Heteroaryl derivative compounds and their uses

Abstract

The present invention relates to a heteroaryl derivative and its use. The heteroaryl derivative of the present invention exhibits excellent inhibitory activity against EGFR and / or HER2, and can therefore be usefully used as a therapeutic agent for the EGFR and / or HER2-related diseases.

Description

[Technical Field]

[0001] The present invention relates to heteroaryl derivative compounds and their pharmaceutical applications. Specifically, the present invention relates to heteroaryl derivative compounds having EGFR and / or HER2 inhibitory activity. [Background technology]

[0002] Protein kinases act as molecular switches and are involved in signaling pathways, but within cells, the switching between the active and inactive states of target proteins by kinases must be smoothly regulated. When this switching between active and inactive states is abnormally controlled, intracellular signaling becomes excessively activated or deactivated, inducing uncontrolled cell division and proliferation. In particular, abnormal activation due to mutations, amplification, and / or overexpression of protein kinase genes can cause the development and progression of various tumors and play a crucial role in the onset of various diseases, including inflammatory diseases, neurodegenerative diseases, and autoimmune diseases.

[0003] The epidermal growth factor receptor (EGFR), a member of the ErbB receptor tyrosine kinase family, is abnormally activated in numerous 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. It is known that EGFR-tyrosine kinase activation leads to continuous cell proliferation, invasion into surrounding tissues, distant metastasis, and angiogenesis, thereby enhancing cell survival.

[0004] Furthermore, EGFR mutations, specifically EGFR Del19 or EGFR L858R, are known to be the main causes of non-small cell lung cancer and head and neck cancer. Drugs such as Iressa and Tarceva, which treat these conditions, have been developed and are currently in clinical use. However, when these drugs are used in patients, acquired resistance, which occurs due to secondary mutations of EGFR based on the drug structure, has been observed, and it has become clear that this is the main cause of actual drug resistance. After using first-generation EGFR inhibitors for an average of about 10 months, acquired resistance called the T790M mutation, located in the gatekeeper of EGFR kinase, develops, rendering the first-generation EGFR inhibitors ineffective. In other words, EGFR Del19 / T790M or EGFR L858R / T790M double mutations occur, rendering conventional drugs ineffective. Osimertinib, a third-generation EGFR-TKI targeted drug that shows high responsiveness to drug resistance caused by the EGFR T790M mutation, has been developed, but drug resistance resulting from this drug has been reported (Niederst MJ et al., Clin Cancer Res, 2015, 17(21):3924-3933). The EGFR C797S mutation has been presented as one of the main mechanisms leading to drug resistance to osimertinib, and it has been reported that approximately 40% of clinical trial patients have the EGFR C797S mutation (Thress KS et al., Nature Medicine, 2015, 21:560-562). Therefore, EGFR Del19 / C797S (EGFR DC) or EGFR L858R / C797S (EGFRLC) could be primary targets.

[0005] In addition, L861Q, G719A, S768I, L718Q, or G724S, which express rare or uncommon EGFR mutations and drug resistance mutations, may also be potential targets.

[0006] HER2 (Human epidermal growth factor receptor 2; also known as ErbB2) is a member of the ErbB receptor tyrosine kinase family. It forms homodimers with other EGFR receptors such as HER1 (EGFR, ErbB1), HER3 (ErbB3), or HER4 (ErbB4), and is activated by autophosphorylation of tyrosine residues within cells. It plays a crucial role in cell proliferation, differentiation, and survival in both normal and cancer cells (Di Fiore PP. et al., Science. 1987, 237(481):178-182). HER2 is known to be overexpressed in various cancers, including breast cancer, gastric cancer, and ovarian cancer (Hardwick RH. et al., Eur. J Surg Oncol. 1997, 23(1):30-35; Korkaya H. et al., Oncogene. 2008, 27(47):6120-6130).

[0007] Thus, there is a growing unmet need for novel compounds that can be effectively used to treat EGFR and / or HER2-related diseases by modulating EGFR activity (especially C797S mutations such as EGFR Del19 / C797S and EGFR L858R / C797S, rare EGFR mutations, or drug resistance mutations) and / or HER2. [Overview of the Initiative] [Problems that the invention aims to solve]

[0008] The object of the present invention is to provide a heteroaryl derivative with a novel structure, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. Another object of the present invention is to provide a method for preparing the heteroaryl derivative compound.

[0009] Another object of the present invention is to provide a pharmaceutical use of the heteroaryl derivative compound. Specifically, a pharmaceutical composition for treating or preventing an EGFR and / or HER2-related disease containing the heteroaryl derivative compound as an active ingredient, the use of the compound for treating or preventing an EGFR and / or HER2-related disease, or a method for treating or preventing an EGFR and / or HER2-related disease including the step of administering the compound are provided.

Means for Solving the Problems

[0010] In order to achieve the above object, as a result of the research efforts of the present inventors, it was confirmed that the heteroaryl derivative compound represented by the following Chemical Formula 1 inhibits the growth of cells in which EGFR and / or HER2 is activated, thereby completing the present invention.

[0011] Heteroaryl derivative compounds The present invention provides a compound represented by the following Chemical Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof: [[ID=了15]]

Chem.

[0012] According to a specific example of the present invention, the compound represented by chemical formula 1, its optical isomers, or pharmaceutically acceptable salts thereof may be within the following range: X1 to X3 are each independently either CH or N; R X -H, -NH2, -NH(-C 1-6 Alkyl), or -N(-C 1-6 Alkyl)(-C 1-6 Alkyl) is; Y is -C 1-6 Alkyl, -(CH2)n aryl, -(CH2)n heteroaryl, or -(CH2)n hydroheteroaryl {wherein one or more H of the -(CH2)n aryl, -(CH2)n heteroaryl, or -(CH2)n hydroheteroaryl ring is -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Alkenyl, -C 1-6 Alkynyl, -CN, -(C=O)NR1R2, -(C=O)OR3, -NR4R5, -OR6, -halo, =O, heterocycloalkyl, aryl, or heteroaryl may be substituted [in which case, one or more H of the heterocycloalkyl, aryl, or heteroaryl may be substituted with -halo]; n is 0, 1, or 2; R1 to R3 are independently -H and -C 1-6 Alkyl or cycloalkyl; R4 and R5 can be independently set to -H or -C 1-6 It is alkyl; R6 is -C 1-6 Alkyl or phenyl {where one or more H of the phenyl ring is -C} 1-6 Alkyl, -C 1-6 It may be substituted with a haloalkyl or halo; R Y1 ~R Y5 These are, independently, -H or -C 1-6 Alkyl, or R Y2 and R Y3 These can link together to form a cycloalkyl group, R Y3 and R Y4 They can be connected to each other to form an aryl; L is -(CH2)m-, -C(=O)-, or nothing (null); m is 0, 1, or 2; Ring Z is aryl, heteroaryl, hydroheteroaryl, cycloalkyl, or heterocycloalkyl {wherein one or more H of the aryl, heteroaryl, hydroheteroaryl, cycloalkyl, or heterocycloalkyl ring is -C 1-6 Alkyl, -C 1-6 Cyanoalkyl, -C 1-6 Haloalkyl, -C 1-6 Alkenyl, -C 1-6 Alkinyl, -CN, -NR7R 8、 -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -SC 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-C 1-6 Haloalkyl, -C(=O)OC 1-6 Alkyl, -S(=O)2-C 1-6 Alkyl, -C (=NOC) 1-6 Alkyl)(C 1-6The substituents may be alkyl), =O, -halo, or Z1, or two or more substituents of the aryl, heteroaryl, hydroheteroaryl, cycloalkyl, or heterocycloalkyl ring may be linked to each other to form a fused ring or spiro ring [wherein one or more H of the fused ring or spiro ring is -C 1-6 [May be substituted with alkyl or Z1] R7 and R8 、 -H and -C are independent of each other. 1-6 Alkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-N(C 1-6 Alkyl)(C 1-6 Alkyl), -(C=O)-C 1-6 Alkyl, or -(C=O)-C 1-6 It is a haloalkyl; Z1 is cycloalkyl, heterocycloalkyl, heterobicycloalkyl, heterospiroalkyl, -C 1-6 Alkyl-heterocycloalkyl, -(C=O)-heterocycloalkyl, -NH-heterocycloalkyl, or heteroaryl {wherein the heterocycloalkyl, heterobicycloalkyl, heterospiroalkyl, -C 1-6 Alkyl-heterocycloalkyl, -(C=O)-heterocycloalkyl, or -NH-heterocycloalkyl contains one or more elements selected from the group consisting of N, O, P, P(=O), and S in the ring, and the heterocycloalkyl, heterobicycloalkyl, heterospiroalkyl, -C 1-6 Alkyl-heterocycloalkyl, -(C=O)-heterocycloalkyl, -NH-heterocycloalkyl, or one or more H in a heteroaryl ring is -C 1-6 Alkyl, -C 1-6 Aminoalkyl, -C 1-6 Haloalkyl, -C 1-6 Alkenyl, -C 1-6 Alkinyl, -C(=O)-C 1-6 Alkyl, -C 1-6 Alkyl-S(=O)2-C 1-6Alkyl, =O, -NR9R 10 , may be substituted with -halo, cycloalkyl, or Z2; R9 and R 10 These are, independently, -H or -C 1-6 It is alkyl; Z2 is a heterocycloalkyl, heterobicycloalkyl, or -NH-heterocycloalkyl, where the heterocycloalkyl, heterobicycloalkyl, or -NH-heterocycloalkyl contains one or more elements selected from the group consisting of N, O, P, P(=O), and S in the ring, and one or more H atoms of the heterocycloalkyl, heterobicycloalkyl, or -NH-heterocycloalkyl ring are -C 1-6 Alkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Alkenyl, -C 1-6 Alkinyl, -C(=O)-C 1-6 Alkyl, -C 1-6 Alkyl-S(=O)2-C 1-6 Alkyl, =O, -NR 11 R 12 , may be substituted with cycloalkyl or Z3; R 11 and R 12 These are, independently, -H or -C 1-6 It is alkyl; Z3 is a heterocycloalkyl, heterobicycloalkyl, or -C 1-6 The alkyl-heterocycloalkyl {wherein the heterocycloalkyl, heterobicycloalkyl, or -C} 1-6 Alkyl-heterocycloalkyl contains one or more elements selected from the group consisting of N, O, P, P(=O), and S within the ring, and the heterocycloalkyl, heterobicycloalkyl, or -C 1-6 One or more H atoms in the alkyl-heterocycloalkyl ring are -C 1-6 They may be substituted with alkyl or cycloalkyl groups.

[0013] According to a specific example of the present invention, the compound represented by chemical formula 1, its optical isomers, or pharmaceutically acceptable salts thereof may be within the following range: X1 is N; X2 and X3 are, independently, CH or N; R X -H, -NH2, or -NH(-C 1-6 It is alkyl.

[0014] According to a specific example of the present invention, the compound represented by chemical formula 1, its optical isomers, or pharmaceutically acceptable salts thereof may be within the following range: Y is -C 1-6 Alkyl, -(CH2)n aryl, -(CH2)n heteroaryl, or -(CH2)n hydroheteroaryl {wherein one or more H of the -(CH2)n aryl, -(CH2)n heteroaryl, or -(CH2)n hydroheteroaryl ring is -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Alkynyl, -CN, -(C=O)NH-cycloalkyl, -(C=O)OC 1-6 Alkyl, -N(C 1-6 Alkyl)(C 1-6 Alkyl), -O(C 1-6 It may be substituted with alkyl, -O-phenyl, -halo, =O, heterocycloalkyl, aryl, or heteroaryl [in which case one or more H of the heterocycloalkyl, aryl, or heteroaryl may be substituted with -halo]; n is either 0 or 1; R Y1 ~R Y5 These are, independently, -H or -C 1-6 Alkyl, or R Y2 and R Y3 These can link together to form a 3-6 membered cycloalkyl ring, R Y3 and R Y4 These molecules can link together to form a phenyl molecule. According to a specific example of the present invention, the compound represented by chemical formula 1, its optical isomers, or pharmaceutically acceptable salts thereof may be within the following range: L is -(CH2)m-, -C(=O)-, or nothing (null); m is either 0 or 1; Ring Z is an aryl, heteroaryl, hydroheteroaryl, 3-7 membered cycloalkyl, or 5-7 membered heterocycloalkyl ring {wherein one or more H of the aryl, heteroaryl, hydroheteroaryl, 3-7 membered cycloalkyl, or 5-7 membered heterocycloalkyl ring is -C 1-6 Alkyl, -C 1-6 Cyanoalkyl, -C 1-6 Haloalkyl, -C 1-6 Alkenyl, -C 1-6 Alkinyl, -CN, -NR7R8, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -SC 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-C 1-6 Haloalkyl, -C(=O)OC 1-6 Alkyl, -S(=O)2-C 1-6 Alkyl, -C (=NOC) 1-6 Alkyl)(C 1-6 It may be substituted with alkyl), =O, -halo, or Z1 [in this case, one or more H of the aryl, heteroaryl, hydroheteroaryl, 3- to 7-membered cycloalkyl, or 5- to 7-membered heterocycloalkyl ring is -C 1-6 [may be substituted with alkyl or -halo], or two or more substituents of the aryl, heteroaryl, hydroheteroaryl, 3- to 7-membered cycloalkyl, or 5- to 7-membered heterocycloalkyl ring can be linked to each other to form a fused ring or spiro ring [wherein one or more H of the fused ring or spiro ring is -C 1-6 [May be substituted with alkyl or Z1] R7 and R8 are independently -H and -C, respectively. 1-6 Alkyl, -C 1-6Alkyl-N(C 1-6 Alkyl)(C 1-6 Alkyl), -(C=O)-C 1-6 Alkyl, or -(C=O)-C 1-6 It is a haloalkyl; Z1 is a 3-7 membered ring cycloalkyl, a 5-7 membered ring heterocycloalkyl, a 6-10 membered ring heterobicycloalkyl, a 6-10 membered ring heterospiroalkyl, -C 1-6 Alkyl-heterocycloalkyl, -(C=O)-heterocycloalkyl, -NH-heterocycloalkyl, or heteroaryl {wherein the 5-7 membered ring heterocycloalkyl, 6-10 membered ring heterobicycloalkyl, 6-10 membered ring heterospiroalkyl, -C 1-6 Alkyl-heterocycloalkyl, -(C=O)-heterocycloalkyl, or -NH-heterocycloalkyl contains one or more elements selected from the group consisting of N, O, P, P(=O), and S in the ring, and the aforementioned 5-7 membered ring heterocycloalkyl, 6-10 membered ring heterobicycloalkyl, 6-10 membered ring heterospiroalkyl, -C 1-6 Alkyl-heterocycloalkyl, -(C=O)-heterocycloalkyl, -NH-heterocycloalkyl, or one or more H in a heteroaryl ring is -C 1-6 Alkyl, -C 1-6 Aminoalkyl, -C 1-6 Haloalkyl, -C 1-6 Alkenyl, -C(=O)-C 1-6 Alkyl, -C 1-6 Alkyl-S(=O)2-C 1-6 Alkyl, =O, -N(C) 1-6 Alkyl)(C 1-6 It may be substituted with alkyl, -halo, cycloalkyl, or Z2; Z2 is a 5-7 membered heterocycloalkyl ring, a 6-10 membered heterobicycloalkyl ring, or an -NH-heterocycloalkyl ring {wherein the 5-7 membered heterocycloalkyl ring, the 6-10 membered heterobicycloalkyl ring, or the -NH-heterocycloalkyl ring contains one or more elements selected from the group consisting of N, O, and S in the ring, and one or more H atoms of the 5-7 membered heterocycloalkyl ring, the 6-10 membered heterobicycloalkyl ring, or the -NH-heterocycloalkyl ring are -C 1-6 Alkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Alkenyl, -C 1-6 Alkinyl, -C(=O)-C 1-6 Alkyl, -C 1-6 Alkyl-S(=O)2-C 1-6 Alkyl, =O, -N(C) 1-6 Alkyl)(C 1-6 Alkyl, 3- to 7-membered ring cycloalkyl, or may be substituted with Z3; Z3 is a 5-7 membered ring heterocycloalkyl, a 6-10 membered ring heterobicycloalkyl, or -C 1-6 The alkyl-heterocycloalkyl {wherein the 5-7 membered ring heterocycloalkyl, 6-10 membered ring heterobicycloalkyl, or -C} 1-6 Alkyl-heterocycloalkyl groups contain one or more elements selected from the group consisting of N, O, and S within their ring, and are 5-7 membered heterocycloalkyl groups, 6-10 membered heterobicycloalkyl groups, or -C groups. 1-6 One or more H atoms in the alkyl-heterocycloalkyl ring are -C 1-6 It may be substituted with an alkyl group or a 3- to 7-membered cycloalkyl ring.

[0015] According to a specific example of the present invention, the compound represented by chemical formula 1 may be selected from the group consisting of the compounds listed in Table 1 below.

[0016] In the present invention, unless otherwise specified, "alkyl" can mean acyclic, cyclic, or saturated hydrocarbons, whether linear or branched. For example, "C1~6 "Alkyl" can mean an alkyl group containing 1 to 6 carbon atoms. Acyclic alkyl groups may include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, isopropyl, secondary (sec)-butyl, isobutyl, or tertiary (tert)-butyl. Cyclic alkyl groups may be used interchangeably with "cycloalkyl" herein, and may include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[0017] In the present invention, "alkoxy" can mean -(O-alkyl) as an alkyl ether group, where alkyl is as defined above. For example, "C 1-6 "alkoxy" is 、 C 1-6 Alkoxy containing alkyl, i.e., -(OC 1-6 It can mean alkyl. 、 As an example, alkoxys may include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy.

