WO2017097216A9 - 五元杂环酰胺类wnt通路抑制剂 - Google Patents

五元杂环酰胺类wnt通路抑制剂 Download PDF

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WO2017097216A9
WO2017097216A9 PCT/CN2016/108964 CN2016108964W WO2017097216A9 WO 2017097216 A9 WO2017097216 A9 WO 2017097216A9 CN 2016108964 W CN2016108964 W CN 2016108964W WO 2017097216 A9 WO2017097216 A9 WO 2017097216A9
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amide
methyl
dimethyl
bipyridyl
group
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PCT/CN2016/108964
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French (fr)
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WO2017097216A1 (zh
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王永辉
朱研
周娟
高羽君
王士群
王栋
刘万登
沈锡明
洪彬彬
刘涛
吴耀东
李春启
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杭州雷索药业有限公司
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Priority to KR1020187016137A priority Critical patent/KR102214225B1/ko
Priority to AU2016368257A priority patent/AU2016368257C1/en
Priority to US16/060,146 priority patent/US10821104B2/en
Priority to EP16872405.2A priority patent/EP3388428B1/en
Priority to JP2018546738A priority patent/JP6630844B2/ja
Publication of WO2017097216A1 publication Critical patent/WO2017097216A1/zh
Publication of WO2017097216A9 publication Critical patent/WO2017097216A9/zh

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    • 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
    • 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
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • 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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to a five-membered heterocyclic amide-like WNT pathway inhibitor, which is a compound which modulates the activity of a Wnt signaling pathway, and provides a preparation method of the compound, and the compound is used for preparing a drug antagonizing the Wnt signaling pathway.
  • Wnt signaling pathway plays an important role in life processes such as axis differentiation, tissue and organogenesis, and tumor formation in multicellular organisms.
  • the Wnt gene encodes a protein expressed as a secreted glycoprotein consisting of 19 members, which binds to the Frizzled (Fzd) family of proteins and LDL receptor related protein (LRP) receptors on the cell membrane. It activates a variety of intracellular signaling pathways such as the Wnt/ ⁇ -catenin pathway, the planar polar pathway, and the Wnt/Ca 2+ pathway, regulating a variety of cellular functions including proliferation, differentiation, death, migration, and polarization (Nusse Roel, Varmus Harold E. (1992). Wnt genes. Cell, 69(7), 1073-1087.).
  • Wnt signaling is involved in early tumor evidence derived from the isolation of the oncogene Int1 activated by viral insertion in mouse breast cancer; nearly 10% of patients with colorectal cancer, head and neck cancer, lung cancer, ovarian cancer, melanoma Cancer development is associated with the induction of functional mutations in the R-spondin family and RNF43/ZNRF3, a Wnt signaling regulator (B Madan, Z Ke, N Harmston, et al. (2015). Wnt addiction of genetically defined cancers reversed by PORCN inhibition. Oncogene, 1-11.).
  • LGK974 (ClinicalTrials.gov Identifier: NCT01351103) designed for the upstream target of the Wnt signaling pathway (PCT), ETC -1922159 (ClinicalTrials.gov Identifier: NCT02521844); PRI-724 (ClinicalTrials.gov Identifier: NCT02413853) designed for the downstream target of the Wnt signaling pathway, CBP/ ⁇ -catenin.
  • PCT Wnt signaling pathway
  • ETC -1922159 ClinicalTrials.gov Identifier: NCT02521844
  • PRI-724 (ClinicalTrials.gov Identifier: NCT02413853) designed for the downstream target of the Wnt signaling pathway, CBP/ ⁇ -catenin.
  • the object of the present invention is to provide a novel five-membered heterocyclic amide WNT pathway inhibitor with a novel structure, which synthesizes and screens a series of compounds having antitumor activity through substitution modification of a group.
  • a five-membered heterocyclic amide WNT pathway inhibitor which is a compound having the following structural formula: and a pharmaceutically acceptable salt thereof:
  • ring A and ring B are each independently selected from an aromatic ring or an aromatic heterocyclic ring containing 1-2 N atoms or O atoms; and X, Y and Z are each independently selected from CR 4 , NR 5 , S atom, One of the O atoms, and the S atom and the O atom are not present at the same time; n is selected from any integer value of 1 to 2; and R 1 and R 2 are each independently selected from hydrogen, halogen, and C 1-6 alkyl.
  • R 3 is a substituted or unsubstituted aryl group, a heterocyclic group, an aryl group, a substituent group on a heterocyclic group From halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, hydroxy, cyano, amino, acyl, sulfo, hetero
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy,
  • ring B is selected from an aromatic ring or an aromatic heterocyclic ring containing 1-2 N atoms or O atoms; and X, Y and Z are each independently selected from one of CR 4 , NR 5 , S atom, and O atom.
  • n is selected from any integer value of 1 to 2;
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 3-6 ring One or more of an alkyl group, a halogenated C 1-6 alkyl group, a C 1-6 alkoxy group, a halogenated C 1-6 alkoxy group, a hydroxyl group, an amino group, an acyl group, an aryl group, or a heterocyclic group;
  • R 3 is a substituted or unsubstituted aryl group, a heterocyclic group, and the substituent group on the aryl group or the heterocyclic group is selected from the group consisting of halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 One or more of an alkoxy group, a halogenated C 1-6 alkoxy group, a hydroxyl group, a cyano
  • n is selected from 1 to 2 An integer value;
  • R 1 , R 2 are hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, amide One of a C 1-6 alkylamido group or a heterocyclic group;
  • R 3 is One of R 4 and R 5 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy
  • One of R 6 is selected from the group consisting of hydrogen, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, amide
  • X, Y, and Z are each independently selected from one of CR 4 , NR 5 , S atom, and O atom, and the S atom and the O atom are not present simultaneously;
  • n is selected from 1 or 2;
  • R 1 , R 2 Is hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, amide, C 1-6 alkyl amide
  • R 3 is One of R 4 and R 5 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy
  • One of R 6 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, amide One;
  • a heterocyclic group is a 3-6 membered heterocycl
  • X and Z are both CR 4 ; or X and Z are NR 5 at the same time; or any of X and Z is CR 4 and the other is NR 5 ; n is selected from 1 or 2; R 1 and R 2 are Hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, amide, C 1-6 alkyl amide, One of heterocyclic groups; R 3 is One of R 6 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, amide One; a heterocyclic group is a 3-6 membered heterocyclic ring selected from one or more N, O heteroatoms.
  • X and Z are both CR 4 ; or X and Z are NR 5 at the same time; or any of X and Z is CR 4 and the other is NR 5 ; or any of X and Z is O atom, and the other NR 5 ; or any of X, Z is O atom, the other is CR 4 ;
  • n is selected from 1 or 2;
  • R 1 , R 2 are hydrogen, halogen, C 1-6 alkyl, C 1- 6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, amido, C 1- 6 alkyl amide group, a heterocyclic group;
  • R 3 is One of R 6 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, amide One;
  • a heterocyclic group is a 3-6 membered heterocyclic ring selected from one or more N,
  • the aryl group is phenyl, naphthyl or anthracenyl;
  • the heterocyclic group is morpholinyl, piperidinyl, pyridyl, pyrimidinyl, pyranyl, thienyl, furyl, pyrrolyl, pyridyl
  • the halogen is one of fluorine, chlorine, bromine and iodine.
  • a five-membered heterocyclic amide WNT pathway inhibitor selected from the following characteristic compounds numbered REX-P-1 to REX-P-56:
  • REX-P-1 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-1-methyl-3-phenyl-1-hydrol -pyrazole-5-amide;
  • REX-P-2 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-5-phenyl-1-hydro-pyrazole-3 - amide;
  • REX-P-3 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-2-phenyl-thiazole-5-amide;
  • REX-P-4 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-5-phenyl-thiazole-2-amide;
  • REX-P-5 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-2-phenyl-thiazole-4-amide;
  • REX-P-6 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-phenyl-thiazole-2-amide;
  • REX-P-7 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-5-phenyl-isoxazole-3-amide;
  • REX-P-8 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-5-phenyl-1,3,4-thiadi Oxazole-2-amide;
  • REX-P-9 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-1-methyl-5-phenyl-1-hydrol -pyrazole-3-amide;
  • REX-P-10 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-methyl-5-phenyl-thiazole-2 - amide;
  • REX-P-11 5-(2-chlorophenyl)-N-((2',3-dimethyl-[2,4'-bipyridin]-5-yl)methyl)-thiazole-2 - amide;
  • REX-P-12 5-(3-chlorophenyl)-N-((2',3-dimethyl-[2,4'-bipyridin]-5-yl)methyl)-thiazole-2 - amide;
  • REX-P-13 5-(4-chlorophenyl)-N-((2',3-dimethyl-[2,4'-bipyridin]-5-yl)methyl)-thiazole-2 - amide;
  • REX-P-15 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-5-(pyrazin-2-yl)thiazole-2 - amide;
  • REX-P-16 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-5-(pyridin-2-yl)-1 hydrogen- Pyrazole-3-amide;
  • REX-P-17 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-5-(3-fluoro-pyridin-2-yl) -1 hydrogen-pyrazole-3-amide;
  • REX-P-18 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-5-(5-fluoro-pyridin-3-yl) -1 hydrogen-pyrazole-3-amide;
  • REX-P-20 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-5-(pyrimidin-2-yl)-1 hydrogen- Pyrazole-3-amide;
  • REX-P-21 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-5-(pyrazin-2-yl)-1 hydrogen -pyrazole-3-amide;
  • REX-P-22 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-2-(3-chlorophenyl)-thiazole-5 - amide;
  • REX-P-23 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-2-(pyridin-2-yl)-thiazole-5 - amide;
  • REX-P-24 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-2-(3-fluoro-pyridin-2-yl) -thiazole-5-amide;
  • REX-P-25 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-2-(5-fluoro-pyridin-3-yl) -thiazole-5-amide;
  • REX-P-26 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-2-(6-methyl-pyridin-2-yl) )-thiazole-5-amide;
  • REX-P-27 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-2-(pyrimidin-2-yl)-thiazole-5 - amide;
  • REX-P-28 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-2-(pyrazin-2-yl)-thiazole- 5-amide;
  • REX-P-29 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-5-(pyridin-2-yl)-isoxazole -3-amide;
  • REX-P-30 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-5-(3-fluoro-pyridin-2-yl) -isoxazole-3-amide;
  • REX-P-31 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-5-(5-fluoro-pyridin-3-yl) -isoxazole-3-amide;
  • REX-P-32 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-5-(6-methyl-pyridin-2-yl) )-isoxazole-3-amide;
  • REX-P-33 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-5-(pyrimidin-2-yl)-isoxazole -3-amide;
  • REX-P-34 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-5-(pyrazin-2-yl)-isophor Oxazole-3-amide;
  • REX-P-35 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-5-(4-acetylpiperazin-1-yl) -isoxazole-3-amide;
  • REX-P-36 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-5-(pyridin-3-yl)thiazole-2- Amide
  • REX-P-37 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-5-(3-fluoro-pyridin-2-yl) Thiazole-2-amide;
  • REX-P-38 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-5-(5-fluoro-pyridin-3-yl) Thiazole-2-amide;
  • REX-P-42 5-(4-acetylpiperazin-1-yl)-N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl) -1,3,4-thiadiazol-2-amide;
  • REX-P-43 5-(4-acetylpiperazin-1-yl)-N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl) -thiazole-2-amide;
  • REX-P-44 2-(4-Acetylpiperazin-1-yl)-N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl) -thiazole-5-amide;
  • REX-P-45 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-5-(3-chlorophenyl)-1,3 , 4-thiadiazol-2-amide;
  • REX-P-46 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-5-(3-fluorophenyl)-1,3 , 4-thiadiazol-2-amide;
  • REX-P-47 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-5-(pyridin-2-yl)-1,3 , 4-thiadiazol-2-amide;
  • REX-P-48 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-5-(3-fluoro-pyridin-2-yl) -1,3,4-thiadiazol-2-amide;
  • REX-P-49 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-5-(5-fluoro-pyridin-3-yl) -1,3,4-thiadiazol-2-amide;
  • REX-P-50 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-5-(6-methyl-pyridin-2-yl) )-1,3,4-thiadiazol-2-amide;
  • REX-P-51 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-5-(pyrimidin-2-yl)-1,3 , 4-thiadiazol-2-amide;
  • REX-P-52 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-5-(pyrazin-2-yl)-1, 3,4-thiadiazol-2-amide;
  • REX-P-53 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-5-(5-methyl-pyridin-3-yl) )-1,3,4-thiadiazol-2-amide;
  • REX-P-54 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-5-(2-methyl-pyridin-3-yl) )-1,3,4-thiadiazol-2-amide;
  • REX-P-55 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-5-(4-methyl-pyridin-3-yl) )-1,3,4-thiadiazol-2-amide;
  • REX-P-56 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-5-(3-methyl-pyridin-2-yl )-1,3,4-thiadiazol-2-amide;
  • Compound as used in the present invention includes all stereoisomers, geometric isomers, tautomers and isotopes.
  • Compounds as used herein may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers.
  • the compound containing an asymmetric carbon atom in the present invention can be isolated in an optically active pure form or in a racemic form.
  • the optically active pure form can be resolved from the racemic mixture or synthesized by using a chiral starting material or a chiral reagent.
  • the "compound” of the present invention also includes tautomeric forms.
  • the tautomeric form is derived from the exchange of a single bond with an adjacent double bond and accompanied by a proton transfer.
