Heteroaryl derivative compounds and uses thereof

Abstract

The present invention relates to heteroaryl derivatives and uses thereof. The heteroaryl derivatives of the present invention exhibit excellent inhibitory activity against EGFR and / or HER2, and can therefore be useful as therapeutic agents for the aforementioned EGFR- and / or HER2-related diseases.

Description

[Technical Field]

[0001] The present invention relates to heteroaryl derivative compounds and their pharmaceutical uses. 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 signal transduction pathways. The switching of target proteins between active and inactive states by kinases within cells must be smoothly regulated. If this switching between active and inactive states is abnormally regulated, intracellular signal transduction is excessively activated or inactivated, leading to uncontrolled cell division and proliferation. In particular, abnormal activation due to mutation, amplification, and / or overexpression of protein kinase genes plays a crucial role in the development and progression of various tumors and in the pathogenesis of various diseases, including inflammatory diseases, degenerative brain diseases, and autoimmune diseases.

[0003] The epidermal growth factor receptor (EGFR), a receptor tyrosine kinase of the ErbB family, is abnormally activated in many epithelial cell tumors, including non-small cell lung cancer (NSCLC), breast cancer, glioma, head and neck squamous cell carcinoma, colorectal cancer, rectal adenocarcinoma, head and neck cancer, gastric cancer, and prostate cancer. EGFR tyrosine kinase activation is known to induce sustained cell proliferation, invasion into surrounding tissues, distant metastasis, angiogenesis, and enhance cell survival.

[0004] Additionally, EGFR mutations, EGFR Del19 and EGFR L858R, are known to be the primary causes of non-small cell lung cancer and head and neck cancer. Drugs, such as Iressa and Tarceva, have been developed and are currently in clinical use. However, when these drugs are administered to patients, acquired resistance, which occurs through secondary EGFR mutations based on the drug structure, has been observed. It has also been revealed that this is the primary cause of actual drug resistance. After an average of 10 months of treatment with first-generation EGFR inhibitors, acquired resistance, known as the T790M mutation located in the EGFR kinase gatekeeper, occurs, rendering the first-generation EGFR inhibitors ineffective. Specifically, the development of EGFR Del19 / T790M or EGFR L858R / T790M double mutations renders conventional treatments ineffective. Osimertinib, a third-generation EGFR-TKI drug with high efficacy against EGFR T790M mutation-induced drug resistance, has been developed, but it has been reported that this drug resistance can occur (Niederst MJ et al., Clin Cancer Res, 2015, 17(21):3924-3933). The EGFR C797S mutation has been proposed as one of the major mechanisms of drug resistance to osimertinib, with approximately 40% of clinical trial patients reported to 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 (EGFR LC) could be the primary targets.

[0005] In addition, rare EGFR mutations (rare or uncommon) and drug-resistant mutations such as L861Q, G719A, S768I, L718Q, or G724S 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, and forms homodimers with other EGFR receptors, HER1 (EGFR, ErbB1), HER3 (ErbB3), or HER4 (ErbB4). It is activated by autophosphorylation at intracellular tyrosine residues and plays an important role in cell proliferation, differentiation, and survival in normal and cancer cells (Di Fiore PP. et al., Science. 1987, 237(481):178-182). HER2 is known to be overexpressed in various carcinomas, such as 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 an unmet need for novel compounds that can be effectively used to treat EGFR- and / or HER2-associated diseases by modulating EGFR activity (especially C797S mutations such as EGFR Del19 / C797S, EGFR L858R / C797S, rare EGFR mutations, or drug resistance mutations) and / or HER2. Summary of the Invention [Problem to be solved by the invention]

[0008] An object of the present invention is to provide a heteroaryl derivative having a novel structure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0009] Another object of the present invention is to provide a method for preparing said heteroaryl derivative compounds.

[0010] Another object of the present invention is to provide a pharmaceutical use of the heteroaryl derivative compound, specifically, to provide a pharmaceutical composition for treating or preventing EGFR- and / or HER2-related diseases, which contains the heteroaryl derivative compound as an active ingredient, a use of the compound for treating or preventing EGFR- and / or HER2-related diseases, or a method for treating or preventing EGFR- and / or HER2-related diseases, which comprises administering the compound. [Means for solving the problem]

[0011] To achieve the above object, the present inventors have conducted extensive research and have found that heteroaryl derivative compounds represented by the following formulas 1, 2, 2a, 2b, or 3 inhibit the proliferation of EGFR- and / or HER2-activated cells, thereby completing the present invention.

[0012] Heteroaryl derivative compounds The present invention provides a compound represented by the following formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula 1, X is CH or O; R1 and R2 are each independently -H, -C 1-6 Alkyl, -C 1-6 haloalkyl, or -halo; R3 is -H, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -OC 1-6 Alkyl, or -OC 1-3 alkyl-OH, {wherein R3 can be linked to a carbon atom in the phenyl ring to form a fused ring, or can be linked to R4 to form a fused ring}; R4 is -H, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6alkyl), -(4- to 6-membered heterocycloalkyl), or -(7- to 11-membered heterobicycloalkyl) {wherein the -NH(C 1-6 alkyl) or -N(C 1-6 Alkyl)(C 1-6 and -(4- to 6-membered heterocycloalkyl) can be linked to ring Y to form a fused ring; one or more H of said -(4- to 6-membered heterocycloalkyl) can be -C 1-6 Alkyl, -C 1-6 Haloalkyl, -(CH2)nOC 1-6 Alkyl, -(CH2)n-NR a R b , -(CH2)nS(=O)2-C 1-3 and optionally substituted with alkyl, -halo, -(CH2)n-(4- to 6-membered heterocycloalkyl), or -(CH2)n-(7- to 11-membered heterobicycloalkyl), wherein one or more H in said -(CH2)n-(4- to 6-membered heterocycloalkyl) or -(CH2)n-(7- to 11-membered heterobicycloalkyl) ring is replaced by -C 1-6 Alkyl, -C 1-6 Haloalkyl, -(CH2)nOC 1-6 Alkyl, -(CH2)nC(=O)-C 1-3 Alkyl, -(CH2)nS(=O)2-C 1-3 Alkyl, -(CH2)nNR a R b or -halo]; one or more H in said -(7- to 11-membered heterobicycloalkyl) may be substituted with -C 1-6 Alkyl, -C 1-6 Haloalkyl, -(CH2)nC(=O)-C 1-3 Alkyl, -(CH2)nC(=O)-(3- to 6-membered cycloalkyl), -(CH2)nS(=O)2-C 1-3 Alkyl, -(CH2)n-NR a R b , -OC 1-6 and optionally substituted with alkyl, -halo, or -(CH2)n-(4- to 6-membered heterocycloalkyl) [wherein one or more H in the -(CH2)n-(4- to 6-membered heterocycloalkyl) or -(CH2)nC(=O)-(3- to 6-membered cycloalkyl) ring is replaced by -C1-6 Alkyl, -C 1-6 optionally substituted with haloalkyl, or -halo]}; n is 0, 1, 2, 3, or 4; R a and R b are independently -H, -C 1-6 Alkyl, -C 1-6 haloalkyl, or -(4-6 membered heterocycloalkyl); Ring Y is phenyl or 5-10 membered heteroaryl {wherein one or more H in said phenyl or 5-10 membered heteroaryl ring is -C 1-6 Alkyl, -C 1-6 Hydroxyalkyl, -C 1-6 optionally substituted with haloalkyl, -(3- to 6-membered cycloalkyl), or -halo}.

