Heteroaryl derivative compounds and uses thereof

Abstract

The invention relates to a heteroaryl derivative and application thereof. The heteroaryl derivative of the present invention exhibits excellent inhibitory activity against EGFR, and thus can be usefully used as a therapeutic agent for EGFR-related diseases.

Description

Technical Field

[0001] The present invention relates to a heteroaryl derivative compound and its medical use. Specifically, the present invention relates to a heteroaryl derivative compound having epidermal growth factor receptor (EGFR) inhibitory activity. Background Art

[0002] Protein kinases are molecular switches involved in signal transduction pathways, and the transition between the active and inactive states of target proteins in cells should be smoothly controlled by kinases. If the transition between the active and inactive states is abnormally controlled, the signal transduction in the cell will be overactivated or inactivated, thereby inducing uncontrolled cell division and proliferation. In particular, abnormal activation caused by mutation, amplification and / or overexpression of protein kinase genes leads to the occurrence and progression of various tumors, or plays a vital role in the occurrence of various diseases such as inflammatory diseases, degenerative brain diseases, autoimmune diseases, etc.

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

[0004] Meanwhile, it is known that EGFR mutations (i.e., EGFR Del19 or EGFR L858R) are the main causes of non-small cell lung cancer and head and neck cancer, and Iressa and Tarceva, which are therapeutic drugs for them, have been developed and used in clinical practice. However, when patients use these drugs, acquired resistance is observed, i.e., secondary mutations of EGFR are caused according to the drug structure, and it is also found that this resistance is the main cause of actual resistance. When the first-generation EGFR inhibitors are applied for an average of about 10 months, acquired resistance, i.e., the T790M mutation located in the EGFR kinase gatekeeper, occurs, so the first-generation EGFR inhibitors do not show efficacy. In other words, the occurrence of EGFR Del19 / T790M or EGFR L858R / T790M double mutations makes existing therapeutic drugs unable to exert their efficacy. Therefore, the third-generation EGFR-TKI targeted drug osimertinib has been developed, which shows high responsiveness to drug resistance caused by EGFR T790M mutation, but there are also reports of drug resistance (Clin Cancer Res, 2015, 17: 21). EGFR C797S mutation is considered to be one of the main mechanisms leading to osimertinib resistance. It is reported that about 40% of clinical trial patients have EGFR C797S mutation (Nature Medicine, 2015, 21: 560-562).

[0005] There is a growing but unmet need for novel compounds that can treat EGFR-related diseases by modulating EGFR activity, particularly C797S mutations, such as EGFR Del19 / T790M / C797S or EGFR L858R / T790M / C797S. Summary of the invention Technical issues

[0006] The object of the present invention is to provide a heteroaryl derivative having a novel structure, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

[0007] Another object of the present invention is to provide a method for preparing heteroaryl derivative compounds.

[0008] Another object of the present invention is to provide the pharmaceutical use of the heteroaryl derivative compound, more specifically, to provide a pharmaceutical composition for treating or preventing EGFR-related diseases comprising the heteroaryl derivative compound as an active ingredient, the use of the compound for treating or preventing EGFR-related diseases, or a method for treating or preventing EGFR-related diseases comprising administering the compound. Technical Solution

[0009] To achieve the above object, the present inventors have made considerable efforts and conducted extensive research, and confirmed that the heteroaryl derivative compound represented by the following chemical formula 1 can inhibit the proliferation of EGFR-activated cells, thereby completing the present invention.

[0010] Heteroaryl derivative compounds

[0011] The present invention provides a compound represented by the following chemical formula 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0012]

Chemical formula 1

[0013] In the above chemical formula 1,

[0014] X1 and X2 are each independently CH or N;

[0015] Rx is -H, -C 1-6 Alkyl, -C 1-6 Hydroxyalkyl, -NH2, -OH, -OC 1-6 Alkyl or -halogen;

[0016] Y1 and Y2 are each independently CH or N;

[0017] Ring W is a cycloalkyl, heterocycloalkyl, aryl or heteroaryl group {wherein at least one H on the ring of the cycloalkyl, heterocycloalkyl, aryl or heteroaryl group may be replaced by -C 1-6 Alkyl, -C 1-6 Alkenyl, -C 1-6 Alkynyl, -C 1-6 Alkyl-cycloalkyl, -C 1-6 Hydroxyalkyl, -OH, -OC 1-6 Alkyl, =O, -C(=O)-H, -C(=O)-C 1-6 alkyl, -C(=O)-cycloalkyl, -S(=O)2-C 1-6 alkyl, -S(=O)2-cycloalkyl, -halogen or cycloalkyl, and the -CH2- on the ring of the heterocycloalkyl may be substituted by -S(=O)2-};

[0018] L is -C(=O)-, -C(=O)-NR a -, -C(=O)-O-, -NR a -C(=O)- or -OC(=O)-;

[0019] R1 is -H, -C 1-6 Alkyl, -C 1-6 Cyanoalkyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Hydroxyhaloalkyl, -C 1-6 Haloalkyl, -(CH2)mC(=O)-OC 1-6 Alkyl, -(CH2)mS(=O)2-R b , -(CH2)m-cycloalkyl, -(CH2)m-heterocycloalkyl, -(CH2)m-aryl or -(CH2)m-heteroaryl {wherein at least one H of the -(CH2)m-cycloalkyl, -(CH2)m-heterocycloalkyl, -(CH2)m-aryl or -(CH2)m-heteroaryl group may be replaced by -C 1-6 Alkyl, -C 1-6 Cyanoalkyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, -CN, -NO2, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)(C 1-6 Alkyl), -OH, -OC 1-6 Alkyl, =O, -C(=O)-C 1-6 Alkyl, -C(=O)-OC 1-6 Alkyl, -S(=O)2-C 1-6 alkyl, -S(=O)2-halogen, -S(=O)2-cycloalkyl, -C 1-6 Alkyl-S(=O)2-C 1-6 Alkyl, -NR c -S(=O)2-C 1-6 The alkyl, -halogen, -(CH2)n-cycloalkyl, -(CH2)n-heterocycloalkyl, -(CH2)n-aryl or -(CH2)n-heteroaryl groups are substituted [wherein at least one of the H groups on the ring of the -(CH2)n-cycloalkyl, -(CH2)n-heterocycloalkyl, -(CH2)n-aryl or -(CH2)n-heteroaryl groups may be replaced by -C 1-6 Alkyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, =O, -S(=O)2-C 1-6 Alkyl, -C 1-6 Alkyl-S(=O)2-C 1-6 -(CH2)m-cycloalkyl or -(CH2)m-heterocycloalkyl -CH2- may be substituted with -S(=O)2-};

[0020] R2 is -C 1-6Alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl {wherein at least one H on the ring of the cycloalkyl, heterocycloalkyl, aryl or heteroaryl group may be replaced by -C 1-6 Alkyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -CN, -NO2, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)(C 1-6 Alkyl), -OH, -OC 1-6 Alkyl or -halogen substituted}, or R2 may be connected to the ring W to form a ring {wherein at least one H of the ring may be -C 1-6 Alkyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -CN, -NO2, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)(C 1-6 Alkyl), -OH, -OC 1-6 alkyl or -halogen substituted};

[0021] R a -H or -C 1-6 alkyl;

[0022] R b -H, -C 1-6 Alkyl, -NH2, -NH-C 1-6 Alkyl or -N(C 1-6 Alkyl)(C 1-6 alkyl);

[0023] R c -H or -C 1-6 Alkyl; and

[0024] m and n are each independently 0, 1, 2, 3 or 4.

