Heteroaryl derivative compounds and uses thereof

Abstract

The present invention relates to a heteroaryl derivative and a use thereof, the heteroaryl derivative of the present invention exhibiting excellent inhibitory activity against EGFR and / or HER2, and being useful as a therapeutic agent for EGFR and / or HER2-related diseases.

Description

Technical Field

[0001] The present disclosure relates to heteroaryl-derived compounds and their medical uses. Specifically, the present disclosure relates to heteroaryl-derived compounds having EGFR and / or HER2 inhibitory activity.

Background Art

[0002] Protein kinases are involved in signal pathways by acting as molecular switches, and the conversion between the active and inactive states of target proteins caused by kinases in cells must be smoothly regulated. If the conversion between the activated and non-activated states is abnormally regulated, intracellular signal transduction is over-activated or inactivated, leading to uncontrollable cell division and proliferation. In particular, abnormal activation caused by mutations, amplifications, and / or overexpressions of protein kinase genes leads to the development and progression of various tumors, or plays a decisive role in the onset of various diseases such as inflammatory diseases, neurodegenerative diseases, and autoimmune diseases.

[0003] Epidermal growth factor receptor (EGFR), a receptor tyrosine kinase in the ErbB family, is abnormally active 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. It is well known that the activation of EGFR-tyrosine kinase leads to continuous cell proliferation, invasion of surrounding tissues, distant metastasis, and angiogenesis, and increases cell survival.

[0004] In addition, it is known that EGFR Del19 or EGFR L858R (an EGFR mutation) is a major cause of non-small cell lung cancer and head and neck cancer, and therapeutic agents Gefitinib and Erlotinib targeting these mutations have been developed and are currently being used in clinical practice. However, when these drugs are used in patients, acquired drug resistance leading to secondary mutations of EGFR based on the drug structure is observed, and it has also been found that this is the true major cause of drug resistance. When the first-generation EGFR inhibitor is used for about 10 months on average, acquired drug resistance called the T790M mutation, which is located at the EGFR kinase gatekeeper, occurs, and thus the first-generation EGFR inhibitor becomes ineffective. In other words, the EGFR Del19 / T790M or EGFR L858R / T790M double mutation occurs, which prevents the existing therapeutic agents from showing efficacy. Osimertinib has been developed, which is a third-generation EGFR-TKI targeted drug and shows high reactivity to drug resistance according to the EGFRT790M mutation, but it has also been reported to cause drug resistance (Niederst MJ. et al., Clin Cancer Res, 2015, 17(21):3924–3933). The EGFR C797S mutation is considered to be one of the main mechanisms leading to resistance to Osimertinib, and it has been reported that about 40% of the 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 EGFRL858R / C797S (EGFR LC) may be the main targets.

[0005] In addition, L861Q, G719A, S768I, L718Q, G724S, etc., which express rare (or uncommon) and drug-resistant mutations of EGFR, may also be potential targets.

[0006] Meanwhile, HER2 (human epidermal growth factor receptor 2; also known as ErbB2), is a receptor tyrosine kinase of the Erb B family, and is related to other EGFR receptors HER1

[0007] (EGFR, ErbB1), HER3 (ErbB3) or HER4 (ErbB4) form homodimers or heterodimers and are activated by autophosphorylation of intracellular tyrosine residues, which play important roles 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 several cancers 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).

[0008] As described above, there is an increasing demand for new compounds that can be effectively used for treating 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, drug - resistant mutations, etc.) and / or HER2.

[0009]

The present invention

[0010]

Technical problem

[0011] 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.

[0012] Another object of the present invention is to provide a method for preparing the heteroaryl derivative compound.

[0013] Another object of the present invention is to provide the pharmaceutical use of the heteroaryl derivative compound, specifically to provide a pharmaceutical composition for treating or preventing EGFR - and / or HER2 - related diseases containing the heteroaryl derivative compound as an active ingredient, and the use of the compound in treating or preventing EGFR - and / or HER2 - related diseases, or a method for treating or preventing EGFR - and / or HER2 - related diseases including administering the compound.

[0014]

Technical solution

[0015] To achieve the above object, the present inventors conducted in - depth research and confirmed that the heteroaryl derivative compounds represented by the following Chemical Formulas 1, 2, 2a, 2b or 3 inhibited the proliferation of EGFR - and / or HER2 - activated cells, thus completing the present invention.

[0016] Heteroaryl derivative compounds

[0017] The present invention provides a compound represented by the following Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0018] [Chemical Formula 1]

[0019]

[0020] In the above Chemical Formula 1,

[0021] X is CH2 or O;

[0022] R1 and R2 are each independently -H, -Calkyl, -C 1-6 haloalkyl, or -halogen;

[0023] R3 is -H, -C 1-6 alkyl, -C 1-6 haloalkyl, -O-C 1-6 alkyl, or -O-C 1-3 alkyl-OH {wherein R3 may be attached to a carbon in the phenyl ring to form a fused ring or attached to R4 to form a fused ring};

[0024] R4 is -H, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)(C 1-6 alkyl), -(4-6 membered heterocycloalkyl), or -(7-11 membered heterobicycloalkyl)

[0025] {wherein the -NH(C 1-6 alkyl) or -N(C 1-6 alkyl)(C 1-6 alkyl) may be attached to ring Y to form a fused ring; at least one H of the -(4-6 membered heterocycloalkyl) may be substituted with -C 1-6 alkyl, -C 1-6 haloalkyl, -(CH2)n-O-C 1-6 alkyl, -(CH2)n-NR a R b 1-3 alkyl, -halogen, -(CH2)n-(4-6 membered heterocycloalkyl), or -(CH2)n-(7-11 membered heterobicycloalkyl) [herein, at least one H of the -(CH2)n-(4-6 membered heterocycloalkyl) or -(CH2)n-(7-11 membered heterobicycloalkyl) ring may be substituted with -C 1-6 alkyl, -C 1-6 haloalkyl, -(CH2)n-O-C 1-6 alkyl, -(CH2)n-C(=O)-C 1-3 alkyl, -(CH2)n-S(=O)2-C 1-3 ​1-3 alkyl, -(CH2)nNR a R b or -halogen]; at least one H of said -(7-11-membered heterobicycloalkyl) may be substituted with -C 1-6 alkyl, -C 1-6 haloalkyl, -(CH2)n-C(=O)-C 1-3 alkyl, -(CH2)n-C(=O)-(3-6-membered cycloalkyl), -(CH2)n-S(=O)2-C 1-3 alkyl, -(CH2)n-NR a R b , -O-C 1-6 alkyl, -halogen, or -

[0026] (CH2)n-(4-6-membered heterocycloalkyl) [as used herein, at least one H of said -(CH2)n-(4-6-membered heterocycloalkyl) or -

[0027] (CH2)n-C(=O)-(3-6-membered cycloalkyl) ring may be substituted with -C 1-6 alkyl, -C 1-6 haloalkyl or -halogen]};

[0028] n is 0, 1, 2, 3 or 4;

[0029] R a and R b are each independently -H, -C 1-6 alkyl, -C 1-6 haloalkyl or -(4-6-membered heterocycloalkyl);

[0030] Ring Y is phenyl or 5-10-membered heteroaryl {wherein at least one H of said phenyl or 5-10-membered heteroaryl ring may be substituted with -C 1-6 alkyl, -C 1-6 hydroxyalkyl, -C 1-6 haloalkyl, -(3-6-membered cycloalkyl) or -halogen}.

