WO2014043866A1 - 噻吩[2,3-d]嘧啶衍生物、其制备方法及其用途 - Google Patents

噻吩[2,3-d]嘧啶衍生物、其制备方法及其用途 Download PDF

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WO2014043866A1
WO2014043866A1 PCT/CN2012/081611 CN2012081611W WO2014043866A1 WO 2014043866 A1 WO2014043866 A1 WO 2014043866A1 CN 2012081611 W CN2012081611 W CN 2012081611W WO 2014043866 A1 WO2014043866 A1 WO 2014043866A1
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alkyl
hydrogen
phenyl
group
formula
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PCT/CN2012/081611
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English (en)
French (fr)
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卢灿忠
雍建平
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中国科学院福建物质结构研究所
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Priority to US14/241,056 priority Critical patent/US9434741B2/en
Priority to PCT/CN2012/081611 priority patent/WO2014043866A1/zh
Priority to EP12884787.8A priority patent/EP2835372B1/en
Publication of WO2014043866A1 publication Critical patent/WO2014043866A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the present invention relates to a novel structure of a thiophene [2,3-d]pyrimidine derivative containing an isoxazole heterocycle and a pharmaceutical composition containing the same, and specifically: the thiophene [2, a 3-d] pyrimidine derivative or a pharmaceutical composition thereof, which comprises a colorectal cancer cell line (HCT-116) and a human lung cancer cell line (A549), which can be used as a drug for treating diseases such as tumors and cancers associated with tyrosine kinases or Lead compound.
  • HCT-116 colorectal cancer cell line
  • A549 human lung cancer cell line
  • Epidermal growth factor (EGF) binding to the Epidermal Growth Factor Receptor (EGFR) activates tyrosine kinase activity and thus activates responses that lead to cell proliferation. Overexpression and increased activity of EGFR will result in uncontrolled cell division.
  • Epidermal growth factor receptor tyrosine kinase is the first discovered protein tyrosine kinase, widely distributed in the cell membrane of various tissues of human body, in most tumors (eg bladder cancer, non-small cell lung cancer) Overexpression in ovarian cancer, breast cancer, gastric cancer, esophageal cancer, etc., the intracellular region of EGFR has a binding site for adenosine triphosphate (ATP), and EGFR inhibitors can compete with ATP binding sites to inhibit The acidification of EGFR blocks the transmission of downstream signals, thereby inhibiting the growth, differentiation and metastasis of tumor cells. Targeted treatment of tumors targeting EGFR receptors is one of the most active areas of research in cancer therapy today, and significant effects have been achieved in clinical studies.
  • ATP adenosine triphosphate
  • Patent WO 2009/104027 discloses that a series of thiophene [2,3-d]pyrimidine derivatives have inhibitory tyrosine kinase activity; Patent WO 2009/104026 discloses certain thiophenes with phenylamino substitution at the 4-position of thiophene [2,3-d] pyrimidine The [2, 3_d] pyrimidine derivative has anticancer activity.
  • Patent WO 2009/104027 discloses that a series of thiophene [2,3-d]pyrimidine derivatives have inhibitory tyrosine kinase activity; Patent WO 2009/104026 discloses certain thiophenes with phenylamino substitution at the 4-position of thiophene [2,3-d] pyrimidine The [2, 3_d] pyrimidine derivative has anticancer activity.
  • the invention is based on the patent WO2009/104027 and the patent WO2009/104026, introducing an isoxazole heterocycle into the nucleus of the porphin [2,3_d] pyrimidine, and synthesizing a series of thiophenes containing an isoxazole heterocycle [2, 3-d] Pyrimidine derivatives, in vitro inhibition of colorectal cancer cell line (HCT-116) and human lung cancer cell line (A549) showed that the compound had a strong colorectal cancer cell line at a concentration of 1 ⁇ 10 - 4 ( (HCT-116). ) and human lung cancer cell line ( ⁇ 549) activity. It can be used as a candidate compound or lead compound for anticancer and oncology drugs. Summary of the invention
  • Activity studies have shown that the compound has activity as a colorectal cancer cell line (HCT-116) and a human lung cancer cell line (A549) as an active ingredient.
  • the invention is achieved by the following technical solutions:
  • and 11 2 may be the same or different and each independently selected from hydrogen, d- 6 alkyl, d- 6 alkoxy, halogenated d- 6 alkyl, halogenated d- 6 alkoxy or hydroxy substituted d- 6
  • R 2 together with the carbon atom to which they are attached form a 4 to 6 membered carbocyclic or heterocyclic ring, said carbocyclic or heterocyclic ring optionally being substituted by R 11 ; said heterocyclic ring containing at least one selected from N, 0 or S Hetero atom
  • Z is -NR 5 -, C (R 6 ) 2 , - S- or - 0- , wherein R 5 is hydrogen or d 6 alkyl, R 6 is the same or different, and is selected from hydrogen, d- 6 alkyl, a halogenated d 6 alkyl group or a hydroxy substituted d- 6 alkyl group;
  • R 3 is selected from the group consisting of hydrogen, halogen, d- 6 alkyl, d- 6 alkoxy, halogenated d- 6 alkyl, halogenated d- 6 alkoxy or hydroxy substituted d- 6 alkyl, n is 0-5 Integer
  • R 4 is selected from hydrogen, d_ 6 alkyl, d_ 6 alkoxy, halo or haloalkyl group d_ 6 d_ 6 alkoxy, optionally substituted with R 'substituted aryl or optionally R 1 "is Heteroaryl
  • R', R 8 , R', R 1 " or R 11 are each independently selected from the group consisting of hydrogen, hydroxy, decyl, aryl, amino, d- 6 alkylamino, bis(d- 6 alkyl)amino, nitro , halogen, d 6 alkyl, d 6 alkoxy, d 6 alkylthio, carboxy, halogenated d 6 alkyl, halogenated d 6 alkoxy, halogenated d- 6 alkylthio, hydroxy substituted d - 6 alkyl groups.
  • RR 2 may be the same or different and each independently selected from hydrogen, d- 6 alkyl, d- 6 alkoxy, halogenated d- 6 alkyl, haloalkoxy, aryl or aryl substituted by R 7 , or
  • R 2 together with the carbon atom to which they are attached form a 4 to 6 membered carbocyclic ring, which is optionally substituted by hydrogen, d- 6 alkyl, halogen, nitro or amino;
  • Z is -NR 5 -, C (R 6 ) 2 , -S- or -0-, wherein R 5 is hydrogen or d 3 alkyl, R 6 is the same or different and is selected from hydrogen, d- 3 alkyl, Or a hydroxy-substituted d- 3- alkyl group;
  • R 3 is selected from hydrogen, halogen, d- 6 alkyl, d- 6 alkoxy or halogenated d- 6 alkyl or halogenated d- 6 alkoxy, and n is an integer from 0 to 5;
  • R 4 is selected from the group consisting of hydrogen, d- 6 alkyl, d- 6 alkoxy, halogenated d- 6 alkyl, aryl or aryl substituted by R'.
  • RR 2 may be the same or different and each independently selected from hydrogen, d- 6 alkyl, CHI alkoxy, halogenated d- 6 alkyl, haloalkoxy, phenyl or phenyl substituted by R 7 , or
  • R 4 is selected from the group consisting of hydrogen, d- 6 alkyl, d- 6 alkoxy, halogenated d- 6 alkyl, phenyl or phenyl substituted by R'.
  • ⁇ and R 2 are each independently selected from hydrogen, d- 3- alkyl, phenyl or phenyl substituted by R 7 , more preferably hydrogen, decyl, ethyl, propyl, isopropyl Base, butyl, isobutyl, tert-butyl or phenyl;
  • Z is - NH-, CH 2 or -0-;
  • R 3 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, decyl, decyloxy or trifluoromethyl, and n is preferably from 1 to 4, more preferably from 2 to 3.
  • R 4 is selected from hydrogen, d- 6 alkyl, d- 6 alkoxy or halogenated d- 6 alkyl, phenyl or substituted phenyl.
  • ⁇ and R 2 may be the same or different and each independently selected from a d- 6 alkyl group, a phenyl group or a phenyl group substituted with R 7 , more preferably hydrogen, decyl group, ethyl group, undertiary Butyl, phenyl,
  • Z is - NH- or - 0-
  • R 3 is preferably ortho or para to the isoxazole ring, more preferably 4-fluoro, 4-chloro, 2-chloro, 4-bromo, 2,4-dichloro, 4-indenyl, 4-anthracene Base, hydrogen, 4-trifluorodecyl or 2,4-dimethoxy;
  • R 4 is selected from hydrogen, decyl or phenyl.
  • ⁇ selected from hydrogen, fluorenyl, phenyl
  • R 2 is selected from hydrogen, decyl, ethyl or tert-butyl.
  • R', R 8 , R9 or R 1 " are each independently selected from the group consisting of hydrogen, hydroxy, aryl, tt, d- 6 alkylamino, bis(d- 6 alkyl)amino, halogen, d- 6 alkyl, d- 6 alkoxy, d- 6 alkylthio, carboxy, halogenated d- 6 alkyl, halogenated d- 6 alkoxy or substituted d- 6 alkylthio.
  • R', R 8 , R' or R 1 " are each independently selected from the group consisting of hydrogen, hydroxy, decyl, cyano, amino, halogen, d- 6 alkyl, alkoxy, d- 6 alkylthio, carboxy.
  • R 7 , R 8 , R' or R 1 " are each independently selected from the group consisting of hydrogen, hydroxy, cyano, amino, halogen, d- 6 alkyl, d- 6 alkoxy, d- 6 alkane sulphur Base or carboxyl group.
  • the isoxazole heterocyclic-containing thiophene [2, 3-d] pyrimidine compound represented by the formula (I) may be selected from a pharmaceutically acceptable acid to form a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salts includes, but is not limited to, salts formed with inorganic acids, such as hydrochlorides, phosphates, salts, hydrobromides, sulfates, sulfinates, nitrates, And a salt thereof, preferably a hydrochloride, a nitrate, a salt or a salt.
  • salts with organic acids such as lactate, oxalate, malate, maleate, fumarate, tartrate, succinate, citrate, sulfonate, p-toluene Sulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, trifluoroacetic acid or amino acid; alkanoate such as citrate, acetate, etc., or
  • n is a salt of 0-4, and the like.
  • Preferred organic acid salts are selected from the group consisting of citrate, acetate, oxalate, citrate, fumarate, maleate, malate, lactate, tartrate, p-benzoate , trifluoroacetate or amino acid salt.
  • pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium.
  • solvate includes hydrates and alcoholates.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the thiophene [2,3-d]pyrimidine compound represented by the above formula (I), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable An acceptable, inert, non-toxic excipient or carrier or diluent.
  • the pharmaceutical composition further comprises one or more selected from the group consisting of a filler, a disintegrant, a lubricant, a glidant, an effervescent agent, a flavoring agent, and a preservative. And pharmaceutically acceptable auxiliary materials for the coating material.
  • the present invention also provides a pharmaceutical preparation comprising the thiophene [2,3-d]pyrimidine compound represented by the above formula (I), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable Accepted, inert, non-toxic excipients or carriers or diluents.
  • the pharmaceutical preparation according to the present invention is characterized in that the preparation is preferably a solid oral preparation, a liquid oral preparation or an injection.
  • the preparation is selected from the group consisting of a tablet, a tablet, an enteric tablet, a chewable tablet, an orally disintegrating tablet, a capsule, a granule, an oral solution, a water injection needle, a lyophilized powder for injection, a large infusion solution. Or a small infusion.
  • the present invention also provides a thiophene[2,3-d]pyrimidine compound represented by the formula (1-4) of Claims 1-4, or a pharmaceutically acceptable salt thereof, particularly for use as a medicament, Tumor/cancer drugs.
  • the present invention also provides a thiophene[2,3-d]pyrimidine compound represented by the formula (I), or a pharmaceutically acceptable salt or solvate thereof, of any of the foregoing, for use as a medicament, in particular for use in therapy A drug that inhibits EGFR transitional expression and/or activity overactive tumors.
  • the present invention also provides a thiophene [2,3-d]pyrimidine compound represented by the formula (I), or a pharmaceutically acceptable salt or solvate thereof, according to any one of the preceding claims, for use in the preparation of a medicament for use in antitumor or cancer. application.
  • the tumor or cancer is selected from the group consisting of: bladder cancer, non-small cell lung cancer, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, head and neck cancer, colon cancer, pharyngeal cancer and pancreatic cancer. And, more preferably, non-small cell lung cancer.
  • the present invention also provides a thiophene [2,3-d]pyrimidine compound and/or a pharmaceutically acceptable salt or solvate represented by the formula (I) according to any of the preceding claims, for use in the preparation of a colorectal cancer cell line.
  • a thiophene [2,3-d]pyrimidine compound and/or a pharmaceutically acceptable salt or solvate represented by the formula (I) according to any of the preceding claims for use in the preparation of a colorectal cancer cell line.
  • Use of (HCT-116) and drugs for human lung cancer cell line (A549) activity are useful for use in the preparation of a colorectal cancer cell line.
  • the present invention also provides a method for preparing an isoxazole heterocyclic-containing oxime 11- [2,3-d]pyrimidine compound represented by the formula (I), characterized in that the method comprises the following steps:
  • the reaction temperature is -2 (TC to reflux conditions, preferably room temperature to reflux conditions).
  • the organic solvent is an aromatic hydrocarbon, a halogenated hydrocarbon, C "C 6 lower alcohols, tetrahydrofuran or Yue sulfoxide (DMF).
  • the solvent is selected from benzene, Yue benzene, diethyl benzene Yue , dichlorodecane, chloroform, isopropanol, tetrahydrofuran or DMF, more preferably isopropanol.
  • the basic acid binding agent is an organic base or an inorganic base
  • the organic base is selected from the group consisting of triethylamine, tripropylamine, DMAP, potassium t-butoxide, etc.
  • the inorganic base is selected from potassium carbonate. , sodium hydride, sodium carbonate, and the like.
  • a preferred acid binding agent is triethylamine.
  • the intermediate 3-substituted phenyl 5-hydroxyindolyl-isoxazole of the formula ( ⁇ ⁇ ) is prepared by the following method:
  • the basic acid binding agent is selected from an organic base selected from the group consisting of an organic base or an inorganic base, and the organic base is selected from the group consisting of triethylamine, tripropylamine, DMAP, DMF, N-mercapto-based, etc.;
  • the inorganic base is selected from the group consisting of potassium carbonate, sodium hydride, sodium carbonate and the like.
