WO2017008708A1 - 吲唑类化合物的制备方法和用途 - Google Patents

吲唑类化合物的制备方法和用途 Download PDF

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WO2017008708A1
WO2017008708A1 PCT/CN2016/089443 CN2016089443W WO2017008708A1 WO 2017008708 A1 WO2017008708 A1 WO 2017008708A1 CN 2016089443 W CN2016089443 W CN 2016089443W WO 2017008708 A1 WO2017008708 A1 WO 2017008708A1
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group
substituted
unsubstituted
dichloropyridin
cancer
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PCT/CN2016/089443
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French (fr)
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段文虎
耿美玉
严伟
丁健
艾菁
赵彬
范珺
彭霞
陈奕
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中国科学院上海药物研究所
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention relates to stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts thereof, prodrugs thereof, and hydrates or solvates thereof, of the carbazole compounds of the formula:
  • Protein kinases are proteins (enzymes) that regulate various cellular functions by phosphorylating specific amino acids on proteins. Proteins regulate activity and ability to bind to other components through changes in conformation.
  • the activity of a protein kinase refers to the rate at which a kinase binds a phosphate group to a substrate, and the rate can be determined by detecting the amount of substrate converted to a product over a period of time. Phosphorylation of the substrate occurs at the activation site of the protein kinase.
  • Tyrosine kinase is a proteinase that catalyzes the transfer of adenosine triphosphate to a protein tyrosine residue. These kinases play an important role in the growth factor-induced cell proliferation, differentiation and migration.
  • Fibroblast growth factor has been identified to have important regulatory roles in many physiological processes, such as organogenesis and angiogenesis. It is known that there are more than 25 subtypes in the FGF family, and the fibroblast growth factor receptor (FGFR) family contains four subtypes (FGFR1-4), all of which are glycoproteins, including extracellular immunity. The globulin region, the transmembrane hydrophobic region, and the tyrosine kinase region within the cytoplasm. Binding of FGF triggers FGFR dimerization, which in turn undergoes autophosphorylation of the receptor and activation of downstream signaling pathways. Certain specific components of the downstream signaling pathway play a very important role in cell growth, metabolism, and survival. Therefore, the FGFR signaling pathway plays an important physiological role in the multi-effect of tumor cell reproduction, migration, infiltration and angiogenesis.
  • FGFR signaling pathway plays an important physiological role in the multi-effect of tumor cell reproduction, migration, infiltration and angiogenesis.
  • the FGF signaling pathway is directly related to human cancer. Different FGF overexpression phenomena have been reported in different types of cancer cells (bladder cancer, kidney cancer, prostate cancer, etc.). Therefore, the FGF signaling pathway is a promising therapeutic target.
  • An object of the present invention is to provide a stereoisomer, a geometric isomer, a tautomer, a pharmaceutically acceptable salt thereof, a prodrug thereof and a hydrate thereof of a carbazole compound having a structure represented by the following formula (I) Solvate
  • Another object of the present invention is to provide a process for preparing the above carbazole compounds.
  • It is still another object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the group consisting of the above carbazole compounds, pharmaceutically acceptable salts thereof, prodrugs thereof, and hydrates or solvates thereof.
  • Still another object of the present invention is to provide a stereoisomer, a geometric isomer, a tautomer, a pharmaceutically acceptable salt thereof, a prodrug thereof, and a hydrate or solvate thereof selected from the above carbazole compounds.
  • One or more as a protein tyrosine kinase inhibitor, especially as a FGFR1-3 inhibitor, in the preparation of prophylaxis and/or treatment associated with abnormal expression of the FGF/FGFR signaling pathway Use in medicines for diseases.
  • R 1 , R 2 , R 3 are each independently selected from the group consisting of H, halogen;
  • R 9 is a substituted or unsubstituted 5-7 membered heteroaryl
  • R 8 and R 10 are each independently selected from the group consisting of H, halogen, C1-C3 alkyl, C1-C3 alkoxy;
  • R 4 , R 5 , R 6 , R 7 are each independently selected from the group consisting of H, halogen, substituted or unsubstituted 3-8 membered heterocycloalkylamino, substituted or unsubstituted C1-C8 alkyl, substituted Or an unsubstituted C1-C8 alkoxy group, a substituted or unsubstituted C1-C8 alkylene-hydroxy group, a substituted or unsubstituted 3-8 membered heterocyclic group, a substituted or unsubstituted 3-8 membered heterocyclic group -oxy, substituted or unsubstituted C1-C8 alkyl-3-8 membered heterocyclic group, substituted or unsubstituted C1-C8 alkylcarbamoyl group, substituted or unsubstituted 3-8 membered heterocyclic group - a C1-C8 alkylcarbamoyl group, a substituted or
  • a heterocyclic ring a substituted or unsubstituted C2-C8 alkyl-O-alkyl group, a substituted or unsubstituted C2-C8 amino-alkyl-carbonyl group, a substituted or unsubstituted C2-C8 amino-alkyl group,
  • the substituted or unsubstituted hydroxy-C1-C8 alkyl group, or Ra, Rb and the attached nitrogen atom together constitute a substituted or unsubstituted 5-7 membered heterocyclic group containing 1-3 hetero atoms selected from N, S, O. ring;
  • M is selected from the group consisting of CH 2 , CH, NH, N, O, S;
  • W is selected from O, NH;
  • said one or more hydrogen atoms on the substituent are substituted with a substituent selected from the group consisting of halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylene-hydroxyl , -Boc, a substituted or unsubstituted 5-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O;
  • the dashed line represents a single bond or a double bond, and the two dashed lines are not single or double bonds at the same time.
  • At least one of the two dashed lines is a double bond.
  • R 9 is not a group selected from the group consisting of:
  • R 6 is When M and W are both NH, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are all H, R 9 is not a group selected from the group consisting of:
  • R 6 is H
  • M and W are both NH
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are all H
  • R 9 is not selected from the group consisting of Group:
  • R 9 is selected from substituted or unsubstituted five- and six-membered heteroaryl groups.
  • said R 9 is selected from the group consisting of unsubstituted or substituted with from 1 to 4 substituents. a group of the following group: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl; wherein the substituent Selected from the group consisting of F, Cl, Br, methyl, methoxy, amino;
  • R 4 , R 5 , R 6 , and R 7 are each independently selected from H, halogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C1- C8 hydroxy-alkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted 3-8 membered heterocyclyl-oxy group, substituted or unsubstituted C1-C8 alkyl-hydroxy-alkyl group a hydroxy group, a substituted or unsubstituted C1-C8 alkyl-3-8 membered heterocyclic group, a substituted or unsubstituted C1-C8 alkylcarbamoyl group, a substituted or unsubstituted 3-8 membered heterocyclic group-C1 -C8 alkylcarbamoyl group, or Wherein, Ra and
  • a heterocyclic ring a substituted or unsubstituted C2-C8 alkyl-O-alkyl group, a substituted or unsubstituted C2-C8 amino-alkyl-carbonyl group, a substituted or unsubstituted C2-C8 amino-alkyl group,
  • the substituted or unsubstituted hydroxy-C1-C8 alkyl group, or Ra, Rb and the attached nitrogen atom together constitute a substituted or unsubstituted 5-7 membered heterocyclic group containing 1-3 hetero atoms selected from N, S, O. ring.
  • R 9 is of the following structure:
  • R 9a , R 9b , R 9c , R 9d , R 9e are each independently selected from H, halogen, C1-C3 alkyl, C1-C3 alkoxy, and preferably from H, F, Cl, Br, methyl and Methoxy
  • U, V, X, Y, Z are each independently selected from C, N, and at least one of them is N; and/or
  • R 8 and R 10 are each independently selected from the group consisting of H, F, Cl, Br, methyl and methoxy.
  • the compound has the structure represented by formula (III) or (IV):
  • R 9a , R 9b , R 9c , R 9d , R 9e are selected from the group consisting of H, halogen, methyl, ethyl, isopropylmethoxy;
  • R 4 , R 5 , R 6 , and R 7 are each independently selected from the group consisting of H, halogen, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, isopropylamino, dimethylamino.
  • the R 9 is a substituted or unsubstituted pyridyl group, wherein one or more hydrogen atoms on the substituent group are substituted with a substituent selected from the group consisting of halogen, C1-C4 alkyl.
  • the compound is selected from the compounds shown in Table 1.
  • a pharmaceutical composition comprising: (a) a therapeutically effective amount of a compound according to the first aspect of the invention, or a stereoisomer thereof, geometrically different A construct, tautomer, pharmaceutically acceptable salt or prodrug, hydrate or solvate thereof, or a combination thereof, and optionally (b) a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is for treating cancer; preferably, the cancer is selected from the group consisting of breast cancer, non-small cell lung cancer, bladder cancer, gastric cancer, pancreatic cancer, prostate cancer, Colon cancer, multiple myeloma, liver cancer, melanoma, head and neck cancer, thyroid cancer, renal cell carcinoma, glioblastoma, and testicular cancer.
  • a third aspect of the invention provides a compound according to the first aspect of the invention, or a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt or prodrug thereof, Use of a hydrate or solvate thereof, or a combination thereof, for the preparation of (i) a medicament for preventing and/or treating a cancer-related disease; (ii) inhibition as a protein tyrosine kinase (preferably FGFR) Agent.
  • FGFR protein tyrosine kinase
  • the tumor is selected from the group consisting of breast cancer, lung cancer, bladder cancer, gastric cancer, pancreatic cancer, prostate cancer, colon cancer, multiple myeloma AML, liver cancer, melanoma, head and neck cancer, and thyroid gland. Cancer, renal cell carcinoma, glioblastoma, and testicular cancer.
  • the tumor is selected from the group consisting of breast cancer, non-small cell lung cancer, bladder cancer, gastric cancer, pancreatic cancer, prostate cancer, colon cancer, multiple myeloma, liver cancer, melanoma, head and neck cancer, and thyroid gland. Cancer, renal cell carcinoma, glioblastoma, testicular cancer, or a combination thereof.
  • a protein tyrosine kinase enzyme activity inhibitor comprising an inhibitory effective amount of a compound according to the first aspect of the invention.
  • Fig. 1 is a graph showing the results of inhibition of growth of human lung cancer NCI-H1581 nude mice xenografts by compound I-46.
  • the inventors have prepared a class of compounds of formula I having tyrosine kinase inhibitory activity after a long and intensive study.
  • the compounds have higher inhibitory activity than the tyrosine kinase inhibitors of the prior art. Based on the above findings, the inventors completed the present invention.
  • substituted means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of C 1 -C 10 alkyl, C 3 -C 10 naphthenic a group, a C 1 -C 10 alkoxy group, a halogen, a hydroxyl group, a carboxyl group (-COOH), a C 1 -C 10 aldehyde group, a C 2 -C 10 acyl group, a C 2 -C 10 ester group, an amino group, a phenyl group;
  • the phenyl group includes an unsubstituted phenyl group or a substituted phenyl group having 1 to 3 substituents selected from the group consisting of halogen, C 1 -C 10 alkyl, cyano, OH, nitro, C 3 ⁇ C 10 cycloalkyl, C 1 -C 10 alkoxy, amino.
  • each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
  • C1-C8 alkyl refers to a straight or branched alkyl group having from 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, Tert-butyl, or a similar group.
  • 3-8 membered heterocyclic group refers to a group formed by a 3 to 8 membered saturated ring having from 1 to 3 hetero atoms selected from the group consisting of N, S, O, such as pyrrolidinyl group, Piperidinyl, piperazinyl, morpholinyl, or the like.
  • C1-C8 alkoxy refers to a straight or branched alkoxy group having from 1 to 8 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso Butoxy, sec-butoxy, tert-butoxy, or the like.
  • halogen refers to F, Cl, Br and I.
  • the definition of C 1 -C 4 alkyl is as defined above.
  • C2-C8 amino-alkyl refers to having "C 1 -C 4 alkylene-NH 2 ", “alkyl-N-alkylene- (total number of carbon atoms 1-4)", or " a group of (alkyl) 2 -N-alkylene-(having a total of 1-4 carbon atoms) structure, such as -CH 2 NH 2 , -C 2 H 5 NH 2 , -C 3 H 7 NH 2 , -C 2 H 4 N(CH 3 ) 2 , or a similar group.
  • the C 1 -C 4 alkylene group is a group in which a C 1 -C 4 alkyl group loses one hydrogen atom, and the C 1 -C 4 alkyl group has the same meaning as defined above.
  • the structural formulae described herein are intended to include all isomeric forms (such as enantiomeric, diastereomeric, and geometric isomers (or conformational isomers): for example, containing asymmetric centers The R, S configuration, the (Z), (E) isomers of the double bond, and the conformational isomers of (Z), (E).
  • isomeric forms such as enantiomeric, diastereomeric, and geometric isomers (or conformational isomers): for example, containing asymmetric centers
  • the individual stereochemical isomers of the compounds of the invention or their enantiomers Mixtures of isomers, diastereomers or geometric isomers (or conformational isomers) are within the scope of the invention.
  • tautomer means that structural isomers having different energies can exceed the low energy barrier and thereby transform each other.
  • proton tautomers ie, proton shifts
  • proton transfer such as 1H-carbazole with 2H-carbazole, 1H-benzo[d]imidazole, and 3H-benzo[d]imidazole.
  • Hydration tautomers include interconversions by some bonding electron recombination.
  • the present invention relates to a stereoisomer, a geometric isomer, a tautomer, a pharmaceutically acceptable salt thereof, a prodrug thereof, and a hydrate or solvent thereof of the carbazole compound represented by the formula (I).
  • M is selected from the group consisting of CH 2 , CH, NH, N, O, S;
  • W is selected from O, NH;
  • the dotted line represents a single bond or a double bond, and the two broken lines are not simultaneously a single bond or a double bond; in another preferred embodiment, at least one of the two broken lines is a double bond.
  • R 1 , R 2 , and R 3 are each independently selected from the group consisting of H, F, Cl, and Br;
  • R 9 is selected from the group consisting of a five-membered and six-membered heteroaryl group, preferably a substituted or unsubstituted group: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, oxazolyl, isoxazolyl , thiazolyl, isothiazolyl, furyl, the substituent is 1-4 substituents, each independently taken from F, Cl, Br, methyl, methoxy, amino.
  • R 8 and R 10 are each independently selected from the group consisting of H, halogen, C1-C3 alkyl, and C1-C3 alkoxy;
  • R 4 , R 5 , R 6 , and R 7 are each independently selected from H, F, Cl, Br, a substituted or unsubstituted amino group, a substituted or unsubstituted cycloalkylamino group, a substituted or unsubstituted heterocycloalkyl group.
  • substituted or unsubstituted alkyl substituted or unsubstituted alkoxy, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted alkylcycloalkane a substituted or unsubstituted alkylcarbamoyl group, a substituted or unsubstituted heteroalkylcarbamoyl group, a substituted or unsubstituted heterocycloalkylalkylcarbamoyl group, a substituted or unsubstituted heterocycloalkyl group, A substituted or unsubstituted alkoxyalkyloxy group.
  • R 9 is of the following structure:
  • R 9a , R 9b , R 9c , R 9d , and R 9e are each independently selected from the group consisting of H, halogen, C1-C3 alkyl, C1-C3 alkoxy, and preferably from H, F, Cl, Br, methyl and A. Oxygen.
  • U, V, X, Y, Z are each independently selected from C or N, and at least one of them is N;
  • the carbazole compound represented by the formula (I) is a compound represented by the following formula (III):
  • M is selected from the group consisting of CH 2 , CH, NH, N, O, S;
  • W is selected from O and NH.
  • R 1 , R 2 , and R 3 are preferably selected from H, F, Cl, and Br;
  • R 8 and R 10 are each independently selected from the group consisting of H, halogen, C1-C3 alkyl, C1-C3 alkoxy, and preferably from H, F, Cl, Br, methyl and methoxy. ;
  • R 9a , R 9b , R 9c , R 9d , and R 9e are each independently selected from the group consisting of H, halogen, C1-C3 alkyl, C1-C3 alkoxy, and preferably from H, F, Cl, Br, methyl and A. Oxygen.
  • U, V, X, Y, Z are each independently selected from C or N, and at least one of them is N;
  • R 4 , R 5 , R 6 , and R 7 are each independently selected from H, F, Cl, Br, a substituted or unsubstituted amino group, a substituted or unsubstituted cycloalkylamino group, a substituted or unsubstituted heterocycloalkyl group.
  • substituted or unsubstituted alkyl substituted or unsubstituted alkoxy, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted alkylcycloalkane a substituted or unsubstituted alkylcarbamoyl group, a substituted or unsubstituted heteroalkylcarbamoyl group, a substituted or unsubstituted heterocycloalkylalkylcarbamoyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted alkoxyalkyloxy group;
  • a more preferred carbazole compound represented by the formula (I) is a compound represented by the following formula (IV) or (V):
  • M is selected from the group consisting of CH 2 , CH, NH, N, O, S;
  • W is selected from O and NH.
  • R 1 , R 2 , and R 3 are preferably selected from H, F, Cl, and Br;
  • R 10 is independently selected from the group consisting of H, halogen, C1-C3 alkyl, C1-C3 alkoxy, and preferably from H, F, Cl, Br, methyl and methoxy. ;
  • R 9a , R 9b , R 9c , R 9d , and R 9e are each independently selected from the group consisting of H, halogen, C1-C3 alkyl, C1-C3 alkoxy, and preferably from H, F, Cl, Br, methyl and A. Oxygen.
  • U, V, X, Y, Z are each independently selected from C or N, and at least one of them is N;
  • R 4 , R 5 , R 6 , and R 7 are each independently selected from H, F, Cl, Br, a substituted or unsubstituted amino group, a substituted or unsubstituted cycloalkylamino group, a substituted or unsubstituted heterocycloalkylamino group.
  • the carbazole compound of the formula (I) of the present invention is selected from the compounds in Table 1 below.
  • the compounds of the present invention can also be prepared in the form of various pharmaceutically acceptable salts.
  • the preparation of the pharmaceutically acceptable salts of the compounds of the present invention can be carried out by direct salt formation with an inorganic or organic acid using the free base of the compound.
  • the inorganic or organic acid may be selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrofluoric acid, hydrobromic acid, formic acid, acetic acid, picric acid, citric acid, maleic acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonate. Acid and p-toluenesulfonic acid and the like.
  • the present invention also relates to four preparation methods of carbazole compounds having the structure of the general formula (I),
  • Method 1 includes the following steps:
  • a pyridine ring is substituted into an alcohol, and then a sulfonate is formed, which is then substituted into an ether, and then hydrazine is made into a carbazole aldehyde and finally cyclized to obtain a target product.
  • the preparation method includes the following steps:
  • Compound 5 is condensed with the corresponding o-phenylenediamine (2-aminophenol or 2-aminophenyl sulfide) compound to give the desired product.
  • Method 2 includes the following steps:
  • the preparation method includes the following steps:
  • Method 3 includes the following steps
  • the hydroxyl group is protected with silyl ether, then iodine is substituted, then nitrogen hydrogen is protected by tetrahydropyran, the silyl ether protecting group is removed, then substituted, and then coupled with the corresponding boric acid, and finally removed.
  • the tetrahydropyran protecting group gives the desired product.
  • the preparation method includes the following steps:
  • Method 4 includes the following steps
  • the compound is prepared from the compound 3 in the first method, substituted by sodium azide, reduced to an amine, and then coupled with bromine oxime to remove the protecting group, and then formed into an aldehyde, and finally cyclized to obtain the target product.
  • the preparation method comprises the following steps:
  • Compound 5 is condensed with the corresponding o-phenylenediamine (2-aminophenol or 2-aminophenyl sulfide) compound to give the desired product.
  • M, U, V, X, Y, Z, R 1 - R 10 are as defined and preferred above.
  • the preparation method of the carbazole compound of the invention has the advantages of mild reaction conditions, abundant raw materials, easy operation and post-treatment.
  • the carbazole compounds have been used as FGFR inhibitors in the treatment of cancer, for example, WO2010129509, US2003207883, US20060079564, etc., it is noted that the compounds of the present invention are included in the claims of US2003207883, US20060079564, but the specific examples thereof In the case where the carbazole 5-position substituent is not involved in the pyridine alkoxy group, the benzyloxy group is substituted, and the inventors have studied the literature and studied the crystal structure of the FGFR and found that the benzyloxy group was replaced.
  • the pyridine alkoxy group can significantly increase the inhibitory effect and selectivity of the compound on FGFR, because the pyridine nitrogen atom can form a hydrogen bond with Asn568 (Mol Cancer Ther; 10 (11), 2011), and the physical and chemical properties of the compound are improved. Its reproductive inhibitory activity against different cell lines is more pronounced, as can be seen in the examples of the invention (I-36 vs. I-38, I-37 vs. I-39).
  • the present inventors designed and synthesized a series of novel carbazole compounds, and through structural optimization, found that small molecule FGFR inhibitors with excellent activity in enzymes, cells, and animals have strong inhibition on FGFR1-3. In view of its role, this series of compounds is expected to be used clinically to treat diseases caused by abnormal expression of FGF/FGFR signaling pathway, such as cancer.
  • the present invention designs and synthesizes a series of novel compounds by studying the structure relationship between the crystal structure of FGFR and other tyrosine kinase inhibitors, and screening these compounds by molecular, cellular and animal models, and found that these compounds are
  • the molecular level can significantly inhibit the activity of FGFR enzyme, and the cell level can also significantly inhibit the proliferation of various cancer cells induced by FGFR, and can also significantly inhibit tumor growth in animals.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount selected from the group consisting of carbazole compounds of the formula (I), pharmaceutically acceptable salts thereof, prodrugs thereof, and hydrates and solvates thereof
  • a pharmaceutically acceptable carrier that can be used to treat a disease associated with cancer or the like.
  • the pharmaceutical composition can be prepared in various forms depending on the route of administration.
  • the present invention also relates to one or more selected from the group consisting of the carbazole compound of the above formula (I), a pharmaceutically acceptable salt thereof, a prodrug thereof, and hydrates and solvates thereof, or a therapeutically effective amount selected from the above
  • a pharmaceutical composition of one or more of the carbazole compound of the formula (I), a pharmaceutically acceptable salt thereof, a prodrug thereof, and a hydrate thereof and a solvate thereof for the treatment of a medicament for a cancer or the like Preferred as protein tyrosine kinase inhibitors, especially as FGFR inhibitors.
  • the FGFR includes one or more of FGFR1, FGFR2, and FGFR3.
  • the cancer includes breast cancer, lung cancer, bladder cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, multiple myeloma AML, liver cancer, melanoma, head and neck cancer, thyroid cancer, renal cell carcinoma, glioblastoma , and testicular cancer. More specifically, these cancers are selected from the group consisting of breast cancer, non-small cell lung cancer, bladder cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, multiple myeloma, liver cancer, melanoma, head and neck cancer, thyroid cancer, and renal cells. Cancer, glioblastoma, and testicular cancer.
  • the present invention provides a pharmaceutical composition comprising the compound or salt of the present invention as an active ingredient for treating cancer, wherein the cancer is selected from the group consisting of breast cancer, non-small cell lung cancer, bladder cancer, stomach cancer, pancreatic cancer, prostate cancer , colon cancer, multiple myeloma, liver cancer, melanoma, head and neck cancer, thyroid cancer, renal cell carcinoma, glioblastoma, and testis Pill cancer and so on.
  • Step 6 Preparation of 3-(6-([1,4'-bipiperidino]-1'-yl)-1H-benzo[d]imidazol-2-yl)-5-(1-3,5-dichloro Pyridin-4-yl)ethoxy)-1H-carbazole
  • Step 4 2–(2–(5–(1-(3,5-Dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-1H-benzo[d]imidazole -6-yl)ethanol
  • Step 2 Preparation of 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(6-(4-methylpiperazin-1-yl)-1H-benzo[ d]imidazol-2-yl)-1H-carbazole
  • Step 2 Preparation of 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(6-(piperidin-1-yl)-1H-benzo[d]imidazole- 2-based)-1H-carbazole
  • Step 1 Preparation of N 1 -methyl-N 1 -(1-methylpiperidin-4-yl)-4-nitrobenzene-1,3-diamine
  • Step 2 2-(5-(1-(3,5-Dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-N-methyl-N-(1-A Isopiperidin-4-yl)-1H-benzo[d]imidazole-6-amine
  • Step 2 Preparation of 2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-N-methyl-1H-benzo[ d] imidazole-6-amine
  • Step 1 Preparation of 2-bromo-N-(2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-1H-benzene And [d]imidazole-6-yl)-N-methylacetamide
  • Step 4 Preparation of N-(2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-1H-benzo[d] Imidazol-6-yl)-2-(dimethylamino)-N-methylacetamide
  • the 3,5-dichloropyridine was replaced by 3-chloropyridine, and the remaining raw materials, reagents and preparation methods were the same as those in the first step of Example 1, to obtain beige crystal 1-(3-chloropyridin-4-yl)ethanol.
  • the 1-(3,5-dichloropyridin-4-yl)ethanol is replaced by 1-(3-chloropyridin-4-yl)ethanol, and the remaining raw materials, reagents and preparation methods are the same as those in the first embodiment.
  • a pale brown oil of 1-(3-chloropyridin-4-yl)ethyl methanesulfonate was obtained.
  • Step 5 Preparation of 5-(1-(3-chloropyridin-4-yl)ethoxy)-3-(5-(piperidin-1-yl)-1H-benzo[d]imidazole-2- -1H-carbazole
  • the 1-(3,5-dichloropyridin-4-yl)ethanol is replaced by 1-(3-fluoropyridin-4-yl)ethanol, and the remaining materials, reagents and preparation methods are the same as those in the first embodiment.
  • a pale brown oil of 1-(3-fluoropyridin-4-yl)ethyl methanesulfonate was obtained.
  • Step 5 Preparation of 5-(1-(3-fluoropyridin-4-yl)ethoxy)-3-(5-(piperidin-1-yl)-1H-benzo[d]imidazol-2-yl )-1H-carbazole
  • Step 2 Preparation of 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(5-((3R,5S)-3,5-dimethylpiperazine-1 -yl)-1H-benzo[d]imidazol-2-yl)-1H-carbazole
  • Step 2 Preparation of 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(5-(4-methyl-1,4-diazepane-1 -yl)-1H-benzo[d]imidazol-2yl)-1H-carbazole
  • Step 2 Preparation of 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(6-(4-ethylpiperazin-1-yl)-1H-benzo[ d]imidazol-2-yl)-1H-carbazole
  • Step 2 Preparation of 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(6-(4-isopropylpiperazin-1-yl)-1H-benzo [d]imidazol-2-yl)-1H-carbazole
  • Step 3 in Example 1 gave 5-(1-(pyridin-4-yl)ethoxy)-1H-indole as a reddish brown oil.
  • Step 5 Preparation of 5-(1-(pyridin-4-yl)ethoxy)-3-(5-(piperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-1H -carbazole
  • Step 5 Preparation of 5-(1-(3-chloro-5-fluoropyridin-4-yl)ethoxy)-3-(5-(piperidin-1-yl)-1H-benzo[d]imidazole -2-yl)-1H-carbazole
  • Step 1 2-(5-(1-(3,5-Dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)benzo[d]oxazole
  • Step 3 Preparation of 5-((tert-butyldimethylsilyl)oxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-carbazole
  • Step 5 Preparation of 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indole Azole
  • Step 8 Preparation of 2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-carbazole -3-yl)-1H-indole-1-carboxylic acid tert-butyl ester
  • Step 9 Preparation of 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(1H-indol-2-yl)-1H-carbazole
  • Step 1 Preparation of N 1 ,N 1 -(2-(dimethylamino)ethyl)-4-nitrobenzene-1,2-diamine
  • Step 2 Preparation of N 1 -(2-(5-(1-(3,5-dichloropyridin-4-yl)methoxy)-1H-indol-3-yl)-1H-benzo[d Imidazolium-6-yl)-N 2 ,N 2 -dimethylethane-1,2-diamine
  • Step 1 Preparation of N 1 ,N 1 -(2-(diethylamino)ethyl)-4-nitrobenzene-1,2-diamine
  • Step 2 N 1 -(2-(5-(1-(3,5-Dichloropyridin-4-yl)methoxy)-1H-indol-3-yl)-1H-benzo[d] Imidazolium-6-yl)-N 2 ,N 2 -diethylethane-1,2-diamine
  • Step 1 Preparation of N 1 ,N 1 -(3-(dimethylamino)propyl)-4-nitrobenzene-1,3-diamine
  • Step 2 N 1 -(2-(5-(1-(3,5-Dichloropyridin-4-yl)methoxy)-1H-indol-3-yl)-1H-benzo[d] Imidazolium-6-yl)-N 3 ,N 3 -dimethylpropane-1,3-diamine
  • Step 1 Preparation of tert-butyl 4-(3-amino-4-nitrophenyl)piperazine-1-carboxylate
  • Step 2 Preparation of 4-(2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-1H-benzo[d] Imidazom-6-yl)piperazine-1-carboxylic acid tert-butyl ester
  • Step 1 Preparation of 4-oxopiperidine-1-carboxylic acid tert-butyl ester
  • Step 2 Preparation of 4-trifluoromethylsulfonyloxy-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester
  • Step 3 Preparation of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-formic acid Tert-butyl ester
  • Step 4 Preparation of 4-(4-amino-3-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester
  • Step 5 Preparation of 4-(2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-1H-benzo[d] Imidazom-6-yl)piperidine-1-carboxylic acid tert-butyl ester
  • Step 4 Preparation of 4-(4-acetamidophenyl)-1-methylpyridine-1-indole methyl sulfate
  • Step 8 Preparation of 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(6-(1-methylpiperidin-4-yl)-1H-benzo[ d]imidazol-2-yl)-1H-carbazole
  • Step 2 Preparation of 2-(4-(2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-1H-benzo [d]imidazol-6-yl)piperazin-1-yl)ethanol
  • Step 1 Preparation of 4-nitro-N 1 -(2-(pyrrolidin-1-yl)ethyl)benzene-1,3-diamine
  • Step 2 Preparation of 2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-N-(2-(pyrrolidin-1) -yl)ethyl)-1H-benzo[d]imidazole-6-amine
  • Step 1 Preparation of N 1 -(2-methoxyethyl)-4-nitrobenzene-1,3-diamine
  • Step 2 Preparation of 2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-N-(2-methoxyethyl )-1H-benzo[d]imidazole-6-amine
  • the 5-hydroxyindole is replaced by 6-fluoro-1-H-indol-5-ol, and the remaining raw materials, reagents and preparation methods are the same as those in the first step of Example 1, to obtain a colorless oil 5-(1) -(3,5-Dichloropyridin-4-yl)ethoxy)-6-fluoro-1H-indole 1.2 g.
