WO2016192132A1 - 作为alk抑制剂的嘧啶衍生物 - Google Patents

作为alk抑制剂的嘧啶衍生物 Download PDF

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WO2016192132A1
WO2016192132A1 PCT/CN2015/081487 CN2015081487W WO2016192132A1 WO 2016192132 A1 WO2016192132 A1 WO 2016192132A1 CN 2015081487 W CN2015081487 W CN 2015081487W WO 2016192132 A1 WO2016192132 A1 WO 2016192132A1
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compound
formula
group
membered
alkyl
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PCT/CN2015/081487
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English (en)
French (fr)
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王学海
许勇
李莉娥
盛锡军
黄璐
张晓林
乐洋
黄文杰
余艳平
田华
肖强
于静
杨菁
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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 WO2016192132A1 publication Critical patent/WO2016192132A1/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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • 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
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention belongs to the field of medical technology, and relates to novel compounds, methods and pharmaceutical compositions for preparing the same, and uses thereof.
  • the present invention relates to novel pyrimidine derivatives as ALK inhibitors, and to the preparation of these compounds for the treatment and prevention of cancer. Use of the drug.
  • 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 can be used for the preparation of a medicament for the treatment of 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 hydrogen, halogen, C 1-6 alkyl, or C 1-6 alkoxy
  • 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 3 is selected from an optionally substituted piperazinyl group, an optionally substituted piperidinyl group, an optionally substituted morpholinyl group, an optional thiomorpholinyl group, or an optionally substituted amino group;
  • R 4 is selected from hydrogen, halogen, C 1-6 alkyl, or C 1-6 alkoxy.
  • R 2 is selected from one of the following:
  • R 3 is selected from 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, acetone.
  • 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 Isethionate and the like.
  • 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, A sodium salt, a potassium salt, a calcium salt, an aluminum salt or an ammonium salt formed by forming an ester with tartaric acid, citric acid, aspartic acid or glutamic acid and then an inorganic base. Or a methylamine salt, ethylamine salt or ethanolamine salt formed by the compound of the formula I with an organic base.
  • the compound of the formula I forms an ester with lysine, arginine or ornithine and then with a corresponding mineral acid salt formed with hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid or phosphoric acid or with formic acid,
  • a corresponding organic acid salt formed from acetic acid, picric acid, methanesulfonic acid and ethanesulfonic acid.
  • 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 i.e., a compound of formula I
  • a prodrug within the scope and spirit of the invention.
  • 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 an intermediate according to a particular embodiment of the invention, said intermediate having a compound of formula 5, wherein the compound of formula 5 is prepared according to formula I of the 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 hydrogen, halogen, C 1-6 alkyl, or C 1-6 alkoxy
  • 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, optionally, the 5-6 membered cycloalkyl group, 5
  • the -6 membered heterocyclic group, the 5-6 membered aryl group and the 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, C 2 8 -alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, C 5-10 aryl, 5-10 membered heteroaryl, C 1-6 alkane Oxyl, C 3-8 cycloalkoxy, -S(O)pR 5 , -C(O)R 5 , -C(O)OR 5 , -NR 6 R 7
  • R 4 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, or C 1-6 alkoxy;
  • R 2 is selected from one of the following:
  • an intermediate according to a particular embodiment of the invention said intermediate having a compound of formula 6, wherein said compound of formula 6 is prepared according to formula I of the invention
  • the intermediate of the compound can be used to prepare the compound of the formula I according to the compound of the formula 6.
  • R 1 is hydrogen, halogen, C 1-6 alkyl, or C 1-6 alkoxy
  • 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, optionally, the 5-6 membered cycloalkyl group, 5
  • the -6 membered heterocyclic group, the 5-6 membered aryl group and the 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, C 2 8 -alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, C 5-10 aryl, 5-10 membered heteroaryl, C 1-6 alkane Oxyl, C 3-8 cycloalkoxy, -S(O)pR 5 , -C(O)R 5 , -C(O)OR 5 , -NR 6 R 7
  • R 4 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, or C 1-6 alkoxy;
  • R 2 is selected from one of the following:
  • an intermediate according to a specific embodiment of the present invention wherein the intermediate has a compound represented by Formula 8, and the compound of Formula 8 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 8.
  • R 1 is hydrogen, halogen, C 1-6 alkyl, or C 1-6 alkoxy
  • 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, optionally, the 5-6 membered cycloalkyl group, 5
  • the -6 membered heterocyclic group, the 5-6 membered aryl group and the 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, C 2 8 -alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, C 5-10 aryl, 5-10 membered heteroaryl, C 1-6 alkane Oxyl, C 3-8 cycloalkoxy, -S(O)pR 5 , -C(O)R 5 , -C(O)OR 5 , -NR 6 R 7
  • R 4 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, or C 1-6 alkoxy;
  • R 2 is selected from one of the following:
  • R 1 , R 2 , and R 4 in the compound represented by Formula 5, the compound represented by Formula 6, and the compound of Formula 8 are as defined in the foregoing description.
  • 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 is hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy
  • R 2 is 5- a 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 a specific example of the present invention, a 5-6 membered cycloalkyl group, 5-6 members
  • the heterocyclic group, the 5-6 membered aryl group and the 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, C 2-8 chain.
  • R 5 , R 6 , R 7 are each independently hydrogen or C 4 -alkyl, p is 0, 1 or 2;
  • R 3 is selected from optionally substituted piperazinyl, optionally substituted a piperidinyl group, an optionally substituted morpholinyl group, an optional thiomorpholinyl group, or an optionally substituted amino group;
  • R 4 is selected from hydrogen, halogen, C 1-6 alkyl, or C 1-6 alkane Oxygen.
  • R 2 may preferably be one of the following:
  • R 3 may preferably be one of the following:
  • 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 formula 1 in the step (1), in the presence of NaH in the first organic solvent, the formula 1 is shown
  • the compound is contacted with the compound of formula 2.
  • the first organic solvent may be at least one selected from the group consisting of N-methylpyrrolidone, DMF, dimethyl sulfoxide, dimethylacetamide, and N,N-dimethylacetamide. DMF is preferred.
  • 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
  • step (2) the compound of formula 3 is contacted with the compound of formula 4 in n-butanol, which contains p-toluenesulfonic acid.
  • the compound of the formula 3 is contacted with the compound of the formula 4 at 80 ° C for 6 hours, whereby the reaction efficiency can be improved while Both react sufficiently to ultimately increase the yield of the compound of formula 5.
  • the molar ratio between the compound of the formula 3, the compound of the formula 4 and p-toluenesulfonic acid is (4-6): (5- 7): (5-7).
  • it is preferably (5-6): (5.5-6.5): (5.5-6.5).
  • the yield of the compound represented by Formula 5 can be improved while saving the raw material cost.
  • the preparation of the compound (intermediate) of the formula 5 can be specifically carried out according to the following steps: the compound of the formula 3 is dissolved in n-butanol, and the compound of the formula 4 is added thereto and For p-toluenesulfonic acid, 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 crude product is isolated by column chromatography to give the compound of formula 5.
  • Step (3) Preparation of a compound (intermediate) represented by formula 6
  • the hydrogenation reaction is carried out in a hydrogen atmosphere using palladium on carbon as a catalyst.
  • the palladium/carbon contains 5% palladium, whereby the reaction potential energy of the two can be effectively reduced, and the reaction efficiency of both is improved.
  • the hydrogen atmosphere is at 1 standard atmosphere. Thereby, the hydrogenation reaction efficiency can be further increased, thereby increasing the yield of the compound represented by Formula 6.
  • the compound of the formula 5 is palladium/carbon in a ratio of (0.5-1 mmol): (35-55 mg), preferably (0.7-0.9 mmol). : (40-50 mg), thereby increasing the yield of the compound represented by Formula 6, while saving the raw material cost.
  • the preparation of the compound (intermediate) of the formula 6 can be carried out according to the following steps: the compound of the formula 5 is placed in a hydrogenation bottle, methanol is added, and the palladium/carbon is replaced by nitrogen. (Pd content 5%) was added to the bottle, and after replacing with hydrogen balloon, the reaction was stirred under hydrogen (1 atm). After the reaction was completed by TLC, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to yield.
  • the compound is a compound of the formula 6.
  • Step (4) Preparation of a compound (intermediate) represented by Formula 8
  • the compound of the formula 6 is contacted with the compound of the formula 7 to obtain the compound of the formula 8, which is carried out by the following steps:
  • (4-1) providing a first dichloromethane solution containing the compound of the formula 6 and triethylamine, and a second dichloromethane solution containing the compound of the formula 7;
  • the compound of the formula 8 can be efficiently produced by the above preparation method while maximizing the yield of the compound of the formula 8.
  • the mixing is carried out by dropwise adding the second dichloromethane solution to the first dichloromethane solution, thereby further enhancing the compound of the formula 6 and the compound of the formula 7 Reaction efficiency.
  • the dropping is performed under ice water bath cooling conditions, and the contact time is 2-5 hours, thereby effectively improving the reaction efficiency of the two.
  • the yield of the compound of formula 8 is increased.
  • the molar ratio of the compound represented by the formula 6 to the compound represented by the formula 7 is (0.5-1): (1-2), preferably (0.7). -0.75): (1-1.2). Thereby, the yield of the compound represented by Formula 8 can be improved while saving the raw material cost.
  • the preparation of the compound (intermediate) of the formula 8 can be carried out in the following steps: dissolving the compound of the formula 6 in dichloromethane, adding triethylamine to the solution, and stirring.
  • the solution of the compound of the formula 7 in dichloromethane was added dropwise under ice-cooling.
  • the reaction mixture was stirred at room temperature for 2 hours, then was diluted with aq.
  • the crude product of the compound is shown, and the obtained crude product is used in the next step without purification.
  • step (5) contacting the compound of formula 8 with a compound of formula 9 to obtain a compound of formula I is carried out by the following steps:
  • the compound of the formula 9 is added to the acetonitrile solution to bring the compound of the formula 8 into contact with the compound of the formula 9.
  • the compound of the formula I can be efficiently produced by employing the above method.
  • step (5) the contacting is carried out under heated reflux conditions for 3-5 hours. This allows the two to be fully reacted, thereby increasing the yield of the compound of formula I.
  • the molar ratio of the compound of the formula 8 to the compound of the formula 9 is (0.5-1.5): (1.5-2.5), preferably (0.8). -1.2): (1.8-2.2).
  • the molar ratio of the compound of the formula 8 to triethylamine is (0.1-0.5): (0.5-1.5):, preferably (0.2-0.25) :(1-1.1).
  • the preparation of the compound of the formula I can be carried out in the following steps: the crude product of the compound of the formula 8 is dissolved in acetonitrile, and triethylamine is sequentially added thereto, and the mixture is stirred at room temperature. The compound of the formula 9 was added, and the mixture was heated to reflux. The residue was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated.
  • the crude product of the compound of formula I is obtained as an organic solvent and the product of the compound of formula I is isolated by column chromatography.
  • 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 hereinbefore described, a compound prepared by the method described above or a pharmaceutical composition as described above for the preparation of a medicament.
  • 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 that inhibits anaplastic lymphoma kinase.
  • 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.
  • the pyrimidine derivative (the compound of the formula I) as an ALK inhibitor according to the present invention has excellent clinical application and medical use as an ALK inhibitor.
  • 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
  • the progress of the reaction in the following examples was monitored by thin layer chromatography (TLC).
  • 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, Yantai Huanghai silica gel 200-300 mesh silica gel is used 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 or prodrug thereof, for the preparation of a compound of formula ⁇ or a pharmaceutically acceptable salt, hydrate, solvate thereof or Methods and intermediates of prodrugs, 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 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 2-1 (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. (8.0g, 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 formula g (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 2-2 (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 the compound of formula 2-2 (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%).
  • the compound of the formula 2-1 (5 g, 25.09 mmol) was dissolved in DMF (100 mL), and NaH (1.1 g, 27.6 mmol) was slowly added at 0 ° C. After the addition, the reaction mixture was further stirred at 0 ° C. After an hour, 2,5,6-trichloropyrimidine (the compound of formula 1) (5.06 g, 27.6 mmol) was added dropwise to the reaction mixture at 0 ° C. After the addition was completed, the mixture was naturally allowed to warm to room temperature and stirred overnight. . After completion of the reaction, it was quenched by the addition of 300 mL of ice water, and extracted with ethyl acetate (200 mL ⁇ 3). The organic phase was combined, washed three times with brine, dried and concentrated under reduced pressure. The compound was shown (yield 2.26 g, yield 26%).