[0018] In the present invention, "halo" may be F, Cl, Br, or I.

[0019] In the present invention, "haloalkyl" can mean a linear or branched alkyl (hydrocarbon) having one or more carbon atoms substituted with a halo as defined herein. Examples of the haloalkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, or n-butyl molecules independently substituted with one or more halogens, such as F, Cl, Br, or I.

[0020] In this specification, “hydroxyalkyl” may mean a linear or branched alkyl (hydrocarbon) having a carbon atom substituted with hydroxy(OH). Examples of such hydroxyalkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, or n-butyl molecules independently substituted with one or more -OH groups.

[0021] In this specification, "aminoalkyl" may mean a linear or branched alkyl (hydrocarbon) having a carbon atom substituted with amino(NR′R′′). Here, R′ and R′′ are, independently, hydrogen and C 1-6 The group consisting of alkyls can be selected, and the selected R′ and R′′ can each be independently substituted or unsubstituted.

[0022] In this specification, "cyanoalkyl" may mean a linear or branched alkyl (hydrocarbon) having carbon atoms substituted with cyano(CN).

[0023] In the present invention, "heterocycloalkyl" can mean a ring containing one or more elements selected from N, O, P, P(=O), and S, and may be saturated or partially unsaturated. Here, in the case of unsaturation, it may be called a heterocycloalkene. Unless otherwise specified, heterocycloalkyls may be monocyclic or polycyclic, such as a spiro ring, bridged ring, or fused ring. Furthermore, "heterocycloalkyl with 3 to 12 atoms" can mean a heterocycloalkyl containing 3 to 12 atoms forming the ring. As an example, heterocycloalkyls include pyrrolidine, piperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, and thiomorpholine. This could include, but is not limited to, omorfoline-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, or (1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane.

[0024] In the present invention, "arene" can mean an aromatic hydrocarbon ring. The arene may be a monocyclic arene or a polycyclic arene. The number of ring-forming carbon atoms in the arene may be 5 to 30, 5 to 20, or 5 to 15. Examples of arenes include, but are not limited to, benzene, naphthalene, fluorene, anthracene, phenanthrene, bibenzene, terbenzene, quaterbenzene, quinquebenzene, sexibenzene, triphenylene, pyrene, benzofluorantene, and chrysene. In this specification, a residue obtained by removing one hydrogen atom from the "arene" is referred to as "aryl".

[0025] In the present invention, "heterearene" may be a ring containing one or more of the following heteroatoms: O, N, P, Si, and S. The number of ring-forming carbon atoms in the heteroarene may be 2 to 30 or 2 to 20. The heteroarene may be a monocyclic heteroarene or a polycyclic heteroarene. The polycyclic heteroarene may have, for example, a bicyclic or tricyclic structure. Examples of heteroarenes include thiophene, purine, pyrrole, pyrazole, imidazole, thiazole, oxazole, isothiazole, oxadiazole, triazole, pyridine, bipyridyl, triazine, acridyl, pyridazine, pyrazine, quinoline, quinazolin, quinoxaline, phenoxane, phthalazine, pyrimidine, pyridopyrimidine, pyridopyrazine, pyrazinopyrazine, isoquinoline, indole, carbazole, imidazopyridazine, imidazopyridine, imidazopyrimidine, pyrazolopyrimidine Examples include, but are not limited to, din, imidazopyrazine or pyrazolopyridine, N-arylcarbazole, N-heteroarylcarbazole, N-alkylcarbazole, benzoxazole, benzimidazole, benzothiazole, benzocarbazole, benzothiophene, dibenzothiophene, thienothiophene, benzofuran, phenanthroline, isoxazole, oxadiazole, thiadiazole, benzothiazole, tetrazole, phenothiadin, dibenzosilol, and dibenzofuran. In one embodiment of the present invention, the heteroarene may also include a bicyclic heterocycloarene comprising an arene ring fused to a heterocycloalkyl ring or a heteroarene fused to a cycloalkyl ring. In this specification, a residue obtained by removing one hydrogen atom from the "heteroarene" is referred to as a "heteroaryl". In the present invention, "hydroaryl" means that one or more double bonds present in "aryl" are replaced by single bonds. In the present invention, "hydroheteroaryl" means that one or more double bonds present in "heteroaryl" are replaced by single bonds.

[0026] In this invention, the term "enantiomer" means a compound or salt of the present invention having the same chemical or molecular formula but being sterically different. Each of these optical isomers and mixtures thereof are also included within the scope of this invention. Unless otherwise specified, a solid line bond (-) linked to a chiral carbon atom represents a solid wedge bond indicating the absolute configuration of the stereocenter. [ka] or Dashed wedge-shaped joint [ka] It can include...

[0027] In this invention, the term "cis" means that the two substituents of the ring are bonded in the same direction, and the term "trans" means that the two substituents of the ring are bonded in different directions.

[0028] The compound of chemical formula 1 in this invention may exist in the form of a "pharmaceutically acceptable salt." As the salt, an acid addition salt formed with a pharmaceutically acceptable free acid is useful. In this invention, the term "pharmaceutically acceptable salt" means any organic or inorganic acid addition salt of the compound that is relatively non-toxic to patients, has a harmless and effective effect, and whose side effects do not reduce the beneficial efficacy of the compound represented by chemical formula 1.

[0029] Acid addition salts are prepared by conventional methods, for example, by dissolving the compound in an excess aqueous acid solution and precipitating the salt with a water-miscible organic solvent, such as methanol, ethanol, acetone, or acetonitrill. The same molar amount of the compound and the acid or alcohol in water are heated, and then the mixture is evaporated and dried, or the precipitated salt can be filtered by suction.

[0030] In this case, organic acids and inorganic acids can be used as free acids. As inorganic acids, hydrochloric acid, phosphoric acid, sulfuric acid, or nitric acid can be used, and as organic acids, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, or hydroiodic acid can be used. However, it is not limited to these.

[0031] Furthermore, pharmaceutically acceptable metal salts can be produced using bases. Alkali metal salts or alkaline earth metal salts are obtained, for example, by dissolving a compound in a solution of excess alkali metal hydroxide or alkaline earth metal hydroxide, filtering out the salt of the insoluble compound, and then evaporating and drying the filtrate. In this case, sodium, potassium, or calcium salts are particularly suitable as metal salts from a pharmaceutical perspective, but are not limited to these. Corresponding silver salts can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

[0032] Unless otherwise specified, the pharmaceutically acceptable salts of the present invention include salts of acidic or basic groups that may be present in the compound of chemical formula 1. For example, pharmaceutically acceptable salts may include sodium, calcium, and potassium salts of the hydroxyl group, and other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate), and p-toluenesulfonate (tosylate), which can be prepared by salt preparation methods known in the art.

[0033] Applications of heteroaryl derivative compounds The present invention provides the use of a compound represented by the following chemical formula 1, its optical isomers, or pharmaceutically acceptable salts thereof. [ka] The compound represented by Chemical Formula 1 of the present invention, its optical isomers, or pharmaceutically acceptable salts thereof exhibit inhibitory activity against various kinases.

[0034] According to one specific example of the present invention, the heteroaryl derivative represented by chemical formula 1 exhibits excellent inhibitory activity against EGFR and / or HER2 kinases, and can therefore be usefully used for the treatment or prevention of EGFR and / or HER2-related diseases, particularly cancer. Specifically, the compound of chemical formula 1 can inhibit EGFR and / or HER2 wild-type or mutant kinases, as supported by experimental examples described later. The EGFR mutation may be, but is not limited to, a C797S mutation such as EGFR Del19 / C797S (EGFR DC) or EGFR L858R / C797S (EGFR LC). Furthermore, the EGFR mutation may be, but is not limited to, EGFR L861Q, EGFR G719A, EGFR S768I, EGFR L718Q, or EGFR G724S. Furthermore, the EGFR mutation may be, but is not limited to, EGFR d746-750, EGFR d746-750 / C797A, EGFR d746-750 / C797S, EGFR d746-750 / T790M / C797S, EGFR D761Y, EGFR G719C, EGFR G719D, EGFR G719S, EGFR L747S, EGFR L792F, EGFR L858R, or EGFR L792F / L858R.

[0035] In the present invention, the cancers include all cancers that can be treated or prevented by inhibiting EGFR and / or HER2 kinase activity, and may be solid tumors or hematological cancers. The types of cancer are not limited to, but include, for example, pseudomyxoma, intrahepatic biliary tract cancer, 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, ovarian epithelial carcinoma, ovarian germ cell carcinoma, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, and choroidal melanoma. Vater's ampulla cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal cavity / 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, kidney cancer, heart 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 origin, gastric lymphoma, gastric cancer, gastric carcinoid tumor, gastrointestinal stromal cancer, Wilms' disease It can be one or more cancers selected from the group consisting of tumors, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid cancer, vaginal cancer, spinal cord cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, squamous cell lung cancer, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, hematological cancer, and thymic cancer. Furthermore, the cancers include not only primary cancers but also metastatic cancers.

[0036] According to one specific example of the present invention, the present invention provides a pharmaceutical composition for the treatment or prevention of EGFR and / or HER2-related diseases, comprising as an active ingredient a compound represented by the chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. Specifically, the EGFR and / or HER2-related disease may be cancer. The type of cancer is as described above.

[0037] The pharmaceutical composition of the present invention may further contain one or more active ingredients exhibiting the same or similar pharmacological effects, in addition to the compound represented by chemical formula 1, its optical isomers, or pharmaceutically acceptable salts thereof. The pharmaceutical composition of the present invention can be used in clinical administration and can be prepared for administration in various oral and parenteral dosage forms.

[0038] Furthermore, according to one specific example of the present invention, a method for treating or preventing EGFR and / or HER2-related disease is provided, comprising the step of administering a therapeutically effective amount of the compound represented by chemical formula 1, its optical isomer, or a pharmaceutically acceptable salt thereof to a subject in need. The subject may be a mammal, including a human.

[0039] As used in this invention, the term “therapeutably effective amount” refers to the amount of the compound represented by Chemical Formula 1 that is effective in treating or preventing EGFR and / or HER2-related diseases. Specifically, “therapeutably effective amount” means an amount sufficient to treat the disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level can be determined according to factors including the individual’s species and severity, age, sex, type of disease, drug activity, sensitivity to the drug, administration time, route of administration and elimination rate, duration of treatment, drugs used concurrently, and other factors known in the medical field. The pharmaceutical compositions of this invention can be administered as individual therapeutic agents or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with commercially available therapeutic agents. They can also be administered single or in combination. It is important to administer an amount that takes all of the above factors into consideration and provides the greatest effect with the minimum amount without side effects, which can be easily determined by those skilled in the art. The dosage of the pharmaceutical compositions of this invention can be determined by a professional according to various factors such as the patient’s condition, age, sex, and comorbidities. The active ingredients of the pharmaceutical compositions of this invention are highly safe and can be used in doses higher than the determined dose.

[0040] Furthermore, according to one specific example of the present invention, the present invention provides uses for the compound represented by chemical formula 1, its optical isomers, or pharmaceutically acceptable salts thereof for use in the preparation of a medicine for use in the treatment or prevention of EGFR and / or HER2-related diseases. The compound represented by chemical formula 1 for the preparation of the medicine can be mixed with acceptable auxiliaries, diluents, carriers, etc., and can be prepared as a compound formulation with other active ingredients to have a synergistic effect of the active ingredients.

[0041] The matters referred to in the uses, compositions, and therapeutic methods of the present invention shall apply equally, insofar as they do not contradict each other. [Effects of the Invention]

[0042] The heteroaryl derivative compounds of the present invention exhibit excellent inhibitory activity against EGFR and / or HER2, and can therefore be usefully used for the treatment or prevention of EGFR and / or HER2-related diseases. [Modes for carrying out the invention]

[0043] The present invention will be described in detail below with reference to examples and experimental examples. However, the following examples and experimental examples are for illustrative purposes only, and the content of the present invention is not limited thereto.

[0044] <Analysis and purification conditions> The compounds synthesized in the examples of the present invention were purified or subjected to structural analysis under the following HPLC conditions.

[0045] 1.HPLC conditions HPLC conditions for analysis (ACQUITY UPLC H-Class Core System) A Waters UPLC system (ACQUITY UPLC PDA Detector) equipped with a Waters mass QDa Detector was used. The column used was Waters ACQUITY UPLC® BEH C18 (1.7 μm, 2.1 × 50 mm), and the column temperature was 30°C. Mobile phase A used water containing 0.1% formic acid, and mobile phase B used acetonitrile containing 0.1% formic acid. Gradient condition (3 minutes at 10-100% B, mobilization rate = 0.6 ml / min)

[0046] Prep-LCMS (Preparative-Liquid chromatography mass spectrometry) for purification Waters Autopurification HPLC system (2767 sample manager, 2545 binary gradient module, 2998 photodiode array detector) with Waters mass QD a A device equipped with a detector was used. The column used was SunFire® Prep C18 OBD manufactured by Waters. TM The column was 5 μm thick and 19 × 50 mm in diameter, and the column temperature was kept at room temperature. Mobile phase A consisted of water containing 0.035% trifluoroacetic acid, and mobile phase B consisted of methanol containing 0.035% trifluoroacetic acid. Gradient condition (10 minutes at 15-100% B, mobilization speed = 25 ml / min)

[0047] Prep-150 LC System for purification (Preparative-Liquid chromatography UV spectrometry) The system used was a Waters Prep 150 LC system (2545 Quaternary gradient module, 2998 Photodiode Array Detector, Fraction collector III). The column used was Waters XTERRA® Prep RP18 OBD. TM The column was 10 μm thick and 30 × 300 mm in size, and the column temperature was kept at room temperature. Gradient conditions (120 minutes at 3-100% B, mobilization rate = 40 ml / min)

[0048] Preparative HPLC System for purification (Preparative-Liquid chromatography UV spectrometry) We used a Teledyne ACCQPrep HP150. The column used was Waters' XTERRA® Prep RP18 OBD. TM The column was 10 μm thick and 30 × 300 mm in size, and the column temperature was kept at room temperature. Gradient conditions (120 minutes at 10-100% B, mobilization rate = 42 ml / min)

[0049] 2.NMR analysis 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)).

[0050] The commercially available reagents used were used without further purification. In this invention, room temperature refers to temperatures of approximately 5°C to 40°C, for example, 10°C to 30°C, or 20°C to 27°C, and is not strictly limited to these ranges. A rotary evaporator was used for concentration or solvent removal under reduced pressure.

[0051] <Preparation Example 1> Preparation of (S)-3-phenylisoxazolidine [ka] Step 1: Preparation of tert-butyl(R)-(3-hydroxy-3-phenylpropoxy)carbamate 7.8 g, 58.6 mmol of tert-butylhydroxycarbamate was dissolved in 140 ml of dimethylformamide, and sodium hydride (2.58 g, 64.5 mmol) was added at 0°C and the mixture was reacted for 30 minutes. Then, (R)-3-chloro-1-phenylpropan-1-ol (5 g, 29.3 mmol) dissolved in 10 ml of dimethylformamide (DMF) was slowly added dropwise at 0°C for 10 minutes, and the mixture was stirred at room temperature for 72 hours. The reaction mixture was terminated by adding aqueous ammonium chloride solution, extracted with ethyl acetate and brine, and the organic layers were combined. The organic layers were dried over sodium sulfate and then concentrated under reduced pressure. The mixture was purified by medium-pressure liquid chromatography (ethyl acetate / n-hexane) to obtain the title compound (2.8 g, 68%). MS(m / z): 150.17[M+1] + UPLC rt(min):1.51

[0052] Step 2: Preparation of tert-butyl(S)-3-phenylisoxazolidine-2-carboxylate The tert-butyl(R)-(3-hydroxy-3-phenylpropoxy)carbamate (2.55 g, 9.54 mmol) obtained in step 1 above and triethylamine (3.13 ml, 22.44 mmol) were dissolved in dichloromethane (250 ml) and cooled to 0°C. Then, methanesulfonyl chloride (1 ml, 13 mmol) was added dropwise, and the mixture was reacted at 0°C for 2 hours. The reaction mixture was extracted with brine and dichloromethane, and the organic layers were combined. The organic layers were dried over sodium sulfate, concentrated under reduced pressure to obtain the title compound, which was used in the next reaction without purification. MS(m / z):194.13[M+1] + UPLC rt(min):1.69

[0053] Step 3: Preparation of (S)-3-phenylisoxazolidine The tert-butyl(S)-3-phenylisoxazolidine-2-carboxylate (2.3 g) obtained in step 2 was dissolved in dichloromethane (90 ml), and then trifluoroacetic acid (14 ml) was added and the mixture was reacted at room temperature for 1 hour. The reaction mixture was neutralized with aqueous sodium bicarbonate solution, and the organic layers were combined. The organic layers were dried over sodium sulfate and then concentrated under reduced pressure. The mixture was purified by medium-pressure liquid chromatography (tetrahydrofuran / n-hexane) to obtain the title compound (1.3 g, 94%). MS(m / z):150.08[M+1] + UPLC rt(min):0.72

[0054] <Preparation Example 2> Preparation of (R)-3-phenylisooxazolidine [ka] The compound of Preparation Example 2 was prepared in the same manner as in Preparation Example 1 and used in the synthesis of the compounds of the Examples shown in [Table 1] below. MS(m / z):150.08[M+1] + UPLC rt(min):0.72

[0055] <Preparation Example 3> Preparation of (R)-3-(3-fluorophenyl)isoxazolidine [ka] Step 1: Preparation of 3-fluoro-N-methoxy-N-methylbenzamide 3-Fluorobenzoic acid (90 g, 642.35 mmol, 1 eq) was dissolved in pyridine (150 mL), and then N-methoxymethaneamine (75.19 g, 770.81 mmol, 1.2 eq, HCl) was added. Subsequently, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI; 147.77 g, 770.81 mmol, 1.2 eq) was added at 15°C. The reaction mixture was stirred at 50°C for 30 minutes. TLC analysis (petroleum ether (PE):ethyl acetate (EA) = 3:1) showed that all the starting materials had disappeared and new, less polar spots were detected. The mixture was concentrated under reduced pressure, the pyridine solvent was removed, and the organic layer was extracted using dichloromethane (DCM; 500 mL), hydrochloric acid (500 mL, 2N), and brine (200 mL). The organic layer was dried over sodium sulfate and then concentrated under reduced pressure to obtain the title compound (110 g, 600.50 mmol, 93.49% yield) as a yellow oil. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.47-7.40(m,1H), 7.39-7.38(m,2H), 7.14-7.13(m,1H), 3.54(s,3H), 3.45(s,3H).