[0031] According to one embodiment of the present invention, the compound represented by Chemical Formula 1 may be in the following ranges:

[0032] X is CH2 or O;

[0033] R1 and R2 are each independently -H or -halogen;

[0034] R3 is -H, -C 1-3 haloalkyl, -O-C 1-3 alkyl or -O-C 1-3Alkyl-OH {wherein R3 may be attached to a carbon in the phenyl ring to form a fused ring, or attached to R4 to form a fused ring};

[0035] R4 is -H, -N(C 1-3 alkyl)(C 1-3 alkyl), -(4-6 membered heterocycloalkyl), or -(7-11 membered heterobicycloalkyl)

[0036] {wherein the -N(C 1-3 alkyl)(C 1-3 alkyl) may be attached to ring Y to form a fused ring; at least one H of the -(4-6 membered heterocycloalkyl) may be substituted with -C 1-6 alkyl, -C 1-6 haloalkyl, -(CH2)n-O-C 1-3 alkyl, -(CH2)n-NR a R b 、-(CH2)n-S(=O)2-C 1-3 alkyl, -halogen, -(CH2)n-(4-6 membered heterocycloalkyl), or -(CH2)n-(7-11 membered heterobicycloalkyl) [In this text, at least one H of the -(CH2)n-(4-6 membered heterocycloalkyl) or -(CH2)n-(7-11 membered heterobicycloalkyl) ring may be substituted with -C 1-3 alkyl, -C 1-6 haloalkyl, -(CH2)n-O-C 1-3 alkyl, -(CH2)n-S(=O)2-C 1-3 alkyl, -(CH2)nN R a R b or -halogen]; at least one H of the -(7-11 membered heterobicycloalkyl) may be substituted with -C 1-3 alkyl, -C 1-6 haloalkyl, -(CH2)n-C(=O)-C 1-3 alkyl, -(CH2)n-C(=O)-(3-6 membered cycloalkyl), -(CH2)n-S(=O)2-C 1-3 alkyl, -(CH2)n-NR a R b 、-O-C 1-3 alkyl, -halogen, or -

[0037] (CH2)n-(4-6 membered heterocycloalkyl) [In this text, at least one H of the -(CH2)n-(4-6 membered heterocycloalkyl) or -

[0038] (CH2)n-C(=O)-(3-6 membered cycloalkyl) ring may be substituted with -halogen]};

[0039] n is 0, 1, 2 or 3;

[0040] R a and R b are each independently -H, -C 1-3 alkyl, -C 1-6 haloalkyl or -(4-6 membered heteroalkyl);

[0041] Ring Y is phenyl, 5-6 membered heteroaryl or 9-10 membered heteroaryl {wherein at least one H of said phenyl, 5-6 membered heteroaryl or 9-10 membered heteroaryl ring may be substituted with -C 1-3 alkyl, -C 1-3 hydroxyalkyl, -(3-6 membered cycloalkyl) or -halogen}.

[0042] According to one embodiment of the present invention, the compound represented by Chemical Formula 1 may be within the following range:

[0043] is

[0044] According to one embodiment of the present invention, the compound represented by Chemical Formula 1 may be within the following range:

[0045] Ring Y is

[0046] {wherein at least one H of Ring Y may be substituted with -C 1-3 alkyl, -C 1-3 hydroxyalkyl, -C 1-3 haloalkyl, -(3-6 membered cycloalkyl) or -halogen}.

[0047] Moreover, the present invention provides a compound represented by the following Chemical Formula 2, its stereoisomers or its pharmaceutically acceptable salts:

[0048] [Chemical Formula 2]

[0049]

[0050] In the above Chemical Formula 2,

[0051] X is CH2 or O;

[0052] R1 and R2 are each independently -H or -halogen;

[0053] R3 is -H, -C 1-3 haloalkyl, -O-C 1-3 alkyl or -O-C 1-3Alkyl-OH, {wherein R3 may be attached to a carbon in the phenyl ring to form a fused ring, or attached to R4 to form a fused ring};

[0054] R4 is -H, -N(C 1-3 alkyl)(C 1-3 alkyl), -(4-6-membered heterocycloalkyl), or -(7-11-membered heterobicycloalkyl)

[0055] {wherein the -N(C 1-3 alkyl)(C 1-3 alkyl) may be attached to ring Y to form a fused ring; at least one H of the -(4-6-membered heterocycloalkyl) may be substituted with -C 1-6 alkyl, -C 1-6 haloalkyl, -(CH2)n-O-C 1-3 alkyl, -(CH2)n-NR a R b , -(CH2)n-S(=O)2-C 1-3 alkyl, -halogen, -(CH2)n-(4-6-membered heterocycloalkyl), or -(CH2)n-(7-11-membered heterobicycloalkyl)

[0056] [In this text, at least one H of the -(CH2)n-(4-6-membered heterocycloalkyl) or -(CH2)n-(7-11-membered heterobicycloalkyl) ring may be substituted with -C 1-3 alkyl, -C 1-6 haloalkyl, -(CH2)n-O-C 1-3 alkyl, -(CH2)n-S(=O)2-C 1-3 alkyl, -(CH2)nN R a R b or -halogen]; at least one H of the -(7-11-membered heterobicycloalkyl) may be substituted with -C 1-3 alkyl, -C 1-6 haloalkyl, -(CH2)n-C(=O)-C 1-3 alkyl, -(CH2)n-C(=O)-(3-6-membered cycloalkyl), -(CH2)n-S(=O)2-C 1-3 alkyl, -(CH2)n-NR a R b , -O-C 1-3 alkyl, -halogen, or -(CH2)n-(4-6-membered heterocycloalkyl) [In this text, at least one H of the -(CH2)n-(4-6-membered heterocycloalkyl) or -(CH2)n-C(=O)-(3-6-membered cycloalkyl) ring may be substituted with -halogen]};

[0057] n is 0, 1, 2, or 3;

[0058] R a and R b each independently is -H, -C 1-3 alkyl, -C 1-6 haloalkyl or -(4-6 membered heterocycloalkyl);

[0059] Ring Y is phenyl, 5- or 6-membered heteroaryl or 9- or 10-membered heteroaryl {wherein at least one H of said phenyl, 5- or 6-membered heteroaryl or 9- or 10-membered heteroaryl ring may be substituted with -C 1-3 alkyl, -C 1-3 hydroxyalkyl, -(3-6 membered cycloalkyl) or -halogen}.

[0060] Moreover, the present invention provides a compound a represented by the following Chemical Formula 2, its stereoisomers or its pharmaceutically acceptable salts:

[0061] [Chemical Formula 2a]

[0062]

[0063] In the above Chemical Formula 2a,

[0064] X, R1, R2, R3, R4 and Ring Y are the same as defined in the above Chemical Formula 2.

[0065] Moreover, the present invention provides a compound represented by the following Chemical Formula 2b, its stereoisomers or its pharmaceutically acceptable salts:

[0066] [Chemical Formula 2b]

[0067]

[0068] In the above Chemical Formula 2b,

[0069] X, R1, R2, R3, R4 and Ring Y are the same as defined in the above Chemical Formula 2.

[0070] In addition, the present invention provides a compound represented by the following Chemical Formula 3, its stereoisomers or its pharmaceutically acceptable salts:

[0071] [Chemical Formula 3]

[0072]

[0073] In the above Chemical Formula 3,

[0074] X is CH2 or O;

[0075] R1 and R2 each independently are -H or -halogen;

[0076] R4 is -(4- to 6-membered heteroalkyl) or -(7- to 11-membered heterobicycloalkyl) {wherein at least one H of said -(4- to 6-membered heteroalkyl) or -(7- to 11-membered heterobicycloalkyl) ring may be substituted with -C 1-3 alkyl, -C 1-3 haloalkyl, -(CH2)n-S(=O)2-C 1-3 alkyl or -halogen};

[0077] n is 0, 1 or 2;

[0078] Ring Y is a 5-membered heteroaryl {wherein at least one H of said 5-membered heteroaryl ring may be substituted with -C 1-3 alkyl or -halogen}.

[0079] According to one embodiment of the present invention, the compounds represented by Chemical Formulas 1, 2, 2a, 2b or 3 may be selected from the compounds listed in Table 1 below.

[0080] In the present invention, unless otherwise specified, the term "alkyl" may refer to a straight-chain or branched-chain acyclic, cyclic or saturated hydrocarbon to which it is attached. For example, "C 1-6 alkyl" may represent an alkyl group containing 1 to 6 carbon atoms. By way of example, acyclic alkyl groups may include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, isopropyl, sec-butyl, isobutyl, tert-butyl, etc. Cyclic alkyl groups may be used interchangeably with "cycloalkyl" as used herein and, by way of example, may include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.