  • the compound of the formula 3-1 (2 g, 5.77 mmol) was dissolved in 60 mL of n-butanol, and 3-nitroaniline (the compound of the formula 4-1) (798 mg, 5.77 mmol) and p-toluenesulfonic acid were added thereto. (993 mg, 5.77 mmol), and 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 crude product was subjected to column chromatography to give the compound of formula 5-1 (yield: 1.24 g, yield: 48%).
  • the compound of the formula 5-1 (400 mg, 0.893 mmol) was placed in a 100 mL hydrogenation flask, 50 ml of methanol was added, and after replacing with nitrogen, 40 mg of palladium carbon (Pd content: 5%) was added to the bottle and replaced with a hydrogen balloon. After stirring under a hydrogen (1 atm) condition, the reaction mixture was filtered, and the filtrate was concentrated to dryness to give a compound of formula 6-1 (yield: 316 mg, yield: 85%).
  • the compound of the formula 5-2 (400 mg, 0.893 mmol) was placed in a 100 mL hydrogenation flask, 50 ml of methanol was added, and after replacing with nitrogen, 40 mg of palladium carbon (Pd content: 5%) was added to the bottle and replaced with a hydrogen balloon. After stirring under a hydrogen (1 atm) condition, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the compound of formula 6-2 (yield 279 mg, yield 75%).
  • the compound of the formula 3-1 (2 g, 5.77 mmol) was dissolved in 60 mL of n-butanol, and the compound of the formula 4-3 (1019 mg, 6.06 mmol) and p-toluenesulfonic acid (1043 mg, 6.06 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 crude product was isolated by column chromatography to give the compound of formula 5-3 (yield: 1544 mg, yield 56%).
  • the compound of the formula 5-3 (427 mg, 0.893 mmol) was placed in a 100 mL hydrogenation flask, and 50 ml of methanol was added. After replacing with nitrogen, 50 mg of palladium on carbon (Pd content: 5%) was added to the bottle, and after replacement with a hydrogen balloon, After stirring under a hydrogen (1 atm) condition, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a compound of formula 6-3 (yield: 376 mg, yield: 80%).
  • Example 7 The synthesis method of Example 8 is referred to Example 7.
  • Example 9 The synthesis method of Example 9 is referred to Example 7.
  • Example 10 The synthesis method of Example 10 is referred to Example 5.
  • Example 11 The synthesis method of Example 11 is referred to Example 6.
  • Example 5 In the case of the synthesis of the compound of the formula 2-2 in Example 12, reference is made to Example 5.
  • the compound of the formula 3-2 (2.0 g, 5.77 mmol) was dissolved in 60 mL of n-butanol, and the compound of the formula 4-3 (1019 mg, 6.06 mmol) and p-toluenesulfonic acid (1043 mg, 6.06 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 crude product was isolated by column chromatography to give the compound of formula 5-8 (yield: 1.71 g, yield 62%).
  • the compound of the formula 5-8 (428 mg, 0.893 mmol) was placed in a 100 mL hydrogenation flask, and 50 ml of methanol was added. After replacing with nitrogen, 50 mg of palladium on carbon (Pd content: 5%) was added to the bottle and replaced with a hydrogen balloon. After stirring under a hydrogen atmosphere (1.0 atm), the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a compound of formula 6-8 (yield: 348 mg, yield 74%).
  • Example 7 The synthesis method of Example 13 is referred to Example 7.
  • Example 14 The synthesis method of Example 14 is referred to Example 7.
  • the compound of the formula 2-3 (4.1 g, 20 mmol) was dissolved in DMF (100 mL), and NaH (1.1 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 (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 300 mL of water and extracted with ethyl acetate (200 mL ⁇ 3). The organic phase was combined and washed three times with saturated brine, dried and concentrated under reduced pressure. Compound (amount of 3.52 g, yield 50%).
  • the compound of the formula 3-3 (2.03 g, 5.77 mmol) was dissolved in 60 mL of n-butanol, and the compound of the formula 4-1 (798 mg, 5.77 mmol) and p-toluenesulfonic acid (993 mg, 5.77 mmol) were added thereto. The mixture was stirred at 70 ° C for 6 hours. After the reaction was completed by TLC, the solvent was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The crude product was obtained by column chromatography to give the compound of formula 5-11 (yield: 2.1 g, yield 80%).
  • the compound of the formula 5-11 (363 mg, 0.8 mmol) was placed in a 100 mL hydrogenation flask, 50 ml of methanol was added, and after replacing with nitrogen, 40 mg of palladium carbon (Pd content: 5%) was added to the bottle and replaced 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 concentrated to dryness to give a compound of formula 6-11 (yield: 254 mg, yield: 75%). LCMS: 423 (M+H + ).
  • the compound of the formula 3-3 (2.03 g, 5.77 mmol) was dissolved in 60 mL of isopropanol, and the compound of the formula 4-2 (798 mg, 5.77 mmol) and p-toluenesulfonic acid (993 mg, 5.77 mmol) were added thereto. The mixture was stirred at 70 ° C for 6 hours. After the reaction was completed by TLC, the solvent was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The crude product was obtained by column chromatography to give the compound of formula 5-12 (yield: 1.89 g, yield 72%).
  • the compound of the formula 5-12 (363 mg, 0.8 mmol) was placed in a 100 mL hydrogenation flask, 50 ml of methanol was added, and after replacing with nitrogen, 40 mg of palladium carbon (Pd content: 5%) was added to the bottle and replaced with a hydrogen balloon. After stirring overnight under hydrogen (1 atm), the reaction mixture was filtered, and the filtrate was concentrated to dryness to give the compound of formula 6-12 (yield 278 mg, yield 82%). LCMS: 423 (M+H + ).
  • Example 17 The synthesis method of Example 17 is referred to Example 7.
  • Example 18 The synthesis method of Example 18 is referred to Example 7.
  • Example 19 The synthesis method of Example 19 is referred to Example 7.
  • the compound of the formula 6-1 (300 mg, 0.717 mmol) was dissolved in methylene chloride (15 mL), and triethylamine (289.67 mg, 399 uL, 2.068 mmol) was added to the solution and stirred under ice-cooling A solution of 2-chloroacetyl chloride (compound of formula 7-1) (85.1 mg, 0.753 mmol) in dichloromethane (2 mL) was then evaporated. The reaction mixture was stirred at room temperature for 2 hr, EtOAc (EtOAc m. The organic solvent was used to obtain 350 mg of the crude product of the compound of formula 8-a, and the obtained crude product was used in the next step without purification.
  • Example 21 to Example 43 Preparation of a compound represented by Formula 8-2 to Formula 8-24
  • the compound of the formula 8-1 (100 mg, 0.202 mmol) was dissolved in dry acetonitrile (3 mL), and triethylamine (102 mg, 1.01 mmol) was sequentially added thereto, and dicarbonyl piperazine was added dropwise with stirring at room temperature.
  • the compound shown by 9-1) (40 mg, 0.404 mmol) was heated under reflux for 5 hours, and the solvent was evaporated evaporated evaporated. The organic layer was dried over magnesium sulfate, filtered, and evaporated to dryness.
  • the compound of the formula 8-11 (100 mg, 0.200 mmol) was dissolved in dry acetonitrile (3 mL), and triethylamine (102 mg, 1.01 mmol) was sequentially added thereto, and the mixture of the formula 9-2 was added dropwise with stirring at room temperature.
  • the compound (19.2 mg, 0.22 mmol) was evaporated to dryness. Filtration and evaporation of the organic solvent under reduced pressure gave a crude product, which was purified by column chromatography to give the compound of formula I-33 (yield: 75 mg, yield 68%).
  • the compound of the formula 8-5 (105 mg, 0.20 mmol) was dissolved in dry acetonitrile (5 mL), and triethylamine (102 mg, 1.01 mmol) was sequentially added thereto, and the mixture of the formula 9-3 was added dropwise under stirring at room temperature.
  • Compound (29 mg, 0.40 mmol) heated under reflux for 4 hr. The solvent was removed, and the residue was diluted with H2HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH
  • the compound of the formula 8-4 (100 mg, 0.202 mmol) was dissolved in dry acetonitrile (4 mL), and triethylamine (102 mg, 1.01 mmol) was sequentially added thereto, and the mixture of the formula 9-4 was added dropwise under stirring at room temperature.
  • the compound 25 mg, 0.404 mmol was evaporated to drynesshhhHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH
  • the compound of the formula 8-10 (105 mg, 0.2 mmol) was dissolved in acetonitrile (3 mL), and triethylamine (102 mg, 1.01 mmol) was sequentially added thereto, and the compound of the formula 9-1 was added dropwise with stirring at room temperature ( 40mg, 0.404mmol), heated under reflux for 3 hours, the solvent was evaporated under reduced pressure. The organic solvent was evaporated to give a crude product, which was purified by column chromatography to give the compound of formula I-100 (yield: 84.8 mg, yield 72%).
  • the compound of the formula 8-10 (105 mg, 0.2 mmol) was dissolved in acetonitrile (3 mL), and triethylamine (102 mg, 1.01 mmol) was sequentially added thereto, and the compound of the formula 9-5 was added dropwise with stirring at room temperature ( 51mg, 0.4mmol), heated under reflux for 4.5 hours, the solvent was evaporated under reduced pressure. The organic solvent was evaporated to give a crude product, which was purified by column chromatography to give the compound of formula I-156 (yield: 74 mg, yield 60%).
  • the compound of the formula 8-1 (100 mg, 0.202 mmol) was dissolved in acetonitrile (3 mL), and triethylamine (102 mg, 1.01 mmol) was sequentially added thereto, and the compound of the formula 9-4 was added dropwise with stirring at room temperature ( 12.5 mg, 0.202 mmol), and heated under reflux for 3 hours.
  • the solvent was evaporated, evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • the compound of the formula 8-10 (105 mg, 0.2 mmol) was dissolved in acetonitrile (3 mL), and triethylamine (102 mg, 1.01 mmol) was sequentially added thereto, and the compound of the formula 9-6 was added dropwise with stirring at room temperature ( 20mg, 0.201mmol), heated under reflux for 5 hours, the solvent was evaporated under reduced pressure. The organic solvent was distilled off to give a crude product which was purified by column chromatography to give the compound of formula I-25 (yield 68.3 mg, yield 64%).
  • the compound of the formula 8-19 (102 mg, 0.200 mmol) was dissolved in acetonitrile (3 mL), and triethylamine (102 mg, 1.01 mmol) was sequentially added thereto, and the compound of the formula 9-8 was added dropwise with stirring at room temperature ( 18.1 mg, 0.21 mmol), and heated under reflux for 3 hours.
  • the solvent was evaporated, evaporated, evaporated, evaporated, evaporated.
  • the organic solvent was evaporated under reduced pressure to give a crude material, which was purified by column chromatography to give the compound of formula I-48 (yield: 87.2 mg, yield 78%).
  • the compound of the formula 8-5 (105 mg, 0.20 mmol) was dissolved in acetonitrile (4 mL), and triethylamine (102 mg, 1.01 mmol) was sequentially added thereto, and the compound of the formula 9-4 was added dropwise with stirring at room temperature ( 12.5 mg, 0.202 mmol), and the mixture was heated to reflux for 5 hr.
  • the organic solvent was evaporated under reduced pressure to give a crude material, which was purified by column chromatography (yield: 76 mg, yield 69%).
  • the compound of the formula 8-22 (103 mg, 0.20 mmol) was dissolved in acetonitrile (4 mL), and triethylamine (102 mg, 1.01 mmol) was sequentially added thereto, and the compound of the formula 9-12 was added dropwise with stirring at room temperature ( 12.4 mg, 0.21 mmol), and the mixture was evaporated to dryness.
  • the organic solvent was evaporated under reduced pressure to give a crude material, which was purified by column chromatography to give the compound of formula I-96 (yield: 85 mg, yield 79%).
  • the compound of the formula 8-24 (106 mg, 0.20 mmol) was dissolved in acetonitrile (4 mL), and triethylamine (102 mg, 1.01 mmol) was sequentially added thereto, and the compound of the formula 9-12 was added dropwise with stirring at room temperature ( The mixture was heated to reflux for 5 hr. The organic solvent was evaporated under reduced pressure to give a crude material, which was purified by column chromatography (yield: 93 mg, yield 82%).
  • Example 49 The synthetic preparation method of the compound of Example 59 is referred to Example 49.
  • Example 44 The synthetic preparation method of the compound described in Example 60 is referred to Example 44.
