WO2016192131A1 - 激酶抑制剂及其应用 - Google Patents

激酶抑制剂及其应用 Download PDF

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WO2016192131A1
WO2016192131A1 PCT/CN2015/081483 CN2015081483W WO2016192131A1 WO 2016192131 A1 WO2016192131 A1 WO 2016192131A1 CN 2015081483 W CN2015081483 W CN 2015081483W WO 2016192131 A1 WO2016192131 A1 WO 2016192131A1
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compound
formula
group
membered
evaporated
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PCT/CN2015/081483
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English (en)
French (fr)
Inventor
王学海
许勇
李莉娥
盛锡军
黄璐
张晓林
乐洋
黄文杰
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湖北生物医药产业技术研究院有限公司
人福医药集团股份公司
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Publication of WO2016192131A1 publication Critical patent/WO2016192131A1/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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention is in the field of medicine and relates to novel compounds as kinase inhibitors. Specifically, the present invention relates to compounds as ALK inhibitors, and to the use of these compounds in the preparation of a medicament for the treatment and prevention of cancer.
  • Non-small-cell carcinoma is synonymous with "non-small cell carcinoma.”
  • Non-small cell lung cancer including squamous cell carcinoma, adenocarcinoma, and large cell carcinoma, has slower growth and cell division and longer metastatic spread than small cell carcinoma.
  • Non-small cell lung cancer accounts for about 80-85% of the total number of lung cancers. The data show that the incidence of lung cancer in China is increasing by 26.9% per year. From 2000 to 2005, the number of lung cancer cases in China is estimated to increase by 120,000. Among them, the number of male lung cancer patients increased from 260,000 in 2000 to 330,000 in 2005, and the number of female lung cancer patients increased from 120,000 to 170,000. In addition, lung cancer has become the "first cancer" in many parts of the country.
  • the treatment of advanced NSCLC has entered the era of individualized treatment.
  • the individualized targeted therapy for clinical application is mainly aimed at EGFR mutant and ALK (Anaplastic lymphoma kinase) fusion genotype lung cancer. Both genetic variant lung cancers have clear molecular targets and target detection.
  • the clinical efficacy of the technology and marketed targeted drugs has been significantly improved.
  • the ALK mutation in lung cancer is mainly caused by the rearrangement of ALK gene and other gene fusion. Gene abnormalities at the ALK locus are reported to be associated with a variety of cancers. Echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion due to chromosomal rearrangement has been reported in non-small cell lung cancer (NSCLC) patient populations.
  • EML4-ALK Echinoderm microtubule-associated protein-like 4
  • crizotinib protein kinase inhibitors
  • NSCLC protein kinase inhibitors
  • crizotinib protein kinase inhibitors
  • patients who are effective in the treatment of crizotinib usually develop resistance after 6 months to 1 year of treatment.
  • the most common adverse events observed in two crizotinib clinical studies were visual impairment, nausea, diarrhea, vomiting, edema, and constipation. The incidence of adverse events was ⁇ 25%. Therefore, the development of a safer and more efficient treatment of cancer, ALK inhibitor drugs have great social and economic benefits, and is also a research hotspot of major pharmaceutical companies.
  • the present invention is directed to solving at least some of the above technical problems or at least providing a useful commercial choice. To this end, it is an object of the present invention to provide a compound which is a kinase inhibitor which can be used for the preparation of a medicament for treating cancer.
  • the invention proposes a compound.
  • the compound is a pharmaceutically acceptable salt, hydrate, solvate, metabolite, or prodrug of a compound of Formula I or a compound of Formula I,
  • R 1 is halogen or In some embodiments of the invention, R 1 may be fluorine, chlorine or
  • R 2 is a 5-6 membered cycloalkyl group, a 5-6 membered heterocyclic group, a 5-6 membered aryl group, or a 5-6 membered heteroaryl group, according to an embodiment of the invention, said 5-6 membered naphthenic acid
  • the base, 5-6 membered heterocyclic group, 5-6 membered aryl group and 5-6 membered heteroaryl group are each independently selected from one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, C 1-8 alkyl.
  • R 2 is one of the following:
  • R 1 is fluorine or chlorine
  • R 2 is one of the following:
  • R 1 is And R 2 is one of the following:
  • the compound of the formula I of the present invention may be at least one selected from the group consisting of:
  • pharmaceutically acceptable salt is a conventional non-toxic salt formed by reacting a compound of the formula I with an inorganic or organic acid.
  • the conventional non-toxic salt can be prepared by reacting a compound of the formula I with an inorganic or organic acid.
  • the inorganic acid may be hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aminosulfonic acid, phosphoric acid, etc.
  • the organic acid may include citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, Methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalene disulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid , hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, and ise
  • a "pharmaceutically acceptable salt" of the compound of formula I may also be obtained by previously reacting a compound of formula I with propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, The tartaric acid, citric acid, aspartic acid or glutamic acid forms an ester and then forms a sodium salt, a potassium salt, a calcium salt, an aluminum salt or an ammonium salt with an inorganic base.
  • the compound of formula I forms a methylamine salt, an ethylamine salt or an ethanolamine salt with an organic base.
  • the compound of the formula I forms an ester with lysine, arginine or ornithine, and then forms a corresponding mineral acid salt with hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid or phosphoric acid or with formic acid or acetic acid.
  • picric acid, methanesulfonic acid and ethanesulfonic acid form the corresponding organic acid salt.
  • prodrug means that once the compound is administered to a subject, the compound is chemically converted by metabolic or chemical processes to provide a compound of formula I and/or Salt and / or solvate. Any compound that can be converted in vivo to provide a biologically active substance (ie, a compound of Formula I) is in the present invention Prodrugs within the scope and subject matter. For example, a compound containing a carboxyl group can form a physiologically hydrolyzable ester which is prepared by hydrolysis in vivo to give the compound of formula I itself.
  • the prodrug is preferably administered orally because hydrolysis occurs in many cases primarily under the influence of digestive enzymes. Parenteral administration can be used when the ester itself is active or hydrolysis occurs in the blood.
  • hydrates, solvates e.g., methanolates, ethanolates, DMSOs
  • Methods of solvation are well known in the art.
  • the invention provides a process for the preparation of a compound of the formula ⁇ .
  • a method of preparing a compound of the formula ⁇ includes:
  • R 1 and R 2 in the compound of Formula 1, the compound of Formula 2, the compound of Formula 3, the compound of Formula 5, and the compound of Formula I are as defined in the foregoing description. .
  • the inventors have found that the method of the above examples of the present invention can rapidly and efficiently prepare the compound of the formula I, and has a short synthetic route, is environmentally friendly, has high yield and purity of the target product, and is easy to obtain, easy to handle and post-treat. Suitable for industrial production.
  • the synthetic route of the compound of formula I is:
  • Step (1) Preparation of a compound (intermediate) represented by Formula 3
  • the compound of the formula 1 is contacted with the compound of the formula 2 in the presence of NaH in the first organic solvent.
  • the first organic solvent may be selected from the group consisting of N-methylpyrrolidone, N,N-dimethylformamide (DMF), dimethyl sulfoxide, dimethylacetamide, N,N- At least one of dimethylacetamide.
  • the first organic solvent is DMF.
  • the compound represented by the formula 1 is contacted with the compound of the formula 2 at 0 °C.
  • the yield of the compound of the formula 3 can be further improved by selecting an appropriate reaction temperature.
  • the molar ratio of the compound of the formula 1 to the compound of the formula 2 may be (25-30): (15-30).
  • the molar ratio of the compound of Formula 1 to the compound of Formula 2 may be (27-28): (20-26). Further, the yield of the compound represented by Formula 3 can be increased while saving the raw material cost.
  • the preparation of the compound (intermediate) of the formula 3 can be carried out according to the following steps: the compound of the formula 2 is dissolved in DMF, and NaH is added in portions at 0 ° C, and the addition is completed. After the reaction mixture was further stirred at 0 ° C for half an hour, 2,5,6-trichloropyrimidine (the compound of the formula 1) was added dropwise to the reaction solution at 0 ° C, and after the completion of the dropwise addition, the mixture was naturally allowed to rise to room temperature. Stir under overnight. After completion of the reaction, the mixture was diluted with ice water and extracted with ethyl acetate. The combined organic layer was washed three times with saturated brine, dried and concentrated under reduced pressure.
  • 2,5,6-trichloropyrimidine the compound of the formula 1
  • Step (2) Preparation of a compound (intermediate) represented by formula 5
  • the compound of the formula 3 is contacted with the compound of the formula 4 in the presence of p-toluenesulfonic acid in isopropanol, and the temperature is raised to 60 to 80 ° C.
  • the stirring reaction was carried out.
  • the compound of Formula 3 and the compound of Formula 4 provide a good reaction environment, thereby increasing the yield of the compound of Formula 5.
  • the compound of the formula 5 is contacted with dioxane hydrochloride, and the reaction is carried out by contact stirring at 15 to 25 ° C for 1.5 to 5 hours. Thereby, the yield of the compound of the formula I can be increased.
  • the present invention provides an intermediate according to a specific embodiment of the present invention, wherein the intermediate is a compound represented by Formula 5, and the compound of Formula 5 is a preparation of Formula I of the present invention.
  • the intermediate of the compound can be used to prepare the compound of the formula I according to the compound of the formula 5.
  • R 1 is halogen or According to a preferred embodiment of the invention, R 1 is fluorine, chlorine or
  • R 2 is one of the following:
  • R 1 is fluorine or chlorine
  • R 2 is one of the following:
  • R 1 is And R 2 is one of the following:
  • the invention proposes a pharmaceutical composition.
  • the pharmaceutical composition contains a compound as described above.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or a combination thereof.
  • the pharmaceutical composition is in the form of a tablet, capsule, injection, powder, powder, syrup, solution, suspension or aerosol.
  • the pharmaceutical composition of the above embodiments of the invention may be present in a suitable solid or liquid carrier or diluent and in a suitable sterilizing device for injection or drip.
  • compositions of the present invention can be prepared according to conventional methods of preparation in the pharmaceutical arts.
  • the compounds and pharmaceutical compositions of the present invention can be administered to mammals clinically, including humans and animals, and can be administered by the route of the mouth, nose, skin, lungs or the gastrointestinal tract. Regardless of the method of administration, the optimal dosage for the individual should be based on the specific treatment regimen. Usually starting with a small dose, gradually increase the dose until the most suitable dose is found. The most preferred route of administration is oral.
  • the invention provides the use of a compound as described above, a compound prepared by the method described above or a pharmaceutical composition as described above for the preparation of a medicament for use as an ALK inhibitor .
  • the use of a compound of the invention in the manufacture of a medicament for the treatment or prevention of a disease responsive to inhibition of anaplastic lymphoma kinase, wherein an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof is administered It can be used for treating a disease responsive to inhibition of anaplastic lymphoma kinase, which is selected from the group consisting of anaplastic large cell lymphoma, non-Hodgkin's lymphoma, inflammatory myofibroblast At least one of a tumor, a neuroblastoma, and a tumor disease.
  • the medicament is for use in at least one of the following: as a kinase inhibitor, inhibiting ALK kinase activity, treating or preventing cancer and inhibiting proliferation of cancer cells.
  • the results of the assay for the in vitro ALK kinase inhibitory activity of the compound show that the compounds of the formula I of the present invention all have good ALK kinase inhibitory activity, and the compounds of the present invention can be used as An ALK inhibitor for the preparation of an anti-tumor therapeutic agent in a disease responsive to inhibition of anaplastic lymphoma kinase.
