WO2021115432A1 - Novel quinazoline-containing compound, and intermediate thereof and use thereof - Google Patents

Novel quinazoline-containing compound, and intermediate thereof and use thereof 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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Chinese (zh)
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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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    • C07D403/02—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
    • 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
    • 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
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    • A61K31/54—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 sulfur as the ring hetero atoms, e.g. sulthiame
    • 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
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    • 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
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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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    • 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
    • C07D487/08—Bridged systems
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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

Provided is a quinazoline-containing compound of formula (IA), (IB) or (IC) or a pharmaceutically acceptable salt or a prodrug molecule thereof. The compound is suitable for use as an Aurora kinase inhibitor, and is therefore suitable for treating diseases characterized by excessive or abnormal cell proliferation, such as those mediated by Aurora, for example, cancers.

Description

新型含喹唑啉类化合物及其中间体与应用Novel quinazoline-containing compounds and their intermediates and applications
相关申请的交叉引用Cross-references to related applications
本申请要求2019年12月11日提交的申请号分别为CN 2019112706899的中国专利申请的优先权，其全部内容通过引用的方式并入本申请中。This application claims the priority of the Chinese patent application of CN 2019112706899 filed on December 11, 2019, the entire content of which is incorporated into this application by reference.
技术领域Technical field
本发明涉及医药技术领域，特别是涉及一种喹唑啉类化合物及其在抑制极光激酶中的应用。The invention relates to the technical field of medicine, in particular to a quinazoline compound and its application in inhibiting aurora kinase.
背景技术Background technique
极光激酶(Aurora)是丝氨酸/苏氨酸激酶，在细胞增殖中起重要作用。其功能是作为有丝分裂和细胞分裂中多方面的调节剂，其中包括中心体、复制、有丝分裂纺锤体形成、染色体排列于主轴、有丝分裂关卡激活和胞质分裂。已经知存在三种相关的哺乳动物极光激酶，被称为Aurora-A、Aurora-B和Aurora-C。它们的蛋白质一级结构均含有一个N端调控区和一个C端催化区，且酶结构域序列相似度达71％，ATP腺嘌呤环结合位点的残基也相同，但在细胞分裂中它们具有完全不同且互不重叠的功能。Aurora A从有丝分裂的S期末至下一个分裂周期的G开始，影响中心体的分离、成熟以及两级纺锤体的形成。Aurora B在有丝分裂早期位于染色体的着丝粒区域，分裂后期则从着丝粒移动到微管。目前对Aurora C功能的研究相对较少。Aurora kinase (Aurora) 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. There are three related mammalian aurora kinases known as Aurora-A, Aurora-B and Aurora-C. 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. It has completely different and non-overlapping functions. 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. Currently, there are relatively few studies on Aurora C functions.
Aurora在静止细胞中的表达较低或不可检测，在细胞周期的G2和有丝分裂阶段出现表达和活性高峰。在哺乳动物细胞中推测Aurora的基质包括组蛋白H3、参与染色体缩合的蛋白和CENP-A、肌球蛋白II调节轻链、蛋白磷酸酶1及TPX2。自1997年发现以来，哺乳动物Aurora激酶家族已经被与肿瘤发生密切的联系起来。对于Aurora A的致癌活性研究已较成熟，而对于Aurora B来说，早期的研究表明其致癌活性仅是间接存在。后续研究证实Aurora B在肿瘤发生中的重要性。例如研究发现Aurora B在胚胎仓鼠细胞中过表达及其在异种移植实验中的应用直接增加肿瘤的发生率、大小和侵袭力。同时，相应的肿瘤显示出染色体的不稳定性及增加的组蛋白H3Ser10磷酸化。更为重要的是，抑制肿瘤细胞中的Aurora B不会引起有丝分裂的停止，而使细胞周期持续进行，不会导致胞质分裂。The expression of 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. For example, studies have found that the overexpression of Aurora B in embryonic hamster cells and its application in xenotransplantation experiments directly increase the incidence, size and invasiveness of tumors. At the same time, the corresponding tumor showed chromosomal instability and increased phosphorylation of histone H3Ser10. More importantly, inhibiting Aurora B in tumor cells will not cause the cessation of mitosis, but will continue the cell cycle without causing cytokinesis.
由于Aurora激酶独特的药理作用机制，以Aurora激酶为靶点的药物开发已成为抗癌药物研究的热点之一。目前还没有Aurora激酶抑制剂用于临床治疗，仅有数个Aurora激酶抑制剂在进行临床实验。尽管药物治疗前景光明，但已报道的小分子都存在不同程度的毒副作用，或者尚待优化的溶解性和/或膜穿透能力，因此，开发Aurora抑制剂仍具有巨大的市场潜力。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.
专利WO 2004/058781公开了一系列带有5元含氮原子的杂芳基的喹唑啉衍生物，它们对Aurora B和/或Aurora A具有抑制活性。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.
发明内容Summary of the invention
本发明所要解决的技术问题是提供一类对Aurora A和/或Aurora B具有抑制活性的新型含喹唑啉类化合物。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.
为解决以上技术问题，本发明采取如下技术方案：In order to solve the above technical problems, the present invention adopts the following technical solutions:
具有式(IA)、(IB)或(IC)所示结构的含喹唑啉类化合物或者其药学上可接受的盐或者其前药，A quinazoline-containing compound having a structure represented by formula (IA), (IB) or (IC) or its pharmaceutically acceptable salt or its prodrug,
Figure PCTCN2020135716-appb-000001
Figure PCTCN2020135716-appb-000001
其中：among them:
R 1为选自氢，卤素，氰基，硝基，C1-6烷氧基，C1-6烷基，C1-6卤代烷基，-CF 2OH或-CHFOH的基团； 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为选自氢，卤素或C1-6烷基的基团； R 2 is a group selected from hydrogen, halogen or C1-6 alkyl;
R 3为选自氢或卤素中的一个或多个基团； R 3 is one or more groups selected from hydrogen or halogen;
R 6为选自氢，卤素或C1-6烷基的基团； R 6 is a group selected from hydrogen, halogen or C1-6 alkyl;
p选自0、1、2、3、4、5或6；p is selected from 0, 1, 2, 3, 4, 5 or 6;
s选自0、1、2、3、4或5；s is selected from 0, 1, 2, 3, 4 or 5;
n为0、1或2；m为0或1；e、f独立选自0、1或2或3或4或5或6且e+f大于0而小于7；n is 0, 1 or 2; m is 0 or 1; e and f are independently selected from 0, 1 or 2 or 3 or 4 or 5 or 6 and e+f is greater than 0 and less than 7;
w、t独立选自0、1、2、3、4、5或6且w+t大于0而小于7；y选自0、1、2、3、4、5或6；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为被第一取代基取代或未取代的下列基团：亚甲基、亚乙基或亚乙烯基，其中第一取代基选自卤素、C1-6烷基、C1-6烷氧基；或者L 1为亚乙炔基， 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不存在，或者L 2为-NH-或-NHC(O)-或-C(O)NH-； L 2 does not exist, or L 2 is -NH- or -NHC(O)- or -C(O)NH-;
R 4和R 5独立地选自氢，被一个、两个、三个或更多个相同或不同的第二取代基取代或未取代的下列基团：C1-6烷基，C1-6烷氧基，膦酰氧基C1-6烷基，C3-6环烷基，C6-16芳烃基，C4-16杂芳烃基，C2-6链烯基，C2-6炔基，C1-6烷基磺酰基、苯磺酰基以及C3-6环烷基C1-4烷基；其中所述第二取代基选自卤素，C1-6烷基，C3-6环烷基，C1-6卤代烷基，羟基，C1-6烷氧基，膦酰氧基，亚磺酰亚胺或S(O) zR 8，其中z为0、1或2；或者， 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 4与R 5结合并与和它们相连的氮原子一起形成被一个、两个、三个或更多个相同或不同的四取代基取代的或未被取代的3至12元的单环或多环杂环，所述多环杂环为并环、螺环或桥环，所述第四取代基选自C1-6烷基，C1-6卤代烷基，C2-6烯基，C2-6卤代烯基，C2-6炔基，C2-6卤代炔基，＝N-OH，＝CR dR d'，卤素，氰基，-OH，膦酰氧基，亚磺酰亚胺，-OR a，-NH 2，-NHR a，杂芳基，杂环基，-(CH 2) qNH 2，-(CH 2) qOH，-COOR a，-CONHR a，-CONH(CH 2) qCOOR a，-NHCOOR a或＝O，R d、R d’独立地为选自氢，烷基或卤素的基团； R 4 and R 5 combine with the nitrogen atom to which they are connected to form a 3- to 12-membered monocyclic ring substituted or unsubstituted with one, two, three or more identical or different tetra-substituents or A polycyclic heterocycle, the polycyclic heterocycle is a fused ring, a spiro ring or a bridged ring, and the fourth substituent is selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 Haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, =N-OH, =CR d R d' , halogen, cyano, -OH, phosphonooxy, sulfinimide, -OR a , -NH 2 , -NHR a , heteroaryl, heterocyclyl, -(CH 2 ) q NH 2 , -(CH 2 ) q OH, -COOR a , -CONHR a , -CONH(CH 2 ) q COOR a , -NHCOOR a or =0, Rd and Rd' are independently groups selected from hydrogen, alkyl or halogen;
R 7选自氢，卤素，羟基，氰基，硝基，被一个或多个相同或不同的第三取代基取代或未取代的下列基团：C1-6烷氧基，C1-6烷基，C1-6卤代烷基，-CF 2OH或-CHFOH的基团，C3-6环烷基，C6-16芳烃基，C4-16杂芳烃基，C2-6链烯基，C2-6炔基，C1-6烷基磺酰基、苯磺酰基以及C3-6环烷基C1-4烷基，其中所述第三取代基选自卤素，C1-6烷基，C3-6环烷基，C1-6卤代烷基，羟基，C1-6烷氧基，膦酰氧基，亚磺酰亚胺或S(O) zR 8，其中z为0、1或2； 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;
所述的R a选自被一个、两个、三个或更多个相同或不同的五取代基取代的或未被取代的下列基团：C1-6烷基，C3-6环烷基，C2-6烯基，-(CH 2) q芳基，含有1-5个选自N，S，P或O的杂原子的杂环烷基的基团，含有1-5个选自N，S，P和O的杂原子的杂芳基，所述第五取代基选自-OH，卤素，硝基，氧代，氰基，膦酰氧基，亚磺酰亚胺，-R 8，-OR 8，-NR 8R 9，-SR 8，-S(O) 2NR 8R 9，-S(O) 2R 8，-NR 8S(O) 2NR 8R 9，-NR 8S(O) 2R 9，-S(O)NR 8R 9，-S(O)R 8，-NR 8S(O)NR 8R 9，-NR 8S(O)R 9，-C(O)NR 8R 9-，-OC(O)R 8，-NR 8R 9C(O)-，C4-10杂环，C6-16芳烃基，C4-16杂芳基，-(CH 2) qOH，-C1-6烷基，-CF 3，-CHF 2或 -CH 2F； 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 , -S(O)NR 8 R 9 , -S(O)R 8 , -NR 8 S(O)NR 8 R 9 , -NR 8 S(O)R 9 , -C (O)NR 8 R 9 -, -OC(O)R 8 , -NR 8 R 9 C(O)-, C4-10 heterocyclic ring, C6-16 aromatic hydrocarbon group, C4-16 heteroaryl group, -(CH 2 ) q OH, -C1-6 alkyl, -CF 3 , -CHF 2 or -CH 2 F;
所述的R 8和R 9在每次出现时各自独立地为选自氢，C1-6烷基，C2-6烯基，C4-8环烯基，C2-6炔基，C3-8环烷基，3至12元单环或多环杂环，-OR 10，-SR 10，卤素，-NR 10R 11，-NO 2和-CN和杂环基； Said 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. Alkyl group, 3- to 12-membered monocyclic or polycyclic heterocyclic ring, -OR 10 , -SR 10 , halogen, -NR 10 R 11 , -NO 2 and -CN and heterocyclic group;
R 10和R 11在每次出现时独立地为选自氢，膦酰基氧基，被一个、两个、三个或更多个相同或不同的六取代基取代的下列基团：C1-6烷基，C2-6烯基，C4-8环烯基，C2-6炔基，C3-8环烷基，3至12元单环或多环杂环；所述第六取代基选自-OH，-SH，-NH 2，-NO 2或-CN； 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;
所述的q在每次出现时独立地为0、1、2、3、4、5、6、7、8、9或10；Said q is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 each time it appears;
当所述的p大于等于2时，所述通式(IA)上相应的亚烷基还可选择地被一个或多个相同或不同的第七取代基取代，所述的第七取代基选自C1-6烷基、C3-8环烷基。When the p is greater than or equal to 2, 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.
根据本发发明的一个优选方面：所述含喹唑啉类化合物的结构如下式(I-a)所示：According to a preferred aspect of the present invention: the structure of the quinazoline-containing compound is shown in the following formula (I-a):
Figure PCTCN2020135716-appb-000002
其中，R 1、R 2、R 3、R 4、R 5、R 6、L 2、m、n、p、s的定义同前文。
Figure PCTCN2020135716-appb-000002
Among them, the definitions of 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.
根据本发发明的另一优选方面：所述含喹唑啉类化合物的结构如下式(I-b)所示：According to another preferred aspect of the present invention: the structure of the quinazoline-containing compound is shown in the following formula (I-b):
Figure PCTCN2020135716-appb-000003
其中，R 1、R 2、R 3、R 4、R 5、R 6、L 2、m、n、p、s的定义同前文。
Figure PCTCN2020135716-appb-000003
Among them, the definitions of 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.
根据本发明的一个具体方面，上述的p为1或2或3且n为1或2。According to a specific aspect of the present invention, the aforementioned p is 1 or 2 or 3 and n is 1 or 2.
在一些实施方式中，n为1，L 2是-NHC(O)-或-C(O)NH-；在另一些实施方式中，n为2，L 2是-NH-。 In some embodiments, n is 1, and L 2 is -NHC(O)- or -C(O)NH-; in other embodiments, n is 2, and L 2 is -NH-.
在根据本发明的一些优选实施方式中，在所述通式(IA)或(IB)或(IC)的与L 2连接的苯环上与L 2相间的位置为F。 In some preferred embodiments according to the present invention, 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.
在根据本发明的一些实施方式中，R 1、R 2、R 6独立地选自氢、甲基、乙基、甲氧基、乙氧基、氟、氯。 In some embodiments according to the present invention, R 1 , R 2 , and R 6 are independently selected from hydrogen, methyl, ethyl, methoxy, ethoxy, fluorine, and chlorine.
在根据本发明的一些优选实施方式中，R 4和R 5独立地选自氢、甲基、乙基、丙基、异丙基、丁基、甲氧基、乙氧基、羟基取代甲基、羟基取代乙基、羟基取代异丙基、膦酰氧基甲基、膦酰氧基乙基、乙烯基、乙炔基、乙烯基甲基、乙炔基甲基、甲氧基乙基、甲氧基丙基、三氟甲基甲基、三氟甲基乙基、环丙基甲基、环丙基乙基、环丙基、环丁基、环戊基、环己基、苯基、羟基取代苯基、氯代苯基、甲基取代苯基、甲磺酰基、苯磺酰基、甲基取代苯磺酰基，且R 4和R 5不同时为氢或烷基。 In some preferred embodiments according to the present invention, 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, methyl-substituted benzenesulfonyl, and R 4 and R 5 are not hydrogen or alkyl at the same time.
在根据本发明的另一些优选实施方式中，R 4与R 5结合并与和它们相连的氮原子一起形成被一个或两个被第四取代基取代的或未被取代的杂环结构，该杂环结构是5元单杂环、6元单杂环或C7-C8螺环或C5-C9桥环，其中该环结构除含有与R 4、R 5相连的氮外，还可选择性的含有另一个N或含有O。 In other preferred embodiments according to the present invention, 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.
在根据本发明的一些优选实施方式中，所述第四取代基选自甲基、乙基、丙基、异丙基、丁基、甲氧基、乙氧基、羟基取代甲基、羟基取代乙基、羟基取代异丙基、膦酰氧基甲基、膦酰氧基乙基、乙烯基、乙炔基、乙烯基甲基、乙炔基甲基、甲氧基乙基、甲氧基丙基、三氟甲基甲基、三氟甲基乙基、环丙基甲基、环丙基乙基、＝N-OH、氟、氯、氰基，-OH，膦酰氧基，亚磺酰亚胺。In some preferred embodiments according to the present invention, the fourth substituent is selected from methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, hydroxy substituted methyl, hydroxy substituted Ethyl, hydroxy-substituted isopropyl, phosphonooxymethyl, phosphonooxyethyl, vinyl, ethynyl, vinylmethyl, ethynylmethyl, methoxyethyl, methoxypropyl , Trifluoromethylmethyl, trifluoromethylethyl, cyclopropylmethyl, cyclopropylethyl, =N-OH, fluorine, chlorine, cyano, -OH, phosphonooxy, sulfinyl Imine.
在根据本发明的另一些优选实施方式中，R 4和R 5中的一个是氢、甲基、乙基、丙基、异丙基或丁基，另一个是羟基取代甲基、羟基取代乙基、羟基取代异丙基、膦酰氧基甲基、膦酰氧基乙基、膦酰氧基异丙基、羟基取代苯基、苯磺酰基。 In other preferred embodiments according to the present invention, 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.
在其中一些实施例中，所述化合物选自：In some embodiments, the compound is selected from:
所述含喹唑啉类化合物为选自如下结构所示化合物：The quinazoline-containing compound is selected from compounds shown in the following structures:
Figure PCTCN2020135716-appb-000004
Figure PCTCN2020135716-appb-000004
Figure PCTCN2020135716-appb-000005
Figure PCTCN2020135716-appb-000005
本发明涵盖以上化合物中的任一种的单独的E或Z同分异构体和/或以上化合物中的任一种的药学上可接受的盐。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.
本发明同时提供抑制患者体内或生物样本中极光激酶的方法，其包含对所述患者投与有效抑制量的本发明化合物或使所述生物样本与有效抑制量的本发明化合物接触。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.
另一方面，本发明提供治疗任何涉及Aurora活性的病症方法，其包含对有需要的个体与治疗有效量的本发明化合物。In another aspect, 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.
本发明还提供了上述化合物的应用。具体技术方案如下：The present invention also provides applications of the above-mentioned compounds. The specific technical solutions are as follows:
上述含喹唑啉类化合物或者其药学上可接受的盐或者其前药分子在制备Aurora抑制剂中的应用。Application of the above-mentioned quinazoline-containing compound or its pharmaceutically acceptable salt or its prodrug molecule in the preparation of Aurora inhibitors.
上述含喹唑啉类化合物或者其药学上可接受的盐或者其前药分子在制备防治肿瘤的药物中的应用。The application of the above-mentioned quinazoline-containing compound or its pharmaceutically acceptable salt or its prodrug molecule in the preparation of drugs for preventing and treating tumors.
在其中一些实施例中，所述肿瘤为实体肿瘤或者血液肿瘤。In some of these embodiments, the tumor is a solid tumor or hematological tumor.
在其中一些实施例中，所述实体肿瘤为乳腺癌、胰腺癌、肺癌、肝癌、胃癌、结肠癌、肾癌、前列腺癌、头颈肿瘤、食道癌、卵巢癌或宫颈癌。In some of these embodiments, 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.
在其中一些实施例中，所述血液肿瘤为淋巴瘤、白血病或骨髓瘤。In some of these embodiments, the hematological tumor is lymphoma, leukemia or myeloma.
本发明还涉及一种药物组合物，其包括一种或多种本发明所述的含喹唑啉类化合物或者其药学上可接受的盐或者其前药，以及药学可接受的载体。所述药物组合物优选为预防和/或治疗癌症的组合物。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.
本发明还提供一种制备含喹唑啉类化合物或者其药学上可接受的盐或者其前药的中间体，该中间体具有通式(III-a)或(III-b)所示结构：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):
Figure PCTCN2020135716-appb-000006
Figure PCTCN2020135716-appb-000006
式(III-a)中，R 1、R 2、R 3、R 6、L 2、m、n、s同前文所述；式(III-b)中，R 1、R 2、R 6、R 4、R 5、p同前文所述，X代表氟、氯、溴或碘。 In formula (III-a), 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.
典型的中间体(III-a)或中间体(III-a)例如是下述实施例中被合成的化合物或由他们可以直接联想到的化合物。Typical intermediates (III-a) or intermediates (III-a) are, for example, the compounds synthesized in the following examples or compounds directly associated with them.
本发明还提供了一种含喹唑啉类化合物或者其药学上可接受的盐或者其前药的制备方法，其包括使前述所述的具有通式(III-b)的中间体与化合物
Figure PCTCN2020135716-appb-000007
发生取代反应生成化合物(I-b)的步骤， 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)
Figure PCTCN2020135716-appb-000007
The step of substitution reaction to produce compound (Ib),
Figure PCTCN2020135716-appb-000008
Figure PCTCN2020135716-appb-000008
式中，其中，R 1、R 2、R 3、R 4、R 5、R 6、L 2、m、n、p、s的定义同前文。 In the formula, 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.
进一步地，所述方法还包括使
Figure PCTCN2020135716-appb-000009
与
Figure PCTCN2020135716-appb-000010
反应生成所述具有通式(III-b)的中间体，其中X代表氟、氯、溴或碘。 Further, the method also includes using
Figure PCTCN2020135716-appb-000009
versus
Figure PCTCN2020135716-appb-000010
The reaction produces the intermediate having the general formula (III-b), where X represents fluorine, chlorine, bromine or iodine.
本发明还提供又一种含喹唑啉类化合物或者其药学上可接受的盐或者其前药的制备方法，其包括使权前文所述的具有通式(III-a)的中间体与
Figure PCTCN2020135716-appb-000011
发生反应生成化合物(I-a)的步骤， 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
Figure PCTCN2020135716-appb-000011
The step of reaction to produce compound (Ia),
Figure PCTCN2020135716-appb-000012
Figure PCTCN2020135716-appb-000012
式中，其中，R 1、R 2、R 3、R 4、R 5、R 6、L 2、m、n、p、s的定义同前文所述。 In the formula, 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.
进一步地，所述方法还包括使
Figure PCTCN2020135716-appb-000013
与
Figure PCTCN2020135716-appb-000014
反应生成所述具有通式(III-a)的中间体，其中X代表氟、氯、溴或碘。 Further, the method also includes using
Figure PCTCN2020135716-appb-000013
versus
Figure PCTCN2020135716-appb-000014
The reaction produces the intermediate having the general formula (III-a), where X represents fluorine, chlorine, bromine or iodine.
