WO2020147774A1 - 喹唑啉衍生物在制备治疗鼻咽癌药物中的应用 - Google Patents

喹唑啉衍生物在制备治疗鼻咽癌药物中的应用 Download PDF

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WO2020147774A1
WO2020147774A1 PCT/CN2020/072407 CN2020072407W WO2020147774A1 WO 2020147774 A1 WO2020147774 A1 WO 2020147774A1 CN 2020072407 W CN2020072407 W CN 2020072407W WO 2020147774 A1 WO2020147774 A1 WO 2020147774A1
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Prior art keywords
compound
preparation
pharmaceutically acceptable
nasopharyngeal carcinoma
isomers
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PCT/CN2020/072407
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English (en)
French (fr)
Inventor
魏霞蔚
陈新海
张丽
陈兆国
胡伯羽
于衍新
周凯
姜奋
夏尚华
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南京明德新药研发有限公司
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Priority to CN202080008721.0A priority Critical patent/CN113286790B/zh
Publication of WO2020147774A1 publication Critical patent/WO2020147774A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D403/02—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

Definitions

  • the present invention relates to the application of a series of quinazoline compounds in the preparation of drugs for the treatment of nasopharyngeal cancer, in particular to the preparation of compounds represented by formula (I), their isomers or their pharmaceutically acceptable salts in the preparation of drugs for the treatment of nasopharyngeal cancer In the application.
  • HER Human epidermal growth factor receptor
  • EGFR Human epidermal growth factor receptor
  • HER is overexpressed or abnormal in a variety of tumor cells such as breast cancer, non-small cell lung cancer, gastric cancer, pancreatic cancer, ovarian cancer, colorectal cancer, head and neck squamous cell carcinoma, malignant glioma and prostate cancer.
  • the phenomenon of activation has been shown that the overexpression or abnormal activation of HER is closely related to the degree of differentiation, malignancy and prognosis of tumors (Baselga. J., Oncologist 2002, 7, 2-8). Therefore, inhibiting HER has become a hot spot in anti-tumor drug research.
  • Pan-HER tyrosine kinase irreversible inhibitor inhibits HER1, HER2 and HER4 at the same time. Studies have shown that this irreversible inhibition of HER family receptors can not only increase the activity of the drug, but also reduce the development of drug resistance. Some drug-resistant tumor cell lines, such as the H1975 cell line resistant to erlotinib, have a significant inhibitory effect. Currently, the only irreversible pan-HER tyrosine kinase inhibitors that have been approved for marketing are Afatinib and Neratinib. Many inhibitors are in clinical research, such as Poziotinib, Dacomitinib, and Canertinib. There is still unmet market demand.
  • the present invention provides the use of a compound represented by formula (I), its isomers or pharmaceutically acceptable salts thereof in the preparation of drugs for treating nasopharyngeal carcinoma,
  • R 1, R 2 and R 3 are each independently selected from H, F, Cl, Br, I, OH, NH 2, CN and optionally substituted with 1, 2 or 3 R a C 1-3 alkyl group; Or R 2 , R 3 and the C atom to which they are connected together form a 5-6 membered heteroaryl group optionally substituted with 1, 2 or 3 R b ;
  • R 4 is selected from C 1-6 alkyl, C 1-6 alkoxy and 4-6 membered heterocycloalkyl-O-, the C 1-6 alkyl, C 1-6 alkoxy and 4-
  • the 6-membered heterocycloalkyl-O- is independently optionally substituted with 1, 2, or 3 R c ;
  • R a , R b and R c are each independently selected from F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2 or 3 R;
  • R is each independently selected from F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl;
  • the 4-6 membered heterocycloalkyl group and the 5-6 membered heteroaryl group respectively contain 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from N, -O-, -S-, -NH- .
  • R a, R b and R c are each independently selected from F, Cl, Br, I, OH, NH 2, CN, CH 3 and CH 2 CH 3, CH 3 and the CH 2 CH 3 is optionally substituted with 1, 2 or 3 R, and other variables are as defined in the present invention.
  • R a, R b and R c are each independently selected from F, Cl, Br, I, OH, NH 2, CN, CH 3, CF 3, CHF 2, CH 2 F and CH 2 CH 3 , other variables are as defined in the present invention.
  • R 1 , R 2 and R 3 are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 and CH 2 CH 3 , and the CH 3 and CH 2 CH 3 optionally substituted by 1, 2 or 3 R a, the other variables are as defined in the present invention.
  • R 1 , R 2 and R 3 are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 and CH 2 CH 3 , and other variables such as this Defined by the invention.
  • R 4 is selected from And tetrahydrofuranyl-O-, the And tetrahydrofuranyl-O- are each independently optionally substituted with 1, 2 or 3 R c , and other variables are as defined in the present invention.
  • R 4 is selected from Other variables are as defined in the present invention.
  • R 4 is selected from Other variables are as defined in the present invention.
  • R 2 , R 3 and the C atom to which they are connected together form an isoxazole optionally substituted with 1, 2 or 3 R b , and other variables are as defined in the present invention.
  • the use of the above-mentioned compound, its isomers or pharmaceutically acceptable salts thereof in the preparation of drugs for the treatment of nasopharyngeal carcinoma is selected from
  • R 1 , R 2 , R 3 and R 4 are as defined in the present invention.
  • the use of the above-mentioned compound, its isomers or pharmaceutically acceptable salts thereof in the preparation of drugs for the treatment of nasopharyngeal carcinoma is selected from
  • R 1 , R 2 , R 3 and R 4 are as defined in the present invention.
  • the present invention provides the application of the following compounds, isomers or pharmaceutically acceptable salts thereof in the preparation of drugs for treating nasopharyngeal carcinoma
  • the present invention also provides the application of the following compounds, isomers or pharmaceutically acceptable salts thereof in the preparation of drugs for treating nasopharyngeal carcinoma
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues , Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of the compound of the present invention, which is prepared from a compound with specific substituents discovered in the present invention and a relatively non-toxic acid or base.
  • the base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salt or similar salts.
  • the acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, the organic acids include such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid; also include salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic
  • the pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound containing an acid radical or a base by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or an organic solvent or a mixture of both.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers Isomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to this Within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of the present invention.
  • enantiomer or “optical isomer” refers to stereoisomers that are mirror images of each other.
  • cis-trans isomer or “geometric isomer” is caused by the inability to rotate freely because of double bonds or single bonds of ring-forming carbon atoms.
  • diastereomer refers to a stereoisomer in which a molecule has two or more chiral centers and the relationship between the molecules is not mirror images.
  • wedge-shaped solid line keys And wedge-shaped dashed key Represents the absolute configuration of a three-dimensional center, with a straight solid line key And straight dashed key Indicates the relative configuration of the three-dimensional center, using wavy lines Represents a wedge-shaped solid line key Or wedge-shaped dotted key Or use wavy lines Represents a straight solid line key And straight dashed key
  • the following formula (A) means that the compound exists as a single isomer of formula (A-1) or formula (A-2) or as two isomers of formula (A-1) and formula (A-2)
  • the following formula (B) means that the compound exists in the form of a single isomer of formula (B-1) or formula (B-2) or in the form of two of formula (B-1) and formula (B-2) A mixture of isomers exists.
  • the following formula (C) represents that the compound exists as a single isomer of formula (C-1) or formula (C-2) or as two isomers of formula (C-1) and formula (C-2) Exist as a mixture.
  • the compound of the present invention may be specific.
  • tautomer or “tautomeric form” means that at room temperature, the isomers of different functional groups are in dynamic equilibrium and can be transformed into each other quickly. If tautomers are possible (such as in solution), the chemical equilibrium of tautomers can be reached.
  • proton tautomer also called prototropic tautomer
  • proton migration such as keto-enol isomerization and imine-ene Amine isomerization.
  • Valence isomers include some recombination of bonding electrons to carry out mutual transformation.