  • the compound of the formula I of the present invention has a remarkable curative effect on the growth inhibition of human lung cancer A549 cells in nude mice, and the curative effect is superior to the existing ALK inhibitor drug crizotinib.
  • the cancer in which the drug can be treated or prevented is preferably lung cancer; inhibiting the proliferation of cancer cells preferably inhibits lung cancer cells.
  • the agents of the present invention are effective as ALK inhibitors for the treatment of one or more neoplastic diseases associated with ALK activity, including but not limited to lung cancer.
  • ALK inhibitors for the treatment of one or more neoplastic diseases associated with ALK activity, including but not limited to lung cancer.
  • the kinase inhibitor of the present invention and its use as an ALK inhibitor have good clinical application and medical use.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS).
  • NMR nuclear magnetic resonance
  • LC-MS liquid chromatography-mass spectrometry
  • TLC thin layer chromatography
  • the system used for the reaction was: dichloromethane and methanol system, n-hexane/petroleum ether and ethyl acetate system, volume ratio of solvent. The adjustment is made according to the polarity of the compound.
  • Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm. ⁇ 0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.
  • the system of the eluent for column chromatography and the developer system for thin layer chromatography using the purified compound in the following examples include: A: dichloromethane and methanol systems, B: n-hexane/petroleum ether and ethyl acetate systems,
  • the volume ratio of the solvent is adjusted depending on the polarity of the compound, and may be adjusted by adding a small amount of an alkaline or acidic reagent such as triethylamine or acetic acid.
  • the starting materials used in the following examples may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Rui Chemicals and other companies.
  • An embodiment of the invention provides a compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, metabolite thereof or Prodrugs, methods and intermediates for the preparation of a compound of the formula guanidine or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, pharmaceutical compositions, and the use of the compounds and pharmaceutical compositions of the invention in the manufacture of a medicament.
  • the compound of formula a (15 g, 106.31 mmol), potassium carbonate (29.38 g, 212.61 mmol) was placed in a 500 mL round bottom flask, 150 ml of DMF was added, and isopropyl mercaptan (the compound of formula b) was added with stirring. (8.5g, 111.62mmol), the mixture was stirred and heated to 80 ° C, and reacted for 5 hours. After the reaction was completed, the reaction solvent was evaporated under reduced pressure. The obtained crude product was washed with water, ethyl acetate, dried, concentrated, and purified by column chromatography. Compound shown by c (yield 19.5 g, yield 95%).
  • the compound of formula e (20.4 g, 88.98 mmol) was placed in a 500 mL hydrogenation flask, and 250 ml of methanol was added. After replacing with nitrogen, 1000 mg of palladium on carbon (Pd content: 5%) was added to the bottle, and after replacement with a hydrogen balloon, The mixture was stirred overnight under a hydrogen atmosphere (1 atm). After the reaction was completed, the reaction mixture was filtered, and the filtrate was evaporated to dryness to give a compound of formula 2-a (yield: 15.95 g, yield: 90%).
  • the compound of formula f (14.2 g, 0.1 mol), potassium carbonate (27.6 g, 0.2 mol) was placed in a 500 mL round bottom flask, 150 ml of DMF was added, and isopropyl mercaptan (the compound of formula b) was added with stirring. (8.0 g, 0.105 mol), the mixture was stirred and heated to 75 ° C, and reacted for 6 hours. After the reaction was completed, the reaction solvent was evaporated under reduced pressure, and the obtained crude product was washed with water, ethyl acetate. The ester was extracted, dried and concentrated, and the compound was obtained by column chromatography (yield: 17.9 g, yield: 92.5%).
  • the compound of the formula h (23.0 g, 0.1 mol) was placed in a 500 mL hydrogenation flask, and 250 ml of methanol was added. After replacing with nitrogen, 1000 mg of palladium carbon (Pd content: 5%) was added to the bottle, and after replacement with a hydrogen balloon, The mixture was stirred overnight under hydrogen (1 atm). After the reaction was completed, the reaction mixture was filtered, and the filtrate was evaporated to dryness to give the compound of formula 2-b (yield: 18.6 g, yield 93.5%).
  • the compound of formula j (15.9 g, 0.1 mmol), potassium carbonate (27.6 g, 0.2 mmol) was placed in a 500 mL round bottom flask, 150 ml of DMF was added, and isopropyl mercaptan (the compound of formula b) was added with stirring. (8.0g, 0.105mol), the mixture was stirred and heated to 80 ° C, and reacted for 5 hours. After the reaction was completed, the reaction solvent was evaporated under reduced pressure. the obtained crude material was washed with water, ethyl acetate, dried, and concentrated. The compound of formula g (yield 18.1 g, yield 93%).
  • the compound of the formula h (23.0 g, 0.1 mol) was placed in a 500 mL hydrogenation flask, and 250 ml of methanol was added. After replacing with nitrogen, 1000 mg of palladium carbon (Pd content: 5%) was added to the bottle, and after replacement with a hydrogen balloon, The mixture was stirred overnight under a hydrogen atmosphere (1.5 atm). After the reaction was completed, the reaction mixture was filtered, and the filtrate was evaporated to dryness to give a compound of formula 2-b (yield: 18.4 g, yield 92%).
  • the compound of formula k (16.4 g, 0.1 mol), potassium carbonate (27.6 g, 0.2 mol) was placed in a 500 mL round bottom flask, 150 ml of DMF was added, and isopropyl mercaptan (the compound of formula b) was added with stirring. (8.0g, 0.105mol), the mixture was stirred and heated to 75 ° C, and reacted for 6 hours. After the reaction was completed, the reaction solvent was evaporated under reduced pressure. the obtained crude material was washed with water, ethyl acetate, dried, and concentrated. The compound of the formula m (amount of 18.3 g, yield 92%).
  • reaction solution was poured into 50 ml of water and extracted with ethyl acetate (50 mL ⁇ 3), Washed, washed with brine, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated, evaporated. 64.85%).
  • the compound of the formula 2-a (5 g, 25.09 mmol) was dissolved in DMF (100 mL), and NaH (0.66 g, 27.6 mmol) was slowly added at 0 ° C. After the addition, the reaction mixture was further stirred at 0 ° C.
  • the compound of the formula 1-c (5.93 g, 27.6 mmol) was added dropwise to the reaction mixture at 0 ° C, and after the addition was completed, the mixture was naturally stirred at room temperature overnight. After completion of the reaction, the mixture was quenched with EtOAc (EtOAc) (EtOAc). 1) A compound of the formula 3-a (amount of 3.41 g, yield 36%) was obtained.
  • the compound of the formula 2-b (5 g, 25.09 mmol) was dissolved in DMF (100 mL). NaH (0.66 g, 27.6 mmol) was slowly added at 0 ° C. After the addition, the reaction mixture was stirred at 0 ° C for half.
  • the compound of the formula 1-c (5.93 g, 27.6 mmol) was added dropwise to the reaction mixture at 0 ° C, and after the addition was completed, the mixture was naturally stirred at room temperature overnight. After completion of the reaction, the mixture was quenched with EtOAc (EtOAc) (EtOAc). 1) A compound of the formula 3-b (amount of 3.23 g, yield 34%) was obtained.
  • the compound of the formula 2-b (5 g, 25.09 mmol) was dissolved in DMF (100 mL). NaH (0.66 g, 27.6 mmol) was slowly added at 0 ° C. After the addition, the reaction mixture was stirred at 0 ° C for half.
  • the compound of the formula 1-a (5.06 g, 27.6 mmol) was added dropwise to the reaction mixture at 0 ° C, and after the addition was completed, the mixture was naturally stirred at room temperature overnight. After completion of the reaction, the mixture was quenched with EtOAc (EtOAc) (EtOAc). 1) Compounds of formula 3-d (The amount was 2.70 g, the yield was 31%).
  • the compound of the formula 3-b (2.2 g, 5.76 mmol) was dissolved in 60 mL of isopropanol, and the compound of the formula 4-a (1.53 g, 5.76 mmol) and p-toluenesulfonic acid (993 mg, 5.76 mmol) were added thereto. The mixture was stirred at a temperature of 80 ° C for 6 hours. After the reaction was completed by TLC, the solvent was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The compound of the formula 5-c (1.92 g, yield 55%) was obtained.
  • the compound of the formula 3-b (2.2 g, 5.76 mmol) was dissolved in 60 mL of isopropanol, and the compound of the formula 4-b (1.53 g, 5.76 mmol) and p-toluenesulfonic acid (993 mg, 5.76 mmol) were added thereto. The mixture was stirred at a temperature of 60 ° C for 10 hours. After the reaction was completed by TLC, the solvent was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The compound of the formula 5-d (2.45 g, yield 70%) was obtained.
  • the compound of the formula 3-c (2 g, 5.45 mmol) was dissolved in 60 mL of isopropanol, and the compound of the formula 4-a (1.53 g, 5.76 mmol) and p-toluenesulfonic acid (993 mg, 5.76 mmol) were added thereto. The mixture was stirred at 70 ° C for 10 hours. After the reaction was completed by TLC, the solvent was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The compound of the formula 5-e (1869 mg, yield 56%) was obtained.
  • the compound of the formula 3-c (2 g, 5.45 mmol) was dissolved in 60 mL of isopropanol, and the compound of the formula 4-b (1.53 g, 5.76 mmol) and p-toluenesulfonic acid (993 mg, 5.76 mmol) were added thereto. The mixture was stirred at a temperature of 80 ° C for 6 hours. After the reaction was completed by TLC, the solvent was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The compound of the formula 5-f (2.504 g, yield 75%) was obtained.
  • the compound of the formula 3-d (2 g, 5.76 mmol) was dissolved in 60 mL of isopropanol, and the compound of the formula 4-a (1.53 g, 5.76 mmol) and p-toluenesulfonic acid (993 mg, 5.76 mmol) were added thereto. The mixture was stirred at a temperature of 80 ° C for 6 hours. After the reaction was completed by TLC, the solvent was evaporated, evaporated, evaporated, evaporated, evaporated. The compound of the formula 5-g (2.12 g, yield 64%) was obtained.
  • the compound of the formula 3-d (2 g, 5.76 mmol) was dissolved in 60 mL of isopropanol, and the compound of the formula 4-b (1.53 g, 5.76 mmol) and p-toluenesulfonic acid (993 mg, 5.76 mmol) were added thereto. The mixture was stirred at a temperature of 60 ° C for 6.5 hours. After the reaction was completed by TLC, the solvent was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The compound of the formula 5-h (2058 mg, yield 62%) was obtained.
  • the compound of the formula 3-e (2 g, 5.68 mmol) was dissolved in 60 mL of isopropanol, and the compound of the formula 4-b (1.53 g, 5.76 mmol) and p-toluenesulfonic acid (993 mg, 5.76 mmol) were added thereto.
  • the mixture was stirred at a temperature of 80 ° C for 6 hours.
  • the solvent was evaporated under reduced pressure, and the residual solid was dispersed in 200 mL of acetic acid.
  • the organic layer was washed with saturated aqueous sodium hydrogen sulfate, water and brine, dried over anhydrous sodium sulfate.
  • the compound of the formula 3-f (1.73 g, 5.24 mmol) was dissolved in 60 mL of isopropanol, and the compound of the formula 4-a (1.53 g, 5.76 mmol) and p-toluenesulfonic acid (993 mg, 5.76 mmol) were added thereto. The mixture was stirred at a temperature of 70 ° C for 5 hours. After the reaction was completed by TLC, the solvent was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The compound of the formula 5-k (1760 mg, yield 60%) was obtained.