[0056] Step 2: Preparation of 1-(3-fluorophenyl)prop-2-en-1-one 3-fluoro-N-methoxy-N-methylbenzamide (110 g, 600.50 mmol, 1 eq) obtained in step 1 was dissolved in tetrahydrofuran (THF; 1 L), and then bromo(vinyl)magnesium (1 M, 630.53 mL, 1.05 eq) was added dropwise at 0°C. The reaction mixture was then stirred at 0°C for 30 minutes. TLC analysis (petroleum ether (PE):ethyl acetate (EA) = 4:1) showed that all of the starting material had disappeared and new, less polar spots were detected. Hydrochloric acid (4 N, 500 mL) was added to terminate the reaction, and the organic layer was extracted using methyl tert-butyl ether (MTBE; 2000 mL) and brine (500 mL). The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The concentrated compound was purified by chromatography (petroleum ether / ethyl acetate = 30 / 1) to obtain the title compound (80 g, 532.80 mmol, 88.73% yield) as a yellow oil. 1 H NMR(400 MHz,CHLOROFORM-d)δ 7.65(m,1H), 7.58-7.52(m,1H), 7.39(m,1H), 7.24-7.17(m,1H), 7.04(dd,J = 17.2,10.4 Hz,1H), 6.39(dd,J = 17.2,1.6 Hz,1H), 5.90(dd,J = 10.4,1.6 Hz,1H).

[0057] Step 3: Preparation of 3-chloro-1-(3-fluorophenyl)propan-1-one The 1-(3-fluorophenyl)prop-2-en-1-one (71 g, 472.86 mmol, 1.0 eq) obtained in step 2 was dissolved in dichloromethane (DCM; 71 mL), and then HCl / dioxane (4 M, 295.54 mL, 2.5 eq) was added at 0°C. The reaction mixture was then stirred at 15°C for 1.5 hours. TLC analysis (petroleum ether (PE):ethyl acetate (EA) = 10:1) showed that all the starting materials had disappeared and the title compound was detected. The reaction mixture was concentrated under reduced pressure, and dichloromethane (DCM; 450 mL) and water (200 mL * 5) were added to extract the organic layer. After drying over sodium sulfate, the mixture was concentrated under reduced pressure to obtain the title compound (73 g, 391.19 mmol, 82.73% yield) as a yellow solid. 1 H NMR(400MHz,CHLOROFORM-d)δ 7.78-7.72(m,1H), 7.69-7.60(m,1H), 7.53-7.44(m,1H), 7.37-7.24(m,1H), 3.93(t,J =6.8 Hz,2H), 3.46(t,J =6.8 Hz,2H).

[0058] Step 4: Preparation of (S)-3-chloro-1-(3-fluorophenyl)propan-1-ol (3aR)-1-methyl-3,3-diphenyl-3a,4,5,6-tetrahydropyrrolo[1,2-c][1,3,2]oxabolol (1M, 32.15 mL, 0.1 eq) was dissolved in tetrahydrofuran (THF; 1.2 L), and then boranetetrahydrofuran (BH3·THF; 1M, 186.48 mL, 0.6 eq) was added dropwise at 0°C under a nitrogen stream. The reaction mixture was stirred at 0°C for 30 minutes. Then, 3-chloro-1-(3-fluorophenyl)propan-1-one (60 g, 309.02 mmol, 1 eq) obtained in step 3, diluted with tetrahydrofuran, was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 30 minutes. TLC analysis (petroleum ether (PE):ethyl acetate (EA) = 5:1) showed that all the starting materials had disappeared, and spots of the title compound were detected. Methanol (100 mL) was added at 0°C to terminate the reaction, and the solvent was blown off under reduced pressure. The concentrated compound was extracted from the organic layer using dichloromethane (DCM; 100 mL x 3) and ammonium chloride (NH4Cl) solution (300 mL). The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The concentrated compound was purified by silica gel chromatography (petroleum ether (PE):ethyl acetate (EA) = 50:1~5:1) to obtain the title compound as a colorless oil (140 g, 664.2 mmol, 71.65% yield, 89.49% purity, 65.5% ee). 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.33(m,1H), 7.16-7.07(m,2H), 7.02-6.96(m,1H), 4.96(m,1H), 3.75(m,1H), 3.57(m,1H), 2.26-2.15(m,2H).

[0059] Step 5: Preparation of tert-butyl(S)-(3-(3-fluorophenyl)-3-hydroxypropoxy)carbamate 50.4 g, 378.52 mmol, 1.05 eq of tert-butylhydroxycarbamate was dissolved in dimethylformamide (DMF; 500 mL), and then sodium hydride (NaH; 15.86 g, 396.55 mmol, 60% purity, 1.1 eq) was added under a nitrogen stream at 0°C. The reaction mixture was stirred at 10°C for 1 hour, and (S)-3-chloro-1-(3-fluorophenyl)propan-1-ol (68 g, 360.5 mmol, 1 eq) obtained in step 4, diluted with dimethylformamide (DMF; 180 mL), was added dropwise at 0°C, and the mixture was stirred at 10°C for 16 hours. TLC analysis (petroleum ether (PE):ethyl acetate (EA) = 2:1) showed that all the starting materials had disappeared, and the title compound was detected. After adding 3 L of aqueous ammonium chloride solution and terminating the reaction, the organic layer was extracted using 2000 mL of ethyl acetate and 2000 mL of brine. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure to obtain the title compound (176 g, 616.87 mmol, 85.56% yield) as a bright yellow solid. 1 H NMR(400 MHz,CHLOROFORM-d)δ 7.67-7.64(m,1H), 7.23-7.17(m,1H), 7.08-7.03(m,2H), 6.88-6.81(m,1H), 4.99-4.84(m,1H), 4.02-3.97(m,1H), 3.96-3.89(m,1H), 1.95-1.89(m,1H), 1.88-1.78(m,1H), 1.42-1.39(m,9H).

[0060] Step 6: Preparation of tert-butyl(R)-3-(3-fluorophenyl)isoxazolidine-2-carboxylate The tert-butyl(S)-(3-(3-fluorophenyl)-3-hydroxypropoxy)carbamate (88 g, 308.44 mmol, 1 eq) and triethylamine (93.63 g, 925.31 mmol, 128.79 mL, 3 eq) obtained in step 5 were dissolved in dichloromethane (DCM; 1 L), and then methanesulfonic anhydride (80.59 g, 462.65 mmol, 1.5 eq) was slowly added at 0°C. The reaction mixture was stirred at 20°C for 12 hours. TLC analysis (petroleum ether (PE):ethyl acetate (EA) = 3:1) showed that all the starting materials had disappeared and new spots were detected. After adding water (2000 mL) to terminate the reaction, the organic layer was extracted using dichloromethane (DCM; 200 mL x 3). The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The concentrated compound was purified by chromatography (petroleum ether (PE):ethyl acetate (EA) = 50:1~5:1), and 88 g of the title compound with an ee value of 82.5% was extracted. The title compound was purified by SFC (column:DAICEL CHIRALPAK AD (250 mm * 50 mm, 10 μm); mobile phase:[Neu-MeOH]; B%:15%-15%, 3.4 min; 380 min) to obtain the title compound as a white solid (51 g, 189.66 mmol, 30.74% yield, 99.4% purity).

[0061] The purity of the optical isomer of tert-butyl(R)-3-(3-fluorophenyl)isoxazolidine-2-carboxylate obtained in step 6 was analyzed under the following SFC conditions. Instrument:CAS-WH-ANA-SFC-C(SHIMADZU LC-30ADsf) Column:Amycoat 50 × 4.6mm ID,3um Mobile phase:Phase A for CO2,and Phase B for MeOH(0.05% DEA); Gradient elution:MeOH(0.05% DEA)in CO2from 5% to 40% Flow rate:3mL / min;Detector:PDA; Column Temp:35℃;Back Pressure:100 Bar

[0062] If the purity of the optical isomer of tert-butyl(R)-3-(3-fluorophenyl)isoxazolidine-2-carboxylate obtained in step 6 is low, it is purified under the following SFC conditions to obtain the desired yellow liquid optical isomer. Column:DAICEL CHIRALPAK AD-H(250mm * 30mm, 5um); Mobile phase:[0.1% NH3H2O ​​MeOH];B%:15%-15%, 3.8min;600min

[0063] Step 7: Preparation of (R)-3-(3-fluorophenyl)isoxazolidine The tert-butyl(R)-3-(3-fluorophenyl)isoxazolidine-2-carboxylate (50 g, 185.94 mmol, 1 eq) obtained in step 6 was dissolved in ethyl acetate (EA; 200 mL), and then HCl / siRNA (4 M, 300 mL, 6.45 eq) was added at 0°C. The reaction mixture was then stirred at 10°C for 1 hour. LCMS analysis revealed that all of the starting material had disappeared, and the mixture was concentrated under reduced pressure to obtain the title compound (32 g, 150.26 mmol, 80.81% yield, 95.62% purity, 100% ee HCl) as a white solid. MS:m / z 168.2[M+H] + 1 H NMR(400 MHz,DMSO-d6)δ 7.53-7.43(m,2H), 7.39(d,J = 7.8 Hz,1H), 7.30-7.23(m,1H), 5.01(t,J = 8.0 Hz,1H), 4.47(m,1H), 4.27(m,1H), 2.87(m,1H), 2.62-2.52(m,1H).

[0064] The following conditions were used for the purification or analysis of the optical isomers of the compound in step 7. Instrument:CAS-WH-ANA-SFC-C(SHIMADZU LC-30ADsf) Column:Chiralpak AY-3 50 × 4.6mm ID,3um; Mobile phase:Phase A for CO2,and Phase B for IPA(0.05% DEA); Gradient elution:B in A from 5% to 40%; Flow rate:3mL / min;Detector:PDA; Column Temp:35℃;Back Pressure:100 Bar

[0065] <Preparation Examples 4-44> Compounds 4 to 44 below were prepared in the same manner as in Preparation Examples 1 to 3, and the compounds of the Examples of the present invention were prepared using the compounds of Preparation Examples 1 to 44.

[0066] <Preparation Example 4> Preparation of (R)-3-(3,5-difluorophenyl)isoxazolidine [ka]

[0067] 1 H NMR(400 MHz,DMSO-d6)δ 7.36-7.27(m,3H), 5.04-4.98(t,J = 7.6 Hz,1H), 4.46-4.36(m,1H), 4.25-4.19(dd,J = 7.6,15.2 Hz,1H), 2.90-2.78(m,1H), 2.56-2.51(m,1H).

[0068] <Preparation Example 5> Preparation of (R)-3-(2,5-difluorophenyl)isoxazolidine [ka]

[0069] <Preparation Example 6> Preparation of (R)-3-(4-fluorophenyl)isoxazolidine [ka]

[0070] <Preparation Example 7> Preparation of (R)-3-(3-chloro-4-fluorophenyl)isoxazolidine [ka] 1 H NMR(400 MHz,DMSO-d6)δ 7.82-7.89(dd,J = 2,7.2,1H), 7.56-7.51(s,J = 15.6,2H), 5.00-4.96(m,1H), 4.46-4.40(m,1H), 4.24-4.20(m,1H), 2.85-2.82(m,1H), 2.54-2.52(m,1H).

[0071] <Preparation Example 8> Preparation of (R)-3-(3-chloro-2-fluorophenyl)isoxazolidine [ka] 1 H NMR(400 MHz,DMSO-d6)δ 7.49-7.42(m,2H), 7.20-7.16(m,1H), 6.56(s,1H), 4.66-4.65(m,1H), 3. 96-3.91(m,1H), 3.67-3.65(m,1H), 2.66-2.61(m,1H), 2.08-2.01(m,1H).

[0072] <Preparation Example 9> Preparation of (R)-3-(3-methoxyphenyl)isoxazolidine [ka] 1H NMR(400 MHz,Chloroform-d)δ 7.25-7.20(m,2H), 7.11-7.09(m,1H), 6.88-6.86(m,1H), 4.80-4.76(m,1 H), 4.46-4.44(m,1H), 4.17-4.15(m,1H), 3.76(s,3H), 2.69-2.66(m,2H).

[0073] <Preparation Example 10> Preparation of (R)-3-(6-methylpyridine-3-yl)isoxazolidine [ka]

[0074] <Preparation Example 11> Preparation of (R)-3-(3-ethynylphenyl)isoxazolidine [ka] 1 H NMR(400 MHz,DMSO-d6)δ 7.49(s,1H), 7.43-7.37(m,1H), 7.36-7.29(m,2H), 6.41(s,1H), 4.38(s,1H), 4.15(s,1H), 3.90(m,1H), 3.71(s,1H), 2.65-2.53(m,1H), 2.11-2.00(m,1H).

[0075] <Preparation Example 12> Preparation of (R)-3-methyl-3-phenylisoxazolidine [ka] 1 H NMR(400 MHz,DMSO-d6)δ 12.88(br s,1H), 7.56-7.46(m,2H), 7.44-7.36(m,2H), 7.34-7.26(m,1H), 3.74-3.62(m,1H), 3.46-3.28(m,1H), 2.72-2.54(m,2H), 1.64(s,3H).

[0076] <Preparation Example 13> Preparation of (R)-3-(2,4-difluorophenyl)isoxazolidine [ka] 1 H NMR(400 MHz,CHLOROFORM-d)δ 7.52-7.47(m,1H), 6.87-6.75(m,2H), 5.30(s,1H), 4.71-4.68(m,1H), 4. 09-4.04(m,1H), 3.91-3.85(m,1H), 2.73-2.64(3,1H), 2.24-2.20(m,1H).

[0077] <Preparation Example 14> Preparation of (R)-3-(naphthalene-1-yl)isoxazolidine [ka] 1 H NMR(400 MHz,CHLOROFORM-d)δ 8.13(br s,1H), 7.89-7.88(m,1H), 7.87-7.78(m,2H), 7.55-7.48(m,3H), 5.54(br s,1H), 5.23-5.20(m,1H,J = 6.4 Hz), 4.15-4.03(m,2H), 2.90-2.81(m,1H), 2.44-2.41(m,1H).

[0078] <Preparation Example 15> Preparation of (R)-3-(thiophene-2-yl)isoxazolidine [ka] 1 H NMR(400 MHz,CHLOROFORM-d)δ 7.23(d,J = 5.0 Hz,1H), 7.04-6.94(m,2H), 4.97-4.58(m,2H), 4.11-3.96(m,2H), 2.75-2.58(m,1H), 2.44-2.33(m,1H).

[0079] <Preparation Example 16> Preparation of (R)-3-(3-(trifluoromethyl)phenyl)isoxazolidine [ka] 1 H NMR(400 MHz,CHLOROFORM-d)δ 7.65(s,1H), 7.59(d,J = 7.7 Hz,1H), 7.53(d,J = 7.8 Hz,1H), 7.46(t,J = 7.7 Hz,1H), 5.64-5.19(m,1H), 4.58(t,J = 7.2 Hz,1H), 4.11(td,J = 8.2,5.2 Hz,1H), 3.94(s,1H), 2.80-2.67(m,1H), 2.36-2.23(m,1H).

[0080] <Preparation Example 17> Preparation of (R)-3-(naphthalene-2-yl)isoxazolidine [ka] 1 H NMR(400 MHz,CHLOROFORM-d)δ 7.91-7.81(m,4H), 7.56-7.46(m,3H), 5.80-5.00(m,1H), 4.68(t,J = 7.2 Hz,1H), 4.19-3.99(m,2H), 2.80-2.72(m,1H), 2.45-2.37(m,1H).

[0081] <Preparation Example 18> Preparation of (R)-3-(3,4-difluorophenyl)isoxazolidine [ka] 1H NMR(400 MHz,CHLOROFORM-d)δ 7.24-7.19(m,1H), 7.12-7.06(m,2H), 5.24(s,1H), 4.46(dd,J1 = 8.4 Hz,J2 = 5.6 Hz,1H), 4.05(dt,J1 = 8.0 Hz,J2 = 5.2 Hz,1H), 3.91-3.85(m,1H), 2.70-2.61(m,1H), 2.25-2.17(m,1H).

[0082] <Preparation Example 19> Preparation of (R)-3-(2,3-difluorophenyl)isoxazolidine [ka] 1 H NMR(CHLOROFORM-d,400 MHz)δ 7.29-7.27(m,1H), 7.06-7.02(m,2H), 5.44(br s,1H), 4.75(dd,J1 = 4.4 Hz,J2 = 8.4 Hz,1H), 4.08(dt,J1 = 5.2 Hz,J2 = 8.0 Hz,1H), 3.86(q,J=8.0 Hz,1H), 2.76-2.66(m,1H), 2.27-2.19(m,1H).

