Heteroaryl derivative compound and its use

Abstract

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

Description

Technical Field

[0001] The present invention relates to a heteroaryl derivative compound and its pharmaceutical use. Specifically, the present invention relates to a heteroaryl derivative compound having EGFR inhibitory activity.

Background Art

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

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

[0004] On the one hand, it is known that EGFR Del19 or EGFR L858R, which are EGFR mutations, are the main causes of non-small cell lung cancer and head and neck cancer. Erlotinib and Tarceva, which are these therapeutic drugs, have been developed and are currently used clinically. However, when such drugs are used in patients, acquired resistance in which secondary mutations of EGFR based on the drug structure occur has been observed, and it has also been clarified that this is the main cause of actual drug resistance. When the first-generation EGFR inhibitor is used for about 10 months on average, acquired resistance called the T790M mutation located at the gatekeeper of the EGFR kinase occurs, and the first-generation EGFR inhibitor becomes ineffective. That is, double mutations of EGFR Del19 / T790M or EGFR L858R / T790M occur, and existing therapeutic agents become ineffective. Osimertinib, a third-generation EGFR-TKI target drug that shows high reactivity to drug resistance caused by the EGFR T790M mutation, has been developed, but it has also been reported that drug resistance will occur similarly (Clin Cancer Res, 2015, 17:21). The EGFR C797S mutation has been presented as one of the main mechanisms leading to drug resistance to osimertinib, and it has been reported that about 40% of clinical trial patients have the EGFR C797S mutation (Nature Medicine, 2015, 21:560-562).

[0005] Thus, by regulating EGFR activity (especially C797S mutations such as EGFR Del19 / T790M / C797S or EGFR L858R / T790M / C797S), the unmet need for novel compounds that can be usefully utilized for the treatment of EGFR-related diseases is increasing.

Summary of the Invention

Problems to be Solved by the Invention

[0006] 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.

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

[0008] Another object of the present invention is to provide a pharmaceutical use of the heteroaryl derivative compound, specifically, a pharmaceutical composition for treating or preventing an EGFR-related disease containing the heteroaryl derivative compound as an active ingredient, a use for treating or preventing an EGFR-related disease using the compound, or a method for treating or preventing an EGFR-related disease including the step of administering the compound.

Means for Solving the Problems

[0009] In order to achieve the above object, as a result of the research efforts of the present inventors, the present invention has been completed by confirming that a heteroaryl derivative compound represented by Formula 1 described below inhibits the growth of cells in which EGFR is activated.

[0010] Heteroaryl derivative compound The present invention provides a compound represented by the following Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

Chemical formula

[0011] According to a specific example of the present invention, the compound represented by the above formula 1, its stereoisomer, or a pharmaceutically acceptable salt thereof may be within the following range: X 1 and X 2 are each independently CH or N {wherein one or more of X 1 or X 2 is N}; Rx is -H or -C 1-6 alkyl; Y 1 and Y 2 are each independently CH or N {wherein one or more of Y 1 or Y 2 is N}; Ring W is heterocycloalkyl, aryl or heteroaryl {wherein one or more H of the heterocycloalkyl, aryl or heteroaryl ring is -C 1-6 alkyl, -C 1-6 alkyl-cycloalkyl, -OH, -O-C 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, -halo, or may be substituted with cycloalkyl, and -CH 2 - of the heterocycloalkyl ring may be substituted with -S(=O) 2 -}; L is -C(=O)-, -C(=O)-NR a -, -C(=O)-O-, -NR a -C(=O)-, or -O-C(=O)-; R 1 is -H, -C 1-6 alkyl, -C 1-6 cyanoalkyl, -C 1-6 aminoalkyl, -C 1-6 hydroxyalkyl, -C 1-6 alkyl -O -C 1-6 alkyl, -C 1-6 hydroxyhaloalkyl, -C 1-6 haloalkyl, -(CH 2 )m -C(=O)-OC 1-6 alkyl, -(CH 2 )m -S(=O) 2 -R b 、-(CH 2 )m -cycloalkyl, -(CH 2 )m -heterocycloalkyl, -(CH 2 )m -aryl, or -(CH 2 )m -heteroaryl, where one or more H of said -(CH 2 )m -cycloalkyl, -(CH 2 )m -heterocycloalkyl, -(CH 2 )m -aryl, or -(CH 2 )m -heteroaryl is -C 1-6 alkyl, -C 1-6 cyanoalkyl, -C 1-6 aminoalkyl, -C 1-6 hydroxyalkyl, -C 1-6 haloalkyl, -CN, -NH 2 、-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 -halo, -S(=O) 2 -cycloalkyl, -C 1-6 alkyl -S(=O) 2 -C 1-6 alkyl, -NR c -S(=O) 2 -C1-6 alkyl, -halo, or -(CH 2 )n - heterocycloalkyl, which may be substituted [wherein one or more Hs of said -(CH 2 )n - heterocycloalkyl ring may be substituted with -C 1-6 alkyl or heterocycloalkyl], and the -CH 2 )m - cycloalkyl or -(CH 2 )m - heterocycloalkyl -CH 2 - may be substituted with -S(=O) 2 -}; R 2 is -C 1-6 alkyl, cycloalkyl, heterocycloalkyl, or heteroaryl {wherein one or more Hs of said cycloalkyl, heterocycloalkyl, or heteroaryl ring may be substituted with -C 1-6 alkyl}, or R 2 is linked to ring W and can form a ring {wherein one or more Hs of said ring may be substituted with -C 1-6 alkyl}; R a is -H or -C 1-6 alkyl; R b is -H, -C 1-6 alkyl, -NH 2 -, -NH -C 1-6 alkyl, or -N(C 1-6 alkyl)(C 1-6 alkyl); R c is -H or -C 1-6 alkyl; m and n are each independently 0, 1, 2, 3, or 4.

[0012] According to a specific example of the present invention, the compound represented by the formula 1, its stereoisomer, or a pharmaceutically acceptable salt thereof may be within the following range: Ring W is

Chemical formula

[0013] According to a specific example of the present invention, the compound represented by the formula 1, its stereoisomer, or a pharmaceutically acceptable salt thereof may be within the following range: Ring W is phenyl and

Chemical formula

[0014] According to a specific example of the present invention, the compound represented by the formula 1 may be selected from the group consisting of the compounds listed in Table 2 described below.

