WO2024022365A1 - Wnt pathway inhibitor compound - Google Patents

Wnt pathway inhibitor compound 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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Prior art keywords
halogenated
compound
alkyl
cycloalkyl
formula
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PCT/CN2023/109227
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French (fr)
Chinese (zh)
Inventor
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/en
Publication of WO2024022365A1 publication Critical patent/WO2024022365A1/en

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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).

Abstract

The present invention relates to a Wnt pathway inhibitor compound represented by formula (I), a pharmaceutical composition comprising the compound, and use of the compound of formula (I) in preventing and/or treating cancers, tumors, inflammatory diseases, autoimmune diseases, or immune-mediated diseases.

Description

一种Wnt通路抑制剂化合物A Wnt pathway inhibitor compound 技术领域Technical field
本发明涉及一种杂环化合物，具体地涉及一种高活性的Wnt通路抑制剂及其用途。The present invention relates to a heterocyclic compound, specifically to a highly active Wnt pathway inhibitor and its use.
背景技术Background technique
Wnt/β-catenin信号转导通路是一条在生物进化中保守的通路。在正常的体细胞中，β-catenin只是作为一种细胞骨架蛋白在胞膜处与E-cadherin形成复合体对维持同型细胞的黏附、防止细胞的移动发挥作用。当Wnt信号通路未被激活时，细胞质内的β-catenin被磷酸化，并与APC、Axin和GSK3β等形成β-catenin降解复合物，从而启动泛素系统经蛋白酶体途径降解β-catenin，使细胞质内的β-catenin维持在较低水平。当细胞受到Wnt信号刺激时，Wnt蛋白与细胞膜上特异性受体Frizzled蛋白结合，激活后的Frizzled受体招募胞内Dishevelled蛋白，抑制GSK3β等蛋白形成的β-catenin降解复合物的降解活性，稳定细胞质中游离状态的β-catenin蛋白。胞浆中稳定积累的β-catenin进入细胞核后结合LEF/TCF转录因子家族，启动下游靶基因(如c-myc、c-jun，Cyclin D1等)的转录。Wnt/β-catenin信号通路的过度激活与多种癌症(包括结肠癌、胃癌、乳腺癌等)的发生密切相关。例如结直肠癌中广泛存在Wnt经典信号通路的异常激活和β-catenin蛋白的核内积聚现象,而通过抑制Wnt信号通路活性可以抑制例如结肠癌等癌症的增殖。85％以上的结直肠癌中均存在APC的突变，突变后的APC阻断β-catenin磷酸化降解，诱导结直肠癌的发生。此外，Axin突变、β-catenin自身突变也可引起β-catenin的胞内聚集，活化Wnt/β-catenin通路。The Wnt/β-catenin signal transduction pathway is a pathway conserved in biological evolution. In normal somatic cells, β-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. When the Wnt signaling pathway is not activated, β-catenin in the cytoplasm is phosphorylated and forms a β-catenin degradation complex with APC, Axin, GSK3β, etc., thereby initiating the ubiquitin system to degrade β-catenin through the proteasome pathway, causing β-catenin in the cytoplasm is maintained at a low level. When cells are stimulated by Wnt signals, Wnt proteins bind to Frizzled proteins, a specific receptor on the cell membrane. The activated Frizzled receptors recruit intracellular Dishevelled proteins, inhibit the degradation activity of β-catenin degradation complexes formed by GSK3β and other proteins, and stabilize Free β-catenin protein in the cytoplasm. β-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/β-catenin signaling pathway is closely related to the occurrence of various cancers (including colon cancer, gastric cancer, breast cancer, etc.). For example, abnormal activation of the Wnt classic signaling pathway and nuclear accumulation of β-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 β-catenin and induces the occurrence of colorectal cancer. In addition, Axin mutations and β-catenin self-mutation can also cause intracellular accumulation of β-catenin and activate the Wnt/β-catenin pathway.
尽管已知抑制Wnt信号通路可以有效预防和/或治疗癌症、肿瘤、炎症性疾病、自身免疫性疾病和免疫介导性疾病，但目前现有技术中尚缺乏令人满意的有效的Wnt通路抑制剂化合物。因此，研究有效的Wnt通路抑制剂化合物，是现有技术中的需要。Although it is known that inhibiting the Wnt signaling pathway can effectively prevent and/or treat cancer, tumors, inflammatory diseases, autoimmune diseases, and immune-mediated diseases, there is currently a lack of satisfactory and effective Wnt pathway inhibition in the existing technology. agent compound. Therefore, research on effective Wnt pathway inhibitor compounds is a need in the existing technology.
发明内容Contents of the invention
一方面，本发明提供了一种具有式(I)结构的抑制Wnt通路活性的化合物或其药学上可接受的盐、同位素衍生物、立体异构体：
On the one hand, 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:
其中， in,
R1、R2各自独立地代表氢、(C1-C6)烷基、卤代(C1-C6)烷基、(C3-C8)环烷基、卤代(C3-C8)环烷基、4-8元杂环烷基、卤代4-8元杂环烷基、-(C1-C6)亚烷基ORa、-卤代(C1-C6)亚烷基ORa、-(C1-C6)亚烷基SRa、-卤代(C1-C6)亚烷基SRa，或者R1、R2与和它们相连的碳原子一起形成3-8元环，所述环可以任选地含有0、1、2或3个选自N、O和S的杂原子；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;
R3表示(C1-C6)烷基、卤代(C1-C6)烷基、(C3-C8)环烷基、卤代(C3-C8)环烷基，或者R3和R1或者R2一起形成4-7元环，所述环可以任选地含有0个或1个选自O和S的杂原子；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;
W6表示CR6或者N；W 6 means CR 6 or N;
R6各自独立地表示氢、卤素、氰基、(C1-C3)烷基、卤代(C1-C3)烷基；R 6 each independently represents hydrogen, halogen, cyano group, (C 1 -C 3 ) alkyl group, or halogenated (C 1 -C 3 ) alkyl group;
Cy表示5-12元芳杂环，其任选地含有1、2、3或4个杂原子，所述杂原子各自独立地选自选自N、O和S，且，Cy与-O-连接位置的邻位不被取代或者被氢取代；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;
R1’表示氢、卤素、(C1-C6)烷基、卤代(C1-C6)烷基、(C3-C8)环烷基、卤代(C3-C8)环烷基、(C3-C8)杂环烷基、卤代(C3-C8)杂环烷基、-ORa、-卤代ORa、-SRa、-卤代SRa；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 ;
R2’表示氢、卤素、(C1-C6)烷基、卤代(C1-C6)烷基、(C3-C8)环烷基、卤代(C3-C8)环烷基、(C3-C8)杂环烷基、卤代(C3-C8)杂环烷基、-ORa、-卤代ORa、-SRa、-卤代SRa；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 ;
R3’表示氢、卤素、(C1-C6)烷基、卤代(C1-C6)烷基、(C3-C8)环烷基、卤代(C3-C8)环烷基、(C3-C8)杂环烷基、卤代(C3-C8)杂环烷基、-ORa、-卤代ORa、-SRa、-卤代SRa；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 ;
m各自独立地表示0、1或2；m independently represents 0, 1 or 2;
Ra各自独立地表示氢、(C1-C6)烷基、卤代(C1-C6)烷基、(C3-C8)环烷基、卤代(C3-C8)环烷基。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.
在一个方面，式(I)结构中的Cy为5元杂芳环或者6元杂芳环。更优选地，Cy为吡啶基、嘧啶基、哒嗪基、吡嗪基、吡唑基、咪唑基或吡咯基。In one aspect, 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.
在又一个方面，式(I)化合物如式(II)所示：
In yet another aspect, a compound of formula (I) is represented by formula (II):
其中，in,
虚线环表示其所在的环为芳香环；The dotted ring indicates that the ring it is in is an aromatic ring;
W1表示CR1’或者N； W 1 means CR 1 ' or N;
W2表示CR2’或者N；W 2 means CR 2 ' or N;
W3表示CR3’或者N；W 3 means CR 3 ' or N;
W4表示CH或者N；W 4 represents CH or N;
W5表示CH或者N；W 5 means CH or N;
R1、R2、R3、R6、W6、R1’、R2’、R3’、Ra、m如权利要求1所述。更优选地，式(II)化合物如以下所示：
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:
在另一个方面，式(I)化合物如式(III)所示：
In another aspect, a compound of formula (I) is represented by formula (III):
其中，in,
虚线环表示其所在的环为芳香环； The dotted ring indicates that the ring it is in is an aromatic ring;
W1’表示CH、N或者NH；W 1 'represents CH, N or NH;
W2’表示CR2’、N或者NR2’；W 2 ' represents CR 2 ', N or NR 2 ';
W3’表示CR3’、N或者NR3’；W 3 ' represents CR 3 ', N or NR 3 ';
W4’表示CH、N或者NH；W 4 'represents CH, N or NH;
R1、R2、R3、R6、W6、R1’、R2’、R3’、Ra、m如权利要求1所述。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 .
更优选地，式(III)化合物如以下所示：
More preferably, the compound of formula (III) is as follows:
在一个方面，R1、R2各自独立地代表氢、(C1-C6)烷基、卤代(C1-C6)烷基、(C3-C8)环烷基、卤代(C3-C8)环烷基、4-8元杂环烷基、卤代4-8元杂环烷基、-(C1-C6)亚烷基ORa、-卤代(C1-C6)亚烷基ORa；优选为氢、(C1-C6)烷基、卤代(C1-C6)烷基。In one aspect, 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.
在一个方面，R3为(C1-C6)烷基。In one aspect, R 3 is (C 1 -C 6 )alkyl.
在一个方面，W6为CR6。In one aspect, W 6 is CR 6 .
在一个方面，R6为氢。In one aspect, R6 is hydrogen.
在一个方面，R1’表示氢、卤素、(C1-C6)烷基、卤代(C1-C6)烷基、(C3-C8)环烷基、卤代(C3-C8)环烷基。更优选地，R1’表示卤代(C1-C6)烷基。In one aspect, 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.
在一个方面，R2’表示氢、卤素、(C1-C6)烷基、卤代(C1-C6)烷基、(C3-C8)环烷基、卤代(C3-C8)环烷基。更优选地，R2’表示氢或者卤素。In one aspect, 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.
在一个方面，R3’表示卤素、(C1-C6)烷基、卤代(C1-C6)烷基、(C3-C8)环烷基、卤代(C3-C8)环烷基、-ORa、-卤代ORa、-SRa、-卤代SRa。优选地，R3’表示卤素、(C1-C6)烷基、卤代(C1-C6)烷基、(C3-C8)环烷基、卤代(C3-C8)环烷基。更优选地，R3’表示卤代(C1-C6)烷基或者卤代(C3-C8)环烷基。In one aspect, 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 . Preferably, 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.
在一些优选的方面，本发明提供了一种化合物，其具有以下结构：

In some preferred aspects, the invention provides a compound having the following structure:

