WO2017097215A1 - Wnt pathway inhibitor embedded with ureas structure - Google Patents

Abstract

Disclosed in the present invention is a Wnt pathway inhibitor embedded with a ureas structure, belonging to compounds that regulate the activities of a Wnt signaling pathway, and a method for preparing such compounds and use of such compounds in preparing drugs for antagonizing the Wnt signaling pathway are provided. The Wnt pathway inhibitor embedded with a ureas structure provided in the present invention has remarkable anti-tumor activities on the basis of the rational drug design for targets, and can be used in developing a new generation of Wnt pathway inhibitor, having a high clinical application value and a considerable market potential.

Description

WNT pathway inhibitor with embedded urea structure Technical field

The present invention relates to a WNT pathway inhibitor embedded with a urea structure, 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. Applications.

Background technique

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/β-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.).

It has been reported that the activation of typical Wnt/β-catenin signaling pathway β-catenin-TCF/LCF transcription complexes is involved in the pathogenesis of neurological diseases, inflammatory fibrotic diseases, metabolic diseases and various types of cancers. Disorders (Kahn, M. (2014). Can we safely target the Wnt pathway? Nature reviews. Nat. Rev. Drug. Discovery, 13(7), 513-532.). In the field of cancer research, 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.). However, these patients currently have no targeted Wnt signaling pathway small molecule targeted drug therapy, non-selective cytotoxic agents and their combination therapy to bring about gastrointestinal reactions, bone marrow hematopoietic inhibition, etc. Adverse reactions seriously affect the quality of life of patients. Currently, drug candidates entering the clinical trial phase are still in the clinical phase I/II phase of safety and conceptual validation, for example, LGK974 (ClinicalTrials.gov Identifier: NCT01351103, designed for the upstream target of the Wnt signaling pathway PORCN) The patent publication number is wo2010101849), ETC-1922159 (ClinicalTrials.gov Identifier: NCT02521844, the compound patent publication number is wo2014189466); PRI-724 designed for the downstream target of the Wnt signaling pathway CBP/β-catenin (ClinicalTrials.gov Identifier: NCT02413853).

In view of this, continue to develop drugs that can regulate Wnt signaling pathway, and find a compound with clear mechanism of action and significant drug effect, which has important clinical and social significance.

Summary of the invention

The object of the present invention is to provide a novel WNT pathway inhibitor, which synthesizes and screens a series of compounds having antitumor activity through substitution modification of a group.

In order to achieve the above object, the present invention adopts the following technical solutions:

A WNT pathway inhibitor embedding a urea structure, which is a compound having the following structural formula: and a pharmaceutically acceptable salt thereof:

Wherein 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 one of CR ₄ and N atoms. 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 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, hydroxy, amino, cyano, acyl, sulfo, aryl, hetero One or more of the cyclic groups; R _{3 is} selected from a substituted or unsubstituted aryl group, a heterocyclic group; when R ₃ is a substituted aryl group, a heterocyclic group, an aryl group, a substituent on a heterocyclic group The group is selected from the group consisting of halogen, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, hydroxy, cyano, amino, acyl, sulfo Or one or more of the heterocyclic groups; R _{4 is} selected from the group consisting of hydrogen, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy One of a C _3-6 cycloalkyl group; a heterocyclic group is a 3-12 membered heterocyclic ring containing one or more N, O, S heteroatoms.

Preferably, it is a compound having the following structural formula: and a pharmaceutically acceptable salt thereof:

Wherein ring B is selected from an aromatic ring or an aromatic heterocyclic ring containing 1-2 N atoms or O atoms; X, Y, Z are each independently selected from one of CR ₄ and N atoms; n is selected from 1 to 1 Any integer value of 2; R ₁ and R ₂ are each independently selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, C _3-6 cycloalkyl, halo C _1-6 alkyl, C _1-6 One or more of an alkoxy group, a halogenated C _1-6 alkoxy group, a hydroxyl group, an amino group, an acyl group, an aryl group, a heterocyclic group; and R _{3 is} selected from a substituted or unsubstituted aryl group, a heterocyclic group; When R ₃ is a substituted aryl or heterocyclic group, 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 alkane One or more of an oxy group, a halogenated C _1-6 alkoxy group, a hydroxyl group, a cyano group, an amino group, an acyl group, a sulfo group or a heterocyclic group; and R _{4 is} selected from the group consisting of hydrogen, C _1-6 alkyl, and halogen. a C _1-6 alkyl group, a C _1-6 alkoxy group, a halogenated C _1-6 alkoxy group, or a C _3-6 cycloalkyl group; the heterocyclic group is one or more N, O 3-12-membered heterocyclic ring of S hetero atom.

More preferably, in the structural formula (2),

Selected from

One of X; Y, Z is independently selected from one of CR ₄ and N atoms; n is selected from 1 or 2; R ₁ and R ₂ are hydrogen, halogen, C _1-6 alkyl, C _{a 1-6} alkoxy group, a halogenated C1-6 alkyl group, a halogenated C1-6 alkoxy group, an amide group, a C _1-6 alkyl amide group, or a heterocyclic group; R ₃ is

One of R _{4 is} selected from the group consisting of hydrogen, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy; R ₅ selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, amide; heterocycle The group is selected from a 3-6 membered heterocyclic ring containing one or more N, O, S heteroatoms.

Preferably, it is a compound having the following structural formula: and a pharmaceutically acceptable salt thereof:

Wherein, any one of X, Y, and Z is an N atom, and the other is CR ₄ ; or any two of X, Y, and Z are N atoms, and the other is CR ₄ ; n is selected from 1 or 2; 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 One of an amide group and a heterocyclic group; R ₃ is

One of R _{4 is} selected from the group consisting of hydrogen, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy; R ₅ is selected from one or more of hydrogen, halogen, C _1-6 alkyl, halogenated C _{1 - 6} alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy; The ring group is a 3-6 membered heterocyclic ring selected from one or more N, O, S heteroatoms.

Preferably, the aryl group is phenyl, naphthyl or anthracenyl; the heterocyclic group is morpholinyl, piperidinyl, pyridyl, pyrimidinyl, pyranyl, thienyl, furyl, pyrrolyl, pyrazolyl, Imidazolyl or thiazolyl; halogen is one of fluorine, chlorine, bromine, and iodine.

