WO2022083616A1 - Composé quinazoline et composition pharmaceutique associée - Google Patents

Composé quinazoline et composition pharmaceutique associée Download PDF

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WO2022083616A1
WO2022083616A1 PCT/CN2021/124884 CN2021124884W WO2022083616A1 WO 2022083616 A1 WO2022083616 A1 WO 2022083616A1 CN 2021124884 W CN2021124884 W CN 2021124884W WO 2022083616 A1 WO2022083616 A1 WO 2022083616A1
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Prior art keywords
alkylene
compound
alkyl
substituted
synthesis
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PCT/CN2021/124884
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English (en)
Chinese (zh)
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WO2022083616A9 (fr
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吴颢
路渊
陈小平
李波燕
周晓
傅水标
何将旗
王维
湛波
朱小惯
兰宏
王家炳
丁列明
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贝达药业股份有限公司
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Priority to CN202180064719.XA priority Critical patent/CN116322697A/zh
Publication of WO2022083616A1 publication Critical patent/WO2022083616A1/fr
Publication of WO2022083616A9 publication Critical patent/WO2022083616A9/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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems

Definitions

  • the present invention relates to a novel compound having cancer therapeutic activity.
  • the present invention also relates to methods for the preparation of these compounds and pharmaceutical compositions containing them.
  • RAS is the gene with the highest mutation rate in human tumors, about 20-30% of all tumors have RAS mutations, about 98% of pancreatic cancer, 52% of colon cancer, 43% of multiple myeloma, And 32% of lung adenocarcinomas have RAS gene mutations.
  • the most common mutation of RAS is point mutation, which often occurs at codons 12, 13, and 61, of which the 12th codon mutation is the most common.
  • KRAS-G12C mutations account for approximately 10-20% of KRAS mutations and 14% in non-small cell lung cancer.
  • AMG510 developed by AMGEN is the first KRAS G12C inhibitor to enter the clinic.
  • AMGEN submitted a New Drug Application for AMG510 to the US FDA for the treatment of KRAS G12C-mutated advanced metastatic non-small cell lung cancer.
  • the FDA has previously granted it Breakthrough Therapy designation.
  • the FDA approved the world's first KRAS-targeted drug, AMG510.
  • ARAXES company patent WO2015054572A1 describes a KRAS inhibitor with a specific axial chiral fragment in the form of a racemate.
  • the molecule theoretically has both R/S chirality, but the patent does not describe which is the dominant active configuration.
  • Jinfang Company's patent WO2020177629A1 discloses the activity data of specific chiral molecules (Table 1). According to the description, the two chiral molecules Z2-1/Z2-2 and Z25-1/Z25-2 with the same axial chiral fragment, the more active molecules Z2-1 and Z25-2 have completely opposite configurations.
  • the present invention provides a chiral KRAS inhibitor with a novel structure.
  • this chiral molecule is more active than its corresponding axial chiral isomer, with a greater than 100-fold difference in activity.
  • the use of chiral molecules with better activity can effectively reduce the dosage of drugs and avoid adverse drug reactions, which has important clinical significance.
  • the present invention provides a chiral compound, a deuterated compound or a pharmaceutically acceptable salt represented by the general formula (I),
  • X is selected from C 3-14 cycloalkyl, 3-14 membered heterocyclyl, 3-14 membered heterocyclylamino; X is optionally further substituted with 1-4 substituents, wherein each substituent is independently Selected from C 1-6 alkyl, amino, C 1-6 aminoalkyl, carbamoyl, C 1-6 carbamoyl alkyl, carboxyl, C 1-6 carboxyalkyl, cyano, C 1-6 cyanoalkyl, halogen, C 1-6 haloalkyl, hydroxy, C 1-6 hydroxyalkyl, said C 1-6 alkyl optionally being selected from one or more of amino, carbamoyl, carboxyl , cyano, halogen, hydroxyl, oxo substituted;
  • R 1 is acryloyl, substituted acryloyl or
  • R 2 is selected from H, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl, C 1-6 alkane substituted by 4-10-membered heterocyclyl base, C 1-6 alkylsulfonyl, C 1-6 alkylsulfinyl, C 1-6 alkylthio, C 2-6 alkynyl, C 1-6 alkylamino, amino, C 1-6 Aminoalkyl, carbamoyl, C 1-6 carbamoylalkyl, C 1-6 carboxyalkyl, cyano, C 1-6 cyanoalkyl, halogen, C 1-6 haloalkyl, substituted or unsubstituted substituted aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3-7 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclyl, hydroxy or
  • R 3 is selected from H, halogen, C 1-6 alkyl, substituted C 1-6 alkyl, C 2-6 alkenyl, substituted C 2-6 alkenyl, C 3-6 cycloalkyl or substituted C 3-6 cycloalkyl;
  • R 4 or R 5 is independently selected from H, halogen, C 1-6 alkyl, substituted C 1-6 alkyl, C 3-6 cycloalkyl, substituted C 3-6 cycloalkyl;
  • R 6 is selected from hydroxyl, oxo, C 1-6 alkoxy, C 3-10 cycloalkyloxy, cyano-substituted cyclopropyl C 1-6 alkyleneoxy, the C 1- 6 alkoxy is optionally further substituted by one or more substituents selected from halogen, hydroxy, C 1-6 alkoxy, C 3-8 cycloalkyl;
  • n are independently selected from 0, 1, 2, 3, 4;
  • X in formula (I) is selected from a 4-10 membered heterocyclyl group optionally further selected from 1-4 members selected from C 1-6 alkyl, cyano substituted by substituents of C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl; preferably more preferably
  • R in formula ( I ) is selected from preferably
  • R 2 in formula (I) is selected from H, halogen or C 1-3 alkyl; preferably H.