  • Example 49 The synthetic preparation method of the compound of Example 61 is referred to Example 49.
  • Example 44 The synthetic preparation method of the compound of Example 62 is referred to Example 44.
  • Example 47 The synthetic preparation method of the compound of Example 63 is referred to Example 47.
  • Example 51 The synthetic preparation method of the compound described in Example 64 is referred to Example 51.
  • Example 51 The synthetic preparation method of the compound described in Example 65 is referred to Example 51.
  • Example 66 The synthetic preparation of the compound described in Example 66 is carried out in the same manner as in Example 44.
  • Example 67 The synthetic preparation of the compound described in Example 67 is carried out in the same manner as in Example 56.
  • Example 68 The synthetic preparation of the compound described in Example 68 was carried out in the same manner as in Example 51.
  • Example 49 The synthetic preparation method of the compound of Example 69 is referred to Example 49.
  • Example 49 The synthetic preparation method of the compound of Example 70 is referred to Example 49.
  • Example 47 The synthetic preparation method of the compound of Example 71 is referred to Example 47.
  • Example 73 The synthetic preparation of the compound described in Example 73 was carried out in the same manner as in Example 53.
  • Example 53 The synthetic preparation method of the compound described in Example 74 is referred to Example 53.
  • Example 45 The synthetic preparation method of the compound described in Example 75 is referred to Example 45.
  • Example 45 For the synthetic preparation of the compound described in Example 76, reference is made to Example 45.
  • Example 45 The synthetic preparation method of the compound described in Example 77 is referred to Example 45.
  • Example 78 The synthetic preparation of the compound described in Example 78 is carried out in the same manner as in Example 53.
  • Example 45 The synthetic preparation method of the compound described in Example 79 is referred to Example 45.
  • Example 52 The synthetic preparation method of the compound described in Example 80 is referred to Example 52.
  • Example 52 The synthetic preparation method of the compound described in Example 81 is referred to Example 52.
  • Example 52 The synthetic preparation method of the compound of Example 82 is referred to Example 52.
  • Example 51 The synthetic preparation method of the compound of Example 83 is referred to Example 51.
  • Example 49 For the synthetic preparation of the compound of Example 84, refer to Example 49.
  • Example 53 The synthetic preparation method of the compound described in Example 85 is referred to Example 53.
  • Example 49 The synthetic preparation method of the compound described in Example 86 is referred to Example 49.
  • Example 45 The synthetic preparation method of the compound described in Example 87 is referred to Example 45.
  • Example 52 The synthetic preparation method of the compound described in Example 88 is referred to Example 52.
  • Example 52 The synthetic preparation method of the compound described in Example 89 is referred to Example 52.
  • Example 54 The synthetic preparation method of the compound described in Example 90 is referred to Example 54.
  • Example 52 The synthetic preparation method of the compound described in Example 91 is referred to Example 52.
  • Example 52 The synthetic preparation method of the compound of Example 92 is referred to Example 52.
  • Example 45 The synthetic preparation method of the compound described in Example 93 is referred to Example 45.
  • Example 45 The synthetic preparation method of the compound described in Example 94 is referred to Example 45.
  • Example 53 The synthetic preparation method of the compound described in Example 96 is referred to Example 53.
  • Example 51 The synthetic preparation method of the compound described in Example 97 is referred to Example 51.
  • Example 49 For the synthetic preparation of the compound described in Example 98, refer to Example 49.
  • Example 49 The synthetic preparation method of the compound described in Example 99 is referred to Example 49.
  • Example 51 The synthetic preparation method of the compound described in Example 100 is referred to Example 51.
  • Example 46 The synthetic preparation method of the compound described in Example 101 is referred to Example 46.
  • Example 44 The synthetic preparation method of the compound described in Example 102 is referred to Example 44.
  • Example 47 For the synthetic preparation of the compound described in Example 103, refer to Example 47.
  • Example 104 The synthetic preparation of the compound described in Example 104 is carried out in the same manner as in Example 49.
  • Example 44 The synthetic preparation method of the compound described in Example 105 is referred to Example 44.
  • Example 106 The synthetic preparation of the compound described in Example 106 is carried out in the same manner as in Example 49.
  • Example 50 The synthetic preparation method of the compound described in Example 107 is referred to Example 50.
  • Example 49 The synthetic preparation method of the compound described in Example 108 is referred to Example 49.
  • Example 58 For the synthetic preparation of the compound described in Example 109, reference is made to Example 58.
  • Example 52 The synthetic preparation method of the compound described in Example 110 is referred to Example 52.
  • Example 45 The synthetic preparation method of the compound described in Example 111 is referred to Example 45.
  • Example 53 The synthetic preparation method of the compound described in Example 112 is referred to Example 53.
  • Example 51 The synthetic preparation method of the compound described in Example 113 is referred to Example 51.
  • Example 51 The synthetic preparation method of the compound described in Example 114 is referred to Example 51.
  • Example 49 For the synthetic preparation of the compound described in Example 115, reference is made to Example 49.
  • Example 51 The synthetic preparation method of the compound described in Example 116 is referred to Example 51.
  • Example 50 The synthetic preparation method of the compound described in Example 117 is referred to Example 50.
  • Example 118 The synthetic preparation of the compound described in Example 118 is carried out in the same manner as in Example 58.
  • Example 46 The synthetic preparation method of the compound described in Example 119 is referred to Example 46.
  • Example 52 The synthetic preparation method of the compound described in Example 120 is referred to Example 52.
  • Example 45 For the synthetic preparation of the compound described in Example 121, refer to Example 45.
  • Example 45 For the synthetic preparation of the compound described in Example 122, refer to Example 45.
  • Example 53 For the synthetic preparation of the compound described in Example 123, refer to Example 53.
  • Example 53 For the synthetic preparation of the compound described in Example 124, reference was made to Example 53.
  • Example 51 The synthetic preparation method of the compound described in Example 125 is referred to Example 51.
  • Example 126 The synthetic preparation of the compound described in Example 126 is carried out in the same manner as in Example 51.
  • Example 127 The synthetic preparation of the compound described in Example 127 is carried out in the same manner as in Example 49.
  • Example 49 For the synthetic preparation of the compound described in Example 128, reference is made to Example 49.
  • Example 44 The synthetic preparation method of the compound described in Example 129 is referred to Example 44.
  • Example 47 For the synthetic preparation of the compound described in Example 131, refer to Example 47.
  • Example 47 For the synthetic preparation of the compound described in Example 132, refer to Example 47.
  • Example 49 The synthetic preparation method of the compound described in Example 133 is referred to Example 49.
  • Example 134 The synthetic preparation of the compound described in Example 134 is carried out in the same manner as in Example 57.
  • Example 57 For the synthetic preparation of the compound described in Example 135, reference is made to Example 57.
  • Example 57 For the synthetic preparation of the compound described in Example 136, refer to Example 57.
  • Example 137 The synthetic preparation of the compound described in Example 137 is carried out in the same manner as in Example 57.
  • Example 138 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.
  • Example 139 Tablets for oral administration, the prescriptions are shown in the table below
  • the active ingredient in the above table is passed through a 100 mesh sieve, and then mixed with a guar gum, sodium carboxymethyl starch, microcrystalline cellulose, magnesium stearate which has passed through a 100 mesh sieve, and then formed into a suitable tableting machine by a suitable tableting machine.
  • the tablets were prepared in a total of 1000 tablets, and the active ingredient (the compound of the present invention) of each tablet was 10 mg.

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Abstract

本发明提供了作为ALK抑制剂的嘧啶衍生物。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、R3和R4如说明书所定义。

Description

作为ALK抑制剂的嘧啶衍生物 技术领域
本发明属于医药技术领域，涉及新颖化合物、制备该化合物的方法和药物组合物以及用途，具体的，本发明涉及作为ALK抑制剂的新型嘧啶衍生物，以及这些化合物在制备用于治疗和预防癌症的药物中的用途。
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，也是目前各大医药企的研究热点。
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 PCTCN2015081487-appb-000001
其中，
R1为氢、卤素、C1-6烷基、或C1-6烷氧基；
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；
R3为选自任选取代的哌嗪基、任选取代的哌啶基、任选取代的吗啉基、任选的硫代吗啉基、或任选取代的氨基；
R4为选自氢、卤素、C1-6烷基、或C1-6烷氧基。
根据本发明的实施例，R2为选自下列之一：
Figure PCTCN2015081487-appb-000002
根据本发明的实施例，R3为选自下列之一：
Figure PCTCN2015081487-appb-000003
