WO2020262998A1 - Novel quinazoline derivative having anti-tumor activity and pharmaceutical composition comprising same - Google Patents

Novel quinazoline derivative having anti-tumor activity and pharmaceutical composition comprising same Download PDF

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WO2020262998A1
WO2020262998A1 PCT/KR2020/008312 KR2020008312W WO2020262998A1 WO 2020262998 A1 WO2020262998 A1 WO 2020262998A1 KR 2020008312 W KR2020008312 W KR 2020008312W WO 2020262998 A1 WO2020262998 A1 WO 2020262998A1
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oxy
phenyl
amino
prop
cancer
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PCT/KR2020/008312
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French (fr)
Korean (ko)
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장선영
강석종
한선영
김예림
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한미약품 주식회사
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Priority claimed from KR1020200077953A external-priority patent/KR20210002012A/en
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Publication of WO2020262998A1 publication Critical patent/WO2020262998A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to a novel quinazoline derivative having anti-tumor activity against cancer having an EGFR mutation and/or a HER2 mutation, and a pharmaceutical composition comprising the same as an active ingredient.
  • Epidermal growth factor receptor is a protein consisting of a receptor portion and a tyrosine kinase portion, and plays a role of transmitting signals from outside the cell to the inside of the cell by passing through the cell membrane.
  • EGFR is called ErbB1 or HER1 (human epidermal growth factor receptor 1), and is a 180kDa transmembrane protein.
  • EGFR together with ErbB2 (HER2), ERbB3 (HER3) and ErbB4 (HER4) constitute the ErbB family.
  • the ligands of EGFR include epidermal growth factor (EGF), transforming growth factor- ⁇ (TGF- ⁇ ), ⁇ -cellulin, and epiregulin , Amphiregulin, heparin-binding EGF-like growth factor (B-EGF) and epigen. 7 proteins are known. When the tyrosine residue of EGFR is phosphorylated by the ligand binding, various downstream signaling pathways of the downstream molecules are activated.
  • mitogen-activated protein kinase MAPK
  • PI3-K phosphoinositide 3-kinase
  • STAT signal transducer and activator of transcription
  • EGFR plays an essential role in normal cell regulation through intracellular signaling.
  • problems such as overexpression of EGFR or expression of EGFR mutations involved in cancer cell activation, and the EGFR mutations involved in cancer cell activation are characterized by activating tyrosine kinase in a ligand-independent manner. Therefore, when EGFR overexpression or EGFR mutation involved in cancer cell activation is expressed, normal cell regulation through signal transduction becomes impossible, and thus cancer cell growth, differentiation, neovascularization, metastasis and resistance expression are induced. It is known.
  • the activating mutation of EGFR and/or HER2 is an exon 20 insertion into the tyrosine kinase domain included in these receptors, and is known as a major cause of non-small cell lung cancer and various cancers.
  • Exon 20 insertion is the third most common group of EGFR mutations found in non-small cell lung cancer. Since there is no response to the tyrosine kinase inhibitor of EGFR and little is known about cancers carrying these mutations, effective targeted therapy is difficult. Therefore, studies to develop targeted therapeutic anticancer agents having excellent anticancer effects against exon 20 insertion of EGFR mutant soldiers are actively underway.
  • non-small cell lung cancers have EGFR-activating mutations.
  • Tyrosine kinase inhibitors such as gefitinib and eroltinib are known to have excellent clinical effects in the majority of patients with conventional sensitizing mutations (including exon 19 and L858R) tumors.
  • About 70% of patients treated with such tyrosine kinase inhibitors improved objective response (OR), progression free survival (PFS), and quality of life compared to patients treated with chemotherapy alone.
  • OR objective response
  • PFS progression free survival
  • quality of life compared to patients treated with chemotherapy alone.
  • about 10 to 12% of EGFR mutant non-small cell lung cancer tumors have in-frame insertion within exon 20 of EGFR 6, 15, 16, and 17, and are generally resistant to tyrosine kinase inhibitors of EGFR.
  • Patients with EGFR exon 20 insertion mutations are known to have low overall response rates of about 3-8% to first-line therapy with erlitinib, gefitinib, or afatinib. .
  • 90% of HER2 mutations in non-small cell lung cancer are exon 20 insertion mutations, and about 3% of non-small cell lung cancer patients have HER2 mutations.
  • the exon 20 insertion mutation among the EGFR mutations is heterogeneous at the molecular level, but will be characterized by in-frame insertion or replication between 3 and 21 bp (corresponding to 1 to 7 amino acids) clustered between amino acid positions 762 and 774 of the EGFR protein Can (Yasuda et al ., 2013). This mutation occurs within the C-terminus of the C-helix or more often in the loop immediately following it.
  • Exon 20 insertion is one of the earliest EGFR mutations identified in non-small cell lung cancer with exon 19 deletion and L858R mutation. The frequency of EGFR exon 20 insertion was reported as 4-10% of all EGFR mutations observed in non-small cell lung cancer (Arcila et al ., 2012).
  • the EGFR exon 20 insertion mutation shows a similar tendency to the conventional activating EGFR mutation.
  • EGFR exon 20 insertion mutations are found prevalent in women, nonsmokers, Asian populations, and people with adenocarcinoma histology (Oxnard et al. , 2013).
  • the crystal structure of the exon 20 insertion EGFR mutation, D770_N771insNPG was revealed, which did not significantly decrease ATP affinity, and the first-generation inhibitor gefitinib ), it has been reported that it can activate EGFR without improving its affinity for (Yasuda et al ., 2013).
  • the A763_Y764insFQEA mutation acts similarly to a conventional non-small cell lung cancer EGFR mutation (Yun, C. -H. et al. , 2008).
  • V769insASV ⁇ 20%)
  • D770insSVD ⁇ 20%)
  • H773insNPH ⁇ 10%) are representative mutations showing low reactivity to existing EGFR tyrosine kinase inhibitors.
  • the exon 20 insertion mutation is the most prominent type of HER2 mutation in non-small cell lung cancer. Appears above %.
  • a representative exon 20 insertion mutation is A775_G776insYVMA, which accounts for about 85% of the HER2 mutations (Arcila et al. , 2012).
  • Non-Patent Document 1 Clin Cancer Res. 19(8), 2240, 2013
  • Non-Patent Document 2 Nat Med. 24 (5), 638, 2018
  • Non-Patent Document 3 Signal Transduction and Targeted Therapy 4; 5, 2019
  • One aspect of the present invention is to selectively and effectively inhibit the growth of cancer cells and resistance to drugs caused by mutations in the tyrosine kinase domain of epithelial growth factor receptors (EGFR and HER2), or cancer having such resistance.
  • EGFR and HER2 epithelial growth factor receptors
  • Another aspect of the present invention is to provide a pharmaceutical composition comprising the novel quinazoline derivative and having antitumor activity by inhibiting the growth of cancer cells.
  • One aspect of the present invention provides a quinazoline derivative, solvate, stereoisomer, or a pharmaceutically acceptable salt thereof represented by the following formula (I).
  • R 1 is aryl or heteroaryl (except when R 1 is unsubstituted phenyl);
  • R 2 is hydrogen, a hydroxy group, a cyano group, a C 1 -C 6 alkyl group, a C 2 -C 6 alkene group, a C 2 -C 6 alkane group, a C 1 -C 3 alkoxy group, (monohalogen, dihalogen, Trihalogen)methyl group, monohalogen, dihalogen, trihalogen, C 3 -C 6 cycloalkyl group, or C 1 -C 6 dialkylamino group;
  • R 3 is hydrogen, a hydroxy group, or a C 1 -C 3 alkoxy group
  • n a and n b are each independently an integer of 1 to 6;
  • R 4, R 5 and R 6 are each independently hydrogen, halogen, N -C 1-6 alkyl, N - hydroxyl omicron], CC 1- 6 alkyl station omicron] (-NHCOC 1 -6) , hydroxycarbonyl (-COOH), C 1- 6 alkoxycarbonyl (-COOC 1 -6), C 1- 6 alkyl, hydroxy, C 1- 6 dialkyl amine or a heterocycle-substituted C 1- 6 alkyl substituent.
  • Another aspect of the present invention is the EGFR and/or HER2 mutation comprising the quinazoline derivative of Formula I, a solvate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. It provides a pharmaceutical composition for preventing or treating cancer having.
  • the quinazoline derivatives, solvates, stereoisomers, or pharmaceutically acceptable salts thereof of formula (I) are used for growth of cancer cells and drugs caused by mutations in the tyrosine kinase domain in the epithelial growth factor receptor. Resistance to, or cancer having such resistance can be selectively and effectively inhibited.
  • EGFR Extracellular Growth Factor Receptor
  • HER2 human epidermal growth factor receptor type2
  • HER2 human epidermal growth factor receptor type2
  • exon 20 refers to the 20th exon gene among exon genes, which is a gene having protein synthesis information in the nucleotide sequence of the gene.
  • halogen includes fluorine, chlorine, bromine or iodine, unless otherwise stated, and may be, for example, fluorine or chlorine, but is not limited thereto.
  • alkyl refers to a saturated monovalent hydrocarbon radical.
  • alkenyl refers to a monovalent hydrocarbon radical containing at least one carbon-carbon double bond, wherein each double bond may have an E- or Z-configuration form.
  • alkynyl refers to a monovalent hydrocarbon radical containing at least one carbon-carbon triple bond.
  • alkyl examples include methyl, ethyl, propyl including n-propyl and isopropyl, butyl including n-butyl, sec-butyl, isobutyl and tert-butyl, n-pentyl, 1-methylbutyl, isopentyl, Pentyl including neopentyl and tert-pentyl, hexyl including n-hexyl, 3,3-dimethylbutyl and isohexyl.
  • Each of the double bond and triple bond of the alkenyl group and the alkynyl group may be present at any position.
  • a substituted alkyl group, alkenyl group and alkynyl group may be substituted at any position as long as each compound is sufficiently stable and suitable for the desired purpose, such as use as a pharmaceutical substance.
  • alkoxy refers to a substituted or unsubstituted, straight-chain or branched hydrocarbon moiety linked with oxygen unless otherwise stated.
  • the alkoxy may include, without limitation, all possible isomers thereof such as, for example, methoxy, ethoxy, propoxy, and butoxy, or isopropoxy, isobutoxy, and t-butoxy.
  • cycloalkyl refers to a substituted or unsubstituted cyclic alkyl, unless otherwise stated, and may mean a single or multiple ring, for example, monohalogen or bi-cycloaliphatic.
  • cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, 2,5-cyclohexadienyl, bicyclo[2.2.2 ]Octyl, adamant-1-yl, decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 2-oxobicyclo[2.2.1]hept-1-yl, or their possible All isomers may be included without limitation.
  • aryl refers to an aromatic group that may be substituted or unsubstituted, unless otherwise stated, including, for example, C 3 -C 30 aryl, C 3 -C 20 aryl, or C 3 -C 10 aryl And the double bonds alternate (resonate) between adjacent carbon atoms or suitable heteroatoms.
  • phenyl, biphenyl, naphthyl, toluyl, naphthalenyl, anthracenyl, or all possible isomers thereof may be included without limitation.
  • Examples of monocyclic heteroaryl include pyrazolyl, pyrrolyl, thiazolyl, oxazolyl, thiophenyl, furanyl, imidazolyl, isoxazolyl, triazolyl, thiazolyl, tetrazolyl, oxadiazolyl, Pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, and groups similar thereto, but are not limited thereto.
  • bicyclic heteroaryl examples include indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, quinoline Mono, isoquinolinyl, purinyl, puropyridinyl, oxochromene, dioxoisoindolin, pyrazolopyridinyl, pyrazolo[1,5-a]pyridinyl and similar groups, but are limited to these. It does not become.
  • Monoheterocycloalkyl may be one comprising C 3 -C 30 heterocycloalkyl, C 3 -C 20 heterocycloalkyl, or C 3 -C 10 heterocycloalkyl, examples of which include piperidinyl, piperazinyl, Morpholinyl, pyrrolidinyl, thiomorpholinyl, imidazolidinyl, tetrahydrofuryl, and similar groups, but are not limited thereto.
  • solvate may mean a compound of the present invention or a salt thereof containing a stoichiometric or non-stoichiometric amount of a solvent bound by a non-covalent intermolecular force.
  • Preferred solvents therefor may be volatile, non-toxic, and/or solvents suitable for administration to humans.
  • stereoisomer may mean a compound of the present invention or a salt thereof having the same chemical formula or molecular formula, but optically or sterically different, and specifically, diastereomers, enantiomers, geometric isomers, or shapes It can be an isomer.
  • derivative refers to a compound obtained by substituting part of the structure of the compound with another atom or group of atoms.
  • the compound according to the present invention may be used in the form of a pharmaceutically acceptable salt derived from an inorganic or organic acid, for example, the salt is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, Pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, It may be a salt derived from salicylic acid, methanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid.
  • the salt is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid,
  • Pharmaceutically acceptable salts of the compounds according to the present invention include dissolving the compound of formula (I) in a water-miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile, and adding an excessive amount of organic acid or an aqueous acid solution of an inorganic acid. It can be prepared by precipitation or crystallization after addition. Subsequently, the solvent or excess acid is evaporated from the mixture and dried to obtain an addition salt, or the precipitated salt can be prepared by suction filtration.
  • a water-miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile
  • One aspect provides a compound, solvate, stereoisomer, or a pharmaceutically acceptable salt thereof represented by the following formula (I):
  • R 1 is aryl or heteroaryl (except when R 1 is unsubstituted phenyl);
  • R 2 is hydrogen, a hydroxy group, a cyano group, a C 1 -C 6 alkyl group, a C 2 -C 6 alkene group, a C 2 -C 6 alkane group, a C 1 -C 3 alkoxy group, (monohalogen, dihalogen, Trihalogen)methyl group, monohalogen, dihalogen, trihalogen, C 3 -C 6 cycloalkyl group, or C 1 -C 6 dialkylamino group;
  • R 3 is hydrogen, a hydroxy group, or a C 1 -C 3 alkoxy group
  • n a and n b are each independently an integer of 1 to 6;
  • R 4, R 5 and R 6 are each independently hydrogen, halogen, N -C 1-6 alkyl, N - hydroxyl omicron], CC 1- 6 alkyl station omicron] (-NHCOC 1 -6) , hydroxycarbonyl (-COOH), C 1- 6 alkoxycarbonyl (-COOC 1 -6), C 1- 6 alkyl, hydroxy, C 1- 6 dialkyl amine or a heterocycle-substituted C 1- 6 alkyl substituent.
  • R 1 is phenyl having a substituent X; Or unsubstituted or heteroaryl having a substituent X; X is a hydroxy group, a cyano group, a nitro group, a (monohalogen, dihalogen, trihalogen) methyl group, monohalogen, dihalogen, trihalogen, C 1 -C 6 alkyl group, C 2 -C 6 alkene group, C It may be a 2 -C 6 alkyne group, a C 1 -C 3 alkoxy group, a C 3 -C 6 cycloalkyl group, or a C 1 -C 6 dialkylamino group.
  • R 1 is phenyl having 1 to 5 substituents X; Or unsubstituted or heteroaryl having a substituent X;
  • R 2 is hydrogen, monohalogen, dihalogen, trihalogen, (monohalogen, dihalogen, trihalogen) methyl group, C 1 -C 6 alkyl group or C 3 -C 6 cycloalkyl group;
  • R 3 is hydrogen or a C 1 -C 3 alkoxy group
  • X is monohalogen, dihalogen, trihalogen, (monohalogen, dihalogen, trihalogen) methyl group, C 1 -C 6 alkyl group, or C 3 -C 6 cycloalkyl group;
  • R 4 is And, wherein R 4, R 5 and R 6 are each independently hydrogen or C 1- 6 alkyl.
  • the heteroaryl may include at least one hetero atom selected from the group consisting of N, O and S.
  • the compound of Formula I may be selected from the group consisting of the following compounds:
  • Another aspect provides a pharmaceutical composition for preventing or treating cancer, comprising a quinazoline derivative, solvate, stereoisomer, or a pharmaceutically acceptable salt thereof according to an embodiment as an active ingredient.
  • the cancer may have one or more of EGFR mutation and HER2 mutation.
  • the EGFR mutation is an activated EGFR mutation, a mutation causing resistance to an EGFR inhibitor, or a combination thereof
  • the HER2 mutation is an activated HER2 mutation, a mutation causing resistance to a HER2 inhibitor, or a combination thereof. It can be.
  • the activating EGFR mutation and the activating HER2 mutation may be exon 20 insertion mutations, respectively.
  • the cancer is lung cancer, liver cancer, esophageal cancer, gastric cancer, colon cancer, small intestine cancer, pancreatic cancer, melanoma, breast cancer, oral cancer, brain tumor, thyroid cancer, parathyroid cancer, kidney cancer, cervical cancer, sarcoma, prostate cancer , Urethral cancer, bladder cancer, testicular cancer, blood cancer, lymphoma, skin cancer, psoriasis, and fibroadenoma.
  • the cancer may be non-small cell lung cancer.
  • the pharmaceutical composition may contain a conventional pharmaceutically acceptable carrier, excipient, or additive.
  • the pharmaceutical composition of the present invention can be formulated according to a conventional method, and various oral dosage forms such as tablets, pills, powders, capsules, syrups, emulsions, microemulsions, or parenteral administration such as intramuscular, intravenous or subcutaneous administration It can be prepared in a dosage form.
  • additives or carriers used include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, stearic acid. Magnesium, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifying agents, and diluents.
  • the additives or carriers include water, saline, aqueous glucose solution, aqueous sugar-like solution, alcohol, glycol, ether (eg, polyethylene glycol 400), oil, fatty acid, fatty acid ester. , Glycerides, surfactants, suspending agents, and emulsifying agents.
  • the compound of Formula I or a pharmaceutically acceptable salt thereof is selective for cancer cell growth and drug resistance, or cancer having such resistance, caused by mutation of the tyrosine kinase domain in EGFR and HER2, and Effectively suppress Accordingly, one aspect is an individual in need of treatment for a cancer caused by an EGFR mutation and/or a HER2 mutation comprising administering to the individual a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition comprising the same (e.g. For example, a patient) provides a method of treating the disease.
  • the dosage of the pharmaceutical composition is an amount effective for the treatment or prevention of an individual or patient, and can be administered orally or parenterally as desired, and when administered orally, 0.01 to 1000 per 1 kg of body weight per day based on the active ingredient. mg, more specifically, to be administered in an amount of 0.1 to 300 mg, for parenteral administration, to be administered in an amount of 0.01 to 100 mg per 1 kg of body weight per day, more specifically 0.1 to 50 mg, based on the active ingredient It can be administered in one to several divided doses.
  • the dosage to be administered to a specific individual or patient should be determined in the light of various related factors such as the patient's weight, age, sex, health status, diet, administration time, administration method, and disease severity, and can be appropriately adjusted or adjusted by an expert.
  • the dosage is not intended to limit the scope of the invention in any way.
  • a physician or veterinarian having ordinary skill in the related art can readily determine and prescribe an effective amount of the required pharmaceutical composition.
  • a physician or veterinarian may start at a level lower than that required to achieve the desired therapeutic effect, starting with the dose of the compound of the invention used in the pharmaceutical composition, and gradually increasing the dose until the desired effect is achieved. Can increase.
  • treating refers to inhibiting a disease, for example, inhibiting a disease, condition or disorder in an individual experiencing or exhibiting a pathology or symptom of a disease, condition or disorder, ie, Preventing the further occurrence of pathology and/or symptoms, or improving a disease, e.g., ameliorating a disease, condition or disorder in an individual experiencing or exhibiting a pathology or symptom of a disease, condition or disorder, i.e. It refers to reversing pathology and/or symptoms, such as reducing disease severity.
  • preventing means preventing a disease, for example, a disease in an individual who may have a tendency to a disease, condition or disorder but has not yet experienced or exhibited the pathology or signs of the disease, It refers to preventing a condition or disorder.
  • the term "individual” or “patient” refers to any animal including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates and humans. .
  • compositions according to one embodiment include within the scope of pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds according to one embodiment in a therapeutically effective amount, alone or in combination with a pharmaceutical carrier.
  • a compound according to one embodiment can be used alone, in combination with a compound according to another embodiment, or in combination with one or more other therapeutic agents, such as anticancer agents or other pharmaceutically active substances.
  • the compound of Formula I or a pharmaceutically acceptable salt thereof according to an embodiment may enhance the therapeutic effect of the anticancer agent by co-administering it with other anticancer agents.
  • Another aspect provides a compound library comprising one or more of the compounds according to the present invention, salts, isomers, hydrates and solvates thereof.
  • Another aspect is a method for preventing or treating cancer comprising administering to an individual the compound, solvate, stereoisomer, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the same according to an embodiment; And a pharmaceutical use of a compound, solvate, stereoisomer, or a pharmaceutically acceptable salt thereof according to an embodiment for the prevention or treatment of cancer; It provides a pharmaceutical use of a compound, solvate, stereoisomer, or a pharmaceutically acceptable salt thereof according to an embodiment for preparing a cancer therapeutic agent.
  • the compound of formula (I) according to the present invention can be prepared using a chemical transformation well known to those skilled in the art of organic/pharmaceutical chemistry according to the method typically shown in Scheme 1 below.
  • Scheme 1 the numbers listed at the bottom of each chemical formula are numbers for identifying the chemical formula.
  • the compound of Formula 6 and the compound of Formula 7 may be prepared using conventional knowledge in the art of organic chemistry.
  • R 1 , R 2 , R 3 , n a , n b and Z are as defined in Formula I.
  • the solvent used in the reaction may be any solvent that does not inhibit the reaction.
  • the solvent used in the reaction is a polar aprotic solvent such as dimethyl sulfoxide, N , N -dimethyl formamide, acetonitrile, and tetrahydrofuran; Polar protic solvents such as methanol, ethanol, 2-propanol, 2-isopropanol, and 2-butanol; Alternatively, a non-polar aprotic solvent such as toluene and 1,4-dioxane may be used. Specifically, it may be 2-isopropanol.
  • the reaction temperature may be 0°C to 150°C, specifically, 0°C or more, 20°C or more, 40°C or more, 60°C or more, or 80°C or more, and 100°C or less, 110°C or less, 120°C or less, 140 It may be less than or equal to °C or less than 150 °C.
  • the compound of Formula 3 was stirred in an ammonia-containing alcohol solution (eg, 7N ammonia-containing methanol solution) to deprotect the acetyl group to prepare the compound of Formula 2.
  • the reaction temperature may be 0°C to room temperature, specifically 0°C or more, 1°C or more, or 2°C or more, and may be 10°C or less, 15°C or less, or room temperature or less. At this time, the room temperature may be 25 °C.
  • the compound of Formula 1 may be prepared by reacting the compound of Formula 2 with the compound of Formula 9, and the compound of Formula 5 may be prepared by reacting the compound of Formula 2 with the compound of Formula 8.
  • the reaction may be carried out in a reaction solution to which a solvent is added, and the solvent may be any solvent that does not inhibit the reaction, for example, the solvent is dimethyl sulfoxide, N , N -dimethyl formamide, aceto Polar aprotic solvents such as nitrile and tetrahydrofuran; Polar protic solvents such as methanol, ethanol, 2-propanol, and 2-butanol; Alternatively, a non-polar aprotic solvent such as toluene and 1,4-dioxane may be used.
  • a base may be additionally added to the reaction solution, and the base may include an organic base such as triethylamine, diisopropylethylamine, and pyridine; And inorganic bases such as sodium carbonate, potassium carbonate, and sodium hydride; You can choose from.
  • the amount of the base added may be 3 equivalents based on 1 equivalent of the compound of Formula 2.
  • the reaction temperature may be 0°C to 150°C, specifically 0°C or more, 20°C or more, 40°C or more, or 60°C or more, and 70°C or less, 90°C or less, 110°C or less, 130°C or less, or 130°C It can be below.
  • the compound of Formula 5 was reacted with an organic acid such as trifluoroacetic acid or an inorganic acid such as concentrated hydrochloric acid in an organic solvent such as methylene chloride to deprotect t -butoxycarbonyl group to prepare a compound of Formula 4.
  • the reaction temperature may be 0° C. to room temperature, preferably room temperature.
  • reaction conditions such as a reaction solvent, a base, and the amount of use of a reactant, are not limited to those described in the present specification, and in any way It cannot be construed as limiting the scope of the rights.
  • Another aspect of the present invention provides a pharmaceutical composition for preventing or treating cancer comprising the compound according to the above aspect or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a pharmaceutical composition comprising a compound of Formula I, a solvate, a stereoisomer, and a pharmaceutically acceptable salt thereof synthesized by this method as an active ingredient, is a cancer cell caused by mutation of the tyrosine kinase domain in EGFR and HER2. Growth and resistance to drugs, or cancer having such resistance.
  • Example 1 1 -(4-((4-((3- Chloro -4-(pyridin-3- Oxy )Phenyl)amino)-7- Methoxyquinazoline Preparation of -6-yl)oxy)piperidin-1-yl)prop-2-en-1-one
  • step 3 was added to compound 5.80 g (13.3 mmol) obtained in the 0 °C in 40 mL 7 N ammonia methanol solution, place the temperature of the reaction mixture slowly to room temperature and stirred for 3 hours.
  • the resulting solid was washed with diethyl ether and then filtered under reduced pressure, and the obtained solid was dried under reduced pressure to obtain 3.40 g (yield: 65%) of the title compound.
  • Example 18 1 -(4-((4-((3- Chloro -4-( Thiazole -2- Oxy )Phenyl)amino)-7- Me Preparation of oxyquinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one
  • Step 2) 1-(4-((4-((3- Chloro -4-( Thiazole -2- Oxy )Phenyl)amino)-7- Methoxyquinazoline Preparation of -6-yl)oxy)piperidin-1-yl)prop-2-en-1-one
  • Example 19 1 -(4-((4-((3- Chloro -4-(4- Fluorophenoxy )Phenyl)amino) Quinazoline Preparation of -6-yl)oxy)piperidin-1-yl)prop-2-en-1-one
  • Step 2) 1-(4-((4-((3- Chloro -4-(4- Fluorophenoxy )Phenyl)amino) Quinazoline -6-
  • step 3) of Example 1 4- chloroquinazolin -6-yl acetate ( WO2008033748 ) was used instead of 4-chloro-7-methoxyquinazolin-6-yl acetate hydrochloride, and 3-chloro-4-( Except for using the compound prepared in step 1) instead of pyridin-3-yloxy) aniline, the steps 3), 4), and 5) of Example 1 were sequentially performed to obtain 26 mg of the title compound (final Step yield: 5%) was obtained.
  • Example 20 1 -(4-((4-((3- Chloro -4-(4- Cyclopropylphenoxy )Phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one
  • Example 2 Except for using 4-bromophenol instead of 3-hydroxypyridine in step 1) of Example 1, the same procedure as in Example 1 was performed to obtain 5.2 g (yield: 93%) of the title compound.
  • Step 2) of Example 1 except that the compound prepared in step 2) was used instead of 3-(2-chloro-4-nitrophenoxy) pyridine in step 2) of Example 1, Steps 3), 4) and 5) were sequentially performed to obtain 154 mg (final step yield: 43%) of the title compound.
  • Example 21 1 -(3-((4-((3- Chloro -4-(pyridin-3- Oxy )Phenyl)amino)-7- Methoxyquinazoline Preparation of -6-yl)oxy)azetidin-1-yl)prop-2-en-1-one
  • Example 1 Using tert-butyl 3-(tosyloxy)azetidine-1-carboxylate ( WO2013170072 ) instead of 1-acryloylpiperidin-4-yl 4-methylbenzenesulfonate in step 5) of Example 1 Except, by performing the same process as in Example 1 to give the title compound 780 mg (yield: 56%).
