CN107056754A - The WNT pathway inhibitors of embedded ureas structure - Google Patents

The WNT pathway inhibitors of embedded ureas structure Download PDF

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Publication number
CN107056754A
CN107056754A CN201611118374.9A CN201611118374A CN107056754A CN 107056754 A CN107056754 A CN 107056754A CN 201611118374 A CN201611118374 A CN 201611118374A CN 107056754 A CN107056754 A CN 107056754A
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bases
hydrogen
methyl
bipyridyls
dimethyl
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CN107056754B (en
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王永辉
朱研
周娟
高羽军
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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Suzhou Sinoway Pharmaceutical Technology Co.,Ltd.
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HANGZHOU LEISUO PHARMACEUTICAL CO Ltd
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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
    • A61K31/495—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

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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Abstract

The invention discloses a kind of WNT pathway inhibitors of embedded ureas structure, belong to the compound of regulation Wnt signal path activity, and there is provided the preparation method of such compound, and application of such compound in the medicine for preparing antagonism Wnt signal paths.The WNT pathway inhibitors for the embedded ureas structure that the present invention is provided, the Rational drug design based on target, significantly, available for the Wnt pathway inhibitors for developing into a new generation, with great clinical value, market potential is considerable for antitumor activity.

Description

The WNT pathway inhibitors of embedded ureas structure
Technical field
The present invention relates to a kind of WNT pathway inhibitors of embedded ureas structure, belong to the change of regulation Wnt signal path activity Compound, and be used to prepare the medicine of antagonism Wnt signal paths there is provided the preparation method of such compound, and such compound In application.
Background technology
Wnt signal paths have in the life processes such as multicellular organisms axle breaks up, histoorgan occurs, tumour formation Important function.The albumen of Wnt gene codes expression is a class secreting type glycoprotein, by 19 member compositions, by with cell membrane Upper Frizzled (Fzd) family proteins and LDH receptor related protein (LDL receptor related Protein, LRP) acceptor combination, activation typical case Wnt/ β-catenin paths, plane pole path, Wnt/Ca2+Path etc. is a variety of thin Intracellular signalling pathways, regulate and control including the various kinds of cell function such as propagation, differentiation, dead, migration, polarization (Nusse Roel, Varmus Harold E.(1992).Wnt genes.Cell,69(7),1073-1087.)。
Find through research report, neurogenic disease, inflammation fibrotic disease, metabolic disease and polytype cancer Swashing for typical Wnt/ β-catenin signal paths β-catenin-TCF/LCF transcription complexs is all related in pathogenesis Imbalance (Kahn, M. (2014) .Can we safely target the Wnt pathway livingNature reviews.Nat.Rev.Drug.Discovery,13(7),513-532.).In cancer research field, Wnt signals participate in swollen Knurl early stage source of evidence isolated oncogene Int1 activated by virus insertion in mouse breast cancer；Nearly 10% knot is straight Intestinal cancer, head and neck cancer, lung cancer, oophoroma, melanoma patients cancer occur with Wnt signals-modulatings element R-spondin families and RNF43/ZNRF3 function mutation induction correlation (B Madan, Z Ke, N Harmston, et al. (2015) .Wnt addiction of genetically defined cancers reversed by PORCN inhibition.Oncogene,1-11.).However, this kind of patient clinically there is no targetedly small point of Wnt signal paths at present Sub- targeted drug treatment, gastrointestinal reaction, the marrow that non-selective cellulotoxic preparation and its combined treatment is brought is made Adverse reaction in terms of blood suppression has a strong impact on the life quality of patient.At present, into clinical experimental stage drug candidates Clinical stage I/II phases verified also in security and conceptual drug effect, for example, for Wnt signal paths upstream target spot LGK974 (the ClinicalTrials.gov Identifier of PORCN designs:NCT01351103, the public affairs of the compound patent The number of opening is wo2010101849), ETC-1922159 (ClinicalTrials.gov Identifier:NCT02521844, should The Publication No. wo2014189466 of compound patent)；Designed for Wnt signal path downstream targets CBP/ β-catenin PRI-724(ClinicalTrials.gov Identifier:NCT02413853)。
In consideration of it, continue develop have can regulate and control the medicine of Wnt signal paths, search out a kind of mechanism of action clearly, The significant compound of drug effect, with important clinical value and social effect.
The content of the invention
Present invention aims at providing a kind of structure novel WNT pathway inhibitors, modified by the substitution of group, synthesis And filter out a series of compounds with antitumor activity.
For achieving the above object, this invention takes following technical scheme：
A kind of WNT pathway inhibitors of embedded ureas structure, for the compound with following general structure and its pharmaceutically Acceptable salt：
Wherein, ring A and ring B are each independently selected from aromatic rings or the aromatic heterocycle containing 1-2 N atom or O atom；X、 Y, Z are each independently selected from CR4, one kind in N atoms；Any integer values of the n in 1~2；R1、R2It is each independently selected from Hydrogen, halogen, C1-6Alkyl, C3-6Cycloalkyl, C2-6Alkenyl, C2-6Alkynyl, halo C1-6Alkyl, C1-6Alkoxy, halo C1-6Alcoxyl One or more in base, hydroxyl, amino, cyano group, acyl group, sulfo group, aryl, heterocyclic radical；R3Selected from substituted or unsubstituted virtue Base, heterocyclic radical；Work as R3During for substituted aryl, heterocyclic radical, the substituted radical on aryl, heterocyclic radical is selected from halogen, C1-6Alkyl, Halo C1-6Alkyl, C1-6Alkoxy, halo C1-6One kind in alkoxy, hydroxyl, cyano group, amino, acyl group, sulfo group, heterocyclic radical or It is several；R4Selected from hydrogen, C1-6Alkyl, halo C1-6Alkyl, C1-6Alkoxy, halo C1-6Alkoxy, C3-6One kind in cycloalkyl； Heterocyclic radical is to contain the heteroatomic 3-12 circle heterocycles of one or more N, O, S.
It is preferred that, for compound and its pharmaceutically acceptable salt with following general structure：
Wherein, ring B is selected from aromatic rings or the aromatic heterocycle containing 1-2 N atom or O atom；X, Y, Z are selected independently of one another From CR4, one kind in N atoms；Any integer values of the n in 1~2；R1、R2It is each independently selected from hydrogen, halogen, C1-6Alkane Base, C3-6Cycloalkyl, halo C1-6Alkyl, C1-6Alkoxy, halo C1-6In alkoxy, hydroxyl, amino, acyl group, aryl, heterocyclic radical One or more；R3Selected from substituted or unsubstituted aryl, heterocyclic radical；Work as R3It is aryl, miscellaneous during for substituted aryl, heterocyclic radical Substituted radical in ring group is selected from halogen, C1-6Alkyl, halo C1-6Alkyl, C1-6Alkoxy, halo C1-6Alkoxy, hydroxyl, cyanogen One or more in base, amino, acyl group, sulfo group, heterocyclic radical；R4Selected from hydrogen, C1-6Alkyl, halo C1-6Alkyl, C1-6Alcoxyl Base, halo C1-6Alkoxy, C3-6One kind in cycloalkyl；Heterocyclic radical is containing the heteroatomic 3-12 members of one or more N, O, S Heterocycle.
It is furthermore preferred that in general structure (2),It is selected from In one kind；X, Y, Z are each independently selected from CR4, one kind in N atoms；N is selected from 1 or 2；R1、 R2For hydrogen, halogen, C1-6Alkyl, C1-6Alkoxy, halo C1-6 alkyl, halo C1-6 alkoxies, amide groups, C1-6Alkylamide One kind in base, heterocyclic radical；R3For In one kind；R4Selected from hydrogen, C1-6Alkyl, halo C1-6Alkyl, C1-6Alkoxy, halo C1-6One in alkoxy Kind；R5Selected from hydrogen, halogen, C1-6Alkyl, halo C1-6Alkyl, C1-6Alkoxy, halo C1-6One kind in alkoxy, amide groups； Heterocyclic radical is selected from containing the heteroatomic 3-6 circle heterocycles of one or more N, O, S.
It is preferred that, for compound and its pharmaceutically acceptable salt with following general structure：
Wherein, any one in X, Y, Z is N atoms, then another is CR4；It is or any two is N atoms in X, Y, Z, then another Individual is CR4；N is selected from 1 or 2；R1、R2For hydrogen, halogen, C1-6Alkyl, C1-6Alkoxy, halo C1-6 alkyl, halo C1-6 alkoxies, Amide groups, C1-6One kind in alkylamidoalkyl, heterocyclic radical；R3For In one kind；R4Selected from hydrogen, C1-6Alkyl, halo C1-6Alkyl, C1-6Alcoxyl Base, halo C1-6One kind in alkoxy；R5Ground is selected from hydrogen, halogen, C1-6Alkyl, halo C1-6Alkyl, C1-6Alkoxy, halo C1-6One or more in alkoxy；Heterocyclic radical is selected from containing the heteroatomic 3-6 circle heterocycles of one or more N, O, S.
