Heteroaryl derivatives, methods for preparing the heteroaryl derivatives, and pharmaceutical compositions containing the heteroaryl derivatives as active ingredients

Abstract

The present invention relates to a pharmaceutical composition comprising the compound of the present invention, its isomer, hydrate, solvate, or pharmaceutically acceptable salt thereof as an active ingredient for the prevention or treatment of cancer. The compound has high inhibitory activity against at least one of epidermal growth factor receptor (EGFR) mutant, or wild-type or mutant ErbB2 and ErbB4, and therefore can be advantageously used in the treatment of cancers expressing these.

Description

[Technical Field]

[0001] The present invention relates to heteroaryl derivatives, stereoisomers thereof, hydrates thereof, solvates thereof, or pharmaceutically acceptable salts thereof, methods for preparing them, and pharmaceutical compositions for preventing or treating cancer, which contain the above substances as active ingredients. [Background technology]

[0002] The development of cancer is associated with various environmental factors, including chemicals, radiation, and viruses, as well as alterations in oncogenes, tumor suppressor genes, and genes involved in apoptosis and DNA repair. Recent advances in understanding the molecular mechanisms of these cancers have enabled a new therapeutic approach, namely, targeted cancer therapy. Generally, targeted therapeutic agents can be tailored to target molecules characteristic of cancer cells. Genes considered as molecular targets include those involved in cancer cell signaling pathways, angiogenesis, the extracellular matrix, cell cycle regulators, apoptosis, and so on. Important targeted therapeutic agents used in modern therapies include tyrosine kinase inhibitors, as well as "signal pathway inhibitors" and "angiogenesis inhibitors." In this context, protein tyrosine kinases have been shown to play an important role in a significant number of malignant tumors. In particular, epidermal growth factor receptor (EGFR), a receptor tyrosine kinase of the ErbB family, is known to be abnormally activated in a significant number of epithelial cell tumors, including non-small cell lung cancer (NSCLC), breast cancer, glioma, head and neck squamous cell carcinoma, colorectal cancer, rectal adenocarcinoma, head and neck cancer, gastric cancer, and prostate cancer. Activation of the EGFR-tyrosine kinase leads to sustained cell proliferation, invasion into surrounding tissues, distant metastasis, and angiogenesis, resulting in increased cell survival.

[0003] Specifically, EGFR is a member of the ErbB tyrosine kinase receptor family, a transmembrane tyrosine kinase with an extracellular ligand-binding domain and an intracellular domain containing a tyrosine kinase domain. These members include EGFR (also referred to as ErbB1 or HER1), HER-2 (also referred to as ErbB2 or neu), ErbB-3, and ErbB-4 (also referred to as HER4). When a ligand binds to the receptor-forming homodimer or heterodimer, an intracellular tyrosine kinase is activated. Consequently, the signal stimulated by EGFR also activates the phosphatidylinositol 3-kinase signaling pathways (PI3K / AKT / mTOR, RAS / RAF / MAPK, and JAK / STAT) (Non-Patent Document 0001). In particular, because EGFR is overexpressed in the majority of non-small cell lung cancers (NSCLC), considerable research has been conducted targeting EGFR as a therapeutic target. Therefore, EGFR TKIs (tyrosine kinase inhibitors) that inhibit the activity of EGFR tyrosine kinase have been developed, and representative drugs include gefitinib (IRESSA™), erlotinib (TARCEVA™), and lapatinib (TYKERB™, TYVERB™).

[0004] On the other hand, in 2004, it was reported that activating mutations of EGFR correlate with response to gefitinib therapy in non-small cell lung cancer (Non-Patent Documents 0002 and 0003). Specifically, the above-mentioned EGFR mutations are known to be broadly classified into sensitizing mutations and resistant mutations, with exon 19 deletions and exon 21 L858R point mutations being the most important sensitizing mutations, accounting for approximately 85 to 90 percent of sensitizing mutations. In particular, it has been known that exon 19 deletion mutations are even more sensitive to TIK. On the other hand, exon 20 T790M point mutation is the most important resistant mutation, known to be found in more than 50 percent of patients who have acquired resistance (Non-Patent Document 0004).

[0005] Somatic mutations identified to date include in-frame deletions in exon 19 or insertions in exon 20, and point mutations that result in the alteration of a single nucleic acid residue in the expressed protein (e.g., L858R, G719S, G719C, G719A, L861Q) (Non-Patent Documents 0005-0007).

[0006] Despite the initial clinical benefit of gefitinib / erlotinib in patients with EGFR-mutated NSCLC, most patients treated with these drugs eventually develop advanced disease. Initial studies of recurrent specimens identified a secondary EGFR mutation, T790M, which rendered gefitinib and erlotinib ineffective inhibitors of EGFR kinase activity (Non-Patent Documents 0008 and 0009). Follow-up studies have demonstrated that approximately 50 percent (24 / 48) of tumors derived from patients who developed resistance to gefitinib or erlotinib harbored the EGFR T790M mutation (Non-Patent Documents 0010-0012). In patients treated with kinase inhibitors, this secondary genetic alteration occurs at a location similar to the "gatekeeper" residue and the secondary resistance allele associated with this residue (e.g., T315I in ABL in imatinib-resistant CML).

[0007] It is also known that EGFR mutations, such as EGFR_del19 and EGFR_L858R, are the main causes of non-small cell lung cancer and head and neck cancer. Therefore, IRESSA and TARCEVA have been developed as therapeutic agents for these cancers and are currently being used in clinical trials.

[0008] However, when these drugs were administered to cancer patients, resistance was observed (secondary mutations in EGFR are based on the structure of these drugs), and it was also found that these mutations were the main cause of actual resistance to the drugs.

[0009] For example, after an average of 10 months of treatment with first-generation EGFR inhibitors, resistance to the T790M mutation located in the EGFR kinase gatekeeper occurs, preventing the efficacy of first-generation EGFR inhibitors. This mutation, called the EGFR_del19_T790M or EGFR_L858R_T790M double mutation, prevents the efficacy of existing therapeutic agents. [Prior art documents] [Non-patent literature]

[0010] (Non-patent document 0001) Nat Rev Cancer 2007;7:169-81

[0011] (Non-patent document 0002) Science 2004;304:1497-500

[0012] (Non-patent document 0003) New England Journal of Medicine 2004;350:2129-39

[0013] (Non-patent document 0004) Clin Cancer Res 2006;12:6494-6501

[0014] (Non-patent document 0005) Fukuoka et al.JCO 2003

[0015] (Non-patent document 0006) Kris et al. JAMA 2003

[0016] (Non-patent document 0007) Shepherd et al.NEJM 2004

[0017] (Non-patent document 0008) Kobayashi et al.NEJM 2005

[0018] (Non-patent document 0009) Pao et al.PLOS Medicine 2005.

[0019] (Non-patent document 0010) Kosaka et al.CCR 2006

[0020] (Non-patent document 0011) Balak et al.CCR 2006

[0021] (Non-patent document 0012) Engelman et al.Science 2007 Summary of the Invention [Means for solving the problem]

[0022] [Technical issues] It is an object of one aspect of the present invention to provide a compound, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof that can be used in the treatment of cancer.

[0023] It is an object of another aspect of the present invention to provide methods for preparing the above compounds.

[0024] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer, which comprises the above-mentioned compound, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. DETAILED DESCRIPTION OF THE INVENTION

[0025] To achieve the above objectives,

[0026] The present invention provides a compound represented by the following chemical formula 1 or 2, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:

[0027] [Chemical formula 1]

[0028] [ka]

[0029] In chemical formula 1,

[0030] E 1 is N or CH,

[0031] R 1 is hydrogen, C 1-5 alkoxy or alkoxy substituted by halogen;

[0032] X 1 is C, N, O or S,

[0033] X 1 When is C, R 2 and R 3 together with the bonded C, form a heteroaryl of 3 to 12 atoms containing at least one N, and the heteroaryl of 3 to 12 atoms is a straight-chain or branched C 1-5 substituted or unsubstituted by alkyl;

[0034] X 1 When is N, R 2 and R 3 are each independently hydrogen or a straight or branched chain C 1-5 alkyl or R 2 and R 3 together with the bonded N, form a heterocycloalkyl of 3 to 12 atoms containing one or more heteroatoms selected from N, O, and S, and its straight-chain or branched C 1-5 Alkyl is C 1-5 Heterocycloalkyl of 3 to 12 atoms, which is substituted or unsubstituted by alkylamino and contains one or more heteroatoms of N, O and S, is a straight or branched C 1-5 Alkyl, C 3-6 Cycloalkyl, C 1-5 Alkylamino, allyl, oxo(=O), C 1-3 unsubstituted or substituted by one or more substituents A selected from the group consisting of alkylcarbonyl and heterocycloalkyl of 3 to 12 atoms containing one or more heteroatoms selected from N and O;

[0035] In addition, in the substituent A, straight or branched C 1-5 Alkyl is C 3-6 Cycloalkyl, C 1-5 It is unsubstituted or substituted by alkylamino or heterocycloalkyl of 3 to 12 atoms containing at least one N, and in the substituent A, the heterocycloalkyl of 3 to 12 atoms is a straight or branched C 1-5 Alkyl, C 3-6 Cycloalkyl, C 1-5 unsubstituted or substituted by a substituent B selected from the group consisting of alkylcarbonyl and heterocycloalkyl of 3 to 12 atoms containing one or more of N and O;

[0036] In addition, in the substituent B, the heterocycloalkyl of 3 to 12 atoms containing one or more of N and O is a straight or branched chain C 1-5 Alkyl, or C 3-6 substituted or unsubstituted by cycloalkyl;

[0037] X 1 When is S or O, R 2 does not exist, R 3 is C 1-5 C substituted by alkylamino 1-5 is alkyl,

[0038] R 4 and R 5 are each independently hydrogen, halogen, or haloalkyl, or R 4 and R 5 together with benzene to form a heteroaryl of 7 to 12 atoms containing N, O and S, and the heteroaryl of 7 to 12 atoms is a straight-chain or branched C 1-5 substituted or unsubstituted by alkyl, or

[0039] [Chemical formula 1]

[0040] [ka]

[0041] In chemical formula 1,

[0042] E 1 is N or CH,

[0043] R 1 is hydrogen, C 1-5 alkoxy or alkoxy substituted by halogen;

[0044] X 1 is C, N, O or S,

[0045] X 1 When is C, R 2 and R 3 together with the bonded C, form a heteroaryl of 3 to 12 atoms containing at least one N, and the heteroaryl of 3 to 12 atoms is a straight-chain or branched C 1-5 substituted with alkyl or heterocycloalkyl of 3 to 12 atoms, or unsubstituted;

[0046] X 1 When is N, R 2 and R 3 are each independently hydrogen or a straight or branched chain C 1-5 alkyl or R 2 and R 3 together with the N to which it is attached form a heterocycloalkyl of 3 to 12 atoms, which heterocycloalkyl contains one or more heteroatoms selected from N, O and S, and its straight or branched C 1-5 Alkyl is C 1-5 Heterocycloalkyl of 3 to 12 atoms, which is substituted or unsubstituted by alkylamino and contains one or more heteroatoms of N, O and S, is a straight or branched C 1-5 Alkyl, C 3-6 Cycloalkyl, C 1-5Alkylamino, allyl, oxo(=O), C 1-3 unsubstituted or substituted by one or more substituents A selected from the group consisting of alkylcarbonyl and heterocycloalkyl of 3 to 12 atoms containing one or more heteroatoms selected from N and O;

[0047] In addition, in the substituent A, straight or branched C 1-5 Alkyl is C 3-6 Cycloalkyl, C 1-5 It is unsubstituted or substituted by alkylamino or heterocycloalkyl of 3 to 12 atoms containing at least one N, and in the substituent A, the heterocycloalkyl of 3 to 12 atoms is a straight or branched C 1-5 Alkyl, C 3-6 Cycloalkyl, C 1-5 unsubstituted or substituted by a substituent B selected from the group consisting of alkylcarbonyl, heterocycloalkyl of 3 to 12 atoms containing one or more of N and O, and oxo;

[0048] In addition, in the substituent B, the heterocycloalkyl of 3 to 12 atoms containing one or more of N and O is a straight or branched chain C 1-5 Alkyl, or C 3-6 substituted or unsubstituted by cycloalkyl;

[0049] X 1 When is S or O, R 2 does not exist, R 3 is C 1-5 C substituted by alkylamino 1-5 is alkyl,

[0050] R 4 and R 5 are each independently hydrogen, halogen, or haloalkyl, or R 4 and R 5together with benzene to form a heteroaryl of 7 to 12 atoms containing one or more heteroatoms selected from N, O and S, and the heteroaryl of 7 to 12 atoms is a straight-chain or branched C 1-5 substituted or unsubstituted by alkyl;

[0051] [Chemical formula 2]

[0052] [ka]

[0053] In chemical formula 2,

[0054] E 2 and E 3 are each independently N or CH;

[0055] However, E 2 is N and E 3 If is CH, it is excluded,

[0056] R 6 is hydrogen, or C 1-5 is an alkoxy,

[0057] R 7 is a linear or branched chain C 1-5 If it is alkyl, R 8 is C 1-5 Alkylamino-substituted straight or branched chain C 1-5 is alkyl, or

[0058] R 7 and R 8 together with the N to which they are attached form a heterocycloalkyl of 3 to 12 atoms, and the heterocycloalkyl of 3 to 12 atoms is a straight-chain or branched C 1-5It is unsubstituted or substituted by alkyl or heterocycloalkyl of 3 to 12 atoms containing at least one N, and the heterocycloalkyl of 3 to 12 atoms containing at least one N is C 3-6 substituted or unsubstituted by cycloalkyl;

[0059] R 9 and R 10 are each independently hydrogen, halogen, or haloalkyl.