由于以上技术方案的实施，本发明与现有技术相比存在如下优势：Due to the implementation of the above technical solutions, the present invention has the following advantages compared with the prior art:
本发明的含喹唑啉类化合物或者其药学上可接受的盐或者其前药分子，是一系列新的化合物，该类化合物具有抑制Aurora活性的作用，通过对肿瘤细胞有丝分裂中G2-M期的阻滞，使肿瘤细胞株产生抗增殖和诱导凋亡的效应，能够成为治疗恶性肿瘤的有效药物，有较大的应用价值。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.
附图说明Description of the drawings
图1描绘了组蛋白H3磷酸化抑制实验的结果。与细胞一起培养的本发明具体实施例化合物呈现组蛋白H3丝氨酸磷酸化的与浓度相关的抑制作用。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.
图2反映了测试化合物对人正常心肌细胞系Histon磷酸化的影响情况。Figure 2 reflects the effect of the test compound on the phosphorylation of Histon in a human normal cardiomyocyte cell line.
图3描绘使用本发明具体实施例化合物的G2/M期细胞生长抑制实验的示范性分布图。Figure 3 depicts an exemplary distribution diagram of G2/M phase cell growth inhibition experiments using specific example compounds of the present invention.
具体实施方式Detailed ways
定义definition
本发明所述化合物中，当任何变量(例如R 1、R 2等)在任何组分中出现超过一次，则其每次出现的定义独立于其它每次出现的定义。同样，允许取代基及变量的组合，只要这种组合使化合物稳定。自取代基划入环系统的线表示所指的键可连接到任何能取代的环原子上。在一广泛方面，容许的取代基包括有机化合物的无环和环状、支链和无支链、碳环和杂环、芳香族和非芳香族碳和杂原子取代基。要理解本领域普通技术人员可选择本发明化合物的取代基及取代型式而提供化学上稳定的并可通过本领域技术和下列提出的 方法自可容易获得的原料容易合成的化合物。如果取代基自身被超过一个基团取代，应理解这些基团可在相同碳原子上或不同碳原子上，只要使结构稳定。 In the compound of the present invention, when any variable (such as R 1 , R 2, etc.) occurs more than once in any component, the definition of each occurrence thereof is independent of the definition of each occurrence of other variables. Likewise, 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. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic carbon and heteroatom substituents of organic compounds. It should be understood that those of ordinary skill in the art can select the substituents and substitution patterns of the compounds of the present invention 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.
本文所用“烷基”意指包括具有特定碳原子数目的支链的和直链的饱和脂肪烃基。例如“C1-C6烷基”中“C1-C6”的定义包括以直链或支链排列的具有1、2、3、4、5或6个碳原子的基团。As used herein, "alkyl" means to include branched and straight chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms. For example, the definition of "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.
如本文所用的术语"杂原子"意思是除碳和氢以外任何元素的原子。优选的杂原子是氮、氧、磷和硫。The term "heteroatom" as used herein means an atom of any element other than carbon and hydrogen. Preferred heteroatoms are nitrogen, oxygen, phosphorus and sulfur.
本文所用“杂烷基”指包含1至3个杂原子的直链或支链的脂肪烃链，而杂烷基链中可用的各碳和杂原子可各自任选相互独立地被取代，且杂原子相互独立地选自O、N、P、PO、PO 2、S、SO和SO 2(例如二甲基氨基甲基、二甲基氨基乙基、二甲基氨基丙基、二乙基氨基甲基、二乙基氨基乙基、二乙基氨基丙基、2-二异丙基氨基乙基、双-2-甲氧基乙基氨基、[2-(二甲基氨基-乙基)-乙基-氨基]-甲基、3-[2-(二甲基氨基-乙基)-乙基-氨基]-丙基、羟基甲基、2-羟基乙基、3-羟基丙基、甲氧基、乙氧基、丙氧基、甲氧基甲基、2-甲氧基乙基)。 As used herein, "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-hydroxyethyl, 3-hydroxypropyl , Methoxy, ethoxy, propoxy, methoxymethyl, 2-methoxyethyl).
本文所指“卤代烃基”指其中一或多个氢原子被卤素原子取代的烃基。卤代烃基包括饱和烷基和不饱和烯基以及炔基，例如-CF 3、-CHF 2、-CH 2F、-CF 2CF 3、-CHFCF 3、-CH 2CF 3、-CF 2CH 3、-CHFCH 3、-CF 2CF 2CF 3、-CF 2CH 2CH 3、-CF＝CF 2、-CCl＝CH 2、-CBr＝CH 2、-CI＝CH 2、-C≡C-CF 3、-CHFCH 2CH 3及-CHFCH 2CF 3。 As used herein, "halogenated hydrocarbon group" refers to a hydrocarbon group in which one or more hydrogen atoms are replaced by halogen atoms. Halogenated hydrocarbon groups include saturated alkyl groups, unsaturated alkenyl groups and alkynyl groups, such as -CF 3 , -CHF 2 , -CH 2 F, -CF 2 CF 3 , -CHFCF 3 , -CH 2 CF 3 , -CF 2 CH 3 , -CHFCH 3 , -CF 2 CF 2 CF 3 , -CF 2 CH 2 CH 3 , -CF=CF 2 , -CCl=CH 2 , -CBr=CH 2 , -CI=CH 2 , -C≡C -CF 3 , -CHFCH 2 CH 3 and -CHFCH 2 CF 3 .
烯基和炔基包括含直链、支链或环状的烯烃和炔烃。Alkenyl and alkynyl groups include linear, branched or cyclic alkenes and alkynes.
本文所用“环烃基”指具有特定碳原子数目的单或多环脂肪烃基，其中该环体系可为饱和的环，也可为不饱和的、非芳香环或螺环化合物，可任选包含双键，如，例如环丙基、环丙烯基、环丁基、环丁烯基、环戊基、环戊烯基、环己基、环己烯基、环庚基、环庚烯基、降冰片基、降冰片烯基、茚满基、金刚烷基、螺庚烷基及螺[4.2]庚烷基。本文所述“环烷基”则指具有特定碳原子数目的单或多环脂肪烷基。环烷基烷基包括非环状的烷基，其中与碳原子结合的氢原子被环烷基取代。"Cyclic hydrocarbon group" as used herein 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. As used herein, "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.
本文所用“杂环”或“杂环基”是指饱和的或者不饱和的、非芳香的单环、二环或者桥连多环或者螺环化合物，包括3-12个碳原子，还带有选自O、N、P和S的杂原子代替一或者多个碳原子。“杂环基”进一步的实施例包括但不限于：咪唑基、吲哚基、异噻唑基、异噁唑基、噁二唑基、噁唑基、氧杂环丁烷基、吡喃基、吡嗪基、吡唑基、哒嗪基、吡啶基、嘧啶基、吡咯基、喹噁啉基、四唑基、噻二唑基、噻唑基、噻吩基、三唑基、1,4-二噁烷基、吡咯烷基、二氢咪唑基、二氢异噁唑基、二氢异噻唑基、二氢噁二唑基、二氢噁唑基、二氢吡嗪基、二氢吡唑基、二氢吡啶基、二氢嘧啶基、二氢吡咯基、二氢四唑基、二氢噻二唑基、二氢噻吩基、二氢三唑基、二氢氮杂环丁烷基、四氢呋喃基、四氢噻吩基，吡咯烷基、吡咯啉基、咪唑烷基、吡唑烷基、吡唑啉基、哌啶基、哌嗪基、二氢吲哚基、异二氢吲哚基、吗啉基、硫吗啉基、高吗啉基、高哌啶基、高哌嗪基、高硫吗啉基、硫吗啉基-S-氧化物、硫吗啉基-S，S-二氧化物、四氢吡喃基、四氢噻吩基、高硫吗啉基-S，S-二氧化物、噁唑烷酮基、二氢呋喃基、二氢吡喃基、四氢噻吩基-S-氧化物、四氢噻吩基-S，S-二氧化物、高硫吗啉1-S-氧化物、2-氧杂-5-氮杂二环[2.2.1]庚烷、8-氧杂-3-氮杂-二环[3.2.1]辛烷、3，8-二氮杂-二环[3.2.1]辛烷、2，5-二氮杂-二环[2.2.1]庚烷、3，8-二氮杂-二环[3.2.1]辛烷、3，9-二氮杂-二环[4.2.1]壬烷和2，6-二氮杂-二环[3.2.2]壬烷，及其N-氧化物。杂环取代基的连接可通过碳原子或通过杂原子实现。杂环烷基烷基指非环状的烷基，其中与碳原子结合的氢原子被杂环烷基取代。As used herein, "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. Further examples of "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, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, tetrahydrofuran Group, tetrahydrothienyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indoline, isoindoline, Morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidinyl, homopiperazinyl, homothiomorpholinyl, thiomorpholinyl-S-oxide, thiomorpholinyl-S, S-di Oxide, tetrahydropyranyl, tetrahydrothienyl, high sulfur morpholinyl-S, S-dioxide, oxazolidinone, dihydrofuranyl, dihydropyranyl, tetrahydrothienyl- S-oxide, tetrahydrothienyl-S, S-dioxide, high-sulfur morpholine 1-S-oxide, 2-oxa-5-azabicyclo[2.2.1]heptane, 8- Oxa-3-aza-bicyclo[3.2.1]octane, 3,8-diaza-bicyclo[3.2.1]octane, 2,5-diaza-bicyclo[2.2.1 ]Heptane, 3,8-diaza-bicyclo[3.2.1]octane, 3,9-diaza-bicyclo[4.2.1]nonane and 2,6-diaza-bicyclo [3.2.2] Nonane, and its N-oxide. The attachment of 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.
本文所用“杂芳基”指单或多环的环，包含代替一个或者多个碳原子的一个或者或多个杂原子，所述的杂原子相同或者不同，并且为如例如N、O、S和P。实例包括呋喃基、噻吩基、吡咯基、噁唑基、噻唑基、异噁唑基、异噻唑基、吡唑基、咪唑基、三唑基、四唑基、噁二唑基、噻二唑基、吡啶基、嘧啶基、 哒嗪基、吡嗪基以及三嗪基。二环杂芳基的实例为吲哚基、异吲哚基、苯并呋喃基、苯并噻吩基、苯并噁唑基、苯并噻唑基、苯并异噁唑基、苯并异噻唑基、苯并咪唑基、吲唑基、异喹啉基、喹啉基、喹喔啉基、肉啉基、2，3-二氮杂萘基、喹唑啉基和苯并三嗪基、中氮茚基、噁唑并吡啶基、咪唑并吡啶基、1，5-二氮杂萘基、二氢吲哚基、异苯并二氢吡喃基、苯并二氢吡喃基、四氢异喹啉基、异二氢吲哚基、异苯并四氢呋喃基、异苯并四氢噻吩基、异苯并噻吩基、苯并噁唑基、吡啶并吡啶基、苯并四氢呋喃基、苯并四氢噻吩基、嘌呤基、苯并间二氧杂环戊烯基、三嗪基、苯并嗪基、吩噻嗪基、蝶啶基、苯并噻唑基、咪唑并吡啶基、咪唑并噻唑基、二氢苯并异噁嗪基、苯并异噁嗪基、苯并噁嗪基、二氢苯并异噻嗪基、苯并吡喃基、苯并噻喃基基、香豆素基、异香豆素基、苯并二氢吡喃酮基、吡啶基-N-氧化物、四氢喹啉基、二氢喹啉基、二氢喹啉酮基、二氢异喹啉酮基、二氢香豆素基、二氢异香豆素基、异二氢吲哚酮基、苯并二氧杂环己烷、苯并噁唑啉酮基、吡咯基-N-氧化物、嘧啶基-N-氧化物、哒嗪基-N-氧化物、吡嗪基-N-氧化物、喹啉基-N-氧化物、吲哚基-N-氧化物、二氢吲哚基-N-氧化物、异喹啉基-N-氧化物、喹唑啉基-N-氧化物、喹喔啉基-N-氧化物、2，3-二氮杂萘基-N-氧化物、咪唑基-N-氧化物、异噁唑基-N-氧化物、噁唑基-N-氧化物、噻唑基-N-氧化物、中氮茚基-N-氧化物、吲唑基-N-氧化物、苯并噻唑基-N-氧化物、苯并咪唑基-N-氧化物、吡咯基-N-氧化物、噁二唑基-N-氧化物、噻二唑基-N-氧化物、三唑基-N-氧化物、四唑基-N-氧化物、苯并噻喃基基-S-氧化物和苯并噻喃基基-S，S-二氧化物。杂芳基烷基包括非环状的烷基，其中结合至碳原子的氢原子被杂芳基代替。As used herein, "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. Examples include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazole Group, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, and triazinyl. Examples of 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, benzoxazolyl, pyridopyridyl, benzotetrahydrofuranyl, benzo Tetrahydrothienyl, purinyl, benzodioxol, triazinyl, benzoxazinyl, phenothiazinyl, pterridinyl, benzothiazolyl, imidazopyridyl, imidazothiazole Group, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl , Isocoumarin, chromanone, pyridyl-N-oxide, tetrahydroquinolinyl, dihydroquinolinone, dihydroquinolinone, dihydroisoquinolinone, Dihydrocoumarin, dihydroisocoumarin, isoindolinone, benzodioxane, benzoxazolinone, pyrrolyl-N-oxide, pyrimidinyl- N-oxide, pyridazinyl-N-oxide, pyrazinyl-N-oxide, quinolinyl-N-oxide, indolyl-N-oxide, indolinyl-N-oxide Compounds, isoquinolinyl-N-oxide, quinazolinyl-N-oxide, quinoxalinyl-N-oxide, 2,3-naphtholinyl-N-oxide, imidazolyl- N-oxide, isoxazolyl-N-oxide, oxazolyl-N-oxide, thiazolyl-N-oxide, indolizinyl-N-oxide, indazolyl-N-oxide , Benzothiazolyl-N-oxide, benzimidazolyl-N-oxide, pyrrolyl-N-oxide, oxadiazolyl-N-oxide, thiadiazolyl-N-oxide, three Azolyl-N-oxide, tetrazolyl-N-oxide, benzothiopyranyl-S-oxide and benzothiopyranyl-S,S-dioxide. Heteroarylalkyl groups include acyclic alkyl groups in which a hydrogen atom bonded to a carbon atom is replaced by a heteroaryl group.
本文所用“卤素”意指包括氯、氟、溴和碘。As used herein, "halogen" is meant to include chlorine, fluorine, bromine and iodine.
除非另有定义，烷基、环烷基、芳基和杂环基取代基可为未被取代的或取代的。例如，(C1-C6)烷基可被一个、两个或三个选自OH、卤素、烷氧基、二烷基氨基或杂环基例如吗啉基、哌啶基等取代基取代。Unless otherwise defined, alkyl, cycloalkyl, aryl, and heterocyclyl substituents may be unsubstituted or substituted. For example, (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.
术语"经取代"指的是在主链的一个或多个碳上具有取代基取代氢的部分。应了解，"取代"或"经……取代"包括隐含条件，即所述取代是根据经取代原子和取代基的允许价数，且取代产生稳定化合物，例如不自发进行诸如由重排、环化、消除等引起的转变。如本文所用，预期术语"经取代"包括有机化合物所有允许的取代基。在广义方面，允许的取代基包括有机化合物的非环状和环状、分支和未分支、碳环和杂环、芳族和非芳族取代基。允许的取代基可以是一个或多个且对于适当的有机化合物而言可相同或不同。对于本发明的目的而言，诸如氮的杂原子可具有氢取代基和/或满足杂原子价数的本文所述有机化合物的任何允许的取代基。取代基可包括例如卤素、羟基、羰基(诸如羧基、烷氧基羰基、甲酰基或酰基)、硫代羰基(诸如硫酯、硫代乙酸酯或硫代甲酸酯)、烷氧基、磷酰基、磷酸酯、膦酸酯、亚膦酸酯、氨基、酰胺基、脒、亚胺、氰基、硝基、叠氮基、巯基、烷硫基、硫酸酯、磺酸酯、氨磺酰基、磺酰氨基、磺酰基、杂环基、C6-16芳烃基或芳族或杂芳族部分。本领域技术人员应了解，若适当，烃链上经取代的部分本身可以经取代。The term "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. In a broad sense, 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. For the purposes of the present invention, 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. Those skilled in the art should understand that, if appropriate, the substituted part of the hydrocarbon chain may itself be substituted.
本文包括式I化合物的游离形式，也包括其药学上可接受的盐及其前药分子。本文所用“游离形式”指非盐形式。本文包括在内的药学上可接受盐不仅包括本文所述特定化合物的示例性盐，也包括所有式I化合物游离形式的典型的药学上可接受的盐。可使用本领域已知技术分离所述化合物特定盐的游离形式。例如，可通过用适当的碱稀水溶液例如氢氧化钠稀水溶液、碳酸钾稀水溶液、稀氨水及碳酸氢钠稀水溶液处理该盐使游离形式再生。游离形式在某些物理性质例如在极性溶剂中溶解度上与其各自盐形式多少有些区别，但是为发明的目的这种酸盐及碱盐在其它药学方面与其各自游离形式相当。This document includes the free form of the compound of formula I, as well as its pharmaceutically acceptable salts and prodrug molecules. As used herein, "free form" refers to the non-salt form. The 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. For example, 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. 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.
本文包括可通过常规化学方法将含有碱性部分或酸性部分的本发明化合物合成本发明的药学上可接受 的盐。通常，通过离子交换色谱或通过游离碱和化学计算量或过量的所需盐形式的无机或有机酸在适当溶剂或多种溶剂的组合中反应制备碱性化合物的盐。类似的，通过和适当的无机或有机碱反应形成酸性化合物的盐。It is included herein that 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. Generally, 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. Similarly, the salt of an acidic compound is formed by reacting with a suitable inorganic or organic base.
本发明化合物的药学上可接受的盐包括通过碱性本发明化合物和无机或有机酸反应形成的本发明化合物的常规无毒盐。例如，常规的无毒盐包括得自无机酸例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等制备的盐，也包括得自有机酸例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2一乙酰氧基一苯甲酸、富马酸、苯磺酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸等制备的盐。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. For example, 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.
如果本发明化合物为酸性的，则适当的“药学上可接受的盐”指通过药学上可接受的无毒碱包括无机碱及有机碱制备的盐。得自无机碱的盐包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。特别优选铵盐、钙盐、镁盐、钾盐和钠盐。得自药学上可接受的有机无毒碱的盐，所述碱包括伯胺、仲胺和叔胺的盐，取代的胺包括天然存在的取代胺、环状胺及碱性离子交换树脂例如精氨酸、甜菜碱、咖啡因、胆碱、N,N'－二苄基乙二胺、二乙胺、2一二乙基氨基乙醇、2一二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N一乙基吗啉、N一乙基哌啶、葡萄糖胺、氨基葡萄糖、组氨酸、羟钴胺、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪,哌啶、呱咤、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇等。If the compound of the present invention is acidic, 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, the 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.
显然的，一个分子中任何取代基或特定位置的变量的定义是独立于分子中其他位置的。很容易理解，本领域普通技术人员可以通过现有技术手段及本发明中所述的方法，选择本发明中的化合物的取代基或取代形式，以提供化学上稳定且容易合成的化合物。Obviously, the definition of any substituent or variable at a specific position in a molecule is independent of other positions in the molecule. It is easy to understand that a person of ordinary skill in the art can select the substituent or substituted form of the compound of the present invention through the existing technical means and the method described in the present invention to provide a chemically stable and easy-to-synthesize compound.
本发明所述化合物可能含有一个或多个不对称中心，并可能由此产生非对映异构体和光学异构体。本发明包括所有可能的非对映异构体及其外消旋混合物、其基本上纯的拆分对映异构体、所有可能的几何异构体及其药学上可接受的盐。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.
本发明包括式I所示化合物的所有立体异构体及其药学上可接受的盐。进一步地，立体异构体的混合物及分离出的特定的立体异构体也包括在本发明中。制备此类化合物的合成过程中，或使用本领域普通技术人员公知的外消旋化或差向异构化方法的过程中，制得的产品可以是立体异构体的混合物。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.
当式I所示化合物存在互变异构体时，除非特别声明，本发明包括任何可能的互变异构体和其药学上可接受的盐，及它们的混合物。When the compound represented by formula I has tautomers, unless otherwise stated, the present invention includes any possible tautomers, pharmaceutically acceptable salts thereof, and mixtures thereof.
另一方面，本发明所述化合物包括使用各种同位素标记的本发明所定义的化合物，例如其中存在放射性同位素，如 3H， 14C和 18F的那些化合物，或者其中存在非放射性同位素，如 2H和 13C的化合物。 On the other hand, 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.
当式I所示化合物及其药学上可接受的盐为溶剂化物或多晶型的形式时，本发明包括任何可能的溶剂化物和多晶型。形成溶剂化物的溶剂类型没有特别的限定，只要该溶剂是药理学上可以接受的。例如，水、乙醇、丙醇、丙酮等类似的溶剂都可以采用。When the compound represented by formula I and its pharmaceutically acceptable salt are in the form of a solvate or polymorph, 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. For example, water, ethanol, propanol, acetone and similar solvents can be used.
本文所用的术语“由Aurora介导的疾病”或“由Aurora介导的病状”意指已知Aurora在其中起作用的任何疾病或其他有害病状，也意指那些通过由Aurora抑制剂治疗而得到缓解的疾病或病状，也意指已知Aurora在其中起作用的任何疾病或其他有害病状或疾病。As used herein, the term "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.
本发明化合物适合用作Aurora激酶抑制剂，在不希望受任何特定理论束缚的情况下，所述化合物尤其适用于治疗其中在疾病、病状或病症中牵涉Aurora激酶活化作用的疾病、病状或病症或减轻其严重性。当在特定疾病、病状或病症中牵涉Aurora激酶活化作用时，所述疾病、病状或病症也可被称为“由 Aurora介导的疾病”或病症。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.
所述疾病或病状包括(但不限于)：病毒感染(例如HIV和卡波济(氏)肉瘤)；炎性以及自体免疫性疾病(例如大肠炎、关节炎、阿尔兹海默病、肾小球肾炎以及伤口愈合)；细菌、真菌和/或寄生感染；白血病、淋巴瘤以及实体瘤(例如癌和肉瘤)、皮肤疾病(例如牛皮廯)；特征在于细胞数目增加的增生疾病(例如成纤维细胞、肝细胞、骨以及骨髓细胞、软骨或者平滑肌细胞或者上皮细胞(例如子宫内膜增生))；骨疾病以及心血管疾病(例如再狭窄以及肥大)。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).
