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) quinazolin-6-yl) -4- (dimethylamino) but-2-enamide

A white solid; mp 230-232 ℃.¹H NMR(400MHz,DMSO-d₆,δppm):δ9.98(s,1H),9.51(s,1H),8.53(d,J＝4.8Hz,1H),8.45(s,1H),8.05(d,J＝9.0Hz,1H),7.84–7.81(m,2H),7.68(d,J＝9.0Hz,1H),7.52(d,J＝7.8Hz,2H),7.33–7.29(m,1H),7.20(d,J＝9.0Hz,1H),6.75(dt,J＝15.5,5.9Hz,1H),6.45(d,J＝15.5Hz,1H),5.24(s,2H),3.03(d,J＝5.6Hz,2H),2.13(s,6H).¹³C NMR(101MHz,DMSO-d₆δ ppm δ 164.35(s),157.23(s),156.74(s),154.22(s),150.81(s),149.61(s),143.11(s),137.63(s),134.45(s),132.84(s),131.97(s),130.12(s),127.46(s),125.59(s),125.50(s),123.90(s),123.59(s),121.96(s),121.52(s),114.67(s),113.36(s),71.66(s),60.20(s),45.62(s), HRMS (ESI) m/z calculated value C₂₆H₂₄Cl₂N₆O₂ ⁺[M+H]⁺523.1416; found 523.1456.

EXAMPLE 2 (E) -N- (5-chloro-4- ((3-chloro-2-fluorophenyl) amino) quinazolin-6-yl) -4- (dimethylamino) but-2-enamide

A white solid; mp: 235-.¹H NMR(400MHz,DMSO-d₆,δppm):δ10.02(s,1H),9.67(s,1H),8.53(s,1H),8.16(d,J＝8.9Hz,1H),7.79(s,2H),7.46(s,1H),7.29(t,J＝7.8Hz,1H),6.83(dt,J＝15.4,5.8Hz,1H),6.53(d,J＝15.5Hz,1H),3.10(dd,J＝5.8,1.1Hz,2H),2.20(s,6H).¹³C NMR(101MHz,DMSO-d₆δ ppm δ 164.30(s),153.49(s),153.07(s),143.15(s),134.72(s),132.00(s),130.10(s),127.10(s),126.08(s),125.49(s),125.45(s),125.40(s),121.47(s),120.39(s),120.22(s),113.69(s),109.82(s),60.24(s),45.66(s). HRMS (ESI) m/z calculated value C₂₀H₁₈Cl₂FN₅O⁺[M+H]⁺434.0951; found 434.0923.

EXAMPLE 3 (E) -N- (5-chloro-4- ((3-chloro-4-fluorophenyl) amino) quinazolin-6-yl) -4- (dimethylamino) but-2-enamide

A white solid; mp 221-223 ℃.¹H NMR(400MHz,DMSO-d₆,δppm):δ10.01(s,1H),9.66(s,1H),8.59(d,J＝16.7Hz,1H),8.16(d,J＝9.0Hz,1H),8.04(d,J＝4.3Hz,1H),7.79–7.66(m,2H),7.45(t,J＝9.0Hz,1H),6.82(dt,J＝15.4,5.8Hz,1H),6.54(d,J＝15.5Hz,1H),3.10(d,J＝5.4Hz,2H),2.20(s,6H).¹³C NMR(101MHz,DMSO-d₆δ ppm Δ 164.43(s),156.77(s),150.82(s),149.61(s),144.08(s),137.60(s),134.56(s),132.03(s),130.11(s),127.45(s),125.56(s),125.11(s),123.87(s),123.57(s),121.94(s),121.55(s),114.71(s),71.72(s),47.17(s). HRMS (ESI) m/z calculated value C₂₀H₁₈Cl₂FN₅O⁺[M+H]⁺434.0951; found 434.0984.

EXAMPLE 4 (E) -N- (5-chloro-4- ((4-phenoxyphenyl) amino) quinazolin-6-yl) -4- (diethylamino) but-2-enamide

A white solid; mp:236-238 ℃.¹H NMR(400MHz,DMSO-d₆,δppm):δ10.31(d,J＝8.3Hz,1H),9.64(s,1H),8.51(s,1H),8.08(d,J＝9.0Hz,1H),7.77–7.71(m,3H),7.40(t,J＝7.9Hz,2H),7.12(d,J＝7.4Hz,1H),7.07(d,J＝8.9Hz,2H),7.04–6.99(m,2H),6.92–6.85(m,1H),6.66(d,J＝14.9Hz,1H),3.29(d,J＝7.1Hz,2H),2.69(s,4H),1.08(t,J＝7.0Hz,6H),¹³C NMR(101MHz,DMSO-d₆,δppm):δ164.11(s),157.58(s),157.21(s),154.29(s),153.42(s),150.16(s),134.56(s),134.48(s),132.17(s),130.51(s),130.10(s),129.11(s),127.42(s),125.43(s),123.69(s),121.98(s),119.58(s),118.59(s),113.39(s),63.25(s),47.01(s),11.32(s). HRMS (ESI) m/z calcd for C₂₈H₂₈ClN₅O₂ ⁺[M+H]⁺502.2010; found 502.2009.

EXAMPLE 5 (E) -N- (5-chloro-4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) quinazolin-6-yl) -4- (piperidin-1-yl) but-2-enamide

A white solid; mp:240 ℃ and 242 ℃.¹H NMR(400MHz,DMSO-d₆,δppm):δ10.03(s,1H),9.57(s,1H),8.55(d,J＝36.7Hz,2H),8.11(d,J＝9.0Hz,1H),7.95–7.83(m,2H),7.73(d,J＝8.9Hz,1H),7.58(d,J＝8.0Hz,2H),7.42–7.32(m,1H),7.26(d,J＝9.0Hz,1H),6.82(dt,J＝15.3,5.8Hz,1H),6.52(d,J＝15.9Hz,1H),5.30(s,2H),3.10(d,J＝5.6Hz,2H),2.36(s,4H),1.59–1.34(m,6H).¹³C NMR(101MHz,DMSO-d₆δ ppm Δ 164.35(s),157.18(s),156.75(s),154.17(s),150.81(s),149.57(s),143.00(s),137.58(s),134.50(s),132.86(s),131.94(s),127.48(s),125.56(s),125.52(s),123.81(s),123.57(s),123.25(s),121.94(s),121.56(s),121.45(s),114.66(s),71.71(s),59.72(s),54.56(s),25.94(s),24.27(s) HRMS (ESI) m/z C calculated value₂₉H₂₈Cl₂FN₆O₂ ⁺[M+H]⁺563.1729; found 563.1796.

EXAMPLE 6 (E) -N- (5-chloro-4- ((4- ((3-fluorobenzyl) oxy) phenyl) amino) quinazolin-6-yl) -4- (piperidin-1-yl) but-2-enamide

A white solid; mp:197 ℃ and 199 ℃.¹H NMR(400MHz,DMSO-d₆,δppm):δ10.06(s,1H),9.57(s,1H),8.46(s,1H),8.08(d,J＝9.0Hz,1H),7.72(d,J＝9.0Hz,1H),7.60(d,J＝8.9Hz,2H),7.45(td,J＝8.0,6.1Hz,1H),7.30(t,J＝7.8Hz,2H),7.16(td,J＝8.6,2.2Hz,1H),7.06(d,J＝9.0Hz,2H),6.82(dt,J＝15.4,5.9Hz,1H),6.53(dd,J＝14.1,8.6Hz,1H),5.16(s,2H),3.10(d,J＝5.0Hz,2H),2.36(s,4H),1.55–1.36(m,6H).¹³C NMR(101MHz,DMSO-d₆δ ppm calculated values δ 164.45(s),163.48(s),161.86(s),155.61(s),154.35(s),149.96(s),143.11(s),140.57(s),140.52(s),134.27(s),131.91(s),130.96(d, J ═ 8.3Hz),127.36(s),125.48(s),123.86(d, J ═ 2.5Hz),115.38(s),115.05(s),114.91(s),114.59(s),114.45(s),113.26(s),69.01(s),59.72(s),54.52(s),25.86(s),24.22(s) hrms (esi) m/z C₃₀H₂₉ClFN₅O₂ ⁺[M+H]⁺546.2072; found 546.2019.