  • Example constitutional formula Name / Analysis data 22 1-(3-((7-methoxy-4-((3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)quinazolin-6-yl)oxy)azetidine -1-yl)prop-2-en-1-one
  • 1 H-NMR 300MHz, DMSO-d 6 ): ⁇ 9.49 (bs, 1H), 8.46 (s, 1H), 8.17 (m, 1H), 7.65 (m, 3H), 7.25 (m, 3H), 6.98 (m, 1H), 6.41 (m, 1H), 6.16 (m, 1H), 5.71 (m, 1H), 5.24 (m, 1H), 4.82 (m, 1H), 4.58 (m, 1H), 4.29 ( m, 1H), 3.95 (m, 1H), 3.95 (s, 3H), 2.43 (s, 3H), 2.21 (s, 3H).
  • Example 27 1 -(3-((4-((3- Cyclopropyl -4-(pyridin-3- Oxy )Phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-1-yl)prop-2-en-1-one
  • Example 28 1 -(3-((4-((3-( Difluoromethyl )-4-(pyridin-3- Oxy )Phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-1-yl)prop-2-en-1-one
  • Step 2) 1-(3-((4-((3-( Difluoromethyl )-4-(pyridin-3- Oxy )Phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-1-yl)prop-2-en-1-one
  • Example 29 1 -(3-((4-((3- Chloro -4-( Thiazole -2- Oxy )Phenyl)amino)-7- Methoxyquinazoline Preparation of -6-yl)oxy)azetidin-1-yl)prop-2-en-1-one
  • EGFR mutant cells As the EGFR mutant cells, a Ba/F3 cell line (CrownBio, China) expressing the EGFR D770_N771insSVD variant was prepared. As the HER2 mutant cells, an H1781 cell line (ATCC, American Type Culture Collection, USA) expressing the HER2 A775insYVMA variant was prepared.
  • RPMI Medium 1640 (1x) medium containing 10% FBS (Fetal Bovine Serum) and 1% penicillin/straptomycin (Gibco BRL) was used. .
  • the cell line stored in the liquid nitrogen tank was taken out, rapidly dissolved at 37°C, and centrifuged to remove the cryopreservation medium. After centrifugation, the recovered cell pellet was well mixed in the culture medium, placed in a culture flask, and passaged under conditions of 37° C. and 5% carbon dioxide to stabilize the cells in logarithmic growth. Thereafter, cells were taken from the flask and centrifuged to remove the culture medium, washed with DPBS (Dulbecco's Phosphate Buffered Saline), and then centrifuged again to remove DPBS, and then diluted to 1 ⁇ 10 5 cells/mL with a culture medium. I did.
  • DPBS Dynabecco's Phosphate Buffered Saline
  • the diluted cells were dispensed into a 96-well plate at 100 ⁇ L per well.
  • the drug (the compound obtained in the example) was treated at the same time, and the H1781 cell line was treated with the drug after 24 hours.
  • the compounds prepared in the above examples were each dissolved in 99.5% dimethyl sulfoxide (hereinafter, DMSO, cell culture grade) to 10 mM to obtain a DMSO solution containing the compound.
  • DMSO dimethyl sulfoxide
  • the DMSO solution containing the compound was diluted to a concentration of 3 ⁇ M in the culture medium, and then diluted in steps of 5 times to prepare a test solution diluted to 0.32 nM (at this time, the concentration of the final DMSO was 1% or less).
  • test solution 50 ⁇ L of the test solution of each compound prepared was added to the 96-well plate in which the cells were dispensed, so that the final concentration of 10 ⁇ L to 0.1 nM was added to 150 ⁇ L per well.
  • the cells treated with the test solution were cultured under conditions of 37° C. and 5% carbon dioxide, but the Ba/F3 cell line was cultured for 72 hours, and the H1781 cell line was cultured for 96 hours.
  • the Ba / F3 cell line was adapted to a 96-well plate was incubated the cells for 30 minutes at room temperature was dispensed the CellTiter-Glo ® Luminescent Cell Assay Reagent (CTG, Promega) per well per 50 ⁇ L. After stabilizing the luminescence signal for 10 minutes, the luminescence intensity was measured with a microplate reader. After culturing the H1781 cell line, the medium was removed, and the cells were fixed with 10% TCA (Trichloroacetic acid, Sigma Cat. Dried. Thereafter, 100 ⁇ L of a 0.4% SRB (sulforhodamine B, sigma Cat. S1402) solution was added to the plate and stained at room temperature for 30 minutes.
  • TCA Terichloroacetic acid
  • the plate was washed with tap water, washed in 1% acetic acid solution, and then exposed to air to dry. Then, 150 ⁇ L of 10 mM trizma base solution was added to dissolve the solid SRB. Absorbance was measured at 540 nM using a microplate reader.
  • the GI 50 value is the concentration at which each compound inhibits cell growth by 50%. (Cell Growth Inhibition) was calculated. The GI 50 value of each compound was determined by the nonlinear regression of GraphPad Prism software; log[inhibitor] vs. It was calculated using normalized response analysis, and the results are shown in Table 3 below.
  • Example Cell growth inhibition (GI 50 , nM) EGRP mutant cells HER2 mutant cells
  • Ba/F3 cell line (EGFR D770_N771insSVD) H1781 cell line (HER2 A775insYVMA)
  • EGFR D770_N771insSVD H1781 cell line
  • HER2 A775insYVMA One 17 10 2 57 11 3 21 33 4 66 81 5 52 20 7 24 14 8 40 35 10 82 36 11 35 25 12 144 101 13 11 47 15 32 59 16 57 72 18 47 32 19 136 164 20 80 117 21 21 20 22 42 25 23 44 24 24 51 27 25 65 25 26 53 52 28 153 42

Abstract

The present invention relates to a novel quinazoline derivative having anti-tumor activity, a solvate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising same as an active ingredient. The novel quinazoline derivative of the present invention can exhibit selective and effective activity for cancer having an EGFR mutant and/or a HER2 mutant.

Description

항 종양 활성을 갖는 신규 퀴나졸린 유도체 및 이를 포함하는 약학 조성물Novel quinazoline derivative having anti-tumor activity and pharmaceutical composition comprising the same
본 출원은 2019년 6월 26일자 한국 특허 출원 제10-2019-0076490호 및 2020년 6월 25일자 한국 특허 출원 제10-2020-0077953호에 기초한 우선권의 이익을 주장하며, 해당 한국 특허 출원의 문헌에 개시된 모든 내용은 본 명세서의 일부로서 포함한다.This application claims the benefit of priority based on Korean Patent Application No. 10-2019-0076490 filed June 26, 2019 and Korean Patent Application No. 10-2020-0077953 filed June 25, 2020. All contents disclosed in the literature are included as part of this specification.
본 발명은 EGFR 돌연변이 및/또는 HER2 돌연변이를 가지는 암에 대해 항 종양 활성을 갖는 신규 퀴나졸린 유도체 및 이를 활성성분으로 포함하는 약학 조성물에 관한 것이다.The present invention relates to a novel quinazoline derivative having anti-tumor activity against cancer having an EGFR mutation and/or a HER2 mutation, and a pharmaceutical composition comprising the same as an active ingredient.
상피세포 성장인자 수용체(epidermal growth factor receptor, EGFR)란 수용체 부분과 티로신 키나아제 부분으로 이루어진 단백질로서, 세포막을 통과하여 세포 외부의 신호를 세포 내부로 전달하는 역할을 한다. EGFR은 ErbB1 또는 HER1(human epidermal growth factor receptor 1)으로 불리며, 180kDa의 막 횡단 단백질로서 N-말단부인 세포 외 ligand 결합 영역, 막 횡단 영역, 세포 내 단백질 활성 효소 영역, C-말단부에 위치한 SH2 결합 영역 등으로 이루어져 있다. 또한, EGFR은 ErbB2 (HER2), ERbB3 (HER3) 및 ErbB4 (HER4)와 함께 ErbB family를 구성한다. 상기 EGFR의 리간드로는 표피생장인자(epidermal growth factor, EGF), 전환성장인자-α(transforming growth factor-α, TGF-α), β-셀룰린(β-cellulin), 에피레귤린(epiregulin), 엠피레귤린(amphiregulin), 헤파린-결합 EGF-유사 성장인자(heparin binding EGF-like growth factor, B-EGF) 및 에피겐(epigen)의 7개 단백질이 알려져 있다. 상기 리간드 결합에 의해 EGFR의 티로신 잔기가 인산화되면 하류 분자들의 다양한 하류 신호 경로가 활성화된다. 악성종양에서 EGFR의 중요한 하류 신호 경로는 미토겐-활성화 단백질 키나아제(Ras-mitogen-activated protein kinase, MAPK), 포스포이노시티드 3-키나아제(phosphoinositide 3-kinase, PI3-K), 포스포리파제-Cγ(phospholipase-Cγ, PLCγ)/단백질 키나아제-C(protein kinase-C, PKC) 및 신호전달 및 전사활성화 인자(signal transducer and activator of transcription, STAT)의 4가지가 대표적이다.Epidermal growth factor receptor (EGFR) is a protein consisting of a receptor portion and a tyrosine kinase portion, and plays a role of transmitting signals from outside the cell to the inside of the cell by passing through the cell membrane. EGFR is called ErbB1 or HER1 (human epidermal growth factor receptor 1), and is a 180kDa transmembrane protein. The N-terminal extracellular ligand-binding region, the transmembrane region, the intracellular protein-activating enzyme region, and the C-terminal SH2 binding It consists of areas, etc. In addition, EGFR together with ErbB2 (HER2), ERbB3 (HER3) and ErbB4 (HER4) constitute the ErbB family. The ligands of EGFR include epidermal growth factor (EGF), transforming growth factor-α (TGF-α), β-cellulin, and epiregulin , Amphiregulin, heparin-binding EGF-like growth factor (B-EGF) and epigen. 7 proteins are known. When the tyrosine residue of EGFR is phosphorylated by the ligand binding, various downstream signaling pathways of the downstream molecules are activated. The important downstream signaling pathways of EGFR in malignancies are mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3-K), and phospholipase- Cγ (phospholipase-Cγ, PLCγ)/protein kinase-C (protein kinase-C, PKC) and signal transducer and activator of transcription (STAT) are four representative.
EGFR은 세포 내의 신호 전달을 통해 정상적인 세포 조절에 필수적인 역할을 한다. 그러나, EGFR의 과발현, 또는 암세포 활성화에 관여하는 EGFR 돌연변이 발현 등의 문제가 발생할 경우가 있으며, 상기 암세포 활성화에 관여하는 EGFR 돌연변이는 리간드-비의존적으로 티로신 키나아제를 활성화하는 특징이 있다. 따라서, EGFR의 과발현, 또는 암세포 활성화에 관여하는 EGFR 돌연변이가 발현될 경우우 신호 전달을 통한 정상적인 세포 조절을 할 수 없게 되므로, 암세포의 성장, 분화, 신생혈관 형성, 전이 및 내성발현 등을 유발하는 것으로 알려져 있다. EGFR plays an essential role in normal cell regulation through intracellular signaling. However, there may be problems such as overexpression of EGFR or expression of EGFR mutations involved in cancer cell activation, and the EGFR mutations involved in cancer cell activation are characterized by activating tyrosine kinase in a ligand-independent manner. Therefore, when EGFR overexpression or EGFR mutation involved in cancer cell activation is expressed, normal cell regulation through signal transduction becomes impossible, and thus cancer cell growth, differentiation, neovascularization, metastasis and resistance expression are induced. It is known.
대부분의 고형암 세포에서 EGFR이 비정상적으로 과발현되어 있거나 돌연변이가 빈번하며, 이 경우 예후가 좋지 않은 것으로 보고되고 있다. 대표적인 돌연변이 중 EGFR 및/또는 HER2의 활성화 돌연변이는 이들 수용체에 포함된 티로신 키나아제 도메인에 엑손 20 삽입된 것으로 비소세포성폐암 및 다양한 암의 주요한 발병 원인으로 알려져 있다. In most solid cancer cells, EGFR is abnormally overexpressed or mutations are frequent, and in this case, the prognosis is reported to be poor. Among the representative mutations, the activating mutation of EGFR and/or HER2 is an exon 20 insertion into the tyrosine kinase domain included in these receptors, and is known as a major cause of non-small cell lung cancer and various cancers.
엑손 20 삽입은 비소세포성폐암에서 발견되는 세 번째로 흔한 EGFR 돌연변이 군이다. EGFR의 티로신 키나아제 저해제에 대한 반응이 없으면서 이러한 돌연변이를 가지고 있는 암에 대해서는 거의 알려지지 않았기 때문에 효과적인 표적 치료가 어려운 상황이다. 따라서, EGFR 돌연변이 군인 엑손 20 삽입에 대한 항암 효과가 우수한 표적 치료 항암제를 개발하기 위한 연구가 활발하게 진행 중에 있다.Exon 20 insertion is the third most common group of EGFR mutations found in non-small cell lung cancer. Since there is no response to the tyrosine kinase inhibitor of EGFR and little is known about cancers carrying these mutations, effective targeted therapy is difficult. Therefore, studies to develop targeted therapeutic anticancer agents having excellent anticancer effects against exon 20 insertion of EGFR mutant soldiers are actively underway.
약 10~15%의 비소세포성폐암에는 EGFR 활성화 돌연변이가 존재한다. 통상적인 감작 돌연변이 (엑손 19와 L858R 포함) 종양을 가지고 있는 대다수의 환자에게 게피티닙 (gefitinib)과 얼로티닙 (eroltinib) 같은 티로신 키나아제 저해제는 우수한 임상적 효과를 나타내는 것으로 알려져 있다. 이와 같은 티로신 키나아제 저해제로 치료받은 환자의 약 70%는 화학 요법을 단독으로 치료받은 환자에 비해 객관적 반응(OR, Objective Response), 진행성 생존율 개선(PFS, Progression Free Survival) 및 삶의 질이 향상되었다. 그러나 EGFR 돌연변이 비소세포성폐암 종양의 약 10~12%는 EGFR 6, 15, 16, 17의 엑손 20 내에서 인 프레임 삽입을 가지며, 일반적으로 EGFR의 티로신 키나아제 저해제에 내성을 가지고 있다. EGFR 엑손 20 삽입 돌연변이 환자들은 얼로티닙(erlitinib), 게피티닙(gefitinib), 또는 아파티닙(afatinib)의 1차 요법에 대한 전반적인 반응률이 약 3~8%의 낮은 수준을 나타내는 것으로 알려져 있다. 또한 비소세포성폐암에서 HER2 돌연변이의 90%는 엑손 20 삽입 돌연변이이며, 비소세포성폐암 환자의 약 3% 정도가 HER2 돌연변이를 가지고 있다.About 10-15% of non-small cell lung cancers have EGFR-activating mutations. Tyrosine kinase inhibitors such as gefitinib and eroltinib are known to have excellent clinical effects in the majority of patients with conventional sensitizing mutations (including exon 19 and L858R) tumors. About 70% of patients treated with such tyrosine kinase inhibitors improved objective response (OR), progression free survival (PFS), and quality of life compared to patients treated with chemotherapy alone. . However, about 10 to 12% of EGFR mutant non-small cell lung cancer tumors have in-frame insertion within exon 20 of EGFR 6, 15, 16, and 17, and are generally resistant to tyrosine kinase inhibitors of EGFR. Patients with EGFR exon 20 insertion mutations are known to have low overall response rates of about 3-8% to first-line therapy with erlitinib, gefitinib, or afatinib. . In addition, 90% of HER2 mutations in non-small cell lung cancer are exon 20 insertion mutations, and about 3% of non-small cell lung cancer patients have HER2 mutations.
비소세포성폐암 내에서, 모든 EGFR 돌연변이는 티로신 키나아제 도메인을 코딩하는 엑손 18~22에 겹쳐 집합한다. 특히, EGFR 돌연변이 중 엑손 20 삽입 돌연변이는 분자 수준에서 이질적이지만 EGFR 단백질의 아미노산 위치 762와 774 사이에 클러스터된 3과 21bp (1에서 7개의 아미노산에 해당) 사이의 인프레임 삽입 또는 복제로 특징지어질 수 있다 (Yasuda et al., 2013). 상기 돌연변이는 C-나선의 C-말단 내에서 발생하거나 또는 바로 뒤 따르는 루프에서 더 자주 발생한다. 엑손 20 삽입은 엑손 19 결실 및 L858R 돌연변이와 함께 비소세포성폐암에서 확인된 가장 초기의 EGFR 돌연변이 중 하나이다. EGFR 엑손 20 삽입의 빈도는 비소세포성폐암에서 관찰된 모든 EGFR 돌연변이의 4~10%로 보고 되었다 (Arcila et al., 2012). In non-small cell lung cancer, all EGFR mutations overlap and aggregate over exons 18-22 encoding the tyrosine kinase domain. In particular, the exon 20 insertion mutation among the EGFR mutations is heterogeneous at the molecular level, but will be characterized by in-frame insertion or replication between 3 and 21 bp (corresponding to 1 to 7 amino acids) clustered between amino acid positions 762 and 774 of the EGFR protein Can (Yasuda et al ., 2013). This mutation occurs within the C-terminus of the C-helix or more often in the loop immediately following it. Exon 20 insertion is one of the earliest EGFR mutations identified in non-small cell lung cancer with exon 19 deletion and L858R mutation. The frequency of EGFR exon 20 insertion was reported as 4-10% of all EGFR mutations observed in non-small cell lung cancer (Arcila et al ., 2012).
또한, EGFR 엑손 20 삽입 돌연변이는 통상적인 활성화 EGFR 돌연변이와 유사한 경향을 보인다. EGFR 엑손 20 삽입 돌연변이는 여성, 비흡연자, 아시아 인구 및 선암 조직학을 가진 사람들에서 많이 발견된다 (Oxnard et al., 2013). 엑손 20 삽입 돌연변이와 관련된 EGFR 활성화 및 약물 내성의 메커니즘과 관련하여, 엑손 20 삽입 EGFR 돌연변이인 D770_N771insNPG의 결정 구조가 밝혀졌으며, 이는 ATP 친화성을 현저하게 감소시키지 않고 1세대 저해제인 게피티닙 (gefitinib)에 대한 친화성을 향상시키지 않으면서 EGFR을 활성화시킬 수 있다고 보고된 바 있다 (Yasuda et al., 2013). 또한, A763_Y764insFQEA 돌연변이는 통상적인 비소세포성폐암 EGFR 돌연변이와 유사하게 작용한다 (Yun, C. -H. et al., 2008). EGFR 엑손 20 삽입 돌연변이 중 V769insASV (~20%), D770insSVD (~20%), H773insNPH (~10%)는 기존 EGFR 티로신 키나아제 저해제에 낮은 반응성을 보이는 대표적인 돌연변이이다.In addition, the EGFR exon 20 insertion mutation shows a similar tendency to the conventional activating EGFR mutation. EGFR exon 20 insertion mutations are found prevalent in women, nonsmokers, Asian populations, and people with adenocarcinoma histology (Oxnard et al. , 2013). Regarding the mechanism of EGFR activation and drug resistance associated with the exon 20 insertion mutation, the crystal structure of the exon 20 insertion EGFR mutation, D770_N771insNPG, was revealed, which did not significantly decrease ATP affinity, and the first-generation inhibitor gefitinib ), it has been reported that it can activate EGFR without improving its affinity for (Yasuda et al ., 2013). In addition, the A763_Y764insFQEA mutation acts similarly to a conventional non-small cell lung cancer EGFR mutation (Yun, C. -H. et al. , 2008). Among the EGFR exon 20 insertion mutations, V769insASV (~20%), D770insSVD (~20%), and H773insNPH (~10%) are representative mutations showing low reactivity to existing EGFR tyrosine kinase inhibitors.
HER2 돌연변이는 EGFR 돌연변이에 비해 훨씬 낮은 빈도 (비소세포성폐암 환자의 ~2%)로 존재하지만, 엑손 20 삽입 돌연변이는 비소세포성폐암에서 가장 두드러진 유형의 HER2 돌연변이로서, 비소세포성폐암 환자의 90% 이상에서 나타난다. 대표적인 엑손 20 삽입 돌연변이는 A775_G776insYVMA로서, HER2 돌연변이의 85% 정도의 비중을 차지한다 (Arcila et al., 2012).Although the HER2 mutation is present at a much lower frequency (~2% of patients with non-small cell lung cancer) than the EGFR mutation, the exon 20 insertion mutation is the most prominent type of HER2 mutation in non-small cell lung cancer. Appears above %. A representative exon 20 insertion mutation is A775_G776insYVMA, which accounts for about 85% of the HER2 mutations (Arcila et al. , 2012).
따라서, EGFR 돌연변이와 HER2 돌연변이를 가지는 암에 대하여 항 종양 활성을 가지는 물질의 개발에 대한 요구가 점점 커지고 있다.Therefore, there is a growing demand for the development of substances having antitumor activity against cancers having EGFR mutation and HER2 mutation.
[선행기술문헌][Prior technical literature]
(비특허문헌 1) Clin Cancer Res. 19(8), 2240, 2013(Non-Patent Document 1) Clin Cancer Res. 19(8), 2240, 2013
(비특허문헌 2) Nat Med. 24 (5), 638, 2018(Non-Patent Document 2) Nat Med. 24 (5), 638, 2018
(비특허문헌 3) Signal Transduction and Targeted Therapy 4; 5, 2019(Non-Patent Document 3) Signal Transduction and Targeted Therapy 4; 5, 2019
본 발명의 일 양상은 상피세포 성장인자 수용체(EGFR 및 HER2) 중 티로신 키나아제 도메인의 돌연변이(mutation)에 의해 유발되는 암세포의 성장 및 약물에 대한 내성, 또는 그러한 내성을 갖는 암을 선택적이고 효과적으로 저해하면서도 부작용이 적은 신규 퀴나졸린 유도체를 제공하는 것이다.One aspect of the present invention is to selectively and effectively inhibit the growth of cancer cells and resistance to drugs caused by mutations in the tyrosine kinase domain of epithelial growth factor receptors (EGFR and HER2), or cancer having such resistance. To provide a novel quinazoline derivative with less side effects.
본 발명의 다른 양상은 상기 신규 퀴나졸린 유도체를 포함하며, 암세포 성장을 억제함으로써 항 종양 활성을 갖는 약학 조성물을 제공하는 것이다.Another aspect of the present invention is to provide a pharmaceutical composition comprising the novel quinazoline derivative and having antitumor activity by inhibiting the growth of cancer cells.
본 발명의 일 양상은, 하기의 화학식 I로 표시되는 퀴나졸린 유도체, 용매화물, 입체 이성질체 또는 이들의 약학적으로 허용 가능한 염을 제공한다.One aspect of the present invention provides a quinazoline derivative, solvate, stereoisomer, or a pharmaceutically acceptable salt thereof represented by the following formula (I).
[화학식 I][Formula I]
Figure PCTKR2020008312-appb-I000001
Figure PCTKR2020008312-appb-I000001
상기 화학식 I 중,In Formula I,
R1은 아릴 또는 헤테로아릴이고 (단, R1이 비치환 페닐인 경우는 제외함); R 1 is aryl or heteroaryl (except when R 1 is unsubstituted phenyl);
R2는 수소, 하이드록시기, 시아노기, C1-C6 알킬기, C2-C6 알켄기, C2-C6 알카인기, C1-C3 알콕시기, (모노할로겐, 다이할로겐, 트라이할로겐)메틸기, 모노할로겐, 다이할로겐, 트라이할로겐, C3-C6 사이클로알킬기, 또는 C1-C6 다이알킬아미노기이고; R 2 is hydrogen, a hydroxy group, a cyano group, a C 1 -C 6 alkyl group, a C 2 -C 6 alkene group, a C 2 -C 6 alkane group, a C 1 -C 3 alkoxy group, (monohalogen, dihalogen, Trihalogen)methyl group, monohalogen, dihalogen, trihalogen, C 3 -C 6 cycloalkyl group, or C 1 -C 6 dialkylamino group;
R3는 수소, 하이드록시기, 또는 C1-C3 알콕시기이고;R 3 is hydrogen, a hydroxy group, or a C 1 -C 3 alkoxy group;
na 및 nb는 각각 독립적으로 1 내지 6의 정수이며;n a and n b are each independently an integer of 1 to 6;
Z는
Figure PCTKR2020008312-appb-I000002
이고, 이때, R4, R5 및 R6은 각각 독립적으로 수소, 할로겐, N-C1-6알킬, N-하이드록실아마이도, C-C1- 6알킬 역아마이도(-NHCOC1 -6), 하이드록시카보닐(-COOH), C1- 6알킬옥시카보닐(-COOC1 -6), C1- 6알킬, 하이드록시, C1- 6다이알킬아민 또는 헤테로사이클로 치환된 C1-6알킬 치환기이다.Z is
Figure PCTKR2020008312-appb-I000002
And, wherein, R 4, R 5 and R 6 are each independently hydrogen, halogen, N -C 1-6 alkyl, N - hydroxyl omicron], CC 1- 6 alkyl station omicron] (-NHCOC 1 -6) , hydroxycarbonyl (-COOH), C 1- 6 alkoxycarbonyl (-COOC 1 -6), C 1- 6 alkyl, hydroxy, C 1- 6 dialkyl amine or a heterocycle-substituted C 1- 6 alkyl substituent.
본 발명의 다른 일 양상은 상기 화학식 I의 퀴나졸린 유도체, 이의 용매화물, 이의 입체 이성질체, 또는 이들의 약학적으로 허용 가능한 염, 및 약학적으로 허용 가능한 담체를 포함하는 EGFR 및/또는 HER2 돌연변이를 갖는 암의 예방 또는 치료용 약학적 조성물을 제공한다.Another aspect of the present invention is the EGFR and/or HER2 mutation comprising the quinazoline derivative of Formula I, a solvate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. It provides a pharmaceutical composition for preventing or treating cancer having.
본 발명의 일 양상에 따른 화학식 I의 퀴나졸린 유도체, 용매화물, 입체 이성질체 또는 이들의 약학적으로 허용 가능한 염은 상피세포 성장인자 수용체 중 티로신 키나아제 도메인의 돌연변이에 의해 유발되는 암세포의 성장 및 약물에 대한 내성, 또는 그러한 내성을 갖는 암을 선택적이고 효과적으로 억제할 수 있다.The quinazoline derivatives, solvates, stereoisomers, or pharmaceutically acceptable salts thereof of formula (I) according to an aspect of the present invention are used for growth of cancer cells and drugs caused by mutations in the tyrosine kinase domain in the epithelial growth factor receptor. Resistance to, or cancer having such resistance can be selectively and effectively inhibited.
이하, 본 발명을 더욱 상세히 설명한다.Hereinafter, the present invention will be described in more detail.
본 발명에서 사용되는 모든 기술용어는, 달리 정의되지 않는 이상, 본 발명의 관련 분야에서 통상의 당업자가 일반적으로 이해하는 바와 같은 의미로 사용된다. 또한, 본 명세서에는 바람직한 방법이나 시료가 기재되나, 이와 유사하거나 동등한 것들도 본 발명의 범주에 포함된다. 또한, 본 명세서에 기재된 수치는 명시하지 않아도 "약"의 의미를 포함하는 것으로 간주한다. 본 명세서에 참고문헌으로 기재되는 모든 간행물의 내용은 전체가 본 명세서에 참고로 통합된다.All technical terms used in the present invention, unless otherwise defined, are used in the same sense as those of ordinary skill in the art generally understand in the related field of the present invention. In addition, although preferred methods or samples are described in the present specification, those similar or equivalent are included in the scope of the present invention. In addition, the numerical values described herein are considered to include the meaning of "about" even if not specified. The contents of all publications mentioned herein by reference are incorporated herein by reference in their entirety.