下述癌症(但不限于)亦可使用本发明的化合物治疗：脑瘤如例如听神经鞘瘤(神经瘤)、星形细胞瘤如神经胶质瘤、纤维性星形细胞瘤、原浆性星形细胞瘤、饲肥星形细胞瘤、多形性成胶质细胞瘤和成胶质细胞瘤、脑淋巴瘤、脑转移、垂体瘤如催乳素瘤、HGH(人(垂体)生长激素)产生瘤以及ACTH产生瘤(促贤上腺皮质激素)、颅咽管瘤、成神经管细胞瘤、脑膜瘤和少突神经胶质瘤；神经瘤(neoplasms)如例如植物神经系统瘤如成神经细胞瘤、神经节瘤、神经节细胞瘤(嗜铬细胞瘤、副神经节瘤)和劲动脉球瘤、周围神经系统瘤如截肢性神经瘤、神经纤维瘤、神经鞘瘤(神经鞘瘤、Schwannoma)以及恶性的神经鞘瘤以及中枢神经系统瘤如脑以及骨髓瘤；肠癌如例如直肠、结肠、肛门、小肠以及十二指肠癌；眼睑瘤如基底细胞癌或者基底细胞癌；胰腺癌；膀胱癌；肺癌(支气管癌)如例如小细胞支气管癌(燕麦[形]细胞癌)以及非小细胞支气管癌如plate epithelial癌、腺癌以及大细胞支气管癌；乳腺癌如例如乳癌如浸润性管癌、粘液癌、小叶浸润性癌、管状癌、囊性腺样癌以及乳头状癌；非-何杰金氏淋巴瘤(NHL)如例如Burkitt氏淋巴瘤、低恶性非-何杰金氏淋巴瘤(NHL)以及mucosis fungoides；子宫癌或子宫内膜癌或者子宫体癌；CUP综合征；卵巢癌如粘蛋白性、子宫内膜性或或者血清性癌；胆囊癌；胆管癌如例如Klatskin瘤；睾丸癌如例如精原细胞瘤以及非-精原细胞瘤；淋巴瘤(淋巴肉瘤)如例如恶性淋巴瘤、何杰金氏病、非何杰金氏淋巴瘤(NHL)如慢性淋巴性白血病、白血病网状内皮组织增殖、免疫细胞瘤、浆细胞瘤(多骨髓瘤)、免疫母细胞瘤、Burkitt氏淋巴瘤、T-zone mycosis fungoides、大细胞退行发育性成淋巴细胞瘤以及成淋巴细胞瘤；喉部癌如例如声带瘤、声门上瘤、声门瘤和声门下喉瘤；骨癌如例如骨软骨瘤、软骨瘤、成软骨细胞瘤、软骨粘液样纤维瘤、骨瘤、骨样骨瘤、成骨细胞瘤、嗜酸细胞肉芽肿、巨细胞瘤、软骨肉瘤、骨肉瘤、尤因肉瘤、网状细胞肉瘤、浆细胞瘤、巨细胞瘤、纤维性结构不良、少年骨囊肿以及动脉瘤骨囊肿；头颈癌如例如唇癌、舌癌、口底癌、口腔癌、牙龈癌、上腭癌、唾液腺、咽喉癌、鼻腔、鼻旁窦癌、喉以及中耳；肝癌如例如肝细胞癌或者肝细胞癌(HCC)；白血病、如例如急性白血病如急性淋巴性/成淋巴细胞白血病(ALL)、急性髓性白血病(AML)；慢性白血病如慢性淋巴性白血病(CLL)、慢性髓性白血病(CML)；胃癌或胃癌如例如乳突、管以及粘液腺癌、印戒细胞癌、腺鳞癌、小细胞癌以及未分化癌；黑素瘤如例如表层蔓延性、结节性、恶性雀斑样痣和肢端雀斑样痣黑[色]素瘤；肾癌如例如肾细胞癌或格拉维次(氏)瘤或Grawitz氏瘤；食管癌或食管癌；阴茎癌；前列腺癌；喉癌或者咽癌如例如鼻咽癌、口咽癌以及喉咽癌；视网膜母细胞瘤如例如阴道癌；plate epithelial癌、腺癌、原位癌、恶性黑素瘤和肉瘤；甲状腺癌如例如乳头状、滤泡性以及甲状腺髓样癌以及退行发育癌；spinalioma、epidormoid癌症以及皮肤plate epithelial癌症；胸腺瘤、尿道癌以及阴户癌。The following cancers (but not limited to) can also be treated with the compounds of the present invention: 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 tumors, peripheral nervous system tumors such as amputation neuroma, neurofibroma, schwannomas (neurinoma, Schwannoma) ) And malignant schwannomas and central nervous system tumors such as brain and myeloma; bowel cancers such as rectum, colon, anus, small intestine, and duodenal cancer; eyelid tumors such as basal cell carcinoma or basal cell carcinoma; pancreatic cancer; Bladder cancer; lung cancer (bronchial cancer) such as, for example, small cell bronchial carcinoma (oat [shaped] cell carcinoma) and non-small cell bronchial carcinoma such as plate epithelial carcinoma, adenocarcinoma, and large cell bronchial carcinoma; breast cancer such as, for example, breast cancer such as invasive tube Carcinoma, mucinous carcinoma, lobular invasive carcinoma, tubular carcinoma, cystic adenoid carcinoma, and papillary carcinoma; non-Hodgkin’s lymphoma (NHL) such as, for example, Burkitt’s lymphoma, low-malignant non-Hodgkin’s lymphoma (NHL) and mucosis fungoides; uterine cancer or endometrial cancer or uterine body cancer; CUP syndrome; ovarian cancer such as mucinous, endometrial or serum cancer; gallbladder cancer; cholangiocarcinoma such as Klatskin tumor; Testicular cancer such as, for example, seminoma and non-seminoma; lymphoma (lymphosarcoma) such as, for example, malignant lymphoma, Hodgkin’s disease, non-Hodgkin’s lymphoma (NHL) such as chronic lymphocytic leukemia, Leukemia reticuloendothelial tissue proliferation, immunocytoma, plasmacytoma (multiple myeloma), immunoblastoma, Burkitt's lymphoma, T-zone mycosis fungoides, large cell degenerative lymphoblastoma, and lymphoblastoma ; Laryngeal cancers such as, for example, vocal cord tumors, supraglottic tumors, glottic tumors, and subglottic laryngeal tumors; bone cancers such as, for example, osteochondroma, chondroma, chondroblastoma, chondromycinoid fibroma, osteoma, osteoid Osteoma, osteoblastoma, eosinophilic granuloma, giant cell tumor, chondrosarcoma, osteosarcoma, Ewing sarcoma, reticulosarcoma, plasmacytoma, giant cell tumor, fibrous dysplasia, juvenile bone cyst, and Aneurysm bone cyst; head and neck cancer such as, for example, lip cancer, tongue cancer, floor of mouth cancer, oral cancer, gum cancer, palate cancer, salivary gland, throat cancer, nasal cavity, paranasal sinus cancer, larynx and middle ear; liver cancer such as, for example, liver Cell carcinoma or hepatocellular carcinoma (HCC); leukemia, such as, for example, acute leukemia such as acute lymphoblastic/lymphoblastic leukemia (ALL), Acute myeloid leukemia (AML); chronic leukemia such as chronic lymphatic leukemia (CLL), chronic myelogenous leukemia (CML); gastric cancer or gastric cancer such as, for example, mastoid, duct and mucinous adenocarcinoma, signet ring cell carcinoma, adenosquamous carcinoma, Small cell carcinoma and undifferentiated carcinoma; melanoma such as, for example, superficial spreading, nodular, malignant lentigines and acral lenticular nevi; kidney cancer such as, for example, renal cell carcinoma or gravitz ( Cancer or Grawitz’s tumor; esophageal or esophageal cancer; penile cancer; prostate cancer; laryngeal or pharynx cancer such as, for example, nasopharyngeal cancer, oropharyngeal cancer, and laryngopharyngeal cancer; retinoblastoma, such as, for example, vaginal cancer; Carcinoma, adenocarcinoma, carcinoma in situ, malignant melanoma and sarcoma; thyroid cancer such as, for example, papillary, follicular and medullary thyroid carcinoma and anaplastic carcinoma; spinalioma, epidormoid cancer and skin plate epithelial cancer; thymoma, urethra Cancer and vulvar cancer.
本发明的化合物可用于预防、短期或者长期治疗上述疾病，还任选与放疗或者其他的″最新技术发展水平的″化合物联用，如例如细胞抑制或者细胞毒性物质、细胞增殖抑制剂、抗血管生成物质、甾体类或者抗体。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.
除在文献中已知的或在实验程序中例证的标准方法外，可采用如下合成方案制备本发明化合物。结合下述的合成方案，能够对本发明中所述的化合物以及合成方法进行更好的理解。所述的合成方案描述了可以用于制备本发明中所述的化合物的方法，所述的方法仅仅是为说明目的的说明性方案描述，并不构成对 本发明所具有的范围的限制。In addition to standard methods known in the literature or exemplified in experimental procedures, the following synthetic schemes can be used to prepare the compounds of the present invention. Combined with the following synthesis scheme, the compound and synthesis method described in the present invention can be better understood. The synthetic schemes describe methods that can be used to prepare the compounds described in the present invention, and the methods are merely illustrative scheme descriptions for illustrative purposes, and do not constitute a limitation on the scope of the present invention.
以下结合实施例对本发明做进一步的描述，但该实施例并非用于限制本发明的保护范围。The present invention will be further described below in conjunction with embodiments, but the embodiments are not intended to limit the protection scope of the present invention.
以下所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对下述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。The technical features of the following embodiments can be combined arbitrarily. In order to make the description concise, all possible combinations of the technical features in the following embodiments are not described. However, as long as there is no contradiction in the combination of these technical features , Should be regarded as the scope of this specification.
以下所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。The following examples only express a few embodiments of the present invention, and the description is more specific and detailed, but it should not be understood as a limitation on the scope of the invention patent. It should be pointed out that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can be made, and these all fall within the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention should be subject to the appended claims.
中间体I(中间体I-1、I-2、I-3以及I-4)合成路线Intermediate I (Intermediate I-1, I-2, I-3 and I-4) synthetic route
Figure PCTCN2020135716-appb-000015
Figure PCTCN2020135716-appb-000015
该路线中，R 1、R 2和R 6的定义同前文所述，中间体I-4中Cl可以替换为氟、溴、碘。 In this route, the definitions of 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.
实施例1:合成中间体4-氯-7-碘-6-甲氧基喹唑啉Example 1: Synthesis of intermediate 4-chloro-7-iodo-6-methoxyquinazoline
Figure PCTCN2020135716-appb-000016
Figure PCTCN2020135716-appb-000016
将4-碘-1-甲基-2-硝基苯(20g，0.076mol)加入到100ml叔丁醇和500ml水中，室温下加入氢氧化钠(20g，0.225mol)和高锰酸钾(24g，0.15mol)，加热至80℃，搅拌过夜。将反应液冷却至室温，过滤除去黑色固体，滤饼用水(20ml×2)冲洗。滤液用甲基叔丁基醚(200ml×2)萃取，去除主要杂质。水相用盐酸酸化至pH＝3-4，用200ml乙酸乙酯萃取两次。合并有机层，用100ml饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩得4-碘-2-硝基苯甲酸(I-1,10g,收率45％)，产品为黄色固体。 1H NMR(400MHz,d6-DMSO):δ7.63(d,J＝8.0Hz,1H),8.16(dd,J＝1.6,8.0Hz,1H),8.35(d,J＝1.2Hz,1H)。 Add 4-iodo-1-methyl-2-nitrobenzene (20g, 0.076mol) to 100ml tert-butanol and 500ml water, add sodium hydroxide (20g, 0.225mol) and potassium permanganate (24g, 0.15 mol), heated to 80°C, and stirred overnight. The reaction solution was cooled to room temperature, the black solid was removed by filtration, and the filter cake was rinsed with water (20ml×2). The filtrate was extracted with methyl tert-butyl ether (200ml×2) to remove the main impurities. The aqueous phase was acidified with hydrochloric acid to pH=3-4, and extracted twice with 200 ml of ethyl acetate. The organic layers were combined, washed with 100 ml of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 4-iodo-2-nitrobenzoic acid (I-1, 10 g, yield 45%), which was a yellow solid. 1 H NMR(400MHz,d6-DMSO): δ7.63(d,J=8.0Hz,1H), 8.16(dd,J=1.6,8.0Hz,1H), 8.35(d,J=1.2Hz,1H) .
将4-碘-2-硝基苯甲酸(8g，27.3mmol)溶于100ml乙酸乙酯中，室温下加入二水合二氯亚锡(18.4g，81.5mmol)，室温搅拌过夜。反应液用饱和碳酸氢钠溶液碱化至pH＝9。滤除固体沉淀物，滤饼用20ml水冲洗两次。收集水层，用浓盐酸酸化至pH＝2。过滤，滤饼干燥得2-氨基-4-碘苯甲酸(I-2,6g，收率83％)为黄色固体。4-iodo-2-nitrobenzoic acid (8 g, 27.3 mmol) was dissolved in 100 ml of ethyl acetate, stannous dichloride dihydrate (18.4 g, 81.5 mmol) was added at room temperature, and the mixture was stirred at room temperature overnight. The reaction solution was basified to pH=9 with saturated sodium bicarbonate solution. The solid precipitate was filtered off, and the filter cake was washed twice with 20 ml of water. The aqueous layer was collected and acidified to pH=2 with concentrated hydrochloric acid. After filtering and drying the filter cake, 2-amino-4-iodobenzoic acid (1-2,6 g, yield 83%) was obtained as a yellow solid.
将2-氨基-4-碘苯甲酸(I-2，6g，22.8mmol)和乙酸甲脒(3.5g，34.2mmol)加入30ml 2-甲氧基乙醇中，氮气保护下加热至130℃，搅拌过夜。反应液浓缩除去溶剂，将残渣用20ml乙酸乙酯稀释，用1.0N碳酸氢钠水溶液碱化。过滤，滤饼用水和乙酸乙酯洗涤，干燥得4-羟基-7-碘喹唑啉(I-3，5g，粗品)，产品为棕色固体。 1H NMR(400MHz,d6-DMSO):δ7.85(s,2H),8.07(s,1H),8.12(s,1H),12.3(s,1H)。 Add 2-amino-4-iodobenzoic acid (I-2, 6g, 22.8mmol) and formamidine acetate (3.5g, 34.2mmol) into 30ml 2-methoxyethanol, heat to 130°C under nitrogen protection, and stir overnight. The reaction solution was concentrated to remove the solvent, the residue was diluted with 20 ml of ethyl acetate, and basified with 1.0 N aqueous sodium bicarbonate solution. After filtration, the filter cake was washed with water and ethyl acetate, and dried to obtain 4-hydroxy-7-iodoquinazoline (I-3, 5 g, crude product), which was a brown solid. 1 H NMR (400MHz, d6-DMSO): δ 7.85 (s, 2H), 8.07 (s, 1H), 8.12 (s, 1H), 12.3 (s, 1H).
将4-羟基-7-碘喹唑啉(5g，18.4mmol)加入到30ml三氯氧磷中，在氮气保护下加热至110℃，反应3小时。将反应混合物冷却至室温，减压蒸馏除去多余的三氯氧磷。将残渣倒入冰水中剧烈搅拌，用2N氢氧化钠水溶液碱化至pH＝9-10，用二氯甲烷萃取。有机层用无水硫酸钠干燥，减压浓缩得4-氯-7-碘-6-甲氧基喹唑啉(I-4,3.0g，收率73％)，产品为黄色固体。 1H NMR(400MHz,CDCl 3):δ7.96(d,J＝8.8Hz,1H),8.02(d,J＝8.8Hz,1H),8.52(s,1H),9.04(s,1H). 4-hydroxy-7-iodoquinazoline (5g, 18.4mmol) was added to 30ml of phosphorus oxychloride, heated to 110°C under the protection of nitrogen, and reacted for 3 hours. The reaction mixture was cooled to room temperature, and excess phosphorus oxychloride was removed by distillation under reduced pressure. The residue was poured into ice water and stirred vigorously, basified to pH=9-10 with a 2N aqueous sodium hydroxide solution, and extracted with dichloromethane. The organic layer was dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 4-chloro-7-iodo-6-methoxyquinazoline (I-4, 3.0 g, yield 73%), which was a yellow solid. 1 H NMR (400MHz, CDCl 3 ): δ 7.96 (d, J = 8.8Hz, 1H), 8.02 (d, J = 8.8Hz, 1H), 8.52 (s, 1H), 9.04 (s, 1H).
中间体II(II-1，II-2，II-3，II-4，II-5)合成路线Intermediate II (II-1, II-2, II-3, II-4, II-5) synthetic route
Figure PCTCN2020135716-appb-000017
Figure PCTCN2020135716-appb-000017
该路线中，R 2和R 6的定义同前文所述，中间体II-5中Cl可以替换为氟、溴、碘，甲氧基可以替换为其他烷氧基例如乙氧基、异丙氧基等。 In this route, the definitions of 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.
实施例2:合成中间体4-氯-7-碘-6-甲氧基喹唑啉Example 2: Synthesis of intermediate 4-chloro-7-iodo-6-methoxyquinazoline
Figure PCTCN2020135716-appb-000018
Figure PCTCN2020135716-appb-000018
将3-羟基-4-碘苯甲酸(3g,11.36mmol)溶于11ml N,N-二甲基甲酰胺中，在0℃下先加入碳酸钾(6.27g,45.45mmol)，再加入碘甲烷(6.45g,45.45mmol)，加料完毕，升至室温搅拌3.5小时。向反应混合物中加入50ml水和50ml乙酸乙酯，收集有机层，用50ml饱和食盐水冲洗，用无水硫酸钠干燥，减压浓缩得到4-碘-3-甲氧基苯甲酸甲酯(II-1，3.27g，收率98％)，产品为棕色油状。 1H NMR(400MHz,CDCl 3):δ3.92(s,3H),3.94(s,3H),7.37(dd,J＝1.6,8.0Hz,1H),7.45(s,1H),7.85(d,J＝8.0Hz,1H)。 Dissolve 3-hydroxy-4-iodobenzoic acid (3g, 11.36mmol) in 11ml N,N-dimethylformamide, add potassium carbonate (6.27g, 45.45mmol) at 0℃, and then add methyl iodide (6.45g, 45.45mmol), after the addition is complete, the temperature is raised to room temperature and stirred for 3.5 hours. 50ml of water and 50ml of ethyl acetate were added to the reaction mixture, the organic layer was collected, washed with 50ml of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain methyl 4-iodo-3-methoxybenzoate (II -1, 3.27g, yield 98%), the product is brown oil. 1 H NMR (400MHz, CDCl 3 ): δ3.92 (s, 3H), 3.94 (s, 3H), 7.37 (dd, J = 1.6, 8.0 Hz, 1H), 7.45 (s, 1H), 7.85 (d , J=8.0Hz, 1H).
将4-碘-3-甲氧基苯甲酸甲酯(2.73g,9.35mmol)溶于25ml冰乙酸中，冷却至10℃缓慢加入3.25ml 70％浓硝酸和12.56ml乙酸酐。反应移至油浴加热至70℃反应2小时。将反应冷却至室温，用氢氧化钠水溶液碱化至pH＝9后，用100ml乙酸乙酯萃取。有机层用饱和食盐水冲洗，无水硫酸钠干燥，浓缩。粗品用硅胶柱层析(含10％乙酸乙酯的正己烷)纯化得到4-碘-5-甲氧基-2-硝基苯甲酸甲酯((II-2，1.6g，收率50％)，产品为淡黄色固体。 1H NMR(400MHz,CDCl 3):δ3.94(s,3H),4.00(s,3H),6.95(s,1H),8.46(s,1H)。 Methyl 4-iodo-3-methoxybenzoate (2.73g, 9.35mmol) was dissolved in 25ml of glacial acetic acid, cooled to 10°C and slowly added 3.25ml of 70% concentrated nitric acid and 12.56ml of acetic anhydride. The reaction was transferred to an oil bath and heated to 70°C for 2 hours. The reaction was cooled to room temperature, basified to pH=9 with aqueous sodium hydroxide, and extracted with 100 ml of ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (10% ethyl acetate in n-hexane) to obtain methyl 4-iodo-5-methoxy-2-nitrobenzoate ((II-2, 1.6g, yield 50%) ), the product is a light yellow solid. 1 H NMR (400MHz, CDCl 3 ): δ 3.94 (s, 3H), 4.00 (s, 3H), 6.95 (s, 1H), 8.46 (s, 1H).
将4-碘-5-甲氧基-2-硝基苯甲酸甲酯(1.6g,4.75mmol)、铁粉(2.65g,47.5mmol)和氯化铵(1.02g,19.0mmol)加入到21ml异丙醇和7ml水中，在氮气保护下加热至88℃搅拌2小时。过滤除去铁粉，滤饼用50ml热异丙醇洗涤。将滤液浓缩至1/3体积，倒入50ml饱和碳酸氢钠中，用50ml二氯甲烷萃取。有机相用无水硫酸钠干燥，减压浓缩得到2-氨基-4-碘-5-甲氧基苯甲酸甲酯((II-3，1.23g,收率84％)，产品为为棕色固体。LC_MS:(ES+):m/z 307.9[M+H] +.t R＝2.732min. 1H NMR(400MHz,CDCl 3):δ3.82(s,3H),3.88(s,3H),7.21(s,1H),7.24(s,1H)。 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. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain methyl 2-amino-4-iodo-5-methoxybenzoate ((II-3, 1.23g, yield 84%), the product was a brown solid .LC_MS:(ES+):m/z 307.9[M+H] + .t R =2.732min. 1 H NMR(400MHz,CDCl 3 ):δ3.82(s,3H),3.88(s,3H), 7.21 (s, 1H), 7.24 (s, 1H).
将2-氨基-4-碘-5-甲氧基苯甲酸甲酯(4.4g,14.0mmol)和乙酸甲脒(2.68g,25.2mmol)加入到2-甲氧基乙醇中，在氮气保护下升温至130℃，搅拌过夜。将反应混合物浓缩，用20ml乙酸乙酯和(1.0N)碳酸氢钠水溶液稀释。将混合物过滤，滤饼用水和乙酸乙酯洗涤后干燥得7-碘-6-甲氧基-4-羟基喹唑啉(II-4，3.8g，粗品)，产品为棕色固体。LC_MS:(ES+):m/z 302.9[M+H] +.t R＝2.073min。 Methyl 2-amino-4-iodo-5-methoxybenzoate (4.4g, 14.0mmol) and formamidine acetate (2.68g, 25.2mmol) were added to 2-methoxyethanol under nitrogen protection The temperature was raised to 130°C and stirred overnight. The reaction mixture was concentrated and diluted with 20 ml of ethyl acetate and (1.0 N) aqueous sodium bicarbonate solution. The mixture was filtered, the filter cake was washed with water and ethyl acetate and then dried to obtain 7-iodo-6-methoxy-4-hydroxyquinazoline (II-4, 3.8 g, crude product), which was a brown solid. LC_MS: (ES+): m/z 302.9[M+H] + .t R =2.073min.