EXAMPLE 7 (E) -N- (5-chloro-4- ((3-chloro-4-fluorophenyl) amino) quinazolin-6-yl) -4- (piperidin-1-yl) but-2-enamide

A white solid; mp 233-.¹H NMR(400MHz,DMSO-d₆,δppm):δ10.05(s,1H),9.68(s,1H),8.53(s,1H),8.12(d,J＝9.0Hz,1H),8.01(s,1H),7.80–7.61(m,2H),7.49–7.39(m,1H),6.82(dt,J＝15.4,5.9Hz,1H),6.52(d,J＝15.7Hz,1H),3.10(d,J＝5.5Hz,2H),2.35(s,4H),1.45(d,J＝52.9Hz,6H).¹³C NMR(101MHz,DMSO-d₆δ ppm δ 164.31(s),157.07(s),154.02(s),150.11(s),143.17(s),136.19(s),134.70(s),132.07(s),127.54(s),125.35(d, J ═ 17.8Hz),124.22(s),121.24(s),119.35(s),117.20(s),116.98(s),113.43(s),59.76(s),54.62(s),26.02(s),24.32(s) hrms (esi) m/z calculated value C₂₃H₂₂Cl₂FN₅O⁺[M+H]⁺474.1264; found 474.1271.

EXAMPLE 8 (E) -N- (5-chloro-4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) quinazolin-6-yl) -4- (pyrrolidin-1-yl) but-2-enamide

A white solid;¹H NMR(400MHz,DMSO-d₆,δppm):δ10.04(s,1H),9.57(s,1H),8.61(d,J＝3.3Hz,1H),8.53(s,1H),8.12(d,J＝9.0Hz,1H),7.96–7.85(m,2H),7.76(d,J＝9.0Hz,1H),7.59(d,J＝6.8Hz,2H),7.38(dd,J＝6.8,5.1Hz,1H),7.28(d,J＝9.0Hz,1H),6.86(dt,J＝15.3,5.7Hz,1H),6.56(d,J＝15.6Hz,1H),5.32(s,2H),3.33–3.28(m,2H),2.66(dd,J＝15.3,13.6Hz,4H),1.76(s,4H).MS:548.9[M+H]⁺。

EXAMPLE 9 (E) -N- (5-chloro-4- ((3-chloro-2-fluorophenyl) amino) quinazolin-6-yl) -4- (pyrrolidin-1-yl) but-2-enamide

A white solid;¹H NMR(400MHz,DMSO-d₆δ ppm δ 10.10(s,1H),9.65(s,1H),8.55(s,1H),8.17(d, J ═ 9.0Hz,1H),7.83(dd, J ═ 13.2,8.7Hz,1H), 7.57-7.43 (m,1H), 7.37-7.24 (m,1H),6.86(dd, J ═ 13.6,7.7Hz,1H),5.76(s,1H),5.33(d, J ═ 4.7Hz,1H),3.31(s,2H),2.68(d, J ═ 1.8Hz,4H),1.24(s,4H), ms calculated value of hresi) m/z (C esi) m/z (calculated value of C)₂₂H₂₀Cl₂FN₅O⁺[M+H]⁺460.1107; found 460.1101.

EXAMPLE 10 (E) -N- (5-chloro-4- ((3-chloro-4-fluorophenyl) amino) quinazolin-6-yl) -4- (pyrrolidin-1-yl) but-2-enamide

A white solid;¹H NMR(400MHz,DMSO-d₆δ ppm calculated values δ 10.04(s,1H),9.67(s,1H),8.58(s,1H),8.15(d, J ═ 9.0Hz,1H),8.05(dd, J ═ 6.8,2.6Hz,1H),7.78(d, J ═ 9.0Hz,1H),7.71(ddd, J ═ 8.9,4.3,2.7Hz,1H),7.47(t, J ═ 9.1Hz,1H),6.87(dt, J ═ 15.4,5.7Hz,1H),6.56(d, J ═ 15.4Hz,1H), 3.32-3.28 (m,2H), 2.70-2.58 (m,4H),1.75 (ms, 4H), m/z calculated values (hrc/z), (hrc), (H), (₂₂H₂₀Cl₂FN₅O⁺[M+H]⁺460.1107; found 460.1100.

EXAMPLE 11 (E) -N- (5-chloro-4- ((3-chloro-2-fluorophenyl) amino) quinazolin-6-yl) -4- (isopropylamino) but-2-enamide

Step 1) Synthesis of 5-chloro-N- (3-chloro-2-fluorophenyl) -6-nitroquinazolin-4-amine

Suspending 5-chloro-6-nitroquinazolin-4-ol (1g,4.5mmol) in thionyl chloride (15mL), stirring at normal temperature, adding DMF (0.5mL), heating the system to 105 ℃ for reaction, heating the system to 90 ℃ after the system is clear (about 3h), refluxing for reaction for 2h, monitoring by LCMS (MeOH quenching system), and directly concentrating the system under reduced pressure after the reaction is finished to obtain a light yellow solid; suspending the solid (1g,4.4mmol) obtained above in dry acetonitrile (15mL), dispersing uniformly by ultrasonic, slowly adding 3-chloro-2-fluoroaniline (2.9g,20mmol) dropwise under ice bath condition, removing ice bath, heating to 50 deg.C for reaction for 2H, monitoring reaction by LCMS, concentrating, adding MeOH, pulping, filtering, collecting filter cake to obtain target product 850mg with yield 53%, MS: 353M + H]⁺；

Step 2) Synthesis of 5-chloro-N- (3-chloro-2-fluorophenyl) quinazoline-4, 6-diamine

5-chloro-N- (3-chloro-2-fluorophenyl) -6-nitroquinazolin-4-amine (350mg,1mmol), iron powder (280mg,5mmol) and ammonium chloride (530mg,10mmol) are respectively added into a mixed solution of ethanol (10ml) and water (1ml), stirring and heating are carried out to 80 ℃ for reaction for 1 hour, diatomite is filtered, the filtrate is respectively washed by ethyl acetate and saturated sodium bicarbonate, the organic phase is dried and concentrated to obtain offwhite solid 290mg, the offwhite solid is directly used for the next step, MS:323[ M + H]⁺；

Step 3) (E) -4-bromo-N- (5-chloro-4- ((3-chloro-2-fluorophenyl) amino) quinazolin-6-yl) but-2-enamide synthesis to a solution of 5-chloro-N- (3-chloro-2-fluorophenyl) quinazoline-4, 6-diamine (65mg,0.2mmol) in NMP (2ml) under ice water bath conditions, a solution of bromocrotonyl chloride (55mg,0.3mmol) in dichloromethane was added, stirred for 30 minutes, quenched with saturated sodium bicarbonate solution, precipitated solid, filtered, washed with ethyl acetate, dried and used directly in the next step; MS:469,471[ M +H]⁺；

Step 4) (E) -N- (5-chloro-4- ((3-chloro-2-fluorophenyl) amino) quinazolin-6-yl) -4- (isopropylamino) but-2-enamide Synthesis of (E) -4-bromo-N- (5-chloro-4- ((3-chloro-2-fluorophenyl) amino) quinazolin-6-yl) but-2-enamide (0.46g,1mmol), isopropylamine (0.2g,3mmol) and diisopropylethylamine (0.3g,3mmol) were added separately to DMF (5ml) under ice-water bath conditions, heated to 50 ℃ and stirred for 2 hours, cooled and added water, ethyl acetate, respectively, the organic phase washed with saturated brine, dried, concentrating, and purifying by column chromatography to obtain light yellow solid product 150mg with yield 33%;