  • R in formula (I) is selected from H, C 1-6 alkyl, substituted C 1-6 alkyl, C 2-6 alkenyl, substituted C 2-6 alkenyl, C 3-6 cycloalkyl or substituted C 3-6 cycloalkyl; preferably C 1-3 alkyl, C 3-6 cycloalkyl or C 2-4 alkenyl; more preferably ethyl, vinyl or cyclo propyl.
  • R 4 or R 5 in formula (I) is selected from H, halogen or C 1-6 alkyl; preferably R 4 is H and R 5 is methyl.
  • R in formula (I) is selected from C 1-6 alkoxy, C 3-8 cycloalkyloxy, cyano-substituted cyclopropyl C 1-6 alkyleneoxy ,
  • the C 1-6 alkoxy group is optionally further substituted by one or more substituents selected from halogen, hydroxyl, methoxy, C 3-8 cycloalkyl; preferably R 6 is selected from
  • Y in formula (I) is selected from preferably more preferably
  • R 8 in formula (I) is selected from H or C 1-6 alkyl; preferably H.
  • the chiral compound represented by general formula (I) is selected from compounds of formula (IA)-(ID),
  • the present invention also provides a chiral compound, a deuterated substance or a pharmaceutically acceptable salt, which is selected from:
  • the present invention provides a pharmaceutical composition
  • the pharmaceutical composition contains the chiral compound, deuterated compound or pharmaceutically acceptable salt of any one of formula (I) and at least one pharmaceutically acceptable excipient, and the pharmaceutical composition
  • the content of the chiral compound is higher than that of its corresponding axial chiral isomer.
  • the present invention also provides a pharmaceutical composition, in which the content of the chiral compound, deuterated compound and pharmaceutically acceptable salt represented by the general formula (I) in the active ingredient is higher than 51%, 61% and 71% , 81%, 91%, 99% or higher.
  • the present invention also provides a pharmaceutical composition, wherein the therapeutically effective amount of at least one compound represented by formula (I), a deuterated substance, a pharmaceutically acceptable salt and a pharmaceutically acceptable adjuvant in the pharmaceutical composition is 0.0001:1 by mass percentage -10.
  • the present invention also provides the use of the chiral compound, deuterated compound, pharmaceutically acceptable salt or pharmaceutical composition containing the compound represented by structural formula (I) in the preparation of medicine; preferably, the medicine is an anticancer medicine.
  • the application is the application of a medicament for the treatment of a disease mediated by KRAS G12C.
  • the disease is cancer.
  • the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophagus Carcinoma, melanoma, colorectal cancer, hepatoma, head and neck tumor, hepatocholangiocarcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, Schwann cell tumor, lung squamous cell Carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
  • the present invention also provides a method for treating and/or preventing cancer, comprising administering a therapeutically effective amount of a chiral compound, a deuterated compound, a pharmaceutically acceptable salt of the general formula (I), or a chiral compound containing the compound represented by the structural formula (I) to a subject to be treated.
  • Pharmaceutical composition preferably the cancer is mediated by a KRAS G12C, HRAS G12C or NRAS G12C mutation.
  • the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic Lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatoma, head and neck tumors, hepatocholangiocarcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, Schwann cells tumor, lung squamous cell carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer or liposarcoma.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • alkyl includes linear or branched monovalent saturated hydrocarbon groups.
  • alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2 -pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc.
  • “ 1-8 " in "C 1-8 alkyl” refers to a group containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms arranged in straight or branched chain form group.
  • C 1-3 alkylene means a divalent saturated hydrocarbon group including straight or branched chains. For example methylene, 1,2-ethylene, 1,3-propylene or 1,2-isopropylene. Similarly, “ 1-6 " in “ C1-6 alkylene” refers to groups containing 1, 2, 3, 4, 5 or 6 carbon atoms arranged in straight or branched chain form.
  • compositions comprising "a” pharmaceutically acceptable excipient can be interpreted to mean that the composition includes “one or more” pharmaceutically acceptable excipients.
  • aryl in the present invention, unless otherwise specified, refers to an unsubstituted or substituted mono- or fused-ring aromatic group comprising atoms of a carbocyclic ring, having a fully conjugated pi-electron system.
  • the aryl group is a 6-14 membered monocyclic or polycyclic aromatic ring group.
  • Preferred are phenyl and naphthyl. Most preferred is phenyl.
  • the aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is the aryl ring.
  • heterocyclyl in the present invention, unless otherwise specified, refers to an unsubstituted or substituted 3-14 membered stable ring consisting of carbon atoms and 1-3 heteroatoms selected from N, O or S. system, which is a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, such as a spiro or bridged ring. Nitrogen or sulfur heteroatoms in heterocyclyl groups can be selectively oxidized, and nitrogen heteroatoms can be selectively quaternized. The heterocyclyl group can be attached to any heteroatom or carbon atom to form a stable structure.
  • heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone and tetrahydro oxadiazolyl.
  • the heterocyclyl group can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl group.
  • spirocyclyl in the present invention, unless otherwise specified, refers to a polycyclic compound in which two monocyclic rings share one carbon atom, and examples of these spirocyclyls include but are not limited to
  • bridged ring group in the present invention, unless otherwise specified, refers to a polycyclic compound in which two monocyclic rings share two or more carbon atoms, and examples of these bridged ring groups include but are not limited to
  • heteroaryl in the present invention, unless otherwise specified, refers to an unsubstituted or substituted stable 5- or 6-membered monocyclic aromatic ring system or an unsubstituted or substituted 9-14 membered benzo-fused
  • Heteroaryl groups can be attached to any heteroatom or carbon atom to form a stable structure.
  • heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridyl Azinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiazolyl, benzene thiadiazolyl, benzotriazolyl adenine, quinolinyl or isoquinolinyl.
  • the heteroaryl group can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring.
  • cycloalkyl refers to a cyclic saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent having 3 to 14 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl .
  • the cycloalkyl group can be fused to an aryl, heterocyclyl or heteroaryl ring, wherein the ring attached to the parent structure is a cycloalkyl group.
  • substituted refers to the replacement of one or more hydrogen atoms in a group with the same or a different substituent, respectively.
  • substituted alkyl groups include, but are not limited to, 2,3-dihydroxypropyl, 2-aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, methoxymethyl, pentafluoroethyl , phenylmethyl, dioxinylmethyl and piperazinylmethyl.
  • substituted alkoxy groups include, but are not limited to, 2-hydroxyethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2-methoxyethoxy, 2-aminoethoxy, 2,3-dihydroxypropoxy, cyclopropylmethoxy, aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3- Hydroxypropoxy.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups, eg, -(alkylene)-OH.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, eg, -(alkylene)-halogen.
  • alkoxy refers to -O-(alkyl).
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
  • the compound represented by formula (I) will be used as a medicine, it is preferable to use a certain purity, for example, at least 60% pure, more suitably at least 75% pure, particularly suitably at least 98% pure (% by weight) Compare).
  • Prodrugs of the compounds of the present invention are included within the scope of the present invention.
  • the prodrugs refer to functional derivatives that are readily converted into the desired compound in vivo.
  • any pharmaceutically acceptable salt, ester, salt of ester or other derivative of a compound of the present application which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the present application or a pharmaceutically active metabolite thereof or Residues.
  • Particularly preferred derivatives or prodrugs are those that increase the bioavailability of the compounds of the present application when administered to a patient (eg, make orally administered compounds more readily absorbed into the blood), or promote the delivery of the parent compound to biological organs or Those compounds that are delivered to the site of action (eg, the brain or lymphatic system). Therefore, the term "administration" in the treatment methods provided by the present invention refers to the administration of the compounds disclosed in the present invention that can treat different diseases, or, although not explicitly disclosed, can be transformed into the disclosed compounds in vivo after administration to a subject compounds of compounds.
  • the compounds of the present invention may contain one or more asymmetric centers and may thereby give rise to diastereomers and optical isomers.
  • the present invention includes all possible diastereomers and racemic mixtures thereof, substantially pure resolved enantiomers thereof, all possible geometric isomers and pharmaceutically acceptable salts thereof.
  • the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof.
  • substitution of compounds of formula (I) with heavier isotopes may provide certain therapeutic advantages due to greater metabolic stability, eg increased in vivo half-life or reduced dosage requirements.
  • the present invention includes any possible solvates and polymorphs.
  • the type of solvent that forms the solvate is not particularly limited as long as the solvent is pharmaceutically acceptable.
  • water, ethanol, propanol, acetone and similar solvents can be used.
  • composition refers to a product comprising a specified amount of each of the specified ingredients, as well as any product produced directly or indirectly from a combination of the specified amounts of each of the specified ingredients. Accordingly, pharmaceutical compositions containing the compounds of the present invention as active ingredients and methods of preparing the compounds of the present invention are also part of the present invention. In addition, some of the crystalline forms of the compounds may exist as polymorphs, and such polymorphs are included in the present invention. In addition, some of the compounds may form solvates with water (ie, hydrates) or common organic solvents, and such solvates are also within the scope of this invention.
  • the pharmaceutical composition provided by the present invention comprises a compound represented by formula (I) (or a pharmaceutically acceptable salt thereof) as an active component, a pharmaceutically acceptable excipient and other optional therapeutic components or Accessories.
  • a pharmaceutically acceptable excipient or a pharmaceutically acceptable excipient
  • other optional therapeutic components or Accessories or Accessories.
  • the most appropriate mode of administration of the active ingredient will depend on the particular subject to be administered, the nature of the subject and the severity of the condition.
  • the pharmaceutical compositions of the present invention may conveniently be presented in unit dosage form and prepared by any of the methods of preparation well known in the art of pharmacy.
