CN108341835A

CN108341835A - Boron-containing compound as tyrosine kinase inhibitor

Info

Publication number: CN108341835A
Application number: CN201710047432.1A
Authority: CN
Inventors: 张寅生; 高勇; 任景; 王庆璘; 赵大敏; 周宇; 吴喆阳
Original assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Current assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority date: 2017-01-22
Filing date: 2017-01-22
Publication date: 2018-07-31
Anticipated expiration: 2037-01-22
Also published as: CN108341835B

Abstract

The application belongs to field of medicaments, in particular to boron-containing compound, preparation method, the pharmaceutical composition containing the compound and its purposes in treating tyrosine kinase mediated cell proliferation disorders as tyrosine kinase inhibitor.The compound of the application has good inhibiting effect for tyrosine kinase.

Description

Boron-containing compounds as tyrosine kinase inhibitors

Technical Field

The application belongs to the field of medicines, and particularly relates to a compound shown in a formula (I), a preparation method thereof, a pharmaceutical composition containing the compound, and application of the compound in treating cell proliferative diseases mediated by tyrosine kinase.

Background

Cancer, one of the leading causes of morbidity and mortality worldwide, is a cell proliferative disease. Protein kinases play a very important role in regulating cell growth, proliferation, invasion, differentiation and the like. One of the major mechanisms by which protein kinases achieve cellular regulation is through transmembrane extracellular signal transduction, which in turn regulates biochemical pathways within the cell. Protein phosphorylation represents a process by which intracellular signals propagate from molecule to molecule, ultimately leading to a cellular response. Protein phosphorylation occurs primarily at serine, threonine or tyrosine residues, and protein kinases have therefore been classified by the specificity of their phosphorylation sites, i.e., serine/threonine kinases and tyrosine kinases. Since phosphorylation is a ubiquitous process in cells and since cellular phenotype is largely influenced by the activity of these pathways, protein kinase inhibitors have important uses in the treatment of human and animal diseases. Among them, tyrosine kinases include, but are not limited to, Epidermal Growth Factor Receptor (EGFR) tyrosine kinase, Anaplastic Lymphoma Kinase (ALK), and Janus kinase (JAK).

Among them, EGFR is a member of the erbB receptor family of transmembrane protein tyrosine kinases, and forms homodimers on cell membranes by binding to its ligand (e.g., the endogenous epidermal growth factor EGF). The formation of these dimers can lead to phosphorylation of key tyrosine residues within the cell, thereby activating multiple downstream signaling pathways within the cell. These intracellular signaling pathways play important regulatory roles in cell proliferation, survival, and anti-apoptotic processes. Dysregulation of EGFR signal transduction pathways, including increased expression of ligands and receptors, EGFR gene amplification and mutation, can promote transformation of normal cells into tumor cells, and play an important role in proliferation, invasion, metastasis and angiogenesis of tumor cells. Therefore, EGFR is an important target for the development of anti-tumor drugs.

Among them, ALK is a cell membrane-spanning Receptor Tyrosine Kinase (RTK), and belongs to the insulin receptor subfamily. Intact ALK has the typical RTK three-part structure, an extracellular region, a lipophilic transmembrane region, and an intracellular tyrosine kinase. ALK fusion proteins, mutations and overexpression are associated with a variety of diseases, such as non-small cell lung cancer, intestinal cancer or renal cancer.

Among them, Janus kinases (JAKs) are a family of tyrosine kinases consisting of JAK1, JAK2, JAK3 and TYK 2. JAKs play a crucial role in cytokine signaling. Downstream substrates of JAK family kinases include transcriptional signal sensing and activation (STAT) proteins. JAK kinases are associated with a variety of diseases, for example JAK3 is associated with many aberrant immune responses, solid tumors or hematologic malignancies; JAK2, for example, is associated with myeloproliferative diseases such as polycythemia vera.

In view of the important role of tyrosine kinase in vivo, the development of tyrosine kinase inhibitors suitable for being used as therapeutic drugs is particularly important, and the invention unexpectedly discovers that a series of boron-containing compounds have good inhibition effect on tyrosine kinase.

Disclosure of Invention

In one aspect, the present application relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof,

wherein,

R¹selected from hydrogen, fluoro, chloro, bromo, iodo, alkyl or alkoxy, wherein alkyl is optionally substituted with fluoro, chloro, bromo or iodo;

x is selected from NH or O;

R⁴and R⁶Each independently selected from hydrogen, alkyl, alkoxy or-NHC (═ O) R^a；

R³And R⁷Each independently selected from hydrogen or alkoxy;

R⁵selected from hydrogen, alkylamino, alkyl, cycloalkyl, alkoxy or heterocycloalkyl, wherein said alkylamino, alkyl, cycloalkyl, alkoxy or heterocycloalkyl is optionally substituted with: o, -S (O)₂R^bAlkyl, -NR^cR^dOr a heterocycloalkyl group;

R^aselected from alkyl, alkenyl, alkynyl, cyano or cycloalkyl;

R^bselected from alkyl groups;

R^cand R^dEach independently selected from hydrogen, alkyl, alkenyl or cycloalkyl;

cy is selected from

R²Each independently selected from fluoro, chloro, bromo, iodo or alkoxy;

n is 0 to 4;

Z¹and Z²Each independently selected from hydrogen or C₁-C₆An alkyl group;

the A ring is a 5-6 membered ring, which is optionally substituted with alkyl.

In some embodiments, R¹Selected from hydrogen, fluorine, chlorine, bromine, iodine, C₁-C₆Alkyl or C₁-C₆Alkoxy radical, wherein C₁-C₆Alkyl is optionally substituted with fluorine, chlorine, bromine or iodine.

In some preferred embodiments, R¹Selected from hydrogen, fluorine, chlorine, bromine, C₁-C₃Alkyl or C₁-C₃Alkoxy radical, wherein C₁-C₃Alkyl is optionally substituted with fluorine.

In some more preferred embodiments, R¹Selected from hydrogen, fluoro, chloro, bromo, methyl or methoxy, wherein methyl is optionally substituted with 1-3 fluoro.

In some most preferred embodiments, R¹Selected from hydrogen, fluorine, chlorine, bromine, methyl, methoxy or trifluoromethyl.

In some most preferred embodiments, R¹Selected from hydrogen, fluorine, chlorine, bromine or methyl.

In some embodiments, R⁴And R⁶Each independently selected from hydrogen and C₁-C₆Alkyl radical, C₁-C₆Alkoxy or-NHC (═ O) R^a。

In some preferred embodiments, R⁴And R⁶Each independently selected from hydrogen and C₁-C₃Alkyl radical, C₁-C₃Alkoxy or-NHC (═ O) R^a

In some more preferred embodiments, R⁴And R⁶Each independently selected from hydrogen and methylor-NHC (═ O) R^a。

In some embodiments, R^aIs selected from C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, cyano or C₃-C₆Cycloalkyl, preferably C₁-C₃Alkyl radical, C₂-C₃Alkenyl radical, C₂-C₃Alkynyl, cyano or C₃-C₆Cycloalkyl, more preferably C₂-C₃Alkenyl, most preferably vinyl.

In some embodiments, R⁴And R⁶At least one is selected from hydrogen.

In some most preferred embodiments, R⁴And R⁶Each independently selected from hydrogen, methyl orAnd R is⁴And R⁶At least one is selected from hydrogen.

In some most preferred embodiments, R⁴And R⁶Each independently selected from hydrogen orAnd R is⁴And R⁶At least one is selected from hydrogen.

In some most preferred embodiments, R⁴And R⁶Each independently selected from hydrogen or methyl, and R⁴And R⁶At least one is selected from hydrogen.

In some embodiments, R³And R⁷Each independently selected from hydrogen or C₁-C₆An alkoxy group.

In some preferred embodiments, R³And R⁷Each independently selected from hydrogen or C₁-C₃An alkoxy group.

In some more preferred embodiments, R³And R⁷Each independently selected from hydrogen, methoxy or isopropyloxy.

In some embodiments, R³And R⁷At least one is selected from hydrogen.

In some most preferred embodiments, R³And R⁷Each independently selected from hydrogen, methoxy or isopropyloxy, and R³And R⁷At least one is selected from hydrogen. In some most preferred embodiments, R³And R⁷Each independently selected from hydrogen or methoxy, and R³And R⁷At least one is selected from hydrogen.

In some embodiments, R⁵Selected from hydrogen, C₁-C₆Alkylamino radical, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl radical, C₁-C₆Alkoxy or 3-6 membered heterocycloalkyl, wherein said C₁-C₆Alkylamino radical, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl radical, C₁-C₆Alkoxy or 3-6 membered heterocycloalkyl optionally substituted with: o, -S (O)₂R^b、C₁-C₆Alkyl, -NR^cR^dOr optionally substituted 3-6 membered heterocycloalkyl.

In some preferred embodiments, R⁵Selected from hydrogen, C₁-C₃Alkylamino radical, C₁-C₃Alkyl radical, C₃-C₆Cycloalkyl radical, C₁-C₃Alkoxy or 5-6 membered heterocycloalkyl, wherein said C₁-C₃Alkylamino radical, C₁-C₃Alkyl radical, C₃-C₆Cycloalkyl radical, C₁-C₃Alkoxy or 5-6 membered heterocycloalkyl optionally substituted with: o, -S (O)₂R^b、C₁-C₆Alkyl, -NR^cR^dOr optionally substituted 5-6 membered heterocycloalkyl.

In some more preferred embodiments, R⁵Selected from hydrogen, ethylamino, ethoxy, tetraHydrofuranyl, tetrahydrothienyl, pyrrolidinyl, tetrahydropyrazolyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1, 4-thiazanyl, 1, 4-dioxanyl, thiomorpholinyl, or 1, 4-dithianyl, wherein the ethylamino, ethoxy, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, tetrahydropyrazolyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1, 4-thiazanyl, 1, 4-dioxanyl, thiomorpholinyl, or 1, 4-dithianyl is optionally substituted with: o, -S (O)₂R^b、C₁-C₃Alkyl, -NR^cR^dOr optionally is covered with C₁-C₆Alkyl-substituted 5-6 membered heterocycloalkyl.

In some more preferred embodiments, R⁵Selected from hydrogen, ethylamino, ethoxy, morpholinyl, piperidinyl, piperazinyl or thiomorpholinyl; wherein ethoxy is optionally substituted by-NR^cR^dPyrrolidinyl, tetrahydropyrazolyl, piperidinyl, or piperazinyl; wherein morpholinyl, piperidinyl, piperazinyl or thiomorpholinyl is optionally substituted with: o, -S (O)₂R^b、C₁-C₃Alkyl, -NR^cR^dOr optionally is covered with C₁-C₃An alkyl-substituted 5-6 membered nitrogen-containing heterocycloalkyl group; wherein ethylamino is optionally substituted by C₁-C₃Alkyl or-NR^cR^dAnd (4) substitution.

In some embodiments, R^bIs selected from C₁-C₆An alkyl group.

In some more preferred embodiments, R^bIs selected from C₁-C₃An alkyl group.

In some embodiments, R^cAnd R^dEach independently selected from hydrogen and C₁-C₆Alkyl radical, C₂-C₆Alkenyl or C₃-C₆A cycloalkyl group.

In some preferred embodiments, R^cAnd R^dAre respectively provided withIndependently selected from hydrogen or C₁-C₃An alkyl group.

In some more preferred embodiments, R⁵Selected from hydrogen, ethylamino, ethoxy, morpholinyl, piperidinyl, piperazinyl or thiomorpholinyl; wherein ethoxy is optionally substituted by-N (CH)₃)₂OrSubstitution; wherein morpholinyl, piperidinyl, piperazinyl or thiomorpholinyl is optionally substituted by ═ O,Methyl, -N (CH)₃)₂Optionally C₁-C₃Pyrrolidinyl substituted by alkyl, optionally C₁-C₃Alkyl-substituted tetrahydropyrazolyl, optionally substituted by C₁-C₃Alkyl-substituted piperidinyl or optionally substituted by C₁-C₃Alkyl substituted piperazinyl substitution; wherein ethylamino is optionally substituted by methyl or-N (CH)₃)₂And (4) substitution.

In some more preferred embodiments, R⁵Selected from hydrogen, ethylamino, ethoxy, Wherein ethoxy is optionally substituted by-N (CH)₃)₂OrSubstitution; wherein Optionally substituted by ═ O,Methyl, -N (CH)₃)₂Pyrrolidinyl, tetrahydropyrazolyl, piperidinyl, piperazinyl, 4-methylpiperazinyl; wherein ethylamino is optionally substituted by methyl or-N (CH)₃)₂And (4) substitution.

In some more preferred embodiments, R⁵Selected from hydrogen, ethylamino, ethoxy, Wherein ethoxy is optionally substituted by-N (CH)₃)₂OrSubstitution; whereinOptionally substituted by methyl orSubstitution; whereinOptionally piperazinyl, 4-methylpiperazinyl or-N (CH)₃)₂Substitution; whereinOptionally substituted with ═ O; in which the ethylamino group is simultaneously substituted by one methyl group and one-N (CH)₃)₂And (4) substitution.

In some most preferred embodiments, R⁵Selected from hydrogen, ethylamino or ethoxy; wherein ethoxy is optionally substituted by-N (CH)₃)₂Substitution; wherein ethylamino is optionally substituted by methyl or-N (CH)₃)₂And (4) substitution.

In some most preferred embodiments, R⁵Selected from hydrogen and ethoxy、 Wherein ethoxy is optionally substitutedSubstitution; whereinOptionally substituted by methyl orSubstitution; whereinOptionally is covered withor-N (CH)₃)₂Substitution; whereinOptionally substituted by ═ O.

In some most preferred embodiments, R⁵Selected from hydrogen,

In some embodiments, R²Each independently selected from fluorine, chlorine, bromine, iodine or C₁-C₆An alkoxy group.

In some preferred embodiments, R²Each independently selected from fluorine, chlorine, bromine, iodine or C₁-C₃An alkoxy group.

Some are more preferableIn alternative embodiments, R²Each independently selected from fluorine, chlorine, bromine, iodine.

In some more preferred embodiments, R²Each independently selected from methoxy, ethoxy or isopropoxy.

In some embodiments, n is 0or 1.

In some embodiments, Cy isComprises thatPreferably, it is

In some embodiments, Cy isComprises that Preferably, it is Wherein m is 1 or 2, R⁸And R⁹Each independently selected from hydrogen or C₁-C₆Alkyl, preferably hydrogen or C₁-C₃Alkyl, most preferably hydrogen or methyl.

In some embodiments, Cy isComprises that Preferably, it is R⁸And R⁹Each independently selected from hydrogen or C₁-C₃Alkyl, preferably hydrogen or methyl, most preferably hydrogen.

In some embodiments, Cy is

In some embodiments, the present application relates to a compound of formula (II) or a compound of formula (III), or a pharmaceutically acceptable salt thereof,

wherein,

R¹、R³、R⁴、R⁵、R⁶、R⁷and X is as defined for compounds of formula (I);

structural unitThe definition of (A) is the same as that of the compound of formula (I).

In some embodiments, the present application relates to compounds of formula (IV) or a pharmaceutically acceptable salt thereof,

wherein,

R¹、R³、R⁵、R⁷and Cy is as defined for compounds of formula (I).

In some embodiments, the present application relates to a compound of formula (V) or formula (VI), or a pharmaceutically acceptable salt thereof,

wherein,

R¹、R³、R⁵、R⁷and X is as defined for compounds of formula (I);

In some embodiments, the present application relates to compounds of formula (VII), or a pharmaceutically acceptable salt thereof,

wherein,

R¹、R³、R⁴、R⁶、R⁷x and Cy are as defined for compounds of formula (I);

Y¹is selected from N or CH;

Y²selected from NH, CH₂S or O;

q is 0 to 11;

R¹²selected from ═ O, -S (═ O)₂R^bAlkyl, -NR^cR^dOr optionally substituted heterocycloalkyl;

R^bselected from alkyl groups;

R^cand R^dEach independently selected from hydrogen, alkyl or cycloalkyl.

In some embodiments, R¹²Selected from ═ O, -S (═ O)₂R^b、C₁-C₆Alkyl, -NR^cR^dOr optionally substituted 3-6 membered heterocycloalkyl.

In some preferred embodiments, R¹²Selected from ═ O, -S (═ O)₂R^b、C₁-C₃Alkyl, -NR^cR^dOr optionally substituted 5-6 membered heterocycloalkyl.

In some more preferred embodiments, R¹²Selected from ═ O, -S (═ O)₂R^b、C₁-C₃Alkyl, -NR^cR^dOr optionally is covered with C₁-C₆Alkyl-substituted 5-6 membered heterocycloalkyl.

In some more preferred embodiments, R¹²Selected from ═ O, -S (═ O)₂R^b、C₁-C₃Alkyl, -NR^cR^dOr optionally is covered with C₁-C₃Alkyl-substituted 5-6 membered heterocycloalkyl.

In some more preferred embodiments, R¹²Selected from ═ O, -S (═ O)₂R^b、C₁-C₃Alkyl, -NR^cR^dOr optionally is covered with C₁-C₃An alkyl-substituted 5-6 membered nitrogen-containing heterocycloalkyl group.

In some embodiments, R^bIs selected from C₁-C₆An alkyl group.

In some embodiments, R^cAnd R^dEach independently selected from hydrogen and C₁-C₆Alkyl or C₃-C₆A cycloalkyl group.

In some preferred embodiments, R^cAnd R^dEach independently selected from hydrogen or C₁-C₃An alkyl group.

In some more preferred embodiments, R¹²Is selected from ═ O,Methyl, -N (CH)₃)₂Optionally C₁-C₃Piperazinyl substituted by alkyl, optionally C₁-C₃Pyrrolidinyl substituted by alkyl, optionally C₁-C₃Alkyl-substituted tetrahydropyrazolyl or optionally substituted by C₁-C₃Alkyl-substituted piperidinyl.

In some more preferred embodiments, R¹²Is selected from ═ O,Methyl or-N (CH)₃)₂。

In some preferred embodiments, q is 0 to 6.

In some more preferred embodiments, q is 0or 1.

In some more preferred embodiments, q is 0.

In some more preferred embodiments, q is 1, and R is¹²And Y²And (4) connecting.

In some most preferred embodiments, the building blocksIs selected from

It will be appreciated that the choice of q does not violate the valence bond joining rule, e.g. R when q is 11¹²Cannot be selected from ═ O, Y²Nor can it be selected from O.

In some embodiments, the application relates to a compound of formula (VIII) or formula (IX), or a pharmaceutically acceptable salt thereof,

wherein,

R¹、R³、R⁴、R⁶、R⁷and X is as defined for compounds of formula (I);

R¹²、Y¹、Y²and q is as defined for compound of formula (VII);

In some embodiments, the present application relates to the following compounds, or pharmaceutically acceptable salts thereof:

in some embodiments, the present application relates to the following compounds:

in another aspect, the present application relates to a pharmaceutical composition comprising a compound of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII) or formula (IX) or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the pharmaceutical compositions of the present application further comprise a pharmaceutically acceptable excipient.