It is preferred that, aryl is phenyl, naphthyl or anthryl；Heterocyclic radical is morpholinyl, piperidyl, pyridine radicals, pyrimidine radicals, pyrans Base, thienyl, furyl, pyrrole radicals, pyrazolyl, imidazole radicals or thiazolyl；Halogen is one kind in fluorine, chlorine, bromine, iodine.
A kind of WNT pathway inhibitors of embedded ureas structure, the feature for being REX-N-1~REX-N-29 selected from following numbering Compound：
REX-N-1：N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -1 hydrogen of -4- phenyl-pyrazoles -1- acyls Amine；
REX-N-2：N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (pyridine -2- bases) -1- hydrogen - Pyrazoles -1- acid amides；
REX-N-3：N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- phenyl -1- hydrogen -1,2,3- three Nitrogen azoles -1- acid amides；
REX-N-4：N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -3- phenyl -1- hydrogen-pyrazoles -1- Acid amides；
REX-N-5：N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (3- fluorophenyls) -1- hydrogen-pyrrole Azoles -1- acid amides；
REX-N-6：4- (3- chlorphenyls)-N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -1- hydrogen-pyrrole Azoles -1- acid amides；
REX-N-7：N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -3- methyl 4-phenyl -1- hydrogen - Pyrazoles -1- acid amides；
REX-N-8：N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -5- methyl 4-phenyl -1- hydrogen - Pyrazoles -1- acid amides；
REX-N-9：4- (2- chlorphenyls)-N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -1- hydrogen-pyrrole Azoles -1- acid amides；
REX-N-10：4- (4- chlorphenyls)-N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -1- hydrogen - Pyrazoles -1- acid amides；
REX-N-11：N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (pyrazine -2- bases) -1- hydrogen - Pyrazoles -1- acid amides；
REX-N-12：N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (2- fluorophenyls) -1- hydrogen - Pyrazoles -1- acid amides；
REX-N-13：N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (4- fluorophenyls) -1- hydrogen - Pyrazoles -1- acid amides；
REX-N-14：N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (pyridin-3-yl) -1- hydrogen - Pyrazoles -1- acid amides；
REX-N-15：N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (pyridin-4-yl) -1- hydrogen - Pyrazoles -1- acid amides；
REX-N-16：N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (3- fluorine pyridine -2- bases) - 1- hydrogen-pyrazoles -1- acid amides；
REX-N-17：N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (5- fluorine pyridine -2- bases) - 1- hydrogen-pyrazoles -1- acid amides；
REX-N-18：N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (3- fluorine pyridin-4-yl) - 1- hydrogen-pyrazoles -1- acid amides；
REX-N-19：N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -5 methyl -4- (pyridine -2- Base) -1- hydrogen-pyrazoles -1- acid amides；
REX-N-20：N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (6- picolines -2- Base) -1- hydrogen-pyrazoles -1- acid amides；
REX-N-21：N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (5- picolines -3- Base) -1- hydrogen-pyrazoles -1- acid amides；
REX-N-22：N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (2- picolines -4- Base) -1- hydrogen-pyrazoles -1- acid amides；
REX-N-23：N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (3- cyano-phenyls) -1- Hydrogen-pyrazoles -1- acid amides；
REX-N-24：N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (pyrimidine -5- bases) -1- hydrogen - Pyrazoles -1- acid amides；
REX-N-25：N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (pyrimidine -2-base) -1- hydrogen - Pyrazoles -1- acid amides；
REX-N-26：N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (pyridazine -3- bases) -1- hydrogen - Pyrazoles -1- acid amides；
REX-N-27：N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (pyrimidine-4-yl) -1- hydrogen - Pyrazoles -1- acid amides；
REX-N-28：4- (4- acetylpiperazine -1- bases)-N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) first Base) -1- hydrogen-pyrazoles -1- acid amides；；
REX-N-29：N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- morpholinyls -1- hydrogen-pyrazoles - 1- acid amides；
The characteristic compounds that foregoing numbering is REX-N-1~REX-N-29, concrete structure is as follows：
" compound " of the present invention, including all stereoisomers, geometric isomer, dynamic isomer and same position Element.
" compound " of the present invention, can be asymmetric, for example, with one or more stereoisomers.Remove Non- to be otherwise noted, all stereoisomers all include, such as enantiomter and diastereoisomer.Containing asymmetric in the present invention The compound of carbon atom, can be separated with the pure form of optical activity or racemic form.The pure form of optical activity can To be synthesized from racemic mixture, or by using chiral raw material or chiral reagent.
" compound " of the present invention, in addition to tautomeric forms.Tautomeric forms are from a list Key and adjacent double bond exchange and together with a proton migration.
Present invention additionally comprises the atom of all isotopes, either in intermediate or last compound.The original of isotope Attached bag is included with identical atomicity but different quality number.For example, the isotope of hydrogen includes deuterium and tritium.
Compound containing aforementioned formula structure, term used herein has following implication：
Term " halogen ", refers to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.
Term " cyano group ", refers to-CN.
Term " hydroxyl ", refers to-OH.
Term " alkyl ", refers to the saturated hydrocarbons group for the straight or branched being made up of carbon atom and hydrogen atom, such as C1-20Alkyl, Preferably C1-6Alkyl, such as methyl, ethyl, propyl group (including n-propyl and isopropyl), butyl (including normal-butyl, isobutyl group, Sec-butyl or the tert-butyl group), amyl group (including n-pentyl, isopentyl, neopentyl), n-hexyl, 2- methylhexyls etc..The alkyl can To be non-substituted or be replaced by one or more substituents, substituent include but is not limited to alkyl, alkoxy, cyano group, Hydroxyl, carbonyl, carboxyl, aryl, heteroaryl, amino, halogen, sulfonyl, sulfinyl, phosphoryl.
Term " amino ", refers to-NH2,-NH (alkyl) and-N (alkyl)2, the implication of alkyl is as previously described.- NH's (alkyl) Structure type isSpecific example includes but is not limited to-NHCH3、-NHCH(CH3)2、-NHC2H5Deng；- N (alkyl)2Knot Configuration formula isSpecific example includes but is not limited to-N (CH3)2、-N(CH3)C2H5Deng.
Term " aryl ", refer to the pi-electron system with total conjugated full carbon is monocyclic or fused rings, generally there are 6-14 Carbon atom, preferably with 6-12 carbon atom, most preferably with 6 carbon atoms.Aryl can be non-substituted or by one or Multiple substituents are replaced, and substituent includes but is not limited to alkyl, alkoxy, cyano group, hydroxyl, carbonyl, carboxyl, aryl, aralkyl Base, amino, halogen, sulfonyl, sulfinyl, phosphoryl.The example of non-substituted aryl include but is not limited to phenyl, naphthyl and Anthryl.
Term " heterocyclic radical ", refers to the monocyclic or fused rings with 3-12 (integer) annular atoms, wherein have 1,2 or 3 rings Atom is selected from one or more of N, O, and remaining annular atom is C, and has π-electron system of total conjugated.Heterocyclic radical can be with It is saturation or unsaturated group or non-substituted or replaced by one or more substituents, substituent bag Include but be not limited to alkyl, alkoxy, cyano group, hydroxyl, carbonyl, carboxyl, aryl, aralkyl, amino, halogen, sulfonyl, sulfenyl Base, phosphoryl.The example of non-substituted heterocyclic radical includes but is not limited to pyrrole radicals, indyl, pyrrolidinyl, imidazole radicals, pyrazoles Base, tetrazole radical, pyridine radicals, quinolyl, isoquinolyl, piperidyl, pyrimidine radicals, pyrazinyl, piperazinyl, furyl, pyranose, Quinoline base.
Term " embedded urea ", refer to urea some nitrogen-atoms be embedded into carbonyl be conjugated ring formed in specific structure, Including but not limited to following several forms：
Present invention also offers a kind of pharmaceutical composition, foregoing compound or its pharmaceutically acceptable salt are included It is used as active ingredient, and one or more pharmaceutically acceptable carriers.
" pharmaceutical composition " of the present invention, refer to the compound or its salts of one or more present invention with the art The preparation for being used to being delivered to bioactive compound into the carrier of organism (such as people) generally received.The mesh of pharmaceutical composition Be advantageous for organism be administered convey.
Term " pharmaceutically acceptable carrier ", refers to active ingredient co-administered and is conducive to active ingredient to be administered Material, including but not limited to State Food and Drug Administration license it is acceptable be used for human or animal (such as domestic animal) Any glidant, sweetener, diluent, preservative, dyestuff/colouring agent, flavoring reinforcing agent, surfactant, wetting agent, point Powder, disintegrant, suspending agent, stabilizer, isotonic agent, solvent or emulsifying agent.For example include but is not limited to calcium carbonate, calcium phosphate, Various sugared and each kind of starch, cellulose derivative, gelatin, vegetable oil and polyethylene glycol.