  • the invention also includes atoms of all isotopes, whether in the intermediate or the final compound.
  • the atoms of an isotope include those having the same number of atoms but different mass numbers.
  • isotopes of hydrogen include deuterium and tritium.
  • halogen means fluoro, chloro, bromo or iodo, preferably fluoro, chloro or bromo.
  • cyano refers to -CN.
  • hydroxy refers to -OH.
  • alkyl refers to a straight or branched saturated hydrocarbon group consisting of a carbon atom and a hydrogen atom, such as a C 1-20 alkyl group, preferably a C 1-6 alkyl group, such as methyl, ethyl, or propyl.
  • Base including n-propyl and isopropyl
  • butyl including n-butyl, isobutyl, sec-butyl or tert-butyl
  • pentyl including n-pentyl, isopentyl, neopentyl
  • the alkyl group may be unsubstituted or substituted by one or more substituents including, but not limited to, alkyl, alkoxy, cyano, hydroxy, carbonyl, carboxyl, aryl, heteroaryl, Amino group, halogen, sulfonyl group, sulfinyl group, phosphoryl group.
  • amino refers to -NH 2 , -NH(alkyl) and -N(alkyl) 2 , and the meaning of the alkyl group is as defined above.
  • -NH (alkyl) is in the form of Specific examples include, but are not limited to, -NHCH 3 , -NHCH(CH 3 ) 2 , -NHC 2 H 5 , etc.;
  • -N(alkyl) 2 has the structural form Specific examples include, but are not limited to, -N(CH 3 ) 2 , -N(CH 3 )C 2 H 5 , and the like.
  • aryl refers to an all-carbon monocyclic or fused ring having a fully conjugated pi-electron system, typically having from 6 to 14 carbon atoms, preferably having from 6 to 12 carbon atoms, and most preferably having six carbon atoms. .
  • the aryl group may be unsubstituted or substituted by one or more substituents including, but not limited to, alkyl, alkoxy, cyano, hydroxy, carbonyl, carboxyl, aryl, aralkyl, amino, halogen. , sulfonyl, sulfinyl, phosphoryl. Examples of unsubstituted aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.
  • heterocyclyl refers to a monocyclic or fused ring having from 3 to 12 (integer) ring atoms, wherein one, two or three ring atoms are selected from one or more of N, O, and the remaining rings
  • the atom is C and has a fully conjugated ⁇ -electron system.
  • the heterocyclic group may be a saturated or unsaturated group, or may be unsubstituted or substituted by one or more substituents including, but not limited to, alkyl, alkoxy, cyano, hydroxy, Carbonyl, carboxyl, aryl, aralkyl, amino, halogen, sulfonyl, sulfinyl, phosphoryl.
  • unsubstituted heterocyclic groups include, but are not limited to, pyrrolyl, indenyl, pyrrolidinyl, imidazolyl, pyrazolyl, tetrazolyl, pyridyl, quinolyl, isoquinolinyl, piperidinyl, Pyrimidinyl, pyrazinyl, piperazinyl, furyl, pyranyl, morpholinyl.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound as described above or a pharmaceutically acceptable salt thereof as an active ingredient, and one or more pharmaceutically acceptable carriers.
  • the "pharmaceutical composition” as used in the present invention refers to a preparation of one or more compounds of the present invention or a salt thereof and a carrier generally accepted in the art for delivery of a biologically active compound to an organism such as a human.
  • the purpose of the pharmaceutical composition is to facilitate The body is administered for delivery.
  • pharmaceutically acceptable carrier means a substance which is co-administered with the active ingredient and which facilitates administration of the active ingredient, including but not limited to acceptable for human or animal use as permitted by the State Food and Drug Administration ( Any of the glidants, sweeteners, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersing agents, disintegrating agents, suspending agents, stabilizers, for example, livestock) , isotonic agents, solvents or emulsifiers. Examples include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
  • the pharmaceutical composition of the present invention can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, Inhalants, gels, microspheres and aerosols, etc.
  • the pharmaceutical composition of the present invention can be produced by a method well known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a sugar coating pill method, a grinding method, an emulsification method, a freeze drying method, and the like.
  • the administration route of the compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof including but not limited to oral, rectal, transmucosal, enteral administration, or topical, transdermal, inhalation, parenteral , sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous.
  • a preferred route of administration is oral administration.
  • the pharmaceutical composition can be formulated by admixing the active compound with apharmaceutically acceptable carrier which is well known in the art.
  • a pharmaceutical composition for oral administration can be obtained by combining the active ingredient with one or more solid carriers, granulating the resulting mixture if necessary, and adding a small amount of excipient if necessary Processed into a mixture or granule to form a tablet or tablet core.
  • the core may be combined with a coating material which is optionally suitable for enteric processing, in the form of a coating formulation which is more advantageous for absorption by an organism such as a human.
  • the invention also provides the use of a compound as described above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for antagonizing the Wnt signaling pathway.
  • the pharmaceutical use is for the treatment of cell proliferative diseases, digestive diseases associated with abnormal Wnt signaling activity.
  • the pharmaceutical use is for the treatment of cancer, including non-small cell lung cancer, anaplastic large cell lymphoma, inflammatory myofibroblastic tumor, nasopharyngeal carcinoma, breast cancer, colorectal cancer, diffuse large B-cell lymphoma, Liver cancer, gastric cancer, esophageal cancer, pancreatic cancer, ovarian cancer, systemic histiocytosis, and neuroblastoma.
  • cancer including non-small cell lung cancer, anaplastic large cell lymphoma, inflammatory myofibroblastic tumor, nasopharyngeal carcinoma, breast cancer, colorectal cancer, diffuse large B-cell lymphoma, Liver cancer, gastric cancer, esophageal cancer, pancreatic cancer, ovarian cancer, systemic histiocytosis, and neuroblastoma.
  • the inventors have determined a series of five-membered heterocyclic amide-like WNT pathway inhibitors, and determined the inhibitory activity of the Wnt pathway STF reporter gene at the molecular level, and found that some compounds have significant inhibitory activity against the Wnt pathway;
  • the zebrafish phenotypic screening experiment was also carried out. Through the tail-streak regeneration inhibition test and the body axis development inhibition test of zebrafish, it was found that some compounds have significant anti-tumor activity in vivo; and some compounds were found by in vivo pharmacodynamic experiments. Anti-tumor in the body The tumor effect is remarkable.
  • the five-membered heterocyclic amide-based WNT pathway inhibitor provided by the present invention based on the rational drug design of the target, obtains a series of novel compounds through the substitution modification of the group; and combines the STF reporter gene Experiments, zebrafish phenotypic screening experiments, optimized screening of a series of compounds with anti-tumor activity. Therefore, it can be used to develop a new generation of Wnt pathway inhibitors, which has great clinical application value for targeted therapy or prevention of diseases mediated by Wnt pathway, and has a considerable market potential.
  • Figure 1 shows the inhibition of body axis development of AB zebrafish after 48 h of treatment.
  • Figure 2 is a graph showing the dose-effect relationship of body axis development inhibition of AB zebrafish after 48 h treatment (mean ⁇ sd)
  • Figure 3 is a graph showing the inhibition of the tail-type regeneration of AB-type zebrafish after 7dpf treatment.
  • Figure 4 is a graph showing the dose-effect relationship of the inhibition of AB-type zebrafish rear-tail regeneration after treatment of 7dpf (mean ⁇ sd)
  • liquid chromatography is carried out using a WatersSymmetry C18 column. Thin layer chromatography was performed using GF254 (0.25 mm). Nuclear magnetic resonance chromatography (NMR) was measured using a Bruker-400 NMR spectrometer; LC/MS was performed using a Waters ZQ mass spectrometer (column: WatersSymmetry C18, mm, 5 ⁇ m, 35 ° C) using ESI (+) ion mode .
  • NMR nuclear magnetic resonance chromatography
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the intermediate REX-P-INT-1 2.9 g was prepared by referring to the "Preparation method of Synthesis Scheme 1" of Example 1.
  • the synthetic route is as follows:
  • the intermediate REX-P-INT-1 3.6 g was prepared by referring to Example 1 "Preparation of Synthesis Scheme One".
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the intermediate REX-P-INT-1 0.8 g was prepared in the same manner as in the "Preparation method of the synthesis scheme 1" of Example 1.
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the intermediate REX-P-INT-2 1.0 g was prepared in the same manner as in the "Preparation method of the synthesis scheme 2" of Example 1.
  • the intermediate REX-P-INT-1 2.7 g was prepared by referring to Example 1 "Preparation Method of Synthesis Scheme One".
  • the synthetic route is as follows:
  • the intermediate REX-P-INT-2 1.0 g was prepared in the same manner as in the "Preparation method of the synthesis scheme 2" of Example 1.
  • the intermediate REX-P-INT-1 2.7 g was prepared by referring to Example 1 "Preparation Method of Synthesis Scheme One".
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • Example 3 The preparation method of this example refers to Example 3, and only the compound 1-1 (ie, o-aminoacetophenone) in Example 3 is substituted for the compound 1-1 of the cost example (ie, 2-amino-4-chlorophenylethyl).
  • the ketone), the other methods were the same, and finally the compound REX-P-13 (120.5 mg, 25.2%) was obtained.
  • the synthetic route is as follows:
  • the preparation method of the present embodiment refers to the synthesis scheme 2 of the embodiment 1, and only the compound 1-1 (ie, acetophenone) in the embodiment 1 is substituted for the compound 1-1 (2-acetylpyridine) of the example, and the rest.
  • the procedure was identical, and finally the compound REX-P-16 (150 mg, 30.2%) was obtained.
  • the synthetic route is as follows:
  • the preparation method of this example refers to Example 2, and only the compound thiobenzamide of the step 2 in Example 2 is substituted for the compound 3-chlorobenzenesulfamide of the example, and the other methods are the same, and finally the compound REX-P is obtained. -22 (100 mg, 20.3%).
  • the synthetic route is as follows:
  • Example 9 The preparation method of this example is the same as in Example 9, except that the compound 1-1 of Example 9 (i.e., benzoyl hydrazide) was substituted for the compound 1-1 of the cost example (i.e., 3-chlorobenzoyl hydrazide), and the rest. The procedure was identical, and finally the compound REX-P-45 (200 mg, 35.4%) was obtained.
  • the compound 1-1 of Example 9 i.e., benzoyl hydrazide
  • the cost example i.e., 3-chlorobenzoyl hydrazide
  • the synthetic route is as follows:
  • Example 9 The preparation method of this example is the same as in Example 9, except that the compound 1-1 (i.e., benzoyl hydrazide) in Example 9 was substituted for the compound 1-1 (i.e., 3-fluorobenzohydrazide) of the Example, and the rest. The procedure was identical, and the compound REX-P-46 (210 mg, 35.8%) was finally obtained.
  • the compound 1-1 i.e., benzoyl hydrazide
  • 3-fluorobenzohydrazide i.e., 3-fluorobenzohydrazide
  • the synthetic route is as follows:
  • Example 9 The preparation method of this example refers to Example 9, and only the compound 1-1 (i.e., benzoyl hydrazide) in Example 9 is substituted for the compound 1-1 (i.e., 2-pyridine formyl hydrazide) of the example embodiment, and the other methods. In the same manner, the compound REX-P-47 (150 mg, 25.8%) was finally obtained.
  • the compound 1-1 i.e., benzoyl hydrazide
  • 2-pyridine formyl hydrazide i.e., 2-pyridine formyl hydrazide
  • the synthetic route is as follows:
  • Example 9 The preparation method of this example refers to Example 9, and only the compound 1-1 of Example 9 (i.e., benzoyl hydrazide) is substituted for the compound 1-1 of the cost example (i.e., 5-fluoronicotinoyl), and the other methods.
  • the compound REX-P-49 100 mg, 18.8% was finally obtained.
  • the synthetic route is as follows:
  • Example 9 The preparation method of this example refers to Example 9, and only the compound 1-1 (i.e., benzoyl hydrazide) in Example 9 is substituted for the compound 1-1 of the cost example (i.e., 6-methylpyridyl hydrazide), and the rest. The procedure was identical, and the compound REX-P-50 (110 mg, 20.3%) was finally obtained.
  • the compound 1-1 i.e., benzoyl hydrazide
  • the cost example i.e., 6-methylpyridyl hydrazide
  • the synthetic route is as follows:
  • Example 9 The preparation method of this example refers to Example 9, and only the compound 1-1 (i.e., benzoyl hydrazide) in Example 9 is substituted for the compound 1-1 (i.e., pyrazine-2-formyl hydrazide) of the example embodiment. The rest of the process was identical, and the compound REX-P-52 (140 mg, 23.2%) was finally obtained.
  • the compound 1-1 i.e., benzoyl hydrazide
  • pyrazine-2-formyl hydrazide i.e., pyrazine-2-formyl hydrazide
  • the synthetic route is as follows:
  • Example 9 The preparation method of this example refers to Example 9, and only the compound 1-1 (i.e., benzoyl hydrazide) in Example 9 is substituted for the compound 1-1 (i.e., pyrimidine-2-carboxylic acid hydrazide) of the example embodiment, and the rest. The procedure was identical, and finally the compound REX-P-51 (100 mg, 18.2%) was obtained.
  • the compound 1-1 i.e., benzoyl hydrazide
  • pyrimidine-2-carboxylic acid hydrazide i.e., pyrimidine-2-carboxylic acid hydrazide
  • the synthetic route is as follows:
  • Example 9 The preparation method of this example refers to Example 9, and only the compound 1-1 (i.e., benzoyl hydrazide) in Example 9 is substituted for the compound 1-1 of the cost example (i.e., 3-fluoronicotinoyl), and the other methods.
