KR20240002289A - Heteroaryl derivative compounds, and uses thereof - Google Patents

Abstract

The present invention relates to heteroaryl derivatives and their uses. Since the heteroaryl derivatives of the present invention exhibit excellent inhibitory activity against EGFR, they can be usefully used as a treatment for the above-mentioned EGFR-related diseases.

Description

Heteroaryl derivative compounds, and uses thereof}

The present invention relates to heteroaryl derivative compounds and their medicinal uses. Specifically, the present invention relates to heteroaryl derivative compounds having EGFR inhibitory activity.

Protein kinases are involved in signal transduction pathways by acting as molecular switches, and the transition between the active and inactive states of the target protein by the kinase within the cell must be smoothly regulated. If the transition between the active and inactive states is abnormally regulated, intracellular signaling is excessively activated or deactivated, leading to uncontrolled cell division and proliferation. In particular, abnormal activation due to mutation, amplification, and/or overexpression of protein kinase genes causes the development and progression of various tumors or plays a critical role in the development of various diseases such as inflammatory diseases, degenerative brain diseases, and autoimmune diseases.

Epidermal growth factor receptor (EGFR), a receptor tyrosine kinase of the ErbB family, is used in non-small cell lung carcinoma (NSCLC), breast cancer, glioma, squamous cell carcinoma of the head and neck, colorectal cancer, and rectal adenocarcinoma. , is abnormally activated in many epithelial tumors, including head and neck cancer, stomach cancer, and prostate cancer, and activation of the EGFR-tyrosine kinase causes continuous cell proliferation, invasion into surrounding tissues, distant metastasis, blood vessel formation, and increases cell survival. Sikkim is known.

Meanwhile, it was known that the EGFR mutation, EGFR Del19 or EGFR L858R, is a major cause of non-small cell lung cancer and head and neck cancer, and their treatments, Iressa and Tarceva, have been developed and are currently used clinically. However, when these drugs were used in patients, acquired resistance, which is a secondary mutation of EGFR based on the structure of the drug, was observed, and it was also revealed that this is the main cause of actual drug resistance. When first-generation EGFR inhibitors are used for an average of 10 months, acquired resistance called the T790M mutation located in the gatekeeper of EGFR kinase occurs, making the first-generation EGFR inhibitors ineffective. In other words, EGFR Del19/T790M or EGFR L858R/T790M double mutation occurs, making existing treatments ineffective. Osimertinib, a third-generation EGFR-TKI targeting drug that shows high responsiveness to drug resistance due to the EGFR T790M mutation, was developed, but it was also reported to cause drug resistance (Clin Cancer Res, 2015, 17: 21). The EGFR C797S mutation has been suggested as one of the main mechanisms causing drug resistance to osimertinib, and approximately 40% of clinical trial patients were reported to have the EGFR C797S mutation (Nature Medicine, 2015, 21:560-562).

In this way, the unmet demand for new compounds that can be useful in the treatment of EGFR-related diseases by regulating EGFR activity (especially C797S mutation such as EGFR Del19/T790M/C797S or EGFR L858R/T790M/C797S) is increasing. .

Clin Cancer Res, 2015, 17:21 Nature Medicine, 2015, 21:560-562

The object of the present invention is to provide a heteroaryl derivative with a novel structure, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

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

Another object of the present invention is to provide a medicinal use of the heteroaryl derivative compound, specifically, a pharmaceutical composition for the treatment or prevention of EGFR-related diseases comprising the heteroaryl derivative compound as an active ingredient, and EGFR-related disease using the compound. To provide a method for treating or preventing a disease or a method for treating or preventing an EGFR-related disease, including the step of administering the compound.

In order to achieve the above object, as a result of research efforts by the present inventors, the present invention was completed by confirming that heteroaryl derivative compounds represented by Chemical Formula 1 mentioned below inhibit the proliferation of EGFR-activated cells.

Heteroaryl derivative compounds

The present invention provides a compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

[Formula 1]

In Formula 1,

X ₁ to X ₃ are each independently CR ₁ , NR ₂ , O, or S;

R ₁ is -H, -C _1-6 alkyl, -C _1-6 aminoalkyl, -C _1-6 hydroxyalkyl, -C _1-6 haloalkyl, -CN, -NR _a R _b , -OR _c , -halo, or -C _3-6 cycloalkyl;

R ₂ is -H or -C _1-6 alkyl;

Y ₁ to Y ₄ are each independently CR ₃ or N {wherein Y ₁ and Y ₂ are connected to each other to form 6-membered aryl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, or 5-6 membered May form a heterocycloalkenyl ring [In this case, at least one H of the 6-membered aryl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkenyl ring is -C _1-6 alkyl, -C _1-6 aminoalkyl, -C _1-6 hydroxyalkyl, -C _1-6 haloalkyl, -CN, -NR _a R _b , -OR _c , =O, -halo, or may be substituted with cycloalkyl]};