[0013] According to an embodiment of the present invention, the compound represented by Formula 1 can be in the following ranges: X is CH or O; R1 and R2 are each independently -H or -halo; R3 is -H, -C 1-3 Haloalkyl, -OC 1-3 Alkyl, or -OC 1-3 alkyl-OH, {wherein R3 can be linked to a carbon atom in the phenyl ring to form a fused ring, or can be linked to R4 to form a fused ring}; R4 is -H, -N(C 1-3 Alkyl)(C 1-3 alkyl), -(4- to 6-membered heterocycloalkyl), or -(7- to 11-membered heterobicycloalkyl) {wherein the -N(C 1-3 Alkyl)(C 1-3 and -(4- to 6-membered heterocycloalkyl) can be linked to ring Y to form a fused ring; one or more H of said -(4- to 6-membered heterocycloalkyl) can be -C 1-6 Alkyl, -C 1-6 Haloalkyl, -(CH2)nOC 1-3 Alkyl, -(CH2)n-NR a R b, -(CH2)nS(=O)2-C 1-3 and optionally substituted with alkyl, -halo, -(CH2)n-(4- to 6-membered heterocycloalkyl), or -(CH2)n-(7- to 11-membered heterobicycloalkyl), wherein one or more H in said -(CH2)n-(4- to 6-membered heterocycloalkyl) or -(CH2)n-(7- to 11-membered heterobicycloalkyl) ring is replaced by -C 1-3 Alkyl, -C 1-6 Haloalkyl, -(CH2)nOC 1-3 Alkyl, -(CH2)nS(=O)2-C 1-3 Alkyl, -(CH2)nNR a R b or -halo]; one or more H in said -(7- to 11-membered heterobicycloalkyl) may be substituted with -C 1-3 Alkyl, -C 1-6 Haloalkyl, -(CH2)nC(=O)-C 1-3 Alkyl, -(CH2)nC(=O)-(3- to 6-membered cycloalkyl), -(CH2)nS(=O)2-C 1-3 Alkyl, -(CH2)n-NR a R b , -OC 1-3 optionally substituted with alkyl, -halo, or -(CH2)n-(4- to 6-membered heterocycloalkyl) [wherein one or more H in the -(CH2)n-(4- to 6-membered heterocycloalkyl) or -(CH2)nC(=O)-(3- to 6-membered cycloalkyl) ring is optionally substituted with -halo]; n is 0, 1, 2, or 3; R a and R b are independently -H, -C 1-3 Alkyl, -C 1-6 haloalkyl, or -(4-6 membered heterocycloalkyl); Ring Y is phenyl, 5- to 6-membered heteroaryl, or 9- to 10-membered heteroaryl {wherein one or more H in the phenyl, 5- to 6-membered heteroaryl, or 9- to 10-membered heteroaryl ring is -C 1-3 Alkyl, -C 1-3optionally substituted with hydroxyalkyl, -(3- to 6-membered cycloalkyl), or -halo}.

[0014] According to an embodiment of the present invention, the compound represented by Formula 1 can be in the following ranges: The aforementioned [ka] is.

[0015] According to an embodiment of the present invention, the compound represented by Formula 1 can be in the following ranges: The ring Y is [ka] wherein one or more H in the ring Y is -C 1-3 Alkyl, -C 1-3 Hydroxyalkyl, -C 1-3 optionally substituted with haloalkyl, -(3- to 6-membered cycloalkyl), or -halo}.

[0016] The present invention also provides a compound represented by the following formula 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula 2, X is CH or O; R1 and R2 are each independently -H or -halo; R3 is -H, -C 1-3 Haloalkyl, -OC 1-3 Alkyl, or -OC 1-3 alkyl-OH, {wherein R3 can be linked to a carbon atom in the phenyl ring to form a fused ring, or can be linked to R4 to form a fused ring}; R4 is -H, -N(C 1-3 Alkyl)(C 1-3alkyl), -(4- to 6-membered heterocycloalkyl), or -(7- to 11-membered heterobicycloalkyl) {wherein the -N(C 1-3 Alkyl)(C 1-3 and -(4- to 6-membered heterocycloalkyl) can be linked to ring Y to form a fused ring; one or more H of said -(4- to 6-membered heterocycloalkyl) can be -C 1-6 Alkyl, -C 1-6 Haloalkyl, -(CH2)nOC 1-3 Alkyl, -(CH2)n-NR a R b , -(CH2)nS(=O)2-C 1-3 and optionally substituted with alkyl, -halo, -(CH2)n-(4- to 6-membered heterocycloalkyl), or -(CH2)n-(7- to 11-membered heterobicycloalkyl), wherein one or more H in said -(CH2)n-(4- to 6-membered heterocycloalkyl) or -(CH2)n-(7- to 11-membered heterobicycloalkyl) ring is replaced by -C 1-3 Alkyl, -C 1-6 Haloalkyl, -(CH2)nOC 1-3 Alkyl, -(CH2)nS(=O)2-C 1-3 Alkyl, -(CH2)nNR a R b or -halo]; one or more H in said -(7- to 11-membered heterobicycloalkyl) may be substituted with -C 1-3 Alkyl, -C 1-6 Haloalkyl, -(CH2)nC(=O)-C 1-3 Alkyl, -(CH2)nC(=O)-(3- to 6-membered cycloalkyl), -(CH2)nS(=O)2-C 1-3 Alkyl, -(CH2)n-NR a R b , -OC 1-3 optionally substituted with alkyl, -halo, or -(CH2)n-(4- to 6-membered heterocycloalkyl) [wherein one or more H in the -(CH2)n-(4- to 6-membered heterocycloalkyl) or -(CH2)nC(=O)-(3- to 6-membered cycloalkyl) ring is optionally substituted with -halo]; n is 0, 1, 2, or 3; Ra and R b are independently -H, -C 1-3 Alkyl, -C 1-6 haloalkyl, or -(4-6 membered heterocycloalkyl); Ring Y is phenyl, 5- to 6-membered heteroaryl, or 9- to 10-membered heteroaryl {wherein one or more H in the phenyl, 5- to 6-membered heteroaryl, or 9- to 10-membered heteroaryl ring is -C 1-3 Alkyl, -C 1-3 optionally substituted with hydroxyalkyl, -(3- to 6-membered cycloalkyl), or -halo}.

[0017] The present invention also provides a compound represented by the following formula 2a, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula 2a, X, R1, R2, R3, R4, and ring Y are as defined in the formula 2.

[0018] The present invention also provides a compound represented by the following formula 2b, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula 2b, X, R1, R2, R3, R4, and ring Y are as defined in the formula 2.

[0019] The present invention also provides a compound represented by the following formula 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula 3, X is CH or O; R1 and R2 are each independently -H or -halo; R4 is -(4- to 6-membered heterocycloalkyl) or -(7- to 11-membered heterobicycloalkyl) {wherein one or more H in the -(4- to 6-membered heterocycloalkyl) or -(7- to 11-membered heterobicycloalkyl) ring is -C 1-3 Alkyl, -C 1-3 Haloalkyl, -(CH2)nS(=O)2-C 1-3 optionally substituted with alkyl, or -halo}; n is 0, 1, or 2; Ring Y is a 5-membered heteroaryl {wherein one or more H in said 5-membered heteroaryl ring is -C 1-3 optionally substituted with alkyl or -halo}.

[0020] According to an embodiment of the present invention, the compound represented by formula 1, 2, 2a, 2b, or 3 may be selected from the group consisting of the compounds listed in Table 1 below.