[0060] Additionally, the present invention provides methods for preparing compounds represented by Formula 1 or 2.

[0061] Additionally, the present invention provides a pharmaceutical composition for preventing or treating cancer, comprising a compound represented by Chemical Formula 1 or 2, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. (Effects of the Invention)

[0062] The compound provided according to one aspect of the present invention, its stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof has high inhibitory activity against wild-type or mutant EGFR (epidermal growth factor receptor), as well as ErbB2, ErbB4, and their mutants, and can therefore be usefully used to treat cancers in which the kinases are expressed.

[0063] Detailed Description of the Preferred Embodiments of the Invention In the following, the invention will be explained in more detail with reference to embodiments.

[0064] The present invention may be embodied in various different forms, and the scope of the present invention is not limited to the embodiments described below. In addition, the present invention is described in detail below in order to more completely explain the present invention to those skilled in the art.

[0065] Throughout this specification, "comprising" a particular component means that it may further include other components, rather than excluding other components, unless specifically stated to the contrary.

[0066] In the structural formulas herein, the symbol "-" connecting atoms and / or groups to each other can mean a single bond, and the symbol "=" can mean a double bond. Such symbols may be omitted, but may also be shown when it is necessary to specify the bonded atom or the bonding position.

[0067] As used herein, a "connection" between atoms may include not only a direct connection between the atoms, but also an indirect connection between the atoms through other atoms and / or groups. In this context, other atoms and / or groups include oxygen, sulfur, C 1-8 Alkylamino, C 1-8 The atoms and / or groups may be substituted or unsubstituted, such as, but not limited to, alkylene groups.

[0068] As used herein, the phrase "substituted or unsubstituted" may mean that one or more hydrogen atoms are replaced by another atom or substituent, or that the group is unsubstituted, unless otherwise specified. Substituents include halogens (chloro (Cl), iodo (I), bromo (Br), fluoro (F), C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, Hydroxyl, C 1-10Alkoxy, amino, nitro, thiol, thioether, imine, cyano, phosphonate, phosphine, carboxy, carbamoyl, carbamic acid, acetal, urea, thiocarbonyl, sulfonyl, sulfonamide, ketone, aldehyde, ester, acetyl, acetoxy, amide, oxygen (=O), haloalkyl (e.g., trifluoromethyl), substituted aminoacyl and aminoalkyl, carbocyclic cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) which may be monocyclic or fused or multiple non-fused rings, heterocycloalkyl (e.g., pyrrolidinyl, piperidinyl) which may be monocyclic or fused or multiple non-fused rings, , piperazinyl, morpholinyl, or thiazinyl), carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic aryl (e.g., phenyl, naphthalenyl, pyrrolyl, indolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothienyl, or benzofuranyl), amino (primary, secondary, or tertiary), aryl, aryloxy, and aryl-alkyl. Furthermore, each of the substituents mentioned above as examples may be substituted or unsubstituted with a substituent selected from these groups of substituents.

[0069] As used herein, "halogen" may be F, Cl, Br or I.

[0070] As used herein, unless otherwise specified, "alkyl" may refer to a saturated hydrocarbon straight or branched chain non-cyclic alkyl, a cyclic alkyl, or an alkyl formed by a combination of both of the above alkyls. 1-8"Alkyl" may refer to an alkyl containing 1 to 8 carbon atoms. By way of example, non-cyclic alkyls may include, but are not limited to, methyl, ethyl, N-propyl, N-butyl, N-pentyl, N-hexyl, N-heptyl, N-octyl, isopropyl, sec-butyl, tert-butyl, isopentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. By way of example, cyclic alkyls may include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. Examples of alkyls formed by the combination of a non-cyclic alkyl and a cyclic alkyl include, but are not limited to, methylcyclopropyl, cyclopropylmethyl, ethylcyclopropyl, cyclopropylmethyl, methylcyclobutyl, cyclobutylmethyl, ethylcyclopentyl, cyclopentylmethyl, and the like.

[0071] As used herein, the term "cycloalkyl" may refer to alkyl, and in particular, means a cyclic alkyl within alkyl, wherein alkyl is as defined above.

[0072] As used herein, "alkoxy" may refer to an alkyl ether group, i.e., -(O-alkyl), where alkyl is as defined above. 1-8 "Alkoxy" is C 1-8 Alkoxy containing alkyl, i.e., -(OC 1-8 alkyl), for example, C 1-8 Alkoxy may include, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, and the like.

[0073] As used herein, "heterocycloalkyl" may refer to a ring containing 1 to 5 ring-forming atoms, i.e., heteroatoms selected from N, O, and S, and may therefore be saturated or partially unsaturated. Unless otherwise specified, heterocycloalkyl may be a monocyclic ring or multiple rings, such as a spirocyclic ring, a bridged ring, or a fused ring. Furthermore, "heterocycloalkyl of 3 to 12 atoms" may refer to a heterocycloalkyl containing 3 to 12 ring-forming atoms, and examples of heterocycloalkyl include pyrrolidine, piperidine, N-methylpiperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, piperidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholine, thiomorpholine, and thiomorpholine. Examples of suitable azabicyclo[3.2.1]octane include, but are not limited to, phosphorus-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]heptane, (1R,5S)-3-azabicyclo[3.2.1]octane, (1s,4s)-2-azabicyclo[2.2.2]octane, (1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane, and the like.

[0074] As used herein, "alkylamino" may refer to -(NR'R"), where R' and R" are each independently selected from hydrogen and C 1-8 alkyl, and in turn, each selected R' and R" may be independently substituted or unsubstituted. 1-8 "Alkylamino" is C 1-8 Alkyl-containing amino, i.e., -NH(C 1-8 alkyl) or -N-(C 1-8 alkyl)2, which may include, but is not limited to, dimethylamino, diethylamino, methylethylamino, methylpropylamino, or ethylpropylamino.

[0075] As used herein, unless otherwise specified, "alkenyl" may refer to a straight or branched chain acyclic or cyclic hydrocarbon having one or more double bonds. 2-8 "Alkenyl" may refer to an alkenyl containing 2 to 8 carbon atoms, including, but not limited to, ethenyl, 1-propenyl, prop-2-en-1-yl [-(CH-CH=CH)] (allyl), 2-butenyl, isopropenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 1-cyclohexenyl, cyclopentadienyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, 1,3-cycloheptadienyl, 1,3,5-cycloheptatrienyl, and the like.

[0076] As used herein, unless otherwise stated, "bicycloalkyl" may mean a bicyclic fused hydrocarbon, spiro hydrocarbon, or bridged hydrocarbon.

[0077] As used herein, "oxazabicycloalkyl" may refer to -(oxaza-bicycloalkyl), i.e., a bicycloalkyl containing one oxygen atom and one nitrogen atom within the cycloalkyl. By way of example, oxazabicycloalkyl may include, but is not limited to, oxazabicyclo[2,2,1]heptane, and the like.

[0078] As used herein, "hydrate" may refer to a compound of the present invention or a salt thereof, which contains a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. The hydrate of the compound of the present invention represented by Chemical Formula 1 may contain a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. The hydrate may contain more than one equivalent of water, preferably 1 to 5 equivalents of water. The hydrate may be prepared by crystallizing the compound of the present invention represented by Chemical Formula 1, its isomer, or a pharmaceutically acceptable salt thereof from water or a solvent containing water.

[0079] As used herein, "solvate" may refer to a compound of the present invention or a salt thereof that includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. In this context, preferred solvents include volatile solvents, non-toxic solvents, and / or solvents that are suitable for administration to humans.

[0080] As used herein, the term "isomer" refers to a compound or salt thereof of the present invention that has the same chemical or molecular formula but differs structurally or three-dimensionally. Such isomers include structural isomers such as tautomers, R- or S-isomers having asymmetric carbon centers, geometric isomers (trans and cis), and stereoisomers such as enantiomers. All such isomers and compounds thereof are within the scope of the present invention. Unless otherwise indicated, a solid bond (-) connecting to an asymmetric carbon atom will be replaced with a solid wedge bond indicating the three-dimensional absolute configuration. [ka] or dashed wedge bond [ka] may be included.

[0081] One aspect of the present invention provides a compound represented by the following chemical formula 1, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:

[0082] [Chemical formula 1]

[0083] [ka]

[0084] In chemical formula 1,

[0085] E 1 is N or CH,

[0086] R 1 is hydrogen, C 1-5 alkoxy or alkoxy substituted by halogen;

[0087] X 1 is C, N, O or S,

[0088] X 1 When is C, R 2 and R 3 together with the bonded C, form a heteroaryl of 3 to 12 atoms containing at least one N, and the heteroaryl of 3 to 12 atoms is a straight-chain or branched C 1-5 substituted or unsubstituted by alkyl;

[0089] X 1 When is N, R 2 and R 3 are each independently hydrogen or a straight or branched chain C 1-5 alkyl or R 2 and R 3 together with the bonded N, form a heterocycloalkyl of 3 to 12 atoms containing one or more heteroatoms selected from N, O, and S, and its straight-chain or branched C 1-5 Alkyl is C 1-5 Heterocycloalkyl of 3 to 12 atoms, which is substituted or unsubstituted by alkylamino and contains one or more heteroatoms of N, O and S, is a straight or branched C 1-5 Alkyl, C 3-6 Cycloalkyl, C 1-5 Alkylamino, allyl, oxo(=O), C 1-3 unsubstituted or substituted by one or more substituents A selected from the group consisting of alkylcarbonyl and heterocycloalkyl of 3 to 12 atoms containing one or more heteroatoms selected from N and O;

[0090] In addition, in the substituent A, straight or branched C 1-5 Alkyl is C 3-6 Cycloalkyl, C 1-5It is unsubstituted or substituted by alkylamino or heterocycloalkyl of 3 to 12 atoms containing at least one N, and in the substituent A, the heterocycloalkyl of 3 to 12 atoms is a straight or branched C 1-5 Alkyl, C 3-6 Cycloalkyl, C 1-5 unsubstituted or substituted by a substituent B selected from the group consisting of alkylcarbonyl and heterocycloalkyl of 3 to 12 atoms containing one or more of N and O;

[0091] In addition, in the substituent B, the heterocycloalkyl of 3 to 12 atoms containing one or more of N and O is a straight or branched chain C 1-5 Alkyl, or C 3-6 substituted or unsubstituted by cycloalkyl;

[0092] X 1 When is S or O, R 2 does not exist, R 3 is C 1-5 C substituted by alkylamino 1-5 is alkyl,

[0093] R 4 and R 5 are each independently hydrogen, halogen, or haloalkyl, or R 4 and R 5 together with benzene to form a heteroaryl of 7 to 12 atoms containing N, O and S, and the heteroaryl of 7 to 12 atoms is a straight-chain or branched C 1-5 It may be substituted or unsubstituted by alkyl, or

[0094] [Chemical formula 1]

[0095] [ka]

[0096] In chemical formula 1,

[0097] E 1 is N or CH,

[0098] R 1 is hydrogen, C 1-5 alkoxy or alkoxy substituted by halogen;

[0099] X 1 is C, N, O or S,

[0100] X 1 When is C, R 2 and R 3 together with the bonded C, form a heteroaryl of 3 to 12 atoms containing at least one N, and the heteroaryl of 3 to 12 atoms is a straight-chain or branched C 1-5 substituted with alkyl or heterocycloalkyl of 3 to 12 atoms, or unsubstituted;

[0101] X 1 When is N, R 2 and R 3 are each independently hydrogen or a straight or branched chain C 1-5 alkyl or R 2 and R 3 together with the N to which it is attached form a heterocycloalkyl of 3 to 12 atoms, which heterocycloalkyl contains one or more heteroatoms selected from N, O and S, and its straight or branched C 1-5 Alkyl is C 1-5 Heterocycloalkyl of 3 to 12 atoms, which is substituted or unsubstituted by alkylamino and contains one or more heteroatoms of N, O and S, is a straight or branched C 1-5 Alkyl, C 3-6 Cycloalkyl, C 1-5 Alkylamino, allyl, oxo(=O), C 1-3unsubstituted or substituted by one or more substituents A selected from the group consisting of alkylcarbonyl and heterocycloalkyl of 3 to 12 atoms containing one or more heteroatoms selected from N and O;

[0102] In addition, in the substituent A, straight or branched C 1-5 Alkyl is C 3-6 Cycloalkyl, C 1-5 It is unsubstituted or substituted by alkylamino or heterocycloalkyl of 3 to 12 atoms containing at least one N, and in the substituent A, the heterocycloalkyl of 3 to 12 atoms is a straight or branched C 1-5 Alkyl, C 3-6 Cycloalkyl, C 1-5 unsubstituted or substituted by a substituent B selected from the group consisting of alkylcarbonyl, heterocycloalkyl of 3 to 12 atoms containing one or more of N and O, and oxo;

[0103] In addition, in the substituent B, the heterocycloalkyl of 3 to 12 atoms containing one or more of N and O is a straight or branched chain C 1-5 Alkyl, or C 3-6 substituted or unsubstituted by cycloalkyl;

[0104] X 1 When is S or O, R 2 does not exist, R 3 is C 1-5 C substituted by alkylamino 1-5 is alkyl,

[0105] R 4 and R 5 are each independently hydrogen, halogen, or haloalkyl, or R 4 and R 5 together with benzene to form a heteroaryl of 7 to 12 atoms containing one or more heteroatoms selected from N, O and S, and the heteroaryl of 7 to 12 atoms is a straight-chain or branched C1-5 It is substituted or unsubstituted by alkyl.