将7-碘-6-甲氧基-4-羟基喹唑啉(3.9g,12.9mmol)加入到三氯氧磷(15ml,161.86mmol)中，氮气保护下加热至110℃反应3小时。将反应冷却至室温，减压蒸馏除去多余的三氯氧磷。将残渣倒入冰水中剧烈搅拌，用氢氧化钠水溶液(2N)碱化至pH＝9-10后，用二氯甲烷萃取。有机层用无水硫酸钠干燥，减压浓缩得到4-氯-7-碘-6-甲氧基喹唑啉(II-5,3.0g，收率73％)，产品为黄色固体。LC_MS:(ES+):m/z 320.9[M+H] +.t R＝2.827min. 1H NMR(400MHz,DMSO-d6):δ4.06(s,3H),7.41(s,1H),8.64(s,1H),8.98(s,1H). 7-iodo-6-methoxy-4-hydroxyquinazoline (3.9 g, 12.9 mmol) was added to phosphorus oxychloride (15 ml, 161.86 mmol), and the mixture was heated to 110°C for 3 hours under the protection of nitrogen. The reaction was cooled to room temperature, and excess phosphorus oxychloride was removed by distillation under reduced pressure. The residue was poured into ice water and stirred vigorously, basified to pH=9-10 with aqueous sodium hydroxide (2N), and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 4-chloro-7-iodo-6-methoxyquinazoline (II-5, 3.0 g, yield 73%), which was a yellow solid. LC_MS:(ES+):m/z 320.9[M+H] + .t R ＝2.827min. 1 H NMR(400MHz,DMSO-d6):δ4.06(s,3H),7.41(s,1H), 8.64(s,1H), 8.98(s,1H).
中间体III-b(III-1)合成路线Intermediate III-b(III-1) synthetic route
Figure PCTCN2020135716-appb-000019
Figure PCTCN2020135716-appb-000019
该路线中，R 1、R 2、R 4、R 5、R 6、p的定义同前文所述，中间体III-1中Cl可以替换为氟、溴、碘。 In this route, 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.
实施例3:合成中间体2-((4-(4-氯喹唑啉-7-基)丁-3-炔-1-基)(乙基)氨基)乙醇Example 3: Synthesis of intermediate 2-((4-(4-chloroquinazolin-7-yl)but-3-yn-1-yl)(ethyl)amino)ethanol
Figure PCTCN2020135716-appb-000020
Figure PCTCN2020135716-appb-000020
将4-氯-7-碘喹唑林(I-4，1.2g，4.14mmol)，2-(丁-3-炔-1-基(乙基)氨基)乙醇(VI-1,875mg,6.21mmol)，和三乙胺(5ml)加入到20ml N,N-二甲基甲酰胺中。在室温加入碘化亚铜(78mg,0.414mmol)和双三苯基膦二氯化钯(290mg,0.414mmol)，反应液在氮气保护下于20℃反应过夜。向反应液中加入80ml水和80ml乙酸乙酯。合并有机层，用50ml饱和食盐水洗涤，用无水硫酸钠干燥，浓缩后用硅胶柱层析(洗脱液是含10％甲醇的二氯甲烷)纯化得2-((4-(4-氯喹唑啉-7-基)丁-3-炔-1-基)(乙基)氨基)乙醇(III-1，400mg，收率32％)，产品为黄色固体。LC_MS:(ES+):m/z 304.1[M+H] +.t R＝1.748min. 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 organic layers were combined, washed with 50 ml of saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (eluent was methylene chloride containing 10% methanol) to obtain 2-((4-(4- Chloroquinazolin-7-yl)but-3-yn-1-yl)(ethyl)amino)ethanol (III-1, 400mg, yield 32%), the product is a yellow solid. LC_MS:(ES+):m/z 304.1[M+H] + .t R =1.748min.
实施例4:合成中间体2-((4-(4-氯-6-甲氧基喹唑啉-7-基)丁-3-炔-1-基)(乙基)氨基)乙醇Example 4: Synthesis of intermediate 2-((4-(4-chloro-6-methoxyquinazolin-7-yl)but-3-yn-1-yl)(ethyl)amino)ethanol
Figure PCTCN2020135716-appb-000021
Figure PCTCN2020135716-appb-000021
目标化合物的制备方法类似于合成中间体2-((4-(4-氯喹唑啉-7-基)丁-3-炔-1-基)(乙基)氨基)乙醇。以2-(丁-3-炔-1-基(乙基)氨基)乙醇和4-氯-7-碘-6-甲氧基喹唑啉作为起始物料制备2-((4-(4-氯-6-甲氧基喹唑啉-7-基)丁-3-炔-1-基)(乙基)氨基)乙醇。LC_MS:(ES+):m/z 334.2[M+H] +.t R＝1.773min. 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. Preparation of 2-((4-(4) 2-(but-3-yn-1-yl(ethyl)amino)ethanol and 4-chloro-7-iodo-6-methoxyquinazoline as starting materials -Chloro-6-methoxyquinazolin-7-yl)but-3-yn-1-yl)(ethyl)amino)ethanol. LC_MS:(ES+):m/z 334.2[M+H] + .t R ＝1.773min.
中间体IV(IV-1，IV-2)合成路线Intermediate IV (IV-1, IV-2) synthetic route
Figure PCTCN2020135716-appb-000022
Figure PCTCN2020135716-appb-000022
该路线中，R 1、R 2、R 6的定义同前文所述。 In this route, the definitions of R 1 , R 2 , and R 6 are the same as those described above.
实施例5:合成中间体7-碘-3-氰基-4-羟基喹啉Example 5: Synthesis of intermediate 7-iodo-3-cyano-4-hydroxyquinoline
Figure PCTCN2020135716-appb-000023
Figure PCTCN2020135716-appb-000023
将2-氨基-4-碘苯甲酸(1.3g,4.08mmol)溶解在5.2ml N,N-二甲基甲酰胺中，加入5.2ml N,N-二甲基甲酰胺二甲基缩醛，氮气保护下加热至120℃过夜。反应混合物减压浓缩得到未经纯化的粗产品(IV-1)；在-78℃，氮气条件下，将正丁基锂(5.6ml,10.56mmol)加入到20ml干燥的四氢呋喃溶液中，然后将溶于5ml干燥四氢呋喃溶液中的乙腈(454mg,11.07mmol)缓慢滴加到反应液中,随后将(E)-2-(((二甲氨基)亚甲基)氨基)-4-碘苯甲酸(粗品,5.03mmol)溶解在10ml干燥的四氢呋喃里，在-78℃缓慢滴加到反应中。该反应常温搅拌两小时后,升温到-10℃,随后慢慢滴加醋酸(1.5g)；反应混合液常温搅拌过夜。将反应液过滤，滤饼用四氢呋喃、甲基叔丁基醚淋洗，干燥得到7-碘-3-氰基-4-羟基喹啉(IV-2，1.2g,两步收率 99％)，产品为白色固体。LC_MS:(ES+):m/z 297.0[M+H] +.t R＝2.082min. Dissolve 2-amino-4-iodobenzoic acid (1.3g, 4.08mmol) in 5.2ml N,N-dimethylformamide, add 5.2ml N,N-dimethylformamide dimethyl acetal, Heat to 120°C overnight under nitrogen protection. The reaction mixture was concentrated under reduced pressure to obtain the unpurified crude product (IV-1); under nitrogen conditions at -78°C, n-butyllithium (5.6ml, 10.56mmol) was added to 20ml of dry tetrahydrofuran solution, and then Acetonitrile (454mg, 11.07mmol) dissolved in 5ml dry tetrahydrofuran solution was slowly added dropwise to the reaction solution, and then (E)-2-(((dimethylamino)methylene)amino)-4-iodobenzoic acid (Crude product, 5.03mmol) was dissolved in 10ml of dry tetrahydrofuran and slowly added dropwise to the reaction at -78°C. After the reaction was stirred at room temperature for two hours, the temperature was raised to -10°C, and then acetic acid (1.5 g) was slowly added dropwise; the reaction mixture was stirred at room temperature overnight. The reaction solution was filtered, the filter cake was rinsed with tetrahydrofuran and methyl tert-butyl ether, and dried to obtain 7-iodo-3-cyano-4-hydroxyquinoline (IV-2, 1.2g, two-step yield 99%) , The product is a white solid. LC_MS:(ES+):m/z 297.0[M+H] + .t R ＝2.082min.
中间体1(1-1，1-2，1-3)的合成路线：Synthetic route of intermediate 1 (1-1, 1-2, 1-3):
Figure PCTCN2020135716-appb-000024
Figure PCTCN2020135716-appb-000024
其中，n的定义同前文，为0、1或2。Among them, the definition of n is the same as the previous text, and is 0, 1, or 2.
实施例6：合成中间体2-(3-氨基-1H-吡唑-5-基)-乙酸Example 6: Synthesis of intermediate 2-(3-amino-1H-pyrazol-5-yl)-acetic acid
Figure PCTCN2020135716-appb-000025
Figure PCTCN2020135716-appb-000025
将丙二腈(30g,0.454mol)与水合肼(3.5ml)在90ml甲醇中加热至回流，以维持反应液回流的速度滴加水合肼(10.5ml)。将反应液继续回流15分钟，然后冷却至0-5℃，搅拌2小时。过滤收集固体沉淀物，滤饼分别用水(100ml)和预冷甲醇(20ml)洗涤，减压抽滤，晾干得到3-氨基-4-氰基-5-(氰乙基)-1H-吡唑(1-1，9.18g，粗品)，产品为黄色固体。LC_MS:(ES+):m/z 148.1[M+H] +.t R＝1.687min； 1H NMR(400MHz,DMSO-d6):δ3.94(s,2H),6.46(s,2H),11.98(s,1H)。 The malononitrile (30g, 0.454mol) and hydrazine hydrate (3.5ml) were heated to reflux in 90ml methanol, and hydrazine hydrate (10.5ml) was added dropwise to maintain the reflux of the reaction solution. The reaction solution was refluxed for 15 minutes, then cooled to 0-5°C and stirred for 2 hours. The solid precipitate was collected by filtration, the filter cake was washed with water (100ml) and pre-cooled methanol (20ml), filtered under reduced pressure, and dried to obtain 3-amino-4-cyano-5-(cyanoethyl)-1H-pyridine. Azole (1-1, 9.18g, crude product), the product is a yellow solid. LC_MS: (ES+): m/z 148.1[M+H] + .t R =1.687min; 1 H NMR(400MHz,DMSO-d6):δ3.94(s,2H),6.46(s,2H), 11.98(s, 1H).
将3-氨基-4-氰基-5-(氰乙基)-1H-吡唑(9.15g,0.06mol)溶于氢氧化钠水溶液(12N,92ml)中，在氮气保护下加热至100℃反应过夜。反应液冷却至0℃，用浓盐酸酸化至pH＝3。所得固体沉淀物经过滤、水洗、减压干燥，得到3-氨基-4-羧基-5-(羧甲基)-1H-吡唑(1-2，粗品)，产品为浅灰色固体，粗品不需进行纯化直接用于下一步反应。LC_MS:(ES+):m/z 185.9[M+H] +.t R＝1.022min；将3-氨基-4-羧基-5-(羧甲基)-1H-吡唑(粗品)加入到50ml水中，在100℃下反应过夜。将反应混合物冷却至室温并过滤，滤液通过减压蒸馏浓缩得到粗品。粗品用乙酸乙酯打浆过滤得到2-(3-氨基-1H-吡唑-5-基)乙酸(1-3，3.75g,两步反应收率42％)，产品为浅灰色固体。LC_MS:(ES+):m/z 142.0[M+H] +.t R＝0.986min. Dissolve 3-amino-4-cyano-5-(cyanoethyl)-1H-pyrazole (9.15g, 0.06mol) in aqueous sodium hydroxide solution (12N, 92ml), and heat to 100°C under the protection of nitrogen React overnight. The reaction solution was cooled to 0°C and acidified to pH=3 with concentrated hydrochloric acid. The obtained solid precipitate was filtered, washed with water, and dried under reduced pressure to obtain 3-amino-4-carboxy-5-(carboxymethyl)-1H-pyrazole (1-2, crude product). The product was a light gray solid, and the crude product was not It needs to be purified and used directly in the next reaction. LC_MS: (ES+): m/z 185.9[M+H] + .t R ＝1.022min; add 3-amino-4-carboxy-5-(carboxymethyl)-1H-pyrazole (crude product) to 50ml In water, react overnight at 100°C. The reaction mixture was cooled to room temperature and filtered, and the filtrate was concentrated by distillation under reduced pressure to obtain a crude product. The crude product was slurried and filtered with ethyl acetate to obtain 2-(3-amino-1H-pyrazol-5-yl)acetic acid (1-3, 3.75g, two-step reaction yield 42%), and the product was a light gray solid. LC_MS:(ES+):m/z 142.0[M+H] + .t R =0.986min.
中间体2(2-1，2-2，2-3)的合成路线：The synthetic route of Intermediate 2 (2-1, 2-2, 2-3):
Figure PCTCN2020135716-appb-000026
Figure PCTCN2020135716-appb-000026
其中，R 3、s、n的定义同前文。 Among them, the definitions of R 3 , s, and n are the same as above.
实施例7：合成中间体2-(3-氨基-1H-吡唑-5-基)-N-(2-氟苯基)乙酰胺Example 7: Synthesis of intermediate 2-(3-amino-1H-pyrazol-5-yl)-N-(2-fluorophenyl)acetamide
Figure PCTCN2020135716-appb-000027
Figure PCTCN2020135716-appb-000027
将2-(3-氨基-1H-吡唑-5-基)乙酸(1g,7.09mmol)和吡啶(1.23g,15.60mmol)溶于10ml N,N-二甲基甲酰胺中，在0℃下滴加三氟乙酸五氟苯酯(3.97g,14.18mmol)，10分钟加完。将得到的反应液升温至室温，搅拌1.5小时，然后加入2-氟苯胺(1.57g,14.18mmol)，继续搅拌2小时。反应液在0℃下用盐酸(1N,25ml)淬灭，用50ml水稀释后，用80ml乙酸乙酯萃取。收集有机相用30ml饱和食盐水冲洗，用无水硫酸钠干燥后，减压蒸馏浓缩得到2,2,2-三氟-N-(5-(2-((2-氟苯基)氨基)-2-乙氧基)-1H-吡唑-3-基)乙酰胺(2-1,1.12g,收率47％)，产品为白色固体，产品不需进行纯化直接用于下一步反应。LC_MS:(ES+):m/z 331.0[M+H] +. t R＝2.364min； 1H NMR(400MHz,DMSO-d6):δ3.81(s,2H),6.48(s,1H),7.15-7.18(m,2H),7.24-7.29(m,1H),7.86-7.90(m,1H),10.00(s,1H),11.93(s,1H),12.61(s,1H)。 Dissolve 2-(3-amino-1H-pyrazol-5-yl)acetic acid (1g, 7.09mmol) and pyridine (1.23g, 15.60mmol) in 10ml N,N-dimethylformamide at 0℃ Pentafluorophenyl trifluoroacetate (3.97g, 14.18mmol) was added dropwise, and the addition was completed in 10 minutes. The obtained reaction solution was warmed to room temperature and stirred for 1.5 hours, then 2-fluoroaniline (1.57 g, 14.18 mmol) was added, and stirring was continued for 2 hours. The reaction solution was quenched with hydrochloric acid (1N, 25ml) at 0°C, diluted with 50ml water, and extracted with 80ml ethyl acetate. The organic phase was collected and washed with 30ml saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2,2,2-trifluoro-N-(5-(2-((2-fluorophenyl)amino) -2-ethoxy)-1H-pyrazol-3-yl)acetamide (2-1, 1.12g, yield 47%), the product is a white solid, and the product is directly used in the next reaction without purification. LC_MS:(ES+):m/z 331.0[M+H] + . T R =2.364min; 1 H NMR(400MHz,DMSO-d6):δ3.81(s,2H),6.48(s,1H), 7.15-7.18 (m, 2H), 7.24-7.29 (m, 1H), 7.86-7.90 (m, 1H), 10.00 (s, 1H), 11.93 (s, 1H), 12.61 (s, 1H).
将2,2,2-三氟-N-(5-(2-((2-氟苯基)氨基)-2-乙氧基)-1H-吡唑-3-基)乙酰胺(1.1g,3.33mmol)加入到8ml稀盐酸和8ml甲醇中，在氮气保护下加热至50℃搅拌4小时。将反应液冷却至室温，用饱和碳酸氢钠水溶液碱化至pH＝7-8，用50ml乙酸乙酯萃取。收集有机相用30ml饱和食盐水冲洗，无水硫酸钠干燥，减压浓缩得到2-(3-氨基-1H-吡唑-5-基)-N-(2-氟苯基)乙酰胺(2-2，540mg，收率69％)为白色固体。LC_MS:(ES+):m/z 235.0[M+H] +.t R＝1.680min； 1H NMR(400MHz,DMSO-d6):δ3.56-3.61(m,2H),4.44-4.89(m,2H),5.20-5.39(m,1H),7.14-7.18(m,2H),7.22-7.28(m,1H),7.92(s,1H),9.85(s,1H),11.25(s,1H)。 2,2,2-Trifluoro-N-(5-(2-((2-fluorophenyl)amino)-2-ethoxy)-1H-pyrazol-3-yl)acetamide (1.1g , 3.33mmol) was added to 8ml dilute hydrochloric acid and 8ml methanol, heated to 50°C under nitrogen and stirred for 4 hours. The reaction solution was cooled to room temperature, basified with saturated aqueous sodium bicarbonate solution to pH=7-8, and extracted with 50 ml of ethyl acetate. The organic phase was collected and washed with 30ml saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2-(3-amino-1H-pyrazol-5-yl)-N-(2-fluorophenyl)acetamide (2 -2,540mg, yield 69%) is a white solid. LC_MS: (ES+): m/z 235.0[M+H] + .t R =1.680min; 1 H NMR(400MHz,DMSO-d6): δ3.56-3.61(m,2H),4.44-4.89(m , 2H), 5.20-5.39 (m, 1H), 7.14-7.18 (m, 2H), 7.22-7.28 (m, 1H), 7.92 (s, 1H), 9.85 (s, 1H), 11.25 (s, 1H) ).
实施例8:合成中间体2-(3-氨基-1H-吡唑-5-基)-N-(3-氟苯基)乙酰胺Example 8: Synthesis of intermediate 2-(3-amino-1H-pyrazol-5-yl)-N-(3-fluorophenyl)acetamide
Figure PCTCN2020135716-appb-000028
Figure PCTCN2020135716-appb-000028
目标化合物合成的方式类似于2-(3-氨基-1H-吡唑-5-基)-N-(2-氟苯基)乙酰胺。用3-氟苯胺作为起始原料来合成2,2,2-三氟-N-(5-(2-((3-氟苯基)氨基)-2-乙氧基)-1H-吡唑-3-基)乙酰胺(2-1,2.4g,收率72％)为白色固体。LC_MS:(ES+):m/z 331.2[M+H] +.t R＝2.350min. 1H NMR(400MHz,d6-DMSO):δ3.74(s,2H),6.47(s,1H),6.86-6.91(m,1H),7.28-7.32(m,1H),7.33-7.38(m,1H),7.57(d,J＝11.6Hz,1H),10.4(s,1H),11.91(s,1H),12.6(br,1H)。中间体2-(3-氨基-1H-吡唑-5-基)-N-(3-氟苯基)乙酰胺(2-2，1.0g,收率58％)，该中间体为黄色固体.LC_MS:(ES+):m/z 235.1[M+H] +.t R＝1.607min.1H NMR(400MHz,d6-DMSO):δ3.48(s,2H),5.30(s,1H),6.83-6.88(m,1H),7.28-7.36(m,2H),7.57-7.61(m,1H),10.26(s,1H)。 The synthesis method of the target compound is similar to 2-(3-amino-1H-pyrazol-5-yl)-N-(2-fluorophenyl)acetamide. Use 3-fluoroaniline as starting material to synthesize 2,2,2-trifluoro-N-(5-(2-((3-fluorophenyl)amino)-2-ethoxy)-1H-pyrazole -3-yl)acetamide (2-1, 2.4g, yield 72%) was a white solid. LC_MS:(ES+):m/z 331.2[M+H] + .t R =2.350min. 1 H NMR(400MHz,d6-DMSO):δ3.74(s,2H),6.47(s,1H), 6.86-6.91(m,1H),7.28-7.32(m,1H),7.33-7.38(m,1H),7.57(d,J=11.6Hz,1H), 10.4(s,1H), 11.91(s, 1H), 12.6(br, 1H). Intermediate 2-(3-amino-1H-pyrazol-5-yl)-N-(3-fluorophenyl)acetamide (2-2, 1.0g, yield 58%), the intermediate is a yellow solid .LC_MS:(ES+):m/z 235.1[M+H] + .t R =1.607min.1H NMR(400MHz,d6-DMSO):δ3.48(s,2H),5.30(s,1H), 6.83-6.88 (m, 1H), 7.28-7.36 (m, 2H), 7.57-7.61 (m, 1H), 10.26 (s, 1H).
实施例9:合成中间体2-(3-氨基-1H-吡唑-5-基)-N-(4-氟苯基)乙酰胺Example 9: Synthesis of intermediate 2-(3-amino-1H-pyrazol-5-yl)-N-(4-fluorophenyl)acetamide
Figure PCTCN2020135716-appb-000029
Figure PCTCN2020135716-appb-000029
目标化合物合成的方式类似于2-(3-氨基-1H-吡唑-5-基)-N-(2-氟苯基)乙酰胺。用4-氟苯胺作为起始原料合成2,2,2-三氟-N-(5-(2-((4-氟苯基)氨基)-2-乙氧基)-1H-吡唑-3-基)乙酰胺(2-1,1.2g,收率51％)为白色固体。 1H NMR(400MHz,DMSO-d6):δ3.72(s,2H),6.47(s,1H),7.14-7.18(m,2H),7.59-7.63(m,2H),10.27(s,1H),11.94(s,1H),12.63(br,1H)。中间体2-(3-氨基-1H-吡唑-5-基)-N-(4-氟苯基)乙酰胺(2-2，618mg,收率73％)为黄色固体。LC_MS:(ES+):m/z 235.0[M+H] +.t R＝1.327min。 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. 1 H NMR (400MHz, DMSO-d6): δ3.72 (s, 2H), 6.47 (s, 1H), 7.14-7.18 (m, 2H), 7.59-7.63 (m, 2H), 10.27 (s, 1H) ), 11.94 (s, 1H), 12.63 (br, 1H). The intermediate 2-(3-amino-1H-pyrazol-5-yl)-N-(4-fluorophenyl)acetamide (2-2,618 mg, yield 73%) was a yellow solid. LC_MS: (ES+): m/z 235.0 [M+H] + .t R = 1.327 min.