进一步地，本发明还提供了一种药物组合物，包含本发明所述的化合物或其及药学上可接受的盐、同位素衍生物或立体异构体。Furthermore, the present invention also provides a pharmaceutical composition comprising the compound of the present invention or its pharmaceutically acceptable salt, isotope derivative or stereoisomer.
进一步地，本发明还提供了本发明所述的化合物或其药学上可接受的盐、同位素衍生物、立体异构体或者本发明所述的药物组合物在制备用于预防和/或治疗癌症、肿瘤、炎症性疾病、自身免疫性疾病或免疫介导性疾病的药物中的用途。特别注意的是，在本文中，当提及式(I)至式(III)结构的“化合物”时，一般地还涵盖其立体异构体、非对映异构体、对映异构体、外消旋混合物和同位素衍生物。Further, 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.
本领域技术人员公知，一种化合物的盐、溶剂合物、水合物是化合物的替代性存在形式，它们都可以在一定条件下转化为所述化合物，因此，特别注意的是在本文中当提到式(I)至式(III)结构的化合物时，一般地还包括它的可药用盐，进而还包括其溶剂合物和水合物。 It is well known to those skilled in the art that salts, solvates, and hydrates of a compound are alternative forms of the compound, and they can all be converted into the compound under certain conditions. Therefore, special attention should be paid to when mentioning these compounds in this article. Compounds with structures of formulas (I) to (III) generally also include their pharmaceutically acceptable salts, and further include their solvates and hydrates.
相似地，在本文中当提到一种化合物时，一般地还包括其前药、代谢产物和氮氧化物。Similarly, reference herein to a compound generally includes its prodrugs, metabolites and nitrogen oxides.
本发明所述的可药用盐可使用例如以下的无机酸或有机酸而形成：“可药用盐”是指这样的盐，在合理的医学判断范围内，其适用于接触人和较低等动物的组织，而没有不适当的毒性、刺激性、过敏反应等，称得上合理的受益/风险比。可以在本发明化合物的最终分离和纯化期间原位制备所述盐，或单独通过将游离碱或游离酸与合适的试剂反应制备所述盐，如下概述。例如，游离碱功能可以与合适的酸反应。可药用的无机酸加成盐的示例是氨基与无机酸(例如，盐酸、氢溴酸、磷酸、硫酸和高氯酸)或有机酸(例如，醋酸、草酸、马来酸、酒石酸、柠檬酸、琥珀酸或丙二酸)形成的盐，或通过使用现有技术中的其他方法如离子交换形成的盐。其他可药用盐包括己二酸盐、海藻酸钠、抗坏血酸盐、天门冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、hernisulfate、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯丙酸盐、磷酸盐、苦味盐、新戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐等。代表性碱金属或碱土金属盐包括钠、锂、钾、钙、镁等的盐。其他可药用盐包括(适当时)无毒铵盐、季铵盐和用反离子形成的胺阳离子，例如，卤化物、氢氧化物、羧酸盐、硫酸盐、磷酸盐、硝酸盐、低级烷基磺酸盐和芳基磺酸盐。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. Examples of pharmaceutically acceptable 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. Other pharmaceutically acceptable 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, pectic acid Salt, persulfate, 3-phenylpropionate, phosphate, bitter salt, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluene Sulfonate, undecanoate, valerate, etc. 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.
本发明的可药用盐可通过常规方法制备，例如通过将本发明的化合物溶解于与水可混溶的有机溶剂(例如丙酮、甲醇、乙醇和乙腈)，向其中添加过量的有机酸或无机酸水溶液，以使得盐从所得混合物中沉淀，从中除去溶剂和剩余的游离酸，然后分离所沉淀的盐。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.
本发明所述的前体或代谢物可以本领域公知的前体或代谢物，只要所述的前体或代谢物通过体内代谢转化形成化合物即可。例如“前药”是指本发明化合物的那些前药，在合理的医学判断范围内，其适用于接触人和更低等动物的组织，而没有不适当的毒性、刺激性、过敏反应等，称得上合理的受益/风险比并且对其预期用途有效。术语“前药”是指在体内迅速经转化产生上述式的母体化合物的化合物，例如通过在体内代谢，或本发明化合物的N-去甲基化。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. For example, "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. The term "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.
本发明所述的“溶剂合物”意指本发明化合物与一个或多个溶剂分子(无论有机的还是无机的)的物理缔合。该物理缔合包括氢键。在某些情形中，例如当一个或多个溶剂分子纳入结 晶固体的晶格中时，溶剂化物将能够被分离。溶剂化物中的溶剂分子可按规则排列和/或无序排列存在。溶剂合物可包含化学计量或非化学计量的溶剂分子。“溶剂合物”涵盖溶液相和可分离的溶剂合物。示例性溶剂合物包括但不限于水合物、乙醇合物、甲醇合物和异丙醇合物。溶剂化方法是本领域公知的。"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.
本发明所述的“立体异构”分为构象异构和构型异构，构型异构还可分为顺反异构和旋光异构(即光学异构)，构象异构是指具有一定构型的有机物分子由于碳、碳单键的旋转或扭曲而使得分子各原子或原子团在空间产生不同的排列方式的一种立体异构现象，常见的有烷烃和环烷烃类化合物的结构，如环己烷结构中出现的椅式构象和船式构象。“立体异构体”是指当本发明化合物含有一个或多个不对称中心，因而可作为外消旋体和外消旋混合物、单一对映异构体、非对映异构体混合物和单一非对映异构体。本发明化合物有不对称中心，每个不对称中心会产生两个光学异构体，本发明的范围包括所有可能的光学异构体和非对映异构体混合物和纯的或部分纯的化合物。本发明所述的化合物可以以互变异构体形式存在，其通过一个或多个双键位移而具有不同的氢的连接点。例如，酮和它的烯醇形式是酮-烯醇互变异构体。各互变异构体及其混合物都包括在本发明的化合物中。所有式(I)至式(III)化合物的对映异构体、非对映异构体、外消旋体、内消旋体、顺反异构体、互变异构体、几何异构体、差向异构体及其混合物等，均包括在本发明范围中。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. "Stereoisomers" 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. Each tautomer and mixtures thereof are included in the compounds of the invention. Enantiomers, diastereomers, racemates, meso, cis-trans isomers, tautomers and geometric isomers of all compounds of formula (I) to formula (III) Isomers, epimers and mixtures thereof are all included in the scope of the present invention.
本发明的“同位素衍生物”是指在本文中化合物被同位素标记的分子。通常用作同位素标记的同位素是：氢同位素，2H和3H；碳同位素：11C,13C和14C；氯同位素：35Cl和37Cl；氟同位素：18F；碘同位素：123I和125I；氮同位素：13N和15N；氧同位素：15O,17O和18O和硫同位素35S。这些同位素标记化合物可以用来研究药用分子在组织中的分布情况。尤其是氘3H和碳13C，由于它们容易标记且方便检测，运用更为广泛。某些重同位素，比如重氢(2H)，的取代能增强代谢的稳定性，延长半衰期从而达到减少剂量的目而提供疗效优势的。同位素标记的化合物一般从已被标记的起始物开始，用已知的合成技术象合成非同位素标记的化合物一样来完成其合成。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. In particular, deuterium 3 H and carbon 13 C are more widely used because they are easy to label and detect. The 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.
本发明还提供了本发明化合物在制备用于预防和/或治疗癌症、肿瘤、炎症性疾病、自身免疫性疾病或免疫介导性疾病的药物中的用途。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.
此外，本发明提供了用于预防和/或治疗癌症、肿瘤、炎症性疾病、自身免疫性疾病、神经退行性疾病、注意力相关疾病或免疫介导性疾病的药物组合物，其包含本发明化合物作为活性成分。所述药物组合物可任选地包含可药用的载体。 Furthermore, 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.
此外，本发明提供了一种预防和/或治疗癌症、肿瘤、炎症性疾病、自身免疫性疾病、神经退行性疾病、注意力相关疾病或免疫介导性疾病的方法，其包括向有此需要的哺乳动物施用本发明化合物。In addition, 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.
炎症性疾病、自身免疫性疾病和免疫介导性疾病的代表性实例可包括但不限于，关节炎、类风湿性关节炎、脊柱关节炎、痛风性关节炎、骨关节炎、幼年型关节炎、其他关节炎性病症、狼疮、系统性红斑狼疮(SLE)、皮肤相关疾病、银屑病、湿疹、皮炎、过敏性皮肤炎、疼痛、肺病、肺部炎症、成人呼吸窘迫综合征(ARDS)、肺结节病、慢性肺部炎症性疾病、慢性阻塞性肺病(COPD)、心血管疾病、动脉粥样硬化、心肌梗塞、充血性心力衰竭、心肌缺血再灌注损伤、炎性肠病、克罗恩病、溃疡性结肠炎、肠易激综合征、哮喘、干燥综合征、自身免疫甲状腺疾病、荨麻疹(风疹)、多发性硬化、硬皮症、器官移植排斥、异种移植、特发性血小板减少性紫癜(ITP)、帕金森病、阿尔兹海默病、糖尿病相关疾病、炎症、盆腔炎性疾病、过敏性鼻炎、过敏性支气管炎、过敏性鼻窦炎、白血病、淋巴瘤、B细胞淋巴瘤、T细胞淋巴瘤、骨髓瘤、急性淋巴性白血病(ALL)、慢性淋巴性白血病(CLL)、急性髓性白血病(AML)、慢性髓性白血病(CML)、毛细胞白血病、何杰金氏病、非何杰金淋巴瘤、多发性骨髓瘤、骨髓增生异常综合征(MDS)、骨髓增生性肿瘤(MPN)、弥漫性大B细胞淋巴瘤和滤泡性淋巴瘤。Representative examples of inflammatory diseases, autoimmune diseases, and immune-mediated 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 sclerosis, scleroderma, organ transplant rejection, xenotransplantation, idiopathic ITP, Parkinson's disease, Alzheimer's disease, diabetes-related diseases, inflammation, pelvic inflammatory disease, allergic rhinitis, allergic bronchitis, allergic sinusitis, leukemia, lymphoma, B Cell lymphoma, T-cell lymphoma, myeloma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), hairy cell leukemia, He Jie King's disease, non-Hodgkin's lymphoma, multiple myeloma, myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), diffuse large B-cell lymphoma, and follicular lymphoma.
癌症或肿瘤的代表性实例可包括但不限于，皮肤癌、膀胱癌、卵巢癌、乳腺癌、胃癌、胰腺癌、前列腺癌、结肠癌、肺癌、骨癌、脑癌、神经细胞瘤、直肠癌、结肠癌、家族性腺瘤性息肉性癌、遗传性非息肉性结直肠癌、食管癌、唇癌、喉癌、下咽癌、舌癌、唾液腺癌、胃癌、腺癌、甲状腺髓样癌、乳头状甲状腺癌、肾癌、肾实质癌、卵巢癌、宫颈癌、子宫体癌、子宫内膜癌、绒毛膜癌、胰腺癌、前列腺癌、睾丸癌、泌尿癌、黑素瘤、脑肿瘤诸如成胶质细胞瘤、星形细胞瘤、脑膜瘤、成神经管细胞瘤和外周神经外胚层肿瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、伯基特淋巴瘤、急性淋巴性白血病(ALL)、慢性淋巴性白血病(CLL)、急性骨髓性白血病(AML)、慢性粒细胞白血病(CML)、成人T细胞白血病淋巴瘤、弥漫性大B细胞淋巴瘤(DLBCL)、肝细胞癌、胆囊癌、支气管癌、小细胞肺癌、非小细胞肺癌、多发性骨髓瘤、基底细胞瘤、畸胎瘤、成视网膜细胞瘤、脉络膜黑素瘤、精原细胞瘤、横纹肌肉瘤、颅咽管瘤、骨肉瘤、软骨肉瘤、肌肉瘤、脂肪肉瘤、纤维肉瘤、尤因肉瘤或浆细胞瘤。Representative examples of 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 neuroectodermal tumors, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphoblastic leukemia ( ALL), chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder Carcinoma, bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, Osteosarcoma, chondrosarcoma, sarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma or plasmacytoma.
当将本发明化合物或其可药用盐与另外的用于治疗癌症或肿瘤的抗癌剂或免疫检查点抑制剂组合施用时，本发明化合物或其可药用盐可提供增强的抗癌作用。The compounds of the present invention, or pharmaceutically acceptable salts thereof, may provide enhanced anticancer effects when administered in combination with additional anticancer agents or immune checkpoint inhibitors used to treat cancer or tumors. .
用于治疗癌症或肿瘤的抗癌剂的代表性实例可包括但不限于细胞信号转导抑制剂、苯丁 酸氮芥、美法仑、环磷酰胺、异环磷酰胺、白消安、卡莫司汀、洛莫司汀、链脲佐菌素、顺铂、卡铂、奥沙利铂、达卡巴嗪、替莫唑胺、丙卡巴肼、甲氨蝶呤、氟尿嘧啶、阿糖胞苷、吉西他滨、巯基嘌呤、氟达拉滨、长春碱、长春新碱、长春瑞滨、紫杉醇、多西紫杉醇、拓扑替康、伊立替康、依托泊苷、曲贝替定、更生霉素、多柔比星、表柔比星、道诺霉素、米托蒽醌、博来霉素、丝裂霉素C、伊沙匹隆、他莫昔芬、氟他胺、戈那瑞林类似物、甲地孕酮、强的松、地塞米松、甲泼尼龙、沙利度胺、干扰素α、亚叶酸钙、西罗莫司、西罗莫司脂化物、依维莫司、阿法替尼、alisertib、amuvatinib、阿帕替尼、阿西替尼、硼替佐米、波舒替尼、布立尼布、卡博替尼、西地尼布、crenolanib、克卓替尼、达拉菲尼、达可替尼、达努塞替、达沙替尼、多维替尼、厄洛替尼、foretinib、ganetespib、吉非替尼、依鲁替尼、埃克替尼、伊马替尼、iniparib、拉帕替尼、lenvatinib、linifanib、linsitinib、马赛替尼、momelotinib、莫替沙尼、来那替尼、尼罗替尼、niraparib、oprozomib、olaparib、帕唑帕尼、pictilisib、普纳替尼、quizartinib、瑞格菲尼、rigosertib、rucaparib、鲁索利替尼、塞卡替尼、saridegib、索拉非尼、舒尼替尼、替拉替尼、tivantinib、替沃扎尼、托法替尼、曲美替尼、凡德他尼、维利帕尼、威罗菲尼、维莫德吉、volasertib、阿仑单抗、贝伐单抗、贝伦妥单抗维多汀、卡妥索单抗、西妥昔单抗、地诺单抗、吉妥珠单抗、伊匹单抗、尼妥珠单抗、奥法木单抗、帕尼单抗、利妥昔单抗、托西莫单抗、曲妥珠单抗、PI3K抑制剂、CSF1R抑制剂、A2A和/或A2B受体拮抗剂、IDO抑制剂、抗PD-1抗体、抗PD-L1抗体、LAG3抗体、TIM-3抗体及抗CTLA-4抗体，或其任意组合。Representative examples of 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 Sarbepilone, tamoxifen, flutamide, gonadorelin analogs, megestrol, prednisone, dexamethasone, methylprednisolone, thalidomide, interferon alpha, leucovorin, Sirolimus, sirolimus lipid, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, brivanib, Cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, danusetid, dasatinib, dovitinib, erlotinib, foretinib, ganetespib, gezotinib fitinib, ibrutinib, icotinib, imatinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motisanib, neratinib, nile niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, secatinib, saridegib, sorafenib, sunitinib, tivantinib, tivantinib, tivozanib, tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vemodegib, volasertib, a Lemtuzumab, bevacizumab, belemtuzumab vedotin, cattuzumab, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab Anti, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, PI3K inhibitor, CSF1R inhibitor, A2A and/or A2B receptor antagonist, IDO Inhibitors, anti-PD-1 antibodies, anti-PD-L1 antibodies, LAG3 antibodies, TIM-3 antibodies and anti-CTLA-4 antibodies, or any combination thereof.
当将本发明化合物或其可药用盐与另外的用于治疗炎症性疾病、自身免疫性疾病和免疫介导性疾病的治疗剂组合施用时，本发明化合物或其可药用盐可提供增强的治疗作用。The compounds of the present invention, or pharmaceutically acceptable salts thereof, may provide enhanced therapeutic effect.
用于治疗炎症性疾病、自身免疫性疾病和免疫介导性疾病的治疗剂的代表性实例可包括但不限于，甾体药物(例如，强的松、氢化波尼松、甲基氢化波尼松、可的松、羟基可的松、倍他米松、地塞米松等)、甲氨蝶呤、来氟米特、抗TNFα剂(例如，依那西普、英夫利昔单抗、阿达利单抗等)、钙调神经磷酸酶抑制剂(例如，他克莫司、吡美莫司等)和抗组胺药(例如，苯海拉明、羟嗪、氯雷他定、依巴斯汀、酮替芬、西替利嗪、左西替利嗪、非索非那定等)，并且选自其中的至少一种或多种治疗剂可包含于本发明药物组合物中。Representative examples of 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-TNFα 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.
本发明的化合物或其可药用盐可作为活性成分通过口服或肠胃外施用，其有效量的范围为在哺乳动物包括人(体重约70kg)的情况下0.1至2,000mg/kg体重/天、优选1至1,000mg/kg体重/天，并且每天以单次或4次分次剂量，或者遵循/不遵循预定时间施用。活性成分的剂量可根据多个相关因素(例如待治疗对象的情况、疾病类型和严重性、施用速率和医生意见) 进行调整。在某些情况下，小于以上剂量的量可能是合适的。如果不引起有害的副作用则可使用大于以上剂量的量并且该量可以每天以分次剂量施用。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.
除此之外，本发明还提供了一种预防和/或治疗肿瘤、癌症、病毒感染、器官移植排斥、神经退行性疾病、注意力相关疾病或自身免疫性疾病的方法，其包括向有此需要的哺乳动物施用本发明的化合物或本发明的药物组合物。In addition, 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.
可根据常规方法中的任何一种将本发明药物组合物配制成用于口服施用或肠胃外施用(包括肌内、静脉内和皮下途径、瘤内注射)的剂型，例如片剂、颗粒、粉末、胶囊、糖浆、乳剂、微乳剂、溶液或混悬液。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.
用于口服施用的本发明药物组合物可通过将活性成分与例如以下的载体混合来制备：纤维素、硅酸钙、玉米淀粉、乳糖、蔗糖、右旋糖、磷酸钙、硬脂酸、硬脂酸镁、硬脂酸钙、明胶、滑石、表面活性剂、助悬剂、乳化剂和稀释剂。Pharmaceutical 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.
在本发明的注射施用的药物组合物中采用的载体的实例可以是水、盐溶液、葡萄糖溶液、葡萄糖样溶液(glucose-like solution)、醇、二醇、醚(例如，聚乙二醇400)、油、脂肪酸、脂肪酸酯、甘油酯、表面活性剂、助悬剂和乳化剂。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.
本发明描述示例性实施方案的过程中，本发明的其它特征将变得显而易见，给出所述实施方案用于说明本发明而不意欲成为其限制，以下实施例使用本发明所公开的方法制备、分离和表征。Other features of the invention will become apparent in the course of describing the exemplary embodiments of the invention which are given to illustrate the invention and are not intended to be limiting thereof. The following examples were prepared using the methods disclosed in the invention. , separation and characterization.
可以用有机合成领域的技术人员已知的多种方式来制备本发明的化合物，可使用下述方法以及有机合成化学领域中已知的合成方法或通过本领域技术人员所了解的其变化形式来合成本发明化合物。优选方法包括但不限于下文所述的这些。在适用于所使用试剂盒材料和适用于所实现转变的溶剂或溶剂混合物中实施反应。有机合成领域的技术人员将理解，分子上存在的官能性与所提出的转变一致。这有时需要加以判断改变合成步骤的顺序或原料以获得期望的本发明化合物。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.
附图说明Description of drawings
图1示出了化合物1对人结肠癌细胞Colo205异种移植瘤肿瘤生长的影响。Figure 1 shows the effect of Compound 1 on tumor growth of human colon cancer cell Colo205 xenograft tumors.
具体实施方式Detailed ways
术语 the term
如果无另外说明，用于本发明申请，包括说明书和权利要求书中的术语，定义如下。如果无另外说明，使用质谱、核磁、HPLC、蛋白化学、生物化学、重组DNA技术和药理的常规方法。在本申请中，如果无另外说明，使用“或”或“和”指“和/或”。Unless otherwise specified, the terms used in this application, including the specification and claims, are defined as follows. If not otherwise stated, conventional methods of mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology were used. In this application, the use of "or" or "and" means "and/or" unless stated otherwise.
在说明书和权利要求书中，给定化学式或名称应涵盖其所有立体异构体和光学异构体及其中存在上述异构体的外消旋体。除非另外指明，否则所有手性(对映异构体和非对映异构体)和外消旋形式均在本发明范围内。所述化合物中还可存在C＝C双键、C＝N双键、环系统等的多种几何异构体，且所有上述稳定异构体均涵盖于本发明内。本发明描述了本发明化合物的顺式-和反式-(或E-和Z-)几何异构体，且其可分离成异构体的混合物或分开的异构体形式。本发明化合物可以光学活性或外消旋形式加以分离。用于制备本发明化合物和其中制备的中间体的所有方法均视为本发明的部分。在制备对映异构体或非对映异构体产物时，其可通过常规方法(例如通过色谱或分段结晶)进行分离。取决于方法条件，以游离(中性)或盐形式获得本发明的终产物。这些终产物的游离形式和盐均在本发明的范围内。如果需要的话，则可将化合物的一种形式转化成另一种形式。可将游离碱或酸转化成盐；可将盐转化成游离化合物或另一种盐；可将本发明异构体化合物的混合物分离成单独的异构体。本发明化合物、其游离形式和盐可以多种互变异构体形式存在，其中氢原子转置到分子的其它部分上且由此分子的原子之间的化学键发生重排。应当理解的是，可存在的所有互变异构体形式均包括在本发明内。In the description and claims, a given chemical formula or name shall cover all its stereoisomers and optical isomers as well as the racemates in which the above-mentioned isomers exist. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are within the scope of the invention. Various geometric isomers of C=C double bonds, C=N double bonds, ring systems, etc. may also exist in the compound, and all the above stable isomers are included in the present invention. This invention describes the cis- and trans- (or E- and Z-) geometric isomers of the compounds of the invention, and they can be separated into mixtures of isomers or separate isomeric forms. 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, their free forms and salts, 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.
除非另有定义，本发明的取代基的定义是各自独立而非互相关联的，例如(列举而非穷举),在一个方面，对于取代基中Ra(或者Ra’)而言，其在不同的取代基的定义中是各自独立的。具体而言，对于Ra(或者Ra’)在一种取代基中选择一种定义时，并不意味着该Ra(或者Ra’)在其他取代基中都具有该相同的定义。更具体而言，例如(仅列举非穷举)对于NRaRa’中，当Ra(或者Ra’)的定义选自氢时，其并不意味着在-C(O)-NRaRa’中，Ra(或者Ra’)必然为氢。在另一个方面，当某一个取代基中存在多于一个Ra(或者Ra’)时，这些Ra(或者Ra’)也是各自独立的。例如，在取代基-(CRaRa’)m-O-(CRaRa’)n-中，在m+n大于等于2的情况下，其中的m+n个Ra(或者Ra’)是各自独立的，它们可以具有相同或者不同的含义。Unless otherwise defined, the definitions of the substituents of the present invention are independent and not related to each other. For example (enumeration rather than exhaustion), in one aspect, for 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. More specifically, for example (by way of non-exhaustive list) for 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. On the other hand, when there is more than one Ra (or Ra ') in a certain substituent, these Ra (or Ra ') are also independent. For example, in the substituent -(CR a R a' ) m -O-(CR a R a' ) n -, when m+n is 2 or more, m+n R a (or R a ') are independent, they can have the same or different meanings.
除非另有定义，否则当取代基被标注为“任选取代的”时，所述取代基选自例如以下取代基，诸如烷基、环烷基、芳基、杂环基、卤素、羟基、烷氧基、氧代、烷酰基、芳基氧基、烷酰基氧基、氨基、烷基氨基、芳基氨基、芳基烷基氨基、二取代的氨基(其中2个氨基取代基选自烷基、芳基或芳基烷基)、烷酰基氨基、芳酰基氨基、芳烷酰基氨基、取代的烷酰基氨基、取代的芳基氨基、取代的芳烷酰基氨基、硫基、烷基硫基、芳基硫基、芳基烷基硫基、芳基硫羰基、芳基烷基硫羰基、烷基磺酰基、芳基磺酰基、芳基烷基磺酰基、氨基磺酰基例 如-SO2NH2、取代的磺酰氨基、硝基、氰基、羧基、氨基甲酰基例如-CONH2、取代的氨基甲酰基例如-CONH烷基、-CONH芳基、-CONH芳基烷基或在氮上具有两个选自烷基、芳基或芳基烷基的取代基的情况、烷氧基羰基、芳基、取代的芳基、胍基、杂环基，例如吲哚基、咪唑基、呋喃基、噻吩基、噻唑基、吡咯烷基、吡啶基、嘧啶基、吡咯烷基、哌啶基、吗啉基、哌嗪基、高哌嗪基等和取代的杂环基。Unless otherwise defined, when a substituent is designated as "optionally substituted," the substituent is selected from, for example, 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, alkylsulfonyl group, arylsulfonyl group, arylalkylsulfonyl group, aminosulfonyl group example Such as -SO 2 NH 2 , substituted sulfonylamino, nitro, cyano, carboxyl, carbamoyl such as -CONH 2 , substituted carbamoyl such as -CONH alkyl, -CONH aryl, -CONH arylalkyl group or has two substituents on the nitrogen selected from alkyl, aryl or arylalkyl, alkoxycarbonyl, aryl, substituted aryl, guanidyl, heterocyclyl, such as indolyl , imidazolyl, furyl, thienyl, thiazolyl, pyrrolidinyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl, etc. and substituted heterocyclic groups .
本文使用的术语“烷基”或“亚烷基”意欲包括具有指定碳原子数的支链和直链饱和脂族烃基团。例如，“C1-C6烷基”表示具有1个至6个碳原子的烷基。烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(例如正丙基和异丙基)、丁基(例如正丁基、异丁基、叔丁基)和戊基(例如正戊基、异戊基、新戊基)。在本文中，烷基优选为具有1至6个、更优选具有1至4个碳原子的烷基。The term "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. For example, "C 1 -C 6 alkyl" means an alkyl group having 1 to 6 carbon atoms. Examples of 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). In this context, the alkyl group is preferably an alkyl group having 1 to 6, more preferably 1 to 4 carbon atoms.
术语“烯基”表示含一个或多个双键且通常长度为2至20个碳原子的直链或支链的烃基。例如，“C2-C6烯基”含有两个至六个碳原子。烯基包括但不限于例如乙烯基、丙烯基、丁烯基、1-甲基-2-丁烯-1-基等。在本文中，烯基优选C2-C6烯基。The term "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. For example, "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.
术语“炔基”表示含一个或多个三键且通常长度为2至20个碳原子的直链或支链的烃基。例如，“C2-C6炔基”含有两个至六个碳原子。代表性炔基包括但不限于例如乙炔基、1-丙炔基、1-丁炔基等。在本文中，炔基优选C2-C6炔基。The term "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. For example, "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.
术语“烷氧基”或“烷基氧基”是指-O-烷基。“C1-C6烷氧基”(或烷基氧基)意欲包括C1、C2、C3、C4、C5、C6烷氧基。烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(例如正丙氧基和异丙氧基)和叔丁氧基。在本文中，烷氧基优选为具有1至6个、更优选具有1至4个碳原子的烷氧基。类似地，“烷基硫基”或“硫硫基”表示具有指定数量碳原子的经硫桥连接的如上文所定义的烷基；例如甲基-S-和乙基-S-。The term "alkoxy" or "alkyloxy" 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. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (eg, n-propoxy and isopropoxy), and tert-butoxy. Herein, the alkoxy group is preferably an alkoxy group having 1 to 6, more preferably 1 to 4 carbon atoms. Similarly, "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-.
术语“羰基”是指由碳和氧两种原子通过双键连接而成的有机官能团(C＝O)。The term "carbonyl" refers to an organic functional group consisting of two atoms, carbon and oxygen, linked by a double bond (C=O).
术语“芳基”，单独或作为较大部分诸如“芳烷基”、“芳基烷氧基”或“芳基氧基烷基”的部分，是指具有总计5至12个环成员的单环、二环或三环的环系统，其中所述系统中的至少一个环为芳族的且其中所述系统中的每个环含有3至7个环成员。在本发明的某些实施方案中，“芳基”是指芳族环系统，其包括但不限于苯基、联苯基、茚满基、1-萘基、2-萘基和四氢萘基。术语“芳烷基”或“芳基烷基”是指连接至芳基环的烷基残基，其非限制性实例包括苄基、苯乙基等。稠合的芳基可在环烷基环或芳族环的合适位置上连接至另一基团。从环系统中画出的虚线表明键可连接至任意合适的环原子。The term "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. A cyclic, bicyclic or tricyclic ring system, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. In certain embodiments of the present invention, "aryl" refers to an aromatic ring system including, but not limited to, phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetralin base. The term "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.
术语“环烷基”是指单环或二环的环状烷基。单环的环状烷基指C3-C8的环状烷基，包括但不限于环丙基、环丁基、环戊基、环己基和降莰烷基。支化环烷基诸如1-甲基环丙基和2-甲 基环丙基包括在“环烷基”的定义中。二环的环状烷基包括桥环、螺环或稠环的环烷基。在本文中，环烷基优选C3-C6环烷基。The term "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. In this context, cycloalkyl is preferably C 3 -C 6 cycloalkyl.
术语“环烯基”是指单环或二环的环状烯基。单环的环状烯基指C3-C8的环状烯基，包括但不限于环丙烯基、环丁烯基、环戊烯基、环己烯基和降莰烯基。支化环烯基诸如1-甲基环丙烯基和2-甲基环丙烯基包括在“环烯基”的定义中。二环的环状烯基包括桥环、螺环或稠环的环状烯基。The term "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.
“卤代”或“卤素”包括氟、氯、溴和碘。“卤代烷基”意欲包括具有指定碳原子数且取代有1个或多个卤素的支链和直链饱和脂族烃基团。卤代烷基的实例包括但不限于氟甲基、二氟甲基、三氟甲基、三氯甲基、五氟乙基、五氯乙基、2,2,2-三氟乙基、七氟丙基和七氯丙基。卤代烷基的实例还包括意欲包括具有指定碳原子数且取代有1个或多个氟原子的支链和直链饱和脂族烃基团的“氟烷基”。"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. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoroethyl Propyl and heptachloropropyl. Examples of 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.
“卤代烷氧基”或“卤代烷基氧基”表示具有指定数量碳原子的经氧桥连接的如上文所定义的卤代烷基。例如，“卤代C1-C6烷氧基”意欲包括C1、C2、C3、C4、C5、C6卤代烷氧基。卤代烷氧基的实例包括但不限于三氟甲氧基、2,2,2-三氟乙氧基和五氟乙氧基。类似地，“卤代烷基硫基”或“硫代卤代烷氧基”表示具有指定数量碳原子的经硫桥连接的如上文所定义的卤代烷基；例如三氟甲基-S-和五氟乙基-S-。"Haloalkoxy" or "haloalkyloxy" means a haloalkyl group as defined above having the specified number of carbon atoms linked via an oxygen bridge. For example, "halo C 1 -C 6 alkoxy" is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , C 6 haloalkoxy. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "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-.
本公开内容中，当提到一些取代基团时使用Cx1-Cx2的表述，这表示所述取代基团中的碳原子数可以是x1至x2个。例如，C0-C8表示所述基团含有0、1、2、3、4、5、6、7或8个碳原子，C1-C8表示所述基团含有1、2、3、4、5、6、7或8个碳原子，C2-C8表示所述基团含有2、3、4、5、6、7或8个碳原子，C3-C8表示所述基团含有3、4、5、6、7或8个碳原子，C4-C8表示所述基团含有4、5、6、7或8个碳原子，C0-C6表示所述基团含有0、1、2、3、4、5或6个碳原子，C1-C6表示所述基团含有1、2、3、4、5或6个碳原子，C2-C6表示所述基团含有2、3、4、5或6个碳原子，C3-C6表示所述基团含有3、4、5或6个碳原子。In this disclosure, the expression 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. For example, C 0 -C 8 means that the group contains 0, 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, and 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, C 1 -C 6 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, and C 3 -C 6 means that the group contains 3, 4, 5 or 6 carbon atoms.
本公开内容中，当提到环状基团(例如芳基、杂芳基、环烷基和杂环烷基)时使用“x1-x2元环”的表述，这表示该基团的环原子数可以是x1至x2个。例如，所述3-12元环状基团可以是3、4、5、6、7、8、9、10、11或12元环，其环原子数可以是3、4、5、6、7、8、9、10、11或12个；3-6元环表示该环状基团可以是3、4、5或6元环，其环原子数可以是3、4、5或6个；3-8元环表示该环状基团可以是3、4、5、6、7或8元环，其环原子数可以是3、4、5、6、7或8个；3-9元环表示该环状基团可以是3、4、5、6、7、8或9元环，其环原子数可以是3、4、5、6、7、8或9个；4-7元环表示该环状基团可以是4、5、6或7元环，其环原子数可以是4、5、6或7个；5-8元环表示该环状基团可以是5、6、7或8元环，其环原子 数可以是5、6、7或8个；5-12元环表示该环状基团可以是5、6、7、8、9、10、11或12元环，其环原子数可以是5、6、7、8、9、10、11或12个；6-12元环表示该环状基团可以是6、7、8、9、10、11或12元环，其环原子数可以是6、7、8、9、10、11或12个。所述环原子可以是碳原子或杂原子，例如选自N、O和S的杂原子。当所述环是杂环时，所述杂环可以含有1、2、3、4、5、6、7、8、9、10或更多个环杂原子，例如选自N、O和S的杂原子。In this disclosure, the expression "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. For example, 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 4, 5, 6 or 7; the 5-8-membered ring means that the cyclic group can be 5, 6, 7 or 8 membered ring, its ring atoms The number can be 5, 6, 7 or 8; 5-12 membered ring means that the cyclic group can be 5, 6, 7, 8, 9, 10, 11 or 12 membered ring, and the number of ring atoms can be 5 , 6, 7, 8, 9, 10, 11 or 12; 6-12 membered ring means that the cyclic group can be 6, 7, 8, 9, 10, 11 or 12 membered ring, and the number of ring atoms can be Be it 6, 7, 8, 9, 10, 11 or 12. The ring atoms may be carbon atoms or heteroatoms, such as heteroatoms selected from N, O and S. When the ring is a heterocycle, 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.
本公开内容中，一个或更多个卤素可以各自独立地选自氟、氯、溴和碘。In this disclosure, one or more halogens may be each independently selected from fluorine, chlorine, bromine, and iodine.