[0106] In a specific embodiment, a compound represented by Formula 1 is provided, wherein:

[0107] E 1 is CH or N,

[0108] R 1 is hydrogen, C 1-3 alkoxy or alkoxy substituted by halogen;

[0109] X 1 is C, N, O or S,

[0110] X 1 When is C, R 2 and R 3 together with the bonded C, form a heteroaryl of 3 to 6 atoms containing at least one N, and the heteroaryl of 3 to 6 atoms is a straight-chain or branched C 1-3 substituted or unsubstituted by alkyl;

[0111] X 1 When is N, R 2 and R 3 are each independently hydrogen or a straight or branched chain C 1-3 alkyl or R 2 and R 3 together with the bonded N, form a heterocycloalkyl of 4 to 10 atoms containing one or more heteroatoms selected from N, O and S, and its straight or branched C 1-3 Alkyl is C 1-3 The heterocycloalkyl of 4 to 10 atoms, which is substituted or unsubstituted by alkylamino and contains one or more heteroatoms of N, O and S, is a straight or branched C 1-3 Alkyl, C 3-6 Cycloalkyl, C 1-3 Alkylamino, allyl, oxo(=O), C 1-3unsubstituted or substituted by one or more substituents A selected from the group consisting of alkylcarbonyl and heterocycloalkyl of 4 to 10 atoms containing one or more heteroatoms selected from N and O;

[0112] In addition, in the substituent A, straight or branched C 1-3 Alkyl is C 3-6 Cycloalkyl, C 1-3 It is unsubstituted or substituted by alkylamino or heterocycloalkyl of 4 to 10 atoms containing at least one N, and in the substituent A, the heterocycloalkyl of 4 to 10 atoms is a straight or branched C 1-3 Alkyl, C 3-6 Cycloalkyl, C 1-3 unsubstituted or substituted by a substituent B selected from the group consisting of alkylcarbonyl and heterocycloalkyl of 4 to 6 atoms containing one or more of N and O;

[0113] In addition, in the substituent B, the heterocycloalkyl of 4 to 6 atoms containing one or more of N and O is a straight or branched chain C 1-3 Alkyl, or C 3-6 substituted or unsubstituted by cycloalkyl;

[0114] X 1 When is S or O, R 2 does not exist, R 3 is C 1-3 alkyl substituted by alkylamino;

[0115] R 4 and R 5 are each independently hydrogen, halogen, or haloalkyl, or R 4 and R 5 together with benzene to form a heteroaryl of 8 to 10 atoms containing N, O and S, and the heteroaryl of 7 to 12 atoms is a straight or branched chain C 1-3It may be substituted or unsubstituted by alkyl.

[0116] In a more specific embodiment, compounds represented by Formula 1 are provided, wherein:

[0117] E 1 is CH,

[0118] R 1 is hydrogen or methoxy,

[0119] X 1 is C, N, S or O,

[0120] X 1 When is C, R 2 and R 3 together with the attached C form a pyrazole, which is substituted or unsubstituted by methyl;

[0121] X 1 When is N, R 2 is methyl and R 3 is dimethyl-aminoethyl or methyl-aminoethyl, or

[0122] R 2 and R 3 together with the N to which they are attached form a morpholino, piperazine, piperidine, pyrrolidine, diazepane, thiomorpholino or oxazabicycloheptane, wherein the morpholino, piperazine, piperidine, pyrrolidine, diazepane, thiomorpholino or oxazabicycloheptane is unsubstituted or substituted by one or more substituents C selected from the group consisting of methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethyl, allyl, oxetanyl, dimethylamino, diethylamino, dimethylaminomethyl, azetidinylmethyl, oxo, methylcarbonyl, piperidinyl, piperazinyl, morpholino, azetidinyl, diazepanyl and pyrrolidinyl;

[0123] Additionally, in substituent C, piperazinyl, piperidinyl, morpholino, and diazepanyl are each independently unsubstituted or substituted with one or more substituents D selected from the group consisting of methyl, isopropyl, piperazinyl, cyclopropyl, and oxo;

[0124] Additionally, in the substituent D, the piperazine is substituted with methyl or cyclopropyl or is unsubstituted;

[0125] X 1 When is S or O,

[0126] R 2 does not exist, R 3 is dimethylaminoethyl,

[0127] R 4 and R 5 are each independently hydrogen, fluoro, chloro or trifluoromethyl, or together with benzene form an indazole which may be unsubstituted or substituted by methyl, or

[0128] E 1 is CH,

[0129] R 1 is hydrogen or methoxy,

[0130] X 1 is C, N, S or O,

[0131] X 1 When is C, R 2 and R 3 together with the attached C form a pyrazole, which is unsubstituted or substituted by methyl or N-methylpiperidine;

[0132] X 1When is N, R 2 is methyl and R 3 is dimethylaminoethyl or methylaminoethyl, or

[0133] R 2 and R 3 together with the N to which they are attached form a morpholino, piperazine, piperidine, pyrrolidine, diazepane, thiomorpholino or oxazabicycloheptane, wherein the morpholino, piperazine, piperidine, pyrrolidine, diazepane, thiomorpholino or oxazabicycloheptane is unsubstituted or substituted by one or more substituents C selected from the group consisting of methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethyl, allyl, oxetanyl, dimethylamino, diethylamino, dimethylaminomethyl, azetidinylmethyl, oxo, methylcarbonyl, piperidinyl, piperazinyl, morpholino, azetidinyl, diazepanyl and pyrrolidinyl;

[0134] Additionally, in substituent C, piperazinyl, piperidinyl, morpholino, and diazepanyl are each independently unsubstituted or substituted with one or more substituents D selected from the group consisting of methyl, isopropyl, piperazinyl, cyclopropyl, and oxo;

[0135] Additionally, in the substituent D, the piperazine is substituted with methyl or cyclopropyl or is unsubstituted;

[0136] X 1 When is S or O, R 2 does not exist, R 3 is dimethylaminoethyl,

[0137] R 4 and R 5are each independently hydrogen, fluoro, chloro, or trifluoromethyl, or together with benzene form an indazole, which is substituted or methyl.

[0138] In a more specific embodiment, compounds represented by Formula 1 are provided, wherein:

[0139] E 1 is CH,

[0140] R 1 is hydrogen or methoxy,

[0141] [ka] teeth,

[0142] [ka] may be

[0143] [ka] teeth, [ka] It may be.

[0144] In a specific embodiment, a compound represented by Formula 1 is provided, wherein:

[0145] E 1 is N,

[0146] R 1 is hydrogen, methoxy, difluoromethoxy or trifluoroethoxy,

[0147] X 1 is N,

[0148] R 2is methyl and R 3 is dimethylaminoethyl or methylaminoethyl, or

[0149] R 2 and R 3 together with the N to which they are attached form a morpholino, piperazine or piperidine, the morpholino, piperazine or piperidine being unsubstituted or substituted with one or more substituents E selected from the group consisting of methyl, piperazinyl, morpholino and oxazabicycloheptane;

[0150] Additionally, in the substituent E, piperazinyl is substituted by methyl or cyclopropyl or is unsubstituted,

[0151] R 4 and R 5 may each independently be hydrogen, fluoro, or trifluoromethyl.

[0152] In a more specific embodiment, compounds represented by Formula 1 are provided, wherein:

[0153] E 1 is N,

[0154] R 1 is hydrogen, methoxy, difluoromethoxy or trifluoroethoxy,

[0155] [ka] teeth, [ka] may be

[0156] [ka] teeth, [ka] It may be.

[0157] Another aspect of the present invention provides a compound represented by the following chemical formula 2, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:

[0158] [Chemical formula 2]

[0159] [ka]

[0160] In chemical formula 2,

[0161] E 2 and E 3 are each independently N or CH;

[0162] However, E 2 is N and E 3 is excluded if CH,

[0163] R 6 is hydrogen, or C 1-5 is an alkoxy,

[0164] R 7 is a linear or branched chain C 1-5 If it is alkyl, R 8 is C 1-5 Alkylamino-substituted straight or branched chain C 1-5 is alkyl, or

[0165] R 7 and R 8 together with the N to which they are attached form a heterocycloalkyl of 3 to 12 atoms, and the heterocycloalkyl of 3 to 12 atoms is a straight-chain or branched C 1-5It is unsubstituted or substituted by alkyl or heterocycloalkyl of 3 to 12 atoms containing at least one N, and the heterocycloalkyl of 3 to 12 atoms containing at least one N is C 3-6 substituted or unsubstituted by cycloalkyl;

[0166] R 9 and R 10 may each independently be hydrogen, halogen, or haloalkyl.

[0167] In a specific embodiment, a compound represented by formula 2 is provided, wherein:

[0168] E 2 and E 3 are each independently N or CH;

[0169] However, E 2 is N and E 3 If is CH, it is excluded,

[0170] R 6 is hydrogen, or C 1-3 is an alkoxy,

[0171] R 7 is a linear or branched chain C 1-3 If it is alkyl, R 8 is C 1-3 Alkylamino-substituted straight or branched chain C 1-3 is alkyl, or

[0172] R 7 and R 8 together with the N bonded thereto form a 4-6 atom heterocycloalkyl, and the 4-6 atom heterocycloalkyl is a straight or branched chain C 1-3It is unsubstituted or substituted by alkyl or heterocycloalkyl of 4 to 6 atoms containing at least one N, and in addition, the heterocycloalkyl of 4 to 6 atoms containing at least one N is C 3-6 substituted or unsubstituted by cycloalkyl;

[0173] R 9 and R 10 may each independently be hydrogen, halogen, or haloalkyl.

[0174] In a more specific embodiment, a compound represented by formula 2 is provided, wherein:

[0175] E 2 and E 3 are each independently N or CH;

[0176] However, E 2 is N and E 3 If is CH, it is excluded,

[0177] R 6 is hydrogen or methoxy,

[0178] R 7 If is methyl, then R 8 is dimethylaminoethyl or methylaminoethyl, or

[0179] R 7 and R 8 together with the N to which they are attached form a morpholino, piperazine, or piperidine, each of which is independently substituted by piperazinyl substituted by methyl or cyclopropyl, or unsubstituted;

[0180] R 9 and R 10 may be hydrogen or fluoro.

[0181] In a more specific embodiment, a compound represented by formula 2 is provided, wherein:

[0182] E 2 and E 3 are each independently N or CH;

[0183] However, E 2 is N and E 3 If is CH, it is excluded,

[0184] R 6 is hydrogen or methoxy,

[0185] [ka] teeth, [ka] may be

[0186] [ka] teeth, [ka] It may be.

[0187] The compound represented by Chemical Formula 1 may be any one of Compound Examples 1 to 129 listed in Table 1 below.

[0188] The compounds represented by Chemical Formula 1 or 2 of the present invention may be used in the form of their pharmaceutically acceptable salts. In particular, the pharmaceutically acceptable salts may be acid addition salts formed with free acids. In the present invention, the acid addition salts may be obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc., non-toxic organic acids such as aliphatic monocarboxylic acid salts and dicarboxylic acid salts, phenyl-substituted alkanoates, hydroxyalkanoates and alkanethioates, aromatic acids, aliphatic and aromatic sulfonic acids, etc., and organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. Pharmaceutically acceptable salts of these types include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, and the like. Acid salts, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, benzenesulfonates, toluenesulfonates, chlorobenzenesulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, β-hydroxybutyrates, glycolates, malates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandelates, and the like may be mentioned.Acid addition salts may be prepared by conventional methods, for example, by dissolving a derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc., adding an organic or inorganic acid to the resulting product, and filtering and drying the resulting precipitate. Alternatively, they may be prepared by distilling off the solvent and excess acid under reduced pressure, drying the resulting product, and crystallizing the dried product in an organic solvent. Furthermore, pharmaceutically acceptable salts may be salts obtained using bases or metal salts. Examples of metal salts include alkali metal salts or alkaline earth metal salts obtained by dissolving a compound in an excess alkali metal hydroxide solution or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. Pharmaceutically suitable alkali metal salts may be sodium, potassium, or calcium. Additionally, the corresponding salts may be obtained by reacting an alkali metal salt or alkaline earth metal salt with an appropriate silver salt (e.g., silver nitrate).

[0189] Additionally, the present invention may provide compounds represented by chemical formula 1 or 2, and pharmaceutically acceptable salts thereof, as well as their stereoisomers, particularly enantiomers, and hydrates and / or solvates that may be prepared therefrom.

[0190] Another aspect of the present invention may be to provide a method for preparing a compound of Formula 1 according to Reaction Scheme 1 below.

[0191] The method for preparing the compound of formula 1 is carried out according to the following reaction scheme 1,

[0192] a step (first step) of reacting compounds of formula 3 and 4 with each other to prepare a compound of formula 5;

[0193] a step (second step) of reacting the compounds of formulas 5 and 6 with each other to prepare a compound of formula 7;

[0194] a third step of reacting the compounds of formula 7 and 8 with each other to prepare a compound of formula 9;

[0195] a fourth step of reducing the compound of formula 9 to prepare a compound of formula 10;

[0196] a fifth step of reacting the compound of formula 10 with acryloyl chloride or acrylic acid to prepare the compound of formula 1; Including,

[0197] [Reaction Scheme 1]

[0198] [ka]

[0199] During the ceremony,

[0200] E 1 , X 1 and R 1 ~R 5 may each be the same as described herein above, and Hal may be a halogen.

[0201] Specifically, the first step may be a process of preparing a compound of formula 5 by reacting compounds of formulas 3 and 4 with diisopropylethylamine (DIPEA) in the presence of a solvent such as dimethyl sulfoxide (DMSO).

[0202] In the second step, the compound of formula 5 prepared in the first step and the compound of formula 6 are reacted with each other and with added p-toluenesulfonic acid monohydrate (pTSA) in the presence of a solvent such as sec-BuOH to prepare the compound of formula 7.

[0203] In the third step, the compound of formula 7 prepared in the second step and the compound of formula 8 are reacted with each other and with added K2CO3 in the presence of a solvent such as dimethyl sulfoxide (DMSO) to prepare the compound of formula 9.