  • keto-enol tautomerization is the tautomerization between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in enantiomers” refer to one of the isomers or pairs of
  • the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or 96% or greater, or 97% or greater, or 98% or greater, or 99% or greater, or 99.5% or greater, or 99.6% or greater, or 99.7% or greater, or 99.8% or greater, or greater than or equal 99.9%.
  • the term “isomer excess” or “enantiomeric excess” refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomer excess (ee value) is 80% .
  • optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If you want to obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated, and the auxiliary group is cleaved to provide pure The desired enantiomer.
  • the molecule when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with an appropriate optically active acid or base, and then passes through a conventional method known in the art The diastereoisomers are resolved, and then the pure enantiomers are recovered.
  • the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which employs a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • radioisotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • heavy hydrogen can be used to replace hydrogen to form deuterated drugs.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • deuterated drugs have reduced toxic side effects and increased drug stability. , Enhance the efficacy, extend the biological half-life of drugs and other advantages.
  • the conversion of all isotopic compositions of the compounds of the present invention, whether radioactive or not, is included in the scope of the present invention.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by substituents, and may include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of.
  • oxygen it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it can be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis that they can be chemically realized.
  • any variable such as R
  • its definition in each case is independent.
  • the group can optionally be substituted with up to two Rs, and R has independent options in each case.
  • combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • the number of atoms in a ring is generally defined as the number of ring members.
  • “5-7 membered ring” refers to a “ring” in which 5-7 atoms are arranged around.
  • C 1-6 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 6 carbon atoms.
  • the C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl groups, etc.; it may Is monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine).
  • C 1-6 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl) , S-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.
  • C 1-3 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
  • Example C 1- 3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n- propyl and isopropyl) and the like.
  • C 1-6 alkoxy refers to those alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule through an oxygen atom.
  • the C 1-6 alkoxy group includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 and C 3 alkoxy etc. .
  • C 1-6 alkoxy examples include but are not limited to methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy) Oxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexoxy and the like.
  • C 1-3 alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like.
  • Examples of C 1-3 alkoxy include but are not limited to methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy) and the like.
  • 4-6 membered heterocycloalkyl by itself or in combination with other terms means a saturated cyclic group consisting of 4 to 6 ring atoms, with 1, 2, 3 or 4 ring atoms.
  • heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein nitrogen atoms are optionally quaternized, and nitrogen and sulfur heteroatoms can be optionally oxidized (ie NO and S(O) p , p Is 1 or 2). It includes monocyclic and bicyclic ring systems, where the bicyclic ring system includes spiro, fused, and bridged rings.
  • a heteroatom may occupy the connection position of the heterocycloalkyl group with the rest of the molecule.
  • the 4-6 membered heterocycloalkyl includes 5-6, 4-, 5-, and 6-membered heterocycloalkyl and the like.
  • 4-6 membered heterocycloalkyl examples include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithiazinyl, isoxazolidinyl, isothiazolidin
  • 5-6 membered heteroaryl ring and “5-6 membered heteroaryl group” can be used interchangeably in the present invention.
  • the term “5-6 membered heteroaryl group” means a ring consisting of 5 to 6 ring atoms. It is composed of a monocyclic group with a conjugated ⁇ -electron system, in which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may optionally be oxidized (ie NO and S(O) p , p is 1 or 2).
  • the 5-6 membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl group includes 5 membered and 6 membered heteroaryl groups.
  • Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl, etc.) Azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,
  • C n-n+m or C n -C n+m includes any specific case of n to n+m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4, C 5, C 6, C 7, C 8, C 9, C 10, C 11, and C 12, also including any one of n + m to n ranges, for example C 1- 3 comprises a C 1-12 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12, etc.; in the same way, from n to n +m means the number of atoms in the ring is n to n+m, for example, 3-12 membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring , 10-membered ring, 11-member
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (for example, an affinity substitution reaction).
  • representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups, such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters, etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; Arylmethyloxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyldi
  • hydroxyl protecting group refers to a protecting group suitable for preventing side reactions of the hydroxyl group.
  • Representative hydroxy protecting groups include, but are not limited to: alkyl groups, such as methyl, ethyl and tert-butyl; acyl groups, such as alkanoyl groups (such as acetyl); arylmethyl groups, such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and so on.
  • alkyl groups such as methyl, ethyl and tert-butyl
  • acyl groups such as alkanoyl groups (such as acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (P
  • the solvent used in the present invention is commercially available.
  • the present invention uses the following abbreviations: aq stands for water; HATU stands for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent amount; CDI stands for Carbonyl diimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for ethyl acetate Esters; EtOH stands for ethanol; MeOH stands for methanol; CB
  • the compound of the present invention has obvious inhibitory activity on HER1, HER2 and HER4; the compound of the present invention exhibits a significant tumor inhibitory effect and is expected to be used as a new method for the treatment of nasopharyngeal carcinoma.
  • the purpose of this test is to detect the in vitro inhibitory activity of the compound against HER1 (ErbB1), HER2 (ErbB2), and HER4 (ErbB4).
  • the enzymes used in this test are human ErbB1, ErbB2 and ErbB4.
  • Eurofins Pharma Discovery Service provides an activity detection method.
  • the results of the inhibitory activity of the test compounds against HER1, HER2, and HER4 are shown in Table 1.
  • test compound buffer 5 ⁇ L
  • peptide substrate poly(Glu, Tyr) 4:1) (2.5 ⁇ L)
  • ErbB 4-20ng, 2.5 ⁇ L
  • MnCl 2 50mM, 1.25 ⁇ L
  • DH 2 O 3.75 ⁇ L
  • [ ⁇ - 33 P]ATP 10 ⁇ L
  • the compound of the present invention has obvious inhibitory activity on HER1, HER2 and HER4.
  • mice Female BALB/c nude mice, 6-8 weeks old, weighing 17-20 grams; Supplier: Beijing Weitong Lihua Co., Ltd.
  • Human nasopharyngeal carcinoma C666-1 cells cultured in a monolayer in vitro, culture conditions are DM medium with 10% fetal bovine serum, 100U/mL penicillin, 100U/mL0 streptomycin and 2mM glutamine, 37°C, 5% CO 2 culture. Use pancreatin-EDTA for routine digestion and passage twice a week. When the cell saturation is 80%-90%, the cells are collected, counted, and seeded.
  • test compound was prepared as a clear solution of 0.1 mg/mL, and the solvent was 10% NMP (N-methylpyrrolidone) + 10% ethylene glycol stearate + 80% water
  • the experimental index is to investigate whether the tumor growth is inhibited, delayed or cured.
  • the tumor diameter was measured with a vernier caliper every 3 days.
  • TGI (%) reflects the tumor growth inhibition rate.
  • TGI(%) [1-(Average tumor volume at the end of a certain treatment group-average tumor volume at the beginning of the treatment group)/(Average tumor volume at the end of treatment in the solvent control group- The average tumor volume at the start of treatment in the solvent control group)] ⁇ 100%.
  • T/C (%) average tumor volume at the end of a certain treatment group/average tumor volume at the end of the solvent control group ⁇ 100%.
  • the body weight of experimental animals is used as a reference index for indirect determination of drug toxicity.
  • the body weight of the mice in the treatment group of this model showed a downward trend, and there was no other morbidity or death.
  • Tumor growth inhibition is calculated by T/C ⁇ .
  • c.p value is calculated based on tumor volume.
  • the in vivo efficacy of the compound of the present invention in the subcutaneous xenograft tumor model of human nasopharyngeal carcinoma C666-1 cells was evaluated.
  • the compound of the present invention exhibited a significant tumor suppressor effect at 1 mg/kg; it is expected to be used as a nasopharyngeal carcinoma New method of treatment.
  • mice Female BALB/c nude mice, 6-8 weeks old, weighing 17-20 grams; Supplier: Beijing Weitong Lihua Co., Ltd.