[0081] In the present disclosure, "alkoxy" may represent -(O-alkyl) as an alkyl ether group, where alkyl is as defined above. For example, "C 1-6 alkoxy" may refer to an alkoxy group containing C 1-6 alkyl, i.e., -(O-C 1-6 alkyl), and, by way of example, may include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.

[0082] In the present invention, "halogen" may be F, Cl, Br or I.

[0083] In the present invention, "haloalkyl" may refer to a straight-chain or branched-chain alkyl (hydrocarbon) having one or more halo-carbon atoms as defined herein. Examples of haloalkyl groups may include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl or n-butyl independently substituted with one or more halogens (such as F, Cl, Br or I).

[0084] In this specification, "hydroxyalkyl" may represent a straight-chain or branched-chain alkyl (hydrocarbon) in which a carbon atom is substituted by a hydroxyl group (OH). Examples of hydroxyalkyl may include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, or n-butyl independently substituted by one or more, such as -OH.

[0085] In this specification, "aminoalkyl" may refer to a straight-chain or branched-chain alkyl (hydrocarbon) in which a carbon atom is substituted by an amino group (NR'R"). Herein, R' and R" may each independently be selected from hydrogen and C 1-6 alkyl, and the selected R' and R" may each independently be substituted or unsubstituted.

[0086] In this specification, "cyanoalkyl" may represent a straight-chain or branched-chain alkyl (hydrocarbon) in which a carbon atom is substituted by a cyano group (CN).

[0087] In the present invention, "cycloalkyl" may refer to a hydrocarbon ring that does not contain heteroatoms (N, O, P, P(=O), S, etc.) in the ring and may be saturated or partially unsaturated. Herein, when the cycloalkyl is unsaturated, it may be referred to as cycloalkenyl. Unless otherwise specified, the cycloalkyl may be monocyclic or polycyclic such as spirocyclic, bridged, or fused rings.

[0088] In the present invention, "heterocycloalkyl" is a ring that contains at least one selected from N, O, P, P(=O), S, and may be saturated or partially unsaturated. Herein, when it is unsaturated, it may be referred to as heterocycloalkene. Unless otherwise specified, the heterocycloalkyl may be monocyclic. Additionally, "3- to 12-membered heterocycloalkyl" may represent a heterocycloalkyl containing 3 to 12 ring-forming atoms. For example, heterocycloalkyl may include, but are 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, tetrahydrothiophene, etc.

[0089] In the present invention, "heterobicycloalkyl" may refer to a polycyclic spirocyclic, bridged, or fused ring that contains at least one selected from N, O, P, P(=O), S, and may be saturated or partially unsaturated. Herein, when the heterobicycloalkyl is unsaturated, it may be referred to as 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, etc.

[0090] In the present invention, "aromatic hydrocarbon" may refer to an aromatic hydrocarbon ring. The aromatic hydrocarbon may be monocyclic or polycyclic. The number of ring carbon atoms in the aromatic hydrocarbon may be 5 or more and 30 or less, 5 or more and 20 or less, or 5 or more and 15 or less. Examples of the aromatic hydrocarbon may include, but are not limited to, benzene, naphthalene, fluorene, anthracene, phenanthrene, biphenyl, terphenyl, quaterphenyl, quinquephenyl, sexiphenyl, benzo[a]pyrene, benzofluoranthene, and the like. In the present specification, a moiety obtained by removing one hydrogen atom from the above "aromatic hydrocarbon" is referred to as "aryl".

[0091] In the present invention, "heteroaromatic hydrocarbon" may be a ring containing at least one or more of O, N, P, Si, and S as heteroatoms. The number of ring-forming carbon atoms in the heteroaromatic hydrocarbon may be 2 or more and 30 or less, or 2 or more and 20 or less. The heteroaromatic hydrocarbon may be a monocyclic heteroaromatic hydrocarbon or a polycyclic heteroaromatic hydrocarbon. The polycyclic heteroaromatic hydrocarbon may have, for example, a bicyclic or tricyclic structure. Examples of the heteroaromatic hydrocarbon may include thiophene, purine, pyrrole, pyrazole, imidazole, thiazole, oxazole, isothiazole, oxadiazole, triazole, pyridine, pyridin-2-one, pyridin-3-one, pyridin-4-one, bipyridine, triazine, acridinyl, pyridazine, pyrazine, quinoline, quinazoline, quinoxaline, phenoxazine, phthalazine, pyrimidine, pyridopyrimidine, pyridopyrazine, pyrazinopyrazine, isoquinoline, indole, carbazole, imidazopyridazine, imidazopyridine, imidazopyrimidine, 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, dibenzofuran, etc., but are not limited thereto. In one embodiment of the present invention, the heteroaromatic hydrocarbon may further include a bicyclic heteroaromatic hydrocarbon containing a heteroaromatic hydrocarbon fused to an aromatic hydrocarbon ring or a cycloalkyl ring fused to a heterocycloalkyl ring. In the present specification, a residue obtained by removing one hydrogen atom from the "heteroaromatic hydrocarbon" is referred to as "heteroaryl".

[0092] In the present invention, "hydroaromatic hydrocarbon" or "hydroaryl" may be a ring in which one or more double bonds in an aromatic hydrocarbon ring are saturated.

[0093] In the present invention, "heterohydroaromatic hydrocarbon" or "heterohydroaryl" may be a ring in which one or more double bonds in the "heteroaromatic hydrocarbon" or "heteroaryl" ring are saturated.

[0094] The "ring" in the present invention may be monocyclic or polycyclic, and the polycyclic may be in the form of a spiro ring, a bridged ring, or a fused ring.

[0095] In the present invention, the term "stereoisomer" refers to compounds of the present invention having the same chemical formula or molecular formula but different spatial arrangements. In this specification, stereoisomers include optical isomers, enantiomers, diastereoisomers, cis-trans isomers, rotational isomers, and atropisomers. These isomers, racemates, and their mixtures are also included within the scope of the present invention. For example, since the stereochemistry is not specified for Chemical Formulas 1, 2, 2a, 2b, or 3 of the present invention, they may include the stereoisomers of Chemical Formulas 1, 2, 2a, 2b, or 3. Unless otherwise specified, the solid bonds attached to asymmetric carbon atoms may include wedge-shaped solid bonds or wedge-shaped dashed bonds representing the absolute arrangement of the stereocenters.

[0096] The compounds represented by Chemical Formulas 1, 2, 2a, 2b, or 3 of the present invention may exist in the form of "pharmaceutically acceptable salts". Accordingly, all pharmaceutically acceptable salts of the compounds represented by the above Chemical Formulas 1, 2, 2a, 2b, or 3 are included within the scope of the compounds of the present invention. The term "pharmaceutically acceptable salt" as used herein refers to a concentration that has a relatively non-toxic and harmless effective effect on a patient, including any organic or inorganic acid addition salts of the compounds represented by Chemical Formulas 1, 2, 2a, 2b, or 3, wherein the side effects caused by these salts do not reduce the beneficial efficacy of the compounds.

[0097] Specifically, the pharmaceutically acceptable salts may be acid addition salts formed from free acids, wherein the acid addition salts may be formed from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc., non-toxic organic acids such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, and alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and organic acids such as trifluoroacetic acid, acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc.

[0098] Examples of pharmaceutically acceptable salts may include sulfates, sulfites, nitrates, phosphates, pyrophosphates, chlorides, bromides, iodides, fluorides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, decanoates, heptanoates, propiolates, oxalates, malonates, succinates, octanedioates, decanedioates, fumarates, maleates, benzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, glycolates, malates, tartrates, mandelates, etc.