[0204] In the fourth step, the nitro group in the compound of formula 9 prepared in the third step is reduced to an amino group to prepare a compound of formula 10. In this case, any reducing agent that can reduce a nitro group may be used without limitation, and one example is SnCl.

[0205] In the fifth step, the reduced compound of formula 10 and acryloyl chloride or acrylic acid are reacted together in the presence of THF solvent to prepare the compound of formula 1.

[0206] Another aspect of the present invention may provide a method for preparing a compound of formula 2 according to reaction scheme 2 below:

[0207] [Reaction Scheme 2]

[0208] [ka]

[0209] In reaction equation 2,

[0210] E 2 , E 3 and R 6 ~R 10 may each be the same as described herein above, and Hal may be a halogen.

[0211] The specific reactions in each step can proceed in the same manner as in Reaction Scheme 1.

[0212] Another aspect of the present invention is a method for producing a semiconductor device comprising:

[0213] A pharmaceutical composition for preventing or treating cancer may be provided, comprising a compound of Formula 1, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0214] The compound of Chemical Formula 1 may exhibit inhibitory activity against one or more of the enzymes EGFR, ErbB2, and ErbB4. In particular, the compound of Chemical Formula 1 or 2 may exhibit inhibitory activity against EGFR, ErbB2, and ErbB4, which belong to the ErbB tyrosine kinase receptor family, and their mutations.

[0215] EGFR mutations include EGFR(E746-A750del), EGFR(G719C), EGFR(G719S), EGFR(L747-E749del, A750P), EGFR(L747-S752del, P753S), EGFR(L747-T751del, Sins), EGFR(L858R), EGFR(L858R, T790M), EGFR(L861Q), EGFR(S752-I759del), EGFR(T790M), EGFR Del19, EGFR Del19 / T790M, EGFR L858R / T790M / C797S, EGFR Del19 / T790M / C797S, EGFR Exon20 ins NPH and EGFR Exon20 ins SVD.

[0216] ErbB2 may be used synonymously with HER2, and the ErbB2 mutation may be HER2 Exon20 ins YVMA.

[0217] In this context, cancer types include, but are not limited to, pseudomyxoma, intrahepatic cholangiocarcinoma, 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 cancer, male breast cancer, brain tumor, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla of Vater cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal cavity and paranasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain tumor, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvis cancer, The cancer may be one or more of the following types selected from the group consisting of: carcinoma, kidney cancer, cardiac cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, stomach cancer, gastric carcinoid, gastrointestinal tract cancer, Wilms' carcinoma, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain tumor, mediastinal cancer, rectal cancer, rectal carcinoid, vaginal cancer, spinal cancer, vestibular schwannoma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsillar cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, squamous cell lung carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, hematological malignancies, and thymic carcinoma. In particular, the cancer may be lung cancer, more particularly non-small cell lung cancer.

[0218] According to the present invention, pharmaceutical compositions for preventing or treating cancer may be used for clinical administration and may be prepared so that they can be administered in a variety of oral and parenteral dosage forms.

[0219] The pharmaceutical compositions of the present invention may comprise a pharmaceutically acceptable carrier, which may include diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, etc., with which the compositions of the present invention may be formulated.

[0220] For example, solid preparations for oral administration may be prepared as tablets, pills, powders, granules, capsules, etc., and such solid preparations may be prepared by mixing one or more compounds with at least one excipient, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. Furthermore, these preparations may be prepared by using lubricants such as magnesium stearate, talc, etc. in addition to simple excipients.

[0221] Furthermore, liquid preparations for oral administration may be prepared as suspensions, oral solutions, emulsions, syrups, etc., and such liquid preparations may contain various excipients, such as wetting agents, sweeteners, flavoring agents, preservatives, etc., in addition to water and liquid paraffin as simple diluents.

[0222] In addition, formulations for parenteral administration may be prepared as sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, etc., and propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, etc. may be used as non-aqueous solvents or dispersion agents.

[0223] Furthermore, parenteral administration may be performed by using injection methods such as subcutaneous injection, intravenous injection, intramuscular injection, or intrapleural injection. In the present invention, for the purpose of preparing a dosage form for parenteral administration, the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof may be mixed with a stabilizer or buffer in water to prepare a pharmaceutical composition as a solution or suspension, and the solution or suspension may be prepared in unit-dose ampoules or vials.

[0224] The compositions may be sterilized and / or contain adjuvants such as preservatives, stabilizing agents, wetting or emulsifying agents, salts for adjusting the osmotic pressure, and / or buffers, as well as other therapeutically valuable substances, and may be formulated according to conventional mixing, granulating and coating methods.

[0225] Hereinafter, the present invention will be described in more detail with reference to embodiments and experimental examples.

[0226] <Conditions for analysis and purification>

[0227] Compounds synthesized according to embodiments of the present invention were purified or structurally analyzed under the following HPLC conditions.

[0228] 1. HPLC conditions for analysis

[0229] HPLC (ACOUITY UPLC H-Class Core System) conditions for analysis

[0230] The analytical equipment used was a Waters UPLC system (ACQUITY UPLC PDA Detector) equipped with a Waters mass spectrometer (MAQDA). The column used was a Waters ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm, 2.1 × 50 mm). The analysis was performed at a column temperature of 30°C.

[0231] 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.

[0232] Gradient conditions (B 10 to 100% in 3 minutes, flow rate = 0.6 ml / min)

[0233] Preparative LCMS (preparative liquid chromatography mass spectrometry) for purification

[0234] The purification equipment used was a Waters automated purification HPLC system (2767 Sample Manager, 2545 Binary Gradient Module, 2998 Photodiode Array Detector) equipped with a Waters mass QDA detector. The column used was a Waters SunFire® Prep C18 OBD™ (5 μm, 19 × 50 mm). The purification was performed at room temperature.

[0235] 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.

[0236] Gradient conditions (15 to 100% B in 10 minutes, flow rate = 25 ml / min)

[0237] Prep-150 LC system for purification (preparative liquid chromatography UV spectroscopy)

[0238] The purification equipment used was a Waters Prep 150 LC system (2545 Quatternary Gradient Module, 2998 Photodiode Array Detector, Fraction Collector III). The column used was a Waters XTERRA® Prep RP18 OBD™ (10 μm, 30 × 300 mm). The purification was performed at room temperature.

[0239] Gradient conditions (B 3 to 100% in 120 minutes, flow rate = 40 ml / min)

[0240] Preparative HPLC system for purification (preparative liquid chromatography UV spectroscopy)

[0241] The purification apparatus used was a Waters ACCQ Prep HP 150. The column used was a Waters XTERRA (registered trademark) Prep RP18 OBD (trademark) (10 μm, 30 × 300 mm), and purification was performed at room temperature.

[0242] Gradient conditions (10 to 100% B in 120 minutes, flow rate = 42 ml / min)

[0243] 2. NMR Interpretation

[0244] NMR analysis was performed using a Bruker AVANCE III 400 or AVANCE III 400 HD, and the data were expressed in ppm (parts per million (δ)).

[0245] In the present invention, the commercially available reagents were used directly without any further purification.

[0246] In the present invention, the term "room temperature" refers to a temperature of about 5°C to 40°C, in one example, a temperature of about 10°C to 30°C, and in another example, a temperature of about 20°C to 27°C, but is not limited to these ranges.

[0247] Concentration under reduced pressure and distillation of the solvent were carried out using a rotary evaporator.

[0248] <Preparation Example>

[0249] 1. Preparation of Isoxazolidine Derivatives

[0250] Preparation Example 1: Preparation of (R)-3-(3-(trifluoromethyl)phenyl)isoxazolidine

[0251] [ka]

[0252] First step: Preparation of N-methoxy-N-methyl-3-(trifluoromethyl)benzamide

[0253] 3-(Trifluoromethyl)benzoic acid (200 g, 1 equivalent) and N-methoxymethylamine (1.2 equivalents) were dissolved in dichloromethane (150 mL), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI, 1.2 equivalents) was added to the solution at 15 °C. The resulting reaction mixture was stirred at room temperature for 3 hours. TLC analysis (petroleum ether:ethyl acetate = PE:EA = 3:1) showed that all starting material had disappeared, and a new, less polar spot had appeared. The organic layer was extracted with dichloromethane (DCM, 500 mL), sulfuric acid (2N, 500 mL), and brine (200 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the target compound (210 g, 85.9% yield) as a yellow oil.

[0254] Second step: Preparation of 1-(3-trifluoromethyl)phenyl)prop-2-en-1-one

[0255] N-Methoxy-N-methyl-3-(trifluoromethyl)benzamide (100 g, 1 equivalent) obtained in the first step of Preparation 1 was dissolved in tetrahydrofuran (THF, 1 L), and bromo(vinyl)magnesium (1 M, 1.05 equivalents) was added dropwise to the resulting product at 0°C. The resulting reaction mixture was then stirred at 10°C for 2 hours. TLC analysis (petroleum ether:ethyl acetate = PE:EA = 4:1) showed that all starting material had disappeared, and a new, less polar spot had appeared. The reaction was then terminated by adding sulfuric acid (4 N, 500 mL). The organic layer was then extracted with methyl tert-butyl ether (MTBE, 2000 mL) and brine (500 mL). The organic layer was dried with sodium sulfate and then concentrated under reduced pressure. The concentrated compound was purified by chromatography (petroleum ether / ethyl acetate = 30 / 1) to obtain the target compound (90 g, 95% yield) in the form of a yellow oil.

[0256] Third step: Preparation of 3-chloro-1-(3-(trifluoromethyl)phenyl)propan-1-one

[0257] 1-(3-(trifluoromethyl)phenyl)prop-2-en-1-one (90 g, 1.0 equivalent) obtained in Step 2 of Preparation Example 1 was dissolved in dichloromethane (DCM, 71 mL), and then HCl / dioxane (4 M, 2.5 equivalents) was added to the obtained product at 0° C. The resulting reaction mixture was then stirred at 15° C. for 1.5 hours. TLC analysis (petroleum ether:ethyl acetate=PE:EA=10:1) showed that all starting materials had disappeared and the target compound was detected. The resulting reaction mixture was concentrated under reduced pressure, and then dichloromethane (DCM, 450 mL) and water (200 mL×5) were added to extract the organic layer. The organic layer was then dried over sodium sulfate and concentrated under reduced pressure to obtain the target compound (90 g, 85% yield) in the form of a yellow solid.

[0258] Fourth step: Preparation of (S)-3-chloro-1-(3-trifluoromethyl)phenyl)propan-1-ol

[0259] (3aR)-1-Methyl-3,3-diphenyl-3a,4,5,6-tetrahydropyrrolo[1,2-c][1,3,2]oxazaborole (1 M, 0.1 equivalent) was dissolved in tetrahydrofuran (THF, 1.2 L), and then borane tetrahydrofuran (BHTHF, 1 M, 186.48 mL, 0.6 equivalent) was added dropwise to the resulting product under a nitrogen gas stream at −30° C. The resulting reaction mixture was then stirred at −30° C. for 30 minutes. 3-Chloro-1-(3-(trifluoromethyl)phenyl)propan-1-one, obtained in the third step of Preparation 1, was then added dropwise to the previously diluted tetrahydrofuran-stirred reaction mixture at −30° C. The reaction mixture was then stirred at 20° C. for 12 hours. TLC analysis (petroleum ether:ethyl acetate = PE:EA = 5:1) showed the disappearance of all starting materials and the detection of a spot for the target compound. The reaction was terminated by adding methanol (100 mL) at 20 °C, and the solvent was evaporated under reduced pressure. The organic layer was extracted from the resulting concentrated compound using dichloromethane (DCM, 100 mL × 3) and ammonium chloride (NH4Cl) solution (300 mL). The organic layer was dried with sodium sulfate and then concentrated under reduced pressure. The resulting concentrated compound was purified using silica gel chromatography (petroleum ether:ethyl acetate = PE:EA = 50:1 → 5:1) to give the target compound (70 g, 73% yield, 89.8% purity, e.g., 67.2%) as a colorless oil.

[0260] Fifth step: Preparation of tert-butyl (S)-(3-hydroxy)-3-(3-(trifluoromethyl)phenyl)propoxy)carbamate

[0261] Tert-butyl hydroxycarbamate (1.05 equiv.) was dissolved in dimethylformamide (DMF, 500 mL), and sodium hydride (NaH, 60% purity, 1.1 equiv.) was added to the resulting product under a nitrogen gas flow at 0°C. The resulting reaction mixture was stirred at 10°C for 1 hour, and then (S)-3-chloro-1-(3-(trifluoromethyl)phenyl)propan-1-ol (50 g, 1 equiv.) obtained in the fourth step of Preparation 1 was pre-diluted in dimethylformamide (DMF, 500 mL) and added dropwise to the stirred reaction mixture at 0°C. The mixture was stirred again for 16 hours at 10°C. TLC analysis (petroleum ether:ethyl acetate = PE:EA = 2:1) showed that all starting material had disappeared and the target compound had been detected. The reaction was quenched by adding aqueous ammonium chloride solution (3 L), and the organic layer was extracted with ethyl acetate (2000 mL) and brine (2000 mL). The organic layer was then dried over sodium sulfate and concentrated under reduced pressure to give the target compound (47 g, 67% yield) in the form of a bright yellow solid. This reaction was carried out twice using the same method.

