WO2024005516A1 - Composé dérivé d'hétéroaryle et son utilisation - Google Patents

Composé dérivé d'hétéroaryle et son utilisation Download PDF

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WO2024005516A1
WO2024005516A1 PCT/KR2023/008973 KR2023008973W WO2024005516A1 WO 2024005516 A1 WO2024005516 A1 WO 2024005516A1 KR 2023008973 W KR2023008973 W KR 2023008973W WO 2024005516 A1 WO2024005516 A1 WO 2024005516A1
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Prior art keywords
cancer
alkyl
halo
ring
membered
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PCT/KR2023/008973
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English (en)
Korean (ko)
Inventor
고이경
이영덕
이화
조서현
황동근
이승주
임혜림
한아름
남수빈
조세린
허명회
손정범
고은화
김남두
최환근
김성환
김대권
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보로노이 주식회사
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Publication of WO2024005516A1 publication Critical patent/WO2024005516A1/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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • the present invention relates to heteroaryl derivative compounds and their medicinal uses. Specifically, the present invention relates to heteroaryl derivative compounds having EGFR inhibitory activity.
  • Protein kinases are involved in signal transduction pathways by acting as molecular switches, and the transition between the active and inactive states of the target protein by the kinase within the cell must be smoothly regulated. If the transition between the active and inactive states is abnormally regulated, intracellular signaling is excessively activated or deactivated, leading to uncontrolled cell division and proliferation. In particular, abnormal activation due to mutation, amplification, and/or overexpression of protein kinase genes causes the development and progression of various tumors or plays a critical role in the development of various diseases such as inflammatory diseases, degenerative brain diseases, and autoimmune diseases.
  • Epidermal growth factor receptor a receptor tyrosine kinase of the ErbB family
  • NSCLC non-small cell lung carcinoma
  • breast cancer glioma, squamous cell carcinoma of the head and neck, colorectal cancer, and rectal adenocarcinoma.
  • EGFR-tyrosine kinase is abnormally activated in many epithelial tumors, including head and neck cancer, stomach cancer, and prostate cancer, and activation of the EGFR-tyrosine kinase causes continuous cell proliferation, invasion into surrounding tissues, distant metastasis, blood vessel formation, and increases cell survival.
  • Sikkim is known.
  • EGFR Del19/T790M or EGFR L858R/T790M double mutation occurs, making existing treatments ineffective.
  • Osimertinib a third-generation EGFR-TKI targeting drug that shows high responsiveness to drug resistance due to the EGFR T790M mutation, has been developed, but it has also been reported to cause drug resistance (Clin Cancer Res, 2015, 17: 21).
  • the EGFR C797S mutation has been suggested as one of the main mechanisms causing drug resistance to osimertinib, and it has been reported that approximately 40% of clinical trial patients have the EGFR C797S mutation (Nature Medicine, 2015, 21:560-562).
  • the purpose of the present invention is to provide heteroaryl derivatives with novel structures, stereoisomers thereof, or pharmaceutically acceptable salts thereof.
  • Another object of the present invention is to provide a method for producing the heteroaryl derivative compound.
  • Another object of the present invention is to provide a medicinal use of the heteroaryl derivative compound, specifically, a pharmaceutical composition for the treatment or prevention of EGFR-related diseases comprising the heteroaryl derivative compound as an active ingredient, and EGFR-related disease using the compound.
  • a method for treating or preventing a disease or a method for treating or preventing an EGFR-related disease including the step of administering the compound.
  • the present invention was completed by confirming that heteroaryl derivative compounds represented by Chemical Formula 1 mentioned below inhibit the proliferation of EGFR-activated cells.
  • X 1 to X 3 are each independently CR 1 , NR 2 , O, or S;
  • R 1 is -H, -C 1-6 alkyl, -C 1-6 aminoalkyl, -C 1-6 hydroxyalkyl, -C 1-6 haloalkyl, -CN, -OR c , -halo, or - C 3-6 cycloalkyl;
  • R 2 is -H or -C 1-6 alkyl
  • Y 1 to Y 4 are each independently CR 3 or N ⁇ here, Y 1 and Y 2 or Y 2 and Y 3 are connected to each other to form 6-membered aryl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl , or may form a 5-6 membered heterocycloalkenyl [In this case, one of the 6-membered aryl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkenyl ring.