术语“杂芳基”意指稳定的3元、4元、5元、6元、或7元芳香单环或芳香二环或7元、8元、9元、10元、11元、12元芳香多环杂环，其为完全不饱和的或部分不饱和的，且其含有碳原子和1个、2个、3个或4个独立地选自N、O和S的杂原子；且包括任何以下多环基团，其中上文所定义的任意杂环与苯环稠合。氮和硫杂原子可任选地被氧化。氮原子为取代的或未取代的(即N或NR，其中R为H或如果被定义，则为另一取代基)。杂环可在得到稳定结构的任何杂原子或碳原子处连接至其侧基。如果所得化合物是稳定的，则本文所述的杂环基可在碳或氮原子上被取代。杂环中的氮可任选地被季铵化。优选地，当杂环中S和O原子的总数超过1时，则这些杂原子彼此不相邻。优选地，杂环中S和O原子的总数不大于1。当使用术语“杂环”时，其意欲包括杂芳基。芳杂基的实施例包括但不限于吖啶基、氮杂环丁基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并硫代呋喃基、苯并噻吩基、苯并噁唑基、苯并噁唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异噁唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、色满基、色烯基、噌啉基、十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、咪唑并吡啶基、假吲哚基(indolenyl)、二氢吲哚基、吲嗪基、吲哚基、3H-吲哚基、靛红酰基(isatinoyl)、异苯并呋喃基、异色满基、异吲唑基、异二氢吲哚基、异吲哚基、异喹啉基、异噻唑基、异噻唑并吡啶基、异噁唑基、异噁唑并吡啶基、亚甲基二氧基苯基、吗啉基、二氮杂萘基、八氢异喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑烷基、噁唑基、噁唑并吡啶基、噁唑烷基、萘嵌间二氮杂苯基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪基、吩噻嗪基、吩噁噻基、吩噁嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、喋啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑并吡啶基、吡唑基、哒嗪基、吡啶并噁唑基、吡啶并咪唑基、吡啶并噻唑基、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2-吡咯烷酮基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四唑基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻 二唑基、噻蒽基、噻唑基、噻吩基、噻唑并吡啶基、噻吩并噻唑基、噻吩并噁唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基和呫吨基、喹啉基、异喹啉基、酞嗪基、喹唑啉基、吲哚基、异吲哚基、二氢吲哚基、1H-吲唑基、苯并咪唑基、1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基、5,6,7,8-四氢-喹啉基、2,3-二氢-苯并呋喃基、色满基、1,2,3,4-四氢-喹喔啉基和1,2,3,4-四氢-喹唑啉基。术语“杂芳基”还可以包括由上述所定义的“芳基”与单环“杂芳基”所形成的联芳基结构，例如但不限于“-苯基联吡啶基-”、“-苯基联嘧啶基”、“-吡啶基联苯基”、“-吡啶基联嘧啶基-”、“-嘧啶基联苯基-”；其中本发明还包括含有例如上述杂环的稠环和螺环化合物。The term "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. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle is not greater than 1. When the term "heterocycle" is used, it is intended to include heteroaryl groups. Examples of 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, imidazopyridyl, pseudoindolenyl, indolenyl, Indolinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolyl, isoindolyl, iso Quinolyl, isothiazolyl, isothiazopyridyl, isoxazolyl, isoxazolopyridyl, methylenedioxyphenyl, morpholinyl, diazanaphthyl, octahydroisoquinoline base, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl , oxazolidinyl, oxazolyl, oxazolopyridyl, oxazolidinyl, naphthyridyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl , phenothiazinyl, phenoxathiyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidinonyl, 4-piperidinonyl, piperonyl, pteridinyl, purinyl, Pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazopyridyl, pyrazolyl, pyridazinyl, pyridoxazolyl, pyridimidazolyl, pyridothiazolyl, pyridyl , pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolinyl, quinoxalinyl, quinuclidinyl, Tetrazolyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydroquinolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4- Thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl Diazolyl, thianthrenyl, thiazolyl, thienyl, thiazolopyridyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazole base, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthyl, quinolyl, isoquinolyl, phthalazinyl, quinolyl Zozolinyl, indolyl, isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3, 4-Tetrahydroisoquinolyl, 5,6,7,8-tetrahydro-quinolyl, 2,3-dihydro-benzofuranyl, chromanyl, 1,2,3,4-tetrahydro -Quinoxalinyl and 1,2,3,4-tetrahydro-quinazolinyl. The term "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.
本文使用的术语“杂环烷基”指的是一个单环杂环烷基体系，或为一个二环杂环烷基体系，同时还包括螺杂环或桥杂环烷基。单环的杂环烷基指的是3-8元、且至少含一个选自O、N、S和P的杂原子的饱和或不饱和但不为芳香性的环状烷基体系。二环杂环烷基体系指的是一个杂环烷基稠合到一个苯基、或一个环烷基、或一个环烯基、或一个杂环烷基、或一个杂芳基上而形成的二环体系。As used herein, the term "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.
本文使用的术语“桥环烷基”指的是共用两个或两个以上碳原子的多环化合物。可分为二环桥环烃及多环桥环烃。前者由两个脂环共用两个以上碳原子所构成；后者是由三个以上的环组成的桥环烃。The term "bridged cycloalkyl" as used herein 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.
本文使用的术语“螺环烷基”指的是单环之间共用一个碳原子(称螺原子)的多环烃。The term "spirocycloalkyl" as used herein refers to polycyclic hydrocarbons that share one carbon atom (called a spiro atom) between single rings.
本文使用的术语“桥环杂基”指的是共用两个或两个以上碳原子的多环化合物，该环中至少含一个选自O、N和S原子的杂原子。可分为二环桥环杂环及多环桥杂环。The term "bridged cycloheteroyl" as used herein 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.
本文使用的术语“杂螺环基”指的是单环之间共用一个碳原子(称螺原子)的多环烃，该环中至少含一个选自O、N和S原子的杂原子。The term "heterospirocyclyl" used herein 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.
本文中所用的术语“取代”意指至少一个氢原子被非氢基团替代，条件是维持正常化合价且所述取代得到稳定的化合物。本文所用的环双键为在两个相邻环原子之间形成的双键(例如C＝C、C＝N或N＝N)。The term "substituted" as used herein 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. As used herein, a cyclic double bond is a double bond formed between two adjacent ring atoms (eg, C=C, C=N, or N=N).
在本发明化合物上存在氮原子(例如胺)的情形下，可通过使用氧化剂(例如mCPBA和/或过氧化氢)进行处理来将这些氮原子转化成N-氧化物以获得本发明的其它化合物。因此，所显示和要求保护的氮原子视为均涵盖所显示氮及其N-氧化物以获得本发明衍生物。In the case where nitrogen atoms (e.g. amines) are present on the compounds of the invention, 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. . Therefore, 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.
当任何变量在化合物的任何组成或式中出现一次以上时，其每次出现时的定义均独立于其在其它每种情况下出现时的定义。因此，例如如果显示基团取代有0-3个R，则所述基团可任选地取代有至多三个R基团，且在每次出现时R独立地选自R的定义。此外，取代基和/或变量的组合仅在上述组合可产生稳定的化合物时才容许存在。 When 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. Thus, for example, if a group is shown substituted with 0-3 R, then 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. Furthermore, combinations of substituents and/or variables are permitted only if such combinations result in stable compounds.
本文使用的术语“患者”是指通过本发明的方法进行治疗的有机体。这类有机体优选包括但不限于哺乳动物(例如鼠类、猿、猴、马、牛、猪、犬、猫等)且最优选是指人类。The term "patient" as used herein refers to an organism to be treated by the methods of the present invention. Such 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.
本文使用的术语“有效量”意指将会引起例如研究人员或临床医师所寻求的组织、系统、动物或人的生物学或医学响应的药物或药剂(即本发明化合物)的量。此外，术语“治疗有效量”意指这样的量：与未接受上述量的相应受试者相比，所述量导致改善的治疗、治愈、预防或减轻疾病、病症或副作用，或降低在疾病或病症的进展速度。有效量可以一个或多个给药、施用或剂量给予且不意欲被特定的制剂或给药途径限制。该术语还包括在其范围内的增强正常生理机能的有效量。As used herein, 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. Furthermore, the term "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.
本文使用的术语“治疗”包括导致改善病症、疾病、障碍等的任何效果，例如减轻、减少、调节、改善或消除，或改善其症状。The term "treatment" as used herein 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.
术语“药用”在本文中用于指如下那些化合物、物质、组合物和/或剂型：在合理医学判断的范围内，其适于与人类和动物的组织接触使用而无过高毒性、刺激性、过敏反应和/或其它问题或并发症，并与合理的益处/风险比相称。The term "pharmaceutically acceptable" is used herein to refer 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.
本文使用的短语“药用载体”意指药用物质、组合物或媒介物，诸如液体或固体填充剂、稀释剂、赋形剂、制造助剂(例如润滑剂、滑石、硬脂酸镁、硬脂酸钙或硬脂酸锌或硬脂酸)或溶剂包囊物质，其涉及将主题化合物从一个器官或身体的部分携带或运送至另一个器官或身体的部分。每种载体在与制剂的其它成分相容和对患者无害的意义上必须是“可接受的”。The phrase "pharmaceutically acceptable carrier" as used herein 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. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient.
术语“药物组合物”意指包含本发明化合物与至少一种其它药用载体的组合物。“药用载体”是指本领域中通常接受用于将生物活性剂递送至动物(具体为哺乳动物)的介质，包括(即)佐剂、赋形剂或媒介物，诸如稀释剂、防腐剂、填充剂、流动调控剂、崩解剂、润湿剂、乳化剂、悬浮剂、增甜剂、矫味剂、芳香剂、抗细菌剂、抗真菌剂、润滑剂和分散剂，这取决于给药模式和剂型的性质。The term "pharmaceutical 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.
特定药学及医学术语Specific pharmaceutical and medical terms
术语“可接受的”，如本文所用，指一个处方组分或活性成分对一般治疗目标的健康没有过分的有害影响。The term "acceptable," as used herein, means that a formulation component or active ingredient does not have undue deleterious effects on the health of the general target of treatment.
术语“癌症”，如本文所用，指一种不能控制的细胞的异常生长，并且在某种条件下能够转移(传播)。这种类型的癌症包括但不限于，实体肿瘤(如膀胱、肠、脑、胸、子宫、心脏、肾、肺、淋巴组织(淋巴瘤)、卵巢、胰腺或其它内分泌器官(如甲状腺)、前列腺、皮肤(黑色素瘤)或血液瘤(如非白血性白血病)。The term "cancer", as used herein, 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).
术语“联合给药”或其类似术语，如本文所用，指将几种所选的治疗药物给一个病人用药， 以相同或不同的给药方式在相同或不同的时间给药。The term "coadministration" or similar terms, as used herein, 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.
术语“增强”或“能增强”，如本文所用，指预期的结果能够在效力或是持续时间方面都有增加或延长。因此，在增强药物的治疗效果方面，术语“能增强”指药物在系统中有提高或延长效力或持续时间的能力。本文所用的“增效值”，指在理想的系统中，能够最大限度地地增强另外一种治疗药物的能力。The term "enhance" or "enhancement," as used herein, means that a desired result can be increased or prolonged in potency or duration. Thus, in terms of enhancing the therapeutic effects of a drug, the term "enhancing" refers to the ability of the drug to increase or prolong its potency or duration in the system. As used herein, "enhancement value" refers to the ability to maximize the enhancement of another therapeutic agent in an ideal system.
术语“免疫性疾病”指对内源性或外源性抗原产生的不良或有害反应的疾病或症状。结果通常会造成细胞的功能障碍、或因此而破坏并造成机能障碍、或破坏可能产生免疫症状的器官或组织。The term "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.
术语“试剂盒”与“产品包装”是同义词。The terms "kit" and "product packaging" are synonymous.
术语“受试者”或“病人”包括哺乳动物和非哺乳动物。哺乳动物包括但不限于，哺乳类：人、非人灵长类如猩猩、猿及猴类；农业动物如牛、马、山羊、绵羊、猪；家畜如兔、狗；实验动物包括啮齿类，如大鼠、小鼠及豚鼠等。非哺乳类动物包括但不限于，鸟、鱼等。在一优选的方面，所选哺乳动物是人。The term "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. In a preferred aspect, the selected mammal is a human.
术语“治疗”、“治疗过程”或“疗法”如本文所用，包括缓和、抑制或改善疾病的症状或状况；抑制并发症的产生；改善或预防潜在代谢综合征；抑制疾病或症状的产生，如控制疾病或情况的发展；减轻疾病或症状；使疾病或症状减退；减轻由疾病或症状引起的并发症，或预防和/或治疗由疾病或症状引起的征兆。The terms "treatment," "treatment," or "therapy" as used herein 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.
如本文所用，某一化合物或药物组合物，给药后，可以使某一疾病、症状或情况得到改善，尤指其严重度得到改善，延迟发病，减缓病情进展，或减少病情持续时间。无论固定给药或临时给药、持续给药或断续给药，可以归因于或与给药有关的情况。As used herein, 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.
给药途径Route of administration
适合的给药途径包括但不限于，口服、静脉注射、直肠、气雾剂、非肠道给药、眼部给药、肺部给药、经皮给药、阴道给药、耳道给药、鼻腔给药及局部给药。此外，仅作举例说明，肠道外给药，包括肌肉注射、皮下注射、静脉注射、髓内注射、心室注射、腹膜内注射、淋巴管内注射、及鼻内注射。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. In addition, by way of example only, parenteral administration includes intramuscular injection, subcutaneous injection, intravenous injection, intramedullary injection, ventricular injection, intraperitoneal injection, intralymphatic injection, and intranasal injection.
在一方面，此处描述的化合物给药方式是局部的而不是全身性的给药方式。在特定的具体实施方案中，长效制剂通过植入给药(例如皮下或肌肉)或通过肌肉注射。此外，在另一具体化实施方案中，药物通过靶向药物给药系统来给药。例如，由器官特异性抗体包裹的脂质体。在这种具体实施例中，所述脂质体被选择性地导向特定器官并被吸收。 In one aspect, the compounds described herein are administered locally rather than systemically. In certain embodiments, long-acting formulations are administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in another specific embodiment, the drug is administered via a targeted drug delivery system. For example, liposomes coated with organ-specific antibodies. In this specific embodiment, the liposomes are selectively targeted to specific organs and absorbed.
药物组合物和剂量Pharmaceutical compositions and dosages
本发明还提供药用组合物，其包含治疗有效量的与一种或多种药用载体(添加剂)和/或稀释剂一起配制的一种或多种本发明的化合物，和任选的一种或多种上述其它治疗剂。可通过任意合适方式给予本发明化合物以用于任意上述用途，例如口服，诸如片剂、丸剂、粉剂、颗粒剂、酏剂、酊剂、悬浮液(包括纳米悬浮液、微悬浮液、喷雾干燥的分散液)、糖浆和乳液；经舌下；含服；经肠胃外，诸如通过皮下、静脉内、肌内或胸骨内注射或输注技术(例如以无菌可注射水性或非水性溶液或悬浮液形式)；经鼻，包括向鼻膜给药，诸如通过吸入喷雾；局部，诸如以乳膏剂或软膏剂形式；或经直肠，诸如以栓剂形式；或经瘤内注射。它们可单独给药，但通常使用基于所选给药途径和标准药学实践选择的药物载体给药。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. in sterile injectable aqueous or non-aqueous solutions or suspensions liquid form); 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. They may be administered alone, but usually with a pharmaceutical carrier chosen based on the chosen route of administration and standard pharmaceutical practice.
根据本领域技术人员认识范围内的诸多因素来调配药用载体。这些因素包括但不限于：所调配活性剂的类型和性质；含有活性剂的组合物所要给予的受试者；组合物的预期给药途径；及所靶向的治疗适应症。药用载体包括水性和非水性液体介质及各种固体和半固体的药用载体。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.
上述载体可包括除活性剂外的诸多不同成分和添加剂，上述其它成分出于本领域技术人员公知的各种原因包括于制剂中，例如稳定剂、粘合剂等。关于合适的药用载体和载体选择中所涉及的因素的描述可参见多个容易获得的来源，例如Allen L.V.Jr.et al.Remington:The Science and Practice of Pharmacy(2Volumes),22nd Edition(2012),Pharmaceutical Press。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.
当然，本发明化合物的剂量方案取决于已知因素而有所变化，诸如具体药剂的药效学特性及其给药模式和途径；接受者的物种、年龄、性别、健康状况、医学病状和重量；症状的性质和程度；同时治疗的种类；治疗频率；给药途径、患者的肾和肝功能及期望效应。根据一般指导，当用于指定效应时，各活性成分的日口服剂量应为约0.001mg/天至约10-5000mg/天，优选地为约0.01mg/天至约1000mg/天，且最优选地为约0.1mg/天至约250mg/天。在恒速输注期间，静脉内最优选剂量应为约0.01mg/kg/分钟至约10mg/kg/分钟。本发明化合物可以单一日剂量给药，或可以每日两次、三次或四次的分开剂量给药总日剂量。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. According to general guidance, when used for the indicated effect, 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. During a constant rate infusion, 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.
所述化合物通常以与根据预期给药形式(例如口服片剂、胶囊剂、酏剂和糖浆剂)适当地选择且与常规药学实践相符合的合适药物稀释剂、赋形剂或载体(在本文中统称为药物载体)的混合物形式进行给药。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.
适于给药的剂型(药物组合物)可含有约1毫克至约2000毫克活性成分/剂量单位。在这些医药组合物中，以组合物的总重量计，活性成分通常将以约0.1-95重量％的量存在。Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 mg to about 2000 mg of active ingredient per dosage unit. In these pharmaceutical compositions, 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.
用于口服给药的典型胶囊剂含有至少一种本发明化合物(250mg)、乳糖(75mg)和硬脂酸镁(15mg)。使该混合物通过60目网筛，并包装成1号明胶胶囊。 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.
典型的可注射制剂可如下制备：以无菌方式将至少一种本发明化合物(250mg)置于瓶中、以无菌方式冻干并密封。为进行使用，将瓶内容物与2mL生理盐水混合，以产生可注射制剂。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.
本发明范围包括(单独或与药物载体组合)包含治疗有效量的至少一种本发明化合物作为活性成分的药物组合物。任选地，本发明化合物可单独使用、与本发明其它化合物组合使用或与一种或多种其它治疗剂(例如抗癌剂或其它药学活性物质)组合使用。Included within the scope of the invention are pharmaceutical 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. Optionally, 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).
不考虑所选择的给药路径，通过本领域技术人员已知的常规方法来将本发明的化合物(其可以合适的水合形式使用)和/或本发明的药物组合物配制成药用剂量形式。Regardless of the chosen route of administration, 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.
可改变活性成分在本发明的药物组合物中的实际剂量水平，从而获得对于实现特定患者的期望的治疗响应、组成和给药模式有效的而对患者无毒的活性成分量。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.
选定的剂量水平会取决于多种因素，包括所用的本发明的特定化合物或其酯、盐或酰胺的活性；给药路径；给药时间；所用的特定化合物的排泄速率；吸收速率和程度；治疗的持续时间；与所用的特定化合物组合使用的其它药物、化合物和/或物质；所治疗的患者的年龄、性别、重量、状况、一般健康和先前的医学史等医学领域公知的因素。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.
具有本领域普通技术的医生或兽医可容易地确定并开出有效量的所需药物组合物。例如，为了达到所期望的治疗效果，医师或兽医可在低于所需的水平开始药物组合物中所用的本发明化合物的较量，并逐步增加剂量直至实现所期望的效果。通常，合适日剂量的本发明化合物将是有效产生治疗效果的最低剂量的化合物的量。此种有效剂量通常取决于上述因素。通常，口服、静脉内、脑室内和皮下剂量的用于患者的本发明化合物的范围为约0.01至约50mg/kg体重/天。如果需要的话，有效日剂量的活性化合物可以两个、三个、四个、五个、六个或更多个亚剂量在一天当中的适当的间隔分别给药，任选地呈单位剂型形式。在本发明的某些方面中，服药为每天一次给药。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. Generally, 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. Typically, 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. If desired, 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.
虽然本发明化合物可单独给药，但优选以药物制剂(组合物)形式给予化合物。Although the compounds of the present invention can be administered alone, it is preferred to administer the compounds in the form of pharmaceutical preparations (compositions).
试剂盒/产品包装Test kit/product packaging
为了用于上述适应症的治疗，试剂盒/产品包装也在此进行描述。这些试剂盒可以由输送器、药包或容器盒组成，容器盒可被划分成多格，以容纳一种或多种容器，如管形瓶、试管及类似物等，每个容器中包含所述方法中的单独一种成分。合适的容器包括瓶子，管形瓶，注射器和试管等。容器由可接受的玻璃或塑料等材料制作而成。For use in the treatment of the above indications, the kit/product packaging is also described herein. These 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.
举例来讲，容器可容纳有一种或多种在此所述的化合物，所述化合物可能以药物化合物形式存在，也可能与在本文中所述的其它成分组成混合物的形式存在。容器可有一个无菌输出口(例如容器可为静脉输液包或瓶，瓶塞可被皮下注射器针头刺破)。这样的试剂盒可容纳有一种化合物，及本文中所述的使用方法的说明、标签或操作说明。 For example, 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). Such kits may contain a compound and instructions for use, labeling, or operating instructions described herein.
一个典型的试剂盒可包括一种或多种容器，为适应商业推广和使用者对化合物使用的需求，每个容器装有一种或多种材料(如试剂，也可以是浓缩的母液，和/或器械)。这些材料包括但不局限于缓冲液，稀释液，滤器，针头，注射器，输送器，包，容器，瓶和/或试管，附有内容清单和/或使用说明书，内置包装也附有说明书。整套的说明都要包括在内。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.
标签可显示在容器上或与容器紧密相关。标签出现在容器上即指标签字母、数字或其它特征被粘贴、铸模、刻在容器上；标签也可出现在装有多种容器的容器盒或运输盒内，如在产品插页中。一个标签可用来提示内容物的某种特定治疗用途。标签也可标示内容物使用说明，诸如在上述方法中描述的。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.
在本说明书中被描述的所有特征(包括任何所述的权利要求、摘要和附图),和/或任何方法或过程中涉及的所有步骤，均有可能以任意一种组合存在，除非某些特征或步骤在同一组合中是相互排斥的。All features described in this specification (including any stated claims, abstract and drawings), and/or all steps involved in any method or process, may exist in any combination, unless certain Features or steps are mutually exclusive in the same combination.
本发明提到的上述特征，或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以任何可提供相同、等同或相似目的的替代性特征取代。因此除有特别说明，所揭示的特征仅为等同或相似特征的一般性例子。The above-mentioned features mentioned in the present invention or the features mentioned in the embodiments may be combined in any combination. All features disclosed in the specification of this case can be used in any combination form, and each feature disclosed in the specification can be replaced by any alternative feature that serves the same, equivalent or similar purpose. Therefore, unless otherwise stated, the features disclosed are only general examples of equivalent or similar features.
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。除非另外说明，否则所有的百分数、比率、比例、或份数按重量计。The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the invention and are not intended to limit the scope of the invention. Experimental methods without specifying specific conditions in the following examples usually follow conventional conditions or conditions recommended by the manufacturer. Unless otherwise stated, all percentages, ratios, proportions, or parts are by weight.
本发明中的重量体积百分比中的单位是本领域技术人员所熟知的，例如是指在100毫升的溶液中溶质的重量(g)。除非另行定义，文中所使用的所有专业与科学用语与本领域技术人员所熟悉的意义相同。此外，任何与所记载内容相似或等同的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。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. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as familiar to one of ordinary skill in the art. In addition, 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.
实施例Example
通用过程general process
未包括制备途径时，本发明所用原料与试剂均为已知产品，可以按照本领域已知的方法合成，或者可通过购买市售产品获得。使用的市售试剂均不需进一步纯化。When the preparation route is not included, 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.
室温是指20-30℃。Room temperature refers to 20-30℃.
反应实施例中无特殊说明，反应均在氮气氛下进行。氮气氛是指反应瓶连接一个约1L的氮气气球。 There are no special instructions in the reaction examples, and the reactions are all carried out under a nitrogen atmosphere. Nitrogen atmosphere means that the reaction bottle is connected to a nitrogen balloon of about 1L.
氢化反应通常抽真空，充入氢气，反复操作3次。氢气氛是指反应瓶连接一个约1L的氢气气球。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.
微波反应使用Initiator+微波反应器。Use of microwave reaction Initiator+microwave reactor.
本发明化合物的结构是通过核磁共振(NMR)和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker AscendTM 500型)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3),氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。以下简写用于NMR信号的多重性：s＝单峰，brs＝宽峰，d＝二重峰，t＝三重峰，m＝多重峰。偶合常数以J值列出，以Hz测量。The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). NMR shifts (δ) are given in units of 10 -6 (ppm). NMR was measured using a (Bruker Ascend TM 500) nuclear magnetic instrument. The measurement solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard It is tetramethylsilane (TMS). The following abbreviations are used for the multiplicity of NMR signals: s = singlet, brs = broad peak, d = doublet, t = triplet, m = multiplet. Coupling constants are listed as J values, measured in Hz.
LC-MS的测定使用Thermo液质联用仪(UltiMate 3000+MSQ PLUS)。HPLC的测定使用Thermo高压液相色谱仪(UltiMate 3000)。反相制备色谱使用Thermo(UltiMate 3000)反相制备色谱仪。快速柱层析使用艾杰尔(FS-9200T)自动过柱机，硅胶预装柱使用三泰预装柱。薄层层析硅胶板用烟台黄海HSGF254或青岛GF254硅胶板，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。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.
本发明中一些中间体的合成方法如下：The synthesis methods of some intermediates in the present invention are as follows:
中间体1
Intermediate 1
中间体1由以下步骤制备：
Intermediate 1 is prepared by the following steps:
第一步：将化合物Int-1a(5.0g,28.09mmol)，Int-1b(5.61g,36.51mmol)和碳酸氢钠(7.08g,84.26mmol)溶于乙醇(50mL)和水(5mL)中，反应液加热回流过夜。LCMS监测反应结束后，冷却至室温，抽滤，滤饼用水洗涤，然后干燥得到灰白色固体Int-1(5.0g,收率78％)。ESI-MS(m/z):227.4[M+H]+。 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] + .
中间体2
Intermediate 2
中间体2由以下步骤制备：
Intermediate 2 is prepared by the following steps:
第一步：将钠氢(1.59g,39.64mmol，含量60％)加入到装有无水四氢呋喃(10mL)两口烧瓶中，置于冰水浴中，将化合物Int-2a(5.0g,26.43mmol)溶解在无水四氢呋喃(30mL)，缓慢滴加到反应液中。30分钟后开始滴加氘代碘甲烷(4.02g,27.75mmol)，滴加完成后缓慢升至室温搅拌过夜。LCMS监测反应结束后，冷却至0℃，缓慢滴加饱和的氯化铵水溶液淬灭反应，乙酸乙酯萃取，有机相干燥得到黄色油状物Int-2b(5.0g,收率91％)。ESI-MS(m/z):207.2[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. After the reaction was monitored by LCMS, it was cooled to 0°C, saturated aqueous ammonium chloride solution was slowly added dropwise to quench the reaction, extracted with ethyl acetate, and the organic phase was dried to obtain yellow oil Int-2b (5.0 g, yield 91%). ESI-MS(m/z):207.2[M+H] + .
第二步：将Int-2b(5.0g,24.24mmol)溶解在甲醇(50mL)中，置于冰水浴中，缓慢滴加氯化亚砜(8.65g,72.73mmol)，滴加完成后升至室温，再升至60℃反应过夜。LCMS监测反应结束后，反应液浓缩得到黄色油状物Int-2c(3.0g,收率79％)。ESI-MS(m/z):157.2[M+H]+。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] + .
第三步：将化合物Int-1a(2.0g,11.23mmol)，Int-2c(3.17g,20.22mmol)和碳酸氢钠(2.83g,33.70mmol)溶于乙醇(20mL)和水(2mL)中，反应液回流过夜。LCMS监测反应结束后，冷却至室温，抽滤，滤饼用水洗涤，然后干燥得到灰白色固体Int-2(1.4g,收率54％)。ESI-MS(m/z):230.3[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%). ESI-MS(m/z):230.3[M+H] + .
中间体3
Intermediate 3
中间体3由以下步骤制备：
Intermediate 3 is prepared by the following steps:
第一步：将钠氢(237mg,5.90mmol，含量60％)加入到装有无水四氢呋喃(5mL)两口烧瓶中，置于冰水浴中，将化合物Int-3a(300mg,1.48mmol)溶解在无水四氢呋喃(10mL)，缓慢滴加到反应液中。30分钟后开始滴加氘代碘甲烷(472mg,2.95mmol)，滴加完成后缓慢升至室温搅拌过夜。LCMS监测反应结束，冷却至0℃，缓慢滴加饱和的氯化铵水溶液淬灭反应，乙酸乙酯萃取，有机相干燥得到黄色油状物Int-3b(312mg,收率96％)。ESI-MS(m/z):221.6[M+H]+。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. LCMS monitored the end of the reaction, cooled to 0°C, slowly added dropwise saturated aqueous ammonium chloride solution to quench the reaction, extracted with ethyl acetate, and dried the organic phase to obtain yellow oil Int-3b (312 mg, yield 96%). ESI-MS(m/z):221.6[M+H] + .
第二步：将Int-3b(312mg,1.42mmol)溶解在甲醇(5mL)中，置于冰水浴中，缓慢滴加氯化亚砜(505mg,4.25mmol)，滴加完成后升至室温，再升至70℃反应过夜。LCMS监测反应结束后，反应液浓缩得到黄色油状物Int-3c(180mg,收率84％)。ESI-MS(m/z):135.4[M+H]+。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] + .
第三步：将化合物Int-3c(180mg,1.05mmol)和化合物4d(200mg,0.95mmol)溶于四氢呋喃(5mL)中，加入N,N-二异丙基丙胺(371mg,2.88mmol)。反应液在室温下搅拌8小时。LCMS监测反应结束。反应液加水稀释，用乙酸乙酯萃取，反应液减压浓缩，残余物通过硅胶柱层析纯化(石油醚/乙酸乙酯＝10/1)灰白色固体Int-3d(105mg,反应收率35％)。ESI-MS(m/z):306.5[M+H]+。Step 3: Dissolve compound Int-3c (180 mg, 1.05 mmol) and compound 4d (200 mg, 0.95 mmol) in tetrahydrofuran (5 mL), and add N, N-diisopropylpropylamine (371 mg, 2.88 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, extracted with ethyl acetate, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) as an off-white solid Int-3d (105 mg, reaction yield 35%) ). ESI-MS(m/z):306.5[M+H] + .
第四步：将化合物Int-3d(105mg,343umol)溶于冰醋酸(2mL)，加入铁粉(77mg,1.37mmol)。反应液在室温下搅拌16小时。LCMS监测反应结束，用硅藻土滤掉残渣，用乙酸乙酯洗涤，浓缩滤液，残余物通过硅胶柱层析纯化(二氯甲烷/甲醇＝10/1)得到化合物Int-3(81mg,反应收率96％)。ESI-MS(m/z):244.4[M+H]+。 Step 4: Dissolve compound Int-3d (105 mg, 343umol) in glacial acetic acid (2mL), and add iron powder (77mg, 1.37mmol). The reaction solution was stirred at room temperature for 16 hours. LCMS monitored the end of the reaction, filtered the residue with diatomaceous earth, washed with ethyl acetate, concentrated the filtrate, and purified the residue by silica gel column chromatography (dichloromethane/methanol=10/1) to obtain compound Int-3 (81 mg, reaction Yield 96%). ESI-MS(m/z):244.4[M+H] + .