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 PCTCN2015081487-appb-000004
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 PCTCN2015081487-appb-000005
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的相邻的两个位置，即该化学式中的圆环标 注的位置
Figure PCTCN2015081487-appb-000006
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～R7的基团及其取代基、以及p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 PCTCN2015081487-appb-000007
Figure PCTCN2015081487-appb-000008
Figure PCTCN2015081487-appb-000009
Figure PCTCN2015081487-appb-000010
Figure PCTCN2015081487-appb-000011
Figure PCTCN2015081487-appb-000012
Figure PCTCN2015081487-appb-000013
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的钠盐、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的甲胺盐、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、磷酸形成的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的对应的有机酸盐。
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，本发明提出了一种中间体，根据本发明的具体实施例，所述中间体具有式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 PCTCN2015081487-appb-000014
其中，R1为氢、卤素、C1-6烷基、或C1-6烷氧基；
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；
R4为选自氢、卤素、C1-6烷基、或C1-6烷氧基；
优选的，R2为选自下列之一：
Figure PCTCN2015081487-appb-000015
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，所述中间体具有式6所示的化合物，该式6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6所示化合物，可用于制备成本发明式I所示化合物。
Figure PCTCN2015081487-appb-000016
其中，R1为氢、卤素、C1-6烷基、或C1-6烷氧基；
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；
R4为选自氢、卤素、C1-6烷基、或C1-6烷氧基；
优选的，R2为选自下列之一：
Figure PCTCN2015081487-appb-000017
根据本发明的第四方面，本发明提出了一种中间体，根据本发明的具体实施例，所述中间体具有式8所示的化合物，该式8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8所示化合物，可用于制备成本发明式I所示化合物。
Figure PCTCN2015081487-appb-000018
其中，R1为氢、卤素、C1-6烷基、或C1-6烷氧基；
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；
R4为选自氢、卤素、C1-6烷基、或C1-6烷氧基；
优选的，R2为选自下列之一：
Figure PCTCN2015081487-appb-000019
根据本发明的具体实施例，其中，式5所示的化合物、式6所示的化合物、式8所示的化合物中的R1、R2、和R4为前面描述中所定义的。
根据本发明的第五方面，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)使所述式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)使所述式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)使所述式5所示化合物发生加氢反应，以便获得式6所示化合物；
(4)使所述式6所示化合物与式7所示化合物进行接触，以便获得式8所示化合物；以及
(5)使所述式8所示化合物与式9所示化合物进行接触，以便获得式I所示化合物，
Figure PCTCN2015081487-appb-000020
根据本发明的实施例，上述式1-9以及式I所示化合物的化合物中，R1为氢、卤素、C1-6烷基、或C1-6烷氧基；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，根据本发明的具体示例，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；R3为选自任选取代的哌嗪基、任选取代的哌啶基、任选取代的吗啉基、任选的硫代吗啉基、或任选取代的氨基；R4为选自氢、卤素、C1-6烷基、或C1-6烷氧基。
根据本发明的具体实施例，R2可以优选为下列之一：
Figure PCTCN2015081487-appb-000021
根据本发明的具体实施例，R3可以优选为下列之一：
Figure PCTCN2015081487-appb-000022
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 PCTCN2015081487-appb-000023
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，使所述式1所示 化合物与所述式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、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。优选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，使所述式1所示化合物与所述式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，所述式3所示化合物与所述式4所示化合物在正丁醇中进行接触，所述正丁醇中含有对甲苯磺酸。
根据本发明的具体实施例，在步骤(2)中，在80摄氏度时，使所述式3所示化合物与所述式4所示化合物接触6小时，由此可以提高反应效率的同时，使二者充分反应，进而最终提高式5所示化合物的产率。根据本发明的具体实施例，在步骤(2)中，所述式3所示化合物、所述式4所示化合物和对甲苯磺酸之间的摩尔比为(4-6)：(5-7)：(5-7)。根据本发明的具体实施例，优选为(5-6)：(5.5-6.5)：(5.5-6.5)。进而可以提高式5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5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3所示化合物溶于正丁醇中，向其中加入式4所示化合物和对甲苯磺酸，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，减压浓缩得粗产品，经柱层析分离得产物，为式5所示化合物。
步骤(3)：式6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(3)中，所述加氢反应是采用钯/碳作为催化剂，在氢气气氛中进行的。根据本发明的具体实施例，所述钯/炭中含有5％的钯，由此可以有效降低二者的反应势能，提高二者的反应效率。根据本发明的具体实施例，所述氢气气氛为的1个标准大气压。由此可以进一步提高加氢反应效率，进而提高式6所示化合物产率。根据本发明的具体实施例，在步骤(3)中，所述式5所示化合物与钯/碳的配比为(0.5-1mmol)：(35-55mg)，优选为(0.7-0.9mmol)：(40-50mg)，由此可以提高式6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6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5所示化合物置于氢化瓶中，加入甲醇，氮气置换后将钯/炭(Pd含量5％)加入到瓶中，用氢气球置换后，在氢气(1atm)条件下搅拌反应，TLC监测反应完毕后将反应液过滤，滤液减压浓缩干即得产 物，为式6所示化合物。
步骤(4)：式8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(4)中，使式6所示化合物与式7所示化合物进行接触，以便获得式8所示化合物，是通过下列步骤进行的：
(4-1)提供含有所述式6所示化合物和三乙胺的第一二氯甲烷溶液，以及含有所述式7所述化合物的第二二氯甲烷溶液；
(4-2)将第一二氯甲烷溶液与所述第二二氯甲烷溶液混合。
采用上述制备方法可以有效地制备得到式8所示化合物，同时可以最大限度地提高式8所示化合物的产率。
根据本发明的具体实施例，混合是通过将所述第二二氯甲烷溶液滴加到所述第一二氯甲烷溶液中进行的，进而可以进一步提高式6所示化合物和式7所示化合物的反应效率。根据本发明的具体实施例，在步骤(4)中，所述滴加是在冰水浴冷却条件下进行的，所述接触时间为2-5小时，由此可以有效提高二者的反应效率，提高式8所示化合物的产率。根据本发明的具体实施例，在步骤(4)中，所述式6所示化合物与所述式7所示化合物的摩尔比为(0.5-1)：(1-2)，优选为(0.7-0.75)：(1-1.2)。由此可以提高式8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8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6所示化合物溶于二氯甲烷中，向溶液中加入三乙胺，搅拌，冰水浴冷却条件下，滴加式7所示化合物的二氯甲烷溶液。将反应混合物在室温下搅拌2小时，用饱和碳酸钠水溶液淬灭，二氯甲烷萃取，合并有机相，经饱和食盐水洗，无水硫酸镁干燥，过滤，减压蒸去有机溶剂得式8所示化合物的粗产品，所得粗产品无需纯化，直接用于下步反应。
步骤(5)：式I所示化合物的制备
根据本发明的具体实施例，在步骤(5)中，使所述式8所示化合物与式9所示化合物进行接触，以便获得式I所示化合物，是通过下列步骤进行的：
提供含有所述式8所示化合物、三乙胺的乙腈溶液，
向所述乙腈溶液中加入所述式9所示化合物，以便使所述式8所示化合物与式9所示化合物进行接触。由此通过采用上述方法可以有效地制备得到式I所示化合物。
根据本发明的具体实施例，在步骤(5)中，所述接触是加热回流条件下进行3-5小时。由此可以使得二者得到充分反应，进而提高式I所示化合物的产率。
根据本发明的具体实施例，在步骤(5)中，所述式8所示化合物与所述式9所示化合物的摩尔比为(0.5-1.5)：(1.5-2.5)，优选为(0.8-1.2)：(1.8-2.2)。根据本发明的具体实施例，在步骤(5)中，所述式8所示化合物与三乙胺的摩尔比为(0.1-0.5)：(0.5-1.5)：，优选为(0.2-0.25)：(1-1.1)。由此可以提高式I所示化合物产率的同时，节省原料成本。
根据本发明的具体实施例，式I所示化合物的制备，具体可以按照下列步骤进行：将式8所示化合物的粗产品溶于乙腈中，并向其中依次加入三乙胺，室温搅拌下滴加式9所示化合物，加热回流，反应毕，减压蒸去溶剂，残留物用水稀释，二氯甲烷萃取，合并有机相，经饱和食盐水洗，无水硫酸镁干燥，过滤，减压蒸去有机溶剂得式I所示化合物的粗产品，经柱层析分离得式I所示化合物的产物。
根据本发明的第六方面，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。
根据本发明的第七方面，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。
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，用于制备成抑制间变性淋巴瘤激酶的抗肿瘤治疗药物。
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。本发明所述的作为ALK抑制剂的嘧啶衍生物(式I所示化合物)，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 PCTCN2015081487-appb-000024
实施例1：制备式2-1所示化合物(中间体)
Figure PCTCN2015081487-appb-000025
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2-1所示化合物(得量15.95g，产率90％).
实施例2：制备式2-2所示化合物(中间体)
Figure PCTCN2015081487-appb-000026
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2-2所示化合物(得量18.6g，产率93.5％).
实施例3：制备式2-2所示化合物(中间体)
Figure PCTCN2015081487-appb-000027
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2-2所示化合物(得量18.4g，产率92％).
实施例4：制备式2-3所示化合物(中间体)
Figure PCTCN2015081487-appb-000028
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2-3所示化合物(得量18.9g，产率92％).
实施例5：制备式6-1所示化合物
Figure PCTCN2015081487-appb-000029
将式2-1所示化合物(5g,25.09mmol)溶于DMF(100mL)中,在0℃下慢慢加入NaH(1.1g,27.6mmol)，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)(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冰水淬灭，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，所得粗品经柱层析得式3-1所示化合物(得量2.26g，产率26％)。
将式3-1所示化合物(2g,5.77mmol)溶于60mL正丁醇中，向其中加入3-硝基苯胺(式4-1所示化合物)(798mg,5.77mmol)和对甲苯磺酸(993mg,5.77mmol),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，减压浓缩得粗产品，经柱层析分离得式5-1所示化合物(得量1.24g，产率48％)。
将式5-1所示化合物(400mg,0.893mmol)置于100mL氢化瓶中，加入50毫升甲醇，氮气置换后将40mg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，TLC监测反应完毕后将反应液过滤，滤液减压浓缩干即得式6-1所示化合物(得量316mg，产率85％)。
实施例6：制备式6-2所示化合物
Figure PCTCN2015081487-appb-000030
将式3-1所示化合物(2g,5.77mmol)溶于60mL异丙醇中，向其中加入式4-2所示化合物(798mg,5.77mmol)和对甲苯磺酸(993mg,5.77mmol),将混合物在70℃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，减压浓缩得粗产品，经柱层析分离得式5-2所示化合物(得量0.84g，产率32.5％)。
将式5-2所示化合物(400mg,0.893mmol)置于100mL氢化瓶中，加入50毫升甲醇，氮气置换后将40mg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，TLC监测反应完毕后将反应液过滤，滤液减压浓缩干即得式6-2所示化合物(得量279mg，产率75％)。
实施例7：制备式6-3所示化合物
Figure PCTCN2015081487-appb-000031
将式3-1所示化合物(2g,5.77mmol)溶于60mL正丁醇中，向其中加入式4-3所示化合物(1019mg,6.06mmol)和对甲苯磺酸(1043mg,6.06mmol),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，减压浓缩得粗产品，经柱层析分离得式5-3所示化合物(得量1544mg，产率56％)。
将式5-3所示化合物(427mg,0.893mmol)置于100mL氢化瓶中，加入50毫升甲醇，氮气置换后将50mg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，TLC监测反应完毕后将反应液过滤，滤液减压浓缩干即得式6-3所示化合物(得量376mg，产率80％)。
实施例8：制备式6-4所示化合物
Figure PCTCN2015081487-appb-000032
实施例8的合成方法参照实施例7。
LCMS:431(M+H+).
实施例9：制备式6-5所示化合物
Figure PCTCN2015081487-appb-000033
实施例9的合成方法参照实施例7。
LCMS:451(M+H+).
实施例10：制备式6-6所示化合物
Figure PCTCN2015081487-appb-000034
实施例10的合成方法参照实施例5。
LCMS:418(M+H+).
实施例11：制备式6-7所示化合物
Figure PCTCN2015081487-appb-000035
实施例11的合成方法参照实施例6。
LCMS:418(M+H+).
实施例12：制备式6-8所示化合物
Figure PCTCN2015081487-appb-000036
实施例12中，式2-2所示化合物的合成方法参照实施例5。
将式3-2所示化合物(2.0g,5.77mmol)溶于60mL正丁醇中，向其中加入式4-3所示化合物(1019mg,6.06mmol)和对甲苯磺酸(1043mg,6.06mmol)，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，减压浓缩得粗产品，经柱层析分离得式5-8所示化合物(得量1.71g，产率62％)。
将式5-8所示化合物(428mg,0.893mmol)置于100mL氢化瓶中，加入50毫升甲醇，氮气置换后将50mg钯炭(Pd含量5％)加入到瓶中，用氢气球置换后，在氢气(1.0atm)条件下搅拌过夜，TLC监测反应完毕后将反应液过滤，滤液减压浓缩干即得式6-8所示化合物(得量348mg，产率74％)。LCMS:418(M+H+).
实施例13：制备式6-9所示化合物
Figure PCTCN2015081487-appb-000037
实施例13的合成方法参照实施例7。
LCMS:432(M+H+).
实施例14：制备式6-10所示化合物
Figure PCTCN2015081487-appb-000038
实施例14的合成方法参照实施例7。
LCMS:452(M+H+).
实施例15：制备式6-11所示化合物
Figure PCTCN2015081487-appb-000039
将式2-3所示化合物(4.1g,20mmol)溶于DMF(100mL)中,在0℃下慢慢加入NaH(1.1g,27.6mmol)，加完后反应液继续在0℃下搅拌半小时，再将式1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，所得粗品经柱层析得式3-3所示化合物(得量3.52g，产率50％)。
将式3-3所示化合物(2.03g,5.77mmol)溶于60mL正丁醇中，向其中加入式4-1所示化合物(798mg,5.77mmol)和对甲苯磺酸(993mg,5.77mmol),将混合物在70℃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，减压浓缩得粗产品，经柱层析分离得式5-11所示化合物(得量2.1g，产率80％)。
将式5-11所示化合物(363mg,0.8mmol)置于100mL氢化瓶中，加入50毫升甲醇，氮气置换后将40mg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，滤液减压浓缩干即得式6-11所示化合物(得量254mg，产率75％)。LCMS:423(M+H+).
实施例16：制备式6-12所示化合物
Figure PCTCN2015081487-appb-000040
将式3-3所示化合物(2.03g,5.77mmol)溶于60mL异丙醇中，向其中加入式4-2所示化合物(798mg,5.77mmol)和对甲苯磺酸(993mg,5.77mmol),将混合物在70℃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，减压浓缩得粗产品，经柱层析分离得式5-12所示化合物(得量1.89g，产率72％)。
将式5-12所示化合物(363mg,0.8mmol)置于100mL氢化瓶中，加入50毫升甲醇，氮气置换后将40mg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，滤液减压浓缩干即得式6-12所示化合物(得量278mg，产率82％)。LCMS:423(M+H+).
实施例17：制备式6-13所示化合物
Figure PCTCN2015081487-appb-000041
实施例17的合成方法参照实施例7。
LCMS:453(M+H+).
实施例18：制备式6-14所示化合物
Figure PCTCN2015081487-appb-000042
实施例18的合成方法参照实施例7。
LCMS:437(M+H+).
实施例19：制备式6-15所示化合物
Figure PCTCN2015081487-appb-000043
实施例19的合成方法参照实施例7。
LCMS:457(M+H+).
