WO2023143501A1 - Wnt pathway inhibitor compound - Google Patents

Wnt pathway inhibitor compound Download PDF

Info

Publication number
WO2023143501A1
WO2023143501A1 PCT/CN2023/073533 CN2023073533W WO2023143501A1 WO 2023143501 A1 WO2023143501 A1 WO 2023143501A1 CN 2023073533 W CN2023073533 W CN 2023073533W WO 2023143501 A1 WO2023143501 A1 WO 2023143501A1
Authority
WO
WIPO (PCT)
Prior art keywords
halo
compound
alkylene
alkyl
reaction
Prior art date
Application number
PCT/CN2023/073533
Other languages
French (fr)
Chinese (zh)
Inventor
陈宇锋
武朋
刘灿丰
李非凡
孙钊
杨寒
吕萌
程万里
金超凡
陈凯旋
陈可可
王友平
朱晓利
何南海
Original Assignee
杭州阿诺生物医药科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 杭州阿诺生物医药科技有限公司 filed Critical 杭州阿诺生物医药科技有限公司
Priority to CN202380009996.XA priority Critical patent/CN116964053A/en
Publication of WO2023143501A1 publication Critical patent/WO2023143501A1/en

Links

Classifications

    • 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
    • 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
    • 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 invention relates to a heterocyclic compound, in particular to a highly active Wnt pathway inhibitor and its application.
  • Wnt/ ⁇ -catenin signal transduction pathway is a pathway conserved in biological evolution.
  • ⁇ -catenin is only a cytoskeleton protein that forms a complex with E-cadherin at the cell membrane to maintain the adhesion of the same type of cells and prevent cell movement.
  • Wnt signaling pathway is not activated, ⁇ -catenin in the cytoplasm is phosphorylated, and forms a ⁇ -catenin degradation complex with APC, Axin, and GSK3 ⁇ , thereby initiating the ubiquitin system to degrade ⁇ -catenin through the proteasome pathway, so that ⁇ -catenin in the cytoplasm was maintained at a low level.
  • Wnt protein When cells are stimulated by Wnt signal, Wnt protein binds to the specific receptor Frizzled protein on the cell membrane, and the activated Frizzled receptor recruits intracellular Dishevelled protein, which inhibits the degradation activity of the ⁇ -catenin degradation complex formed by GSK3 ⁇ and other proteins, stabilizing Free ⁇ -catenin protein in the cytoplasm.
  • the stably accumulated ⁇ -catenin 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.).
  • Wnt/ ⁇ -catenin signaling pathway is closely related to the occurrence of various cancers (including colon cancer, gastric cancer, breast cancer, etc.).
  • abnormal activation of Wnt classic signaling pathway and nuclear accumulation of ⁇ -catenin protein widely exist in colorectal cancer, and the proliferation of cancers such as colon cancer can be inhibited by inhibiting the activity of Wnt signaling pathway.
  • APC mutations exist in more than 85% of colorectal cancers, and the mutated APC blocks the phosphorylation and degradation of ⁇ -catenin and induces the occurrence of colorectal cancer.
  • mutations of Axin and ⁇ -catenin itself can also cause the intracellular accumulation of ⁇ -catenin and activate the Wnt/ ⁇ -catenin pathway.
  • the inventors unexpectedly found that the compound of the formula (I) structure of the present invention or its pharmaceutically acceptable salt, isotopic derivatives, and stereoisomers are effective Wnt pathway inhibitors, and have excellent Wnt pathway inhibitory activity.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, isotopic 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 are connected to them
  • the carbon atoms together 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, halo (C 1 -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, halo (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;
  • X means CR 4 or N
  • R 4 each independently represent hydrogen, halogen, cyano, (C 1 -C 3 ) alkyl, halo (C 1 -C 3 ) alkyl;
  • L represents -O- or -(CR m R m ')-, wherein R m and R m ' each independently represent hydrogen, (C 1 -C 3 ) alkyl, (C 3 -C 8 ) cycloalkyl , or R m , R m 'and the carbon atom connected to it form a 3-5 membered ring, and the ring may contain 0 or 1 heteroatom selected from O and S;
  • Cy represents a 5-12 membered aromatic heterocycle, which optionally contains 1, 2, 3 or 4 heteroatoms, each of which is independently selected from N, O, S;
  • R 5 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 6 represents halogen, (C 1 -C 6 ) alkyl, halo (C 1 -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, halo (C 3 -C 8 ) cycloalkane radical, (C 3 -C 8 )heterocycloalkyl, halo(C 3 -C 8 )heterocycloalkyl, (C 2 -C 6 )alkynyl, halo(C 2 -C 6 )alkynyl, -(C 1 -C 6 )alkylene OR a , -halogenated (C 1 -C 6 )alkylene OR a , -(C 3 -C 8 )cycloalkylene OR a , -halogenated (C 3 -C 8 )cycloalkylene OR a , -(C 1 -C 6 )alkylene SR a , -halogen
  • R 7 each independently represent hydrogen, halogen, (C 1 -C 3 ) alkyl, halo (C 1 -C 3 ) alkyl;
  • n and n independently represent 0, 1 or 2;
  • R a and R a ' 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.
  • R 6 when R 6 is attached to a carbon atom, R 6 represents halogen, (C 1 -C 6 ) alkyl, halo (C 1 -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, Halo(C 3 -C 8 )cycloalkyl, (C 3 -C 8 )heterocycloalkyl, halo(C 3 -C 8 )heterocycloalkyl, (C 2 -C 6 )alkynyl, halo Substituted (C 2 -C 6 )alkynyl, -(C 1 -C 6 )alkylene OR a , -halogenated (C 1 -C 6 )alkylene OR a , -(C 3 -C 8 )alkylene OR a , -(C 3 -C 8 )alkylene Cycloalkyl OR a , -Halo(C 3 -
  • R 6 represents halogen, (C 1 -C 6 ) alkyl, halo (C 1 -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, halo ( C 3 -C 8 )cycloalkyl, (C 3 -C 8 )heterocycloalkyl, halo(C 3 -C 8 )heterocycloalkyl, (C 2 -C 6 )alkynyl, halo(C 2 -C 6 )alkynyl, -(C 1 -C 6 )alkylene OR a , -halo(C 1 -C 6 )alkylene OR a , -(C 3 -C 8 )cycloalkylene OR a , -halogenated (C 3 -C 8 )cycloalkylene OR a , -(C 1 -C 6 )alkylene SR
  • R 6 represents halogen, (C 1 -C 6 ) alkyl, halo (C 1 -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, halo (C 3 -C 8 ) cycloalkyl.
  • R 1 and R 2 each independently represent hydrogen, (C 1 -C 6 ) alkyl, halogenated (C 1 -C 6 ) alkyl, (C 3 -C 8 ) cycloalkane group, halo(C 3 -C 8 )cycloalkyl, -(C 1 -C 6 )alkylene OR a , -(C 1 -C 6 )alkylene SR a ; or R 1 , R 2 and Together with the carbon atoms to which they are attached, 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 is C 1 -C 6 )alkyl or halo(C 1 -C 6 )alkyl.
  • R 3 is (C 1 -C 6 )alkyl.
  • Cy is a 5-6 membered monocyclic aromatic heterocycle, or Cy is a 9-10 membered bicyclic aromatic heterocycle.
  • Cy is pyridyl, pyrimidinyl, pyrazolyl, imidazolyl or pyrrolyl.
  • R6 and L are connected at the ortho position of Cy.
  • R 5 is located at the meta position of R 6 , and is located at the meta or para position of L.
  • X is CR 4 .
  • R4 is hydrogen
  • connection of Cy to R 5 and R 6 is as follows:
  • connection of Cy to R 5 and R 6 is as follows:
  • R is selected from:
  • the present invention also provides a class of compounds or pharmaceutically acceptable salts, isotopic derivatives, and stereoisomers thereof, wherein the compounds have the following structure:
  • the present invention also provides a pharmaceutical composition, which comprises the aforementioned compound or a pharmaceutically acceptable salt, isotope derivative, stereoisomer, and optionally a pharmaceutically acceptable carrier.
  • the present invention also provides the aforementioned compounds or their pharmaceutically acceptable salts, isotope derivatives, stereoisomers, or the aforementioned pharmaceutical compositions used in the prevention and/or treatment of cancer, tumors, and inflammatory diseases , use in medicines for autoimmune diseases or immune-mediated diseases.
  • the pharmaceutically acceptable salts of the present invention may be formed using, for example, the following inorganic or organic acids:
  • “Pharmaceutically acceptable salt” means a salt which, within the scope of reasonable medical judgment, is suitable for use in contact with humans and lower other animals tissue, without undue toxicity, irritation, allergic reaction, etc., can be called a reasonable benefit/risk ratio.
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or alone by reacting the free base or acid with a suitable reagent, as outlined below. For example, a free base function can be reacted with a suitable acid.
  • inorganic acid addition salts are amino acids with inorganic acids (e.g., hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric) or organic acids (e.g., acetic, oxalic, maleic, tartaric, lemon acid, succinic acid or malonic acid), or by using other methods known in the art such as ion exchange.
  • inorganic acids e.g., hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric
  • organic acids e.g., acetic, oxalic, maleic, tartaric, lemon acid, succinic acid or malonic acid
  • salts include adipate, sodium alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, Camphorsulfonate, Citrate, Cyclopentanepropionate, Digluconate, Lauryl Sulfate, Ethylate, Formate, Fumarate, Glucoheptonate, Glycerin Phosphate, gluconate, hernisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate Salt, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectate Salt, persulf
  • alkali or alkaline earth metal salts include those 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, for example, halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower Alkylsulfonates and arylsulfonates.
  • the pharmaceutically acceptable salts of the present invention can be prepared by conventional methods, for example, by dissolving the compound of the present invention in a water-miscible organic solvent (such as acetone, methanol, ethanol and acetonitrile), adding an excess of organic acid or inorganic Aqueous acid solution, so that the salt is precipitated from the resulting mixture, the solvent and remaining free acid are removed therefrom, and the precipitated salt is isolated.