In another aspect, the present application relates to a method of treating a tyrosine kinase mediated disease in a mammal, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of formula (i), formula (ii), formula (iii), formula (iv), formula (v), formula (vi), formula (vii), formula (viii) or formula (ix), including but not limited to EGFR tyrosine kinase, ALK or JAK; such diseases include, but are not limited to, cell proliferative diseases (e.g., cancer).

In another aspect, the present application relates to a method of treating a disease mediated by EGFR tyrosine kinase in a mammal, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of formula (iv), (v) or (vi) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Such diseases include, but are not limited to, cell proliferative diseases (e.g., cancer).

In another aspect, the application relates to a method of treating a disease mediated by ALK or JAK in a mammal, including but not limited to a cell proliferative disease (e.g., cancer), comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of formula (vii), formula (viii), or formula (ix), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

In yet another aspect, the present application relates to the use of a compound of formula (i), formula (ii), formula (iii), formula (iv), formula (v), formula (vi), formula (vii), formula (viii) or formula (ix), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of a disease mediated by a tyrosine kinase, including but not limited to EGFR tyrosine kinase, ALK or JAK, including but not limited to a cell proliferative disease such as cancer.

In yet another aspect, the present application relates to the use of a compound of formula (iv), (v) or (vi), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of a disease mediated by EGFR tyrosine kinase, including but not limited to cell proliferative disorders (e.g., cancer).

In a further aspect, the application relates to the use of a compound of formula (vii), formula (viii) or formula (ix), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of a disease mediated by ALK or JAK, including but not limited to cell proliferative disorders (e.g., cancer).

Definition of

The following terms used in the present application have the following meanings, unless otherwise specified. A particular term should not be considered as ambiguous or unclear without special definition, but rather construed according to ordinary meaning in the art. When a trade name appears herein, it is intended to refer to its corresponding commodity or its active ingredient.

The term "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, so long as the valence of the particular atom is normal and the substituted compound is stable.

The terms "optionally" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, ethyl is "optionally" substituted with fluoro or chloro, meaning that ethyl may be unsubstituted (e.g., -CH₂CH₃) Monosubstituted (e.g. -CH)₂CH₂F、CHClCH₂F) Polysubstituted (e.g. -CHFCH)₂F、-CHClCH₂F、-CH₂CHCl₂、-CH₂CHF₂Etc.) or fully substituted (-CFClCF)₃、-CF₂CF₃). It will be appreciated by those skilled in the art that any group containing one or more substituents will not incorporate any substitution or substitution pattern which is sterically impossible and/or cannot be synthesized.

Herein C_m-nIt is the moiety that has an integer number of carbon atoms in the given range. E.g. "C_1-6By "is meant that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms; "C_3-6By "is meant that the group may have 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

The dotted line (- - - - -) in the structural unit or the substituent group herein indicates that the atom in the structural unit or the substituent group and the substituted group may form a covalent bond when bonded to a specific atom. For example,quiltSubstituted, meaning a substituent groupWherein the C atom to which is attached may be substituted with a substituentAny atom on the above forms a covalent bond, and the formed group includes, but is not limited to, those not violating the valence bond connection rule When- - -is not attached to a particular atom (e.g.,) It is meant that- - -can be attached to any atom of the structural unit as long as the valence bond attachment rules are not violated. Thus, for example, structural unitsComprises thatAlso include, for exampleAnd the like.

When any variable (e.g. R)²、R⁸、R⁹Or R¹²) When a compound occurs more than one time in its composition or structure, its definition in each case is independent. Thus, for example, (R)²)_nRepresents a group represented by n R²Substituted, then each R²All have independent options; specifically, for example, when n ═ 2, it represents that one group is substituted with 2R²And each R is substituted²There is a separate option.

The term "alkylamino" refers to the group-NH-alkyl.

Term(s) for"trifluoromethyl" means-CF₃A group.

The term "alkyl" refers to a group of formula C_nH_2n+1A hydrocarbon group of (1). The alkyl group may be linear or branched. For example, the term "C_1-6Alkyl "means an alkyl group having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, and the like). Similarly, the alkyl portion of an alkoxy group (i.e., alkyl) has the same definition as above; the term "C_1-3Alkyl "refers to an alkyl group containing 1 to 3 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl).

The term "alkoxy" refers to-O-alkyl.

The term "alkylamino" refers to-NH-alkyl.

The term "alkenyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group having at least one double bond, consisting of carbon atoms and hydrogen atoms. Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1, 3-butadienyl, and the like. For example, the term "C_2-6Alkyl "refers to an alkenyl group containing 2 to 6 carbon atoms; the term "C₂-C₃Alkenyl "means an alkenyl group having 2 to 3 carbon atoms (e.g., ethenyl, 1-propenyl, 2-propenyl).

The term "cycloalkyl" refers to a carbon ring that is fully saturated and may exist as a single ring, a bridged ring, or a spiro ring. Unless otherwise indicated, the carbocycle is typically a 3 to 10 membered ring. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo [2.2.1] heptyl), bicyclo [2.2.2] octyl, adamantyl, and the like.

The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and may exist as a monocyclic, bicyclic, or spiro ring. Unless otherwise indicated, the heterocyclic ring is typically a 3 to 7 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen. Examples of 3-membered heterocycloalkyl include, but are not limited to, oxiranyl, thietanyl, cycloazenyl, non-limiting examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, examples of 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyrazolyl, pyrrolinyl, examples of 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1, 4-thiaxanyl, 1, 4-dioxanyl, thiomorpholinyl, 1, 2-dithianyl, 1, 4-dithianyl, tetrahydropyranyl, examples of 7-membered heterocycloalkyl include, but are not limited to, azepanyl, oxepanyl, Thiepanyl. Monocyclic heterocycloalkyl groups having 5 or 6 ring atoms are preferred.

The term "treating" means administering a compound or formulation described herein to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:

(i) preventing the occurrence of a disease or condition in a mammal, particularly when such mammal is susceptible to the disease condition, but has not yet been diagnosed as having the disease condition;

(ii) inhibiting the disease or disease state, i.e., arresting its development;

(iii) alleviating the disease or condition, i.e., causing regression of the disease or condition.

The term "therapeutically effective amount" means an amount of a compound of the present application that (i) treats or prevents a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound of the present application that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art with their own knowledge and this disclosure.

The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As the pharmaceutically acceptable salt, for example, a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, and the like can be mentioned.

The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or salts thereof and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.

The term "pharmaceutically acceptable adjuvants" refers to those adjuvants which do not have a significant irritating effect on the organism and do not impair the biological activity and properties of the active compound. Suitable adjuvants are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

The words "comprise" or "comprise" and variations thereof such as "comprises" or "comprising," are to be understood in an open, non-exclusive sense, i.e., "including but not limited to.

The intermediates and compounds of the present application may also exist in different tautomeric forms, and all such forms are included within the scope of the present application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as proton transfer tautomers) include interconversion via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is an imidazole moiety, wherein the proton can migrate between two ring nitrogens. Valence tautomers include interconversion by recombination of some of the bonding electrons.

The present application also includes isotopically-labeled compounds of the present application, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as respectively²H、³H、¹¹C、¹³C、¹⁴C、¹³N、¹⁵N、¹⁵O、¹⁷O、¹⁸O、³¹P、³²P、³⁵S、¹⁸F、¹²³I、¹²⁵I and³⁶cl, and the like.

Certain isotopically-labelled compounds of the present application (e.g. with³H and¹⁴c-labeled ones) can be used in compound and/or substrate tissue distribution assays. Tritiated (i.e. by tritiation)³H) And carbon-14 (i.e.¹⁴C) Isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes, such as¹⁵O、¹³N、¹¹C and¹⁸f can be used in Positron Emission Tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by following procedures analogous to those disclosed in the schemes and/or in the examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

In addition, heavier isotopes are used (such as deuterium (i.e., deuterium)²H) Substitution may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), and thus may be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is replaced by at least one hydrogenAnd deuterium is substituted.

The compounds of the present application may be asymmetric, e.g., having one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds of the present application containing asymmetric carbon atoms can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized by using chiral starting materials or chiral reagents.

The pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, for example, can be formulated into solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols, and the like.

Typical routes of administration of a compound of the present application or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

The pharmaceutical compositions of the present application can be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, lyophilizing, and the like.

In some embodiments, the pharmaceutical composition is in an oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These adjuvants enable the compounds of the present application to be formulated as tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions and the like, for oral administration to a patient.

Solid oral compositions may be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: the active compounds are mixed with solid adjuvants, optionally the mixture obtained is milled, if desired with further suitable adjuvants, and the mixture is then processed to granules, to give tablets or dragee cores. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.

The pharmaceutical compositions may also be adapted for parenteral administration, as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.

In all methods of administration of the compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII) or formula (IX) described herein, the compounds are administered in a daily dose of 0.01 to 200mg/kg body weight, in single or divided doses.

The compounds of the present application may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations thereof with other chemical synthetic methods, and equivalents thereof known to those skilled in the art, with preferred embodiments including, but not limited to, the examples of the present application.

The chemical reactions of the embodiments herein are carried out in a suitable solvent that is compatible with the chemical changes of the present application and the reagents and materials required therefor. In order to obtain the compounds of the present application, it is sometimes necessary for a person skilled in the art to modify or select the synthesis steps or reaction schemes based on the existing embodiments.

An important consideration in the art of synthetic route planning is the selection of suitable protecting Groups for reactive functional Groups (such as amino Groups in the present application), for example, reference may be made to Greene's Protective Groups in organic Synthesis (4th Ed.) Hoboken, New Jersey: John Wiley & Sons, Inc. all references cited herein are incorporated herein in their entirety.

In some embodiments, the compounds of formula (i) herein may be prepared by those skilled in the art of organic synthesis via scheme 1 using standard methods in the art:

route 1:

wherein,

R¹、R³、R⁴、R⁵、R⁶、R⁷x and Cy are as defined for compounds of formula (I).

In some embodiments, the compounds of formula (i) herein may be prepared by those skilled in the art of organic synthesis via scheme 2 using standard methods in the art:

route 2:

wherein,

In some embodiments, the compounds of formula (II), formula (IV), formula (V), formula (VII), or formula (VIII) may be prepared by methods described above with reference to schemes 1-2.

In some embodiments, the compounds of formula (iii) herein may be prepared by one skilled in the art of organic synthesis via scheme 3 using standard methods in the art:

route 3:

wherein,

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷x and n are as defined for compounds of formula (III).

In some embodiments, the compounds of formula (iv) herein may be prepared by those skilled in the art of organic synthesis via scheme 4 using standard methods in the art:

route 4:

wherein,

R¹、R³、R⁵、R⁶、R⁷x and Cy are as defined for compounds of formula (IV).

As shown in scheme 4, a compound of formula 12a is reacted with acryloyl chloride to provide a compound of formula 13a, and the compound of formula 13a is reduced to the nitro group to provide a compound of formula 14a (the compound of formula 14a is also commercially available or synthesized with reference to TW 201512176A). Reacting a compound of formula 3 (commercially available as such) with a compound of formula 4a (commercially available or as referred to WO2011022337A1, WO2012109164A1) under basic conditions to obtain a compound of formula 5 a. Reacting the compound shown in the formula 14a with the compound shown in the formula 5a under an acidic condition to obtain the compound shown in the formula (IV).

In some embodiments, the compounds of formula (iv) herein may be prepared by those skilled in the art of organic synthesis via scheme 5 using standard methods in the art:

route 5:

wherein,

R¹、R³、R⁵、R⁷x and Cy are as defined for formula (IV)A compound (I) is provided.

As shown in scheme 5a, a compound of formula 15a (which can be synthesized with reference to TW 201512176A) and a compound of formula 4a are reacted under heating to obtain a compound of formula (iv).

In some embodiments, compounds of formula (vi) herein can be prepared by those skilled in the art of organic synthesis via scheme 6 using standard methods in the art:

route 6:

wherein,

R¹、R²、R³、R⁵、R⁷x and n are as defined for compounds of formula (VI).

As shown in scheme 6, compounds of formula 3a and compounds of formula 9a (which are directly commercially available) are reacted under basic conditions to provide compounds of formula 10. The compound of formula 10a and the compound of formula 14a are reacted under acidic conditions to provide the compound of formula 16 a. Removing the pinacol protection from the compound of the formula 16a to obtain the compound of the formula (VI).

In some embodiments, the compounds of formula (vii) herein may be prepared by those skilled in the art of organic synthesis via scheme 7 using standard methods in the art:

route 7:

wherein,

R¹、R³、R⁴、R⁶、R⁷、R¹²、X、Y¹、Y²q, and Cy are as defined for the compound of formula (VII).

In some embodiments, the compounds of formula (IX) herein may be prepared by those skilled in the art of organic synthesis via scheme 8 using standard procedures in the art:

route 8:

wherein,

R¹、R²、R³、R⁴、R⁶、R⁷、R¹²、X、Y¹、Y²q and n are as defined for compounds of formula (IX);

the following abbreviations are used in this application:

the invention employs the following abbreviations: eq represents equivalent, equivalent; TLC for thin layer chromatography; EtOH stands for ethanol; MeOH represents methanol; HCl represents hydrogen chloride; DCM represents dichloromethane; n-BuOH represents n-butanol; 2-BuOH represents sec-butyl alcohol; PTSA represents p-toluenesulfonic acid; DIAD represents diisopropyl azodicarboxylate; DMF represents N, N-dimethylformamide; DMSO represents dimethyl sulfoxide; BOC represents tert-butylcarbonyl as an amine protecting group; O/N stands for overnight; THF represents tetrahydrofuran; boc₂O represents di-tert-butyl dicarbonate; TFA represents trifluoroacetic acid; DIPEA stands for diisopropylethylamine.

Detailed Description

The present invention is described in detail below by way of examples, but is not meant to be limited to any of the disadvantages of the present invention. Having described the present application in detail and disclosed specific embodiments thereof, it will be apparent to those skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof. All solvents used herein are commercially available and can be used without further purification. The starting compounds for the syntheses described herein are commercially available or can be prepared by methods known in the art.

Example 1 preparation of N- (3- ((5-chloro-4- ((1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxazol-6-yl) amino) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide (Compound I-1)

Step (1) preparation of 6- ((2, 5-dichloropyrimidin-4-yl) amino) benzo [ c ] [1,2] oxaborzol-1 (3H) -ol (Compound 3)

To a reaction flask were added compound 1(4.92g, 26.85mmol), compound 2(4.0g, 26.85mmol), DIPEA (6.94g, 53.70mmol) and n-butanol (40mL), and the mixture was refluxed under nitrogen for 1 hour. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, 50mL of water was added to the concentrate, and ultrasonic treatment was carried out to precipitate a solid, which was washed with suction filtration and water, and finally dried under reduced pressure at 50 ℃ to obtain Compound 3(7.94 g).

¹H-NMR(500M,DMSO-d₆)δ9.63(s,1H),9.28(s,1H),8.36～8.37(d,J＝0.5Hz,1H),7.79(s,1H),7.58～7.60(dd,J＝2Hz,3.4Hz,1H),7.43～7.45(d,J＝8Hz,1H),5.01(s,2H).

HRMS(ESI,[M+H]⁺)m/z：295.9991.

Step (2) preparation of N- (3- ((5-chloro-4- ((1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxazol-6-yl) amino) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide (Compound I-1)

To a reaction flask was added compound 3(0.30g, 1.01mmol), compound 4(0.24g, 1.11mmol), trifluoroacetic acid (0.23g, 2.02mmol), sec-butanol (10 mL); the microwave is heated to 140 ℃ and the power is 150W, and the reaction is carried out for 1 hour. After completion of the reaction, saturated aqueous sodium bicarbonate was added to adjust the pH to basic, dichloromethane (20mL, three times) was extracted, and the organic phases were combined and dried over anhydrous magnesium sulfate. The drying agent was removed by suction filtration and the filtrate was concentrated under reduced pressure to remove the solvent. Column chromatography (100% dichloromethane to 5% methanol/dichloromethane gradient elution) followed by concentration under reduced pressure and drying afforded compound I-1(0.16 g).

¹H-NMR(500M,DMSO-d₆)δ9.93(s,1H),9.18(s,1H),8.91(s,1H),8.13(s,1H),8.09(s,1H),7.86(s,1H),7.76～7.80(t,J＝10.5Hz,1H),7.40～7.42(t,J＝7.0Hz,1H),7.28～7.30(d,J＝8.5Hz,1H),6.97～6.98(d,J＝8.5Hz,1H),6.39～6.45(dd,J＝10.0Hz,17.0Hz,1H),6.20～6.23(d,J＝17.0Hz,1H),5.71～5.73(d,J＝10.5Hz,1H),4.95(s,2H),4.10(s，3H).

HRMS(ESI,[M+H]⁺)m/z：452.1148.

Example 2 preparation of N- (3- ((5-chloro-4- ((1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxazol-6-yl) amino) pyrimidin-2-yl) amino) phenyl) acrylamide (Compound I-2)

Compound I-2 was prepared by the method of step (2) of reference example 1, starting from compounds 3 and 5.

¹H-NMR(500M,DMSO-d₆)δ10.01(s,1H),9.28(s,1H),9.18(s,1H),8.95(s,1H),8.14(s,1H),7.74(s,1H),7.72～7.74(m,2H),7.43～7.45(d,J＝8.0Hz,1H),7.37～7.39(d,J＝8.0Hz,1H),7.23～7.24(d,J＝7.5Hz,1H),7.02～7.06(t,J＝8.0Hz,1H),6.42～6.48(m,1H),6.22～6.26(m,1H),5.72～5.75(dd,J＝1.5Hz,10.0Hz,1H),5.01(s,2H).

HRMS(ESI,[M+H]⁺)m/z：422.1066.

Example 3 preparation of N- (3- ((4- ((1-hydroxy-1, 3-dihydrobenzo [ C ] [1,2] oxaborzol-6-yl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) acrylamide (Compound I-3)

Step (1) preparation of 6- ((2-chloro-5-methylpyridin-4-yl) amino) benzo [ c ] [1,2] oxaborzol-1 (3H) -ol (Compound 3-5)

Compounds 3 to 5 were prepared by the method of step (1) of reference example 1 using compounds 1 to 5 and compound 2 as starting materials.

¹H-NMR(500M,DMSO-d₆)δ9.35(s，1H),9.24(s，1H),7.93～7.95(m，2H),7.70～7.72(dd，J＝2.0Hz，8.5Hz，1H),7.38～7.40(d，J＝8.0Hz，1H),4.98(s，2H),3.95(s，3H).

HRMS(ESI,[M+H]⁺)m/z：292.0652.

