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WO2025214341A1 - Composé dihydrofuro[3,4-f]quinazoline, son procédé de préparation et son utilisation en médecine - Google Patents

Composé dihydrofuro[3,4-f]quinazoline, son procédé de préparation et son utilisation en médecine

Info

Publication number
WO2025214341A1
WO2025214341A1 PCT/CN2025/087757 CN2025087757W WO2025214341A1 WO 2025214341 A1 WO2025214341 A1 WO 2025214341A1 CN 2025087757 W CN2025087757 W CN 2025087757W WO 2025214341 A1 WO2025214341 A1 WO 2025214341A1
Authority
WO
WIPO (PCT)
Prior art keywords
cancer
compound
kras
pharmaceutically acceptable
pharmaceutical composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/087757
Other languages
English (en)
Chinese (zh)
Inventor
李心
沈峰
桂斌
陈阳
贺峰
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Hengrui Pharmaceutical Co Ltd
Jiangsu Hengrui Pharmaceutical Co Ltd
Original Assignee
Shanghai Hengrui Pharmaceutical Co Ltd
Jiangsu Hengrui Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Hengrui Pharmaceutical Co Ltd, Jiangsu Hengrui Pharmaceutical Co Ltd filed Critical Shanghai Hengrui Pharmaceutical Co Ltd
Publication of WO2025214341A1 publication Critical patent/WO2025214341A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present disclosure relates to the field of medicine and relates to a dihydrofuro[3,4-f]quinazoline compound, a preparation method thereof, and its pharmaceutical application.
  • the present disclosure relates to a dihydrofuro[3,4-f]quinazoline compound represented by Formula 1, a preparation method thereof, a pharmaceutical composition containing the compound, and its use in the preparation of a medicament for inhibiting KRAS amplification and/or mutant activity.
  • the KRAS protein encoded by the KARS gene, is a small GTPase that belongs to the RAS superprotein family. Within cells, the KRAS protein transitions between inactive and activated states. When bound to guanosine diphosphate (GDP), KRAS is inactive, and when bound to guanosine triphosphate (GTP), it is activated, leading to the activation of downstream signaling pathways.
  • GDP guanosine diphosphate
  • GTP guanosine triphosphate
  • KRAS can be activated by upstream growth factors and other tyrosine kinases (such as EGFR). Following activation, KRAS activates downstream pathways such as the RAS-RAF-MEK-ERK and PI3K-AKT-mTOR signaling pathways, which regulate cell proliferation and growth.
  • KRAS is one of the most common oncogenes in solid tumors. Approximately 19% of tumors harbor KRAS mutations, including ⁇ 90% of pancreatic cancers, ⁇ 50% of colon cancers, and ⁇ 30% of lung adenocarcinomas. KRAS mutations also occur in a certain proportion of other cancer types, such as bile duct cancer, cervical cancer, bladder cancer, liver cancer, and breast cancer. The most common sites of gene mutation are codons 12, 13, and 61, with mutations at codon 12 being the most common. KRAS mutations increase the activation of RAS in the GTP-bound state, activating downstream pathways. Furthermore, KRAS amplification/overexpression or upstream activation can occur in tumors, all of which can lead to persistent activation of the RAS downstream pathway and contribute to tumorigenesis.
  • KRAS protein lacks traditional small molecule binding sites on its surface and has an extremely high affinity for guanylate, making it difficult to competitively inhibit with small molecules, it has long been considered an undruggable drug target.
  • KRAS has been and remains a highly sought-after target for drug development.
  • inhibitors targeting KRAS G12C and G12D have been approved or are in clinical trials, so there is still a need to develop pan-KRAS inhibitors for the treatment of multiple KRAS-mutant tumors or KRAS-dependent tumors.
  • Typical compounds of the present disclosure include, but are not limited to:
  • Another aspect of the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound shown in Table A of the present disclosure or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present disclosure further relates to the use of a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for inhibiting KRAS amplification and/or KRAS mutant activity; in some embodiments, the KRAS mutant is selected from one or more of KRAS G12A, G12C, G12D, G12V, G12R, G12S, G13A, G13C, G13D, G13R, G13S, G13V, Q61E, Q61H, Q61K, Q61L, Q61P, Q61R, A146T, A146P, A146V and A146T mutations; in some embodiments, it is KRAS G12D and/or KRAS G12V mutation.
  • the present disclosure further relates to the use of a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for treating and/or preventing a disease or condition mediated by KRAS amplification and/or KRAS mutation.