[0099] The acid addition salts can be prepared by conventional methods. For example, the compounds represented by Chemical Formula 1, 2, 2a, 2b or 3 can be dissolved in organic solvents such as methanol, ethanol, acetone, dichloromethane, acetonitrile, etc., and an organic acid or an inorganic acid is added to form a precipitate. The obtained precipitate is filtered and dried, or the solvent and the excess acid are removed by distillation under reduced pressure, and the crystals are dried in an organic solvent.

[0100] In addition, the pharmaceutically acceptable salts can be salts obtained using a base or a metal salt. As an example of a metal salt, an alkali metal salt or an alkaline earth metal salt can be obtained by dissolving the compound in an excess solution of an alkali metal hydroxide or an alkaline earth metal hydroxide, filtering the insoluble compound salt, and then evaporating and drying the filtrate. Sodium, potassium or calcium salts can be used as pharmaceutically suitable alkali metal salts. In addition, the corresponding silver salts can be obtained by reacting an alkali metal or an alkaline earth metal with a suitable silver salt (such as silver nitrate), or can be prepared by a salt production method known in the art.

[0101] Uses of heteroaryl derivative compounds

[0102] The present invention provides the use of the compounds represented by the following Chemical Formula 1, 2, 2a, 2b or 3, their stereoisomers or their pharmaceutically acceptable salts.

[0103] [Chemical Formula 1]

[0104]

[0105] [Chemical Formula 2]

[0106]

[0107] [Chemical Formula 2a]

[0108]

[0109] [Chemical Formula 2b]

[0110]

[0111] [Chemical Formula 3]

[0112]

[0113] The compounds represented by Chemical Formula 1, 2, 2a, 2b or 3 of the present invention, their stereoisomers or their pharmaceutically acceptable salts exhibit inhibitory activity against a variety of kinases.

[0114] According to one embodiment of the present invention, the heteroaryl derivatives represented by Chemical Formula 1, 2, 2a, 2b or 3 exhibit excellent inhibitory activity against EGFR and / or HER2 kinases, and thus can be used for treating or preventing EGFR- and / or HER2-related diseases, particularly cancer. Specifically, the compounds of Chemical Formula 1, 2, 2a, 2b or 3 can inhibit EGFR and / or HER2 wild-type or mutant kinases, which is supported by the experimental examples to be described below. The EGFR mutation can be a C797S mutation, such as EGFR Del19 / C797S (EGFR DC) or EGFR L858R / C797S (EGFR LC), but is not limited thereto. Further, the EGFR mutation can be EGFR L861Q, EGFR G719A, EGFR S768I, EGFR L718Q, or EGFR G724S, but is not limited thereto. In addition, the EGFR mutation can be 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, but is not limited thereto.

[0115] In the present disclosure, cancer includes any cancer that can exhibit a therapeutic or prophylactic effect due to inhibition of EGFR and / or HER2 kinase activity, and can be a solid cancer or a blood cancer. As non-limiting examples, the cancer can be one or more selected from the following: pseudomyxoma, intrahepatic bile duct cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphocytic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, bile duct cancer, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, cancer of the ampulla of Vater, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvic 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 site, gastric lymphoma, gastric cancer, gastric cancer, gastrointestinal stromal cancer, nephroblastoma, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational choriocarcinoma, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal cancer, vaginal cancer, spinal cord cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsillar cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, squamous cell carcinoma of the lung, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, blood cancer, and thymic cancer. Cancer includes not only primary cancer but also metastatic cancer.

[0116] According to one embodiment of the present invention, the present invention provides a pharmaceutical composition for treating or preventing EGFR- and / or HER2-related diseases, which contains a compound represented by Chemical Formula 1, 2, 2a, 2b, or 3, its stereoisomer, or its pharmaceutically acceptable salt as an active ingredient. Specifically, the EGFR- and / or HER2-related disease can be cancer. The types of cancer are the same as those described above.

[0117] In addition to the compound represented by Chemical Formula 1, 2, 2a, 2b, or 3, its stereoisomer, or its pharmaceutically acceptable salt, the pharmaceutical composition of the present invention may further contain one or more active ingredients that exhibit the same or similar pharmacological effects.

[0118] The pharmaceutical composition of the present invention can be used for clinical administration and can be prepared into various oral and parenteral dosage forms for administration.

[0119] In addition, according to an embodiment of the present invention, the present invention provides the use of the compound represented by the above chemical formula 1, 2, 2a, 2b or 3, its stereoisomer or its pharmaceutically acceptable salt in the preparation of a drug for treating or preventing EGFR- and / or HER2-related diseases. Specifically, the EGFR- and / or HER2-related diseases may be cancers. The types of cancers are the same as those described above.

[0120] In addition, according to an embodiment of the present invention, the present invention provides the use of the compound represented by the above chemical formula 1, 2, 2a, 2b or 3, its stereoisomer or its pharmaceutically acceptable salt in the preparation of a drug for treating or preventing cancer diseases, and the types of cancers are the same as those described above.

[0121] In addition, according to an embodiment of the present invention, the present invention provides a method for treating or preventing EGFR- and / or HER2-related diseases, including: administering to a subject in need a therapeutically effective amount of the compound represented by the above chemical formula 1, 2, 2a, 2b or 3, its stereoisomer or its pharmaceutically acceptable salt. The subject may be a mammal, including a human. Specifically, the EGFR- and / or HER2-related diseases may be cancers. The types of cancers are the same as those described above.

[0122] In addition, according to an embodiment of the present invention, the present invention provides a method for treating or preventing cancer, including: administering to a subject in need a therapeutically effective amount of the compound represented by chemical formula 1, 2, 2a, 2b or 3, its stereoisomer or its pharmaceutically acceptable salt. The types of cancers are the same as those described above.

[0123] In addition, according to an embodiment of the present invention, the present invention provides a method for inhibiting EGFR and / or HER2, including: administering to a subject in need a therapeutically effective amount of the compound represented by chemical formula 1, 2, 2a, 2b or 3, its stereoisomer or its pharmaceutically acceptable salt.

[0124] As used herein, the term "therapeutically effective amount" refers to the amount of a compound represented by Formula 1, 2, 2a, 2b, or 3 that is effective for treating or preventing EGFR diseases and / or HER2-related diseases. Specifically, a "therapeutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level can be determined based on factors including the type and severity of the subject, age, gender, type of disease, drug activity, drug sensitivity, administration time, administration route and excretion rate, treatment cycle, co-administered drugs, and other factors well known in the medical field. The pharmaceutical compositions of the present invention can be administered as a sole therapeutic agent, or can be co-administered with other therapeutic agents, and can be administered sequentially or simultaneously with commercially available therapeutic agents. In addition, the pharmaceutical compositions of the present invention can be administered in a single dose or multiple doses. Considering all of the above factors, it is important to administer the minimum amount that can achieve the maximum effect without side effects, and this amount can be easily determined by those skilled in the art. The dose of the pharmaceutical compositions of the present disclosure can be determined by medical experts based on various factors such as the condition, age, gender, complications, etc. of the patient. Since the active ingredient of the pharmaceutical compositions of the present disclosure has excellent safety, it can be used at a dose higher than the determined dose.

[0125] As used herein, the term "prevention" refers to any act of inhibiting or delaying the onset, spread, and recurrence of a disease by administering a compound, and the term "treatment" refers to any act of improving or beneficially altering the symptoms of a disease by administering a compound.

[0126] Furthermore, 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 additive.

[0127] Examples of additives used in the pharmaceutical composition may include sweeteners, binders, solvents, solubilizers, wetting agents, emulsifiers, isotonic agents, absorbents, 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, glyceryl stearate, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth, alginic acid, sodium alginate, methyl cellulose, sodium carboxymethyl cellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor, etc.

[0128] The pharmaceutical composition can be formulated into various dosage forms for oral administration (e.g., tablets, pills, powders, capsules, syrups or emulsions) or parenteral administration (e.g., intramuscular injection, intravenous injection or subcutaneous injection).