中间体4
Intermediate 4
中间体4由以下步骤制备：
Intermediate 4 is prepared by the following steps:
第一步：将化合物Int-4a(1.01g,5mmol)和氢氧化钾(842mg,15mmol)溶于无水二甲基亚砜(10mL)中，随后将氘代碘甲烷(1.59g,11mmol)滴加至反应液中。反应液在室温下搅拌8小时。LCMS监测反应结束。反应液加水稀释，乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤，滤液浓缩得到化合物Int-4b(1.0g，收率84％)的粗品。ESI-MS(m/z):236.3[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] + .
第二步：将化合物Int-4b(1.0g,4.25mmol)溶于盐酸二氧六环溶液(4M,10mL)中。反应液在室温下搅拌4小时。LCMS监测反应结束。反应液减压浓缩，得到化合物Int-4c(720mg)的粗品。ESI-MS(m/z):136.1[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] + .
第三步：将化合物Int-4c(720mg,4.19mmol)和化合物Int-3d(872mg,4.19mmol)溶于四氢呋喃(10mL)中，加入N,N-二异丙基丙胺(1.62g,12.57mmol)。反应液在室温下搅拌8小时。LCMS监测反应结束。反应液加水稀释，过滤，滤饼用水洗涤，干燥得到灰白色固体Int-4d(993mg,，两步反应收率77％)。ESI-MS(m/z):307.2[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] + .
第四步：将化合物Int-4d(306mg,1mmol)和碳酸钾(207mg,1.5mmol)溶于甲醇(10mL)中，将连二亚硫酸钠(871mg,5mmol)溶于水中并滴加至反应液。反应液在室温下搅拌15分钟。LCMS监测原料反应完全。将盐酸二氧六环溶液(4M,1.25mL)加入反应液中。反应液继续在室温下搅拌8小时。将氨甲醇溶液滴加至反应液，调节反应液pH至10，反应液减压浓缩，残余物通过硅胶柱层析纯化(二氯甲烷/甲醇＝10/1)得到化合物Int-4(30mg， 收率13％)。ESI-MS(m/z):242.3[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. Ammonia methanol solution was added dropwise to the reaction solution, the pH of the reaction solution was adjusted to 10, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=10/1) to obtain compound Int-4 (30 mg, Yield 13%). ESI-MS(m/z):242.3[M+H] + .
中间体5
Intermediate 5
中间体5由以下步骤制备：
Intermediate 5 is prepared by the following steps:
第一步：将化合物Int-5a(500mg,3.86mmol)，6-氟-烟腈Int-5b(518.39mg,4.25mmol)和碳酸铯(1.89g,5.79mmol)溶解于乙腈(10mL)中，在室温条件下搅拌过夜。LCMS监测反应结束。反应液用乙酸乙酯稀释，依次用水和饱和食盐水洗涤，有机相通过无水硫酸钠干燥，浓缩后通过硅胶柱层析纯化(石油醚/乙酸乙酯＝5/1)，得到黄色油状物5c(680mg，收率76％)。ESI-MS(m/z):232.4[M+H]+。Step 1: Dissolve compound Int-5a (500mg, 3.86mmol), 6-fluoro-nicotinonitrile Int-5b (518.39mg, 4.25mmol) and cesium carbonate (1.89g, 5.79mmol) in acetonitrile (10mL). Stir overnight at room temperature. LCMS monitored the reaction to completion. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine in sequence, the organic phase was dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain a yellow oil. 5c (680 mg, yield 76%). ESI-MS(m/z):232.4[M+H] + .
第二步：将化合物Int-5c(680mg,2.94mmol)和Raney Nickel(0.5mL,水混悬液)溶解分散于甲醇(10mL)和氨水(1mL)中，用氢气球抽换气，室温条件下搅拌过夜。LCMS监测反应结束，反应液用甲醇稀释，硅藻土滤层抽滤，有机相浓缩，浓缩后通过硅胶柱层析纯化(二氯甲烷/甲醇＝10/1)得到黄色油状物Int-5(220mg,收率31％)。ESI-MS(m/z):236.4[M+H]+。Step 2: Dissolve and disperse compound Int-5c (680 mg, 2.94 mmol) and Raney Nickel (0.5 mL, aqueous suspension) in methanol (10 mL) and ammonia water (1 mL). Use a hydrogen balloon to aerate at room temperature. Stir overnight. LCMS monitors the end of the reaction. The reaction solution is diluted with methanol, filtered through a diatomaceous earth filter layer, and the organic phase is concentrated. After concentration, it is purified by silica gel column chromatography (dichloromethane/methanol=10/1) to obtain yellow oil Int-5 ( 220mg, yield 31%). ESI-MS(m/z):236.4[M+H] + .
中间体6
Intermediate 6
中间体6由以下步骤制备：
Intermediate 6 is prepared by the following steps:
第一步：将化合物Int-1a(500mg,2.81mmol)和化合物Int-6a(602mg,3.65mmol)溶于乙醇(20mL)和水(2mL)中，随后加入碳酸氢钠(707mg,8.34mmol)，将反应液的温度升高到80℃，搅拌16小时。待反应液冷却至室温，向反应液加入水(12mL)，过滤后得到灰白色固体Int-6(385mg，收率57％)，ESI-MS(m/z):239.4[M+H]+。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] + .
中间体7
Intermediate 7
中间体7由以下步骤制备：
Intermediate 7 is prepared by the following steps:
第一步：将2-(三氟甲基)嘧啶-5-醇Int-7a(1.0g,6.09mmol)，6-氟-烟腈Int-5b(1.01g,7.31mmol)和碳酸铯(3.97g,12.19mmol)溶解于DMF(10mL)中，在80℃条件下搅拌过夜。LCMS监测反应结束。反应液用乙酸乙酯稀释，依次用水和饱和食盐水洗涤，有机相通过无水硫酸钠干燥，浓缩后通过硅胶柱层析纯化(石油醚/乙酸乙酯＝5/1)，得到黄色油状物Int-7b(1.3g，收率80％)。Step 1: Combine 2-(trifluoromethyl)pyrimidin-5-ol Int-7a (1.0g, 6.09mmol), 6-fluoro-nicotinonitrile Int-5b (1.01g, 7.31mmol) and cesium carbonate (3.97 g, 12.19 mmol) was dissolved in DMF (10 mL), and stirred at 80°C overnight. LCMS monitored the reaction to completion. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine in sequence, the organic phase was dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain a yellow oil. Int-7b (1.3g, yield 80%).
第二步：将化合物Int-7b(1.3g,4.88mmol)和Raney Nickel(0.5mL,水混悬液)溶解分散于甲醇(10mL)和氨水(1mL)中，用氢气球抽换气，室温条件下搅拌过夜。LCMS监测反应结束，反应液用甲醇稀释，硅藻土滤层抽滤，有机相浓缩，得到黄色油状物Int-7(700mg,收率53％)。ESI-MS(m/z):271.3[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. ESI-MS(m/z):271.3[M+H] + .
中间体8
Intermediate 8
中间体8由以下步骤制备：
Intermediate 8 is prepared by the following steps:
第一步：将6-(三氟甲基)吡啶-3-醇Int-8a(1.0g，6.13mmol)溶于二甲亚砜(10mL)中，加入碳酸铯(2.0g，6.13mmol)，室温搅拌30分钟后加入2-氟吡啶-5-甲醛Int-8b(1.53g，12.26mmol)，反应混合物继续搅拌2小时后终止反应。反应液用乙酸乙酯稀释，依次用水和饱和食盐水洗涤，有机相无水硫酸钠干燥，过滤浓缩，残余物通过硅胶柱层析纯化得到产物Int-8c(1.5g，收率91％)。1HNMR(500MHz,DMSO-d6)δ10.04(s,1H),8.79-8.70(m,2H),8.37(dd,J＝8.6,2.3Hz,1H),8.05(d,J＝1.0Hz,2H),7.42(d,J＝8.6Hz,1H)。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. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine in sequence, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography to obtain the product Int-8c (1.5 g, yield 91%). 1 HNMR (500MHz, DMSO-d6) δ10.04 (s, 1H), 8.79-8.70 (m, 2H), 8.37 (dd, J = 8.6, 2.3Hz, 1H), 8.05 (d, J = 1.0Hz, 2H), 7.42 (d, J = 8.6Hz, 1H).
第二步：将化合物Int-8c(1.53g，5.70mmol)溶于乙醇(5mL)，加入盐酸羟胺(792mg，11.41mmol)，室温搅拌过夜。反应液浓缩得到粗品肟，重新溶解于醋酸(5mL)中，加入锌粉(1.94g，29.66mmol)，室温搅拌2小时，LCMS检测反应完全。反应混合物过滤，滤液浓缩除去大部分醋酸，加乙酸乙酯稀释，然后用NaOH溶液(2N)碱化至pH＝11。混合物过滤，滤液浓缩得到化合物Int-8(1.3g)，直接用于下一步反应。ESI-MS(m/z):270.5[M+H]+。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 reaction mixture was filtered, and the filtrate was concentrated to remove most of the acetic acid, diluted with ethyl acetate, and then basified to pH=11 with NaOH solution (2N). The mixture was filtered, and the filtrate was concentrated to obtain compound Int-8 (1.3g), which was directly used in the next reaction. ESI-MS(m/z):270.5[M+H] + .
中间体9
Intermediate 9
中间体9由以下步骤制备：
Intermediate 9 is prepared by the following steps:
第一步：将化合物Int-9a(500mg,3.83mmol)，6-氟-烟腈Int-5b(514.47mg,4.21mmol)和碳酸铯(1.87g,5.75mmol)溶解于乙腈(10mL)中，在室温条件下搅拌过夜。LCMS监测反应结束。反应液用乙酸乙酯稀释，依次用水和饱和食盐水洗涤，有机相通过无水硫酸钠干燥，浓缩后通过硅胶柱层析纯化(石油醚/乙酸乙酯＝5/1)，得到黄色油状物Int-9b(630mg，收率70％)。ESI-MS(m/z):233.4[M+H]+。Step 1: Dissolve compound Int-9a (500mg, 3.83mmol), 6-fluoro-nicotinonitrile Int-5b (514.47mg, 4.21mmol) and cesium carbonate (1.87g, 5.75mmol) in acetonitrile (10mL). Stir overnight at room temperature. LCMS monitored the reaction to completion. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine in sequence, the organic phase was dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain a yellow oil. Int-9b (630 mg, yield 70%). ESI-MS(m/z):233.4[M+H] + .
第二步：将化合物Int-9b(630mg,2.71mmol)和Raney Nickel(0.5mL,水混悬液)溶解分散于甲醇(10mL)和氨水(1mL)中，用氢气球抽换气，室温条件下搅拌过夜。LCMS监测反应结束，反应液用甲醇稀释，硅藻土滤层抽滤，有机相浓缩，浓缩后通过硅胶柱层析纯化(二氯甲烷/甲醇＝10/1)得到黄色油状物Int-9(200mg,收率31％)。ESI-MS(m/z):237.4[M+H]+。 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. The reaction solution is diluted with methanol, filtered through a diatomaceous earth filter layer, and the organic phase is concentrated. After concentration, it is purified by silica gel column chromatography (dichloromethane/methanol=10/1) to obtain yellow oil Int-9 ( 200mg, yield 31%). ESI-MS(m/z):237.4[M+H] + .
中间体10
Intermediate 10
中间体10由以下步骤制备：
Intermediate 10 was prepared by the following steps:
第一步：将2-(甲硫基)-5-羟基嘧啶Int-10a(300mg,2.11mmol)溶于乙腈(5mL)中，加入碳酸铯(1.37g,4.22mmol)，室温搅拌30分钟后加入2-氟吡啶-5-甲醛Int-8b(316mg,2.53mmol)，反应混合物搅拌过夜。LCMS监测反应结束。反应液用水稀释，再用乙酸乙酯萃取，有机相无水硫酸钠干燥，过滤浓缩，残余物通过硅胶柱层析纯化(石油醚/乙酸乙酯＝3/1)，得到黄色固体产物Int-10b(511mg,收率97％)。ESI-MS(m/z):248.5[M+H]+。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. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain the yellow solid product Int- 10b (511 mg, yield 97%). ESI-MS(m/z):248.5[M+H] + .
第二步：将化合物Int-10b(400mg,1.62mmol)和3,4-二甲氧基苄胺(405mg,2.43mmol)溶于二氯甲烷(5mL)和甲醇(0.5mL)中,室温搅拌2小时后，加入醋酸硼氢化钠(2.06g,9.71mmol)，反应混合物搅拌过夜。LCMS监测反应结束。反应液用水稀释，再用乙酸乙酯萃取，有机相无水硫酸钠干燥，过滤浓缩，得到黄色液体Int-10c(630mg,收率98％)。ESI-MS(m/z):399.4[M+H]+。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] + .
第三步：将化合物Int-10c(630mg,1.58mmol),二碳酸二叔丁酯(345mg，1.58mmol) 和三乙胺(239mg,2.37mmol)溶于二氯甲烷(5mL)中，室温搅拌2小时后，LCMS监测反应结束。反应液用水稀释，再用乙酸乙酯萃取，有机相无水硫酸钠干燥，过滤浓缩，残余物通过硅胶柱层析纯化(石油醚/乙酸乙酯＝1/1)得到黄色油状Int-10d(402mg,收率51％)。ESI-MS(m/z):499.4[M+H]+。Step 3: Combine compound Int-10c (630mg, 1.58mmol) and di-tert-butyl dicarbonate (345mg, 1.58mmol) and triethylamine (239 mg, 2.37 mmol) were dissolved in dichloromethane (5 mL). After stirring at room temperature for 2 hours, LCMS monitored that the reaction was completed. 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. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain yellow oil Int-10d ( 402mg, yield 51%). ESI-MS(m/z):499.4[M+H] + .
第四步：将化合物Int-10d(402mg,0.86mmol)加入至三氟乙酸(1.5mL),室温搅拌过夜，，LCMS监测反应结束。反应液用水稀释，用氢氧化钠调节溶液至PH＝8，在用二氯甲烷萃取，有机相无水硫酸钠干燥，过滤浓缩，残余物通过硅胶柱层析纯化(二氯甲烷/甲醇＝10/1)得到黄色油状物Int-10(80mg,收率39％)。ESI-MS(m/z):249.4[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. The reaction solution was diluted with water, adjusted to pH=8 with sodium hydroxide, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=10 /1) Obtained yellow oil Int-10 (80 mg, yield 39%). ESI-MS(m/z):249.4[M+H] + .
本发明中实施例化合物的合成方法如下：The synthesis method of the example compounds in the present invention is as follows:
实施例1Example 1
(S)-4,7,8-三甲基-2-(((6-((2-(三氟甲基)嘧啶-5-基)氧代)吡啶-3-基)甲基)氨基)-7,8-二氢蝶啶-6(5H)-酮
(S)-4,7,8-trimethyl-2-(((6-((2-(trifluoromethyl)pyrimidin-5-yl)oxo)pyridin-3-yl)methyl)amino )-7,8-dihydropterin-6(5H)-one
实施例1由以下步骤制备：
Example 1 is prepared by the following steps:
第一步：将化合物Int-1(50mg,220.59umol)和化合物Int-7(77.49mg,286.77umol)溶于正丁醇(2mL)中，加入对甲苯磺酸一水合物(3.89mg,27umol)，反应液在微波条件下，160℃搅拌3小时。待反应液冷却至室温，反应液减压浓缩，残余物用Pre-HPLC纯化得到白色固体1(21.43mg,收率21％)。ESI-MS(m/z):461.2[M+H]+；1H NMR(500MHz,DMSO-d6)δ10.35(s,1H),9.06(s,2H),8.20(d,J＝2.3Hz,1H),7.99(dd,J＝8.5,2.4Hz,2H),7.29(d,J＝8.4Hz,1H),4.55(d,J＝6.0Hz,2H),4.23(d,J＝6.9Hz,1H),3.07(s,3H),2.24(s,3H),1.36(d,J＝6.9Hz,3H). 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%). ESI-MS (m/z): 461.2[M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ10.35 (s, 1H), 9.06 (s, 2H), 8.20 (d, J = 2.3 Hz,1H),7.99(dd,J＝8.5,2.4Hz,2H),7.29(d,J＝8.4Hz,1H),4.55(d,J＝6.0Hz,2H),4.23(d,J＝6.9 Hz,1H),3.07(s,3H),2.24(s,3H),1.36(d,J=6.9Hz,3H).
实施例2
Example 2
(S)-4,7-二甲基-8-(甲基-d3)-2-(((6-((2-(三氟甲基)嘧啶-5-基)氧代)吡啶-3-基)甲基)氨基)-7,8-二氢蝶啶-6(5H)-酮(S)-4,7-dimethyl-8-(methyl-d3)-2-(((6-((2-(trifluoromethyl)pyrimidin-5-yl)oxo)pyridine-3 -(yl)methyl)amino)-7,8-dihydropterin-6(5H)-one
实施例2由以下步骤制备：
Example 2 is prepared by the following steps:
第一步：将化合物Int-2(100mg,435.39umol)和化合物Int-7(152.94mg,566.00umol)溶于正丁醇(2mL)中，加入对甲苯磺酸一水合物(8.27mg,43.54umol)，反应液在微波条件下，160℃搅拌3小时。待反应液冷却至室温，反应液减压浓缩，残余物用Prep-HPLC纯化得到白色固体2(38.22mg,收率18％)。ESI-MS(m/z):464.2[M+H]+；1H NMR(500MHz,DMSO-d6)δ9.80(s,1H),9.03(s,2H),8.12(d,J＝2.2Hz,1H),7.92(dd,J＝8.5,2.2Hz,1H),7.22(d,J＝8.5Hz,1H),6.97(t,J＝6.4Hz,1H),4.47-4.28(m,2H),3.98(q,J＝6.8Hz,1H),2.11(s,3H),1.17(d,J＝6.8Hz,3H).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%). ESI-MS (m/z): 464.2[M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.80 (s, 1H), 9.03 (s, 2H), 8.12 (d, J = 2.2 Hz,1H),7.92(dd,J＝8.5,2.2Hz,1H),7.22(d,J＝8.5Hz,1H),6.97(t,J＝6.4Hz,1H),4.47-4.28(m,2H ),3.98(q,J＝6.8Hz,1H),2.11(s,3H),1.17(d,J＝6.8Hz,3H).
实施例3Example 3
(S)-4-甲基-2-(((6-((2-(三氟甲基)嘧啶-5-基)氧代)吡啶-3-基)甲基)氨基)-6a,7,8,9-四氢吡咯并[2,1-h]蝶啶-6(5H)-酮
(S)-4-methyl-2-(((6-((2-(trifluoromethyl)pyrimidin-5-yl)oxo)pyridin-3-yl)methyl)amino)-6a,7 ,8,9-tetrahydropyrrolo[2,1-h]pteridin-6(5H)-one
实施例3由以下步骤制备：
Example 3 is prepared by the following steps:
第一步：将化合物Int-6(80mg,335.19umol)和化合物Int-7(117.74mg,435.74umol)溶于正丁醇(2mL)中，加入对甲苯磺酸一水合物(6.37mg,33.52umol)，反应液在微波条件下，160℃搅拌3小时。待反应液冷却至室温，反应液减压浓缩，残余物用Pre-HPLC纯化得到白色固体3(99.37mg,收率62％)。ESI-MS(m/z):473.2[M+H]+；1H NMR(500MHz,DMSO-d6)δ9.74(s,1H),9.03(d,J＝1.9Hz,2H),8.12(d,J＝2.4Hz,1H),7.92(dd,J＝8.5,2.4Hz,1H),7.21(d,J＝8.4Hz,1H),6.98(t,J＝6.4Hz,1H),4.46-4.26(m,2H),4.02-3.92(m,1H),3.60-3.48(m,1H),3.44-3.35(m,1H),2.19-2.14(m,1H),2.10(s,3H),1.99-1.79(m,3H).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%). ESI-MS (m/z): 473.2[M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.74 (s, 1H), 9.03 (d, J = 1.9Hz, 2H), 8.12 ( d,J＝2.4Hz,1H),7.92(dd,J＝8.5,2.4Hz,1H),7.21(d,J＝8.4Hz,1H),6.98(t,J＝6.4Hz,1H),4.46- 4.26(m,2H),4.02-3.92(m,1H),3.60-3.48(m,1H),3.44-3.35(m,1H),2.19-2.14(m,1H),2.10(s,3H), 1.99-1.79(m,3H).
实施例4Example 4
4',8'-二甲基-2'-(((6-((2-(三氟甲基)嘧啶-5-基)氧代)吡啶-3-基)甲基)氨基)-5',8'-二氢-6'H-螺[环丙烷-1,7'-蝶啶]-6'-酮
4',8'-Dimethyl-2'-(((6-((2-(trifluoromethyl)pyrimidin-5-yl)oxo)pyridin-3-yl)methyl)amino)-5 ',8'-Dihydro-6'H-spiro[cyclopropane-1,7'-pteridin]-6'-one
实施例4由以下步骤制备：
Example 4 is prepared by the following steps:
第一步：将钠氢(1.59g,39.76mmol，含量60％)加入到装有无水四氢呋喃(20mL)两口烧瓶中，置于冰水浴中，将化合物Int-4a(2g,9.94mmol)溶解在无水四氢呋喃(10mL)，缓慢滴加到反应液中。30分钟后开始滴加碘甲烷(3.53g,24.85mmol)，滴加完成后缓慢升至室温搅拌过夜。LCMS监测反应结束，冷却至0℃，缓慢滴加饱和的氯化铵水溶液淬灭反应，乙酸乙酯萃取，有机相干燥得到黄色油状物4a(1.7g,收率79％)。ESI-MS(m/z):216.2[M+H]+。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. LCMS monitored the end of the reaction, cooled to 0°C, slowly added dropwise a saturated ammonium chloride aqueous solution to quench the reaction, extracted with ethyl acetate, and dried the organic phase to obtain yellow oil 4a (1.7g, yield 79%). ESI-MS(m/z):216.2[M+H] + .
第二步：将4a(1.7g,7.90mmol)溶解在甲醇(5mL)中，置于冰水浴中，缓慢滴加氯化亚砜(2.82g,23.69mmol)，滴加完成后升至室温，再升至70℃反应过夜。LCMS监测反应结束后，反应液浓缩得到黄色固体4b(1.2g,收率91％)。ESI-MS(m/z):130.2[M+H]+。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] + .
第三步：将化合物Int-3d(500mg,2.40mmol)和化合物4b(597.17mg,3.61mmol)溶于四氢呋喃(10mL)中，加入N,N-二异丙基乙基胺(1.26mL,7.20mmol)。反应液在室温下搅拌8小时。LCMS监测反应结束。反应液加水稀释，用乙酸乙酯萃取，反应液减压浓缩，残余物通过硅胶柱层析纯化(石油醚/乙酸乙酯＝5/1)黄色油状物4c(200mg,反应收率27％)。ESI-MS(m/z):301.3[M+H]+。Step 3: Dissolve compound Int-3d (500mg, 2.40mmol) and compound 4b (597.17mg, 3.61mmol) in tetrahydrofuran (10mL), add N,N-diisopropylethylamine (1.26mL, 7.20 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. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1). Yellow oil 4c (200 mg, reaction yield 27%) . ESI-MS(m/z):301.3[M+H] + .
第四步：将化合物4c(200mg,665.12umol)和化合物Int-7(270.21mg,215.67umol)溶于N,N-二甲基甲酰胺(5mL)中，加入N,N-二异丙基乙基胺(27.89mg,2.00mmol)。反应液在室温下搅拌8小时。LCMS监测反应结束。反应液加水稀释，用乙酸乙酯萃取，反应液减压浓缩，残余物通过硅胶柱层析纯化(石油醚/乙酸乙酯＝1/1)得到化合物4d(300mg， 收率84％)。ESI-MS(m/z):535.2[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. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain compound 4d (300 mg, Yield 84%). ESI-MS(m/z):535.2[M+H] + .
第五步：将化合物4d(250mg,467.77umol)溶于甲醇(5mL)中，加入钯碳(5.68mg,46.78umol)，然后反应体系用氢气置换。反应液在室温下搅拌8小时。LCMS监测反应结束，用硅藻土过滤残渣，反应液减压浓缩，残余物用Prep-HPLC纯化得到白色固体4(24.02mg,收率10％)。ESI-MS(m/z):473.2[M+H]+；1H NMR(500MHz,DMSO-d6)δ9.87(s,1H),9.03(s,2H),8.11(d,J＝2.3Hz,1H),7.91(dd,J＝8.4,2.2Hz,1H),7.22(d,J＝8.4Hz,1H),7.10-6.90(m,1H),4.36(d,J＝6.4Hz,2H),2.72(s,3H),2.11(s,3H),1.37-1.20(m,2H),1.20-1.07(m,2H).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%). ESI-MS (m/z): 473.2[M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.87 (s, 1H), 9.03 (s, 2H), 8.11 (d, J = 2.3 Hz,1H),7.91(dd,J＝8.4,2.2Hz,1H),7.22(d,J＝8.4Hz,1H),7.10-6.90(m,1H),4.36(d,J＝6.4Hz,2H ),2.72(s,3H),2.11(s,3H),1.37-1.20(m,2H),1.20-1.07(m,2H).
实施例5Example 5
4'-甲基-8'-(甲基-d3)-2'-(((6-((2-(三氟甲基)嘧啶-5-基)氧代)吡啶-3-基)甲基)氨基)-5',8'-二氢-6'H-螺[环丙烷-1,7'-蝶啶]-6'-酮
4'-Methyl-8'-(methyl-d3)-2'-(((6-((2-(trifluoromethyl)pyrimidin-5-yl)oxo)pyridin-3-yl)methyl methyl)amino)-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pteridin]-6'-one
实施例5参照实施例4的合成方法得到。ESI-MS(m/z):476.7[M+H]+；1H NMR(500MHz,DMSO-d6)δ9.88(s,1H),9.04(s,2H),8.12(d,J＝2.3Hz,1H),7.92(dd,J＝8.4,2.4Hz,1H),7.23(d,J＝8.4Hz,1H),7.00(t,J＝6.3Hz,1H),4.37(d,J＝6.3Hz,2H),2.12(s,3H),1.31-1.24(m,2H),1.18-1.08(m,2H).Example 5 was obtained by referring to the synthesis method of Example 4. ESI-MS (m/z): 476.7[M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.88 (s, 1H), 9.04 (s, 2H), 8.12 (d, J = 2.3 Hz,1H),7.92(dd,J＝8.4,2.4Hz,1H),7.23(d,J＝8.4Hz,1H),7.00(t,J＝6.3Hz,1H),4.37(d,J＝6.3 Hz,2H),2.12(s,3H),1.31-1.24(m,2H),1.18-1.08(m,2H).
实施例6Example 6
4,7,7-三甲基-8-(甲基-d3)-2-(((6-((2-(三氟甲基)嘧啶-5-基)氧代)吡啶-3-基)甲基)氨基)-7,8-二氢蝶啶-6(5H)-酮
4,7,7-Trimethyl-8-(methyl-d3)-2-(((6-((2-(trifluoromethyl)pyrimidin-5-yl)oxo)pyridin-3-yl) )methyl)amino)-7,8-dihydropterin-6(5H)-one
实施例6由以下步骤制备：
Example 6 is prepared by the following steps:
第一步：将化合物Int-3(55mg,225umol)和化合物Int-7(73mg,270umol)溶于正丁醇(2mL)中，加入对甲苯磺酸一水合物(3.89mg,27umol)，反应液在微波条件下，160℃搅拌3小时。待反应液冷却至室温，反应液减压浓缩，残余物用Pre-HPLC纯化得到白色固体6(24mg,收率21％)。ESI-MS(m/z):478.6[M+H]+；1H NMR(500MHz,DMSO-d6)δ9.80(s,1H),9.04(s,2H),8.13(d,J＝2.3Hz,1H),7.93(dd,J＝8.4,2.4Hz,1H),7.23(d,J＝8.4Hz,1H),6.99(t,J＝6.2Hz,1H),4.38(d,J＝6.3Hz,2H),2.13(s,3H),1.32(s,6H).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%). ESI-MS (m/z): 478.6 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.80 (s, 1H), 9.04 (s, 2H), 8.13 (d, J = 2.3 Hz,1H),7.93(dd,J＝8.4,2.4Hz,1H),7.23(d,J＝8.4Hz,1H),6.99(t,J＝6.2Hz,1H),4.38(d,J＝6.3 Hz,2H),2.13(s,3H),1.32(s,6H).
实施例7Example 7
4,7,7,8-四甲基-2-(((6-((2-(三氟甲基)嘧啶-5-基)氧代)吡啶-3-基)甲基)氨基)-7,8-二氢蝶啶-6(5H)-酮
4,7,7,8-Tetramethyl-2-(((6-((2-(trifluoromethyl)pyrimidin-5-yl)oxo)pyridin-3-yl)methyl)amino)- 7,8-dihydropterin-6(5H)-one
实施例7由以下步骤制备：
Example 7 is prepared by the following steps:
第一步：将钠氢(275mg,6.89mmol，含量60％)加入到装有无水四氢呋喃(5mL)两口烧瓶中，置于冰水浴中，将化合物7a(350mg,1.72mmol)溶解在无水四氢呋喃(10mL)， 缓慢滴加到反应液中。30分钟后开始滴加碘甲烷(366mg,2.58mmol)，滴加完成后缓慢升至室温搅拌过夜。LCMS监测反应结束，冷却至0℃，缓慢滴加饱和的氯化铵水溶液淬灭反应，乙酸乙酯萃取，有机相干燥得到黄色油状物7b(370mg,收率98％)。ESI-MS(m/z):218.7[M+H]+。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. LCMS monitored the end of the reaction, cooled to 0°C, slowly added dropwise a saturated aqueous ammonium chloride solution to quench the reaction, extracted with ethyl acetate, and dried the organic phase to obtain yellow oil 7b (370 mg, yield 98%). ESI-MS(m/z):218.7[M+H] + .
第二步：将7b(370mg,1.70mmol)溶解在甲醇(5mL)中，置于冰水浴中，缓慢滴加氯化亚砜(405mg,3.41mmol)，滴加完成后升至室温，再升至70℃反应过夜。LCMS监测反应结束后，反应液浓缩得到黄色油状物7c(200mg,收率86％)。ESI-MS(m/z):132.7[M+H]+。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%). ESI-MS(m/z):132.7[M+H] + .
第三步：将化合物7c(200mg,1.19mmol)和化合物Int-3d(225mg,1.08mmol)溶于四氢呋喃(5mL)中，加入N,N-二异丙基丙胺(420mg,3.25mmol)。反应液在室温下搅拌8小时。LCMS监测反应结束。反应液加水稀释，用乙酸乙酯萃取，反应液减压浓缩，残余物通过硅胶柱层析纯化(石油醚/乙酸乙酯＝10/1)白色固体7d(70mg,反应收率21％)。ESI-MS(m/z):303.3[M+H]+。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. The reaction solution was diluted with water, extracted with ethyl acetate, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) as a white solid 7d (70 mg, reaction yield 21%). ESI-MS(m/z):303.3[M+H] + .
第四步：将化合物7d(70mg,231umol)和化合物Int-7(75mg,278umol)溶于四氢呋喃(5mL)中，加入N,N-二异丙基丙胺(90mg,694umol)。反应液在室温下搅拌8小时。LCMS监测反应结束。反应液加水稀释，用乙酸乙酯萃取，反应液减压浓缩，残余物通过硅胶柱层析纯化(石油醚/乙酸乙酯＝1/1)得到化合物7e(90mg，收率72％)。ESI-MS(m/z):538.7[M+H]+。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. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain compound 7e (90 mg, yield 72%). ESI-MS(m/z):538.7[M+H] + .
第五步：将化合物7e(90mg,177umol)溶于甲醇(5mL)中，加入钯碳(10mg,89umol)，然后反应体系用氢气置换。反应液在室温下搅拌8小时。LCMS监测反应结束，用硅藻土过滤残渣，反应液减压浓缩，残余物用Prep-HPLC纯化得到白色固体7(21mg,收率25％)。ESI-MS(m/z):475.7[M+H]+；1H NMR(500MHz,DMSO-d6)δ9.82(s,1H),9.04(s,2H),8.13(d,J＝2.3Hz,1H),7.93(dd,J＝8.4,2.4Hz,1H),7.23(d,J＝8.4Hz,1H),7.00(t,J＝6.3Hz,1H),4.38(d,J＝6.3Hz,2H),2.94(s,3H),2.14(s,3H),1.33(s,6H)。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%). ESI-MS (m/z): 475.7[M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.82 (s, 1H), 9.04 (s, 2H), 8.13 (d, J = 2.3 Hz,1H),7.93(dd,J＝8.4,2.4Hz,1H),7.23(d,J＝8.4Hz,1H),7.00(t,J＝6.3Hz,1H),4.38(d,J＝6.3 Hz,2H),2.94(s,3H),2.14(s,3H),1.33(s,6H).
实施例8Example 8
(S)-2-(((6-((2-氯嘧啶-5-基)氧代)吡啶-3-基)甲基)氨基)-4,7,8-三甲基-7,8-二氢蝶啶-6(5H)-酮
(S)-2-(((6-((2-chloropyrimidin-5-yl)oxo)pyridin-3-yl)methyl)amino)-4,7,8-trimethyl-7,8 -Dihydropterin-6(5H)-one
实施例8由以下步骤制备：
Example 8 was prepared by the following steps:
第一步：将化合物Int-1(50.00mg,220.59umol)和化合物Int-9(67.87mg,286.77umol)溶于正丁醇(2mL)中，加入对甲苯磺酸一水合物(4.19mg,22.06umol)，反应液在微波条件下，160℃搅拌3小时。待反应液冷却至室温，反应液减压浓缩，残余物用Prep-HPLC纯化得到白色固体8(10.69mg,收率11％)。ESI-MS(m/z):427.6[M+H]+；1H NMR(500MHz,DMSO-d6)δ9.82(s,1H),8.78(s,2H),8.10(d,J＝2.3Hz,1H),7.89(dd,J＝8.5,2.4Hz,1H),7.17(d,J＝8.5Hz,1H),6.98(t,J＝6.3Hz,1H),4.42-4.30(m,2H),3.99(q,J＝6.8Hz,1H),2.91(s,3H),2.11(s,3H),1.18(d,J＝6.8Hz,3H).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%). ESI-MS (m/z): 427.6 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.82 (s, 1H), 8.78 (s, 2H), 8.10 (d, J = 2.3 Hz,1H),7.89(dd,J＝8.5,2.4Hz,1H),7.17(d,J＝8.5Hz,1H),6.98(t,J＝6.3Hz,1H),4.42-4.30(m,2H ),3.99(q,J＝6.8Hz,1H),2.91(s,3H),2.11(s,3H),1.18(d,J＝6.8Hz,3H).
实施例9Example 9
(S)-4,7,8-三甲基-2-(((6-((6-(三氟甲基)吡啶-3-基)氧代)吡啶-3-基)甲基)氨基)-7,8-二氢蝶啶-6(5H)-酮
(S)-4,7,8-trimethyl-2-(((6-((6-(trifluoromethyl)pyridin-3-yl)oxo)pyridin-3-yl)methyl)amino )-7,8-dihydropterin-6(5H)-one
实施例9由以下步骤制备：
Example 9 is prepared by the following steps:
第一步：将化合物Int-1(50.00mg,220.59umol)和化合物Int-8(77.02mg,286.77umol)溶于正丁醇(2mL)中，加入对甲苯磺酸一水合物(4.19mg,22.06umol)，反应液在微波条件下，160℃搅拌3小时。待反应液冷却至室温，反应液减压浓缩，残余物用Pre-HPLC纯化得到白色固体9(64.26mg,收率63％)。ESI-MS(m/z):460.6[M+H]+；1H NMR(500MHz, DMSO-d6)δ9.80(s,1H),8.62(s,1H),8.12(s,1H),7.95(d,J＝8.6Hz,1H),7.89(d,J＝8.4Hz,1H),7.85(d,J＝8.6Hz,1H),7.15(d,J＝8.5Hz,1H),6.95(t,J＝6.3Hz,1H),4.46-4.28(m,2H),3.98(q,J＝6.9Hz,1H),2.91(s,3H),2.11(s,3H),1.17(d,J＝6.8Hz,3H).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%). ESI-MS(m/z):460.6[M+H] + ; 1 H NMR(500MHz, DMSO-d6)δ9.80(s,1H),8.62(s,1H),8.12(s,1H),7.95(d,J＝8.6Hz,1H),7.89(d,J＝8.4Hz,1H) ,7.85(d,J＝8.6Hz,1H),7.15(d,J＝8.5Hz,1H),6.95(t,J＝6.3Hz,1H),4.46-4.28(m,2H),3.98(q, J＝6.9Hz,1H),2.91(s,3H),2.11(s,3H),1.17(d,J＝6.8Hz,3H).
实施例10Example 10
(S)-2-(((6-((6-氯吡啶-3-基)氧代)吡啶-3-基)甲基)氨基)-4,7,8-三甲基-7,8-二氢蝶啶-6(5H)-酮
(S)-2-(((6-((6-chloropyridin-3-yl)oxo)pyridin-3-yl)methyl)amino)-4,7,8-trimethyl-7,8 -Dihydropterin-6(5H)-one
实施例10由以下步骤制备：
Example 10 was prepared by the following steps:
第一步：将化合物Int-1(50.00mg,220.59umol)和化合物Int-5(67.58mg,286.77umol)溶于正丁醇(2mL)中，加入对甲苯磺酸一水合物(4.19mg,22.06umol)，反应液在微波条件下，160℃搅拌3小时。待反应液冷却至室温，反应液减压浓缩，残余物用Pre-HPLC纯化得到白色固体10(49.62mg,收率52％)。ESI-MS(m/z):426.6[M+H]+；1H NMR(500MHz,Chloroform-d)δ8.19(d,J＝2.9Hz,1H),8.06(d,J＝2.4Hz,1H),7.70(dd,J＝8.4,2.5Hz,1H),7.42(dd,J＝8.6,2.9Hz,1H),7.27(d,J＝8.6Hz,1H),6.88(d,J＝8.4Hz,1H),5.34(s,1H),4.54-4.39(m,2H),4.00(q,J＝6.9Hz,1H),2.95(s,3H),2.15(s,3H),1.33(d,J＝6.9Hz,3H).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%). ESI-MS (m/z): 426.6 [M+H] + ; 1 H NMR (500MHz, Chloroform-d) δ8.19 (d, J = 2.9 Hz, 1H), 8.06 (d, J = 2.4 Hz, 1H),7.70(dd,J＝8.4,2.5Hz,1H),7.42(dd,J＝8.6,2.9Hz,1H),7.27(d,J＝8.6Hz,1H),6.88(d,J＝8.4 Hz,1H),5.34(s,1H),4.54-4.39(m,2H),4.00(q,J＝6.9Hz,1H),2.95(s,3H),2.15(s,3H),1.33(d ,J＝6.9Hz,3H).
根据以上实施例描述的合成路线和中间体的合成方法，可以得到以下实施例。

