HK40074494A

HK40074494A - Heteroaryl derivative, method for producing same, and pharmaceutical composition comprising same as effective component

Info

Publication number: HK40074494A
Application number: HK42022063384.6A
Authority: HK
Inventors: 李尹镐; 姜朱曦; 姜世仁; 金焕; 金承洙; 石知润; 高利炅; 金多恩; A‧R‧韩; 柳忞汐; 黄东根; 高银和; 崔焕根; 李宣和; 孙正范; 金南斗
Original assignee: 株式会社沃若诺伊; 株式会社沃若诺伊生物; 株式会社B2S生物
Priority date: 2019-03-19
Filing date: 2022-07-11
Publication date: 2023-01-06

Description

Heteroaryl derivatives, process for preparing the same, and pharmaceutical composition containing the same as active ingredient

The application is based on the application date of 3/19/2020 and the application number of 202080022186.4, and the invention name is: a divisional application of a patent application of "a heteroaryl derivative, a process for producing the same, and a pharmaceutical composition containing the same as an active ingredient".

Technical Field

The present disclosure relates to heteroaryl derivatives, particularly 6- (isoxazolidin-2-yl) -N-phenylpyrimidin-4-amine derivatives, and more particularly to stereoisomers thereof, hydrates thereof, or pharmaceutically acceptable salts thereof, a preparation method thereof, and a pharmaceutical composition for preventing or treating cancer comprising the same as an active ingredient.

Background

Cancer is associated with a variety of environmental factors, including chemicals, radiation, and viruses, as well as changes in oncogenes, tumor suppressor genes, and genes involved in apoptosis and DNA repair. Recently, understanding of the molecular mechanisms of cancer has made targeted chemotherapy possible, which is a new therapeutic approach. Targeted therapeutics can generally be designed to target molecules characteristic of cancer cells, thereby exerting their effect. The molecular target is a gene associated with a signal transduction pathway, angiogenesis, cell matrix, cell cycle regulator, or apoptosis of cancer cells. Important targeted therapeutics currently used include signal transduction pathway inhibitors and angiogenesis inhibitors, including tyrosine kinase inhibitors. Protein tyrosine kinases have been found to play an important role in many malignancies. In particular, Epidermal Growth Factor Receptor (EGFR) is a tyrosine kinase receptor of the ErbB family, is abnormally activated in many epithelial cell tumors including non-small cell lung cancer (NSCLC), breast cancer, glioma, head and neck squamous cell carcinoma, colorectal cancer, rectal adenocarcinoma (rectal adenocarcinoma), head and neck cancer, gastric cancer, and prostate cancer, and it is well known that activation of EGFR-tyrosine kinase leads to sustained cell proliferation, invasion of peripheral tissues, distant metastasis (distanstatiss), and angiogenesis, and increases cell survival.

Specifically, EGFR, which is one of ErbB tyrosine kinase receptor family, is a transmembrane tyrosine kinase having an extracellular ligand binding domain and an intracellular domain including a tyrosine kinase domain, and may include EGFR (referred to as ErbB1 or HER1), HER2 (referred to as ErbB2 or neu), ErbB3, and ErbB4 (referred to as HER 4). When a ligand binds to a receptor forming a homodimer or heterodimer, intracellular tyrosine kinases are activated, and signals stimulated by EGFR activate signal transduction pathways such as phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway, RAS/RAF/MAPK pathway, and JAK/STAT pathway (non-patent document 0001). EGFR is particularly overexpressed in more than half of cases of non-small cell lung cancer (NSCLC), and thus, many studies have been conducted on EGFR as a target for treatment. EGFR Tyrosine Kinase Inhibitors (TKIs) have been developed which inhibit EGFR tyrosine kinase activity, and representative drugs include gefitinib (gefitinib) (IRESSA)^TM) Erlotinib (TARCEVA)^TM) Lapatinib (TYKERB)^TM,TYVERB^TM) And so on.

Meanwhile, it was reported in 2004 that activating mutations of EGFR were associated with a response to gefitinib therapy in non-small cell lung cancer (non-patent documents 0002 to 0003). Specifically, the EGFR mutation is roughly classified into a sensitive mutation (sensitive mutation) and a resistant mutation (resistant mutation), and deletion of exon 19 and L858R point mutation of exon 21 are the most important sensitive mutations, which account for about 85% to about 90%. In particular, deletion mutations of exon 19 are known to be more highly susceptible to TKI. In contrast, the T790M point mutation of exon 20 is known to be the most important resistance mutation and found in more than 50% of acquired resistance patients (non-patent document 0004).

The somatic mutations identified so far include not only in-frame deletion of exon 19 or insertion of exon 20, but also point mutations in which a single nucleic acid residue is modified in the expressed protein (e.g., L858R, G719S, G719C, G719A, and L861Q) (non-patent documents 0005 to 0007).

Although gefitinib/erlotinib had an initial clinical effect in NSCLC patients with EGFR mutations, most patients eventually developed advanced cancer during treatment with these agents. In preliminary studies on relapse samples, secondary EGFR mutations (i.e., T790M) were identified that render gefitinib and erlotinib inhibitors ineffective against EGFR kinase activity (non-patent documents 0008 and 0009). It was confirmed in subsequent studies that about 50% (24/48) of the EGFR T790M mutations were found in tumors derived from patients resistant to gefitinib or erlotinib (non-patent documents 0010 to 0012). In patients treated with kinase inhibitors, this secondary genetic modification is caused at a position similar to the gatekeeper residue and the secondary resistance allele associated therewith (e.g., T315I in ABL in imatinib (imatinib) -resistant CML).

EGFR _ del19 or EGFR _ L858R, which are known to be EGFR mutations, are the main cause of non-small cell lung cancer and head and neck cancer, and their therapeutic drugs ereisma (Iressa) and Taseba have been developed and are currently being used in clinical practice. However, when these drugs are used in patients, acquired resistance in which EGFR secondary mutations based on the drug structure occur is observed, and this has also been found to be a major cause of actual resistance. Acquired resistance, known as the T790M mutation, at the EGFR kinase gatekeeper occurs when the first generation EGFR inhibitor is used for an average of 10 months, and thus the first generation EGFR inhibitor fails to function. In other words, EGFR _ del19_ T790M or EGFR _ L858R _ T790M double mutations occur such that existing therapeutics cannot exhibit efficacy.

[ cited documents ]

[ non-patent document ]

(non-patent document 1) Nat Rev Cancer 2007; 7:169-81.

(non-patent document 2) Science 2004; 304:1497-500.

(non-patent document 3) New England Journal of Medicine 2004; 350:2129-39.

(non-patent document 4) Clin Cancer Res 2006; 12:6494-6501.

(non-patent document 5) JCO 2003 of Fukuoka et al.

(non-patent document 6) JAMA 2003 of Kris et al.

(non-patent document 7) NEJM 2004 by Shepherd et al.

(non-patent document 8) NEJM 2005 to Kobayashi et al.

(non-patent document 9) PLOS Medicine 2005 by Pao et al.

(non-patent document 10) CCR 2006 of Kosaka et al.

(non-patent document 11) CCR 2006 of Balak et al.

(non-patent document 12) Science 2007 by Engelman et al.

Disclosure of Invention

One or more embodiments include a compound, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, which exhibits an inhibitory effect on EGFR wild type or mutant, and thus can be used for treating cancer.

One or more embodiments include a method of making a compound.

One or more embodiments include a pharmaceutical composition for preventing or treating cancer, which includes the compound, its stereoisomer, its hydrate, or a pharmaceutically acceptable salt thereof, as an active ingredient.

One or more embodiments include a pharmaceutical composition for preventing or treating cancer by inhibiting Epidermal Growth Factor Receptor (EGFR) wild type or EGFR mutants.

However, the technical problems to be solved by the present disclosure are not limited to the above technical problems, and other technical problems not mentioned will become apparent from the following description to those skilled in the art.

According to an aspect of the present disclosure, there is provided a compound represented by the following formula 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof:

[ formula 1]

Wherein, in formula 1, R¹Is hydrogen, halogen, C_1-8Alkyl, or C_1-8Alkoxy radical, wherein R₁C of (A)_1-8Alkyl and C_1-8Alkoxy is each independently unsubstituted or substituted with one or more halogen,

R²is hydrogen or-NR⁷R⁸Wherein R is⁷And R⁸Each independently is hydrogen or C_1-8Alkyl, or R⁷And R⁸Are taken together with the N atom to which they are attached to form a 3-to 12-membered heterocycloalkyl group, and R⁷And R⁸C of (A)_1-8Alkyl and 3-to 12-membered heterocycloalkyl are each independently unsubstituted or substituted with one or more substituents selected from the group consisting of: c_1-8Alkyl radical, C_1-8Alkoxy group, and C_1-8An alkylamino group(s) of an alkyl group,

R³is hydrogen, -NR⁹R¹⁰OR-OR¹¹Wherein R is⁹、R¹⁰And R¹¹Each independently is hydrogen or C_1-8Alkyl, or R⁹And R¹⁰Together with the N atom to which they are attached to form a 3-to 12-membered heterocycloalkyl or 3-to 12-membered heteroaryl, R⁹、R¹⁰And R¹¹C of (A)_1-8The alkyl, 3-to 12-membered heterocycloalkyl, and 3-to 12-membered heteroaryl are each independently unsubstituted or substituted with one or more groups selected fromSubstituent R of the group: hydroxy, C _1-8Alkyl radical, C_1-8Alkoxy radical, C_1-8Alkylamino radical, C_1-8Alkylcarbonyl, -NR¹²R¹³And 3-to 12-membered heterocycloalkyl, the substituents R further each independently being unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen; a carbonyl group; unsubstituted or via hydroxy or C_1-8Alkylamino substituted C_1-8An alkyl group; c_2-8An alkenyl group; c_1-8An alkoxy group; c_1-8An alkylamino group; c_1-8An alkylcarbonyl group; and unsubstituted or substituted by C_1-8Alkyl-substituted 3-to 12-membered heterocycloalkyl, R¹²And R¹³Each independently is hydrogen, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_1-8Alkylcarbonyl group, C_2-8Alkenylcarbonyl, or unsubstituted or substituted by C_1-8Alkyl-substituted 3-to 12-membered heterocycloalkyl,

R⁴is-NH (C ═ O) R¹⁴C＝CR¹⁵R¹⁶Wherein R is¹⁴、R¹⁵And R¹⁶Each independently of the others is hydrogen, halogen, or unsubstituted or C_1-8Alkylamino substituted C_1-8An alkyl group, a carboxyl group,

R⁵is C_1-8Alkyl, 3-to 12-membered aryl, 3-to 12-membered heteroaryl, or 3-to 12-membered heterocycloalkyl, wherein R⁵C of (A)_1-8Alkyl, 3-to 12-membered aryl, 3-to 12-membered heteroaryl, and 3-to 12-membered heterocycloalkyl are each independently unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen, cyano, unsubstituted or halogen-substituted C_1-8Alkyl radical, C_2-8Alkenyl radical, C_1-8Alkoxy radical, C _2-8Alkynyl and C_1-8Alkylamino, and

R⁶is hydrogen or C_1-8An alkyl group.

According to another aspect of the present disclosure, there is provided a method of preparing a compound of formula 1, the method comprising: preparing a compound of formula 5 from a compound of formula 4; preparing a compound of formula 6 from the compound of formula 5; and preparing a compound of formula 1 from the compound of formula 6;

[ formula 4]

[ formula 5]

[ formula 6]

[ formula 1]

Wherein, in formula 4, G is a leaving group, and R¹To R⁶Are the same as defined above.

According to another aspect of the present disclosure, there is provided a pharmaceutical composition for preventing or treating cancer, which includes a compound of the present disclosure, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, as an active ingredient.

Drawings

The above and other objects, features, and advantages of the present disclosure will become more apparent to those skilled in the art from the detailed description of exemplary embodiments of the present disclosure with reference to the accompanying drawings.

Fig. 1 shows experimental data results of confirming whether cancer is inhibited or not by observing for 21 days without administration after oral administration of the compound of example to a PDX (Exon20 ins V769_ D770ins ASV) cell line xenograft in-vivo model for 28 days.

Detailed description of the preferred embodiments

Exemplary embodiments of the present disclosure will be described in detail below with reference to the accompanying drawings. While the present disclosure has been shown and described in connection with exemplary embodiments thereof, it will be apparent to those skilled in the art that various modifications can be made without departing from the spirit and scope of the disclosure.

Hereinafter, the present disclosure will be described in detail with reference to embodiments thereof.

Embodiments of the present disclosure may be modified into various other forms, and the scope of the present disclosure is not limited to the embodiments described below. Furthermore, the embodiments of the present disclosure are provided so that this disclosure will be more fully described to those skilled in the art.

Throughout the specification, "comprising" an element means that other elements are not excluded unless otherwise specifically stated, and also means that other elements may be further included.

In the structural formulae of the present specification, the symbol "-" for bonding an atom and/or a group may represent a single bond, and the symbol "-" may represent a double bond. The above symbols may be omitted, and may also be represented as necessary, such as when a bonding atom or bonding site is specified.

In the present specification, "linkage" between atoms may include not only a case of direct linkage between atoms but also a case of indirect linkage between atoms via another atom and/or a group. In this case, the other atoms and/or groups may be oxygen, sulfur, C _1-8Alkylamino radical, C_1-8Alkylene, and the like, although the disclosure is not limited thereto, and the atom and/or the group may be substituted or unsubstituted.

In this specification, "substituted or unsubstituted" may mean that, unless otherwise specified, one or more hydrogen atoms are unsubstituted or substituted with another atom or substituent. The substituents may be one or more selected from the group consisting of: halogen (chlorine (Cl), iodine (I), bromine (Br), and fluorine (F)), C_1～10Alkyl radical, C_2～10Alkenyl radical, C_2～10Alkynyl, hydroxy, C_1～10Alkoxy, amino, nitro, mercapto, thioether, imine, cyano, phosphonic (phosphonato), phosphine, carboxyl, carbamoyl, carbamic acid, acetal, urea, thiocarbonyl, sulfonyl, sulfonamide, ketone, aldehyde, ester, acetylAcetoxy (isotoxy), amide, oxo (═ O), haloalkyl (e.g., trifluoromethyl), substituted aminoacyl and aminoalkyl, monocyclic or fused or non-fused polycyclic carbocyclic cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or monocyclic or fused or non-fused polycyclic heterocycloalkyl (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl (morpholino), or thiazinyl); carbocyclic or heterocyclic monocyclic or fused or non-fused polycyclic aryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolyl, isoquinolyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothienyl, or benzofuryl), amino (primary, secondary, or tertiary), aryl, aryloxy, and aryl-alkyl, although the disclosure is not limited thereto. Furthermore, each of the substituents listed above may again be unsubstituted or substituted with a substituent selected from these substituents.

In the present specification, "halogen" may be F, Cl, Br, or I.

In this specification, unless otherwise specified, "alkyl" may refer to straight or branched chain saturated hydrocarbons in acyclic, cyclic, or combinations. Further, "C" is_1-8Alkyl "may refer to an alkyl group containing 1 to 8 carbon atoms. Examples of the acyclic alkyl group may include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, and 2, 3-dimethylbutyl. Examples of the cyclic alkyl group may include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of alkyl groups in which the acyclic and cyclic alkyl groups are combined may include, but are not limited to, methylcyclopropyl, cyclopropylmethyl, ethylcyclopropyl, cyclopropylethyl, methylcyclobutyl, cyclobutylmethyl, ethylcyclopentyl, and cyclopentylmethyl.

In the present specification, when described as "cycloalkyl", it may particularly refer to a cyclic alkyl group among alkyl groups, wherein the alkyl group is the same as defined above.

In the present specification, "alkoxy" may refer to- (O-alkyl) in the form of an alkyl ether group, wherein the alkyl group is the same as defined above. Further, "C" is _1-8Alkoxy "may mean containing C_1-8Alkoxy radicals of alkyl radicals, i.e. - (O-C)_1-8Alkyl group), and the C_1-8Examples of alkoxy groups may include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and n-pentoxy.

In the present specification, "heterocycloalkyl" may refer to a ring containing 1 to 5 heteroatoms selected from N, O, and S as ring member atoms (ring-member atoms), and may be saturated or partially unsaturated. Unless otherwise specified, heterocycloalkyl groups can be a single ring or multiple rings, such as spiro, bridged, or fused rings. Further, "C" is_3-12The heterocycloalkyl group "may refer to a heterocycloalkyl group having 3 to 12 atoms forming a ring, and examples of the heterocycloalkyl group may include, but are not limited to, pyrrolidine, piperidine, N-methylpiperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane (dioxanone), phthalimide, piperidine, pyrimidine-2, 4(1H,3H) -dione, 1, 4-dioxane, morpholine, thiomorpholine (thiomorpholine), thiomorpholine-S-oxide, thiomorpholine-S, S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran (thiopyran), pyrone (pyrone), tetrahydrofuran, tetrahydrothiophene, quinuclidine (quinuclidine), tropane (tropane), 2-azaspiro [ 3.3.3 ]Heptane, (1R,5S) -3-azabicyclo [3.2.1 ]]Octane, (1S,4S) -2-azabicyclo [2.2.2 ] S]Octane and (1R,4R) -2-oxa-5-azabicyclo [2.2.2 ] e]Octane.

In this specification, "alkylamino" may refer to- (NR 'R "), wherein R' and R" may each be independently selected from hydrogen and C_1-8Alkyl, and the selected R 'and R' may each independently be substituted or unsubstituted. Further, "C_1-8Alkylamino "may mean a radical containing C_1-8Amino groups of alkyl radicals, i.e. -N-H (C)_1-8Alkyl) or-N- (C)_1-8Alkyl radical)₂And may include dimethylAmino, diethylamino, methylethylamino, methylpropylamino, or ethylpropylamino, but the disclosure is not limited thereto.

In the present specification, "aryl group" may refer to an aromatic ring from which hydrogen has been removed from an aromatic hydrocarbon ring, and may be monocyclic or polycyclic. The "3-to 12-membered aryl group" may mean an aryl group containing 3 to 12 atoms forming a ring, and examples thereof may include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, biphenyl, and terphenyl.

In the present specification, "heteroaryl" may refer to an aromatic ring containing N, O, and at least one heteroatom of S as a ring-forming atom (ring-forming atom), and may be monocyclic or polycyclic. Further, "3 to 12-membered heteroaryl" may refer to a heteroaryl group containing 3 to 12 ring member atoms, and examples thereof may include, but are not limited to, thienyl, thiophene, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isothiazolyl, oxadiazolyl, triazolyl, pyridyl, bipyridyl, pyrimidinyl, triazinyl, triazolyl, acridinyl, pyridazinyl, pyrazinyl, quinolyl, quinazoline, quinoxalinyl, phenoxazinyl, phthalazinyl, pyrimidinyl, pyridopyrimidinyl, pyridopyrazinyl, pyrazinyl, isoquinolin, indole, carbazole, imidazopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, pyrazolopyrimidyl, imidazopyrazinyl or pyrazolopyridyl, N-arylcarbazole, N-heteroarylcarbazole, N-alkylcarbazole group, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, a pharmaceutically acceptable carrier, a pharmaceutically acceptable carrier, a pharmaceutically acceptable carrier, a pharmaceutically acceptable carrier, a, Benzoxazole, benzimidazole, benzothiazole, benzocarbazole, benzothiophene, dibenzothienyl, thienothiophene, benzofuranyl, phenanthroline (phenanthroline), isoxazolyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, tetrazolyl, phenothiazinyl, dibenzosilacyclopentadiene (dibenzofuranyl), and dibenzofuranyl.

In the present specification, "hydroxyl group" may mean-OH.

In the present specification, "carbonyl group" may mean- (C ═ O)) -, and in the case where a cycloalkyl group, an aryl group, or a heterocycloalkyl group is substituted with a carbonyl group, may mean that a hydrogen atom is substituted with (═ O).

In this specificationIn the specification, "alkylcarbonyl" may refer to- (C (═ O) -alkyl), wherein alkyl is as defined above. Further, "C" is_1-8Alkylcarbonyl "may mean a compound containing C_1-8Carbonyl groups of alkyl radicals, i.e., - (C (═ O) -C_1-8Alkyl), and examples thereof may include, but are not limited to, a methylcarbonyl group (acetyl group, - (C ═ O) -CH)₃) Ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, sec-butylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl, n-octylcarbonyl, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, and cyclohexylcarbonyl.

In this specification, unless otherwise specified, "alkenyl" may refer to a straight or branched non-cyclic or cyclic hydrocarbon having one or more double bonds. Further, "C_2-8The alkenyl group "may mean an alkenyl group having 2 to 8 carbon atoms, and examples thereof may include, but are not limited to, ethenyl, 1-propenyl, prop-2-en-1-yl [ - (CH)₂-CH＝CH₂)]2-butenyl, isopropenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 1-cyclohexenyl, cyclopentadienyl, 1, 3-cyclohexadienyl, 1, 4-cyclohexadienyl, 1, 3-cycloheptadienyl, and 1,3, 5-cycloheptatrienyl.

In the present specification, "alkenylcarbonyl" may refer to- (C (═ O) -alkenyl), wherein alkenyl is the same as defined above. Further, "C_2-8Alkenylcarbonyl "may mean a compound containing C_2-8Carbonyl groups of alkenyl radicals, i.e., - (C (═ O) -C_2-8Alkenyl).

In the present specification, "cyano" may mean- (CN).

In this specification, unless otherwise specified, "alkynyl" may refer to a straight or branched chain acyclic or cyclic hydrocarbon having one or more triple bonds. Further, "C" is_2-8Alkynyl "may refer to alkynyl groups containing 2 to 8 carbon atoms, and examples thereof may include, but are not limited to, ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, and hexyn-2-yl.

In the present specification, "aralkyl" may refer to- (alkyl-aryl), wherein alkyl and aryl are the same as defined above. Further, "3-to 8-membered aralkyl group" may refer to an aralkyl group having 3 to 8 carbon atoms.

In this specification, unless otherwise specified, "bicycloalkyl" may refer to a fused, spiro, or bridged bicyclic hydrocarbon.

In the present specification, "diazabicycloalkyl" may refer to- (diaza-bicycloalkyl), i.e., may be represented as bicycloalkyl, including two nitrogen atoms in the cycloalkyl. Examples of diazabicycloalkyl groups may include, but are not limited to, diazabicyclo [3,2,1] heptane, diazabicyclo [3,1,1] heptane, and diazabicyclo [2,2,1] heptane.

In the present specification, "oxaazabicycloalkyl" may refer to- (oxaaza-bicycloalkyl), i.e. may be represented by bicycloalkyl including one oxygen atom and one nitrogen atom in the cycloalkyl. For example, oxaazabicycloalkyl may include oxaazabicyclo [2,2,1] heptane, although the disclosure is not limited thereto.

In the present specification, "sulfonate" may refer to alkyl sulfonate or aryl sulfonate, and the alkyl sulfonate may be substituted with — (OS (═ O)₂-alkyl) and the aryl sulfonate may be represented by (OS (═ O)₂-aryl) is represented. Wherein alkyl and aryl are as defined above.

In the present specification, "hydrate" may refer to a compound of the present disclosure or a salt thereof containing a stoichiometric or non-stoichiometric amount of water bonded by non-covalent intermolecular forces. The hydrate of the compound represented by formula 1 may contain stoichiometric or non-stoichiometric water bound by non-covalent intermolecular forces. The hydrate may contain 1 equivalent or more, preferably about 1 equivalent to about 5 equivalents of water. Such a hydrate may be prepared by crystallizing the compound represented by formula 1 of the present disclosure, an isomer thereof, or a pharmaceutically acceptable salt thereof from water or a solvent containing water.

In this specification, "solvate" may refer to a compound of the present disclosure or a salt thereof containing a stoichiometric or non-stoichiometric amount of solvent bonded by non-covalent intermolecular forces. Thus, suitable solvents include volatile solvents, non-toxic solvents, and/or solvents suitable for administration to a human.

In this specification, "isomers" may refer to compounds of the present disclosure or salts thereof having the same chemical formula or molecular formula but differing structurally or spatially. Such isomers include structural isomers (such as tautomers), R or S isomers with asymmetric carbon centers, stereoisomers (such as geometric isomers (trans or cis)), and optical isomers (mirror image isomers). All such isomers and mixtures thereof are also within the scope of the present disclosure.

Embodiments of the present disclosure provide a compound represented by the following formula 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[ formula 1]

In one embodiment, in formula 1, R¹Is hydrogen, halogen, C_1-8Alkyl, or C_1-8Alkoxy radical, wherein R₁C of (A)_1-8Alkyl and C_1-8Alkoxy is each independently unsubstituted or substituted with one or more halogen,

R²is hydrogen or-NR⁷R⁸Wherein R is ⁷And R⁸Each independently is hydrogen or C_1-8Alkyl, or R⁷And R⁸Are taken together with the N atom to which they are attached to form a 3-to 12-membered heterocycloalkyl group, and R⁷And R⁸C of (A)_1-8Alkyl and 3-to 12-membered heterocycloalkyl are each independently unsubstituted or substituted with one or more substituents selected from the group consisting of: c_1-8Alkyl radical, C_1-8Alkoxy group, and C_1-8An alkylamino group(s) of an alkyl group,

R³is hydrogen, -NR⁹R¹⁰OR-OR¹¹Wherein R is⁹、R¹⁰And R¹¹Each independently is hydrogen or C_1-8Alkyl, or R⁹And R¹⁰Together with the N atom to which they are attached to form a 3-to 12-membered heterocycloalkyl or 3-to 12-membered heteroaryl, R⁹、R¹⁰And R¹¹C of (A)_1-8Alkyl, 3-to 12-membered heterocycloalkyl,And 3-to 12-membered heteroaryl are each independently unsubstituted or substituted with one or more substituents R selected from the group consisting of: hydroxy, C_1-8Alkyl radical, C_1-8Alkoxy radical, C_1-8Alkylamino radical, C_1-8Alkylcarbonyl, -NR¹²R¹³And 3-to 12-membered heterocycloalkyl, the substituents R further each independently being unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen; a carbonyl group; unsubstituted or via hydroxy or C_1-8Alkylamino substituted C_1-8An alkyl group; c_2-8An alkenyl group; c_1-8An alkoxy group; c_1-8An alkylamino group; c _1-8An alkylcarbonyl group; and unsubstituted or substituted by C_1-8Alkyl-substituted 3-to 12-membered heterocycloalkyl, R¹²And R¹³Each independently is hydrogen, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_1-8Alkylcarbonyl group, C_2-8Alkenylcarbonyl, or unsubstituted or substituted by C_1-8Alkyl-substituted 3-to 12-membered heterocycloalkyl,

R⁵is C_1-8Alkyl, 3-to 12-membered aryl, 3-to 12-membered heteroaryl, or 3-to 12-membered heterocycloalkyl, wherein R⁵C of (A)_1-8Alkyl, 3-to 12-membered aryl, 3-to 12-membered heteroaryl, and 3-to 12-membered heterocycloalkyl are each independently unsubstituted or substituted with one or more substituents J selected from the group consisting of: halogen, cyano, unsubstituted or halogen-substituted C_1-8Alkyl, 3-to 12-membered aryl, 3-to 12-membered heteroaryl, 3-to 12-membered heterocycloalkyl, C_2-8Alkenyl radical, C_1-8Alkoxy radical, C_2-8Alkynyl and C_1-8Alkylamino, wherein substituents J are further each independently unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen, unsubstituted or halogen-substituted C_1-8Alkyl radical, C_1-8Alkoxy group, and C_1-8Alkylamino, and

R⁶is hydrogen or C _1-8An alkyl group.