  • a more preferred basic acid binding agent is triethylamine.
  • the reaction temperature is from 0 to reflux temperature, preferably from room temperature to reflux temperature.
  • the intermediate 3-substituted phenyl 5-aminoindolyl-isoxazole of formula (IV) is prepared by the following method:
  • an isoxazole compound of the formula (( ⁇ ) obtained (preferably obtained by the aforementioned method) is reacted with a sulfonyl chloride to obtain a compound of the formula (V), and according to a preferred embodiment of the present invention, the sulfonyl chloride in the step (3) It is selected from the group consisting of sulfonyl chloride, benzenesulfonyl chloride, substituted benzenesulfonyl chloride (e.g., halobenzenesulfonyl chloride, alkylbenzenesulfonyl chloride), and the like, more preferably sulfonyl chloride.
  • the reaction temperature is -5 degrees to reflux temperature, preferably room temperature to reflux temperature.
  • the reaction solvent is selected from the group consisting of benzene, toluene, halogenated aromatic hydrocarbons, halogenated alkanes (e.g., chloroform or dichloromethane), tetrahydrofuran, acetonitrile, and ionic liquids. More preferably, the reaction is refluxed in a dichloromethane system.
  • the preferred reaction solvent in the step (5) is water or an organic solvent (e.g., an alcohol, a halogenated hydrocarbon, an aromatic hydrocarbon, etc.) or a mixture thereof, preferably a reaction system of ethanol and water.
  • an organic solvent e.g., an alcohol, a halogenated hydrocarbon, an aromatic hydrocarbon, etc.
  • the preferred synthetic route is as follows:
  • the 5,6-disubstituted-4-chloro-thiophene [2,3-d]pyrimidine represented by the formula ⁇ is prepared by the following procedure: (1) 3-amino 4, 5-disubstituted ⁇ " ⁇ "2-decanoic acid oxime ester (VII) and cerium acetate form a 5,6-disubstituted thienopyrimidinone compound ( ⁇ ) under the action of reagent 1, preferably, the reaction temperature is 0 degree To reflux temperature, more preferably from room temperature to reflux temperature;
  • the compound (VIII) forms a 5,6-disubstituted-4-chloro-thiophene[2,3-d]pyrimidine represented by the formula II under the action of the reagent 2, preferably, the reaction temperature is 0 degree to The reflux temperature is more preferably room temperature to reflux temperature. Specifically, the following reaction formula can be seen.
  • Reagent 1 is selected from the group consisting of: benzene, toluene, ethylene glycol monoterpene ether, ethylene glycol dioxime ether, ethylene glycol monoethyl ether, ethylene glycol diethyl ether, ethanol, 1,2-dichloroethane Alkane and ionic liquid, etc.;
  • Reagent 2 is selected from the group consisting of: thionyl chloride, trichlorooxan, pentachlorobenzene substituted reagent, and the like.
  • a compound of the formula (VI) is prepared by refluxing a zinc powder and ammonium chloride in an ethanol/water system; (6) 3-amino-4,5-disubstituted anthracene-2-indole The ester (VII) and cerium acetate form a 5,6-disubstituted thienopyrimidinone compound (VIII) under the action of the reagent 1;
  • a pharmaceutically acceptable salt or solvate of the compound of formula (I) can be formed.
  • the compounds of formula I include, but are not limited to, their optical isomers, racemates and mixtures thereof.
  • the halogen or halogen atom is selected from the group consisting of fluorine, chlorine or bromine.
  • the alkyl group is a linear or branched alkyl group, such as d- 6 alkyl, preferably d- 3 alkyl, including but not limited to decyl, ethyl, propyl, isopropyl, butyl, iso Butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and the like.
  • the 4 to 6 membered carbocyclic ring is selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl. It is preferably a cyclopentyl group or a cyclohexyl group.
  • said heterocyclic ring containing at least one hetero atom selected from N, 0, S is selected from the group consisting of tetrahydrofuran, tetrahydromethane, azetidine, pyrrolidinyl, acridine, tetrahydropyrrole, 3-Dihydrothiazole, 1, 3-dihydrooxazole, piperidine, piperidine, thiophene*, thiazine, preferably piperazinyl, morphinyl or piperidinyl.
  • the aryl group is a monocyclic or bicyclic aromatic hydrocarbon group, for example a C 6 14 aryl group, preferably phenyl or naphthyl, more preferably phenyl.
  • the heteroaryl group is a monocyclic or bicyclic heteroaromatic hydrocarbon group, wherein the hetero atom-containing ring is preferably a 5- or 6-membered heteroaryl group containing at least one, preferably 1 to 4 or S or 0
  • An aromatic ring of a hetero atom preferably a pyridyl group, a pyrimidinyl group, a quinolinyl group, an isoquinolinyl group, a quinazoline group, a quinalinyl group, a fluorenyl group, a pyrrolyl group, a thiol group, a furan group Benzo, benzofuranyl, benzothiazolidine 11 , thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, furazolyl, thiadiazolyl, tetrazolyl, etc., more preferably It is a pyrroly
  • an effective amount refers to: an amount of the at least one compound and/or at least one pharmaceutically acceptable salt that is effective to "treat" a disease or discomfort in an individual. It can reduce the number of cancer or tumor cells; reduce the size of tumors; inhibit or prevent the invasion of tumor cells into peripheral organs. For example: tumors spread into soft tissues or bones; inhibit or prevent tumor metastasis; inhibit or prevent tumor growth; To alleviate one or more symptoms associated with cancer; reduce morbidity and mortality; improve quality of life; or a combination of the above effects.
  • An effective amount may be an amount that reduces the symptoms of the disease by inhibiting EGFR activity.
  • the effects of in vivo experiments can be measured by assessing, for example, survival, time to Di sease progression ion (TPP), response rate (RR) duration of response, and/or quality of life.
  • Effective amount may vary with the route of administration, the amount of excipients, and other drugs Combined changed.
  • the term "effective amount” may also mean a dose effective to inhibit overexpression and/or activity of EGFR by said at least one compound and/or at least one pharmaceutically acceptable salt thereof.
  • the compounds of the present invention all have antitumor and anticancer activities, in particular, have anti-colorectal cancer cell beads (HCT-116) activity and anti-human lung cancer cell A549 activity.
  • the compounds of the present invention have inhibitory activity at a concentration of 10"M", and the activity of the compound of the example can be 50% or more, preferably 60% or more, more preferably 80% or more.
  • Most of the compounds are for colorectal cancer cell beads (HCT- 116) It has strong inhibitory activity with human lung cancer cell A549.
  • compound S-101 is fine for colorectal cancer at 1 10"M concentration.
  • the inhibition rate of the bead was 68.8%, and the inhibition rate of human lung cancer cell A549 was 88%, and the compound S-3 was at the concentration of 1 ⁇ 10" ⁇ against the colorectal cancer cell beads (HCT-116).
  • the inhibition rate of the human lung cancer cell A549 was as high as 89.4%, and the inhibition rate of the human lung cancer cell A549 was as high as 89.4%.
  • the compounds of the invention are useful as drug candidates or lead compounds for the treatment of tumors, cancers. Specific embodiment
  • AVANCE III NMR 400MHz, DMS0-d 6 , TMS for internal standard
  • ion trap liquid quality instrument DECAX-30000 LCQ Deca XP
  • Shimadzu FTIR-8400S made by Shimadzu Corporation, Japan
  • XT5 digital display Micro-melting point measuring instrument manufactured by Beijing Keyi Electro-optical Instrument Factory, temperature uncorrected
  • adjustable wavelength microplate microplate reader Molecular Devies SPECTRAMAX190
  • Trichloroacetic acid (TCA), acetic acid and Triis base unbuffer were domestic analytical reagents.
  • TCA Triis base unbuffer
  • Example 1 ( ⁇ ⁇ ) Synthesis of intermediate 3-substituted phenyl-5-hydroxyindenyl-isoxazole and intermediate of formula (IV) 3-substituted phenyl 5-aminoindenyl-isoxazole
  • R 3 is H as an example:
  • the dimethyl acetate monoethyl ether and 2.14 g (1,8 g (1 g) were added to a 250 mL round bottom single-necked round bottom flask, followed by the addition of 100 mL of ethylene glycol monoethyl ether and 2.14 g (1. 14 g (10 g (10mmo l)).
  • 20mmo l) Barium acetate the system is refluxed under stirring, after the TLC detection reaction is completed, the system is cooled, and then distilled under reduced pressure to 30 mL of ethylene glycol monoethyl ether.
  • the system is refrigerated for several hours, and a large amount of solid is precipitated and filtered.
  • the filter cake was washed several times with refrigerated diethyl ether, and the filter cake was dried in vacuo and used directly in the next step.
  • the remaining compound was synthesized according to the synthesis of 5-mercapto-4-[(3-phenyl-isoxazol-5-yl)-methoxy-]-thiophene [2,3-d]pyrimidine.
  • the structures were characterized by IR, ' ⁇ MR, ESI-MS and other analytical methods.
  • the physical property constants and optical data of the preferred compounds are described in the form of a list: Structure, code and structure of the compound
  • the colorectal cancer cell line (HCT-116) in logarithmic growth phase is inoculated into a 96-well culture plate, and after adhering for 24 hours, 1 10 - 4 M of the drug is added.
  • the concentration was set to 3 replicate wells, and the corresponding concentration of physiological saline control and cell-free zero-adjustment were set.
  • the tumor/cancer cells were cultured for 72 hours at 37 ° C and 5% CO 2 ; (2) The culture plate was taken out.
  • the cells were fixed with 10% cold triacetic acid (TCA) solution per well and placed at 4 °C for 1 hour; (3) The fixative was discarded, washed 5 times with distilled water, and naturally dried in air; (4) Then added by 1% The SRB solution prepared from glacial acetic acid was stained at room temperature for 15 minutes; (5) The supernatant was removed, washed 5 times with 1% acetic acid solution, and air-dried; (6) Finally, the solution was added to the Tris solution and oscillated on the plate shaker. minute. The absorbance at a wavelength of 560 nm (A 56 neighbor:) was measured using a tunable wavelength microplate reader. The enzyme inhibition rate was calculated using the following formula.
  • the compound of the formula (I) or a salt thereof was measured to inhibit the activity of colorectal cancer cell beads (HCT-116) and human lung cancer cell A549 at a concentration of 1 ⁇ 10 -4 Torr.
  • the experimental results are shown in Table 5 and Table 6 below.

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Abstract

提供一种式（I）所示的含异噁唑杂环的噻吩［2,3-d］嘧啶衍生物或其药学上可接受的盐，它们的制备方法、用途和药物组合物。该类化合物可用于治疗肿瘤、癌症等疾病。

Description

噻吩 [2, 3-d]嘧啶衍生物、 其制备方法及其用途
技术领域
本发明涉及一类结构新颖的含异噁唑杂环的噻吩 [2, 3-d]嘧啶衍生物及含该类衍生物的药物 组合物及其用途， 具体而言： 该类噻吩 [2, 3-d]嘧啶衍生物或其药物组合物具有抑制大肠癌细胞 株（HCT-116)和人肺癌细胞株（A549) , 可作为治疗与酪氨酸激酶有关的肿瘤、 癌症等疾病的药物 或先导化合物。 背景技术
表皮生长因子（Epidermal Growth Factor, EGF) 与表皮生长因子受体（Epidermal Growth Factor Receptor, EGFR)结合可以激活酪氨酸激酶的活性，并因此激活导致细胞增殖的反应。 EGFR 的过度表达和活性增强都将导致不可控的细胞分裂。
表皮生长因子受体酪氨酸激酶 (EGFR-TK)是最早发现的蛋白酪氨酸激酶， 广泛地分布于人体 各组织的细胞膜上， 其在大多数肿瘤（如： 膀胱癌、 非小细胞肺癌、 卵巢癌、 乳腺癌、 胃癌、 食 道癌等）中过表达， EGFR的胞内区有三磷酸腺苷（ATP)的结合位点， EGFR抑制剂可以竟争性的与 ATP结合位点相结合， 从而抑制 EGFR的碑酸化， 阻断下游信号的传导， 进而抑制肿瘤细胞的生 长、 分化和转移。 以 EGFR受体为靶点进行靶向治疗肿瘤是当今癌症治疗中研究十分活跃的领域 之一， 在临床研究中也已取得了显著的疗效。
专利 WO2009/104027 公开了一系列噻吩 [2, 3_d]嘧啶衍生具有抑制酪氨酸激酶活性； 专利 WO2009/104026公开了噻吩 [2, 3_d]嘧啶的 4-位带有苯氨基取代的某些噻吩 [2, 3_d]嘧啶衍生物 具有抗癌活性。 上述文献引入本文作为参考。
本发明基于专利 WO2009/104027和专利 WO2009/104026 , 将异噁唑杂环引入瘘吩 [2, 3_d]嘧 啶母核，合成了一系列含异噁唑杂环的噻吩 [2, 3-d]嘧啶衍生物，体外抑制大肠癌细胞株 (HCT-116) 和人肺癌细胞株（A549)活性表明该类化合物在 1 χ 10—4Μ 浓度下具有较强的抑大肠癌细胞株 (HCT-116)和人肺癌细胞株 (Α549)活性。 可作为抗癌、 肿瘤药物的候选化合物或先导化合物。 发明内容
本发明的目的在于，提供了如式（I)所示的含异噁唑杂环的噻吩 [2, 3-d]嘧啶化合物。 经过活 性研究表明， 以该化合物作为活性成分具有抑大肠癌细胞株 (HCT-116)和人肺癌细胞株 (A549)活 性。 本发明通过如下技术方案实现：
一种式（I)所示的含异噁唑杂环的噻吩 [2, 3-d]嘧啶衍生物， 或其药学上可接受的盐， 或溶剂 化物:
Figure imgf000003_0001
其中： 和112可以相同或不同，各自独立地选自氢， d_6烷基， d_6烷氧基、 卤代 d_6烷基、 卤代 d— 6烷氧基或羟基取代的 d-6的烷基， 任选被 R7取代的芳基或任选被 R8取代的杂芳基； 或者！^和 R2与其相连的碳原子一起形成 4至 6元碳环或杂环， 所述碳环或杂环任选被 R11 取代； 所述杂环含有至少 1个选自 N， 0或 S的杂原子；
Z为 -NR5-， C (R6) 2， - S-或 - 0- , 其中 R5为氢或 d_6烷基， R6相同或不同， 选自氢、 d-6的烷 基、 卤代 d_6烷基或者羟基取代的 d-6的烷基；
R3选自氢、 卤素、 d_6烷基、 d_6烷氧基、 卤代 d_6烷基、 卤代 d_6烷氧基或羟基取代的 d-6的烷基， n为 0~5的整数；
R4选自氢、 d_6烷基、 d_6烷氧基、 卤代 d_6烷基或卤代 d_6烷氧基， 任选被 R'取代的芳基 或任选被 R1"取代的杂芳基；
R'、 R8、 R'、 R1"或 R11各自独立地选自氢， 羟基， 巯基， 氛基， 氨基， d— 6烷基氨基， 二（d— 6 烷基）氨基， 硝基， 卤素， d_6烷基， d_6烷氧基， d_6烷硫基， 羧基， 卤代 d_6烷基， 卤代 d_6 烷氧基， 卤代 d— 6烷硫基， 羟基取代的 d-6的烷基。
根据本发明的优选技术方案， 式（I)中：
R R2可以相同或不同， 各自独立地选自氢， d_6烷基， d_6烷氧基、 卤代 d_6烷基、 卤代 烷氧基， 芳基或被 R7取代的芳基， 或者
！^和 R2与其相连的碳原子一起形成 4至 6元碳环， 所述碳环任选被氢， d_6烷基， 卤素， 硝基或氨基取代；
Z为 -NR5-， C (R6) 2， -S-或 -0-, 其中 R5为氢或 d_3烷基， R6相同或不同， 选自氢， d-3的烷 基， 或者羟基取代的 d_3烷基；
R3选自氢、 卤素， d_6烷基、 d_6烷氧基或卤代 d_6烷基或卤代 d_6烷氧基， n为 0-5的整 数；
R4选自氢， d_6烷基， d_6烷氧基， 卤代 d_6烷基， 芳基或被 R'取代的芳基。
根据本发明的优选技术方案， 式（I)中： R R2可以相同或不同， 各自独立地选自氢， d_6烷基， CH烷氧基、 卤代 d_6烷基、 卤代 烷氧基， 苯基或被 R7取代的苯基， 或者
或者！^和 R2与其相连的碳原子一起形成 4至 6元碳环；
R4选自氢， d_6烷基， d_6烷氧基， 卤代 d_6烷基， 苯基或被 R'取代的苯基。
根据本发明的优选方案， ^和 R2各自独立地选自氢， d_3烷基， 苯基或被 R7取代的苯基， 更优选为氢、 曱基、 乙基、 丙基、 异丙基、 丁基、 异丁基、 叔丁基或苯基；
Z为— NH-, CH2或 -0-；
R3选自氢、 氟、 氯、 溴、 曱基、 曱氧基或三氟曱基， n优选为 1-4， 更优选为 2-3.