  • the compound REX-P-48 150 mg, 28.2% was finally obtained.
  • the synthetic route is as follows:
  • Example 9 The preparation method of this example refers to Example 9, and only the compound 1-1 of Example 9 (i.e., benzoyl hydrazide) is substituted for the compound 1-1 of the cost example (i.e., 3-methylnicotinoyl), and the rest.
  • the procedure was identical and the compound REX-P-56 (150 mg, 26.2%) was finally obtained.
  • the synthetic route is as follows:
  • Example 9 The preparation method of this example refers to Example 9, and only the compound 1-1 (i.e., benzoyl hydrazide) in Example 9 is substituted for the compound 1-1 of the cost example (i.e., 4-methylisonicotidine). The rest of the method was the same, and finally the compound REX-P-55 (100 mg, 20.2%).
  • the compound 1-1 i.e., benzoyl hydrazide
  • the cost example i.e., 4-methylisonicotidine
  • the synthetic route is as follows:
  • Example 9 The preparation method of this example refers to Example 9, and only the compound 1-1 (i.e., benzoyl hydrazide) in Example 9 is substituted for the compound 1-1 of the cost example (i.e., 5-methylisonicotinoxime). The rest of the methods were identical, and finally the compound REX-P-53 (120 mg, 22.5%) was obtained.
  • the compound 1-1 i.e., benzoyl hydrazide
  • the cost example i.e., 5-methylisonicotinoxime
  • Example 25 zebrafish phenotypic screening experiment
  • Zebrafish is a vertebrate with up to 85% homology with the human genome. It has similar tissue and organ function and signaling pathways to humans, and has unique advantages such as high egg production, rapid development, and embryonic transparency, making zebrafish Successfully applied to human disease research and high-throughput screening of living drugs.
  • Wnt signaling pathway is widely distributed in invertebrates and vertebrates. It is a highly conserved signaling pathway in the process of evolution. It participates in the regulation of cell growth, apoptosis, self-renewal and survival genes in vivo, and maintains normal in organisms.
  • Physiological functions such as embryonic development and tissue repair regeneration (Wolfram Goessling, Trista E. North, Sabine Loewer, et al.
  • Wnt signaling pathway dysregulation is also closely related to cancer, for example, 80% to 90% of colorectal cancers contain Wnt signaling pathway genes.
  • Adenomatous Polyposis Coli (APC) functional mutation Hans Clevers, Roel Nusse. (2012). Wnt/ ⁇ -Catenin Signaling and Disease. Cell, 149(6): 1192-1205.).
  • RESULTS The 3 hpf (hours post fertilization) type AB zebrafish eggs were selected for the development of the body axis phenotype.
  • the group was administered at a final concentration ranging from 100 ⁇ M to 0.001 ⁇ M and the vehicle control group.
  • the AB eggs were added to a 6-well plate, 3 mL of fish water per well, and the DMSO concentration was ⁇ 1% (v/v).
  • the AB eggs after dosing were imaged at 48 hpf in a 28.5 °C biochemical incubator, and the px values (pixels) of the body length of each group of juvenile fish were measured by NIS-Elements D 3.1 software.
  • the IC 50 value of each compound in the development of AB zebrafish body axis was calculated by nonlinear fitting using GraphPad Prism 6.0.
  • IC 50 is calculated for 50% inhibition concentration
  • the present invention selects a part of the compounds in Table 1 to perform a zebrafish tail-scissing regeneration phenotype test retest.
  • the 3dpf (days post fertilization) type AB zebrafish juveniles were selected for shear tail fin modeling, and were randomly divided into groups of 10 ⁇ M to 0.001 ⁇ M and a control group, 15 juveniles per group. Add to 6-well plate, 3 mL fish water per well, DMSO concentration ⁇ 1% (v / v). The AB eggs after dosing were imaged at 7 dpf in a biochemical incubator at 28.5 °C. The px values (pixels) of the caudal fin regeneration length of each group were analyzed by NIS-Elements D 3.1 software.
  • the IC 50 value of each compound in the tail-type regeneration of AB type zebrafish was calculated by nonlinear fitting using GraphPad Prism 6.0.
  • a series of compounds such as LGK-974 (control) and REX-P-4 (Examples) were tested for Wnt signaling by HEK293T-STF cell line stably transfected with STF reporter gene and L-Wnt3a secreted cell line.
  • pathway inhibitory activity the activity was represented by an index of the IC 50, IC 50 i.e. STF reporter gene Luciferase activity is inhibited by 50% the concentration of the compound.
  • a series of compounds such as REX-P-4 prepared in the examples of the present invention were measured using the Wnt reporter gene platform of Crown Bio, and the results are shown in Table 3. The results indicate that the compounds provided by the present invention have better Wnt signaling pathway inhibitory activity at the molecular level.
  • the compound REX-P-7 prepared in the examples of the present invention was subjected to human and mouse in vitro liver particle metabolism stability experiments and PK assay in BABL/C mice.
  • the PK test method was as follows: 18 rats were divided into two groups of 9 rats each. One group was administered intravenously at a dose of 5 mg/kg; one group was orally administered at a dose of 10 mg/kg. Each group collected blood through the orbital veins at 0, 0.083, 0.25, 0.5, 1, 2, 4, 8, 24 h after administration. About 100 ⁇ L of blood was collected by eyelid blood collection into a clean EP tube containing EDTA (final concentration of EDTA was 0.25 mg/mL). The blood collection tube was quickly inverted at least 5 times after collection to ensure uniform mixing and then placed on ice. Blood collected at each time point was centrifuged at 8000 rpm for 5 minutes at 4 ° C to obtain plasma. Another 1.5 mL centrifuge tube was used to mark the compound name, animal number, and time point, and the plasma was transferred to the tube. Plasma was stored at -80 ° C until analysis.

Abstract

本发明公开了一种五元杂环酰胺类WNT通路抑制剂，属于调节Wnt信号通路活性的化合物，并提供了该类化合物的制备方法，及该类化合物在制备拮抗Wnt信号通路的药物中的应用。本发明提供的五元杂环酰胺类WNT通路抑制剂，基于靶标的合理药物设计，抗肿瘤活性显著，可用于开发成新一代的Wnt通路抑制剂，具有极大的临床应用价值，市场潜力可观。

Description

五元杂环酰胺类WNT通路抑制剂 技术领域
本发明涉及一种五元杂环酰胺类WNT通路抑制剂，属于调节Wnt信号通路活性的化合物，并提供了该类化合物的制备方法，及该类化合物用于在制备拮抗Wnt信号通路的药物中的应用。
背景技术
Wnt信号通路在多细胞生物体轴分化、组织器官发生、肿瘤形成等生命过程中具有重要作用。Wnt基因编码表达的蛋白是一类分泌型糖蛋白，由19个成员组成，通过与细胞膜上Frizzled(Fzd)家族蛋白及低密度脂蛋白受体相关蛋白(LDL receptor related protein，LRP)受体结合，激活典型Wnt/β-catenin通路、平面极通路、Wnt/Ca2+通路等多种细胞内信号途径，调控着包括增殖、分化、死亡、迁移、极化等多种细胞功能(Nusse Roel,Varmus Harold E.(1992).Wnt genes.Cell,69(7),1073-1087.)。
经研究报道发现，神经性疾病、炎症纤维化疾病、代谢性疾病以及多种类型癌症的发病机制中都有涉及到典型Wnt/β-catenin信号通路β-catenin-TCF/LCF转录复合物的激活的失调(Kahn,M.(2014).Can we safely target the Wnt pathway？Nature reviews.Nat.Rev.Drug.Discovery,13(7),513-532.)。在癌症研究领域中，Wnt信号参与肿瘤早期证据来源于小鼠乳腺癌中分离得到因病毒***而激活的癌基因Int1；近10％的结直肠癌、头颈癌、肺癌、卵巢癌、黑色素瘤患者癌症发生与Wnt信号调控元件R-spondin家族和RNF43/ZNRF3的功能突变诱导相关(B Madan,Z Ke,N Harmston,et al.(2015).Wnt addiction of genetically defined cancers reversed by PORCN inhibition.Oncogene,1-11.)。然而，这类患者目前临床上尚无针对性的Wnt信号通路小分子靶向药物治疗，非选择性的细胞毒制剂及其联合治疗方案所带来的胃肠道反应、骨髓造血抑制等方面的不良反应严重影响患者的生存质量。目前，进入临床试验阶段药物候选物还处于安全性和概念性药效验证的临床I/II期阶段，例如，针对Wnt信号通路上游靶点PORCN设计的LGK974(ClinicalTrials.gov Identifier:NCT01351103)，ETC-1922159(ClinicalTrials.gov Identifier:NCT02521844)；针对Wnt信号通路下游靶点CBP/β-catenin设计的PRI-724(ClinicalTrials.gov Identifier:NCT02413853)。鉴于此，继续研制具有可以调控Wnt信号通路的药物，寻找到一种作用机制明确、药效显著的化合物，具有重要的临床价值和社会意义。
发明内容
本发明目的在于提供一种结构新颖的五元杂环酰胺类WNT通路抑制剂，通过基团的取代修饰，合成并筛选出一系列具有抗肿瘤活性的化合物。
为实现上述发明目的，本发明采取了以下技术方案：
一种五元杂环酰胺类WNT通路抑制剂，为具有如下结构通式的化合物及其药学上可接受的盐：
Figure PCTCN2016108964-appb-000001
其中，环A和环B各自独立地选自芳香环、或含1-2个N原子或O原子的芳香杂环；X、Y、Z各自独立地选自CR4、NR5、S原子、O原子中的一种，且S原子和O原子不同时存在；n选自1～2中的任一整数值；R1、R2各自独立地选自氢、卤素、C1-6烷基、C3-6环烷基、C2-6烯基、C2-6炔基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基、氨基、酰基、磺基、芳基、杂环基中的一种或几种；R3为取代或未取代的芳基、杂环基，芳基、杂环基上的取代基团选自卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基、氰基、氨基、酰基、磺基、杂环基中的一种或几种；R4、R5各自独立地选自氢、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C3-6环烷基中的一种；杂环基为选自一个或多个N、O、S杂原子的3-12元杂环。
优选的，为具有如下结构通式的化合物及其药学上可接受的盐：
Figure PCTCN2016108964-appb-000002