  • the present disclosure further relates to the use of a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for treating and/or preventing cancer;
  • the cancer is selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pleural cancer, peritoneal cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, bladder cancer, anal cancer, joint cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer,
  • the present disclosure further relates to a method for inhibiting KRAS amplification and/or KRAS mutant activity, comprising administering a therapeutically effective amount of a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same to a patient in need thereof.
  • the present disclosure further relates to a method for treating and/or preventing diseases or conditions mediated by KRAS amplification and/or KRAS mutations, comprising administering to a patient in need thereof a therapeutically effective amount of a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the present disclosure further relates to a method for treating and/or preventing cancer, comprising administering a therapeutically effective amount of a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same to a patient in need thereof.
  • the present disclosure further relates to a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.
  • the present disclosure further relates to a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in inhibiting the activity of KRAS amplification and/or KRAS mutants.
  • the present disclosure further relates to a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in treating and/or preventing diseases or conditions mediated by KRAS amplification and/or KRAS mutations.
  • the present disclosure further relates to a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in treating and/or preventing cancer.
  • the diseases or conditions described herein are diseases or conditions that are treated and/or prevented by inhibiting KRAS amplification and/or KRAS mutant activity.
  • the diseases or conditions mediated by KRAS amplification and/or KRAS mutations described in the present disclosure are cancers.
  • the KRAS mutations are selected from one or more of KRAS G12A, G12C, G12D, G12V, G12R, G12S, G13A, G13C, G13D, G13R, G13S, G13V, Q61E, Q61H, Q61K, Q61L, Q61P, Q61R, A146T, A146P, A146V, and A146T mutations, and in some embodiments are KRAS G12D and/or KRAS G12V mutations.
  • the cancer Selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, stomach cancer, lung cancer, liver cancer, kidney cancer, pleural cancer, peritoneal cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, bladder cancer, anal cancer, joint cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, melanoma, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma and glioblastoma; in some embodiments selected from pan
  • the colorectal cancer described in the present disclosure is colon cancer or rectal cancer.
  • the brain cancer described in the present disclosure is selected from glioblastoma multiforme or neuroblastoma; soft tissue cancer is selected from fibrosarcoma, gastrointestinal sarcoma, rhabdomyomas, leiomyosarcomas, dedifferentiated liposarcoma, pleomorphic liposarcoma, malignant fibrous histiocytoma, round cell sarcoma and synovial sarcoma; lymphoma is selected from Hodgkin's disease and non-Hodgkin's lymphoma (e.g., mantle cell lymphoma, diffuse large B-cell lymphoma, follicle center lymphoma, marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma and peripheral T-cell lymphoma); in some embodiments, liver cancer is hepatocellular carcinoma; lung cancer (also known as bronchogenic carcinoma) is selected from non-small cell lung cancer and non-Hodgkin's
  • the active compound can be formulated into a form suitable for administration by any appropriate route, and the compositions of the present disclosure can be formulated using one or more pharmaceutically acceptable carriers by conventional methods.
  • the active compounds of the present disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or insufflation.
  • the compounds of the present disclosure can also be formulated into dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges, or syrups.
  • a unit dosage form of a compound or composition of the present disclosure can be a tablet, capsule, cachet, bottled solution, powder, granule, lozenge, suppository, reconstituted powder, or liquid formulation.
  • Suitable unit dosage forms can range from 0.1 to 1000 mg.
  • the pharmaceutical composition of the present disclosure may contain one or more excipients in addition to the active compound, selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.
  • the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.
  • the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution, based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In some embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution.
  • the pharmaceutical composition contains 0.01% to 99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% of a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% of a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition contains 1% to 99% of a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition contains 2% to 98% of a pharmaceutically acceptable excipient.
  • Tablets contain the active ingredient in admixture with nontoxic, pharmaceutically acceptable excipients suitable for tablet preparation. These excipients may include inert excipients, granulating agents, disintegrants, binders, and lubricants. Tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained-release effect over a longer period of time.
  • Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or with a water-soluble carrier or oil-soluble vehicle.
  • Aqueous suspensions contain the active substance in admixture with excipients suitable for the preparation of aqueous suspensions. Such excipients are suspending agents, dispersing agents, or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.
  • Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil or mineral oil.
  • the oil suspension may contain a thickener.
  • the above-mentioned sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by adding antioxidants.
  • compositions of the present disclosure may also be in the form of oil-in-water emulsions.