  • R 3 is -H, -C 1-6 alkyl, -C 1-6 aminoalkyl, -C 1-6 hydroxyalkyl, -C 1-6 haloalkyl, -CN, -OR c , -halo, or - C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-10 membered heteroaryl ⁇ wherein the -C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, or 5-10 membered
  • One or more H of the original heteroaryl ring may be substituted with -C 1-6 alkyl, -OC 1-6 alkyl, or -halo ⁇ ;
  • W 1 and W 2 are each independently -C 1-6 alkyl, or W 1 and W 2 may be linked to each other to form a 4-7 membered ring together with the P atom;
  • Z 1 is CH or N
  • V 1 is -C 1-6 alkyl, -C 1-6 haloalkyl, -OC 1-6 alkyl, -OC 1-6 haloalkyl, or -halo;
  • R a and R b are each independently -C 1-6 alkyl or -C 1-6 haloalkyl
  • R c is -H, -C 1-6 alkyl, -C 1-6 haloalkyl, or phenyl;
  • R d is -H, -C 1-6 alkyl, -OH, or -OC 1-6 alkyl
  • X 1 and X 2 are each independently CR 1 , NR 2 , O, or S;
  • R 2 is -H or -C 1-6 alkyl
  • R 3 is -H, -C 1-6 alkyl, -CN, -OR c , -halo, or -C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, or 5-10 membered heteroaryl; ⁇ Wherein, one or more H of the -C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, or 5-10 membered heteroaryl ring is -C 1-6 alkyl, -OC 1-6 alkyl, or -can be substituted with halo ⁇ ;
  • W 1 and W 2 are each independently -C 1-6 alkyl, or W 1 and W 2 may be linked to each other to form a 5-6 membered ring with the P atom;
  • Z 1 is CH or N
  • V 1 is -C 1-6 alkyl, -OC 1-6 alkyl, -OC 1-6 haloalkyl, or -halo;
  • Ring A is a single ring heterocycloalkyl or multiple ring heterocycloalkyl ⁇ wherein the single ring heterocycloalkyl or multiple ring heterocycloalkyl contains any one or more of N, O, or S atoms in the ring. And, at least one H of the single-ring heterocycloalkyl or multi-ring heterocycloalkyl is -C 1-6 alkyl, -C 1-6 aminoalkyl, -C 1-6 haloalkyl, -C 1-6 halo.
  • R a and R b are each independently -H, -C 1-6 alkyl, or -C 1-6 haloalkyl;
  • R c is -H, -C 1-6 alkyl, -C 1-6 haloalkyl, or phenyl;
  • R d is -H, -C 1-6 alkyl, or -OC 1-6 alkyl
  • n 0, 1, or 2.
  • the compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof may be in the following range:
  • X 1 and X 2 are each independently CR 1 , NH, O, or S;
  • X 3 is CR 1 ;
  • R 1 is -H, -C 1-4 alkyl or -halo.
  • the compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof may be in the following range:
  • R 3 is -H, -C 1-4 alkyl, -CN, -OC 1-4 alkyl, -OC 1-4 haloalkyl, -O-phenyl, -halo, or -C 3-6 cycloalkyl, 4- 6-membered heterocycloalkyl, phenyl, or 5-10 membered heteroaryl ⁇ wherein one or more H of the -C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, or 5-10 membered heteroaryl ring may be substituted with -C 1-4 alkyl, -OC 1-4 alkyl, or -halo ⁇ .
  • the compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof may be in the following range:
  • Z 1 is CH or N
  • V 1 is -C 1-4 alkyl, -OC 1-4 alkyl, -OC 1-4 haloalkyl, or -halo;
  • Ring A is a single ring heterocycloalkyl or multiple ring heterocycloalkyl ⁇ wherein the single ring heterocycloalkyl or multiple ring heterocycloalkyl contains any one or more of N, O, or S atoms in the ring. And, at least one H of the single-ring heterocycloalkyl or multi-ring heterocycloalkyl is -C 1-4 alkyl, -C 1-4 aminoalkyl, -C 1-4 haloalkyl, -C 1-4 halo.
  • R a and R b are each independently -C 1-4 alkyl or -C 1-4 haloalkyl
  • n 0 or 1.
