WO2023045816A1 - Composé benzocycloheptane utilisé comme inhibiteur d'axl - Google Patents

Composé benzocycloheptane utilisé comme inhibiteur d'axl Download PDF

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Publication number
WO2023045816A1
WO2023045816A1 PCT/CN2022/118860 CN2022118860W WO2023045816A1 WO 2023045816 A1 WO2023045816 A1 WO 2023045816A1 CN 2022118860 W CN2022118860 W CN 2022118860W WO 2023045816 A1 WO2023045816 A1 WO 2023045816A1
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compound
formula
pharmaceutically acceptable
acceptable salt
alkyl
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PCT/CN2022/118860
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English (en)
Chinese (zh)
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马昌友
张林林
李冬冬
冯海威
吴有智
吴舰
徐丹
朱春霞
田舟山
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南京正大天晴制药有限公司
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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
    • 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
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the technical field of medicine, and particularly relates to pyrimidine compounds, which are AXL kinase inhibitors.
  • the invention also relates to the use of the compounds in the treatment of diseases associated with AXL activity.
  • RTKs Receptor tyrosine kinases
  • Ligand-receptor binding induces receptor dimerization and activation of its intracellular kinase domain, which in turn leads to the recruitment, phosphorylation and activation of multiple downstream signaling cascades (Robinson, D.R. et al., Oncogene, 19:5548-5557, 2000).
  • RTKs have been identified in the human genome that regulate a variety of cellular processes, including cell survival, growth, differentiation, proliferation, adhesion, and motility (Segaliny, A.I. et al., J. Bone Oncol, 4:1 -12, 2015).
  • AXL (also known as UFO, ARK, and Tyro7) belongs to the TAM family of receptor tyrosine kinases, which also includes Mer and Tyro3. Among them, AXL and Tyro3 have the most similar gene structure, while AXL and Mer have the most similar amino acid sequence of tyrosine kinase domain. Like other receptor tyrosine kinases (RTKs), the structure of the TAM family consists of an extracellular domain, a transmembrane domain, and a conserved intracellular kinase domain. The extracellular domain of AXL has a unique structure that juxtaposes immunoglobulin and type III fibronectin repeat units and is reminiscent of a neutrophil adhesion molecule.
  • TAM family members have a common ligand—growth arrest specific protein 6 (Gas6), which can bind to all TAM receptor tyrosine kinases. After AXL binds to Gas6, it will lead to receptor dimerization and AXL autophosphorylation, thereby activating multiple downstream signal transduction pathways and participating in multiple processes of tumorigenesis (Linger, R.M et al., Ther.Targets, 14(10 ), 1073-1090, 2010; Rescigno, J. et al., Oncogene, 6(10), 1909-1913, 1991).
  • Gas6 growth arrest specific protein 6
  • AXL is widely expressed in normal tissues of the human body, such as monocytes, macrophages, platelets, endothelial cells, cerebellum, heart, skeletal muscle, liver, and kidney, among which the expression is highest in cardiac muscle and skeletal muscle, and bone marrow CD34+ cells and stromal cells also have a higher expression High expression, very low expression in normal lymphoid tissue (Wu YM, Robinson DR, Kung HJ, Cancer Res, 64(20), 7311-7320, 2004; hung BI et al., DNA Cell Biol, 22(8), 533-540 , 2003).
  • AXL gene was overexpressed or ectopically expressed in hematopoietic cells, mesenchymal cells and endothelial cells.
  • the overexpression of AXL kinase is particularly prominent.
  • Inhibition of AXL receptor tyrosine kinase can reduce the pro-survival signals of tumor cells, block the invasion ability of tumors, and increase the sensitivity of targeted drug therapy and chemotherapy. Therefore, finding effective AXL inhibitors is an important direction for the development of tumor-targeted drugs.
  • the present invention provides a benzocycloheptane compound represented by formula I or a pharmaceutically acceptable salt thereof,
  • R 1 and R 2 are halogen
  • R 3 is independently selected from: hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, Wherein said C 1-6 alkyl or C 1-6 alkoxy is optionally substituted by hydroxyl, halogen, cyano or C 1-3 alkoxy;
  • R 4 and R 5 are independently selected from C 1-6 alkyl, hydroxyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • n is an integer selected from 1-3.
  • R 1 is fluoro
  • R 2 is chloro
  • R 3 is independently selected from deuterium, halogen, C 1-6 alkyl,
  • R 3 is independently selected from C 1-6 alkyl or
  • R 3 is independently selected from C 1-3 alkyl or
  • R 3 is independently selected from methyl or
  • R 4 and R 5 are independently selected from C 1-6 alkyl groups.