实施例10：合成中间体2-(3-氨基-1H-吡唑-5-基)-N-(2,3-二氟苯基)乙酰胺Example 10: Synthesis of intermediate 2-(3-amino-1H-pyrazol-5-yl)-N-(2,3-difluorophenyl)acetamide
Figure PCTCN2020135716-appb-000030
Figure PCTCN2020135716-appb-000030
目标化合物合成的方式类似于2-(3-氨基-1H-吡唑-5-基)-N-(2-氟苯基)乙酰胺。用2,3-二氟苯胺作为起始原料来合成N-(5-(2-((2,3-二氟苯基)氨基)-2-乙氧基)-1H-吡唑-3-基)-2,2,2-三氟乙酰胺(2-1,780mg，收率31％)为白色固体。 1H NMR(400MHz,DMSO-d6):δ3.84(s,2H),6.49(s,1H),7.15-7.24(m,2H),7.67-7.71(m,1H),10.22(s,1H),11.94(s,1H),12.63(s,1H)。中间体2-(3-氨基-1H-吡唑-5-基)-N-(2,3-二氟苯基)乙酰胺(2-2，300mg，收率53％)为白色固体。 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. 1 H NMR (400MHz, DMSO-d6): δ 3.84 (s, 2H), 6.49 (s, 1H), 7.15-7.24 (m, 2H), 7.67-7.71 (m, 1H), 10.22 (s, 1H) ), 11.94 (s, 1H), 12.63 (s, 1H). The intermediate 2-(3-amino-1H-pyrazol-5-yl)-N-(2,3-difluorophenyl)acetamide (2-2,300 mg, yield 53%) was a white solid.
实施例11：合成中间体5-(2-((3-氟苯基)氨基)乙基)-1H-吡唑-3-胺Example 11: Synthesis of intermediate 5-(2-((3-fluorophenyl)amino)ethyl)-1H-pyrazol-3-amine
Figure PCTCN2020135716-appb-000031
Figure PCTCN2020135716-appb-000031
将2-(3-氨基-1H-吡唑-5-基)-N-(3-氟苯基)乙酰胺(2-2,234mg,1.0mmol)加入到10ml干燥的四氢呋喃溶液中，冷却至0℃，在氮气保护下滴加1ml硼烷二甲硫醚络合物。所得混合物在加热至70℃，搅拌2小时。反应液冷却至0℃，用盐酸(2N,30ml)淬灭。所得混合物在室温下搅拌过夜，用氢氧化钠碱化至pH＝9，用40ml乙酸乙酯萃取。收集有机相用20ml饱和食盐水冲洗后，用无水硫酸钠干燥，减压浓缩得到粗品。粗品用硅胶柱层析(含5％甲醇的二氯甲烷)纯化得到5-(2-((3-氟苯基)氨基)乙基)-1H-吡唑-3-胺(2-3，150mg,收率68％)，产品为黄色油状物。LC_MS:(ES+):m/z 221.1[M+H] +.t R＝1.744min. 1H NMR(400MHz,CDCl 3):δ2.84(t,J＝6.4Hz,2H),3.36(t,J＝6.4Hz,2H),5.5(s,1H),6.27-6.31(m,1H),6.34-6.41(m,2H),7.06-7.12(m,1H)。 Add 2-(3-amino-1H-pyrazol-5-yl)-N-(3-fluorophenyl)acetamide (2-2,234mg, 1.0mmol) to 10ml of dry tetrahydrofuran solution and cool to 0 ℃, 1ml of borane dimethyl sulfide complex was added dropwise under the protection of nitrogen. The resulting mixture was heated to 70°C and stirred for 2 hours. The reaction solution was cooled to 0°C and quenched with hydrochloric acid (2N, 30ml). The resulting mixture was stirred at room temperature overnight, basified with sodium hydroxide to pH=9, and extracted with 40 ml of ethyl acetate. The collected organic phase was washed with 20 ml of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (5% methanol in dichloromethane) to obtain 5-(2-((3-fluorophenyl)amino)ethyl)-1H-pyrazol-3-amine (2-3, 150mg, yield 68%), the product is yellow oil. LC_MS:(ES+):m/z 221.1[M+H] + .t R =1.744min. 1 H NMR(400MHz,CDCl 3 ):δ2.84(t,J=6.4Hz,2H), 3.36(t , J=6.4 Hz, 2H), 5.5 (s, 1H), 6.27-6.31 (m, 1H), 6.34-6.41 (m, 2H), 7.06-7.12 (m, 1H).
中间体3(3-1、3-2、3-3、3-4)合成路线Intermediate 3 (3-1, 3-2, 3-3, 3-4) synthetic route
Figure PCTCN2020135716-appb-000032
Figure PCTCN2020135716-appb-000032
实施例12:合成中间体5-(氨甲基)-1H-吡唑-3-氨Example 12: Synthesis of intermediate 5-(aminomethyl)-1H-pyrazole-3-amine
Figure PCTCN2020135716-appb-000033
Figure PCTCN2020135716-appb-000033
将3-硝基-1H-吡唑-5-甲酸甲酯(5g,29.22mmol)加入到70ml氨水中，常温搅拌过夜。将反应液倒入稀盐酸(1N,40ml)中,再用30ml稀释。浓缩反应液得到3-硝基-5-甲酰基-1H-吡唑(3-1,4g,收率88％)，产品为白色固体.LC_MS:(ES+):m/z 156.7[M+H] +.t R＝1.437min； 1H NMR(400MHz,DMSO-d6):δ7.04(s,2H),7.50(s,1H)。 3-Nitro-1H-pyrazole-5-carboxylic acid methyl ester (5g, 29.22mmol) was added to 70ml ammonia water and stirred overnight at room temperature. The reaction solution was poured into dilute hydrochloric acid (1N, 40ml), and then diluted with 30ml. The reaction solution was concentrated to obtain 3-nitro-5-formyl-1H-pyrazole (3-1,4g, yield 88%), the product was a white solid. LC_MS: (ES+): m/z 156.7[M+H ] + .t R = 1.437 min; 1 H NMR (400 MHz, DMSO-d6): δ 7.04 (s, 2H), 7.50 (s, 1H).
在溶解有3-硝基-1H-吡唑-5-甲酰胺(2.5g,16.02mmol)的甲醇溶液中加入钯碳(10％,250mg)，置换氢气，于氢气氛围下(氢气球)常温搅拌4小时。过滤钯碳，用甲醇淋洗2次。将母液减压浓缩得到3-氨基-5-甲酰基-1H-吡唑(3-2,2g,收率99％)，产品为白色固体。LC_MS:(ES+):m/z 126.9[M+H] +.t R＝0.927min； 1H NMR(400MHz,DMSO-d6):δ4.60-5.01(m,2H),5.60-5.92(m,1H),7.00-7.70(m,2H),11.84-12.03(m,1H)。 Add palladium on carbon (10%, 250mg) to the methanol solution with 3-nitro-1H-pyrazole-5-carboxamide (2.5g, 16.02mmol) dissolved in it, replace hydrogen, and place it under a hydrogen atmosphere (hydrogen balloon) at room temperature Stir for 4 hours. The palladium carbon was filtered and rinsed twice with methanol. The mother liquor was concentrated under reduced pressure to obtain 3-amino-5-formyl-1H-pyrazole (3-2,2 g, yield 99%), which was a white solid. LC_MS: (ES+): m/z 126.9[M+H] + .t R = 0.927min; 1 H NMR (400MHz, DMSO-d6): δ4.60-5.01(m, 2H), 5.60-5.92(m , 1H), 7.00-7.70 (m, 2H), 11.84-12.03 (m, 1H).
将3-氨基-5-甲酰基-1H-吡唑(1.2g,9.51mmol)溶于50ml干燥的四氢呋喃中，冷却至0℃，在氮气保护下缓慢滴加硼烷二甲硫醚溶液(9.5ml,95.15mmol)。将反应加热至70℃搅拌18小时。冷却至0℃，加入稀盐酸(2N,50ml)后，在常温下搅拌过夜。用氢氧化钠溶液碱化至pH＝9，用乙酸乙酯(40ml)萃取两次。将水相浓缩到三分之一体积后加入碳酸钾(2.6g,19.03mmol)和二碳酸二叔丁酯(2.07g,9.51mmol)，常温搅拌过夜。加水稀释，用乙酸乙酯(50ml)萃取，合并有机相用饱和食盐水(50ml)洗两次,用无水硫酸钠干燥,减压浓缩得到粗品。粗品通过硅胶柱层析纯化(含20-50％乙酸乙酯的正己烷)得到3-氨基-5-((N,N-双叔丁氧羰氨基)甲基)-1H-吡唑(3-3,400mg,收率13％)，产品为白色固体。LC_MS:(ES+):m/z 313.0[M+H] +.t R＝2.617min。 Dissolve 3-amino-5-formyl-1H-pyrazole (1.2g, 9.51mmol) in 50ml of dry tetrahydrofuran, cool to 0℃, and slowly add borane dimethyl sulfide solution (9.5 ml, 95.15mmol). The reaction was heated to 70°C and stirred for 18 hours. Cool to 0°C, add dilute hydrochloric acid (2N, 50ml), and stir overnight at room temperature. It was basified to pH=9 with sodium hydroxide solution, and extracted twice with ethyl acetate (40 ml). 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. The crude product was purified by silica gel column chromatography (20-50% ethyl acetate in n-hexane) to obtain 3-amino-5-((N,N-bis-tert-butoxycarbonylamino)methyl)-1H-pyrazole (3 -3,400mg, yield 13%), the product is a white solid. LC_MS: (ES+): m/z 313.0[M+H] + .t R =2.617min.
将3-氨基-5-((N,N-双叔丁氧羰氨基)甲基)-1H-吡唑(400mg,1.28mmol)加入到氯化氢的甲醇溶液(4M,5ml)中，常温搅拌过夜。减压浓缩得到粗产品，用二氯甲烷打浆后过滤得到5-(氨甲基)-1H-吡唑-3-胺 (3-4，200mg,收率>100％)，产品为白色固体。LC_MS:(ES+):m/z 113.0[M+H] +.t R＝0.848min。 Add 3-amino-5-((N,N-bis-tert-butoxycarbonylamino)methyl)-1H-pyrazole (400mg, 1.28mmol) to the methanol solution of hydrogen chloride (4M, 5ml), and stir overnight at room temperature . Concentrated under reduced pressure to obtain a crude product, which was slurried with dichloromethane and filtered to obtain 5-(aminomethyl)-1H-pyrazol-3-amine (3-4, 200 mg, yield>100%), and the product was a white solid. LC_MS: (ES+): m/z 113.0 [M+H] + .t R = 0.848 min.
中间体4(4-1)的合成路线Synthetic route of intermediate 4(4-1)
Figure PCTCN2020135716-appb-000034
Figure PCTCN2020135716-appb-000034
该路线中，s、R 3的定义同前文。 In this route, the definitions of s and R 3 are the same as above.
实施例13:合成中间体2,5-二氧吡咯烷-1-基-3-氟苯甲酸酯Example 13: Synthesis of intermediate 2,5-dioxopyrrolidin-1-yl-3-fluorobenzoate
Figure PCTCN2020135716-appb-000035
Figure PCTCN2020135716-appb-000035
将3-氟苯甲酸(1g,7.1mmol)和N-羟基丁二酰亚胺(0.9g,7.8mmol)加入到20ml二氯甲烷和1ml N,N-二甲基甲酰胺的混合溶液中，在0℃缓慢加入二环己基碳二亚胺(1.6g,7.8mmol)的二氯甲烷溶液。氮气保护下常温搅拌过夜。过滤收集滤饼，滤饼用乙酸乙酯重结晶得2,5-二氧吡咯烷-1-基-3-氟苯甲酸酯(4-1，1.2g,收率76％)为白色固体。 1H NMR(400MHz,DMSO-d6):δ2.91(s,4H),7.73-7.76(m,2H),7.87-7.90(m,1H),7.96-7.99(m,1H)。 Add 3-fluorobenzoic acid (1g, 7.1mmol) and N-hydroxysuccinimide (0.9g, 7.8mmol) to a mixed solution of 20ml dichloromethane and 1ml N,N-dimethylformamide, A solution of dicyclohexylcarbodiimide (1.6 g, 7.8 mmol) in dichloromethane was slowly added at 0°C. Stir at room temperature overnight under nitrogen protection. The filter cake was collected by filtration, and the filter cake was recrystallized with ethyl acetate to obtain 2,5-dioxopyrrolidin-1-yl-3-fluorobenzoate (4-1, 1.2g, yield 76%) as a white solid . 1 H NMR (400MHz, DMSO-d6): δ 2.91 (s, 4H), 7.73-7.76 (m, 2H), 7.87-7.90 (m, 1H), 7.96-7.99 (m, 1H).
中间体5(5-1)的合成路线：Synthetic route of intermediate 5(5-1):
Figure PCTCN2020135716-appb-000036
Figure PCTCN2020135716-appb-000036
该路线中，R 3的定义同前文。 In this route, the definition of R 3 is the same as above.
实施例14:合成中间体N-((3-氨基-1H-吡唑-5-基)甲基)-3-氟苯甲酰胺Example 14: Synthesis of intermediate N-((3-amino-1H-pyrazol-5-yl)methyl)-3-fluorobenzamide
Figure PCTCN2020135716-appb-000037
Figure PCTCN2020135716-appb-000037
将3-氨基-5-(甲氨基)-1H-吡唑(3-4,140mg,1.25mmol)，三乙胺(253mg,2.50mmol)和2,5-二氧吡咯烷-1-基-3-氟苯甲酸酯(4-1,296mg,1.25mmol)加入到5ml N,N-二甲基甲酰胺溶液中，常温搅拌3小时。向反应液中加入30ml水，用30ml乙酸乙酯萃取。收集有机相，用30ml饱和食盐水洗两次，用无水硫酸钠干燥，浓缩旋干得到粗产品，并用硅胶柱层析(含5-10％甲醇和1％氨水的二氯甲烷)纯化得到N-((3-氨基-1H-吡唑-5-基)甲基)-3-氟苯甲酰胺(5-1，160mg,收率55％)，产品为棕色固体。LC_MS:(ES+):m/z234.9[M+H] +.t R＝1.213min. Combine 3-amino-5-(methylamino)-1H-pyrazole (3-4,140mg, 1.25mmol), triethylamine (253mg, 2.50mmol) and 2,5-dioxopyrrolidin-1-yl-3 -Fluorobenzoate (4-1,296mg, 1.25mmol) was added to 5ml of N,N-dimethylformamide solution and stirred at room temperature for 3 hours. 30 ml of water was added to the reaction solution, and extraction was performed with 30 ml of ethyl acetate. The organic phase was collected, washed twice with 30ml saturated brine, dried over anhydrous sodium sulfate, concentrated and spin-dried to obtain a crude product, and purified by silica gel column chromatography (dichloromethane containing 5-10% methanol and 1% ammonia) to obtain N -((3-Amino-1H-pyrazol-5-yl)methyl)-3-fluorobenzamide (5-1, 160mg, yield 55%), the product is a brown solid. LC_MS:(ES+):m/z234.9[M+H] + .t R ＝1.213min.
中间体6(6-1，6-2，6-3，6-4)合成路线：Intermediate 6 (6-1, 6-2, 6-3, 6-4) synthetic route:
Figure PCTCN2020135716-appb-000038
Figure PCTCN2020135716-appb-000038
该路线中，m的定义同前文，为0或1。In this route, m is defined as 0 or 1.
实施例15：合成中间体3-(叠氮甲基)-1H-吡唑-5-羧酸Example 15: Synthesis of intermediate 3-(azidomethyl)-1H-pyrazole-5-carboxylic acid
Figure PCTCN2020135716-appb-000039
Figure PCTCN2020135716-appb-000039
将2-重氮乙酸乙酯(18ml,171mmol)与2-丙炔-1-醇(9.59g,171mmol)加入到180ml甲苯中，氮气保护下加热至110℃反应过夜。减压浓缩除去溶剂，残渣用40ml乙酸乙酯稀释，室温搅拌10min。过滤，滤 饼用10ml乙酸乙酯洗涤。将滤饼加入到80ml乙酸乙酯中，在80℃下搅拌5min，冷却至室温，过滤，滤饼用20ml乙酸乙酯洗涤，减压干燥后得3-(羟甲基)-1H-吡唑-5-羧酸乙酯(6-1,7.2g，收率30％)，产品为白色固体。LC_MS:(ES+):m/z 170.8[M+H] +.t R＝1.410min； 1H NMR(400MHz,CDCl 3):δ1.28(t,J＝7.2Hz,3H),4.24-4.26(m,2H),4.49-4.50(m,2H),5.38(s,1H),6.58(s,1H),13.38(s,1H)。 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. LC_MS: (ES+): m/z 170.8[M+H] + .t R =1.410min; 1 H NMR (400MHz, CDCl 3 ): δ1.28(t,J=7.2Hz,3H), 4.24-4.26 (m, 2H), 4.49-4.50 (m, 2H), 5.38 (s, 1H), 6.58 (s, 1H), 13.38 (s, 1H).
将3-(羟甲基)-1H-吡唑-5-羧酸乙酯(5g,29.41mmol)加入到80ml二氯甲烷中。氮气保护下加入0.1ml N,N-二甲基甲酰胺。冷却至0℃,20分钟内缓慢滴加(10.50g,88.24mmol)氯化亚砜。滴加完毕，升至室温搅拌半小时。减压浓缩除去溶剂，加入80ml二氯甲烷，用饱和碳酸氢钠水溶液碱化至pH＝7-8。收集有机层，用50ml饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩得3-(氯甲基)-1H-吡唑-5-羧酸乙酯(6-2,5.45g,粗品)为无色油状。LC_MS:(ES+):m/z 188.7[M+H] +.t R＝2.378min。 Ethyl 3-(hydroxymethyl)-1H-pyrazole-5-carboxylate (5 g, 29.41 mmol) was added to 80 ml of dichloromethane. Add 0.1ml N,N-dimethylformamide under nitrogen protection. Cool to 0°C, slowly add (10.50g, 88.24mmol) thionyl chloride dropwise within 20 minutes. After the addition is complete, warm to room temperature and stir for half an hour. Concentrate under reduced pressure to remove the solvent, add 80 ml of dichloromethane, and basify with saturated sodium bicarbonate aqueous solution to pH=7-8. The organic layer was collected, washed with 50 ml of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain ethyl 3-(chloromethyl)-1H-pyrazole-5-carboxylate (6-2, 5.45 g, crude product) It is a colorless oil. LC_MS: (ES+): m/z 188.7[M+H] + .t R =2.378 min.
将3-(氯甲基)-1H-吡唑-5-羧酸乙酯(5.4g,28.72mmol)溶于50ml N,N-二甲基甲酰胺中，室温加入叠氮化钠(2.24g,34.46mmol)。氮气保护下加热至50℃搅拌1小时。将反应液冷却至室温，倒入150ml水中，用饱和碳酸氢钠水溶液碱化至pH＝7-8后用200ml乙酸乙酯萃取。合并有机层，用100ml饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩后用硅胶柱层析纯化(含20％乙酸乙酯的正己烷)得3-(叠氮甲基)-1H-吡唑-5-羧酸乙酯(6-3,4.7g,收率84％)，产品为白色固体.LC_MS:(ES+):m/z 195.7[M+H] +.t R＝2.362min；1H NMR(400MHz,CDCl 3):δ1.39(t,J＝7.2Hz,3H),4.38-4.43(q,2H),4.47(s,2H),6.86(s,1H),12.19(br,1H)。 Dissolve 3-(chloromethyl)-1H-pyrazole-5-carboxylic acid ethyl ester (5.4g, 28.72mmol) in 50ml N,N-dimethylformamide, add sodium azide (2.24g , 34.46mmol). Under the protection of nitrogen, heat to 50°C and stir for 1 hour. The reaction solution was cooled to room temperature, poured into 150 ml of water, basified with saturated aqueous sodium bicarbonate solution to pH=7-8, and then extracted with 200 ml of ethyl acetate. The organic layers were combined, washed with 100 ml of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (20% ethyl acetate in n-hexane) to obtain 3-(azidomethyl)-1H- Ethyl pyrazole-5-carboxylate (6-3, 4.7g, yield 84%), the product is a white solid. LC_MS: (ES+): m/z 195.7[M+H] + .t R =2.362min ; 1H NMR (400MHz, CDCl 3 ): δ1.39 (t, J = 7.2Hz, 3H), 4.38-4.43 (q, 2H), 4.47 (s, 2H), 6.86 (s, 1H), 12.19 (br ,1H).
将3-(叠氮甲基)-1H-吡唑-5-羧酸乙酯(1.58g,8.1mmol)和氢氧化锂(1.02g,24.31mmol)加入到12ml甲醇-6ml四氢呋喃-3ml水中，氮气保护下30℃搅拌过夜。冷却至室温，用15ml 2N稀盐酸酸化，减压浓缩得3-(叠氮甲基)-1H-吡唑-5-羧酸(6-4，2g,粗品)，产品为黄色油状，粗品不需纯化直接用于下一步反应。LC_MS:(ES+):m/z 167.7[M+H] +.t R＝1.482min. Add 3-(azidomethyl)-1H-pyrazole-5-carboxylic acid ethyl ester (1.58g, 8.1mmol) and lithium hydroxide (1.02g, 24.31mmol) into 12ml methanol-6ml tetrahydrofuran-3ml water, Stir at 30°C overnight under nitrogen protection. Cool to room temperature, acidify with 15ml 2N dilute hydrochloric acid, and concentrate under reduced pressure to obtain 3-(azidomethyl)-1H-pyrazole-5-carboxylic acid (6-4, 2g, crude product). The product is yellow oily, but the crude product is not It needs to be purified and used directly in the next reaction. LC_MS:(ES+):m/z 167.7[M+H] + .t R =1.482min.
合成中间体7(7-1，7-2)Synthesis of Intermediate 7 (7-1, 7-2)
Figure PCTCN2020135716-appb-000040
Figure PCTCN2020135716-appb-000040
该路线中，m、s、R 3的定义同前文。 In this route, the definitions of m, s, and R 3 are the same as above.