[0025] According to one embodiment of the present invention, the compound represented by Chemical Formula 1, its stereoisomer or a pharmaceutically acceptable salt thereof may be within the following range:

[0026] X1 and X2 are each independently CH or N {wherein at least one of X1 or X2 is N};

[0027] Rx is -H or -C 1-6 alkyl;

[0028] Y1 and Y2 are each independently CH or N {wherein at least one of Y1 or Y2 is N};

[0029] Ring W is a heterocycloalkyl, aryl or heteroaryl group {wherein at least one H on the heterocycloalkyl, aryl or heteroaryl ring may be replaced by -C 1-6 Alkyl, -C 1-6 Alkyl-cycloalkyl, -OH, -OC 1-6 Alkyl, =O, -C(=O)-H, -C(=O)-C 1-6 alkyl, -C(=O)-cycloalkyl, -S(=O)2-C 1-6 alkyl, -S(=O)2-cycloalkyl, -halogen or cycloalkyl, and the -CH2- on the ring of the heterocycloalkyl may be substituted by -S(=O)2-};

[0030] L is -C(=O)-, -C(=O)-NR a -, -C(=O)-O-, -NR a -C(=O)- or -OC(=O)-;

[0031] R1 is -H, -C 1-6 Alkyl, -C 1-6 Cyanoalkyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Hydroxyhaloalkyl, -C 1-6 Haloalkyl, -(CH2)mC(=O)-OC 1-6 Alkyl, -(CH2)mS(=O)2-R b , -(CH2)m-cycloalkyl, -(CH2)m-heterocycloalkyl, -(CH2)m-aryl or -(CH2)m-heteroaryl {wherein at least one H of the -(CH2)m-cycloalkyl, -(CH2)m-heterocycloalkyl, -(CH2)m-aryl or -(CH2)m-heteroaryl group may be replaced by -C 1-6 Alkyl, -C 1-6 Cyanoalkyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, -CN, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)(C 1-6 alkyl), -C(=O)-C 1-6 Alkyl, -C(=O)-OC 1-6 Alkyl, -S(=O)2-C 1-6 alkyl, -S(=O)2-halogen, -S(=O)2-cycloalkyl, -C 1-6 Alkyl-S(=O)2-C 1-6 Alkyl, -NRc -S(=O)2-C 1-6 Alkyl, -halogen or -(CH2)n-heterocycloalkyl [wherein at least one H on the ring of the -(CH2)n-heterocycloalkyl may be replaced by -C 1-6 -(CH2)m-cycloalkyl or -(CH2)m-heterocycloalkyl], and the -CH2- of the -(CH2)m-cycloalkyl or -(CH2)m-heterocycloalkyl may be substituted with -S(=O)2-};

[0032] R2 is -C 1-6 Alkyl, cycloalkyl, heterocycloalkyl or heteroaryl {wherein at least one H on the ring of the cycloalkyl, heterocycloalkyl or heteroaryl may be replaced by -C 1-6 alkyl}, or R2 may be connected to ring W to form a ring {wherein at least one H of the ring may be -C 1-6 alkyl substituted};

[0033] R a -H or -C 1-6 alkyl;

[0034] R b -H, -C 1-6 Alkyl, -NH2, -NH-C 1-6 Alkyl or -N(C 1-6 Alkyl)(C 1-6 alkyl);

[0035] R c -H or -C 1-6 Alkyl; and

[0036] m and n are each independently 0, 1, 2, 3 or 4.

[0037] According to one embodiment of the present invention, the compound represented by Chemical Formula 1, its stereoisomer or a pharmaceutically acceptable salt thereof may be within the following range:

[0038] Ring W is a heterocycloalkyl group selected from The group consisting of {wherein at least one H on the heterocycloalkyl ring may be replaced by -C 1-6 Alkyl, -OH, -OC 1-6 Alkyl, =O, -S(=O)2-C 1-6 alkyl, -S(=O)2-cycloalkyl or -halogen substituted}.

[0039] According to one embodiment of the present invention, the compound represented by Chemical Formula 1, its stereoisomer or a pharmaceutically acceptable salt thereof may be within the following range:

[0040] Ring W is an aryl or heteroaryl group selected from phenyl and The group consisting of {wherein at least one H on the heteroaryl ring can be replaced by -C1-6 Alkyl, -C 1-6 Hydroxyalkyl, -OC 1-6 Alkyl, -S(=O)2-C 1-6 alkyl or -S(=O)2-cycloalkyl}.

[0041] According to one embodiment of the present invention, the compound represented by the above Chemical Formula 1 can be selected from the group consisting of the compounds listed in Table 2 below.

[0042] According to one embodiment of the present invention, the compound represented by Chemical Formula 1, its stereoisomer or a pharmaceutically acceptable salt thereof may be a compound represented by the following Chemical Formula A, its stereoisomer or a pharmaceutically acceptable salt thereof:

[0043]

Chemical formula A

[0044] In the above chemical formula A,

[0045] X1 and X2 are each independently CH or N;

[0046] Rx is -H, -C 1-6 Alkyl, -C 1-6 Hydroxyalkyl, -NH2, -OH, -OC 1-6 Alkyl or -halogen;

[0047] Y1 is CH or N;

[0048] Ring W is a 5-6 membered heteroaryl or phenyl group {wherein at least one H on the 5-6 membered heteroaryl or phenyl ring may be -C 1-6 Alkyl, -C 1-6 Alkenyl, -C 1-6 Alkynyl, -C 1-6 Alkyl-cycloalkyl, -C 1-6 Hydroxyalkyl, -OH, -OC 1-6 The -CH2- on the ring of the heterocycloalkyl group may be substituted by -S(=O)2-};

[0049] Z1 is -(CH2CH2)-, -(CH2CH2CH2)- or -(CH2CH2CH2CH2)-{wherein at least one of the H in -(CH2CH2)-, -(CH2CH2CH2)- or -(CH2CH2CH2CH2)- may be replaced by -C 1-3 alkyl substituted};

[0050] Z2 is -(CH2)- or -O-;

[0051] Z3 is a bond (blank), -(CH2)- or -(CH2CH2)-;

[0052] L is -C(=O)-, -C(=O)-NR a -, -C(=O)-O-, -NR a -C(=O)- or -OC(=O)-;

[0053] R1 is -H, -C 1-6 Alkyl, -C 1-6 Cyanoalkyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Hydroxyhaloalkyl, -C 1-6 Haloalkyl, -(CH2)mC(=O)-OC 1-6 Alkyl, -(CH2)mS(=O)2-R b , -(CH2)m-cycloalkyl, -(CH2)m-heterocycloalkyl, -(CH2)m-aryl or -(CH2)m-heteroaryl {wherein at least one H of the -(CH2)m-cycloalkyl, -(CH2)m-heterocycloalkyl, -(CH2)m-aryl or -(CH2)m-heteroaryl group may be replaced by -C 1-6 Alkyl, -C 1-6 Cyanoalkyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, -CN, -NO2, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)(C 1-6 Alkyl), -OH, -OC 1-6 Alkyl, =O, -S(=O)2-C 1-6 alkyl, -S(=O)2-halogen, -S(=O)2-cycloalkyl, -C 1-6 Alkyl-S(=O)2-C 1-6 Alkyl, -NR c -S(=O)2-C 1-6 The alkyl, -halogen, -(CH2)n-cycloalkyl, -(CH2)n-heterocycloalkyl, -(CH2)n-aryl or -(CH2)n-heteroaryl groups are substituted [wherein at least one of the H groups on the ring of the -(CH2)n-cycloalkyl, -(CH2)n-heterocycloalkyl, -(CH2)n-aryl or -(CH2)n-heteroaryl groups may be replaced by -C 1-6 Alkyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C1-6 Haloalkyl, =O, -S(=O)2-C 1-6 Alkyl, -C 1-6 Alkyl-S(=O)2-C 1-6 -(CH2)m-cycloalkyl or -(CH2)m-heterocycloalkyl -CH2- may be substituted with -S(=O)2-};

[0054] R a -H or -C 1-6 alkyl;

[0055] R b -H, -C 1-6 Alkyl, -NH2, -NH-C 1-6 Alkyl or -N(C 1-6 Alkyl)(C 1-6 alkyl);

[0056] R c -H or -C 1-6 Alkyl; and

[0057] m and n are each independently 0, 1, 2 or 3.

[0058] According to one embodiment of the present invention, the compound represented by Chemical Formula A, its stereoisomer or a pharmaceutically acceptable salt thereof may be within the following range:

[0059] X1 and X2 are each independently CH or N {wherein at least one of X1 or X2 is N};

[0060] Rx is -H or -C 1-6 alkyl;

[0061] Y1 is CH or N;

[0062] Ring W is a 5-6 membered heteroaryl group {wherein at least one H on the ring of the 5-6 membered heteroaryl group may be -C 1-6 alkyl or cycloalkyl substituted};

[0063] Z1 is -(CH2CH2)-, -(CH2CH2CH2)- or -(CH2CH2CH2CH2)-{wherein at least one of the H in -(CH2CH2)-, -(CH2CH2CH2)- or -(CH2CH2CH2CH2)- may be replaced by -C 1-3 alkyl substituted};

[0064] Z2 is -(CH2)- or -O-;

[0065] Z3 is a bond (blank), -(CH2)- or -(CH2CH2)-;

[0066] L is -C(=O)-, -C(=O)-NR a -or -C(=O)-O-;

[0067] R1 is -H, -C 1-6 Alkyl, -C 1-6 Cyanoalkyl, -C 1-6 Haloalkyl, -(CH2)mS(=O)2-R b , -(CH2)m-cycloalkyl, -(CH2)m-heterocycloalkyl or -(CH2)m-aryl {wherein at least one H of the -(CH2)m-cycloalkyl, -(CH2)m-heterocycloalkyl or -(CH2)m-aryl group may be replaced by -C 1-6 Alkyl, -C 1-6 Cyanoalkyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, -S(=O)2-C 1-6 Alkyl, -C 1-6 Alkyl-S(=O)2-C 1-6 Alkyl, -NR c -S(=O)2-C 1-6 Alkyl, -halogen or -(CH2)n-heterocycloalkyl [wherein at least one H on the ring of the -(CH2)n-heterocycloalkyl may be replaced by -C 1-6 -(CH2)m-cycloalkyl or -(CH2)m-heterocycloalkyl], and the -CH2- of the -(CH2)m-cycloalkyl or -(CH2)m-heterocycloalkyl may be substituted with -S(=O)2-};

[0068] R a -H or -C 1-6 alkyl;

[0069] R b -H or -C 1-6 alkyl;

[0070] R c -H or -C 1-6 Alkyl; and

[0071] m and n are each independently 0, 1, 2 or 3.