[0129] For example, the pharmaceutical composition can be formulated into oral preparations. Additives used at this time may include cellulose, calcium silicate, corn starch, lactose, sucrose, glucose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifying agents, diluents, etc. Specifically, oral solid preparations may include tablets, pills, powders, granules, capsules, etc., and these solid preparations can be formulated by mixing at least one excipient in the composition, such as starch, calcium carbonate, sucrose, lactose, gelatin, etc. In addition, in addition to simple excipients, lubricants such as magnesium stearate and talc can also be used. In addition, examples of oral liquid preparations may include suspensions, emulsions, syrups, etc. In addition to the commonly used simple diluents water and liquid paraffin, various excipients such as wetting agents, sweeteners, flavoring agents, preservatives, etc. can be added.

[0130] In addition, preparations for parenteral administration may include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations and suppositories. As non-aqueous solvents and suspensions, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, etc. can be used. As the matrix of suppositories, witepsol, polyethylene glycol, Tween 61, cocoa butter, lauroyl fat, glycerogelatin, etc. can be used. At the same time, injections may contain conventional additives, such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers, preservatives, etc.

[0131] In addition, the pharmaceutical composition can also be made into a compound preparation with other active agents to exert the synergistic effect of the active ingredients.

[0132] Matters mentioned in the uses, compositions and treatment methods of the present invention are equally applicable except where they are inconsistent with each other.

[0133]

Beneficial effects

[0134] The heteroaryl-derived compound of the present invention exhibits excellent inhibitory activity against EGFR and / or HER2, and thus can be effectively used for the treatment or prevention of EGFR and / or HER2-related diseases.

[0135]

Best mode

[0136] The present invention will be described in detail below through examples and experimental examples. However, the following examples and experimental examples are only used to illustrate the present invention, and the scope of the present invention is not limited to these examples.

[0137] <Analysis and purification conditions>

[0138] In the embodiments of the present invention, the synthesized compounds are purified under the following HPLC and MPLC conditions, or their structures are analyzed by NMR.

[0139] 1. HPLC and MPLC

[0140] HPLC analysis conditions (ACQUITY UPLC H-Class Core System)

[0141] A Waters UPLC system (ACQUITY UPLC PDA detector) equipped with a QDa mass detector from Waters Corporation is used. The ACQUITY BEH C18 (1.7 μm, 2.1 × 50 mm) column from Waters Corporation is used, and the column temperature is set at 30 °C.

[0142] Water containing 0.1% formic acid is used as mobile phase A, and acetonitrile containing 0.1% formic acid is used as mobile phase B.

[0143] Gradient conditions (10 - 100% B, for 3 minutes, flow rate = 0.6 ml / min)

[0144] Preparative HPLC purification system (Preparative liquid chromatography ultraviolet spectrometry)

[0145] The ACCQPrep HP150 device manufactured by Teledyne ISCO is used. The Prep RP18OBD from Waters Corporation TM (10 μm, 30 × 300 mm) is used, and the column temperature is set at room temperature.

[0146] Gradient conditions (10 - 100% B, for 120 minutes, flow rate = 42 ml / min)

[0147] Medium pressure liquid chromatography (MPLC) for purification

[0148] Medium-pressure liquid chromatography is performed using the CombiFlash Rf+UV from Teledyne ISCO.

[0149] 2. NMR analysis

[0150] NMR analysis is performed using an AVANCE III 400 or AVANCE III 400HD manufactured by Bruker Corporation, and the data are expressed in parts per million (δ) (ppm).

[0151] All reagents used are commercially available reagents and can be used without further purification. In the present invention, the ambient temperature or room temperature refers to a temperature of about 5 °C to 40 °C, such as 10 °C to 30 °C, or for example 20 °C to 27 °C, and is not strictly limited to the above range. Vacuum concentration or solvent distillation is performed using a rotary evaporator.

[0152] <Preparation Example 1> Preparation of (S)-3-phenylisoxazolidine

[0153]

[0154] Step 1: Preparation of tert-butyl (R)-(3-hydroxy-3-phenylpropoxy)carbamate

[0155] Dissolve tert-butyl hydroxycarbamate (7.8 g, 58.6 mmol) in dimethylformamide (DMF; 140 ml), then add sodium hydride (2.58 g, 64.5 mmol) at 0 °C, and react the reaction mixture for 30 minutes. Then, (R)-3-chloro-1-phenylpropan-1-ol (5 g, 29.3 mmol) dissolved in dimethylformamide (10 ml) was slowly added dropwise over 10 minutes at 0 °C, and the reaction mixture was stirred at room temperature for 72 hours. The reaction was terminated by adding an aqueous ammonium chloride solution, 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 concentrate was purified by medium-pressure liquid chromatography (ethyl acetate / hexane) to obtain the target compound (2.8 g, 68%).

[0156] MS (m / z): 150.17 [M+H] + , UPLC r.t. (min): 1.51

[0157] Step 2: Preparation of tert-butyl (S)-3-phenylisoxazolidine-2-carboxylate

[0158] The (R)-(3-hydroxy-3-phenylpropoxy)carbamic acid tert-butyl ester (2.55 g, 9.54 mmol) and triethylamine (3.13 ml, 22.44 mmol) obtained in the above step 1 were mixed with dichloromethane (250 ml), and then cooled to 0 °C. Then methanesulfonyl chloride (1 ml, 13 mmol) was added dropwise and reacted at 0 °C for 2 hours. The organic matter was extracted from the reaction mixture with brine and dichloromethane. 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 purification.

[0159] MS (m / z): 194.13 [M+H] + , UPLC r.t. (min): 1.69

[0160] Step 3: Preparation of (S)-3-phenylisoxazolidine

[0161] (S)-tert-Butyl 3-phenylisoxazolidine-2-carboxylate (2.3 g) obtained in Step 2 above was dissolved in dichloromethane (DCM; 90 ml), and then trifluoroacetic acid (14 ml) was added. The reaction mixture was reacted at room temperature for 1 hour. The reaction mixture was neutralized with an aqueous sodium bicarbonate solution and the organic layer was extracted. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The concentrate was purified by medium pressure liquid chromatography (tetrahydrofuran / n-hexane) to obtain the target compound (1.3 g, 94%).

[0162] MS (m / z): 150.08 [M+H] + , UPLC r.t. (min): 0.72

[0163] <Preparation Example 2> Preparation of (R)-3-phenylisoxazolidine

[0164]

[0165] The compound of Preparation Example 2 was prepared in a similar manner to Preparation Example 1 above and was used for the synthesis of the compounds of the examples shown in Table 1 below.

[0166] MS (m / z): 150.08 [M+H] + , UPLC r.t. (min): 0.72

[0167] <Preparation Example 3> Preparation of (R)-3-(3-fluorophenyl) isoxazolidine

[0168]

[0169] Step 1: Preparation of 3-fluoro-N-methoxy-N-methylbenzamide

[0170] 3-Fluorobenzoic acid (90 g, 642.35 mmol, 1 eq.) was dissolved in pyridine (150 mL), and then N-methoxymethanamine (75.19 g, 770.81 mmol, 1.2 eq., HCl) was added. Then, 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 starting materials had disappeared and a new less polar spot was detected. The pyridine solvent was removed by concentration under reduced pressure, and the organic layer was extracted with dichloromethane (500 mL), hydrochloric acid (500 mL, 2N), 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), which was a yellow oil.

[0171] 11H 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).

[0172] Step 2: Preparation of 1-(3-fluorophenyl)prop-2-en-1-one

[0173] Dissolve 3-fluoro-N-methoxy-N-methyl-benzamide (110 g, 600.50 mmol, 1 eq.) obtained in the above step 1 in tetrahydrofuran (THF; 1 L), and then dropwise add bromo(vinyl)magnesium (1 M, 630.53 mL, 1.05 eq.) at 0 °C. Then, stir the reaction mixture at 0 °C for 30 minutes. According to the result of TLC analysis (petroleum ether (PE): ethyl acetate (EA) = 4:1), all starting materials disappeared, and a new spot with low polarity was detected. Terminate the reaction by adding hydrochloric acid (4 N, 500 mL), and then extract the organic layer with methyl tert-butyl ether (MTBE; 2000 mL) and brine (500 mL). Dry the organic layer over sodium sulfate, concentrate it under reduced pressure, and purify it by chromatography (petroleum ether / ethyl acetate = 30 / 1) after concentration to obtain the target compound (80 g, 532.80 mmol, yield 88.73%), which is a yellow oil.

