WO2024088110A1 - 一种作为蛋白激酶抑制剂的含吲唑结构的杂环大环化合物及其制备方法 - Google Patents

一种作为蛋白激酶抑制剂的含吲唑结构的杂环大环化合物及其制备方法 Download PDF

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WO2024088110A1
WO2024088110A1 PCT/CN2023/124971 CN2023124971W WO2024088110A1 WO 2024088110 A1 WO2024088110 A1 WO 2024088110A1 CN 2023124971 W CN2023124971 W CN 2023124971W WO 2024088110 A1 WO2024088110 A1 WO 2024088110A1
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cancer
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butyl
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邵黎明
程华
余海华
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复旦大学
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    • 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
    • A61K31/529—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim forming part of bridged ring systems
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    • 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
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
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    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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Definitions

  • the invention belongs to the pharmaceutical field and relates to multi-target inhibitors of various protein kinases and preparation methods and applications thereof.
  • Protein kinases play a pivotal role in many aspects of the body. They control cell metabolism, transcription, division, movement and programmed cell death. They are also involved in immune response and nervous system function. There are many types of gene mutations involved in protein kinases, and fusion gene is one of them.
  • a fusion gene is a hybrid gene formed from two previously separate genes. There are three main situations in which fusion genes are generated: translocation, interstitial deletion, or chromosomal inversion. To date, more than 10,861 cancer-related fusion gene mutations have been discovered, and fusion mutations are distributed in almost all cancer types.
  • kinase-related mutations 35% of all fusion mutations are kinase-related mutations. Since most kinase fusion mutations are functional gain-of-function mutations, kinase fusion mutations have become an effective indicator and target of oncogenic mutations, such as EML4-ALK, CD74-ROS1, KIF5B-RET-related mutations, FGFR2 fusion mutations, FGFR3, and other fusion mutations are more evenly distributed in different tumor types, such as BRAF, NTRK1, NTRK3, etc.
  • oncogenic mutations such as EML4-ALK, CD74-ROS1, KIF5B-RET-related mutations, FGFR2 fusion mutations, FGFR3, and other fusion mutations are more evenly distributed in different tumor types, such as BRAF, NTRK1, NTRK3, etc.
  • the human anaplastic lymphoma kinase (ALK) locus encodes a classic receptor tyrosine kinase (RTK).
  • ALK fusion mutation was first reported in 1999 as TPM3-ALK in anaplastic large cell lymphoma. It was not until the report on EML4-ALK fusion mutation in non-small cell lung cancer was published in Nature that it really attracted people's attention, and started a wave of targeted drug development for solid tumor fusion mutations.
  • ALK gene fusion has become a mature and popular target. Since crizotinib was approved by the US FDA as a first-line drug for the treatment of ALK-positive non-small cell lung cancer in 2011, new small molecule kinase inhibitors have continued to emerge. These small molecule inhibitors not only overcome the problem of crizotinib resistance, but also prolong the patient's survival and reduce the toxic side effects of the drug. So far, first-generation, second-generation and third-generation small molecule inhibitors have been developed.
  • the first generation is mainly represented by Crizotinib, which opened the upsurge of ALK gene fusion inhibitors; the second generation is mainly aimed at the secondary resistance produced after the use of Crizotinib; the drugs that should be marketed are: Ceritinib, Alectinib, Brigatinib, and the third-generation inhibitors include: Lorlatinib, Entrectinib, Ensartinib.
  • the third-generation inhibitors should not only be effective against the secondary resistance produced by the first and second generations, but also have the effect of The inhibitory activity of targets such as ALK, NTRK1/2/3, ROS1, TRK, EGFR, FGFR, etc. must also be effective in cases of brain metastases, which requires that the third-generation small molecules have CNS-related properties.
  • One aspect of the present invention provides a cyclic compound of formula (I) and a pharmaceutically acceptable salt, prodrug or solvate thereof,
  • Z 1 , Z 2 , and Z 3 are independently selected from CH and N, respectively; preferably, Z 1 is selected from N, Z 2 is selected from N, and Z 3 is selected from CH; or Z 1 is selected from CH, Z 2 is selected from N, and Z 3 is selected from N.
  • This bond means that the position of attachment to the benzene ring can be any unsubstituted position on the benzene ring, including
  • n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; preferably, n is selected from 1, 2, 3, 4.
  • X, Y, W are independently selected from O, NH, NR 4 R 5 , S, C ⁇ O, CR 4 R 5 , R 4 and R 5 are independently selected from hydrogen, C1-C5 alkyl, C1-C5 alkoxy;
  • R 1 is selected from H, halogen, NR 6 R 7 , CR 6 R 7 , a benzene ring containing 1 to 3 substituents, a 5-12 membered heterocycle, R 6 and R 7 are each independently selected from hydrogen, C1-C5 alkyl;
  • the 5-12 membered heterocyclic ring is protected by a C1-C10 alkyl group, a C1-C10 alkoxy group, a C1-C10 cycloalkyl group, a C1-C10 alkylamide, a C1-C10 cycloalkylamide, a C1-C10 alkylsulfonamide, a C1-C10 cycloalkylsulfonamide, an amino protecting group, a phenyl group, a 5-12 membered heterocyclic ring, a C1-C10 alkyl group, a C1-C10 alkoxy group ...alkyl group, a C1-C10 alkyl group
  • the membered heterocyclic ring is optionally substituted;
  • R 2 and R 3 are independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, carboxyl, amide, sulfonic acid, sulfonamide, sulfonate, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 alkoxy, mono-substituted or poly-substituted halogenated alkyl or alkoxy;
  • R 2 and R 3 are independently selected from H, F, Cl, Br, I;
  • R2 is F and R3 is H; or R2 is Cl and R3 is H; or R2 is H and R3 is F.
  • R 1 is selected from H, F, Cl, Br;
  • R 1 is selected from H or Cl
  • R 1 is selected from NR 6 R 7 , CR 6 R 7 , a benzene ring containing 1-3 substituents, a 5-12-membered cyclic ring, a 5-12-membered spiro ring, a 5-12-membered bridged ring, and R 6 and R 7 are each independently selected from hydrogen, C1-C5 alkyl;
  • the 5-12 membered cyclic, spirocyclic and bridged rings are optionally substituted by C1-C10 alkyl, C1-C10 alkoxy, C1-C10 cycloalkyl, C1-C10 alkylamide, C1-C10 cycloalkylamide, C1-C10 alkylsulfonamide, C1-C10 cycloalkylsulfonamide, amino protecting group, phenyl, 5-12 membered heterocyclic ring;
  • R 1 is selected from the following formula:
  • R is selected from C1-C10 alkyl, C3-C12 cycloalkyl, C1-C10 alkylamide, C1-C10 cycloalkylamide, benzene ring, pyrimidine, piperidinyl, C1-C10 alkylsulfonamide, C1-C10 cycloalkylsulfonamide, amino protecting group; heterocyclic ring can be saturated, partially saturated or unsaturated, and can be monocyclic, cyclic, spirocyclic or bridged, and all the above alkyl groups can be straight chain or branched alkane;
  • R is selected from
  • R is selected from H, O, CH3, CH2CH3 , CH2CH2CH3 , CH2CH2CH2CH3, CH( CH3 ) 2 , cyclopropyl , cyclobutyl, cyclopentyl, cycloheptyl, C1-C4 alkylamide, C1 -C6 cycloalkylamide , benzene ring , pyrimidine , piperidinyl, C1- C6 alkylsulfonamide, C1-C6 cycloalkylsulfonamide, and amino protecting group.
  • R1 is selected from the following specific fragments,
  • the site where X is connected to the benzene ring where R2 is located can be represented by Preferably, the specific general formula is as follows
  • At least one of R 2 and R 3 is halogen
  • X, Y, and W are independently selected from CH 2 , NH, and O.
  • X is CH 2 , Y is NH, and W is O; the general formula is as follows:
  • R 1 is Cl, and the compound is selected from:
  • Another aspect of the present invention provides a method for preparing a compound of formula I:
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, prodrug or solvate thereof.
  • Another aspect of the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, prodrug and solvate thereof for use in the manufacture of a method for treating mammalian tumors, acute and chronic inflammatory diseases, inflammatory bowel diseases, skin diseases, diabetes, eye diseases, diseases associated with angiogenesis or angiogenesis in mammals, diseases associated with chronic pain, and other uses that can be achieved by regulating protein kinases.
  • Another aspect of the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, prodrug and solvate thereof in the preparation of Use in a drug for treating or preventing a disorder or disease mediated by an activated or resistant mutant form of ALK, preferably, the disorder or disease mediated by the activated or resistant mutant form of ALK is lung cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor, thyroid cancer, bile duct cancer, endometrial cancer, renal cancer, anaplastic large cell lymphoma, acute myeloid leukemia, multiple myeloma or mesothelioma.
  • the hydrogen mentioned includes various isotopes of hydrogen such as deuterium and tritium.
  • pharmaceutically acceptable salt includes salts of acidic or basic groups which may be present in the compounds of the present invention.
  • alkyl, alkenyl, alkynyl, and cycloalkyl moieties may be optionally substituted independently by one or more groups selected from the following: hydroxy, oxo, halogen, cyano, nitro, trifluoromethyl, azido, amino, carboxyl, and mercapto.
  • Saturated or unsaturated hydrocarbon groups such as alkyl, alkanediyl or alkenyl, including combinations with heteroatoms, such as alkoxy, may each be straight-chain or branched.
  • Step 1 Synthesis of tert-butyl (2-(4-fluoro-2-methylphenoxy)ethyl)carbamate
  • diisopropyl azodicarboxylate (3.8 g, 18.8 mmol) was added dropwise to a solution of 4-fluoro-2-methylphenol (3.2 g, 25.4 mmol), N-(tert-butyloxycarbonyl)ethanolamine (3.0 g, 18.6 mmol), and triphenylphosphine (4.9 g, 18.6 mmol) in THF (25 mL).
  • the organic solvent was removed by rotary evaporation under reduced pressure, and the obtained solid was slurried in a solvent of cold n-hexane (25 mL), and most of the triphenylphosphine oxide by-product was removed by filtration.
  • Step 3 Synthesis of tert-butyl (2-(2-(3-cyano-4-fluorobenzyl)-4-fluorophenoxy)ethyl)carbamate
  • Step 4 Synthesis of tert-butyl (2-(2-((3-amino-1H-indazol-5-yl)methyl)-4-fluorophenoxy)ethyl)carbamate
  • Step 5 Synthesis of tert-butyl (2-(2-((3-((2,6-dichloropyrimidin-4-yl)amino)-1H-indazol-5-yl)methyl)-4-fluorophenoxy)ethyl)carbamate
  • 2,4,6-trichloropyrimidine (455 mg, 2.5 mmol) was added to tert-butyl (2-(2-((3-amino-1H-indazol-5-yl)methyl)-4-fluorophenoxy)ethyl)carbamate (500 mg, 1.25 mmol) and DIPEA (0.4 mL, 1.9 mmol) in DMF (10 mL) solvent, and the reaction mixture was stirred at room temperature overnight. After monitoring the reaction completion, the mixture was poured into water (50 mL), extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure.
  • Step 6 Synthesis of trifluoroacetate salt of 5-(2-(2-aminoethoxy)-5-fluorobenzyl)-N-(2,6-dichloropyrimidin-4-yl)-1H-indazol-3-amine
  • Trifluoroacetic acid (4 mL) was added to a solution of tert-butyl (2-(2-((3-((2,6-dichloropyrimidin-4-yl)amino)-1H-indazol-5-yl)methyl)-4-fluorophenoxy)ethyl)carbamate (600 mg, 1.09 mmol) in DCM (10 mL), and the mixture was stirred at room temperature for 4 hours.
  • Example 1 The synthesis steps of this compound are the same as those in Example 1. It is another final product in the synthesis steps of Example 1 and is an isomer with Example 1.
  • the mixed solution was directly purified by reverse phase column chromatography (Biotage C18 reverse phase column, MeCN/0.05% ammonia water as eluent) to obtain the target compound macrocyclic compound 5 5 -fluoro-1 2 -morpholino-3 1 H-6-oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-benzocyclononyl (3 mg, yield: 47%) was obtained as a white solid.
  • Example 3 The specific steps of the synthesis operation refer to Example 3 to obtain white solid 5 5 -fluoro- 1 2 -(4-methylpiperazin-1-yl)-3 1 H-6-oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclononanone;
  • Example 5 Macrocyclic Compound 1 2 -(4-ethylpiperazin-1-yl)-5 5 -fluoro-3 1 H-6-oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclononanone
  • Example 3 The specific steps of the synthesis operation refer to Example 3 to obtain macrocyclic 12-(4-ethylpiperazin-1-yl)-5 5 -fluoro-3 1 H-6-oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclononanone as a white solid;
  • Example 6 Macrocyclic Compound 1-(4-(5 5 -fluoro-3 1 H-6-oxa-2,9-aza-3(3,5)-indazole-1(4,6)-
  • Example 3 The specific steps of the synthesis operation refer to Example 3 to obtain the macrocyclic compound 1-(4-(5 5 -fluoro-3 1 H-6-oxa-2,9-aza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclononyl-12-yl)piperazin-1-yl)ethan-1-one as a white solid;
  • Example 7 Macrocyclic Compound 5 5 -Fluoro-1 2 -(4-methoxypiperazin-1-yl)-3 1 H-6-oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclononanone
  • Example 9 5 -Fluoro-1 2 -(4-methyl-1,4-diazepin-1-yl)-3 1 H-6-oxa-2,9-diazepin-3(3,5)-indazole-1(4,6)-pyrimidine 5(1,2)-phenylcyclononyl
  • Example 3 The specific steps of the synthesis operation refer to Example 3 to obtain a white solid.
  • Example 12 5 5 -Fluoro-1 2 -(4-acetylhomopiperazin-1-yl)-3 1 H-6-oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine 5(1,2)-phenylcyclononyl
  • Example 3 The specific steps of the synthesis operation refer to Example 3 to obtain a white solid.
  • Example 13 5 -Fluoro-1 2 -(4-1,4-dioxa-8-aza[4.5]decane-1-yl)-3 1 H-6-oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine 5(1,2)-phenylcyclononyl
  • Example 3 The specific steps of the synthesis operation refer to Example 3 to obtain a white solid.
  • Example 3 The specific steps of the synthesis operation refer to Example 3 to obtain a white solid.
  • Example 15 5 5 -fluoro-1 2 -(4-isopropylpiperazin-1-yl)-3 1 H-6-oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine 5(1,2)-phenylcyclononyl
  • Example 3 The specific steps of the synthesis operation refer to Example 3 to obtain a white solid.
  • Example 16 5 5 -Fluoro- 1 2 -(4-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester-1-yl)-3 1 H-6-oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine 5(1,2)-phenylcyclononyl
  • Example 3 The specific steps of the synthesis operation refer to Example 3 to obtain a white solid.
  • Example 17 5 5 -fluoro-1 2 -(4-butylpiperazin-1-yl)-3 1 H-6-oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine 5(1,2)-phenylcyclononyl
  • Example 3 The specific steps of the synthesis operation refer to Example 3 to obtain a white solid.
  • Example 18 5 5 -Fluoro-1 2 -(2-ethylamino-1-yl)-3 1 H-6-oxa-2,10-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclododecane
  • Example 3 The specific steps of the synthesis operation refer to Example 3 to obtain a white solid.
  • Example 3 The specific steps of the synthesis operation refer to Example 3 to obtain a white solid.
  • Example 20 5 5 -Fluoro-1 2 -(4-(methylsulfonyl)piperazin-1-yl)-3 1 H-6-oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine 5(1,2)-phenylcyclononyl
  • Example 3 The specific steps of the synthesis operation refer to Example 3 to obtain a white solid.
  • Example 21 5 5 -Fluoro- 1 2 -(4-(tetrahydroquinoline)piperazin-1-yl)-3 1 H-6-oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine 5(1,2)-phenylcyclononyl
  • Example 3 The specific steps of the synthesis operation refer to Example 3 to obtain a white solid.
  • Example 22 5 5 -Fluoro- 1 2 -(3-methyl-3,9 ⁇ 2 -diazaspiro[5.5]undec-1-yl)-3 1 H-6-oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine 5(1,2)-phenylcyclononyl
  • Example 3 The specific steps of the synthesis operation refer to Example 3 to obtain a white solid.
  • Example 3 The specific steps of the synthesis operation refer to Example 3 to obtain a white solid.
  • Example 3 The specific steps of the synthesis operation refer to Example 3 to obtain a white solid.
  • Example 3 The specific steps of the synthesis operation refer to Example 3 to obtain a white solid.
  • Example 27 1 2 -(4-methylpiperazinephenyl-1-yl)-5 5 -fluoro-3 1 H-6-oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclononanone
  • Example 28 Macrocyclic compound 5 5 -fluoro- 1 6 -(4-morpholin-1-yl)-3 1 H-6-oxa-2,9-diaza-3(3,5)-indazole-1(4,2)-pyrimidine-5(1,2)-phenylcyclononanone
  • Example 3 The specific steps of the synthesis operation refer to Example 3 to obtain a white solid.
  • Example 29 5 5 -fluoro- 1 6 -(4-methylpiperazin-1-yl)-3 1 H-6-oxa-2,9-diaza-3(3,5)-indazole-1(4,2)-pyrimidine-5(1,2)-phenylcyclononanone
  • Example 30 5 5 -Fluoro-1 6 -(4-formylpiperazin-1-yl)-3 1 H-6-oxa-2,9-diaza-3(3,5)-indazole-1(4,2)-pyrimidine-5(1,2)-phenylcyclononanone
  • Step 1 Synthesis of tert-butyl (3-(5-fluoro-2-methylphenoxy)propyl)carbamate
  • Step 2 Synthesis of tert-butyl (3-(2-(bromomethyl)-5-fluorophenoxy)propyl)carbamate
  • Step 3 Synthesis of tert-butyl (3-(2-(3-cyano-4-fluorobenzyl)-5-fluorophenoxy)propyl)carbamate
  • Step 4 Synthesis of tert-butyl (3-(2-(((3-amino-1H-indazol-5-yl)methyl)-5-fluorophenoxy)propyl)carbamate
  • Step 5 Synthesis of tert-butyl (2-(2-((3-((2,6-dichloropyrimidin-4-yl)amino)-1H-indazol-5-yl)methyl)-4-fluorophenoxy)propyl)carbamate
  • Step 6 Synthesis of 5-(2-(3-aminopropoxy)-4-fluorobenzyl)-N-(2,6-dichloropyrimidin-4-yl)-1H- Indazol-3-amine trifluoroacetate
  • Example 32 1 2 -chloro- 5 5 -fluoro-3 1 H-6-oxa-2,10-diaza-3 (3,5)-indazole-1 (4,6)-pyrimidine-5 (1,2)-benzocyclodecane:
  • Example 3 The synthesis steps are shown in Example 3 to obtain a white solid.
  • Example 3 The synthesis steps are shown in Example 3 to obtain a white solid.
  • Example 3 The synthesis steps are shown in Example 3 to obtain a white solid.
  • Example 3 The synthesis steps are shown in Example 3 to obtain a white solid.
  • Example 36 5 5 -Fluoro-1 2 -(4-acetylpiperazin-1-yl)-3 1 H-6-oxa-2,10-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclododecane
  • Example 3 The synthesis steps are shown in Example 3 to obtain a white solid.
  • Example 37 5 5 -Fluoro-1 2 -(4-methoxypiperidin-1-yl)-3 1 H-6-oxa-2,10-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclododecane
  • Example 38 5 5 -Fluoro-1 2 -(4-cyclopropylpiperazin-1-yl)-3 1 H-6-oxa-2,10-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclododecane
  • Example 3 The synthesis steps are shown in Example 3 to obtain a white solid.
  • Example 39 5 5 -Fluoro-1 2 -(4-methylhomopiperazin-1-yl)-3 1 H-6-oxa-2,10-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclododecane
  • Example 3 The synthesis steps are shown in Example 3 to obtain a white solid.
  • Example 40 5 5 -Fluoro-1 2 -(4-1,4-dioxa-8-aza[4.5]decane-1-yl)-3 1 H-6-oxa-2,10-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclododecane
  • Example 3 The synthesis steps are shown in Example 3 to obtain a white solid.