R ₃ is -H, -C _1-6 alkyl, -C _1-6 aminoalkyl, -C _1-6 hydroxyalkyl, -C _1-6 haloalkyl, -CN, -NR _a R _b , -OR _c , -halo, cycloalkyl, heterocycloalkyl, aryl, -O-aryl, or heteroaryl, {wherein one or more H of the cycloalkyl, heterocycloalkyl, aryl, -O-aryl, or heteroaryl ring is - C _1-6 alkyl, -C _1-6 alkenyl, -C _1-6 alkynyl, -C _1-6 aminoalkyl, -C _1-6 hydroxyalkyl, -C _1-6 haloalkyl, -CN, may be substituted with -NR _a R _b , -OR _c , or -halo]};

L is NR ₄ or nothing (null);

R ₄ may be -H or -C _1-6 alkyl, or may be linked with Y ₁ to form a 4-7 membered ring with the N atom;

W may be -C _1-6 alkyl, or may be connected with R ₄ to form a 4-7 membered ring with the N atom and -S(=O) ₂ -;

Z ₁ and Z ₂ are each independently CH or N;

V ₁ and V ₂ are each independently -C _1-6 alkyl, -C _1-6 haloalkyl, -OC _1-6 alkyl, -OC _1-6 haloalkyl, -halo, or heteroaryl {where: one or more H of the heteroaryl ring may be substituted with -C _1-6 alkyl, -C _1-6 haloalkyl, -halo, or -S(=O) ₂ -C _1-6 alkyl};

Ring A is a single ring heterocycloalkyl or multiple ring heterocycloalkyl {wherein one or more H of the single ring heterocycloalkyl or multiple ring heterocycloalkyl is -C _1-6 alkyl, -C _{1- 6} aminoalkyl, -C _1-6 hydroxyalkyl, -C _1-6 haloalkyl, -C _1-6 alkyl-OC _1-6 alkyl, -CN, -C _1-6 alkyl-CN, -C _{1- 6} Haloalkyl-CN, -NR _a R _b , -OR _c , =O. =NR _d , -halo, -C(=O)-C _1-6 alkyl, or -(CH ₂ )n-heterocycloalkyl [In this case, the -(CH ₂ )n-heterocycloalkyl One or more H of the ring is -C _1-6 alkyl, -C _1-6 aminoalkyl, -C _1-6 hydroxyalkyl, -C _1-6 haloalkyl, -CN, -NR _a R _b , -OR _c , =O. =NR _d , or -can be substituted with halo]};

n is 0, 1, 2, 3, or 4;

R _a and R _b are each independently -H or -C _1-6 alkyl;

R _c is -H, -C _1-6 alkyl, or -C _1-6 haloalkyl;

R _d is -H, -C _1-6 alkyl, -OH, or -OC _1-6 alkyl.

According to an embodiment of the present invention, the compound represented by Formula 1, its optical isomer, or a pharmaceutically acceptable salt thereof may be in the following range:

X ₁ to X ₃ are each independently CR ₁ , NR ₂ , O, or S;

R ₁ is -H;

R ₂ is -H;

Y ₁ to Y ₄ are each independently CR ₃ {here, Y ₁ and Y ₂ may be connected to each other to form a 5-6 membered heteroaryl ring [In this case, one or more of the 5-6 membered heteroaryl ring H may be substituted with -C _1-6 alkyl, -C _1-6 haloalkyl, or -halo]};

R ₃ is -H, -C _1-6 alkyl, -C _1-6 hydroxyalkyl, -C _1-6 haloalkyl, -OR _c , -halo, or cycloalkyl {wherein one of the cycloalkyl rings H above may be substituted with -C _1-6 alkyl, -C _1-6 haloalkyl, or -halo]};

L is NR ₄ or nothing (null);

R ₄ may be -H or -C _1-6 alkyl, or may be linked with Y ₁ to form a 5-6 membered ring with the N atom;

W may be -C _1-6 alkyl, or may be connected with R ₄ to form a 5-6 membered ring with the N atom and -S(=O) ₂ -;

Z ₁ and Z ₂ are each independently CH;

V ₁ is -OC _1-6 alkyl or -OC _1-6 haloalkyl;

V ₂ is heteroaryl {wherein one or more H of the heteroaryl ring may be substituted with -C _1-6 alkyl or -halo};

Ring A is a single ring heterocycloalkyl or multiple ring heterocycloalkyl {wherein one or more H of the single ring heterocycloalkyl or multiple ring heterocycloalkyl is -C _1-6 alkyl, -C _{1- 6} May be substituted with haloalkyl, -halo, or -(CH ₂ )n-heterocycloalkyl [In this case, at least one H of the -(CH ₂ )n-heterocycloalkyl ring is -C _1-6 alkyl, may be substituted with -C _1-6 haloalkyl, -OR _c , or -halo]};

n is 0, 1, or 2;

R _c is -H, -C _1-6 alkyl, or -C _1-6 haloalkyl.