[0174] 1 1H 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).

[0175] Step 3: Preparation of 3-chloro-1-(3-fluorophenyl)prop-1-one

[0176] The 1-(3-fluorophenyl)prop-2-en-1-one (71 g, 472.86 mmol, 1.0 eq.) obtained in the above step 2 was dissolved in dichloromethane (71 mL), and then HCl / dioxane (4 M, 295.54 mL, 2.5 eq.) was added at 0 °C. Then, the reaction mixture was stirred at 15 °C for 1.5 h. TLC analysis (petroleum ether (PE): ethyl acetate (EA) = 10:1) showed that all starting materials 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), which was a yellow solid.

[0177] 1 H NMR (400 MHz, 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).

[0178] Step 4: Preparation of (S)-3-chloro-1-(3-fluorophenyl)prop-1-ol

[0179] (3aR)-1-Methyl-3,3-diphenyl-3a,4,5,6-tetrahydropyrrolo[1,2-c][1,3,2]oxazaborole (oxazaborole) (1 M, 32.15 mL, 0.1 eq.) was dissolved in tetrahydrofuran (THF; 1.2 L), and then borane tetrahydrofuran (BH3·THF; 1 M, 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. Then, 3-chloro-1-(3-fluorophenyl)propan-1-one (60 g, 309.02 mmol, 1 eq.) obtained in step 3 and diluted in tetrahydrofuran was added dropwise to the reaction mixture 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 that all starting materials disappeared and the target compound spot was detected. The reaction was terminated by adding methanol (100 mL) at 0 °C, and then the solvent was evaporated under reduced pressure. The organic layer was extracted from the concentrated compound with dichloromethane (100 mL * 3) and ammonium chloride (NH4Cl) solution (300 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The concentrated compound was purified by silica gel chromatography (petroleum ether (PE): ethyl acetate (EA) = 50:1 to 5:1) to obtain the target compound (140 g, 664.2 mmol, 71.65% yield, 89.49% purity, 65.5% e.e.), which was a colorless oil.

[0180] 1 1H 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).

[0181] Step 5: Preparation of tert-butyl (S)-(3-(3-fluorophenyl)-3-hydroxypropoxy)carbamate Dissolve tert-butyl hydroxycarbamate (50.4 g, 378.52 mmol, 1.05 eq.) in dimethylformamide (500 mL), and dissolve sodium hydride (NaH; 15.86 g, 396.55 mmol, 60% purity, 1.1 eq.) under a nitrogen atmosphere at 0 °C. Stir the reaction mixture at 10 °C for 1 hour, then add dropwise (S)-3-chloro-1-(3-fluorophenyl)propan-1-ol (68 g, 360.5 mmol, 1 eq.) diluted in dimethylformamide (180 mL) at 0 °C, and stir the reaction mixture at 10 °C for 16 hours. TLC analysis (petroleum ether (PE): ethyl acetate (EA) = 2:1) shows that all starting materials have disappeared and the target compound is detected. Add an aqueous ammonium chloride solution (3 L) to terminate the reaction, and then extract the organic layer with ethyl acetate (2000 mL) and brine (2000 mL). After drying the organic layer over sodium sulfate, concentrate it under reduced pressure to obtain the target compound (176 g, 616.87 mmol, yield 85.56%) as a bright yellow solid.

[0182] 1 1H 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).

[0183] Step 6: Preparation of tert-butyl (R)-3-(3-fluorophenyl) isoxazolidine-2-carboxylate

[0184] (S)-(3-(3-Fluorophenyl)-3-hydroxypropoxy)carbamic acid tert-butyl ester (88 g, 308.44 mmol, 1 eq.) and triethylamine (93.63 g, 925.31 mmol, 128.79 mL, 3 eq.) obtained in the above step 5 were dissolved in dichloromethane (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. The result of TLC analysis (petroleum ether (PE): ethyl acetate (EA) = 3:1) showed that all starting materials disappeared and new spots were detected. The reaction was terminated by adding water (2000 mL), and the organic layer was extracted with dichloromethane (DCM; 200 mL * 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), and the target compound (88 g) was extracted with an ee value of 82.5%. The target 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 target compound (51 g, 189.66 mmol, 30.74% yield, 99.4% purity), which was a white solid.

[0185] The purity of the (R)-tert-butyl 3-(3-fluorophenyl)isoxazolidine-2-carboxylate enantiomer obtained in step 6 was analyzed under the following SFC conditions.

[0186] Instrument: CAS-WH-ANA-SFC-C (SHIMADZU LC-30ADsf)

[0187] Column: Amycoat 50×4.6 mm I.D., 3 μm

[0188] Mobile phase: Phase A was CO2, and phase B was MeOH (0.05% DEA);

[0189] Gradient elution: MeOH (0.05% DEA) from 5% to 40% in CO2

[0190] Flow rate: 3 mL / min; Detector: PDA;

[0191] Column temperature: 35 °C; Back pressure: 100 Bar

[0192] When the enantiomeric purity of the (R)-tert-butyl 3-(3-fluorophenyl)isoxazolidine-2-carboxylate obtained in step 6 was low, the product was purified under the following SFC conditions to obtain the desired enantiomer, which was a yellow liquid.

[0193] Column: DAICEL CHIRALPAK AD-H (250 mm × 30 mm, 5 μm);

[0194] Mobile phase: [0.1% NH₃H₂O MeOH]; B%: 15% - 15%, 3.8 min; 600 minutes

[0195] Step 7: Preparation of (R)-3-(3-fluorophenyl) isoxazolidine

[0196] Dissolve tert-butyl (R)-3-(3-fluorophenyl)isoxazolidine-2-carboxylate (50 g, 185.94 mmol, 1 eq.) obtained in Step 6 in ethyl acetate (EA; 200 mL), and then add HCl / EtOAc (4 M, 300 mL, 6.45 eq.) at 0 °C. Then, stir the reaction mixture at 10 °C for 1 hour. The LCMS analysis result shows that all starting materials disappear to obtain a solid. The reaction product is concentrated under reduced pressure to obtain the target compound (32 g, 150.26 mmol, 80.81% yield, 95.62% purity, 100% e.e. HCl), which is a white solid.

[0197] MS: m / z 168.2 [M + H] +

[0198] 1 ¹H 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).

[0199] In the above Step 7, the following conditions are used to purify or analyze the enantiomers of the compound.

[0200] Instrument: CAS-WH-ANA-SFC-C (SHIMADZU LC-30ADsf)

[0201] Column: Chiralpak AY-3 50 × 4.6 mm I.D., 3 μm;

[0202] Mobile phase: Phase A is CO₂, and Phase B is IPA (0.05% DEA);

[0203] Gradient elution: B from 5% to 40% in A;

[0204] Flow rate: 3 mL / min; Detector: PDA;

[0205] Column temperature: 35 °C; Back pressure: 100 Bar

[0206] <Preparation Examples 4 to 9>

[0207] The compounds of Preparation Examples 4 to 9 below were prepared in a similar manner to Preparation Examples 1 to 3 above, and the compounds of the examples of the present invention were prepared using the compounds of Preparation Examples 1 to 9.

[0208] <Preparation Example 4> Preparation of (R)-3-(3,5-difluorophenyl)isoxazolidine

[0209]

[0210] 1 1H 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).

[0211] <Preparation Example 5> Preparation of (R)-3-(2,5-difluorophenyl)isoxazolidine

[0212]

[0213] <Preparation Example 6> Preparation of (R)-3-(4-fluorophenyl)isoxazolidine

[0214]

[0215] <Preparation Example 7> Preparation of (R)-3-(2,4-difluorophenyl)isoxazolidine

[0216]

[0217] 1 1H 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).