  • Step 6 5-(1-(3,5-Dichloropyridin-4-yl)ethoxy)-6-fluoro-3-(6-(piperidin-1-yl)-1H-benzo[d Imidazol-2-yl)-1H-carbazole
  • the 5-hydroxyindole is replaced by 4-fluoro-1-H-indol-5-ol, and the remaining raw materials, reagents and preparation methods are the same as those in the first step in Example 1, to obtain a colorless oil 5-(1) -(3,5-Dichloropyridin-4-yl)ethoxy)-4-fluoro-1H-indole.
  • Step 3 Preparation of 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-4-fluoro-3-(6-(piperidin-1-yl)-1H-benzo[ d]imidazol-2-yl)-1H-carbazole
  • Step 6 3-(6-([1,4'-Piperidyl]-1'-yl)-1H-benzo[d]imidazol-2-yl)-5-((3,5-dichloropyridine- 4-yl)methoxy)-1H-carbazole
  • Step 3 3-(6-([1,4'bipiperidinyl]-1'-yl)-1H-benzo[d]imidazol-2-yl)-5-((2,6-dichlorobenzyloxy) -1H-carbazole
  • Step 4 3-(6-(piperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-5-(pyridine-2-methoxy)-1H-carbazole
  • Step 4 3-(6-(piperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-5-(pyridine-3-methoxy)-1H-carbazole
  • Step 4 Preparation of 3-(6-(piperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-5-(pyridine-4-methoxy)-1H-carbazole
  • step 2 the white waxy solid 1-(3,5-dichloropyridin-4-yl)propyl methanesulfonate was obtained.
  • Step 5 Preparation of 5-(1-(3,5-dichloropyridin-4-yl)propoxy)-3-(6-(piperidin-1-yl)-1H-benzo[d]imidazole- 2-based)-1H-carbazole
  • Example 2 gave (R)-2-(2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-1H- Benzo[d]imidazol-6-yl)ethanol
  • Example 4 gave (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(6-(piperidin-1-yl)-1H-benzo [d]imidazol-2-yl)-1H-carbazole.
  • Example 3 gave (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(6-(4-methylpiperazin-1-yl)- 1H-benzo[d]imidazol-2-yl)-1H-carbazole
  • Example 10 gave (R)-N-(2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-1H-benzene And [d]imidazol-6-yl)-2-(dimethylamino)-N-methylacetamide
  • the 3,5-dichloropyridine was replaced with 2,4-dichloropyridine, and the remaining raw materials, reagents and preparation methods were the same as those in the first step of Example 1, to obtain a colorless oil 1-(2,4-dichloro Pyridin-3-yl)ethanol.
  • Step 5 Preparation of 5-(1-(2,4-dichloropyridin-3-yl)ethoxy)-3-(6-(piperidin-1-yl)-1H-benzo[d]imidazole- 2-based)-1H-carbazole
  • Step 2 Preparation of 3-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy) -1H-carbazole
  • Step 2 Preparation of 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(6-fluoro-5-(piperidin-1-yl)-1H-benzo[ d]imidazol-2-yl)-1H-carbazole
  • Step 2 Preparation of 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(5-(2-methoxyethoxy)-1H-benzo[d] Imidazolyl-2-yl)-1H-carbazole
  • Step 2 Preparation of 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(7-(piperidin-1-yl)-1H-benzo[d]imidazole- 2-based-1H-carbazole
  • Step 2 Preparation of 3-(7-chloro-1H-benzo[d]imidazol-2-yl)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H- Carbazole
  • Step 4 Preparation of 3-(5-(piperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-N-(pyridin-4-ylmethyl)-1H-indazole-5 -amine
  • the 4-pyridinecarboxaldehyde was replaced with 3,5-dichloro-4-pyridinecarboxaldehyde, and the remaining remaining starting materials, reagents and preparation methods were the same as those in the step 2 in Example 56 to obtain a light brown oil N-((3,5) -Dichloropyridin-4-yl)methyl)-1H-indole-5-amine.
  • Step 3 Preparation of N-((3,5-dichloropyridin-4-yl)methyl)-3-(5(piperidin-1-yl)-1H-benzo[d]imidazol-2-yl) -1H-carbazole-5-amine
  • Step 3 Preparation of tert-butyl-5-((1-(3,5-dichloropyridin-4-yl)ethyl)amino)-1H-indole-1-carboxylate
  • Step 5 Preparation of 5-((1-(3,5-dichloropyridin-4-yl)ethyl)amino)-1H-indazole-3-carbaldehyde
  • Step 6 Preparation of N-(1-(3,5-dichloropyridin-4-yl)ethyl)-3-(5(piperidin-1-yl)-1H-benzo[d]imidazole-2- -1H-carbazole-5-amine
  • the 3,5-dichloropyridine is replaced by 3-chloropyridine, and the acetaldehyde is replaced by N,N-dimethylformamide.
  • the remaining raw materials, reagents and preparation methods are the same as those in the first step in the first embodiment. Solid 3-chloroisonicotinaldehyde.
  • the 1-(3,5-dichloropyridin-4-yl)ethanol is replaced by (3-chloropyridin-4-yl)methanol, and the remaining raw materials, reagents and preparation methods are the same as those in the second step of the first embodiment.
  • Step 6 5-((3-Chloropyridin-4-yl)methoxy)-3-(5-(piperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-1H -carbazole
  • Example 4 gave (S)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(6-(piperidin-1-yl)-1H-benzo [d]imidazol-2-yl)-1H-carbazole.
  • Example 3 gave (S)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(6-(4-methylpiperazin-1-yl)- 1H-benzo[d]imidazol-2-yl)-1H-carbazole
  • the enzyme reaction substrate Poly(Glu, Tyr) 4:1 was diluted with potassium-free PBS (10 mM sodium phosphate buffer, 150 mM NaCl, pH 7.2-7.4) to 20 ⁇ g/mL, 125 ⁇ L/well coated with the enzyme plate. The reaction was carried out at 37 ° C for 12-16 hours. After discarding the liquid in the well, the plate was washed, and the plate was washed three times with 200 ⁇ L/well of T-PBS (PBS containing 0.1% Tween-20) for 5 minutes each time. The plate was dried in an oven at 37 ° C for 1-2 hours.
  • reaction buffer 50 mM HEPES pH 7.4, 50 mM MgCl 2 , 0.5 mM MnCl 2 , 0.2 mM Na 3 VO 4 , 1 mM DTT
  • the compound was diluted with DMSO to a suitable concentration, 1 ⁇ L/well or containing the corresponding concentration of DMSO (negative control well), and then the FGFR1, FGFR2 kinase domain recombinant protein diluted with 49 ⁇ L of reaction buffer was added to initiate the reaction, and each experiment was required.
  • the reaction was carried out for 1 hour at 37 ° C on a shaker (100 rpm).
  • the plate was washed three times with T-PBS.
  • One anti-PY99 dilution was added to 100 ⁇ L/well, and the reaction was shaken at 37 ° C for 0.5 hour.
  • the plate was washed three times with T-PBS.
  • a second anti-horseradish peroxidase-labeled goat anti-mouse IgG dilution was added at 100 ⁇ L/well, and shaken at 37 ° C for 0.5 hour.
  • the plate was washed three times with T-PBS.
  • the inhibition rate of the sample is obtained by the following formula:
  • IC 50 values were obtained by four-parameter regression using software attached to the microplate reader.
  • the enzyme activity test at the molecular level showed that the carbazole compound of the present invention has a good inhibitory effect on FGFR1 tyrosine kinase at a concentration of nM, and the half-inhibition concentration of some compounds on FGFR1 is about 1 nM, which is a strong class.
  • a potent FGFR1 tyrosine kinase inhibitor is a potent FGFR1 tyrosine kinase inhibitor.
  • A indicates an IC 50 of less than 10 nM
  • C means IC 50 is greater than 100nM
  • CCK-8 cell counting kit Doj indo for growth inhibition of BaF3/TEL-FGFR1 cells (in which TEL-FGFR1 kinase domain fusion protein is stably expressed in the cytosol, FGFR1 is continuously activated, is a FGFR1-dependent cell line) ) Detection.
  • the specific steps are as follows: BaF3/TEL-FGFR1 cells in logarithmic growth phase are inoculated into 96-well culture plates at a suitable density, 90 ⁇ L per well, and cultured overnight, different concentrations of compounds are added for 72 hr, and a solvent control group is set ( Negative control).
  • the carbazole compound of the present invention has a good proliferation inhibitory effect on BaF3/TEL-FGFR1 cells at a concentration of nM, and the half inhibitory concentration of some compounds on BaF3/TEL-FGFR1 cells is About 1nM.
  • A indicates that the IC 50 is less than 8nM
  • C means IC 50 is less than 200nM
  • CCK-8 cell counting kit for growth inhibition of acute myeloid leukemia cell line KG1 cells (FGFR1OP2-FGFR1 kinase domain fusion protein stably expressed in cytoplasm, FGFR1 sustained activation, FGFR1-dependent cell line) Dojindo) detection.
  • the specific steps are as follows: KG1 cells in logarithmic growth phase were inoculated into 96-well culture plates at a suitable density, 90 ⁇ L per well, and after incubation overnight, different concentrations of compounds were added for 72 hr, and a solvent control group (negative control) was set. After the compound was treated for 72h, the effect of the compound on cell proliferation was detected by CCK-8 cell counting kit (Dojindo).
  • inhibition rate (%) (OD negative control well-OD administration well) / OD negative control well ⁇ 100%.
  • IC 50 values were obtained by four-parameter regression using software attached to the microplate reader.
  • the carbazole compound of the present invention has a good proliferation inhibitory effect on the acute myeloid leukemia cell line KG1 at a concentration of nM, and the half inhibitory concentration of most compounds on KG1 cells is Below 10nM.
  • the pyridine ring compound I-36 inhibited the proliferation of KG1 cells by 59.7% at a concentration of 40 nM, and the half-inhibition concentration of the benzene ring compound I-38 exceeded 200 nM.
  • A indicates that the IC 50 is less than 8nM
  • C means IC 50 is less than 200nM
  • the compound was detected by the CCK-8 cell counting kit (Dojindo) for the growth inhibition assay of gastric cancer cell line KATOIII cells (gastric cancer cell line, FGFR2 gene amplification leads to continuous activation of FGFR2, which is an FGFR2-dependent cell line).
  • the specific steps are as follows: KATOIII cells in logarithmic growth phase were inoculated into 96-well culture plates at a suitable density, 90 ⁇ L per well, and cultured overnight, different concentrations of compounds were added for 72 hr, and a solvent control group (negative control) was set. After the compound was treated for 72h, the effect of the compound on cell proliferation was detected by CCK-8 cell counting kit (Dojindo).
  • inhibition rate (%) (OD negative control well-OD administration well) / OD negative control well ⁇ 100%.
  • IC 50 values were obtained by four-parameter regression using software attached to the microplate reader.
  • the carbazole compound of the present invention has a good proliferation inhibitory effect on the gastric cancer cell line KATOIII at a concentration of nM.
  • A indicates that the IC 50 is less than 8nM
  • C means IC 50 is less than 200nM
  • the tumor tissue in the vigorous growth period was cut into 1.5 mm 3 and inoculated subcutaneously in the right axilla of nude mice under aseptic conditions.
  • the diameter of the transplanted tumor was measured by a vernier caliper in a nude mouse subcutaneous transplanted tumor, and the animals were randomly divided into groups after the average tumor volume was grown to about 115 mm 3 .
  • I-46 10 mg/kg and 2 mg/kg groups were orally administered once a day for 21 days; the positive control drug AZD4547 20 mg/kg group was administered orally once a day for 21 days; the solvent control group was given Solvent.
  • the diameter of the transplanted tumor was measured twice a week during the entire experiment, and the body weight of the mice was weighed.
  • TGI% [1-(TVt-TV 0 ) / (CVt - CV 0 )] ⁇ 100%
  • TVt is the tumor volume measured by the treatment group each time
  • TV 0 is The tumor volume obtained when the therapeutic component was administered by the cage
  • CVt was the tumor volume measured per control group
  • CV 0 was the tumor volume obtained when the control group was administered in a cage.
  • Figure 1 The experimental results showed that the TGI% of the compound of the present invention I-46 under the conditions of 10 mg/kg and 2 mg/kg were 96.9% and 44.5%, respectively, which was higher than the TGI% of the positive control drug AZD4547 20 mg/kg. %), with excellent inhibition.

Abstract

本发明提供了一种吲唑类化合物的制备方法和用途，具体地，本发明提供了一种如下式(I)所示的化合物，其中，各基团的定义如说明书中所述。本发明化合物具有优异的酪氨酸激酶抑制活性，相较于现有技术中的化合物，本发明化合物具有更低的抑制浓度，故能够用于制备一系列治疗与酪氨酸激酶活性相关的疾病的药物。

Description

吲唑类化合物的制备方法和用途 技术领域
本发明涉及如式所示结构的吲唑类化合物的立体异构体、几何异构体、互变异构体、其药用盐、其前药及其水合物或溶剂合物，也涉及所述化合物的制备方法、包含所述化合物的药物组合物以及其作为蛋白酪氨酸激酶抑制剂，特别是作为FGFR抑制剂，在治疗癌症等相关疾病的药物中的用途。
背景技术
蛋白激酶是一种通过对蛋白质上特定氨基酸的磷酸化来调节各种细胞功能的蛋白质(酶)。蛋白质通过构象的改变来调节活性以及与其他组分结合能力。蛋白质激酶的活性指的是，激酶将磷酸基团结合到底物上的速率，该速率可以通过检测一定时间内转化为产物的底物的量来进行测定。底物的磷酸化发生在蛋白质激酶的活化位点上。
酪氨酸激酶是一种可以催化将三磷酸腺苷转移到蛋白质酪氨酸残基的蛋白质酶。这些激酶在生长因子传导引发细胞增殖、分化和迁移过程中扮演者重要的角色。
成纤维细胞生长因子(FGF)已经被确认在许多生理过程中有重要的调节作用，例如器官生成和血管生成等等。目前已知，在FGF家族中有超过25种亚型，成纤维细胞生长因子受体(FGFR)家族共包含四个亚型(FGFR1-4)，他们都是糖蛋白，包含细胞外的类免疫球蛋白区域、跨膜的疏水区域和细胞质内的酪氨酸激酶区域。FGF的结合引发FGFR二聚，进而发生受体的自磷酸化和下游信号通路的活化。下游信号通路的某些特定组分对于细胞生长、代谢和存活有非常重要的作用。因此，FGFR信号通路对于肿瘤细胞的繁殖、迁移、浸润和血管生成有多效性的重要生理作用。
目前，已有证据表明FGF信号通路与人类癌症有直接的关联。在不同种类的癌细胞中(膀胱癌、肾癌和前列腺癌等等)都被报道出有不同的FGF过表达现象。因此，FGF信号通路是一个有前景的治疗靶点。
综上所述，本领域迫切需要开发新型的酪氨酸激酶抑制剂。
发明内容
本发明的一个目的在于提供具有下式(I)所示结构的吲唑类化合物的立体异构体、几何异构体、互变异构体、其药用盐、其前药及其水合物或溶剂合物
Figure PCTCN2016089443-appb-000001
本发明的另一个目的在于提供制备上述吲唑类化合物的方法。
本发明的再一个目的在于提供包含治疗有效量的选自上述吲唑类化合物、其药用盐、其前药及其水合物或溶剂合物中的一种或多种的药物组合物。
本发明的又一个目的在于提供选自上述吲唑类化合物的立体异构体、几何异构体、互变异构体、其药用盐、其前药及其水合物或溶剂合物中的一种或多种作为蛋白酪氨酸激酶抑制剂，尤其是作为FGFR1-3抑制剂，在制备预防和/或治疗与FGF/FGFR信号通路异常表达相关 疾病的药物中的用途。
本发明的第一方面，提供了一种如下式(I)所示的化合物：
Figure PCTCN2016089443-appb-000002
其中：
R1、R2、R3各自独立地选自下组：H、卤素；
R9为取代或未取代的5-7元杂芳基；
R8、R10各自独立地选自下组：H、卤素、C1～C3烷基、C1～C3烷氧基；
R4、R5、R6、R7各自独立地选自下组：H、卤素、取代或未取代的3-8元杂环烷基氨基、取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷氧基、取代或未取代的C1-C8亚烷基-羟基、取代或未取代的3-8元杂环基、取代或未取代的3-8元杂环基-氧基、取代或未取代的C1-C8烷基-3-8元杂环基、取代或未取代的C1-C8烷基氨基甲酰基、取代或未取代的3-8元杂环基-C1-C8烷基氨基甲酰基、取代或未取代的C1-C8烷氧基-烷基-氧基，或
Figure PCTCN2016089443-appb-000003
其中，Ra、Rb各自独立地选自下组：H、取代或未取代的C1-C8烷基、含1-3个选自N、S、O的杂原子的取代或未取代的5-7元杂环、取代或未取代的C2-C8烷基-O-烷基、取代或未取代的C2-C8胺基-烷基-羰基、取代或未取代的C2-C8胺基-烷基、取代或未取代的羟基-C1-C8烷基、或Ra、Rb与相连的氮原子共同构成含1-3个选自N、S、O的杂原子的取代或未取代的5-7元杂环；
M选自下组：CH2、CH、NH、N、O、S；
W选自O、NH；
其中，所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C1-C8烷基、C1-C8烷氧基、C1-C8亚烷基-羟基、-Boc、含1-3个选自N、S、O的杂原子的取代或未取代的5-7元杂环；
虚线代表单键或双键，且两条虚线不同时为单键或双键。
在另一优选例中，两条虚线中至少有一条为双键。
在另一优选例中，当R6为
Figure PCTCN2016089443-appb-000004
M、W均为NH，R1、R2、R3、R4、R5、R6、R7、R8均为H时，R9不为选自下组的基团：
Figure PCTCN2016089443-appb-000005
Figure PCTCN2016089443-appb-000006
当R6为
Figure PCTCN2016089443-appb-000007
M、W均为NH、R1、R2、R3、R4、R5、R6、R7、R8均为H时，R9不为选自下组的基团：
Figure PCTCN2016089443-appb-000008
当R6为H，M、W均为NH、R1、R2、R3、R4、R5、R6、R7、R8均为H时，R9不为选自下组的基团：
Figure PCTCN2016089443-appb-000009
在另一优选例中，R9选自取代或未取代的五元及六元杂芳基，优选地，所述的R9选自未取代的或被1-4个取代基取代的选自下组的基团：吡啶基、嘧啶基、吡嗪基、哒嗪基、三嗪基、噁唑基、异恶唑基、噻唑基、异噻唑基、呋喃基；其中，所述的取代基选自下组：F、Cl、Br、甲基、甲氧基、氨基；
R4、R5、R6、R7分别独立的选自H、卤素、取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷氧基、取代或未取代的C1-C8羟基-烷基、取代或未取代的3-8元杂环基、取代或未取代的3-8元杂环基-氧基、取代或未取代的C1-C8烷基-羟基-烷基-羟基、取代或未取代的C1-C8烷基-3-8元杂环基、取代或未取代的C1-C8烷基氨基甲酰基、取代或未取代的3-8元杂环基-C1-C8烷基氨基甲酰基，或
Figure PCTCN2016089443-appb-000010
其中，Ra、Rb各自独立地选自下组：H、取代或未取代的C1-C8烷基、含1-3个选自N、S、O的杂原子的取代或未取代的5-7元杂环、取代或未取代的C2-C8烷基-O-烷基、取代或未取代的C2-C8胺基-烷基-羰基、取代或未取代的C2-C8胺基-烷基、取代或未取代的羟基-C1-C8烷基、或Ra、Rb与相连的氮原子共同构成含1-3个选自N、S、O的杂原子的取代或未取代的5-7元杂环。
在另一优选例中，R9为以下结构：
Figure PCTCN2016089443-appb-000011
其中：
R9a、R9b、R9c、R9d、R9e各自独立地选自H、卤素、C1～C3烷基、C1～C3烷氧基，并优选自H、F、Cl、Br、甲基和甲氧基；
U、V、X、Y、Z各自独立地选自C、N，且其中至少一个为N；和/或
R8、R10各自独立地选自H、F、Cl、Br、甲基和甲氧基。
在另一优选例中，所述化合物具有式(III)或(IV)所示的结构：
Figure PCTCN2016089443-appb-000012
其中：
R9a、R9b、R9c、R9d、R9e选自下组：H、卤素、甲基、乙基、异丙基甲氧基；
R4、R5、R6、R7各自独立地选自下组：H、卤素、甲氧基、乙氧基、异丙氧基、甲氨基、乙氨基、异丙氨基、二甲基氨基、二乙基氨基、二异丙基氨基、(1-甲基哌啶)-甲基-氨基、哌啶基、1-甲基哌啶基、1-乙基哌啶基、1-异丙基哌啶基、1-Boc哌啶基、吡咯烷基、哌嗪基、1-甲基哌嗪基、1-乙基哌嗪基、1-异丙基哌嗪基、1-羟基乙基哌嗪基、1-甲氧基乙基哌嗪基、1-甲氨基乙基哌嗪基、1-Boc-哌嗪基、2,6-二甲基哌嗪基、高哌嗪基、1-甲基高哌嗪基、1-乙 基高哌嗪基、1-异丙基高哌嗪基、吗啉基、C1～C3二甲基氨基烷基氨基、C1～C3二乙基氨基烷基氨基、C1～C3二异丙基氨基烷基氨基、C1～C3吡咯烷烷基氨基、C1～C3哌啶烷基氨基、C1～C3羟基烷基、C1～C3氨基烷基、C1～C3甲氧基烷基氨基、C1～C3乙氧基烷基氨基、C1～C3异丙氧基烷基氨基、C1～C3甲氧基烷基、C1～C3乙氧基烷基、C1～C3异丙氧基烷基、二甲基氨基乙酰基氨基、二乙基氨基乙酰基氨基、二异丙基氨基乙酰基氨基、二甲基氨基丙酰基氨基、二乙基氨基丙酰基氨基、二异丙基氨基丙酰基氨基、甲氧基乙基氧基、乙氧基乙基氧基、甲氧基丙基氧基、乙氧基丙基氧基。
在另一优选例中，所述的R9为取代或未取代的吡啶基，其中，取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C1-C4烷基。
在另一优选例中，所述的化合物选自表1中所示的化合物。