According to an embodiment of the present invention, the compound represented by Formula 1 may be selected from the group consisting of compounds listed in Table 1 below.

In the present invention, “alkyl”, unless otherwise specified, may mean a straight-chain or branched-chain acyclic, cyclic, or saturated hydrocarbon in which these are combined. For example, “C _1-6 alkyl” can mean alkyl containing 1 to 6 carbon atoms. Acyclic alkyl may include, for example, methyl, ethyl, n -propyl, n -butyl, isopropyl, sec )-butyl, isobutyl, or tertiary ( tert )-butyl, etc. It is not limited to this. Cyclic alkyl may be used interchangeably with “cycloalkyl” herein and may include, but is limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, as examples. It doesn't work.

In the present invention, “alkoxy” may mean -(O-alkyl) as an alkyl ether group, where alkyl is as defined above. For example, “C _1-6 alkoxy” may mean alkoxy containing C _1-6 alkyl, that is, -(OC _1-6 alkyl). As an example, alkoxy is methoxy (methoxy). ), ethoxy , n -propoxy, isopropoxy, n -butoxy , isobutoxy , sec -butoxy ), or tert -butoxy, etc., but is not limited thereto.

In the present invention, “halo” may be F, Cl, Br, or I.

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

As used herein, “hydroxyalkyl” may mean straight 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 one or more halogens, such as -OH.

As used herein, “aminoalkyl” may refer to a straight-chain or branched-chain alkyl (hydrocarbon) having a carbon atom substituted with amino (NR'R"). Here, R' and R" are each independently hydrogen, It may be selected from the group consisting of C _1-6 alkyl, and N protecting group (eg, Boc), and the selected R' and R" may each be independently substituted or unsubstituted.

As used herein, “cyanoalkyl” may mean straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with cyano (CN).

In the present invention, “cycloalkyl” may refer to a hydrocarbon ring that does not contain heteroatoms (N, O, P, P(=O), or S, etc.) in the ring and may be saturated or partially unsaturated. there is. Here, when unsaturated, it may be referred to as cycloalkenyl. Unless otherwise stated, cycloalkyls may be single rings or multiple rings such as spiro rings, bridged rings, or fused rings.

In the present invention, “heterocycloalkyl” may mean a ring containing one or more elements selected from N, O, P, P(=O), and S in the ring, and may be saturated or partially unsaturated. Here, when unsaturated, it may be referred to as a heterocycloalkene. Unless otherwise stated, heterocycloalkyl may be a single ring or multiple rings such as spiro rings, bridged rings, or fused rings. In addition, “heterocycloalkyl of 3 to 12 atoms” may mean heterocycloalkyl containing 3 to 12 atoms forming a ring. As an example, heterocycloalkyl includes pyrrolidine, piperidine, Imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4 (1 H , 3 H ) -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, (1 R ,5 S )-3-azabicyclo[3.2.1 ]Including octane, (1 s ,4 s )-2-azabicyclo[2.2.2]octane, or (1 R ,4 R )-2-oxa-5-azabicyclo[2.2.2]octane, etc. It can be done, but is not limited to this.

In the present invention, “arene” may mean an aromatic hydrocarbon ring. The arenes may be monocyclic arenes or polycyclic arenes. 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 arenes include benzene, naphthalene, fluorene, anthracene, phenanthrene, bibenzene, terbenzene, quarterbenzene, quincbenzene, sexybenzene, triphenylene, pyrene, benzofluoranthene, chrysene, etc. , but is not limited to these. In this specification, the residue obtained by removing one hydrogen atom from the “arene” is referred to as “aryl.”