¹H NMR(400MHz,DMSO-d₆)δ10.18(s,1H),9.66(s,1H),8.56(s,1H),8.14(d,J＝9.0Hz,1H),7.82(d,J＝8.9Hz,2H),7.49(t,J＝7.6Hz,1H),7.31(t,J＝8.1Hz,1H),6.89(dt,J＝15.4,5.8Hz,1H),6.60(d,J＝15.4Hz,1H),3.63(s,2H),3.33(br,1H),3.06(s,1H),1.15(d,J＝6.3Hz,6H).MS:448[M+H]⁺。

EXAMPLE 12 (E) -N- (5-chloro-4- ((3-chloro-2-fluorophenyl) amino) quinazolin-6-yl) -4- (cyclopropylamino) but-2-enamide

The synthesis was carried out in the same manner as in example 11 except that cyclopropylamine was used in place of isopropylamine in step 4);¹H NMR(400MHz,DMSO-d₆)δ10.00(s,1H),9.65(s,1H),8.54(s,1H),8.16(d,J＝9.0Hz,1H),7.89–7.77(m,2H),7.49(ddd,J＝8.3,6.8,1.6Hz,1H),7.30(td,J＝8.1,1.4Hz,1H),6.92(dt,J＝15.4,5.3Hz,1H),6.49(dt,J＝15.5,1.8Hz,1H),3.43(dd,J＝5.4,1.8Hz,2H),3.33(br,1H),2.16(tt,J＝6.7,3.6Hz,1H),0.43-.039(m,2H),0.32–0.24(m,2H).MS:446[M+H]⁺。

EXAMPLE 13 (E) -N- (5-chloro-4- ((3-chloro-2-fluorophenyl) amino) quinazolin-6-yl) -4- (methylamino) but-2-enamide monotrifluoroacetate

The synthesis was carried out in the same manner as in example 11, except that isopropylamine of step 4) was replaced with methylamine hydrochloride for the reaction and the product of the preparation of the mono-trifluoroacetate was purified via the preparative liquid phase;

¹H NMR(400MHz,DMSO-d₆)δ10.29(s,1H),9.71(s,1H),8.73(s,2H),8.57(s,1H),8.12(d,J＝9.1Hz,1H),7.82(s,2H),7.49(s,1H),7.31(d,J＝7.2Hz,1H),6.82(dt,J＝15.5,6.5Hz,1H),6.65(d,J＝15.5Hz,1H),3.84(q,J＝5.9Hz,2H),2.67–2.53(m,3H).MS:420[M+H]⁺。

EXAMPLE 14 (E) -N- (5-chloro-4- ((3-chloro-2-fluorophenyl) amino) quinazolin-6-yl) -4- (cyclobutylamino) but-2-enamide

The synthesis was carried out in the same manner as in example 11 except that cyclobutylamine was used in place of isopropylamine in step 4);¹H NMR(400MHz,DMSO-d₆)δ10.01(s,1H),9.66(s,1H),8.50(s,1H),8.14(d,J＝9.0Hz,1H),7.78(s,2H),7.45(t,J＝7.5Hz,1H),7.28(t,J＝8.2Hz,1H),6.89(dt,J＝15.4,5.3Hz,1H),6.51(d,J＝15.4Hz,1H),3.29(d,J＝5.3Hz,2H),3.33(br,1H),3.20(p,J＝7.6Hz,1H),2.11(q,J＝8.5,7.9Hz,2H),1.76-1.55(m,4H).MS:460[M+H]⁺。

EXAMPLE 15 (E) -N- (5-chloro-4- ((3-chloro-2-fluorophenyl) amino) quinazolin-6-yl) -4- (isopropyl (methyl) amino) but-2-enamide

The synthesis was carried out in the same manner as in example 11 except that isopropylamine of step 4) was replaced with isopropylmethylamine;¹H NMR(400MHz,DMSO-d₆)δ10.05(s,1H),9.66(s,1H),8.54(s,1H),8.16(d,J＝9.1Hz,1H),7.87–7.75(m,2H),7.46(s,1H),7.28(t,J＝8.2Hz,1H),6.83(dt,J＝15.4,5.7Hz,1H),6.53(dt,J＝15.4,1.8Hz,1H),3.21(dd,J＝5.8,1.6Hz,2H),2.83(p,J＝6.6Hz,1H),2.16(s,3H),0.99(d,J＝6.5Hz,6H).MS:462[M+H]⁺。

EXAMPLE 16 (E) -N- (5-chloro-4- ((3-chloro-2-fluorophenyl) amino) quinazolin-6-yl) -4- (cyclobutyl (methyl) amino) but-2-enamide

The synthesis was carried out in the same manner as in example 11, except that cyclopropylamine of step 4) was replaced with cyclobutylmethyl amine;¹H NMR(400MHz,DMSO-d₆)δ10.05(s,1H),9.66(s,1H),8.54(s,1H),8.17(d,J＝9.1Hz,1H),7.88–7.76(m,2H),7.48(s,1H),7.29(t,J＝8.1Hz,1H),6.84(dt,J＝15.4,5.9Hz,1H),6.52(d,J＝15.4Hz,1H),3.09–3.02(m,2H),2.93–2.81(m,1H),2.06(s,3H),1.99(dd,J＝9.8,7.2Hz,2H),1.80(tt,J＝11.2,8.9Hz,2H),1.61(ddt,J＝18.1,10.4,8.1Hz,2H).MS:474[M+H]⁺。

EXAMPLE 17 (E) -N- (5-chloro-4- ((3-chloro-2-fluorophenyl) amino) quinazolin-6-yl) -4- (cyclopropyl (methyl) amino) but-2-enamide

The synthesis was carried out in the same manner as in example 11 except that cyclopropylmethylamine was used in place of isopropylamine in step 4);¹H NMR(400MHz,DMSO-d₆)δ10.02(s,1H),9.66(s,1H),8.50(s,1H),8.14(s,1H),7.77(s,2H),7.48–7.42(m,1H),7.28(s,1H),6.85(s,1H),6.49(s,1H),4.11(s,1H),3.16(s,2H),2.29(s,3H),0.46(s,2H),0.35(s,2H).MS:460[M+H]⁺。

EXAMPLE 18 (E) -N- (5-chloro-4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) quinazolin-6-yl) -4- (cyclopropyl (methyl) amino) but-2-enamide

The synthesis was carried out in the same manner as in example 11 except that 3-chloro-4- (pyridin-2-ylmethoxy) aniline was used in place of 3-chloro-2-fluoroaniline of step 1) and cyclopropylmethylamine was used in place of isopropylamine of step 4);

¹H NMR(400MHz,DMSO-d₆)δ10.00(s,1H),9.57(s,1H),8.60(ddd,J＝4.8,1.8,0.9Hz,1H),8.52(s,1H),8.12(d,J＝9.0Hz,1H),7.94–7.84(m,2H),7.75(d,J＝9.0Hz,1H),7.62–7.54(m,2H),7.38(ddd,J＝7.6,4.8,1.2Hz,1H),7.27(d,J＝9.0Hz,1H),6.86(dt,J＝15.4,6.1Hz,1H),6.49(dt,J＝15.4,1.6Hz,1H),5.31(s,2H),3.38–3.30(m,2H),2.29(s,3H),1.77(tt,J＝6.6,3.6Hz,1H),0.46(dt,J＝6.1,3.0Hz,2H),0.39–0.31(m,2H).MS:549[M+H]⁺。

EXAMPLE 19 (E) -N- (5-chloro-4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) quinazolin-6-yl) -4- (cyclobutyl (methyl) amino) but-2-enamide

The synthesis was carried out in the same manner as in example 11, except that 3-chloro-4- (pyridin-2-ylmethoxy) aniline was used in place of 3-chloro-2-fluoroaniline of step 1) and cyclobutylmethylamine was used in place of isopropylamine of step 4);