Step (2) preparation of N- (3- ((4- ((1-hydroxy-1, 3-dihydrobenzo [ C ] [1,2] oxazol-6-yl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) acrylamide (Compound I-3)

Compound I-3 was prepared by the method of step (2) of reference example 1, starting from compounds 3-5 and 5.

MS(ESI,[M+H]⁺)m/z：417.2.

Example 4 preparation of (3- ((2- ((5-Acrylamido-4- (2- (dimethylamino) ethoxy) -2-methoxyphenyl) amino) -5-chloropyrimidin-4-yl) amino) phenyl) boronic acid (Compound I-4)

Preparation of Compound 5-1:

step (1) preparation of 2-fluoro-4-methoxy-5-nitroaniline (Compound 8-1)

To reaction flask 1 were added compound 8(20.0g, 141.70mmol), methyl tert-butyl ether (160mL) and tetrahydrofuran (40mL), and the mixture was stirred at 0 ℃ for 30 minutes; concentrated nitric acid (65%, 15.11g, 155.87mmol) was slowly added dropwise to the reaction mixture, reacted at 0 ℃ for 1 hour, washed with methyl tert-butyl ether by suction filtration to give the nitrate of compound 8, and dichloromethane (100mL) was added to the nitrate to give a dichloromethane suspension of the nitrate. Concentrated sulfuric acid (98%, 139.20g, 142mmol) was added to reaction flask 2, and the resulting dichloromethane suspension of nitrate salt of compound 8 was added dropwise to reaction flask 2 at 0 ℃. After reacting for 3 hours, completely reacting, and adding ammonia water to adjust the pH value to be alkaline; the organic phase was washed with brine, and dried over anhydrous magnesium sulfate. The drying agent was removed by suction filtration, the solvent was removed by concentration under reduced pressure, and finally dried in an oven (45 ℃ C.) under reduced pressure to give compound 8-1(22.768 g).

¹H-NMR(500M,DMSO-d₆)δ7.37～7.39(d，J＝9.0Hz，1H),7.18～7.20(d，J＝12.5Hz，1H),5.24(s，2H),3.82(s，3H).

HRMS(ESI,[M+H]⁺)m/z：187.0511.

Step (2) preparation of 2- (2- (dimethylamino) ethoxy) -4-methoxy-5-nitroaniline (Compound 8-2)

N, N-dimethylethanolamine (2.87g, 32.2mmol) was placed in a 250mL three-necked flask and dissolved by adding 40mL of DMF. Sodium hydride (59%, 1.31g, 32.2mmol) was added slowly with stirring at-5 ℃ for additional 50 minutes, and a solution of compound 8-1(3g, 16.12mmol) in DMF (9mL) was added dropwise over 30 minutes. After stirring was continued for 30 minutes, the temperature was returned to room temperature and the mixture was stirred overnight. The reaction was quenched by addition of 15mL of water, concentrated under reduced pressure to remove the solvent by evaporation, and purified by column chromatography to give 8-2(4g) as a brown oily compound.

¹H NMR(500MHz,DMSO-d₆)δ7.30(s,1H),6.82(s,1H),4.81(s,2H),4.23(t,J＝5.8Hz,2H),3.88(s,3H),2.72(t,J＝5.8Hz,2H),2.27(s,6H).

HRMS(ESI,[M+H]⁺)m/z：256.1384.

Step (3) preparation of N- (2- (2- (dimethylamino) ethoxy) -4-methoxy-5-nitrophenyl) acrylamide (Compound 8-3)

Compound 8-2(3.56g, 13.95mmol) was placed in a 100mL three-necked flask, 70mL of tetrahydrofuran and triethylamine (5.8mL,41.8mmol) were added, and the mixture was placed in a low-temperature reaction tank at-10 ℃. A solution of acryloyl chloride (1.28g, 16.74mmol) in tetrahydrofuran (20mL) was added dropwise over 30 minutes. The reaction was continued at-10 ℃ for 1 hour. After returning to room temperature, the reaction was completed after 3 hours. The reaction was quenched by addition of 20mL of saturated sodium carbonate solution and the reaction solvent tetrahydrofuran was mostly evaporated to dryness. 100mL of saturated sodium carbonate solution was added, sonicated for 10 minutes, filtered, the filter cake was washed with water, and dried under reduced pressure to give compound 8-3(4.1 g).

¹H NMR(500MHz,DMSO-d₆)δ9.52(s,1H),8.70(s,1H),7.04(s,1H),6.62(dd,J＝17.0,10.2Hz,1H),6.28(dd,J＝17.0,2.0Hz,1H),5.79(dd,J＝10.2,2.0Hz,1H),4.35(t,J＝5.8Hz,2H),4.00(s,3H),2.73(t,J＝5.8Hz,2H),2.27(s,6H).

HRMS(ESI,[M+H]⁺)m/z：310.1421.

Step (4) preparation of N- (5-amino-2- (2- (dimethylamino) ethoxy) -4-methoxyphenyl) acrylamide (Compound 5-1)

Placing the compound 8-3(3.5g,11.32mmol) in a 100mL eggplant-shaped bottle, adding ethanol (20mL) and water (5mL), adding iron powder (3.79g, 67.9mmol) and ammonium chloride (424mg, 7.92mmol), heating to 80 ℃, reacting for 2 hours, removing most of the solvent by reduced pressure evaporation, extracting with dichloromethane (50mL, three times), washing with a small amount of water, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, evaporating to dryness, and purifying by column chromatography to obtain the compound 5-1(1.5 g).

¹H NMR(300MHz,DMSO-d₆)δ9.79(s,1H),7.44(s,1H),6.67(s,1H),6.33(dd,J＝16.9,9.9Hz,1H),6.18(dd,J＝17.0,2.3Hz,1H),5.70(dd,J＝9.8,2.3Hz,1H),4.45(brs,2H),4.01(t,J＝5.4Hz,2H),3.73(s,3H),2.44(t,J＝5.4Hz,2H),2.23(s,6H).

HRMS(ESI,[M+H]⁺)m/z：280.1646.

Preparation of Compound I-4:

step (1) preparation of 2, 5-dichloro-N- (3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) pyrimidin-4-amine (compound 3-10)

Compounds 3 to 10 were prepared by the method of step (1) of reference example 1 using Compounds 1 and 2 to 1 as starting materials.

¹H-NMR(500M,DMSO-d₆)δ9.53(s，1H),8.37(s，1H),7.84(s，1H),7.79～7.81(d，J＝8.0Hz，1H),7.49～7.50(d，J＝7.5Hz，1H),7.41～7.44(t，J＝7.5Hz，1H),1.31(s，12H).

HRMS(ESI,[M+H]⁺)m/z：366.0941.

Step (2) preparation of N- (5- ((5-chloro-4- ((3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) amino) pyrimidin-2-yl) amino) -2- (2- (dimethylamino) ethoxy) -4-methoxyphenyl) acrylamide (Compound I-26)

Compound I-26 was prepared by substituting trifluoroacetic acid for p-toluenesulfonic acid using compound 3-10 and compound 5-1 as starting materials in the same manner as in step (2) of example 1.

Step (3) preparation of (3- ((2- ((5-acrylamido-4- (2- (dimethylamino) ethoxy) -2-methoxyphenyl) amino) -5-chloropyrimidin-4-yl) amino) phenyl) boronic acid (Compound I-4)

Compound I-26(200mg, 0.328mmol) was placed in a 100mL single-neck flask, acetone (2mL) and water (2mL) were added, sodium periodate (141mg, 0.657mmol) and ammonium acetate (51mg, 0.657mmol) were added, and the reaction was completed at room temperature for 2 hours. Extracting with ethyl acetate (10mL for three times), washing with water, drying with anhydrous sodium sulfate, filtering, evaporating to dryness, and purifying by column chromatography to obtain compound I-4(50 mg).

¹H NMR(500MHz,DMSO-d₆)δ9.61(s,1H),8.59(s,1H),8.23(s,1H),8.04(s,1H),7.97(s,1H),7.91(s,1H),7.83～7.76(m,2H),7.45(d,J＝7.2Hz,1H),7.21～7.13(m,1H),6.86(s,1H),6.46(dd,J＝16.9,10.1Hz,1H),6.19(d,J＝16.8Hz,1H),5.72(d,J＝10.5Hz,1H),5.36-5.31(m,1H),4.19～4.13(m,2H),3.78(s,3H),2.64～2.57(m,2H),2.28(s,6H).

MS(ESI,[M+H]⁺)m/z：527.0.

Example 5 preparation of (4- ((2- ((5-Acrylamido-4- (2- (dimethylamino) ethoxy) -2-methoxyphenyl) amino) -5-chloropyrimidin-4-yl) amino) phenyl) boronic acid (Compound I-5)

Step (1) preparation of 2, 5-dichloro-N- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) pyrimidin-4-amine (compound 3-11)

Compounds 3 to 11 were prepared by the method of step (1) of reference example 1 using Compounds 1 and 2 to 2 as starting materials.

¹H-NMR(500M,DMSO-d₆)δ9.58(s，1H),8.42(s，1H),7.68～7.70(d，J＝8.0Hz，2H),7.63～7，65(d，J＝8.0Hz，2H),1.31(s，12H).

HRMS(ESI,[M+H]⁺)m/z：366.0937.

Step (2) preparation of (4- ((2- ((5-Acrylamido-4- (2- (dimethylamino) ethoxy) -2-methoxyphenyl) amino) -5-chloropyrimidin-4-yl) amino) phenyl) boronic acid (Compound I-5)

Compound I-5 was prepared by the method of step (2) in the synthesis of compound I-26 in reference example 4, starting from compounds 3-11 and 5-1.

¹H-NMR(500M,DMSO-d₆)δ9.66(br，1H),8.57(s，1H),8.14～8.18(d，2H),8.06(s，1H),7.82(m，2H),7.63(m，4H),6.89～6.91(d，1H),6.47(m，1H),6.15～6.18(d，1H),5.67～5.69(d，1H),4.21(br，2H),3.77(s，3H),2.67(s，2H),2.32(s，6H).

MS(ESI,[M+H]⁺)m/z：527.3.

Example 6 preparation of N- (5- ((5-chloro-4- ((2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) amino) pyrimidin-2-yl) -2- (2- (dimethylamino) ethoxy) -4-methoxyphenyl) acrylamide (Compound I-6)

Step (1) preparation of 2, 5-dichloro-N- (2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) pyrimidin-4-amine (compound 3-12)

Compounds 3 to 12 were prepared by the method of step (1) of reference example 1 using Compound 1 and Compounds 2 to 3 as starting materials.

¹H-NMR(500M,DMSO-d₆)δ9.68(s，1H),8.44(s，1H),8.12～8.13(d，J＝8.5Hz，1H),7.72～7.73(d，J＝7.0Hz，1H),7.57～7.61(t，J＝7.5Hz，1H),7.20～7.23(t，J＝7.5Hz，1H),1.29(s，12H).

HRMS(ESI,[M+H]⁺)m/z：366.0945.

Step (2) preparation of N- (5- ((5-chloro-4- ((2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) amino) pyrimidin-2-yl) -2- (2- (dimethylamino) ethoxy) -4-methoxyphenyl) acrylamide (Compound I-6)

Compound I-6 was prepared by the method of step (2) in the synthesis of compound I-26 in reference example 4, starting from compounds 3-12 and 5-1.

MS(ESI,[M+H]⁺)m/z：527.3.

Example 7 preparation of N- (5- ((5-chloro-4- ((1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxazol-5-yl) amino) pyrimidin-2-yl) amino) -2- (2- (dimethylamino) ethoxy) -4-methoxyphenyl) acrylamide (Compound I-7)

Step (1) preparation of 5- ((2, 5-dichloropyrimidin-4-yl) amino) benzo [ c ] [1,2] oxaborzol-1 (3H) -ol (Compound 3-13)

Compounds 3 to 13 were prepared by the method of step (1) of reference example 1 using compounds 1 and 2 to 4 as starting materials.

¹H-NMR(500M,MeOD)δ7.07～7.10(t，J＝7.5Hz，1H),6.75(s，1H),6.69～6.71(d，J＝7.0Hz，1H),6.64～6.65(d，J＝7.5Hz，1H),4.51(s，2H).

MS(ESI,[M+H]⁺)m/z：295.9.

Step (2) preparation of N- (5- ((5-chloro-4- ((1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxazol-5-yl) amino) pyrimidin-2-yl) amino) -2- (2- (dimethylamino) ethoxy) -4-methoxyphenyl) acrylamide (Compound I-7)

Compound I-7 was prepared by the method of step (2) in the synthesis of compound I-26 in reference example 4, starting from compounds 3-13 and 5-1.

¹H-NMR(500M,DMSO-d₆)δ9.63(s，1H),8.96(br，1H),8.65(s，1H),8.24(s，1H),8.14(s，1H),8.08(s，1H),7.81(s，1H),7.53(s，2H),6.90(s，1H),6.44～6.49(dd，1H),6.14～6.18(d，1H),5.68～5.70(d，J＝10.5Hz，1H),4.78(s，2H),4.19～4.21(t，J＝5.5Hz，2H),3.75(s，3H),2.62～2.64(t，J＝5.5Hz，2H),2.29(s，6H).

MS(ESI,[M+H]⁺)m/z：538.9.

Example 7a preparation of 2- (2-Acrylamido-4- ((5-chloro-4- ((1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxaborolan-5-yl) amino) pyrimidin-2-yl) amino) -5-methoxyphenoxy) -N, N-dimethylethane-1-ammonium methanesulfonate (Compound I-7-21)

Adding the compound I-7(341mg, 633mmol, 1eq) into methanol (50mL), adding accurately weighed methanesulfonic acid (60mg, 632mmol, 1eq), stirring for 20 minutes, clarifying the solution, concentrating the reaction solution to obtain a crude product 360mg, adding diethyl ether (40mL), pulping, filtering, washing the filter cake with diethyl ether (10mL), and drying to obtain the compound I-7-21(329mg) with the purity of 95.93% (UPLC).

¹H NMR(500MHz,DMSO-d₆)δ9.55(s,1H),9.28(s,1H),9.00(brs,1H),8.87(s,1H),8.46(brs,1H),8.12(s,1H),8.09(s,1H),7.79(s,1H),7.57(dd,J＝8and 12Hz,2H),6.90(s,1H),6.61(dd,J＝10and 16.5Hz,1H),6.19(dd,J＝1.5and 15.5Hz,1H),5.72(d,J＝10.5Hz,1H),4.80(s,1H),4.47(t,J＝5,2H),3.79(s,3H),3.61(d,J＝8.5Hz,2H),2.94(d,J＝3.5Hz,6H),2.38(s,3H).

MS(ESI,[M+H]⁺):m/z 539.1.

Example 8 preparation of N-5- ((5-chloro-4- ((1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxazol-7-yl) amino) pyrimidin-2-yl) amino) -2- (2- (dimethylamino) ethoxy) -4-methoxyphenyl) acrylamide (Compound I-8)

Step (1) preparation of 7- ((2, 5-dichloropyrimidin-4-yl) amino) benzo [ c ] [1,2] oxaborzol-1 (3H) -ol (Compound 3-14)

Compounds 3 to 14 were prepared by the method of step (1) of reference example 1 using compounds 1 and 2 to 5 as starting materials.

¹H NMR(500MHz,DMSO-d₆)δ9.52(s,1H),8.95(s,1H),8.46(s,1H),8.03(d,J＝8.0Hz,1H),7.56(t,J＝7.8Hz,1H),7.21(d,J＝7.8Hz,1H),5.04(s,2H).

MS(ESI,[M+H]⁺)m/z：295.9.

Step (2) preparation of N-5- ((5-chloro-4- ((1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxazol-7-yl) amino) pyrimidin-2-yl) amino) -2- (2- (dimethylamino) ethoxy) -4-methoxyphenyl) acrylamide (Compound I-8)

Compound I-8 was prepared by the method of step (2) in the synthesis of compound I-26 in reference example 4, starting from compounds 3-14 and 5-1.

¹H NMR(500MHz,DMSO-d₆)δ9.63(d,J＝17.1Hz,2H),8.42-8.32(m,2H),8.28-8.18(m,2H),8.13(s,1H),7.30-7.22(m,1H),7.00(d,J＝7.5Hz,1H),6.92(s,1H),6.47(dd,J＝17.0,10.2Hz,1H),6.17(d,J＝16.9Hz,1H),5.70(d,J＝10.3Hz,1H),4.99(s,2H),4.21(t,J＝5.7Hz,2H),3.77(s,3H),2.63(t,J＝5.7Hz,2H),2.29(s,6H).

HRMS(ESI,[M+H]⁺)m/z：539.1932.

Example 8a preparation of N-5- ((5-chloro-4- ((1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxazol-7-yl) amino) pyrimidin-2-yl) amino) -2- (2- (dimethylamino) ethoxy) -4-methoxyphenyl) acrylamide mesylate (Compound I-8-21)

Compound I-8(215mg, 0.38mmol) was placed in a 50mL single-necked eggplant-type bottle, and 3mL of methanol was added. Methanesulfonic acid (36mg, 0.38mmol) in 1mL methanol (1mL) was added dropwise and stirred at room temperature for 30 min. The reaction solution was heated to 50 ℃ and stirred for 1 hour. Evaporating the reaction solution to dryness, adding 3mL of acetone and 5 drops of methanol, pulping, performing ultrasonic treatment for 1 minute, filtering, washing a filter cake with a small amount of acetone, and drying to obtain a compound I-8-21(180 mg).

¹H NMR(500MHz,DMSO-d₆)δ10.19(s,1H),9.69～9.50(m,2H),9.02(brs,1H),8.78(brs,1H),8.20(s,1H),8.15～8.04(m,2H),7.39～7.29(m,1H),7.08(d,J＝7.6Hz,1H),6.91(s,1H),6.80(dd,J＝16.9,10.2Hz,1H),6.19(d,J＝17.0Hz,1H),5.71(d,J＝10.3Hz,1H),5.00(s,2H),4.50-4.40(m,2H),3.82(s,3H),3.62-3.57(m,2H),2.90(s,6H),2.37(s,3H).

MS(ESI,[M+H]⁺)m/z：539.1.

Example 9 preparation of N-5- ((5-chloro-4- ((1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxazol-4-yl) amino) pyrimidin-2-yl) amino) -2- (2- (dimethylamino) ethoxy) -4-methoxyphenyl) acrylamide (Compound I-9)

Step (1) preparation of 4- ((2, 5-dichloropyrimidin-4-yl) amino) benzo [ c ] [1,2] oxaborzol-1 (3H) -ol (Compound 3-15)

Compounds 3 to 15 were prepared by the method of step (1) of reference example 1 using compounds 1 and 2 to 6 as starting materials.

¹H-NMR(500M,DMSO-d₆)δ9.52(s,1H),9.03(s,1H),8.37(s,1H),7.69～7.70(m,1H),7.44～7.45(d,J＝6.5Hz，2H),4.93(s,2H).