In the present invention, “heteroarene” may be a ring containing one or more of O, N, P, Si, and S as a heterogeneous element. The number of ring-forming carbon atoms of the heteroarene may be 2 to 30 or 2 to 20. The heteroarene may be a monocyclic heteroarene or a polycyclic heteroarene. Polycyclic heteroarene may have, for example, a 2-ring or 3-ring structure. Examples of heteroarenes include thiophene, purine, pyrrole, pyrazole, imidazole, thiazole, oxazole, isothiazole, oxadiazole, triazole, pyridine, bipyridyl, triazine, acridyl, and pyridazine. , pyrazine, quinoline, quinazoline, quinoxaline, phenoxazine, phthalazine, pyrimidine, pyrido pyrimidine, pyrido pyrazine, pyrazino pyrazine, isoquinoline, indole, carbazole, imidazopyridazine, imidazopyridine. , imidazopyrimidine, pyrazolopyrimidine, imidazopyrazine or pyrazolopyridine, N -arylcarbazole, N -heteroarylcarbazole, N -alkylcarbazole, benzoxazole, benzoimidazole, benzothiazole , benzocarbazole, benzothiophene, dibenzothiophene, thienothiophene, benzofuran, phenanthroline, isoxazole, oxadiazole, thiadiazole, benzothiazole, tetrazole, phenothiazine , dibenzosilol, and dibenzofuran, etc., but are not limited to these. In one embodiment of the invention, heteroarenes may also include bicyclic heterocyclo-arenes, including an arene ring fused to a heterocycloalkyl ring or a heteroarene fused to a cycloalkyl ring. In this specification, the residue obtained by removing one hydrogen atom from the “heteroarene” is referred to as “heteroaryl.”

In the present invention, the term “enantiomer” refers to a compound of the present invention or a salt thereof that has the same chemical or molecular formula but is sterically different. Each of these optical isomers and mixtures thereof are also included within the scope of the present invention. Unless otherwise stated, the solid bond (-) connecting an asymmetric carbon atom is a solid wedge bond indicating the absolute configuration of the stereocenter. or wedge-dotted join may include.

The compound of Formula 1 of the present invention may exist in the form of a “pharmaceutically acceptable salt.” As a salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. The term "pharmaceutically acceptable salt" of the present invention refers to any of the compounds at a concentration that is relatively non-toxic and harmless to patients and has an effective effect, and side effects due to the salt do not reduce the beneficial efficacy of the compound represented by Formula 1. refers to all organic or inorganic acid addition salts.

In the present invention, the term "cis" refers to the case where the bonding directions of two substituents of the ring are the same, and the term "trans" refers to the case where the bonding directions of the two substituents of the ring are different. .

Acid addition salts are prepared by conventional methods, for example, by dissolving the compound in an excess of aqueous acid solution and precipitating the salt using a water-miscible organic solvent, such as methanol, ethanol, acetone or acetonitrile. Equimolar amounts of the compound and acid or alcohol in water can be heated, and the mixture can then be evaporated to dryness, or the precipitated salt can be filtered off with suction.

At this time, organic acids and inorganic acids can be used as free acids. Hydrochloric acid, phosphoric acid, sulfuric acid, or nitric acid can be used as inorganic acids, and methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, etc. can be used as organic acids. Maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, glue Gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, or hydroiodic acid, etc. can be used. However, it is not limited to these.

Additionally, a pharmaceutically acceptable metal salt can be prepared using a base. The alkali metal salt or alkaline earth metal salt is obtained, for example, 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. At this time, it is pharmaceutically suitable to prepare metal salts, especially sodium, potassium, or calcium salts, but is not limited to these. Additionally, the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with an appropriate silver salt (e.g., silver nitrate).

Pharmaceutically acceptable salts of the present invention include salts of acidic or basic groups that may be present in the compound of formula (1), unless otherwise indicated. For example, pharmaceutically acceptable salts may include sodium, calcium, and potassium salts of the hydroxy group, and other pharmaceutically acceptable salts of the amino group may include hydrobromide, sulfate, hydrogen sulfate, phosphate, Hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate), and p-toluenesulfonate (tosylate) salts are known in the art. It can be produced through a known salt production method.

Uses of Heteroaryl Derivative Compounds

The present invention provides the use of a compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1]

Formula 1 is as defined above.

The compound represented by Formula 1 of the present invention, its optical isomer, or a pharmaceutically acceptable salt thereof exhibits inhibitory activity against various kinases.

According to one embodiment of the present invention, the heteroaryl derivative represented by Formula 1 exhibits excellent inhibitory activity against EGFR kinase and can be usefully used in the treatment or prevention of EGFR-related diseases, especially 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.) It can be useful in the treatment or prevention of carcinoma induced by EGFR.

In the present invention, the cancer includes all cancers that can exhibit therapeutic or preventive efficacy due to inhibition of EGFR kinase activity, and may be solid cancer or blood cancer. The type of cancer is not limited, but includes, for example, pseudomyxoma, intrahepatic bile duct cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, oral cavity 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, colon cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma , ampulla of Vater cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, sinonasal 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 cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, stomach cancer. , gastric carcinoid cancer, gastrointestinal stromal cancer, Wilms cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal cancer. Carcinoid cancer, vaginal cancer, spinal 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 , it may be one or more types selected from the group consisting of pleural cancer, blood cancer, and thymic cancer. Additionally, the cancer includes not only primary cancer but also metastatic cancer.

According to one embodiment of the present invention, the present invention provides a pharmaceutical composition for the treatment or prevention of EGFR-related diseases containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. to provide. Specifically, the EGFR-related disease may be cancer. The types of cancer are as mentioned above.

