WO2024022365A1 - Composé inhibiteur de la voie wnt - Google Patents

Composé inhibiteur de la voie wnt Download PDF

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Publication number
WO2024022365A1
WO2024022365A1 PCT/CN2023/109227 CN2023109227W WO2024022365A1 WO 2024022365 A1 WO2024022365 A1 WO 2024022365A1 CN 2023109227 W CN2023109227 W CN 2023109227W WO 2024022365 A1 WO2024022365 A1 WO 2024022365A1
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halogenated
compound
alkyl
cycloalkyl
formula
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PCT/CN2023/109227
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English (en)
Chinese (zh)
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陈宇锋
武朋
陈凯旋
金超凡
王友平
陈可可
陈梦
何南海
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杭州阿诺生物医药科技有限公司
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Priority to CN202380010281.6A priority Critical patent/CN117396482A/zh
Publication of WO2024022365A1 publication Critical patent/WO2024022365A1/fr

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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
    • C07D475/04—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4 with a nitrogen atom directly attached in position 2

Definitions

  • the present invention relates to a heterocyclic compound, specifically to a highly active Wnt pathway inhibitor and its use.
  • the Wnt/ ⁇ -catenin signal transduction pathway is a pathway conserved in biological evolution.
  • ⁇ -catenin In normal somatic cells, ⁇ -catenin only functions as a cytoskeletal protein that forms a complex with E-cadherin at the cell membrane to maintain the adhesion of cells of the same type and prevent cell movement.
  • ⁇ -catenin in the cytoplasm is phosphorylated and forms a ⁇ -catenin degradation complex with APC, Axin, GSK3 ⁇ , etc., thereby initiating the ubiquitin system to degrade ⁇ -catenin through the proteasome pathway, causing ⁇ -catenin in the cytoplasm is maintained at a low level.
  • Frizzled proteins When cells are stimulated by Wnt signals, Wnt proteins bind to Frizzled proteins, a specific receptor on the cell membrane.
  • Frizzled receptors recruit intracellular Dishevelled proteins, inhibit the degradation activity of ⁇ -catenin degradation complexes formed by GSK3 ⁇ and other proteins, and stabilize Free ⁇ -catenin protein in the cytoplasm.
  • ⁇ -catenin stably accumulated in the cytoplasm enters the nucleus and binds to the LEF/TCF transcription factor family to initiate the transcription of downstream target genes (such as c-myc, c-jun, Cyclin D1, etc.).
  • Excessive activation of the Wnt/ ⁇ -catenin signaling pathway is closely related to the occurrence of various cancers (including colon cancer, gastric cancer, breast cancer, etc.).
  • abnormal activation of the Wnt classic signaling pathway and nuclear accumulation of ⁇ -catenin protein are widespread in colorectal cancer, and inhibiting the activity of the Wnt signaling pathway can inhibit the proliferation of cancers such as colon cancer.
  • APC mutations exist in more than 85% of colorectal cancers. The mutated APC blocks the phosphorylation and degradation of ⁇ -catenin and induces the occurrence of colorectal cancer.
  • Axin mutations and ⁇ -catenin self-mutation can also cause intracellular accumulation of ⁇ -catenin and activate the Wnt/ ⁇ -catenin pathway.
  • the present invention provides a compound having the structure of formula (I) that inhibits Wnt pathway activity or a pharmaceutically acceptable salt, isotope derivative, or stereoisomer thereof:
  • R 1 and R 2 each independently represent hydrogen, (C 1 -C 6 )alkyl, halogenated (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, halogenated (C 3 - C 8 ) cycloalkyl, 4-8 membered heterocycloalkyl, halogenated 4-8 membered heterocycloalkyl, -(C 1 -C 6 )alkylene OR a , -halogenated (C 1 -C 6 )alkylene OR a , -(C 1 -C 6 )alkylene SR a , -halogenated (C 1 -C 6 )alkylene SR a , or R 1 , R 2 and the carbon atoms connected to them Together they form a 3-8 membered ring which may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O and S;
  • R 3 represents (C 1 -C 6 ) alkyl, halogenated (C 1 -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, halogenated (C 3 -C 8 ) cycloalkyl, or R 3 and R 1 or R 2 together form a 4-7 membered ring, which may optionally contain 0 or 1 heteroatoms selected from O and S;
  • W 6 means CR 6 or N
  • R 6 each independently represents hydrogen, halogen, cyano group, (C 1 -C 3 ) alkyl group, or halogenated (C 1 -C 3 ) alkyl group;
  • Cy represents a 5-12 membered aromatic heterocycle, which optionally contains 1, 2, 3 or 4 heteroatoms, each of which is independently selected from the group consisting of N, O and S, and Cy and -O- Ortho positions of the attachment position are unsubstituted or substituted by hydrogen;
  • R 1 ' represents hydrogen, halogen, (C 1 -C 6 ) alkyl, halogenated (C 1 -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, halogenated (C 3 -C 8 ) Cycloalkyl, (C 3 -C 8 ) heterocycloalkyl, halogenated (C 3 -C 8 ) heterocycloalkyl, -OR a , -halogenated OR a , -SR a , -halogenated SR a ;
  • R 2 ' represents hydrogen, halogen, (C 1 -C 6 ) alkyl, halogenated (C 1 -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, halogenated (C 3 -C 8 ) Cycloalkyl, (C 3 -C 8 ) heterocycloalkyl, halogenated (C 3 -C 8 ) heterocycloalkyl, -OR a , -halogenated OR a , -SR a , -halogenated SR a ;
  • R 3 ' represents hydrogen, halogen, (C 1 -C 6 ) alkyl, halogenated (C 1 -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, halogenated (C 3 -C 8 ) Cycloalkyl, (C 3 -C 8 ) heterocycloalkyl, halogenated (C 3 -C 8 ) heterocycloalkyl, -OR a , -halogenated OR a , -SR a , -halogenated SR a ;
  • n independently represents 0, 1 or 2;
  • R a each independently represents hydrogen, (C 1 -C 6 )alkyl, halogenated (C 1 -C 6 )alkyl, (C 3 -C 8 ) cycloalkyl, halogenated (C 3 -C 8 ) Cycloalkyl.
  • Cy in the structure of formula (I) is a 5-membered heteroaromatic ring or a 6-membered heteroaromatic ring. More preferably, Cy is pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, imidazolyl or pyrrolyl.
  • the dotted ring indicates that the ring it is in is an aromatic ring
  • W 1 means CR 1 ' or N
  • W 2 means CR 2 ' or N
  • W 3 means CR 3 ' or N
  • W 4 represents CH or N
  • W 5 means CH or N
  • R 1 , R 2 , R 3 , R 6 , W 6 , R 1 ', R 2 ', R 3 ', R a and m are as described in claim 1 . More preferably, the compound of formula (II) is as follows:
  • the dotted ring indicates that the ring it is in is an aromatic ring
  • W 1 ' represents CH, N or NH
  • W 2 ' represents CR 2 ', N or NR 2 ';
  • W 3 ' represents CR 3 ', N or NR 3 ';
  • W 4 ' represents CH, N or NH
  • R 1 , R 2 , R 3 , R 6 , W 6 , R 1 ', R 2 ', R 3 ', R a and m are as described in claim 1 .
  • R 1 and R 2 each independently represent hydrogen, (C 1 -C 6 )alkyl, halo (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, halo (C 3 -C 8 )cycloalkyl, 4-8 membered heterocycloalkyl, halogenated 4-8 membered heterocycloalkyl, -(C 1 -C 6 )alkylene OR a , -halogenated (C 1 -C 6 )alkylene OR a ; preferably hydrogen, (C 1 -C 6 )alkyl, or halogenated (C 1 -C 6 )alkyl.
  • R 3 is (C 1 -C 6 )alkyl.
  • W 6 is CR 6 .
  • R6 is hydrogen
  • R 1 ' represents hydrogen, halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, halo(C 3 -C 8 )cycloalkyl. More preferably, R 1 ' represents halo(C 1 -C 6 )alkyl.
  • R 2 ' represents hydrogen, halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, halo(C 3 -C 8 )cycloalkyl. More preferably, R 2 ' represents hydrogen or halogen.
  • R 3 ' represents halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, halo(C 3 -C 8 ) Cycloalkyl, -OR a , -halogenated OR a , -SR a , -halogenated SR a .
  • R 3 ' represents halogen, (C 1 -C 6 ) alkyl, halogenated (C 1 -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, halogenated (C 3 -C 8 )cycloalkyl. More preferably, R 3 ' represents halo(C 1 -C 6 )alkyl or halo(C 3 -C 8 )cycloalkyl.