[0015] According to a specific example of the present invention, the compound represented by the formula 1, its stereoisomer, or a pharmaceutically acceptable salt thereof may be the compound represented by the following formula A, its stereoisomer, or a pharmaceutically acceptable salt thereof:

Chemical formula

[0016] According to a specific example of the present invention, the compound represented by the formula A, its stereoisomer, or a pharmaceutically acceptable salt thereof may be in the following range: X 1 and X 2 are each independently CH or N {wherein one or more of X 1 or X 2 is N}; Rx is -H or -C 1-6 alkyl; Y 1 is CH or N; Ring W is a 5- to 6-membered heteroaryl {wherein one or more Hs of the 5- to 6-membered heteroaryl ring may be substituted with -C 1-6 alkyl or cycloalkyl}; Z 1 is -(CH 2 CH 2 )-, -(CH 2 CH 2 CH 2 )-, or -(CH 2 CH 2 CH 2 CH 2 )- {wherein one or more Hs of the -(CH 2 CH 2 )-, -(CH 2 CH 2 CH 2 ), or -(CH 2 CH 2 CH 2 CH 2 )- may be substituted with -C 1-3 alkyl}; Z 2 is -(CH 2 )- or -O-; Z 3 is a bond (null), -(CH 2 )-, or -(CH 2 CH 2 )- and L is -C(=O)-, -C(=O)-NR a -, or -C(=O)-O-; R 1 is -H, -C 1-6 alkyl, -C 1-6 cyanoalkyl, -C 1-6 haloalkyl, -(CH 2 )m-S(=O) 2 -R b -, -(CH 2 )m-cycloalkyl, -(CH 2 )m-heterocycloalkyl, or -(CH 2 )m-aryl {wherein one or more Hs of said -(CH 2 )m-cycloalkyl, -(CH 2 )m-heterocycloalkyl, or -(CH 2 )m-aryl may be substituted with -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, -halo, or -(CH 2 )n-heterocycloalkyl [wherein one or more Hs of said -(CH 2 )n-heterocycloalkyl ring may be substituted with -C 1-6 alkyl or heterocycloalkyl], and the -CH 2 )m-cycloalkyl or -(CH 2 )m-heterocycloalkyl may be substituted with -S(=O) 2 -]; 2}; R a is -H or -C 1-6 alkyl; Rb is -H or -C 1-6 is alkyl; R c is -H or -C 1-6 is alkyl; m and n are each independently 0, 1, 2, or 3.

[0017] According to a specific example of the present invention, the compound represented by the formula A, its stereoisomer, or a pharmaceutically acceptable salt thereof may be within the following range: Ring W is

Chemical formula

Chemical formula

[0018] In the present invention, "alkyl" can mean a straight-chain or branched-chain acyclic, cyclic, or saturated hydrocarbon to which these are bonded, unless otherwise specified. For example, "C 1-6"Alkyl" can mean an alkyl containing 1 to 6 carbon atoms. Acyclic alkyl can include, for example, but is not limited to, methyl, ethyl, n-propyl, n-butyl, isopropyl, secondary (sec)-butyl, isobutyl, or tertiary (tert)-butyl. Cyclic alkyl can be used interchangeably with "cycloalkyl" herein and can include, for example, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[0019] Unless otherwise specified, "alkenyl" in the present invention can mean an unsaturated hydrocarbon containing at least one or more double bonds. For example, "C 2-6 alkenyl" can contain 2 to 6 carbon atoms and can contain at least one or more double bonds. By way of example, it can include, but is not limited to, ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, hexa-1-enyl, etc.

[0020] Unless otherwise specified, "alkynyl" in the present invention can mean an unsaturated hydrocarbon containing at least one or more triple bonds. For example, "C 2-6 alkynyl" can contain 2 to 6 carbon atoms and can contain at least one or more triple bonds. By way of example, it can include, but is not limited to, ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-ynyl, hexa-1-ynyl, etc.

[0021] "Alkoxy" in the present invention can mean -(O-alkyl) as an alkyl ether group, where alkyl is as defined above. For example, "C 1-6 alkoxy" is an alkoxy containing C 1-6 alkyl, that is, -(O-C 1-6"(alkyl)" can be meant. As an example, alkoxy can include, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, etc.

[0022] "Halo" in the present invention may be F, Cl, Br, or I.

[0023] "Haloalkyl" in the present invention can mean a straight-chain or branched-chain alkyl (hydrocarbon) having one or more carbon atoms substituted with halo as defined in the present application. Examples of the haloalkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl or n-butyl independently substituted with one or more halogens, for example, F, Cl, Br, or I.

[0024] "Hydroxyalkyl" in the present specification can mean a straight-chain or branched-chain alkyl (hydrocarbon) having a carbon atom substituted with hydroxy (OH). Examples of the hydroxyalkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl or n-butyl independently substituted with -OH.

[0025] "Aminoalkyl" in the present specification can mean a straight-chain or branched-chain alkyl (hydrocarbon) having a carbon atom substituted with amino (NR’R’’). Here, R’ and R’’ can each independently be selected from the group consisting of hydrogen, C 1-6 alkyl, and an N-protecting group (for example, Boc), and the selected R’ and R’’ can each independently be substituted or unsubstituted.

[0026] "Cyanoalkyl" as used herein can mean a straight-chain or branched-chain alkyl (hydrocarbon) having a carbon atom substituted with cyano (CN).

[0027] "Heterocycloalkyl" in the present invention can mean a ring containing one or more selected from N, O, P, P(=O), and S in the ring, and may be saturated or partially unsaturated. Here, in the case of unsaturation, it can be referred to as heterocycloalkene. Unless otherwise specified, heterocycloalkyl may be a monocyclic or polycyclic ring such as a spiro ring, a bridged ring, or a fused ring. Also, "3- to 12-atom heterocycloalkyl" can mean a heterocycloalkyl containing 3 to 12 atoms forming the ring. As an example, heterocycloalkyl can include, but is not limited to, pyrrolidine, piperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, 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.

[0028] "Arene" in the present invention can mean an aromatic hydrocarbon ring. The arene may be a monocyclic arene or a polycyclic arene. The number of ring-forming carbon atoms of the arene 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 arene include, but are not limited to, benzene, naphthalene, fluorene, anthracene, phenanthrene, biphenyl, terphenyl, quaterphenyl, kinkquaterphenyl, sexiphenyl, triphenylene, pyrene, benzofluoranthene, chrysene, etc. In the present specification, a residue obtained by removing one hydrogen atom from the said "arene" is referred to as "aryl".