  • the compound of the formula 3-f (1.73 g, 5.24 mmol) was dissolved in 60 mL of isopropanol, and the compound of the formula 4-b (1.53 g, 5.76 mmol) and p-toluenesulfonic acid (993 mg, 5.76 mmol) were added thereto. The mixture was stirred at a temperature of 80 ° C for 6 hours. After the reaction was completed by TLC, the solvent was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The compound of the formula 5-1 (2.58 g, yield 88%) was obtained.
  • the compound of the formula 3-g (1.76 g, 5.24 mmol) was dissolved in 60 mL of isopropanol, and the compound of the formula 4-a (1.53 g, 5.76 mmol) and p-toluenesulfonic acid (993 mg, 5.76 mmol) were added thereto. ), the mixture is at a temperature of 60 ° C, The reaction was stirred for 12 hours. After the reaction was completed by TLC, the solvent was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The compound of the formula 5-m (1479 mg, yield 50%) was obtained.
  • the compound of the formula 3-g (1.76 g, 5.24 mmol) was dissolved in 60 mL of isopropanol, and the compound of the formula 4-b (1.53 g, 5.76 mmol) and p-toluenesulfonic acid (993 mg, 5.76 mmol) were added thereto. The mixture was stirred at a temperature of 80 ° C for 5 hours. After the reaction was completed by TLC, the solvent was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The compound of the formula 5-n (1.625 g, yield 55%) was obtained.
  • the compound of the formula 5-g (400 mg, 0.694 mmol) was placed in a 100 mL reaction flask, and 50 ml of dioxane hydrochloride (2M) was added thereto, and the mixture was stirred at 20 ° C for 2 hours. After completion of the reaction, the mixture was filtered and washed with diethyl ether. The filter cake gave the product of the compound of formula I-1 (281 mg, yield: 85%).
  • the compound of the formula 5-h (400 mg, 0.694 mmol) was placed in a 100 mL reaction flask, and 50 ml of dioxane hydrochloride (2M) was added thereto, and the mixture was stirred at 15 ° C for 5 hours. After completion of the reaction, the mixture was filtered and washed with diethyl ether. The filter cake gave the product of the compound of formula I-2 (231 mg, yield 70%).
  • the compound of the formula 5-i (400 mg, 0.688 mmol) was placed in a 100 mL reaction flask, and 50 ml of dioxane hydrochloride (2M) was added thereto, and the mixture was stirred at 20 ° C for 2.5 hours. After completion of the reaction, the mixture was filtered and washed with diethyl ether. The filter cake gave the product of the compound of formula I-3 (385 mg, yield 92%).
  • the compound of the formula 5-j (400 mg, 0.688 mmol) was placed in a 100 mL reaction flask, 50 ml of dioxane hydrochloride (2M) was added, and the mixture was stirred at 25 ° C for 1.5 hours. After completion of the reaction, the mixture was filtered and washed with diethyl ether. The filter cake is shown in formula I-4 The product of the compound (352 mg, yield 84%).
  • the compound of the formula 5-k (400 mg, 0.715 mmol) was placed in a 100 mL reaction flask, and 50 ml of dioxane hydrochloride (2M) was added thereto, and the mixture was stirred at 20 ° C for 3 hours. After the completion of the reaction, the mixture was filtered and washed with diethyl ether. The filter cake gave the product of the compound of formula I-5 (356 mg, yield: 85%).
  • the compound of the formula 5-1 (400 mg, 0.715 mmol) was placed in a 100 mL reaction flask, and 50 ml of dioxane hydrochloride (2M) was added thereto, and the mixture was stirred at 20 ° C for 2 hours. After completion of the reaction, the mixture was filtered and washed with diethyl ether. The filter cake gave the product of the compound of formula I-6 (335 mg, yield 80%).
  • the compound of the formula 5-m (400 mg, 0.709 mmol) was placed in a 100 mL reaction flask, and 50 ml of dioxane hydrochloride (2M) was added thereto, and the mixture was stirred at 15 ° C for 2.5 hours. After completion of the reaction, the mixture was filtered and washed with diethyl ether. The filter cake gave the product of the compound of formula I-7 (293 mg, yield 70%).
  • the compound of the formula 5-n (400 mg, 0.709 mmol) was placed in a 100 mL reaction flask, and 50 ml of dioxane hydrochloride (2M) was added thereto, and the mixture was stirred at 18 ° C for 4 hours. After completion of the reaction, the mixture was filtered and washed with diethyl ether. The filter cake gave the product of the compound of formula I-8 (327 mg, yield 78%).
  • the compound of the formula 5-c (400 mg, 0.676 mmol) was placed in a 100 mL reaction flask, and 50 ml of dioxane hydrochloride (2M) was added thereto, and the mixture was stirred at 25 ° C for 2 hours. After completion of the reaction, the mixture was filtered and washed with diethyl ether. The filter cake gave the product of the compound of formula I-9 (399 mg, yield 93%).
  • the compound of the formula 5-d (400 mg, 0.676 mmol) was placed in a 100 mL reaction flask, and 50 ml of dioxane hydrochloride (2M) was added thereto, and the mixture was stirred at 20 ° C for 5 hours. After completion of the reaction, the mixture was filtered and washed with diethyl ether. The filter cake gave the product of the compound of formula I-10 (390 mg, yield 91%).
  • the compound of the formula 5-e (400 mg, 0.670 mmol) was placed in a 100 mL reaction flask, and 50 ml of dioxane hydrochloride (2M) was added thereto, and the mixture was stirred at 25 ° C for 1.5 hours. After completion of the reaction, the mixture was filtered and washed with diethyl ether. The filter cake gave the product of the compound of formula I-11 (343 mg, yield 80%).
  • the compound of the formula 5-f (400 mg, 0.670 mmol) was placed in a 100 mL reaction flask, and 50 ml of dioxane hydrochloride (2M) was added thereto, and the mixture was stirred at 25 ° C for 2 hours. After completion of the reaction, the mixture was filtered and washed with diethyl ether. The filter cake gave the product of the compound of formula I-12 (360 mg, yield 84%).
  • the compound of the formula 5-a (400 mg, 0.677 mmol) was placed in a 100 mL reaction flask, and 50 ml of dioxane hydrochloride (2M) was added thereto, and the mixture was stirred at 15 ° C for 3 hours. After completion of the reaction, the mixture was filtered and washed with diethyl ether. The filter cake gave the product of the compound of formula I-13 (317 mg, yield 74%).
  • the compound of the formula 5-b (400 mg, 0.677 mmol) was placed in a 100 mL reaction flask, and 50 ml of dioxane hydrochloride (2M) was added thereto, and the mixture was stirred at 20 ° C for 2 hours. After completion of the reaction, the mixture was filtered and washed with diethyl ether. The filter cake gave the product of the compound of formula I-14 (334 mg, yield 78%).
  • Example 43 Determination of ALK kinase inhibitory activity
  • the inhibitory activity of the compound of the present invention against ALK kinase in vitro was measured by the following method, which is expressed by the index of IC50, which is the concentration of the compound when the activity of ALK kinase is inhibited by 50%.
  • Staurosporine (Sigma, Cat. No. S4400-1MG, Lot. No. 046K4080)
  • the compound was mixed into the intermediate plate and shaken for 10 minutes.
  • A1 in a 96-well plate was transferred to A1 and A2 in a 384-well plate.
  • A2 in a 96-well plate was transferred to A3 and A4 in a 384-well plate.
  • the kinase was added to 1X kinase buffer to form a 2.5 fold enzyme solution.
  • the FAM-labeled polypeptide and ATP were added to 1X kinase buffer to form a 2.5-fold substrate solution.
  • test plate already contained 5 ⁇ l of a 10% solution of the compound in DMSO.
  • the conversion rate data is read on Caliper.
  • the compounds I-1, I-2, I-3, I-7, I-8, I-9, I-12 and I-14 of the present invention each have an IC50 of less than 10 nM
  • the compound I-4 of the present invention The IC50 of I-5, I-6, I-10, I-11, and I-13 are all less than 100 nM, and at 10 nM to 100 nM, all compounds have IC50 values of less than 100 nM.
  • Example 44 Tablets for oral administration, see Table 2 for prescriptions
  • Table 2 Tablet prescriptions for oral administration
  • Example 45 Effect of the compound of the present invention on the growth of human lung cancer A549 cells transplanted in nude mice
  • A549 cells of logarithmic growth phase lung cancer cell line A549 were prepared, and the concentration of A549 cells was adjusted to 3 ⁇ 10 7 /mL with sterile PBS.
  • 0.1 ml of A549 cells were inoculated subcutaneously in the back of BALB/c-nu mice, and the volume of subcutaneous transplanted tumors was 75 mm. At around 3 (about 10 days), the model was manufactured successfully.
  • tumor volume and weight-bearing principle of tumor-bearing mice were divided into the following 8 groups, 12 in each group:
  • model control group the same amount of normal saline was administered once a day for 30 days;
  • oxaliplatin group intraperitoneal injection of 10 mg / kg oxaliplatin, once every other day, a total of 8 times;
  • crizotinib group intragastric administration of crizotinib capsules (produced by Pfizer, trade name: seri) powder, the dose is 25mg / kg, 2 times / day, a total of 8 times;
  • the compound group of the formula I-1 the tablet powder prepared according to the example 44 was administered by gavage at a dose of 10 mg/kg twice daily for 30 days;
  • the test results in Table 4 showed that compared with the model control group, the inhibition effects of the treatment groups on the growth of human lung cancer A549 cells in nude mice were significantly different, especially compared with the model control group.
  • the compound of formula I-1 has a significant difference in the inhibition of human lung cancer A549 cell xenografts in nude mice (P ⁇ 0.01), and is combined with the chemotherapy oxaliplatin group and the ALK inhibitor crizotinib group.
  • the average tumor inhibition rate is improved, which indicates that the compound of the present invention has extremely remarkable curative effect in treating non-small cell lung cancer, and has the advantages of low toxicity and side effects while obtaining remarkable pharmacological effects, and an unexpected technique is obtained. effect.