According to the synthetic routes and synthetic methods of intermediates described in the above examples, the following examples can be obtained.

对照例1Comparative example 1
(S)-2-(((6-(4-fluorophenoxy)pyridin-3-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one
(S)-2-(((6-(4-fluorophenoxy)pyridin-3-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one
对照例1参照专利WO2019209757中描述的compound 54的合成方法得到。ESI-MS(m/z):409.8[M+H]+；1H NMR(500MHz,DMSO-d6)δ9.80(s,1H),8.07(d,J＝2.3Hz,1H),7.79(dd,J＝8.6,2.3Hz,1H),7.28–7.18(m,2H),7.18–7.08(m,2H),7.01–6.88(m,2H),4.44–4.26(m,2H),3.98(q,J＝6.9Hz,1H),2.91(s,3H),2.11(s,3H),1.17(d,J＝6.7Hz,3H).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] + ; 1 H NMR (500MHz, DMSO-d6) δ9.80 (s, 1H), 8.07 (d, J = 2.3Hz, 1H), 7.79 ( dd,J＝8.6,2.3Hz,1H),7.28–7.18(m,2H),7.18–7.08(m,2H),7.01–6.88(m,2H),4.44–4.26(m,2H),3.98( q,J＝6.9Hz,1H),2.91(s,3H),2.11(s,3H),1.17(d,J＝6.7Hz,3H).
对照例2Comparative example 2
(S)-2-(((6-(4-fluorophenoxy)pyridin-3-yl)methyl)amino)-7,8-dimethyl-7,8-dihydropteridin-6(5H)-one
(S)-2-(((6-(4-fluorophenoxy)pyridin-3-yl)methyl)amino)-7,8-dimethyl-7,8-dihydropteridin-6(5H)-one
对照例2参照专利WO2019209757中描述的compound 56的合成方法得到。ESI-MS(m/z):395.7[M+H]+；1H NMR(500MHz,Chloroform-d)δ8.11(d,J＝2.3Hz,1H),7.66(dd,J＝8.5,2.4Hz,1H),7.19(s,1H),7.03–6.96(m,4H),6.77(d,J＝8.4Hz,1H),4.54–4.38(m,2H),4.01(q,J＝6.9Hz,1H),2.97(s,3H),1.38(dd,J＝6.9,1.3Hz,3H).Comparative Example 2 was obtained by referring to the synthesis method of compound 56 described in patent WO2019209757. ESI-MS (m/z): 395.7[M+H] + ; 1 H NMR (500MHz, Chloroform-d) δ8.11 (d, J = 2.3 Hz, 1H), 7.66 (dd, J = 8.5, 2.4 Hz,1H),7.19(s,1H),7.03–6.96(m,4H),6.77(d,J＝8.4Hz,1H),4.54–4.38(m,2H),4.01(q,J＝6.9Hz ,1H),2.97(s,3H),1.38(dd,J=6.9,1.3Hz,3H).
Wnt通路抑制剂生物学筛选和结果Wnt pathway inhibitor biological screening and results
试验例1：Colo205-LUC-TCF/LEF-M1报告细胞系的构建Test Example 1: Construction of Colo205-LUC-TCF/LEF-M1 reporter cell line
Colo205细胞系(中科院细胞库,Cat#TCHu102)购买于中科院细胞库，扩增传代培养后，于细胞的指数生长期，以lipo3000脂质体转染的方法，转染带有TCF/LEF转录因子驱动的萤光素酶报告质粒(Promega)。该质粒带有抗性基因，可以进行抗性筛选。转染在10cm培养皿中进行，使用无抗性的常规完全培养基。2天后，更换带有抗性的培养基，继续培养。之后每2天更换抗性培养基，并将悬浮细胞丢弃，原始培养基离心去除细胞和碎片后保留，作为适应性培养基。当细胞长满培养皿后，将细胞消化下来，计数，传代于96孔板，使每孔中 含有的细胞数量平均为1.5个/孔，传代时使用适应培养基。其余细胞进行冻存。传代后培养4小时，让细胞贴壁，然后在显微镜下观察各孔的细胞数量。每孔仅1个细胞的孔进行标记，其为单克隆孔。而后正常培养，每2天更换培养基，并进行观察。前期单克隆细胞有继续生长的孔，进行2次标记，可更换为正常的带抗性培养基。当有单克隆孔中的细胞长满96孔板板孔时，将其消化传代到24孔培养板，24孔板长满后，传代到1个96孔板和1个6孔板，其中96孔板细胞传代到至少6孔，其中3孔加入已知的Wnt抑制剂，另外3孔不作处理。24h后，96孔板细胞加入萤光检测试剂，检测萤光强度。选择其中不处理时有萤光表达，且抑制后萤之光降低的细胞系，进一步培养。Colo205-LUC-TCF/LEF-M1细胞系为上述筛选出的细胞系之一，其生长曲线、细胞形态、细胞生长状态与原始Colo205细胞相似，且其加抑制剂处理和不处理的萤光信号之比在所有细胞系中属于较大的，比值在4h时抑制可达4-5倍，完全适用于后期的Wnt抑制剂的筛选。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. When the cells fill the culture dish, digest the cells, count them, and passage them into a 96-well plate so that each well has The average number of cells contained was 1.5 cells/well, and adaptation medium was used during passage. The remaining cells were cryopreserved. After passage, incubate for 4 hours to allow the cells to adhere to the wall, and then observe the number of cells in each well under a microscope. Wells with only 1 cell per well are labeled and are monoclonal wells. Then culture normally, replace the culture medium every 2 days, and observe. In the early stage, monoclonal cells have wells where they can continue to grow. They are marked twice and can be replaced with normal resistant medium. When 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.
试验例2：化合物对Colo205-LUC-TCF/LEF M1报告细胞系抑制能力的检测Test Example 2: Detection of the inhibitory ability of compounds against Colo205-LUC-TCF/LEF M1 reporter cell line
Colo205-LUC-TCF/LEF M1细胞株为稳定转染pGL4.49-LUC2-TCF/LEF载体的报告工具细胞，其β-catenin Wnt通路持续激活，加入抑制剂后，Wnt通路被抑制，载体上TCF/LEF顺式元件调控的萤火虫萤光素酶表达量下降，后续加入检测底物后，检测到的光信号相应下降，从而检测出化合物的抑制效果。The Colo205-LUC-TCF/LEF M1 cell line is a reporter tool cell stably transfected with the pGL4.49-LUC2-TCF/LEF vector. Its β-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.
向96孔细胞培养板的每孔中加入100μL，最高浓度20μM的化合物，化合物浓度做3倍梯度稀释。然后向各孔中接种10000个稳定转染过报告基因的colo205细胞和100μL培养基，同时进行相应的处理作为阳性、阴性对照孔。将细胞放入5％CO2细胞培养箱，37℃培养4h，4小时后，去除培养液，向各孔添加含相应的萤火虫荧光素酶底物的试剂(Promega)100μL，测定荧光素酶报告基因的活性。用SpectraMax在全波长模式下读取发光强度。仅由DMSO处理的细胞的光信号强度为阳性对照，无细胞孔的光信号强度为阴性对照，计算各化合物的IC50的浓度。Colo 205报告基因检测数据汇总于下表1。Add 100 μL of a compound with a maximum concentration of 20 μM to each well of a 96-well cell culture plate, and make a 3-fold gradient dilution of the compound concentration. Then, 10,000 colo205 cells stably transfected with the reporter gene and 100 μL of culture medium were inoculated into each well, and corresponding treatments were performed as positive and negative control wells. Place the cells into a 5% CO2 cell culture incubator and incubate at 37°C for 4 hours. After 4 hours, remove the culture medium and add 100 μL of reagent (Promega) containing the corresponding firefly luciferase substrate to each well to measure the luciferase report. Gene activity. 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.
表1化合物对Colo205-LUC-TCF/LEF报告基因抑制的IC50值