본 명세서에서 사용된 용어 “EGFR(Epidermal Growth Factor Receptor)”은 암세포의 성장, 분화 및 생존에 대한 신호전달 경로의 활성화에 중요한 역할을 하는 수용체를 의미하며, 구체적으로 수용체 부분과 티로신 키나아제 부분으로 이루어진 단백질을 의미한다.The term “EGFR (Epidermal Growth Factor Receptor)” as used herein refers to a receptor that plays an important role in the activation of signaling pathways for growth, differentiation and survival of cancer cells, and specifically, consisting of a receptor portion and a tyrosine kinase portion. Means protein.
본 명세서에서 사용된 용어 “HER2(human epidermal growth factor receptor type2)”는 신호전달을 통해 세포 성장 및 증식에 관여하는 단백질을 의미한다.The term "HER2 (human epidermal growth factor receptor type2)" as used herein refers to a protein involved in cell growth and proliferation through signal transduction.
본 명세서 “엑손(exon) 20”은 유전자의 염기 배열 중 단백질 합성 정보를 가진 유전자인 엑손 유전자 중 20번째 엑손 유전자를 의미한다. In the present specification, “exon 20” refers to the 20th exon gene among exon genes, which is a gene having protein synthesis information in the nucleotide sequence of the gene.
본 명세서에서 용어 "할로겐"은 다른 언급이 없으면, 불소, 염소, 브롬 또는 요오드를 포함하며, 예를 들어 불소 또는 염소일 수 있으나 이들로 제한되는 것은 아니다.In the present specification, the term "halogen" includes fluorine, chlorine, bromine or iodine, unless otherwise stated, and may be, for example, fluorine or chlorine, but is not limited thereto.
본 명세서에서 용어 "알킬"은 포화된 1가의 탄화수소 라디칼을 지칭한다. 본 발명에 사용된 용어 "알켄일"은 적어도 하나의 탄소-탄소 이중결합을 함유하는 1가의 탄화수소 라디칼을 지칭하는데, 이때, 각각의 이중결합은 E- 또는 Z-입체배치형태를 가질 수 있다. 본 발명에 사용된 용어 "알카인일"은 적어도 하나의 탄소-탄소 삼중결합을 함유하는 1가의 탄화수소 라디칼을 지칭한다. 이러한 알킬, 알켄일 및 알카인일 기들은 직선형, 즉, 직쇄형이거나 측쇄형일 수 있다. 각각의 정의에 따라, 알킬 기 내에서 탄소 원자의 수는 1개, 2개, 3개, 4개, 5개 또는 6개, 또는 1개, 2개, 3개, 또는 4개일 수 있다. 알킬의 예는 메틸, 에틸, n-프로필과 아이소프로필을 포함하는 프로필, n-부틸, sec-부틸, 아이소부틸 및 tert-부틸을 포함하는 부틸, n-펜틸, 1-메틸부틸, 아이소펜틸, 네오펜틸 및 tert-펜틸을 포함하는 펜틸, n-헥실, 3,3-다이메틸부틸 및 아이소헥실을 포함하는 헥실이다. 알켄일 기와 알카인일 기의 이중결합 및 삼중결합 각각은 임의의 위치에 존재할 수 있다. 알켄일 및 알카인일의 예는 에텐일, 프로프-1-에닐, 프로프-2-에닐 (=알릴), 부트-2-에닐, 2-메틸프로프-2-에닐, 3-메틸부트-2-에닐, 헥스-3-에닐, 헥스-4-에닐, 프로프-2-이닐(= 프로파길), 부트-2-이닐, 부트-3-이닐, 헥스-4-이닐 또는 헥스-5-이닐이다. 각각의 화합물이 충분히 안정적이고, 의약 물질로서의 용도와 같이 원하는 목적에 적합하기만 하다면, 치환된 알킬기, 알켄일기 및 알카인일 기는 임의의 위치에서 치환될 수 있다.The term "alkyl" as used herein refers to a saturated monovalent hydrocarbon radical. The term "alkenyl" as used herein refers to a monovalent hydrocarbon radical containing at least one carbon-carbon double bond, wherein each double bond may have an E- or Z-configuration form. The term "alkynyl" as used herein refers to a monovalent hydrocarbon radical containing at least one carbon-carbon triple bond. These alkyl, alkenyl and alkynyl groups may be straight, ie straight or branched. According to each definition, the number of carbon atoms in the alkyl group may be 1, 2, 3, 4, 5 or 6, or 1, 2, 3, or 4. Examples of alkyl include methyl, ethyl, propyl including n-propyl and isopropyl, butyl including n-butyl, sec-butyl, isobutyl and tert-butyl, n-pentyl, 1-methylbutyl, isopentyl, Pentyl including neopentyl and tert-pentyl, hexyl including n-hexyl, 3,3-dimethylbutyl and isohexyl. Each of the double bond and triple bond of the alkenyl group and the alkynyl group may be present at any position. Examples of alkenyl and alkynyl are ethenyl, prop-1-enyl, prop-2-enyl (=allyl), but-2-enyl, 2-methylprop-2-enyl, 3-methylbut -2-enyl, hex-3-enyl, hex-4-enyl, prop-2-ynyl (= propargyl), but-2-ynyl, but-3-ynyl, hex-4-ynyl or hex-5 -It's Inil. A substituted alkyl group, alkenyl group and alkynyl group may be substituted at any position as long as each compound is sufficiently stable and suitable for the desired purpose, such as use as a pharmaceutical substance.
본 명세서에서 용어 "알콕시"는 다른 언급이 없으면, 치환 또는 비치환될 수 있는, 직쇄형, 또는 분지형 탄화수소 잔기가 산소로 연결된 것을 나타낸다. 상기 알콕시는 예를 들면, 메톡시, 에톡시, 프로폭시, 및 부톡시, 또는 아이소프로폭시, 아이소부톡시, 및 t-부톡시와 같이 이들의 가능한 모든 이성질체들을 제한없이 포함할 수 있다.In the present specification, the term “alkoxy” refers to a substituted or unsubstituted, straight-chain or branched hydrocarbon moiety linked with oxygen unless otherwise stated. The alkoxy may include, without limitation, all possible isomers thereof such as, for example, methoxy, ethoxy, propoxy, and butoxy, or isopropoxy, isobutoxy, and t-butoxy.
본 명세서에서 용어 “사이클로알킬”은 다른 언급이 없으면, 치환 또는 비치환될 수 있는 환상 알킬을 의미하며, 단일 또는 다중 고리 예를 들면 모노할로겐 또는 바이-사이클로지방족을 의미할 수 있다. 예를 들어, 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로헥실, 사이클로헥세닐, 사이클로헵틸, 사이클로헵텐일, 사이클로옥틸, 사이클로옥텐일, 2,5-사이클로헥사다이에닐, 바이사이클로[2.2.2]옥틸, 아다만트-1-일, 데카하이드로나프틸, 옥소사이클로헥실, 다이옥소사이클로헥실, 싸이오사이클로헥실, 2-옥소바이사이클로[2.2.1]헵트-1-일, 또는 이들의 가능한 모든 이성질체들을 제한 없이 포함할 수 있다.In the present specification, the term “cycloalkyl” refers to a substituted or unsubstituted cyclic alkyl, unless otherwise stated, and may mean a single or multiple ring, for example, monohalogen or bi-cycloaliphatic. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, 2,5-cyclohexadienyl, bicyclo[2.2.2 ]Octyl, adamant-1-yl, decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 2-oxobicyclo[2.2.1]hept-1-yl, or their possible All isomers may be included without limitation.
본 명세서에서 용어 "아릴"은 다른 언급이 없으면, 치환 또는 비치환될 수 있는 방향족 그룹을 나타내며, 예컨대 C3-C30 아릴, C3-C20 아릴, 또는 C3-C10 아릴을 포함하는 것일 수 있으며, 인접하는 탄소 원자 또는 적합한 이형 원자들 사이에서 이중 결합이 교대(공명)한다. 예를 들어, 페닐, 바이페닐, 나프틸, 톨루일, 나프탈레닐, 안트라세닐, 또는 이들의 가능한 모든 이성질체들을 제한없이 포함할 수 있다.In the present specification, the term "aryl" refers to an aromatic group that may be substituted or unsubstituted, unless otherwise stated, including, for example, C 3 -C 30 aryl, C 3 -C 20 aryl, or C 3 -C 10 aryl And the double bonds alternate (resonate) between adjacent carbon atoms or suitable heteroatoms. For example, phenyl, biphenyl, naphthyl, toluyl, naphthalenyl, anthracenyl, or all possible isomers thereof may be included without limitation.
본 명세서에서 용어 "헤테로아릴"은 다른 언급이 없으면 B, N, O, S, P(=O), Si 및 P로부터 선택된 하나 이상의 헤테로 원자를 포함하는 모노사이클릭 또는 바이사이클릭 이상의, 치환 또는 비치환될 수 있는, 방향족 그룹을 의미한다. 모노사이클릭 헤테로아릴의 예로는 피라졸릴, 피롤릴, 싸이아졸릴, 옥사졸릴, 싸이오펜일, 퓨란일, 이미다졸릴, 아이소옥사졸릴, 트리아졸릴, 싸이다이아졸릴, 테트라졸릴, 옥사다이아졸릴, 피리딘일, 피리다진일, 피리미딘일, 피라진일, 싸이아졸릴 및 이와 유사한 그룹을 들 수 있으나 이들로 제한되는 것은 아니다. 바이사이클릭 헤테로아릴의 예로는 인돌일, 벤조싸이오펜일, 벤조퓨란일, 벤즈이미다졸릴, 벤즈옥사졸릴, 벤즈아이속사졸릴, 벤즈싸이아졸릴, 벤즈싸이아다이아졸릴, 벤즈트리아졸릴, 퀴놀린일, 아이소퀴놀린일, 퓨린일, 퓨로피리딘일, 옥소크로멘, 다이옥소아이소인돌린, 피라졸로피리디닐, 피라졸로[1,5-a]피리디닐 및 이와 유사한 그룹을 들 수 있으나 이들로 제한되는 것은 아니다.In the present specification, the term "heteroaryl" refers to monocyclic or bicyclic or more, substituted or unless otherwise stated, including one or more heteroatoms selected from B, N, O, S, P(=O), Si and P It means an aromatic group, which can be unsubstituted. Examples of monocyclic heteroaryl include pyrazolyl, pyrrolyl, thiazolyl, oxazolyl, thiophenyl, furanyl, imidazolyl, isoxazolyl, triazolyl, thiazolyl, tetrazolyl, oxadiazolyl, Pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, and groups similar thereto, but are not limited thereto. Examples of bicyclic heteroaryl include indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, quinoline Mono, isoquinolinyl, purinyl, puropyridinyl, oxochromene, dioxoisoindolin, pyrazolopyridinyl, pyrazolo[1,5-a]pyridinyl and similar groups, but are limited to these. It does not become.
본 명세서에서 용어 "헤테로사이클로알킬"은 다른 언급이 없으면, B, N, O, S, P(=O), Si 및 P로부터 선택된 하나 이상의 헤테로 원자를 포함하는 모노사이클릭의 치환 또는 비치환될 수 있는, 환상 알킬을 나타낸다. 모노헤테로사이클로알킬은 C3-C30 헤테로사이클로알킬, C3-C20 헤테로사이클로알킬, 또는 C3-C10 헤테로사이클로알킬을 포함하는 것일 수 있으며, 그 예로는 피페리딘일, 피페라진일, 모르폴리닐, 피롤리딘일, 싸이오모르폴린일, 이미다졸리딘일, 테트라하이드로퓨릴, 및 이와 유사한 그룹을 들 수 있으나 이들로 제한되는 것은 아니다.In the present specification, the term "heterocycloalkyl" is, unless otherwise stated, B, N, O, S, P(=O), Si and P to be substituted or unsubstituted of a monocyclic containing one or more heteroatoms. Represents cyclic alkyl, which can be. Monoheterocycloalkyl may be one comprising C 3 -C 30 heterocycloalkyl, C 3 -C 20 heterocycloalkyl, or C 3 -C 10 heterocycloalkyl, examples of which include piperidinyl, piperazinyl, Morpholinyl, pyrrolidinyl, thiomorpholinyl, imidazolidinyl, tetrahydrofuryl, and similar groups, but are not limited thereto.
본 명세서에서 용어 "내지"를 이용하여 표시된 수치 범위는 용어 "내지" 전과 후에 기재되는 수치를 각각 하한 및 상한으로서 포함하는 범위를 말한다. In this specification, the numerical range indicated by using the term "to" refers to a range including the numerical values described before and after the term "to" as lower and upper limits, respectively.
본 명세서에서 용어 "용매화물(solvate)"은 비공유적 분자간력에 의해 결합된 화학양론적 또는 비화학양론적량의 용매를 포함하고 있는 본 발명의 화합물 또는 그것의 염을 의미할 수 있다. 그에 관한 바람직한 용매들로는 휘발성, 비독성, 및/또는 인간에게 투여되기에 적합한 용매들일 수 있다.In the present specification, the term "solvate" may mean a compound of the present invention or a salt thereof containing a stoichiometric or non-stoichiometric amount of a solvent bound by a non-covalent intermolecular force. Preferred solvents therefor may be volatile, non-toxic, and/or solvents suitable for administration to humans.
본 명세서에서 용어 "입체 이성질체"는 동일한 화학식 또는 분자식을 가지지만 광학적 또는 입체적으로 다른 본 발명의 화합물 또는 그것의 염을 의미할 수 있고, 구체적으로, 부분입체이성질체, 거울상이성질체, 기하이성질체, 또는 형상이성질체일 수 있다.In the present specification, the term "stereoisomer" may mean a compound of the present invention or a salt thereof having the same chemical formula or molecular formula, but optically or sterically different, and specifically, diastereomers, enantiomers, geometric isomers, or shapes It can be an isomer.
본 명세서에서 용어 "유도체(derivative)"는 상기 화합물의 구조 일부를 다른 원자나 원자단으로 치환하여 얻어지는　화합물을 말한다.In this specification, the term "derivative" refers to a compound obtained by substituting part of the structure of the compound with another atom or group of atoms.
또한, 본 발명에 따른 화합물은 무기산 또는 유기산으로부터 유도된 약학적으로 허용 가능한 염 형태로 사용될 수 있으며, 예를 들면 상기 염은 염산, 브롬화수소산, 황산, 인산, 질산, 아세트산, 글리콜산, 락트산, 피루브산, 말론산, 석신산, 글루타르산, 푸마르산, 말산, 만델산, 타르타르산, 시트르산, 아스코르브산, 팔미트산, 말레산, 하이드록시말레산, 벤조산, 하이드록시벤조산, 페닐아세트산, 신남산, 살리실산, 메탄술폰산, 벤젠술폰산 또는 톨루엔술폰산 등으로부터 유도된 염일 수 있다.In addition, the compound according to the present invention may be used in the form of a pharmaceutically acceptable salt derived from an inorganic or organic acid, for example, the salt is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, Pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, It may be a salt derived from salicylic acid, methanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid.
본 발명에 따른 화합물의 약제학적으로 허용 가능한 염은, 화학식 I의 화합물을 수혼화성 유기용매, 예를 들면 아세톤, 메탄올, 에탄올, 또는 아세토나이트릴등에 녹이고 과량의 유기산을 가하거나 무기산의 산 수용액을 가한 후 침전시키거나 결정화시켜서 제조할 수 있다. 이어서 이 혼합물에서 용매나 과량의 산을 증발시킨 후 건조시켜서 부가염을 얻거나 또는 석출된 염을 흡인 여과시켜 제조할 수 있다.Pharmaceutically acceptable salts of the compounds according to the present invention include dissolving the compound of formula (I) in a water-miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile, and adding an excessive amount of organic acid or an aqueous acid solution of an inorganic acid. It can be prepared by precipitation or crystallization after addition. Subsequently, the solvent or excess acid is evaporated from the mixture and dried to obtain an addition salt, or the precipitated salt can be prepared by suction filtration.
일 양상은 하기의 화학식 I로 표시되는 화합물, 용매화물, 입체 이성질체 또는 이들의 약학적으로 허용 가능한 염을 제공한다:One aspect provides a compound, solvate, stereoisomer, or a pharmaceutically acceptable salt thereof represented by the following formula (I):
[화학식 I][Formula I]
Figure PCTKR2020008312-appb-I000003
Figure PCTKR2020008312-appb-I000003
상기 화학식 I 중,In Formula I,
R1은 아릴 또는 헤테로아릴이고 (단, R1이 비치환 페닐인 경우는 제외함); R 1 is aryl or heteroaryl (except when R 1 is unsubstituted phenyl);
R2는 수소, 하이드록시기, 시아노기, C1-C6 알킬기, C2-C6 알켄기, C2-C6 알카인기, C1-C3 알콕시기, (모노할로겐, 다이할로겐, 트라이할로겐)메틸기, 모노할로겐, 다이할로겐, 트라이할로겐, C3-C6 사이클로알킬기, 또는 C1-C6 다이알킬아미노기이고; R 2 is hydrogen, a hydroxy group, a cyano group, a C 1 -C 6 alkyl group, a C 2 -C 6 alkene group, a C 2 -C 6 alkane group, a C 1 -C 3 alkoxy group, (monohalogen, dihalogen, Trihalogen)methyl group, monohalogen, dihalogen, trihalogen, C 3 -C 6 cycloalkyl group, or C 1 -C 6 dialkylamino group;
R3는 수소, 하이드록시기, 또는 C1-C3 알콕시기이고;R 3 is hydrogen, a hydroxy group, or a C 1 -C 3 alkoxy group;
na 및 nb는 각각 독립적으로 1 내지 6의 정수이며;n a and n b are each independently an integer of 1 to 6;
Z는
Figure PCTKR2020008312-appb-I000004
이고, 이때, R4, R5 및 R6은 각각 독립적으로 수소, 할로겐, N-C1-6알킬, N-하이드록실아마이도, C-C1- 6알킬 역아마이도(-NHCOC1 -6), 하이드록시카보닐(-COOH), C1- 6알킬옥시카보닐(-COOC1 -6), C1- 6알킬, 하이드록시, C1- 6다이알킬아민 또는 헤테로사이클로 치환된 C1-6알킬 치환기이다.Z is
Figure PCTKR2020008312-appb-I000004
And, wherein, R 4, R 5 and R 6 are each independently hydrogen, halogen, N -C 1-6 alkyl, N - hydroxyl omicron], CC 1- 6 alkyl station omicron] (-NHCOC 1 -6) , hydroxycarbonyl (-COOH), C 1- 6 alkoxycarbonyl (-COOC 1 -6), C 1- 6 alkyl, hydroxy, C 1- 6 dialkyl amine or a heterocycle-substituted C 1- 6 alkyl substituent.
상기 화학식 I에서, R1은 치환체 X를 갖는 페닐; 또는 비치환 혹은 치환체 X를 갖는 헤테로아릴이고; X는 하이드록시기, 시아노기, 나이트로기, (모노할로겐, 다이할로겐, 트라이할로겐)메틸기, 모노할로겐, 다이할로겐, 트라이할로겐, C1-C6 알킬기, C2-C6 알켄기, C2-C6 알카인기, C1-C3 알콕시기, C3-C6 사이클로알킬기, 또는 C1-C6 다이알킬아미노기인 것일 수 있다.In Formula I, R 1 is phenyl having a substituent X; Or unsubstituted or heteroaryl having a substituent X; X is a hydroxy group, a cyano group, a nitro group, a (monohalogen, dihalogen, trihalogen) methyl group, monohalogen, dihalogen, trihalogen, C 1 -C 6 alkyl group, C 2 -C 6 alkene group, C It may be a 2 -C 6 alkyne group, a C 1 -C 3 alkoxy group, a C 3 -C 6 cycloalkyl group, or a C 1 -C 6 dialkylamino group.
또한, 상기 화학식 I 에서, R1은 1 내지 5개의 치환체 X를 갖는 페닐; 또는 비치환 혹은 치환체 X를 갖는 헤테로아릴이고; Further, in Formula I, R 1 is phenyl having 1 to 5 substituents X; Or unsubstituted or heteroaryl having a substituent X;
R2는 수소, 모노할로겐, 다이할로겐, 트라이할로겐, (모노할로겐, 다이할로겐, 트라이할로겐)메틸기, C1-C6 알킬기 또는 C3-C6 사이클로알킬기이며;R 2 is hydrogen, monohalogen, dihalogen, trihalogen, (monohalogen, dihalogen, trihalogen) methyl group, C 1 -C 6 alkyl group or C 3 -C 6 cycloalkyl group;
R3는 수소 또는 C1-C3 알콕시기이고;R 3 is hydrogen or a C 1 -C 3 alkoxy group;
X는 모노할로겐, 다이할로겐, 트라이할로겐, (모노할로겐, 다이할로겐, 트라이할로겐)메틸기, C1-C6 알킬기, 또는 C3-C6 사이클로알킬기이며;X is monohalogen, dihalogen, trihalogen, (monohalogen, dihalogen, trihalogen) methyl group, C 1 -C 6 alkyl group, or C 3 -C 6 cycloalkyl group;
Z는
Figure PCTKR2020008312-appb-I000005
이고, 이때 R4, R5 및 R6은 각각 독립적으로 수소 또는 C1- 6알킬이다.Z is
Figure PCTKR2020008312-appb-I000005
And, wherein R 4, R 5 and R 6 are each independently hydrogen or C 1- 6 alkyl.
상기 헤테로아릴은 N, O 및 S로 이루어진 군에서 선택된 1종 이상의 헤테로 원자를 포함할 수 있다. The heteroaryl may include at least one hetero atom selected from the group consisting of N, O and S.
일 구체예에서, 상기 화학식 I의 화합물은 하기 화합물로 이루어진 군에서 선택되는 것일 수 있다:In one embodiment, the compound of Formula I may be selected from the group consisting of the following compounds:
1-(4-((4-((3-클로로-4-(피리딘-3-일옥시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;1-(4-((4-((3-chloro-4-(pyridin-3-yloxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl ) Prop-2-en-1-one;
(1-(4-((7-메톡시-4-((3-메틸-4-((6-메틸피리딘-3-일)옥시)페닐)아미노)퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;(1-(4-((7-methoxy-4-((3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)quinazolin-6-yl)oxy)pi Peridin-1-yl)prop-2-en-1-one;
1-(4-((4-((3-클로로-4-(4-플루오로페녹시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;1-(4-((4-((3-chloro-4-(4-fluorophenoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl ) Prop-2-en-1-one;
1-(4-((4-((3-플루오로-4-(4-플루오로페녹시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;1-(4-((4-((3-fluoro-4-(4-fluorophenoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1- I) prop-2-en-1-one;
1-(4-((4-((3-클로로-4-((6-메틸피리딘-3-일)옥시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;1-(4-((4-((3-chloro-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperi Din-1-yl)prop-2-en-1-one;
1-(4-((4-((3-클로로-4-(피리딘-4-일옥시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;1-(4-((4-((3-chloro-4-(pyridin-4-yloxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl ) Prop-2-en-1-one;
1-(4-((4-((3-클로로-4-((6-플루오로피리딘-3-일)옥시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;1-(4-((4-((3-chloro-4-((6-fluoropyridin-3-yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)pi Peridin-1-yl)prop-2-en-1-one;
1-(4-((4-((3-클로로-4-((5-플루오로피리딘-2-일)옥시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;1-(4-((4-((3-chloro-4-((5-fluoropyridin-2-yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)pi Peridin-1-yl)prop-2-en-1-one;
1-(4-((4-((4-(4-클로로페녹시)-3-플루오로페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;1-(4-((4-((4-(4-chlorophenoxy)-3-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl ) Prop-2-en-1-one;
1-(4-((4-((3-클로로-4-((1-메틸-1H)-피라졸-4-일)옥시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;1-(4-((4-((3-chloro-4-((1-methyl-1 H )-pyrazol-4-yl)oxy)phenyl)amino)-7-methoxyquinazoline-6- Yl)oxy)piperidin-1-yl)prop-2-en-1-one;
1-(4-((4-((3-클로로-4-((1-메틸-1H)-피라졸-5-일)옥시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;1-(4-((4-((3-chloro-4-((1-methyl-1 H )-pyrazol-5-yl)oxy)phenyl)amino)-7-methoxyquinazoline-6- Yl)oxy)piperidin-1-yl)prop-2-en-1-one;
1-(4-((4-((3-클로로-4-((1-메틸-3-(트라이플루오로메틸)-1H-피라졸-5-일)옥시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;1-(4-((4-((3-chloro-4-((1-methyl-3-(trifluoromethyl)-1 H -pyrazol-5-yl)oxy)phenyl)amino)-7 -Methoxyquinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one;
1-(4-((4-((4-(4-플루오로페녹시)-3-메틸페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;1-(4-((4-((4-(4-fluorophenoxy)-3-methylphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl) Prop-2-en-1-one;
1-(4-((4-((4-(4-플루오로페녹시)-3-(트라이플루오로메틸)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;1-(4-((4-((4-(4-fluorophenoxy)-3-(trifluoromethyl)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperi Din-1-yl)prop-2-en-1-one;
1-(4-((4-((3-클로로-4-(3,4-다이플루오로페녹시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;1-(4-((4-((3-chloro-4-(3,4-difluorophenoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidine- 1-yl)prop-2-en-1-one;
1-(4-((4-((3-클로로-4-(4-클로로페녹시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;1-(4-((4-((3-chloro-4-(4-chlorophenoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl) Prop-2-en-1-one;
1-(4-((4-((3-클로로-4-(4-(트라이플루오로메틸)페녹시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;1-(4-((4-((3-chloro-4-(4-(trifluoromethyl)phenoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidine -1-yl)prop-2-en-1-one;
1-(4-((4-((3-클로로-4-(싸이아졸-2-일옥시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;1-(4-((4-((3-chloro-4-(thiazol-2-yloxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1- I) prop-2-en-1-one;
1-(4-((4-((3-클로로-4-(4-플루오로페녹시)페닐)아미노)퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;1-(4-((4-((3-chloro-4-(4-fluorophenoxy)phenyl)amino)quinazolin-6-yl)oxy)piperidin-1-yl)prop-2 -En-1-one;
1-(4-((4-((3-클로로-4-(4-사이클로프로필페녹시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;1-(4-((4-((3-chloro-4-(4-cyclopropylphenoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl ) Prop-2-en-1-one;
1-(3-((4-((3-클로로-4-(피리딘-3-일옥시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)아제티딘-1-일)프로프-2-엔-1-온;1-(3-((4-((3-chloro-4-(pyridin-3-yloxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-1-yl) Prop-2-en-1-one;
1-(3-((7-메톡시-4-((3-메틸-4-((6-메틸피리딘-3-일)옥시)페닐)아미노)퀴나졸린-6-일)옥시)아제티딘-1-일)프로프-2-엔-1-온;1-(3-((7-methoxy-4-((3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)quinazolin-6-yl)oxy)azetidine -1-yl)prop-2-en-1-one;
1-(3-((4-((3-클로로-4-((6-메틸피리딘-3-일)옥시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)아제티딘-1-일)프로프-2-엔-1-온;1-(3-((4-((3-chloro-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidine -1-yl)prop-2-en-1-one;
1-(3-((7-메톡시-4-((3-메틸-4-(피리딘-3-일옥시)페닐)아미노)퀴나졸린-6-일)옥시)아제티딘-1-일)프로프-2-엔-1-온;1-(3-((7-methoxy-4-((3-methyl-4-(pyridin-3-yloxy)phenyl)amino)quinazolin-6-yl)oxy)azetidin-1-yl) Prop-2-en-1-one;
1-(3-((4-((3-클로로-4-((1-메틸-1H-피라졸-4-일)옥시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)아제티딘-1-일)프로프-2-엔-1-온;1-(3-((4-((3-chloro-4-((1-methyl-1 H -pyrazol-4-yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl )Oxy)azetidin-1-yl)prop-2-en-1-one;
1-(3-((4-((3-클로로-4-(4-플루오로페녹시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)아제티딘-1-일)프로프-2-엔-1-온;1-(3-((4-((3-chloro-4-(4-fluorophenoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-1-yl) Prop-2-en-1-one;
1-(3-((4-((3-사이클로프로필-4-(피리딘-3-일옥시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)아제티딘-1-일)프로프-2-엔-1-온;1-(3-((4-((3-cyclopropyl-4-(pyridin-3-yloxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-1-yl ) Prop-2-en-1-one;
1-(3-((4-((3-(다이플루오로메틸)-4-(피리딘-3-일옥시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)아제티딘-1-일)프로프-2-엔-1-온; 및1-(3-((4-((3-(difluoromethyl)-4-(pyridin-3-yloxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidine -1-yl)prop-2-en-1-one; And
1-(3-((4-((3-클로로-4-(싸이아졸-2-일옥시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)아제티딘-1-일)프로프-2-엔-1-온.1-(3-((4-((3-chloro-4-(thiazol-2-yloxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-1-yl ) Prop-2-en-1-one.