The pharmaceutical composition of the present invention may further include one or more active ingredients exhibiting the same or similar medicinal efficacy in addition to the compound represented by Formula 1, its optical isomer, or a pharmaceutically acceptable salt thereof.

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

In addition, according to one embodiment of the present invention, the step of administering a therapeutically effective amount of the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof. Provided is a method of treating or preventing EGFR-related diseases, including: The subject may be a mammal, including humans.

The term “therapeutically effective amount” used in the present invention refers to the amount of the compound represented by Formula 1 that is effective in treating or preventing EGFR-related diseases. Specifically, “therapeutically effective amount” means an amount sufficient to treat the disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is determined by the type and severity of the individual, age, gender, type of disease, It can be determined based on factors including the activity of the drug, sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, drugs used simultaneously, and other factors well known in the medical field. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with commercially available therapeutic agents. And it can be administered single or multiple times. Considering all of the above factors, it is important to administer an amount that can achieve maximum effect with the minimum amount without side effects, and can be easily determined by a person skilled in the art. The administered dose of the pharmaceutical composition of the present invention may be determined by an expert depending on various factors such as the patient's condition, age, gender, and complications. Since the active ingredient of the pharmaceutical composition of the present invention has excellent safety, it can be used at a dose exceeding the determined dosage.

In addition, according to one embodiment of the present invention, the present invention provides a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutical thereof for use in the production of a medicament for use in the treatment or prevention of EGFR-related diseases. Provides acceptable uses of salts. The compound represented by Formula 1 for the manufacture of drugs can be mixed with acceptable auxiliaries, diluents, carriers, etc., and can be prepared as a complex preparation with other active agents to have a synergistic effect of the active ingredients.

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

Since the heteroaryl derivative compound of the present invention exhibits excellent inhibitory activity against EGFR, it can be usefully used in the treatment or prevention of the above-mentioned EGFR-related diseases.

Hereinafter, the present invention will be described in detail through examples and experimental examples. However, the following examples and experimental examples only illustrate the present invention, and the content of the present invention is not limited thereto.

<Analysis and purification conditions>

The compounds synthesized in the examples of the present invention were purified or subjected to structural analysis under the following HPLC conditions.

1. HPLC conditions for analysis

HPLC conditions for analysis (ACQUITY UPLC H-Class Core System)

An UPLC system (ACQUITY UPLC PDA Detector) manufactured by Waters was used equipped with a mass QDA Detector manufactured by Waters. The column used was Waters' ACQUITY UPLC ^® BEH C18 (1.7 ㎛, 2.1

Mobile phase A used water containing 0.1% formic acid, and mobile phase B used acetonitrile containing 0.1% formic acid.

Gradient condition (10-100% B for 3 minutes, moving speed = 0.6 ml/min)

Preparative-LCMS (Preparative-Liquid chromatography mass spectrometry)

An Autopurification HPLC system manufactured by Waters (2767 sample manager, 2545 binary gradient module, 2998 Photodiode Array Detector) equipped with a mass QDA Detector manufactured by Waters was used. The column used was Waters' SunFire ^® Prep C18 OBD ^TM (5 ㎛, 19

Mobile phase A used water containing 0.035% trifluoroacetic acid, and mobile phase B used methanol containing 0.035% trifluoroacetic acid.

Gradient condition (15-100% B for 10 minutes, moving speed = 25 ml/min)

Prep-150 LC System for purification (Preparative-Liquid chromatography UV spectrometry)

Equipment manufactured by Waters was used in the Prep 150 LC system (2545 Quaternary gradient module, 2998 Photodiode Array Detector, Fraction collector III) manufactured by Waters. The column used was Waters' XTERRA ^® Prep RP18 OBD ^TM (10 ㎛, 30

Gradient condition (3-100% B for 120 minutes, moving speed = 40 ml/min)

2. NMR analysis

NMR analysis was performed using AVANCE III 400 or AVANCE III 400 HD manufactured by Bruker, and data were expressed in ppm (parts per million (δ)).

The commercial reagents used were used without further purification. In the present invention, room temperature or room temperature refers to a temperature of 5°C to 40°C, as an example, 10°C to 30°C, and as another example, 20°C to 27°C, and is not strictly limited to the above range. Concentration or solvent distillation under reduced pressure was performed using a rotary evaporator.