  • R 4 and R 5 are independently selected from C 1-3 alkyl groups.
  • R 4 and R 5 are methyl.
  • R 3 is independently selected from methyl or
  • m is 1 or 2.
  • n is 2.
  • the aforementioned compound of formula I has a structure as shown in formula II or a pharmaceutically acceptable salt thereof:
  • R 1 , R 2 , and R 3 are consistent with those in the compound of formula I;
  • R 6 is selected from: deuterium, halogen, C 1-6 alkyl or C 1-6 alkoxy, wherein said C 1-6 alkyl or C 1-6 alkoxy can optionally be replaced by one or more Deuterium, methoxy, hydroxyl, halogen or cyano are substituted.
  • R 6 is selected from: deuterium, halogen, or C 1-6 alkyl.
  • R 6 is C 1-6 alkyl.
  • R 6 is C 1-3 alkyl.
  • R 6 is methyl
  • the aforementioned compound of formula II has a structure as shown in formula III or a pharmaceutically acceptable salt thereof:
  • R 1 is fluoro
  • the aforementioned compound of formula III has a structure as shown in formula IV or a pharmaceutically acceptable salt thereof:
  • R 1 is fluoro.
  • the aforementioned compound of formula III has a structure as shown in formula V or a pharmaceutically acceptable salt thereof:
  • R 1 is fluoro
  • the aforementioned compound of formula IV has a structure as shown in formula IV-I or a pharmaceutically acceptable salt thereof:
  • the aforementioned compound of formula IV-I has a structure as shown in formula IV-I-I or IV-I-II or a pharmaceutically acceptable salt thereof:
  • the aforementioned compound of formula IV has a structure as shown in formula IV-II or a pharmaceutically acceptable salt thereof:
  • the aforementioned compound of formula IV-II has a structure as shown in formula IV-II-I or IV-II-II or a pharmaceutically acceptable salt thereof:
  • the aforementioned compound of formula V has a structure as shown in formula V-I or a pharmaceutically acceptable salt thereof:
  • the aforementioned compound of formula V-I has a structure as shown in formula V-I-I or formula V-I-II or a pharmaceutically acceptable salt thereof:
  • the aforementioned compound of formula V has a structure as shown in formula V-II or a pharmaceutically acceptable salt thereof:
  • the aforementioned compound of formula V-II has a structure as shown in formula V-II-I or formula V-II-II or a pharmaceutically acceptable salt thereof:
  • the present invention provides the following compounds, or pharmaceutically acceptable salts thereof,
  • the present invention provides the following compounds, or pharmaceutically acceptable salts thereof,
  • the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of formula I, II, III, IV, IV-I, IV-II, IV-I-I, IV-I-II, IV- II-I, IV-II-II, V, V-I, V-II, V-I-I, V-II-I or V-II-II compound or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of formula I, II, III, IV, IV-I, IV-II, IV-I-I, IV-I-II, IV-II-I, IV-II-I, IV-II-II, V, V-I, V-II, V-I-I, V-II-I or V-II-II compound or a pharmaceutically acceptable salt thereof, and a or multiple pharmaceutically acceptable carriers.
  • compositions described herein may be administered by any suitable route or method, such as orally or parenterally (eg, intravenously).
  • the therapeutically effective amount of compound II, V-II-I or V-II-II is from about 0.001 mg to 50 mg/Kg body weight/day, preferably from 0.01 mg to 50 mg/Kg body weight/day.
  • compositions of the present invention are generally provided in the form of tablets, capsules or solutions.
  • Tablets may contain a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the carrier includes, but is not limited to, diluents, disintegrants, binders, lubricants, colorants or preservatives.
  • Capsules include hard capsules and soft capsules.
  • the pharmaceutical composition of the present invention can be administered by intravenous injection, intramuscular injection or subcutaneous injection. It is usually provided as a sterile aqueous solution or suspension, or as a lyophilized powder, adjusted to appropriate pH and isotonicity.
  • the present invention also provides formula I, II, III, IV, IV-I, IV-II, IV-I-I, IV-I-I, IV-II-I, IV-II-I, IV-II-II, V, Use of compounds V-I, V-II, V-I-I, V-I-II, V-II-I or V-II-II in the preparation of medicines for preventing and/or treating diseases or disease states mediated by AXL protein kinase.