Abstract

本发明提供了激酶抑制剂及其应用。该化合物为式I所示化合物或式I所示化合物的可药用盐、水合物、溶剂化物、代谢产物或前药，其中，R1、R2如说明书所定义。

Description

激酶抑制剂及其应用 技术领域
本发明属于医药领域，涉及作为激酶抑制剂的新颖化合物，具体的，本发明涉及作为ALK抑制剂的化合物，以及这些化合物在制备用于治疗和预防癌症的药物中的应用。
背景技术
非小细胞肺癌(Non-small-cell carcinoma,NSCLC)与“非小细胞癌”同义。非小细胞型肺癌，包括鳞癌、腺癌、大细胞癌，与小细胞癌相比其癌细胞生长分裂较慢，扩散转移相对较晚。非小细胞肺癌约占肺癌总数的80-85％。数据显示，目前我国肺癌发病率每年增长26.9％，自2000年至2005年间，中国肺癌的发病人数估计增加12万人。其中，男性肺癌病人从2000年的26万人增加到2005年的33万人，同期女性肺癌患者从12万人增加到17万人。此外，肺癌也成为全国多地区的“众癌之首”。北京市肺癌发病率自2001年至2010年增长56％。十年间，北京新发癌症患者中五分之一为肺癌患者；浙江省肿瘤医院发布的2011年浙江省“癌谱”中，肺癌依然是排名第一的癌症；广州地区与30年前相比，肺癌发病率增长了7倍。
随着分子医学进展和靶向药物的不断涌现，晚期NSCLC的治疗已进入到个体化治疗的时代。目前临床应用的个体化靶向治疗主要针对EGFR突变型和ALK(Anaplastic lymphoma kinase，间变性淋巴瘤激酶)融合基因型肺癌，这两种基因变异型肺癌均具有明确的分子靶点、靶点检测技术及上市的靶向药物，临床疗效得到明显提高。肺癌中ALK变异主要为ALK基因发生重排与其他基因融合。据报道ALK基因位点上的基因异常与多种癌症有关。由于染色体重排导致的棘皮动物微管关联蛋白样4(EML4)-ALK融合在非小细胞肺癌(NSCLC)患者群中已有报道。
虽然人们已经研究了大量的对蛋白激酶有抑制活性的化合物，且一些蛋白激酶抑制剂如克唑替尼等已经上市用于NSCLC的治疗，但是会产生耐药性，存在一定程度的缺陷。如克唑替尼治疗有效的患者通常在用药6个月至1年后就会发生耐药。而且，两项克唑替尼临床研究观察到的最常见的不良反应为视力障碍、恶心、腹泻、呕吐、水肿和便秘，不良反应发生率≥25％。因而，开发出更安全、高效的治疗癌症的新型ALK抑制剂药物具有巨大的社会价值和经济效益，也是目前各大药企的研究热点。
因此，目前的ALK抑制剂仍有待改进。
发明内容
本发明旨在至少在一定程度上解决上述技术问题之一或至少提供一种有用的商业选择。为此，本发明的一个目的在于提出一种能够用于制备治疗癌症的药物的作为激酶抑制剂的化合物。
根据本发明的一个方面，本发明提出了一种化合物。根据本发明的实施例，所述化合物为式I所示化合物或式I所示化合物的可药用盐、水合物、溶剂化物、代谢产物、或前药，
Figure PCTCN2015081483-appb-000001
其中，
R1为卤素或
Figure PCTCN2015081483-appb-000002
在本发明的一些实施例中，R1可以为氟、氯或
Figure PCTCN2015081483-appb-000003
R2为5-6元环烷基、5-6元杂环基、5-6元芳基、或5-6元杂芳基，根据本发明的实施例，所述5-6元环烷基、5-6元杂环基、5-6元芳基和5-6元杂芳基各自独立地被一个或多个选自卤素、羟基、氰基、硝基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、C5-10芳基、5-10元杂芳基、C1-6烷氧基、C3-8环烷氧基、-S(O)pR5、-C(O)R5、-C(O)OR5、-NR6R7或-C(O)NR7的取代基取代，其中，R5、R6、R7各自独立地为氢或Cl-4烷基，p为0、1或2。
在本发明的一些实施例中，R2为下列之一：
Figure PCTCN2015081483-appb-000004
根据本发明的实施例，R1为氟或氯，且R2为下列之一：
Figure PCTCN2015081483-appb-000005
根据本发明的实施例，R1为
Figure PCTCN2015081483-appb-000006
且R2为下列之一：
Figure PCTCN2015081483-appb-000007
本领域技术人员可以理解，根据本领域中使用的惯例，在本申请的结构式中，
Figure PCTCN2015081483-appb-000008
用于描绘化学键，所述化学键为部分或取代基与核心结构或骨架结构相连的点。另外，本申请的结构式中，
Figure PCTCN2015081483-appb-000009
用于描述苯环上的取代基位置为结构式中的与取代基化学键相邻的两个位置，即在该化学式中的圆环标注的位置可发生单取代。
由此，在本说明书通篇中，本领域技术人员可对式I所示化合物中所述R1～R4的基团及其取代基进行选择，以提供本发明的实施例中所述的、稳定的式I所示化合物或其可药用盐、水合物、溶剂化物、代谢产物或前药。
根据本发明的实施例，本发明所述式I所示化合物可以为选自下列的至少一种：
Figure PCTCN2015081483-appb-000011
Figure PCTCN2015081483-appb-000012
在本发明中所使用的术语，“可药用盐”为通式I所示化合物与无机酸或有机酸反应形成的常规的无毒盐。例如，所述常规的无毒盐可通过通式I所示化合物与无机酸或有机酸反应制得。其中，无机酸可以为盐酸、氢溴酸、硫酸、硝酸、胺基磺酸和磷酸等，有机酸可以为包括柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、苯磺酸、对甲苯磺酸、甲磺酸、萘磺酸、乙磺酸、萘二磺酸、马来酸、苹果酸、丙二酸、富马酸、琥珀酸、丙酸、草酸、三氟乙酸、硬酯酸、扑酸、羟基马来酸、苯乙酸、苯甲酸、水杨酸、谷氨酸、抗坏血酸、对胺基苯磺酸、2-乙酰氧基苯甲酸和羟乙磺酸等。或者通式I所示化合物的“可药用盐”也可以通过预先使式I所示化合物与丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、天冬氨酸或谷氨酸形成酯后再与无机碱形成钠盐、钾盐、钙盐、铝盐或铵盐。或者通式I所示化合物与有机碱形成甲胺盐、乙胺盐或乙醇胺盐。或者通式I所示化合物与赖氨酸、精氨酸、鸟氨酸形成酯后再与盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸形成对应的无机酸盐或与甲酸、乙酸、苦味酸、甲磺酸和乙磺酸形成对应的有机酸盐。
在本发明中所使用的术语，“前药”表示一旦将所述化合物给予受试者，所述化合物就通过代谢过程或化学过程来进行化学转化，从而得到式I所示化合物和/或其盐和/或溶剂化物。可在体内转化以提供生物活性物质(即式I所示化合物)的任何化合物是在本发明的 范围和主旨内的前药。例如，含有羧基的化合物可形成生理上可水解的酯，其通过在体内水解以得到式I所示化合物本身而充当前药。所述前药优选口服给药，这是因为水解在许多情况下主要在消化酶的影响下发生。当酯本身具有活性或水解发生在血液中时，可使用肠胃外给药。
还应该理解的是，本发明式I所示化合物的水合物、溶剂化物(例如甲醇化物、乙醇化物、DMSO化物)也在本发明的范围内。溶剂化的方法是本领域公知的。
根据本发明的第二方面，本发明提出了一种制备式Ι所示化合物的方法。根据本发明的实施例，制备式Ι所示化合物的方法包括：
(1)使式1所示化合物与式2所示化合物进行接触，以便获得式3所示化合物；
(2)使式3所示化合物与式4所示化合物进行接触，以便获得式5所示化合物；
(3)使式5所示化合物与盐酸二氧六环进行接触，以便获得式I所示化合物，
Figure PCTCN2015081483-appb-000013
根据本发明的实施例，式1所示化合物、式2所示化合物、式3所示化合物、式5所示化合物、式I所示化合物中的R1和R2为前面描述中所定义的。
发明人发现，利用本发明上述实施例的方法能够快速有效地制备式I所示化合物，且合成路线短、环境友好、目标产物的收率和纯度较高，原料易得、操作及后处理简单、适合工业化生产。
在本发明的一个实施例中，式I所示化合物的合成路线为：
Figure PCTCN2015081483-appb-000014
下面对在本发明的实施例中所采用的制备式I所示化合物的一般方法进行描述：
步骤(1)：式3所示化合物(中间体)的制备
根据本发明的具体实施例，在步骤(1)中，在第一有机溶剂中，在存在NaH时，使式1所示化合物与式2所示化合物接触。根据本发明的具体示例，第一有机溶剂可以为选自N-甲基吡咯烷酮、N,N-二甲基甲酰胺(DMF)、二甲基亚砜、二甲基乙酰胺、N,N-二甲基乙酰胺中的至少一种。在本发明的一个具体示例中，第一有机溶剂为DMF。由此，可以为式1所示化合物和式2所示化合物提供良好的反应环境，进而提高式3所示化合物的收率。
根据本发明的具体示例，在步骤(1)中，在0摄氏度时，使式1所示化合物与式2所示化合物接触。通过选择适宜的反应温度，可以进一步提高制备式3所示化合物的收率。根据本发明的另一个具体示例，在步骤(1)中，式1所示化合物与式2所示化合物的摩尔比可以为(25-30)：(15-30)。根据本发明的优选实施例，式1所示化合物与式2所示化合物的摩尔比可以为(27-28)：(20-26)。进而可以提高式3所示化合物产率的同时，节省原料成本。
根据本发明的一个具体实施例，式3所示化合物(中间体)的制备，具体可以按照下列步骤进行：将式2所示化合物溶于DMF中，在0℃下分批加入NaH，加完后反应液继续在0℃下搅拌半小时，再将2,5,6-三氯嘧啶(式1所示化合物)在0℃下滴入反应液，滴加完毕后，将混合物自然升至室温下搅拌过夜。反应完毕后滴加冰水淬灭，并用乙酸乙酯萃取，合并有机相，经饱和食盐水洗三次后，干燥，减压浓缩，所得粗品经柱层析得产物，为式3所示化合物。
步骤(2)：式5所示化合物(中间体)的制备
根据本发明的具体实施例，在步骤(2)中，在异丙醇中、存在对甲苯磺酸条件下，使式3所示化合物与式4所示化合物接触，并升温至60～80℃进行搅拌反应。由此，可以为 式3所示化合物和式4所示化合物提供良好的反应环境，进而提高式5所示化合物的收率。
步骤(3)：式I所示化合物的制备
根据本发明的具体实施例，在步骤(3)中，式5所示化合物与盐酸二氧六环进行接触，在15-25摄氏度条件下接触搅拌1.5～5小时进行反应。由此，可以提高式I所示化合物的产率。
根据本发明的第三方面，本发明提出了一种中间体，根据本发明的具体实施例，所述中间体为式5所示的化合物，该式5所示化合物是制备本发明式I所示化合物的中间体，利用式5所示化合物，可用于制备成本发明式I所示化合物。
Figure PCTCN2015081483-appb-000015
其中，R1为卤素或
Figure PCTCN2015081483-appb-000016
根据本发明的优选实施例，R1为氟、氯或
Figure PCTCN2015081483-appb-000017
R2为下列之一：
Figure PCTCN2015081483-appb-000018
根据本发明的实施例，R1为氟或氯，且R2为下列之一：
Figure PCTCN2015081483-appb-000019
根据本发明的实施例，R1为
Figure PCTCN2015081483-appb-000020
且R2为下列之一：
Figure PCTCN2015081483-appb-000021