[0021] In the present invention, unless otherwise specified, "alkyl" can mean a straight or branched chain acyclic, cyclic, or saturated hydrocarbon having these combined thereto. For example, "C 1-6 "Alkyl" may refer to an alkyl containing 1 to 6 carbon atoms. Examples of acyclic alkyl include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, isopropyl, secondary (sec)-butyl, isobutyl, or tertiary (tert)-butyl. Examples of cyclic alkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[0022] In the present invention, "alkoxy" can refer to an alkyl ether group, -(O-alkyl), where alkyl is as defined above. For example, "C 1-6 "Alkoxy" means C 1-6Alkoxy containing alkyl, i.e., -(OC 1-6 Alkoxy can refer to alkoxy groups, and by way of example, alkoxy can include, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, and the like.

[0023] In the present invention, "halo" may be F, Cl, Br, or I.

[0024] In the present invention, the term "haloalkyl" refers to a straight or branched chain alkyl (hydrocarbon) having carbon atoms substituted with one or more halo groups, as defined herein. Examples of haloalkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, or n-butyl, each independently substituted with one or more halogen atoms, such as F, Cl, Br, or I.

[0025] As used herein, "hydroxyalkyl" refers to a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with hydroxy (OH). Examples of hydroxyalkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, or n-butyl, each independently substituted with one or more -OH.

[0026] As used herein, "aminoalkyl" can refer to a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with an amino (NR'R"), where R' and R" are each independently hydrogen and C 1-6 alkyl, wherein each selected R' and R" may be independently substituted or unsubstituted.

[0027] As used herein, "cyanoalkyl" can mean a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with cyano (CN).

[0028] In the present invention, "cycloalkyl" can refer to a hydrocarbon ring that does not contain heteroatoms (such as N, O, P, P(=O), or S) within the ring, and may be saturated or partially unsaturated. When unsaturated, it may be referred to as cycloalkenyl. Unless otherwise specified, cycloalkyl can be a single ring or multiple rings, such as a spiro ring, a bridged ring, or a fused ring.

[0029] In the present invention, "heterocycloalkyl" refers to a ring containing one or more selected from N, O, P, P(=O), and S within the ring, and may be saturated or partially unsaturated. When unsaturated, it may be referred to as a heterocycloalkene. Unless otherwise specified, heterocycloalkyl may be a monocyclic ring. Furthermore, "heterocycloalkyl of 3 to 12 atoms" can refer to a heterocycloalkyl containing 3 to 12 atoms forming the ring. For example, heterocycloalkyl can include, but is not limited to, 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, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, or tetrahydrothiophene.

[0030] In the present invention, "heterobicycloalkyl" refers to a polycyclic ring, such as a spiro ring, a bridged ring, or a fused ring, containing one or more atoms selected from N, O, P, P(=O), and S within the ring, and may be saturated or partially unsaturated. When unsaturated, it may be referred to as a heterobicycloalkene. Examples of heterobicycloalkyl include, but are not limited to, 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.

[0031] In the present invention, "arene" may refer to an aromatic hydrocarbon ring. The arene may be a monocyclic arene or a polycyclic arene. The number of ring carbon atoms of 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, benzofluoranthene, and chrysene. In this specification, a residue obtained by removing one hydrogen atom from the above-mentioned "arene" is referred to as "aryl."

[0032] In the present invention, a "heteroarene" may be a ring containing one or more heteroatoms selected from O, N, P, Si, and S. The number of ring 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 two- or three-ring structure. Examples of heteroarenes include thiophene, purine, pyrrole, pyrazole, imidazole, thiazole, oxazole, isothiazole, oxadiazole, triazole, pyridine, pyridin-2-one, pyridin-3-one, pyridin-4-one, bipyridyl, triazine, acridyl, pyridazine, pyrazine, quinoline, quinazoline, quinoxaline, phenoxazine, phthalazine, pyrimidine, pyridopyrimidine, pyridopyrazine, pyrazinopyrazine, isoquinoline, indole, carbazole, imidazopyridazine, imidazopyridine, isoquinoline, indole, carbazole, imidazopyridazine, isoquinoline ... Examples of heteroarenes include, but are not limited to, midazopyrimidine, pyrazolopyrimidine, imidazopyrazine or pyrazolopyridine, N-arylcarbazole, N-heteroarylcarbazole, N-alkylcarbazole, benzoxazole, benzimidazole, benzothiazole, benzocarbazole, benzothiophene, dibenzothiophene, thienothiophene, benzofuran, phenanthroline, isoxazole, oxadiazole, thiadiazole, benzothiazole, tetrazole, phenothiazine, dibenzosilole, and dibenzofuran. In one embodiment of the present invention, heteroarenes can also include bicycloheterocycloarenes, which include 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."

[0033] As used herein, a "hydroarene" or "hydroaryl" refers to an aromatic hydrocarbon ring in which one or more double bonds are saturated.

[0034] As used herein, a "heterohydroarene" or "heterohydroaryl" is a "heteroarene" or "heteroaryl" ring in which one or more double bonds are saturated.

[0035] In the present invention, a "ring" may be a monocyclic or polycyclic ring, which may be a spiro ring, a bridged ring, or a fused ring.

[0036] As used herein, the term "stereoisomer" refers to a compound that has the same chemical or molecular formula but is sterically different. As used herein, stereoisomers include optical isomers, enantiomers, diastereomers, cis / trans isomers, rotamers, and atropisomers, and each of these isomers, racemates, and mixtures thereof are also included within the scope of the present invention. For example, Formula 1, 2, 2a, 2b, or 3 of the present invention does not specify the stereochemical structure and can therefore include the stereoisomers of Formula 1, 2, 2a, 2b, or 3. Unless otherwise specified, a solid bond connected to an asymmetric carbon atom [ka] is a solid wedge bond indicating the absolute arrangement of stereocenters [ka] or dashed wedge bond [ka] may include:

[0037] The compounds of formula 1, 2, 2a, 2b, or 3 of the present invention can exist in the form of "pharmaceutically acceptable salts." Thus, the category of the compounds of the present invention includes pharmaceutically acceptable salts of the compounds of formula 1, 2, 2a, 2b, or 3. The term "pharmaceutically acceptable salts" as used herein refers to any and all organic or inorganic acid addition salts of the compounds of formula 1, 2, 2a, 2b, or 3, which have a non-toxic, non-harmful effective concentration in patients, and the side effects attributable to the salts do not reduce the beneficial efficacy of the compounds of formula 1, 2, 2a, 2b, or 3.

[0038] In particular, the pharmaceutically acceptable salts may be acid addition salts formed with free acids, which may be derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, and the like, non-toxic organic acids such as aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates and alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids, and organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, stannic acid, fumaric acid, and the like.

[0039] Examples of such pharmaceutically acceptable salts include sulfate, sulfite, nitrate, phosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, benzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, glycolate, malate, tartrate, mandelate, and the like.

[0040] The acid addition salts can be prepared by a conventional method. For example, the acid addition salts can be prepared by dissolving the derivative of Formula 1, 2, 2a, 2b, or 3 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, or acetonitrile, adding an organic or inorganic acid, filtering the resulting precipitate, and drying the precipitate. Alternatively, the acid addition salts can be prepared by distilling the solvent and excess acid under reduced pressure, drying the precipitate, and then crystallizing the precipitate in an organic solvent.

[0041] The pharmaceutically acceptable salt may also be a salt obtained using a base or a metal salt. As an example of a metal salt, an alkali metal or alkaline earth metal salt can be obtained by dissolving a compound in an excess amount of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. As the alkali metal salt, sodium, potassium, or calcium salts are pharmaceutically acceptable. The corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal with an appropriate silver salt (e.g., silver nitrate), and can be prepared by a salt preparation method known in the art.