Pharmaceutical composition of the present invention, can be configured to solid-state, semisolid, liquid or gaseous state preparation, such as tablet, ball Agent, capsule, pulvis, granule, paste, emulsion, suspending agent, solution, suppository, injection, inhalant, gel, microballoon And aerosol etc..
Pharmaceutical composition of the present invention, can be using method well known in the art manufacture, such as conventional mixing method, molten Solution, granulation, dragee method processed, levigate method, emulsion process, freeze-drying etc..
The method of administration of compound of the present invention or its pharmaceutically acceptable salt or its pharmaceutical composition, including but It is not limited to oral, rectum, saturating mucous membrane, through enteral administration, or local, percutaneous, suction, parenteral, sublingual, intravaginal, intranasal, eye Interior, intraperitoneal, intramuscular, subcutaneous, intravenous administration.It is preferred that method of administration be administered orally.
, can be by the way that reactive compound be mixed with pharmaceutically acceptable carrier well known in the art for being administered orally Close, to prepare the pharmaceutical composition.These carriers can make the compound of the present invention be formulated into tablet, pill, lozenge, sugar-coat Agent, capsule, liquid, gel, slurry agent, suspending agent etc., for the oral administration to patient.For example, for being administered orally Pharmaceutical composition, tablet can be obtained in the following way：Active component is merged with one or more solid carriers, if needed By gained granulating mixture, and a small amount of excipient processing resulting mixture or particle is added if desired, to form tablet Or label.Label can be combined with the optional coating material for being adapted to enteric, be processed into and be more beneficial for organism (such as people) absorption Coated preparation form.
Antagonism Wnt letters are being prepared present invention also offers a kind of foregoing compound or its pharmaceutically acceptable salt Application in the medicine of number path.
It is preferred that, pharmaceutical applications are for treating the cell proliferation disorders related to abnormal Wnt signals activity, digestion Systemic disease.
It is preferred that, pharmaceutical applications are for treating cancer, including non-small cell lung cancer, primary cutaneous type, inflammation Property myofibroblastoma, nasopharyngeal carcinoma, breast cancer, colorectal cancer, Diffuse Large B-Cell Lymphoma, liver cancer, stomach cancer, cancer of the esophagus, pancreas Gland cancer, oophoroma, body tissue's cellular proliferative disorder and neuroblastoma.
In the present invention, a series of embedded urea structure class WNT pathway inhibitors that inventor obtains to synthesis, from molecular water The flat inhibitory activity for determining Wnt path STF reporter genes, it is found that part of compounds has significant inhibitory activity to Wnt paths； In addition, the experiment of zebra fish phenotypic screen has also been carried out, by cutting the experiment of tail Regeneration and the development suppression of body axle to zebra fish Experiment, it is found that the antitumor activity of part of compounds in vivo is notable.
Compared with prior art, a kind of embedded urea structure class WNT pathway inhibitors that the present invention is provided, the conjunction based on target Drug design is managed, is modified by the substitution of group, a series of novel compound of structures is obtained；And combine STF reporter genes Experiment, the experiment of zebra fish phenotypic screen, optimal screening go out a series of compounds with antitumor activity.Therefore, available for opening The Wnt pathway inhibitors of a new generation are sent out into, are had for the disease that targeted therapy or prevention are mediated by Wnt paths great clinical Application value, market potential is considerable.
Brief description of the drawings
Fig. 1 suppresses figure for AB type zebra fish bodies axle development after processing 48h
Fig. 2 suppresses dose-effect graph of a relation (mean ± sd) for AB type zebra fish bodies axle development after processing 48h
Fig. 3 cuts tail Regeneration figure for AB type zebra fish after processing 7dpf
Fig. 4 cuts tail Regeneration dose-effect relationship figure (mean ± sd) for AB type zebra fish after processing 7dpf
Fig. 5 is the growth change situation map of colon cancer PDX MODEL Cs R3150 Zhong Ge treatment groups and control group mice gross tumor volume
Fig. 6 is compound changes of weight situation map in CR3150 models
Embodiment
The following is the specific embodiment of the present invention, technical scheme is further described, but it is of the invention Protection domain be not limited to these embodiments.Every change or equivalent substitute without departing substantially from present inventive concept is included in this hair Within bright protection domain.
In the target compound preparation method that the present invention is provided, liquid chromatogram uses WatersSymmetry C18 chromatograms Post.Thin-layer chromatography uses GF254 (0.25 millimeter).Nuclear magnetic resonance chromatogram (NMR) uses Bruker-400 nmr determinations； Liquid matter is used in conjunction (LC/MS) and uses Waters ZQ mass detector (pillars：WatersSymmetryC18, millimeter, 5 microns, 35 DEG C), using ESI (+) ion mode.
In addition, all operations for being related to oxidizable or facile hydrolysis raw material are all carried out under nitrogen protection.Unless otherwise Illustrate, the raw material that the present invention is used all is marketable material, need not be further purified and can directly use.
Embodiment one, N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -1 hydrogen of -4- phenyl-pyrazoles -1- Acid amides【Numbering is REX-N-1】Preparation
Synthetic route is as follows：
Synthetic schemes one：Intermediate REX-N-INT-1 synthesis
Step one：Compound 1-2 preparation
In the tetrahydrofuran solution that compound 1-1 (5.0g, 24.2mmol) is dissolved in 200ml dryings, in ice-water bath Be added dropwise isopropylmagnesium chloride (12.7ml, 25.5mmol), be stirred at room temperature 1 hour, by N- formyl-morpholines (2.5ml, In the tetrahydrofuran solution for 24.2mmol) being dissolved in 50ml dryings, room temperature, which is added drop-wise in reaction system, to be stirred for one hour, reaction Frozen water is added after end reaction is quenched, be extracted with ethyl acetate, saturated common salt washing, anhydrous sodium sulfate drying uses silicon after concentration Glue post is purified, and obtains compound 1-2 (3.0g, 79.6%).
MSm/z[ESI]：156.0[M+1].
Step 2：Compound 1-3 preparation
Compound 1-2 (3.0g, 19.4mmol), 2- methyl -4- pyridine boronic acids (3.2g, 23.2mmol) are dissolved in In 200mlN, dinethylformamide, under nitrogen protective condition respectively into system add potassium carbonate (10.7g, 77.6mmol), tetra-triphenylphosphine palladium (1.1g, 1.0mmol), is stirred overnight under the conditions of 100 DEG C, and reaction terminates to add into system Enter frozen water 200ml, be extracted with ethyl acetate, saturated common salt washing, anhydrous sodium sulfate drying is purified with silicagel column after concentration, obtained To compound 1-3 (1.8g, 44.0%).
MSm/z[ESI]：213.1[M+1].
Step 3：Compound 1-4 preparation
Compound 1-3 (1.8g, 8.5mmol) is dissolved in 50ml absolute ethyl alcohols, hydrochloric acid hydroxyl is added into system respectively Amine (1.2g, 17.0mmol), sodium acetate (1.4g, 17.0mmol), are stirred at room temperature 2 hours, and reaction terminates to add ice into system Reaction is quenched in water 50ml, is extracted with ethyl acetate, and saturated common salt washing, anhydrous sodium sulfate drying is purified after concentration with silicagel column, Obtain compound 1-4 (1.8g, 93.4%).
MSm/z[ESI]：228.1[M+1].
Step 4：Compound R EX-N-INT-1 preparation
Compound 1-4 (1.8g, 7.9mmol) is dissolved in 30ml ethanol solutions, 10% palladium carbon is separately added into (200mg), hydrochloric acid (1.5ml, 12.0N) are reacted at room temperature under an atmospheric pressure hydrogen atmosphere and stayed overnight, reaction terminate filtering, it is dense Contracting, is purified with silicagel column, obtains compound R EX-N-INT-1 (1.4g, 85.2%).
MSm/z[ESI]：214.1[M+1].
Synthetic schemes two：Compound R EX-N-1 synthesis
Step one：Intermediate REX-N-INT-2 preparation
Compound 2-1 (5.0g, 34.0mmol), triethylamine (14.1ml, 102.0mmol) are dissolved in 100ml dryings In dichloromethane, paratoluensulfonyl chloride (6.5g, 34.0mmol) is dissolved in the dichloromethane of 50ml dryings and is added drop-wise to system In, completion of dropping is stirred at room temperature 2 hours, and reaction terminates to add frozen water 200ml into system, is extracted with ethyl acetate, saturation food Salt is washed, and anhydrous sodium sulfate drying is purified after concentration with silicagel column, obtains compound R EX-N-INT-2 (10.0g, 97.6%).
MSm/z[ESI]：303.0[M+1].