  • a water-miscible organic solvent such as acetone, methanol, ethanol and acetonitrile
  • the precursors or metabolites described in the present invention may be precursors or metabolites known in the art, as long as the precursors or metabolites are transformed into compounds through in vivo metabolism.
  • prodrugs refer to those prodrugs of the compounds of the present invention which, within the scope of sound medical judgment, are suitable for use in contact with human and lower animal tissues without undue toxicity, irritation, allergic response, etc., Qualified as having a reasonable benefit/risk ratio and valid for its intended use.
  • prodrug refers to a compound that is rapidly transformed in vivo to yield the parent compound of the above formula, for example by in vivo metabolism, or N-demethylation of a compound of the invention.
  • Solvate as used herein means a physical association of a compound of the present invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In some cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, solvates will be able to be isolated. Solvent molecules in solvates 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 isolatable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.
  • Steps of “Stereoisomerism” described in the present invention is divided into conformational isomerism and configurational isomerism, and configurational isomerism can also be divided into cis-trans isomerism and optical isomerism (i.e. optical isomerism), conformational isomerism refers to having Due to the rotation or twisting of carbon and carbon single bonds in organic molecules of a certain configuration, a stereoisomerism phenomenon in which each atom or atomic group of the molecule has a different arrangement in space, the common structures are alkanes and cycloalkanes. Such as the chair conformation and boat conformation that appear in the structure of cyclohexane.
  • Stepoisomer 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 can produce two optical isomers, and the scope of the present invention includes all possible optical isomers and diastereoisomer mixtures and pure or partially pure compounds .
  • the compounds described herein may exist in tautomeric forms having different points of attachment of hydrogens by 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 an isotopically labeled molecule of a compound herein.
  • Isotopes commonly used for isotope labeling 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 isotope-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 of their easy labeling and convenient detection.
  • substitution of some heavy isotopes, such as deuterium ( 2 H) can enhance the stability of metabolism, prolong the half-life and thus achieve the purpose of reducing the dose and provide therapeutic advantages.
  • Isotopically labeled compounds generally start from labeled starting materials using known synthetic techniques such as the synthesis of non-isotopic Labeled compounds to complete their synthesis.
  • the present invention also provides the use of the compound of the present invention in the preparation of medicaments for preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease.
  • the present invention provides a pharmaceutical composition for preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease, neurodegenerative disease, attention-related disease or immune-mediated disease, which comprises the present invention compounds as active ingredients.
  • the pharmaceutical composition may optionally comprise a pharmaceutically acceptable carrier.
  • the present invention provides a method of preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease, neurodegenerative disease, attention-related disease or immune-mediated disease, which includes the need for
  • the mammal of the present invention is administered the compound of formula (I) or its pharmaceutically acceptable salt, isotope derivative, stereoisomer or the pharmaceutical composition of the present invention.
  • inflammatory, autoimmune, and immune-mediated diseases may include, but are not limited to, arthritis, rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, juvenile arthritis , Other Arthritis Conditions, Lupus, Systemic Lupus Erythematosus (SLE), Skin Related Disorders, Psoriasis, Eczema, Dermatitis, Atopic Dermatitis, Pain, Pulmonary 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, s
  • cancer or tumor 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 Carcinoma, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine body cancer, endometrium Carcinoma, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma
  • the compound of the present invention or a pharmaceutically acceptable salt thereof when administered in combination with another anticancer agent or immune checkpoint inhibitor for the treatment of cancer or tumors, the compound of the present invention or a pharmaceutically acceptable salt thereof can provide enhanced anticancer effects .
  • anticancer agents useful in the treatment of cancer or tumors may include, but are not limited to, inhibitors of cell signaling, chlorambucil, guanfalan, cyclophosphamide, ifosfamide, busulfan, carbamate, Mustin, lomustine, streptozotocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, 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, ixabepilone
  • therapeutic agents useful in the treatment of inflammatory, autoimmune, and immune-mediated diseases can include, but are not limited to, steroidal drugs (e.g., prednisone, prednisone, prednisone, methylphenidate, Cortisone, cortisone, hydroxycortisone, betamethasone, dexamethasone, etc.), methotrexate, leflunomide, anti-TNF ⁇ agents (eg, etanercept, infliximab, adalib monoclonal antibody, etc.), calcineurin inhibitors (eg, tacrolimus, piguanolimus, etc.), and antihistamines (eg, diphenhydramine, hydroxyzine, loratadine, ebazan Tin, ketotifen, cetirizine, levocetirizine, fexofenadine, etc.), and at least one or more therapeutic agents selected from them can 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 as an active ingredient.
  • the dose of the active ingredient can be adjusted according to 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 the opinion of the physician. In some cases, amounts less than the above dosages may be appropriate. Amounts greater than the above doses may be used if no deleterious side effects are caused and such amounts may be administered in divided doses daily.
  • 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 comprises the following A compound of the invention or a compound or pharmaceutical composition of the invention is administered to a mammal in need thereof.
  • compositions of the present invention can be formulated into dosage forms 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 carriers such as cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, stearic acid, Magnesium stearate, calcium stearate, gelatin, talc, surfactant, suspending agent, emulsifier and diluent.
  • carriers such as cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, stearic acid, Magnesium stearate, calcium stearate, gelatin, talc, surfactant, suspending agent, emulsifier and diluent.
  • Examples of carriers employed in the pharmaceutical composition for injection administration of the present invention may be water, saline solution, glucose solution, glucose-like solution, alcohol, glycol, ether (for example, 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, using the methods described below as well as synthetic methods known in the art of synthetic organic chemistry or by variations thereof known to those skilled in the art Synthesis of compounds of the invention. Preferred methods include, but are not limited to, those described below. Reactions are performed in solvents or solvent mixtures appropriate to the kit materials used and to the transformations effected. Those skilled in the art of organic synthesis will appreciate that the functionality present on the molecule is consistent with the proposed transitions. 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 the tumor volume of human colon cancer cell Colo205 xenograft tumor in nude mice.
  • a given chemical formula or name shall encompass all stereoisomers and optical isomers thereof and racemates in which such isomers exist. Unless otherwise indicated, all chiral (enantiomers and diastereoisomers) and racemic forms are within the scope of the invention.
  • the present invention describes cis- and trans- (or E- and Z-) geometric isomers of the compounds of the invention and which may be isolated as a mixture of isomers or as separated isomeric forms.
  • the compounds of the invention may be isolated in optically active or racemic forms.
  • the compounds of the invention may exist in various tautomeric forms in which the hydrogen atoms are transposed to other parts of the molecule and thus 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 within the present invention.
  • substituents in the present invention are independent and not interrelated, for example (listed but not exhaustive), in one aspect, for R a (or R a ') in the substituent, its are independent of each other in the definitions of the different substituents. Specifically, when one definition is selected for R a (or R a ') in one substituent, it does not mean that the R a (or R a ') has the same definition in other substituents.
  • 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 (or R a ') when there is more than one R a (or R a ') in a certain substituent, these R a (or R a ') are also independently independent.
  • substituent is selected from, for example, the following substituents, such as alkyl, cycloalkyl, aryl, heterocyclyl, halogen, hydroxy, Alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amino (wherein 2 amino substituents are selected from alkyl radical, aryl or arylalkyl), alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thio, alkylthio , arylthio, arylalkylthio, arylthiocarbonyl, arylalkylthiocarbonyl, alkylsul
  • substituents such as alkyl, cycloalkyl,
  • carbamoyl such as -CONH 2
  • substituted carbamoyl such as -CONHalkyl, -CONHaryl, -CONHarylalkyl or on nitrogen
  • heterocyclic group such as indolyl, imidazolyl, furan base, thienyl, thiazolyl, pyrrolidinyl, pyridyl, Pyrimidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl, etc. and substituted heterocyclic groups.
  • alkyl or "alkylene” as used herein is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the indicated 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, t-butyl), and Pentyl (eg n-pentyl, isopentyl, neopentyl).
  • the alkyl group is preferably an alkyl group having 1 to 6, 1 to 4, more preferably 1 to 3 carbon atoms.
  • alkenyl denotes a straight or branched chain hydrocarbon group containing one or more double bonds and generally 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, eg vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.
  • alkynyl denotes a straight or branched chain hydrocarbon group containing one or more triple bonds and generally having a length of 2 to 20 carbon atoms.
  • C2 - C6 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.
  • 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” denotes an alkyl group as defined above having the indicated number of carbon atoms attached through a sulfur bridge; eg methyl-S- and ethyl-S-.
  • aryl alone or as part of a larger moiety such as “aralkyl”, “arylalkoxy” or “aryloxyalkyl”, refers to a single group having a total of 5 to 12 ring members Cyclic, bicyclic or tricyclic ring systems, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • aryl refers to an aromatic ring system which includes, but is not limited to, phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthalene 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.
  • a fused aryl group can be attached to another group at a suitable position on the cycloalkyl ring or aromatic ring. Dashed lines drawn from ring systems indicate that bonds may be attached to any suitable ring atom.
  • cycloalkyl refers to a monocyclic or bicyclic cyclic alkyl group.
  • Monocyclic cyclic alkyl refers to C3-C8 cyclic alkyl, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and norbornyl.
  • Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included within the definition of "cycloalkyl”.
  • bicyclic cyclic alkyl group Cycloalkyl groups including bridged rings, spiro rings or fused rings.
  • the cycloalkyl group is preferably a cycloalkyl group having 3 to 8, more preferably 3 to 6 carbon atoms.
  • 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 within the definition of "cycloalkenyl”.
  • Bicyclic cyclic alkenyl groups include bridged, spiro, or fused cyclic alkenyl groups.
  • Halo or halogen includes fluoro, chloro, bromo and iodo.