[0042] Uses of heteroaryl derivative compounds The present invention provides use of a compound represented by the following formula 1, 2, 2a, 2b, or 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0043] [ka] [ka] [ka] [ka] [ka] The compounds of the present invention represented by formula 1, 2, 2a, 2b, or 3, their stereoisomers, or pharmaceutically acceptable salts thereof exhibit inhibitory activity against a variety of kinases.

[0044] According to one embodiment of the present invention, the heteroaryl derivatives represented by Formula 1, 2, 2a, 2b, or 3 exhibit excellent inhibitory activity against EGFR and / or HER2 kinases and are therefore useful for the treatment or prevention of EGFR- and / or HER2-related diseases, particularly cancer. Specifically, the compounds of Formula 1, 2, 2a, 2b, or 3 can inhibit wild-type or mutant EGFR and / or HER2 kinases, as demonstrated by the experimental examples described below. 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). The EGFR mutation may also be, but is not limited to, EGFR L861Q, EGFR G719A, EGFR S768I, EGFR L718Q, or EGFR G724S. The EGFR mutation may also 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.

[0045] In the present invention, the cancer includes all cancers for which the inhibition of HER2 and / or EGFR kinase activity can show therapeutic or preventive efficacy, and may be a solid cancer or a blood cancer. The type of cancer is not limited, but may be, 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 lymphocytic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell tumor, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colon cancer, Chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla of Vater cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, childhood brain tumor, childhood lymphoma, childhood leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvis cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, The cancer may be one or more selected from the group consisting of malignant bone tumor, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary origin, gastric lymphoma, stomach cancer, gastric carcinoid tumor, gastrointestinal stromal tumor, Wilms' tumor, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone tumor, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid tumor, vaginal cancer, spinal cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsillar cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, blood cancer, and thymic cancer. In addition, the cancer includes not only primary cancer but also metastatic cancer.

[0046] According to one embodiment of the present invention, there is provided a pharmaceutical composition for treating or preventing an EGFR- and / or HER2-related disease, comprising, as an active ingredient, a compound represented by Formula 1, 2, 2a, 2b, or 3, a stereoisomer 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.

[0047] 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 Formula 1, 2, 2a, 2b, or 3, its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0048] The pharmaceutical composition of the present invention can be used for clinical administration and can be prepared so as to be administered in various oral and parenteral dosage forms.

[0049] According to one embodiment of the present invention, there is provided a use of a compound represented by formula 1, 2, 2a, 2b, or 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing an EGFR- and / or HER2-related disease. Specifically, the EGFR- and / or HER2-related disease may be cancer. The type of cancer is as described above.

[0050] According to one embodiment of the present invention, there is provided a use of a compound represented by formula 1, 2, 2a, 2b, or 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing cancer, the type of which is as described above.

[0051] Furthermore, according to one embodiment of the present invention, there is provided a method for treating or preventing an EGFR- and / or HER2-related disease, comprising administering a therapeutically effective amount of a compound represented by Formula 1, 2, 2a, 2b, or 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof. The subject may be a mammal, including a human. Specifically, the EGFR- and / or HER2-related disease may be cancer. The type of cancer is as described above.

[0052] Furthermore, according to one embodiment of the present invention, there is provided a method for treating or preventing cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by Formula 1, 2, 2a, 2b, or 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The type of cancer is as described above.

[0053] Furthermore, according to one embodiment of the present invention, there is provided a method for inhibiting EGFR and / or HER2, comprising administering a therapeutically effective amount of a compound represented by formula 1, 2, 2a, 2b, or 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0054] The term "therapeutically effective amount" as used herein refers to an amount of a compound represented by Formula 1, 2, 2a, 2b, or 3 effective in treating or preventing EGFR- and / or HER2-related diseases. Specifically, "therapeutically effective amount" refers to an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to any medical treatment. The effective dose level can be determined based on factors including the type and severity of the individual, age, sex, type of disease, drug activity, drug sensitivity, administration time, administration route and excretion rate, treatment duration, concurrently used drugs, and other factors known in the medical field. The pharmaceutical composition of the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with commercially available therapeutic agents. It can be administered in single or multiple doses. Taking all of the above factors into consideration, it is important to administer an amount that achieves maximum efficacy with the minimum amount without side effects, and this can be easily determined by one of ordinary skill in the art. The dosage of the pharmaceutical composition of the present invention can be determined by a specialist depending on various factors, such as the patient's condition, age, sex, and comorbidities. The active ingredient of the pharmaceutical composition of the present invention is highly safe and can be used in amounts greater than the determined dose.

[0055] As used herein, "prevention" refers to any action in which the onset, spread, and recurrence of the disease are inhibited or delayed by administering the compound, and "treatment" refers to any action in which the symptoms of the disease are ameliorated or beneficially altered by administering the compound.

[0056] According to one embodiment of the present invention, the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, diluent, or excipient. In one embodiment, the present invention provides a pharmaceutical composition comprising a compound represented by Formula 1, 2, 2a, 2b, or 3, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0057] Examples of additives used in the pharmaceutical composition may include sweeteners, binders, solvents, solubilizers, wetting agents, emulsifiers, isotonicity agents, absorption agents, disintegrants, antioxidants, preservatives, lubricants, fillers, flavoring agents, etc. For example, the additives may include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, magnesium aluminosilicate, starch, gelatin, tragacanth gum, alginic acid, sodium alginate, methylcellulose, sodium carboxymethylcellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor, etc.

[0058] The pharmaceutical compositions can be formulated in a variety of dosage forms for oral administration (e.g., tablets, pills, powders, capsules, syrups, or emulsions) or parenteral administration (e.g., intramuscular, intravenous, or subcutaneous injection).

[0059] For example, the pharmaceutical composition may be formulated as a preparation for oral administration, and additives used therein may include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifiers, diluents, etc. Specifically, solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations may be formulated by mixing the composition with at least one excipient, such as starch, calcium carbonate, sucrose, lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc may be used. Liquid preparations for oral administration include suspensions, emulsions, syrups, etc., and may include various excipients, such as wetting agents, sweeteners, flavoring agents, preservatives, etc., in addition to commonly used simple diluents such as water and liquid paraffin.

[0060] Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases may include witepsol, macrogol, Tween 61, cocoa butter, laurin butter, and glycerogelatin.

[0061] It can also be produced as a combined preparation with other active ingredients to enhance the effect of the active ingredient.

[0062] The descriptions of the uses, compositions, and treatment methods of the present invention are equally applicable unless they contradict each other. [Effects of the Invention]

[0063] The heteroaryl derivative compounds of the present invention exhibit excellent inhibitory activity against EGFR and / or HER2, and can therefore be usefully used in the treatment or prevention of the above-mentioned EGFR- and / or HER2-related diseases. DETAILED DESCRIPTION OF THE INVENTION

[0064] The present invention will be described in detail below with reference to examples and experimental examples. However, the following examples and experimental examples are merely illustrative of the present invention and are not intended to limit the scope of the present invention.

[0065] <Conditions for analysis and purification> The compounds synthesized in the examples of the present invention were purified under the following HPLC and MPLC conditions, or structural analysis was carried out by NMR.

[0066] 1. HPLC and MPLC 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. A Waters ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm, 2.1 × 50 mm) column was used, and the column temperature was set to 30°C.

[0067] Mobile phase A was water containing 0.1% formic acid, and mobile phase B was acetonitrile containing 0.1% formic acid.