  • the compound represented by Formula 1 may be selected from the group consisting of compounds listed in Table 1 below.
  • alkyl may mean a straight-chain or branched-chain acyclic, cyclic, or saturated hydrocarbon in which these are combined.
  • C 1-6 alkyl can mean alkyl containing 1 to 6 carbon atoms.
  • Acyclic alkyl may include, for example, methyl, ethyl, n -propyl, n -butyl, isopropyl, sec )-butyl, isobutyl, or tertiary ( tert )-butyl, etc. It is not limited to this.
  • Cyclic alkyl may be used interchangeably with “cycloalkyl” herein and may include, but is limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, as examples. It doesn't work.
  • alkoxy may mean -(O-alkyl) as an alkyl ether group, where alkyl is as defined above.
  • C 1-6 alkoxy may mean alkoxy containing C 1-6 alkyl, that is, -(OC 1-6 alkyl).
  • alkoxy is methoxy (methoxy). ), ethoxy , n -propoxy, isopropoxy, n -butoxy , isobutoxy , sec -butoxy ), or tert -butoxy, etc., but is not limited thereto.
  • halo may be F, Cl, Br, or I.
  • haloalkyl may mean a straight or branched chain alkyl (hydrocarbon) having carbon atoms substituted with one or more halo as defined herein.
  • haloalkyls include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, or n -butyl independently substituted with one or more halogens, such as F, Cl, Br, or I. .
  • aminoalkyl may refer to a straight-chain or branched-chain alkyl (hydrocarbon) having a carbon atom substituted with amino (NR'R").
  • R' and R" are each independently hydrogen, It may be selected from the group consisting of C 1-6 alkyl, and N protecting group (eg, Boc), and the selected R' and R" may each be independently substituted or unsubstituted.
  • cyanoalkyl may mean straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with cyano (CN).
  • unsaturated it may be referred to as cycloalkenyl.
  • cycloalkyls can be single rings or multiple rings such as spiro rings, bridged rings, or fused rings.
  • unsaturated it may be referred to as a heterocycloalkene.
  • heterocycloalkyl may be a single ring or multiple rings such as spiro rings, bridged rings, or fused rings.
  • heterocycloalkyl of 3 to 12 atoms may mean heterocycloalkyl containing 3 to 12 atoms forming a ring.
  • heterocycloalkyl includes pyrrolidine, piperidine, Imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4 (1 H , 3 H ) -Dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine- S -oxide, thiomorpholine- S , S -oxide, piperazine, pyran, pyridone, 3-pyrroline, thiophyte Ran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]heptane, (1 R ,5 S )-3-azabicyclo[3.2.1]octane, ( It may include 1 S , 4 S ,
  • arene may mean an aromatic hydrocarbon ring.
  • the arenes may be monocyclic arenes or polycyclic arenes.
  • the number of ring-forming carbon atoms of the arene may be 5 or more and 30 or less, 5 or more and 20 or less, or 5 or more and 15 or less.
  • examples of arenes include benzene, naphthalene, fluorene, anthracene, phenanthrene, bibenzene, terbenzene, quarterbenzene, quincbenzene, sexybenzene, triphenylene, pyrene, benzofluoranthene, chrysene, etc. , but is not limited to these.
  • the residue obtained by removing one hydrogen atom from the “arene” is referred to as “aryl.”
  • heteroene may be a ring containing one or more of O, N, P, Si, and S as a heterogeneous element.
  • the number of ring-forming carbon atoms of the heteroarene may be 2 to 30 or 2 to 20.
  • the heteroarene may be a monocyclic heteroarene or a polycyclic heteroarene.
  • Polycyclic heteroarene may have, for example, a 2-ring or 3-ring structure.
  • pyrazine quinoline, quinazoline, quinoxaline, phenoxazine, phthalazine, pyrimidine, pyrido pyrimidine, pyrido pyrazine, pyrazino pyrazine, isoquinoline, indole, carbazole, imidazopyridazine, imidazopyridine.
  • stereoisomer refers to a compound that has the same chemical or molecular formula but is sterically different.
  • stereoisomers include optical isomers, enantiomers, diastereomers, cis/trans isomers, rotamers, and atropisomers. Includes, and each of these isomers, racemics, and mixtures thereof are also included within the scope of the present invention.