MS(ESI,[M+H]⁺)m/z：295.9.

Step (2) preparation of N-5- ((5-chloro-4- ((1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxazol-4-yl) amino) pyrimidin-2-yl) amino) -2- (2- (dimethylamino) ethoxy) -4-methoxyphenyl) acrylamide (Compound I-9)

Compound I-9 was prepared by the method of step (2) in the synthesis of compound I-26 in reference example 4, starting from compounds 3-15 and 5-1.

¹H-NMR(500M,DMSO-d₆)δ9.57(s，1H),9.15(s，1H),8.49(s，1H),8.15(s，1H),8.04(s，1H),7.82(s，1H),7.51～7.55(m，2H),7.25～7.28(t，J＝7.5Hz，1H),6.79(s，1H),6.41～6.46(dd，1H),6.18～6.21(d，1H),5.71～5.74(d，J＝10.5Hz，1H),4.95(s，2H),4.12～4.14(t，J＝5.5Hz，2H),3.73(s，3H),2.54～2.57(t，J＝5.5Hz，3H),2.26(s，6H).

MS(ESI,[M+H]⁺)m/z：539.3.

Example 9a preparation of 2- (2-acrylamido-4- ((5-chloro-4- ((1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxazol-4-yl) amino) pyrimidin-2-yl) amino) -5-methoxyphenoxy) -N, N-dimethylethane-1-ammonium methanesulfonate (Compound I-9-21)

Compound I-9-21 was prepared by the method of step (3) in the synthesis of Compound I-8-21 in reference example 8, starting with Compound I-9.

¹H-NMR(500M,DMSO-d₆)δ9.57(br，1H),9.26(br，2H),8.62(br，1H),8.13(s，1H),8.01(s，1H),7.59～7.60(d，J＝7.0Hz，1H),7.50～7.51(t，J＝6.0Hz，2H),7.31～7.34(t，J＝14.5Hz，1H),7.12～7.14(d，J＝8.0Hz，1H),6.82(s，1H),6.61～6.67(dd，J＝17.0，10.5Hz，1H),6.22～6.25(d，J＝17.0Hz，1H),5.74～5.76(d，J＝10.0Hz，1H),4.95(s，2H),4.40(br，2H),3.77(s，3H),3.58(br，2H),2.92(s，6H),2.39(s，3H).

MS(ESI,[M+H]⁺)m/z：539.3.

Example 10 preparation of N- (5- ((5-chloro-4- ((1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxazol-6-yl) oxy) pyrimidin-2-yl) amino) -2- (2- (dimethylamino) ethoxy) -4-methoxyphenyl) acrylamide (Compound I-10)

Step (1) preparation of 6- ((2, 5-dichloropyridin-4-yl) oxy) benzo [ c ] [1,2] oxaborzol-1 (3H) -ol (Compound 3-16)

Compounds 3 to 16 were prepared by the method of step (1) of reference example 1 using compounds 1 and 2 to 7 as starting materials.

¹H-NMR(500M,DMSO-d₆)δ9.30(s，1H),8.83(s，1H),7.53～7.56(m，2H),7.40～7.42(d，J＝8.5Hz，1H),5.05(s，2H).

MS(ESI,[M+H]⁺)m/z：296.9.

Step (2) preparation of N- (5- ((5-chloro-4- ((1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxazol-6-yl) oxy) pyrimidin-2-yl) amino) -2- (2- (dimethylamino) ethoxy) -4-methoxyphenyl) acrylamide (Compound I-10)

Compound I-10 was prepared by the method of step (2) in the synthesis of compound I-26 in reference example 4, starting from compounds 3-16 and 5-1.

¹H-NMR(500M,DMSO-d₆)δ9.53(s，1H),9.24(br，1H),8.34(s，2H),7.97(s，1H),7.46(s，1H),7.40～7.41(d，J＝8.0Hz，1H),7.33～7.35(d，J＝8.5Hz，1H),6.78(s，1H),6.42～6.48(dd，1H),6.18～6.21(d，1H),5.71～5.73(d，J＝10.5Hz，1H),5.00(s，2H),4.11～4.13(t，J＝5.0Hz，2H),3.73(s，3H),2.58(t，2H),2.26(s，6H).

MS(ESI,[M+H]⁺)m/z：540.3.

EXAMPLE 11 preparation of N- (5- ((5-chloro-4- ((5-fluoro-1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxazol-6-yl) amino) pyrimidin-2-yl) amino) -2- (2- (dimethylamino) ethoxy) -4-methoxyphenyl) acrylamide (Compound I-11)

Step (1) preparation of 6- ((2, 5-dichloropyridin-4-yl) amino) -5-fluorobenzo [ c ] [1,2] oxaborzol-1 (3H) -ol (Compound 3-17)

Compounds 3 to 17 were prepared by the method of step (1) of reference example 1 using compounds 1 and 2 to 8 as starting materials.

¹H-NMR(500M,DMSO-d₆)δ9.66(s，1H),9.34(br，1H),8.39(s，1H),7.71～7.72(d，J＝8.0Hz，1H),7.40～7.42(d，J＝10.0Hz，1H),5.02(s，2H).

MS(ESI,[M+H]⁺)m/z：313.9.

Step (2) preparation of N- (5- ((5-chloro-4- ((5-fluoro-1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxazol-6-yl) amino) pyrimidin-2-yl) amino) -2- (2- (dimethylamino) ethoxy) -4-methoxyphenyl) acrylamide (Compound I-11)

Compound I-11 was prepared by the method of step (2) in the synthesis of compound I-26 in reference example 4, starting from compounds 3-17 and 5-1.

¹H-NMR(500M,DMSO-d₆)δ9.49(s，1H),9.23(br，1H),8.75(s，1H),8.07～8.08(d，J＝8.0Hz，1H),8.05(s，1H),7.73～7.75(d，J＝7.5Hz，1H),7.61(s，1H),7.22～7.24(d，J＝10.0Hz，1H),6.78(s，1H),6.46～6.50(m，1H),6.17～6.21(dd，1H),5.70～5.72(d，J＝10.5Hz，1H),4.98(s，2H),4.13～4.14(t，2H),3.78(s，3H),2.69(t，2H),2.33(s，6H).

MS(ESI,[M+H]⁺)m/z：557.1.

EXAMPLE 12 preparation of N- (5- ((5-chloro-4- ((1-hydroxy-3, 4-dihydro-1H-benzo [ c ] [1,2] oxaborolin-7-yl) amino) pyrimidin-2-yl) amino) -2- (2- (dimethylamino) ethoxy) -4-methoxyphenyl) propenylamide (Compound I-12)

Step (1) preparation of 7- ((2, 5-dichloropyrimidin-4-yl) amino) -3, 4-dihydro-1H-benzo [ c ] [1,2] oxaborolnin-1-ol (Compound 3-18)

Compounds 3 to 18 were prepared by the method of step (1) of reference example 1 using compounds 1 and 2 to 9 as starting materials.

¹H-NMR(500M,DMSO-d₆)δ9.53(s，1H),846(br，1H),8.35(s，1H),7.76(s，1H),7.55～7.56(d，J＝8Hz，1H),7.23～7.25(d，J＝8.5Hz，1H),4.09～4.11(t，J＝5.5Hz，2H),2.86～2.89(t，J＝5.5Hz，2H).

MS(ESI,[M+H]⁺)m/z：310.0

Step (2) preparation of N- (5- ((5-chloro-4- ((1-hydroxy-3, 4-dihydro-1H-benzo [ c ] [1,2] oxaborozin-7-yl) amino) pyrimidin-2-yl) amino) -2- (2- (dimethylamino) ethoxy) -4-methoxyphenyl) propenylamide (Compound I-12)

Compound I-12 was prepared by the method of step (2) in the synthesis of compound I-26 in reference example 4, starting from compounds 3-18 and 5-1.

¹H-NMR(500M,DMSO-d₆)δ9.68(s，1H),8.64(s，1H),8.37(s，1H),8.24(s，1H),8.04(s，1H),7.87(s，1H),7.78～7.80(d，J＝8.0Hz，1H),7.70(s，1H),7.04～7.05(d，J＝8.0Hz，1H),6.85(s，1H),6.58(m，1H),6.17～6.20(dd，1H),5.70～5.72(d，J＝10Hz，1H),4.02(br，2H),4.04～4.07(t，J＝5.5Hz，2H),3.79(s，3H),2.79～2.81(t，J＝5.5Hz，4H),2.38(s，6H).

MS(ESI,[M+H]⁺)m/z：551.4.

Example 13 preparation of N- (3- ((4- ((1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxazol-6-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide (Compound I-13)

Adding compounds 3-19(260mg, 0.698mmol), compound 2(131mg, 0.767mmol) and ethanol as solvent into a reaction flask; heated to reflux for 4 hours under nitrogen. The reaction solution was evaporated to dryness by rotary evaporation and purified by column chromatography to give compound I-13(390mg, 83%).

¹H NMR(500MHz,DMSO-d₆)δ9.90(s,1H),9.14(s,1H),8.65(s,1H),8.39-8.25(m,2H),7.88(brs,1H),7.70～7.57(m,2H),7.40(dd,J＝8.8,2.2Hz,1H),7.24(d,J＝7.4Hz,1H),6.97(d,J＝8.9Hz,1H),6.40(dd,J＝16.9,10.1Hz,1H),6.21(dd,J＝17.0,2.1Hz,1H),5.72(dd,J＝10.1,2.1Hz,1H),4.93(s,2H),3.75(s,3H).

HRMS(ESI,[M+H]⁺)m/z：486.1252.

Example 14 preparation of N- (3- ((4- ((1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxazol-6-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) acrylamide (Compound I-14)

Starting from compounds 3 to 20 and 2, compound I-14 was prepared by the method of step (1) of reference example 13.

¹H NMR(500MHz,DMSO-d₆)δ10.21～10.01(m,2H),9.33(brs,1H),8.44(s,1H),7.72(s,1H),7.64(brs,1H),7.54(d,J＝7.9Hz,1H),7.42(d,J＝7.9Hz,1H),7.32～7.21(m,2H),6.93(brs,1H),6.45(dd,J＝17.0,10.1Hz,1H),6.23(dd,J＝17.0,2.1Hz,1H),5.74(dd,J＝10.1,2.1Hz,1H),5.04(s,2H).

HRMS(ESI,[M+H]⁺)m/z：456.1514.

Example 15 preparation of N- (5- ((5-chloro-4- ((1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxazol-6-yl) amino) pyrimidin-2-yl) amino) -2- (2- (dimethylamino) ethoxy) -4-methoxyphenyl) acrylamide (Compound I-15)

Compound I-15 was prepared by the method of step (2) in the synthesis of compound I-26 in reference example 4, starting from compounds 3 and 5-1.

¹H NMR(500MHz,DMSO-d₆)δ9.61(s,1H),9.16(s,1H),8.78(s,1H),8.21(s,1H),8.05(s,1H),7.85(s,1H),7.83～7.70(m,2H),7.22(d,J＝8.1Hz,1H),6.85(s,1H),6.43(dd,J＝17.0,10.2Hz,1H),6.16(d,J＝17.0Hz,1H),5.70(d,J＝10.2Hz,1H),4.93(s,2H),4.14(t,J＝5.7Hz,2H),3.79(s,3H),2.58(t,J＝5.7Hz,2H),2.27(s,6H).

HRMS(ESI,[M+H]⁺)m/z：539.2084.

Example 15 preparation of 15a N- (5- ((5-chloro-4- ((1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxazol-6-yl) amino) pyrimidin-2-yl) amino) -2- (2- (dimethylamino) ethoxy) -4-methoxyphenyl) acrylamide mesylate (Compound I-15-21)

Compound I-15-21 was prepared by the method of step (3) in the synthesis of Compound I-8-21 in reference example 8, starting with Compound I-15.

¹H NMR(500MHz,DMSO-d₆)δ9.34(s,1H),9.13(s,1H),8.77(s,1H),8.14(s,1H),8.06(s,1H),7.82-7.73(m,3H),7.25(d,J＝8.1Hz,1H),6.85(s,1H),6.51(s,1H),6.21(dd,J＝16.9,2.0Hz,1H),5.74(dd,J＝10.0,2.1Hz,1H),4.94(s,2H),4.37(t,J＝5.1Hz,2H),3.83(s,3H),3.49～3.31(m,2H),2.84(s,6H),2.36(s,3H).

MS(ESI,[M+H]⁺)m/z：539.1.

Example preparation of 166- ((5-chloro-2- ((2-methoxyphenyl) amino) pyrimidin-4-yl) amino) benzo [ c ] [1,2] oxaborzol-1 (3H) -ol (Compound I-16)

Compound I-16 was prepared by the method of step (2) of reference example 1 using compound 3 and compound 6-4 as starting materials.

¹H NMR(500MHz,DMSO-d₆)δ9.21(s,1H),9.03(s,1H),8.13(s,1H),7.95(d,J＝7.8Hz,1H),7.88(s,1H),7.71(s,1H),7.64(d,J＝8.1Hz,1H),7.40(d,J＝8.0Hz,1H),6.98(d,J＝8.0Hz,1H),6.92(t,J＝7.6Hz,1H),6.71(t,J＝7.6Hz,1H),5.03(s,2H),3.82(s,3H).

HRMS(ESI,[M+H]⁺)m/z：383.1143.

Example 17 preparation of N- (5- ((5-chloro-4- ((1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxazol-6-yl) amino) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl (meth) amino) -4-methoxyphenyl) acrylamide (Compound I-17)

Step (1) N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹Preparation of (E) -methyl-4-nitrophenyl-1, 2-diamine (Compound 8-4)

To a reaction flask was added Compound 8-1(11.00g, 59.14), N¹,N¹,N²Trimethyl-1, 2-diamine (9.06g, 88.71mmol), potassium carbonate (12.26g, 88.71mmol) and the solvent DMF (60 mL). Under the protection of nitrogen, the mixture was heated to 90 ℃. After completion of the reaction, water was added to the reaction, extracted with ethyl acetate (three times 100mL), the organic phases were combined and washed with brine, the organic phase was dried over anhydrous magnesium sulfate, then the drying agent was removed by suction filtration, the solvent was removed by concentration under reduced pressure, and finally dried under reduced pressure in an oven at 50 ℃ to obtain compound 8-4(14.858 g).

¹H-NMR(500M,MeOD)δ7.33(s，1H),6.81(s，1H),3.88(s，3H),3.16～3.19(t，J＝6.5Hz，2H),2.77(s，3H),2.60～2.62(t，J＝6.5Hz，2H),2.33(s，6H).

MS(ESI,[M+H]⁺)m/z：269.1.

Step (2) preparation of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5-nitrophenyl) acrylamide (Compound 8-5)

To a reaction flask, add compound 8-4(1.0g, 3.73mmol), tetrahydrofuran (10mL) and water (1mL) and stir at 0 ℃; 3-Chloropropylchloride (0.57g, 4.47mmol) was added dropwise to the reaction flask. After the completion of the dropwise addition, the reaction was warmed to room temperature, and after the completion of the reaction, solid sodium hydroxide (0.597g, 14.92mmol) was further added to the reaction mixture. After stirring, the mixture was concentrated under reduced pressure to remove tetrahydrofuran, a small amount of water was added, and the mixture was extracted with ethyl acetate (10mL, three times). The organic phases were combined, dried over anhydrous magnesium sulphate, freed from the drying agent by suction filtration, concentrated under reduced pressure to remove the solvent and finally dried in an oven at 50 ℃ under reduced pressure to give compound 8-5(1.09 g).

¹H-NMR(500M,DMSO-d₆)δ8.58(s，1H),6.89～6.894(s，1H),6.50～6.56(dd，1H),6.39～6.43(dd，1H),5.82～5.84(d，J＝10.5Hz，1H),3.97(s，3H),3.20～3.22(t，J＝5.5Hz，2H),2.81(s，3H),2.59～2.62(t，J＝5.5Hz，2H),2.33(s，6H).

MS(ESI,[M+H]⁺)m/z：323.1.

Step (3) preparation of N- (5-amino-2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (Compound 5-2)

To a reaction flask were added compound 8-5(1.0g, 3.10mmol), iron powder (0.869g, 15.52mmol), ammonium chloride (0.830g, 15.52mmol), solvent ethanol (14mL) and water (4mL), and the reaction was heated to 85 ℃. After completion of the reaction, water (20mL) was added, followed by extraction with ethyl acetate (40mL, three times), and the organic phases were combined and washed with saturated brine. The resulting organic phase was dried over anhydrous magnesium sulfate, then the drying agent was removed by suction filtration, and the filtrate was concentrated under reduced pressure to remove the solvent. Finally, the mixture was dried in an oven at 50 ℃ under reduced pressure to obtain Compound 5-2(0.628g)

¹H-NMR(500M,DMSO-d₆)δ10.06(br，1H),7.66(s，1H),6.80(s，1H),6.28～6.33(dd，J＝9.5Hz，16.5Hz，1H),6.18～6.22(dd，J＝2.0Hz，17.0Hz，1H),5.69～5.72(dd，J＝1.5Hz，10.0Hz，1H),4.62(br，2H),2.18～2.80(t，J＝5.5Hz，2H),2.61(s，3H),2.17(s，6H).

HRMS(ESI,[M+H]⁺)m/z：293.1976.

Step (4) preparation of N- (5- ((5-chloro-4- ((1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxazol-6-yl) amino) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl (meth) amino) -4-methoxyphenyl) acrylamide (Compound I-17)

Compound I-17 was prepared by the method of step (2) in the synthesis of compound I-26 in reference example 4, starting from compound 3 and compound 5-2.

¹H NMR(500MHz,DMSO-d₆)δ9.97(s,1H),9.14(s,1H),8.78(s,1H),8.48(s,1H),8.08(s,1H),7.86(s,1H),7.80(s,1H),7.77(d,J＝9.6Hz,1H),7.23(d,J＝8.2Hz,1H),6.95(s,1H),6.46～6.36(m,1H),6.18(d,J＝16.8Hz,1H),5.72(d,J＝11.4Hz,1H),4.93(s,2H),3.79(s,3H),2.91～2.84(m,2H),2.67(s,3H),2.41～2.31(m,2H),2.24(s,6H).

MS(ESI,[M+H]⁺)m/z：552.2.

Example 18 preparation of N- (2- (2- (dimethylamino) ethoxy) -5- ((5-fluoro-4- ((1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxaborzol-6-yl) amino) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide (Compound I-18)

Step (1) preparation of 6- ((2-chloro-5-fluoropyrimidin-4-yl) amino) benzo [ c ] [1,2] oxaborzol-1 (3H) -ol (Compound 3-22)

Compounds 3 to 22 were prepared by the method of step (1) of reference example 1 using compounds 1 to 8 and compound 2 as starting materials.