[0072] According to one embodiment of the present invention, the compound represented by Chemical Formula A, its stereoisomer or a pharmaceutically acceptable salt thereof may be within the following range:

[0073] Ring W is or phenyl {wherein or at least one of the H atoms on the phenyl ring may be replaced by -C 1-6 Alkyl, -C 1-6Hydroxyalkyl, -OC 1-6 Alkyl, -S(=O)2-C 1-6 alkyl or -S(=O)2-cycloalkyl}.

[0074] In the present invention, unless otherwise specified, "alkyl" may refer to a straight or branched acyclic hydrocarbon, a cyclic hydrocarbon or a saturated hydrocarbon bonded thereto. 1-6 "Alkyl" may refer to an alkyl group containing 1 to 6 carbon atoms. Acyclic alkyl groups may include methyl, ethyl, n-propyl, n-butyl, isopropyl, sec-butyl, isobutyl, tert-butyl, etc., but are not limited thereto. In the present specification, cyclic alkyl groups may be used interchangeably with "cycloalkyl", for example, may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc., but are not limited thereto.

[0075] In the present invention, unless otherwise specified, "alkenyl" may refer to an unsaturated hydrocarbon containing at least one double bond. 2-6 The "alkyl" group may contain 2 to 6 carbon atoms and may contain at least one double bond. For example, it may include vinyl, prop-1-enyl, but-1-enyl, pent-1-enyl, hex-1-enyl, etc., but is not limited thereto.

[0076] In the present invention, unless otherwise specified, "alkynyl" may refer to an unsaturated hydrocarbon containing at least one triple bond. 2-6 The "alkynyl group" may contain 2 to 6 carbon atoms and may contain at least one triple bond. For example, it may include ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-ynyl, hex-1-ynyl, etc., but is not limited thereto.

[0077] In the present invention, "alkoxy" may refer to -(O-alkyl) as an alkyl ether group, wherein the alkyl group has the same meaning as above. 1-6 "Alkoxy" may refer to a group containing C 1-6 Alkoxy of alkyl, i.e. -(OC 1-6 Alkyl); as examples, alkoxy may include but are not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.

[0078] In the present invention, "halogen" may be F, Cl, Br or I.

[0079] In the present invention, "haloalkyl" may refer to a straight or branched alkyl (hydrocarbon) having one or more carbon atoms substituted by halogen as defined herein. Examples of haloalkyl include methyl, ethyl, propyl, isopropyl, isobutyl or n-butyl, which are independently substituted by one or more halogens such as F, Cl, Br or I, but are not limited thereto.

[0080] In the present invention, "hydroxyalkyl" may refer to a straight or branched alkyl (hydrocarbon) group in which a carbon atom is substituted with a hydroxyl group (-OH). Examples of hydroxyalkyl groups include methyl, ethyl, propyl, isopropyl, isobutyl or n-butyl groups independently substituted with -OH, but are not limited thereto.

[0081] In the present invention, "aminoalkyl" may refer to a straight or branched alkyl (hydrocarbon) chain whose carbon atom is replaced by an amino group-(NR'R"). Here, R' and R" may be independently selected from hydrogen, C 1-6 The group consisting of an alkyl group and an N protecting group (such as Boc), wherein the selected R' and R" may each independently be substituted or unsubstituted.

[0082] In the present invention, "cyanoalkyl" may refer to a straight or branched chain alkyl (hydrocarbon) group in which a carbon atom is substituted with a cyano group (-CN).

[0083] In the present invention, "heterocycloalkyl" may refer to a ring containing one or more selected from N, O, P, P(=O) and S, and may be saturated or partially unsaturated. Here, when unsaturated, the heterocycloalkyl may be referred to as heterocycloolefin. Unless otherwise specified, the heterocycloalkyl may be a monocyclic or polycyclic ring, such as a spirocyclic ring, a bridged ring or a cyclic ring. In addition, "3-12 membered heterocycloalkyl" may refer to a heterocycloalkyl containing 3 to 12 atoms forming a ring, and as an example, the heterocycloalkyl may include pyrrolidine, piperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4 (1H, 3H) -dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine The invention also includes, but is not limited to, phenoxy-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]heptane, (1R,5S)-3-azabicyclo[3.2.1]octane, (1S,4S)-2-azabicyclo[2.2.2]octane or (1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane, etc.

[0084] In the present invention, "aromatic hydrocarbon" may refer to an aromatic hydrocarbon ring. Aromatic hydrocarbons may be monocyclic aromatic hydrocarbons or polycyclic aromatic hydrocarbons. The number of carbon atoms forming the aromatic hydrocarbon ring 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 aromatic hydrocarbons may include benzene, naphthalene, fluorene, anthracene, phenanthrene, biphenyl, terphenyl, quaterphenyl, pentaphenyl, sexphenyl, triphenylene, pyrene, benzofluoranthene, chrysene, etc., but are not limited thereto. In this specification, the part obtained by removing a hydrogen atom from the above-mentioned "aromatic hydrocarbon" is referred to as "aryl".

[0085] In the present invention, "heteroaromatic hydrocarbon" can be a ring containing one or more of O, N, P, Si and S as a heteroatom. The number of carbon atoms forming the heteroaromatic hydrocarbon ring can be 2 or more and 30 or less, or 2 or more and 20 or less. The heteroaromatic hydrocarbon can be a monocyclic heteroaromatic hydrocarbon or a polycyclic heteroaromatic hydrocarbon. The polycyclic heteroaromatic hydrocarbon can have, for example, a bicyclic or tricyclic structure. Examples of heteroaromatic hydrocarbons may include thiophene, purine, pyrrole, pyrazole, imidazole, thiazole, oxazole, isothiazole, oxadiazole, triazole, pyridine, bipyridine, triazine, acridinyl, pyridazine, pyrazine, quinoline, quinazoline, quinoxaline, phenoxazine, phthalazine, pyrimidine, pyridopyrimidine, pyridopyrazine, pyrazinopyrazine, isoquinoline, indole, carbazole, imidazopyridazine, imidazopyridine, imidazopyridine, 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 to this. In one embodiment of the present invention, heteroaromatic hydrocarbons can also include a kind of bicyclic heteroaromatic hydrocarbons, which include aromatic hydrocarbon rings with the ring of heterocycloalkyl or heteroaromatic hydrocarbons with the ring of cycloalkyl. In this specification, the part obtained by removing a hydrogen atom from the above-mentioned "heteroaromatic hydrocarbons" is called "heteroaryl".

[0086] In the present invention, "stereoisomer" refers to a compound having the same chemical formula or molecular formula but different stereostructures. Stereoisomers in this specification include optical isomers, enantiomers, diastereomers, cis / trans isomers, rotational isomers and atropisomers, and each of these isomers, racemates and mixtures thereof is also included in the scope of the present invention. For example, since the stereochemical structure of Chemical Formula 1 of the present invention is not specified, stereoisomers of Chemical Formula 1 may be included. Unless otherwise specified, the real bond connected to the asymmetric carbon atom is May include wedge-shaped real bonds representing the absolute arrangement of stereocenters or wedge-shaped virtual key

[0087] The compound represented by Chemical Formula 1 of the present invention may exist in the form of a "pharmaceutically acceptable salt". Therefore, the pharmaceutically acceptable salts of the compound represented by the above Chemical Formula 1 are included in the scope of the compounds of the present invention. The term "pharmaceutically acceptable salt" of the present invention refers to any organic or inorganic acid addition salt of the compound represented by Chemical Formula 1, the concentration of which has a relatively non-toxic and harmless effective effect on the patient, wherein the side effects caused by these salts do not reduce the beneficial effects of the compound.

