WO2021115432A1 - Nouveau composé contenant de la quinazoline, intermédiaire de celui-ci, et utilisation associée - Google Patents

Nouveau composé contenant de la quinazoline, intermédiaire de celui-ci, et utilisation associée Download PDF

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WO2021115432A1
WO2021115432A1 PCT/CN2020/135716 CN2020135716W WO2021115432A1 WO 2021115432 A1 WO2021115432 A1 WO 2021115432A1 CN 2020135716 W CN2020135716 W CN 2020135716W WO 2021115432 A1 WO2021115432 A1 WO 2021115432A1
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alkyl
substituted
group
quinazoline
ethyl
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王亚农
高阳
周洁
方进
蒋涛
周明月
茆廷玉
成晓峰
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苏州长禾药业股份有限公司
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • 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
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    • 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
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    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
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    • 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
    • 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
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • 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
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • 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
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • 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
    • C07F9/65583—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 each of the hetero rings containing nitrogen as ring hetero atom

Definitions

  • the invention relates to the technical field of medicine, in particular to a quinazoline compound and its application in inhibiting aurora kinase.
  • Aurora kinase is a serine/threonine kinase that plays an important role in cell proliferation. Its function is to act as a regulator in many aspects of mitosis and cell division, including centrosome, replication, mitotic spindle formation, chromosome arrangement on the main axis, mitotic checkpoint activation and cytokinesis.
  • Their protein primary structure contains an N-terminal regulatory region and a C-terminal catalytic region, and the sequence similarity of the enzyme domain is 71%.
  • the residues of the ATP adenine ring binding site are also the same, but they are in cell division.
  • Aurora A affects the separation and maturation of centrosomes and the formation of two-stage spindles from the end of the S phase of mitosis to the beginning of the G of the next division cycle.
  • Aurora B is located in the centromeric region of the chromosome in the early stage of mitosis, and moves from the centromere to the microtubules in the late stage.
  • Aurora C functions.
  • Aurora in resting cells is low or undetectable, and peaks of expression and activity appear in the G2 and mitotic phases of the cell cycle. It is speculated that the matrix of Aurora in mammalian cells includes histone H3, proteins involved in chromosome condensation and CENP-A, myosin II regulating light chain, protein phosphatase 1 and TPX2. Since its discovery in 1997, the mammalian Aurora kinase family has been closely linked to tumorigenesis. The carcinogenic activity of Aurora A has been relatively mature, while for Aurora B, early studies have shown that its carcinogenic activity only exists indirectly. Follow-up studies confirmed the importance of Aurora B in tumorigenesis.
  • Aurora kinase inhibitors Due to the unique pharmacological mechanism of Aurora kinase, drug development targeting Aurora kinase has become one of the hot spots in the research of anticancer drugs. At present, there are no Aurora kinase inhibitors for clinical treatment, and only a few Aurora kinase inhibitors are undergoing clinical trials. Although the prospect of drug therapy is bright, the reported small molecules have different degrees of toxic side effects, or the solubility and/or membrane penetration ability to be optimized. Therefore, the development of Aurora inhibitors still has huge market potential.
  • Patent WO 2004/058781 discloses a series of quinazoline derivatives with 5-membered nitrogen-containing heteroaryl groups, which have inhibitory activity on Aurora B and/or Aurora A.
  • the technical problem to be solved by the present invention is to provide a new type of quinazoline-containing compound with inhibitory activity against Aurora A and/or Aurora B.
  • the present invention adopts the following technical solutions:
  • R 1 is a group selected from hydrogen, halogen, cyano, nitro, C1-6 alkoxy, C1-6 alkyl, C1-6 haloalkyl, -CF 2 OH or -CHFOH;
  • R 2 is a group selected from hydrogen, halogen or C1-6 alkyl
  • R 3 is one or more groups selected from hydrogen or halogen
  • R 6 is a group selected from hydrogen, halogen or C1-6 alkyl
  • p is selected from 0, 1, 2, 3, 4, 5 or 6;
  • s is selected from 0, 1, 2, 3, 4 or 5;
  • w and t are independently selected from 0, 1, 2, 3, 4, 5 or 6 and w+t is greater than 0 and less than 7; y is selected from 0, 1, 2, 3, 4, 5 or 6;
  • L 1 is the following group substituted or unsubstituted by a first substituent: methylene, ethylene or vinylene, wherein the first substituent is selected from halogen, C1-6 alkyl, and C1-6 alkoxy ; Or L 1 is an ethynylene group,
  • L 2 does not exist, or L 2 is -NH- or -NHC(O)- or -C(O)NH-;