  • the pharmaceutical composition of the present invention comprises a pharmaceutically acceptable carrier and a compound represented by formula (I) or its stereoisomer, tautomer, polymorph, solvate, pharmaceutically acceptable salt thereof, its prodrugs.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, combined with one or more other compounds with therapeutic activity are also included in the pharmaceutical composition of the present invention.
  • compositions of the present invention include pharmaceutical compositions suitable for oral, rectal, topical and parenteral (including subcutaneous, intramuscular, intravenous) administration.
  • Tablets or capsules containing a compound or pharmaceutical composition of the present invention may contain one or more accessory ingredients.
  • each tablet or capsule contains about 0.05 mg to 5 g of active ingredient.
  • the present invention also provides pharmaceutical compositions suitable for injection, including sterile aqueous solutions or dispersions. Further, the above-mentioned pharmaceutical compositions can be prepared in sterile powder form for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the pharmaceutical compositions provided by the present invention may be in a form suitable for topical administration, eg, an aerosol, cream, ointment, lotion, dusting powder, or other similar dosage forms. Further, the pharmaceutical composition provided by the present invention can be in a form suitable for use in a transdermal drug delivery device.
  • the pharmaceutical composition provided by the present invention can be in the form of rectal administration by using a solid as a carrier. Unit-dose suppositories are the most typical dosage form. Suppositories can be conveniently prepared by first mixing the pharmaceutical composition with softened or melted excipients, then cooling and moulding.
  • the formulations described above may also include, as appropriate, one or more additional adjuvant components such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants and preservatives (including antioxidants) etc. Further, other adjuvants may also include osmotic enhancers that adjust the isotonic pressure of the drug and blood.
  • additional adjuvant components such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants and preservatives (including antioxidants) etc.
  • other adjuvants may also include osmotic enhancers that adjust the isotonic pressure of the drug and blood.
  • the pharmaceutical composition comprising the compound represented by formula (I), or a pharmaceutically acceptable salt thereof, can be prepared in the form of a powder or a concentrated solution.
  • the dosage level of the drug is about 0.01 mg/kg body weight to 150 mg/kg body weight per day, or 0.5 mg to 7 g per patient per day. It will be appreciated, however, that lower or higher doses than those described above may be required.
  • the specific dosage level and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, route of administration, excretion rate, drug combination condition and the severity of the specific disease being treated.
  • Fig. 1 is the X-ray single crystal diffraction pattern A of compound 1a prepared in Example 1A.
  • Fig. 2 is the X-ray single crystal diffraction pattern B of compound 1a prepared in Example 1A.
  • Figure 3 is an absolute configuration diagram of compound 1a prepared in Example 1A.
  • Figure 4 is an in vivo pharmacodynamic study A on the human pancreatic cancer MIA PaCa-2 CDX tumor model.
  • Figure 5 is an in vivo pharmacodynamic study B on the human pancreatic cancer MIA PaCa-2 CDX tumor model.
  • Figure 6 is an in vivo pharmacodynamic study of a human lung cancer PDX tumor model.
  • CDI carbonyldiimidazole
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
  • DIEA N,N-diisopropylethylamine
  • Dioxane Dioxane
  • HOAc glacial acetic acid
  • NIS N-iodosuccinimide
  • NCS N-chlorosuccinimide
  • POCl 3 phosphorus oxychloride
  • TFA trifluoroacetic acid
  • TEA triethylamine
  • Toluene toluene
  • Sphos Pd G2 Chloro(2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) );
  • Pd(PPh 3 ) 4 tetrakis(triphenylphosphine)palladium
  • 2,2,2-Trichloroethane-1,1-diol (66.4 g) and Na 2 SO 4 (503.4 g) were dissolved in water (560 mL) and then heated to 55°C.
  • the resulting mixture was stirred at 90°C for 3 hours and a yellow precipitate formed.
  • the mixture was cooled to room temperature.
  • the solid was collected by filtration, rinsed with water, and air-dried to give the product as a tan solid (47 g, 99% yield), compound M1-3.
  • Example 1 Compound 1 (1-(7-(7-(5-methyl-1H-indazol-4-yl)-2-(1 methylpiperidin-4-yl)-8-(2, 2,2-Trifluoroethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one )Synthesis
  • DIEA (480.12 mg) was added to compound 1-4 (600 mg), 1,4- tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (280.25 mg) at room temperature In dioxane (10 mL), the mixture was stirred at room temperature for 3 hours.
  • a single crystal of the DMSO solvate of the isomer 1a was obtained by culturing the single crystal by the liquid surface diffusion method in the DMSO/H 2 O system.
  • the crystal size for the crystal diffraction experiment was 0.03 ⁇ 0.19 ⁇ 0.23 mm, and the single crystal was tested with a Bruker D8 Venture Photon II diffractometer.
  • the light source was CuK ⁇ radiation, and the scanning method was scanning.
  • the crystal structure was analyzed by the direct method (Shelxs97), and all 100 non-hydrogen atomic positions were obtained.
  • the least squares method was used to correct the structural parameters and identify the atomic species, and the geometric calculation method and the difference Fourier method were used to obtain all the hydrogen atom positions.
  • the results of single crystal structure analysis show that the molecular arrangement in the crystalline state belongs to the first space group, the compound should have optical activity, and the Flack coefficient is 0.044(12), which can confirm that the absolute configuration of the compound in the crystal is the S configuration.