根据本发明的第四方面，本发明提出了一种药物组合物。根据本发明的具体实施例，该药物组合物含有前面所述的化合物。根据本发明的具体示例，药物组合物进一步包含药学上可接受的载体、赋形剂、稀释剂、辅剂、媒介物或其组合。
根据本发明的具体实施例，药物组合物呈片剂、胶囊、注射剂、粉针剂、粉剂、糖浆、溶液状、悬浮液或气雾剂。由此可以显著提高该药物组合物的适用性。并且本发明上述实施例的药物组合物可以存在于适宜的固体或液体的载体或稀释液中和适宜的用于注射或滴注的消毒器具中。
本发明的药物组合物的各种剂型可按照药学领域的常规制备方法制备。本发明的化合物和药物组合物可对哺乳动物临床使用，包括人和动物，可以通过口、鼻、皮肤、肺或者胃肠道等的途径给药。不管采用何种服用方法，个人的最佳剂量应依据具体的治疗方案而定。通常情况下是从小剂量开始，逐渐增加剂量一直到找到最适合的剂量。最优选的给药途径为口服。
根据本发明的第五方面，本发明提出了前面所述的化合物、前面所述的方法制备得到的化合物或前面所述的药物组合物在制备药物中的用途，所述药物用作ALK抑制剂。
根据本发明的实施例，本发明化合物在制备用于治疗或预防对抑制间变性淋巴瘤激酶有响应的疾病的药物中的用途，其中施用有效量的本发明化合物或其药学可接受的盐，可用于治疗对抑制间变性淋巴瘤激酶有响应的疾病，所述对抑制间变性淋巴瘤激酶有响应的疾病为选自间变性大细胞淋巴瘤、非霍奇金淋巴瘤、炎性肌纤维母细胞瘤、神经母细胞瘤和肿瘤疾病中的至少一种。
根据本发明的具体实施例，所述药物用于下列至少之一：用作激酶抑制剂，抑制ALK激酶活性、治疗或者预防癌症和抑制癌细胞的增殖。根据本发明的具体示例，本发明对所述化合物在体外ALK激酶抑制活性测定实验结果显示，本发明所述式I所示化合物均具有良好的ALK激酶抑制活性，本发明所述化合物可用作ALK抑制剂，用于制备成对抑制间变性淋巴瘤激酶有响应的疾病的抗肿瘤治疗药物。
根据本发明的具体示例，本发明所述式I所示化合物对人肺癌A549细胞裸鼠移植瘤生长的抑制作用均具有显著的疗效，且疗效优于现有ALK抑制剂药物克唑替尼。本发明所述 药物可以治疗或者预防的癌症优选肺癌；抑制癌细胞的增殖优选抑制肺癌细胞。
因此，本发明所述药物能够有效作为ALK抑制剂，用于治疗一种或一种以上与ALK活性有关的肿瘤疾病，所述肿瘤疾病包括但不限于肺癌。本发明所述的激酶抑制剂及其应用，其作为ALK抑制剂，具有良好的临床应用和医药用途。
本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。
具体实施方式
下面详细描述本发明的实施例。下面描述的实施例是示例性的，仅用于解释本发明，而不能理解为对本发明的限制。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。
在下面所描述的具体实施例中，化合物结构是通过核磁共振(NMR)或/和液质联用色谱(LC-MS)来确定。其中，NMR位移(δ)以百万分之一(ppm)的单位给出，NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)；液质联用色谱LC-MS的测定用Agilent 1200Infinity Series质谱仪。HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18150×4.6mm色谱柱)。
下面实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂的体系有：二氯甲烷和甲醇体系，正己烷/石油醚和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节。薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。
下面实施例中纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷和甲醇体系，B：正己烷/石油醚和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
下面实施例中所使用的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。
本发明的实施例提供了式I所示化合物或其可药用盐、水合物、溶剂化物、代谢物或 前药，制备式Ι所示化合物或其可药用盐、水合物、溶剂化物或前药的方法和中间体、药物组合物、以及本发明的化合物和药物组合物在制备药物中的用途。
Figure PCTCN2015081483-appb-000022
实施例1：制备式2-a所示化合物(中间体)
Figure PCTCN2015081483-appb-000023
将式a所示化合物(15g,106.31mmol)，碳酸钾(29.38g,212.61mmol)置于500mL圆底瓶中，加入150毫升DMF，在搅拌下加入异丙硫醇(式b所示化合物)(8.5g,111.62mmol)，将混合物搅拌加热至80℃，反应5小时，反应完毕后减压蒸去反应溶剂，所得粗品经水洗，乙酸乙酯萃取，干燥后浓缩，经柱层析得式c所示化合物(得量19.5g，产率95％)。
将式c所示化合物(19.5g,98.86mmol)和间氯过氧苯甲酸(mCPBA，式d所示化合物)(60.2g，348.84mmol)置于1000mL圆底瓶中，加入500毫升二氯甲烷，将混合物在室温下搅拌过夜，用饱和亚硫酸钠水溶液淬灭，二氯甲烷萃取，经饱和碳酸钾溶液，饱和食盐水洗，干燥，旋干，再经柱层析得式e所示化合物(得量20.4g，产率90％)。
将式e所示化合物(20.4g,88.98mmol)置于500mL氢化瓶中，加入250毫升甲醇，氮气置换后将1000mg钯炭(Pd含量5％)加入到瓶中，用氢气球置换后，在氢气(1atm)条件下搅拌过夜，监测反应完毕后将反应液过滤，滤液减压旋干即得式2-a所示化合物(得量15.95g，产率90％).
实施例2：制备式2-b所示化合物(中间体)
Figure PCTCN2015081483-appb-000024
将式f所示化合物(14.2g,0.1mol)，碳酸钾(27.6g,0.2mol)置于500mL圆底瓶中，加入150毫升DMF，在搅拌下加入异丙硫醇(式b所示化合物)(8.0g,0.105mol)，将混合物搅拌加热至75℃，反应6小时，反应完毕后减压蒸去反应溶剂，所得粗品经水洗，乙酸乙 酯萃取，干燥后浓缩，经柱层析得式g所示化合物(得量17.9g，产率92.5％)。
将式g所示化合物(19.8g,0.1mol)和间氯过氧苯甲酸(mCPBA，式d所示化合物)(60.9g，0.35mol)置于1000mL圆底瓶中，加入500毫升二氯甲烷，将混合物在室温下搅拌过夜，用饱和亚硫酸钠溶液淬灭，二氯甲烷萃取，经饱和碳酸钾溶液，饱和食盐水洗，干燥，旋干，再经柱层析得式h所示化合物(得量21.1g，产率92％)。
将式h所示化合物(23.0g,0.1mol)置于500mL氢化瓶中，加入250毫升甲醇，氮气置换后将1000mg钯炭(Pd含量5％)加入到瓶中，用氢气球置换后，在氢气(1atm)条件下搅拌过夜，监测反应完毕后将反应液过滤，滤液减压旋干即得式2-b所示化合物(得量18.6g，产率93.5％).
实施例3：制备式2-b所示化合物(中间体)
Figure PCTCN2015081483-appb-000025
将式j所示化合物(15.9g,0.1mmol)，碳酸钾(27.6g,0.2mmol)置于500mL圆底瓶中，加入150毫升DMF，在搅拌下加入异丙硫醇(式b所示化合物)(8.0g,0.105mol)，将混合物搅拌加热至80℃，反应5小时，反应完毕后减压蒸去反应溶剂，所得粗品经水洗，乙酸乙酯萃取，干燥后浓缩，经柱层析得式g所示化合物(得量18.1g，产率93％)。
将式g所示化合物(19.8g,0.1mol)和间氯过氧苯甲酸(mCPBA，式d所示化合物)(48.7g，0.28mol)置于1000mL圆底瓶中，加入500毫升二氯甲烷，将混合物在室温下搅拌过夜，用饱和亚硫酸钠溶液淬灭，二氯甲烷萃取，经饱和碳酸钾溶液，饱和食盐水洗，干燥，旋干，再经柱层析得式h所示化合物(得量21.5g，产率93.5％)。
将式h所示化合物(23.0g,0.1mol)置于500mL氢化瓶中，加入250毫升甲醇，氮气置换后将1000mg钯炭(Pd含量5％)加入到瓶中，用氢气球置换后，在氢气(1.5atm)条件下搅拌过夜，监测反应完毕后将反应液过滤，滤液减压旋干即得式2-b所示化合物(得量18.4g，产率92％).
实施例4：制备式2-c所示化合物(中间体)
Figure PCTCN2015081483-appb-000026
将式k所示化合物(16.4g,0.1mol)，碳酸钾(27.6g,0.2mol)置于500mL圆底瓶中，加入150毫升DMF，在搅拌下加入异丙硫醇(式b所示化合物)(8.0g,0.105mol),将混合物搅拌加热至75℃，反应6小时，反应完毕后减压蒸去反应溶剂，所得粗品经水洗，乙酸乙酯萃取，干燥后浓缩，经柱层析得式m所示化合物(得量18.3g，产率92％)。
将式m所示化合物(20.3g,0.1mol)和间氯过氧苯甲酸(mCPBA，式d所示化合物)(60.9g，0.35mol)置于1000mL圆底瓶中，加入500毫升二氯甲烷，将混合物在室温下搅拌过夜，用饱和亚硫酸钠溶液淬灭，二氯甲烷萃取，经饱和碳酸钾溶液，饱和食盐水洗，干燥，旋干，再经柱层析得式n所示化合物(得量21.7g，产率92.5％)。
将式n所示化合物(23.5g,0.1mol)置于500mL氢化瓶中，加入250毫升甲醇，氮气置换后将1000mg钯炭(Pd含量5％)加入到瓶中，用氢气球置换后，在氢气(1atm)条件下搅拌过夜，监测反应完毕后将反应液过滤，滤液减压旋干即得式2-c所示化合物(得量18.9g，产率92％)。
实施例5：制备式4-a所示化合物(中间体)
Figure PCTCN2015081483-appb-000027
将(叔丁氧羰基)甘氨酸(式6所示化合物)(1g,5.7mmol)溶于15mL干燥的DMF中，依次加入N，N-二异丙基乙胺(DIPEA)(2.21g,17mmol)，HATU(化学名称为2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯)(2.34g,6.15mmol)和间苯二胺(式7所示化合物)(616mg,5.7mmol),室温下搅拌反应过夜，将反应液倒入50毫升水中，并用乙酸乙酯萃取(50mL×3),合并有机相，经饱和碳酸钠水溶液洗，食盐水洗，无水硫酸钠干燥，过滤，减压浓缩得粗产品，再经柱层析分析(PE/EA＝2:1)得式4-a所示化合物产品(937mg,收率62％)。
实施例6：制备式4-a所示化合物(中间体)
将(叔丁氧羰基)甘氨酸(式6所示化合物)(1g,5.7mmol)溶于15mL干燥的DMF中，依次加入N，N-二异丙基乙胺(DIPEA)(2.21g,17mmol)，HATU(化学名称为2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯)(2.34g,6.15mmol)和间苯二胺(式7所示化合物)(627mg,5.8mmol),室温下搅拌反应过夜，将反应液倒入50毫升水中，并用乙酸乙酯萃取(50mL×3),合并有机相，经饱和碳酸钠水溶液洗，食盐水洗，无水硫酸钠干燥，过滤，减压浓缩得粗产品，再经柱层析分析(PE/EA＝6:1)得式4-a所示化合物产品(980mg,收率 64.85％)。