¹H NMR(400MHz,DMSO-d₆)δ10.01(s,1H),9.57(s,1H),8.60(dt,J＝4.9,1.3Hz,1H),8.52(s,1H),8.12(d,J＝9.0Hz,1H),7.94–7.84(m,2H),7.74(d,J＝9.0Hz,1H),7.62–7.55(m,2H),7.37(ddd,J＝7.7,4.8,1.2Hz,1H),7.27(d,J＝9.0Hz,1H),6.83(dt,J＝15.4,6.0Hz,1H),6.52(dt,J＝15.4,1.8Hz,1H),5.31(s,2H),3.05(dd,J＝6.0,1.6Hz,2H),2.93–2.78(m,1H),2.06(s,3H),2.03–1.95(m,2H),1.87–1.72(m,2H),1.60(tdd,J＝15.0,7.0,4.9Hz,2H).MS:563[M+H]⁺。

EXAMPLE 20 (R, E) -N- (5-chloro-4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) quinazolin-6-yl) -3- (1-methylpyrrolidin-2-yl) acrylamide

The synthesis was carried out in the same manner as in example 11, except that 3-chloro-4- (pyridin-2-ylmethoxy) aniline was used in place of 3-chloro-2-fluoroaniline of step 1) and (R, E) -3- (1-methylpyrrolidin-2-yl) acryloyl chloride was used in place of bromocrotonyl chloride of step 3) for the reaction;

¹H NMR(400MHz,DMSO-d₆)δ10.00(s,1H),9.57(s,1H),8.60(d,J＝4.8Hz,1H),8.52(s,1H),8.13(d,J＝9.0Hz,1H),7.89(dd,J＝14.2,5.4Hz,2H),7.75(d,J＝9.0Hz,1H),7.58(d,J＝8.2Hz,2H),7.37(t,J＝6.1Hz,1H),7.27(d,J＝8.9Hz,1H),6.72(dd,J＝15.3,7.5Hz,1H),6.52(d,J＝15.3Hz,1H),5.31(s,2H),3.04(s,1H),2.79(q,J＝8.0Hz,1H),2.22(s,3H),2.18(d,J＝9.2Hz,1H),2.02(dq,J＝14.4,8.3,7.8Hz,1H),1.74(q,J＝8.4Hz,2H),1.61(d,J＝18.1Hz,1H).MS:549[M+H]⁺。

EXAMPLE 21 (E) -N- (5-chloro-4- ((3-chloro-2, 4-difluorophenyl) amino) quinazolin-6-yl) -4- (dimethylamino) but-2-enamide

The synthesis was carried out in the same manner as in example 11 except that 2, 4-difluoro-3-chloroaniline was used in place of 3-chloro-2-fluoroaniline of step 1) and dimethylamine hydrochloride was used in place of isopropylamine of step 4);

¹H NMR(400MHz,DMSO-d₆)δ10.02(s,1H),9.58(s,1H),8.50(s,1H),8.17(d,J＝9.0Hz,1H),7.78(s,2H),7.40(s,1H),6.83(dt,J＝15.5,5.8Hz,1H),6.53(dt,J＝15.5,1.7Hz,1H),3.10(dd,J＝5.9,1.6Hz,2H),2.21(s,6H).MS:452[M+H]⁺。

EXAMPLE 22 (E) -N- (5-chloro-4- ((3-chloro-2, 4-difluorophenyl) amino) quinazolin-6-yl) -4- (isopropylamino) but-2-enamide

The synthesis was carried out in the same manner as in example 11 except that 2, 4-difluoro-3-chloroaniline was used in place of 3-chloro-2-fluoroaniline of step 1) to carry out the reaction;

¹H NMR(400MHz,DMSO-d₆)δ10.04(s,1H),9.59(s,1H),8.46(s,1H),8.13(d,J＝9.0Hz,1H),7.75(d,J＝14.5Hz,2H),7.44–7.34(m,1H),6.91(dt,J＝15.4,5.3Hz,1H),6.54(dt,J＝15.4,1.8Hz,1H),3.43(dd,J＝5.4,1.8Hz,2H),3.33(br,1H),2.82(p,J＝6.2Hz,1H),1.05(d,J＝6.2Hz,6H).MS:466[M+H]⁺。

EXAMPLE 23 Synthesis of (E) -N- (4- ((3-chloro-2-fluorophenyl) amino) -5-methylquinazolin-6-yl) -4- (dimethylamino) but-2-enamide

Step 1) 5-Methylquinazolin-4-ol

2-amino-6-methyl-benzoic acid (4.53g,30mmol) and formamidine acetate (3.12g,30.00mmol) were added to ethanol (40mL), heated to 80 ℃ for 24h of reflux reaction, monitored by LCMS, and after completion of the reaction, the system was cooled to room temperature, and a large amount of solid precipitated. Filtering, and washing a filter cake by using a small amount of petroleum ether. Collecting and drying to obtain a product 5-methyl quinazoline-4-alcohol (3.66g,22.85mmol, yield 76.17%); MS 161[ M + H ]]⁺。

Step 2) 5-methyl-6-nitroquinazolin-4-ol

Slowly add 5-methyl quinazolin-4-ol (3.66g,22.85mmol) to H at ambient temperature₂SO₄(30mL), cooling to-20 deg.C in ice salt bath, and adding KNO in batches₃(2.54g,25.14mmol) (about 20 min), and the system temperature is controlled below-10 ℃. Slowly heating the system to 10 ℃ for reaction for 2h, monitoring by HPLC, slowly pouring the system into crushed ice after the reaction is finished, separating out a large amount of solid, filtering, washing a filter cake for 3 times by using water, collecting, and drying to obtain a product, namely 5-methyl-6-nitro quinazoline-4-ol (3.2g,15.60mmol, yield 68.26%).

¹H NMR(400MHz,DMSO-d₆)δ8.45(s,1H),8.14(d,J＝8.9Hz,1H),7.92(s,1H)7.63(d,J＝8.9Hz,1H),2.77(s,3H).

Step 3) N- (3-chloro-2-fluorophenyl) -5-methyl-6-nitroquinazolin-4-amine

Suspending 5-methyl-6-nitro quinazoline-4-alcohol (1g,4.87mmol) in thionyl chloride (15mL), stirring at normal temperature, adding DMF (0.5mL), heating the system to 100 ℃ for reaction, after the system is clear (about 3h), refluxing for 2h, monitoring by LCMS (MeOH quenching system), and directly concentrating the system under reduced pressure after the reaction is finished to obtain a brown solid; suspending the solid (1g,4.47mmol) obtained above in 1, 2-dichloromethane (15mL), ultrasonically dispersing uniformly, slowly dropwise adding 3-chloro-2-fluoroaniline (2.60g,17.89mmol) under the condition of ice bath, removing the ice bath, heating to 50 ℃ for reaction for 1h, monitoring the reaction by LCMS, depressurizing the system to evaporate the solvent, adding MeOH into the residue, ultrasonically dispersing uniformly, filtering, and collecting a filter cake to obtain a product (990mg,2.98mmol, yield 66.54%).

Step 4) N- (3-chloro-2-fluorophenyl) -5-methyl quinazoline-4, 6-diamine

N- (3-chloro-2-fluoro-phenyl) -5-methyl-6-nitro-quinolin-4-amine (990mg,2.98mmol) was suspended in methanol (10mL), and Raney Ni (34.93mg, 595.10. mu. mol) was added to replace H₂Stirring for 30min at normal temperature under atmosphere for 3 times, gradually dissolving and clarifying the system, and monitoring by LCMS. After the reaction was complete, the pad was filtered through celite, and the filtrate was concentrated to give the product (890mg,2.94mmol, 98.80% yield).