[0029] In the present invention, the "heteroarene" is a ring containing one or more of the hetero elements O, N, P, Si, and S. The number of carbon atoms forming the ring of the heteroarene may be 2 or more and 30 or less, or 2 or more and 20 or less. The heteroarene may be a monocyclic heteroarene or a polycyclic heteroarene. The polycyclic heteroarene may have, for example, a bicyclic or tricyclic structure. Examples of the heteroarene include thiophene, purine, pyrrole, pyrazole, imidazole, thiazole, oxazole, isothiazole, oxadiazole, triazole, pyridine, bipyridyl, triazine, acridyl, 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 and dibenzofuran, etc., but are not limited thereto. In one embodiment of the present invention, the heteroarene may also include a bicyclic heterocyclo-arene containing an arene ring condensed with a heterocycloalkyl ring or a heteroarene condensed with a cycloalkyl ring. In this specification, the residue obtained by removing one hydrogen atom from the said "heteroarene" is referred to as "heteroaryl".

[0030] As used herein, the term "stereoisomer" means a compound having the same chemical formula or molecular formula but being stereochemically different. Stereoisomers as used herein include optical isomers, enantiomers, diasteromers, cis / trans isomers, rotamers, and atropisomers, and each of these isomers, racemates, and mixtures thereof are also included within the scope of the present invention. For example, since the stereochemical structure of Formula 1 of the present invention is not specified, it can include the above stereoisomers of Formula 1. Unless otherwise specified, a solid line bond

Chem.

Chem.

Chem.

[0031] The compound represented by Formula 1 in the present invention can exist in the form of a "pharmaceutically acceptable salt". Therefore, the scope of the compounds of the present invention includes pharmaceutically acceptable salts of the compounds represented by the above Formula 1. The term "pharmaceutically acceptable salt" as used in the present invention means any and all organic acid or inorganic acid addition salts of the compound that are non-toxic to patients, have a harmless effective action at a concentration, and the side effects caused by this salt do not reduce the beneficial efficacy of the compound represented by Formula 1.

[0032] In particular, the pharmaceutically acceptable salt may be an acid addition salt formed by a free acid. Here, the acid addition salt is an inorganic acid such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc., aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates and alkanedioates, aromatic acids, non-toxic organic acids such as aliphatic and aromatic sulfonic acids, trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc.

[0033] Examples of such pharmaceutically acceptable salts include sulfate, sulfite, nitrate, phosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, benzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, glycolate, maleate, tartrate, mandelate, etc.

[0034] The acid addition salt can be produced by a conventional method. For example, the derivative of formula 1 is dissolved in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc., an organic acid or an inorganic acid is added, the resulting precipitate is filtered, dried, and produced, or the solvent and the excess acid are distilled off under reduced pressure, then dried, and crystallized under an organic solvent to produce it.

[0035] Alternatively, the pharmaceutically acceptable salt may be a salt obtained using a base or a metal salt. As an example of a metal salt, an alkali metal or alkaline earth metal salt can be obtained by dissolving the compound in an excess of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. As an alkali metal salt, sodium, potassium or calcium salts can be pharmaceutically compatible. Also, the corresponding salts can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate) and can be produced by methods for producing salts known in the art.

[0036] Use of heteroaryl derivative compound The present invention provides the use of a compound represented by the following formula 1, its stereoisomers, or pharmaceutically acceptable salts thereof. [Chemical formula] The compound represented by formula 1 of the present invention, its stereoisomers, or pharmaceutically acceptable salts thereof exhibit inhibitory activity against various kinases.

[0037] According to one specific example of the present invention, since the heteroaryl derivative represented by formula 1 exhibits excellent inhibitory activity against EGFR kinase, it can be usefully used for the treatment or prevention of EGFR-related diseases, particularly cancer. In particular, the heteroaryl derivative compound of the present invention exhibits excellent inhibitory activity against EGFR mutations (e.g., EGFR Del19 / C797S, EGFR L858R / C797S, EGFR Del19 / T790M / C797S, or EGFR L858R / T790M / C797S, etc.), and thus can be usefully used for the treatment or prevention of cancers induced by EGFR.

[0038] In the present invention, the cancer includes all cancers that can exhibit a therapeutic or preventive effect by inhibiting EGFR kinase activity, and may be a solid cancer or a hematological cancer. The type of cancer is not limited, and examples include pseudomyxoma, intrahepatic bile duct cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, fungiform polyp, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell tumor, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, bile duct cancer, colorectal cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, Farter's dilated part cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal and paranasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain tumor, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvic cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone tumor, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary origin, gastric lymphoma, gastric cancer, gastric carcinoid tumor, gastrointestinal stromal tumor, Wilms tumor, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone tumor, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid tumor, vaginal cancer, spinal cord cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi 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, hematological cancer, and thymic cancer, and can be one or more selected from the group consisting of. In addition, the cancer includes not only primary cancer but also metastatic cancer.

[0039] According to one specific example of the present invention, the present invention provides a pharmaceutical composition for treating or preventing EGFR-related diseases containing, as an active ingredient, the compound represented by the above formula 1, its stereoisomer, or a pharmaceutically acceptable salt thereof. Specifically, the EGFR-related disease may be cancer. The type of cancer is as described above.

[0040] The pharmaceutical composition of the present invention may further contain one or more active ingredients showing the same or similar drug effects in addition to the compound represented by the above formula 1, its stereoisomer, or pharmaceutically acceptable salts thereof.

[0041] The pharmaceutical composition of the present invention can be used in clinical administration and can be manufactured so as to be administered in various dosage forms, both oral and parenteral.

[0042] Also, according to one specific example of the present invention, the present invention provides the use of the compound represented by the above formula 1, its stereoisomers, or pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment or prevention of EGFR-related diseases. Specifically, the EGFR-related disease may be cancer. The types of the cancer are as described above.

[0043] Also, according to one specific example of the present invention, the present invention provides the use of the compound represented by the above formula 1, its stereoisomers, or pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment or prevention of cancer diseases. The types of the cancer are as described above.

[0044] Also, according to one specific example of the present invention, provided is a method for treating or preventing an EGFR-related disease, comprising the step of administering a therapeutically effective amount of the compound represented by the above formula 1, its stereoisomers, or pharmaceutically acceptable salts thereof, to a subject in need thereof. The subject may be a mammal including a human. Specifically, the EGFR-related disease may be cancer. The types of the cancer are as described above.

[0045] Also, according to one specific example of the present invention, the present invention provides a method for treating or preventing cancer, comprising the step of administering a therapeutically effective amount of the compound represented by the above formula 1, its stereoisomers, or pharmaceutically acceptable salts thereof, to a subject in need thereof. The types of the cancer are as described above.

[0046] Also, according to one specific example of the present invention, the present invention provides a method for inhibiting EGFR, comprising the step of administering a therapeutically effective amount of the compound represented by the above formula 1, its stereoisomers, or pharmaceutically acceptable salts thereof, to a subject in need thereof.