[0088] In particular, pharmaceutically acceptable salts may be acid addition salts formed from free acids. Here, acid addition salts may be obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, hypophosphorous acid, etc.; non-toxic organic acids such as aliphatic monocarboxylates and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates and alkandioates, aromatic acids, aliphatic and aromatic sulfonic acids; organic acids such as trifluoroacetic acid, acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, p-toluenesulfonic acid, tartaric acid, fumaric acid, etc.

[0089] Examples of pharmaceutically acceptable salts may include sulfate, sulfite, nitrate, phosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, octanoate, acrylate, formate, isobutyrate, decanoate, 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.

[0090] The acid addition salt can be prepared by conventional methods, for example, the derivative represented by Chemical Formula 1 can be dissolved in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile, etc., and an organic acid or an inorganic acid is added to form a precipitate, and then the precipitate is filtered and dried, or the solvent and an excess of acid are distilled under reduced pressure, and then the reaction product is dried and crystallized in an organic solvent.

[0091] In addition, pharmaceutically acceptable salts can be salts obtained using alkali or metal salts. As examples of metal salts, alkali metal salts or alkaline earth metal salts can be obtained by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate. Sodium salts, potassium salts or calcium salts can be used as alkali metal salts pharmaceutically. In addition, the corresponding salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate), or can be prepared by salt production methods known in the art.

[0092] Uses of heteroaryl derivative compounds

[0093] The present invention provides the use of a compound represented by the following chemical formula 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0094]

Chemical formula 1

[0095] The compound represented by Chemical Formula 1 of the present invention, its stereoisomer or a pharmaceutically acceptable salt thereof exhibits inhibitory activity against various kinases.

[0096] According to an embodiment of the present invention, the heteroaryl derivative represented by the above chemical formula 1 exhibits excellent inhibitory activity against EGFR kinases, and thus can be effectively used to treat or prevent EGFR-related diseases, particularly cancer. In particular, the heteroaryl derivative compounds of the present invention exhibit excellent inhibitory activity against EGFR mutations (e.g., EGFR Del19 / C797S, EGFR L858R / C797S, EGFRDel19 / T790M / C797S or EGFR L858R / T790M / C797S, etc.), and thus can be effectively used to treat or prevent cancers induced by EGFR.

[0097] In the present invention, cancer includes all cancers that can be prevented or treated by inhibiting EGFR kinase activity, and may be solid cancer or blood cancer. For example, the cancer can be one or more types selected from the group consisting of pseudomyxoma, intrahepatic biliary 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 cancer, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary cancer, colorectal cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla of Vater cancer, 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 Intestinal cancer, meningioma, esophageal cancer, glioma, renal pelvis 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' cell cancer, 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 thymus cancer, but not limited to these. Furthermore, the cancer includes primary cancer and metastatic cancer.

[0098] According to an embodiment of the present invention, the present invention provides a pharmaceutical composition for treating or preventing EGFR-related diseases, comprising a compound represented by the above chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. Specifically, the EGFR-related disease may be cancer. The type of cancer is as described above.

[0099] In addition to the compound represented by the above Chemical Formula 1, its stereoisomers or pharmaceutically acceptable salts thereof, the pharmaceutical composition of the present invention may further include at least one active ingredient exhibiting the same or similar efficacy.

[0100] The pharmaceutical composition of the present invention can be used for clinical administration, and can be prepared for administration in various oral and parenteral dosage forms.

[0101] 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, its stereoisomer or its pharmaceutically acceptable salt in the preparation of a drug for treating or preventing EGFR-related diseases. Specifically, the EGFR-related disease may be cancer. The type of cancer is as described above.

[0102] In addition, according to an embodiment of the present invention, the present invention provides a use of the compound represented by the above Chemical Formula 1, its stereoisomer or a pharmaceutically acceptable salt thereof in preparing a drug for treating or preventing cancer. The types of cancer are as described above.

[0103] In addition, according to an embodiment of the present invention, the present invention provides a method for treating or preventing EGFR-related diseases, comprising administering a therapeutically effective amount of a compound represented by the above-mentioned Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a subject in need. The subject may be a mammal, including a human being. Specifically, the EGFR-related disease may be cancer. The type of cancer is as described above.

[0104] In addition, according to an embodiment of the present invention, the present invention provides a method for treating or preventing cancer, comprising administering a therapeutically effective amount of the compound represented by the above Chemical Formula 1, its stereoisomer or a pharmaceutically acceptable salt thereof to a subject in need thereof. The types of cancer are as described above.

[0105] In addition, according to an embodiment of the present invention, the present invention provides a method for inhibiting EGFR, comprising administering a therapeutically effective amount of the compound represented by the above Chemical Formula 1, its stereoisomer or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0106] The term "therapeutically effective amount" as used herein refers to the amount of the compound represented by Chemical Formula 1 that is effective for treating and preventing EGFR-related diseases. Specifically, "therapeutically effective amount" refers to an amount sufficient to treat a disease at a reasonable benefit / risk ratio suitable for medical treatment, and the effective dose level can be determined according to the type and severity of the subject, age, sex, disease type, drug activity, sensitivity to the drug, administration time, route of administration, excretion rate, duration of treatment, drugs used simultaneously, and other factors well known in the medical field. The pharmaceutical composition of the present invention can be administered as a single therapeutic agent, or it can be administered in combination with other therapeutic agents, or it can be administered sequentially or simultaneously with commercially available therapeutic agents. In addition, the pharmaceutical composition of the present invention can be administered single or multiple times. Taking into account all of the above factors, it is important to administer an amount that can achieve the maximum effect with the minimum amount and without side effects, which can be easily determined by those skilled in the art. The dosage of the pharmaceutical composition of the present invention can be determined by experts based on various factors such as the patient's condition, age, sex, complications, etc. Since the active ingredient of the pharmaceutical composition of the present invention has excellent safety, the dosage of the active ingredient can even exceed the predetermined dose.

[0107] In the present invention, the term "prevention" refers to any action of inhibiting or delaying the occurrence, spread and recurrence of a disease by administering a compound, and the term "treatment" refers to any action of improving or beneficially changing the symptoms of a disease by administering a compound.

[0108] In addition, according to an 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 Chemical Formula 1, a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable additive.

[0109] 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, additives may include lactose, glucose, sucrose, mannitol, sorbitol, cellulose, glycine, silicon dioxide, talc, stearic acid, tristearin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth gum, alginic acid, sodium alginate, methylcellulose, sodium carboxymethylcellulose, agar, water, ethanol, polyethylene glycol, polyvinyl pyrrolidone, sodium chloride, calcium chloride, orange flavor, strawberry flavor, vanilla flavor, etc.

[0110] The pharmaceutical composition can be combined into various preparation forms for oral administration (such as tablets, pills, powders, capsules, syrups or emulsions) or parenteral administration (such as intramuscular injections, intravenous injections or subcutaneous injections).

[0111] For example, the pharmaceutical composition can be combined into a preparation for oral administration, and the additive used herein can include cellulose, calcium silicate, corn starch, lactose, sucrose, glucose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talcum powder, surfactant, suspending agent, emulsifier, diluent, etc. Specifically, solid preparations for oral administration can include tablets, pills, powders, granules, capsules, etc., and these solid preparations can be prepared by mixing at least one excipient in the composition, such as starch, calcium carbonate, sucrose, lactose and gelatin. In addition, in addition to simple excipients, lubricants such as magnesium stearate and talcum powder can also be used. In addition, examples of liquid preparations for oral administration can include suspending agents, emulsions, syrups, etc. In addition to commonly used simple diluents water and liquid paraffin, various excipients such as wetting agents, sweeteners, aromatics and preservatives can also be included.

[0112] In addition, the preparation for parenteral administration can include sterile aqueous solution, non-aqueous solution, suspension, emulsion, lyophilized preparation and suppository. As non-aqueous solvent and suspension, vegetable oils such as propylene glycol, polyethylene glycol, olive oil, injectable esters such as ethyl oleate, etc. can be used. As the matrix of suppository, Witepsol, Macrogol, Tween 61, cocoa butter, laurel fat, glycerin gelatin, etc. can be used. Meanwhile, conventional additives such as solubilizer, isotonic agent, suspending agent, emulsifier, stabilizer and preservative can be included in injection.