A WNT pathway inhibitor embedding a urea structure selected from the following characteristic compounds numbered REX-N-1 to REX-N-29:

REX-N-1: N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-phenyl-1hydro-pyrazole-1- Amide

REX-N-2: N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(pyridin-2-yl)-1-hydrogen -pyrazole-1-amide;

REX-N-3: N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-phenyl-1-hydro-1,2, 3-triazole-1-amide;

REX-N-4: N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-3-phenyl-1-hydro-pyrazole-1 - amide;

REX-N-5: N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(3-fluorophenyl)-1-hydrogen -pyrazole-1-amide;

REX-N-6: 4-(3-Chlorophenyl)-N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-1-hydrogen -pyrazole-1-amide;

REX-N-7: N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-3-methyl-4-phenyl-1-hydrol -pyrazole-1-amide;

REX-N-8: N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-5-methyl-4-phenyl-1-hydrol -pyrazole-1-amide;

REX-N-9: 4-(2-chlorophenyl)-N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-1-hydrogen -pyrazole-1-amide;

REX-N-10: 4-(4-chlorophenyl)-N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-1-hydrogen -pyrazole-1-amide;

REX-N-11: N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(pyrazin-2-yl)-1- Hydrogen-pyrazole-1-amide;

REX-N-12: N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(2-fluorophenyl)-1-hydrogen -pyrazole-1-amide;

REX-N-13: N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(4-fluorophenyl)-1-hydrogen -pyrazole-1-amide;

REX-N-14: N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(pyridin-3-yl)-1-hydrogen -pyrazole-1-amide;

REX-N-15: N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(pyridin-4-yl)-1-hydrogen -pyrazole-1-amide;

REX-N-16: N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(3-fluoropyridin-2-yl)- 1-hydro-pyrazole-1-amide;

REX-N-17: N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(5-fluoropyridin-2-yl)- 1-hydro-pyrazole-1-amide;

REX-N-18: N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(3-fluoropyridin-4-yl)- 1-hydro-pyrazole-1-amide;

REX-N-19: N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-5-methyl-4-(pyridin-2-yl) 1-hydrogen-pyrazole-1-amide;

REX-N-20: N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(6-methylpyridin-2-yl) 1-hydrogen-pyrazole-1-amide;

REX-N-21: N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(5-methylpyridin-3-yl) 1-hydrogen-pyrazole-1-amide;

REX-N-22: N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(2-methylpyridin-4-yl) 1-hydrogen-pyrazole-1-amide;

REX-N-23: N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(3-cyanophenyl)-1- Hydrogen-pyrazole-1-amide;

REX-N-24: N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(pyrimidin-5-yl)-1-hydrogen -pyrazole-1-amide;

REX-N-25: N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(pyrimidin-2-yl)-1-hydrogen -pyrazole-1-amide;

REX-N-26: N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(pyridazin-3-yl)-1- Hydrogen-pyrazole-1-amide;

REX-N-27: N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(pyrimidin-4-yl)-1-hydrogen -pyrazole-1-amide;

REX-N-28: 4-(4-Acetylpiperazin-1-yl)-N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl) 1-hydro-pyrazole-1-amide;

REX-N-29: N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-morpholinyl-1-hydro-pyrazole- 1-amide;

The above-mentioned characteristic compounds are numbered REX-N-1 to REX-N-29, and the specific structure is as follows:

"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. For example, isotopes of hydrogen include deuterium and tritium.

For compounds containing the foregoing general structure, the terms used herein have the following meanings:

The term "halogen" means fluoro, chloro, bromo or iodo, preferably fluoro, chloro or bromo.

The term "cyano" refers to -CN.

The term "hydroxy" refers to -OH.

The term "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), Is n-hexyl, 2-methylhexyl and the like. 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.

The term "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.

The term "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.

The term "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 π-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. Examples of 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 term "embedded urea" refers to a specific structure formed by the insertion of a certain nitrogen atom of urea into a ring conjugated to a carbonyl group, including but not limited to the following forms:

The present invention also provides 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 delivery of the drug to the organism.

The term "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, and glues. Capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols, and the like.

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.

For oral administration, the pharmaceutical composition can be formulated by admixing the active compound with apharmaceutically acceptable carrier which is well known in the art. These carriers enable the compounds of the present invention to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient. For example, 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.

Preferably, the pharmaceutical use is for the treatment of cell proliferative diseases, digestive diseases associated with abnormal Wnt signaling activity.

Preferably, 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.

In the present invention, the inventors have determined the inhibitory activity of the Wnt pathway STF reporter gene at a molecular level by synthesizing a series of in-situ urea structure-like WNT pathway inhibitors, and found that some compounds have significant inhibitory activity against the Wnt pathway; A zebrafish phenotypic screening experiment was also carried out. It was found that the anti-tumor activity of some compounds in vivo was remarkable by the zebrafish tail-scission regeneration inhibition test and the body axis development inhibition test.

Compared with the prior art, the present invention provides an embedded urea structure-like WNT pathway inhibitor, based on a rational drug design of a target, and obtains a series of novel compounds by substitution modification of the group; and combined with the STF report Genetic 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.

DRAWINGS

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)

Figure 5 is a graph showing the growth of tumor volume in each treatment group and control group of colon cancer PDX model CR3150.

Figure 6 is a graph showing the changes in body weight in the CR3150 model.

Detailed ways

The following is a specific embodiment of the present invention, and the technical solutions of the present invention are further described, but the scope of the present invention is not limited to the embodiments. Changes or equivalents that do not depart from the inventive concept are intended to be included within the scope of the invention.

In the preparation method of the target compound provided by the present invention, 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 μm, 35 ° C) using ESI (+) ion mode .

In addition, all operations involving materials that are susceptible to oxidation or hydrolysis are carried out under nitrogen. Unless otherwise stated, the starting materials used in the present invention are commercially available starting materials and can be used directly without further purification.

Example 1. N-((2',3-Dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-phenyl-1hydro-pyrazole-1-amide [ Preparation number REX-N-1]

The synthetic route is as follows:

Synthesis scheme 1: Synthesis of intermediate REX-N-INT-1

Step 1: Preparation of Compound 1-2

Compound 1-1 (5.0 g, 24.2 mmol) was dissolved in 200 ml of dry tetrahydrofuran solution, and isopropylmagnesium chloride (12.7 ml, 25.5 mmol) was added dropwise in an ice water bath, and stirred at room temperature for 1 hour to give N-formyl group. The porphyrin (2.5 ml, 24.2 mmol) was dissolved in 50 ml of dry tetrahydrofuran solution, and added dropwise to the reaction system at room temperature for another hour. After the reaction was completed, the reaction was quenched by the addition of ice water, and extracted with ethyl acetate. The mixture was dried over sodium sulfate (MgSO4).