  • R 4 and R 5 are independently selected from hydrogen, the following groups substituted or unsubstituted by one, two, three or more second substituents which are the same or different: C1-6 alkyl, C1-6 alkane Oxy, phosphonooxy C1-6 alkyl, C3-6 cycloalkyl, C6-16 aromatic hydrocarbon group, C4-16 heteroaromatic hydrocarbon group, C2-6 alkenyl group, C2-6 alkynyl group, C1-6 alkane Sulfonyl, benzenesulfonyl and C3-6 cycloalkyl C1-4 alkyl; wherein the second substituent is selected from halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, Hydroxy, C1-6 alkoxy, phosphonooxy, sulfinimide or S(O) z R 8 , where z is 0, 1 or 2; or,
  • R 7 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, the following groups substituted or unsubstituted by one or more of the same or different third substituents: C1-6 alkoxy, C1-6 alkyl , C1-6 haloalkyl, -CF 2 OH or -CHFOH group, C3-6 cycloalkyl, C6-16 aromatic hydrocarbon group, C4-16 heteroaromatic hydrocarbon group, C2-6 alkenyl group, C2-6 alkynyl group , C1-6 alkylsulfonyl, benzenesulfonyl and C3-6 cycloalkyl C1-4 alkyl, wherein the third substituent is selected from halogen, C1-6 alkyl, C3-6 cycloalkyl, C1 -6 haloalkyl, hydroxy, C1-6 alkoxy, phosphonooxy, sulfinimide or S(O) z R 8 , where z is 0, 1 or 2;
  • Said Ra is selected from the following groups substituted or unsubstituted by one, two, three or more identical or different penta-substituents: C1-6 alkyl, C3-6 cycloalkyl, C2-6 alkenyl, -(CH 2 ) q aryl, a heterocycloalkyl group containing 1-5 heteroatoms selected from N, S, P or O, containing 1-5 selected from N, S, P and O heteroatom heteroaryl group, the fifth substituent is selected from -OH, halogen, nitro, oxo, cyano, phosphonooxy, sulfinimide, -R 8 , -OR 8 , -NR 8 R 9 , -SR 8 , -S(O) 2 NR 8 R 9 , -S(O) 2 R 8 , -NR 8 S(O) 2 NR 8 R 9 , -NR 8 S(O) 2 R 9 , -NR 8 S(O) 2 R 9
  • R 8 and R 9 are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C4-8 cycloalkenyl, C2-6 alkynyl, C3-8 ring at each occurrence.
  • Each occurrence of R 10 and R 11 is independently selected from hydrogen, phosphonooxy, and the following groups substituted with one, two, three or more identical or different hexa-substituents: C1-6 Alkyl, C2-6 alkenyl, C4-8 cycloalkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 3- to 12-membered monocyclic or polycyclic heterocyclic ring; the sixth substituent is selected from- OH, -SH, -NH 2 , -NO 2 or -CN;
  • Said q is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 each time it appears;
  • the corresponding alkylene group on the general formula (IA) may optionally be substituted by one or more seventh substituents that are the same or different, and the seventh substituent is selected From C1-6 alkyl, C3-8 cycloalkyl.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 2 , m, n, p, and s are the same as in the foregoing.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 2 , m, n, p, and s are the same as in the foregoing.
  • p is 1 or 2 or 3 and n is 1 or 2.
  • n is 1, and L 2 is -NHC(O)- or -C(O)NH-; in other embodiments, n is 2, and L 2 is -NH-.
  • the position between L 2 and L 2 on the benzene ring connected to L 2 of the general formula (IA) or (IB) or (IC) is F.
  • R 1 , R 2 , and R 6 are independently selected from hydrogen, methyl, ethyl, methoxy, ethoxy, fluorine, and chlorine.
  • R 4 and R 5 are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, hydroxy substituted methyl , Hydroxy substituted ethyl, hydroxy substituted isopropyl, phosphonooxymethyl, phosphonooxyethyl, vinyl, ethynyl, vinylmethyl, ethynylmethyl, methoxyethyl, methoxy Cyclopropyl, trifluoromethylmethyl, trifluoromethylethyl, cyclopropylmethyl, cyclopropylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, hydroxy substituted Phenyl, chlorophenyl, methyl-substituted phenyl, methanesulfonyl, benzenesulfonyl
  • R 4 and R 5 combine with the nitrogen atom to which they are connected to form a heterocyclic structure substituted or unsubstituted by one or two fourth substituents.
  • the heterocyclic structure is a 5-membered monocyclic heterocyclic ring, a 6-membered monocyclic heterocyclic ring or a C7-C8 spiro ring or a C5-C9 bridged ring, wherein the ring structure contains the nitrogen connected to R 4 and R 5 as well as optional Contains another N or contains O.
  • one of R 4 and R 5 is hydrogen, methyl, ethyl, propyl, isopropyl or butyl, and the other is hydroxy substituted methyl, hydroxy substituted ethyl Group, hydroxy-substituted isopropyl, phosphonooxymethyl, phosphonooxyethyl, phosphonoisopropyl, hydroxy-substituted phenyl, benzenesulfonyl.
  • the compound is selected from:
  • the quinazoline-containing compound is selected from compounds shown in the following structures:
  • the present invention encompasses individual E or Z isomers of any of the above compounds and/or pharmaceutically acceptable salts of any of the above compounds.
  • the present invention also provides a method for inhibiting aurora kinase in a patient's body or a biological sample, which comprises administering an effective inhibitory amount of the compound of the present invention to the patient or contacting the biological sample with an effective inhibitory amount of the compound of the present invention.
  • the present invention provides a method for treating any condition involving Aurora activity, which comprises an individual in need and a therapeutically effective amount of a compound of the present invention.