  • Human nasopharyngeal carcinoma CNE-1 cells were cultured in a monolayer in vitro with 10% fetal calf serum, 100U/mL penicillin, 100U/mL0 streptomycin and 2mM glutamine in RPMI-1640 medium, 37°C, 5% CO 2 culture. Use pancreatin-EDTA for routine digestion and passage twice a week. When the cell saturation is 80%-90%, the cells are collected, counted, and seeded.
  • CNE-1 cells double-no RPMI-1640 medium
  • test compound was prepared as a clear solution of 0.1 mg/mL, and the solvent was 10% NMP (N-methylpyrrolidone) + 10% ethylene glycol stearate + 80% water
  • the experimental index is to investigate whether the tumor growth is inhibited, delayed or cured.
  • the tumor diameter was measured with a vernier caliper every 3 days.
  • TGI (%) reflects the tumor growth inhibition rate.
  • TGI(%) [1-(Average tumor volume at the end of a certain treatment group-average tumor volume at the beginning of the treatment group)/(Average tumor volume at the end of treatment in the solvent control group- The average tumor volume at the start of treatment in the solvent control group)] ⁇ 100%.
  • T/C (%) average tumor volume at the end of a certain treatment group/average tumor volume at the end of the solvent control group ⁇ 100%.
  • the body weight of experimental animals is used as a reference index for indirect determination of drug toxicity.
  • the body weight of the mice in the treatment group of this model showed a downward trend, and there was no other morbidity or death.
  • Tumor growth inhibition is calculated by T/C.
  • c.p value is calculated based on tumor volume.
  • the in vivo efficacy of the compound of the present invention in human nasopharyngeal carcinoma CNE-1 cell subcutaneous xenograft tumor model was evaluated.
  • the compound of the present invention exhibited a significant tumor suppressor effect at 1 mg/kg; it is expected to be used as a nasopharyngeal carcinoma New method of treatment.

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Abstract

式(I)所示喹唑啉类化合物、其异构体或其药学上可接受的盐在制备治疗鼻咽癌药物中的应用。

Description

喹唑啉衍生物在制备治疗鼻咽癌药物中的应用
相关申请的引用
本申请主张如下优先权：
CN201910049769.5，申请日：2019-01-18。
技术领域
本发明涉及一系列喹唑啉类化合物在制备治疗鼻咽癌药物中的应用，具体涉及式(I)所示化合物、其异构体或其药学上可接受的盐在制备治疗鼻咽癌药物中的的应用。
技术背景
人类表皮生长因子受体(HER,EGFR)是蛋白酪氨酸激酶家族的一员，广泛分布于人体各组织细胞膜上，可以调节细胞的增殖，生长，转移和凋亡。其结构由三部分组成：胞外的配体结合区、跨膜区以及胞内的酪氨酸激酶区。根据受体的结构差异，可以将HER区分为四种亚型，分别为HER1(EGFR,ErbB-1)、HER2(ErbB-2)、HER3(ErbB-3)及HER4(ErbB-4)。研究发现，HER在乳腺癌、非小细胞肺癌、胃癌、胰腺癌、卵巢癌、结直肠癌、头颈部鳞癌、恶性胶质瘤以及前列腺癌等多种肿瘤细胞中均存在过表达或异常激活的现象。另外，研究表明，HER的过表达或异常激活与肿瘤的分化程度、恶性程度及预后等密切相关(Baselga.J.,Oncologist 2002,7,2-8)。因此，抑制HER成为了抗肿瘤药物研究的热点。
目前，已经上市的靶向性的HER抑制剂包括吉非替尼(Gefitinib)、埃罗替尼(Erlotinib)、拉帕替尼(Lapatinib)等。然而，由于这些上市药物有效应答率不高，容易产生耐药性以及存在一些毒副作用，因此迫切需要研发其他具有优良抗肿瘤效果，同时能够克服耐药性，并且耐受性良好的抗肿瘤药物。
Pan-HER酪氨酸激酶不可逆抑制剂同时抑制HER1、HER2以及HER4，研究表明，这种对HER家族受体的不可逆抑制除了能提高药物的活性外，还能减少耐药性的产生，同时对一些产生耐药的肿瘤细胞系，如对埃罗替尼耐药的H1975细胞系，具有显著的抑制效果。目前已经被批准上市的pan-HER酪氨酸激酶不可逆抑制剂只有Afatinib和Neratinib，多个抑制剂处于临床研究，如：Poziotinib,Dacomitinib,Canertinib，仍有未满足的市场需求。
因此，有必要进一步开发Pan-HER酪氨酸激酶不可逆抑制剂，用于癌症的治疗。
发明内容
本发明提供了式(I)所示化合物、其异构体或其药学上可接受的盐在制备治疗鼻咽癌药物中的应用，
Figure PCTCN2020072407-appb-000001
其中，
R 1、R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R a取代的C 1-3烷基；或者R 2、R 3与它们相连的C原子共同形成任选被1、2或3个R b取代的5-6元杂芳基；
R 4选自C 1-6烷基、C 1-6烷氧基和4-6元杂环烷基-O-，所述C 1-6烷基、C 1-6烷氧基和4-6元杂环烷基-O-分别独立地任选被1、2或3个R c取代；
R a、R b和R c分别独立地选自F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R取代的C 1-3烷基；
R各自独立地选自F、Cl、Br、I、OH、NH 2、CN和C 1-3烷基；
所述4-6元杂环烷基和5-6元杂芳基分别包含1、2、3或4个独立选自N、-O-、-S-、-NH-的杂原子或杂原子团。
本发明的一些方案中，上述R a、R b和R c分别独立地选自F、Cl、Br、I、OH、NH 2、CN、CH 3和CH 2CH 3，所述CH 3和CH 2CH 3任选被1、2或3个R取代，其它变量如本发明所定义。
本发明的一些方案中，上述R a、R b和R c分别独立地选自F、Cl、Br、I、OH、NH 2、CN、CH 3、CF 3、CHF 2、CH 2F和CH 2CH 3，其它变量如本发明所定义。
本发明的一些方案中，上述R 1、R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3和CH 2CH 3，所述CH 3和CH 2CH 3任选被1、2或3个R a取代，其它变量如本发明所定义。
本发明的一些方案中，上述R 1、R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3和CH 2CH 3，其它变量如本发明所定义。
本发明的一些方案中，上述R 4选自
Figure PCTCN2020072407-appb-000002
和四氢呋喃基-O-，所述
Figure PCTCN2020072407-appb-000003
Figure PCTCN2020072407-appb-000004