[0047] The term "therapeutically effective amount" as used in the present invention refers to the amount of the compound represented by Formula 1 that is effective for the treatment or prevention of EGFR-related diseases. Specifically, "therapeutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dosage level can be determined according to factors such as the type and severity of the individual, age, gender, type of disease, activity of the drug, sensitivity to the drug, administration time, administration route and excretion rate, treatment period, factors including drugs used simultaneously, and other factors known in the pharmaceutical field. The pharmaceutical composition in the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with commercially available therapeutic agents. And it can be administered once or multiple times. It is important to administer an amount that can obtain the maximum effect with the minimum amount without side effects considering all the above factors, and it can be easily determined by those skilled in the art. The dosage of the pharmaceutical composition of the present invention can be determined by an expert according to various factors such as the patient's condition, age, gender and complications. Since the active ingredient of the pharmaceutical composition in the present invention is excellent in safety, it can also be used in amounts exceeding the determined dosage.

[0048] "Prevention" as used in the present invention means all acts by which the administration of the compound inhibits or delays the occurrence, spread and recurrence of the disease, and "treatment" means all acts by which the symptoms of the disease are improved or beneficially changed by the administration of the compound.

[0049] Further, according to a specific example 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, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable additive.

[0050] Examples of additives used in the pharmaceutical composition can include sweeteners, binders, solvents, solubilizers, wetting agents, emulsifiers, isotonic agents, absorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, flavoring agents, etc. For example, the additives can include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, magnesium aluminosilicate, starch, gelatin, tragacanth gum, alginic acid, sodium alginate, methyl cellulose, sodium carboxymethyl cellulose, agar, water, ethanol, polyethylene glycol, polyvinyl pyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor, etc.

[0051] The pharmaceutical composition can be formulated in various dosage forms for oral administration (e.g., tablets, pills, powders, capsules, syrups or emulsions) or parenteral administration (e.g., intramuscular, intravenous or subcutaneous injection).

[0052] For example, the pharmaceutical composition can be formulated as a preparation for oral administration, and additives used at this time can include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifiers, diluents, etc. Specifically, solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations can be formulated by mixing at least one excipient, e.g., starch, calcium carbonate, sucrose, lactose, gelatin, etc., in the composition. Also, in addition to simple excipients, lubricants such as magnesium stearate and talc can be used. Further, liquid preparations for oral administration include suspending agents, emulsions, syrups, etc., and in addition to water and liquid paraffin, which are simple diluents frequently used, various excipients, e.g., wetting agents, sweeteners, flavoring agents, preservatives, etc., can be included.

[0053] In addition, formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, 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 base of suppositories, witepsol, macrogol, tween 61, cacao butter, laurin fat, glycerogelatin, etc. can be used. On the other hand, injections may contain conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizing agents, preservatives, and the like.

[0054] In addition, it can be manufactured as a combined preparation together with other active preparations and can have an enhancing effect on the active ingredient.

[0055] The matters described in the uses, compositions, and treatment methods of the present invention are similarly applicable as long as they do not conflict with each other.

Effects of the Invention

[0056] The heteroaryl derivative compound in the present invention exhibits excellent inhibitory activity against EGFR, and thus can be usefully used for the treatment or prevention of the EGFR-related diseases.

Modes for Carrying Out the Invention

[0057] Hereinafter, the present invention will be described in detail based on examples and experimental examples. However, the following examples and experimental examples are merely illustrative of the present invention, and the content of the present invention is not limited thereto.

[0058] <Analysis and Tablet Conditions> The compounds synthesized in the examples of the present invention were tableted or subjected to structural analysis under the following conditions.

[0059] 1. HPLC and MPLC HPLC for analysis (ACQUITY UPLC H-Class Core System) Equipment with a Waters mass QDa Detector attached to a Waters UPLC system (ACQUITY UPLC PDA Detector) was used. A Waters ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm, 2.1 × 50 mm) column was used, and the column temperature was set at 30 °C. Mobile phase A was water containing 0.1% formic acid, and mobile phase B was acetonitrile containing 0.1% formic acid. Gradient condition (3 minutes with 10 - 100% B, flow rate = 0.6 ml / min)

[0060] Preparative HPLC System for tablets (Preparative-Liquid chromatography UV spectrometry) The Teledyne ACCQPrep HP150 equipment was used. A Waters XTERRA (registered trademark) Prep RP18 OBD (trademark) (10 μm, 30 × 300 mm) column was used, and the column temperature was at room temperature. Gradient condition (120 minutes with 10 - 100% B, flow rate = 42 ml / min)

[0061] Medium pressure liquid chromatography for tablets (Medium pressure liquid chromatography; MPLC) The Teledyne ISCO CombiFlash Rf + UV was used to perform medium - pressure liquid chromatography.

[0062] 2. NMR analysis NMR analysis was performed using a Bruker AVANCE III 400 or AVANCE III 400 HD, and the data was shown in ppm (parts per million (δ)).

[0063] The commercially available reagents used were used without additional tablets. In the present invention, room temperature or normal temperature refers to a temperature in the range of 5 °C to 40 °C, for example, 10 °C to 30 °C, and as another example, about 20 °C to 27 °C, and is not strictly limited within the above range. Concentration under reduced pressure or solvent evaporation was performed using a rotary evaporator.

[0064] Production Example: Production of Intermediate Compounds in the Present Invention <Production Example 1> Production of 2-(cis-3-Fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine [Chemical Formula]

[0065] Step 1: Production of cis-tert-butyl 3-fluoro-4-methoxypiperidine-1-carboxylate cis-tert-Butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate (1 g, 1.0 eq) was dissolved in tetrahydrofuran (THF; 23 mL), and then sodium hydride (NaH; 0.22 g, 60% purity, 1.2 eq) was added under a nitrogen stream at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes, and methyl iodide (0.31 mL, 1.1 eq) was added dropwise at 0 °C one drop at a time. Then, the reaction mixture was stirred at room temperature for 3 hours. As a result of LCMS analysis, all of the starting material disappeared and the target compound was detected. The reaction mixture was concentrated under reduced pressure, ethyl acetate (EA; 100 mL) and saturated aqueous sodium hydrogen carbonate solution (200 mL × 2) were added, and the organic layer was extracted. After drying over sodium sulfate, it was concentrated under reduced pressure to obtain the target compound (1.0 g, 94% yield) as a yellow oil. MS: m / z 234.3 [M+H] +