Step 2：Compound 2-3 preparation
Respectively by compound R EX-N-INT-2 (10.0g, 33.2mmol), phenyl boric acid (6.1g, 49.8mmol), potassium carbonate (13.7g, 99.6mmol), tetra-triphenylphosphine palladium (1.8g, 0.2mmol) are dissolved in 120ml glycol dimethyl ethers and 24ml water In the mixed solvent, reaction system is stirred overnight under the conditions of nitrogen protection, 90 DEG C, and reaction terminates to add frozen water into system Reaction is quenched in 200ml, is extracted with ethyl acetate, and saturated common salt washing, anhydrous sodium sulfate drying is purified after concentration with silicagel column, Obtain compound 2-3 (3.2g, 67.3%).
MSm/z[ESI]：145.1[M+1].
Step 3：Compound R EX-N-1 preparation
Respectively by compound 2-3 (3.2g, 22.3mmol), two (trichloromethyl) carbonic esters (7.9g, 26.8mmol), N, N- Diisopropylethylamine (7.3ml, 44.6mmol) is dissolved in the dichloromethane of 50ml dryings, is stirred at room temperature 30 minutes, respectively will Compound R EX-N-INT-1 (4.8g, 22.3mmol), N, N- diisopropylethylamine (7.3ml, 44.6mmol) are dissolved in 30ml and done Dry dichloromethane is added drop-wise in reaction system, and half an hour is stirred at room temperature in completion of dropping, and reaction terminates to add frozen water into system 200ml, is extracted with ethyl acetate, and saturated common salt washing, anhydrous sodium sulfate drying is purified after concentration with silicagel column, obtains chemical combination Thing REX-N-1 (2.5g, 29.0%).
MSm/z[ESI]：384.2[M+1].
1H-NMR(400MHz,DMSO-d6):δ=9.24 (t, J=6.0Hz, 1H), 8.77 (s, 1H), 8.51-8.53 (m, 2H), 8.31 (s, 1H), 7.75 (s, 1H), 7.73 (s, 2H), 7.25-7.43 (m, 5H), 4.53 (d, J=6.0Hz, 2H), 2.53 (s,3H),2.33(s,3H).
Embodiment two, 4- (2- chlorphenyls)-N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -1- hydrogen - Pyrazoles -1- acid amides【Numbering is REX-N-9】Preparation
Synthetic route is as follows：
Intermediate REX-N-INT-2 preparation：
With reference to the preparation method of embodiment one, intermediate REX-N-INT-2 (1.0 grams) is first made.
Step one：Compound 1-2 preparation
Respectively by compound R EX-N-INT-2 (1.0g, 3.3mmol), adjacent chlorophenylboronic acid (0.8g, 5.0mmol), potassium carbonate (1.4g, 9.9mmol), tetra-triphenylphosphine palladium (180.0mg, 0.02mmol) are dissolved in 20ml glycol dimethyl ethers and 4ml water In the mixed solvent, reaction system is stirred overnight under the conditions of nitrogen protection, 90 DEG C, and reaction terminates to add frozen water into system Reaction is quenched in 50ml, is extracted with ethyl acetate, and saturated common salt washing, anhydrous sodium sulfate drying is purified with silicagel column after concentration, obtained To compound 1-2 (379.5mg, 64.6%).
MSm/z[ESI]：179.0[M+1].
Step 2：Compound R EX-N-9 preparation
With reference to the preparation method of embodiment one, intermediate REX-P-INT-1 (452.0 milligrams) is first made.
Respectively by compound 1-2 (379.5mg, 2.1mmol), two (trichloromethyl) carbonic esters (742.8mg, 2.5mmol), DIPEA (0.7ml, 4.2mmol) is dissolved in the dichloromethane of 20ml dryings, is stirred at room temperature 30 minutes, respectively By compound R EX-N-INT-1 (452.0mg, 2.1mmol), N, N- diisopropylethylamine (0.7ml, 4.2mmol) is dissolved in The dichloromethane that 10ml is dried is added drop-wise in reaction system, and half an hour is stirred at room temperature in completion of dropping, and reaction terminates to add into system Enter frozen water 50ml, be extracted with ethyl acetate, saturated common salt washing, anhydrous sodium sulfate drying is purified with silicagel column after concentration, obtained Compound R EX-N-9 (373.1mg, 42.6%).
MSm/z[ESI]：418.1[M+1].
1H-NMR(400MHz,CDCl3) δ=8.58 (d, J=18.4Hz, 3H), 7.92 (s, 1H), 7.68 (s, 2H), 7.53-7.35 (m, 5H), 7.30 (d, J=7.1Hz, 1H), 4.69 (d, J=6.1Hz, 2H), 2.75 (s, 3H), 2.40 (s, 3H).
Embodiment three, 4- (4- chlorphenyls)-N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -1- hydrogen - Pyrazoles -1- acid amides【Numbering is REX-N-10】Preparation
Synthetic route is as follows：
The preparation method of embodiment three is with reference to embodiment two, and the adjacent chlorophenylboronic acid wherein in step one is replaced by chlorobenzene boron Compound R EX-N-10 (545.4mg, 52.3%) is finally made in acid, remaining preparation method be the same as Example two.
MSm/z[ESI]：418.1[M+1].
1H-NMR(400MHz,CDCl3) δ=8.63-8.52 (m, 2H), 8.45 (d, J=11.9Hz, 1H), 7.85 (s, 1H), 7.69-7.58 (m, 2H), 7.43 (dd, J=15.5,7.1Hz, 4H), 7.35 (d, J=8.3Hz, 2H), 4.68 (d, J= 6.2Hz,2H),2.74(s,3H),2.39(s,3H).
Example IV, N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (3- fluorophenyls) -1- hydrogen - Pyrazoles -1- acid amides【Numbering is REX-N-5】Preparation
The preparation method of example IV is with reference to embodiment two, and the adjacent chlorophenylboronic acid wherein in step one is replaced by a fluorobenzene boron Compound R EX-N-5 (456.1mg, 44.7%) is finally made in acid, remaining preparation method be the same as Example two.
MSm/z[ESI]：402.2[M+1].
1H-NMR(400MHz,CDCl3) δ=8.86 (t, J=3.2Hz, 1H), 8.68 (s, 1H), 8.49 (s, 1H), 7.91 (s, 1H), 7.86-7.80 (m, 4H), 7.39-7.21 (m, 3H), 7.02 (t, J=1.6Hz, 1H), 4.74 (d, J=6.4Hz, 2H),2.91(s,3H),2.47(s,3H).
Embodiment five, 4- (3- chlorphenyls)-N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -1- hydrogen - Pyrazoles -1- acid amides【Numbering is REX-N-6】Preparation
The preparation method of embodiment five is with reference to embodiment two, chlorophenylboronic acid generation between the adjacent chlorophenylboronic acid quilt wherein in step one Replace, remaining method is identical, finally obtained compound R EX-N-6 (502.6mg, 48.2%).
MSm/z[ESI]：418.1[M+1].
1H-NMR(400MHz,CDCl3) δ=8.66 (s, 1H), 8.50 (s, 1H), 7.91 (s, 1H), 7.82-7.72 (m, 4H), 7.52 (t, J=1.6Hz, 1H), 7.42-7.28 (m, 4H), 4.73 (d, J=6.4Hz, 2H), 2.92 (s, 3H), 2.48 (s,3H).
Embodiment six, N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (pyrazine -2- bases) -1- hydrogen - Pyrazoles -1- acid amides【Numbering is REX-N-11】Preparation
The preparation method of embodiment six is with reference to embodiment two, and the adjacent chlorophenylboronic acid wherein in step one is by 2- pyrazine boric acid generations Replace, remaining method is identical, finally obtained compound R EX-N-11 (531.7mg, 55.2%).
MSm/z[ESI]：386.2[M+1].
1H-NMR(400MHz,CDCl3) δ=9.39 (t, J=1.6Hz, 1H), 9.19 (d, J=1.6Hz, 1H), 9.05 (s, 1H), 8.64-8.62 (m, 1H), 8.53-8.51 (m, 3H), 8.45 (s, 1H), 7.74 (d, J=1.6Hz, 1H), 7.40 (s, 1H), (s, the 3H) of 7.34 (dd, J=4.8,1.2Hz, 1H), 4.53 (d, J=6.0Hz, 2H), 2.53 (s, 3H), 2.33
Embodiment seven, N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (pyridine -2- bases) -1- hydrogen - Pyrazoles -1- acid amides【Numbering is REX-N-2】Preparation
Step one：Compound 1-2 preparation
Respectively by compound R EX-N-INT-3 (2.46g, 12.66mmol), adjacent bromopyridine (2g, 12.66mmol), carbonic acid Potassium (3.50g, 25.32mmol), tetra-triphenylphosphine palladium (0.88g, 0.759mmol) are dissolved in 20ml glycol dimethyl ethers and 4ml The in the mixed solvent of water, reaction system is stirred overnight under the conditions of nitrogen protection, 90 DEG C, and reaction terminates to add ice into system Reaction is quenched in water 50ml, is extracted with ethyl acetate, and saturated common salt washing, anhydrous sodium sulfate drying is purified after concentration with silicagel column, Obtain compound 1-2 (600mg, 32.7%).
