WO2021088787A1 - Composé quinazoline utilisé comme inhibiteur d'axl - Google Patents

Composé quinazoline utilisé comme inhibiteur d'axl Download PDF

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WO2021088787A1
WO2021088787A1 PCT/CN2020/126083 CN2020126083W WO2021088787A1 WO 2021088787 A1 WO2021088787 A1 WO 2021088787A1 CN 2020126083 W CN2020126083 W CN 2020126083W WO 2021088787 A1 WO2021088787 A1 WO 2021088787A1
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compound
group
methyl
phenyl
optionally substituted
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PCT/CN2020/126083
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Chinese (zh)
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李冬冬
马昌友
冯海威
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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Priority to CN202080067248.3A priority Critical patent/CN114555588B/zh
Publication of WO2021088787A1 publication Critical patent/WO2021088787A1/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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the field of medical technology, and particularly relates to quinazoline compounds, which are AXL kinase inhibitors.
  • the present invention also relates to the use of the compound to treat diseases related to AXL activity.
  • Receptor tyrosine kinase is a multi-domain transmembrane protein that can be used as a sensor for extracellular ligands. 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 signal cascades (Robinson, DR et al., Oncogene, 19:5548-5557, 2000). So far, 58 RTKs have been identified in the human genome. They can regulate a variety of cellular processes, including cell survival, growth, differentiation, proliferation, adhesion, and movement (Segaliny, AI, etc., 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 structures, while AXL and Mer have the most similar tyrosine kinase domain amino acid sequences. Like other receptor tyrosine kinases (RTKs), the structure of the TAM family includes an extracellular domain, a transmembrane domain, and a conserved intracellular kinase domain. The extracellular domain of AXL has a unique structure in which immunoglobulin and type III fibronectin repeat units are juxtaposed and is reminiscent of a structure of neutrophil adhesion molecules.
  • TAM tumorigenesis
  • Gas6 growth inhibitory specific protein 6
  • AXL and Gas6 After the combination of AXL and Gas6, it will cause receptor dimerization and AXL autophosphorylation, thereby activating multiple downstream signal transduction pathways, and participating in multiple processes of tumorigenesis (Linger, RM, etc., Ther. Targets, 14 (10 ), 1073-1090, 2010; Rescigno, J. et al., Oncogene, 6(10), 1909-1913, 1991).
  • AXL is widely expressed in normal human tissues, such as monocytes, macrophages, platelets, endothelial cells, cerebellum, heart, skeletal muscle, liver and kidney, etc., among which myocardium and skeletal muscle have the highest expression, and bone marrow CD34+ cells and stromal cells are also relatively High expression, low expression in normal lymphoid tissues (Wu YM, Robinson DR, Kung HJ, Cancer Res, 64(20), 7311-7320, 2004; hung BI, etc., DNA Cell Biol, 22(8), 533-540 , 2003).
  • AXL gene is overexpressed or ectopic expressed in hematopoietic cells, mesenchymal cells and endothelial cells.
  • the overexpression of AXL kinase is particularly prominent.
  • the pro-survival signal of tumor cells can be reduced, the invasion ability of tumors can be blocked, and the sensitivity of targeted drug therapy and chemotherapy can be increased. Therefore, finding effective AXL inhibitors is an important direction of current tumor-targeted drug research and development.
  • the present invention provides a quinazoline compound represented by formula I or a pharmaceutically acceptable salt thereof,
  • X is CH or N
  • Y 1 is CH or N
  • Y 2 is CHR 1 , O or NR 2 ;
  • R 1 is hydrogen, C1-C6 alkyl, halogen, nitro, amino or hydroxyl
  • R 2 is hydrogen or C1-C6 alkyl
  • n is selected from 0 or 1;
  • n is selected from 1, 2 or 3;
  • R 3 is selected from phenyl, 5-6 membered heteroaryl, 9-12 membered benzoheterocyclyl or 9-12 membered benzooxoheterocyclyl, wherein the group is optionally substituted by one or more R 5 replaced;
  • R 5 is selected from halogen, C1-C4 alkyl,
  • R 4 is selected from phenyl, 5-6 membered heteroaryl or 9-12 membered benzoheterocyclyl, wherein said group is optionally substituted with one or more R 6 ;
  • R 6 is selected from halogen, C1-C4 alkyl
  • R a is hydrogen, C1-C4 alkyl or 3-6 membered cycloalkyl
  • R b is hydrogen or C1-C4 alkyl
  • R a, R b and the N to which they are attached together form a 5-7 membered monocyclic saturated heterocyclic ring, the group may be optionally substituted with one or more halogen or C1-C3 alkyl substituent;
  • R c is C1-C4 alkyl or phenyl optionally substituted by halogen or C1-C3 alkyl.