(E) -4-bromo-N- (4- ((3-chloro-2-fluorophenyl) amino) -5-methylquinazolin-6-yl) but-2-enamide

Adding N- (3-chloro-2-fluorophenyl) -5-methyl quinazoline-4, 6-diamine (50mg,165.16 mu mol) into NMP (3ml), dropwise adding an acetonitrile solution of (E) -bromocrotonyl chloride (45mg,250 mu mol) under stirring at normal temperature, reacting for 15 minutes, monitoring by LCMS (liquid crystal display system), quenching the system by using an excessive saturated sodium bicarbonate aqueous solution after the reaction is finished, adjusting the pH to be approximately equal to 8, precipitating a large amount of solid, filtering, washing by using ethyl acetate, and drying to obtain 700mg of a crude product for later use, wherein MS is 449,451[ M + H ], (MS)]⁺。

(E) -N- (4- ((3-chloro-2-fluorophenyl) amino) -5-methylquinazolin-6-yl) -4- (dimethylamino) but-2-enamide (E) -4-bromo-N- (4- ((3-chloro-2-fluorophenyl) amino) -5-methylquinazolin-6-yl) but-2-enamide (50mg, 165.16. mu. mol) was added to DMF (3mL), dimethylamine hydrochloride and diisopropylethylamine were added, respectively, with stirring at room temperature, heated to 50 ℃ for 2 hours, LCMS monitored for completion of the reaction, the system was quenched with excess saturated aqueous sodium bicarbonate solution, adjusted to pH 8, a large amount of solid was precipitated, filtered, purification of solid prep. plate (DCM/MeOH ═ 10:1) gave the target product (25mg,60.40 μmol, yield 36.57%).

¹H NMR(400MHz,DMSO-d₆)δ9.76(s,1H),8.89(s,1H),8.41(s,1H),7.69(br,2H),7.19(br,3H),6.76(dt,J＝15.4,5.8Hz,1H),6.40(d,J＝15.5Hz,1H),3.08(d,J＝5.9Hz,2H),2.72(s,3H),2.19(s,6H).MS:414[M+H]⁺。

EXAMPLE 24 (E) -N- (4- ((3-chloro-2-fluorophenyl) amino) -5-methylquinazolin-6-yl) -4- (isopropylamino) but-2-enamide

The synthesis was carried out in the same manner as in example 23 except that isopropylamine was used in place of dimethylamine hydrochloride in step 6);¹H NMR(400MHz,DMSO-d₆)δ9.73(s,1H),8.91(s,1H),8.48-8.44(m,1H),7.81–7.51(m,2H),7.40–7.02(m,3H),6.90–6.78(m,1H),6.40(d,J＝16.2Hz,1H),3.33(br,1H),2.82-2.79(m,4H),2.71(d,J＝3.6Hz,2H),1.02(d,J＝6.2Hz,6H).MS:428[M+H]⁺。

EXAMPLE 25 (E) -N- (4- ((3-chloro-2-fluorophenyl) amino) -5-methylquinazolin-6-yl) -4- (cyclopropylamino) but-2-enamide

The synthesis was carried out in the same manner as in example 23 except that cyclopropylamine was used instead of step 6) dimethylamine hydrochloride;¹H NMR(400MHz,DMSO-d₆)δ9.73(s,1H),8.06(s,1H),7.67(d,J＝8.3Hz,1H),7.39(s,2H),7.33–7.12(m,3H),6.85(dt,J＝15.4,5.1Hz,1H),6.39(d,J＝15.4Hz,1H),3.38–3.33(m,4H),2.80–2.67(s,3H),1.01(d,J＝6.2Hz,4H).MS:426[M+H]⁺。

EXAMPLE 26 (E) -N- (4- ((3-chloro-2-fluorophenyl) amino) -5-methylquinazolin-6-yl) -4- (methylamino) but-2-enamide

The synthesis was carried out in the same manner as in example 23 except that methylamine hydrochloride was used in place of dimethylamine hydrochloride in step 6);¹H NMR(400MHz,DMSO-d₆)δ9.83(s,1H),8.25(s,1H),7.64(br,3H),7.19(s,3H),6.80(d,J＝15.6Hz,1H),6.43(d,J＝15.5Hz,1H),3.45(br,3H),2.72(s,3H),2.40(s,3H).MS:400[M+H]⁺。

EXAMPLE 27 (E) -N- (4- ((3-chloro-2-fluorophenyl) amino) -5-methylquinazolin-6-yl) -4- (cyclobutylamino) but-2-enamide

The synthesis was carried out in the same manner as in example 23 except that cyclobutylamine was used in place of dimethylamine hydrochloride in step 6);¹H NMR(400MHz,DMSO-d₆)δ9.74(s,1H),8.91(s,1H),8.38(br,1H),7.64(s,2H),7.43–6.90(m,3H),6.82(dt,J＝15.6,5.3Hz,1H),6.39(d,J＝15.4Hz,1H),3.33-3.27(m,3H),3.20(d,J＝7.7Hz,1H),2.72(s,3H),2.11(q,J＝8.2,5.8Hz,2H),1.79–1.48(m,4H).MS:440[M+H]⁺。

EXAMPLE 28 (E) -N- (4- ((3-chloro-2-fluorophenyl) amino) -5-methylquinazolin-6-yl) -4- (isopropyl (methyl) amino) but-2-enamide

To and withThe synthesis was carried out in the same manner as in example 23 except that isopropyl methylamine was used instead of dimethylamine hydrochloride in step 6);¹H NMR(400MHz,DMSO-d₆)δ9.95-9.66(m,1H),8.91-8.45(m,1H),7.84(d,J＝23.3Hz,1H),7.68–7.58(m,2H),7.36–6.99(m,3H),6.75(d,J＝15.2Hz,1H),6.39(d,J＝17.9Hz,1H),3.20(d,J＝5.7Hz,2H),2.83(q,J＝6.5Hz,1H),2.72(d,J＝22.2Hz,3H),2.16(s,3H),0.99(d,J＝6.5Hz,6H).MS:442[M+H]⁺。

EXAMPLE 29 (R, E) -N- (4- ((3-chloro-2-fluorophenyl) amino) -5-methylquinazolin-6-yl) -3- (1-methylpyrrolidin-2-yl) acrylamide

The synthesis was carried out in the same manner as in example 23, except that (R, E) -3- (1-methylpyrrolidin-2-yl) acryloyl chloride was used in place of crotonyl bromide in step 5);

¹H NMR(400MHz,DMSO-d₆)δ9.65(s,1H)8.46(s,1H),7.90–7.80(m,1H),7.61-7.46(m,2H),7.36-6.99(m,3H),6.66(td,J＝19.5,17.8,7.4Hz,1H),6.39(dd,J＝27.3,15.4Hz,1H),3.03(d,J＝8.5Hz,1H),2.26–2.13(m,6H),2.00(d,J＝11.3Hz,2H),1.77(td,J＝6.6,6.0,2.8Hz,2H),1.59(s,2H).MS:440[M+H]⁺。

EXAMPLE 30 (E) -N- (4- ((3-chloro-2, 4-difluorophenyl) amino) -5-methylquinazolin-6-yl) -4- (dimethylamino) but-2-enamide

The synthesis was carried out in the same manner as in example 23 except that 3-chloro-2, 4-difluoroaniline was used in place of 3-chloro-2-fluoroaniline of step 3) to obtain a reaction product;¹H NMR(400MHz,DMSO-d₆)δ9.96(s,1H),9.74(s,1H),8.86(s,1H),8.41(s,1H),7.78(s,1H),7.62(s,1H),6.99(s,1H),6.80–6.71(m,1H),6.38(d,J＝15.4Hz,1H),3.08(d,J＝5.9Hz,2H),2.71(s,3H),2.19(s,6H).MS:432[M+H]⁺。

EXAMPLE 31 (E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -5-methylquinazolin-6-yl) -4- (dimethylamino) but-2-enamide

The synthesis was carried out in the same manner as in example 23 except that 3-chloro-4-fluoroaniline was used in place of 3-chloro-2-fluoroaniline of step 3);

¹H NMR(400MHz,DMSO-d₆)δ9.90(s,1H),8.99(s,1H),8.51(s,1H),8.02(dd,J＝6.9,2.6Hz,1H),7.83(d,J＝8.8Hz,1H),7.72–7.59(m,2H),7.43(t,J＝9.1Hz,1H),6.78(dt,J＝15.4,5.9Hz,1H),6.45(d,J＝15.5Hz,1H),3.12–3.06(m,2H),2.72(s,3H),2.20(s,6H).MS:414[M+H]⁺。

EXAMPLE 32 (E) -N- (4- ((3-chloro-2, 4-difluorophenyl) amino) -5-methylquinazolin-6-yl) -4- (isopropylamino) but-2-enamide