In another embodiment, in the compound represented by formula 1, R¹Is hydrogen, halogen, C_1-8Alkyl, or C_1-8Alkoxy radical, wherein R¹C of (A)_1-8Alkoxy is each independently unsubstituted or substituted with one or more halogen,

R²is hydrogen or-NR⁷R⁸Wherein R is⁷And R⁸Each independently is hydrogen or C_1-8Alkyl, or R⁷And R⁸Together with the N atom to which they are attached to form a 3-to 12-membered heterocycloalkyl, R⁷And R⁸C of (A)_1-8Each alkyl is independently unsubstituted or substituted with one or more substituents selected from the group consisting of: c_1-8Alkoxy and C_1-8Alkylamino, and by reacting R⁷Is linked to R⁸The 3-to 12-membered heterocycloalkyl group formed is unsubstituted or substituted with one or more substituents selected from the group consisting of: c_1-8Alkyl and C_1-8An alkoxy group,

R³is hydrogen, -NR⁹R¹⁰OR-OR¹¹Wherein R is⁹、R¹⁰And R¹¹Each independently is hydrogen or C_1-8Alkyl, or R⁹And R¹⁰Together with the N atom to which they are attached to form a 3-to 12-membered heterocycloalkyl or 3-to 12-membered heteroaryl, R⁹、R¹⁰And R¹¹C of (A)_1-8Each alkyl is independently unsubstituted or substituted with one or more substituents selected from the group consisting of: c_1-8Alkoxy and C_1-8Alkylamino, and by reacting R ⁹Is linked to R¹⁰The 3-to 12-membered heterocycloalkyl group formed is unsubstituted or substituted with one or more substituents R selected from the group consisting of^aAnd (3) substitution: hydroxy, C_1-8Alkyl radical, C_1-8Alkoxy radical, C_1-8Alkylamino radical, C_1-8Alkylcarbonyl, -NR¹²R¹³And 3-to12-membered heterocycloalkyl, wherein the substituent R^aC of (A)_1-8Alkyl radical, C_1-8Alkoxy radical, C_1-8Alkylamino, and C_1-8The alkylcarbonyl groups are further each independently unsubstituted or substituted with one or more substituents selected from the group consisting of: c_1-8Alkyl radical, C_1-8Alkoxy radical, C_1-8Alkylamino, and 3-to 12-membered heterocycloalkyl, substituent R^aThe 3-to 12-membered heterocycloalkyl of (a) is further unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen; a carbonyl group; unsubstituted or via hydroxy or C_1-8Alkylamino substituted C_1-8An alkyl group; c_2-8An alkenyl group; c_1-8An alkoxy group; c_1-8An alkylamino group; c_1-8An alkylcarbonyl group; and unsubstituted or substituted by C_1-8Alkyl-substituted 3-to 12-membered heterocycloalkyl, R¹²And R¹³Each independently is hydrogen, C_1-8Alkylcarbonyl group, C_2-8Alkenylcarbonyl, or unsubstituted or substituted by C_1-8Alkyl-substituted 3-to 12-membered heterocycloalkyl, and by reacting R⁹Is linked to R¹⁰The 3-to 12-membered heteroaryl group formed is unsubstituted or C_1-8The substitution of the alkyl group is carried out,

R⁴is-NH (C ═ O) R¹⁴C＝CR¹⁵R¹⁶Wherein R is¹⁴Is hydrogen or halogen, and R¹⁵And R¹⁶Each independently of the others being hydrogen or unsubstituted or substituted by C_1-8Alkylamino substituted C_1-8An alkyl group, a carboxyl group,

R⁵is C substituted by 3-to 12-membered aryl or 3-to 12-membered heteroaryl_1-8Alkyl, 3-to 12-membered aryl, or 3-to 12-membered heteroaryl, wherein R⁵Each of the 3-to 12-membered aryl and 3-to 12-membered heteroaryl of (a) is independently unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen, cyano, unsubstituted or halogen-substituted C_1-8Alkyl radical, C_1-8Alkoxy group, and C_2-8Alkynyl, and R⁵The 3-to 12-membered aryl or 3-to 12-membered heteroaryl substituted alkyl of (a) is unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen, does notSubstituted or halogen-substituted C_1-8Alkyl, and C_1-8Alkylamino, and

R⁶is hydrogen or C_1-8An alkyl group.

In another embodiment, in the compound represented by formula 1, R¹Is hydrogen, halogen, C_1-4Alkyl, or C_1-4Alkoxy radical, wherein R¹C of (A)_1-4Alkoxy is each independently unsubstituted or substituted with one or more halogen,

R²is hydrogen or-NR⁷R⁸Wherein R is⁷And R⁸Together with the N atom to which they are attached to form a 3-to 8-membered heterocycloalkyl group, by reaction of R ⁷Is connected to R⁸The 3-to 8-membered heterocycloalkyl group formed being unsubstituted or substituted by one or more C_1-4The substitution of the alkyl group is carried out,

R³is hydrogen, -NR⁹R¹⁰OR-OR¹¹Wherein R is⁹、R¹⁰And R¹¹Each independently is C_1-6Alkyl, or R⁹And R¹⁰Together with the N atom to which they are attached to form a 3-to 10-membered heterocycloalkyl or 3-to 8-membered heteroaryl, R⁹、R¹⁰And R¹¹C of (A)_1-6Each alkyl is independently unsubstituted or substituted with one or more substituents selected from the group consisting of: c_1-4Alkylamino and C_1-4Alkoxy by reacting R⁹And R¹⁰The 3-to 10-membered heterocycloalkyl group formed by the linkage is unsubstituted or substituted with one or more substituents R selected from the group consisting of^bAnd (3) substitution: hydroxy, C_1-6Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino radical, C_1-4Alkylcarbonyl, -NR¹²R¹³And 3-to 10-membered heterocycloalkyl, substituent R^bC of (A)_1-6Alkyl radical, C_1-4Alkoxy group, and C_1-4The alkylamino groups are further each independently unsubstituted or substituted with one or more substituents selected from the group consisting of: c_1-6Alkyl radical, C_1-4Alkoxy group, and C_1-4Alkylamino radical, substituent R^bThe 3-to 10-membered heterocycloalkyl of (a) is further unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen; a carbonyl group; unsubstituted or substituted by C _1-4Alkylamino substituted C_1-6An alkyl group; c_2-4An alkenyl group; c_1-4An alkylamino group; c_1-4An alkylcarbonyl group; and unsubstituted or substituted by C_1-4Alkyl-substituted 3-to 8-membered heterocycloalkyl, R¹²And R¹³Each independently is hydrogen, C_2-4Alkenylcarbonyl, or unsubstituted or substituted by C_1-4Alkyl-substituted 3-to 8-membered heterocycloalkyl, and by reacting R⁹And R¹⁰The 3-to 8-membered heteroaryl group formed by the linkage being unsubstituted or C_1-4The substitution of alkyl groups is carried out,

R⁴is-NH (C ═ O) R¹⁴C＝CR¹⁵R¹⁶Wherein R is¹⁴Is hydrogen or halogen, and R¹⁵And R¹⁶Each independently of the others being hydrogen or C_1-4Alkylamino substituted C_1-4An alkyl group, a carboxyl group,

R⁵is C substituted by 3-to 8-membered aryl or 3-to 8-membered heteroaryl_1-4Alkyl, 3-to 8-membered aryl, or 3-to 8-membered heteroaryl, wherein R⁵Each of the 3-to 8-membered aryl and 3-to 8-membered heteroaryl of (a) is independently unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen, cyano, unsubstituted or halogen-substituted C_1-4Alkyl radical, C_1-4Alkoxy group, and C_2-4Alkynyl, and R⁵C substituted with 3-to 8-membered aryl or 3-to 8-membered heteroaryl of_1-4Alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen, unsubstituted or halogen-substituted C_1-4Alkyl, and C_1-4Alkylamino, and

R⁶Is hydrogen or C_1-4An alkyl group.

R²is hydrogen or-NR⁷R⁸Wherein R is⁷And R⁸Together with the N atom to which they are attached to form a 3-to 8-membered heterocycloalkyl group having one or two N atoms by linking R⁷And R⁸The 3-to 8-membered heterocycloalkyl group formed by the linkage being unsubstituted or substituted by one or more C_1-4The substitution of the alkyl group is carried out,

R³is hydrogen, -NR⁹R¹⁰OR-OR¹¹Wherein R is⁹、R¹⁰And R¹¹Each independently is C_1-6Alkyl, or R⁹And R¹⁰Together with the N atom to which they are attached to form a 3-to 10-membered heterocycloalkyl having one or two heteroatoms selected from the group consisting of N and O, or a 3-to 8-membered heteroaryl having one or two heteroatoms selected from the group consisting of N and O, R⁹、R¹⁰And R¹¹C of (A)_1-6Each alkyl is independently unsubstituted or substituted with one or more substituents selected from the group consisting of: c_1-4Alkylamino and C_1-4Alkoxy by reacting R⁹And R¹⁰The 3-to 8-membered heterocycloalkyl group formed by the linkage is unsubstituted or substituted with one or more substituents R selected from the group consisting of ^cAnd (3) substitution: hydroxy, C_1-6Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino radical, C_1-4Alkylcarbonyl, -NR¹²R¹³And 3-to 10-membered heterocycloalkyl having one or two heteroatoms selected from the group consisting of N and O, substituent R^cC of (A)_1-6Alkyl radical, C_1-4Alkoxy group, and C_1-4The alkylamino groups are further each independently unsubstituted or substituted with one or more substituents selected from the group consisting of: c_1-6Alkyl radical, C_1-4Alkoxy group, and C_1-4Alkylamino radical, substituent R^cThe 3-to 10-membered heterocycloalkyl of (a) is further unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen; a carbonyl group; unsubstituted or substituted by C_1-4Alkylamino substituted C_1-6An alkyl group; c_2-4An alkenyl group;C_1-4an alkylamino group; c_1-4An alkylcarbonyl group; and unsubstituted or substituted by C_1-4Alkyl-substituted 3-to 8-membered heterocycloalkyl having one or two heteroatoms selected from the group consisting of N and O, R¹²And R¹³Each independently is hydrogen; c_2-4An alkenylcarbonyl group; or unsubstituted or substituted by C_1-4Alkyl-substituted 3-to 8-membered heterocycloalkyl having one or two N atoms, and prepared by reacting R⁹And R¹⁰The 3-to 8-membered heteroaryl group formed by the linkage being unsubstituted or C_1-4The substitution of the alkyl group is carried out,

R⁴is-NH (C ═ O) R¹⁴C＝CR¹⁵R¹⁶Wherein R is¹⁴Is hydrogen or halogen, and R ¹⁵And R¹⁶Each independently of the other is hydrogen or C_1-4Alkylamino substituted C_1-4An alkyl group, which is a radical of an alkyl group,

R⁶is hydrogen or C_1-4An alkyl group.

In another embodiment, in the compound represented by formula 1, R¹Is hydrogen, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, or propoxy, wherein R¹The methoxy, ethoxy, and propoxy groups of (A) are each independently unsubstituted or substituted with one or more fluoro or chloro groups,

R²is hydrogen or-NR⁷R⁸Wherein R is⁷And R⁸To which they are connectedThe linking N atoms are linked together to form azetidine (azetidine), pyrrolidine, piperazine, piperidine or diazepane by the addition of R ⁷And R⁸The azetidine, pyrrolidine, piperazine, piperidine or diazepane formed by the linkage is unsubstituted or substituted with one or more methyl or ethyl groups,

R³is hydrogen, -NR⁹R¹⁰OR-OR¹¹Wherein R is⁹、R¹⁰And R¹¹Each independently being methyl, ethyl, propyl, butyl, or pentyl, or R⁹And R¹⁰With the N atom to which they are attached to form azetidine, pyrrolidine, piperazine, piperidine, diazepane, morpholine, diazabicycloheptane, oxaazabicycloheptane, diazabicyclooctane, oxaazabicyclooctane, imidazole, pyrrole, hexahydropyrrolopyrrole, or tetrahydrofuranylpyrrole, wherein R is⁹、R¹⁰And R¹¹Each methyl, ethyl, propyl, butyl, or pentyl group of (a) is independently unsubstituted or substituted with one or more substituents selected from the group consisting of: dimethylamino, diethylamino, methylethylamino, methylpropylamino, ethylpropylamino, methoxy, and ethoxy by reacting R⁹And R¹⁰The azetidine, pyrrolidine, piperazine, piperidine, diazepane, morpholine, diazabicycloheptane, oxaazabicycloheptane, diazabicyclooctane, oxaazabicyclooctane, hexahydropyrrolopyrrole, or tetrahydrofuranylpyrrole formed by the linkage are each independently unsubstituted or substituted with one or more substituents R selected from the group consisting of ^dAnd (3) substitution: hydroxy, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, dimethylamino, diethylamino, methylethylamino, methylpropylamino, ethylpropylamino, acetyl, azetidine, pyrrolidine, piperazine, piperidine, diazepane, morpholine, oxetane (oxyethane), diazabicycloheptane, oxaazabicycloheptane, diazabicyclooctane, oxaazabicyclooctane, oxaazaspiroheptaneAzaspiro-octanes, hexahydropyrrolopyrazines, and-NR¹²R¹³Substituent R^dEach methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, dimethylamino, diethylamino, methylethylamino, methylpropylamino, or ethylpropylamino of (a) is further independently unsubstituted or substituted with one or more substituents selected from the group consisting of: cyclopropyl, cyclobutyl, methoxy, ethoxy, dimethylamino, diethylamino and methylethylamino, substituent R^dThe azetidine, pyrrolidine, piperazine, piperidine, diazepane, morpholine, oxetane, diazabicycloheptane, oxaazabicycloheptane, diazabicyclooctane, oxaazabicyclooctane, oxaazaspiroheptane, azaspirooctane, or hexahydropyrrolopyrazine of (a) further each independently is unsubstituted or substituted with one or more substituents selected from the group consisting of: fluorine, chlorine, carbonyl, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, methyl substituted by dimethylamino, methyl substituted by diethylamino, ethyl substituted by diethylamino, vinyl, propenyl, butenyl, dimethylamino, diethylamino, methylethylamino, methylpropylamino, ethylpropylamino, acetyl, azetidine unsubstituted or substituted by methyl or ethyl, pyrrolidine unsubstituted or substituted by methyl or ethyl, piperazine unsubstituted or substituted by methyl or ethyl, piperidine unsubstituted or substituted by methyl or ethyl, diazepane unsubstituted or substituted by methyl or ethyl, morpholine unsubstituted or substituted by methyl or ethyl, and oxetane unsubstituted or substituted by methyl or ethyl, R ¹²Each independently of the other being hydrogen or prop-2-en-1-one, R¹³Is an azetidine unsubstituted or substituted with methyl, ethyl, or propyl; pyrrolidine unsubstituted or substituted with methyl, ethyl, or propyl; or unsubstituted or methyl-, ethyl-, or propyl-substituted piperidine, and by reacting R⁹And R¹⁰The imidazole or pyrrole formed by the connection being unsubstituted or substituted by methyl or ethylThe substitution is carried out by the following steps,

R⁴is-NH (C ═ O) R¹⁴C＝CR¹⁵R¹⁶Wherein R is¹⁴Is hydrogen, fluorine, or chlorine, and R¹⁵And R¹⁶Each independently hydrogen, a methyl group substituted with a dimethylamino group or a diethylamino group, or an ethyl group substituted with a dimethylamino group or a diethylamino group,

R⁵is methyl substituted with phenyl, naphthyl, pyridine, or pyrrole; ethyl substituted with phenyl, naphthyl, pyridine, or pyrrole; a phenyl group; a naphthyl group; pyrrole; or thiophene, in which R⁵Each phenyl, naphthyl, pyrrole, pyridine, or thiophene of (a) is independently unsubstituted or substituted with one or more substituents selected from the group consisting of: fluorine; chlorine; a cyano group; methyl unsubstituted or substituted by fluorine or chlorine; ethyl unsubstituted or substituted by fluorine or chlorine; a methoxy group; ethoxy, and ethynyl, and R⁵Each phenyl, naphthyl, pyridine, or pyrrole (which is a substituent of methyl or ethyl) of (a) is independently unsubstituted or substituted with one or more substituents selected from the group consisting of: fluorine; chlorine; methyl unsubstituted or substituted by fluorine or chlorine; ethyl unsubstituted or substituted by fluorine or chlorine; a dimethylamino group; and diethylamino, and

R⁶And may be hydrogen, methyl, or ethyl.

Another embodiment may provide a compound represented by the following formula 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[ formula 2]

Wherein, in formula 2, R¹Is hydrogen or C_1-4Alkoxy radical, R³is-X-Y-Z, wherein X and Y are each independently a single bond or a 3-to 8-membered heterocycloalkyl group containing at least one N atom, and Z is-NR¹⁷R¹⁸Or represented by the following formula 3,

[ formula 3]

When Z is-NR¹⁷R¹⁸When at least one of X and Y is a 3-to 8-membered heterocycloalkyl group containing at least one N atom, wherein R¹⁷And R¹⁸Each independently of the others being hydrogen or unsubstituted or substituted by C_1-4Alkylamino substituted C_1-4Alkyl, or R¹⁷And R¹⁸Together with the N atom to which they are attached to form a 3-to 12-membered heterocycloalkyl,

when Z is formula 3, L is unsubstituted or substituted by C_1-4Alkyl substituted C_1-4Alkylene, M being-NR¹⁹or-O-, T and Q are each independently of the other hydrogen or unsubstituted or C_1-4Alkylamino substituted C_1-4Alkyl, T and Q being linked to one another to form unsubstituted or C_1-4Alkyl-substituted 3-to 12-membered heterocycloalkyl, or T and Q are linked to each other and further linked between two or more different atoms of the ring member atoms to form unsubstituted or C_1-4An alkyl-substituted 3-to 12-membered bridged or fused heterocycloalkyl group, and R ¹⁹Is hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_1-6Alkylcarbonyl group, C_1-4Alkylamino, or 3-to 8-membered heterocycloalkyl, and

R⁵is 3-to 8-membered aralkyl, 3-to 8-membered aryl, or 3-to 8-membered heteroaryl, wherein R is⁵Each of the 3-to 8-membered aralkyl, 3-to 8-membered aryl, and 3-to 8-membered heteroaryl of (a) is independently unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen, cyano, C_1-4Alkyl, and C_1-4An alkoxy group.

In another embodiment, in the compound represented by formula 2, R¹And may be hydrogen, methoxy, or ethoxy.

In another embodiment, in the compound represented by formula 2, R¹And R⁵As defined above in formula 2,

R³is-X-Y-Z, wherein X and Y are each independently a single bond, a nitrogen heterocycleButane, pyrrolidine, piperidine, or piperazine, and Z is-NR¹⁷R¹⁸Or represented by the following formula 3,

[ formula 3]

When Z is-NR¹⁷R¹⁸When X and Y are azetidine, pyrrolidine, piperidine, or piperazine, wherein R is¹⁷And R¹⁸Each independently being methyl or ethyl, or R¹⁷And R¹⁸Together with the N atom to which they are attached to form an azaspiro octane,

when Z is formula 3, L is methylene, ethylene, propylene, or butylene, unsubstituted or substituted with methyl or ethyl,

M is-NR¹⁹or-O-and T and Q are each independently methyl or ethyl unsubstituted or substituted with dimethylamino; or M is-NR¹⁹And T and Q are linked to each other to form unsubstituted or methyl-or ethyl-substituted piperazine; or M is-NR¹⁹And T and Q are linked to each other and further linked between two or more different atoms of the ring member atoms to form an unsubstituted or methyl-or ethyl-substituted 6-to 8-membered diazabicycloalkyl group; or M is-O-and T and Q are linked to each other to form morpholine, unsubstituted or substituted with methyl or ethyl; or M is-O-and T and Q are linked to each other and further linked between two or more different atoms of the ring member atoms to form a 6-to 8-membered oxazabicycloalkyl which is unsubstituted or substituted by methyl or ethyl, and

R¹⁹can be methyl, ethyl, propyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, prop-2-en-1-yl, acetyl, dimethylamino, or oxetane.

In another embodiment, in the compound represented by formula 2, R⁵Is phenyl, benzyl, pyridine, or thiophene, and wherein the phenyl, benzyl, pyridine, or thiophene may each independently be unsubstituted or selected from one or more of the group consisting of Substituent of group (iv): fluoro, chloro, cyano, or methyl unsubstituted or substituted with one or more fluoro, and methoxy.

In another embodiment, in the compound represented by the following formula 2, R⁵As defined above in formula 2,

R¹is hydrogen or methoxy, R³is-X-Y-Z, wherein X and Y are each independently a single bond, pyrrolidine, or piperidine, and Z is dimethylamino, azaspirooctane, or represented by the following formula 3,

[ formula 3]

When Z is dimethylamino or azaspiro octane, at least one of X and Y is pyrrolidine or piperidine,

when Z is formula 3 and X and Y are single bonds, formula 3 is piperazine, morpholine, methylethylamino, hexahydropyrrolopyrrole, or tetrahydrofuropyrrole, unsubstituted or substituted with one or more substituents selected from the group consisting of: methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, and dimethylamino, and

when Z is formula 3 and at least one of X and Y is pyrrolidine or piperidine, formula 3 may be piperazine, morpholine, diazabicycloheptane, oxaazabicycloheptane, hexahydropyrrolopyrrole, or tetrahydrofuranylpyrrole, unsubstituted or substituted with one or more substituents selected from the group consisting of: methyl, ethyl, propyl, oxetane, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, acetyl, and dimethylamino.

In another embodiment, in the compound represented by formula 1, R¹Can be hydrogen, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, propoxy, or

R²Can be hydrogen or

R³Can be hydrogen,

R⁴(may be)

R⁵(may be)

In other embodiments, the compound represented by formula 1 may be any one selected from the compounds of examples 1 to 1059 listed in table 1 below.

The compound represented by formula 1 of the present disclosure may be used in the form of a pharmaceutically acceptable salt thereof. In particular, the pharmaceutically acceptable salt may be an acid addition salt formed from the free acid. In this connection, acid addition salts can be obtained from: inorganic acids (such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, and phosphorous acid); non-toxic organic acids (such as aliphatic monocarboxylates and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates, and alkanedioates, aromatic acids, and aliphatic and aromatic sulfonic acids); or an organic acid (such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, and fumaric acid). Non-limiting examples of such pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, hydroiodide, hydrofluoride, acetate, propionate, decanoate, octanoate, acrylate, formate, isobutyrate, decanoate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1, 4-dioate, hexane-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, hydrogen sulfite, hydrogen carbonate, and an organic carbonate, an organic solvent, an organic carbonate, benzenesulfonate, tosylate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, beta-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate. The acid addition salt can be prepared using a general method, for example, by dissolving the derivative of formula 1 in an organic solvent (such as methanol, ethanol, acetone, dichloromethane, or acetonitrile), filtering and drying a precipitate generated by adding an organic acid or an inorganic acid thereto, or can be prepared by distilling the solvent and an excess of the acid under reduced pressure, followed by drying and crystallization in an organic solvent. Further, the pharmaceutically acceptable salt may be a salt obtained using a base or a metal salt. As an example of the metal salt, an alkali metal or alkaline earth metal salt can be obtained by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, evaporating and drying the filtrate. As an alkali metal salt, sodium, potassium, or calcium salts may be pharmaceutically acceptable. In addition, salts corresponding thereto can be obtained by reacting alkali metal or alkaline earth metal salts with suitable silver salts (e.g., silver nitrate).

Further, the present disclosure may provide not only the compound represented by formula 1 and pharmaceutically acceptable salts thereof, but also stereoisomers thereof, particularly enantiomers thereof, and hydrates and/or solvates that may be prepared therefrom.

Another embodiment of the present disclosure may provide a method of preparing the compound of formula 1.

The preparation method of the compound of formula 1 may include:

preparing a compound of formula 5 from a compound of formula 4;

preparing a compound of formula 6 from the compound of formula 5; and

preparing the compound of formula 1 from the compound of formula 6.

[ formula 4]

[ formula 5]

[ formula 6]

[ formula 1]

In formula 4, G is a leaving group, and R¹To R⁶May each be the same as defined in the specification. The leaving group may be a functional group such as halogen, sulfonate, or alkoxy, and is not limited as long as it is a functional group capable of dissociating from the compound of formula 4 to prepare the compound of formula 5.

The compound of formula 5 can be prepared from the compound of formula 4 by reacting the compound of formula 4 with R³-H reaction. The reaction may be carried out in a solvent such as Dimethylsulfoxide (DMSO). The reaction temperature may range from about 40 ℃ to about 100 ℃, the reaction time may range from about 90 minutes to about 150 minutes, and the conditions may not be limited as long as the reaction can be smoothly performed.

Meanwhile, the compound of formula 5 may be prepared from the compound of formula 4 by reacting the compound of formula 4 with R after reacting with a heterocycloalkyl group such as piperidone³-H reaction.

The compound of formula 6 can be prepared from the compound of formula 5 by reduction of the compound present in R¹Para position of (2), R²Meta of (a), and R³The nitro group in the ortho position. In particular, the process may be a process of reducing only a nitro group without reducing other functional groups or compounds. Any reducing agent for reducing the nitro group can be used without limitation, and for example, SnCl can be used₂。

The preparation of the compound of formula 1 from the compound of formula 6 may be performed by reacting the compound of formula 6 with acrylic acid or an acrylic acid halide.

In addition, the preparation of the compound of formula 4 may include: preparing a compound of formula 8 from a compound of formula 7; and preparing the compound of formula 4 from the compound of formula 8.

[ formula 7]

[ formula 8]

In formula 7 or 8, each G is independently a leaving group, and R⁵And R⁶May each be the same as defined in the specification. The leaving group may be a functional group such as halogen, sulfonate, or alkoxy, and is not limited as long as it is a functional group capable of preparing the compound of formula 8 from the compound of formula 7 and the compound of formula 4 from the compound of formula 8.

The preparation of the compound of formula 8 from the compound of formula 7 may be performed in a solvent such as Dimethylsulfoxide (DMSO). The reaction temperature may range from about 60 ℃ to about 120 ℃, the reaction time may range from about 30 minutes to about 90 minutes, and the conditions may not be limited as long as the reaction can be smoothly performed.

In preparing the compound of formula 4 from the compound of formula 8, the reaction temperature may range from about 80 ℃ to about 120 ℃, the reaction time may range from about 45 minutes to about 90 minutes, and the conditions may not be limited as long as the reaction can be smoothly performed.

Another embodiment of the present disclosure may provide a pharmaceutical composition for preventing or treating cancer, which includes a compound of formula 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

The compound of formula 1 may exhibit inhibitory activity against Epidermal Growth Factor Receptor (EGFR) mutation and ERBB2 and ERBB 4. In other words, the compound of formula 1 may inhibit EGFR mutations, or one or more wild type or mutant kinases selected from ERBB2 and ERBB 4.

The EGFR mutation may be one or more selected from the group consisting of: EGFR Del19/T790M, EGFR L858R/T790M, EGFR L858R, EGFR Exon20 ins NPH, EGFR Exon20 ins SVD, EGFR Exon20 ins FQEA, EGFR Exon20 ins H, and EGFR Exon20 ins ASV.

The ERBB2 mutation may be Her2 Exon20 ins YVMA.

The type of cancer is not limited, and the cancer may be, for example, one or more selected from the group consisting of: pseudomyxoma, intrahepatic bile duct cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphocytic leukemia, basal cell carcinoma, epithelial ovarian cancer, ovarian germ cell carcinoma, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, Fratercalar's abdomen cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal and paranasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, childhood brain cancer, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, colon cancer, cervical cancer, Glioma, renal pelvis cancer, kidney cancer, heart cancer, duodenum cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulva cancer, ureter cancer, urinary tract cancer, carcinoma of unknown primary site, gastric lymphoma, stomach cancer, gastric carcinoid tumor, gastrointestinal stromal tumor, Wilms ' cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal carcinoid tumor, vaginal cancer, spinal cord cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, skin cancer, anal carcinoma, rhabdomyosarcoma, laryngeal carcinoma, pleural carcinoma, leukemia, and lymphoma, And thymus gland cancer.

The pharmaceutical composition for preventing or treating cancer according to the present disclosure may be used for clinical administration, and may be prepared to be administered in various oral and parenteral formulations.

The pharmaceutical compositions of the present disclosure may include a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may include diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants, and the compositions of the present disclosure may be formulated in combination therewith.

Examples of solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and these solid preparations may be formulated by mixing one or more compounds with one or more excipients (for example, starch, calcium carbonate, sucrose, lactose, or gelatin). In addition to simple excipients, lubricants such as magnesium stearate and talc may be used for formulation.

Examples of liquid preparations for oral administration include suspensions, liquids for internal use, emulsions, syrups, and the like, and these liquid preparations may include various excipients, for example, wetting agents, sweetening agents, flavoring agents, preservatives, and the like, in addition to simple common diluents such as water and liquid paraffin.

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, and the like. Non-limiting examples of non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils (such as olive oil), and injectable esters (such as ethyl oleate).