  • X is CH.
  • X is N.
  • Y 1 is N.
  • Y 1 is CH.
  • Y 2 is CHR 1 or O
  • R 1 is hydrogen, C1-C6 alkyl, halogen, nitro, amino, or hydroxyl.
  • Y 2 is O.
  • Y 2 is CHR 1
  • R 1 is hydrogen, methyl, ethyl, isopropyl, fluorine, chlorine, bromine, hydroxyl, or amino; in some typical embodiments, Y 2 is CH 2 .
  • X is CH
  • Y 1 is N
  • Y 2 is CH 2 .
  • X is N
  • Y 1 is CH
  • Y 2 is O
  • n is 1.
  • n is 2.
  • Q is NH, and m and n are 1.
  • R 3 is selected from phenyl, 5-6 membered heteroaryl, or 9-12 membered benzoheterocyclyl, wherein the group is optionally substituted with one or more R 5 ;
  • R 5 is selected from halogen, C1-C4 alkyl,
  • R 3 is selected from phenyl, pyridyl, thienyl, furyl, 1H-pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyrazine base, Wherein the group is optionally substituted with one or more R 5 .
  • R 3 is selected from phenyl, pyridyl, thienyl, furyl, 1H-pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyrazine base, Wherein the group is optionally substituted with one or more R 5 .
  • R 3 is selected from phenyl, pyridyl, Wherein the group is optionally substituted with one or more R 5 .
  • R 3 is selected from phenyl, pyridyl, Wherein the group is optionally substituted with one or more R 5 .
  • R 5 is selected from fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl,
  • R 5 is selected from fluorine, chlorine, methyl,
  • R 4 is phenyl optionally substituted with one or more R 6.
  • R 6 is selected from
  • R 6 is
  • R a is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, cyclopropyl or cyclopentyl.
  • R b is hydrogen, methyl, ethyl, n-propyl, or isopropyl.
  • R a , R b and the N to which they are attached together form a morpholinyl, pyrrolidinyl, piperazinyl, or homopiperazinyl group, wherein the group is optionally composed of one or more One fluorine, chlorine, bromine, methyl or ethyl substitution.
  • R a is methyl
  • R b is hydrogen or methyl
  • R a, R b and the N to which they are attached together form a morpholine ring, pyrrolidinyl, piperazinyl Or homopiperazinyl, where the group is optionally substituted with a methyl group.
  • R a is methyl
  • R b is hydrogen or methyl
  • R c is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl optionally substituted with one or more methyl groups.
  • R c is methyl, isopropyl, or phenyl optionally substituted with one methyl.
  • R 5 is selected from fluorine, chlorine, methyl,
  • R 5 is selected from fluorine, chlorine, methyl,
  • R 5 is selected from fluorine, chlorine, methyl,
  • the aforementioned compound of formula I has a structure as shown in formula II,
  • the aforementioned compound of formula I has a structure as shown in formula III,
  • R 3 is as defined in the compound of formula I.
  • R 3 is selected from phenyl, Wherein the group is optionally substituted with one or two R 5 , wherein R 5 is selected from fluorine, chlorine, methyl,
  • R 3 is selected from phenyl, Wherein the group is optionally substituted with one or two R 5 , wherein R 5 is selected from fluorine, chlorine, methyl,
  • R 3 is selected from phenyl, Wherein said group is optionally substituted with a substituent R 5, wherein R 5 is selected from fluoro, methyl,
  • R 3 is selected from phenyl, Wherein said group is optionally substituted with a substituent R 5, wherein R 5 is selected from fluoro, methyl,
  • R 3 is selected from phenyl, Wherein said group is optionally substituted with a substituent R 5, wherein R 5 is selected from fluoro, methyl,
  • R 3 is selected from phenyl, Wherein said group is optionally substituted with a substituent R 5, wherein R 5 is selected from fluoro, methyl,
  • R 3 is selected from
  • R 3 is selected from
  • the aforementioned compound of formula I has a structure as shown in formula IV,
  • R 3 is as defined in the compound of formula I.