[0068] Gradient condition (10-100% B for 3 minutes, migration rate = 0.6 ml / min)

[0069] Preparative HPLC System for purification (Preparative-Liquid chromatography UV spectrometry) The ACCQPrep HP150 equipment manufactured by Teledyne was used. A Waters XTERRA® Prep RP18 OBD (trademark pending) column (10 μm, 30×300 mm) was used, and the column temperature was set to room temperature.

[0070] Gradient condition (10-100% B for 120 minutes, migration rate = 42 ml / min)

[0071] Medium pressure liquid chromatography (MPLC) for purification Medium pressure liquid chromatography was performed using a Teledyne ISCO CombiFlash Rf+UV.

[0072] 2.NMR analysis NMR analysis was carried out using a Bruker AVANCE III 400 or AVANCE III 400 HD, and the data were expressed in ppm (parts per million (δ)).

[0073] Commercially available reagents were used without further purification. In the present invention, room temperature or ordinary temperature refers to a temperature of about 5°C to 40°C, for example, 10°C to 30°C, or another example, 20°C to 27°C, but is not strictly limited to this range. Concentration or solvent distillation removal under reduced pressure was performed using a rotary evaporator.

[0074] <Production Example 1> Production of (S)-3-phenylisoxazolidine [ka]

[0075] Step 1: Preparation of tert-butyl (R)-(3-hydroxy-3-phenylpropoxy)carbamate tert-Butyl hydroxycarbamate (7.8 g, 58.6 mmol) was dissolved in dimethylformamide (DMF; 140 mL) and then sodium hydride (2.58 g, 64.5 mmol) was added at 0 °C. The mixture was allowed to react for 30 minutes. (R)-3-chloro-1-phenylpropan-1-ol (5 g, 29.3 mmol) dissolved in dimethylformamide (10 mL) was slowly added dropwise at 0 °C for 10 minutes and stirred at room temperature for 72 hours. Aqueous ammonium chloride solution was added to the reaction mixture to terminate the reaction, and the organic matter was extracted with ethyl acetate and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The target compound (2.8 g, 68%) was obtained by purification using medium-pressure liquid chromatography (ethyl acetate / n-hexane).

[0076] MS(m / z):150.17[M+H] + UPLC rt(min):1.51

[0077] 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 and triethylamine (3.13 mL, 22.44 mmol) were dissolved in dichloromethane (250 mL) and cooled to 0°C. Methanesulfonyl chloride (1 mL, 13 mmol) was added dropwise and reacted at 0°C for 2 hours. The reaction mixture was extracted with brine and dichloromethane to form organic matter. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the target compound, which was used in the next reaction without further purification.

[0078] MS(m / z):194.13[M+H] + , UPLC rt(min): 1.69

[0079] Step 3: Preparation of (S)-3-phenylisoxazolidine tert-Butyl (S)-3-phenylisoxazolidine-2-carboxylate (2.3 g) obtained in Step 2 was dissolved in dichloromethane (DCM; 90 ml), and trifluoroacetic acid (14 ml) was added. The mixture was allowed to react at room temperature for 1 hour. The reaction mixture was neutralized with aqueous sodium bicarbonate, and the organic layer was extracted. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The product was purified by medium-pressure liquid chromatography (tetrahydrofuran / n-hexane) to obtain the target compound (1.3 g, 94%).

[0080] MS(m / z):150.08[M+H] + UPLC rt(min): 0.72

[0081] <Production Example 2> Production of (R)-3-phenylisoxazolidine [ka] The compound of Preparation Example 2 was prepared by a method similar to that of Preparation Example 1, and used in the synthesis of the example compounds shown in Table 1 below.

[0082] MS(m / z):150.08[M+H] + UPLC rt(min): 0.72

[0083] <Production Example 3> Production of (R)-3-(3-fluorophenyl)isoxazolidine [ka]

[0084] 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), followed by the addition of N-methoxymethanamine (75.19 g, 770.81 mmol, 1.2 eq, HCl). Then, at 15 °C, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI; 147.77 g, 770.81 mmol, 1.2 eq) was added. The reaction mixture was stirred at 50 °C for 30 min. TLC analysis (petroleum ether (PE):ethyl acetate (EA) = 3:1) showed the complete disappearance of the starting material, and a new spot with low polarity was detected. The mixture was concentrated under reduced pressure to remove the pyridine solvent, and the organic layer was extracted with dichloromethane (500 mL), hydrochloric acid (500 mL, 2 N), and brine (200 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the target compound (110 g, 600.50 mmol, 93.49% yield) as a yellow oil.

[0085] 1 H NMR (400MHz, 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).

[0086] Step 2: Preparation of 1-(3-fluorophenyl)prop-2-en-1-one 3-Fluoro-N-methoxy-N-methyl-benzamide (110 g, 600.50 mmol, 1 eq) obtained in Step 1 was dissolved in tetrahydrofuran (THF; 1 L), and 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 the starting material had completely disappeared, and a new spot with low polarity was detected. Hydrochloric acid (4 N, 500 mL) was added to terminate the reaction, and the organic layer was extracted with methyl tert-butyl ether (MTBE; 2000 mL) and brine (500 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The concentrated compound was purified by chromatography (petroleum ether / ethyl acetate=30 / 1) to obtain the target compound (80 g, 532.80 mmol, 88.73% yield) as a yellow oil.

[0087] 1 H NMR (400MHz, 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).

[0088] Step 3: Preparation of 3-chloro-1-(3-fluorophenyl)propan-1-one 1-(3-Fluorophenyl)prop-2-en-1-one (71 g, 472.86 mmol, 1.0 eq) obtained in Step 2 was dissolved in dichloromethane (71 mL), and 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 the starting material had completely disappeared and the target compound was detected. The reaction mixture was concentrated under reduced pressure, and dichloromethane (450 mL) and water (200 mL * 5) were added to extract the organic layer. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the target compound (73 g, 391.19 mmol, 82.73% yield) as a yellow solid.

[0089] 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).

[0090] 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]oxazaborole (1M, 32.15 mL, 0.1 eq) was dissolved in tetrahydrofuran (THF; 1.2 L), and then borane tetrahydrofuran (BH3·THF; 1M, 186.48 mL, 0.6 eq) was added dropwise at 0°C under a nitrogen atmosphere. The reaction mixture was stirred at 0°C for 30 min. 3-Chloro-1-(3-fluorophenyl)propan-1-one (60 g, 309.02 mmol, 1 eq) obtained in Step 3, diluted in tetrahydrofuran, was then added dropwise at 0°C. The reaction mixture was stirred at 0°C for 30 min. TLC analysis (petroleum ether (PE):ethyl acetate (EA) = 5:1) showed the complete disappearance of the starting material, and a spot of the desired compound was detected. Methanol (100 mL) was added at 0°C to complete the reaction, and the solvent was evaporated under reduced pressure. The organic layer was extracted from the concentrated compound using dichloromethane (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 using silica gel chromatography (petroleum ether (PE):ethyl acetate (EA) = 50:1 to 5:1) to obtain the target compound as a colorless oil (140 g, 664.2 mmol, 71.65% yield, 89.49% purity, 65.5% ee).

[0091] 1 H NMR (400MHz, 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).