实施例16：合成中间体3-(氨基甲基)-N-(3-氟苯基)-1H-吡唑-5-酰胺Example 16: Synthesis of intermediate 3-(aminomethyl)-N-(3-fluorophenyl)-1H-pyrazole-5-amide
Figure PCTCN2020135716-appb-000041
Figure PCTCN2020135716-appb-000041
将3-(叠氮甲基)-1H-吡唑-5-羧酸(6-4,2g,8.1mmol)，3-氟苯胺(1.08g,9.72mmol),N,N-二异丙基乙胺(2.09g,16.20mmol)，和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(4.62g,12.15mmol)加入到10ml N,N-二甲基甲酰胺中，在氮气保护下室温搅拌1小时。反应液用40ml水和60ml乙酸乙酯萃取，分液，收集有机层并用30ml饱和食盐水洗涤，用无水硫酸钠干燥，减压浓缩得到的粗品经硅胶柱层析(含20％乙酸乙酯的己烷)纯化得到3-(叠氮甲基)-N-(3-氟苯基)-1H-吡唑-5-酰胺(7-1,120mg,收率6％)，产品为白色固体。Combine 3-(azidomethyl)-1H-pyrazole-5-carboxylic acid (6-4,2g, 8.1mmol), 3-fluoroaniline (1.08g, 9.72mmol), N,N-diisopropyl Ethylamine (2.09g, 16.20mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (4.62g, 12.15mmol) Add to 10ml N,N-dimethylformamide, and stir at room temperature for 1 hour under the protection of nitrogen. 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.
将3-(叠氮甲基)-N-(3-氟苯基)-1H-吡唑-5-酰胺(120mg,0.46mmol)和三苯基膦(182mg,0.69mmol)加入到3ml四氢呋喃中，氮气保护下加热至45℃搅拌1小时。加入41mg水，继续搅拌1小时。反应液冷至室温，用2ml 2N稀释的盐酸酸化，加入10ml水和20ml乙酸乙酯。收集水层，用饱和碳酸钠溶液碱 化至pH 10，用二氯甲烷(20ml×3)萃取。合并有机层，用无水硫酸钠干燥，减压浓缩得3-(氨基甲基)-N-(3-氟苯基)-1H-吡唑-5-酰胺(7-2，100mg，收率93％)，产品为白色固体，粗品无须纯化直接用于下一步反应。LC_MS:(ES+):m/z 234.9[M+H] +.t R＝1.558min. Add 3-(azidomethyl)-N-(3-fluorophenyl)-1H-pyrazole-5-amide (120mg, 0.46mmol) and triphenylphosphine (182mg, 0.69mmol) to 3ml of tetrahydrofuran , Under the protection of nitrogen, heat to 45°C and stir for 1 hour. Add 41 mg of water and continue stirring for 1 hour. The reaction solution was cooled to room temperature, acidified with 2ml of 2N diluted hydrochloric acid, and 10ml of water and 20ml of ethyl acetate were added. The aqueous layer was collected, basified to pH 10 with saturated sodium carbonate solution, and extracted with dichloromethane (20ml×3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3-(aminomethyl)-N-(3-fluorophenyl)-1H-pyrazole-5-amide (7-2, 100mg, yield 93%), the product is a white solid, and the crude product is directly used in the next reaction without purification. LC_MS:(ES+):m/z 234.9[M+H] + .t R =1.558min.
化合物I-a(I-a-1，I-a-2)的合成路线Synthetic route of compound I-a (I-a-1, I-a-2)
Figure PCTCN2020135716-appb-000042
Figure PCTCN2020135716-appb-000042
该路线中，各取代基的定义同前文，III-1中，Cl可以替换为氟、溴、碘。In this route, the definition of each substituent is the same as in the preceding paragraph. In III-1, Cl can be replaced with fluorine, bromine, or iodine.
实施例17：合成化合物2-(3-((7-(4-(乙基(2-羟基乙基)氨基)丁-1-炔-1-基)喹唑啉-4-基)氨基)-1H-吡唑-5-基)-N-(2-氟苯基)乙酰胺(化合物5)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)
Figure PCTCN2020135716-appb-000043
Figure PCTCN2020135716-appb-000043
将2-(3-氨基-1H-吡唑-5-基)-N-(2-氟苯基)乙酰胺(2-2，45.1mg,0.19mmol)和2-((4-(4-氯喹唑啉-7-基))丁-3-炔-1-基)(乙基)氨基)乙醇(III-1，70.4mg,0.23mmol)加入到2ml异丙醇中，氮气保护下加热至90℃反应2小时。将反应冷至室温，加入5％氨水甲醇溶液碱化至pH8-9。将反应液浓缩，用薄层层析硅胶板(含8％甲醇和0.1％氨水的二氯甲烷)纯化得2-(3-((7-(4-(乙基(2-羟基乙基)氨基)丁-1-炔-1-基)喹唑啉-4-基)氨基)-1H-吡唑-5-基)-N-(2-氟苯基)乙酰胺(化合物5，15mg,收率15％)，产品黄色固体。LC_MS:(ES+):m/z 502.3[M+H] +.t R＝1.302min； 1H NMR(400MHz,DMSO-d6):δ1.00(t,J＝7.2Hz,3H),2.56-2.61(m,6H),2.79(t,J＝7.2Hz,2H),3.46-3.52(m,2H),3.82(s,2H),4.34(s,1H),6.66-6.84(m,1H),7.15-7.19(m,2H),7.24-7.30(m,1H),7.50-7.52(m,1H),7.71(s,1H),7.90-7.94(m,1H),8.56-8.59(m,2H),10.00(s,1H),10.45(s,1H),12.40(s,1H). Combine 2-(3-amino-1H-pyrazol-5-yl)-N-(2-fluorophenyl)acetamide (2-2, 45.1 mg, 0.19 mmol) and 2-((4-(4- Chloroquinazolin-7-yl)) but-3-yn-1-yl)(ethyl)amino)ethanol (III-1, 70.4mg, 0.23mmol) was added to 2ml of isopropanol and heated to React at 90°C for 2 hours. The reaction was cooled to room temperature and basified to pH 8-9 by adding 5% ammonia methanol solution. The 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. LC_MS: (ES+): m/z 502.3[M+H] + .t R =1.302min; 1 H NMR(400MHz,DMSO-d6):δ1.00(t,J=7.2Hz,3H),2.56- 2.61(m,6H),2.79(t,J=7.2Hz,2H),3.46-3.52(m,2H),3.82(s,2H),4.34(s,1H),6.66-6.84(m,1H) ,7.15-7.19(m,2H),7.24-7.30(m,1H),7.50-7.52(m,1H),7.71(s,1H),7.90-7.94(m,1H),8.56-8.59(m, 2H), 10.00 (s, 1H), 10.45 (s, 1H), 12.40 (s, 1H).
实施例18：合成化合物2-(3-((7-(4-(乙基(2-羟基乙基)氨基)丁-1-炔-1-基)喹唑啉-4-基)氨基)-1H-吡唑-5-基)-N-(3-氟苯基)乙酰胺(化合物3)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)
Figure PCTCN2020135716-appb-000044
Figure PCTCN2020135716-appb-000044
目标化合物3的制备的方式类似于合成2-(3-((7-(4-(乙基(2-羟基乙基)氨基)丁-1-炔-1-基)喹唑啉-4-基)氨基)-1H-吡唑-5-基)-N-(2-氟苯基)乙酰胺。以2-(3-氨基-1H-吡唑-5-基)-N-(3-氟苯基)乙酰胺和2-((4-(4-氯喹唑啉-7-基)丁-3-炔-1-基)(乙基)氨基)乙醇(III-1)作为起始原料合成2-(3-((7-(4-(乙基(2-羟基乙基)氨基)丁-1-炔-1-基)喹唑啉-4-基)氨基)-1H-吡唑-5-基)-N-(3-氟苯基)乙酰胺(化合物3，24mg,收率26％)，产品黄色固体。LC_MS:(ES+):m/z 502.4[M+H] +.t R＝1.680min. 1H NMR(400MHz,DMSO-d6):δ1.05(t,J＝7.2Hz,3H),2.56-2.64(m,4H),2.72-2.82(m,2H),3.43-3.52(m,2H),3.75(s,2H),4.28-4.37(m,1H),6.72-6.84(m,1H),6.87-6.91(m,1H),7.31-7.37(m,2H),7.43-7.56(m,1H),7.62(d,J＝11.6Hz,1H),7.70(s,1H),8.58(s,2H), 10.45(s,2H),12.41(s,1H). 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. With 2-(3-amino-1H-pyrazol-5-yl)-N-(3-fluorophenyl)acetamide and 2-((4-(4-chloroquinazolin-7-yl)but-3 -Alkyn-1-yl)(ethyl)amino)ethanol (III-1) was used as the starting material to synthesize 2-(3-((7-(4-(ethyl(2-hydroxyethyl)amino)butyl- 1-Alkyn-1-yl)quinazolin-4-yl)amino)-1H-pyrazol-5-yl)-N-(3-fluorophenyl)acetamide (Compound 3, 24mg, yield 26% ), the product is a yellow solid. LC_MS:(ES+):m/z 502.4[M+H] + .t R =1.680min. 1 H NMR(400MHz,DMSO-d6):δ1.05(t,J=7.2Hz,3H),2.56- 2.64(m,4H),2.72-2.82(m,2H),3.43-3.52(m,2H),3.75(s,2H),4.28-4.37(m,1H),6.72-6.84(m,1H), 6.87-6.91(m,1H),7.31-7.37(m,2H),7.43-7.56(m,1H), 7.62(d,J=11.6Hz,1H), 7.70(s,1H), 8.58(s, 2H), 10.45(s,2H), 12.41(s,1H).
实施例19：合成化合物2-(3-((7-(4-(乙基(2-羟乙基)氨基)丁-1-炔-1-基)-6-甲氧基喹唑啉-4-基)氨基)-1H-吡唑-5-基)-N-(3-氟苯基)乙酰胺盐酸盐(化合物3的盐酸盐)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)
Figure PCTCN2020135716-appb-000045
Figure PCTCN2020135716-appb-000045
目标化合物制备的方式类似于合成2-(3-((7-(4-(乙基(2-羟基乙基)氨基)丁-1-炔-1-基)喹唑啉-4-基)氨基)-1H-吡唑-5-基)-N-(2-氟苯基)乙酰胺。以2-(3-氨基-1H-吡唑-5-基)-N-(3-氟苯基)乙酰胺和2-((4-(4-氯-6-甲氧基喹唑啉-7-基)丁-3-炔-1-基)(乙基)氨基)乙醇为起始原料合成2-(3-((7-(4-(乙基(2-羟乙基)氨基)丁-1-炔-1-基)-6-甲氧基喹唑啉-4-基)氨基)-1H-吡唑-5-基)-N-(3-氟苯基)乙酰胺盐酸盐(46mg,收率71％)黄色固体。LC_MS:(ES+):m/z 532.2[M+H] +.t R＝1.771min. 1H NMR(400MHz,DMSO-d6):δ1.27(t,J＝7.2Hz,3H),3.12(t,J＝7.6Hz,2H),3.26-3.34(m,4H),3.38-3.46(m,2H),3.79(t,J＝5.2Hz,2H),3.83(s,2H),4.01(s,3H),5.25-5.51(m,1H),6.84(s,1H),6.88-6.92(m,1H),7.33-7.39(m,2H),7.60-7.69(m,1H),7.93(s,1H),8.31(s,1H),8.85(s,1H),9.93(s,1H),10.63(s,1H),11.67-11.98(br,1H). 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. With 2-(3-amino-1H-pyrazol-5-yl)-N-(3-fluorophenyl)acetamide and 2-((4-(4-chloro-6-methoxyquinazoline- Synthesis of 2-(3-((7-(4-(ethyl(2-hydroxyethyl)amino) with 7-yl)but-3-yn-1-yl)(ethyl)amino)ethanol as starting material But-1-yn-1-yl)-6-methoxyquinazolin-4-yl)amino)-1H-pyrazol-5-yl)-N-(3-fluorophenyl)acetamide hydrochloride Salt (46 mg, 71% yield) yellow solid. LC_MS:(ES+):m/z 532.2[M+H] + .t R =1.771min. 1 H NMR(400MHz,DMSO-d6):δ1.27(t,J=7.2Hz,3H),3.12( t,J=7.6Hz,2H),3.26-3.34(m,4H),3.38-3.46(m,2H),3.79(t,J=5.2Hz,2H),3.83(s,2H),4.01(s ,3H),5.25-5.51(m,1H),6.84(s,1H),6.88-6.92(m,1H),7.33-7.39(m,2H),7.60-7.69(m,1H),7.93(s ,1H), 8.31(s,1H), 8.85(s,1H), 9.93(s,1H), 10.63(s,1H), 11.67-11.98(br,1H).
实施例20：合成化合物2-(3-((7-(4-(乙基(2-羟基乙基)氨基)丁-1-炔-1-基)喹唑啉-4-基)-1H-吡唑-5-基)-N-(4-氟苯基)乙酰胺(化合物6)Example 20: Synthesis of compound 2-(3-((7-(4-(ethyl(2-hydroxyethyl)amino)but-1-yn-1-yl)quinazolin-4-yl)-1H -Pyrazol-5-yl)-N-(4-fluorophenyl)acetamide (Compound 6)
Figure PCTCN2020135716-appb-000046
Figure PCTCN2020135716-appb-000046
目标化合物制备的方式类似于合成2-(3-((7-(4-(乙基(2-羟基乙基)氨基)丁-1-炔-1-基)喹唑啉-4-基)氨基)-1H-吡唑-5-基)-N-(2-氟苯基)乙酰胺。以2-(3-氨基-1H-吡唑-5-基)-N-(4-氟苯基)乙酰胺和2-((4-(4-氯喹唑啉-7-基)丁-3-炔-1-基)(乙基)氨基)乙醇(III-1)为起始原料合成2-(3-((7-(4-(乙基(2-羟基乙基)氨基)丁-1-炔-1-基)喹唑啉-4-基)-1H-吡唑-5-基)-N-(4-氟苯基)乙酰胺(化合物6，52.9mg,收率62％)黄色固体。LC_MS:(ES+):m/z 502.0[M+H] +.t R＝1.488min； 1H NMR(400MHz,DMSO-d6):δ1.10(s,3H),2.64-3.18(m,8H),3.56-3.64(m,2H),3.74-3.83(m,2H),6.77(s,1H),7.16(t,J＝8.8Hz,2H),7.52-7.54(m,1H),7.63-7.67(m,2H),7.74(s,1H),8.56-8.63(m,2H),10.39(s,1H),10.48(br,1H),12.47(s,1H). 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. With 2-(3-amino-1H-pyrazol-5-yl)-N-(4-fluorophenyl)acetamide and 2-((4-(4-chloroquinazolin-7-yl)but-3 -Alkyn-1-yl)(ethyl)amino)ethanol (III-1) as the starting material to synthesize 2-(3-((7-(4-(ethyl(2-hydroxyethyl)amino)but- 1-Alkyn-1-yl)quinazolin-4-yl)-1H-pyrazol-5-yl)-N-(4-fluorophenyl)acetamide (Compound 6, 52.9mg, yield 62%) Yellow solid. LC_MS: (ES+): m/z 502.0[M+H] + .t R = 1.488min; 1 H NMR (400MHz, DMSO-d6): δ1.10(s, 3H), 2.64-3.18( m,8H),3.56-3.64(m,2H),3.74-3.83(m,2H),6.77(s,1H),7.16(t,J=8.8Hz,2H),7.52-7.54(m,1H) , 7.63-7.67 (m, 2H), 7.74 (s, 1H), 8.56-8.63 (m, 2H), 10.39 (s, 1H), 10.48 (br, 1H), 12.47 (s, 1H).
实施例21:合成化合物N-(2,3-二氟苯基)-2-(3-((7-(4-(乙基(2-羟基乙基)氨基)丁-1-炔-1-基)喹唑啉-4-基)氨基)-1H-吡唑-5-基)乙酰胺(化合物4)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)
Figure PCTCN2020135716-appb-000047
Figure PCTCN2020135716-appb-000047
目标化合物制备的方式类似于合成2-(3-((7-(4-(乙基(2-羟基乙基)氨基)丁-1-炔-1-基)喹唑啉-4-基)氨基)-1H-吡唑-5-基)-N-(2-氟苯基)乙酰胺。以2-(3-氨基-1H-吡唑-5-基)-N-(2,3-二氟苯基)乙酰胺和2-((4-(4-氯喹唑啉-7-基)丁-3-炔-1-基)(乙基)氨基)乙醇(III-1)为原料合成N-(2,3-二氟苯基)-2-(3-((7-(4-(乙基(2-羟基乙基)氨基)丁-1-炔-1-基)喹唑啉-4-基)氨基)-1H-吡唑-5-基)乙酰胺(化合物4，16.5mg，产率11％)黄色固体。 LC_MS:(ES+):m/z 520.23[M+H] +.t R＝1.573min； 1H NMR(400MHz,DMSO-d6):δ1.00(t,J＝7.2Hz,3H),2.58-2.62(m,6H),2.79(t,J＝7.2Hz,2H),3.48-3.51(m,2H),3.85(s,2H),4.36(s,1H),6.80(s,1H),7.15-7.24(m,2H),7.51(s,1H),7.72-7.74(m,2H),8.59(s,2H),10.24(s,1H),10.45(s,1H),12.43(s,1H). 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. With 2-(3-amino-1H-pyrazol-5-yl)-N-(2,3-difluorophenyl)acetamide and 2-((4-(4-chloroquinazolin-7-yl) But-3-yn-1-yl)(ethyl)amino)ethanol (III-1) is used as raw material to synthesize N-(2,3-difluorophenyl)-2-(3-((7-(4- (Ethyl(2-hydroxyethyl)amino)but-1-yn-1-yl)quinazolin-4-yl)amino)-1H-pyrazol-5-yl)acetamide (Compound 4, 16.5mg , Yield 11%) Yellow solid. LC_MS: (ES+): m/z 520.23[M+H] + .t R =1.573min; 1 H NMR(400MHz,DMSO-d6):δ1.00(t,J=7.2Hz,3H),2.58- 2.62 (m, 6H), 2.79 (t, J = 7.2 Hz, 2H), 3.48-3.51 (m, 2H), 3.85 (s, 2H), 4.36 (s, 1H), 6.80 (s, 1H), 7.15 -7.24(m,2H),7.51(s,1H),7.72-7.74(m,2H),8.59(s,2H),10.24(s,1H),10.45(s,1H),12.43(s,1H) ).
实施例22：合成化合物2-(乙基(4-(4-((5-(2-((3-氟苯基)氨基)乙基)-1H-吡唑-3-基)氨基)喹唑啉-7-基)丁-3-炔-1-基氨基)乙醇(化合物7)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)
Figure PCTCN2020135716-appb-000048
Figure PCTCN2020135716-appb-000048
目标化合物制备的方式类似于合成2-(3-((7-(4-(乙基(2-羟基乙基)氨基)丁-1-炔-1-基)喹唑啉-4-基)氨基)-1H-吡唑-5-基)-N-(2-氟苯基)乙酰胺。以5-(2-((3-氟苯基)氨基)-乙基)-1H-吡唑-3-胺(2-3)和2-((4-(4-氯喹唑啉-7-基)丁-3-炔-1-基)(乙基)氨基)乙醇(III-1)为起始原料合成2-(乙基(4-(4-((5-(2-((3-氟苯基)氨基)乙基)-1H-吡唑-3-基)氨基)喹唑啉-7-基)丁-3-炔-1-基-氨基)乙醇(化合物7，27mg,收率15％)黄色固体。LC_MS:(ES+):m/z 488.1[M+H] +.t R＝1.898min. 1H NMR(400MHz,DMSO-d6):δ1.00(t,J＝7.2Hz,3H),2.54-2.65(m,6H),2.70-2.82(m,2H),2.87(t,J＝7.2Hz,2H),3.29-3.33(m,2H),3.44-3.54(m,2H),4.27-4.41(m,1H),6.08-6.13(m,1H),6.27-6.32(m,1H),6.37-6.45(m,2H),6.62-6.81(m,1H),7.05-7.11(m,1H),7.51(d,J＝8.8Hz,1H),7.70(s,1H),8.56-8.58(m,2H),10.42(s,1H),12.28(s,1H). 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. With 5-(2-((3-fluorophenyl)amino)-ethyl)-1H-pyrazol-3-amine (2-3) and 2-((4-(4-chloroquinazoline-7- Yl)but-3-yn-1-yl)(ethyl)amino)ethanol (III-1) was used as the starting material to synthesize 2-(ethyl(4-(4-((5-(2-((3 -Fluorophenyl)amino)ethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)but-3-yn-1-yl-amino)ethanol (compound 7, 27mg, yield 15%) yellow solid. LC_MS: (ES+): m/z 488.1[M+H] + .t R = 1.898min. 1 H NMR (400MHz, DMSO-d6): δ1.00(t, J=7.2 Hz,3H),2.54-2.65(m,6H),2.70-2.82(m,2H), 2.87(t,J=7.2Hz,2H), 3.29-3.33(m,2H),3.44-3.54(m, 2H), 4.27-4.41(m,1H), 6.08-6.13(m,1H), 6.27-6.32(m,1H), 6.37-6.45(m,2H), 6.62-6.81(m,1H), 7.05 7.11 (m, 1H), 7.51 (d, J = 8.8Hz, 1H), 7.70 (s, 1H), 8.56-8.58 (m, 2H), 10.42 (s, 1H), 12.28 (s, 1H).
实施例23：合成化合物N-((3-((7-(4-(乙基(2-羟基乙基)氨基)丁-1-炔-1-基)喹唑啉-4-基)氨基)-1H-吡唑-5-基)甲基)-3-氟苯甲酰胺(化合物9)Example 23: Synthesis of compound N-((3-((7-(4-(ethyl(2-hydroxyethyl)amino)but-1-yn-1-yl)quinazolin-4-yl)amino )-1H-pyrazol-5-yl)methyl)-3-fluorobenzamide (compound 9)
Figure PCTCN2020135716-appb-000049
Figure PCTCN2020135716-appb-000049
目标化合物制备的方式类似于合成2-(3-((7-(4-(乙基(2-羟基乙基)氨基)丁-1-炔-1-基)喹唑啉-4-基)氨基)-1H-吡唑-5-基)-N-(2-氟苯基)乙酰胺。以N-((3-氨基-1H-吡唑-5-基)甲基)-3-氟苯甲酰胺(5-1)和2-((4-(4-氯喹唑啉-7-基)丁-3-炔-1-基)(乙基)氨基)乙醇(III-1)为原料合成N-((3-((7-(4-(乙基(2-羟基乙基)氨基)丁-1-炔-1-基)喹唑啉-4-基)氨基)-1H-吡唑-5-基)甲基)-3-氟苯甲酰胺(化合物9)16.8mg，收率6.5％)黄色固体。LC_MS:(ES+):m/z 502.1[M+H] +.t R＝1.992min； 1H NMR(400MHz,DMSO-d6):δ1.00(t,J＝7.0Hz,3H),2.56-2.61(m,6H),2.77-2.80(m,2H),3.46-3.50(m,2H),4.35(t,J＝5.0Hz,1H),4.53-4.54(m,2H),6.79(br,1H),7.38-7.43(m,1H),7.50-7.58(m,2H),7.71-7.78(m,3H),8.52-8.58(m,2H),9.15(t,J＝5.2Hz,1H),10.47-10.48(m,1H),12.47-12.50(m,1H). 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. With N-((3-amino-1H-pyrazol-5-yl)methyl)-3-fluorobenzamide (5-1) and 2-((4-(4-chloroquinazolin-7-yl) )But-3-yn-1-yl)(ethyl)amino)ethanol (III-1) as raw material to synthesize N-((3-((7-(4-(ethyl(2-hydroxyethyl)amino) )But-1-yn-1-yl)quinazolin-4-yl)amino)-1H-pyrazol-5-yl)methyl)-3-fluorobenzamide (compound 9) 16.8mg, yield 6.5%) yellow solid. LC_MS: (ES+): m/z 502.1[M+H] + .t R =1.992min; 1 H NMR(400MHz,DMSO-d6):δ1.00(t,J=7.0Hz,3H),2.56- 2.61(m,6H),2.77-2.80(m,2H),3.46-3.50(m,2H), 4.35(t,J=5.0Hz,1H),4.53-4.54(m,2H),6.79(br, 1H), 7.38-7.43(m,1H),7.50-7.58(m,2H),7.71-7.78(m,3H),8.52-8.58(m,2H),9.15(t,J=5.2Hz,1H) , 10.47-10.48 (m, 1H), 12.47-12.50 (m, 1H).