  • Haloalkyl is intended to include branched and straight chain saturated aliphatic hydrocarbon groups having the indicated 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, heptafluoro Propyl and Heptachloropropyl.
  • haloalkyl also include "fluoroalkyl” intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and substituted with 1 or more fluorine atoms.
  • fluoroalkyl intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and substituted with 1 or more fluorine atoms.
  • halocycloalkyl is intended to include branched cycloalkyl groups having the indicated number of carbon atoms substituted with one or more halogens.
  • Haloalkoxy or "haloalkyloxy” means a haloalkyl group as defined above having the indicated number of carbon atoms attached through an oxygen bridge.
  • haloC 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” denotes a haloalkyl group as defined above having the indicated number of carbon atoms attached through a sulfur bridge; for example trifluoromethyl-S- and pentafluoroethyl -S-.
  • -halo(C 1 -C 6 )alkylene OR a , -halo(C 1 -C 6 )alkylene SR a , -halo(C 1 -C 6 )alkylene NR a R a ′, -Halo(C 1 -C 6 )alkylene CN, -Halo(C 3 -C 8 )cycloalkylene OR a , -Halo(C 3 -C 8 )cycloalkane
  • the group SR a , -halogenated (C 3 -C 8 )cycloalkylene NR a R a ′, -halogenated (C 3 -C 8 )cycloalkylene CN, etc.
  • C x1 -C x2 is used when referring to some substituent groups, which means that the number of carbon atoms in the substituent groups may be from x 1 to x 2 .
  • 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 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 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
  • x 1 -x 2 -membered ring is used when referring to cyclic groups (such as aryl, heteroaryl, cycloalkyl and heterocycloalkyl), which means that the group's The number of ring atoms may be x1 to x2 .
  • the 3-12 membered cyclic group may be a 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 membered ring, and the number of ring atoms may be 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; 3-6-membered ring means that the cyclic group can be 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 A 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 A 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 ring atoms may be carbon atoms or heteroatoms, for example selected from N, O and S.
  • the heterocyclic ring 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.
  • the one or more halogens may each be independently selected from fluorine, chlorine, bromine and iodine.
  • heteroaryl means a specified number of stable monocyclic or polycyclic aromatic groups containing heteroatoms, preferably 3-membered, 4-membered, 5-membered, 6-membered, or 7-membered aromatic monocyclic or aromatic bicyclic Or 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered aromatic polycyclic heterocycles, which are fully unsaturated or partially unsaturated, and which 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, wherein any heterocycle defined above is fused to a benzene ring.
  • the heteroaryl group herein is preferably a 5- to 12-membered heteroaryl group. Nitrogen and sulfur heteroatoms can be optionally oxidized. The nitrogen atom is substituted or unsubstituted (ie N or NR, where R is H or another substituent if defined). A heterocycle can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclyl groups described herein may be substituted on carbon or nitrogen atoms if the resulting compound is stable. The nitrogen in the heterocycle can 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.
  • heterocycle is intended to include heteroaryl.
  • heteroaryl groups include, but are not limited to, acridinyl, azetidinyl, aziocinyl, benzimidazolyl, benzofuryl, benzothiofuranyl, benzothienyl, benzooxa Azolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2, 3-b] Tetrahydrofu
  • heteroaryl may also include biaryl structures formed by the above-defined “aryl” and a monocyclic “heteroaryl”, such as but not limited to "-phenylbipyridyl-", “- "Phenyl bipyrimidyl”, “-pyridyl biphenyl”, “-pyridyl bipyrimidyl-”, “-pyrimidyl biphenyl-”; wherein the present invention also includes condensed rings containing, for example, the above-mentioned heterocycles and Spiro compound.
  • heterocycloalkyl refers to a monocyclic heterocycloalkyl system, or a bicyclic heterocycloalkyl system, and also includes spiroheterocycle or bridged heterocycloalkyl.
  • monocyclic heterocycloalkyl means It is a 3-8 membered, saturated or unsaturated but not aromatic cyclic alkyl system containing at least one heteroatom selected from O, N, S and P.
  • the bicyclic heterocycloalkyl system refers to a heterocycloalkyl fused to a phenyl group, or a cycloalkyl group, or a cycloalkenyl group, or a heterocycloalkyl group, or a heteroaryl group formed two-ring system.
  • bridged cycloalkyl refers to polycyclic compounds sharing two or more carbon atoms. Can be divided into bicyclic bridged ring hydrocarbons and polycyclic bridged ring hydrocarbons. The former is composed of two alicyclic rings sharing more than two carbon atoms; the latter is a bridged ring hydrocarbon composed of more than three rings.
  • spirocycloalkyl refers to polycyclic hydrocarbons in which monocyclic rings share one carbon atom (called a spiro atom).
  • bridged ring heterogroup refers to a polycyclic compound sharing two or more atoms, and the ring contains at least one heteroatom selected from O, N and S atoms. It can be divided into bicyclic bridged heterocycles and polycyclic bridged heterocycles.
  • heterospirocyclyl refers to a polycyclic hydrocarbon that shares one carbon atom (called a spiro atom) between monocyclic 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 valences are maintained and that the substitution results in a stable compound.
  • nitrogen atoms e.g. amines
  • these nitrogen atoms can be converted to 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
  • both shown and claimed nitrogen atoms are considered to cover both the shown nitrogen and its N-oxides to obtain the derivatives of the present invention.
  • any variable occurs more than one time in any composition or formula of a compound, its definition on each occurrence is independent of its definition at every other occurrence.
  • a group is shown to be substituted with 0-3 R, then said group may be optionally substituted with up to three R groups, and R at each occurrence is independently selected from the definition of R.
  • combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • patient refers to an organism being treated by the methods of the present invention.
  • organisms preferably include, but are not limited to, mammals (eg, murine, ape, monkey, equine, bovine, porcine, canine, feline, etc.) and most preferably refer to humans.
  • the term "effective amount” means an amount that will elicit, for example, the amount sought by a researcher or clinician.
  • therapeutically effective amount means an amount which results in improved treatment, cure, prevention or alleviation of a disease, disorder or side effect, or a reduction in the or the rate of disease progression.
  • An effective amount may be given in one or more administrations, applications or doses and is not intended to be limited by a particular formulation or route of administration. The term also includes within its scope amounts effective to enhance normal physiological function.
  • treating includes any effect that results in amelioration of a condition, disease, disorder, etc., such as alleviation, reduction, regulation, amelioration or elimination, or amelioration of the symptoms thereof.
  • pharmaceutically acceptable refers to those compounds, substances, compositions and/or dosage forms: within the scope of sound medical judgment, they are suitable for use in contact with human and animal tissues without excessive toxicity, irritation sex, allergic reactions, and/or other problems or complications, commensurate with 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 involved in the carrying or transport of a subject compound from one organ or body part to another.
  • manufacturing aid e.g. lubricant, talc, magnesium stearate, calcium stearate or zinc stearate or stearic acid
  • solvent-encapsulated substances involved in the carrying or transport of a subject compound from one organ or body part to another.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • composition means a composition comprising a compound of the present invention together with at least one other pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier means 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, fragrances, antibacterial agents, antifungal agents, lubricants and dispersants, depending on Mode of administration and nature of dosage form.
  • acceptable means that a formulation ingredient or active ingredient does not have an undue adverse effect on health for the general purpose of treatment.
  • cancer refers to an abnormal growth of cells that cannot be controlled and, under certain conditions, is capable of metastasizing (spreading). Cancers of this type include, but are not limited to, solid tumors (eg, bladder, bowel, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (eg, thyroid), prostate , skin (melanoma), or blood cancer (such as non-leukemic leukemia).
  • solid tumors eg, bladder, bowel, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (eg, thyroid), prostate , skin (melanoma), or blood cancer (such as non-leukemic leukemia).
  • administration in combination refers to the administration of several selected therapeutic agents to a patient, in the same or different modes of administration at the same or different times.
  • enhancing or “capable of enhancing”, as used herein, means that the desired result can be enhanced in potency or sustained time has been increased or extended.
  • capable of potentiating refers to the ability of the drug to increase or prolong its potency or duration in the system.
  • potency value refers to the ability to maximize the enhancement of another therapeutic drug in an ideal system.
  • immune disease refers to a disease or condition of an adverse or deleterious reaction to an endogenous or exogenous antigen.
  • the result is usually dysfunction of the cells, or destruction thereof and dysfunction, or destruction of 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, and pigs; domestic animals such as rabbits and dogs; experimental animals include rodents, Such as rats, mice and guinea pigs.
  • Non-mammalian animals include, but are not limited to, birds, fish, and the like.
  • the selected mammal is a human.
  • treatment includes alleviating, suppressing or ameliorating the symptoms or conditions of a disease; inhibiting the development of complications; ameliorating or preventing the underlying metabolic syndrome; inhibiting the development of diseases or symptoms, Such as controlling the development of a disease or condition; alleviating a disease or a symptom; causing a disease or a symptom to regress; alleviating a complication caused by a disease or a symptom, or preventing and/or treating a sign caused by a disease or a symptom.
  • a certain compound or pharmaceutical composition after administration, can improve a certain disease, symptom or situation, especially improve its severity, delay the onset, slow down the progression of the disease, or reduce the duration of the disease. Circumstances that may be attributable to or related to the administration, whether fixed or episodic, continuous or intermittent.
  • Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transdermal, vaginal, ear canal , nasal administration and topical administration.
  • parenteral administration includes intramuscular injection, subcutaneous injection, intravenous injection, intramedullary injection, intraventricular injection, intraperitoneal injection, intralymphatic injection, and intranasal injection.
  • the compounds described herein are administered locally rather than systemically.
  • the depot formulation is 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 are selectively directed to and taken up by specific organs.
  • the raw materials and reagents used in the present invention are known products, which can be synthesized according to methods known in the art, or can be obtained by purchasing commercially available products. All commercially available reagents were used without further purification.
  • Room temperature means 20-30°C.