<Example 1> N2-(4-((2S,6R)-2,6-dimethylmorpholino)-2-ethoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl )-N4-(2-(isopropylsulfonyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine Preparation

Step 1: Preparation of 1-bromo-4-ethoxy-2-fluoro-5-nitrobenzene

4-Bromo-5-fluoro-2-nitrophenol (1.0 g, 4.24 mmol), iodoethane (0.685 mL, 8.47 mmol), and K ₂ CO ₃ (1.171 g, 8.47 mmol) were dissolved in DMSO (11.6 mL). ) and stirred at 60°C for 3 hours. After adding water and salt water and extracting the organic matter with ethyl acetate, the collected organic layer was dried with sodium sulfate and concentrated. The concentrated mixture was purified through column chromatography (0-20% hexane/ethyl acetate), and the target compound (1.1 g, 98 % yield) was obtained as a yellow liquid.

Step 2: Preparation of (2S,6R)-4-(2-bromo-5-ethoxy-4-nitrophenyl)-2,6-dimethylmorpholine

1-Bromo-4-ethoxy-2-fluoro-5-nitrobenzene (1 g, 3.79 mmol) prepared in Step 1 and (2S,6R)-2,6-dimethylmorpholine (0.56 mL) , 4.54 mmol) and K ₂ CO ₃ (1.57 g, 11.36 mmol) were dissolved in DMSO (9.5 mL) and stirred at 60°C for 16 hours. After extracting the organic matter with water and ethyl acetate, the collected organic layer was dried with sodium sulfate and concentrated. The obtained yellow solid target compound (1.36 g, 100% yield) was used in the next reaction without further purification.

MS (m/z): 359 [M+1] ⁺

Step 3: (2S,6R)-4-(5-ethoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)-2,6-dimethylmorpholine manufacturing

(2S,6R)-4-(2-bromo-5-ethoxy-4-nitrophenyl)-2,6-dimethylmorpholine (1.5 g, 4.18 mmol), 1-methyl prepared in Step 2 -4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.74 g, 8.35 mmol), K ₂ CO ₃ (1.73 g 12.53 mmol) was dissolved in 1,4-dioxane/water = 4/1 (16 mL), then PdCl ₂ (dtbpf) (0.14 g, 0.21 mmol) was added under nitrogen and stirred at 100°C for 1 hour. After filtering through Celite, it was concentrated. The reaction mixture was purified through column chromatography (0-5% dichloromethane/methanol), and the target compound (1 g, 66.4 % yield) was obtained as a yellow solid.

MS (m/z): 361 [M+1] ⁺

Step 4: Preparation of 4-((2S,6R)-2,6-dimethylmorpholino)-2-ethoxy-5-(1-methyl-1H-pyrazol-4-yl)aniline

(2S,6R)-4-(5-ethoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)-2,6-dimethylmor prepared in Step 3 Pauline (1 g, 2.77 mmol) and Pd/C (0.1 g) were dissolved in methanol (15 mL) and stirred at room temperature under a hydrogen stream for 1 hour. After filtration through Celite, the filtrate was concentrated. The obtained liquid target compound (0.7 g, 76% yield) was used in the next reaction without further purification.

MS (m/z): 331 [M+1] ⁺

Step 5: 2-Chloro-N-(2-(isopropylsulfonyl)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyri Preparation of midin-4-amine

(2-(Isopropylsulfonyl)aniline (2.75 g, 13.82 mmol) was dissolved in DMF (63 mL), then sodium hydride (0.553 g, 13.82 mmol, 60%) was added at 0°C and stirred for 30 minutes. Add 2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (4 g, 12.57 mmol) and incubate at 50°C. It was stirred for 2 hours. Water and salt water were added, and the organic matter was extracted with ethyl acetate. The collected organic layer was dried using sodium sulfate and concentrated. The reaction mixture was dissolved in dichloromethane, and then ethyl ether was added to obtain the target compound (4.6) as a yellow solid. g, 76% yield) was obtained.

MS (m/z): 481 [M+1] ⁺

Step 6: N2-(4-((2S,6R)-2,6-dimethylmorpholino)-2-ethoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)- N4-(2-(isopropylsulfonyl)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-dia Manufacturing of folk medicine

2-Chloro-N-(2-(isopropylsulfonyl)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d prepared in Step 5 ]Pyrimidin-4-amine (100 mg, 0.22 mmol), 4-((2S,6R)-2,6-dimethylmorpholino)-2-ethoxy-5-(1- prepared in Step 4 Methyl-1H-pyrazol-4-yl)aniline (76 mg, 0.22 mmol) and Cs ₂ CO ₃ (217 mg, 0.66 mmol) were dissolved in dioxane (3.7 mL), and then Pd ₂ (dba) ₃ under nitrogen. (20.3 mg, 0.022 mmol) and Xphos (10.6 mg, 0.022 mmol) were added and stirred at 110°C for 1 hour. After filtering through Celite, it was concentrated. The reaction mixture was purified through column chromatography (dichloromethane/methanol), and the target compound (100 mg, 60% yield) was obtained as a brown liquid.