  • the present invention also provides methods for preventing and/or treating diseases or disease states mediated by AXL protein kinase, which comprises administering the formula I, II, III, IV, IV of the present invention to individuals in need -I, IV-II, IV-I-I, IV-II-I, IV-II-I, IV-II-I, V, V-I, V-II, V-I-I, V-II-I or V -II-II compound or the pharmaceutical composition of the present invention.
  • the present invention also provides the formula I, II, III, IV, IV-I, IV-II, IV-I-I of the present invention for preventing and/or treating AXL protein kinase-mediated diseases or disease states , IV-I-II, IV-II-I, IV-II-II, V, V-I, V-II, V-I-I, V-II-I or V-II-II compound or the medicine of the present invention combination.
  • AXL protein kinase mediated diseases or conditions include, but are not limited to, autoimmune diseases.
  • the present invention provides a kind of preparation formula I, II, III, IV, IV-I, IV-II, IV-I-I, IV-I-II, IV-II-I, IV-II-II, V , V-I, V-II, V-I-I, V-II-I or V-II-II compound methods, including but not limited to the following synthetic schemes:
  • R a and R b are independently selected from halogen.
  • R a is chloro
  • Rb is chloro
  • the compound of formula H-1, formula H-2 is in solvent (for example N,N-dimethylformamide or tetrahydrofuran), base (for example N, N-diisopropylethylamine or hexamethyldisilazylamine
  • solvent for example N,N-dimethylformamide or tetrahydrofuran
  • base for example N, N-diisopropylethylamine or hexamethyldisilazylamine
  • H-3 compound is prepared under the condition of lithium base
  • H-4 compound is prepared in a solvent (such as acetonitrile) by fluorination reaction to prepare H-5 compound
  • H-5 compound is prepared by reacting in a reducing agent (such as palladium carbon)
  • a reducing agent such as palladium carbon
  • Compound H-6, compound H-3 and compound H-6 undergo a nucleophilic substitution reaction in a solvent (such as isopropanol) to generate compound H-7
  • H-7 is prepared by
  • a “compound” of the invention may be asymmetric, eg, possess one or more chiral centers. Unless otherwise specified, the “compound” of the present invention refers to any one stereoisomer or a mixture of two or more stereoisomers. Stereoisomers include, but are not limited to, enantiomers and diastereomers.
  • the compounds containing asymmetric carbon atoms of the present invention can be isolated in an optically active pure form or in the form of a mixture of two or more stereoisomers. Optically pure forms can be resolved from mixtures of two or more stereoisomers, or synthesized by using chiral starting materials or reagents.
  • R 3 when the m of the compound of formula I is 2 or 3, R 3 can be independently selected from the same or different groups, for example, when m is 2, one R 3 can be methyl, and the other R 3 can be chlorine.
  • C 1-6 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.
  • substituted means that any one or more hydrogen atoms on a specific atom or group are replaced by a substituent, as long as the valence of the specific atom or group is normal and the substituted compound is stable.
  • any variable eg R3
  • its definition is independent at each occurrence.
  • R3 when a group is substituted by one or more R3 , there are independent options for R3 in each case.
  • R3 when m of the compound of formula I is 2, one R3 can be methyl and the other R3 can be chloro.
  • substituents and/or variations thereof are permissible only if such combinations result in stable compounds.
  • alkyl refers to a saturated aliphatic hydrocarbon group, including straight or branched chain saturated hydrocarbon groups, having the indicated number of carbon atoms.
  • C 1-6 alkyl includes C 1 alkyl, C 2 alkyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, C 6 alkyl, examples include, but are not limited to, methyl , ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, n-hexyl, 2-hexyl, 3-hexyl, etc. It can be divalent, eg methylene, ethylene.
  • alkoxy refers to a group having an alkyl-O-structure, and the alkyl group includes a linear or branched saturated monovalent hydrocarbon group.
  • C 13 alkoxy includes methoxy, ethoxy, n-propoxy, isopropoxy.
  • middle Refers to the chemical bond connection.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • C2-6 alkenyl is used to denote a straight or branched chain hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon double bond which may be located in the group anywhere in the regiment. Examples include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, and the like.
  • C2-6 alkynyl is used to denote a straight or branched chain hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond which may be located in the group anywhere in the regiment. Examples include, but are not limited to, ethynyl, propynyl, butynyl, and the like.
  • deuterium substitution means that one or more CH bonds in a compound or group are replaced by CD bonds, and the deuterium substitution can be monosubstitution, disubstitution, multiple substitution or full substitution.
