CN115894455B

CN115894455B - Quinazoline compound, composition and application thereof

Info

Publication number: CN115894455B
Application number: CN202211212428.3A
Authority: CN
Inventors: 张强; 杨磊夫; 郑南桥
Original assignee: Beijing Scitech MQ Pharmaceuticals Ltd
Current assignee: Beijing Scitech MQ Pharmaceuticals Ltd
Priority date: 2021-09-30
Filing date: 2022-09-29
Publication date: 2024-04-19
Anticipated expiration: 2042-09-29
Also published as: CN115894455A

Abstract

The invention provides a quinazoline compound, a composition and application thereof, and in particular relates to a compound shown in a formula (I), a stereoisomer thereof and pharmaceutically acceptable salts thereof, a composition thereof and application thereof in preparing medicaments serving as tyrosine kinase inhibitors. The compound has good inhibitory activity on EGFR, HER2 kinase and 20 exon mutation thereof.

Description

Quinazoline compound, composition and application thereof

Technical Field

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

Background

Epidermal growth factor receptor (ErbB) tyrosine kinase can regulate cell proliferation, migration, differentiation, apoptosis, and cell movement through a variety of pathways. In many forms of malignancy, erbB family members, and portions thereof, are often overexpressed, amplified, or mutated, making them important tumor therapeutic targets. The family of protein kinases includes: erbB1/EGFR/HER1, erbB2/HER2, erbB3/HER3 and ErbB4/HER4. Wherein, based on EGFR and HER2, several kinase inhibitors for treating non-small cell lung cancer and breast cancer have been successfully developed .(Dienstmann R.,et.al.,(2001)Personalizing Therapy with Targeted Agents in Non-Small Cell Lung Cancer.ONCOTARGET.2(3),165.;Mitri Z.,et.al.(2012)The HER2 Receptor in Breast Cancer:Pathophysiology,Clinical Use,and New Advances in Therapy.,Chemotherapy Research&Practice.,Volum 2012(23),743193.).

However, the expression of EGFR and HER2 is not stable, and the amplification and rearrangement of genes often occurs, so that the antigen phenotype on the surface of tumor cells is changed, and the curative effects of the existing targeting drugs on different mutations of EGFR and HER2 are very different, wherein the inhibition capability on Ins20 is the weakest, so that Ins20 mutation becomes drug-resistant mutation, and the existing multi-generation targeting drugs have little effect. The 20 exon mutations of the EGFR and HER2 genes occur at similar positions, but EGFR20 exon insertion mutations are of many types, and 122 have now been found; in comparison, the HER2 gene 20 exon insertion mutation types are fewer, most commonly the a775_g776insYVMA point, and the mutation accounts for nearly 70%. Statistics have also shown that about 3% of NSCLC patients carry HER2 mutations, of which about 90% are 20 exon mutant patients of the HER2 gene. For these EGFR/HER 220 exon mutant patients, the efficacy of existing targeted TKIs drugs is very limited.

There are also a small number of current projects being investigated for EGFR/HER2 Ins20 mutations. Wave Ji Tini (Poziotinib) is a broad spectrum HER inhibitor developed by han mei, and clinical data shows that it also has a certain effect on 20 exon mutation of EGFR/HER2, but Poziotinib has a higher adverse reaction rate. The related 20 exon mutations of pyrroltinib are also being studied clinically. Up to now, there is a tremendous unmet medical need for both indications, 20 exon mutations for EGFR and HER2 genes, especially for the HER2a775_g776insYVMA mutation.

Disclosure of Invention

In one aspect, the invention provides a compound shown in formula (I), a stereoisomer and pharmaceutically acceptable salts thereof,

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

r ₁ is hydrogen, hydroxy, 4-7 membered heteroalicyclic or-NR ^aR^b,

R ^a、R^b is each independently hydrogen, C ₁-C₆ alkyl, C ₃-C₆ cycloalkyl, C ₁-C₆ alkyl substituted with hydroxy, C ₁-C₆ alkyl substituted with C _1-C₃ alkoxy, or C ₁-C₆ alkyl substituted with C _3-C₆ cycloalkyl;

The 4-7 membered heteroalicyclic is a heteroalicyclic containing 1-2 heteroatoms selected from N, O or S, and is unsubstituted or substituted with one or two of C ₁-C₃ alkyl, C ₁-C₄ acyl, hydroxy, cyano, aminoacyl, mono-or di-C ₁-C₃ alkyl substituted aminoacyl, C _1-C₃ alkyl sulfonyl, C _1-C₃ alkyl sulfoxide, oxo (=o);

R ₂ is aryl or heteroaryl substituted or unsubstituted with 1 to 3 substituents selected from halogen, cyano, C ₁-C₃ alkyl, C ₁-C₃ alkoxy, halo C ₁-C₃ alkyl, hydroxy, C ₃-C₄ cycloalkyl, C ₂-C₃ alkynyl, C ₂-C₃ alkenyl or-NR' R ";

R ₃、R₄、R₅ is each independently hydrogen, halogen, C ₁-C₆ alkyl, halogenated C ₁-C₃ alkyl, -O- (CH ₂)n-R₆),

R ₆ is hydrogen, C ₁-C₃ alkyl, aryl or heteroaryl substituted or unsubstituted by 1 to 3 substituents selected from halogen, cyano, hydroxy, C ₁-C₃ alkyl, C ₁-C₃ alkoxy, halogenated C ₁-C₃ alkyl, C ₃-C₄ cycloalkyl, C ₂-C₃ alkynyl, C ₂-C₃ alkenyl or-NR 'R', n is an integer from 0 to 3,

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

R ', R' are each independently H or C ₁-C₃ alkyl.

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

R ₁ is 4-7 membered heteroalicyclic or-NR ^aR^b,

R ^a、R^b is each independently hydrogen, C ₁-C₃ alkyl, C ₃-C₆ cycloalkyl, C ₁-C₃ alkyl substituted with hydroxy, C ₁-C₃ alkyl substituted with C _1-C₃ alkoxy;

The 4-7 membered heteroalicyclic group is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, thiomorpholinyl, and the above groups are unsubstituted or substituted with one or two of methyl, ethyl, propyl, isopropyl, aldehyde, acetyl, propionyl, hydroxy, cyano, aminoacyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, methylsulfonyl, ethylsulfoxide, propylsulfoxide, isopropylsulfoxide, oxo (=o).

More preferably, R ₁ is 1-methylpyrrolidin-2-yl, 1-ethylpyrrolidin-2-yl, 1-propylpyrrolidin-2-yl, 1-isopropylpyrrolidin-2-yl, pyrrolidin-1-yl, piperidin-1-yl, 1-methylpiperazin-4-yl, 1-ethylpiperazin-4-yl, morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, thiomorpholinyl, dimethylamino, diethylamino, dipropylamino, diisopropylamino, methylethylamino, methylpropylamino, methylamino, ethylamino, propylamino, isopropylamino, cyclopropylamino, cyclobutylamino, methylisopropylamino, N-methyl-N-cyclopropylamino, N-methyl-N-cyclobutylamino or ethylpropylamino;

More preferably, R ₁ is 1-methylpyrrolidin-2-yl or dimethylamino.

According to a preferred embodiment, R ₂ is aryl or heteroaryl substituted or unsubstituted with 1 to 3 substituents selected from fluoro, chloro, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethyl, hydroxy, cyclopropyl, cyclobutyl, ethynyl, vinyl;

The aryl is phenyl, naphthyl, and the heteroaryl is pyridyl, pyrimidinyl, pyrrolyl, thienyl, furyl, imidazolyl, indazolyl or indolyl.

More preferably, R ₂ is phenyl, 2-chlorophenyl, 2-fluorophenyl, 2-methoxyphenyl, 2-methylphenyl, 2-cyanophenyl, 3-chlorophenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-methylphenyl, 3-cyanophenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-methylphenyl, 4-cyanophenyl, 3, 4-dimethoxyphenyl, 3, 4-dimethylphenyl, 3, 4-dichlorophenyl, 3, 4-difluorophenyl, 1-methyl-1H-indol-6-yl, 1H-indazol-6-yl.

According to a preferred embodiment, R ₃、R₄、R₅ is each independently hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, -O- (CH ₂)n-R₆,

R ₆ is hydrogen, methyl, ethyl, propyl, isopropyl or aryl or heteroaryl substituted or unsubstituted by 1 to 3 substituents selected from fluorine, chlorine, cyano, hydroxy, 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 each independently H or methyl,

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

More preferably, R ₃、R₄、R₅ is each independently hydrogen, fluorine, chlorine, -O- (CH ₂)n-R₆),

R ₆ is aryl or heteroaryl substituted or unsubstituted by 1 to 3 substituents selected from fluorine, chlorine, cyano, hydroxy, methyl, ethyl, methoxy, ethoxy, fluoromethyl, fluoroethyl, difluoromethyl, trifluoromethyl, n is an integer from 0 to 3,

The aryl is phenyl and the heteroaryl is pyridyl.

Also preferably, R ₃、R₄、R₅ is each independently hydrogen, fluoro, chloro, phenoxy, 2-fluorophenoxy, 3-fluorophenoxy, 4-fluorophenoxy, 2-pyridyloxy, 3-pyridyloxy, 4-pyridyloxy, pyridin-2-ylmethoxy, pyridin-3-ylmethoxy, pyridin-4-ylmethoxy, 3-fluorobenzyloxy, 2-fluorobenzyloxy, 4-fluorobenzyloxy, 3-chlorobenzyloxy, 2-chlorobenzyloxy, 4-chlorobenzyloxy;

Most preferably, each R ₃、R₄ is independently hydrogen, fluoro, chloro, R ₅ is hydrogen, fluoro, chloro, pyridin-2-ylmethoxy, pyridin-3-ylmethoxy, pyridin-4-ylmethoxy, 3-fluorobenzyloxy, 2-fluorobenzyloxy, 4-fluorobenzyloxy, 3-chlorobenzyloxy, 2-chlorobenzyloxy, 4-chlorobenzyloxy.

According to a preferred embodiment, the compound has the structure of formula (II):

Wherein, the specific description of R ₁、R₃、R₄、R₅ is as described above,

R ₇、R₈ is each independently hydrogen, halogen, cyano, C ₁-C₃ alkyl, C ₁-C₃ alkoxy, halo C ₁-C₃ alkyl, hydroxy, C ₃-C₄ cycloalkyl, C ₂-C₃ alkynyl, C ₂-C₃ alkenyl or-NR 'R ", R' R" are each independently H or C ₁-C₃ alkyl.

More preferably, R ₇、R₈ is each independently hydrogen, fluoro, chloro, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethyl, hydroxy, cyclopropyl, cyclobutyl, ethynyl, vinyl.

More preferably, each R ₇、R₈ is independently hydrogen, fluoro, chloro, cyano, methyl, methoxy. Typical compounds according to the application are as follows:

In another aspect, the application provides a pharmaceutical composition comprising a compound of the application, a pharmaceutically acceptable salt, stereoisomer, 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 application also relates to a method of treating EGFR, HER2, etc. kinase-mediated diseases or conditions, including those mentioned previously, comprising administering to a patient (human or other mammal, especially a human) in need thereof a therapeutically effective amount of a compound of the application or a salt thereof.

Drawings

The above and other objects, features and other advantages of the present invention will be more clearly understood from the following detailed description taken in conjunction with the accompanying drawings, in which,

FIG. 1 shows the effect of PYROTINIB on T/C values of tumor-bearing mice over time;

FIG. 2 shows the effect of the compound of example 53 of the present application on T/C values of tumor-bearing mice over time.

Detailed Description

Unless otherwise indicated, the following terms used in the present application (including the specification and claims) have the definitions set forth below. In the present application, the use of "or" and "means" and/or "unless stated otherwise. Furthermore, the use of the term "including" and other forms, such as "comprising," "containing," and "having," is 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 specifically indicated otherwise, alkyl represents a saturated straight-chain, branched-chain hydrocarbon group having the indicated number of carbon atoms, the term C ₁-C₆ alkyl represents an alkyl moiety containing from 1 to 6 carbon atoms, and similarly C ₁-C₃ alkyl represents an alkyl moiety containing from 1 to 3 carbon atoms, e.g., C ₁-C₆ alkyl includes 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-methylpentyl, and the like.

When substituent terms such as "alkyl" are used in combination with other substituent terms, such as in the terms "C ₁-C₃ alkoxy C ₁-C₆ alkylthio" or "hydroxy substituted C ₁-C₆ 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. Examples of "C ₁-C₃ alkoxy C ₁-C₆ alkylthio" include, but are not limited to, methoxymethylthio, methoxyethylthio, ethoxypropylthio, and the like. Examples of "hydroxy-substituted C ₁-C₆ 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 as previously described with-O-, e.g., methoxy, ethoxy, and the like. Similarly, alkylthio is an alkyl-S-group formed from a straight or branched chain alkyl group as previously described with-S-, e.g., methylthio, ethylthio, and the like.

Alkenyl and alkynyl include straight chain, branched alkenyl or alkynyl groups, the terms C ₂-C₆ alkenyl or C ₂-C₆ alkynyl groups denote straight chain or branched hydrocarbon groups having at least one alkenyl or alkynyl group.

The term "haloalkyl", for example "haloc ₁-C₆ alkyl", means a group having one or more halogen atoms, which may be the same or different, on one or more carbon atoms of an alkyl moiety comprising 1 to 6 carbon atoms. Examples of "halo C ₁-C₆ alkyl" may include, but are not limited to, -CF ₃ (trifluoromethyl), -CCl ₃ (trichloromethyl), 1-difluoroethyl, 2-trifluoroethyl, hexafluoroisopropyl, and the like. Similarly, the term "halo C ₁-C₆ alkoxy" means a haloalkyl-O-group formed from said halo C ₁-C₆ alkyl and-O-, which may be, for example, trifluoromethoxy, trichloromethoxy, and the like.

The term "C ₁-C₄ acyl" includes formyl (aldehyde) (-CHO), acetyl (CH ₃ CO-), propionyl (C ₂H₅ CO-) and the like. The term "aminoacyl" refers to NH ₂ CO-.

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

The term "aryl" means a group or moiety comprising an aromatic, mono-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, means an unsubstituted or substituted stable 4 to 7 membered non-aromatic monocyclic saturated ring system consisting of carbon atoms and 1 to 3 heteroatoms selected from N, O, S, wherein N, S heteroatoms may optionally be oxidized and N heteroatoms may optionally be quaternized. Examples of such heterocycles include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, 1, 3-dioxolanyl, piperidinyl, piperazinyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, 1, 3-dioxanyl, 1, 4-dioxanyl, 1, 3-oxathiolanyl, 1, 3-dithianyl, 1, 4-oxathiolanyl, 1, 4-dithianyl, morpholinyl, thiomorpholinyl.

The term "heteroaryl" as used herein means a group or moiety comprising an aromatic mono-or bi-cyclic radical (containing 5 to 10 ring atoms) comprising 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. The term also includes bicyclic heteroaryl groups containing an aryl ring moiety fused to a heterocycloalkyl ring moiety or containing 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, but also an unsubstituted or substituted benzofused heteroaromatic ring system of 9 or 10 ring atoms or bicyclic heteroaromatic ring system, which consist of carbon atoms and from 1 to 3 heteroatoms selected from N, O, S, in which N, S heteroatoms may be oxidized and N heteroatoms may also be quaternized. Heteroaryl groups may be attached to any heteroatom or carbon atom that results in the creation of 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, benzofuryl, isobenzofuryl, 2, 3-dihydrobenzofuryl, 1, 3-benzodioxolyl, dihydrobenzodioxanyl, benzothienyl, indolizinyl, indolyl, isoindolyl indolinyl, benzimidazolyl, dihydrobenzimidazolyl, benzoxazolyl, dihydrobenzoxazolyl, benzothiazolyl, benzisothiazolyl, dihydrobenzisothiazolyl, indazolyl, imidazopyridinyl, pyrazolopyridinyl, 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 a-C (O) -group. The terms "halogen" and "halo" denote chloro, fluoro, bromo or iodo substituents. "oxo" means an oxygen moiety of a double bond; for example, if directly attached to a carbon atom, a carbonyl moiety is formed (c=o). "hydroxy" 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 will be appreciated 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 a water-soluble form. The present invention includes all such solvated and unsolvated forms.