  • Example 42 5 5 -Fluoro-1 2 -(4-methylpiperidin-1-yl)-3 1 H-6-oxa-2,10-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclododecane
  • Example 3 The synthesis steps are shown in Example 3 to obtain a white solid.
  • Step 1 Synthesis of tert-butyl (2-(4-fluoro-2-methylphenoxy)butyl)carbamate
  • Step 2 Synthesis of tert-butyl (2-(2-(bromomethyl)-4-fluorophenoxy)butyl)carbamate
  • Step 3 Synthesis of tert-butyl (2-(2-(3-cyano-4-fluorobenzyl)-4-fluorophenoxy)butyl)carbamate
  • Step 4 Synthesis of tert-butyl (2-(2-((3-amino-1H-indazol-5-yl)methyl)-4-fluorophenoxy)butyl)carbamate
  • Step 5 Synthesis of tert-butyl (2-(2-((3-((2,6-dichloropyrimidin-4-yl)amino)-1H-indazol-5-yl)methyl)-4-fluorophenoxy)butyl)carbamate
  • Step 6 Synthesis of trifluoroacetate salt of 5-(2-(2-aminobutoxy)-5-fluorobenzyl)-N-(2,6-dichloropyrimidin-4-yl)-1H-indazol-3-amine
  • Example 43 1 2 -chloro- 5 5 -fluoro-3 1 H-6-oxa-2,11-diaza-3 (3,5)-indazole-1 (4,6)-pyrimidine-5 (1,2)-benzocyclopentane
  • Example 2 The synthesis steps are detailed in Example 1, and a white solid is obtained. Melting point:
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid. Melting point:
  • Example 46 5 5 -fluoro- 1 2 -(4-acetylpiperazin-1-yl)-3 1 H-6-oxa-2,11-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-benzylcyclophosphamide
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 47 5 5 -fluoro- 1 2 -(4-isopropylpiperazin-1-yl)-3 1 H-6-oxa-2,11-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-benzylcyclophosphamide
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 48 5 5 -fluoro- 1 2 -(4-cyclopropylpiperazin-1-yl)-3 1 H-6-oxa-2,11-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-benzylcyclophosphamide
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 49 5 5 -fluoro- 1 2 -(4-morpholin-1-yl)-3 1 H-6-oxa-2,11-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-benzyl cyclophosphamide
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 50 5 5 -fluoro- 1 2 -(4-methoxypiperidin-1-yl)-3 1 H-6-oxa-2,11-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-benzyl cyclophosphamide
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 51 5 5 -Fluoro- 1 2 -(4-1,4-dioxa-812-azaspiro[4.5]decane-1-yl)-3 1 H-6-oxa-2,11-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-benzyl cyclophosphamide
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 52 5 5 -Fluoro- 1 2 -(4-methylhomopiperazin-1-yl)-3 1 H-6-oxa-2,11-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-benzylcyclophosphamide
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 53 5 5 -Fluoro-1 2 -(4-piperidin-1-yl)-3 1 H-6-oxa-2,11-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-benzyl cyclophosphamide
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Step 1 Synthesis of tert-butyl (2-(4-chloro-2-methylphenoxy)ethyl)carbamate
  • Step 3 Synthesis of tert-butyl (2-(2-(3-cyano-4-chlorobenzyl)-4-fluorophenoxy)ethyl)carbamate
  • Step 4 Synthesis of tert-butyl (2-(2-((3-amino-1H-indazol-5-yl)methyl)-4-chlorophenoxy)ethyl)carbamate
  • Step 5 Synthesis of tert-butyl (2-(2-((3-((2,6-dichloropyrimidin-4-yl)amino)-1H-indazol-5-yl)methyl)-4-chlorophenoxy)ethyl)carbamate
  • tert-butyl (2-(2-((3-((2,6-dichloropyrimidin-4-yl)amino)-1H-indazol-5-yl)methyl)-4-fluorophenoxy)ethyl)carbamate to obtain tert-butyl (2-(2-((3-((2,6-dichloropyrimidin-4-yl)amino)-1H-indazol-5-yl)methyl)-4-chlorophenoxy)ethyl)carbamate (600 mg, yield: 87%).
  • Step 6 Synthesis of trifluoroacetate salt of 5-(2-(2-aminoethoxy)-5-chlorobenzyl)-N-(2,6-dichloropyrimidin-4-yl)-1H-indazol-3-amine
  • Example 54 1 2 ,5 5 -dichloro-3 1 H-6-oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-benzocyclononyl
  • Example 1 The synthesis steps are detailed in Example 1 to obtain a white solid.
  • Example 55 5 -chloro- 12- (4-methylpiperazin-1-yl)-31H- 6 -oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclononanone
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 56 5 -chloro- 12- (4-acetylpiperazin-1-yl)-31H- 6 -oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclononanone
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 57 5 -chloro- 12- (4-ethylpiperazin-1-yl)-31H- 6 -oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclononanone
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 58 5 -chloro- 12- (4-methylhomopiperazin-1-yl) -31H -6-oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclononanone
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 59 5 -chloro- 12- (4-isopropylpiperazin-1-yl)-31H- 6 -oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclononanone
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 60 5 -chloro- 12- (4-cyclopropylpiperazin-1-yl)-31H- 6 -oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclononanone
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 61 5 -chloro- 12- (4-morpholin-1-yl)-31H- 6 -oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclononanone
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 62 5 -chloro- 12- (4-methylpiperidin-1-yl)-31H- 6 -oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclononanone
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 63 5 -chloro- 12- (4-methoxypiperidin-1-yl)-31H- 6 -oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclononanone
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 64 5 -chloro- 12- (4-1,4-dioxa-812-azaspiro[4.5]decane-1-yl) -31H -6-oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclononanone
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Step 1 Synthesis of tert-butyl (2-(5-fluoro-2-methylphenoxy)ethyl)carbamate
  • Step 3 Synthesis of tert-butyl (2-(2-(3-cyano-5-fluorobenzyl)-4-fluorophenoxy)ethyl)carbamate
  • Step 4 Synthesis of tert-butyl (2-(2-((3-amino-1H-indazol-5-yl)methyl)-5-fluorophenoxy)ethyl)carbamate
  • Step 5 Synthesis of tert-butyl (2-(2-((3-((2,6-dichloropyrimidin-4-yl)amino)-1H-indazol-5-yl)methyl)-5-fluorophenoxy)ethyl)carbamate
  • tert-butyl (2-(2-((3-((2,6-dichloropyrimidin-4-yl)amino)-1H-indazol-5-yl)methyl)-4-fluorophenoxy)ethyl)carbamate to obtain tert-butyl (2-(2-((3-((2,6-dichloropyrimidin-4-yl)amino)-1H-indazol-5-yl)methyl)-4-chlorophenoxy)ethyl)carbamate (600 mg, yield: 87%).
  • Step 6 Synthesis of trifluoroacetate salt of 5-(2-(2-aminoethoxy)-5-fluorobenzyl)-N-(2,6-dichloropyrimidin-4-yl)-1H-indazol-3-amine
  • Example 65 1 2 ,5 5 -dichloro-3 1 H-6-oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-benzocyclononyl
  • Example 1 The synthesis steps are detailed in Example 1 to obtain a white solid.
  • Example 66 5 -Fluoro- 12- (4-methylpiperazin-1-yl)-31H- 6 -oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclononanone
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 67 5 5 -fluoro- 1 2 -(4-ethylpiperazin-1-yl)-3 1 H-6-oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclononanone
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 68 5 5 -fluoro- 1 2 -(4-isopropylpiperazin-1-yl)-3 1 H-6-oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclononanone
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 69 5 5 -fluoro- 1 2 -(4-methylhomopiperazin-1-yl)-3 1 H-6-oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclononanone
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 70 5 5 -fluoro- 1 2 -(4-acetylpiperazin-1-yl)-3 1 H-6-oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclononanone
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 71 5 5 -fluoro- 1 2 -(4-acetylhomopiperazin-1-yl)-3 1 H-6-oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclononanone
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 72 5 5 -fluoro- 1 2 -(4-cyclopropylpiperazin-1-yl)-3 1 H-6-oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclononanone
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 73 5 -Fluoro- 12- (4-morpholin-1-yl) -31H -6-oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclononanone
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 74 5 -Fluoro- 12- (4-piperidin-1-yl)-31H- 6 -oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclononanone
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 75 5 -Fluoro- 12- (4-methoxypiperidin-1-yl) -31H -6-oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclononanone
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Step 1 Synthesis of tert-butyl (2-(3-fluoro-5-methylphenoxy)ethyl)carbamate
  • Step 2 Synthesis of tert-butyl (2-(3-(bromomethyl)-5-fluorophenoxy)ethyl)carbamate
  • Step 3 Synthesis of tert-butyl (2-(3-(3-(3-cyano-4-fluorobenzyl)-5-fluorophenoxy)ethyl)carbamate
  • Step 4 Synthesis of tert-butyl (2-(3-(((3-amino-1H-indazol-5-yl)methyl)-5-fluorophenoxy)ethyl)carbamate
  • Step 5 Synthesis of tert-butyl (2-(3-((3-((3-((2,6-dichloropyrimidin-4-yl)amino)-1H-indazol-5-yl)methyl)-5-fluorophenoxy)ethyl)carbamate
  • tert-butyl (2-(2-((3-((2,6-dichloropyrimidin-4-yl)amino)-1H-indazol-5-yl)methyl)-4-fluorophenoxy)ethyl)carbamate to obtain tert-butyl (2-(2-((3-((2,6-dichloropyrimidin-4-yl)amino)-1H-indazol-5-yl)methyl)-4-chlorophenoxy)ethyl)carbamate (600 mg, yield: 87%).
  • Step 6 Synthesis of trifluoroacetate salt of 5-(3-(2-aminoethoxy)-5-fluorobenzyl)-N-(2,6-dichloropyrimidin-4-yl)-1H-indazol-3-amine
  • Example 76 1 2 -chloro- 5 4 -fluoro-3 1 H-6-oxa-2,9-diaza-3 (3,5)-indazole-1 (4,6)-pyrimidine-5 (1,2)-benzocyclononyl
  • Example 1 The synthesis steps are detailed in Example 1 to obtain a white solid.
  • Example 77 5 5 -fluoro- 1 2 -(4-methylpiperazin-1-yl)-3 1 H-6-oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,3)-phenylcyclononanone
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 78 5 5 -fluoro- 1 2 -(4-isopropylpiperazin-1-yl)-3 1 H-6-oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,3)-phenylcyclononanone
  • Example 1 The synthesis steps are detailed in Example 1 to obtain a white solid.
  • Example 79 5 5 -fluoro- 1 2 -(4-acetylpiperazin-1-yl)-3 1 H-6-oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,3)-phenylcyclononanone
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 80 5 5 -fluoro- 1 2 -(4-methylhomopiperazin-1-yl)-3 1 H-6-oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,3)-phenylcyclononanone
  • Example 1 The synthesis steps are detailed in Example 1 to obtain a white solid.
  • Example 81 5 5 -fluoro- 1 2 -(4-cyclopropylpiperazin-1-yl)-3 1 H-6-oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,3)-phenylcyclononanone
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 82 5 -Fluoro- 12- (4-ethylpiperazin-1-yl)-31H- 6 -oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,3)-phenylcyclononanone
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 83 5 -Fluoro- 12- (4-piperidin-1-yl)-31H- 6 -oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,3)-phenylcyclononanone
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 84 5 -Fluoro- 12- (4-acetylhomopiperazin-1-yl)-31H- 6 -oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,3)-phenylcyclononanone
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 85 5 -Fluoro- 12- (4-butylpiperazin-1-yl) -31H -6-oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,3)-phenylcyclononanone
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 86 5 5 -fluoro- 1 2 -(4-methanesulfonic acid piperazin-1-yl)-3 1 H-6-oxa-2,9-diaza-3(3,5)-indazole-1(4,6)-pyrimidine-5(1,3)-phenylcyclononanone
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Step 5 Synthesis of tert-butyl (2-(2-((3-((2,6-dichloropyrimidin-4-yl)amino)-1H-indazol-5-yl)methyl)-4-fluorophenoxy)ethyl)carbamate
  • tert-butyl (2-(2-((3-((2,6-dichloropyrimidin-4-yl)amino)-1H-indazol-5-yl)methyl)-4-fluorophenoxy)ethyl)carbamate to obtain tert-butyl (2-(2-((3-((2,6-dichloropyrimidin-4-yl)amino)-1H-indazol-5-yl)methyl)-4-chlorophenoxy)ethyl)carbamate (600 mg, yield: 87%).
  • Example 87 1 2 -chloro- 5 5 -chloro-3 1 H-6-oxa-2,9-diaza-3 (3,6)-indazole-1 (4,6)-pyrimidine-5 (1,2)-benzocyclononyl
  • Example 1 The synthesis steps are detailed in Example 1 to obtain a white solid.
  • Example 88 5 -Fluoro- 12- (4-methylpiperazin-1-yl)-31H- 6 -oxa-2,9-diaza-3(3,6)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclononanone
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 89 5 5 -fluoro- 1 2 -(4-methoxypiperazin-1-yl)-3 1 H-6-oxa-2,9-diaza-3(3,6)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclononanone
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 90 5 5 -fluoro- 1 2 -(4-acetylpiperazin-1-yl)-3 1 H-6-oxa-2,9-diaza-3(3,6)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclononanone
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 91 5 5 -fluoro- 1 2 -(4-piperidin-1-yl)-3 1 H-6-oxa-2,9-diaza-3(3,6)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclononanone
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 92 5 5 -fluoro- 1 2 -(4-isopropylpiperazin-1-yl)-3 1 H-6-oxa-2,9-diaza-3(3,6)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclononanone
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 93 5 -Fluoro- 12- (4-homopiperazin-1-yl) -31H -6-oxa-2,9-diaza-3(3,6)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclononanone
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 94 5 -Fluoro- 12- (4-cyclopropylpiperazin-1-yl) -31H -6-oxa-2,9-diaza-3(3,6)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclononanone
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 95 5 -Fluoro- 12- (4-piperidin-1-yl)-31H- 6 -oxa-2,9-diaza-3(3,6)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclononanone
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • tert-butyl (2-(2-((3-((2,6-dichloropyrimidin-4-yl)amino)-1H-indazol-5-yl)methyl)-4-fluorophenoxy)ethyl)carbamate to obtain tert-butyl (2-(2-((3-((2,6-dichloropyrimidin-4-yl)amino)-1H-indazol-5-yl)methyl)-4-chlorophenoxy)ethyl)carbamate (600 mg, yield: 87%).
  • Example 96 1 2 -chloro- 5 5 -fluoro-3 1 H-6-oxa-2,9-diaza-3 (3,6)-indazole-1 (4,6)-pyrimidine-5 (1,2)-benzocyclononyl
  • Example 1 The synthesis steps are detailed in Example 1 to obtain a white solid.
  • Example 97 5 -chloro- 12- (4-methylpiperazin-1-yl) -31H -6-oxa-2,9-diaza-3(3,6)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclononanone
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 98 5 -chloro- 12- (4-ethylpiperazin-1-yl)-31H- 6 -oxa-2,9-diaza-3(3,6)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclononanone
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 99 5 -chloro- 12- (4-cyclopropylpiperazin-1-yl) -31H -6-oxa-2,9-diaza-3(3,6)-indazole-1(4,6)-pyrimidine-5(1,2)-phenylcyclononanone
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • tert-butyl (2-(2-((3-((2,6-dichloropyrimidin-4-yl)amino)-1H-indazol-5-yl)methyl)-4-fluorophenoxy)ethyl)carbamate to obtain tert-butyl (2-(2-((3-((2,6-dichloropyrimidin-4-yl)amino)-1H-indazol-5-yl)methyl)-4-chlorophenoxy)ethyl)carbamate (600 mg, yield: 87%).
  • Example 100 1 2 -chloro- 5 5 -fluoro-3 1 H-6-oxa-2,11-diaza-3 (3,6)-indazole-1 (4,6)-pyrimidine-5 (1,2)-Benzocyclopentacyclohexene
  • Example 1 The synthesis steps are detailed in Example 1 to obtain a white solid.
  • Example 101 5-5 -Fluoro- 12- (4-methylpiperazin-1-yl) -31H -6-oxa-2,11-diaza-3(3,6)-indazole-1(4,6)-pyrimidine-5(1,2)-benzylcyclophosphamide
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 102 5 -Fluoro- 12- (4-ethylpiperazin-1-yl) -31H -6-oxa-2,11-diaza-3(3,6)-indazole-1(4,6)-pyrimidine-5(1,2)-benzylcyclophosphamide
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • tert-butyl (2-(2-((3-((2,6-dichloropyrimidin-4-yl)amino)-1H-indazol-5-yl)methyl)-4-fluorophenoxy)ethyl)carbamate to obtain tert-butyl (2-(2-((3-((2,6-dichloropyrimidin-4-yl)amino)-1H-indazol-5-yl)methyl)-4-chlorophenoxy)ethyl)carbamate (600 mg, yield: 87%).
  • tert-butyl (2-(2-((3-((2,6-dichloropyrimidin-4-yl)amino)-1H-indazol-5-yl)methyl)-4-fluorophenoxy)ethyl)carbamate to obtain tert-butyl (2-(2-((3-((2,6-dichloropyrimidin-4-yl)amino)-1H-indazol-5-yl)methyl)-4-chlorophenoxy)ethyl)carbamate (600 mg, yield: 87%).
  • Example 103 1 2 -chloro- 5 5 -fluoro-3 1 H-6-oxa-2,10-diaza-3 (3,6)-indazole-1 (4,6)-pyrimidine-5 (1,2)-benzocyclopentacyclohexene
  • Example 1 The synthesis steps are detailed in Example 1 to obtain a white solid.
  • Example 104 5 -Fluoro- 12- (4-methylpiperazin-1-yl) -31H -6-oxa-2,10-diaza-3(3,6)-indazole-1(4,6)-pyrimidine-5(1,2)-benzylcyclophosphamide
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 105 5 -Fluoro- 12- (4-morpholin-1-yl)-31H- 6 -oxa-2,10-diaza-3(3,6)-indazole-1(4,6)-pyrimidine-5(1,2)-benzylcyclophosphamide
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Example 106 5 5 -fluoro- 1 2 -(4-isopropylpiperazin-1-yl)-3 1 H-6-oxa-2,10-diaza-3(3,6)-indazole-1(4,6)-pyrimidine-5(1,2)-benzylcyclophosphamide
  • Example 3 The synthesis steps are detailed in Example 3 to obtain a white solid.
  • Embodiment 107 is a diagrammatic representation of Embodiment 107.
  • Percent inhibition (max-conversion)/(max-min)*100. "max” represents DMSO control; “min” represents low control.
  • IC 50 values of all compounds 1-15 are shown in the table. *** represents IC 50 ⁇ 100nmol, ** represents 100nmol ⁇ IC50 ⁇ 5000nmol, and * represents IC 50 >5000nmol
  • Reagents Gibco DMEM/F12 culture medium, Gibco 0.25% trypsin/EDTA cell digestion solution, MTT (5 mg/ml), DMSO, PBS.
  • Instruments 37°C, 5% CO2 incubator, TECAN Infinite TM 200 series multifunctional microplate reader, clean bench, cell counting chamber.
  • control group contained the same volume of solvent as the experimental group, diluted with complete medium. 200 ⁇ l per well;
  • the dissolved drug was diluted with culture medium to concentrations of 0.1, 1, 10, 100, 1000, and 10000 nM, with 200 ⁇ l per well.