[0262] Sixth step: Preparation of tert-butyl (R)-3-(3-(trifluoromethyl)phenyl)oxazolidine-2-carboxylate

[0263] (S)-(3-hydroxy)-3-(3-(trifluoromethyl)phenyl)propoxy)carbamate (94 g, 1 equivalent) obtained in the fifth step of Preparation Example 1 and triethylamine (EtN, 3 equivalents) were dissolved in dichloromethane (DCM, 1 L), and methanesulfonic anhydride (1.5 equivalents) was slowly added to the resulting product at 0°C. The resulting reaction mixture was stirred at 20°C for 12 hours. TLC analysis (petroleum ether:ethyl acetate = PE:EA = 3:1) showed that all starting material had disappeared and a new spot was detected. The reaction was quenched by adding water (2000 mL), and the organic layer was extracted with dichloromethane (DCM, 200 mL × 3). The organic layer was then dried over sodium sulfate and concentrated under reduced pressure. The obtained concentrated compound was purified by chromatography (petroleum ether:ethyl acetate=PE:EA=50:1→5:1) to extract 60 g of the target compound with an ee value of 74.3%.

[0264] The enantiomeric purity of the target compound obtained in the sixth step was analyzed under the following SFC conditions.

[0265] Equipment: CAS-WH-ANA-SFC-C (SHIMADZU LC-30ADsf)

[0266] Column: Amycoat (50 x 4.6 mm, inner diameter 3 μm)

[0267] Mobile phase: CO2 in phase A, MeOH (0.05% DEA) in phase B

[0268] Gradient elution: MeOH (0.05% DEA) in CO2, 5% → 40%

[0269] Flow rate: 3 mL / min, detector: PDA, and

[0270] Column temperature: 35°C, back pressure: 100 bar

[0271] Seventh Step: Preparation of (R)-3-(3-(trifluoromethyl)phenyl)isoxazolidine

[0272] tert-Butyl (R)-3-(3-(trifluoromethyl)phenyl)oxazolidine-2-carboxylate (35 g, 1 eq.) was dissolved in ethyl acetate (EA, 200 mL), and then HCl / EtOAc (4 M, 6.45 eq.) was added to the resulting product at 0° C. The resulting reaction mixture was then stirred for 1 h at 10° C. LCMS analysis showed that all starting material had disappeared. Subsequent concentration under reduced pressure afforded the target compound (24 g, 100% yield, 90% purity, eeHCl 75%) in the form of a white solid.

[0273] For the purpose of purifying or analyzing the enantiomers of the compound obtained in the seventh step, the following conditions were used:

[0274] Equipment: CAS-WH-ANA-SFC-C (SHIMADZU LC-30ADsf)

[0275] Column: Chiralpak AY-3 (50 x 4.6 mm, inner diameter 3 μm)

[0276] Mobile phase: CO2 in phase A and IPA (0.05% DEA) in phase B

[0277] Gradient elution: 5% → 40% B in A

[0278] Flow rate: 3 mL / min, detector: PDA, and

[0279] Column temperature: 35°C, back pressure: 100 bar

[0280] The (R)-3-(3-(trifluoromethyl)phenyl)isoxazolidine (24 g) obtained in the seventh step was purified under the following SFC conditions to give the desired enantiomer (15 g, purity 100%, ee 100%).

[0281] (Column: DAICEL CHIRALPAK AD-H (250 mm x 30 mm, 5 μm), and

[0282] Mobile phase: [0.1% NH3H2O ​​MEOH], B%:15%→15%, 3.8 min, 600 min)

[0283] Using the same method as in Preparation Example 1, compounds of Preparation Examples 2 to 9 were prepared, and the compounds of Preparation Examples 1 to 9 were used to prepare compound examples of the present invention.

[0284] Preparation Example 2: Preparation of (R)-3-(3-fluoro-5-(trifluoromethyl)phenyl)isoxazolidine

[0285] [ka]

[0286] Preparation Example 3: Preparation of (R)-3-(4-chloro-3-(trifluoromethyl)phenyl)isoxazolidine

[0287] [ka]

[0288] Preparation Example 4: Preparation of 3-(3-chloro-5-(trifluoromethyl)phenyl)isoxazolidine

[0289] [ka]

[0290] Preparation Example 5: Preparation of (R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)isoxazolidine

[0291] [ka]

[0292] Preparation Example 6: Preparation of (R)-3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidine

[0293] [ka]

[0294] Preparation Example 7: Preparation of (R)-3-(3,5-difluorophenyl)isoxazolidine

[0295] [ka]

[0296] Preparation Example 8: Preparation of (R)-3-phenylisoxazolidine

[0297] [ka]

[0298] Preparation Example 9: Preparation of (R)-3-(1-methyl-1H-indazol-4-yl)isoxazolidine

[0299] [ka]

[0300] 2. Preparation of Aniline Derivatives

[0301] <Preparation Example 1> Preparation of N-(5-amino-4-methoxy-2-morpholinophenyl)acrylamide

[0302] [ka]

[0303] First step: Preparation of tert-butyl (4-fluoro-2-methoxy-5-nitrophenyl)carbamate

[0304] 4-Fluoro-2-methoxy-5-nitroaniline (10 g, 1 equiv.) was dissolved in DCM (130 mL), and then BocO (14.97 mL, 1.2 equiv.), 4-dimethylaminopyridine (DMAP, 0.656 g, 0.1 equiv.), and triethylamine (TEA, 14.98 mL, 2 equiv.) were added. The resulting reaction mixture was stirred for 12 hours at room temperature. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by chromatography (ethyl acetate / hexane = 8 / 1) to give the target compound (10.5 g, 68.3% yield).

[0305] Second step: Preparation of tert-butyl (2-methoxy-4-morpholino-5-nitrophenyl)carbamate

[0306] Tert-butyl (4-fluoro-2-methoxy-5-nitrophenyl)carbamate (500 mg, 1 equivalent) and morpholine (0.183 mL, 1.2 equivalents) were dissolved in DMSO (5 mL), and potassium carbonate (KCO, 362 mg, 1.5 equivalents) was added to the resulting product and stirred at 70°C for 2 hours. After the reaction, the organic layer was extracted with ethyl acetate (EA, 50 mL) and water (20 mL). The organic layer was dried with sodium sulfate and then concentrated under reduced pressure. The concentrated compound was purified using chromatography (ethyl acetate / hexane = 7 / 1) to give the target compound (252 mg, yield 40.8%).

[0307] Third step: Preparation of tert-butyl (5-amino-2-methoxy-4-morpholinomethyl)carbamate

[0308] Tert-butyl (2-methoxy-4-morpholino-5-nitrophenyl)carbamate (252 mg, 1 equivalent) was dissolved in methanol (5 mL), and the resulting product was added with 10% Pd / C (25 mg, 0.1 w / w) and stirred for 2 hours at room temperature under a hydrogen atmosphere. After the reaction, the mixture was filtered through a Celite filter and concentrated under reduced pressure to give the target compound (235 mg, 100% yield) without further purification.

[0309] Fourth step: Preparation of tert-butyl (5-acrylamido-2-methoxy-4-morpholinophenyl)carbamate

[0310] tert-Butyl (5-amino-2-methoxy-4-morpholinophenyl)carbamate (340 mg, 1 equiv.) was dissolved in DCM (4 mL), and the resulting product was added with acrylic acid (0.094 mL, 1.3 equiv.), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, 262 mg, 1.3 equiv.), and N,N-diisopropylethylamine (DIPEA, 0.551 mL, 3.0 equiv.). The resulting reaction mixture was then stirred for 2 hours at room temperature. After the reaction, the organic layer was extracted with dichloromethane (DCM, 50 mL) and aqueous sodium carbonate (20 mL). The organic layer was dried with sodium sulfate and then concentrated under reduced pressure. The concentrated compound was purified using chromatography (dichloromethane / methanol = 20 / 1) to give the target compound (290 mg, 73% yield).

[0311] Fifth step: Preparation of N-(5-amino-4-methoxy-2-morpholinophenyl)acrylamide

[0312] Tert-butyl (5-acrylamido-2-methoxy-4-morpholinophenyl)carbamate (290 mg, 1 equivalent) was dissolved in dichloromethane (DCM, 4 mL), and then TFA (1 mL, 0.5 v / v) was added to the resulting product. The resulting reaction mixture was then stirred at room temperature for 1 hour. After the reaction, the mixture was concentrated under reduced pressure, and then the organic layer was extracted with dichloromethane (DCM, 50 mL) and aqueous sodium carbonate solution (20 mL). The organic layer was dried with sodium sulfate, and the target compound (210 mg, 98% yield) was obtained without further purification.

[0313] Preparation Example 2: Preparation of N-(5-amino-6-methoxy-2-(4-methylpiperazin-1-yl)pyridin-3-yl)acrylamide

[0314] [ka]

[0315] To prepare N-(5-amino-6-methoxy-2-(4-methylpiperazin-1-yl)pyridin-3-yl)acrylamide, synthesis was carried out in the same manner as in Preparation Example 1 using the intermediate of Preparation Example 2-1 below.

[0316] <Preparation Example 2-1> Preparation of 2-methoxy-6-(4-methylpiperazin-1-yl)-5-nitropyridin-3-amine

[0317] [ka]

[0318] First step: Preparation of 1-(6-chloro-3-nitropyridin-2-yl)-4-methylpiperazine

[0319] 2,6-Dichloro-3-nitropyridine (5 g, 1.0 equiv.) was dissolved in acetonitrile (50 mL), and then 1-methylpiperazine (2.88 mL, 1.0 equiv.) and triethylamine (5.42 mL, 1.5 equiv.) were added to the resulting product at 0 °C. The resulting reaction mixture was stirred for 10 minutes at room temperature. UPLC / MS analysis showed that all starting materials had disappeared, and the target compound was detected. Dichloromethane (DCM, 200 mL) was added to the reaction mixture, which was then washed with water (100 mL) and brine (100 mL). The organic layer was then dried over sodium sulfate and concentrated under reduced pressure. The concentrated compound was purified using silica gel chromatography (EA in hexane, 0% → 100%) to give the target compound (6 g, 90% yield) as a yellow solid.

[0320] Second step: Preparation of 1-(6-methoxy-3-nitropyridin-2-yl)-4-methylpiperazine

[0321] Methanol (0.57 mL, 1.2 equivalents) was added to tetrahydrofuran (THF, 40 mL), and then sodium hydride (NaH, 0.4 g, 1.4 equivalents) was slowly added to the resulting product at 0°C. The resulting reaction mixture was stirred for 10 minutes at 0°C. Subsequently, 1-(6-chloro-3-nitropyridin-2-yl)-4-methylpiperazine (3 g, 1.0 equivalents) obtained in the first step of Preparation Example 2-1 was dissolved in tetrahydrofuran (THF, 40 mL), and the resulting product was slowly added to the above reaction mixture. The reaction mixture was stirred for 1 hour at room temperature under a nitrogen atmosphere. UPLC / MS analysis showed that all starting materials had disappeared, and the target compound was detected. The organic layer was then extracted with ethyl acetate (EA, 100 mL) and water (50 mL). The organic layer was then dried over sodium sulfate and concentrated under reduced pressure to obtain the target compound (2.9 g, 99% yield) in the form of a yellow solid.

[0322] Third Step: Preparation of 1-(5-bromo-6-methoxy-3-nitropyridin-2-yl)-4-methylpiperazine

[0323] 1-(6-Methoxy-3-nitropyridin-2-yl)-4-methylpiperazine (2 g, 1.0 equivalent) obtained in the second step of Preparation Example 2-1 was dissolved in acetonitrile (40 ml), and then N-bromosuccinimide (NBS, 2.1 g, 1.5 equivalents) was slowly added to the resulting product at 0 ° C. The resulting reaction mixture was then stirred at room temperature for 1 hour. UPLC / MS analysis showed that all starting materials had disappeared and the target compound was detected. The precipitate formed by the reaction was then filtered under reduced pressure to obtain the target compound (1.5 g, 57% yield) in the form of a yellow solid.

[0324] Fourth step: Preparation of 2-methoxy-6-(4-methylpiperazin-1-yl)-5-nitropyridin-3-amine

[0325] 1-(5-Bromo-6-methoxy-3-nitropyridin-2-yl)-4-methylpiperazine (0.5 g, 1.0 equivalent) obtained in the third step of Preparation Example 2-1 and dimethyl sulfoxide (DMSO, 5 ml) were placed in a microwave tube, and copper(I) iodide (57 mg, 0.2 equivalent), potassium carbonate (313 mg, 1.5 equivalent), L-prolyl (69 mg, 0.4 equivalent), and ammonium hydroxide (28%, 0.315 ml, 1.5 equivalent) were added. The resulting reaction mixture was stirred at 100 °C for 1 hour using a microwave reactor. UPLC / MS revealed that all starting materials had disappeared and the target compound was detected. The organic layer from the reaction mixture was extracted with ethyl acetate (EA, 100 ml) and water (50 ml). The organic layer was then dried over sodium sulfate and concentrated under reduced pressure. The concentrated compound was purified using silica gel chromatography (MeOH in DCM, 0%→20%) to give the target compound (0.08 g, 20% yield) in the form of an orange oil.

[0326] The aniline compounds of the following Preparation Examples 3 to 17 were prepared by the same method as in Preparation Example 1 or 2. In addition, the anilines prepared by the methods of Preparation Examples 1 to 17 were used to prepare example compounds of the present invention.