MS m/z [ESI]: 156.0 [M + 1].

Step 2: Preparation of Compound 1-3

Compound 1-2 (3.0 g, 19.4 mmol) and 2-methyl-4-pyridine boronic acid (3.2 g, 23.2 mmol) were dissolved in 200 ml of N,N-dimethylformamide under nitrogen atmosphere. Potassium carbonate (10.7 g, 77.6 mmol) and tetrakistriphenylphosphine palladium (1.1 g, 1.0 mmol) were added to the system, and the mixture was stirred overnight at 100 ° C. After the reaction was completed, 200 ml of ice water was added to the system, and the mixture was extracted with ethyl acetate. The mixture was washed with saturated brine and dried over anhydrous sodium sulfate.

MS m/z [ESI]: 213.1 [M + 1].

Step 3: Preparation of Compound 1-4

Compound 1-3 (1.8 g, 8.5 mmol) was dissolved in 50 ml of absolute ethanol, and hydroxylamine hydrochloride (1.2 g, 17.0 mmol) and sodium acetate (1.4 g, 17.0 mmol) were added to the system, and the mixture was stirred at room temperature for 2 hours. After the completion of the reaction, 50 ml of ice water was added to the mixture, and the mixture was evaporated. EtOAcjjjjjjjjj

MS m/z [ESI]: 228.1 [M + 1].

Step 4: Preparation of Compound REX-N-INT-1

Compound 1-4 (1.8 g, 7.9 mmol) was dissolved in 30 ml of absolute ethanol solution, and 10% palladium carbon (200 mg) and hydrochloric acid (1.5 ml, 12.0 N) were respectively added to react under a hydrogen atmosphere at room temperature overnight. After completion of the reaction, the mixture was filtered, concentrated, and purified using silica gel column to afford compound REX-N-INT-1 (1.4 g, 85.2%).

MS m / z [ESI]: 214.1 [M + 1].

Synthesis scheme 2: Synthesis of compound REX-N-1

Step 1: Preparation of intermediate REX-N-INT-2

Compound 2-1 (5.0 g, 34.0 mmol), triethylamine (14.1 ml, 102.0 mmol) was dissolved in 100 ml of dry dichloromethane, p-toluenesulfonyl chloride (6.5 g, 34.0 mmol) was dissolved in 50 ml dried Dichloromethane was added dropwise to the system, and the mixture was stirred at room temperature for 2 hours. At the end of the reaction, 200 ml of ice water was added to the system, which was extracted with ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate. The compound REX-N-INT-2 (10.0 g, 97.6%) was obtained.

MS m / z [ESI]: 303.0 [M + 1].

Step 2: Preparation of Compound 2-3

Compound REX-N-INT-2 (10.0 g, 33.2 mmol), phenylboronic acid (6.1 g, 49.8 mmol), potassium carbonate (13.7 g, 99.6 mmol), tetrakistriphenylphosphine palladium (1.8 g, 0.2 mmol) Dissolved in a mixed solvent of 120 ml of ethylene glycol dimethyl ether and 24 ml of water, and the reaction system was stirred under nitrogen atmosphere at 90 ° C overnight. After the reaction was completed, 200 ml of ice water was added to the system to quench the reaction, and extracted with ethyl acetate. The mixture was washed with saturated brine and dried over anhydrous sodium sulfate.

MS m / z [ESI]: 145.1 [M + 1].

Step 3: Preparation of Compound REX-N-1

Compound 2-3 (3.2 g, 22.3 mmol), bis(trichloromethyl)carbonate (7.9 g, 26.8 mmol), N,N-diisopropylethylamine (7.3 ml, 44.6 mmol) were dissolved in The compound REX-N-INT-1 (4.8 g, 22.3 mmol) and N,N-diisopropylethylamine (7.3 ml, 44.6 mmol) were dissolved in 50 ml of dry dichloromethane at room temperature for 30 minutes. 30 ml of dry methylene chloride was added dropwise to the reaction system, and the mixture was stirred at room temperature for half an hour. After the reaction was completed, 200 ml of ice water was added to the system, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. Purification by silica gel column gave Compound REX-N-1 (2.5 g, 29.0%).

MS m / z [ESI]: 384.2 [M + 1].

^{1 H-NMR (400MHz, DMSO} -d 6): 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 = 6.0 Hz, 2H), 2.53 (s, 3H), 2.33 (s, 3H).

Example 2, 4-(2-chlorophenyl)-N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-1-hydro-pyridyl Preparation of oxazol-1-amide [No. REX-N-9]

The synthetic route is as follows:

Preparation of intermediate REX-N-INT-2:

Referring to the preparation method of Example 1, an intermediate REX-N-INT-2 (1.0 g) was obtained.

Step 1: Preparation of Compound 1-2

Compound REX-N-INT-2 (1.0 g, 3.3 mmol), o-chlorobenzeneboronic acid (0.8 g, 5.0 mmol), potassium carbonate (1.4 g, 9.9 mmol), tetratriphenylphosphine palladium (180.0 mg, respectively). 0.02 mmol) dissolved in 20 ml of ethylene glycol dimethyl ether and 4 In a mixed solvent of ml of water, the reaction system was stirred under a nitrogen atmosphere at 90 ° C overnight. After the reaction was completed, 50 ml of ice water was added to the system to quench the reaction, which was extracted with ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, it was purified with a silica gel column to afford Compound 1-2 (379.5mg, 64.6%).

MS m/z [ESI]: 179.0 [M + 1].

Step 2: Preparation of Compound REX-N-9

Referring to the preparation method of Example 1, the intermediate REX-P-INT-1 (452.0 mg) was prepared.

Compound 1-2 (379.5 mg, 2.1 mmol), bis(trichloromethyl)carbonate (742.8 mg, 2.5 mmol), and N,N-diisopropylethylamine (0.7 ml, 4.2 mmol) were dissolved in The compound REX-N-INT-1 (452.0 mg, 2.1 mmol) and N,N-diisopropylethylamine (0.7 ml, 4.2 mmol) were dissolved in 20 ml of dry dichloromethane at room temperature for 30 minutes. 10 ml of dry methylene chloride was added dropwise to the reaction system, and the mixture was stirred at room temperature for half an hour. At the end of the reaction, 50 ml of ice water was added to the system, and the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and evaporated. Purification by silica gel column gave compound REX-N-9 (373.1 mg, 42.6%).