[0113] The pharmaceutical composition can also be formulated as a combined preparation with other active agents to achieve a synergistic effect of the active ingredients.

[0114] Matters described in the uses, compositions and methods of treatment of the present invention apply equally unless they contradict each other.

Beneficial Effects

[0115] The heteroaryl derivative compounds of the present invention can exhibit excellent inhibitory activity on EGFR, and thus can be used to treat or prevent EGFR-related diseases. DETAILED DESCRIPTION [Best Mode]

[0116] The present invention will be described in detail below by way of 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 thereto.

[0117] <Analysis and purification conditions>

[0118] The compounds synthesized in the examples of the present invention were purified or structurally analyzed under the following conditions.

[0119] 1. High Performance Liquid Chromatography (HPLC) and Medium Pressure Liquid Chromatography (MPLC)

[0120] High-performance liquid chromatography (ACQUITY UPLC H-Class Core System) for analysis

[0121] A UPLC system (ACQUITY UPLC PDA detector) produced by Waters was used, which was equipped with a mass QDa detector produced by Waters. BEH C18 (1.7 μm, 2.1 × 50 mm) column, column temperature set at 30 °C.

[0122] Water containing 0.1% formic acid was used as mobile phase A, and acetonitrile containing 0.1% formic acid was used as mobile phase B.

[0123] Gradient conditions (10-100% B, 3 min, flow rate = 0.6 mL / min)

[0124] Preparative HPLC system for purification (preparative liquid chromatography-ultraviolet spectroscopy)

[0125] The ACCQPrep HP150 equipment produced by Teledyne ISCO was used. Prep RP18 OBD TM (10 μm, 30 × 300 mm) chromatographic column, and the column temperature was set to room temperature.

[0126] Gradient conditions (10-100% B, 120 min, flow rate = 42 mL / min)

[0127] Medium Pressure Liquid Chromatography (MPLC) for Purification

[0128] Medium pressure liquid chromatography analysis was performed using CombiFlash Rf+UV ​​produced by Teledyne ISCO.

[0129] 2. Nuclear Magnetic Resonance Analysis

[0130] The nuclear magnetic resonance analysis was performed using AVANCE III 400 or AVANCE III 400HD produced by Bruker, and the data were expressed in parts per million (δ) (ppm).

[0131] The commercial reagents used do not require further purification. In the present invention, ambient temperature or room temperature refers to a temperature of about 5°C to 40°C, such as 10°C to 30°C, and also such as 20°C to 27°C, and is not strictly limited to the above range. A rotary evaporator is used for reduced pressure concentration or solvent distillation.

[0132] Preparation Example: Preparation of the intermediate compound of the present invention

[0133] <Preparation Example 1> Preparation of 2-(cis-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine

[0134]

[0135] Step 1: Preparation of cis-tert-butyl 3-fluoro-4-methoxypiperidine-1-carboxylate

[0136] Cis-3-fluoro-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (1 g, 1.0 eq.) was dissolved in tetrahydrofuran (THF; 23 mL), and sodium hydride (NaH; 0.22 g, purity 60%, 1.2 eq.) was added at 0°C in a nitrogen atmosphere. The reaction mixture was stirred at 0°C for 30 minutes, and iodomethane (0.31 mL, 1.1 eq.) was added dropwise at 0°C. Then, the reaction mixture was stirred at room temperature for 3 hours. LCMS analysis confirmed that the starting material was completely consumed and the target compound was detected. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (EA; 100 mL) and saturated sodium bicarbonate aqueous solution (200 mL*2) 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 (1.0 g, yield 94%) as a yellow oil.

[0137] MS: m / z 234.3[M+H] + .

[0138] Step 2: Preparation of cis-3-fluoro-4-methoxypiperidine hydrochloride

[0139] The cis-3-fluoro-4-methoxypiperidine-1-carboxylic acid tert-butyl ester (1.0 g, 1.0 eq.) obtained in step 1 was dissolved in dichloromethane (DCM; 24 mL), and then HCl / dioxane (4 M, 3.7 mL, 3.0 eq.) was added at 0°C. The reaction mixture was then stirred at room temperature for 12 hours. LCMS analysis confirmed that the starting material was completely consumed and the target compound was detected. The reaction mixture was concentrated under reduced pressure and ether (60 mL) was added to obtain a solid. The precipitate was filtered and dried to obtain the target compound (0.56 g, 77% yield) as a white solid.

[0140] MS: m / z 134.3[M+H] + .

[0141] Step 3: Preparation of 2-(cis-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine

[0142] At room temperature, cis-3-fluoro-4-methoxypiperidine hydrochloride (0.56 g, 1.0 eq.) and 2-chloropyrimidine-4-amine (0.32 g, 0.8 eq.) obtained in step 2 were dissolved in isopropanol (IPA; 8 mL), and N,N-diisopropylethylamine (DIPEA; 2.52 mL, 4.0 eq.) was added. The reaction mixture was stirred at 120°C for 12 hours. LCMS analysis confirmed that the starting material was completely consumed and the target compound was detected. The reaction mixture was concentrated under reduced pressure, and the concentrated compound was purified by MPLC (n-hexane / ethyl acetate) to obtain the target compound as a white solid (0.59 g, yield 83%).

[0143] 1 H NMR(400MHz, CDCl3) δ7.92(d,J=5.6Hz,1H),5.75(d,J=5.6Hz,1H),4.77(ddtd, J=48.3,6.2,2.6,0.9Hz,1H),4.62(s,2H),4.50(dddd,J=14.0,7.8,6.2,1.4Hz, 1H),4.21(dddd,J=13.5,6.5,3.9,1.4Hz,1H),3.67-3.49(m,2H),3.47(s,3H), 3.40(dddd,J=13.7,8.8,3.7,1.8Hz,1H),1.99-1.88(m,1H),1.82-1.72(m,1H).

[0144] MS: m / z 227.3[M+H] + .

[0145] <Preparation Example 2> Preparation of 2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-amine

[0146]

[0147] Step 1: Preparation of 4-bromo-1-(cyclopropylsulfonyl)-1H-pyrazole

[0148] 4-Bromo-1H-pyrazole (10 g, 1 eq.) was dissolved in dichloromethane (DCM; 170 mL), and cyclopropanesulfonyl chloride (7.62 mL, 1.1 eq.) and triethylamine (TEA; 12.33 mL, 1.3 eq.) were then added thereto. The reaction mixture was stirred at room temperature for 19 hours. LCMS analysis confirmed that the starting material had been completely consumed and the target compound was detected. Water (100 mL) was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane (DCM; 200 mL). The organic layer was concentrated under reduced pressure and purified by MPLC (n-hexane / ethyl acetate) to obtain the target compound (10 g, yield 59%).

[0149] MS: m / z 250.3[M+H] + .

[0150] Step 2: 1-(Cyclopropylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolidone Preparation of azoles

[0151] 4-Bromo-1-(cyclopropylsulfonyl)-1H-pyrazole (10 g, 1 eq.) obtained in step 1 was dissolved in 1,4-dioxane (133 mL), and then diboric acid pinacol ester (12.14 g, 1.2 eq.) and potassium acetate (7.82 g, 2 eq.) were added. The reaction mixture was degassed for 10 minutes, and then [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (1.17 g, 0.04 eq.) was added. Then, in a nitrogen atmosphere, the reaction mixture was stirred at 110°C for 16 hours. LCMS analysis results showed that all starting materials had disappeared and the target compound was detected. The reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to obtain the target compound (11 g, 93%), which was used for the next step without purification.

[0152] MS: m / z 299.3[M+H] + .

[0153] Step 3: Preparation of 2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-amine

[0154] 1-(Cyclopropylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.3 g, 1 eq.) obtained in the above step 2 was dissolved in acetonitrile (ACN; 15 mL), and then 2-chloropyrimidine-4-amine (1 g, 1 eq.) and aqueous sodium carbonate solution (2 M, 11.57 mL, 3 eq.) were added. The reaction mixture was degassed for 10 minutes, and then bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]palladium dichloride (0.109 g, 0.02 eq.) was added. The reaction mixture was stirred at 100° C. for 2 hours in a nitrogen atmosphere. LCMS analysis results showed that all starting materials had disappeared and the target compound was detected. The reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure and purified by MPLC (ethyl acetate / dichloromethane) to obtain the target compound (1 g, yield 49%).

[0155] MS: m / z 266.3[M+H] + .

[0156] <Preparation Examples 3 to 15>

[0157] The preparation methods of the compounds of the following Preparation Examples 3 to 9 are similar to the above <Preparation Example 1>. In addition, the preparation methods of the compounds of the following Preparation Examples 10 to 15 are similar to the above <Preparation Example 2>. Table 1 summarizes the names and chemical structures of the compounds of Preparation Examples 3 to 15.