  • the oil phase may be a vegetable oil, a mineral oil, or a mixture thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavorings, preservatives, and antioxidants.
  • Such formulations may also contain demulcents, preservatives, colorants, and antioxidants.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous solutions.
  • Acceptable vehicles or solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution.
  • Sterile injectable formulations may be sterile injectable oil-in-water microemulsions in which the active ingredient is dissolved in an oil phase.
  • the injectable solution or microemulsion may be injected into the patient's bloodstream by local bolus injection.
  • it is preferred that the solutions and microemulsions be administered in a manner that maintains a constant circulating concentration of the disclosed compound.
  • a continuous intravenous drug delivery device may be used.
  • An example of such a device is the Deltec CADD-PLUSTM 5400 intravenous pump.
  • compositions of the present disclosure may be in the form of sterile water for injection or oil suspensions for intramuscular and subcutaneous administration.
  • the suspensions may be prepared using suitable dispersants or wetting agents and suspending agents as described above according to known techniques.
  • Sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in parenteral, nontoxic diluents or solvents.
  • sterile fixed oils may be conveniently used as solvents or suspension media. For this purpose, any blended fixed oil may be used.
  • fatty acids may also be used to prepare injections.
  • the disclosed compounds can be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.
  • the compounds of the present disclosure can be administered by preparing water-suspended dispersible powders and granules by adding water.
  • These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, a suspending agent, or one or more preservatives.
  • the dosage of a drug depends on a variety of factors, including but not limited to the following: the activity of the specific compound used, the severity of the disease, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment method such as the mode of treatment, the daily dose of the compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.
  • the compounds of the present disclosure may include all forms of rotational isomers and conformationally restricted states thereof. Also included are atropisomers, the term "atropisomer" being a stereoisomer resulting from hindered rotation around a single bond, where the energy difference due to steric strain or other contributing factors forms a sufficiently high rotation barrier to allow separation of individual conformers.
  • certain compounds of the present disclosure may exist in the form of a mixture of atropisomers (e.g., an equal proportion mixture, a mixture enriched in one atropisomer, etc.) or a purified atropisomer.
  • Non-limiting examples include:
  • tautomer or tautomeric form refers to structural isomers of different energies that can interconvert via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • proton migration such as keto-enol and imine-enamine, lactam-lactim isomerizations.
  • An example of a keto-enol equilibrium is shown below:
  • stereoisomer refers to isomers with the same structure but different arrangements of atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (such as racemates, mixtures of diastereomers).
  • the substituents in the compounds of the present disclosure may have additional asymmetric atoms. All of these stereoisomers and their mixtures are included within the scope of the present disclosure.
  • Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers and (D)- and (L)-isomers can be prepared by chiral synthesis, chiral reagents or other conventional techniques.
  • An isomer of a compound disclosed herein can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, or, when the molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), by forming a diastereomeric salt with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art to obtain the pure isomer. Furthermore, separation of enantiomers and diastereoisomers is typically accomplished by chromatography.
  • a basic functional group e.g., an amino group
  • an acidic functional group e.g., a carboxyl group
  • separation of enantiomers and diastereoisomers is typically accomplished by chromatography.
  • the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or include both Two configurations; key
  • the configuration is not specified, that is, it can be Z configuration or E configuration, or contain both configurations.
  • isotopic derivatives refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass.
  • isotopes that can be incorporated into compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, such as, respectively, 2 H (deuterium, D), 3 H (tritium, T), 2 C, 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I, and 131 I, etc., in some embodiments, deuterium.
  • deuterated drugs Compared to non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, whether radioactive or not, are encompassed by the present disclosure.
  • Each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom, where the deuterium replacement can be partial or complete.
  • Partial deuterium replacement refers to the replacement of at least one hydrogen atom with at least one deuterium atom.
  • Optionally or “optionally” means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not.
  • C 1-6 alkyl optionally substituted with halogen or cyano means that halogen or cyano may but need not be present, and the description includes instances where the alkyl is substituted with halogen or cyano and instances where the alkyl is not substituted with halogen or cyano.
  • Substituted means that one or more hydrogen atoms, such as 1 to 6, and in some embodiments 1 to 3, in a group are independently replaced by a corresponding number of substituents.
  • substituents such as 1 to 6, and in some embodiments 1 to 3, in a group are independently replaced by a corresponding number of substituents.
  • an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.