MS m/z [ESI]: 418.1 [M + 1].

¹ H-NMR (400 MHz, CDCl ₃ ) δ = 8.58 (d, J = 18.4 Hz, 3H), 7.92 (s, 1H), 7.68 (s, 2H), 7.53 - 7.35 (m, 5H), 7.30 (d) , J = 7.1 Hz, 1H), 4.69 (d, J = 6.1 Hz, 2H), 2.75 (s, 3H), 2.40 (s, 3H).

Example 3, 4-(4-chlorophenyl)-N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-1-hydro-pyridyl Preparation of oxazol-1-amide [No. REX-N-10]

The synthetic route is as follows:

The preparation method of the third embodiment is referred to the second embodiment, wherein the o-chlorobenzene boronic acid in the first step is replaced by p-chlorobenzene boronic acid, and the other preparation methods are the same as those in the second embodiment, and finally the compound REX-N-10 (545.4 mg, 52.3%) is obtained. ).

MS m/z [ESI]: 418.1 [M + 1].

¹ H-NMR (400 MHz, CDCl ₃ ) δ = 8.63 - 8.52 (m, 2H), 8.45 (d, J = 11.9 Hz, 1H), 7.85 (s, 1H), 7.69 - 7.58 (m, 2H), 7.43 (dd, J = 15.5, 7.1 Hz, 4H), 7.35 (d, J = 8.3 Hz, 2H), 4.68 (d, J = 6.2 Hz, 2H), 2.74 (s, 3H), 2.39 (s, 3H) .

Example 4, N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(3-fluorophenyl)-1-hydro-pyridyl Preparation of oxazol-1-amide [No. REX-N-5]

The preparation method of the fourth embodiment is as follows. In the second embodiment, the o-chlorobenzene boronic acid in the first step is replaced by m-fluorophenylboronic acid, and the other preparation method is the same as that in the second embodiment. Finally, the compound REX-N-5 (456.1 mg, 44.7%) is obtained. ).

MS m / z [ESI]: 402.2 [M + 1].

¹ H-NMR (400 MHz, CDCl ₃ ) δ = 8.86 (t, J = 3.2 Hz, 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 = 1.6 Hz, 1H), 4.74 (d, J = 6.4 Hz, 2H), 2.91 (s, 3H), 2.47 (s, 3H) .

Example 5, 4-(3-chlorophenyl)-N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-1-hydro-pyridyl Preparation of oxazol-1-amide [No. REX-N-6]

The preparation method of the fifth embodiment is as follows. In the second embodiment, the o-chlorobenzeneboronic acid of the step one is replaced by m-chlorobenzeneboronic acid, and the other methods are the same, and finally the compound REX-N-6 (502.6 mg, 48.2%) is obtained.

MS m/z [ESI]: 418.1 [M + 1].

¹ H-NMR (400 MHz, CDCl ₃ ) δ = 8.66 (s, 1H), 8.50 (s, 1H), 7.91 (s, 1H), 7.82 - 7.72 (m, 4H), 7.52 (t, J = 1.6 Hz) , 1H), 7.42 - 7.28 (m, 4H), 4.73 (d, J = 6.4 Hz, 2H), 2.92 (s, 3H), 2.48 (s, 3H).

Example 6. N-((2',3-Dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(pyrazin-2-yl)-1-hydro- Preparation of pyrazole-1-amide [No. REX-N-11]

The preparation method of the sixth embodiment is as follows. In the second embodiment, the o-chlorobenzeneboronic acid of the step one is replaced by 2-pyrazineboronic acid, and the other methods are the same, and finally the compound REX-N-11 (531.7 mg, 55.2%) is obtained.

MS m/z [ESI]: 386.2 [M + 1].

¹ H-NMR (400 MHz, CDCl ₃ ) δ = 9.39 (t, J = 1.6 Hz, 1H), 9.19 (d, J = 1.6 Hz, 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 = 1.6 Hz, 1H), 7.40 (s, 1H), 7.34 (dd, J = 4.8, 1.2 Hz, 1H) , 4.53 (d, J = 6.0 Hz, 2H), 2.53 (s, 3H), 2.33 (s, 3H).

Example 7. N-((2',3-Dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(pyridin-2-yl)-1-hydro-pyridyl Preparation of oxazol-1-amide [No. REX-N-2]

Step 1: Preparation of Compound 1-2

Compound REX-N-INT-3 (2.46 g, 12.66 mmol), o-bromopyridine (2 g, 12.66 mmol), potassium carbonate (3.50 g, 25.32 mmol), tetratriphenylphosphine palladium (0.88 g, 0.759 mmol) Dissolved in a mixed solvent of 20 ml of ethylene glycol dimethyl ether and 4 ml of water, and the reaction system was stirred under nitrogen atmosphere at 90 ° C overnight. After the reaction was completed, 50 ml of ice water was added to the system to quench the reaction, and extracted with ethyl acetate. The mixture was washed with saturated brine and dried over anhydrous sodium sulfate.

MS m/z [ESI]: 146.0 [M + 1].

Step 2: Preparation of Compound REX-N-2

Referring to the preparation method of Example 1, the intermediate REX-N-INT-1 (1.0 g) was obtained.

Compound 1-2 (300 mg, 2.07 mmol), bis(trichloromethyl)carbonate (417 mg, 2.07 mmol), N,N-diisopropylethylamine (267 mg, 0.34 ml, 2.07 mmol) were dissolved in The compound REX-N-INT-1 (441 mg, 2.07 mmol) and N,N-diisopropylethylamine (801 mg, 1.00 ml, 6.20 mmol) were dissolved in 20 ml of dry dichloromethane at room temperature for 30 minutes. 10 ml of dry methylene chloride was added dropwise to the reaction system, and the mixture was stirred at room temperature for half an hour. After the reaction was completed, 50 ml of ice water was added to the system, and the mixture was extracted with ethyl acetate. Purification by silica gel column gave Compound REX-N-2 (50 mg, 6.3%).

MS m / z [ESI]: 385.1 [M + 1]. ¹ H-NMR ((400 MHz, DMSO-d ₆ ), δ = 9.33 (t, J = 6 Hz, 1H), 8.89 (d, J = 0.4 Hz, 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).