In addition, parenteral administration can be via subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. In this regard, for formulating a formulation for parenteral administration, a solution or suspension may be prepared by mixing the compound represented by formula 1 or a pharmaceutically acceptable salt thereof with a stabilizer or a buffer in water, followed by preparing into an ampoule or vial unit dosage form. The compositions may be sterilized and/or include adjuvants, such as preserving, stabilizing, wetting, or emulsifying agents, salts for controlling osmotic pressure, and/or buffers, as well as other therapeutically effective materials, and may be formulated using conventional methods, such as mixing, granulating, or coating. Hereinafter, the present disclosure will be described in detail with reference to the following examples and experimental examples.

However, these examples and experimental examples are provided for illustrative purposes only and are not intended to limit the scope of the present disclosure.

< analysis and purification conditions >

The compounds synthesized in the examples of the present disclosure were purified or subjected to structural analysis under the following HPLC conditions.

1. Analytical HPLC conditions

Analytical HPLC conditions (ACQUITY UPLC H-Class core System)

The UPLC system manufactured by Waters (acquisition UPLC PDA detector) was used, equipped with a quality QDA detector manufactured by Waters. The column used was ACQUITY available from WatersBEH C18(1.7 μm,2.1X50mm) and a column temperature of 30 ℃.

Water containing 0.1% formic acid was used as mobile phase a and acetonitrile containing 0.1% formic acid was used as mobile phase B.

Gradient conditions (10-100% B for 3 min; flow rate 0.6ml/min)

Preparative liquid chromatography-mass spectrometry (Prep-LCMS) for purification

An automated purification HPLC system manufactured by Waters (2767 sample manager, 2545 binary gradient module, 2998 photodiode array detector) was used, equipped with a quality QDA detector manufactured by Waters. The columns used were available from WatersPrep C18 OBDTM (5 μm,19x50mm) and column temperature was room temperature.

Water containing 0.035% trifluoroacetic acid was used as mobile phase a and methanol containing 0.035% trifluoroacetic acid was used as mobile phase B.

Gradient conditions (15-100% B for 10 min; 25ml/min flow rate)

Preparative liquid chromatography UV Spectroscopy (Prep-150 LC System) for purification

A Prep 150LC system (2545 Quaternary gradient Module, 2998 photodiode array Detector, fraction collector III) manufactured by Waters was used. The columns used were available from WatersPrep RP18 OBDTM (10 μm,30 × 300mm) and column temperature was room temperature.

Gradient conditions (3-100% B for 120 min; flow rate 40ml/min)

NMR analysis

NMR analysis was performed using AVANCE III 400 or AVANCE III 400HD manufactured by Bruker, and the data are expressed in parts per million (ppm) (δ).

Commercially available reagents were used without further purification. In the present disclosure, room temperature means a temperature of 5 ℃ to 40 ℃, for example, 10 ℃ to 30 ℃, for example, 20 ℃ to 27 ℃, and is not strictly limited to the above range. For concentration under reduced pressure or removal of the solvent by distillation, a rotary evaporator was used.

< preparation example >

1. Preparation of isoxazolidine derivatives

< preparation example 1> preparation of (S) -3-phenylisoxazolidine

Procedure 1: preparation of (R) - (3-hydroxy-3-phenylpropoxy) carbamic acid tert-butyl ester

Tert-butyl hydroxycarbamate (7.8g,58.6mmol) was dissolved in dimethylformamide (140ml), to which was then added sodium hydride (2.58g,64.5mmol) at 0 ℃ and the reaction was allowed to proceed for 30 minutes. Then, (R) -3-chloro-1-phenylpropan-1-ol (5g,29.3mmol) dissolved in dimethylformamide (10ml) was slowly added dropwise at 0 ℃ for 10 minutes, followed by stirring at room temperature for 72 hours. An aqueous ammonium chloride solution was added to the reaction mixture to terminate the reaction, followed by extraction with ethyl acetate and brine, thereby combining organic layers. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by medium-pressure liquid chromatography (ethyl acetate/n-hexane) to obtain the objective compound (R) - (3-hydroxy-3-phenylpropoxy) carbamic acid tert-butyl ester (2.8g, 68%).

MS (M/z):150.17[ M +1] +, UPLC retention time (min):1.51

Procedure 2: preparation of (S) -3-phenylisoxazolidine-2-carboxylic acid tert-butyl ester

The compound (R) - (3-hydroxy-3-phenylpropoxy) carbamic acid tert-butyl ester (2.55g,9.54mmol) obtained in procedure 1 of preparation example 1 and triethylamine (3.13ml,22.44mmol) were dissolved in dichloromethane (250ml), followed by cooling to 0 ℃. Subsequently, methanesulfonyl chloride (1ml,13mmol) was added dropwise, and the reaction was allowed to proceed at 0 ℃ for 2 hours. The reaction mixture was extracted with brine and dichloromethane, thereby combining organic layers. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure, to obtain the target compound, 3-phenylisoxazolidine-2-carboxylic acid tert-butyl ester, which was then used in the subsequent reaction without purification.

MS (M/z):194.13[ M +1] +, UPLC retention time (min):1.69

Procedure 3: preparation of (S) -3-phenylisoxazolidine

The compound, tert-butyl 3-phenylisoxazolidine-2-carboxylate (2.3g), obtained in procedure 2 of preparation example 1 was dissolved in dichloromethane (90ml), to which trifluoroacetic acid (14ml) was then added, and the reaction was allowed to proceed at room temperature for 1 hour. The reaction mixture was neutralized with aqueous sodium bicarbonate solution, and then the organic layers were combined. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by medium-pressure liquid chromatography (tetrahydrofuran/n-hexane), thereby obtaining the target compound 3-phenylisoxazolidine (1.3g, 94%).

MS (M/z) 150.08[ M +1] +, UPLC retention time (min) 0.72

< preparation example 2> preparation of (R) -3-phenylisoxazolidine

Preparation example 2 was carried out in the same manner as preparation example 1, and the compounds of the examples shown in table 1 below were used for the synthesis.

MS (M/z) 150.08[ M +1] +, UPLC retention time (min) 0.72

< preparation example 3> preparation of (R) -3- (3-fluorophenyl) isoxazolidine

Procedure 1: preparation of 3-fluoro-N-methoxy-N-methylbenzamide

3-fluorobenzoic acid (90g,642.35mmol,1eq) was dissolved in pyridine (150mL) and N-methoxymethylamine (75.19g,770.81mmol,1.2eq, HCl) was added thereto. Then, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI; 147.77g,770.81mmol,1.2eq) was added at 15 ℃. The reaction mixture was stirred at 50 ℃ for 30 minutes. As a result of TLC analysis (PE: EA ═ 3:1), all starting material disappeared and a new spot of low polarity was detected. The pyridine solvent was removed by concentration under reduced pressure, and the organic layer was extracted with dichloromethane (DCM; 500mL), hydrochloric acid (500mL,2N), and brine (200 mL). The organic layer was dried over sodium sulfate and then concentrated under reduced pressure, thereby obtaining the objective compound 3-fluoro-N-methoxy-N-methylbenzamide (110g, 600.50mmol, yield 93.49%) as a yellow oil.

¹H NMR (400Mhz, chloroform-d) delta ppm 7.47-7.40(m,1H),7.39-7.38(m,2H),7.14-7.13(m,1H),3.54(s,3H),3.45(s, 3H).

Procedure 2: preparation of 1- (3-fluorophenyl) prop-2-en-1-one

3-fluoro-N-methoxy-N-methyl-benzamide (110g,600.50mmol,1eq) obtained in procedure 1 of preparation 3 was dissolved in tetrahydrofuran (THF; 1L) and (vinyl) magnesium bromide (1M,630.53mL,1.05eq) was added dropwise at 0 ℃. Subsequently, the reaction mixture was stirred at 0 ℃ for 30 minutes. As a result of TLC analysis (PE: EA ═ 4:1), all starting material disappeared and a new spot of low polarity was detected. Hydrochloric acid (4N,500mL) was added to quench the reaction, and the organic layer was extracted with methyl tert-butyl ether (MTBE; 2000mL) and brine (500 mL). The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The concentrated compound was purified using chromatography (petroleum ether/ethyl acetate ═ 30/1), to give the target compound 1- (3-fluorophenyl) prop-2-en-1-one (80g, 532.80mmol, 88.73% yield) as a yellow oil.

¹H NMR (400MHz, chloroform-d) δ ppm 7.65(m,1H),7.58-7.52(m,1H),7.39(m,1H),7.24-7.17(m,1H),7.04(dd, J ═ 17.2,10.4Hz,1H),6.39(dd, J ═ 17.2,1.6Hz,1H),5.90(dd, J ═ 10.4,1.6Hz, 1H).

Procedure 3: preparation of 3-chloro-1- (3-fluorophenyl) propan-1-one

1- (3-fluorophenyl) prop-2-en-1-one (71g,472.86mmol,1.0eq) obtained in procedure 2 of preparation 3 was dissolved in dichloromethane (DCM; 71mL) and then HCl/dioxane (4M,295.54mL,2.5eq) was added at 0 ℃. Subsequently, the reaction mixture was stirred at 15 ℃ for 1.5 hours. As a result of TLC analysis (PE: EA ═ 10:1), all starting material disappeared and the target compound was detected. The reaction mixture was concentrated under reduced pressure, dichloromethane (DCM; 450mL) and water (200mL × 5) were added to extract the organic layer, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the objective compound 3-chloro-1- (3-fluorophenyl) propan-1-one (73g, 391.19mmol, yield 82.73%) as a yellow solid.

¹H NMR (400MHz, chloroform-d) δ 7.78-7.72(m,1H),7.69-7.60(m,1H),7.53-7.44(m,1H),7.37-7.24(m,1H),3.93(t, J6.8 Hz,2H),3.46(t, J6.8 Hz, 2H).

Procedure 4: preparation of (S) -3-chloro-1- (3-fluorophenyl) propan-1-ol

Reacting (3aR) -1-methyl-3, 3-diphenyl-3 a,4,5, 6-tetrahydropyrrolo [1,2-c][1,3,2]Oxazaborole (oxazaborole) (1M,32.15mL,0.1eq) was dissolved in tetrahydrofuran (THF; 1.2L) and borane tetrahydrofuran (BH) was added dropwise at 0 ℃ under a nitrogen atmosphere ₃THF; 1M,186.48mL,0.6 eq). The reaction mixture was stirred at 0 ℃ for 30 minutes. Subsequently, 3-chloro-1- (3-fluorophenyl) propan-1-one (60g,309.02mmol,1eq) obtained in procedure 3 of preparation example 3 diluted in tetrahydrofuran was added dropwise to the reaction mixture at 0 ℃. The reaction mixture was stirred at 0 ℃ for 30 minutes. As a result of TLC analysis (PE: EA ═ 5:1), all starting materials disappeared and the point of the target compound was detected. Methanol (100mL) was added at 0 ℃ to stop the reaction, and then the solvent was removed under reduced pressure. Dichloromethane (DCM; 100 mL. multidot.3) and ammonium chloride (NH) were used₄Cl) solution (300mL) extracted the organic layer from the concentrated compound. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The concentrated compound was purified using silica gel chromatography (PE: EA ═ 50:1 to 5:1) to give (S) -3-chloro-1- (3-fluorophenyl) propan-1-ol (140g, 664.2mmol, yield 71.65%, purity 89.49%, 65.5% ee) as a colorless oil.

¹H NMR (400MHz, chloroform-d) delta ppm 7.33(m,1H),7.16-7.07(m,2H),7.02-6.96(m,1H),4.96(m,1H),3.75(m,1H),3.57(m,1H),2.26-2.15(m, 2H).

Procedure 5: preparation of (S) - (3- (3-fluorophenyl) -3-hydroxypropoxy) carbamic acid tert-butyl ester

Tert-butyl hydroxycarbamate (50.4g,378.52mmol,1.05eq) is dissolved in dimethylformamide (DMF; 500mL) and sodium hydride (NaH; 15.86g, 396.55mmol, 60% purity, 1.1eq) is added at 0 ℃ under nitrogen. The reaction mixture was stirred at 10 ℃ for 1 hour, and (1R) -3-chloro-1- (3-fluorophenyl) propan-1-ol obtained in procedure 4 of preparation example 3 diluted in dimethylformamide (DMF; 180mL) was added dropwise at 0 ℃ followed by stirring at 10 ℃ for 16 hours. As a result of TLC analysis (PE: EA ═ 2:1), all starting materials disappeared and the target compound was detected. Aqueous ammonium chloride (3L) was added to stop the reaction, and the organic layer was extracted with ethyl acetate (2,000mL) and brine (2,000 mL). The organic layer was dried over sodium sulfate and then concentrated under reduced pressure to obtain pale yellow solid tert-butyl (S) - (3- (3-fluorophenyl) -3-hydroxypropoxy) carbamate (176g, 616.87mmol, yield 85.56%).

¹H NMR (400MHz, chloroform-d) Δ ppm 7.67-7.64(m,1H),7.23-7.17(m,1H),7.08-7.03(m,2H),6.88-6.81(m,1H),4.99-4.84(m,1H),4.02-3.97(m,1H),3.96-3.89(m,1H),1.95-1.89(m,1H),1.88-1.78(m,1H),1.42-1.39(m, 9H)).

Procedure 6: preparation of (R) -3- (3-fluorophenyl) isoxazolidine-2-carboxylic acid tert-butyl ester

Tert-butyl (S) - (3- (3-fluorophenyl) -3-hydroxypropoxy) carbamate (88g,308.44mmol,1eq) obtained in procedure 5 of preparation 3 and Et₃N (93.63g, 925.31mmol, 128.79mL, 3eq) was dissolved in dichloromethane (DCM; 1L) and methanesulfonic anhydride (80.59g,462.65mmol,1.5eq) was added slowly at 0 ℃. The reaction mixture was stirred at 20 ℃ for 12 hours. As a result of TLC analysis (PE: EA ═ 3:1), all starting material disappeared and a new spot was detected. Water (2,000mL) was added to quench the reaction, and the organic layer was extracted with dichloromethane (DCM; 200 mL. multidot.3). The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The concentrated compound was purified by chromatography (PE: EA ═ 50:1 to 5:1) to extract 88g of the target compound with an ee value of 82.5%. By SFC (column: DAICEL CHIRALPAK AD (250mm 50mm,10 μm), mobile phase: [ Neu-MeOH](ii) a B%: 15% -15%, 3.4 min; 380min) to obtain (R) -3- (3-fluorophenyl) isoxazolidine-2-carboxylic acid tert-butyl ester as white solid (51g, 189.66mmol, yield 30.74%, purity 99.4%).

The purity of the optical isomer of tert-butyl (R) -3- (3-fluorophenyl) isoxazolidine-2-carboxylate obtained in the procedure 6 was analyzed under the following SFC conditions.

The instrument comprises the following steps: CAS-WH-ANA-SFC-C (SHIMADZU LC-30ADsf)

Pipe column: amycoat 50X 4.6mm I.D.,3 μm

Mobile phase: phase A is CO₂Phase B is methanol (0.05% DEA);

gradient elution: MeOH (0.05% DEA) in CO₂Medium, 5% to 40%;

flow rate: 3 mL/min; a detector: a PDA;

temperature of the pipe column: 35 ℃; back pressure: 100 bar

When the optical isomer of tert-butyl (R) -3- (3-fluorophenyl) isoxazolidine-2-carboxylate obtained in the procedure 6 is low in purity, purification is performed under the following SFC conditions, thereby obtaining a yellow liquid optical isomer.

(column: DAICEL CHIRALPAK AD-H (250mm 30mm, 5 μm);

mobile phase: [ 0.1% NH3H2O MEOH ]; b%: 15% -15%, 3.8 min; 600min)

Procedure 7: preparation of (R) -3- (3-fluorophenyl) isoxazolidine

Tert-butyl (R) -3- (3-fluorophenyl) isoxazolidine-2-carboxylate (50g,185.94mmol,1eq) was dissolved in ethyl acetate (EA; 200mL) and then HCl/EtOAc (4M,300mL,6.45eq) was added at 0 ℃. Subsequently, the reaction mixture was stirred at 10 ℃ for 1 hour. The results of LCMS analysis showed that all starting material disappeared and, after concentration under reduced pressure, gave (R) -3- (3-fluorophenyl) isoxazolidine as a white solid (32g, 150.26mmol, 80.81% yield, 95.62% purity, 100% ee HCl).

MS:m/z 168.2[M+H]+

¹H NMR(400MHz,DMSO-d6)δppm 7.53-7.43(m,2H),7.39(d,J＝7.8Hz,1H),7.30-7.23(m,1H),5.01(t,J＝8.0Hz,1H),4.47(m,1H),4.27(m,1H),2.87(m,1H),2.62-2.52(m,1H)。

The optical isomers of the compounds in procedure 7 were purified or analyzed using the following conditions.

Pipe column: chiralpak AY-350 × 4.6mm I.D., 3 μm;

mobile phase: phase AIs CO₂Phase B is IPA (0.05% DEA);

gradient elution: b in A, 5% to 40%;

flow rate: 3 mL/min; a detector: a PDA;

temperature of the pipe column: 35 ℃; back pressure: 100 bar

The compounds of preparation examples 4 to 52 were prepared in the same manner as preparation examples 1 to 3, and the compounds of preparation examples 1 to 52 were used to prepare the compounds of the examples of the present disclosure.

< preparation example 4> preparation of (R) -3- (3, 5-difluorophenyl) isoxazolidine

¹H NMR(400MHz,DMSO-d6)δ＝7.36-7.27(m,3H),5.04-4.98(t,J＝7.6Hz,1H),4.46-4.36(m,1H),4.25-4.19(dd,J＝7.6,15.2Hz,1H),2.90-2.78(m,1H),2.56-2.51(m,1H)。

< preparation example 5> preparation of (R) -3- (2, 5-difluorophenyl) isoxazolidine

< preparation example 6> preparation of (R) -3- (4-fluorophenyl) isoxazolidine

< preparation example 7> preparation of (R) -3- (4-chlorophenyl) isoxazolidine

< preparation example 8> preparation of (R) -3- (2, 6-difluorophenyl) isoxazolidine

¹H NMR (400MHz, methanol-d 4) δ 7.61(tt,1H, J ═ 6.4,8.4Hz),7.1-7.2(m,2H),5.49(t,1H, J ═ 8.4Hz),4.68(dt,1H, J ═ 4.0,8.0Hz),4.4-4.5(m,1H),3.0-3.1(m,1H),2.87(qd,1H, J ═ 8.4,12.4 Hz).

< preparation example 9> preparation of (R) -3- (3-chloro-4-fluorophenyl) isoxazolidine

¹H NMR(400MHz,DMSO-d6)δ＝7.82-7.89(dd,J＝2,7.2,1H),7.56-7.51(s,J＝15.6,2H),5.0-4.96(m,1H),4.46-4.4(m,1H),4.24-4.20(m,1H),2.85-2.82(m,1H),2.54-2.52(m,1H)。

< preparation example 10> preparation of (R) -3- (3-chloro-2-fluorophenyl) isoxazolidine

¹H NMR(400MHz,DMSO-d6)δ＝7.49-7.42(m,2H),7.20-7.16(m,1H),6.56(s,1H),4.66-4.65(m,1H),3.96-3.91(m,1H),3.67-3.65(m,1H),2.66-2.61(m,1H),2.08-2.01(m,1H)。

< preparation example 11> preparation of (R) -3- (2-fluoro-3-methylphenyl) isoxazolidine

¹H NMR (400MHz, chloroform-d) δ 12.6(s,1H),7.46(t,1H, J ═ 7.2Hz),7.3-7.1(m,1H),7.1-7.0(m,1H),5.25(t,1H, J ═ 8.0Hz),4.6-4.4(m,1H),4.38(q,1H, J ═ 7.6Hz),3.0-2.8(m,1H),2.7-2.5(m,1H),2.26(s, 3H).

< preparation example 12> preparation of (R) -3- (3-methoxyphenyl) isoxazolidine

¹H NMR(400MHz,CDCl₃)δ7.25-7.20(m,2H),7.11-7.09(m,1H),6.88-6.86(m,1H),4.80-4.76(m,1H),4.46-4.44(m,1H),4.17-4.15(m,1H),3.76(s,3H),2.69-2.66(m,2H)。

< preparation example 13> preparation of (R) -3- (4-chloro-3-fluorophenyl) isoxazolidine

< preparation example 14> preparation of (R) -3- (3, 4-dichloro-2-fluorophenyl) isoxazolidine

< preparation example 15> preparation of (R) -3- (6-methylpyridin-3-yl) isoxazolidine

< preparation example 16> preparation of (R) -3- (3-chloro-2, 4-difluorophenyl) isoxazolidine

¹H NMR(DMSO-d6,400MHz)δ＝7.51(dt,J＝6.8,8.4Hz,1H),7.28(dt,J＝2.0,8.8Hz,1H),6.60(br s,1H),4.64(br s,1H),3.94(dt,J＝5.2,8.0Hz,1H),3.76-3.57(m,1H),2.68-2.61(m,1H),2.10-2.01(m,1H)；

< preparation example 17> preparation of (R) -3- (3, 4-dichlorophenyl) isoxazolidine

¹H NMR(400MHz,DMSO-d6)δ＝7.83(d,J＝2.0Hz,1H),7.73(d,J＝8.4Hz,1H),7.53(dd,J＝2.0,8.4Hz,1H),4.99-4.95(m,1H),4.43-4.38(m,1H),4.21-4.17(m,1H),2.85-2.82(m,1H),2.52-2.48(m,1H)。

< preparation example 18> preparation of (R) -3- (3-ethynylphenyl) isoxazolidine

¹H NMR(400MHz,DMSO-d6)δ＝7.49(s,1H),7.43-7.37(m,1H),7.36-7.29(m,2H),6.41(s,1H),4.38(s,1H),4.15(s,1H),3.90(m,1H),3.71(s,1H),2.65-2.53(m,1H),2.11-2.00(m,1H)。

< preparation example 19> preparation of (S) -3-methyl-3-phenylisoxazolidine

¹H NMR(400MHz,DMSO-d6)δ12.86(br s,1H),7.55-7.45(m,2H),7.44-7.37(m,2H),7.35-7.28(m,1H),3.79-3.63(m,1H),3.44-3.32(m,1H),2.75-2.56(m,2H),1.64(s,3H)。

< preparation example 20> preparation of (R) -3-methyl-3-phenylisoxazolidine

¹H NMR(400MHz,DMSO-d6)δ12.88(br s,1H),7.56-7.46(m,2H),7.44-7.36(m,2H),7.34-7.26(m,1H),3.74-3.62(m,1H),3.46-3.28(m,1H),2.72-2.54(m,2H),1.64(s,3H)。

< preparation example 21> preparation of (R) -3- (2, 4-difluorophenyl) isoxazolidine

¹H NMR (400MHz, chloroform-d) delta 7.52-7.47 (m,1H),6.87-6.75(m,2H),5.30(s,1H),4.71-4.68(m,1H),4.09-4.04(m,1H),3.91-3.85(m, 1H)),2.73-2.64(3,1H),2.24-2.20(m,1H)。

< preparation example 22> preparation of (R) -3- (2, 3-difluorophenyl) isoxazolidine

¹H NMR (chloroform-d, 400MHz) δ 7.27-7.29(m,1H),7.02-7.06(m,2H),5.44(br s,1H),4.75(dd, J1 ═ 4.4Hz, J2 ═ 8.4Hz,1H),4.08(dt, J1 ═ 5.2Hz, J2 ═ 8.0Hz,1H),3.86(q, J ═ 8.0Hz,1H),2.66-2.76(m,1H),2.19-2.27(m, 1H).

< preparation example 23> preparation of (R) -3- (3, 4-difluorophenyl) isoxazolidine

¹H NMR (400MHz, chloroform-d) δ 7.24-7.19(m,1H),7.12-7.06(m,2H),5.24(s,1H),4.46(dd, J1 ═ 8.4Hz, J2 ═ 5.6Hz,1H),4.05(dt, J1 ═ 8.0Hz, J2 ═ 5.2Hz,1H),3.91-3.85(m,1H),2.70-2.61(m,1H),2.25-2.17(m, 1H).

< preparation example 24> preparation of (R) -3- (4-chloro-2-fluorophenyl) isoxazolidine

¹H NMR (400MHz, deuterium oxide) delta 7.48-7.38(m,1H),7.34-7.22(m,2H),5.29-5.20(m,1H),4.58-4.50(m,1H),4.36-4.27(m,1H),2.96-2.84(m,1H),2.79-2.66(m, 1H).

< preparation example 25> preparation of (R) -3- (naphthalen-2-yl) isoxazolidine

¹H NMR (400MHz, chloroform-d) δ 7.91-7.81(m,4H),7.56-7.46(m,3H),5.80-5.00(m,1H),4.68(t, J ═ 7.2Hz,1H),4.19-3.99(m,2H),2.8-2.72(m,1H),2.45-2.37(m,1H)。

< preparation example 26> preparation of (R) -3- (naphthalen-1-yl) isoxazolidine

¹H NMR (400MHz, chloroform-d) δ 8.13(br s,1H),7.9 to 7.9(m,1H),7.7 to 7.8(m,2H),7.5 to 7.6(m,3H),5.3 to 5.9(m,1H),5.22(br t,1H, J ═ 6.4Hz),3.9 to 4.2(m,2H),2.8 to 2.9(m,1H),2.3 to 2.5(m, 1H).

< preparation example 27> preparation of (R) -3- (thien-2-yl) isoxazolidine

¹H NMR (400MHz, chloroform-d) δ 7.23(d, J ═ 5.0Hz,1H),7.04-6.99(m,1H),6.99-6.94(m,1H),4.97-4.58(m,2H),4.11-3.96(m,2H),2.75-2.58(m,1H),2.44-2.33(m, 1H).

< preparation example 28> preparation of (R) -3- (2-chloro-3-fluorophenyl) isoxazolidine

¹H NMR (400MHz, chloroform-d) δ 7.45(d, J ═ 7.6Hz,1H),7.22(m,1H),7.02(m,1H),5.44(m,1H),4.87(dd, J ═ 4.0,8.7Hz,1H),4.10(m,1H),3.79(m,1H),2.86-2.75(m,1H),2.21-2.10(m, 1H).

< preparation example 29> preparation of (R) -3- (3-chloro-5-fluorophenyl) isoxazolidine

¹H NMR (400MHz, chloroform-d) Δ 7.19(s,1H),7.08-6.93(m,2H),5.79-5.03(m,1H),4.56-4.42(m,1H),4.17-4.02(m,1H),3.87(s,1H),2.78-2.63(m,1H),2.32-2.18(m, 1H).

< preparation example 30> preparation of (R) -3- (3-chlorophenyl) isoxazolidine

¹H NMR(400MHz,DMSO-d6)δ＝7.71-7.63(m,1H),7.57-7.41(m,3H),5.01(t,J＝8.0Hz,1H),4.47(m,1H),4.26(m,1H),2.94-2.81(m,1H),2.63-2.52(m,1H)。

< preparation example 31> preparation of (R) -3- (2,3, 4-trifluorophenyl) isoxazolidine

< preparation example 32> preparation of (R) -3- (3-chloro-2, 5-difluorophenyl) isoxazolidine

< preparation example 33> preparation of (R) -3- (2,3, 6-trifluorophenyl) isoxazolidine

< preparation example 34> preparation of (R) -3- (2-chloro-3, 6-difluorophenyl) isoxazolidine

< preparation example 35> preparation of (R) -3- (3-chloro-2-methylphenyl) isoxazolidine

< preparation example 36> preparation of (R) -3- (2, 3-dichlorophenyl) isoxazolidine

¹H NMR(DMSO-d6,400MHz)HNMR_7,δ＝7.61-7.44(m,2H),7.37-7.30(m,1H),6.67(d,J＝6.0Hz,1H),4.79-4.63(m,1H),3.94(td,J＝4.0,8.0Hz,1H),3.63(d,J＝8.0Hz,1H),2.78-2.74(m,1H),1.99-1.91(m,1H)。

< preparation example 37> preparation of (R) -3- (isoxazolidin-3-yl) benzonitrile

¹H NMR(400MHz,DMSO-d6)δ＝8.04(s,1H),7.90-7.87(m,2H),7.69-7.62(m,1H),5.05(t,J＝7.8Hz,1H),4.48-4.43(m,1H),4.27-4.21(m,1H),2.92-2.82(m,1H),2.62-2.53(m,1H)。

< preparation example 38> preparation of (R) -3- (3- (trifluoromethyl) phenyl) isoxazolidine

¹H NMR (400MHz, chloroform-d) δ 7.65(s,1H),7.59(d, J ═ 7.7Hz,1H),7.53(d, J ═ 7.8Hz,1H),7.46(t, J ═ 7.7Hz,1H),5.64-5.19(m,1H),4.58(t, J ═ 7.2Hz,1H),4.11(td, J ═ 8.2,5.2Hz,1H),3.94(s,1H),2.80-2.67(m,1H),2.36-2.23(m, 1H).