다른 양상은 일 구체예에 따른 퀴나졸린 유도체, 용매화물, 입체 이성질체 또는 이들의 약학적으로 허용 가능한 염을 활성성분으로 포함하는, 암의 예방 또는 치료용 약학적 조성물을 제공한다. 상기 암은 EGFR 돌연변이 및 HER2 돌연변이 중 1종 이상을 갖는 것일 수 있다.Another aspect provides a pharmaceutical composition for preventing or treating cancer, comprising a quinazoline derivative, solvate, stereoisomer, or a pharmaceutically acceptable salt thereof according to an embodiment as an active ingredient. The cancer may have one or more of EGFR mutation and HER2 mutation.
다른 일 구체예에서, 상기 EGFR 돌연변이는 활성화 EGFR 돌연변이, EGFR 저해제에 대한 내성을 유발하는 돌연변이 또는 이들의 조합이고, 상기 HER2 돌연변이는 활성화 HER2 돌연변이, HER2 저해제에 대한 내성을 유발하는 돌연변이 또는 이들의 조합인 것일 수 있다.In another embodiment, the EGFR mutation is an activated EGFR mutation, a mutation causing resistance to an EGFR inhibitor, or a combination thereof, and the HER2 mutation is an activated HER2 mutation, a mutation causing resistance to a HER2 inhibitor, or a combination thereof. It can be.
또 다른 일 구체예에서, 상기 활성화 EGFR 돌연변이 및 활성화 HER2 돌연변이는 각각 엑손 20 삽입 돌연변이일 수 있다.In another embodiment, the activating EGFR mutation and the activating HER2 mutation may be exon 20 insertion mutations, respectively.
또 다른 일 구체예에서, 상기 암은 폐암, 간암, 식도암, 위암, 대장암, 소장암, 췌장암, 흑색종, 유방암, 구강암, 뇌종양, 갑상선암, 부갑상선암, 신장암, 자궁경부암, 육종, 전립선암, 요도암, 방광암, 고환암, 혈액암, 림프종, 피부암, 건선 및 섬유선종으로 이루어지는 군으로부터 선택된 것일 수 있다.In another embodiment, the cancer is lung cancer, liver cancer, esophageal cancer, gastric cancer, colon cancer, small intestine cancer, pancreatic cancer, melanoma, breast cancer, oral cancer, brain tumor, thyroid cancer, parathyroid cancer, kidney cancer, cervical cancer, sarcoma, prostate cancer , Urethral cancer, bladder cancer, testicular cancer, blood cancer, lymphoma, skin cancer, psoriasis, and fibroadenoma.
또 다른 일 구체예에서, 상기 암은 비소세포성폐암일 수 있다.In another embodiment, the cancer may be non-small cell lung cancer.
또 다른 일 구체예에서, 상기 약학적 조성물은 통상적인 약학적으로 허용되는 담체, 부형제 또는 첨가제를 포함할 수 있다. 본 발명의 약학적 조성물은 통상적인 방법에 따라 제제화할 수 있으며, 정제, 환제, 산제, 캅셀제, 시럽, 에멀젼, 마이크로에멀젼 등의 다양한 경구 투여 형태 또는 근육 내, 정맥 내 또는 피하 투여와 같은 비경구 투여 형태로 제조될 수 있다.In another embodiment, the pharmaceutical composition may contain a conventional pharmaceutically acceptable carrier, excipient, or additive. The pharmaceutical composition of the present invention can be formulated according to a conventional method, and various oral dosage forms such as tablets, pills, powders, capsules, syrups, emulsions, microemulsions, or parenteral administration such as intramuscular, intravenous or subcutaneous administration It can be prepared in a dosage form.
일 구체예에 따른 약학적 조성물이 경구 제형의 형태로 제조되는 경우, 사용되는 첨가제 또는 담체의 예로는 셀룰로오스, 규산칼슘, 옥수수전분, 락토오스, 수크로스, 덱스트로스, 인산칼슘, 스테아르산, 스테아르산 마그네슘, 스테아르산 칼슘, 젤라틴, 탈크, 계면활성제, 현탁제, 유화제, 희석제 등을 들 수 있다. 본 발명의 약학적 조성물이 주사제의 형태로 제조되는 경우 상기 첨가제 또는 담체로는 물, 식염수, 포도당 수용액, 유사 당수용액, 알콜, 글리콜, 에테르(예: 폴리에틸렌글리콜 400), 오일, 지방산, 지방산에스테르, 글리세라이드, 계면활성제, 현탁제, 유화제 등을 들 수 있다.When the pharmaceutical composition according to an embodiment is prepared in the form of an oral dosage form, examples of additives or carriers used include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, stearic acid. Magnesium, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifying agents, and diluents. When the pharmaceutical composition of the present invention is prepared in the form of an injection, the additives or carriers include water, saline, aqueous glucose solution, aqueous sugar-like solution, alcohol, glycol, ether (eg, polyethylene glycol 400), oil, fatty acid, fatty acid ester. , Glycerides, surfactants, suspending agents, and emulsifying agents.
일 구체예에 따른 화학식 I의 화합물 또는 이의 약학적으로 허용 가능한 염은, EGFR 및 HER2 중 티로신 키나아제 도메인의 돌연변이에 의해 유발되는 암세포의 성장 및 약물에 대한 내성, 또는 그러한 내성을 갖는 암을 선택적이고 효과적으로 억제한다. 따라서, 일 양상은 개체에 본 발명의 화합물 또는 이를 포함하는 약학적 조성물을 치료 유효량으로 투여하는 단계를 포함하는, EGFR 돌연변이 및/또는 HER2 돌연변이에 의해 유발되는 암의 치료를 필요로 하는 개체 (예를 들어, 환자)에서 상기 질환을 치료하는 방법을 제공한다.The compound of Formula I or a pharmaceutically acceptable salt thereof according to an embodiment is selective for cancer cell growth and drug resistance, or cancer having such resistance, caused by mutation of the tyrosine kinase domain in EGFR and HER2, and Effectively suppress Accordingly, one aspect is an individual in need of treatment for a cancer caused by an EGFR mutation and/or a HER2 mutation comprising administering to the individual a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition comprising the same (e.g. For example, a patient) provides a method of treating the disease.
상기 약학 조성물의 투여량은 개체 또는 환자의 치료 또는 예방에 유효한 양으로서, 목적하는 바에 따라 경구 또는 비경구 투여할 수 있으며, 경구 투여 시는 활성성분을 기준으로 하루에 체중 1 kg당 0.01 내지 1000 mg, 보다 구체적으로는 0.1 내지 300 mg의 양으로 투여되도록, 비경구 투여 시는 활성성분을 기준으로 하루에 체중 1 kg당 0.01 내지 100 mg, 보다 구체적으로는 0.1 내지 50 mg의 양으로 투여되도록 1 내지 수회에 나누어 투여할 수 있다. 특정 개체 또는 환자에 대한 투여 용량은 환자의 체중, 연령, 성별, 건강 상태, 식이, 투여 시간, 투여 방법, 질환의 중증도 등의 여러 관련 인자에 비추어 결정되어야 하는 것이고 전문가에 의해 적절히 가감될 수 있는 것으로 이해되어야 하며, 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하기 위한 것은 아니다. 관련 기술 분야의 통상의 기술을 갖는 의사 또는 수의사는 요구되는 제약 조성물의 유효량을 용이하게 결정 및 처방할 수 있다. 예를 들어, 의사 또는 수의사는 제약 조성물에 사용되는 본 발명의 화합물의 용량을 목적하는 치료효과를 달성하는데 요구되는 것보다 낮은 수준에서 출발하여, 목적하는 효과가 달성될 때까지 투여량을 점진적으로 증가시킬 수 있다.The dosage of the pharmaceutical composition is an amount effective for the treatment or prevention of an individual or patient, and can be administered orally or parenterally as desired, and when administered orally, 0.01 to 1000 per 1 kg of body weight per day based on the active ingredient. mg, more specifically, to be administered in an amount of 0.1 to 300 mg, for parenteral administration, to be administered in an amount of 0.01 to 100 mg per 1 kg of body weight per day, more specifically 0.1 to 50 mg, based on the active ingredient It can be administered in one to several divided doses. The dosage to be administered to a specific individual or patient should be determined in the light of various related factors such as the patient's weight, age, sex, health status, diet, administration time, administration method, and disease severity, and can be appropriately adjusted or adjusted by an expert. It should be understood that the dosage is not intended to limit the scope of the invention in any way. A physician or veterinarian having ordinary skill in the related art can readily determine and prescribe an effective amount of the required pharmaceutical composition. For example, a physician or veterinarian may start at a level lower than that required to achieve the desired therapeutic effect, starting with the dose of the compound of the invention used in the pharmaceutical composition, and gradually increasing the dose until the desired effect is achieved. Can increase.
본 명세서에서 용어 "치료하는" 또는 "치료"는 질환을 저해하는 것, 예를 들어, 질환, 병태 또는 장애의 병리 또는 징후를 경험하거나 또는 나타내는 개체에서 질환, 병태 또는 장애를 저해하는 것 즉, 병리 및/또는 징후의 추가적인 발생을 막는 것, 또는 질환을 개선시키는 것, 예를 들어, 질환, 병태 또는 장애의 병리 또는 징후를 경험하거나 또는 나타내는 개체에서 질환, 병태 또는 장애를 개선시키는 것 즉, 병리 및/또는 징후를 반전시키는 것, 예컨대 질환 중증도를 감소시키는 것을 말한다. The term "treating" or "treatment" as used herein refers to inhibiting a disease, for example, inhibiting a disease, condition or disorder in an individual experiencing or exhibiting a pathology or symptom of a disease, condition or disorder, ie, Preventing the further occurrence of pathology and/or symptoms, or improving a disease, e.g., ameliorating a disease, condition or disorder in an individual experiencing or exhibiting a pathology or symptom of a disease, condition or disorder, i.e. It refers to reversing pathology and/or symptoms, such as reducing disease severity.
본 명세서에서 용어 "예방하는" 또는 "예방"은 질환을 예방하는 것, 예를 들어 질환, 병태 또는 장애의 성향이 있을 수 있지만 질환의 병리 또는 징후를 아직 경험하지 않았거나 나타내지 않는 개체에서 질환, 병태 또는 장애를 예방하는 것을 말한다.As used herein, the term "preventing" or "prevention" means preventing a disease, for example, a disease in an individual who may have a tendency to a disease, condition or disorder but has not yet experienced or exhibited the pathology or signs of the disease, It refers to preventing a condition or disorder.
본 명세서에서 용어 "개체" 또는 "환자"는 포유류, 예를 들어, 마우스, 래트, 기타 설치류, 토끼, 개, 고양이, 돼지, 소, 양, 말 또는 영장류 및 인간을 포함하는 임의의 동물을 말한다.As used herein, the term "individual" or "patient" refers to any animal including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates and humans. .
일 구체예에 따른 약학적 조성물은 활성 성분으로서 치료 유효량의 일 구체예에 따른 화합물 중 적어도 하나를 단독으로, 또는 제약 담체와의 조합으로 포함하는 제약 조성물을 그의 범주 내에 포함한다. 임의로, 일 구체예에 따른 화합물은 단독으로, 다른 구체예에 따른 화합물과 조합으로, 또는 하나 이상의 다른 치료제들, 예를 들어 항암제 또는 다른 제약 활성 물질과 조합으로 사용될 수 있다. Pharmaceutical compositions according to one embodiment include within the scope of pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds according to one embodiment in a therapeutically effective amount, alone or in combination with a pharmaceutical carrier. Optionally, a compound according to one embodiment can be used alone, in combination with a compound according to another embodiment, or in combination with one or more other therapeutic agents, such as anticancer agents or other pharmaceutically active substances.
일 구체예에 따른 화학식 I의 화합물 또는 이의 약학적으로 허용 가능한 염은, 다른 항암제와 함께 병용 투여함으로써 항암제의 치료효과를 강화시킬 수 있다.The compound of Formula I or a pharmaceutically acceptable salt thereof according to an embodiment may enhance the therapeutic effect of the anticancer agent by co-administering it with other anticancer agents.
또 다른 양상은 본 발명에 따른 화합물, 이의 염, 이성질체, 수화물 및 용매화물 중 하나 이상을 포함하는 화합물 라이브러리를 제공한다.Another aspect provides a compound library comprising one or more of the compounds according to the present invention, salts, isomers, hydrates and solvates thereof.
또 다른 양상은 일 구체예에 따른 화합물, 용매화물, 입체 이성질체 또는 이의 약학적으로 허용 가능한 염, 또는 이를 포함하는 상기 약학적 조성물을 개체에 투여하는 단계를 포함하는 암의 예방 또는 치료방법; 및 암의 예방 또는 치료를 위한 일 구체예에 따른 화합물, 용매화물, 입체 이성질체 또는 이의 약학적으로 허용 가능한 염의 의약적 용도; 암 치료제를 제조하기 위한 일 구체예에 따른 화합물, 용매화물, 입체 이성질체 또는 이의 약학적으로 허용 가능한 염의 의약적 용도를 제공한다. Another aspect is a method for preventing or treating cancer comprising administering to an individual the compound, solvate, stereoisomer, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the same according to an embodiment; And a pharmaceutical use of a compound, solvate, stereoisomer, or a pharmaceutically acceptable salt thereof according to an embodiment for the prevention or treatment of cancer; It provides a pharmaceutical use of a compound, solvate, stereoisomer, or a pharmaceutically acceptable salt thereof according to an embodiment for preparing a cancer therapeutic agent.
이하, 본 발명에 따르는 화합물의 제조방법에 대하여 상세하게 설명한다.Hereinafter, a method for preparing the compound according to the present invention will be described in detail.
본 발명에 따른 상기 화학식 I의 화합물은 하기 반응식 1에 대표적으로 도시된 방법에 따라 유기/의약 화학 기술 분야의 통상의 기술자에게 잘 알려진 화학적 변환을 이용하여 제조할 수 있다. 하기 반응식 1에서 각 화학식의 하단에 기재된 번호는 화학식을 식별하기 위한 번호이다. The compound of formula (I) according to the present invention can be prepared using a chemical transformation well known to those skilled in the art of organic/pharmaceutical chemistry according to the method typically shown in Scheme 1 below. In the following Scheme 1, the numbers listed at the bottom of each chemical formula are numbers for identifying the chemical formula.
[반응식 1][Scheme 1]
Figure PCTKR2020008312-appb-I000006
Figure PCTKR2020008312-appb-I000006
상기 화학식 6의 화합물 및 화학식 7의 화합물은 당해 유기화학 기술분야에서 통상의 지식을 이용하여 제조할 수 있다.The compound of Formula 6 and the compound of Formula 7 may be prepared using conventional knowledge in the art of organic chemistry.
상기 반응식 1에서, R1, R2, R3, na, nb 및 Z는 상기 화학식 I에서 정의한 바와 같다. In Scheme 1, R 1 , R 2 , R 3 , n a , n b and Z are as defined in Formula I.
상기 화학식 6의 화합물을 화학식 7의 화합물과 반응시켜 화학식 3의 화합물을 제조하기 위해, 상기 반응에 사용되는 용매는 상기 반응을 저해하지 않는 임의의 용매일 수 있다. 반응에 사용되는 용매는 다이메틸술폭사이드, N, N-다이메틸 포름아미드, 아세토니트릴, 테트라하이드로퓨란 등의 극성 비양성자성 용매; 메탄올, 에탄올, 2-프로판올, 2-아이소프로판올, 2-부탄올 등의 극성 양성자성 용매; 또는 톨루엔, 1,4-다이옥산 등의 비극성 비양성자성 용매를 사용할 수 있다. 구체적으로는 2-아이소프로판올일 수 있다. 반응온도는 0℃ 내지 150℃ 일 수 있으며, 구체적으로, 0℃ 이상, 20℃ 이상, 40℃ 이상, 60℃ 이상 또는 80℃ 이상일 수 있고, 100℃ 이하, 110℃ 이하, 120℃ 이하, 140℃ 이하 또는 150℃ 이하일 수 있다. In order to react the compound of Formula 6 with the compound of Formula 7 to prepare the compound of Formula 3, the solvent used in the reaction may be any solvent that does not inhibit the reaction. The solvent used in the reaction is a polar aprotic solvent such as dimethyl sulfoxide, N , N -dimethyl formamide, acetonitrile, and tetrahydrofuran; Polar protic solvents such as methanol, ethanol, 2-propanol, 2-isopropanol, and 2-butanol; Alternatively, a non-polar aprotic solvent such as toluene and 1,4-dioxane may be used. Specifically, it may be 2-isopropanol. The reaction temperature may be 0℃ to 150℃, specifically, 0℃ or more, 20℃ or more, 40℃ or more, 60℃ or more, or 80℃ or more, and 100℃ or less, 110℃ or less, 120℃ or less, 140 It may be less than or equal to ℃ or less than 150 ℃.
상기 화학식 3의 화합물을 암모니아 함유 알코올 용액 (예: 7N 암모니아 함유 메탄올 용액) 중에서 교반을 수행하여 아세틸기를 탈보호함으로써 화학식 2의 화합물을 제조하였다. 반응온도는 0℃ 내지 상온일 수 있으며, 구체적으로 0℃ 이상, 1℃ 이상 또는 2℃ 이상일 수 있고, 10℃ 이하, 15℃ 이하 또는 상온 이하일 수 있다. 이때, 상온은 25℃일 수 있다.The compound of Formula 3 was stirred in an ammonia-containing alcohol solution (eg, 7N ammonia-containing methanol solution) to deprotect the acetyl group to prepare the compound of Formula 2. The reaction temperature may be 0°C to room temperature, specifically 0°C or more, 1°C or more, or 2°C or more, and may be 10°C or less, 15°C or less, or room temperature or less. At this time, the room temperature may be 25 ℃.
상기 화학식 2의 화합물과 화학식 9의 화합물을 반응시켜 화학식 1의 화합물을 제조하고, 상기 화학식 2의 화합물과 화학식 8의 화합물을 반응시켜 화학식 5의 화합물을 제조할 수 있다. 상기 반응은 용매를 첨가한 반응액에서 진행될 수 있으며, 상기 용매는 상기 반응을 저해하지 않는 임의의 용매일 수 있으며, 예컨대, 상기 용매는 다이메틸술폭사이드, N, N-다이메틸 포름아미드, 아세토니트릴, 테트라하이드로퓨란 등의 극성 비양성자성 용매; 메탄올, 에탄올, 2-프로판올, 2-부탄올 등의 극성 양성자성 용매; 또는 톨루엔, 1,4-다이옥산 등의 비극성 비양성자성 용매를 사용할 수 있다. 또한, 상기 반응액에 추가로 염기를 첨가할 수도 있으며, 상기 염기는 트라이에틸아민, 다이아이소프로필에틸아민, 피리딘 등의 유기염기; 및 탄산나트륨, 탄산칼륨, 수소화나트륨 등의 무기염기; 중 선택될 수 있다. 상기 염기의 첨가량은 상기 화학식 2의 화합물 1당량을 기준으로 3당량일 수 있다. 반응온도는 0℃ 내지 150℃ 일 수 있으며, 구체적으로 0℃ 이상, 20℃ 이상, 40℃ 이상 또는 60℃ 이상일 수 있고, 70℃ 이하, 90℃ 이하, 110℃ 이하, 130℃ 이하 또는 130℃ 이하일 수 있다. The compound of Formula 1 may be prepared by reacting the compound of Formula 2 with the compound of Formula 9, and the compound of Formula 5 may be prepared by reacting the compound of Formula 2 with the compound of Formula 8. The reaction may be carried out in a reaction solution to which a solvent is added, and the solvent may be any solvent that does not inhibit the reaction, for example, the solvent is dimethyl sulfoxide, N , N -dimethyl formamide, aceto Polar aprotic solvents such as nitrile and tetrahydrofuran; Polar protic solvents such as methanol, ethanol, 2-propanol, and 2-butanol; Alternatively, a non-polar aprotic solvent such as toluene and 1,4-dioxane may be used. In addition, a base may be additionally added to the reaction solution, and the base may include an organic base such as triethylamine, diisopropylethylamine, and pyridine; And inorganic bases such as sodium carbonate, potassium carbonate, and sodium hydride; You can choose from. The amount of the base added may be 3 equivalents based on 1 equivalent of the compound of Formula 2. The reaction temperature may be 0℃ to 150℃, specifically 0℃ or more, 20℃ or more, 40℃ or more, or 60℃ or more, and 70℃ or less, 90℃ or less, 110℃ or less, 130℃ or less, or 130℃ It can be below.
상기 화학식 5의 화합물을 메틸렌클로라이드와 같은 유기용매 중에서 트라이플루오로아세트산과 같은 유기산 또는 진한 염산과 같은 무기산과 반응시켜 t-부톡시카보닐기를 탈보호하여 화학식 4의 화합물을 제조하였다. 반응온도는 0℃ 내지 상온일 수 있으며, 바람직하게는 상온일 수 있다.The compound of Formula 5 was reacted with an organic acid such as trifluoroacetic acid or an inorganic acid such as concentrated hydrochloric acid in an organic solvent such as methylene chloride to deprotect t -butoxycarbonyl group to prepare a compound of Formula 4. The reaction temperature may be 0° C. to room temperature, preferably room temperature.
상기 화학식 4의 화합물을 테트라하이드로퓨란 등의 유기용매와 물의 혼합용매 또는 메틸렌클로라이드과 같은 비극성 용매에서, 탄산수소나트륨과 같은 무기 염기 또는 피리딘, 트라이에틸아민과 같은 유기 염기 존재 하에 화학식 10의 화합물과 축합반응시켜 화학식 1의 화합물을 제조하였다. 반응온도는 0℃ 내지 상온일 수 있으며, 바람직하게는 0℃ 일 수 있다. Condensation of the compound of Formula 4 with the compound of Formula 10 in the presence of an inorganic base such as sodium hydrogen carbonate or an organic base such as pyridine or triethylamine in a mixed solvent of water and an organic solvent such as tetrahydrofuran or a non-polar solvent such as methylene chloride By reacting, a compound of Formula 1 was prepared. The reaction temperature may be 0°C to room temperature, and preferably 0°C.
상기 화학식 1의 제조방법을 구체적인 예를 들어 설명하였으나, 구체적인 반응조건 예를 들어, 반응용매, 염기, 반응물질의 사용량 등은 본 명세서에 설명된 것으로만 한정되는 것은 아니며, 어떤 식으로든 본 발명의 권리범위를 제한하는 것으로 해석될 수 없다. Although the preparation method of Formula 1 has been described with a specific example, specific reaction conditions, such as a reaction solvent, a base, and the amount of use of a reactant, are not limited to those described in the present specification, and in any way It cannot be construed as limiting the scope of the rights.
본 발명은 다른 일 양상은 상기 일 양상에 따른 화합물 또는 그 약제학적으로 허용 가능한 염을 활성성분으로서 포함하는 암의 예방 또는 치료용 약학적 조성물을 제공한다.Another aspect of the present invention provides a pharmaceutical composition for preventing or treating cancer comprising the compound according to the above aspect or a pharmaceutically acceptable salt thereof as an active ingredient.
이러한 제조 방법에 의해 합성된 화학식 I의 화합물, 용매화물, 입체 이성질체 및 이의 약학적으로 허용 가능한 염을 활성 성분으로 포함하는 약학적 조성물은, EGFR 및 HER2 중 티로신 키나아제 도메인의 돌연변이에 의해 유발되는 암세포의 성장 및 약물에 대한 내성, 또는 그러한 내성을 갖는 암을 치료하는데 사용될 수 있다. A pharmaceutical composition comprising a compound of Formula I, a solvate, a stereoisomer, and a pharmaceutically acceptable salt thereof synthesized by this method as an active ingredient, is a cancer cell caused by mutation of the tyrosine kinase domain in EGFR and HER2. Growth and resistance to drugs, or cancer having such resistance.
이하, 본 발명을 하기 실시예 및 실험예에 의해 더욱 구체적으로 설명한다. 그러나, 이들 실시예 및 실험예는 본 발명에 대한 이해를 돕기 위한 것일 뿐, 어떤 의미로든 본 발명의 범위가 이들에 의해 제한되는 것은 아니다.Hereinafter, the present invention will be described in more detail by the following examples and experimental examples. However, these Examples and Experimental Examples are only intended to aid understanding of the present invention, and the scope of the present invention is not limited thereto in any sense.
실시예Example 1: 11: 1 -(4-((4-((3--(4-((4-((3- 클로로Chloro -4-(피리딘-3--4-(pyridin-3- 일옥시Oxy )페닐)아미노)-7-)Phenyl)amino)-7- 메톡시퀴나졸린Methoxyquinazoline -6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온의 제조Preparation of -6-yl)oxy)piperidin-1-yl)prop-2-en-1-one
Figure PCTKR2020008312-appb-I000007
Figure PCTKR2020008312-appb-I000007
단계 1) 3-(2-Step 1) 3-(2- 클로로Chloro -4--4- 나이트로페녹시Nitrophenoxy )피리딘의 제조) Preparation of pyridine
3-하이드록시피리딘 2.38 g (25.1 mmol)을 N, N-다이메틸아세트아미드 60 mL로 묽히고, 수소화나트륨 1.0 g (25.1 mmol)을 가하고 상온에서 1시간 동안 교반시켰다. 반응 혼합물에 2-클로로-1-플루오로-4-나이트로벤젠 4.0 g (22.8 mmol)을 상온에서 천천히 가하고 80 ℃에서 2 시간 동안 교반시켰다. 반응이 완결된 후 결과의 반응 혼합물을 상온으로 냉각한 후 에틸 아세테이트로 묽히고 포화 염수로 세척하였다. 결과로 분리된 유기층을 무수황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하여 얻어진 잔사를 컬럼 크로마토그래피 (에틸 아세테이트 : 헥산 = 1 : 4(부피비))로 분리하여 표제 화합물 4.16 g (수율: 73 %)을 얻었다.2.38 g (25.1 mmol) of 3-hydroxypyridine was diluted with 60 mL of N, N -dimethylacetamide, 1.0 g (25.1 mmol) of sodium hydride was added, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture, 4.0 g (22.8 mmol) of 2-chloro-1-fluoro-4-nitrobenzene was slowly added at room temperature, followed by stirring at 80° C. for 2 hours. After the reaction was completed, the resulting reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure, and the resulting residue was separated by column chromatography (ethyl acetate: hexane = 1: 4 (volume ratio)), and the title compound 4.16 g (yield: 73%) Got it.