  • the “deuteration” method adopts conventional methods in the art, for example, commercially available deuterated raw materials can be used, or deuterium can be introduced into the compound according to the method disclosed in the prior art.
  • an effective amount or “therapeutically effective amount” refers to a sufficient amount of a non-toxic drug or agent to achieve the desired effect.
  • pharmaceutically acceptable carrier refers to those carriers that have no obvious stimulating effect on the body and will not impair the biological activity and performance of the active compound. Including but not limited to any diluents, disintegrants, binders, glidants, and wetting agents approved by the State Food and Drug Administration that can be used on humans or animals.
  • pharmaceutically acceptable salt refers to a salt that retains the biological effectiveness of the free acids and bases of the specified compound without adverse biological effects.
  • acid including organic and inorganic acids
  • base including organic and inorganic bases
  • IMDM (Iscove's Modified Dulbecco's Medium): Iscove (person's name) modified Dulbecco (person's name) medium.
  • reaction conditions such as reactants, solvents, bases, amounts of compounds used, reaction temperature, reaction time, etc. are not limited to the following examples.
  • the compounds of the present invention can also be conveniently prepared by combining various synthetic methods described in this description or known in the art, and such combinations can be easily performed by those skilled in the art.
  • Isomer mixture A was chirally resolved by chiral liquid chromatography (column: Chiralpak IF, 2x25cm, filler particle size 5 ⁇ m; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: Methanol; Flow rate: 20ml/min; Gradient: 50% B isogradient within 9min; Detection wavelength: 220/254nm), obtained isomer 1, isomer 2, and the mixture of isomer 3, 4 respectively 30mg.
  • Isomer mixture B was chirally resolved by chiral liquid chromatography (Chiralpak IF, 2x25cm, filler particle size 5 ⁇ m; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: Methanol; flow rate: 20ml/min; gradient: 50% B isogradient within 17min; detection wavelength: 220/254nm), obtained isomer 5, isomer 6, and 30mg of the mixture of isomers 7 and 8 respectively.
  • the mixture of isomers 7 and 8 was chirally resolved by chiral liquid chromatography (Chiralpak ID, 2x25cm, filler particle size 5 ⁇ m; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile Phase B: methanol; flow rate: 20ml/min; gradient: 10% B isogradient within 19min; detection wavelength: 220/254nm), and isomer 7 and isomer 8 were obtained respectively.
  • the specific structure of the positive drug (BGB324) used in the activity test is as follows:
  • Test 1 Compound AXL Kinase Inhibitory Activity
  • 1 ⁇ enzyme buffer 200 ⁇ L of Enzymatic buffer kinase 5X, 10 ⁇ L of 500 mM MgCl2, 10 ⁇ L of 100 mM DTT, 6.26 ⁇ L
  • DMSO dilute the compounds and positive drugs prepared in the examples from 10 mM to 100 ⁇ M, and titrate with a compound titrator (Tecan, D300e), and the titrator will automatically spray the required concentration into each well.
  • 1 concentration is 1 ⁇ M, 1/2 log gradient dilution, a total of 8 concentrations. Centrifuge at 2500rpm for 30s and incubate at room temperature for 15min.
  • ATP (Sigma, A7699) was diluted with 1 ⁇ enzyme buffer, from 10 mM to 75 ⁇ M (5 ⁇ ), and the final concentration was 15 ⁇ M; substrate TK Substrate 3-biotin (Cisbio, 61TK0BLC) was diluted with 1 ⁇ enzyme buffer solution from 500 ⁇ M to 5 ⁇ M (5 ⁇ ), and the final concentration was 1 ⁇ M; ATP was mixed with the substrate in equal volume, and 4 ⁇ L was added to each well using a BioTek automatic liquid dispenser; centrifuged at 2500 rpm for 30 s, at 25 ° C React for 45 minutes.
  • Streptavidin-XL665 (Cisbio, 610SAXLG) was diluted from 16.67 ⁇ M to 250nM (4 ⁇ ) with HTRF KinEASE detection buffer (cisbio), and the final concentration was 62.5nM;
  • TK Antibody-Cryptate (Cisbio) was diluted with HTRF KinEASE detection buffer (cisbio) was diluted from 100 ⁇ to 5 ⁇ , and the final concentration was 1 ⁇ ;
  • XL665 was mixed with Antibody in equal volume, 10 ⁇ L was added to each well using a BioTek automatic dispenser, centrifuged at 2500 rpm for 30 seconds, and reacted at 25°C for 1 hour. After the reaction, the multifunctional plate reader HTRF was used for detection.