The synthesis was carried out in the same manner as in example 23 except that 3-chloro-4-fluoroaniline was used in place of 3-chloro-2-fluoroaniline of step 3) and isopropylamine was used in place of dimethylamine hydrochloride of step 6) for reaction;

¹H NMR(400MHz,DMSO-d₆)δ9.91(s,1H),8.33(s,1H),7.65(br,2H),7.28(br,3H),6.84(dt,J＝15.4,5.7Hz,1H),6.48(d,J＝15.4Hz,1H),3.53(d,J＝5.7Hz,2H),3.33(br,1H),2.96(q,J＝6.3Hz,1H),2.72(s,3H),1.11(d,J＝6.3Hz,6H).MS:446[M+H]⁺。

EXAMPLE 1 Small molecule Compounds inhibit EGFR^WTAnd testing of HER2 kinase activity

Reagents and consumables: ULightTM-labeled Ploy GT Peptide (Perkin Elmer, Cat. No. TRF-0100-M); ULight TM-labeled JAK-1(Try1023) Peptide (Perkin Elmer, Cat. TRF-0121-M); Eu-W1024-labeled Anti-phosphor Antibody (PT66) (Perkin Elmer, Cat. AD 0068); 10 × Detection Buffer (Perkin Elmer, Cat. No. CR 97-100); her2 kinase (Carna Biosciences, Cat 08-016); EGFR kinase (Carna Biosciences, Cat 08-115); HEPES (GIBCO, catalog number 15630-; EGTA (Sigma, cat # 03777-10G); EDTA (Sigma, cat # EDS-100G); MgCl₂(Sigma, catalog number 63069-100 ML); DTT (Sigma, catalog number 43816-10 ML); tween-20(Sigma, catalog number P7949-100 ML); DMSO (Life Science, Cat No. 0231-500 ML); 384 well plates (Perkin Elmer, cat # 607290); multifunctional plate reader (Perkin Elmer, catalog number Envision)

Compound solution preparation: test compounds were dissolved in DMSO to make 10mM stock. Compounds were diluted to 0.25mM (100-fold final dilution) in DMSO and diluted in 3-fold concentration gradients, 11 gradients, prior to use. When adding medicine, the medicine is diluted by buffer solution into 4 times of the dilution solution with final concentration.

HER2 kinase assay: buffer solution was prepared by using 40nM 4 Xher 2 kinase solution, 40. mu.M 4 XATP solution, 400nM 4 XULight^TM-labeled Ploy GT Peptide substrate solution. After the preparation, the enzyme was mixed with the compounds of different concentrations prepared by dilution in advance, and left at room temperature for 5 minutes, with multiple wells being provided for each concentration. The corresponding substrate and ATP were added and the reaction was carried out at room temperature for 120 minutes (positive and negative controls were set). After the reaction, PT66 detection antibody was added, and the mixture was incubated at room temperature for 60 minutes and then detected by Envision.

EGFR^WTAnd (3) kinase detection: buffer solution was prepared, and 3.48nM 4X EGFR kinase solution, 600. mu.M 4X ATP solution, 400nM 4X ULight solution were prepared using the buffer solution^TM-labeled JAK-1(Try1023) Peptide substrate solution. After the preparation, the enzyme was mixed with the compounds of different concentrations prepared by dilution in advance, and left at room temperature for 5 minutes, with multiple wells being provided for each concentration. The corresponding substrate and ATP were added and the reaction was carried out at room temperature for 120 minutes (positive and negative controls were set). After the reaction, PT66 detection antibody was added, and the mixture was incubated at room temperature for 60 minutes and then detected by Envision.

And (3) data calculation: the well readings (10000 ═ pore EU665 value)/(pore EU615 value), and the inhibition rates were calculated using Excel tablesRate of production ═ [ (positive control reading from well-experimental reading)/(positive control reading from well-negative control reading from well)]100%. The compound concentration and corresponding inhibition rate are input into GraphPad Prism to be treated and IC is calculated₅₀The value is obtained.

Table 2 tests show that the compounds of the present application can inhibit EGFR^WTAnd HER2 tyrosine kinase activity, in particular wherein some of the compounds exhibit potent inhibitory effects. The test results are summarized in table 2 below.

Table 2 lists EGFR by some of the compounds in this application^WTAnd HER2 tyrosine kinase inhibitory activity, wherein A represents IC₅₀Less than or equal to 50nM, B represents IC₅₀Greater than 50nM but less than or equal to 500nM, C represents IC₅₀Greater than 500nM but less than or equal to 5000nM, D represents IC₅₀Above 5000nM, NT indicates no correlation.

TABLE 2 results of the determination of EGFR and HER2 kinase inhibitory Activity of the Compounds of the present invention

EXAMPLE 2 test for inhibition of cell proliferation by Small molecule Compounds

The in vitro antiproliferative activity of the compounds of the invention on BT474, NCI-N87, HCC-827 and Ba/F3EGFRvIII cell lines cultured in vitro was tested using the CCK8 method.

Reagents and consumables: RPMI1640(ThermoFisher, Cat. No. C11875500 BT); DMEM (ThermoFisher, C11995500 BT); fetal bovine serum (Hyclone, cat # SV 30087.03); 0.25% trypsin-EDTA (ThermoFisher, Cat. No. 25200072); penicillin-streptomycin (Hyclone, catalog No. SV 30010); DSMO (Life Science, Cat No. 0231-; CCK8 test kit (Dojindo, Cat. No. CK 04-100); 96-well plates (Corning, catalog No. 3599); multifunctional plate reader (Perkin Elmer, catalog number Envision)

Cell line: BT474 (from Chinese academy of sciences cell Bank), NCI-N87 (from ATCC) and HCC-827 (from ATCC), Ba/F3EGFRvIII from Kangyuan Bo Biotech (Beijing) Ltd; wherein, BT474, NCI-N87 and Ba/F3EGFRvIII are cultured in RPMI1640 medium containing 10% fetal calf serum, 100U/mL penicillin and 100. mu.g/mL streptomycin, and HCC-827 is cultured in DMEM medium containing 10% fetal calf serum, 100U/mL penicillin and 100. mu.g/mL streptomycin.

The specific experimental method comprises the following steps:

1. the test compound was dissolved in DSMO to form a stock solution, and the stock solution was diluted with a gradient and then diluted with the corresponding medium to obtain a 20-fold working concentration solution.

2. Cells in the logarithmic growth phase were diluted with the culture medium to adjust to a specific cell concentration, and 80. mu.L of the cell suspension was added to a 96-well plate so that the cell densities of BT474, NCI-N87, HCC-827 and Ba/F3EGFRvIII were 10000 cells/well, 8000 cells/well, 5000 cells/well and 8000 cells/well, respectively. The cells were cultured overnight in a 5% carbon dioxide incubator at 37 ℃. Wherein Ba/F3EGFRvIII cells directly enter the next step of dosing treatment, and BT474, NCI-N87 and HCC-827 need to be cultured overnight for adherence and then are treated by drugs.

3. 20 μ L of drug solution per well was added to the 96-well plate that had been seeded with cells. The highest concentration of the tested compound was 10. mu.M, 10 concentrations, 4-fold gradient dilution, double wells. At the same time, a control group without drug was set.

4. After 72 hours of cell culture, cell viability was measured using CCK 8. Dose-response curves were generated and IC calculated using GraphPad Prism software₅₀。

Table 3 lists the results of the antiproliferative activity assay of representative compounds of the invention on BT474, NCI-N87, HCC-827 and Ba/F3EGFRvIII cells. Wherein A represents IC₅₀Less than or equal to 50nM, B represents IC₅₀Greater than 50nM but less than or equal to 500nM, C represents IC₅₀Greater than 500nM but less than or equal to 5000nM, D represents IC₅₀Above 5000nM, NT indicates no correlation.