The term "isomer" in the present 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 manner in which atoms are spatially arranged. Certain compounds described herein contain one or more asymmetric centers and thus can produce enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R) -or (S) -depending on absolute stereochemistry. The chemical entities, pharmaceutical compositions and methods of the present application are intended to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. The optically active (R) -and (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical activity of a compound may be analyzed by any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of dominance 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 may be performed as follows: (1) By formation of 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 chromatography or liquid chromatography in a chiral environment, for example on a chiral support (e.g. silica gel with chiral ligands bound thereto) or in the presence of a chiral solvent. Those skilled in the art will appreciate that when converting a desired stereoisomer into 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 by asymmetric transformation of one enantiomer into the other.

When a compound described herein contains an olefinic double bond, it is intended that the compound include the various cis and trans isomers unless specified otherwise.

"Tautomers" are structurally different isomers that can be converted to each other by tautomerization. "tautomerization" is a form of isomerization and includes proton transfer or proton transfer tautomerization, which can be considered a subset of acid-base chemistry. "proton transfer tautomerization" or "proton transfer tautomerization" refers to proton transfer accompanied by bond level transformations, often the exchange of single bonds with adjacent double bonds. When tautomerization may occur (e.g., in solution), chemical equilibrium of the tautomers may be reached. One example of tautomerism is keto-enol tautomerism.

The compounds of the present invention as active ingredients, as well as the process for preparing the compounds, are all the subject matter 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 free form for therapy 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 salts 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 the compounds of the present invention with a suitable free base or acid. Including but not limited to salts 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 methods. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartate, benzenesulfonates, benzoates, bisulphates, borates, butyrates, camphorites, camphorsulphonates, citrates, digluconates, dodecylsulphates, ethanesulphonates, formates, fumarates, glucoheptonates, glycerophosphate, gluconate, hemisulphates, caprates, hydroiodites, 2-hydroxyethanesulphonates, lactonates, lactates, laurates, laurylsulphates, malates, maleates, methanesulfonates, 2-naphthalenesulphonates, nicotinates, nitrates, oleates, palmitates, pamonates, pectates, persulphates, per 3-phenylpropionates, phosphates, picrates, propionates, stearates, sulphates, thiocyanates, p-toluene sulphonates, undecanoates and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include suitable non-toxic ammonium, quaternary ammonium, and amine cations formed using, for example, halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

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

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

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 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 simultaneous co-administration of each agent or by sequential administration of each agent, in either case with the objective of achieving the optimal effect of the drug. Co-administration includes simultaneous delivery of the dosage forms, as well as separate individual dosage forms for each compound. Thus, administration of the compounds of the present invention may be used concurrently with other therapies known in the art, for example, in cancer treatment using radiation therapy or additional therapies such as cytostatic agents, cytotoxic agents, other anticancer agents, etc., to ameliorate cancer symptoms. The invention is not limited to the order of administration; the compounds of the invention may be administered previously, concurrently, or after other anticancer or cytotoxic agents.

For the preparation of the pharmaceutical compositions of this invention, one or more compounds or salts of formula (I) as the active ingredient may be intimately admixed with pharmaceutical carriers according to conventional pharmaceutical compounding techniques, which carriers may take a wide variety of forms depending of the preparation formulated for administration (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, published by the United states society of pharmacy and the United kingdom pharmaceutical society.

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

The therapeutic compound may also be administered to a mammal other than a human. The dosage of the drug to be administered to a mammal will depend on the species of the animal and its disease condition or its state of imbalance. The therapeutic compound may be administered to the animal in the form of a capsule, bolus, or medicinal tablet. Therapeutic compounds may also be administered to animals by injection or infusion. We have prepared these pharmaceutical forms according to conventional means that meet the veterinary practice standards. Alternatively, the pharmaceutical composition may be mixed with an animal feed for feeding to the animal, and thus the concentrated feed additive or ready mix may be prepared for mixing with a 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 comprises the use of the compounds of the invention or pharmaceutically acceptable derivatives thereof for the manufacture of a medicament for the treatment of cancers and autoimmune diseases associated with the tyrosine kinases EGFR, HER 2. Agents for such cancers (including non-solid tumors, primary or metastatic cancers, as noted elsewhere herein, and including one or more other treatments that are resistant or refractory to cancer) and other diseases (including, but not limited to, ocular fundus disease, psoriasis, atherosclerosis, pulmonary fibrosis, liver fibrosis, myelofibrosis, 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 tumor, thyroid cancer, chronic myelogenous leukemia, acute myelogenous leukemia, non-hodgkin lymphoma, nasopharyngeal carcinoma, esophageal cancer, brain tumor, B-cell and T-cell lymphoma, multiple myeloma, biliary sarcoma, cholangiocarcinoma.

Detailed Description

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

The present application will be described in further detail with reference to specific embodiments in order to make the objects, technical solutions and advantages of the present application more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the application. The examples are not to be construed as limiting the specific techniques or conditions described in the literature in this field or as per the specifications of the product. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention. The term "and/or" as used herein includes any and all combinations of one or more of the associated listed items. The examples provided below will better illustrate the application, all temperatures being in degrees celsius unless otherwise indicated. The nomenclature of some of the compounds of the present application is translated according to chemdraw nomenclature.

Synthesis of intermediates

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

(R, E) -3- (1-methylpyrrolidin-2-yl) acrylic acid (160 mg,1 mmol) was added to dried dichloromethane (3 ml), oxalyl chloride (130 mg,1 mmol), DMF (1 drop, catalytic amount) was added separately, stirred at room temperature for 3 hours, the reaction system became cloudy, clear, concentrated to give an off-white solid;

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

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

5-Chloro-6-nitroquinazolin-4-ol (2.25 g,10 mmol) is added into a round bottom flask of thionyl chloride (20 ml), dry DMF (2 ml) is added in batches under the ice water bath condition, then the oil bath is regulated to 95 ℃ for heating reaction for 1 hour, after the system is dissolved, the oil bath temperature is regulated to 90 ℃ for continuous reflux reaction for 2 hours, cooling is carried out, and a pale yellow solid product is obtained by concentration; dissolving the obtained product in 1, 2-dichloroethane (50 ml) under ice-water bath condition, slowly adding triethylamine (3.05 g,30 mmol), adding 3-chloro-2-fluoroaniline (2.20 g,15 mmol), heating to 60 ℃ for reaction for 2 hours, cooling after the reaction is finished, concentrating, adding methanol, stirring and pulping, filtering to obtain 3.01 g of yellow solid product, and obtaining 85% yield, LC-MS:353[ M+H ] ⁺;

Step 2): n- (3-chloro-2-fluorophenyl) -6-nitro-5-phenylquinazolin-4-amine

5-Chloro-N- (3-chloro-2-fluorophenyl) -6-nitroquinazolin-4-amine (154 mg,436 mu mol), phenylboronic acid (160 mg,1.31 mmol), pd (dppf) Cl ₂(31.86mg,43.55μmol)、Na₂CO₃ (138.47 mg,1.31 mmol) are dissolved in a mixed solvent of 1, 4-dioxane (5 mL) and H ₂ O (0.5 mL), the temperature is slowly raised to 100 ℃ under the protection of argon, the reaction is carried out for 15 hours, the mixture is cooled and filtered, the mixture is washed by using a mixed solution of dichloromethane and methanol, and the filtrate is concentrated to obtain a product which is directly subjected to the next reaction; LC-MS 395[ M+H ] ⁺;

Step 3): n ⁴ - (3-chloro-2-fluorophenyl) -5-phenylquinazoline-4, 6-diamine

N- (3-chloro-2-fluorophenyl) -6-nitro-5-phenylquinazolin-4-amine (72 mg, 183. Mu. Mol), NH ₄ Cl (97.75 mg,1.83 mmol), fe (51.03 mg, 914. Mu. Mol) were placed in EtOH (20 mL) and H ₂ O (5 mL) and reacted under argon at 80℃for 1 hour. LCMS monitored complete disappearance of starting material. The reaction was stirred with DCM and MeOH and filtered, and the filter cake was washed with MeOH. The filtrate was evaporated to dryness and extracted with DCM and saturated aqueous sodium bicarbonate, and the organic phase was dried and evaporated to dryness. Preparation of silica gel plate purification using DCM/MeOH 100:4 to obtain 52mg of the product with a yield of 77%, LC-MS:365[ M+H ] ⁺;

Step 4): n ⁴ - (3-chloro-2-fluorophenyl) -5-phenylquinazoline-4, 6-diamine (36.5 mg,0.1 mol) was dissolved in NMP (1 mL), placed in an ice-water bath at 0℃to which (R, E) -3- (1-methylpyrrolidin-2-yl) acryloyl chloride (26.0 mg,0.15 mol) was added and stirred at room temperature for 0.5 hours. The reaction solution was quenched with MeOH, filtered, and purified by high performance preparative liquid phase (C18 column, 0.05% aqueous trifluoroacetic acid and acetonitrile gradient elution to give 33mg of mono-trifluoroacetate as a white solid product, yield 54％;¹H NMR(400MHz,DMSO-d₆)δ9.91(s,1H),9.45(s,1H),8.74(s,1H),8.10–8.00(m,3H),7.60(s,3H),7.48(s,2H),7.28(d,J＝7.6Hz,1H),7.17(dd,J＝16.3,8.1Hz,2H),6.64(dd,J＝15.3,8.7Hz,1H),6.31(d,J＝15.4Hz,1H),3.95(q,J＝8.5Hz,1H),3.68–3.60(m,1H),3.10(t,J＝9.4Hz,1H),2.74(d,J＝4.1Hz,3H),2.27-2.24(m,1H),2.10–1.90(m,2H),1.88–1.73(m,1H).MS:502[M+H]⁺.

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

The synthesis was carried out in the same manner as in example 1 except that 3-chlorobenzeneboronic acid was used in place of phenylboronic acid in step 2 to give a white solid product of monotrifluoroacetate salt ;¹H NMR(400MHz,DMSO-d₆)δ9.90(s,1H),9.58(s,1H),8.74(s,1H),8.05–7.95(br,3H),7.58(brs,3H),7.39(s,1H),7.28(s,2H),7.18(s,1H),6.65(dd,J＝15.3,8.7Hz,1H),6.34(dd,J＝15.1,4.2Hz,1H),3.99(br,1H),3.65(d,J＝11.0Hz,1H),3.10(p,J＝8.7Hz,1H),2.75(s,3H),2.26–2.21(m,1H),2.08–1.93(m,2H),1.89–1.77(m,1H).MS:536[M+H]⁺.

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

The synthesis was carried out in the same manner as in example 1 except that 3-methoxyphenylboronic acid was used in place of phenylboronic acid in step 2 to obtain a white solid product of monotrifluoroacetate salt ;¹H NMR(400MHz,DMSO-d₆)δ10.02(s,1H),9.45(s,1H),8.76(s,1H),8.07(d,J＝9.0Hz,2H),7.95(d,J＝9.0Hz,1H),7.51(t,J＝8.0Hz,1H),7.40–7.26(m,2H),7.25–7.12(m,2H),7.08(s,1H),7.00(d,J＝7.5Hz,1H),6.67(d,J＝15.4Hz,1H),6.44–6.32(m,1H),3.99(s,1H),3.79(s,3H),3.66(s,1H),3.11(p,J＝9.1Hz,1H),2.75(s,3H),2.30–2.21(m,1H),2.03–2.00(m,2H),1.87–1.77(m,1H).MS:532[M+H]⁺.

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

The synthesis was carried out in the same manner as in example 1 except that 3-cyanobenzeneboronic acid was used in place of phenylboronic acid in step2 to give a white solid product of monotrifluoroacetate salt ;¹H NMR(400MHz,DMSO-d₆)δ9.41–9.19(m,1H),8.69(s,1H),8.16–7.80(m,4H),7.71–7.45(m,3H),7.32–6.85(m,3H),6.48(d,J＝15.5Hz,1H),6.05(d,J＝15.5Hz,1H),3.00(ddd,J＝10.0,7.1,3.4Hz,1H),2.76–2.60(m,1H),2.13(brs,4H),2.00–1.87(m,1H),1.70(tt,J＝9.2,6.3Hz,2H),1.50(dt,J＝14.3,8.2Hz,1H).MS:527[M+H]⁺.

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

The synthesis was carried out in the same manner as in example 1 except that 3-methylphenylboronic acid was used in place of phenylboronic acid in step2 to obtain a white solid product of monotrifluoroacetate salt ;¹H NMR(400MHz,DMSO-d₆)δ10.00(s,1H),9.43(s,1H),8.73(s,1H),8.09–7.89(m,3H),7.48(t,J＝7.6Hz,1H),7.40(d,J＝7.7Hz,1H),7.29(br,2H),7.25–7.23(m,2H),7.19–7.17(m,1H),6.65(d,J＝15.4Hz,1H),6.34(d,J＝15.2Hz,1H),3.97(s,1H),3.67(d,J＝9.8Hz,1H),3.10(s,1H),2.74(s,3H),2.37(s,3H),2.26–2.22(m,1H),2.03–1.97(m,2H),1.89–1.76(m,1H).MS:516[M+H]⁺.

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

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-4-fluoroaniline was used in place of 3-chloro-2-fluoroaniline in step 1 to carry out the reaction, and finally a white solid product of monotrifluoroacetate was obtained ;¹H NMR(400MHz,DMSO-d₆)δ10.10(s,1H),9.57(s,1H),8.80(s,1H),8.06(d,J＝8.9Hz,1H),7.94(d,J＝8.9Hz,1H),7.75–7.61(m,4H),7.53–7.51(m,2H),7.35(t,J＝9.0Hz,1H),7.23(s,1H),6.77–6.74(m,1H),6.65(d,J＝15.3Hz,1H),6.34(d,J＝15.3Hz,1H),4.05–3.88(m,1H),3.65(d,J＝9.0Hz,1H),3.09(d,J＝10.6Hz,1H),2.74(d,J＝2.6Hz,3H),2.26–2.23(m,1H),2.13–1.89(m,2H),1.87–1.77(m,1H).MS:502[M+H]⁺.

EXAMPLE 7 (R, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -5- (3-chlorophenyl) quinazolin-6-yl) -3- (1-methylpyrrolidin-2-yl) acrylamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-4-fluoroaniline was used in place of 3-chloro-2-fluoroaniline in step 1 and 3-chlorobenzeneboronic acid was used in place of phenylboronic acid in step 2 to obtain a white solid product of monotrifluoroacetate salt ;¹H NMR(400MHz,DMSO-d₆)δ10.17(s,1H),9.73(s,1H),8.81(s,1H),8.06(d,J＝8.9Hz,1H),7.95(d,J＝8.9Hz,1H),7.65–7.56(m,5H),7.43(d,J＝7.4Hz,1H),7.38(t,J＝9.0Hz,1H),6.87(d,J＝8.4Hz,1H),6.68(d,J＝15.3Hz,1H),6.38(d,J＝15.2Hz,1H),4.00(s,1H),3.69–3.65(m,1H),3.11(s,1H),2.75(s,3H),2.27–2.23(m,1H),2.11–1.93(m,2H),1.86–1.82(m,1H).MS:536[M+H]⁺.