1H-NMR (300MHz, CDCl3): δ 8.56 (m, 1H), 8.50 (m, 1H), 8.43 (m, 1H), 8.14 (m, 1H), 7.42 (m, 2H), 6.97 (d, 1H). 1 H-NMR (300MHz, CDCl 3 ): δ 8.56 (m, 1H), 8.50 (m, 1H), 8.43 (m, 1H), 8.14 (m, 1H), 7.42 (m, 2H), 6.97 (d , 1H).
단계 2) 3-Step 2) 3- 클로로Chloro -4-(피리딘-3--4-(pyridin-3- 일옥시Oxy )아닐린의 제조) Preparation of aniline
철 5.56 g (99.6 mmol)과 염화암모늄 0.62 g (11.6 mmol)을 50 % 에탄올 수용액 50 mL에 묽히고 100에서 1시간 동안 교반시켰다. 상기 단계 1)에서 제조된 화합물 4.16 g (16.6 mmol)을 50 % 에탄올 수용액 10 mL에 녹인 후 상기 철이 활성화된 반응 플라스크에 넣고 100℃ 에서 3시간 동안 교반시켰다. 반응이 완결된 후 결과의 반응 혼합물을 셀라이트 충진된 필터로 여과시켜 철을 제거하고, 결과의 여과액은 감압 증류하였다. 결과로 얻어진 잔사를 다이클로로메탄으로 묽히고 포화 중탄산나트륨 수용액으로 세척하였다. 결과로 분리된 유기층을 무수황산나트륨으로 건조한 뒤, 감압 여과 및 감압 증류하여 표제 화합물 3.43 g (수율: 94 %)을 얻었다. 5.56 g (99.6 mmol) of iron and 0.62 g (11.6 mmol) of ammonium chloride were diluted in 50 mL of a 50% ethanol aqueous solution and stirred at 100 for 1 hour. 4.16 g (16.6 mmol) of the compound prepared in step 1) was dissolved in 10 mL of a 50% ethanol aqueous solution, and then put into the iron-activated reaction flask and stirred at 100°C for 3 hours. After the reaction was completed, the resulting reaction mixture was filtered through a filter filled with Celite to remove iron, and the resulting filtrate was distilled under reduced pressure. The resulting residue was diluted with dichloromethane and washed with a saturated aqueous sodium bicarbonate solution. The resulting separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure to obtain 3.43 g (yield: 94%) of the title compound.
1H-NMR (300MHz, DMSO-d6): δ 8.31 (m, 1H), 8.29 (m, 1H), 7.21 (m, 1H), 7.15 (m, 1H), 6.93 (m, 1H), 6.79 (m, 1H), 6.60 (m, 1H), 3.71 (s, 2H). 1 H-NMR (300MHz, DMSO-d 6 ): δ 8.31 (m, 1H), 8.29 (m, 1H), 7.21 (m, 1H), 7.15 (m, 1H), 6.93 (m, 1H), 6.79 (m, 1H), 6.60 (m, 1H), 3.71 (s, 2H).
단계 3) 4-((3-Step 3) 4-((3- 클로로Chloro -4-(-4-( 피리딘3Pyridine3 -- 일옥시Oxy )페닐)아미노)-7-)Phenyl)amino)-7- 메톡시퀴나졸린Methoxyquinazoline -6-일 아세테이트의 제조Preparation of -6-yl acetate
상기 단계 2)에서 제조된 화합물 3.43 g (15.6 mmol)을 아이소프로판올 90 mL로 묽히고, 4-클로로-7-메톡시퀴나졸린-6-일 아세테이트 염산염 (KR1013319) 4.50 g (15.6 mmol)을 가하여 90℃에서 7시간 동안 교반하였다. 반응이 완결된 후 결과의 반응 혼합물을 여과한 뒤 2-아이소프로판올 50 mL로 세척하였다. 얻어진 고체를 50℃의 건조 오븐에서 건조하여 표제 화합물 5.80 g (수율: 85 %)을 얻었다.3.43 g (15.6 mmol) of the compound prepared in step 2) was diluted with 90 mL of isopropanol, and 4.50 g (15.6 mmol) of 4-chloro-7-methoxyquinazolin-6-yl acetate hydrochloride ( KR1013319 ) was added thereto. The mixture was stirred at 90° C. for 7 hours. After the reaction was completed, the resulting reaction mixture was filtered and washed with 50 mL of 2-isopropanol. The obtained solid was dried in a drying oven at 50° C. to obtain 5.80 g (yield: 85%) of the title compound.
단계 4) 4-((3-Step 4) 4-((3- 클로로Chloro -4-(피리딘-3--4-(pyridin-3- 일옥시Oxy )페닐)아미노)-7-)Phenyl)amino)-7- 메톡시퀴나졸린Methoxyquinazoline -6-올의 제조Preparation of -6-ol
상기 단계 3)에서 얻어진 화합물 5.80 g (13.3 mmol)을 0℃에서 7N 암모니아 메탄올 용액 40 mL에 가한 후, 반응 혼합물의 온도를 서서히 상온까지 올려 3시간 동안 교반시켰다. 생성된 고체를 다이에틸에테르로 세척한 후 감압 여과하였으며, 얻어진 고체를 감압 하에 건조시켜 표제 화합물 3.40 g (수율: 65 %)을 얻었다.The step 3) was added to compound 5.80 g (13.3 mmol) obtained in the 0 ℃ in 40 mL 7 N ammonia methanol solution, place the temperature of the reaction mixture slowly to room temperature and stirred for 3 hours. The resulting solid was washed with diethyl ether and then filtered under reduced pressure, and the obtained solid was dried under reduced pressure to obtain 3.40 g (yield: 65%) of the title compound.
단계 5) 1-(4-((4-((3-Step 5) 1-(4-((4-((3- 클로로Chloro -4-(피리딘-3--4-(pyridin-3- 일옥시Oxy )페닐)아미노)-7-)Phenyl)amino)-7- 메톡시퀴나졸린Methoxyquinazoline -6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온의 제조Preparation of -6-yl)oxy)piperidin-1-yl)prop-2-en-1-one
상기 단계 4)에서 얻어진 화합물 300 mg (0.76 mmol)을 N, N-다이메틸아세트아미드 5 mL로 묽히고 1-아크릴로일피페리딘-4-일 4-메틸벤젠술포네이트 (WO2014116070) 353 mg (1.14 mmol), 탄산칼륨 210 mg (1.52 mmol)을 가한 후, 70℃에서 16시간 동안 교반하였다. 반응이 완결된 후 결과의 반응 혼합물을 상온으로 냉각한 후 에틸 아세테이트로 묽히고 포화 염수로 세척하였다. 결과로 분리된 유기층을 무수황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하여 얻어진 잔사를 컬럼 크로마토그래피 (다이클로로메탄 : 메탄올 = 20 : 1(부피비))로 분리하여 표제 화합물 150 mg (최종 단계 수율: 37 %)을 얻었다.300 mg (0.76 mmol) of the compound obtained in step 4) was diluted with 5 mL of N, N -dimethylacetamide , and 1-acryloylpiperidin-4-yl 4-methylbenzenesulfonate ( WO2014116070 ) 353 mg ( 1.14 mmol) and potassium carbonate 210 mg (1.52 mmol) were added, followed by stirring at 70° C. for 16 hours. After the reaction was completed, the resulting reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure, and the obtained residue was separated by column chromatography (dichloromethane: methanol = 20: 1 (volume ratio)), and the title compound 150 mg (final step yield: 37%).
1H-NMR (300MHz, DMSO-d6): δ 9.57 (bs, 1H), 8.52 (s, 1H), 8.36 (m, 2H), 8.19 (m, 1H), 7.96 (s, 1H), 7.87 (m, 1H), 7.44 (m, 1H), 7.35 (m, 3H), 6.88 (m, 1H), 6.14 (m, 1H), 5.70 (m, 1H), 4.84 (m, 1H), 3.94 (s, 3H), 3.83 (m, 2H), 3.52 (m, 2H), 2.01 (m, 2H), 1.70 (m, 2H). 1 H-NMR (300MHz, DMSO-d 6 ): δ 9.57 (bs, 1H), 8.52 (s, 1H), 8.36 (m, 2H), 8.19 (m, 1H), 7.96 (s, 1H), 7.87 (m, 1H), 7.44 (m, 1H), 7.35 (m, 3H), 6.88 (m, 1H), 6.14 (m, 1H), 5.70 (m, 1H), 4.84 (m, 1H), 3.94 ( s, 3H), 3.83 (m, 2H), 3.52 (m, 2H), 2.01 (m, 2H), 1.70 (m, 2H).
MS (ESI+): m/z = 532.1 [M+H]+.MS (ESI + ): m/z = 532.1 [M+H] + .
상기 실시예 1의 방법과 동일하거나 유사한 방법으로 하기 표 1 에 나타낸 실시예 2 내지 실시예 17의 화합물을 각각 제조하였다.The compounds of Examples 2 to 17 shown in Table 1 below were prepared by the same or similar method as the method of Example 1.
실시예Example 구조식constitutional formula 명칭 / 분석 데이터Name / Analysis data
1One
Figure PCTKR2020008312-appb-I000008
Figure PCTKR2020008312-appb-I000008
 		1-(4-((4-((3-클로로-4-(피리딘-3-일옥시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온1-(4-((4-((3-chloro-4-(pyridin-3-yloxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl ) Prop-2-en-1-one
1H-NMR (300MHz, DMSO-d6): δ 9.57 (bs, 1H), 8.52 (s, 1H), 8.36 (m, 2H), 8.19 (m, 1H), 7.96 (s, 1H), 7.87 (m, 1H), 7.44 (m, 1H), 7.35 (m, 3H), 6.88 (m, 1H), 6.14 (m, 1H), 5.70 (m, 1H), 4.84 (m, 1H), 3.94 (s, 3H), 3.83 (m, 2H), 3.52 (m, 2H), 2.01 (m, 2H), 1.70 (m, 2H).MS (ESI+): m/z = 532.1 [M+H]+. 1 H-NMR (300MHz, DMSO-d 6 ): δ 9.57 (bs, 1H), 8.52 (s, 1H), 8.36 (m, 2H), 8.19 (m, 1H), 7.96 (s, 1H), 7.87 (m, 1H), 7.44 (m, 1H), 7.35 (m, 3H), 6.88 (m, 1H), 6.14 (m, 1H), 5.70 (m, 1H), 4.84 (m, 1H), 3.94 ( s, 3H), 3.83 (m, 2H), 3.52 (m, 2H), 2.01 (m, 2H), 1.70 (m, 2H).MS (ESI + ): m/z = 532.1 [M+H] + .
22
Figure PCTKR2020008312-appb-I000009
Figure PCTKR2020008312-appb-I000009
 		(1-(4-((7-메톡시-4-((3-메틸-4-((6-메틸피리딘-3-일)옥시)페닐)아미노)퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온(1-(4-((7-methoxy-4-((3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)quinazolin-6-yl)oxy)pi Peridin-1-yl)prop-2-en-1-one
1H-NMR (300MHz, DMSO-d6): δ 9.42 (bs, 1H), 8.43 (s, 1H), 8.17 (m, 1H), 7.95 (s, 1H), 7.68 (m, 2H), 7.25 (m, 3H), 6.98 (m, 1H), 6.88 (m, 1H), 6.14 (m, 1H), 5.70 (m, 1H), 4.82 (m, 1H), 3.93 (s, 3H), 3.89 (m, 2H), 3.50 (m, 2H), 2.43 (s, 3H), 2.20 (s, 3H), 2.00 (m, 2H), 1.69 (m, 2H).MS (ESI+): m/z = 526.2 [M+H]+. 1 H-NMR (300MHz, DMSO-d 6 ): δ 9.42 (bs, 1H), 8.43 (s, 1H), 8.17 (m, 1H), 7.95 (s, 1H), 7.68 (m, 2H), 7.25 (m, 3H), 6.98 (m, 1H), 6.88 (m, 1H), 6.14 (m, 1H), 5.70 (m, 1H), 4.82 (m, 1H), 3.93 (s, 3H), 3.89 ( m, 2H), 3.50 (m, 2H), 2.43 (s, 3H), 2.20 (s, 3H), 2.00 (m, 2H), 1.69 (m, 2H).MS (ESI + ): m/z = 526.2 [M+H] + .
33
Figure PCTKR2020008312-appb-I000010
Figure PCTKR2020008312-appb-I000010
 		1-(4-((4-((3-클로로-4-(4-플루오로페녹시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온1-(4-((4-((3-chloro-4-(4-fluorophenoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl ) Prop-2-en-1-one
1H-NMR (300MHz, DMSO-d6): δ 9.51 (bs, 1H), 8.50 (s, 1H), 8.14 (m, 1H), 7.94 (s, 1H), 7.80 (m, 1H), 7.25 (m, 4H), 7.03 (m, 2H), 6.88 (m, 1H), 6.13 (m, 1H), 5.69 (m, 1H), 4.82 (m, 1H), 3.93 (s, 3H), 3.86 (m, 2H), 3.51 (m, 2H), 2.00 (m, 2H), 1.70 (m, 2H).MS (ESI+): m/z = 549.2 [M+H]+. 1 H-NMR (300MHz, DMSO-d 6 ): δ 9.51 (bs, 1H), 8.50 (s, 1H), 8.14 (m, 1H), 7.94 (s, 1H), 7.80 (m, 1H), 7.25 (m, 4H), 7.03 (m, 2H), 6.88 (m, 1H), 6.13 (m, 1H), 5.69 (m, 1H), 4.82 (m, 1H), 3.93 (s, 3H), 3.86 ( m, 2H), 3.51 (m, 2H), 2.00 (m, 2H), 1.70 (m, 2H). MS (ESI + ): m/z = 549.2 [M+H] + .
44
Figure PCTKR2020008312-appb-I000011
Figure PCTKR2020008312-appb-I000011
 		1-(4-((4-((3-플루오로-4-(4-플루오로페녹시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온1-(4-((4-((3-fluoro-4-(4-fluorophenoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1- Day) prop-2-en-1-one
1H-NMR (300MHz, DMSO-d6): δ 9.56 (s, 1H), 8.53 (s, 1H), 8.04 (m, 1H), 7.98 (s, 1H), 7.62 (m, 1H), 7.27 (m, 4H), 7.06 (m, 2H), 6.86 (m, 1H), 6.16 (m, 1H), 5.71 (m, 1H), 4.81 (m, 1H), 3.96 (s, 3H), 3.87 (m, 2H), 3.52 (m, 2H), 2.02 (m, 2H), 1.72 (m, 2H).MS (ESI+): m/z = 533.2 [M+H]+. 1 H-NMR (300MHz, DMSO-d 6 ): δ 9.56 (s, 1H), 8.53 (s, 1H), 8.04 (m, 1H), 7.98 (s, 1H), 7.62 (m, 1H), 7.27 (m, 4H), 7.06 (m, 2H), 6.86 (m, 1H), 6.16 (m, 1H), 5.71 (m, 1H), 4.81 (m, 1H), 3.96 (s, 3H), 3.87 ( m, 2H), 3.52 (m, 2H), 2.02 (m, 2H), 1.72 (m, 2H). MS (ESI + ): m/z = 533.2 [M+H] + .
55
Figure PCTKR2020008312-appb-I000012
Figure PCTKR2020008312-appb-I000012
 		1-(4-((4-((3-클로로-4-((6-메틸피리딘-3-일)옥시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온1-(4-((4-((3-chloro-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperi Din-1-yl)prop-2-en-1-one
1H-NMR (300MHz, DMSO-d6): δ 9.54 (s, 1H), 8.52 (s, 1H), 8.22 (d, 2H), 7.96 (s, 1H), 7.83 (m, 1H), 7.28 (m, 2H), 7.21 (m, 2H), 6.89 (m, 1H), 6.14 (d, 1H), 5.70 (d, 1H), 4.82 (m, 1H), 3.95 (s, 3H), 3.86 (m, 2H), 3.51 (m, 2H), 2.45 (s, 3H), 2.01 (m, 2H), 1.72 (m, 2H).MS (ESI+): m/z = 546.5 [M+H]+. 1 H-NMR (300MHz, DMSO-d 6 ): δ 9.54 (s, 1H), 8.52 (s, 1H), 8.22 (d, 2H), 7.96 (s, 1H), 7.83 (m, 1H), 7.28 (m, 2H), 7.21 (m, 2H), 6.89 (m, 1H), 6.14 (d, 1H), 5.70 (d, 1H), 4.82 (m, 1H), 3.95 (s, 3H), 3.86 ( m, 2H), 3.51 (m, 2H), 2.45 (s, 3H), 2.01 (m, 2H), 1.72 (m, 2H).MS (ESI + ): m/z = 546.5 [M+H] + .
66
Figure PCTKR2020008312-appb-I000013
Figure PCTKR2020008312-appb-I000013
 		1-(4-((4-((3-클로로-4-(피리딘-4-일옥시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온1-(4-((4-((3-chloro-4-(pyridin-4-yloxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl ) Prop-2-en-1-one
1H-NMR (300MHz, DMSO-d6): δ 9.74 (s, 1H), 8.59 (s, 1H), 8.31 (m, 1H), 8.04 (m, 2H), 7.75 (m, 2H), 7.65 (m, 1H), 7.29 (s, 1H), 6.85 (m, 1H), 6.23 (m, 2H), 6.10 (m, 1H), 5.68 (m, 1H), 4.84 (m, 1H), 3.97 (s, 3H), 3.89 (m, 2H), 3.55 (m, 2H), 2.03 (m, 2H), 1.73 (m, 2H).MS (ESI+): m/z = 532.2 [M+H]+. 1 H-NMR (300MHz, DMSO-d 6 ): δ 9.74 (s, 1H), 8.59 (s, 1H), 8.31 (m, 1H), 8.04 (m, 2H), 7.75 (m, 2H), 7.65 (m, 1H), 7.29 (s, 1H), 6.85 (m, 1H), 6.23 (m, 2H), 6.10 (m, 1H), 5.68 (m, 1H), 4.84 (m, 1H), 3.97 ( s, 3H), 3.89 (m, 2H), 3.55 (m, 2H), 2.03 (m, 2H), 1.73 (m, 2H).MS (ESI + ): m/z = 532.2 [M+H] + .
77
Figure PCTKR2020008312-appb-I000014
Figure PCTKR2020008312-appb-I000014
 		1-(4-((4-((3-클로로-4-((6-플루오로피리딘-3-일)옥시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온1-(4-((4-((3-chloro-4-((6-fluoropyridin-3-yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)pi Peridin-1-yl)prop-2-en-1-one
1H-NMR (300MHz, DMSO-d6): δ 9.55 (s, 1H), 8.53 (s, 1H), 8.19 (s, 1H), 8.01 (m, 1H), 7.97 (m, 1H), 7.82 (m, 1H), 7.64 (m, 1H), 7.26 (m, 3H), 6.86 (m, 1H), 6.15 (m, 1H), 5.71 (m, 1H), 4.83 (m, 1H), 3.96 (s, 3H), 3.88 (m, 2H), 3.54 (m, 2H), 2.09 (m, 2H), 1.72 (m, 2H).MS (ESI+): m/z = 550.2 [M+H]+. 1 H-NMR (300MHz, DMSO-d 6 ): δ 9.55 (s, 1H), 8.53 (s, 1H), 8.19 (s, 1H), 8.01 (m, 1H), 7.97 (m, 1H), 7.82 (m, 1H), 7.64 (m, 1H), 7.26 (m, 3H), 6.86 (m, 1H), 6.15 (m, 1H), 5.71 (m, 1H), 4.83 (m, 1H), 3.96 ( s, 3H), 3.88 (m, 2H), 3.54 (m, 2H), 2.09 (m, 2H), 1.72 (m, 2H).MS (ESI + ): m/z = 550.2 [M+H] + .
88
Figure PCTKR2020008312-appb-I000015
Figure PCTKR2020008312-appb-I000015
 		1-(4-((4-((3-클로로-4-((5-플루오로피리딘-2-일)옥시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온1-(4-((4-((3-chloro-4-((5-fluoropyridin-2-yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)pi Peridin-1-yl)prop-2-en-1-one
1H-NMR (300MHz, DMSO-d6): δ 9.55 (s, 1H), 8.51 (s, 1H), 8.13 (m, 2H), 8.09 (s, 1H), 7.89 (m, 2H), 7.35 (d, 1H), 7.25 (s, 1H), 7.20 (m, 1H), 6.89 (m, 1H), 6.15 (d, 1H), 5.70 (d, 1H), 4.83 (m, 1H), 3.97 (s, 3H), 3.89 (m, 2H), 3.52 (m, 2H), 2.02 (m, 2H), 1.71 (m, 2H).MS (ESI+): m/z = 550.2 [M+H]+. 1 H-NMR (300MHz, DMSO-d 6 ): δ 9.55 (s, 1H), 8.51 (s, 1H), 8.13 (m, 2H), 8.09 (s, 1H), 7.89 (m, 2H), 7.35 (d, 1H), 7.25 (s, 1H), 7.20 (m, 1H), 6.89 (m, 1H), 6.15 (d, 1H), 5.70 (d, 1H), 4.83 (m, 1H), 3.97 ( s, 3H), 3.89 (m, 2H), 3.52 (m, 2H), 2.02 (m, 2H), 1.71 (m, 2H).MS (ESI + ): m/z = 550.2 [M+H] + .
99
Figure PCTKR2020008312-appb-I000016
Figure PCTKR2020008312-appb-I000016
 		1-(4-((4-((4-(4-클로로페녹시)-3-플루오로페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온1-(4-((4-((4-(4-chlorophenoxy)-3-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl ) Prop-2-en-1-one
1H-NMR (300MHz, DMSO-d6): δ 9.60 (bs, 1H), 8.52 (s, 1H), 8.08 (m, 1H), 7.95 (s, 1H), 7.63 (m, 1H), 7.44 (m, 2H), 7.31 (m, 2H), 7.02 (m, 2H), 6.88 (m, 1H), 6.13 (m, 1H), 5.69 (m, 1H), 4.82 (m, 1H), 3.94 (s, 3H), 3.87 (m, 2H), 3.51 (m, 2H), 1.99 (m, 2H), 1.70 (m, 2H);MS (ESI+): m/z = 549.2 [M+H]+. 1 H-NMR (300MHz, DMSO-d 6 ): δ 9.60 (bs, 1H), 8.52 (s, 1H), 8.08 (m, 1H), 7.95 (s, 1H), 7.63 (m, 1H), 7.44 (m, 2H), 7.31 (m, 2H), 7.02 (m, 2H), 6.88 (m, 1H), 6.13 (m, 1H), 5.69 (m, 1H), 4.82 (m, 1H), 3.94 ( s, 3H), 3.87 (m, 2H), 3.51 (m, 2H), 1.99 (m, 2H), 1.70 (m, 2H); MS (ESI + ): m/z = 549.2 [M+H] + .
1010
Figure PCTKR2020008312-appb-I000017
Figure PCTKR2020008312-appb-I000017
 		1-(4-((4-((3-클로로-4-((1-메틸-1H)-피라졸-4-일)옥시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온1-(4-((4-((3-chloro-4-((1-methyl-1 H )-pyrazol-4-yl)oxy)phenyl)amino)-7-methoxyquinazoline-6- Yl)oxy)piperidin-1-yl)prop-2-en-1-one
1H-NMR (300MHz, DMSO-d6): δ 9.46 (s, 1H), 8.46 (s, 1H), 8.04 (m, 1H), 7.93 (s, 1H), 7.74 (s, 1H), 7.65 (m, 1H) , 7.37 (s, 1H) , 7.22 (s, 1H), 7.11 (d, 1H), 6.82 (m, 1H), 6.13 (m, 1H) , 5.66 (m, 1H), 4.80 (m, 1H), 3.93 (s, 3H), 3.84 (m, 2H), 3.80 (s, 3H), 3.56 (m,2H), 2.00 (m, 2H), 1.68 (m, 2H).MS (ESI+): m/z = 535.2 [M+H]+. 1 H-NMR (300MHz, DMSO-d 6 ): δ 9.46 (s, 1H), 8.46 (s, 1H), 8.04 (m, 1H), 7.93 (s, 1H), 7.74 (s, 1H), 7.65 (m, 1H), 7.37 (s, 1H), 7.22 (s, 1H), 7.11 (d, 1H), 6.82 (m, 1H), 6.13 (m, 1H), 5.66 (m, 1H), 4.80 ( m, 1H), 3.93 (s, 3H), 3.84 (m, 2H), 3.80 (s, 3H), 3.56 (m,2H), 2.00 (m, 2H), 1.68 (m, 2H).MS (ESI) + ): m/z = 535.2 [M+H] + .
1111
Figure PCTKR2020008312-appb-I000018
Figure PCTKR2020008312-appb-I000018
 		1-(4-((4-((3-클로로-4-((1-메틸-1H)-피라졸-5-일)옥시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온1-(4-((4-((3-chloro-4-((1-methyl-1 H )-pyrazol-5-yl)oxy)phenyl)amino)-7-methoxyquinazoline-6- Yl)oxy)piperidin-1-yl)prop-2-en-1-one
1H-NMR (300MHz, DMSO-d6): δ 9.56 (s, 1H), 8.52 (s, 1H), 8.18 (s, 1H), 7.96 (s, 1H), 7.83 (d, 1H), 7.34 (m, 2H), 7.25 (s, 1H), 6.89 (m, 1H), 6.14 (d, 1H), 5.70 (d, 1H), 5.60 (s, 1H), 4.83 (m, 1H), 3.95 (s, 3H), 3.86 (m, 2H), 3.73 (s, 3H), 3.51 (m, 2H), 2.08 (m, 2H), 1.70 (m, 2H).MS (ESI+): m/z = 535.2 [M+H]+. 1 H-NMR (300MHz, DMSO-d 6 ): δ 9.56 (s, 1H), 8.52 (s, 1H), 8.18 (s, 1H), 7.96 (s, 1H), 7.83 (d, 1H), 7.34 (m, 2H), 7.25 (s, 1H), 6.89 (m, 1H), 6.14 (d, 1H), 5.70 (d, 1H), 5.60 (s, 1H), 4.83 (m, 1H), 3.95 ( s, 3H), 3.86 (m, 2H), 3.73 (s, 3H), 3.51 (m, 2H), 2.08 (m, 2H), 1.70 (m, 2H).MS (ESI + ): m/z = 535.2 [M+H] + .
1212
Figure PCTKR2020008312-appb-I000019
Figure PCTKR2020008312-appb-I000019
 		1-(4-((4-((3-클로로-4-((1-메틸-3-(트라이플루오로메틸)-1H-피라졸-5-일)옥시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온1-(4-((4-((3-chloro-4-((1-methyl-3-(trifluoromethyl)-1 H -pyrazol-5-yl)oxy)phenyl)amino)-7 -Methoxyquinazoline-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one
1H-NMR (300MHz, DMSO-d6): δ 9.59 (s, 1H), 8.55 (s, 1H), 8.24 (m, 1H), 7.97 (s, 1H), 7.87 (m, 1H), 7.49 (d, 1H), 7.27 (s, 1H), 6.86 (m, 1H), 6.15 (m, 2H), 5.71 (m, 1H), 4.82 (m, 1H), 3.96 (s, 3H), 3.86 (s, 3H), 3.84 (m, 2H), 3.55 (m, 2H), 2.03 (m, 2H), 1.73 (m,2H).MS (ESI+): m/z = 603.2 [M+H]+. 1 H-NMR (300MHz, DMSO-d 6 ): δ 9.59 (s, 1H), 8.55 (s, 1H), 8.24 (m, 1H), 7.97 (s, 1H), 7.87 (m, 1H), 7.49 (d, 1H), 7.27 (s, 1H), 6.86 (m, 1H), 6.15 (m, 2H), 5.71 (m, 1H), 4.82 (m, 1H), 3.96 (s, 3H), 3.86 ( s, 3H), 3.84 (m, 2H), 3.55 (m, 2H), 2.03 (m, 2H), 1.73 (m,2H).MS (ESI + ): m/z = 603.2 [M+H] + .