Table 1 IC 50 values of compounds for inhibition of Colo205-LUC-TCF/LEF reporter gene

试验例3：化合物对Wnt突变细胞株(Colo205、DU4475、NCI-H929和HepG2)和非Wnt突变细胞株(Hela和RKO)的增殖抑制试验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)
试验中使用的细胞株为Wnt通路持续激活的，且其增殖为Wnt通路依赖型的Colo205、DU4475、NCI-H929和HepG2细胞系；而正常情况下Wnt通路不激活，且增殖不依赖于Wnt通路的HELA和RKO细胞系作为对照细胞系，判断本发明的化合物对于Wnt依赖的增殖的抑制作用不是由于其它非特异毒性造成的。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.
将培养于各自培养基中的Colo205、Du4475、NCI-H929、HepG2、HELA和RKO细胞株在对数生长期时处理，收集细胞后制备成已知浓度的均匀的细胞悬液，然后向96孔细胞培养板中加入细胞悬液，使每孔中含有1000个细胞。放入5％CO2胞培养箱，37℃培养20-24h。第二天向各细胞培养孔中加入已经完全溶解的，3倍梯度稀释的化合物，使细胞培养孔中的最终最高浓度为20μM，继续培养96h。本试验使用Promega的细胞活性检测试验进行检测，细胞增殖越多，则最终的信号强度越强。检测仪器为SpectraMax，全波长模式。仅加入DMSO的孔作为阳性对照孔，未接种细胞的孔为阴性对照孔，计算各化合物对于Wnt持续激活或增殖依赖的细胞的增殖抑制的IC50值，以及对于Wnt未激活的或增殖不依赖的细胞的增殖抑制的IC50值，评估化合物对于Wnt通路的抑制作用和对于正常细胞的毒性作用。结果如下表2所示。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 μM, and continue culturing for 96 hours. This test uses Promega's cell viability detection test. The more cells proliferate, the stronger the final signal intensity will be. 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.
表2化合物对Wnt突变细胞株的增殖抑制的IC50值