TABLE 3 results of assays for antiproliferative activity of representative compounds of the invention on BT474, NCI-N87, HCC-827 and Ba/F3EGFRvIII cells

The results in Table 3 show that the above compounds of the present application all exhibit excellent to good anti-tumor proliferation activity against BT474, NCI-N87 and Ba/F3EGFRvIII cells. Furthermore, the compounds of the present application also showed excellent proliferation inhibitory activity against HCC-827 cell line.

EXAMPLE 3 pharmacokinetic testing of Small molecule Compounds

In the test, after a part of compounds of the application are administrated to SD rats by single oral administration and intravenous injection, the pharmacokinetic characteristics of the compounds of the application are researched, and the ability of the compounds of the application to penetrate blood brain barrier is researched. At the same time, Pyrroltinib (PYROTINIB), neritinib (neritinib) were tested accordingly and compared to the compounds of the present application.

Reagents, instruments and animals used

TABLE 4 test reagents

TABLE 5 test instrument

TABLE 6 mice for testing

(II) sample preparation

1. Intravenous Injection (IV)Group (2): weighing appropriate amount of test compound, dissolving in appropriate volume of solvent (DMSO/Solutol/H)₂O5/10/85V/V, added to 2meq HCl), stirred, vortexed and/or sonicated. After obtaining the solution, the solvent was gradually increased to a final volume to reach the target concentration, vortexed, sonicated to obtain a homogeneous solution, which was filtered through a 0.22 μm PVDF filter.

2. Oral (PO) group: weighing appropriate amount of test compound, dissolving in appropriate volume of solvent (DMSO/Solutol/H)₂O5/10/85V/V, added to 2meq HCl), stirred, vortexed and/or sonicated. After obtaining the solution, gradually increasing the solvent to the final volume to reach the target concentration, and performing vortex and ultrasonic treatment to obtain a uniform solution.

(III) rat dosing and sampling

Animals were randomly grouped according to their body weight, and the body weight of each group was equivalent (not more than ± 20% of the average body weight). Meanwhile, group IV did not fast, group PO fasted overnight (>12 hours), and food was given 2 hours after dosing. All animals had free access to water. The dosing and pharmacokinetic sampling regimes are given in tables 7 and 8 below, respectively.

TABLE 7 dosing regimen

TABLE 8 pharmacokinetic sampling protocol

Rats were dosed according to the protocol described above and blood and brain tissue samples were collected and processed at predetermined time points (collection and processing was performed according to methods routine in the art).

(IV) analysis of samples

The brain was weighed and homogenized by adding 4 times of ultrapure water. The whole blood sample and the brain homogenate were added to 6 volumes of acetonitrile, vortexed for 1min, centrifuged at 4500rpm for 15min at 4 ℃, the supernatant diluted 2 times with ultrapure water, and the sample was analyzed by LC/MS.

(V) data analysis:

pharmacokinetic parameter calculations will be performed using WinNonlin software. If applicable, the following pharmacokinetic parameters are calculated for the plasma drug concentration-time data: CL (clearance rate); v_d(apparent volume of distribution); t is_1/2(elimination half-life); c_max(peak concentration); t is_max(time to peak); AUC (area under plasma concentration-time curve); MRT (mean residence time); f% (bioavailability).

The test results are shown in tables 9-15 below, which respectively show the blood concentration of rat and the pharmacokinetic parameter values of compound 1 and 2, 19 and 20, and pyrroltinib and lalatinib of the example in the present application at each time point, and also show the concentration of compound 1 and 2, 19 and 20, and pyrroltinib and lalatinib in brain and blood of rat and the ratio thereof. As can be seen from the above results, compounds 1 and 2, 19 and 20 of the present application all exhibited excellent ability to penetrate the blood brain barrier, far superior to marketed pirtinib and leratinib. The results also show that the compound of the application not only has excellent EGFR and HER2 kinase inhibition activity, but also can inhibit cell proliferation at a cellular level, and simultaneously has excellent capability of penetrating through a blood brain barrier, thereby being expected to be applied to related diseases mediated by EGFR and/or HER2 kinase, especially related diseases of brain metastasis.

TABLE 9 rat plasma concentrations of Compounds 1 and 2 of the examples of the present application

TABLE 10 rat pharmacokinetic parameters of the Compounds of examples 1 and 2 of the present application

TABLE 11 rat plasma concentrations of Compounds 19 and 20 of the examples of this application

TABLE 12 rat pharmacokinetic parameters for the compounds of examples 19 and 20 of the present application

TABLE 13 plasma concentrations of pyrroltinib and leratinib in rats

TABLE 14 rat pharmacokinetic parameters for pyrroltinib and leratinib

TABLE 15 concentrations and ratios of compounds 1 and 2, 19 and 20, and pyrrolatinib and leratinib in brain and whole blood of examples of this application (PO10mg/kg, sampling time, administration 2h)

Examples	Blood concentration (ng/mL)	Brain concentration (ng/g)	Brain/blood ratio
				Pyrotinib	884	25.8	0.0291
Neratinib	440	14.4	0.0366
				1	256	373	1.46
2	616	3168	5.45
				19	446	788	1.77
20	109	116	1.06

The results in tables 9 and 10 show that examples 1 and 2 have excellent pharmacokinetic parameters and are suitable for the development of oral inhibitors. The results in table 15 show that both example 1 and example 2 have extremely strong blood-brain barrier penetrating properties and are suitable for the treatment of primary brain tumors and the treatment of brain metastasis tumors. The results in tables 11-12 and table 15 also show that examples 19 and 20 also have excellent pharmacokinetic properties, while having strong blood-brain barrier penetration properties. As can be seen from the results of table 3, table 9, table 10, tables 11 to 12 and table 15, the compounds of the present invention are expected to be developed as therapeutic agents for glioma.

As described above, the compounds of the present application all showed excellent inhibitory activity against EGFR kinase and also showed good to excellent inhibitory activity against HER2 kinase; on the cellular aspect, all compounds of the present application showed excellent proliferation-inhibiting activity on Ba/F3EGFRvIII cell lines; meanwhile, pharmacokinetic tests also find that the compound shows excellent capability of penetrating the blood brain barrier (far better than the drugs on the market), so that the compound is expected to be a therapeutic drug for the diseases especially for the EGFRvIII induced tumors such as glioma or EGFR/HER2 driven tumor transcephalic.

None of the approved quinazoline drugs such as Gefitinib (Gefitinib), Erlotinib (Erlotinib), Icotinib (Icotinib), Afatinib (Afatinib), and Lapatinib (Lapatinib) effectively penetrate the blood-brain barrier. Meanwhile, most of the current compounds taking quinazoline as a mother nucleus are substituted at the 6-position and the 7-position of a quinazoline ring, but are hardly substituted at the 5-position, the applicant researches and discovers that an allylamide group is introduced at the 6-position of the quinazoline ring, and a halogen (such as Cl) or alkyl (such as methyl) substitution is introduced at the 5-position of the quinazoline ring, wherein the allylamide group can form non-reversible covalent binding with an EGFR or HER2 target, and the halogen or alkyl introduced at the 5-position can lock the orientation of the allylamide group, so that covalent binding of the allylamide with the EGFR or HER2 target is more favorably realized. This design not only achieves strong covalent binding of the compounds of the invention to the EGFR or HER2 target, but also greatly improves the blood brain penetration of the compounds of the invention.

The foregoing is a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various improvements and modifications can be made to the embodiment of the present invention without departing from the principle of the present invention, and these improvements and modifications should also be construed as the protection scope of the present invention.

Claims

1. A compound shown as a formula (I), an isomer, a hydrate, a solvate, a pharmaceutically acceptable salt and a prodrug thereof,

in the formula (I), m is 0, 1 or 2;

a is halogen, C₁-C₃An alkyl group; z is NH or O;

R₁is hydrogen, hydroxy, 4-7 membered heteroalicyclic or-NR^aR^b，

the 4-7-membered heteroalicyclic group is a heteroalicyclic group containing 1-2 heteroatoms selected from N, O or S, which is unsubstituted or C₁-C₃Alkyl radical, C₁-C₄Alkanoyl, hydroxy, cyano, aminoacyl, mono-or disubstituted C₁-C₃Aminoacyl, C_1-C₃Alkyl sulfone group, C_1-C₃One or two of alkyl sulfoxide group and oxo (═ O) are substituted;

r 'and R' are each independently H or C₁-C₃Alkyl group of (1).