1313
Figure PCTKR2020008312-appb-I000020
Figure PCTKR2020008312-appb-I000020
 		1-(4-((4-((4-(4-플루오로페녹시)-3-메틸페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온1-(4-((4-((4-(4-fluorophenoxy)-3-methylphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl) Prop-2-en-1-one
1H-NMR (300MHz, DMSO-d6): δ 9.40 (s, 1H), 8.44 (s, 1H), 7.95 (s, 1H), 7.66 (m, 2H), 7.22 (m, 3H), 6.96 (m, 3H), 6.89 (m, 1H), 6.14 (d, 1H), 5.70 (d, 1H), 4.81 (m, 1H), 3.94 (s, 3H), 3.86 (m, 2H), 3.50 (m, 2H), 2.20 (s, 3H), 2.04 (m, 2H), 1.72 (m, 2H).MS (ESI+): m/z = 529.3 [M+H]+. 1 H-NMR (300MHz, DMSO-d 6 ): δ 9.40 (s, 1H), 8.44 (s, 1H), 7.95 (s, 1H), 7.66 (m, 2H), 7.22 (m, 3H), 6.96 (m, 3H), 6.89 (m, 1H), 6.14 (d, 1H), 5.70 (d, 1H), 4.81 (m, 1H), 3.94 (s, 3H), 3.86 (m, 2H), 3.50 ( m, 2H), 2.20 (s, 3H), 2.04 (m, 2H), 1.72 (m, 2H). MS (ESI + ): m/z = 529.3 [M+H] + .
1414
Figure PCTKR2020008312-appb-I000021
Figure PCTKR2020008312-appb-I000021
 		1-(4-((4-((4-(4-플루오로페녹시)-3-(트라이플루오로메틸)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온1-(4-((4-((4-(4-fluorophenoxy)-3-(trifluoromethyl)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperi Din-1-yl)prop-2-en-1-one
1H-NMR (300MHz, DMSO-d6): δ 9.62 (s, 1H), 8.49 (s, 1H), 8.24 (m, 1H), 8.12 (m, 1H), 7.96 (s, 1H), 7.29 (m, 3H), 7.14 (m, 3H), 6.89 (m, 1H), 6.14 (d, 1H), 5.70 (d, 1H), 4.81 (m, 1H), 3.95 (s, 3H), 3.88 (m, 2H), 3.51 (m, 2H), 2.01 (m, 2H), 1.71 (m, 2H).MS (ESI+): m/z = 583.3 [M+H]+. 1 H-NMR (300MHz, DMSO-d 6 ): δ 9.62 (s, 1H), 8.49 (s, 1H), 8.24 (m, 1H), 8.12 (m, 1H), 7.96 (s, 1H), 7.29 (m, 3H), 7.14 (m, 3H), 6.89 (m, 1H), 6.14 (d, 1H), 5.70 (d, 1H), 4.81 (m, 1H), 3.95 (s, 3H), 3.88 ( m, 2H), 3.51 (m, 2H), 2.01 (m, 2H), 1.71 (m, 2H). MS (ESI + ): m/z = 583.3 [M+H] + .
1515
Figure PCTKR2020008312-appb-I000022
Figure PCTKR2020008312-appb-I000022
 		1-(4-((4-((3-클로로-4-(3,4-다이플루오로페녹시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온1-(4-((4-((3-chloro-4-(3,4-difluorophenoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidine- 1-yl)prop-2-en-1-one
1H-NMR (300MHz, DMSO-d6): δ 9.57 (s, 1H), 8.53 (s, 1H), 8.19 (s, 1H), 7.97 (s, 1H), 7.83 (m, 1H), 7.47 (m, 1H), 7.29 (m, 2H), 7.13 (m, 1H), 6.90 (m, 1H), 6.78 (m, 1H), 6.15 (m, 1H), 5.72 (m, 1H), 4.84 (m, 1H), 3.96 (s, 3H), 3.85 (m, 2H), 3.55 (m, 2H), 2.02 (m, 2H), 1.73 (m, 2H).MS (ESI+): m/z = 603.2 [M+H]+. 1 H-NMR (300MHz, DMSO-d 6 ): δ 9.57 (s, 1H), 8.53 (s, 1H), 8.19 (s, 1H), 7.97 (s, 1H), 7.83 (m, 1H), 7.47 (m, 1H), 7.29 (m, 2H), 7.13 (m, 1H), 6.90 (m, 1H), 6.78 (m, 1H), 6.15 (m, 1H), 5.72 (m, 1H), 4.84 ( m, 1H), 3.96 (s, 3H), 3.85 (m, 2H), 3.55 (m, 2H), 2.02 (m, 2H), 1.73 (m, 2H).MS (ESI + ): m/z = 603.2 [M+H] + .
1616
Figure PCTKR2020008312-appb-I000023
Figure PCTKR2020008312-appb-I000023
 		1-(4-((4-((3-클로로-4-(4-클로로페녹시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온1-(4-((4-((3-chloro-4-(4-chlorophenoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl) Prop-2-en-1-one
1H-NMR (300MHz, DMSO-d6): δ 9.56 (s, 1H), 8.53 (s, 1H), 8.17 (m, 1H), 7.97 (s, 1H), 7.85 (m, 1H), 7.43 (m, 2H), 7.26 (m, 2H), 6.98 (m, 2H), 6.90 (m, 1H), 6.15 (m, 1H), 5.71 (m, 1H), 4.82 (m, 1H), 3.96 (s, 3H), 3.89 (m, 2H), 3.53 (m, 2H), 2.02 (m, 2H), 1.74 (m, 2H).MS (ESI+): m/z = 565.1 [M+H]+. 1 H-NMR (300MHz, DMSO-d 6 ): δ 9.56 (s, 1H), 8.53 (s, 1H), 8.17 (m, 1H), 7.97 (s, 1H), 7.85 (m, 1H), 7.43 (m, 2H), 7.26 (m, 2H), 6.98 (m, 2H), 6.90 (m, 1H), 6.15 (m, 1H), 5.71 (m, 1H), 4.82 (m, 1H), 3.96 ( s, 3H), 3.89 (m, 2H), 3.53 (m, 2H), 2.02 (m, 2H), 1.74 (m, 2H).MS (ESI + ): m/z = 565.1 [M+H] + .
1717
Figure PCTKR2020008312-appb-I000024
Figure PCTKR2020008312-appb-I000024
 		1-(4-((4-((3-클로로-4-(4-(트라이플루오로메틸)페녹시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온1-(4-((4-((3-chloro-4-(4-(trifluoromethyl)phenoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidine -1-yl)prop-2-en-1-one
1H-NMR (300MHz, DMSO-d6): δ 9.58 (s, 1H), 8.54 (s, 1H), 8.22 (s, 1H), 7.97 (s, 1H), 7.89 (d, 1H), 7.76 (m, 2H), 7.39 (d, 1H), 7.26 (s, 1H), 7.11 (m, 2H), 6.89 (m, 1H), 6.15 (d, 1H), 5.70 (d, 1H), 4.83 (m, 1H), 3.95 (s, 3H), 3.89 (m, 2H), 3.52 (m, 2H), 2.01 (m, 2H), 1.72 (m, 2H).MS (ESI+): m/z = 599.2 [M+H]+. 1 H-NMR (300MHz, DMSO-d 6 ): δ 9.58 (s, 1H), 8.54 (s, 1H), 8.22 (s, 1H), 7.97 (s, 1H), 7.89 (d, 1H), 7.76 (m, 2H), 7.39 (d, 1H), 7.26 (s, 1H), 7.11 (m, 2H), 6.89 (m, 1H), 6.15 (d, 1H), 5.70 (d, 1H), 4.83 ( m, 1H), 3.95 (s, 3H), 3.89 (m, 2H), 3.52 (m, 2H), 2.01 (m, 2H), 1.72 (m, 2H).MS (ESI + ): m/z = 599.2 [M+H] + .
실시예Example 18: 118: 1 -(4-((4-((3--(4-((4-((3- 클로로Chloro -4-(-4-( 싸이아졸Thiazole -2--2- 일옥시Oxy )페닐)아미노)-7-)Phenyl)amino)-7- 메Me 톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온의 제조Preparation of oxyquinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one
Figure PCTKR2020008312-appb-I000025
Figure PCTKR2020008312-appb-I000025
단계 1) 3-Step 1) 3- 클로로Chloro -4-(-4-( 싸이아졸Thiazole -2--2- 일옥시Oxy )아닐린의 제조) Preparation of aniline
4-아미노-2-클로로페놀 2.8 g (19.5 mmol)과 2-브로모싸이아졸 3.0 g (18.3 mmol)을 N, N-다이메틸아세트아마이드 30 mL에 묽히고, 터트-부톡시칼륨 2.4 g (21.4 mmol)을 가한 후 질소 가스 하 150℃에서 5시간 동안 교반시켰다. 반응이 완결된 후 결과의 반응 혼합물을 에틸 아세테이트에 묽히고 포화염수로 세척하였다. 결과로 분리된 유기층을 무수황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하였다. 결과로 얻어진 잔사를 컬럼 크로마토그래피 (헥산 : 에틸 아세테이트 = 2 : 1(부피비))로 분리하여 표제 화합물 1.2 g (수율: 27 %)을 얻었다. 2.8 g (19.5 mmol) of 4-amino-2-chlorophenol and 3.0 g (18.3 mmol) of 2-bromothiazole were diluted in 30 mL of N, N -dimethylacetamide, and 2.4 g of tert-butoxy potassium ( 21.4 mmol) was added and then stirred at 150° C. for 5 hours under nitrogen gas. After the reaction was completed, the resulting reaction mixture was diluted with ethyl acetate and washed with saturated brine. The resulting separated organic layer was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 2: 1 (volume ratio)) to give 1.2 g (yield: 27%) of the title compound.
1H-NMR (300MHz, CDCl3): δ 7.20 (d, 1H), 7.14 (d, 1H), 6.78 (m, 2H), 6.61 (m, 1H), 3.75 (s, 2H). 1 H-NMR (300 MHz, CDCl 3 ): δ 7.20 (d, 1H), 7.14 (d, 1H), 6.78 (m, 2H), 6.61 (m, 1H), 3.75 (s, 2H).
단계 2) 1-(4-((4-((3-Step 2) 1-(4-((4-((3- 클로로Chloro -4-(-4-( 싸이아졸Thiazole -2--2- 일옥시Oxy )페닐)아미노)-7-)Phenyl)amino)-7- 메톡시퀴나졸린Methoxyquinazoline -6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온의 제조Preparation of -6-yl)oxy)piperidin-1-yl)prop-2-en-1-one
상기 실시예 1의 단계 2)에서 3-클로로-4-(피리딘-3-일옥시)아닐린 대신 상기 단계 1)에서 제조된 화합물을 사용하는 것을 제외하고는, 상기 실시예 1의 단계 3), 4), 5)의 공정을 순차적으로 수행하여 표제 화합물 11 mg (최종 단계 수율: 4 %)을 얻었다.Step 3) of Example 1, except that the compound prepared in Step 1) was used instead of 3-chloro-4-(pyridin-3-yloxy)aniline in Step 2) of Example 1, Steps 4) and 5) were sequentially performed to obtain 11 mg of the title compound (final step yield: 4%).
1H-NMR (300MHz, DMSO-d6): δ 9.60 (s, 1H), 8.55 (s, 1H), 8.20 (s, 1H), 7.97 (s, 1H), 7.89 (m, 1H), 7.56 (d, 1H), 7.27 (m, 3H), 6.89 (m, 1H), 6.16 (m, 1H), 5.72 (m, 1H), 4.84 (m, 1H), 3.96 (s, 3H), 3.85 (m, 2H), 3.51 (m, 2H), 2.02 (m, 2H), 1.70 (m, 2H). 1 H-NMR (300MHz, DMSO-d 6 ): δ 9.60 (s, 1H), 8.55 (s, 1H), 8.20 (s, 1H), 7.97 (s, 1H), 7.89 (m, 1H), 7.56 (d, 1H), 7.27 (m, 3H), 6.89 (m, 1H), 6.16 (m, 1H), 5.72 (m, 1H), 4.84 (m, 1H), 3.96 (s, 3H), 3.85 ( m, 2H), 3.51 (m, 2H), 2.02 (m, 2H), 1.70 (m, 2H).
MS (ESI+): m/z = 538.1 [M+H]+.MS (ESI + ): m/z = 538.1 [M+H] + .
실시예Example 19: 119: 1 -(4-((4-((3--(4-((4-((3- 클로로Chloro -4-(4--4-(4- 플루오로페녹시Fluorophenoxy )페닐)아미노))Phenyl)amino) 퀴나졸린Quinazoline -6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온의 제조Preparation of -6-yl)oxy)piperidin-1-yl)prop-2-en-1-one
Figure PCTKR2020008312-appb-I000026
Figure PCTKR2020008312-appb-I000026
단계 1) 3-Step 1) 3- 클로로Chloro -4-(4--4-(4- 플루오로페녹시Fluorophenoxy )아닐린의 제조) Preparation of aniline
상기 실시예 1의 단계 1)에서 3-하이드록시피리딘 대신 4-플루오로페놀을 사용하는 것을 제외하고는 실시예 1의 단계 1), 2)의 공정을 순차적으로 수행하여 표제 화합물 10.3 g (수율: 79 %)을 얻었다. 10.3 g of the title compound (yield : 79%) was obtained.
1H-NMR (300MHz, DMSO-d6): δ 7.13 (m, 2H), 6.89 (d, 1H), 6.78 (m, 2H), 6.70 (s, 1H), 6.51 (m, 1H), 5.30 (s, 2H). 1 H-NMR (300MHz, DMSO-d 6 ): δ 7.13 (m, 2H), 6.89 (d, 1H), 6.78 (m, 2H), 6.70 (s, 1H), 6.51 (m, 1H), 5.30 (s, 2H).
단계 2) 1-(4-((4-((3-Step 2) 1-(4-((4-((3- 클로로Chloro -4-(4--4-(4- 플루오로페녹시Fluorophenoxy )페닐)아미노))Phenyl)amino) 퀴나졸린Quinazoline -6--6-
일)Work) 옥시Oxy )피페리딘-1-일)) Piperidin-1-yl) 프로프Prof -2-엔-1-온의 제조Preparation of -2-en-1-one
상기 실시예 1의 단계 3)에서 4-클로로-7-메톡시퀴나졸린-6-일 아세테이트 염산염 대신 4-클로로퀴나졸린-6-일 아세테이트 (WO2008033748)를 사용하고, 3-클로로-4-(피리딘-3-일옥시)아닐린 대신 상기 단계 1)에서 제조된 화합물을 사용하는 것을 제외하고는 실시예 1의 단계 3), 4), 5)의 공정을 순차적으로 수행하여 표제 화합물 26 mg (최종 단계 수율: 5 %)을 얻었다. In step 3) of Example 1, 4- chloroquinazolin -6-yl acetate ( WO2008033748 ) was used instead of 4-chloro-7-methoxyquinazolin-6-yl acetate hydrochloride, and 3-chloro-4-( Except for using the compound prepared in step 1) instead of pyridin-3-yloxy) aniline, the steps 3), 4), and 5) of Example 1 were sequentially performed to obtain 26 mg of the title compound (final Step yield: 5%) was obtained.
1H-NMR (300MHz, DMSO-d6): δ 9.64 (s, 1H), 8.48 (s, 1H), 8.18 (m, 1H), 7.96 (s, 1H), 7.80 (m, 1H), 7.76 (m, 1H), 7.60 (m, 1H), 7.22 (m, 3H), 7.00 (m, 2H), 6.89 (m, 1H), 6.12 (m, 1H), 5.68 (m, 1H), 4.86 (m, 1H), 3.86 (m, 2H), 3.50 (m, 2H), 2.05 (m, 2H), 1.65 (m, 2H). 1 H-NMR (300MHz, DMSO-d 6 ): δ 9.64 (s, 1H), 8.48 (s, 1H), 8.18 (m, 1H), 7.96 (s, 1H), 7.80 (m, 1H), 7.76 (m, 1H), 7.60 (m, 1H), 7.22 (m, 3H), 7.00 (m, 2H), 6.89 (m, 1H), 6.12 (m, 1H), 5.68 (m, 1H), 4.86 ( m, 1H), 3.86 (m, 2H), 3.50 (m, 2H), 2.05 (m, 2H), 1.65 (m, 2H).
MS (ESI+): m/z = 520.2 [M+H]+.MS (ESI + ): m/z = 520.2 [M+H] + .
실시예Example 20: 120: 1 -(4-((4-((3--(4-((4-((3- 클로로Chloro -4-(4--4-(4- 사이클로프로필페녹시Cyclopropylphenoxy )페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온 의 제조)Phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one
Figure PCTKR2020008312-appb-I000027
Figure PCTKR2020008312-appb-I000027
단계 1) 1-(4-Step 1) 1-(4- 브로모페녹시Bromophenoxy )-2-)-2- 클로로Chloro -4--4- 나이트로벤젠의Nitrobenzene 제조 Produce
상기 실시예 1의 단계 1)에서 3-하이드록시피리딘 대신 4-브로모페놀을 사용하는 것을 제외하고는 상기 실시예 1과 동일한 공정을 수행하여 표제 화합물 5.2 g (수율: 93 %)을 얻었다. Except for using 4-bromophenol instead of 3-hydroxypyridine in step 1) of Example 1, the same procedure as in Example 1 was performed to obtain 5.2 g (yield: 93%) of the title compound.
1H-NMR (300MHz, CDCl3): δ 8.38 (m, 1H), 8.07 (m, 1H), 7.55 (m, 2H), 6.97 (m, 2H), 6.92 (m, 1H). 1 H-NMR (300 MHz, CDCl 3 ): δ 8.38 (m, 1H), 8.07 (m, 1H), 7.55 (m, 2H), 6.97 (m, 2H), 6.92 (m, 1H).
단계 2) 2-Step 2) 2- 클로로Chloro -1-(4--1-(4- 사이클로프로필페녹시Cyclopropylphenoxy )-4-)-4- 나이트로벤젠의Nitrobenzene 제조 Produce
상기 단계 1)에서 제조된 화합물 2.4 g (7.3 mmol)과 사이클로프로필 보론산 816 mg (9.5 mmol)을 톨루엔 : 증류수 (4: 1 (부피비)) 혼합용매 24 mL로 묽히고 팔라듐(II)아세테이트 168 mg (0.73 mmol), 트라이사이클로헥실포스핀 204 mg (0.73 mmol)과 제삼인산칼륨 4.7 g (9.5 mmol)을 넣고 100℃ 에서 12시간 동안 교반시켰다. 반응이 완결되면 결과의 반응 혼합물을 상온으로 식히고 셀라이트 충진된 필터로 여과한 후, 여과액을 에틸아세테이트로 묽히고 물로 세척하였다. 결과로 분리된 유기층을 무수황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하여 표제 화합물 2.0 g (수율: 95 %)을 얻었다.2.4 g (7.3 mmol) of the compound prepared in step 1) and 816 mg (9.5 mmol) of cyclopropyl boronic acid were diluted with 24 mL of a mixed solvent of toluene: distilled water (4: 1 (volume ratio)), and palladium (II) acetate 168 mg (0.73 mmol), 204 mg (0.73 mmol) of tricyclohexylphosphine and 4.7 g (9.5 mmol) of tricyclohexylphosphine were added and stirred at 100°C for 12 hours. When the reaction was completed, the resulting reaction mixture was cooled to room temperature, filtered through a filter filled with Celite, and the filtrate was diluted with ethyl acetate and washed with water. The resulting separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure to obtain 2.0 g (yield: 95%) of the title compound.
1H-NMR (300MHz, CDCl3): δ 8.35 (m, 1H), 8.01 (m, 1H), 7.13 (m, 2H), 6.98 (m, 2H), 6.83 (m, 1H), 1.91 (m, 1H), 0.98 (m, 2H), 0.69 (m, 2H). 1 H-NMR (300MHz, CDCl 3 ): δ 8.35 (m, 1H), 8.01 (m, 1H), 7.13 (m, 2H), 6.98 (m, 2H), 6.83 (m, 1H), 1.91 (m , 1H), 0.98 (m, 2H), 0.69 (m, 2H).
단계 3) 1-(4-((4-((3-Step 3) 1-(4-((4-((3- 클로로Chloro -4-(4--4-(4- 사이클로프로필페녹시Cyclopropylphenoxy )페닐)아미노)-7-)Phenyl)amino)-7-
메톡시퀴나졸린Methoxyquinazoline -6-일)-6-days) 옥시Oxy )피페리딘-1-일)) Piperidin-1-yl) 프로프Prof -2-엔-1--2-en-1- 온 의Come 제조 Produce
상기 실시예 1의 단계 2)에서 3-(2-클로로-4-나이트로페녹시)피리딘 대신 상기 단계 2)에서 제조된 화합물을 사용하는 것을 제외하고는, 상기 실시예 1의 단계 2), 3), 4), 5)의 공정을 순차적으로 수행하여 표제 화합물 154 mg (최종 단계 수율: 43 %)을 얻었다. Step 2) of Example 1, except that the compound prepared in step 2) was used instead of 3-(2-chloro-4-nitrophenoxy) pyridine in step 2) of Example 1, Steps 3), 4) and 5) were sequentially performed to obtain 154 mg (final step yield: 43%) of the title compound.
1H-NMR (300MHz, DMSO-d6): δ 9.50 (s, 1H), 8.49 (s, 1H), 8.11 (m, 1H), 7.94 (s, 1H), 7.72 (m, 1H), 7.22 (s, 1H), 7.08 (m, 3H), 6.85 (m, 3H), 6.12 (m, 1H), 5.69 (m, 1H), 4.78 (m, 1H), 3.93 (s, 3H), 3.87 (m, 2H), 3.56 (m, 2H), 2.05 (m, 2H), 1.90 (m, 1H), 1.67 (m, 2H), 0.91 (m, 2H), 0.61 (m, 2H). 1 H-NMR (300MHz, DMSO-d 6 ): δ 9.50 (s, 1H), 8.49 (s, 1H), 8.11 (m, 1H), 7.94 (s, 1H), 7.72 (m, 1H), 7.22 (s, 1H), 7.08 (m, 3H), 6.85 (m, 3H), 6.12 (m, 1H), 5.69 (m, 1H), 4.78 (m, 1H), 3.93 (s, 3H), 3.87 ( m, 2H), 3.56 (m, 2H), 2.05 (m, 2H), 1.90 (m, 1H), 1.67 (m, 2H), 0.91 (m, 2H), 0.61 (m, 2H).
MS (ESI+): m/z = 571.2 [M+H]+.MS (ESI + ): m/z = 571.2 [M+H] + .
실시예Example 21: 121: 1 -(3-((4-((3--(3-((4-((3- 클로로Chloro -4-(피리딘-3--4-(pyridin-3- 일옥시Oxy )페닐)아미노)-7-)Phenyl)amino)-7- 메톡시퀴나졸린Methoxyquinazoline -6-일)옥시)아제티딘-1-일)프로프-2-엔-1-온의 제조Preparation of -6-yl)oxy)azetidin-1-yl)prop-2-en-1-one
Figure PCTKR2020008312-appb-I000028
Figure PCTKR2020008312-appb-I000028
단계 1) Step 1) 터트Turt -부틸 3-((4-((3--Butyl 3-((4-((3- 클로로Chloro -4-(피리딘-3--4-(pyridin-3- 일옥시Oxy )페닐)아미노)-7-)Phenyl)amino)-7-
메톡시퀴나졸린Methoxyquinazoline -6-일)-6-days) 옥시Oxy )) 아제티딘Azetidine -1--One- 카복시레이트의Carboxylate 제조 Produce
상기 실시예 1의 단계 5)에서 1-아크릴로일피페리딘-4-일 4-메틸벤젠술포네이트 대신 터트-부틸 3-(토실옥시)아제티딘-1-카복시레이트 (WO2013170072)을 사용하는 것을 제외하고, 상기 실시예 1과 동일한 공정을 수행하여 표제 화합물 780 mg (수율: 56 %)을 얻었다. Using tert-butyl 3-(tosyloxy)azetidine-1-carboxylate ( WO2013170072 ) instead of 1-acryloylpiperidin-4-yl 4-methylbenzenesulfonate in step 5) of Example 1 Except, by performing the same process as in Example 1 to give the title compound 780 mg (yield: 56%).
1H-NMR (300MHz, DMSO-d6): δ 8.69 (s, 1H), 8.36 (m, 2H), 8.04 (s, 1H), 7.95 (m, 1H), 7.61 (m, 1H), 7.28 (m, 3H), 7.11 (m, 2H), 5.09 (m, 1H), 4.40 (m, 2H), 4.13 (m, 2H), 4.02 (s, 3H), 1.45 (s, 9H). 1 H-NMR (300MHz, DMSO-d 6 ): δ 8.69 (s, 1H), 8.36 (m, 2H), 8.04 (s, 1H), 7.95 (m, 1H), 7.61 (m, 1H), 7.28 (m, 3H), 7.11 (m, 2H), 5.09 (m, 1H), 4.40 (m, 2H), 4.13 (m, 2H), 4.02 (s, 3H), 1.45 (s, 9H).
단계 2) 6-(Step 2) 6-( 아제티딘Azetidine -3--3- 일옥시Oxy )-N-(3-)-N-(3- 클로로Chloro -4-(피리딘-3--4-(pyridin-3- 일옥시Oxy )페닐)-7- 메톡시퀴나졸린-4-아민의 제조)Phenyl)-7-methoxyquinazolin-4-amine Preparation
상기 단계 1)에서 제조된 화합물 150 mg (0.27 mmol)을 다이클로로메탄 3.0 mL에 묽히고 0℃ 로 냉각시킨 후, 트라이플루오로아세트산 1 mL (12.86 mmol)을 가한 후 상온에서 1시간 동안 교반시켰다. 반응이 완결된 후 결과의 반응혼합물을 감압 증류하여 용매를 제거한 후 클로로포름 : 2-아이소프로판올 (3 : 1(부피비)) 혼합용매로 묽히고 포화 중탄산나트륨 수용액과 증류수로 순차적으로 세척하였다. 결과로 분리된 유기층을 무수황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하여 표제 화합물 100 mg (수율: 81 %)을 얻었다.150 mg (0.27 mmol) of the compound prepared in step 1) was diluted in 3.0 mL of dichloromethane, cooled to 0°C, and 1 mL (12.86 mmol) of trifluoroacetic acid was added, followed by stirring at room temperature for 1 hour. . After the reaction was completed, the resulting reaction mixture was distilled under reduced pressure to remove the solvent, diluted with a mixed solvent of chloroform: 2-isopropanol (3:1 (volume ratio)), and washed sequentially with a saturated aqueous sodium bicarbonate solution and distilled water. The resulting separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure to obtain 100 mg (yield: 81%) of the title compound.
1H-NMR (300MHz, DMSO-d6): δ 9.56 (s, 1H), 8.52 (s, 1H), 8.34 (m, 2H), 8.14 (s, 1H), 7.80 (m, 1H), 7.52 (s, 1H), 7.44 (m, 1H), 7.40 (m, 1H), 7.29 (m, 3H), 5.18 (m, 1H), 4.18 (m, 2H), 3.96 (s, 3H), 3.76 (m, 2H). 1 H-NMR (300MHz, DMSO-d 6 ): δ 9.56 (s, 1H), 8.52 (s, 1H), 8.34 (m, 2H), 8.14 (s, 1H), 7.80 (m, 1H), 7.52 (s, 1H), 7.44 (m, 1H), 7.40 (m, 1H), 7.29 (m, 3H), 5.18 (m, 1H), 4.18 (m, 2H), 3.96 (s, 3H), 3.76 ( m, 2H).