实施例7：制备式4-b所示化合物(中间体)
Figure PCTCN2015081483-appb-000028
将(叔丁氧羰基)甘氨酸(式6所示化合物)(1g,5.7mmol)溶于15mL干燥的DMF中，依次加入N，N-二异丙基乙胺(DIPEA)(2.21g,17mmol)，HATU(化学名称为2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯)(2.34g,6.15mmol)和对苯二胺(式8所示化合物)(648mg,6.0mmol),室温下搅拌反应过夜，将反应液倒入50毫升水中，并用乙酸乙酯萃取(50mL×3),合并有机相，经饱和碳酸钠水溶液洗，食盐水洗，无水硫酸钠干燥，过滤，减压浓缩得粗产品，再经柱层析分析(PE/EA＝4:1)得式4-b所示化合物产品(1013mg,收率67％)。
实施例8：制备式3-a所示化合物
Figure PCTCN2015081483-appb-000029
将式2-a所示化合物(5g,25.09mmol)溶于DMF(100mL)中,在0℃下慢慢加入NaH(0.66g,27.6mmol)，加完后反应液继续在0℃下搅拌半小时，再将式1-c所示化合物(5.93g,27.6mmol)在0℃下滴入反应液，滴加完毕后，将混合物自然升至室温下搅拌过夜。反应完毕后加入300mL水淬灭，并用乙酸乙酯萃取(200mL×3)，合并有机相，经饱和食盐水洗三次后，干燥，减压浓缩，所得粗品经柱层析(PE/EA＝4:1)得式3-a所示化合物(得量3.41g，产率36％)。
实施例9：制备式3-b所示化合物
Figure PCTCN2015081483-appb-000030
将式2-b所示化合物(5g,25.09mmol)溶于DMF(100mL)中,在0℃下慢慢加入NaH(0.66g,27.6mmol)，加完后反应液继续在0℃下搅拌半小时，再将式1-c所示化合物(5.93g,27.6mmol)在0℃下滴入反应液，滴加完毕后，将混合物自然升至室温下搅拌过夜。反应完毕后加入300mL水淬灭，并用乙酸乙酯萃取(200mL×3)，合并有机相，经饱和食盐水洗三次后，干燥，减压浓缩，所得粗品经柱层析(PE/EA＝4:1)得式3-b所示化合物(得量3.23g，产率34％)。
实施例10：制备式3-c所示化合物
Figure PCTCN2015081483-appb-000031
将式2-c所示化合物(20.5g,0.1mol)溶于DMF(300mL)中,在0℃下慢慢加入NaH(2.64g,0.11mol)，加完后反应液继续在0℃下搅拌半小时，再将式1-c所示化合物(23.65g,0.1mol)在0℃下滴入反应液，滴加完毕后，将混合物自然升至室温下搅拌过夜。反应完毕后加入600mL水淬灭，并用乙酸乙酯萃取(600mL×3)，合并有机相，经饱和食盐水洗三次后，干燥，减压浓缩，所得粗品经柱层析(PE/EA＝4:1)得式3-c所示化合物(得量11.52g，产率30％)。
实施例11：制备式3-d所示化合物
Figure PCTCN2015081483-appb-000032
将式2-b所示化合物(5g,25.09mmol)溶于DMF(100mL)中,在0℃下慢慢加入NaH(0.66g,27.6mmol)，加完后反应液继续在0℃下搅拌半小时，再将式1-a所示化合物(5.06g,27.6mmol)在0℃下滴入反应液，滴加完毕后，将混合物自然升至室温下搅拌过夜。反应完毕后加入300mL水淬灭，并用乙酸乙酯萃取(200mL×3)，合并有机相，经饱和食盐水洗三次后，干燥，减压浓缩，所得粗品经柱层析(PE/EA＝4:1)得式3-d所示化合物 (得量2.70g，产率31％)。
实施例12：制备式3-e所示化合物
Figure PCTCN2015081483-appb-000033
将式2-c所示化合物(20.5g,0.1mol)溶于DMF(300mL)中,在0℃下慢慢加入NaH(2.64g,0.11mol)，加完后反应液继续在0℃下搅拌半小时，再将式1-a所示化合物(22.04g,0.12mol)在0℃下滴入反应液，滴加完毕后，将混合物自然升至室温下搅拌过夜。反应完毕后加入600mL水淬灭，并用乙酸乙酯萃取(600mL×3)，合并有机相，经饱和食盐水洗三次后，干燥，减压浓缩，所得粗品经柱层析(PE/EA＝4:1)得式3-e所示化合物(得量13.39g，产率38％)。
实施例13：制备式3-f所示化合物
Figure PCTCN2015081483-appb-000034
将式2-b所示化合物(20g,0.1mol)溶于DMF(500mL)中,在0℃下慢慢加入NaH(2.64g,0.11mol)，加完后反应液继续在0℃下搅拌半小时，再将式1-b所示化合物(18.4g,0.11mol)在0℃下滴入反应液，滴加完毕后，将混合物自然升至室温下搅拌过夜。反应完毕后加入500mL水淬灭，并用乙酸乙酯萃取(600mL×3)，合并有机相，经饱和食盐水洗三次后，干燥，减压浓缩，所得粗品经柱层析(PE/EA＝4:1)得式3-f所示化合物(得量14.6g，产率44％)。
实施例14：制备式3-g所示化合物
Figure PCTCN2015081483-appb-000035
将式2-c所示化合物(20g,0.1mol)溶于DMF(500mL)中,在0℃下慢慢加入NaH(2.64g,0.11mol)，加完后反应液继续在0℃下搅拌半小时，再将式1-b所示化合物(18.4g,0.11 mol)在0℃下滴入反应液，滴加完毕后，将混合物自然升至室温下搅拌过夜。反应完毕后加入500mL水淬灭，并用乙酸乙酯萃取(600mL×3)，合并有机相，经饱和食盐水洗三次后，干燥，减压浓缩，所得粗品经柱层析(PE/EA＝4:1)得式3-g所示化合物(得量15.11g，产率45％)。
实施例15：制备式5-a所示化合物
Figure PCTCN2015081483-appb-000036
将式3-a所示化合物(1.98g,5.24mmol)溶于60mL异丙醇中，向其中加入式4-a所示化合物(1.53g,5.76mmol)和对甲苯磺酸(993mg,5.76mmol),将混合物在70℃温度下，搅拌反应8小时。TLC检测反应完毕后，减压蒸去溶剂，将残留固体物分散于200mL乙酸乙酯中，依次用饱和碳酸氢钠水溶液，水和饱和食盐水洗涤，用无水硫酸钠干燥，减压浓缩得式5-a所示化合物(1.27g，产率40％)。
实施例16：制备式5-b所示化合物
Figure PCTCN2015081483-appb-000037
将式3-a所示化合物(1.98g,5.24mmol)溶于60mL异丙醇中，向其中加入式4-b所示化合物(1.53g,5.76mmol)和对甲苯磺酸(993mg,5.76mmol),将混合物在65℃温度下，搅拌反应8小时。TLC检测反应完毕后，减压蒸去溶剂，将残留固体物分散于200mL乙酸乙酯中，依次用饱和碳酸氢钠水溶液，水和饱和食盐水洗涤，用无水硫酸钠干燥，减压浓缩得式5-b所示化合物(2.01g，产率63％)。
实施例17：制备式5-c所示化合物
Figure PCTCN2015081483-appb-000038
将式3-b所示化合物(2.2g,5.76mmol)溶于60mL异丙醇中，向其中加入式4-a所示化合物(1.53g,5.76mmol)和对甲苯磺酸(993mg,5.76mmol),将混合物在80℃温度下，搅拌反应6小时。TLC检测反应完毕后，减压蒸去溶剂，将残留固体物分散于200mL乙酸乙酯中，依此用饱和碳酸氢钠水溶液，水和饱和食盐水洗涤，用无水硫酸钠干燥，减压浓缩得式5-c所示化合物(1.92g，产率55％)。
实施例18：制备式5-d所示化合物
Figure PCTCN2015081483-appb-000039
将式3-b所示化合物(2.2g,5.76mmol)溶于60mL异丙醇中，向其中加入式4-b所示化合物(1.53g,5.76mmol)和对甲苯磺酸(993mg,5.76mmol),将混合物在60℃温度下，搅拌反应10小时。TLC检测反应完毕后，减压蒸去溶剂，将残留固体物分散于200mL乙酸乙酯中，依此用饱和碳酸氢钠水溶液，水和饱和食盐水洗涤，用无水硫酸钠干燥，减压浓缩得式5-d所示化合物(2.45g，产率70％)。
实施例19：制备式5-e所示化合物
Figure PCTCN2015081483-appb-000040
将式3-c所示化合物(2g,5.45mmol)溶于60mL异丙醇中，向其中加入式4-a所示化合物(1.53g,5.76mmol)和对甲苯磺酸(993mg,5.76mmol),将混合物在70℃温度下，搅拌反应10小时。TLC检测反应完毕后，减压蒸去溶剂，将残留固体物分散于200mL乙酸乙酯中，依此用饱和碳酸氢钠水溶液，水和饱和食盐水洗涤，用无水硫酸钠干燥，减压浓缩得式5-e所示化合物(1869mg，产率56％)。
实施例20：制备式5-f所示化合物
Figure PCTCN2015081483-appb-000041
将式3-c所示化合物(2g,5.45mmol)溶于60mL异丙醇中，向其中加入式4-b所示化合物(1.53g,5.76mmol)和对甲苯磺酸(993mg,5.76mmol),将混合物在80℃温度下，搅拌反应6小时。TLC检测反应完毕后，减压蒸去溶剂，将残留固体物分散于200mL乙酸乙酯中，依此用饱和碳酸氢钠水溶液，水和饱和食盐水洗涤，用无水硫酸钠干燥，减压浓缩得式5-f所示化合物(2.504g，产率75％)。
实施例21：制备式5-g所示化合物
Figure PCTCN2015081483-appb-000042
将式3-d所示化合物(2g,5.76mmol)溶于60mL异丙醇中，向其中加入式4-a所示化合物(1.53g,5.76mmol)和对甲苯磺酸(993mg,5.76mmol),将混合物在80℃温度下，搅拌反应6小时。TLC检测反应完毕后，减压蒸去溶剂，将残留固体物分散于200mL乙酸乙酯中，依次用饱和碳酸氢钠水溶液，水和饱和食盐水洗涤，用无水硫酸钠干燥，减压浓 缩得式5-g所示化合物(2.12g，产率64％)。
实施例22：制备式5-h所示化合物
Figure PCTCN2015081483-appb-000043
将式3-d所示化合物(2g,5.76mmol)溶于60mL异丙醇中，向其中加入式4-b所示化合物(1.53g,5.76mmol)和对甲苯磺酸(993mg,5.76mmol),将混合物在60℃温度下，搅拌反应6.5小时。TLC检测反应完毕后，减压蒸去溶剂，将残留固体物分散于200mL乙酸乙酯中，依此用饱和碳酸氢钠水溶液，水和饱和食盐水洗涤，用无水硫酸钠干燥，减压浓缩得式5-h所示化合物(2058mg，产率62％)。
实施例23：制备式5-i所示化合物
Figure PCTCN2015081483-appb-000044
将式3-e所示化合物(2g,5.68mmol)溶于60mL异丙醇中，向其中加入式4-a所示化合物(1.53g,5.76mmol)和对甲苯磺酸(993mg,5.76mmol),将混合物在80℃温度下，搅拌反应6小时。TLC检测反应完毕后，减压蒸去溶剂，将残留固体物分散于200mL乙酸乙酯中，依次用饱和碳酸氢钠水溶液，水和饱和食盐水洗涤，用无水硫酸钠干燥，减压浓缩得式5-i所示化合物(2376mg，产率72％)。
实施例24：制备式5-j所示化合物
Figure PCTCN2015081483-appb-000045