其中，环B选自芳香环、或含1-2个N原子或O原子的芳香杂环；X、Y、Z各自独立地选自CR4、NR5、S原子、O原子中的一种，且S原子和O原子不同时存在；n选自1～2中的任一整数值；R1、R2各自独立地选自氢、卤素、C1-6烷基、C3-6环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基、氨基、酰基、芳基、杂环基中的一种或几种；R3为取代或未取代的芳基、杂环基，芳基、杂环基上的取代基团选自卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基、氰基、氨基、酰基、磺基、杂环基中的一种或几种；R4、R5各自独立地选自氢、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C3-6环烷基中的一种；杂环基为选自一个或多个N、O、S杂原子的3-6元杂环。
更优选的，结构通式(2)中，
Figure PCTCN2016108964-appb-000003
选自
Figure PCTCN2016108964-appb-000004
Figure PCTCN2016108964-appb-000005
中的一种；X、Y、Z各自独立地选自CR4、NR5、S原子、O原子中的一种，且S原子和O原子不同时存在；n选自1～2中的任一整数值；R1、R2为氢、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、酰胺基、C1-6烷基酰胺基、杂环基中的一种；R3为
Figure PCTCN2016108964-appb-000006
中的一种；R4、R5各自独立地选自氢、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基中的一种；R6选自氢、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、酰胺基中的一种；杂环基为选自一个或多个N、O杂原子的3-6元杂环。
优选的，为具有如下结构通式的化合物及其药学上可接受的盐：
Figure PCTCN2016108964-appb-000007
其中，X、Y、Z各自独立地选自CR4、NR5、S原子、O原子中的一种，且S原子和O原子不同时存在；n选自1或2；R1、R2为氢、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、酰胺基、C1-6烷基酰胺基、杂环基中的一种；R3为
Figure PCTCN2016108964-appb-000008
Figure PCTCN2016108964-appb-000009
中的一种；R4、R5各自独立地选自氢、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基中的一种；R6选自氢、卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、酰胺基中的一种；杂环基为选自一个或多个N、O杂原子的3-6元杂环。
优选的，为具有如下结构通式的化合物及其药学上可接受的盐：
Figure PCTCN2016108964-appb-000010
其中，X、Z同时为CR4；或X、Z同时为NR5；或X、Z中任一为CR4，另一则为NR5；n选自1或2；R1、R2为氢、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、酰胺 基、C1-6烷基酰胺基、杂环基中的一种；R3为
Figure PCTCN2016108964-appb-000011
Figure PCTCN2016108964-appb-000012
中的一种；R6选自氢、卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、酰胺基中的一种；杂环基为选自一个或多个N、O杂原子的3-6元杂环。
优选的，为具有如下结构通式的化合物及其药学上可接受的盐：
Figure PCTCN2016108964-appb-000013
其中，X、Z同时为CR4；或X、Z同时为NR5；或X、Z中任一为CR4，另一则为NR5；或X、Z中任一为O原子，另一则为NR5；或X、Z中任一为O原子，另一则为CR4；n选自1或2；R1、R2为氢、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、酰胺基、C1- 6烷基酰胺基、杂环基中的一种；R3为
Figure PCTCN2016108964-appb-000014
Figure PCTCN2016108964-appb-000015
中的一种；R6选自氢、卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、酰胺基中的一种；杂环基为选自一个或多个N、O杂原子的3-6元杂环。
优选的，芳基为苯基、萘基或蒽基；所述的杂环基为吗啉基、哌啶基、吡啶基、嘧啶基、吡喃基、噻吩基、呋喃基、吡咯基、吡唑基、咪唑基或噻唑基；卤素为氟、氯、溴、碘中的一种。
一种五元杂环酰胺类WNT通路抑制剂，选自如下编号为REX-P-1～REX-P-56的特征化合物：
REX-P-1：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-1-甲基-3-苯基-1-氢-吡唑-5-酰胺；
REX-P-2：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-苯基-1-氢-吡唑-3-酰胺；
REX-P-3：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-2-苯基-噻唑-5-酰胺；
REX-P-4：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-苯基-噻唑-2-酰胺；
REX-P-5：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-2-苯基-噻唑-4-酰胺；
REX-P-6：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-4-苯基-噻唑-2-酰胺；
REX-P-7：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-苯基-异恶唑-3-酰胺；
REX-P-8：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-苯基-1,3,4-噻二唑-2-酰胺；
REX-P-9：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-1-甲基-5-苯基-1-氢-吡唑-3-酰胺；
REX-P-10：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-4-甲基-5-苯基-噻唑-2-酰胺；
REX-P-11：5-(2-氯苯基)-N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-噻唑-2-酰胺；
REX-P-12：5-(3-氯苯基)-N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-噻唑-2-酰胺；
REX-P-13：5-(4-氯苯基)-N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-噻唑-2-酰胺；
REX-P-14：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(吡啶-2-基)噻唑-2-酰胺；
REX-P-15：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(吡嗪-2-基)噻唑-2-酰胺；
REX-P-16：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(吡啶-2-基)-1氢-吡唑-3-酰胺；
REX-P-17：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(3-氟-吡啶-2-基)-1氢-吡唑-3-酰胺；
REX-P-18：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(5-氟-吡啶-3-基)-1氢-吡唑-3-酰胺；
REX-P-19：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(6-甲基-吡啶-2-基)-1氢-吡唑-3-酰胺；
REX-P-20：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(嘧啶-2-基)-1氢-吡唑-3-酰胺；
REX-P-21：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(吡嗪-2-基)-1氢-吡唑-3-酰胺；
REX-P-22：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-2-(3-氯苯基)-噻唑-5-酰胺；
REX-P-23：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-2-(吡啶-2-基)-噻唑-5-酰胺；
REX-P-24：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-2-(3-氟-吡啶-2-基)-噻唑-5-酰胺；
REX-P-25：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-2-(5-氟-吡啶-3-基)-噻唑-5-酰胺；
REX-P-26：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-2-(6-甲基-吡啶-2-基)-噻唑-5-酰胺；
REX-P-27：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-2-(嘧啶-2-基)-噻唑-5-酰胺；
REX-P-28：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-2-(吡嗪-2-基)-噻唑-5-酰胺；
REX-P-29：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(吡啶-2-基)-异恶唑-3-酰胺；
REX-P-30：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(3-氟-吡啶-2-基)-异恶唑-3-酰胺；
REX-P-31：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(5-氟-吡啶-3-基)-异恶唑-3-酰胺；
REX-P-32：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(6-甲基-吡啶-2-基)-异恶唑-3-酰胺；
REX-P-33：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(嘧啶-2-基)-异恶唑-3-酰胺；
REX-P-34：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(吡嗪-2-基)-异恶唑-3-酰胺；
REX-P-35：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(4-乙酰哌嗪-1-基)-异恶唑-3-酰胺；
REX-P-36：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(吡啶-3-基)噻唑-2-酰胺；
REX-P-37：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(3-氟-吡啶-2-基)噻唑-2-酰胺；
REX-P-38：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(5-氟-吡啶-3-基)噻唑-2-酰胺；
REX-P-39：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(6-甲基-吡啶-2-基)噻唑-2-酰胺；
REX-P-40：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(嘧啶-2-基)噻唑-2-酰胺；
REX-P-41：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(嘧啶-5-基)噻唑-2-酰胺；
REX-P-42：5-(4-乙酰哌嗪-1-基)-N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-1,3,4-噻二唑-2-酰胺；
REX-P-43：5-(4-乙酰哌嗪-1-基)-N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-噻唑-2-酰胺；
REX-P-44：2-(4-乙酰哌嗪-1-基)-N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-噻唑-5-酰胺；
REX-P-45：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(3-氯苯基)-1,3,4-噻二唑-2-酰胺；
REX-P-46：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(3-氟苯基)-1,3,4-噻二唑-2-酰胺；
REX-P-47：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(吡啶-2-基)-1,3,4-噻二唑-2-酰胺；
REX-P-48：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(3-氟-吡啶-2-基)-1,3,4-噻二唑-2-酰胺；
REX-P-49：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(5-氟-吡啶-3-基)-1,3,4-噻二唑-2-酰胺；
REX-P-50：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(6-甲基-吡啶-2-基)-1,3,4-噻二唑-2-酰胺；
REX-P-51：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(嘧啶-2-基)-1,3,4-噻二唑-2-酰胺；
REX-P-52：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(吡嗪-2-基)-1,3,4-噻二唑-2-酰胺；
REX-P-53：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(5-甲基-吡啶-3-基)-1,3,4-噻二唑-2-酰胺；
REX-P-54：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(2-甲基-吡啶-3-基)-1,3,4-噻二唑-2-酰胺；
REX-P-55：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(4-甲基-吡啶-3-基)-1,3,4-噻二唑-2-酰胺；
REX-P-56：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(3-甲基-吡啶-2-基)-1,3,4-噻二唑-2-酰胺；
前述编号为REX-P-1～REX-P-56的特征化合物，具体结构如下：
Figure PCTCN2016108964-appb-000016
本发明所述的“化合物”，包括所有立体异构体、几何异构体、互变异构体和同位素。
本发明所述的“化合物”，可以是不对称的，例如，具有一个或多个立体异构体。除非另有说明，所有立体异构体都包括，如对映异构体和非对映异构体。本发明中含有不对称碳原子的化合物，可以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。
本发明所述的“化合物”，还包括互变异构体形式。互变异构体形式来源于一个单键与相邻的双键交换并一起伴随一个质子的迁移。
本发明还包括所有同位素的原子，无论是在中间体或最后的化合物。同位素的原子包括具有相同的原子数、但不同质量数的。例如，氢的同位素包括氘和氚。
含有前述通式结构的化合物，本文中所用的术语具有如下含义：
术语“卤素”，指氟、氯、溴或碘，优选氟、氯或溴。
术语“氰基”，指-CN。
术语“羟基”，指-OH。
术语“烷基”，指由碳原子和氢原子组成的直链或支链的饱和烃基团，如C1-20烷基，优选为C1-6烷基，例如甲基、乙基、丙基(包括正丙基和异丙基)、丁基(包括正丁基、异丁基、仲丁基或叔丁基)、戊基(包括正戊基、异戊基、新戊基)、正己基、2-甲基己基等。所述烷基可以是非取代的、或是被一个或多个取代基所取代，取代基包括但不限于烷基、烷氧基、氰基、羟基、羰基、羧基、芳基、杂芳基、氨基、卤素、磺酰基、亚磺酰基、磷酰基。
术语“氨基”，指-NH2、-NH(烷基)和-N(烷基)2，烷基的含义如前所述。-NH(烷基)的结构形式为
Figure PCTCN2016108964-appb-000017
具体例子包括但不限于-NHCH3、-NHCH(CH3)2、-NHC2H5等；-N(烷基)2的结构形式为
Figure PCTCN2016108964-appb-000018
具体例子包括但不限于-N(CH3)2、-N(CH3)C2H5等。
术语“芳基”，指具有完全共轭的π电子体系的全碳单环或稠合环，通常具有6-14个碳原子，优选具有6-12个碳原子，最优选具有6个碳原子。芳基可以是非取代的、或被一个或多个取代基所取代，取代基包括但不限于烷基、烷氧基、氰基、羟基、羰基、羧基、芳基、芳烷基、氨基、卤素、磺酰基、亚磺酰基、磷酰基。非取代的芳基的实例包括但不限于苯基、萘基和蒽基。