[0327] <Preparation Example 3> Preparation of N-(5-amino-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0328] [ka]

[0329] Preparation Example 4: Preparation of N-(5-amino-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide

[0330] [ka]

[0331] Preparation Example 5: Preparation of N-(5-amino-2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-4-methoxyphenyl)acrylamide

[0332] [ka]

[0333] Preparation Example 6: Preparation of N-(5-amino-4-methoxy-2-thiomorpholinophenyl)acrylamide

[0334] [ka]

[0335] Preparation Example 7: Preparation of N-(5-amino-2((2-(dimethylamino)ethyl)thio)-4-methoxyphenyl)acrylamide

[0336] [ka]

[0337] Preparation Example 8: Preparation of N-(5-amino-2-(4-methylpiperazin-1-yl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)acrylamide

[0338] [ka]

[0339] Preparation Example 9: Preparation of N-(5-amino-2-((2-(dimethylamino)ethyl)(methyl)amino)-6-methoxypyridin-3-yl)acrylamide

[0340] [ka]

[0341] Preparation Example 10: Preparation of N-(5-amino-6-(difluoromethoxy)-2-(4-methylpiperazin-1-yl)pyridin-3-yl)acrylamide

[0342] [ka]

[0343] Preparation Example 11: Preparation of N-(5-amino-6-methoxy-2-morpholinopyridin-3-yl)acrylamide

[0344] [ka]

[0345] Preparation Example 12: Preparation of N-(5-amino-2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-6-methoxypyridin-3-yl)acrylamide

[0346] [ka]

[0347] Preparation Example 13: Preparation of (S)—N-(5-amino-2-(4-(4-cyclopropyl-3-methylpiperazin-1-yl)piperidin-1-yl)-6-methoxypyridin-3-yl)acrylamide

[0348] [ka]

[0349] Preparation Example 14: Preparation of (R)—N-(5-amino-2-(4-(4-cyclopropyl-3-methylpiperazin-1-yl)piperidin-1-yl)-6-methoxypyridin-3-yl)acrylamide

[0350] [ka]

[0351] Preparation Example 15: Preparation of N-(2-(4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)piperidin-1-yl)-5-amino-6-methoxypyridin-3-yl)acrylamide

[0352] [ka]

[0353] Preparation Example 16: Preparation of N-(2-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)piperidin-1-yl)-5-amino-6-methoxypyridin-3-yl)acrylamide

[0354] [ka]

[0355] Preparation Example 17: Preparation of N-(5-amino-2-((2-(dimethylamino)ethyl)(methyl)amino)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)acrylamide

[0356] [ka]

[0357] 3. Preparation of Exemplary Compounds of the Invention

[0358] <Embodiment 1> Preparation of (R)-N-(2-(4-(4-cyclopropyl-1-yl)piperidin-1-yl)-5-((6-(3-(3-fluoro-5-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide

[0359] [ka]

[0360] First Step: Preparation of (R)-2-(6-chloropyrimidin-4-yl)-3-(3-fluoro-5-(trifluoromethyl)phenyl)isoxazolidine

[0361] 4,6-Dichloropyrimidine (1.8 g, 1.1 equivalents), (R)-3-(fluoro-5-trimethylfluoromethyl)phenyl)isoxazolidine (3 g, 1 equivalent), and N-N-diisopropylethylamine (DIPEA, 5.8 ml, 3 equivalents) were dissolved in dimethyl sulfoxide (DMSO, 37 ml) and the resulting reaction solution was stirred for 60 minutes at 100°C. After the reaction was completed, extraction was carried out using dichloromethane and water. The collected organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified using medium-pressure liquid chromatography (MPLC) (ethyl acetate / hexane) to obtain the target compound (3.95 g, 100% yield) in the form of a clear liquid. The resulting product was then used in the next reaction without any purification.

[0362] Second step: Preparation of (R)-N-(4-fluoro-2-methoxy-5-nitrophenyl)-6-)(3-(3-fluoro-5-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-amine

[0363] (R)-2-(6-chloropyrimidin-4-yl)-3-(3-fluoro-5-(trifluoromethyl)phenyl)isoxazolidine (3.95 g, 1 equivalent), 4-fluoro-2-methoxy-5-nitroaniline (2.3 g, 1.1 equivalents), and methanesulfonic acid (10 g, 5 equivalents) obtained in the first step were added to sec-butanol (114 ml) and dissolved therein, and the resulting product was heated at 100°C for 12 hours. After completion of the reaction, extraction was carried out using dichloromethane (DCM) and water. The collected organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified using medium-pressure liquid chromatography (MPLC) (ethyl acetate / hexane) to obtain the target compound (2 g, 28% yield).

[0364] Third Step: Preparation of (R)—N-(4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy-5-nitrophenyl)-6-(3-(3-fluoro-5-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-amine

[0365] (R)-N-(4-fluoro-2-methoxy-5-nitrophenyl)-6-(3-(3-fluoro-5-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-amine (450 mg, 1 equivalent) obtained in the second step and potassium carbonate (375 mg, 3 equivalents) were dissolved in dimethyl sulfoxide (DMSO, 9 ml), and then 1-cyclopropyl-4-(piperidin-4-yl)piperazine) hydrochloride (245 mg, 1.1 equivalents) was added to the resulting product, which was then stirred at 70° C. for 2 hours. After completion of the reaction, extraction was carried out using ethyl acetate and water. Subsequently, the collected organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the desired target compound (621 mg, 100%), which was then used in the next reaction without any purification.

[0366] Fourth step: Preparation of (R)-4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-N1-(6-(3-(3-fluoro-5-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)-6-methoxybenzene-1,3-diamine

[0367] (R)-N-(4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy-5-nitrophenyl)-6-(3-(3-fluoro-5-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-amine (621 mg, 1 equivalent) obtained in the third step and SnCl22H2O (1020 mg, 5 equivalents) were dissolved in ethyl acetate (4.5 ml), and the resulting product was stirred at 60 °C for 2 hours. The temperature of the resulting reaction solution was lowered to room temperature, and aqueous ammonia was added dropwise until the pH value reached 5. Subsequently, anhydrous sodium carbonate was added to the resulting reaction mixture to adjust the pH value to 7. Subsequently, the reaction mixture was filtered through Celite and washed several times with ethyl acetate. The filtrate obtained was concentrated under reduced pressure to obtain the target compound (491 mg, 83%), which was then used in the next reaction without any purification.

[0368] Fifth step: Preparation of (R)—N-(2-(4-(4-cyclopropyl-1-yl)piperidin-1-yl)-5-((6-(3-(3-fluoro-5-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide

[0369] (R)-4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-N1-(6-(3-(3-fluoro-5-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)-6-methoxybenzene-1,3-diamine (491 mg, 1 equivalent) obtained in the fourth step was dissolved in dichloromethane (DCM, 7.5 ml), and the resulting product was added with ethylene dichloride (EDC, 215 mg, 1.5 equivalents), acrylic acid (77 μl, 1.5 equivalents), and N-N-diisopropylethylamine (DIPEA, 261 μl, 2 equivalents). The resulting reaction solution was reacted at room temperature for 1 hour, and then the reaction was quenched with aqueous sodium bicarbonate solution. The compound was extracted with ethyl acetate and brine. The resulting organic layer was dried under reduced pressure, concentrated under reduced pressure, and then purified using medium pressure liquid chromatography (MPLC) (dichloromethane / methanol) to afford the target compound (488 mg, 87% yield).

[0370] <Embodiment 98> Preparation of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((4-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyridin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0371] [ka]

[0372] First step: Preparation of (R)-2-(2-chloropyridin-4-yl)-3-(3,5-difluorophenyl)isoxazolidine

[0373] 4-Bromo-2-chloropyridine (57.3 mg, 1.1 equivalents), (R)-3-(3,5-difluorophenyl)isoxazolidine (50 ml, 1 equivalent) obtained in Preparation Example 7 of "1. Preparation of Isoxazolidine Derivatives" above, and cesium carbonate (176 mg, 2 equivalents) were dissolved in 1,4-dioxane (0.7 ml). The temperature of the resulting reaction solution was raised to 70°C, and then Xantphos (15 mg, 0.1 equivalents) and tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3, 15 mg, 0.1 equivalents) were added to the resulting reaction mixture. The resulting reaction solution was reacted for 60 minutes at 100°C. After the reaction, the catalyst was removed from the reaction solution using a Celite filter, and the resulting product was washed with ethyl acetate. The resulting organic layer was concentrated under reduced pressure and then purified using medium pressure liquid chromatography (ethyl acetate / n-hexane) to give the target compound (30 mg, yield 37.4%).

[0374] Second step: Preparation of (R)—N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((4-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyridin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0375] (R)-2-(2-chloropyridin-4-yl)-3-(3,5-difluorophenyl)isoxazolidine (30 mg, 1 equivalent) obtained in the first step above, N-(5-amino-2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-4-methoxyphenyl)acrylamide (36.4 mg, 0.9 equivalent) obtained in Preparation Example 5 of "2. Preparation of Aniline Derivatives" above, and potassium carbonate (28 mg, 2 equivalents) were directly added to and dissolved in sec-butanol (1 mL). The temperature of the resulting reaction solution was raised to 70 °C, and then Xphos (10 mg, 0.2 equivalents) and tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3, 18 mg, 0.2 equivalents) were added to the resulting reaction mixture. The resulting reaction solution was then reacted for 60 minutes at 100° C. After the reaction, the resulting organic layer was concentrated under reduced pressure and then purified using medium pressure liquid chromatography (dichloromethane / methanol) to obtain the target compound (yield 45%).

[0376] All of the exemplary compounds of the present invention (i.e., exemplary compounds 1-129) were prepared by methods similar to those of Example 1 or 98. However, among these exemplary compounds, the reaction intermediates required to prepare exemplary compounds 108, 109, and 114-117 were prepared by methods similar to those of the first step of Example 98, as described below.

[0377] <Preparation of Reaction Intermediates of Compound Examples 108 and 109> Preparation of (R)-2-(2-chloropyrimidin-4-yl)-3-phenylisoxazolidine

[0378] [ka]

[0379] <Preparation of Reaction Intermediates of Compound Examples 114, 115, 116 and 117> Preparation of (R)-2-(4-chloro-1,3,5-triazin-2-yl)-3-(3,5-difluorophenyl)isoxazolidine

[0380] [ka]

[0381] Compound examples 108 and 109 were prepared by a method similar to that of embodiment 98 using the compounds described in <Preparation of reaction intermediates of compound examples 108 and 109>, whereas compound examples 114 to 117 were prepared by a method similar to that of embodiment 98 using the compounds described in <Preparation of reaction intermediates of compound examples 114, 115, 116 and 117>.

[0382] The compound names, chemical structural formulas, and NMR and MS analysis results for each example compound are listed in Table 1 below.

[0383] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 Table 1-44 Table 1-45 Table 1-46 Table 1-47 Table 1-48 Table 1-49 Table 1-50 Table 1-51 Table 1-52 Table 1-53 Table 1-54 Table 1-55 Table 1-56 Table 1-57 Table 1-58 Table 1-59 Table 1-60 Table 1-61 Table 1-62 Table 1-63 Table 1-64 Table 1-65 Table 1-66 Table 1-67 Table 1-68 Table 1-69 Table 1-70 Table 1-71 Table 1-72 Table 1-73 Table 1-74 Table 1-75 Table 1-76 Table 1-77 [Table 1-78] [Table 1-79] [Table 1-80]

[0384] <Experimental Example 1> Evaluation of Ba / F3 proliferation inhibitory activity

[0385] The following experiment was carried out to evaluate the inhibitory activity of compounds according to the invention on the proliferation of Ba / F3 cells expressing EGFR mutations.

[0386] For Ba / F3 cells, RPMI-1640 medium (R&D Systems) containing 10% FBS and 5 ng / ml IL-3 was used. Transduced Ba / F3 cells were cultured in the same medium as above, except that 1 μg / ml puromycin (Invitrogen) was further added.

[0387] Twenty-four hours before compound treatment, 3,000–5,000 cells were dispensed into each well of a 96-well white clear-bottom plate (Corning). Compounds were diluted with dimethyl sulfoxide (e.g., 3:1 dilution ratio, totaling 12 concentrations) and injected at 0.5 μL each to achieve final concentrations ranging from 0.3 nM to 50 μM. Seventy-two hours after compound treatment, viability was measured using CellTiter-Glo luminescent cell viability reagent (Promega). The cells were stored at room temperature for 10 minutes, and then luminescence intensity was measured using a reader (i.e., Synergy Neo (Biotek)). Each experiment was performed in triplicate.

[0388] The obtained values ​​were calculated as cell growth rate (%) compared to the control. Graphs were then drawn and the GI was calculated using the program GraphPad Prism version 5.0. 50 values ​​were calculated.

[0389] Table 2 below shows the evaluation results of the inhibitory activity against the proliferation of Ba / F3 cells expressing EGFR mutation.

[0390] [Table 2-1] [Table 2-2]

[0391] A:GI 50 <50nM, B: 50nM ≤ GI 50 <500nM,

[0392] C: 500nM≦GI 50 <5000nM, D:5000nM≦GI 50

[0393] Table 3 below shows the results of evaluation of inhibitory activity against the proliferation of Ba / F3 cells expressing wild-type or mutant ErbB2 (HER2).

[0394] [Table 3]

[0395] A:GI 50 <50nM, B: 50nM ≤ GI 50 <500nM,

[0396] C: 500nM≦GI 50 <5000nM, D:5000nM≦GI 50

[0397] As shown in Tables 2 and 3, it can be confirmed that the compound examples according to the present invention have high inhibitory activity against EGFR mutation and wild-type or ErbB2 mutation in Ba / F3 cell line.