단계 3) 1-(3-((4-((3-Step 3) 1-(3-((4-((3- 클로로Chloro -4-(피리딘-3--4-(pyridin-3- 일옥시Oxy )페닐)아미노)-7-)Phenyl)amino)-7- 메톡시퀴나졸린Methoxyquinazoline -6-일)옥시)아제티딘-1-일)프로프-2-엔-1-온의 제조Preparation of -6-yl)oxy)azetidin-1-yl)prop-2-en-1-one
상기 단계 2)에서 제조된 화합물 100 mg (0.22 mmol)과 탄산수소나트륨 36 mg (0.44 mmol) 을 테트라하이드로퓨란 2 mL 및 증류수 0.5 mL에 묽히고 아크릴로일 클로라이드 18 μL (0.22 mmol)를 0℃ 에서 천천히 가하여 30분 동안 교반시켰다. 반응이 완결된 후 결과의 반응혼합물을 클로로포름 : 2-아이소프로판올 (3 : 1(부피비)) 혼합용매로 묽히고 포화 중탄산나트륨 수용액으로 세척하였다. 결과로 분리된 유기층을 무수황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하여 얻어진 잔사를 컬럼 크로마토그래피 (클로로포름 : 메탄올 = 8 : 1(부피비))로 분리하여 표제 화합물 8 mg (최종 단계 수율: 7 %)을 얻었다.100 mg (0.22 mmol) of the compound prepared in step 2) and 36 mg (0.44 mmol) of sodium hydrogen carbonate were diluted in 2 mL of tetrahydrofuran and 0.5 mL of distilled water, and 18 μL (0.22 mmol) of acryloyl chloride was added at 0°C. Slowly added at and stirred for 30 minutes. After the reaction was completed, the resulting reaction mixture was diluted with a mixed solvent of chloroform:2-isopropanol (3:1 (volume ratio)) and washed with a saturated aqueous sodium bicarbonate solution. The resulting separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure, and the obtained residue was separated by column chromatography (chloroform: methanol = 8: 1 (volume ratio)), and the title compound 8 mg (final step yield: 7%) ).
1H-NMR (300MHz, DMSO-d6): δ 9.57 (s, 1H), 8.54 (s, 1H), 8.37 (m, 2H), 8.16 (s, 1H), 7.82 (m, 1H), 7.57 (s, 1H), 7.36 (m, 1H), 7.29 (m, 3H), 6.39 (m, 1H), 6.16 (m, 1H), 5.72 (m, 1H), 5.25 (m, 1H), 4.77 (m, 1H), 4.56 (m, 1H), 4.28 (m, 1H), 4.00 (m, 1H), 3.97 (s, 3H). 1 H-NMR (300MHz, DMSO-d 6 ): δ 9.57 (s, 1H), 8.54 (s, 1H), 8.37 (m, 2H), 8.16 (s, 1H), 7.82 (m, 1H), 7.57 (s, 1H), 7.36 (m, 1H), 7.29 (m, 3H), 6.39 (m, 1H), 6.16 (m, 1H), 5.72 (m, 1H), 5.25 (m, 1H), 4.77 ( m, 1H), 4.56 (m, 1H), 4.28 (m, 1H), 4.00 (m, 1H), 3.97 (s, 3H).
MS (ESI+): m/z = 504.1 [M+H]+. MS (ESI + ): m/z = 504.1 [M+H] + .
상기 실시예 21의 방법과 동일하거나 유사한 방법으로 하기 표 2에 나타낸 실시예 22 내지 실시예 26의 화합물을 각각 제조하였다. Compounds of Examples 22 to 26 shown in Table 2 below were prepared in the same or similar manner as in Example 21.
실시예Example 구조식constitutional formula 명칭 / 분석 데이터Name / Analysis data
2222
Figure PCTKR2020008312-appb-I000029
Figure PCTKR2020008312-appb-I000029
 		1-(3-((7-메톡시-4-((3-메틸-4-((6-메틸피리딘-3-일)옥시)페닐)아미노)퀴나졸린-6-일)옥시)아제티딘-1-일)프로프-2-엔-1-온1-(3-((7-methoxy-4-((3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)quinazolin-6-yl)oxy)azetidine -1-yl)prop-2-en-1-one
1H-NMR (300MHz, DMSO-d6): δ 9.49 (bs, 1H), 8.46 (s, 1H), 8.17 (m, 1H), 7.65 (m, 3H), 7.25 (m, 3H), 6.98 (m, 1H), 6.41 (m, 1H), 6.16 (m, 1H), 5.71 (m, 1H), 5.24 (m, 1H), 4.82 (m, 1H), 4.58 (m, 1H), 4.29 (m, 1H), 3.95 (m, 1H), 3.95 (s, 3H), 2.43 (s, 3H), 2.21 (s, 3H). MS (ESI+): m/z = 498.2 [M+H]+. 1 H-NMR (300MHz, DMSO-d 6 ): δ 9.49 (bs, 1H), 8.46 (s, 1H), 8.17 (m, 1H), 7.65 (m, 3H), 7.25 (m, 3H), 6.98 (m, 1H), 6.41 (m, 1H), 6.16 (m, 1H), 5.71 (m, 1H), 5.24 (m, 1H), 4.82 (m, 1H), 4.58 (m, 1H), 4.29 ( m, 1H), 3.95 (m, 1H), 3.95 (s, 3H), 2.43 (s, 3H), 2.21 (s, 3H). MS (ESI + ): m/z = 498.2 [M+H] + .
2323
Figure PCTKR2020008312-appb-I000030
Figure PCTKR2020008312-appb-I000030
 		1-(3-((4-((3-클로로-4-((6-메틸피리딘-3-일)옥시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)아제티딘-1-일)프로프-2-엔-1-온1-(3-((4-((3-chloro-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidine -1-yl)prop-2-en-1-one
1H-NMR (300MHz, DMSO-d6): δ 9.52 (s, 1H), 8.51 (s, 1H), 8.19 (s, 1H), 8.11 (s, 1H), 7.75 (m, 1H), 7.55 (s, 1H), 7.22 (m, 4H), 6.37 (m, 1H), 6.09 (m, 1H), 5.69 (m, 1H), 5.21 (m, 1H), 4.80 (m, 1H), 4.54 (m, 1H), 4.28 (m, 1H), 3.96 (m, 1H), 3.94 (s, 3H), 2.43 (s, 3H).MS (ESI+): m/z = 518.2 [M+H]+. 1 H-NMR (300MHz, DMSO-d 6 ): δ 9.52 (s, 1H), 8.51 (s, 1H), 8.19 (s, 1H), 8.11 (s, 1H), 7.75 (m, 1H), 7.55 (s, 1H), 7.22 (m, 4H), 6.37 (m, 1H), 6.09 (m, 1H), 5.69 (m, 1H), 5.21 (m, 1H), 4.80 (m, 1H), 4.54 ( m, 1H), 4.28 (m, 1H), 3.96 (m, 1H), 3.94 (s, 3H), 2.43 (s, 3H).MS (ESI + ): m/z = 518.2 [M+H] + .
2424
Figure PCTKR2020008312-appb-I000031
Figure PCTKR2020008312-appb-I000031
 		1-(3-((7-메톡시-4-((3-메틸-4-(피리딘-3-일옥시)페닐)아미노)퀴나졸린-6-일)옥시)아제티딘-1-일)프로프-2-엔-1-온1-(3-((7-methoxy-4-((3-methyl-4-(pyridin-3-yloxy)phenyl)amino)quinazolin-6-yl)oxy)azetidin-1-yl) Prop-2-en-1-one
1H-NMR (300MHz, DMSO-d6): δ 9.44 (s, 1H), 8.46 (s, 1H), 8.33 (m, 2H), 7.65 (m, 2H), 7.57 (s, 1H), 7.42 (m, 1H), 7.30 (m, 1H), 7.26 (s, 1H), 7.06 (d, 1H), 6.42 (m, 1H), 6.17 (m, 1H), 5.71 (m, 1H), 5.23 (m, 1H), 4.82 (m, 1H), 4.59 (m, 1H), 4.31 (m, 1H), 3.96 (s, 3H), 2.21 (s, 3H).MS (ESI+): m/z = 484.1 [M+H]+. 1 H-NMR (300MHz, DMSO-d 6 ): δ 9.44 (s, 1H), 8.46 (s, 1H), 8.33 (m, 2H), 7.65 (m, 2H), 7.57 (s, 1H), 7.42 (m, 1H), 7.30 (m, 1H), 7.26 (s, 1H), 7.06 (d, 1H), 6.42 (m, 1H), 6.17 (m, 1H), 5.71 (m, 1H), 5.23 ( m, 1H), 4.82 (m, 1H), 4.59 (m, 1H), 4.31 (m, 1H), 3.96 (s, 3H), 2.21 (s, 3H).MS (ESI + ): m/z = 484.1 [M+H] + .
2525
Figure PCTKR2020008312-appb-I000032
Figure PCTKR2020008312-appb-I000032
 		1-(3-((4-((3-클로로-4-((1-메틸-1H-피라졸-4-일)옥시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)아제티딘-1-일)프로프-2-엔-1-온1-(3-((4-((3-chloro-4-((1-methyl-1 H -pyrazol-4-yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl )Oxy)azetidin-1-yl)prop-2-en-1-one
1H-NMR (300MHz, DMSO-d6): δ 9.47 (s, 1H), 8.48 (s, 1H), 8.01 (m, 1H), 7.75 (s, 1H), 7.65 (m, 1H), 7.54 (s, 1H), 7.37 (s, 1H), 7.25 (s, 1H), 7.12 (d, 1H), 6.38 (m, 1H), 6.10 (m, 1H), 5.71 (m, 1H), 5.21 (m, 1H), 4.81 (m, 1H), 4.51 (m, 1H), 4.26 (m, 1H), 3.98 (m, 1H), 3.95 (s, 3H), 3.81 (s, 3H).MS (ESI+): m/z = 517.2 [M+H]+. 1 H-NMR (300MHz, DMSO-d 6 ): δ 9.47 (s, 1H), 8.48 (s, 1H), 8.01 (m, 1H), 7.75 (s, 1H), 7.65 (m, 1H), 7.54 (s, 1H), 7.37 (s, 1H), 7.25 (s, 1H), 7.12 (d, 1H), 6.38 (m, 1H), 6.10 (m, 1H), 5.71 (m, 1H), 5.21 ( m, 1H), 4.81 (m, 1H), 4.51 (m, 1H), 4.26 (m, 1H), 3.98 (m, 1H), 3.95 (s, 3H), 3.81 (s, 3H).MS (ESI) + ): m/z = 517.2 [M+H]+.
2626
Figure PCTKR2020008312-appb-I000033
Figure PCTKR2020008312-appb-I000033
 		1-(3-((4-((3-클로로-4-(4-플루오로페녹시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)아제티딘-1-일)프로프-2-엔-1-온1-(3-((4-((3-chloro-4-(4-fluorophenoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-1-yl) Prop-2-en-1-one
1H-NMR (300MHz, DMSO-d6): δ 9.51 (s, 1H), 8.51 (s, 1H), 8.10 (m, 1H), 7.78 (m, 1H), 7.55 (s, 1H), 7.25 (m, 4H), 7.03 (m, 2H), 6.41 (m, 1H), 6.16 (m, 1H), 5.70 (m, 1H), 5.25 (m, 1H), 4.81 (m, 1H), 4.57 (m, 1H), 4.30 (m, 1H), 3.95 (m, 1H), 3.95 (s, 3H).MS (ESI+): m/z = 521.1 [M+H]+. 1 H-NMR (300MHz, DMSO-d 6 ): δ 9.51 (s, 1H), 8.51 (s, 1H), 8.10 (m, 1H), 7.78 (m, 1H), 7.55 (s, 1H), 7.25 (m, 4H), 7.03 (m, 2H), 6.41 (m, 1H), 6.16 (m, 1H), 5.70 (m, 1H), 5.25 (m, 1H), 4.81 (m, 1H), 4.57 ( m, 1H), 4.30 (m, 1H), 3.95 (m, 1H), 3.95 (s, 3H). MS (ESI + ): m/z = 521.1 [M+H] + .
실시예Example 27: 127: 1 -(3-((4-((3--(3-((4-((3- 사이클로프로필Cyclopropyl -4-(피리딘-3--4-(pyridin-3- 일옥시Oxy )페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)아제티딘-1-일)프로프-2-엔-1-온의 제조)Phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-1-yl)prop-2-en-1-one
Figure PCTKR2020008312-appb-I000034
Figure PCTKR2020008312-appb-I000034
단계 1) 3-(2-Step 1) 3-(2- 브로모Bromo -4--4- 나이트로페녹시Nitrophenoxy )피리딘의 제조) Preparation of pyridine
3-하이드록시피리딘 0.95 g (10.0 mmol)을 N, N-다이메틸아세트아미드 20 mL 로 묽히고, 수소화나트륨 0.4 g (10.0 mmol)을 가하고 상온에서 1시간 동안 교반시켰다. 반응 혼합물에 2-브로모-1-플루오로-4-나이트로벤젠 2.0g (9.10 mmol)을 상온에서 천천히 가하고 80℃ 에서 1시간 동안 교반시켰다. 반응이 완결된 후 결과의 반응 혼합물을 상온으로 냉각한 후 에틸 아세테이트로 묽히고 포화 염수로 세척하였다. 결과로 분리된 유기층을 무수황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하여 얻어진 잔사를 컬럼 크로마토그래피 (에틸 아세테이트 : 헥산 = 1 : 4(부피비))로 분리하여 표제 화합물 2.1 g (수율: 78 %)을 얻었다.0.95 g (10.0 mmol) of 3-hydroxypyridine was diluted with 20 mL of N, N -dimethylacetamide, 0.4 g (10.0 mmol) of sodium hydride was added, and the mixture was stirred at room temperature for 1 hour. 2.0 g (9.10 mmol) of 2-bromo-1-fluoro-4-nitrobenzene was slowly added to the reaction mixture at room temperature, followed by stirring at 80° C. for 1 hour. After the reaction was completed, the resulting reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure, and the resulting residue was separated by column chromatography (ethyl acetate: hexane = 1: 4 (volume ratio)), and 2.1 g of the title compound (yield: 78%) Got it.
1H-NMR (300MHz, DMSO-d6): δ 8.60 (d, 1H), 8.53 (dd, 2H), 8.25 (dd, 1H), 7.68 (m, 1H), 7.56 (m, 1H), 7.14 (d, 1H). 1 H-NMR (300MHz, DMSO-d 6 ): δ 8.60 (d, 1H), 8.53 (dd, 2H), 8.25 (dd, 1H), 7.68 (m, 1H), 7.56 (m, 1H), 7.14 (d, 1H).
단계 2) 3-(2-Step 2) 3-(2- 사이클로프로필Cyclopropyl -4--4- 나이트로페녹시Nitrophenoxy )피리딘의 제조) Preparation of pyridine
상기 단계 1)에서 제조된 화합물 1.0 g (3.39 mmol)과 사이클로프로필 보론산 0.32 g (3.73 mmol)을 1,4-다이옥산 : 물 (5 : 1(부피비)) 혼합용매 20 mL로 묽히고 탄산세슘 3.31 g (10.2 mmol)과 비스(트라이페닐포스핀)팔라듐(II) 다이클로라이드 0.24 g (0.34 mmol)를 가하고 100℃에서 18시간 동안 교반시켰다. 반응이 완결된 후 결과의 반응혼합물을 실온으로 냉각시키고 셀라이트 충진된 필터에 에틸 아세테이트로 세척하며 감압 여과한 후, 결과의 여액을 포화 염화암모늄 수용액과 포화염수로 순차적으로 세척하였다. 결과로 분리된 유기층을 무수황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하여 얻어진 잔사를 컬럼 크로마토그래피 (에틸 아세테이트 : 헥산 = 1 : 3(부피비))로 분리하여 표제 화합물 0.55 g (수율: 63 %)을 얻었다.1.0 g (3.39 mmol) of the compound prepared in step 1) and 0.32 g (3.73 mmol) of cyclopropyl boronic acid were diluted with 20 mL of a mixed solvent of 1,4-dioxane: water (5:1 (volume ratio)), and cesium carbonate 3.31 g (10.2 mmol) and 0.24 g (0.34 mmol) of bis(triphenylphosphine)palladium(II) dichloride were added, followed by stirring at 100°C for 18 hours. After the reaction was completed, the resulting reaction mixture was cooled to room temperature, washed with ethyl acetate on a filter filled with Celite, and filtered under reduced pressure, and the resulting filtrate was sequentially washed with a saturated aqueous ammonium chloride solution and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure, and the resulting residue was separated by column chromatography (ethyl acetate: hexane = 1: 3 (volume ratio)), and 0.55 g of the title compound (yield: 63%) Got it.
1H-NMR (300MHz, CDCl3): δ 8.48 (dd, 2H), 8.01 (d, 1H), 7.85 (d, 1H), 7.35 (d, 2H), 6.87 (d, 1H), 2.27 (m, 1H), 1.08 (q, 2H), 0.84 (q, 2H). 1 H-NMR (300MHz, CDCl 3 ): δ 8.48 (dd, 2H), 8.01 (d, 1H), 7.85 (d, 1H), 7.35 (d, 2H), 6.87 (d, 1H), 2.27 (m , 1H), 1.08 (q, 2H), 0.84 (q, 2H).
단계 3) 1-(3-((4-((3-Step 3) 1-(3-((4-((3- 사이클로프로필Cyclopropyl -4-(피리딘-3--4-(pyridin-3- 일옥시Oxy )페닐)아미노)-7-)Phenyl)amino)-7-
메톡시퀴나졸린Methoxyquinazoline -6-일)-6-days) 옥시Oxy )) 아제티딘Azetidine -1-일)-1 day) 프로프Prof -2-엔-1-온의 제조Preparation of -2-en-1-one
상기 실시예 1의 단계 2)에서 3-클로로-4-(피리딘-3-일옥시)아닐린 대신 상기 단계 2)에서 제조된 화합물을 사용하는 것을 제외하고, 실시예 1의 단계 2), 3), 4)와 실시예 22의 공정을 순차적으로 수행하여 표제 화합물 4 mg (최종 단계 수율: 1 %)을 얻었다.Steps 2) and 3) of Example 1, except that the compound prepared in Step 2) was used instead of 3-chloro-4-(pyridin-3-yloxy)aniline in Step 2) of Example 1 above. , 4) and the steps of Example 22 were sequentially performed to obtain 4 mg of the title compound (final step yield: 1%).
1H-NMR (300MHz, DMSO-d6): δ 9.41 (s, 1H), 8.45 (s, 1H), 8.34 (m, 1H), 8.30 (d, 1H), 7.68 (dd, 1H), 7.56 (s, 1H), 7.39 (m, 1H), 7.37 (m, 2H), 7.24 (s, 1H), 7.05 (d, 1H), 6.43 (m, 1H), 6.17 (m, 1H), 5.72 (dd, 1H), 5.23 (m, 1H), 4.82 (m, 1H), 4.58 (m, 1H), 4.30 (m, 1H), 3.96 (m, 1H), 3.96 (s, 3H), 2.03 (m, 1H), 0.92 (m, 2H), 0.86 (m, 2H). 1 H-NMR (300MHz, DMSO-d 6 ): δ 9.41 (s, 1H), 8.45 (s, 1H), 8.34 (m, 1H), 8.30 (d, 1H), 7.68 (dd, 1H), 7.56 (s, 1H), 7.39 (m, 1H), 7.37 (m, 2H), 7.24 (s, 1H), 7.05 (d, 1H), 6.43 (m, 1H), 6.17 (m, 1H), 5.72 ( dd, 1H), 5.23 (m, 1H), 4.82 (m, 1H), 4.58 (m, 1H), 4.30 (m, 1H), 3.96 (m, 1H), 3.96 (s, 3H), 2.03 (m , 1H), 0.92 (m, 2H), 0.86 (m, 2H).
MS (ESI+): m/z = 510.4 [M+H]+.MS (ESI + ): m/z = 510.4 [M+H] + .
실시예Example 28: 128: 1 -(3-((4-((3-(-(3-((4-((3-( 다이플루오로메틸Difluoromethyl )-4-(피리딘-3-)-4-(pyridin-3- 일옥시Oxy )페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)아제티딘-1-일)프로프-2-엔-1-온의 제조)Phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-1-yl)prop-2-en-1-one
Figure PCTKR2020008312-appb-I000035
Figure PCTKR2020008312-appb-I000035
단계 1) 2-(Step 1) 2-( 다이플루오로메틸Difluoromethyl )-4-나이트로-1-)-4-nitro-1- 페녹시벤젠의Of phenoxybenzene 제조 Produce
1-클로로-2-(다이플루오로메틸)-4-나이트로벤젠 (US20170226089) 2.1 g (10.1 mmol)을 N, N-다이메틸포름아마이드 21 mL 로 묽히고 페놀 952 ㎎ (10.1 mmol), 탄산칼륨 1.5 g (11.1 mmol)을 가한 후 90℃에서 3시간 동안 교반시켰다. 반응이 완결되면 결과의 반응혼합물을 상온으로 냉각한 후 에틸 아세테이트로 묽히고 포화 염수로 세척하였다. 결과로 분리된 유기층을 무수황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하여 얻어진 잔사를 컬럼 크로마토그래피 (에틸 아세테이트 : 헥산 = 1 : 5(부피비))로 분리하여 표제 화합물 2.0 g (수율: 75 %)을 얻었다.1-chloro-2-(difluoromethyl)-4-nitrobenzene ( US20170226089 ) 2.1 g (10.1 mmol) was diluted with 21 mL of N, N -dimethylformamide , and phenol 952 mg (10.1 mmol), carbonic acid After adding 1.5 g (11.1 mmol) of potassium, the mixture was stirred at 90° C. for 3 hours. When the reaction was complete, the resulting reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure, and the obtained residue was separated by column chromatography (ethyl acetate: hexane = 1: 5 (volume ratio)), and 2.0 g of the title compound (yield: 75%) Got it.
1H-NMR (300MHz, CDCl3): δ 8.61 (m, 2H), 8.53 (s, 1H), 8.30 (m, 1H), 7.51 (m, 2H), 7.08-6.88 (m, 1H). 1 H-NMR (300 MHz, CDCl 3 ): δ 8.61 (m, 2H), 8.53 (s, 1H), 8.30 (m, 1H), 7.51 (m, 2H), 7.08-6.88 (m, 1H).
단계 2) 1-(3-((4-((3-(Step 2) 1-(3-((4-((3-( 다이플루오로메틸Difluoromethyl )-4-(피리딘-3-)-4-(pyridin-3- 일옥시Oxy )페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)아제티딘-1-일)프로프-2-엔-1-온의 제조)Phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-1-yl)prop-2-en-1-one
상기 실시예 1의 단계 2)에서 3-(2-클로로-4-나이트로페녹시)피리딘 대신 상기 단계 1)에서 제조된 화합물을 사용하는 것을 제외하고, 실시예 1의 단계 2), 3), 4)와 실시예 22의 공정을 순차적으로 수행하여 표제 화합물 11 mg (최종 단계 수율: 4 %)을 얻었다. Steps 2) and 3) of Example 1, except that the compound prepared in step 1) was used instead of 3-(2-chloro-4-nitrophenoxy) pyridine in step 2) of Example 1 , 4) and the steps of Example 22 were sequentially performed to obtain 11 mg of the title compound (final step yield: 4%).
1H-NMR (300MHz, DMSO-d6): δ 9.59 (s, 1H), 8.50 (s, 1H), 8.42 (m, 2H), 8.07 (s, 1H), 8.04 (m, 1H), 7.58 (s, 1H), 7.46 (m, 2H), 7.26 (m, 2H), 7.12 (m, 1H), 6.37 (m, 1H), 6.16 (m, 1H), 5.72 (m, 1H), 5.24 (m, 1H), 4.80 (m, 1H), 4.55 (m, 1H), 4.27 (m, 1H), 4.04 (m, 1H), 3.95 (s, 3H). 1 H-NMR (300MHz, DMSO-d 6 ): δ 9.59 (s, 1H), 8.50 (s, 1H), 8.42 (m, 2H), 8.07 (s, 1H), 8.04 (m, 1H), 7.58 (s, 1H), 7.46 (m, 2H), 7.26 (m, 2H), 7.12 (m, 1H), 6.37 (m, 1H), 6.16 (m, 1H), 5.72 (m, 1H), 5.24 ( m, 1H), 4.80 (m, 1H), 4.55 (m, 1H), 4.27 (m, 1H), 4.04 (m, 1H), 3.95 (s, 3H).
MS (ESI+): m/z = 520.2 [M+H]+.MS (ESI + ): m/z = 520.2 [M+H] + .
실시예Example 29: 129: 1 -(3-((4-((3--(3-((4-((3- 클로로Chloro -4-(-4-( 싸이아졸Thiazole -2--2- 일옥시Oxy )페닐)아미노)-7-)Phenyl)amino)-7- 메톡시퀴나졸린Methoxyquinazoline -6-일)옥시)아제티딘-1-일)프로프-2-엔-1-온의 제조Preparation of -6-yl)oxy)azetidin-1-yl)prop-2-en-1-one
Figure PCTKR2020008312-appb-I000036
Figure PCTKR2020008312-appb-I000036
단계 1) 1-(3-((4-((3-Step 1) 1-(3-((4-((3- 클로로Chloro -4-(-4-( 싸이아졸Thiazole -2--2- 일옥시Oxy )페닐)아미노)-7-)Phenyl)amino)-7- 메톡시Methoxy
퀴나졸린Quinazoline -6-일)-6-days) 옥시Oxy )) 아제티딘Azetidine -1-일)-1 day) 프로프Prof -2-엔-1-온의 제조Preparation of -2-en-1-one
상기 실시예 1의 단계 3)에서 3-클로로-4-(피리딘-3-일옥시)아닐린 대신 상기 실시예 19의 단계 1)에서 제조된 화합물을 사용하는 것을 제외하고, 실시예 1의 단계 3), 4)와 실시예 22의 공정을 순차적으로 수행하여 표제 화합물 154 mg (최종 단계 수율: 43 %)을 얻었다. Step 3 of Example 1, except that the compound prepared in step 1) of Example 19 was used instead of 3-chloro-4-(pyridin-3-yloxy)aniline in step 3) of Example 1 ), 4) and the processes of Example 22 were sequentially performed to obtain 154 mg of the title compound (final step yield: 43%).
1H-NMR (300MHz, DMSO-d6): δ 9.61 (s, 1H), 8.57 (s, 1H), 8.18 (m, 1H), 7.89 (m, 1H), 7.57 (m, 2H), 7.25 (m, 3H), 6.40 (m, 1H), 6.12 (m, 1H), 5.73 (m, 1H), 5.26 (m, 1H), 4.81 (m, 1H), 4.58 (m, 1H), 4.31 (m, 1H), 4.00 (m, 1H), 3.98 (s, 3H). 1 H-NMR (300MHz, DMSO-d 6 ): δ 9.61 (s, 1H), 8.57 (s, 1H), 8.18 (m, 1H), 7.89 (m, 1H), 7.57 (m, 2H), 7.25 (m, 3H), 6.40 (m, 1H), 6.12 (m, 1H), 5.73 (m, 1H), 5.26 (m, 1H), 4.81 (m, 1H), 4.58 (m, 1H), 4.31 ( m, 1H), 4.00 (m, 1H), 3.98 (s, 3H).