  • the nitrogen atmosphere refers to a nitrogen balloon of about 1 L connected to the reaction flask.
  • the hydrogenation reaction is usually vacuumized and filled with hydrogen, and the operation is repeated 3 times.
  • the hydrogen atmosphere means that the reaction bottle is connected with a hydrogen balloon of about 1L.
  • microwave reaction use Initiator+ microwave reactor.
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • LC-MS Thermo liquid mass spectrometer
  • UltiMate 3000+MSQ PLUS Thermo liquid mass spectrometer
  • a Thermo high pressure liquid chromatograph UltiMate 3000
  • Reverse-phase preparative chromatography Thermo (UltiMate 3000) reverse-phase preparative chromatography was used.
  • Fast column chromatography uses Agel (FS-9200T) automatic column passing machine, and silica gel prepacked column uses Santai Prepacked columns.
  • Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used for thin-layer chromatography silica gel plates, and the specifications used for thin-layer chromatography separation and purification products are 0.4mm to 0.5mm.
  • the first step the compound Int-1a (5.0g, 28.09mmol), Int-1b (5.61g, 36.51mmol) and sodium bicarbonate (7.08g, 84.26mmol) were dissolved 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, suction filtered, 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] + .
  • the first step sodium hydrogen (1.59g, 39.64mmol, content 60%) was added to a two-necked flask filled with anhydrous tetrahydrofuran (10mL), placed in an ice-water bath, compound Int-2a (5.0g, 26.43mmol) It was dissolved in anhydrous tetrahydrofuran (30 mL), and slowly added dropwise to the reaction solution. After 30 minutes, the dropwise addition of deuteroiodomethane (4.02 g, 27.75 mmol) was started, and after the dropwise addition was completed, the mixture was slowly raised to room temperature and stirred overnight.
  • the third step the compound Int-1a (2.0g, 11.23mmol), Int-2c (3.17g, 20.22mmol) and sodium bicarbonate (2.83g, 33.70mmol) were dissolved 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, suction filtered, the filter cake was washed with water, and then dried to obtain off-white solid Int-2 (1.4 g, yield 54%).
  • the first step the compound Int-3a (10.17g, 55.26mmol) was dissolved in ethanol (50mL), at room temperature Hydrazine salt Int-3b (5.0 g, 46.05 mmol) was added under conditions, and the reaction was refluxed overnight.
  • the third step Dissolve compound Int-3e (1.1g, 3.74mmol) in methanol (10mL), add ammonia water (1mL) and Raney nickel (3mL suspension) to the reaction system in turn, replace hydrogen by hydrogen balloon and The reaction was carried out under atmosphere and room temperature for 16 hours, and the reaction was monitored by LCMS to complete.
  • ESI-MS m/z
  • the third step Dissolve the compound Int-4c (897mg, 3.18mmol) in methanol (30mL), add ammonia water (3mL) and Raney nickel (3mL suspension) to the reaction system in turn, replace the hydrogen with a hydrogen balloon and in a hydrogen atmosphere 1.
  • the reaction was carried out at room temperature for 3 hours, and the reaction was monitored by LCMS to complete.
  • ESI-MS m/z: 328.3 [M+CH 3 CN+H] + .
  • the first step the second step: the compound Int-5a (3.0g, 19.73mmol), Int-3d (2.41g, 19.73mmol) and cesium carbonate (12.85g, 39.45mmol) were added in acetonitrile (30mL), room temperature Stirred for 16 hours, LCMS monitored the completion of the reaction. Acetonitrile was distilled off under reduced pressure, and the residue was extracted by adding water and ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration.
  • the first step sodium hydrogen (153mg, 4.0mmol, content 60%) was added to anhydrous tetrahydrofuran (5mL)
  • compound Int-2a 500 mg, 2.09 mmol
  • anhydrous tetrahydrofuran (10 mL) was dissolved in anhydrous tetrahydrofuran (10 mL), and slowly added dropwise to the reaction solution.
  • iodomethane 593 mg, 4.18 mmol
  • Step 2 Dissolve Int-6b (500mg, 1.97mmol) in methanol (50mL), place in an ice-water bath, slowly add thionyl chloride (704mg, 5.92mmol) dropwise, and rise to room temperature after the addition is complete, Then rise to 60°C and react overnight. After the reaction was monitored by LCMS, the reaction solution was concentrated to obtain Int-6c (300 mg, yield 60%) as a yellow oil.
  • the third step the compound Int-1a (250mg, 1.40mmol), Int-6c (343mg, 1.69mmol) and sodium bicarbonate (353mg, 4.21mmol) were dissolved in ethanol (20mL) and water (2mL), the reaction solution Reflux overnight. After the reaction was monitored by LCMS, it was cooled to room temperature, filtered with suction, the filter cake was washed with water, and then dried to obtain an off-white solid Int-6 (170 mg, yield 43%).
  • ESI-MS (m/z): 277.2 [M+H] + .
  • the first step compound Int-5b (400mg, 1.57mmol) and cesium carbonate (1.03g, 3.15mmol) were added to N,N-dimethylformamide (8mL), then 1,1 - Difluoro-2-iodoethane (0.56 mL, 6.28 mmol). After the reaction solution was stirred at room temperature for 24 hours, LCMS monitored that only a small amount of raw materials remained in the reaction solution, adding water to quench the reaction, extracting with ethyl acetate, combining the organic phases and washing with saturated brine, drying over anhydrous sodium sulfate, and concentrating under reduced pressure The organic phase yielded a mixture of Int-7a and Int-7a'. ESI-MS (m/z): 319.1 [M+H] + .
  • the second step Dissolve the product of the first step in methanol (50mL), add ammonia water (5mL) and Raney nickel suspension (5mL) to the reaction system in turn, replace the hydrogen with a hydrogen balloon and react in a hydrogen atmosphere at room temperature After 2 hours, LCMS monitored the reaction to be complete.
  • ESI-MS (m/z): 323.3 [M+H] + .
  • Step 1 Add compound Int-8a (2.0g, 12.26mmol), Na 2 CO 3 (2.6g, 24.52mmol) into water (60mL), stir to dissolve, add iodine (3.11g, 12.26mmol) into the reaction solution and stirred at room temperature for 3 hours.
  • LCMS monitored the disappearance of the raw materials, adjusted the pH of the reaction solution to 5-6 with dilute hydrochloric acid, and extracted with ethyl acetate.
  • Step 2 Dissolve compound Int-8b (0.5g, 1.73mmol), benzyl bromide (337mg, 1.98mmol) in DMF (5mL), add K 2 CO 3 (364mg, 2.64mmol), and stir at 50°C for 2 hours , LCMS monitors the end of translation.
  • ESI-MS (m/z): 380.2 [M+H] + .
  • the third step compound Int-8c (500mg, 1.32mmol), cyclopropylboronic acid (566mg, 6.59mmol), tricyclohexylphosphine (74mg, 263umol), palladium acetate (29mg, 131umol), potassium phosphate (559mg, 2.63 mmol) was added to dioxane (30 mL) and water (3 mL), and the reaction system was replaced with nitrogen, then stirred at 90° C. for 17 hours under the protection of nitrogen atmosphere. LCMS monitored the reaction to be complete.
  • ESI-MS (m/z): 204.5 [M+H] + .
  • Step 5 Compounds Int-8e (172mg, 0.85mmol), Int-3d (144mg, 1.18mmol), Cs 2 CO 3 (0.64g, 2.0mmol) were added to DMF (5mL), stirred at 20°C for 17 hours , LCMS monitored the reaction to be complete. The reaction solution was added into water (100 mL), stirred for 30 minutes, and suction filtered to obtain a yellow solid Int-8f (170 mg, yield 65%). ESI-MS (m/z): 306.2 [M+H] + .
  • Step 6 Add compound Int-8f (90mg, 295umol), Raney nickel (0.5mL, aqueous suspension) into methanol (5mL), add ammonia water (0.1ml), and replace the reaction system with hydrogen in a hydrogen atmosphere Stir at room temperature for 2 hours, and the reaction is complete as monitored by LCMS.
  • the reaction solution was suction-filtered with celite, and the filtrate was concentrated to obtain a yellow solid Int-8 (85 mg), which was directly used in the next reaction without purification.
  • ESI-MS (m/z): 310.3 [M+H] + .
  • Second step dissolve compound Int-9b (2.0g, 9.61mmol) and compound Int-3d (1.17g, 9.61mmol) in N,N-dimethylformamide (10ml), add cesium carbonate (6.26g , 19.21 mmol). The reaction was stirred at room temperature for 4 hours. LCMS monitored the completion of the reaction. The reaction solution was diluted with water, the resulting suspension was filtered, and the filter cake was dried by a vacuum rotary evaporator to obtain a brown solid compound Int-9c (1.78 g, yield 59%). ESI-MS (m/z): 311.1 [M+H] + .
  • the first step under a nitrogen atmosphere, compound Int-5b (500mg, 1.97mmol) and cesium carbonate (1.28g, 3.93mmol) were added to N,N-dimethylformamide (10mL), and then added to the reaction solution 2,2,2-Trifluoroethyl trifluoromethanesulfonate (0.58 mL, 3.93 mmol) was added dropwise.
  • the second step Dissolve the product of the first step in methanol (60mL), add ammonia water (6mL) and Raney nickel suspension (6mL) to the reaction system in turn, replace the hydrogen with a hydrogen balloon and react in a hydrogen atmosphere at room temperature After 2 hours, LCMS monitored the reaction to be complete.
  • ESI-MS (m/z): 382.3 [M+CH 3 CN+H] + .
  • the first step compound Int-5b (400mg, 1.57mmol) and cesium carbonate (1.03g, 3.15mmol) were added to N,N-dimethylformamide (8mL), and then 1-fluoro - 2-iodoethane (548 mg, 3.15 mmol). After the reaction solution was stirred at room temperature for 16 hours, LCMS monitored the completion of the reaction, adding water to quench the reaction, extracting with ethyl acetate, combining the organic phases and washing with saturated brine, drying over anhydrous sodium sulfate, and concentrating the organic phase under reduced pressure to obtain the compound Int- Mixture of 11a and Int-11a'.