R4选自氢、 d— 6烷基、 d— 6烷氧基或卤代 d— 6烷基， 苯基或取代苯基。
根据本发明的更优选方案， ^和 R2可以相同或不同， 各自独立地选自 d_6烷基， 苯基或被 R7取代的苯基， 更优选为氢、 曱基、 乙基、 叔丁基、 苯基，；
Z为- NH-或 - 0-，
R3优选在异噁唑环的邻位或对位， 更优选为 4-氟、 4-氯、 2-氯、 4-溴、 2, 4-二氯、 4-曱基、 4-曱氧基、 氢、 4-三氟曱基或 2, 4-二曱氧基；
R4选自氢、 曱基或苯基。
根据本发明， 更优选！^选自氢， 曱基， 苯基； R2选自氢， 曱基， 乙基或叔丁基。
根据本发明的优选技术方案， 其中：
R'、 R8、 R9或 R1"各自独立地选自氢， 羟基， 氛基， tt, d_6烷基氨基， 二（d_6烷基）氨 基， 卤素， d— 6烷基， d— 6烷氧基， d— 6烷硫基， 羧基， 卤代 d— 6烷基， 卤代 d— 6烷氧基或代 d— 6 烷硫基。
进一步的， R'、 R8、 R'或 R1"各自独立地选自氢， 羟基， 巯基， 氰基， 氨基， 卤素， d_6烷基， 烷氧基， d_6烷硫基， 羧基。 更进一步地， R7、 R8、 R'或 R1"各自独立地选自氢， 羟基， 氰基， 氨基， 卤素， d— 6烷基， d— 6烷氧基， d— 6烷硫基或羧基。
Figure imgf000004_0001
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Figure imgf000011_0001
式（I)所示的含异噁唑杂环的噻吩 [2, 3-d]嘧啶化合物，可以分别选择与药学上可接受的酸形 成药学上可接受的盐。 其中术语 "药学上可接受的盐" 包括但不限于与无机酸形成的盐， 如盐酸 盐、 磷酸盐、 二碑酸盐、 氢溴酸盐、 硫酸盐、 亚磺酸盐、 硝酸盐、 及其类似盐， 优选盐酸盐、 硝 酸盐、 疏酸盐或碑酸盐。 也包括与有机酸形成的盐， 如乳酸盐、 草酸盐、 苹果酸盐、 马来酸盐、 富马酸盐、 酒石酸盐、 琥珀酸盐、 柠檬酸盐、 磺酸盐、 对曱苯磺酸盐、 2-羟乙基磺酸盐、 苯曱酸 盐、 水杨酸盐、 硬脂酸盐、 三氟乙酸或氨基酸； 链烷酸盐如曱酸盐、 乙酸盐等， 或者
H00C- (CH2) n-C00H其中 n是 0-4的盐， 及其类似盐。 优选的有机酸盐选自曱酸盐、 乙酸盐、 草 酸盐、 柠檬酸盐、 富马酸盐、 马来酸盐、 苹果酸盐、 乳酸盐、 酒石酸盐、 对曱苯確酸盐、 三氟乙 酸盐或氨基酸盐。 类似地， 药学上可接受的阳离子包括但不限于钠、 钾、 钙、 铝、 锂和铵。
术语 "溶剂化物" 包括水合物和醇合物。
本发明还提供一种药物组合物， 其包括前述的式（I)所示的噻吩 [2, 3-d]嘧啶化合物， 或其药 学上可接受的盐或溶剂化物， 以及至少一种药学上可接受的、 惰性的、 无毒的赋形剂或载体或稀 释剂。
根据所述的药物组合物， 其特征在于， 所述药物组合物还包含一种或多种选自填充剂、崩解 剂、 润滑剂、 助流剂、 泡腾剂、 矫味剂、 防腐剂和包衣材料的药学可接受的辅助材料。
本发明还提供一种药物制剂， 其包含前述的式（I)所示的噻吩 [2, 3-d]嘧啶化合物， 或其药学 上可接受的盐或溶剂化物， 以及至少一种药学上可接受的、 惰性的、 无毒的赋形剂或载体或稀释 剂。
根据本发明的药物制剂， 其特征在于， 所述制剂优选为固体口服制剂、 液体口服制剂或注射 剂。
根据本发明的药物制剂， 所述制剂选自片剂、 片、 肠溶片、 咀嚼片、 口崩片、 胶囊、 颗 粒剂、 口服溶液剂、 注射用水针、 注射用冻干粉针、 大输液或小输液。 本发明还提供一种用作药物的权利要求 1-4 的式（I)所示的噻吩 [2, 3-d]嘧啶化合物或其药 学上可接受的盐， 尤其是一种有效用于治疗肿瘤 /癌症的药物。
本发明还提供用作药物的前述任一项的式（I)所示的噻吩 [2, 3-d]嘧啶化合物或其药学上可 接受的盐或溶剂化物，尤其是一种用于治疗对于抑制 EGFR过渡表达和 /或活性过高有效的肿瘤的 药物。
本发明还提供一种前述任一项的式（I)所示的噻吩 [2, 3-d]嘧啶化合物或其药学上可接受的盐 或溶剂化物在制备用于抗肿瘤或癌症药物中的应用。
根据本发明所述的应用， 其中所述的肿瘤或癌症选自： 膀胱癌、 非小细胞肺癌、 卵巢癌、 乳 腺癌、 胃癌、 食道癌、 肺癌、 头颈癌、 结肠癌、 咽癌和胰腺癌等， 更优选非小细胞肺癌。
根据本发明， 还提供一种权利要求 卜 8 中任一项的式（I)所示的噻吩 [2, 3-d]嘧啶化合物和 / 或药学上可接受的盐在制备抑制 EGFR的过渡表达和 /或活性过高的抑制剂中的应用。
本发明还提供了一种前述任一项的式（I)所示的噻吩 [2, 3-d]嘧啶化合物和 /或药学上可接受 的盐或溶剂化物在制备用于抑大肠癌细胞株 (HCT-116)和人肺癌细胞株 (A549)活性的药物中的应 用。
本发明还提供了一种式（I)所示的含异噁唑杂环的瘘11分 [2, 3-d]嘧啶化合物的制备方法，其特 征在于， 所述的方法包括如下步骤：
式 I I 所示的 5, 6-二取代 -4-氯 -噻吩 [2, 3-d]嘧啶和式 I I I 所示的 3-取代苯基 -5-羟曱基- 异噁唑或式 IV 所示的 3-取代苯基 -5-氨曱基-异噁唑，在干燥的有机溶剂和碱性縛酸剂体系中反 应制备得到式（1-1)或式（1-2)所示的化合物：
Figure imgf000012_0001
同时， 对于 Z为其他取代基的式（I )化合物， 例如 R5为其他取代基的 -NR5， C (R6) 2， S时， 可采用 （Π )与 -NH ( R5 )或 C1-C (R6) 2或 3-取代苯基 -5-巯基异噁唑通过相应的偶联反应制备， 其中 3-取代苯基 -5-巯基异噁唑以丙炔硫醇为原料， 采用式（Π Ι )的合成过程制备。
根据本发明， 所述反应温度为 -2 (TC至回流条件， 优选室温至回流条件。
根据本发明， 所述有机溶剂为芳烃， 卤代烃， C「C6低级醇类， 四氢呋喃或二曱基亚砜（DMF )。 优选地， 所述溶剂选自苯、 曱苯、 二曱苯、 二氯曱烷、 氯仿、 异丙醇、 四氢呋喃或 DMF， 更优选 异丙醇。
根据本发明，所述的碱性縛酸剂为有机碱或无机碱，所述的有机碱选自三乙胺、三丙胺、 DMAP、 叔丁醇钾等； 所述的无机碱选自碳酸钾、 氢化钠、 碳酸钠等。 优选的縛酸剂为三乙胺。
根据本发明， 所述式（Π Ι)的中间体 3-取代苯基 5-羟曱基-异噁唑通过如下的方法制备：
( 1 )取代苯曱醛与羟胺或羟胺盐酸盐在曱醇 /水体系中， 在碳酸钠的催化下反应生成相应的 苯曱醛肟；
( 2 )将步骤（1 )制得的苯曱酸肟与丙炔醇在 溴丁二酰亚胺（NCS )和碱性縛酸剂的作用 下通过 1, 3-偶极环加成反应形成式（ Π Ι )异噁唑化合物。
根据本发明， 优选地， 所述的碱性縛酸剂选自有机碱或无机碱， 所述有机碱选自三乙胺、 三 丙胺、 DMAP、 DMF、 N-曱基吗淋等； 所述的无机碱选自碳酸钾、 氢化钠、 碳酸钠等。 更优选的碱 性縛酸剂为三乙胺。
所述反应温度为 0度至回流温度， 优选为室温至回流温度。
根据本发明， 所述式（IV)的中间体 3-取代苯基 5-氨曱基-异噁唑通过如下的方法制备：
( 3 )式（ Π Ι )的异噁唑化合物（优选通过前述方法获得 )与磺酰氯反应获得式（ V )化合物，； 根据本发明的优选技术方案， 步骤（3 )中， 所述磺酰氯选自： 曱磺酰氯、 苯磺酰氯、 取代苯 磺酰氯（如卤代苯磺酰氯、 烷基苯磺酰氯）等， 更优选为曱磺酰氯。 所述反应温度为 -5度至回 流温度， 优选室温至回流温度。 所述反应溶剂选自苯、 曱苯、 卤代芳烃、 卤代烷烃（如氯仿或二 氯曱烷）、 四氢呋喃、 乙腈及离子液体。 更优选地， 所述反应在二氯曱烷体系中回流反应。
( 4 )式（ V )化合物与叠氮化钠反应， 优选在 DMF体系中， 60°C温度下反应获得式（ VI )化 合物；
( 5 )式（ VI )化合物与氯化铵及锌粉、 铁粉或 4 ^催化还原制备式（ IV )化合物， 优选所述 催化剂在无机酸条件下进行催化， 优选为盐酸或硫酸， 所述催化剂优选为锌粉和氯化铵。
步骤（ 5 )中优选的反应溶剂是水或有机溶剂 (例如醇类， 卤代烃类， 芳烃类等 )或其混合物， 优选为乙醇和水的反应体系。
优选的合成路线如下所示：
Figure imgf000014_0001
同时，对于 Z为其他取代基的式（ III )或（ IV )化合物，例如 R5为其他取代基的 _NR5， C (R6) 2， S时， 可采用相应的丙炔基氯， 丙炔疏醇制备。
根据本发明， 所述式 Π所示的 5, 6-二取代 -4-氯 -噻吩 [2, 3-d]嘧啶通过如下的过程制备： ( 1 )将 3-氨基 4, 5-二取代瘘《^"2-曱酸曱酯（ VII )和醋酸曱脒在试剂 1的作用下形成 5, 6- 二取代的噻吩并嘧啶酮化合物（νπι )， 优选地， 所述反应温度为 0度至回流温度， 更优选为室 温至回流温度；
( 2 )化合物（ VIII )在试剂 2作用下形成式 II所示的 5, 6-二取代 -4-氯 -噻吩 [2, 3-d]嘧啶， 优选地， 所述反应温度为 0度至回流温度， 更优选为室温至回流温度。 具体可见下述反应式
M
Figure imgf000015_0001