将式3-e所示化合物(2g,5.68mmol)溶于60mL异丙醇中，向其中加入式4-b所示化合物(1.53g,5.76mmol)和对甲苯磺酸(993mg,5.76mmol),将混合物在80℃温度下，搅拌反应6小时。TLC检测反应完毕后，减压蒸去溶剂，将残留固体物分散于200mL乙酸 乙酯中，依此用饱和碳酸氢钠水溶液，水和饱和食盐水洗涤，用无水硫酸钠干燥，减压浓缩得式5-j所示化合物(2.310g，产率70％)。
实施例25：制备式5-k所示化合物
Figure PCTCN2015081483-appb-000046
将式3-f所示化合物(1.73g,5.24mmol)溶于60mL异丙醇中，向其中加入式4-a所示化合物(1.53g,5.76mmol)和对甲苯磺酸(993mg,5.76mmol),将混合物在70℃温度下，搅拌反应5小时。TLC检测反应完毕后，减压蒸去溶剂，将残留固体物分散于200mL乙酸乙酯中，依此用饱和碳酸氢钠水溶液，水和饱和食盐水洗涤，用无水硫酸钠干燥，减压浓缩得式5-k所示化合物(1760mg，产率60％)。
实施例26：制备式5-l所示化合物
Figure PCTCN2015081483-appb-000047
将式3-f所示化合物(1.73g,5.24mmol)溶于60mL异丙醇中，向其中加入式4-b所示化合物(1.53g,5.76mmol)和对甲苯磺酸(993mg,5.76mmol),将混合物在80℃温度下，搅拌反应6小时。TLC检测反应完毕后，减压蒸去溶剂，将残留固体物分散于200mL乙酸乙酯中，依此用饱和碳酸氢钠水溶液，水和饱和食盐水洗涤，用无水硫酸钠干燥，减压浓缩得式5-l所示化合物(2.58g，产率88％)。
实施例27：制备式5-m所示化合物
Figure PCTCN2015081483-appb-000048
将式3-g所示化合物(1.76g,5.24mmol)溶于60mL异丙醇中，向其中加入式4-a所示化合物(1.53g,5.76mmol)和对甲苯磺酸(993mg,5.76mmol),将混合物在60℃温度下， 搅拌反应12小时。TLC检测反应完毕后，减压蒸去溶剂，将残留固体物分散于200mL乙酸乙酯中，依此用饱和碳酸氢钠水溶液，水和饱和食盐水洗涤，用无水硫酸钠干燥，减压浓缩得式5-m所示化合物(1479mg，产率50％)。
实施例28：制备式5-n所示化合物
Figure PCTCN2015081483-appb-000049
将式3-g所示化合物(1.76g,5.24mmol)溶于60mL异丙醇中，向其中加入式4-b所示化合物(1.53g,5.76mmol)和对甲苯磺酸(993mg,5.76mmol),将混合物在80℃温度下，搅拌反应5小时。TLC检测反应完毕后，减压蒸去溶剂，将残留固体物分散于200mL乙酸乙酯中，依此用饱和碳酸氢钠水溶液，水和饱和食盐水洗涤，用无水硫酸钠干燥，减压浓缩得式5-n所示化合物(1.625g，产率55％)。
实施例29：制备式I-1所示化合物
将式5-g所示化合物(400mg,0.694mmol)置于100mL反应瓶中,加入50毫升盐酸二氧六环(2M)，20℃条件下搅拌2小时，监测反应完毕后过滤，用乙醚洗涤滤饼得式I-1所示化合物的产物(281mg，产率85％)。
MS m/z(ESI)：475.9(M+H+)
实施例30：制备式I-2所示化合物
将式5-h所示化合物(400mg,0.694mmol)置于100mL反应瓶中,加入50毫升盐酸二氧六环(2M)，15℃条件下搅拌5小时，监测反应完毕后过滤，用乙醚洗涤滤饼得式I-2所示化合物的产物(231mg，产率70％)。
MS m/z(ESI)：475.9(M+H+)
实施例31：制备式I-3所示化合物
将式5-i所示化合物(400mg,0.688mmol)置于100mL反应瓶中,加入50毫升盐酸二氧六环(2M)，20℃条件下搅拌2.5小时，监测反应完毕后过滤，用乙醚洗涤滤饼得式I-3所示化合物的产物(385mg，产率92％)。
MS m/z(ESI)：481.0(M+H+)
实施例32：制备式I-4所示化合物
将式5-j所示化合物(400mg,0.688mmol)置于100mL反应瓶中,加入50毫升盐酸二氧六环(2M)，25℃条件下搅拌1.5小时，监测反应完毕后过滤，用乙醚洗涤滤饼得式I-4所示 化合物的产物(352mg，产率84％)。
MS m/z(ESI)：480.9(M+H+)
实施例33：制备式I-5所示化合物
将式5-k所示化合物(400mg,0.715mmol)置于100mL反应瓶中,加入50毫升盐酸二氧六环(2M)，20℃条件下搅拌3小时，监测反应完毕后过滤，用乙醚洗涤滤饼得式I-5所示化合物的产物(356mg，产率85％)。
MS m/z(ESI)：459.5(M+H+)
实施例34：制备式I-6所示化合物
将式5-l所示化合物(400mg,0.715mmol)置于100mL反应瓶中,加入50毫升盐酸二氧六环(2M)，20℃条件下搅拌2小时，监测反应完毕后过滤，用乙醚洗涤滤饼得式I-6所示化合物的产物(335mg，产率80％)。
MS m/z(ESI)：459.5(M+H+)
实施例35：制备式I-7所示化合物
将式5-m所示化合物(400mg,0.709mmol)置于100mL反应瓶中,加入50毫升盐酸二氧六环(2M)，15℃条件下搅拌2.5小时，监测反应完毕后过滤，用乙醚洗涤滤饼得式I-7所示化合物的产物(293mg，产率70％)。
MS m/z(ESI)：464.6(M+H+)
实施例36：制备式I-8所示化合物
将式5-n所示化合物(400mg,0.709mmol)置于100mL反应瓶中,加入50毫升盐酸二氧六环(2M)，18℃条件下搅拌4小时，监测反应完毕后过滤，用乙醚洗涤滤饼得式I-8所示化合物的产物(327mg，产率78％)。
MS m/z(ESI)：464.6(M+H+)
实施例37：制备式I-9所示化合物
将式5-c所示化合物(400mg,0.676mmol)置于100mL反应瓶中,加入50毫升盐酸二氧六环(2M)，25℃条件下搅拌2小时，监测反应完毕后过滤，用乙醚洗涤滤饼得式I-9所示化合物的产物(399mg，产率93％)。
MS m/z(ESI)：507.5(M+H+)
实施例38：制备式I-10所示化合物
将式5-d所示化合物(400mg,0.676mmol)置于100mL反应瓶中,加入50毫升盐酸二氧六环(2M)，20℃条件下搅拌5小时，监测反应完毕后过滤，用乙醚洗涤滤饼得式I-10所示化合物的产物(390mg，产率91％)。
MS m/z(ESI)：507.5(M+H+)
实施例39：制备式I-11所示化合物
将式5-e所示化合物(400mg,0.670mmol)置于100mL反应瓶中,加入50毫升盐酸二氧六环(2M)，25℃条件下搅拌1.5小时，监测反应完毕后过滤，用乙醚洗涤滤饼得式I-11所示化合物的产物(343mg，产率80％)。
MS m/z(ESI)：512.6(M+H+)
实施例40：制备式I-12所示化合物
将式5-f所示化合物(400mg,0.670mmol)置于100mL反应瓶中,加入50毫升盐酸二氧六环(2M)，25℃条件下搅拌2小时，监测反应完毕后过滤，用乙醚洗涤滤饼得式I-12所示化合物的产物(360mg，产率84％)。
MS m/z(ESI)：512.6(M+H+)
实施例41：制备式I-13所示化合物
将式5-a所示化合物(400mg,0.677mmol)置于100mL反应瓶中,加入50毫升盐酸二氧六环(2M)，15℃条件下搅拌3小时，监测反应完毕后过滤，用乙醚洗涤滤饼得式I-13所示化合物的产物(317mg，产率74％)。
MS m/z(ESI)：506.5(M+H+)
实施例42：制备式I-14所示化合物
将式5-b所示化合物(400mg,0.677mmol)置于100mL反应瓶中,加入50毫升盐酸二氧六环(2M)，20℃条件下搅拌2小时，监测反应完毕后过滤，用乙醚洗涤滤饼得式I-14所示化合物的产物(334mg，产率78％)。
MS m/z(ESI)：506.5(M+H+)
实施例43：ALK激酶抑制活性的测定
采用以下方法来测定本发明的化合物在体外对ALK激酶的抑制活性，该抑制活性采用IC50这一指标来表示，IC50即ALK激酶的活性被抑制50％时的化合物的浓度。
简写及定义
mg  毫克
mL  毫升
μg  微克
μl  微升
mM  毫摩尔
EDTA  乙二胺四乙酸
DMSO  二甲亚砜
SD  标准偏差
SOP  标准操作程序
实验材料：
ALK(Carna,Cat.No 08-105,Lot.No.08CBS-0112)
ALK L1196M(Carna,Cat.No 08-529,Lot.No.11CBS-1134)
Peptide FAM-P22(GL Biochem,Cat.No.112393,Lot.No.P080401-XY112393)
ATP(Sigma,Cat.No.A7699-1G,CAS No.987-65-5)
DMSO(Sigma,Cat.No.D2650,Lot.No.474382)
EDTA(Sigma,Cat.No.E5134,CAS No.60-00-4)
96孔板(Corning,Cat.No.3365,Lot.No.22008026)
384孔板(Corning,Cat.No.3573,Lot.No.12608008)
Staurosporine(Sigma,Cat.No.S4400-1MG,Lot.No.046K4080)
实验方法：
1.配制1倍的激酶缓冲液和终止液
1)1倍激酶缓冲液
50mM HEPES,pH 7.5
0.0015％Brij-35
10mM MgCl2
2mM DTT
2)终止液
100mM HEPES,pH 7.5
0.015％Brij-35
0.2％Coating Reagent#3
50mM EDTA
2.化合物配制
1)将化合物稀释50倍最终所需的最高抑制浓度的100％DMSO溶液。转移100μL这个化合物稀释液在96孔板中。例如，如果需要最高的抑制剂浓度为1μM，在这一步就制备50μM的DMSO溶液。
2)将化合物按3倍序列稀释成10个浓度。
3)添加100μl 100％DMSO到2个空的没有化合物控制和无酶控制的相同的96孔板中。标记源板。
4)中间板的制备
从源板中转移10μL化合物到一个新的96孔板中作为中间板。
添加90μL1倍激酶缓冲液到每一个中间板的孔中。
混合化合物到中间板中并且振荡10分钟。
3.准备试验板
从96孔中间板中每一个孔中转移5μl到384孔板中作为重复。例如，96孔板中的A1转移到384孔板中的A1和A2。96孔板中的A2转移到384孔板的A3和A4。
4.激酶反应
1)配制2.5倍酶溶液
将激酶加入1倍激酶缓冲液，形成2.5倍酶溶液。
2)配制2.5倍的底物溶液
将FAM标记的多肽和ATP加入1倍激酶缓冲液，形成2.5倍底物溶液。
3)试验板已含有5μl化合物的10％的DMSO溶液。
4)转移2.5倍酶溶液到试验板。
5)室温下孵育10分钟
6)转移2.5倍肽溶液到试验板。
7)激酶的反应和停止
28℃下孵育20分钟。加入25μl停止液终止反应。
5.Caliper读取数据
Caliper上读取转化率数据。
6.曲线拟合
1)从Caliper上复制转化率数据。
2)把转化率转化成抑制率数据。其中max是指DMSO对照的转化率，min是指无酶活对照的转化率。Percent inhibition＝(max-conversion)/(max-min)*100.