EXAMPLE 8 (R, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -5- (3-methoxyphenyl) quinazolin-6-yl) -3- (1-methylpyrrolidin-2-yl) acrylamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-4-fluoroaniline was used in place of 3-chloro-2-fluoroaniline in step 1 and 3-methoxyphenylboronic acid was used in place of phenylboronic acid in step 2 to obtain a white solid product of monotrifluoroacetate salt ;¹H NMR(400MHz,DMSO-d₆)δ10.15(s,1H),9.56(s,1H),8.81(s,1H),8.09(d,J＝9.0Hz,1H),7.94(d,J＝8.9Hz,1H),7.71(d,J＝6.9Hz,1H),7.57(t,J＝7.9Hz,1H),7.41–7.36(m,2H),7.22(d,J＝8.4Hz,1H),7.12(s,1H),7.06(d,J＝7.5Hz,1H),6.82(d,J＝9.0Hz,1H),6.68(dd,J＝15.4,8.7Hz,1H),6.39(d,J＝15.3Hz,1H),3.99(s,1H),3.80(s,3H),3.67(s,1H),3.11(s,1H),2.75(s,3H),2.30–2.21(m,1H),2.12–1.92(m,2H),1.90–1.78(m,1H).MS:532[M+H]⁺.

EXAMPLE 9 (R, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -5- (3-cyanophenyl) quinazolin-6-yl) -3- (1-methylpyrrolidin-2-yl) acrylamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-4-fluoroaniline was used in place of 3-chloro-2-fluoroaniline in step1 and 3-cyanobenzeneboronic acid was used in place of phenylboronic acid in step 2 to obtain a white solid product of monotrifluoroacetate salt ;¹H NMR(400MHz,DMSO-d₆)δ10.18(s,1H),9.79(s,1H),8.79(s,1H),8.05(d,J＝8.9Hz,1H),7.99–7.91(m,3H),7.74(d,J＝7.9Hz,1H),7.68(t,J＝7.7Hz,1H),7.61(s,1H),7.36(t,J＝9.0Hz,1H),6.87(s,1H),6.67(d,J＝15.3Hz,1H),6.36(d,J＝15.5Hz,1H),4.00(s,1H),3.67(s,1H),3.11(s,1H),2.76(s,3H),2.27–2.24(m,1H),2.13–1.92(m,2H),1.86–1.83(m,1H).MS:527[M+H]⁺.

EXAMPLE 10 (R, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -5- (m-tolyl) quinazolin-6-yl) -3- (1-methylpyrrolidin-2-yl) acrylamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-4-fluoroaniline was used in place of 3-chloro-2-fluoroaniline in step1 and 3-methylphenylboronic acid was used in place of phenylboronic acid in step 2 to obtain the white solid product of monotrifluoroacetate salt ;¹H NMR(400MHz,DMSO-d₆)δ10.03(s,1H),9.54(s,1H),8.82(s,1H),8.09(d,J＝8.9Hz,1H),7.94(d,J＝8.9Hz,1H),7.71–7.68(m,1H),7.60–7.45(m,2H),7.42–7.27(m,4H),6.80–6.61(m,2H),6.37(d,J＝15.3Hz,1H),3.98(s,1H),3.69–3.64(m,1H),3.13–3.10(m,1H),2.75(s,3H),2.40(s,3H),2.28–2.21(m,1H),2.08–2.03(m,2H),1.89–1.77(m,1H).MS:516[M+H]⁺.

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

The synthesis was carried out in the same manner as in example 1 except that (E) -4- (dimethylamino) but-2-enoyl chloride was used instead of (R, E) -3- (1-methylpyrrolidin-2-yl) acryloyl chloride in step 4 to react, and finally a white solid product of monotrifluoroacetate was obtained ;¹H NMR(400MHz,DMSO-d₆)δ9.78(s,1H),9.48(s,1H),8.74(s,1H),8.10–7.95(m,3H),7.59(br,3H),7.51–7.45(m,2H),7.29(t,J＝7.4Hz,1H),7.20–7.16(m,2H),6.64–6.57(m,1H),6.26(d,J＝15.4Hz,1H),3.94–3.76(m,2H),2.75(br,6H).MS:476[M+H]⁺.

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

The synthesis was carried out in the same manner as in example 1 except that 3-chlorobenzeneboronic acid was used in place of phenylboronic acid in step 2 and (E) -4- (dimethylamino) but-2-enoyl chloride was used in place of (R, E) -3- (1-methylpyrrolidin-2-yl) acryloyl chloride in step 4 to obtain a white solid product in free form ;¹H NMR(400MHz,DMSO-d₆)δ10.11(s,1H),9.67(s,1H),8.73(s,1H),8.16–7.80(m,3H),7.55(br,3H),7.39-7.29(m,2H),7.18(t,J＝8.2Hz,1H),6.65(dt,J＝14.7,7.0Hz,1H),6.31(d,J＝15.3Hz,1H),3.89(d,J＝7.0Hz,2H),2.77(s,6H).MS:510[M+H]⁺.

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

The synthesis was carried out in the same manner as in example 1 except that 3-methoxyphenylboronic acid was used instead of phenylboronic acid in step 2, and (E) -4- (dimethylamino) but-2-enoyl chloride was used instead of (R, E) -3- (1-methylpyrrolidin-2-yl) acryloyl chloride in step 4, to obtain a white solid product in the free state ;¹H NMR(400MHz,DMSO-d₆)δ10.27(s,1H),9.58(s,1H),8.85(s,1H),8.13(d,J＝8.9Hz,1H),7.99(d,J＝8.9Hz,1H),7.91(t,J＝7.9Hz,1H),7.61(br,1H),7.51(t,J＝7.9Hz,1H),7.38–7.34(m,1H),7.26–7.16(m,1H),7.14(d,J＝8.4Hz,1H),7.09(br,1H),7.01(d,J＝7.5Hz,1H),6.66(dt,J＝15.0,7.0Hz,1H),6.34(d,J＝15.0Hz,1H),3.89(d,J＝7.0Hz,2H),3.78(s,3H),2.76(s,6H).MS:506[M+H]⁺.

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

The synthesis was carried out in the same manner as in example 1 except that 3-cyanobenzeneboronic acid was used in place of phenylboronic acid in step 2 and (E) -4- (dimethylamino) but-2-enoyl chloride was used in place of (R, E) -3- (1-methylpyrrolidin-2-yl) acryloyl chloride in step 4 to obtain a white solid product in the free state ;¹H NMR(400MHz,DMSO-d₆)δ10.12(s,1H),9.70(s,1H),8.61(s,1H),8.00(d,J＝8.8Hz,1H),7.89(s,3H),7.67-7.41(m,3H),7.28(br,1H),7.14(t,J＝8.2Hz,1H),6.63(dt,J＝15.3,7.0Hz,1H),6.28(d,J＝15.3Hz,1H),3.88(d,J＝7.0Hz,2H),2.76(s,6H).MS:501[M+H]⁺.

EXAMPLE 15 (E) -N- (4- ((3-chloro-2-fluorophenyl) amino) -5- (m-tolyl) quinazolin-6-yl) -4- (dimethylamino) but-2-enamide

The synthesis was carried out in the same manner as in example 1 except that 3-methylphenylboronic acid was used instead of phenylboronic acid in step 2 and (E) -4- (dimethylamino) but-2-enoyl chloride was used instead of (R, E) -3- (1-methylpyrrolidin-2-yl) acryloyl chloride in step 4 to obtain a white solid product in the free state ;¹H NMR(400MHz,DMSO-d₆)δ10.13(s,1H),9.52(s,1H),8.79(s,1H),8.09(d,J＝8.9Hz,1H),8.00–7.89(m,2H),7.48(t,J＝7.6Hz,1H),7.43–7.29(m,3H),7.26(d,J＝7.5Hz,1H),7.20(t,J＝8.2Hz,1H),6.64(dt,J＝15.3,7.0Hz,1H),6.31(d,J＝15.3Hz,1H),3.88(d,J＝7.0Hz,2H),2.76(s,6H),2.37(s,3H).MS:490[M+H]⁺.

EXAMPLE 16 (E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -5-phenylquinazolin-6-yl) -4- (dimethylamino) but-2-enamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-4-fluoroaniline was used instead of 3-chloro-2-fluoroaniline in step 1, and (E) -4- (dimethylamino) but-2-enoyl chloride was used instead of (R, E) -3- (1-methylpyrrolidin-2-yl) acryloyl chloride in step 4, to obtain a white solid product in free form ;¹H NMR(400MHz,DMSO-d₆)δ10.29(s,1H),9.66(s,1H),8.85(s,1H),8.09(d,J＝8.9Hz,1H),7.97(d,J＝8.9Hz,1H),7.70–7.61(m,4H),7.54–7.51(m,2H),7.36(t,J＝9.0Hz,1H),6.79–6.75(m,1H),6.64(dt,J＝15.0,7.0Hz,1H),6.31(d,J＝15.0Hz,1H),3.88(d,J＝7.0Hz,2H),2.76(s,6H).MS:476[M+H]⁺.

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

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-4-fluoroaniline was used instead of 3-chloro-2-fluoroaniline in step 1, 3-chlorobenzeneboronic acid was used instead of phenylboronic acid in step 2, and (E) -4- (dimethylamino) but-2-enoyl chloride was used instead of (R, E) -3- (1-methylpyrrolidin-2-yl) acryloyl chloride in step 4 to obtain a white solid product in free form ;¹H NMR(400MHz,DMSO-d₆)δ10.22–10.10(m,1H),9.77(d,J＝7.1Hz,1H),8.83(s,1H),8.06(d,J＝9.0Hz,1H),7.96(dd,J＝9.0Hz,1H),7.68–7.54(m,4H),7.47–7.34(m,2H),6.90-6.86(m,1H),6.66(dt,J＝15.1,7.0Hz,1H),6.34(d,J＝15.1Hz,1H),3.90(d,J＝7.0Hz,2H),2.77(s,6H).MS:510[M+H]⁺.

EXAMPLE 18 (E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -5- (3-methoxyphenyl) quinazolin-6-yl) -4- (dimethylamino) but-2-enamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-4-fluoroaniline was used instead of 3-chloro-2-fluoroaniline in step 1, 3-methoxyphenylboronic acid was used instead of phenylboronic acid in step 2, and (E) -4- (dimethylamino) but-2-enoyl chloride was used instead of (R, E) -3- (1-methylpyrrolidin-2-yl) acryloyl chloride in step 4 to obtain a white solid product of monotrifluoroacetate salt ;¹H NMR(400MHz,DMSO-d₆)δ10.11(s,1H),9.61(s,1H),8.84(s,1H),8.09(d,J＝8.9Hz,1H),7.96(d,J＝8.9Hz,1H),7.71–7.68(m,1H),7.57(t,J＝7.9Hz,1H),7.50–7.45(m,1H),7.39(t,J＝9.0Hz,1H),7.23–7.20(m,1H),7.12(br,1H),7.06(d,J＝7.5Hz,1H),6.84–6.81(m,1H),6.66(dt,J＝15.1,7.1Hz,1H),6.34(d,J＝15.1Hz,1H),3.89(d,J＝7.1Hz,2H),3.80(s,3H),2.76(s,6H).MS:506[M+H]⁺.

EXAMPLE 19 (E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -5- (3-cyanophenyl) quinazolin-6-yl) -4- (dimethylamino) but-2-enamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-4-fluoroaniline was used instead of 3-chloro-2-fluoroaniline in step 1, 3-cyanobenzeneboronic acid was used instead of phenylboronic acid in step 2, and (E) -4- (dimethylamino) but-2-enoyl chloride was used instead of (R, E) -3- (1-methylpyrrolidin-2-yl) acryloyl chloride in step 4 to obtain a white solid product of monotrifluoroacetate salt ;¹H NMR(400MHz,DMSO-d₆)δ10.00(s,1H),9.79(s,1H),8.78(s,1H),8.05–7.91(m,4H),7.75–7.62(m,4H),7.35(t,J＝9.0Hz,1H),6.86(s,1H),6.65(dt,J＝15.3,7.1Hz,1H),6.30(d,J＝15.3Hz,1H),3.89(d,J＝7.1Hz,2H),2.77(s,6H).MS:501[M+H]⁺.

EXAMPLE 20 (E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -5- (m-tolyl) quinazolin-6-yl) -4- (dimethylamino) but-2-enamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-4-fluoroaniline was used instead of 3-chloro-2-fluoroaniline in step 1, 3-methylphenylboronic acid was used instead of phenylboronic acid in step 2, and (E) -4- (dimethylamino) but-2-enoyl chloride was used instead of (R, E) -3- (1-methylpyrrolidin-2-yl) acryloyl chloride in step 4 to obtain a white solid product in free form ;¹H NMR(400MHz,DMSO-d₆)δ10.12(s,1H),9.58(s,1H),8.83(s,1H),8.08(d,J＝8.9Hz,1H),7.95(d,J＝8.9Hz,1H),7.70–7.68(m,1H),7.55(t,J＝7.6Hz,1H),7.48(d,J＝7.7Hz,1H),7.42–7.33(m,2H),7.31(d,J＝7.4Hz,1H),6.78–6.74(m,1H),6.65(dt,J＝15.1,7.1Hz,1H),6.32(d,J＝15.1Hz,1H),3.88(d,J＝7.1Hz,2H),2.76(s,6H),2.39(s,3H).MS:490[M+H]⁺.

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

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-2, 4-difluoroaniline was used in place of 3-chloro-2-fluoroaniline in step 1, and (E) -4- (dimethylamino) but-2-enoyl chloride was used in place of (R, E) -3- (1-methylpyrrolidin-2-yl) acryloyl chloride in step 4 to obtain a white solid product of monotrifluoroacetate salt ;¹H NMR(400MHz,DMSO-d₆)δ10.04(s,1H),9.55(s,1H),8.75(s,1H),8.05(d,J＝8.9Hz,1H),8.01–7.83(m,2H),7.59(br,3H),7.47(br,2H),7.31(t,J＝9.1Hz,1H),7.20(s,1H),6.62(dt,J＝15.4,7.1Hz,1H),6.28(d,J＝15.4Hz,1H),3.87(d,J＝7.0Hz,2H),2.75(s,6H).MS:494[M+H]⁺.

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

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-2, 4-difluoroaniline was used in place of 3-chloro-2-fluoroaniline in step1, 3-chlorobenzeneboronic acid was used in place of phenylboronic acid in step 2, and (E) -4- (dimethylamino) but-2-enoyl chloride was used in place of (R, E) -3- (1-methylpyrrolidin-2-yl) acryloyl chloride in step 4 to obtain a white solid product in free form ;¹H NMR(400MHz,DMSO-d₆)δ10.01(s,1H),9.66(s,1H),8.67(s,1H),7.99(s,1H),7.90(s,2H),7.53(s,3H),7.36(s,1H),7.29(s,1H),6.64(dt,J＝14.7,7.1Hz,1H),6.31(d,J＝15.3Hz,1H),3.89(d,J＝6.9Hz,2H),2.76(s,6H).MS:528[M+H]⁺.

EXAMPLE 23 (E) -N- (4- ((3-chloro-2, 4-difluorophenyl) amino) -5- (3-methoxyphenyl) quinazolin-6-yl) -4- (dimethylamino) but-2-enamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-2, 4-difluoroaniline was used in place of 3-chloro-2-fluoroaniline in step 1, 3-methoxyphenylboronic acid was used in place of phenylboronic acid in step 2, and (E) -4- (dimethylamino) but-2-enoyl chloride was used in place of (R, E) -3- (1-methylpyrrolidin-2-yl) acryloyl chloride in step 4 to obtain a white solid product of monotrifluoroacetate salt ;¹H NMR(400MHz,DMSO-d₆)δ9.99(s,1H),9.50(s,1H),8.72(s,1H),8.05(d,J＝8.9Hz,1H),7.94(d,J＝9.2Hz,2H),7.49(t,J＝7.9Hz,1H),7.31(t,J＝8.9Hz,1H),7.22(s,1H),7.12(d,J＝7.8Hz,1H),7.07(s,1H),6.99(d,J＝7.3Hz,1H),6.64(dt,J＝14.6,7.1Hz,1H),6.31(d,J＝15.3Hz,1H),3.87(d,J＝6.7Hz,2H),3.78(s,3H),2.75(s,6H).MS:524[M+H]⁺.