  • IC 50 values of all compounds are shown in the table. *** represents IC 50 ⁇ 100nmol, ** represents 100nmol ⁇ IC50 ⁇ 5000nmol, and * represents IC 50 >5000nmol
  • Table 2 H2228 inhibition rate activity table *** represents IC 50 ⁇ 100nmol, ** represents 100nmol ⁇ IC50 ⁇ 5000nmol, * represents IC 50 >5000nmol

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Abstract

提供一种作为蛋白激酶抑制剂的含吲唑结构的杂环大环化合物及其制备方法，该化合物具有通式(I)的结构。还提供了该化合物在药学上可接受的盐类，前药和溶剂化物。进一步地，提供了一种在制备治疗或预防由激活或抗性突变体形式的ALK等靶点介导的障碍或疾病的药物中的用途，优选地，所述激活或抗性突变体形式(包含但不限于EML4-ALK融合突变)的ALK介导的障碍或疾病为肺癌，卵巢癌、宫颈癌、结肠直肠癌、乳腺癌、胰腺癌、胶质瘤、胶质母细胞瘤、黑色素瘤、前列腺癌、白血病、淋巴瘤、非霍奇金淋巴瘤、胃癌、肺癌、肝细胞癌、胃肠道基质瘤、甲状腺癌、胆管癌、子宫内膜癌、肾癌、间变性大细胞淋巴癌、急性髓细胞白血病、多发性骨髓瘤或间皮瘤等。

Description

一种作为蛋白激酶抑制剂的含吲唑结构的杂环大环化合物及其制备方法 技术领域
本发明属于制药领域，涉及多种蛋白激酶的多靶点抑制剂及其制备方法与应用。
背景技术
蛋白激酶在机体内的多方面都起着举足轻重的作用，它们控制细胞的新陈代谢、转录、分裂、运动和细胞程序性死亡，它们也参与免疫反应和神经系统功能。蛋白激酶涉及到的基因突变包括很多种，融合基因是其中的一种。
融合基因是从两个先前分开的基因形成的杂合基因。融合基因的产生主要有三种情况：易位、中间缺失，或染色体倒位。迄今为止，人们总共发现了超过10,861个癌症相关的融合基因突变，融合突变分布于几乎所有的癌症类型。
目前临床上，在所有融合突变中，有35％是与激酶相关的突变，由于激酶融合突变大多数是功能持续获得性突变，使得激酶融合突变成为一个有效的致癌突变指标和靶点。如EML4-ALK、CD74-ROS1，KIF5B-RET相关的突变，FGFR2的融合突变，FGFR3，而另外一些融合突变则比较均匀的分布在不同的肿瘤类型，如BRAF、NTRK1、NTRK3等。
人源的间变性淋巴瘤激酶(ALK)基因座编码是经典的受体酪氨酸激酶(RTK)，ALK融合突变最早报道于1999年变性大细胞淋巴瘤中的TPM3-ALK，直到发表在《Nature》上有关非小细胞肺癌EML4-ALK融合突变的报道才真正引起了人们的重视，开启了固体瘤融合突变靶向性药物研发的热潮。
随着科研人员对ALK基因融合的理解和基因测序技术的发展，ALK基因融合已经成为一个成熟又热门的靶点。从2011年克唑替尼被美国FDA批准作为一线用药治疗ALK阳性非小细胞肺癌以来，不断涌现新型小分子激酶抑制剂。这些小分子抑制剂不仅克服了克唑替尼的耐药性问题，而且延长了病人生存期并降低了药物的毒副作用。目前为止，已经开发出了一代，二代和三代小分子抑制剂。第一代主要以Crizotinib为代表，开启了ALK基因融合抑制剂的热潮；第二代主要是针对Crizotinib用药后产生的继发性耐药；目前应上市的药物有：Ceritinib，Alectinib，Brigatinib，第三代抑制剂包括：Lorlatinib，Entrectinib，Ensartinib，第三代抑制剂不仅要对一代和二代产生的继发性耐药有效，具有对 ALK,NTRK1/2/3,ROS1,TRK，EGFR，FGFR等靶点的抑制活性，还必须对脑转移的病例有效，这就要求第三代的小分子具有CNS的相关性质。
发明内容
本发明的一个方面提供式(I)的环状化合物及其药学上可接受的盐、前药或溶剂化物，
其中
Z1，Z2，Z3分别独立地选自CH和N；优选地，Z1选自N，Z2选自N，Z3选自CH；或Z1选自CH，Z2选自N，Z3选自N。
这种键表示与苯环连接的位置可以是苯环上的任何无取代位点，包括
n为1，2，3，4，5，6，7，8，9或10；优选地，n选自1，2，3，4。
X，Y，W分别独立地选自O，NH，NR4R5，S，C＝O，CR4R5，R4和R5各自独立地选自氢、C1-C5烷基，C1-C5烷氧基；
R1选自H，卤素，NR6R7，CR6R7，含1-3个取代基的苯环，5-12元杂环，R6和R7各自独立地选自氢、C1-C5烷基；
所述5-12元杂环被C1-C10烷基、C1-C10烷氧基、C1-C10环烷基、C1-C10烷基酰胺，C1-C10环烷基酰胺、C1-C10烷基磺酰胺，C1-C10环烷基磺酰胺、氨基保护基、苯基、5-12 元杂环任选地取代；
R2，R3分别独立地选自氢，卤素，氨基，硝基，氰基，羟基，羧基，酰胺基，磺酸基，磺酰胺基，磺酸酯基，未取代的或取代的C1-C6烷基,未取代的或取代的C1-C6烷氧基，一取代或多取代的卤代烷基或烷氧基；
在某些实施例中，R2和R3分别独立选自H，F，Cl，Br，I；
在某些实施例中，R2为F，R3为H；或R2为Cl，R3为H；或R2为H，R3为F。
在一些实施例中，R1选自H，F，Cl，Br；
在一些实施例中，R1选自H或Cl；
在一些实施例中，R1选自NR6R7，CR6R7，，含1-3个取代基的苯环，5-12元并环，5-12元螺环，5-12元桥环，R6和R7各自独立地选自氢、C1-C5烷基；
所述5-12元并环、螺环和桥环被C1-C10烷基、C1-C10烷氧基、C1-C10环烷基、C1-C10烷基酰胺，C1-C10环烷基酰胺、C1-C10烷基磺酰胺，C1-C10环烷基磺酰胺、氨基保护基、苯基、5-12元杂环任选地取代；
在一些实施例中，R1选自以下通式：
其中m’，n’，m”和n”分别独立地选自1，2，3，4，5；R选自C1-C10烷基，C3-C12环烷基，C1-C10烷基酰胺，C1-C10环烷基酰胺，苯环，嘧啶，哌啶基，C1-C10烷基磺酰胺，C1-C10环烷基磺酰胺，氨基保护基；杂环可为饱和，部分饱和和不饱和，可为单环，并环，螺环，桥环，上述所有烷基可以是直链也可以是带支链的烷烃；
在某些实施例中，R1选自
R选自H,O,CH3,CH2CH3,CH2CH2CH3,CH2CH2CH2CH3,CH(CH3)2，环丙基，环丁基，环戊基，环庚基，C1-C4烷基酰胺，C1-C6环烷基酰胺，苯环，嘧啶，哌啶基，C1-C6烷基磺酰胺，C1-C6环烷基磺酰胺，氨基保护基。
在一些实施例中，R1选自以下具体片段，
在某些实施例中，X与R2所在的苯环连接的位点可以表示为优选地，具体通式如下
所述R2和R3中至少有一个为卤素；
在某些实施例中，X与Y,W分别独立地选自CH2，NH，O。
在某些实施例中，X为CH2，Y为NH，W为O；通式如下：
在某些实施例中，R1为Cl，所述化合物选自：
本发明的另一个方面提供式I的化合物的制备方法：
提供一条式I通用的路线1
本发明的又一个方面提供包含式(I)化合物或其药学上可接受的盐、前药和溶剂化物的药用组合物。
本发明的再一个方面提供式(I)化合物或其药学上可接受的盐、前药和溶剂化物用于制造治疗哺乳动物的肿瘤、急性和慢性炎症疾病、炎症性肠道疾病、皮肤病、糖尿病、眼部疾病、与哺乳动物的血管发生或血管再生相关的疾病、与慢性疼痛相关的疾病、和其它由可以通过调控蛋白激酶来实现治疗的用途。
本发明的另一个方面提供式(I)化合物或其药学上可接受的盐、前药和溶剂化物在制备 治疗或预防由激活或抗性突变体形式的ALK介导的障碍或疾病的药物中的用途，优选地，所述激活或抗性突变体形式的ALK介导的障碍或疾病为肺癌，卵巢癌、宫颈癌、结肠直肠癌、乳腺癌、胰腺癌、胶质瘤、胶质母细胞瘤、黑色素瘤、前列腺癌、白血病、淋巴瘤、非霍奇金淋巴瘤、胃癌、肺癌、肝细胞癌、胃肠道基质瘤、甲状腺癌、胆管癌、子宫内膜癌、肾癌、间变性大细胞淋巴癌、急性髓细胞白血病、多发性骨髓瘤或间皮瘤。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
如果没有另外指出，本发明全部公开内容采用以下术语定义：
所述的氢包括氢的各种同位素，如氘和氚。
术语“药学上可接受的盐”，除非另有说明，包括可存在于本发明化合物中的酸性基团的盐或碱性基团的盐。
所述烷基、烯基、炔基、环烷基部分可各自独立地被一个或多个选自以下的基团任选取代：羟基、氧代、卤素、氰基、硝基、三氟甲基、叠氮基、氨基、羧基、巯基。
饱和或不饱和烃基，例如烷基、烷二基或烯基，包括与杂原子的结合，例如烷氧基，均可以分别是直链或带有支链的。
实施例1-31的合成步骤：
第一步：合成(2-(4-氟-2-甲基苯氧基)乙基)氨基甲酸叔丁酯
在室温下，向4-氟-2-甲基苯酚(3.2g，25.4mmol)，N-(叔丁氧羰基)乙醇胺(3.0g，18.6mmol)，三苯基膦(4.9g，18.6mmol)的THF(25mL)溶液中滴加偶氮二羧酸二异丙酯(3.8g，18.8mmol)。监测反应完全后，减压旋转蒸发除去有机溶剂，将所得固体在冷正己烷(25mL)的溶剂中打浆，过滤除去大部分三苯基膦氧化物副产物。然后减压旋蒸得到粗产品，通过快速正相色谱法(以PE/EA＝1：10为洗脱液)纯化混合物，得到(2-(4-氟-2-甲基苯氧基)乙基)氨基甲酸叔丁酯(3.2g，产率:72％)为无色油状物。
1H NMR(400MHz,,CDCl3)δ7.17(s,1H),6.92(s,1H),6.70(s,2H),4.48(s,1H),2.99(s,2H),2.48(s,2H),2.18(s,3H),1.55(s,2H),1.35(s,2H),1.31(s,9H).
第二步：(2-(2-(溴甲基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯
向(2-(4-氟-2-甲基苯氧基)乙基)氨基甲酸叔丁酯(3.0g,14mmol)的四氯化碳(50mL)溶剂中分别加入NBS(2.9g，16.3mmoL)和AIBN(200mg，1.2mmoL)，将该混合物加热回流过夜，监测反应原料完全反应后，冷却到室温，过滤后减压蒸除去有机溶剂得到粗产品，直接用正向柱层析(PE/EA为洗脱液)纯化，得到(2-(2-(溴甲基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯(3.0g，产率:63％)为黄色油状。
LC-MS(M+H+)249.1
1H NMR(400MHz,DMSO)δ6.89(d,J＝38.1Hz,4H),3.86(s,2H),3.26(d,J＝4.6Hz,2H),2.10(s,3H),1.33(s,9H).
第三步：合成(2-(2-(3-氰基-4-氟苄基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯
向2(-2(溴甲基)--4-氟苯氧基)乙基)氨基甲酸叔丁酯(2.9g，8.35mmoL)，(3-氰基-4-氟苯基)硼酸(2.1g，12.7mmoL)的THF(25mL)溶液中加入PdCl2(dppf)CH2Cl2的络合物(1.36g，1.67mmoL)和Cs2CO3(4.0g,12.3mmoL)，将该反应混合物加热回流过夜，监测反应完全后，冷却到室温，过滤后减压旋蒸，再溶解到乙酸乙酯，分别用水，饱和食盐水洗涤，无水硫酸钠干燥后减压除去溶剂得到粗产品，直接用正向柱层析(PE/EA为洗脱液)纯化，得到(2-(2-(3-氰基-4-氟苄基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯(1.6g，产率:50％)为白色固体。
LC-MS(M+H+)289.3
1H NMR(400MHz,DMSO)δ7.79(t,J＝7.5Hz,1H),7.45(d,J＝10.6Hz,1H),7.33(d,J＝8.0Hz,1H),7.22–7.15(m,1H),7.06–6.90(m,4H),3.98(s,2H),3.90(dd,J＝13.7,8.6Hz,3H),3.32–3.27(m,2H),1.36(s,10H).
第四步：合成(2-(2-((3-氨基-1H-吲唑-5-基)甲基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯
向(2-(3-氰基-4-氟苄基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯(1.6g，4.1mmoL)的正丁醇(20mL)溶剂中加入水合肼(8mL)，将该反应混合液加热至120℃并维持过夜，监测反应完全后，加入水(5mL)后减压旋蒸除去正丁醇，再分别用HCl(2N)，饱和NaHCO3，水和饱和饱和食盐水洗涤，无水硫酸钠干燥后减压除去溶剂得到粗产品，直接用做下一步。LCMS:401.3[M+1]+。
第五步：合成(2-(2-((3-((2,6-二氯嘧啶-4-基)氨基)-1H-吲唑-5-基)甲基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯
向(2-(2-((3-氨基-1H-吲唑-5-基)甲基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯(500mg，1.25mmoL)和DIPEA(0.4mL,1.9mmoL)的DMF(10mL)溶剂中加2,4,6-三氯嘧啶(455mg，2.5mmoL)，将该反应混合液在室温下搅拌过夜，监测反应完全后，将混合液倒入水(50mL)，用乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥后减压旋蒸 除去溶剂得到粗产品，直接用正向柱层析(PE/EA为洗脱液)纯化，得到(2-(2-((3-((2,6-二氯嘧啶-4-基)氨基)-1H-吲唑-5-基)甲基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯(600mg，产率:87％)。
1H NMR(400MHz,DMSO)δ12.65(s,0H),11.10(s,0H),7.79(s,1H),7.64–7.46(m,2H),7.33(s,1H),6.92(s,3H),3.90(q,J＝11.6Hz,3H),3.06(s,2H),2.11(d,J＝10.1Hz,2H),1.32(d,J＝10.5Hz,9H).
第六步：合成5-(2-(2-氨基乙氧基)-5-氟苄基)-N-(2,6-二氯嘧啶-4-基)-1H-吲唑-3-胺的三氟乙酸盐
向(2-(2-((3-((2,6-二氯嘧啶-4-基)氨基)-1H-吲唑-5-基)甲基)-4氟苯氧基)乙基)氨基甲酸叔丁酯(600mg，1.09mmoL)的DCM(10mL)溶液中加入三氟乙酸(4mL)，在室温下搅拌4小时，监测反应原料完全转化后，直接减压旋蒸除去溶剂得到粗产品5-(2-(2-氨基乙氧基)-5-氟苄基)-N-(2,6-二氯嘧啶-4-基)-1H-吲唑-3-胺的三氟乙酸盐(592mg，产率:100％)。直接用于下一步反应。
实施例1 12-氯-55-氟-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1,2)-苯并环壬基的合成，即大环环合物1。
将5-(2-(2-氨基乙氧基)-5-氟苄基)-N-(2,6-二氯嘧啶-4-基)-1H-吲唑-3-胺的三氟乙酸盐(590mg，1.08mmoL)和K2CO3(450mg,3.26mmoL)的混合物加热到100℃并维持过夜，监测反应原料完全转化后，将混合液倒入水(50mL)，用乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥后减压旋蒸除去溶剂得到粗产品，直接用反相柱层析(Biotage的C18反相柱,以MeCN/0.05％的氨水为洗脱剂)纯化，得到目标化合物。大环环合物1为白色固体(60mg，收率：14％)；
LC-MS(M+H+):411.1127
1H NMR(400MHz,DMSO-d6)δ12.39(s,1H),9.87(s,1H),7.32(s,1H),7.30–7.24(m,3H),7.09(d,J＝8.6Hz,1H),6.99(td,J＝8.7,3.1Hz,1H),6.90(dd,J＝9.0,4.7Hz,1H),6.05(s,1H),3.93–3.80(m,4H),3.37–3.34(m,2H),3.30(m,2H)。
实施例2 16-氯-55-氟-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(2,4)-嘧啶-5(1,2)-苯并环壬基的合成
该化合物合成步骤与实施例1相同，是实施例1合成步骤中的另一终产物，与实施例1为同分异构体
LC-MS(M+H+):411.1127
1H NMR(400MHz,DMSO)δ12.61(s,1H),9.64(s,1H),7.49(d,J＝6.8Hz,1H),7.40(d,J＝8.6Hz,1H),7.27(d,J＝8.7Hz,1H),7.20(dd,J＝8.9,2.7Hz,1H),7.07(ddd,J＝11.6,8.8,4.0Hz,2H),6.82(s,1H),5.51(s,1H),4.11(s,2H),3.98(s,2H),3.23(s,2H)。
实施例3大环环合物55-氟-12-吗啉代-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1,2)-苯并环壬基的合成
将大环环合物12-氯-55-氟-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1,2)-苯并环壬基(6mg，0.014mmoL)和对甲苯磺酸的一水合物(3mg，0.015mmoL)的异丁醇(2mL)溶剂加热到120℃并维持3小时(微波加热)，监测到反应原料完全转化为产物，直接将混合液用反相柱层析(Biotage的C18反相柱,以MeCN/0.05％的氨水为洗脱剂)纯化，得到目标化合物大环环合物55-氟-12-吗啉代-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1,2)-苯并环壬基(3mg，产率:47％)为白色固体，
LC-MS(M+H+):462.2045
1H NMR(400MHz,DMSO-d6)δ12.08(s,1H),9.07(s,1H),7.36(s,1H),7.17(dd,J＝14.4,8.5Hz,2H),7.00(d,J＝8.5Hz,1H),6.91(t,J＝7.5Hz,1H),6.81(dd,J＝8.8,4.7Hz,1H),5.34(s,1H),3.78(d,J＝10.0Hz,4H),3.60(s,4H),3.19(m,2H),2.59(dd,J＝9.1,4.3Hz,2H)。
实施例4大环环合物55-氟-12-(4-甲基哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环壬酮的合成
合成操作具体步骤参照实施例3，得到白色固体55-氟-12-(4-甲基哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环壬酮；
LC-MS(M+H+):475.2365，
1H NMR(400MHz,DMSO-d6)δ12.30(s,1H),9.87(s,1H),7.37(s,1H),7.26(d,J＝9.4Hz,3H),7.10(s,1H),7.03–6.94(m,2H),6.88(dd,J＝9.0,4.4Hz, 2H),5.52(s,1H),4.25(s,2H),3.86(d,J＝22.2Hz,2H),3.16(m,br,4H),2.86(m,br,7H)。
实施例5：大环环合物12-(4-乙基哌嗪-1-基)-55-氟-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环壬酮
合成操作具体步骤参照实施例3，得到大环12-(4-乙基哌嗪-1-基)-55-氟-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环壬酮，白色固体；
LC-MS(M+H+):489.2518，
1H NMR(400MHz,DMSO-d6)δ12.30(s,1H),9.75(s,1H),9.14(s,1H),7.37(s,1H),7.31–7.23(m,2H),7.10(s,1H),6.99(td,J＝8.7,3.2Hz,1H),6.88(dd,J＝8.9,4.5Hz,1H),5.53(s,1H),4.26(s,2H),3.89(s,2H),3.84(s,2H),3.60(d,J＝10.4Hz,2H),3.44(m,2H),3.25–3.11(m,2H),3.05(s,2H),1.26(t,J＝7.3Hz,2H),1.20(t,J＝7.3Hz,3H)。
实施例6大环环合物1-(4-(55-氟-31H-6-氧杂-2,9-氮杂-3(3,5)-吲唑-1(4,6)-
嘧啶-5(1,2)-苯环环壬基-12-基)哌嗪-1-乙酰基)-1-酮
合成操作具体步骤参照实施例3，得到大环化合物1-(4-(55-氟-31H-6-氧杂-2,9-氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1,2)-苯环环壬基-12-基)哌嗪-1-基)乙-1-酮，白色固体；
LC-MS(M+H+):503.2310
1H NMR(400MHz,DMSO-d6)δ12.44(s,1H),10.10(s,1H),8.78(s,1H),7.29(s,3H),7.11(s,1H),7.05–6.96(m,1H),6.89(d,J＝4.3Hz,1H),5.53(s,1H),3.93(m,2H),3.85(s,2H),3.61(m,8H),3.09(d,J＝29.3Hz,2H),2.06(s,3H)。
实施例7：大环环合物55-氟-12-(4-甲氧基哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环壬酮
合成操作具体步骤参照实施例3，得到55-氟-12-(4-甲氧基哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环壬酮白色固体，
LC-MS(M+H+):490.2362，
1H NMR(400MHz,DMSO-d6)δ12.05(s,1H),8.96(s,1H),7.38(s,1H),7.21–7.12(m,2H),7.00(d,J＝8.5Hz,1H),6.90(td,J＝8.8,3.0Hz,1H),6.81(dd,J＝8.9,4.7Hz,1H),6.13(s,1H),5.37(s,1H),3.78(m,3H),3.21(s,3H),3.15(m,2H),3.04(t,J＝10.0Hz,2H),2.62–2.56(m,2H),2.13(m,2H),1.81(m,2H),1.36–1.27(m,2H)。
实施例8.55-氟-12-(4-联哌啶-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶5(1,2)-苯环环壬基的合成
合成操作具体步骤参照实施例3，得到白色固体
LC-MS(M+H+)543.2995
1H NMR(400MHz,DMSO)δ12.11(s,1H),9.02(s,1H),7.44(s,1H),7.22(dd,J＝18.0,8.5Hz,2H),7.06(d,J＝8.4Hz,1H),7.01–6.93(m,1H),6.92–6.84(m,1H),4.24(d,J＝12.6Hz,2H),3.84(s,2H),3.16(s,1H),3.00(d,J＝12.0Hz,2H),2.69(d,J＝14.0Hz,2H),2.26(s,2H),1.75(d,J＝11.4Hz,2H),1.64(d,J＝12.0Hz,2H),1.48–1.45(m,4H),1.36(s,4H),1.23(s,2H).