[0066] Step 2: Production of cis-3-fluoro-4-methoxypiperidine hydrochloride The cis-tert-butyl 3-fluoro-4-methoxypiperidine-1-carboxylate (1.0 g, 1.0 eq) obtained from the above step 1 was dissolved in dichloromethane (DCM; 24 mL), and then hydrochloric acid (HCl) / dioxane (4 M, 3.7 mL, 3.0 eq) was added at 0 °C. Then, the reaction mixture was stirred at room temperature for 12 hours. As a result of LCMS analysis, all of the starting material disappeared and the target compound was detected. The reaction mixture was concentrated under reduced pressure, and diethyl 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. MS: m / z 134.3 [M+H]+

[0067] Step 3: Production of 2-(cis-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine The cis-3-fluoro-4-methoxypiperidine hydrochloride (0.56 g, 1.0 eq) obtained from the above step 2 and 2-chloropyrimidin-4-amine (0.32 g, 0.8 eq) were dissolved in isopropyl alcohol (IPA; 8 mL) at room temperature, and then N,N-diisopropylethylamine (DIPEA; 2.52 mL, 4.0 eq) was added. The reaction mixture was stirred at 120 °C for 12 hours. As a result of LCMS analysis, all the starting materials disappeared and the target compound was detected. The reaction mixture was concentrated under reduced pressure, and the concentrated compound was purified by MPLC (hexane / ethyl acetate) to obtain the target compound (0.59 g, 83% yield) as a white solid.

[0068] 1 H NMR (400 MHz, CDCl 3 ) δ 7.92 (d, J = 5.6 Hz, 1H), 5.75 (d, J = 5.6 Hz, 1H), 4.77 (ddtd, J = 48.3, 6.2, 2.6, 0.9 Hz, 1H), 4.62 (s, 2H), 4.50 (dddd, J = 14.0, 7.8, 6.2, 1.4 Hz, 1H), 4.21 (dddd, J = 13.5, 6.5, 3.9, 1.4 Hz, 1H), 3.67 - 3.49 (m, 2H), 3.47 (s, 3H), 3.40 (dddd, J = 13.7, 8.8, 3.7, 1.8 Hz, 1H), 1.99 - 1.88 (m, 1H), 1.82 - 1.72 (m, 1H). MS: m / z 227.3 [M+H] +

[0069] <Production Example 2> Production of 2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-amine

Chemical formula

[0070] Step 1: Production of 4-bromo-1-(cyclopropylsulfonyl)-1H-pyrazole 4-Bromo-1H-pyrazole (10 g, 1 eq) was dissolved in dichloromethane (DCM; 170 mL), and then cyclopropanesulfonyl chloride (7.62 mL, 1.1 eq) and triethylamine (TEA; 12.33 mL, 1.3 eq) were added. The reaction mixture was stirred at room temperature for 19 h. As a result of LCMS analysis, all starting materials disappeared and the target compound was detected. Water (100 mL) was added to the reaction mixture, and extraction was performed using dichloromethane (DCM; 200 mL). After the organic layer was concentrated under reduced pressure, purification was carried out by MPLC (hexane / ethyl acetate) to obtain the target compound (10 g, 59% yield). MS: m / z 250.3 [M+H] +

[0071] Step 2: Production of 1-(cyclopropylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 4-Bromo-1-(cyclopropylsulfonyl)-1H-pyrazole (10 g, 1 eq) obtained from the above step 1 was dissolved in 1,4-dioxane (133 mL), and then bis(pinacolato)diboron (12.14 g, 1.2 eq) and potassium acetate (7.82 g, 2 eq) were added. After the reaction mixture was degassed for 10 minutes, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (1.17 g, 0.04 eq) was added. Then, the reaction mixture was stirred at 110 °C for 16 h under a nitrogen atmosphere. As a result of LCMS analysis, all starting materials 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%) and used in the next reaction without forming tablets. MS: m / z 299.3 [M+H] +

[0072] Step 3: Production of 2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-amine 1-(Cyclopropylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.3 g, 1 eq) obtained from the above step 2 was dissolved in acetonitrile (ACN; 15 mL), and then 2-chloropyrimidin-4-amine (1 g, 1 eq) and an aqueous sodium carbonate solution (2 M, 11.57 mL, 3 eq) were added. After degassing the reaction mixture for 10 minutes, bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium (0.109 g, 0.02 eq) was added. The reaction mixture was stirred at 100 °C for 2 hours under a nitrogen atmosphere. As a result of LCMS analysis, all the starting materials disappeared and the target compound was detected. The reaction mixture was filtered through diatomaceous earth. After concentrating the filtrate under reduced pressure, it was purified by MPLC (ethyl acetate / dichloromethane) to obtain the target compound (1 g, 49% yield). MS: m / z 266.3 [M+H] +

[0073] <Production Example 3> to <Production Example 15> In the same manner as in the above <Production Example 1>, the compounds of the following Production Examples 3 to 9 were produced. Also, in the same manner as in the above <Production Example 2>, the compounds of the following Production Examples 10 to 15 were produced. The compound names and chemical structural formulas of Production Examples 3 to 15 are tabulated and shown in Table 1.

[0074]

Table 1

[0075] <Production Example 16> Production of 4-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one

Chem.

[0076] Step 1: 2-Methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one 1-Methyl-1H-pyrazol-5-ol (6 g, 1 eq) was dissolved in acetonitrile (ACN; 204 mL), and then potassium carbonate (25.4 g, 3 eq) was added. After the reaction mixture was stirred at room temperature for 30 minutes, 2-(trimethylsilyl)ethoxymethyl chloride (14.1 mL, 1.3 eq) was slowly added, and the mixture was stirred at room temperature for 3 hours. As a result of LCMS analysis, all of the starting material disappeared and the target compound was detected. The reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, hexane was poured in, and the precipitated solid was filtered and dried to obtain the target compound (14 g, 100% yield). MS: m / z 229.3 [M+H] +

[0077] Step 2: Production of 4-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one 2-Methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (5 g, 1 eq) obtained from 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. As a result of LCMS analysis, all of the starting material disappeared and the target compound was detected. A 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 a 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 / hexane) to obtain the target compound (6 g, 89% yield). MS: m / z 307.3 [M+H] +

[0078] <Production Example 17> Production of 4-(4-aminopyrimidin-2-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one

Chemical formula

[0079] Step 1: Production of tert-butyl (tert-butoxycarbonyl)(2-chloropyrimidin-4-yl)carbamate 2-Chloropyrimidin-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 sequentially added at 0 °C. The reaction mixture was stirred at 50 °C for 1 hour. As a result of LCMS analysis, all the starting materials 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 the organic layer was washed several times with saturated aqueous sodium chloride solution (100 mL × 2). The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The concentrated compound was purified by MPLC (hexane / ethyl acetate) to obtain the target compound (22.5 g, 88% yield). MS: m / z 330.3 [M+H] +