Example VIII, N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(2-fluorophenyl)-1-hydro-pyridyl Preparation of oxazol-1-amide [No. REX-N-12]

The preparation method of the eighth embodiment is as follows. In the second embodiment, the o-chlorobenzeneboronic acid of the step one is replaced by 2-fluorobenzeneboronic acid, and the other methods are the same, and finally the compound REX-N-12 (50 mg, 13.2%) is obtained.

MS m / z [ESI]: 402.2 [M + 1].

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ = 9.38 (t, J = 1.6 Hz, 1H), 8.68 (d, J = 1.6 Hz, 1H), 8.52 - 8.53 (m, 2H), 8.33 (s) , 1H), 7.91 (t, J = 1.6 Hz, 1H), 7.74 (m, 1H), 7.42 (s, 1H), 7.25 - 7.36 (m, 4H), 4.53 (d, J = 6.0 Hz, 2H) , 2.58 (s, 3H), 2.34 (s, 3H).

Example N, N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(4-fluorophenyl)-1-hydro-pyridyl Preparation of oxazol-1-amide [No. REX-N-13]

The preparation method of the ninth embodiment is as follows. In the second embodiment, the o-chlorobenzeneboronic acid of the step one is replaced by 4-fluorobenzeneboronic acid, and the other methods are the same, and finally the compound REX-N-13 (60 mg, 15.2%) is obtained.

MS m / z [ESI]: 402.2 [M + 1].

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ = 9.30 (t, J = 1.6 Hz, 1H), 8.81 (d, J = 1.6 Hz, 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), 7.23–7.26 (m, 1H), 4.52 (d, J) =6.0 Hz, 2H), 2.58 (s, 3H), 2.34 (s, 3H).

Example X, N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(pyridin-3-yl)-1-hydro-pyridyl Preparation of oxazol-1-amide [No. REX-N-14]

The preparation method of the tenth embodiment is as follows. In the seventh embodiment, the one-step bromopyridine is replaced by m-bromopyridine, and the other methods are the same, and finally the compound REX-N-14 (40 mg, 10.2%) is obtained.

MS m / z [ESI]: 385.1 [M + 1].

¹ H-NMR ((400 MHz, DMSO-d ₆ ), δ = 9.33 (t, J = 6 Hz, 1H), 8.89 (d, J = 0.4 Hz, 1H), 8.50 - 8.58 (m, 3H), 8.39 ( d, J = 0.8 Hz, 1H), 7.87 - 7.91 (m, 1H), 7.79 - 7.84 (m, 1H), 7.73 (d, J = 1.6 Hz, 1H), 7.40 (s, 1H), 7.32 - 7.36 (m, 1H), 7.25–7.29 (m, 1H), 4.52 (d, J=6 Hz, 2H), 2.53 (s, 3H), 2.33 (s, 3H).

Example XI, N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(pyridin-4-yl)-1-hydro- Preparation of pyrazole-1-amide [No. REX-N-15]

The preparation method of the eleventh embodiment is referred to the seventh embodiment, wherein one of the steps of the o-bromopyridine is replaced by p-bromopyridine, and the other methods are the same, and finally the compound REX-N-15 (50 mg, 12.2%) is obtained.

MS m / z [ESI]: 385.1 [M + 1].

¹ H-NMR ((400 MHz, CDCl ₃ ), δ = 8.63 (s, 1H), 8.55 - 8.58 (m, 3H), 8.41 (d, J = 0.8 Hz, 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=6 Hz, 2H), 2.62 (s, 3H) 2.37 (s, 3H).

Example XII, N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(3-fluoropyridin-2-yl)-1 -Preparation of hydrogen-pyrazole-1-amide [No. REX-N-16]

The preparation method of the twelfth embodiment is as follows. In the seventh embodiment, the o-bromopyridine of the step is replaced by 2-bromo-3-fluoro-pyridine, and the other methods are the same, and finally the compound REX-N-16 (30 mg, 8.5%) is obtained. .

MS m / z [ESI]: 403.1 [M + 1].

¹ H-NMR ((400 MHz, DMSO-d ₆ ), δ = 9.42 (t, J = 6 Hz, 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=6 Hz, 2H), 2.54 (s, 3H), 2.34 (s, 3H).

Example XIII, N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(5-fluoropyridin-2-yl)-1 -Preparation of hydrogen-pyrazole-1-amide [No. REX-N-17]

The preparation method of the thirteenth embodiment is referred to the seventh embodiment, wherein the one of the steps of the o-bromopyridine is replaced by 3-bromo-5fluoro-pyridine, and the other methods are the same, and finally the compound REX-N-17 (35 mg, 8.9%) is obtained. .

MS m / z [ESI]: 403.1 [M + 1].

¹ H-NMR ((400 MHz, CDCl ₃ ), δ = 8.63 (s, 1H), 8.55 - 8.58 (m, 3H), 8.41 (d, J = 0.8 Hz, 1H), 7.92 (s, 1H), 7. – 7.65 (m, 2H), 7.50–7.53 (m, 1H), 7.31 (s, 1H), 7.22–7.23 (m, 1H), 4.39 (d, J=6 Hz, 2H), 2.62 (s, 3H) , 2.37 (s, 3H).

Example XIV, N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(3-fluoropyridin-4-yl)-1 - Preparation of hydrogen-pyrazole-1-amide [No. REX-N-18]

The preparation method of the fourteenth embodiment is referred to the seventh embodiment, wherein the one of the steps of the o-bromopyridine is replaced by 3-fluoro-4-bromo-pyridine, and the other methods are the same, and finally the compound REX-N-18 (55 mg, 12.5%) is obtained. .

MS m / z [ESI]: 403.1 [M + 1].

¹ H-NMR ((400 MHz, CDCl ₃ ), δ = 8.77 (s, 1H), 8.55 - 8.61 (m, 3H), 8.46 (d, J = 0.8 Hz, 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 = 6 Hz, 2H), 2.64 (s, 3H), 2.39 (s, 3H).

Example X. N-((2',3-Dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-5-methyl-4-(pyridin-2-yl) Preparation of 1-hydrogen-pyrazole-1-amide [No. REX-N-19]

The preparation method of the fifteenth embodiment is referred to the seventh embodiment, wherein the intermediate REX-N-INT-3 of the step one is replaced by the intermediate REX-N-INT-4, and the other methods are the same, and finally the compound REX-N- is obtained. 19 (65 mg, 14.5%).

