WO2020262998A1 - Nouveau dérivé de quinazoline ayant une activité antitumorale et composition pharmaceutique le comprenant - Google Patents

Nouveau dérivé de quinazoline ayant une activité antitumorale et composition pharmaceutique le comprenant 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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English (en)
Korean (ko)
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장선영
강석종
한선영
김예림
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한미약품 주식회사
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Publication of WO2020262998A1 publication Critical patent/WO2020262998A1/fr

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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

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Abstract

La présente invention concerne un nouveau dérivé de quinazoline ayant une activité antitumorale, un solvate de celui-ci, un stéréoisomère de celui-ci, ou un sel pharmaceutiquement acceptable de celui-ci, et une composition pharmaceutique le comprenant en tant que principe actif. Le nouveau dérivé de quinazoline de la présente invention peut présenter une activité sélective et efficace contre le cancer ayant un mutant EGFR et/ou un mutant HER2.
PCT/KR2020/008312 2019-06-26 2020-06-26 Nouveau dérivé de quinazoline ayant une activité antitumorale et composition pharmaceutique le comprenant WO2020262998A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021231400A1 (fr) * 2020-05-12 2021-11-18 Accutar Biotechnology, Inc. Bis-aryl éthers contenant de la n-acyl azétidine en tant qu'inhibiteurs de l'egfr/her2
EP3822263A4 (fr) * 2018-07-04 2022-03-16 Daiichi Sankyo Company, Limited Dérivé de quinazoline de type éther de biaryle

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WO2005026151A1 (fr) * 2003-09-16 2005-03-24 Astrazeneca Ab Dérivés de quinozaline en tant qu'inhibiteurs de la tyrosine kinase
US8188102B2 (en) * 2007-06-05 2012-05-29 Hanmi Holdings Co., Ltd. Amide derivative for inhibiting the growth of cancer cells
WO2020009156A1 (fr) * 2018-07-04 2020-01-09 第一三共株式会社 Dérivé de quinazoline de type éther de biaryle

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WO2005026151A1 (fr) * 2003-09-16 2005-03-24 Astrazeneca Ab Dérivés de quinozaline en tant qu'inhibiteurs de la tyrosine kinase
US8188102B2 (en) * 2007-06-05 2012-05-29 Hanmi Holdings Co., Ltd. Amide derivative for inhibiting the growth of cancer cells
WO2020009156A1 (fr) * 2018-07-04 2020-01-09 第一三共株式会社 Dérivé de quinazoline de type éther de biaryle

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DONG QIUJU, YU PENGFEI, YE LIANG, ZHANG JIANZHAO, WANG HONGBO, ZOU FANGXIA, TIAN JINGWEI, KURIHARA HIROSHI: "PCC0208027, a novel tyrosine kinase inhibitor, inhibits tumor growth of NSCLC by targeting EGFR and HER2 aberrations", SCIENTIFIC REPORTS, vol. 9, no. 1, 1 December 2019 (2019-12-01), XP055773225, DOI: 10.1038/s41598-019-42245-3 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3822263A4 (fr) * 2018-07-04 2022-03-16 Daiichi Sankyo Company, Limited Dérivé de quinazoline de type éther de biaryle
WO2021231400A1 (fr) * 2020-05-12 2021-11-18 Accutar Biotechnology, Inc. Bis-aryl éthers contenant de la n-acyl azétidine en tant qu'inhibiteurs de l'egfr/her2

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