实施例9 55-氟-12-(4-甲基-1,4-二氮杂-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶5(1,2)-苯环环壬基
合成操作具体步骤参照实施例3，得到白色固体
LC-MS(M+H+)489.2528
1H NMR(400MHz,DMSO)δ12.10(s,1H),9.00(s,1H),7.46(s,1H),7.23(dd,J＝16.9,8.6Hz,2H),7.07(d,J＝7.4Hz,1H),6.96(s,1H),6.87(s,1H),5.75(d,J＝5.1Hz,1H),5.29(d,J＝4.9Hz,1H),3.84(s,4H),3.66(s,2H),3.50(s,2H),3.40(s,3H),2.56(s,2H),2.29–2.21(m,4H),1.86(s,2H).
实施例10 55-氟-12-(4-环丙基哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶5(1,2)-苯环环壬基
合成操作具体步骤参照实施例3，得到白色固体
LC-MS(M+H+)501.2534
1H NMR(400MHz,DMSO)δ12.13(s,1H),9.04(s,1H),7.40(s,1H),7.24–7.17(m,2H),7.06(s,1H),6.95(s,1H),6.84(d,J＝4.9Hz,1H),6.33–6.04(m,1H),5.40(s,1H),3.40(s,6H),2.56(s,4H),1.63(s,1H),0.49–0.33(m,4H).0571
实施例11 55-氟-12-(4-甲基哌啶-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶5(1,2)-苯环环壬基
合成操作具体步骤参照实施例3，得到白色固体。
LC-MS(M+H+)474.2419
1H NMR(400MHz,DMSO)δ12.12(s,1H),9.02(s,1H),7.59(d,J＝25.8Hz,3H),7.46(s,1H),7.24(s,2H),7.07(s,1H),6.92(d,J＝33.9Hz,2H),5.48–5.36(m,1H),4.19(s,2H),3.84(s,4H),3.41(s,2H),2.74(s,2H),1.63(s,2H),1.38(s,3H),1.04–0.90(m,3H).0572
实施例12 55-氟-12-(4-乙酰基高哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶5(1,2)-苯环环壬基
合成操作具体步骤参照实施例3，得到白色固体。
LC-MS(M+H+)517.2477
1H NMR(400MHz,DMSO)δ12.10(d,J＝5.2Hz,1H),8.99(d,J＝5.1Hz,1H),7.44(dd,J＝11.9,5.0Hz,1H),7.26–7.17(m,2H),7.06(s,1H),6.95(s,1H),6.91–6.83(m,1H),5.75(d,J＝5.1Hz,1H),5.34(d,J＝5.0Hz,1H),3.84(s,4H),3.73(s,1H),3.58(s,4H),3.49(s,1H),3.41(s,4H),1.98(d,J＝22.2Hz,3H),1.79(d,J＝36.3Hz,2H).0573
实施例13 55-氟-12-(4-1,4-二氧杂-8-氮杂[4.5]癸烷-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶5(1,2)-苯环环壬基
合成操作具体步骤参照实施例3，得到白色固体。
LC-MS(M+H+)518.2322
1H NMR(400MHz,DMSO)δ12.13(s,1H),9.06(s,1H),7.45(s,1H),7.29–7.20(m,2H),7.07(s,1H),6.97(s,1H),6.89(s,1H),6.27(s,1H),5.45(s,1H),3.92(s,4H),3.89–3.82(m,4H),3.56(s,4H),3.41(s,2H),1.69–1.59(m,4H).0574
实施例14 55-氟-12-(4-丙基哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶5(1,2)-苯环环壬基
合成操作具体步骤参照实施例3，得到白色固体.。
LC-MS(M+H+)503.2687
1H NMR(400MHz,DMSO)δ12.12(s,1H),9.08(s,1H),7.43(s,1H),7.22(dd,J＝18.5,8.6Hz,2H),7.05(d,J＝8.4Hz,1H),6.96(s,1H),6.87(s,1H),5.75(d,J＝3.5Hz,1H),5.39(s,1H),3.83(s,4H),3.41(s,6H),2.41(s,2H),2.27(s,2H),1.48(s,2H),1.23(s,3H),0.87(s,4H).
实施例15 55-氟-12-(4-异丙基哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶5(1,2)-苯环环壬基
合成操作具体步骤参照实施例3，得到白色固体，
LC-MS(M+H+)503.2679
1H NMR(400MHz,DMSO)δ12.09(d,J＝15.2Hz,1H),9.06(s,1H),8.61(s,1H),7.39(d,J＝25.5Hz,1H),7.25(s,2H),7.01(d,J＝22.2Hz,2H),6.87(s,1H),5.20(s,1H),3.85(s,4H),3.41(s,8H),3.16(s,1H),2.72(d,J＝19.9Hz,2H),0.99(d,J＝6.1Hz,6H).0604
实施例16 55-氟-12-(4-3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶5(1,2)-苯环环壬基
合成操作具体步骤参照实施例3，得到白色固体。
LC-MS(M+H+)629.3364
1H NMR(400MHz,DMSO)δ11.87(s,1H),8.79(s,1H),8.35(s,1H),7.14(s,1H),6.99(d,J＝20.9Hz,2H),6.82(s,1H),6.67(s,1H),4.98(s,-1H),3.59(s,4H),3.27(s,10H),1.15(s,17H).
实施例17 55-氟-12-(4-丁基哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶5(1,2)-苯环环壬基
合成操作具体步骤参照实施例3，得到白色固体。
LC-MS(M+H+)517.2842
1H NMR(400MHz,DMSO)δ12.06(s,1H),9.05(s,1H),7.34(s,1H),7.19(s,2H),6.91(d,J＝51.4Hz,2H),5.18(s,1H),3.76(d,J＝28.1Hz,8H),2.38(s,8H),1.28(s,4H),0.93–0.75(m,3H).
实施例18 55-氟-12-(2-乙胺-1-基)-31H-6-氧杂-2,10-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环十二烷
合成操作具体步骤参照实施例3，得到白色固体。
LC-MS(M+H+)448.2261
1H NMR(400MHz,DMSO)δ12.24(s,1H),9.73(s,1H),7.16–7.09(m,3H),6.93(d,J＝7.9Hz,1H),6.83(s,1H),6.75(s,1H),5.89(s,1H),3.71(d,J＝10.8Hz,4H),3.27(s,2H).
实施例19 55-氟-12-(4-(哌嗪)-嘧啶-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶5(1,2)-苯环环壬基
合成操作具体步骤参照实施例3，得到白色固体。
LC-MS(M+H+)：539.2430
1H NMR(400MHz,DMSO)δ12.15(s,1H),9.14(s,1H),8.40(t,J＝4.6Hz,2H),7.45(s,1H),7.22(dd,J＝15.8,8.5Hz,2H),7.08(d,J＝6.8Hz,1H),6.98(s,1H),6.89(t,J＝4.9Hz,1H),6.67(t,J＝4.9Hz,1H),5.46(d,J＝4.4Hz,1H),3.83(s,8H),3.57(s,4H),3.43(s,2H).0608
实施例20 55-氟-12-(4-(甲基磺酰基)哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶5(1,2)-苯环环壬基
合成操作具体步骤参照实施例3，得到白色固体。
LC-MS(M+H+)539.1986
1H NMR(400MHz,DMSO)δ12.11(s,1H),9.03(s,1H),7.26(t,J＝12.5Hz,3H),7.07(d,J＝9.2Hz,1H),6.98(s,1H),6.89(s,1H),6.18(s,1H),5.32(s,1H),4.13(s,1H),3.84(d,J＝10.0Hz,5H),3.18(d,J＝4.9Hz,2H),2.97(s,5H).
实施例21 55-氟-12-(4-(四氢喹啉)哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶5(1,2)-苯环环壬基
合成操作具体步骤参照实施例3，得到白色固体。
LC-MS(M+H+)508.2261
1H NMR(400MHz,DMSO)δ12.15(d,J＝15.4Hz,1H),7.45(d,J＝23.3Hz,1H),7.29(s,1H),7.24(s,5H),7.10(d,J＝7.5Hz,1H),7.01(s,1H),6.91(s,1H),4.69(s,2H),3.89(s,2H),3.79(s,2H),3.25(t,J＝10.5Hz,2H),2.93(s,2H),1.27(s,2H).
实施例22 55-氟-12-(3-甲基-3,9λ2-二氮杂螺[5.5]十一烷-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶5(1,2)-苯环环壬基
合成操作具体步骤参照实施例3，得到白色固体。
LC-MS(M+H+)543.2986
1H NMR(400MHz,CDCl3)δ7.94(s,1H),7.18(s,2H),7.01(s,1H),6.82(s,1H),6.63(s,1H),5.92(d,J＝20.5Hz,-1H),3.87(s,2H),3.62(s,1H),3.47(s,2H),3.29(s,2H),2.46(s,3H),2.34(s,4H),1.65–1.59(m,4H),1.45(s,4H),1.27–1.22(m,4H),0.84(s,2H).
实施例23 55-氟-12-(4-(苯基)哌啶-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶5(1,2)-苯环环壬基
合成操作具体步骤参照实施例3，得到白色固体。
LC-MS(M+H+):536.2567
1H NMR(400MHz,DMSO)δ12.10(d,J＝15.7Hz,1H),8.64(d,J＝10.5Hz,1H),7.43(d,J＝24.7Hz,1H),7.32(d,J＝7.3Hz,2H),7.25(s,1H),7.22–7.19(m,2H),7.09(s,1H),6.98(s,1H),6.89(dd,J＝8.9,4.7Hz,1H),5.28(s,1H),3.82(s,3H),3.41(s,2H),2.81(s,4H),1.23(s,4H).
实施例24 55-氟-12-(4-(环己基)哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶5(1,2)-苯环环壬基
合成操作具体步骤参照实施例3，得到白色固体。
LC-MS(M+H+):543.2990
1H NMR(400MHz,DMSO)δ11.90(s,1H),8.84(s,1H),7.20(s,1H),7.07–6.93(m,2H),6.82(s,1H),6.72(s,1H),6.63(s,1H),5.15(s,1H),3.60(s,4H),2.92(s,1H),2.44(s,2H),2.28(s,4H),2.17(s,2H),1.48(s,6H),0.95(s,6H).
实施例25 55-氟-12-(4-(环丙乙酰基)哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶5(1,2)-苯环环壬基
合成操作具体步骤参照实施例3，得到白色固体
LC-MS(M+H+):529.2475
1H NMR(400MHz,DMSO)δ11.87(s,1H),8.83(s,1H),7.12(s,1H),6.92(s,2H),6.75(s,1H),6.65(s,1H),6.57(s,1H),6.00(s,1H),5.11(s,1H),3.53(s,6H),3.22(s,4H),2.66(s,1H),0.46(s,4H).
实施例26 55-氟-12-(4-(环戊基)哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶5(1,2)-苯环环壬基
合成操作具体步骤参照实施例3，得到白色固体。
LC-MS(M+H+):529.2838
1H NMR(400MHz,DMSO)δ12.07(s,1H),9.03(s,1H),7.37(s,1H),7.16(d,J＝19.8Hz,2H),7.00(s,1H),6.90(s,1H),6.81(s,1H),5.32(s,1H),3.76(s,4H),2.61(s,2H),2.38(s,4H),2.25(s,5H),1.61(d,J＝51.1Hz,4H),1.28(s,4H).
实施例27 12-(4-甲基哌嗪苯基-1-基)-55-氟-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环壬酮
氮气保护下，将20mg大环原料，30mg(4-(4-甲基哌嗪-1-基)苯基)硼酸，碳酸钾，4(三苯基膦)钯溶于5mL THF中，加入几滴水，随后回流反应6小时，降到室温后，直接加硅胶旋干，过柱得到白色产物。
LC-MS(M+H+):551.2363
1H NMR(400MHz,DMSO)δ12.23(d,J＝20.2Hz,1H),9.57(s,1H),7.23(s,9H),6.46(s,-1H),4.19(s,2H),3.92(s,2H),3.80(s,2H),3.60(s,-2H),2.87(s,6H).
实施例28：大环化合物55-氟-16-(4-吗啉-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,2)-嘧啶-5(1，2)-苯环壬酮
合成操作具体步骤参照实施例3，得到白色固体，
LC-MS(M+H+):462.3，1H NMR(400MHz,DMSO-d6)δ12.72(s,1H),9.73–9.46(m,1H),8.76(s,1H),7.42(d,J＝8.7Hz,1H),7.30–7.22(m,3H),7.06–6.98(m,3H),5.29(s,1H),4.14(s,2H),3.98(s,2H),3.78–3.74(m,2H),3.69(d,J＝4.5Hz,2H),3.64(d,J＝4.3Hz,2H),3.32(m,2H),3.11(m,2H)。
实施例29：55-氟-16-(4-甲基哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,2)-嘧啶-5(1，2)-苯环壬酮
合成操作具体步骤参照实施例3，白色固体；
LC-MS(M+H+):475.3
1H NMR(400MHz,DMSO-d6)δ12.54(s,1H),9.81(s,1H),9.04(s,1H),7.38(d,J＝8.6Hz,1H),7.24(t,J＝9.0Hz,2H),7.07–6.98(m,3H),5.26(s,1H),4.62(d,J＝13.1Hz,2H),4.10(s,2H),3.96(s,2H),3.49(d,J＝11.5Hz,2H),3.09(d,J＝42.3Hz,4H),2.84(s,3H)。
实施例30 55-氟-16-(4-甲酰基哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,2)-嘧啶-5(1，2)-苯环壬酮
合成操作具体步骤参照实施例3，白色固体，
LC-MS(M+H+):503.2
1H NMR(400MHz,DMSO-d6)δ12.69(s,1H),9.77–9.59(m,1H),8.78(s,1H),7.41(d,J＝8.6Hz,1H),7.30–7.20(m,2H),7.06–6.98(m,4H),5.28(s,1H),4.14(s,2H),3.98(s,2H),3.72(s,2H),3.35-3.57(m,6H),3.09(d,J＝30.6Hz,2H),2.06(m,3H)。
实施例31 55-氟-16-(4-甲氧基哌啶-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,2)-嘧啶-5(1，2)-苯环壬酮
合成操作具体步骤参照实施例3，白色固体，
LC-MS(M+H+):490.2，
1H NMR(400MHz,DMSO-d6)δ12.76(s,1H),9.87(s,1H),8.42(s,1H),7.43 (d,J＝8.7Hz,1H),7.26(dd,J＝13.7,8.9Hz,2H),7.07–6.97(m,3H),5.27(s,1H),4.15(s,2H),3.99(m,5H),3.30(s,5H),3.05(d,J＝57.1Hz,2H),1.91(d,J＝3.7Hz,2H),1.69–1.58(m,1H),1.52(d,J＝6.8Hz,2H)。
实施例32-42的合成步骤：
第一步：合成(3-(5-氟-2-甲基苯氧基)丙基)氨基甲酸叔丁酯
参见(2-(4-氟-2-甲基苯氧基)乙基)氨基甲酸叔丁酯的合成，得到(3-(5-氟-2-甲基苯氧基)丙基)氨基甲酸叔丁酯为无色油状物。
1H NMR(400MHz,,CDCl3)δ6.81–6.69(m,2H),6.64(s,1H),4.11–3.97(m,1H),3.90(d,J＝5.4Hz,2H),3.26(s,2H),2.14(s,3H),1.95–1.87(m,2H),1.36(s,9H).
第二步：合成(3-(2-(溴甲基)-5-氟苯氧基)丙基)氨基甲酸叔丁酯
参见(2-(2-(溴甲基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯的合成，得到(3-(2-(溴甲基)-5-氟苯氧基)丙基)氨基甲酸叔丁酯为黄色油状。
1H NMR(400MHz,,CDCl3)δ7.01(dd,J＝8.4,3.0Hz,1H),6.98–6.89(m,1H),6.78(d,J＝4.0Hz,1H),4.96(s,1H),4.47(d,J＝13.6Hz,2H),4.11–3.95(m,2H),3.35(s,2H),2.01(s,2H),1.40(s,9H).
第三步：合成(3-(2-(3-氰基-4-氟苄基)-5-氟苯氧基)丙基)氨基甲酸叔丁酯
参见(2-(2-(3-氰基-4-氟苄基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯的合成，得到((3-(2-(3-氰基-4-氟苄基)-5-氟苯氧基)丙基)氨基甲酸叔丁酯为白色固体。
1H NMR(400MHz,,CDCl3)δ7.72–7.29(m,3H),6.71(d,J＝34.0Hz,3H),4.96(s,1H),4.55(s,2H),4.07(s,2H),1.42(s,9H).
第四步：合成(3-(2-(((3-氨基-1H-吲唑-5-基)甲基)-5-氟苯氧基)丙基)氨基甲酸叔丁酯
参见(2-(2-((3-氨基-1H-吲唑-5-基)甲基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯的合成，得到(3-(2-(((3-氨基-1H-吲唑-5-基)甲基)-5-氟苯氧基)丙基)氨基甲酸叔丁酯为白色固体；LCMS:415.3[M+1]+。
第五步：合成(2-(2-((3-((2,6-二氯嘧啶-4-基)氨基)-1H-吲唑-5-基)甲基)-4-氟苯氧基)丙基)氨基甲酸叔丁酯
参见(2-(2-((3-((2,6-二氯嘧啶-4-基)氨基)-1H-吲唑-5-基)甲基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯的合成，得到(2-(2-((3-((2,6-二氯嘧啶-4-基)氨基)-1H-吲唑-5-基)甲基)-4-氟苯氧基)丙基)氨基甲酸叔丁酯(600mg，产率:87％)。
13C NMR(151MHz,DMSO)δ206.30,162.04,161.35,158.26,158.01,131.72,117.87,116.26,114.10,112.88,112.58,109.85,108.74,102.98,77.29,65.83,59.58,54.72,36.78,35.00,30.50,28.60,20.49,13.91.
1H NMR(400MHz,DMSO)δ12.69(s,1H),11.18(s,1H),7.95(d,J＝2.0Hz,1H),7.40(d,J＝8.6Hz,1H),7.32(d,J＝8.6Hz,1H),6.98(s,2H),6.85(s,3H),5.76(d,J＝2.0Hz,2H),3.97(s,2H),3.06(d,J＝6.8Hz,2H),1.82(d,J＝6.4Hz,2H),1.35(s,9H).