  • Formula 1 of the present invention may include the stereoisomers of Formula 1 because the stereochemical structure is not specified. Solid bonds connecting asymmetric carbon atoms, unless otherwise noted. The solid wedge-shaped bond represents the absolute arrangement of the stereogenic centers. or wedge-dotted join may include.
  • the compound represented by Formula 1 of the present invention may exist in the form of a “pharmaceutically acceptable salt.” Accordingly, the scope of the compound of the present invention includes pharmaceutically acceptable salts of the compound represented by Formula 1 above.
  • pharmaceutically acceptable salt refers to any of the compounds at a concentration that is relatively non-toxic and harmless to patients and has an effective effect, and side effects due to the salt do not reduce the beneficial efficacy of the compound represented by Formula 1. refers to all organic or inorganic acid addition salts.
  • These pharmaceutically acceptable salts include sulfate, sulfite, nitrate, phosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, and acrylate. , formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, benzoate, phthalate, benzenesulfonate, toluenesulfo. It may include nate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, glycolate, malate, tartrate, mandelate, etc.
  • a pharmaceutically acceptable metal salt can be prepared using a base.
  • the alkali metal salt or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare metal salts, especially sodium, potassium, or calcium salts, but is not limited to these.
  • the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with an appropriate silver salt (e.g., silver nitrate).
  • the present invention provides the use of a compound represented by the following formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • the compound represented by Formula 1 of the present invention exhibits inhibitory activity against various kinases.
  • the heteroaryl derivative represented by Formula 1 exhibits excellent inhibitory activity against EGFR kinase and can be usefully used in the treatment or prevention of EGFR-related diseases, especially cancer.
  • the heteroaryl derivative compound of the present invention exhibits excellent inhibitory activity against EGFR mutations (e.g., EGFR Del19/C797S, EGFR L858R/C797S, EGFR Del19/T790M/C797S, or EGFR L858R/T790M/C797S, etc.) It can be useful in the treatment or prevention of carcinoma induced by EGFR.
  • the cancer includes all cancers that can exhibit therapeutic or preventive efficacy due to inhibition of EGFR kinase activity, and may be solid cancer or blood cancer.
  • the type of cancer is not limited, but includes, for example, pseudomyxoma, intrahepatic bile duct cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, oral cavity cancer, mycosis fungoides, acute myeloid leukemia, Acute lymphocytic leukemia, basal cell cancer, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colon cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma , ampulla of Vater cancer,
  • Carcinoid cancer vaginal cancer, spinal cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer , it may be one or more types selected from the group consisting of pleural cancer, blood cancer, and thymic cancer. Additionally, the cancer includes not only primary cancer but also metastatic cancer.
  • the present invention provides a pharmaceutical composition for the treatment or prevention of EGFR-related diseases containing the compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the EGFR-related disease may be cancer.
  • the types of cancer are as mentioned above.
  • the present invention provides a compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for the production of a medicament for the treatment or prevention of EGFR-related diseases.
  • the EGFR-related disease may be cancer.
  • the types of cancer are as mentioned above.
  • the present invention relates to the use of a compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for use in the manufacture of a drug for the treatment or prevention of cancer diseases.
  • a compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for use in the manufacture of a drug for the treatment or prevention of cancer diseases.
  • the types of cancer are as mentioned above.
  • administering a therapeutically effective amount of the compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof.
  • a method of treating or preventing EGFR-related diseases including:
  • the subject may be a mammal, including humans.
  • the EGFR-related disease may be cancer.
  • the types of cancer are as mentioned above.
  • the present invention provides a step of administering a therapeutically effective amount of the compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof.
  • a method of treating or preventing cancer including: The types of cancer are as mentioned above.
  • the present invention provides a step of administering a therapeutically effective amount of the compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof. It provides a method of inhibiting EGFR, comprising:
  • therapeutically effective amount used in the present invention refers to the amount of the compound represented by Formula 1 that is effective in treating or preventing EGFR-related diseases.
  • therapeutically effective amount means an amount sufficient to treat the disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is determined by the type and severity of the individual, age, gender, type of disease, It can be determined based on factors including the activity of the drug, sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, drugs used simultaneously, and other factors well known in the medical field.