  • Example 2 Compound 2 (1-(7-(2-cyclohexyl-7-(5-methyl-1H-indazol-4-yl)-8-(2,2,2-trifluoroethoxy) )-6-vinylquinazolin-4-yl)-2,-1,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one) synthesis
  • Example 3 Compound 3 (1-(7-(2-tetrahydrofuran-3-yl-7-(5-methyl-1H-indazol-4-yl)-8-(2,2,2-trifluoro Ethoxy)-6-vinylquinazolin-4-yl)-2,-1,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one) of synthesis
  • Example 4 Compound 4 (1-(7-(6-ethyl-7-(5-methyl-1H-indazol-4-yl)-2-(1-methylpiperidin-4-yl) -8-(2,2,2-Trifluoroethoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-ene-1- ketone) synthesis
  • Example 5 Compound 5 (1-(7-(7-(5-methyl-1H-indazol-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-8-( 2,2,2-Trifluoroethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-ene-1 -ketone) synthesis
  • Step 8 Synthesis of Compounds 5-8
  • Example 6 Compound 6(1-(7-(7-(5-methyl-1H-indazol-4-yl)-2-(N-methylpyrrol-3-yl)-8-(2, 2,2-Trifluoroethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one )Synthesis
  • N-methylpyrrole-3-carboxylic acid 600 mg was dissolved in SOCl 2 (5.5 mL), the temperature was raised to 70° C., and the reaction was stirred for 1 h. Concentrated in vacuo to remove thionyl chloride to give the desired product as a white solid, compound 6-1 (68 mg, crude).
  • Example 7 Compound 7 (1-(7-(2-(1-ethylpiperidin-4-yl)-7-(5-methyl-1H-indazol-4-yl)-8-(2 ,2,2-Trifluoroethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-ene-1- ketone) synthesis
  • Example 8 Compound 8 (1-(7-(6-Chloro-8-ethoxy-7-(5-methyl-1H-indazol-4-yl)-2-(1-methylpiperidine) Synthesis of -4-yl)-quinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one)
  • compound 8-2 120 mg was dissolved in a mixed solvent of DCM (6 mL) and TFA (3 mL), moved to 40° C. and reacted for about 1 h. After the reaction was completed, the solvent was directly concentrated to remove the solvent to obtain a brown oil crude product 8-3 (73 mg, crude product).
  • Example 9 Compound 9 (1-(7-(8-ethoxy-7-(5-methyl-1H-indazol-4-yl)-2-(1-methylpiperidin-4-yl) )-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one) synthesis
  • Example 10 Compound 10 (1-(7-(6-Chloro-8-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-(1-methylpiperidine) Synthesis of -4-yl)-quinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one)
  • Example 11 Compound 11 (1-(7-(8-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-(1-methylpiperidin-4-yl) )-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one) synthesis
  • compound 11-1 (205 mg) was dissolved in a mixed solvent of DCM (6 mL) and TFA (3 mL), moved to 40° C. to react for about 1 h. After the reaction was completed, the solvent was directly concentrated to remove the solvent to obtain a brown oil crude product 11-2 (152 mg, crude product).
  • Example 12 Compound 12 (1-(7-(2-(1-acetylpiperidin-4-yl)-7-(5-methyl-1H-indazol-4-yl)-8-(2, 2,2-Trifluoroethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one )Synthesis
  • Example 13 Compound 13 (1-(7-(6-cyclopropyl-8-(2-methoxyethoxy)-7-(5-methyl-1H-indazol-4-yl)- 2-(1-Methylpiperidin-4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one )Synthesis
  • Example 14 Compound 14 (1-(7-(6-Cyclopropyl-8-(2-methoxyethoxy)-7-(5-methyl-1H-indazol-4-yl)- 2-(1-Methylpiperidin-4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one )Synthesis
  • Example 15 Compound 15 (1-(7-(6-cyclopropyl-8-(2,2-difluoroethoxy)-7-(5-methyl-1H-indazol-4-yl) -2-(1-Methylpiperidin-4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1- ketone) synthesis
  • Example 16 Compound 16 (1-(7-(8-ethoxy-6-ethyl-7-(5-methyl-1H-indazol-4-yl)-2-(1-methylpiperin) Synthesis of pyridin-4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one)
  • Embodiments 17-22 respectively adopt cyclobutanol, isopropanol, difluoroethanol, 2-fluoroethanol, ethylene glycol methyl ether and cyclopropyl methanol to react with compounds 1-5 to obtain corresponding products, and then follow the synthetic steps of 16
  • the corresponding final product compounds 17-22 were synthesized.
  • Example 23 Compound 23 (1-(7-(6-Chloro-7-(5-methyl-1H-indazol-4-yl)-2-(1-methylpiperidin-4-yl)- 8-(2,2,2-Trifluoroethoxy)quinazoline-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-ene-1- ketone) synthesis
  • Example 26 Compound 26 (1-(7-(6-ethyl-2-(1-(2-methoxyethyl)piperidin-4-yl)-7-(5-methyl-1H- Indazol-4-yl)-8-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl) Synthesis of prop-2-en-1-one)
  • piperidine-4-carboxylic acid (7.000 g) was added to THF (200 mL) and water (40 mL), triethylamine (16.45 g) was added, and (2,5-dioxapyrrolidine-1- base) 2-trimethylsilyl ethyl carbonate (15.46g), stirred at room temperature until the reaction was completed, concentrated THF, cooled, acidified to pH2-3 with 1N HCl, extracted three times with DCM, washed twice with organic phase brine , dried and concentrated to obtain the target product 26-1 (16 g, crude product).