< preparation example 39> preparation of (R) -3-benzylisoxazolidine

¹H NMR (400MHz, chloroform-d) δ 12.85-12.47(m,1H),7.37-7.27(m,5H),4.51-4.41(m,1H),4.36-4.18(m,2H),3.60(dd, J ═ 4.8,13.6Hz,1H),3.12(dd, J ═ 10.4,13.6Hz,1H),2.53-2.42(m,1H),2.41-2.30(m, 1H).

< preparation example 40> preparation of (S) -3-benzylisoxazolidine

¹H NMR (400MHz, chloroform-d) δ 12.74-12.40(m,1H),7.28-7.18(m,5H),4.42-4.32(m,1H),4.25-4.10(m,2H),3.50(dd, J ═ 4.8,13.6Hz,1H),3.03(dd, J ═ 10.4,13.2Hz,1H),2.44-2.33(m,1H),2.32-2.20(m, 1H).

< preparation example 41> preparation of (S) -3- (3-chloro-2-methoxybenzyl) isoxazolidine

¹H NMR (400MHz, chloroform-d) δ 12.97-12.35(m,2H),7.34(dd, J ═ 1.6,8.0Hz,1H),7.24(dd, J ═ 1.2,7.6Hz,1H),7.10-7.00(m,1H),4.44(dt, J ═ 5.6,7.6Hz,1H),4.39-4.27(m,2H),3.95(s,3H),3.54(dd, J ═ 5.2,13.6Hz,1H),3.22(dd, J ═ 10.0,13.6Hz,1H),2.53-2.42(m,1H),2.42-2.29(m, 1H).

< preparation example 42> preparation of (S) -3- (3-fluoro-2-methylbenzyl) isoxazolidine

¹H NMR (400MHz, chloroform-d) δ 7.14-7.07(m,1H),6.98(d, J7.6 Hz,1H),6.91(t, J8.8 Hz,1H),4.08-3.98(m,1H),3.82(q, J7.6 Hz,1H),3.68-3.59(m,1H),2.96(dd, J7.2, 14.0Hz,1H),2.70(dd, J7.2, 14.0Hz,1H),2.25(d, J2.4 Hz,3H),1.98-1.88(m, 1H).

< preparation example 43> preparation of (S) -3- (3-fluorobenzyl) isoxazolidine

¹H NMR (400MHz, chloroform-d) δ 7.26(dt, J1 ═ 6.0Hz, J2 ═ 7.6Hz,1H),7.01(d, J ═ 7.6Hz,1H),6.96-6.89(m,2H),4.87(s,1H),3.99(dt, J1 ═ 5.6Hz, J2 ═ 8.4Hz,1H),3.80(q, J ═ 8.0Hz,1H),3.68-3.59(m,1H),2.93(dd,J1＝7.2Hz,J2＝14.0Hz,1H),2.67(dd,J1＝7.2Hz,J2＝14.0Hz,1H),2.31-2.22(m,1H),1.94-1.85(m,1H)。

< preparation example 44> preparation of (S) -3- (3, 5-difluorobenzyl) isoxazolidine

¹H NMR (400MHz, chloroform-d) δ 6.77(dd, J1 ═ 2.4Hz, J2 ═ 8.4Hz,2H),6.66(tt, J1 ═ 2.4Hz, J2 ═ 9.2Hz,1H),4.89(br s,1H),4.02(dt, J1 ═ 5.2Hz, J2 ═ 8.4Hz,1H),3.77(q, J ═ 8.0Hz,1H),3.66-3.59(m,1H),2.89(dd, J1 ═ 7.6Hz, J2 ═ 14.0Hz,1H),2.65(dd, J1 ═ 6.8Hz, J2 ═ 14.0, 1H),2.34-2.26, 1H), 1.85(m, 1H).

< preparation example 45> preparation of (S) -3- (isoxazolidin-3-ylmethyl) -N, N-dimethylaniline

< preparation example 46> preparation of (S) -3- (pyridin-2-ylmethyl) isoxazolidine

¹H NMR(DMSO-d6,400MHz)δ＝8.54-8.41(m,1H),7.70(dt,J＝2.0,7.6Hz,1H),7.32-7.18(m,2H),5.98(br s,1H)),3.86-3.54(m,3H),2.91-2.70(m,2H),2.18-2.10(m,1H),1.85-1.74(m,1H)。

< preparation example 47> preparation of (S) -3- (pyridin-3-ylmethyl) isoxazolidine

¹H NMR(CDCl₃,400MHz)δ8.55-8.45(m,2H),7.61(m,1H),7.27-7.22(m,1H),4.04(s,1H),3.87-3.73(m,1H),3.70-3.55(m,1H),2.92(m,1H),2.69(m,1H),2.37-2.24(m,1H),1.99-1.82(m,1H)。

< preparation example 48> preparation of (S) -3- (4- (trifluoromethyl) benzyl) isoxazolidine

< preparation example 49> preparation of (S) -3- (3-chloro-2-methylbenzyl) isoxazolidine

< preparation example 50> preparation of (S) -3- (2, 3-dichlorobenzyl) isoxazolidine

< preparation example 51> preparation of (S) -3- (3-chloro-2-fluorobenzyl) isoxazolidine

< preparation example 52> preparation of (S) -3- (2-chloro-3-fluorobenzyl) isoxazolidine

2. Preparation of Compounds of the examples of the disclosure

< preparation example 1> preparation example 4

Procedure 1: preparation of (R) -2- (6-chloropyrimidin-4-yl) -3-phenylisoxazolidine

4, 6-dichloropyrimidine (500mg,3.36mmol) and (R) -3-phenylisoxazolidine (526mg,3.52mmol) were dissolved in dimethyl sulfoxide (DMSO,7ml) solvent, and the reaction solution was stirred at 60 ℃ for 30 minutes. After completion of the reaction, extraction was performed using ethyl acetate and water. The collected organic layer was washed with brine, dried over anhydrous sodium sulfate, then concentrated under reduced pressure, and purified by MPLC (ethyl acetate/hexane), thereby obtaining clear liquid (R) -2- (6-chloropyrimidin-4-yl) -3-phenylisoxazolidine (800mg, 91%) as a target compound.

MS (M/z):262.07[ M +1], UPLC retention time (min):1.58

NMR:¹H NMR(400MHz,DMSO-d6)δ8.48(s,1H),7.42-7.22(m,5H),7.09(s,1H),5.56-5.43(m,1H),4.27-4.17(m,1H),4.00-3.88(m,1H),2.97-2.80(m,1H),2.37-2.22(m,1H)。

Procedure 2: preparation of (R) -N- (4-fluoro-2-methoxy-5-nitrophenyl) -6- (3-phenylisoxazolidin-2-yl) pyrimidin-4-amine

Preparation of Compounds of examples of the disclosure [2 ] ](R) -2- (6-Chloropyrimidin-4-yl) -3-phenylisoxazolidine (800mg,3.06mmol), 4-fluoro-2-methoxy-5-nitroaniline (626mg,3.36mmol) and potassium carbonate (1,267mg,9.17mmol) obtained in preparation example 1 of procedure 1 in (1) were added to and dissolved in sec-butanol (12ml), followed by sonication for 5 minutes under a nitrogen atmosphere to remove the gas. Reacting tris (dibenzylideneacetone) dipalladium (0) (Pd)₂(dba)₃(ii) a 280mg,0.306mmol) and Xphos (146mg,0.306mmol) were added to the reaction mixture, followed by stirring at 100 ℃ for 1 hour. After completion of the reaction, the reaction product was filtered through celite and washed with ethyl acetate. The obtained filtrate was concentrated and then purified by MPLC (ethyl acetate/hexane), thereby obtaining a target compound (960mg, 76%).

MS (M/z):412.13[ M +1], UPLC retention time (min):1.70

NMR:¹H NMR(400MHz,DMSO-d6)δ9.08(s,1H),9.01(s,1H),8.34(s,1H),7.47-7.21(m,6H),6.79(s,1H),5.59-5.46(m,1H),4.26-4.14(m,1H),4.01(s,3H),3.94-3.76(m,1H),2.87-2.71(m,1H),2.36-2.19(m,1H))。

Procedure 3: preparation of (R) -N1- (2- (dimethylamino) ethyl) -5-methoxy-N1-methyl-2-nitro-N4- (6- (3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) benzene-1, 4-diamine

(R) -N- (4-fluoro-2-methoxy-5-nitrophenyl) -6- (3-phenylisoxazolidin-2-yl) pyrimidin-4-amine (100mg,0.243mmol) and potassium carbonate (67.2mg,0.486mmol) obtained in procedure 2 of preparation example 1 in [2. preparation of the compound of the example of the present disclosure ] were dissolved in dimethyl sulfoxide (DMSO,1.5mL), followed by addition of N1, N1, N2-trimethylethane-1, 2-diamine (0.035mL,0.267mmol) and stirring at 70 ℃ for 2 hours. After completion of the reaction, extraction was performed using ethyl acetate and water. The collected organic layer was washed with brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the objective compound (110mg, 92%), which was then used for the next reaction without purification.

MS (M/z):494.24[ M +1], UPLC retention time (min):1.23

Procedure 4: preparation of (R) -N1- (2- (dimethylamino) ethyl) -5-methoxy-N1-methyl-N4- (6- (3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) benzene-1, 2, 4-triamine

Preparation of Compounds of examples of the disclosure [2 ]](R) -N1- (2- (dimethylamino) ethyl) -5-methoxy-N1-methyl-2-nitro-N4- (6- (3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) benzene-1, 4-diamine (110mg,0.223mmol) and SnCl obtained in procedure 3 of preparation example 1₂·2H₂O (251mg,1.114mmol) was dissolved in ethyl acetate (1.5ml), followed by stirring at 50 ℃ for 1 hour. After the temperature of the reaction solution was lowered to room temperature, an aqueous ammonia solution was added dropwise until the pH reached 5. Anhydrous sodium carbonate was added to the reaction mixture to adjust the pH to 7. The reaction mixture was filtered through celite and washed several times with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the objective compound (90mg, 87%), which was then used for the next reaction without purification.

MS (M/z):464.27[ M +1], UPLC retention time (min):1.03

Procedure 5: preparation of (R) -N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((6- (3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide

(R) -N1- (2- (dimethylamino) ethyl) -5-methoxy-N1-methyl-N4- (6- (3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) benzene-1, 2, 4-triamine (85mg,0.183mmol) obtained in procedure 4 of preparation example 1 was dissolved in tetrahydrofuran (THF; 1.5ml), and then a saturated aqueous solution of sodium hydrogencarbonate (NaHCO. TM.) was added thereto₃(ii) a 1.5ml), and while the resulting solution was vigorously stirred at 0 ℃, the solution was slowly added dropwise diluted in tetrahydrofuran (THF; 0.5mL) of acryloyl chloride (30. mu.L, 0.367 mmol). After stirring for 10 minutes, extraction was performed using ethyl acetate and distilled water, and the collected organic layer was dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and purified using a Prep-150 LC system for purification, thereby obtaining the objective compound (58mg, 61%).

MS (M/z):518.28[ M +1], UPLC retention time (min):1.11

NMR:¹H NMR (400MHz, methanol-d 4) Δ 8.15(s,1H),7.97(s,1H),7.43(s,2H),7.33(s,2H),7.24(s,1H),6.93(s,1H),6.61-6.35(m,3H),5.90-5.75(m,1H),5.60-5.43(m,1H),4.23-4.06(m,1H),4.03-3.93(m,1H),3.91(s,3H),3.45-3.36(m,2H),3.20-3.06(m,2H),2.85-2.79(m,1H),2.77(s,6H),2.73-2.65(m,3H),2.42-2.27(m, 1H).

< preparation example 2> preparation example 56

4, 6-dichloropyrimidine (4.23g), the (R) -3-phenylisoxazolidine obtained in preparation example 2 (6g), and N, N-diisopropylethylamine (DIPEA; 18.91ml) were added to and dissolved in dimethylsulfoxide (DMSO; 135ml) solvent. The reaction solution was allowed to react at 80 ℃ for 30 minutes. Ethyl acetate was added to the reaction mixture to dilute the reaction solution, and extraction was performed with ethyl acetate and brine to combine organic layers. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by medium-pressure liquid chromatography (ethyl acetate/n-hexane), thereby obtaining the objective compound (R) -2- (6-chloropyrimidin-4-yl) -3-phenylisoxazolidine (yield 48.6%).

4-fluoro-2-methoxy-5-nitroaniline (4.23g), (R) -2- (6-chloropyrimidin-4-yl) -3-phenylisoxazolidine (1.84g) obtained in preparation example 2, procedure 1, and potassium carbonate (2.56g) were added to and dissolved in sec-butyl alcohol (20.60ml) solvent. After the temperature of the reaction solution was raised to 60 ℃, Xphos (0.295g) and tris (dibenzylideneacetone) dipalladium (0) (Pd) were added ₂(dba)₃(ii) a 0.425g) was added to the reaction mixture solution. The reaction solution was allowed to react at 100 ℃ for 120 minutes. After the reaction, the organic layer was concentrated under reduced pressure and purified by medium pressure liquid chromatography (ethyl acetate/N-hexane), thereby obtaining the objective compound (R) -N- (4-fluoro-2-methoxy-5-nitrophenyl) -6- (3-phenylisoxazolidin-2-yl) pyrimidin-4-amine (yield 58.9%).

Procedure 3: preparation of (R) -1- (5-methoxy-2-nitro-4- ((6- (3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) piperidin-4-one

(R) -N- (4-fluoro-2-methoxy-5-nitrophenyl) -6- (3-phenylisoxazolidin-2-yl) pyrimidin-4-amine (1.6g) obtained in procedure 2 of preparation example 2 was added to and dissolved in dimethylsulfoxide (DMSO; 15ml) solvent, and then potassium carbonate (1.98g) and piperidin-4-one hydrochloride (1.45g) were added to the reaction solution. Subsequently, the reaction solution was allowed to react at 70 ℃ for 120 minutes. After the reaction, water was added to the reaction mixture to dilute the reaction solution, followed by extraction with ethyl acetate and brine, and the organic layer was concentrated under reduced pressure and purified by medium pressure liquid chromatography (dichloromethane/methanol), thereby obtaining the target compound (R) -1- (5-methoxy-2-nitro-4- ((6- (3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) piperidin-4-one (yield 96%).

Procedure 4: preparation of (R) -N- (4- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -2-methoxy-5-nitrophenyl) -6- (3-phenylisoxazolidin-2-yl) pyrimidin-4-amine

(R) -1- (5-methoxy-2-nitro-4- ((6- (3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) piperidin-4-one (1.8g) obtained in procedure 3 of preparation example 2 was added to and dissolved in a dichloromethane (15mL) solvent, and then 1-cyclopropylpiperazine (0.495mL) and sodium triacetoxyborohydride (1.45g) were added thereto. Subsequently, the reaction solution was allowed to react at room temperature for 16 hours. A 2N aqueous sodium hydroxide solution was added to the reaction mixture to terminate the reaction, followed by extraction with a dichloromethane solvent and brine, concentration of the organic layer under reduced pressure and purification by medium pressure liquid chromatography (dichloromethane/methanol), thereby obtaining the target compound (R) -N- (4- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -2-methoxy-5-nitrophenyl) -6- (3-phenylisoxazolidin-2-yl) pyrimidin-4-amine (yield 73.5%).

Procedure 5: preparation of (R) -4- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -6-methoxy-N1- (6- (3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) benzene-1, 3-diamine

(R) -N- (4- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -2-methoxy-5-nitrophenyl) -6- (3-phenylisoxazolidin-2-yl) pyrimidin-4-amine (1.6g) obtained in procedure 4 of preparation example 2 was added to and dissolved in ethyl acetate (20ml) and methanol (2ml), followed by addition of tin (II) chloride dihydrate (2.84g,12.56mmol) thereto. Subsequently, the reaction solution was allowed to react at 60 ℃ for 120 minutes. An aqueous sodium bicarbonate solution was added to the reaction mixture to terminate the reaction, and then the resulting mixture was filtered through celite and washed with ethyl acetate solvent. The filtrate was extracted with ethyl acetate and brine, and then the organic layer was concentrated under reduced pressure and purified by medium pressure liquid chromatography (dichloromethane/methanol), thereby obtaining the objective compound (R) -4- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -6-methoxy-N1- (6- (3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) benzene-1, 3-diamine (yield 77%).

Procedure 6: preparation of (R) -N- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- (3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide

(R) -4- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -6-methoxy-N1- (6- (3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) benzene-1, 3-diamine (1.18g) obtained in procedure 5 of preparation example 2 was dissolved in a THF (16mL) solvent, and an aqueous sodium hydrogencarbonate solution (16mL) was then added thereto. The resulting solution was added to and dissolved in ethyl acetate (20ml) and methanol (2 ml). After the temperature of the reaction solution was lowered to 0 ℃, a solution of acryloyl chloride (0.315mL) dissolved in THF (4mL) was slowly added dropwise. After that, the reaction solution was reacted at 0 ℃ for 30 minutes, and then an aqueous sodium bicarbonate solution was added to the reaction mixture to terminate the reaction, followed by extraction with ethyl acetate and brine. The organic layer was concentrated under reduced pressure and purified by medium pressure liquid chromatography (dichloromethane/methanol), thereby obtaining the target compound (R) -N- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- (3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide (yield 84%).

As another method, (R) -4- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -6-methoxy-N1- (6- (3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) benzene-1, 3-diamine (128mg) obtained in procedure 5 of preparation example 2 was dissolved in dichloromethane (2mL), to which dichloroethane (EDC; 48mg), acrylic acid (0.017mL), and N, N-diisopropylethylamine (DIPEA; 0.108mL) were then added. The reaction solution was allowed to react at room temperature for 1 hour, and then the reaction was terminated with an aqueous sodium hydrogencarbonate solution. The compound was extracted with dichloromethane solvent and brine. The organic layer was dried under reduced pressure, concentrated under reduced pressure, and then purified by medium-pressure liquid chromatography (dichloromethane/methanol), thereby obtaining the objective compound (yield 86%).

The compounds of all examples of the present disclosure (compounds of examples 1 to 1059) were prepared in the same manner as in preparation example 1 or 2 in [2. preparation of compounds of examples of the present disclosure ], and the names, chemical formulae, and NMR and UPLC analysis results of the compounds of the examples were summarized and are shown in table 1 below.

[ Table 1]

< Experimental example 1> evaluation of inhibitory Activity on proliferation of Ba/F3 and Lung cancer cells

To evaluate the inhibitory activity of the compounds according to the present disclosure on the proliferation of Ba/F3 and lung cancer cells expressing EGFR mutations, the following experiments were performed.

In the lung cancer cell line expressing the EGFR gene, a549 was cultured in dmem (Invitrogen) supplemented with 10% FBS (hyclone), and RPMI-1640(Invitrogen) supplemented with 10% FBS was used for other cancer cells. For Ba/F3 cells, RPMI-1640 containing 10% FBS and 5ng/ml IL-3(R & D system) was used. Transduced Ba/F3 cells were cultured in the same medium supplemented with 1. mu.g/ml puromycin (Invitrogen).

3,000 to 5,000 cells were dispensed into each well of a white clear bottom 96-well plate (Corning) 24 hours prior to treatment with each compound. Each compound was diluted in dimethyl sulfoxide (3-fold (3X) for 12 concentrations) and 0.5. mu.l/well of compound was injected to bring the final concentration to 0.3nM to 50. mu.M. To measure live cells, after 72 hours of treatment with the compound, the cells were stored at room temperature for 10 minutes using CellTiter-Glo luminescent cell viability reagent (Promega), and then their luminescence intensity was measured using a reader (SynergyNeo, Biotek). Each experiment was repeated three times.

The results were calculated as the cell growth rate (%) compared to the control group. GI calculation Using GraphPad Prism version 5.0 Programming₅₀The value is obtained.

Table 2 below shows the results of evaluation of inhibitory activity against Ba/F3 cells expressing EGFR mutation and ERBB2(HER2) mutation.

[ Table 2]

A：GI₅₀＜50nM；B：50nM≤GI₅₀＜500nM；

C：500nM≤GI₅₀＜5000nM；D：5000nM≤GI_s0

In addition, the following Table 3 shows the activity of the compounds of each experimental example on Ba/F3 cell line in Exon20 in which NPH is inserted into EGFR.

[ Table 3]

A：GI₅₀＜50nM；B：50nM≤GI₅₀＜500nM；

C：500nM≤GI₅₀＜5000nM；D：5000nM≤GI₅₀

As shown in tables 2 and 3, it can be seen that example compounds of the present disclosure exhibit high inhibitory activity against EGFR single or double mutations and ERBB2 mutation in Ba/F3 cell line.

In addition, table 4 below shows proliferation inhibitory activity (GI) against EGFR mutant lung cancer cell lines (i.e., PC9, PC9GR, and H1975 cells) and EGFR wild-type cell line a549₅₀) The evaluation result of (1).

[ Table 4]

From table 4, it can be seen that example compounds of the present disclosure have excellent proliferation inhibitory ability on PC9, PC9GR, and H1975 cells belonging to EGFR mutant lung cancer cell lines.

Fig. 1 shows experimental data results of confirming whether cancer is inhibited or not by observing for 21 days without administration after oral administration of the compound of example to a PDX (Exon20 ins V769_ D770ins ASV) cell line xenograft in vivo model for 28 days (Champions Oncology, Inc.).

Referring to fig. 1, it can be confirmed that the compounds of the embodiments of the present disclosure effectively inhibit cancer by reducing the size of tumor in animal models.

[ Table 5]

In addition, table 5 shows the results of discovery (eurofin) KINOMEscan (scanMAX platform) kinase profiling on the compounds of examples 4, 6, 9, 30, 57, 236, 238, 239, 241 and 242. As can be seen from table 5, these compounds were demonstrated to exhibit high inhibitory activity against EGFR mutations as well as ERBB2 and ERBB 4. It was confirmed that the compounds of the examples have high selectivity for the EGFR gene. Thus, these compounds are useful in the treatment of cancers that express these kinases. In particular, these compounds exhibit remarkably excellent inhibitory activity against the proliferation of lung cancer cell lines, and thus can be effectively used for the treatment of lung cancer, breast cancer, and brain cancer.

As is apparent from the foregoing description, the compounds according to the embodiments of the present disclosure, stereoisomers thereof, hydrates thereof, or pharmaceutically acceptable salts thereof exhibit high inhibitory activity not only on Epidermal Growth Factor Receptor (EGFR) wild type or mutation, but also on ERBB2, ERBB4, and mutations thereof, and thus may be effectively used for treating cancers expressing these kinases.

Although the present disclosure has been described in detail with reference to exemplary preparation examples, and experimental examples, the scope of the present disclosure is not limited to the specific example compounds, but should be construed by the appended claims. Furthermore, those skilled in the art will appreciate that changes and modifications may be made in various forms without departing from the scope of the present disclosure.

Claims

1. A compound represented by the following formula 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof,

[ formula 1]

Wherein R is¹Is hydrogen, halogen, C_1-8Alkyl, or C_1-8Alkoxy radical, wherein R¹The C of_1-8Alkyl and C_1-8Each alkoxy is independently unsubstituted or substituted with one or more halo;

R²is hydrogen or-NR⁷R⁸Wherein R is⁷And R⁸Each independently is hydrogen or C_1-8Alkyl, or R⁷And R⁸Together with the nitrogen atom to which they are attached form a 3-to 12-membered heterocycloalkyl group, wherein R⁷And R⁸The C of_1-8Alkyl or 3-to 12-membered heterocycloalkyl are each independently unsubstituted or substituted with one or more substituents selected from the group consisting of: c_1-8Alkyl radical, C_1-8Alkoxy group, and C_1-8An alkylamino group;

R³is hydrogen, -NR⁹R¹⁰OR-OR¹¹Wherein R is⁹、R¹⁰And R¹¹Each independently is hydrogen or C_1-8Alkyl, or R⁹And R¹⁰Together with the nitrogen atom to which they are attached form a 3-to 12-membered heterocycloalkyl or 3-to 12-membered heteroaryl, wherein R ⁹、R¹⁰And R¹¹Of C_1-8Each alkyl, 3-to 12-membered heterocycloalkyl, or 3-to 12-membered heteroaryl is independently unsubstituted or substituted with one or more substituents R selected from the group consisting of: hydroxy, C_1-8Alkyl radical, C_1-8Alkoxy radical, C_1-8Alkylamino radical, C_1-8Alkylcarbonyl, -NR¹²R¹³And a 3-to 12-membered heterocycloalkyl group,

wherein the substituents R are further independently unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen; a carbonyl group; unsubstituted or via hydroxy or C_1-8Alkylamino substituted C_1-8An alkyl group; c_2-8An alkenyl group; c_1-8An alkoxy group; c_1-8An alkylamino group; c_1-8An alkylcarbonyl group; and unsubstituted or substituted by C_1-8Alkyl-substituted 3 to 12 membered heterocycloalkyl, R¹²And R¹³Each independently is hydrogen, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_1-8Alkylcarbonyl group, C_2-8Alkenylcarbonyl, or unsubstituted or substituted by C_1-8Alkyl-substituted 3 to 12 membered heterocycloalkyl;

R⁴is-NH (C ═ O) R¹⁴C＝CR¹⁵R¹⁶Wherein R is¹⁴、R¹⁵And R¹⁶Each independently of the others is hydrogen, halogen, or unsubstituted or C_1-8Alkylamino substituted C_1-8An alkyl group;

R⁵is C_1-8Alkyl, 3-to 12-membered aryl, 3-to 12-membered heteroaryl, or 3-to 12-membered heterocycloalkyl, wherein R is⁵The C of_1-8Alkyl, 3-to 12-membered aryl, 3-to 12-membered heteroaryl, or 3-to 12-membered heterocycloalkyl are each independently unsubstituted or substituted with one or more substituents J selected from the group consisting of: halogen, cyano, unsubstituted or halogen-substituted C _1-8Alkyl, 3-to 12-membered aryl, 3-to 12-membered heteroaryl, 3-to 12-membered heterocycloalkyl, C_2-8Alkenyl radical, C_1-8Alkoxy radical, C_2-8Alkynyl and C_1-8Alkylamino, and wherein the substituent J is further independently unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen, unsubstituted or halogen-substituted C_1-8Alkyl radical, C_1-8Alkoxy group, and C_1-8An alkylamino group; and

R⁶is hydrogen, or C_1-8An alkyl group.