[0158] [Table 1]

[0159] <Preparation Example 16> Preparation of 4-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one

[0160]

[0161] Step 1: 2-Methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one

[0162] 1-Methyl-1H-pyrazole-5-ol (6 g, 1 eq.) was dissolved in acetonitrile (ACN; 204 mL), and potassium carbonate (25.4 g, 3 eq.) was then added. The reaction mixture was stirred at room temperature for 30 minutes, and then 2-(trimethylsilyl)ethoxymethyl chloride (14.1 mL, 1.3 eq.) was slowly added and stirred at room temperature for 3 hours. LCMS analysis results showed that all starting materials had disappeared and the target compound was detected. The reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, poured into n-hexane, and the precipitated solid was filtered and dried to obtain the target compound (14 g, yield 100%).

[0163] MS: m / z 229.3[M+H] + .

[0164] Step 2: 4-Bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazole-3- Preparation of ketone

[0165] The 2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (5 g, 1 eq.) obtained in the above step 1 was dissolved in acetonitrile (ACN; 110 mL), and then N-bromosuccinimide (NBS; 5.07 g, 1.3 eq.) was slowly added at 0°C. The reaction mixture was stirred at 15°C for 1 hour. LCMS analysis results showed that all starting materials had disappeared and the target compound was detected. Saturated aqueous sodium thiosulfate solution (100 mL) was added to the reaction mixture to terminate the reaction. The organic layer was extracted with ethyl acetate (EA; 200 mL) and washed several times with saturated aqueous sodium chloride solution (100 mL*2). Then, the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The concentrated compound was purified by chromatography (ethyl acetate / n-hexane) to obtain the target compound (6 g, yield 89%).

[0166] MS: m / z 307.3[M+H] + .

[0167] <Preparation Example 17> Preparation of 4-(4-aminopyrimidin-2-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one

[0168]

[0169] Step 1: Preparation of tert-butyl (tert-butyloxycarbonyl)(2-chloropyrimidin-4-yl)carbamate

[0170] 2-Chloropyrimidine-4-amine (10 g, 1 eq.) was dissolved in tetrahydrofuran (THF; 77 mL), and then di-tert-butyl dicarbonate (44.8 mL, 2.5 eq.), triethylamine (TEA; 32.3 mL, 3 eq.) and 4-(dimethylamino)pyridine (0.943 g, 0.1 eq.) were added in sequence at 0°C. The reaction mixture was stirred at 50°C for 1 hour. LCMS analysis results showed that all starting materials had disappeared and the target compound was detected. The organic layer was extracted with ethyl acetate (EA; 200 mL) and saturated aqueous ammonium chloride solution (100 mL), and washed several times with saturated aqueous sodium chloride solution (100 mL*2). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The concentrated compound was purified by MPLC (n-hexane / ethyl acetate) to obtain the target compound (22.5 g, yield 88%).

[0171] MS: m / z 330.3[M+H] + .

[0172] Step 2: (tert-Butyloxycarbonyl)(2-(2-methyl-3-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2, Preparation of tert-butyl 3-dihydro-1H-pyrazol-4-yl)pyrimidin-4-yl)carbamate

[0173] Tert-butyl (tert-butyloxycarbonyl)(2-chloropyrimidin-4-yl)carbamate (12.88 g, 6 eq.) obtained in the above step 1, 4-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (2 g, 1 eq.) obtained in the above <Preparation Example 16>, biboronic acid pinacol ester (9.92 g, 6 eq.) and sodium carbonate (3.45 g, 5 eq.) were dissolved in acetonitrile (ACN; 100 mL) and water (10 mL), and then degassed for 10 minutes. Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride (Pd(amphos)Cl2; 0.69 g, 0.15 eq.) was added to the reaction mixture, and stirred at 100°C for 2 hours in a nitrogen atmosphere. LCMS analysis results showed that all starting materials had disappeared and the target compound was detected. The reaction mixture was filtered through celite. The filtrate was evaporated to dryness under reduced pressure, and the concentrated compound was purified by MPLC (methanol / dichloromethane) to obtain the target compound (2.5 g, purity 75%, yield 55%).

[0174] MS: m / z 522.3[M+H] + .

[0175] Step 3: 4-(4-aminopyrimidin-2-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2- Preparation of dihydro-3H-pyrazol-3-one

[0176] Tert-butyl (tert-butyloxycarbonyl)(2-(2-methyl-3-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrazol-4-yl)pyrimidin-4-yl)carbamate (3 g, 5.75 mmol) obtained in the above step 2 was dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP; 30 mL), and trifluoroacetic acid (TFA; 6.65 mL, 15 eq.) was added, and stirred at 15°C for 3 hours. LCMS analysis results showed that all starting materials had disappeared and the target compound was detected. Saturated aqueous sodium bicarbonate solution (100 mL) was slowly added to the reaction mixture, and then extracted with ethyl acetate (EA; 200 mL). The organic layer was washed several times with saturated sodium chloride solution (100 mL*2). Then, the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The concentrated compound was purified by MPLC (methanol / dichloromethane) to obtain the target compound (1.1 g, yield 59.5%).

[0177] MS: m / z 322.3[M+H] + .

[0178] <Preparation Example 18> Preparation of 4-(4-aminopyrimidin-2-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one

[0179]

[0180] The preparation method of the compound of Preparation Example 18 is similar to that of Preparation Example 17 above.

[0181] MS: m / z 321.3[M+H] + .

[0182] Example: Preparation of the compounds of the present invention

[0183] <Example 1> Preparation of (6-((2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-(isopropylamino)pyridin-3-yl)(3-((methylsulfonyl)methyl)azetidin-1-yl)methanone

[0184]

[0185] Step 1: Preparation of 6-chloro-4-(isopropylamino)nicotinate

[0186] Methyl 4,6-dichloronicotinate (6 g, 1 eq.) was dissolved in acetonitrile (ACN; 58 mL), and then isopropylamine (2.74 mL, 1.1 eq.) and diisopropylethylamine (DIPEA; 10.17 mL, 2 eq.) were added. The reaction mixture was stirred at 80 ° C for 16 hours. The reaction mixture was concentrated under reduced pressure, water (100 mL) was added, and then extracted with ethyl acetate (EA; 200 mL). The organic layer was washed several times with a saturated sodium chloride solution (100 mL*2). Then, the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The concentrated compound was purified by chromatography (ethyl acetate / n-hexane) to obtain the target compound (6.4 g, yield 96%).

[0187] Step 2: Preparation of 6-chloro-4-(isopropylamino)nicotinic acid

[0188] The 6-chloro-4-(isopropylamino)nicotinic acid methyl ester (6.4 g, 1 eq.) obtained in step 1 was dissolved in tetrahydrofuran (THF; 50 mL), methanol (50 mL) and water (50 mL), and then an aqueous sodium hydroxide solution (6 M; 23.32 mL, 5 eq.) was added. The reaction mixture was stirred at 80°C for 2 hours. LCMS analysis results showed that all starting materials had disappeared and the target compound was detected. The reaction mixture was titrated with 6N hydrochloric acid solution until the pH value reached 4. The precipitated solid was filtered and washed with water. The obtained solid was dried in a reduced pressure oven to obtain the target compound (5.3 g, yield 88%).

[0189] Step 3: (6-chloro-4-(isopropylamino)pyridin-3-yl)(3-((methylsulfonyl)methyl)azetidine- Preparation of 1-methyl) ketone

[0190] 6-Chloro-4-(isopropylamino)nicotinic acid (600 mg, 1 eq.) obtained in step 2 above was dissolved in dichloromethane (DCM; 5 mL), and then 3-((methylsulfonyl)methyl)azetidine (809 mg, 1.1 eq.), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine-3-oxide hexafluorophosphate (HATU; 2.1 g, 2 eq.), and diisopropylethylamine (DIPEA; 2 mL, 5 eq.) were added in sequence. The reaction mixture was stirred at room temperature for 6 hours. LCMS analysis results showed that all starting materials had disappeared and the target compound was detected. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium bicarbonate solution (10 mL) was added, and then extracted with ethyl acetate (EA; 10 mL). The organic layer was washed with saturated aqueous sodium chloride solution (10 mL*2). Then, the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The concentrated compound was purified by chromatography (ethyl acetate / n-hexane) to obtain the target compound (500 mg, yield 52%).

[0191] Step 4: (6-((2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-(isopropyl Preparation of (3-( ...