MS (m/z): 759 [M+1] ⁺

Step 7: N2-(4-((2S,6R)-2,6-dimethylmorpholino)-2-ethoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)- Preparation of N4-(2-(isopropylsulfonyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

N2-(4-((2S,6R)-2,6-dimethylmorpholino)-2-ethoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl prepared in Step 6 )-N4-(2-(isopropylsulfonyl)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4 -Diamine (100 mg, 0.13 mmol) was dissolved in dioxane (2.2 mL), then trifluoroacetic acid (0.5 mL) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated and dissolved in dichloromethane/methanol/ammonia solution = 1/1/1, and then stirred at room temperature for 2 hours. Water and salt water were added, and organic matter was extracted with ethyl acetate. The collected organic layer was dried using sodium sulfate and concentrated. The reaction mixture was purified by supercritical fluid chromatography, and the target compound (44 mg, 53% yield) was obtained as a yellow solid.

MS (m/z): 645 [M+1] ⁺

<Example 2> to <Example 65>

The compounds of Examples 2 to 65 were prepared in a similar manner to Example 1, and the chemical structures, compound names, NMR and LC-MS analysis results of the compounds of Examples 1 to 65 are summarized in Table 1 below.

[Table 1]

<Experimental Example 1> Evaluation of Ba/F3 cell proliferation inhibitory activity

The following experiment was performed to evaluate the inhibitory activity of the compound represented by Formula 1 according to the invention on the proliferation of Ba/F3 cells expressing mutations in EGFR.

BaF3-EGFR(WT) and BaF3-EGFR(Del19/T790M/C797S) cells were seeded at 3 Υ 10 ³ /100 μl/well in a clear bottom white 96-well plate, and then serially diluted in 3-fold at 12 different concentrations ( Culture medium containing 0.00001 - 2 mM) of the compound and DMSO control was added at 0.5 μl/well to a final concentration of 0.00005 - 10 μM, and then cultured in a CO ₂ incubator at 37°C for 72 hours. After 72 hours, the plate treated with the compound was taken out, treated with 100 μl/well of CellTiter-Glo ^® 2.0 Assay (Promega) solution, and mixed well. The mixture was mixed well at room temperature for about 10 minutes, and the fluorescence was measured using a microplate reader. Data were calculated as GI ₅₀ (μM) values using GraphPad Prism 8.3.0 (GraphPad software Inc., San Diego) as a percentage relative to vehicle-treated cells. The results were calculated as cell growth ratio (%) compared to the control group. GraphPad Prism version 5.0 program was used to draw graphs and calculate GI ₅₀ (μM) values.

Table 2 below shows the results of evaluating the proliferation inhibitory activity of Ba/F3 cells expressing EGFR mutations.

[Table 2]

(A: GI ₅₀ ≤ 0.05 μM; B: 0.05 μM < GI ₅₀ ≤ 0.1 μM; C: 0.1 μM < GI ₅₀ ≤ 1 μM; D: GI ₅₀ > 1 μM)

As shown in Table 2 above, it can be seen that the example compounds of the present invention exhibit high inhibitory ability against enzymes or cell lines containing the EGFR C797S mutation.

Above, the present invention has been described in detail through preferred examples and experimental examples, but the scope of the present invention is not limited to the specific example compounds and should be interpreted in accordance with the appended claims. Additionally, those skilled in the art should understand that many modifications and variations are possible without departing from the scope of the present invention.

Claims (4)

A compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]
A compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]