NT表示未检测Table 2 IC 50 values of compounds inhibiting the proliferation of Wnt mutant cell lines


NT means not detected
上述结果表明，本发明化合物对于突变细胞株Colo205、DU4475、NCI-H929和HepG2具有显著的抑制活性，而对Hela和RKO细胞株基本不具有显著抑制活性，这表明本发明化合物具有显著的Wnt依赖的增殖抑制作用。The above results show that the compound of the present invention has significant inhibitory activity against mutant cell lines Colo205, DU4475, NCI-H929 and HepG2, but has basically no significant inhibitory activity against Hela and RKO cell lines, which indicates that the compound of the present invention has significant Wnt dependence. proliferation inhibitory effect.
试验例4：本发明化合物小鼠药代动力学评价Test Example 4: Evaluation of the pharmacokinetics of the compound of the present invention in mice
1、实验材料1. Experimental materials
ICR小鼠：雄性，25-35g，购自上海斯莱克实验动物有限公司。ICR mice: male, 25-35g, purchased from Shanghai Slack Experimental Animal Co., Ltd.
试剂：DMSO(二甲亚砜)、PEG-400(聚乙二醇400)、Solutol HS-15、超纯水、甲醇、乙腈、甲酸、普萘洛尔(内标)、甲苯磺丁脲(内标)、ICR小鼠空白血浆(EDTA-K2抗凝)Reagents: DMSO (dimethyl sulfoxide), PEG-400 (polyethylene glycol 400), Solutol HS-15, ultrapure water, methanol, acetonitrile, formic acid, propranolol (internal standard), tolbutamide ( Internal standard), ICR mouse blank plasma (EDTA-K2 anticoagulant)
仪器：SCIEX LC-MS/MS(Exion LC，QTRAP 6500 Plus液质联用仪)Instrument: SCIEX LC-MS/MS (Exion LC, QTRAP 6500 Plus liquid mass spectrometer)
2、实验方法2. Experimental methods
称取一定量实施例1、2、3、5、6、9、10化合物和对照例1化合物，分别用5％体积的DMSO溶解，再加入其他相应溶媒(见表3)配成澄清溶液，小鼠静脉或灌胃给药后15min、30min、1h、2h、4h、8h、24h(静脉给药组加采5min)眼眶采血100μL，置EDTA-K2抗凝离心管中，30min内3000g离心(4℃)10min分离血浆，-80℃保存待测。Weigh a certain amount of the compounds of Examples 1, 2, 3, 5, 6, 9, and 10 and the compound of Comparative Example 1, respectively, dissolve them in 5% volume of DMSO, and then add other corresponding solvents (see Table 3) to prepare a clear solution. 15min, 30min, 1h, 2h, 4h, 8h, 24h (an extra 5min in the intravenous administration group) after intravenous or intragastric administration of mice, 100 μL of blood was collected from the orbit, placed in an EDTA-K2 anticoagulant centrifuge tube, and centrifuged at 3000g within 30min ( Separate plasma for 10 minutes at 4°C) and store at -80°C for testing.
精密称取一定量化合物用DMSO溶解至2mg/ml，作为储备液。准确吸取适量化合物储备液，用乙腈-水(8:2)溶液稀释配制标准系列溶液，准确吸取标准系列溶液1μL，加小鼠 空白血浆19μL，混匀，配成系列浓度血浆基质标准曲线。准确吸取给药后小鼠血浆样品各20μL，加400μL含内标的乙腈溶液(普萘洛尔50ng/ml、甲苯磺丁脲100ng/ml)，涡旋5min，4000rpm离心10min，取上清液200μL，加200μL超纯水，混匀后用LC-MS/MS分析。Precisely weigh a certain amount of the compound and dissolve it in DMSO to 2 mg/ml as a stock solution. Accurately draw an appropriate amount of compound stock solution, dilute it with acetonitrile-water (8:2) solution to prepare a standard series solution, accurately draw 1 μL of the standard series solution, and add mice Take 19 μL of blank plasma and mix well to prepare a series of concentration plasma matrix standard curves. Accurately draw 20 μL of each mouse plasma sample after administration, add 400 μL of acetonitrile solution containing internal standard (propranolol 50 ng/ml, tolbutamide 100 ng/ml), vortex for 5 min, centrifuge at 4000 rpm for 10 min, and take 200 μL of the supernatant. , add 200 μL ultrapure water, mix and analyze by LC-MS/MS.
3、数据处理3. Data processing
LC-MS测定血药浓度后，用WinNonlin 8.1软件，非房室模型计算药代动力学参数，结果见表3。After measuring the blood drug concentration by LC-MS, WinNonlin 8.1 software and non-compartmental model were used to calculate the pharmacokinetic parameters. The results are shown in Table 3.
表3化合物小鼠药代动力学参数