  • the invention provides a compound having the following structure:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention or its pharmaceutically acceptable salt, isotope derivative or stereoisomer.
  • the present invention also provides the compounds of the present invention or their pharmaceutically acceptable salts, isotope derivatives, stereoisomers or pharmaceutical compositions of the present invention for use in the prevention and/or treatment of cancer. , tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases. It is particularly noted that in this article, when referring to the "compound” of the structure of formula (I) to formula (III), its stereoisomers, diastereomers, and enantiomers are also generally covered. , racemic mixtures and isotope derivatives.
  • reference herein to a compound generally includes its prodrugs, metabolites and nitrogen oxides.
  • Pharmaceutically acceptable salts of the present invention may be formed using, for example, the following inorganic or organic acids: "Pharmaceutically acceptable salts" refer to salts that, within the scope of reasonable medical judgment, are suitable for use in contact with humans and lower and other animal tissues without undue toxicity, irritation, allergic reactions, etc., which can be called a reasonable benefit/risk ratio.
  • the salts may be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base or free acid with a suitable reagent, as summarized below. For example, the free base functionality can be reacted with a suitable acid.
  • inorganic acid addition salts are amino acids with inorganic acids (for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid) or organic acids (for example, acetic acid, oxalic acid, maleic acid, tartaric acid, lemon acid). acid, succinic acid or malonic acid), or by using other methods in the art such as ion exchange.
  • inorganic acids for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids for example, acetic acid, oxalic acid, maleic acid, tartaric acid, lemon acid.
  • succinic acid or malonic acid or by using other methods in the art such as ion exchange.
  • salts include adipate, sodium alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, Camphor sulfonate, citrate, cyclopentane propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerin Phosphate, gluconate, hernisulfate, enanthate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malic acid Salt, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamateate, pec
  • Representative alkali metal or alkaline earth metal salts include salts of sodium, lithium, potassium, calcium, magnesium, and the like.
  • Other pharmaceutically acceptable salts include, where appropriate, nontoxic ammonium salts, quaternary ammonium salts, and amine cations formed with counterions, e.g., halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower Alkyl sulfonates and aryl sulfonates.
  • the pharmaceutically acceptable salts of the present invention can be prepared by conventional methods, for example, by dissolving the compounds of the present invention in water-miscible organic solvents (such as acetone, methanol, ethanol, and acetonitrile), and adding an excess of organic acid or inorganic acid thereto.
  • the aqueous acid is used to precipitate the salt from the resulting mixture, the solvent and remaining free acid are removed therefrom, and the precipitated salt is isolated.
  • the precursors or metabolites described in the present invention may be those known in the art, as long as the precursors or metabolites are converted into compounds through in vivo metabolism.
  • prodrugs refer to those prodrugs of the compounds of the present invention which, within the scope of reasonable medical judgment, are suitable for contact with tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., Demonstrates a reasonable benefit/risk ratio and is effective for its intended use.
  • prodrug refers to a compound that is rapidly converted in vivo to produce the parent compound of the formula above, for example by metabolism in the body, or N-demethylation of a compound of the invention.
  • Solvate as used herein means a physical association of a compound of the invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain situations, such as when one or more solvent molecules are incorporated into the junction When placed in the crystal lattice of a crystalline solid, the solvate will be able to be separated.
  • the solvent molecules in a solvate may exist in regular and/or disordered arrangements. Solvates may contain stoichiometric or non-stoichiometric amounts of solvent molecules.
  • “Solvate” encompasses both solution phase and isolable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methoxides, and isopropoxides. Solvation methods are well known in the art.
  • the "stereoisomerism" mentioned in the present invention is divided into conformational isomerism and configurational isomerism.
  • Configurational isomerism can also be divided into cis-trans isomerism and optical isomerism (ie, optical isomerism).
  • Conformational isomerism refers to having A stereoisomerism phenomenon in which organic molecules of a certain configuration are arranged differently in space due to the rotation or distortion of carbon and carbon single bonds.
  • Common structures include alkanes and cycloalkanes. Such as the chair conformation and boat conformation that appear in the cyclohexane structure.
  • Stepoisomers means when a compound of the present invention contains one or more asymmetric centers and is thus available as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and single Diastereomers.
  • the compound of the present invention has an asymmetric center, and each asymmetric center will produce two optical isomers.
  • the scope of the present invention includes all possible optical isomers and diastereoisomer mixtures and pure or partially pure compounds. .
  • the compounds described in this invention may exist as tautomeric forms, which have different points of attachment of hydrogens through the displacement of one or more double bonds. For example, a ketone and its enol form are keto-enol tautomers.
  • an “isotopic derivative” of the present invention refers to a molecule in which the compound is isotopically labeled.
  • the isotopes commonly used as isotope labels are: hydrogen isotopes, 2 H and 3 H; carbon isotopes: 11 C, 13 C and 14 C; chlorine isotopes: 35 Cl and 37 Cl; fluorine isotopes: 18 F; iodine isotopes: 123 I and 125 I; nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotope 35 S.
  • These isotopically labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues.
  • deuterium 3 H and carbon 13 C are more widely used because they are easy to label and detect.
  • substitution of certain heavy isotopes, such as deuterium ( 2H ) can enhance metabolic stability, extend half-life, thereby reducing dosage and providing therapeutic advantages.
  • Isotopically labeled compounds generally start from labeled starting materials and are synthesized using known synthetic techniques as for non-isotopically labeled compounds.
  • the present invention also provides the use of the compounds of the present invention in the preparation of medicaments for preventing and/or treating cancer, tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases.
  • the present invention provides pharmaceutical compositions for the prevention and/or treatment of cancer, tumors, inflammatory diseases, autoimmune diseases, neurodegenerative diseases, attention-related diseases or immune-mediated diseases, comprising the present invention compound as the active ingredient.
  • the pharmaceutical composition may optionally include a pharmaceutically acceptable carrier.
  • the present invention provides a method for preventing and/or treating cancer, tumors, inflammatory diseases, autoimmune diseases, neurodegenerative diseases, attention-related diseases, or immune-mediated diseases, comprising A compound of the invention is administered to a mammal.
  • inflammatory diseases may include, but are not limited to, arthritis, rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, juvenile arthritis , other arthritic conditions, lupus, systemic lupus erythematosus (SLE), skin-related disorders, psoriasis, eczema, dermatitis, atopic dermatitis, pain, lung disease, lung inflammation, adult respiratory distress syndrome (ARDS) , pulmonary sarcoidosis, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease (COPD), cardiovascular disease, atherosclerosis, myocardial infarction, congestive heart failure, myocardial ischemia-reperfusion injury, inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, asthma, Sjogren's syndrome, autoimmune thyroid disease, urticaria (rubella), multiple s
  • cancers or tumors may include, but are not limited to, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neuroblastoma, rectal cancer , colon cancer, familial adenomatous polyposis carcinoma, hereditary nonpolyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, Papillary thyroid cancer, renal cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine corpus cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary cancer, melanoma, brain tumors such as Glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral tumors
  • the compounds of the present invention may provide enhanced anticancer effects when administered in combination with additional anticancer agents or immune checkpoint inhibitors used to treat cancer or tumors. .
  • anti-cancer agents used to treat cancer or tumors may include, but are not limited to, cell signaling inhibitors, phenbutanol, Nitrogen mustard, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, cisplatin, carboplatin, oxaliplatin, dacarba Azine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan , irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, daunorubicin, mitoxantrone, bleomycin, mitomycin C, irinotecan Sarbe
  • the compounds of the present invention may provide enhanced therapeutic effect.
  • therapeutic agents for treating inflammatory diseases, autoimmune diseases, and immune-mediated diseases may include, but are not limited to, steroidal drugs (e.g., prednisone, prednisone, methylprednisone pine, cortisone, hydroxycortisone, betamethasone, dexamethasone, etc.), methotrexate, leflunomide, anti-TNF ⁇ agents (e.g., etanercept, infliximab, adalivir monoclonal antibodies, etc.), calcineurin inhibitors (e.g., tacrolimus, pimecrolimus, etc.) and antihistamines (e.g., diphenhydramine, hydroxyzine, loratadine, ebas cetirizine, ketotifen, cetirizine, levocetirizine, fexofenadine, etc.), and at least one or more therapeutic agents selected therefrom may be included in the pharmaceutical composition of the present invention.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof can be administered orally or parenterally as an active ingredient, and its effective amount ranges from 0.1 to 2,000 mg/kg body weight/day, in the case of mammals including humans (body weight about 70 kg). 1 to 1,000 mg/kg body weight/day is preferred and administered as a single or 4 divided doses per day, or with/without following a predetermined time.