实施例24：合成化合物3-(((7-(4-(乙基(2-羟基乙基)氨基)丁-1-炔-1-基)喹唑啉-4-基)氨基)甲基)-N-(3-氟苯基)-1H-吡唑啉-5-甲酰胺(化合物8)Example 24: Synthesis of compound 3-((((7-(4-(ethyl(2-hydroxyethyl)amino)but-1-yn-1-yl)quinazolin-4-yl)amino)methyl )-N-(3-Fluorophenyl)-1H-pyrazoline-5-carboxamide (Compound 8)
Figure PCTCN2020135716-appb-000050
Figure PCTCN2020135716-appb-000050
目标化合物制备的方式类似于合成2-(3-((7-(4-(乙基(2-羟基乙基)氨基)丁-1-炔-1-基)喹唑啉-4-基)氨 基)-1H-吡唑-5-基)-N-(2-氟苯基)乙酰胺。以3-(氨基甲基)-N-(3-氟苯基)-1H-吡唑-5-甲酰胺(7-2)和2-((4-(4-氯喹唑啉-7-基)丁-3-炔-1-基)(乙基)氨基)乙醇(III-1)为起始原料合成3-(((7-(4-(乙基(2-羟基乙基)氨基)丁-1-炔-1-基)喹唑啉-4-基)氨基)甲基)-N-(3-氟苯基)-1H-吡唑啉-5-甲酰胺(化合物8，22.5mg，产率13％)浅黄色固体。LC_MS:(ES+):m/z 502.2[M+H] +.t R＝1.835min； 1H NMR(400MHz,DMSO-d6):δ0.99(t,J＝7.2Hz,3H),2.55-2.60(m,6H),2.78(t,J＝7.2Hz,2H),3.44-3.48(m,2H),4.35(s,1H),4.82(d,J＝5.2Hz,2H),6.70(s,1H),6.89(t,J＝8.8Hz,1H),7.31-7.37(m,1H),7.49(d,J＝9.2Hz,1H),7.60(s,1H),7.67(s,1H),7.74(d,J＝12Hz,1H),8.26(d,J＝8.8Hz,1H),8.51(s,1H),8.89(t,J＝5.6Hz,1H),10.24(s,1H),13.45(s,1H). 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. With 3-(aminomethyl)-N-(3-fluorophenyl)-1H-pyrazole-5-carboxamide (7-2) and 2-((4-(4-chloroquinazolin-7-yl )But-3-yn-1-yl)(ethyl)amino)ethanol (III-1) as starting material to synthesize 3-(((7-(4-(ethyl(2-hydroxyethyl)amino) But-1-yn-1-yl)quinazolin-4-yl)amino)methyl)-N-(3-fluorophenyl)-1H-pyrazoline-5-carboxamide (Compound 8, 22.5mg , Yield 13%) Light yellow solid. LC_MS: (ES+): m/z 502.2[M+H] + .t R =1.835min; 1 H NMR(400MHz,DMSO-d6):δ0.99(t,J=7.2Hz,3H), 2.55- 2.60(m,6H), 2.78(t,J=7.2Hz,2H),3.44-3.48(m,2H), 4.35(s,1H), 4.82(d,J=5.2Hz,2H), 6.70(s ,1H), 6.89(t,J=8.8Hz,1H),7.31-7.37(m,1H),7.49(d,J=9.2Hz,1H),7.60(s,1H),7.67(s,1H) ,7.74(d,J=12Hz,1H),8.26(d,J=8.8Hz,1H),8.51(s,1H),8.89(t,J=5.6Hz,1H),10.24(s,1H), 13.45(s,1H).
实施例25：合成化合物2-(乙基(4-(4-((5-(2-((3-氟苯基)氨基)-2-乙氧基)-1H-吡唑-3-基)氨基)喹唑啉-7-基)丁-3-炔-1-基)氨基)磷酸二氢乙酯(化合物10)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)
Figure PCTCN2020135716-appb-000051
Figure PCTCN2020135716-appb-000051
将2-(3-((7-(4-(乙基(2-羟基乙基)氨基)丁-1-炔-1-基)喹唑啉-4-基)氨基)-1H-吡唑-5-基)-N-(3-氟苯基)乙酰胺(化合物3，50mg,0.1mmol)，四氮唑(35mg,0.5mmol)和二叔丁基二乙基磷酰胺(125mg,0.5mmol)加入到3ml N,N-二甲基乙酰胺中，氮气保护下20℃搅拌过夜。加入过氧化氢(60mg,0.5mmol)，所得到的混合物在20℃下再搅拌2小时。向反应液中加入30ml水和30ml乙酸乙酯。收集有机层，用50ml水洗涤，无水硫酸钠干燥,减压浓缩得粗品，通过硅胶柱层析(含5％甲醇的二氯甲烷)纯化得到二叔丁基(2-(乙基(4-(4-((5-(2-((3-氟苯基)氨基)-2-乙氧基)-1H-吡唑-3-基)氨基)喹唑啉-7-基)丁-3-炔-1-基)氨基)乙基)磷酸酯(16mg，收率23％)，产品为淡黄色固体。LC_MS:(ES+):m/z 694.3[M+H] +.t R＝2.189min. The 2-(3-((7-(4-(ethyl(2-hydroxyethyl)amino)but-1-yn-1-yl)quinazolin-4-yl)amino)-1H-pyrazole -5-yl)-N-(3-fluorophenyl)acetamide (compound 3, 50mg, 0.1mmol), tetrazole (35mg, 0.5mmol) and di-tert-butyldiethylphosphoramide (125mg, 0.5 mmol) was added to 3ml of N,N-dimethylacetamide and stirred overnight at 20°C under nitrogen protection. Hydrogen peroxide (60 mg, 0.5 mmol) was added, and the resulting mixture was stirred for another 2 hours at 20°C. 30 ml of water and 30 ml of ethyl acetate were added to the reaction solution. The organic layer was collected, washed with 50ml water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane containing 5% methanol) to obtain di-tert-butyl (2-(ethyl (4 -(4-((5-(2-((3-Fluorophenyl)amino)-2-ethoxy)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)butan- 3-yn-1-yl)amino)ethyl)phosphate (16mg, yield 23%), the product is a pale yellow solid. LC_MS:(ES+):m/z 694.3[M+H] + .t R ＝2.189min.
将二叔丁基(2-(乙基(4-(4-((5-(2-((3-氟苯基)氨基)-2-乙氧基)-1H-吡唑-3-基)氨基)喹唑啉-7-基)丁-3-炔-1-基)氨基)乙基)磷酸酯(16mg,0.023mmol)溶于入3ml二氧六环中，加入0.2ml 4M盐酸二氧六环溶液。氮气保护下20℃搅拌过夜。反应液浓缩，用高效液相色谱法制备得到目标化合物10(5mg，收率37％)，黄色固体。LC_MS:(ES+):m/z 582.3[M+H] +.t R＝1.712min.1H NMR(400MHz,DMSO-d6):δ1.26(t,J＝7.2Hz,3H),3.03(t,J＝7.2Hz,2H),3.27-3.32(m,2H),3.44-3.47(m,4H),3.78(s,2H),4.15-4.19(m,2H),6.73(s,1H),6.87-6.93(m,1H),7.30-7.33(m,1H),7.35-7.39(m,1H),7.60-7.66(m,2H),7.81(s,1H),8.68(d,J＝8.8Hz,1H),8.74(s,1H),10.47(s,1H),11.10(br,1H). Di-tert-butyl(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)ethyl)phosphate (16mg, 0.023mmol) was dissolved in 3ml dioxane, and 0.2ml 4M hydrochloric acid was added. Oxyhexanol solution. Stir at 20°C overnight under nitrogen protection. The reaction solution was concentrated and prepared by high performance liquid chromatography to obtain the target compound 10 (5 mg, yield 37%) as a yellow solid. LC_MS:(ES+):m/z 582.3[M+H] + .t R =1.712min.1H NMR(400MHz,DMSO-d6):δ1.26(t,J=7.2Hz,3H),3.03(t ,J=7.2Hz,2H),3.27-3.32(m,2H),3.44-3.47(m,4H),3.78(s,2H),4.15-4.19(m,2H),6.73(s,1H), 6.87-6.93(m,1H),7.30-7.33(m,1H),7.35-7.39(m,1H),7.60-7.66(m,2H),7.81(s,1H),8.68(d,J=8.8 Hz, 1H), 8.74 (s, 1H), 10.47 (s, 1H), 11.10 (br, 1H).
实施例26：合成化合物2-((4-(4-((5-(2-((2,3-二氟苯基)氨基)-2-氧乙基)-1H-吡唑-3-基)氨基)喹唑啉-7-基)丁-3-炔-1-基)(乙基)氨基)磷酸二氢乙酯(化合物11)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)
Figure PCTCN2020135716-appb-000052
Figure PCTCN2020135716-appb-000052
目标化合物制备的方式类似于合成2-(乙基(4-(4-((5-(2-((3-氟苯基)氨基)-2-乙氧基)-1H-吡唑-3-基)氨基)喹唑啉-7-基)丁-3-炔-1-基)氨基)磷酸二氢乙酯。以N-(2,3-二氟苯基)-2-(3-((7-(4-(乙基(2-羟基乙基)氨基)丁-1-炔-1-基)喹唑啉-4-基)氨基)-1H-吡唑-5-基)乙酰胺为原料2-((4-(4-((5-(2-((2,3-二氟苯基)氨基)-2-氧乙基)-1H-吡唑-3-基)氨基)喹唑啉-7-基)丁-3-炔-1-基)(乙基)氨基)磷酸二氢乙酯黄色固体(化合物11，35毫克，收率 69％)。LC_MS:(ES+):m/z 600.1[M+H] +.t R＝1.645min.1H NMR(400MHz,DMSO-d6):δ1.27(t,J＝7.0Hz,3H),3.06(t,J＝7.2Hz,2H),3.29-3.34(m,2H),3.44-3.52(m,4H),3.91(s,2H),4.16-4.24(m,2H),6.78(s,1H),7.17-7.22(m,2H),7.69-7.72(m,1H),7.77(d,J＝8.8Hz,1H),7.85(s,1H),8.78(d,J＝8.4Hz,1H),8.91(s,1H),10.30(s,1H),11.78(br,1H). 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. N-(2,3-difluorophenyl)-2-(3-((7-(4-(ethyl(2-hydroxyethyl)amino)but-1-yn-1-yl)quinazole 2-((4-(4-((5-(2-((2,3-difluorophenyl)) amino)-1H-pyrazol-5-yl)acetamide as starting material )-2-Oxyethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)but-3-yn-1-yl)(ethyl)amino)ethyl dihydrogen phosphate yellow Solid (Compound 11, 35 mg, yield 69%). LC_MS:(ES+):m/z 600.1[M+H] + .t R =1.645min.1H NMR(400MHz,DMSO-d6):δ1.27(t,J=7.0Hz,3H),3.06(t ,J=7.2Hz,2H),3.29-3.34(m,2H),3.44-3.52(m,4H),3.91(s,2H),4.16-4.24(m,2H),6.78(s,1H), 7.17-7.22(m,2H),7.69-7.72(m,1H),7.77(d,J=8.8Hz,1H),7.85(s,1H),8.78(d,J=8.4Hz,1H),8.91 (s,1H),10.30(s,1H),11.78(br,1H).
实施例27：合成化合物2-(乙基(4-(4-((5-(2-((2-氟苯基)氨基)-2-乙氧基)-1H-吡唑-3-基)氨基)喹唑啉-7-基)丁-3-炔-1-基)氨基)磷酸二氢乙酯(化合物12)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)
Figure PCTCN2020135716-appb-000053
Figure PCTCN2020135716-appb-000053
目标化合物制备的方式类似于合成2-(乙基(4-(4-((5-(2-((3-氟苯基)氨基)-2-乙氧基)-1H-吡唑-3-基)氨基)喹唑啉-7-基)丁-3-炔-1-基)氨基)磷酸二氢乙酯。以2-(3-((7-(4-(乙基(2-羟基乙基)氨基)丁-1-炔-1-基)喹唑啉-4-基)氨基)-1H-吡唑-5-基)-N-(2-氟苯基)乙酰胺为原料合成2-(乙基(4-(4-((5-(2-((2-氟苯基)氨基)-2-乙氧基)-1H-吡唑-3-基)氨基)喹唑啉-7-基)丁-3-炔-1-基)氨基)磷酸二氢乙酯黄色固体化合物(化合物12，30mg，收率70％)。LC_MS:(ES+):m/z 582.2[M+H] +.t R＝1.318min.1H NMR(400MHz,DMSO-d6):δ1.27(t,J＝7.0Hz,3H),3.06(t,J＝7.4Hz,2H),3.29-3.34(m,2H),3.46-3.50(m,4H),3.89(s,2H),4.17-4.22(m,2H),6.78(s,1H),7.16-7.21(m,2H),7.25-7.29(m,1H),7.78(d,J＝8.4Hz,1H),7.84(s,1H),7.89-7.93(m,1H),8.78(d,J＝8.8Hz,1H),8.92(s,1H),10.07(s,1H),11.87(br,1H). 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. As 2-(3-((7-(4-(ethyl(2-hydroxyethyl)amino)but-1-yn-1-yl)quinazolin-4-yl)amino)-1H-pyrazole -5-yl)-N-(2-fluorophenyl)acetamide as starting material to synthesize 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 yellow solid compound (Compound 12, 30mg , Yield 70%). LC_MS:(ES+):m/z 582.2[M+H] + .t R =1.318min.1H NMR(400MHz,DMSO-d6):δ1.27(t,J=7.0Hz,3H),3.06(t ,J=7.4Hz,2H),3.29-3.34(m,2H),3.46-3.50(m,4H),3.89(s,2H),4.17-4.22(m,2H),6.78(s,1H), 7.16-7.21(m,2H),7.25-7.29(m,1H),7.78(d,J=8.4Hz,1H),7.84(s,1H),7.89-7.93(m,1H),8.78(d, J = 8.8Hz, 1H), 8.92 (s, 1H), 10.07 (s, 1H), 11.87 (br, 1H).
化合物I-a的合成路线Synthetic route of compound I-a
Figure PCTCN2020135716-appb-000054
Figure PCTCN2020135716-appb-000054
该路线中，各取代基的定义同前文。In this route, the definition of each substituent is the same as the above.
实施例28：合成化合物2-(3-((7-(4-(乙基(2-羟基乙基)氨基)丁-1-烯-1-基)喹唑啉-4-基)氨基)-1H-吡唑-5-基)-N-(3-氟苯基)乙酰胺(化合物1)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)
Figure PCTCN2020135716-appb-000055
Figure PCTCN2020135716-appb-000055
将2-(3-氨基-1H-吡唑-5-基)-N-(3-氟苯基)乙酰胺(2-2，161mg,0.688mmol)和4-氯-7-碘喹唑啉(1-4，200mg,0.688mmol)加入4ml异丙醇中，氮气保护下加热至90℃搅拌1小时。过滤收集固体沉淀物，滤饼在10ml含10％氨水的甲醇中搅拌10分钟。过滤，滤饼干燥得N-(3-氟苯)-2-(3-((7-碘喹唑啉-4-基)氨基)-1H-吡唑-5-基)乙酰胺(III-a,140mg，收率42％)为白色固体。LC_MS:(ES+):m/z 489.3[M+H] +.t R＝2.270min. 1H NMR(400MHz,DMSO-d6):δ3.77(s,2H),6.80(s,1H),6.87-6.91(m,1H),7.31-7.39(m,2H),7.60-7.64(m,1H),7.86-7.88(m,1H),8.16(s,1H),8.40-8.42(m,1H),8.58(s,1H),10.45(s,1H),10.52(s,1H),12.45(s,1H)。 Combine 2-(3-amino-1H-pyrazol-5-yl)-N-(3-fluorophenyl)acetamide (2-2, 161mg, 0.688mmol) and 4-chloro-7-iodoquinazoline (1-4, 200mg, 0.688mmol) was added to 4ml of isopropanol, heated to 90°C under nitrogen and stirred for 1 hour. The solid precipitate was collected by filtration, and the filter cake was stirred in 10 ml of methanol containing 10% ammonia water for 10 minutes. Filter and dry the filter cake to obtain N-(3-fluorobenzene)-2-(3-((7-iodoquinazolin-4-yl)amino)-1H-pyrazol-5-yl)acetamide (III- a, 140 mg, yield 42%) is a white solid. LC_MS: (ES+): m/z 489.3[M+H] + .t R ＝2.270min. 1 H NMR(400MHz,DMSO-d6):δ3.77(s,2H),6.80(s,1H), 6.87-6.91 (m, 1H), 7.31-7.39 (m, 2H), 7.60-7.64 (m, 1H), 7.86-7.88 (m, 1H), 8.16 (s, 1H), 8.40-8.42 (m, 1H) ), 8.58 (s, 1H), 10.45 (s, 1H), 10.52 (s, 1H), 12.45 (s, 1H).
将N-(3-氟苯)-2-(3-((7-碘喹唑啉-4-基)氨基)-1H-吡唑-5-基)乙酰胺(III-a,70mg,0.14mmol)和(E)-2-(乙基(4-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)叔-3-烯-1-基)氨基)乙醇(V-2,154mg,0.57mmol)加入到N,N-二甲基甲酰胺(2mL)-水(0.5mL)中，室温加入碳酸钾(76mg,0.358mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(10mg,0.014mmol)，氮气保护下升至90℃反应4h。反应液冷至室温，加入20ml水和20ml乙酸乙酯，收集有机层，用20mL盐水洗涤，无水硫酸钠干燥，减压浓缩得到粗残渣，经硅胶柱层析(含10％甲醇的二氯甲烷)纯化得到杂质较少的产品。采用预薄层色谱法(含10％甲醇和1％氨水的二氯甲烷)对产物进行进一步纯化，得2-(3-((7-(4-(乙基(2-羟基乙基)氨基)丁-1-烯-1-基)喹唑啉-4-基)氨基)-1H-吡唑-5-基)-N-(3-氟苯基)乙酰胺(13mg，收率18％)，产品为黄色固体。LC_MS:(ES+):m/z 504.5[M+H] +.t R＝1.603min. 1H NMR(400MHz,DMSO-d6):δ1.24-1.27(m,3H),2.67-2.64(m,2H),3.23-3.33(m,6H),3.69-3.84(m,4H),6.56-6.62(m,1H),6.67-6.83(m,2H),,6.86-6.91(m,1H),7.32-7.37(m,2H),7.60-7.64(m,1H),7.67-7.77(m,2H),8.57(s,2H),9.51(s,1H),10.39(s,1H),10.52(s,1H),12.45(s,1H). The N-(3-fluorobenzene)-2-(3-((7-iodoquinazolin-4-yl)amino)-1H-pyrazol-5-yl)acetamide (III-a, 70mg, 0.14 mmol) and (E)-2-(ethyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) tert-3-ene-1 -Base) amino) ethanol (V-2, 154mg, 0.57mmol) was added to N, N- dimethylformamide (2mL)-water (0.5mL), potassium carbonate (76mg, 0.358mmol) and [1 ,1'-Bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (10mg, 0.014mmol), heated to 90℃ under nitrogen protection and reacted for 4h. The 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. 1 H NMR(400MHz, DMSO-d6): δ1.24-1.27(m,3H), 2.67-2.64(m ,2H),3.23-3.33(m,6H),3.69-3.84(m,4H),6.56-6.62(m,1H),6.67-6.83(m,2H),,6.86-6.91(m,1H), 7.32-7.37(m,2H),7.60-7.64(m,1H),7.67-7.77(m,2H),8.57(s,2H),9.51(s,1H),10.39(s,1H),10.52( s,1H), 12.45(s,1H).
实施例29：生物活性测试Example 29: Biological Activity Test
一、Aurora酶活性抑制实验1. Aurora enzyme activity inhibition experiment
使用Reaction Biology Corporation对Aurora A和B的抑制活性进行测定。将激酶与底物，100μM ATP和从1μM开始的抑制剂化合物的3倍系列稀释液一起孵育。DMSO用作对照。遵循制造商的建议，使用ADP-Glo TM激酶测定系统(Promega，麦迪逊，威斯康星州)对激酶活性进行定量。使用下述级别：对于IC 50而言，I≤10nM,10nM<II≤100nM,100nM<III<1μM,IV≥1μM,具体结果见表1。 The inhibitory activity of Aurora A and B was measured using Reaction Biology Corporation. The kinase is incubated with the substrate, 100 μM ATP, and a 3-fold serial dilution of the inhibitor compound starting from 1 μM. DMSO was used as a control. Following the manufacturer's recommendations, 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<1μM, IV≥1μM, and the specific results are shown in Table 1.