[0218] <Preparation Example 8> Preparation of (R)-3-(3,4-difluorophenyl)isoxazolidine

[0219]

[0220] 1 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).

[0221] <Preparation Example 9> Preparation of (R)-3-(2,3-difluorophenyl)isoxazolidine

[0222]

[0223] 1 1H 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).

[0224] <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

[0225]

[0226] Step 1: Preparation of (R)-2-(6-chloropyrimidin-4-yl)-3-(2,3-difluorophenyl) isoxazolidine

[0227] Dissolve 4,6-dichloropyrimidine (3 g, 1 eq.) and (R)-3-(2,3-difluorophenyl)isoxazolidine (4.1 g, 1.1 eq.) in ethanol (20 ml). Then, add N,N-diisopropylethylamine (DIPEA; 7.74 mL, 2.2 eq.). Stir the reaction solution at 100 °C for 3 hours. After completion of the reaction, the reaction solution is extracted with ethyl acetate and water. The collected organic layer is washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by MPLC (ethyl acetate / hexane) to obtain the target compound (5.94 g, 99% yield), which is a clear liquid.

[0228] Step 2: Preparation of (R)-6-(3-(2,3-difluorophenyl) isoxazolidine-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-methoxybenz yl)pyrimidin-4-amine

[0229] Add (R)-2-(6-chloropyrimidin-4-yl)-3-(2,3-difluorophenyl)isoxazolidine (50 mg, 1 eq.) obtained in the above 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.), and dissolve them in 1,4-dioxane (1.7 ml). Then, degas by sonication for 5 minutes under nitrogen. Add palladium acetate (Pd(OAc)₂; 7.54 mg, 0.2 eq.) and BINAP (20.92 mg, 0.2 eq.) to the reaction mixture, and then stir at 90 °C for 6 hours. After completion of the reaction, filter the reaction mixture through diatomaceous earth and wash with dichloromethane. Concentrate the obtained filtrate and purify by prep-HPLC to obtain the target compound (20 mg, 16.8%).

[0230] 1 H NMR (400 MHz, 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).

[0231] <Examples 2 to 113>

[0232] The compounds of all examples of the present invention (compounds of Examples 2 to 113) were prepared in a similar manner to Example 1 above, and the names, chemical structural formulas, NMR, and LCMS analysis results of the compounds of each of the above examples are summarized and shown in Table 1 below.

[0233] [Table 1]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293] <Example 1> Evaluation of the Proliferation Inhibitory Activity of Ba / F3 Cells Overexpressing EGFR Mutations

[0294] The following experiment was conducted to evaluate the inhibitory activity of the compounds of the present invention on the proliferation of Ba / F3 cells expressing EGFR Del19 / C797S (EGFR DC) and EGFR L858R / C797S (EGFR LC) mutations.

[0295] Ba / F3 cells were cultured in a medium (RPMI-1640) containing 10% fetal bovine serum (FBS) and 5 ng / ml IL-3 (R&D Systems). Transduced Ba / F3 cells were cultured by adding 1 μg / ml puromycin (Invitrogen) to the same medium.

[0296] Twenty-four hours before treatment with the compound, 3,000 to 5,000 cells were seeded on a well plate (white transparent bottom 96-well plate, Corning). The compound was diluted in dimethyl sulfoxide (3-fold dilution, a total of 12 concentrations) and injected at 1 μl each time, such that the final concentration was 0.2 nM to 5 μM. Seventy-two hours after treatment with the compound, the live cells were incubated for 10 minutes at room temperature using the CellTiter-Glo luminescent cell viability reagent (Promega), and the luminescence intensity was measured using a reader (Synergy Neo, Biotek). Each test was repeated three times. The result value was calculated as the cell growth rate (%) compared to the control group. A graph was made using the GraphPad Prism version 8.3.0 program, and the GI 50 value was calculated.

[0297] Table 2 below shows the evaluation results of the inhibitory activity on the proliferation of Ba / F3 cells expressing EGFR Del19 / C797S (EGFR DC) and EGFR L858R / C797S (EGFR LC) mutations.

[0298] [Table 2]

[0299]

[0300]

[0301] (A: GI 50 <100 nM; B: 100 nM ≤ GI 50 <1000 nM; C: 1000 nM ≤ GI 50 <10,000 nM; D: 10,000 nM ≤ GI 50 )

[0302] As shown in Table 2 above, it can be seen that the compounds of the embodiments of the present invention exhibit high inhibitory ability against overexpressing cell lines including EGFR Del19 / C797S (EGFRDC) and EGFR L858R / C797S (EGFR LC) mutations.

[0303] As described above, the present invention has been described in detail through preferred preparation examples, examples and experimental examples, but the scope of the present invention is not limited to the specific compounds of the embodiments of the present invention, and should be interpreted by the claims. In addition, those skilled in the art should understand that many modifications and variations can be made without departing from the scope of the present invention.

Claims

1. A compound represented by the following Chemical Formula 1, its stereoisomers or pharmaceutically acceptable salts thereof: [Chemical Formula 1] In the above Chemical Formula 1, X is CH2 or O; R1 and R2 are each independently -H, -C 1-6 alkyl, -C 1-6 haloalkyl or -halogen; R3 is -H, -C 1-6 alkyl, -C 1-6 haloalkyl, -O-C 1-6 alkyl or -O-C 1-3 alkyl-OH {wherein R3 may be connected to a carbon in the phenyl ring to form a fused ring or connected to R4 to form a fused ring}; R4 is -H, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)(C 1-6 alkyl), -(4-6 membered heterocycloalkyl) or -(7-11 membered heterobicycloalkyl) {wherein the -NH(C 1-6 alkyl) or -N(C 1-6 alkyl)(C 1-6 alkyl) may be connected to ring Y to form a fused ring; at least one H of the -(4-6 membered heterocycloalkyl) may be substituted with -C 1-6 alkyl, -C 1-6 haloalkyl, -(CH2)n-O-C 1-6 alkyl, -(CH2)n-NR a R b 、-(CH2)n-S(=O)2-C 1-3 alkyl, -halogen, -(CH2)n-(4-6 membered heterocycloalkyl) or - (CH2)n-(7-11 membered heterobicycloalkyl), [herein, at least one H of the -(CH2)n-(4-6 membered heterocycloalkyl) or - (CH2)n-(7-11 membered heterobicycloalkyl) ring may be substituted with -C 1-6 alkyl, -C 1-6 haloalkyl, -(CH2)n-O-C 1-6 alkyl, -(CH2)n-C(=O)-C 1-3 alkyl, -(CH2)n-S(=O)2-C 1-3 alkyl, -(CH2)nNR a R bor - halogen]; at least one H of said -(7 - 11 - membered hetero - bicycloalkyl) may be substituted with - C 1-6 alkyl, - C 1-6 haloalkyl, -(CH2)n - C(=O) - C 1-3 alkyl, -(CH2)n - C(=O) - (3 - 6 - membered cycloalkyl), -(CH2)n - S(=O)2 - C 1-3 alkyl, -(CH2)n - NR a R b , - O - C 1-6 alkyl, - halogen, or - (CH2)n - (4 - 6 - membered heterocycloalkyl) [wherein, at least one H of said -(CH2)n - (4 - 6 - membered heterocycloalkyl) or - (CH2)n - C(=O) - (3 - 6 - membered cycloalkyl) ring may be substituted with - C 1-6 alkyl, - C 1-6 haloalkyl or - halogen]}; 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 - 6 - membered heterocycloalkyl); ring Y is phenyl or 5 - 10 - membered heteroaryl {wherein at least one H of said phenyl or 5 - 10 - membered heteroaryl ring may be substituted with - C 1-6 alkyl, - C 1-6 hydroxyalkyl, - C 1-6 haloalkyl, -(3 - 6 - membered cycloalkyl) or - halogen}.