  • the pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with commercially available therapeutic agents.
  • the administered dose of the pharmaceutical composition of the present invention may be determined by an expert depending on various factors such as the patient's condition, age, gender, and complications. Since the active ingredient of the pharmaceutical composition of the present invention has excellent safety, it can be used at a dose exceeding the determined dosage.
  • prevention refers to all actions that inhibit or delay the occurrence, spread, and recurrence of the disease by administering the compound
  • treatment means improving the symptoms of the disease or improving the symptoms of the disease by administering the compound. It refers to all actions that are beneficially changed.
  • the pharmaceutical composition may further include a pharmaceutically acceptable carrier, diluent, or excipient.
  • the present invention provides a pharmaceutical composition comprising the compound represented by Formula 1, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable additive.
  • additives used in the pharmaceutical composition may include sweeteners, binders, solvents, solubilizers, wetting agents, emulsifiers, isotonic agents, absorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, flavoring agents, etc.
  • the additives include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, magnesium aluminosilicate, starch, gelatin, gum tragacanth, It may contain alginic acid, sodium alginate, methylcellulose, sodium carboxymethylcellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor, etc.
  • the pharmaceutical composition may be formulated in various formulation forms for oral administration (e.g., tablets, pills, powders, capsules, syrups or emulsions) or parenteral administration (e.g., intramuscular, intravenous or subcutaneous injection).
  • oral administration e.g., tablets, pills, powders, capsules, syrups or emulsions
  • parenteral administration e.g., intramuscular, intravenous or subcutaneous injection.
  • the pharmaceutical composition can be formulated into a formulation for oral administration, and additives used in this case include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, It may contain calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifiers, diluents, etc.
  • solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations contain at least one excipient, such as starch, calcium carbonate, sucrose, and lactose. It can be formulated by mixing , gelatin, etc.
  • liquid preparations for oral administration include suspensions, emulsions, syrups, etc., and in addition to the commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, preservatives, etc. may be included.
  • preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories.
  • Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate.
  • injectables may contain conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, preservatives, etc.
  • heteroaryl derivative compound of the present invention exhibits excellent inhibitory activity against EGFR, it can be usefully used in the treatment or prevention of the above-mentioned EGFR-related diseases.
  • room temperature or room temperature refers to a temperature of 5°C to 40°C, as an example, 10°C to 30°C, and as another example, 20°C to 27°C, and is not strictly limited to the above range.
  • Concentration or solvent distillation under reduced pressure was performed using a rotary evaporator.
  • tert-butyl (3,4-difluoro-2-iodophenyl) carbamate (1.0 equivalent) obtained in step 2 was dissolved in dichloromethane (DCM; 0.2 M) and then added to trifluoroacetic acid (TFA; 60.0 M). equivalent) was added and stirred at room temperature for 30 minutes.
  • the reaction mixture was concentrated and purified by MPLC (dichloromethane:methanol) to obtain the target compound as a yellow solid (yield: 54%, MS (ESI): m/z 255 [M+H] + ).
  • Example 1 (2,3-difluoro-6-((2-((4-(9-(1-fluoro-2-methylpropan-2-yl)-3,9-diazaspiro[ 5.5]undecan-3-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidine- Preparation of 4-yl) amino) phenyl) dimethylphosphine oxide
  • Step 2 (2,3-difluoro-6-((2-((4-(9-(1-fluoro-2-methylpropan-2-yl)-3,9-diazaspiro[ 5.5]undecan-3-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-7-((2-(trimethylsilyl)ethoxy)
  • Step 3 (2,3-difluoro-6-((2-((4-(9-(1-fluoro-2-methylpropan-2-yl)-3,9-diazaspiro[ 5.5]undecan-3-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
  • Example 2 The compounds of Examples 2 to 282 were prepared in a similar manner to Example 1, and the chemical structures, compound names, NMR, and LC-MS analysis results of the compounds of Examples 1 to 282 are summarized in Table 1 below.
  • the compound according to the present invention was reacted with purified human EGFR[Del19(d746-750)/T790M/C797S] (668-end, SignalChem) enzyme and a specific substrate to evaluate the enzyme inhibition ability in the following manner.