MSm/z[ESI]：146.0[M+1].
Step 2：Compound R EX-N-2 preparation
With reference to the preparation method of embodiment one, intermediate REX-N-INT-1 (1.0 grams) is first made.
Respectively by compound 1-2 (300mg, 2.07mmol), two (trichloromethyl) carbonic esters (417mg, 2.07mmol), N, N- diisopropylethylamine (267mg, 0.34ml, 2.07mmol) is dissolved in the dichloromethane of 20ml dryings, is stirred at room temperature 30 points Clock, respectively by compound R EX-N-INT-1 (441mg, 2.07mmol), DIPEA (801mg, 1.00ml, The dichloromethane for 6.20mmol) being dissolved in 10ml dryings is added drop-wise in reaction system, and half an hour is stirred at room temperature in completion of dropping, reaction Terminate to add frozen water 50ml into system, be extracted with ethyl acetate, saturated common salt washing, anhydrous sodium sulfate drying is used after concentration Silicagel column is purified, and obtains compound R EX-N-2 (50mg, 6.3%).
MSm/z[ESI]：385.1[M+1].
1H-NMR((400MHz,DMSO-d6), δ=9.33 (t, J=6Hz, 1H), 8.89 (d, J=0.4Hz, 1H)), 8.56-8.58 (m, 1H), 8.50-8.54 (m, 2H), 8.39 (d, J=0.8Hz, 1H), 7.87-7.91 (m, 1H), 7.79-7.84 (m, 1H), 7.73 (d, J=1.6Hz, 1H), 7.40 (s, 1H), 7.32-7.36 (m, 1H), 7.25-7.29 (m, 1H), 4.52 (d, J=6Hz, 2H), 2.53 (s, 3H) 2.33 (s, 3H)
Embodiment eight, N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (2- fluorophenyls) -1- hydrogen - Pyrazoles -1- acid amides【Numbering is REX-N-12】Preparation
The preparation method of embodiment eight is with reference to embodiment two, and the adjacent chlorophenylboronic acid wherein in step one is by 2- fluorobenzoic boric acid generations Replace, remaining method is identical, finally obtained compound R EX-N-12 (50mg, 13.2%).
MSm/z[ESI]：402.2[M+1].
1H-NMR(400MHz,DMSO-d6) δ=9.38 (t, J=1.6Hz, 1H), 8.68 (d, J=1.6Hz, 1H), 8.52- 8.53 (m, 2H), 8.33 (s, 1H), 7.91 (t, J=1.6Hz, 1H), 7.74 (m, 1H), 7.42 (s, 1H), 7.25-7.36 (m, 4H), (s, the 3H) of 4.53 (d, J=6.0Hz, 2H), 2.58 (s, 3H), 2.34
Embodiment nine, N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (4- fluorophenyls) -1- hydrogen - Pyrazoles -1- acid amides【Numbering is REX-N-13】Preparation
The preparation method of embodiment nine is with reference to embodiment two, and the adjacent chlorophenylboronic acid wherein in step one is by 4- fluorobenzoic boric acid generations Replace, remaining method is identical, finally obtained compound R EX-N-13 (60mg, 15.2%).
MSm/z[ESI]：402.2[M+1].
1H-NMR(400MHz,DMSO-d6) δ=9.30 (t, J=1.6Hz, 1H), 8.81 (d, J=1.6Hz, 1H), 8.52- 8.53(m,2H),8.33(s,1H),7.81–7.83(m,2H),7.73(m,1H),7.42(s,1H),7.33–7.34(m,1H), (s, the 3H) of 7.23-7.26 (m, 1H), 4.52 (d, J=6.0Hz, 2H), 2.58 (s, 3H), 2.34
Embodiment ten, N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (pyridin-3-yl) -1- hydrogen - Pyrazoles -1- acid amides【Numbering is REX-N-14】Preparation
The preparation method of embodiment ten is with reference to embodiment seven, adjacent bromopyridine bromopyridine replacement by between wherein in step one, Remaining method is identical, finally obtained compound R EX-N-14 (40mg, 10.2%).
MSm/z[ESI]：385.1[M+1].
1H-NMR((400MHz,DMSO-d6), δ=9.33 (t, J=6Hz, 1H), 8.89 (d, J=0.4Hz, 1H), 8.50- 8.58 (m, 3H), 8.39 (d, J=0.8Hz, 1H), 7.87-7.91 (m, 1H), 7.79-7.84 (m, 1H), 7.73 (d, J= 1.6Hz, 1H), 7.40 (s, 1H), 7.32-7.36 (m, 1H), 7.25-7.29 (m, 1H), 4.52 (d, J=6Hz, 2H), 2.53 (s,3H),2.33(s,3H).
Embodiment 11, N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (pyridin-4-yl) -1- Hydrogen-pyrazoles -1- acid amides【Numbering is REX-N-15】Preparation
The preparation method of embodiment 11 is with reference to embodiment seven, and the adjacent bromopyridine wherein in step one is by bromopyridine generation Replace, remaining method is identical, finally obtained compound R EX-N-15 (50mg, 12.2%).
MSm/z[ESI]：385.1[M+1].
1H-NMR((400MHz,CDCl3), δ=8.63 (s, 1H), 8.55-8.58 (m, 3H), 8.41 (d, J=0.8Hz, 1H),7.92(s,1H),7.61–7.65(m,2H),7.52–7.53(m,1H),7.51(s,1H),7.22–7.23(m,1H), 7.25-7.29 (m, 1H), 4.68 (d, J=6Hz, 2H), 2.62 (s, 3H) 2.37 (s, 3H)
Embodiment 12, N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (3- fluorine pyridines -2- Base) -1- hydrogen-pyrazoles -1- acid amides【Numbering is REX-N-16】Preparation
The preparation method of embodiment 12 is with reference to embodiment seven, and the adjacent bromopyridine wherein in step one is by the fluoro- pyrroles of 2- bromo- 3 Pyridine is replaced, and remaining method is identical, finally obtained compound R EX-N-16 (30mg, 8.5%).
MSm/z[ESI]：403.1[M+1].
1H-NMR((400MHz,DMSO-d6), δ=9.42 (t, J=6Hz, 1H), 8.68 (s, 1H), 8.49-8.52 (m, 3H), 8.38 (s, 1H), 7.84-7.87 (m, 1H), 7.75 (s, 1H), 7.34-7.44 (m, 3H), 4.53 (d, J=6Hz, 2H), 2.54(s,3H),2.34(s,3H).
Embodiment 13, N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (5- fluorine pyridines -2- Base) -1- hydrogen-pyrazoles -1- acid amides【Numbering is REX-N-17】Preparation
The preparation method of embodiment 13 is with reference to embodiment seven, and the adjacent bromopyridine wherein in step one is by the fluoro- pyrroles of 3- bromo- 5 Pyridine is replaced, and remaining method is identical, finally obtained compound R EX-N-17 (35mg, 8.9%).
MSm/z[ESI]：403.1[M+1].
1H-NMR((400MHz,CDCl3), δ=8.63 (s, 1H), 8.55-8.58 (m, 3H), 8.41 (d, J=0.8Hz, 1H),7.92(s,1H),7.53–7.65(m,2H),7.50–7.53(m,1H),7.31(s,1H),7.22–7.23(m,1H), (s, the 3H) of 4.39 (d, J=6Hz, 2H), 2.62 (s, 3H), 2.37
Embodiment 14, N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (3- fluorine pyridines -4- Base) -1- hydrogen-pyrazoles -1- acid amides【Numbering is REX-N-18】Preparation
The preparation method of embodiment 14 is with reference to embodiment seven, and the adjacent bromopyridine wherein in step one is by the bromo- pyrroles of 3- fluoro- 4 Pyridine is replaced, and remaining method is identical, finally obtained compound R EX-N-18 (55mg, 12.5%).
MSm/z[ESI]：403.1[M+1].
1H-NMR((400MHz,CDCl3), δ=8.77 (s, 1H), 8.55-8.61 (m, 3H), 8.46 (d, J=0.8Hz, 1H),8.09(s,1H),7.76(s,1H),7.49–7.52(m,2H),7.33(s,1H),7.24–7.26(m,1H),4.71(d,J =6Hz, 2H), 2.64 (s, 3H), 2.39 (s, 3H)
Embodiment 15, N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -5- methyl -4- (pyridine -2- Base) -1- hydrogen-pyrazoles -1- acid amides【Numbering is REX-N-19】Preparation
The preparation method of embodiment 15 is with reference to embodiment seven, and the intermediate REX-N-INT-3 wherein in step one is by Mesosome REX-N-INT-4 is replaced, and remaining method is identical, finally obtained compound R EX-N-19 (65mg, 14.5%).