  • the present invention also provides applications of the above-mentioned compounds.
  • the specific technical solutions are as follows:
  • the tumor is a solid tumor or hematological tumor.
  • the solid tumor is breast cancer, pancreatic cancer, lung cancer, liver cancer, stomach cancer, colon cancer, kidney cancer, prostate cancer, head and neck cancer, esophageal cancer, ovarian cancer, or cervical cancer.
  • the hematological tumor is lymphoma, leukemia or myeloma.
  • the present invention also relates to a pharmaceutical composition, which comprises one or more of the quinazoline-containing compounds of the present invention, or pharmaceutically acceptable salts or prodrugs thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is preferably a composition for preventing and/or treating cancer.
  • the present invention also provides an intermediate for preparing a quinazoline compound or its pharmaceutically acceptable salt or its prodrug.
  • the intermediate has a structure represented by the general formula (III-a) or (III-b):
  • R 1 , R 2 , R 3 , R 6 , L 2 , m, n, and s are the same as described above; in formula (III-b), R 1 , R 2 , R 6 , R 4 , R 5 , and p are the same as described above, and X represents fluorine, chlorine, bromine or iodine.
  • Typical intermediates (III-a) or intermediates (III-a) are, for example, the compounds synthesized in the following examples or compounds directly associated with them.
  • the present invention also provides a preparation method of a quinazoline-containing compound or its pharmaceutically acceptable salt or its prodrug, which comprises making the aforementioned intermediate and compound having the general formula (III-b) The step of substitution reaction to produce compound (Ib),
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 2 , m, n, p, and s have the same definitions as above.
  • the method also includes using versus The reaction produces the intermediate having the general formula (III-b), where X represents fluorine, chlorine, bromine or iodine.
  • the present invention also provides yet another preparation method of quinazoline-containing compound or its pharmaceutically acceptable salt or its prodrug, which comprises making the intermediate with general formula (III-a) described above and The step of reaction to produce compound (Ia),
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 2 , m, n, p, and s have the same definitions as described above.
  • the method also includes using versus The reaction produces the intermediate having the general formula (III-a), where X represents fluorine, chlorine, bromine or iodine.
  • the present invention has the following advantages compared with the prior art:
  • the quinazoline-containing compound or its pharmaceutically acceptable salt or its prodrug molecule of the present invention is a series of new compounds.
  • This type of compound has the effect of inhibiting Aurora activity and can inhibit the G2-M phase of tumor cell mitosis.
  • the blockade of the tumor cell line produces anti-proliferation and apoptosis-inducing effects. It can be an effective drug for the treatment of malignant tumors and has greater application value.
  • Figure 1 depicts the results of histone H3 phosphorylation inhibition experiments.
  • the compounds of the specific examples of the present invention cultured with cells exhibited a concentration-dependent inhibitory effect on histone H3 serine phosphorylation.
  • Figure 2 reflects the effect of the test compound on the phosphorylation of Histon in a human normal cardiomyocyte cell line.
  • Figure 3 depicts an exemplary distribution diagram of G2/M phase cell growth inhibition experiments using specific example compounds of the present invention.
  • any variable such as R 1 , R 2, etc.
  • the definition of each occurrence thereof is independent of the definition of each occurrence of other variables.
  • combinations of substituents and variables are allowed as long as the combination stabilizes the compound.
  • the line drawn from the substituent into the ring system indicates that the bond in question can be connected to any substitutable ring atom.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic carbon and heteroatom substituents of organic compounds.
  • substituents and substitution patterns of the compounds of the present invention can be selected to provide chemically stable compounds that can be easily synthesized from readily available raw materials by the techniques in the art and the methods proposed below. If the substituents themselves are substituted by more than one group, it should be understood that these groups may be on the same carbon atom or on different carbon atoms, as long as the structure is stabilized.
  • alkyl means to include branched and straight chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms.
  • C1-C6 in “C1-C6 alkyl” includes groups having 1, 2, 3, 4, 5, or 6 carbon atoms arranged in a linear or branched chain.
  • heteroatom as used herein means an atom of any element other than carbon and hydrogen. Preferred heteroatoms are nitrogen, oxygen, phosphorus and sulfur.
  • heteroalkyl refers to a straight or branched aliphatic hydrocarbon chain containing 1 to 3 heteroatoms, and each of the carbons and heteroatoms available in the heteroalkyl chain may each be optionally substituted independently of each other, and
  • the heteroatoms are independently selected from O, N, P, PO, PO 2 , S, SO and SO 2 (e.g., dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, diethyl Aminomethyl, diethylaminoethyl, diethylaminopropyl, 2-diisopropylaminoethyl, bis-2-methoxyethylamino, [2-(dimethylamino-ethyl )-Ethyl-amino]-methyl, 3-[2-(dimethylamino-ethyl)-ethyl-amino]-propyl, hydroxymethyl, 2-hydroxyethy
  • halogenated hydrocarbon group refers to a hydrocarbon group in which one or more hydrogen atoms are replaced by halogen atoms.
  • Alkenyl and alkynyl groups include linear, branched or cyclic alkenes and alkynes.