  • the reaction buffer was used in the composition of 40mM Tris-HCl pH 7.4, 2mM MgCl 2 , 0.5 mg/ml BSA, and 50 ⁇ M DTT, and reactions of all test substances were performed on the reaction buffer.
  • the enzyme activity reaction solution, ADP-Glo reaction solution, and enzyme activity detection solution were reacted at a ratio of 2:2:1, and the degree of enzyme activity inhibition was measured by Luminescence.
  • the degree of enzyme activity inhibition according to the treatment concentration of each compound was calculated based on the luminescence of the enzyme activity in the solvent control group that was not treated with the compound.
  • IC 50 ( ⁇ M) values were calculated using GraphPad Prism 8.4.3 (GraphPad software Inc., San Diego). The results are shown in Table 2 below.
  • Ba/F3 cells were cultured using RPMI-1640 containing 10% FBS, and 24 hours before treatment with the compound, 3000 cells were seeded into each well of a white clear bottom 96 well plate (Corning). .
  • the compound was diluted in dimethyl sulfoxide (diluted 3 times, total of 12 concentrations) and injected at 1 ⁇ l each so that the final concentration was 0.2 nM - 5 ⁇ M.
  • Measurement of living cells is done by reacting in a CO 2 incubator at 37°C for 72 hours after treatment with the compound, then using Cell Titer-Glo luminescent cell-viability reagent (Promega), storing it at room temperature for 10 minutes, and then using a reader (SynergyNeo2, Biotek). The luminescence intensity was measured using . The results were calculated as cell growth ratio (%) compared to the control group.
  • GI 50 values were calculated using GraphPad Prism 8.4.3 (GraphPad software Inc., San Diego), and the results are shown in Table 3

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Abstract

La présente invention concerne un dérivé d'hétéroaryle et son utilisation. Le dérivé d'hétéroaryle de la présente invention présente une excellente activité inhibitrice contre l'EGFR, et peut ainsi être efficacement utilisé en tant qu'agent thérapeutique pour des maladies associées à l'EGFR.
PCT/KR2023/008973 2022-06-28 2023-06-27 Composé dérivé d'hétéroaryle et son utilisation WO2024005516A1 (fr)

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KR20220079222 2022-06-28
KR20220079226 2022-06-28

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140024620A1 (en) * 2010-10-14 2014-01-23 Ariad Pharmaceuticals, Inc. Methods for Inhibiting Cell Proliferation in EGFR-Driven Cancers
US20140066406A1 (en) * 2008-05-21 2014-03-06 Ariad Pharmaceuticals, Inc. Phosphorus Derivatives as Kinase Inhibitors
CN110526941A (zh) * 2018-05-24 2019-12-03 北京赛特明强医药科技有限公司 一种含有间氯苯胺类取代基的吡咯并嘧啶类化合物、制备方法及其应用
KR20200032146A (ko) * 2017-07-19 2020-03-25 치아타이 티안큉 파마수티컬 그룹 주식회사 Egfr 키나제 억제제로써의 아릴-인-산소 화합물
WO2020253862A1 (fr) * 2019-06-21 2020-12-24 上海翰森生物医药科技有限公司 Inhibiteur du dérivé d'oxyde de phosphore aryle contenant de l'azote, son procédé de préparation et son utilisation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140066406A1 (en) * 2008-05-21 2014-03-06 Ariad Pharmaceuticals, Inc. Phosphorus Derivatives as Kinase Inhibitors
US20140024620A1 (en) * 2010-10-14 2014-01-23 Ariad Pharmaceuticals, Inc. Methods for Inhibiting Cell Proliferation in EGFR-Driven Cancers
KR20200032146A (ko) * 2017-07-19 2020-03-25 치아타이 티안큉 파마수티컬 그룹 주식회사 Egfr 키나제 억제제로써의 아릴-인-산소 화합물
CN110526941A (zh) * 2018-05-24 2019-12-03 北京赛特明强医药科技有限公司 一种含有间氯苯胺类取代基的吡咯并嘧啶类化合物、制备方法及其应用
WO2020253862A1 (fr) * 2019-06-21 2020-12-24 上海翰森生物医药科技有限公司 Inhibiteur du dérivé d'oxyde de phosphore aryle contenant de l'azote, son procédé de préparation et son utilisation

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