本发明的第二方面，提供了一种药物组合物，所述的药物组合物包括：(a)治疗有效量的如本发明第一方面所述的化合物，或其立体异构体、几何异构体、互变异构体、药学上可接受的盐或前药、其水合物或溶剂合物，或其组合，以及任选的(b)药学上可接受的载体。
在另一优选例中，所述的药物组合物用于治疗癌症；较佳地，所述的癌症选自下组：乳腺癌、非小细胞肺癌、膀胱癌、胃癌、胰腺癌、前列腺癌、结肠癌、多发性骨髓瘤、肝癌、黑色素瘤、头颈癌、甲状腺癌、肾细胞癌、胶质母细胞癌、和睾丸癌等等。
本发明的第三方面，提供了一种如本发明第一方面所述的化合物，或其立体异构体、几何异构体、互变异构体、药学上可接受的盐或前药、其水合物或溶剂合物，或其组合的用途，其特征在于，用于制备(i)预防和/或治疗癌症相关疾病的药物；(ii)作为蛋白酪氨酸激酶(优选为FGFR)抑制剂。
在另一优选例中，所述的肿瘤选自下组：乳腺癌、肺癌、膀胱癌、胃癌、胰腺癌、前列腺癌、结肠癌、多发性骨髓瘤AML、肝癌、黑色素瘤、头颈癌、甲状腺癌、肾细胞癌、胶质母细胞癌、和睾丸癌。
在另一优选例中，所述的肿瘤选自：乳腺癌、非小细胞肺癌、膀胱癌、胃癌、胰腺癌、前列腺癌、结肠癌、多发性骨髓瘤、肝癌、黑色素瘤、头颈癌、甲状腺癌、肾细胞癌、胶质母细胞癌、睾丸癌，或其组合。
本发明的第四方面，提供了一种蛋白酪氨酸激酶酶活抑制剂，所述抑制剂含有抑制有效量的如本发明第一方面所述的化合物。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1为化合物I-46对人肺癌NCI-H1581裸小鼠移植瘤的生长抑制作用结果图。
具体实施方式
本发明人经过长期而深入的研究，制备得到了一类具有酪氨酸激酶抑制活性的式I化合物。与现有技术中的酪氨酸激酶抑制剂相比，所述的化合物具有更高的抑制活性。基于上述发现，发明人完成了本发明。
术语
在本文中，除特别说明之处，术语“取代”指基团上的一个或多个氢原子被选自下组的取代基取代：C1～C10烷基、C3～C10环烷基、C1～C10烷氧基、卤素、羟基、羧基(-COOH)、C1～C10醛基、C2～C10酰基、C2～C10酯基、氨基、苯基；所述的苯基包括未取代的苯基或具有1-3个取代基的取代苯基，所述取代基选自：卤素、C1-C10烷基、氰基、OH、硝基、C3～C10环烷基、C1～C10烷氧基、氨基。
除特别说明之处，本发明的所有化合物之中，各手性碳原子可以任选地为R构型或S构型，或R构型和S构型的混合物。
术语“C1～C8烷基”指具有1～8个碳原子的直链或支链烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、或类似基团。
术语“3-8元杂环基”指具有选自下组的1-3个杂原子的3～8元饱和环失去一个氢原子形成的基团：N、S、O，例如吡咯烷基、哌啶基、哌嗪基、吗啉基、或类似基团。
术语“C1～C8烷氧基”指具有1-8个碳原子的直链或支链烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基、或类似基团。
术语“卤素”指F、Cl、Br和I。
术语“C2-C8胺基-烷基-羰基”指具有“羰基-C2～C8亚烷基-NH2”、“烷基-N-亚烷基-羰基(碳原子总数为2-8)”、或“(烷基)2-N-亚烷基-羰基(碳原子总数为2-8)”结构的基团，例如CH3NH-C(＝O)-、C2H5NH-C(＝O)-、C3H7NH-C(＝O)-、(CH3)2N-C(＝O)-，或类似基团。其中，C1～C4烷基的定义如前所述。
术语“C2-C8胺基-烷基”指具有“C1～C4亚烷基-NH2”、“烷基-N-亚烷基-(碳原子总数为1-4)”、或“(烷基)2-N-亚烷基-(碳原子总数为1-4)”结构的基团，例如-CH2NH2、-C2H5NH2、-C3H7NH2、-C2H4N(CH3)2，或类似基团。其中，C1～C4亚烷基为C1～C4烷基失去一个氢原子形成的基团，C1～C4烷基的定义如前所述。
除非特别说明，本发明所描述的结构式意在包括所有的同分异构形式(如对映异构，非对映异构和几何异构体(或构象异构体)：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体和(Z)、(E)的构象异构体。因此分发明的化合物的单个立体化学异构体或其对映异构体、非对映异构体或几何异构体(或构象异构体)的混合物都属于本发明的范围。
术语“互变异构体”表示具有不同能量的结构同分异构体可以超过低能垒，从而互相转化。比如，质子互变异构体(即质子移变)包括通过质子迁移进行互变，如1H-吲唑与2H-吲唑、1H-苯并[d]咪唑与3H-苯并[d]咪唑，化合价互变异构体包括包括通过一些成键电子重组而进行互变。
式(I)化合物
具体而言，本发明涉及通式(I)所示的吲唑类化合物的立体异构体、几何异构体、互变异构体、其药用盐、其前药及其水合物或溶剂合物：
Figure PCTCN2016089443-appb-000013
其中：
M选自CH2、CH、NH、N、O、S；
W选自O、NH；
虚线代表单键或双键，且两条虚线不同时为单键或双键；在另一优选例中，两条虚线中至少有一条为双键。
R1、R2、R3分别独立的选自H、F、Cl、Br；
R9选自五元及六元杂芳基，优选为取代或未取代的以下基团：吡啶基、嘧啶基、吡嗪基、哒嗪基、三嗪基、噁唑基、异恶唑基、噻唑基、异噻唑基、呋喃基，所述取代基为1-4个取代基，分别独立取自F、Cl、Br、甲基、甲氧基、氨基。
R8、R10分别独立选自H、卤素、C1～C3烷基、C1～C3烷氧基；
R4、R5、R6、R7分别独立的选自H、F、Cl、Br、取代或未取代的氨基、取代或未取代的的环烷氨基、取代或未取代的杂环烷基氨基、取代或未取代的烷基、取代或未取代的烷氧基、取代或未取代的杂环烷基、取代或未取代的杂环烷氧基、取代或未取代的烷基杂环烷基、取代或未取代的烷基氨基甲酰基、取代或未取代的杂烷基氨基甲酰基、取代或未取代的杂环烷基烷基氨基甲酰基、取代或未取代的杂环烷基、取代或未取代的烷氧基烷基氧基。
优选实施方式中，R9为以下结构：
Figure PCTCN2016089443-appb-000014
其中：
R9a、R9b、R9c、R9d、R9e分别独立选自H、卤素、C1～C3烷基、C1～C3烷氧基，并优选自H、F、Cl、Br、甲基和甲氧基。
U、V、X、Y、Z分别独立选自C或N，且其中至少一个为N；
优选地，通式(I)所示的吲唑类化合物为下式(III)所示的化合物：
Figure PCTCN2016089443-appb-000015
其中：
M选自CH2、CH、NH、N、O、S；
W选自O、NH。
R1、R2、R3优选自H、F、Cl、Br；
R8、R10分别独立选自H、卤素、C1～C3烷基、C1～C3烷氧基，并优选自H、F、Cl、Br、甲基和甲氧基。；
R9a、R9b、R9c、R9d、R9e分别独立选自H、卤素、C1～C3烷基、C1～C3烷氧基，并优选自H、F、Cl、Br、甲基和甲氧基。
U、V、X、Y、Z分别独立选自C或N，且其中至少一个为N；
R4、R5、R6、R7分别独立的选自H、F、Cl、Br、取代或未取代的氨基、取代或未取代的 的环烷氨基、取代或未取代的杂环烷基氨基、取代或未取代的烷基、取代或未取代的烷氧基、取代或未取代的杂环烷基、取代或未取代的杂环烷氧基、取代或未取代的烷基杂环烷基、取代或未取代的烷基氨基甲酰基、取代或未取代的杂烷基氨基甲酰基、取代或未取代的杂环烷基烷基氨基甲酰基、取代或未取代的杂环烷基、取代或未取代的烷氧基烷基氧基；
更优选的通式(I)所示的吲唑类化合物为下式(IV)或(V)所示的化合物：
Figure PCTCN2016089443-appb-000016
其中：
M选自CH2、CH、NH、N、O、S；
W选自O、NH。
R1、R2、R3优选自H、F、Cl、Br；
R10独立选自H、卤素、C1～C3烷基、C1～C3烷氧基，并优选自H、F、Cl、Br、甲基和甲氧基。；
R9a、R9b、R9c、R9d、R9e分别独立选自H、卤素、C1～C3烷基、C1～C3烷氧基，并优选自H、F、Cl、Br、甲基和甲氧基。
U、V、X、Y、Z分别独立选自C或N，且其中至少一个为N；
R4、R5、R6、R7分别独立选自H、F、Cl、Br、取代或未取代的氨基、取代或未取代的的环烷氨基、取代或未取代的杂环烷基氨基、取代或未取代的烷基、取代或未取代的烷氧基、取代或未取代的杂环烷基、取代或未取代的杂环烷氧基、取代或未取代的烷基杂环烷基、取代或未取代的烷基氨基甲酰基、取代或未取代的杂烷基氨基甲酰基、取代或未取代的杂环烷基烷基氨基甲酰基、取代或未取代的杂环烷基、取代或未取代的烷氧基烷基氧基，优选自H、F、Cl、Br、甲氧基、乙氧基、异丙氧基、甲氨基、乙氨基、异丙氨基、二甲基氨基、二乙基氨基、二异丙基氨基、1(1-甲基哌啶)-1-甲基氨基、哌啶基、1-甲基哌啶基、1-乙基哌啶基、1-异丙基哌啶基、1-Boc哌啶基、吡咯烷基、哌嗪基、1-甲基哌嗪基、1-乙基哌嗪基、1-异丙基哌嗪基、1-羟基乙基哌嗪基、1-甲氧基乙基哌嗪基、1-甲氨基乙基哌嗪基、1-Boc-哌嗪基、2,6-二甲基哌嗪基、高哌嗪基、1-甲基高哌嗪基、1-乙基高哌嗪基、1-异丙基高哌嗪基、吗啉基、C1-C3烷基、C1～C3二甲基氨基烷基氨基、C1～C3二乙基氨基烷基氨基、C1～C3二异丙基氨基烷基氨基、C1～C3吡咯烷烷基氨基、C1～C3哌啶烷基氨基、C1～C3羟基烷基、C1～C3氨基烷基、C1～C3甲氧基烷基氨基、C1～C3乙氧基烷基氨基、C1～C3异丙氧基烷基氨基、C1～C3甲氧基烷基、C1～C3乙氧基烷基、C1～C3异丙氧基烷基、二甲基氨基乙酰基氨基、二乙基氨基乙酰基氨基、二异丙基氨基乙酰基氨基、二甲基氨基丙酰基氨基、二乙基氨基丙酰基氨基、二异丙基氨基丙酰基氨基、甲氧基乙基氧基、乙氧基乙基氧基、甲氧基丙基氧基、乙氧基丙基氧基。
优选的，本发明通式(I)所示的吲唑类化合物选自下表1中的化合物
表1
Figure PCTCN2016089443-appb-000017
Figure PCTCN2016089443-appb-000018
Figure PCTCN2016089443-appb-000019
Figure PCTCN2016089443-appb-000020
Figure PCTCN2016089443-appb-000021
Figure PCTCN2016089443-appb-000022
Figure PCTCN2016089443-appb-000023
优选地，本发明的化合物还可以制备成各种药用盐的形式，本发明化合物的药用盐的制备，可以采用化合物的游离碱，与无机或有机酸直接成盐反应进行。无机或有机酸可选自盐酸、硫酸、磷酸、硝酸、氢氟酸、氢溴酸、甲酸、乙酸、苦味酸、柠檬酸、马来酸、甲烷磺酸、三氟甲烷磺酸、乙烷磺酸和对甲苯磺酸等。
式(I)化合物的制备方法
本发明还涉及具有通式(I)结构的吲唑类化合物的四种制备方法，
方法1包括如下步骤：
Figure PCTCN2016089443-appb-000024
从化合物1出发将吡啶环取代做成醇，再做成磺酸酯，然后取代成醚，再将吲哚做成吲唑醛最后环合得到目标产物。
具体地，所述制备方法包括如下步骤：
1.化合物1在碱性条件下与相应的醛反应生成醇2；
2.化合物2与甲基磺酰氯作用生成磺酸酯3；
3.化合物3与相应的5-羟基吲哚在碱性条件下取代成醚4；
4.化合物4在酸性条件下与亚硝酸钠作用生成吲唑醛5；
5.化合物5与相应的邻苯二胺(2-氨基苯酚或2-氨基苯硫醚)化合物缩合得到目标产物。
方法2包括如下步骤：
Figure PCTCN2016089443-appb-000025
从化合物1出发将相应的醛(酮)与相应的氨基吲哚缩合还原，再将吲哚做成吲唑醛最后环合得到目标产物。
具体的说，所述制备方法包括如下步骤：
1.化合物1在还原剂作用下与相应的5-氨基吲哚反应生成吲哚2；
2.化合物2在酸性条件下与亚硝酸钠作用生成吲唑醛3；
3.化合物5与相应的邻苯二胺(2-氨基苯酚或2-氨基苯硫醚)化合物缩合得到目标产物。
方法3包括如下步骤
Figure PCTCN2016089443-appb-000026
从化合物1出发将羟基用硅醚保护，再进行碘代，然后再用四氢吡喃保护氮氢，脱除硅醚保护基后进行取代，然后再与相应的硼酸进行偶联，最后脱除四氢吡喃保护基得到目标产物。
具体的说，所述制备方法包括如下步骤：
1.化合物1在碱性条件下与叔丁基二甲基氯硅烷反应生成硅醚2；
2.化合物2在N-碘代丁二酰亚胺条件下进行碘代得到化合物3；
3.化合物3在酸性条件下上四氢吡喃保护基得到化合物4；
4.化合物4在四丁基氟化铵作用下脱保护得到吲唑醇5；
5.化合物5在碱性条件下与方法1中化合物3发生取代，得到化合物6；
6.化合物6与相应的硼酸在钯催化剂作用下进行偶联反应得到化合物7；
7.化合物7在酸性条件下脱除保护基得到目标产物。
方法4包括如下步骤
Figure PCTCN2016089443-appb-000027
化合物从方法1中化合物3出发，经叠氮钠取代、还原后成胺，再与溴吲哚偶联，脱除保护基，然后做成醛，最后环合得到目标产物。
具体地说，所述制备方法包括如下步骤：
1.化合物1在叠氮钠作用下取代成叠氮化合物2；
2.化合物2在锌粉氯化铵条件下还原成胺3；
3.化合物3与溴吲哚经Buchwald偶联得到化合物4；
4.化合物4在亚硝酸作用下生成化合物5；
化合物5与相应的邻苯二胺(2-氨基苯酚或2-氨基苯硫醚)化合物缩合得到目标产物。
其中，M、U、V、X、Y、Z、R1-R10如前所定义和优选。
本发明的吲唑类化合物的制备方法具有反应条件温和、原料丰富易得、操作及后处理简单等优点。
式(I)化合物的用途
吲唑类化合物作为FGFR抑制剂在治疗癌症方面已有应用，例如WO2010129509,US2003207883，US20060079564等，需要指出的是，US2003207883，US20060079564两份专利的权利要求中包含本发明的化合物，但是其具体实施例中，在吲唑5位取代基中并未涉及吡啶烷氧基的实施例，而是苄氧基取代，而本发明人通过文献调研以及对FGFR的晶体结构研究后发现，将苄氧基替换为吡啶烷氧基后可以显著提高化合物对FGFR的抑制作用和选择性，因为吡啶氮原子可以与Asn568形成氢键作用(Mol Cancer Ther；10(11),2011),另外化合物理化性质得到改善，其对不同细胞株的生殖抑制活性更加明显，这一点在本发明的实施例中可以体现出来(I-36相对于I-38,I-37相对于I-39)。
本发明人设计合成了一系列结构新颖的吲唑类化合物，通过结构优化，发现了在酶、细胞、以及动物体内均有优异活性的小分子FGFR抑制剂，并且对FGFR1-3均有强烈抑制作用，该系列化合物有望在临床上用于治疗FGF/FGFR信号通路异常表达所引起的疾病，如癌症等。
本发明通过对FGFR的晶体结构和其它的酪氨酸激酶抑制剂构效关系的研究，设计合成了一系列结构新颖的化合物，通过分子、细胞以及动物模型对这些化合物进行筛选，发现这些化合物在分子水平能够明显抑制FGFR酶活性，细胞水平对FGFR诱导的各种癌细胞增殖也有显著抑制作用，而且在动物体内也可以显著抑制肿瘤生长。
本发明还涉及一种药物组合物，所述药物组合物包含治疗有效量的选自式(I)所示吲唑类化合物、其药用盐、其前药及其水合物和溶剂合物中的一种或多种以及任选地，药学上可接受的载体，其可用于治疗癌症等相关的疾病。所述药物组合物可以根据不同给药途径而制备成各种形式。
本发明还涉及选自上述式(I)所示吲唑类化合物、其药用盐、其前药及其水合物和溶剂合物中的一种或多种或者上述包含治疗有效量的选自式(I)所示吲唑类化合物、其药用盐、其前药及其水合物和溶剂合物中的一种或多种的药物组合物在治疗癌症等相关疾病的药物中的用途，优选作为蛋白酪氨酸激酶抑制剂，尤其是作为FGFR抑制剂。所述的FGFR包括FGFR1、FGFR2、FGFR3中的一种或多种。
所述的癌症包括乳腺癌、肺癌、膀胱癌、胃癌、胰腺癌、前列腺癌、结肠癌、多发性骨髓瘤AML、肝癌、黑色素瘤、头颈癌、甲状腺癌、肾细胞癌、胶质母细胞癌、和睾丸癌。更特别的是，这些癌症选自：乳腺癌、非小细胞肺癌、膀胱癌、胃癌、胰腺癌、前列腺癌、结肠癌、多发性骨髓瘤、肝癌、黑色素瘤、头颈癌、甲状腺癌、肾细胞癌、胶质母细胞癌、和睾丸癌。此外，本发明提供一种用于治疗癌症的包括本发明化合物或盐作为活性组分的药物组合物，其中癌症选自：乳腺癌、非小细胞肺癌、膀胱癌、胃癌、胰腺癌、前列腺癌、结肠癌、多发性骨髓瘤、肝癌、黑色素瘤、头颈癌、甲状腺癌、肾细胞癌、胶质母细胞癌、和睾 丸癌等等。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例1：
3-(6-([1,4’联哌啶]-1’-基)-1H-苯并[d]咪唑-2-基)-5-(1-3,5二氯吡啶-4-基)乙氧基)-1H-吲唑(I-1)
Figure PCTCN2016089443-appb-000028
步骤1:制备1-(3,5-二氯吡啶-4-基)乙醇
Figure PCTCN2016089443-appb-000029
将11.4毫升二异丙基胺溶于80毫升干燥的四氢呋喃中，0℃下，滴加33.8毫升正丁基锂的四氢呋喃溶液(2.4摩尔每升)，滴加完毕后，降温至-78℃搅拌1小时，滴加10克3,5-二氯吡啶的20毫升四氢呋喃溶液，30分钟滴完，该温度下继续搅拌1小时后，滴加7.6毫升乙醛的20毫升四氢呋喃溶液，30分钟滴完，继续搅拌2小时后，加入200毫升饱和氯化铵水溶液，搅拌1小时后加入乙酸乙酯萃取，分液后有机相用饱和氯化钠水溶液洗涤后无水硫酸钠干燥，过滤浓缩，残余物柱层析(乙酸乙酯：石油醚＝10:90)分离得12克白色固体，收率92％。
1H NMR(300MHz,CDCl3)δ8.44(s,2H),5.59–5.46(m,1H),2.82(d,J＝9.6Hz,1H),1.63(d,J＝7.8Hz,3H).
步骤2：制备1-(3,5-二氯吡啶-4-基)乙基甲磺酸酯
Figure PCTCN2016089443-appb-000030
将12克1-(3,5-二氯吡啶-4-基)乙醇溶于100毫升二氯甲烷中，加入8.7毫升三乙胺，0℃下滴加6.3毫升甲基磺酰氯，滴加完毕后恢复至室温，继续搅拌1小时，加入水和二氯甲烷分液，有机相用饱和氯化钠水溶液洗涤后无水硫酸钠干燥，过滤浓缩,残余物柱层析(乙酸乙酯：石油醚＝10:90)分离得14.5克白色固体，收率86％。
1H NMR(300MHz,CDCl3)δ(ppm):8.51(s,2H),6.36(q,J＝6.9Hz,1H),2.97(s,3H),1.81(d,J＝6.9Hz,3H).
步骤3：制备5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲哚
Figure PCTCN2016089443-appb-000031
将10克1-(3,5-二氯吡啶-4-基)乙基甲磺酸酯，5.4克5-羟基吲哚以及14.47克碳酸铯溶于200毫升N,N-二甲基甲酰胺中，升温至80℃，搅拌1小时后停止加热，反应液浓缩至干，残余物柱层析(乙酸乙酯：石油醚＝10:90)分离得11克淡黄色油状物，收率96％。
1H NMR(400MHz,CDCl3)δ:8.40(s,2H),8.11(s,1H),7.23(d,J＝8.8Hz,1H),7.14(t,J＝2.8Hz,1H),6.99(d,J＝2.4Hz,1H),6.88(dd,J＝8.8,2.4Hz,1H),6.40(m,1H),6.02(q,J＝6.7Hz,1H),1.79(d,J＝6.7Hz,3H).
步骤4：制备5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-甲醛
Figure PCTCN2016089443-appb-000032
将11克5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲哚溶于560毫升二氧六环和560毫升水的混合溶液中，加入28克亚硝酸钠，冷却至0℃，滴加120毫升氯化氢水溶液(2摩尔每升)，滴加完毕后，恢复至室温搅拌3小时，加入乙酸乙酯萃取，有机相用饱和氯化钠水溶液洗涤后无水硫酸钠干燥，过滤浓缩,残余物柱层析(乙酸乙酯：二氯甲烷＝10:90)分离得3.7克棕色固体，收率36％。
1H NMR(300MHz,CDCl3)δ:10.13(s,1H),8.37(s,2H),7.52(s,1H),7.41(d,J＝9.0Hz,1H),7.13(d,J＝9.1Hz,1H),6.07(q,J＝6.7Hz,1H),1.78(d,J＝6.7Hz,3H).
步骤5：制备5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺
Figure PCTCN2016089443-appb-000033
将3克2-硝基-5-氟苯胺，3.23克4-哌啶基哌啶溶于50毫升N-甲基吡咯烷酮，加入6.7毫升三乙胺，加热至100℃，3小时候停止加热，恢复至室温，加入乙酸乙酯萃取，分液后有机相用饱和氯化钠水溶液洗涤后无水硫酸钠干燥，过滤浓缩，残余物柱层析(二氯甲烷：甲醇＝97:3)分离得3.53克黄色固体，收率60％。
步骤6:制备3-(6-([1,4’联哌啶]-1’-基)-1H-苯并[d]咪唑-2-基)-5-(1-3,5二氯吡啶-4-基)乙氧基)-1H-吲唑
将16毫克5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺溶于10毫升甲醇，加入3毫克10％钯碳，氢气氛围中，室温下搅拌1小时后，过滤浓缩，残余物溶于10毫升乙醇，加入14毫克5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-甲醛回流2小时后停止加热，反应液浓缩至干，残余物柱层析(二氯甲烷：甲醇＝95:5)，得黄色固体9毫克，收率30％。
1H NMR(300MHz,CD3OD)δ8.87(s,2H),8.26(s,1H),8.00(s,1H),7.93-7.90(m,1H),7.63-7.60(m,1H),7.51-7.48(m,1H),6.67(q,J＝6.4Hz,1H),4.14(m,2H),3.22-3.11(m,7H),2.46(m,2H),2.37–2.04(m,8H),1.96(s,2H).
实施例2：
2–(2–(5–(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-1H-苯并[d]咪唑-6-基)乙醇(I-2)
Figure PCTCN2016089443-appb-000034
步骤1：制备4-硝基苯基乙醇乙酸酯
Figure PCTCN2016089443-appb-000035
将300毫克4-硝基苯乙醇溶于10毫升二氯甲烷中，加入290微升吡啶，22毫克4-二甲基氨基吡啶，室温下滴加340微升乙酸酐，搅拌过夜后，反应液加水分液，水相二氯甲烷萃取，有机相用饱和氯化钠水溶液洗涤后无水硫酸钠干燥，过滤浓缩，残余物柱层析(乙酸乙酯：石油醚＝10:90)分离得323毫克无色油状物，收率86％。
1H NMR(300MHz,CDCl3)δ:8.17(d,J＝8.4Hz,2H),7.38(d,J＝8.4Hz,2H),4.32(t,J＝6.7Hz,2H),3.05(t,J＝6.7Hz,2H),2.03(s,3H).
步骤2：制备4-氨基苯基乙醇乙酸酯
Figure PCTCN2016089443-appb-000036
将310毫克4-硝基苯基乙醇乙酸酯溶于10毫升甲醇中，加入933毫克甲酸铵，150毫克10％钯碳，加热回流1小时，恢复至室温后，过滤浓缩，残余物柱层析(乙酸乙酯：石油醚＝20:80)分离得220毫克浅棕色油状物，收率83％。
1H NMR(30MHz,CDCl3)δ:7.01(d,J＝8.4Hz,2H),6.66(d,J＝8.4Hz,2H),4.21(t,J＝7.1Hz,2H),3.11(s,3H),2.82(t,J＝7.1Hz,2H),2.03(s,3H).
步骤3：制备2-(4-氨基-3-硝基苯基)乙醇
Figure PCTCN2016089443-appb-000037
0℃下，向3毫升三氟乙酸酐中滴加200毫克4-氨基苯基乙醇乙酸酯，搅拌10分钟后，一次性加入135毫克硝酸钾，恢复至室温搅拌过夜，减压蒸馏除去过量三氟乙酸酐，残余物加饱和碳酸氢钠水溶液中和后，乙酸乙酯萃取，有机相用饱和氯化钠水溶液洗涤后无水硫酸钠干燥，过滤浓缩，得260毫克红棕色油状物，加入5毫升甲醇，324毫克碳酸钾，室温下搅拌半小时，过滤浓缩得130毫克橙色固体，两步收率82％。
1H NMR(300MHz,Acetone)δ:7.86(d,J＝2.0Hz,1H),7.29(dd,J＝8.6,2.0Hz,1H),6.95(d,J＝8.6Hz,1H),6.84(s,1H),3.74–3.63(m,3H),2.69(m,6.4Hz,2H).
步骤4：2–(2–(5–(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-1H-苯并[d]咪唑-6-基)乙醇
将5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成2-(4-氨基-3-硝基苯基)乙醇，其余所需原料、试剂及制备方法同实施例1中的步骤6，得米色固体2–(2–(5–(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-1H-苯并[d]咪唑-6-基)乙醇
1H NMR(300MHz,DMSO)δ:13.44(s,1H),12.72(s,1H),8.61-8.60(m,1H),7.82(s,1H),7.64-7.35(m,1H),7.56-7.30(m,1H),7.52(d,J＝8.1Hz,1H),7.57–7.51(m,1H),7.54(d,J＝9.0Hz,1H),7.30(s,1H),7.15(dd,J＝9.0,2.4Hz,1H),7.07(dd,J＝8.2,1.4Hz,1H),6.10(q,J＝6.7Hz,1H),4.71–4.61(m,1H),3.74–3.60(m,2H),2.91–2.81(m,2H),1.78(d,J＝6.6Hz,3H).
实施例3：
5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(6-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑(I-3)
Figure PCTCN2016089443-appb-000038
步骤1：制备5-(4-甲基哌嗪-1-基)-2-硝基苯胺
Figure PCTCN2016089443-appb-000039
将4-哌啶基哌啶换成4-甲基哌嗪，其余所需原料、试剂及制备方法同实施例1中的步骤5，得黄色固体5-(4-甲基哌嗪-1-基)-2-硝基苯胺。
1H NMR(300MHz,DMSO)δ7.80(d,J＝9.7Hz,1H),7.25(s,2H),6.39(dd,J＝9.8,2.6Hz,1H),6.21(d,J＝2.6Hz,1H),3.30(m,4H),2.43–2.37(m,4H),2.20(s,3H).
步骤2：制备5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(6-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑
将5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成5-(4-甲基哌嗪-1-基)-2-硝基苯胺，其余所需原料、试剂及制备方法同实施例1中的步骤6，得黄色固体5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(6-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑
1H NMR(300MHz,DMSO)δ:13.41-13.36(m,1H),12.60-12.55(m,1H),8.60(s,2H),7.84-7.80(m,1H),7.58-7.30(m,1H),7.52(d,J＝8.1Hz,1H),7.19-6.88(m,1H),7.13(d,J＝8.8Hz,1H),6.99-6.98(m,1H),6.10(q,J＝6.7Hz,1H),3.13(s,4H),2.24(s,4H),1.78(d,J＝6.7Hz,3H).
实施例4
5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(6-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑(I-4)
Figure PCTCN2016089443-appb-000040
步骤1：制备5-(哌啶-1-基)-2-硝基苯胺
Figure PCTCN2016089443-appb-000041
将4-哌啶基哌啶换成哌啶，其余所需原料、试剂及制备方法同实施例1中的步骤5，得黄色固体5-(哌啶-1-基)-2-硝基苯胺。
1H NMR(300MHz,CDCl3)δ:7.98(d,J＝9.7Hz,1H),6.26(dd,J＝9.7,2.4Hz,1H),6.14(s,2H),5.91(d,J＝2.4Hz,1H),3.36(s,4H),1.65(m,6H).
步骤2：制备5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(6-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑
将5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成5-(哌啶-1-基)-2-硝基苯胺，其余所需原料、试剂及制备方法同实施例1中的步骤6，得黄色固体5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(6-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑
1H NMR(300MHz,DMSO)δ13.40-13.35(m,1H),12.58-12.52(m,1H),8.60(s,2H),7.84-7.80(m,1H),7.57-7.30(m,1H),7.52(d,J＝8.1Hz,1H),7.19-6.88(m,1H),7.13(d,J＝8.8Hz,1H),6.99-6.98(m,1H),6.10(q,J＝6.7Hz,1H),3.15-3.07(m,4H),1.78(d,J＝6.7Hz,3H),1.73-1.69(m,4H),1.58-1.50(m,2H),
实施例5
3-(1H-苯并[d]咪唑-2-基-5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑(I-5)
Figure PCTCN2016089443-appb-000042
将67毫克5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-甲醛、22毫克邻苯二胺溶于2毫升乙醇中，回流2小时后停止加热，反应液浓缩至干，残余物柱层析(二氯甲烷：甲醇＝97:3)，得淡黄色固体67毫克，收率79％。
1H NMR(300MHz,DMSO)δ：13.48(s,1H),12.86(s,1H),8.61(s,2H),7.83(d,J＝2.3Hz,1H),7.78–7.72(m,1H),7.55(d,J＝9.0Hz,1H),7.51–7.45(m,1H),7.22(dd,J＝5.9,3.2Hz,2H),7.16(dd,J＝9.0,2.4Hz,1H),6.10(q,J＝6.6Hz,1H),1.78(d,J＝6.6Hz,3H).
实施例6
2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-N-甲基-N-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑-6-胺(I-6)
Figure PCTCN2016089443-appb-000043
步骤1：制备N1-甲基-N1-(1-甲基哌啶-4-基)-4-硝基苯-1,3-二胺
Figure PCTCN2016089443-appb-000044
将4-哌啶基哌啶换成N,1-二甲基哌啶-4-胺，其余所需原料、试剂及制备方法同实施例1中的步骤5，得黄色固体N1-甲基-N1-(1-甲基哌啶-4-基)-4-硝基苯-1,3-二胺。
1H NMR(300MHz,DMSO)δ:7.80(d,J＝9.8Hz,1H),7.23(s,2H),6.29(dd,J＝9.8,2.7Hz,1H),6.07(d,J＝2.6Hz,1H),3.72–3.59(m,1H),2.85-2.80(m,5H),2.17(s,3H),2.01(t,J＝10.8Hz,2H),1.77(qd,J＝12.1,3.6Hz,2H),1.56(m,2H).
步骤2：2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-N-甲基-N-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑-6-胺
将5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成N1-甲基-N1-(1-甲基哌啶-4-基4-硝基苯-1,3-二胺，其余所需原料、试剂及制备方法同实施例1中的步骤6，得黄色固体2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-N-甲基-N-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑-6-胺。
1H NMR(300MHz,DMSO)δ13.38-13.31(m,1H),12.52-12.38(m,1H),8.60- 8.58(m,2H),7.83(dd,J＝15.9,2.1Hz,1H),7.57–7.27(m,2H),7.15(d,J＝2.4Hz,1H),7.14–6.84(m,2H),6.79(d,J＝2.1Hz,1H),6.09(q,J＝6.7Hz,1H),3.52(m,6.6Hz,1H),2.85(d,J＝11.8Hz,2H),2.83-2.74(s,3H),2.18(s,3H),1.99(t,J＝10.3Hz,2H),1.83–1.56(m,7H).
实施例7
5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(6-甲氧基-1H-苯并[d]咪唑-2-基)-1H-吲唑(I-7)
Figure PCTCN2016089443-appb-000045
将5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成2-硝基-4-甲氧基苯胺，其余所需原料、试剂及制备方法同实施例1中的步骤6，得浅粉色固体5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(6-甲氧基-1H-苯并[d]咪唑-2-基)-1H-吲唑。
1H NMR(300MHz,DMSO)δ:13.43-13.39(m,1H),12.70(s,1H),8.60(s,2H),7.83-7.79(m,1H),7.62-7.34(m,1H),7.53(d,J＝8.1Hz,1H),7.24-6.94(m,1H),7.14(d,J＝8.8Hz,1H),6.85(d,J＝8.1Hz,,1H),6.10(q,J＝6.7Hz,1H),3.86-3.80(m,3H),1.78(d,J＝6.7Hz,3H).
实施例8
2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-N-甲基-1H-苯并[d]咪唑-6-胺(I-8)
Figure PCTCN2016089443-appb-000046
步骤1：制备N1-甲基-4-硝基苯-1,3-二胺
Figure PCTCN2016089443-appb-000047
将4-哌啶基哌啶换成甲胺盐酸盐，其余所需原料、试剂及制备方法同实施例1中的步骤5，得黄色固体N1-甲基-4-硝基苯-1,3-二胺
1H NMR(400MHz,DMSO)δ7.72(d,J＝9.5Hz,1H),7.37(s,2H),6.95(d,J＝2.4Hz,1H),5.99(dd,J＝9.5,2.4Hz,1H),5.77(d,J＝2.0Hz,1H),2.69(d,3H).
