WO2017097215A1 - Inhibiteur de la voie wnt doté d'une structure urées - Google Patents

Inhibiteur de la voie wnt doté d'une structure urées Download PDF

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WO2017097215A1
WO2017097215A1 PCT/CN2016/108963 CN2016108963W WO2017097215A1 WO 2017097215 A1 WO2017097215 A1 WO 2017097215A1 CN 2016108963 W CN2016108963 W CN 2016108963W WO 2017097215 A1 WO2017097215 A1 WO 2017097215A1
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group
amide
methyl
bipyridyl
dimethyl
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PCT/CN2016/108963
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English (en)
Chinese (zh)
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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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杭州雷索药业有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—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
    • 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
    • A61K31/495—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

Definitions

  • 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.
  • Wnt signaling pathway plays an important role in life processes such as axis differentiation, tissue and organogenesis, and tumor formation in multicellular organisms.
  • the Wnt gene encodes a protein expressed as a secreted glycoprotein consisting of 19 members, which binds to the Frizzled (Fzd) family of proteins and LDL receptor related protein (LRP) receptors on the cell membrane. It activates a variety of intracellular signaling pathways such as the Wnt/ ⁇ -catenin pathway, the planar polar pathway, and the Wnt/Ca 2+ pathway, regulating a variety of cellular functions including proliferation, differentiation, death, migration, and polarization (Nusse Roel, Varmus Harold E. (1992). Wnt genes. Cell, 69(7), 1073-1087.).
  • Wnt signaling is involved in early tumor evidence derived from the isolation of the oncogene Int1 activated by viral insertion in mouse breast cancer; nearly 10% of patients with colorectal cancer, head and neck cancer, lung cancer, ovarian cancer, melanoma Cancer development is associated with the induction of functional mutations in the R-spondin family and RNF43/ZNRF3, a Wnt signaling regulator (B Madan, Z Ke, N Harmston, et al. (2015). Wnt addiction of genetically defined cancers reversed by PORCN inhibition. Oncogene, 1-11.).
  • LGK974 (ClinicalTrials.gov Identifier: NCT01351103, designed for the upstream target of the Wnt signaling pathway 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/ ⁇ -catenin (ClinicalTrials.gov Identifier: NCT02413853).
  • 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.
  • a WNT pathway inhibitor embedding a urea structure which is a compound having the following structural formula: and a pharmaceutically acceptable salt thereof:
  • ring A and ring B are each independently selected from an aromatic ring or an aromatic heterocyclic ring containing 1-2 N atoms or O atoms; and X, Y and Z are each independently selected from 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
  • 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,
  • 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;
  • 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
  • the heterocyclic group is one or more N, O 3-12-membered heterocyclic ring of S hetero atom.
  • 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
  • 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
  • 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.
  • 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-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-26 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-4-(pyridazin-3-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;
  • Compound as used in the present invention includes all stereoisomers, geometric isomers, tautomers and isotopes.
  • Compounds as used herein may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers.
  • the compound containing an asymmetric carbon atom in the present invention can be isolated in an optically active pure form or in a racemic form.
  • the optically active pure form can be resolved from the racemic mixture or synthesized by using a chiral starting material or a chiral reagent.
  • the "compound” of the present invention also includes tautomeric forms.
  • the tautomeric form is derived from the exchange of a single bond with an adjacent double bond and accompanied by a proton transfer.
  • the invention also includes atoms of all isotopes, whether in the intermediate or the final compound.
  • the atoms of an isotope include those having the same number of atoms but different mass numbers.
  • isotopes of hydrogen include deuterium and tritium.
  • halogen means fluoro, chloro, bromo or iodo, preferably fluoro, chloro or bromo.
  • cyano refers to -CN.
  • hydroxy refers to -OH.
  • alkyl refers to a straight or branched saturated hydrocarbon group consisting of a carbon atom and a hydrogen atom, such as a C 1-20 alkyl group, preferably a C 1-6 alkyl group, such as methyl, ethyl, or propyl.
  • Base including n-propyl and isopropyl
  • butyl including n-butyl, isobutyl, sec-butyl or tert-butyl
  • pentyl including n-pentyl, isopentyl, neopentyl
  • the alkyl group may be unsubstituted or substituted by one or more substituents including, but not limited to, alkyl, alkoxy, cyano, hydroxy, carbonyl, carboxyl, aryl, heteroaryl, Amino group, halogen, sulfonyl group, sulfinyl group, phosphoryl group.