  • R 3 is phenyl optionally substituted with one or more R 5 , wherein R 5 is selected from
  • R 3 is phenyl substituted with one R 5 , wherein R 5 is
  • the aforementioned compound of formula I has a structure as shown in formula V,
  • the aforementioned compound of formula I has a structure as shown in formula VI,
  • R 4 is as defined in the compound of formula I.
  • the aforementioned compound of formula I has a structure as shown in formula VII,
  • R 4 is as defined in the compound of formula I.
  • the aforementioned compound of formula I has a structure as shown in formula VIII,
  • R 3 is as defined in the compound of formula I.
  • R 3 is selected from phenyl, said phenyl is optionally substituted with R 5, wherein R 5 is selected from With a compound of formula I R a, R b and R c are defined.
  • R a is hydrogen or C1-C4 alkyl.
  • R a is hydrogen or C1-C4 alkyl
  • R b is hydrogen
  • R a is C1-C4 alkyl
  • R b is hydrogen
  • R c is C1-C4 alkyl.
  • R c is methyl, ethyl, n-propyl, isopropyl, n-butyl, or tert-butyl.
  • the present invention provides the following compounds or pharmaceutically acceptable salts thereof,
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, II, III, IV, V, VI, VII or VIII or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, II, III, IV, V, VI, VII or formula VIII or a pharmaceutically acceptable salt thereof, And one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition of the present invention can be administered by any suitable route or method, for example, oral or parenteral (for example, intravenous) administration.
  • the therapeutically effective amount of the compound of formula I, II, III, IV, V, VI, VII or VIII 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.
  • the pharmaceutical composition of the present invention is usually provided in the form of tablets, capsules or solutions.
  • the tablet may contain the 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 lyophilized powder, and adjusted to suitable pH and isotonicity.
  • the present invention also provides the use of a compound of formula I, II, III, IV, V, VI, VII or VIII in the preparation of a medicament for the prevention and/or treatment of AXL protein kinase-mediated diseases or disease states .
  • the present invention also provides a method for preventing and/or treating diseases or disease states mediated by AXL protein kinase, which comprises administering the formula I, II, III, IV, V of the present invention to an individual in need , VI, VII or VIII compound or the pharmaceutical composition of the present invention.
  • the present invention also provides the compound of formula I, II, III, IV, V, VI, VII or VIII of the present invention or the compound of the present invention for preventing and/or treating diseases or disease states mediated by AXL protein kinase Pharmaceutical composition.
  • the compound of the present invention has a significant inhibitory effect on AXL.
  • diseases or disease states mediated by the AXL protein kinase include but are not limited to autoimmune diseases.
  • the present invention provides a method for preparing compounds of formula III, IV, VI and VII, including but not limited to the following synthetic schemes:
  • R 3 and R 4 are as described in the definition of formula I above;
  • the compound of formula 1-1 and the compound of formula 1-2 are prepared under the conditions of a solvent (such as tetrahydrofuran) and a base (such as lithium bis(trimethylsilyl)amide), formula 1-3 and formula i- 1 or ii-1 in a solvent (e.g. dioxane) with a base (e.g. cesium carbonate) and a palladium catalyst (e.g. 1,1'-bisdiphenylphosphine ferrocene dichloride palladium) through the Suzuki coupling reaction
  • a solvent such as tetrahydrofuran
  • a base such as lithium bis(trimethylsilyl)amide
  • formula 1-3 and formula i- 1 or ii-1 in a solvent (e.g. dioxane) with a base (e.g. cesium carbonate) and a palladium catalyst (e.g. 1,1'-bisdiphenylphosphine ferrocene dichloride palladium)
  • the compound of formula 1-1 and the compound of formula 9-1 are prepared under the conditions of a solvent (such as tetrahydrofuran) and a base (such as lithium bis(trimethylsilyl)amide), and formula 9-2 and Formula i-2 or ii-2 is used to prepare formula VI compound by Suzuki coupling reaction; formula 9-2 can be used with formula iii-2 to prepare formula VII compound through Buchwald-Hartwig coupling reaction.
  • a solvent such as tetrahydrofuran
  • a base such as lithium bis(trimethylsilyl)amide
  • Z is a phenyl group or a 5-6 membered heteroaryl group, and the definitions of Ra and R b are as described in the previous formula I;.