第六步：合成5-5-(2-(3-氨基丙氧基)-4-氟苄基)-N-(2,6-二氯嘧啶-4-基)-1H- 吲唑-3-胺的三氟乙酸盐
参见5-(2-(2-氨基乙氧基)-5-氟苄基)-N-(2,6-二氯嘧啶-4-基)-1H-吲唑-3-胺的三氟乙酸盐的合成，得到粗产品5-(2-(3-氨基丙氧基)-4-氟苄基)-N-(2,6-二氯嘧啶-4-基)-1H-吲唑-3-胺的三氟乙酸盐(592mg，产率:100％)。直接用于下一步反应。
实施例32：12-氯-55-氟-31H-6-氧杂-2,10-二氮杂3(3,5)-吲唑-1(4,6)-嘧啶-5(1,2)-苯并环十烷：
合成步骤见实施例3，得到白色固体。
LC-MS(M+H+):425.1287
1H NMR(400MHz,DMSO)δ8.95(d,J＝18.7Hz,1H),7.83(s,1H),7.73(s,1H),7.34(s,1H),7.29–7.24(m,1H),6.99(s,2H),6.61(s,1H),6.38(s,2H),4.01(s,4H),3.03(s,2H),2.27(d,J＝41.9Hz,2H).
LC-MS(M+H+)425.1290
实施例33 55-氟-12-(4-甲基哌嗪-1-基)-31H-6-氧杂-2,10-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环十二烷
合成步骤见实施例3，得到白色固体。
1H NMR(400MHz,dmso)δ12.20(s,1H),8.71(s,1H),7.21(s,3H),6.91(d,J＝81.5Hz,3H),6.19(s,1H),5.73(d,J＝23.6Hz,1H),5.34(d,J＝22.5Hz,1H),3.78(dd,J＝61.8,22.3Hz,4H),2.82(s,2H),2.44(s,4H),2.32(d,J＝19.6Hz,4H),2.18(d,J＝22.3Hz,3H),1.24(s,4H).
LC-MS(M+H+)489.2524
实施例34 55-氟-12-(4-乙基哌嗪-1-基)-31H-6-氧杂-2,10-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环十二烷
合成步骤见实施例3，得到白色固体。
1H NMR(400MHz,CDCl3)δ9.83(s,1H),7.95(s,1H),7.06(s,3H),6.81(s,1H),6.60(s,1H),5.18(s,1H),4.89(s,1H),3.86(s,4H),3.43(d,J＝22.4Hz,6H),2.87(dd,J＝29.6,18.8Hz,2H),2.43(s,4H),1.97(s,2H),1.13(d,J＝61.0Hz,3H).
LC-MS(M+H+)503.2676
实施例35 55-氟-12-(4-吗啉-1-基)-31H-6-氧杂-2,10-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环十二烷
合成步骤见实施例3，得白色固体。
1H NMR(400MHz,DMSO)δ12.20(s,1H),8.94(s,1H),7.53(s,1H),7.25(d,J＝33.1Hz,2H),7.01(d,J＝40.8Hz,2H),6.83(s,1H),6.12(s,1H),5.35(s,1H),3.73(d,J＝96.0Hz,10H),3.19(s,2H),1.78(s,2H).
LC-MS(M+H+)476.2185
实施例36 55-氟-12-(4-乙酰基哌嗪-1-基)-31H-6-氧杂-2,10-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环十二烷
合成步骤见实施例3，得白色固体。
1H NMR(400MHz,DMSO)δ12.24(s,1H),8.98(s,1H),7.57(s,1H),7.28(d,J＝31.1Hz,2H),7.04(d,J＝42.5Hz,2H),6.85(s,1H),6.19(s,1H),5.41(d,J＝4.7Hz,1H),3.88(d,J＝11.9Hz,4H),3.52–3.43(m,6H),3.23(s,2H),2.08–2.00(m,3H),1.82(s,2H).
LC-MS(M+H+)517.2470
实施例37 55-氟-12-(4-甲氧基哌啶-1-基)-31H-6-氧杂-2,10-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环十二烷
合成步骤参见实施例3，得到白色固体。
1H NMR(400MHz,DMSO)δ12.22(s,1H),8.89(s,1H),7.59(s,1H),7.33(d,J＝9.0Hz,1H),7.24(d,J＝8.3Hz,1H),7.13(dd,J＝32.7,8.1Hz,2H),6.99(d,J＝8.7Hz,1H),6.87(d,J＝5.8Hz,1H),6.13(s,1H),5.43(s,1H),3.93–3.81(m,6H),3.28(s,3H),3.24(s,2H),3.09(t,J＝11.5Hz,2H),2.30(s,1H),1.86(d,J＝18.0Hz,4H),1.36(d,J＝10.6Hz,2H).
LC-MS(M+H+)504.2515
实施例38 55-氟-12-(4-环丙基哌嗪-1-基)-31H-6-氧杂-2,10-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环十二烷
合成步骤见实施例3，得到白色固体。
1H NMR(400MHz,DMSO)δ12.22(s,1H),8.92(s,1H),7.58(s,1H),7.43–7.20(m,2H),7.09(d,J＝8.5Hz,1H),7.00(d,J＝9.8Hz,1H),6.87(s,1H),6.14(s,1H),5.40(s,1H),3.89(s,4H),3.38(s,4H),3.23(s,2H),2.57(s,4H),1.82(s,2H),1.64(s,1H),0.40(d,J＝34.2Hz,4H).
LC-MS(M+H+)515.2679
实施例39 55-氟-12-(4-甲基高哌嗪-1-基)-31H-6-氧杂-2,10-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环十二烷
合成步骤见实施例3，得到白色固体。
1H NMR(400MHz,DMSO)δ12.18(s,1H),8.83(s,1H),7.60(s,1H),7.32(s,1H),7.23(d,J＝7.9Hz,2H),7.19–7.03(m,2H),6.92(d,J＝53.0Hz,2H),6.03(s,1H),5.28(s,1H),3.88(s,4H),3.64(s,2H),3.49(s,2H),3.22(s,2H),2.54(s,2H),2.29(s,2H),2.25(s,3H),1.83(s,4H),1.22(s,2H).
LC-MS(M+H+)503.2679
实施例40 55-氟-12-(4-1,4-二氧杂-8-氮杂[4.5]癸烷-1-基)-31H-6-氧杂-2,10-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环十二烷
合成步骤参考实施例3，得到白色固体。
1H NMR(400MHz,DMSO)δ12.16(s,1H),8.85(s,1H),7.53(s,1H),7.23(dd,J＝34.7,9.8Hz,2H),6.98–6.92(m,1H),6.81(s,1H),6.11(s,1H),5.70(s,1H),5.39(s,1H),3.85(d,J＝10.9Hz,6H),3.50(s,3H),3.19–3.07(m,4H),1.93(s,2H),1.78(s,2H),1.57(s,2H),1.24–1.08(m,2H).
LC-MS(M+H+)532.2471
实施例41 55-氟-12-(4-哌啶哌啶-1-基)-31H-6-氧杂-2,10-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环十二烷
合成步骤见实施例3，得到白色固体。
1H NMR(400MHz,DMSO)δ12.00(s,1H),8.65(s,1H),7.36(s,1H),7.11(s,1H),7.02(d,J＝8.5Hz,1H),6.88(s,1H),6.77(s,1H),6.65(d,J＝6.5Hz,1H),5.54(s,2H),5.19(s,1H),4.01(d,J＝12.8Hz,2H),3.67(s,4H),2.97(d,J＝26.5Hz,4H),2.70(d,J＝11.7Hz,2H),2.47(t,J＝12.5Hz,3H),1.56(d,J＝26.9Hz,2H),1.28–1.21(m,6H),1.14(s,4H).
LC-MS(M+H+)557.3152
实施例42 55-氟-12-(4-甲基哌啶-1-基)-31H-6-氧杂-2,10-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环十二烷
合成步骤见实施例3，得到白色固体。
1H NMR(400MHz,DMSO)δ12.21(s,1H),8.87(s,1H),7.59(s,1H),7.38–7.18(m,2H),7.04(dd,J＝42.0,9.0Hz,2H),6.88(s,1H),6.10(s,1H),5.41(s,1H),4.16(s,2H),3.87(d,J＝14.9Hz,4H),3.22(s,2H),2.71(d,J＝12.7Hz,2H),1.86–1.74(m,2H),1.61(s,3H),1.04(d,J＝13.5Hz,2H),0.92(d,J＝6.1Hz,3H).
LC-MS(M+H+)488.2581
实施例43-53的合成步骤：
第一步：合成(2-(4-氟-2-甲基苯氧基)丁基)氨基甲酸叔丁酯
参见(2-(4-氟-2-甲基苯氧基)乙基)氨基甲酸叔丁酯的合成，得到(2-(4-氟-2-甲基苯氧基)丁基)氨基甲酸叔丁酯(3.2g，产率:47％)为无色油状物。
1H NMR(400MHz,,CDCl3)δ6.86–6.72(m,2H),6.73–6.63(m,1H),4.74(s,1H),3.95–3.85(m,2H),3.17(s,2H),2.18(s,2H),1.80(t,J＝7.2Hz,2H),1.66(s,2H),1.43(s,9H).
第二步：合成(2-(2-(溴甲基)-4-氟苯氧基)丁基)氨基甲酸叔丁酯
参见(2-(2-(溴甲基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯的合成，得到(2-(2-(溴甲基)-4-氟苯氧基)丁基)氨基甲酸叔丁酯(3.0g，产率:63％)为黄色油状。
1H NMR(400MHz,,CDCl3)δ6.95(s,1H),6.78–6.58(m,2H),4.36(s,1H),4.01–3.76(m,2H),3.17(s,2H),2.07(s,2H),1.77(d,J＝7.6Hz,2H),1.62(s,2H),1.36(s,9H).
第三步：合成(2-(2-(3-氰基-4-氟苄基)-4-氟苯氧基)丁基)氨基甲酸叔丁酯
参见(2-(2-(3-氰基-4-氟苄基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯的合成，得到(2-(2-(3-氰基-4-氟苄基)-4-氟苯氧基)丁基)氨基甲酸叔丁酯(1.6g，产率:50％)为白色固体。
1H NMR(400MHz,,CDCl3)δ7.45(t,J＝7.0Hz,1H),7.02(d,J＝7.7Hz,1H),6.94(d,J＝9.9Hz,1H),6.85(d,J＝8.5Hz,1H),6.75(d,J＝8.3Hz,1H),6.70(dd,J＝8.4,4.1Hz,1H),3.90(s,2H),3.84(s,2H),3.07(s,2H),1.70–1.62(m,2H),1.52–1.44(m,2H),1.37(s,9H).
第四步：合成(2-(2-((3-氨基-1H-吲唑-5-基)甲基)-4-氟苯氧基)丁基)氨基甲酸叔丁酯
参见(2-(2-((3-氨基-1H-吲唑-5-基)甲基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯的合成，得到(2-(2-((3-氨基-1H-吲唑-5-基)甲基)-4-氟苯氧基)丁基)氨基甲酸叔丁酯为白色固体；LCMS:438.3[M+1]+。
第五步：合成(2-(2-((3-((2,6-二氯嘧啶-4-基)氨基)-1H-吲唑-5-基)甲基)-4-氟苯氧基)丁基)氨基甲酸叔丁酯
参见(2-(2-((3-((2,6-二氯嘧啶-4-基)氨基)-1H-吲唑-5-基)甲基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯的合成，得到(2-(2-((3-((2,6-二氯嘧啶-4-基)氨基)-1H-吲唑-5-基)甲基)-4-氟苯氧基)丁基)氨基甲酸叔丁酯(600mg，产率:87％)。
1H NMR(400MHz,DMSO)δ12.67(s,1H),7.77(s,1H),7.37(d,J＝8.3Hz,1H),7.27(s,1H),6.94(d,J＝10.1Hz,3H),6.80(s,1H),3.91(d,J＝17.3Hz,4H),2.88(d,J＝9.5Hz,2H),1.63(s,2H),1.45(s,2H),1.33(s,9H).
第六步：合成5-(2-(2-氨基丁氧基)-5-氟苄基)-N-(2,6-二氯嘧啶-4-基)-1H-吲唑-3-胺的三氟乙酸盐
参见5-(2-(2-氨基乙氧基)-5-氟苄基)-N-(2,6-二氯嘧啶-4-基)-1H-吲唑-3-胺的三氟乙酸盐合成方法，得到粗产品5-(2-(2-氨基丁氧基)-5-氟苄基)-N-(2,6- 二氯嘧啶-4-基)-1H-吲唑-3-胺的三氟乙酸盐(592mg，产率:100％)。直接用于下一步反应。
实施例43：12-氯-55-氟-31H-6-氧杂-2,11-二氮杂3(3,5)-吲唑-1(4,6)-嘧啶-5(1,2)-苯并环戊烷
合成步骤详见实施例1，得到白色固体。熔点：
1H NMR(400MHz,DMSO)δ12.16(s,1H),8.67(s,1H),7.21(s,3H),6.98(s,1H),6.78(d,J＝34.3Hz,2H),6.17(s,1H),5.32(s,1H),3.84(s,2H),3.69(s,2H),3.37(s,4H),2.80(s,2H),2.31(s,4H),2.17(s,3H),1.23(d,J＝37.2Hz,4H).
LC-MS(M+H+)439.1444
实施例44：55-氟-12-(4-甲基哌嗪-1-基)-31H-6-氧杂-2,11-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯甲环磷酰胺
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：503.2683
1H NMR(400MHz,DMSO)δ12.16(s,1H),8.67(s,1H),7.21(s,3H),6.98(s,1H),6.78(d,J＝34.3Hz,2H),6.17(s,1H),5.32(s,1H),3.84(s,2H),3.69(s,2H),3.37(s,4H),2.80(s,2H),2.31(s,4H),2.17(s,3H),1.23(d,J＝37.2Hz,4H).
实施例45：55-氟-12-(4-乙基哌嗪-1-基)-31H-6-氧杂-2,11-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯甲环磷酰胺
合成步骤详见实施例3，得到白色固体。熔点：
LC-MS(M+H+)：517.2839
1H NMR(400MHz,DMSO)δ11.96(s,1H),8.47(s,1H),7.01(s,3H),6.78(s,1H),6.63(s,1H),6.54(s,1H),5.98(s,1H),5.13(s,1H),3.65(s,4H),3.49(s,4H),2.93(s,2H),2.61(s,2H),2.17(s,4H),0.78(s,3H).
实施例46：55-氟-12-(4-乙酰基哌嗪-1-基)-31H-6-氧杂-2,11-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯甲环磷酰胺
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：531.2638
1H NMR(400MHz,DMSO)δ12.20(s,1H),8.74(s,1H),7.21(s,3H),7.01(s,1H),6.84(d,J＝9.0Hz,1H),6.74(s,1H),6.27(s,1H),5.37(s,1H),3.87(s,2H),3.69(s,2H),3.49(s,4H),3.41(s,3H),2.87(s,2H),2.03(d,J＝3.9Hz,4H),1.22(s,4H).
实施例47：55-氟-12-(4-异丙基哌嗪-1-基)-31H-6-氧杂-2,11-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯甲环磷酰胺
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：531.2997
1H NMR(400MHz,DMSO)δ12.32(s,1H),8.83(s,1H),7.43–7.29(m,3H),7.15(s,1H),6.99(s,1H),6.90(s,1H),6.34(s,1H),5.49(s,1H),4.01(s,2H),3.86(s,2H),3.63(s,2H),3.12(s,2H),2.97(s,2H),2.80(s,4H),2.46(s,1H),1.47(s,4H),1.11(d,J＝7.0Hz,6H).
实施例48：55-氟-12-(4-环丙基哌嗪-1-基)-31H-6-氧杂-2,11-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯甲环磷酰胺
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：529.2851
1H NMR(400MHz,DMSO)δ12.20(s,1H),8.71(s,1H),7.58(d,J＝24.9Hz,3H),7.39(s,1H),7.23(s,2H),6.22(s,1H),3.95–3.66(m,4H),2.87(d,J＝24.3Hz,4H),2.58(s,2H),1.81(s,1H),1.59(d,J＝46.1Hz,2H),1.39(d,J＝4.8Hz,4H),1.23(s,2H),0.40(d,J＝33.7Hz,4H).
实施例49：55-氟-12-(4-吗啉-1-基)-31H-6-氧杂-2,11-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯甲环磷酰胺
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：490.2373
1H NMR(400MHz,DMSO)δ12.23(s,1H),8.62(s,1H),7.64–7.58(m,3H),7.42(s,1H),7.25(s,1H),6.91(d,J＝36.6Hz,1H),4.00–3.64(m,6H),2.78(d,J＝71.0Hz,2H),1.93–1.47(m,2H),1.41(q,J＝5.7Hz,4H).
实施例50：55-氟-12-(4-甲氧基哌啶-1-基)-31H-6-氧杂-2,11-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯甲环磷酰胺
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：518.2677
1H NMR(400MHz,DMSO)δ12.20(s,1H),8.67(d,J＝6.4Hz,1H),7.31–7.19(m,3H),7.06–6.98(m,1H),6.90–6.74(m,2H),6.20(s,1H),5.39(d,J＝6.1Hz,1H),3.90(s,3H),3.74(s,2H),3.20(d,J＝18.7Hz,2H),3.10(d,J＝9.6Hz,2H),2.85(s,2H),2.55(s,1H),1.87(s,2H),1.38(d,J＝11.9Hz,4H),1.24(s,4H).
实施例51：55-氟-12-(4-1,4-二氧杂-8l2-氮杂螺[4.5]癸烷-1-基)-31H-6-氧杂-2,11-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯甲环磷酰胺
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：546.2622
1H NMR(400MHz,DMSO)δ12.21(s,1H),8.70(s,1H),7.24(dd,J＝20.7,9.6Hz,3H),7.03(s,1H),6.87(s,2H),6.23(s,1H),5.42(s,1H),3.93(d,J＝3.1Hz,4H),3.90(s,2H),3.74(s,2H),3.55(d,J＝6.4Hz,4H),2.86(s,2H),1.62(s,4H),1.33(s,2H),1.24(s,2H).
实施例52：55-氟-12-(4-甲基高哌嗪-1-基)-31H-6-氧杂-2,11-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯甲环磷酰胺
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：517.2829
1H NMR(400MHz,DMSO)δ12.17(d,J＝3.7Hz,1H),8.64(s,1H),7.29(s,1H),7.21(d,J＝15.7Hz,2H),7.02(s,1H),6.87(s,1H),5.26(s,1H),3.89(s,2H),3.69(d,J＝33.8Hz,3H),3.07(s,2H),2.84(s,2H),2.56(s,2H),2.27(s,4H),1.86(s,2H),1.23(d,J＝4.3Hz,6H).
实施例53：55-氟-12-(4-哌啶哌啶-1-基)-31H-6-氧杂-2,11-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯甲环磷酰胺
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：571.3305
1H NMR(400MHz,DMSO)δ12.19(s,1H),8.66(s,1H),7.24(dd,J＝19.5,9.7Hz,3H),7.03(s,1H),6.87(s,1H),6.79(s,1H),6.19(s,1H),5.38(s,1H),4.25(s,2H),3.89(s,2H),3.74(s,2H),3.18(d,J＝8.6Hz,2H),2.99–2.81(m,4H),2.70(s,2H),2.46–2.42(m,5H),1.76(s,2H),1.61(d,J＝11.9Hz,2H),1.47(s,4H),1.37(s,4H).
实施例54-64的合成步骤：
第一步：合成(2-(4-氯-2-甲基苯氧基)乙基)氨基甲酸叔丁酯
参见(2-(4-氟-2-甲基苯氧基)乙基)氨基甲酸叔丁酯的合成，得到(2-(4-氯-2-甲基苯氧基)乙基)氨基甲酸叔丁酯(3.2g，产率:47％)为无色油状物。
1H NMR(400MHz,,CDCl3)δ7.13–6.94(m,2H),6.63(d,J＝8.8Hz,1H),4.86(s,1H),3.91(d,J＝6.8Hz,2H),3.48(s,2H),2.13(s,3H),1.39(s,9H).
第二步：(2-(2-(溴甲基)-4-氯苯氧基)乙基)氨基甲酸叔丁酯
参见(2-(2-(溴甲基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯的合成，得到(2-(2-(溴甲基)-4-氯苯氧基)乙基)氨基甲酸叔丁酯(3.0g，产率:63％)为黄色油状。
1H NMR(400MHz,,CDCl3)δ7.09(s,2H),6.69(d,J＝8.3Hz,1H),4.99(s,1H),3.96(d,J＝5.1Hz,2H),3.54(d,J＝6.8Hz,2H),2.18(s,3H),1.45(s,9H).