  • Cyclic hydrocarbon group refers to a mono- or polycyclic aliphatic hydrocarbon group with a specific number of carbon atoms, wherein the ring system may be a saturated ring, or an unsaturated, non-aromatic or spiro compound, and may optionally contain double Bonds, such as, for example, cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, norbornyl Group, norbornenyl, indanyl, adamantyl, spiroheptyl and spiro[4.2]heptyl.
  • cycloalkyl refers to a mono- or polycyclic aliphatic alkyl group having a specific number of carbon atoms. Cycloalkylalkyl groups include non-cyclic alkyl groups in which a hydrogen atom bonded to a carbon atom is replaced by a cycloalkyl group.
  • heterocyclic ring or “heterocyclic group” refers to a saturated or unsaturated, non-aromatic monocyclic, bicyclic or bridged polycyclic or spiro ring compound, including 3-12 carbon atoms, and Heteroatoms selected from O, N, P, and S replace one or more carbon atoms.
  • heterocyclyl include, but are not limited to: imidazolyl, indolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, oxetanyl, pyranyl, Pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinoxolinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, 1,4-di Oxalyl, pyrrolidinyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl , Dihydropyridyl, dihydropyrimidinyl, di
  • heterocyclic substituents can be achieved through carbon atoms or through heteroatoms.
  • Heterocycloalkylalkyl refers to an acyclic alkyl group in which a hydrogen atom bonded to a carbon atom is replaced by a heterocycloalkyl group.
  • heteroaryl refers to a mono- or polycyclic ring, containing one or more heteroatoms instead of one or more carbon atoms, and the heteroatoms are the same or different, and are, for example, N, O, S And P.
  • heteroatoms include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazole Group, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, and triazinyl.
  • bicyclic heteroaryl groups are indolyl, isoindolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl , Benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, cinnolinyl, 2,3-naphtholinyl, quinazolinyl and benzotriazinyl, medium Azindanyl, oxazolopyridyl, imidazopyridyl, 1,5-naphthazine, indolinyl, isochromanyl, chromanyl, tetrahydro Isoquinolinyl, isoindoline, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, be
  • halogen is meant to include chlorine, fluorine, bromine and iodine.
  • alkyl, cycloalkyl, aryl, and heterocyclyl substituents may be unsubstituted or substituted.
  • (C1-C6)alkyl may be substituted with one, two or three substituents selected from OH, halogen, alkoxy, dialkylamino, or heterocyclic groups such as morpholinyl, piperidinyl and the like.
  • substituted refers to a moiety that has a substituent on one or more carbons of the main chain instead of hydrogen. It should be understood that “substitution” or “substitution” includes implicit conditions, that is, the substitution is based on the permissible valence of the substituted atom and the substituent, and the substitution produces a stable compound, for example, it does not spontaneously proceed such as by rearrangement, Changes caused by cyclization, elimination, etc. As used herein, the term “substituted” is expected to include all permitted substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents may be one or more and may be the same or different for appropriate organic compounds.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any permitted substituents of organic compounds described herein that satisfy the valence of the heteroatoms.
  • Substituents may include, for example, halogen, hydroxy, carbonyl (such as carboxy, alkoxycarbonyl, formyl or acyl), thiocarbonyl (such as thioester, thioacetate or thioformate), alkoxy, Phosphoryl, phosphate, phosphonate, phosphonite, amino, amide, amidine, imine, cyano, nitro, azide, mercapto, alkylthio, sulfate, sulfonate, sulfonate Acyl, sulfonylamino, sulfonyl, heterocyclyl, C6-16 aromatic hydrocarbon group or aromatic or heteroaromatic moiety.
  • the substituted part of the hydrocarbon chain may itself be substituted.
  • free form refers to the non-salt form.
  • pharmaceutically acceptable salts included herein include not only the exemplary salts of the specific compounds described herein, but also the typical pharmaceutically acceptable salts of all the compounds of formula I in the free form.
  • the free form of the particular salt of the compound can be isolated using techniques known in the art.
  • the free form of the salt can be regenerated by treating the salt with a suitable dilute aqueous alkali solution such as a dilute aqueous sodium hydroxide solution, a dilute aqueous potassium carbonate solution, a dilute ammonia water, and a dilute aqueous sodium bicarbonate solution.
  • a suitable dilute aqueous alkali solution such as a dilute aqueous sodium hydroxide solution, a dilute aqueous potassium carbonate solution, a dilute ammonia water, and a dilute aqueous sodium bicarbonate solution.
  • the free forms are somewhat different from their respective salt forms in certain physical properties such as solubility in polar solvents, but for the purpose of the invention, the acid and base salts are equivalent to their respective free forms in other pharmaceutical aspects.
  • the compound of the present invention containing a basic part or an acidic part can be synthesized into the pharmaceutically acceptable salt of the present invention by conventional chemical methods.
  • the salt of the basic compound is prepared by ion exchange chromatography or by reacting a free base with a stoichiometric amount or excess of an inorganic or organic acid in the desired salt form in a suitable solvent or a combination of solvents.
  • the salt of an acidic compound is formed by reacting with a suitable inorganic or organic base.