  • ESI-MS (m/z): 301.2 [M+H] + .
  • the second step Dissolve the product of the first step in methanol (50mL), add ammonia water (5mL) and Raney nickel suspension (5mL) to the reaction system in turn, replace the hydrogen with a hydrogen balloon and react in a hydrogen atmosphere at room temperature After 2 hours, LCMS monitored the reaction to be complete.
  • ESI-MS (m/z): 305.1 [M+H] + .
  • the first step Dissolve compound Int-3d (120mg, 0.1mmol) and compound Int-12a (200mg, 0.1mmol) in N,N-dimethylformamide (5mL), add cesium carbonate (383mg, 1.2mmol ). The reaction was stirred at room temperature for 4 hours. LCMS monitored the complete reaction of starting material. The reaction solution was diluted with water, the obtained suspension was filtered, and the filter cake was dried under reduced pressure to obtain a white solid Int-12b (265 mg, yield 88%). ESI-MS (m/z): 307.1 [M+H] + .
  • the first step compound Int-13a (700mg, 3.54mmol), Int-3d (433mg, 3.54mmol) and cesium carbonate (2.31g, 7.09mmol) were added in N,N-dimethylformamide (10mL) , reacted at 50° C. for 16 hours, and monitored the completion of the reaction by LCMS. N,N-dimethylformamide was distilled off under reduced pressure, then added with water and ethyl acetate for extraction, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain a white solid Int-13b ( 711 mg, yield 67%).
  • Step 2 Dissolve compound Int-13b (355mg, 1.18mmol) in methanol (35mL), add ammonia (3.5mL) () and Raney nickel (3.5mL suspension) to the reaction system in turn, and replace the hydrogen with a hydrogen balloon
  • the reaction was carried out under hydrogen atmosphere and room temperature for 3 hours, and the reaction was monitored by LCMS.
  • ESI-MS (m/z): 304.2 [M+H] + .
  • the third step Dissolve the compound Int-14c (250mg, 0.78mmol) in methanol (5mL), add ammonia water (1mL) and Raney nickel (3mL suspension) to the reaction system in turn, replace the hydrogen with a hydrogen balloon and in a hydrogen atmosphere 1.
  • the reaction was carried out at room temperature for 16 hours, and the reaction was monitored by LCMS.
  • ESI-MS (m/z): 325.3 [M+H] + .
  • Step 3 Dissolve compound Int-15d (213mg, 0.67mmol) in methanol (22mL), add ammonia water (2.2mL) and Raney nickel (2.2mL, aqueous suspension) to the reaction system in turn, and replace by hydrogen balloon Hydrogen was reacted for 16 hours under a hydrogen atmosphere at room temperature, and the reaction was completed by LCMS monitoring.
  • the reaction solution was diluted with methanol, filtered with suction, and the filtrate was concentrated to obtain the crude product Int-15.
  • ESI-MS (m/z): 325.2 [M+H] + .
  • Step 1 Compounds Int-16a (1.00 g, 11.89 mmol), Int-16b (3.38 g, 23.78 mmol) and sodium ethoxide (1.62 g, 23.78 mmol) were sequentially added to dimethyl sulfoxide (10 mL). The reaction solution was stirred at 60° C. for 16 hours. After the reaction was completed, 6N hydrochloric acid was added to quench the reaction, extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain the crude product Int-16c.
  • Step 2 Compound Int-16c (1.94g), hydrazine hydrate (673mg, 10.75mmol, 80%) and acetic acid (5mL) were added to methanol (35mL), and the reaction solution was refluxed under nitrogen atmosphere for 16 hours. After the reaction was monitored by LCMS, the solvent was distilled off under reduced pressure, then diluted with water and sodium carbonate (solid) was added to pH 9, extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and reduced pressure Concentration of the organic phase afforded Int-16d as a brown solid (1.73 g, 82% for two steps). ESI-MS (m/z): 177.5 [M+H] + .
  • the third step Compounds Int-16d (200 mg, 1.14 mmol), Int-15b (336 mg, 1.70 mmol) and potassium carbonate (314 mg, 2.27 mmol) were added into acetonitrile (10 mL). The reaction solution was stirred at 80°C for 16 hours.
  • Step 4 Dissolve compound Int-16e (228mg, 0.78mmol) in methanol (23mL), add ammonia water (2.3mL) and Raney nickel (2.3mL, aqueous suspension) to the reaction system in turn, and replace by hydrogen balloon hydrogen and reacted for 3 hours under a hydrogen atmosphere at room temperature, and LCMS monitored the completion of the reaction.
  • the reaction solution was diluted with methanol, filtered with suction, and the filtrate was concentrated to obtain the crude product Int-16.
  • ESI-MS (m/z): 297.3 [M+H] + .
  • Step 1 Dissolve compound Int-16e' (80mg, 0.27mmol) in methanol (8mL), add ammonia (0.8mL) and Raney nickel (0.8mL, aqueous suspension) to the reaction system in turn, and pass through a hydrogen balloon The hydrogen gas was replaced and reacted for 3 hours under a hydrogen atmosphere at room temperature, and the reaction was completed by LCMS monitoring. The reaction solution was diluted with methanol, filtered with suction, and the filtrate was concentrated to obtain the crude product Int-17. ESI-MS (m/z): 297.2 [M+H] + .
  • the first step Dissolve compound Int-18a (2.03g, 10mmol) in anhydrous dimethyl sulfoxide (10mL), add potassium hydroxide (1.68g, 30mmol) and deuteroiodomethane (2.17g, 15mmol) .
  • the reaction was stirred at room temperature for 12 hours.
  • LCMS detects that the reaction is complete.
  • the reaction solution was quenched with water, extracted with dichloromethane, the combined organic phases were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product of compound Int-18b (2.3 g).
  • ESI-MS (m/z): 238.3 [M+H] + .
  • Step 3 Compounds Int-18c (450 mg, 3 mmol) and Int-18d (539 mg, 3 mmol) were dissolved in tetrahydrofuran (3 mL), and N,N-diisopropylethylamine (1 g, 7.78 mmol) was added. The reaction was stirred at room temperature for 4 hours. LCMS detects that the reaction is complete.
  • Step 4 Compound Int-18e (400 mg, 1.30 mmol) was dissolved in methanol (5 mL), potassium carbonate (269 mg, 1.94 mmol) was added, followed by sodium dithionite (677 mg, 3.89 mmol). The reaction was stirred at room temperature for 30 minutes. Aqueous hydrochloric acid (2 mL, 4M) was then added. The reaction was stirred at room temperature for 8 hours. LCMS detects that the reaction is complete.
  • Embodiment 1 is prepared by the following steps:
  • the first step Dissolve compound Int-1 (1.0g, 4.41mmol) and compound Int-3 (1.71g, 5.74mmol) in n-butanol (6mL), add p-toluenesulfonic acid monohydrate (83mg, 0.44 mmol), reaction solution Stir at 160° C. for 4 hours under microwave conditions. After the reaction liquid was cooled to room temperature, the reaction liquid was concentrated under reduced pressure, and the residue was directly purified by reverse preparative HPLC to obtain white solid 1 (987 mg, yield 45%).
  • Embodiment 2 is prepared by the following steps:
  • the first step Dissolve compound Int-2 (50mg, 0.22mmol) and compound Int-3 (84mg, 0.28mmol) in n-butanol (2mL), add p-toluenesulfonic acid monohydrate (4mg, 0.02mmol) , 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 reverse preparative HPLC to obtain a white solid 2 (36 mg, yield 34%).
  • the first step Dissolve compound Int-5b (500mg, 1.97mmol) in N,N-dimethylformamide (10mL), then add cesium carbonate (1.28g, 3.93mmol) and deuterated iodoethane (633mg , 3.93 mmol). The reaction was stirred at room temperature for 4 hours. LCMS monitored the completion of the reaction. The reaction solution was diluted with saturated aqueous sodium chloride and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a mixture of compounds 3a and 3a'. ESI-MS (m/z): 288.9 [M+H] + .
  • Step 2 Dissolve the products 3a and 3a' obtained in the previous step in methanol (15mL) and ammonia water (1mL), add Raney Nickel (1mL, aqueous suspension), and stir the reaction system at room temperature for 12 hours after replacing hydrogen .
  • the reaction solution was filtered through celite, and the filtrate was concentrated.
  • Step 3 Dissolve compound 3b (60mg, 0.21mmol) in n-butanol (3mL), add compound Int-1 (31mg, 0.14mmol) and p-toluenesulfonic acid monohydrate (3mg, 0.02mmol), The reaction solution Stir 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 reverse preparative HPLC to obtain a white solid 3 (29 mg, yield 29%).
  • Step 4 Starting from compound 3b' (60 mg, 0.21 mmol), a white solid 3' (20 mg, yield 18%) was obtained by a method similar to the third step.
  • the first step Dissolve compound Int-5b (200mg, 0.79mmol) in N,N-dimethylformamide (5mL), then add cesium carbonate (513mg, 1.57mmol) and 2-iodopropane (268mg, 1.57 mmol). The reaction was stirred at room temperature for 4 hours. LCMS monitored the completion of the reaction. The reaction solution was diluted with saturated aqueous sodium chloride and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a mixture of compounds 4a and 4a'. ESI-MS (m/z): 297.2 [M+H] + .
  • the third step Dissolve compound 4b (62mg, 0.21mmol) in n-butanol (3mL), add compound Int-1 (31mg, 0.14mmol) and p-toluenesulfonic acid monohydrate (3mg, 0.02mmol), react liquid in Stir at 160°C for 3 hours under microwave conditions. After the reaction liquid was cooled to room temperature, the reaction liquid was concentrated under reduced pressure, and the residue was purified by reverse preparative HPLC to obtain white solid 4 (13 mg, yield 13%).