术语“杂环基”，指具有3-12个(整数)环原子的单环或稠合环，其中有1、2或3个环原子选自N、O中的一个或多个，其余环原子为C，且具有完全共轭的π-电子体系。杂环基可以是饱和的、或非饱和的基团，也可以是非取代的、或被一个或多个取代基所取代，取代基包括但不限于烷基、烷氧基、氰基、羟基、羰基、羧基、芳基、芳烷基、氨基、卤素、磺酰基、亚磺酰基、磷酰基。非取代的杂环基的实例包括但不限于吡咯基、吲哚基、吡咯烷基、咪唑基、吡唑基、四唑基、吡啶基、喹啉基、异喹啉基、哌啶基、嘧啶基、吡嗪基、哌嗪基、呋喃基、吡喃基、吗啉基。
本发明还提供了一种药物组合物，包含如前所述的化合物或其药学上可接受的盐作为活性成份，以及一种或多种药学上可接受的载体。
本发明所述的“药物组合物”，指一种或多种本发明的化合物或其盐与在本领域中通常接受的用于将生物活性化合物输送至有机体(例如人)的载体的制剂。药物组合物的目的是有利于对有 机体给药输送。
术语“药学上可接受的载体”，指与活性成份共同给药的、且有利于活性成份给药的物质，包括但不限于国家食品药品监督管理局许可的可接受的用于人或动物(例如家畜)的任何助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味增强剂、表面活性剂、润湿剂、分散剂、崩解剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。例如包括但不限于碳酸钙、磷酸钙、各种糖和各类淀粉、纤维素衍生物、明胶、植物油和聚乙二醇。
本发明所述的药物组合物，可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等等。
本发明所述的药物组合物，可以采用本领域熟知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
本发明所述的化合物或其药学上可接受的盐或其药物组合物的给药途径，包括但不限于口服、直肠、透黏膜、经肠给药，或者局部、经皮、吸入、肠胃外、舌下、***内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。优选的给药途径是口服给药。
对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的载体混合，来配制该药物组合物。这些载体能使本发明的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，以用于对患者的口服给药。例如，用于口服给药的药物组合物，可采用如下方式获得片剂：将活性成分与一种或多种固体载体合并，如果需要将所得混合物制粒，并且如果需要加入少量的赋形剂加工成混合物或颗粒，以形成片剂或片芯。片芯可与任选适合肠溶的包衣材料结合，加工成更有利于有机体(例如人)吸收的包衣制剂形式。
本发明还提供了一种如前所述的化合物或其药学上可接受的盐在制备拮抗Wnt信号通路的药物中的应用。
优选的，制药用途为用于治疗与异常的Wnt信号活性相关的细胞增殖性疾病、消化***疾病。
更优选的，制药用途为用于治疗癌症，包括非小细胞肺癌、间变性大细胞淋巴瘤、炎性肌纤维母细胞瘤、鼻咽癌、乳腺癌、结直肠癌、弥漫大B细胞淋巴瘤、肝癌、胃癌、食道癌、胰腺癌、卵巢癌、全身组织细胞增生症和神经母细胞瘤。
本发明中，发明人对合成得到的一系列的五元杂环酰胺类WNT通路抑制剂，从分子水平测定Wnt通路STF报告基因的抑制活性，发现部分化合物对Wnt通路具有显著的抑制活性；此外，还进行了斑马鱼表型筛选实验，通过对斑马鱼的剪尾再生抑制试验和体轴发育抑制试验，发现部分化合物在体内的抗肿瘤活性显著；并通过体内药效实验等，发现部分化合物在体内的抗肿 瘤效果显著。
与现有技术相比，本发明提供的五元杂环酰胺类WNT通路抑制剂，基于靶标的合理药物设计，通过基团的取代修饰，获得了一系列结构新颖的化合物；并结合STF报告基因实验、斑马鱼表型筛选实验，优化筛选出一系列具有抗肿瘤活性的化合物。因此，可用于开发成新一代的Wnt通路抑制剂，对于靶向治疗或预防由Wnt通路介导的疾病具有极大的临床应用价值，市场潜力可观。
附图说明
图1为处理48h后AB型斑马鱼体轴发育抑制图
图2为处理48h后AB型斑马鱼体轴发育抑制量效关系图(mean±sd)
图3为处理7dpf后AB型斑马鱼剪尾再生抑制图
图4为处理7dpf后AB型斑马鱼剪尾再生抑制量效关系图(mean±sd)
具体实施方式
以下是本发明的具体实施例，对本发明的技术方案做进一步的描述，但是本发明的保护范围并不限于这些实施例。凡是不背离本发明构思的改变或等同替代均包括在本发明的保护范围之内。
本发明提供的目标化合物制备方法中，液相色谱采用WatersSymmetry C18色谱柱。薄层色谱采用GF254(0.25毫米)。核磁共振色谱(NMR)使用Bruker-400核磁共振仪测定；液质连用(LC/MS)使用Waters ZQ质谱检测器(柱子：WatersSymmetryC18，毫米，5微米，35℃)，采用ESI(+)离子模式。
此外，凡涉及易氧化或易水解的原料的所有操作都在氮气保护下进行。除非另有说明，本发明使用的原料都是市售原料、无需进一步纯化可以直接使用。
实施例1、N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-苯基-1-氢-吡唑-3-酰胺【编号为REX-P-2】的制备
合成路线如下：
Figure PCTCN2016108964-appb-000019
Figure PCTCN2016108964-appb-000020
合成方案一：中间体REX-P-INT-1的合成
步骤一：化合物1-2的制备
将化合物1-1(5.0g,24.2mmol)溶解在200ml干燥的四氢呋喃溶液中，在冰水浴中滴加异丙基氯化镁(12.7ml,25.5mmol)，室温搅拌1小时，将N-甲酰基吗啉(2.5ml,24.2mmol)溶解在50ml干燥的四氢呋喃溶液中，室温滴加到反应体系中再搅拌一小时，反应结束后加入冰水淬灭反应，用乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩后用硅胶柱提纯，得到化合物1-2(3.0g,79.6％)。
MSm/z[ESI]：156.0[M+1]。
步骤二：化合物1-3的制备
将化合物1-2(3.0g,19.4mmol)、2-甲基-4-吡啶硼酸(3.2g,23.2mmol)溶解在200ml N,N-二甲基甲酰胺中，在氮气保护条件下分别向体系中加入碳酸钾(10.7g,77.6mmol)、四三苯基膦钯(1.1g,1.0mmol)，在100℃条件下搅拌过夜，反应结束向体系中加入冰水200ml，用乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩后用硅胶柱提纯，得到化合物1-3(1.8g,44.0％)。
MSm/z[ESI]：213.1[M+1]。
步骤三：化合物1-4的制备
将化合物1-3(1.8g,8.5mmol)溶解在50ml无水乙醇中，分别向体系中加入盐酸羟胺(1.2g,17.0mmol)、醋酸钠(1.4g,17.0mmol)，室温搅拌2小时，反应结束向体系中加入冰水50ml淬灭反应，用乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩后用硅胶柱提纯，得到化合物1-4(1.8g,93.4％)。
MSm/z[ESI]：228.1[M+1]。
步骤四：化合物REX-P-INT-1的制备
将化合物1-4(1.8g,7.9mmol)溶解在30ml无水乙醇溶液中，分别加入10％的钯碳(200mg)、盐酸(1.5ml，12.0N)在一个大气压氢气条件下室温反应过夜，反应结束过滤、浓缩，用 硅胶柱提纯，得到化合物REX-P-INT-1(1.4g，85.2％)。
MSm/z[ESI]：214.1[M+1]。
合成方案二：化合物REX-P-2的制备
步骤一：化合物REX-P-INT-2的制备
将氢化钠(1.2g,50.0mmol)溶解在30ml N,N-二甲基甲酰胺中，分别将化合物1-1(5.0g,42.0mmol)、草酸二乙酯(56.9ml,420.0mmol)溶解在100ml N,N-二甲基甲酰胺中滴加到体系中，滴加完毕50℃条件下搅拌2小时，反应结束向体系中加入冰水200ml，用乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩后用硅胶柱提纯，得到化合物REX-P-INT-2(8.6g,92.8％)。
MSm/z[ESI]：221.1[M+1]。
步骤二：化合物1-3的制备
将化合物REX-P-INT-2(8.6g,39.1mmol)溶解在50ml无水乙醇中，加入水合肼(2.3g,46.9mmol)，将反应体系在室温条件下搅拌5小时，反应结束向体系中加入饱和碳酸氢钠溶液100ml淬灭反应，用乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩后用硅胶柱提纯，得到化合物1-3(3.4g,40.7％)。
MSm/z[ESI]：217.1[M+1]。
步骤三：化合物1-4的制备
将化合物1-3(3.4g,15.9mmol)溶解在40ml干燥的甲醇中，加入氢氧化钠溶液(140ml,4M)，将体系在室温条件下搅拌2小时，反应结束后浓缩出去甲醇，再用1M的盐酸将体系的pH值调到3左右，用乙酸乙酯萃取，无水硫酸钠干燥，浓缩后用硅胶柱提纯，得到化合物1-4(2.4g,80.4％)。
MSm/z[ESI]：189.1[M+1]。
步骤四：化合物REX-P-2的制备
分别将化合物1-4(2.4g,12.8mmol)、REX-P-INT-1(2.7g,12.8mmol)溶解在50ml干燥的二甲亚砜中，分别加入N,N-二异丙基乙胺(6.3ml,38.4mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(5.8g,15.4mmol)，将体系在室温条件下搅拌2小时，反应结束后加入冰水200ml淬灭反应，用乙酸乙酯萃取，无水硫酸钠干燥，浓缩后用硅胶柱提纯，得到化合物REX-P-2(3.0g,61.3％)。
MSm/z[ESI]：384.2[M+1]。
1H-NMR(400MHz,DMSO-d6):δ＝13.79(s,1H),8.85-9.36(m,1H),8.48-8.54(m,2H),7.65-7.85(m,3H),7.30-7.50(m,5H),7.10(s,1H),4.45-4.58(m,2H),2.53(s,3H),2.33(s,3H).
实施例2、N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-2-苯基-噻唑-5-酰胺【编号为REX-P-3】的制备
合成路线如下：
Figure PCTCN2016108964-appb-000021
步骤一：化合物1-2的制备
将氯乙酸乙酯(5.0g,40.9mmol)、甲酸乙酯(3.0g,40.9mmol)溶解在100ml干燥的甲苯中，冰水浴条件下加入乙醇钠(3.3g,48.5mmol),将反应体系在0℃条件下搅拌5小时，再升至室温搅拌12小时，反应结束后向体系中加入冰水200ml淬灭，用***萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩后用硅胶柱提纯，得到化合物1-2(4.5g,73.3％)。
MSm/z[ESI]：151.0[M+1]。
步骤二：化合物1-3的制备
分别将化合物1-2(4.5g,30.0mmol)、硫代苯甲酰胺(4.1g,30.0mmol)溶解在50ml干燥的甲苯中，加入硫酸镁(7.2g,59.8mmol)，将反应体系在100℃条件下搅拌4小时，反应结束向体系中加入冰水100ml淬灭，用乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩后用硅胶柱提纯，得到化合物1-3(3.2g,45.9％)。
MSm/z[ESI]：234.1[M+1]。
步骤三：化合物1-4的制备
将化合物1-3(3.2g,13.8mmol)溶解在50ml干燥的甲醇中，加入氢氧化钠溶液(130ml,4M)，将体系在室温条件下搅拌2小时，反应结束后浓缩出去甲醇，再用1M的盐酸将体系的pH值调到3左右，用乙酸乙酯萃取，无水硫酸钠干燥，浓缩后用硅胶柱提纯，得到化合物1-4(2.3g,81.8％)。
MSm/z[ESI]：206.0[M+1]。
步骤四：化合物REX-P-3的制备
参照实施例1“合成方案一的制备方法”先制得中间体REX-P-INT-1 2.9克。
分别将化合物1-4(2.3g,11.3mmol)、REX-P-INT-1(2.9g,13.6mmol)溶解在50ml干燥的二甲亚砜中，分别加入N,N-二异丙基乙胺(5.5ml,38.4mmol)、2-(7-偶氮苯并三氮唑)- N,N,N',N'-四甲基脲六氟磷酸酯(5.1g,13.6mmol)，将体系在室温条件下搅拌2小时，反应结束后加入冰水200ml淬灭反应，用乙酸乙酯萃取，无水硫酸钠干燥，浓缩后用硅胶柱提纯，得到化合物REX-P-3(2.8g,61.3％)。
MSm/z[ESI]：401.1[M+1]。
1H-NMR(400MHz,DMSO-d6):δ＝8.56(d,J＝5.2Hz,1H),8.51(d,J＝2.0Hz,1H),8.26(s,1H),7.92-7.98(m,2H),7.65-7.68(m,1H),7.44-7.51(m,3H),7.30(s,1H),7.21-7.24(m,1H),7.16(t,J＝6.0Hz,1H),4.66(d,J＝6.0Hz,2H),2.61(s,3H),2.35(s,3H).
实施例3、N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-苯基-噻唑-2-酰胺【编号为REX-P-4】的制备
合成路线如下：
Figure PCTCN2016108964-appb-000022
步骤一：化合物1-2的制备
将化合物1-1(5.0g,29.1mmol)、三乙胺(8.5ml,61.1mmol)溶解在干燥的二氯甲烷中，冰水浴条件下滴加草酰氯单乙酯(4.4g,32.0mmol)，将反应体系在室温条件下搅拌72小时，反应结束后向体系中加入冰水200ml淬灭，用二氯甲烷萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩后用硅胶柱提纯，得到化合物1-2(5.0g,73.0％)。
MSm/z[ESI]：236.1[M+1]。
步骤二：化合物1-3的制备
将化合物1-2(5.0g,21.3mmol)溶解在50ml干燥的三氯甲烷中，加入五硫化二磷(9.0g,42.6mmol)，将反应体系在60℃条件下搅拌过夜，反应结束向体系中加入冰水100ml淬灭，用二氯甲烷萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩后用硅胶柱提纯，得到化合物1-3(4.5g,90.8％)。
MSm/z[ESI]：234.1[M+1]。
步骤三：化合物1-4的制备
将化合物1-3(4.5g,19.3mmol)溶解在80ml干燥的甲醇中，加入氢氧化钠溶液(150ml,4M)，将体系在室温条件下搅拌2小时，反应结束后浓缩出去甲醇，再用1M的盐酸将体系的pH值调到3左右，用乙酸乙酯萃取，无水硫酸钠干燥，浓缩后用硅胶柱提纯，得到化合物1-4(3.3g,82.3％)。
MSm/z[ESI]：206.0[M+1]。
步骤四：化合物REX-P-4的制备
参照实施例1“合成方案一的制备方法”先制得中间体REX-P-INT-1 3.6克。
分别将化合物1-4(3.3g,15.9mmol)、REX-P-INT-1(3.6g,17.0mmol)溶解在50ml干燥的二甲亚砜中，分别加入N,N-二异丙基乙胺(6.8ml,47.7mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(7.2g,19.1mmol)，将体系在室温条件下搅拌2小时，反应结束后加入冰水200ml淬灭反应，用乙酸乙酯萃取，无水硫酸钠干燥，浓缩后用硅胶柱提纯，得到化合物REX-P-4(2.3g,35.9％)。
MSm/z[ESI]：401.1[M+1]。
1H-NMR(400MHz,DMSO-d6):δ＝8.58(d,J＝5.2Hz,1H),8.55(d,J＝2.0Hz,1H),7.99(s,1H),7.78(t,J＝6.0Hz,1H),7.65-7.68(m,1H),7.58-7.62(m,2H),7.37-7.47(m,3H),7.32(s,1H),7.22-7.25(m,1H),4.70(d,J＝6.4Hz,2H),2.63(s,3H),2.36(s,3H).
实施例4、N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-2-苯基-噻唑-4-酰胺【编号为REX-P-5】的制备
合成路线如下：
Figure PCTCN2016108964-appb-000023
步骤一：化合物1-2的制备
将化合物1-1(1.0g,7.3mmol)、3-溴丙酮酸(1.2g,7.3mmol)溶解在50ml干燥的1,4-二氧六环中，回流条件下搅拌2小时，反应结束后向体系中加入冰水100ml淬灭，用乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩后用硅胶柱提纯，得到化合物1-2(0.8g,53.5％)。
MSm/z[ESI]：206.0[M+1]。
步骤二：化合物REX-P-5的制备
参照实施例1“合成方案一的制备方法”先制得中间体REX-P-INT-1 0.9克。
分别将化合物1-2(0.8g,3.9mmol)、REX-P-INT-1(0.9g,4.3mmol)溶解在20ml干燥的二甲亚砜中，分别加入N,N-二异丙基乙胺(1.7ml,11.7mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1.8g,4.7mmol)，将体系在室温条件下搅拌2小时，反应结束后加入冰水50ml淬灭反应，用乙酸乙酯萃取，无水硫酸钠干燥，浓缩后用硅胶柱提纯，得到化合物REX-P-5(0.7g,44.7％)。
MSm/z[ESI]：401.1[M+1]。
1H-NMR(400MHz,DMSO-d6):δ＝9.20(t,J＝6.0Hz,1H),8.51-8.55(m,2H),8.35(s,1H),8.05-8.11(m,2H),7.72(s,1H),7.53-7.57(m,3H),7.40(s,1H),7.34(d,J＝4.8Hz,1H),4.57(d,J＝6Hz,2H),2.53(s,3H),2.35(s,3H).