[0080] Step 2: Production of tert-butyl (tert-butoxycarbonyl)(2-(2-methyl-3-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrazol-4-yl)pyrimidin-4-yl)carbamate tert-Butyl (tert-butoxycarbonyl)(2-chloropyrimidin-4-yl)carbamate (12.88 g, 6 eq) obtained from 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 from the above <Production Example 16>, bis(pinacolato)diboron (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. To the reaction mixture, bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (Pd(amphos)Cl 2After adding (0.69 g, 0.15 eq), the mixture was stirred at 100 °C for 2 hours under a nitrogen atmosphere. As a result of LCMS analysis, all starting materials disappeared and the target compound was detected. The reaction mixture was filtered through diatomaceous earth. 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, 75% purity, 55% yield). MS: m / z 522.3 [M+H] +

[0081] Step 3: Production of 4-(4-aminopyrimidin-2-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one After dissolving tert-butyl (tert-butoxycarbonyl)(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 from the above step 2 in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP; 30 mL), trifluoroacetic acid (TFA; 6.65 mL, 15 eq) was added, and then the mixture was stirred at 15 °C for 3 hours. As a result of LCMS analysis, all starting materials disappeared and the target compound was detected. After slowly adding a saturated aqueous sodium hydrogen carbonate solution (100 mL) to the reaction mixture, extraction was carried out using ethyl acetate (EA; 200 mL). The organic layer was washed several times with a 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 MPLC (methanol / dichloromethane) to obtain the target compound (1.1 g, 59.5% yield). MS: m / z 322.3 [M+H] +

[0082] <Production Example 18> Production of 4-(4-aminopyridin-2-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one

Chemical Structure

[0083] Example: Production of the compound of the present invention <Example 1> Preparation of (6-((2-(1-(Cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-(isopropylamino)pyridin-3-yl)(3-((methylsulfonyl)methyl)acetidin-1-yl)methanone

Chemical Structure

[0084] Step 1: Production of methyl 6-chloro-4-(isopropylamino)nicotinate 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. After concentrating the reaction mixture under reduced pressure, water (100 mL) was added, and then the mixture was extracted with ethyl acetate (EA; 200 mL). The organic layer was washed several times with a 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 / hexane) to obtain the target compound (6.4 g, 96% yield).

[0085] Step 2: Production of 6-chloro-4-(isopropylamino)nicotinic acid Methyl 6-chloro-4-(isopropylamino)nicotinate (6.4 g, 1 eq) obtained from the previous 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. As a result of LCMS analysis, all of the starting material disappeared and the target compound was detected. The reaction mixture was added dropwise with an aqueous hydrochloric acid solution (6 N) until the pH of the reaction mixture reached 4. The precipitated solid was filtered and washed away with water. The obtained solid was dried in a vacuum oven to obtain the target compound (5.3 g, 88% yield).

[0086] Step 3: Preparation of (6-chloro-4-(isopropylamino)pyridin-3-yl)(3-((methylsulfonyl)methyl)azetidin-1-yl)methanone 6-Chloro-4-(isopropylamino)nicotinic acid (600 mg, 1 eq) obtained from the previous Step 2 was dissolved in dichloromethane (DCM; 5 mL), and then 3-((methylsulfonyl)methyl)acetidine (809 mg, 1.1 eq), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazol[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU; 2.1 g, 2 eq), and diisopropylethylamine (DIPEA; 2 mL, 5 eq) were sequentially added. The reaction mixture was stirred at room temperature for 6 hours. As a result of LCMS analysis, all of the starting material 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 extraction was performed using ethyl acetate (EA; 10 mL). The organic layer was washed away 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 / hexane) to obtain the target compound (500 mg, 52% yield).

[0087] Step 4: 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 (6-Chloro-4-(isopropylamino)pyridin-3-yl)(3-((methylsulfonyl)methyl)acetidin-1-yl)methanone (70 mg, 1 eq) obtained from the above 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 from Production Example 2 above were added. After the reaction mixture was degassed for 5 minutes, Brettphos Pd(II) G3 (20 mg, 0.1 eq) was added. Then, the reaction mixture was stirred at 120 °C for 12 hours. As a result of LCMS analysis, all the starting materials disappeared and the target compound was detected. The reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure and purified by Prep-HPLC to obtain the target compound (30 mg, 26% yield). 1 H NMR (400 MHz, Chloroform-d) δ 9.81 (s, 1H), 8.62 (d, J = 0.6 Hz, 1H), 8.44 (d, J = 0.6 Hz, 1H), 8.41 (d, J = 5.8 Hz, 1H), 8.22 (d, J = 7.2 Hz, 1H), 7.91 (s, 1H), 7.71 (s, 1H), 6.96 (d, J = 5.8 Hz, 1H), 4.55 (t, J = 8.9 Hz, 2H), 4.18 (s, 2H), 3.85 (h, J = 6.4 Hz, 1H), 3.40 (d, J = 7.1 Hz, 2H), 3.34 (qd, J = 8.1, 5.6 Hz, 1H), 2.96 (s, 3H), 2.83 (tt, J = 8.0, 4.7 Hz, 1H), 1.57 - 1.49 (m, 2H), 1.38 (d, J = 6.4 Hz, 6H), 1.26 - 1.20 (m, 2H); MS m / z: 575.31 [M + H] + 。

[0088] <Example 80> (S)-N-(cyanomethyl)-1 1 ,6-dimethyl-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxamide production

Chemical formula

[0089] Step 1: Preparation of (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)pyrimidin-4-yl)amino)nicotinamide (S)-4-((4-((tert-Butyldimethylsilyl)oxy)butan-2-yl)amino)-6-chloro-N-(cyanomethyl)nicotinamide (0.37 g, 1 eq), obtained by the same method as in Example 1 above, 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) and cesium carbonate (0.912 g, 3 eq) obtained from Production Example 17 above were added. After the reaction mixture was degassed for 10 minutes, Brettphos Pd(II) G3 (0.28 g, 0.3 eq) was added. Then, the reaction mixture was stirred at 120 °C for 3 hours under a nitrogen atmosphere. As a result of LCMS analysis, all the starting materials disappeared and the target compound was detected. The reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure and purified by chromatography (methanol / dichloromethane) to obtain the target compound (0.17 g, 27% yield).