  • Step 4 Starting from compound 4b' (60 mg, 0.21 mmol), a white solid 4' (5 mg, yield 5%) can be obtained by a method similar to the third step.
  • Embodiment 5 is prepared by the following steps:
  • the first step Dissolve compound Int-9 (100mg, 0.32mmol) and compound Int-1 (48mg, 0.21mmol) in n-butanol (3mL), add p-toluenesulfonic acid monohydrate (6mg, 0.03mmol) , 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 reverse preparative HPLC to obtain white solid 5 (20 mg, yield 13%).
  • Embodiment 6 is prepared by the following steps:
  • the first step intermediate Int-1 (37mg, 0.16mmol), intermediate Int-11 (55mg, 0.18mmol) and trifluoroacetic acid (2mg, 0.02mmol) were dissolved in n-butanol (2mL), and the The reaction was carried out at 160° C. for 4 hours. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain a white solid 6 (21 mg, yield 26%).
  • Embodiment 7 is prepared by the following steps:
  • the first step intermediate Int-1 (39mg, 0.17mmol), intermediate Int-10 (65mg, 0.19mmol) and trifluoroacetic acid (2mg, 0.02mmol) were dissolved in n-butanol (2mL), and the The reaction was carried out at 160° C. for 4 hours. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain 7 (24 mg, yield 26%) as a white solid.
  • Embodiment 8 is prepared by the following steps:
  • the first step intermediate Int-1 (38mg, 0.17mmol), intermediate Int-7 (60mg, 0.19mmol) and trifluoroacetic acid (2mg, 0.02mmol) were dissolved in n-butanol (2mL), and the The reaction was carried out at 160° C. for 4 hours. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain 8 (24 mg, yield 27%) as a white solid.
  • Embodiment 9 is prepared by the following steps:
  • the first step intermediate Int-1 (34mg, 0.15mmol), intermediate Int-8 (51mg, 0.16mmol) and trifluoroacetic acid (2mg, 0.02mmol) were dissolved in n-butanol (2mL), and the The reaction was carried out at 160° C. for 4 hours. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain white solid 9 (16 mg, yield 21%).
  • Example 10 was prepared by the following steps:
  • the first step intermediate Int-2 (50mg, 0.22mmol), intermediate Int-13 (85mg, 0.28mmol) and p-toluenesulfonic acid monohydrate (4mg, 0.02mmol) were dissolved in n-butanol (2mL) In the microwave, the reaction was carried out at 160°C for 3 hours. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain white solid 10 (23 mg, yield 21%).
  • Example 11 was prepared by the following steps:
  • the first step Dissolve compound Int-12 (100mg, 0.34mmol) and compound Int-1 (75mg, 0.34mmol) in n-butanol (3mL), add p-toluenesulfonic acid monohydrate (6mg, 0.03mmol) ,The reaction solution Stir 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 reverse preparative HPLC to obtain white solid 11 (80 mg, yield 48%).
  • Example 12 was prepared by the following steps:
  • the first step Dissolve compound Int-1 (50mg, 0.22mmol) and compound Int-14 (93mg, 0.29mmol) in n-butanol (2mL), add p-toluenesulfonic acid monohydrate (4mg, 0.02mmol) , 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 reverse preparative HPLC to obtain white solid 12 (36 mg, yield 30%).
  • Example 13 was prepared by the following steps:
  • the first step intermediate Int-1 (40mg, 0.18mmol), intermediate Int-15 (69mg, 0.21mmol) and trifluoroacetic acid (2mg, 0.02mmol) were dissolved in n-butanol (2mL), and the The reaction was carried out at 160° C. for 3 hours. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain white solid 13 (37 mg, yield 41%).
  • Example 14 was prepared by the following steps:
  • the first step Dissolve compound Int-1a (500mg, 2.81mmol) and compound 14a (602mg, 3.65mmol) in ethanol (20mL) and water (2mL), then add sodium bicarbonate (707mg, 8.34mmol), and The temperature of the reaction liquid was raised to 80° C. and stirred for 16 hours. After the reaction solution was cooled to room temperature, water (12 mL) was added to the reaction solution, and after filtration, off-white solid 14b (385 mg, yield 57%) was obtained, ESI-MS (m/z): 239.4 [M+H] + .
  • Second step Dissolve compound 14b (42mg, 0.17mmol) and compound Int-3 (68mg, 0.23mmol) in n-butanol (2mL), add p-toluenesulfonic acid monohydrate (3mg, 0.01mmol), react The 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 reverse preparative HPLC to obtain white solid 14 (15 mg, yield 17%).
  • Example 15 was prepared by the following steps:
  • the first step Ethyl formate (3.17g, 42.73mmol) and solid sodium ethoxide (3.49g, 50.50mmol) were sequentially added into dry tetrahydrofuran (140mL). After compound 15a (7 g, 38.85 mmol) was added at a temperature of 5-10° C., the reaction solution was heated to 50° C. and kept stirring for 2 hours, and the disappearance of the raw material was monitored by HPLC. Tetrahydrofuran was distilled off under reduced pressure to obtain yellow oil 15b, which was directly used in the next step.
  • Step 2 add 150ml of absolute ethanol to the oil 15b obtained in the previous step, stir and dissolve at room temperature, add trifluoroacetamidine (4.35g, 33.01mmol, purity 85%) dropwise, and keep stirring at 30°C for 5 hours, Then the temperature was raised to 80° C. and stirring was continued for 2 hours, and the disappearance of the raw material was monitored by HPLC. After the reaction solution cooled down, about 100ml of ethanol was evaporated under reduced pressure, and the remaining residue was added to 300ml of ice water, adjusted to pH 3 with concentrated hydrochloric acid, stirred for 0.5 hours, filtered with suction, and the filter cake was dried to obtain yellow solid compound 15c (4.37g, yield 41%, purity 99%).
  • ESI-MS (m/z): 271.4 [M+H] + .
  • Step 3 Add compound 15c (4.0g, 14.80mmol) to 60ml of acetonitrile, dropwise add phosphorus oxychloride (6.81g, 44.41mmol), stir for 10 minutes after the addition, heat up to 80°C, keep stirring for 2 Hours, HPLC monitoring raw material conversion is complete. Acetonitrile was removed under reduced pressure, and the residue was added to 200 mL of ice water, stirred for 0.5 hours, and filtered with suction to obtain a yellow solid 15d (3.9 g, yield 86%, purity 95%).
  • the fourth step Compound 15d (2.0g, 6.93mmol), trimethylboroxane (2.61g, 20.79mmol), palladium acetate (155mg, 0.69mol), potassium phosphate (2.94g, 13.86mmol) in sequence
  • 1,4-dioxane 150 mL
  • water 15 mL
  • HPLC HPLC monitors that the conversion of the raw material is complete
  • the filtrate is concentrated.
  • ESI-MS (m/z): 269.1 [M+H] + .
  • Step 5 Compound 15e (1.0 g, 3.73 mmol) was added to 20 mL of methanol, 10% palladium on carbon (100 mg) was added, and the reaction system was replaced with hydrogen and stirred overnight at room temperature. The reaction liquid was filtered with celite, and the filtrate was concentrated to obtain compound 15f (630 mg, yield 92%, purity 97%). ESI-MS (m/z): 177.1 [MH] - .
  • Step 6 Add compound 15f (0.5g, 2.81mmol), Cs 2 CO 3 (1.83g, 5.61mmol), Int-3d (514mg, 4.21mmol) to N,N-dimethylformamide (10mL ), stirred overnight at 20°C, HPLC monitored the disappearance of the raw materials, the reaction solution was added to 50ml of ice water, stirred for 0.5 hours, and filtered with suction to obtain 15g of a yellow solid (510mg, yield 64%, purity 99%).
  • ESI-MS (m/z): 281.3 [M+H] + .
  • Step 7 Dissolve compound 15g (100mg, 0.36mmol) in methanol (5mL), add ammonia water (0.2mL), add RaneyNickel (0.5mL, water suspension), and stir the reaction system at room temperature after replacing hydrogen 2 hours.
  • the reaction liquid was filtered with celite, and the filtrate was concentrated to obtain compound 15h (95 mg, yield 93%, purity 90%), ESI-MS (m/z): 284.9 [M+H] + .
  • Step 8 Dissolve compound 15h (95 mg, 0.33 mmol) in n-butanol (3 mL), add compound Int-1 (79 mg, 0.35 mmol) and p-toluenesulfonic acid monohydrate (3 mg, 0.02 mmol), and react The solution was stirred at 160° C. for 3 hours under microwave conditions. After the reaction liquid was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by reverse preparative HPLC to obtain white solid 15 (31 mg, yield 21%, purity 99%).
  • Example 16 was prepared by the following steps:
  • Example 17 was prepared by the following steps:
  • Example 18 was prepared by the following steps:
  • the first step compound 18a (1.01g, 5mmol) and potassium hydroxide (842mg, 15mmol) were dissolved in anhydrous dimethyl sulfoxide (10mL), then deuteroiodomethane (1.59g, 11mmol) was added dropwise into the reaction solution. The reaction solution was stirred at room temperature for 8 hours. LCMS monitored the completion of the reaction. The reaction solution was diluted with water, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude compound 18b (1.0 g, yield 84%). ESI-MS (m/z): 236.3 [M+H] + .
  • Second step Compound 18b (1.0 g) was dissolved in dioxane hydrochloride solution (4M, 10 mL). The reaction was stirred at room temperature for 4 hours. LCMS monitored the completion of the reaction. The reaction solution was concentrated under reduced pressure to obtain a crude product of Compound 18c (720 mg). ESI-MS (m/z): 136.1 [M+H] + .