EXAMPLE 24 (E) -N- (4- ((3-chloro-2, 4-difluorophenyl) amino) -5- (3-cyanophenyl) quinazolin-6-yl) -4- (dimethylamino) but-2-enamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-2, 4-difluoroaniline was used in place of 3-chloro-2-fluoroaniline in step 1, 3-cyanobenzeneboronic acid was used in place of phenylboronic acid in step 2, and (E) -4- (dimethylamino) but-2-enoyl chloride was used in place of (R, E) -3- (1-methylpyrrolidin-2-yl) acryloyl chloride in step 4 to obtain a white solid product in free form ;¹H NMR(400MHz,DMSO-d₆)δ9.96(s,1H),9.65(s,1H),8.52(s,1H),8.15–7.51(m,7H),7.24(s,1H),6.62(dt,J＝15.3,7.1Hz,1H),6.27(d,J＝15.3Hz,1H),3.88(d,J＝7.1Hz,2H),2.76(s,6H).MS:519[M+H]⁺.

EXAMPLE 25 (E) -N- (4- ((3-chloro-2, 4-difluorophenyl) amino) -5- (m-tolyl) quinazolin-6-yl) -4- (dimethylamino) but-2-enamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-2, 4-difluoroaniline was used in place of 3-chloro-2-fluoroaniline in step 1, 3-methylphenylboronic acid was used in place of phenylboronic acid in step 2, and (E) -4- (dimethylamino) but-2-enoyl chloride was used in place of (R, E) -3- (1-methylpyrrolidin-2-yl) acryloyl chloride in step 4 to obtain a white solid product of monotrifluoroacetate salt ;¹H NMR(400MHz,DMSO-d₆)δ9.89(s,1H),9.49(s,1H),8.73(s,1H),8.00(dd,J＝43.0,8.7Hz,3H),7.52–7.36(m,2H),7.36–7.22(m,3H),7.17(s,1H),6.63(dt,J＝14.7,7.1Hz,1H),6.29(d,J＝15.3Hz,1H),3.87(d,J＝7.6Hz,2H),2.81–2.70(m,6H),2.37(s,3H).MS:508[M+H]⁺.

EXAMPLE 26 (R, E) -N- (4- ((3-chloro-2, 4-difluorophenyl) amino) -5-phenylquinazolin-6-yl) -3- (1-methylpyrrolidin-2-yl) acrylamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-2, 4-difluoroaniline was used in place of 3-chloro-2-fluoroaniline in step 1 to carry out the reaction, and finally a white solid product of monotrifluoroacetate was obtained ;¹H NMR(400MHz,DMSO-d₆)δ9.94(s,1H),9.49(s,1H),8.73(s,1H),8.10–7.88(m,3H),7.59–7.48(m,5H),7.30(t,J＝9.3Hz,1H),7.06(s,1H),6.64(dd,J＝15.3,8.7Hz,1H),6.32(d,J＝15.4Hz,1H),4.03–3.91(m,1H),3.66(dd,J＝11.4,7.9Hz,1H),3.16–3.04(m,1H),2.74(br,3H),2.29–2.20(m,1H),2.08–1.92(m,2H),1.87–1.74(m,1H).MS:520[M+H]⁺.

EXAMPLE 27 (R, E) -N- (4- ((3-chloro-2, 4-difluorophenyl) amino) -5- (3-chlorophenyl) quinazolin-6-yl) -3- (1-methylpyrrolidin-2-yl) acrylamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-2, 4-difluoroaniline was used in place of 3-chloro-2-fluoroaniline in step 1 and 3-chlorobenzeneboronic acid was used in place of phenylboronic acid in step 2 to obtain a white solid product of monotrifluoroacetate salt ;¹H NMR(400MHz,DMSO-d₆)δ10.02(s,1H),9.62(s,1H),8.70(s,1H),7.99–7.91(m,3H),7.61–7.26(m,6H),6.66(dd,J＝15.3,8.6Hz,1H),6.35(d,J＝15.5Hz,1H),3.99(s,1H),3.66(t,J＝6.8Hz,1H),3.13–3.08(m,1H),2.75(br,3H),2.29–2.22(m,1H),2.08–1.94(m,2H),1.89–1.76(m,1H).MS:554[M+H]⁺.

EXAMPLE 28 (R, E) -N- (4- ((3-chloro-2, 4-difluorophenyl) amino) -5- (3-methoxyphenyl) quinazolin-6-yl) -3- (1-methylpyrrolidin-2-yl) acrylamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-2, 4-difluoroaniline was used in place of 3-chloro-2-fluoroaniline in step 1 and 3-methoxyphenylboronic acid was used in place of phenylboronic acid in step 2 to obtain a white solid product of monotrifluoroacetate salt ;¹H NMR(400MHz,DMSO-d₆)δ9.98(s,1H),9.48(s,1H),8.73(s,1H),8.07(d,J＝9.0Hz,1H),7.95(s,2H),7.51(t,J＝7.9Hz,1H),7.32(t,J＝8.9Hz,1H),7.22(s,1H),7.14(d,J＝8.5Hz,1H),7.07(s,1H),7.00(d,J＝7.4Hz,1H),6.67(dd,J＝15.4,8.8Hz,1H),6.36(d,J＝15.5Hz,1H),3.97(d,J＝9.8Hz,1H),3.78(br,3H),3.66(s,1H),3.10(t,J＝9.6Hz,1H),2.75(d,J＝4.1Hz,3H),2.29-2.21(m,1H),2.01-1.93(m,2H),1.87-1.79(m,1H).MS:550[M+H]⁺.

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

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-2, 4-difluoroaniline was used in place of 3-chloro-2-fluoroaniline in step 1 and 3-cyanobenzeneboronic acid was used in place of phenylboronic acid in step 2 to obtain a white solid product in the free state ;¹H NMR(400MHz,DMSO-d₆)δ9.96(s,1H),9.61(s,1H),8.63(s,1H),7.89(br,4H),7.63(s,3H),7.23(s,1H),6.64(dd,J＝15.3,8.8Hz,1H),6.31(dd,J＝15.1Hz,1H),3.98(s,1H),3.65(d,J＝9.6Hz,1H),3.10(t,J＝9.6Hz,1H),2.75(br,3H),2.26–2.24(m,1H),2.14–1.91(m,2H),1.85–1.75(m,1H).MS:545[M+H]⁺.

EXAMPLE 30 (R, E) -N- (4- ((3-chloro-2, 4-difluorophenyl) amino) -5- (m-tolyl) quinazolin-6-yl) -3- (1-methylpyrrolidin-2-yl) acrylamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-2, 4-difluoroaniline was used in place of 3-chloro-2-fluoroaniline in step 1 and 3-methylphenylboronic acid was used in place of phenylboronic acid in step 2 to obtain the product as a white solid of monotrifluoroacetate salt ;¹H NMR(400MHz,DMSO-d₆)δ10.00(s,1H),9.48(s,1H),8.73(s,1H),8.07(d,J＝9.0Hz,1H),7.99–7.79(m,2H),7.48(t,J＝7.6Hz,1H),7.40(d,J＝7.7Hz,1H),7.36–7.22(m,3H),7.17(s,1H),6.66(dd,J＝15.2,8.7Hz,1H),6.35(d,J＝15.4Hz,1H),3.98(s,1H),3.65(d,J＝9.8Hz,1H),3.10(s,1H),2.75(br,3H),2.37(s,3H),2.29-2.20(m,4.2Hz,1H),2.10–1.92(m,2H),1.87–1.77(m,1H).MS:534[M+H]⁺.

EXAMPLE 31 (R, E) -N- (4- ((3-chloro-2, 4-difluorophenyl) amino) -5- (1H-indazol-6-yl) quinazolin-6-yl) -3- (1-methylpyrrolidin-2-yl) acrylamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-2, 4-difluoroaniline was used in place of 3-chloro-2-fluoroaniline in step1, and (1H-indazol-6-yl) boric acid was used in place of phenylboric acid in step 2 to carry out the reaction, to finally obtain a white solid product of monotrifluoroacetate ;¹H NMR(400MHz,DMSO-d₆)δ13.35(s,1H),9.84(s,1H),9.41(s,1H),8.72(s,1H),8.22(s,1H),8.08(d,J＝8.4Hz,1H),7.97(br,3H),7.71(s,1H),7.25(d,J＝9.6Hz,1H),7.11(d,J＝7.5Hz,2H),6.63(dd,J＝15.4,8.8Hz,1H),6.28(d,J＝15.4Hz,1H),3.97–3.84(m,1H),3.62(d,J＝11.6Hz,1H),3.07(t,J＝9.9Hz,1H),2.68(br,3H),2.25-2.15(m,1H),2.08–1.90(m,2H),1.85-1.73(m,1H).MS:560[M+H]⁺.

EXAMPLE 32 (E) -N- (4- ((3-chloro-2, 4-difluorophenyl) amino) -5- (3, 4-dimethoxyphenyl) quinazolin-6-yl) -4- (dimethylamino) but-2-enamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-2, 4-difluoroaniline was used in place of 3-chloro-2-fluoroaniline in step 1, 3, 4-dimethoxyphenylboronic acid was used in place of phenylboronic acid in step 2, and (E) -4- (dimethylamino) but-2-enoyl chloride was used in place of (R, E) -3- (1-methylpyrrolidin-2-yl) acryloyl chloride in step 4 to obtain a white solid product of monotrifluoroacetate salt ;¹H NMR(400MHz,DMSO-d₆)δ10.01(s,1H),9.46(s,1H),8.76(s,1H),8.12(d,J＝9.0Hz,1H),7.94(d,J＝9.0Hz,2H),7.46(s,1H),7.34(t,J＝9.1Hz,1H),7.17(d,J＝8.2Hz,1H),7.07(s,1H),6.98(d,J＝8.1Hz,1H),6.67(dd,J＝14.7,7.1Hz,1H),6.36(d,J＝15.3Hz,1H),3.92–3.85(m,2H),3.82(s,3H),3.74(s,3H),2.76(s,6H).MS:554[M+H]⁺.

EXAMPLE 33 (R, E) -N- (4- ((3-chloro-2, 4-difluorophenyl) amino) -5- (3, 4-dimethoxyphenyl) quinazolin-6-yl) -3- (1-methylpyrrolidin-2-yl) acrylamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-2, 4-difluoroaniline was used in place of 3-chloro-2-fluoroaniline in step 1 and 3, 4-dimethoxyphenylboronic acid was used in place of phenylboronic acid in step 2 to carry out the reaction, and finally a white solid product of monotrifluoroacetate was obtained ;¹H NMR(400MHz,DMSO-d₆)δ10.01(s,1H),9.41(s,1H),8.73(s,1H),8.23–8.06(m,1H),7.93(d,J＝9.5Hz,2H),7.45–7.28(m,2H),7.23–7.12(m,1H),7.06(s,1H),6.98(d,J＝8.2Hz,1H),6.68(dd,J＝15.3,8.8Hz,1H),6.40(d,J＝15.3Hz,1H),3.99(s,1H),3.82(s,3H),3.74–3.73(m,3H),3.71–3.60(m,1H),3.11(t,J＝9.7Hz,1H),2.79–2.71(m,3H),2.27–2.23(m,1H),2.05–1.95(m,2H),1.85–1.80(m,1H).MS:580[M+H]⁺.

EXAMPLE 34 (E) -N- (4- ((3-chloro-2, 4-difluorophenyl) amino) -5- (1H-indazol-6-yl) quinazolin-6-yl) -4- (dimethylamino) but-2-enamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-2, 4-difluoroaniline was used in place of 3-chloro-2-fluoroaniline in step 1, (1H-indazol-6-yl) boric acid was used in place of phenylboric acid in step 2, and (E) -4- (dimethylamino) but-2-enoyl chloride was used in place of (R, E) -3- (1-methylpyrrolidin-2-yl) acryloyl chloride in step 4 to obtain a white solid product of monotrifluoroacetate ;¹H NMR(400MHz,DMSO-d₆)δ13.36(s,1H),9.69(s,1H),9.43(s,1H),8.71(s,1H),8.22(s,1H),8.07(d,J＝8.9Hz,1H),7.97(d,J＝8.5Hz,3H),7.70(s,1H),7.31–7.19(m,1H),7.15–7.03(m,2H),6.60(dt,J＝14.6,7.0Hz,1H),6.22(d,J＝15.3Hz,1H),2.70–2.67(m,6H),2.05–1.93(m,2H).MS:534[M+H]⁺.

EXAMPLE 35 (E) -N- (4- ((3-chloro-2, 4-difluorophenyl) amino) -5- (1-methyl-1H-indol-6-yl) quinazolin-6-yl) -4- (dimethylamino) but-2-enamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-2, 4-difluoroaniline was used in place of 3-chloro-2-fluoroaniline in step 1, (1-methyl-1H-indol-6-yl) boric acid was used in place of phenylboric acid in step 2, and (E) -4- (dimethylamino) but-2-enoyl chloride was used in place of (R, E) -3- (1-methylpyrrolidin-2-yl) acryloyl chloride in step 4 to obtain a white solid product in free form ;¹H NMR(400MHz,DMSO-d₆)δ8.93(s,1H),8.61(s,1H),8.19–8.08(m,1H),7.97–7.82(m,2H),7.77(d,J＝8.0Hz,1H),7.62(s,1H),7.48(br 1H),7.23(t,J＝9.1Hz,1H),7.05(d,J＝8.1Hz,1H),6.98(s,1H),6.64–6.53(m,2H),6.08–6.00(m,1H),3.80(s,3H),2.96(d,J＝6.0Hz,2H),2.09(s,6H).MS:547[M+H]⁺.

EXAMPLE 36 (R, E) -N- (4- ((3-chloro-2, 4-difluorophenyl) amino) -5- (1-methyl-1H-indol-6-yl) quinazolin-6-yl) -3- (1-methylpyrrolidin-2-yl) acrylamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-2, 4-difluoroaniline was used in place of 3-chloro-2-fluoroaniline in step 1, and (1-methyl-1H-indol-6-yl) boric acid was used in place of phenylboric acid in step 2 to carry out the reaction, to finally obtain a white solid product in the free state ;¹H NMR(400MHz,DMSO-d₆)δ8.94(s,1H),8.60(s,1H),8.20–8.09(m,1H),7.96–7.84(m,2H),7.76(d,J＝8.1Hz,1H),7.62(s,1H),7.48(d,J＝3.1Hz,1H),7.23(td,J＝9.1,2.1Hz,1H),7.05(dt,J＝8.1,2.0Hz,1H),6.97(s,1H),6.56(br,1H),6.48(dd,J＝15.3,7.9Hz,1H),6.04(d,J＝15.3Hz,1H),3.80(s,3H),3.40(s,2H),3.02(s,1H),2.12(s,3H),1.92(s,1H),1.79–1.62(m,2H),1.46(s,1H).MS:573[M+H]⁺.