实施例20：制备式8-1所示化合物
Figure PCTCN2015081487-appb-000044
将式6-1所示化合物(300mg,0.717mmol)溶于干燥的二氯甲烷中(15mL)，向溶液中加入三乙胺(289.67mg,399uL,2.868mmol)，搅拌，冰水浴冷却条件下，滴加2-氯乙酰氯(式7-1所示化合物)(85.1mg,0.753mmol)的二氯甲烷(2mL)溶液。将反应混合物在室温下搅拌2小时，用饱和碳酸钠水溶液淬灭，二氯甲烷萃取(20mL×3)，合并有机相，经饱和食盐水洗，无水硫酸镁干燥，过滤，减压蒸 去有机溶剂得式8-a所示化合物的粗产品350mg，所得粗产品无需纯化，可直接用于下步反应。
实施例21～实施例43：制备式8-2～式8-24所示化合物
式8-2～式8-24所示化合物的结构式见下表，式8-2～式8-24所示化合物的合成方法，均参照实施例20。
Figure PCTCN2015081487-appb-000045
Figure PCTCN2015081487-appb-000046
Figure PCTCN2015081487-appb-000047
实施例44：制备式I-11所示化合物
Figure PCTCN2015081487-appb-000048
将式8-1所示化合物(100mg,0.202mmol)溶于干燥的乙腈(3mL)中，并向其中依次加入三乙胺(102mg,1.01mmol)，室温搅拌下滴加二羰基哌嗪(式9-1所示化合物)(40mg,0.404mmol)，加热回流5小时，减压蒸去溶剂，残留物用水稀释，二氯甲烷萃取(20mL×3)，合并有机相，经饱和食盐水洗，无水硫酸镁干燥，过滤，减压蒸去有机溶剂得粗产品，经柱层析分离得式I-11所示化合物(得量68.8mg，产率61％)。
1H NMR(400MHz,cd3od)δ8.67(d,J＝8.3Hz,1H),8.16(s,1H),7.91–7.85(m,2H),7.67–7.59(m,1H),7.35–7.27(m,2H),7.22(dd,J＝5.0,1.6Hz,2H),3.41–3.34(m,2H),3.27(d,J＝5.1Hz,4H),3.20(q,J＝7.3Hz,1H),2.86–2.75(m,2H),1.28(d,6H).LCMS:t＝0.716min,558(M+H+).
实施例45：制备式I-33所示化合物
Figure PCTCN2015081487-appb-000049
将式8-11所示化合物(100mg,0.200mmol)溶于干燥的乙腈(3mL)中，并向其中依次加入三乙胺(102mg,1.01mmol)，室温搅拌下滴加式9-2所示化合物(19.2mg,0.22mmol)，加热回流4.5小时，减压蒸去溶剂，残留物用水稀释，二氯甲烷萃取(20mL×3)，合并有机相，经饱和食盐水洗，无水硫酸镁干燥，过滤，减压蒸去有机溶剂得粗产品，经柱层析分离得式I-33所示化合物(得量75mg，产率68％)。
1H NMR(400MHz,cd3od)δ8.41(d,J＝5.5Hz,1H),8.15(s,1H),7.91(s,1H),7.87(d,J＝5.5Hz,1H),7.33–7.22(m,3H),3.81–3.68(m,4H),3.37(dd,J＝16.2,9.4Hz,1H),3.19(s,2H),2.67–2.54(m,4H),1.33(d,J＝6.8Hz,6H).LCMS:t＝0.667min,551.2(M+H+).
实施例46：制备式I-93所示化合物
Figure PCTCN2015081487-appb-000050
将式8-5所示化合物(105mg,0.20mmol)溶于干燥的乙腈(5mL)中，并向其中依次加入三乙胺(102mg,1.01mmol)，室温搅拌下滴加式9-3所示化合物(29mg,0.40mmol)，加热回流4小时，减压蒸 去溶剂，残留物用水稀释，二氯甲烷萃取(20mL×3)，合并有机相，经饱和食盐水洗，无水硫酸镁干燥，过滤，减压蒸去有机溶剂得粗产品，经柱层析分离得式I-93所示化合物(得量60.5mg，产率44％)。
实施例47：制备式I-3所示化合物
Figure PCTCN2015081487-appb-000051
将式8-4所示化合物(100mg,0.202mmol)溶于干燥的乙腈(4mL)中，并向其中依次加入三乙胺(102mg,1.01mmol)，室温搅拌下滴加式9-4所示化合物(25mg,0.404mmol)，加热回流4小时，减压蒸去溶剂，残留物用水稀释，二氯甲烷萃取(20mL×3)，合并有机相，经饱和食盐水洗，无水硫酸镁干燥，过滤，减压蒸去有机溶剂得粗产品，经柱层析分离得式I-3所示化合物(得量78.8mg，产率75％)。1H NMR(400MHz,cd3od)δ9.32(d,J＝8.6Hz,1H),8.35(dd,J＝4.4,1.4Hz,1H),8.18(s,1H),7.54(dd,J＝8.7,4.4Hz,1H),7.32–7.19(m,4H),3.85(m,,1H),3.80-3.66(m,2H),3.44(s,2H),2.88–2.74(m,2H),1.31(d,J＝5.6Hz,6H).
LCMS:t＝0.654min,520.2(M+H+).
实施例48：制备式I-100所示化合物
Figure PCTCN2015081487-appb-000052
将式8-10所示化合物(105mg,0.2mmol)溶于乙腈(3mL)中，并向其中依次加入三乙胺(102mg,1.01mmol)，室温搅拌下滴加式9-1所示化合物(40mg,0.404mmol)，加热回流3小时，减压蒸去溶剂，残留物用水稀释，二氯甲烷萃取(20mL×3)，合并有机相，经饱和食盐水洗，无水硫酸镁干燥，过滤，减压蒸去有机溶剂得粗产品，经柱层析分离得式I-100所示化合物(得量84.8mg，产率72％)。
实施例49：制备式I-24所示化合物
Figure PCTCN2015081487-appb-000053
将式8-10所示化合物(105mg,0.2mmol)溶于乙腈(3mL)中，并向其中依次加入三乙胺(102mg,1.01mmol)，室温搅拌下滴加式9-5所示化合物(51mg,0.4mmol)，加热回流4.5小时，减压蒸去溶剂，残留物用水稀释，二氯甲烷萃取(20mL×3)，合并有机相，经饱和食盐水洗，无水硫酸镁干燥，过滤，减压蒸去有机溶剂得粗产品，经柱层析分离得式I-156所示化合物(得量74mg，产率60％)。
1H NMR(400MHz,cd3od)δ9.10(d,J＝8.4Hz,1H),8.36(d,J＝3.3Hz,1H),8.14(s,1H),7.76(d,J＝8.6Hz,1H),7.58(dd,J＝8.7,4.3Hz,1H),7.45(d,J＝2.0Hz,1H),7.09(dd,J＝8.6,2.1Hz,1H),3.90–3.78(m,4H),3.24(d,J＝7.4Hz,2H),3.13(d,J＝11.9Hz,2H),2.87(s,6H),2.36(t,J＝11.3Hz,2H),2.08(d,J＝11.4Hz,2H),1.91(dd,J＝12.0,3.5Hz,2H),1.30(d,J＝6.9Hz,6H).LCMS:t＝0.611min,617.3(M+H+).
实施例50：制备式I-17所示化合物
Figure PCTCN2015081487-appb-000054
将式8-1所示化合物(100mg,0.202mmol)溶于乙腈(3mL)中，并向其中依次加入三乙胺(102mg,1.01mmol)，室温搅拌下滴加式9-4所示化合物(12.5mg,0.202mmol)，加热回流3小时，减压蒸去溶剂，残留物用水稀释，二氯甲烷萃取(20mL×3)，合并有机相，经饱和食盐水洗，无水硫酸镁干燥，过滤，减压蒸去有机溶剂得粗产品，经柱层析分离得式I-17所示化合物(得量57.7mg，产率55％)。数据：1H NMR(400MHz,cd3od)δ8.66(d,J＝8.4Hz,1H),8.15(s,1H),7.94–7.83(m,2H),7.68–7.56(m,1H),7.29(dt,J＝8.0,6.4Hz,2H),7.24–7.17(m,2H),3.70–3.61(m,2H),3.39(s,2H),3.35–3.31(m,1H),2.80–2.70(m,2H),1.26(d,J＝6.8Hz,6H).LCMS:t＝0.694min,519.2(M+H+)
实施例51：制备式I-25所示化合物
Figure PCTCN2015081487-appb-000055
将式8-10所示化合物(105mg,0.2mmol)溶于乙腈(3mL)中，并向其中依次加入三乙胺(102mg,1.01mmol)，室温搅拌下滴加式9-6所示化合物(20mg,0.201mmol)，加热回流5小时，减压蒸去溶剂，残留物用水稀释，二氯甲烷萃取(20mL×3)，合并有机相，经饱和食盐水洗，无水硫酸镁干燥，过滤，减 压蒸去有机溶剂得粗产品，经柱层析分离得式I-25所示化合物(得量68.3mg，产率64％)。
1H NMR(400MHz,cd3od)δ9.09(d,J＝8.5Hz,1H),8.35(dd,J＝4.4,1.3Hz,1H),8.14(s,1H),7.73(d,J＝8.6Hz,1H),7.57(dd,J＝8.7,4.4Hz,1H),7.45(d,J＝2.2Hz,1H),7.08(dd,J＝8.6,2.2Hz,1H),3.89–3.77(m,4H),3.21(s,2H),2.42(s,6H),1.30(d,J＝6.9Hz,6H).LCMS:t＝0.641min,534.2(M+H+).
实施例52：制备式I-34所示化合物
Figure PCTCN2015081487-appb-000056
将式8-11所示化合物(100mg,0.200mmol)溶于乙腈(3mL)中，并向其中依次加入三乙胺(102mg,1.01mmol)，室温搅拌下滴加式9-7所示化合物(21mg,0.21mmol)，加热回流5小时，减压蒸去溶剂，残留物用水稀释，二氯甲烷萃取(20mL×3)，合并有机相，经饱和食盐水洗，无水硫酸镁干燥，过滤，减压蒸去有机溶剂得粗产品，经柱层析分离得式I-34所示化合物(得量88mg，产率78％)。1H NMR(400MHz,cd3od)δ8.42(d,J＝5.4Hz,1H),8.16(s,1H),7.94(s,1H),7.88(d,J＝5.5Hz,1H),7.27(q,J＝3.7Hz,3H),3.37(dd,J＝17.1,10.3Hz,1H),3.24(s,2H),2.82(b,8H),2.56(s,3H),1.34(dd,J＝11.1,6.8Hz,6H).LCMS:t＝0.683min,564.2(M+H+).
实施例53：制备式I-48所示化合物
Figure PCTCN2015081487-appb-000057
将式8-19所示化合物(102mg,0.200mmol)溶于乙腈(3mL)中，并向其中依次加入三乙胺(102mg,1.01mmol)，室温搅拌下滴加式9-8所示化合物(18.1mg,0.21mmol)，加热回流3小时，减压蒸去溶剂，残留物用水稀释，二氯甲烷萃取(20mL×3)，合并有机相，经饱和食盐水洗，无水硫酸镁干燥，过滤，减压蒸去有机溶剂得粗产品，经柱层析分离得式I-48所示化合物(得量87.2mg，产率78％)。
1H NMR(400MHz,cd3od)δ8.64(s,1H),8.53(d,J＝4.0Hz,1H),8.23(s,1H),7.74(d,J＝2.0Hz,1H),7.48(dd,J＝8.3,1.9Hz,2H),7.34(d,J＝8.4Hz,1H),4.15(d,J＝9.1Hz,2H),3.96(dt,J＝13.7,6.9Hz,1H),3.73–3.48(m,8H),2.23(s,3H),1.29(d,J＝6.9Hz,6H).