[0192] The (6-chloro-4-(isopropylamino)pyridin-3-yl)(3-((methylsulfonyl)methyl)azetidin-1-yl)methanone (70 mg, 1 eq.) obtained in step 3 was dissolved in 1,4-dioxane (2 mL), and then 2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (64 mg, 1.2 eq.) and cesium carbonate (198 mg, 3 eq.) obtained in the above Preparation Example 2 were added. The reaction mixture was degassed for 5 minutes, and then methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (II) (20 mg, 0.1 eq.) was added. Then, the reaction mixture was stirred at 120° C. for 12 hours. LCMS analysis results showed that all starting materials had disappeared and the target compound was detected. The reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure and purified by preparative HPLC to obtain the target compound (30 mg, yield 26%).

[0193] 1H NMR (400MHz, chloroform-d) δ9.81 (s, 1H), 8.62 (d, J = 0.6Hz, 1H), 8.44 (d, J = 0.6Hz, 1H), 8.41 (d, J = 5.8Hz, 1H),8.22(d,J=7.2Hz,1H),7.91(s,1H),7.71(s,1H),6.96(d,J=5.8Hz,1H),4.55(t,J=8.9Hz,2H ),4.18(s,2H),3.85(h,J=6.4Hz,1H),3.40(d,J=7.1Hz,2H),3.34(qd,J=8.1,5.6Hz,1H),2.96(s ,3H),2.83(tt,J=8.0,4.7Hz,1H),1.57-1.49(m,2H),1.38(d,J=6.4Hz,6H),1.26-1.20(m,2H); MS m / z:575.31[M+H] + .

[0194] <Example 80> (S)-N-(cyanomethyl)-1 1 ,6-dimethyl-1 1 H-9-Oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazole heterocycle Jiufan-4 5 - Preparation of formamide

[0195]

[0196] Step 1: (S)-4-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)amino)-N-(cyanomethyl)-6- ((2-(2-methyl-3-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrazol-4-yl)pyrimidine- Preparation of 4-amino)nicotinamide

[0197] (S)-4-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)amino)-6-chloro-N-(cyanomethyl)nicotinamide (0.37 g, 1 eq.) obtained in a manner similar to that of Example 1 was dissolved in 1,4-dioxane (4.67 mL), and then 4-(4-aminopyrimidin-2-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (0.3 g, 1 eq.) obtained in the above Preparation Example 17 and cesium carbonate (0.912 g, 3 eq.) were added. The reaction mixture was degassed for 10 minutes, and then methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.28 g, 0.3 eq.) was added. Then, in a nitrogen atmosphere, the reaction mixture was stirred at 120°C for 3 hours. LCMS analysis results showed that all starting materials had disappeared and the target compound was detected. The reaction mixture was filtered through diatomaceous earth. After the filtrate was concentrated under reduced pressure, it was purified by chromatography (methanol / dichloromethane) to obtain the target compound (0.17 g, yield 27%).

[0198] Step 2: (S)-N-(cyanomethyl)-6-((2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino Preparation of 4-((4-hydroxybutyl-2-yl)amino)nicotinamide

[0199] (S)-4-((4-((tert-butyldimethylsilyl)oxy)but-2-yl)amino)-N-(cyanomethyl)-6-((2-(2-methyl-3-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)nicotinamide (0.16 g, 1 eq.) obtained in step 1 was dissolved in tetrahydrofuran (THF; 5 mL), and then tetrabutylammonium fluoride (1 M, 0.469 mL, 2 eq.) was added at 0°C. Then, the reaction mixture was stirred at 80°C for 3 hours. LCMS analysis results showed that all starting materials had disappeared and the target compound was detected. The reaction mixture was concentrated under reduced pressure and purified by reverse phase chromatography (0.035% trifluoroacetic acid in methanol / water) to obtain the target compound (0.06 g, yield 58%).

[0200] Step 3: (S)-N-(cyanomethyl)-1 1 ,6-dimethyl-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4 (2,4)-Pyridine-1(4,5)-pyrazole heterocyclic 9-fan-4 5 - Preparation of formamide

[0201] (S)-N-(cyanomethyl)-6-((2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-((4-hydroxybutyl-2-yl)amino)nicotinamide (2 mg, 1 eq.) obtained in step 2 was dissolved in tetrahydrofuran (THF; 0.5 mL), and then cyanomethylenetri-n-butylphosphine (CMBP; 0.05 mL, 4 eq.) was added. The reaction mixture was degassed for 10 minutes and stirred at 60° C. for 2 hours under a nitrogen atmosphere. LCMS analysis results showed that all starting materials had disappeared and the target compound was detected. The reaction mixture was concentrated under reduced pressure and purified by reverse phase chromatography (0.035% trifluoroacetic acid in methanol / water) to obtain the target compound (5 mg, yield 26%).

[0202] 1 H NMR (400MHz, chloroform-d) δ8.89 (s, 1H), 8.45 (d, J = 7.3Hz, 1H), 8.36 (d, J = 5.7Hz, 1H) ,8.35(s,1H),8.13(s,1H),6.51(d,J=5.8Hz,1H),6.43-6.37(m,1H),4.68(td ,J=10.0,3.2Hz,1H),4.31(dd,J=9.2,5.7Hz,2H),4.28-4.23(m,1H),4.09(dt ,J=9.2,4.4Hz,1H),3.80(s,3H),2.20-2.13(m,2H),1.47(d,J=6.6Hz,3H);MS m / z:420.17[M+H] + .

[0203] <Example 2> to <Example 79> and <Example 81> to <Example 134>

[0204] The preparation methods of all compounds of the examples of the present invention (compounds of Examples 1 to 134) are similar to the above-mentioned Example 1 or 80. The compound names, chemical structural formulas, NMR and LCMS analysis results of the compounds of the above-mentioned examples are summarized and shown in Table 2 below.

[0205] [Table 2]

[0237] <Experimental Example 1> Evaluation of EGFR C797S enzyme inhibitory activity

[0238] The compounds of the present invention were reacted with purified human epidermal growth factor receptor (EGFR) (d746-750 / T790M / C797S) (668-end, SignalChem) enzyme and specific substrate, and the enzyme inhibitory activity was evaluated as follows. The reaction buffer consisted of 40mM Tris-HCl (pH 7.4), 20mM MgCl2, 0.5mg / mL BSA and 50μM DTT, and the reactions of all test substances were carried out in the reaction buffer. The compounds were diluted continuously from 10mM DMSO stock solution in 12 gradients, and the enzyme activity was measured when the final compound concentration was 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001, 0.0003, 0.0001 and 0μM. In this test, human epidermal growth factor receptor (d746-750 / T790M / C797S) (3ng) enzyme was reacted with purified ATP (5μM) and enzyme substrate (0.2μg) at 25°C for 1 hour, and then the enzyme activity was determined using the in vitro ADP-GloTM kinase assay (Promega). The enzyme activity reaction solution, ADP-Glo ​​reaction solution and enzyme activity detection solution were reacted in a ratio of 2:2:1, and the enzyme activity inhibition was determined by luminescence. Based on the enzyme activity luminescence of the solvent control group that was not treated with the compound, the degree of inhibition of the enzyme activity by the treatment concentration of each compound was calculated, and the concentration of each compound that inhibited the enzyme activity by 50% was determined as IC 50(nM) values ​​were calculated using GraphPad Prism 8.4.3 (GraphPad Software, San Diego). The results are summarized in Table 3 below.

[0239] [Table 3] (A:IC 50 <50nM; B: 50nM≤IC 50 <500nM; C: 500nM≤IC 50 <5000nM; D: 5000nM≤IC 50 )

[0240] <Experimental Example 2> Evaluation of the inhibitory activity on the proliferation of Ba / F3 cells overexpressing EGFR C797S

[0241] In order to evaluate the inhibitory activity of the compounds of the present invention on the proliferation of Ba / F3 cells expressing EGFR Del19 / T790M / C797S mutation, the following experiment was performed.

[0242] Ba / F3 cells were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS), and 3000 cells were seeded into each well of a white transparent bottom 96-well plate (Corning) 24 hours before treatment with the compound. The compound was diluted with dimethyl sulfoxide (3-fold dilution, a total of 12 concentrations), and 1 μL was injected for each concentration to make a final concentration of 0.2nM to 5μM. After 72 hours of treatment with the compound, the living cells were reacted in a carbon dioxide incubator at 37°C for 72 hours, and then reacted at room temperature for 10 minutes using Cell Titer-Glo cell viability luminescent reagent (Promega), and the luminescence intensity was measured using a microplate reader (SynergyNeo2, Biotek). The calculated result value is the cell growth rate (%) compared with the control group. GI was calculated using the GraphPadPrism version 8.4.3 (GraphPad Software, San Diego) program 50 The results are summarized in Table 4 below.