  • the pharmaceutically acceptable salt of the compound of the present invention includes the conventional non-toxic salt of the compound of the present invention formed by reacting a basic compound of the present invention with an inorganic or organic acid.
  • conventional non-toxic salts include salts prepared from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc., and also include salts derived from organic acids such as acetic acid, propionic acid, succinic acid, and glycolic acid.
  • Stearic acid lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pyruvic acid, maleic acid, hydroxymaric acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2- Acetoxymonobenzoic acid, fumaric acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid and other salts prepared.
  • a suitable "pharmaceutically acceptable salt” refers to a salt prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganous, potassium, sodium, zinc, and the like. Particularly preferred are ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, and substituted amines include naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as refined Amino acid, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethyl Diamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine , Piperidine, quama, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.
  • the compound of the present invention may contain one or more asymmetric centers, and may produce diastereomers and optical isomers from this.
  • the present invention includes all possible diastereomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers and their pharmaceutically acceptable salts.
  • the present invention includes all stereoisomers of the compound represented by formula I and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers and specific isolated stereoisomers are also included in the present invention. In the synthetic process of preparing such compounds, or in the process of using racemization or epimerization methods well known to those of ordinary skill in the art, the product obtained may be a mixture of stereoisomers.
  • the present invention includes any possible tautomers, pharmaceutically acceptable salts thereof, and mixtures thereof.
  • the compounds of the present invention include compounds defined in the present invention labeled with various isotopes, such as those in which radioactive isotopes such as 3 H, 14 C and 18 F are present, or non-radioactive isotopes such as 2 H and 13 C compounds.
  • the present invention includes any possible solvate and polymorph.
  • the type of solvent that forms the solvate is not particularly limited, as long as the solvent is pharmacologically acceptable.
  • water, ethanol, propanol, acetone and similar solvents can be used.
  • disease mediated by Aurora or “condition mediated by Aurora” means any disease or other harmful condition in which Aurora is known to play a role, and also means those resulting from treatment with an Aurora inhibitor Alleviated diseases or conditions also mean any diseases or other harmful conditions or diseases in which Aurora is known to play a role.
  • the compounds of the present invention are suitable for use as Aurora kinase inhibitors. Without wishing to be bound by any particular theory, the compounds are particularly suitable for the treatment of diseases, conditions or disorders in which the activation of Aurora kinase is involved in the diseases, conditions or conditions. Reduce its severity. When Aurora kinase activation is involved in a specific disease, condition or condition, the disease, condition or condition may also be referred to as "Aurora-mediated disease" or condition.
  • the diseases or conditions include (but are not limited to): viral infections (such as HIV and Kaposi's sarcoma); inflammatory and autoimmune diseases (such as colitis, arthritis, Alzheimer’s disease, renal small Glomerulonephritis and wound healing); bacterial, fungal and/or parasitic infections; leukemias, lymphomas and solid tumors (e.g. cancer and sarcoma), skin diseases (e.g. cowhide); proliferative diseases characterized by increased cell numbers (e.g. fibroblasts) Cells, hepatocytes, bone and bone marrow cells, cartilage or smooth muscle cells or epithelial cells (such as endometrial hyperplasia)); bone diseases and cardiovascular diseases (such as restenosis and hypertrophy).
  • viral infections such as HIV and Kaposi's sarcoma
  • inflammatory and autoimmune diseases such as colitis, arthritis, Alzheimer’s disease, renal small Glomerulonephritis and wound healing
  • bacterial, fungal and/or parasitic infections
  • brain tumors such as, for example, acoustic schwannomas (neuroma), astrocytomas such as gliomas, fibrous astrocytomas, protoplasmic astrocytomas Glioblastoma, feeding astrocytoma, glioblastoma multiforme and glioblastoma, brain lymphoma, brain metastases, pituitary tumors such as prolactinoma, HGH (human (pituitary) growth hormone) production Tumors and ACTH-producing tumors (corticosteroids), craniopharyngiomas, medulloblastomas, meningiomas and oligodendrogliomas; neuromas such as, for example, autonomic nervous system tumors such as neuroblasts Tumors, gangliomas, gangliocytomas (pheochromocytoma, paraganglioma) and glomus tumor
  • neuromas such as, for example, autonomic nervous system tumors such as neuroblast
  • the compounds of the present invention can be used for the prevention, short-term or long-term treatment of the above diseases, and optionally combined with radiotherapy or other "state-of-the-art" compounds, such as, for example, cytostatic or cytotoxic substances, cell proliferation inhibitors, anti-vascular Produce substances, steroids or antibodies.
  • R 1 , R 2 and R 6 are the same as those described above, and Cl in Intermediate I-4 can be replaced with fluorine, bromine, and iodine.
  • R 2 and R 6 are the same as described above, Cl in Intermediate II-5 can be replaced with fluorine, bromine, and iodine, and methoxy can be replaced with other alkoxy groups such as ethoxy and isopropoxy Base and so on.
  • Methyl 4-iodo-5-methoxy-2-nitrobenzoate (1.6g, 4.75mmol), iron powder (2.65g, 47.5mmol) and ammonium chloride (1.02g, 19.0mmol) were added to 21ml Isopropanol and 7ml of water were heated to 88°C under the protection of nitrogen and stirred for 2 hours.