步骤2：制备2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-N-甲基-1H-苯并[d]咪唑-6-胺
将5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成N1-甲基-4-硝基苯-1,3-二胺，其余所需原料、试剂及制备方法同实施例1中的步骤6，得米色固体2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-N-甲基-1H-苯并[d]咪唑-6-胺
1H NMR(300MHz,DMSO)δ13.29(s,1H),12.29(s,1H),8.60(s,2H),7.81(s,1H),7.50(d,J＝9.0Hz,1H),7.41(s,1H),7.12(dd,J＝9.0,2.4Hz,1H),6.58(dd,J＝8.7,2.0Hz,1H),6.49(s,1H),6.08(q,J＝6.7Hz,1H),2.73(s,3H),1.78(d,J＝6.7Hz,3H).
实施例9
5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(6-氟-1H-苯并[d]咪唑-2-基)-1H-吲唑(I-9)
Figure PCTCN2016089443-appb-000048
将5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成2-硝基-5-氟苯胺，其余所需原料、试剂及制备方法同实施例1中的步骤6，得白色固体5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(6-氟-1H-苯并[d]咪唑-2-基)-1H-吲唑
1H NMR(300MHz,DMSO)δ:13.53-13.51(m,1H),12.99(s,1H),8.62-8.61(m,2H),7.78(s,1H),7.74-7.43(m,1H),7.55(d,J＝8.1Hz,1H),7.51-7.19(m,1H),7.16(dd,J＝9.0,2.4Hz,1H),7.11-7.04(m,1H),6.10(q,J＝6.7Hz,1H),1.78(d,J＝6.7Hz,3H).
实施例10
N-(2-(5-(1-(3,5二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-1H-苯并[d]咪唑-6-基)-2-(二甲基氨基)-N-甲基乙酰胺(I-10)
Figure PCTCN2016089443-appb-000049
步骤1:制备2-溴-N-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-1H-苯并[d]咪唑-6-基)-N-甲基乙酰胺
Figure PCTCN2016089443-appb-000050
将400毫克2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基))-1H-吲唑-3-基)-N-甲基-1H-苯并[d]咪唑-6-胺，0.25毫升三乙胺溶于10毫升N,N-二甲基乙酰胺，冰浴下滴加88微升溴乙酰氯，移至室温搅拌过夜，加入水用乙酸乙酯萃取，分液后有机相用饱和氯化钠水溶液洗涤后无水硫酸钠干燥，过滤浓缩，残余物柱层析(二氯甲烷：甲醇＝97:3)分离得260毫克黄色固体2-溴-N-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-1H-苯并[d]咪唑-6-基)-N-甲基乙酰胺，收率51％。
步骤4:制备N-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-1H-苯并[d]咪唑-6-基)-2-(二甲氨基)-N-甲基乙酰胺
将260毫克2-溴-N-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-1H-苯并[d]咪唑-6-基)-N-甲基乙酰胺溶于2M浓度的10毫升二甲胺的四氢呋喃溶液中，室温搅拌过夜，旋干反应液，残余物柱层析(二氯甲烷：甲醇＝97:3)分离得180毫克黄色固体N-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-1H-苯并[d]咪唑-6-基)-2-(二甲氨基)-N-甲基乙酰胺，收率74％
1H NMR(300MHz,CDCl3)δ8.31(s,2H),7.82(s,1H),7.66(d,J＝7.9Hz,1H),7.53(s,1H),7.41(d,J＝9.0Hz,1H),7.07(dd,J＝9.1,2.0Hz,1H),6.97(d,J＝8.4Hz,1H),6.09(q,J＝6.5Hz,1H),3.55(s,2H),3.24(s,3H),2.66(s,6H),1.75(d,J＝6.5Hz,3H).
实施例11
5-(1-(3-氯吡啶-4-基)乙氧基)-3-(5-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑(I-11)
Figure PCTCN2016089443-appb-000051
步骤一：制备1-(3-氯吡啶-4-基)乙醇
Figure PCTCN2016089443-appb-000052
将3,5-二氯吡啶换成3-氯吡啶，其余所需原料、试剂及制备方法同实施例1中的步骤1，得米色晶体1-(3-氯吡啶-4-基)乙醇
1H NMR(300MHz,CDCl3)δ:8.32(m,,2H),7.54(d,J＝5.0Hz,1H),5.15(q,J＝6.5Hz,1H),1.42(d,J＝6.5Hz,3H).
步骤2：制备1-(3-氯吡啶-4-基)乙基甲磺酸酯
Figure PCTCN2016089443-appb-000053
将1-(3,5-二氯吡啶-4-基)乙醇换成1-(3-氯吡啶-4-基)乙醇，其余所需原料、试剂及制备方法同实施例1中的步骤2，得淡棕色油状物1-(3-氯吡啶-4-基)乙基甲磺酸酯。
1H NMR(300MHz,CDCl3)δ:8.59(s,1H),8.55(d,J＝5.1Hz,1H),7.47(d,J＝5.1Hz,1H),6.03(q,J＝6.5Hz,1H),2.99(s,3H),1.68(d,J＝6.5Hz,3H).
步骤3：制备5-(1-(3-氯吡啶-4-基)乙氧基)-1H-吲哚
Figure PCTCN2016089443-appb-000054
将1-(3,5-二氯吡啶-4-基)乙基甲磺酸酯换成1-(3-氯吡啶-4-基)乙基甲磺酸酯，其余所需原料、试剂及制备方法同实施例1中的步骤3，得无色油状物5-(1-(3-氯吡啶-4-基)乙氧基)-1H-吲哚
1H NMR(300MHz,CDCl3)δ:8.56(s,1H),8.41(d,J＝5.0Hz,1H),8.06(s,1H),7.50(d,J＝5.0Hz,1H),7.28–7.22(m,1H),7.16(m,1H),6.89(m,1H),6.84(dd,J＝8.7,2.3Hz,1H),6.40(s,1H),5.64(q,J＝6.4Hz,1H),1.64(d,J＝6.4Hz,3H).
步骤4：制备5-(1-(3-氯吡啶-4-基)乙氧基)-1H-吲唑-3-甲醛
Figure PCTCN2016089443-appb-000055
将5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲哚换成5-(1-(3-氯吡啶-4-基)乙氧基)-1H-吲哚，其余所需原料、试剂及制备方法同实施例1中的步骤4，得无色油状物5-(1-(3-氯吡啶-4-基)乙氧基)-1H-吲唑-3-甲醛.
1H NMR(400MHz,CDCl3)δ:10.21(s,1H),8.60(s,1H),8.43(d,J＝5.1Hz,1H),7.55(m,1H),7.46(m,2H),7.15(dd,J＝9.1,2.3Hz,1H),5.76(q,J＝6.4Hz,1H),1.67(d,J＝6.4Hz,3H).
步骤5：制备5-(1-(3-氯吡啶-4-基)乙氧基)-3-(5-(哌啶-1-基)-1H-苯并[d]咪唑-2- 基)-1H-吲唑
将5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成5-(哌啶-1-基)-2-硝基苯胺，5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-甲醛换成5-(1-(3-氯吡啶-4-基)乙氧基)-1H-吲唑-3-甲醛，其余所需原料、试剂及制备方法同实施例1中的步骤6，得黄色固体5-(1-(3-氯吡啶-4-基)乙氧基)-3-(5-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑
1H NMR(300MHz,CDCl3)δ11.11(s,1H),8.55(s,1H),8.37(d,J＝5.0Hz,1H),7.98(s,1H),7.62–7.51(m,1H),7.44(d,J＝5.0Hz,1H),7.29-7.26(m,2H),7.14–6.94(m,3H),5.77(dd,J＝12.4,6.0Hz,1H),3.20–3.06(m,4H),1.75(s,5H),1.60(d,J＝6.4Hz,4H).
实施例12
5-(1-(3-氟吡啶-4-基)乙氧基)-3-(5-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑(I-12)
Figure PCTCN2016089443-appb-000056
步骤一：制备1-(3-氟吡啶-4-基)乙醇
Figure PCTCN2016089443-appb-000057
将3,5-二氯吡啶换成3-氟吡啶，其余所需原料、试剂及制备方法同实施例1中的步骤1，得无色油状物1-(3-氟吡啶-4-基)乙醇
1H NMR(400MHz,CDCl3)δ：8.41(d,J＝4.8Hz,1H),8.38(s,1H),7.50(t,J＝5.5Hz,1H),5.26–5.18(m,1H),2.26(d,J＝4.2Hz,1H),1.52(d,J＝6.5Hz,3H).
步骤2：制备1-(3-氟吡啶-4-基)乙基甲磺酸酯
Figure PCTCN2016089443-appb-000058
将1-(3,5-二氯吡啶-4-基)乙醇换成1-(3-氟吡啶-4-基)乙醇，其余所需原料、试剂及制备方法同实施例1中的步骤2，得淡棕色油状物1-(3-氟吡啶-4-基)乙基甲磺酸酯。
1H NMR(300MHz,CDCl3)δ8.49：(m,2H),7.43(t,J＝5.5Hz,1H),5.99(q,J＝6.6Hz,1H),3.00(s,3H),1.73(d,J＝6.6Hz,3H).
步骤3：制备5-(1-(3-氟吡啶-4-基)乙氧基)-1H-吲哚
Figure PCTCN2016089443-appb-000059
将1-(3,5-二氯吡啶-4-基)乙基甲磺酸酯换成1-(3-氟吡啶-4-基)乙基甲磺酸酯，其余所需原料、试剂及制备方法同实施例1中的步骤3，得无色油状物5-(1-(3-氟吡啶-4-基)乙氧基)-1H-吲哚
1H NMR(300MHz,CDCl3)δ：8.43(d,J＝1.6Hz,1H),8.35(d,J＝4.9Hz,1H),8.07(s,1H),7.52–7.45(m,1H),7.29–7.23(m,1H),7.19–7.14(m,1H),6.98(d,J＝2.2Hz,1H),6.87(dd,J＝8.8,2.4Hz,1H),6.41(s,1H),5.64(q,J＝6.5Hz,1H),1.66(d,J＝6.5Hz,3H).
步骤4：制备5-(1-(3-氟吡啶-4-基)乙氧基)-1H-吲唑-3-甲醛
Figure PCTCN2016089443-appb-000060
将5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲哚换成5-(1-(3-氟吡啶-4-基)乙氧基)-1H-吲哚，其余所需原料、试剂及制备方法同实施例1中的步骤4，得棕色油状物5-(1-(3-氟吡啶-4-基)乙氧基)-1H-吲唑-3-甲醛.
1H NMR(300MHz,CDCl3)δ10.21(s,1H),8.50(s,1H),8.40(d,J＝5.0Hz,1H),7.61(d,J＝2.2Hz,1H),7.49(m,2H),7.18(dd,J＝9.0,2.3Hz,1H),5.77(q,J＝6.4Hz,1H),1.70(d,J＝6.4Hz,3H).
步骤5：制备5-(1-(3-氟吡啶-4-基)乙氧基)-3-(5-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑
将5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成5-(哌啶-1-基)-2-硝基苯胺，5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-甲醛换成5-(1-(3-氟吡啶-4-基)乙氧基)-1H-吲唑-3-甲醛，其余所需原料、试剂及制备方法同实施例1中的步骤6，得黄色固体5-(1-(3-氟吡啶-4-基)乙氧基)-3-(5-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑
1H NMR(300MHz,DMSO)δ:13.45-13.40(m,1H),12.62-12.55(m,1H),8.60(s,1H),8.41(d,J＝4.8Hz,1H)7.91-7.88(m,1H),7.59-7.39(m,3H),7.33-6.90(m,1H),7.20-7.17(m),6.99-6.92(m,1H),5.81(q,J＝6.7Hz,1H),1.67-1.66(m,7H),1.57-1.53(m,2H).
实施例13
5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-((3R,5S)-3,5-二甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑(I-13)
Figure PCTCN2016089443-appb-000061
步骤1：制备5-((3R,5S)-3,5-二甲基哌嗪-1-基)-2-硝基苯胺
Figure PCTCN2016089443-appb-000062
将4-哌啶基哌啶换成(2R,6S)-2,6-二甲基哌嗪，其余所需原料、试剂及制备方法同实施例1中的步骤5，得黄色固体5-((3R,5S)-3,5-二甲基哌嗪-1-基)-2-硝基苯胺。
1H NMR(300MHz,DMSO)δ7.78(d,J＝9.8Hz,1H),7.23(s,2H),6.40(dd,J＝9.8,2.2Hz,1H),6.20(d,J＝2.2Hz,1H),3.69(d,J＝11.7Hz,2H),2.82–2.67(m,2H),2.31(t,J＝11.4Hz,2H),1.01(d,J＝6.2Hz,6H).
步骤2：制备5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-((3R,5S)-3,5-二甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑
将5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成5-((3R,5S)-3,5-二甲基哌嗪-1-基)-2-硝基苯胺，其余所需原料、试剂及制备方法同实施例1中的步骤6，得黄色固体5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-((3R,5S)-3,5-二甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑
1H NMR(300MHz,DMSO)δ13.43-13.38(m,1H),12.62-12.54(m,1H),8.60(s, 2H),7.87-7.80(m,1H),7.58-7.30(m,1H),7.52(d,J＝8.1Hz,1H),7.19-6.86(m,1H),7.18-7.12(m,1H),6.99-6.96(m,1H),6.10(q,J＝6.7Hz,1H),3.51-3.47(m,2H),2.97(s,2H),2.26-2.17(m,2H),1.78(d,J＝6.7Hz,3H),1.11-1.06(m,6H).
实施例14
5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(4-甲基-1,4-二氮杂环庚烷-1-基)-1H-苯并[d]咪唑-2基)-1H-吲唑(I-14)
Figure PCTCN2016089443-appb-000063
步骤1：制备5-(4-甲基-1,4-二氮杂环庚烷-1-基)-2-硝基苯胺
Figure PCTCN2016089443-appb-000064
将4-哌啶基哌啶换成1-甲基-1,4-二氮杂环庚烷，其余所需原料、试剂及制备方法同实施例1中的步骤5，得黄色固体5-(4-甲基-1,4-二氮杂环庚烷-1-基)-2-硝基苯胺
1H NMR(300MHz,DMSO)δ7.79(d,J＝9.8Hz,1H),7.22(s,2H),6.24(dd,J＝9.8,2.6Hz,1H),6.02(d,J＝2.6Hz,1H),3.57–3.51(m,2H),3.47(t,J＝6.2Hz,2H),2.62–2.55(m,2H),2.47–2.40(m,2H),2.25(s,3H),1.92–1.81(m,2H).
步骤2：制备5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(4-甲基-1,4-二氮杂环庚烷-1-基)-1H-苯并[d]咪唑-2基)-1H-吲唑
将5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成5-(4-甲基-1,4-二氮杂环庚烷-1-基)-2-硝基苯胺，其余所需原料、试剂及制备方法同实施例1中的步骤6，得黄色固体5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(4-甲基-1,4-二氮杂环庚烷-1-基)-1H-苯并[d]咪唑-2基)-1H-吲唑。
1H NMR(300MHz,DMSO)δ13.38-13.30(m,1H),12.45-12.32(m,1H),8.60-8,58(m,2H),7.86-7.80(m,1H),7.53-7.26(m,2H),7.13(dd,J＝9.0,2.2Hz,1H),6.95-6.63(m,1H),6.76-6.71(m,1H),6.10(q,J＝6.7Hz,1H),3.57-3.54(m,2H),3.47(t,J＝6.0Hz,2H),2.72-2.67(m,2H),2.50(s,2H),2.28(s,3H),2.07-1.90(m,2H),1.78(d,J＝6.7Hz,3H).
实施例15
5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(6-(4-乙基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑(I-15)
Figure PCTCN2016089443-appb-000065
步骤1：制备5-(4-乙基哌嗪-1-基)-2-硝基苯胺
Figure PCTCN2016089443-appb-000066
将4-哌啶基哌啶换成4-乙基哌嗪，其余所需原料、试剂及制备方法同实施例1中的步骤5，得黄色固体5-(4-乙基哌嗪-1-基)-2-硝基苯胺。
1H NMR(300MHz,DMSO)δ：7.80(d,J＝9.7Hz,1H),7.27(s,2H),6.38(d,J＝9.7Hz,1H),6.21(s,1H),3.34–3.24(m,4H),2.48–2.40(m,4H),2.35(q,J＝7.0Hz,2H),1.02(t,J＝7.1Hz,3H)..
步骤2：制备5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(6-(4-乙基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑
将5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成5-(4-乙基哌嗪-1-基)-2-硝基苯胺，其余所需原料、试剂及制备方法同实施例1中的步骤6，得黄色固体5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(6-(4-乙基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑
1H NMR(300MHz,DMSO)δ:13.42-13.37(m,1H),12.62-12.56(m,1H),8.60(s,2H),7.84-7.80(m,1H),7.58-7.30(m,1H),7.52(d,J＝8.1Hz,1H),7.19-6.88(m,1H),7.13(d,J＝8.8Hz,1H),6.99-6.98(m,1H),6.10(q,J＝6.7Hz,1H),3.12(s,4H),2.55(s,4H),2.41-2.35(m,2H),1.78(d,J＝6.7Hz,3H),1.09-1.02(m,3H).
实施例16
5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(6-(4-异丙基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑(I-16)
Figure PCTCN2016089443-appb-000067
步骤1：制备5-(4-异丙基哌嗪-1-基)-2-硝基苯胺
Figure PCTCN2016089443-appb-000068
将4-哌啶基哌啶换成4-异丙基哌嗪，其余所需原料、试剂及制备方法同实施例1中的步骤5，得黄色固体5-(4-异丙基哌嗪-1-基)-2-硝基苯胺。
1H NMR(300MHz,DMSO)δ：7.80(d,J＝9.7Hz,1H),7.27(s,2H),6.38(dd,J＝9.7,2.5Hz,1H),6.19(d,J＝2.5Hz,1H),3.32–3.25(m,4H),2.71--2.62(m,1H),2.56–2.47(m,4H),0.98(d,J＝6.5Hz,6H).
步骤2：制备5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(6-(4-异丙基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑
将5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成5-(4-异丙基哌嗪-1-基)-2-硝基苯胺，其余所需原料、试剂及制备方法同实施例1中的步骤6，得黄色固体5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(6-(4-异丙基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑
1H NMR(300MHz,DMSO)δ13.42-13.37(m,1H),12.61-12.55(m,1H),8.60(s,2H),7.84-7.80(m,1H),7.58-7.30(m,1H),7.52(d,J＝8.1Hz,1H),7.19-6.88(m,1H),7.13(d,J＝8.8Hz,1H),6.99-6.98(m,1H),6.10(q,J＝6.7Hz,1H),3.12(s,4H),2.63(m,5H),1.78(d,J＝6.7Hz,3H),1.02(d,J＝6.0Hz,3H).
实施例17
3-(5-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-5-(1-(吡啶-4-基)乙氧基)-1H-吲唑(I-17)
Figure PCTCN2016089443-appb-000069
步骤1：制备1-(吡啶-4-基)乙醇
Figure PCTCN2016089443-appb-000070
将1.21克4-乙酰基吡啶溶于25毫升甲醇中，冰水浴下分批加入757毫克硼氢化钠，加料完毕后，恢复至室温搅拌2小时，反应液浓缩至干，加入乙酸乙酯，依次用水、饱和氯化钠水溶液洗涤之后，无水硫酸钠干燥，过滤浓缩，残余物柱层析分离(二氯甲烷：甲醇＝98:2)得1.08克白色固体1-(吡啶-4-基)乙醇，收率88％
1H NMR(400MHz,CDCl3)δ：8.52(d,J＝4.8Hz,2H),7.31(d,J＝4.8Hz,2H),4.96-4.83(m,IH),1.50(d,J＝6.5Hz,3H).
步骤2：制备1-(吡啶-4-基)乙基甲磺酸酯
Figure PCTCN2016089443-appb-000071
将1-(3,5-二氯吡啶-4-基)乙醇换成1-(吡啶-4-基)乙醇，其余所需原料、试剂及制备方法同实施例1中的步骤2，得淡棕色油状物1-(吡啶-4-基)乙基甲磺酸酯。
1H NMR(300MHz,CDCl3)δ8.64(d,J＝4.5Hz,2H),7.30(d,J＝4.5Hz,2H),5.70(q,J＝6.6Hz,1H),2.92(s,3H),1.70(d,J＝6.6Hz,3H).
步骤3：制备5-(1-(吡啶-4-基)乙氧基)-1H-吲哚
Figure PCTCN2016089443-appb-000072
将1-(3,5-二氯吡啶-4-基)乙基甲磺酸酯换成1-(吡啶-4-基)乙基甲磺酸酯，其余所需原料、试剂及制备方法同实施例1中的步骤3，得红棕色油状物5-(1-(吡啶-4-基)乙氧基)-1H-吲哚
1H NMR(300MHz,CDCl3)δ8.56(d,J＝4.8Hz,2H),7.34(d,J＝4.7Hz,2H),7.23(s,1H),7.15(t,J＝2.7Hz,1H),6.97(s,1H),6.86(dd,J＝8.8,2.4Hz,1H),6.40-6.38(m,1H),5.29(q,J＝6.5Hz,1H),1.64(d,J＝6.5Hz,3H).
步骤4：制备5-(1-(吡啶-4-基)乙氧基)-1H-吲唑-3-甲醛
Figure PCTCN2016089443-appb-000073
将5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲哚换成5-(1-(吡啶-4-基)乙氧基)-1H-吲哚，其余所需原料、试剂及制备方法同实施例1中的步骤4，得无色油状物5-(1-(吡啶-4-基)乙氧基)-1H-吲唑-3-甲醛.
1H NMR(300MHz,CDCl3)δ10.20(s,1H),8.59(d,J＝5.4Hz,2H),7.56(d,J＝1.4Hz,1H),7.44(d,J＝9.0Hz,1H),7.39(d,J＝5.4Hz,2H),7.15(dd,J＝9.0,1.4Hz,1H),5.45(q,J＝6.3Hz,1H),1.66(d,J＝6.4Hz,3H).
步骤5：制备5-(1-(吡啶-4-基)乙氧基)-3-(5-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑
将5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成5-(哌啶-1-基)-2-硝基苯胺， 5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-甲醛换成5-(1-(吡啶-4-基)乙氧基)-1H-吲唑-3-甲醛，其余所需原料、试剂及制备方法同实施例1中的步骤6，得黄色固体5-(1-(吡啶-4-基)乙氧基)-3-(5-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑
1H NMR(400MHz,DMSO)δ13.42(s,1H),12.60(s,1H),8.55(d,J＝5.9Hz,2H),7.87(s,1H),7.53-7.50(m,3H),7.46(s,1H),7.18(dd,J＝9.0,2.3Hz,1H),6.96(m,2H),5.60(q,J＝6.4Hz,1H),3.11(s,4H),1.69(s,4H),1.61(d,J＝6.4Hz,3H),1.55(m,2H).
实施例18
5-(1-(3-氯-5-氟吡啶-4-基)乙氧基)-3-(5-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑(I-18)
Figure PCTCN2016089443-appb-000074
步骤一：制备1-(3氯-5-氟吡啶-4-基)乙醇
Figure PCTCN2016089443-appb-000075
将3,5-二氯吡啶换成3-氯-5-氟吡啶，其余所需原料、试剂及制备方法同实施例1中的步骤1，得无色油状物1-(3-氯-5-氟吡啶-4-基)乙醇
1H NMR(300MHz,CDCl3)δ8.39(s,1H),8.35(d,J＝1.5Hz,1H),5.41–5.29(m,1H),2.49(d,J＝8.2Hz,1H),1.63(d,J＝6.8Hz,3H).
步骤2：制备1-(3-氯-5-氟吡啶-4-基)乙基甲磺酸酯
Figure PCTCN2016089443-appb-000076
将1-(3,5-二氯吡啶-4-基)乙醇换成1-(3-氯-5-氟吡啶-4-基)乙醇，其余所需原料、试剂及制备方法同实施例1中的步骤2，得白色蜡状固体1-(3-氯-5-氟吡啶-4-基)乙基甲磺酸酯。
1H NMR(300MHz,CDCl3)δ8.46(s,1H),8.42(s,1H),6.19(q,J＝6.7Hz,1H),2.98(s,3H),1.79(d,J＝6.7Hz,3H).
步骤3：制备5-(1-(3-氯-5-氟吡啶-4-基)乙氧基)-1H-吲哚
Figure PCTCN2016089443-appb-000077
将1-(3,5-二氯吡啶-4-基)乙基甲磺酸酯换成1-(3-氯-5-氟吡啶-4-基)乙基甲磺酸酯，其余所需原料、试剂及制备方法同实施例1中的步骤3，得无色油状物5-(1-(3-氯-5-氟吡啶-4-基)乙氧基)-1H-吲哚
1H NMR(300MHz,CDCl3)δ8.36(s,1H),8.29(s,1H),8.07(s,1H),7.23(d,J＝9.0Hz,1H),7.18–7.12(m,1H),7.05(s,1H),6.88(dd,J＝8.8,2.2Hz,1H),6.42(s,1H),5.86(q,J＝6.6Hz,1H),1.79(d,J＝6.6Hz,3H).
步骤4：制备5-(1-(3-氯-5-氟吡啶-4-基)乙氧基)-1H-吲唑-3-甲醛
Figure PCTCN2016089443-appb-000078
将5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲哚换成5-(1-(3-氯-5-氟吡啶-4-基)乙氧基)-1H-吲哚，其余所需原料、试剂及制备方法同实施例1中的步骤4，得棕色油状物5-(1-(3-氯-5-氟吡啶-4-基)乙氧基)-1H-吲唑-3-甲醛.
1H NMR(300MHz,CDCl3)δ11.37(s,1H),10.20(s,1H),8.39(s,1H),8.30(s,1H),7.64(s,1H),7.44(d,J＝9.0Hz,1H),7.17(dd,J＝9.0,1.9Hz,1H),5.95(q,J＝6.5Hz,1H),1.81(d,J＝6.5Hz,3H).
步骤5：制备5-(1-(3-氯-5-氟吡啶-4-基)乙氧基)-3-(5-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑
将5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成5-(哌啶-1-基)-2-硝基苯胺，5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-甲醛换成5-(1-(3-氯-5-氟吡啶-4-基)乙氧基)-1H-吲唑-3-甲醛，其余所需原料、试剂及制备方法同实施例1中的步骤6，得黄色固体5-(1-(3-氯-5-氟吡啶-4-基)乙氧基)-3-(5-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑
1H NMR(300MHz,CD3OD)δ8.39(s,1H),8.34(d,J＝1.9Hz,1H),7.90(d,J＝2.2Hz,1H),7.57(d,J＝8.8Hz,1H),7.48(d,J＝9.3Hz,1H),7.23(s,1H),7.15(dd,J＝9.1,2.3Hz,1H),7.09(dd,J＝8.9,2.2Hz,1H),6.10(q,J＝6.1Hz,1H),3.20–3.12(m,4H),1.82(m,7H),1.62(m,2H).
实施例19
2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)苯并[d]噁唑(I-19)
Figure PCTCN2016089443-appb-000079
步骤1：2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)苯并[d]噁唑
将100毫克制备5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-甲醛，36毫克2-氨基苯酚溶于5毫升乙醇中，回流4小时后停止加热，恢复至室温后，反应液浓缩至干，加入5毫升三氯甲烷，150毫克2,3-二氯-5,6-二氰基对苯醌，室温下搅拌2小时后加热回流2小时，恢复至室温后加入50毫升三氯甲烷，用饱和碳酸氢钠水溶液、饱和氯化钠水溶液洗涤之后，无水硫酸钠干燥，柱层析分离(二氯甲烷：甲醇＝98:2)得90毫克米黄色固体，收率60％。
1H NMR(300MHz,CDCl3)δ12.39：(s,1H),8.44(s,2H),7.87–7.80(m,1H),7.71(d,J＝2.0Hz,1H),7.65–7.60(m,1H),7.57(d,J＝9.1Hz,1H),7.46–7.36(m,2H),7.20(dd,J＝9.1,2.4Hz,1H),6.17(q,J＝6.7Hz,1H),1.85(d,J＝6.7Hz,3H).
实施例20
2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)苯并[d]噻唑(I-20)
Figure PCTCN2016089443-appb-000080
将5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成2-氨基苯硫酚，其余所需原料、试剂及制备方法同实施例1中的步骤6，得白色固体2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)苯并[d]噻唑
1H NMR(300MHz,CDCl3)δ8.40：(s,2H),8.13(d,J＝8.1Hz,1H),7.90(d,J＝8.0Hz,1H),7.81(d,J＝2.2Hz,1H),7.56–7.48(m,1H),7.43–7.34(m, 2H),7.17(dd,J＝9.0,2.4Hz,1H),6.16(q,J＝6.7Hz,1H),1.82(d,J＝6.7Hz,3H).
实施例21
5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(1H-吲哚-2-基)-1H-吲唑(I-21)
Figure PCTCN2016089443-appb-000081
步骤1：制备5-((叔丁基二甲基甲硅烷基)氧基)-1H-吲唑
Figure PCTCN2016089443-appb-000082
将1.34克1H-吲唑-5-醇,1.2克咪唑溶于100毫升N,N-二甲基甲酰胺中，0℃下分批加入2.3克叔丁基二甲基氯硅烷，加料完毕后恢复至室温搅拌过夜，0℃下向反应液中加水，乙酸乙酯萃取，有机相用饱和氯化钠水溶液洗涤后无水硫酸钠干燥，过滤浓缩,残余物柱层析(乙酸乙酯：石油醚＝30:70)分离得2.4克黄色固体，收率97％。
1H NMR(300MHz,CDCl3)δ：7.96(s,1H),7.35(d,J＝8.8Hz,1H),7.12(s,1H),6.98(dd,J＝8.8,2.1Hz,1H),1.01(s,9H),0.21(s,6H).