和四氢呋喃基-O-分别独立地任选被1、2或3个R c取代，其它变量如本发明所定义。
本发明的一些方案中，上述R 4选自
Figure PCTCN2020072407-appb-000005
其它变量如本发明所定义。
本发明的一些方案中，上述R 4选自
Figure PCTCN2020072407-appb-000006
Figure PCTCN2020072407-appb-000007
其它变量如本发明所定义。
本发明的一些方案中，上述R 2、R 3与它们相连的C原子共同形成任选被1、2或3个R b取代的异恶唑，其它变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2020072407-appb-000008
选自
Figure PCTCN2020072407-appb-000009
其它变量如本发明所定义。
本发明还有一些方案由上述变量任意组合而来。
本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐在制备治疗鼻咽癌药物中的应用，其选自
Figure PCTCN2020072407-appb-000010
其中，
R 1、R 2、R 3和R 4如本发明所定义。
本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐在制备治疗鼻咽癌药物中的应用，其选自
Figure PCTCN2020072407-appb-000011
其中，
R 1、R 2、R 3和R 4如本发明所定义。
本发明提供了下列化合物、其异构体或其药学上可接受的盐在制备治疗鼻咽癌药物中的应用
Figure PCTCN2020072407-appb-000012
本发明还提供了下列化合物、其异构体或其药学上可接受的盐在制备治疗鼻咽癌药物中的应用
Figure PCTCN2020072407-appb-000013
Figure PCTCN2020072407-appb-000014
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。
除非另有说明，用楔形实线键
Figure PCTCN2020072407-appb-000015
和楔形虚线键
Figure PCTCN2020072407-appb-000016
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2020072407-appb-000017
和直形虚线键
Figure PCTCN2020072407-appb-000018
表示立体中心的相对构型，用波浪线
Figure PCTCN2020072407-appb-000019
表示楔形实线键
Figure PCTCN2020072407-appb-000020
或楔形虚线键
Figure PCTCN2020072407-appb-000021
或用波浪线
Figure PCTCN2020072407-appb-000022
表示直形实线键
Figure PCTCN2020072407-appb-000023
和直形虚线键
Figure PCTCN2020072407-appb-000024
除非另有说明，当化合物中存在双键结构，如碳碳双键、碳氮双键和氮氮双键，且双键上的各个原子均连接有两个不同的取代基时(包含氮原子的双键中，氮原子上的一对孤对电子视为其连接的一个取代基)，如果该化合物中双键上的原子与其取代基之间用波浪线
Figure PCTCN2020072407-appb-000025
连接，则表示该化合物的(Z)型异构体、(E)型异构体或两种异构体的混合物。例如下式(A)表示该化合物以式(A-1)或式(A-2)的单一异构体形式存在或以式(A-1)和式(A-2)两种异构体的混合物形式存在；下式(B)表示该化合物以式(B-1)或式(B-2)的单一异构体形式存在或以式(B-1)和式(B-2)两种异构体的混合物形式存在。下式(C)表示该化合物以式(C-1)或式(C-2)的单一异构体形式存在或以式(C-1)和式(C-2)两种异构体的混合物形式存在。
Figure PCTCN2020072407-appb-000026
本发明的化合物可以存在特定的。除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例 是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。
除非另有规定，环上原子的数目通常被定义为环的元数，例如，“5-7元环”是指环绕排列5-7个原子的“环”。
除非另有规定，术语“C 1-6烷基”用于表示直链或支链的由1至6个碳原子组成的饱和碳氢基团。所述C 1-6烷基包括C 1-5、C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 6和C 5烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1-6烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)、丁基(包括n-丁基，异丁基，s-丁基和t-丁基)、戊基(包括n-戊基，异戊基和新戊基)、己基等。
除非另有规定，术语“C 1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C 1-3烷基包括C 1-2和C 2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1- 3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。
除非另有规定，术语“C 1-6烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至6个碳原子的烷基基团。所述C 1-6烷氧基包括C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 6、C 5、C 4和C 3烷氧基等。C 1-6烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)、丁氧基(包括n-丁氧基、异丁氧基、s-丁氧基和t-丁氧基)、戊氧基(包括n-戊氧基、异戊氧基和新戊氧基)、己氧基等。
除非另有规定，术语“C 1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷氧基包括C 1-2、C 2-3、C 3和C 2烷氧基等。C 1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。
除非另有规定，术语“4-6元杂环烷基”本身或者与其他术语联合分别表示由4至6个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“4-6元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述4-6元杂环烷基包括5-6元、4元、5元和6元杂环烷基等。4-6元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基或高哌啶基等。
除非另有规定，本发明术语“5-6元杂芳环”和“5-6元杂芳基”可以互换使用，术语“5-6元杂芳基”表示由5至6个环原子组成的具有共轭π电子体系的单环基团，其1、2、3或4个环原子为独立选自O、S和 N的杂原子，其余为碳原子。其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。5-6元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-6元杂芳基包括5元和6元杂芳基。所述5-6元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、三唑基(1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基和4H-1,2,4-三唑基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基或嘧啶基(包括2-嘧啶基和4-嘧啶基等)。
除非另有规定，C n-n+m或C n-C n+m包括n至n+m个碳的任何一种具体情况，例如C 1-12包括C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11、和C 12，也包括n至n+m中的任何一个范围，例如C 1-12包括C 1- 3、C 1-6、C 1-9、C 3-6、C 3-9、C 3-12、C 6-9、C 6-12、和C 9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：aq代表水；HATU代表O-(7-氮杂苯并三唑-1-基)-N，N，N'，N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC 代表叔丁氧羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH 3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc 2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl 2代表氯化亚砜；CS 2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；NCS代表1-氯吡咯烷-2,5-二酮；n-Bu 4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点；LDA代表二异丙基胺基锂。