2. The compound, stereoisomer, hydrate thereof, or pharmaceutically acceptable salt thereof according to claim 1, wherein R¹Is hydrogen, halogen, C_1-8Alkyl, or C_1-8Alkoxy radical, wherein R¹The C of_1-8Alkoxy is unsubstituted or substituted by one or more halogen,

R²is hydrogen or-NR⁷R⁸Wherein R is⁷And R⁸Each independently is hydrogen or C_1-8Alkyl, or R⁷And R⁸Together with the nitrogen atom to which they are attached form a 3-to 12-membered heterocycloalkyl, R⁷And R⁸The C of_1-8Each alkyl is independently unsubstituted or substituted with one or more substituents selected from the group consisting of: c_1-8Alkoxy and C_1-8Alkylamino, and by reacting R⁷And R⁸Connecting the formed 3 to12-membered heterocycloalkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of: c _1-8Alkyl and C_1-8An alkoxy group,

R³is hydrogen, -NR⁹R¹⁰OR-OR¹¹Wherein R is⁹、R¹⁰And R¹¹Each independently is hydrogen or C_1-8Alkyl, or R⁹And R¹⁰Together with the nitrogen atom to which they are attached form a 3-to 12-membered heterocycloalkyl or 3-to 12-membered heteroaryl, R⁹、R¹⁰And R¹¹The C of_1-8Each alkyl is independently unsubstituted or substituted with one or more substituents selected from the group consisting of: c_1-8Alkoxy and C_1-8Alkylamino, and through R⁹And R¹⁰The 3-to 12-membered heterocycloalkyl group formed is unsubstituted or substituted with one or more substituents R selected from the group consisting of^aAnd (3) substitution: hydroxy, C_1-8Alkyl radical, C_1-8Alkoxy radical, C_1-8Alkylamino radical, C_1-8Alkylcarbonyl, -NR¹²R¹³And 3-to 12-membered heterocycloalkyl, wherein the substituent R^aThe C of_1-8Alkyl radical, C_1-8Alkoxy radical, C_1-8Alkylamino, and C_1-8The alkylcarbonyl groups are further each independently unsubstituted or substituted with one or more substituents selected from the group consisting of: c_1-8Alkyl radical, C_1-8Alkoxy radical, C_1-8Alkylamino, and 3-to 12-membered heterocycloalkyl, said substituent R^aSaid 3-to 12-membered heterocycloalkyl of (a) is further unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen; a carbonyl group; unsubstituted or via hydroxy or C _1-8Alkylamino substituted C_1-8An alkyl group; c_2-8An alkenyl group; c_1-8An alkoxy group; c_1-8An alkylamino group; c_1-8An alkylcarbonyl group; and unsubstituted or substituted by C_1-8Alkyl-substituted 3 to 12 membered heterocycloalkyl, R¹²And R¹³Each independently is hydrogen, C_1-8Alkylcarbonyl group, C_2-8Alkenylcarbonyl, or unsubstituted or substituted by C_1-8An alkyl-substituted 3-to 12-membered heterocycloalkyl group,and through R⁹And R¹⁰The 3-to 12-membered heteroaryl group formed is unsubstituted or C_1-8The substitution of the alkyl group is carried out,

R⁴is-NH (C ═ O) R¹⁴C＝CR¹⁵R¹⁶Wherein R is¹⁴Is hydrogen or halogen, and R¹⁵And R¹⁶Each independently of the others being hydrogen, or unsubstituted or substituted by C_1-8Alkylamino substituted C_1-8An alkyl group, a carboxyl group,

R⁵is C substituted with 3-to 12-membered aryl or 3-to 12-membered heteroaryl_1-8Alkyl, 3 to 12 membered aryl, or 3 to 12 membered heteroaryl, wherein R is⁵Each of the 3-to 12-membered aryl and the 3-to 12-membered heteroaryl of (a) is independently unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen, cyano, unsubstituted or halogen-substituted C_1-8Alkyl radical, C_1-8Alkoxy group, and C_2-8Alkynyl, and R⁵The C substituted with 3-to 12-membered aryl or 3-to 12-membered heteroaryl of_1-8Alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen, unsubstituted or halogen-substituted C _1-8Alkyl radical, C_1-8Alkoxy group, and C_1-8Alkylamino, and

R⁶is hydrogen or C_1-8An alkyl group.

3. The compound, stereoisomer, hydrate thereof, or pharmaceutically acceptable salt thereof according to claim 1, wherein R¹Is hydrogen, halogen, C_1-4Alkyl, or C_1-4Alkoxy radical, wherein R¹The C of_1-4Alkoxy is each independently unsubstituted or substituted with one or more halogen,

R²is hydrogen or-NR⁷R⁸Wherein R is⁷And R⁸Together with the nitrogen atom to which they are attached form a 3-to 8-membered heterocycloalkyl group, and through R⁷And R⁸The 3-to 8-membered heterocycloalkyl group formed is unsubstituted or substituted by one or more C_1-4The substitution of the alkyl group is carried out,

R³is hydrogen, -NR⁹R¹⁰OR-OR¹¹Wherein R is⁹、R¹⁰And R¹¹Each independently is C_1-6Alkyl, or R⁹And R¹⁰Together with the nitrogen atom to which they are attached form a 3-to 10-membered heterocycloalkyl or 3-to 8-membered heteroaryl, R⁹、R¹⁰And R¹¹The C of_1-6Each alkyl is independently unsubstituted or substituted with one or more substituents selected from the group consisting of: c_1-4Alkoxy and C_1-4Alkylamino radical, via R⁹And R¹⁰The 3-to 10-membered heterocycloalkyl group formed is unsubstituted or substituted with one or more substituents R selected from the group consisting of^bAnd (3) substitution: hydroxy, C_1-6Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino radical, C_1-4Alkylcarbonyl, -NR ¹²R¹³And 3-to 10-membered heterocycloalkyl, and the substituent R^bThe C of_1-6Alkyl radical, C_1-4Alkoxy group, and C_1-4The alkylamino groups are further each independently unsubstituted or substituted with one or more substituents selected from the group consisting of: c_1-6Alkyl radical, C_1-4Alkoxy group, and C_1-4Alkylamino radical, the substituent R^bSaid 3-to 10-membered heterocycloalkyl of (a) is further unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen; a carbonyl group; unsubstituted or substituted by C_1-4Alkylamino substituted C_1-6An alkyl group; c_2-4An alkenyl group; c_1-4An alkylamino group; c_1-4An alkylcarbonyl group; and unsubstituted or substituted by C_1-4Alkyl-substituted 3 to 8-membered heterocycloalkyl, R¹²And R¹³Each independently is hydrogen, C_2-4Alkenylcarbonyl, or unsubstituted or substituted by C_1-4Alkyl-substituted 3 to 8-membered heterocycloalkyl, and through R⁹And R¹⁰The 3-to 8-membered heteroaryl group formed is unsubstituted or C_1-4The substitution of the alkyl group is carried out,

R⁵is C substituted with 3-to 8-membered aryl or 3-to 8-membered heteroaryl_1-4Alkyl, 3-to 8-membered aryl, or 3-to 8-membered heteroaryl, wherein R is⁵Each of the 3-to 8-membered aryl and 3-to 8-membered heteroaryl of (a) is independently unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen, cyano, unsubstituted or halogen-substituted C _1-4Alkyl radical, C_1-4Alkoxy group, and C_2-4Alkynyl, and R⁵The C substituted with 3-to 8-membered aryl or 3-to 8-membered heteroaryl of_1-4Alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen, unsubstituted or halogen-substituted C_1-4Alkyl, and C_1-4Alkylamino, and

R⁶is hydrogen or C_1-4An alkyl group.

4. The compound, stereoisomer, hydrate thereof, or pharmaceutically acceptable salt thereof according to claim 1, wherein R¹Is hydrogen, halogen, C_1-4Alkyl, or C_1-4Alkoxy radical, wherein R¹The C of_1-4Alkoxy is unsubstituted or substituted by one or more halogen,

R²is hydrogen or-NR⁷R⁸Wherein R is⁷And R⁸Together with the nitrogen atom to which they are attached form a 3-to 8-membered heterocycloalkyl having one or two N atoms, and through R⁷And R⁸The 3-to 8-membered heterocycloalkyl group formed is unsubstituted or substituted by one or more C_1-4The substitution of the alkyl group is carried out,

R³is hydrogen, -NR⁹R¹⁰OR-OR¹¹Wherein R is⁹、R¹⁰And R¹¹Each independently is C_1-6Alkyl, or R⁹And R¹⁰Together with the nitrogen atom to which they are attached form a 3-to 10-membered heterocycloalkyl having one or two heteroatoms selected from the group consisting of N and O, or a 3-to 8-membered heteroaryl having one or two heteroatoms selected from the group consisting of N and O, R ⁹、R¹⁰And R¹¹Of C_1-6Each alkyl is independently unsubstituted or substituted with one or more substituents selected from the group consisting of: c_1-4Alkylamino and C_1-4Alkoxy radical, through R⁹And R¹⁰The 3-to 10-membered heterocycloalkyl group formed is unsubstituted or substituted with one or more substituents R selected from the group consisting of^cAnd (3) substitution: hydroxy, C_1-6Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino radical, C_1-4Alkylcarbonyl, -NR¹²R¹³And 3-to 10-membered heterocycloalkyl having one or two heteroatoms selected from the group consisting of N and O, the substituent R^cThe C of_1-6Alkyl radical, C_1-4Alkoxy group, and C_1-4The alkylamino groups are further each independently unsubstituted or substituted with one or more substituents selected from the group consisting of: c_1-6Alkyl radical, C_1-4Alkoxy group, and C_1-4Alkylamino radical, the substituent R^cSaid 3-to 10-membered heterocycloalkyl of (a) is further unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen; a carbonyl group; unsubstituted or substituted by C_1-4Alkylamino substituted C_1-6An alkyl group; c_2-4An alkenyl group; c_1-4An alkylamino group; c_1-4An alkylcarbonyl group; and unsubstituted or substituted by C_1-4Alkyl-substituted 3-to 8-membered heterocycloalkyl having one or two heteroatoms selected from the group consisting of N and O, R ¹²And R¹³Each independently is hydrogen; c_2-4An alkenylcarbonyl group; or unsubstituted or substituted by C_1-4Alkyl-substituted 3-to 8-membered heterocycloalkyl having one or two N atoms, and through R⁹And R¹⁰The 3-to 8-membered heteroaryl group formed is unsubstituted or C_1-4The substitution of the alkyl group is carried out,

R⁵is C substituted with 3-to 8-membered aryl or 3-to 8-membered heteroaryl_1-4Alkyl, 3-to 8-membered aryl, or 3-to 8-membered heteroaryl, wherein R is⁵Each of the 3-to 8-membered aryl and 3-to 8-membered heteroaryl of (a) is independently unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen, cyano, unsubstituted or halogen-substituted C_1-4Alkyl radical, C_1-4Alkoxy group, and C_2-4Alkynyl, and R⁵The C substituted with 3-to 8-membered aryl or 3-to 8-membered heteroaryl of_1-4Alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen, unsubstituted or halogen-substituted C_1-4Alkyl, and C_1-4Alkylamino, and

R⁶is hydrogen or C_1-4An alkyl group.

5. The compound of claim 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula 1 is represented by formula 2 below:

[ formula 2]

Wherein, in formula 2, R¹Is hydrogen or C_1-4An alkoxy group,

R³is-X-Y-Z, wherein X and Y are each independently a single bond or a 3-to 8-membered heterocycloalkyl group containing at least one N atom, and Z is-NR¹⁷R¹⁸Or represented by the following formula 3,

[ formula 3]

When Z is-NR¹⁷R¹⁸When at least one of X and Y is a 3-to 8-membered heterocycloalkyl group containing at least one N atom, wherein R is¹⁷And R¹⁸Each independently of the others being hydrogen or unsubstituted or substituted by C_1-4Alkylamino substituted C_1-4Alkyl, or R¹⁷And R¹⁸Together with the nitrogen atom to which they are attached to form a 3-to 12-membered heterocycloalkyl,

when Z is formula 3, L is unsubstituted or substituted by C_1-4Alkyl substituted C_1-4Alkylene, M being-NR¹⁹or-O-, T and Q are each independently of the other hydrogen or unsubstituted or C_1-4Alkylamino substituted C_1-4Alkyl, T and Q being linked to one another to form unsubstituted or C_1-4An alkyl-substituted 3 to 12 membered heterocycloalkyl, or T and Q are linked to each other and further linked between two or more different atoms of the ring member atoms to form unsubstituted or C_1-4An alkyl-substituted 3-to 12-membered bridged or fused heterocycloalkyl group, and R¹⁹Is hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_1-6Alkylcarbonyl group, C_1-4Alkylamino, or 3-to 8-membered heterocycloalkyl, and

R⁵is 3 to 8 membered aralkyl, 3 to 8 membered aryl, or 3 to 8 membered heteroaryl, wherein R is ⁵Each of the 3-to 8-membered aralkyl, 3-to 8-membered aryl, and 3-to 8-membered heteroaryl of (a) is independently unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen, cyano, C_1-4Alkyl, and C_1-4An alkoxy group.

6. The compound, stereoisomer, hydrate thereof, or pharmaceutically acceptable salt thereof according to claim 5, wherein R¹Is hydrogen, methoxy, or ethoxy.

7. The compound, stereoisomer, hydrate thereof, or pharmaceutically acceptable salt thereof according to claim 5, wherein R³is-X-Y-Z, wherein X and Y are each independently a single bond, azetidine, pyrrolidine, piperidine, or piperazine, and Z is-NR¹⁷R¹⁸Or represented by the following formula 3,

[ formula 3]

When Z is-NR¹⁷R¹⁸When X and Y are azetidine, pyrrolidine, piperidine, or piperazine, wherein R is¹⁷And R¹⁸Each independently being methyl or ethyl, or R¹⁷And R¹⁸Together with the nitrogen atom to which they are attached form an azaspirooctane,

when Z is formula 3, L is the following group unsubstituted or substituted with methyl or ethyl: methylene, ethylene, propylene, or butylene,

m is-NR¹⁹or-O-and T and Q are each independently methyl or ethyl unsubstituted or substituted with dimethylamino; or M is-NR ¹⁹And T and Q are linked to each other to form unsubstituted or methyl-or ethyl-substituted piperazine; or M is-NR¹⁹And T and Q are linked to each other and further between two or more different atoms of the ring member atoms to form a 6-to 8-membered diazabicycloalkyl group which is unsubstituted or substituted with methyl or ethyl; or M is-O-and T and Q are linked to each other to form morpholine which is unsubstituted or substituted by methyl or ethyl; or M is-O-and T and Q are linked to each other and further linked between two or more different atoms of the ring member atoms to form a 6-to 8-membered oxazabicycloalkyl which is unsubstituted or substituted by methyl or ethyl, and

R¹⁹is hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, prop-2-en-1-yl, acetyl, dimethylamino, or oxetane.

8. The compound, stereoisomer, hydrate thereof, or pharmaceutically acceptable salt thereof according to claim 5, wherein R⁵Is phenyl, benzyl, pyridine, or thiophene, wherein the phenyl, the benzyl, the pyridine, and the thiophene are each independently unsubstituted or substituted with one or more substituents selected from the group consisting of: fluoro, chloro, cyano, methyl unsubstituted or substituted with at least one fluoro, and methoxy.

9. The compound, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound represented by formula 1 is any one of the following compounds 1 to 1059:

1) n- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((6- ((S) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

2) n- (4-methoxy-2-morpholino-5- ((6- ((S) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

3) n- (4-methoxy-2- (4-methylpiperazin-1-yl) -5- ((6- ((S) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

4) n- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

5) n- (4-methoxy-2-morpholino-5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

6) n- (4-methoxy-2- (4-methylpiperazin-1-yl) -5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

7) n- (2- (4-cyclopropylpiperazin-1-yl) -4-methoxy-5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

8) N- (2- (2- (dimethylamino) ethoxy) -4-methoxy-5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

9) n- (4-methoxy-2- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

10) n- (4-methoxy-2- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) -5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

11) n- (4-methoxy-2- (4-morpholinopiperidin-1-yl) -5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

12) n- (2- (4- (dimethylamino) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

13) n- (2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -4-methoxy-5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

14) n- (2- ((S) -3- (dimethylamino) pyrrolidin-1-yl) -4-methoxy-5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

15) n- (2- (4-ethylpiperazin-1-yl) -4-methoxy-5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

16) N- (2- (4-acetylpiperazin-1-yl) -4-methoxy-5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

17) n- (4-methoxy-2- ((2-methoxyethyl) (methyl) amino) -5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

18) n- (4-methoxy-2- (4- (oxetan-3-yl) piperazin-1-yl) -5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

19) n- (4-methoxy-2- (2-methyl-1H-imidazol-1-yl) -5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

20) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide;

21) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide;

22) n- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((6- ((R) -3- (3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

23) n- (5- ((6- ((R) -3- (3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide;

24) N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((6- ((R) -3- (3-methoxyphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

25) n- (4-methoxy-5- ((6- ((R) -3- (3-methoxyphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-methylpiperazin-1-yl) phenyl) acrylamide;

26) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

27) n- (2- (4- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (3-methoxyphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

28) n- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

29) n- (2- (4-methylpiperazin-1-yl) -5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

30) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-morpholinopiperidin-1-yl) phenyl) acrylamide;

31) n- (5- ((6- ((R) -3- (3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

32) N- (4-methoxy-2- (5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) -5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

33) n- (2- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -4-methoxy-5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

34) n- (2- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -4-methoxy-5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

35) n- (4-methoxy-2- (3-methyl-3, 6-diazabicyclo [3.1.1] hept-6-yl) -5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

36) n- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((6- ((R) -3- (6-methylpyridin-3-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

37) n- (5- ((6- ((R) -3- (4-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide;

38) n- (5- ((6- ((R) -3- (3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-morpholinopiperidin-1-yl) phenyl) acrylamide;

39) N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((6- ((R) -3- (4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

40) n- (4-methoxy-5- ((6- ((R) -3- (3-methoxyphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

41) n- (2- (4- (4-ethylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (6-methylpyridin-3-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

42) n- (2- (4-ethylpiperazin-1-yl) -4-methoxy-5- ((6- ((R) -3- (6-methylpyridin-3-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

43) n- (4-methoxy-5- ((6- ((R) -3- (6-methylpyridin-3-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2-morpholinophenyl) acrylamide;

44) n- (4-methoxy-2- (4-methylpiperazin-1-yl) -5- ((6- ((R) -3- (6-methylpyridin-3-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

45) n- (4-methoxy-5- ((6- ((R) -3- (6-methylpyridin-3-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-morpholinopiperidin-1-yl) phenyl) acrylamide;

46) n- (2- (4-cyclopropylpiperazin-1-yl) -4-methoxy-5- ((6- ((R) -3- (6-methylpyridin-3-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

47) N- (4-methoxy-2- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (6-methylpyridin-3-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

48) n- (4-methoxy-2- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) -5- ((6- ((R) -3- (6-methylpyridin-3-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

49) n- (2- (4-acetylpiperazin-1-yl) -4-methoxy-5- ((6- ((R) -3- (6-methylpyridin-3-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

50) n- (2- (4-dimethylaminopiperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (6-methylpyridin-3-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

51) n- (2- ((1R,4R) -5-ethyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) -4-methoxy-5- ((6- ((R) -3- (6-methylpyridin-3-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

52) n- (4-methoxy-2- (4- (5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) piperidin-1-yl) -5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

53) n- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

54) N- (2- (4- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

55) n- (2- (4- (4-ethylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

56) n- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

57) n- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

58) n- (5- ((6- ((R) -3- (4-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

59) n- (5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

60) n- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 4-dichloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

61) N- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

62) n- (5- ((6- ((R) -3- (3-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

63) n- (5- ((6- ((R) -3- (4-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

64) n- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

65) n- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (3-methoxyphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

66) n- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

67) n- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (6-methylpyridin-3-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

68) N- (2- (4- (4-cyclobutylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

69) n- (2- (4- (4-cyclobutylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (3-methoxyphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

70) n- (5- ((6- ((R) -3- (3-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-cyclobutylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

71) n- (5- ((6- ((R) -3- (4-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-cyclobutylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

72) n- (2- (4- (4-cyclobutylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

73) n- (5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-cyclobutylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

74) n- (2- (4- (4-cyclobutylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 4-dichloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

75) N- (5- ((6- ((R) -3- (4-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-cyclobutylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

76) n- (2- (4- (4-cyclobutylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

77) n- (2- (4- (4-cyclobutylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

78) n- (2- (4- (4-cyclobutylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2-fluoro-3-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

79) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4- (oxetan-3-yl) piperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

80) n- (5- ((6- ((R) -3- (3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4- (oxetan-3-yl) piperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

81) n- (4-methoxy-5- ((6- ((R) -3- (3-methoxyphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4- (oxetan-3-yl) piperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

82) N- (5- ((6- ((R) -3- (4-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4- (oxetan-3-yl) piperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

83) n- (5- ((6- ((R) -3- (4-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4- (oxetan-3-yl) piperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

84) n- (5- ((6- ((R) -3- (3, 4-dichloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4- (oxetan-3-yl) piperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

85) n- (5- ((6- ((R) -3- (4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4- (oxetan-3-yl) piperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

86) n- (5- ((6- ((R) -3- (3-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4- (oxetan-3-yl) piperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

87) n- (2- (4- (4-allylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

88) n- (2- (4- (4-allylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

89) N- (2- (4- (4-allylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

90) n- (2- (4- (4-allylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

91) n- (2- (4- (4- (cyclopropylmethyl) piperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

92) n- (2- (4- (4- (cyclopropylmethyl) piperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

93) n- (2- (4- (4- (cyclopropylmethyl) piperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

94) n- (5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4- (cyclopropylmethyl) piperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

95) n- (2- (4- (4- (cyclopropylmethyl) piperazin-1-yl) piperidin-1-yl) -5- ((6- ((S) -3- (2, 6-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

96) N- (5- ((6- ((R) -3- (3-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4- (cyclopropylmethyl) piperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

97) n- (2- (4- (4-cyclopentylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

98) n- (2- (4- (4-cyclopentylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

99) n- (5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-cyclopentylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

100) n- (2- (4- (4-cyclopentylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

101) n- (5- ((6- ((R) -3- (3-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-cyclopentylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

102) n- (4-methoxy-5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4- (tetrahydro-2H-pyran-4-yl) piperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

103) N- (2- (4- (2-oxa-6-azaspiro [3.3] hept-6-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

104) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (5-ethylhexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

105) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- ((3aR,6aS) -tetrahydro-1H-furo [3,4-c ] pyrrol-5 (3H) -yl) piperidin-1-yl) phenyl) acrylamide;

106) n- (2- (4- (4-cyclopropyl-3, 3-dimethylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

107) n- (2- (4- ((2R,5S) -4-cyclopropyl-2, 5-dimethylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

108) n- (2- (4- ((2S,5R) -4-cyclopropyl-2, 5-dimethylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

109) N- (2- (4- ((R) -4-cyclopropyl-3-methylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

110) n- (2- (4- ((S) -4-cyclopropyl-3-methylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

111) n- (2- (4- ((S) -4-cyclopropyl-2-methylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

112) n- (2- (4- ((R) -4-cyclopropyl-2-methylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

113) n- (2- (4- ((2S,5S) -4-cyclopropyl-2, 5-dimethylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

114) n- (2- (4- ((2R,5R) -4-cyclopropyl-2, 5-dimethylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

115) N- (2- (4- ((1R,5S) -8-cyclopropyl-3, 8-diazabicyclo [3.2.1] oct-3-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

116) n- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-ethoxyphenyl) acrylamide;

117) n- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) - (E) -4- (dimethylamino) but-2-enamide;

118) n- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((S) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

119) n- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4- (((R) -1,1, 1-trifluoropropan-2-yl) oxy) phenyl) acrylamide;

120) n- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) -2-fluoroacrylamide;

121) N- (5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((2S,5S) -4-cyclopropyl-2, 5-dimethylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

122) n- (5- ((6- ((R) -3- (3-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((2R,5R) -4-cyclopropyl-2, 5-dimethylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

123) n- (2- (4- ((2S,5S) -4-cyclopropyl-2, 5-dimethylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2-fluoro-3-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

124) n- (2- (4- ((2R,5R) -4-cyclopropyl-2, 5-dimethylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2-fluoro-3-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

125) n- (5- ((6- ((R) -3- (3-cyanophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((S) -4-cyclopropyl-3-methylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

126) n- (5- ((6- ((R) -3- (3-cyanophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((R) -4-cyclopropyl-3-methylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

127) N- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2, 3-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

128) n- (5- ((6- ((R) -3- (3-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((2S,5S) -4-cyclopropyl-2, 5-dimethylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

129) n- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((S) -3- (2, 6-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

130) n- (5- ((6- ((R) -3- (4-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

131) n- (5- ((6- ((R) -3- (3-cyanophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((R) -4-cyclopropyl-2-methylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

132) n- (5- ((6- ((R) -3- (3-cyanophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((S) -4-cyclopropyl-2-methylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

133) n- (5- ((6- ((R) -3- (3-cyanophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (8-cyclopropyl-3, 8-diazabicyclo [3.2.1] oct-3-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

134) N- (2- (4- (8-cyclopropyl-3, 8-diazabicyclo [3.2.1] oct-3-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

135) n- (2- (4- (8-cyclopropyl-3, 8-diazabicyclo [3.2.1] oct-3-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2, 3-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

136) n- (2- (4- ((S) -4-cyclopropyl-3-methylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2, 6-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

137) n- (2- (4- ((R) -4-cyclopropyl-3-methylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2, 6-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

138) n- (5- ((6- ((R) -3- (3-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

139) n- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

140) n- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2-fluoro-3-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

141) N- (5- ((6- ((R) -3- (3-cyanophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

142) n- (5- ((6- ((R) -3- (2-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (8-cyclopropyl-3, 8-diazabicyclo [3.2.1] oct-3-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

143) n- (5- ((6- ((R) -3- (2-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((R) -4-cyclopropyl-2-methylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

144) n- (5- ((6- ((R) -3- (2-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((S) -4-cyclopropyl-2-methylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

145) n- (5- ((6- ((R) -3- (3-chloro-2-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

146) n- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (naphthalen-1-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

147) n- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (thiophen-2-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

148) N- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (3- (trifluoromethyl) phenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

149) n- (5- ((6- ((R) -3- (3-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((R) -4-cyclopropyl-2-methylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

150) n- (5- ((6- ((R) -3- (3-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((S) -4-cyclopropyl-2-methylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

151) n- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (naphthalen-2-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

152) n- (5- ((6- ((R) -3- (3-chloro-2-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((R) -4-cyclopropyl-3-methylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

153) n- (5- ((6- ((R) -3- (3-chloro-2-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((S) -4-cyclopropyl-3-methylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

154) n- (5- ((6- ((R) -3- (3-chloro-2-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (8-cyclopropyl-3, 8-diazabicyclo [3.2.1] oct-3-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

155) N- (2- (4- ((R) -4-cyclopropyl-3-methylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (naphthalen-1-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

156) n- (2- (4- ((S) -4-cyclopropyl-3-methylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (naphthalen-1-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

157) n- (5- ((6- ((R) -3- (3-chloro-5-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((S) -4-cyclopropyl-3-methylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

158) n- (5- ((6- ((R) -3- (3-chloro-5-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((R) -4-cyclopropyl-3-methylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

159) n- (5- ((6- ((R) -3- (3-chloro-5-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((R) -4-cyclopropyl-2-methylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

160) n- (5- ((6- ((R) -3- (3-chloro-5-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((S) -4-cyclopropyl-2-methylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

161) n- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

162) N- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2, 3-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

163) n- (5- ((6- ((R) -3- (3-chloro-5-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

164) n- (5- ((6- ((R) -3- (2-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

165) n- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-ethynylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

166) n- (2- (4- ((R) -4-cyclopropyl-3-methylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (2,3, 6-trifluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

167) n- (2- (4- ((S) -4-cyclopropyl-3-methylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (2,3, 6-trifluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

168) n- (5- ((6- ((R) -3- (3-chloro-2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

169) N- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (2,3, 6-trifluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

170) n- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (2,3, 4-trifluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

171) n- (2- (4- ((2S,5S) -4-cyclopropyl-2, 5-dimethylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

172) n- (2- (4- ((2R,5R) -4-cyclopropyl-2, 5-dimethylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

173) n- (2- (4- ((2R,5S) -4-cyclopropyl-2, 5-dimethylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

174) n- (2- (4- ((2S,5R) -4-cyclopropyl-2, 5-dimethylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

175) N- (2- (4- ((S) -4-cyclopropyl-3-methylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2, 3-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

176) n- (2- (4- ((R) -4-cyclopropyl-3-methylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2, 3-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

177) n- (5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((S) -4-cyclopropyl-3-methylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

178) n- (5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((2R,5R) -4-cyclopropyl-2, 5-dimethylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

179) n- (5- ((6- ((R) -3- (3-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((S) -4-cyclopropyl-3-methylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

180) n- (5- ((6- ((R) -3- (3-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((R) -4-cyclopropyl-3-methylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

181) N- (5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-cyclopropyl-3, 3-dimethylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

182) n- (2- (4- (4-cyclobutylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2, 3-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

183) n- (5- ((6- ((R) -3- (3-cyanophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-cyclobutylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

184) n- (2- (4- (4-cyclobutylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (naphthalen-1-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

185) n- (5- ((6- ((R) -3- (3-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-cyclobutylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

186) n- (2- (4- (4-cyclobutylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

187) n- (2- (4- (4-cyclobutylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (2,3, 4-trifluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

188) N- (5- ((6- ((R) -3- (3-chloro-2-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-cyclobutylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