步骤2：制备5-((叔丁基二甲基甲硅烷基)氧基)-3-碘-1H-吲唑
Figure PCTCN2016089443-appb-000083
将2克5-((叔丁基二甲基甲硅烷基)氧基)-1H-吲唑溶于50毫升二氯甲烷中，冷却至10℃，分批加入2.24克N-碘代丁二酰亚胺，加料完毕后，恢复至室温搅拌5小时，冷却至0℃，加入少量硫代硫酸钠溶液，搅拌1小时后分液，水相二氯甲烷萃取，合并有机相，用饱和氯化钠水溶液洗涤后无水硫酸钠干燥，过滤浓缩,残余物柱层析(乙酸乙酯：石油醚＝10:90)分离得3.03克黄色固体，收率99％。
1H NMR(300MHz,CDCl3)δ：7.34(d,J＝8.9Hz,1H),7.03(dd,J＝8.9,2.2Hz,1H),6.85(d,J＝2.2Hz,1H),1.01(s,9H),0.22(s,6H).
步骤3：制备5-((叔丁基二甲基甲硅烷基)氧基)-3-碘-1-(四氢-2H-吡喃-2-基)-1H-吲唑
Figure PCTCN2016089443-appb-000084
将2克5-((叔丁基二甲基甲硅烷基)氧基)-3-碘-1H-吲唑溶于30毫升二氯甲烷、30毫升四氢呋喃中，冷却至10℃，依次滴加175微升甲烷磺酸、1.5毫升3,4-二氢-2H-吡喃，恢复至室温搅拌过夜，反应液加入20毫升饱和碳酸氢钠水溶液淬灭，分液，水相用二氯甲烷萃取，合并有机相，用饱和氯化钠水溶液洗涤后无水硫酸钠干燥，过滤浓缩,残余物柱层析(乙酸乙酯：石油醚＝3:97)分离得2克无色油状物，收率82％。
1H NMR(300MHz,CDCl3)δ7.42(d,J＝9.0Hz,1H),7.01(dd,J＝8.9,2.3Hz,1H),6.81(d,J＝2.2Hz,1H),5.63(dd,J＝9.4,2.6Hz,1H),4.02(d,J＝11.3Hz,1H),3.73(m,1H),2.61–2.45(m,1H),2.08(m,2H),1.81–1.61(m,3H),1.01(s,9H),0.21(s,6H).
步骤4：制备3-碘-1-(四氢-2H-吡喃-2-基)-1H-吲唑-5-醇
Figure PCTCN2016089443-appb-000085
将600毫克5-((叔丁基二甲基甲硅烷基)氧基)-3-碘-1-(四氢-2H-吡喃-2-基)-1H-吲唑溶于12毫升四氢呋喃中，加入410毫克四丁基氟化铵的2毫升四氢呋喃溶液，室温下搅拌1小时，反应液浓缩至干，加入50毫升乙酸乙酯，依次用水、饱和氯化钠水溶液洗涤后，无水硫酸钠干燥，过滤浓缩,残余物柱层析(乙酸乙酯：石油醚＝10:90)分离得450毫克白色固体，收率100％。
1H NMR(300MHz,CDCl3)δ7.37(d,J＝9.0Hz,1H),7.01(dd,J＝9.0,2.0Hz,1H),6.74(d,J＝2.0Hz,1H),5.58(d,J＝9.6Hz,1H),3.98(d,J＝10.1Hz,1H),3.67(t,J＝9.4Hz,1H),2.451-2.41(m,1H),2.17–1.95(m,2H),1.73-1.60(m,3H).
步骤5：制备5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-碘-1-(四氢-2H-吡喃-2-基)-1H-吲唑
Figure PCTCN2016089443-appb-000086
将5-羟基吲哚换成3-碘-1-(四氢-2H-吡喃-2-基)-1H-吲唑-5-醇，其余所需原料、试剂及制备方法同实施例1中的步骤3，得白色固体5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-碘-1-(四氢-2H-吡喃-2-基)-1H-吲唑。
1H NMR(300MHz,CDCl3)δ8.42(s,2H),7.44(dd,J＝9.1,2.1Hz,1H),7.15(dd,J＝9.1,2.4Hz,1H),6.70(d,J＝2.2Hz,1H),6.06(q,J＝6.6Hz,1H),5.64–5.55(m,1H),4.06–3.92(m,1H),3.75–3.62(m,1H),2.56–2.39(m,1H),2.20–1.95(m,3H),1.81(d,J＝6.7Hz,3H),1.75–1.61(m,4H).
步骤6：制备1H-吲哚-1-羧酸叔丁酯
Figure PCTCN2016089443-appb-000087
将500毫克吲哚，1.02g二碳酸二叔丁酯，溶于20毫升二氯甲烷中，加入52毫克4-二甲基氨基吡啶，室温下搅拌过夜，反应液加水分液，水相二氯甲烷萃取，合并有机相，用饱和氯化钠水溶液洗涤后无水硫酸钠干燥，过滤浓缩,残余物柱层析(乙酸乙酯：石油醚＝2:98)分离得810毫克无色油状物，收率87％。
步骤7：制备(1-(叔丁氧羰基)-1H-吲哚-2-基)硼酸
Figure PCTCN2016089443-appb-000088
将300毫克1H-吲哚-1-羧酸叔丁酯溶于5毫升四氢呋喃中，加入1.5毫升三异丙基硼酸酯，冷却至0℃，滴加760微升二异丙基氨基锂溶液(2摩尔每升)，滴毕室温下继续搅拌6小时，加入饱和氯化铵水溶液淬灭，加入乙酸乙酯萃取，有机相用饱和氯化钠水溶液洗涤后无水硫酸钠干燥，过滤浓缩得480毫克棕黄色固体，收率100％。
1H NMR(300MHz,CDCl3)δ：8.02(d,J＝8.5Hz,1H),7.61(d,J＝7.8Hz,1H),7.49(s,1H),7.36(t,J＝7.8Hz,1H),7.29–7.22(m,2H),7.10(s,2H),1.75 (s,9H).
步骤8：制备2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-基)-1H-吲哚-1-羧酸叔丁酯
Figure PCTCN2016089443-appb-000089
将25毫克5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-碘-1-(四氢-2H-吡喃-2-基)-1H-吲唑、25毫克(1-(叔丁氧羰基)-1H-吲哚-2-基)硼酸、31毫克碳酸铯溶于3毫升二氧六环中，氩气置换后加入7毫克[1,1’-双(二苯基膦)二茂铁]二氯化钯，80℃下搅拌2小时，恢复至室温后，反应液浓缩至干，柱层析(乙酸乙酯：石油醚＝5:95)分离得23毫克白色固体，收率78％
1H NMR(300MHz,CDCl3)δ8.38(s,1H),8.29(d,J＝8.5Hz,1H),7.60(d,J＝7.8Hz,1H),7.49(dd,J＝9.0,2.8Hz,1H),7.39(t,J＝7.8Hz,1H),7.29(d,J＝7.0Hz,1H),7.11(dd,J＝9.0,2.3Hz,1H),6.92(s,1H),6.74(d,J＝5.3Hz,1H),5.94(q,J＝6.3Hz,1H),5.72–5.63(m,1H),4.04(d,J＝9.8Hz,1H),3.79–3.67(m,1H),2.63–2.47(m,1H),2.20–2.00(m,2H),1.75(d,J＝6.7Hz,4H),1.68(dd,J＝11.5,5.6Hz,2H),1.02(d,J＝9.1Hz,8H).
步骤9：制备5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(1H-吲哚-2-基)-1H-吲唑
Figure PCTCN2016089443-appb-000090
将30毫克2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-基)-1H-吲哚-1-羧酸叔丁酯溶于3毫升甲醇中，加入1毫升氯化氢/乙醇溶液(4摩尔每升)，室温下搅拌48小时，浓缩至干，30％氢氧化钠水溶液中和后乙酸乙酯萃取，有机相用饱和氯化钠水溶液洗涤后无水硫酸钠干燥，过滤浓缩,残余物柱层析(二氯甲烷：甲醇＝97:3)分离得10毫克淡粉色固体，收率48％。
1H NMR(300MHz,CDCl3)δ：9.05(s,1H),8.45(s,2H),7.71(d,J＝7.6Hz,1H),7.39(t,J＝8.5Hz,2H),7.31(d,J＝2.0Hz,1H),7.24–7.12(m,2H),6.97(s,1H),6.14(q,J＝6.7Hz,1H),1.86(d,J＝6.7Hz,3H).
实施例22
N1-(2-(5-(1-(3,5-二氯吡啶-4-基)甲氧基)-1H-吲哚-3-基)-1H-苯并[d]咪唑-6-基)-N2,N2-二甲基乙烷-1,2-二胺(I-22)
Figure PCTCN2016089443-appb-000091
步骤1：制备N1,N1-(2-(二甲基氨基)乙基)-4-硝基苯-1,2-二胺
Figure PCTCN2016089443-appb-000092
将4-哌啶基哌啶换成N1,N1-二甲基乙烷-1,2-二胺，其余所需原料、试剂及制备方法同 实施例1中的步骤6，得黄色固体N1,N1-(2-(二甲基氨基)乙基)-4-硝基苯-1,2-二胺。
1H NMR(300MHz,DMSO)δ：7.71(d,J＝9.6Hz,1H),7.34(s,2H),6.81(t,J＝5.2Hz,1H),6.05(dd,J＝9.6,2.4Hz,1H),5.83(d,J＝2.4Hz,1H),3.12(q,6.7Hz,2H),2.42(t,J＝6.7Hz,2H),2.18(s,6H).
步骤2：制备N1-(2-(5-(1-(3,5-二氯吡啶-4-基)甲氧基)-1H-吲哚-3-基)-1H-苯并[d]咪唑-6-基)-N2,N2-二甲基乙烷-1,2-二胺
将5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成N1,N1-(2-(二甲基氨基)乙基)-4-硝基苯-1,2-二胺，其余所需原料、试剂及制备方法同实施例1中的步骤6，得黄色固体N1-(2-(5-(1-(3,5-二氯吡啶-4-基)甲氧基)-1H-吲哚-3-基)-1H-苯并[d]咪唑-6-基)-N2,N2-二甲基乙烷-1,2-二胺
1H NMR(300MHz,DMSO)δ:13.43-13.27(m,1H),12.40-12.30(m,1H),8.60(s,2H),7.83-7.79(m,1H),7.53-7.50(m,1H),7.45-7.17(m,1H),7.14-7.10(m,1H),6.86-6.54(m,1H),6.64-6.61(m,1H),6.08(q,J＝6.7Hz,1H),5.30(t,J＝6.0Hz,1H),3.19-3.09(m,2H),2.55-2.47(m,2H),2.25-1.78(d,J＝6.7Hz,3H).
实施例23
N1-(2-(5-(1-(3,5-二氯吡啶-4-基)甲氧基)-1H-吲哚-3-基)-1H-苯并[d]咪唑-6-基)-N2,N2-二乙基乙烷-1,2-二胺(I-23)
Figure PCTCN2016089443-appb-000093
步骤1：制备N1,N1-(2-(二乙基氨基)乙基)-4-硝基苯-1,2-二胺
Figure PCTCN2016089443-appb-000094
将4-哌啶基哌啶换成N1,N1-二乙基乙烷-1,2-二胺，其余所需原料、试剂及制备方法同实施例1中的步骤5，得黄色固体N1,N1-(2-(二乙基氨基)乙基)-4-硝基苯-1,2-二胺。
1H NMR(300MHz,DMSO)δ：7.71(d,J＝9.5Hz,1H),7.34(s,2H),6.78(t,J＝5.2Hz,1H),6.03(dd,J＝9.6,2.4Hz,1H),5.84(d,J＝2.4Hz,1H),3.10(q,6.7Hz,2H),2.62–2.50(m,6H),0.96(t,J＝7.1Hz,6H).
步骤2：N1-(2-(5-(1-(3,5-二氯吡啶-4-基)甲氧基)-1H-吲哚-3-基)-1H-苯并[d]咪唑-6-基)-N2,N2-二乙基乙烷-1,2-二胺
将5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成N1,N1-(2-(二乙基氨基)乙基)-4-硝基苯-1,2-二胺，其余所需原料、试剂及制备方法同实施例1中的步骤6，得黄色固体N1-(2-(5-(1-(3,5-二氯吡啶-4-基)甲氧基)-1H-吲哚-3-基)-1H-苯并[d]咪唑-6-基)-N2,N2-二乙基乙烷-1,2-二胺
1H NMR(400MHz,DMSO)δ:13.39-13.31(m,1H),12.46-12.36(m,1H),8.60(s,2H),7.83-7.79(m,1H),7.53–7.49(m,1H),7.47–7.20(m,1H),7.14-7.12(m,1H),6.90-6.58(m,1H),6.65-6.61(m,1H),6.10-6.06(m,1H),3.24(s,2H),3.10–2.62(m,6H),1.77(d,J＝6.7Hz,3H),1.09(m,6H).
实施例24
N1-(2-(5-(1-(3,5-二氯吡啶-4-基)甲氧基)-1H-吲哚-3-基)-1H-苯并[d]咪唑-6- 基)-N3,N3-二甲基丙烷-1,3-二胺(I-24)
Figure PCTCN2016089443-appb-000095
步骤1：制备N1,N1-(3-(二甲基氨基)丙基)-4-硝基苯-1,3-二胺
Figure PCTCN2016089443-appb-000096
将4-哌啶基哌啶换成N1,N1-二甲基丙烷-1,3-二胺，其余所需原料、试剂及制备方法同实施例1中的步骤5，得黄色固体N1,N1-(2-(二甲基氨基)丙基)-4-硝基苯-1,3-二胺。
1H NMR(300MHz,DMSO)δ：7.71(d,J＝9.6Hz,1H),7.34(s,2H),6.95(t,J＝4.3Hz,1H),6.01(dd,J＝9.6,2.1Hz,1H),5.81(d,J＝2.1Hz,1H),3.05(q,6.2Hz,2H),2.27(t,J＝7.0Hz,2H),2.13(s,6H),1.74–1.61(m,2H).
步骤2：N1-(2-(5-(1-(3,5-二氯吡啶-4-基)甲氧基)-1H-吲哚-3-基)-1H-苯并[d]咪唑-6-基)-N3,N3-二甲基丙烷-1,3-二胺
将5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成N1,N1-(3-(二甲基氨基)丙基)-4-硝基苯-1,3-二胺，其余所需原料、试剂及制备方法同实施例1中的步骤6，得黄色固体N1-(2-(5-(1-(3,5-二氯吡啶-4-基)甲氧基)-1H-吲哚-3-基)-1H-苯并[d]咪唑-6-基)-N3,N3-二甲基丙烷-1,3-二胺
1H NMR(300MHz,DMSO)δ13.34-13.27(m,1H),12.40-12.28(m,1H),8.60(s,2H),7.83-7.79(m,1H),7.50-7.48(m,1H),7.43-7.16(m,1H),7.13-7.11(m,1H),6.82-6.50(m,1H),6.60-6.58(m,1H),6.08(q,J＝6.7Hz,1H),5.54(s,1H),3.12-3.04(m,2H),2.35(m,2H),2.20-2.17(m,6H),1.78-1.76(m,5H).
实施例25
4-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-1H-苯并[d]咪唑-6-基)哌嗪-1-羧酸叔丁酯(I-25)
Figure PCTCN2016089443-appb-000097
步骤1：制备4-(3-氨基-4-硝基苯基)哌嗪-1-羧酸叔丁酯
Figure PCTCN2016089443-appb-000098
将4-哌啶基哌啶换成哌嗪-1-羧酸叔丁酯，其余所需原料、试剂及制备方法同实施例1中的步骤5，得黄色固体4-(3-氨基-4-硝基苯基)哌嗪-1-羧酸叔丁酯。
1H NMR(400MHz,CDC13)δ:8.02(d,J＝9.6Hz,1H),6.22(dd,J＝9.6,2.4Hz,1H),6.15(s,2H),5.91(d,J＝2.4Hz,1H),3.42-3.47(m,4H),3.31-3.35(m,4H),1.41(s,9H).
步骤2：制备4-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-1H-苯并[d]咪唑-6-基)哌嗪-1-羧酸叔丁酯
将5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成4-(3-氨基-4-硝基苯基)哌嗪-1-羧酸 叔丁酯，其余所需原料、试剂及制备方法同实施例1中的步骤6，得米色固体4-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-1H-苯并[d]咪唑-6-基)哌嗪-1-羧酸叔丁酯
1H NMR(300MHz,DMSO)δ:13.43-13.38(m,1H),12.65-12.62(m,1H),8.61(s,2H),7.83-7.79(m,1H),7.59-7.32(m,1H),7.52(d,J＝8.1Hz,1H),7.23-6.90(m,1H),7.13(d,J＝8.8Hz,1H),6.99-6.98(m,1H),6.09(q,J＝6.7Hz,1H),3.52(s,4H),3.09(s,4H),1.78(d,J＝6.7Hz,3H),1.43(s,9H).
实施例26
5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(6-(哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑盐酸盐(I-26)
Figure PCTCN2016089443-appb-000099
将12毫克4-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-1H-苯并[d]咪唑-6-基)哌嗪-1-羧酸叔丁酯溶于1毫升甲醇中，加入1毫升氯化氢/乙醇溶液(4摩尔每升)，室温下搅拌48小时，反应液浓缩至干，干燥后得5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(6-(哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑盐酸盐
1H NMR(300MHz,DMSO)δ：9.19(s,2H),8.59(s,1H),7.98(s,1H),7.74–7.63(m,2H),7.29(d,J＝7.1Hz,1H),7.19(d,J＝9.2Hz,2H),6.20(q,J＝6.6Hz,1H),3.45(s,4H),3.30(s,4H),1.80(d,J＝6.6Hz,2H).
实施例27
4-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-1H-苯并[d]咪唑-6-基)哌啶-1-甲酸叔丁酯(I-27)
Figure PCTCN2016089443-appb-000100
步骤1：制备4-氧代哌啶-1-羧酸叔丁酯
Figure PCTCN2016089443-appb-000101
将2克4-氧代哌啶酮盐酸盐溶于25毫升甲醇中，加入3.1毫升三乙胺，依次加入4.4克二碳酸二叔丁酯、95毫克4-二甲基氨基吡啶，室温下搅拌4小时后反应液浓缩，加乙酸乙酯溶解，有机相用饱和碳酸氢钠溶液和水依次洗涤后，无水硫酸钠干燥，过滤浓缩，得乳白色固体2.57克，收率8％
1H NMR(300MHz,CDCl3)δ：3.71(t,J＝6.2Hz,4H),2.44(t,J＝6.2Hz,4H),1.49(s,9H).
步骤2：制备4-三氟甲基磺酰氧基-5,6-二氢吡啶-1(2H)-甲酸叔丁酯
Figure PCTCN2016089443-appb-000102
将6.5毫升二异丙基氨基锂溶液(2摩尔每升)溶于10毫升四氢呋喃中，-78℃下滴加2克4-氧代哌啶-1-羧酸叔丁酯的15毫升四氢呋喃溶液，滴毕，继续搅拌30分钟，-78℃下滴加3.26克N-苯基双(三氟甲烷磺酰)亚胺的15毫升四氢呋喃溶液，该温度下搅拌1小时后恢 复至室温，反应液加入乙酸乙酯萃取，有机相用饱和氯化铵溶液洗涤之后无水硫酸钠干燥，过滤浓缩，残余物柱层析(乙酸乙酯：石油醚＝5：95)分离得2.26克浅棕色油状物，收率75％。
1H NMR(300MHz,CDCl3)δ：5.76(s,1H),4.05(s,2H),3.63(s,2H),2.44(s,2H),1.47(s,9H).
步骤3：制备4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-5,6-二氢吡啶-1(2H)-甲酸叔丁酯
Figure PCTCN2016089443-appb-000103
将330毫克4-三氟甲基磺酰氧基-5,6-二氢吡啶-1(2H)-甲酸叔丁酯，356毫克联硼酸频那醇酯，324毫克醋酸钾溶液10毫升1,4-二氧六环中，加入37毫克1,1’-双二苯基膦二茂铁二氯化钯，80℃下搅拌2小时，恢复至室温后，过滤浓缩，残余物柱层析(乙酸乙酯：石油醚＝5：95)分离得250毫克白色固体，收率81％。
1H NMR(300MHz,CDCl3)δ：6.46(s,1H),3.94(d,J＝2.6Hz,2H),3.43(t,J＝5.4Hz,2H),2.22(s,2H),1.45(s,9H),1.26(s,12H).
步骤4：制备4-(4-氨基-3-硝基苯基)-5,6-二氢吡啶-1(2H)-甲酸叔丁酯
Figure PCTCN2016089443-appb-000104
将50毫克2-硝基-4-溴苯胺、85毫克4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-5,6-二氢吡啶-1(2H)-甲酸叔丁酯、95毫克碳酸钾溶于4毫升N,N-二甲基甲酰胺中，加入15毫克1,1’-双二苯基膦二茂铁二氯化钯，80℃下搅拌2小时，恢复至室温后，过滤浓缩，残余物柱层析(乙酸乙酯：石油醚＝20：80)分离得250毫克棕色固体29毫克，收率40％。
1H NMR(300MHz,CDCl3)δ：8.09(s,1H),7.46(dd,J＝8.7,1.9Hz,1H),6.79(d,J＝8.7Hz,1H),6.09(s,2H),6.01(s,1H),4.07(d,J＝2.3Hz,2H),3.63(t,J＝5.7Hz,2H),2.48(s,2H),1.49(s,9H).
步骤5：制备4-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-1H-苯并[d]咪唑-6-基)哌啶-1-甲酸叔丁酯
将5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成4-(4-氨基-3-硝基苯基)-5,6-二氢吡啶-1(2H)-甲酸叔丁酯，其余所需原料、试剂及制备方法同实施例1中的步骤6，得黄色固体4-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-1H-苯并[d]咪唑-6-基)哌啶-1-甲酸叔丁酯
1H NMR(300MHz,DMSO)δ13.45(s,1H),12.76(s,1H),8.60(s,2H),7.82(m,1H),7.67-7.37(m,1H),7.53-7.28(m,2H),7.17-7.10(m,2H),6.10(q,J＝6.7Hz,1H),4.11(s,2H),2.84(s,3H),1.88-1.77(m,2H),1.78(d,J＝6.7Hz,3H),1.44(s,9H).
实施例28
5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(6-(哌啶-4-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑盐酸盐(I-28)
Figure PCTCN2016089443-appb-000105
将4-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-1H-苯并[d]咪唑-6-基)哌嗪-1-羧酸叔丁酯换成4-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-1H-苯并[d]咪唑-6-基)哌啶-1-甲酸叔丁酯，其余所需原料、试剂及制备方法同实施例25，得5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(6-(哌啶-4-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑盐酸盐
1H NMR(400MHz,DMSO)δ：9.15(s,2H),8.58(s,2H),8.12(s,1H),7.80(d,J＝7.8Hz,1H),7.73–7.61(m,2H),7.40(d,J＝7.6Hz,1H),7.19(d,J＝8.5Hz,1H),6.24(q,J＝6.5Hz,1H),3.40(d,J＝12.5Hz,2H),3.05(s,3H),2.01(s,4H),1.80(d,J＝6.5Hz,3H).
实施例29
5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(6-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑(I-29)
Figure PCTCN2016089443-appb-000106
步骤1：制备N-(4-溴苯基)乙酰胺
Figure PCTCN2016089443-appb-000107
将5克4-溴苯胺溶于50毫升二氯甲烷中加入13毫升三乙胺，冰水浴下滴加2.7毫升乙酰氯，滴毕，室温下搅拌2小时，加水分液，有机相用饱和氯化钠水溶液洗涤后无水硫酸钠干燥，过滤浓缩，残余物柱层析(乙酸乙酯：石油醚＝40:60)分离得3.6克黄色固体，收率58％。
1H NMR(300MHz,CDCl3)δ：7.40(m,4H),2.16(s,3H).
步骤2：制备N-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯基)乙酰胺
Figure PCTCN2016089443-appb-000108
将4-三氟甲基磺酰氧基-5,6-二氢吡啶-1(2H)-甲酸叔丁酯换成N-(4-溴苯基)乙酰胺，其余所需原料、试剂及制备方法同实施例28，步骤3，得黄色油状物N-(4-(4,4,5,5-四甲基-1,3-二氧戊环-2-基)苯基)乙酰胺。
1H NMR(300MHz,CDCl3)δ：7.76(d,J＝8.0Hz,2H),7.51(d,J＝8.0Hz,2H),2.18(s,3H),1.33(s,12H).
步骤3：制备N-(4-(吡啶-4-基)苯基)乙酰胺
Figure PCTCN2016089443-appb-000109
将1.95克4-吡啶盐酸盐、3.13克N-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯基)乙酰胺、4.3克碳酸钠溶于20毫升去离子水、80毫升四氢呋喃中，加入360毫克1,1’- 双二苯基膦二茂铁二氯化钯，回流4小时后停止加热，恢复至室温后浓缩，残余物柱层析(二氯甲烷：甲醇＝97:3)得1.96克黄色固体，收率84％。
1H NMR(300MHz,CDCl3)δ8.63(d,J＝6.2Hz,2H),7.68–7.57(m,4H),7.49(d,J＝6.2Hz,2H),2.22(s,3H).
步骤4：制备4-(4-乙酰氨基苯基)-1-甲基吡啶-1-鎓甲基硫酸盐
Figure PCTCN2016089443-appb-000110
将1.4克N-(4-(吡啶-4-基)苯基)乙酰胺溶于20毫升N,N-二甲基甲酰胺中，加入1.2毫升硫酸二甲酯，室温下搅拌6小时，加入40毫升乙醚，搅拌10分钟后，加入20毫升乙醇，搅拌10分钟后过滤，滤饼乙醇洗涤，干燥得1.7克黄色固体，收率76％。
1H NMR(400MHz,DMSO)δ：10.35(s,1H),8.93(d,J＝6.8Hz,2H),8.43(d,J＝6.8Hz,2H),8.08(d,J＝8.8Hz,2H),7.82(d,J＝8.8Hz,2H),4.28(s,3H),2.11(s,3H).
步骤5：制备N-(4-(1-甲基哌啶-4-基)苯基)乙酰胺
Figure PCTCN2016089443-appb-000111
将200毫克4-(4-乙酰氨基苯基)-1-甲基吡啶-1-鎓甲基硫酸盐溶于20毫升乙醇中，加入550毫克甲酸铵、100毫克10％钯碳，回流18小时，恢复至室温后，反应液浓缩，2摩尔每升氢氧化钠水溶液碱化后，二氯甲烷萃取，有机相用饱和氯化钠水溶液洗涤后无水硫酸钠干燥，过滤浓缩，得116毫克白色固体，收率84％。
1H NMR(400MHz,CDCl3)δ7.40(d,J＝8.2Hz,2H),7.29(s,1H),7.16(d,J＝8.2Hz,2H),2.97(d,J＝11.2Hz,2H),2.49–2.39(m,1H),2.32(s,3H),2.15(s,3H),2.08–2.00(m,2H),1.84–1.74(m,4H).
步骤6：制备N-(4-(1-甲基哌啶-4-基)-2-硝基苯基)乙酰胺
Figure PCTCN2016089443-appb-000112
冰浴下向2毫升乙酸、5毫升乙酸酐混合溶液中加入140微升65％硝酸、两滴98％浓硫酸，搅拌10分钟后，滴加232毫克N-(4-(1-甲基哌啶-4-基)苯基)乙酰胺的3毫升乙酸溶液，滴毕，恢复至室温搅拌4小时，加入2摩尔每升氢氧化钠水溶液碱化后，二氯甲烷萃取，有机相用饱和氯化钠水溶液洗涤后无水硫酸钠干燥，过滤浓缩，得300毫克橙色油状物，收率100％。
1H NMR(300MHz,CDCl3)δ:10.21(s,1H),8.67(d,J＝8.7Hz,1H),8.05(d,J＝1.7Hz,1H),7.53(dd,J＝8.7,1.7Hz,1H),3.24(d,J＝11.7Hz,2H),2.70–2.55(m,1H),2.47(s,3H),2.40–2.24(m,5H),2.11–1.83(m,7H).
步骤7：制备4-(1-甲基哌啶-4-基)-2-硝基苯胺
Figure PCTCN2016089443-appb-000113
将277毫克N-(4-(1-甲基哌啶-4-基)-2-硝基苯基)乙酰胺溶于5毫升甲醇中，加1毫升 20％氢氧化钾水溶液，室温下搅拌过夜，反应液浓缩至干，加入二氯甲烷溶解，有机相水洗、饱和氯化钠水溶液洗涤后无水硫酸钠干燥，过滤浓缩，得300毫克橙色油状物，收率100％。
1H NMR(300MHz,DMSO)δ：7.74(d,J＝1.8Hz,1H),7.34(dd,J＝8.7,1.8Hz,1H),7.31(s,2H),6.97(d,J＝8.7Hz,1H),2.83(d,J＝11.3Hz,2H),2.43–2.30(m,1H),2.17(s,3H),1.98–1.86(m,2H),1.75–1.64(m,2H),1.64–1.48(m,2H).
步骤8：制备5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(6-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑
将5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成4-(1-甲基哌啶-4-基)-2-硝基苯胺，其余所需原料、试剂及制备方法同实施例1中的步骤6，得黄色固体5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(6-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑。
1H NMR(300MHz,DMSO)δ:13.44(s,1H),12.73(s,1H),8.60(s,2H),7.82(m,1H),7.66-7.36(m,1H),7.55-7.29(m,2H),7.16-7.10(m,2H),6.10(q,J＝6.7Hz,1H),2.94-2.89(m,2H),2.60-2.50(m,2H),2.23-2.21(m,3H),2.01-1.96(m,2H),1.79-1.69(m,7H).