  • amino refers to -NH 2 , -NH(alkyl) and -N(alkyl) 2 , and the meaning of the alkyl group is as defined above.
  • -NH (alkyl) is in the form of Specific examples include, but are not limited to, -NHCH 3 , -NHCH(CH 3 ) 2 , -NHC 2 H 5 , etc.;
  • -N(alkyl) 2 has the structural form Specific examples include, but are not limited to, -N(CH 3 ) 2 , -N(CH 3 )C 2 H 5 , and the like.
  • aryl refers to an all-carbon monocyclic or fused ring having a fully conjugated pi-electron system, typically having from 6 to 14 carbon atoms, preferably having from 6 to 12 carbon atoms, and most preferably having six carbon atoms. .
  • the aryl group may be unsubstituted or substituted by one or more substituents including, but not limited to, alkyl, alkoxy, cyano, hydroxy, carbonyl, carboxyl, aryl, aralkyl, amino, halogen. , sulfonyl, sulfinyl, phosphoryl. Examples of unsubstituted aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.
  • heterocyclyl refers to a monocyclic or fused ring having from 3 to 12 (integer) ring atoms, wherein one, two or three ring atoms are selected from one or more of N, O, and the remaining rings
  • the atom is C and has a fully conjugated ⁇ -electron system.
  • the heterocyclic group may be a saturated or unsaturated group, or may be unsubstituted or substituted by one or more substituents including, but not limited to, alkyl, alkoxy, cyano, hydroxy, Carbonyl, carboxyl, aryl, aralkyl, amino, halogen, sulfonyl, sulfinyl, phosphoryl.
  • unsubstituted heterocyclic groups include, but are not limited to, pyrrolyl, indenyl, pyrrolidinyl, imidazolyl, pyrazolyl, tetrazolyl, pyridyl, quinolyl, isoquinolinyl, piperidinyl, Pyrimidinyl, pyrazinyl, piperazinyl, furyl, pyranyl, morpholinyl.
  • 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
  • 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.
  • 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.
  • solid, semi-solid, liquid or gaseous preparations such as tablets, pills, and glues.
  • the pharmaceutical composition of the present invention can be produced by a method well known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a sugar coating pill method, a grinding method, an emulsification method, a freeze drying method, and the like.
  • the administration route of the compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof including but not limited to oral, rectal, transmucosal, enteral administration, or topical, transdermal, inhalation, parenteral , sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous.
  • a preferred route of administration is oral administration.
  • the pharmaceutical composition can be formulated by admixing the active compound with apharmaceutically acceptable carrier which is well known in the art.
  • a pharmaceutical composition for oral administration can be obtained by combining the active ingredient with one or more solid carriers, granulating the resulting mixture if necessary, and adding a small amount of excipient if necessary Processed into a mixture or granule to form a tablet or tablet core.
  • the core may be combined with a coating material which is optionally suitable for enteric processing, in the form of a coating formulation which is more advantageous for absorption by an organism such as a human.
  • the invention also provides the use of a compound as described above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for antagonizing the Wnt signaling pathway.
  • the pharmaceutical use is for the treatment of cell proliferative diseases, digestive diseases associated with abnormal Wnt signaling activity.
  • the pharmaceutical use is for the treatment of cancer, including non-small cell lung cancer, anaplastic large cell lymphoma, inflammatory myofibroblastic tumor, nasopharyngeal carcinoma, breast cancer, colorectal cancer, diffuse large B-cell lymphoma, liver cancer , gastric cancer, esophageal cancer, pancreatic cancer, ovarian cancer, systemic histiocytosis and neuroblastoma.
  • cancer including non-small cell lung cancer, anaplastic large cell lymphoma, inflammatory myofibroblastic tumor, nasopharyngeal carcinoma, breast cancer, colorectal cancer, diffuse large B-cell lymphoma, liver cancer , gastric cancer, esophageal cancer, pancreatic cancer, ovarian cancer, systemic histiocytosis and neuroblastoma.
  • the inventors have determined 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.
  • 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.
  • 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.
  • liquid chromatography is carried out using a WatersSymmetry C18 column. Thin layer chromatography was performed using GF254 (0.25 mm). Nuclear magnetic resonance chromatography (NMR) was measured using a Bruker-400 NMR spectrometer; LC/MS was performed using a Waters ZQ mass spectrometer (column: WatersSymmetry C18, mm, 5 ⁇ m, 35 ° C) using ESI (+) ion mode .
  • NMR nuclear magnetic resonance chromatography
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the intermediate REX-P-INT-1 (452.0 mg) was prepared.
  • 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. ).
  • the preparation method of the fourth embodiment is as follows.
  • 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.
  • the compound REX-N-5 (456.1 mg, 44.7%) is obtained. ).
  • the preparation method of the fifth embodiment is as follows.
  • 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.
  • the preparation method of the sixth embodiment is as follows.
  • 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.
  • the preparation method of the eighth embodiment is as follows.