LCMS:t＝0.661min,559.3(M+H+)
实施例54：制备式I-48所示化合物
Figure PCTCN2015081487-appb-000058
将式8-9所示化合物(99mg,0.200mmol)溶于乙腈(3mL)中，并向其中依次加入三乙胺(102mg,1.01mmol)，室温搅拌下滴加式9-8所示化合物(341mg,0.200mmol)，加热回流4小时，减压蒸去溶剂，残留物用水稀释，二氯甲烷萃取(20mL×3)，合并有机相，经饱和食盐水洗，无水硫酸镁干燥，过滤，减压蒸去有机溶剂得粗产品，经柱层析分离得式I-50所示化合物(得量100.6mg，产率80％)。
1H NMR(400MHz,cd3od)δ9.29(d,J＝8.5Hz,1H),8.36(dd,J＝4.4,1.4Hz,1H),8.16(s,1H),7.62(dd,J＝8.7,4.4Hz,1H),7.51(s,4H),3.84(dt,J＝13.7,6.9Hz,1H),3.78–3.64(m,4H),3.17(s,2H),3.04(d,J＝11.8Hz,2H),2.70–2.56(m,4H),2.33–2.18(m,3H),1.95(d,J＝12.7Hz,2H),1.66(td,J＝12.0,3.6Hz,2H),1.30(t,J＝9.2Hz,6H).LCMS:t＝0.639min,629.3(M+H+)
实施例55：制备式I-36所示化合物
Figure PCTCN2015081487-appb-000059
将式8-5所示化合物(105mg,0.20mmol)溶于乙腈(4mL)中，并向其中依次加入三乙胺(102mg,1.01mmol)，室温搅拌下滴加式9-4所示化合物(12.5mg,0.202mmol)，加热回流5小时，减压蒸去溶剂，残留物用水稀释，二氯甲烷萃取(20mL×3)，合并有机相，经饱和食盐水洗，无水硫酸镁干燥，过滤，减压蒸去有机溶剂得粗产品，经柱层析分离得式I-36所示化合物(得量76mg，产率69％)。
实施例56：制备式I-42所示化合物
Figure PCTCN2015081487-appb-000060
将式8-14所示化合物(100mg,0.20mmol)溶于乙腈(4mL)中，并向其中依次加入三乙胺(102mg,1.01mmol)，室温搅拌下滴加式9-11所示化合物(15mg,0.205mmol)，加热回流4.5小时，减压蒸去溶剂，残留物用水稀释，二氯甲烷萃取(20mL×3)，合并有机相，经饱和食盐水洗，无水硫酸镁干燥，过滤，减压蒸去有机溶剂得粗产品，经柱层析分离得式I-42所示化合物(得量82.7mg，产率77％)。
实施例57：制备式I-96所示化合物
Figure PCTCN2015081487-appb-000061
将式8-22所示化合物(103mg,0.20mmol)溶于乙腈(4mL)中，并向其中依次加入三乙胺(102mg,1.01mmol)，室温搅拌下滴加式9-12所示化合物(12.4mg,0.21mmol)，加热回流3小时，减压蒸去溶剂，残留物用水稀释，二氯甲烷萃取(20mL×3)，合并有机相，经饱和食盐水洗，无水硫酸镁干燥，过滤，减压蒸去有机溶剂得粗产品，经柱层析分离得式I-96所示化合物(得量85mg，产率79％)。
实施例58：制备式I-111所示化合物
Figure PCTCN2015081487-appb-000062
将式8-24所示化合物(106mg,0.20mmol)溶于乙腈(4mL)中，并向其中依次加入三乙胺(102mg,1.01mmol)，室温搅拌下滴加式9-12所示化合物(15.4mg,0.21mmol)，加热回流5小时，减压蒸去溶剂，残留物用水稀释，二氯甲烷萃取(20mL×3)，合并有机相，经饱和食盐水洗，无水硫酸镁干燥，过滤，减压蒸去有机溶剂得粗产品，经柱层析分离得式I-111所示化合物(得量93mg，产率82％)。
实施例59：
Figure PCTCN2015081487-appb-000063
实施例59所述化合物的合成制备方法参照实施例49。
1H NMR(400MHz,cd3od)δ9.29(d,J＝8.5Hz,1H),8.36(dd,J＝4.4,1.4Hz,1H),8.16(s,1H),7.61(dd,J＝8.7,4.4Hz,1H),7.50(s,4H),3.80-3.87(m,,1H),3.15(s,2H),3.02(d,J＝11.8Hz,2H),2.31(s,6H),2.28–2.15(m,3H),1.90(d,J＝12.4Hz,2H),1.72–1.56(m,2H),1.31(d,J＝6.9Hz,6H).LCMS:t＝0.646min,587.3(M+H+).
实施例60：
Figure PCTCN2015081487-appb-000064
实施例60所述化合物的合成制备方法参照实施例44。
1H NMR(400MHz,cd3od)δ9.30(d,J＝8.6Hz,1H),8.38(d,J＝4.1Hz,1H),8.18(s,1H),7.63(dd,J＝8.6,4.3Hz,1H),7.51(s,3H),4.10(dd,J＝14.4,7.3Hz,1H),3.82-3.86(m,1H),3.42-3.40(m,2H),3.32-3.29(m,2H),2.83-2.86(m,2H),1.02–0.66(m,6H).LCMS:t＝0.679min,559.2(M+H+).
实施例61：
Figure PCTCN2015081487-appb-000065
实施例61所述化合物的合成制备方法参照实施例49。
1H NMR(400MHz,cd3od)δ9.33(d,J＝8.6Hz,1H),8.35(dd,J＝4.4,1.4Hz,1H),8.19(s,1H),7.90(s,1H),7.54(dd,J＝8.7,4.4Hz,1H),7.33–7.21(m,3H),3.84-3.81(m,1H),3.12(s,2H),2.97(d,J＝11.8Hz,2H),2.30(s,6H),2.26–2.11(m,3H),1.94–1.81(m,2H),1.62-1.33(m,2H),1.32(d,J＝6.9Hz,6H).LCMS:t＝0.658min,587.3(M+H+).
实施例62：
Figure PCTCN2015081487-appb-000066
实施例62所述化合物的合成制备方法参照实施例44。
1H NMR(400MHz,cd3od)δ9.29(d,J＝8.4Hz,1H),8.37(dd,J＝4.4,1.3Hz,1H),8.17(s,1H),7.62(dd,J＝8.7,4.4Hz,1H),7.57–7.44(m,3H),3.81-3.88(m,1H),3.74–3.63(m,2H),3.44-3.37(m,3H),2.82-2.79(m,2H),1.32(d,J＝6.9Hz,6H).
LCMS:t＝0.696min,559.2(M+H+).
实施例63：
Figure PCTCN2015081487-appb-000067
实施例63所述化合物的合成制备方法参照实施例47。
1H NMR(400MHz,cd3od)δ9.29(d,J＝8.4Hz,1H),8.37(dd,J＝4.4,1.3Hz,1H),8.17(s,1H),7.94(s,1H),7.54(dd,J＝8.7,4.4Hz,1H),7.26-7.23(m,3H),3.87-3.80(m,1H),3.67-3.64(m,2H),3.43(s,2H),2.79-2.76(m,2H),1.32(d,J＝6.9Hz,6H).
LCMS:t＝0.673min,520.2(M+H+).
实施例64：
Figure PCTCN2015081487-appb-000068
实施例64所述化合物的合成制备方法参照实施例51。
1H NMR(400MHz,cd3od)δ9.29(d,J＝8.7Hz,1H),8.37(dd,J＝4.4,1.4Hz,1H),8.17(s,1H),7.64-7.61(m,1H),7.53-7.48(m,4H),3.87-3.80(m,1H),3.14(s,2H),2.38(s,6H),1.30(d,J＝6.9Hz,6H).
LCMS:t＝0.670min,504.2(M+H+).
实施例65：
Figure PCTCN2015081487-appb-000069
实施例65所述化合物的合成制备方法参照实施例51。
1H NMR(400MHz,cd3od)δ9.33(d,J＝8.7Hz,1H),8.36(dd,J＝4.4,1.4Hz,1H),8.19(s,1H),7.90(s,1H),7.55(dd,J＝8.7,4.4Hz,1H),7.32–7.20(m,3H),3.87-3.80(m,1H),3.11(s,2H),2.35(s,6H),1.32(d,J＝6.9Hz,6H).LCMS:t＝0.689min,504.1(M+H+).
实施例66：
Figure PCTCN2015081487-appb-000070
实施例66所述化合物的合成制备方法参照实施例44。
1H NMR(400MHz,CD3OD)δ8.62(d,J＝8.0Hz,1H),8.14(s,1H),7.94(d,J＝7.6Hz,1H),7.89(dd,J＝8.0,1.6Hz,1H),7.74–7.67(m,1H),7.50(dt,J＝6.7,5.9Hz,4H),7.34(dd,J＝11.2,4.1Hz,1H),4.49–4.44(m,1H),3.88–3.80(m,1H),3.44–3.37(m,2H),2.88–2.79(m,2H),1.24(d,J＝6.7Hz,6H).LCMS:t＝0.695min,557(M),580.3(M+Na+).
实施例67：
Figure PCTCN2015081487-appb-000071
实施例67所述化合物的合成制备方法参照实施例56。
LCMS:561.2(M+H+).
实施例68：
Figure PCTCN2015081487-appb-000072
实施例68所述化合物的合成制备方法参照实施例51。
1H NMR(400MHz,CD3OD)δ8.62(d,J＝8.4Hz,1H),8.13(s,1H),7.88(dd,J＝8.0,1.6Hz,1H),7.74–7.65(m,1H),7.55–7.43(m,4H),7.37–7.27(m,1H),3.33(d,J＝5.7Hz,1H),3.15(s,2H),2.39(s,6H),1.28–1.21(m,6H).
LCMS:t＝0.685min,503.2(M+H+).
实施例69：
Figure PCTCN2015081487-appb-000073
实施例69所述化合物的合成制备方法参照实施例49。
1H NMR(400MHz,CD3OD)δ8.62(d,J＝8.3Hz,1H),8.13(s,1H),7.88(dd,J＝8.0,1.5Hz,1H),7.75–7.65(m,1H),7.56–7.43(m,4H),7.32(dd,J＝11.2,4.1Hz,1H),3.33(m,1H),3.15(s,2H),3.03(d,J＝11.9Hz,2H),2.37(s,6H),2.27-2.22(m,2H),1.94-1.91(m,2H),1.68-1.65(m,2H),1.25(d,6H).
LCMS:t＝0.654min,586.3(M+H+).
实施例70：
Figure PCTCN2015081487-appb-000074
实施例70所述化合物的合成制备方法参照实施例49。
1H NMR(400MHz,cd3od)δ8.69(d,J＝8.3Hz,1H),8.15(s,1H),7.90–7.83(m,2H),7.67–7.58(m,1H),7.31(ddd,J＝12.1,5.7,1.6Hz,2H),7.25–7.14(m,2H),3.38–3.31(m,1H),3.13(s,2H),3.00(d,J＝11.9Hz,2H),2.50–2.31(m,7H),2.23(dd,J＝12.0,10.2Hz,2H),1.91(d,J＝13.0Hz,2H),1.65(td,J＝12.2,3.7Hz,2H),1.26(d,6H).
LCMS:t＝0.673min,586.3(M+H+).
实施例71：
Figure PCTCN2015081487-appb-000075
实施例71所述化合物的合成制备方法参照实施例47。
1H NMR(400MHz,cd3od)δ8.63(d,J＝8.5Hz,1H),8.14(s,1H),7.89(dd,J＝8.0,1.4Hz,1H),7.74–7.65(m,1H),7.50(q,J＝9.1Hz,4H),7.32(t,J＝7.2Hz,1H),3.77(dd,J＝17.8,12.7Hz,2H),3.69(s,2H),3.37–3.32(m,1H),3.03–2.90(m,2H),1.95(s,3H),1.25(d,6H).
LCMS:t＝0.673min,519.2(M+H+)
实施例72：
Figure PCTCN2015081487-appb-000076
实施例72所述化合物的合成制备方法参照实施例53。
1H NMR(400MHz,cd3od)δ8.24-8.19(m,2H),7.98(d,J＝7.2Hz,1H),7.74(b,1H),7.67–7.49(m,3H),7.34(d,J＝8.6Hz,2H),4.26(s,2H),3.92–3.46(m,8H),3.42–3.34(m,1H),1.23(d,J＝6.8Hz,6H).
LCMS:t＝0.675min,544.3(M+H+)
实施例73：
Figure PCTCN2015081487-appb-000077
实施例73所述化合物的合成制备方法参照实施例53。
1H NMR(400MHz,cd3od)δ8.69(b,1H),8.58(d,J＝4.1Hz,1H),8.25(s,1H),7.73–7.53(m,3H),7.35(d,J＝8.5Hz,2H),4.31(s,2H),3.99-3.92(m,1H),3.85–3.57(m,8H),1.27(d,J＝6.8Hz,6H).
LCMS:t＝0.665min,545.3(M+H+)
实施例74：
Figure PCTCN2015081487-appb-000078
实施例74所述化合物的合成制备方法参照实施例53。
1H NMR(400MHz,cd3od)δ8.68(b,1H),8.60(dd,J＝4.5,1.2Hz,1H),8.28(s,1H),7.82(t,J＝1.9Hz,1H),7.61(dd,J＝8.3,4.4Hz,1H),7.47–7.31(m,2H),7.15(d,J＝8.5Hz,1H),4.27(s,2H),3.97(dt,J＝13.7,6.8Hz,1H),3.65(dd,J＝24.0,19.1Hz,8H),1.27(t,J＝14.4Hz,6H).