  • Conversion%_sample is the conversion rate reading of the sample
  • Conversion%_min represents the conversion rate reading of the well without enzyme activity
  • Conversion%_max Represents the conversion reading for wells with no compound inhibition.
  • Example title compound AXL inhibitory activity IC50(nM) Example 1 Isomer 1 14.82 Example 1 Isomer 2 22.42 Example 1 Isomer 3 0.94 Example 1 Isomer 4 0.68 Example 1 Isomer 5 31.65 Example 1 Isomer 6 44.14
  • Example 1 Isomer 7 3.47
  • Example 1 Isomer 8 4.99 Positive drug (BGB324) 2.25
  • Test 2 Detection of compound's inhibition of cell proliferation
  • MV-4-11 human myelomonocytic leukemia cell line, culture medium: IMDM+10% fetal bovine serum
  • IMDM+10% fetal bovine serum fetal bovine serum
  • Isomers 1-8 of Example 1 have good antiproliferative activity on MV-4-11 cells.
  • test compound The inhibitory effect of the test compound and the positive drug on the growth of human acute monocytic leukemia cell MV-4-11 xenografted tumor model in nude mice in vivo.
  • MV-4-11 cells in the logarithmic growth phase, count the cells and resuspend, adjust the cell concentration to 7.0 ⁇ 10 7 cells/mL; inject 200 ⁇ L (14 ⁇ 10 6 cells/only) to establish the MV-4-11 xenograft tumor model.
  • the tumor volume reaches 100-300 mm 3 , tumor-bearing mice with good health and similar tumor volume are selected.
  • the compound and positive drug were vortexed with an appropriate solvent and ultrasonically dissolved to completely dissolve the compound, then an appropriate volume of buffer solution was slowly added, vortexed to mix the liquid evenly, and drug preparations of different concentrations were obtained.
  • Isomers 1-8 of Example 1 have better activity in vivo.

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Abstract

L'invention concerne un composé benzocycloheptane utilisé comme inhibiteur d'AXL et son procédé de préparation. La structure du composé benzocycloheptane est représentée par la formule générale I. Le composé benzocycloheptane possède une activité inhibitrice de l'AXL et peut être utilisé comme inhibiteur d'AXL.
PCT/CN2022/118860 2021-09-22 2022-09-15 Composé benzocycloheptane utilisé comme inhibiteur d'axl WO2023045816A1 (fr)

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CN202111104565.0A CN115838383A (zh) 2021-09-22 2021-09-22 作为axl抑制剂的苯并环庚烷类化合物
CN202111104565.0 2021-09-22

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101535276A (zh) * 2006-10-23 2009-09-16 赛福伦公司 作为ALK和c-MET抑制剂的2，4-二氨基嘧啶稠合双环衍生物
WO2015038868A1 (fr) * 2013-09-13 2015-03-19 Cephalon, Inc. Dérivés de 2,4-diaminopyrimidine bicycliques condensés
WO2018102366A1 (fr) * 2016-11-30 2018-06-07 Ariad Pharmaceuticals, Inc. Anilinopyrimidines en tant qu'inhibiteurs de kinase 1 progénitrices hématopoïétiques (hpk1)
WO2021088787A1 (fr) * 2019-11-07 2021-05-14 南京正大天晴制药有限公司 Composé quinazoline utilisé comme inhibiteur d'axl
WO2021239133A1 (fr) * 2020-05-29 2021-12-02 南京正大天晴制药有限公司 Composé de pyrimidine utilisé en tant qu'inhibiteur d'axl

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101535276A (zh) * 2006-10-23 2009-09-16 赛福伦公司 作为ALK和c-MET抑制剂的2，4-二氨基嘧啶稠合双环衍生物
WO2015038868A1 (fr) * 2013-09-13 2015-03-19 Cephalon, Inc. Dérivés de 2,4-diaminopyrimidine bicycliques condensés
WO2018102366A1 (fr) * 2016-11-30 2018-06-07 Ariad Pharmaceuticals, Inc. Anilinopyrimidines en tant qu'inhibiteurs de kinase 1 progénitrices hématopoïétiques (hpk1)
WO2021088787A1 (fr) * 2019-11-07 2021-05-14 南京正大天晴制药有限公司 Composé quinazoline utilisé comme inhibiteur d'axl
WO2021239133A1 (fr) * 2020-05-29 2021-12-02 南京正大天晴制药有限公司 Composé de pyrimidine utilisé en tant qu'inhibiteur d'axl

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