  • the compound of formula 1-1 and the compound of formula 1-2 are prepared in the presence of a base (for example, lithium bis(trimethylsilyl)amide) and a solvent (for example, tetrahydrofuran), and the compound of formula 1-3 and the compound of formula vi
  • a base for example, lithium bis(trimethylsilyl)amide
  • a solvent for example, tetrahydrofuran
  • the compound is prepared by Suzuki coupling reaction to prepare the compound of formula vii.
  • the compound of formula vii is hydrolyzed under alkaline conditions to prepare the compound of formula vii.
  • the compound of formula viii and formula ix is used in condensing agent (such as HATU), base (such as triethylamine) and solvent (such as Formula x is prepared under the conditions of DMF).
  • the "compounds” of the present invention may be asymmetric, for example, having one or more chiral centers. Unless otherwise specified, the “compound” in 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 compound containing asymmetric carbon atoms of the present invention can be isolated in an optically pure form or a mixture of two or more stereoisomers. The optically pure form can be resolved from a mixture of two or more stereoisomers, or synthesized by using chiral raw materials or chiral reagents.
  • the "compounds" of the present invention also include tautomeric forms.
  • the tautomeric form is derived from the exchange of a single bond with an adjacent double bond accompanied by the migration of a proton. E.g: Under certain conditions, it can be transformed into
  • C1-C6 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.
  • element refers to the number of skeletal atoms that make up the ring.
  • “5-7 membered” means that the number of backbone atoms constituting the ring is 5, 6, or 7. Therefore, for example, pyridine, piperidine, piperazine, and benzene are six-membered rings, while thiophene and pyrrole are five-membered rings.
  • alkyl refers to a saturated aliphatic hydrocarbon group, including straight or branched chain saturated hydrocarbon groups having the indicated number of carbon atoms.
  • C1-C4 alkyl includes C1 alkyl, C2 alkyl, C3 alkyl and C4 alkyl. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl , Isobutyl, tert-butyl, etc.
  • cycloalkyl refers to a monocyclic saturated hydrocarbon system without heteroatoms or double bonds.
  • 3-6 membered cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • heteroaryl refers to a monovalent aryl group containing at least one heteroatom independently selected from nitrogen, oxygen, and sulfur.
  • heteroaryl examples include, but are not limited to, pyridyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, furyl, pyrazinyl, and thiazolyl.
  • 9-12 membered benzoheterocyclyl refers to a bicyclic ring system with 9-12 ring atoms, one of which is a benzene ring, and the other is saturated, partially unsaturated or unsaturated containing 1-2
  • 9-12 membered benzooxoheterocyclic group refers to a bicyclic ring system with 9-12 ring atoms, one of which is a benzene ring, and the other is saturated or partially unsaturated containing 1-2 options.
  • a 5-6 membered heterocyclic ring from N, O, S heteroatoms, and at least one ring atom on the heterocyclic ring is grouped Replace as long as the valence is satisfied. Examples include, but are not limited to
  • 5-7 membered monocyclic saturated heterocyclic ring refers to a saturated monocyclic ring comprising 5-7 ring atoms, which contains 1 to 2 identical or different heteroatoms, and the heteroatoms are independently selected from nitrogen, Sulfur or oxygen atoms, and the remaining ring atoms are carbon. Examples include, but are not limited to, morpholinyl, pyrrolidinyl, piperazinyl, or homopiperazinyl.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • hydroxyl refers to -OH.
  • nitro refers to -NO 2 .
  • amino refers to -NH 2 .
  • the substituents R 5 and R 6 may be bonded to any atom on the ring, as long as the valence allows. Combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds. Those skilled in the art can understand that for any group containing one or more R 5 or R 6 substituents, any substitution or substitution pattern that is impossible to exist in space and/or cannot be synthesized will not be introduced.
  • middle and middle Both refer to the chemical bond junction.
  • connection site When appearing in double or multiple rings And when the connection location is uncertain, it means that the connection site is limited to Any atom on the single ring, as long as the valence allows. E.g, It means that the connection site is only located on any carbon atom on the benzene ring in the bicyclic ring, and must meet the requirements of atomic valence bonds, which specifically refers to
  • pharmaceutically acceptable salt refers to a salt that retains the biological efficacy of the free acid and base of a specific compound without biological adverse effects.
  • acid including organic acid and inorganic acid
  • base addition salt including organic base and inorganic base
  • the pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound containing acid or base by conventional chemical methods. In general, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or organic solvent or a mixture of both.