LCMS:t＝0.680min,545.3(M+H+)
实施例75：
Figure PCTCN2015081487-appb-000079
实施例75所述化合物的合成制备方法参照实施例45。
1H NMR(400MHz,cd3od)δ9.29(d,J＝8.5Hz,1H),8.36(dd,J＝4.3,1.2Hz,1H),8.16(s,1H),7.61(dt,J＝8.6,4.2Hz,1H),7.51(s,4H),3.86-3.84(m,1H),3.76(dd,J＝10.4,5.8Hz,4H),3.17(s,2H),2.62-2.60(m,4H),1.31(d,J＝6.9Hz,6H).
LCMS:t＝0.679min,546.2(M+H+)
实施例76：
Figure PCTCN2015081487-appb-000080
实施例76所述化合物的合成制备方法参照实施例45。
1H NMR(400MHz,cd3od)δ9.34(d,J＝8.6Hz,1H),8.36(dd,J＝4.4,1.3Hz,1H),8.19(s,1H),7.92(s,1H),7.55(dd,J＝8.7,4.4Hz,1H),7.37–7.20(m,3H),3.86-2.83(m,1H),3.75–3.70(m,4H),3.15(s,2H),2.62–2.52(m,4H),1.32(d,J＝6.9Hz,6H).
LCMS:t＝0.698min,546.2(M+H+)
实施例77：
Figure PCTCN2015081487-appb-000081
实施例77所述化合物的合成制备方法参照实施例45。
1H NMR(400MHz,cd3od)δ8.62(d,J＝8.2Hz,1H),8.13(s,1H),7.88(d,J＝7.9Hz,1H),7.70(t,J＝7.9Hz,1H),7.50(q,J＝8.9Hz,4H),7.32(t,J＝7.6Hz,1H),3.82–3.68(m,4H),3.32-3.30(m,1H),3.17(s,2H),2.62-2.60(m,4H),1.24(d,J＝6.8Hz,6H).
LCMS:t＝0.698min,545.2(M+H+).
实施例78：
Figure PCTCN2015081487-appb-000082
实施例78所述化合物的合成制备方法参照实施例53。
1H NMR(400MHz,cd3od)δ8.72(s,1H),8.59(dd,J＝4.4,1.1Hz,1H),8.23(s,1H),7.68(s,1H),7.57(s,1H),7.35(d,J＝8.6Hz,1H),7.18(s,1H),4.23(s,2H),3.98(dt,J＝13.6,6.8Hz,1H),3.78–3.49(m,8H),1.29(d,J＝6.9Hz,6H).
LCMS:t＝0.636min,575.2(M+H+).
实施例79：
Figure PCTCN2015081487-appb-000083
实施例79所述化合物的合成制备方法参照实施例45。
1H NMR(400MHz,cd3od)δ9.07(d,J＝8.6Hz,1H),8.39(dd,J＝4.4,1.3Hz,1H),8.17(s,1H),7.74(d,J＝8.6Hz,1H),7.58(dd,J＝8.7,4.4Hz,1H),7.45(d,J＝2.2Hz,1H),7.09(dd,J＝8.6,2.3Hz,1H),4.17(s,2H),3.99(s,4H),3.91–3.79(m,4H),3.47(s,4H),1.30(d,J＝6.9Hz,6H).
LCMS:t＝0.646min,576.2(M+H+).
实施例80：
Figure PCTCN2015081487-appb-000084
实施例80所述化合物的合成制备方法参照实施例52。
1H NMR(400MHz,cd3od)δ9.33(d,J＝8.5Hz,1H),8.35(dd,J＝4.4,1.3Hz,1H),8.19(s,1H),7.90(s,1H),7.54(dd,J＝8.7,4.4Hz,1H),7.27(ddd,J＝10.4,6.1,1.6Hz,3H),3.89-3.82(m,1H),3.18(s,2H),2.62(b,8H),2.34(s,3H),1.31(d,J＝6.5Hz,6H).
LCMS:t＝0.632min,559.2(M+H+).
实施例81：
Figure PCTCN2015081487-appb-000085
实施例81所述化合物的合成制备方法参照实施例52。
1H NMR(400MHz,cd3od)δ9.29(d,J＝8.4Hz,1H),8.36(d,J＝4.3Hz,1H),8.16(d,J＝1.0Hz,1H),7.61(dd,J＝8.7,4.3Hz,1H),7.50(s,4H),3.87-3.80(m,1H),3.21(s,2H),2.69(b,8H),2.40(s,3H),1.31(d,J＝6.9Hz,6H).LCMS:t＝0.638min,559.2(M+H+).
实施例82：
Figure PCTCN2015081487-appb-000086
实施例82所述化合物的合成制备方法参照实施例52。
1H NMR(400MHz,cd3od)δ9.11(d,J＝8.4Hz,1H),8.36(dd,J＝4.4,1.3Hz,1H),8.15(s,1H),7.75(d,J＝8.6Hz,1H),7.58(dd,J＝8.7,4.4Hz,1H),7.44(d,J＝2.2Hz,1H),7.08(dd,J＝8.6,2.2Hz,1H),3.90–3.78(m,4H),3.27(s,2H),2.84(b,8H),2.56(s,3H),1.30(d,J＝6.9Hz,6H).LCMS:t＝0.650min,589.3(M+H+).
实施例83：
Figure PCTCN2015081487-appb-000087
实施例83所述化合物的合成制备方法参照实施例51。
1H NMR(400MHz,cd3od)δ8.41(d,J＝5.5Hz,1H),8.15(s,1H),7.91(s,1H),7.88(d,J＝5.5Hz,1H),7.34–7.21(m,3H),3.42-3.34(m,1H),3.17(s,2H),2.38(d,J＝7.7Hz,6H),1.33(d,J＝6.8Hz,6H).LCMS:t＝0.673min,509.1(M+H+).
实施例84：
Figure PCTCN2015081487-appb-000088
实施例84所述化合物的合成制备方法参照实施例49。
1H NMR(400MHz,cd3od)δ8.41(d,J＝5.5Hz,1H),8.15(s,1H),7.95(s,1H),7.87(d,J＝5.5Hz,1H),7.27(td,J＝5.5,2.6Hz,3H),3.38(dd,J＝13.6,6.8Hz,1H),3.21(s,2H),3.17–3.00(m,3H),2.82(s,6H),2.31(dd,J＝11.9,10.3Hz,2H),2.03(d,J＝11.7Hz,2H),1.90–1.73(m,2H),1.33(d,J＝6.8Hz,6H).LCMS:t＝0.612min,592.3(M+H+).
实施例85：
Figure PCTCN2015081487-appb-000089
实施例85所述化合物的合成制备方法参照实施例53。
1H NMR(400MHz,cd3od)δ8.25(s,1H),8.02(b,1H),7.94(d,J＝5.4Hz,1H),7.86(s,1H),7.54(d,J＝8.3Hz,1H),7.45(t,J＝8.1Hz,1H),7.25(d,J＝7.9Hz,1H),4.19(d,J＝5.5Hz,2H),3.59(dd,J＝14.0,7.0Hz,8H),3.45(dt,J＝13.6,6.8Hz,2H),1.32(d,J＝6.8Hz,6H).
LCMS:t＝0.685min,549.1(M+H+)
实施例86：
Figure PCTCN2015081487-appb-000090
实施例86所述化合物的合成制备方法参照实施例49。
1H NMR(400MHz,cd3od)δ9.02(d,J＝8.7Hz,1H),8.27(d,J＝3.4Hz,1H),8.13(s,1H),7.71(d,J＝2.0Hz,1H),7.44(dd,J＝8.2,2.0Hz,1H),7.34–7.22(m,2H),3.85(dt,J＝13.7,6.8Hz,1H),3.18(d,J＝8.2Hz,2H),3.05–2.96(m,2H),2.82(s,6H),2.34–2.15(m,5H),2.00(d,J＝11.4Hz,2H),1.77(dt,J＝12.1,8.5Hz,2H),1.29(t,J＝6.3Hz,6H).
LCMS:t＝0.647min,601.3(M+H+)
实施例87：
Figure PCTCN2015081487-appb-000091
实施例87所述化合物的合成制备方法参照实施例45。
1H NMR(400MHz,cd3od)δ9.01(d,J＝8.8Hz,1H),8.28–8.23(m,1H),8.12(s,1H),7.71(d,J＝2.2Hz,1H),7.40(dt,J＝7.3,3.7Hz,1H),7.30(dd,J＝8.8,4.3Hz,1H),7.24(d,J＝8.3Hz,1H),3.82(dt,J＝13.7,6.9Hz,1H),3.74–3.65(m,4H),3.14(s,2H),2.56-2.54(m,4H),2.21(s,3H),1.29(d,J＝6.9Hz,6H).
LCMS:t＝0.681min,560.2(M+H+)
实施例88：
Figure PCTCN2015081487-appb-000092
实施例88所述化合物的合成制备方法参照实施例52。
1H NMR(400MHz,cd3od)δ9.01(d,J＝8.7Hz,1H),8.27(dd,J＝4.3,1.1Hz,1H),8.12(s,1H),7.72(d,J＝2.1Hz,1H),7.41(dd,J＝8.2,2.2Hz,1H),7.33–7.22(m,2H),3.84(dt,J＝13.7,6.9Hz,1H),3.22(d,J＝7.3Hz,2H),2.99(s,4H),2.71(s,4H),2.64(s,3H),2.21(s,3H),1.30(d,J＝6.9Hz,6H).
LCMS:t＝0.676min,573.3(M+H+)
实施例89：
Figure PCTCN2015081487-appb-000093
实施例89所述化合物的合成制备方法参照实施例52。
LCMS:598.6(M+H+).
实施例90：
实施例90所述化合物的合成制备方法参照实施例54。
1H NMR(400MHz,cd3od)δ9.33(d,J＝8.2Hz,1H),8.35(dd,J＝4.4,1.3Hz,1H),8.19(s,1H),7.90(s,1H), 7.53(dd,J＝8.7,4.4Hz,1H),7.34-7.18(m,3H),3.85(dt,J＝13.7,6.8Hz,1H),3.77-3.64(m,4H),3.14(s,2H),2.98(d,J＝11.5Hz,2H),2.61(d,J＝4.3Hz,4H),2.23(t,J＝11.2Hz,3H),1.92(d,J＝12.6Hz,2H),1.63-1.52(m,2H),1.30(d,J＝6.9Hz,6H).
LCMS:t＝0.646min,629.3(M+H+)
实施例91
Figure PCTCN2015081487-appb-000095
实施例91所述化合物的合成制备方法参照实施例52。
LCMS:572.3(M+H+).
实施例92
Figure PCTCN2015081487-appb-000096
实施例92所述化合物的合成制备方法参照实施例52。
LCMS:592.5(M+H+).
实施例93
Figure PCTCN2015081487-appb-000097
实施例93所述化合物的合成制备方法参照实施例45。
LCMS:559.1(M+H+).
实施例94
Figure PCTCN2015081487-appb-000098
实施例94所述化合物的合成制备方法参照实施例45。
LCMS:579.5(M+H+).
实施例95
Figure PCTCN2015081487-appb-000099
实施例95所述化合物的合成制备方法参照实施例53。
LCMS:558(M+H+).
实施例96
Figure PCTCN2015081487-appb-000100
实施例96所述化合物的合成制备方法参照实施例53。
LCMS:577(M+H+)
实施例97
Figure PCTCN2015081487-appb-000101
实施例97所述化合物的合成制备方法参照实施例51。
LCMS:517.1(M+H+).
实施例98
Figure PCTCN2015081487-appb-000102
实施例98所述化合物的合成制备方法参照实施例49。
LCMS:600.2(M+H+).
实施例99
Figure PCTCN2015081487-appb-000103
实施例99所述化合物的合成制备方法参照实施例49。
LCMS:620.1(M+H+).
实施例100
Figure PCTCN2015081487-appb-000104
实施例100所述化合物的合成制备方法参照实施例51。
LCMS:509.1(M+H+).
实施例101
Figure PCTCN2015081487-appb-000105
实施例101所述化合物的合成制备方法参照实施例46。
LCMS:531.1(M+H+).
实施例102
Figure PCTCN2015081487-appb-000106
实施例102所述化合物的合成制备方法参照实施例44。
LCMS:588.1(M+H+).
实施例103
Figure PCTCN2015081487-appb-000107
实施例103所述化合物的合成制备方法参照实施例47。
LCMS:549.1(M+H+).
实施例104
Figure PCTCN2015081487-appb-000108
实施例104所述化合物的合成制备方法参照实施例49。
LCMS:616.2(M+H+).