化合物依据本领域常规命名原则或者使用
Figure PCTCN2020072407-appb-000027
软件命名，市售化合物采用供应商目录名称。
技术效果
本发明化合物对HER1,HER2和HER4抑制活性明显；本发明化合物展现了显著的抑瘤作用，有望用作鼻咽癌的治疗新方法。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
实施例1
Figure PCTCN2020072407-appb-000028
合成路线：
Figure PCTCN2020072407-appb-000029
第一步
将化合物1-1(300.0mg,1.28mmol)溶于氯化亚砜(3.0mL,41.45mmol)，加入N,N-二甲基甲酰胺(47.30μL,614.84μmol)，反应液加热至80℃，搅拌1小时。反应液减压浓缩，剩余物室温下加入化合物苯并异噁唑-5-胺(171.8mg,1.28mmol)的异丙醇(10mL)溶液，混合物加热至90℃，搅拌1小时。反应液冷却到20℃，过滤，固体用异丙醇(10mL)洗涤，在空气中干燥得化合物1-2。 1H NMR(400MHz,DMSO-d 6)δ11.51(s,1H),9.35(s,1H),8.90(s,1H),8.72(s,1H),8.23(s,1H),7.85-8.00(m,2H),7.50(s,1H),4.03(s,3H),2.41(s,3H)。LC-MS:m/z＝351.0[M+H] +。
第二步
将化合物1-2(400.0mg,1.14mmol)溶于乙醇(10mL)，加入氢氧化钠(228.4mg,5.71mmol)的水(2mL)溶液，反应液在10℃下搅拌1小时。反应液加入醋酸(0.5mL)和水(10mL)，继续搅拌0.5小时。过滤反应液，固体用水(10mL)洗涤，减压干燥，得到化合物1-3。 1H NMR(400MHz,DMSO-d 6)δ10.89(s,1H),9.67(s,1H),9.38(s,1H),8.42(s,1H),8.08(d,J＝2.8Hz,1H),7.80-7.90(m,1H),7.74(s,1H),7.19(s,1H),7.03(d,J＝8.8Hz,1H),3.97(s,3H)。LC-MS:m/z＝309.0[M+H] +。
第三步
将化合物1-3(100.0mg,324.37μmol)溶于N,N-二甲基乙酰胺(5mL)，加入碳酸钾(89.,7mg,648.74μmol)和化合物A-1(1034mg,308.15μmol)，反应液在70℃下搅拌16小时。反应液冷却到20℃，加水(30mL)稀释，用乙酸乙酯(20mL x 3)萃取。合并的有机相，依次用水(30mL x 3)，饱和食盐水(30mL x 2)洗涤，用无水硫酸钠干燥。过滤，滤液减压浓缩，剩余物用制备薄层层析板分离纯化(二氯甲烷:甲醇＝15:1)，得到实施例1。 1H NMR(400MHz,DMSO-d 6)δ9.68(s,1H),9.46(s,1H),8.44(s,1H),8.23(d,J＝2.4Hz 1H),8.00-8.10(m,1H),7.76(s,1H),7.50(d,J＝9.6Hz 1H),6.77(dd,J 1＝16.8Hz,J 2＝10.4Hz,1H),6.22(dd,J 1＝16.8Hz,J 2＝2.4Hz,1H),5.73(dd,J 1＝10.4Hz,J 2＝2.4Hz,1H),4.90-5.10(m,1H),4.55-4.65(m,2H),3.98(s,3H),2.15-2.35(m,2H),1.80-2.00(m,4H),1.60-1.70(m,1H),1.45-1.55(m,1H)。LC-MS:m/z＝472.1[M+H] +。
实施例2
Figure PCTCN2020072407-appb-000030
合成路线：
Figure PCTCN2020072407-appb-000031
第一步
将化合物1-1(200.0mg,853.94μmol)溶于氯化亚砜(3mL)，加入N,N-二甲基甲酰胺(6μL 85.39μmol)。反应液加热至80℃，搅拌1小时。反应液减压浓缩，剩余物室温下加入3-氯-4-氟苯胺(130.0mg,893.09μmol)的异丙醇(5mL)溶液，混合物加热至90℃并搅拌3小时。反应液减压浓缩，剩余物室温下加入乙酸乙酯(15mL)，悬浊液室温下搅拌1小时，悬浊液过滤后滤饼真空干燥，得到化合物2-2。LC-MS:m/z＝320.1[M+H] +。
第二步
将化合物2-2(50.0mg,156.39μmol)溶于N,N-二甲基甲酰胺(1mL)中，加入碳酸铯(100.0mg,306.92μmol)和化合物A-1(50.0mg,149.07μmol)，反应液在90℃搅拌45分钟。反应液冷却到15℃，倒入水(30mL)中，用乙酸乙酯(20mL x 3)萃取。合并的有机相，依次用水(30mL)和饱和食盐水(30mL)洗涤，用无水硫酸钠干燥。过滤，滤液减压浓缩，剩余物用制备薄层层析板分离纯化(乙酸乙酯:四氢呋喃＝4:1)，得到实施例2。 1H NMR(400MHz,DMSO-d 6)δ9.68(s,1H),8.51(s,1H),8.19(dd,J 1＝6.8Hz,J 2＝2.8Hz,,1H),7.95(s,1H),7.78-7.84(m,1H),7.46(t,J＝9.2Hz,1H),7.21(s,1H),6.77(dd,J 1＝16.4Hz,J 2＝10.4Hz,1H),6.22(dd,J 1＝16.4Hz,J 2＝2.4Hz,1H),5.73(dd,J 1＝10.4Hz,J 2＝2.4Hz,1H),4.97-5.11(m,1H),4.58-4.63(m,2H),3.92(s,3H),2.30-2.38(m,1H),2.20-2.27(m,1H),2.00-2.09(m,2H),1.84-1.97(m,2H),1.65(t,J＝10.4Hz,1H),1.49(t,J＝10.4Hz,1H)。LC-MS:m/z＝483.1[M+H] +。
实施例3
Figure PCTCN2020072407-appb-000032
合成路线：
Figure PCTCN2020072407-appb-000033
第一步
将化合物3-1(4.00g,11.29mmol)溶于N,N-二甲基乙酰胺(20mL)，加入碳酸钾(2.34g,16.94mmol)和化合物A-4(5.60g,14.68mmol)，反应液在75℃下搅拌16小时。反应液冷却到30℃，加入水(60mL)稀释，用乙酸乙酯(60mL x 3)萃取。合并有机相，依次用水溶液(100mL x 3)，饱和食盐水(60mL x 2)洗涤，用无水硫酸钠干燥。过滤，滤液减压浓缩，剩余物用硅胶柱层析法分离纯化(乙酸乙酯:石油醚＝1:1)，得到化合物3-2。 1H NMR(400MHz,CDCl 3)δ8.64(s,1H),8.49(t,J＝8.4Hz,1H),7.26-7.40(m,3H),7.13(s,1H),4.60-4.75(m,1H),4.15-4.40(m,2H),3.94(s,3H),1.75-2.20(m,6H),1.55-1.70(m,2H),1.43(s,9H)。LC-MS:m/z＝563.1[M+H] +。
第二步
将化合物3-2(2.70g,4.80mmol)和吡啶盐酸盐(10.80g,93.46mmol)的混合物，在氮气保护下加热到170℃，搅拌3小时，得到化合物3-3。LC-MS:m/z＝449.0[M+H] +。
第三步
将化合物3-3(13.00g,4.63mmol)和三乙胺(7.00g,69.18mmol)溶于甲醇(20mL)中，加入二碳酸二叔丁酯(9.63g,44.12mmol)，反应液在10℃下搅拌1小时。反应液减压浓缩，剩余物用水(20mL)打浆，过滤得 到的固体依次用饱和氯化铵溶液(10mL x 3)，石油醚(10mL)洗涤，干燥后得到化合物3-4。LC-MS:m/z＝649.1[M+H] +。
第四步
将化合物3-4(3.00g,4.62mmol)溶于甲醇(50mL)中，加入碳酸钾(3.19g,23.09mmol)，在40℃搅拌14小时。向反应液中加水(30mL)，用醋酸调至pH＝6。过滤，固体用水(30mL)洗涤，在空气下干燥得到化合物3-5。 1H NMR(400MHz,DMSO-d 6)δ9.54(brs,1H),8.22(s,1H),7.68(s,1H),7.61(t,J＝8.4Hz,1H),7.50-7.60(m,1H),6.94(s,1H),4.90-5.00(m,1H),4.10-4.20(m,2H),2.10-2.20(m,2H),1.70-2.00(m,4H),1.60-1.70(m,2H),1.44(s,9H)。LC-MS:m/z＝549.1[M+H] +。
第五步