实施例30
4-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-1H-苯并[d]咪唑-6-基)吗啉(I-30)
Figure PCTCN2016089443-appb-000114
步骤1：制备5-吗啉-2-硝基苯胺
Figure PCTCN2016089443-appb-000115
将4-哌啶基哌啶换成吗啉，其余所需原料、试剂及制备方法同实施例1中的步骤5，得黄色固体5-吗啉-2-硝基苯胺
1H NMR(400MHz,DMSO)δ:7.73:(d,J＝9.7Hz,1H),7.20(s,2H),6.30(dd,J＝2.7,9.7Hz,1H),6.12(d,J＝2.7Hz,1H),3.61(t,J＝4.8Hz,4H),3.18(t,J＝5.0Hz,4H).
步骤2：制备4-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-1H-苯并[d]咪唑-6-基)吗啉
将5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成5-吗啉-2-硝基苯胺，其余所需原料、试剂及制备方法同实施例1中的步骤6，得黄色固体4-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-1H-苯并[d]咪唑-6-基)吗啉。
1H NMR(300MHz,DMSO)δ:13.40(s,1H),12.61(s,1H),8.61(s,2H),7.81(s,1H),7.57(s,1H),7.53(d,J＝9.0Hz,1H),7.14(dd,J＝9.0,2.4Hz,1H),6.99(d,J＝8.4Hz,1H),6.91(s,1H),6.10(q,J＝6.7Hz,1H),3.80(s,4H),3.12(s,4H),1.78(d,J＝6.7Hz,3H).
实施例31
2-(4-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-1H-苯并[d]咪唑-6-基)哌嗪-1-基)乙醇(I-31)
Figure PCTCN2016089443-appb-000116
步骤1：制备2-(4-(3-氨基-4-硝基苯基)哌嗪-1-基)乙醇
Figure PCTCN2016089443-appb-000117
将4-哌啶基哌啶换成吗啉，其余所需原料、试剂及制备方法同实施例1中的步骤5，得黄色固体5-吗啉-2-硝基苯胺
1H NMR(300MHz,DMSO)δ7.80:(d,J＝9.7Hz,1H),7.26(s,2H),6.39(d,J＝9.9Hz,1H),6.20(s,1H),4.46(s,1H),3.53(t,J＝6.2Hz,2H),3.36–3.26(m,6H),2.53–2.48(m,2H),2.42(t,J＝5.9Hz,2H).
步骤2：制备2-(4-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-1H-苯并[d]咪唑-6-基)哌嗪-1-基)乙醇
将5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成2-(4-(3-氨基-4-硝基苯基)哌嗪-1-基)乙醇，其余所需原料、试剂及制备方法同实施例1中的步骤6，得黄色固体2-(4-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-1H-苯并[d]咪唑-6-基)哌嗪-1-基)乙醇
1H NMR(300MHz,DMSO)δ:13.41-13.36(m,1H),12.60-12.55(m,1H),8.60(s,2H),7.84-7.80(m,1H),7.58-7.30(m,1H),7.52(d,J＝8.1Hz,1H),7.19-6.88(m,1H),7.14(d,J＝8.8Hz,1H),6.70-6.95(m,1H),6.10(q,J＝6.7Hz,1H),4.47-4.42(m,1H),3.60-3.52(m,2H),3.13(m,4H),2.61(m,4H),2.48-2.43(m,2H),1.78(d,J＝6.7Hz,3H).
实施例32
2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-N-(2-(吡咯烷-1-基)乙基)-1H-苯并[d]咪唑-6-胺(I-32)
Figure PCTCN2016089443-appb-000118
步骤1：制备4-硝基-N1-(2-(吡咯烷-1-基)乙基)苯-1,3-二胺
Figure PCTCN2016089443-appb-000119
将4-哌啶基哌啶换成2-(吡咯烷-1-基)乙胺，其余所需原料、试剂及制备方法同实施例1中的步骤5，得黄色固体4-硝基-N1-(2-(吡咯烷-1-基)乙基)苯-1,3-二胺
1H NMR(300MHz,DMSO)δ:7.70(d,J＝9.6Hz,1H),7.32(s,2H),6.87(s,1H),6.03(d,J＝9.6Hz,1H),5.82(s,1H),3.14(s,2H),2.58(s,2H),2.46(s,4H),1.67(s,4H).
步骤2：制备2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-N-(2-(吡咯烷-1-基)乙基)-1H-苯并[d]咪唑-6-胺
将5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成4-硝基-N1-(2-(吡咯烷-1-基)乙基)苯-1,3-二胺，其余所需原料、试剂及制备方法同实施例1中的步骤6，得黄色固体2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-N-(2-(吡咯烷-1-基)乙基)-1H-苯并[d]咪唑-6-胺.
1H NMR(400MHz,DMSO)δ13.35-13.28(m,1H),12.41-12.30(m,1H),8.60(s,2H),7.83-7.80(m,1H),7.52-7.49(m,1H),7.44-7.17(m,1H),7.14-7.11(m,1H),6.85-6.53(m,1H),6.63-6.60(m,1H),6.08(q,J＝6.7Hz,1H),5.39(t,J＝6..0Hz,1H),3.17-3.12(m,2H),2.68-2.64(m,2H),2.55(m,4H),1.77(d,J＝6.7Hz,3H),1.71(s,2H).
实施例33
2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-N-(2-甲氧基乙基)-1H-苯并[d]咪唑-6-胺(I-33)
Figure PCTCN2016089443-appb-000120
步骤1：制备N1-(2-甲氧基乙基)-4-硝基苯-1,3-二胺
Figure PCTCN2016089443-appb-000121
将4-哌啶基哌啶换成2-甲氧基乙胺，其余所需原料、试剂及制备方法同实施例1中的步骤5，得黄色固体N1-(2-甲氧基乙基)-4-硝基苯-1,3-二胺。
1H NMR(300MHz,DMSO)δ7.72(dd,J＝9.5,2.1Hz,1H),7.33(s,2H),6.99(s,1H),6.06(d,J＝9.5Hz,1H),5.85(s,1H),3.51–3.44(m,2H),3.28(d,J＝2.5Hz,3H),3.25–3.18(m,2H).
步骤2：制备2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-N-(2-甲氧基乙基)-1H-苯并[d]咪唑-6-胺
将5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成N1-(2-甲氧基乙基)-4-硝基苯-1,3-二胺，其余所需原料、试剂及制备方法同实施例1中的步骤6，得黄色固体2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-N-(2-甲氧基乙基)-1H-苯并[d]咪唑-6-胺.
1H NMR(300MHz,DMSO)δ13.34-13.27(m,1H),12.42-12.30(m,1H),8.60(s,2H),7.80(s,1H),7.50(d,J＝8.1Hz,1H),7.44-7.19(m,1H),,7.14-7.10(m,1H),6.88-6.55(m,1H),6.64(d,J＝7.5Hz,1H),6.08(q,J＝6.7Hz,1H),5.55(s,1H),3.55(s,2H),3.31(s,3H),3.22(s,2H0,1.78(d,J＝6.7Hz,3H).
实施例34
5-(1-(3,5-二氯吡啶-4-基)乙氧基)-6氟-3-(6-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑(I-34)
Figure PCTCN2016089443-appb-000122
步骤1：制备1-苄氧基-2-氟-4-硝基苯
Figure PCTCN2016089443-appb-000123
将3克2-氟-4-硝基苯酚，7.9克碳酸钾和2.5毫升溴苄溶于100毫升丙酮，加热回流3小时，过滤浓缩，残余物柱层析(石油醚：二氯甲烷＝70:30)分离得3.85克白色固体1-苄氧基-2-氟-4-硝基苯，收率82％。
1H NMR(300MHz,DMSO)δ8.23–8.07(m,2H),7.55–7.32(m,6H),5.35(s,2H).
步骤2:制备2-(5-(苄氧基)-4-氟-2-硝基苯)乙腈
Figure PCTCN2016089443-appb-000124
将3克1-苄氧基-2-氟-4-硝基苯，2.28克4-氯苯氧乙腈溶于50毫升干燥的N,N-二甲基甲酰胺中，冷至-10℃后滴加3克叔丁醇钾的N,N-二甲基甲酰胺溶液10毫升，2小时后反应结束。倒入100毫升浓度为1M的盐酸冰浴中。用乙酸乙酯萃取，分液后有机相用饱和氯化钠水溶液洗涤后无水硫酸钠干燥，过滤浓缩，残余物柱层析(石油醚：二氯甲烷＝40:60)分离得2.9克产物与2-(3-(苄氧基)-2-氟-6-硝基苯)乙腈的混合物，收率84％。
步骤3:制备6-氟-1-H-吲哚-5-醇
Figure PCTCN2016089443-appb-000125
将2.9克2-(5-(苄氧基)-4-氟-2-硝基苯)乙腈溶于85毫升甲醇和15毫升乙酸的混合溶液中，加入钯炭。加压3公斤，加热50℃反应10小时。过滤浓缩，残余物柱层析(石油醚：乙酸乙酯＝90:10)分离得850毫克产物和4-氟-1-H-吲哚-5-醇的混合物，收率55％。
步骤4:制备5-(1-(3,5-二氯吡啶-4-基)乙氧基)-6-氟-1H-吲哚
Figure PCTCN2016089443-appb-000126
将5-羟基吲哚换成6-氟-1-H-吲哚-5-醇，其余所需原料、试剂及制备方法同实施例1中的步骤3，得无色油状物5-(1-(3,5-二氯吡啶-4-基)乙氧基)-6-氟-1H-吲哚1.2克。
1H NMR(300MHz,CDCl3)δ8.43(s,2H),8.20(s,1H),7.14–7.08(m,2H),6.97(d,J＝8.1Hz,1H),6.41–6.34(m,1H),5.98(q,J＝6.7Hz,1H),1.83(d,J＝6.7Hz,3H).
步骤5：制备5-(1-(3,5-二氯吡啶-4-基)丙氧基)-6-氟-1H-吲哚-3-甲醛
Figure PCTCN2016089443-appb-000127
将5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲哚换成5-(1-(3,5-二氯吡啶-4-基)乙氧基)-6-氟-1H-吲哚，其余所需原料、试剂及制备方法同实施例1中的步骤4，得棕色固体5-(1-(3,5-二氯吡啶-4-基)丙氧基)-6-氟-1H-吲哚-3-甲醛。
1H NMR(300MHz,DMSO)δ14.13(s,1H),10.05(s,1H),8.63(s,2H),7.64(d,J＝10.6Hz,1H),7.41(d,J＝8.0Hz,1H),6.10(q,J＝6.7Hz,1H),1.79(d,J＝6.7Hz,3H).
步骤6：5-(1-(3,5-二氯吡啶-4-基)乙氧基)-6-氟-3-(6-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑
将5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成5-(哌啶-1-基)-2-硝基苯胺，5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲哚-3-甲醛换成5-(1-(3,5-二氯吡啶-4-基)丙氧基)-6-氟-1H-吲哚-3-甲醛，其余所需原料、试剂及制备方法同实施例1中的步骤6，得白色固体5-(1-(3,5-二氯吡啶-4-基)乙氧基)-6-氟-3-(6-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑
1H NMR(400MHz,DMSO)δ13.49-13.44(m,1H),12.65-12.58(m,1H),8.63(s,2H),7.92-7.86(m,1H),7.57-7.30(m,1H),7.53(d,J＝9.0Hz,1H),7.19-6.88(m,1H),6.97-6.95(m,1H),6.12(q,J＝6.6Hz,1H),3.10(s,4H),1.81(d,J＝6.6Hz,3H),1.68(s,4H),1.54(m,2H).
实施例35
5-(1-(3,5-二氯吡啶-4-基)乙氧基)-4-氟-3-(6-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑(I-35)
Figure PCTCN2016089443-appb-000128
步骤1：制备5-(1-(3,5-二氯吡啶-4-基)乙氧基)-4-氟-1H-吲哚
Figure PCTCN2016089443-appb-000129
将5-羟基吲哚换成4-氟-1-H-吲哚-5-醇，其余所需原料、试剂及制备方法同实施例1中的步骤3，得无色油状物5-(1-(3,5-二氯吡啶-4-基)乙氧基)-4-氟-1H-吲哚。
1H NMR(300MHz,CDCl3)δ8.42(s,2H),7.15(m,1H),6.94(m,1H),6.80(m,1H),6.60(m,1H),5.98(q,J＝6.7Hz,1H),1.83(d,J＝6.7Hz,3H).
步骤2:制备5-(1-(3,5-二氯吡啶-4-基)丙氧基)-4-氟-1H-吲哚-3-甲醛
Figure PCTCN2016089443-appb-000130
将5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲哚换成5-(1-(3,5-二氯吡啶-4-基)乙氧基)-4-氟-1H-吲哚，其余所需原料、试剂及制备方法同实施例1中的步骤4，得棕色固体5-(1-(3,5-二氯吡啶-4-基)丙氧基)-4-氟-1H-吲哚-3-甲醛。
1H NMR(400MHz,DMSO)δ10.10(d,J＝4.0Hz,1H),8.61(s,2H),7.41(d,J＝8.9Hz,1H),7.26–7.10(m,1H),6.04(q,J＝6.6Hz,1H),1.79(d,J＝6.7Hz,3H).
步骤3：制备5-(1-(3,5-二氯吡啶-4-基)乙氧基)-4-氟-3-(6-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑
将5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成5-(哌啶-1-基)-2-硝基苯胺，5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲哚-3-甲醛换成5-(1-(3,5-二氯吡啶-4-基)丙氧基)-4-氟-1H-吲哚-3-甲醛，其余所需原料、试剂及制备方法同实施例1中的步骤6，得黄色固体5-(1-(3,5-二氯吡啶-4-基)乙氧基)-4-氟-3-(6-(哌啶-1-基)-1H-苯并[d]咪唑-2- 基)-1H-吲唑。
1H NMR(300MHz,DMSO)δ13.78(m,1H),12.59-12.52(m,1H),8.62(s,2H),7.50(m,1H),7.33-7.30(m,1H),7.21–7.08(m,1H),6.92(m,2H),5.99(q,J＝6.7Hz,1H),3.09(s,4H),1.81(d,J＝6.7Hz,3H),1.67(s,4H),1.54(m,2H).
实施例36
3-(6-([1,4’联哌啶]-1’-基)-1H-苯并[d]咪唑-2-基)-5-((3,5二氯吡啶-4-基)甲氧基)-1H-吲唑(I-36)
Figure PCTCN2016089443-appb-000131
步骤1：制备3，5-二氯吡啶甲醛
Figure PCTCN2016089443-appb-000132
将乙醛换成N,N-二甲基甲酰胺，其余所需原料、试剂及制备方法同实施例1中的步骤1，得白色固体3,5-二氯吡啶甲醛
1H NMR(300MHz,CDCl3)δ:10.45(s,1H),8.63(s,2H).
步骤2：制备(3,5-二氯吡啶-4-基)甲醇
Figure PCTCN2016089443-appb-000133
将2克3，5-二氯吡啶甲醛溶于100毫升甲醇中，0℃下分批加如650毫克硼氢化钠，室温搅拌2小时后反应结束。旋干溶剂，加入200毫升乙酸乙酯，然后用水洗，分液后有机相用饱和氯化钠水溶液洗涤后无水硫酸钠干燥，过滤浓缩，残余物柱层析(石油醚：乙酸乙酯＝70:30)分离得1.665克(3,5-二氯吡啶-4-基)甲醇，收率82％。
1H NMR(300MHz,CDCl3)δ:10.45(s,1H),8.63(s,2H).
步骤3：制备3,5-二氯-4-(氯甲基)吡啶盐酸盐
Figure PCTCN2016089443-appb-000134
20毫克(3,5-二氯吡啶-4-基)甲醇溶于5毫升二氯亚砜中，氩气下回流1小时，得黄色固体，减压浓缩溶剂得22毫克3,5-二氯-4-(氯甲基)吡啶盐酸盐
1H NMR(300MHz,DMSO)δ8.72(s,2H),4.87(s,2H).
步骤4：5-(3,5-二氯吡啶-4-基)甲氧基)-1H-吲哚
Figure PCTCN2016089443-appb-000135
将1-(3,5-二氯吡啶-4-基)乙基甲磺酸酯换成(3，5-二氯吡啶-4-基)甲基甲磺酸酯，其余所需原料、试剂及制备方法同实施例1中的步骤3，得黄色油状物5-(3,5-二氯吡啶-4-基)甲氧基)-1H-吲哚。
1H NMR(300MHz,CDCl3)δ8.55(s,2H),8.14(s,1H),7.31(d,J＝8.8Hz,1H),7.27(d,J＝2.4Hz,1H),7.22(m,1H),6.94(dd,J＝8.8,2.4Hz,1H),6.51(m,1H),5.29(s,2H).
步骤5：制备5-(3,5-二氯吡啶-4-基)甲氧基)-1H-吲唑-3-甲醛
Figure PCTCN2016089443-appb-000136
将5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲哚换成5-(3,5-二氯吡啶-4-基)甲氧基)-1H-吲哚，其余所需原料、试剂及制备方法同实施例1中的步骤4，得棕色固体5-(3,5-二氯吡啶-4-基)甲氧基)-1H-吲唑-3-甲醛。
1H NMR(300MHz,CDCl3)δ10.27(s,1H),8.55(s,2H),7.84(d,J＝2.3Hz,1H),7.48(d,J＝9.1Hz,1H),7.16(dd,J＝9.1,2.4Hz,1H),5.32(s,2H).
步骤6：3-(6-([1,4’联哌啶]-1’-基)-1H-苯并[d]咪唑-2-基)-5-((3,5二氯吡啶-4-基)甲氧基)-1H-吲唑
将5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲哚-3-甲醛换成5-(3,5-二氯吡啶-4-基)甲氧基)-1H-吲唑-3-甲醛，其余所需原料、试剂及制备方法同实施例1中的步骤6，得黄色固体3-(6-([1,4’联哌啶]-1’-基)-1H-苯并[d]咪唑-2-基)-5-((2,6二氯苄)氧基)-1H-吲唑
1H NMR(300MHz,CD3OD)δ:8.61(s,2H),8.11(d,J＝2.2Hz,1H),7.61-7.53(m,2H),7.30(s,1H),7.19–7.09(m,2H),5.45(s,2H),4.14(m,2H),3.22-3.11(m,7H),2.46(m,2H),2.37–2.04(m,8H),1.96(s,2H).
实施例37
5-((3,5-二氯吡啶-4-基)甲氧基)-3-(6-(哌啶-1-基-1H-苯并[d]咪唑-2-基)-1H-吲唑(I-37)
Figure PCTCN2016089443-appb-000137
将5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲哚-3-甲醛换成5-(3,5-二氯吡啶-4-基)甲氧基)-1H-吲唑-3-甲醛，5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成5-(哌啶-1-基)-2-硝基苯胺，其余所需原料、试剂及制备方法同实施例1中的步骤6，得黄色固体5-((3,5-二氯吡啶-4-基)甲氧基)-3-(6-(哌啶-1-基-1H-苯并[d]咪唑-2-基)-1H-吲唑
1H NMR(300MHz,CD3OD)δ:8.61(s,2H),8.11(d,J＝2.2Hz,1H),7.61-7.53(m,2H),7.30(s,1H),7.19–7.09(m,2H),5.45(s,2H),3.26–3.14(m,4H),1.89–1.75(m,4H),1.68–1.57(m,2H).
实施例38
3-(6-([1,4’联哌啶]-1’-基)-1H-苯并[d]咪唑-2-基)-5-((2,6二氯苄氧基)-1H-吲唑(I-38)
Figure PCTCN2016089443-appb-000138
步骤1：制备5-(2,6-二氯苄氧基)-1H-吲哚
Figure PCTCN2016089443-appb-000139
将1-(3,5-二氯吡啶-4-基)乙基甲磺酸酯换成2,6-二氯溴苄，其余所需原料、试剂及制 备方法同实施例1中的步骤3，得黄色油状物5-(2,6-二氯苄氧基)-1H-吲哚。
1H NMR(300MHz,CDCl3)δ8.11(s,1H),7.40–7.17(m,6H),6.97(m,1H),6.51(s,1H),5.32(s,2H).
步骤2：制备5-(2,6-二氯苄氧基)-1H-吲唑-3-甲醛
Figure PCTCN2016089443-appb-000140
将5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲哚换成5-(2,6-二氯苄氧基)-1H-吲哚，其余所需原料、试剂及制备方法同实施例1中的步骤4，得棕色固体5-(2,6-二氯苄氧基)-1H-吲唑-3-甲醛。
1H NMR(300MHz,DMSO)δ10.18(s,1H),7.71(d,J＝2.3Hz,1H),7.65(d,J＝9.0Hz,1H),7.59(m,1H),7.56(s,1H),7.48(m,1H),7.19(m,1H),5.31(s,2H).
步骤3：3-(6-([1,4’联哌啶]-1’-基)-1H-苯并[d]咪唑-2-基)-5-((2,6二氯苄氧基)-1H-吲唑
将5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲哚-3-甲醛换成5-(2,6-二氯苄氧基)-1H-吲唑-3-甲醛，其余所需原料、试剂及制备方法同实施例1中的步骤6，得黄色固体3-(6-([1,4’联哌啶]-1’-基)-1H-苯并[d]咪唑-2-基)-5-((2,6二氯苄)氧基)-1H-吲唑
1H NMR(300MHz,CD3OD)δ:8.11(d,J＝2.0Hz,1H),7.62–7.45(m,4H),7.41-7.35(m,1H),7.28-7.27(m,1H),7.17-7.09(m,2H),5.47(s,2H),4.15(m,2H),3.23-3.11(m,7H),2.47(m,2H),2.38–2.04(m,8H),1.97(s,2H)
实施例39
5-((2,6-二氯苄基)氧基)-3-(6-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑(I-39)
Figure PCTCN2016089443-appb-000141
将5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲哚-3-甲醛换成5-(2,6-二氯苄氧基)-1H-吲唑-3-甲醛，5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成5-(哌啶-1-基)-2-硝基苯胺，其余所需原料、试剂及制备方法同实施例1中的步骤6，得黄色固体3-(6-([1,4’联哌啶]-1’-基)-1H-苯并[d]咪唑-2-基)-5-((2,6二氯苄)氧基)-1H-吲唑
1H NMR(300MHz,CD3OD)δ:8.11(d,J＝2.0Hz,1H),7.62–7.45(m,4H),7.41-7.35(m,1H),7.28-7.27(m,1H),7.17-7.09(m,2H),5.47(s,2H),3.22–3.14(m,4H),1.86–1.75(m,4H),1.68–1.58(m,2H).
实施例40
3-(6-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-5-(吡啶-2-甲氧基)-1H-吲唑(I-40)
Figure PCTCN2016089443-appb-000142
步骤1：制备2-氯甲基吡啶盐酸盐
Figure PCTCN2016089443-appb-000143
将5毫升二氯亚砜用冰浴冷却，滴加1克的2-吡啶甲醇。滴加完毕后回流反应2小时。旋干反应液得黄色固体2-氯甲基吡啶盐酸盐。
1H NMR(300MHz，CDCl3)δ:4.68(2H，s)，7.25(m，1H)，7.49(d，J＝7.8Hz，1H)，7.71–7.76(td，J＝7.7，1.8Hz，1H)，8.58(m，1H)。
步骤2：制备5-(吡啶-2-甲氧基)-1H-吲哚
Figure PCTCN2016089443-appb-000144
将1-(3,5-二氯吡啶-4-基)乙基甲磺酸酯换成2-氯甲基吡啶盐酸盐，其余所需原料、试剂及制备方法同实施例1中的步骤3，得绿色固体物5-(吡啶-2-甲氧基)-1H-吲哚。
1H NMR(300MHz,CDCl3)δ8.55(s,2H),8.14(s,1H),7.31(d,J＝8.8Hz,1H),7.27(d,J＝2.4Hz,1H),7.22(m,1H),6.94(dd,J＝8.8,2.4Hz,1H),6.51(m,1H),5.29(s,2H).
步骤3：制备5-(吡啶-2-甲氧基)-1H-吲唑-3-甲醛
Figure PCTCN2016089443-appb-000145
将5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲哚换成5-(吡啶-2-甲氧基)-1H-吲哚，其余所需原料、试剂及制备方法同实施例1中的步骤4，得棕色固体5-(吡啶-2-甲氧基)-1H-吲唑-3-甲醛。
1H NMR(300MHz，CDCl3)δ10.23(s，1H)，8.64(d，J＝4.0Hz，1H)，7.76(m，2H)，7.56(d，J＝7.7Hz，1H)，7.43(d，J＝8.9Hz，1H)，7.18(d，J＝8.8Hz，1H)，5.28(d，J＝7.3Hz，2H)。
步骤4：3-(6-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-5-(吡啶-2-甲氧基)-1H-吲唑
将5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成5-(哌啶-1-基)-2-硝基苯胺，5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲哚-3-甲醛换成5-(吡啶-2-甲氧基)-1H-吲唑-3-甲醛，其余所需原料、试剂及制备方法同实施例1中的步骤6，得黄色固体3-(6-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-5-(吡啶-2-甲氧基)-1H-吲唑
1H NMR(300MHz,CD3OD)δ:8.57(d,J＝4.9Hz,1H),8.02(d,J＝2.0Hz,1H),7.90(td,J＝7.7,1.7Hz,1H),7.71-7.69(m,1H),7.62–7.50(m,2H),7.44–7.35(m,1H),7.29–7.21(m,2H),7.11(dd,J＝8.8,2.2Hz,1H),5.32(s,2H),3.25–3.11(m,4H),1.89–1.74(m,4H),1.69–1.56(m,2H).
实施例41
3-(6-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-5-(吡啶-3-甲氧基)-1H-吲唑(I-41)
Figure PCTCN2016089443-appb-000146
步骤1：制备3-氯甲基吡啶盐酸盐
Figure PCTCN2016089443-appb-000147
将1克的3-吡啶甲醇溶于15毫升二氯甲烷中，冰浴冷却。滴加二氯亚砜2毫升，移至 室温搅拌3小时。旋干反应液得黄色固体3-氯甲基吡啶盐酸盐。
1H NMR(300MHz，CDCl3)δ4.60(s，2H)，7.33(dd，J＝3.0，4.8Hz，1H)，7.74(1H，dt，J＝7.9，1.9Hz)，8.58(1H，dd，J＝3.3，1.5Hz)，8.63(1H，d，J＝2.0Hz)。
步骤2：5-(吡啶-3-甲氧基)-1H-吲哚
Figure PCTCN2016089443-appb-000148
将1-(3,5-二氯吡啶-4-基)乙基甲磺酸酯换成3-氯甲基吡啶盐酸盐，其余所需原料、试剂及制备方法同实施例1中的步骤3，得绿色固体物5-(吡啶-3-甲氧基)-1H-吲哚。
1H NMR(300MHz,CDCl3)δ8.55(s,2H),8.14(s,1H),7.31(d,J＝8.8Hz,1H),7.27(d,J＝2.4Hz,1H),7.22(m,1H),6.94(dd,J＝8.8,2.4Hz,1H),6.51(m,1H),5.29(s,2H).
步骤3：制备5-(吡啶-3-甲氧基)-1H-吲唑-3-甲醛
Figure PCTCN2016089443-appb-000149
将5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲哚换成5-(吡啶-3-甲氧基)-1H-吲哚，其余所需原料、试剂及制备方法同实施例1中的步骤4，得棕色固体5-(吡啶-3-甲氧基)-1H-吲唑-3-甲醛。
1H NMR(300MHz，CDCl3)δ10.28(s，1H)，8.77(s，1H)，8.63(d，J＝4.6Hz，1H)，7.85(d，J＝7.6Hz，1H)，7.79(s，1H)，7.50(d，J＝9Hz，1H)，7.43–7.34(m，1H)，7.20(d，J＝9Hz，1H)，5.17(s，2H)。
步骤4：3-(6-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-5-(吡啶-3-甲氧基)-1H-吲唑
将5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成5-(哌啶-1-基)-2-硝基苯胺，5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲哚-3-甲醛换成5-(吡啶-3-甲氧基)-1H-吲唑-3-甲醛，其余所需原料、试剂及制备方法同实施例1中的步骤6，得黄色固体3-(6-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-5-(吡啶-3-甲氧基)-1H-吲唑。
1H NMR(300MHz,CD3OD)δ:8.72(s,1H),8.51(d,J＝5.0Hz,1H),8.08–7.97(m,2H),7.63–7.45(m,3H),7.28(s,1H),7.22(dd,J＝9.1,2.2Hz,1H),7.12(dd,J＝8.8,2.1Hz,1H),5.30(s,2H),3.24–3.15(m,4H),1.86–1.74(m,4H),1.64(d,J＝5.2Hz,2H).