实施例5、N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-4-苯基-噻唑-2-酰胺【编号为REX-P-6】的制备
合成路线如下：
Figure PCTCN2016108964-appb-000024
步骤一：化合物1-2的制备
将化合物1-1(1.0g,7.5mmol)、2-溴苯乙酮(1.5g,7.5mmol)溶解在80ml的苯和10ml的无水乙醇的混合溶剂中，室温搅拌18小时，再将反应体系升温至60℃搅拌2小时，反应结束后向体系中加入饱和碳酸氢钠溶液100ml淬灭，用乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩后用硅胶柱提纯，得到化合物1-2(0.9g,51.4％)。
MSm/z[ESI]：234.1[M+1]。
步骤二：化合物1-3的制备
将化合物1-2(0.9g,3.9mmol)溶解在10ml干燥的甲醇中，加入氢氧化钠溶液(20ml,4M)，将体系在室温条件下搅拌2小时，反应结束后浓缩出去甲醇，再用1M的盐酸将体系的pH值调到3左右，用乙酸乙酯萃取，无水硫酸钠干燥，浓缩后用硅胶柱提纯，得到化合物1-3(0.7g,88.3％)。
MSm/z[ESI]：206.0[M+1]。
步骤三：化合物REX-P-6的制备
参照实施例1“合成方案一的制备方法”先制得中间体REX-P-INT-1 0.8克。
分别将化合物1-3(0.7g,3.4mmol)、REX-P-INT-1(0.8g,3.7mmol)溶解在10ml干燥的二甲亚砜中，分别加入N,N-二异丙基乙胺(1.5ml,11.2mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1.7g,4.4mmol)，将体系在室温条件下搅拌2小时，反应结束后加入冰水200ml淬灭反应，用乙酸乙酯萃取，无水硫酸钠干燥，浓缩后用硅胶柱提纯，得到化合物REX-P-6(0.5g,37.5％)。
MSm/z[ESI]：401.1[M+1]。
1H-NMR(400MHz,DMSO-d6):δ＝9.55(t,J＝6.4Hz,1H),8.51-8.55(m,2H),8.43(s,1H),8.07-8.11(m,2H),7.74(d,J＝1.6Hz,1H),7.46-7.52(m,2H),7.38-7.43(m,2H),7.32-7.35(m,1H),4.57(d,J＝6.4Hz,2H),2.53(s,3H),2.34(s,3H).
实施例6、N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-苯基-异恶唑-3-酰胺【编号为REX-P-7】的制备
合成路线如下：
Figure PCTCN2016108964-appb-000025
步骤一：化合物1-2的制备
将化合物1-1(1.0g,4.9mmol)溶解在10ml干燥的甲醇中，加入氢氧化钠溶液(20ml,4M)，将体系在室温条件下搅拌2小时，反应结束后浓缩出去甲醇，再用1M的盐酸将体系的pH值调到3左右，用乙酸乙酯萃取，无水硫酸钠干燥，浓缩后用硅胶柱提纯，得到化合物1-2(0.7g,79.5％)。
MSm/z[ESI]：190.0[M+1]。
步骤二：化合物REX-P-7的制备
参照实施例1“合成方案一的制备方法”先制得中间体REX-P-INT-1 0.9克。
分别将化合物1-2(0.7g,3.9mmol)、REX-P-INT-1(0.9g,4.3mmol)溶解在10ml干燥的二甲亚砜中，分别加入N,N-二异丙基乙胺(1.6ml,11.7mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1.9g,5.0mmol)，将体系在室温条件下搅拌2小时，反应结束后加入冰水200ml淬灭反应，用乙酸乙酯萃取，无水硫酸钠干燥，浓缩后用硅胶柱提纯，得到化合物REX-P-7(1.2g,79.8％)。
MSm/z[ESI]：385.2[M+1]。
1H-NMR(400MHz,DMSO-d6):δ＝9.47(t,J＝6.0Hz,1H),8.48-8.65(m,2H),7.90-7.98(m,2H),7.71(s,1H),7.52-7.61(m,3H),7.37-7.43(m,2H),7.34(d,J＝4.8Hz,1H),4.54(d,J＝6.0Hz,2H),2.54(s,3H),2.34(s,3H).
实施例7、N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-1-甲基-5-苯基-1-氢-吡唑-3-酰胺【编号为REX-P-9】的制备
合成路线如下：
Figure PCTCN2016108964-appb-000026
步骤一：化合物1-2的制备
参照实施例1“合成方案二的制备方法”先制得中间体REX-P-INT-2 1.0克。
分别将化合物REX-P-INT-2(1.0g,4.5mmol)、甲基肼硫酸盐(1.0g,6.8mmol)、氢氧化钠(0.5g,13.6mmol)溶解在50ml无水乙醇中，将反应体系在70℃条件下搅拌过夜，反应结束向体系中加入冰水100ml淬灭反应，用乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩后用硅胶柱提纯，得到化合物1-2(0.3g,28.7％)。
MSm/z[ESI]：231.1[M+1]。
步骤二：化合物1-3的制备
将化合物1-2(0.3g,1.3mmol)溶解在5ml干燥的甲醇中，加入氢氧化钠溶液(10ml,4M)，将体系在室温条件下搅拌2小时，反应结束后浓缩出去甲醇，再用1M的盐酸将体系的pH值调到3左右，用乙酸乙酯萃取，无水硫酸钠干燥，浓缩后用硅胶柱提纯，得到化合物1-3(242.7mg,92.4％)。
MSm/z[ESI]：203.1[M+1]。
步骤三：化合物REX-P-9的制备
参照实施例1“合成方案一的制备方法”先制得中间体REX-P-INT-1 2.7克。
分别将化合物1-3(242.7mg,1.2mmol)、REX-P-INT-1(303.7mg,1.4mmol)溶解在20ml干燥的二甲亚砜中，分别加入N,N-二异丙基乙胺(0.6ml,3.6mmol)、2-(7-偶氮苯并三氮唑)- N,N,N',N'-四甲基脲六氟磷酸酯(527.3mg,1.4mmol)，将体系在室温条件下搅拌2小时，反应结束后加入冰水50ml淬灭反应，用乙酸乙酯萃取，无水硫酸钠干燥，浓缩后用硅胶柱提纯，得到化合物REX-P-9(361.8mg,75.9％)。
MSm/z[ESI]：398.2[M+1]。
1H-NMR(400MHz,DMSO-d6):δ＝9.17(t,J＝6.0Hz,1H),8.51-8.54(m,2H),7.75-7.79(m,2H),7.71-7.73(m,1H),7.40-7.47(m,3H),7.31-7.36(m,3H),4.53(d,J＝6.0Hz,2H),4.12(s,3H),2.54(s,3H),2.35(s,3H).
实施例8、N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-1-甲基-3-苯基-1-氢-吡唑-5-酰胺【编号为REX-P-1】的制备
合成路线如下：
Figure PCTCN2016108964-appb-000027
步骤一：化合物1-2的制备
参照实施例1“合成方案二的制备方法”先制得中间体REX-P-INT-2 1.0克。
分别将化合物REX-P-INT-2(1.0g,4.5mmol)、甲基肼硫酸盐(1.0g,6.8mmol)、氢氧化钠(0.5g,13.6mmol)溶解在50ml无水乙醇中，将反应体系在70℃条件下搅拌过夜，反应结束向体系中加入冰水100ml淬灭反应，用乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩后用硅胶柱提纯，得到化合物1-2(247.5mg,23.9％)。
MSm/z[ESI]：231.1[M+1]。
步骤二：化合物1-3的制备
将化合物1-2(247.5mg g,1.1mmol)溶解在5ml干燥的甲醇中，加入氢氧化钠溶液(10ml,4M)，将体系在室温条件下搅拌2小时，反应结束后浓缩出去甲醇，再用1M的盐酸将体系的pH值调到3左右，用乙酸乙酯萃取，无水硫酸钠干燥，浓缩后用硅胶柱提纯，得到化合物1-3(207.0mg,93.1％)。
MSm/z[ESI]：203.1[M+1]。
步骤三：化合物REX-P-1的制备
参照实施例1“合成方案一的制备方法”先制得中间体REX-P-INT-1 2.7克。
分别将化合物1-3(207.0mg,1.0mmol)、REX-P-INT-1(260.3mg,1.2mmol)溶解在20ml干燥的二甲亚砜中，分别加入N,N-二异丙基乙胺(0.5ml,3.0mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(452.0mg,1.2mmol)，将体系在室温条件下搅拌2小时，反应结束后加入冰水50ml淬灭反应，用乙酸乙酯萃取，无水硫酸钠干燥，浓缩后用硅胶柱提纯，得到化合物REX-P-1(256.2mg,64.5％)。
MSm/z[ESI]：398.2[M+1]。
1H-NMR(400MHz,DMSO-d6):δ＝8.87(t,J＝6.0Hz,1H),8.53(d,J＝5.2Hz,1H),8.49(s,1H),7.68(s,1H),7.45-7.61(m,5H),7.42(s,1H),7.36(d,J＝4.8Hz,1H),6.80(s,1H),4.487(d,J＝6.0Hz,2H),3.92(s,3H),2.541(s,3H),2.33(s,3H).
实施例9、N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-苯基-1,3,4-噻二唑-2-酰胺【编号为REX-P-8】的制备
合成路线如下：
Figure PCTCN2016108964-appb-000028
步骤一：化合物1-2的制备
将化合物1-1(2g,14.6mmol)、三乙胺(4ml,2.9g,29.3mmol)溶解在干燥的二氯甲烷中，冰水浴条件下滴加草酰氯单乙酯(2g,14.6mmol)，将反应体系在室温条件下搅拌24小时，反应结束后向体系中加入冰水200ml淬灭，用二氯甲烷萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩后用硅胶柱提纯，得到化合物1-2(2g,57.6％)。
MSm/z[ESI]：237.1[M+1]。
步骤二：化合物1-3的制备
将化合物1-2(0.5g,2.1mmol)溶解在50ml干燥的四氢呋喃中，加入劳森试剂(1g, 2.5mmol)，将反应体系在70℃条件下搅拌过夜，反应结束向体系中加入冰水100ml淬灭，用乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩后用硅胶柱提纯，得到化合物1-3(200mg,40.8％)。
MSm/z[ESI]：235.1[M+1]。
1H-NMR(400MHz,DMSO-d6):δ＝8.07-8.11(m,2H),7.57-7.67(m,3H),7.99(s,1H),4.46(q,J＝7.2Hz,2H),1.374(t,J＝7.2Hz,3H).
步骤三：化合物1-4的制备
将化合物1-3(150mg,0.6mmol)溶解在10ml干燥的甲醇中，加入氢氧化钠溶液(2ml,1M)，将体系在室温条件下搅拌2小时，反应结束后浓缩出去甲醇，再用1M的盐酸将体系的pH值调到3左右，过滤干燥，得到化合物1-4(120mg,90.8％)。
MSm/z[ESI]：207.0[M+1]。
步骤四：化合物REX-P-8的制备
参照实施例1“合成方案一的制备方法”先制得中间体REX-P-INT-1 1克。
分别将化合物1-4(100mg,0.48mmol)、REX-P-INT-1(103mg,0.48mmol)溶解在5ml干燥的二甲亚砜中，分别加入N,N-二异丙基乙胺(188mg,1.4mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(203mg,0.53mmol)，将体系在室温条件下搅拌2小时，反应结束后加入冰水200ml淬灭反应，用乙酸乙酯萃取，无水硫酸钠干燥，浓缩后用硅胶柱提纯，得到化合物REX-P-8(45m g,23.0％)。
MSm/z[ESI]：402.1[M+1]。
1H-NMR(400MHz,DMSO-d6):δ＝9.93(s,1H),8.50-8.55(m,2H),8.06(d,J＝6.8Hz,2H),7.73(s,1H),7.56-7.66(m,3H),7.40(s,1H),7.34(d,J＝4.4Hz,1H),4.56(d,J＝4Hz,2H),2.53(s,3H),2.33(s,3H).
实施例10、5-(4-氯苯基)-N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-噻唑-2-酰胺【编号为REX-P-13】的制备
合成路线如下：
Figure PCTCN2016108964-appb-000029
本实施例的制备方法参照实施例3，仅将实施例3中的化合物1-1(即邻氨基苯乙酮)替代成本实施例的化合物1-1(即2-氨基-4-氯苯乙酮)，其余方法相同，最终制得化合物REX-P-13(120.5mg,25.2％)。
MSm/z[ESI]：435.9[M+1]。
1H-NMR(400MHz,DMSO-d6):δ＝9.55(t,J＝6.0Hz,1H),8.47-8.49(m,2H),7.78-7.80(m,2H),7.67(s,1H),7.51-7.52(m,2H),7.37(s,1H),7.30-7.31(m,1H),4.51(d,J＝6Hz,2H),2.52(s,3H),2.32(s,3H).
实施例11、N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(吡啶-2-基)-1氢-吡唑-3-酰胺【编号为REX-P-16】的制备
合成路线如下：
Figure PCTCN2016108964-appb-000030
本实施例的制备方法参照实施例1的合成方案二，仅将实施例1中的化合物1-1(即苯乙酮)替代成本实施例的化合物1-1(2-乙酰基吡啶)，其余方法相同，最终制得化合物REX-P-16(150mg,30.2％)。
MSm/z[ESI]：385.3[M+1]。
1H-NMR(400MHz,DMSO-d6):δ＝13.93(q,1H),8.99(t,J＝6.0Hz,1H),8.60(s,1H),8.46-8.49(m,2H),7.87-7.92(m,2H),7.67(s,1H),7.31-7.38(m,3H),4.49(d,J＝6Hz,2H),2.52(s,3H),2.32(s,3H).
实施例13、N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-2-(3-氯苯基)-噻唑-5-酰胺【编号为REX-P-22】的制备
合成路线如下：
Figure PCTCN2016108964-appb-000031
本实施例的制备方法参照实施例2，仅将实施例2中的步骤2化合物硫代苯甲酰胺替代成本实施例的化合物3-氯苯硫酰胺，其余方法相同，最终制得化合物REX-P-22(100mg,20.3％)。
MSm/z[ESI]：401.5[M+1]。
1H-NMR(400MHz,DMSO-d6):δ＝9.45(s,1H),8.53(s,3H),7.90-8.08(m,2H),7.48-7.81(m,3H),7.31-7.45(m,2H),4.53(d,J＝6Hz,2H),2.33(s,3H),1.25(s,3H).