  • the dosage of the active ingredient may depend on a number of relevant factors (such as the condition of the subject to be treated, the type and severity of the disease, the rate of administration and physician opinion) Make adjustments. In some cases, amounts less than the above dosages may be appropriate. Amounts greater than the above dosages may be used if they do not cause deleterious side effects and may be administered in divided doses per day.
  • the present invention also provides a method for preventing and/or treating tumors, cancers, viral infections, organ transplant rejection, neurodegenerative diseases, attention-related diseases or autoimmune diseases, which includes providing such A compound of the invention or a pharmaceutical composition of the invention is administered to a mammal in need thereof.
  • the pharmaceutical composition of the present invention can be formulated into a dosage form for oral administration or parenteral administration (including intramuscular, intravenous and subcutaneous routes, intratumoral injection) according to any of conventional methods, such as tablets, granules, powders , capsules, syrups, emulsions, microemulsions, solutions or suspensions.
  • compositions of the present invention for oral administration can be prepared by mixing the active ingredient with a carrier such as: cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, hard Magnesium fatty acid, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifiers and diluents.
  • a carrier such as: cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, hard Magnesium fatty acid, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifiers and diluents.
  • Examples of carriers used in the pharmaceutical composition for injection administration of the present invention may be water, saline solution, glucose solution, glucose-like solution, alcohol, glycol, ether (e.g., polyethylene glycol 400 ), oils, fatty acids, fatty acid esters, glycerides, surfactants, suspending agents and emulsifiers.
  • the compounds of the present invention can be prepared in a variety of ways known to those skilled in the art of organic synthesis.
  • the following methods can be used as well as synthetic methods known in the field of organic synthetic chemistry or through variations thereof known to those skilled in the art. Synthesize the compounds of the invention. Preferred methods include, but are not limited to, those described below.
  • the reaction is carried out in a solvent or solvent mixture suitable for the kit materials used and for the transformations achieved.
  • Those skilled in the art of organic synthesis will understand that the functionality present on the molecule is consistent with the proposed transformation. This sometimes requires judgment to alter the order of synthetic steps or starting materials to obtain the desired compound of the invention.
  • Figure 1 shows the effect of Compound 1 on tumor growth of human colon cancer cell Colo205 xenograft tumors.
  • the compounds of the present invention can be isolated in optically active or racemic form. All methods for preparing the compounds of the invention and the intermediates prepared therein are considered to be part of the invention. When preparing enantiomeric or diastereomeric products, they can be separated by conventional methods, for example by chromatography or fractional crystallization. Depending on the process conditions, the final product of the invention is obtained in free (neutral) or salt form. Both free forms and salts of these end products are within the scope of this invention. If desired, one form of the compound can be converted into another form. The free base or acid can be converted into a salt; the salt can be converted into the free compound or another salt; and mixtures of isomeric compounds of the invention can be separated into individual isomers.
  • the compounds of the present invention may exist in a variety of tautomeric forms in which hydrogen atoms are transposed to other parts of the molecule and thereby the chemical bonds between the atoms of the molecule are rearranged. It is to be understood that all tautomeric forms which may exist are included in the present invention.
  • the definitions of the substituents of the present invention are independent and not related to each other.
  • R a (or R a ') in the substituent it The definitions of different substituents are independent of each other. Specifically, when one definition is chosen for R a (or R a ') in one substituent, it does not mean that R a (or R a ') has the same definition in other substituents.
  • NR a R a ' when the definition of R a (or R a ') is selected from hydrogen, it does not mean that in -C(O)-NR In a R a ', R a (or R a ') must be hydrogen.
  • R a when there is more than one Ra (or Ra ') in a certain substituent, these Ra (or Ra ') are also independent.
  • substituents such as alkyl, cycloalkyl, aryl, heterocyclyl, halogen, hydroxyl, Alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amino (where 2 amino substituents are selected from alkyl group, aryl or arylalkyl), alkanoylamino, arolylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thio, alkylthio , arylthio group, arylalkylthio group, arylthiocarbonyl group, arylalkylthiocarbonyl group, alkyls
  • alkyl or "alkylene” as used herein is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • C 1 -C 6 alkyl means an alkyl group having 1 to 6 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (such as n-propyl and isopropyl), butyl (such as n-butyl, isobutyl, tert-butyl), and Pentyl (e.g. n-pentyl, isopentyl, neopentyl).
  • the alkyl group is preferably an alkyl group having 1 to 6, more preferably 1 to 4 carbon atoms.
  • alkenyl refers to a straight or branched hydrocarbon radical containing one or more double bonds and usually having a length of 2 to 20 carbon atoms.
  • C2-C6 alkenyl contains two to six carbon atoms.
  • Alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like. In this context, alkenyl is preferably C 2 -C 6 alkenyl.
  • alkynyl refers to a straight or branched hydrocarbon radical containing one or more triple bonds and usually having a length of 2 to 20 carbon atoms.
  • C 2 -C 6 alkynyl contains two to six carbon atoms.
  • Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, and the like. In this context, the alkynyl group is preferably a C 2 -C 6 alkynyl group.
  • alkoxy refers to -O-alkyl.
  • C 1 -C 6 alkoxy (or alkyloxy) is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy.
  • alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (eg, n-propoxy and isopropoxy), and tert-butoxy.
  • the alkoxy group is preferably an alkoxy group having 1 to 6, more preferably 1 to 4 carbon atoms.
  • alkylthio or “thiothio” means a sulfur-bridged alkyl group as defined above having the specified number of carbon atoms; for example, methyl-S- and ethyl-S-.
  • aryl alone or as part of a larger moiety such as “aralkyl”, “arylalkoxy” or “aryloxyalkyl”, refers to a single ring member having a total of 5 to 12 ring members.
  • aryl refers to an aromatic ring system including, but not limited to, phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetralin base.
  • aralkyl or "arylalkyl” refers to an alkyl residue attached to an aryl ring, non-limiting examples of which include benzyl, phenethyl, and the like.
  • the fused aryl group can be attached to another group at a suitable position on the cycloalkyl ring or aromatic ring.
  • the dashed lines drawn from the ring system indicate that bonds can be attached to any suitable ring atom.
  • cycloalkyl refers to a monocyclic or bicyclic cyclic alkyl group.
  • Monocyclic cyclic alkyl refers to C 3 -C 8 cyclic alkyl, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and norbornyl.
  • Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methyl
  • the base cyclopropyl is included in the definition of "cycloalkyl”.
  • Bicyclic cyclic alkyl groups include bridged, spiro or fused cyclic cycloalkyl groups.
  • cycloalkyl is preferably C 3 -C 6 cycloalkyl.
  • cycloalkenyl refers to a monocyclic or bicyclic cyclic alkenyl group.
  • Monocyclic cyclic alkenyl refers to C 3 -C 8 cyclic alkenyl, including but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and norbornenyl.
  • Branched cycloalkenyl groups such as 1-methylcyclopropenyl and 2-methylcyclopropenyl are included in the definition of "cycloalkenyl”.
  • Bicyclic cyclic alkenyl groups include bridged, spiro or condensed ring cyclic alkenyl groups.
  • Halo or halogen includes fluorine, chlorine, bromine and iodine.
  • Haloalkyl is intended to include branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted with one or more halogens.
  • haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoroethyl Propyl and heptachloropropyl.
  • haloalkyl groups also include "fluoroalkyl groups” which are intended to include branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted with one or more fluorine atoms.
  • Haloalkoxy or "haloalkyloxy” means a haloalkyl group as defined above having the specified number of carbon atoms linked via an oxygen bridge.
  • halo C 1 -C 6 alkoxy is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , C 6 haloalkoxy.
  • haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy.
  • haloalkylthio or “thiohaloalkoxy” means a sulfur-bridged haloalkyl group as defined above having the specified number of carbon atoms; for example, trifluoromethyl-S- and pentafluoroethyl -S-.
  • C x1 -C x2 is used when referring to some substituent groups, which means that the number of carbon atoms in the substituent group may be x1 to x2.
  • C 0 -C 8 means that the group contains 0, 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms
  • C 1 -C 8 means that the group contains 1, 2, 3 , 4, 5, 6, 7 or 8 carbon atoms
  • C 2 -C 8 means that the group contains 2, 3, 4, 5, 6, 7 or 8 carbon atoms
  • C 3 -C 8 means that the group The group contains 3, 4, 5, 6, 7 or 8 carbon atoms
  • C 4 -C 8 means that the group contains 4, 5, 6, 7 or 8 carbon atoms
  • C 0 -C 6 means that the group contains 4, 5, 6, 7 or 8 carbon atoms.