[0398] Although the present invention has been described in detail above through preferred preparation examples, compound examples, and experimental examples, the scope of the present invention is not limited to these specific compound examples, but is defined by the appended claims. Furthermore, it should be understood that those skilled in the art may make various modifications and changes without departing from the scope of the present invention. The present invention provides, for example, the following items. (Item 1) A compound, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following chemical formula 1: [ka] In the above Chemical Formula 1, E 1 is N or CH, R 1 But hydrogen, C 1-5 alkoxy or alkoxy substituted by halogen; X 1 is C, N, O or S, X 1 When is C, R 2 and R 3 together with the bonded C to form a heteroaryl of 3 to 12 atoms containing at least one N, and the heteroaryl of 3 to 12 atoms is a straight-chain or branched-chain C 1-5 substituted with alkyl or heterocycloalkyl of 3 to 12 atoms, or unsubstituted; X 1 When is N, R 2 and R 3 are each independently hydrogen or a straight or branched chain C 1-5 alkyl or R 2 and R 3 together with the N to which it is bonded form a heterocycloalkyl of 3 to 12 atoms, the heterocycloalkyl containing one or more heteroatoms selected from N, O and S, and the straight or branched C 1-5 Alkyl is C 1-5 The heterocycloalkyl having 3 to 12 atoms is unsubstituted or substituted by alkylamino and contains one or more heteroatoms selected from N, O, and S, and is selected from linear or branched C 1-5 Alkyl, C 3-6 Cycloalkyl, C 1-5 Alkylamino, allyl, oxo(=O), C 1-3 unsubstituted or substituted by one or more substituents A selected from the group consisting of alkylcarbonyl and heterocycloalkyl of 3 to 12 atoms containing one or more heteroatoms selected from N and O; In addition, in the substituent A, the linear or branched C1-5 Alkyl is C 3-6 Cycloalkyl, C 1-5 The substituent A is unsubstituted or substituted by alkylamino or heterocycloalkyl of 3 to 12 atoms containing at least one N, and the heterocycloalkyl of 3 to 12 atoms is a straight-chain or branched-chain C 1-5 Alkyl, C 3-6 Cycloalkyl, C 1-5 unsubstituted or substituted by a substituent B selected from the group consisting of alkylcarbonyl, heterocycloalkyl of 3 to 12 atoms containing one or more of N and O, and oxo; In addition, in the substituent B, the heterocycloalkyl having 3 to 12 atoms containing one or more of N and O is a straight-chain or branched C 1-5 Alkyl, or C 3-6 substituted or unsubstituted by cycloalkyl; X 1 When is S or O, R 2 However, it does not exist, and R 3 But C 1-5 C substituted by alkylamino 1-5 is alkyl, R 4 and R 5 are each independently hydrogen, halogen, or haloalkyl, or R 4 and R 5 together with benzene to form a heteroaryl of 7 to 12 atoms containing one or more heteroatoms selected from N, O and S, and the heteroaryl of 7 to 12 atoms is a straight-chain or branched-chain C 1-5 substituted or unsubstituted by alkyl; The compound, its stereoisomer, its hydrate, its solvate, or its pharmaceutically acceptable salt. (Item 2) The compound is represented by Formula 1, wherein: E 1 is CH, R 1 is hydrogen or methoxy, X 1 is C, N, S or O, X 1 When is C, R 2 and R 3 together with the attached C form a pyrazole, said pyrazole being unsubstituted or substituted by methyl or N-methylpiperidine; X 1 When is N, R 2 is methyl, and R 3 is dimethylaminoethyl or methylaminoethyl, or R 2 and R 3 together with the N to which they are attached form a morpholino, piperazine, piperidine, pyrrolidine, diazepane, thiomorpholino or oxazabicycloheptane, wherein said morpholino, piperazine, piperidine, pyrrolidine, diazepane, thiomorpholino or oxazabicycloheptane is unsubstituted or substituted by one or more substituents C selected from the group consisting of methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethyl, allyl, oxetanyl, dimethylamino, diethylamino, dimethylaminomethyl, azetidinylmethyl, oxo, methylcarbonyl, piperidinyl, piperazinyl, morpholino, azetidinyl, diazepanyl and pyrrolidinyl; Additionally, in the substituent C, the piperazinyl, piperidinyl, morpholino, and diazepanyl are each independently substituted or unsubstituted by one or more substituents D selected from the group consisting of methyl, isopropyl, piperazinyl, cyclopropyl, and oxo; Additionally, in the substituent D, the piperazine is substituted with methyl or cyclopropyl, or is unsubstituted; X 1 When is S or O, R 2 However, it does not exist, and R 3 is dimethylaminoethyl, R 4 and R 5 are each independently hydrogen, fluoro, chloro or trifluoromethyl, or together with benzene form an indazole, said indazole being substituted or unsubstituted by methyl; Item 1. A compound according to item 1, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof. (Item 3) The compound is represented by Formula 1, wherein:

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Claims

1. A compound, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following chemical formula 1: 【Chemistry 1】 In the above Chemical Formula 1, E １ is N or CH; R １ But hydrogen, C １－５ alkoxy or alkoxy substituted by halogen; X １ is C, N, O or S; X １ When is C, R ２ and R ３ together with the bonded C to form a heteroaryl of 3 to 12 atoms containing at least one N, and the heteroaryl of 3 to 12 atoms is a straight-chain or branched C １－５ substituted or unsubstituted by alkyl or heterocycloalkyl of 3 to 12 atoms; X １ When is N, R ２ and R ３ are each independently hydrogen or a straight or branched chain C １－５ alkyl or R ２ and R ３ together with the N to which it is attached form a heterocycloalkyl of 3 to 12 atoms, said heterocycloalkyl containing one or more heteroatoms selected from N, O and S, and said straight or branched C １－５ The alkyl is C １－５ The heterocycloalkyl of 3 to 12 atoms, which is substituted by alkylamino or unsubstituted and contains one or more heteroatoms selected from N, O and S, is a straight-chain or branched C １－５ Alkyl, C ３－６ Cycloalkyl, C １－５ Alkylamino, allyl, oxo (=O), C １－３ unsubstituted or substituted by one or more substituents A selected from the group consisting of alkylcarbonyl and heterocycloalkyl of 3 to 12 atoms containing one or more heteroatoms selected from N and O; In addition, in the substituent A, the linear or branched C １－５ The alkyl is C ３－６ Cycloalkyl, C １－５ The substituent A is unsubstituted or substituted by alkylamino or heterocycloalkyl of 3 to 12 atoms containing at least one N, and the heterocycloalkyl of 3 to 12 atoms is straight-chain or branched C １－５ Alkyl, C ３－６ Cycloalkyl, C １－５ unsubstituted or substituted by a substituent B selected from the group consisting of alkylcarbonyl, heterocycloalkyl of 3 to 12 atoms containing one or more of N and O, and oxo; In addition, in the substituent B, the heterocycloalkyl having 3 to 12 atoms containing one or more of N and O is a straight-chain or branched C １－５ Alkyl, or C ３－６ substituted or unsubstituted by cycloalkyl; X １ is S or O, then R ２ However, it does not exist, and R ３ But C １－５ C substituted by alkylamino １－５ is alkyl, 1) When E 1 is N, R ４ and R ５ are each independently hydrogen, halogen, or haloalkyl, or R ４ and R ５ together with benzene to form a heteroaryl of 7 to 12 atoms containing one or more heteroatoms selected from N, O and S, and the heteroaryl of 7 to 12 atoms is a straight-chain or branched-chain C １－５ substituted or unsubstituted by alkyl, or 2) When E 1 is CH, R 4 is haloalkyl and R 5 is halogen, or R 4 and R 5 together with the benzene form a heteroaryl of 7 to 12 atoms containing one or more heteroatoms selected from N, O and S, and said heteroaryl of 7 to 12 atoms is substituted with a straight or branched chain C 1-5 alkyl or is unsubstituted; The compound, its stereoisomer, its hydrate, its solvate, or its pharmaceutically acceptable salt.

2. The compound is represented by Formula 1, wherein: E １ is N, R １ is hydrogen, methoxy, difluoromethoxy or trifluoroethoxy; X １ is N, R ２ is methyl, and R ３ is dimethylaminoethyl or methylaminoethyl, or R ２ and R ３ together with the N to which they are attached form a morpholino, piperazine or piperidine, said morpholino, piperazine or piperidine being unsubstituted or substituted with one or more substituents E selected from the group consisting of methyl, piperazinyl, morpholino and oxazabicycloheptane; Additionally, in the substituent E, the piperazinyl is substituted with methyl or cyclopropyl, or is unsubstituted; R ４ and R ５ are each independently hydrogen, fluoro or trifluoromethyl; 2. The compound of claim 1, its stereoisomer, its hydrate, its solvate, or its pharmaceutically acceptable salt.