实施例14、N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(3-氯苯基)-1,3,4-噻二唑-2-酰胺【编号为REX-P-45】的制备
合成路线如下：
Figure PCTCN2016108964-appb-000032
本实施例的制备方法参照实施例9，仅将实施例9中的化合物1-1(即苯甲酰肼)替代成本实施例的化合物1-1(即3-氯苯甲酰肼)，其余方法相同，最终制得化合物REX-P-45(200mg,35.4％)。
MSm/z[ESI]：436.3[M+1]。
1H-NMR(400MHz,DMSO-d6):δ＝10.00(t,J＝6.0Hz,1H),8.53-8.55(m,2H),8.13-8.14(m,2H),8.04(d,J＝6.8Hz,2H),7.72-7.75(m,2H),7.62-7.65(m,1H),7.43(s,1H),7.37-7.38(m,1H),,4.56(d,J＝4Hz,2H),2.54(s,3H),2.34(s,3H).
实施例15、N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(3-氟苯基)-1,3,4-噻二唑-2-酰胺【编号为REX-P-46】的制备
合成路线如下：
Figure PCTCN2016108964-appb-000033
本实施例的制备方法参照实施例9，仅将实施例9中的化合物1-1(即苯甲酰肼)替代成本实施例的化合物1-1(即3-氟苯甲酰肼)，其余方法相同，最终制得化合物REX-P-46(210mg,35.8％)。
MSm/z[ESI]：420.4[M+1]。
1H-NMR(400MHz,CDCl3):δ＝8.57-8.59(m,2H),7.94(s,1H),7.74-7.77(m,2H),7.66(s,1H),7.46-7.56(m,1H),7.33(s,1H),7.25-7.27(m,2H),4.74(d,J＝4Hz,2H),2.63(s,3H),2.37(s,3H).
实施例16、N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(吡啶-2-基)-1,3,4-噻二唑-2-酰胺【编号为REX-P-47】的制备
合成路线如下：
Figure PCTCN2016108964-appb-000034
本实施例的制备方法参照实施例9，仅将实施例9中的化合物1-1(即苯甲酰肼)替代成本实施例的化合物1-1(即2-吡啶甲酰肼)，其余方法相同，最终制得化合物REX-P-47(150mg,25.8％)。
MSm/z[ESI]：403.4[M+1]。
1H-NMR(400MHz,CDCl3):δ＝8.63(t,J＝6.0Hz,1H),8.52-8.57(m,2H),8.24–8.28(m,2H),7.82(s,1H),7.63(s,1H),7.26-7.27(m,1H),7.19-7.20(m,1H),4.70(d,J＝4Hz,2H),2.57(s,3H),2.30(s,3H).
实施例17、N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(5-氟-吡啶-3-基)-1,3,4-噻二唑-2-酰胺【编号为REX-P-49】的制备
合成路线如下：
Figure PCTCN2016108964-appb-000035
本实施例的制备方法参照实施例9，仅将实施例9中的化合物1-1(即苯甲酰肼)替代成本实施例的化合物1-1(即5-氟烟酰肼)，其余方法相同，最终制得化合物REX-P-49(100mg,18.8％)。
MSm/z[ESI]：420.9[M+1]。
1H-NMR(400MHz,DMSO-d6):δ＝9.96(t,J＝6.0Hz,1H),9.06(s,1H),8.76(s,1H),8.35-8.44(m,2H),7.66(s,1H),7.27-7.34(m,1H),4.50(d,J＝4Hz,2H),2.45(s,3H),2.26(s,3H).
实施例18、N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(6-甲基-吡啶-2-基)-1,3,4-噻二唑-2-酰胺【编号为REX-P-50】的制备
合成路线如下：
Figure PCTCN2016108964-appb-000036
本实施例的制备方法参照实施例9，仅将实施例9中的化合物1-1(即苯甲酰肼)替代成本实施例的化合物1-1(即6-甲基吡啶酰肼)，其余方法相同，最终制得化合物REX-P-50(110mg,20.3％)。
MSm/z[ESI]：417.0[M+1]。
1H-NMR(400MHz,DMSO-d6):δ＝9.97(t,J＝6.0Hz,1H),8.52-8.53(m,1H),8.13-8.14(m,1H),7.93–7.95(m,1H),7.74(s,1H),7.49-7.51(m,1H),7.41(s,1H),7.34-7.35(m,1H),4.56(d,J＝4Hz,2H),2.57(s,3H),2.53(s,3H),2.34(s,3H).
实施例19、N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(吡嗪-2-基)-1,3,4-噻二唑-2-酰胺【编号为REX-P-52】的制备
合成路线如下：
Figure PCTCN2016108964-appb-000037
本实施例的制备方法参照实施例9，仅将实施例9中的化合物1-1(即苯甲酰肼)替代成本实施例的化合物1-1(即吡嗪-2-甲酰肼)，其余方法相同，最终制得化合物REX-P-52(140mg,23.2％)。
MSm/z[ESI]：404.0[M+1]。
1H-NMR(400MHz,DMSO-d6):δ＝9.48(s,1H),8.66(s,1H),8.59(s,1H),8.48-8.49(m,2H),8.33-8.34(m,1H),7.60(s,1H),7.23-7.25(m,1H),7.16-7.18(m,1H),4.67(d,J＝4Hz,2H),2.54(s,3H),2.29(s,3H).
实施例20、N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(嘧啶-2-基)-1,3,4-噻二唑-2-酰胺【编号为REX-P-51】的制备
合成路线如下：
Figure PCTCN2016108964-appb-000038
本实施例的制备方法参照实施例9，仅将实施例9中的化合物1-1(即苯甲酰肼)替代成本实施例的化合物1-1(即嘧啶-2-甲酰肼)，其余方法相同，最终制得化合物REX-P-51(100mg,18.2％)。
MSm/z[ESI]：404.0[M+1]。
1H-NMR(400MHz,DMSO-d6):δ＝9.98(d,2H),8.51(d,1H),7.85(s,1H),7.61-7.64(m,1H),7.42(s,1H),7.35-7.36(m,2H),4.68(d,J＝4Hz,2H),2.59(s,3H),2.35(s,3H).
实施例21、N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(3-氟-吡啶-2-基)-1,3,4-噻二唑-2-酰胺【编号为REX-P-48】的制备
合成路线如下：
Figure PCTCN2016108964-appb-000039
本实施例的制备方法参照实施例9，仅将实施例9中的化合物1-1(即苯甲酰肼)替代成本实施例的化合物1-1(即3-氟烟酰肼)，其余方法相同，最终制得化合物REX-P-48(150mg,28.2％)。
MSm/z[ESI]：421.0[M+1]。
1H-NMR(400MHz,DMSO-d6):δ＝8.52-8.58(m,3H),7.87-7.88(m,2H),7.64-7.68(m,1H),7.44(s,1H),7.36-7.37(m,2H),4.69(d,J＝4Hz,2H),2.60(s,3H),2.36(s,3H).
实施例22、N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(3-甲基-吡啶-2-基)-1,3,4-噻二唑-2-酰胺【编号为REX-P-56】的制备
合成路线如下：
Figure PCTCN2016108964-appb-000040
本实施例的制备方法参照实施例9，仅将实施例9中的化合物1-1(即苯甲酰肼)替代成本实施例的化合物1-1(即3-甲基烟酰肼)，其余方法相同，最终制得化合物REX-P-56(150mg,26.2％)。
MSm/z[ESI]：417.0[M+1]。
1H-NMR(400MHz,DMSO-d6):δ＝9.89(s,1H),8.46(s,2H),8.06-8.07(m,1H),7.68-7.69(m,1H),7.44(s,1H),7.29-7.35(m,3H),4.50(d,J＝4Hz,2H),2.50(s,3H),2.47(s,3H),2.29(s,3H).
实施例23、N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(4-甲基-吡啶-3-基)-1,3,4-噻二唑-2-酰胺【编号为REX-P-55】的制备
合成路线如下：
Figure PCTCN2016108964-appb-000041
本实施例的制备方法参照实施例9，仅将实施例9中的化合物1-1(即苯甲酰肼)替代成本实施例的化合物1-1(即4-甲基异烟酰肼)，其余方法相同，最终制得化合物REX-P-55(100mg, 20.2％)。
MSm/z[ESI]：417.0[M+1]。
1H-NMR(400MHz,DMSO-d6):δ＝9.95(s,1H),8.84(s,1H),8.46-8.54(m,3H),7.67(s,1H),7.31-7.43(m,3H),4.50(d,J＝4Hz,2H),2.50(s,3H),2.47(s,3H),2.29(s,3H).
实施例24、N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(5-甲基-吡啶-3-基)-1,3,4-噻二唑-2-酰胺【编号为REX-P-53】的制备
合成路线如下：
Figure PCTCN2016108964-appb-000042
本实施例的制备方法参照实施例9，仅将实施例9中的化合物1-1(即苯甲酰肼)替代成本实施例的化合物1-1(即5-甲基异烟酰肼)，其余方法相同，最终制得化合物REX-P-53(120mg,22.5％)。
MSm/z[ESI]：417.0[M+1]。
1H-NMR(400MHz,DMSO-d6):δ＝9.97(s,1H),8.99(s,1H),8.47-8.59(m,3H),8.24(s,1H),7.69(s,1H),7.29-7.36(m,2H),4.50(d,J＝4Hz,2H),2.47(s,3H),2.37(s,3H),2.29(s,3H).
实施例25、斑马鱼表型筛选实验
斑马鱼是一种脊椎动物，与人类基因组同源性高达85％，与人类有近似的组织器官功能和信号传导通路，并且具有产卵量高、发育迅速、胚胎透明等独特优势，使得斑马鱼成功地应用于人类疾病研究和活体药物高通量筛选。Wnt信号通路广泛存在于无脊椎动物和脊椎动物，是一类在进化过程中高度保守的信号通路，参与生物体内调控有关细胞生长、凋亡、自我更新和生存基因的表达，维持生物体中正常的胚胎发育和组织修复再生等生理功能(Wolfram Goessling,Trista E.North,Sabine Loewer,et al.(2009).Genetic Interaction of PGE2and Wnt Signaling Regulates Developmental Specification of Stem Cells and Regeneration.Cell,136(6):1136-1147.)。Wnt信号通路失调与癌症发生也密切相关，例如80％～90％的结直肠癌中都含有影响Wnt信号通路基因 Adenomatous Polyposis Coli(APC)功能突变(Hans Clevers,Roel Nusse.(2012).Wnt/β-Catenin Signaling and Disease.Cell,149(6):1192-1205.)。
研究表明，斑马鱼在体轴发育和再生修复方面的表型与Wnt信号通路密切相关(Xiaolei Wang,Jesung Moon,Michael E.Dodge,et al.(2013).The Development of Highly Potent Inhibitors for Porcupine.Journal of Medicinal Chemistry,56,2700-2007.)。
因此，利用Wnt信号通路的在不同物种间的保守性以及斑马鱼表型筛选方面的优势，我们考察化合物对正常AB型斑马鱼体轴发育和再生修复的影响，来探讨化合物在体内抗Wnt信号通路活性的强弱。
实验(一)化合物对AB型斑马鱼体轴发育抑制试验
方法：选取3hpf(hours post fertilization)的AB型斑马鱼鱼卵进行体轴发育表型试验，按受试终浓度在100μM～0.001μM范围内给药组以及溶剂对照组进行随机分组，每组20个AB鱼卵加至6孔板内，每孔3mL鱼水，DMSO浓度≤1％(v/v)。加药处理后的AB鱼卵至于28.5℃生化培养箱孵育至48hpf时进行图像采集，利用NIS-Elements D 3.1软件分析测量各组幼鱼体轴长度px值(pixels)。根据不同浓度化合物对各组幼鱼体轴发育生长的抑制率，运用GraphPad Prism 6.0进行非线性拟合计算各化合物在AB型斑马鱼体轴发育上的IC50值。
计算公式为：
Figure PCTCN2016108964-appb-000043
结果：本发明实施例制备的REX-P-4等一系列化合物，对AB型斑马鱼体轴发育抑制的活性测定结果见表一；REX-P-4处理AB型斑马鱼48hpf后体轴发育抑制状态见图1，量效关系(mean±sd)见图2。
表一 实施例化合物对AB型斑马鱼体轴发育抑制的活性测定
Compounds IC50(μM)
LGK-974 0.583
REX-P-2 8.233
REX-P-16 >10
REX-P-9 >20
REX-P-1 29.88
REX-P-3 0.144
REX-P-22 0.178
REX-P-4 0.0369
REX-P-12 >100
REX-P-13 >10
REX-P-8 0.021
REX-P-45 0.014
REX-P-46 0.01
REX-P-47 0.163
REX-P-48 0.896
REX-P-49 0.052
REX-P-50 0.064
REX-P-51 >10
REX-P-52 0.64
REX-P-56 0.062
REX-P-5 >40
REX-P-6 >100
REX-P-7 0.024
注：IC50为计算50％抑制率浓度
进一步的，本发明选择表1中的部分化合物进行斑马鱼剪尾再生表型试验复验。
实验(二)化合物对AB型斑马鱼剪尾再生抑制试验
选取3dpf(days post fertilization)的AB型斑马鱼幼鱼进行剪尾鳍造模处理，按受试终浓度在10μM～0.001μM范围内给药组以及溶剂对照组进行随机分组，每组15个幼鱼加至6孔板内，每孔3mL鱼水，DMSO浓度≤1％(v/v)。加药处理后的AB鱼卵至于28.5℃生化培养箱孵育至7dpf时进行图像采集，利用NIS-Elements D 3.1软件分析测量各组幼鱼尾鳍再生长度px值(pixels)。根据不同浓度化合物对各组幼鱼尾鳍再生的抑制率，运用GraphPad Prism 6.0进行非线性拟合计算各化合物在AB型斑马鱼剪尾再生上的IC50值。
计算公式为：
Figure PCTCN2016108964-appb-000044
结果：本发明实施例制备的REX-P-4等一系列化合物，对AB型斑马鱼剪尾再生抑制的活性测定结果见表二；REX-P-4处理3dpf剪尾造模AB型斑马鱼至7dpf尾鳍再生抑制见图3，量效关系(mean±sd)见图4。
表二 实施例化合物对AB型斑马鱼剪尾再生抑制的活性测定
Compounds IC50(μM)
LGK-974 0.462
REX-P-2 3.908
REX-P-3 0.084
REX-P-22 0.028
REX-P-8 0.027
REX-P-45 0.023
REX-P-46 0.016
REX-P-47 0.207
REX-P-48 0.721
REX-P-49 0.137
REX-P-50 0.111
REX-P-52 0.746
REX-P-7 0.047
实施例26、Super-Top-Flash(STF)报告基因试验
化合物LGK-974(对照药)、REX-P-4等一系列化合物(实施例)采用稳定转染STF报告基因的HEK293T-STF细胞株同L-Wnt3a分泌细胞株共培养方式测定其对Wnt信号通路的抑制活 性，该活性采用IC50这一指标来表示，IC50即STF报告基因表达的Luciferase活性被抑制50％时的化合物的浓度。
本发明实施例制备的REX-P-4等一系列化合物，利用CrownBio公司的Wnt报告基因平台进行测定，测定结果见表三。结果表明，本发明提供的化合物从分子水平上有较好的Wnt信号通路抑制活性。
表三 实施例化合物对Wnt通路STF报告基因抑制的活性测定
Compounds IC50(nM)
LGK-974 0.574
REX-P-2 1.76
REX-P-16 16.756
REX-P-9 >1000
REX-P-1 92.58
REX-P-3 <0.1
REX-P-22 0.72
REX-P-4 <0.1
REX-P-12 9.16
REX-P-13 >1000
REX-P-8 1.92
REX-P-45 0.31
REX-P-46 0.125
REX-P-47 0.673
REX-P-49 0.248
REX-P-50 0.389
REX-P-52 1.384
REX-P-5 >1000
REX-P-6 >1000
REX-P-7 0.69
实施例27、体内代谢稳定性及体内PK实验
选取本发明实施例制备的化合物REX-P-7进行了人、小鼠体外肝微粒代谢稳定性实验及在BABL/C小鼠中PK测定。
PK测试方法为：18只大鼠分为两组，每组9只。其中一组通过静脉给药，剂量为5mg/kg；一组通过口服给药，剂量为10mg/kg。每一组在给药后0、0.083、0.25、0.5、1、2、4、8、24h分别通过眼眶静脉收集血液。通过眼眶采血的方式将约100μL血液收集到含EDTA的干净EP管中(EDTA的终浓度为0.25mg/mL)。在收集完成后迅速将采血管倒置至少5次，以确保混合均匀，然后放置在冰上。采集到的各时间点血液在4℃，8000rpm离心5分钟以获得血浆。另取1.5mL离心管标记好化合物名称，动物编号，时间点，将血浆转移至该管中。血浆保存在-80℃直至分析。