  • a group containing 0, 1, 2, 3, 4, 5 or 6 carbon atoms means that the group contains 1, 2, 3, 4, 5 or 6 carbon atoms
  • C 2 -C 6 means that the group contains 2, 3, 4, 5 or 6 carbon atoms
  • C 3 -C 6 means that the group contains 3, 4, 5 or 6 carbon atoms.
  • x1-x2 membered ring is used when referring to cyclic groups (such as aryl, heteroaryl, cycloalkyl, and heterocycloalkyl), which means that the ring atoms of the group The number can be x1 to x2.
  • the 3-12-membered cyclic group can be a 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12-membered ring, and the number of ring atoms can be 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • 3-6 membered ring means that the cyclic group can be a 3, 4, 5 or 6 membered ring, and the number of ring atoms can be 3, 4, 5 or 6 ;
  • 3-8 membered ring means that the cyclic group can be 3, 4, 5, 6, 7 or 8 membered ring, and the number of ring atoms can be 3, 4, 5, 6, 7 or 8; 3-9
  • the membered ring means that the cyclic group can be a 3, 4, 5, 6, 7, 8 or 9-membered ring, and the number of ring atoms can be 3, 4, 5, 6, 7, 8 or 9; 4-7
  • the membered ring means that the cyclic group can be a 4, 5, 6 or 7-membered ring, and the number of ring atoms can be
  • the ring atoms may be carbon atoms or heteroatoms, such as heteroatoms selected from N, O and S.
  • the heterocycle may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more ring heteroatoms, for example selected from N, O and S of heteroatoms.
  • one or more halogens may be each independently selected from fluorine, chlorine, bromine, and iodine.
  • heteroaryl means a stable 3-membered, 4-membered, 5-membered, 6-membered, or 7-membered aromatic monocyclic ring or aromatic bicyclic ring or a 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, or 12-membered aromatic ring.
  • Aromatic polycyclic heterocycles that are fully unsaturated or partially unsaturated and contain carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; and include Any of the following polycyclic groups in which any heterocycle as defined above is fused to a benzene ring. Nitrogen and sulfur heteroatoms may optionally be oxidized.
  • Nitrogen atoms are substituted or unsubstituted (ie, N or NR, where R is H or another substituent, if defined).
  • Heterocycles can be attached to their pendant groups at any heteroatom or carbon atom that results in a stable structure. If the resulting compound is stable, the heterocyclyl groups described herein may be substituted on the carbon or nitrogen atom.
  • the nitrogen in the heterocycle may optionally be quaternized.
  • the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to each other.
  • the total number of S and O atoms in the heterocycle is not greater than 1.
  • heterocycle it is intended to include heteroaryl groups.
  • aryl hetero groups include, but are not limited to, acridinyl, azetidinyl, azecinyl, benzimidazolyl, benzofuryl, benzothiofuranyl, benzothienyl, benzox Azolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2, 3-b] Tetrahydrofuryl, furanyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl,
  • heteroaryl may also include a biaryl structure formed by the above-defined “aryl” and a monocyclic “heteroaryl”, such as but not limited to "-phenylbipyridyl-", “- "Phenylbipyrimidinyl”, “-pyridylbiphenyl”, “-pyridylbipyrimidinyl-", “-pyrimidinylbiphenyl-”; wherein the present invention also includes fused rings containing, for example, the above-mentioned heterocyclic rings and Spirocyclic compounds.
  • heterocycloalkyl refers to a monocyclic heterocycloalkyl system, or to a bicyclic heterocycloalkyl system, and also includes spiroheterocyclic or bridged heterocycloalkyl groups.
  • Monocyclic heterocycloalkyl refers to a cyclic alkyl system that is 3-8 membered and contains at least one heteroatom selected from O, N, S and P.
  • Bicyclic heterocycloalkyl system refers to a heterocycloalkyl group fused to a phenyl group, a cycloalkyl group, a cycloalkenyl group, a heterocycloalkyl group, or a heteroaryl group. Two-ring system.
  • bridged cycloalkyl refers to polycyclic compounds sharing two or more carbon atoms. It can be divided into two-ring bridged cyclic hydrocarbons and polycyclic bridged cyclic hydrocarbons. The former is composed of two alicyclic rings sharing more than two carbon atoms; the latter is a bridged cyclic hydrocarbon composed of more than three rings.
  • spirocycloalkyl refers to polycyclic hydrocarbons that share one carbon atom (called a spiro atom) between single rings.
  • bridged cycloheteroyl refers to a polycyclic compound sharing two or more carbon atoms and containing at least one heteroatom selected from O, N and S atoms in the ring. It can be divided into two-ring bridged heterocycles and polycyclic bridged heterocycles.
  • heterospirocyclyl refers to polycyclic hydrocarbons sharing one carbon atom (called a spiro atom) between single rings, and the ring contains at least one heteroatom selected from O, N and S atoms.
  • substituted means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that normal valency is maintained and that the substitution results in a stable compound.
  • nitrogen atoms e.g. amines
  • these nitrogen atoms can be converted into N-oxides by treatment with oxidizing agents (e.g. mCPBA and/or hydrogen peroxide) to obtain other compounds of the invention.
  • oxidizing agents e.g. mCPBA and/or hydrogen peroxide
  • the nitrogen atoms shown and claimed are deemed to encompass the nitrogen atoms shown and their N-oxides to obtain the derivatives of the invention.
  • any variable occurs more than once in any composition or formula of a compound, its definition on each occurrence is independent of its definition on every other occurrence.
  • the group may be optionally substituted with up to three R groups, with R on each occurrence being independently selected from the definition of R.
  • substituents and/or variables are permitted only if such combinations result in stable compounds.
  • patient refers to an organism to be treated by the methods of the present invention.
  • organisms preferably include, but are not limited to, mammals (eg, rodents, apes, monkeys, horses, cattle, pigs, dogs, cats, etc.) and most preferably refer to humans.
  • the term "effective amount” means an amount of a drug or agent (i.e., a compound of the invention) that will elicit the biological or medical response in a tissue, system, animal, or human, for example, that is sought by a researcher or clinician.
  • therapeutically effective amount means an amount that results in improved treatment, cure, prevention, or alleviation of a disease, disorder, or side effect, or a reduction in the risk of a disease, disorder, or side effect as compared to a corresponding subject that does not receive such amount. or the rate at which the condition progresses.
  • An effective amount may be administered in one or more administrations, administrations or doses and is not intended to be limited to a particular formulation or route of administration. The term also includes within its scope an amount effective to enhance normal physiological functions.
  • treatment includes any effect resulting in amelioration of a condition, disease, disorder, etc., such as alleviation, reduction, regulation, amelioration or elimination, or amelioration of symptoms thereof.
  • pharmaceutically acceptable refers to those compounds, substances, compositions and/or dosage forms which, within the scope of reasonable medical judgment, are suitable for use in contact with human and animal tissue without excessive toxicity, irritation sexual, allergic reactions and/or other problems or complications, and proportionate to a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier means a pharmaceutical substance, composition or vehicle such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc, magnesium stearate, calcium stearate or zinc stearate or stearic acid) or solvent encapsulated substances which involve carrying or transporting the subject compounds from one organ or part of the body to another.
  • manufacturing aid e.g., lubricant, talc, magnesium stearate, calcium stearate or zinc stearate or stearic acid
  • solvent encapsulated substances which involve carrying or transporting the subject compounds from one organ or part of the body to another.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient.
  • composition means a composition comprising a compound of the invention and at least one other pharmaceutically acceptable carrier.
  • “Pharmaceutically acceptable carrier” refers to a medium generally accepted in the art for the delivery of biologically active agents to animals, particularly mammals, including (i.e.) adjuvants, excipients or vehicles such as diluents, preservatives , fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatics, antibacterial agents, antifungal agents, lubricants and dispersants, depending on Mode of administration and nature of dosage form.
  • acceptable means that a formulation component or active ingredient does not have undue deleterious effects on the health of the general target of treatment.
  • cancer refers to an abnormal growth of cells that is uncontrollable and, under certain conditions, capable of metastasis (spread).
  • This type of cancer includes, but is not limited to, solid tumors (such as bladder, bowel, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovaries, pancreas or other endocrine organs (such as thyroid), prostate , skin (melanoma) or blood tumors (such as non-leukemic leukemia).