MS m/z [ESI]: 399.4 [M + 1].

¹ H-NMR ((400MHz, CDCl ₃ ), 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 = 6 Hz, 2H), 2.63 (s, 3H), 2.56 (s, 3H), 2.37 ( s, 3H).

Example X. N-((2',3-Dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(6-methylpyridin-2-yl)- Preparation of 1-hydro-pyrazole-1-amide [No. REX-N-20]

The preparation method of the sixteenth embodiment is referred to the seventh embodiment, wherein the step one of the o-bromopyridine is replaced by 2-bromo-6-methyl-pyridine, and the other methods are the same, and finally the compound REX-N-20 (50 mg, 11.5) is obtained. %).

MS m/z [ESI]: 399.4 [M + 1].

¹ H-NMR ((400 MHz, DMSO-d ₆ ), δ = 9.33 (t, J = 6 Hz, 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), 4.53 (d, J=6 Hz, 2H), 2.54 (s, 3H) ), 2.50 (s, 3H), 2.34 (s, 3H).

Example XVII, N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(5-methylpyridin-3-yl)- Preparation of 1-hydro-pyrazole-1-amide [No. REX-N-21]

The preparation method of the seventeenth embodiment is referred to the seventh embodiment, wherein the one of the steps of the o-bromopyridine is replaced by 3-bromo-5-methyl-pyridine, and the other methods are the same, and finally the compound REX-N-21 (10 mg, 10.5) is obtained. %).

MS m/z [ESI]: 399.4 [M + 1].

¹ H-NMR ((400MHz, CDCl ₃ ), 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=6 Hz, 2H), 2.63 (s, 3H), 2.39 (s, 3H) , 2.37 (s, 3H).

Example 18, N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(2-methylpyridin-4-yl)- Preparation of 1-hydro-pyrazole-1-amide [No. REX-N-22]

The preparation method of the eighteenth embodiment is referred to the seventh embodiment, wherein one step of the o-bromopyridine is replaced by 2-methyl-4-bromo-pyridine, and the other methods are the same, and finally the compound REX-N-22 (40 mg, 10.3) is obtained. %).

MS m/z [ESI]: 399.4 [M + 1].

¹ H-NMR ((400 MHz, DMSO-d ₆ ), δ = 9.33 (t, J = 6 Hz, 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), 4.53 (d, J=6 Hz, 2H), 2.54 (s, 3H) ), 2.50 (s, 3H), 2.34 (s, 3H).

Example 19 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(3-cyanophenyl)-1-hydrogen -Preparation of pyrazole-1-amide [No. REX-N-23]

The preparation method of the nineteenth embodiment is referred to the seventh embodiment, wherein the one of the steps of the o-bromopyridine is replaced by m-bromophenylacetonitrile, and the other methods are the same, and finally the compound REX-N-23 (100 mg, 20.3%) is obtained.

MS m/z [ESI]: 409.4 [M + 1].

¹ H-NMR ((400 MHz, CDCl ₃ ), δ = 8.56 - 8.60 (m, 3H), 8.27 (d, J = 0.8 Hz, 2H), 7.60 - 7.67 (m, 4H), 6.44 - 6.45 (m, 2H), 4.68 (d, J = 6 Hz, 2H), 2.64 (s, 3H), 2.37 (s, 3H).

Example Twenty-N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(pyrimidin-5-yl)-1-hydro- Preparation of pyrazole-1-amide [No. REX-N-24]

The preparation method of Example 20 is as follows. In the seventh embodiment, the one of the steps of the o-bromopyridine is replaced by 5-bromo-pyrimidineacetonitrile, and the other methods are the same, and finally the compound REX-N-24 (80 mg, 15.8%) is obtained.

MS m/z [ESI]: 386.1 [M + 1].

¹ H-NMR ((400 MHz, CDCl ₃ ), 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 = 6 Hz, 2H), 2.63 (s, 3H), 2.38 (s, 3H).

Example 21, N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(pyrimidin-2-yl)-1-hydrogen -Preparation of pyrazole-1-amide [No. REX-N-25]

The preparation method of the twenty-first embodiment is the same as in the seventh embodiment, wherein the one of the steps of the o-bromopyridine is replaced by 5-bromo-pyrimidine acetonitrile, and the other methods are the same, and finally the compound REX-N-25 (100 mg, 18.8%) is obtained.

MS m/z [ESI]: 386.1 [M + 1].

¹ H-NMR ((400 MHz, CDCl ₃ ), δ = 8.96 (s, 1H), 8.55 (d, J = 0.8 Hz, 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 = 6 Hz, 2H), 2.63 (s, 3H), 2.37 (s, 3H).

Example Twenty-two, N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(pyridazin-3-yl)-1- Preparation of hydrogen-pyrazole-1-amide [No. REX-N-26]

The preparation method of the twenty-second embodiment is referred to the seventh embodiment, wherein the one of the steps of the o-bromopyridine is replaced by 5-bromo-pyrimidine acetonitrile, and the other methods are the same, and finally the compound REX-N-26 (100 mg, 18.5%) is obtained.

MS m/z [ESI]: 386.1 [M + 1].

¹ H-NMR ((400 MHz, CDCl ₃ ), δ=9.11 (s, 1H), 8.58 (s, 1H), 8.58 (d, J = 0.8 Hz, 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=6 Hz, 2H), 2.63 (s, 3H), 2.38 (s) , 3H).

Example 23, 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. (2009). Genetic Interaction of PGE2 and Wnt Signaling Regulates Developmental Specification of Stem Cells and Regeneration. Cell, 136 (6 ): 1136-1147.). Wnt signaling pathway dysregulation is also closely related to cancer development. For example, 80% to 90% of colorectal cancers contain functional mutations affecting the Wnt signaling pathway gene Adenomatous Polyposis Coli (APC) (Hans Clevers, Roel Nusse. (2012). Wnt/ β-Catenin Signaling and Disease. Cell, 149(6): 1192-1205.).

Studies have shown that the phenotype of zebrafish in body axis development and regeneration is closely related to Wnt signaling pathway (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 the conservation of Wnt signaling pathways between different species and the zebrafish phenotypic screening, we investigated the effects of compounds on the development and regeneration of normal AB zebrafish to explore the anti-Wnt signal of compounds in vivo. The strength of the pathway activity.

Experiment (1) Compound for the inhibition of body type development of AB type zebrafish

METHODS: 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 μM to 0.001 μM 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. According to the inhibition rate of different concentrations of compounds on the development of body axis of each group of fish, 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.