  • the third step Compound 18c (720 mg) and compound 18d (872 mg, 4.19 mmol) were dissolved in tetrahydrofuran (10 mL), and N,N-diisopropylpropylamine (1.62 g, 12.57 mmol) was added. The reaction solution was stirred at room temperature for 8 hours. LCMS monitored the completion of the reaction. The reaction solution was diluted with water, filtered, the filter cake was washed with water, and dried to obtain off-white solid 18d (993 mg, yield 77% in two steps). ESI-MS (m/z): 307.2 [M+H] + .
  • Step 4 Dissolve compound 18d (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 was stirred at room temperature for 15 minutes. LCMS monitored the complete reaction of starting material. Dioxane hydrochloride solution (4M, 1.25 mL) was added to the reaction solution. The reaction was continued to stir at room temperature for 8 hours.
  • Step 5 Dissolve Int-3 (35mg, 0.12mmol) and compound 18e (28mg, 0.12mmol) in n-butanol (3mL), add p-toluenesulfonic acid monohydrate (2mg, 0.01mmol), and the reaction solution Stir 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 reverse preparative HPLC to obtain white solid 18 (10 mg, yield 17%).
  • the first step trifluoromethanesulfonic anhydride (1.25 g, 4.44 mmol) was added to compound 19a (400 mg, 3.70 mmol) and 4-dimethylaminopyridine (543 mg, 4.44 mmol) in dichloromethane under ice bath conditions solution (10 mL). After reacting at room temperature for 16 hours, the reaction was quenched by adding saturated aqueous ammonium chloride solution, extracted with dichloromethane, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain the crude product of compound 19b , used directly in the next reaction.
  • Step 3 Dissolve the mixture of 19c and 19c' (283mg, 0.82mmol) in methanol (30mL), add ammonia water (3mL) and Raney nickel (3mL, aqueous suspension) to the reaction system in turn, and pass through the hydrogen balloon The hydrogen was replaced and reacted for 2 hours under a hydrogen atmosphere at room temperature, and the reaction was completed by LCMS monitoring. The reaction solution was diluted with methanol, filtered through celite, and the filtrate was concentrated to obtain a mixture of 19d and 19d', which was directly used in the next reaction. ESI-MS (m/z): 349.3 [M+H] + .
  • the fourth step Int-2 (80mg, 0.35mmol), the mixture of 19d and 19d' (146mg, crude product) and p-toluenesulfonic acid monohydrate (4mg, 0.03mmol) were dissolved in n-butanol (2mL), in React under the condition of microwave at 160° C. for 3 hours. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain white solids 19 (28 mg, yield 15%) and 19' (17 mg, yield 9%), respectively.
  • Example 20 was prepared by the following steps:
  • the first step Dissolve compound Int-6 (50mg, 0.18mmol) and compound Int-3 (70mg, 0.23mmol) in n-butanol (6mL), add p-toluenesulfonic acid monohydrate (3mg, 18umol), 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 reverse preparative HPLC to obtain a white solid 20 (3.9 mg, yield 4%).
  • Example 21 was prepared by the following steps:
  • the first step Compound 15d (550mg, 1.91mmol), cyclopropylboronic acid (818mg, 9.53mmol), palladium acetate (42mg, 0.19mmol), tricyclohexylphosphine (106mg, 0.38mmol) and potassium phosphate (1.21g , 5.72mmol) was added to the mixed solution of 1,4-dioxane (50mL) and water (5mL). After the reaction system was replaced with nitrogen, it was reacted at 110°C under nitrogen atmosphere for 16 hours, and the reaction was monitored by LCMS.
  • the second step Dissolving compound 21a (530mg, 1.80mmol) in methanol (10mL), adding palladium carbon (10%, 21mg) to the reaction system, displacing hydrogen through a hydrogen balloon and reacting under hydrogen atmosphere and room temperature for 16 hours, LCMS monitored the completion of the reaction.
  • the reaction solution was diluted with methanol, suction filtered, and the filtrate was concentrated to obtain brown oily liquid 21b (330 mg, yield 89%).
  • Step 4 Dissolve compound 21c (350mg, 1.14mmol) in methanol (20mL), add ammonia water (3.5mL) and Raney nickel (3.5mL, aqueous suspension) to the reaction system in turn, replace the hydrogen with a hydrogen balloon and The reaction was carried out under hydrogen atmosphere and room temperature for 16 hours, and the reaction was monitored by LCMS to complete.
  • ESI-MS (m/z): 311.2 [M+H] + .
  • Step 5 Dissolve compound Int-1 (50mg, 0.22mmol) and compound 21d (82.13mg, 0.26mmol) in n-butanol (2mL), add p-toluenesulfonic acid monohydrate (4.19mg, 22umol), 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 reverse preparative HPLC to obtain a white solid 21 (48.18 mg, yield 43%).
  • Example 22 was prepared by the following steps:
  • the first step Dissolve compound Int-18 (50mg, 0.17mmol) and compound Int-3 (40.85mg, 0.17mmol) in n-butanol (2mL), add p-toluenesulfonic acid monohydrate (2.89mg, 17umol ), 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 reverse preparative HPLC to obtain a white solid 22 (20 mg, yield 23%).
  • Example 23 was prepared by the following steps:
  • Step 2 Add compound 23a (1.0g, 3.73mmol) to 20ml of methanol, add palladium carbon (10%, 100mg), replace hydrogen in the reaction system and stir at room temperature overnight, filter the reaction solution with diatomaceous earth, and concentrate the filtrate , to obtain compound 23b (677 mg, yield 94%, purity 97%).
  • Step 3 Add compound 23b (0.5g, 2.81mmol), Cs 2 CO 3 (1.83g, 5.61mmol), Int-3d (514mg, 4.21mmol) to N,N-dimethylformamide (10mL ), stirred overnight at 20°C, and the disappearance of raw materials was monitored by HPLC. The reaction solution was added to 50 ml of ice water, stirred for 0.5 hours, and filtered with suction to obtain a yellow solid 23c (530 mg, yield 64%, purity 99%). ESI-MS (m/z): 294.3 [M+H] + .
  • Step 4 Dissolve compound 23c (100mg, 0.36mmol) in methanol (5mL), add ammonia water (0.2mL), add Raney Nickel (0.5mL, aqueous suspension), and replace hydrogen in the reaction system at room temperature Stir for 2 hours.
  • the reaction liquid was filtered with celite, and the filtrate was concentrated to obtain compound 23d (97 mg, yield 93%, purity 90%), ESI-MS (m/z): 298.5 [M+H] + .
  • Step 5 Dissolve compound Int-1 (79.74mg, 0.35mmol) and compound 23d (104.93mg, 0.35mmol) in n-butanol (2mL), add p-toluenesulfonic acid monohydrate (6.68mg, 0.35umol ), 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 reverse preparative HPLC to obtain a white solid 23 (33 mg, yield 19%).
  • Example 25 was prepared by the following steps:
  • Step 1 Compound Int-8c (930 mg, 2.45 mmol) was dissolved in tetrahydrofuran (10 mL), and n-butyllithium (1.5 mL, 2M in hexane) was slowly added dropwise to the solution at -78°C. The reaction solution was further stirred at -78°C for 10 minutes. Then N,N-dimethylformamide (359mg, 4.91mmol) was slowly added dropwise to the reaction solution, and the reaction solution was stirred at -78°C for 1 hour. LCMS detects that the reaction is complete.
  • Step 3 Dissolve compound 25b (247mg, crude product) in dichloromethane (5mL), slowly add boron tribromide (308mg, 1.23mmol) into the solution at -78°C, and react at -78°C Stirring was continued for 30 minutes.
  • LCMS detects that the reaction is complete.
  • Step 4 Dissolve compound 25c (82mg, 0.39mmol) and compound Int-2 (47mg, 0.39mmol) in N,N-dimethylformamide (3mL), add cesium carbonate (251mg, 0.77mmol), The reaction solution was stirred at 50°C for 12 hours. LCMS detects that the reaction is complete. The reaction solution was diluted with water, and filtered under reduced pressure to obtain compound 25d (98 mg, yield 80%).
  • Step 6 Dissolve compound 25e (20mg, 0.06mmol) and Int-2 (15mg, 0.06mmol) in n-butanol (3mL), add p-toluenesulfonic acid monohydrate (2mg, 0.01mmol), and the reaction solution Stir 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 compound 25 (7 mg, yield 22%) as a white solid.
  • Example 26 was prepared by the following steps:
  • Step 1 Dissolve compound 26a (1.0g, 4.65mmol) in anhydrous tetrahydrofuran (20mL), under the protection of nitrogen, cool down to -78°C, and slowly add n-butyllithium (3.05mL, 4.88mmol) dropwise, After one hour, dropwise addition of triisopropyl borate (0.79 mL, 6.97 mmol) was started, and the reaction was completed after two hours by LCMS. Water was slowly added dropwise to quench the reaction.
  • Second step Compounds 26b and 26b' (400mg, 1.73mmol), Int-3d (232.48mg, 1.90mmol) and N,N-diisopropylethylamine (671.1mg, 5.19mmol) were added to acetonitrile (10mL ), reacted at 120° C. for 4 hours, and LCMS monitored the end of the reaction.
  • the third step Dissolve compound 26c (180mg, 0.54mmol) in methanol (30mL), add ammonia water (5mL) and Raney nickel (3.5mL, aqueous suspension) to the reaction system in turn, replace hydrogen by hydrogen balloon and in The reaction was carried out under hydrogen atmosphere and room temperature for 3 hours, and the reaction was monitored by LCMS to complete. The reaction solution was diluted with methanol, filtered with suction, and the filtrate was concentrated to obtain a brown oily liquid 26d (150 mg, yield 82%). ESI-MS (m/z): 338.5 [M+H] + .
  • Step 4 Dissolve compound 26d (74.39mg, 0.22mmol) in n-butanol (2mL), add compound Int-1 (50mg, 0.22mmol) and p-toluenesulfonic acid monohydrate (4.19mg, 22umol), The reaction solution was stirred at 160° C. for 3 hours under microwave conditions. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by reverse-phase preparative HPLC to obtain 26 (38.57 mg, yield 33%) as a white solid.