第三步：合成(2-(2-(3-氰基-4-氯苄基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯
参见(2-(2-(3-氰基-4-氟苄基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯的合成，得到(2-(2-(3-氰基-4-氯苄基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯(1.6g，产率:50％)为白色固体。
1H NMR(400MHz,,CDCl3)δ7.42(s,2H),7.12(d,J＝6.9Hz,1H),6.91(s,1H),6.79(d,J＝7.3Hz,2H),3.94(d,J＝12.6Hz,4H),3.24(s,2H),2.13–2.01(m,1H),1.92(s,2H),1.43(dd,J＝3.3,1.7Hz,9H).
第四步：合成(2-(2-((3-氨基-1H-吲唑-5-基)甲基)-4-氯苯氧基)乙基)氨基甲酸叔丁酯
参见(2-(2-((3-氨基-1H-吲唑-5-基)甲基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯的合成，得到(2-(2-((3-氨基-1H-吲唑-5-基)甲基)-4-氯苯氧基)乙基)氨基甲酸叔丁酯为白色固体；LCMS:418.3[M+1]+。
第五步：合成(2-(2-((3-((2,6-二氯嘧啶-4-基)氨基)-1H-吲唑-5-基)甲基)-4-氯苯氧基)乙基)氨基甲酸叔丁酯
参见(2-(2-((3-((2,6-二氯嘧啶-4-基)氨基)-1H-吲唑-5-基)甲基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯的合成，得到(2-(2-((3-((2,6-二氯嘧啶-4-基)氨基)-1H-吲唑-5-基)甲基)-4-氯苯氧基)乙基)氨基甲酸叔丁酯(600mg，产率:87％)。
1H NMR(400MHz,DMSO)δ12.69(s,1H),7.82(s,1H),7.34(s,2H),7.16(d,J＝12.0Hz,2H),6.95(d,J＝9.0Hz,1H),3.94(d,J＝14.2Hz,4H),2.44(s,2H),1.35(d,J＝3.8Hz,9H).
第六步：合成5-(2-(2-氨基乙氧基)-5-氯苄基)-N-(2,6-二氯嘧啶-4-基)-1H-吲唑-3-胺的三氟乙酸盐
参见5-(2-(2-氨基乙氧基)-5-氟苄基)-N-(2,6-二氯嘧啶-4-基)-1H-吲唑-3-胺的三氟乙酸盐合成方法，得到粗产品5-(2-(2-氨基乙氧基)-5-氯苄基)-N-(2,6-二氯嘧啶-4-基)-1H-吲唑-3-胺的三氟乙酸盐(592mg，产率:100％)。直接用于下一步反应。
实施例54：12,55-二氯31H-6-氧杂-2,9-二氮杂3(3,5)-吲唑-1(4,6)-嘧啶-5(1,2)-苯并环壬基
合成步骤详见实施例1，得到白色固体。
LC-MS(M+H+)：426.0269
1H NMR(400MHz,DMSO)δ12.37(s,1H),9.86(s,1H),7.44(s,1H),7.31–7.16(m,4H),7.05(s,1H),6.92(s,1H),6.02(s,1H),3.84(d,J＝19.1Hz,4H),3.37(s,2H).
实施例55：55-氯-12-(4-甲基哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环壬酮
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：491.2072
1H NMR(400MHz,DMSO)δ12.11(s,1H),9.10(s,1H),7.43(d,J＝10.2Hz,2H),7.25–7.17(m,2H),7.06(s,1H),6.91(d,J＝8.7Hz,1H),6.25(s,1H),5.40(s,1H),3.85(d,J＝18.3Hz,4H),3.43(s,6H),2.36(s,4H),2.21(s,3H).
实施例56：55-氯-12-(4-乙酰基哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环壬酮
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：519.2023
1H NMR(400MHz,DMSO)δ12.22(s,1H),9.20(s,1H),7.53(d,J＝9.7Hz,2H),7.37–7.26(m,2H),7.14(d,J＝9.0Hz,1H),7.00(d,J＝9.1Hz,1H),6.35(s,1H),5.50(s,1H),3.94(d,J＝17.4Hz,4H),3.53(s,6H),2.55–2.48(m,4H),2.46(s,2H),1.14(d,J＝6.9Hz,3H).
实施例57：55-氯-12-(4-乙基哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环壬酮
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：505.2231
1H NMR(400MHz,DMSO)δ12.22(s,1H),9.20(s,1H),7.53(d,J＝9.7Hz,2H),7.37–7.26(m,2H),7.14(d,J＝9.0Hz,1H),7.00(d,J＝9.1Hz,1H),6.35(s,1H),5.50(s,1H),3.94(d,J＝17.4Hz,4H),3.53(s,6H),2.55–2.48(m,4H),2.46(s,2H),1.14(d,J＝6.9Hz,3H).
实施例58：55-氯-12-(4-甲基高哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环壬酮
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：505.2230
1H NMR(400MHz,DMSO)δ11.82(s,1H),8.75(s,1H),7.16(d,J＝7.5Hz,2H),6.96–6.88(m,2H),6.78(d,J＝8.7Hz,1H),6.64(d,J＝8.6Hz,1H),5.89(s,1H),5.02(d,J＝3.5Hz,1H),3.63–3.51(m,4H),3.39(s,2H),3.23(s,2H),3.14(s,2H),2.90(s,1H),2.29(s,2H),2.00(s,3H),1.60(s,2H),0.96(s,1H).
实施例59：55-氯-12-(4-异丙基哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环壬酮
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：519.2380
1H NMR(400MHz,DMSO)δ12.08(s,1H),9.05(s,1H),7.43–7.37(m,2H),7.17(d,J＝8.3Hz,2H),7.01(d,J＝8.6Hz,1H),6.87(d,J＝8.9Hz,1H),5.36(s,1H),3.81(d,J＝18.0Hz,4H),3.38(s,8H),2.63(s,1H),0.98–0.93(m,6H).
实施例60：55-氯-12-(4-环丙基哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环壬酮
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：517.2231
1H NMR(400MHz,DMSO)δ12.12(s,1H),9.09(d,J＝4.3Hz,1H),7.44(dd,J＝8.7,4.8Hz,2H),7.20(dt,J＝8.7,4.5Hz,2H),7.04(d,J＝8.5Hz,1H),6.91(dd,J＝8.9,4.6Hz,1H),5.40(d,J＝4.2Hz,1H),3.84(d,J＝17.8Hz,4H),3.40(s,8H),2.58(d,J＝5.9Hz,4H),1.23(d,J＝4.6Hz,1H),0.44(d,J＝6.4Hz,2H),0.36(s,2H).
实施例61：55-氯-12-(4-吗啉-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环壬酮
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：478.1756
1H NMR(400MHz,DMSO)δ12.10(s,1H),9.12(s,1H),7.40(d,J＝11.9Hz,2H),7.18(d,J＝8.5Hz,2H),7.02(d,J＝8.5Hz,1H),6.88(d,J＝8.6Hz,1H),5.37(s,1H),3.82(d,J＝19.4Hz,4H),3.63(d,J＝5.7Hz,4H),3.37(s,6H).
实施例62：55-氯-12-(4-甲基哌啶-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环壬酮
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：490.2119
1H NMR(400MHz,DMSO)δ12.10(s,1H),9.02(s,1H),7.43(s,2H),7.29–7.15(m,2H),7.05(d,J＝9.6Hz,1H),6.90(d,J＝9.6Hz,1H),6.20(s,1H), 5.40(s,1H),4.20(s,2H),3.84(d,J＝18.6Hz,4H),2.87–2.62(m,3H),1.78–1.47(m,4H),0.99(d,J＝52.0Hz,7H).
实施例63：55-氯-12-(4-甲氧基哌啶-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环壬酮
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：506.2071
1H NMR(400MHz,DMSO)δ12.12(s,1H),9.06(d,J＝5.8Hz,1H),7.44(s,2H),7.19(d,J＝6.9Hz,2H),7.06(d,J＝8.2Hz,1H),6.92(d,J＝8.2Hz,1H),5.43(d,J＝6.8Hz,1H),3.85(d,J＝17.1Hz,4H),3.42(s,3H),3.28(d,J＝3.8Hz,2H),3.17(d,J＝6.1Hz,4H),2.90(d,J＝12.3Hz,1H),1.47–1.14(m,4H).
实施例64：55-氯-12-(4-1,4-二氧杂-8l2-氮杂螺[4.5]癸烷-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环壬酮
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：534.2024
1H NMR(400MHz,DMSO)δ12.13(s,1H),9.04(s,1H),7.44(s,1H),7.21(s,1H),7.02(s,2H),6.92(s,2H),6.27(s,1H),5.75(s,1H),3.94(d,J＝7.0Hz,6H),3.84(d,J＝13.5Hz,4H),3.57(s,1H),2.15(s,4H),1.24(s,2H),1.17(s,2H).
实施例65-75的合成步骤：
第一步：合成(2-(5-氟-2-甲基苯氧基)乙基)氨基甲酸叔丁酯
参见(2-(4-氟-2-甲基苯氧基)乙基)氨基甲酸叔丁酯的合成，得到(2-(4-氯-2-甲基苯氧基)乙基)氨基甲酸叔丁酯(3.2g，产率:47％)为无色油状物。
1H NMR(400MHz,,CDCl3)δ7.03(q,J＝6.7,5.9Hz,1H),6.50(s,2H),4.93(s,1H),3.94(dq,J＝11.5,5.4Hz,2H),3.52(d,J＝16.1Hz,2H),2.15(d,J＝4.2Hz,3H),1.44(d,J＝4.2Hz,9H).
第二步：(2-(2-(溴甲基)-5-氟苯氧基)乙基)氨基甲酸叔丁酯
参见(2-(2-(溴甲基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯的合成，得到(2-(2-(溴甲基)-4-氯苯氧基)乙基)氨基甲酸叔丁酯(3.0g，产率:63％)为黄色油状。
1H NMR(400MHz,CDCl3)δ7.26(d,J＝3.2Hz,1H),7.19(d,J＝8.2Hz,1H),6.75(d,J＝8.7Hz,1H),5.24(s,1H),4.45(s,2H),4.04(s,2H),3.56(s,2H),1.42(s,9H).
第三步：合成(2-(2-(3-氰基-5-氟苄基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯
参见(2-(2-(3-氰基-4-氟苄基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯的合成，得到(2-(2-(3-氰基-4-氯苄基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯(1.6g，产率:50％)为白色固体。
1H NMR(400MHz,CDCl3)δ7.41(s,2H),7.08(dt,J＝20.1,8.1Hz,2H),6.54(s,2H),4.79(s,1H),3.93(s,4H),3.45(s,2H),1.42(s,9H).
第四步：合成(2-(2-((3-氨基-1H-吲唑-5-基)甲基)-5-氟苯氧基)乙基)氨基甲酸叔丁酯
参见(2-(2-((3-氨基-1H-吲唑-5-基)甲基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯的合成，得到(2-(2-((3-氨基-1H-吲唑-5-基)甲基)-4-氯苯氧基)乙基)氨基甲酸叔丁酯为白色固体；LCMS:401.3[M+1]+。
第五步：合成(2-(2-((3-((2,6-二氯嘧啶-4-基)氨基)-1H-吲唑-5-基)甲基)-5-氟苯氧基)乙基)氨基甲酸叔丁酯
参见(2-(2-((3-((2,6-二氯嘧啶-4-基)氨基)-1H-吲唑-5-基)甲基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯的合成，得到(2-(2-((3-((2,6-二氯嘧啶-4-基)氨基)-1H-吲唑-5-基)甲基)-4-氯苯氧基)乙基)氨基甲酸叔丁酯(600mg，产率:87％)。
1H NMR(400MHz,,CDCl3)δ12.46(s,1H),10.91(s,1H),7.57(s,1H),7.26–7.08(m,1H),6.94(s,1H),6.78(d,J＝21.9Hz,1H),6.64(s,1H),6.50(s,1H),3.73(s,2H),1.15(s,9H).
第六步：合成5-(2-(2-氨基乙氧基)-5-氟苄基)-N-(2,6-二氯嘧啶-4-基)-1H-吲唑-3-胺的三氟乙酸盐
参见5-(2-(2-氨基乙氧基)-5-氟苄基)-N-(2,6-二氯嘧啶-4-基)-1H-吲唑-3-胺的三氟乙酸盐合成方法，得到粗产品5-(2-(2-氨基乙氧基)-5-氯苄基)-N-(2,6-二氯嘧啶-4-基)-1H-吲唑-3-胺的三氟乙酸盐(592mg，产率:100％)。直接用于下一步反应。
实施例65：12,55-二氯31H-6-氧杂-2,9-二氮杂3(3,5)-吲唑-1(4,6)-嘧啶-5(1,2)-苯并环壬基
合成步骤详见实施例1，得到白色固体。
LC-MS(M+H+)：411.1129
1H NMR(400MHz,DMSO)δ12.48(s,1H),9.87(s,1H),7.27(s,4H),7.12(s,1H),6.84(s,1H),6.68(s,1H),6.15–6.01(m,1H),3.86(d,J＝30.5Hz,4H),3.39(s,2H).
实施例66：55-氟-12-(4-甲基哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环壬酮
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：475.2369
1H NMR(400MHz,DMSO)δ11.94(s,1H),8.92(s,1H),7.19(d,J＝14.7Hz,2H),7.02(d,J＝8.3Hz,1H),6.85(s,1H),6.63(d,J＝11.3Hz,1H),6.52(s,1H),6.03(s,1H),5.22(d,J＝5.2Hz,1H),3.65(s,2H),3.26(s,3H),2.33(s,4H),2.18(s,2H),2.04(s,2H),1.91(s,6H).
实施例67：55-氟-12-(4-乙基哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环壬酮
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：489.2521
1H NMR(400MHz,DMSO)δ11.87(s,1H),8.86(s,1H),7.11(s,2H),6.93(s,1H),6.78(d,J＝8.2Hz,1H),6.60(s,1H),6.46(s,1H),6.03(s,1H),5.15(s,1H),3.63(s,2H),3.56(s,2H),2.26(s,4H),2.15(d,J＝17.9Hz,4H),0.80(s,3H).
实施例68：55-氟-12-(4-异丙基哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环壬酮
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：503.2678
1H NMR(400MHz,DMSO)δ11.92(s,1H),9.01(s,1H),7.14(s,2H),7.00(d,J＝8.0Hz,1H),6.83(s,1H),6.62(s,1H),6.53(s,1H),6.06(s,1H),5.21(d,J＝7.2Hz,1H),3.69(s,2H),3.62(s,2H),3.30(s,4H),2.52(s,2H),2.31(s,4H),1.71(d,J＝6.2Hz,1H),0.80(d,J＝22.6Hz,6H).
实施例69：55-氟-12-(4-甲基高哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环壬酮
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：489.2520
1H NMR(400MHz,DMSO)δ11.82(s,1H),8.75(s,1H),7.11(d,J＝23.4Hz,2H),6.93(s,1H),6.76(s,1H),6.55(s,1H),6.41(s,1H),5.93(s,1H),5.02(s,1H),3.62(s,2H),3.54(s,2H),2.24(s,8H),2.00(d,J＝9.7Hz,4H),1.65–1.59(m,3H).
实施例70：55-氟-12-(4-乙酰基哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环壬酮
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：503.2309
1H NMR(400MHz,DMSO)δ11.90(s,1H),8.92(d,J＝5.9Hz,1H),7.15(d,J＝ 11.6Hz,2H),6.98(d,J＝7.4Hz,1H),6.80(d,J＝8.3Hz,1H),6.59(d,J＝8.4Hz,1H),6.46(s,1H),6.11(s,1H),5.19(t,J＝4.2Hz,1H),3.66(s,2H),3.58(s,2H),3.30(s,4H),3.22(s,2H),2.28(d,J＝5.7Hz,7H).
实施例71：55-氟-12-(4-乙酰基高哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环壬酮
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：517.2472
1H NMR(400MHz,DMSO)δ11.87(s,1H),8.79(s,1H),7.15(d,J＝15.5Hz,2H),6.97(d,J＝8.1Hz,1H),6.80(s,1H),6.60(s,1H),6.45(s,1H),6.16–5.96(m,1H),5.54(d,J＝7.3Hz,2H),3.72–3.48(m,4H),3.36(s,6H),2.55(s,3H),1.83–1.72(m,4H),1.01(s,2H).
实施例72：55-氟-12-(4-环丙基哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环壬酮
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：501.2521
1H NMR(400MHz,DMSO)δ11.61(s,1H),8.61(d,J＝19.6Hz,1H),6.89(s,2H),6.71(s,1H),6.53(s,1H),6.33(s,1H),6.20(s,1H),5.81(s,1H),4.91(d,J＝19.7Hz,1H),3.33(d,J＝28.9Hz,6H),2.76(s,4H),1.90(s,2H),1.68–1.55(m,2H),1.17(s,1H),0.78(s,4H).
实施例73：55-氟-12-(4-吗啉-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环壬酮
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：462.2045
1H NMR(400MHz,dmso)δ11.70(s,1H),8.73(s,1H),6.95(s,2H),6.77(t, J＝6.1Hz,1H),6.59(s,1H),6.44–6.35(m,1H),6.26(s,1H),4.96(d,J＝4.3Hz,1H),3.42(d,J＝32.6Hz,4H),3.23(s,4H),2.97(s,8H).
实施例74：55-氟-12-(4-哌啶哌啶-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环壬酮
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：543.2986
1H NMR(400MHz,DMSO)δ11.84(s,1H),8.79(s,1H),7.11(d,J＝16.0Hz,2H),6.94(d,J＝8.4Hz,1H),6.76(s,1H),6.56(s,2H),6.42(s,1H),6.00(s,1H),5.15(s,1H),4.00(s,1H),3.59(d,J＝32.8Hz,4H),2.46(s,2H),1.81(d,J＝4.5Hz,4H),1.18(d,J＝44.9Hz,10H).
实施例75：55-氟-12-(4-甲氧基哌啶-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环壬酮
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：490.2361
1H NMR(400MHz,DMSO)δ11.85(s,1H),8.80(s,1H),7.14(s,2H),6.94(d,J＝8.2Hz,1H),6.77(s,1H),6.55(d,J＝11.1Hz,2H),6.03(s,1H),5.17(s,1H),3.59(d,J＝34.7Hz,7H),3.02(s,3H),2.96(s,2H),2.34(s,2H),1.64(s,2H),1.14(s,2H).
实施例76-86的合成步骤：
第一步：合成(2-(3-氟-5-甲基苯氧基)乙基)氨基甲酸叔丁酯
参见(2-(5-氟-2-甲基苯氧基)乙基)氨基甲酸叔丁酯的合成，得到(2-(4-氯-2-甲基苯氧基)乙基)氨基甲酸叔丁酯(3.2g，产率:47％)为无色油状物。
1H NMR(400MHz,,CDCl3)δ6.30(s,2H),6.26–6.17(m,1H),4.90(s,1H),3.78(t,J＝5.0Hz,2H),3.32(s,2H),2.11(s,3H),1.27(s,9H).
第二步：合成(2-(3-(溴甲基)-5-氟苯氧基)乙基)氨基甲酸叔丁酯
参见(2-(2-(溴甲基)-5-氟苯氧基)乙基)氨基甲酸叔丁酯的合成，得到(2-(2-(溴甲基)-4-氯苯氧基)乙基)氨基甲酸叔丁酯(3.0g，产率:63％)为黄色油状。
11H NMR(400MHz,CDCl3)δ7.12(s,1H),6.44(s,1H),6.37(d,J＝13.0Hz,1H),4.94(s,1H),3.80(s,2H),3.38(s,2H),2.21(d,J＝2.6Hz,2H),1.30(s,9H).