MSm/z[ESI]：399.4[M+1].
1H-NMR((400MHz,CDCl3), δ=8.55-8.59 (m, 3H), 7.79-7.81 (m, 1H), 7.71-7.74 (m, 1H), 7.69 (s, 1H), 7.47-7.50 (m, 2H), 7.32 (s, 1H), 7.18-7.28 (m, 2H), 4.65 (d, J=6Hz, 2H), 2.63(s,3H),2.56(s,3H),2.37(s,3H).
Embodiment 16, N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (6- picolines -2- Base) -1- hydrogen-pyrazoles -1- acid amides【Numbering is REX-N-20】Preparation
The preparation method of embodiment 16 with reference to embodiment seven, adjacent bromopyridine wherein in step one by the bromo- 6- methyl of 2-- Pyridine is replaced, and remaining method is identical, finally obtained compound R EX-N-20 (50mg, 11.5%).
MSm/z[ESI]：399.4[M+1].
1H-NMR((400MHz,DMSO-d6), δ=9.33 (t, J=6Hz, 1H), 8.85 (s, 1H), 8.52-8.53 (m, 2H),8.36(s,1H),7.69–7.70(m,1H),7.41(s,1H),7.34–7.36(m,1H),7.13–7.16(m,1H), (s, the 3H) of 4.53 (d, J=6Hz, 2H), 2.54 (s, 3H), 2.50 (s, 3H), 2.34
Embodiment 17, N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (5- picolines -3- Base) -1- hydrogen-pyrazoles -1- acid amides【Numbering is REX-N-21】Preparation
The preparation method of embodiment 17 with reference to embodiment seven, adjacent bromopyridine wherein in step one by the bromo- 5- methyl of 3-- Pyridine is replaced, and remaining method is identical, finally obtained compound R EX-N-21 (10mg, 10.5%).
MSm/z[ESI]：399.4[M+1].
1H-NMR((400MHz,CDCl3), δ=9.36-8.62 (m, 3H), 8.53 (s, 1H), 8.38 (s, 1H), 7.92 (s, 1H), 7.66 (s, 1H), 7.59-7.62 (m, 2H), 7.32 (s, 1H), 7.23-7.24 (m, 1H), 4.68 (d, J=6Hz, 2H), 2.63(s,3H),2.39(s,3H),2.37(s,3H).
Embodiment 18, N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (2- picolines -4- Base) -1- hydrogen-pyrazoles -1- acid amides【Numbering is REX-N-22】Preparation
The preparation method of embodiment 18 is with reference to embodiment seven, and the adjacent bromopyridine wherein in step one is bromo- by 2- methyl -4- Pyridine is replaced, and remaining method is identical, finally obtained compound R EX-N-22 (40mg, 10.3%).
MSm/z[ESI]：399.4[M+1].
1H-NMR((400MHz,DMSO-d6), δ=9.33 (t, J=6Hz, 1H), 8.85 (s, 1H), 8.52-8.53 (m, 2H),8.36(s,1H),7.69–7.70(m,2H),7.41(s,1H),7.34–7.36(m,1H),7.13–7.16(m,1H), (s, the 3H) of 4.53 (d, J=6Hz, 2H), 2.54 (s, 3H), 2.50 (s, 3H), 2.34
Embodiment 19, N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (3- cyano-phenyls) -1- Hydrogen-pyrazoles -1- acid amides【Numbering is REX-N-23】Preparation
The preparation method of embodiment 19 is with reference to embodiment seven, bromobenzylcyanide generation between the adjacent bromopyridine quilt wherein in step one Replace, remaining method is identical, finally obtained compound R EX-N-23 (100mg, 20.3%).
MSm/z[ESI]：409.4[M+1].
1H-NMR((400MHz,CDCl3), δ=8.56-8.60 (m, 3H), 8.27 (d, J=0.8Hz, 2H), 7.60-7.67 (m, 4H), 6.44-6.45 (m, 2H), 4.68 (d, J=6Hz, 2H), 2.64 (s, 3H), 2.37 (s, 3H)
Embodiment 20, N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (pyrimidine -5- bases) -1- Hydrogen-pyrazoles -1- acid amides【Numbering is REX-N-24】Preparation
The preparation method of embodiment 20 is with reference to embodiment seven, and the adjacent bromopyridine wherein in step one is by the bromo- pyrimidine second of 5- Nitrile is replaced, and remaining method is identical, finally obtained compound R EX-N-24 (80mg, 15.8%).
MSm/z[ESI]：386.1[M+1].
1H-NMR((400MHz,CDCl3), δ=9.16 (s, 1H), 8.91 (s, 2H), 8.56-8.59 (m, 3H), 7.95 (s, 2H), 7.63-7.65 (m, 2H), 7.31 (s, 1H), 7.22-7.23 (m, 1H), 4.69 (d, J=6Hz, 2H), 2.63 (s, 3H), 2.38(s,3H).
Embodiment 21, N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (pyrimidine -2-base) - 1- hydrogen-pyrazoles -1- acid amides【Numbering is REX-N-25】Preparation
The preparation method of embodiment 21 is with reference to embodiment seven, and the adjacent bromopyridine wherein in step one is by the bromo- pyrimidines of 5- Acetonitrile is replaced, and remaining method is identical, finally obtained compound R EX-N-25 (100mg, 18.8%).
MSm/z[ESI]：386.1[M+1].
1H-NMR((400MHz,CDCl3), δ=8.96 (s, 1H), 8.55 (d, J=0.8Hz, 2H), 8.55-8.57 (m, 2H),8.30(s,1H),7.66(s,1H),7.32(s,1H),7.22–7.23(m,1H),7.14–7.16(m,1H),4.69(d,J =6Hz, 2H), 2.63 (s, 3H), 2.37 (s, 3H)
Embodiment 22, N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (pyridazine -3- bases) - 1- hydrogen-pyrazoles -1- acid amides【Numbering is REX-N-26】Preparation
The preparation method of embodiment 22 is with reference to embodiment seven, and the adjacent bromopyridine wherein in step one is by the bromo- pyrimidines of 5- Acetonitrile is replaced, and remaining method is identical, finally obtained compound R EX-N-26 (100mg, 18.5%).
MSm/z[ESI]：386.1[M+1].
1H-NMR((400MHz,CDCl3), δ=9.11 (s, 1H), 8.58 (s, 1H), 8.58 (d, J=0.8Hz, 2H), 8.35 (s, 1H), 7.66 (s, 1H), 7.50-7.52 (m, 1H), 7.32 (s, 1H), 7.22-7.24 (m, 1H), 4.69 (d, J= 6Hz,2H),2.63(s,3H),2.38(s,3H).
Embodiment 23, the experiment of zebra fish phenotypic screen
Zebra fish is a kind of vertebrate, and 85% is up to human genome homology, has approximate organizer with the mankind Official's function and signal transduction pathway, and with the unique advantage such as egg laying amount height, blastoprolepsis, embryo be transparent so that zebra fish It is applied successfully to human diseases research and live body medicament high flux screening.Wnt signal paths are widely present in invertebrate And vertebrate, it is the signal path that a class is highly conserved during evolution, the relevant cell growth of the interior regulation and control of participation organism, Apoptosis, self-renewing and lifetime because expression, maintain the physiology such as normal embryonic development and tissue repair regeneration in organism Function (Wolfram Goessling, Trista E.North, Sabine Loewer, et al. (2009) .Genetic Interaction of PGE2 and Wnt Signaling Regulates Developmental Specification of Stem Cells and Regeneration.Cell,136(6):1136-1147.).Wnt signal paths are lacked of proper care and cancer Generation is also closely related, such as all contains in 80%~90% colorectal cancer and have an impact Wnt signal path Gene As denomatous Polyposis Coli (APC) function mutation (Hans Clevers, Roel Nusse. (2012) .Wnt/ β-Catenin Signaling and Disease.Cell,149(6):1192-1205.)。
Research shows that phenotype and Wnt signal path of the zebra fish in terms of the development of body axle and Regeneration and Repair are closely related (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.)。
Therefore, using excellent in terms of conservative of the Wnt signal paths between different plant species and zebra fish phenotypic screen Gesture, we investigate compound normal AB types zebra fish body axle is developed and Regeneration and Repair influence, to inquire into compound in vivo The power of anti-Wnt signal paths activity.
Test (one) compound and experiment is suppressed to the development of AB type zebra fish bodies axle
Method：The AB type zebra fish fish-egg for choosing 3hpf (hours post fertilization) carries out body axle development table Type is tested, and by tested final concentration, administration group and solvent control group are grouped at random in the range of 100 μM~0.001 μM, often 20 AB fish-eggs of group are added in 6 orifice plates, per hole 3mL fish and water, DMSO concentration≤1% (v/v).AB fish-eggs after agent-feeding treatment as 28.5 DEG C of biochemical cultivation cases are incubated to IMAQ is carried out during 48hpf, are measured using the software analysis of NIS-Elements D 3.1 Each group juvenile fish body shaft length px values (pixels).Suppression according to various concentrations compound to each group juvenile fish body axle development growth Rate, carries out nonlinear fitting with GraphPadPrism 6.0 and calculates IC of each compound in AB type zebra fish bodies axle developmentally50 Value.