  • the iron powder was removed by filtration, and the filter cake was washed with 50 ml of hot isopropanol.
  • the filtrate was concentrated to 1/3 volume, poured into 50ml saturated sodium bicarbonate, and extracted with 50ml dichloromethane.
  • R 1 , R 2 , R 4 , R 5 , R 6 , and p are as defined above, and Cl in Intermediate III-1 can be replaced with fluorine, bromine, or iodine.
  • the 4-chloro-7-iodoquinazoline (I-4, 1.2g, 4.14mmol), 2-(but-3-yn-1-yl(ethyl)amino)ethanol (VI-1,875mg, 6.21mmol) ), and triethylamine (5ml) were added to 20ml N,N-dimethylformamide.
  • Cuprous iodide (78mg, 0.414mmol) and bistriphenylphosphine palladium dichloride (290mg, 0.414mmol) were added at room temperature, and the reaction solution was reacted at 20°C overnight under the protection of nitrogen. 80 ml of water and 80 ml of ethyl acetate were added to the reaction solution.
  • the preparation method of the target compound is similar to the synthetic intermediate 2-((4-(4-chloroquinazolin-7-yl)but-3-yn-1-yl)(ethyl)amino)ethanol.
  • LC_MS:(ES+):m/z 334.2[M+H] + .t R 1.773min.
  • R 1 , R 2 , and R 6 are the same as those described above.
  • n is the same as the previous text, and is 0, 1, or 2.
  • R 3 , s, and n are the same as above.
  • the synthesis method of the target compound is similar to 2-(3-amino-1H-pyrazol-5-yl)-N-(2-fluorophenyl)acetamide.
  • LC_MS:(ES+):m/z 331.2[M+H] + .t R 2.350min.
  • the synthesis method of the target compound is similar to 2-(3-amino-1H-pyrazol-5-yl)-N-(2-fluorophenyl)acetamide.
  • Synthesis of 2,2,2-trifluoro-N-(5-(2-((4-fluorophenyl)amino)-2-ethoxy)-1H-pyrazole using 4-fluoroaniline as starting material 3-yl)acetamide (2-1, 1.2g, yield 51%) is a white solid.
  • the synthesis method of the target compound is similar to 2-(3-amino-1H-pyrazol-5-yl)-N-(2-fluorophenyl)acetamide. Using 2,3-difluoroaniline as the starting material to synthesize N-(5-(2-((2,3-difluorophenyl)amino)-2-ethoxy)-1H-pyrazole-3- Yl)-2,2,2-trifluoroacetamide (2-1,780 mg, yield 31%) as a white solid.
  • the aqueous phase was concentrated to one third of the volume, potassium carbonate (2.6 g, 19.03 mmol) and di-tert-butyl dicarbonate (2.07 g, 9.51 mmol) were added, and the mixture was stirred at room temperature overnight. Dilute with water and extract with ethyl acetate (50ml). The combined organic phases are washed twice with saturated brine (50ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product.
  • m is defined as 0 or 1.
  • Ethyl 2-diazoacetate (18ml, 171mmol) and 2-propyn-1-ol (9.59g, 171mmol) were added to 180ml of toluene, and heated to 110°C under nitrogen to react overnight.
  • the solvent was removed by concentration under reduced pressure, and the residue was diluted with 40 ml of ethyl acetate and stirred at room temperature for 10 min. After filtering, the filter cake was washed with 10 ml of ethyl acetate.
  • the filter cake was added to 80ml ethyl acetate, stirred at 80°C for 5min, cooled to room temperature, filtered, the filter cake was washed with 20ml ethyl acetate, and dried under reduced pressure to obtain 3-(hydroxymethyl)-1H-pyrazole Ethyl-5-carboxylate (6-1, 7.2g, yield 30%), the product is a white solid.
  • the reaction solution was extracted with 40ml water and 60ml ethyl acetate, separated, the organic layer was collected and washed with 30ml saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the crude product obtained was subjected to silica gel column chromatography (containing 20% ethyl acetate). Hexane) to obtain 3-(azidomethyl)-N-(3-fluorophenyl)-1H-pyrazole-5-amide (7-1, 120mg, yield 6%), the product is a white solid.
  • Example 17 Synthesis of compound 2-(3-((7-(4-(ethyl(2-hydroxyethyl)amino)but-1-yn-1-yl)quinazolin-4-yl)amino) -1H-pyrazol-5-yl)-N-(2-fluorophenyl)acetamide (compound 5)
  • reaction solution was concentrated and purified by thin-layer chromatography on a silica gel plate (dichloromethane containing 8% methanol and 0.1% ammonia) to obtain 2-(3-((7-(4-(ethyl(2-hydroxyethyl)) Amino)but-1-yn-1-yl)quinazolin-4-yl)amino)-1H-pyrazol-5-yl)-N-(2-fluorophenyl)acetamide (compound 5, 15mg, Yield 15%), the product is a yellow solid.