MS (ESI+): m/z = 510.1 [M+H]+.MS (ESI + ): m/z = 510.1 [M+H] + .
실험예Experimental example 1: One: EGFREGFR 돌연변이 및 Mutation and HER2HER2 돌연변이 세포 성장 억제 시험 Mutant cell growth inhibition test
실시예에서 얻어진 화합물 중 대표적인 화합물들에 대하여, EGFR 돌연변이 세포 및 HER2 돌연변이 세포의 활성에 미치는 영향을 확인하는 실험을 실시하였다. For representative compounds among the compounds obtained in Examples, an experiment was conducted to confirm the effect on the activity of EGFR mutant cells and HER2 mutant cells.
상기 EGFR 돌연변이 세포로는, EGFR D770_N771insSVD 변이형을 발현하는 Ba/F3 세포주(CrownBio, China)를 준비하였다. 상기 HER2 돌연변이 세포로는, HER2 A775insYVMA 변이형을 발현하는 H1781 세포주 (ATCC사, American Type Culture Collection, USA)를 준비하였다.As the EGFR mutant cells, a Ba/F3 cell line (CrownBio, China) expressing the EGFR D770_N771insSVD variant was prepared. As the HER2 mutant cells, an H1781 cell line (ATCC, American Type Culture Collection, USA) expressing the HER2 A775insYVMA variant was prepared.
상기 EGFR 돌연변이 세포 및 HER2 돌연변이 세포의 성장을 위한 배양 배지로는, 10% FBS(Fetal Bovine Serum)와 1% 페니실린/스트랩토마이신 (Gibco BRL)을 함유하는 RPMI Medium 1640 (1x) 배지를 사용하였다.As the culture medium for the growth of the EGFR mutant cells and HER2 mutant cells, RPMI Medium 1640 (1x) medium containing 10% FBS (Fetal Bovine Serum) and 1% penicillin/straptomycin (Gibco BRL) was used. .
구체적으로, 액체 질소 탱크에 보관되어 있던 세포주를 꺼내어 37℃에서 빠르게 녹인 후 원심 분리하여 냉동보관 배지를 제거하였다. 원심 분리 후, 회수된 세포 펠렛 (pellet)을 상기 배양 배지에 잘 섞어서 배양 플라스크에 넣고 37℃, 5 % 이산화탄소 조건 하에 계대 배양하여 세포 생장기 (logarithmic growth)로 세포를 안정화시켰다. 그 후, 상기 플라스크로부터 세포를 취해 원심 분리하여 배양 배지를 제거하고 DPBS (Dulbecco's Phosphate Buffered Saline)로 세척한 다음, 다시 원심 분리하여 DPBS를 제거한 후 배양 배지로 1 × 105 세포/mL가 되도록 희석하였다. 96-웰(96-well) 플레이트에 상기 희석된 세포를 웰 (well) 당 100μL씩 분주하였다. Ba/F3 세포주의 경우 약물(실시예에서 얻어진 화합물)과 동시에 처리하였고, H1781 세포주는 24 시간 이후에 약물을 처리하였다. Specifically, the cell line stored in the liquid nitrogen tank was taken out, rapidly dissolved at 37°C, and centrifuged to remove the cryopreservation medium. After centrifugation, the recovered cell pellet was well mixed in the culture medium, placed in a culture flask, and passaged under conditions of 37° C. and 5% carbon dioxide to stabilize the cells in logarithmic growth. Thereafter, cells were taken from the flask and centrifuged to remove the culture medium, washed with DPBS (Dulbecco's Phosphate Buffered Saline), and then centrifuged again to remove DPBS, and then diluted to 1 × 10 5 cells/mL with a culture medium. I did. The diluted cells were dispensed into a 96-well plate at 100 μL per well. In the case of the Ba/F3 cell line, the drug (the compound obtained in the example) was treated at the same time, and the H1781 cell line was treated with the drug after 24 hours.
상기 실시예에서 제조된 화합물들을 각각 99.5% 다이메틸설폭사이드(이하 DMSO, 세포 배양급)에 10 mM이 되도록 용해시켜 화합물 함유 DMSO 용액을 얻었다. 상기 화합물 함유 DMSO 용액을 배양 배지에 3 μM의 농도로 희석한 후 5 배씩 계단식으로 희석하여 0.32 nM까지 희석한 시험용액을 준비하였다 (이때, 최종 DMSO의 농도는 1% 이하가 되도록 하였다).The compounds prepared in the above examples were each dissolved in 99.5% dimethyl sulfoxide (hereinafter, DMSO, cell culture grade) to 10 mM to obtain a DMSO solution containing the compound. The DMSO solution containing the compound was diluted to a concentration of 3 μM in the culture medium, and then diluted in steps of 5 times to prepare a test solution diluted to 0.32 nM (at this time, the concentration of the final DMSO was 1% or less).
세포를 분주한 96-웰 플레이트에 준비한 각 화합물의 시험용액을 50μL씩 가하여 웰 당 150μL에 10μL 내지 0.1nM의 최종 농도가 되도록 하였다. 시험용액을 처리한 세포를 37℃, 5% 이산화탄소 조건 하에 세포를 배양하되, 상기 Ba/F3 세포주는 72시간 동안 배양하고, 상기 H1781 세포주는 96시간 동안 배양하였다.50 μL of the test solution of each compound prepared was added to the 96-well plate in which the cells were dispensed, so that the final concentration of 10 μL to 0.1 nM was added to 150 μL per well. The cells treated with the test solution were cultured under conditions of 37° C. and 5% carbon dioxide, but the Ba/F3 cell line was cultured for 72 hours, and the H1781 cell line was cultured for 96 hours.
상기 Ba/F3 세포주는 세포를 배양시킨 96-웰 플레이트를 30 분간 상온에 적응시킨 후 CellTiter-Glo® Luminescent Cell Assay Reagent (CTG, Promega)를 웰 당 50μL씩 분주하였다. 10 분간 발광 신호를 안정화시킨 후 미세판 판독기 (microplate reader)로 발광 세기를 측정하였다. 상기 H1781 세포주는 배양 후 배지를 제거하고 4℃ 에서 10% TCA(Trichloroacetic acid, Sigma Cat. T0699) solution으로 30분간 세포를 고정시킨 다음, TCA solution을 버리고 플레이트를 증류수로 세척한 후 공기 중에 노출시켜 말렸다. 그 후, 상기 플레이트에 0.4% SRB(sulforhodamine B, sigma Cat. S1402) solution 100 μL를 넣어 30분간 상온에서 염색시켰다. 상기 플레이트를 수돗물로 세척하고 1% 아세트산 용액(acetic acid solution)에서 세척한 후 공기 중에 노출시켜 말렸다. 그 후, 10 mM trizma base solution 150 μL를 넣어 고체상의 SRB를 용해시켰다. 마이크로플레이트 리더(microplate reader)를 이용하여 540 nM에서 흡광도를 측정하였다.The Ba / F3 cell line was adapted to a 96-well plate was incubated the cells for 30 minutes at room temperature was dispensed the CellTiter-Glo ® Luminescent Cell Assay Reagent (CTG, Promega) per well per 50μL. After stabilizing the luminescence signal for 10 minutes, the luminescence intensity was measured with a microplate reader. After culturing the H1781 cell line, the medium was removed, and the cells were fixed with 10% TCA (Trichloroacetic acid, Sigma Cat. Dried. Thereafter, 100 μL of a 0.4% SRB (sulforhodamine B, sigma Cat. S1402) solution was added to the plate and stained at room temperature for 30 minutes. The plate was washed with tap water, washed in 1% acetic acid solution, and then exposed to air to dry. Then, 150 μL of 10 mM trizma base solution was added to dissolve the solid SRB. Absorbance was measured at 540 nM using a microplate reader.
측정된 값을 근거로, 시험물질을 처리하지 않은 웰의 최종 세포밀도 값에서 초기 세포밀도 값을 뺀 후 그 값을 100%로 하였을 때 각 화합물이 세포 성장을 50 % 억제한 농도로 GI50 값(Cell Growth Inhibition)을 산출하였다. 각 화합물의 GI50 값은 그래프패드프리즘(GraphPad Prism) 소프트웨어의 nonlinear regression; log[inhibitor] vs. normalized response 분석을 이용하여 산출하였으며, 그 결과는 하기 표 3에 나타낸 바와 같다. Based on the measured value, when the initial cell density value is subtracted from the final cell density value of the well not treated with the test substance and the value is 100%, the GI 50 value is the concentration at which each compound inhibits cell growth by 50%. (Cell Growth Inhibition) was calculated. The GI 50 value of each compound was determined by the nonlinear regression of GraphPad Prism software; log[inhibitor] vs. It was calculated using normalized response analysis, and the results are shown in Table 3 below.
실시예Example Cell growth inhibition (GI50, nM)Cell growth inhibition (GI 50 , nM)
EGRP 돌연변이 세포EGRP mutant cells HER2 돌연변이 세포HER2 mutant cells
Ba/F3 세포주(EGFR D770_N771insSVD)Ba/F3 cell line (EGFR D770_N771insSVD) H1781 세포주(HER2 A775insYVMA)H1781 cell line (HER2 A775insYVMA)
1One 1717 1010
22 5757 1111
33 2121 3333
44 6666 8181
55 5252 2020
77 2424 1414
88 4040 3535
1010 8282 3636
1111 3535 2525
1212 144144 101101
1313 1111 4747
1515 3232 5959
1616 5757 7272
1818 4747 3232
1919 136136 164164
2020 8080 117117
2121 2121 2020
2222 4242 2525
2323 4444 2424
2424 5151 2727
2525 6565 2525
2626 5353 5252
2828 153153 4242

Claims (12)

  1. 하기의 화학식 I로 표시되는 퀴나졸린 유도체, 용매화물, 입체 이성질체 또는 이들의 약학적으로 허용 가능한 염:Quinazoline derivatives, solvates, stereoisomers, or pharmaceutically acceptable salts thereof represented by the following formula (I):
    [화학식 I][Formula I]
    Figure PCTKR2020008312-appb-I000037
    Figure PCTKR2020008312-appb-I000037
    상기 화학식 I 중,In Formula I,
    R1은 아릴 또는 헤테로아릴이고 (단, R1이 비치환 페닐인 경우는 제외함); R 1 is aryl or heteroaryl (except when R 1 is unsubstituted phenyl);
    R2는 수소, 하이드록시기, 시아노기, C1-C6 알킬기, C2-C6 알켄기, C2-C6 알카인기, C1-C3 알콕시기, (모노할로겐, 다이할로겐, 트라이할로겐)메틸기, 모노할로겐, 다이할로겐, 트라이할로겐, C3-C6 사이클로알킬기, 또는 C1-C6 다이알킬아미노기이고; R 2 is hydrogen, a hydroxy group, a cyano group, a C 1 -C 6 alkyl group, a C 2 -C 6 alkene group, a C 2 -C 6 alkane group, a C 1 -C 3 alkoxy group, (monohalogen, dihalogen, Trihalogen)methyl group, monohalogen, dihalogen, trihalogen, C 3 -C 6 cycloalkyl group, or C 1 -C 6 dialkylamino group;
    R3는 수소, 하이드록시기, 또는 C1-C3 알콕시기이고;R 3 is hydrogen, a hydroxy group, or a C 1 -C 3 alkoxy group;
    na 및 nb는 각각 독립적으로 1 내지 6의 정수이며;n a and n b are each independently an integer of 1 to 6;
    Z는
    Figure PCTKR2020008312-appb-I000038
    이고, 이때, R4, R5 및 R6은 각각 독립적으로 수소, 할로겐, N-C1-6알킬, N-하이드록실아마이도, C-C1- 6알킬 역아마이도(-NHCOC1 -6), 하이드록시카보닐(-COOH), C1- 6알킬옥시카보닐(-COOC1 -6), C1- 6알킬, 하이드록시, C1- 6다이알킬아민 또는 헤테로사이클로 치환된 C1-6알킬 치환기이다.    Z is
    Figure PCTKR2020008312-appb-I000038
    And, wherein, R 4, R 5 and R 6 are each independently hydrogen, halogen, N -C 1-6 alkyl, N - hydroxyl omicron], CC 1- 6 alkyl station omicron] (-NHCOC 1 -6) , hydroxycarbonyl (-COOH), C 1- 6 alkoxycarbonyl (-COOC 1 -6), C 1- 6 alkyl, hydroxy, C 1- 6 dialkyl amine or a heterocycle-substituted C 1- 6 alkyl substituent.
  2. 청구항 1에 있어서, The method according to claim 1,
    상기 화학식 I 중,In Formula I,
    R1은 치환체 X를 갖는 페닐; 또는 비치환 혹은 치환체 X를 갖는 헤테로아릴이고; R 1 is phenyl with substituent X; Or unsubstituted or heteroaryl having a substituent X;
    X는 하이드록시기, 시아노기, 나이트로기, (모노할로겐, 다이할로겐, 트라이할로겐)메틸기, 모노할로겐, 다이할로겐, 트라이할로겐, C1-C6 알킬기, C2-C6 알켄기, C2-C6 알카인기, C1-C3 알콕시기, C3-C6 사이클로알킬기, 또는 C1-C6 다이알킬아미노기인 것인, 퀴나졸린 유도체, 용매화물, 입체 이성질체 또는 이들의 약학적으로 허용 가능한 염.X is a hydroxy group, a cyano group, a nitro group, a (monohalogen, dihalogen, trihalogen) methyl group, monohalogen, dihalogen, trihalogen, C 1 -C 6 alkyl group, C 2 -C 6 alkene group, C 2 -C 6 alkyne group, C 1 -C 3 alkoxy group, C 3 -C 6 cycloalkyl group, or C 1 -C 6 dialkylamino group, quinazoline derivatives, solvates, stereoisomers, or pharmaceutical thereof Salt acceptable as.
  3. 청구항 1에 있어서,The method according to claim 1,
    상기 화학식 I 중,In Formula I,
    R1은 1 내지 5개의 치환체 X를 갖는 페닐; 또는 비치환 혹은 치환체 X를 갖는 헤테로아릴이고; R 1 is phenyl having 1 to 5 substituents X; Or unsubstituted or heteroaryl having a substituent X;
    R2는 수소, 모노할로겐, 다이할로겐, 트라이할로겐, (모노할로겐, 다이할로겐, 트라이할로겐)메틸기, C1-C6 알킬기 또는 C3-C6 사이클로알킬기이며;R 2 is hydrogen, monohalogen, dihalogen, trihalogen, (monohalogen, dihalogen, trihalogen) methyl group, C 1 -C 6 alkyl group or C 3 -C 6 cycloalkyl group;
    R3는 수소 또는 C1-C3 알콕시기이고;R 3 is hydrogen or a C 1 -C 3 alkoxy group;
    X는 모노할로겐, 다이할로겐, 트라이할로겐, (모노할로겐, 다이할로겐, 트라이할로겐)메틸기, C1-C6 알킬기, 또는 C3-C6 사이클로알킬기이며;X is monohalogen, dihalogen, trihalogen, (monohalogen, dihalogen, trihalogen) methyl group, C 1 -C 6 alkyl group, or C 3 -C 6 cycloalkyl group;
    Z는
    Figure PCTKR2020008312-appb-I000039
    이고, 이때 R4, R5 및 R6은 각각 독립적으로 수소 또는 C1- 6알킬인, 퀴나졸린 유도체, 용매화물, 입체 이성질체 또는 이들의 약학적으로 허용 가능한 염.    Z is
    Figure PCTKR2020008312-appb-I000039
    And, wherein R 4, R 5 and R 6 are each independently hydrogen or C 1- 6 alkyl, quinazoline derivatives, solvates, stereoisomers or pharmaceutically acceptable salts thereof.
  4. 청구항 1에 있어서, The method according to claim 1,
    상기 헤테로아릴은 N, O 및 S로 이루어진 군에서 선택된 1종 이상의 헤테로 원자를 포함하는 것인, 퀴나졸린 유도체, 용매화물, 입체 이성질체 또는 이들의 약학적으로 허용 가능한 염.The heteroaryl is one containing at least one hetero atom selected from the group consisting of N, O and S, a quinazoline derivative, a solvate, a stereoisomer, or a pharmaceutically acceptable salt thereof.
  5. 청구항 1에 있어서, The method according to claim 1,
    하기 화합물로 이루어진 군에서 선택되는 것인, 퀴나졸린 유도체, 용매화물, 입체 이성질체 또는 이들의 약학적으로 허용 가능한 염:Quinazoline derivatives, solvates, stereoisomers, or pharmaceutically acceptable salts thereof, selected from the group consisting of the following compounds:
    1-(4-((4-((3-클로로-4-(피리딘-3-일옥시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;1-(4-((4-((3-chloro-4-(pyridin-3-yloxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl ) Prop-2-en-1-one;
    (1-(4-((7-메톡시-4-((3-메틸-4-((6-메틸피리딘-3-일)옥시)페닐)아미노)퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;(1-(4-((7-methoxy-4-((3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)quinazolin-6-yl)oxy)pi Peridin-1-yl)prop-2-en-1-one;
    1-(4-((4-((3-클로로-4-(4-플루오로페녹시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;1-(4-((4-((3-chloro-4-(4-fluorophenoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl ) Prop-2-en-1-one;
    1-(4-((4-((3-플루오로-4-(4-플루오로페녹시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;1-(4-((4-((3-fluoro-4-(4-fluorophenoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1- I) prop-2-en-1-one;
    1-(4-((4-((3-클로로-4-((6-메틸피리딘-3-일)옥시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;1-(4-((4-((3-chloro-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperi Din-1-yl)prop-2-en-1-one;
    1-(4-((4-((3-클로로-4-(피리딘-4-일옥시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;1-(4-((4-((3-chloro-4-(pyridin-4-yloxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl ) Prop-2-en-1-one;
    1-(4-((4-((3-클로로-4-((6-플루오로피리딘-3-일)옥시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;1-(4-((4-((3-chloro-4-((6-fluoropyridin-3-yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)pi Peridin-1-yl)prop-2-en-1-one;
    1-(4-((4-((3-클로로-4-((5-플루오로피리딘-2-일)옥시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;1-(4-((4-((3-chloro-4-((5-fluoropyridin-2-yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)pi Peridin-1-yl)prop-2-en-1-one;
    1-(4-((4-((4-(4-클로로페녹시)-3-플루오로페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;1-(4-((4-((4-(4-chlorophenoxy)-3-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl ) Prop-2-en-1-one;
    1-(4-((4-((3-클로로-4-((1-메틸-1H)-피라졸-4-일)옥시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;1-(4-((4-((3-chloro-4-((1-methyl-1 H )-pyrazol-4-yl)oxy)phenyl)amino)-7-methoxyquinazoline-6- Yl)oxy)piperidin-1-yl)prop-2-en-1-one;
    1-(4-((4-((3-클로로-4-((1-메틸-1H)-피라졸-5-일)옥시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;1-(4-((4-((3-chloro-4-((1-methyl-1 H )-pyrazol-5-yl)oxy)phenyl)amino)-7-methoxyquinazoline-6- Yl)oxy)piperidin-1-yl)prop-2-en-1-one;
    1-(4-((4-((3-클로로-4-((1-메틸-3-(트라이플루오로메틸)-1H-피라졸-5-일)옥시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;1-(4-((4-((3-chloro-4-((1-methyl-3-(trifluoromethyl)-1 H -pyrazol-5-yl)oxy)phenyl)amino)-7 -Methoxyquinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one;
    1-(4-((4-((4-(4-플루오로페녹시)-3-메틸페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;1-(4-((4-((4-(4-fluorophenoxy)-3-methylphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl) Prop-2-en-1-one;
    1-(4-((4-((4-(4-플루오로페녹시)-3-(트라이플루오로메틸)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;1-(4-((4-((4-(4-fluorophenoxy)-3-(trifluoromethyl)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperi Din-1-yl)prop-2-en-1-one;
    1-(4-((4-((3-클로로-4-(3,4-다이플루오로페녹시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;1-(4-((4-((3-chloro-4-(3,4-difluorophenoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidine- 1-yl)prop-2-en-1-one;
    1-(4-((4-((3-클로로-4-(4-클로로페녹시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;1-(4-((4-((3-chloro-4-(4-chlorophenoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl) Prop-2-en-1-one;
    1-(4-((4-((3-클로로-4-(4-(트라이플루오로메틸)페녹시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;1-(4-((4-((3-chloro-4-(4-(trifluoromethyl)phenoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidine -1-yl)prop-2-en-1-one;
    1-(4-((4-((3-클로로-4-(싸이아졸-2-일옥시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;1-(4-((4-((3-chloro-4-(thiazol-2-yloxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1- I) prop-2-en-1-one;
    1-(4-((4-((3-클로로-4-(4-플루오로페녹시)페닐)아미노)퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;1-(4-((4-((3-chloro-4-(4-fluorophenoxy)phenyl)amino)quinazolin-6-yl)oxy)piperidin-1-yl)prop-2 -En-1-one;
    1-(4-((4-((3-클로로-4-(4-사이클로프로필페녹시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;1-(4-((4-((3-chloro-4-(4-cyclopropylphenoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl ) Prop-2-en-1-one;
    1-(3-((4-((3-클로로-4-(피리딘-3-일옥시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)아제티딘-1-일)프로프-2-엔-1-온;1-(3-((4-((3-chloro-4-(pyridin-3-yloxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-1-yl) Prop-2-en-1-one;
    1-(3-((7-메톡시-4-((3-메틸-4-((6-메틸피리딘-3-일)옥시)페닐)아미노)퀴나졸린-6-일)옥시)아제티딘-1-일)프로프-2-엔-1-온;1-(3-((7-methoxy-4-((3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)quinazolin-6-yl)oxy)azetidine -1-yl)prop-2-en-1-one;
    1-(3-((4-((3-클로로-4-((6-메틸피리딘-3-일)옥시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)아제티딘-1-일)프로프-2-엔-1-온;1-(3-((4-((3-chloro-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidine -1-yl)prop-2-en-1-one;
    1-(3-((7-메톡시-4-((3-메틸-4-(피리딘-3-일옥시)페닐)아미노)퀴나졸린-6-일)옥시)아제티딘-1-일)프로프-2-엔-1-온;1-(3-((7-methoxy-4-((3-methyl-4-(pyridin-3-yloxy)phenyl)amino)quinazolin-6-yl)oxy)azetidin-1-yl) Prop-2-en-1-one;
    1-(3-((4-((3-클로로-4-((1-메틸-1H-피라졸-4-일)옥시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)아제티딘-1-일)프로프-2-엔-1-온;1-(3-((4-((3-chloro-4-((1-methyl-1 H -pyrazol-4-yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl )Oxy)azetidin-1-yl)prop-2-en-1-one;
    1-(3-((4-((3-클로로-4-(4-플루오로페녹시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)아제티딘-1-일)프로프-2-엔-1-온;1-(3-((4-((3-chloro-4-(4-fluorophenoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-1-yl) Prop-2-en-1-one;
    1-(3-((4-((3-사이클로프로필-4-(피리딘-3-일옥시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)아제티딘-1-일)프로프-2-엔-1-온;1-(3-((4-((3-cyclopropyl-4-(pyridin-3-yloxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-1-yl ) Prop-2-en-1-one;
    1-(3-((4-((3-(다이플루오로메틸)-4-(피리딘-3-일옥시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)아제티딘-1-일)프로프-2-엔-1-온; 및1-(3-((4-((3-(difluoromethyl)-4-(pyridin-3-yloxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidine -1-yl)prop-2-en-1-one; And
    1-(3-((4-((3-클로로-4-(싸이아졸-2-일옥시)페닐)아미노)-7-메톡시퀴나졸린-6-일)옥시)아제티딘-1-일)프로프-2-엔-1-온.1-(3-((4-((3-chloro-4-(thiazol-2-yloxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-1-yl ) Prop-2-en-1-one.
  6. 청구항 1의 퀴나졸린 유도체, 용매화물, 입체 이성질체 또는 이들의 약학적으로 허용 가능한 염을 활성성분으로 포함하는, 암의 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating cancer, comprising the quinazoline derivative, solvate, stereoisomer or pharmaceutically acceptable salt thereof of claim 1 as an active ingredient.
  7. 청구항 6에 있어서, The method of claim 6,
    상기 암은 EGFR(epidermal growth factor receptor) 돌연변이 및 HER2(human epidermal growth factor receptor 2) 돌연변이 중 1종 이상을 갖는 암인 것인, 암의 예방 또는 치료용 약학적 조성물.The cancer is a cancer having one or more of an epidermal growth factor receptor (EGFR) mutation and a human epidermal growth factor receptor 2 (HER2) mutation, a pharmaceutical composition for preventing or treating cancer.
  8. 청구항 7에 있어서, The method of claim 7,
    상기 EGFR 돌연변이 및 HER2 돌연변이는 각각 엑손 20 삽입 돌연변이인, 암의 예방 또는 치료용 약학적 조성물.The EGFR mutation and HER2 mutation are each exon 20 insertion mutation, a pharmaceutical composition for the prevention or treatment of cancer.
  9. 청구항 7에 있어서, The method of claim 7,
    상기 EGFR 돌연변이는 활성화 EGFR 돌연변이, EGFR 저해제에 대한 내성을 유발하는 돌연변이 또는 이들의 조합이고,The EGFR mutation is an activated EGFR mutation, a mutation causing resistance to an EGFR inhibitor, or a combination thereof,
    상기 HER2 돌연변이는 활성화 HER2 돌연변이, HER2 저해제에 대한 내성을 유발하는 돌연변이 또는 이들의 조합인 것인, 암의 예방 또는 치료용 약학적 조성물.The HER2 mutation is an activated HER2 mutation, a mutation causing resistance to a HER2 inhibitor, or a combination thereof, a pharmaceutical composition for preventing or treating cancer.
  10. 청구항 6에 있어서, The method of claim 6,
    상기 암은 폐암, 간암, 식도암, 위암, 대장암, 소장암, 췌장암, 흑색종, 유방암, 구강암, 뇌종양, 갑상선암, 부갑상선암, 신장암, 자궁경부암, 육종, 전립선암, 요도암, 방광암, 고환암, 혈액암, 림프종, 피부암, 건선 및 섬유선종으로 이루어지는 군으로부터 선택된 것인, 암의 예방 또는 치료용 약학적 조성물.The cancer is lung cancer, liver cancer, esophageal cancer, stomach cancer, colon cancer, small intestine cancer, pancreatic cancer, melanoma, breast cancer, oral cancer, brain tumor, thyroid cancer, parathyroid cancer, kidney cancer, cervical cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, testicular cancer , Hematologic cancer, lymphoma, skin cancer, psoriasis and fibroadenoma that is selected from the group consisting of, a pharmaceutical composition for the prevention or treatment of cancer.
  11. 청구항 6에 있어서, The method of claim 6,
    상기 암은 비소세포성 폐암인 것인, 암의 예방 또는 치료용 약학적 조성물.The cancer is non-small cell lung cancer, the pharmaceutical composition for preventing or treating cancer.
  12. 청구항 6에 있어서,The method of claim 6,
    상기 약학적 조성물은, 정제, 환제, 산제, 캅셀제, 시럽, 에멀젼 또는 마이크로에멀젼을 포함하는 제제학적으로 허용된 형태로 제제화되는, 암의 예방 또는 치료용 약학적 조성물.The pharmaceutical composition is formulated in a pharmaceutically acceptable form including tablets, pills, powders, capsules, syrups, emulsions or microemulsions, a pharmaceutical composition for preventing or treating cancer.
PCT/KR2020/008312 2019-06-26 2020-06-26 Novel quinazoline derivative having anti-tumor activity and pharmaceutical composition comprising same WO2020262998A1 (en)

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