[0092] Step 5: Preparation of tert-butyl (S)-(3-(3-fluorophenyl)-3-hydroxypropoxy)carbamate tert-Butyl hydroxycarbamate (50.4 g, 378.52 mmol, 1.05 eq) was dissolved in dimethylformamide (500 mL) and sodium hydride (NaH; 15.86 g, 396.55 mmol, 60% purity, 1.1 eq) was added at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at 10 °C for 1 hour, and then (S)-3-chloro-1-(3-fluorophenyl)propan-1-ol (68 g, 360.5 mmol, 1 eq) obtained in Step 4 above, diluted in dimethylformamide (180 mL), was added dropwise at 0 °C and stirred at 10 °C for 16 hours. TLC analysis (petroleum ether (PE):ethyl acetate (EA) = 2:1) showed that the starting material had completely disappeared and the desired compound had been detected. After the reaction was completed by adding ammonium chloride aqueous solution (3 L), the organic layer was extracted with ethyl acetate (2000 mL) and brine (2000 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the target compound (176 g, 616.87 mmol, 85.56% yield) as a bright yellow solid.

[0093] 1 H NMR (400MHz, 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).

[0094] Step 6: Preparation of tert-butyl (R)-3-(3-fluorophenyl)isoxazolidine-2-carboxylate tert-Butyl (S)-(3-(3-fluorophenyl)-3-hydroxypropoxy)carbamate (88 g, 308.44 mmol, 1 eq) obtained in Step 5 and triethylamine (93.63 g, 925.31 mmol, 128.79 mL, 3 eq) were dissolved in dichloromethane (1 L), and 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 the starting material had completely disappeared, and a new spot was detected. Water (2000 mL) was added to terminate the reaction, and the organic layer was extracted with dichloromethane (DCM; 200 mL x 3). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The concentrated compound was purified by chromatography (petroleum ether (PE):ethyl acetate (EA) = 50:1 to 5:1) to extract the target compound (88 g) with an ee of 82.5%. The target compound was purified by SFC (column: DAICEL CHIRALPAK AD (250 mm x 50 mm, 10 μm); mobile phase: [Neu-MeOH]; B%: 15%-15%, 3.4 min; 380 min) to obtain the target compound as a white solid (51 g, 189.66 mmol, 30.74% yield, 99.4% purity).

[0095] The purity of the optical isomers of tert-butyl (R)-3-(3-fluorophenyl)isoxazolidine-2-carboxylate obtained in Step 6 was analyzed under the following SFC conditions.

[0096] Instrument:CAS-WH-ANA-SFC-C(SHIMADZU LC-30ADsf) Column: Amycoat 50×4.6mm ID, 3μm Mobile phase:Phase A for CO2, and Phase B for MeOH(0.05%DEA); Gradient elution:MeOH(0.05%DEA)in CO2from 5%to40% Flow rate:3mL / min;Detector:PDA; Column Temp:35℃;Back Pressure:100 Bar When the purity of the optical isomer of tert-butyl (R)-3-(3-fluorophenyl)isoxazolidine-2-carboxylate obtained in Step 6 was low, it was purified under the following SFC conditions to obtain the desired optical isomer as a yellow liquid. Column:DAICEL CHIRALPAK AD-H(250mm×30mm, 5μm); Mobile phase:[0.1%NH3H2O ​​MeOH];B%:15%-15%, 3.8min;600min

[0097] Step 7: Preparation of (R)-3-(3-fluorophenyl)isoxazolidine 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 HCl / EtOAc (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 showed that all of the starting material had disappeared, and the mixture was concentrated under reduced pressure to give the target compound (32 g, 150.26 mmol, 80.81% yield, 95.62% purity, 100% eeHCl) as a white solid.

[0098] MS: m / z 168.2 [M+H] + 1 H NMR (400MHz, 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).

[0099] For the purification or analysis of optical isomers of the compound in step 7 above, the following conditions were used.

[0100] Instrument:CAS-WH-ANA-SFC-C(SHIMADZU LC-30ADsf) Column:Chiralpak AY-3 50×4.6mm ID, 3μm; Mobile phase:Phase A for CO2, and Phase B for IPA(0.05%DEA); Gradient elution:B in A from 5%to40%; Flow rate:3mL / min;Detector:PDA; Column Temp:35℃;Back Pressure:100 Bar

[0101] <Production Examples 4 to 9> The compounds of the following Preparation Examples 4 to 9 were prepared by methods similar to those of the above Preparation Examples 1 to 3, and the compounds of Preparation Examples 1 to 9 were used to prepare the example compounds of the present invention.

[0102] <Production Example 4> Production of (R)-3-(3,5-difluorophenyl)isoxazolidine [ka]

[0103] 1 H NMR (400MHz, 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).

[0104] <Production Example 5> Production of (R)-3-(2,5-difluorophenyl)isoxazolidine [ka]

[0105] <Production Example 6> Production of (R)-3-(4-fluorophenyl)isoxazolidine [ka]

[0106] <Production Example 7> Production of (R)-3-(2,4-difluorophenyl)isoxazolidine [ka]

[0107] 1 H NMR (400MHz, 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).

[0108] <Production Example 8> Production of (R)-3-(3,4-difluorophenyl)isoxazolidine [ka]

[0109] 1 H NMR (400MHz, CHLOROFORM-d)δ 7.24-7.19(m, 1H), 7.12-7.06(m, 2H), 5.24(s, 1H), 4.46(dd, J1=8.4 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).

[0110] <Production Example 9> Production of (R)-3-(2,3-difluorophenyl)isoxazolidine [ka]

[0111] 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).

[0112] Example 1: Preparation of (R)-6-(3-(2,3-difluorophenyl)isoxazolidin-2-yl)-N-(5-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-4-(9-(1-fluoro-2-methylpropan-2-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-2-methoxyphenyl)pyrimidin-4-amine [ka]

[0113] Step 1: Preparation of (R)-2-(6-chloropyrimidin-4-yl)-3-(2,3-difluorophenyl)isoxazolidine 4,6-Dichloropyrimidine (3 g, 1 eq) and (R)-3-(2,3-difluorophenyl)isoxazolidine (4.1 g, 1.1 eq) were dissolved in ethanol (20 mL), followed by the addition of N,N-diisopropylethylamine (DIPEA; 7.74 mL, 2.2 eq). The reaction solution was stirred at 100°C for 3 hours. After the reaction was complete, the mixture was extracted with ethyl acetate and water. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by MPLC (ethyl acetate / hexane) to give the target compound (5.94 g, 99% yield) as a clear liquid.

[0114] Step 2: Preparation of (R)-6-(3-(2,3-difluorophenyl)isoxazolidin-2-yl)-N-(5-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-4-(9-(1-fluoro-2-methylpropan-2-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-2-methoxyphenyl)pyrimidin-4-amine (R)-2-(6-chloropyrimidin-4-yl)-3-(2,3-difluorophenyl)isoxazolidine (50 mg, 1 eq) obtained in Step 1, 5-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-4-(9-(1-fluoro-2-methylpropan-2-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-2-methoxyaniline (150 mg, 2 eq), and cesium carbonate (109 mg, 2 eq) were dissolved in 1,4-dioxane (1.7 ml) and sonicated under nitrogen for 5 minutes to remove gas. Palladium acetate (Pd(OAc)2; 7.54 mg, 0.2 eq) and BINAP (20.92 mg, 0.2 eq) were added to the reaction mixture, which was then stirred at 90 °C for 6 hours. After the reaction was completed, the reaction mixture was filtered through Celite and washed with dichloromethane. The filtrate was concentrated and purified by prep-HPLC to obtain the target compound (20 mg, 16.8%).