  • Example 18 Synthesis of compound 2-(3-((7-(4-(ethyl(2-hydroxyethyl)amino)but-1-yn-1-yl)quinazolin-4-yl)amino) -1H-pyrazol-5-yl)-N-(3-fluorophenyl)acetamide (compound 3)
  • the method of preparing target compound 3 is similar to the synthesis of 2-(3-((7-(4-(ethyl(2-hydroxyethyl)amino)but-1-yn-1-yl)quinazoline-4- (Yl)amino)-1H-pyrazol-5-yl)-N-(2-fluorophenyl)acetamide.
  • Example 19 Synthesis of compound 2-(3-((7-(4-(ethyl(2-hydroxyethyl)amino)but-1-yn-1-yl)-6-methoxyquinazoline- 4-yl)amino)-1H-pyrazol-5-yl)-N-(3-fluorophenyl)acetamide hydrochloride (hydrochloride of compound 3)
  • the target compound is prepared in a similar way to the synthesis of 2-(3-((7-(4-(ethyl(2-hydroxyethyl)amino)but-1-yn-1-yl)quinazolin-4-yl) Amino)-1H-pyrazol-5-yl)-N-(2-fluorophenyl)acetamide.
  • the target compound is prepared in a similar way to the synthesis of 2-(3-((7-(4-(ethyl(2-hydroxyethyl)amino)but-1-yn-1-yl)quinazolin-4-yl) Amino)-1H-pyrazol-5-yl)-N-(2-fluorophenyl)acetamide.
  • Example 21 Synthesis of compound N-(2,3-difluorophenyl)-2-(3-((7-(4-(ethyl(2-hydroxyethyl)amino)but-1-yne-1 -Yl)quinazolin-4-yl)amino)-1H-pyrazol-5-yl)acetamide (compound 4)
  • the target compound is prepared in a similar way to the synthesis of 2-(3-((7-(4-(ethyl(2-hydroxyethyl)amino)but-1-yn-1-yl)quinazolin-4-yl) Amino)-1H-pyrazol-5-yl)-N-(2-fluorophenyl)acetamide.
  • Example 22 Synthesis of the compound 2-(ethyl(4-(4-((5-(2-((3-fluorophenyl)amino)ethyl)-1H-pyrazol-3-yl)amino)quine Oxazolin-7-yl)but-3-yn-1-ylamino)ethanol (compound 7)
  • the target compound is prepared in a similar way to the synthesis of 2-(3-((7-(4-(ethyl(2-hydroxyethyl)amino)but-1-yn-1-yl)quinazolin-4-yl) Amino)-1H-pyrazol-5-yl)-N-(2-fluorophenyl)acetamide.
  • the target compound is prepared in a similar way to the synthesis of 2-(3-((7-(4-(ethyl(2-hydroxyethyl)amino)but-1-yn-1-yl)quinazolin-4-yl) Amino)-1H-pyrazol-5-yl)-N-(2-fluorophenyl)acetamide.
  • the target compound is prepared in a similar way to the synthesis of 2-(3-((7-(4-(ethyl(2-hydroxyethyl)amino)but-1-yn-1-yl)quinazolin-4-yl) Amino)-1H-pyrazol-5-yl)-N-(2-fluorophenyl)acetamide.
  • Example 25 Synthesis of the compound 2-(ethyl(4-(4-((5-(2-((3-fluorophenyl)amino)-2-ethoxy)-1H-pyrazol-3-yl )Amino)quinazolin-7-yl)but-3-yn-1-yl)amino)dihydroethyl phosphate (compound 10)
  • Example 26 Synthesis of compound 2-((4-(4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1H-pyrazole-3- (Yl)amino)quinazolin-7-yl)but-3-yn-1-yl)(ethyl)amino)dihydroethyl phosphate (compound 11)
  • the target compound is prepared in a similar way to the synthesis of 2-(ethyl(4-(4-((5-(2-((3-fluorophenyl)amino)-2-ethoxy)-1H-pyrazole-3 -Yl)amino)quinazolin-7-yl)but-3-yn-1-yl)amino)ethyl dihydrogen phosphate.
  • Example 27 Synthesis of the compound 2-(ethyl(4-(4-((5-(2-((2-fluorophenyl)amino)-2-ethoxy)-1H-pyrazol-3-yl )Amino)quinazolin-7-yl)but-3-yn-1-yl)amino)ethyl dihydrogen phosphate (compound 12)
  • the target compound is prepared in a similar way to the synthesis of 2-(ethyl(4-(4-((5-(2-((3-fluorophenyl)amino)-2-ethoxy)-1H-pyrazole-3 -Yl)amino)quinazolin-7-yl)but-3-yn-1-yl)amino)ethyl dihydrogen phosphate.
  • Example 28 Synthesis of compound 2-(3-((7-(4-(ethyl(2-hydroxyethyl)amino)but-1-en-1-yl)quinazolin-4-yl)amino) -1H-pyrazol-5-yl)-N-(3-fluorophenyl)acetamide (compound 1)
  • reaction solution was cooled to room temperature, 20ml water and 20ml ethyl acetate were added, the organic layer was collected, washed with 20ml brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude residue, which was subjected to silica gel column chromatography (10% methanol in dichloromethane). Methane) is purified to obtain products with less impurities.