  • Example 27 Compound 27 (1-(7-(6-ethyl-2-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-7-(5-methyl) -1H-Indazol-4-yl)-8-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2 Synthesis of -yl)prop-2-en-1-one)
  • Example 28 Compound 28 (1-(7-(6-ethyl-7-(5-methyl-1H-indazol-4-yl)-2-(1-(oxetan-3-yl) )piperidin-4-yl)-8-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl ) synthesis of prop-2-en-1-one)
  • Example 29 Compound 29 (1-(7-(6-ethyl-2-(1-(2-hydroxy-2-methylpropyl)azetidin-3-yl)-7-(5 -Methyl-1H-indazol-4-yl)-8-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nona Synthesis of yl-2-yl)prop-2-en-1-one).
  • Compound 29-6 was subjected to two Suzuki coupling reactions to synthesize compound 29-8 , and then the double bond is reduced, and the protecting group of the nitrogen atom is removed to obtain the shared intermediate 29-10.
  • Compound 29-10 can be obtained by microwave reaction with methyl propylene oxide in triethylamine and ethanol system with reference to the synthesis steps of 27-11, followed by deprotection of trifluoroacetic acid to obtain compound 29-12. Reaction with acryloyl chloride under neutral conditions affords compound 29.
  • Example 30 Compound 30 (3-(3-(4-(2-Acryloyl-2,7-diazaspiro[3.5]nonan-7-yl)-6-ethyl-7-(5 -Methyl-1H-indazol-4-yl)-8-(2,2,2-trifluoroethoxy)quinazolin-2-yl)azetidin-1-yl)propionitrile) Synthesis
  • Examples 31, 33, 34, 35 and 37 were synthesized with reference to the method of Example 28, sharing intermediates 29-10 with oxetanone, tetrahydropyranone, cyclobutanone, cyclopentanone and acetaldehyde, respectively.
  • the corresponding target compounds were prepared under the conditions of reductive amination, and then deprotected and acryloyl groups were introduced to obtain target compounds 31, 33, 34, 35 and 37 respectively.
  • the synthetic operation of embodiment 32 refers to the synthetic operation of embodiment 30, adopts the method of 1,4-addition, methyl vinyl sulfone reacts with common intermediate 29-10 to obtain the corresponding product, and then deprotection and introduction of acryloyl group finally obtain the target Compound Example 32.
  • the synthetic procedure of embodiment 36 is: use common intermediate 29-10 and cyclopropylcarbonyl chloride to react in dichloromethane and sodium bicarbonate aqueous solution system to obtain corresponding compound, then deprotect and introduce acryloyl group to finally obtain target compound embodiment 36.
  • Example 38 Compound 38 (1-(7-(8-(2-hydroxy-2-methylpropoxy)-7-(5-methyl-1H-indazol-4-yl)-2-( 1-Methylpiperidin-4-yl)-6-vinylquinazoline-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-ene-1 -ketone) synthesis
  • Example 38 Synthetic operation of Example 38 Referring to the operation of Example 16, 2-methyl-1,2-propanediol was used to react with the common intermediate 1-5 to obtain compound 38-1, and then two coupling reactions were carried out according to Example 16, Deprotection and acryloylation steps complete the synthesis of 38.
  • Examples 39 and 40 were respectively reacted with difluoroethanol and 1-(hydroxymethyl)cyclopropanecarbonitrile with the common intermediates 1-5 to obtain the corresponding target compounds, and then the final products 39 and 40 were prepared according to the steps of Example 16. synthesis
  • Example 41 Compound 41 (1-(6-(7-(5-methyl-1H-indazol-4-yl)-2-(1-methylpiperidin-4-yl)-8-(2 ,2,2-Trifluoroethoxy)-6-vinylquinazolin-4-yl)-2,6-diazaspiro[3.3]hept-2-yl)prop-2-ene-1- ketone) synthesis
  • Examples 42, 43 and 44 refer to the synthesis of 41-1 using 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester, (S)-4-N-tert-butoxy Carbonyl-2-methylpiperazine and tert-butyl(S)-2-(cyanomethyl)piperazine-1-carboxylate react with common intermediates 1-4 to obtain the corresponding compounds, followed by the synthesis of reference 25 The steps complete the synthesis of target products 42, 43 and 44.
  • Example 45 Compound 45 (1-(7-(7-(5-methyl-1H-indazol-4-yl)-2-(1-(2-(methylsulfonyl)ethyl)piperidine -4-yl)-8-(2,2,2-trifluoroethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2 Synthesis of -yl)prop-2-en-1-one)
  • Example 51 Compound 51 (1-(7-(7-(5-methyl-1H-indazol-4-yl)-2-(piperidin-4-yl)-8-(2,2,2 -Trifluoroethoxy)-6-vinylquinazoline-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one) of synthesis
  • Example 47 is synthesized with reference to the steps of Example 1, and the corresponding target product can be obtained by reacting acrylonitrile with the common intermediate 45-1, followed by deprotection and introduction of an acryloyl group to finally obtain the target compound 47.