[0083] <Preparation Example 20> Preparation of (R)-3-(3-chloro-2,4-difluorophenyl)isoxazolidine [ka] 1 H NMR(DMSO-d6,400 MHz)δ 7.51(dt,J = 6.8,8.4 Hz,1H), 7.28(dt,J = 2.0,8.8 Hz,1H), 6.60(br s,1H), 4.64(br s,1H), 3.94(dt,J = 5.2,8.0 Hz,1H), 3.76 -3.57(m,1H), 2.68-2.61(m,1H), 2.10-2.01(m,1H).

[0084] <Preparation Example 21> Preparation of (R)-3-(4-chloro-2-fluorophenyl)isoxazolidine [ka] 1 H NMR(400 MHz,DEUTERIUM OXIDE)δ 7.48-7.38(m,1H), 7.34-7.22(m,2H), 5.29-5.20(m,1H), 4.58-4.50(m,1H), 4.36-4.27(m,1H), 2.96-2.84(m,1H), 2.79-2.66(m,1H).

[0085] <Preparation Example 22> Preparation of (R)-3-(4-chloro-3-fluorophenyl)isoxazolidine [ka]

[0086] <Preparation Example 23> Preparation of (R)-3-(isoxazolidine-3-yl)-N,N-dimethylaniline [ka]

[0087] <Preparation Example 24> Preparation of (S)-3-(5-fluoropyridine-3-yl)isoxazolidine [ka]

[0088] <Preparation Example 25> Preparation of (R)-3-(5-fluoropyridine-3-yl)isoxazolidine [ka]

[0089] <Preparation Example 26> Preparation of (R)-3-fluoro-5-(isoxazolidine-3-yl)benzonitrile [ka]

[0090] <Preparation Example 27>Preparation of (S)-3-Fluoro-5-(isoxazolidin-3-yl)benzonitrile

Chemical Structure

[0091] <Preparation Example 28>Preparation of (R)-3-(1-Methyl-1H-pyrazol-4-yl)isoxazolidine

Chemical Structure

[0092] <Preparation Example 29>Preparation of (R)-3-(Furan-2-yl)isoxazolidine

Chemical Structure

[0093] <Preparation Example 30>Preparation of (R)-3-(5-Chloropyridin-3-yl)isoxazolidine

Chemical Structure

[0094] <Preparation Example 31>Preparation of (S)-3-(5-Chloropyridin-3-yl)isoxazolidine

Chemical Structure

[0095] <Preparation Example 32>Preparation of (R)-3-(3-(Difluoromethyl)phenyl)isoxazolidine

Chemical Structure

[0096] <Preparation Example 33> Preparation of (S)-3-(3-(difluoromethyl)phenyl)isoxazolidine [ka]

[0097] <Preparation Example 34> Preparation of (R)-3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidine [ka]

[0098] <Preparation Example 35> Preparation of (S)-3-benzylisoxazolidine [ka] 1 H NMR(400 MHz,CHLOROFORM-d)δ 12.7-12.4(m,1H), 7.28-7.18(m,5H), 4.42-4.32(m,1H), 4.25-4.10(m,2H), 3.50(dd,J = 4.8,13.6 Hz,1H), 3.03(dd,J = 10.4,13.2 Hz,1H), 2.44-2.33(m,1H), 2.32-2.20(m,1H).

[0099] <Preparation Example 36> Preparation of Isopropyl(R)-3-(Isoxazolidine-3-yl)benzoate [ka] The title compound was prepared using 3-(isopropoxycarbonyl)benzoic acid from the following <Preparation Example 36-1> as an intermediate, in the same manner as in <Preparation Example 3>.

[0100] <Preparation Example 36-1> Preparation of 3-(isopropoxycarbonyl)benzoic acid [ka] Step 1: Preparation of 3-(isopropoxycarbonyl)benzoic acid Isophthalic acid (40 g, 1 eq) was dissolved in isopropyl alcohol (150 mL) and tetrahydrofuran (THF; 450 mL), and then concentrated sulfuric acid (concentrated H2SO4; 38.5 mL, 3 eq) was added. The reaction mixture was stirred at 75 °C for 48 hours. After completion of the reaction, it was concentrated under reduced pressure. After concentrating the organic solvent, the organic layer was extracted with ethyl acetate (EA; 500 mL) and water (200 mL). The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The concentrated compound was purified using chromatography (dichloromethane / methanol = 8 / 1) to obtain the title compound (23.25 g, 46.5% yield) as a transparent oil.

[0101] <Preparation Example 37> Preparation of (R)-3-(isoxazolidin-3-yl)benzoic acid

Chemical formula

[0102] <Preparation Example 38> Preparation of (R)-N-cyclohexyl-3-(isoxazolidin-3-yl)benzamide

Chemical formula

[0103] <Preparation Example 39> Preparation of (R)-3-(3-(benzyloxy)phenyl)isoxazolidine

Chemical formula

[0104] <Preparation Example 39-1> Preparation of 3-(benzyloxy)-N-methoxy-N-methylbenzamide [ka] Step 1: Preparation of 3-(benzyloxy)benzoate methyl 3-hydroxybenzoate methyl (20 g, 1.0 eq) was dissolved in acetone (260 mL), and then (bromomethyl)benzene (18.76 mL, 1.2 eq) and potassium carbonate (54.5 g, 3 eq) were added. The reaction mixture was stirred at 60 °C for 16 hours. TLC analysis (hexane:ethyl acetate = 3:2) showed that all the starting materials had disappeared and the title compound was detected. The reaction mixture was concentrated under reduced pressure, and dichloromethane (DCM; 300 mL x 2) and water (200 mL) were added. The organic layer was extracted, dried over sodium sulfate, and then concentrated under reduced pressure. The concentrated compound was recrystallized using hexane to obtain the title compound (29.27 g, 92% yield) as a white solid.

[0105] Step 2: Preparation of 3-(benzyloxy)benzoic acid The 3-(benzyloxy)benzoate methyl (29 g, 1.0 eq) obtained in step 1 was dissolved in methanol (MeOH; 300 ml), and then potassium hydroxide (KOH; 6 M, 4.5 eq) was added. The reaction mixture was then stirred at 80°C for 3 hours. TLC analysis (hexane:ethyl acetate = 7:3) showed that all of the starting material had disappeared, and new, less polar spots were detected. The reaction mixture was concentrated under reduced pressure, water (100 ml) was added, and hydrochloric acid (3N) was added dropwise to acidify the solution to pH 1. The resulting precipitate was filtered under reduced pressure and dried to obtain the title compound (27 g, 99% yield) as a white solid.

[0106] Step 3: Preparation of 3-(benzyloxy)-N-methoxy-N-methylbenzamide 3-(benzyloxy)benzoic acid (20 g, 1.0 eq) obtained in step 2 above was dissolved in dichloromethane (DCM; 700 ml), and then 1,1-carboxyldiimidazole (9.40 g, 1.1 eq) was slowly added. The reaction mixture was stirred at room temperature for 2 hours, then N,O-dimethylhydroxylamine hydrochloride (15.63 g, 1.1 eq) was added, and the mixture was stirred at 40°C for 18 hours. UPLC / MS analysis showed that all the starting materials had disappeared, and the title compound was detected. The reaction mixture was washed with hydrochloric acid (1N, 500 ml) and saturated aqueous solution of sodium bicarbonate (500 ml), dried over sodium sulfate, and then concentrated under reduced pressure to obtain the title compound (90 g, 85% yield) as a pale yellow oil.

[0107] <Preparation Example 40> Preparation of (R)-3-(3-phenoxyphenyl)isoxazolidine [ka] The title compound was prepared using the same method as in <Preparation Example 39> described above.

[0108] <Preparation Example 41> Preparation of (R)-3-(3-bromo-5-fluorophenyl)isoxazolidine hydrochloride [ka] Step 1: Preparation of 3-bromo-5-fluoro-N-methoxy-N-methylbenzamide 3-Bromo-5-fluorobenzoic acid (10 g, 1 eq) was dissolved in dichloromethane (110 mL), and then N,O-dimethylhydroxylamine hydrochloride (5.4 g, 1.2 eq), triethylamine (TEA; 5.7 mL, 0.9 eq), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI; 11.5 g, 1.2 eq) were added sequentially at room temperature. The reaction mixture was stirred at room temperature for 3 hours. TLC analysis (dichloromethane) showed that all the starting materials had disappeared, and new, less polar spots were detected. The organic layer was extracted using ethyl acetate (EA; 300 mL) and saturated sodium bicarbonate aqueous solution (400 mL x 2). After drying the organic layer over sodium sulfate, it was concentrated under reduced pressure to obtain the title compound (11.2 g, 94.0% yield) as a yellow oil.

[0109] Step 2: 1-(3-bromo-5-fluorophenyl)prof-2-en-1-one 3-bromo-5-fluoro-N-methoxy-N-methylbenzamide (11.2 g, 1 eq) obtained in step 1 was dissolved in tetrahydrofuran (THF; 220 mL), and then bromo(vinyl)magnesium (0.7 M, 93 mL, 1.5 eq) was added dropwise at 0°C. The reaction mixture was then stirred at 0°C for 1 hour. TLC analysis (hexane:dichloromethane = 1:1) showed that all of the starting material had disappeared and new, less polar spots were detected. Hydrochloric acid (1 N, 50 mL) was added to terminate the reaction, and the organic layer was extracted using ethyl acetate (EA; 300 mL) and hydrochloric acid (1 N, 400 mL x 2). The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The concentrated compound was purified by chromatography (hexane:dichloromethane = 1:1) to obtain the title compound (7.9 g, 76% yield) as a colorless oil.

[0110] Step 3: Preparation of 1-(3-bromo-5-fluorophenyl)-3-chloropropan-1-one The 1-(3-bromo-5-fluorophenyl)prof-2-en-1-one (7.9 g, 1.0 eq) obtained in step 2 was dissolved in dichloromethane (DCM; 13 mL), and then hydrochloric acid (HCl) / dioxane (4 M, 13 mL, 1.2 eq) was added at 0°C. The reaction mixture was then stirred at room temperature for 12 hours. TLC analysis (hexane:dichloromethane = 1:1) showed that all the starting materials had disappeared and the title compound was detected. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (EA; 300 mL) and saturated sodium bicarbonate aqueous solution (400 mL * 2) were added to extract the organic layer. After drying with sodium sulfate, the mixture was concentrated under reduced pressure to obtain the title compound (8.9 g, 97% yield) as a yellow oil.

[0111] Step 4: Preparation of (S)-1-(3-bromo-5-fluorophenyl)-3-chloropropan-1-ol (3aR)-1-methyl-3,3-diphenyl-3a,4,5,6-tetrahydropyrrolo[1,2-c][1,3,2]oxabolol (1M, 6.7mL, 0.2eq) was dissolved in tetrahydrofuran (THF; 84mL), and then boranedimethyl sulfide (BH3·Me2S; 1M, 21.8mL, 1.3eq) was added dropwise at 0°C under a nitrogen stream. The reaction mixture was stirred at 0°C for 30 minutes, and then 1-(3-bromo-5-fluorophenyl)-3-chloropropan-1-one (8.9g, 1eq) obtained in step 3, diluted in tetrahydrofuran, was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 2 hours. TLC analysis (hexane:dichloromethane = 1:1) showed that all of the starting material had disappeared, and a spot of the title compound was detected. Methanol (20 mL) was added at 20°C to terminate the reaction, and the solvent was blown off under reduced pressure. The concentrated compound was extracted organically using ethyl acetate (EA; 300 mL) and hydrochloric acid (1 N, 400 mL x 2). The organic layer was dried over sodium sulfate and then concentrated under reduced pressure to obtain the title compound (8.5 g, 95% yield) as a yellow oil.

[0112] Step 5: Preparation of tert-butyl(S)-(3-(3-bromo-5-fluorophenyl)-3-hydroxypropoxy)carbamate 9.3 g, 2.2 eq of tert-butylhydroxycarbamate was dissolved in dimethylformamide (DMF; 80 mL), and then sodium hydride (NaH; 3.1 g, 60% purity, 2.4 eq) was added under a nitrogen stream at 0°C. The reaction mixture was stirred at 0°C for 30 minutes. (S)-1-(3-bromo-5-fluorophenyl)-3-chloropropan-1-ol (8.5 g, 1 eq) obtained in step 4, diluted with dimethylformamide (DMF; 10 mL), was added dropwise at 0°C, and the mixture was stirred at room temperature for 12 hours. TLC analysis (dichloromethane: EA = 9:1) showed that all the starting materials had disappeared, and the title compound was detected. After adding brine (50 mL) to terminate the reaction, the organic layer was extracted using ethyl acetate (EA; 300 mL) and saturated sodium bicarbonate aqueous solution (400 mL x 3). The organic layer was dried over sodium sulfate and then concentrated under reduced pressure to obtain the title compound (9.2 g, 79% yield) as a yellow oil.

[0113] Step 6: Preparation of tert-butyl(R)-3-(3-bromo-5-fluorophenyl)isoxazolidine-2-carboxylate The tert-butyl(S)-(3-(3-bromo-5-fluorophenyl)-3-hydroxypropoxy)carbamate (9.2 g, 1 eq) and triphenylphosphine (Ph3P; 8.6 g, 1.3 eq) obtained in step 5 were dissolved in dichloromethane (DCM; 110 mL), and then diisopropyl azodicarboxylate (DIAD; 6.6 g, 1.3 eq), diluted with dichloromethane (DCM; 20 mL) at 0°C, was slowly added. The reaction mixture was stirred at 0°C for 2 hours. TLC analysis (dichloromethane (DCM):ethyl acetate (EA) = 9:1) showed that all the starting materials had disappeared and new spots were detected. The reaction mixture was concentrated under reduced pressure, and the concentrated compound was purified by chromatography (dichloromethane:ethyl acetate = 10:0 to 9:1) to obtain the title compound (7.7 g, 88% yield) as a yellow oil.

[0114] Step 7: Preparation of (R)-3-(3-bromo-5-fluorophenyl)isoxazolidine hydrochloride The tert-butyl(R)-3-(3-bromo-5-fluorophenyl)isoxazolidine-2-carboxylate (7.7 g, 1 eq) obtained in step 6 was dissolved in dichloromethane (DCM; 40 mL), and then HCl / dioxane (4 M, 28 mL, 5 eq) was added at room temperature. The reaction mixture was then stirred at room temperature for 2 hours. LC-MS analysis revealed that all of the starting material had disappeared. To obtain a solid, diethyl ether (200 mL) was added, and the resulting precipitate was filtered and dried to obtain the title compound (5.3 g, yield 84%) as a white solid. The following conditions were used for the purification or analysis of the optical isomers of the compound in step 7. Instrument:CAS-WH-ANA-SFC-C(SHIMADZU LC-30ADsf) Column:Chiralpak AY-3 50 × 4.6mm ID,3um; Mobile phase:Phase A for CO2,and Phase B for IPA(0.05% DEA); Gradient elution:B in A from 5% to 40%; Flow rate:3 mL / min;Detector:PDA; Column Temp:35℃;Back Pressure:100 Bar

[0115] The (R)-3-(3-bromo-5-fluorophenyl)isoxazolidine hydrochloride (5.3 g) obtained in step 7 above was purified under the following SFC conditions to obtain the desired optical isomer (100% purity, 100% ee). Column:DAICEL CHIRALPAK AD-H(250mm * 30mm,5um); Mobile phase:[0.1% NH3H2O ​​MeOH];B%:15%-15%,3.8min;600min 1H NMR(400 MHz,DMSO-d6)δ 7.62-7.58(m,2H), 7.43(dt,J = 9.8,2.0 Hz,1H), 4.93(t,J = 7.4 Hz,1H), 4.36(td,J = 8.1,4.4 Hz,1H), 4.12(q,J = 7.8 Hz,1H), 2.81(dtd,J = 12.4,7.9,4.4 Hz,1H), 2.49-2.41(m,1H).

[0116] <Preparation Example 42> Preparation of (R)-3-(3′,5-difluoro-[1,1′-biphenyl]-3-yl)isoxazolidine hydrochloride [ka] Step 1: Preparation of tert-butyl(R)-3-(3-bromo-5-fluorophenyl)isoxazolidine-2-carboxylate The (R)-3-(3-bromo-5-fluorophenyl)isoxazolidine hydrochloride (1 g, 1 eq) obtained in <Preparation Example 41> and triethylamine (TEA; 1.5 mL, 3 eq) were dissolved in tetrahydrofuran (7 mL), and then di-tert-butyl dicarbonate (Boc2O; 1.0 mL, 1.2 eq) was slowly added at 0°C. The reaction mixture was then stirred at 50°C for 2 hours. TLC analysis (DCM) revealed that all of the starting material had disappeared and new spots with different polarity were detected. The organic layer was extracted using ethyl acetate (EA; 70 mL) and saturated sodium bicarbonate aqueous solution (100 mL x 2). After drying the organic layer over sodium sulfate, it was concentrated under reduced pressure to obtain the title compound (1.1 g, 95% yield) as a pale yellow oil.

[0117] Step 2: Preparation of tert-butyl(R)-3-(3′,5-difluoro-[1,1′-biphenyl]-3-yl)isoxazolidine-2-carboxylate The tert-butyl(R)-3-(3-bromo-5-fluorophenyl)isoxazolidine-2-carboxylate (350 mg, 1 eq), (3-fluorophenyl)boronic acid (170 mg, 1.2 eq), and K2CO3 (280 mg, 2 eq) obtained in step 1 were dissolved in 1,4-dioxane (5 mL) at room temperature under a nitrogen atmosphere. Then, tetrakis(triphenylphosphine)palladium (0) (110 mg, 0.1 eq) was added to the reaction mixture at 80 °C and stirred for 3 hours. TLC analysis (DCM) showed that all the starting materials had disappeared and new spots with different polarities were detected. The organic layer was extracted using ethyl acetate (EA; 70 mL) and saturated sodium bicarbonate aqueous solution (100 mL x 2). The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The concentrated compound was purified using chromatography (hexane:dichloromethane = 5:5 to 0:10) to obtain the title compound (320 mg, 88% yield) as a colorless oil.