实施例42
3-(6-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-5-(吡啶-4-甲氧基)-1H-吲唑(I-42)
Figure PCTCN2016089443-appb-000150
步骤1：制备4-氯甲基吡啶盐酸盐
Figure PCTCN2016089443-appb-000151
将1克的4-吡啶甲醇溶于15毫升二氯甲烷中，冰浴冷却。滴加二氯亚砜2毫升，移至室温搅拌3小时。旋干反应液得黄色固体4-氯甲基吡啶盐酸盐。
1H NMR(300MHz，CDCl3)δ4.55(s，2H)，7.34(d，J＝5.9Hz，2H)，8.62(d，J＝5.9Hz，2H)。
步骤2：5-(吡啶-4-甲氧基)-1H-吲哚
Figure PCTCN2016089443-appb-000152
将1-(3,5-二氯吡啶-4-基)乙基甲磺酸酯换成4-氯甲基吡啶盐酸盐，其余所需原料、试剂及制备方法同实施例1中的步骤3，得绿色固体物5-(吡啶-4-甲氧基)-1H-吲哚。
1H NMR(300MHz,CDCl3)δ8.55(s,2H),8.14(s,1H),7.31(d,J＝8.8Hz,1H),7.27(d,J＝2.4Hz,1H),7.22(m,1H),6.94(dd,J＝8.8,2.4Hz,1H),6.51(m,1H),5.29(s,2H).
步骤3：制备5-(吡啶-4-甲氧基)-1H-吲唑-3-甲醛
Figure PCTCN2016089443-appb-000153
将5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲哚换成5-(吡啶-4-甲氧基)-1H-吲哚，其余所需原料、试剂及制备方法同实施例1中的步骤4，得棕色固体5-(吡啶-4-甲氧基)-1H-吲唑-3-甲醛。
1H NMR(300MHz,CDCl3)δ10.15(s，1H)，8.59(d，J＝5.1Hz，2H)，7.67(d，J＝9.1Hz，1H)，7.59(s，1H)，7.50(d，J＝5.2Hz，2H)，7.30–7.24(m，1H)，5.27(s，2H)。
步骤4：制备3-(6-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-5-(吡啶-4-甲氧基)-1H-吲唑
将5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成5-(哌啶-1-基)-2-硝基苯胺，5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲哚-3-甲醛换成5-(吡啶-4-甲氧基)-1H-吲唑-3-甲醛，其余所需原料、试剂及制备方法同实施例1中的步骤6，得黄色固体3-(6-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-5-(吡啶-4-甲氧基)-1H-吲唑。
1H NMR(300MHz,CD3OD)δ:8.55-8.54(m,2H),8.00(d,J＝2.0Hz,1H),7.61(d,J＝6.0Hz,2H),7.60-7.53(m,2H),7.25(dd,J＝9.1,2.4Hz,1H),7.24-7.23(m,1H),7.08(dd,J＝8.8,2.1Hz,1H),5.31(s,2H),3.19–3.08(m,4H),1.87–1.71(m,4H),1.66–1.55(m,2H).
实施例43
5-(1-(3,5-二氯吡啶-4-基)丙氧基)-3-(6-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑(I-43)
Figure PCTCN2016089443-appb-000154
步骤一：制备1-(3,5-二氯吡啶-4-基)丙醇
Figure PCTCN2016089443-appb-000155
将乙醛换成丙醛，其余所需原料、试剂及制备方法同实施例1中的步骤1，得黄色色油状物1-(3,5-二氯吡啶-4-基)丙醇
步骤2：制备1-(3,5-二氯吡啶-4-基)丙基甲磺酸酯
Figure PCTCN2016089443-appb-000156
将1-(3,5-二氯吡啶-4-基)乙醇换成1-(3,5-二氯吡啶-4-基)丙醇，其余所需原料、试剂及制备方法同实施例1中的步骤2，得白色蜡状固体1-(3,5-二氯吡啶-4-基)丙基甲磺酸酯。
1H NMR(300MHz,CDCl3)δ8.51(s，2H)，6.09(m，1H)，2.94(s，3H),2.35-2.23(m，1H)，2.04(m，1H)1.03(t,J＝7.4，3H).
步骤3：5-(1-(3,5-二氯吡啶-4-基)丙氧基)-1H-吲哚
Figure PCTCN2016089443-appb-000157
将1-(3,5-二氯吡啶-4-基)乙基甲磺酸酯换成1-(3,5-二氯吡啶-4-基)丙基甲磺酸酯，其余所需原料、试剂及制备方法同实施例1中的步骤3，得无色油状物5-(1-(3,5-二氯吡啶-4-基)丙氧基)-1H-吲哚
1H NMR(300MHz，CDCl3)δ8.52(s，2H)，7.42-7.31(m，1H)，7.26(s，1H)7.12(s，1H)，7.01(m，1H)，6.53(m，1H)，5.92-5.84(m，1H)，2.47(m，1H)，2.25-2.10(m，1H)，1.24(t，J＝7.4Hz，3H).
步骤4：制备5-(1-(3,5-二氯吡啶-4-基)丙氧基)-1H-吲哚-3-甲醛
Figure PCTCN2016089443-appb-000158
将5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲哚换成5-(1-(3,5-二氯吡啶-4-基)丙氧基)-1H-吲哚，其余所需原料、试剂及制备方法同实施例1中的步骤4，得棕色固体5-(1-(3,5-二氯吡啶-4-基)丙氧基)-1H-吲哚-3-甲醛.
1H NMR(300MHz，CDCl3)δ10.20(s，1H)，8.43(s，2H)，7.62(d，J＝2.1Hz，1H)，7.43(d，J＝9.1Hz，1H)，7.20(dd，J＝9.1，2.1Hz，1H)，5.86(m，1H)，2.35(m，7.6Hz，1H)，2.16–2.00(m，1H)，1.11(t，J＝7.4Hz，3H)。
步骤5：制备5-(1-(3,5-二氯吡啶-4-基)丙氧基)-3-(6-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑
将5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成5-(哌啶-1-基)-2-硝基苯胺，5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲哚-3-甲醛换成5-(1-(3,5-二氯吡啶-4-基)丙氧基)-1H-吲哚-3-甲醛，其余所需原料、试剂及制备方法同实施例1中的步骤6，得黄色固体5-(1-(3,5-二氯吡啶-4-基)丙氧基)-3-(6-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑
1H NMR(400MHz,MeOD)δ:8.41(s,2H),7.84(d,J＝2.1Hz,1H),7.57(d,J＝8.8Hz,1H),7.46(d,J＝9.0Hz,1H),7.25(s,1H),7.16(dd,J＝9.0,1.7Hz,1H),7.09(dd,J＝8.8,2.0Hz,1H),6.04–5.90(m,1H),3.23–3.05(m,4H),2.46–2.27(m,1H),2.16–2.01(m,1H),1.89–1.70(m,4H),1.62-1.58(m,2H),1.13(t,J＝7.4Hz,3H).
实施例44
(R)-2–(2–(5–(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-1H-苯并[d]咪唑-6-基)乙醇(I-44)
Figure PCTCN2016089443-appb-000159
将1-(3,5-二氯吡啶-4-基)乙醇换成(S)-1-(3,5-二氯吡啶-4-基)乙醇,其余所需原料、试剂及制备方法同实施例2，得(R)-2–(2–(5–(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-1H-苯并[d]咪唑-6-基)乙醇
1H NMR(300MHz,DMSO)δ:13.44(s,1H),12.72(s,1H),8.61-8.60(m,1H),7.82(s,1H),7.64-7.35(m,1H),7.56-7.30(m,1H),7.52(d,J＝8.1Hz,1H),7.57–7.51(m,1H),7.54(d,J＝9.0Hz,1H),7.30(s,1H),7.15(dd,J＝9.0,2.4Hz,1H),7.07(dd,J＝8.2,1.4Hz,1H),6.10(q,J＝6.7Hz,1H),4.71–4.61(m,1H),3.74–3.60(m,2H),2.91–2.81(m,2H),1.78(d,J＝6.6Hz,3H).
实施例45
(R)-5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(6-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑(I-48)
Figure PCTCN2016089443-appb-000160
将1-(3,5-二氯吡啶-4-基)乙醇换成(S)-1-(3,5-二氯吡啶-4-基)乙醇,其余所需原料、试剂及制备方法同实施例4，得(R)-5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(6-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑.
1H NMR(300MHz,DMSO)δ13.40-13.35(m,1H),12.58-12.52(m,1H),8.60(s,2H),7.84-7.80(m,1H),7.57-7.30(m,1H),7.52(d,J＝8.1Hz,1H),7.19-6.88(m,1H),7.13(d,J＝8.8Hz,1H),6.99-6.98(m,1H),6.10(q,J＝6.7Hz,1H),3.15-3.07(m,4H),1.78(d,J＝6.7Hz,3H),1.73-1.69(m,4H),1.58-1.50(m,2H)
实施例46
(R)-5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(6-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑(I-46)
Figure PCTCN2016089443-appb-000161
将1-(3,5-二氯吡啶-4-基)乙醇换成(S)-1-(3,5-二氯吡啶-4-基)乙醇,其余所需原料、试剂及制备方法同实施例3，得(R)-5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(6-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑
1H NMR(300MHz,DMSO)δ:13.41-13.36(m,1H),12.60-12.55(m,1H),8.60(s,2H),7.84-7.80(m,1H),7.58-7.30(m,1H),7.52(d,J＝8.1Hz,1H),7.19-6.88(m,1H),7.13(d,J＝8.8Hz,1H),6.99-6.98(m,1H),6.10(q,J＝6.7Hz,1H),3.13(s,4H),2.24(s,4H),1.78(d,J＝6.7Hz,3H).
实施例47
(R)-N-(2-(5-(1-(3,5二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-1H-苯并[d]咪唑-6- 基)-2-(二甲基氨基)-N-甲基乙酰胺(I-50)
Figure PCTCN2016089443-appb-000162
将1-(3,5-二氯吡啶-4-基)乙醇换成(S)-1-(3,5-二氯吡啶-4-基)乙醇,其余所需原料、试剂及制备方法同实施例10，得(R)-N-(2-(5-(1-(3,5二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)-1H-苯并[d]咪唑-6-基)-2-(二甲基氨基)-N-甲基乙酰胺
1H NMR(300MHz,CDCl3)δ8.31(s,2H),7.82(s,1H),7.66(d,J＝7.9Hz,1H),7.53(s,1H),7.41(d,J＝9.0Hz,1H),7.07(dd,J＝9.1,2.0Hz,1H),6.97(d,J＝8.4Hz,1H),6.09(q,J＝6.5Hz,1H),3.55(s,2H),3.24(s,3H),2.66(s,6H),1.75(d,J＝6.5Hz,3H)
实施例48
5-(1-(2,4-二氯吡啶-3-基)乙氧基)-3-(6-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑(I-48)
Figure PCTCN2016089443-appb-000163
步骤1：制备1-(2,4-二氯吡啶-3-基)乙醇
Figure PCTCN2016089443-appb-000164
将3,5-二氯吡啶换成2,4-二氯吡啶，其余所需原料、试剂及制备方法同实施例1中的步骤1，得无色油状物1-(2,4-二氯吡啶-3-基)乙醇。
1H NMR(300MHz,CDCl3)δ：8.19(d,J＝5.2Hz,1H),7.28(d,J＝5.2Hz,1H),5.56(dq,J＝9.7,6.9Hz,1H),2.84(d,J＝9.7Hz,1H),1.66(d,J＝6.9Hz,3H).
步骤2：制备1-(2,4-二氯吡啶-3-基)乙基甲磺酸酯
Figure PCTCN2016089443-appb-000165
将1-(3,5-二氯吡啶-4-基)乙醇换成1-(2,4-二氯吡啶-3-基)乙醇，其余所需原料、试剂及制备方法同实施例1中的步骤2，得白色蜡状固体1-(2,4-二氯吡啶-3-基)乙基甲磺酸酯
1H NMR(300MHz,CDCl3)δ:8.27(d,J＝5.3Hz,1H),7.33(d,J＝5.3Hz,1H),6.43(q,J＝6.9Hz,1H),2.96(s,3H),1.84(d,J＝6.9Hz,3H).
步骤3：制备5-(1-(2,4-二氯吡啶-3-基)乙氧基)-1H-吲哚
Figure PCTCN2016089443-appb-000166
将1-(3,5-二氯吡啶-4-基)乙基甲磺酸酯换成1-(2,4-二氯吡啶-3-基)乙基甲磺酸酯，其余所需原料、试剂及制备方法同实施例1中的步骤3，得无色油状物5-(1-(2,4-二氯吡啶-3-基)乙氧基)-1H-吲哚
1H NMR(300MHz,CDCl3)δ：8.12(d,J＝5.2Hz,1H),8.04(s,1H),7.23(d,J＝8.9Hz,1H),7.20(d,J＝5.2Hz,1H),7.16–7.13(m,1H),7.03(d,J＝2.4Hz,1H),6.89(dd,J＝8.8,2.4Hz,1H),6.41-6.39(m,1H),6.05(q,J＝6.7Hz,1H),1.81(d,J＝6.7Hz,3H).
步骤4：制备5-(1-(2,4-二氯吡啶-3-基)乙氧基)-1H-吲唑-3-甲醛
Figure PCTCN2016089443-appb-000167
将5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲哚换成5-(1-(2,4-二氯吡啶-3-基)乙氧基)-1H-吲哚，其余所需原料、试剂及制备方法同实施例1中的步骤4，得棕色固体5-(1-(2,4-二氯吡啶-3-基)乙氧基)-1H-吲唑-3-甲醛。
1H NMR(300MHz,CDCl3)δ10.91(s,1H),10.20(s,1H),8.15(d,J＝5.2Hz,1H),7.65(d,J＝2.4Hz,1H),7.43(d,J＝9.1Hz,1H),7.26(d,J＝5.2Hz,1H),7.20(dd,J＝9.1,2.4Hz,1H),6.15(q,J＝6.7Hz,1H),1.84(d,J＝6.7Hz,3H).
步骤5：制备5-(1-(2,4-二氯吡啶-3-基)乙氧基)-3-(6-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑
将5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成5-(哌啶-1-基)-2-硝基苯胺，5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-甲醛换成5-(1-(2,4-二氯吡啶-3-基)乙氧基)-1H-吲唑-3-甲醛，其余所需原料、试剂及制备方法同实施例1中的步骤6，得黄色固体5-(1-(2,4-二氯吡啶-3-基)乙氧基)-3-(6-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑。
1H NMR(300MHz,CD3OD)δ：8.12(d,J＝5.3Hz,1H),7.85(d,J＝2.0Hz,1H),7.57(d,J＝8.4Hz,1H),7.47(d,J＝9.0Hz,1H),7.39(d,J＝5.1Hz,1H),7.23(s,1H),7.17(dd,J＝9.0,2.3Hz,1H),7.09(d,J＝8.6Hz,1H),6.26(q,J＝6.6Hz,1H),3.17(s,4H),1.89–1.75(m,7H),1.62(s,2H).
实施例49
3-(5,6-二氯-1H-苯并[d]咪唑-2-基)-5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑(I-49)
Figure PCTCN2016089443-appb-000168
步骤1：制备4,5-二氯苯-1,2-二胺
Figure PCTCN2016089443-appb-000169
将400毫克4,5-二氯-2-硝基苯胺溶于10毫升甲醇中，加入80毫克10％钯碳加氢催化剂，室温下常压氢化反应8小时，过滤浓缩，残余物硅胶柱层析(乙酸乙酯：石油醚＝30:70)分离得140毫克棕黄色固体，收率41％。
1H NMR(300MHz,DMSO)δ：6.62(s,2H),4.85(s,4H).
步骤2：制备3-(5,6-二氯-1H-苯并[d]咪唑-2-基)-5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑
将邻苯二胺换成4,5-二氯苯-1,2-二胺，其余所需原料、试剂及制备方法同实施例5， 得黄色固体3-(5,6-二氯-1H-苯并[d]咪唑-2-基)-5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑
1H NMR(300MHz,DMSO)δ：13.64(s,1H),13.21(s,1H),8.63(s,2H),7.93(s,1H),7.74(d,J＝2.4Hz,1H),7.64(s,1H),7.57(d,J＝9.0Hz,1H),7.17(dd,J＝9.0,2.4Hz,1H),6.10(q,J＝6.7Hz,1H),1.79(d,J＝6.7Hz,3H).
实施例50
5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(哌啶-1-基)-6-氟-1H-苯并[d]咪唑-2-基)-1H-吲唑(I-50)
Figure PCTCN2016089443-appb-000170
步骤1：制备4-氟-2-硝基-5-(哌啶-1-基)苯胺
Figure PCTCN2016089443-appb-000171
将500毫克4,5-二氟-2-硝基苯胺溶于5毫升哌啶中，100℃加热2小时，加入50毫升水，乙酸乙酯萃取，有机相水洗，饱和食盐水洗，无水硫酸钠干燥后，浓缩柱层析(乙酸乙酯：石油醚＝20:80)分离得570毫克橙色固体，收率83％。
1H NMR(300MHz,CDCl3)δ7.75(d,J＝14.1Hz,1H),6.06(s,2H),6.02(d,J＝7.6Hz,1H),3.26–3.15(m,4H),1.77–1.61(m,6H).
步骤2：制备5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(6-氟-5-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑
将5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成4-氟-2-硝基-5-(哌啶-1-基)苯胺，其余所需原料、试剂及制备方法同实施例1中的步骤6，得黄色固体5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(哌啶-1-基)-6-氟-1H-苯并[d]咪唑-2-基)-1H-吲唑
1H NMR(300MHz,CD3OD)δ8.43(s,2H),7.80(d,J＝2.4Hz,1H),7.47(d,J＝9.0Hz,1H),7.43–7.35(m,1H),7.27–7.19(m,1H),7.17(dd,J＝9.0,2.4Hz,1H),6.22(q,J＝6.7Hz,1H),3.11–2.98(m,4H),1.89–1.74(m,7H),1.63(m,2H).
实施例51
5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(7-甲基-1H-苯并[d]咪唑-2-基)-1H-吲唑(I-51)
Figure PCTCN2016089443-appb-000172
将5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成2-甲基-6-硝基苯胺，其余所需原料、试剂及制备方法同实施例1中的步骤6，得棕黄色固体5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(7-甲基-1H-苯并[d]咪唑-2-基)-1H-吲唑
1H NMR(300MHz,CD3OD)δ8.42(s,2H),7.73(s,1H),7.49(d,J＝9.0Hz,1H), 7.36(s,1H),7.23–7.12(m,2H),7.05(d,J＝7.2Hz,1H),6.21(q,J＝6.7Hz,1H),2.68(m,3H),1.82(d,J＝6.7Hz,3H).
实施例52
5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(6-甲基-1H-苯并[d]咪唑-2-基)-1H-吲唑(I-52)
Figure PCTCN2016089443-appb-000173
将邻苯二胺换成4-甲基-1,2-苯二胺，其余所需原料、试剂及制备方法同实施例5，得黄色固体5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(6-甲基-1H-苯并[d]咪唑-2-基)-1H-吲唑
1H NMR(300MHz,CD3OD)δ8.43(s,2H),7.81(s,1H),7.67–7.32(m,3H),7.17(dd,J＝9.0,2.1Hz,1H),7.11(d,J＝7.8Hz,1H),6.24(q,J＝6.6Hz,1H),2.50(s,3H),1.83(d,J＝6.6Hz,3H).
实施例53
5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(2-甲氧基乙氧基)-1H-苯并[d]咪唑-2-基)-1H-吲唑(I-53)
Figure PCTCN2016089443-appb-000174
步骤1：制备4-(2-甲氧基乙氧基)-2-硝基苯胺
Figure PCTCN2016089443-appb-000175
将500毫克3-硝基-4-氨基苯酚、541毫克1-溴-2-甲氧基乙烷溶于10毫升N,N-二甲基甲酰胺中，加入1.34克碳酸钾，升温至60℃反应过夜，反应液浓缩至干，残余物柱层析(乙酸乙酯：石油醚＝20:80)，的350毫克橙色固体，收率50％。
步骤2：制备5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(2-甲氧基乙氧基)-1H-苯并[d]咪唑-2-基)-1H-吲唑
将5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成4-(2-甲氧基乙氧基)-2-硝基苯胺，其余所需原料、试剂及制备方法同实施例1中的步骤6，得黄色固体5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(5-(2-甲氧基乙氧基)-1H-苯并[d]咪唑-2-基)-1H-吲唑
1H NMR(300MHz,CD3OD)δ8.44(s,2H),7.81(s,1H),7.56(d,J＝8.5Hz,1H),7.48(d,J＝8.5Hz,1H),7.18(m,2H),6.96(dd,J＝8.8,2.2Hz,1H),6.24(q,J＝6.6Hz,1H),4.25–4.16(m,2H),3.85–3.77(m,2H),3.47(s,3H),1.84(d,J＝6.6Hz,3H).
实施例54
5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(7-(哌啶-1-基)-1H-苯并[d]咪唑-2-基-1H-吲唑(I-54)
Figure PCTCN2016089443-appb-000176
步骤1：制备2-硝基-3-(哌啶-1-基)苯胺
Figure PCTCN2016089443-appb-000177
将4,5-二氟-2-硝基苯胺换成2-硝基-3-氯苯胺，其余所需原料、试剂及制备方法同实施例1中的步骤1，得褐色浆状物2-硝基-3-(哌啶-1-基)苯胺
1H NMR(300MHz,CDCl3)δ7.09(t,J＝8.1Hz,1H),6.34(m,2H),4.76(s,2H),3.03–2.90(m,4H),1.73–1.61(m,4H),1.56(m,2H).
步骤2：制备5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(7-(哌啶-1-基)-1H-苯并[d]咪唑-2-基-1H-吲唑
将5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成2-硝基-3-(哌啶-1-基)苯胺，其余所需原料、试剂及制备方法同实施例1中的步骤6，得黄色固体5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(7-(哌啶-1-基)-1H-苯并[d]咪唑-2-基-1H-吲唑。
1H NMR(300MHz,DMSO)δ13.45(s,1H),12.76(s,1H),8.56(s,2H),8.08(s,1H),7.54(d,J＝9.1Hz,1H),7.20(d,J＝8.7Hz,1H),7.05(t,J＝7.7Hz,1H),6.98(d,J＝7.7Hz,1H),6.53(d,J＝7.5Hz,1H),6.20(q,J＝6.7Hz,1H),3.60(s,4H),1.81(m,7H),1.66(s,2H).
实施例55
3-(7-氯-1H-苯并[d]咪唑-2-基)-5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑(I-55)
Figure PCTCN2016089443-appb-000178
步骤1：制备3-氯-1,2-苯二胺
Figure PCTCN2016089443-appb-000179
将500毫克2-硝基-3-氯苯胺溶于8毫升乙醇中，加入5毫升盐酸(3摩尔每升)，再加入3.27克二水氯化亚锡，回流三小时。反应液浓缩，饱和碳酸氢钠溶液中和后加入乙酸乙酯，过滤后分液，有机相水洗，饱和氯化钠水溶液洗涤后，无水硫酸钠干燥，过滤浓缩，残余物柱层析得367毫克棕色液体3-氯-1,2-苯二胺，收率89％。
1H NMR(300MHz,DMSO)δ：6.55–6.44(m,2H),6.38(t,J＝7.8Hz,1H),4.80(s,2H),4.60(s,2H).
步骤2：制备3-(7-氯-1H-苯并[d]咪唑-2-基)-5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑
将邻苯二胺换成3-氯-1,2-苯二胺，其余所需原料、试剂及制备方法同实施例5，得黄 色固体3-(7-氯-1H-苯并[d]咪唑-2-基)-5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑。
1H NMR(300MHz,CD3OD)δ8.42(s,2H),7.77(s,1H),7.48(m,2H),7.30–7.16(m,3H),6.23(q,6.6Hz,1H),3.35(s,2H),1.82(d,J＝6.6Hz,3H).
实施例56
3-(5-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-N-(吡啶-4-基甲基)-1H-吲唑-5-胺(I-56)
Figure PCTCN2016089443-appb-000180
步骤1：制备5-氨基吲哚
Figure PCTCN2016089443-appb-000181
将1克5-硝基吲哚溶于40毫升乙醇中，加入200毫克10％钯碳，氢气氛围下搅拌6小时，过滤浓缩得680毫克粉色固体5-氨基吲哚，收率86％
1H NMR(300MHz,DMSO)δ10.55(s,1H),7.09(dd,J＝12.9,5.6Hz,2H),6.68(s,1H),6.48(dd,J＝8.5,2.0Hz,1H),6.12(d,J＝2.0Hz,1H),4.40(s,2H).
步骤2：制备N-(吡啶-4-基甲基)-1H-吲哚-5-胺
Figure PCTCN2016089443-appb-000182
将50毫克5-氨基吲哚溶于2毫升甲醇中，加入50毫克4-吡啶甲醛，室温下搅拌过夜，加入30毫克硼氢化钠，搅拌1小时后加入饱和碳酸氢钠溶液淬灭，乙酸乙酯萃取后水洗，饱和氯化钠水溶液洗涤，无水硫酸钠干燥后过滤浓缩，残余物柱层析得60毫克棕色油状物N-(吡啶-4-基甲基)-1H-吲哚-5-胺，收率71％。
1H NMR(300MHz,DMSO)δ10.60(s,1H),8.46(d,J＝5.9Hz,2H),7.37(d,J＝5.4Hz,2H),7.12(m,2H),6.56(dd,J＝8.8,2.0Hz,1H),6.50(s,1H),6.10(s,1H),5.78(t,J＝6.4Hz,1H),4.30(d,J＝6.1Hz,2H).
步骤3：制备5-((吡啶-4-基甲基)氨基)-1H-吲唑-3-甲醛
Figure PCTCN2016089443-appb-000183
将5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲哚换成N-(吡啶-4-基甲基)-1H-吲哚-5-胺，其余所需原料、试剂及制备方法同实施例1中的步骤4，得黄色固体5-((吡啶-4-基甲基)氨基)-1H-吲唑-3-甲醛。
1H NMR(300MHz,DMSO)δ10.19(s,1H),8.48(d,J＝5.4Hz,2H),8.23(s,1H),7.87(m,2H),7.11(d,J＝5.4Hz,2H),5.46(s,2H).
步骤4：制备3-(5-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-N-(吡啶-4-基甲基)-1H-吲唑-5-胺
将5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成5-(哌啶-1-基)-2-硝基苯胺，5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-甲醛换成5-((吡啶-4-基甲基)氨基)-1H-吲唑-3-甲醛，其余所需原料、试剂及制备方法同实施例1中的步骤6，得黄色固体3-(5-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-N-(吡啶-4-基甲基)-1H-吲唑-5-胺
1H NMR(300MHz,CD3OD)δ：8.61(d,J＝2.0Hz,1H),8.45(d,J＝6.2Hz,2H),7.85(dd,J＝9.1,2.1Hz,1H),7.75(d,J＝9.0Hz,1H),7.56(s,1H),7.27(d,J＝6.1Hz,2H),7.20(s,1H),7.09(dd,J＝8.6,2.1Hz,1H),5.53(s,2H),3.21–3.12(m,4H),1.80(m,4H),1.63(m,2H).
实施例57
N-((3,5-二氯吡啶-4-基)甲基)-3-(5(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑-5-胺(I-57)
Figure PCTCN2016089443-appb-000184
步骤1：制备N-((3,5-二氯吡啶-4-基)甲基)-1H-吲哚-5-胺
Figure PCTCN2016089443-appb-000185
将4-吡啶甲醛换成3,5-二氯-4-吡啶甲醛，其余其余所需原料、试剂及制备方法同实施例56中的步骤2，得浅棕色油状物N-((3,5-二氯吡啶-4-基)甲基)-1H-吲哚-5-胺。
1H NMR(400MHz,CDCl3)δ8.46(s,2H),8.00(s,1H),7.22(d,J＝8.6Hz,1H),7.14(t,J＝2.7Hz,1H),7.03(d,J＝1.8Hz,1H),6.73(dd,J＝8.8,2.1Hz,1H),6.41(d,J＝0.4Hz,1H),4.63(s,2H).
步骤2：制备5-(((3,5-二氯吡啶-4-基)甲基)氨基)-1H-吲唑-3-甲醛
Figure PCTCN2016089443-appb-000186
将5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲哚换成N-((3,5-二氯吡啶-4-基)甲基)-1H-吲哚-5-胺，其余所需原料、试剂及制备方法同实施例1中的步骤4，得黄色固体5-(((3,5-二氯吡啶-4-基)甲基)氨基)-1H-吲唑-3-甲醛。
1H NMR(300MHz,CDCl3)δ10.26(s,1H),8.35(d,J＝2.6Hz,3H),7.68(dd,J＝8.9,2.1Hz,1H),7.59(d,J＝9.1Hz,1H),5.56(s,2H).
步骤3：制备N-((3,5-二氯吡啶-4-基)甲基)-3-(5(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑-5-胺
将5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成5-(哌啶-1-基)-2-硝基苯胺，5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-甲醛换成5-(((3,5-二氯吡啶-4-基)甲基)氨基)-1H-吲唑-3-甲醛，其余所需原料、试剂及制备方法同实施例1中的步骤6，得黄色固体N-((3,5-二氯吡啶-4-基)甲基)-3-(5(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑-5-胺。
1H NMR(300MHz,CD3OD)δ8.61(s,1H),8.38(s,2H),7.65(s,2H),7.57(d,J＝9.0Hz,1H),7.22(s,1H),7.09(dd,J＝8.8,2.0Hz,1H),5.65(s,2H),3.21–3.12(m,4H),1.85–1.74(m,4H),1.62(m,2H).