  • the product was further purified by pre-thin-layer chromatography (dichloromethane containing 10% methanol and 1% ammonia) to obtain 2-(3-((7-(4-(ethyl(2-hydroxyethyl)amino) )But-1-en-1-yl)quinazolin-4-yl)amino)-1H-pyrazol-5-yl)-N-(3-fluorophenyl)acetamide (13mg, yield 18% ), the product is a yellow solid.
  • LC_MS: (ES+): m/z 504.5[M+H] + .t R 1.603min.
  • the inhibitory activity of Aurora A and B was measured using Reaction Biology Corporation.
  • the kinase is incubated with the substrate, 100 ⁇ M ATP, and a 3-fold serial dilution of the inhibitor compound starting from 1 ⁇ M.
  • DMSO was used as a control.
  • the kinase activity was quantified using the ADP-Glo TM Kinase Assay System (Promega, Madison, Wisconsin). Use the following levels: For IC 50 , I ⁇ 10nM, 10nM ⁇ II ⁇ 100nM, 100nM ⁇ III ⁇ 1 ⁇ M, IV ⁇ 1 ⁇ M, and the specific results are shown in Table 1.
  • the proteins are separated by gel electrophoresis, printed on a nitrocellulose membrane, and detected with anti-histone H3 and anti-phospho-histone H3 antibodies (both from Cell Signaling Technology).
  • the inhibitory results of representative inhibitors on SW620 histone H3 phosphorylation are shown in Figure 1, and the results of representative inhibitors on AC16 human cardiomyocyte histone Histone phosphorylation are shown in Figure 2.
  • Propidium iodide binds to double-stranded DNA stoichiometrically, and is therefore suitable for determining the cell ratio in the G1, S, and G2/M phases of the cell cycle based on the cell DNA content.
  • Cells in the G0 and G1 phases have diploid DNA (2N) content, while cells in the G2 or mitotic phase have tetraploid DNA (4N) content.
  • the cell pellet was washed with buffered saline solution (PBS), 70% ice-bath pre-cooled absolute ethanol was slowly added, gently pipetted to mix, and fixed at 4°C for 2 hours or at -20°C for 1 hour. After washing with PBS, incubate with propidium iodide and RNase 9:1 solution in the dark for at least 20 minutes. DNA measurement is done in Becton Dickinson FACS Analyzer with argon laser (500mW, emission wavelength 488nm); the data obtained is evaluated by FlowJo software (Flowjo, LLC, Ashland, OR). The effect of representative inhibitors on the polyploidy of U87-MG cells is shown in Figure 2.

Abstract

L'invention concerne un composé contenant de la quinazoline de formule (IA), (IB) ou (IC) ou un sel pharmaceutiquement acceptable ou une molécule de promédicament de celui-ci. Le composé est approprié pour être utilisé en tant qu'inhibiteur de kinase Aurora, et est par conséquent approprié pour le traitement de maladies caractérisées par une prolifération cellulaire excessive ou anormale, telle que celles induites par Aurora, par exemple, les cancers.
PCT/CN2020/135716 2019-12-11 2020-12-11 Nouveau composé contenant de la quinazoline, intermédiaire de celui-ci, et utilisation associée WO2021115432A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004058781A1 (fr) * 2002-12-24 2004-07-15 Astrazeneca Ab Derives de phosphonooxy quinazoline et leur utilisation pharmaceutique
CN1620296A (zh) * 2001-12-24 2005-05-25 阿斯特拉曾尼卡有限公司 作为Aurora激酶抑制剂的取代喹唑啉衍生物
CN1835945A (zh) * 2003-06-17 2006-09-20 阿斯利康(瑞典)有限公司 作为Aurora激酶抑制剂的喹唑啉衍生物
CN104098551A (zh) * 2013-04-03 2014-10-15 广东东阳光药业有限公司 作为欧若拉激酶抑制剂的取代喹唑啉类衍生物
CN105503837A (zh) * 2015-12-31 2016-04-20 中山大学 具有Aurora激酶抑制活性的取代喹唑啉类衍生物及其应用

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101074227B (zh) * 2002-12-24 2010-09-29 阿斯利康(瑞典)有限公司 膦酰氧基喹唑啉衍生物及其药物用途

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1620296A (zh) * 2001-12-24 2005-05-25 阿斯特拉曾尼卡有限公司 作为Aurora激酶抑制剂的取代喹唑啉衍生物
WO2004058781A1 (fr) * 2002-12-24 2004-07-15 Astrazeneca Ab Derives de phosphonooxy quinazoline et leur utilisation pharmaceutique
CN1835945A (zh) * 2003-06-17 2006-09-20 阿斯利康(瑞典)有限公司 作为Aurora激酶抑制剂的喹唑啉衍生物
CN104098551A (zh) * 2013-04-03 2014-10-15 广东东阳光药业有限公司 作为欧若拉激酶抑制剂的取代喹唑啉类衍生物
CN105503837A (zh) * 2015-12-31 2016-04-20 中山大学 具有Aurora激酶抑制活性的取代喹唑啉类衍生物及其应用

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