  • a “pharmaceutical composition” refers to a mixture containing one or more compounds described herein, or pharmaceutically acceptable salts or prodrugs thereof, together with other chemical components, and other components such as pharmaceutically acceptable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.
  • “Pharmaceutically acceptable salts” refer to salts of the compounds of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective for use in mammals and possess the desired biological activity. Salts may be prepared during the final isolation and purification of the compound, or separately by reacting a suitable group with a suitable base or acid.
  • Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids and organic acids.
  • pharmaceutically acceptable refers to compounds, materials, compositions and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio, and effective for the intended use.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • MS was determined using Agilent 1200/1290DAD-6110/6120 Quadrupole MS liquid chromatography-mass spectrometer (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), Waters ACQuity UPLC-QD/SQD (manufacturer: Waters, MS model: Waters ACQuity Qda Detector/Waters SQ Detector), and THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).
  • HPLC High performance liquid chromatography
  • Chiral HPLC analysis was performed using an Agilent 1260DAD high performance liquid chromatograph.
  • HPLC High performance liquid chromatography
  • the CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm ⁇ 0.5mm.
  • Silica gel column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.
  • the average kinase inhibition rate and IC50 value were determined using a NovoStar microplate reader (BMG, Germany).
  • the known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Darui Chemicals.
  • Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.
  • Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.
  • the pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.
  • the hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.
  • Microwave reactions were performed using a CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature.
  • the reaction progress in the examples was monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • A dichloromethane/methanol system
  • B petroleum ether/ethyl acetate.
  • the volume ratio of the solvents was adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.
  • the isomeric mixture 1c (1 g) was separated by chiral column (Shimadzu LC-20AP, chromatographic column: DAICELCHIRALPAK IG, 20 ⁇ 250 mm, 5 ⁇ m; mobile phase A: n-hexane, mobile phase B: ethanol (0.1% 7 M NH 3 in MeOH), gradient ratio: A:B: 80:20, flow rate: 20 mL/min) to give the title compounds 1c-1 (450 mg, yield: 45%), 1c-2 (450 mg, yield: 45%).
  • the reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane. Water was added, and the aqueous phase was extracted with dichloromethane (15 mL ⁇ 2). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to obtain 1 g (211 mg, yield: 82.8%) of the title compound.
  • the isomer mixture 1h (90 mg) was separated by chiral column (Gilson-281, chromatographic column: CHIRALPAK IG, 20 ⁇ 250 mm, 5 ⁇ m; mobile phase A: n-hexane, mobile phase B: ethanol (0.1% 7 M ammonia methanol solution), gradient ratio: A:B: 70:30, flow rate: 20 mL/min), and the compound with a shorter retention time, namely 1 (30 mg, yield: 33.3%), was collected.
  • Example 2 The synthetic route of Example 1 was followed in steps 4 to 6, and the starting material compound 1c-1 in the fourth step was replaced by compound 1c-2 to obtain the title compound 2 (5 mg, yield: 8.4%).
  • Example 2 The synthetic route of Example 1 was followed in steps 4 to 6, and the raw material compound 1c-1 in the fourth step was replaced by ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a-yl)methanol to give the title compound 3 (300 mg, yield: 22.2%).
  • the compound was then further diluted 20-fold with culture medium. 10 ⁇ L of the test compound diluted in culture medium was added to each well of the plate. The final compound concentration was determined by a 5-fold series of nine concentration points, starting at 10 or 1 ⁇ M. Wells containing 0.5% DMSO served as vehicle controls, while wells containing only culture medium and 0.5% DMSO served as blank controls. After centrifugation at 2000 rpm for 3 minutes, the cell plate was placed in an incubator for 5 days. On the seventh day, the 96-well cell culture plate was removed and 50 ⁇ L of luminescent cell activity detection reagent was added to each well.
  • 3D Cell Viability Assay (Promega, G9683) was shaken at room temperature for 25 minutes, then pipetted to mix thoroughly and 100 ⁇ L was transferred from each well to a white opaque OptiPlate TM -96-well plate (PerkinElmer, 6005290). Luminescence signals were read using a multi-function microplate reader (PerkinElmer, EnVision 2105).
  • the IC50 value of the inhibitory activity of the compound was calculated using Graphpad Prism software. The results are shown in the table below.
  • SD rats were used as test animals, and the drug concentrations in the plasma of the rats at different times after oral administration (i.g.) of the example compounds were determined by LC-MS/MS to study the pharmacokinetic behavior of the disclosed compounds in rats and evaluate their pharmacokinetic characteristics.