(II) 其中， Reagent 1选自： 苯， 曱苯， 乙二醇单曱醚， 乙二醇二曱醚， 乙二醇单乙醚， 乙二醇 二乙醚， 乙醇， 1,2-二氯乙烷及离子液体等； Reagent 2选自： 二氯亚砜， 三氯氧碑， 五氯化碑 氯取代试剂等。
根据本发明，提供一种式（I)所示的含异噁唑杂环的噻吩 [2, 3-d]嘧啶化合物的制备方法， 其 特征在于， 所述的方法包括如下步骤：
(1 )取代苯曱醛与羟胺或羟胺盐酸盐在曱醇 /水体系中， 在碳酸钠的催化下， 优选室温至回 流温度下反应生成相应的苯曱醛肟；
(2)将步骤（1 )制得的苯曱酸肟与丙炔醇在 ^溴丁二酰亚胺（NCS)和三乙胺的作用下通 过 1, 3-偶极环加成反应形成式（ ΠΙ )异噁唑化合物；
( 3 )式（ ΠΙ )的异噁唑化合物与曱磺酰氯反应， 优选在二氯曱烷体系中、 室温下获得式（ V ) 化合物；
( 4 )式（ V )化合物与叠氮化钠反应， 优选在 DMF体系中， 60°C温度下反应获得式（ VI )化 合物；
( 5 )式（ VI )化合物在锌粉和氯化铵催化下， 在乙醇 /水体系中回流制备式（ IV )化合物； (6) 3-氨基 4, 5-二取代瘘 2-曱酸曱酯（VII )和醋酸曱脒在试剂 1 的作用下形成 5, 6- 二取代的噻吩并嘧啶酮化合物（VIII );
( 7 )化合物（ VIII )在试剂 2作用下形成式 II所示的 5, 6-二取代 -4-氯 -噻吩 [2, 3-d]嘧啶， ( 8 )式 II 所示 5, 6-二取代 -4-氯 -噻吩 [2, 3-d]嘧啶与式 II I 所示的 3-取代苯基 -5-羟曱基 -异噁唑或式 IV 所示的 3-取代苯基 -5-氨曱基-异噁唑， 在干燥的有机溶剂和碱性縛酸剂体系中 反应制备得到式（1-1)或式（1-2)所示的化合物。
如果需要， 可以形成式（I)化合物的药学上可接受的盐或溶剂化物。 根据本发明，所述的式 I化合物， 包括但不限于： 它们的光学异构体，外消旋体及其混合物。 根据本发明， 所述卤素或卤原子选自氟、 氯或溴。
根据本发明， 所述烷基为直链或支链烷基， 如 d_6烷基， 优选 d_3烷基， 包括但不限于曱基， 乙基， 丙基， 异丙基， 丁基， 异丁基， 叔丁基， 正戊基， 异戊基， 新戊基， 正己基等。
根据本发明， 所述的 4至 6元碳环选自环丁基， 环戊基， 环己基。 优选为环戊基或环己基。 根据本发明， 所述的含有至少一个选自 N, 0, S杂原子的杂环选自四氢呋喃， 四氢瘘喻， 氮 杂环丁烷， 吡咯烷基， 吖啶， 四氢吡咯， 1， 3-二氢噻唑， 1， 3-二氢噁唑， 哌啶， 哌 ， 吗 *， 硫代吗 *， 噻嗪， 优选为哌嗪基、 吗琳基或哌啶基。
根据本发明，所述芳基为单环或双环芳香烃基，例如 C6_14芳基，所述芳基优选为苯基或萘基， 更优选为苯基。
根据本发明， 所述杂芳基为单环或双环杂芳香烃基，其中含杂原子的环优选为 5员或 6员杂芳 基， 其含有至少一个， 优选有 1-4个^ S或 0杂原子的芳香环， 所述杂芳基优选为吡啶基， 嘧啶 基， 喹琳基， 异喹琳基， 喹唑琳基， 喹喔琳基， 吲哚基， 吡咯基， 噻喻基， 呋喃基， 苯并呋喃基， 苯并噻 11分基， 噻唑基， 异噻唑基， 噁唑基， 异噁唑基， 吡唑基， 呋咱基， 噻二唑基， 四唑基等， 更优选为吡咯基， 噻喻基， 呋喃基， 吲哚基， 苯并呋喃基。
术语 "有效量" 指的是： 所述至少一种化合物和 /或至少一种药学上可接受的盐对于能有效 "治疗' 个体的一种疾病或不适的用量。 如果是癌症时， 有效量能减少癌症或肿瘤细胞的数目； 缩小肿瘤的大小； 抑制或阻止肿瘤细胞向周边器官的侵入。 例如： 肿瘤蔓延入软组织或骨骼中； 抑制或阻止肿瘤的转移；抑制或阻止肿瘤的生长；一定程度上减轻一种或多种与癌症相关的症状； 减少发病率和死亡率； 提高生活质量； 或者是上述效果的结合。 有效量可以是通过抑制 EGFR活性 来减少疾病症状的用量。 对于癌症治疗， 体内实验的效果可以通过评估如存活期、 疾病进展时间 (Time to Di sease Progress ion, TTP)、 反应率 (response Rates, RR)持续反应期和 /或生活质 量来测量。 专业人员已经意识到， 有效量可以随着给药的途径、 赋形剂的用量、 以及与其他药物 的合用而改变。
术语 "有效量" 还可指得是所述至少一种化合物和 /或其至少一种药学上可接受的盐对抑制 EGFR的过度表达和 /或活性过高有效的剂量。
本发明的化合物均具有抗肿瘤、 抗癌活性， 尤其是具有抗大肠癌细胞珠 (HCT-116)活性和抗 人肺癌细胞 A549活性。 本发明的化合物在 1 10"M浓度下均具有抑制活性， 实施例化合物的活 性可以达到 50%以上，优选 60%以上，更优选 80%以上。其中大多数化合物对大肠癌细胞珠 (HCT-116) 和人肺癌细胞 A549同时具有较强的抑制活性。 例如化合物 S-101在 1 10"M浓度下对大肠癌细 胞珠（HCT-116)的抑制率为 68. 8%, 而且对人肺癌细胞 A549的抑制率为 88%， 化合物 S-3在 1 χ 10"Μ 浓度下对大肠癌细胞珠（HCT-116)的抑制率为 70%， 而且对人肺癌细胞 A549 的抑制率为 86. 4%, 化合物 S-83在 1 10"M浓度下对人肺癌细胞 A549的抑制率高达 89. 4%。 因而本发明的 化合物可用作治疗肿瘤、 癌症的候选药物或先导化合物。 具体的实施方式
下面结合实施例对本发明作进一步的说明。 需要说明的是， 实施例化合物不是对本发明保 护范围的限制， 任何在本发明 ^出上做出的改进和变化都不违背本发明的精神。
其中， 中间体和目标化合物的合成过程均以实施例中的代表说明， 其余的中间体和目标化 合物的合成过程同代表化合物。
仪器与试剂
AVANCE I I I 核磁共振仪（400MHz, DMS0-d6, TMS 为内标） ， 离子阱液质连用仪 (DECAX-30000 LCQ Deca XP) , Shimadzu FTIR-8400S (日本岛津公司生产）， XT5 数字显示显微 熔点测定仪（北京市科仪电光仪器厂制造，温度未经校正），可调波长式微孔板酶标仪 (Molecular Devies SPECTRAMAX190)„化学试剂均为市售的分析纯或化学纯试剂， RPMI1640购自 Gibco公司， 磺酰罗丹明 B (Sulforodamine B, SRB) 购自 Sigma公司， 三氯乙酸（TCA)、 醋酸和 Tr i s base unbuffer 均为国产分析纯试剂。 实施例 1式（Ι Π)中间体 3-取代苯基 -5-羟曱基 -异噁唑及式（IV)中间体 3-取代苯基 5-氨曱基 -异噁唑的合成
其中以 R3为 H作为示例：
(1)
Figure imgf000017_0001
10. 0 ol 苯曱酸溶解在 30 mL 30% CH30H和 H20溶液中， 加入装有磁力搅拌器的三角瓶 中， 搅拌下加入 10. 0 ol盐酸羟氨， 等盐酸羟氨溶解后緩慢加入 5. 0 ol干燥研细的碳酸 钠。 室温反应， TLC检测反应完成后， 体系减压蒸除曱醇后， 加入 30 mL H2O， 二氯曱烷（3 x 30 mL)萃取， 合并有机层， 无水疏酸钠干燥有机层. 脱溶剂即得苯曱醛肟粗产物， 收率 86. 2 % 该粗产物不用分离纯化直接进行下步反应。
(2) 3-苯基 -5-羟曱基-异噁唑
Figure imgf000018_0001
将 10.0 ol苯曱酸肟和 30 mL干燥的二氯曱烷加入 250 mL单口圓底烧瓶中， 搅拌下加入 1.60g (12.0 mmol) N-氯丁二酰亚胺（NCS)， 微微加热至 NCS 全部溶解后， 滴加 0.56 g (10.0 mmol)2-丙炔 -1-醇， 随后緩慢滴加入 20 mL含 10.1 g (10.0 mmol)三乙胺的二氯曱烷溶液， 加 完后体系回流. TLC检测反应完成后，母液水洗， 无水硫酸钠干燥，柱分离（^;*«： V^m 5: 1—2: 1)即得 3-苯基 -5-羟曱基-异噁唑， 收率 76.8 %
(3) 3-苯基 -5-氨曱基-异噁唑
Figure imgf000018_0002
将 10.0 ol 5-羟曱基 -3-苯基-异噁唑和 30 mL干燥的二氯曱烷加入 250 mL单口圓底烧 瓶中， 冰浴搅拌下将含 1.01g(10.0 mmol) 三乙胺的 20 mL二氯曱烷溶液加入体系中， 接着将溶 有 1.37g (12.0 mmol) 曱磺酰氯 (MsCl)的 5 mL二氯曱烷溶液緩慢滴加入体系中， 冰浴反应 2 h 后， 室温反应。 TLC检测反应完成后， 母液水洗， 5 %的碳酸氢钠溶液洗， 水洗， 无水^■酸钠干 燥， 减压脱溶剂得粗产物 5-曱磺酸 -3-苯基-异噁唑 -5-曱醇酯， 收率 68.0 %。 粗产物不必纯化直 接进行下步反应。
将 5.0 ol 5-曱磺酸 -3-苯基-异噁唑 -5-曱醇酯溶解在 20 mL干燥的 DMF 中， 加入 0.34 g (5.20 mmol)叠氮化钠， 室温搅拌溶解后， 置于 45°C-50°C油浴中反应， TLC指示反应完成后， 过滤， 滤饼用乙醚（2 x 30 mL)洗涤， 合并有机层， 向有机层中加 100 mL水， 用乙醚（5 x 30 mL) 萃取， 合并有机层， 有机层水洗 2次， 无水疏酸钠干燥， 脱溶剂后得粗产物 3-苯基 -5-叠氮曱基 -异噁唑， 收率 90% ， 粗产物直接进行下面的还原反应.