As a result：A series of compounds such as REX-N-1 prepared by the embodiment of the present invention, develop to AB type zebra fish bodies axle and suppress Determination of activity the results are shown in Table one；Body axle development holddown is shown in Fig. 1 after REX-N-1 processing AB type zebra fish 48hpf, and dose-effect is closed Fig. 2 sees in system (mean ± sd).
The embodiment compound of table one develops the determination of activity suppressed to AB type zebra fish bodies axle
Compounds IC50(μM)
LGK-974 0.583
REX-N-1 0.063
REX-N-5 0.039
REX-N-6 0.366
REX-N-2 1.768
REX-N-11 2.393
REX-N-9 0.015
REX-N-10 >10
REX-N-7 0.491
REX-N-8 0.227
REX-N-12 0.274
REX-N-13 1.055
REX-N-14 3.133
REX-N-15 2.589
REX-N-16 4.58
REX-N-17 0.08
REX-N-18 30.596
REX-N-19 2.57
REX-N-20 1.109
REX-N-21 1.421
REX-N-22 >100
REX-N-23 5.588
REX-N-24 22.3
REX-N-25 13.4
REX-N-26 >100
Note：IC50To calculate 50% inhibiting rate concentration
Further, the present invention carries out the experiment reinspection that zebra fish cuts tail regeneration phenotype to the compound in table 1.
Experiment (two) compound cuts the experiment of tail Regeneration to AB type zebra fish
The AB type zebra fish juvenile fish for choosing 3dpf (days post fertilization) carries out cutting tail fin modeling processing, By tested final concentration, administration group and solvent control group are grouped at random in the range of 10 μM~0.001 μM, every group of 15 childrens Fish is added in 6 orifice plates, per hole 3mL fish and water, DMSO concentration≤1% (v/v).AB fish-eggs after agent-feeding treatment are as 28.5 DEG C of biochemistry Incubator is incubated to IMAQ is carried out during 7dpf, and each group juvenile fish tail fin is measured using the software analysis of NIS-Elements D 3.1 Regenerate length px values (pixels).The inhibiting rate regenerated according to various concentrations compound to each group juvenile fish tail fin, is used GraphPad Prism 6.0 carry out each compound of nonlinear fitting calculating and cut the IC in tail regeneration in AB type zebra fish50Value.
As a result：A series of compounds such as REX-N-1 prepared by the embodiment of the present invention, tail Regeneration is cut to AB type zebra fish Determination of activity the results are shown in Table two；REX-N-1 processing 3dpf cuts tail modeling AB types zebra fish to 7dpf tail fin Regenerations and sees figure 3, dose-effect relationship (mean ± sd) is shown in Fig. 4.
The embodiment compound of table two cuts the determination of activity of tail Regeneration to AB type zebra fish
Embodiment 24, Super-Top-Flash (STF) reporter gene assay
A series of compounds such as compound L GK-974 (comparison medicine), REX-N-1 (embodiment) are using stable transfection STF reports The HEK293T-STF cell lines for accusing gene determine its suppression to Wnt signal paths with L-Wnt3a secretory cells strain co-cultivation mode System activity, the activity uses IC50This index represents, IC50That is the Luciferase activity of STF reporter gene expressions is pressed down The concentration of compound when making 50%.
A series of compounds such as REX-N-1 prepared by the embodiment of the present invention, utilize the Wnt reporter genes of CrownBio companies Platform is measured, and measurement result is shown in Table three.As a result show, the compound that the present invention is provided has preferably from molecular level Wnt signal path inhibitory activity.
The determination of activity that the embodiment compound of table three suppresses to Wnt path STF reporter genes
Compounds IC50(nM)
LGK-974 0.574
REX-N-1 0.123
REX-N-5 0.845
REX-N-6 3.86
REX-N-2 2.5
REX-N-11 14.2
REX-N-9 18.8
REX-N-10 589.38
REX-N-7 4.01
REX-N-8 1.89
REX-N-12 5.99
REX-N-13 6.98
REX-N-14 3.45
REX-N-15 13.87
REX-N-16 6.258
REX-N-17 0.39
REX-N-18 80.549
REX-N-19 8.602
REX-N-20 0.801
REX-N-21 172.181
REX-N-22 3.779
REX-N-23 3.089
REX-N-24 8.534
REX-N-25 16.103
Embodiment 25, metabolic stability in vitro and internal PK experiments
The compound R EX-N-1 for choosing preparation of the embodiment of the present invention has carried out people, the external liver particle metabolic stability of mouse Experiment and the PK measure in BABL/C mouse.
PK method of testings are：18 rats are divided into two groups, every group 9.One of which is by intravenously administrable, and dosage is 5mg/ kg；One group is administered orally, and dosage is 10mg/kg.Each group upon administration 0,0.083,0.25,0.5,1,2,4,8,24h Blood is collected by orbital vein respectively.By about 100 μ L blood collections to the clean EP containing EDTA by way of eye socket is taken a blood sample In pipe (EDTA final concentration of 0.25mg/mL).It is rapid after the completion of collection to be inverted heparin tube at least 5 times, to ensure mixing Uniformly, it is then placed within ice.Each time point blood collected is at 4 DEG C, and 8000rpm centrifuges 5 minutes to obtain blood plasma.Separately take 1.5mL centrifuge tubes have marked compound name, and number of animals at time point, blood plasma is transferred in the pipe.Blood plasma is stored in -80 DEG C until analysis.
Specific experiment result is as follows, as a result shows that REX-N-1 has preferable bioavilability and half-life period：
PK and metabolic stability in vitro experimental result in the embodiment compound body of table four
Embodiment 26, the effect experiment in CR3150 transplanted tumor in nude mice
Patient's colon tumor CR3150 fritters that a diameter of 2-4mm is cut into 1640 culture medium are inoculated into the skin of nude mice Under, treat tumour length to 500-700mm3Passed on afterwards with nude mice.Treat forth generation (P4) tumour length to 500-700mm3When, Tumour is cut into a diameter of 2-4mm fritter in 1640 culture medium to be used to test nude mice by subcutaneous inoculation.Skin on the right side of female mice Lower inoculated tumour fritter.Routine observation tumour growth situation, treats tumour growth to average external volume 200mm3During left and right, according to tumour Size divides three groups at random.Solvent, positive control drug LGK974, the compound R EX-N-1 of embodiment 1 are given respectively, according to 5mg/kg, BID is administered 28 days.Periodic observation gross tumor volume and changes of weight.
Gross tumor volume calculation formula is：Major diameter × minor axis2/2。
Relative tumor inhibiting rate TGI (%)：TGI%=(1-T/C) × 100%.
T/C% is Relative tumor appreciation rate, i.e., in sometime point, treatment group and control group relative tumour volume or knurl weight Percent value.T and C are respectively the relative tumour volume (RTV) or knurl weight for the treatment of group and control group in a certain particular point in time (TW)。
Calculation formula is as follows：
T/C%=TRTV/CRTV× 100% (TRTV：The average RTV for the treatment of group；CRTV：The average RTV of vehicle control group；RTV= Vt/V0, V0The knurl volume of the animal, V during for packettFor the knurl volume of the animal after treatment).Or,
T/C%=TTW/CTW× 100% (TTW：Average knurl weight during treatment group's experiment termination；CTW：Vehicle control group experiment is eventually Average knurl weight during knot).
Five, Fig. 5 and Fig. 6 is the results are shown in Table, the result shows：Solvent group, LGK974, REX-N-1 respectively according to 5mg/kg, After PO, BID are administered 28 days, changes of weight rate is 1.41%, -9.73% and -8.28% respectively.After administration 28 days, LGK974, table Reveal notable antitumor action, TGI is that 102.62%, T/C is 9.04% (P<0.003)；REX-N-1, also shows significant Antitumor action, TGI is that 99.52%, T/C is 11.81% (P<0.003).
In a word, in this CR3150 colon cancer PDX model, LGK974 and REX-N-1 are under 5mg/kg dosage, administration 28 My god, BID shows significant antitumor activity.