将化合物3-5(70.0mg,127.41μmol)溶于N,N-二甲基甲酰胺(3mL)，加入碳酸钾(35.2mg,254.81μmol)和化合物A-2(64.78mg,254.81μmol)，混合物在70℃下搅拌16小时。反应液冷却到30℃，加水(10mL)，用乙酸乙酯(10mL x 3)萃取。合并的有机相，依次用水(30mL x 2)和饱和食盐水(30mL)洗涤，无水硫酸钠干燥。过滤，滤液减压浓缩，剩余物用硅胶柱层析法(乙酸乙酯:石油醚＝1:1)分离纯化，得到化合物3-6。 1H NMR(400MHz,CDCl 3)δ9.77(s,1H),8.43(s,1H),7.97(s,1H),7.55-7.65(m,2H),7.43(s,1H),4.95-5.05(m,2H),4.75-4.90(m,1H),4.10-4.20(m,2H),2.10-2.20(m,2H),1.90-2.20(m,2H),1.70-1.80(m,2H),1.55-1.70(m,2H),1.44(s,9H)。LC-MS:m/z＝631.1[M+H] +。
第六步
将化合物3-6(35.0mg,55.43μmol)溶于氯化氢的二氧六环溶液(4N,5mL)中，反应液在10℃搅拌0.3小时。反应液减压浓缩，得到化合物3-7的盐酸盐。LC-MS:m/z＝531.0[M+H] +。
第七步
在0℃下，将化合物3-7的盐酸盐(30.0mg,52.84μmol)溶于四氢呋喃(3mL)和水(3mL)的混合溶剂，加入碳酸氢钠(13.3mg,158.51μmol)，缓慢滴入丙烯酰氯(3.8mg,42.27μmol)，反应液在0℃继续搅拌0.5小时。加入甲醇(1mL)淬灭，减压浓缩，剩余物用制备薄层层析板分离纯化(二氯甲烷:甲醇＝10:1)，得到实施例3。 1H NMR(400MHz,DMSO-d 6)δ9.78(s,1H),8.42(s,1H),7.93(s,1H),7.60-7.70(m,2H),7.43(s,1H),6.77(dd,J 1＝16.8Hz,J 2＝10.4Hz,1H),6.19(dd,J 1＝16.8Hz,J 2＝2.0Hz,1H),5.70(dd,J 1＝10.4Hz,J 2＝2.0Hz,1H),4.95-5.05(m,2H),4.85-4.95(m,1H),4.55-4.65(m,2H),2.20-2.35(m,2H),1.80-2.10(m,4H),1.60-1.75(m,1H),1.50-1.60(m,1H)。LC-MS:m/z＝585.1[M+H] +。
实施例4
Figure PCTCN2020072407-appb-000034
合成路线：
Figure PCTCN2020072407-appb-000035
第三步
将化合物3-1(2.00g,5.65mmol)和碳酸钾(1.56g,11.29mmol)加入N,N-二甲基乙酰胺(20mL)中，再加入化合物A-3(4.20g,8.47mmol)。反应加热至70℃，搅拌16小时。反应液冷却到30℃，倒入水(30mL)中，用乙酸乙酯(20mL x 3)萃取。合并有机相，依次用水(30mL x 3)和饱和食盐水(30mL x 3)洗涤，用无水硫酸钠干燥。过滤，滤液减压浓缩，剩余物用硅胶柱层析法分离纯化(石油醚:乙酸乙酯＝1:1)，得到化合物4-2和5-1。
化合物4-2: 1H NMR(400MHz,CDCl 3)δ8.67(s,1H),8.42(t,J＝8.4Hz,1H),7.26-7.40(m,3H),6.96(s,1H),4.80-4.90(m,1H),4.15-4.35(m,2H),4.00(s,3H),2.10-2.35(m,4H),1.90-2.10(m,4H),1.48(s,9H)。根据二维核磁NOE鉴定:哌啶环与氧原子相连碳上的单氢与桥环上的亚甲基氢未见相关，确定为顺式结构。LC-MS:m/z 563.2[M+H] +。
化合物5-1: 1H NMR(400MHz,CDCl 3)δ8.70(s,1H),8.53(t,J＝8.4Hz,1H),7.26-7.40(m,3H),7.21(s,1H),4.70-4.80(m,1H),4.20-4.40(m,2H),4.01(s,3H),2.10-2.20(m,4H),1.85-2.00(m,2H),1.65-1.80(m,2H),1.50(s,9H)。根据二维核磁NOE鉴定:哌啶环与氧原子相连碳上的单氢与桥环上的亚甲基氢相关，确定为反式结构。LC-MS:m/z 563.2[M+H] +。
第四步
将化合物4-2(400.0mg,709.92μmol)溶于氯化氢的二氧六环溶液(4N,6mL)中，反应液在0℃反应0.3小时。反应液减压浓缩，加水(10mL)稀释，用乙酸乙酯(10mL)洗涤。水相用碳酸钾固体调整pH＝10，用乙酸乙酯(10mL x 3)萃取。合并有机相，用无水硫酸钠干燥，滤液减压浓缩，剩余物用制备薄层层析板分离纯化(甲醇:二氯甲烷＝1:10)，得到化合物4-3。 1H NMR(400MHz,DMSO-d 6)δ9.96(s,1H),8.39(s,1H),7.96(s,1H),7.55-7.65(m,2H),7.26(s,1H),4.95-5.00(m,1H),3.90-4.05(m,5H),2.45-2.50(m,2H),2.25-2.35(m,2H),2.10-2.20(m,2H),1.90-2.05(m,2H)。
第五步
在0℃下将化合物4-3(230.0mg,496.41μmol)溶于四氢呋喃(6mL)和水(6mL)的混合溶剂，加入碳酸氢钠(125.1mg,1.49mmol)后，缓慢滴入丙烯酰氯(35.9mg,397.12μmol)。反应液在0℃下，继续搅拌0.5小时。加入甲醇(1mL)淬灭，减压浓缩，剩余物用制备薄层层析板分离纯化(二氯甲烷:甲醇＝10:1)，得到化合物实施例4。 1H NMR(400MHz,DMSO-d 6)δ9.63(s,1H),8.39(s,1H),7.74(s,1H),7.50-7.60(m,2H),7.26(s,1H),6.75(dd,J 1＝16.4Hz,J 2＝10.0Hz,1H),6.19(dd,J 1＝16.4Hz,J 2＝2.4Hz,1H),5.70(dd,J 1＝10.0Hz,J 2＝2.4Hz,1H),4.88-4.90(m,1H),4.50-4.61(m,2H),3.97(s,3H),2.20-2.30(m,2H),1.95-2.15(m,5H),1.80-1.95(m,1H)。LC-MS:m/z＝517.1[M+H] +。
实施例5
Figure PCTCN2020072407-appb-000036
合成路线：
Figure PCTCN2020072407-appb-000037
第一步
参考实施例4第四步得到化合物5-2。 1H NMR(400MHz,DMSO-d 6)δ10.13(s,1H),8.39(s,1H),8.10(s,1H),7.55-7.70(m,2H),7.23(s,1H),4.90-5.00(m,1H),3.90-4.05(m,2H),3.94(s,3H),2.30-2.40(m,2H),2.10-2.20(m,2H),1.80-2.00(m,4H)。
第二步
参考实施例4第五步得到化合物实施例5。 1H NMR(400MHz,DMSO-d 6)δ9.67(s,1H),8.39(s,1H),7.80(s,1H),7.55-7.70(m,2H),7.26(s,1H),6.77(dd,J 1＝16.4Hz,J 2＝10.4Hz,1H),6.23(dd,J 1＝16.4Hz,J 2＝2.4Hz,1H),5.72(dd,J 1＝10.4Hz,J 2＝2.4Hz,1H),4.90-5.10(m,1H),4.55-4.60(m,2H),3.92(s,3H),2.20-2.40(m,2H),1.80-2.10(m,4H),1.66(t,J＝10.4Hz,1H),1.50(t,J＝10.4Hz,1H)。LC-MS:m/z＝517.1[M+H] +。
实施例6
Figure PCTCN2020072407-appb-000038
合成路线：
Figure PCTCN2020072407-appb-000039
第一步
将化合物3-5(150.0mg,273.0μmol)加入到N,N-二甲基甲酰胺(3mL)中，氮气保护下加入钠氢(60％纯度,32.8mg,819.1μmol)，0℃下搅拌30分钟，加入溴乙烷(74.4mg,682.54μmol)，升至15℃继续搅拌30分钟。向反应液中加入水(5mL)淬灭，用乙酸乙酯(10mL x 3)萃取，合并的有机相，依次用水(10mL x 3)，饱和食盐水(10mL x 1)洗涤，用硫酸钠干燥，过滤，滤液减压浓缩，剩余物用硅胶柱层析法分离纯化(乙酸乙酯:石油醚＝1:0)，得到化合物6-2。 1H NMR(400MHz,DMSO-d 6)δ9.62(br s,1H),8.39(s,1H),7.82(s,1H),7.68-7.55(m,1H),7.21(s,1H),4.82(m,1H),4.25-4.19(m,2H),4.18-4.13(m,2H),2.19(m,2H),1.92(m,2H),1.79(m,2H),1.65(m,2H),1.45(s,9H),1.43-1.41(m,3H)。LC-MS:m/z＝577.3[M+H] +。
第二步
将化合物6-2(50.0mg,86.6μmol)加入到乙酸乙酯(0.5mL)中，室温下加入氯化氢的乙酸乙酯溶液(4N,1.7mL)，15℃下搅拌10分钟。反应液减压浓缩得到化合物6-3的盐酸盐。LC-MS:m/z＝477.1[M+H] +.