5.0 mmol 5_叠氮曱基 _3_苯基-异噁唑溶解在 80 mL 乙醇和 20 mL 水的混合溶液中， 将 0.17g(2.6 mmol)的锌粉和 0.28g(5.2 ol)的 NH4C1加入体系， 回流 lh， 真空脱去乙醇， 向体 系加入 20 mL水， 用 20% 的氢氧化钠溶液调至 pH值到 12, 向体系中加入 50 mL DCM, 搅拌均匀 后， 过滤， 滤渣在用少量的水溶解， 过滤， 合并两次的滤液， 分出有机层， 有机层， 水洗， 无水 硫酸钠干燥，真空脱溶剂， 残渣柱分离 10: 1)得产物 3-苯基 -5-氨曱基-异噁唑， 收率 75%· 浅黄色固体， m. p: 39—40 °C , 'H-NMR (400MHZ, CDC13, TMS) , δ ppm: 1. 60 ( s, 2H. NH2 ) , 3. 91 (s, 2H, CH2) , 6. 40 (s, 1H) , 7. 39 (m, 2H, Ar-H) , 7. 76 (m, 2H, Ar-H) . 实施例 1
中间体（ I I )的合成（以 6_叔丁基 -4-氯 -瘘喻 [2, 3-d]嘧啶的合成为例说明）：
Figure imgf000019_0001
将 1. 13g (10mmo l) 3_氨基 -5"*_丁基-噻 2-曱酸曱酯加入 250mL圓底单口圓底烧瓶中， 接 着加入 l OOmL乙二醇单乙醚和 2. 14g (20mmo l)醋酸曱脒， 体系在搅拌下回流反应， TLC检测反应 完成后， 体系冷却， 然后减压蒸榴至乙二醇单乙醚有 30mL , 体系冷藏数小时， 有大量的固体析 出， 过滤， 滤饼用冷藏的乙醚洗漆数次， 滤饼真空干燥后直接用于下步反应。
称取上述粗产物 5克加入 l OOmL圓底单口圓底烧瓶中， 緩慢滴加 3滴 DMF的三氯氧碑溶液 20mL， 体系回流反应 6h后， 减压蒸除过量的三氯氧碑后， 冷却后拌硅胶， 柱分离 （V (石油醚）： V (乙酸乙酯） =4: 1—1: 1 )即得目标化合物 64又丁基 -4-氯 -噻吩 [2, 3-d]嘧啶， 浅黄色固体， 1H-NMR (400MHz, CDC13, TMS) , δ ppm: 1. 43 ( s, 9H, 3CH3 ) , 7. 19 (s, 1H) , 8. 84 (s, lH)。 实施例 3
5-曱基 _4_ [ (3-苯基-异噁唑 -5-基) -曱氧基-] -噻吩 [2, 3-d]嘧啶的合成
Figure imgf000019_0002
将 0. 184 g (1 ol)的 4-氯 -瘘吩 [2, 3-d]嘧啶溶解在 5 mL干燥的异丙醇中， 搅拌下将溶有 0. 175g (l mmol) 5_羟曱基 _3_苯基-异噁唑的 5 mL异丙醇溶液緩慢滴加入反应体系， 接着加入 0. 101 g (1 ol)新蒸的三乙胺， 体系室温搅拌 30 min后， 60°C反应， TLC检测反应完成后， 反应液真空浓缩， 残渣直接柱分离 K ^=9: 1—4: 1 即得目标化合物 5-曱基 -4- [ (3-苯 基-异噁唑 -5-基) -曱氧基-] -噻吩 [2, 3-d]嘧啶（下表 S-1)。 其余的化合物按照 5-曱基 -4- [ (3-苯 基-异噁唑 -5-基） -曱氧基-] -噻吩 [2, 3-d]嘧啶的合成过程合成。 其结构均通过 IR, 'Η MR, ESI-MS等分析方法进行了表征。 优选出的化合物的物性常数及光谙数据以列表的形式进行说明： 化合物的结构、 代号及
Figure imgf000020_0001
表 1- 优选的化合物
Figure imgf000020_0002
Figure imgf000021_0001
Figure imgf000022_0001
-表 1 化合物的物态及 IR数据
Figure imgf000022_0002
s- -22 白色固体 3105, 1567, 1545, 1457, 1441, 1312, 1028, 817
s- -23 白色固体 3107, 1567, 1545, 1457, 1440, 1312, 1028, 820
s- -24 白色固体 3107, 1565, 1548, 1457, 1444, 1312, 1028, 815
s- -25 白色固体 3107, 1567, 1548, 1457, 1444, 1312, 1028, 830
s- -26 白色固体 3107, 1566, 1548, 1456, 1443, 1312, 1028, 835
s- -27 白色固体 3107, 1567, 1548, 1457, 1444, 1312, 1028, 817
s- -28 白色固体 3107, 1567, 1548, 1457, 1444, 1312, 1028, 817
s- -29 白色固体 3107, 1567, 1548, 1457, 1444, 1312, 1028, 817
s- -30 白色固体 3107, 1567, 1548, 1457, 1444, 1312, 1028, 817
s- -31 白色固体 3237, 3103, 1567, 1546, 1442, 1309, 1026, 770
s- -32 白色固体 3237, 3103, 1567, 1546, 1442, 1309, 1026, 770
s- -33 白色固体 3237, 3103, 1567, 1546, 1442, 1309, 1026, 770
s- -34 白色固体 3237, 3103, 1567, 1546, 1442, 1309, 1026, 770
s- -35 白色固体 3237, 3103, 1567, 1546, 1442, 1309, 1026, 770
s- -36 白色固体 3237, 3103, 1567, 1546, 1442, 1309, 1026, 770
s- -37 白色固体 3237, 3103, 1567, 1546, 1442, 1309, 1026, 770
s- -38 白色固体 3237, 3103, 1567, 1546, 1442, 1309, 1026, 770
s- -39 白色固体 3237, 3103, 1567, 1546, 1442, 1309, 1026, 770
s- -40 白色固体 3237, 3103, 1567, 1546, 1442, 1309, 1026, 770
s- -41 白色固体 3103, 1567, 1546, 1442, 1309, 1026, 770
s- -42 白色固体 3103, 1567, 1546, 1442, 1309, 1026, 812
s- -43 白色固体 3103, 1567, 1546, 1442, 1309, 1026, 835
s- -44 白色固体 3103, 1567, 1546, 1442, 1309, 1026, 850
s- -45 白色固体 3103, 1567, 1546, 1442, 1309, 1026, 832
s- -46 白色固体 3103, 1567, 1546, 1442, 1309, 1026, 867
s- -47 白色固体 3103, 1567, 1546, 1442, 1309, 1026, 856
s- -48 白色固体 3103, 1567, 1546, 1442, 1309, 1026, 834
s- -49 白色固体 3103, 1567, 1546, 1442, 1309, 1026, 865
s- -50 白色固体 3103, 1567, 1546, 1442, 1309, 1026, 823
s- -51 白色固体 3237, 3103, 1567, 1546, 1442, 1309, 1026, 770
s- -52 白色固体 3237, 3103, 1567, 1546, 1442, 1309, 1026, 815
s- -53 白色固体 3237, 3103, 1567, 1546, 1442, 1309, 1026, 834
s- -54 白色固体 3237, 3103, 1567, 1546, 1442, 1309, 1026, 850
s- -55 白色固体 3237, 3103, 1567, 1546, 1442, 1309, 1026, 867
s- -56 白色固体 3237, 3103, 1567, 1546, 1442, 1309, 1026, 834
s- -57 白色固体 3237, 3103, 1567, 1546, 1442, 1309, 1026, 821
s- -58 白色固体 3237, 3103, 1567, 1546, 1442, 1309, 1026, 845
s- -59 白色固体 3237, 3103, 1567, 1546, 1442, 1309, 1026, 860
s- -60 白色固体 3237, 3103, 1567, 1546, 1442, 1309, 1026, 835
s- -61 白色固体 3109, 1571, 1549, 1510, 1461, 1431, 1363, 1322, 1036, 775 s- -62 白色固体 3109, 1571, 1549, 1510, 1461, 1431, 1363, 1322, 1036, 810 s- -63 白色固体 3109, 1571, 1549, 1510, 1461, 1431, 1363, 1322, 1036, 823 s- -64 白色固体 3109, 1571, 1549, 1510, 1461, 1431, 1363, 1322, 1036, 835 s- -65 白色固体 3109, 1571, 1549, 1510, 1461, 1431, 1363, 1322, 1036, 840 s- -66 白色固体 3109, 1571, 1549, 1510, 1461, 1431, 1363, 1322, 1036, 860 s- -67 白色固体 3109, 1571, 1549, 1510, 1461, 1431, 1363, 1322, 1036, 851 s- -68 白色固体 3109, 1571, 1549, 1510, 1461, 1431, 1363, 1322, 1036, 875 s- -69 白色固体 3109, 1571, 1549, 1510, 1461, 1431, 1363, 1322, 1036, 835 s- -70 白色固体 3109, 1571, 1549, 1510, 1461, 1431, 1363, 1322, 1036, 832 s- -71 白色固体 3237, 3103, 1567, 1546, 1442, 1309, 1026, 775
s- -72 白色固体 3237, 3103, 1567, 1546, 1442, 1309, 1026, 821
s- -73 白色固体 3237, 3103, 1567, 1546, 1442, 1309, 1026, 835
s- -74 白色固体 3237, 3103, 1567, 1546, 1442, 1309, 1026, 845
s- -75 白色固体 3237, 3103, 1567, 1546, 1442, 1309, 1026, 835
s- -76 白色固体 3237, 3103, 1567, 1546, 1442, 1309, 1026, 851
s- -77 白色固体 3237, 3103, 1567, 1546, 1442, 1309, 1026, 823
s- -78 白色固体 3237, 3103, 1567, 1546, 1442, 1309, 1026, 853
s- -79 白色固体 3237, 3103, 1567, 1546, 1442, 1309, 1026, 835
s- -80 白色固体 3237, 3103, 1567, 1546, 1442, 1309, 1026, 843
s- -81 白色固体 3109, 1571, 1549, 1510, 1461, 1431, 1363, 1322, 1036, 775 s- -82 白色固体 3109, 1571, 1549, 1510, 1461, 1431, 1363, 1322, 1036, 845 s- -83 白色固体 3109, 1571, 1549, 1510, 1461, 1431, 1363, 1322, 1036, 845 s- -84 白色固体 3109, 1571, 1549, 1510, 1461, 1431, 1363, 1322, 1036, 845 s- -85 白色固体 3109, 1571, 1549, 1510, 1461, 1431, 1363, 1322, 1036, 845 s- -86 白色固体 3109, 1571, 1549, 1510, 1461, 1431, 1363, 1322, 1036, 845 s- -87 白色固体 3109, 1571, 1549, 1510, 1461, 1431, 1363, 1322, 1036, 845 s- -88 白色固体 3111, 1571, 1548, 1512, 1461, 1429, 1372, 1322, 1036, 846 s- -89 白色固体 3109, 1571, 1549, 1510, 1461, 1431, 1363, 1322, 1036, 845 s- -90 白色固体 3109, 1571, 1549, 1510, 1461, 1431, 1363, 1322, 1036, 827 s- -91 白色固体 3237, 3109, 1571, 1549, 1461, 1431, 1363, 1322, 1036, 775 s- -92 白色固体 3230, 3109, 1571, 1549, 1461, 1431, 1363, 1322, 1036, 845 s- -93 白色固体 3368, 3109, 1571, 1549, 1461, 1431, 1363, 1322, 1036, 845 s- -94 白色固体 3228, 3109, 1571, 1549, 1461, 1431, 1363, 1322, 1036, 845 s- -95 白色固体 3231, 3109, 1571, 1549, 1461, 1431, 1363, 1322, 1036, 845 s- -96 白色固体 3238, 3109, 1571, 1549, 1461, 1431, 1363, 1322, 1036, 845 s- -97 白色固体 3210, 3109, 1571, 1549, 1461, 1431, 1363, 1322, 1036, 845 s- -98 白色固体 3218, 3111, 1571, 1548, 1461, 1429, 1372, 1322, 1036, 846 s- -99 白色固体 3228, 3109, 1571, 1549, 1461, 1431, 1363, 1322, 1036, 845 s- -100 白色固体 3218, 3109, 1571, 1549, 1461, 1431, 1363, 1322, 1036, 827 s- -101 白色固体 3103, 1567, 1546, 1442, 1309, 1026, 770
s- -102 白色固体 3107, 1567, 1548, 1457, 1444, 1312, 1028, 817
s- -103 白色固体 3107, 1567, 1548, 1457, 1444, 1312, 1028, 821
s- -104 白色固体 3107, 1567, 1548, 1457, 1444, 1312, 1028, 836
s- -105 白色固体 3107, 1567, 1548, 1457, 1444, 1312, 1028, 829
s- -106 白色固体 3107, 1567, 1548, 1457, 1444, 1312, 1028, 817
s- -107 白色固体 3107, 1567, 1548, 1457, 1444, 1312, 1028, 845 S-108 白色固体 3107, 1567, 1548, 1457, 1444, 1312, 1028, 847
S-109 白色固体 3107, 1567, 1548, 1457, 1444, 1312, 1028, 817
S-110 白色固体 3107, 1567, 1548, 1457, 1444, 1312, 1028, 816
S-lll 白色固体 3237, 3103, 1567, 1546, 1442, 1309, 1026, 770
S-112 白色固体 3230, 3107, 1567, 1548, 1457, 1444, 1312, 1028, 817
S-113 白色固体 3368, 3107, 1567, 1548, 1457, 1444, 1312, 1028, 821
S-114 白色固体 3228, 3107, 1567, 1548, 1457, 1444, 1312, 1028, 836
S-115 白色固体 3231, 3107, 1567, 1548, 1457, 1444, 1312, 1028, 829
S-116 白色固体 3238, 3107, 1567, 1548, 1457, 1444, 1312, 1028, 817
S-117 白色固体 3210, 3107, 1567, 1548, 1457, 1444, 1312, 1028, 845
S-118 白色固体 3218, 3107, 1567, 1548, 1457, 1444, 1312, 1028, 847
S-119 白色固体 3228, 3107, 1567, 1548, 1457, 1444, 1312, 1028, 817
S-120 白色固体 3218, 3107, 1567, 1548, 1457, 1444, 1312, 1028, 816
S-121 白色固体 3109, 1561, 1531, 1510, 1455, 1434, 1386, 1311, 1028, 826
S-122 白色固体 3124, 2957, 1613, 1571, 1562, 1460, 1396, 1311, 1075, 1058, 888
S-123 白色固体 3124, 2957, 1613, 1571, 1562, 1460, 1396, 1311, 1075, 1058, 888
S-124 白色固体 3124, 2957, 1613, 1571, 1562, 1460, 1432, 1311, 1075, 1058, 888
S-125 白色固体 3124, 2957, 1613, 1571, 1562, 1460, 1432, 1311, 1075, 1058, 888
S-126 白色固体 3124, 2957, 1613, 1571, 1562, 1460, 1396, 1311, 1075, 1058, 888
S-127 白色固体 3124, 2957, 1613, 1571, 1562, 1460, 1396, 1311, 1075, 1058, 888
S-128 白色固体 3124, 2957, 1613, 1571, 1562, 1460, 1432, 1311, 1075, 1058, 888
S-129 白色固体 3124, 2957, 1613, 1571, 1562, 1460, 1432, 1311, 1075, 1058, 888
S-130 白色固体 3124, 2957, 1613, 1571, 1562, 1460, 1432, 1311, 1075, 1058, 888
S-131 白色固体 3237, 3109, 1561, 1531, 1510, 1455, 1434, 1386, 1028, 826
S-132 白色固体 3230, 3124, 2957, 1613, 1571, 1562, 1460, 1396, 1311, 1075, 888
S-133 白色固体 3368, 3124, 2957, 1613, 1571, 1562, 1460, 1432, 1396, 888
S-134 白色固体 3228, 3124, 2957, 1613, 1571, 1562, 1460, 1432, 1396, 888
S-135 白色固体 3231, 3124, 2957, 1613, 1571, 1562, 1460, 1432, 1396, 1075
S-136 白色固体 3238, 3124, 2957, 1613, 1571, 1562, 1460, 1432, 1396, 1075
S-137 白色固体 3210, 3124, 2957, 1613, 1571, 1562, 1460, 1432, 1396, 1311
S-138 白色固体 3218, 3124, 2957, 1613, 1571, 1562, 1460, 1432, 1396, 1075
S-139 白色固体 3228, 3124, 2957, 1613, 1571, 1562, 1460, 1432, 1396, 1311, 1057
S-140 白色固体 3218, 3124, 2957, 1613, 1571, 1562, 1460, 1432, 1396, 1311 表 3 -表 1 中化合物的 ^NMR数据
编号 1 HNMR (400MHz, DMSO-o
S-1 2. 54 (s, 3H, CH3) , 5. 82 (s, 2H, CH2) , 7. 22 (s, 1H, i soxazole-H) , 7. 47 (s, 1H) , 7. 48-7. 53 (m, 3H) , 7. 88-7. 90 (m, 2H) , 8. 70 (s, 1H) .
S-2 2. 36 (s, 3H, Ph-CH3) , 2. 53 (s, 3H, CH3) , 5. 80 (s, 2H, CH2) , 7. 18 (s, 1H, i soxazole-H) , 7. 33 (d, 2H, 7=8. 0 Hz) , 7. 47 (s, 1H) , 7. 79 (d, 2H, 7=8. 0 Hz) , 8. 69 (s, 1H) .
S-3 2. 51 (s, 3H, CH3) , 3. 82 (s, 3H, Ph-0CH3) , 5. 79 (s, 2H, CH2) , 7. 07 (d, 2H, 7=8. 8 Hz) , 7. 15 (s, 1H, i soxazole-H) , 7. 47 (s, 1H) , 7. 84 (d, 2H, 7=8. 8 Hz) , 8. 69 (s, 1H) . S-4 2.51 (s, 3H, CH3), 5.82 (s, 2H, CH2) , 7.25 (s, IH, isoxazole-H), 7.47 (s, IH) , 7.59 (d, 2H, 7=8.4 Hz), 7.93 (d, 2H, 7=8.4 Hz) , 8.69 (s, IH) .