¹H NMR(500MHz,DMSO-d₆)δ10.04(s,1H),9.29(s,1H),8.31(s,1H),7.91(s,1H),7.71(d,J＝8.1Hz,1H),7.42(d,J＝8.1Hz,1H),4.99(s,2H).

HRMS(ESI,[M+H]⁺)m/z：280.0472.

Step (2) preparation of N- (2- (2- (dimethylamino) ethoxy) -5- ((5-fluoro-4- ((1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxaborzol-6-yl) amino) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide (Compound I-18)

Compound I-18 was prepared by the method of step (2) in the synthesis of compound I-26 in reference example 4, starting from compound 3-22 and compound 5-1.

¹H NMR(500MHz,DMSO-d₆)δ9.65(s,1H),9.32(s,1H),8.38(s,1H),8.03(d,J＝3.6Hz,1H),7.91～7.86(m,2H),7.64(s,1H),7.49(d,J＝7.9Hz,1H),7.25(d,J＝8.2Hz,1H),7.12(d,J＝7.9Hz,1H),6.86(s,1H),6.44(dd,J＝17.0,10.2Hz,1H),6.17(d,J＝16.9Hz,1H),5.71(d,J＝11.3Hz,1H),4.93(s,2H),4.14(t,J＝5.4Hz,2H),3.82(s,3H),2.57(t,J＝5.4Hz,2H),2.26(s,6H).

MS(ESI,[M+H]+)m/z：523.1.

Example 19 preparation of N- (2- (2- (dimethylamino) ethoxy) -5- ((4- ((1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxazol-6-yl) amino) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide (Compound I-19)

Step (1) preparation of 6- ((2-chloropyrimidin-4-yl) amino) benzo [ c ] [1,2] oxaborzol-1 (3H) -ol (Compound 3-23)

Compounds 3 to 23 were prepared by the method of step (1) of reference example 1 using compounds 1 to 9 and compound 2 as starting materials.

¹H NMR(500MHz,DMSO-d₆)δ10.10(s,1H),9.28(s,1H),8.14(d,J＝5.7Hz,1H),7.90-7.79(m,2H),7.41(d,J＝8.1Hz,1H),6.76(d,J＝5.7Hz,1H),4.97(s,2H).

HRMS(ESI,[M+H]⁺)m/z：262.0543.

Step (2) preparation of N- (2- (2- (dimethylamino) ethoxy) -5- ((4- ((1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxazol-6-yl) amino) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide (Compound I-19)

Compound I-19 was prepared by the method of step (2) in the synthesis of compound I-26 in reference example 4, starting with compound 3-23 and compound 5-1.

¹H NMR(500MHz,DMSO-d₆)δ9.69(s,1H),9.32(s,1H),8.46(s,1H),7.95(d,J＝5.7Hz,1H),7.89(d,J＝8.3Hz,1H),7.76(s,1H),7.62(s,1H),7.24(d,J＝8.3Hz,1H),6.88(s,1H),6.44(dd,J＝16.9,10.2Hz,1H),6.21-6.13(m,2H),5.71(d,J＝10.6Hz,1H),4.92(s,2H),4.15(t,J＝5.6Hz,2H),3.83(s,3H),2.58(t,J＝5.6Hz,2H),2.26(s,6H).

MS(ESI,[M+H]⁺)m/z：505.1.

Example 19a preparation of 2- (2-acrylamido-4- ((4- ((1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxazol-6-yl) amino) pyrimidin-2-yl) amino) -5-methoxyphenoxy) -N, N-dimethylethane-1-ammonium methanesulfonate (Compound I-19-21)

To a reaction flask was added compound I-19(0.53g, 1.05mmol), methanol (3mL) and stirred at room temperature; methanesulfonic acid (100.98mg, 1.12mmol) in methanol (2mL) was slowly added to the reaction. After the reaction was gradually cleared, the reaction mixture was heated to 50 ℃ and reacted for 1 hour. Then concentrating under reduced pressure to remove methanol, adding methyl tert-butyl ether (5mL) and pulping; a solid was obtained by suction filtration, and finally dried under reduced pressure to obtain Compound I-19-21(0.546 g).

¹H NMR(500MHz,DMSO-d₆)δ9.41(s,1H),9.39(s,1H),9.16(s,1H),8.37(s，1H),7.95～7.96(d,J＝6.0Hz,1H),7.88～7.90(d,J＝8.0Hz,1H),7.77(s,1H),7.69(br,1H),7.25～7.27(d,J＝8.5Hz,1H),6.89(s,1H),6.53～6.59(dd,J＝17.0,10.5Hz,1H),6.21-6.24(m,2H),5.74～5.76(d,J＝10.5Hz,1H),4.93(s,2H),4.38～4.40(t,J＝4.0Hz,2H),3.88(s,3H),3.44(m,2H),2.84(s,6H),2.37(s,3H).

MS(ESI,[M+H]⁺)m/z：505.1.

EXAMPLE 20 preparation of N- (5- ((5-chloro-4- ((1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxazol-1-6-yl) amino) pyrimidin-2-yl) amino) -2- (2- (dimethylamino) ethoxy) -4-methoxyphenyl) acrylamide (Compound I-20)

Step (1) preparation of 6- ((2, 5-dichloropyridin-4-yl) amino) -3, 3-dimethylbenzo [ C ] [1,2] oxazol-1 (3H) -ol (Compound 3-24) (preparation of Compound 3-24)

Compounds 3 to 24 were prepared by the method of step (1) of reference example 1 using Compound 1 and Compounds 2 to 10 as starting materials.

¹H NMR(500MHz,DMSO-d₆)δ9.55(s,1H),9.08(s,1H),8.36(s,1H),7.72(d,1H),7.57(dd,1H),7.44(d,1H),1.47(s,6H).

HRMS(ESI,[M+H]⁺)m/z：324.0759.

Step (2) preparation of N- (5- ((5-chloro-4- ((1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxazol-1-6-yl) amino) pyrimidin-2-yl) amino) -2- (2- (dimethylamino) ethoxy) -4-methoxyphenyl) acrylamide (compound I-20) compound I-20 was prepared by the method of step (2) in the synthesis of compound I-26 in reference example 4, starting with compounds 3-24 and 5-1.

¹H NMR(500MHz,DMSO-d₆)δ9.64(s,1H),8.69(s,1H),8.25(s,1H),8.05(s,1H),7.92(s,1H),7.82～7.71(m,2H),7.23(d,J＝8.2Hz,1H),6.87(s,1H),6.47(dd,J＝17.0,10.2Hz,1H),6.20(d,J＝16.9Hz,1H),5.72(d,J＝10.2Hz,1H),4.15(t,J＝5.7Hz,2H),3.79(s,3H),2.58(t,J＝5.7Hz,2H),2.26(s,6H),1.43(s,6H).

MS(ESI,[M+H]⁺)m/z：567.1.

Example 21 preparation of N- (3- ((4- ((1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxaborzol-6-yl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) acrylamide (Compound I-21)

Step (1) preparation of 6- ((2-chloro-5-methylpyrimidin-4-yl) amino) benzo [ c ] [1,2] oxaborzol-1 (3H) -ol (Compound 3-25)

Compounds 3 to 25 were prepared by the method of step (1) of reference example 1 using compounds 1 to 10 and compound 2 as starting materials.

¹H NMR(500MHz,DMSO-d₆)δ9.24(s,1H),8.94(s,1H),8.02(s,1H),7.84(s,1H),7.64(d,J＝8.1Hz,1H),7.41(d,J＝8.1Hz,1H),4.99(s,2H),2.17(s,3H).

HRMS(ESI,[M+H]⁺)m/z：276.0692.

Step (2) preparation of N- (3- ((4- ((1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxazol-6-yl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) acrylamide (Compound I-21)

Compound I-21 was prepared by the method of step (2) of reference example 1, starting from compound 3-25 and compound 5.

¹H NMR(500MHz,DMSO-d₆)δ9.97(s,1H),9.11(s,1H),8.87(s,1H),8.36(s,1H),7.92-7.87(m,2H),7.83(dd,J＝8.2,1.9Hz,1H),7.76(s,1H),7.49(d,J＝8.1Hz,1H),7.34(d,J＝8.2Hz,1H),7.21(d,J＝7.9Hz,1H),7.04(t,J＝8.1Hz,1H),6.45(dd,J＝17.0,10.2Hz,1H),6.22(dd,J＝17.0,2.1Hz,1H),5.72(dd,J＝10.1,2.1Hz,1H),4.98(s,2H),2.12(s,3H).

HRMS(ESI,[M+H]⁺)m/z：402.1720.

Example 22 preparation of N- (3- ((4- ((1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxaborzol-6-yl) amino) pyrimidin-2-yl) amino) phenyl) acrylamide (Compound I-22)

Compound I-22 was prepared by the method of step (2) of reference example 1, starting from compound 3-25 and compound 5.

¹H NMR(500MHz,DMSO-d₆)δ9.16(s,1H),8.34(s,1H),7.94(s,1H),7.86(d,J＝8.8Hz,1H),7.82(s,1H),7.69(dd,J＝8.2,2.1Hz,1H),7.36(d,J＝8.2Hz,1H),7.18(s,1H),6.59(d,J＝2.6Hz,1H),6.33(dd,J＝8.8,2.6Hz,1H),5.00(s,2H),3.80(s,3H),3.12～3.00(m,4H),2.48～2.43(m,4H),2.23(s,3H),2.10(s,3H).

HRMS(ESI,[M+H]⁺)m/z：461.2462.

Example 23 preparation of N- (3- ((5-fluoro-4- ((1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxazol-6-yl) amino) pyrimidin-2-yl) amino) phenyl) acrylamide (Compound I-23)

Compound I-23 was prepared by the method of step (2) of reference example 1, starting from compound 3-22 and compound 5.

¹H NMR(500MHz,DMSO-d₆)δ10.01(s,1H),9.40(s,1H),9.15(s,1H),9.11(s,1H),8.10(d,J＝3.6Hz,1H),7.95～7.90(m,2H),7.82(s,1H),7.46(d,J＝8.0Hz,1H),7.35(d,J＝8.1Hz,1H),7.25(d,J＝7.8Hz,1H),7.12(t,J＝8.0Hz,1H),6.46(dd,J＝17.0,10.1Hz,1H),6.24(d,J＝15.7Hz,1H),5.73(d,J＝10.7Hz,1H),4.98(s,2H).

HRMS(ESI,[M+H]⁺)m/z：406.1700.

Example 24 preparation of N- (3- ((5-bromo-4- ((1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxazol-6-yl) amino) pyrimidin-2-yl) amino) phenyl) acrylamide (Compound I-24)

Step (1) preparation of 6- ((5-bromo-2-chloro-pyrimidin-4-yl) amino) benzo [ c ] [1,2] oxaborzol-1 (3H) -ol (compound 3-26)

Compounds 3 to 26 were prepared by the method of step (1) of reference example 1 using compounds 1 to 11 and compound 2 as starting materials.

¹H NMR(500MHz,DMSO-d₆)δ9.41(s,1H),9.27(s,1H),8.45(s,1H),7.76(s,1H),7.55(d,J＝8.1Hz,1H),7.43(d,J＝8.1Hz,1H),5.01(s,2H).

HRMS(ESI,[M+H]⁺)m/z：339.9653.

Step (2) preparation of N- (3- ((5-bromo-4- ((1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxazol-6-yl) amino) pyrimidin-2-yl) amino) phenyl) acrylamide (Compound I-24)

Compound I-24 was prepared by the method of step (2) of reference example 1, starting from compound 3-26 and compound 5.

¹H NMR(500MHz,DMSO-d₆)δ9.99(s,1H),9.27(s,1H),9.17(s,1H),8.69(s,1H),8.21(s,1H),7.80(s,1H),7.72～7.66(m,2H),7.44～7.35(m,2H),7.25～7.19(m,1H),7.01(t,J＝8.1Hz,1H),6.44(dd,J＝17.0,10.1Hz,1H),6.23(d,J＝16.9Hz,1H),5.77～5.69(m,1H),5.01(s,2H).

HRMS(ESI,[M+H]⁺)m/z：466.0649.

EXAMPLE 25 preparation of N- (2- (2- (dimethylamino) ethoxy) -5- ((4- ((1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxaborolan-6-yl) amino) (trifluoromethyl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide (Compound I-25)

Step (1) preparation of (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) benzo [ c ] [1,2] oxaborole-1- (3H) -ol (Compound 3-27)

6-aminobenzo [ c ] [1,2] oxaborole-1 (3H) -ol (4.000g, 26.854mmol, 1eq) and 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (5.826g, 26.854mmol, 1eq) were dissolved in isopropanol (100mL), N-Diisopropylethylamine (DIPEA) (6.941g, 53.707mmol, 2eq) was added dropwise under ice-water bath (0 ℃), reacted overnight at room temperature, the reaction solution was concentrated to dryness, and the residue was dissolved in 250mL of ethyl acetate, washed with water and saturated brine once, dried, filtered, concentrated under reduced pressure, and purified by preparative chromatography to give compound 3-27(2.2g) with a purity of 99% (UPLC).

¹H NMR(500MHz,DMSO-d₆)δ9.60(s,1H),9.23(brs,1H),8.57(s,1H),7.69(d,J＝1.5Hz,1H),7.50(dd,J＝2.0and8.5Hz,1H),7.45(d,J＝8.0Hz,1H),5.02(s,2H).

MS(ESI):m/z 330.0[M+H]⁺,228.1[M-H]^-.

Step (2) preparation of N- (2- (2- (dimethylamino) ethoxy) -5- ((4- ((1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxaborolan-6-yl) amino) (trifluoromethyl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide (Compound I-25)

Adding the compounds 3-27(500mg, 1.518mmol, 1.0eq), N- (5-amino-2- (2- (dimethylamino) ethoxy) -4-methoxyphenyl) acrylamide (509mg, 1.821mmol, 1.2eq) to 2-butanol (20mL), adding p-toluenesulfonic acid (433mg, 2.276mmol, 1.5eq), stirring at room temperature for 1 minute, heating and refluxing for 1 hour, completing the reaction, cooling to room temperature, adding a methanol solution of ammonia (7mol/L) to adjust the pH to 8, concentrating to prepare sand, and performing column chromatography to obtain the compound I-25(664mg) with purity of 97% (UPLC).

¹H NMR(500MHz,DMSO-d₆)δ10.12(brs,1H),9.48(s,1H),9.06(s,1H),8.45(s,1H),8.25(s,1H),8.06(s,1H),7.61(m,1H),7.51(d,J＝8.0Hz,1H),7.11(d,J＝8.0Hz,1H),6.81(s,1H),6.70(m,1H),6.20(dd,J＝1.5and17Hz,1H),5.68(d,J＝10.5Hz,2H),4.95(s,2H),4.35(s,2H),3.80(s,3H),3.39(s,2H),2.78(d,J＝3.0Hz,6H).

MS(ESI):m/z 573.0[M+H]⁺.

Example 25a preparation of (2-acrylamido-4- ((4- ((1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxaborolan-6-yl) amino) -5- (trifluoromethyl) amino) -5-methoxyphenoxy) -N, N-dimethylethane-1-ammonium methanesulfonate (Compound I-25-21)

Compound I-25(567mg, 0.991mmol, 1.0eq) was dissolved in methanol (25mL), methanesulfonic acid (95.2mg, 0.991mmol, 1.0eq) was added with stirring, the reaction solution was clarified after 10 minutes of stirring, and the reaction solution was concentrated to dryness to give compound I-25-21(640mg) with a purity of 97% (UPLC).

¹H NMR(500MHz,DMSO-d₆)δ9.95(brs,1H),9.60(brs,1H),9.41(s,1H),8.39(brs,1H),7.99(s,1H),7.62(m,1H),7.51(m,1H),7.29(s,1H),7.12(d,J＝8.0Hz,1H),6.86(s,1H),6.73(m,1H),6.20(m,1H),5.71(m,1H),4.98(s,2H),4.42(s,2H),3.82(s,3H),3.59(d,J＝4.5Hz,2H),2.90(d,J＝4.5Hz,6H).2.40(s,3H).

MS(ESI):m/z 573.1[M+H]⁺.

Example preparation of 266- ((5-chloro-2- ((2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) benzo [ c ] [1,2] oxaborzol-1 (3H) -ol (Compound I-26)

Compound I-26 was prepared by the method of step (2) of reference example 1, starting from compound 3 and compound 6.

¹H-NMR(500M,DMSO-d₆)δ9.21(s,1H)，8.67(s,1H)，8.06(s,1H)，7.88(s,1H)，7.62～7.66(m,3H)，7.35～7.37(d,J＝8.5Hz,1H)，6.63～6.634(d,J＝2.0Hz,1H)，6.34～6.36(d,J＝9.0Hz,1H)，5.01(s,2H)，3.79(s，3H)，3.25(m，4H)2.99(m，4H)，2.61(s，3H).

HRMS(ESI,[M+H]⁺)m/z：481.1911.

Example 276 preparation of- ((5-chloro-2- ((2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) benzo [ c ] [1,2] oxaborzol-1 (3H) -ol (Compound I-17)

Compound I-17 was prepared by the method of step (2) of reference example 1 using compound 3 and compound 6-2 as starting materials.

¹H NMR(500MHz,DMSO-d₆)δ9.20(s,1H),8.85(s,1H),8.04(s,1H),7.87(brs,1H),7.64(d,J＝8.1Hz,1H),7.60(s,1H),7.56(d,J＝8.6Hz,1H),7.34(d,J＝8.1Hz,1H),6.56(d,J＝2.5Hz,1H),6.33～6.26(m,1H),4.99(s,2H),3.77(s,3H),3.62(d,J＝12.0Hz,2H),2.62～2.53(m,3H),2.49～2.20(m,8H),2.15(s,3H),1.85-1.77(m,2H),1.53～1.42(m,2H).

HRMS(ESI,[M+H]⁺)m/z：564.2754.

Example 286 preparation of- ((5-chloro-2- (phenylamino) pyrimidin-4-yl) amino) benzo [ c ] [1,2] oxaborzol-1 (3H) -ol (Compound I-28)

Compound I-28 was prepared by the method of step (2) of reference example 1, starting from compound 3 and compound 6-3.

¹H NMR(500MHz,DMSO-d₆)δ10.40(s,1H),10.07(s,1H),8.35(s,1H),7.86(s,1H),7.58(d,J＝8.1Hz,1H),7.51-7.37(m,3H),7.15(t,J＝7.7Hz,2H),6.99(t,J＝7.3Hz,1H),5.04(s,2H).

HRMS(ESI,[M+H]⁺)m/z：353.0968.

Example preparation of 296- ((5-chloro-2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) benzo [ c ] [1,2] oxaborzol-1 (3H) -ol (Compound I-29)

Compound I-29 was prepared by the method of step (2) of reference example 1, starting from compounds 3 and 6-1.