EXAMPLE 37 (E) -4- (dimethylamino) -N- (4- ((2-fluorophenyl) amino) -5-phenylquinazolin-6-yl) but-2-enamide

The synthesis was carried out in the same manner as in example 1 except that 2-fluoroaniline was used instead of 3-chloro-2-fluoroaniline in step 1 and (E) -4- (dimethylamino) but-2-enoyl chloride was used instead of (R, E) -3- (1-methylpyrrolidin-2-yl) acryloyl chloride in step 4 to obtain a white solid product in free form ;¹H NMR(400MHz,DMSO-d₆)δ10.18(s,1H),9.59(s,1H),8.87(s,1H),8.12(d,J＝8.9Hz,1H),8.00(d,J＝8.9Hz,2H),7.60(d,J＝6.8Hz,3H),7.53–7.46(m,2H),7.22–7.15(m,3H),6.62(dt,J＝14.7,7.1Hz,1H),6.28(d,J＝15.4Hz,1H),3.86(d,J＝7.0Hz,2H),2.75(s,6H).MS:442[M+H]⁺.

EXAMPLE 38 (E) -N- (5- (3-chlorophenyl) -4- ((2-fluorophenyl) amino) quinazolin-6-yl) -4- (dimethylamino) but-2-enamide

The synthesis was carried out in the same manner as in example 1 except that 2-fluoroaniline was used instead of 3-chloro-2-fluoroaniline in step 1, 3-chlorobenzeneboronic acid was used instead of phenylboronic acid in step 2, and (E) -4- (dimethylamino) but-2-enoyl chloride was used instead of (R, E) -3- (1-methylpyrrolidin-2-yl) acryloyl chloride in step 4 to obtain a white solid product in free form ;¹H NMR(400MHz,DMSO-d₆)δ10.19(s,1H),9.71(d,J＝5.0Hz,1H),8.83(s,1H),8.06(t,J＝5.9Hz,2H),7.98(d,J＝8.9Hz,1H),7.60(q,J＝8.1,7.4Hz,3H),7.42(d,J＝7.3Hz,1H),7.26–7.15(m,3H),6.65(dt,J＝14.7,7.1Hz,1H),6.32(d,J＝15.3Hz,1H),3.89(d,J＝7.0Hz,2H),2.76(s,6H).MS:476[M+H]⁺.

EXAMPLE 39 (E) -4- (dimethylamino) -N- (4- ((2-fluorophenyl) amino) -5- (3-methoxyphenyl) quinazolin-6-yl) but-2-enamide

The synthesis was carried out in the same manner as in example 1 except that 2-fluoroaniline was used instead of 3-chloro-2-fluoroaniline in step 1, 3-methoxyphenylboronic acid was used instead of phenylboronic acid in step 2, and (E) -4- (dimethylamino) but-2-enoyl chloride was used instead of (R, E) -3- (1-methylpyrrolidin-2-yl) acryloyl chloride in step 4 to obtain a white solid product of monotrifluoroacetate salt ;¹H NMR(400MHz,DMSO-d₆)δ10.07(s,1H),9.53(d,J＝2.2Hz,1H),8.84(s,1H),8.16–8.02(m,2H),7.98(d,J＝8.9Hz,1H),7.62–7.46(m,2H),7.28–7.07(m,5H),7.01(d,J＝7.5Hz,1H),6.65(dt,J＝14.7,7.1Hz,1H),6.32(d,J＝15.4Hz,1H),3.88(d,J＝7.0Hz,2H),3.78(s,3H),2.76(s,6H).MS:472[M+H]⁺.

EXAMPLE 40 (E) -N- (5- (3-cyanophenyl) -4- ((2-fluorophenyl) amino) quinazolin-6-yl) -4- (dimethylamino) but-2-enamide

The synthesis was carried out in the same manner as in example 1 except that 2-fluoroaniline was used instead of 3-chloro-2-fluoroaniline in step 1, 3-cyanobenzeneboronic acid was used instead of phenylboronic acid in step 2, and (E) -4- (dimethylamino) but-2-enoyl chloride was used instead of (R, E) -3- (1-methylpyrrolidin-2-yl) acryloyl chloride in step 4 to obtain a white solid product of monotrifluoroacetate salt ;¹H NMR(400MHz,DMSO-d₆)δ10.00(s,1H),9.78–9.58(m,1H),8.79(s,1H),8.34(s,1H),8.01(s,4H),7.81–7.66(m,2H),7.44(s,1H),7.25–7.10(m,3H),6.63(dt,J＝14.8,7.1Hz,1H),6.28(d,J＝15.3Hz,1H),3.88(d,J＝7.1Hz,2H),2.76(s,6H).MS:467[M+H]⁺.

EXAMPLE 41 (E) -4- (dimethylamino) -N- (4- ((2-fluorophenyl) amino) -5- (m-tolyl) quinazolin-6-yl) but-2-enamide

The synthesis was carried out in the same manner as in example 1 except that 2-fluoroaniline was used instead of 3-chloro-2-fluoroaniline in step 1, 3-methylphenylboronic acid was used instead of phenylboronic acid in step 2, and (E) -4- (dimethylamino) but-2-enoyl chloride was used instead of (R, E) -3- (1-methylpyrrolidin-2-yl) acryloyl chloride in step 4 to obtain a white solid product of monotrifluoroacetate salt ;¹H NMR(400MHz,DMSO-d₆)δ10.00(s,1H),9.50(d,J＝4.1Hz,1H),8.82(d,J＝3.4Hz,1H),8.10(d,J＝8.7Hz,1H),8.03(s,1H),7.96(d,J＝8.9Hz,1H),7.50-7.45(m,2H),7.40(d,J＝7.9Hz,1H),7.33(s,1H),7.24(d,J＝15.5Hz,1H),7.23–7.13(m,3H),6.63(dt,J＝14.7,7.1Hz,1H),6.29(d,J＝15.4Hz,1H),3.87(d,J＝7.0Hz,2H),2.75(s,6H),2.38(s,3H).MS:456[M+H]⁺.

EXAMPLE 42 (E) -4- (dimethylamino) -N- (4- ((2-fluorophenyl) amino) -5- (1H-indazol-6-yl) quinazolin-6-yl) but-2-enamide

The synthesis was carried out in the same manner as in example 1 except that 2-fluoroaniline was used instead of 3-chloro-2-fluoroaniline in step1, (1H-indazol-6-yl) boric acid was used instead of phenylboric acid in step 2, and (E) -4- (dimethylamino) but-2-enoyl chloride was used instead of (R, E) -3- (1-methylpyrrolidin-2-yl) acryloyl chloride in step 4 to obtain a white solid product in free form ;¹H NMR(400MHz,DMSO-d₆)δ13.35(s,1H),9.06(s,1H),8.66(s,1H),8.27(t,J＝8.2Hz,1H),8.20(s,1H),8.04(d,J＝8.9Hz,1H),7.97–7.90(m,2H),7.67(s,1H),7.17–7.05(m,3H),7.03–6.94(m,2H),6.55(dt,J＝15.6,5.9Hz,1H),6.00(d,J＝15.5Hz,1H),2.90(d,J＝6.0Hz,2H),2.05(s,6H).MS:482[M+H]⁺.

EXAMPLE 43 (E) -4- (dimethylamino) -N- (4- ((2-fluorophenyl) amino) -5- (1-methyl-1H-indol-6-yl) quinazolin-6-yl) but-2-enamide

The synthesis was carried out in the same manner as in example 1 except that 2-fluoroaniline was used instead of 3-chloro-2-fluoroaniline in step 1, (1-methyl-1H-indol-6-yl) boric acid was used instead of phenylboric acid in step 2, and (E) -4- (dimethylamino) but-2-enoyl chloride was used instead of (R, E) -3- (1-methylpyrrolidin-2-yl) acryloyl chloride in step 4 to obtain a white solid product of monotrifluoroacetate salt ;¹H NMR(400MHz,DMSO-d₆)δ9.69(s,1H),9.28(s,1H),8.75(s,1H),8.16(d,J＝8.9Hz,1H),7.98–7.94(m,2H),7.76(d,J＝8.0Hz,1H),7.65(s,1H),7.48(br,1H),7.38(s,1H),7.16–7.00(m,4H),6.67–6.53(m,2H),6.24(d,J＝15.3Hz,1H),3.80(br,5H),2.71(s,6H).MS:495[M+H]⁺.

EXAMPLE 44 (R, E) -N- (4- ((2-fluorophenyl) amino) -5-phenylquinazolin-6-yl) -3- (1-methylpyrrolidin-2-yl) acrylamide

The synthesis was carried out in the same manner as in example 1 except that 2-fluoroaniline was used in place of 3-chloro-2-fluoroaniline in step 1 to carry out the reaction, and finally a white solid product of monotrifluoroacetate was obtained ;¹H NMR(400MHz,DMSO-d₆)δ10.30(s,1H),9.59(d,J＝4.0Hz,1H),8.88(d,J＝2.8Hz,1H),8.15(dd,J＝8.9,2.6Hz,1H),8.00(dd,J＝9.0,1.8Hz,2H),7.67–7.54(m,3H),7.56–7.46(m,3H),7.20(dq,J＝7.4,2.8Hz,3H),6.65(dd,J＝15.3,8.8Hz,1H),6.34(d,J＝15.3Hz,1H),4.02–3.93(m,1H),3.65(br,1H),3.11(t,J＝11.8Hz,1H),2.74(s,3H),2.25–2.22(m,1H),2.06–1.94(m,2H),1.90–1.76(m,1H).MS:468[M+H]⁺.

EXAMPLE 45 (R, E) -N- (5- (3-chlorophenyl) -4- ((2-fluorophenyl) amino) quinazolin-6-yl) -3- (1-methylpyrrolidin-2-yl) acrylamide

The synthesis was carried out in the same manner as in example 1 except that 2-fluoroaniline was used instead of 3-chloro-2-fluoroaniline in step 1 and 3-chlorobenzeneboronic acid was used instead of phenylboronic acid in step 2 to obtain a white solid product of monotrifluoroacetate salt ;¹H NMR(400MHz,DMSO-d₆)δ10.19(s,1H),9.66(s,1H),8.82(s,1H),8.11–8.02(m,2H),7.97(d,J＝9.0Hz,1H),7.64–7.56(m,3H),7.50(s,1H),7.42(d,J＝7.5Hz,1H),7.24–7.15(m,3H),6.68(dd,J＝15.3,8.8Hz,1H),6.36(d,J＝15.3Hz,1H),4.00(d,J＝7.5Hz,1H),3.66(d,J＝12.3Hz,1H),3.11(d,J＝9.4Hz,1H),2.75(br,3H),2.26–2.23(m,1H),2.09–1.94(m,2H),1.90–1.78(m,1H).MS:502[M+H]⁺.

EXAMPLE 46 (R, E) -N- (4- ((2-fluorophenyl) amino) -5- (3-methoxyphenyl) quinazolin-6-yl) -3- (1-methylpyrrolidin-2-yl) acrylamide

The synthesis was carried out in the same manner as in example 1 except that 2-fluoroaniline was used instead of 3-chloro-2-fluoroaniline in step 1 and 3-methoxyphenylboronic acid was used instead of phenylboronic acid in step 2 to obtain a white solid product in the free state ;¹H NMR(400MHz,DMSO-d₆)δ9.19(s,1H),8.65(s,1H),8.25(t,J＝8.1Hz,1H),8.01(d,J＝8.9Hz,1H),7.90(d,J＝8.9Hz,1H),7.49(t,J＝7.9Hz,1H),7.23–7.04(m,6H),6.98(d,J＝7.4Hz,1H),6.64–6.47(m,1H),6.17(d,J＝15.3Hz,1H),3.78(s,3H),3.25-3.10(m,3H),2.33(br,3H),2.04(s,1H),1.81(s,2H),1.63(s,1H).MS:498[M+H]⁺.

EXAMPLE 47 (R, E) -N- (5- (3-cyanophenyl) -4- ((2-fluorophenyl) amino) quinazolin-6-yl) -3- (1-methylpyrrolidin-2-yl) acrylamide

The synthesis was carried out in the same manner as in example 1 except that 2-fluoroaniline was used instead of 3-chloro-2-fluoroaniline in step 1 and 3-cyanobenzeneboronic acid was used instead of phenylboronic acid in step 2 to obtain a white solid product of monotrifluoroacetate salt ;¹H NMR(400MHz,DMSO-d₆)δ9.95(s,1H),9.65(s,1H),8.78(s,1H),8.13(d,J＝1.5Hz,1H),8.10–8.07(m,1H),8.01(s,2H),7.87(d,J＝7.7Hz,1H),7.74(s,2H),7.57(t,J＝7.6Hz,1H),7.34(s,1H),7.14(d,J＝18.0Hz,2H),6.64(dd,J＝15.3,8.8Hz,1H),6.32(dd,J＝15.4,4.2Hz,1H),3.99(s,1H),3.72–3.61(m,1H),3.10(t,J＝9.4Hz,1H),2.75(br,3H),2.26-2.24(m,1H),2.28-1.95(m,2H),1.84-1.81(m,1H).MS:493[M+H]⁺.

EXAMPLE 48 (R, E) -N- (4- ((2-fluorophenyl) amino) -5- (m-tolyl) quinazolin-6-yl) -3- (1-methylpyrrolidin-2-yl) acrylamide

The synthesis was carried out in the same manner as in example 1 except that 2-fluoroaniline was used instead of 3-chloro-2-fluoroaniline in step 1 and 3-methylphenylboronic acid was used instead of phenylboronic acid in step 2 to obtain the product of monotrifluoroacetate as a white solid ;¹H NMR(400MHz,DMSO-d₆)δ10.23(s,1H),9.52(s,1H),8.84(s,1H),8.13(d,J＝9.0Hz,1H),8.02-7.98(m,2H),7.51-7.47(m,2H),7.41(d,J＝7.7Hz,1H),7.33(d,J＝2.2Hz,1H),7.27(d,J＝7.6Hz,1H),7.24-7.16(m,3H),6.67(dd,J＝15.4,8.8Hz,1H),6.36(d,J＝15.4Hz,1H),3.98(s,1H),3.67(s,1H),3.10(s,1H),2.74(s,3H),2.38(s,3H),2.26-2.21(m,1H),2.05-1.95(m,2H),1.89–1.78(m,1H).MS:482[M+H]⁺.

EXAMPLE 49 (R, E) -N- (4- ((2-fluorophenyl) amino) -5- (1H-indazol-6-yl) quinazolin-6-yl) -3- (1-methylpyrrolidin-2-yl) acrylamide

The synthesis was carried out in the same manner as in example 1 except that 2-fluoroaniline was used instead of 3-chloro-2-fluoroaniline in step 1 and (1H-indazol-6-yl) boric acid was used instead of phenylboric acid in step 2 to obtain a white solid product in the free state ;¹H NMR(400MHz,DMSO-d₆)δ13.32(s,1H),9.09(s,1H),8.67(s,1H),8.32–8.19(m,2H),8.05(d,J＝8.9Hz,1H),7.94(dd,J＝17.2,8.6Hz,2H),7.67(s,1H),7.17–7.05(m,3H),7.03–6.94(m,2H),6.58–6.33(m,1H),6.03(d,J＝15.3Hz,1H),3.32(br,2H),3.05(s,1H),2.16(s,3H),1.94(s,1H),1.72(br,2H),1.49(s,1H).MS:508[M+H]⁺.

EXAMPLE 50 (R, E) -N- (4- ((2-fluorophenyl) amino) -5- (1-methyl-1H-indol-6-yl) quinazolin-6-yl) -3- (1-methylpyrrolidin-2-yl) acrylamide

The synthesis was carried out in the same manner as in example 1 except that 2-fluoroaniline was used instead of 3-chloro-2-fluoroaniline in step 1 and (1-methyl-1H-indol-6-yl) boric acid was used instead of phenylboronic acid in step 2 to obtain the product of monotrifluoroacetate as a white solid ;¹H NMR(400MHz,DMSO-d₆)δ10.03(s,1H),9.32(s,1H),8.80(s,1H),8.25–8.17(m,1H),7.98-7.90(m,2H),7.77(d,J＝8.0Hz,1H),7.66(s,1H),7.52–7.43(m,2H),7.17–7.01(m,4H),6.66(dd,J＝15.4,8.7,Hz,1H),6.56(s,1H),6.31(d,J＝15.3Hz,1H),3.92(d,J＝7.7Hz,1H),3.81(s,3H),3.67–3.61(m,1H),3.08(br,1H),2.69(br,3H),2.21-2.18(m,1H),2.07–1.88(m,2H),1.82–1.75(m,1H).MS:521[M+H]⁺.