实施例58
N-(1-(3,5-二氯吡啶-4-基)乙基)-3-(5(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑-5-胺(I-58)
Figure PCTCN2016089443-appb-000187
步骤1：制备1-(3,5-二氯吡啶-4-基)乙胺
将3克1-(3,5-二氯吡啶-4-基)乙基甲磺酸酯溶于60毫升N,N-二甲基甲酰胺中，加入1.08克叠氮化钠，加热至50℃反应1小时，恢复至室温后加入100毫升乙酸乙酯，有机相用300毫升水洗涤后浓缩至微干，加入60毫升乙醇、20毫升水，再加入1.48克氯化铵，1.08克锌粉，室温下搅拌过夜，反应液过滤后浓缩，加入100毫升乙酸乙酯，有机相依次用水和饱和氯化钠水溶液洗涤后用无水硫酸钠干燥，过滤浓缩，残余物柱层析得1.5克浅黄色油状物1-(3,5-二氯吡啶-4-基)乙胺，收率70.7％
1H NMR(300MHz,DMSO)δ8.53(s,1H),4.63(q,J＝7.2Hz,1H),2.30(s,2H),1.40(d,J＝7.1Hz,3H).
步骤2：制备叔丁基-5-溴-1H-吲哚-1-羧酸酯
Figure PCTCN2016089443-appb-000188
1克5-溴吲哚溶于50毫升二氯甲烷中，加入1.22克二碳酸二叔丁酯、60毫克4-二甲氨基吡啶，室温下搅拌1小时，反应液浓缩，残余物柱层析得浅黄色油状物叔丁基-5-溴-1H-吲哚-1-羧酸酯1.34克，收率88.7％
1H NMR(400MHz,CDCl3)δ8.02(d,J＝7.7Hz,1H),7.69(s,1H),7.59(d,J＝3.4Hz,1H),7.39(d,J＝8.7Hz,1H),6.50(d,J＝3.7Hz,1H),1.67(s,9H).
步骤3：制备叔丁基-5-((1-(3,5-二氯吡啶-4-基)乙基)氨基)-1H-吲哚-1-羧酸酯
Figure PCTCN2016089443-appb-000189
将20毫克1-(3,5-二氯吡啶-4-基)乙胺，30毫克叔丁基-5-溴-1H-吲哚-1-羧酸酯溶于1.5毫升无水甲苯中，依次加入6毫克三叔丁基四氟化硼酸盐、24毫克叔丁醇钠和9毫克三(二亚苄基丙酮)二钯，氩气置换后升温至100℃反应1小时，反应液浓缩，残余物柱层析得24毫克无色油状物叔丁基-5-((1-(3,5-二氯吡啶-4-基)乙基)氨基)-1H-吲哚-1-羧酸酯，收率60.7％
1H NMR(300MHz,CDCl3)δ8.35(s,2H),7.86(d,J＝10.1Hz,1H),7.46(d,J＝3.1Hz,1H),6.64(d,J＝8.3Hz,2H),6.35(d,J＝3.6Hz,1H),5.49–5.35(m,1H),4.61(d,J＝9.2Hz,1H),1.66(d,J＝7.0Hz,3H),1.62(s,9H).
步骤4：制备N-(-(3,5-二氯吡啶-4-基)乙基)吲哚-5-胺
Figure PCTCN2016089443-appb-000190
将10毫克叔丁基-5-((1-(3,5-二氯吡啶-4-基)乙基)氨基)-1H-吲哚-1-羧酸酯溶于1毫升4摩尔每升的氯化氢乙醇溶液中，室温下搅拌3小时，反应液浓缩，加入1毫升甲醇，20毫克碳酸钾，加热回流2小时，反应液过滤浓缩得N-(-(3,5-二氯吡啶-4-基)乙基)吲哚-5-胺。
1H NMR(300MHz,CDCl3)δ8.33(s,2H),7.91(s,1H),7.15(d,J＝8.6Hz,1H),7.07(t,J＝2.6Hz,1H),6.76(s,1H),6.61(dd,J＝8.6,2.0Hz,1H),6.33(s, 1H),5.44(q,J＝7.1Hz,1H),1.66(d,J＝7.0Hz,3H).
步骤5：制备5-((1-(3,5-二氯吡啶-4-基)乙基)氨基)-1H-吲唑-3-甲醛
Figure PCTCN2016089443-appb-000191
将5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲哚换成N-(-(3,5-二氯吡啶-4-基)乙基)吲哚-5-胺，其余所需原料、试剂及制备方法同实施例1中的步骤4，得黄色固体5-((1-(3,5-二氯吡啶-4-基)乙基)氨基)-1H-吲唑-3-甲醛。
1H NMR(300MHz,CDCl3)δ10.30(s,1H),8.49(s,1H),8.43(s,2H),8.09(s,2H),7.71–7.59(m,2H),6.12(q,J＝7.5Hz,1H),1.62(d,J＝7.3Hz,3H).
步骤6：制备N-(1-(3,5-二氯吡啶-4-基)乙基)-3-(5(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑-5-胺
将5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成5-(哌啶-1-基)-2-硝基苯胺，5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-甲醛换成5-((1-(3,5-二氯吡啶-4-基)乙基)氨基)-1H-吲唑-3-甲醛，其余所需原料、试剂及制备方法同实施例1中的步骤6，得黄色固体N-(1-(3,5-二氯吡啶-4-基)乙基)-3-(5(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑-5-胺。
实施例59
5-((3-氯吡啶-4-基)甲氧基)-3-(5-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑(I-59)
Figure PCTCN2016089443-appb-000192
步骤1：制备3-氯异烟醛
Figure PCTCN2016089443-appb-000193
将3,5-二氯吡啶换成3-氯吡啶，乙醛换成N,N-二甲基甲酰胺，其余所需原料、试剂及制备方法同实施例1中的步骤1，得浅黄色固体3-氯异烟醛。
1H NMR(400MHz,CDCl3)δ10.49(s,1H),8.79(s,1H),8.69(d,J＝4.9Hz,1H),7.71(d,J＝4.9Hz,1H).
步骤2：制备(3-氯吡啶-4-基)甲醇
Figure PCTCN2016089443-appb-000194
将3,5-二氯吡啶甲醛换成3-氯异烟醛，其余所需原料、试剂及制备方法同实施例36中的步骤2，得白色固体(3-氯吡啶-4-基)甲醇。
1H NMR(400MHz,CDCl3)δ8.50-8.48(m,2H),7.54(d,J＝4.9Hz,1H),4.82(s,2H).
步骤3：制备(3-氯吡啶-4-基)甲基甲磺酸酯
Figure PCTCN2016089443-appb-000195
将1-(3,5-二氯吡啶-4-基)乙醇换成(3-氯吡啶-4-基)甲醇，其余所需原料、试剂及制备方法同实施例1中的步骤2，得白色固体(3-氯吡啶-4-基)甲基甲磺酸酯。
1H NMR(300MHz,CDCl3)δ8.55(d,J＝5.0Hz,1H),7.45(d,J＝5.0Hz,1H),5.33(s,2H),3.12(s,3H).
步骤4：5-((3-氯吡啶-4-基)甲氧基)-1H-吲哚
Figure PCTCN2016089443-appb-000196
将1-(3,5-二氯吡啶-4-基)乙基甲磺酸酯换成(3-氯吡啶-4-基)甲基甲磺酸酯，其余所需原料、试剂及制备方法同实施例1中的步骤3，得白色固体5-((3-氯吡啶-4-基)甲氧基)-1H-吲哚。
1H NMR(300MHz,CDCl3)δ8.58(s,1H),8.50(d,J＝5.0Hz,1H),8.18(s,1H),7.63(dd,J＝5.0,0.6Hz,1H),7.33(d,J＝8.8Hz,1H),7.21(t,J＝2.8Hz,1H),7.15(d,J＝2.5Hz,1H),6.96(dd,J＝8.8,2.4Hz,1H),6.49(t,J＝3.0Hz,1H),5.21(s,2H).
步骤5：制备5-((3-氯吡啶-4-基)甲氧基)-1H-吲唑-3-甲醛
Figure PCTCN2016089443-appb-000197
将5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲哚换成5-((3-氯吡啶-4-基)甲氧基)-1H-吲哚，其余所需原料、试剂及制备方法同实施例1中的步骤4，得棕色固体5-((3-氯吡啶-4-基)甲氧基)-1H-吲唑-3-甲醛。
1H NMR(300MHz,DMSO)δ10.16(s,1H),8.69(s,1H),8.57(d,J＝4.7Hz,1H),7.71–7.58(m,3H),7.30(d,J＝8.9Hz,1H),5.31(s,2H).
步骤6：5-((3-氯吡啶-4-基)甲氧基)-3-(5-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑
将5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲哚-3-甲醛换成5-((3-氯吡啶-4-基)甲氧基)-1H-吲唑-3-甲醛，5-([1,4’-联哌啶]-1’-基)-2-硝基苯胺换成5-(哌啶-1-基)-2-硝基苯胺，其余所需原料、试剂及制备方法同实施例1中的步骤6，得黄色固体3-(6-([1,4’联哌啶]-1’-基)-1H-苯并[d]咪唑-2-基)-5-((2,6二氯苄)氧基))-1H-吲唑
1H NMR(300MHz,CD3OD)δ8.59(s,1H),8.51(d,J＝5.0Hz,1H),8.03(s,1H),7.76(d,J＝4.9Hz,1H),7.58(d,J＝3.6Hz,1H),7.55(d,J＝3.9Hz,1H),7.30–7.23(m,2H),7.10(d,J＝8.8Hz,1H),5.37(s,2H),3.22–3.13(m,4H),1.85–1.75(m,4H),1.67–1.58(m,2H).
实施例60
(S)-5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(6-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑(I-48)
Figure PCTCN2016089443-appb-000198
将1-(3,5-二氯吡啶-4-基)乙醇换成(R)-1-(3,5-二氯吡啶-4-基)乙醇,其余所需原料、试剂及制备方法同实施例4，得(S)-5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(6-(哌啶-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑.
1H NMR(300MHz,DMSO)δ13.40-13.35(m,1H),12.58-12.52(m,1H),8.60 (s,2H),7.84-7.80(m,1H),7.57-7.30(m,1H),7.52(d,J＝8.1Hz,1H),7.19-6.88(m,1H),7.13(d,J＝8.8Hz,1H),6.99-6.98(m,1H),6.10(q,J＝6.7Hz,1H),3.15-3.07(m,4H),1.78(d,J＝6.7Hz,3H),1.73-1.69(m,4H),1.58-1.50(m,2H)
实施例61
(S)-5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(6-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑(I-46)
Figure PCTCN2016089443-appb-000199
将1-(3,5-二氯吡啶-4-基)乙醇换成(R)-1-(3,5-二氯吡啶-4-基)乙醇,其余所需原料、试剂及制备方法同实施例3，得(S)-5-(1-(3,5-二氯吡啶-4-基)乙氧基)-3-(6-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-1H-吲唑
1H NMR(300MHz,DMSO)δ:13.41-13.36(m,1H),12.60-12.55(m,1H),8.60(s,2H),7.84-7.80(m,1H),7.58-7.30(m,1H),7.52(d,J＝8.1Hz,1H),7.19-6.88(m,1H),7.13(d,J＝8.8Hz,1H),6.99-6.98(m,1H),6.10(q,J＝6.7Hz,1H),3.13(s,4H),2.24(s,4H),1.78(d,J＝6.7Hz,3H).
实施例62
化合物分子水平对FGFR1和FGFR2酶活的影响
1、试验方法
将酶反应底物Poly(Glu,Tyr)4:1用无钾离子的PBS(10mM磷酸钠缓冲液，150mM NaCl,pH7.2-7.4)稀释成20μg/mL，125μL/孔包被酶标板，置37℃反应12-16小时。弃去孔中液体后洗板，用200μL/孔的T-PBS(含0.1％Tween-20的PBS)洗板三次，每次5分钟。于37℃烘箱中干燥酶标板1-2小时。
每孔加入用反应缓冲液(50mM HEPES pH 7.4,50mM MgCl2,0.5mM MnCl2,0.2mM Na3VO4,1mM DTT)稀释的ATP溶液50μL，终浓度5μM。化合物用DMSO稀释成合适的浓度，1μL/孔或者或含相应浓度的DMSO(阴性对照孔)，再加入用49μL反应缓冲液稀释的FGFR1、FGFR2激酶域重组蛋白启动反应，每次实验需设无ATP对照孔两孔。置37℃摇床(100rpm)反应1小时。T-PBS洗板三次。加入一抗PY99稀释液100μL/孔，37℃摇床反应0.5小时。T-PBS洗板三次。加入二抗辣根过氧化物酶标记羊抗鼠的IgG稀释液100μL/孔，37℃摇床反应0.5小时。T-PBS洗板三次。加入2mg/ml的OPD显色液100μL/孔(用含有0.03％H2O2的0.1M柠檬酸-柠檬酸钠缓冲液(pH＝5.4)稀释)，25℃避光反应1-10分钟。加入2M H2SO4 50μL/孔中止反应，用可调波长式微孔板酶标仪SPECTRA MAX 190读数，波长为490nm。
样品的抑制率通过下列公式求得：
Figure PCTCN2016089443-appb-000200
IC50值采用酶标仪随机附带软件以四参数法回归求得。
2、实验结果
分子水平的酶活性测试表明，本发明的吲唑类化合物在浓度为nM水平时对FGFR1酪氨酸激酶有很好的抑制效果，部分化合物对FGFR1的半数抑制浓度在1nM左右，是一类强效的FGFR1酪氨酸激酶抑制剂。
其中在浓度为10nM时，吡啶环化合物I-36和I-37对FGFR1酶活抑制作用(抑制率分别为100％，55.4％)明显强于苯环化合物I-38和I-39(抑制率分别为50％，2.4％)。该实验结果证实，相对于US2003207883，US20060079564两份专利，本发明更具有创造性。
表2.化合物对FGFR1和FGFR2酶活抑制活性
实施例中的化合物 FGFR1 FGFR2
I-1 A –
I-2 A –
I-3 A –
I-4 A –
I-5 A –
I-6 A –
I-7 A –
I-8 A –
I-9 A –
I-10 A –
I-11 A A
I-12 B A
I-13 A A
I-14 A A
I-15 A A
I-16 A A
I-17 B A
I-18 A A
I-19 A A
I-20 B –
I-21 A A
I-22 A –
I-23 A –
I-24 A –
I-25 A –
I-26 A –
I-27 B –
I-28 A –
I-29 A –
I-30 A –
I-31 A –
I-32 A –
I-33 A –
I-34 A –
I-35 B –
I-36 A(100％@10nM) –
I-37 A(55.4％@10nM) –
I-38 B(50％@10nM) –
I-39 B(2.4％@10nM) –
I-40 B –
I-41 A –
I-42 B –
I-43 A –
I-44 A –
I-45 A –
I-46 A –
I-47 A –
I-58 A –
其中：A表示IC50小于10nM
B表示IC50小于100nM
C表示IC50大于100nM
实施例63
化合物对FGFR1依赖的BaF3/TEL-FGFR1细胞增殖的影响
1、试验方法
化合物对BaF3/TEL-FGFR1细胞(细胞中TEL-FGFR1激酶区融合蛋白稳定表达在胞浆中，FGFR1持续激活，为FGFR1依赖性细胞株)的生长抑制检测CCK-8细胞计数试剂盒(Doj indo)检测。具体步骤如下：处于对数生长期的BaF3/TEL-FGFR1细胞按合适密度接种至96孔培养板中，每孔90μL，培养过夜后，加入不同浓度的化合物作用72hr，并设定溶剂对照组(阴性对照)。待化合物作用细胞72h后，化合物对细胞增殖的影响采用CCK-8细胞计数试剂盒(Dojindo)检测，每孔加入10μL CCK-8试剂，置于37℃培养箱中放置2-4小时后，用全波长式微孔板酶标仪SpectraMax 190读数，测定波长为450nm。采用以下列公式计算化合物对肿瘤细胞生长的抑制率(％)：抑制率(％)＝(OD阴性对照孔-OD给药孔)/OD阴性对照孔×100％。IC50值采用酶标仪随机附带软件以四参数法回归求得。
2、实验结果
由表3结果可以看出，本发明的吲唑类化合物在浓度为nM水平时对BaF3/TEL-FGFR1细胞有很好的增殖抑制效果，部分化合物对BaF3/TEL-FGFR1细胞的半数抑制浓度在1nM左右。
其中在浓度为200nM时，吡啶环化合物I-36对BaF3/TEL-FGFR1细胞增殖抑制作用(抑制率79％)明显强于苯环化合物I-38(抑制率3％)。该实验结果进一步证实，相对于US2003207883，US20060079564两份专利中所公开的化合物(其中R9部分为苯基)，本发明化合物具有更好的抑制活性。
表3.化合物对BaF3/TEL-FGFR1细胞增殖的影响
实施例中的化合物 活性
I-2 A
I-3 A
I-4 A
I-5 B
I-6 A
I-10 A
I-12 D
I-13 A
I-14 B
I-15 A
I-16 A
I-17 D
I-18 A
I-36 C(79％@200nM)
I-38 D(3％@200nM)
其中：A表示IC50小于8nM
B表示IC50小于40nM
C表示IC50小于200nM
D表示IC50大于200nM
实施例64
化合物对急性髓源白血病细胞株KG1细胞增殖的影响
试验方法
化合物对急性髓源白血病细胞株KG1细胞(细胞中FGFR1OP2-FGFR1激酶区融合蛋白稳定表达在胞浆中，FGFR1持续激活，为FGFR1依赖性细胞株)的生长抑制检测CCK-8细胞计数试剂盒(Dojindo)检测。具体步骤如下：处于对数生长期的KG1细胞按合适密度接种至96孔培养板中，每孔90μL，培养过夜后，加入不同浓度的化合物作用72hr，并设定溶剂对照组(阴性对照)。待化合物作用细胞72h后，化合物对细胞增殖的影响采用CCK-8细胞计数试剂盒(Dojindo)检测，每孔加入10μL CCK-8试剂，置于37℃培养箱中放置2-4小时后，用全波长式微孔板酶标仪SpectraMax 190读数，测定波长为450nm。采用以下列公式计算化合物对肿瘤细胞生长的抑制率(％)：抑制率(％)＝(OD阴性对照孔-OD给药孔)/OD阴性对照孔×100％。IC50值采用酶标仪随机附带软件以四参数法回归求得。
实验结果
由表4结果可以看出，本发明的吲唑类化合物在浓度为nM水平时对急性髓源白血病细胞株KG1细胞有很好的增殖抑制效果，绝大部分化合物对KG1细胞的半数抑制浓度在10nM以下。
其中吡啶环化合物I-36在浓度为40nM时，对KG1细胞增殖抑制率为59.7％，而苯环化合物I-38的半数抑制浓度超过200nM。
表4.化合物对KG1细胞增殖的影响
实施例中的化合物 活性
I-21 D
I-22 A
I-23 A
I-24 A
I-25 B
I-26 A
I-27 D
I-28 B
I-29 A
I-30 A
I-31 A
I-32 A
I-33 A
I-34 B
I-37 B(59.7％@40nM)
I-39 D
I-40 D
I-41 C
I-42 D
I-43 C
I-44 A
I-45 A
I-46 A
I-47 A
其中：A表示IC50小于8nM
B表示IC50小于40nM
C表示IC50小于200nM
D表示IC50大于200nM
实施例65
化合物对胃癌细胞株KATOIII细胞增殖的影响
试验方法
化合物对胃癌细胞株KATOIII细胞(胃癌细胞株，FGFR2基因扩增导致FGFR2持续活化，为FGFR2依赖性细胞株)的生长抑制检测CCK-8细胞计数试剂盒(Dojindo)检测。具体步骤如下：处于对数生长期的KATOIII细胞按合适密度接种至96孔培养板中，每孔90μL，培养过夜后，加入不同浓度的化合物作用72hr，并设定溶剂对照组(阴性对照)。待化合物作用细胞72h后，化合物对细胞增殖的影响采用CCK-8细胞计数试剂盒(Dojindo)检测，每孔加入10μL CCK-8试剂，置于37℃培养箱中放置2-4小时后，用全波长式微孔板酶标仪SpectraMax 190读数，测定波长为450nm。采用以下列公式计算化合物对肿瘤细胞生长的抑制率(％)：抑制率(％)＝(OD阴性对照孔-OD给药孔)/OD阴性对照孔×100％。IC50值采用酶标仪随机附带软件以四参数法回归求得。
实验结果
由表5结果可以看出，本发明的吲唑类化合物在浓度为nM水平时对胃癌细胞株KATOIII细胞有很好的增殖抑制效果。
表5.化合物对KATOIII细胞增殖的影响
实施例中的化合物 活性
I-1 C
I-2 A
I-3 A
I-4 A
I-6 A
I-7 A
I-8 A
I-9 C
I-10 A
其中：A表示IC50小于8nM
B表示IC50小于40nM
C表示IC50小于200nM
实施例66
化合物对非小细胞肺癌细胞NCI-H1581裸小鼠移植瘤生长的影响
1.实验方法：
取生长旺盛期的瘤组织剪切成1.5mm3左右，在无菌条件下，接种于裸小鼠右侧腋窝皮下。裸小鼠皮下移植瘤用游标卡尺测量移植瘤直径，待肿瘤平均体积生长至115mm3左右后将动物随机分组。I-46 10mg/kg和2mg/kg组，每天口服给药一次，连续给药21天；阳性对照药物AZD4547 20mg/kg组，每天口服给药一次，连续给药21天；溶剂对照组给等量溶剂。整个实验过程中，每周2次测量移植瘤直径，同时称量小鼠体重。肿瘤体积增长抑制率TGI％，计算公式如下：TGI％＝[1-(TVt-TV0)/(CVt-CV0)]×100％，TVt为治疗组每次测量的瘤体积；TV0为治疗组分笼给药时所得瘤体积；CVt为对照组每次测量的瘤体积；CV0为对照组分笼给药时所得瘤体积。实验结果如图1所示。结果显示，本发明化合物I-46在10mg/kg和2mg/kg给药条件下的TGI％分别为96.9％和44.5％，高于阳性对照药物AZD4547 20mg/kg给药条件下的TGI％(73.9％)，具有优异的抑制效果。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种如下式(I)所示的化合物：
    Figure PCTCN2016089443-appb-100001
    其中：
    R1、R2、R3各自独立地选自下组：H、卤素；
    R9为取代或未取代的5-7元杂芳基；
    R8、R10各自独立地选自下组：H、卤素、C1～C3烷基、C1～C3烷氧基；
    R4、R5、R6、R7各自独立地选自下组：H、卤素、取代或未取代的3-8元杂环烷基氨基、取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷氧基、取代或未取代的C1-C8亚烷基-羟基、取代或未取代的3-8元杂环基、取代或未取代的3-8元杂环基-氧基、取代或未取代的C1-C8烷基-3-8元杂环基、取代或未取代的C1-C8烷基氨基甲酰基、取代或未取代的3-8元杂环基-C1-C8烷基氨基甲酰基、取代或未取代的C1-C8烷氧基-烷基-氧基，或
    Figure PCTCN2016089443-appb-100002
    其中，Ra、Rb各自独立地选自下组：H、取代或未取代的C1-C8烷基、含1-3个选自N、S、O的杂原子的取代或未取代的5-7元杂环、取代或未取代的C2-C8烷基-O-烷基、取代或未取代的C2-C8胺基-烷基-羰基、取代或未取代的C2-C8胺基-烷基、取代或未取代的羟基-C1-C8烷基、或Ra、Rb与相连的氮原子共同构成含1-3个选自N、S、O的杂原子的取代或未取代的5-7元杂环；
    M选自下组：CH2、CH、NH、N、O、S；
    W选自O、NH；
    其中，所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C1-C8烷基、C1-C8烷氧基、C1-C8亚烷基-羟基、-Boc、含1-3个选自N、S、O的杂原子的取代或未取代的5-7元杂环；
    虚线代表单键或双键，且两条虚线不同时为单键或双键。
  2. 如权利要求1所述的化合物，其特征在于，
    R9选自取代或未取代的五元及六元杂芳基，优选地，所述的R9选自未取代的或被1-4个取代基取代的选自下组的基团：吡啶基、嘧啶基、吡嗪基、哒嗪基、三嗪基、噁唑基、异恶唑基、噻唑基、异噻唑基、呋喃基；其中，所述的取代基选自下组：F、Cl、Br、甲基、甲氧基、氨基；
    R4、R5、R6、R7分别独立的选自H、卤素、取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷氧基、取代或未取代的C1-C8羟基-烷基、取代或未取代的3-8元杂环基、取代或未取代的3-8元杂环基-氧基、取代或未取代的C1-C8烷基-羟基-烷基-羟基、取代或未取代的C1-C8烷基-3-8元杂环基、取代或未取代的C1-C8烷基氨基甲酰基、取代或未取代的3-8元杂环基-C1-C8烷基氨基甲酰基，或
    Figure PCTCN2016089443-appb-100003
    其中，Ra、Rb各自独立地选自下组： H、取代或未取代的C1-C8烷基、含1-3个选自N、S、O的杂原子的取代或未取代的5-7元杂环、取代或未取代的C2-C8烷基-O-烷基、取代或未取代的C2-C8胺基-烷基-羰基、取代或未取代的C2-C8胺基-烷基、取代或未取代的羟基-C1-C8烷基、或Ra、Rb与相连的氮原子共同构成含1-3个选自N、S、O的杂原子的取代或未取代的5-7元杂环。
  3. 如权利要求1所述的化合物，其特征在于，R9为以下结构：
    Figure PCTCN2016089443-appb-100004
    其中：
    R9a、R9b、R9c、R9d、R9e各自独立地选自H、卤素、C1～C3烷基、C1～C3烷氧基，并优选自H、F、Cl、Br、甲基和甲氧基；
    U、V、X、Y、Z各自独立地选自C、N，且其中至少一个为N；和/或
    R8、R10各自独立地选自H、F、Cl、Br、甲基和甲氧基。
  4. 如权利要求3所述的化合物，其特征在于，所述化合物具有式(III)或(IV)所示的结构：
    Figure PCTCN2016089443-appb-100005
    其中：
    R9a、R9b、R9c、R9d、R9e选自下组：H、卤素、甲基、乙基、异丙基甲氧基；
    R4、R5、R6、R7各自独立地选自下组：H、卤素、甲氧基、乙氧基、异丙氧基、甲氨基、乙氨基、异丙氨基、二甲基氨基、二乙基氨基、二异丙基氨基、(1-甲基哌啶)-甲基-氨基、哌啶基、1-甲基哌啶基、1-乙基哌啶基、1-异丙基哌啶基、1-Boc哌啶基、吡咯烷基、哌嗪基、1-甲基哌嗪基、1-乙基哌嗪基、1-异丙基哌嗪基、1-羟基乙基哌嗪基、1-甲氧基乙基哌嗪基、1-甲氨基乙基哌嗪基、1-Boc-哌嗪基、2,6-二甲基哌嗪基、高哌嗪基、1-甲基高哌嗪基、1-乙基高哌嗪基、1-异丙基高哌嗪基、吗啉基、C1～C3二甲基氨基烷基氨基、C1～C3二乙基氨基烷基氨基、C1～C3二异丙基氨基烷基氨基、C1～C3吡咯烷烷基氨基、C1～C3哌啶烷基氨基、C1～C3羟基烷基、C1～C3氨基烷基、C1～C3甲氧基烷基氨基、C1～C3乙氧基烷基氨基、C1～C3异丙氧基烷基氨基、C1～C3甲氧基烷基、C1～C3乙氧基烷基、C1～C3异丙氧基烷基、二甲基氨基乙酰基氨基、二乙基氨基乙酰基氨基、二异丙基氨基乙酰基氨基、二甲基氨基丙酰基氨基、二乙基氨基丙酰基氨基、二异丙基氨基丙酰基氨基、甲氧基乙基氧基、乙氧基乙基氧基、甲氧基丙基氧基、乙氧基丙基氧基。
  5. 如权利要求1所述的化合物，其特征在于，所述的R9为取代或未取代的吡啶基，其中，取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C1-C4烷基。
  6. 如权利要求1所述的化合物，其特征在于，所述的化合物选自下组：
    Figure PCTCN2016089443-appb-100006
    Figure PCTCN2016089443-appb-100007
    Figure PCTCN2016089443-appb-100008
    Figure PCTCN2016089443-appb-100009
  7. 一种药物组合物，其特征在于，包括：(a)治疗有效量的选自根据权利要求1～6中任一项所述的化合物，或其立体异构体、几何异构体、互变异构体、药学上可接受的盐或前药、其水合物或溶剂合物，或其组合，以及任选的(b)药学上可接受的载体。
  8. 如权利要求1-6中任一所述的化合物，或其立体异构体、几何异构体、互变异构体、药学上可接受的盐或前药、其水合物或溶剂合物，或其组合的用途，其特征在于，用于制备(i)预防和/或治疗癌症相关疾病的药物；(ii)作为蛋白酪氨酸激酶(优选为FGFR)抑制剂。
  9. 如权利要求8所述的用途，其特征在于，所述的肿瘤选自下组：乳腺癌、肺癌、膀胱癌、胃癌、胰腺癌、前列腺癌、结肠癌、多发性骨髓瘤AML、肝癌、黑色素瘤、头颈癌、甲状腺癌、肾细胞癌、胶质母细胞癌、和睾丸癌。
    在另一优选例中，所述的肿瘤选自：乳腺癌、非小细胞肺癌、膀胱癌、胃癌、胰腺癌、前列腺癌、结肠癌、多发性骨髓瘤、肝癌、黑色素瘤、头颈癌、甲状腺癌、肾细胞癌、胶质母细胞癌、睾丸癌，或其组合。
  10. 一种蛋白酪氨酸激酶酶活抑制剂，其特征在于，含有抑制有效量的如权利要求1-6所述的化合物。
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