[0090] Step 2: Preparation of (S)-N-(cyanomethyl)-6-((2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-((4-hydroxybutan-2-yl)amino)nicotinamide (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)pyrimidin-4-yl)amino)nicotinamide (0.16 g, 1 eq) obtained from the above 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. As a result of LCMS analysis, all the starting materials 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 methanol / water) to obtain the target compound (0.06 g, 58% yield).

[0091] Step 3: (S)-N-(cyanomethyl)-1 1 ,6-dimethyl-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidina-4(2,4)-pyridina-1(4,5)-pyrazolacyclononaphane-4 5 -carboxamide preparation (S)-N-(Cyanomethyl)-6-((2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-((4-hydroxybutan-2-yl)amino)nicotinamide (2 mg, 1 eq) obtained from the above step 2 was dissolved in tetrahydrofuran (THF; 0.5 mL), and then cyanomethylene tributylphosphorane (CMBP; 0.05 mL, 4 eq) was added. After the reaction mixture was degassed for 10 minutes, it was stirred at 60 °C for 2 hours under a nitrogen atmosphere. As a result of LCMS analysis, all the starting materials 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 methanol / water) to obtain the target compound (5 mg, 26% yield). 1 H NMR (400 MHz, Chloroform-d) δ 8.89 (s, 1H), 8.45 (d, J = 7.3 Hz, 1H), 8.36 (d, J = 5.7 Hz, 1H), 8.35 (s, 1H), 8.13 (s, 1H), 6.51 (d, J = 5.8 Hz, 1H), 6.43 - 6.37 (m, 1H), 4.68 (td, J = 10.0, 3.2 Hz, 1H), 4.31 (dd, J = 9.2, 5.7 Hz, 2H), 4.28 - 4.23 (m, 1H), 4.09 (dt, J = 9.2, 4.4 Hz, 1H), 3.80 (s, 3H), 2.20 - 2.13 (m, 2H), 1.47 (d, J = 6.6 Hz, 3H); MS m / z: 420.17 [M+H] + .

[0092] <Example 2> to <Example 79>, <Example 81> to <Example 134> By the same method as in Example 1 or 80 above, all other example compounds of the present invention (compounds of Examples 1 to 134) were produced, and the compound names, chemical structural formulas, NMR and LCMS analysis results of each example compound are summarized in Table 2 below and shown.

[0093]

Table 2

[0094] <Experimental Example 1> Evaluation of EGFR C797S Enzyme Inhibitory Activity The compound according to the present invention was reacted with the purified human EGFR (d746-750 / T790M / C797S) (668-end, SignalChem) enzyme and a specific substrate, and the enzyme inhibitory ability was evaluated by the following method. The reaction buffer was 40 mM Tris-HCl pH 7.4, 20 mM MgCl 2, used in the composition of 0.5 mg / ml BSA and 50 μM DTT, and the reaction of all test substances consists of the reaction buffer above. The compound was diluted by a 12-step dilution series from a 10 mM DMSO stock, and the enzyme activity was measured at the final compound concentrations of 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001, 0.0003, 0.0001, 0 μM. During the test, the human EGFR (d746 - 750 / T790M / C797S) (3 ng) enzyme was reacted with purified ATP (5 μM), enzyme substrate (0.2 μg) at 25 °C for 1 hour, and then the enzyme activity was confirmed 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 2:2:1 ratio, and the degree of enzyme activity inhibition was measured by luminescence. Based on the luminescence of the enzyme activity of the solvent control group without compound treatment, the degree of enzyme activity inhibition by the treatment concentration of each compound was calculated. At this time, the concentration of each compound that inhibits enzyme activity by 50% was defined as the IC 50 (nM) value and determined using GraphPad Prism 8.4.3 (GraphPad software Inc., San Diego). The results are as summarized in Table 3 below.

[0095]

Table 3

[0096] <Experimental Example 2> Evaluation of the inhibitory activity of EGFR C797S overexpressing Ba / F3 cell proliferation In order to evaluate the inhibitory activity of the compounds according to the present invention against the proliferation of Ba / F3 expressing the EGFR Del19 / T790M / C797S mutation, the following experiments were conducted.

[0097] Ba / F3 cells were cultured using RPMI-1640 containing 10% FBS. Cells were dispensed at 3000 cells per well into white clear bottom 96 well plates (Corning) 24 hours before treatment with the compound. The compound was diluted in dimethyl sulfoxide (diluted 3-fold each time, for a total of 12 concentrations), and 1 μl was injected into each well so that the final concentration ranged from 0.2 nM to 5 μM. Measurement of viable cells was performed after treatment with the compound, reacting at 37 °C in a CO 2 incubator for 72 hours, storing at room temperature for 10 minutes using Cell Titer-Glo luminescent cell-viability reagent (Promega), and then measuring the luminescence intensity using a reader (Synergy Neo2, Biotek). The resulting values were calculated as the growth rate (%) of the cells compared to the control group. GI 50 values were calculated using GraphPad Prism 8.4.3 (GraphPad software Inc., San Diego). The results are as tabulated in Table 4 below.

[0098]

Table 4

[0099] As shown in Tables 3 and 4 above, it can be known that the example compounds of the present invention exhibit high inhibitory ability against enzymes or cell lines containing the EGFR C797S mutation.