S-5 2.51 (s, 3H, CH3), 5.82 (s, 2H, CH2) , 7.25 (s, IH, isoxazole-H), 7.47 (s, IH) , 7.59 (d, 2H, 7=8.4 Hz), 7.93 (d, 2H, 7=8.4 Hz) , 8.69 (s, IH) .
S-6 2.53 (s, 3H, CH3), 5.84 (s, 2H, CH2) , 7.11 (s, IH, isoxazole-H), 7.47-7.54 (m, 3H) , 7.64-7.66 (m, IH), 7.71-7.73 (m, IH), 8.70 (s, IH).
S-7 2.53 (s, 3H, CH3), 5.85 (s, 2H, CH2) , 7.13 (s, IH, isoxazole-H), 7.47 (d, IH, 7=1.2 Hz), 7.58-7.60 (m, IH), 7.76 (s, IH), 7.85 (d, IH, 7=2.0 Hz) , 8.70 (s, IH) .
S-8 2.54 (s, 3H, CH3), 5.82 (s, 2H, CH2) , 7.25 (s, IH, isoxazole-H), 7.47 (s, IH) , 7.74 (d, 2H, 7=6.8 Hz) , 7.87 (d, 2H, 7=8.8 Hz) , 8.69 (s, IH) .
S-9 2.52 (s, 3H, CH3), 5.85 (s, 2H, CH2) , 7.18 (s, IH, isoxazole-H), 7.49 (s, IH) , 7.78 (d, 2H, 7=6.8 Hz) , 7.92 (d, 2H, 7=8.8 Hz) , 8.72 (s, IH) .
S-10 2.54 (s, 3H, CH3), 3.83 (s, 6H, 20CH3) , 5.82 (s, 2H, CH2) , 7.22 (s, IH, isoxazole-H), 7.23-7.24 (m, 2H) , 7.62 (d, IH, 7=2.0 Hz) , 8.70 (s, IH) .
S-ll 2.54 (s, 3H, CH3), 4.22 (t, IH, 7=6.6 Hz, NH) , 5.82 (s, 2H, CH2) , 7.22 (s, IH, isoxazole-H), 7.47 (s, IH), 7.48-7.53 (m, 3H) , 7.88-7.90 (m, 2H) , 8.70 (s, IH).
S-12 2.36 (s, 3H, Ph-CH3) , 2.53 (s, 3H, CH3) , 4.29 (t, IH, 7=6.4 Hz, NH) , 5.80 (s, 2H, CH2), 7.18 (s, IH, isoxazole-H), 7.33 (d, 2H, 7=8.0 Hz) , 7.47 (s, IH), 7.79 (d, 2H, 7=8.0 Hz), 8.69 (s, IH).
S-13 2.51 (s, 3H, CH3), 3.82 (s, 3H, Ph-0CH3) , 4.28 (t, IH, 7=6.5 Hz, NH) , 5.79 (s, 2H, CH2), 7.07 (d, 2H, 7=8.8 Hz) , 7.15 (s, IH, isoxazole-H), 7.47 (s, IH) , 7.84 (d, 2H, 7=8.8 Hz), 8.69 (s, IH).
S-14 2.51 (s, 3H, CH3), 4.28 (t, IH, 7=6.5 Hz, NH) , 5.82 (s, 2H, CH2) , 7.25 (s, IH, isoxazole-H), 7.47 (s, IH), 7.59 (d, 2H, 7=8.4 Hz) , 7.93 (d, 2H, 7=8.4 Hz) , 8.69 (s, IH).
S-15 2.51 (s, 3H, CH3), 4.31 (t, IH, 7=6.5 Hz, NH) , 5.82 (s, 2H, CH2) , 7.25 (s, IH, isoxazole-H), 7.47 (s, IH), 7.59 (d, 2H, 7=8.4 Hz) , 7.93 (d, 2H, 7=8.4 Hz) , 8.69 (s, IH).
S-16 2.53 (s, 3H, CH3), 4.33 (t, IH, 7=6.5 Hz, NH) , 5.84 (s, 2H, CH2) , 7.11 (s, IH, isoxazole-H), 7.47-7.54 (m, 3H) , 7.64-7.66 (m, IH), 7.71-7.73 (m, IH), 8.70 (s, IH).
S-17 2.53 (s, 3H, CH3), 4.38 (t, IH, 7=6.5 Hz, NH) , 5.85 (s, 2H, CH2) , 7.13 (s, IH, isoxazole-H), 7.47 (d, IH, 7=1.2 Hz), 7.58-7.60 (m, IH) , 7.76 (s, IH) , 7.85 (d, IH, 7=2.0 Hz), 8.70 (s, IH).
S-18 2.54 (s, 3H, CH3), 4.32 (t, IH, 7=6.5 Hz, NH) , 5.82 (s, 2H, CH2) , 7.25 (s, IH, isoxazole-H), 7.47 (s, IH), 7.74 (d, 2H, 7=6.8 Hz) , 7.87 (d, 2H, 7=8.8 Hz) , 8.69 (s, IH).
S-19 2.52 (s, 3H, CH3), 4.37 (t, IH, 7=6.5 Hz, NH) , 5.85 (s, 2H, CH2) , 7.18 (s, IH, isoxazole-H), 7.49 (s, IH), 7.78 (d, 2H, 7=6.8 Hz) , 7.92 (d, 2H, 7=8.8 Hz) , 8.72 (s, IH).
S-20 2.54 (s, 3H, CH3), 3.83 (s, 6H, 20CH3) , 4.26 (t, IH, 7=6.5 Hz, NH) , 5.82 (s, 2H, CH2) , 7.22 (s, IH, isoxazole-H), 7.23-7.24 (m, 2H) , 7.62 (d, IH, 7=2.0 Hz) , 8.70 (s, IH) .
S-21 5.83 (s, 2H, CH2), 6.81 (s, IH, isoxazole-H), 7.38-7.42 (m, 3H) , 7.51-7.62 (m, 8H) , 92
Figure imgf000027_0001
119T80/Z10ZN3/X3d 998£請 ΪΟΖ OAV LZ
Figure imgf000028_0001
119T80/Z10ZN3/X3d 998£請 ΪΟΖ OAV 82
Figure imgf000029_0001
119T80/Z10ZN3/X3d 998£請 ΪΟΖ OAV CH2), 7.08 (d, 2H, 7=8.8 Hz) , 7.17 (s, IH, isoxazole-H), 7.44 (s, IH) , 7.84 (d, 2H, 7=8.8 Hz), 8.78 (s, IH).
S-74 1.45 (s, 9H, 3CH3) , 4.28 (t, IH, 7=6.5 Hz, NH) , 5.86 (s, 2H, CH2) , 7.27 (s, IH, isoxazole-H), 7.44 (s, IH), 7.62 (d, 2H, 7=8.4 Hz) , 7.95 (d, 2H, 7=8.4 Hz) , 8.78 (s, IH).
S-75 1.45 (s, 9H, 3CH3) , 4.31 (t, IH, 7=6.5 Hz, NH) , 5.85 (s, 2H, CH2) , 7.26 (s, IH, isoxazole-H), 7.44 (s, IH), 7.60 (d, 2H, 7=8.4 Hz) , 7.94 (d, 2H, 7=8.4 Hz) , 8.78 (s, IH).
S-76 1.49 (s, 9H, 3CH3) , 4.33 (t, IH, 7=6.5 Hz, NH) , 5.87 (s, 2H, CH2) , 7.12 (s, IH, isoxazole-H), 7.44 (s, IH), 7.48-7.58 (m, 2H) , 7.67 (d, IH, 7=8.0 Hz) , 7.73 (d, IH, 7=7.2 Hz), 8.79 (s, IH).
S-77 1.49 (s, 9H, 3CH3) , 4.38 (t, IH, 7=6.5 Hz, NH) , 5.87 (s, 2H, CH2) , 7.12 (s, IH, isoxazole-H), 7.44 (s, IH), 7.75 (d, IH, 7=8.4 Hz) , 7.85 (d, IH, 7=2.0 Hz) , 8.79 (s, IH).
S-78 1.45 (s, 9H, 3CH3) , 4.32 (t, IH, 7=6.5 Hz, NH) , 5.85 (s, 2H, CH2) , 7.27 (s, IH, isoxazole-H), 7.44 (s, IH), 7.74 (d, 2H, 7=8.8 Hz) , 7.87 (d, 2H, 7=8.8 Hz) , 8.78 (s, IH).
S-79 1.45 (s, 9H, 3CH3) , 4.37 (t, IH, 7=6.5 Hz, NH) , 5.86 (s, 2H, CH2) , 7.26 (s, IH, isoxazole-H), 7.44 (s, IH), 7.60 (d, 2H, 7=8.4 Hz) , 7.94 (d, 2H, 7=8.4 Hz) , 8.78 (s, IH).
S-80 1.45 (s, 9H, 3CH3) , 3.93 (s, 6H, 20CH3) , 4.26 (t, IH, 7=6.5 Hz, NH) , 5.86 (s, 2H, CH2), 7.08 (m, IH), 7.17 (s, IH, isoxazole-H), 7.23-7.25 (m, 2H) 7.44 (s, IH) , 8.78 (s, IH).
S-81 1.34 (t, 3H, CH2CH3, 7=7.2 Hz) , 2.92 (q, 2H, CH2CH3, 7=0.8 Hz) , 5.81 (s, 2H, CH2) ,
7.25 (s, IH, isoxazole-H), 7.26-7.27 (m, IH), 7.51-7.53 (m, 3H) , 7.88-7.91 (m, 2H) ,
8.68 (s, IH).
S-82 1.34 (t, 3H, CH2CH3, 7=7.6 Hz) , 2.36 (s, 3H, Ph- CH3) , 2.97 (q, 2H, CH2CH3, 7=1.2 Hz) , 5.79 (s, 2H, CH2), 7.21 (s, IH, isoxazole-H), 7.27 (s, IH) , 7.31 (d, 2H, 7=7.6 Hz) , 7.79 (d, 2H, 7=8.4 Hz), 8.68 (s, IH) .
S-83 1.32 (t, 3H, CH2CH3, 7=7.6 Hz) , 2.97 (q, 2H, CH2CH3, 7=1.2 Hz), 3.93 (s, 3H, Ph- 0CH3) , 5.78 (s, 2H, CH2), 7.08 (d, 2H, J= 8.8 Hz) , 7.18 (s, IH, isoxazole-H), 7.26 (s, IH) , 7.83 (d, 2H, 7=8.8 Hz) , 8.67 (s, IH).
S-84 1.32 (t, 3H, CH2CH3, 7=7.6 Hz) , 2.96 (q, 2H, CH2CH3, 7=1.2 Hz), 5.81 (s, 2H, CH2) , 7.26 (s, IH, isoxazole-H), 7.28 (s, IH), 7.60 (d, 2H, 7=8.8 Hz) , 7.93 (d, 2H, 7=8.8 Hz), 8.68 (s, IH).
S-85 1.32 (t, 3H, CH2CH3, 7=7.6 Hz) , 2.96 (q, 2H, CH2CH3, 7=1.2 Hz), 5.81 (s, 2H, CH2) , 7.26 (s, IH, isoxazole-H), 7.28 (s, IH), 7.60 (d, 2H, 7=8.8 Hz) , 7.93 (d, 2H, 7=8.8 Hz), 8.68 (s, IH).
S-86 1.33 (t, 3H, CH2CH3, 7=7.6 Hz) , 2.97 (q, 2H, CH2CH3, 7=1.2 Hz), 5.83 (s, 2H, CH2) , 7.13 (s, IH, isoxazole-H), 7.27 (s, IH), 7.47-7.58 (m, 2H) , 7.64-7.66 (m, IH), 7.67-7.72 (m, IH), 8.69 (s, IH).
S-87 1.33 (t, 3H, CH2CH3, 7=7.6 Hz) , 2.95 (q, 2H, CH2CH3, 7=1.2 Hz), 5.83 (s, 2H, CH2) , 7.16 (s, IH, isoxazole-H), 7.26 (s, IH), 7.58-7.60 (m, IH), 7.75 (d, IH, 7=8.4 Hz) , 7.85 (s, IH), 8.69 (s, IH). S-88 1.32 (t, 3H, CH2CH3, 7=7.6 Hz) , 2.96 (q, 2H, CH2CH3, 7=1.2 Hz), 5.81 (s, 2H, CH2) , 7.27 (s, IH, isoxazole-H), 7.28 (s, IH), 7.74 (d, IH, 7=8.4 Hz) , 7.86 (d, IH, 7=8.4 Hz), 8.66 (s, IH).
S-89 1.32 (t, 3H, CH2CH3, 7=7.6 Hz) , 2.96 (q, 2H, CH2CH3, 7=1.2 Hz), 5.81 (s, 2H, CH2) , 7.27 (s, IH, isoxazole-H), 7.28 (s, IH), 7.74 (d, IH, 7=8.4 Hz) , 7.86 (d, IH, 7=8.4 Hz), 8.66 (s, IH).
S-90 1.34 (t, 3H, CH2CH3, 7=7.2 Hz) , 2.92 (q, 2H, CH2CH3, 7=0.8 Hz) , 3.83 (s, 6H, 20CH3) , 5.81 (s, 2H, CH2), 7.25 (s, IH, isoxazole-H), 7.23-7.24 (m, 2H) , 7.62 (d, IH, 7=2.0 Hz), 8.70 (s, IH).
S-91 1.34 (t, 3H, CH2CH3, 7=7.2 Hz) , 2.92 (q, 2H, CH2CH3, 7=0.8 Hz) , 4.22 (t, IH, 7=6.6 Hz, NH), 5.81 (s, 2H, CH2) , 7.25 (s, IH, isoxazole-H), 7.26-7.27 (m, IH) , 7.51-7.53 (m, 3H) , 7.88-7.91 (m, 2H) , 8.68 (s, IH).
S-92 1.34 (t, 3H, CH2CH3, 7=7.6 Hz) , 2.36 (s, 3H, Ph- CH3) , 2.97 (q, 2H, CH2CH3, 7=1.2 Hz) , 4.29 (t, IH, 7=6.4 Hz, NH) , 5.79 (s, 2H, CH2) , 7.21 (s, IH, isoxazole-H), 7.27 (s, IH), 7.31 (d, 2H, 7=7.6 Hz) , 7.79 (d, 2H, 7=8.4 Hz), 8.68 (s, IH) .