第三步：合成(2-(3-(3-(3-氰基-4-氟苄基)-5-氟苯氧基)乙基)氨基甲酸叔丁酯
参见(2-(2-(3-氰基-4-氟苄基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯的合成，得到(2-(2-(3-氰基-4-氯苄基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯(1.6g，产率:50％)为白色固体。
1H NMR(400MHz,,CDCl3)δ7.41(d,J＝12.0Hz,2H),7.20(s,2H),6.56(s,1H),6.48(d,J＝11.3Hz,1H),3.95(s,2H),3.47(s,2H),2.55(s,1H),2.05(s,2H),1.38(s,9H).0629
第四步：合成(2-(3-(((3-氨基-1H-吲唑-5-基)甲基)-5-氟苯氧基)乙基)氨基甲酸叔丁酯
参见(2-(2-((3-氨基-1H-吲唑-5-基)甲基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯的合成，得到(2-(2-((3-氨基-1H-吲唑-5-基)甲基)-4-氯苯氧基)乙基)氨基甲酸叔丁酯为白色固体；LCMS:401.3[M+1]+。
第五步：合成(2-(3-((3-((3-((2,6-二氯嘧啶-4-基)氨基)-1H-吲唑-5-基)甲基)-5-氟苯氧基)乙基)氨基甲酸叔丁酯
参见(2-(2-((3-((2,6-二氯嘧啶-4-基)氨基)-1H-吲唑-5-基)甲基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯的合成，得到(2-(2-((3-((2,6-二氯嘧啶-4-基)氨基)-1H-吲唑-5-基)甲基)-4-氯苯氧基)乙基)氨基甲酸叔丁酯(600mg，产率:87％)。
1H NMR(400MHz,DMSO)δ12.76(s,1H),11.28(s,1H),8.16(s,1H),7.48(s,2H),7.26(s,1H),6.97(s,1H),3.95(s,2H),3.28–3.26(m,2H),2.43(s,2H),2.11(s,2H),1.32(s,9H).
第六步：合成5-(3-(2-氨基乙氧基)-5-氟苄基)-N-(2,6-二氯嘧啶-4-基)-1H-吲唑-3-胺的三氟乙酸盐
参见5-(2-(2-氨基乙氧基)-5-氟苄基)-N-(2,6-二氯嘧啶-4-基)-1H-吲唑-3-胺的三氟乙酸盐合成方法，得到粗产品5-(2-(2-氨基乙氧基)-5-氯苄基)-N-(2,6-二氯嘧啶-4-基)-1H-吲唑-3-胺的三氟乙酸盐(592mg，产率:100％)。直接用于下一步反应。
实施例76：12-氯-54-氟-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1,2)-苯并环壬基
合成步骤详见实施例1，得到白色固体。
LC-MS(M+H+)：411.1129
1H NMR(400MHz,DMSO)δ12.40(s,1H),9.76(s,1H),7.46(s,1H),7.30(s,1H),7.21(s,2H),6.95(s,2H),6.69(s,1H),6.61(s,1H),5.85(s,1H),3.45(s,2H),2.09(s,2H),1.99(s,2H).
实施例77：55-氟-12-(4-甲基哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，3)-苯环壬酮
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：475.2369
1H NMR(400MHz,CDCl3)δ10.68(s,1H),7.80(s,-1H),7.38(s,1H),6.67(s,2H),5.30(s,1H),5.06(s,1H),3.83(s,2H),3.58–3.47(m,3H),2.33(s,4H),0.89(s,2H).
实施例78：55-氟-12-(4-异丙基哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，3)-苯环壬酮
合成步骤详见实施例1，得到白色固体。
LC-MS(M+H+)：503.2667
1H NMR(400MHz,CDCl3)δ9.85(s,-1H),7.91(s,1H),7.08(s,2H),6.64(d, J＝30.4Hz,3H),5.32(d,J＝17.4Hz,1H),3.82(s,2H),3.52(s,4H),3.11(s,1H),2.56(s,4H),2.20(d,J＝4.5Hz,4H),1.06(s,6H).
实施例79：55-氟-12-(4-乙酰基哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，3)-苯环壬酮
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：503.2318
1H NMR(400MHz,CDCl3)δ9.65(s,1H),7.83(s,1H),7.38(s,2H),7.14(s,3H),6.57(s,1H),3.51(s,4H),2.23(s,3H),2.06(s,4H),1.19(s,4H).
实施例80：55-氟-12-(4-甲基高哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，3)-苯环壬酮
合成步骤详见实施例1，得到白色固体。
LC-MS(M+H+)：489.2511
1H NMR(400MHz,CDCl3)δ10.10(s,0H),7.96(s,1H),7.40(s,1H),7.22(s,1H),7.04(s,1H),6.68(d,J＝27.4Hz,2H),5.27(s,-1H),3.57(s,5H),2.73(s,4H),2.43(s,6H),2.07(s,4H),1.33(s,2H).
实施例81：55-氟-12-(4-环丙基哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，3)-苯环壬酮
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：501.2525
1H NMR(400MHz,CDCl3)δ9.74(s,1H),7.87(d,J＝26.5Hz,1H),6.98(s,2H),6.64(s,1H),5.24(s,-1H),3.43(s,2H),3.15(s,1H),2.60(d,J＝24.2Hz,4H),2.17(d,J＝20.9Hz,4H),1.29(s,4H),0.42(d,J＝10.1Hz,4H).
实施例82：55-氟-12-(4-乙基哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，3)-苯环壬酮
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：489.2523
1H NMR(400MHz,CDCl3)δ9.92(s,1H),7.80–7.75(m,1H),7.23(s,1H),7.05(s,1H),6.97(s,1H),6.53(s,1H),6.47(s,1H),5.20(s,1H),4.82(s,1H),3.68(s,4H),3.40(s,4H),2.37(s,4H),2.07(s,4H),1.00(d,J＝6.5Hz,3H).
实施例83：55-氟-12-(4-哌啶哌啶-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，3)-苯环壬酮
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：543.2993
1H NMR(400MHz,CDCl3)δ10.12(s,1H),8.00(s,1H),7.43(s,2H),6.73(s,2H),6.49(s,1H),5.31(s,1H),5.05(s,1H),3.85(s,4H),3.61(s,4H),2.49 (s,10H),1.18(s,4H).
实施例84：55-氟-12-(4-乙酰基高哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，3)-苯环壬酮
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：517.2471
1H NMR(400MHz,CDCl3)δ10.29(s,1H),7.92(s,1H),7.40(s,3H),6.42(d,J＝10.0Hz,2H),5.25(s,1H),3.65(s,8H),2.72(s,3H),2.05(s,6H),1.07(d,J＝140.4Hz,2H).
实施例85：55-氟-12-(4-丁基哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，3)-苯环壬酮
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：517.2837
1H NMR(400MHz,CDCl3)δ9.68(s,1H),7.80(s,1H),7.35(s,2H),7.10(s,2H),6.50(s,2H),5.37–5.15(m,1H),3.65(s,4H),3.40(s,4H),2.36(s,4H),1.87(s,4H),1.39(s,3H),0.82(s,4H).
实施例86：55-氟-12-(4-甲磺酸哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,5)-吲唑-1(4,6)-嘧啶-5(1，3)-苯环壬酮
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：539.1981
1H NMR(400MHz,cdcl3)δ9.80(s,1H),7.84(s,1H),7.45(s,2H),7.34(s,1H),7.09(s,1H),6.65(s,1H),6.47(s,1H),5.64(s,1H),3.92(s,4H),3.23(s,4H),2.77(s,4H),2.30(s,3H),1.64(s,4H).
实施例87-95的合成步骤
合成(2-(3-(3-(4-氰基-3-氟苄基)-5-氟苯氧基)乙基)氨基甲酸叔丁酯
参见(2-(2-(3-氰基-4-氟苄基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯的合成，得到(2-(2-(3-氰基-4-氯苄基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯(1.6g，产率:50％)为白色固体。
LC-MS(M+H+)289.3
1H NMR(400MHz,DMSO)δ7.79(t,J＝7.5Hz,1H),7.45(d,J＝10.6Hz,1H),7.33(d,J＝8.0Hz,1H),7.22–7.15(m,1H),7.06–6.90(m,4H),3.98(s,2H),3.90(dd,J＝13.7,8.6Hz,3H),3.32–3.27(m,2H),1.36(s,10H).
合成(2-(3-(((3-氨基-1H-吲唑-5-基)甲基)-5-氟苯氧基)乙基)氨基甲酸叔丁酯
参见(2-(2-((3-氨基-1H-吲唑-5-基)甲基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯的合成，得到(2-(2-((3-氨基-1H-吲唑-5-基)甲基)-4-氯苯氧基)乙基)氨基甲酸叔丁酯为白色固体；LCMS:401.3[M+1]+。
第五步：合成(2-(2-((3-((2,6-二氯嘧啶-4-基)氨基)-1H-吲唑-5-基)甲基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯
参见(2-(2-((3-((2,6-二氯嘧啶-4-基)氨基)-1H-吲唑-5-基)甲基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯的合成，得到(2-(2-((3-((2,6-二氯嘧啶-4-基)氨基)-1H-吲唑-5-基)甲基)-4-氯苯氧基)乙基)氨基甲酸叔丁酯(600mg，产率:87％)。
1H NMR(400MHz,DMSO)δ12.41(s,1H),7.66(s,2H),7.11(s,1H),6.89–6.77(m,3H),6.73(td,J＝9.4,8.8,3.9Hz,2H),3.79(s,2H),3.68(t,J＝5.6Hz,2H),1.12(d,J＝5.9Hz,9H).
合成5-(3-(2-氨基乙氧基)-5-氟苄基)-N-(2,6-二氯嘧啶-4-基)-1H-吲唑-3-胺的三氟乙酸盐
参见5-(2-(2-氨基乙氧基)-5-氟苄基)-N-(2,6-二氯嘧啶-4-基)-1H-吲唑-3-胺的三氟乙酸盐合成方法，得到粗产品5-(2-(2-氨基乙氧基)-5-氯苄基)-N-(2,6-二氯嘧啶-4-基)-1H-吲唑-3-胺的三氟乙酸盐(592mg，产率:100％)。直接用于下一步反应。
实施例87：12-氯-55-氯-31H-6-氧杂-2,9-二氮杂-3(3,6)-吲唑-1(4,6)-嘧啶-5(1,2)-苯并环壬基
合成步骤详见实施例1，得到白色固体。
LC-MS(M+H+)：411.1127
1H NMR(400MHz,CDCl3)δ9.14(s,1H),7.41(s,1H),7.36(d,J＝7.5Hz,1H),7.10(d,J＝7.8Hz,1H),6.94(d,J＝7.4Hz,1H),6.76–6.66(m,2H),6.58(s,1H),6.18(s,1H),6.01(s,1H),4.33(s,5H),4.33(s,4H),4.10–3.96(m,2H),3.63(s,4H),2.07(s,3H),2.02(s,2H).
实施例88：55-氟-12-(4-甲基哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,6)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环壬酮
LC-MS(M+H+)：475.2368
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：475.2368
1H NMR(400MHz,DMSO)δ9.37(s,1H),7.67(d,J＝8.0Hz,1H),7.22(d,J＝8.0Hz,1H),7.16(dd,J＝9.2,3.1Hz,1H),7.11(dd,J＝9.0,4.9Hz,1H),7.05(s,1H),6.92–6.85(m,1H),6.13(d,J＝5.2Hz,3H),3.58(s,7H),2.84(s,7H),2.37–2.19(m,3H).
实施例89：55-氟-12-(4-甲氧基哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,6)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环壬酮
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：490.2362
1H NMR(400MHz,CDCl3)δ9.14(s,1H),7.41(s,1H),7.36(d,J＝7.5Hz,1H),7.10(d,J＝7.8Hz,1H),6.94(d,J＝7.4Hz,1H),6.76–6.66(m,2H),6.58(s,1H),6.18(s,1H),6.01(s,1H),4.33(s,5H),4.33(s,4H),4.10–3.96(m,2H),3.63(s,4H),2.07(s,3H),2.02(s,2H).
实施例90：55-氟-12-(4-乙酰基哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,6)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环壬酮
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：517.2465
1H NMR(400MHz,CDCl3)δ9.14(s,1H),7.41(s,1H),7.36(d,J＝7.5Hz,1H),7.10(d,J＝7.8Hz,1H),6.94(d,J＝7.4Hz,1H),6.76–6.66(m,2H),6.58(s,1H),6.18(s,1H),6.01(s,1H),4.33(s,5H),4.33(s,4H),4.10–3.96(m,2H),3.63(s,4H),2.07(s,3H),2.02(s,2H).
实施例91：55-氟-12-(4-哌啶-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,6)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环壬酮
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：474.2407
1H NMR(400MHz,CDCl3)δ9.04(s,1H),7.48(d,J＝32.9Hz,1H),7.35(s,2H),7.09(s,1H),6.99(s,2H),6.77(s,2H),6.21(s,1H),4.12(s,2H),3.49(s,4H),2.37(s,1H),2.21(s,1H).
实施例92：55-氟-12-(4-异丙基哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,6)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环壬酮
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：503.2681
1H NMR(400MHz,CDCl3)δ9.54(s,1H),7.41(d,J＝8.3Hz,1H),7.13(d,J＝7.8Hz,1H),6.91(s,2H),6.76(s,1H),6.26(s,1H),5.07(s,1H),4.30(s,2H),3.65(s,2H),3.48(s,2H),3.09(s,4H),2.59(s,4H),2.20(s,1H),1.08(s,6H).
实施例93：55-氟-12-(4-高哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,6)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环壬酮
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：489.2526
1H NMR(400MHz,CDCl3)δ9.55(s,1H),7.40(s,1H),7.12(s,1H),6.91(s,2H),6.77(s,1H),6.16(s,1H),5.01(s,1H),4.30(s,2H),3.81(s,2H),3.65(s,2H),2.61(d,J＝43.3Hz,4H),2.37(s,4H),2.01(s,3H),1.25(s,2H).
实施例94：55-氟-12-(4-环丙基哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,6)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环壬酮
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：501.2525
1H NMR(400MHz,CDCl3)δ9.55(s,1H),7.12(s,1H),6.91(s,2H),6.77(s,1H),6.16(s,1H),5.01(s,1H),4.30(s,2H),3.81(s,2H),3.65(s,2H),2.61(d,J＝43.3Hz,4H),2.01(s,3H),1.25(s,2H).
实施例95：55-氟-12-(4-哌啶哌啶-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,6)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环壬酮
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：543.2995
1H NMR(400MHz,CDCl3)δ9.40(s,1H),7.26(s,-1H),7.13(s,1H),6.81(s,2H),6.62(s,2H),6.22(s,1H),4.17(s,4H),3.15(s,6H),2.57(s,5H),1.54(s,10H).
实施例96-99的合成步骤：
合成(2-(3-(3-(4-氰基-3-氯苄基)-5-氟苯氧基)乙基)氨基甲酸叔丁酯
参见(2-(2-(3-氰基-4-氟苄基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯的合成，得到(2-(2-(3-氰基-4-氯苄基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯(1.6g，产率:50％)为白色固体。
1H NMR(400MHz,,CDCl3)δ7.30(s,1H),7.26(d,J＝2.3Hz,1H),7.19(s,2H),7.11(s,1H),6.74(s,1H),4.78(s,1H),3.97(s,2H),3.52(s,2H),1.42(s,9H).
合成(2-(3-(((3-氨基-1H-吲唑-5-基)甲基)-5-氯苯氧基)乙基)氨基甲酸叔丁酯
参见(2-(2-((3-氨基-1H-吲唑-5-基)甲基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯的合成，得到(2-(2-((3-氨基-1H-吲唑-5-基)甲基)-4-氯苯氧基)乙基)氨基甲酸叔丁酯为白色固体；LCMS:401.3[M+1]+。
合成(2-(2-((3-((2,6-二氯嘧啶-4-基)氨基)-1H-吲唑-5-基)甲基)-4-氯苯氧基)乙基)氨基甲酸叔丁酯
参见(2-(2-((3-((2,6-二氯嘧啶-4-基)氨基)-1H-吲唑-5-基)甲基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯的合成，得到(2-(2-((3-((2,6-二氯嘧啶-4-基)氨基)-1H-吲唑-5-基)甲基)-4-氯苯氧基)乙基)氨基甲酸叔丁酯(600mg，产率:87％)。
1H NMR(400MHz,,CDCl3)δ7.30(s,1H),7.26(d,J＝2.3Hz,1H),7.19(s,2H),7.11(s,1H),6.74(s,1H),4.78(s,1H),3.97(s,2H),3.52(s,2H),1.42 (s,9H).
合成5-(3-(2-氨基乙氧基)-5-氯苄基)-N-(2,6-二氯嘧啶-4-基)-1H-吲唑-3-胺的三氟乙酸盐
参见5-(2-(2-氨基乙氧基)-5-氟苄基)-N-(2,6-二氯嘧啶-4-基)-1H-吲唑-3-胺的三氟乙酸盐合成方法，得到粗产品5-(2-(2-氨基乙氧基)-5-氯苄基)-N-(2,6-二氯嘧啶-4-基)-1H-吲唑-3-胺的三氟乙酸盐(592mg，产率:100％)。直接用于下一步反应。
实施例96：12-氯-55-氟-31H-6-氧杂-2,9-二氮杂-3(3,6)-吲唑-1(4,6)-嘧啶-5(1,2)-苯并环壬基
合成步骤详见实施例1，得到白色固体。
LC-MS(M+H+)：427.0832
1H NMR(400MHz,DMSO)δ9.33(s,1H),7.95(s,1H),7.72(d,J＝8.0Hz,1H),7.34(s,1H),7.18(d,J＝9.0Hz,2H),6.91(s,1H),6.61(s,1H),6.40(s,2H),4.58(d,J＝49.0Hz,2H),3.83(d,J＝113.8Hz,4H).
实施例97：55-氯-12-(4-甲基哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,6)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环壬酮
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：491.2072
1H NMR(400MHz,CDCl3)δ9.56(s,1H),7.40(d,J＝8.0Hz,1H),7.18(s,1H),7.13(d,J＝8.6Hz,2H),7.03(d,J＝8.8Hz,1H),6.87(d,J＝8.7Hz,1H),6.27(s,1H),4.31(s,2H),3.77(s,2H),3.64(s,4H),2.45(s,4H),2.32(s,3H),2.17(s,2H).
实施例98：55-氯-12-(4-乙基哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,6)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环壬酮
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：505.2231
1H NMR(400MHz,CDCl3)δ9.56(s,1H),7.40(d,J＝8.1Hz,1H),7.18(s,1H),7.12(d,J＝8.3Hz,1H),7.03(d,J＝8.5Hz,1H),6.87(d,J＝8.7Hz,1H),6.26(s,1H),4.31(s,2H),3.64(s,2H),3.37(s,2H),3.10(s,2H),2.45(s,4H),2.18(d,J＝8.3Hz,4H),1.11(s,3H).
实施例99：55-氯-12-(4-环丙基哌嗪-1-基)-31H-6-氧杂-2,9-二氮杂-3(3,6)-吲唑-1(4,6)-嘧啶-5(1，2)-苯环壬酮
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：517.2231
1H NMR(400MHz,CDCl3)δ9.56(s,1H),7.74(s,1H),7.42(s,1H),7.18(s,2H),7.13(s,1H),7.03(s,1H),6.88(s,1H),6.26(s,1H),4.33(s,2H),3.71(s,4H),3.59(s,2H),3.49(s,2H),2.65(s,6H).
实施例100-102的合成步骤
合成(2-(3-(3-(4-氰基-3-氟苄基)-5-氟苯氧基)丙基)氨基甲酸叔丁酯
参见(2-(2-(3-氰基-4-氟苄基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯的合成，得到(2-(2-(3-氰基-4-氯苄基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯(1.6g，产率:50％)为白色固体。
1H NMR(400MHz,,CDCl3)δ7.45(t,J＝7.0Hz,1H),7.02(d,J＝7.7Hz,1H),6.94(d,J＝9.9Hz,1H),6.85(d,J＝8.5Hz,1H),6.75(d,J＝8.3Hz,1H),6.70(dd,J＝8.4,4.1Hz,1H),3.90(s,2H),3.84(s,2H),3.07(s,2H),1.70–1.62(m,2H),1.52–1.44(m,2H),1.37(s,9H).