  • coadministration refers to the administration of several selected therapeutic agents to a single patient, Administer in the same or different ways and at the same or different times.
  • enhancing refers to the ability of the drug to increase or prolong its potency or duration in the system.
  • enhancement value refers to the ability to maximize the enhancement of another therapeutic agent in an ideal system.
  • immune disease refers to a disease or condition resulting from an adverse or harmful response to endogenous or exogenous antigens. The result is usually dysfunction of cells, or damage to organs or tissues that may produce immune symptoms.
  • subject or “patient” includes mammals and non-mammals.
  • Mammals include, but are not limited to, mammals: humans, non-human primates such as orangutans, apes and monkeys; agricultural animals such as cattle, horses, goats, sheep, pigs; domestic animals such as rabbits and dogs; experimental animals including rodents, Such as rats, mice and guinea pigs.
  • Non-mammals include, but are not limited to, birds, fish, etc.
  • the selected mammal is a human.
  • treatment include alleviating, inhibiting, or ameliorating symptoms or conditions of a disease; inhibiting the development of complications; ameliorating or preventing underlying metabolic syndrome; inhibiting the development of a disease or symptoms, Such as controlling the development of a disease or condition; alleviating a disease or symptoms; making a disease or symptoms subside; alleviating complications caused by a disease or symptoms, or preventing and/or treating signs caused by a disease or symptoms.
  • a compound or pharmaceutical composition when administered, can ameliorate a disease, symptom or condition, especially its severity, delay its onset, slow down its progression, or reduce its duration. Circumstances that may be attributed to or related to the administration, whether fixed or temporary, continuous or intermittent.
  • Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transdermal, vaginal, and ear canal administration. , nasal administration and topical administration.
  • parenteral administration includes intramuscular injection, subcutaneous injection, intravenous injection, intramedullary injection, ventricular injection, intraperitoneal injection, intralymphatic injection, and intranasal injection.
  • the compounds described herein are administered locally rather than systemically.
  • long-acting formulations are administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection.
  • the drug is administered via a targeted drug delivery system.
  • liposomes coated with organ-specific antibodies In this specific embodiment, the liposomes are selectively targeted to specific organs and absorbed.
  • compositions and dosages are provided.
  • the invention also provides pharmaceutical compositions comprising a therapeutically effective amount of one or more compounds of the invention formulated with one or more pharmaceutical carriers (additives) and/or diluents, and optionally a one or more of the other therapeutic agents mentioned above.
  • the compounds of the invention for any of the above uses may be administered by any suitable means, for example orally, such as tablets, pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups and emulsions; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion techniques (e.g.
  • nasally including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally, such as in the form of a suppository; or intratumoral injection.
  • nasally including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally, such as in the form of a suppository; or intratumoral injection.
  • nasally including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally, such as in the form of a suppository; or intratumoral injection.
  • nasally including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally, such as in the form of a suppository; or intratumoral injection.
  • nasally
  • Pharmaceutical carriers are formulated based on many factors within the scope of those skilled in the art. These factors include, but are not limited to: the type and nature of the active agent formulated; the subject to whom the composition containing the active agent is to be administered; the intended route of administration of the composition; and the targeted therapeutic indication. Pharmaceutical carriers include aqueous and non-aqueous liquid media and various solid and semi-solid pharmaceutical carriers.
  • the above-mentioned carrier may include many different ingredients and additives in addition to the active agent.
  • the above-mentioned other ingredients are included in the formulation for various reasons known to those skilled in the art, such as stabilizers, binders, etc.
  • Descriptions of suitable pharmaceutical carriers and factors involved in carrier selection can be found in several readily available sources, such as Allen L.V. Jr. et al. Remington: The Science and Practice of Pharmacy (2Volumes), 22nd Edition (2012) ,Pharmaceutical Press.
  • Dosage regimens for the compounds of the invention will, of course, vary depending on known factors such as the pharmacodynamic properties of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition and weight of the recipient ; Nature and extent of symptoms; type of concurrent treatment; frequency of treatment; route of administration, patient's renal and hepatic function, and expected effects.
  • the daily oral dosage of each active ingredient should be from about 0.001 mg/day to about 10-5000 mg/day, preferably from about 0.01 mg/day to about 1000 mg/day, and most preferably The range is about 0.1 mg/day to about 250 mg/day.
  • the most preferred intravenous dose should be from about 0.01 mg/kg/minute to about 10 mg/kg/minute.
  • the compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses of two, three or four times daily.
  • the compounds are typically formulated with a suitable pharmaceutical diluent, excipient or carrier (herein (collectively referred to as pharmaceutical carriers) are administered in the form of a mixture.
  • a suitable pharmaceutical diluent, excipient or carrier herein (collectively referred to as pharmaceutical carriers) are administered in the form of a mixture.
  • Dosage forms suitable for administration may contain from about 1 mg to about 2000 mg of active ingredient per dosage unit.
  • the active ingredient will generally be present in an amount of about 0.1 to 95% by weight, based on the total weight of the composition.
  • a typical capsule for oral administration contains at least one compound of the invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). Pass the mixture through a 60 mesh screen and package into size 1 gelatin capsules.
  • a typical injectable formulation may be prepared by aseptically placing at least one compound of the invention (250 mg) in a vial, aseptically lyophilizing and sealing. For use, mix the contents of the vial with 2 mL of physiological saline to produce an injectable formulation.
  • compositions comprising as active ingredient a therapeutically effective amount of at least one compound of the invention, alone or in combination with a pharmaceutical carrier.
  • the compounds of the invention may be used alone, in combination with other compounds of the invention, or in combination with one or more other therapeutic agents (eg, anticancer agents or other pharmaceutically active substances).
  • the compounds of the invention (which may be used in a suitably hydrated form) and/or the pharmaceutical compositions of the invention are formulated into pharmaceutical dosage forms by conventional methods known to those skilled in the art.
  • the actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention can be varied to obtain an amount of the active ingredient that is effective in achieving the desired therapeutic response, composition, and mode of administration for a particular patient without being toxic to the patient.
  • the dosage level selected will depend on a variety of factors, including the activity of the particular compound of the invention employed, or its ester, salt or amide; the route of administration; the time of administration; the rate of excretion of the particular compound employed; the rate and extent of absorption. ;The duration of treatment; other drugs, compounds and/or substances used in combination with the specific compound used; factors well known in the medical field such as age, sex, weight, condition, general health and previous medical history of the patient being treated.
  • a physician or veterinarian of ordinary skill in the art can readily determine and prescribe an effective amount of the desired pharmaceutical composition. For example, to achieve a desired therapeutic effect, a physician or veterinarian may initiate a trial of a compound of the invention used in a pharmaceutical composition at a level lower than required and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a compound of the invention will be the lowest dose of compound effective to produce a therapeutic effect. Such effective doses will generally depend on the factors noted above.
  • oral, intravenous, intracerebroventricular, and subcutaneous dosages of a compound of the invention for use in a patient range from about 0.01 to about 50 mg/kg body weight/day.
  • an effective daily dose of active compound may be administered separately in two, three, four, five, six or more sub-doses at appropriate intervals throughout the day, optionally in unit dosage form. In certain aspects of the invention, administration is once daily.
  • compositions can be administered alone, it is preferred to administer the compounds in the form of pharmaceutical preparations (compositions).
  • kits can be composed of a conveyor, a drug pack or a container box, which can be divided into multiple compartments to accommodate one or more containers, such as vials, test tubes and the like, each container containing all a single ingredient in the method described.
  • Suitable containers include bottles, vials, syringes and test tubes.
  • Containers are made of acceptable materials such as glass or plastic.
  • the container may contain one or more compounds described herein, either as a pharmaceutical compound or in a mixture with other ingredients described herein.
  • the container may have a sterile outlet (for example, the container may be an IV bag or bottle, and the stopper may be pierced by a hypodermic needle).
  • kits may contain a compound and instructions for use, labeling, or operating instructions described herein.
  • a typical kit may include one or more containers, each containing one or more materials (such as reagents, or concentrated stock solutions, and/ or equipment). These materials include, but are not limited to, buffers, diluents, filters, needles, syringes, delivery devices, bags, containers, bottles and/or test tubes, accompanied by a list of contents and/or instructions for use, as may the built-in packaging. The entire set of instructions must be included.
  • Labels can appear on the container or be closely associated with the container. When a label appears on a container, it means that the label's letters, numbers, or other features are pasted, molded, or engraved on the container; the label may also appear inside a container box or shipping box containing a variety of containers, such as in a product insert. A label may be used to indicate a specific therapeutic use of the contents. The label may also indicate instructions for use of the contents, such as described in the method above.