EXAMPLE 51 (E) -N- (5- (3, 4-dimethoxyphenyl) -4- ((2-fluorophenyl) amino) quinazolin-6-yl) -4- (dimethylamino) but-2-enamide

The synthesis was carried out in the same manner as in example 1 except that 2-fluoroaniline was used instead of 3-chloro-2-fluoroaniline in step 1, 3, 4-dimethoxyphenylboronic acid was used instead of phenylboronic acid in step 2, and (E) -4- (dimethylamino) but-2-enoyl chloride was used instead of (R, E) -3- (1-methylpyrrolidin-2-yl) acryloyl chloride in step 4 to obtain a white solid product in free form ;¹H NMR(400MHz,DMSO-d₆)δ8.96(s,1H),8.63(s,1H),8.28(td,J＝8.4,2.0Hz,1H),8.05(d,J＝8.9Hz,1H),7.87(d,J＝8.9Hz,1H),7.35(d,J＝2.5Hz,1H),7.22–7.11(m,3H),7.13–7.03(m,2H),6.94(d,J＝8.2Hz,1H),6.61(dt,J＝15.5,5.9Hz,1H),6.12(d,J＝15.6Hz,1H),3.82(s,3H),3.73(s,3H),2.98(d,J＝5.8Hz,2H),2.12(s,6H).MS:502[M+H]⁺.

EXAMPLE 52 (R, E) -N- (5- (3, 4-dimethoxyphenyl) -4- ((2-fluorophenyl) amino) quinazolin-6-yl) -3- (1-methylpyrrolidin-2-yl) acrylamide

The synthesis was carried out in the same manner as in example 1 except that 2-fluoroaniline was used instead of 3-chloro-2-fluoroaniline in step 1 and 3, 4-dimethoxyphenylboronic acid was used instead of phenylboronic acid in step 2 to obtain a white solid product in the free state ;¹H NMR(400MHz,DMSO-d₆)δ8.96(s,1H),8.64(s,1H),8.28(dd,J＝8.4,7.3Hz,1H),8.05(d,J＝8.9Hz,1H),7.87(d,J＝8.9Hz,1H),7.36(s,1H),7.16(d,J＝7.4Hz,3H),7.11–7.04(m,2H),6.94(d,J＝8.2Hz,1H),6.49(dd,J＝15.4,7.7Hz,1H),6.10(d,J＝15.4Hz,1H),3.82(s,3H),3.73(s,3H),3.31(s,2H),3.00(s,1H),2.12(br,3H),2.00–1.90(m,1H),1.75-1.65(m,2H),1.49(s,1H).MS:528[M+H]⁺.

EXAMPLE 53 (E) -N- (4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -5-phenylquinazolin-6-yl) -4- (dimethylamino) but-2-enamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-4- (pyridin-2-ylmethoxy) aniline was used instead of 3-chloro-2-fluoroaniline in step 1, and (E) -4- (dimethylamino) but-2-enoyl chloride was used instead of (R, E) -3- (1-methylpyrrolidin-2-yl) acryloyl chloride in step 4 to obtain a white solid product in free form ;¹H NMR(400MHz,DMSO-d₆)δ9.27(s,1H),8.64(s,1H),8.58-8.56(m,1H),7.96(d,J＝8.9Hz,1H),7.90–7.80(m,2H),7.69–7.57(m,4H),7.55–7.46(m,3H),7.39–7.31(m,1H),7.11(d,J＝9.1Hz,1H),6.86(s,1H),6.70–6.53(m,2H),6.13(d,J＝15.4Hz,1H),5.21(s,2H),3.20(d,J＝6.2Hz,2H),2.28(s,6H).MS:565[M+H]⁺.

EXAMPLE 54 (E) -N- (4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -5- (3-methoxyphenyl) quinazolin-6-yl) -4- (dimethylamino) but-2-enamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-4- (pyridin-2-ylmethoxy) aniline was used in place of 3-chloro-2-fluoroaniline in step 1, 3-methoxyphenylboronic acid was used in place of phenylboronic acid in step 2, and (E) -4- (dimethylamino) but-2-enoyl chloride was used in place of (R, E) -3- (1-methylpyrrolidin-2-yl) acryloyl chloride in step 4 to obtain a white solid product in free form ;¹H NMR(400MHz,DMSO-d₆)δ9.21(s,1H),8.63(s,1H),8.57(s,1H),7.97(d,J＝8.7Hz,1H),7.86–7.84(m,2H),7.60-7.53(m,3H),7.38–7.31(m,1H),7.25–6.98(m,5H),6.83–6.52(m,2H),6.14(d,J＝15.3Hz,1H),5.21(s,2H),3.79(s,3H),3.19–3.12(m,2H),2.25(s,6H).MS:595[M+H]⁺.

EXAMPLE 55 (E) -N- (4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -5- (3, 4-dimethoxyphenyl) quinazolin-6-yl) -4- (dimethylamino) but-2-enamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-4- (pyridin-2-ylmethoxy) aniline was used in place of 3-chloro-2-fluoroaniline in step 1,3, 4-dimethoxyphenylboronic acid was used in place of phenylboronic acid in step 2, and (E) -4- (dimethylamino) but-2-enoyl chloride was used in place of (R, E) -3- (1-methylpyrrolidin-2-yl) acryloyl chloride in step 4 to obtain the product as a white solid in free form ;¹H NMR(400MHz,DMSO-d₆)δ9.09(s,1H),8.64–8.54(m,2H),8.03(d,J＝8.9Hz,1H),7.90–7.80(m,2H),7.60–7.49(m,2H),7.39–7.31(m,1H),7.24(d,J＝8.2Hz,1H),7.16(s,2H),7.08(dS,1H),6.99(d,J＝8.2Hz,1H),6.84(d,J＝9.0Hz,1H),6.63(dt,J＝15.4,6.0Hz,1H),6.16(d,J＝15.4Hz,1H),5.22(s,2H),3.88(s,3H),3.74(s,3H),3.05(d,J＝6.1Hz,2H),2.17(s,6H).MS:625[M+H]⁺.

EXAMPLE 56 (E) -N- (4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -5- (m-tolyl) quinazolin-6-yl) -4- (dimethylamino) but-2-enamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-4- (pyridin-2-ylmethoxy) aniline was used in place of 3-chloro-2-fluoroaniline in step 1, 3-methylphenylboronic acid was used in place of phenylboronic acid in step 2, and (E) -4- (dimethylamino) but-2-enoyl chloride was used in place of (R, E) -3- (1-methylpyrrolidin-2-yl) acryloyl chloride in step 4 to obtain a white solid product in free form ;¹H NMR(400MHz,DMSO-d₆)δ9.16(s,1H),8.63(s,1H),8.60–8.53(m,1H),7.98(d,J＝8.9Hz,1H),7.90–7.80(m,2H),7.64–7.45(m,4H),7.39–7.24(m,3H),7.13(d,J＝9.0Hz,1H),6.94(s,1H),6.71–6.54(m,2H),6.11(d,J＝15.5Hz,1H),5.21(s,2H),3.08–3.01(m,2H),2.39(s,3H),2.17(s,6H).MS:579[M+H]⁺.

EXAMPLE 57 (R, E) -N- (4- ((3-chloro-2-fluorophenyl) amino) -5- (3, 4-dimethoxyphenyl) quinazolin-6-yl) -3- (1-methylpyrrolidin-2-yl) acrylamide

The synthesis was carried out in the same manner as in example 1 except that 3, 4-dimethoxyphenylboronic acid was used in place of phenylboronic acid in step 2 to give a white solid product of monotrifluoroacetate salt ;¹H NMR(400MHz,DMSO-d₆)δ10.02(s,1H),9.40(s,1H),8.77(s,1H),8.18–8.01(m,2H),7.94(d,J＝8.9Hz,1H),7.51(s,1H),7.33(t,J＝7.4Hz,1H),7.24–7.14(m,2H),7.07(s,1H),7.03–6.95(m,1H),6.68(ddd,J＝15.3,8.8,3.3Hz,1H),6.40(dd,J＝15.3,3.5Hz,1H),3.99(s,1H),3.83(s,3H),3.73(s,3H),3.66(br,1H),3.14–3.11(m,1H),2.75(br,3H),2.27–2.25(m,1H),2.12–1.92(m,2H),1.88–1.76(m,1H).MS:562[M+H]⁺.

EXAMPLE 58 (R, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -5- (3, 4-dimethoxyphenyl) quinazolin-6-yl) -3- (1-methylpyrrolidin-2-yl) acrylamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-4-fluoroaniline was used in place of 3-chloro-2-fluoroaniline in step 1 and 3, 4-dimethoxyphenylboronic acid was used in place of phenylboronic acid in step2 to obtain a white solid product of monotrifluoroacetate salt ;¹H NMR(400MHz,DMSO-d₆)δ9.93(s,1H),9.45(s,1H),8.78(s,1H),8.11(d,J＝8.9Hz,1H),7.92(d,J＝8.9Hz,1H),7.63(d,J＝6.7Hz,1H),7.45-7.40(m,2H),7.24(d,J＝8.2Hz,1H),7.10(s,1H),7.02(d,J＝8.2Hz,1H),6.94(d,J＝9.0Hz,1H),6.69(dd,J＝15.2,8.7Hz,1H),6.42(d,J＝15.4Hz,1H),3.99(s,1H),3.88(s,3H),3.74(s,3H),3.67(s,1H),3.20–3.06(m,1H),2.75(dd,J＝4.5,2.3Hz,3H),2.31–2.20(m,1H),2.11–1.92(m,2H),1.85-1.82(m,1H).MS:562[M+H]⁺.

EXAMPLE 59 (R, E) -N- (4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -5-phenylquinazolin-6-yl) -3- (1-methylpyrrolidin-2-yl) acrylamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-4- (pyridin-2-ylmethoxy) aniline was used in place of 3-chloro-2-fluoroaniline in step 1 to obtain a white solid product of monotrifluoroacetate salt ;¹H NMR(400MHz,DMSO-d₆)δ10.26(s,1H),9.68(s,1H),8.93(s,1H),8.63–8.56(m,1H),8.16(d,J＝8.9Hz,1H),8.01–7.85(m,2H),7.67(p,J＝3.1Hz,3H),7.58–7.50(m,5H),7.43–7.35(m,1H),7.19(d,J＝9.1Hz,1H),6.80–6.62(m,2H),6.36(d,J＝15.3Hz,1H),5.27(s,2H),3.98(br,1H),3.67(s,1H),3.10(s,1H),2.74(s,3H),2.29–2.17(m,1H),2.13–1.89(m,2H),1.88–1.76(m,1H).MS:591[M+H]⁺.

EXAMPLE 60 (R, E) -N- (4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -5- (3-methoxyphenyl) quinazolin-6-yl) -3- (1-methylpyrrolidin-2-yl) acrylamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-4- (pyridin-2-ylmethoxy) aniline was used in place of 3-chloro-2-fluoroaniline in step 1 and 3-methoxyphenylboronic acid was used in place of phenylboronic acid in step 2 to obtain the product of monotrifluoroacetate as a white solid ;¹H NMR(400MHz,DMSO-d₆)δ10.41(s,1H),9.70(s,1H),8.97(s,1H),8.64–8.57(m,1H),8.22(d,J＝9.0Hz,1H),8.03–7.87(m,2H),7.78(s,1H),7.64–7.53(m,3H),7.45–7.36(m,1H),7.23(dd,J＝8.9,2.7Hz,2H),7.17–7.03(m,2H),6.83(dd,J＝8.9,2.6Hz,1H),6.70(ddd,J＝15.3,8.7,2.3Hz,1H),6.42(d,J＝15.3Hz,1H),5.29(s,2H),3.99(d,J＝8.3Hz,1H),3.81(s,3H),3.69(d,J＝8.1Hz,1H),3.11(d,J＝9.9Hz,1H),2.75(s,3H),2.26–2.22(m,1H),2.16–1.90(m,2H),1.91–1.79(m,1H).MS:621[M+H]⁺.

EXAMPLE 61 (R, E) -N- (4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -5- (3, 4-dimethoxyphenyl) quinazolin-6-yl) -3- (1-methylpyrrolidin-2-yl) acrylamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-4- (pyridin-2-ylmethoxy) aniline was used in place of 3-chloro-2-fluoroaniline in step 1 and 3, 4-dimethoxyphenylboronic acid was used in place of phenylboronic acid in step 2 to obtain the product of monotrifluoroacetate as a white solid ;¹H NMR(400MHz,DMSO-d₆)δ10.39(s,1H),9.61(s,1H),8.94(s,1H),8.60(br,1H),8.24(d,J＝9.0Hz,1H),8.00–7.83(m,3H),7.55-7.53(m,2H),7.40-7.38(m,1H),7.27-7.25(m,2H),7.12(br,1H),7.04(d,J＝8.4Hz,1H),6.92(d,J＝9.0Hz,1H),6.71(dd,J＝15.6,8.9Hz,1H),6.45(d,J＝15.2Hz,1H),5.28(s,2H),4.00(s,1H),3.87(s,3H),3.75(s,3H),3.68(t,J＝11.0Hz,1H),3.13-3.10(m,1H),2.75(s,3H),2.27-2.23(m,1H),2.14–1.97(m,2H),1.87-1.84(m,1H).MS:651[M+H]⁺.

EXAMPLE 62 (R, E) -N- (4- ((3-chloro-2-fluorophenyl) amino) -5- (1-methyl-1H-indol-6-yl) quinazolin-6-yl) -3- (1-methylpyrrolidin-2-yl) acrylamide

The synthesis was carried out in the same manner as in example 1 except that (1-methyl-1H-indol-6-yl) boric acid was used instead of phenylboronic acid in step 2 to carry out the reaction, and finally a white solid product of monotrifluoroacetate was obtained ;¹H NMR(400MHz,DMSO-d₆)δ9.92(s,1H),9.31(s,1H),8.76(s,1H),8.19(d,J＝8.9Hz,1H),7.96(d,J＝9.0Hz,1H),7.86-7.79(m,2H),7.65(s,1H),7.49(s,1H),7.35–7.23(m,2H),7.18–7.02(m,2H),6.66(dd,J＝15.3,8.7Hz,1H),6.57(s,1H),6.31(d,J＝15.3Hz,1H),3.93(s,1H),3.81(s,3H),3.65-3.62(m,1H),3.12–3.02(m,1H),2.70(br,3H),2.24–2.16(m,1H),2.07–1.89(m,2H),1.85–1.69(m,1H).MS:555[M+H]⁺.

EXAMPLE 63 (R, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -5- (1H-indazol-6-yl) quinazolin-6-yl) -3- (1-methylpyrrolidin-2-yl) acrylamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-4-fluoroaniline was used in place of 3-chloro-2-fluoroaniline in step 1 and (1H-indazol-6-yl) boric acid was used in place of phenylboric acid in step 2 to carry out the reaction, and finally a white solid product of monotrifluoroacetate was obtained ;¹H NMR(400MHz,DMSO-d₆)δ13.46(s,1H),10.08(s,1H),9.57–9.50(m,1H),8.82(d,J＝3.3Hz,1H),8.29(s,1H),8.15(d,J＝9.2Hz,1H),8.05(d,J＝8.3Hz,1H),7.97(d,J＝9.0Hz,1H),7.75(s,1H),7.33(dd,J＝6.8,2.6Hz,1H),7.27–7.24(m,2H),7.17(d,J＝8.2Hz,1H),6.71–6.55(m,2H),6.32(d,J＝15.4Hz,1H),3.97–3.87(m,1H),3.63(d,J＝11.4Hz,1H),3.08–3.05(m,1H),2.70(br,3H),2.21–2.18(m,1H),2.07–1.89(m,2H),1.82–1.78(m,1H).MS:542[M+H]⁺.