[0115] 1 H NMR (400MHz, Chloroform-d) δ 8.31 (d, J=1.0 Hz, 1H), 7.86 (d, J=2.0 Hz, 1H), 7.73(s, 1H), 7.37-7.29(m, 1H), 7.11-7.00(m, 2H), 6.91(s, 1H), 6.73(s, 1H), 6.65(d, J=1.0 Hz, 1H), 5.92(dd, J=8.8, 4.8 Hz, 1H), 4.14(td, J=8.1, 4.0 Hz, 1H), 3.94(q, J=8.0 Hz, 1H), 3.88(s, 3H), 3.82(s, 3H), 2.84(qt, J=11.3, 5.2 Hz, 4H), 2.56-2.49(m, 4H), 2.47(s, 1H), 2.42(s, 1H), 2.37-2.25(m, 2H), 1.59-1.52(m, 8H), 1.39(s, 3H), 1.34(s, 3H).

[0116] <Examples 2 to 113> All example compounds of the present invention (Examples 2 to 113 compounds) were prepared by a method similar to that of Example 1, and the compound name, chemical structure, NMR, and LCMS analysis results of each example compound are summarized in Table 1 below.

[0117]

Table 1

[0118] <Experimental Example 1> Evaluation of the growth inhibitory activity of EGFR mutation-overexpressing Ba / F3 cells To evaluate the inhibitory activity of the compounds according to the present invention on the proliferation of Ba / F3 cells expressing EGFR Del19 / C797S (EGFR DC) and EGFR L858R / C797S (EGFR LC) mutations, the following experiment was carried out.

[0119] Ba / F3 cells were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS) and 5 ng / ml IL-3 (R&D Systems). Transduced Ba / F3 cells were cultured in the same medium supplemented with 1 μg / ml puromycin (Invitrogen).

[0120] 24 hours before compound treatment, 3,000–5,000 cells were dispensed into a well plate (white clear bottom 96-well plate, Corning). The compounds were diluted in dimethyl sulfoxide (3-fold dilutions, a total of 12 concentrations) and injected in 1 μl aliquots to final concentrations ranging from 0.2 nM to 5 μM. 72 hours after compound treatment, viability was measured using CellTiter-Glo luminescent cell-viability reagent (Promega). After 10 minutes of storage at room temperature, luminescence intensity was measured using a microplate reader (Synergy Neo, Biotek). Each test was repeated three times. Results were calculated as the percentage of cell growth compared to the control group. Graphs were plotted using GraphPad Prism version 8.3.0, and GI data were analyzed. 50 values ​​were calculated.

[0121] Table 2 below shows the results of evaluating the growth inhibitory activity of Ba / F3 cells expressing EGFR Del19 / C797S (EGFR DC) and EGFR L858R / C797S (EGFR LC) mutations.

[0122] [Table 2] As shown in Table 2 above, it is clear that the example compounds of the present invention exhibit high inhibitory activity against overexpressing cell lines containing EGFR Del19 / C797S (EGFR DC) and EGFR L858R / C797S (EGFR LC) mutations.

[0123] Although the present invention has been described in detail above by way of preferred preparation examples, examples, and experimental examples, the scope of the present invention is not limited to the specific example compounds, but should be interpreted by the appended claims. In addition, it should be understood that a person skilled in the art can make many modifications and variations without departing from the scope of the present invention.

Claims

1. A compound represented by the following formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: 【Chemistry 26】 In the formula 1, X is CH ２ or O; R １ and R ２ are each independently —H, —C １－６ Alkyl, -C １－６ haloalkyl, or -halo; R ３ is -H, -C １－６ Alkyl, -C １－６ Haloalkyl, —O—C １－６ Alkyl, or —O—C １－３ alkyl-OH, wherein the R ３ may be linked to a carbon atom in the phenyl ring to form a fused ring, or R ４ can be linked to form a fused ring; R ４ is -H, -NH(C １－６ alkyl), -N(C １－６ alkyl) (C １－６ alkyl), -(4- to 6-membered heterocycloalkyl), or -(7- to 11-membered heterobicycloalkyl) {wherein the —NH(C １－６ alkyl) or -N(C １－６ alkyl) (C １－６ and -(4- to 6-membered heterocycloalkyl) can be linked to ring Y to form a fused ring; one or more H of said -(4- to 6-membered heterocycloalkyl) can be -C １－６ Alkyl, -C １－６ Haloalkyl, -(CH ２ ) n-O-C １－６ Alkyl, -(CH ２ ) n-NR ａ R ｂ , -(CH ２ )n-S(=O) ２ -C １－３ Alkyl, -halo, -(CH ２ )n-(4- to 6-membered heterocycloalkyl), or —(CH ２ )n-(7- to 11-membered heterobicycloalkyl) [in which case, the —(CH ２ )n-(4- to 6-membered heterocycloalkyl) or —(CH ２ ) One or more H in the n-(7- to 11-membered heterobicycloalkyl) ring is —C １－６ Alkyl, -C １－６ Haloalkyl, -(CH ２ ) n-O-C １－６ Alkyl, -(CH ２ )n-C(=O)-C １－３ Alkyl, -(CH ２ )n-S(=O) ２ -C １－３ Alkyl, -(CH ２ ) nNR ａ R ｂ or -halo]; one or more H in said -(7- to 11-membered heterobicycloalkyl) is optionally substituted with -C １－６ Alkyl, -C １－６ Haloalkyl, -(CH ２ )n-C(=O)-C １－３ Alkyl, -(CH ２ )n-C(=O)-(3- to 6-membered cycloalkyl), -(CH ２ )n-S(=O) ２ -C １－３ Alkyl, -(CH ２ ) n-NR ａ R ｂ , —O—C １－６ alkyl, -halo, or -(CH ２ )n-(4- to 6-membered heterocycloalkyl) [wherein, —(CH ２ )n-(4- to 6-membered heterocycloalkyl) or —(CH ２ ) one or more H in the n-C(=O)-(3- to 6-membered cycloalkyl) ring is —C １－６ Alkyl, -C １－６ optionally substituted with haloalkyl, or -halo]; n is 0, 1, 2, 3, or 4; R ａ and R ｂ are each independently —H, —C １－６ Alkyl, -C １－６ haloalkyl, or -(4- to 6-membered heterocycloalkyl); Ring Y is phenyl or 5-10 membered heteroaryl, wherein one or more H in said phenyl or 5-10 membered heteroaryl ring is -C １－６ Alkyl, -C １－６ Hydroxyalkyl, —C １－６ and optionally substituted with haloalkyl, -(3- to 6-membered cycloalkyl), or -halo.