  • the unit of weight-volume percentage in the present invention is well known to those skilled in the art, for example, it refers to the weight (g) of the solute in 100 ml of solution.
  • all technical and scientific terms used herein have the same meaning as familiar to one of ordinary skill in the art.
  • any methods and materials similar or equivalent to those described can be used in the method of the present invention.
  • the preferred implementation methods and materials described in this article are for demonstration purposes only.
  • the raw materials and reagents used in the present invention are all known products and can be synthesized according to methods known in the art, or can be obtained by purchasing commercially available products. None of the commercially available reagents were used without further purification.
  • Room temperature refers to 20-30°C.
  • Nitrogen atmosphere means that the reaction bottle is connected to a nitrogen balloon of about 1L.
  • the hydrogenation reaction is usually evacuated, filled with hydrogen, and repeated three times.
  • the hydrogen atmosphere refers to the reaction bottle connected to a hydrogen balloon of about 1L.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • LC-MS was measured using a Thermo liquid mass spectrometer (UltiMate 3000+MSQ PLUS).
  • HPLC measurement used a Thermo high-pressure liquid chromatograph (UltiMate 3000).
  • Reverse-phase preparative chromatography used Thermo (UltiMate 3000) reverse-phase preparative chromatography.
  • the flash column chromatography uses Aijer (FS-9200T) automatic column machine, and the silica gel prepacked column uses Santai Prepacked columns.
  • Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates.
  • the specifications used for thin layer chromatography separation and purification products are 0.4mm ⁇ 0.5mm.
  • Step 1 Dissolve compounds Int-1a (5.0g, 28.09mmol), Int-1b (5.61g, 36.51mmol) and sodium bicarbonate (7.08g, 84.26mmol) in ethanol (50mL) and water (5mL) , the reaction solution was heated to reflux overnight. After the reaction was monitored by LCMS, it was cooled to room temperature, filtered with suction, and the filter cake was washed with water and then dried to obtain off-white solid Int-1 (5.0 g, yield 78%). ESI-MS(m/z):227.4[M+H] + .
  • Step 1 Add sodium hydrogen (1.59g, 39.64mmol, content 60%) into a two-necked flask containing anhydrous tetrahydrofuran (10mL), place it in an ice-water bath, and add compound Int-2a (5.0g, 26.43mmol) Dissolve in anhydrous tetrahydrofuran (30 mL) and slowly add dropwise to the reaction solution. After 30 minutes, deuterated methyl iodide (4.02g, 27.75mmol) was added dropwise. After the dropwise addition was completed, the mixture was slowly raised to room temperature and stirred overnight.
  • Step 2 Dissolve Int-2b (5.0g, 24.24mmol) in methanol (50mL), place it in an ice water bath, slowly add thionyl chloride (8.65g, 72.73mmol) dropwise, and raise to room temperature, and then raised to 60°C for overnight reaction. After the reaction was monitored by LCMS, the reaction solution was concentrated to obtain yellow oil Int-2c (3.0 g, yield 79%). ESI-MS(m/z):157.2[M+H] + .
  • Step 3 Dissolve compounds Int-1a (2.0g, 11.23mmol), Int-2c (3.17g, 20.22mmol) and sodium bicarbonate (2.83g, 33.70mmol) in ethanol (20mL) and water (2mL) , the reaction solution was refluxed overnight. After the reaction was monitored by LCMS, it was cooled to room temperature, filtered with suction, and the filter cake was washed with water and then dried to obtain off-white solid Int-2 (1.4 g, yield 54%).
  • Step 1 Add sodium hydrogen (237 mg, 5.90 mmol, content 60%) into a two-necked flask containing anhydrous tetrahydrofuran (5 mL), place it in an ice-water bath, and dissolve compound Int-3a (300 mg, 1.48 mmol) in Anhydrous tetrahydrofuran (10 mL) was slowly added dropwise to the reaction solution. After 30 minutes, deuterated methyl iodide (472 mg, 2.95 mmol) was added dropwise. After the dropwise addition was completed, the mixture was slowly raised to room temperature and stirred overnight.
  • Step 2 Dissolve Int-3b (312mg, 1.42mmol) in methanol (5mL), place it in an ice water bath, slowly add thionyl chloride (505mg, 4.25mmol) dropwise, and raise to room temperature after the dropwise addition is completed. Then raise to 70°C and react overnight. After the reaction was monitored by LCMS, the reaction solution was concentrated to obtain yellow oil Int-3c (180 mg, yield 84%). ESI-MS(m/z):135.4[M+H] + .
  • Step 1 Dissolve compound Int-4a (1.01g, 5mmol) and potassium hydroxide (842mg, 15mmol) in anhydrous dimethyl sulfoxide (10mL), and then add deuterated methyl iodide (1.59g, 11mmol) Add dropwise to the reaction solution. The reaction solution was stirred at room temperature for 8 hours. LCMS monitored the reaction to completion. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain the crude compound Int-4b (1.0 g, yield 84%). ESI-MS(m/z):236.3[M+H] + .
  • Step 2 Dissolve compound Int-4b (1.0g, 4.25mmol) in dioxane hydrochloride solution (4M, 10mL). The reaction solution was stirred at room temperature for 4 hours. LCMS monitored the reaction to completion. The reaction solution was concentrated under reduced pressure to obtain a crude product of compound Int-4c (720 mg). ESI-MS(m/z):136.1[M+H] + .
  • Step 3 Dissolve compound Int-4c (720mg, 4.19mmol) and compound Int-3d (872mg, 4.19mmol) in tetrahydrofuran (10mL), add N,N-diisopropylpropylamine (1.62g, 12.57mmol) ). The reaction solution was stirred at room temperature for 8 hours. LCMS monitored the reaction to completion. The reaction solution was diluted with water, filtered, and the filter cake was washed with water and dried to obtain off-white solid Int-4d (993 mg, two-step reaction yield 77%). ESI-MS(m/z):307.2[M+H] + .
  • Step 4 Dissolve compound Int-4d (306 mg, 1 mmol) and potassium carbonate (207 mg, 1.5 mmol) in methanol (10 mL). Dissolve sodium dithionite (871 mg, 5 mmol) in water and add dropwise to the reaction solution. The reaction solution was stirred at room temperature for 15 minutes. LCMS monitored the complete reaction of raw materials. Dioxane hydrochloride solution (4M, 1.25mL) was added to the reaction solution. The reaction solution was continued to stir at room temperature for 8 hours.
  • Step 1 Dissolve compound Int-1a (500mg, 2.81mmol) and compound Int-6a (602mg, 3.65mmol) in ethanol (20mL) and water (2mL), then add sodium bicarbonate (707mg, 8.34mmol) , raise the temperature of the reaction solution to 80°C, and stir for 16 hours. After the reaction solution was cooled to room temperature, water (12 mL) was added to the reaction solution. After filtration, off-white solid Int-6 (385 mg, yield 57%) was obtained. ESI-MS (m/z): 239.4 [M+H] + .
  • Step 2 Dissolve and disperse compound Int-7b (1.3g, 4.88mmol) and Raney Nickel (0.5mL, aqueous suspension) in methanol (10mL) and ammonia water (1mL), ventilate with a hydrogen balloon, and keep at room temperature Stir overnight under these conditions.
  • LCMS monitored the completion of the reaction.
  • the reaction solution was diluted with methanol, filtered through a diatomaceous earth filter layer, and the organic phase was concentrated to obtain Int-7 (700 mg, yield 53%) as a yellow oil.
  • Step 1 Dissolve 6-(trifluoromethyl)pyridin-3-ol Int-8a (1.0g, 6.13mmol) in dimethyl sulfoxide (10mL), add cesium carbonate (2.0g, 6.13mmol), After stirring at room temperature for 30 minutes, 2-fluoropyridine-5-carboxaldehyde Int-8b (1.53g, 12.26mmol) was added, and the reaction mixture was continued to stir for 2 hours before the reaction was terminated.
  • Step 2 Dissolve compound Int-8c (1.53g, 5.70mmol) in ethanol (5mL), add hydroxylamine hydrochloride (792mg, 11.41mmol), and stir at room temperature overnight.
  • the reaction solution was concentrated to obtain crude oxime, which was redissolved in acetic acid (5 mL), zinc powder (1.94 g, 29.66 mmol) was added, and the mixture was stirred at room temperature for 2 hours.
  • LCMS detected that the reaction was complete.
  • the mixture was filtered, and the filtrate was concentrated to obtain compound Int-8 (1.3g), which was directly used in the next reaction.