EXAMPLE 64 (R, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -5- (1-methyl-1H-indol-6-yl) quinazolin-6-yl) -3- (1-methylpyrrolidin-2-yl) acrylamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-4-fluoroaniline was used instead of 3-chloro-2-fluoroaniline in step 1 and (1-methyl-1H-indol-6-yl) boric acid was used instead of phenylboric acid in step 2 to carry out the reaction, and finally a white solid product of monotrifluoroacetate was obtained ;¹H NMR(400MHz,DMSO-d₆)δ10.08(s,1H),9.43(s,1H),8.83(s,1H),8.22(d,J＝9.0Hz,1H),7.96(d,J＝8.9Hz,1H),7.86(d,J＝8.0Hz,1H),7.69(s,1H),7.57(s,1H),7.29(s,1H),7.27–7.19(m,2H),7.11(d,J＝8.0Hz,1H),6.68-6.65(m,3H),6.36(d,J＝15.3Hz,1H),3.96–3.89(m,1H),3.81(s,3H),3.64(s,1H),3.08(s,1H),2.73–2.67(m,3H),2.21-2.18(m,1H),2.06–1.91(m,2H),1.81-1.79(m,1H).MS:555[M+H]⁺.

EXAMPLE 65 (R, E) -N- (4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -5- (m-tolyl) quinazolin-6-yl) -3- (1-methylpyrrolidin-2-yl) acrylamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-4- (pyridin-2-ylmethoxy) aniline was used in place of 3-chloro-2-fluoroaniline in step 1 and 3-methylphenylboronic acid was used in place of phenylboronic acid in step 2 to obtain the product as a white solid in the free state ;¹H NMR(400MHz,DMSO-d₆)δ10.12(s,1H),9.60(s,1H),8.89(s,1H),8.59(br,1H),8.15(d,J＝8.9Hz,1H),7.98–7.85(m,2H),7.59–7.47(m,4H),7.41–7.35(m,2H),7.31(d,J＝7.5Hz,1H),7.21(d,J＝9.0Hz,1H),6.76(d,J＝9.0Hz,1H),6.68(dd,J＝15.3,8.7Hz,1H),6.37(d,J＝15.4Hz,1H),5.26(s,2H),3.99(s,1H),3.67(d,J＝9.3Hz,1H),3.12(d,J＝9.4Hz,1H),2.74(br,3H),2.40(s,3H),2.26-2.24(m,1H),2.04–1.98(m,2H),1.88–1.77(m,1H).MS:605[M+H]⁺.

EXAMPLE 66 (E) -N- (4- ((3-chloro-2-fluorophenyl) amino) -5- (1-methyl-1H-indol-6-yl) quinazolin-6-yl) -4- (dimethylamino) but-2-enamide

The synthesis was carried out in the same manner as in example 1 except that (1-methyl-1H-indol-6-yl) boronic acid was used in place of phenylboronic acid in step 2 and (E) -4- (dimethylamino) but-2-enoyl chloride was used in place of (R, E) -3- (1-methylpyrrolidin-2-yl) acryloyl chloride in step 4 to give the product as a white solid in the free state ;¹H NMR(400MHz,DMSO-d₆)δ8.89(s,1H),8.64(s,1H),8.13(d,J＝8.9Hz,1H),7.97(t,J＝7.6Hz,1H),7.91(d,J＝8.9Hz,1H),7.77(d,J＝8.0Hz,1H),7.61(s,1H),7.48(s,1H),7.19(t,J＝7.4Hz,1H),7.12(dd,J＝15.2,7.1Hz,2H),7.04(d,J＝8.1Hz,1H),6.57(d,J＝8.3,5.9Hz,2H),6.02(d,J＝15.5Hz,1H),3.79(s,3H),2.92(d,J＝5.9Hz,2H),2.06(s,6H).MS:529[M+H]⁺.

EXAMPLE 67 (E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -5- (1-methyl-1H-indol-6-yl) quinazolin-6-yl) -4- (dimethylamino) but-2-enamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-4-fluoroaniline was used instead of 3-chloro-2-fluoroaniline in step 1, (1-methyl-1H-indol-6-yl) boric acid was used instead of phenylboric acid in step 2, and (E) -4- (dimethylamino) but-2-enecarboxylic acid chloride was used instead of (R, E) -3- (1-methylpyrrolidin-2-yl) acrylic acid chloride in step 4 to obtain a white solid product in free form ;¹H NMR(400MHz,DMSO-d₆)δ9.02(s,1H),8.67(s,1H),8.14(d,J＝9.0Hz,1H),7.87(dd,J＝16.0,8.5Hz,2H),7.65(s,1H),7.56(s,1H),7.25(d,J＝6.7Hz,1H),7.18(t,J＝9.1Hz,1H),7.09(d,J＝8.0Hz,1H),7.03(s,1H),6.68–6.52(m,3H),6.08(d,J＝15.4Hz,1H),3.80(s,3H),2.94(d,J＝6.1Hz,2H),2.08(s,6H).MS:529[M+H]⁺.

EXAMPLE 68 (E) -N- (4- ((3-chloro-4- ((3-fluorobenzyl) oxy) phenyl) amino) -5-phenylquinazolin-6-yl) -4- (dimethylamino) but-2-enamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-4- ((3-fluorobenzyl) oxy) aniline was used instead of 3-chloro-2-fluoroaniline in step 1, and (E) -4- (dimethylamino) but-2-enoyl chloride was used instead of (R, E) -3- (1-methylpyrrolidin-2-yl) acryloyl chloride in step 4 to obtain a white solid product of monotrifluoroacetate salt ;¹H NMR(400MHz,DMSO-d₆)δ10.05(s,1H),9.63(s,1H),8.83(s,1H),8.07(d,J＝8.9Hz,1H),7.94(d,J＝8.9Hz,1H),7.69–7.61(m,3H),7.53(d,J＝7.0Hz,3H),7.53–7.40(m,1H),7.33–7.12(m,5H),6.74(d,J＝9.0Hz,1H),6.63(dt,J＝14.8,7.1Hz,1H),6.30(d,J＝15.4Hz,1H),5.20(s,2H),3.87(d,J＝7.0Hz,2H),2.75(s,6H).MS:582[M+H]⁺.

EXAMPLE 69 (E) -N- (4- ((3-chloro-4- ((3-fluorobenzyl) oxy) phenyl) amino) -5- (3-methoxyphenyl) quinazolin-6-yl) -4- (dimethylamino) but-2-enamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-4- ((3-fluorobenzyl) oxy) aniline was used in place of 3-chloro-2-fluoroaniline in step 1, 3-methoxyphenylboronic acid was used in place of phenylboronic acid in step 2, and (E) -4- (dimethylamino) but-2-enoyl chloride was used in place of (R, E) -3- (1-methylpyrrolidin-2-yl) acryloyl chloride in step 4 to obtain the product as a white solid in free form ;¹H NMR(400MHz,DMSO-d₆)δ9.14(s,1H),8.63(s,1H),7.98(d,J＝8.9Hz,1H),7.85(d,J＝8.9Hz,1H),7.65–7.52(m,2H),7.45(t,J＝8.0Hz,1H),7.30–7.27(m,2H),7.22(dd,J＝16.7,8.2Hz,1H),7.18–7.12(m,2H),7.08(s,1H),7.03–7.00(m,2H),6.73(d,J＝9.0,Hz,1H),6.60(dt,J＝15.5,5.9Hz,1H),6.10(d,J＝15.5Hz,1H),5.18(s,2H),3.79(s,3H),2.98(d,J＝5.9Hz,2H),2.12(s,6H).MS:612[M+H]⁺.

EXAMPLE 70 (E) -N- (4- ((3-chloro-4- ((3-fluorobenzyl) oxy) phenyl) amino) -5- (3, 4-dimethoxyphenyl) quinazolin-6-yl) -4- (dimethylamino) but-2-enamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-4- ((3-fluorobenzyl) oxy) aniline was used in place of 3-chloro-2-fluoroaniline in step 1,3, 4-dimethoxyphenylboronic acid was used in place of phenylboronic acid in step 2, and (E) -4- (dimethylamino) but-2-enoyl chloride was used in place of (R, E) -3- (1-methylpyrrolidin-2-yl) acryloyl chloride in step 4 to obtain the product as a white solid in free form ;¹H NMR(400MHz,DMSO-d₆)δ10.01(s,1H),9.36(s,1H),8.64(s,1H),8.01(d,J＝8.9Hz,1H),7.86(d,J＝8.8Hz,1H),7.55(d,J＝2.6Hz,1H),7.45(td,J＝8.1,6.0Hz,1H),7.31–7.07(m,6H),7.00(d,J＝8.1Hz,1H),6.86(d,J＝9.0Hz,1H),6.64(dd,J＝14.6,7.7Hz,1H),6.32(d,J＝15.3Hz,1H),5.19(s,2H),3.88(s,3H),3.74(brs,5H),2.66(s,6H).MS:642[M+H]⁺.

EXAMPLE 71 (E) -N- (4- ((3-chloro-4- ((3-fluorobenzyl) oxy) phenyl) amino) -5- (m-tolyl) quinazolin-6-yl) -4- (dimethylamino) but-2-enamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-4- ((3-fluorobenzyl) oxy) aniline was used in place of 3-chloro-2-fluoroaniline in step 1, 3-methylphenylboronic acid was used in place of phenylboronic acid in step 2, and (E) -4- (dimethylamino) but-2-enoyl chloride was used in place of (R, E) -3- (1-methylpyrrolidin-2-yl) acryloyl chloride in step 4 to obtain the product as a white solid in free form ;¹H NMR(400MHz,DMSO-d₆)δ9.13(s,1H),8.63(s,1H),7.98(d,J＝8.9Hz,1H),7.85(d,J＝8.9Hz,1H),7.60(s,1H),7.55(t,J＝7.5Hz,1H),7.52–7.39(m,2H),7.33(s,1H),7.31–7.22(m,3H),7.26–7.09(m,2H),6.94(s,1H),6.67(d,J＝9.0,Hz,1H),6.59(dt,J＝15.5,5.9Hz,1H),6.09(d,J＝15.5Hz,1H),5.18(s,2H),2.97(d,J＝6.2,Hz,2H),2.39(s,3H),2.12(s,6H).MS:596[M+H]⁺.

EXAMPLE 72 (R, E) -N- (4- ((3-chloro-4- ((3-fluorobenzyl) oxy) phenyl) amino) -5-phenylquinazolin-6-yl) -3- (1-methylpyrrolidin-2-yl) acrylamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-4- ((3-fluorobenzyl) oxy) aniline was used instead of 3-chloro-2-fluoroaniline in step 1 to obtain a white solid product in the free state ;¹H NMR(400MHz,DMSO-d₆)δ9.16(s,1H),8.64(s,1H),7.97(d,J＝8.9Hz,1H),7.86(d,J＝8.9Hz,1H),7.69–7.56(m,4H),7.53–7.39(m,3H),7.30–7.07(m,4H),6.85(s,1H),6.66(d,J＝9.0Hz,1H),6.47(dd,J＝15.4,7.7Hz,1H),6.05(d,J＝15.4Hz,1H),5.17(s,2H),2.99(dd,J＝9.7,6.8Hz,1H),2.63(t,J＝7.9Hz,1H),2.13–2.08(m,4H),2.01–1.86(m,1H),1.76–1.62(m,2H),1.55–1.40(m,1H).MS:608[M+H]⁺.

EXAMPLE 73 (R, E) -N- (4- ((3-chloro-4- ((3-fluorobenzyl) oxy) phenyl) amino) -5- (3-methoxyphenyl) quinazolin-6-yl) -3- (1-methylpyrrolidin-2-yl) acrylamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-4- ((3-fluorobenzyl) oxy) aniline was used in place of 3-chloro-2-fluoroaniline in step 1 and 3-methoxyphenylboronic acid was used in place of phenylboronic acid in step 2 to obtain a white solid product in the free state ;¹H NMR(400MHz,DMSO-d₆)δ9.14(d,J＝2.4Hz,1H),8.63(s,1H),7.99(d,J＝8.9Hz,1H),7.85(d,J＝8.9Hz,1H),7.65–7.52(m,2H),7.44(dd,J＝8.1,5.9Hz,1H),7.31–6.99(m,8H),6.73(d,J＝9.0Hz,1H),6.49(dd,J＝15.4,7.7Hz,1H),6.09(d,J＝15.4Hz,1H),5.18(s,2H),3.79(s,3H),2.99(dd,J＝9.6,6.9Hz,1H),2.66–2.64(m,1H),2.15–2.10(s,4H),1.94–1.92(m,1H),1.74–1.68(m,2H),1.54–1.43(m,1H).MS:638[M+H]⁺.

EXAMPLE 74 (R, E) -N- (4- ((3-chloro-4- ((3-fluorobenzyl) oxy) phenyl) amino) -5- (3, 4-dimethoxyphenyl) quinazolin-6-yl) -3- (1-methylpyrrolidin-2-yl) acrylamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-4- ((3-fluorobenzyl) oxy) aniline was used in place of 3-chloro-2-fluoroaniline in step 1 and 3, 4-dimethoxyphenylboronic acid was used in place of phenylboronic acid in step 2 to obtain a white solid product in the free state ;¹H NMR(400MHz,DMSO-d₆)δ9.05(d,J＝3.1Hz,1H),8.62(s,1H),8.04(d,J＝8.9Hz,1H),7.84(d,J＝8.9Hz,1H),7.57(dS,1H),7.45(td,J＝8.0,6.0Hz,1H),7.26(dd,J＝15.0,7.4Hz,3H),7.17(t,J＝7.4Hz,3H),7.08(S,1H),6.99(d,J＝8.2Hz,1H),6.84(d,J＝9.0Hz,1H),6.51(dd,J＝15.4,7.7Hz,1H),6.13(d,J＝15.3Hz,1H),5.18(s,2H),3.88(s,3H),3.74(s,3H),,3.01–2.98(m,1H),2.67–2.64(m,1H),2.19–2.05(m,4H),1.96–1.94(tm,1H),1.73–1.66(m,2H),1.56–1.42(m,1H).MS:668[M+H]⁺.

EXAMPLE 75 (R, E) -N- (4- ((3-chloro-4- ((3-fluorobenzyl) oxy) phenyl) amino) -5- (m-tolyl) quinazolin-6-yl) -3- (1-methylpyrrolidin-2-yl) acrylamide

The synthesis was carried out in the same manner as in example 1 except that 3-chloro-4- ((3-fluorobenzyl) oxy) aniline was used in place of 3-chloro-2-fluoroaniline in step 1 and 3-methylphenylboronic acid was used in place of phenylboronic acid in step 2 to obtain a white solid product in the free state ;¹H NMR(400MHz,DMSO-d₆)δ9.11(d,J＝1.6Hz,1H),8.63(s,1H),7.99(dd,J＝8.9,1.4Hz,1H),7.85(d,J＝8.9Hz,1H),7.63–7.39(m,4H),7.35–7.21(m,4H),7.19–7.09(m,2H),6.94(s,1H),6.67(d,J＝8.9Hz,1H),6.48(dd,J＝15.4,7.7Hz,1H),6.07(d,J＝15.4Hz,1H),5.18(s,2H),2.99(dd,J＝9.7,7.0Hz,1H),2.65–2.63(m,1H),2.39(s,3H),2.14–2.10(m,4H),1.95–1.90(m,1H),1.72–1.67(m,2H),1.54–1.43(m,1H).MS:622[M+H]⁺.