  • 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.
  • the preparation method of the ninth embodiment is as follows.
  • 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.
  • the preparation method of the tenth embodiment is as follows.
  • 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.
  • 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.
  • the preparation method of the twelfth embodiment is as follows.
  • 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. .
  • 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. .
  • 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. .
  • 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%).
  • 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. %).
  • 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. %).
  • 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. %).
  • 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.
  • Example 20 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.
  • 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.
  • 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.
  • Zebrafish is a vertebrate with up to 85% homology with the human genome. It has similar tissue and organ function and signaling pathways to humans, and has unique advantages such as high egg production, rapid development, and embryonic transparency, making zebrafish Successfully applied to human disease research and high-throughput screening of living drugs.
  • Wnt signaling pathway is widely distributed in invertebrates and vertebrates. It is a highly conserved signaling pathway in the process of evolution. It participates in the regulation of cell growth, apoptosis, self-renewal and survival genes in vivo, and maintains normal in organisms.
  • Physiological functions such as embryonic development and tissue repair regeneration (Wolfram Goessling, Trista E. North, Sabine Loewer, et al.
  • Wnt signaling pathway dysregulation is also closely related to cancer 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/ ⁇ -Catenin Signaling and Disease. Cell, 149(6): 1192-1205.).
  • APC Adenomatous Polyposis Coli
  • RESULTS The 3 hpf (hours post fertilization) type AB zebrafish eggs were selected for the development of the body axis phenotype.
  • the group was administered at a final concentration ranging from 100 ⁇ M to 0.001 ⁇ M and the vehicle control group.
  • the AB eggs were added to a 6-well plate, 3 mL of fish water per well, and the DMSO concentration was ⁇ 1% (v/v).
  • the AB eggs after dosing were imaged at 48 hpf in a 28.5 °C biochemical incubator, and the px values (pixels) of the body length of each group of juvenile fish were measured by NIS-Elements D 3.1 software.
  • the IC 50 value of each compound in the development of AB zebrafish body axis was calculated by nonlinear fitting using GraphPad Prism 6.0.
  • IC 50 is calculated for 50% inhibition concentration
  • the present invention retests the zebrafish tail-splitting phenotype of the compounds in Table 1.
  • the 3dpf (days post fertilization) type AB zebrafish juveniles were selected for shear tail fin modeling, and were randomly divided into groups of 10 ⁇ M to 0.001 ⁇ M and a control group, 15 juveniles per group. Add to 6-well plate, 3 mL fish water per well, DMSO concentration ⁇ 1% (v / v). The AB eggs after dosing were imaged at 7 dpf in a biochemical incubator at 28.5 °C. The px values (pixels) of the caudal fin regeneration length of each group were analyzed by NIS-Elements D 3.1 software.
  • the IC 50 value of each compound in the tail-type regeneration of AB type zebrafish was calculated by nonlinear fitting using GraphPad Prism 6.0.
  • REX-N-23 1.984 REX-N-24 11.1 REX-N-25 3.8 REX-N-26 32.2
  • 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.
  • 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 ⁇ L of blood was collected by eyelid blood collection into a clean EP tube containing EDTA (final concentration of EDTA was 0.25 mg/mL). The blood collection tube was quickly inverted at least 5 times after collection to ensure uniform mixing and then placed on ice. Blood collected at each time point was centrifuged at 8000 rpm for 5 minutes at 4 ° C to obtain plasma. Another 1.5 mL centrifuge tube was used to mark the compound name, animal number, and time point, and the plasma was transferred to the tube. Plasma was stored at -80 ° C until analysis.
  • 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 .
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • LGK974 and REX-N-1 were administered at a dose of 5 mg/kg for 28 days, and BID showed significant antitumor activity.

Abstract

La présente invention concerne un inhibiteur de la voie Wnt doté d'une structure urées, appartenant à des composés qui régulent les activités d'une voie de signalisation Wnt, et un procédé de préparation de ces composés. L'invention concerne en outre l'utilisation de ces composés dans la préparation de médicaments antagonistes de la voie de signalisation Wnt. L'inhibiteur de la voie Wnt doté d'une structure urées décrit dans la présente invention présente de remarquables activités anti-tumorales sur la base de la conception rationnelle de médicaments pour des cibles, et peut être utilisé pour développer une nouvelle génération d'inhibiteur de la voie Wnt, présentant une grande valeur d'application clinique et un potentiel de commercialisation considérable.
PCT/CN2016/108963 2015-12-07 2016-12-07 Inhibiteur de la voie wnt doté d'une structure urées WO2017097215A1 (fr)

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