[0100] As described above, the present invention has been described in detail through preferred production examples, examples, and experimental examples. However, the scope of the present invention is not limited to specific example compounds and should be analyzed according to the appended claims. Also, 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 formula A, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: 【Chemical Formula 18】 In the formula A above, X １ and X ２ is each independently CH or N; Rx is -H, -C １－６ alkyl, -C １－６ hydroxyalkyl, -NH ２ , -OH, -O-C １－６ alkyl, or -halo; Y １ is CH or N; Ring W is 5- to 6-membered heteroaryl or phenyl {wherein one or more Hs of the 5- to 6-membered heteroaryl or phenyl ring are optionally substituted with -C １－６ alkyl, -C １－６ alkenyl, -C １－６ alkynyl, -C １－６ alkyl-cycloalkyl, -C １－６ hydroxyalkyl, -OH, -O-C １－６ alkyl, =O, -halo, or cycloalkyl, and -CH ２ - of the heterocycloalkyl ring may be substituted with -S(=O) ２ -}; Z １ is -(CH ２ CH ２ ), -(CH ２ CH ２ CH ２ ), or -(CH ２ CH ２ CH ２ CH ２ ); where one or more Hs of said -(CH ２ CH ２ ), -(CH ２ CH ２ CH ２ ), or -(CH ２ CH ２ CH ２ CH ２ ) may be replaced by -C １－３ alkyl; Z ２ is -(CH ２ )- or -O-; Z ３ is a bond (null), -(CH ２ )-, or -(CH ２ CH ２ )- and L is -C(=O)-, -C(=O)-NR ａ -, -C(=O)-O-, -NR ａ -C(=O)-, or -O-C(=O)-; R １ is -H, -C １－６ alkyl, -C １－６ cyanoalkyl, -C １－６ aminoalkyl, -C １－６ hydroxyalkyl, -C １－６ alkyl -O -C １－６ alkyl, -C １－６ hydroxyhaloalkyl, -C １－６ haloalkyl, -(CH ２ )m -C(=O)-OC １－６ alkyl, -(CH ２ )m -S(=O) ２ -R ｂ , -(CH ２ )m -cycloalkyl, -(CH ２ )m -heterocycloalkyl, -(CH ２ )m -aryl, or -(CH ２ )m -heteroaryl {wherein one or more H of said -(CH ２ )m -cycloalkyl, -(CH ２ )m -heterocycloalkyl, -(CH ２ )m -aryl, or -(CH ２ )m -heteroaryl are -C １－６ alkyl, -C １－６ cyanoalkyl, -C １－６ aminoalkyl, -C １－６ hydroxyalkyl, -C １－６ haloalkyl, -CN, -NO ２ , -NH ２ , -NH -C １－６ alkyl, -N(C １－６ alkyl)(C １－６ alkyl), -OH, -O -C １－６ alkyl, =O, -S(=O) ２ -C １－６ alkyl, -S(=O) ２ -halo, -S(=O) ２ -cycloalkyl, -C １－６ alkyl -S(=O) ２ -C １－６ alkyl, -NR ｃ -S(=O) ２ -C １－６ alkyl, -halo, -(CH ２ ),n-cycloalkyl, -(CH ２ ),n-heterocycloalkyl, -(CH ２ ),n-aryl, or -(CH ２ ),n-heteroaryl, and may be substituted [wherein, the -(CH ２ ),n-cycloalkyl, -(CH ２ ),n-heterocycloalkyl, -(CH ２ ),n-aryl, or -(CH ２ ),n-heteroaryl ring, one or more Hs are -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 alkyl, -halo, cycloalkyl, or heterocycloalkyl, and may be substituted], the -(CH ２ ),m-cycloalkyl or -(CH ２ ),m-heterocycloalkyl -CH ２ - may be substituted with -S(=O) ２ -}; R ａ is -H or -C １－６ alkyl; R ｂ is -H, -C １－６ alkyl, -NH ２ , -NH-C １－６ alkyl, or -N(C １－６ alkyl)(C １－６ alkyl); R ｃ is -H or -C １－６ alkyl; m and n are each independently 0, 1, 2, or 3.

2. X １ and X ２ are each independently CH or N {wherein one or more of X １ or X ２ is N}; Rx is -H or -C １－６ alkyl; Y １ is CH or N; Ring W is a 5- to 6-membered heteroaryl {where one or more Hs of the 5- to 6-membered heteroaryl ring may be substituted with -C １－６ alkyl or cycloalkyl}; Z １ is -(CH ２ CH ２ ), -(CH ２ CH ２ CH ２ ), or -(CH ２ CH ２ CH ２ CH ２ ); where one or more H of said -(CH ２ CH ２ ), -(CH ２ CH ２ CH ２ ), or -(CH ２ CH ２ CH ２ CH ２ ) may be replaced by -C １－３ alkyl; Z ２ is -(CH ２ )- or -O-; Z ３ is a bond (null), -(CH ２ ), - or -(CH ２ CH ２ ), and L is -C(=O)-, -C(=O)-NR ａ -, or -C(=O)-O-; R １ is -H, -C １－６ alkyl, -C １－６ cyanoalkyl, -C １－６ haloalkyl, -(CH ２ )m -S(=O) ２ -R ｂ , -(CH ２ )m -cycloalkyl, -(CH ２ )m -heterocycloalkyl, or -(CH ２ )m -aryl {wherein one or more Hs of said -(CH ２ )m -cycloalkyl, -(CH ２ )m -heterocycloalkyl, or -(CH ２ )m -aryl are -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, -halo, or -(CH ２ )n -heterocycloalkyl may be substituted [wherein one or more Hs of said -(CH ２ )n -heterocycloalkyl ring may be substituted with -C １－６ alkyl or heterocycloalkyl], and -CH ２ - of said -(CH ２ )m -cycloalkyl or -(CH ２ )m -heterocycloalkyl may be substituted with -S(=O) ２ -}; R ａ is -H or -C １－６ alkyl; R ｂ is -H or -C １－６ alkyl; R ｃ is -H or -C １－６ alkyl; m and n are each independently 0, 1, 2, or 3; A compound represented by formula A according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

3. Ring W is 【Chemical Formula 19】 or phenyl {wherein the 【Chemical 20】 or one or more Hs of the phenyl ring is / are -C １－６ alkyl, -C １－６ hydroxyalkyl, -O-C １－６ alkyl, -S(=O) ２ -C １－６ alkyl, or -S(=O) ２ -cycloalkyl, which may be substituted; compound represented by formula A according to claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula A is selected from the group consisting of the following compounds: 【Table 5】

5. A pharmaceutical composition comprising a compound represented by 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 as an active ingredient a compound according to any one of claims 1 to 4, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition according to claim 6, which inhibits EGFR.

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

9. The cancer is one or more 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, fungating polyp, acute myeloid leukemia, acute lymphocytic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell tumor, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, bile duct cancer, colorectal cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, cancer of the Vater ampulla, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal and paranasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain tumor, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvic cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone tumor, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary origin, gastric lymphoma, gastric cancer, gastric carcinoid tumor, gastrointestinal stromal tumor, Wilms tumor, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone tumor, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid tumor, vaginal cancer, spinal cord cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi 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, the pharmaceutical composition according to claim 6.

10. Use of a compound represented by formula A according to any one of claims 1 to 4, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment or prevention of an EGFR-related disease.

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

12. Administering a therapeutically effective amount of a compound represented by formula A according to any one of claims 1 to 4, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, comprising pseudomyxoma, intrahepatic bile duct cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, fungating polyp, acute myeloid leukemia, acute lymphocytic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell tumor, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, bile duct cancer, colorectal cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, Vater ampulla cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal and paranasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain tumor, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvic cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone tumor, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary origin, gastric lymphoma, gastric cancer, gastric carcinoid tumor, gastrointestinal stromal tumor, Wilms tumor, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone tumor, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid tumor, vaginal cancer, spinal cord cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi 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 a method for treating or preventing one or more diseases selected from the group consisting of thymic cancer.

Images