S-93 1.32 (t, 3H, CH2CH3, 7=7.6 Hz) , 2.97 (q, 2H, CH2CH3, 7=1.2 Hz), 3.93 (s, 3H, Ph- 0CH3) , 4.28 (t, IH, 7=6.5 Hz, NH) , 5.78 (s, 2H, CH2) , 7.08 (d, 2H, J= 8.8 Hz) , 7.18 (s, IH, isoxazole-H), 7.26 (s, IH), 7.83 (d, 2H, 7=8.8 Hz) , 8.67 (s, IH).
S-94 1.32 (t, 3H, CH2CH3, 7=7.6 Hz) , 2.96 (q, 2H, CH2CH3, 7=1.2 Hz), 4.28 (t, IH, 7=6.5 Hz, NH), 5.81 (s, 2H, CH2) , 7.26 (s, IH, isoxazole-H), 7.28 (s, IH) , 7.60 (d, 2H, 7=8.8 Hz) , 7.93 (d, 2H, 7=8.8 Hz) , 8.68 (s, IH).
S-95 1.32 (t, 3H, CH2CH3, 7=7.6 Hz) , 2.96 (q, 2H, CH2CH3, 7=1.2 Hz), 4.31 (t, IH, 7=6.5 Hz, NH), 5.81 (s, 2H, CH2) , 7.26 (s, IH, isoxazole-H), 7.28 (s, IH) , 7.60 (d, 2H, 7=8.8 Hz) , 7.93 (d, 2H, 7=8.8 Hz) , 8.68 (s, IH).
S-96 1.33 (t, 3H, CH2CH3, 7=7.6 Hz) , 2.97 (q, 2H, CH2CH3, 7=1.2 Hz), 4.33 (t, IH, 7=6.5 Hz, NH), 5.83 (s, 2H, CH2) , 7.13(s, IH, isoxazole-H), 7.27 (s, IH) , 7.47-7.58 (m, 2H), 7.64-7.66 (m, IH) , 7.67-7.72 (m, IH) , 8.69 (s, IH).
S-97 1.33 (t, 3H, CH2CH3, 7=7.6 Hz) , 2.95 (q, 2H, CH2CH3, 7=1.2 Hz), 4.38 (t, IH, 7=6.5 Hz, NH), 5.83 (s, 2H, CH2) , 7.16 (s, IH, isoxazole-H), 7.26 (s, IH) , 7.58-7.60 (m, IH), 7.75 (d, IH, 7=8.4 Hz), 7.85 (s, IH) , 8.69 (s, IH) .
S-98 1.32 (t, 3H, CH2CH3, 7=7.6 Hz) , 2.96 (q, 2H, CH2CH3, 7=1.2 Hz), 4.32 (t, IH, 7=6.5 Hz, NH), 5.81 (s, 2H, CH2) , 7.27 (s, IH, isoxazole-H), 7.28 (s, IH) , 7.74 (d, IH, 7=8.4 Hz), 7.86 (d, IH, 7=8.4 Hz), 8.66 (s, IH) .
S-99 1.32 (t, 3H, CH2CH3, 7=7.6 Hz) , 2.96 (q, 2H, CH2CH3, 7=1.2 Hz), 4.37 (t, IH, 7=6.5 Hz, NH), 5.81 (s, 2H, CH2) , 7.27 (s, IH, isoxazole-H), 7.28 (s, IH) , 7.74 (d, IH, 7=8.4 Hz), 7.86 (d, IH, 7=8.4 Hz), 8.66 (s, IH) .
S-100 1.34 (t, 3H, CH2CH3, 7=7.2 Hz) , 2.92 (q, 2H, CH2CH3, 7=0.8 Hz) , 3.83 (s, 6H, 20CH3) , 4.26 (t, IH, 7=6.5 Hz, NH) , 5.81 (s, 2H, CH2) , 7.25 (s, IH, isoxazole-H), 7.23-7.24 (m, 2H) , 7.62 (d, IH, 7=2.0 Hz) , 8.70 (s, IH) .
S-101 2.44 (s, 3H, CH3), 2.47 (s, 3H, CH3) , 5.80 (s, 2H, CH2) , 7.21 (s, IH, isoxazole-H), 7.51-7.52 (m, 3H) , 7.88-7.90 (m, 2H) , 8.62 (s, IH).
S-102 2.21(s, 3H, CH3), 2.26 (s, 3H, CH3) , 2.51 (s, 3H, CH3) , 5.80 (s, 2H, CH2) , 7.16 (s, IH, isoxazole-H), 7.33 (d, IH, 7=7.6 Hz) , 7.79 (d, IH, 7=6.8 Hz) , 8.62 (s, IH) .
S-103 2.43 (s, 3H, CH3), 2.47 (s, 3H, CH3) , 3.82 (s, 3H, Ph— 0CH3) , 5.78 (s, 2H, CH2) , 7.05 (d,
Figure imgf000032_0001
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's)39 "8 ' (ZH r "8=7 'HZ 'P) 98 "i ' (ZH 8 "8=7 'HZ 'P L 'L ' (H-9IOZBXOST 'Ηχ 's) w '
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'(¾) 's)08 "5 '(HN 'ZH 5 "9=7 Ήΐ 'ΐ)8ε ' (¾3 's)it7 ' (¾3 's)et? ill-S
"(HI 's)e9 "8
'(HI 'ω)ε/, "i- "/, '(HI 'iD)99 ' - W ' '(HZ '∞) 85 'L-Lr "i ' (H-9IOZBXOST 'Ηχ 's)
'(¾) 's)38 "5 '(HN 'ZH 5 "9=7 Ήΐ ' εε ' (¾3 's) 6t? ' (¾3 's)et? 9II-S
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's)39 "8 ' (ZH 8 "8=7 'HZ 'P)t?6 "i ' (ZH r "8=7 'HZ 'P)09 "i ' (H-9IOZBXOST 'Ηχ 's) w '
'(¾) 's)8i "5 '(HN 'ZH 5 "9=7 'HI ' ) K ' (¾3 's)6t? ' (¾3 's)et? 5II-S
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's)39 "8 ' (ZH 8 "8=7 'HZ 'P)t?6 "i ' (ZH r "8=7 'HZ 'P)09 "i ' (H-9IOZBXOST 'Ηχ 's) w '
'(¾) 's)8i "5 '(HN 'ZH 5 "9=7 'HI ' ) 83 ' (¾3 's)6t? ' (¾3 's)et?
Figure imgf000032_0002
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Figure imgf000032_0003
'HI 'P)6i "/, ' (ZH 9 "/,=/ 'HI 'Ρ)εε "/, '(H-9IOZBXOST 'Ηχ 's)9i · , ' (¾3 's)08 "5 '(HN 'ZH "9=7 'HI 6Z ' (¾3 's) IS ' (¾3 's) 93 ' (¾3 's) zu-s
"(HI 's) 39 "8 '(HZ 'ω)06 "i-88 "i '(He 'ui) - ,-χς · , ' (H-9IOZBXOST 'Ηχ 's)
'(¾) 's)08 "5 '(HN 'ZH 9 "9=7 'HI ' CHD 's)it7 ' (¾3 III-S
"(HI 's) 39 "8 ' (ZH 0 =Γ Ήΐ 'Ρ) Z9 "i '(HZ '∞) 'L-il "i ' (H-9IOZBXOST 'Ηχ 's ' '(¾) 's)08 "5 ' CHDOZ: Ή9 's)e8 ' (¾3 ' (¾3 on-s
"(HI 's)39 "8 '(ZH t? "8=r 'HZ 'P) 98 "i ' (ZH 8 "8=7 'HZ 'P L 'L '(H-9IOZBXOST Ήχ 's)w ' '(¾) 's)08 "5 ' (¾3 ' (¾3 's)et? 60I-S
"(HI 's)39 "8 '(ZH t? "8=r 'HZ 'P) 98 "i ' (ZH 8 "8=7 'HZ 'P L 'L '(H-9IOZBXOST Ήχ 's)w ' '(¾) 's)08 "5 ' (¾3 ' (¾3 's)et? 80I-S
"(HI 's)69 "8 '(HI 's)S8 "i ' (ZH r "8=7 'HI 'P) 5i "i '(HI 'ω)09 "i-85 "i '(HI 's) 93 "i '(H-9IOZBXOST Ήχ 's)w ' '(¾) 's)08 "5 ' (¾3 Lr ' (¾3 's)et? iOI-S
"(HI 's)e9 "8 '(HI '^ L 'L-U 'L '(HI 'ia)99 'i- W ' '(HZ 'ω) 85 "i-it? "i '(H-9IOZBXOST Ήχ 's)w ' '(¾) 's)J8 "5 ' (¾3 's) 6t? ' (¾3 's)et? 90I-S
"(HI 's)39 "8 ' (ZH 8 "8=7 'HZ 'P) t?6 "i ' (ZH "8=7 'HZ 'P)09 "i '(H-9IOZBXOST Ήχ 's)w' '(¾) Ήζ: 's) 8i "S ' (¾3 Ήε 's) 6t? ' (¾3 Ήε 's)et? 50I-S
"(HI 's)39 "8 ' (ZH 8 "8=7 'HZ 'P) t?6 "i ' (ZH "8=7 'HZ 'P)09 "i '(H-9IOZBXOST Ήχ 's)w' '(¾) Ήζ: 's) 8i "S ' (¾3 Ήε 's) 6t? ' (¾3 Ήε 's)et? t^ox-s
"(HI 's)39 "8 ' (ZH 8 "8=7 'HZ 'P) t?8 "i ' (H-9IOZBXOST 'Ηχ 's) w ·Α ' (ZH 8 "8=7
119T80/Z10ZN3/X3d 998£請 ΪΟΖ OAV '(HZ 'ω) 85 "i-it? "/, '(H-9IOZBXOST 'Ηχ 's) 60 'L ' (¾3 's) 18 "5 ' (HN 'zH 5 "9=7
'HI '^)93 'CHD 'ω) 36 -68 ' (¾3 'ω) 98 -t?8 Ί ' (¾33 'Ht? 'ω)58 Ί-1% "I 9ex-s
Figure imgf000033_0001
'Ρ)ε6 "/, ' (ZH "8=7 'P)65 "i ' (H-9IOZBXOST 'Ηχ 's) ' (¾3 's)6i "5 '(HN 'ZH 5 "9=7 'HI ' ) K ' (H3 'ω)ε6 -I6 ' (H3 'ω)ε8 Ί ' (Ht? '∞) i8 "I-I8I eex-s
"(HI 's)39 "8 '(ZH t?"8=r Ήΐ 'P) 98 "i ' (ZH "8=7 'HI 'Ρ)ε/, "/, '(H-9IOZBXOST 'Ηχ 's)W ' (¾3 'HZ 's) 6i "5 ' (HN 'zH 5 "9=7
'HI ^)LZ '(¾) 'ω)06 -88 ' (¾3 'ω)/,8 -ε8 '(¾)∑： 'Ht? 'ω) t?8 "1-38 "I t^ex-s
"(HI 's)39 "8 ' (ZH 8 "8=7 'HZ 'P) 38 "i ' (H-9IOZBXOST 'Ηχ 's)n'i ' (ZH 8 "8=7 ' ) iO "/, '(¾) 's)8i "5 ' (HN 'zH 5 "9=7 'HI ' CHDO-Md Ήε 'S 6 '(¾) 'HZ 'ω) 16 -88 ' (¾3 'ω) 98 -t?8 '(¾)∑： 'Ht? 'ω) t?8 "1-38 "I εεχ-s
"(HI 's)39 "8 ' (ZH 0 "8=7 'P)8i "i ' (ZH 0 "8=7
' )εε "/, '(H-9IOZBXOST Ήχ 's)9i · , ' (¾3 's) 8i "5 ' (HN 'zH 5 "9=7 'HI LZ
'CHD 'ZH 9 =/ 'H3 ' ) 15 Ί ' (¾3 'ZH 8 =" 'H3 '^)05 ' (¾33 'Ht? '∞) t?8 "1-38 "I
"(HI 's)e9 "8 '(HZ 'ω)06 "i-88 "i '(Ηε 'ω) 35 "i-I5 "i ' (H-9IOZBXOST 'Ηχ 's)or ' (¾3 's) 8i "5 ' (HN 'zH 5 "9=7
'HI '(¾) 'ω)ε6 -06 ' (¾3 'ω)58 -ε8 '(¾)∑： 'Ht? 'ω) t?8 "1-38 "I ιεχ-s
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' (ZH "8=7 'P)8i "/, ' (ZH r "8=7 'P) IL "i ' (H-9IOZBXOST 'Ηχ 's)8I 'L ' (¾3
's)6i "5 ' CHDOZ: Ή9 'S 8 ' (¾3 'ω) i8 -t?8 '(¾)∑： 'Ht? 'ω)ε8 "1-38 "I οεχ-s
"(HI 's)e9 "8
' (ZH r "8=7 'P) 98 "i ' (ZH r "8=7 'P) 5i "i ' (H-9IOZBXOST 'Ηχ 's) 8I 'L ' (¾3
's)6i "5 '(¾) 'ω)06 -88 ' (¾3 'ω) i8 -t?8 '(¾)∑： 'Ht? 'ω)ε8 "1-38 "I 6ZIS
"(HI 's)39 "8
' (ZH r "8=7 'HI 'P) 98 "i ' (ZH "8=7 'HI 'P L 'L ' (H-9IOZBXOST 'Ηχ 's) ' (¾3
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Figure imgf000033_0002
'HI 'P) 58 "/, '(HI 'w)9L 'L- 'L '(HI 'ω)09 "i-85 "i ' (H-9IOZBXOST 'Ηχ 's)n ·, ' (¾3
's)I8 "5 '(¾) 'ω)ε6 -16 ' (¾3 'ω) t?8 '(¾)∑： 'Ht? 'ω)ε8 "1-38 "I LZl-S
"(HI 's)e9 "8 '(HZ 'ω)ε/, "i-^9 "i '(HZ '∞) 85 "i-it? "i ' (H-9IOZBXOST 'Ηχ 's) 60 ' ' (¾3
's)I8 "5 '(¾) 'ω) Z6 -68 ' (¾3 'ω) 98 -t?8 '(¾)∑： 'Ht? 'ω)58 "1-38 "I 9ZIS
"(HI 's) 39 "8 ' (ZH 8 "8=7 'HZ 'Ρ)ε6 "i ' (ZH r "8=7 'HZ 'P) 65 "i ' (H-9IOZBXOST 'Ηχ 's)e3 "/, '(¾) 's)6i "5 '(HZ 'ω)ε6 -I6 '(HZ 'ω)ε8 ' (Ht? '∞) i8 "I-I8I ξΖΙ-S
"(HI 's)39 "8
' (ZH r "8=7 'HI 'P) 98 "i ' (ZH "8=7 'HI 'P L 'L ' (H-9IOZBXOST 'Ηχ 's) ' (¾3
's)6i "5 '(¾) 'ω)06 -88 ' (¾3 'ω)/,8 -ε8 '(¾)∑： 'Ht? 'ω) t?8 "1-38 "I HIS
"(HI 's)39 "8 ' (ZH 8 "8=7 ' ) 38 "i '(H-9IOZBXOST Ήχ 's)ei 'L ' (ZH 8 "8=7 'HZ 'P) iO "i ' (¾3 'HZ 's) 8i "5 ' CHDO-Md Ήε 'S 6 '(¾) 'HZ 'ω) 16 -88 ' (¾3 'ω) 98 -t?8 '(¾)∑： 'Ht? 'ω) t?8 "1-38 "I
"(HI 's)39 "8
' (ZH 0 "8=7 'HZ 'P)8i "/, ' (ZH 0 "8=7 'Ρ)εε "i ' (H-9IOZBXOST 'Ηχ 's)9i ·, ' (¾3
's)8i "5 '(¾) 'ω) 35 -I5 ' (¾3 'ω)05 -6t? '(¾)∑： 'Ht? 'ω) t?8 "1-38 "I zzi-s
"(HI 's)e9 "8 '(HZ 'ω)06 "i-88 "i '(Ηε 'ω) Ζζ "i-I5 "i ' (H-9IOZBXOST 'Ηχ 's)or ' (¾3
's)8i "5 '(¾) 'ω)ε6 -I6 ' (¾3 'ω) t?8 '(¾)∑： 'Ht? 'ω) t?8 "1-38 "I I-S
119T80/Z10ZN3/X3d 998£請 ΪΟΖ OAV 7. 64-7. 73 (m, 2H) , 8. 63 (s, 1H) .