实施例105
Figure PCTCN2015081487-appb-000109
实施例105所述化合物的合成制备方法参照实施例44。
LCMS:610.1(M+H+).
实施例106
Figure PCTCN2015081487-appb-000110
实施例106所述化合物的合成制备方法参照实施例49。
LCMS:586.2(M+H+).
实施例107
Figure PCTCN2015081487-appb-000111
实施例107所述化合物的合成制备方法参照实施例50。
LCMS:555.1(M+H+)
实施例108
Figure PCTCN2015081487-appb-000112
实施例108所述化合物的合成制备方法参照实施例49。
LCMS:622.2(M+H+)
实施例109
Figure PCTCN2015081487-appb-000113
实施例109所述化合物的合成制备方法参照实施例58。
LCMS:530.2(M+H+).
实施例110
Figure PCTCN2015081487-appb-000114
实施例110所述化合物的合成制备方法参照实施例52。
LCMS:593.5(M+H+)
实施例111
Figure PCTCN2015081487-appb-000115
实施例111所述化合物的合成制备方法参照实施例45。
LCMS:580.5(M+H+)
实施例112
Figure PCTCN2015081487-appb-000116
实施例112所述化合物的合成制备方法参照实施例53。
LCMS:578(M+H+)
实施例113
Figure PCTCN2015081487-appb-000117
实施例113所述化合物的合成制备方法参照实施例51。
LCMS:518.1(M+H+)
实施例114
Figure PCTCN2015081487-appb-000118
实施例114所述化合物的合成制备方法参照实施例51。
LCMS:538.5(M+H+)
实施例115
Figure PCTCN2015081487-appb-000119
实施例115所述化合物的合成制备方法参照实施例49。
LCMS:621.6(M+H+)
实施例116
Figure PCTCN2015081487-appb-000120
实施例116所述化合物的合成制备方法参照实施例51。
LCMS:539.1(M+H+)
实施例117
Figure PCTCN2015081487-appb-000121
实施例117所述化合物的合成制备方法参照实施例50。
LCMS:550.1(M+H+)
实施例118
Figure PCTCN2015081487-appb-000122
实施例118所述化合物的合成制备方法参照实施例58。
LCMS:544.2(M+H+).
实施例119
Figure PCTCN2015081487-appb-000123
实施例119所述化合物的合成制备方法参照实施例46。
LCMS:562.1(M+H+)
实施例120
Figure PCTCN2015081487-appb-000124
实施例120所述化合物的合成制备方法参照实施例52。
LCMS:578.2(M+H+).
实施例121
Figure PCTCN2015081487-appb-000125
实施例121所述化合物的合成制备方法参照实施例45。
LCMS:585.5(M+H+).
实施例122
Figure PCTCN2015081487-appb-000126
实施例122所述化合物的合成制备方法参照实施例45。
LCMS:565.1(M+H+)
实施例123
Figure PCTCN2015081487-appb-000127
实施例123所述化合物的合成制备方法参照实施例53。
LCMS:583(M+H+)
实施例124
Figure PCTCN2015081487-appb-000128
实施例124所述化合物的合成制备方法参照实施例53。
LCMS:563(M+H+)
实施例125
Figure PCTCN2015081487-appb-000129
实施例125所述化合物的合成制备方法参照实施例51。
LCMS:543.5(M+H+)
实施例126
Figure PCTCN2015081487-appb-000130
实施例126所述化合物的合成制备方法参照实施例51。
LCMS:523.1(M+H+)
实施例127
Figure PCTCN2015081487-appb-000131
实施例127所述化合物的合成制备方法参照实施例49。
LCMS:626.6(M+H+)
实施例128
Figure PCTCN2015081487-appb-000132
实施例128所述化合物的合成制备方法参照实施例49。
LCMS:606.2(M+H+)
实施例129
Figure PCTCN2015081487-appb-000133
实施例129所述化合物的合成制备方法参照实施例44。
LCMS:564.1(M+H+)
实施例130
Figure PCTCN2015081487-appb-000134
实施例130所述化合物的合成制备方法参照实施例46。
LCMS:567.1(M+H+)
实施例131
Figure PCTCN2015081487-appb-000135
实施例131所述化合物的合成制备方法参照实施例47。
LCMS:525.1(M+H+).
实施例132
Figure PCTCN2015081487-appb-000136
实施例132所述化合物的合成制备方法参照实施例47。
LCMS:525.1(M+H+).
实施例133
Figure PCTCN2015081487-appb-000137
实施例133所述化合物的合成制备方法参照实施例49。
LCMS:592.2(M+H+).
实施例134
Figure PCTCN2015081487-appb-000138
实施例134所述化合物的合成制备方法参照实施例57。
LCMS:516.2(M+H+).
实施例135
Figure PCTCN2015081487-appb-000139
实施例135所述化合物的合成制备方法参照实施例57。
LCMS:516.2(M+H+).
实施例136
Figure PCTCN2015081487-appb-000140
实施例136所述化合物的合成制备方法参照实施例57。
LCMS:531.2(M+H+).
实施例137
Figure PCTCN2015081487-appb-000141
实施例137所述化合物的合成制备方法参照实施例57。
LCMS:531.2(M+H+).
实施例138：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-159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 <100
I-2 <100
I-3 <100
I-4 <100
I-5 <100
I-6 <100
I-7 <100
I-8 <100
I-10 <10
I-11 <10
I-12 <10
I-14 <10
I-15 <10
I-16 <10
I-17 <10
I-18 <10
I-19 <100
I-20 <100
I-21 <100
I-22 124
I-23 <10
I-24 <100
I-25 <100
I-26 <10
I-27 <100
I-28 <100
I-29 <100
I-30 <10
I-31 <10
I-32 <10
I-33 <10
I-34 <10
I-35 <10
I-36 <10
I-42 <100
I-45 <100
I-46 <100
I-47 <100
I-48 <100
I-49 <100
I-50 <100
I-52 <100
I-53 <100
I-54 <100
I-55 <10
I-56 <10
I-57 <10
I-58 <10
I-59 <100
I-60 <100
I-61 138
I-62 <100
I-63 <100
I-64 <10
I-65 124
I-66 <100
I-67 <100
I-68 <100
I-69 <100
I-70 <100
I-71 <100
I-72 <100
I-73 <100
I-74 <10
I-75 <10
I-76 <100
I-77 <10
I-80 <10
I-81 100
I-82 <10
I-83 <10
I-84 <100
I-86 <100
I-87 <100
I-90 <100
I-91 <100
I-93 <100
I-96 <100
I-97 <100
I-98 <10
I-99 <10
I-100 <100
I-107 <100
I-109 <100
I-110 <100
I-111 <100
I-113 <100
I-114 <100
I-115 <100
I-116 <100
I-119 <100
I-121 <100
I-122 <100
I-123 <100
I-129 <100
I-132 <100
I-144 <100
I-157 <100
I-158 <100
I-159 <10
实施例139：用于口服给药的片剂，处方见下表
成分 原料药(克)
活性成分 10
瓜尔胶 15
微晶纤维素 150
羧甲基淀粉钠 25
硬脂酸镁 2
制备成 1000片
将上表中的活性成分过100目筛，再与过100目筛的瓜尔胶、羧甲基淀粉钠、微晶纤维素、硬脂酸镁混合均匀，再用合适的压片机形成为片剂，共制备成1000片，每片的活性成分(本发明的化合物)为10mg。
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 (25)

  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 PCTCN2015081487-appb-100001
    其中，
    R1为氢、卤素、C1-6烷基、或C1-6烷氧基；
    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；
    R3为任选取代的哌嗪基、任选取代的哌啶基、任选取代的吗啉基、任选的硫代吗啉基、或任选取代的氨基；
    R4为氢、卤素、C1-6烷基、或C1-6烷氧基。
  2. 根据权利要求1所述的化合物，其特征在于，R2为下列之一：
    Figure PCTCN2015081487-appb-100002
  3. 根据权利要求1或2所述的化合物，其特征在于，R3为下列之一：
    Figure PCTCN2015081487-appb-100003
  4. 一种制备式Ι所示化合物的方法，其特征在于，包括：
    (1)使式1所示化合物与式2所示化合物进行接触，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所示化合物进行接触，以便获得式5所示化合物；
    (3)使所述式5所示化合物发生加氢反应，以便获得式6所示化合物；
    (4)使所述式6所示化合物与式7所示化合物进行接触，以便获得式8所示化合物；以及
    (5)使所述式8所示化合物与式9所示化合物进行接触，以便获得式I所示化合物，
    Figure PCTCN2015081487-appb-100004
    其中，
    R1为氢、卤素、C1-6烷基、或C1-6烷氧基；
    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；
    R3为任选取代的哌嗪基、任选取代的哌啶基、任选取代的吗啉基、任选的硫代吗啉基、或任选取代的氨基；
    R4为氢、卤素、C1-6烷基、或C1-6烷氧基。
  5. 根据权利要求4所述的方法，其特征在于，R2为下列之一：
    Figure PCTCN2015081487-appb-100005
  6. 根据权利要求4或5所述的方法，其特征在于，R3为下列之一：
    Figure PCTCN2015081487-appb-100006
  7. 根据权利要求4-6中任一项所述的方法，其特征在于，在步骤(1)中，在第一有机溶剂中，在存在NaH时，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4-9中任一项所述的方法，其特征在于，在步骤(1)中，在0摄氏度时，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4-10中任一项所述的方法，其特征在于，在步骤(2)中，在正丁醇中、存在对甲苯磺酸条件下，使所述式3所示化合物与所述式4所示化合物接触。
  12. 根据权利要求4-11中任一项所述的方法，其特征在于，在步骤(2)中，在80摄氏度时，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4-12中任一项所述的方法，其特征在于，在步骤(3)中，所述加氢反应是采用钯/碳作为催化剂，在氢气气氛中进行的。
  14. 根据权利要求4-13中任一项所述的方法，其特征在于，在步骤(4)中，使所述式6所示化合物与式7所示化合物进行接触，以便获得式8所示化合物，是通过下列步骤进行的：
    (4-1)提供含有所述式6所示化合物和三乙胺的第一二氯甲烷溶液，以及含有所述式7所述化合物的第二二氯甲烷溶液；
    (4-2)将所述第一二氯甲烷溶液与所述第二二氯甲烷溶液混合。
  15. 根据权利要求14所述的方法，其特征在于，所述混合是通过将所述第二二氯甲烷溶液滴加到所述第一二氯甲烷溶液中进行的。
  16. 根据权利要求15所述的方法，其特征在于，在步骤(4)中，所述滴加是在冰水浴冷却条件下进行的。
  17. 根据权利要求4-16中任一项所述的方法，其特征在于，在步骤(4)中，所述接触时间为2-5 小时。
  18. 根据权利要求4-17中任一项所述的方法，其特征在于，在步骤(5)中，使所述式8所示化合物与式9所示化合物进行接触，以便获得式I所示化合物，是通过下列步骤进行的：
    提供含有所述式8所示化合物、三乙胺乙腈溶液，
    向所述乙腈溶液中加入所述式9所示化合物，以便使所述式8所示化合物与所述式9所示化合物进行接触。
  19. 根据权利要求4-18中任一项所述的方法，其特征在于，在步骤(5)中，所述接触是加热回流条件下进行3-5小时。
  20. 一种中间体，所述中间体为式5所示的化合物，
    Figure PCTCN2015081487-appb-100007
    其中，R1为氢、卤素、C1-6烷基、或C1-6烷氧基；
    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；
    R4为氢、卤素、C1-6烷基、或C1-6烷氧基。
  21. 一种中间体，所述中间体为式6所示的化合物，
    Figure PCTCN2015081487-appb-100008
    其中，R1为氢、卤素、C1-6烷基、或C1-6烷氧基；
    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；
    R4为氢、卤素、C1-6烷基、或C1-6烷氧基。
  22. 一种中间体，所述中间体为式8所示的化合物，
    Figure PCTCN2015081487-appb-100009
    其中，R1为氢、卤素、C1-6烷基、或C1-6烷氧基；
    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；
    R4为选自氢、卤素、C1-6烷基、或C1-6烷氧基。
  23. 根据权利要求20-22中任一项所述的中间体，其特征在于，R2为下列之一：
    Figure PCTCN2015081487-appb-100010
  24. 权利要求1-3中任一项所述的化合物在制备药物中的用途，所述药物用于抑制间变性淋巴瘤激酶。
  25. 一种抑制间变性淋巴瘤激酶的方法，其特征在于，包括：对治疗对象给药权利要求1-3中任一项所述的化合物。
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