  • Examples 46, 53, 54, 55, 56, 57, 59, 60, 61, 62, 65, 66, 67, 68, 70 and 71 refer to Example 28 by reductive amination using different ketones or aldehydes Reaction with shared intermediate 45-1 to obtain the corresponding product, then deprotection and introduction of acetyl group to synthesize the final target product;
  • Embodiment 48 refers to Example 27, and uses shared intermediate 45-1 to react with methyl propylene oxide to generate corresponding The product, then deprotection and introduction of an acryloyl group to finally obtain the target compound 48;
  • Examples 49, 58, 63, 64, 69 adopt an alkylation strategy to react with the common intermediate 45-1 to generate the corresponding product, and then deprotection and The introduction of the acryloyl group finally yields the final target product.
  • the corresponding synthetic intermediates are as follows:
  • Example 72 Compound 72 (2-fluoro-1-(7-(7-(5-methyl-1H-indazol-4-yl)-2-(1-methylpiperidin-4-yl)- 8-(2,2,2-Trifluoroethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)propan-2 -en-1-one) synthesis
  • Example 75 Compound 75 ((E)-1-(7-(6-Chloro-7-(5-methyl-1H-indazol-4-yl)-2-(1-methylpiperidine-4 -yl)-8-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)-4-( Synthesis of dimethylamino)but-2-en-1-one)
  • Example 73 refers to the synthesis procedure of 50, except that difluoroethanol is used instead of trifluoroethanol.
  • Example 74 refers to the synthetic procedure of 72.
  • Example 1A the compounds of Examples 2 to 75 were resolved by substantially the same method, and the corresponding chiral isomers 2a to 75a were obtained respectively.
  • the structure of compound 9a is The structural formula of compound 47a is
  • the CALU-1 cells were plated in a 96-well ultra-low adsorption plate at 1000 cells and 190 ⁇ L/well. After overnight incubation, compound solutions with gradient concentrations were prepared, and 10 ⁇ L of the DMSO solution of each concentration of the test compound was added to the cells in each well. 0 nM (all final concentrations of DMSO were 0.25%). Incubate for 120 hours at 37°C, 5% CO2 . Add 60 ⁇ L of Cell-titer Glo working solution to each well, shake and mix well, incubate at room temperature for 10 minutes, read the Luminescence luminescence value with a multi-function microplate reader, and convert the luminescence value reading into inhibition percentage:
  • Curve fitting was performed with Graphpad Prism software and IC50 values were obtained.
  • Example compounds have good inhibitory activity on CALU-1 cells, especially the Y substituent is selected from Compared with other ring structure molecules directly connected to the quinazoline ring through the C atom on the ring, it has better activity. See Table 2 for IC50 data of the compounds of the examples for inhibition of CALU-1 cells.
  • MIA-PACA-2 cells were plated in a 96-well ultra-low adsorption plate at 600 cells and 160 ⁇ L/well. After overnight incubation, compound solutions with gradient concentrations were prepared, and 40 ⁇ L of DMSO solution of each concentration of the test compound was added to each well of cells respectively. 0 nM (all final concentrations of DMSO were 0.25%). Incubate for 96h at 37°C, 5% CO2 . Add 50 ⁇ L of Cell-titer Glo working solution to each well, incubate at room temperature for 10 min after shaking and mixing, read the Luminescence luminescence value with a multi-function microplate reader, and convert the luminescence value reading into the inhibition percentage:
  • Curve fitting was performed with Graphpad Prism software and IC50 values were obtained.
  • Table 3 shows the IC50 data of some compounds in the examples for inhibition of MIA-PACA-2 cells.
  • H358 cells were plated in 96-well ultra-low adsorption plates at 2000 cells and 190 ⁇ L/well. After overnight incubation, compound solutions with gradient concentrations were prepared, and 10 ⁇ L of DMSO solution of each concentration of the test compound was added to each well of cells respectively. 0 nM (all final concentrations of DMSO were 0.25%). Incubate for 96h at 37°C, 5% CO2 . Add 50 ⁇ L of Cell-titer Glo working solution to each well, incubate at room temperature for 10 min after shaking and mixing, read the Luminescence luminescence value with a multi-function microplate reader, and convert the luminescence value reading into the inhibition percentage:
  • Table 3 shows the IC50 data of some compounds in the examples for inhibition of H358 cells.
  • Example E In vivo pharmacodynamic studies on human pancreatic cancer MIA PaCa-2 CDX tumor model
  • the classical mouse tumor model test was used to observe the tumor inhibition rate TGI (%) of the target compound after oral administration to evaluate its anti-tumor activity.