2. The compound represented by Formula 1 according to claim 1, its stereoisomers or its pharmaceutically acceptable salts, wherein X is CH2 or O; R1 and R2 are each independently - H or - halogen; R3 is - H, - C 1-3 haloalkyl, - O - C 1-3 alkyl or - O - C 1-3 alkyl - OH {wherein R3 may be connected to a carbon in the phenyl ring to form a fused ring, or connected to R4 to form a fused ring}; R4 is - H, - N(C 1-3 alkyl)(C 1-3 alkyl), -(4 - 6 - membered heterocycloalkyl) or -(7 - 11 - membered hetero - bicycloalkyl) {wherein said - N(C 1-3 alkyl)(C 1-3(4-6 membered heteroalkyl) may be linked to ring Y to form a fused ring; at least one H of said -(4-6 membered heteroalkyl) may be substituted with -C 1-6 alkyl, -C 1-6 haloalkyl, -(CH2)n-O-C 1-3 alkyl, -(CH2)n-NR a R b , -(CH2)n-S(=O)2-C 1-3 alkyl, -halogen, -(CH2)n-(4-6 membered heteroalkyl) or -(CH2)n-(7-11 membered heterobicycloalkyl) [herein, at least one H of said -(CH2)n-(4-6 membered heteroalkyl) or -(CH2)n-(7-11 membered heterobicycloalkyl) ring may be substituted with -C 1-3 alkyl, -C 1-6 haloalkyl, -(CH2)n-O-C 1-3 alkyl, -(CH2)n-S(=O)2-C 1-3 alkyl, -(CH2)nNR a R b or -halogen]; at least one H of said -(7-11 membered heterobicycloalkyl) may be substituted with -C 1-3 alkyl, -C 1-6 haloalkyl, -(CH2)n-C(=O)-C 1-3 alkyl, -(CH2)n-C(=O)-(3-6 membered cycloalkyl), -(CH2)n-S(=O)2-C 1-3 alkyl, -(CH2)n-NR a R b , -O-C 1-3 alkyl, -halogen, or - (CH2)n-(4-6 membered heteroalkyl) [herein, at least one H of said -(CH2)n-(4-6 membered heteroalkyl) or - (CH2)n-C(=O)-(3-6 membered cycloalkyl) ring may be substituted with -halogen]}; 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 -(4-6 membered heteroalkyl); ring Y is phenyl, 5-6 membered heteroaryl or 9-10 membered heteroaryl {wherein at least one H of said phenyl, 5-6 membered heteroaryl or 9-10 membered heteroaryl ring may be substituted with -C 1-3 alkyl, -C 1-3 hydroxyalkyl, -(3-6 membered cycloalkyl) or -halogen}.

3. The compound represented by Chemical Formula 1 according to Claim 1, its stereoisomers or its pharmaceutically acceptable salts, wherein 4. The compound represented by Chemical Formula 1 according to Claim 1, its stereoisomers or its pharmaceutically acceptable salts, wherein Ring Y is {wherein at least one H of said Ring Y may be substituted with -C 1-3 alkyl, -C 1-3 hydroxyalkyl, -C 1-3 haloalkyl, -(3-6 membered cycloalkyl) or -halogen}.

5. The compound represented by the following Chemical Formula 2, its stereoisomers or its pharmaceutically acceptable salts: [Chemical Formula 2] In the above Chemical Formula 2, X is CH2 or O; R1 and R2 are each independently -H or -halogen; R3 is -H, -C 1-3 haloalkyl, -O-C 1-3 alkyl or -O-C 1-3 alkyl-OH {wherein R3 may be connected to the carbon in the phenyl ring to form a fused ring, or connected to R4 to form a fused ring}; R4 is -H, -N(C 1-3 alkyl)(C 1-3 alkyl), -(4-6 membered heterocycloalkyl) or -(7-11 membered heterobicycloalkyl) {wherein the -N(C 1-3 alkyl)(C 1-3 alkyl) may be connected to Ring Y to form a fused ring; at least one H of the -(4-6 membered heterocycloalkyl) may be substituted with -C 1-6 alkyl, -C 1-6 haloalkyl, -(CH2)n-O-C 1-3 alkyl, -(CH2)n-NR a R b 、-(CH2)n-S(=O)2-C 1-3 alkyl, -halogen, -(CH2)n-(4-6 membered heterocycloalkyl), or -(CH2)n-(7-11 membered heterobicycloalkyl) [In this article, at least one H of the -(CH2)n-(4-6 membered heterocycloalkyl) or -(CH2)n-(7-11 membered heterobicycloalkyl) ring may be substituted with -C 1-3 alkyl, -C1-6 haloalkyl, -(CH2)n-O-C 1-3 alkyl, -(CH2)n-S(=O)2-C 1-3 alkyl, -(CH2)nNR a R b or -halogen]; at least one H of said -(7-11 membered heterobicycloalkyl) may be substituted with -C 1-3 alkyl, -C 1-6 haloalkyl, -(CH2)n-C(=O)-C 1-3 alkyl, -(CH2)n-C(=O)-(3-6 membered cycloalkyl), -(CH2)n-S(=O)2-C 1-3 alkyl, -(CH2)n-NR a R b , -O-C 1-3 alkyl, -halogen, or -(CH2)n-(4-6 membered heterocycloalkyl) [as used herein, at least one H of said -(CH2)n-(4-6 membered heterocycloalkyl) or - (CH2)n-C(=O)-(3-6 membered cycloalkyl) ring may be substituted with -halogen]}; 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 -(4-6 membered heterocycloalkyl); Ring Y is phenyl, 5-6 membered heteroaryl or 9-10 membered heteroaryl {wherein at least one H of said phenyl, 5-6 membered heteroaryl or 9-10 membered heteroaryl ring may be substituted with -C 1-3 alkyl, -C 1-3 hydroxyalkyl, -(3-6 membered cycloalkyl) or -halogen}.

6. A compound represented by the following Chemical Formula 3, its stereoisomers or its pharmaceutically acceptable salts: [Chemical Formula 3] In Chemical Formula 3 above, X is CH2 or O; R1 and R2 are each independently -H or -halogen; R4 is -(4-6 membered heterocycloalkyl) or -(7-11 membered heterobicycloalkyl) {wherein at least one H of said -(4-6 membered heterocycloalkyl) or -(7-11 membered heterobicycloalkyl) ring may be substituted with -C 1-3 alkyl, -C 1-3 haloalkyl, -(CH2)n-S(=O)2-C 1-3 alkyl or -halogen}; n is 0, 1 or 2; Ring Y is a 5 - membered heteroaryl group {wherein, at least one H of the 5 - membered heteroaryl ring may be substituted with - C 1-3 alkyl or - halogen}.

7. A compound selected from the following compounds, their stereoisomers or their pharmaceutically acceptable salts:

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

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

10. The pharmaceutical composition according to claim 9, wherein the pharmaceutical composition inhibits EGFR and / or HER2.

11. The pharmaceutical composition according to claim 10, wherein the composition inhibits any one or more selected from the following 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 L858R, and EGFR L792F / L858R.

12. The pharmaceutical composition according to claim 9, wherein the cancer is one or more selected from the following: pseudomyxoma, intrahepatic bile duct cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, bile duct cancer, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, cancer of the ampulla of Vater, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvic 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 site, gastric lymphoma, gastric cancer, gastric cancer, gastrointestinal stromal cancer, Wilms tumor, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational choriocarcinoma, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal cancer, vaginal cancer, spinal cord cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi 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. Use of a compound according to any one of claims 1 to 7, its stereoisomers, or its pharmaceutically acceptable salts in the preparation of a medicament for the treatment or prevention of EGFR- and / or HER2-related diseases.

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

15. A method for treating or preventing at least one disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein the disease is selected from the group consisting of: Pseudomyxoma, intrahepatic bile duct cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, bile duct cancer, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, cancer of the ampulla of Vater, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvic cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue tumor, malignant bone tumor, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoid, gastrointestinal stromal cancer, Wilms' tumor, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational choriocarcinoma, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid, 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, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, blood cancer, and thymic cancer.

Images