S-137 1. 82-1. 83 (m, 4H, 2CH2) , 2. 82-2. 84 (m, 2H, CH2) , 2. 91— 2. 93 (m, 2H, CH2) , 4. 28 (t, 1H, 7=6. 5 Hz, NH) , 5. 81 (s, 2H, CH2) , 7. 11 (s, 1H, i soxazole— H) , 7. 58-7. 60 (m, 1H) , 7. 74-7. 76 (m, 1H) , 7. 85 (d, 1H, 7=2. 0 Hz) , 8. 63 (s, 1H) .
S-138 1. 82-1. 83 (m, 4H, 2CH2) , 2. 84-2. 87 (m, 2H, CH2) , 2· 88— 2· 91 (m, 2H, CH2) , 4. 28 (t, 1H, 7=6. 5 Hz, NH) , 5. 79 (s, 2H, CH2) , 7. 23 (s, 1H, i soxazole— H) , 7. 73 (d, 1H, 7=8. 4 Hz) , 7. 86 (d, 1H, 7=8. 4 Hz) , 8. 62 (s, 1H) .
S-139 1. 82-1. 83 (m, 4H, 2CH2) , 2. 84-2. 87 (m, 2H, CH2) , 2. 88— 2. 90 (m, 2H, CH2) , 4. 27 (t, 1H, 7=6. 5 Hz, NH) , 5. 79 (s, 2H, CH2) , 7. 18 (s, 1H, i soxazole— H) , 7. 75 (d, 2H, 7=8. 4 Hz) , 7. 86 (d, 2H, 7=8. 4 Hz) , 8. 63 (s, 1H) .
S-140 1. 82-1. 83 (m, 4H, 2CH2) , 2. 84-2. 87 (m, 2H, CH2) , 3. 83 (s, 6H, 20CH3) , 4. 26 (t, 1H, 7=6. 5 Hz, NH) , 5. 79 (s, 2H, CH2) , 7. 18 (s, 1H, i soxazole— H) , 7. 72 (d, 2H, 7=8. 4 Hz) , 7. 78 (d, 2H, 7=8. 4 Hz) , 8. 63 (s, 1H) . 实施例 4 本发明化合物药学上可接受的盐的制备
以 5-曱基 -4- [ (3-苯基-异噁唑 -5-基) -曱氧基-] -瘘吩 [2, 3-d]嘧啶 的盐酸盐和醋酸盐的制 备来说明之， 其余化合物的盐的制备同该过程。
(1) 5-曱基 _4_ [ (3-苯基-异噁唑 -5-基) -曱氧基-] -噻吩 [2, 3-d]嘧啶盐酸盐的制备 将 0. 5 mmol的 5_曱基 -4- [ (3-苯基-异噁唑 _5_基) -曱氧基-] -噻吩 [2, 3-d]嘧啶加入 20 mL ( V V, 1: 1) 5%的盐酸溶液和曱醇混合溶液中， 微热搅拌使其溶解后， 室温緩慢蒸发结晶即得 5-曱 基 -4- [ (3-苯基-异噁唑 -5-基) -曱氧基-] -噻吩 [2, 3-d]嘧啶盐酸盐， 白色固体， 收率： 72%。
(2) 5-曱基 _4_ [ (3-苯基-异噁唑 -5-基) -曱氧基-] -噻吩 [2, 3-d]嘧啶醋酸盐的制备： 将 0· 5 ol 5-曱基 -4- [ (3-苯基-异噁唑 -5-基) -曱氧基-] -噻吩 [2, 3_d]嘧啶加入盛有 10 mL 干燥二氯曱烷的 50 mL单口圓底烧瓶中， 搅拌下加入 2 mL冰乙酸， 30°C— 40°C搅拌 l—2h,冷却 后冷藏结晶， 过滤， 真空干燥后即得 5-曱基 -4- [ (3-苯基-异噁唑 -5-基) -曱氧基-] -噻吩 [2, 3-d] 嘧啶乙酸盐， 无色固体， 收率： 58%。 实施例 5
采用 SRB 法进行了抗大肠癌细胞株（HCT-116)和人肺癌细胞株（A549)活性筛选， 筛选过程 参考文献（Li Μ· H.； Miao Z. H.； Tan W. F. et al. Cl in. Cancer Res. 2004, 10 (24) : 8266—8274)。
具体的实验步骤如下：
(1) 根据肿瘤细胞的生长速率， 将处于对数生长期的大肠癌细胞株 (HCT-116)接种于 96孔 培养板， 贴壁生长 24小时后， 将 1 10—4M的药品加入， 其浓度设 3个复孔， 并设相应浓度的生 理盐水对照及无细胞调零孔， 肿瘤 /癌细胞在 37 °C、 5%C02条件下培养 72小时； （2) 取出培养板， 每孔用 10%冷三乙酸（TCA)溶液固定细胞， 4 °C放置 1小时； （3) 弃固定液， 用蒸榴水洗涤 5次， 空气中自然干燥； （4) 然后加入由 1%的冰乙酸配制的 SRB溶液， 室温染色 15分钟； (5) 去上清 液， 用 1%的醋酸溶液洗涤 5次， 空气干燥； （6) 最后加入 Tr i s溶液， 在平板震荡器上震荡 5分 钟。 用可调波长式微孔板酶标仪测 560nm波长下的吸光度值（A56„：)。 采用如下的公式计算酶抑制 率。
Figure imgf000035_0001
测得式（I)所示的化合物或其盐在 1 χ 10—4Μ浓度下抑制大肠癌细胞珠 (HCT-116) 和人肺癌 细胞 A549的活性。 实验结果见下表 5和表 6
表 5- 式（I)中部分实施例化合物抑制大肠癌细胞珠 (HCT-116)活性测试结果
Figure imgf000035_0002
式（I)中部分实施例化合物抑制人肺癌细胞 A549的活性测试结果
Figure imgf000035_0003

Claims

权利 要求
1.一种式（I)所示的噻吩 [2 -d]嘧啶衍生物或其药学上可接受的盐或溶剂化物，
Figure imgf000036_0001
其中：
R R2可以相同或不同， 各自独立地选自氢， d_6烷基， d_6烷氧基、 卤代 d_6烷基、 卤代 烷氧基或羟基取代的 d-6的烷基， 任选被 R7取代的芳基或任选被 R8取代的杂芳基；
或者！^和 R2与其相连的碳原子一起形成 4至 6元碳环或杂环， 所述碳环或杂环任选被 R11 取代； 所述杂环含有至少 1个选自 N， 0或 S的杂原子；
Z为 -NR5-， C (R6) 2， -S-或 -0-, 其中 R5为氢或 d_6烷基， R6相同或不同， 选自氢， d-6的烷 基， 卤代 d-6的烷基或羟基取代的 d-6的烷基；
R3选自氢、 卤素、 d_6烷基、 d_6烷氧基、 卤代 d_6烷基， 卤代 d_6烷氧基或羟基取代的 d-6的烷基， n为 0~5的整数；
R4选自氢、 d_6烷基、 d_6烷氧基、 卤代 d_6烷基或卤代 d_6烷氧基， 任选被 R'取代的芳基 或任选被 R1"取代的杂芳基；
R'、 R8、 R'、 R1"或 R11各自独立地选自氢， 羟基， 巯基， 氛基， 氨基， d— 6烷基氨基， 二（d— 6 烷基）氨基， 硝基， 卤素， d_6烷基， d_6烷氧基， d_6烷硫基， 羧基， 卤代 d_6烷基， 卤代 d_6 烷氧基或代 d— 6烷硫基。
2. 根据权利要求 1的噻吩 [2, 3-d]嘧啶衍生物或其药学上可接受的盐或溶剂化物， 其中
R R2可以相同或不同， 各自独立地选自氢， d_3烷基， CH烷氧基、 卤代 d_6烷基、 卤代 烷氧基， 苯基或被 R7取代的苯基， 或者
！^和 R2与其相连的碳原子一起形成 4至 6元碳环， 所述碳环任选被氢， d_6烷基， 卤素， 硝基或氨基取代；
R4选自氢， d_6烷基， d_6烷氧基， 卤代 d_6烷基， 苯基或被 R'取代的苯基。
3. 根据权利要求 1或 2的噻吩 [2, 3-d]嘧啶衍生物或其药学上可接受的盐或溶剂化物， 其中
R R2各自独立地选自氢， d_3烷基， 苯基或被 R7取代的苯基， 更优选为氢、 曱基、 乙基、 丙基、 异丙基、 丁基、 异丁基、 叔丁基或苯基； Z为— NH-, CH2或 -0-;
R3选自氢、 氟、 氯、 溴、 曱基、 曱氧基或三氟曱基， n优选为 1-4， 更优选为 2-3.
R4选自氢、 d— 6烷基、 d— 6烷氧基或卤代 d— 6烷基， 苯基或取代苯基。
还更优选地， ^和112可以相同或不同， 各自独立地选自 d— 6烷基， 苯基或被 R7取代的苯基， 更优选为氢、 曱基、 乙基、 叔丁基、 苯基， 更优选！^选自氢， 曱基， 苯基； R2选自氢， 曱基， 乙 基或叔丁基；
Z为 -NH-或 -0-， R3优选在异噁唑环的邻位或对位， 更优选为 4-氟、 4-氯、 2-氯、 4-溴、 2, 4-二氯、 4-曱基、 4-曱氧基、 氢、 4-三氟曱基或 2, 4-二曱氧基；
R4选自氢、 曱基或苯基。
4. 根据权利要求 1-3任一项的噻吩 [2, 3-d]嘧啶衍生物或其药学上可接受的盐， 其中所述的化
Figure imgf000037_0001
S-10 S-1 1 S-12
Figure imgf000038_0001
Il9l80/Z10ZN3/X3d 998£請 ΪΟΖ OAV 
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000040_0002
Figure imgf000041_0001
Figure imgf000042_0001
S-124 S-125 S-126
Figure imgf000043_0001
5. 一种药物组合物， 其包括权利要求 1-4任一项式（I)所示的噻吩 [2, 3-d]嘧啶化合物， 或其药 学上可接受的盐， 以及至少一种药学上可接受的、 惰性的、 无毒的赋形剂或载体或稀释剂。 优选地， 所述药物组合物还包含一种或多种选自填充剂、 崩解剂、 润滑剂、 助流剂、 泡腾剂、 矫味剂、 防腐剂和包衣材料的药学可接受的辅助材料。
6. 根据权利要求 5所述的药物组合物， 其特征在于， 所述药物组合物为制剂形式， 优选为固体 口服制剂、 液体口服制剂或注射剂。 优选地， 所述制剂选自片剂、 片、 肠溶片、 咀嚼片、 口崩片、 胶囊、 颗粒剂、 口服溶液剂、 注射用水针、 注射用冻干粉针、 大输液或小输液。
7. 用作药物的权利要求 1-4的式（I)所示的噻吩 [2, 3-d]嘧啶化合物或其药学上可接受的盐， 尤 其是一种用于治疗肿瘤 /癌症的药物。
8. —种权利要求 1-4任一项的式（I)所示的瘘喻 [2, 3-d]嘧啶化合物或其药学上可接受的盐在制 备用于抗肿瘤或癌症药物中的应用。 优选所述的肿瘤或癌症选自： 膀胱癌、 非小细胞肺癌、 卵 巢癌、 乳腺癌、 胃癌、 食道癌、 肺癌、 头颈癌、 结肠癌、 咽癌和胰腺癌等， 更优选非小细胞肺 癌。
9. 一种权利要求 卜 4 中任一项的式（I)所示的噻吩 [2, 3-d]嘧啶化合物和 /或药学上可接受的盐 在制备抑制 EGFR的过渡表达和 /或活性过高的抑制剂中的应用。
10. 一种权利要求 1-4任一项的式（ I )所示的噻吩 [2, 3-d]嘧啶化合物的制备方法，其特征在于： 所述的方法包括如下步骤：
2, 5, 6-三取代 -4-氯 -噻吩 [2, 3-d]嘧啶（式 11)和 3-取代苯基 -5-羟曱基-异噁唑（式 111)或 3- -5-氨曱基-异噁唑 (式 VI)为原料， 在干燥的有机溶剂和碱性縛酸剂体系中反应制备：
Figure imgf000044_0001
如果需要， 形成式 I化合物的药学上可接受的盐或溶剂化物。
PCT/CN2012/081611 2012-09-19 2012-09-19 噻吩[2,3-d]嘧啶衍生物、其制备方法及其用途 WO2014043866A1 (zh)

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