第三步
参考实施例3第七步得到化合物实施例6。 1H NMR(400MHz,DMSO-d 6)δ9.65(s,1H),8.39(s,1H),7.80(s,1H),7.67-7.55(m,2H),7.21(s,1H),6.78(dd,J 1＝16.8Hz,J 2＝10.4Hz,1H),6.22(dd,J 1＝16.8Hz,J 2＝2.4Hz,1H),5.73(dd,J 1＝10.4Hz,J 2＝2.4Hz,1H),5.00-4.85(m,1H),4.62(m,2H),4.20(q,J＝6.8Hz,2H),3.17(d,J＝5.2Hz,3H),2.39-2.30(m,1H),2.25(m,1H),2.06-1.93(m,2H),1.89(m,2H),1.67(m,1H),1.52(m,1H)。LC-MS:m/z＝531.2[M+H] +。
实施例7
Figure PCTCN2020072407-appb-000040
合成路线：
Figure PCTCN2020072407-appb-000041
第一步
将化合物3-5(150.0mg,273.02μmol)加入到N,N-二甲基甲酰胺(5mL)中，然后加入氟化钾(47.6mg,819.05μmol)，碳酸亚乙酯(72.1mg,819.05μmol)。反应液加热至110℃，搅拌3小时。反应液降至室温，加水(20mL)淬灭，用乙酸乙酯(10mL x 3)萃取，合并的有机相，依次用水(5mL x 3)，饱和食盐水(5mL)洗涤，用硫酸钠干燥，过滤，滤液减压浓缩，剩余物经制备薄层层析板分离纯化(二氯甲烷:甲醇＝20:1)，得到化合物7-2。LC-MS:m/z＝593.2[M+H] +。
第二步
参考实施例6第二步得到化合物7-3盐酸盐。LC-MS:m/z＝493.0[M+H] +。
第三步
参考实施例3第七步得到化合物实施例7。 1H NMR(400MHz,MeOD-d 4)δ8.27(s,1H),7.69(s,1H),7.50(t,J＝8.0Hz,1H),7.35(br d,J＝8.8Hz,1H),7.12(s,1H),6.65(dd,J 1＝16.8Hz,J 2＝10.8Hz,1H),6.24(dd,J 1＝16.8Hz,J 2＝1.6Hz,1H),5.70(dd,J 1＝10.4Hz,J 2＝1.6Hz,1H),5.03-4.90(m,1H),4.66(m,1H),4.52(m,1H),4.14(m,2H),3.94-3.83(m,2H),2.38-2.27(m,1H),2.23(m,1H),2.07-1.93(m,2H),1.89(m,2H),1.77(m,1H),1.66(m,1H).LC-MS:m/z＝547.1[M+H] +。
实施例8
Figure PCTCN2020072407-appb-000042
合成路线：
Figure PCTCN2020072407-appb-000043
第一步
参考实施例7第一步得到化合物8-2。LC-MS:m/z＝619.2[M+H] +。
第二步
参考实施例6第二步得到化合物8-3盐酸盐。LC-MS:m/z＝519.0[M+H] +。
第三步
参考实施例3第七步得到化合物实施例8。 1H NMR(400MHz,MeOD-d 4)δ8.39(s,1H),7.82(s,1H),7.62(t,J ＝8.4Hz,1H),7.46(dd,J 1＝8.8Hz,J 2＝1.6Hz,1H),7.19(s,1H),6.76(dd,J 1＝16.4Hz,J 2＝10.4Hz,1H),6.36(dd,J 1＝16.8Hz,J 2＝1.6Hz,1H),5.81(dd,J 1＝10.4Hz,J 2＝1.6Hz,1H),5.23(m,1H),5.08-4.94(m,1H),4.78(m,1H),4.68-4.61(m,1H),4.06(s,2H),4.04-3.99(m,1H),3.93(m,1H),2.46-2.36(m,2H),2.32(m,1H),2.26-2.19(m,1H),2.18-2.10(m,1H),2.06-1.94(m,3H),1.87(m,1H),1.76(m,1H).LC-MS:m/z＝573.3[M+H] +。
生物化学检测：体外评价
实验例1：酶活性评价
本试验目的是检测化合物对HER1(ErbB1)，HER2(ErbB2)，HER4(ErbB4)的体外抑制活性。本试验采用的酶为人源ErbB1，ErbB2和ErbB4，Eurofins Pharma Discovery Service提供活性检测方法，测试化合物对HER1，HER2，HER4抑制活性结果如表1所示。
实验步骤和方法(96孔板)：
加入5倍稀释的测试化合物缓冲液(5μL)，多肽底物poly(Glu,Tyr)(4:1)(2.5μL)，ErbB(4-20ng,2.5μL)，MnCl 2(50mM,1.25μL)，dH 2O(3.75μL)，[γ- 33P]ATP(10μL)，在30℃孵化10分钟。加入3％磷酸终止反应，取10μL标本转移至Filtermate A，用75mM磷酸清洗滤片3次，用甲醇清洗1次，滤片转移到密封塑料口袋，加入闪烁液混合物(4mL)，在闪烁发光计数仪检测发出的光子强度，将酶样本的cpm(次数/分钟)与内控样品的cpm进行比较，光子强度的高低反映了酪氨酸激酶活性的强弱。
表1：本发明化合物体外酶活性筛选试验结果
化合物 HER1IC 50(nM) HER2IC 50(nM) HER4IC 50(nM)
实施例2 11 5 2
实施例3 18 11 10
实施例4 40 69 61
实施例5 6.0 b 5.5 b 3.5 b
实施例6 12 5 3
实施例7 6 3 6
实施例8 16 5 3
b:测试2次的平均值。
结论：本发明化合物对HER1,HER2和HER4抑制活性明显。
实验例2：人鼻咽C666-1细胞皮下异种移植肿瘤BALB/c裸小鼠模型的体内药效学研究:
实验目的：研究本专利待测化合物对人鼻咽癌C666-1细胞皮下异种移植瘤在BALB/c裸小鼠模型体内药效进行评估
实验动物：雌性BALB/c裸小鼠,6－8周龄，体重17-20克；供应商：北京维通利华有限公司提供
实验方法与步骤:
2.1细胞培养
人鼻咽癌C666-1细胞，体外单层培养，培养条件为DM培养基中加10％胎牛血清，100U/mL青霉素，100U/mL0链霉素和2mM谷氨酰胺，37℃，5％CO 2培养。一周两次用胰酶-EDTA进行常规消化处理传代。当细胞饱和度为80％-90％时，收取细胞，计数，接种。
2.2肿瘤细胞接种(肿瘤接种)
将0.1ml(4×10 6)C666-1细胞(双无DM培养基)皮下接种于每只小鼠的右后背，接种后第3天开始给药
2.3受试物的配制:
受试化合物配制成0.1mg/mL的澄清溶液，溶媒为10％NMP(N-甲基吡咯烷酮)+10％乙二醇硬脂酸酯+80％水
2.4肿瘤测量和实验指标
实验指标是考察肿瘤生长是否被抑制、延缓或治愈。每3天用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：V＝0.5a×b 2，a和b分别表示肿瘤的长径和短径。
化合物的抑瘤疗效用TGI(％)或肿瘤增殖率T/C(％)评价。TGI(％)，反映肿瘤生长抑制率。TGI(％)的计算：TGI(％)＝[1-(某处理组给药结束时平均瘤体积－该处理组开始给药时平均瘤体积)/(溶剂对照组治疗结束时平均瘤体积－溶剂对照组开始治疗时平均瘤体积)]×100％。
肿瘤增殖率T/C(％)：计算公式如下：T/C(％)＝某处理组给药结束时平均瘤体积/溶剂对照组治疗结束时平均瘤体积×100％。
2.5统计分析
统计分析，包括每个组的每个时间点的肿瘤体积的平均值和标准误(SEM)(具体数据见表5-1)。治疗组在试验结束时给药后第21天表现出最好的治疗效果，因此基于此数据进行统计学分析评估组间差异。两组间比较用T-test进行分析，三组或多组间比较用one-way ANOVA进行分析，经检验，F值有显著性差异，应用Games-Howell法进行检验。用SPSS 17.0进行所有数据分析。p<0.05认为有显著性差异。
2.6试验结果
2.6.1死亡率、发病率及体重变化情况
实验动物的体重作为间接测定药物毒性的参考指标。在此模型治疗组小鼠体重有下降趋势，无其他发病或死亡现象。
2.6.2抗肿瘤药效评价指标
表2本发明化合物对人鼻咽癌C666-1细胞皮下异种移植瘤模型的抑瘤药效评价
(基于给药后第21天肿瘤体积计算得出)
Figure PCTCN2020072407-appb-000044
注：
a.平均值±SEM。
b.肿瘤生长抑制由T/C\计算。
c.p值根据肿瘤体积计算。
2.7试验结论和讨论
在本实验评价了本发明化合物在人鼻咽癌C666-1细胞皮下异种移植瘤模型中的体内药效，本发明化合物在1mg/kg展现了显著的抑瘤作用；有望用作鼻咽癌的治疗新方法。