  • an effective amount or “therapeutically effective amount” refers to a sufficient amount of a drug or medicament that is non-toxic but can achieve the desired effect.
  • pharmaceutically acceptable carrier refers to those carriers that have no obvious stimulating effect on the body and do not impair the biological activity and performance of the active compound. Including, but not limited to, any diluents, disintegrants, adhesives, glidants, and wetting agents approved by the State Food and Drug Administration that can be used for humans or animals.
  • Sudki coupling reaction refers to the cross-coupling of aryl or alkenyl boronic acid or boronic acid ester with chlorine, bromine, iodo aromatic hydrocarbon or alkene under the catalysis of palladium complex.
  • Buchwald-Hartwig coupling reaction refers to the palladium-catalyzed cross-coupling reaction of amines and aromatic halides to produce C-N bonds.
  • nM nmol/L
  • HATU 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • DIPEA N,N-diisopropylethylamine
  • DMSO dimethyl sulfoxide
  • Pd 2 (dba) 3 Tris(dibenzylideneacetone)dipalladium
  • Pd(dppf)Cl 2 1,1'-bisdiphenylphosphinoferrocene palladium dichloride
  • Xantphos 4,5-bisdiphenylphosphine-9,9-dimethylxanthene
  • HEPES 4-hydroxyethylpiperazine ethanesulfonic acid.
  • 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 specification or known in the art, and such combinations can be easily performed by those skilled in the art.
  • Example 2 According to the method of Example 1, using compound 1-3 (50 mg, 0.11 mmol) and (4-isopropoxyphenyl)boronic acid (31 mg, 0.17 mmol) as raw materials, the title compound (40 mg) was obtained.
  • Example 2 According to the method of Example 1, using compound 1-3 (50 mg, 0.11 mmol) and 4-chloro-2-isopropoxyphenylboronic acid (36.4 mg, 0.17 mmol) as raw materials, the title compound (40 mg) was obtained.
  • Example 2 According to the method of Example 1, using compound 1-3 (50 mg, 0.11 mmol) and (4-phenoxyphenyl)boronic acid (36 mg, 0.17 mmol) as raw materials, the title compound 13 (38 mg) was obtained.
  • Example 2 According to the method of Example 1, using compound 1-3 (50mg, 0.11mmol) and (1-methyl-1H-indazol-5-yl)boronic acid (30mg, 0.17mmol) as raw materials, the title compound (10mg) was obtained .
  • Example 2 According to the method of Example 1, using compound 1-3 (50 mg, 0.11 mmol) and benzo[d]thiazol-5-ylboronic acid (30.5 mg, 0.17 mmol) as raw materials, the title compound 30 (35 mg) was obtained.
  • Example 2 According to the method of Example 1, using compound 1-3 (50 mg, 0.11 mmol) and (1H-indazol-5-yl)boronic acid (50 mg, 0.17 mmol) as starting materials, the title compound (40 mg) was obtained.
  • Example 35 using compound x-1 (102 mg, 0.23 mmol) and 3-isopropoxyphenylboronic acid (64 mg, 0.35 mmol) as raw materials, the title compound (44 mg) was obtained.
  • the compound 1-3 (153mg, 0.35mmol), 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)isoindolin-1-one (143 mg, 0.52 mmol) was used as the starting material to obtain the title compound (15 mg).
  • Example 1 According to the method of Example 1, the compound 1-3 (188mg, 0.43mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaboroborin-2-yl )-3,4-dihydro-2H-benzo[b][1,4]oxazine (166mg, 0.64mmol) as starting material to obtain the title compound (60mg).
  • the Mobility shift assay was used to establish an AXL kinase activity detection platform for compound activity determination.
  • Conversion%_sample is the conversion rate reading of the sample
  • Conversion%_min Mean value of negative control wells, representing the conversion rate readings of wells without enzyme activity
  • Conversion%_max The mean value of the positive control wells, representing the conversion rate readings of the wells without compound inhibition.
  • Biological activity test 2 The compound of the present invention inhibits the proliferation of MV-4-11 cells
  • MV-4-11 human myeloid monocytic leukemia cell line, culture medium: IMDM+10% fetal bovine serum
  • IMDM+10% fetal bovine serum was purchased from Nanjing Kebai Biotechnology Co., Ltd. and placed in an incubator at 37°C and 5% CO 2 bring up.
  • the cells in the logarithmic growth phase were plated in a 96-well plate at a cell density of 8000 cells/well, and a blank control group was set at the same time.