¹H NMR(500MHz,DMSO-d6)δ9.21(s,1H),9.02(brs,1H),8.87(s,1H),8.07(s,1H),7.87(s,1H),7.64(d,J＝7.8Hz,1H),7.45～7.35(m,3H),6.74(d,J＝8.6Hz,2H),5.02(s,2H),3.10～2.99(m,4H),2.65～2.54(m,4H),2.32(s,3H).

HRMS(ESI,[M+H]⁺)m/z：451.1826.

Example preparation of 306- ((5-chloro-2- ((4- (4-dimethylamino) piperidin-1-yl) -2-methoxyphenyl) amino) pyrimidin-4-yl) amino) benzo [ c ] [1,2] oxaborzol-1 (3H) -ol (Compound I-30)

Compound I-30 was prepared by the method of step (2) of reference example 1 using compound 3 and compound 6-5 as starting materials.

¹H NMR(500MHz,DMSO-d₆)δ9.20(s,1H),8.85(s,1H),8.05(s,1H),7.88(s,1H),7.65(d,J＝8.0Hz,1H),7.62～7.54(m,2H),7.35(d,J＝8.1Hz,1H),6.58(s,1H),6.32(d,J＝8.3Hz,1H),5.00(s,2H),3.78(s,3H),3.62(d,J＝11.7Hz,2H),2.61(t,J＝12.1Hz,2H),2.25～2.12(m,7H),1.88～1.79(m,2H),1.53～1.41(m,2H).

HRMS(ESI,[M+H]⁺)m/z：509.2259.

Example preparation of 316- ((5-chloro-2- ((2-isopropyl-5-methyl-4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) benzo [ c ] [1,2] oxaborzol-1 (3H) -ol (Compound I-31)

Compound I-31 was prepared by the method of step (2) of reference example 1 using compound 3 and compound 6-6 as starting materials.

¹H NMR(500MHz,DMSO-d₆)δ9.04(s,1H),8.10(s,1H),7.80(s,1H),7.63(s,1H),7.57(dd,J＝8.1,2.0Hz,1H),7.53(s,1H),7.41(d,J＝8.1Hz,1H),6.73(s,1H),4.99(s,2H),4.58～4.51(m,1H),3.14～3.07(m,2H),2.74～2.64(m,2H),2.05～1.94(m,1H),1.84(s,3H),1.83(s,3H),1.62～1.53(m,4H),1.27(s,3H),1.26(s,3H).

HRMS(ESI,[M+H]⁺)m/z：508.2320.

Example preparation of 327- ((5-chloro-2- ((2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) benzo [ c ] [1,2] oxaborzol-1 (3H) -ol (Compound I-32)

Compound I-32 was prepared by the method of step (2) of reference example 1, starting from compound 3-14 and compound 6-6.

¹H NMR(500MHz,DMSO-d₆)δ8.43(s,1H),8.24-8.14(m,2H),7.95(s,1H),7.60(s,1H),7.32(t,J＝7.7Hz,1H),7.07(d,J＝7.4Hz,1H),6.83(s,1H),5.00(s,2H),4.58-4.48(m,1H),3.10-3.05(m,2H),2.80-2.72(m,1H),2.68-2.61(m,2H),2.20(s,3H),1.67-1.51(m,4H),1.25(s,3H),1.24(s,3H).

MS(ESI,[M+H]⁺)m/z：508.1.

Example 337 preparation of- ((5-chloro-2- ((2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) benzo [ c ] [1,2] oxaborzol-1 (3H) -ol (Compound I-33)

Compound I-33 was prepared by the method of step (2) in the synthesis of reference example 1, starting from compound 3-14 and compound 6-2.

¹H NMR(500MHz,DMSO-d6)δ9.61(s,1H),8.34(s,1H),8.24(s,1H),8.18(s,1H),8.10(s,1H),7.38(d,J＝8.5Hz,1H),7.28(t,J＝7.5Hz,1H),7.03(d,J＝7.5Hz,1H),6.64(s,1H),6.49(dd,J＝1.5,7Hz,1H),5.01(s,2H),3.76(s,3H),3.73(m,2H),2.69(t,J＝11.5Hz,2H),2.57～2.37(m,5H),2.34(s,3H),1.86(d,J＝11.5Hz,2H),1.51～1.58(m,2H),1.23～1.28(m,4H).

MS(ESI,[M+H]⁺)m/s:564.1.

Example preparation of 347- ((5-chloro-2- ((4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) amino) pyrimidin-4-yl) amino) benzo [ c ] [1,2] oxaborzol-1 (3H) -ol (Compound I-34)

Compound I-34 was prepared by the method of step (2) of reference example 1, starting from compound 3-14 and compound 6-5.

¹H NMR(500MHz,DMSO-d₆)δ9.61(s，1H),8.34(s，1H),8.24(br，1H),8.18(s，1H),8.10(s，1H),7.37～7.38(d，J＝8.5Hz，1H),7.27～7.30(t，J＝7.5Hz，1H),7.03～7.04(d，J＝7.0Hz，1H),6.64～6.65(d，J＝2.0Hz，1H),6.49～6.51(dd，J＝2.5Hz，9.0Hz，1H),5.00(s，2H),3.76(s，3H),3.72～3.75(t，2H),2.67～2.72(t，J＝11.0Hz，2H),2.25(s，6H),1.86～1.88(m，2H),1.49～1.57(m，2H).

MS(ESI,[M+H]⁺)m/z：509.2.

Example 356 preparation of- ((2- ((2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzo [ c ] [1,2] oxaborzol-1 (3H) -ol (Compound I-35)

Compound I-35 was prepared by the method of step (2) of reference example 1, starting from compound 3-25 and compound 6.

HRMS(ESI,[M+H]⁺)m/z：461.2462.

Example 366- ((2- ((2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) benzo [ c ] [1,2] oxaborzol-1 (3H) -ol (Compound I-36) preparation

Compound I-36 was prepared by the method of step (2) of reference example 1, starting from compound 3-23 and compound 6.

¹H NMR(500MHz,DMSO-d₆)δ9.36(s,1H),9.18(s,1H),7.96-7.90(m,2H),7.88(d,J＝8.7Hz,1H),7.75(d,J＝8.0Hz,1H),7.46(s,1H),7.32(d,J＝8.1Hz,1H),6.64(s,1H),6.47(d,J＝8.5Hz,1H),6.18(d,J＝5.4Hz,1H),4.97(s,2H),3.83(s,3H),3.17～3.12(m,4H),2.63～2.55(m,4H),2.32(s,3H).

HRMS(ESI,[M+H]⁺)m/z：447.2316.

Example 376 preparation of- ((5-fluoro-2- ((2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) benzo [ c ] [1,2] oxaborzol-1 (3H) -ol (Compound I-37)

Compound I-37 was prepared by the method of step (2) of reference example 1, starting from compound 3-22 and compound 6.

¹H NMR(500MHz,DMSO-d₆)δ9.35(s,1H),9.20(s,1H),8.08～7.97(m,2H),7.81～7.69(m,2H),7.48(s,1H),7.34(d,J＝8.0Hz,1H),6.61(s,1H),6.41(dd,J＝8.9,2.8Hz,1H),4.99(s,2H),3.80(s,3H),3.15～3.02(m,4H),2.50～2.43(m,4H),2.25(s,3H).

HRMS(ESI,[M+H]⁺)m/z：465.2192.

Example preparation of 386- ((5-bromo-2- ((2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) benzo [ c ] [1,2] oxaborzol-1 (3H) -ol (Compound I-38)

Compound I-38 was prepared by the method of step (2) of reference example 1, starting from compound 3-26 and compound 6.

¹H NMR(500MHz,DMSO-d₆)δ9.18(s,1H),8.60(s,1H),8.12(s,1H),7.83(s,1H),7.65-7.58(m,2H),7.55(d,J＝8.7Hz,1H),7.35(d,J＝8.2Hz,1H),6.57(d,J＝2.5Hz,1H),6.28(d,J＝8.5Hz,1H),5.00(s,2H),3.78(s,3H),3.09～3.04(m,4H),2.47～2.41(m,4H),2.23(s,3H).

HRMS(ESI,[M+H]⁺)m/z：525.1382.

Example 39 preparation of (3- ((5-chloro-2- ((2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) boronic acid (Compound I-39)

Dissolve compound 3-10(1g, 2.73mmol) and compound 6-6(0.96g, 3.0mmol) in 2-butanol (10mL) with stirring, and finally add trifluoroacetic acid (0.47g, 4.10 mmol). Microwave reaction at 120 deg.c for 2 hr. And after the reaction is finished, decompressing and concentrating to remove the solvent, adding 50mL of ethyl acetate to dilute the reaction solution, adjusting the pH of a water layer to 7-8 by using a saturated sodium bicarbonate solution, standing for layering, extracting the water layer for three times by using 50mL of ethyl acetate, combining organic layers, decompressing and concentrating to remove the solvent, and obtaining a crude product of the compound I-39-1. And separating by column chromatography to obtain compound I-39-1(1.02 g).

Compound I-39-1(700mg, 1.21mmol) was added to a 100mL single-neck flask, dissolved in 50mL tetrahydrofuran and 10mL purified water, followed by addition of sodium periodate (259mg, 1.21mmol), and the reaction was stirred at room temperature with dropwise addition of 2mol/L aqueous hydrochloric acid (0.605mL, 1.21mmol) on an ice bath. After the reaction, the solution was concentrated under reduced pressure to give a brown oil. A mixed solution (50mL) of dichloromethane/methanol (dichloromethane to methanol volume ratio of 10:1) is added to dissolve, a saturated sodium bicarbonate solution is used for adjusting the pH value to 6-7, and an aqueous layer is extracted three times by using a mixed solution (10mL) of dichloromethane/methanol (dichloromethane to methanol volume ratio of 10:1) to combine organic layers. The solvent was removed by concentration under reduced pressure to give a brown oil, which was isolated by column chromatography to give Compound I-39(110 mg).

¹H NMR(500MHz,DMSO-d₆)δ8.108(s,1H),7.995(s,2H),7.893(s,1H),7.737(s,1H)7.644～7.613(m,2H),7.566(s,1H),7.346～7.316(m,1H),6.740(s,1H),4.534～4.486(m,1H),3.314～3.273(m,2H),3.031～2.872(m,3H),1.998(s,3H),1.935～1.1.831(m,2H),1.784～1.710(m,2H),1.287～1.266(d,6H).

¹³C NMR(125MHz,DMSO-d6)δ157.88,156.83,155.02,144.84,138.15,136.54,130.74,130.28,130.11,128.30,128.06,127.41,126.28,121.38,111.51,104.39,71.71,44.13,35.25,29.26,22.40,18.86.

MS(ESI,[M+H]⁺)m/z：496.

Example 40 preparation of (3- ((5-chloro-2- ((2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) boronic acid (Compound I-40)

Compound 3-10(960mg, 2.63mmol) and compound 6-1(880mg, 2.89mmol) were dissolved in 2-butanol (10mL) with stirring and finally trifluoroacetic acid (0.45g, 3.95mmol) was added. Microwave reaction at 110 deg.c for 2 hr. After the reaction, the solvent was removed by concentration under reduced pressure, the reaction mixture was diluted with 50mL of methylene chloride and 10mL of purified water, the pH of the aqueous layer was adjusted to 7 with a saturated sodium bicarbonate solution, the aqueous layer was extracted three times with methylene chloride (10mL) by standing for layer separation, and the organic layers were combined and concentrated under reduced pressure to remove the solvent, to give a crude product of the compound I-40-1. Separating by column chromatography to obtain compound I-40-1(900 mg).

To a 100mL single-neck flask was added compound I-40-1(1.2g, 1.89mmol), followed by addition of 4.8mL each of methanol and n-pentane, stirring to dissolve, and finally addition of isobutylboronic acid (0.77g, 7.55mmol) and 1mol/L aqueous hydrochloric acid (3.6mL, 3.6 mmol). Stir vigorously at room temperature for 5 hours. The mixture was allowed to stand for separation, the pentane layer was discarded, the methanol layer was extracted three times with 10mL of n-pentane, the solvent was removed by concentration under reduced pressure, the mixture was dissolved in a mixed solution (50mL) of methylene chloride/methanol (the volume ratio of methylene chloride to methanol was 10:1), and the pH was adjusted to neutrality with a saturated sodium bicarbonate solution. The aqueous layer was extracted with a mixed solution (10mL) of methylene chloride/methanol (volume ratio of methylene chloride to methanol: 10:1) three times and the organic layers were combined and separated by column chromatography to give compound I-40(200 mg).

¹H NMR(500MHz,DMSO-d₆)δ8.705(s,1H),8.035～8.012(m,3H),7.890(s,1H),7.659～7.643(m,1H),7.618～7.590(m,2H),7.577～7.542(m,1H),6.574～6.569(m,1H),6.343～6.322(m,1H),3.776(s,3H),3.659～3.633(m,2H),3.180(s,1H),2.636～2.591(m,4H),2.475～2.368(m,4H),2.234(s,3H),1.860～1.837(m,2H),1.550～1.485(m,2H),1.307～1.188(m,2H).

¹³C NMR(125MHz,DMSO-d₆)δ158.67,156.53,154.99,150.91,148.25,138.23,130.20,129.74,127.80,125.59,122.91,120.90,107.76,103.65,100.90,61.35,56.02,55.23,49.38,49.07,48.66,45.75,28.20.

MS(ESI,[M+H]⁺)m/z：552.1.

EXAMPLE 41 preparation of (3- ((5-chloro-2- ((4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) amino) pyrimidin-4-yl) amino) phenyl) boronic acid (Compound I-41)

Dissolve compound 3-10(2g, 5.46mmol) and compound 6-5(1.5g, 6.02mmol) in 2-butanol (10mL) with stirring, and finally add trifluoroacetic acid (0.94g, 8.24 mmol). The reaction was heated with a microwave at 120 ℃ for 2 hours. After the reaction, the solvent was removed under reduced pressure, a mixed solution (50mL) of dichloromethane/methanol (dichloromethane to methanol volume ratio 10:1) was added, the pH of the aqueous layer was adjusted to neutrality with a saturated aqueous solution of sodium bicarbonate, the mixture was allowed to stand for separation, the aqueous layer was extracted three times with a mixed solution (50mL) of dichloromethane/methanol (dichloromethane to methanol volume ratio 10:1), the organic layers were combined, and the solvent was removed by concentration under reduced pressure to give a crude product of compound I-41-1. Separating by column chromatography to obtain compound I-41-1(2 g).

To a 100mL single-neck flask was added compound I-41-1(870mg, 1.5mmol), 3.8mL each of methanol and n-pentane was added and dissolved with stirring, and finally isobutylboronic acid (611mg, 6mmol) and 1mol/L aqueous hydrochloric acid (2.85mL, 0.285mmol) were added. Stir vigorously at room temperature for 12 hours. Standing for layering, removing a pentane layer, extracting a methanol layer twice with 10mL of n-pentane, adjusting the pH value to 6-7 with a saturated sodium bicarbonate aqueous solution, extracting twice with 50mL of a dichloromethane/methanol (the volume ratio of dichloromethane to methanol is 10:1) mixed solution, retaining an organic layer, concentrating under reduced pressure to remove a solvent to obtain a yellow oily substance, and performing column chromatography to obtain a compound I-41(120 mg).

¹H NMR(500MHz,DMSO-d₆)δ8.753(s,1H),8.052～8.8.042(m,3H),7.893(s,1H),7.655～7.615(m,3H),7.562～7.547(m,1H),7.297～7.266(m,1H),6.613～6.610(m,1H),6.364～6.348(m,1H),3.787(s,3H),3.768～3.743(m,2H),3.270～3.223(m,1H),2.721(s,6H),2.657～2.633(m,2H),2.125～2.102(m,2H),1.787～1.722(m,2H).

¹³C NMR(125MHz,DMSO-d6)δ158.89,156.54,155.00,150.88,147.51,138.19,130.25,129.86,127.83,125.66,122.85,121.43,108.04,103.71,101.31,62.80,56.09,48.67,26.03.

MS(ESI,[M+H]⁺)m/z：497.1.

Example 426 preparation of- ((5-chloro-2- ((4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) benzo [ c ] [1,2] oxaborzol-1 (3H) -ol (Compound I-42)

Compound 3(1g,3.3mmol), compound 6-7(1.2g,3.96mmol), p-toluenesulfonic acid (682mg,3.96mmol) were placed in a 250mL three-necked flask, 2-butanol (50mL) was added, nitrogen substitution was performed, then heating and refluxing were performed for 6 hours, after the reaction was completed, the solvent was removed by concentration under reduced pressure, 20mL of ethyl acetate, 20mL of dichloromethane, and 100mL of water were added, the pH of the system was adjusted to 10 with saturated aqueous sodium carbonate solution, and the organic phase was separated and collected. The aqueous phase was extracted twice with 20mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent, giving the crude compound I-42-1, which was used in the next step without purification.

Suspending the compound I-42-1 in 20mL of methanol, adding 4mL of concentrated hydrochloric acid under magnetic stirring, heating and stirring at 50 ℃ in an oil bath for 2.5h, cooling the system to room temperature after the reaction is finished, separating out white solid, filtering to remove the solid, and concentrating the filtrate under reduced pressure to dryness. The residue was taken up in 20mL of water and adjusted to pH 8 with saturated aqueous sodium carbonate solution, whereupon a grey solid precipitated. The gray solid was slurried with ethanol (5mL) overnight and suction filtered to give compound I-42(100 mg).

¹H NMR(500MHz,DMSO-d₆)δ9.13(s,1H),8.89(s,1H),8.10(s,1H),7.84(s,1H),7.63(d,J＝5.0Hz,1H),7.46(d,J＝6.0Hz,2H),7.41(d,J＝7.0Hz,1H),6.95(d,J＝5.5Hz,2H),5.02(s,2H),3.02(d,J＝9.0Hz,2H),2.57(d,J＝11.5Hz,2H),2.44(s,1H),1.63～1.06(m,6H).

MS(ESI,[M+H]⁺)m/z：436.1.

Example 436- ((5-chloro-2- ((4-morpholinylphenyl) amino) pyrimidin-4-yl) amino) benzo [ c ] [1,2] oxaborzol-1 (3H) -ol (Compound I-43) preparation

Placing compound 3(0.5g,1.69mmol), compound 6-8(361mg,2.02mmol) and trifluoroacetic acid (0.38mL,5.07mmol) in a 100mL three-necked flask, adding 10mL of 2-butanol, replacing with nitrogen, heating in oil bath under reflux for 5h, after the reaction is finished, evaporating the solvent under reduced pressure. The residue was taken up in 30mL of dichloromethane and 20mL of water and the pH was adjusted to 8 with saturated aqueous sodium carbonate solution. The layers were separated and the aqueous phase was extracted twice more with 20mL of dichloromethane. The water phase is emulsion, and is filtered to obtain off-white powdery solid. The solid was dried under vacuum at 50 ℃ for 4 hours to give Compound I-43(400 mg).