[0118] Step 3: Preparation of (R)-3-(3′,5-difluoro-[1,1′-biphenyl]-3-yl)isoxazolidine hydrochloride The tert-butyl(R)-3-(3′,5-difluoro-[1,1′-biphenyl]-3-yl)isoxazolidine-2-carboxylate (320 mg, 1 eq) obtained in step 2 was dissolved in dichloromethane (DCM; 2 mL), and then HCl / dioxane (4 M, 1 mL, 5 eq) was added at room temperature. The reaction mixture was then stirred at room temperature for 2 hours. LCMS analysis revealed that all of the starting material had disappeared. To obtain a solid, diethyl ether (10 mL) was added, and the resulting precipitate was filtered and dried to obtain the title compound (240 mg, 91% yield) as a white solid.

[0119] <Preparation Example 43> Preparation of (R)-3-(3-([1,2,4]triazolo[1,5-a]pyridine-7-yl)phenyl)isoxazolidine [ka] The title compound was prepared using the same method as in <Preparation Example 42> described above.

[0120] <Preparation Example 44> Preparation of (R)-3-(3-fluoro-5-thiomorpholinophenyl)isoxazolidine [ka] Using the compound from <Preparation Example 41> above, S N The compounds were prepared using methods such as Ar.

[0121] <Example 1> Preparation of (R)-N-(4-(4-methylpiperazine-1-yl)phenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine [ka] Step 1: Preparation of (R)-2-(6-chloropyrimidine-4-yl)-3-phenylisoxazolidine 4,6-Dichloropyrimidine (600 mg, 1 eq) and (R)-3-phenylisoxazolidine (631 mg, 1.05 eq) were dissolved in dimethyl sulfoxide (DMSO, 7 ml) as a solvent, and then N,N-diisopropylethylamine (DIPEA; 1.41 mL, 2 eq) was added. The reaction solution was stirred at 60°C for 30 minutes. After the reaction was complete, the mixture was extracted with ethyl acetate and water. The collected organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified with MPLC (ethyl acetate / hexane) to obtain the title compound (810 mg, 77% yield) as a clear liquid.

[0122] Step 2: Preparation of (R)-N-(4-(4-methylpiperazine-1-yl)phenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine (R)-2-(6-chloropyrimidine-4-yl)-3-phenylisoxazolidine (139 mg, 1 eq), 4-(4-methylpiperazine-1-yl)aniline (152 mg, 1.5 eq), and potassium carbonate (220 mg, 3 eq) obtained in step 1 were added to sec-butanol (1.8 ml), dissolved, and then sonicated under nitrogen for 5 minutes to remove gas. Tris(dibenzylideneacetone)dipalladium(0)(Pd2(dba)3; 47 mg, 0.1 eq) and X-phos (Xphos; 51 mg, 0.2 eq) were added to the reaction mixture, and the mixture was stirred at 100°C for 1 hour. After the reaction was complete, the mixture was filtered through Celite and washed with dichloromethane. The obtained filtrate was concentrated and purified by Prep-HPLC to obtain the title compound (71 mg, 32%). 1 H NMR(400 MHz,Chloroform-d)δ 8.23(s,1H), 7.42(d,J = 7.4 Hz,2H), 7.34(dd,J = 8.4,6.7 Hz,2H), 7.20-7.16(m,2H), 6.97-6.91(m,2H), 6.38(s,1H), 5.64(dd,J = 8.6,4.7 Hz,1H), 4.10(td,J = 7.8,4.5 Hz,1H), 3.85(q,J = 7.8 Hz,1H), 3.23(t,J = 5.1 Hz,4H), 2.71(dtd,J = 12.2,7.9,4.4 Hz,1H), 2.64(t,J = 5.0 Hz,4H), 2.38(s,3H), 2.37-2.32(m,1H), 2.04(s,1H).

[0123] <Examples 2-237> All the compounds of the present invention (compounds 1 to 237) were prepared using the same method as in Example 1, and the compound name, chemical structure, and NMR and LCMS analysis results of each compound are summarized in Table 1 below. [Table 1] TIFF0007896880000053.tif194166 TIFF0007896880000054.tif232166 TIFF0007896880000055.tif185166 TIFF0007896880000056.tif223166 TIFF0007896880000057.tif204166 TIFF0007896880000058.tif213166 TIFF0007896880000059.tif232166 TIFF0007896880000060.tif204166 TIFF0007896880000061.tif232166 TIFF0007896880000062.tif233166 TIFF0007896880000063.tif223166 TIFF0007896880000064.tif232166 TIFF0007896880000065.tif232166 TIFF0007896880000066.tif232166 TIFF0007896880000067.tif232166 TIFF0007896880000068.tif204166 TIFF0007896880000069.tif201166 TIFF0007896880000070.tif233166 TIFF0007896880000071.tif233166 TIFF0007896880000072.tif194166 TIFF0007896880000073.tif223166 TIFF0007896880000074.tif232166 TIFF0007896880000075.tif197166 TIFF0007896880000076.tif229166 TIFF0007896880000077.tif226166 TIFF0007896880000078.tif223166 TIFF0007896880000079.tif222166 TIFF0007896880000080.tif232166 TIFF0007896880000081.tif232166 TIFF0007896880000082.tif226166 TIFF0007896880000083.tif232166 TIFF0007896880000084.tif232166 TIFF0007896880000085.tif232166 TIFF0007896880000086.tif223166 TIFF0007896880000087.tif232166 TIFF0007896880000088.tif204166 TIFF0007896880000089.tif213166 TIFF0007896880000090.tif222166 TIFF0007896880000091.tif232166 TIFF0007896880000092.tif233166 TIFF0007896880000093.tif194166 TIFF0007896880000094.tif232166 TIFF0007896880000095.tif203166 TIFF0007896880000096.tif194166 TIFF0007896880000097.tif222166 TIFF0007896880000098.tif178166 TIFF0007896880000099.tif232166 TIFF0007896880000100.tif194166 TIFF0007896880000101.tif232166 TIFF0007896880000102.tif213166 TIFF0007896880000103.tif213166 TIFF0007896880000104.tif213166 TIFF0007896880000105.tif232166 TIFF0007896880000106.tif232166 TIFF0007896880000107.tif194166 TIFF0007896880000108.tif194166 TIFF0007896880000109.tif232166 TIFF0007896880000110.tif232166 TIFF0007896880000111.tif184166 TIFF0007896880000112.tif232166 TIFF0007896880000113.tif233166 TIFF0007896880000114.tif232166 TIFF0007896880000115.tif204166 TIFF0007896880000116.tif194166 TIFF0007896880000117.tif232166 TIFF0007896880000118.tif232166 TIFF0007896880000119.tif232166 TIFF0007896880000120.tif232166 TIFF0007896880000121.tif233166 TIFF0007896880000122.tif223166 TIFF0007896880000123.tif232166 TIFF0007896880000124.tif232166 TIFF0007896880000125.tif232166 TIFF0007896880000126.tif184166 TIFF0007896880000127.tif232166 TIFF0007896880000128.tif232166 TIFF0007896880000129.tif232166 TIFF0007896880000130.tif232166 TIFF0007896880000131.tif232166 TIFF0007896880000132.tif204166 TIFF0007896880000133.tif232166 TIFF0007896880000134.tif232166 TIFF0007896880000135.tif232166 TIFF0007896880000136.tif197166 TIFF0007896880000137.tif232166 TIFF0007896880000138.tif232166 TIFF0007896880000139.tif223166 TIFF0007896880000140.tif232166 TIFF0007896880000141.tif232166 TIFF0007896880000142.tif204166 TIFF0007896880000143.tif232166 TIFF0007896880000144.tif203166 TIFF0007896880000145.tif222166 TIFF0007896880000146.tif207166 TIFF0007896880000147.tif232166 TIFF0007896880000148.tif232166 TIFF0007896880000149.tif232166 TIFF0007896880000150.tif232166 TIFF0007896880000151.tif203166 TIFF0007896880000152.tif232166 TIFF0007896880000153.tif232166 TIFF0007896880000154.tif232166 TIFF0007896880000155.tif232166 TIFF0007896880000156.tif194166 TIFF0007896880000157.tif223166 TIFF0007896880000158.tif232166 TIFF0007896880000159.tif232166 TIFF0007896880000160.tif213166 TIFF0007896880000161.tif137166

[0124] <Experimental Example 1> Evaluation of Ba / F3 cell proliferation inhibitory activity of EGFR mutation overexpression To evaluate the inhibitory activity of the compounds according to the present invention against Ba / F3 proliferation expressing EGFR C797S, L861Q, G719A, S768I, L718Q, and / or G724S mutations, the following experiments were performed.

[0125] Ba / F3 cells were cultured in RPMI-1640 containing 10% FBS and 5 ng / ml IL-3 (R&D Systems). Transduced Ba / F3 cells were cultured in the same medium with 1 μg / ml puromycin (Invitrogen) added.

[0126] Cells were aliquoted into each well of a white clear-bottom 96-well plate (Corning) at a rate of 3000-5000 cells 24 hours prior to compound treatment. The compound was diluted with dimethyl sulfoxide (3-fold dilution, totaling 12 concentrations), and 1 μl was injected at a time to achieve a final concentration of 0.2 nM-5 μM. Viability of cells was measured 72 hours after compound treatment, using CellTiter-Glo luminescentcell-viability reagent (Promega), after which the cells were stored at room temperature for 10 minutes, and the luminescence intensity was measured using a reader (SynergyNeo, Biotek). Each test was repeated three times. The results were calculated as the cell proliferation rate (%) compared to the control group. Graphs were plotted using the GraphPad Prism version 8.3.0 program, and GI was measured. 50 The value was calculated.

[0127] Table 2 below shows the results of the evaluation of the proliferation inhibitory activity of Ba / F3 cells expressing EGFR Del19 / C797S (EGFR DC) and EGFR L858R / C797S (EGFR LC) mutations. [Table 2] TIFF0007896880000163.tif248165 TIFF0007896880000164.tif145165

[0128] Table 3 below shows the results of evaluating the proliferation inhibitory activity of Ba / F3 cells such as L861Q, G719A, S768I, L718Q, or G724S, which express rare (rare or uncommon) EGFR and drug resistance mutations. [Table 3]

[0129] Table 4 below shows the activity values ​​for EGFR family mutant enzymes obtained by commissioning Reaction Biology (https: / / www.reactionbiology.com / ), an external contract research organization. [Table 4]

[0130] As shown in Tables 2-4 above, the example compounds of the present invention exhibit high inhibitory activity against overexpression cell lines or enzymes, including EGFRC797S mutations and rare mutations.

[0131] Although the present invention has been described in detail above with reference to preferred preparation examples, examples, and experimental examples, the scope of the present invention is not limited to specific example compounds and should be interpreted according to the attached claims. Furthermore, a person with ordinary skill in the art should understand that many modifications and variations are possible without departing from the scope of the present invention.

Claims

1. The compound represented by the following chemical formula 1, its optical isomer, or its pharmaceutically acceptable salt: [Transformation 50] In the aforementioned chemical formula 1, X １ ~X ３ Each of these is independently either CH or N; R Ｘ is -H, -C １－６ alkyl, -C １－６ aminoalkyl, -NH ２ , -NH(-C １－６ alkyl), or -N(-C １－６ alkyl)(-C １－６ alkyl); Y is -C １－６ Alkyl, -(CH ２ ) n aryl, - (CH ２ ) n hydroaryl, - (CH ２ )n heteroaryl, or -(CH ２ ) is an n-hydroheteroaryl {where the above-(CH ２ ) n aryl, - (CH ２ ) n hydroaryl, - (CH ２ )n heteroaryl, or -(CH ２ ) One or more H in the n-hydroheteroaryl ring is -C １－６ Alkyl, -C １－６ Aminoalkyl, -C １－６ Hydroxyalkyl, -C １－６ Haloalkyl, -C １－６ Alkyl-O-C １－６ Alkyl, -C １－６ Alkenyl, -C １－６ Alkinyl, -CN, -(C=O)NR １ R ２ , -(C=O) OR ３ , -NR ４ R ５ , -OR ６ , -halo, =O, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl may be substituted [in this case, one or more H of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is -C １－６ Alkyl, -C １－６ [May be substituted with a haloalkyl or -halo]; n is 0, 1, 2, 3, or 4; R １ ~R ３ These are independently -H and -C １－６ Alkyl or cycloalkyl; R ４ and R ５ These are, independently, -H or -C １－６ It is alkyl; R ６ is -H, -C １－６ Alkyl or phenyl {wherein one or more H of the phenyl ring is -C} １－６ Alkyl, -C １－６ {May be substituted with haloalkyl or halo}; R Ｙ１ ~R Ｙ５ These are, independently, -H or -C １－６ Alkyl, or R Ｙ２ and R Ｙ３ These can link together to form cycloalkyl or heterocycloalkyl groups, R Ｙ４ and R Ｙ５ These can link together to form cycloalkyl or heterocycloalkyl groups, R Ｙ３ and R Ｙ４ These can link together to form aryl or heteroaryl groups; L is - (CH ２ )m-, -C(=O)-, or nothing (null); m is 0, 1, 2, 3, or 4; Ring Z is an aryl, heteroaryl, hydroaryl, hydroheteroaryl, cycloalkyl, or heterocycloalkyl ring {wherein one or more H of the aryl, heteroaryl, hydroaryl, hydroheteroaryl, cycloalkyl, or heterocycloalkyl ring is -C １－６ Alkyl, -C １－６ Cyanoalkyl, -C １－６ Hydroxyalkyl, -C １－６ Aminoalkyl, -C １－６ Haloalkyl, -C １－６ Alkenyl, -C １－６ Alkinyl, -CN, -OH 、 -O-C １－６ Alkyl, -O-C １－６ Haloalkyl, -S-C １－６ Alkyl, -S-C １－６ Haloalkyl, -C(=O)-C １－６ Alkyl, -C(=O)-C １－６ Haloalkyl, -C(=O)O-C １－６ Alkyl, -S (=O) ２ -C １－６ Alkyl, -C (=N-O-C) １－６ (Alkyl) (C １－６ Alkyl), =O, -halo, or Z １ It may be substituted with, or two or more substituents of the aryl, heteroaryl, hydroaryl, hydroheteroaryl, cycloalkyl, or heterocycloalkyl ring may be linked to each other to form a fused ring or spiro ring [wherein one or more H of the fused ring or spiro ring is -C １－６ Alkyl, -C １－６ Haloalkyl, -O-C １－６ Alkyl, -halo, or Z １ [May be replaced by]}; Z １ is cycloalkyl, heterocycloalkyl, heterobicycloalkyl, heterospiroalkyl, -C １－６ alkyl-heterocycloalkyl, -(C=O)-heterocycloalkyl, -NH-heterocycloalkyl, aryl, or heteroaryl {wherein the heterocycloalkyl, heterobicycloalkyl, heterospiroalkyl, -C １－６ alkyl-heterocycloalkyl, -(C=O)-heterocycloalkyl, or -NH-heterocycloalkyl contains one or more selected from the group consisting of N, O, P, P(=O) and S in the ring, and one or more H of the heterocycloalkyl, heterobicycloalkyl, heterospiroalkyl, -C １－６ alkyl-heterocycloalkyl, -(C=O)-heterocycloalkyl, -NH-heterocycloalkyl, aryl, or heteroaryl ring is -C １－６ alkyl, -C １－６ aminoalkyl, -C １－６ haloalkyl, -C １－６ alkyl-NH-C １－６ alkyl, -C １－６ ​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ R ９ and R １０ These are, independently, -H or -C １－６ It is alkyl; Z ２ These are heterocycloalkyl, heterobicycloalkyl, heterospiroalkyl, and -C １－６ Alkyl-heterocycloalkyl, -(C=O)-heterocycloalkyl, -NH-heterocycloalkyl, aryl, or heteroaryl {wherein the heterocycloalkyl, heterobicycloalkyl, heterospiroalkyl, -C １－６ Alkyl-heterocycloalkyl, -(C=O)-heterocycloalkyl, or -NH-heterocycloalkyl contains one or more elements selected from the group consisting of N, O, P, P(=O), and S in the ring, and the heterocycloalkyl, heterobicycloalkyl, heterospiroalkyl, -C １－６ Alkyl-heterocycloalkyl, -(C=O)-heterocycloalkyl, -NH-heterocycloalkyl, aryl, or one or more H in a heteroaryl ring is -C １－６ Alkyl, -C １－６ Aminoalkyl, -C １－６ Hydroxyalkyl, -C １－６ Haloalkyl, -C １－６ Alkenyl, -C １－６ Alkinyl, -C(=O)-C １－６ Alkyl, -C １－６ Alkyl-S (=O) ２ -C １－６ Alkyl, =O, -NR １１ R １２ , cycloalkyl, or Z ３ It may be replaced with}; R １１ and R １２ These are, independently, -H or -C １－６ It is alkyl; Z ３ These are heterocycloalkyl, heterobicycloalkyl, heterospiroalkyl, and -C １－６ Alkyl-heterocycloalkyl, -(C=O)-heterocycloalkyl, or -NH-heterocycloalkyl {wherein the heterocycloalkyl, heterobicycloalkyl, heterospiroalkyl, -C １－６ Alkyl-heterocycloalkyl, -(C=O)-heterocycloalkyl, or -NH-heterocycloalkyl contains one or more elements selected from the group consisting of N, O, P, P(=O), and S in the ring, and the heterocycloalkyl, heterobicycloalkyl, heterospiroalkyl, -C １－６ One or more H atoms in an alkyl-heterocycloalkyl, -(C=O)-heterocycloalkyl, or -NH-heterocycloalkyl ring are -C １－６ They may be substituted with alkyl or cycloalkyl groups.