3)将数据导入MS Excel并使用XLFit excel add-in version 4.3.1进行曲线拟合。
使用的公式是:
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))下表显示了本发明式I-1～式I-14所示的化合物在体外ALK激酶抑制测定中的活性。结果显示，本发明所述式I所示化合物均具有良好的ALK激酶抑制活性，本发明所述化合物可用作ALK抑制剂，用于治疗 一种或一种以上与ALK活性有关的肿瘤疾病，用于制备成抑制间变性淋巴瘤激酶的抗肿瘤治疗药物。
化合物编号 IC50(nM)
I-1 <10
I-2 <10
I-3 <10
I-4 <100
I-5 <100
I-6 <100
I-7 <10
I-8 <10
I-9 <10
I-10 <100
I-11 <100
I-12 <10
I-13 <100
I-14 <10
从上述化合物对ALK激酶抑制活性实验测定实验结果可以看出，本发明所述化合物对于间变性淋巴瘤激酶具有很高的抑制活性。本发明所述化合物I-1，I-2，I-3，I-7，I-8，I-9，I-12和I-14的IC50均小于10nM，本发明所述化合物I-4，I-5，I-6，I-10，I-11，I-13的IC50均小于100nM，其在10nM-100nM，所有化合物的IC50值都小于100nM。这些结果表明，本发明所述化合物是优良的ALK抑制剂，可以有效地治疗与ALK活性有关的肿瘤疾病。
实施例44：用于口服给药的片剂，处方见表2
表2：用于口服给药的片剂处方
成分 原料药(克)
活性成分 25
乳糖 40
微晶纤维素 100
交联聚维酮 6
硬脂酸镁 1.5
制备成 1000片
制备工艺：
将本发明所述化合物的活性成分气流粉碎，粉碎压力0.3Mpa，D90＝50微米，处方量称取，然后与处方量的微晶纤维素在多项运动混合机中混合均匀，再加入交联聚维酮、乳糖、硬脂酸镁混合均匀，在旋转压片机上用直接压片工艺压制而成为片剂，共制备成1000片，每片的活性成分(本发明的化合物)为25mg。
实施例45：本发明的化合物对人肺癌A549细胞裸鼠移植瘤生长的影响
(1)人肺癌裸鼠移植瘤模型的制备
SPF级BALB/c-nu小鼠36只，6周龄，重量l6g-18g。取对数生长期肺癌细胞株A549细胞，用无菌PBS调整A549细胞浓度为3×107/mL，在BALB/c-nu小鼠背部皮下接种A549细胞0.1ml，待皮下移植瘤体积达75mm3左右时(约10天)，模型制造成功。
(2)分组与给药
按瘤体积和荷瘤鼠体重均衡原则分为如下8组，每组12只：
A、模型对照组：灌胃等量的生理盐水1次/日，共给药30日；
B、奥沙利铂组：腹腔注射10mg/kg奥沙利铂，隔日给药1次，共计8次；
C、克唑替尼组：灌胃给予克唑替尼胶囊(辉瑞公司生产，商品名：赛可瑞)粉末，剂量为25mg/kg，2次/日，给药共计8次；
D、式I-1所示化合物组：灌胃给予按照实施例44制备的片剂粉末，剂量为10mg/kg，2次/日，共给药30日；
给药期间每4日用游标卡尺测量移植瘤最长径(L)和最短径(w)。末次给药48小时后脱臼处死小鼠，切除移植瘤，称取瘤重。瘤重抑制率(％)IR＝(1-实验组瘤重均值/模型对照组瘤重均值)×100％。通过瘤重的比较来体现药物对人肺癌A549细胞裸鼠抑制瘤生长的影响。数据以均数±标准差(x±s)表示，采用SPSS15.0软件进行方差分析。
(3)结果与分析
本发明式I-1所示化合物对人肺癌A549细胞裸鼠移植瘤生长的影响的实验结果见表4。
表4
组别 瘤重(mg) 平均抑瘤率(％)
模型对照组 402.3±76.7 /
奥沙利铂组 216.3±51.0* 44.05
克唑替尼组 195.0±47.8* 49.33
式I-1所示化合物组 177.6±45.0** 53.20
注：与模型对照组比较，*P＜0.05，**P＜0.01。
表4的试验结果表明：与模型对照组相比，各治疗组对人肺癌A549细胞裸鼠移植瘤生长的抑制作用均具有显著性差异，尤其是与模型对照组相比，本发明所述的式I-1所示化合物在对人肺癌A549细胞裸鼠移植瘤生长的抑制作用方面具有极显著性差异(P＜0.01)，与化疗奥沙利铂组、ALK抑制剂克唑替尼组相比，平均抑瘤率有所提高，这说明本发明的化合物在治疗非小细胞肺癌方面具有极其显著的疗效，在获得显著药效的同时具有毒副作用低的优势，获得了预料不到的技术效果。
同理，本发明应用式I-2所示化合物至式I-14所示化合物对人肺癌A549细胞裸鼠移植瘤生长的影响进行了实验，结果见表5。
表5
组别 瘤重(mg) 平均抑瘤率(％)
模型对照组 402.3±76.7 /
奥沙利铂组 216.3±51.0* 44.05
克唑替尼组 195.0±47.8* 49.33
式I-2所示化合物组 172.7±43.5** 53.20
式I-3所示化合物组 175.3±43.2** 52.90
式I-4所示化合物组 179.9±44.6** 54.22
式I-5所示化合物组 184.5±50.3** 55.01
式I-6所示化合物组 182.8±49.6** 53.72
式I-7所示化合物组 170.3±42.5** 50.34
式I-8所示化合物组 172.1±43.1** 51.00
式I-9所示化合物组 174.4±45.8** 53.21
式I-10所示化合物组 175.6±46.9** 54.30
式I-11所示化合物组 173.9±50.2** 52.69
式I-12所示化合物组 176.8±51.9** 53.70
式I-13所示化合物组 185.0±42.1** 56.12
式I-14所示化合物组 183.2±43.7** 55.80
注：与模型对照组比较，*P＜0.05，**P＜0.01。
表5的结果显示，本发明式I化合物，尤其所述的式I-2所示化合物至式I-14所示化合物在对人肺癌A549细胞裸鼠移植瘤生长的抑制作用方面均具有显著的疗效，在获得显著药效的同时具有毒副作用低的优势，均获得了预料不到的技术效果。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不一定指的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任何的一个或多个实施例或示例中以合适的方式结合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在不脱离本发明的原理和宗旨的情况下在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (19)

  1. 一种化合物，其为式I所示化合物或式I所示化合物的可药用盐、水合物、溶剂化物、代谢产物、或前药，
    Figure PCTCN2015081483-appb-100001
    其中，
    R1为卤素或
    Figure PCTCN2015081483-appb-100002
    R2为5-6元环烷基、5-6元杂环基、5-6元芳基、或5-6元杂芳基，任选地，所述5-6元环烷基、5-6元杂环基、5-6元芳基和5-6元杂芳基各自独立地被一个或多个选自卤素、羟基、氰基、硝基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、C5-10芳基、5-10元杂芳基、C1-6烷氧基、C3-8环烷氧基、-S(O)pR5、-C(O)R5、-C(O)OR5、-NR6R7或-C(O)NR7的取代基取代，
    其中，R5、R6、R7各自独立地为氢或Cl-4烷基，
    p为0、1或2。
  2. 根据权利要求1所述的化合物，其特征在于，R1为氟、氯或
    Figure PCTCN2015081483-appb-100003
    R2为下列之一：
    Figure PCTCN2015081483-appb-100004
  3. 根据权利要求1或2所述的化合物，其特征在于，R1为氟或氯，且R2为下列之一：
    Figure PCTCN2015081483-appb-100005
  4. 根据权利要求1或2所述的化合物，其特征在于，R1为
    Figure PCTCN2015081483-appb-100006
    且R2为下列之一：
    Figure PCTCN2015081483-appb-100007
  5. 根据权利要求1-4中任一项所述的化合物，其特征在于，所述化合物为选自下列的一种或其可药用盐、水合物、溶剂化物、代谢产物或前药：
    Figure PCTCN2015081483-appb-100008
    Figure PCTCN2015081483-appb-100009
  6. 一种制备权利要求1-5中任一项所述化合物的方法，其特征在于，包括：
    (1)使式1所示化合物与式2所示化合物接触，以便获得式3所示化合物；
    (2)使所述式3所示化合物与式4所示化合物接触，以便获得式5所示化合物；
    (3)使所述式5所示化合物与盐酸二氧六环进触，以便获得式I所示化合物，
    Figure PCTCN2015081483-appb-100010
    其中，R1、R2如权利要求1-5中任一项所定义的。
  7. 根据权利要求6所述的方法，其特征在于，在步骤(1)中，在第一有机溶剂中、在存在NaH条件下，使所述式1所示化合物与所述式2所示化合物接触。
  8. 根据权利要求7所述的方法，其特征在于，所述第一有机溶剂为选自N-甲基吡咯烷酮、N,N-二甲基甲酰胺、二甲基亚砜、二甲基乙酰胺、N,N-二甲基乙酰胺中的至少一种。
  9. 根据权利要求8所述的方法，其特征在于，所述第一有机溶剂为N,N-二甲基甲酰胺。
  10. 根据权利要求6-9中任一项所述的方法，其特征在于，在步骤(1)中，在0摄氏度条件下，使所述式1所示化合物与所述式2所示化合物接触。
  11. 根据权利要求6-10中任一项所述的方法，其特征在于，在步骤(2)中，在异丙醇中、存在对甲苯磺酸条件下，所述式3所示化合物与所述式4所示化合物接触。
  12. 根据权利要求6-11中任一项所述的方法，其特征在于，在步骤(2)中，在60～80摄氏度条件下，使所述式3所示化合物与所述式4所示化合物接触。
  13. 根据权利要求6-12中任一项所述的方法，其特征在于，在步骤(3)中，在15-25摄氏度条件下，使所述式5所示化合物与盐酸二氧六环接触1.5-5小时。
  14. 一种中间体，所述中间体为式5所示的化合物，
    Figure PCTCN2015081483-appb-100011
    其中，
    R1为卤素或
    Figure PCTCN2015081483-appb-100012
    R2为5-6元环烷基、5-6元杂环基、5-6元芳基、或5-6元杂芳基，任选地，所述5-6元环烷基、5-6元杂环基、5-6元芳基和5-6元杂芳基各自独立地被一个或多个选自卤素、羟基、氰基、硝基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、C5-10芳基、5-10元杂芳基、C1-6烷氧基、C3-8环烷氧基、-S(O)pR5、-C(O)R5、-C(O)OR5、-NR6R7或-C(O)NR7的取代基取代，
    其中，R5、R6、R7各自独立地为氢、或Cl-4烷基，
    p为0、1或2。
  15. 根据权利要求14所述的中间体，其特征在于，R1为氟、氯或
    Figure PCTCN2015081483-appb-100013
    R2为下列之一：
    Figure PCTCN2015081483-appb-100014
  16. 根据权利要求14或15所述的中间体，其特征在于，R1为氟或氯，且R2为下列之一：
    Figure PCTCN2015081483-appb-100015
  17. 根据权利要求14或15所述的中间体，其特征在于，R1为
    Figure PCTCN2015081483-appb-100016
    且R2为下列之一：
    Figure PCTCN2015081483-appb-100017
  18. 权利要求1-5中任一项所述的化合物在制备药物中的用途，所述药物用作ALK抑制剂。
  19. 一种抑制ALK、治疗或者预防癌症、或者抑制癌细胞增殖的方法，其特征在于，包括：对治疗对象给药权利要求1-5中任一项所述的化合物。
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