¹H NMR(500MHz,DMSO-d₆)δ8.99(s,1H),8.84(s,1H),8.07(s,1H),7.86(s,1H),7.64(d,J＝8.0Hz,1H),7.43～7.40(m,3H),6.78～6.73(m,2H),5.02(s,2H),3.73(t,J＝4.5,5.0Hz,4H),2.98(t,J＝4.5,5.0Hz,4H).

MS(ESI,[M+H]⁺)m/z：438.1.

Example preparation of 446- ((5-chloro-2- ((4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) amino) pyrimidin-4-yl) amino) benzo [ c ] [1,2] oxaborzol-1 (3H) -ol (Compound I-44)

Compound 3(0.5g,1.69mmol), compound 6-9(418mg,2.02mmol) were placed in a 100mL three-necked flask, 5mL of 2-butanol was added, trifluoroacetic acid (0.38mL,5.07mmol) was further added thereto, nitrogen gas was replaced, the mixture was heated in an oil bath under reflux for 4 hours, and the solvent was removed by concentration under reduced pressure after the completion of the reaction. Ammonia gas in methanol was added to adjust pH 8, and methanol was added to the solution. Column chromatography gave the crude product, which was slurried with ethyl acetate (5mL) and filtered under suction to give compound I-44(340 mg).

¹H NMR(500MHz,DMSO-d₆)δ9.18(s,1H),9.05(s,1H),8.86(s,1H),8.08(s,1H),7.85(s,1H),7.64(d,J＝8.0Hz,1H),7.46～7.40(m,3H),6.71(d,J＝9.0Hz,2H),5.02(s,2H),3.98(t,J＝6.0,5.5Hz,2H),2.77(t,J＝5.5,6.0Hz,2H),2.69～2.33(m,4H),1.69(t,J＝3.5,3.0Hz,4H).

MS(ESI,[M+H]⁺)m/z：466.1.

Example 456 preparation of- ((2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) benzo [ c ] [1,2] oxaborzol-1- (3H) -ol (Compound I-45)

Compound 2(2.0g,13.4mmol), compounds 1-9(2.0g,13.4mmol), n-butanol (30mL), DIPEA (4.4mL,26.8mmol) were placed in a 100mL three-necked flask, replaced with nitrogen, heated in an oil bath under reflux for 9h, and the solvent was dried by spinning after the reaction was complete to give a brown oil. 60mL of water was added to the oil, sonicated until a solid appeared, and filtered with suction to give a yellow solid. The yellow solid was slurried with 10mL of ethanol and suction filtered to give off-white powder compound 3-23(1.84 g).

The compound 3-23(0.5g,2.3mmol) and the compound 6-1(484mg,2.5mmol) were placed in a 100mL three-necked flask, 5mL of 2-butanol was added, trifluoroacetic acid (0.5mL,6.9mmol) was further added thereto, nitrogen gas was replaced, the mixture was heated in an oil bath under reflux for 3 hours, and the solvent was spin-dried after the reaction. Ammonia gas in methanol was added to adjust pH 8, and methanol was added to the solution. And (4) performing column chromatography to obtain a crude product. The crude product was purified by TLC to give Compound I-45(110 mg).

¹H NMR(500MHz,DMSO-d₆)δ9.40(s,1H),9.28(s,1H),8.93(s,1H),8.15(s,1H),7.95(d,J＝5.5Hz,1H),7.78(d,J＝8.0Hz,1H),7.61(d,J＝7.5Hz,2H),7.32(d,J＝8.0Hz,1H),6.85(d,J＝9.0Hz,2H),6.21(d,J＝6.0Hz,1H),4.97(s,2H),3.08(t,J＝4.5,4.5Hz,4H),2.51(t,J＝5.0,5.0Hz,4H),2.29(s,3H).

MS(ESI,[M+H]⁺)m/z：417.1.

Example preparation of 467- ((5-chloro-2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) benzo [ c ] [1,2] oxaborzol-1 (3H) -ol (Compound I-46)

Compound 3-14(500mg,1.69mmol), compound 6-1(387mg,2.02mmol), 2-butanol (5mL) and trifluoroacetic acid (0.4mL,5.07mmol) were placed in a 25mL pressure resistant tube and reacted with microwave heating at 140 ℃ for 2 hours. The reaction mixture was filtered with suction, and the filter cake was washed with a mixed solvent of ethanol and methylene chloride (10mL:10 mL). The filtrate was evaporated to dryness under reduced pressure to give an oil, which was dissolved in 30mL of dichloromethane, the pH was adjusted to 8 with saturated aqueous sodium carbonate solution, and the organic phase was separated and taken out. The aqueous phase was extracted with 15mL dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate and chromatographed to give the crude product. The crude product was slurried with ethanol (10mL) and suction filtered to give a white solid, compound I-46(140 mg).

¹H NMR(500MHz,DMSO-d₆)δ9.60(s,1H),9.22(s,1H),8.45(s,1H),8.40(s,1H),8.17(s,1H),7.48～7.41(m,3H),7.10(d,J＝7.5Hz,1H),6.90(d,J＝9.0Hz,2H),5.03(s,2H),3.09(t,J＝4.5,5.0Hz,4H),2.47(t,J＝4.5,5.0Hz,4H),2.23(s,3H).

MS(ESI,[M+H]⁺)m/z：451.2.

Example preparation of 471- (4- ((5-chloro-4- ((1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxazol-5-yl) amino) pyrimidin-2-yl) amino) phenyl) -4-methylpiperazine-1, 4-dimesylate (Compound I-47)

The compound 3-31(1.5g,5.2mmol) and the compound 6-1(1.19g,6.2mmol) were placed in a 250mL three-necked flask, 15mL of 2-butanol was added thereto, trifluoroacetic acid (1.0mL,15.0mmol) was further added thereto, nitrogen gas was replaced, the mixture was heated under reflux for 6 hours in an oil bath, and after the reaction was completed, the solvent was removed by concentration under reduced pressure. Chloroform was added to the residue until the solution became clear, a saturated aqueous solution of sodium hydrogencarbonate was adjusted to pH 7, and the organic phase was separated and washed once with saturated brine. Drying with anhydrous sodium sulfate, concentrating under reduced pressure to dryness, purifying by column chromatography to obtain brown crude product, pulping the crude product with ethyl acetate (10mL), vacuum filtering to obtain off-white solid (1g), suspending in acetone, adding 0.22g methanesulfonic acid, heating in 50 deg.C oil bath, stirring for 40 min, and concentrating under reduced pressure to remove solvent. Adding ethanol, concentrating under reduced pressure to dry, and repeating for 2 times. Acetone (6mL) was slurried and suction filtered to give a white solid, Compound I-47(517 mg).

¹H NMR(500MHz,DMSO-d₆)δ9.88(s,1H),9.70(s,2H),8.29(s,1H),7.73(d,J＝7.5Hz,2H),7.56(d,J＝7.5Hz,1H),7.34(d,J＝8.5Hz,2H),6.92(d,J＝8.5Hz,2H),4.93(s,2H),3.78(d,J＝13.0Hz,2H),3.54(d,J＝11.5Hz,2H),3.20～2.88(m,7H),2.41(s,6H).

MS(ESI,[M+H]⁺)m/z：451.0.

Example 487 preparation of- ((5-chloro-2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) -3, 4-dihydro-1H-benzo [ c ] [1,2] boran-1-ol (Compound I-48)

Compound 3-18(0.5g,1.613mmol) and compound 6-1(0.37g,1.694mmol) were dissolved in 2-butanol (8mL) with stirring, trifluoroacetic acid (0.55g,4.839mmol) was added, and the reaction was heated with microwave at 160 ℃ for 1.5 hours. And after the reaction is finished, adding 10mL of purified water and 10mL of dichloromethane to dilute the reaction solution, adjusting the pH value of a water layer to 7-8 by using a saturated sodium bicarbonate solution to generate a large amount of gray solid, and performing suction filtration on the suspension to obtain a white-like solid. Dissolving the solid in 10ml of methanol, heating until the solid refluxes, closing the heating, naturally cooling to room temperature, and carrying out suction filtration to obtain the off-white solid. Drying in vacuo afforded Compound I-48(247 mg).

¹H NMR(500MHz,DMSO-d₆)δ8.976(s,1H),8.755(s,1H),8.412(s,1H),8.050(s,1H),7.798～7.794(m,1H),7.596～7.581(m,1H),7.397～7.379(m,2H),7.208～7.191(m,1H),6.732～6.714(m,2H),4.122～4.099(t,2H),3.025～3.005(m,4H),2.558～2.873(m,2H),2.454～2.434(m,4H),2.221(s,3H).

¹³C NMR(125MHz,DMSO-d₆)δ158.40,156.73,146.45,133.00,127.20,120.85,116.13,63.83,55.18,49.37,46.25,31.97.

MS(ESI,[M+H]⁺)m/z：465.1.

Example preparation of 496- ((5-chloro-2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -5-fluorobenzo [ c ] [1,2] oxaborzol-1 (3H) -ol (Compound I-49)

Compounds 3-32(0.5g,1.59mmol) and 6-1(0.367g,1.67mmol) were dissolved in 2-butanol (8mL) and stirred to dissolve, trifluoroacetic acid (0.54g,4.78mmol) was added, and the reaction was heated to reflux for 6 hours. After the reaction is finished, the 2-butanol is removed by rotary evaporation under reduced pressure. 10mL of purified water and 10mL of methylene chloride were added thereto, and the pH of the aqueous layer was adjusted to 7 to 8 with a saturated aqueous solution of sodium bicarbonate to obtain a suspension. The suspension was suction filtered to give an off-white solid. Drying in vacuo afforded Compound I-49(310 mg).

¹H NMR(500MHz,DMSO-d₆)δ9.269(s,1H),8.980(s,1H),8.824(s,1H),8.066(s,1H),7.765～7.750(m,2H),7.437～7.417(m,1H),7.261～7.244(m,2H),6.627～6.609(m,2H),5.042(s,2H),3.184～3.173(m,4H),2.999(br,4H),2.280(s,3H).

¹³C NMR(125MHz,DMSO-d₆)δ158.32,157.53,131.76,120.26,116.06,109.78,109.60,70.15,54.93,49.07.

MS(ESI,[M+H]⁺)m/z：469.2.

Example preparation of- ((5-chloro-2- ((4- (4- (dimethylamino) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) benzo [ c ] [1,2] oxaborzol-1 (3H) -ol (Compound I-50)

Compound 3(2g,6.76mmol) and compound 6-10(1.55g,7.10mmol) were dissolved in 2-butanol (20mL) with stirring, trifluoroacetic acid (2.31g,20.28mmol) was added, and the reaction was heated to reflux for 6 hours. And (3) after the reaction is finished, evaporating 2-butanol under reduced pressure, adding 10mL of purified water and 10mL of dichloromethane into the residue, adjusting the pH value of a water layer to 7-8 by using a saturated sodium bicarbonate solution to obtain a suspension, carrying out suction filtration on the suspension to obtain an off-white solid, and carrying out vacuum drying to obtain a compound I-50(1 g).

¹H NMR(500MHz,CDCl₃-d₁)δ8.767～8.744(m,2H),8.481～8.465(m,1H),8.205～8.157(m,2H),8.127～8.107(m,1H),7.685～7.653(m,2H),5.912(s,2H),4.430(br,2H),3.483～3.444(m,2H),3.134-3.119(m,7H),2.746(br,2H),2.484～2.462(m,2H).

¹³C NMR(125MHz,CDCl₃-d₁)δ161.96,160.01,157.60,153.37,150.99,141.03,136.36,129.22,127.55,125.24,125.16,121.56,108.20,75.07,65.99,54.19,44.97,31.69.

MS(ESI,[M+H]⁺)m/z：479.1.

Example preparation of 514- ((5-chloro-2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) benzo [ c ] [1,2] oxaborzol-1 (3H) -ol (Compound I-51)

The compounds 3-33(0.5g,1.69mmol) and 6-1(0.34g,1.77mmol) were dissolved in 2-butanol (8mL) with stirring, and trifluoroacetic acid (0.578g,5.07mmol) was added thereto, followed by reaction with microwave heating at 140 ℃ for 2 hours. After the reaction, the solvent was distilled off under reduced pressure to give a brown oil. The reaction solution was diluted with 10mL of purified water and 10mL of dichloromethane, and the pH of the aqueous layer was adjusted to 7-8 with a saturated aqueous solution of sodium bicarbonate to give a large amount of gray solid. The suspension was filtered with suction to give a grey solid. 50mL of ethanol is added into the mixture to be heated and dissolved, then the mixture is naturally cooled to room temperature, and a sample is filtered by suction to obtain a gray solid. Drying in vacuo afforded Compound I-51(180 mg).

¹H NMR(500MHz,CDCl₃-d₁)δ8.956-8.889(m,1H),8.644～8.526(m,2H),8.439～8.267(m,2H),8.248～8.094(m,2H),7.759～7.607(m,2H),6.023～5.997(m,2H),4.153(br,4H),3.751(br,4H),3.441(s,3H).

¹³C NMR(125MHz,CDCl₃-d₁)δ161.84,160.34,157.84,152.23,150.05,136.83,135.65,132.19,131.80,131.11,124.72,121.12,108.10,74.20,58.46,53.03,48.95.

MS(ESI,[M+H]⁺)m/z：451.1.

Example 526 preparation of- ((5-fluoro-2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) benzo [ c ] [1,2] oxaborzol-1 (3H) -ol (Compound I-52)

Compound 3-22(1.0g,3.57mmol) and compound 6-1(0.72g,3.75mmol) were dissolved in 2-butanol (8mL) with stirring, trifluoroacetic acid (1.22g,10.71mmol) was added, and the reaction was heated with microwave at 160 ℃ for 2 hours. After the reaction, the solvent was distilled off under reduced pressure to give a brown oil. The reaction solution was diluted with 10mL of purified water and 10mL of dichloromethane, and the pH of the aqueous layer was adjusted to 7-8 with a saturated sodium bicarbonate solution. The dichloromethane layer was evaporated under reduced pressure to remove the solvent to give an oil. The oil was dissolved by heating with 10mL of methanol, then cooled naturally to room temperature, and the sample was filtered with suction to give a gray solid. Drying in vacuo afforded Compound I-52(200 mg).

¹H NMR(500MHz,CDCl₃-d₁)δ8.843(s,1H),8.689～8.682(m,1H),8.586～8.570(m,1H),8.278～8.242(m,3H),8.154～8.137(m,1H),7.749～7.731(m,2H),5.944(s,3H),4.043～4.035(m,4H),3.586(br,4H),3.282(s,3H).

¹³C NMR(125MHz,CDCl₃-d₁)δ159.79,154.50,154.42,152.95,150.15,145.64,143.55,143.38,141.28,137.36,128.51,126.65,125.23,124.88,121.37,75.09,58.59,53.42,49.14.

MS(ESI,[M+H]⁺)m/z：435.1

Example 534 preparation of (4- ((5-chloro-4- ((1-hydroxy-1, 3-dihydrobenzo [ c ] [1,2] oxazol-6-yl) amino) pyrimidin-2-yl) amino) phenyl) thiomorpholine 1, 1-dioxide (Compound I-53)

Compound 3(0.498g,1.68mmol) and compound 6-11(0.40g,1.76mmol) were dissolved in 2-butanol (8mL) with stirring, and trifluoroacetic acid (0.574g,5.04mmol) was added and the reaction was heated with a microwave at 140 ℃ for 2 hours. And after the reaction is finished, adding 5mL of purified water and 10mL of chloroform to dilute the reaction solution, and adjusting the pH value of a water layer to 7-8 by using a saturated sodium bicarbonate solution. The aqueous layer was discarded, the organic layer was evaporated under reduced pressure to remove the solvent, 10mL of ethanol was added to the residue and heated to reflux to dissolve it, then it was naturally cooled to room temperature, the sample was filtered under suction to obtain a gray solid, which was dried under vacuum to obtain Compound I-53(400 mg).

¹H NMR(500MHz,DMSO-d₆)δ9.172(s,1H),9.044(s,1H),8.856(s,1H),8.080(s,1H),7.855(s,1H),7.652～7.636(m,1H),7.460～7.404(m,3H),6.833～6.816(m,2H),5.026(s,2H),3.640(br,4H),3.105(br,4H).

¹³C NMR(125MHz,DMSO-d₆)δ158.31,156.83,155.03,142.97,137.80,133.71,127.62,126.60,121.75,120.91,116.93,103.61,70.36,50.34,48.14.

MS(ESI,[M+H]⁺)m/z：486.0.

Example preparation of 546- ((5-chloro-2- ((4- (4- (ethylsulfonyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) benzo [ c ] [1,2] oxaborzol-1 (3H) -ol (Compound I-54)

Compound 3(0.537g,1.27mmol) and compound 6-12(0.36g,1.33mmol) were dissolved in 2-butanol (8mL), and trifluoroacetic acid (0.45g,3.99mmol) was added thereto with stirring and dissolved, followed by reaction with microwave heating at 140 ℃ for 2 hours. After the reaction, the solvent was distilled off under reduced pressure. The reaction solution was diluted with 10mL of purified water and 50mL of ethyl acetate, and the pH of the aqueous layer was adjusted to 7-8 with a saturated aqueous solution of sodium bicarbonate. Extraction was performed twice with ethyl acetate (50mL), the combined organic layers were evaporated under reduced pressure to remove the solvent, and the residue was purified by column chromatography and dried in vacuo to give compound I-54(120 mg).

¹H NMR(500MHz,DMSO-d₆)δ9.169(s,1H),9.026(s,1H),8.848(s,1H),8.070(s,1H),7.862～7.859(m,1H),7.647～7.633(m,1H),7.445～7.403(m,3H),6.783～6.765(m,2H),5.032(s,2H),3.305～3.282(m,2H),3.125～3.066(m,8H),1.261～1.231(t,3H).

¹³C NMR(125MHz,DMSO-d₆)δ158.31,156.84,155.01,145.83,137.82,133.84,127.59,126.60,121.75,120.57,117.12,103.54,70.36,56.50,49.87,45.69,42.89,19.02,7.95.

MS(ESI,[M+H]⁺)m/z：528.