189) n- (5- ((6- ((R) -3- (3-chloro-5-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-cyclobutylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

190) n- (2- (4- (4-cyclobutylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (naphthalen-2-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

191) n- (2- (4- (4-cyclobutylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-ethynylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

192) n- (5- ((6- ((R) -3- (2-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-cyclobutylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

193) n- (5- ((6- ((R) -3- (3-chloro-2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-cyclobutylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

194) n- (2- (4- (4-cyclobutylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (2,3, 6-trifluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

195) N- (5- ((6- ((R) -3- (2, 3-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4- (oxetan-3-yl) piperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

196) n- (5- ((6- ((R) -3- (3-cyanophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4- (oxetan-3-yl) piperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

197) n- (5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4- (oxetan-3-yl) piperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

198) n- (4-methoxy-5- ((6- ((R) -3- (naphthalen-1-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4- (oxetan-3-yl) piperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

199) n- (5- ((6- ((R) -3- (3-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4- (oxetan-3-yl) piperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

200) n- (4-methoxy-5- ((6- ((R) -3- (naphthalen-2-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4- (oxetan-3-yl) piperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

201) n- (5- ((6- ((R) -3- (2-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4- (oxetan-3-yl) piperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

202) N- (5- ((6- ((R) -3- (3-chloro-2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4- (oxetan-3-yl) piperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

203) n- (2- (4- (4- (cyclopropylmethyl) piperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

204) n- (2- (4- (4- (cyclopropylmethyl) piperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2, 3-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

205) n- (2- (4- (4-cyclopentylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

206) n- (2- (4- (4-cyclopentylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2, 3-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

207) n- (5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4- (tetrahydro-2H-pyran-4-yl) piperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

208) n- (5- ((6- ((R) -3- (2, 3-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4- (tetrahydro-2H-pyran-4-yl) piperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

209) N- (2- (4- (4-allylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2, 3-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

210) n- (2- (4- (4-allylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-cyanophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

211) n- (2- (4- (4-allylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (4-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

212) n- (2- (4- (4-allylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

213) n- (2- (4- (4-allylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-chloro-2-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

214) n- (2- (4- (4-allylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-chloro-5-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

215) n- (2- (4- (4-allylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (3-methoxyphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

216) N- (2- (4- (4-allylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-ethynylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

217) n- (2- ((1S,4S) -5-ethyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) -4-methoxy-5- ((6- ((R) -3- (6-methylpyridin-3-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

218) n- (4-methoxy-5- ((6- ((R) -3- (6-methylpyridin-3-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (oxetan-3-yl) piperazin-1-yl) phenyl) acrylamide;

219) n- (2- (4- (2- (dimethylamino) ethyl) piperazin-1-yl) -4-methoxy-5- ((6- ((R) -3- (6-methylpyridin-3-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

220) n- (2- (4-isopropylpiperazin-1-yl) -4-methoxy-5- ((6- ((R) -3- (6-methylpyridin-3-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

221) n- (2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (6-methylpyridin-3-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

222) n- (2- ((S) -3- (dimethylamino) pyrrolidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (6-methylpyridin-3-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

223) N- (4-methoxy-2- ((2-methoxyethyl) (methyl) amino) -5- ((6- ((R) -3- (6-methylpyridin-3-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

224) n- (2- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -4-methoxy-5- ((6- ((R) -3- (6-methylpyridin-3-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

225) n- (2- (4-cyclopentylpiperazin-1-yl) -4-methoxy-5- ((6- ((R) -3- (6-methylpyridin-3-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

226) n- (2- (4-cyclopentylpiperazin-1-yl) -4-methoxy-5- ((6- ((R) -3- (6-methylpyridin-3-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

227) n- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (6-methylpyridin-3-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

228) n- (2- (4- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (6-methylpyridin-3-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

229) n- (4-methoxy-2- (4- ((2-methoxyethyl) (methyl) amino) piperidin-1-yl) -5- ((6- ((R) -3- (6-methylpyridin-3-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

230) N- (2- (4- (4-isopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (6-methylpyridin-3-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

231) n- (2- (4- ((R) -3- (dimethylamino) pyrrolidin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (6-methylpyridin-3-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

232) n- (2- (4- (4-acetylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (6-methylpyridin-3-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

233) n- (2- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -4-methoxy-5- ((6- ((R) -3- (6-methylpyridin-3-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

234) n- (4-methoxy-2- (4- ((1R,4R) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) piperidin-1-yl) -5- ((6- ((R) -3- (6-methylpyridin-3-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

235) n- (4-methoxy-5- ((6- ((R) -3- (6-methylpyridin-3-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-morpholino- [1,4 '-bipiperidin ] -1' -yl) phenyl) acrylamide;

236) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-ethylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

237) N- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((R) -3- (dimethylamino) pyrrolidin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

238) n- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

239) n- (2- (4- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

240) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-ethylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

241) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (dimethylamino) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

242) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -4-methoxyphenyl) acrylamide;

243) n- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

244) N- (2- (4- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

245) n- (2- (4- (dimethylamino) piperidin-1-yl) -5- ((6- ((R) -3- (3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

246) n- (2- (4-ethylpiperazin-1-yl) -5- ((6- ((R) -3- (3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

247) n- (2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -5- ((6- ((R) -3- (3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

248) n- (2- (4- (4-ethylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

249) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (3-ethyl-3, 6-diazabicyclo [3.1.1] hept-6-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

250) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((S) -3- (dimethylamino) pyrrolidin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

251) N- (2- (4- (4-acetylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

252) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (6-ethyl-3, 6-diazabicyclo [3.1.1] hept-3-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

253) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2-4- (dimethylamino) -1,4 '-bipiperidin-1' -yl) -4-methoxyphenyl) acrylamide;

254) n- (5- ((6- ((R) -3- (4-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-ethylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

255) n- (5- ((6- ((R) -3- (4-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-ethylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

256) n- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (4-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

257) n- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

258) N- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

259) n- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

260) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- ((1S,4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) piperidin-1-yl) phenyl) acrylamide;

261) n- (2- (4- (4-ethylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- (3-methyl-3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

262) n- (5- ((6- ((R) -3- (4-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-ethylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

263) n- (5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-ethylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

264) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((1S,4S) -5-ethyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

265) N- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-isopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

266) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((2S,6R) -2, 6-dimethylmorpholino) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

267) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((1R,4R) -5-ethyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

268) n- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 4-dichloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

269) n- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((S) -3-methyl-3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

270) n- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3-methyl-3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

271) N- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((R) -3-morpholinopyrrolidin-1-yl) phenyl) acrylamide;

272) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((S) -3-morpholinopyrrolidin-1-yl) phenyl) acrylamide;

273) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (oxetan-3-yl) piperazin-1-yl) phenyl) acrylamide;

274) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4-methyl-3-oxopiperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

275) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((1-isopropylpiperidin-4-yl) amino) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

276) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((2- (dimethylamino) ethyl) (methyl) amino) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

277) n- (2- (4- (cyclopropylmethyl) piperazin-1-yl) -4-methoxy-5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

278) N- (2- (4- (2- (dimethylamino) ethyl) piperazin-1-yl) -4-methoxy-5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

279) n- (2- (4-cyclopentylpiperazin-1-yl) -4-methoxy-5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

280) n- (2- ((1R,4R) -5-ethyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) -4-methoxy-5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

281) n- (2- ((1S,4S) -5-ethyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) -4-methoxy-5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

282) n- (4-methoxy-2- (4-methyl-1H-imidazol-1-yl) -5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

283) n- (2- (4- (4-isopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

284) n- (2- (4- (4-acetylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

285) n- (2- (4- ((2S,6R) -2, 6-dimethylmorpholino) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

286) N- (2- (4- ((S) -3- (dimethylamino) pyrrolidin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

287) n- (5- ((6- ((R) -3- (3, 4-dichloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (oxetan-3-yl) piperazin-1-yl) phenyl) acrylamide;

288) n- (5- ((6- ((R) -3- (3, 4-dichloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide;

289) n- (5- ((6- ((R) -3- (3, 4-dichloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide;

290) n- (5- ((6- ((R) -3- (3, 4-dichloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (dimethylamino) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

291) n- (5- ((6- ((R) -3- (3, 4-dichloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -4-methoxyphenyl) acrylamide;

292) n- (5- ((6- ((R) -3- (3, 4-dichloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-ethylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

293) N- (5- ((6- ((R) -3- (3, 4-dichloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-ethylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

294) n- (5- ((6- ((R) -3- (3, 4-dichloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((R) -3-morpholinopyrrolidin-1-yl) phenyl) acrylamide;

295) n- (5- ((6- ((R) -3- (3, 4-dichloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((S) -3-morpholinopyrrolidin-1-yl) phenyl) acrylamide;

296) n- (5- ((6- ((R) -3- (4-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (oxetan-3-yl) piperazin-1-yl) phenyl) acrylamide;

297) n- (5- ((6- ((R) -3- (2, 3-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-ethylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

298) n- (2- (4-acetylpiperazin-1-yl) -5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

299) n- (2- (4-cyclopropylpiperazin-1-yl) -5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

300) N- (5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-propylpiperazin-1-yl) phenyl) acrylamide;

301) n- (5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((S) -3- (dimethylamino) pyrrolidin-1-yl) -4-methoxyphenyl) acrylamide;

302) n- (5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((S) -3-morpholinopyrrolidin-1-yl) phenyl) acrylamide;

303) n- (5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-isopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

304) n- (5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((R) -3- (dimethylamino) pyrrolidin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

305) n- (5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (dimethylamino) - (1,4 '-bipiperidin) -1' -yl) -4-methoxyphenyl) acrylamide;

306) n- (5- ((6- ((S) -3- (2, 6-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide;

307) N- (5- ((6- ((S) -3- (2, 6-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide;

308) n- (5- ((6- ((S) -3- (2, 6-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (dimethylamino) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

309) n- (5- ((6- ((S) -3- (2, 6-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((2S,6R) -2, 6-dimethylmorpholino) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

310) n- (2- (4- (4-acetylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((S) -3- (2, 6-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

311) n- (5- ((6- ((S) -3- (2, 6-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-isopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

312) n- (5- ((6- ((S) -3- (2, 6-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-ethylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

313) n- (5- ((6- ((S) -3- (2, 6-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((S) -3, 4-dimethylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

314) N- (5- ((6- ((S) -3- (2, 6-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((R) -3- (dimethylamino) pyrrolidin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

315) n- (5- ((6- ((S) -3- (2, 6-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((S) -3- (dimethylamino) pyrrolidin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

316) n- (5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((3aS,6aS) -1-methylhexahydropyrrolo [3,4-b ] pyrrol-5 (1H) -yl) phenyl) acrylamide;

317) n- (5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((3aR,6aR) -1-methylhexahydropyrrolo [3,4-b ] pyrrol-5 (1H) -yl) phenyl) acrylamide;

318) n- (2- (4- (4-ethylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2-fluoro-3-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

319) n- (5- ((6- ((R) -3- (2-fluoro-3-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((2-methoxyethyl) (methyl) amino) phenyl) acrylamide;

320) n- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2-fluoro-3-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

321) N- (5- ((6- ((R) -3- (3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((S) -3-morpholinopyrrolidin-1-yl) phenyl) acrylamide;

322) n- (2- (4- ((1R,5S) -8-oxa-3-azabicyclo [3.2.1] oct-3-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

323) n- (5- ((6- ((R) -3- (3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((R) -3-morpholinopyrrolidin-1-yl) phenyl) acrylamide;

324) n- (2- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

325) n- (5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2-morpholinophenyl) acrylamide;

326) n- (5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide;

327) n- (5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((2-methoxyethyl) (methyl) amino) phenyl) acrylamide;

328) N- (2- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

329) n- (2- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

330) n- (5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (2-methyl-1H-imidazol-1-yl) phenyl) acrylamide;

331) n- (5- ((6- ((R) -3- (3-cyanophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((3aR,6aR) -1-methylhexahydropyrrolo [3,4-b ] pyrrol-5 (1H) -yl) phenyl) acrylamide;

332) n- (5- ((6- ((R) -3- (3-cyanophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((3aS,6aS) -1-methylhexahydropyrrolo [3,4-b ] pyrrol-5 (1H) -yl) phenyl) acrylamide;

333) n- (2- (4-cyclopropylpiperazin-1-yl) -5- ((6- ((R) -3- (2, 3-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

334) n- (5- ((6- ((R) -3- (2, 3-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-isopropylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

335) N- (5- ((6- ((R) -3- (2, 3-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((S) -3, 4-dimethylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

336) n- (5- ((6- ((R) -3- (2, 3-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((R) -3, 4-dimethylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

337) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((S) -2-methylmorpholino) phenyl) acrylamide;

338) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((R) -2-methylmorpholino) phenyl) acrylamide;

339) n- (2- (4- (4-acetylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2, 3-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

340) n- (5- ((6- ((R) -3- (2, 3-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((S) -3- (dimethylamino) pyrrolidin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

341) n- (2- (4, 4-difluoro- [1,4 '-bipiperidin ] -1' -yl) -5- ((6- ((R) -3- (2, 3-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

342) N- (5- ((6- ((R) -3- (2, 3-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4-propylpiperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

343) n- (2- (4-acetylpiperazin-1-yl) -5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

344) n- (2- (4-cyclopropylpiperazin-1-yl) -5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

345) n- (5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) acrylamide;

346) n- (5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-isopropylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

347) n- (5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((2-methoxyethyl) (methyl) amino) phenyl) acrylamide;

348) n- (2- (4-cyclopentylpiperazin-1-yl) -5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

349) n- (5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (2- (dimethylamino) ethyl) piperazin-1-yl) -4-methoxyphenyl) acrylamide;

350) N- (5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide;

351) n- (5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-ethylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

352) n- (5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

353) n- (2- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

354) n- (5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((1S,4S) -5-ethyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) -4-methoxyphenyl) acrylamide;

355) n- (2- (4- (6-azaspiro [2.5] oct-6-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

356) n- (5- ((6- ((R) -3- (3-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- ((S) -2-methylmorpholino) piperidin-1-yl) phenyl) acrylamide;

357) N- (5- ((6- ((R) -3- (3-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- ((R) -2-methylmorpholino) piperidin-1-yl) phenyl) acrylamide;

358) n- (5- ((6- ((R) -3- (3-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-cyclopropyl-1, 4-diazepan-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

359) n- (5- ((6- ((R) -3- (3-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide;

360) n- (5- ((6- ((R) -3- (3-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide;

361) n- (5- ((6- ((R) -3- (3-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (dimethylamino) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

362) n- (2- (4- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2-fluoro-3-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

363) n- (2- (4-acetylpiperazin-1-yl) -5- ((6- ((R) -3- (4-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

364) N- (5- ((6- ((R) -3- (4-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-cyclopropylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

365) n- (5- ((6- ((R) -3- (4-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((S) -3-morpholinopyrrolidin-1-yl) phenyl) acrylamide;

366) n- (5- ((6- ((S) -3- (2, 6-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -4-methoxyphenyl) acrylamide;

367) n- (5- ((6- ((S) -3- (2, 6-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((R) -3-morpholinopyrrolidin-1-yl) phenyl) acrylamide;

368) n- (5- ((6- ((S) -3- (2, 6-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((S) -3-morpholinopyrrolidin-1-yl) phenyl) acrylamide;

369) n- (5- ((6- ((S) -3- (2, 6-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (dimethylamino) - [1,4 '-bipiperidin ] -1' -yl) -4-methoxyphenyl) acrylamide;

370) n- (5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((3S,5R) -4-ethyl-3, 5-dimethylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

371) N- (5- ((6- ((R) -3- (4-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide;

372) n- (5- ((6- ((R) -3- (4-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide;

373) n- (2- (4- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (4-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

374) n- (5- ((6- ((R) -3- (4-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((2S,6R) -2, 6-dimethylmorpholino) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

375) n- (2- (4- (4-acetylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (4-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

376) n- (5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -4-methoxyphenyl) acrylamide;

377) n- (5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (5-methyl-1H-imidazol-1-yl) phenyl) acrylamide;

378) N- (5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-morpholinopiperidin-1-yl) phenyl) acrylamide;

379) n- (5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (tetrahydro-2H-pyran-4-yl) piperazin-1-yl) phenyl) acrylamide;

380) n- (2- (4- (cyclopropylmethyl) piperazin-1-yl) -5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

381) n- (2- (4- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

382) n- (5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((1S,4S) -5-ethyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

383) n- (5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (oxetan-3-yl) piperazin-1-yl) phenyl) acrylamide;

384) n- (5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (dimethylamino) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

385) N- (5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((1R,4R) -5-ethyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) -4-methoxyphenyl) acrylamide;

386) n- (5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-methyl-1H-imidazol-1-yl) phenyl) acrylamide;

387) n- (5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- ((2-methoxyethyl) (methyl) amino) piperidin-1-yl) phenyl) acrylamide;

388) n- (5- ((6- ((R) -3- (3-cyanophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- ((R) -3-methylmorpholino) piperidin-1-yl) phenyl) acrylamide;

389) n- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-cyanophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

390) n- (5- ((6- ((R) -3- (3-cyanophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-hydroxypiperidin-1-yl) -4-methoxyphenyl) acrylamide;

391) n- (5- ((6- ((R) -3- (3-cyanophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (oxetan-3-yl) piperazin-1-yl) phenyl) acrylamide;

392) N- (5- ((6- ((R) -3- (3-cyanophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide;

393) n- (5- ((6- ((R) -3- (3-cyanophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide;

394) n- (5- ((6- ((R) -3- (3-cyanophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (dimethylamino) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

395) n- (5- ((6- ((R) -3- (3-cyanophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -4-methoxyphenyl) acrylamide;

396) n- (5- ((6- ((R) -3- (3-cyanophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-ethylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

397) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2-morpholinophenyl) - (E) -4- (dimethylamino) but-2-enamide;

398) n- (5- ((6- ((R) -3- (3-cyanophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

399) N- (5- ((6- ((R) -3- (3-cyanophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-ethylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

400) n- (5- ((6- ((R) -3- (3-cyanophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-morpholinopiperidin-1-yl) phenyl) acrylamide;

401) n- (5- ((6- ((R) -3- (4-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-ethylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

402) n- (1- (2-acrylamido-4- ((6- ((R) -3- (4-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -5-methoxyphenyl) piperidin-4-yl) -N- (1-isopropylpiperidin-4-yl) acrylamide;

403) n- (5- ((6- ((R) -3- (4-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (dimethylamino) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

404) n- (5- ((6- ((R) -3- (4-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((R) -3- (dimethylamino) pyrrolidin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

405) n- (5- ((6- ((R) -3- (4-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((S) -3- (dimethylamino) pyrrolidin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

406) N- (5- ((6- ((R) -3- (4-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((R) -3-morpholinopyrrolidin-1-yl) phenyl) acrylamide;

407) n- (5- ((6- ((R) -3- (4-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((S) -3-morpholinopyrrolidin-1-yl) phenyl) acrylamide;

408) n- (5- ((6- ((R) -3- (4-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-isopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

409) n- (5- ((6- ((R) -3- (4-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-ethylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

410) n- (5- ((6- ((R) -3- (4-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (dimethylamino) - [1,4 '-bipiperidin ] -1' -yl) -4-methoxyphenyl) acrylamide;

411) n- (5- ((6- ((R) -3- (3-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-ethylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

412) n- (5- ((6- ((R) -3- (3-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-ethylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

413) N- (5- ((6- ((R) -3- (3-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((R) -3- (dimethylamino) pyrrolidin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

414) n- (5- ((6- ((R) -3- (3-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (dimethylamino) - [1,4 '-bipiperidine ] -1' -yl) -4-methoxyphenyl) acrylamide;

415) n- (5- ((6- ((R) -3- (3-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((2S,6R) -2, 6-dimethylmorpholino) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

416) n- (5- ((6- ((R) -3- (3-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

417) n- (5- ((6- ((R) -3- (3-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-morpholinopiperidin-1-yl) phenyl) acrylamide;

418) n- (2- (4- ((R) -3- (dimethylamino) pyrrolidin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2-fluoro-3-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

419) n- (5- ((6- ((R) -3- (4-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((R) -3-morpholinopyrrolidin-1-yl) phenyl) acrylamide;

420) N- (2- (4- (dimethylamino) - [1,4 '-bipiperidin ] -1' -yl) -5- ((6- ((R) -3- (2-fluoro-3-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

421) n- (2- (4- (4-acetylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2-fluoro-3-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

422) n- (5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((2- (dimethylamino) ethyl) (methyl) amino) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

423) n- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

424) n- (5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-ethylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

425) n- (5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((1R,4R) -5-ethyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

426) n- (5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-morpholino- [1,4 '-bipiperidin ] -1' -yl) phenyl) acrylamide;

427) N- (2- (4- (4-acetylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

428) n- (5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-isopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

429) n- (5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((R) -3- (dimethylamino) pyrrolidin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

430) n- (5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

431) n- (5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4- (2- (dimethylamino) ethyl) piperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

432) n- (5- ((6- ((R) -3- (3-cyanophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4-propylpiperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

433) n- (5- ((6- ((R) -3- (3-cyanophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4, 4-difluoro- [1,4 '-bipiperidin ] -1' -yl) -4-methoxyphenyl) acrylamide;

434) N- (2- (4- (4-acetylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-cyanophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

435) n- (5- ((6- ((R) -3- (3-cyanophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((S) -3- (dimethylamino) pyrrolidin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

436) n- (2- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

437) n- (2- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

438) n- (2- (4-cyclopropylpiperazin-1-yl) -5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

439) n- (4-methoxy-5- ((6- ((R) -3- (naphthalen-1-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (oxetan-3-yl) piperazin-1-yl) phenyl) acrylamide;

440) n- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((6- ((R) -3- (naphthalen-1-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

441) N- (4-methoxy-2- (4-methylpiperazin-1-yl) -5- ((6- ((R) -3- (naphthalen-1-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

442) n- (2- (4- (dimethylamino) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (naphthalen-1-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

443) n- (2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (naphthalen-1-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

444) n- (2- (4-ethylpiperazin-1-yl) -4-methoxy-5- ((6- ((R) -3- (naphthalen-1-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

445) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- ((3aR,6aR) -1-methylhexahydropyrrolo [3,4-b ] pyrrol-5 (1H) -yl) piperidin-1-yl) phenyl) acrylamide;

446) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- ((3aS,6aS) -1-methylhexahydropyrrolo [3,4-b ] pyrrol-5 (1H) -yl) piperidin-1-yl) phenyl) acrylamide;

447) n- (5- ((6- ((R) -3- (2-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- ((3aR,6aR) -1-methylhexahydropyrrolo [3,4-b ] pyrrol-5 (1H) -yl) piperidin-1-yl) phenyl) acrylamide;

448) N- (5- ((6- ((R) -3- (2-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- ((3aS,6aS) -1-methylhexahydropyrrolo [3,4-b ] pyrrol-5 (1H) -yl) piperidin-1-yl) phenyl) acrylamide;

449) n- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((6- ((R) -3- (3- (trifluoromethyl) phenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

450) n- (4-methoxy-2- (4-methylpiperazin-1-yl) -5- ((6- ((R) -3- (3- (trifluoromethyl) phenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

451) n- (2- (4- (dimethylamino) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (3- (trifluoromethyl) phenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

452) n- (2- (4-ethylpiperazin-1-yl) -4-methoxy-5- ((6- ((R) -3- (3- (trifluoromethyl) phenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

453) n- (4-methoxy-2- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3- (trifluoromethyl) phenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

454) n- (5- ((6- ((R) -3- (4-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

455) N- (5- ((6- ((R) -3- (4-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-morpholinopiperidin-1-yl) phenyl) acrylamide;

456) n- (5- ((6- ((R) -3- (4-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -4-methoxyphenyl) acrylamide;

457) n- (5- ((6- ((R) -3- (3, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide;

458) n- (5- ((6- ((R) -3- (3, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide;

459) n- (5- ((6- ((R) -3- (3, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (dimethylamino) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

460) n- (5- ((6- ((R) -3- (3, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-ethylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

461) n- (5- ((6- ((R) -3- (3-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-isopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

462) N- (2- (4- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

463) n- (5- ((6- ((R) -3- (3-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-cyclopropylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

464) n- (2- (4-acetylpiperazin-1-yl) -5- ((6- ((R) -3- (3-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

465) n- (5- ((6- ((R) -3- (3-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((R) -3-morpholinopyrrolidin-1-yl) phenyl) acrylamide;

466) n- (2- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -5- ((6- ((R) -3- (3-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

467) n- (5- ((6- ((R) -3- (3-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2-morpholinophenyl) acrylamide;

468) n- (5- ((6- ((R) -3- (3-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((S) -3- (dimethylamino) pyrrolidin-1-yl) -4-methoxyphenyl) acrylamide;

469) n- (5- ((6- ((R) -3- (3-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -4-methoxyphenyl) acrylamide;

470) N- (5- ((6- ((R) -3- (3-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (oxetan-3-yl) piperazin-1-yl) phenyl) acrylamide;

471) n- (2- (4- (4-acetylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

472) n- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

473) n- (5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- ((1R,4R) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) piperidin-1-yl) phenyl) acrylamide;

474) n- (2- ((S) -4-cyclopropyl-2-methylpiperazin-1-yl) -5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

475) n- (5- ((6- ((R) -3- (2, 3-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-isopropylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

476) n- (5- ((6- ((R) -3- (2, 3-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (dimethylamino) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

477) N- (5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4-methylpiperazin-1-yl) - [1,4 '-bipiperidin ] -1' -yl) phenyl) acrylamide;

478) n- (5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (dimethylamino) - [1,4 '-bipiperidin ] -1' -yl) -4-methoxyphenyl) acrylamide;

479) n- (2- ((S) -4-cyclopropyl-3-methylpiperazin-1-yl) -5- ((6- ((R) -3- (2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

480) n- (5- ((6- ((R) -3- (2, 3-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-ethylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

481) n- (5- ((6- ((R) -3- (2, 3-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide;

482) n- (4-methoxy-2- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (naphthalen-1-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

483) n- (4-methoxy-2- (4-morpholinopiperidin-1-yl) -5- ((6- ((R) -3- (naphthalen-1-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

484) N- (2- (4- (4-ethylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (naphthalen-1-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

485) n- (5- ((6- ((R) -3- (3-chloro-2-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

486) n- (5- ((6- ((R) -3- (3-chloro-2-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-morpholinopiperidin-1-yl) phenyl) acrylamide;

487) n- (5- ((6- ((R) -3- (3-chloro-2-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-ethylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

488) n- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (naphthalen-1-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

489) n- (2- (4- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (naphthalen-1-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

490) n- (2- (4- (4-isopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (naphthalen-1-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

491) N- (2- (4- ((2S,6R) -2, 6-dimethylmorpholino) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (naphthalen-1-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

492) n- (5- ((6- ((R) -3- (3-cyanophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((R) -3- (dimethylamino) pyrrolidin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

493) n- (2- (4- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-cyanophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

494) n- (5- ((6- ((R) -3- (3-cyanophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-isopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

495) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (3-methoxy-3-methylbutoxy) phenyl) acrylamide;

496) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (3-methoxy-3-methylbutoxy) phenyl) - (E) -4- (dimethylamino) but-2-enamide;

497) n- (2- (4- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

498) N- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

499) n- (5- ((6- ((R) -3- (3, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((R) -3- (dimethylamino) pyrrolidin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

500) n- (5- ((6- ((R) -3- (3, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((S) -3- (dimethylamino) pyrrolidin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

501) n- (5- ((6- ((R) -3- (3, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-isopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

502) n- (5- ((6- ((R) -3- (3, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

503) n- (5- ((6- ((R) -3- (3, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-morpholinopiperidin-1-yl) phenyl) acrylamide;

504) n- (4-methoxy-2- (4-morpholinopiperidin-1-yl) -5- ((6- ((R) -3- (3- (trifluoromethyl) phenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

505) N- (2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (3- (trifluoromethyl) phenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

506) n- (4-methoxy-2- ((R) -3-morpholinopyrrolidin-1-yl) -5- ((6- ((R) -3- (3- (trifluoromethyl) phenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