表1：Aurora酶活性抑制结果Table 1: Inhibition results of Aurora enzyme activity
化合物编号Compound number Aurora AAurora A Aurora BAurora B  To 化合物编号Compound number Aurora AAurora A Aurora BAurora B
BarasertibBarasertib IIIIII IIII  To  To  To  To
11 IIII II  To 77 IV IV IIII
22 IIII II  To 88 III III IIIIII
33 IIII IIII  To 99 II IIII
44 IIII II  To 1010 II II
55 IIIIII IIII  To 1111 IIII IIII
66 IIIIII IIII  To 1212 IIIIII IIIIII
Barasertib的结构式如下：The structural formula of Barasertib is as follows:
Figure PCTCN2020135716-appb-000056
Figure PCTCN2020135716-appb-000056
二、癌细胞组蛋白H3磷酸化抑制实验及对人正常心肌细胞系Histone磷酸化的影响分析实验2. Cancer cell histone H3 phosphorylation inhibition experiment and the effect analysis experiment on human normal cardiomyocyte cell line Histone phosphorylation
在转移性SW620结肠癌，U87MG胶质瘤，A375皮肤恶性黑色素瘤，SH-SY5Y神经母细胞瘤或AC16人心肌细胞系中测试了根据本发明的一些抑制剂和Barasertib对蛋白质表达的影响。通过蛋白印迹法(Western blotting)检测反应标记，使用比色检测法测定肿瘤裂解物的蛋白浓度。使用含100mM PMSF蛋白酶抑制剂(Beyotime，ST506-2)的RIPA缓冲液(Beyotime，P0013)制备总蛋白提取物。在SDS-PAGE凝胶的每条泳道上装载25微克蛋白。通过凝胶电泳法分离蛋白，印渍于硝基纤维素膜上，并使用抗组蛋白H3和抗磷酸化组蛋白H3抗体(均来自Cell Signaling Technology)探测。代表性抑制剂对SW620组蛋白H3磷酸化的抑制结果见图1，代表性抑制剂对AC16人心肌细胞组蛋白Histone磷酸化的影响结果见图2。The effects of some inhibitors according to the present invention and Barasertib on protein expression were tested in metastatic SW620 colon cancer, U87MG glioma, A375 skin malignant melanoma, SH-SY5Y neuroblastoma or AC16 human cardiomyocyte cell line. The reaction marker was detected by Western blotting, and the protein concentration of tumor lysate was determined by colorimetric detection. The total protein extract was prepared using RIPA buffer (Beyotime, P0013) containing 100 mM PMSF protease inhibitor (Beyotime, ST506-2). Load 25 micrograms of protein on each lane of the SDS-PAGE gel. 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.
三、细胞周期分析实验3. Cell cycle analysis experiment
碘化丙啶(PI)化学计量地与双链DNA结合，因此基于细胞DNA含量适于测定细胞周期的G1、S和G2/M期中的细胞比例。G0和G1期中的细胞具有二倍体DNA(2N)含量，而G2或有丝分裂期中的细胞具有四倍体DNA(4N)含量。Propidium iodide (PI) 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.
对于PI染色，将3.0×104cells/mL密度的转移性SW620结肠癌，U87MG胶质瘤，A375皮肤恶性黑色素瘤或SH-SY5Y神经母细胞瘤细胞接种，12小时后或将0.1％DMSO加入作为对照或将根据本发明的一些具体抑制剂和对照抑制剂Barasertib以各种浓度(在0.1％DMSO中)加入。将细胞与抑制剂或与DMSO一起孵育24小时。然后将细胞以胰蛋白酶分离，并离心。细胞沉淀以缓冲盐溶液(PBS)洗涤，缓慢加入70％冰浴预冷无水乙醇，轻轻吹打混匀，4℃固定2小时或-20℃固定1小时。再以PBS洗涤后，与碘化丙啶和RNA酶的9∶1溶液一起在黑暗中孵育至少20分钟。DNA测定在具有氩激光(500mW，发射波长488nm)的Becton Dickinson FACS Analyzer中完成；得到的数据以FlowJo software(Flowjo,LLC,Ashland,OR)评价。代表性抑制剂对U87-MG细胞多倍性的影响见图2。For PI staining, metastatic SW620 colon cancer, U87MG glioma, A375 skin malignant melanoma or SH-SY5Y neuroblastoma cells with a density of 3.0×104cells/mL were inoculated, 12 hours later or 0.1% DMSO added as a control Or, some specific inhibitors and control inhibitors Barasertib according to the present invention are added at various concentrations (in 0.1% DMSO). The cells were incubated with inhibitors or with DMSO for 24 hours. The cells were then trypsinized and centrifuged. 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.
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。The description of the above embodiments is only used to help understand the method and the core idea of the present invention. It should be pointed out that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and modifications can be made to the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims (15)

  1. 具有式(IA)、(IB)或(IC)所示结构的含喹唑啉类化合物或者其药学上可接受的盐或者其前药，A quinazoline-containing compound having a structure represented by formula (IA), (IB) or (IC) or its pharmaceutically acceptable salt or its prodrug,
    Figure PCTCN2020135716-appb-100001
    Figure PCTCN2020135716-appb-100001
    其中：among them:
    R 1为选自氢，卤素，氰基，硝基，C1-6烷氧基，C1-6烷基，C1-6卤代烷基，-CF 2OH或-CHFOH的基团； 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为选自氢，卤素或C1-6烷基的基团； R 2 is a group selected from hydrogen, halogen or C1-6 alkyl;
    R 3为选自氢或卤素中的一个或多个基团； R 3 is one or more groups selected from hydrogen or halogen;
    R 6为选自氢，卤素或C1-6烷基的基团； R 6 is a group selected from hydrogen, halogen or C1-6 alkyl;
    p选自0、1、2、3、4、5或6；p is selected from 0, 1, 2, 3, 4, 5 or 6;
    s选自0、1、2、3、4或5；s is selected from 0, 1, 2, 3, 4 or 5;
    n为0、1或2；m为0或1；e、f独立选自0、1或2或3或4或5或6且e+f大于0而小于7；n is 0, 1 or 2; m is 0 or 1; e and f are independently selected from 0, 1 or 2 or 3 or 4 or 5 or 6 and e+f is greater than 0 and less than 7;
    w、t独立选自0、1、2、3、4、5或6且w+t大于0而小于7；y选自0、1、2、3、4、5或6；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为被第一取代基取代或未取代的下列基团：亚甲基、亚乙基或亚乙烯基，其中第一取代基选自卤素、C1-6烷基、C1-6烷氧基；或者L 1为亚乙炔基， 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不存在，或者L 2为-NH-或-NHC(O)-或-C(O)NH-； L 2 does not exist, or L 2 is -NH- or -NHC(O)- or -C(O)NH-;
    R 4和R 5独立地选自氢，被一个、两个、三个或更多个相同或不同的第二取代基取代或未取代的下列基团：C1-6烷基，C1-6烷氧基，膦酰氧基C1-6烷基，C3-6环烷基，C6-16芳烃基，C4-16杂芳烃基，C2-6链烯基，C2-6炔基，C1-6烷基磺酰基、苯磺酰基以及C3-6环烷基C1-4烷基；其中所述第二取代基选自卤素，C1-6烷基，C3-6环烷基，C1-6卤代烷基，羟基，C1-6烷氧基，膦酰氧基，亚磺酰亚胺或S(O) zR 8，其中z为0、1或2；或者， 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 4与R 5结合并与和它们相连的氮原子一起形成被一个、两个、三个或更多个相同或不同的四取代基取代的或未被取代的3至12元的单环或多环杂环，所述多环杂环为并环、螺环或桥环，所述第四取代基选自C1-6烷基，C1-6卤代烷基，C2-6烯基，C2-6卤代烯基，C2-6炔基，C2-6卤代炔基，＝N-OH，＝CR dR d'，卤素，氰基，-OH，膦酰氧基，亚磺酰亚胺，-OR a，-NH 2，-NHR a，杂芳基，杂环基，-(CH 2) qNH 2，-(CH 2) qOH，-COOR a，-CONHR a，-CONH(CH 2) qCOOR a，-NHCOOR a或＝O，R d、R d’独立地为选自氢，烷基或卤素的基团； R 4 and R 5 combine with the nitrogen atom to which they are connected to form a 3- to 12-membered monocyclic ring substituted or unsubstituted with one, two, three or more identical or different tetra-substituents or A polycyclic heterocycle, the polycyclic heterocycle is a fused ring, a spiro ring or a bridged ring, and the fourth substituent is selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 Haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, =N-OH, =CR d R d' , halogen, cyano, -OH, phosphonooxy, sulfinimide, -OR a , -NH 2 , -NHR a , heteroaryl, heterocyclyl, -(CH 2 ) q NH 2 , -(CH 2 ) q OH, -COOR a , -CONHR a , -CONH(CH 2 ) q COOR a , -NHCOOR a or =0, Rd and Rd' are independently groups selected from hydrogen, alkyl or halogen;
    R 7选自氢，卤素，羟基，氰基，硝基，被一个或多个相同或不同的第三取代基取代或未取代的下列 基团：C1-6烷氧基，C1-6烷基，C1-6卤代烷基，-CF 2OH或-CHFOH的基团，C3-6环烷基，C6-16芳烃基，C4-16杂芳烃基，C2-6链烯基，C2-6炔基，C1-6烷基磺酰基、苯磺酰基以及C3-6环烷基C1-4烷基，其中所述第三取代基选自卤素，C1-6烷基，C3-6环烷基，C1-6卤代烷基，羟基，C1-6烷氧基，膦酰氧基，亚磺酰亚胺或S(O) zR 8，其中z为0、1或2； 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;
    所述的R a选自被一个、两个、三个或更多个相同或不同的五取代基取代的或未被取代的下列基团：C1-6烷基，C3-6环烷基，C2-6烯基，-(CH 2) q芳基，含有1-5个选自N，S，P或O的杂原子的杂环烷基的基团，含有1-5个选自N，S，P和O的杂原子的杂芳基，所述第五取代基选自-OH，卤素，硝基，氧代，氰基，膦酰氧基，亚磺酰亚胺，-R 8，-OR 8，-NR 8R 9，-SR 8，-S(O) 2NR 8R 9，-S(O) 2R 8，-NR 8S(O) 2NR 8R 9，-NR 8S(O) 2R 9，-S(O)NR 8R 9，-S(O)R 8，-NR 8S(O)NR 8R 9，-NR 8S(O)R 9，-C(O)NR 8R 9-，-OC(O)R 8，-NR 8R 9C(O)-，C4-10杂环，C6-16芳烃基，C4-16杂芳基，-(CH 2) qOH，-C1-6烷基，-CF 3，-CHF 2或-CH 2F； 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 , -S(O)NR 8 R 9 , -S(O)R 8 , -NR 8 S(O)NR 8 R 9 , -NR 8 S(O)R 9 , -C (O)NR 8 R 9 -, -OC(O)R 8 , -NR 8 R 9 C(O)-, C4-10 heterocyclic ring, C6-16 aromatic hydrocarbon group, C4-16 heteroaryl group, -(CH 2 ) q OH, -C1-6 alkyl, -CF 3 , -CHF 2 or -CH 2 F;
    所述的R 8和R 9在每次出现时各自独立地为选自氢，C1-6烷基，C2-6烯基，C4-8环烯基，C2-6炔基，C3-8环烷基，3至12元单环或多环杂环，-OR 10，-SR 10，卤素，-NR 10R 11，-NO 2和-CN和杂环基； Said 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. Alkyl group, 3- to 12-membered monocyclic or polycyclic heterocyclic ring, -OR 10 , -SR 10 , halogen, -NR 10 R 11 , -NO 2 and -CN and heterocyclic group;
    R 10和R 11在每次出现时独立地为选自氢，膦酰基氧基，被一个、两个、三个或更多个相同或不同的六取代基取代的下列基团：C1-6烷基，C2-6烯基，C4-8环烯基，C2-6炔基，C3-8环烷基，3至12元单环或多环杂环；所述第六取代基选自-OH，-SH，-NH 2，-NO 2或-CN； 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;
    所述的q在每次出现时独立地为0、1、2、3、4、5、6、7、8、9或10；Said q is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 each time it appears;
    当所述的p大于等于2时，所述通式(IA)上相应的亚烷基还可选择地被一个或多个相同或不同的第七取代基取代，所述的第七取代基选自C1-6烷基、C3-8环烷基。When the p is greater than or equal to 2, 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.
  2. 根据权利要求1所述的含喹唑啉类化合物或者其药学上可接受的盐或者其前药，其特征在于：所述含喹唑啉类化合物的结构如下式(I-a)或(I-b)所示：The quinazoline-containing compound or its pharmaceutically acceptable salt or its prodrug according to claim 1, wherein the structure of the quinazoline-containing compound is as shown in formula (Ia) or (Ib) Show:
    Figure PCTCN2020135716-appb-100002
    Figure PCTCN2020135716-appb-100002
    其中，R 1、R 2、R 3、R 4、R 5、R 6、L 2、m、n、p、s的定义同前述权利要求。 Wherein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 2 , m, n, p, s are defined as in the preceding claims.
  3. 根据权利要求1或2所述的含喹唑啉类化合物或者其药学上可接受的盐或者其前药，其特征在于：p为1或2或3且n为1或2。The quinazoline-containing compound or its pharmaceutically acceptable salt or its prodrug according to claim 1 or 2, wherein p is 1 or 2 or 3 and n is 1 or 2.
  4. 根据权利要求1或2所述的含喹唑啉类化合物或者其药学上可接受的盐或者其前药，其特征在于：n为1，L 2是-NHC(O)-或-C(O)NH-；或者，n为2，L 2是-NH-。 The quinazoline-containing compound or its pharmaceutically acceptable salt or its prodrug according to claim 1 or 2, characterized in that: n is 1, L 2 is -NHC(O)- or -C(O ) NH-; or, n is 2, and L 2 is -NH-.
  5. 根据权利要求1或2所述的含喹唑啉类化合物或者其药学上可接受的盐或者其前药，其特征在于：在所述通式(IA)或(IB)或(IC)的与L 2连接的苯环上与L 2相间的位置为F。 The quinazoline-containing compound or its pharmaceutically acceptable salt or its prodrug according to claim 1 or 2, characterized in that: in the formula (IA) or (IB) or (IC) and on the benzene ring attached to L 2 with L 2 phases position F.
  6. 根据权利要求1或2所述的含喹唑啉类化合物或者其药学上可接受的盐或者其前药，其特征在于：R 1、R 2、R 6独立地选自氢、甲基、乙基、甲氧基、乙氧基、氟、氯。 The quinazoline-containing compound or its pharmaceutically acceptable salt or its prodrug according to claim 1 or 2, characterized in that: R 1 , R 2 , R 6 are independently selected from hydrogen, methyl, ethyl Group, methoxy, ethoxy, fluorine, chlorine.
  7. 根据权利要求1所述的含喹唑啉类化合物或者其药学上可接受的盐或者其前药，其特征在于：The quinazoline-containing compound or its pharmaceutically acceptable salt or its prodrug according to claim 1, characterized in that:
    R 4和R 5独立地选自氢、甲基、乙基、丙基、异丙基、丁基、甲氧基、乙氧基、羟基取代甲基、羟基取代乙基、羟基取代异丙基、膦酰氧基甲基、膦酰氧基乙基、乙烯基、乙炔基、乙烯基甲基、乙炔基甲基、甲氧基乙基、甲氧基丙基、三氟甲基甲基、三氟甲基乙基、环丙基甲基、环丙基乙基、环丙基、环丁基、环戊基、环己基、苯基、羟基取代苯基、氯代苯基、甲基取代苯基、甲磺酰基、苯磺酰基、甲基取代苯磺 酰基，且R 4和R 5不同时为氢或烷基。 R 4 and R 5 are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, hydroxy-substituted methyl, hydroxy-substituted ethyl, and hydroxy-substituted isopropyl , Phosphonooxymethyl, phosphonooxyethyl, vinyl, ethynyl, vinylmethyl, ethynylmethyl, methoxyethyl, methoxypropyl, trifluoromethylmethyl, Trifluoromethylethyl, cyclopropylmethyl, cyclopropylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, hydroxy-substituted phenyl, chlorophenyl, methyl-substituted Phenyl, methanesulfonyl, benzenesulfonyl, methyl substituted benzenesulfonyl, and R 4 and R 5 are not hydrogen or alkyl at the same time.
  8. 根据权利要求1所述的含喹唑啉类化合物或者其药学上可接受的盐或者其前药，其特征在于：The quinazoline-containing compound or its pharmaceutically acceptable salt or its prodrug according to claim 1, characterized in that:
    R 4与R 5结合并与和它们相连的氮原子一起形成被一个或两个被第四取代基取代的或未被取代的杂环结构，该杂环结构是5元单杂环、6元单杂环或C7-C8螺环或C5-C9桥环，其中该环结构除含有与R 4、R 5相连的氮外，还可选择性的含有另一个N或含有O。 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, 6-membered heterocyclic ring. A single heterocyclic ring or a C7-C8 spiro ring or a C5-C9 bridged ring, where the ring structure may optionally contain another N or O in addition to the nitrogen connected to R 4 and R 5.
  9. 根据权利要求1或8所述的所述的含喹唑啉类化合物或者其药学上可接受的盐或者其前药，其特征在于：The quinazoline-containing compound or its pharmaceutically acceptable salt or its prodrug according to claim 1 or 8, characterized in that:
    所述第四取代基选自甲基、乙基、丙基、异丙基、丁基、甲氧基、乙氧基、羟基取代甲基、羟基取代乙基、羟基取代异丙基、膦酰氧基甲基、膦酰氧基乙基、乙烯基、乙炔基、乙烯基甲基、乙炔基甲基、甲氧基乙基、甲氧基丙基、三氟甲基甲基、三氟甲基乙基、环丙基甲基、环丙基乙基、＝N-OH、氟、氯、氰基，-OH，膦酰氧基，亚磺酰亚胺。The fourth substituent is selected from methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, hydroxy substituted methyl, hydroxy substituted ethyl, hydroxy substituted isopropyl, phosphonyl Oxymethyl, phosphonooxyethyl, vinyl, ethynyl, vinylmethyl, ethynylmethyl, methoxyethyl, methoxypropyl, trifluoromethylmethyl, trifluoromethyl Base ethyl, cyclopropyl methyl, cyclopropyl ethyl, =N-OH, fluorine, chlorine, cyano, -OH, phosphonooxy, sulfinimide.
  10. 根据权利要求1或2所述的所述的含喹唑啉类化合物或者其药学上可接受的盐或者其前药，其特征在于：R 4和R 5中的一个是氢、甲基、乙基、丙基、异丙基或丁基，另一个是羟基取代甲基、羟基取代乙基、羟基取代异丙基、膦酰氧基甲基、膦酰氧基乙基、膦酰氧基异丙基、羟基取代苯基、苯磺酰基。 The quinazoline-containing compound or its pharmaceutically acceptable salt or its prodrug according to claim 1 or 2, wherein one of R 4 and R 5 is hydrogen, methyl, ethyl Group, propyl, isopropyl or butyl, the other is hydroxy-substituted methyl, hydroxy-substituted ethyl, hydroxy-substituted isopropyl, phosphonooxymethyl, phosphonooxyethyl, phosphonooxyiso Propyl, hydroxy substituted phenyl, benzenesulfonyl.
  11. 一种含喹唑啉类化合物或者其药学上可接受的盐或者其前药，其特征在于：所述含喹唑啉类化合物为选自如下结构所示化合物：A quinazoline-containing compound or its pharmaceutically acceptable salt or a prodrug thereof, characterized in that: the quinazoline-containing compound is selected from compounds represented by the following structures:
    Figure PCTCN2020135716-appb-100003
    Figure PCTCN2020135716-appb-100003
    Figure PCTCN2020135716-appb-100004
    Figure PCTCN2020135716-appb-100004
  12. 如权利要求1至11中任一项权利要求所述的含喹唑啉类化合物或者其药学上可接受的盐或者其前药在制备预防和/或治疗由极光激酶介导的疾病的药物中的应用。The quinazoline-containing compound or its pharmaceutically acceptable salt or its prodrug according to any one of claims 1 to 11 is used in the preparation of a medicine for preventing and/or treating diseases mediated by aurora kinase Applications.
  13. 如权利要求1至11中任一项权利要求所述的含喹唑啉类化合物或者其药学上可接受的盐或者其前药在制备预防和/或治疗肿瘤的药物中的应用。The use of the quinazoline-containing compound or its pharmaceutically acceptable salt or its prodrug according to any one of claims 1 to 11 in the preparation of a drug for preventing and/or treating tumors.
  14. 一种药物组合物，其特征在于：包括一种或多种如权利要求1至11中任一项权利要求所述的含喹唑啉类化合物或者其药学上可接受的盐或者其前药，以及药学可接受的载体。A pharmaceutical composition, characterized by comprising one or more quinazoline-containing compounds according to any one of claims 1 to 11, or pharmaceutically acceptable salts or prodrugs thereof, And a pharmaceutically acceptable carrier.
  15. 一种制备含如权利要求1至11中任一项所述的喹唑啉类化合物或者其药学上可接受的盐或者其前药的中间体，其特征在于，该中间体具有通式(III-a)或(III-b)所示结构：An intermediate for preparing the quinazoline compound or its pharmaceutically acceptable salt or its prodrug as claimed in any one of claims 1 to 11, characterized in that the intermediate has the general formula (III The structure shown in -a) or (III-b):
    Figure PCTCN2020135716-appb-100005
    Figure PCTCN2020135716-appb-100005
    式(III-a)中，R 1、R 2、R 3、R 6、L 2、m、n、s同前文所述；式(III-b)中，R 1、R 2、R 6、R 4、R 5、p同前文所述，X代表氟、氯、溴或碘。 In formula (III-a), 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.
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WO2004058781A1 (en) * 2002-12-24 2004-07-15 Astrazeneca Ab Phosphonooxy quinazoline derivatives and their pharmaceutical use
CN1620296A (en) * 2001-12-24 2005-05-25 阿斯特拉曾尼卡有限公司 Substituted quinazoline derivatives as inhibitors of aurora kinases
CN1835945A (en) * 2003-06-17 2006-09-20 阿斯利康(瑞典)有限公司 Chinazoline derivatives as aurora kinase inhibitors
CN104098551A (en) * 2013-04-03 2014-10-15 广东东阳光药业有限公司 Substituted quinazoline derivative as aurora kinase inhibitor
CN105503837A (en) * 2015-12-31 2016-04-20 中山大学 Substitute quinazolines derivative with Aurora kinase inhibitory activity and application thereof

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CN1620296A (en) * 2001-12-24 2005-05-25 阿斯特拉曾尼卡有限公司 Substituted quinazoline derivatives as inhibitors of aurora kinases
WO2004058781A1 (en) * 2002-12-24 2004-07-15 Astrazeneca Ab Phosphonooxy quinazoline derivatives and their pharmaceutical use
CN1835945A (en) * 2003-06-17 2006-09-20 阿斯利康(瑞典)有限公司 Chinazoline derivatives as aurora kinase inhibitors
CN104098551A (en) * 2013-04-03 2014-10-15 广东东阳光药业有限公司 Substituted quinazoline derivative as aurora kinase inhibitor
CN105503837A (en) * 2015-12-31 2016-04-20 中山大学 Substitute quinazolines derivative with Aurora kinase inhibitory activity and application thereof

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