2. X is CH ２ or O; R １ and R ２ are each independently —H or -halo; R ３ is -H, -C １－３ Haloalkyl, —O—C １－３ Alkyl, or —O—C １－３ alkyl-OH, wherein the R ３ may be linked to a carbon atom in the phenyl ring to form a fused ring, or R ４ can be linked to form a fused ring; R ４ is -H, -N(C １－３ alkyl) (C １－３ alkyl), -(4- to 6-membered heterocycloalkyl), or -(7- to 11-membered heterobicycloalkyl) {wherein said -N(C １－３ alkyl) (C １－３ and -(4- to 6-membered heterocycloalkyl) can be linked to ring Y to form a fused ring; one or more H of said -(4- to 6-membered heterocycloalkyl) can be -C １－６ Alkyl, -C １－６ Haloalkyl, -(CH ２ ) n-O-C １－３ Alkyl, -(CH ２ ) n-NR ａ R ｂ , -(CH ２ )n-S(=O) ２ -C １－３ Alkyl, -halo, -(CH ２ )n-(4- to 6-membered heterocycloalkyl), or —(CH ２ )n-(7- to 11-membered heterobicycloalkyl) [in which case, the —(CH ２ )n-(4- to 6-membered heterocycloalkyl) or —(CH ２ ) One or more H in the n-(7- to 11-membered heterobicycloalkyl) ring is —C １－３ Alkyl, -C １－６ Haloalkyl, -(CH ２ ) n-O-C １－３ Alkyl, -(CH ２ )n-S(=O) ２ -C １－３ Alkyl, -(CH ２ ) nNR ａ R ｂ or -halo]; one or more H in said -(7- to 11-membered heterobicycloalkyl) is optionally substituted with -C １－３ Alkyl, -C １－６ Haloalkyl, -(CH ２ )n-C(=O)-C １－３ Alkyl, -(CH ２ )n-C(=O)-(3- to 6-membered cycloalkyl), -(CH ２ )n-S(=O) ２ -C １－３ Alkyl, -(CH ２ ) n-NR ａ R ｂ , —O—C １－３ alkyl, -halo, or -(CH ２ )n-(4- to 6-membered heterocycloalkyl) [wherein, —(CH ２ )n-(4- to 6-membered heterocycloalkyl), or —(CH ２ ) one or more H in the n-C(=O)-(3- to 6-membered cycloalkyl) ring may be replaced with -halo; n is 0, 1, 2, or 3; R ａ and R ｂ are each independently —H, —C １－３ Alkyl, -C １－６ haloalkyl, or -(4- to 6-membered heterocycloalkyl); Ring Y is phenyl, 5- to 6-membered heteroaryl, or 9- to 10-membered heteroaryl, wherein one or more H in said phenyl, 5- to 6-membered heteroaryl, or 9- to 10-membered heteroaryl ring is -C １－３ Alkyl, -C １－３ optionally substituted with hydroxyalkyl, -(3- to 6-membered cycloalkyl), or -halo); 2. A compound represented by formula 1 according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

3. The aforementioned 【Chemistry 27】 That is, 2. A compound represented by formula 1 according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

4. The ring Y is 【Chemistry 28】 wherein one or more H of the ring Y is —C １－３ Alkyl, -C １－３ Hydroxyalkyl, —C １－３ optionally substituted with haloalkyl, -(3- to 6-membered cycloalkyl), or -halo; 2. A compound represented by formula 1 according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

5. A compound represented by the following formula 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: 【Chemistry 29】 In the formula 2, X is CH ２ or O; R １ and R ２ are each independently —H or -halo; R ３ is -H, -C １－３ Haloalkyl, —O—C １－３ Alkyl, or —O—C １－３ alkyl-OH, wherein the R ３ may be linked to a carbon atom in the phenyl ring to form a fused ring, or R ４ can be linked to form a fused ring; R ４ is -H, -N(C １－３ alkyl) (C １－３ alkyl), -(4- to 6-membered heterocycloalkyl), or -(7- to 11-membered heterobicycloalkyl) {wherein said -N(C １－３ alkyl) (C １－３ and -(4- to 6-membered heterocycloalkyl) can be linked to ring Y to form a fused ring; one or more H of said -(4- to 6-membered heterocycloalkyl) can be -C １－６ Alkyl, -C １－６ Haloalkyl, -(CH ２ ) n-O-C １－３ Alkyl, -(CH ２ ) n-NR ａ R ｂ , -(CH ２ )n-S(=O) ２ -C １－３ Alkyl, -halo, -(CH ２ )n-(4- to 6-membered heterocycloalkyl), or —(CH ２ )n-(7- to 11-membered heterobicycloalkyl) [in which case, the —(CH ２ )n-(4- to 6-membered heterocycloalkyl) or —(CH ２ ) One or more H in the n-(7- to 11-membered heterobicycloalkyl) ring is —C １－３ Alkyl, -C １－６ Haloalkyl, -(CH ２ ) n-O-C １－３ Alkyl, -(CH ２ )n-S(=O) ２ -C １－３ Alkyl, -(CH ２ ) nNR ａ R ｂ or -halo]; one or more H in said -(7- to 11-membered heterobicycloalkyl) is optionally substituted with -C １－３ Alkyl, -C １－６ Haloalkyl, -(CH ２ )n-C(=O)-C １－３ Alkyl, -(CH ２ )n-C(=O)-(3- to 6-membered cycloalkyl), -(CH ２ )n-S(=O) ２ -C １－３ Alkyl, -(CH ２ ) n-NR ａ R ｂ , —O—C １－３ alkyl, -halo, or -(CH ２ )n-(4- to 6-membered heterocycloalkyl) [wherein, —(CH ２ )n-(4- to 6-membered heterocycloalkyl), or —(CH ２ ) one or more H in the n-C(=O)-(3- to 6-membered cycloalkyl) ring may be replaced with -halo; n is 0, 1, 2, or 3; R ａ and R ｂ are each independently —H, —C １－３ Alkyl, -C １－６ haloalkyl, or -(4- to 6-membered heterocycloalkyl); Ring Y is phenyl, 5- to 6-membered heteroaryl, or 9- to 10-membered heteroaryl, wherein one or more H in said phenyl, 5- to 6-membered heteroaryl, or 9- to 10-membered heteroaryl ring is -C １－３ Alkyl, -C １－３ optionally substituted with hydroxyalkyl, -(3- to 6-membered cycloalkyl), or -halo}.

6. A compound represented by the following formula 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: 【Transformation 30】 In the formula 3, X is CH ２ or O; R １ and R ２ are each independently —H or -halo; R ４ is -(4- to 6-membered heterocycloalkyl), or -(7- to 11-membered heterobicycloalkyl), wherein one or more H in said -(4- to 6-membered heterocycloalkyl) or -(7- to 11-membered heterobicycloalkyl) ring is -C １－３ Alkyl, -C １－３ Haloalkyl, -(CH ２ )n-S(=O) ２ -C １－３ optionally substituted with alkyl, or -halo; n is 0, 1, or 2; Ring Y is a 5-membered heteroaryl {wherein one or more H in said 5-membered heteroaryl ring is —C １－３ optionally substituted with alkyl or -halo}.

7. A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of the following compounds: Table 3

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7, its stereoisomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

9. A pharmaceutical composition for preventing or treating cancer, comprising the compound according to any one of claims 1 to 7, its stereoisomer or a pharmaceutically acceptable salt thereof as an active ingredient.

10. The pharmaceutical composition of claim 9, which inhibits EGFR and / or HER2.

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

12. The 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 lymphocytic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell tumor, 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 and paranasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain tumor, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvis cancer, kidney cancer, heart cancer, duodenal cancer, and malignant soft tissue.

10. The pharmaceutical composition of claim 9, wherein the cancer is one or more selected from the group consisting of cancer, malignant bone tumor, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, stomach cancer, gastric carcinoid tumor, gastrointestinal stromal tumor, Wilms' tumor, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone tumor, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid tumor, vaginal cancer, spinal cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsillar cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, blood cancer, and thymic cancer.

13. 10. Use of a compound according to any one of claims 1 to 7, its stereoisomer, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in the treatment or prevention of an EGFR- and / or HER2-related disease.

14. A method for treating or preventing an EGFR- and / or HER2-related disease, comprising administering to a subject in need thereof a therapeutically effective amount of the compound according to any one of claims 1 to 7, its stereoisomer, or a pharmaceutically acceptable salt thereof.

15. A method for treating 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 lymphocytic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell tumor, 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 and paranasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain tumor, childhood lymphoma, childhood leukemia, small intestine cancer, Meningioma, esophageal cancer, glioma, renal pelvis cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone tumor, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, stomach cancer, gastric carcinoid tumor, gastrointestinal stromal tumor, Wilms' tumor, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate A method for treating or preventing one or more diseases selected from the group consisting of adenocarcinoma, metastatic bone tumor, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid tumor, vaginal cancer, spinal cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsillar cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, blood cancer, and thymic cancer.

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