合成(2-(3-(((3-氨基-1H-吲唑-5-基)甲基)-5-氟苯氧基)丙基)氨基甲酸叔丁酯
参见(2-(2-((3-氨基-1H-吲唑-5-基)甲基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯的合成，得到(2-(2-((3-氨基-1H-吲唑-5-基)甲基)-4-氯苯氧基)乙基)氨基甲酸叔丁酯为白色固体；LCMS:401.3[M+1]+。
合成(2-(2-((3-((2,6-二氯嘧啶-4-基)氨基)-1H-吲唑-5-基)甲基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯
参见(2-(2-((3-((2,6-二氯嘧啶-4-基)氨基)-1H-吲唑-5-基)甲基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯的合成，得到(2-(2-((3-((2,6-二氯嘧啶-4-基)氨基)-1H-吲唑-5-基)甲基)-4-氯苯氧基)乙基)氨基甲酸叔丁酯(600mg，产率:87％)。
1H NMR(400MHz,CDCl3)δ7.76(s,1H),7.71(s,1H),7.53(s,1H),7.35(s,1H),6.98(s,1H),6.86(s,1H),6.70(s,1H),4.00(s,2H),3.90(s,2H),3.56(s,4H),2.04(s,4H),1.85(s,9H).
合成5-(3-(2-氨基乙氧基)-5-氟苄基)-N-(2,6-二氯嘧啶-4-基)-1H-吲唑-3-胺的三氟乙酸盐
参见5-(2-(2-氨基乙氧基)-5-氟苄基)-N-(2,6-二氯嘧啶-4-基)-1H-吲唑-3-胺的三氟乙酸盐合成方法，得到粗产品5-(2-(2-氨基乙氧基)-5-氯苄基)-N-(2,6-二氯嘧啶-4-基)-1H-吲唑-3-胺的三氟乙酸盐(592mg，产率:100％)。直接用于下一步反应。
实施例100：12-氯-55-氟-31H-6-氧杂-2,11-二氮杂3(3,6)-吲唑-1(4,6)-嘧啶-5 (1,2)-苯并环戊环己烯
合成步骤详见实施例1，得到白色固体。
LC-MS(M+H+)：439.1448
1H NMR(400MHz,DMSO)δ8.60(s,1H),7.92–7.75(m,2H),7.48(d,J＝7.0Hz,1H),7.34(d,J＝7.5Hz,1H),6.92(s,2H),6.72(s,1H),6.39(s,2H),4.00(s,3H),3.37(s,2H),1.94(s,5H).
实施例101：55-氟-12-(4-甲基哌嗪-1-基)-31H-6-氧杂-2,11-二氮杂-3(3,6)-吲唑-1(4,6)-嘧啶-5(1，2)-苯甲环磷酰胺
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：503.2682
1H NMR(400MHz,CDCl3)δ8.85(s,1H),7.45(d,J＝8.1Hz,1H),7.30–7.19(m,2H),7.06(d,J＝8.9Hz,1H),6.81–6.69(m,2H),6.36(s,1H),4.99(s,1H),4.28(s,2H),4.01(s,2H),3.59(s,4H),3.38(s,2H),2.63(d,J＝10.8Hz,2H),2.05(d,J＝38.6Hz,4H),1.11(d,J＝7.9Hz,7H).
实施例102：55-氟-12-(4-乙基哌嗪-1-基)-31H-6-氧杂-2,11-二氮杂-3(3,6)-吲唑-1(4,6)-嘧啶-5(1，2)-苯甲环磷酰胺
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：517.2839
1H NMR(400MHz,CDCl3)δ8.85(s,1H),7.45(d,J＝8.1Hz,1H),7.30–7.19(m,2H),7.06(d,J＝8.9Hz,1H),6.81–6.69(m,2H),6.36(s,1H),4.99(s,1H),4.28(s,2H),4.01(s,2H),3.59(s,4H),3.38(s,2H),2.63(d,J＝10.8Hz,2H),2.05(d,J＝38.6Hz,4H),1.11(d,J＝7.9Hz,7H).
实施例103-106的合成步骤
合成(2-(3-(3-(4-氰基-3-氟苄基)-5-氟苯氧基)丙基)氨基甲酸叔丁酯
参见(2-(2-(3-氰基-4-氟苄基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯的合成，得到(2-(2-(3-氰基-4-氯苄基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯(1.6g，产率:50％)为白色固体。
1H NMR(400MHz,,CDCl3)δ7.56–7.41(m,1H),6.82–6.73(m,2H),6.46(s,1H),4.97(dt,J＝12.3,6.2Hz,1H),4.85(s,1H),4.15(td,J＝6.1,2.0Hz,2H),3.36(t,J＝5.4Hz,2H),2.08(q,J＝6.3Hz,2H),1.44(s,9H),1.27(d,J＝6.2Hz,9H).
合成(2-(3-(((3-氨基-1H-吲唑-5-基)甲基)-5-氟苯氧基)丙基)氨基甲酸叔丁酯
参见(2-(2-((3-氨基-1H-吲唑-5-基)甲基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯的合成，得到(2-(2-((3-氨基-1H-吲唑-5-基)甲基)-4-氯苯氧基)乙基)氨基甲酸叔丁酯为白色固体；LCMS:425.3[M+1]+。
合成(2-(2-((3-((2,6-二氯嘧啶-4-基)氨基)-1H-吲唑-5-基)甲基)-4-氟苯氧基)丙基)氨基甲酸叔丁酯
参见(2-(2-((3-((2,6-二氯嘧啶-4-基)氨基)-1H-吲唑-5-基)甲基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯的合成，得到(2-(2-((3-((2,6-二氯嘧啶-4-基)氨基)-1H-吲唑-5-基)甲基)-4-氯苯氧基)乙基)氨基甲酸叔丁酯(600mg，产率:87％)。
参见(2-(2-((3-((2,6-二氯嘧啶-4-基)氨基)-1H-吲唑-5-基)甲基)-4-氟苯氧基)乙基)氨基甲酸叔丁酯的合成，得到(2-(2-((3-((2,6-二氯嘧啶-4-基)氨基)-1H-吲唑-5-基)甲基)-4-氯苯氧基)乙基)氨基甲酸叔丁酯(600mg，产率:87％)。
1H NMR(400MHz,DMSO)δ12.57(s,1H),7.26(s,1H),7.02(s,1H),7.00(s,1H),6.98(d,J＝8.8Hz,1H),6.92(d,J＝8.8Hz,1H),6.87(s,1H),4.00(s,2H),3.91(s,2H),3.10(s,2H),1.98(s,1H),1.83(s,2H),1.36(s,9H).
合成5-(3-(2-氨基乙氧基)-5-氟苄基)-N-(2,6-二氯嘧啶-4-基)-1H-吲唑-3-胺的三氟乙酸盐
参见5-(2-(2-氨基乙氧基)-5-氟苄基)-N-(2,6-二氯嘧啶-4-基)-1H-吲唑-3-胺的三氟乙酸盐合成方法，得到粗产品5-(2-(2-氨基乙氧基)-5-氯苄基)-N-(2,6-二氯嘧啶-4-基)-1H-吲唑-3-胺的三氟乙酸盐(592mg，产率:100％)。直接用于下一 步反应。
实施例103：12-氯-55-氟-31H-6-氧杂-2,10-二氮杂3(3,6)-吲唑-1(4,6)-嘧啶-5(1,2)-苯并环戊环己烯
合成步骤详见实施例1，得到白色固体。
LC-MS(M+H+)425.1285
1H NMR(400MHz,DMSO)δ8.95(d,J＝18.7Hz,1H),7.83(s,1H),7.73(s,1H),7.34(s,1H),6.99(s,2H),6.61(s,1H),6.38(s,2H),4.01(s,4H),3.03(s,2H),2.27(d,J＝41.9Hz,2H).
实施例104：55-氟-12-(4-甲基哌嗪-1-基)-31H-6-氧杂-2,10-二氮杂-3(3,6)-吲唑-1(4,6)-嘧啶-5(1，2)-苯甲环磷酰胺
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：489.2524
1H NMR(400MHz,CDCl3)δ9.23(s,1H),7.42(d,J＝7.7Hz,1H),7.35(s,1H),7.27(s,1H),7.15(d,J＝8.1Hz,1H),7.02(s,1H),6.78(d,J＝18.3Hz,2H),6.26(s,1H),5.30(d,J＝3.5Hz,4H),4.35(s,2H),4.12(d,J＝7.2Hz,2H),3.76(s,4H),2.62(t,J＝1.1Hz,3H),2.44(s,2H),2.05(d,J＝3.3Hz,2H).
实施例105：55-氟-12-(4-吗啉-1-基)-31H-6-氧杂-2,10-二氮杂-3(3,6)-吲唑-1(4,6)-嘧啶-5(1，2)-苯甲环磷酰胺
合成步骤详见实施例3，得到白色固体。
1H NMR(400MHz,CDCl3)δ9.05(s,1H),7.45(d,J＝7.7Hz,1H),7.00(s,2H), 6.82(s,1H),6.77(s,1H),6.66(s,1H),6.23(s,1H),5.30(s,1H),4.47(s,2H),4.12(d,J＝7.1Hz,2H),3.77(s,8H),2.05(s,2H).
实施例106：55-氟-12-(4-异丙基哌嗪-1-基)-31H-6-氧杂-2,10-二氮杂-3(3,6)-吲唑-1(4,6)-嘧啶-5(1，2)-苯甲环磷酰胺
合成步骤详见实施例3，得到白色固体。
LC-MS(M+H+)：517.2839
1H NMR(400MHz,CDCl3)δ8.15(d,J＝1.4Hz,1H),8.08(t,J＝1.9Hz,1H),8.02(s,1H),7.89(d,J＝2.6Hz,1H),3.79(s,4H),3.59(s,2H),3.41(d,J＝5.1Hz,2H),3.23(s,1H),2.82(s,4H),2.59–2.50(m,4H),1.07(s,3H),1.06(s,3H).
实施例107
性能测试1：ALK激酶抑制率实验
生物学实施例
ALK激酶抑制实验
Ⅰ流动性变化分析
1.制备用于检测激酶的1x激酶基缓冲液和停止缓冲液
1)1x激酶基缓冲液
50毫米HEPES,pH 7.5
0.0015％Brij-35
2)停止缓冲
100mm HEPES,pH 7.5
0.015％Brij-35
涂布试剂3号
50mM EDTA
2.复合准备
1)用100％DMSO将化合物稀释至最终所需的最高抑制剂浓度的50倍。将100μl的复合稀释液转移到96孔板的孔中。例如，若要求的抑制剂浓度为5μM，则在此步骤中配制复方DMSO溶液250μM，若要求的抑制剂浓度为0.1μM，则在此步骤中配制复方DMSO溶液5μM。
2)在同一96孔板的两个空孔中加入100μl 100％DMSO，无化合物对照和无酶对照。将印版标记为源印版。
3)制备中间板，将10μl的化合物从源板转移到新的96孔板作为中间板。在中间板各孔中加入90μl的1x激酶缓冲液。将混合物在中间板上搅拌10分钟。
3.准备试验板
1)将每孔5μl的样品从96孔中间板转移到384孔板中，一份一份。例如，将96孔板的A1转移到384孔板的A1和A2。9 6孔板的A2转移到384孔板的A3、A4，以此类推。
4.激酶反应
1)配制2.5倍酶溶液
在1x激酶基缓冲液中加入激酶。
2)配制2.5倍肽溶液
在1x激酶缓冲液中加入fam标记的肽和ATP。
3)实验板已含有5μL的化合物在10％的DMSO中。
4)转移2.5倍酶液到试验板
5)384孔试板每孔加10μl 2.5x酶液。
6)室温孵育10分钟。
7)转移2.5倍肽溶液到实验板
在384孔实验板的每孔中加入10μL的2.5x肽溶液。
8)激酶反应停止
在28℃下孵育一段时间。
加入25μL的停止缓冲液停止反应。
5.卡尺阅读
收集卡尺数据。
6.曲线拟合
1)从卡尺程序复制转换数据。
2)将转换值转换为抑制值。
抑制百分比＝(max-conversion)/(max-min)*100。“max”代表DMSO控制；“min”代表低控制。
3)对XLFit excel插件5.4.0.8版本的数据进行拟合，得到IC50值。所用公式为:Y＝Bottom+(Top-Bottom)/(1+(IC50/X)^HillSlope)
全部化合物1-15的IC50值如表所示。***代表IC50<100nmol,**代表100nmol<IC50<5000nmol,*代表IC50>5000nmol
表1 ALK激酶抑制率测试结果


***代表IC50<100nmol,**代表100nmol<IC50<5000nmol,*代表IC50>5000nmol
实施例108
性能测试2：H2228抑制率实验
细胞活性实验
1.细胞：NCI-H2228细胞，来自中国上海市睿智化学测试中心。
2.试剂：Gibco DMEM/F12培养基，Gibco 0.25％胰酶/EDTA细胞消化液，MTT(5mg/ml)，DMSO，PBS。
3.仪器：37℃，5％CO2培养箱，TECAN InfiniteTM200系列多功能酶标仪，超净工作台，细胞计数板。
4.实验耗材：96孔板。
NCI-H2228细胞的活性测试实验步骤：
1.铺板。将处于对数生长期的细胞用消化液消化，新鲜培养基终止，对细胞进行计数，用新鲜培养基将细胞浓度调整到5*104个/ml，每孔加200μL，设调零孔(只加培养基)3个，其他边缘用无菌PBS填充。
2.于37℃下在5％CO2中孵育24小时，让细胞铺满孔底60％左右。
3.给药。将药物用DMSO溶解，配成10mmol/L母液，再用DMSO将其进行稀释，制成1mmol/L、100μmol/L、10μmol/L、1mol/L、0.1mol/L溶液，给药时，取上述浓度溶液1μL用培养基稀释成1mL，即给药浓度为10μmol/L、1μmol/L、100nmol/L、10nmol/L、1nmol/L、0.1nmol/L、0nmol/L(对照组，加1μL DMSO用培养基稀释成1ml)。给药时，将原有孔内液体吸尽，加入含不同浓度药物的新鲜培养基，每孔200μl。
调零孔，只加培养基；
对照组，含与实验组相同体积的溶剂，用完全培养基稀释。每孔200μl；
实验组，将已溶解的药物用培养基稀释成0.1、1、10、100、1000、10000nM浓度，每孔200μl。
4.于37℃下在5％CO2中孵育。
5. 72h后，每孔加入20μL MTT溶液(5mg/ml)，继续培养4h。
6.将96孔板用平板离心机离心，1000转/5分钟。
7.终止培养，小心吸去孔内的培养液。
8.每孔加入150μl二甲基亚砜(DMSO)，低速震荡10min，待结晶物充分溶解后，在酶标仪，490nm波长处测其吸光值。
全部化合物的IC50值如表所示。***代表IC50<100nmol,**代表100nmol<IC50<5000nmol,*代表IC50>5000nmol
表2 H2228抑制率活性表


***代表IC50<100nmol,**代表100nmol<IC50<5000nmol,*代表IC50>5000nmol

Claims (16)

  1. 式(I)所示的化合物、其药学上可接受的盐、前药或溶剂化物，
    其中
    Z1，Z2，Z3分别独立地选自CH和N；
    优选地，Z1选自N，Z2选自N，Z3选自CH；或Z1选自CH，Z2选自N，Z3选自N；
    n为1，2，3，4，5，6，7，8，9或10；优选地，n选自1，2，3，4；
    X，Y，W分别独立地选自O，NH，NR4R5，S，C＝O，CR4R5，R4和R5各自独立地选自氢、C1-C5烷基，C1-C5烷氧基；
    R1选自H，卤素，NR6R7，CR6R7，含1-3个取代基的苯环，5-12元杂环，R6和R7各自独立地选自氢、C1-C5烷基；
    所述5-12元杂环被C1-C10烷基、C1-C10烷氧基、C1-C10环烷基、C1-C10烷基酰胺，C1-C10环烷基酰胺、C1-C10烷基磺酰胺，C1-C10环烷基磺酰胺、氨基保护基、苯基、5-12元杂环任选地取代；
    R2，R3分别独立地选自氢，卤素，氨基，硝基，氰基，羟基，羧基，酰胺基，磺酸基，磺酰胺基，磺酸酯基，C1-C6烷基,C1-C6烷氧基。
  2. 根据权利要求1所示的化合物、其药学上可接受的盐、前药或溶剂化物，其中R1选自H，F，Cl，Br；优选地，R1选自H或Cl。
  3. 根据权利要求1所示的化合物、其药学上可接受的盐、前药或溶剂化物，其中R1选自NR6R7，CR6R7，，含1-3个取代基的苯环，5-12元并环，5-12元螺环，5-12元桥环，R6和R7各自独立地选自氢、C1-C5烷基；
    所述5-12元并环、螺环和桥环被C1-C10烷基、C1-C10烷氧基、C1-C10环烷基、C1-C10 烷基酰胺，C1-C10环烷基酰胺、C1-C10烷基磺酰胺，C1-C10环烷基磺酰胺、氨基保护基、苯基、5-12元杂环任选地取代。
  4. 根据权利要求1所示的化合物、其药学上可接受的盐、前药或溶剂化物，其中R1选自
    m’，n’，m”和n”分别独立地选自0，1，2，3，4或5；
    R选自H,O,C1-C10烷基，C1-C10烷氧基，C3-C12环烷基，C1-C10烷基酰胺，C1-C10环烷基酰胺，苯环，嘧啶，哌啶基，C1-C10烷基磺酰胺，C1-C10环烷基磺酰胺，氨基保护基。
  5. 根据权利要求1所示的化合物、其药学上可接受的盐、前药或溶剂化物，其中R1选自
    R选自H,O,CH3,CH2CH3,CH2CH2CH3,CH2CH2CH2CH3,CH(CH3)2，环丙基，环丁基，环戊基，环庚基，C1-C4烷基酰胺，C1-C6环烷基酰胺，苯环，嘧啶，哌啶基，C1-C6烷基磺酰胺，C1-C6环烷基磺酰胺，氨基保护基。
  6. 根据权利要求1所示的化合物、其药学上可接受的盐、前药或溶剂化物，其中R1选自以下具体片段，
  7. 根据权利要求1所示的化合物、其药学上可接受的盐、前药或溶剂化物，其中X与吲唑苯环连接的位点可以表示为优选地，具体通式如下：
  8. 根据权利要求1所示的化合物、其药学上可接受的盐、前药或溶剂化物，其中X与R2所在的苯环连接的位点可以表示为优选地，具体通式如下
    所述R2和R3中至少有一个为卤素。
  9. 根据权利要求1所示的化合物、其药学上可接受的盐、前药或溶剂化物，其中X与Y,W分别独立地选自CH2，NH，O。
  10. 根据权利要求1所示的化合物、其药学上可接受的盐、前药或溶剂化物，其中X为CH2，Y为NH，W为O；通式如下：
  11. 根据权利要求1所示的化合物、其药学上可接受的盐、前药或溶剂化物，其中R2和R3分别独立选自H，F，Cl，Br，I。
  12. 根据权利要求1所示的化合物、其药学上可接受的盐、前药或溶剂化物，其中R2 为F，R3为H；或R2为Cl，R3为H；或R2为H，R3为F。
  13. 根据权利要求1所示的化合物、其药学上可接受的盐、前药或溶剂化物，其中R1为Cl，所述化合物选自：
  14. 根据权利要求1所示的化合物、其药学上可接受的盐、前药或溶剂化物，
    所述化合物选自：



  15. 权利要求1-14中任意一项所述化合物、其药学上可接受的盐、前药或溶剂化物在制备治疗或预防由激活或抗性突变体形式的ALK介导的障碍或疾病的药物中的用途；
    优选地，所述激活或抗性突变体形式的ALK介导的障碍或疾病为肺癌，卵巢癌、宫颈癌、结肠直肠癌、乳腺癌、胰腺癌、胶质瘤、胶质母细胞瘤、黑色素瘤、前列腺癌、白血病、淋巴瘤、非霍奇金淋巴瘤、胃癌、肺癌、肝细胞癌、胃肠道基质瘤、甲状腺癌、胆管 癌、子宫内膜癌、肾癌、间变性大细胞淋巴癌、急性髓细胞白血病、多发性骨髓瘤或间皮瘤。
  16. 一种药物组合物，所述的药物组合物包括治疗有效量的如权利要求1-14任意一项所述化合物、其药学上可接受的盐、前药或溶剂化物作为活性成分以及药学上可接受的载体或赋形剂。
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