[0243] [Table 4] (A:GI 50 <500nM; B: 500nM≤GI 50 <5000nM; C: 5000nM≤GI 50 )

[0244] As shown in Table 3 and Table 4 above, it can be seen that the compounds of the examples of the present invention have high inhibitory activity against enzymes or cell lines containing the EGFR C797S mutation.

[0245] As mentioned above, the present invention has been described in detail by preferred preparation examples, embodiments and experimental examples, but the scope of the present invention is not limited to the specific compounds of the embodiments of the present invention, but should be interpreted according to the appended claims. In addition, it should be understood by those skilled in the art that various modifications and variations can also be made without departing from the scope of the present invention.

Claims

1. A compound represented by the following chemical formula A, its stereoisomer or a pharmaceutically acceptable salt thereof: 【Chemical formula A】 In the above chemical formula A, X1 and X2 are each independently CH or N; Rx is -H, -C 1-6 Alkyl, -C 1-6 Hydroxyalkyl, -NH2, -OH, -OC 1-6 Alkyl or -halogen; Y1 is CH or N; Ring W is a 5-6 membered heteroaryl or phenyl group {wherein at least one H on the 5-6 membered heteroaryl or phenyl ring may be -C 1-6 Alkyl, -C 1-6 Alkenyl, -C 1-6 Alkynyl, -C 1-6 Alkyl-cycloalkyl, -C 1-6 Hydroxyalkyl, -OH, -OC 1-6 The -CH2- on the ring of the heterocycloalkyl group may be substituted by -S(=O)2-}; Z1 is -(CH2CH2)-, -(CH2CH2CH2)- or -(CH2CH2CH2CH2)-{wherein at least one of the H in -(CH2CH2)-, -(CH2CH2CH2)- or -(CH2CH2CH2CH2)- may be replaced by -C 1-3 alkyl substituted}; Z2 is -(CH2)- or -O-; Z3 is a bond (blank), -(CH2)- or -(CH2CH2)-; L is -C(=O)-, -C(=O)-NR a -, -C(=O)-O-, -NR a -C(=O)- or -O-C(=O)-; R1 is -H, -C 1-6 Alkyl, -C 1-6 Cyanoalkyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Hydroxyhaloalkyl, -C 1-6 Haloalkyl, -(CH2)mC(=O)-OC 1-6 Alkyl, -(CH2)mS(=O)2-R b , -(CH2)m-cycloalkyl, -(CH2)m-heterocycloalkyl, -(CH2)m-aryl or -(CH2)m-heteroaryl {wherein at least one H of the -(CH2)m-cycloalkyl, -(CH2)m-heterocycloalkyl, -(CH2)m-aryl or -(CH2)m-heteroaryl group may be replaced by -C 1-6 Alkyl, -C 1-6 Cyanoalkyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, -CN, -NO2, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)(C 1-6 Alkyl), -OH, -OC 1-6 Alkyl, =O, -S(=O)2-C 1-6 alkyl, -S(=O)2-halogen, -S(=O)2-cycloalkyl, -C 1-6 Alkyl-S(=O)2-C 1-6 Alkyl, -NR c -S(=O)2-C 1-6 The alkyl, -halogen, -(CH2)n-cycloalkyl, -(CH2)n-heterocycloalkyl, -(CH2)n-aryl or -(CH2)n-heteroaryl groups are substituted [wherein at least one of the H groups on the ring of the -(CH2)n-cycloalkyl, -(CH2)n-heterocycloalkyl, -(CH2)n-aryl or -(CH2)n-heteroaryl groups may be replaced by -C 1-6 Alkyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, =O, -S(=O)2-C 1-6 Alkyl, -C 1-6 Alkyl-S(=O)2-C 1-6 -(CH2)m-cycloalkyl or -(CH2)m-heterocycloalkyl -CH2- may be substituted with -S(=O)2-}; R a -H or -C 1-6 alkyl; R b -H, -C 1-6 Alkyl, -NH2, -NH-C 1-6 Alkyl or -N(C 1-6 Alkyl)(C 1-6 alkyl); R c -H or -C 1-6 Alkyl; and m and n are each independently 0, 1, 2 or 3.

2. The compound represented by chemical formula A according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein X1 and X2 are each independently CH or N {wherein at least one of X1 or X2 is N}; Rx is -H or -C 1-6 alkyl; Y1 is CH or N; Ring W is a 5-6 membered heteroaryl group {wherein at least one H on the ring of the 5-6 membered heteroaryl group may be -C 1-6 alkyl or cycloalkyl substituted}; Z1 is -(CH2CH2)-, -(CH2CH2CH2)- or -(CH2CH2CH2CH2)-{wherein at least one of the H in -(CH2CH2)-, -(CH2CH2CH2)- or -(CH2CH2CH2CH2)- may be replaced by -C 1-3 alkyl substituted}; Z2 is -(CH2)- or -O-; Z3 is a bond (blank), -(CH2)- or -(CH2CH2)-; L is -C(=O)-, -C(=O)-NR a -or -C(=O)-O-; R1 is -H, -C 1-6 Alkyl, -C 1-6 Cyanoalkyl, -C 1-6 Haloalkyl, -(CH2)mS(=O)2-R b , -(CH2)m-cycloalkyl, -(CH2)m-heterocycloalkyl or -(CH2)m-aryl {wherein at least one H of the -(CH2)m-cycloalkyl, -(CH2)m-heterocycloalkyl or -(CH2)m-aryl group may be replaced by -C 1-6 Alkyl, -C 1-6 Cyanoalkyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, -S(=O)2-C 1-6 Alkyl, -C 1-6 Alkyl-S(=O)2-C 1-6 Alkyl, -NR c -S(=O)2-C 1-6 Alkyl, -halogen or -(CH2)n-heterocycloalkyl [wherein at least one H on the ring of the -(CH2)n-heterocycloalkyl may be replaced by -C 1-6 -(CH2)m-cycloalkyl or -(CH2)m-heterocycloalkyl], and the -CH2- of the -(CH2)m-cycloalkyl or -(CH2)m-heterocycloalkyl may be substituted with -S(=O)2-}; R a -H or -C 1-6 alkyl; R b -H or -C 1-6 alkyl; R c -H or -C 1-6 Alkyl; and m and n are each independently 0, 1, 2 or 3.

3. The compound represented by chemical formula A according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein Ring W is or phenyl {wherein or at least one of the H atoms on the phenyl ring may be replaced by -C 1-6 Alkyl, -C 1-6 Hydroxyalkyl, -OC 1-6 Alkyl, -S(=O)2-C 1-6 alkyl or -S(=O)2-cycloalkyl}.

4. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein The compound represented by the chemical formula A is selected from the group consisting of the following compounds:

5. A pharmaceutical composition comprising A compound represented by the chemical formula A according to any one of claims 1 to 4, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

6. A pharmaceutical composition for preventing or treating cancer, comprising The compound according to any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof as an active ingredient.

7. The pharmaceutical composition according to claim 6, wherein The pharmaceutical composition inhibits epidermal growth factor receptor (EGFR).

8. The pharmaceutical composition according to claim 7, wherein The pharmaceutical composition inhibits at least any one selected from the group consisting of EGFR Del19 / C797S, EGFR L858R / C797S, EGFR Del19 / T790M / C797S and EGFR L858R / T790M / C797S.

9. The pharmaceutical composition according to claim 6, wherein The cancer is at least one cancer selected from the group consisting of pseudomyxoma, intrahepatic biliary 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 cancer, ovarian epithelial cancer, ovarian germ cell cancer, 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, 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 pelvis cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue tumor, malignant bone tumor, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureter cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoid, gastrointestinal stromal tumor, Wilms' cell cancer, 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 thymus cancer.

10. Use of the compound represented by Chemical Formula A according to any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing EGFR-related diseases.

11. A method for treating or preventing EGFR-related diseases, comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by Chemical Formula A, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 4.

12. 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 represented by Chemical Formula A, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 4, wherein the disease is selected from the group consisting of the following diseases: Pseudomyxoma, intrahepatic biliary 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 cancer, ovarian epithelial cancer, ovarian germ cell cancer, 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, 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 pelvis cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue tumor, malignant bone tumor, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureter cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoid, gastrointestinal stromal cancer, Wilms' cell cancer, 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 thymus cancer.

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