具体实验结果如下，结果表明REX-P-7有较好的生物利用度和半衰期：
表四 实施例化合物体内PK及体外代谢稳定性实验结果
Figure PCTCN2016108964-appb-000045

Claims (12)

  1. 一种五元杂环酰胺类WNT通路抑制剂，为具有如下结构通式的化合物及其药学上可接受的盐：
    Figure PCTCN2016108964-appb-100001
    其中，环A和环B各自独立地选自芳香环、或含1-2个N原子或O原子的芳香杂环；
    X、Y、Z各自独立地选自CR4、NR5、S原子、O原子中的一种，且S原子和O原子不同时存在；
    n选自1～2中的任一整数值；
    R1、R2各自独立地选自氢、卤素、C1-6烷基、C3-6环烷基、C2-6烯基、C2-6炔基、卤代C1- 6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基、氨基、酰基、磺基、芳基、杂环基中的一种或几种；
    R3为取代或未取代的芳基、杂环基，芳基、杂环基上的取代基团选自卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基、氰基、氨基、酰基、磺基、杂环基中的一种或几种；
    R4、R5各自独立地选自氢、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C3-6环烷基中的一种；
    所述的杂环基为选自一个或多个N、O、S杂原子的3-12元杂环。
  2. 根据权利要求1所述的五元杂环酰胺类WNT通路抑制剂，为具有如下结构通式的化合物及其药学上可接受的盐：
    Figure PCTCN2016108964-appb-100002
    其中，环B选自芳香环、或含1-2个N原子或O原子的芳香杂环；
    X、Y、Z各自独立地选自CR4、NR5、S原子、O原子中的一种，且S原子和O原子不同时存在；
    n选自1～2中的任一整数值；
    R1、R2各自独立地选自氢、卤素、C1-6烷基、C3-6环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基、氨基、酰基、芳基、杂环基中的一种或几种；
    R3为取代或未取代的芳基、杂环基，芳基、杂环基上的取代基团选自卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基、氰基、氨基、酰基、磺基、杂环基中的一种或几种；
    R4、R5各自独立地选自氢、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C3-6环烷基中的一种；
    所述的杂环基为选自一个或多个N、O、S杂原子的3-6元杂环。
  3. 根据权利要求2所述的五元杂环酰胺类WNT通路抑制剂，其特征在于：所述的结构通式(2)中，
    Figure PCTCN2016108964-appb-100003
    选自
    Figure PCTCN2016108964-appb-100004
    Figure PCTCN2016108964-appb-100005
    中的一种；
    X、Y、Z各自独立地选自CR4、NR5、S原子、O原子中的一种，且S原子和O原子不同时存在；
    n选自1～2中的任一整数值；
    R1、R2为氢、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、酰胺基、C1-6烷基酰胺基、杂环基中的一种；
    R3为
    Figure PCTCN2016108964-appb-100006
    Figure PCTCN2016108964-appb-100007
    中的一种；
    R4、R5各自独立地选自氢、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基中的一种；
    R6选自氢、卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、酰胺基中的一种；
    所述的杂环基为选自一个或多个N、O杂原子的3-6元杂环。
  4. 根据权利要求2所述的五元杂环酰胺类WNT通路抑制剂，为具有如下结构通式的化合物及其药学上可接受的盐：
    Figure PCTCN2016108964-appb-100008
    其中，X、Y、Z各自独立地选自CR4、NR5、S原子、O原子中的一种，且S原子和O原子不同时存在；
    n选自1或2；
    R1、R2为氢、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、酰胺基、C1-6烷基酰胺基、杂环基中的一种；
    R3为
    Figure PCTCN2016108964-appb-100009
    Figure PCTCN2016108964-appb-100010
    中的一种；
    R4、R5各自独立地选自氢、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基中的一种；
    R6选自氢、卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、酰胺基中的一种；
    所述的杂环基为选自一个或多个N、O杂原子的3-6元杂环。
  5. 根据权利要求4所述的五元杂环酰胺类WNT通路抑制剂，为具有如下结构通式的化合物及其药学上可接受的盐：
    Figure PCTCN2016108964-appb-100011
    其中，X、Z同时为CR4；或X、Z同时为NR5；或X、Z中任一为CR4，另一则为NR5；
    n选自1或2；
    R1、R2为氢、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、酰胺基、C1-6烷基酰胺基、杂环基中的一种；
    R3为
    Figure PCTCN2016108964-appb-100012
    Figure PCTCN2016108964-appb-100013
    中的一种；
    R6选自氢、卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、酰胺基中的一种；
    所述的杂环基为选自一个或多个N、O杂原子的3-6元杂环。
  6. 根据权利要求4所述的五元杂环酰胺类WNT通路抑制剂，为具有如下结构通式的化合物及其药学上可接受的盐：
    Figure PCTCN2016108964-appb-100014
    其中，X、Z同时为CR4；或X、Z同时为NR5；或X、Z中任一为CR4，另一则为NR5；或X、Z中任一为O原子，另一则为NR5；或X、Z中任一为O原子，另一则为CR4；
    n选自1或2；
    R1、R2为氢、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、酰胺基、C1-6烷基酰胺基、杂环基中的一种；
    R3为
    Figure PCTCN2016108964-appb-100015
    Figure PCTCN2016108964-appb-100016
    中的一种；
    R6选自氢、卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、酰胺基中的一种；
    所述的杂环基为选自一个或多个N、O杂原子的3-6元杂环。
  7. 根据权利要求1～6任一项所述的五元杂环酰胺类WNT通路抑制剂，其特征在于：所述的芳基为苯基、萘基或蒽基；所述的杂环基为吗啉基、哌啶基、吡啶基、嘧啶基、吡喃基、噻吩基、呋喃基、吡咯基、吡唑基、咪唑基或噻唑基；所述的卤素为氟、氯、溴、碘中的一种。
  8. 一种五元杂环酰胺类WNT通路抑制剂，选自如下特征化合物：
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-1-甲基-3-苯基-1-氢-吡唑-5-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-苯基-1-氢-吡唑-3-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-2-苯基-噻唑-5-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-苯基-噻唑-2-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-2-苯基-噻唑-4-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-4-苯基-噻唑-2-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-苯基-异恶唑-3-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-苯基-1,3,4-噻二唑-2-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-1-甲基-5-苯基-1-氢-吡唑-3-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-4-甲基-5-苯基-噻唑-2-酰胺；
    5-(2-氯苯基)-N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-噻唑-2-酰胺；
    5-(3-氯苯基)-N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-噻唑-2-酰胺；
    5-(4-氯苯基)-N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-噻唑-2-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(吡啶-2-基)噻唑-2-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(吡嗪-2-基)噻唑-2-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(吡啶-2-基)-1氢-吡唑-3-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(3-氟-吡啶-2-基)-1氢-吡唑-3-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(5-氟-吡啶-3-基)-1氢-吡唑-3-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(6-甲基-吡啶-2-基)-1氢-吡唑- 3-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(嘧啶-2-基)-1氢-吡唑-3-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(吡嗪-2-基)-1氢-吡唑-3-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-2-(3-氯苯基)-噻唑-5-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-2-(吡啶-2-基)-噻唑-5-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-2-(3-氟-吡啶-2-基)-噻唑-5-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-2-(5-氟-吡啶-3-基)-噻唑-5-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-2-(6-甲基-吡啶-2-基)-噻唑-5-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-2-(嘧啶-2-基)-噻唑-5-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-2-(吡嗪-2-基)-噻唑-5-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(吡啶-2-基)-异恶唑-3-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(3-氟-吡啶-2-基)-异恶唑-3-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(5-氟-吡啶-3-基)-异恶唑-3-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(6-甲基-吡啶-2-基)-异恶唑-3-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(嘧啶-2-基)-异恶唑-3-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(吡嗪-2-基)-异恶唑-3-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(4-乙酰哌嗪-1-基)-异恶唑-3-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(吡啶-3-基)噻唑-2-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(3-氟-吡啶-2-基)噻唑-2-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(5-氟-吡啶-3-基)噻唑-2-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(6-甲基-吡啶-2-基)噻唑-2-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(嘧啶-2-基)噻唑-2-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(嘧啶-5-基)噻唑-2-酰胺；
    5-(4-乙酰哌嗪-1-基)-N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-1,3,4-噻二唑-2-酰胺；
    5-(4-乙酰哌嗪-1-基)-N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-噻唑-2-酰胺；
    2-(4-乙酰哌嗪-1-基)-N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-噻唑-5-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(3-氯苯基)-1,3,4-噻二唑-2-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(3-氟苯基)-1,3,4-噻二唑-2-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(吡啶-2-基)-1,3,4-噻二唑-2-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(3-氟-吡啶-2-基)-1,3,4-噻二唑-2-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(5-氟-吡啶-3-基)-1,3,4-噻二唑-2-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(6-甲基-吡啶-2-基)-1,3,4-噻二唑-2-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(嘧啶-2-基)-1,3,4-噻二唑-2-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(吡嗪-2-基)-1,3,4-噻二唑-2-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(5-甲基-吡啶-3-基)-1,3,4-噻二唑-2-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(2-甲基-吡啶-3-基)-1,3,4-噻二唑-2-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(4-甲基-吡啶-3-基)-1,3,4-噻二唑-2-酰胺；
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-5-(3-甲基-吡啶-2-基)-1,3,4-噻二唑-2-酰胺。
  9. 一种药物组合物，包含如权利要求1定义的化合物或其药学上可接受的盐作为活性成份，以及一种或多种药学上可接受的载体。
  10. 一种如权利要求1定义的化合物或其药学上可接受的盐在制备拮抗Wnt信号通路的药物中的应用。
  11. 如权利要求10所述的用途，其特征在于：用于治疗与异常的Wnt信号活性相关的细胞增殖性疾病、消化***疾病。
  12. 如权利要求11所述的用途，其特征在于：用于治疗癌症，包括非小细胞肺癌、间变性大细胞淋巴瘤、炎性肌纤维母细胞瘤、鼻咽癌、乳腺癌、结直肠癌、弥漫大B细胞淋巴瘤、肝癌、胃癌、食道癌、胰腺癌、卵巢癌、全身组织细胞增生症和神经母细胞瘤。
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