2. The compound according to claim 1, wherein the compound has the following general formula,

in the formula (II), the compound is shown in the specification,

a is halogen, C₁-C₃An alkyl group; z is NH or O;

R₁is hydrogen, hydroxy, 4-7 membered heteroalicyclic or-NR^aR^b，

r 'and R' are each independently H or C₁-C₃Alkyl group of (1).

3. The compound, its isomers, hydrates, solvates, pharmaceutically acceptable salts thereof, and prodrugs thereof according to claim 1 or 2, characterized in that a is Cl, F or methyl; z is NH.

4. The compound, its isomers, hydrates, solvates, pharmaceutically acceptable salts and prodrugs thereof according to claim 1 or 2 or 3, wherein R is₁Is 4-7 membered heteroalicyclic or-NR^aR^b，

R^a、R^bEach independently is hydrogen, C₁-C₃Alkyl, C substituted by hydroxy₁-C₃Alkyl radical, C_1-C₃Alkoxy-substituted C₁-C₃An alkyl group;

5. The compound, its isomers, hydrates, solvates, pharmaceutically acceptable salts and prodrugs thereof according to claim 4, wherein R is₁Is pyrrolidin-1-yl, piperidin-1-yl, 1-methylpiperazin-4-yl, 1-ethylpiperazin-4-yl, morpholinyl, tetrahydrofuran 2-yl, tetrahydrofuran 3-yl, tetrahydropyran 2-yl, tetrahydropyran 3-yl, thiomorpholinyl, dimethylamino, diethylamino, dipropylamino, diisopropylamino, methylethylamino, methylpropylamino or ethylpropylamino.

6. The compound, its isomers, hydrates, solvates, pharmaceutically acceptable salts and prodrugs thereof according to claim 5, wherein R is₁Is dimethylamino.

7. The compound, isomers, hydrates, solvates, pharmaceutically acceptable salts thereof, and prodrugs thereof according to claim 1, wherein m is 0 or 1,

R₁is 4-7 membered heteroalicyclic or-NR^aR^b，

the 4-7-membered heteroalicyclic group is pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, tetrahydrofuryl, tetrahydropyranyl, thiomorpholinyl, and the above groups are unsubstituted or substituted by one or two of methyl, ethyl, propyl, isopropyl, aldehyde, acetyl, propionyl, hydroxyl, cyano, aminoacyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, methylsulfonyl, ethylsulfoxide, propylsulfoxide, isopropylsulfoxide, and oxo (═ O);

preferably, m is 0 or 1,

R₁is 1-methyl-pyrrolidin-2-yl, 1-ethyl-pyrrolidin-2-yl, 1-isopropyl-pyrrolidin-2-yl, methylamino, ethylamino, propylamino, isopropylamino, cyclopropylamino, cyclobutylamino, methylisopropylamino, N-methyl-N-cyclopropylamino, N-methyl-N-cyclobutylamino, pyrrolidin-1-yl, piperidin-1-yl, 1-methylpiperazin-4-yl, 1-ethylpiperazin-4-yl, morpholinyl, tetrahydrofuran 2-yl, tetrahydrofuran 3-yl, tetrahydropyran 2-yl, tetrahydropyran 3-yl, thiomorpholinyl, dimethylamino, diethylamino, methyl-amino, methyl-N-cyclopropylamino, N-methyl-N-cyclobutylamino, pyrrolidin-1-yl, piperidin-1-yl, 1-methylpiperazin-4-yl, morpholinyl, tetrahydrofuran 2-yl, tetrahydrofuran 3-yl, tetrahydropyran-3-yl, thiomorpholinyl, dimethylamino, diethylamino, amino, or amino, Dipropylamino, diisopropylamino, methylethylamino, methylpropylamino or ethylpropylamino.

8. The compound, its isomer, hydrate, solvate, pharmaceutically acceptable salt thereof, and prodrug thereof according to claim 1 or 2,

R₂、R₃、R₄、R₅、R₆each independently hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, -O- (CH)₂)n-R₇And R is₂、R₃、R₄、R₅、R₆At least 3 of which are hydrogen,

r 'and R' are respectively H or methyl,

9. The compound, its isomer, hydrate, solvate, pharmaceutically acceptable salt thereof, and prodrug thereof according to claim 8,

R₂、R₃、R₄、R₅、R₆each independently of the others being hydrogen, fluorine, chlorine, -O- (CH)₂)n-R₇And R is₂、R₃、R₄、R₅、R₆At least 3 of which are hydrogen,

the aryl group is phenyl and the heteroaryl group is pyridyl.

10. The compound, its isomers, hydrates, solvates, pharmaceutically acceptable salts and prodrugs thereof according to claim 9, wherein R is₂、R₃、R₄、R₅、R₆Each independently is hydrogen, fluoro, chloro, phenoxy, 2-fluorophenoxy, 3-fluorophenoxy, 4-fluorophenoxy, pyridin-2-ylmethoxy, pyridin-3-ylmethoxy, pyridin-4-ylmethoxy, 3-fluorobenzyloxy, 2-fluorobenzyloxy, 4-fluorobenzyloxy, 3-chlorobenzyloxy, 2-chlorobenzyloxy, 4-chlorobenzyloxy, and R is₂、R₃、R₄、R₅、R₆At least 3 of which are hydrogen.

11. The compound, its isomer, hydrate, solvate, pharmaceutically acceptable salt thereof, and prodrug thereof according to any one of claims 1 or 7,

R₂、R₃、R₅、R₆each independently is hydrogenFluorine, chlorine, methyl, ethyl, propyl, isopropyl, R₄Is hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, -O- (CH)₂)n-R₇And R is₂、R₃、R₄、R₅、R₆At least 2 of which are hydrogen,

r 'and R' are respectively H or methyl,

preferably, R₂、R₃、R₅、R₆Each independently of the others being hydrogen, fluorine, chlorine, R₄Is hydrogen, fluorine, chlorine, phenoxy, 2-fluorophenoxy, 3-fluorophenoxy, 4-fluorophenoxy, pyridin-2-ylmethoxy, pyridin-3-ylmethoxy, pyridin-4-ylmethoxy, 3-fluorobenzyloxy, 2-fluorobenzyloxy, 4-fluorobenzyloxy, 3-chlorobenzyloxy, 2-chlorobenzyloxy, 4-chlorobenzyloxy, and R is₂、R₃、R₄、R₅、R₆At least 2 of which are hydrogen.

12. The compound according to claim 2, isomers, hydrates, solvates, pharmaceutically acceptable salts thereof, and prodrugs thereof, which is selected from the group consisting of:

13. the compound according to claim 1 or 2, an isomer, hydrate, solvate, pharmaceutically acceptable salt thereof, and prodrug thereof, selected from the group consisting of:

14. a pharmaceutical composition comprising a compound of any one of claims 1 to 13, a pharmaceutically acceptable salt, isomer, solvate, or prodrug thereof, and one or more pharmaceutically acceptable carriers or excipients.

15. The pharmaceutical composition of claim 14, wherein the pharmaceutical composition further comprises one or more additional therapeutic agents.

16. Use of a compound, pharmaceutically acceptable salt, isomer, solvate or prodrug thereof according to any of claims 1-13 for the manufacture of a medicament for the treatment of cancer and autoimmune diseases associated with the tyrosine kinases EGFR, HER2, wherein the cancer and autoimmune diseases comprise: fundus disease, dry eye, psoriasis, vitiligo, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, crohn's disease, atheroma, pulmonary fibrosis, hepatic fibrosis, myelofibrosis, non-small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myelogenous leukemia, acute myelogenous leukemia, non-hodgkin's lymphoma, nasopharyngeal cancer, esophageal cancer, brain tumor, B-cell and T-cell lymphoma, multiple myeloma, biliary tract cancer sarcoma, bile duct cancer.