2. X １ ~X ３ Each of these is independently either CH or N; R Ｘ -H, -NH ２ , -NH(-C １－６ Alkyl), or -N(-C) １－６ Alkyl) (-C １－６ It is alkyl; Y is -C １－６ Alkyl, -(CH ２ ) n aryl, - (CH ２ )n heteroaryl, or -(CH ２ ) is an n-hydroheteroaryl {where the above-(CH ２ ) n aryl, - (CH ２ )n heteroaryl, or -(CH ２ ) One or more H in the n-hydroheteroaryl ring is -C １－６ Alkyl, -C １－６ Haloalkyl, -C １－６ Alkenyl, -C １－６ Alkinyl, -CN, -(C=O)NR １ R ２ , -(C=O) OR ３ , -NR ４ R ５ , -OR ６ , -halo, =O, heterocycloalkyl, aryl, or heteroaryl may be substituted [in this case, one or more H of the heterocycloalkyl, aryl, or heteroaryl may be substituted with -halo]; n is 0, 1, or 2; R １ ~R ３ These are independently -H and -C １－６ Alkyl or cycloalkyl; R ４ and R ５ These are, independently, -H or -C １－６ It is alkyl; R ６ is, -C １－６ Alkyl or phenyl {wherein one or more H of the phenyl ring is -C} １－６ Alkyl, -C １－６ {May be substituted with haloalkyl or halo}; R Ｙ１ ~R Ｙ５ These are, independently, -H or -C １－６ Alkyl, or R Ｙ２ and R Ｙ３ These can link together to form a cycloalkyl group, R Ｙ３ and R Ｙ４ They can be connected to each other to form an aryl; L is - (CH ２ )m-, -C(=O)-, or nothing (null); m is 0, 1, or 2; Ring Z is an aryl, heteroaryl, hydroheteroaryl, cycloalkyl, or heterocycloalkyl ring {wherein one or more H of the aryl, heteroaryl, hydroheteroaryl, cycloalkyl, or heterocycloalkyl ring is -C １－６ Alkyl, -C １－６ Cyanoalkyl, -C １－６ Haloalkyl, -C １－６ Alkenyl, -C １－６ Alkinyl, -CN, -O-C １－６ Alkyl, -O-C １－６ Haloalkyl, -S-C １－６ Alkyl, -C(=O)-C １－６ Alkyl, -C(=O)-C １－６ Haloalkyl, -C(=O)O-C １－６ Alkyl, -S (=O) ２ -C １－６ Alkyl, -C (=N-O-C) １－６ (Alkyl) (C １－６ Alkyl), =O, -halo, or Z １ It may be substituted with, or two or more substituents of the aryl, heteroaryl, hydroheteroaryl, cycloalkyl, or heterocycloalkyl ring may be linked to each other to form a fused ring or spiro ring [wherein one or more H of the fused ring or spiro ring is -C １－６ Alkyl or Z １ [May be replaced by]}; Z １ These are cycloalkyl, heterocycloalkyl, heterobicycloalkyl, heterospiroalkyl, and -C １－６ Alkyl-heterocycloalkyl, -(C=O)-heterocycloalkyl, -NH-heterocycloalkyl, or heteroaryl {wherein the heterocycloalkyl, heterobicycloalkyl, heterospiroalkyl, -C １－６ Alkyl-heterocycloalkyl, -(C=O)-heterocycloalkyl, or -NH-heterocycloalkyl contains one or more elements selected from the group consisting of N, O, P, P(=O), and S in the ring, and the heterocycloalkyl, heterobicycloalkyl, heterospiroalkyl, -C １－６ Alkyl-heterocycloalkyl, -(C=O)-heterocycloalkyl, -NH-heterocycloalkyl, or one or more H in a heteroaryl ring is -C １－６ Alkyl, -C １－６ Aminoalkyl, -C １－６ Haloalkyl, -C １－６ Alkenyl, -C １－６ Alkinyl, -C(=O)-C １－６ Alkyl, -C １－６ Alkyl-S (=O) ２ -C １－６ Alkyl, =O, -NR ９ R １０ , -halo, cycloalkyl, or Z ２ It may be replaced with}; R ９ and R １０ These are, independently, -H or -C １－６ It is alkyl; Z ２ is a heterocycloalkyl, heterobicycloalkyl, or -NH-heterocycloalkyl {wherein the heterocycloalkyl, heterobicycloalkyl, or -NH-heterocycloalkyl contains one or more elements selected from the group consisting of N, O, P, P(=O), and S in the ring, and one or more H in the heterocycloalkyl, heterobicycloalkyl, or -NH-heterocycloalkyl ring is -C １－６ Alkyl, -C １－６ Hydroxyalkyl, -C １－６ Alkenyl, -C １－６ Alkinyl, -C(=O)-C １－６ Alkyl, -C １－６ Alkyl-S (=O) ２ -C １－６ Alkyl, =O, -NR １１ R １２ , cycloalkyl, or Z ３ It may be replaced with}; R １１ and R １２ These are, independently, -H or -C １－６ It is alkyl; Z ３ This refers to heterocycloalkyl, heterobicycloalkyl, or -C １－６ The alkyl-heterocycloalkyl {wherein the heterocycloalkyl, heterobicycloalkyl, or -C} １－６ Alkyl-heterocycloalkyl contains one or more elements selected from the group consisting of N, O, P, P(=O), and S within the ring, and the heterocycloalkyl, heterobicycloalkyl, or -C １－６ One or more H atoms in the alkyl-heterocycloalkyl ring are -C １－６ They may be substituted with alkyl or cycloalkyl groups; A compound represented by chemical formula 1 as described in claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

3. X １ is N; X ２ and X ３ Each of these is independently either CH or N; R Ｘ -H, -NH ２ , or -NH(-C １－６ It is alkyl; A compound represented by chemical formula 1 as described in claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

4. Y is -C １－６ Alkyl, -(CH ２ ) n aryl, - (CH ２ )n heteroaryl, or -(CH ２ ) is an n-hydroheteroaryl {where the above-(CH ２ ) n aryl, - (CH ２ )n heteroaryl, or -(CH ２ ) One or more H in the n-hydroheteroaryl ring is -C １－６ Alkyl, -C １－６ Haloalkyl, -C １－６ Alkynyl, -CN, -(C=O)NH-cycloalkyl, -(C=O)O-C １－６ Alkyl, -N(C) １－６ (Alkyl) (C １－６ Alkyl), -O (C １－６ It may be substituted with alkyl), -O-phenyl, -halo, =O, heterocycloalkyl, aryl, or heteroaryl [in which case, one or more H of the heterocycloalkyl, aryl, or heteroaryl may be substituted with -halo]; n is either 0 or 1; R Ｙ１ ~R Ｙ５ These are, independently, -H or -C １－６ Alkyl, or R Ｙ２ and R Ｙ３ These can link together to form a 3-6 membered ring cycloalkyl, R Ｙ３ and R Ｙ４ These are molecules that can link together to form phenyl; A compound represented by chemical formula 1 as described in claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

5. L is - (CH ２ )m-, -C(=O)-, or nothing (null); m is either 0 or 1; Ring Z is an aryl, heteroaryl, hydroheteroaryl, 3- to 7-membered cycloalkyl, or 5- to 7-membered heterocycloalkyl ring {wherein one or more H of the aryl, heteroaryl, hydroheteroaryl, 3- to 7-membered cycloalkyl, or 5- to 7-membered heterocycloalkyl ring is -C １－６ Alkyl, -C １－６ Cyanoalkyl, -C １－６ Haloalkyl, -C １－６ Alkenyl, -C １－６ Alkinyl, -CN, -O-C １－６ Alkyl, -O-C １－６ Haloalkyl, -S-C １－６ Alkyl, -C(=O)-C １－６ Alkyl, -C(=O)-C １－６ Haloalkyl, -C(=O)O-C １－６ Alkyl, -S (=O) ２ -C １－６ Alkyl, -C (=N-O-C) １－６ (Alkyl) (C １－６ Alkyl), =O, -halo, or Z １ It may also be substituted with [wherein one or more H of the aryl, heteroaryl, hydroheteroaryl, 3- to 7-membered cycloalkyl, or 5- to 7-membered heterocycloalkyl ring is -C １－６ [May be substituted with alkyl or -halo], or two or more substituents of the aryl, heteroaryl, hydroheteroaryl, 3- to 7-membered cycloalkyl, or 5- to 7-membered heterocycloalkyl ring may be linked to each other to form a fused ring or spiro ring [wherein one or more H of the fused ring or spiro ring is -C １－６ Alkyl or Z １ [May be replaced by]}; Z １ These include 3-7 membered ring cycloalkyls, 5-7 membered ring heterocycloalkyls, 6-10 membered ring heterobicycloalkyls, 6-10 membered ring heterospiroalkyls, and -C １－６ Alkyl-heterocycloalkyl, -(C=O)-heterocycloalkyl, -NH-heterocycloalkyl, or heteroaryl {wherein the 5-7 membered ring heterocycloalkyl, 6-10 membered ring heterobicycloalkyl, 6-10 membered ring heterospiroalkyl, -C １－６ Alkyl-heterocycloalkyl, -(C=O)-heterocycloalkyl, or -NH-heterocycloalkyl contains one or more selected from the group consisting of N, O, P, P(=O), and S in the ring, and the 5-7 membered ring heterocycloalkyl, 6-10 membered ring heterobicycloalkyl, 6-10 membered ring heterospiroalkyl, -C １－６ Alkyl-heterocycloalkyl, -(C=O)-heterocycloalkyl, -NH-heterocycloalkyl, or one or more H in a heteroaryl ring is -C １－６ Alkyl, -C １－６ Aminoalkyl, -C １－６ Haloalkyl, -C １－６ Alkenyl, -C(=O)-C １－６ Alkyl, -C １－６ Alkyl-S (=O) ２ -C １－６ Alkyl, =O, -N(C) １－６ (Alkyl) (C １－６ Alkyl), -halo, cycloalkyl, or Z ２ It may be replaced with}; Z ２ The is a 5-7 membered heterocycloalkyl ring, a 6-10 membered heterobicycloalkyl ring, or an -NH-heterocycloalkyl ring {wherein the 5-7 membered heterocycloalkyl ring, the 6-10 membered heterobicycloalkyl ring, or the -NH-heterocycloalkyl ring contains one or more elements selected from the group consisting of N, O, and S in the ring, and one or more H in the 5-7 membered heterocycloalkyl ring, the 6-10 membered heterobicycloalkyl ring, or the -NH-heterocycloalkyl ring is -C １－６ Alkyl, -C １－６ Hydroxyalkyl, -C １－６ Alkenyl, -C １－６ Alkinyl, -C(=O)-C １－６ Alkyl, -C １－６ Alkyl-S (=O) ２ -C １－６ Alkyl, =O, -N(C) １－６ (Alkyl) (C １－６ Alkyl), 3-7 membered ring cycloalkyl, or Z ３ It may be replaced with}; Z ３ These are 5-7 membered heterocycloalkyl rings, 6-10 membered heterobicycloalkyl rings, or -C １－６ It is an alkyl-heterocycloalkyl {wherein the 5-7 membered ring heterocycloalkyl, 6-10 membered ring heterobicycloalkyl, or -C}. １－６ Alkyl-heterocycloalkyl contains one or more elements selected from the group consisting of N, O, and S within the ring, and is a 5-7 membered ring heterocycloalkyl, a 6-10 membered ring heterobicycloalkyl, or -C １－６ One or more H atoms in the alkyl-heterocycloalkyl ring are -C １－６ They may be substituted with alkyl groups or 3- to 7-membered cycloalkyl rings; A compound represented by chemical formula 1 as described in claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

6. X1 is N; X² is either CH or N; X 3 is CH; R X is -H; Y is a -C1-6 alkyl, -(CH2)n aryl, -(CH2)n hydroaryl, -(CH2)n heteroaryl, or -(CH2)n hydroheteroaryl {wherein one or more H of the -(CH2)n aryl, -(CH2)n hydroaryl, -(CH2)n heteroaryl, or -(CH2)n hydroheteroaryl ring is a -C1-6 alkyl, -C1-6 aminoalkyl, -C1-6 hydroxyalkyl, -C1-6 haloalkyl, -C1-6 alkyl-O-C1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -CN, -(C=O)NR1R2, -(C=O)OR3, -NR4R5, -OR6 , -halo, =O, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl may be substituted [in this case, one or more H of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl may be substituted with -C1-6 alkyl, -C1-6 haloalkyl, or -halo]; n is 0, 1, or 2; R1 to R3 are each independently -H, -C1-6 alkyl, or cycloalkyl; R4 and R5 are each independently -H or -C1-6 alkyl; R 6 is -H, -C1-6 alkyl, or phenyl {wherein one or more H of the phenyl ring may be substituted with -C1-6 alkyl, -C1-6 haloalkyl, or halo}; Each of RY1 to RY5 is independently a -H or -C1-6 alkyl group, or RY2 and RY3 can be linked together to form a cycloalkyl or heterocycloalkyl group, RY4 and RY5 can be linked together to form a cycloalkyl or heterocycloalkyl group, and RY3 and RY4 can be linked together to form an aryl or heteroaryl group; L is -(CH2)m- or nothing (null); m is 0, 1, or 2; Ring Z is an aryl, heteroaryl, hydroheteroaryl, 3- to 7-membered cycloalkyl, or 5- to 7-membered heterocycloalkyl ring {wherein one or more H of the aryl, heteroaryl, hydroheteroaryl, 3- to 7-membered cycloalkyl, or 5- to 7-membered heterocycloalkyl ring is -C1-6 alkyl, -C1-6 cyanoalkyl, -C1-6 haloalkyl, -C1-6 alkenyl, -C1-6 alkynyl, -CN, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -S-C1-6 alkyl, -C(=O)-C1-6 alkyl, -C(=O)-C1-6 haloalkyl, -C(=O)O-C1-6 alkyl, -S(=O)2-C1-6 alkyl, -C(=N-O-C1-6 alkyl)(C1-6 The substituents may be substituted with alkyl, =O, -halo, or Z1 [wherein one or more H atoms of the aryl, heteroaryl, hydroheteroaryl, 3- to 7-membered cycloalkyl, or 5- to 7-membered heterocycloalkyl ring may be substituted with -C1-6 alkyl or -halo], or two or more substituents of the aryl, heteroaryl, hydroheteroaryl, 3- to 7-membered cycloalkyl, or 5- to 7-membered heterocycloalkyl ring may be linked to each other to form a fused ring or spiro ring [wherein one or more H atoms of the fused ring or spiro ring may be substituted with -C1-6 alkyl or Z1]; Z1 is a 3-7 membered ring cycloalkyl, a 5-7 membered ring heterocycloalkyl, a 6-10 membered ring heterobicycloalkyl, a 6-10 membered ring heterospiroalkyl, -C1-6 alkyl-heterocycloalkyl, -(C=O)-heterocycloalkyl, -NH-heterocycloalkyl, or heteroaryl {wherein the 5-7 membered ring heterocycloalkyl, 6-10 membered ring heterobicycloalkyl, 6-10 membered ring heterospiroalkyl, -C1-6 alkyl-heterocycloalkyl, -(C=O)-heterocycloalkyl, or -NH-heterocycloalkyl contains one or more elements selected from the group consisting of N, O, P, P(=O) and S in the ring, and the 5-7 membered ring heterocycloalkyl, 6-10 membered ring heterobicycloalkyl, 6-10 membered ring heterospiroalkyl, -C1-6 Alkyl-heterocycloalkyl, -(C=O)-heterocycloalkyl, -NH-heterocycloalkyl, or one or more H in a heteroaryl ring may be substituted with -C1-6 alkyl, -C1-6 aminoalkyl, -C1-6 haloalkyl, -C1-6 alkenyl, -C(=O)-C1-6 alkyl, -C1-6 alkyl-S(=O)2-C1-6 alkyl, =O, -N(C1-6 alkyl)(C1-6 alkyl), -halo, cycloalkyl, or Z2; Z2 is a 5-7 membered ring heterocycloalkyl, a 6-10 membered ring heterobicycloalkyl, or a -NH-heterocycloalkyl {wherein the 5-7 membered ring heterocycloalkyl, the 6-10 membered ring heterobicycloalkyl, or the -NH-heterocycloalkyl contains one or more elements selected from the group consisting of N, O, and S in the ring, and one or more H in the 5-7 membered ring heterocycloalkyl, the 6-10 membered ring heterobicycloalkyl, or the -NH-heterocycloalkyl ring is -C1-6 alkyl, -C1-6 hydroxyalkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C(=O)-C1-6 alkyl, -C1-6 alkyl-S(=O)2-C1-6 alkyl,=O, -N(C1-6 alkyl)(C1-6 alkyl), a 3-7 membered ring cycloalkyl, or Z3 It may be replaced with}; Z3 is a 5-7 membered heterocycloalkyl ring, a 6-10 membered heterobicycloalkyl ring, or a -C1-6 alkyl-heterocycloalkyl ring {wherein the 5-7 membered heterocycloalkyl ring, the 6-10 membered heterobicycloalkyl ring, or the -C1-6 alkyl-heterocycloalkyl ring contains one or more elements selected from the group consisting of N, O, and S in the ring, and one or more H atoms of the 5-7 membered heterocycloalkyl ring, the 6-10 membered heterobicycloalkyl ring, or the -C1-6 alkyl-heterocycloalkyl ring may be substituted with a -C1-6 alkyl or a 3-7 membered cycloalkyl ring; A compound represented by chemical formula 1 as described in claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