RESULTS: The results of the determination of the activity of REX-N-1 and other compounds prepared in the examples of the present invention on the developmental inhibition of AB zebrafish are shown in Table 1. The development of body axis after treatment of AB type zebrafish with 48hpf by REX-N-1 The suppression state is shown in Fig. 1, and the dose-effect relationship (mean±sd) is shown in Fig. 2.

Activity of the compounds of Table 1 for the inhibition of body axis development of AB zebrafish

Compounds	IC 50 (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: IC ₅₀ is calculated for 50% inhibition concentration

Further, the present invention retests the zebrafish tail-splitting phenotype of the compounds in Table 1.

Experiment (2) Compounds on the inhibition of tail-type regeneration of AB zebrafish

The 3dpf (days post fertilization) type AB zebrafish juveniles were selected for shear tail fin modeling, and were randomly divided into groups of 10 μM to 0.001 μM 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. According to the inhibition rate of different concentrations of compounds on the caudal fin regeneration of each group of young fish, 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.

RESULTS: The results of the determination of the activity of REX-N-1 and other compounds prepared in the examples of the present invention on the inhibition of tail-type regeneration of AB-type zebrafish are shown in Table 2; REX-N-1 treatment of 3dpf-cutting model AB-type zebrafish The inhibition of tail fin regeneration to 7dpf is shown in Fig. 3, and the dose-effect relationship (mean±sd) is shown in Fig. 4.

Table 2 Determination of the activity of the compound of the example on the inhibition of tail-type regeneration of AB zebrafish

Compounds	IC 50 (μM)
LGK-974	0.462
REX-N-1	0.018
REX-N-5	0.044
REX-N-6	0.078
REX-N-2	0.397
REX-N-11	1.819
REX-N-9	0.061
REX-N-10	3.195
REX-N-7	0.317
REX-N-8	0.164
REX-N-12	0.053
REX-N-13	0.429
REX-N-14	3.94
REX-N-15	1.795
REX-N-16	1.631
REX-N-17	0.215
REX-N-18	12.382
REX-N-19	1.523
REX-N-20	0.489
REX-N-21	0.778
REX-N-22	>100

REX-N-23	1.984
REX-N-24	11.1
REX-N-25	3.8
REX-N-26	32.2

Example 24, Super-Top-Flash (STF) Reporter Gene Test

A series of compounds such as LGK-974 (control) and REX-N-1 (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-N-1 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.

Table 3 Determination of the activity of the compound of the example against the STnt reporter gene in the Wnt pathway

Compounds	IC 50 (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

Example 25, in vitro metabolic stability and PK experiment in vivo

The compound REX-N-1 prepared in the examples of the present invention was used to carry out 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 μL 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.

The specific experimental results are as follows. The results show that REX-N-1 has good bioavailability and half-life:

Table 4 Example of in vivo PK and in vitro metabolic stability test results

Example twenty-sixth, efficacy test in CR3150 nude mice xenografts

The patient colon tumor CR3150 was cut into 1640 diameter medium pieces into a subcutaneous diameter of 2-4 mm and inoculated into the nude mice, and passaged on nude mice after the tumor grew to 500-700 mm ³ . When the fourth-generation (P4) tumor grew to 500-700 mm ³ , the tumor was cut into 1640 diameter pieces in a 1640 culture medium for subcutaneous inoculation in experimental nude mice. Female mice were subcutaneously inoculated with tumor fragments on the right side. The tumor growth was observed regularly. When the tumor grew to an average volume of about 200 mm ³ , it was randomly divided into three groups according to the tumor size. The solvent, the positive control drug LGK974, and the compound of Example 1 REX-N-1 were administered separately for 5 days at 5 mg/kg and BID. Regular observations of tumor volume and body weight changes.

The tumor volume calculation formula is: long diameter × short diameter ² /2.

Relative tumor inhibition rate TGI (%): TGI% = (1-T/C) × 100%.

T/C% is the relative tumor growth rate, that is, the percentage of tumor volume or tumor weight relative to the treatment group and the control group at a certain time point. T and C are the relative tumor volume (RTV) or tumor weight (TW) of the treatment group and the control group at a specific time point, respectively.

Calculated as follows:

T/C%=T _RTV /C _RTV ×100% (T _RTV : treatment group mean RTV; C _RTV : vehicle control group mean RTV; RTV = V _t /V ₀ , V ₀ is the tumor volume of the animal at the time of grouping, V _t is the tumor volume of the animal after treatment). or,

T/C% = T _TW / C _TW × 100% (T _TW : mean tumor weight at the end of the treatment group; C _TW : mean tumor weight at the end of the vehicle control experiment).

The results are shown in Table 5, Figure 5 and Figure 6. The results showed that the solvent group, LGK974, and REX-N-1 were administered at 5 mg/kg, PO, and BID for 28 days, respectively, and the body weight change rates were 1.41% and -9.73%, respectively. And -8.28%. After 28 days of administration, LGK974 showed significant anti-tumor effect with a TGI of 102.62% and a T/C of 9.04% (P < 0.003); REX-N-1 also showed significant anti-tumor effect with a TGI of 99.52%. , T/C was 11.81% (P < 0.003).

In conclusion, in this CR3150 colon cancer PDX model, LGK974 and REX-N-1 were administered at a dose of 5 mg/kg for 28 days, and BID showed significant antitumor activity.

Antitumor efficacy of the compounds in Table 5 in the CR3150 model

Claims (10)

1. A WNT pathway inhibitor embedding a urea structure, which is a compound having the following structural formula: and a pharmaceutically acceptable salt thereof:

   

   Wherein 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;

   X, Y, and Z are each independently selected from one of CR ₄ and N atoms;

   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 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, halo C _{1 - 6} alkane. One or more of a group, a C _1-6 alkoxy group, a halogenated C _1-6 alkoxy group, a hydroxyl group, an amino group, a cyano group, an acyl group, a sulfo group, an aryl group, or a heterocyclic group;

   R _{3 is} selected from a substituted or unsubstituted aryl group, a heterocyclic group; when R ₃ is a substituted aryl group or a heterocyclic group, the substituent group on the aryl group or the heterocyclic group is selected from a halogen group, a C _1-6 alkane group. One or more of a group, a halogenated C _1-6 alkyl group, a C _1-6 alkoxy group, a halogenated C _1-6 alkoxy group, a hydroxyl group, a cyano group, an amino group, an acyl group, a sulfo group, a heterocyclic group Species