  • Step 2 Dissolve and disperse compound Int-9b (630 mg, 2.71 mmol) and Raney Nickel (0.5 mL, aqueous suspension) in methanol (10 mL) and ammonia water (1 mL), and use a hydrogen balloon to ventilate at room temperature. Stir overnight.
  • LCMS monitors the end of the reaction.
  • Step 1 Dissolve 2-(methylthio)-5-hydroxypyrimidine Int-10a (300 mg, 2.11 mmol) in acetonitrile (5 mL), add cesium carbonate (1.37 g, 4.22 mmol), and stir at room temperature for 30 minutes.
  • 2-Fluoropyridine-5-carboxaldehyde Int-8b (316 mg, 2.53 mmol) was added and the reaction mixture was stirred overnight.
  • LCMS monitored the reaction to completion. The reaction solution was diluted with water, and then extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step 2 Dissolve compound Int-10b (400mg, 1.62mmol) and 3,4-dimethoxybenzylamine (405mg, 2.43mmol) in dichloromethane (5mL) and methanol (0.5mL), and stir at room temperature After 2 hours, sodium acetate borohydride (2.06g, 9.71mmol) was added and the reaction mixture was stirred overnight. LCMS monitored the reaction to completion. The reaction solution was diluted with water, and then extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain yellow liquid Int-10c (630 mg, yield 98%). ESI-MS(m/z):399.4[M+H] + .
  • Step 4 Add compound Int-10d (402 mg, 0.86 mmol) to trifluoroacetic acid (1.5 mL), stir at room temperature overnight, and monitor the end of the reaction with LCMS.
  • Example 1 is prepared by the following steps:
  • Step 1 Dissolve compound Int-1 (50mg, 220.59umol) and compound Int-7 (77.49mg, 286.77umol) in n-butanol (2mL), add p-toluenesulfonic acid monohydrate (3.89mg, 27umol ), the reaction solution was stirred at 160°C for 3 hours under microwave conditions. After the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by Pre-HPLC to obtain white solid 1 (21.43 mg, yield 21%).
  • Example 2 is prepared by the following steps:
  • Step 1 Dissolve compound Int-2 (100mg, 435.39umol) and compound Int-7 (152.94mg, 566.00umol) in n-butanol (2mL), add p-toluenesulfonic acid monohydrate (8.27mg, 43.54 umol), the reaction solution was stirred at 160°C for 3 hours under microwave conditions. After the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to obtain white solid 2 (38.22 mg, yield 18%).
  • Example 3 is prepared by the following steps:
  • Step 1 Dissolve compound Int-6 (80mg, 335.19umol) and compound Int-7 (117.74mg, 435.74umol) in n-butanol (2mL), add p-toluenesulfonic acid monohydrate (6.37mg, 33.52 umol), the reaction solution was stirred at 160°C for 3 hours under microwave conditions. After the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by Pre-HPLC to obtain white solid 3 (99.37 mg, yield 62%).
  • Example 4 is prepared by the following steps:
  • Step 1 Add sodium hydrogen (1.59g, 39.76mmol, content 60%) into a two-necked flask containing anhydrous tetrahydrofuran (20mL), place it in an ice-water bath, and dissolve compound Int-4a (2g, 9.94mmol) Anhydrous tetrahydrofuran (10 mL) was slowly added dropwise to the reaction solution. After 30 minutes, methyl iodide (3.53g, 24.85mmol) was added dropwise. After the dropwise addition was completed, the mixture was slowly raised to room temperature and stirred overnight.
  • Step 2 Dissolve 4a (1.7g, 7.90mmol) in methanol (5mL), place it in an ice water bath, slowly add thionyl chloride (2.82g, 23.69mmol) dropwise, and raise to room temperature after the dropwise addition is completed. Then raise to 70°C and react overnight. After the reaction was monitored by LCMS, the reaction solution was concentrated to obtain yellow solid 4b (1.2 g, yield 91%). ESI-MS(m/z):130.2[M+H] + .
  • Step 4 Dissolve compound 4c (200mg, 665.12umol) and compound Int-7 (270.21mg, 215.67umol) in N,N-dimethylformamide (5mL), add N,N-diisopropyl Ethylamine (27.89 mg, 2.00 mmol).
  • the reaction solution was stirred at room temperature for 8 hours.
  • LCMS monitored the reaction to completion.
  • the reaction solution was diluted with water and extracted with ethyl acetate.
  • the reaction solution was concentrated under reduced pressure.
  • Step 5 Dissolve compound 4d (250 mg, 467.77umol) in methanol (5 mL), add palladium on carbon (5.68 mg, 46.78umol), and then replace the reaction system with hydrogen. The reaction solution was stirred at room temperature for 8 hours. LCMS monitored the completion of the reaction, and the residue was filtered through diatomaceous earth. The reaction solution was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to obtain white solid 4 (24.02 mg, yield 10%).
  • Example 5 was obtained by referring to the synthesis method of Example 4.
  • Example 6 is prepared by the following steps:
  • Step 1 Dissolve compound Int-3 (55mg, 225umol) and compound Int-7 (73mg, 270umol) in n-butanol (2mL), add p-toluenesulfonic acid monohydrate (3.89mg, 27umol), and react The solution was stirred under microwave conditions at 160°C for 3 hours. After the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by Pre-HPLC to obtain white solid 6 (24 mg, yield 21%).
  • Example 7 is prepared by the following steps:
  • Step 1 Add sodium hydrogen (275 mg, 6.89 mmol, content 60%) into a two-necked flask containing anhydrous tetrahydrofuran (5 mL), place it in an ice-water bath, and dissolve compound 7a (350 mg, 1.72 mmol) in anhydrous Tetrahydrofuran (10mL), Slowly add dropwise to the reaction solution. After 30 minutes, methyl iodide (366 mg, 2.58 mmol) was added dropwise. After the dropwise addition was completed, the mixture was slowly raised to room temperature and stirred overnight.
  • Step 2 Dissolve 7b (370mg, 1.70mmol) in methanol (5mL), place it in an ice-water bath, slowly add thionyl chloride (405mg, 3.41mmol) dropwise, and after the dropwise addition is completed, rise to room temperature, and then React overnight at 70°C. After the reaction was monitored by LCMS, the reaction solution was concentrated to obtain yellow oil 7c (200 mg, yield 86%).
  • Step 3 Dissolve compound 7c (200 mg, 1.19 mmol) and compound Int-3d (225 mg, 1.08 mmol) in tetrahydrofuran (5 mL), and add N, N-diisopropylpropylamine (420 mg, 3.25 mmol).
  • the reaction solution was stirred at room temperature for 8 hours.
  • LCMS monitored the reaction to completion.
  • Step 4 Dissolve compound 7d (70 mg, 231umol) and compound Int-7 (75mg, 278umol) in tetrahydrofuran (5mL), and add N,N-diisopropylpropylamine (90mg, 694umol).
  • the reaction solution was stirred at room temperature for 8 hours.
  • LCMS monitored the reaction to completion.
  • the reaction solution was diluted with water and extracted with ethyl acetate.
  • the reaction solution was concentrated under reduced pressure.
  • Step 5 Dissolve compound 7e (90 mg, 177 umol) in methanol (5 mL), add palladium on carbon (10 mg, 89 umol), and then replace the reaction system with hydrogen. The reaction solution was stirred at room temperature for 8 hours. LCMS monitored the completion of the reaction, and the residue was filtered through diatomaceous earth. The reaction solution was concentrated under reduced pressure. The residue was purified by Prep-HPLC to obtain white solid 7 (21 mg, yield 25%).
  • Example 8 was prepared by the following steps:
  • Step 1 Dissolve compound Int-1 (50.00mg, 220.59umol) and compound Int-9 (67.87mg, 286.77umol) in n-butanol (2mL), add p-toluenesulfonic acid monohydrate (4.19mg, 22.06umol), the reaction solution was stirred at 160°C for 3 hours under microwave conditions. After the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to obtain white solid 8 (10.69 mg, yield 11%).
  • Example 9 is prepared by the following steps:
  • Step 1 Dissolve compound Int-1 (50.00mg, 220.59umol) and compound Int-8 (77.02mg, 286.77umol) in n-butanol (2mL), add p-toluenesulfonic acid monohydrate (4.19mg, 22.06umol), the reaction solution was stirred at 160°C for 3 hours under microwave conditions. After the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by Pre-HPLC to obtain white solid 9 (64.26 mg, yield 63%).