7. A compound selected from the group consisting of the following compounds, an optical isomer thereof, or a pharmaceutically acceptable salt thereof: (1) (R)-N-(4-(4-methylpiperazine-1-yl)phenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (2) (S)-N-(4-(4-methylpiperazine-1-yl)phenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (3) (S)-6-(3-benzylisoxazolidine-2-yl)-N-(4-(4-methylpiperazine-1-yl)phenyl)pyrimidine-4-amine; (4) (R)-N-(3-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (5) (R)-N-(2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (6) (R)-N-(4-(4-(4-cyclopropylpiperazine-1-yl)piperidine-1-yl)-2-methoxyphenyl)-6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-amine; (7) (R)-6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)-N-(2-methoxy-5-(1-methyl-1H-pyrazole-4-yl)-4-morpholinophenyl)pyrimidine-4-amine; (8)(R)-6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)-N-(2-methoxy-5-(1-methyl-1H-pyrazole-4-yl)-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (9)(R)-6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)-N-(2-methoxy-5-(1-methyl-1H-pyrazole-5-yl)-4-morpholinophenyl)pyrimidine-4-amine; (10)(R)-1'-(4-((6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazole-4-yl)phenyl)-N,N-dimethyl-[1,4'-bipiperidine]-4-amine; (11)(R)-6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)-N-(3-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)-5-(methylsulfonyl)phenyl)pyrimidine-4-amine; (12)(R)-6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)-N-(3-(methylsulfonyl)-5-(4-morpholinopiperidine-1-yl)phenyl)pyrimidine-4-amine; (13)(R)-6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)-N-(3-(4-methylpiperazine-1-yl)-5-(methylsulfonyl)phenyl)pyrimidine-4-amine; (14)(R)-2-(3-((6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)-5-((4-methylpiperazine-1-yl)methyl)phenyl)-2-methylpropanenitrile; (15)(R)-2-(3-((6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)-5-(4-methylpiperazine-1-yl)phenyl)-2-methylpropanenitrile; (16) (R)-N-(4-(4-methylpiperazine-1-yl)phenyl)-6-(3-(3-phenoxyphenyl)isoxazolidine-2-yl)pyrimidine-4-amine; (17)(R)-6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)-N-(4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (18)(R)-6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)-N-(4-(4-methylpiperazine-1-yl)phenyl)pyrimidine-4-amine; (19)(R)-N １ -(6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-yl)-N ４ -(2-(dimethylamino)ethyl)-N ４ -Methylbenzene-1,4-diamine; (20)(R)-6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)-N-(2-methoxy-5-methyl-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (21)(R)-6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)-N-(2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (22)(R)-6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)-N-(4-(4-(dimethylamino)piperidine-1-yl)-2-methoxyphenyl)pyrimidine-4-amine; (23)(R)-6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)-N-(4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)-3-(trifluoromethyl)phenyl)pyrimidine-4-amine; (24)(R)-6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)-N-(4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)-3-(methylsulfonyl)phenyl)pyrimidine-4-amine; (25)(R)-6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)-N-(5-ethyl-2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (26)(R)-6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)-N-(3-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (27)(R)-N-(2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)-6-(3-(3-(trifluoromethyl)phenyl)isoxazolidine-2-yl)pyrimidine-4-amine; (28)(R)-6-(3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidine-2-yl)-N-(2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (29)(R)-6-(3-(3-fluorophenyl)isoxazolidine-2-yl)-N-(2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (30)(R)-6-(3-(2,5-difluorophenyl)isoxazolidine-2-yl)-N-(2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (31)(R)-6-(3-(3-chloro-4-fluorophenyl)isoxazolidine-2-yl)-N-(2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (32)(R)-6-(3-(2,3-difluorophenyl)isoxazolidine-2-yl)-N-(2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (33)(R)-6-(3-(4-fluorophenyl)isoxazolidine-2-yl)-N-(2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (34)(R)-6-(3-(2,4-difluorophenyl)isoxazolidine-2-yl)-N-(2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (35)(R)-N-(2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)-6-(3-(thiophen-2-yl)isoxazolidine-2-yl)pyrimidine-4-amine; (36)(R)-N-(2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)-6-(3-(naphthalene-1-yl)isoxazolidine-2-yl)pyrimidine-4-amine; (37)(R)-6-(3-(3-ethynylphenyl)isoxazolidine-2-yl)-N-(2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (38)(R)-N-(2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)-6-(3-(6-methylpyridine-3-yl)isoxazolidine-2-yl)pyrimidine-4-amine; (39)(R)-6-(3-(3-([1,2,4]triazolo[1,5-a]pyridine-7-yl)phenyl)isoxazolidine-2-yl)-N-(4-(4-methylpiperazine-1-yl)phenyl)pyrimidine-4-amine; (40)(R)-6-(3-(3-fluoro-5-thiomorpholinophenyl)isoxazolidine-2-yl)-N-(4-(4-methylpiperazine-1-yl)phenyl)pyrimidine-4-amine; (41)(R)-N-(2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)-6-(3-(3-methoxyphenyl)isoxazolidine-2-yl)pyrimidine-4-amine; (42)(R)-6-(3-methyl-3-phenylisoxazolidine-2-yl)-N-(4-(4-methylpiperazine-1-yl)phenyl)pyrimidine-4-amine; (43) Isopropyl(R)-3-(2-(6-((4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)isoxazolidine-3-yl)benzoate; (44) (R)-N-cyclohexyl-3-(2-(6-((4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)isoxazolidine-3-yl)benzamide; (45)(R)-6-(3-(3',5-difluoro-[1,1'-biphenyl]-3-yl)isoxazolidine-2-yl)-N-(4-(4-methylpiperazine-1-yl)phenyl)pyrimidine-4-amine; (46)(R)-N,N-dimethyl-7-(2-methyl-4-((6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-yl)amino)phenyl)-7-azaspiro[3.5]nonane-2-amine; (47)(R)-N,N-dimethyl-2-(2-methyl-4-((6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-yl)amino)phenyl)-2-azaspiro[3.5]nonane-7-amine; (48)(R)-3-(1-methylpiperidine-4-yl)-N-(6-((R)-3-phenylisoxazolidine-2-yl)pyrimidine-4-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-amine; (49) (6aR,8S)-8-(4-cyclopropylpiperazine-1-yl)-2-methoxy-N-(6-((R)-3-phenylisoxazolidine-2-yl)pyrimidine-4-yl)-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazine-3-amine; (50) N-(4-(4-(5-ethylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)piperidine-1-yl)-2-methoxyphenyl)-6-((R)-3-phenylisooxazolidine-2-yl)pyrimidine-4-amine; (51)(R)-N-(2-methoxy-4-(4-((1-methylpiperidine-4-yl)amino)piperidine-1-yl)phenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (52)(R)-N-(2-methyl-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (53)(R)-N-(3-methyl-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (54)(R)-N-(4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (55)(R)-N-(2-ethoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (56) N-(4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)-2-(((R)-1,1,1-trifluoropropane-2-yl)oxy)phenyl)-6-((R)-3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (57) N-(2-methoxy-4-(4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)piperidine-1-yl)phenyl)-6-((R)-3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (58)(R)-N-(2-methoxy-4-(4-(oxetan-3-yl)piperazine-1-yl)phenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (59) N-(4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-methoxyphenyl)-6-((R)-3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (60)(R)-1-(4-(1-(3-methoxy-4-((6-(3-phenylisooxazolidine-2-yl)pyrimidine-4-yl)amino)phenyl)piperidine-4-yl)piperazine-1-yl)ethane-1-one; (61)(R)-N-(4-(4-(4-cyclopropyl-3,3-dimethylpiperazine-1-yl)piperidine-1-yl)-2-methoxyphenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (62)(R)-N-(2-methoxy-4-(4-(pyrrolidin-1-yl)piperidine-1-yl)phenyl)-6-(3-phenylisooxazolidine-2-yl)pyrimidine-4-amine; (63)(R)-N-(4-(4-(4-cyclopropylpiperazine-1-yl)-[1,4'-bipiperidine]-1'-yl)-2-methoxyphenyl)-6-(3-phenylisooxazolidine-2-yl)pyrimidine-4-amine; (64)(R)-N-(4-(2-(dimethylamino)ethoxy)-2-methoxyphenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (65)(R)-N-(4-((2-(dimethylamino)ethyl)thio)-2-methoxyphenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (66)(R)-N-(2-methoxy-4-thiomorpholinophenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (67)(R)-N-(2-methoxy-4-(4-methyl-1,4-diazepan-1-yl)phenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (68)(R)-N-(4-(4-allylpiperazine-1-yl)phenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (69) N-(4-((R)-3-(dimethylamino)pyrrolidine-1-yl)phenyl)-6-((R)-3-phenylisooxazolidine-2-yl)pyrimidine-4-amine; (70) N-(4-((S)-2-((dimethylamino)methyl)pyrrolidine-1-yl)phenyl)-6-((R)-3-phenylisooxazolidine-2-yl)pyrimidine-4-amine; (71)(R)-N-(1-(1-(2-(dimethylamino)ethyl)piperidine-4-yl)-1H-pyrazole-4-yl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (72)(R)-(4-methylpiperazine-1-yl)(4-((6-(3-phenylisooxazolidine-2-yl)pyrimidine-4-yl)amino)phenyl)methanone; (73)(R)-6-(3-phenylisooxazolidine-2-yl)-N-(3-(trifluoromethyl)phenyl)pyrimidine-4-amine; (74) N-(5-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-fluoropyridine-3-yl)-6-((R)-3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (75)(R)-1-(4-((6-(3-phenylisooxazolidine-2-yl)pyrimidine-4-yl)amino)phenyl)pyrrolidine-2-one; (76)(R)-2-methyl-5-((6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-yl)amino)isoindorin-1-one; (77)(R)-6-(3-phenylisooxazolidine-2-yl)-N-(4-(piperazine-1-yl)phenyl)pyrimidine-4-amine; (78) (R)-N-(6-(3-phenylisooxazolidine-2-yl)pyrimidine-4-yl)-1,2,3,4-tetrahydroisoquinoline-6-amine; (79)(R)-N-(5-(4-(dimethylamino)piperidine-1-yl)pyridine-2-yl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (80)(R)-N-(8-(1-methyl-1H-pyrazole-5-yl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (81)(R)-1-cyclopropyl-4-(3-methoxy-4-((6-(3-phenylisooxazolidine-2-yl)pyrimidine-4-yl)amino)phenyl)-1,4-azaphosfinan 4-oxide; (82) N-(4-((2R,6S)-2,6-dimethylmorpholino)phenyl)-6-((R)-3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (83) 6-((R)-3-phenylisooxazolidine-2-yl)-N-((R)-7-(pyrrolidine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)pyrimidine-4-amine; (84)(R)-N,N-dimethyl-1'-(4-((6-(3-phenylisooxazolidine-2-yl)pyrimidine-4-yl)amino)phenyl)-[1,4'-bipiperidine]-4-amine; (85)(R)-N-(5-((6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)-2-(4-(dimethylamino)-[1,4'-bipiperidine]-1'-yl)-4-methoxyphenyl)propionamide; (86) 3-Chloro-N-(5-((6-((R)-3-(3,5-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)-2-(4-(hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)piperidine-1-yl)-4-methoxyphenyl)propanamide; (87)(R)-N-(5-((6-(3-(2,4-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)-4-methoxy-2-(4-(4-methylpiperazine-1-yl)-[1,4'-bipiperidine]-1'-yl)phenyl)propionamide; (88)(R)-7-(5-methoxy-2-methyl-4-((6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-yl)amino)phenyl)-N,N-dimethyl-7-azaspiro[3.5]nonane-2-amine; (89)(R)-N-(2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)-6-(3-(naphthalene-2-yl)isoxazolidine-2-yl)pyrimidine-4-amine; (90)(R)-6-(3-(3,4-difluorophenyl)isoxazolidine-2-yl)-N-(2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (91)(R)-N-(5-ethyl-2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)-6-(3-(4-fluorophenyl)isoxazolidine-2-yl)pyrimidine-4-amine; (92)(R)-6-(3-(2,3-difluorophenyl)isoxazolidine-2-yl)-N-(5-ethyl-2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (93)(R)-6-(3-(2,4-difluorophenyl)isoxazolidine-2-yl)-N-(5-ethyl-2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (94)(R)-6-(3-(2,5-difluorophenyl)isoxazolidine-2-yl)-N-(5-ethyl-2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (95)(R)-6-(3-(2,4-difluorophenyl)isoxazolidine-2-yl)-N-(3-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (96)(R)-6-(3-(4-fluorophenyl)isoxazolidine-2-yl)-N-(3-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (97) N-(4-(4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)piperidine-1-yl)-2-methoxyphenyl)-6-((R)-3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (98)(R)-N-(4-(4-(diethylamino)piperidine-1-yl)-2-methoxyphenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (99) N-(2-methoxy-4-((R)-2-methyl-4-(1-methylpiperidine-4-yl)piperazine-1-yl)phenyl)-6-((R)-3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (100) Isopropyl(R)-3-(2-(6-((2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)isoxazolidine-3-yl)benzoate; (101)(R)-N-(2-methoxy-4-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)phenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (102)(R)-N-(3-methoxy-4-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)phenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (103)(R)-6-(3-(2,5-difluorophenyl)isoxazolidine-2-yl)-N-(3-methyl-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (104)(R)-6-(3-(2,4-difluorophenyl)isoxazolidine-2-yl)-N-(3-methyl-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (105)(R)-6-(3-(4-chloro-2-fluorophenyl)isoxazolidine-2-yl)-N-(3-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (106)(R)-6-(3-(2,5-difluorophenyl)isoxazolidine-2-yl)-N-(3-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (107)(R)-N-(3-methyl-4-(4-methylpiperazine-1-yl)phenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (108)(R)-N-(2-methyl-4-morpholinophenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (109)(R)-N-(5-ethyl-2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (110)(R)-N-(2-methoxy-4-morpholinophenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (111)(R)-N4-(2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-2,4-diamine; (112)(R)-N-(2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)-4-(3-phenylisoxazolidine-2-yl)-1,3,5-triazine-2-amine; (113)(R)-2-methoxy-N4-(1-methylpiperidine-4-yl)-N1-(6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-yl)benzene-1,4-diamine; (114)(R)-N-(2-methoxy-5-methyl-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (115)(R)-1'-(3-methoxy-4-((6-(3-phenylisooxazolidine-2-yl)pyrimidine-4-yl)amino)phenyl)-N,N-dimethyl-[1,4'-bipiperidine]-4-amine; (116) N-(4-(4-((1R,4R)-5-ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)piperidine-1-yl)-2-methoxyphenyl)-6-((R)-3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (117)(R)-N-(3-ethyl-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (118)(R)-N-(4-(4-(4-ethylpiperazine-1-yl)piperidine-1-yl)-2-methoxyphenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (119)(R)-N-(4-(4-(dimethylamino)piperidine-1-yl)-2-methoxyphenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (120)(R)-N-(2-methoxy-4-(4-morpholinopiperidine-1-yl)phenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (121)(R)-2-(4-(1-(2-methoxy-4-((6-(3-phenylisooxazolidine-2-yl)pyrimidine-4-yl)amino)phenyl)piperidine-4-yl)piperazine-1-yl)ethane-1-ol; (122)(R)-1-(4-(4-((6-(3-phenylisooxazolidine-2-yl)pyrimidine-4-yl)amino)phenyl)piperazine-1-yl)ethane-1-one; (123)(R)-N-(3,5-difluoro-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (124)(R)-N-(4-(4-(oxetan-3-yl)piperazine-1-yl)phenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (125)(R)-6-(3-(3-chloro-2-fluorophenyl)isoxazolidine-2-yl)-N-(3-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (126)(R)-6-(3-(2,3-difluorophenyl)isoxazolidine-2-yl)-N-(3-methyl-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (127)(R)-N-(4-(4-(dimethylamino)piperidine-1-yl)phenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (128)(R)-6-(3-(2,3-difluorophenyl)isoxazolidine-2-yl)-N-(3-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (129)(R)-6-(3-(4-chloro-3-fluorophenyl)isoxazolidine-2-yl)-N-(2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (130)(R)-6-(3-(3-chloro-2,4-difluorophenyl)isoxazolidine-2-yl)-N-(2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (131)(R)-6-(3-(3-(dimethylamino)phenyl)isoxazolidine-2-yl)-N-(2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (132)(R)-N-(5-chloro-2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (133)(R)-N-(1-methyl-1H-pyrazole-4-yl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (134) tert-butyl(R)-7-((6-(3-phenylisooxazolidine-2-yl)pyrimidine-4-yl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate; (135)(R)-N-(4-(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)phenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (136) N-(4-(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)phenyl)-6-((R)-3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (137)(R)-3-(3-methoxy-4-((6-(3-phenylisooxazolidine-2-yl)pyrimidine-4-yl)amino)phenyl)oxazolidine-2-one; (139)(R)-N-(4-(4-methylpiperazine-1-yl)-3-(2,2,2-trifluoroethoxy)phenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (140) 6-((R)-3-(2,3-difluorophenyl)isoxazolidine-2-yl)-N-(4-(3-fluoro-4-(4-methylpiperazine-1-yl)piperidine-1-yl)-2-methoxyphenyl)pyrimidine-4-amine; (141)(R)-6-(3-(2,3-difluorophenyl)isoxazolidine-2-yl)-N-(2-methoxy-4-(1-methylpiperidine-4-yl)phenyl)pyrimidine-4-amine; (142)(R)-6-(3-(2,3-difluorophenyl)isoxazolidine-2-yl)-N-(5-isopropyl-2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (143)(R)-N-(5-cyclopropyl-2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (144)(R)-N-(4-(4-methylpiperazine-1-yl)-2-(3-((methylsulfonyl)methyl)azetidine-1-yl)phenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (145)(R)-1-(5-((6-(3-(2,3-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)-4-methoxy-2-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)ethane-1-one; (146)(R,E)-1-(5-((6-(3-(2,3-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)-4-methoxy-2-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)ethane-1-one O-methyloxime; (147)(R)-N-(2-methoxy-5-(1-methyl-1H-pyrazole-4-yl)-6-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)pyridine-3-yl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (148)(R)-6-(3-(4-fluorophenyl)isoxazolidine-2-yl)-N-(2-methoxy-5-(1-methyl-1H-pyrazole-4-yl)-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (149)(R)-6-(3-(2,3-difluorophenyl)isoxazolidine-2-yl)-N-(2-methoxy-5-(1-methyl-1H-pyrazole-4-yl)-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (150)(R)-N-(6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-6'-amine; (151)(R)-6'-((6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'-one; (152)(R)-1-(6-((6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)-5-methoxy-1'-methylspiro[indoline-3,4'-piperidine]-1-yl)-2,2,2-trifluoroethane-1-one; (153)(R)-6-((6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)-7-methoxyspiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one; (154)(R)-N-(6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-yl)-5-methoxy-1'-methylspiro[indoline-3,4'-piperidine]-6-amine; (155)(R)-6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)-N-(4-(1-methylpiperidine-4-yl)-2,3-dihydrobenzofuran-7-yl)pyrimidine-4-amine; (156)(R)-N-(6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-yl)-3-methoxy-7-(4-methylpiperazine-1-yl)-9H-carbazole-2-amine; (157)(R)-6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)-N-(4-(piperidine-4-yl)-2,3-dihydrobenzofuran-7-yl)pyrimidine-4-amine; (158)(R)-6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)-N-(4-(1-methyl-1H-pyrazole-5-yl)-2,3-dihydrobenzofuran-7-yl)pyrimidine-4-amine; (159)(R)-6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)-N-(2,3-dihydrobenzofuran-7-yl)pyrimidine-4-amine; (160)(R)-6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)-N-(4-(1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)-2,3-dihydrobenzofuran-7-yl)pyrimidine-4-amine; (161)(R)-N-(2-(4-(4-cyclopropylpiperazine-1-yl)piperidine-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)-4-methoxyphenyl)propionamide; (162)(R)-N-(5-(1-methyl-1H-pyrazole-4-yl)-4-(4-methylpiperazine-1-yl)-2,3-dihydrobenzofuran-7-yl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (163)(R)-N-(2-(4-(4-cyclopropylpiperazine-1-yl)piperidine-1-yl)-4-methoxy-5-((6-(3-(thiophen-2-yl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)phenyl)propionamide; (164)(R)-N-(5-(1-methyl-1H-pyrazole-4-yl)-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)-2-(2,2,2-trifluoroethoxy)phenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (165)(R)-N-(5-(1-methyl-1H-pyrazole-4-yl)-4-(4-morpholinopiperidine-1-yl)-2-(2,2,2-trifluoroethoxy)phenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (166)(R)-N-(5-(1-methyl-1H-pyrazole-4-yl)-4-(4-methylpiperazine-1-yl)-2-(2,2,2-trifluoroethoxy)phenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (167)(R)-N-(5-(1-methyl-1H-pyrazole-4-yl)-4-morpholino-2-(2,2,2-trifluoroethoxy)phenyl)-6-(3-phenylisoxazolidine-2-yl)pyrimidine-4-amine; (168)(S)-6-(3-(5-fluoropyridine-3-yl)isoxazolidine-2-yl)-N-(2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (169)(R)-6-(3-(5-fluoropyridine-3-yl)isoxazolidine-2-yl)-N-(2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (170)(R)-3-fluoro-5-(2-(6-((2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)isoxazolidine-3-yl)benzonitrile; (171)(S)-3-fluoro-5-(2-(6-((2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)isoxazolidine-3-yl)benzonitrile; (172) tert-butyl(R)-3-(4-((6-((R)-3-(2,3-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)phenyl)isoxazolidine-2-carboxylate; (173) 6-((R)-3-(2,3-difluorophenyl)isoxazolidine-2-yl)-N-(4-((R)-2-methylisoxazolidine-3-yl)phenyl)pyrimidine-4-amine; (174) 6-((R)-3-(2,3-difluorophenyl)isoxazolidine-2-yl)-N-(4-((R)-isoxazolidine-3-yl)phenyl)pyrimidine-4-amine; (175) tert-butyl(S)-3-(4-((6-((R)-3-(2,3-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)phenyl)isoxazolidine-2-carboxylate; (176) 6-((R)-3-(2,3-difluorophenyl)isoxazolidine-2-yl)-N-(4-((S)-2-methylisoxazolidine-3-yl)phenyl)pyrimidine-4-amine; (177) 6-((R)-3-(2,3-difluorophenyl)isoxazolidine-2-yl)-N-(4-((S)-isoxazolidine-3-yl)phenyl)pyrimidine-4-amine; (178)(R)-6-(3-(1-methyl-1H-pyrazole-4-yl)isoxazolidine-2-yl)-N-(4-(4-methylpiperazine-1-yl)phenyl)pyrimidine-4-amine; (179)(R)-6-(3-(furan-2-yl)isoxazolidine-2-yl)-N-(4-(4-methylpiperazine-1-yl)phenyl)pyrimidine-4-amine; (180)(R)-6-(3-(5-chloropyridine-3-yl)isoxazolidine-2-yl)-N-(4-(4-methylpiperazine-1-yl)phenyl)pyrimidine-4-amine; (181)(S)-6-(3-(5-chloropyridine-3-yl)isoxazolidine-2-yl)-N-(4-(4-methylpiperazine-1-yl)phenyl)pyrimidine-4-amine; (182)(R)-6-(3-(5-chloropyridine-3-yl)isoxazolidine-2-yl)-N-(2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (183)(S)-6-(3-(5-chloropyridine-3-yl)isoxazolidine-2-yl)-N-(2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (184)(R)-6-(3-(3-(difluoromethyl)phenyl)isoxazolidine-2-yl)-N-(2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (185)(S)-6-(3-(3-(difluoromethyl)phenyl)isoxazolidine-2-yl)-N-(2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (186) tert-butyl(R)-3-(3-((6-((R)-3-(2,3-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)phenyl)isoxazolidine-2-carboxylate; (187) tert-butyl(S)-3-(3-((6-((R)-3-(2,3-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)phenyl)isoxazolidine-2-carboxylate; (188)(R)-N-(6-(3-(2,3-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-yl)cyclopropanecarboxamide; (189)(R)-N-(6-(3-(2,3-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-yl)benzamide; (190)(R)-N-(cyclopentylmethyl)-6-(3-(2,3-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-amine; (191)(R)-6-(3-(2,3-difluorophenyl)isoxazolidine-2-yl)-N-(4-fluorobenzyl)pyrimidine-4-amine; (192)(R)-6-(3-(2,3-difluorophenyl)isoxazolidine-2-yl)-N-(1-(methylsulfonyl)piperidine-4-yl)pyrimidine-4-amine; (193)(R)-6-((6-(3-(2,3-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)-5-methoxy-2-methylisoindoline-1-one; (194)(R)-3-((6-(3-(2,3-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)-1H-indazole-6-carbonitrile; (195)(R)-6-(3-(2,3-difluorophenyl)isoxazolidine-2-yl)-N-(4-(9-(1-fluoro-2-methylpropane-2-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-2-methoxy-5-(1-methyl-1H-pyrazole-4-yl)phenyl)pyrimidine-4-amine; (196)(R)-N-(2,5-dichloro-4-(9-(1-fluoro-2-methylpropan-2-yl)-3,9-diazaspiro[5.5]undecane-3-yl)phenyl)-6-(3-(2,3-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-amine; (197)(R)-6-(3-(2,3-difluorophenyl)isoxazolidine-2-yl)-N-(3-methyl-5-(3-((methylsulfonyl)methyl)azetidine-1-yl)-4-(4-morpholinopiperidine-1-yl)phenyl)pyrimidine-4-amine; (198)(R)-N-(5-(3-chloro-1-methyl-1H-pyrazole-4-yl)-2-methoxy-4-(4-methylpiperazine-1-yl)phenyl)-6-(3-(2,3-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-amine; (199)(R)-6-(3-(2,3-difluorophenyl)isoxazolidine-2-yl)-N-(2-methoxy-4-(4-methylpiperazine-1-yl)-5-vinylphenyl)pyrimidine-4-amine; (200)(R)-6-(3-(2,3-difluorophenyl)isoxazolidine-2-yl)-N-(5-ethynyl-2-methoxy-4-(4-methylpiperazine-1-yl)phenyl)pyrimidine-4-amine; (201)(R)-6-(3-(2,3-difluorophenyl)isoxazolidine-2-yl)-N-(3-methoxy-6-(1-methyl-1H-pyrazole-4-yl)-5-(4-methylpiperazine-1-yl)pyridine-2-yl)pyrimidine-4-amine; (202)(R)-6-(3-(2,3-difluorophenyl)isoxazolidine-2-yl)-N-(2-methoxy-5-(1-methyl-1H-pyrazole-4-yl)-6-(4-methylpiperazine-1-yl)pyridine-3-yl)pyrimidine-4-amine; (203) 6-((R)-3-(2,3-difluorophenyl)isoxazolidine-2-yl)-N-(3-(1-methyl-1H-pyrazole-4-yl)-5-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidine-1-yl)-4-morpholinophenyl)pyrimidine-4-amine; (204)(R)-6-(3-(2,3-difluorophenyl)isoxazolidine-2-yl)-N4-(2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)-N2-methylpyrimidine-2,4-diamine; (205)(R)-4-(3-(2,3-difluorophenyl)isoxazolidine-2-yl)-N-(2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyridine-2-amine; (206)(R)-N-(4-(4-(4-allylpiperazine-1-yl)piperidine-1-yl)-2-methoxyphenyl)-6-(3-(2,3-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-amine; (207)(R)-6-(3-(2,3-difluorophenyl)isoxazolidine-2-yl)-N-(4-(4-(4-ethylpiperazine-1-yl)piperidine-1-yl)-2-methoxyphenyl)pyrimidine-4-amine; (208)(R)-N-(4-(4-(4-cyclobutylpiperazine-1-yl)piperidine-1-yl)-2-methoxyphenyl)-6-(3-(2,3-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-amine; (209)(R)-6-(3-(2,3-difluorophenyl)isoxazolidine-2-yl)-N-(2-methoxy-4-(4-(4-(oxetan-3-yl)piperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (210)(R)-N-(4-(4-(4-(cyclopropylmethyl)piperazine-1-yl)piperidine-1-yl)-2-methoxyphenyl)-6-(3-(2,3-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-amine; (211)(R)-6-(3-(2,3-difluorophenyl)isoxazolidine-2-yl)-N-(2-methoxy-4-(4-(6-methyl-2,6-diazaspiro[3,3]heptan-2-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (212) 6-((R)-3-(2,3-difluorophenyl)isoxazolidine-2-yl)-N-(4-(4-((R)-3-(dimethylamino)pyrrolidine-1-yl)piperidine-1-yl)-2-methoxyphenyl)pyrimidine-4-amine; (213) 6-((R)-3-(2,3-difluorophenyl)isoxazolidine-2-yl)-N-(4-(4-((R)-3,4-dimethylpiperazine-1-yl)piperidine-1-yl)-2-methoxyphenyl)pyrimidine-4-amine; (214) 6-((R)-3-(2,3-difluorophenyl)isoxazolidine-2-yl)-N-(4-(4-((S)-3,4-dimethylpiperazine-1-yl)piperidine-1-yl)-2-methoxyphenyl)pyrimidine-4-amine; (215) 6-((R)-3-(2,3-difluorophenyl)isoxazolidine-2-yl)-N-(4-(4-((3S,5R)-4-ethyl-3,5-dimethylpiperazine-1-yl)piperidine-1-yl)-2-methoxyphenyl)pyrimidine-4-amine; (216) 6-((R)-3-(2,3-difluorophenyl)isoxazolidine-2-yl)-N-(4-(4-((S)-2,4-dimethylpiperazine-1-yl)piperidine-1-yl)-2-methoxyphenyl)pyrimidine-4-amine; (217) 6-((R)-3-(2,3-difluorophenyl)isoxazolidine-2-yl)-N-(4-(4-((R)-2,4-dimethylpiperazine-1-yl)piperidine-1-yl)-2-methoxyphenyl)pyrimidine-4-amine; (218)(R)-6-(3-(2,3-difluorophenyl)isoxazolidine-2-yl)-N-(2-methoxy-4-(3-(4-methylpiperazine-1-yl)azetidine-1-yl)phenyl)pyrimidine-4-amine; (219) 6-((R)-3-(2,3-difluorophenyl)isoxazolidine-2-yl)-N-(4-(4-(6-ethyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)piperidine-1-yl)-2-methoxyphenyl)pyrimidine-4-amine; (220) 6-((R)-3-(2,3-difluorophenyl)isoxazolidine-2-yl)-N-(4-(4-(3-ethyl-3,6-diazabicyclo[3.1.1]heptan-6-yl)piperidine-1-yl)-2-methoxyphenyl)pyrimidine-4-amine; (221)(R)-6-(3-(2,3-difluorophenyl)isoxazolidine-2-yl)-N-(2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine; (222)(R)-6-(3-(2,3-difluorophenyl)isoxazolidine-2-yl)-N-(4-(4-(4-isopropylpiperazine-1-yl)piperidine-1-yl)-2-methoxyphenyl)pyrimidine-4-amine; (223)(R)-1-(1-(4-((6-(3-(2,3-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)-3-methoxyphenyl)piperidine-4-yl)-4-methylpiperazine-2-one; (224)(R)-4-(1-(4-((6-(3-(2,3-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)-3-methoxyphenyl)piperidine-4-yl)-1-methylpiperazine-2-one; (225)(R)-1-methyl-5-(2-(6-((4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)isoxazolidine-3-yl)pyridine-2(1H)-one; (226)(R)-5-(2-(6-((2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)isoxazolidine-3-yl)-1-methylpyridine-2(1H)-one; (227)(S)-1-methyl-5-(2-(6-((4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)isoxazolidine-3-yl)pyridine-2(1H)-one; (228)(S)-5-(2-(6-((2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)isoxazolidine-3-yl)-1-methylpyridine-2(1H)-one; (229) N-(4-(4-methylpiperazine-1-yl)phenyl)-6-(3-phenylbenzo[d]isoxazole-2(3H)-yl)pyrimidine-4-amine; (230) N-(2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)-6-(3-phenylbenzo[d]isoxazole-2(3H)-yl)pyrimidine-4-amine; (231)(S)-N-(4-(4-methylpiperazine-1-yl)phenyl)-6-(7-phenyl-5-oxa-6-azaspiro[2.4]heptan-6-yl)pyrimidine-4-amine; (232)(R)-N-(4-(4-methylpiperazine-1-yl)phenyl)-6-(7-phenyl-5-oxa-6-azaspiro[2.4]heptan-6-yl)pyrimidine-4-amine; (233)(S)-N-(2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)-6-(7-phenyl-5-oxa-6-azaspiro[2.4]heptan-6-yl)pyrimidine-4-amine; (234)(R)-N-(2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)-6-(7-phenyl-5-oxa-6-azaspiro[2.4]heptan-6-yl)pyrimidine-4-amine; (235)(R)-6-(3-isopropylisoxazolidine-2-yl)-N-(4-(4-methylpiperazine-1-yl)phenyl)pyrimidine-4-amine; (236)(S)-6-(3-isopropylisoxazolidine-2-yl)-N-(4-(4-methylpiperazine-1-yl)phenyl)pyrimidine-4-amine; and (237)(R)-6-(3-(2,3-difluorophenyl)isoxazolidine-2-yl)-N-(2-methoxy-4-(4-(4-(2-(methylsulfonyl)ethyl)piperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4-amine.