溶媒A：5％DMSO+10％PEG-400+10％Solutol+75％H2O
B：5％DMSO+10％PEG 400+85％H2O
C：5％DMSO+20％Solutol+75％H2OTable 3 Compound pharmacokinetic parameters in mice

Solvent A: 5% DMSO+10% PEG-400+10% Solutol+75% H 2 O
B: 5% DMSO+10% PEG 400+85% H 2 O
C: 5% DMSO+20% Solutol+75% H 2 O
上述结果表明，本发明化合物经小鼠口服吸收给药后，检测到的最高血药浓度(Cmax)和吸收曲线下面积(AUC)均显著优于对照例。这表明新的结构特征具有改善和提高口服吸收特征的能力。 The above results show that after the compound of the present invention is orally absorbed and administered to mice, the maximum detected blood concentration (Cmax) and the area under the absorption curve (AUC) are significantly better than those of the control example. This demonstrates the ability of new structural features to improve and enhance oral absorption characteristics.
试验例5：化合物1(W421)对Colo205小鼠Xenograft模型的肿瘤增长抑制试验Test Example 5: Tumor growth inhibition test of Compound 1 (W421) on Colo205 mouse Xenograft model
本研究用人结肠癌细胞Colo205的BALB/c Nude裸鼠移植瘤模型中化合物1的体内抗肿瘤活性进行评价。This study used human colon cancer cell Colo205 BALB/c Nude nude mouse transplanted tumor model to evaluate the in vivo anti-tumor activity of compound 1.
雌性BALB/c Nude裸鼠皮下接种人结肠癌细胞Colo205，建立Colo205 BALB/c Nude裸鼠移植瘤模型。待肿瘤生长至平均肿瘤体积为100mm3左右后，根据肿瘤体积大小采用随机分组法将荷瘤小鼠分为4组：溶剂处理对照组、1.5mg/kg化合物1组、3mg/kg化合物1组和10mg/kg化合物1组。化合物1口服给药，每天给药一次，给药周期15天，每隔一天测量肿瘤体积(图1)，Day 15称量体重和测量肿瘤体积(表4)。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).
表4化合物1在体内抑制人结肠癌细胞Colo205肿瘤体积(day15)

a.平均值±SEM。
b.肿瘤生长抑制由T/C(TRTV/CRTV)(TRTV：治疗组平均RTV；CRTV：溶媒对照组平均
RTV；RTV＝Vt/V0，V0为分组时该动物的瘤体积，Vt为治疗后该动物的瘤体积)。
c.p值根据肿瘤体积计算，多组间比较用one-way ANOVA进行分析，如果方差齐性检验
p>0.05，则选用Dunnett t，反之则选用Games-Howell。Table 4 Compound 1 inhibits tumor volume of human colon cancer cell Colo205 in vivo (day15)

a. Mean ± SEM.
b. Tumor growth inhibition is determined by T/C (TRTV/CRTV) (TRTV: average RTV of the treatment group; CRTV: average RTV of the vehicle control group
RTV; RTV=Vt/V0, V0 is the tumor volume of the animal when grouped, Vt is the tumor volume of the animal after treatment).
The cp value is calculated based on the tumor volume, and comparisons between multiple groups are analyzed using one-way ANOVA. If the homogeneity of variances is tested
If p>0.05, Dunnett's t is used, otherwise Games-Howell is used.
图1和表4的结果表明，本发明化合物，特别是化合物1具有明显的体内抑制人结肠癌细胞Colo205肿瘤体积的功能。 The results in Figure 1 and Table 4 show that the compounds of the present invention, especially Compound 1, have an obvious function of inhibiting the tumor volume of human colon cancer cell Colo205 in vivo.

Claims (21)

  1. 一种具有式(I)结构的化合物或其药学上可接受的盐、同位素衍生物、立体异构体：
    A compound having the structure of formula (I) or a pharmaceutically acceptable salt, isotope derivative, or stereoisomer thereof:
    其中，in,
    R1、R2各自独立地代表氢、(C1-C6)烷基、卤代(C1-C6)烷基、(C3-C8)环烷基、卤代(C3-C8)环烷基、4-8元杂环烷基、卤代4-8元杂环烷基、-(C1-C6)亚烷基ORa、-卤代(C1-C6)亚烷基ORa、-(C1-C6)亚烷基SRa、-卤代(C1-C6)亚烷基SRa，或者R1、R2与和它们相连的碳原子一起形成3-8元环，所述环可以任选地含有0、1、2或3个选自N、O和S的杂原子；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;
    R3表示(C1-C6)烷基、卤代(C1-C6)烷基、(C3-C8)环烷基、卤代(C3-C8)环烷基，或者R3和R1或者R2一起形成4-7元环，所述环可以任选地含有0个或1个选自O和S的杂原子；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;
    W6表示CR6或者N；W 6 means CR 6 or N;
    R6各自独立地表示氢、卤素、氰基、(C1-C3)烷基、卤代(C1-C3)烷基；R 6 each independently represents hydrogen, halogen, cyano group, (C 1 -C 3 ) alkyl group, or halogenated (C 1 -C 3 ) alkyl group;
    Cy表示5-12元芳杂环，其任选地含有1、2、3或4个杂原子，所述杂原子各自独立地选自选自N、O和S，且，Cy与-O-连接位置的邻位不被取代或者被氢取代；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;
    R1’表示氢、卤素、(C1-C6)烷基、卤代(C1-C6)烷基、(C3-C8)环烷基、卤代(C3-C8)环烷基、(C3-C8)杂环烷基、卤代(C3-C8)杂环烷基、-ORa、-卤代ORa、-SRa、-卤代SRa；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 ;
    R2’表示氢、卤素、(C1-C6)烷基、卤代(C1-C6)烷基、(C3-C8)环烷基、卤代(C3-C8)环烷基、(C3-C8)杂环烷基、卤代(C3-C8)杂环烷基、-ORa、-卤代ORa、-SRa、-卤代SRa；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 ;
    R3’表示氢、卤素、(C1-C6)烷基、卤代(C1-C6)烷基、(C3-C8)环烷基、卤代(C3-C8)环烷基、(C3-C8)杂环烷基、卤代(C3-C8)杂环烷基、-ORa、-卤代ORa、-SRa、-卤代SRa；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 ;
    m各自独立地表示0、1或2；m independently represents 0, 1 or 2;
    Ra各自独立地表示氢、(C1-C6)烷基、卤代(C1-C6)烷基、(C3-C8)环烷基、卤代(C3-C8)环烷基。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.
  2. 根据权利要求1所述的具有式(I)结构的化合物或其药学上可接受的盐、同位素衍生物、立体异构体，其中，Cy为5元杂芳环或者6元杂芳环。 The compound having the structure of formula (I) or its pharmaceutically acceptable salt, isotope derivative, or stereoisomer according to claim 1, wherein Cy is a 5-membered heteroaromatic ring or a 6-membered heteroaromatic ring.
  3. 根据前述任一权利要求所述的具有式(I)结构的化合物或其药学上可接受的盐、同位素衍生物、立体异构体，其中，Cy为吡啶基、嘧啶基、哒嗪基、吡嗪基、吡唑基、咪唑基或吡咯基。The compound having the structure of formula (I) according to any of the preceding claims, or a pharmaceutically acceptable salt, isotope derivative, or stereoisomer thereof, wherein Cy is pyridyl, pyrimidinyl, pyridazinyl, pyridinyl, Azinyl, pyrazolyl, imidazolyl or pyrrolyl.
  4. 根据权利要求1所述的具有式(I)结构的化合物或其药学上可接受的盐、同位素衍生物、立体异构体，其中，式(I)化合物如式(II)所示：
    The compound having the structure of formula (I) or its pharmaceutically acceptable salt, isotope derivative, or stereoisomer according to claim 1, wherein the compound of formula (I) is represented by formula (II):
    其中，in,
    虚线环表示其所在的环为芳香环；The dotted ring indicates that the ring it is in is an aromatic ring;
    W1表示CR1’或者N；W 1 means CR 1 ' or N;
    W2表示CR2’或者N；W 2 means CR 2 ' or N;
    W3表示CR3’或者N；W 3 means CR 3 ' or N;
    W4表示CH或者N；W 4 represents CH or N;
    W5表示CH或者N；W 5 means CH or N;
    R1、R2、R3、R6、W6、R1’、R2’、R3’、Ra、m如权利要求1所述。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 .
  5. 根据权利要求4所述的具有式(II)结构的化合物或其药学上可接受的盐、同位素衍生物、立体异构体，其中，式(II)化合物如以下所示：

    The compound having the structure of formula (II) or its pharmaceutically acceptable salt, isotope derivative, or stereoisomer according to claim 4, wherein the compound of formula (II) is as follows:

  6. 根据权利要求1所述的具有式(I)结构的化合物或其药学上可接受的盐、同位素衍生物、立体异构体，其中，式(I)化合物如式(III)所示：
    The compound having the structure of formula (I) or its pharmaceutically acceptable salt, isotope derivative, or stereoisomer according to claim 1, wherein the compound of formula (I) is represented by formula (III):
    其中，in,
    虚线环表示其所在的环为芳香环；The dotted ring indicates that the ring it is in is an aromatic ring;
    W1’表示CH、N或者NH；W 1 'represents CH, N or NH;
    W2’表示CR2’、N或者NR2’；W 2 ' represents CR 2 ', N or NR 2 ';
    W3’表示CR3’、N或者NR3’；W 3 ' represents CR 3 ', N or NR 3 ';
    W4’表示CH、N或者NH；W 4 'represents CH, N or NH;
    R1、R2、R3、R6、W6、R1’、R2’、R3’、Ra、m如权利要求1所述。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 .
  7. 根据权利要求6所述的具有式(III)结构的化合物或其药学上可接受的盐、同位素衍生物、立体异构体，其中，式(III)化合物如以下所示：
    The compound having the structure of formula (III) or a pharmaceutically acceptable salt, isotope derivative, or stereoisomer thereof according to claim 6, wherein the compound of formula (III) is as follows:
  8. 根据前述任一权利要求所述的具有式(I)结构的化合物或其药学上可接受的盐、同位素衍生物、立体异构体，其中，R1、R2各自独立地代表氢、(C1-C6)烷基、卤代(C1-C6)烷基、(C3-C8)环烷基、卤代(C3-C8)环烷基、4-8元杂环烷基、卤代4-8元杂环烷基、-(C1-C6)亚烷基ORa、-卤代(C1-C6)亚烷基ORa；更优选为氢、(C1-C6)烷基、卤代(C1-C6)烷基。The compound having the structure of formula (I) according to any of the preceding claims, or a pharmaceutically acceptable salt, isotope derivative, or stereoisomer thereof, wherein 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 heterocycle Alkyl, halogenated 4-8 membered heterocycloalkyl, -(C 1 -C 6 ) alkylene OR a , -halogenated (C 1 -C 6 ) alkylene OR a ; more preferably hydrogen, ( C 1 -C 6 )alkyl, halogenated (C 1 -C 6 )alkyl.
  9. 根据前述任一权利要求所述的具有式(I)结构的化合物或其药学上可接受的盐、同位素衍生物、立体异构体，其中，R3为(C1-C6)烷基。The compound having the structure of formula (I) according to any of the preceding claims, or a pharmaceutically acceptable salt, isotope derivative, or stereoisomer thereof, wherein R 3 is (C 1 -C 6 ) alkyl.
  10. 根据前述任一权利要求所述的具有式(I)结构的化合物或其药学上可接受的盐、同位素衍生物、立体异构体，其中，其中，W6为CR6。The compound having the structure of formula (I) according to any of the preceding claims, or a pharmaceutically acceptable salt, isotope derivative, or stereoisomer thereof, wherein W 6 is CR 6 .
  11. 根据前述任一权利要求所述的具有式(I)结构的化合物或其药学上可接受的盐、同位素衍生物、立体异构体，其中，R6为氢。The compound having the structure of formula (I) according to any of the preceding claims, or a pharmaceutically acceptable salt, isotope derivative, or stereoisomer thereof, wherein R 6 is hydrogen.
  12. 根据前述任一权利要求所述的具有式(I)结构的化合物或其药学上可接受的盐、同位素衍生物、立体异构体，其中，R1’表示氢、卤素、(C1-C6)烷基、卤代(C1-C6)烷基、(C3-C8)环烷基、卤代(C3-C8)环烷基。The compound having the structure of formula (I) according to any of the preceding claims, or a pharmaceutically acceptable salt, isotope derivative, or stereoisomer thereof, wherein 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.
  13. 根据权利要求11所述的具有式(I)结构的化合物或其药学上可接受的盐、同位素衍生物、立体异构体，其中，R1’表示卤代(C1-C6)烷基。The compound having the structure of formula (I) or a pharmaceutically acceptable salt, isotope derivative, or stereoisomer thereof according to claim 11, wherein R 1 ' represents a halogenated (C 1 -C 6 ) alkyl group .
  14. 根据前述任一权利要求所述的具有式(I)结构的化合物或其药学上可接受的盐、同位素衍生物、立体异构体，其中，R2’表示氢、卤素、(C1-C6)烷基、卤代(C1-C6)烷基、(C3-C8)环烷基、卤代(C3-C8)环烷基。The compound having the structure of formula (I) according to any of the preceding claims, or a pharmaceutically acceptable salt, isotope derivative, or stereoisomer thereof, wherein 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.
  15. 根据权利要求13所述的具有式(I)结构的化合物或其药学上可接受的盐、同位素衍生物、立体异构体，其中，R2’表示氢或者卤素。 The compound having the structure of formula (I) or its pharmaceutically acceptable salt, isotope derivative, or stereoisomer according to claim 13, wherein R 2 ' represents hydrogen or halogen.
  16. 根据前述任一权利要求所述的具有式(I)结构的化合物或其药学上可接受的盐、同位素衍生物、立体异构体，其中，R3’表示卤素、(C1-C6)烷基、卤代(C1-C6)烷基、(C3-C8)环烷基、卤代(C3-C8)环烷基、-ORa、-卤代ORa、-SRa、-卤代SRa。The compound having the structure of formula (I) according to any of the preceding claims, or a pharmaceutically acceptable salt, isotope derivative, or stereoisomer thereof, wherein 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 , -haloOR a , - SR a , -halogenated SR a .
  17. 根据权利要求15所述的具有式(I)结构的化合物或其药学上可接受的盐、同位素衍生物、立体异构体，其中，R3’表示卤素、(C1-C6)烷基、卤代(C1-C6)烷基、(C3-C8)环烷基、卤代(C3-C8)环烷基。The compound having the structure of formula (I) or its pharmaceutically acceptable salt, isotope derivative, or stereoisomer according to claim 15, wherein 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.
  18. 根据前述任一权利要求所述的具有式(I)结构的化合物或其药学上可接受的盐、同位素衍生物、立体异构体，其中，R3’表示卤代(C1-C6)烷基或者卤代(C3-C8)环烷基。The compound having the structure of formula (I) according to any of the preceding claims, or a pharmaceutically acceptable salt, isotope derivative, or stereoisomer thereof, wherein R 3 ' represents halogenated (C 1 -C 6 ) Alkyl or halo(C 3 -C 8 )cycloalkyl.
  19. 一种化合物或其药学上可接受的盐、同位素衍生物、立体异构体，其中所述化合物具有如下结构：

    A compound or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein the compound has the following structure:

  20. 药物组合物，包含前述任一权利要求所述的化合物或其药学上可接受的盐、同位素衍生物、立体异构体，以及任选的药学上可接受的载体。A pharmaceutical composition comprising a compound according to any preceding claim or a pharmaceutically acceptable salt, isotope derivative, stereoisomer thereof, and optionally a pharmaceutically acceptable carrier.
  21. 权利要求1-19中任一项所述的化合物或其药学上可接受的盐、同位素衍生物、立体异构体或者权利要求20所述的药物组合物在制备用于预防和/或治疗癌症、肿瘤、炎症性疾病、自身免疫性疾病或免疫介导性疾病的药物中的用途。 The compound according to any one of claims 1 to 19 or its pharmaceutically acceptable salt, isotope derivative, stereoisomer or the pharmaceutical composition according to claim 20 is used for the prevention and/or treatment of cancer. , tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases.
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WO2023143501A1 (en) * 2022-01-29 2023-08-03 杭州阿诺生物医药科技有限公司 Wnt pathway inhibitor compound

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