实验例3 人鼻咽CNE-1细胞皮下异种移植肿瘤BALB/c裸小鼠模型的体内药效学研究:
实验目的：研究本专利待测化合物对人鼻咽癌CNE-1细胞皮下异种移植瘤在BALB/c裸小鼠模型体内药效进行评估
实验动物：雌性BALB/c裸小鼠,6－8周龄，体重17-20克；供应商：北京维通利华有限公司提供
实验方法与步骤:
3.1细胞培养
人鼻咽癌CNE-1细胞，体外单层培养，培养条件为RPMI-1640培养基中加10％胎牛血清，100U/mL青霉素，100U/mL0链霉素和2mM谷氨酰胺，37℃，5％CO 2培养。一周两次用胰酶-EDTA进行常规消化处理传代。当细胞饱和度为80％-90％时，收取细胞，计数，接种。
3.2肿瘤细胞接种(肿瘤接种)
将0.1ml(8×10 6)CNE-1细胞(双无RPMI-1640培养基)皮下接种于每只小鼠的右后背，接种后第3天开始给药。
3.3受试物的配制:
受试化合物配制成0.1mg/mL的澄清溶液，溶媒为10％NMP(N-甲基吡咯烷酮)+10％乙二醇硬脂酸酯+80％水
3.4肿瘤测量和实验指标
实验指标是考察肿瘤生长是否被抑制、延缓或治愈。每3天用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：V＝0.5a×b 2，a和b分别表示肿瘤的长径和短径。
化合物的抑瘤疗效用TGI(％)或肿瘤增殖率T/C(％)评价。TGI(％)，反映肿瘤生长抑制率。TGI(％)的计算：TGI(％)＝[1-(某处理组给药结束时平均瘤体积－该处理组开始给药时平均瘤体积)/(溶剂对照组治疗结束时平均瘤体积－溶剂对照组开始治疗时平均瘤体积)]×100％。
肿瘤增殖率T/C(％)：计算公式如下：T/C(％)＝某处理组给药结束时平均瘤体积/溶剂对照组治疗结束时平均瘤体积×100％。
3.5统计分析
统计分析，包括每个组的每个时间点的肿瘤体积的平均值和标准误(SEM)(具体数据见表5-1)。治疗组在试验结束时给药后第21天表现出最好的治疗效果，因此基于此数据进行统计学分析评估组间差异。两组间比较用T-test进行分析，三组或多组间比较用one-way ANOVA进行分析，经检验，F值有显著性差异，应用Games-Howell法进行检验。用SPSS 17.0进行所有数据分析。p<0.05认为有显著性差异。
3.6试验结果
3.6.1死亡率、发病率及体重变化情况
实验动物的体重作为间接测定药物毒性的参考指标。在此模型治疗组小鼠体重有下降趋势，无其他发病或死亡现象。
3.6.2抗肿瘤药效评价指标
表3本发明化合物对人鼻咽癌CNE-1细胞皮下异种移植瘤模型的抑瘤药效评价
(基于给药后第21天肿瘤体积计算得出)
Figure PCTCN2020072407-appb-000045
注：
a.平均值±SEM。
b.肿瘤生长抑制由T/C计算。
c.p值根据肿瘤体积计算。
4.7试验结论和讨论
在本实验评价了本发明化合物在人鼻咽癌CNE-1细胞皮下异种移植瘤模型中的体内药效，本发明化合物在1mg/kg展现了显著的抑瘤作用；有望用作鼻咽癌的治疗新方法。

Claims (13)

  1. 式(I)所示化合物、其异构体或其药学上可接受的盐在制备治疗鼻咽癌药物中的应用，
    Figure PCTCN2020072407-appb-100001
    其中，
    R 1、R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R a取代的C 1-3烷基；或者R 2、R 3与它们相连的C原子共同形成任选被1、2或3个R b取代的5-6元杂芳基；
    R 4选自C 1-6烷基、C 1-6烷氧基和4-6元杂环烷基-O-，所述C 1-6烷基、C 1-6烷氧基和4-6元杂环烷基-O-分别独立地任选被1、2或3个R c取代；
    R a、R b和R c分别独立地选自F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R取代的C 1-3烷基；R各自独立地选自F、Cl、Br、I、OH、NH 2、CN和C 1-3烷基；
    所述4-6元杂环烷基和5-6元杂芳基分别包含1、2、3或4个独立选自N、-O-、-S-、-NH-的杂原子或杂原子团。
  2. 根据权利要求1所述化合物、其异构体或其药学上可接受的盐在制备治疗鼻咽癌药物中的应用，其中，R a、R b和R c分别独立地选自F、Cl、Br、I、OH、NH 2、CN、CH 3和CH 2CH 3，所述CH 3和CH 2CH 3任选被1、2或3个R取代。
  3. 根据权利要求2所述化合物、其异构体或其药学上可接受的盐在制备治疗鼻咽癌药物中的应用，其中，R a、R b和R c分别独立地选自F、Cl、Br、I、OH、NH 2、CN、CH 3、CF 3、CHF 2、CH 2F和CH 2CH 3。
  4. 根据权利要求1～3任一项所述化合物、其异构体或其药学上可接受的盐在制备治疗鼻咽癌药物中的应用，其中，R 1、R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3和CH 2CH 3，所述CH 3和CH 2CH 3任选被1、2或3个R a取代。
  5. 根据权利要求4所述化合物、其异构体或其药学上可接受的盐在制备治疗鼻咽癌药物中的应用，其中，R 1、R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3和CH 2CH 3。
  6. 根据权利要求1～3任一项所述化合物、其异构体或其药学上可接受的盐在制备治疗鼻咽癌药物中的应用，其中，R 4选自
    Figure PCTCN2020072407-appb-100002
    和四氢呋喃基-O-，所述
    Figure PCTCN2020072407-appb-100003
    和四氢呋喃基-O-分别独立地任选被1、2或3个R c取代。
  7. 根据权利要求6所述化合物、其异构体或其药学上可接受的盐在制备治疗鼻咽癌药物中的应用，其中，R 4选自
    Figure PCTCN2020072407-appb-100004
  8. 根据权利要求1～3任一项所述化合物、其异构体或其药学上可接受的盐在制备治疗鼻咽癌药物中的应用，其中，R 2、R 3与它们相连的C原子共同形成任选被1、2或3个R b取代的异恶唑。
  9. 根据权利要求1所述化合物、其异构体或其药学上可接受的盐在制备治疗鼻咽癌药物中的应用，其中，结构单元
    Figure PCTCN2020072407-appb-100005
    选自
    Figure PCTCN2020072407-appb-100006
  10. 根据权利要求1～9任一项所述化合物、其异构体或其药学上可接受的盐在制备治疗鼻咽癌药物中的应用，其选自
    Figure PCTCN2020072407-appb-100007
    其中，
    R 1、R 2、R 3和R 4如权利要求1～7所定义。
  11. 根据权利要求10所述化合物、其异构体或其药学上可接受的盐在制备治疗鼻咽癌药物中的应用，其选自
    Figure PCTCN2020072407-appb-100008
    其中，
    R 1、R 2、R 3和R 4如权利要求10所定义。
  12. 下列化合物、其异构体或其药学上可接受的盐在制备治疗鼻咽癌药物中的应用
    Figure PCTCN2020072407-appb-100009
  13. 根据权利要求12所述化合物、其异构体或其药学上可接受的盐在制备治疗鼻咽癌药物中的应用，其选自
    Figure PCTCN2020072407-appb-100010
    Figure PCTCN2020072407-appb-100011
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WO2015154725A1 (zh) * 2014-04-11 2015-10-15 四川海思科制药有限公司 喹唑啉衍生物及其制备方法和在医药上的应用
WO2019120213A1 (zh) * 2017-12-19 2019-06-27 南京明德新药研发股份有限公司 喹唑啉衍生物及其应用

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015154725A1 (zh) * 2014-04-11 2015-10-15 四川海思科制药有限公司 喹唑啉衍生物及其制备方法和在医药上的应用
WO2019120213A1 (zh) * 2017-12-19 2019-06-27 南京明德新药研发股份有限公司 喹唑啉衍生物及其应用

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