8. A pharmaceutical composition for the prevention or treatment of cancer, comprising as an active ingredient a compound according to any one of claims 1 to 7, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

9. The pharmaceutical composition according to claim 8, which inhibits EGFR and / or HER2.

10. EGFR Del19 / C797S, EGFR L858R / C797S, EGFR L861Q, EGFR G719A, EGFR S768I, EGFR L718Q, EGFR G724S, EGFR d746-750, EGFR d746-750 / C797A, EGFR d746-750 / C797S, EGFR d746-750 / T790M / C797S, EGFR D761Y, EGFR G719C, EGFR G719D, EGFR G719S, EGFR L747S, EGFR L792F, EGFR L858R, EGFR The pharmaceutical composition according to claim 9, which inhibits one or more selected from the group consisting of L792F / L858R, ERBB2 / HER2, and ERBB4 / HER4.

11. The aforementioned cancers include pseudomyxoma, intrahepatic biliary tract cancer, 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, ovarian epithelial carcinoma, ovarian germ cell carcinoma, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla of Vater cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal cavity / 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, kidney cancer, heart cancer, duodenal cancer, and malignant soft cell carcinoma. The pharmaceutical composition according to claim 8, comprising one or more selected from the group consisting of tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary origin, gastric lymphoma, gastric cancer, gastric carcinoid tumor, gastrointestinal stromal cancer, Wilms' tumor, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid cancer, vaginal cancer, spinal cord cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, squamous cell lung cancer, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, hematological cancer, and thymic cancer.

12. A pharmaceutical composition for treating or preventing EGFR and / or HER2-related diseases, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 7, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

13. Use of a compound according to any one of claims 1 to 7, an optical isomer thereof, or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical for use in the treatment or prevention of EGFR and / or HER2-related diseases.

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