  • Example 10 was prepared by the following steps:
  • Step 1 Dissolve compound Int-1 (50.00mg, 220.59umol) and compound Int-5 (67.58mg, 286.77umol) in n-butanol (2mL), add p-toluenesulfonic acid monohydrate (4.19mg, 22.06umol), the reaction solution was stirred at 160°C for 3 hours under microwave conditions. After the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by Pre-HPLC to obtain a white solid 10 (49.62 mg, yield 52%).
  • Comparative Example 1 was obtained by referring to the synthesis method of compound 54 described in patent WO2019209757.
  • ESI-MS (m/z): 409.8[M+H] + ;
  • Test Example 1 Construction of Colo205-LUC-TCF/LEF-M1 reporter cell line
  • the Colo205 cell line (Cell Bank of the Chinese Academy of Sciences, Cat#TCHu102) was purchased from the Cell Bank of the Chinese Academy of Sciences. After expansion and subculture, the cells were transfected with TCF/LEF transcription factors using lipo3000 lipofectamine transfection during the exponential growth phase of the cells.
  • Driver luciferase reporter plasmid (Promega). This plasmid contains a resistance gene and can be used for resistance screening. Transfections were performed in 10 cm dishes using conventional complete medium without resistance. After 2 days, replace the medium with resistance and continue culturing. Afterwards, the resistant medium was replaced every 2 days, and the suspended cells were discarded. The original medium was centrifuged to remove cells and debris and retained as adaptive medium.
  • the cells in a single clone well fill the wells of the 96-well plate, they are digested and passaged to a 24-well culture plate. After the 24-well plate is full, they are passaged to a 96-well plate and a 6-well plate, of which 96 The cells in the well plate were passaged into at least 6 wells, of which 3 wells were added with known Wnt inhibitors, and the other 3 wells were left untreated. After 24 hours, fluorescent detection reagent was added to the cells in the 96-well plate to detect the fluorescence intensity. Select cell lines that have fluorescent expression when not treated and whose fluorescent light is reduced after inhibition for further culture.
  • Colo205-LUC-TCF/LEF-M1 cell line is one of the above-selected cell lines. Its growth curve, cell morphology, and cell growth status are similar to those of the original Colo205 cells, and its fluorescent signals are treated with and without inhibitors. The ratio is relatively large among all cell lines, and the ratio can be inhibited 4-5 times at 4 hours, which is completely suitable for the screening of Wnt inhibitors in the later stage.
  • Test Example 2 Detection of the inhibitory ability of compounds against Colo205-LUC-TCF/LEF M1 reporter cell line
  • the Colo205-LUC-TCF/LEF M1 cell line is a reporter tool cell stably transfected with the pGL4.49-LUC2-TCF/LEF vector. Its ⁇ -catenin Wnt pathway is continuously activated. After the inhibitor is added, the Wnt pathway is inhibited. The expression level of firefly luciferase regulated by the TCF/LEF cis-element decreases. After the detection substrate is subsequently added, the detected light signal decreases accordingly, thereby detecting the inhibitory effect of the compound.
  • Luminescence intensity was read with SpectraMax in full wavelength mode.
  • the light signal intensity of cells treated only with DMSO was a positive control, and the light signal intensity of wells without cells was a negative control.
  • the IC 50 concentration of each compound was calculated.
  • Colo 205 reporter gene testing data is summarized in Table 1 below.
  • Test Example 3 Proliferation inhibitory test of compounds on Wnt mutant cell lines (Colo205, DU4475, NCI-H929 and HepG2) and non-Wnt mutant cell lines (Hela and RKO)
  • the cell lines used in the experiment are Colo205, DU4475, NCI-H929 and HepG2 cell lines that are continuously activated by the Wnt pathway, and their proliferation is dependent on the Wnt pathway. Under normal circumstances, the Wnt pathway is not activated, and proliferation is not dependent on the Wnt pathway.
  • the HELA and RKO cell lines were used as control cell lines to determine that the inhibitory effect of the compounds of the present invention on Wnt-dependent proliferation was not due to other non-specific toxicity.
  • the Colo205, Du4475, NCI-H929, HepG2, HELA and RKO cell lines cultured in their respective culture media were treated during the logarithmic growth phase.
  • the cells were collected and prepared into a uniform cell suspension of known concentration, and then injected into 96 wells. Add cell suspension to the cell culture plate so that each well contains 1,000 cells. Place in a 5% CO2 cell culture incubator and culture at 37°C for 20-24h. The next day, add the completely dissolved compound in a 3-fold gradient dilution to each cell culture well so that the final maximum concentration in the cell culture well is 20 ⁇ M, and continue culturing for 96 hours. This test uses Promega's cell viability detection test.
  • the detection instrument is SpectraMax, full wavelength mode.
  • the wells with only DMSO added were used as positive control wells, and the wells with no cells seeded were used as negative control wells.
  • the IC 50 values of each compound for inhibiting the proliferation of Wnt-activated or proliferation-dependent cells were calculated, as well as for Wnt-inactivated or proliferation-independent cells.
  • the IC 50 value of cell proliferation inhibition was used to evaluate the inhibitory effect of the compound on the Wnt pathway and the toxic effect on normal cells. The results are shown in Table 2 below.
  • Test Example 4 Evaluation of the pharmacokinetics of the compound of the present invention in mice
  • ICR mice male, 25-35g, purchased from Shanghai Slack Experimental Animal Co., Ltd.
  • DMSO dimethyl sulfoxide
  • PEG-400 polyethylene glycol 400
  • Solutol HS-15 ultrapure water
  • methanol methanol
  • acetonitrile formic acid
  • propranolol internal standard
  • tolbutamide Internal standard
  • ICR mouse blank plasma EDTA-K2 anticoagulant
  • Test Example 5 Tumor growth inhibition test of Compound 1 (W421) on Colo205 mouse Xenograft model
  • mice Female BALB/c Nude nude mice were subcutaneously inoculated with human colon cancer cell Colo205 to establish a Colo205 BALB/c Nude nude mouse transplanted tumor model. After the tumors grew to an average tumor volume of about 100 mm, the tumor-bearing mice were randomly divided into 4 groups according to the tumor volume: solvent-treated control group, 1.5 mg/kg compound group 1, and 3 mg/kg compound 1 group. and 10 mg/kg compound group 1. Compound 1 was administered orally once a day for 15 days, and tumor volume was measured every other day (Figure 1). Body weight and tumor volume were measured on Day 15 (Table 4).

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Abstract

La présente invention concerne un composé inhibiteur de la voie Wnt représenté par la formule (I), une composition pharmaceutique comprenant le composé, et l'utilisation du composé représenté par la formule (I) dans la prévention et/ou le traitement de cancers, de tumeurs, de maladies inflammatoires, de maladies auto-immunes ou de maladies à médiation immunitaire.
PCT/CN2023/109227 2022-07-28 2023-07-26 Composé inhibiteur de la voie wnt WO2024022365A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104379583A (zh) * 2012-06-15 2015-02-25 广州源生医药科技有限公司 作为wnt信号传导抑制剂的化合物、组合物及其应用
CN106458983A (zh) * 2014-03-20 2017-02-22 拜耳制药股份公司 新型化合物
CN109310690A (zh) * 2016-04-27 2019-02-05 萨穆梅德有限公司 异喹啉-3-基甲酰胺类及其制备和其用途
CN112218865A (zh) * 2018-04-24 2021-01-12 沃泰克斯药物股份有限公司 喋啶酮化合物及其用途
WO2022089454A1 (fr) * 2020-10-28 2022-05-05 杭州阿诺生物医药科技有限公司 Composé inhibiteur de la voie wnt à haute activité
WO2023143501A1 (fr) * 2022-01-29 2023-08-03 杭州阿诺生物医药科技有限公司 Composé inhibiteur de la voie wnt

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104379583A (zh) * 2012-06-15 2015-02-25 广州源生医药科技有限公司 作为wnt信号传导抑制剂的化合物、组合物及其应用
CN106458983A (zh) * 2014-03-20 2017-02-22 拜耳制药股份公司 新型化合物
CN109310690A (zh) * 2016-04-27 2019-02-05 萨穆梅德有限公司 异喹啉-3-基甲酰胺类及其制备和其用途
CN112218865A (zh) * 2018-04-24 2021-01-12 沃泰克斯药物股份有限公司 喋啶酮化合物及其用途
WO2022089454A1 (fr) * 2020-10-28 2022-05-05 杭州阿诺生物医药科技有限公司 Composé inhibiteur de la voie wnt à haute activité
WO2023143501A1 (fr) * 2022-01-29 2023-08-03 杭州阿诺生物医药科技有限公司 Composé inhibiteur de la voie wnt

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