  • Compound 1 Weigh a certain amount of the test compound and add 5% DMSO + 10% HS15 + 17% (w/v) SBE- ⁇ -CD to prepare 2.0 mg/mL and 6.0 mg/mL colorless clear solutions.
  • Compounds 2 and 3 Weigh a certain amount of each test compound, add 5% DMSO + 10% HS15 + 17% (w/v) SBE- ⁇ -CD to prepare a 2.0 mg/mL yellow suspension.
  • Compound 1 Dosage: 20.0 mg/kg and 60 mg/kg, both in a dosing volume of 10 mL/kg.
  • Compounds 2 and 3 The dosage was 20.0 mg/kg, and the administration volume was 10 mL/kg.
  • test compound content in rat plasma was determined after administration of different compounds: Compound 1 (20 mg/kg/60 mg/kg) was measured. 25 ⁇ L/20 ⁇ L of rat plasma samples were collected at various times after administration. 200 ⁇ L/250 ⁇ L of internal standard acetonitrile solution were added, vortexed, and centrifuged at 4000 rpm for 15 minutes. The supernatant was then analyzed by LC-MS/MS.
  • rat plasma samples were collected at various times after administration, 200 ⁇ L of internal standard acetonitrile solution was added, the mixture was vortexed, and the mixture was centrifuged at 4000 rpm for 15 minutes. The supernatant was then analyzed by LC-MS/MS.
  • Compound 3 20 ⁇ L of rat plasma samples were collected at various times after administration, 250 ⁇ L of internal standard acetonitrile solution was added, the mixture was vortexed, and the mixture was centrifuged at 4000 rpm for 15 minutes. The supernatant was then analyzed by LC-MS/MS.
  • the disclosed compounds have high blood concentrations and high exposure in rats, and have pharmacokinetic advantages.

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Abstract

La présente divulgation concerne un composé dihydrofuro[3,4-f]quinazoline, son procédé de préparation et son utilisation en médecine. Plus particulièrement, la présente divulgation concerne un composé dihydrofuro[3,4-f]quinazoline représenté par la formule (1), son procédé de préparation, une composition pharmaceutique contenant le composé, et une utilisation du composé en tant qu'agent thérapeutique, en particulier une utilisation du composé dans la préparation d'un médicament pour inhiber l'amplification KRAS et/ou l'activité mutante.
PCT/CN2025/087757 2024-04-08 2025-04-08 Composé dihydrofuro[3,4-f]quinazoline, son procédé de préparation et son utilisation en médecine Pending WO2025214341A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023072188A1 (fr) * 2021-10-29 2023-05-04 贝达药业股份有限公司 Inhibiteurs de kras g12d et leur utilisation en médecine
WO2023150284A2 (fr) * 2022-02-03 2023-08-10 Mirati Therapeutics, Inc. Inhibiteurs de pan-kras de quinazoline
WO2023183585A1 (fr) * 2022-03-25 2023-09-28 Eli Lilly And Company Inhibiteurs de kras
WO2023244713A1 (fr) * 2022-06-16 2023-12-21 Ensem Therapeutics, Inc. Dérivés de quinazoline, compositions et procédés associés
CN117624194A (zh) * 2022-08-25 2024-03-01 贝达药业股份有限公司 Kras g12d抑制剂及其在医药上的应用
WO2025092798A1 (fr) * 2023-10-30 2025-05-08 江苏恒瑞医药股份有限公司 Composé hétéroaryle fusionné, son procédé de préparation et son utilisation en médecine

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023072188A1 (fr) * 2021-10-29 2023-05-04 贝达药业股份有限公司 Inhibiteurs de kras g12d et leur utilisation en médecine
WO2023150284A2 (fr) * 2022-02-03 2023-08-10 Mirati Therapeutics, Inc. Inhibiteurs de pan-kras de quinazoline
WO2023183585A1 (fr) * 2022-03-25 2023-09-28 Eli Lilly And Company Inhibiteurs de kras
WO2023244713A1 (fr) * 2022-06-16 2023-12-21 Ensem Therapeutics, Inc. Dérivés de quinazoline, compositions et procédés associés
CN117624194A (zh) * 2022-08-25 2024-03-01 贝达药业股份有限公司 Kras g12d抑制剂及其在医药上的应用
WO2025092798A1 (fr) * 2023-10-30 2025-05-08 江苏恒瑞医药股份有限公司 Composé hétéroaryle fusionné, son procédé de préparation et son utilisation en médecine

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