507) n- (4-methoxy-2- ((S) -3-morpholinopyrrolidin-1-yl) -5- ((6- ((R) -3- (3- (trifluoromethyl) phenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

508) n- (5- ((6- ((R) -3- (3-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((S) -3- (dimethylamino) pyrrolidin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

509) n- (4-methoxy-2- (4-methylpiperazin-1-yl) -5- ((6- ((R) -3- (naphthalen-2-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

510) n- (2- (4- (dimethylamino) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (naphthalen-2-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

511) n- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((6- ((R) -3- (naphthalen-2-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

512) N- (2- (4- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (naphthalen-2-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

513) n- (2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (naphthalen-2-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

514) n- (2- (4-ethylpiperazin-1-yl) -4-methoxy-5- ((6- ((R) -3- (naphthalen-2-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

515) n- (2- (4- (4-ethylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (naphthalen-2-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

516) n- (5- ((6- ((R) -3- (2, 3-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide;

517) n- (5- ((6- ((R) -3- (2, 3-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2-morpholinophenyl) acrylamide;

518) n- (2- (4-cyclopropylpiperazin-1-yl) -5- ((6- ((R) -3- (2, 3-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

519) n- (2- (4-acetylpiperazin-1-yl) -5- ((6- ((R) -3- (2, 3-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

520) N- (5- ((6- ((R) -3- (2, 3-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (oxetan-3-yl) piperazin-1-yl) phenyl) acrylamide;

521) n- (5- ((6- ((R) -3- (2, 3-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-morpholinopiperidin-1-yl) phenyl) acrylamide;

522) n- (2- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -5- ((6- ((R) -3- (2, 3-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

523) n- (2- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -5- ((6- ((R) -3- (2, 3-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

524) n- (5- ((6- ((R) -3- (2, 3-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((1S,4S) -5-ethyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) -4-methoxyphenyl) acrylamide;

525) n- (5- ((6- ((R) -3- (2, 3-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((1R,4R) -5-ethyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) -4-methoxyphenyl) acrylamide;

526) n- (5- ((6- ((R) -3- (2, 3-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -4-methoxyphenyl) acrylamide;

527) N- (5- ((6- ((R) -3- (2, 3-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-methyl-1H-imidazol-1-yl) phenyl) acrylamide;

528) n- (5- ((6- ((R) -3- (3-chloro-2-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((2S,6R) -2, 6-dimethylmorpholino) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

529) n- (5- ((6- ((R) -3- (3-chloro-2-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- ((S) -2-methylmorpholino) piperidin-1-yl) phenyl) acrylamide;

530) n- (5- ((6- ((R) -3- (3-chloro-2-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- ((R) -2-methylmorpholino) piperidin-1-yl) phenyl) acrylamide;

531) n- (2- (4- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-chloro-2-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

532) n- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-chloro-2-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

533) n- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-fluorophenyl) acrylamide;

534) N- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methylphenyl) acrylamide;

535) n- (4-methoxy-2- (4- ((S) -2-methylmorpholino) piperidin-1-yl) -5- ((6- ((R) -3- (naphthalen-1-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

536) n- (4-methoxy-2- (4- ((R) -2-methylmorpholino) piperidin-1-yl) -5- ((6- ((R) -3- (naphthalen-1-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

537) n- (5- ((6- ((R) -3- (3-chloro-5-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide;

538) n- (5- ((6- ((R) -3- (3-chloro-5-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide;

539) n- (5- ((6- ((R) -3- (3-chloro-5-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- ((3aR,6aR) -1-methylhexahydropyrrolo [3,4-b ] pyrrol-5 (1H) -yl) piperidin-1-yl) phenyl) acrylamide;

540) n- (5- ((6- ((R) -3- (3-chloro-5-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- ((3aS,6aS) -1-methylhexahydropyrrolo [3,4-b ] pyrrol-5 (1H) -yl) piperidin-1-yl) phenyl) acrylamide;

541) N- (5- ((6- ((R) -3- (4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- ((3aR,6aR) -1-methylhexahydropyrrolo [3,4-b ] pyrrol-5 (1H) -yl) piperidin-1-yl) phenyl) acrylamide;

542) n- (5- ((6- ((R) -3- (3, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (3-methyl-3, 6-diazabicyclo [3.1.1] hept-6-yl) phenyl) acrylamide;

543) n- (5- ((6- ((R) -3- (3, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((2S,6R) -2, 6-dimethylmorpholino) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

544) n- (2- (4- (4-acetylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

545) n- (5- ((6- ((R) -3- (3, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-ethylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

546) n- (5- ((6- ((R) -3- (3, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (dimethylamino) - [1,4 '-bipiperidin ] -1' -yl) -4-methoxyphenyl) acrylamide;

547) n- (5- ((6- ((R) -3- (3, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4-propylpiperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

548) N- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (4-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

549) n- (4-methoxy-5- ((6- ((R) -3- (3-methoxyphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-propylpiperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

550) n- (2- (4- (4-isopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (naphthalen-2-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

551) n- (5- ((6- ((R) -3- (2-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide;

552) n- (5- ((6- ((R) -3- (2-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide;

553) n- (5- ((6- ((R) -3- (2-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (dimethylamino) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

554) n- (4-methoxy-2- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (naphthalen-2-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

555) N- (4-methoxy-2- (4-morpholinopiperidin-1-yl) -5- ((6- ((R) -3- (naphthalen-2-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

556) n- (2- (4- (4-acetylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (naphthalen-2-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

557) n- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (naphthalen-2-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

558) n- (5- ((6- ((R) -3- (2-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -4-methoxyphenyl) acrylamide;

559) n- (5- ((6- ((R) -3- (2-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-ethylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

560) n- (5- ((6- ((R) -3- (2-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

561) n- (5- ((6- ((R) -3- (2, 3-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (tetrahydro-2H-pyran-4-yl) piperazin-1-yl) phenyl) acrylamide;

562) N- (5- ((6- ((R) -3- (2, 3-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) acrylamide;

563) n- (2- (4-cyclopentylpiperazin-1-yl) -5- ((6- ((R) -3- (2, 3-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

564) n- (2- ((R) -4-cyclopropyl-3-methylpiperazin-1-yl) -5- ((6- ((R) -3- (2, 3-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

565) n- (5- ((6- ((R) -3- (2, 3-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

566) n- (5- ((6- ((R) -3- (2, 3-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (2- (dimethylamino) ethyl) piperazin-1-yl) -4-methoxyphenyl) acrylamide;

567) n- (2- (4- (cyclopropylmethyl) piperazin-1-yl) -5- ((6- ((R) -3- (2, 3-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

568) n- (2- ((S) -4-cyclopropyl-3-methylpiperazin-1-yl) -5- ((6- ((R) -3- (2, 3-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

569) N- (5- ((6- ((R) -3- (2, 3-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-ethylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

570) n- (2- (4-ethylpiperazin-1-yl) -4-methoxy-5- ((6- ((R) -3- (2,3, 4-trifluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

571) n- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((6- ((R) -3- (2,3, 4-trifluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

572) n- (4-methoxy-2- (4-methylpiperazin-1-yl) -5- ((6- ((R) -3- (2,3, 4-trifluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

573) n- (2- (4- (dimethylamino) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (2,3, 4-trifluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

574) n- (2- (4- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (2,3, 4-trifluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

575) n- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (2,3, 4-trifluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

576) N- (2- (4- ((2S,6R) -2, 6-dimethylmorpholino) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (2,3, 4-trifluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

577) n- (5- ((6- ((R) -3- (3, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -4-methoxyphenyl) acrylamide;

578) n- (5- ((6- ((R) -3- (3, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((R) -3-morpholinopyrrolidin-1-yl) phenyl) acrylamide;

579) n- (5- ((6- ((R) -3- (3, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((S) -3-morpholinopyrrolidin-1-yl) phenyl) acrylamide;

580) n- (5- ((6- ((R) -3- (3-chloro-2-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-isopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

581) n- (5- ((6- ((R) -3- (3-chloro-2-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4, 4-difluoro- [1,4 '-bipiperidine ] -1' -yl) -4-methoxyphenyl) acrylamide;

582) n- (5- ((6- ((R) -3- (3-chloro-2-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4-propylpiperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

583) N- (5- ((6- ((R) -3- (3-chloro-2-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide;

584) n- (5- ((6- ((R) -3- (3-chloro-2-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide;

585) n- (5- ((6- ((R) -3- (3-chloro-2-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-ethylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

586) n- (5- ((6- ((R) -3- (3-chloro-2-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -4-methoxyphenyl) acrylamide;

587) n- (5- ((6- ((R) -3- (3-chloro-5-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (3- (4-cyclopropylpiperazin-1-yl) azetidin-1-yl) -4-methoxyphenyl) acrylamide;

588) n- (2- (3- (4-cyclopropylpiperazin-1-yl) azetidin-1-yl) -5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

589) n- (5- ((6- ((R) -3- (3-chloro-5-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-morpholinopiperidin-1-yl) phenyl) acrylamide;

590) N- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-chloro-5-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

591) n- (5- ((6- ((R) -3- (3-chloro-5-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-hydroxypiperidin-1-yl) -4-methoxyphenyl) acrylamide;

592) n- (2- (4- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-chloro-5-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

593) n- (5- ((6- ((R) -3- (3-chloro-5-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-isopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

594) n- (5- ((6- ((R) -3- (3-chloro-5-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((2S,6R) -2, 6-dimethylmorpholino) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

595) n- (5- ((6- ((R) -3- (3-chloro-5-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- ((S) -2-methylmorpholino) piperidin-1-yl) phenyl) acrylamide;

596) n- (5- ((6- ((R) -3- (3-chloro-5-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- ((R) -2-methylmorpholino) piperidin-1-yl) phenyl) acrylamide;

597) N- (5- ((6- ((R) -3- (3-chloro-5-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (oxetan-3-yl) piperazin-1-yl) phenyl) acrylamide;

598) n- (5- ((6- ((R) -3- (2-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-morpholinopiperidin-1-yl) phenyl) acrylamide;

599) n- (5- ((6- ((R) -3- (3-chloro-2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -4-methoxyphenyl) acrylamide;

600) n- (5- ((6- ((R) -3- (3-chloro-2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-ethylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

601) n- (2- (4- (4-acetylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

602) n- (5- ((6- ((R) -3- (2-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-ethylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

603) n- (5- ((6- ((R) -3- (3-chloro-2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide;

604) N- (5- ((6- ((R) -3- (3-chloro-2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide;

605) n- (5- ((6- ((R) -3- (3-chloro-2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

606) n- (5- ((6- ((R) -3- (3-chloro-2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-morpholinopiperidin-1-yl) phenyl) acrylamide;

607) n- (5- ((6- ((R) -3- (2, 3-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((1S,4S) -5-ethyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

608) n- (2- (4- (4-acetylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2, 3-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

609) n- (5- ((6- ((R) -3- (2, 3-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-isopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

610) n- (5- ((6- ((R) -3- (2, 3-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((R) -3- (dimethylamino) pyrrolidin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

611) N- (5- ((6- ((R) -3- (2, 3-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

612) n- (2- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -5- ((6- ((R) -3- (3, 4-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

613) n- (5- ((6- ((R) -3- (2, 3-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((2- (dimethylamino) ethyl) (methyl) amino) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

614) n- (5- ((6- ((R) -3- (2, 3-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-morpholino- [1,4 '-bipiperidin ] -1' -yl) phenyl) acrylamide;

615) n- (5- ((6- ((R) -3- (3, 4-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2-morpholinophenyl) acrylamide;

616) n- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((6- ((R) -3- (3-ethynylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

617) n- (5- ((6- ((R) -3- (3-ethynylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide;

618) N- (2- (4- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-ethynylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

619) n- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-ethynylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

620) n- (4-methoxy-2- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2,3, 4-trifluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

621) n- (4-methoxy-2- (4-morpholinopiperidin-1-yl) -5- ((6- ((R) -3- (2,3, 4-trifluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

622) n- (2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (2,3, 4-trifluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

623) n- (4-methoxy-2- ((R) -3-morpholinopyrrolidin-1-yl) -5- ((6- ((R) -3- (2,3, 4-trifluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

624) n- (4-methoxy-2- ((S) -3-morpholinopyrrolidin-1-yl) -5- ((6- ((R) -3- (2,3, 4-trifluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

625) N- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((S) -3- ((dimethylamino) methyl) pyrrolidin-1-yl) -4-methoxyphenyl) acrylamide;

626) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((S) -3- ((dimethylamino) methyl) pyrrolidin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

627) n- (5- ((6- ((R) -3- (3-chloro-5-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (dimethylamino) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

628) n- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((6- ((R) -3- (2,3, 6-trifluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

629) n- (4-methoxy-2- (4-methylpiperazin-1-yl) -5- ((6- ((R) -3- (2,3, 6-trifluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

630) n- (2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (2,3, 6-trifluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

631) n- (2- (4-ethylpiperazin-1-yl) -4-methoxy-5- ((6- ((R) -3- (2,3, 6-trifluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

632) N- (4-methoxy-2- (4-morpholinopiperidin-1-yl) -5- ((6- ((R) -3- (2,3, 6-trifluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

633) n- (3- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -5- (4-methylpiperazin-1-yl) phenyl) acrylamide;

634) n- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

635) n- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-chloro-2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

636) n- (2- (4- (4-acetylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-chloro-2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

637) n- (2- (4- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-chloro-2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

638) n- (5- ((6- ((R) -3- (3-chloro-2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (dimethylamino) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

639) N- (5- ((6- ((R) -3- (3-chloro-2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-ethylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

640) n- (2- (4- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

641) n- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (2,3, 6-trifluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

642) n- (2- (4- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (2,3, 6-trifluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

643) n- (2- (4- (4-isopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (2,3, 6-trifluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

644) n- (2- (4- ((2S,6R) -2, 6-dimethylmorpholino) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (2,3, 6-trifluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

645) N- (4-methoxy-2- (4- ((S) -2-methylmorpholino) piperidin-1-yl) -5- ((6- ((R) -3- (2,3, 6-trifluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

646) n- (4-methoxy-2- (4- ((R) -2-methylmorpholino) piperidin-1-yl) -5- ((6- ((R) -3- (2,3, 6-trifluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

647) n- (2- (4- (dimethylamino) piperidin-1-yl) -5- ((6- ((R) -3- (3-ethynylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

648) n- (2- (4-ethylpiperazin-1-yl) -5- ((6- ((R) -3- (3-ethynylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

649) n- (5- ((6- ((R) -3- (3-ethynylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

650) n- (5- ((6- ((R) -3- (3-ethynylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-morpholinopiperidin-1-yl) phenyl) acrylamide;

651) n- (2- (4- ((2S,6R) -2, 6-dimethylmorpholino) piperidin-1-yl) -5- ((6- ((R) -3- (3-ethynylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

652) N- (2- (4- (4-ethylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-ethynylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

653) n- (2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -5- ((6- ((R) -3- (3-ethynylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

654) n- (2- (4-cyclopropylpiperazin-1-yl) -5- ((6- ((R) -3- (3-ethynylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

655) n- (2- (4- (dimethylamino) - [1,4 '-bipiperidin ] -1' -yl) -5- ((6- ((R) -3- (3-ethynylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

656) n- (2- (4- (dimethylamino) - [1,4 '-bipiperidin ] -1' -yl) -4-methoxy-5- ((6- ((R) -3- (2,3, 4-trifluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

657) n- (5- ((6- ((R) -3- (3-chloro-2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((S) -2-methylmorpholino) phenyl) acrylamide;

658) n- (5- ((6- ((R) -3- (3-chloro-2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((2S,6S) -2, 6-dimethylmorpholino) -4-methoxyphenyl) acrylamide;

659) N- (4-methoxy-2- ((S) -2-methylmorpholino) -5- ((6- ((R) -3- (naphthalen-2-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

660) n- (2- ((2S,6S) -2, 6-dimethylmorpholino) -4-methoxy-5- ((6- ((R) -3- (naphthalen-2-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

661) n- (5- ((6- ((R) -3- (2-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-isopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

662) n- (2- ((S) -3, 4-dimethylpiperazin-1-yl) -4-methoxy-5- ((6- ((R) -3- (naphthalen-2-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

663) n- (4-methoxy-2- ((R) -2-methylmorpholino) -5- ((6- ((R) -3- (naphthalen-2-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

664) n- (2- ((2S,6R) -2, 6-dimethylmorpholino) -4-methoxy-5- ((6- ((R) -3- (naphthalen-2-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

665) n- (5- ((6- ((R) -3- (3-chloro-2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((S) -3, 4-dimethylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

666) n- (5- ((6- ((R) -3- (3-chloro-2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((R) -2-methylmorpholino) phenyl) acrylamide;

667) N- (5- ((6- ((R) -3- (3-chloro-2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((2S,6R) -2, 6-dimethylmorpholino) -4-methoxyphenyl) acrylamide;

668) n- (5- ((6- ((R) -3- (3-chloro-2, 4-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-isopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

669) n- (5- ((6- ((R) -3- (3, 4-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide;

670) n- (5- ((6- ((R) -3- (3, 4-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide;

671) n- (2- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -5- ((6- ((R) -3- (3, 4-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

672) n- (5- ((6- ((R) -3- (3, 4-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-ethylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

673) n- (2- (4-cyclopropylpiperazin-1-yl) -5- ((6- ((R) -3- (3, 4-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

674) N- (5- ((6- ((R) -3- (3, 4-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((1R,4R) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) phenyl) acrylamide;

675) n- (2- (4-acetylpiperazin-1-yl) -5- ((6- ((R) -3- (3, 4-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

676) n- (5- ((6- ((R) -3- (3, 4-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((1R,4R) -5-ethyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) -4-methoxyphenyl) acrylamide;

677) n- (5- ((6- ((R) -3- (3, 4-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (dimethylamino) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

678) n- (5- ((6- ((R) -3- (3, 4-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((1S,4S) -5-ethyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) -4-methoxyphenyl) acrylamide;

679) n- (5- ((6- ((R) -3- (3, 4-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((2-methoxyethyl) (methyl) amino) phenyl) acrylamide;

680) n- (5- ((6- ((R) -3- (3, 4-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-isopropylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

681) N- (5- ((6- ((R) -3- (3, 4-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

682) n- (5- ((6- ((R) -3- (3, 4-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -4-methoxyphenyl) acrylamide;

683) n- (5- ((6- ((R) -3- (3, 4-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-morpholinopiperidin-1-yl) phenyl) acrylamide;

684) n- (5- ((6- ((R) -3- (3, 4-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((1S,4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) phenyl) acrylamide;

685) n- (5- ((6- ((R) -3- (3, 4-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) acrylamide;

686) n- (5- ((6- ((R) -3- (3, 4-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (2- (dimethylamino) ethyl) piperazin-1-yl) -4-methoxyphenyl) acrylamide;

687) n- (2- (4- (cyclopropylmethyl) piperazin-1-yl) -5- ((6- ((R) -3- (3, 4-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

688) N- (2- (4- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 4-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

689) n- (5- ((6- ((R) -3- (3, 4-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-isopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

690) n- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 4-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

691) n- (5- ((6- ((R) -3- (2-chloro-3, 6-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-cyclopropylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

692) n- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2-chloro-3, 6-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

693) n- (2- (4- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2-chloro-3, 6-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

694) N- (5- ((6- ((R) -3- (4-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide;

695) n- (5- ((6- ((R) -3- (4-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -4-methoxyphenyl) acrylamide;

696) n- (5- ((6- ((R) -3- (3, 4-dichloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

697) n- (5- ((6- ((R) -3- (3, 4-dichloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-morpholinopiperidin-1-yl) phenyl) acrylamide;

698) n- (2- (4-ethylpiperazin-1-yl) -4-methoxy-5- ((6- ((R) -3- (3-methoxyphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

699) n- (2- (4- (4-ethylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (3-methoxyphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

700) n- (2- (4- (6-azaspiro [2.5] oct-6-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

701) N- (5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide;

702) n- (5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide;

703) n- (5- ((6- ((R) -3- (3-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((S) -3- (dimethylamino) pyrrolidin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

704) n- (2- (4- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

705) n- (2- (4- (4-acetylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

706) n- (5- ((6- ((R) -3- (3-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((2S,6R) -2, 6-dimethylmorpholino) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

707) n- (5- ((6- ((R) -3- (3-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-isopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

708) N- (5- ((6- ((R) -3- (4-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-isopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

709) n- (5- ((6- ((R) -3- (4-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((2S,6R) -2, 6-dimethylmorpholino) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

710) n- (2- (4- ((2S,6R) -2, 6-dimethylmorpholino) piperidin-1-yl) -5- ((6- ((R) -3- (3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

711) n- (5- ((6- ((R) -3- (3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-isopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

712) n- (5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((2S,6R) -2, 6-dimethylmorpholino) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

713) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (3- (dimethylamino) azetidin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

714) n- (5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((2S,6R) -2, 6-dimethylmorpholino) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

715) N- (5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-isopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

716) n- (2- (4- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

717) n- (2- (4- (4-cyclopropyl-1, 4-diazepan-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

718) n- (2- (4, 4-difluoro- [1,4 '-bipiperidin ] -1' -yl) -5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

719) n- (5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

720) n- (5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-morpholinopiperidin-1-yl) phenyl) acrylamide;

721) n- (5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-ethylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

722) N- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4-methyl-2-oxopiperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

723) n- (5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-ethylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

724) n- (5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-isopropylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

725) n- (5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-cyclopropylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

726) n- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (3-methoxyphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

727) n- (2- (4- ((2S,6R) -2, 6-dimethylmorpholino) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (3-methoxyphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

728) n- (2- (4- ((R) -3- (dimethylamino) pyrrolidin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (3-methoxyphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

729) N- (2- (4- ((S) -3- (dimethylamino) pyrrolidin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (3-methoxyphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

730) n- (4-methoxy-5- ((6- ((R) -3- (3-methoxyphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (oxetan-3-yl) piperazin-1-yl) phenyl) acrylamide;

731) n- (2- (4- (dimethylamino) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (3-methoxyphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

732) n- (5- ((6- ((R) -3- (4-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

733) n- (5- ((6- ((R) -3- (4-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((R) -3-morpholinopyrrolidin-1-yl) phenyl) acrylamide;

734) n- (5- ((6- ((R) -3- (4-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((S) -3-morpholinopyrrolidin-1-yl) phenyl) acrylamide;

735) n- (2- (4- ((2- (dimethylamino) ethyl) (methyl) amino) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

736) N- (4-methoxy-2- (4- ((2-methoxyethyl) (methyl) amino) piperidin-1-yl) -5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

737) n- (2- (4- ((1S,4S) -5-ethyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

738) n- (2- (4- ((1R,4R) -5-ethyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

739) n- (2- (4- (4- (2- (dimethylamino) ethyl) piperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

740) n- (2- (4- (dimethylamino) - [1,4 '-bipiperidin ] -1' -yl) -4-methoxy-5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

741) n- (2- (4- (4-acetylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

742) n- (5- ((6- ((R) -3- (3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

743) N- (5- ((6- ((R) -3- (3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-morpholinopiperidin-1-yl) phenyl) acrylamide;

744) n- (2- (4- ((S) -3- (dimethylamino) pyrrolidin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

745) n- (5- ((6- ((R) -3- (3-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (oxetan-3-yl) piperazin-1-yl) phenyl) acrylamide;

746) n- (5- ((6- ((R) -3- (3-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide;

747) n- (5- ((6- ((R) -3- (3-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

748) n- (2- (4- ((R) -3- (dimethylamino) pyrrolidin-1-yl) piperidin-1-yl) -5- ((6- (3- (3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

749) n- (2- (4- (dimethylamino) - [1,4 '-bipiperidin ] -1' -yl) -5- ((6- ((R) -3- (3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

750) N- (5- ((6- ((R) -3- (4-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-morpholinopiperidin-1-yl) phenyl) acrylamide;

751) n- (5- ((6- ((R) -3- (4-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

752) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((2S,6S) -2, 6-dimethylmorpholino) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

753) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4- (2- (dimethylamino) ethyl) piperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

754) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (piperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

755) n- (5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (dimethylamino) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

756) n- (5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -4-methoxyphenyl) acrylamide;

757) N- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- ((S) -2-methylmorpholino) piperidin-1-yl) phenyl) acrylamide;

758) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- ((R) -2-methylmorpholino) piperidin-1-yl) phenyl) acrylamide;

759) n- (2- (4- ((1R,5S) -8-oxa-3-azabicyclo [3.2.1] oct-3-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

760) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((S) -3, 4-dimethylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

761) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((R) -2, 4-dimethylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

762) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((S) -2, 4-dimethylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

763) n- (2- (4- (4-acetylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

764) N- (5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((S) -3- (dimethylamino) pyrrolidin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

765) n- (5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

766) n- (5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-morpholinopiperidin-1-yl) phenyl) acrylamide;

767) n- (5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-ethylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

768) n- (5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (dimethylamino) - [1,4 '-bipiperidin ] -1' -yl) -4-methoxyphenyl) acrylamide;

769) n- (5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((R) -3- (dimethylamino) pyrrolidin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

770) n- (2- (4- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 4-dichloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

771) N- (5- ((6- ((R) -3- (3, 4-dichloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((R) -3- (dimethylamino) pyrrolidin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

772) n- (5- ((6- ((R) -3- (3, 4-dichloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((S) -3- (dimethylamino) pyrrolidin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

773) n- (5- ((6- ((R) -3- (3, 4-dichloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((2S,6R) -2, 6-dimethylmorpholino) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

774) n- (2- (4- (4-acetylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 4-dichloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

775) n- (4-methoxy-5- ((6- ((R) -3- (3-methoxyphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-morpholinopiperidin-1-yl) phenyl) acrylamide;

776) n- (2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (3-methoxyphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

777) n- (4-methoxy-5- ((6- ((R) -3- (3-methoxyphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((R) -3-morpholinopyrrolidin-1-yl) phenyl) acrylamide;

778) N- (4-methoxy-5- ((6- ((R) -3- (3-methoxyphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((S) -3-morpholinopyrrolidin-1-yl) phenyl) acrylamide;

779) n- (2- (4- (4-acetylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (3-methoxyphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

780) n- (2- (4- (4-isopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (3-methoxyphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

781) n- (2- (4- (dimethylamino) - [1,4 '-bipiperidin ] -1' -yl) -4-methoxy-5- ((6- ((R) -3- (3-methoxyphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

782) n- (5- ((6- ((R) -3- (4-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-morpholinopiperidin-1-yl) phenyl) acrylamide;

783) n- (5- ((6- ((R) -3- (4-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((R) -3- (dimethylamino) pyrrolidin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

784) n- (5- ((6- ((R) -3- (4-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((S) -3- (dimethylamino) pyrrolidin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

785) N- (5- ((6- ((R) -3- (4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide;

786) n- (5- ((6- ((R) -3- (4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-morpholinopiperidin-1-yl) phenyl) acrylamide;

787) n- (2- (4- ((R) -3- (dimethylamino) pyrrolidin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3-phenylisoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

788) n- (5- ((6- ((R) -3- (3-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-morpholinopiperidin-1-yl) phenyl) acrylamide;

789) n- (5- ((6- ((R) -3- (3-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide;

790) n- (5- ((6- ((R) -3- (3-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (dimethylamino) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

791) n- (5- ((6- ((R) -3- (3-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-ethylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

792) n- (5- ((6- ((R) -3- (3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (oxetan-3-yl) piperazin-1-yl) phenyl) acrylamide;

793) N- (5- ((6- ((R) -3- (4-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide;

794) n- (5- ((6- ((R) -3- (4-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -4-methoxyphenyl) acrylamide;

795) n- (5- ((6- ((R) -3- (4-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide;

796) n- (2- (4- (4-acetylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (4-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

797) n- (5- ((6- ((R) -3- (4-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (dimethylamino) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

798) n- (5- ((6- ((R) -3- (4-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-ethylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

799) n- (5- ((6- ((R) -3- (4-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((S) -3- (dimethylamino) pyrrolidin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

800) N- (5- ((6- ((R) -3- (4-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((R) -3- (dimethylamino) pyrrolidin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

801) n- (5- ((6- ((R) -3- (4-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (oxetan-3-yl) piperazin-1-yl) phenyl) acrylamide;

802) n- (2- (4- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (4-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