Antitumor drug effect of the compound of table five in CR3150 models

Claims (10)

1. a kind of WNT pathway inhibitors of embedded ureas structure, for the compound with following general structure and its pharmaceutically may be used The salt of receiving：
Wherein, ring A and ring B are each independently selected from aromatic rings or the aromatic heterocycle containing 1-2 N atom or O atom；
X, Y, Z are each independently selected from CR4, one kind in N atoms；
Any integer values of the n in 1~2；
R1、R2It is each independently selected from hydrogen, halogen, C1-6Alkyl, C3-6Cycloalkyl, C2-6Alkenyl, C2-6Alkynyl, halo C1-6Alkyl, C1-6Alkoxy, halo C1-6One or more in alkoxy, hydroxyl, amino, cyano group, acyl group, sulfo group, aryl, heterocyclic radical；
R3Selected from substituted or unsubstituted aryl, heterocyclic radical；Work as R3During for substituted aryl, heterocyclic radical, on aryl, heterocyclic radical Substituted radical is selected from halogen, C1-6Alkyl, halo C1-6Alkyl, C1-6Alkoxy, halo C1-6Alkoxy, hydroxyl, cyano group, amino, One or more in acyl group, sulfo group, heterocyclic radical；
R4Selected from hydrogen, C1-6Alkyl, halo C1-6Alkyl, C1-6Alkoxy, halo C1-6Alkoxy, C3-6One kind in cycloalkyl；
Described heterocyclic radical is to contain the heteroatomic 3-12 circle heterocycles of one or more N, O, S.
2. the WNT pathway inhibitors of embedded ureas structure according to claim 1, for the chemical combination with following general structure Thing and its pharmaceutically acceptable salt：
Wherein, ring B is selected from aromatic rings or the aromatic heterocycle containing 1-2 N atom or O atom；
X, Y, Z are each independently selected from CR4, one kind in N atoms；
Any integer values of the n in 1~2；
R1、R2It is each independently selected from hydrogen, halogen, C1-6Alkyl, C3-6Cycloalkyl, halo C1-6Alkyl, C1-6Alkoxy, halo C1-6 One or more in alkoxy, hydroxyl, amino, acyl group, aryl, heterocyclic radical；
R3Selected from substituted or unsubstituted aryl, heterocyclic radical；Work as R3During for substituted aryl, heterocyclic radical, on aryl, heterocyclic radical Substituted radical is selected from halogen, C1-6Alkyl, halo C1-6Alkyl, C1-6Alkoxy, halo C1-6Alkoxy, hydroxyl, cyano group, amino, One or more in acyl group, sulfo group, heterocyclic radical；
R4Selected from hydrogen, C1-6Alkyl, halo C1-6Alkyl, C1-6Alkoxy, halo C1-6Alkoxy, C3-6One kind in cycloalkyl；
Described heterocyclic radical is to contain the heteroatomic 3-12 circle heterocycles of one or more N, O, S.
3. the WNT pathway inhibitors of embedded ureas structure according to claim 2, it is characterised in that：Described structure is led to In formula (2),It is selected fromIn one Kind；
X, Y, Z are each independently selected from CR4, one kind in N atoms；
N is selected from 1 or 2；
R1、R2For hydrogen, halogen, C1-6Alkyl, C1-6Alkoxy, halo C1-6 alkyl, halo C1-6 alkoxies, amide groups, C1-6Alkane One kind in base amide groups, heterocyclic radical；
R3For In one kind；
R4Selected from hydrogen, C1-6Alkyl, halo C1-6Alkyl, C1-6Alkoxy, halo C1-6One kind in alkoxy；
R5Selected from hydrogen, halogen, C1-6Alkyl, halo C1-6Alkyl, C1-6Alkoxy, halo C1-6One kind in alkoxy, amide groups；
Described heterocyclic radical is selected from containing the heteroatomic 3-6 circle heterocycles of one or more N, O, S.
4. the WNT pathway inhibitors of embedded ureas structure according to claim 2, for the chemical combination with following general structure Thing and its pharmaceutically acceptable salt：
Wherein, any one in X, Y, Z is N atoms, then another is CR4；It is or any two is N atoms in X, Y, Z, then another Individual is CR4；
N is selected from 1 or 2；
R1、R2For hydrogen, halogen, C1-6Alkyl, C1-6Alkoxy, halo C1-6 alkyl, halo C1-6 alkoxies, amide groups, C1-6Alkane One kind in base amide groups, heterocyclic radical；
R3For In one kind；
R4Selected from hydrogen, C1-6Alkyl, halo C1-6Alkyl, C1-6Alkoxy, halo C1-6One kind in alkoxy；
R5Ground is selected from hydrogen, halogen, C1-6Alkyl, halo C1-6Alkyl, C1-6Alkoxy, halo C1-6One or more in alkoxy；
Described heterocyclic radical is selected from containing the heteroatomic 3-6 circle heterocycles of one or more N, O, S.
5. the WNT pathway inhibitors of the embedded ureas structure according to any one of Claims 1 to 4, it is characterised in that：It is described Aryl be phenyl, naphthyl or anthryl；Described heterocyclic radical is morpholinyl, piperidyl, pyridine radicals, pyrimidine radicals, pyranose, thiophene Base, furyl, pyrrole radicals, pyrazolyl, imidazole radicals or thiazolyl；Halogen is one kind in fluorine, chlorine, bromine, iodine.
6. a kind of WNT pathway inhibitors of embedded ureas structure, selected from following characteristic compounds：
N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -1 hydrogen of -4- phenyl-pyrazoles -1- acid amides；
N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (pyridine -2- bases) -1- hydrogen-pyrazoles -1- acid amides；
N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- phenyl -1- hydrogen -1,2,3- triazole -1- acid amides；
N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -3- phenyl -1- hydrogen-pyrazoles -1- acid amides；
N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (3- fluorophenyls) -1- hydrogen-pyrazoles -1- acid amides；
4- (3- chlorphenyls)-N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -1- hydrogen-pyrazoles -1- acid amides；
N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -3- methyl 4-phenyls -1- hydrogen-pyrazoles -1- acid amides；
N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -5- methyl 4-phenyls -1- hydrogen-pyrazoles -1- acid amides；
4- (2- chlorphenyls)-N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -1- hydrogen-pyrazoles -1- acid amides；
4- (4- chlorphenyls)-N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -1- hydrogen-pyrazoles -1- acid amides；
N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (pyrazine -2- bases) -1- hydrogen-pyrazoles -1- acid amides；
N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (2- fluorophenyls) -1- hydrogen-pyrazoles -1- acid amides；
N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (4- fluorophenyls) -1- hydrogen-pyrazoles -1- acid amides；
N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (pyridin-3-yl) -1- hydrogen-pyrazoles -1- acid amides；
N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (pyridin-4-yl) -1- hydrogen-pyrazoles -1- acid amides；
N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (3- fluorine pyridine -2- bases) -1- hydrogen-pyrazoles -1- acyls Amine；
N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (5- fluorine pyridine -2- bases) -1- hydrogen-pyrazoles -1- acyls Amine；
N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (3- fluorine pyridin-4-yl) -1- hydrogen-pyrazoles -1- acyls Amine；
N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -5 methyl -4- (pyridine -2- bases) -1- hydrogen-pyrazoles -1- Acid amides；
N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (6- picoline -2- bases) -1- hydrogen-pyrazoles -1- Acid amides；
N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (5- picoline -3- bases) -1- hydrogen-pyrazoles -1- Acid amides；
N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (2- picoline -4- bases) -1- hydrogen-pyrazoles -1- Acid amides；
N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (3- cyano-phenyls) -1- hydrogen-pyrazoles -1- acid amides；
N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (pyrimidine -5- bases) -1- hydrogen-pyrazoles -1- acid amides；
N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (pyrimidine -2-base) -1- hydrogen-pyrazoles -1- acid amides；
N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (pyridazine -3- bases) -1- hydrogen-pyrazoles -1- acid amides；
N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- (pyrimidine-4-yl) -1- hydrogen-pyrazoles -1- acid amides；
4- (4- acetylpiperazine -1- bases)-N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -1- hydrogen-pyrazoles -1- Acid amides；；
N- ((2', 3- dimethyl-[2,4'- bipyridyls] -5- bases) methyl) -4- morpholinyls -1- hydrogen-pyrazoles -1- acid amides.
7. a kind of pharmaceutical composition, activity is used as comprising compound such as defined in claim 1 or its pharmaceutically acceptable salt Composition, and one or more pharmaceutically acceptable carriers.
8. it is a kind of if compound defined in claim 1 or its pharmaceutically acceptable salt are being prepared antagonism Wnt signal paths Application in medicine.
9. purposes as claimed in claim 8, it is characterised in that：For treating the cell related to abnormal Wnt signals activity Proliferative diseases, disease of digestive system.
10. application as claimed in claim 9, it is characterised in that：For treating cancer, including non-small cell lung cancer, a denaturation Large celllymphoma, inflammatory myofibroblastic tumor, nasopharyngeal carcinoma, breast cancer, colorectal cancer, Diffuse Large B-Cell Lymphoma, liver Cancer, stomach cancer, cancer of the esophagus, cancer of pancreas, oophoroma, body tissue's cellular proliferative disorder and neuroblastoma.
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