EXAMPLE 76 (E) -N- (4- ((3, 4-dichloro-2-fluorophenyl) amino) -5-phenylquinazolin-6-yl) -4- (dimethylamino) but-2-enamide

The synthesis was carried out in the same manner as in example 1 except that 3, 4-dichloro-2-fluoroaniline was used instead of 3-chloro-2-fluoroaniline in step 1, and (E) -4- (dimethylamino) but-2-enoyl chloride was used instead of (R, E) -3- (1-methylpyrrolidin-2-yl) acryloyl chloride in step 4, to obtain a white solid product in free form ;¹H NMR(400MHz,DMSO-d₆)δ9.15(s,1H),8.70(s,1H),8.28(t,J＝8.6Hz,1H),8.01(d,J＝8.9Hz,1H),7.92(d,J＝8.9Hz,1H),7.62–7.58(m,3H),7.48–7.44(m,3H),7.09(s,1H),6.57(dt,J＝15.5,5.9Hz,1H),6.06(dt,J＝15.5,1.7Hz,1H),3.02–2.95(m,2H),2.13(s,6H).MS:510[M+H]⁺.

EXAMPLE 77 (R, E) -N- (4- ((3, 4-dichloro-2-fluorophenyl) amino) -5-phenylquinazolin-6-yl) -3- (1-methylpyrrolidin-2-yl) acrylamide

The synthesis was carried out in the same manner as in example 1 except that 3, 4-dichloro-2-fluoroaniline was used in place of 3-chloro-2-fluoroaniline in step 1 to carry out the reaction, and finally a white solid product in the free state was obtained ;¹H NMR(400MHz,DMSO-d₆)δ9.15(s,1H),8.70(s,1H),8.28(t,J＝8.6Hz,1H),8.02(d,J＝8.9Hz,1H),7.92(d,J＝8.9Hz,1H),7.61–7.58(m,3H),7.50–7.43(m,3H),7.09(d,J＝2.6Hz,1H),6.47(dd,J＝15.4,7.8Hz,1H),6.05(d,J＝15.3Hz,1H),3.02(s,1H),2.67(br,1H),2.15–2.13(m,4H),1.95–1.93(m,1H),1.72–1.68(m,2H),1.58–1.43(m,1H).MS:536[M+H]⁺.

Experimental example 1 test of Small molecule Compounds for inhibiting EGFR ^WT and HER2 kinase Activity

Reagent and consumable: ULightTM-labeled Ploy GT PEPTIDE (PERKIN ELMER, catalog number TRF-0100-M); ULightTM-labeled JAK-1 (Try 1023) Peptide (PERKIN ELMER, catalog number TRF-0121-M); eu-W1024-labeled Anti-Phosphotyrosine Antibody (PT 66) (PERKIN ELMER, catalog number AD 0068); 10 Xdetection Buffer (PERKIN ELMER, catalog number CR 97-100); HER2 kinase (Carna Biosciences, catalog No. 08-016); EGFR kinase (Carna Biosciences, catalog number 08-115); HEPES (GIBCO, catalog number 15630-080); EGTA (Sigma, catalog number 03777-10G); EDTA (Sigma, catalog number EDS-100G); mgCl ₂ (Sigma, catalog number 63069-100 ML); DTT (Sigma, catalog number 43816-10 ML); tween-20 (Sigma, catalog number P7949-100 ML); DMSO (LIFE SCIENCE, catalog number 0231-500 ML); 384 well plates (PERKIN ELMER, catalog number 607290); multifunctional board machine (PERKIN ELMER, catalog number Envision)

Compound solution preparation: test compounds were dissolved in DMSO to make a 10mM stock solution. The compound was diluted to 0.25mM (100 times the final concentration of the dilution) in DMSO before use and 3-fold concentration gradient dilutions were made for a total of 11 gradients. The compound was diluted with buffer to a 4-fold final concentration when added.

HER2 kinase assay: a buffer solution was prepared, and 40nM 4X HER2 kinase solution, 40. Mu.M 4X ATP solution, 400nM 4X ULight ^TM -labeled Ploy GT PEPTIDE substrate solution was prepared using the buffer solution. After the preparation was completed, the enzyme was mixed with the compound of different concentration prepared by pre-dilution, and left at room temperature for 5 minutes, with duplicate wells being set for each concentration. The corresponding substrate and ATP were added and reacted at room temperature for 120 minutes (with negative and positive controls set). After the reaction, PT66 detection antibody was added and incubated at room temperature for 60 minutes and then detected by Envision.

EGFR ^WT kinase assay: buffer was prepared and 3.48nM 4 XEGFR kinase solution, 600. Mu.M 4 XATP solution, 400nM 4X ULight ^TM -labeled JAK-1 (Try 1023) Peptide substrate solution was prepared using the buffer. After the preparation was completed, the enzyme was mixed with the compound of different concentration prepared by pre-dilution, and left at room temperature for 5 minutes, with duplicate wells being set for each concentration. The corresponding substrate and ATP were added and reacted at room temperature for 120 minutes (with negative and positive controls set). After the completion of the reaction, PT66 detection antibody was added, and the reaction was incubated at room temperature for 60 minutes and then detected by Envision.

And (3) data calculation: well readings and inhibition ratios were calculated using an Excel table, well readings = 10000 (well EU 665)/(well EU 615), inhibition ratio = [ (positive control well readings-experimental well readings)/(positive control well readings-negative control well readings) ] × 100%. The compound concentrations and corresponding inhibition rate inputs GRAPHPAD PRISM are processed to calculate IC ₅₀ values.

Tables 1 and 2 set forth the results of assays for EGFR ^WT and HER2 tyrosine kinase inhibitory activity of the compounds of the present application, wherein A represents IC ₅₀ less than or equal to 10nM, B represents IC ₅₀ greater than 10nM but less than or equal to 100nM, and C represents IC ₅₀ greater than 100nM and less than or equal to 1000nM.

TABLE 1 determination of EGFR kinase inhibitory Activity of the Compounds of the invention

TABLE 2 determination of HER2 kinase inhibitory Activity of the Compounds of the invention

From the results of tables 1 and 2 above, it can be seen that the compounds of the present application exhibit very excellent inhibitory activity against both HER2 and EGFR kinases, and can be used for the treatment of EGFR and HER2 kinase mediated tumors and other diseases.

Experimental example 2 test of small molecule Compounds for inhibiting cell proliferation

The application uses CTG method to test the anti-proliferation activity of the compound in vitro on HCC-827, ba/F3 ERBB2A775_G776insYVMA and Ba/F3 EGFR D770_N771insSVD cell lines cultured in vitro.

Reagent and consumable: RPMI1640 (ThermoFisher, catalog number C11875500 BT); DMEM (thermo fisher, C11995500 BT); fetal bovine serum (Hyclone, cat# SV 30087.03); 0.25% trypsin-EDTA (ThermoFisher, cat. 25200072); penicillin-streptomycin (Hyclone, catalog number SV 30010); DSMO (LIFE SCIENCE, catalog number 0231-500 ML); CTG test kit (Promega, catalog No. G9243); 96-well plates (Corning, catalog No. 3599); multifunctional board machine (PERKIN ELMER, catalog number Envision)

Cell line: HCC-827 (from ATCC), ba/F3 ERBB 2A 775_G776insYVMA and Ba/F3 EGFR D770_N771insSVD (all from Kang Yuanbo Biotechnology (Beijing) Co., ltd.); during the culture, the above cells were cultured in RPMI1640 medium containing 10% fetal bovine serum, 100U/mL penicillin and 100. Mu.g/mL streptomycin, and HCC-827 was cultured in DMEM medium containing 10% fetal bovine 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 DMSO to form a stock solution and subjected to gradient dilution, followed by dilution with the corresponding medium to give a 5-fold working concentration solution.

2. Cells in the logarithmic growth phase were diluted with culture medium to a specific cell density, and 80. Mu.L of the cell suspension was added to a 96-well plate so that the cell plating densities of HCC-827, ba/F3 ERBB 2A 775-G776 insYVMA, and Ba/F3 EGFRD770_N771 insSVD were 3000 cells/well. Wherein, ba/F3 ERBB 2A 775-G776 insYVMA and Ba/F3 EGFR D770-N771 insSVD directly enter the next step of compound treatment, while HCC-827 needs to be placed in a 37 ℃ and 5% carbon dioxide incubator for culturing overnight and then compound treatment is carried out.

3. Mu.L of the compound solution was added to each well of the 96-well plate which had been seeded with cells. The highest concentration of the tested compound is 10 mu M, 9 concentrations are added, 4-time gradient dilution is carried out, and double holes are formed. A control group without compound was also set.

4. After the cells were further cultured for 72 hours, cell viability was detected using CTG detection kit. The signal values were read with a multifunctional reader (PERKIN ELMER), and a dose-response curve was made with GRAPHPAD PRISM software and IC ₅₀ was calculated.

Tables 3 and 4 set forth the results of antiproliferative activity assays of representative compounds of the present invention on HCC-827, ba/F3 ERBB 2A 775_G776insYVMA and Ba/F3 EGFR D770_N771insSVD cells. Wherein A represents IC ₅₀ or less than or equal to 100nM, B represents IC ₅₀ greater than 100nM but less than or equal to 1000nM, and C represents IC ₅₀ greater than 1000nM.

TABLE 3 determination of the antiproliferative Activity of representative Compounds of the invention on Ba/F3 EGFRD770_N771 insSVD cells

TABLE 4 determination of the antiproliferative Activity of representative Compounds of the invention on Ba/F3 ERBB2A775_G776 insYVMA cells

The results in Table 4 show that the compounds of the present application exhibit excellent tumor cell proliferation inhibiting activity against the Ba/F3 ERBB 2A 775-G776sYAMA cell line.

Experimental example 3 Small molecule Compound mice tumor-bearing efficacy test

This test investigated the effect of the compounds of the present application on tumor growth by orally administering a portion of the compounds of the present application to a model of Ba/F3 ERBB 2a 775_g776 insYVMA-nude mice tumor-bearing. Meanwhile, pyrroltinib was used as a control for comparison.

Table 5 experimental instrument:

table 6 experimental animals and cells:

reagent: RPMI1640 (ThermoFisher, catalog number C11875500 BT); fetal bovine serum (Hyclone, cat# SV 30087.03); 0.25% trypsin-EDTA (ThermoFisher, cat. 25200072); penicillin-streptomycin (Hyclone, catalog number SV 30010); DSMO (LIFE SCIENCE, catalog number 0231-500 ML); solutol (Sigma, 70142-34-6-1 kg)

Test compound formulation: weighing a compound to be tested with proper weight, completely dissolving in a solvent (DMSO) with proper volume, performing vortex or ultrasonic treatment, adding a proper amount of Solutol, mixing, and finally adding sterilized drinking water, stirring, and performing vortex mixing to obtain a uniform solution or suspension.

The method comprises the following steps: all experiments were approved by the animal welfare Committee, and the right dorsal subcutaneous of the log phase Ba/F3 ERBB2A775_G776 insYVMA vaccinated immunodeficient nude mice (BALB/c nude, female, 6-7 weeks old, body weight 18+ -2G) was given a cell inoculum size of 4X 10 ⁶/animal, and animals were randomized into dosing and control groups after tumor growth to 150-200mm ³. For the administration group, each test compound solution was administered, and the control group was administered with the vehicle solution without the test substance once daily for about 2 weeks. The dose of each test compound was set at 30mg/kg (based on the effective compound concentration) and the test compound was prepared as-is. During the experiment, tumor-bearing diameters were measured 2 times per week while weighing the mice. The calculation formula of Tumor Volume (TV) is: tv=1/2×a×b ², where a and b represent length and width, respectively. The relative tumor volume (relative tumor volume, RTV) is calculated from the measured results, the calculation formula being: rtv=vt/V0. Where V0 is the tumor volume measured at the time of group administration and Vt is the tumor volume at each measurement. The evaluation index of the anti-tumor activity is relative tumor proliferation rate T/C (%), and the calculation formula is as follows: T/C (%) = (TRTV/CRTV) ×100%, TRTV: administration group RTV; CRTV: control RTV. T and C represent the average tumor volumes at a time point of the administration group and the control group, respectively.

The experimental results are shown in table 7 below and in fig. 1-2. As shown in the graph, pyrotinib had a certain antitumor effect at a dose of 30mg/kg, and the T/C value at day 14 of administration was 38.3%. The compound of example 53 of the present application has a remarkable antitumor effect at a dose of 30mg/kg, and a T/C value of 22.7% at 11 days of administration. In combination with the previous results of the test for the cell proliferation activity of Ba/F3 HER2A 775-G776sYAMA, it is clear that the compound of the application not only has excellent anti-tumor cell proliferation activity on the 20 exon insertion mutation of HER2 (HER 2A 775-G776 insYVMA) in vitro, but also shows significantly better anti-tumor activity than Pyrotinib in the Ba/F3 ERBB 2A 775-G776 insYVMA nude mice tumor-bearing model, and the tested compound (example 53) also achieves tumor shrinkage, while at the same dose (30 mg/kg), the tumors of the Pyrotinib group still significantly remain to grow.

TABLE 7T/C (%)

* QD means once daily administration

By combining all test results, it can be found that the application synthesizes a series of compounds by introducing a substituent group at the 5-position of quinazoline and simultaneously removing the substituent group at the 7-position. The compound of the application has good to excellent inhibitory activity on proliferation of HER2 and EGFR kinase, and Ba/F3 HER 2A 775-G776 insYVMA and Ba/F3 EGFR D770-N771 insSVD cells, especially on Ba/F3 HER 2A 775-G776 insYVMA cell model, the compound of the application has an effect which is even obviously better than Pyrotinib in vitro tumor-bearing model test, and can be applied to treatment of HER2, EGFR kinase or 20 exon mutation or other mutation-mediated related diseases.

While the foregoing is directed to the preferred embodiments of the present invention, it will be apparent to those skilled in the art that various changes and modifications can be made in the embodiments of the invention without departing from the spirit of the invention, and such changes and modifications should also be considered to be within the scope of the invention.

Claims

1. A compound shown in a formula (I), a stereoisomer and pharmaceutically acceptable salts thereof,

In the formula (I), m is 0 and 1;

R ₁ is 1-methylpyrrolidin-2-yl or dimethylamino;

R ₂ is phenyl, 3-chlorophenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-methylphenyl, 3-cyanophenyl, 3, 4-dimethoxyphenyl, 1-methyl-1H-indol-6-yl, 1H-indazol-6-yl;

R ₃、R₄ is each independently hydrogen, fluorine, chlorine,

R ₅ is hydrogen, fluorine, chlorine, pyridine-2-methoxyl, 3-fluorobenzyloxy and 3-chlorobenzyloxy.

2. The compound of claim 1, stereoisomers thereof, and pharmaceutically acceptable salts thereof, selected from the group consisting of:

。

3. A pharmaceutical composition comprising a compound, stereoisomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, and one or more pharmaceutically acceptable carriers or excipients.

4. The pharmaceutical composition of claim 3, wherein the pharmaceutical composition further comprises one or more additional therapeutic agents.

5. Use of a compound according to any one of claims 1-2, a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancers and autoimmune diseases associated with the tyrosine kinases EGFR, HER 2.

6. The use according to claim 5, wherein the cancer and autoimmune disease is ocular fundus disease, dry eye, psoriasis, vitiligo, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, crohn's disease, atherosclerosis, pulmonary fibrosis, liver 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, nasopharyngeal carcinoma, esophageal cancer, brain tumor, lymphoma, multiple myeloma, biliary tract carcinoma sarcoma, cholangiocarcinoma.