  • test compound and the positive drug were dissolved in dimethyl sulfoxide to prepare a 10 mM stock solution, and stored in a refrigerator at -80°C for a long time.
  • the 10 mM compound stock solution was diluted with dimethyl sulfoxide to obtain a 200-fold concentration of the working solution (the highest concentration was 200 ⁇ M, a 3-fold gradient, a total of 10 concentrations), and 3 ⁇ L of each concentration was added to 197 ⁇ L of complete Dilute in the culture medium to obtain a 3-fold concentration of the working solution, and then add 50 ⁇ L to 100 ⁇ L of cell culture medium (final concentration of dimethyl sulfoxide is 0.5%, v/v), and two replicate holes are set for each concentration.
  • the signal value of the test substance the average value of the fluorescence signal of the cell + medium + compound group;
  • Signal value of blank group mean value of fluorescence signal of medium group (containing 0.5% DMSO);
  • Signal value of the negative control group the mean value of the fluorescence signal of the cell + medium group (containing 0.5% DMSO).
  • mice Collect logarithmic growth phase MV-4-11 cells, resuspend the cells after counting, adjust the cell concentration to 7.0 ⁇ 10 7 cells/mL; inject into the right axillary subcutaneously before nude mice, Each animal was inoculated with 200 ⁇ L (14 ⁇ 10 6 cells/animal) to establish a MV-4-11 transplanted tumor model. When the tumor volume reaches 100-300mm 3 , select tumor-bearing mice with good health and similar tumor volume.
  • Solvent control group PEG400 & citrate buffer (20:80, v:v).
  • RTV relative tumor volume
  • TV initial is the tumor volume measured during group administration
  • TV t is the tumor volume at each measurement during the administration period.
  • TGI (%) The calculation formula of tumor growth inhibition rate TGI (%) is:
  • TGI 100% ⁇ [1-(TV t(T) -TV initial(T) )/(TV t(C) -TV initial(C) )]
  • TV t(T) represents the tumor volume measured each time in the treatment group
  • TV initial(T) represents the tumor volume of the treatment group when the group is administered
  • TV t(C) represents the tumor volume measured each time in the solvent control group
  • TV initial (C) represents the tumor volume of the solvent control group when administered in groups.
  • RTV T represents the RTV of the treatment group
  • RTV C represents the RTV of the solvent control group.
  • test data was calculated and related statistical processing with Microsoft Office Excel 2007 software.
  • the experimental data in the table are related data obtained at the end of the experiment (the end of the experiment is defined as: the end of the experiment after 21 days or the tumor volume of the solvent control group reaches 2000mm 3 (whichever comes first)).

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Abstract

L'invention concerne un composé de quinazoline utilisé en tant qu'inhibiteur d'AXL. La structure du composé de quinazoline est telle que représentée dans la formule générale (I), et la définition de chaque substituant est telle que décrite dans la description. L'invention concerne en outre un procédé de préparation associé. Le composé de quinazoline de la présente invention présente une activité inhibitrice d'AXL significative, et peut être utilisé en tant qu'inhibiteur d'AXL.
PCT/CN2020/126083 2019-11-07 2020-11-03 Composé quinazoline utilisé comme inhibiteur d'axl WO2021088787A1 (fr)

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WO2022268026A1 (fr) * 2021-06-23 2022-12-29 南京正大天晴制药有限公司 Composés de 1,2,4-triazole en tant qu'inhibiteurs d'axl
WO2023045816A1 (fr) * 2021-09-22 2023-03-30 南京正大天晴制药有限公司 Composé benzocycloheptane utilisé comme inhibiteur d'axl
WO2023207960A1 (fr) * 2022-04-27 2023-11-02 浙江海正药业股份有限公司 Dérivé à base de pyrimidine fusionné, son procédé de préparation et son utilisation

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WO2022268026A1 (fr) * 2021-06-23 2022-12-29 南京正大天晴制药有限公司 Composés de 1,2,4-triazole en tant qu'inhibiteurs d'axl
WO2023045816A1 (fr) * 2021-09-22 2023-03-30 南京正大天晴制药有限公司 Composé benzocycloheptane utilisé comme inhibiteur d'axl
WO2023207960A1 (fr) * 2022-04-27 2023-11-02 浙江海正药业股份有限公司 Dérivé à base de pyrimidine fusionné, son procédé de préparation et son utilisation

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