Experimental example 1 Activity experiments on inhibition of EGFR (WT), EGFR (T790M/L858R) and EGFR (T790M) in vitro

1.1 EGFR (WT) inhibitory Activity Screen

With kinase buffer (50mM HEPES, 10mM MgCl)₂2mM DTT, 1mM EGTA, 0.01% Tween 20) 100 ng/. mu.L of EGFR (WT) stock solution was diluted, 6. mu.L of diluted EGFR (WT) stock solution (final concentration of 0.5 ng/. mu.L) was added to each well, and different compounds of each concentration dissolved in DMSO were added to each well, 7 different concentrations were set for each compound, and 2 duplicate wells were set for a blank control well (containing no enzyme) and a negative control well (containing enzyme, adding vehicle DMSO). After the enzyme had reacted with the compound or vehicle for 10 minutes, 5X 25. mu.M ATP (final concentration of 5. mu.M) prepared with kinase buffer and 5X 0.5. mu.M substrate (final concentration of 0.1. mu.M, ULight-poly GT) were mixed in a 1:1 ratio and then 4. mu.L of the mixture per well was added to the wells; after the plate is sealed and the plate is coated with the membrane, after 1 hour at room temperature, 5. mu.L of 4X 40mM EDTA (final concentration 10mM) is added to each well for 5min at room temperature, 5. mu.L of 4X 8nM detection reagent (final concentration 2nM, Eu-anti-phosphorus-tyrosinanthrobinding) is added to each well, the mixture is incubated for 1 hour at room temperature, and the detection is carried out by an Htrf method of a plate reader (excitation 320nM, emission 665 nM). Calculating the inhibition ratio, and calculating IC₅₀Values (table 1).

1.2 EGFR (T790M/L858R) inhibition Activity screening

With kinase buffer (50mM HEPES, 10mM MgCl)₂2mM DTT, 1mM EGTA, 0.01% Tween 20) 70 ng/. mu.L of EGFR (T790M L858R) stock solution was diluted, 6. mu.L of diluted EGFR (T790M L858R) (final concentration of 0.02 ng/. mu.L) was added to each well, 7 different concentrations of each compound were added to each well, and blank control wells (containing no enzyme) and negative pairs were set for each compoundA plurality of wells (containing enzyme and adding a solvent DMSO) are provided with 2 wells. After the enzyme reacts with the compound or the solvent for 30min, 5 × 5 μ M ATP (final concentration of 1 μ M) prepared with a kinase buffer solution and 5 × 0.5 μ M substrate (final concentration of 0.1 μ M, ULight-poly GT) are mixed in a ratio of 1:1, and then 4 μ L of the mixture per well is added to the well; after the plate is sealed and the plate is covered with a membrane, after 1 hour at room temperature, 5. mu.L of 4X 40mM EDTA (final concentration 10mM) is added to each well for 5min at room temperature, and 5. mu.L of 4X 8nM detection reagent (final concentration 2nM, Eu-anti-phosphorus-tyrosinanthroside) is added to each well for 1 hour at room temperature; and (3) detecting by a plate reader Htrf method (excitation is 320nm, and emission is 665 nm). Calculating the inhibition ratio, and calculating IC₅₀Values (table 1).

1.3 EGFR (T790M) inhibitory Activity screening

With kinase buffer (50mM HEPES, 50mM MgCl)₂、10mM MnCl₂1mM DTT, 25mM SEB) 114.8 ng/. mu.L of EGFR (T790M) stock was diluted, 6. mu.L of diluted EGFR (T790M) (final concentration of 1.5 ng/. mu.L) was added to each well, DMSO-solubilized various concentrations of different compounds were added to each well, 7 concentrations of each compound were set, and 2 replicate wells were set for a blank control well (no enzyme) and a negative control well (enzyme-containing, vehicle DMSO). After the enzyme reacts with the compound or vehicle for 10min, 5 × 20 μ M ATP (final concentration of 4 μ M) prepared with kinase buffer and 5 × 5 μ M Substrate (final concentration of 1 μ M TK Substrate-Substrate) were mixed at a ratio of 1:1, and then 4 μ L of the mixture per well was added to the wells; after the plate is sealed and the membrane is sealed, after the reaction is carried out for 1h at room temperature, 5 mu L of 1 multiplied TK Antibody and 62.5nM XL-665 are added into each hole, and after the mixture is mixed according to the ratio of 1:1, 10 mu L of each hole is added into each hole; after the plate is sealed by a sealing film, incubating for 1 hour at room temperature; and (3) detecting by a plate reader Htrf method (excitation is 320nm, and emission is 665 nm).

In the present invention, EGFR (WT) refers to wild EGFR; EGFR (T790M/L858R) refers to EGFR with double mutations of T790M and L858R; EGFR (T790M) refers to EGFR with the T790M mutation.

Table 1 shows the activity data of the compounds on wild-type EGFR, two mutant EGFR (T790M/L858R, T790M). Provision of a Compound whose Activity is designated "AIC of₅₀Less than or equal to 10 nM; IC provided by a compound whose activity is designated as "B₅₀Is 10-100 nM; IC provided by a compound whose activity is designated as "C₅₀Is 100-1000 nM; activity assignment IC provided by "D" Compounds₅₀1000-10000 nM; IC provided by a compound whose activity is designated as "E₅₀Is more than or equal to 10000 nM.

Table 1: inhibitory Activity of Compounds on EGFR (WT), EGFR (T790M/L858R) and EGFR (T790M)

Experimental example 2 inhibitory Activity test on in vitro kinases ALK (WT), ALK (C1156Y) and ALK (L1196M)

2.1 ALK (WT) inhibitory Activity Screen

With kinase buffer (50mM HEPES, 10mM MgCl)₂2mM DTT, 1mM EGTA, 0.01% Tween 20) 330 ng/. mu.L of ALK (WT) stock solution was diluted, 6. mu.L of diluted ALK (WT) (final concentration of 0.01 ng/. mu.L) was added to each well, DMSO-dissolved different compounds at respective concentrations were added to each well, 7 concentrations of each compound were set, a blank control well (containing no enzyme) and a negative control well (containing enzyme, adding vehicle DMSO) were set, and 2 replicate wells were set. After the enzyme reacts with the compound or the solvent for 10min, 50uM ATP (final concentration of 10uM) prepared by using a kinase buffer solution and 0.5 muM substrate (final concentration of 0.1 muM, ULight-poly GT) are mixed according to a ratio of 1:1, and then 4 muL of the mixture is added into each well; after the plate was covered with a membrane, after reaction at room temperature for 2 hours, 5. mu.L of 40mM EDTA (final concentration: 10mM) was added to each well, 5min at room temperature, and 5. mu.L of 8nM reagent (final concentration) was added to each wellEu-anti-phosphorus-tyrosine antibody at a concentration of 2 nM), incubating at room temperature for 1 hour; BMG instruments read plates (excitation 620nm, emission 665 nm). Calculating the inhibition ratio, and calculating IC₅₀Values (table 2).

2.2 ALK (C1156Y) inhibition Activity screening

With kinase buffer (50mM HEPES, 10mM MgCl)₂2mM DTT, 1mM EGTA, 0.01% Tween 20) 325 ng/. mu.L of ALK (C1156Y) stock solution was diluted, 6. mu.L of diluted ALK (C1156Y) (final concentration of 0.03ng/ul) was added to each well, DMSO-dissolved different compounds were added to each well at respective concentrations, 7 concentrations were set for each compound, and blank control wells (no enzyme) and negative control wells (enzyme-containing, vehicle DMSO-added) were set at 2 duplicate wells. After the enzyme has reacted with the compound or vehicle for 10min, 5 × 50 μ M ATP (final concentration 10 μ M) prepared in kinase buffer is mixed with 5 × 500nM substrate (final concentration 100nM, ULight-poly-GT) in a 1:1 ratio, and 4 μ L of the mixture per well is added to the wells; after the plate was sealed and the plate was coated with a membrane, after reacting at room temperature for 2 hours, 5. mu.L of 4X 40mM EDTA (final concentration: 10mM) was added to each well for 5 minutes at room temperature, and 5. mu.L of 4X 8nM detection reagent (final concentration: 2nM, Ab detection antibody, PE) was added to each well and incubated at room temperature for 1 hour; BMG instruments read plates (excitation 320or 340nm, emission 665 nm). Calculating the inhibition ratio, and calculating IC₅₀Values (table 2).

2.3 ALK (L1196M) inhibitory Activity screening

With kinase buffer (50mM HEPES, 10mM MgCl)₂2mM DTT, 1mM EGTA, 0.01% Tween 20) 271 ng/. mu.L of ALK (L1196M) stock solution was diluted, 6ul of diluted ALK (L1196M) (final concentration of 0.03 ng/. mu.L) was added to each well, DMSO-dissolved different compounds at various concentrations were added to the wells, 7 concentrations were set for each compound, and blank control wells (no enzyme) and negative control wells (enzyme-containing, vehicle DMSO-added) were set for 2 replicate wells. After the enzyme has reacted with the compound or vehicle for 10min, 5 × 50 μ M ATP (final concentration 10 μ M) prepared in kinase buffer is mixed with 5 × 500nM substrate (final concentration 100nM, ULight-poly-GT) in a 1:1 ratio, and 4 μ L of the mixture per well is added to the wells; sealing plate filmAfter sealing the plates, after reacting at room temperature for 2 hours, 5. mu.L of 4X 40mM EDTA (final concentration 10mM) was added to each well, and at room temperature for 5min, 5. mu.L of 4X 8nM detection reagent (final concentration 2nM, Ab detection antibody, PE) was added to each well, followed by incubation at room temperature for 1 hour; BMG instruments read plates (excitation 320or 340nm, emission 665 nm). Calculating the inhibition ratio, and calculating IC₅₀Values (table 2).

In the present invention, ALK (WT) means wild ALK, unless otherwise specified; ALK (C1156Y) refers to ALK with a C1156Y mutation; ALK (L1196M) refers to ALK with the L1196M mutation.

Table 2 shows the activity data of compounds on ALK (WT), ALK (C1156Y), ALK (L1196M). Activity IC provided by a Compound designated "A₅₀Less than or equal to 30 nM; IC provided by a compound whose activity is designated as "B₅₀Is 30-100 nM; IC provided by a compound whose activity is designated as "C₅₀Is 100-1000 nM; activity assignment IC provided by "D" Compounds₅₀Is more than or equal to 1000 nM.

Table 2: inhibitory Activity of Compounds on ALK (WT), ALK (C1156Y) and ALK (L1196M)

Experimental example 3 inhibition of in vitro kinase JAK1, JAK2, and JAK3

3.1 JAK1 inhibitory Activity screening

With kinase buffer (50mM HEPES, 10mM MgCl)₂2mM DTT, 1mM EGTA, 0.01% Tween 20) 50 ng/. mu.L of JAK1 stock solution was diluted, 6. mu.L of diluted JAK1 (final concentration of 0.5 ng/. mu.L) was added to each well, DMSO-dissolved different compounds were added to each well, 7 concentrations of each compound were set, and blank control wells (containing no enzyme) and negative control wells were set simultaneously(containing enzyme, adding DMSO) and setting 2 multiple holes. After 30min of reaction of the enzyme with the compound or vehicle, 5 × 250 μ M ATP (final concentration 50 μ M) and 5 × 0.5 μ M substrate (final concentration 0.1 μ M, μ M Light-poly GT) in kinase buffer were mixed as 1:1 mixing, adding 4 mu L of mixture into each hole; after the plate was sealed with a membrane, after reacting at room temperature for 2 hours, 5. mu.L of 4X 40mM EDTA (final concentration: 10mM) was added to each well for 5 minutes at room temperature, and 5. mu.L of 4X 8nM detection reagent (final concentration: 2nM, Ab detection antibody, PE) was added to each well and incubated at room temperature for 1 hour; htrf method (excitation 620nm, emission 665 nm). Calculating the inhibition ratio, and calculating IC₅₀Values (table 1).

3.2 JAK2 inhibitory Activity screening

With kinase buffer (50mM HEPES, 10mM MgCl)₂2mM DTT, 1mM EGTA, 0.01% Tween 20) 50 ng/. mu.L of JAK2 stock solution was diluted, 6. mu.L of diluted JAK2 (final concentration of 0.005 ng/. mu.L) was added to each well, DMSO-dissolved different compounds at respective concentrations were added to each well, 7 concentrations of each compound were set, and 2 duplicate wells were set with a blank control well (containing no enzyme) and a negative control well (containing enzyme, adding vehicle DMSO). After 30min of reaction of the enzyme with the compound or vehicle, 5 × 100 μ M ATP (final concentration 20 μ M) and 5 × 0.5 μ M substrate (final concentration 0.1 μ M, μ M Light-poly GT) in kinase buffer were mixed as 1:1 mixing, adding 4 mu L of mixture into each hole; after the plate was sealed and the plate was coated with a membrane, after reacting at room temperature for 2 hours, 5. mu.L of 4X 40mM EDTA (final concentration: 10mM) was added to each well for 5 minutes at room temperature, and 5. mu.L of 4X 8nM detection reagent (final concentration: 2nM, Ab detection antibody, PE) was added to each well and incubated at room temperature for 1 hour; htrf method (excitation 620nm, emission 665 nm). Calculating the inhibition ratio, and calculating IC₅₀Values (table 1).

3.3 JAK3 inhibitory Activity screening

With kinase buffer (50mM HEPES, 10mM MgCl)₂2mM DTT, 1mM EGTA, 0.01% Tween 20) 50 ng/. mu.L of JAK3 stock solution was diluted, 6. mu.L of diluted JAK3 (final concentration of 0.01 ng/. mu.L) was added to each well, and different compounds dissolved in DMSO at respective concentrations were added to each wellEach compound was set at 7 concentrations, blank control wells (no enzyme) and negative control wells (enzyme, vehicle DMSO) were set at 2 replicate wells. After 30min of reaction of the enzyme with the compound or vehicle, 5 × 100 μ M ATP (final concentration 20 μ M) and 5 × 0.5 μ M substrate (final concentration 0.1 μ M, μ M Light-poly GT) in kinase buffer were mixed as 1:1 mixing, adding 4 mu L of mixture into each hole; after the plate was sealed and the plate was coated with a membrane, after reacting at room temperature for 2 hours, 5. mu.L of 4X 40mM EDTA (final concentration: 10mM) was added to each well for 5 minutes at room temperature, and 5. mu.L of 4X 8nM detection reagent (final concentration: 2nM, Ab detection antibody, PE) was added to each well and incubated at room temperature for 1 hour; htrf method (excitation 620nm, emission 665 nm). Calculating the inhibition ratio, and calculating IC₅₀Values (table 1).

3.4 TYK2 inhibition Activity screening

With kinase buffer (50mM HEPES, 10mM MgCl)₂2mM DTT, 1mM EGTA, 0.01% Tween 20) 50ng/μ L of TYK2 stock solution was diluted, 6 μ L of diluted TYK2 (final concentration of 0.5ng/μ L) was added per well, DMSO-dissolved different compounds at various concentrations were added to the wells, 7 concentrations per compound, blank control empty (no enzyme) and negative control wells (enzyme containing, vehicle DMSO), 2 replicate wells. After 30min of reaction of the enzyme with the compound or vehicle, 5 × 100 μ M ATP (final concentration of 20 μ M) and 5 × 0.5 μ M substrate (final concentration of 0.1 μ M, μ Light-poly GT) in kinase buffer were mixed as described in 1:1 mixing, adding 4 mu L of mixture into each hole; after the plate was sealed and the plate was coated with a membrane, after reacting at room temperature for 2 hours, 5. mu.L of 4X 40mM EDTA (final concentration: 10mM) was added to each well for 5 minutes at room temperature, and 5. mu.L of 4X 8nM detection reagent (final concentration: 2nM, Ab detection antibody, PE) was added to each well and incubated at room temperature for 1 hour; plate reading (excitation 620nm, emission 665nm) was done with MD instruments. Calculating the inhibition ratio, and calculating IC₅₀Values (table 3).

Table 3 shows the activity data of compounds against JAK1, JAK2, JAK 3. Activity IC provided by a Compound designated "A₅₀Less than or equal to 10 nM; IC provided by a compound whose activity is designated as "B₅₀Is 10-100 nM; IC provided by a compound whose activity is designated as "C₅₀Is 100-1000 nM; activity assignment IC provided by "D" Compounds₅₀Is more than or equal to 1000 nM.

Table 3: inhibitory Activity of Compounds against JAK1, JAK2, JAK3, TYK2

In the activity test experiments described above, the following terms, if not otherwise specified, have the following meanings:

EDTA refers to ethylene diamine tetraacetic acid; EGTA refers to ethylene glycol bis (2-aminoethyl ether) tetraacetic acid; DTT refers to dithiothreitol; 0.01% Tween 20 refers to Tween 20 with a mass fraction of 0.01%; "4-fold gradient dilution" means that 3 volumes of the diluted solution are added to 1 volume of stock solution 1 to give stock solution 2; then 1 volume of stock solution 2 is taken and added with 3 volumes of diluted solution to obtain stock solution 3; by analogy, solutions with different concentrations are obtained; "Final concentration" means the concentration in the whole reaction system at the start of the reaction, and is based on the total volume of the reaction; "X" indicates a multiple, i.e., a multiple of the current concentration based on the final concentration.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof,

wherein,

x is selected from NH or O;

R³And R⁷Each independently selected from hydrogen or alkoxy;

R^aselected from alkyl, alkenyl, alkynyl, cyano or cycloalkyl;

R^bselected from alkyl groups;

cy is selected fromOr

R²Each independently selected from fluoro, chloro, bromo, iodo or alkoxy;

n is 0 to 4;

Z¹and Z²Each independently selected from hydrogen or C₁-C₆An alkyl group;

the A ring is a 5-6 membered ring, which is optionally substituted with alkyl.

2. A compound of formula (II) or a compound of formula (III) or a pharmaceutically acceptable salt thereof,

wherein,

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷x, n and Z²Is as defined in claim 1;

m is 1 or 2;

R⁸and R⁹Each independently selected from hydrogen or C₁-C₆An alkyl group.

3. A compound of formula (V) or formula (VI) or a pharmaceutically acceptable salt thereof,

wherein,

R¹、R²、R³、R⁵、R⁷、R⁸、R⁹、m、n、Z²and X is as defined in claim 2.

4. A compound of formula (VII) or a pharmaceutically acceptable salt thereof,

wherein,

R¹、R³、R⁴、R⁶、R⁷x and Cy are as defined in claim 1;

Y¹is selected from N or CH;

Y²selected from NH, CH₂S or O;

q is 0 to 11;

R^bselected from alkyl groups;

R^cand R^dEach independently selected from hydrogen, alkyl or cycloalkyl.

5. A compound of formula (VIII) or a compound of formula (IX) or a pharmaceutically acceptable salt thereof,

wherein,

R¹、R²、R³、R⁴、R⁶、R⁷x, n and Z²Is as defined in claim 1;

R¹²、Y¹、Y²and q is as defined in claim 4;

m is 1 or 2;

6. The following compounds, or a pharmaceutically acceptable salt thereof,

7. the following compounds are described in detail,

8. a pharmaceutical composition comprising a compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, or a compound of claim 7.

9. Use of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, a compound according to claim 7, or a pharmaceutical composition according to claim 8, in the manufacture of a medicament for the treatment of a tyrosine kinase mediated disease.

10. The use of claim 9, wherein the tyrosine kinase is selected from EGFR tyrosine kinase, ALK or JAK.