3. A compound, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is any one of the following compounds 1 to 126, i.e. (1) (R)—N-(2-(4-(4-cyclopropyl-1-yl)piperidin-1-yl)-5-((6-(3-(3-fluoro-5-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (2) (R)—N-(2-(4-cyclopropyl-1-yl)-5-((6-(3-(3-fluoro-5-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (3) (R)—N-(5-((6-(3-(3-fluoro-5-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide, (4) (R)—N-(2-(4-ethylpiperazin-1-yl)-5-((6-(3-(3-fluoro-5-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (5) N-(2-((R)-4-cyclopropyl-3-methylpiperazin-1-yl)-5-((6-((R)-3-(3-fluoro-5-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (6) N-(2-((S)-4-cyclopropyl-3-methylpiperazin-1-yl)-5-((6-((R)-3-(3-fluoro-5-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (7) N-(2-((S)-3,4-dimethylpiperazin-1-yl)-4-methoxy-5-((6-((R)-3-(3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)phenyl)acrylamide, (8) N-(2-((R)-3,4-dimethylpiperazin-1-yl)-4-methoxy-5-((6-((R)-3-(3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)phenyl)acrylamide, (9) N-(2-((R)-4-cyclopropyl-3-methylpiperazin-1-yl)-4-methoxy-5-((6-((R)-3-(3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)phenyl)acrylamide, (10) N-(2-((S)-4-cyclopropyl-3-methylpiperazin-1-yl)-4-methoxy-5-((6-((R)-3-(3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)phenyl)acrylamide, (11) N-(2-((R)-3,4-dimethylpiperazin-1-yl)-5-((6-((R)-3-(3-fluoro-5-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (12) N-(2-((S)-3,4-dimethylpiperazin-1-yl)-5-((6-((R)-3-(3-fluoro-5-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (13) (R)—N-(2-(4-(4-cyclopropyl-1-yl)-[1,4′-bipiperidin]-1′-yl)-4-methoxy-5-((6-(3-(3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)phenyl)acrylamide, (14) (R)—N-(4-methoxy-2-(4-(4-methylpiperazin-1-yl)-[1,4′-bipiperidin]-1′-yl)-5-((6-(3-(3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)phenyl)acrylamide, (15) (R)—N-(2-(4-(dimethylamino)piperidin-1-yl)-5-((6-(3-(3-fluoro-5-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (16) (R)—N-(2-(4-(diethylamino)piperidin-1-yl)-5-((6-(3-(3-fluoro-5-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (17) (R)—N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-(3-(3-fluoro-5-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (18) (R)—N-(5-((6-(3-(3-fluoro-5-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxy-2-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)acrylamide, (19) (R)—N-(2-(4-(azetidin-1-yl)piperidin-1-yl)-5-((6-(3-(3-fluoro-5-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (20) (R)—N-(2-(4-(diethylamino)piperidin-1-yl)-4-methoxy-5-((6-(3-(3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)phenyl)acrylamide, (21) (R)—N-(2-(4-(azetidin-1-yl)piperidin-1-yl)-4-methoxy-5-((6-(3-(3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)phenyl)acrylamide, (22) (R)—N-(4-methoxy-2-(4-(pyrrolidin-1-yl)piperidin-1-yl)-5-((6-(3-(3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)phenyl)acrylamide, (23) (R)—N-(4-methoxy-2-(4-(oxetan-3-yl)piperazin-1-yl)-5-((6-(3-(3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)phenyl)acrylamide, (24) (R)—N-(2-(4-allylpiperazin-1-yl)-4-methoxy-5-((6-(3-(3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)phenyl)acrylamide, (25) (R)—N-(2-(4-(cyclopropylmethyl)piperazin-1-yl)-4-methoxy-5-((6-(3-(3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)phenyl)acrylamide, (26) (R)—N-(4-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-5-((6-(3-(3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)phenyl)acrylamide, (27) (R)—N-(4-methoxy-2-morpholino-5-((6-(3-(3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)phenyl)acrylamide, (28) N-(2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-4-methoxy-5-((6-((R)-3-(3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)phenyl)acrylamide, (29) (R)—N-(2-(4-cyclopropyl-1,4-diazepan-1-yl)-4-methoxy-5-((6-(3-(3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)phenyl)acrylamide, (30) N-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-4-methoxy-5-((6-((R)-3-(3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)phenyl)acrylamide, (31) (R)—N-(2-(4-methylpiperazin-1-yl)-5-((6-(3-(3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)phenyl)acrylamide, (32) (R)—N-(5-((6-(3-(4-chloro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide, (33) (R)—N-(5-((6-(3-(4-chloro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-2-(4-ethylpiperazin-1-yl)-4-methoxyphenyl)acrylamide, (34) (R)—N-(5-((6-(3-(4-chloro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-2-(4-(4-cyclopropyl-1-yl)piperidin-1-yl)-4-methoxyphenyl)acrylamide, (35) (R)—N-(5-((6-(3-(4-chloro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-2-(4-(dimethylamino)piperidin-1-yl)-4-methoxyphenyl)acrylamide, (36) (R)—N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-(3-(4-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (37) (R)—N-(5-((6-(3-(4-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide, (38) (R)—N-(2-(4-ethylpiperazin-1-yl)-5-((6-(3-(4-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (39) (R)—N-(2-(4-(dimethylamino)piperidin-1-yl)-5-((6-(3-(4-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (40) (R)—N-(5-((6-(3-(4-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxy-2-(4-methyl-1,4-diazepan-1-yl)phenyl)acrylamide, (41) (R)—N-(2-(4-allylpiperazin-1-yl)-5-((6-(3-(4-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (42) (R)—N-(2-(4-(cyclopropylmethyl)piperazin-1-yl)-5-((6-(3-(4-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (43) N-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-5-((6-((R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (44) N-(2-((S)-3,4-dimethylpiperazin-1-yl)-5-((6-((R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (45) N-(2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-5-((6-((R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (46) (R)—N-(2-(4-acetylpiperazin-1-yl)-5-((6-(3-(4-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)piperidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (47) (R)—N-(2-(4-(diethylamino)piperidin-1-yl)-5-((6-(3-(4-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (48) (R)—N-(2-(4-(azetidin-1-yl)piperidin-1-yl)-5-((6-(3-(4-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (49) (R)—N-(2-(4-(4-cyclopropyl-1-yl)piperidin-1-yl)-5-((6-(3-(4-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (50) N-(5-((6-(3-(3-chloro-5-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-2-(4-ethylpiperazin-1-yl)-4-methoxyphenyl)acrylamide, (51) N-(5-((6-(3-(3-chloro-5-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-2-(4-(4-cyclopropyl-1-yl)piperidin-1-yl)-4-methoxyphenyl)acrylamide, (52) N-(2-(4-((S)-4-cyclopropyl-3-methylpiperazin-1-yl)piperidin-1-yl)-5-((6-((R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (53) N-(2-(4-((R)-4-cyclopropyl-3-methylpiperazin-1-yl)piperidin-1-yl)-5-((6-((R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (54) N-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-5-((6-((R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (55) (R)—N-(5-((6-(3-(4-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxy-2-(4-propylpiperazin-1-yl)phenyl)acrylamide, (56) N-(5-((6-((R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxy-2-((S)-2-methylmorpholino)phenyl)acrylamide, (57) N-(5-((6-((R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxy-2-((R)-2-methylmorpholino)phenyl)acrylamide, (58) N-(5-((6-((R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxy-2-(4-((S)-2-methylmorpholino)piperidin-1-yl)phenyl)acrylamide, (59) N-(5-((6-((R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxy-2-(4-((R)-2-methylmorpholino)piperidin-1-yl)phenyl)acrylamide, (60) (R)—N-(5-((6-(3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide, (61) (R)—N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-(3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (62) (R)—N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (63) (R)—N-(5-((6-(3-(4-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxy-2-morpholinophenyl)acrylamide, (64) (R)—N-(5-((6-(3-(4-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxy-2-(4-morpholinopiperidin-1-yl)phenyl)acrylamide, (65) (R)—N-(5-((6-(3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxy-2-morpholinophenyl)acrylamide, (66) (R)—N-(5-((6-(3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxy-2-(4-morpholinopiperidin-1-yl)phenyl)acrylamide, (67) N-(2-(4-((S)-4-cyclopropyl-3-methylpiperazin-1-yl)piperidin-1-yl)-5-((6-((R)-3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (68) N-(2-(4-((R)-4-cyclopropyl-3-methylpiperazin-1-yl)piperidin-1-yl)-5-((6-((R)-3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (69) (R)—N-(5-((6-(3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxy-2-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide, (70) (R)—N-(2-(2-(dimethylamino)ethoxy)-5-((6-(3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (71) (R)—N-(2-(4-(azetidin-1-yl)piperidin-1-yl)-5-((6-(3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (72) N-(2-((R)-2-(azetidin-1-ylmethyl)pyrrolidin-1-yl)-5-((6-((R)-3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (73) N-(2-(4-((2S,6R)-2,6-dimethylmorpholino)piperidin-1-yl)-5-((6-((R)-3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (74) (R)—N-(5-((6-(3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxy-2-(4-(4-methyl-3-oxopiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide, (75) N-(5-((6-((R)-3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxy-2-((S)-2-methylmorpholino)phenyl)acrylamide, (76) N-(2-((S)-3,4-dimethylpiperazin-1-yl)-5-((6-((R)-3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (77) (R)—N-(2-(4-(4-cyclopropyl-1,4-diazepan-1-yl)piperidin-1-yl)-5-((6-(3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (78) (R)—N-(5-((6-(3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-2-(4-(4-isopropylpiperazin-1-yl)piperidin-1-yl)-4-methoxyphenyl)acrylamide, (79) N-(5-((6-((R)-3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxy-2-((R)-2-methylmorpholino)phenyl)acrylamide, (80) N-(2-((R)-3,4-dimethylpiperazin-1-yl)-5-((6-((R)-3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (81) (R)—N-(2-(4-cyclopropylpiperazin-1-yl)-5-((6-(3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (82) (R)—N-(2-(4-(diethylamino)piperidin-1-yl)-5-((6-(3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (83) (R)—N-(2-(4-(4-cyclopropyl-3,3-dimethylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (84) (R)—N-(5-((6-(3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxy-2-(4-(4-(oxetan-3-yl)piperazin-1-yl)piperidin-1-yl)phenyl)acrylamide, (85) (R)—N-(5-((6-(3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxy-2-(4-methyl-3-oxopiperazin-1-yl)phenyl)acrylamide, (86) N-(2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-5-((6-((R)-3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (87) (R)—N-(5-((6-(3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxy-2-(methyl(2-(methylamino)ethyl)amino)phenyl)acrylamide, (88) N-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-5-((6-((R)-3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (89) N-(2-(4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)piperidin-1-yl)-5-((6-((R)-3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (90) (R)—N-(5-((6-(3-(2-fluoro-3-trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide, (91) (R)—N-(2-(4-(4-acetylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (92) N-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-5-((6-((R)-3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (93) (R)—N-(5-((6-(3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxy-2-(4-propylpiperazin-1-yl)phenyl)acrylamide, (94) (R)—N-(2-(4-allylpiperazin-1-yl)-5-((6-(3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (95) N-(2-((S)-3-((dimethylamino)methyl)pyrrolidin-1-yl)-5-((6-((R)-3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (96) N-(2-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)piperidin-1-yl)-5-((6-((R)-3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, (97) (R)—N-(5-((6-(3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxy-2-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)acrylamide, (98) (R)—N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((4-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyridin-2-yl)amino)-4-methoxyphenyl)acrylamide, (99) (R)—N-(5-((4-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyridin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, (100) (R)—N-(5-((4-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyridin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide, (101) (R)—N-(5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-2-((2-(dimethylamino)ethyl)thio)-4-methoxyphenyl)acrylamide, (102) (R)—N-(5-((6-(3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-6-methoxy-2-(4-methylpiperazin-1-yl)pyridin-3-yl)acrylamide, (103) (R)—N-(5-((6-(3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-2-(4-methylpiperazin-1-yl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)acrylamide, (104) (R)—N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-(3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-6-methoxypyridin-3-yl)acrylamide, (105) (R)—N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-6-methoxypyridin-3-yl)acrylamide, (106) (R)—N-(6-(difluoromethoxy)-5-((6-(3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-2-(4-methylpiperazin-1-yl)pyridin-3-yl)acrylamide, (107) (R)—N-(5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxy-2-thiomorpholinophenyl)acrylamide, (108) (R)—N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-phenylisoxazolidin-2-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, (109) (R)—N-(4-methoxy-2-(4-methylpiperazin-1-yl)-5-((4-(3-phenylisoxazolidin-2-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, (110) (R)—N-(5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-6-methoxypyridin-3-yl)acrylamide, (111) (R)—N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-6-methoxypyridin-3-yl)acrylamide, (112) (R)—N-(5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-6-methoxy-2-(4-methylpiperazin-1-yl)pyridin-3-yl)acrylamide, (113) (R)—N-(5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-6-methoxy-2-morpholinopyridin-3-yl)acrylamide, (114) (R)—N-(5-((4-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)-1,3,5-triazin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, (115) (R)—N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((4-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)-1,3,5-triazin-2-yl)amino)-4-methoxyphenyl)acrylamide, (116) (R)—N-(5-((4-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)-1,3,5-triazin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide, (117) (R)—N-(5-((4-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)-1,3,5-triazin-2-yl)amino)-4-methoxy-2-morpholinophenyl)acrylamide, (118) 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)-6-methoxypyridin-3-yl)acrylamide, (119) 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)-6-methoxypyridin-3-yl)acrylamide, (120) N-(2-(4-((S)-4-cyclopropyl-3-methylpiperazin-1-yl)piperidin-1-yl)-5-((6-((R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-6-methoxypyridin-3-yl)acrylamide, (121) N-(2-(4-((S)-4-cyclopropyl-3-methylpiperazin-1-yl)piperidin-1-yl)-6-methoxy-5-((6-((R)-3-(3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)pyridin-3-yl)acrylamide, (122) N-(2-(4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)piperidin-1-yl)-5-((6-((R)-3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-6-methoxypyridin-3-yl)acrylamide, (123) N-(2-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)piperidin-1-yl)-5-((6-((R)-3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-6-methoxypyridin-3-yl)acrylamide, (124) (R)—N-(5-((6-(3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)acrylamide, (125) N-(4-methoxy-5-((6-(3-(1-methyl-1H-indazol-4-yl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-2-(4-methylpiperazin-1-yl)phenyl)acrylamide, and (126) N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-4-methoxy-5-((6-(3-(1-methyl-1H-indazol-4-yl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)phenyl)acrylamide, A compound, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, which is any one of:

4. 1. A method for preparing a compound of formula 1, carried out according to reaction scheme 1 below, said method comprising: a step (first step) of reacting compounds of formula 3 and 4 with each other to prepare a compound of formula 5; a step (second step) of reacting the compounds of Chemical Formula 5 and Chemical Formula 6 with each other to prepare a compound of Chemical Formula 7; a step (third step) of reacting the compounds of Chemical Formula 7 and Chemical Formula 8 with each other to prepare a compound of Chemical Formula 9; a fourth step of reducing the compound of formula 9 to prepare a compound of formula 10; a fifth step of reacting the compound of formula 10 with acryloyl chloride or acrylic acid to prepare the compound of formula 1; Including, The reaction formula 1 【Transformation 7】 and In the reaction scheme 1, E １ is N, R １ But hydrogen, C １－５ alkoxy or alkoxy substituted by halogen; X １ is C, N, O or S; X １ When is C, R ２ and R ３ together with the bonded C to form a heteroaryl of 3 to 12 atoms containing at least one N, and the heteroaryl of 3 to 12 atoms is a straight-chain or branched C １－５ substituted or unsubstituted by alkyl or heterocycloalkyl of 3 to 12 atoms; X １ When is N, R ２ and R ３ are each independently hydrogen or a straight or branched chain C １－５ alkyl or R ２ and R ３ together with the N to which it is attached form a heterocycloalkyl of 3 to 12 atoms, said heterocycloalkyl containing one or more heteroatoms selected from N, O and S, and said straight or branched C １－５ The alkyl is C １－５ The heterocycloalkyl having 3 to 12 atoms and containing one or more heteroatoms selected from N, O and S is unsubstituted or substituted by alkylamino, and is a straight-chain or branched C １－５ Alkyl, C ３－６ Cycloalkyl, C １－５ Alkylamino, allyl, oxo (=O), C １－３ unsubstituted or substituted by one or more substituents A selected from the group consisting of alkylcarbonyl and heterocycloalkyl of 3 to 12 atoms containing one or more heteroatoms selected from N and O; In addition, in the substituent A, the linear or branched C １－５ The alkyl is C ３－６ Cycloalkyl, C １－５ The substituent A is unsubstituted or substituted by alkylamino or heterocycloalkyl of 3 to 12 atoms containing at least one N, and the heterocycloalkyl of 3 to 12 atoms is a straight-chain or branched C １－５ Alkyl, C ３－６ Cycloalkyl, C １－５ unsubstituted or substituted by a substituent B selected from the group consisting of alkylcarbonyl, heterocycloalkyl of 3 to 12 atoms containing one or more of N and O, and oxo; In addition, in the substituent B, the heterocycloalkyl having 3 to 12 atoms containing one or more of N and O is a straight-chain or branched C １－５ Alkyl, or C ３－６ substituted or unsubstituted by cycloalkyl; X １ is S or O, then R ２ However, it does not exist, and R ３ But C １－５ C substituted by alkylamino １－５ is alkyl, R ４ and R ５ are each independently hydrogen, halogen, or haloalkyl, or R ４ and R ５ together with benzene to form a heteroaryl of 7 to 12 atoms containing one or more heteroatoms selected from N, O and S, and the heteroaryl of 7 to 12 atoms is a straight-chain or branched-chain C １－５ substituted or unsubstituted by alkyl; The method wherein Hal is a halogen.

5. A pharmaceutical composition for preventing or treating cancer, comprising the compound according to any one of claims 1 to 3, its stereoisomer, its hydrate, its solvate, or its pharmaceutically acceptable salt as an active ingredient, and a pharmaceutically acceptable carrier.

6. 6. The pharmaceutical composition for preventing or treating cancer according to claim 5, wherein the compound exhibits an inhibitory effect on one or more of the enzymes ABL1, BLK, CDK4-cyclin D1, EGFR (epidermal growth factor receptor), ErbB2, and ErbB4, as well as mutants thereof.

7. The cancer is selected from the group consisting of pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell carcinoma, epithelial ovarian cancer, ovarian germ cell cancer, male breast cancer, brain tumor, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, and chronic myeloma. Myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla of Vater cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal cavity and paranasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, childhood brain tumor, childhood lymphoma, childhood leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvis cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant 7. The pharmaceutical composition for preventing or treating cancer according to claim 5 or 6, wherein the cancer is one or more types selected from the group consisting of bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, stomach cancer, gastric carcinoid, gastrointestinal cancer, Wilms' carcinoma, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain tumor, mediastinal cancer, rectal cancer, rectal carcinoid, vaginal cancer, spinal cancer, vestibular schwannoma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsillar cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, squamous cell lung carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, hematological malignancies, and thymic carcinoma.

8. A pharmaceutical composition for preventing or treating cancer according to claim 7, wherein the cancer is lung cancer.

9. A pharmaceutical composition for preventing or treating cancer as described in claim 7, wherein the cancer is non-small cell lung cancer.

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