In Formula 1,
X ₁ to X ₃ are each independently CR ₁ , NR ₂ , O, or S;
R ₁ is -H, -C _1-6 alkyl, -C _1-6 aminoalkyl, -C _1-6 hydroxyalkyl, -C _1-6 haloalkyl, -CN, -NR _a R _b , -OR _c , -halo, or -C _3-6 cycloalkyl;
R ₂ is -H or -C _1-6 alkyl;
Y ₁ to Y ₄ are each independently CR ₃ or N {wherein Y ₁ and Y ₂ are connected to each other to form 6-membered aryl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, or 5-6 membered May form a heterocycloalkenyl ring [In this case, at least one H of the 6-membered aryl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkenyl ring is -C _1-6 alkyl, -C _1-6 aminoalkyl, -C _1-6 hydroxyalkyl, -C _1-6 haloalkyl, -CN, -NR _a R _b , -OR _c , =O, -halo, or may be substituted with cycloalkyl]};
R ₃ is -H, -C _1-6 alkyl, -C _1-6 aminoalkyl, -C _1-6 hydroxyalkyl, -C _1-6 haloalkyl, -CN, -NR _a R _b , -OR _c , -halo, cycloalkyl, heterocycloalkyl, aryl, -O-aryl, or heteroaryl {wherein one or more H of the cycloalkyl, heterocycloalkyl, aryl, -O-aryl, or heteroaryl ring is - C _1-6 alkyl, -C _1-6 alkenyl, -C _1-6 alkynyl, -C _1-6 aminoalkyl, -C _1-6 hydroxyalkyl, -C _1-6 haloalkyl, -CN, may be substituted with -NR _a R _b , -OR _c , or -halo]};
L is NR ₄ or nothing (null);
R ₄ may be -H or -C _1-6 alkyl, or may be linked with Y ₁ to form a 4-7 membered ring with the N atom;
W may be -C _1-6 alkyl, or may be connected with R ₄ to form a 4-7 membered ring with the N atom and -S(=O) ₂ -;
Z ₁ and Z ₂ are each independently CH or N;
V ₁ and V ₂ are each independently -C _1-6 alkyl, -C _1-6 haloalkyl, -OC _1-6 alkyl, -OC _1-6 haloalkyl, -halo, or heteroaryl {where: one or more H of the heteroaryl ring may be substituted with -C _1-6 alkyl, -C _1-6 haloalkyl, -halo, or -S(=O) ₂ -C _1-6 alkyl};
Ring A is a single ring heterocycloalkyl or multiple ring heterocycloalkyl {wherein one or more H of the single ring heterocycloalkyl or multiple ring heterocycloalkyl is -C _1-6 alkyl, -C _{1- 6} aminoalkyl, -C _1-6 hydroxyalkyl, -C _1-6 haloalkyl, -C _1-6 alkyl-OC _1-6 alkyl, -CN, -C _1-6 alkyl-CN, -C _{1- 6} Haloalkyl-CN, -NR _a R _b , -OR _c , =O. =NR _d , -halo, -C(=O)-C _1-6 alkyl, or -(CH ₂ )n-heterocycloalkyl [In this case, the -(CH ₂ )n-heterocycloalkyl One or more H of the ring is -C _1-6 alkyl, -C _1-6 aminoalkyl, -C _1-6 hydroxyalkyl, -C _1-6 haloalkyl, -CN, -NR _a R _b , -OR _c , =O. =NR _d , or -can be substituted with halo]};
n is 0, 1, 2, 3, or 4;
R _a and R _b are each independently -H or -C _1-6 alkyl;
R _c is -H, -C _1-6 alkyl, or -C _1-6 haloalkyl;
R _d is -H, -C _1-6 alkyl, -OH, or -OC _1-6 alkyl. According to claim 1,
X ₁ to X ₃ are each independently CR ₁ , NR ₂ , O, or S;
R ₁ is -H;
R ₂ is -H;
Y ₁ to Y ₄ are each independently CR ₃ {here, Y ₁ and Y ₂ may be connected to each other to form a 5-6 membered heteroaryl ring [In this case, one or more of the 5-6 membered heteroaryl ring H may be substituted with -C _1-6 alkyl, -C _1-6 haloalkyl, or -halo]};
R ₃ is -H, -C _1-6 alkyl, -C _1-6 hydroxyalkyl, -C _1-6 haloalkyl, -OR _c , -halo, or cycloalkyl {wherein one of the cycloalkyl rings H above may be substituted with -C _1-6 alkyl, -C _1-6 haloalkyl, or -halo]};
L is NR ₄ or nothing (null);
R ₄ may be -H or -C _1-6 alkyl, or may be linked with Y ₁ to form a 5-6 membered ring with the N atom;
W may be -C _1-6 alkyl, or may be connected with R ₄ to form a 5-6 membered ring with the N atom and -S(=O) ₂ -;
Z ₁ and Z ₂ are each independently CH;
V ₁ is -OC _1-6 alkyl or -OC _1-6 haloalkyl;
V ₂ is heteroaryl {wherein one or more H of the heteroaryl ring may be substituted with -C _1-6 alkyl or -halo};
Ring A is a single ring heterocycloalkyl or multiple ring heterocycloalkyl {wherein one or more H of the single ring heterocycloalkyl or multiple ring heterocycloalkyl is -C _1-6 alkyl, -C _{1- 6} May be substituted with haloalkyl, -halo, or -(CH ₂ )n-heterocycloalkyl [In this case, at least one H of the -(CH ₂ )n-heterocycloalkyl ring is -C _1-6 alkyl, may be substituted with -C _1-6 haloalkyl, -OR _c , or -halo]};
n is 0, 1, or 2;
R _c is -H, -C _1-6 alkyl, or -C _1-6 haloalkyl;
A compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. According to claim 1,
A compound, an optical isomer thereof, and a pharmaceutically acceptable salt thereof, wherein the compound represented by Formula 1 is selected from the group consisting of the following compounds:




. A pharmaceutical composition for preventing or treating cancer, containing the compound according to any one of claims 1 to 3, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.