  • MIA PaCa-2 cells Human pancreatic cancer MIA PaCa-2 cells were cultured in monolayer in vitro, cultured in DMEM/F12 medium with 10% fetal bovine serum, 1% double antibody, and cultured in a 37°C 5% CO 2 incubator. Routine treatment passaging was performed twice a week. When the cell saturation is 80%-90% and the number reaches the requirement, the cells are collected, counted, and seeded. 0.2 mL (5 ⁇ 10 6 cells) of MIA PaCa-2 cells (plus Matrigel, 1:1 by volume) were subcutaneously inoculated into the right back of each mouse, and the tumors were grouped into groups when the average tumor volume reached about 149 mm 3 . medicine.
  • Example F In vivo pharmacodynamic study of human non-small cell lung cancer PDX tumor model
  • the classical mouse tumor model test was used to observe the tumor inhibition rate TGI (%) of the target compound after oral administration to evaluate its anti-tumor activity.
  • the cell line was derived from HEK293 cells overexpressing hERG potassium ion channel, and the cells were cultured in a 37°C, 5% CO2 incubator.
  • PBS phosphate buffered saline
  • digest the cells with trypsin/EDTA for 2-3 minutes add cell culture medium to stop the digestion, pipette gently and Transfer to a centrifuge tube, centrifuge at 1000 rpm for 3 minutes, pour off the supernatant, add the cell culture medium, mix the cells by gently pipetting, and then transfer to a petri dish for subculture, or drop the cells on a circular
  • the cells were cultured in cell culture medium on glass slides until the cells adhered for the experiments.
  • Cell culture medium composition DMEM, 15% fetal bovine serum and 1% 100x penicillin-streptomycin.
  • composition of intracellular fluid and extracellular fluid is shown in Table 4.
  • the stably transfected cells were dropped on a circular glass slide and placed in a petri dish, the cell density was less than 50%, and cultured overnight.
  • the experimental cells were transferred to a cell bath embedded in an inverted microscope platform and perfused with extracellular fluid at a rate of 2.7 ml/min. After 5 minutes of stabilization, the experiment can be started.
  • Membrane currents were recorded using a HEKA EPC-10 patch clamp amplifier and PATCHMASTER acquisition system (HEKA Instruments Inc., D-67466 Lambrecht, Pfalz, Germany). All experiments were performed at room temperature (22-24°C).
  • Electrodes (BF150-110-10) were straightened using a P-97 microelectrode puller (Sutter Instrument Company, One Digital Drive, Novato, CA 94949) in the experiments.
  • the inner diameter of the electrode is 1-1.5mm, and the water entry resistance after filling with the inner liquid is 2-4M ⁇ .
  • the electrophysiological stimulation scheme of hERG potassium channel is to first clamp the membrane voltage at -80mV, give the cell a continuous 2s, +20mV voltage stimulation, activate the hERG potassium channel, and then repolarize to -50mV for 5s to generate an outward tail current,
  • the stimulation frequency was every 15s.
  • the current value is the peak value of the tail current.
  • the channel currents were recorded in the whole-cell recording mode. First perfuse extracellular fluid (about 2 ml per minute) and record continuously, and wait for the current to stabilize (the current decay (Run-Down) is less than 5% within 5 minutes), at which time the peak tail current is the control current value. Then, the extracellular fluid containing the drug to be tested was perfused and recorded continuously until the inhibitory effect of the drug on the hERG current reached a steady state. At this time, the peak value of the tail current was the current value after the drug was added. The standard of steady state is judged by whether the last three consecutive current recording lines overlap.
  • the final concentrations of the compounds were 30, 10, 3.3, 1.1, 0.37 ⁇ M;
  • the final concentration of DMSO was 3:1000.
  • test data in the report needs to meet the following criteria:
  • Inhibition of cardiac hERG potassium channel by drugs is the main reason for drug-induced QT prolongation syndrome.
  • Compound 1a has almost no blocking effect on hERG potassium channel in the tested concentration range (IC 50 >30 ⁇ M);
  • Compound D2 has moderate blocking effect on hERG potassium channel in the tested concentration range (3 ⁇ M ⁇ predicted IC 50 ⁇ 10 ⁇ M) , the compound has a certain degree of cardiac risk due to its effect on hERG.
  • Example H In vitro CYP enzyme inhibition assay
  • the human liver microsome incubation system was used to reflect the activities of various enzymes by the amount of metabolites generated.
  • Experimental method Weigh an appropriate amount of the analyte standard and dilute it to 2 mM with DMSO to obtain a working solution; the probe substrate is prepared with pure acetonitrile, and the positive control inhibitor is prepared with DMSO. The concentrations are shown in Table 8. Take 1 ⁇ L of the test compound/positive control inhibitor, 1 ⁇ L of the probe substrate, 1 ⁇ L of human liver microsomes (20 mg/mL) and 177 ⁇ L of PBS buffer to prepare a reaction mixture (the final concentration of the test compound/positive control inhibitor in the incubation reaction is 10 ⁇ M ). The above mixture was pre-incubated at 37°C for 5 minutes.
  • Inhibiton% 100%*(1-Test compound Aear ratio/Control Aear ratio), the experimental results are shown in Table 9.

Abstract

L'invention concerne un nouveau composé ayant une activité thérapeutique contre le cancer. La présente invention concerne également une méthode pour préparer ces composés et une composition pharmaceutique les contenant.
PCT/CN2021/124884 2020-10-21 2021-10-20 Composé quinazoline et composition pharmaceutique associée WO2022083616A1 (fr)

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