803) n- (5- ((6- ((R) -3- (4-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (dimethylamino) - [1,4 '-bipiperidin ] -1' -yl) -4-methoxyphenyl) acrylamide;

804) n- (5- ((6- ((R) -3- (3, 4-dichloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-isopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

805) n- (5- ((6- ((R) -3- (4-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (dimethylamino) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

806) n- (2- (4- (4-acetylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (4-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

807) N- (5- ((6- ((R) -3- (4-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-isopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

808) n- (5- ((6- ((R) -3- (4-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (dimethylamino) - [1,4 '-bipiperidine ] -1' -yl) -4-methoxyphenyl) acrylamide;

809) n- (2- (4- (4-acetylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

810) n- (2- (4- ((R) -3- (dimethylamino) pyrrolidin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

811) n- (2- (4- ((S) -3- (dimethylamino) pyrrolidin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

812) n- (2- (4- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

813) n- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

814) N- (2- (4- ((2S,6R) -2, 6-dimethylmorpholino) piperidin-1-yl) -5- ((6- ((R) -3- (4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

815) n- (2- (4- (4-acetylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

816) n- (5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((S) -3- (dimethylamino) pyrrolidin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

817) n- (2- (4, 4-difluoro- [1,4 '-bipiperidin ] -1' -yl) -5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

818) n- (5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide;

819) n- (5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (dimethylamino) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

820) n- (2- (4- (8-oxa-3-azabicyclo [3.2.1] oct-3-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

821) N- (5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- ((S) -2-methylmorpholino) piperidin-1-yl) phenyl) acrylamide;

822) n- (5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- ((R) -2-methylmorpholino) piperidin-1-yl) phenyl) acrylamide;

823) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2-morpholinophenyl) acrylamide;

824) n- (5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2-morpholinophenyl) acrylamide;

825) n- (5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2-morpholinophenyl) acrylamide;

826) n- (2- (4- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

827) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((3S,5R) -4-ethyl-3, 5-dimethylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

828) N- (2- (4- (6-azaspiro [2.5] oct-6-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

829) n- (2- (4- (4-cyclopropyl-1, 4-diazepan-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

830) n- (2- (4-cyclopropylpiperazin-1-yl) -5- ((6- ((R) -3- (3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

831) n- (2- (4-acetylpiperazin-1-yl) -5- ((6- ((R) -3- (3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

832) n- (2- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -5- ((6- ((R) -3- (3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

833) n- (2- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -5- ((6- ((R) -3- (3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

834) n- (5- ((6- ((R) -3- (3-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -4-methoxyphenyl) acrylamide;

835) N- (2- (4- ((1S,4S) -5-ethyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

836) n- (5- ((6- ((R) -3- (4-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((S) -3- (dimethylamino) pyrrolidin-1-yl) -4-methoxyphenyl) acrylamide;

837) n- (5- ((6- ((R) -3- (3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- ((1S,4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) piperidin-1-yl) phenyl) acrylamide;

838) n- (5- ((6- ((R) -3- (3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((2-methoxyethyl) (methyl) amino) phenyl) acrylamide;

839) n- (2- ((S) -3- (dimethylamino) pyrrolidin-1-yl) -5- ((6- ((R) -3- (3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

840) n- (5- ((6- ((R) -3- (3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2-morpholinophenyl) acrylamide;

841) n- (5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((3S,5R) -4-ethyl-3, 5-dimethylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

842) N- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- ((R) -3-methylmorpholino) piperidin-1-yl) phenyl) acrylamide;

843) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- ((S) -3-methylmorpholino) piperidin-1-yl) phenyl) acrylamide;

844) n- (5- ((6- ((R) -3- (2-fluoro-3-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2-morpholinophenyl) acrylamide;

845) n- (5- ((6- ((R) -3- (2-fluoro-3-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide;

846) n- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((6- ((R) -3- (2-fluoro-3-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

847) n- (2- (4-ethylpiperazin-1-yl) -5- ((6- ((R) -3- (2-fluoro-3-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

848) n- (5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -4-methoxyphenyl) acrylamide;

849) N- (5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-ethylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

850) n- (5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((S) -3, 4-dimethylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

851) n- (5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((R) -3, 4-dimethylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

852) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

853) n- (5- ((6- ((R) -3- (4-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((2-methoxyethyl) (methyl) amino) phenyl) acrylamide;

854) n- (5- ((6- ((R) -3- (4-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2-morpholinophenyl) acrylamide;

855) n- (5- ((6- ((R) -3- (2-fluoro-3-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

856) N- (5- ((6- ((R) -3- (2-fluoro-3-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-morpholinopiperidin-1-yl) phenyl) acrylamide;

857) n- (5- ((6- ((R) -3- (4-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- ((1S,4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) piperidin-1-yl) phenyl) acrylamide;

858) n- (5- ((6- ((R) -3- (4-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((1S,4S) -5-ethyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

859) n- (5- ((6- ((R) -3- (4-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((1R,4R) -5-ethyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

860) n- (2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -5- ((6- ((R) -3- (2-fluoro-3-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

861) n- (5- ((6- ((R) -3- (3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (2-methyl-1H-imidazol-1-yl) phenyl) acrylamide;

862) n- (2- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -5- ((6- ((R) -3- (4-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

863) N- (2- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -5- ((6- ((R) -3- (4-chloro-3-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

864) n- (2- (4- (dimethylamino) piperidin-1-yl) -5- ((6- ((R) -3- (2-fluoro-3-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

865) n- (5- ((6- ((R) -3- (3, 4-dichloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (dimethylamino) - [1,4 '-bipiperidin ] -1' -yl) -4-methoxyphenyl) acrylamide;

866) n- (2- (4- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (4-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

867) n- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((R) -3- (4-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

868) n- (5- ((6- ((R) -3- (4-chlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((2S,6R) -2, 6-dimethylmorpholino) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

869) n- (5- ((6- ((R) -3- (4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (dimethylamino) - [1,4 '-bipiperidin ] -1' -yl) -4-methoxyphenyl) acrylamide;

870) N- (2- (4- (dimethylamino) - [1,4 '-bipiperidin ] -1' -yl) -5- ((6- ((R) -3- (4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

871) n- (2- (4- ((1R,5S) -8-oxa-3-azabicyclo [3.2.1] oct-3-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

872) n- (2- (4- (6-azaspiro [2.5] oct-6-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

873) n- (5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- ((S) -2-methylmorpholino) piperidin-1-yl) phenyl) acrylamide;

874) n- (5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- ((R) -2-methylmorpholino) piperidin-1-yl) phenyl) acrylamide;

875) n- (5- ((6- ((R) -3- (2, 3-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((3aR,6aR) -1-methylhexahydropyrrolo [3,4-b ] pyrrol-5 (1H) -yl) phenyl) acrylamide;

876) n- (5- ((6- ((R) -3- (2, 3-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((3aS,6aS) -1-methylhexahydropyrrolo [3,4-b ] pyrrol-5 (1H) -yl) phenyl) acrylamide;

877) N- (5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) piperidin-1-yl) phenyl) acrylamide;

878) n- (5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((3S,5R) -4-ethyl-3, 5-dimethylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

879) n- (2- ((S) -4-cyclopropyl-2-methylpiperazin-1-yl) -5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

880) n- (2- ((R) -4-cyclopropyl-2-methylpiperazin-1-yl) -5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

881) n- (5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (oxetan-3-yl) piperazin-1-yl) phenyl) acrylamide;

882) n- (5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide;

883) n- (5- ((6- ((R) -3- (2, 3-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((S) -3, 4-dimethylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

884) N- (5- ((6- ((R) -3- (2, 3-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((R) -3, 4-dimethylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

885) n- (5- ((6- ((R) -3- (2, 3-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((R) -2, 4-dimethylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

886) n- (5- ((6- ((R) -3- (2, 3-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((S) -2, 4-dimethylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

887) n- (2- (8-oxa-3-azabicyclo [3.2.1] oct-3-yl) -5- ((6- ((R) -3- (2, 3-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

888) n- (5- ((6- ((R) -3- (2, 3-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((S) -2-methylmorpholino) phenyl) acrylamide;

889) n- (5- ((6- ((R) -3- (2, 3-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((R) -2-methylmorpholino) phenyl) acrylamide;

890) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((3aR,6aR) -1-methylhexahydropyrrolo [3,4-b ] pyrrol-5 (1H) -yl) phenyl) acrylamide;

891) N- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((3aS,6aS) -1-methylhexahydropyrrolo [3,4-b ] pyrrol-5 (1H) -yl) phenyl) acrylamide;

892) n- (5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((3aR,6aR) -1-methylhexahydropyrrolo [3,4-b ] pyrrol-5 (1H) -yl) phenyl) acrylamide;

893) n- (5- ((6- ((R) -3- (2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((3aS,6aS) -1-methylhexahydropyrrolo [3,4-b ] pyrrol-5 (1H) -yl) phenyl) acrylamide;

894) n- (2- (4- (4- (sec-butyl) piperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

895) n- (5- ((6- ((S) -3- (2, 6-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-ethylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

896) n- (5- ((6- ((S) -3- (2, 6-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

897) n- (5- ((6- ((S) -3- (2, 6-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-morpholinopiperidin-1-yl) phenyl) acrylamide;

898) N- (5- ((6- ((S) -3- (2, 6-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((3aR,6aR) -1-methylhexahydropyrrolo [3,4-b ] pyrrol-5 (1H) -yl) phenyl) acrylamide;

899) n- (5- ((6- ((S) -3- (2, 6-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((3aS,6aS) -1-methylhexahydropyrrolo [3,4-b ] pyrrol-5 (1H) -yl) phenyl) acrylamide;

900) n- (5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((S) -3, 4-dimethylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

901) n- (5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((R) -3, 4-dimethylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

902) n- (2- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

903) n- (2- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

904) n- (5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((2-methoxyethyl) (methyl) amino) phenyl) acrylamide;

905) N- (5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-cyclopropylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

906) n- (5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((S) -3- (dimethylamino) pyrrolidin-1-yl) -4-methoxyphenyl) acrylamide;

907) n- (2- (4-acetylpiperazin-1-yl) -5- ((6- ((R) -3- (3-chloro-4-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

908) n- (5- ((6- ((R) -3- (2-fluoro-3-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (oxetan-3-yl) piperazin-1-yl) phenyl) acrylamide;

909) n- (2- (4-cyclopropylpiperazin-1-yl) -5- ((6- ((R) -3- (2-fluoro-3-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

910) n- (2- (4- ((S) -3- (dimethylamino) pyrrolidin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (2-fluoro-3-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

911) n- (5- ((6- ((R) -3- (2-fluoro-3-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-isopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

912) N- (2- (4- ((2S,6R) -2, 6-dimethylmorpholino) piperidin-1-yl) -5- ((6- ((R) -3- (2-fluoro-3-methylphenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

913) n- (5- ((6- ((R) -3- (3-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-ethylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

914) n- (5- ((6- ((R) -3- (3-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((R) -3- (dimethylamino) pyrrolidin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

915) n- (5- ((6- ((R) -3- (3-chloro-2-fluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (dimethylamino) - [1,4 '-bipiperidin ] -1' -yl) -4-methoxyphenyl) acrylamide;

916) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((S) -3, 4-dimethylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

917) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((R) -3, 4-dimethylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

918) n- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((R) -2, 4-dimethylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

919) N- (5- ((6- ((R) -3- (3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((S) -2, 4-dimethylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

920) n- (5- ((6- ((R) -3- (2, 3-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-morpholinopiperidin-1-yl) phenyl) acrylamide;

921) n- (5- ((6- ((R) -3- (2, 3-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

922) n- (5- ((6- ((R) -3- (2, 3-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-ethylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

923) n- (5- ((6- ((R) -3- (2, 3-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (oxetan-3-yl) piperazin-1-yl) phenyl) acrylamide;

924) n- (5- ((6- ((R) -3- (2, 3-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide;

925) n- (5- ((6- ((R) -3- (2, 3-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide;

926) N- (5- ((6- ((R) -3- (2, 3-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (dimethylamino) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

927) n- (5- ((6- ((R) -3- (2, 3-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -4-methoxyphenyl) acrylamide;

928) n- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((6- ((R) -3- (thiophen-2-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

929) n- (4-methoxy-2- (4-methylpiperazin-1-yl) -5- ((6- ((R) -3- (thiophen-2-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

930) n- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (thiophen-2-yl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

931) n- (5- ((6- ((R) -3- (3, 4-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4- (oxetan-3-yl) piperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

932) n- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((R) -3- (3, 4-dichlorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

933) N- (5- ((6- ((R) -3- (2-chloro-3, 6-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

934) n- (5- ((6- ((R) -3- (2-chloro-3, 6-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((S) -4-cyclopropyl-3-methylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

935) n- (5- ((6- ((R) -3- (2-chloro-3, 6-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((R) -4-cyclopropyl-3-methylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

936) n- (5- ((6- ((S) -3- (2-chloro-3, 6-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

937) n- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((S) -3- (2,3, 6-trifluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

938) n- (5- ((6- ((R) -3- (3-chloro-2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

939) n- (5- ((6- ((R) -3- (3-chloro-2, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-cyclopropylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

940) N- (2- (4-cyclopropylpiperazin-1-yl) -4-methoxy-5- ((6- ((R) -3- (3- (trifluoromethyl) phenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

941) n- (2- (4- ((S) -4-cyclopropyl-3-methylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (3- (trifluoromethyl) phenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

942) n- (2- (4- ((R) -4-cyclopropyl-3-methylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (3- (trifluoromethyl) phenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

943) n- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (3- (trifluoromethyl) phenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

944) n- (2- (4- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (3- (trifluoromethyl) phenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

945) n- (5- ((6- ((S) -3-benzylisoxazolin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide;

946) n- (5- ((6- ((S) -3-benzylisoxazolin-2-yl) pyrimidin-4-yl) amino) -2- (4-ethylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

947) N- (5- ((6- ((S) -3-benzylisooxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide;

948) n- (2- (4-acetylpiperazin-1-yl) -5- ((6- ((S) -3-benzylisoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

949) n- (5- ((6- ((S) -3-benzylisooxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((1R,4R) -5-ethyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) -4-methoxyphenyl) acrylamide;

950) n- (5- ((6- ((S) -3-benzylisooxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((1S,4S) -5-ethyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) -4-methoxyphenyl) acrylamide;

951) n- (5- ((6- ((S) -3-benzylisooxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (dimethylamino) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

952) n- (5- ((6- ((S) -3-benzylisooxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-cyclopropylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

953) n- (5- ((6- ((S) -3-benzylisooxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- ((2-methoxyethyl) (methyl) amino) phenyl) acrylamide;

954) n- (5- ((6- ((S) -3-benzylisooxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-isopropylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

955) N- (5- ((6- ((S) -3-benzylisoxazolin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

956) n- (5- ((6- ((R) -3-benzylisoxazolin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

957) n- (5- ((6- ((S) -3-benzylisooxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -4-methoxyphenyl) acrylamide;

958) n- (5- ((6- ((S) -3-benzylisoxazolin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (oxetan-3-yl) piperazin-1-yl) phenyl) acrylamide;

959) n- (5- ((6- ((S) -3-benzylisooxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (cyclopropylmethyl) piperazin-1-yl) -4-methoxyphenyl) acrylamide;

960) n- (5- ((6- ((S) -3-benzylisooxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (2-methyl-1H-imidazol-1-yl) phenyl) acrylamide;

961) n- (5- ((6- ((S) -3-benzylisooxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (2- (dimethylamino) ethyl) piperazin-1-yl) -4-methoxyphenyl) acrylamide;

962) n- (5- ((6- ((S) -3-benzylisooxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -4-methoxyphenyl) acrylamide;

963) N- (5- ((6- ((S) -3-benzylisoxazolin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) acrylamide;

964) n- (5- ((6- ((S) -3-benzylisoxazolin-2-yl) pyrimidin-4-yl) amino) -2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -4-methoxyphenyl) acrylamide;

965) n- (5- ((6- ((S) -3-benzylisooxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-morpholinopiperidin-1-yl) phenyl) acrylamide;

966) n- (5- ((6- ((R) -3-benzylisoxazolin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2-morpholinophenyl) acrylamide;

967) n- (5- ((6- ((R) -3-benzylisooxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (cyclopropylmethyl) piperazin-1-yl) -4-methoxyphenyl) acrylamide;

968) n- (5- ((6- ((R) -3-benzylisoxazolin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide;

969) n- (5- ((6- ((S) -3-benzylisooxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) phenyl) acrylamide;

970) n- (5- ((6- ((S) -3-benzylisooxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) acrylamide;

971) N- (5- ((6- ((S) -3-benzylisoxazolin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (tetrahydro-2H-pyran-4-yl) piperazin-1-yl) phenyl) acrylamide;

972) n- (5- ((6- ((S) -3-benzylisoxazolin-2-yl) pyrimidin-4-yl) amino) -2- (4-cyclopentylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

973) n- (5- ((6- ((R) -3-benzylisooxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide;

974) n- (5- ((6- ((R) -3-benzylisoxazolin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) acrylamide;

975) n- (5- ((6- ((R) -3-benzylisoxazolin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- (tetrahydro-2H-pyran-4-yl) piperazin-1-yl) phenyl) acrylamide;

976) n- (5- ((6- ((R) -3-benzylisooxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (2- (dimethylamino) ethyl) piperazin-1-yl) -4-methoxyphenyl) acrylamide;

977) n- (5- ((6- ((R) -3-benzylisoxazolin-2-yl) pyrimidin-4-yl) amino) -2- (4-cyclopentylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

978) n- (5- ((6- ((S) -3-benzylisooxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (2- (diethylamino) ethoxy) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

979) N- (5- ((6- ((S) -3- (2, 3-dichlorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-morpholinopiperidin-1-yl) phenyl) acrylamide;

980) n- (2- (4- ((R) -4-cyclopropyl-3-methylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((S) -3- (2, 3-dichlorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

981) n- (2- (4- ((S) -4-cyclopropyl-3-methylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((S) -3- (2, 3-dichlorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

982) n- (5- ((6- ((S) -3- (2, 3-dichlorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide;

983) n- (5- ((6- ((S) -3- (2, 3-dichlorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide;

984) n- (5- ((6- ((S) -3- (2, 3-dichlorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -4-methoxyphenyl) acrylamide;

985) n- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((S) -3- (pyridin-3-ylmethyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

986) N- (2- (4- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((S) -3- (pyridin-3-ylmethyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

987) n- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((S) -3- (pyridin-3-ylmethyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

988) n- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (pyridin-3-ylmethyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

989) n- (2- (4- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (pyridin-3-ylmethyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

990) n- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (pyridin-3-ylmethyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

991) n- (5- ((6- ((S) -3- (3-fluorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide;

992) n- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((6- ((S) -3- (3-fluorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

993) N- (2- (4- ((S) -4-cyclopropyl-3-methylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((S) -3- (3-fluorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

994) n- (2- (4- ((R) -4-cyclopropyl-3-methylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((S) -3- (3-fluorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

995) n- (2- (4- ((1R,5S) -8-cyclopropyl-3, 8-diazabicyclo [3.2.1] oct-3-yl) piperidin-1-yl) -5- ((6- ((S) -3- (3-fluorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

996) n- (5- ((6- ((S) -3- (3-fluorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-morpholinopiperidin-1-yl) phenyl) acrylamide;

997) n- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((S) -3- (3-fluorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

998) n- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((S) -3- (3-fluorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

999) n- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((S) -3- (3-fluoro-2-methylbenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

1000) N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((6- ((S) -3- (3-fluoro-2-methylbenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

1001) n- (5- ((6- ((S) -3- (3-fluoro-2-methylbenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide;

1002) n- (2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -5- ((6- ((S) -3- (3-fluoro-2-methylbenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

1003) n- (2- (4-ethylpiperazin-1-yl) -5- ((6- (S) - (3- (3-fluoro-2-methylbenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

1004) n- (2- (4- ((R) -4-cyclopropyl-3-methylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((S) -3- (3-fluoro-2-methylbenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

1005) n- (2- (4- ((S) -4-cyclopropyl-3-methylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((S) -3- (3-fluoro-2-methylbenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

1006) n- (5- ((6- ((S) -3- (2-chloro-3-fluorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-cyclopropylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

1007) N- (5- ((6- ((S) -3- (2-chloro-3-fluorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

1008) n- (5- ((6- ((S) -3- (2, 3-dichlorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-ethylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

1009) n- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((S) -3- (2, 3-dichlorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

1010) n- (5- ((6- ((S) -3- (2, 3-dichlorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((2S,6R) -2, 6-dimethylmorpholino) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

1011) n- (5- ((6- ((S) -3- (2, 3-dichlorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- ((R) -2-methylmorpholino) piperidin-1-yl) phenyl) acrylamide;

1012) n- (2- (4- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((S) -3- (2, 3-dichlorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

1013) n- (5- ((6- ((S) -3- (2, 3-dichlorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxy-2- (4- ((S) -2-methylmorpholino) piperidin-1-yl) phenyl) acrylamide;

1014) N- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((S) -3- (2, 3-dichlorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

1015) n- (5- ((6- ((S) -3- (2, 3-dichlorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-isopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

1016) n- (5- ((6- ((S) -3- (3-chloro-2-fluorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide;

1017) n- (5- ((6- ((S) -3- (3-chloro-2-fluorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-cyclopropylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

1018) n- (5- ((6- ((S) -3- (3-chloro-2-fluorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((S) -4-cyclopropyl-3-methylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

1019) n- (5- ((6- ((S) -3- (3-chloro-2-fluorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((R) -4-cyclopropyl-3-methylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

1020) n- (5- ((6- ((S) -3- (3-chloro-2-fluorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

1021) N- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((S) -3- (3-chloro-2-fluorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

1022) n- (2- (4- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((S) -3- (3-chloro-2-fluorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

1023) n- (2- (4- (4-cyclobutylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((S) -3- (2, 3-dichlorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

1024) n- (2- (4- (4-allylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((S) -3- (2, 3-dichlorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

1025) n- (5- ((6- ((S) -3- (3-chloro-2-methylbenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

1026) n- (5- ((6- ((S) -3- (3-chloro-2-methylbenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-cyclopropylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

1027) n- (5- ((6- ((S) -3- (3-chloro-2-methylbenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((R) -4-cyclopropyl-3-methylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

1028) N- (5- ((6- ((S) -3- (3-chloro-2-methylbenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((S) -4-cyclopropyl-3-methylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

1029) n- (2- (4- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((S) -3- (3-chloro-2-methylbenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

1030) n- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((S) -3- (3-chloro-2-methylbenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

1031) n- (5- ((6- ((S) -3- (3, 5-difluorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide;

1032) n- (2- (4-cyclopropylpiperazin-1-yl) -5- ((6- (S) - (3- (3, 5-difluorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

1033) n- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((S) -3- (3, 5-difluorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

1034) n- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((S) -3- (3, 5-difluorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

1035) N- (2- (4- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((S) -3- (3, 5-difluorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

1036) n- (5- ((6- ((S) -3- (2-chloro-3-fluorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((R) -4-cyclopropyl-3-methylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

1037) n- (5- ((6- ((S) -3- (2-chloro-3-fluorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- ((S) -4-cyclopropyl-3-methylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

1038) n- (2- (4-cyclopropylpiperazin-1-yl) -5- ((6- ((S) -3- (3-fluoro-2-methylbenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

1039) n- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((S) -3- (3-fluoro-2-methylbenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

1040) n- (2- (4- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((S) -3- (3-fluoro-2-methylbenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

1041) N- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((S) -3- (2-chloro-3-fluorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

1042) n- (2- (4- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((S) -3- (2-chloro-3-fluorobenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

1043) n- (2- (4-cyclopropylpiperazin-1-yl) -5- ((6- ((S) -3- (3- (dimethylamino) benzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

1044) n- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((S) -3- (3- (dimethylamino) benzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

1045) n- (2- (4- ((S) -4-cyclopropyl-3-methylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((S) -3- (3- (dimethylamino) benzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

1046) n- (2- (4- ((R) -4-cyclopropyl-3-methylpiperazin-1-yl) piperidin-1-yl) -5- ((6- ((S) -3- (3- (dimethylamino) benzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

1047) N- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((S) -3- (3- (dimethylamino) benzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

1048) n- (2- (4- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((S) -3- (3- (dimethylamino) benzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

1049) n- (2- (4-cyclopropylpiperazin-1-yl) -4-methoxy-5- ((6- ((S) -3- (4- (trifluoromethyl) benzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

1050) n- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- (S) -3- (4- (trifluoromethyl) benzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

1051) n- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((S) -3- (4- (trifluoromethyl) benzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

1052) n- (2- (4- ((1S,4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((S) -3- (4- (trifluoromethyl) benzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

1053) N- (5- ((6- ((S) -3- (3-chloro-2-methoxybenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4-cyclopropylpiperazin-1-yl) -4-methoxyphenyl) acrylamide;

1054) n- (5- ((6- ((S) -3- (3-chloro-2-methoxybenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxyphenyl) acrylamide;

1055) n- (2- (4- ((1R,4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) piperidin-1-yl) -5- ((6- ((S) -3- (3-chloro-2-methoxybenzyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) -4-methoxyphenyl) acrylamide;

1056) n- (2- (4- ((R) -4-cyclopropyl-3-methylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((S) -3- (pyridin-3-ylmethyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

1057) n- (2- (4- ((S) -4-cyclopropyl-3-methylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((S) -3- (pyridin-3-ylmethyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

1058) n- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((R) -3- (pyridin-2-ylmethyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide;

1059) n- (2- (4- (4-cyclopropylpiperazin-1-yl) piperidin-1-yl) -4-methoxy-5- ((6- ((S) -3- (pyridin-2-ylmethyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide.

10. A process for preparing a compound of formula 1, the process comprising:

preparing a compound of formula 5 from a compound of formula 4;

preparing a compound of formula 6 from the compound of formula 5; and

preparing the compound of formula 1 from the compound of formula 6,

[ formula 4]

[ formula 5]

[ formula 6]

[ formula 1]

Wherein, in formula 4, G is a leaving group, and R¹To R⁶Are the same as defined in claim 1.

11. The method of claim 10, wherein the compound of formula 4 is prepared by preparing a compound of formula 8 from a compound of formula 7 and preparing the compound of formula 4 from the compound of formula 8,

[ formula 7]

[ formula 8]

Wherein, in formula 7 or 8, each G is independently a leaving group, and R⁵To R⁶Are the same as defined in claim 1.

12. A pharmaceutical composition for preventing or treating cancer, comprising: a compound of formula 1 according to claim 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, as an active ingredient; and a pharmaceutically acceptable carrier.

13. The pharmaceutical composition of claim 12, wherein the compound of formula 1 inhibits an Epidermal Growth Factor Receptor (EGFR) mutation, or one or more wild-type or mutant kinases selected from ERBB2 and ERBB 4.

14. The pharmaceutical composition of claim 13, wherein the EGFR mutation comprises one or more selected from the group consisting of: EGFR Del19/T790M, EGFR L858R/T790M, EGFR L858R, EGFR Exon20 ins NPH, EGFR Exon20 ins SVD, EGFR Exon20 ins FQEA, EGFR Exon20 ins H, and EGFR Exon20 ins ASV, and the mutation of the ERBB2 is Her2 Exon20 ins YVMA.

15. The pharmaceutical composition of claim 12, wherein the cancer comprises one or more selected from the group consisting of: pseudomyxoma, intrahepatic bile duct cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphocytic leukemia, basal cell carcinoma, epithelial ovarian cancer, ovarian germ cell carcinoma, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, Fratercalar's abdomen cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal and paranasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, childhood brain cancer, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, colon cancer, cervical cancer, Glioma, renal pelvis cancer, kidney cancer, heart cancer, duodenum cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulva cancer, ureter cancer, urinary tract cancer, carcinoma of unknown primary site, gastric lymphoma, stomach cancer, gastric carcinoid tumor, gastrointestinal stromal tumor, Wilms ' cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal carcinoid tumor, vaginal cancer, spinal cord cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, skin cancer, anal carcinoma, rhabdomyosarcoma, laryngeal carcinoma, pleural carcinoma, leukemia, and lymphoma, And thymus gland cancer.

16. Use of a compound represented by formula 1 as defined in claim 1, a stereoisomer thereof, a hydrate thereof or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention or treatment of cancer.