   R _{4 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, C _3-6 cycloalkyl Species

   The heterocyclic group is a 3-12 membered heterocyclic ring containing one or more N, O, S heteroatoms.
2. The WNT pathway inhibitor embedding the urea structure according to claim 1, which is a compound having the following structural formula: and a pharmaceutically acceptable salt thereof:

   

   Wherein ring B is selected from an aromatic ring or an aromatic heterocyclic ring containing 1-2 N atoms or O atoms;

   X, Y, and Z are each independently selected from one of CR ₄ and N atoms;

   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 cycloalkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _{1 One or more of -6} alkoxy, hydroxy, amino, acyl, aryl, heterocyclic;

   R _{3 is} selected from a substituted or unsubstituted aryl group, a heterocyclic group; when R ₃ is a substituted aryl group or a heterocyclic group, the substituent group on the aryl group or the heterocyclic group is selected from a halogen group, a C _1-6 alkane group. One or more of a group, a halogenated C _1-6 alkyl group, a C _1-6 alkoxy group, a halogenated C _1-6 alkoxy group, a hydroxyl group, a cyano group, an amino group, an acyl group, a sulfo group, a heterocyclic group Species

   R _{4 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, C _3-6 cycloalkyl Species

   The heterocyclic group is a 3-12 membered heterocyclic ring containing one or more N, O, S heteroatoms.
3. The WNT pathway inhibitor embedding the urea structure according to claim 2, wherein in the structural formula (2),

   

   Selected from

   

   

   One of them;

   X, Y, and Z are each independently selected from one of CR ₄ and N atoms;

   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 alkane One of an amide group and a heterocyclic group;

   R ₃ is

   

   

   One of them;

   R _{4 is} selected from the group consisting of hydrogen, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy;

   R _{5 is} selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, amide;

   The heterocyclic group is a 3-6 membered heterocyclic ring selected from one or more N, O, S heteroatoms.
4. The WNT pathway inhibitor embedding the urea structure according to claim 2, which is a compound having the following structural formula: and a pharmaceutically acceptable salt thereof:

   

   Wherein, any one of X, Y, and Z is an N atom, and the other is CR ₄ ; or any two of X, Y, and Z are N atoms, and the other is CR ₄ ;

   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 alkane One of an amide group and a heterocyclic group;

   R ₃ is

   

   

   One of them;

   R _{4 is} selected from the group consisting of hydrogen, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy;

   R ₅ is selected from one or more of hydrogen, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy;

   The heterocyclic group is a 3-6 membered heterocyclic ring selected from one or more N, O, S heteroatoms.
5. The WNT pathway inhibitor embedding a urea structure according to any one of claims 1 to 4, wherein the aryl group is a phenyl group, a naphthyl group or an anthracenyl group; Orolinyl, piperidinyl, pyridyl, pyrimidinyl, pyranyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl or thiazolyl; halogen is one of fluorine, chlorine, bromine and iodine.
6. A WNT pathway inhibitor embedded with a urea structure selected from the following characteristic compounds:

   N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-phenyl-1 hydrogen-pyrazole-1-amide;

   N-((2',3-Dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(pyridin-2-yl)-1-hydro-pyrazole-1- Amide

   N-((2',3-Dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-phenyl-1-hydro-1,2,3-triazole- 1-amide;

   N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-3-phenyl-1-hydro-pyrazole-1-amide;

   N-((2',3-Dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(3-fluorophenyl)-1-hydro-pyrazole-1- Amide

   4-(3-Chlorophenyl)-N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-1-hydro-pyrazole-1- Amide

   N-((2',3-Dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-3-methyl-4-phenyl-1-hydro-pyrazole-1- Amide

   N-((2',3-Dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-5-methyl-4-phenyl-1-hydro-pyrazole-1- Amide

   4-(2-chlorophenyl)-N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-1-hydro-pyrazole-1- Amide

   4-(4-chlorophenyl)-N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-1-hydro-pyrazole-1- Amide

   N-((2',3-Dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(pyrazin-2-yl)-1-hydro-pyrazole-1 - amide;

   N-((2',3-Dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(2-fluorophenyl)-1-hydro-pyrazole-1- Amide

   N-((2',3-Dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(4-fluorophenyl)-1-hydro-pyrazole-1- Amide

   N-((2',3-Dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(pyridin-3-yl)-1-hydro-pyrazole-1- Amide

   N-((2',3-Dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(pyridin-4-yl)-1-hydro-pyrazole-1- Amide

   N-((2',3-Dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(3-fluoropyridin-2-yl)-1-hydro-pyrazole -1-amide;

   N-((2',3-Dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(5-fluoropyridin-2-yl)-1-hydro-pyrazole -1-amide;

   N-((2',3-Dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(3-fluoropyridin-4-yl)-1-hydro-pyrazole -1-amide;

   N-((2',3-Dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-5-methyl-4-(pyridin-2-yl)-1-hydro-pyridyl Oxazole-1-amide;

   N-((2',3-Dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(6-methylpyridin-2-yl)-1-hydro-pyridyl Oxazole-1-amide;

   N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(5-methylpyridin-3-yl)-1-hydro-pyridyl Oxazole-1-amide;

   N-((2',3-Dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(2-methylpyridin-4-yl)-1-hydro-pyridyl Oxazole-1-amide;

   N-((2',3-Dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(3-cyanophenyl)-1-hydro-pyrazole-1 - amide;

   N-((2',3-Dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(pyrimidin-5-yl)-1-hydro-pyrazole-1- Amide

   N-((2',3-Dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(pyrimidin-2-yl)-1-hydro-pyrazole-1- Amide

   N-((2',3-Dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(pyridazin-3-yl)-1-hydro-pyrazole-1 - amide;

   N-((2',3-Dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(pyrimidin-4-yl)-1-hydro-pyrazole-1- Amide

   4-(4-acetylpiperazin-1-yl)-N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-1-hydro-pyridyl Oxazole-1-amide;

   N-((2',3-Dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-morpholinyl-1-hydro-pyrazole-1-amide.
7. A pharmaceutical composition comprising, as an active ingredient, a compound as defined in claim 1 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
8. Use of a compound as defined in claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for antagonizing the Wnt signaling pathway.
9. The use according to claim 8, which is for treating a cell proliferative disease or a digestive system disease associated with abnormal Wnt signaling activity.
10. The use according to claim 9 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.

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