  • Example 27 was prepared by the following steps:
  • the first step under ice-water bath conditions, di-tert-butyl carbonic anhydride (1.75g, 8.02mmol) was added dropwise to a dichloromethane solution of Int-13 (2.03g, 6.68mmol) and triethylamine (1.39mL, 10.02mmol). methane (40mL) solution. After the reaction solution was stirred at room temperature for 16 hours, water was added to quench the reaction.
  • Second step Compound 27a (300mg, 0.74mmol), zinc cyanide (174mg, 1.49mmol), tetrakistriphenylphosphine palladium (172mg, 0.15mol) and N,N-dimethylformamide (10mL) were added into a round bottom flask. After the reaction solution was stirred at 120° C. for 24 hours under nitrogen protection, the reaction was monitored by LCMS.
  • Step 3 Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of compound 27b in dichloromethane (6 mL). After the reaction solution was stirred at room temperature for 5 hours, the reaction was monitored by LCMS to complete. Concentrated by vacuum distillation To the reaction solution, an aqueous sodium hydroxide solution was added to pH 8, extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated to obtain the crude product 27c.
  • ESI-MS (m/z): 295.3 [M+H] + .
  • Step 4 Dissolve compound Int-2 (45mg, 0.20mmol) in n-butanol (3mL), add compound 27c (64mg, 0.22mmol) and p-toluenesulfonic acid monohydrate (8mg, 44umol), and the reaction solution Stir at 160° C. for 3 hours under microwave conditions. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain a white solid 27 (16 mg, yield 8%).
  • Example 28 was prepared by the following steps:
  • ESI-MS (m/z): 385.1 [M+H] + .
  • the second step 28b (400mg, 1.04mmol), n-butyl bis (1-adamantyl) phosphine (37mg, 103umol), 28c (492mg, 2.08mmol), TBAF (56mg, 259umol), palladium acetate (23mg , 103umol), cesium carbonate (1.02g, 3.12mmol), water (1mL) were added to n-butanol (7mL), and stirred at 110°C for 17 hours under nitrogen protection.
  • Step 3 Add compound 28d (273mg, 627umol) into dichloromethane (3ml), add trifluoroacetic acid (1ml), and stir at room temperature for 2 hours.
  • LCMS showed that the conversion of the raw material was complete. Distilled under reduced pressure, the residue was sequentially added to 10ml of ethyl acetate and 10ml of saturated aqueous sodium bicarbonate solution for liquid separation. The organic phase was washed with water, dried over sodium sulfate, and concentrated to obtain a brown oil, which was directly used in the next step.
  • ESI-MS (m/z): 336.0 [M+H] + .
  • Step 4 Add compound 28e, Int-1 (79mg, 351umol) and p-toluenesulfonic acid (6mg, 35umol) obtained in the previous step into n-butanol (2mL), stir in microwave at 160°C for 3 hours. LCMS Display ingredients disappear. The reaction solution was purified by reverse-phase preparative HPLC to obtain a white solid 28 (20 mg, yield 6% in two steps).
  • Example 30 was prepared by the following steps:
  • the first step Dissolve compound 30a (1.10g, 5mmol) in anhydrous tetrahydrofuran (10mL), cool the solution to 0°C, and slowly add sodium hydride (478mg, 60% dispersion in mineral oil) to the reaction under nitrogen atmosphere in the liquid. The reaction solution was stirred at 0°C for 10 minutes. Then methyl iodide (1.42 g, 10 mmol) was added dropwise to the reaction solution. The reaction solution was slowly warmed to room temperature and stirring was continued for 2 hours. LCMS detects that the reaction is complete.
  • the second step Dissolve compound 30b (1.17g) in methanol (10mL), slowly add thionyl chloride (1.19g, 10mmol) dropwise to the reaction solution at room temperature, then the reaction solution is heated to 70°C and continued Stir at this temperature for 2 hours. LCMS detects that the reaction is complete. After the reaction liquid was cooled to room temperature, the reaction liquid was concentrated under reduced pressure to obtain compound 30c (918 mg, crude product).
  • Step 4 Dissolve compound 30d (320 mg, 1 mmol) and compound Int-3 (300 mg, 1 mmol) in N, N-dimethylformamide (5 mL), add N, N-diisopropylethylamine ( 390 mg, 3 mmol). The reaction was stirred at room temperature for 4 hours. LCMS detects that the reaction is complete.
  • Step 5 Dissolve compound 30e (430 mg, 0.74 mmol) in methanol (5 mL), add 10% palladium on carbon (394 mg), and stir the reaction system at room temperature for 6 hours after replacing hydrogen. LCMS detects that the reaction is complete. The reaction solution was filtered with celite, the filtrate was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to obtain compound 30 (15 mg, yield 4%) as a white solid.
  • Example 31 was prepared by the following steps:
  • Step 1 Compound 30 (10 mg, 0.02 mmol) was dissolved in dichloromethane (2 mL), and boron tribromide (10 mg, 0.04 mmol) was slowly added dropwise to the reaction solution at -78°C. The reaction continued to stir at -78°C for 30 minutes. LCMS detects that the reaction is complete. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, the organic phases were combined and washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by Prep-HPLC to obtain white solid compound 31 (8 mg , yield 80%).
  • Example 34 was prepared by the following steps:
  • the first step compound 27a (675mg, 1.67mmol), vinylboronic acid pinacol ester (1.29g, 8.36mmol), tetrakistriphenylphosphine palladium (194mg, 0.17mol), sodium carbonate (354mg, 3.34mmol) , water (3 mL) and 1,4-dioxane (17 mL) were added to a round bottom flask. After the reaction solution was stirred for 16 hours at 120° C. under nitrogen protection, the reaction was monitored by LCMS.
  • the second step sodium periodate (907mg, 4.24mmol) was added to 34a (559mg, 1.41mmol) in the mixed solution of tetrahydrofuran (12mL) and water (3mL), after the reaction solution was stirred at room temperature for one minute, to To this was added potassium osmate (41 mg, 0.14 mmol). After the reaction solution was stirred at 40° C. for 2 hours, the reaction was monitored by LCMS to complete. Add water and ethyl acetate for extraction, combine the organic phases and successively use thiosulfur NaCl aqueous solution and saturated brine were washed, dried over anhydrous sodium sulfate, and the organic phase was concentrated to obtain the crude product 34b.
  • ESI-MS (m/z): 398.3 [M+H] + .
  • Step 4 Thionyl chloride (0.13 mL, 1.80 mmol) was added dropwise to a solution of 34c (359 mg, 0.90 mmol) in dichloromethane (14 mL). After the reaction solution was stirred at room temperature for 2 hours, the reaction was monitored by LCMS to complete. The reaction solution was concentrated by distillation under reduced pressure to obtain the crude product 34d. ESI-MS (m/z): 418.2 [M+H] + .
  • Step 5 Trimethylsilyl cyanide (178 mg, 1.80 mmol) was added dropwise to a solution of cesium fluoride (119 mg, 1.80 mmol) in acetonitrile (8 mL) at 10°C. After the reaction solution was stirred for 30 minutes, cesium carbonate (586 mg, 1.80 mmol) and the above crude product 34d were added thereto, and the reaction solution was heated to 40° C. and continued to stir at this temperature for 16 hours. After the reaction was monitored by LCMS, water and ethyl acetate were added for extraction, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated to obtain the crude product 34e. ESI-MS (m/z): 409.3 [M+H] + .
  • Step 6 Trifluoroacetic acid (2 mL) was added dropwise to a solution of the above crude product 34e in dichloromethane (8 mL). After the reaction solution was stirred at room temperature for 1.5 hours, the reaction was monitored by LCMS to complete. The reaction solution was concentrated by distillation under reduced pressure, aqueous sodium hydroxide solution was added to pH 8, extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated to obtain the crude product 34f.
  • ESI-MS (m/z): 309.3 [M+H] + .
  • Step 7 Dissolve compound Int-1 (50mg, 0.22mmol) in n-butanol (2mL), add compound 34f (82mg, crude product) and p-toluenesulfonic acid monohydrate (8mg, 44umol), and the reaction solution is in Stir at 160°C for 3 hours under microwave conditions. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain 34 (20 mg, 4% yield in four steps) as a white solid.
  • Example 35 was prepared by the following steps:
  • Step 1 Dissolve compound 35a (300mg, 1.82mmol) in anhydrous tetrahydrofuran (5mL), under the protection of nitrogen, cool down to -78°C, and slowly add n-butyl lithium (1.19mL, 1.91mmol) dropwise. After 1 hour, dropwise addition of triisopropyl borate (0.63 mL, 2.73 mmol) was started, and the reaction was completed after 2 hours by LCMS monitoring. Water was slowly added dropwise to quench the reaction.
  • Step 3 Dissolve compound 35c (270mg, 0.95mmol) in methanol (30mL), add ammonia water (3.5mL) and Raney nickel (3.5mL, aqueous suspension) to the reaction system in turn, replace the hydrogen with a hydrogen balloon and The reaction was carried out under a hydrogen atmosphere at room temperature for 3 hours, and the reaction was monitored by LCMS to complete. The reaction solution was diluted with methanol, filtered with suction, and the filtrate was concentrated to obtain a brown oily liquid 35d (270 mg, yield 98%). ESI-MS (m/z): 271.5 [M+H] + .
  • Step 4 Dissolve compound 35d (82.36mg, 0.29mmol) in n-butanol (2mL), add compound Int-1 (50mg, 0.22mmol) and p-toluenesulfonic acid monohydrate (4.19mg, 22umol), The reaction solution was stirred at 160° C. for 3 hours under microwave conditions. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by reverse-phase preparative HPLC to obtain 35 (1.07 mg, yield 1%) as a white solid.
  • Example 36 was prepared by the following steps:
  • the second step compound 36b (300mg, 0.84mmol), cyclopropylboronic acid (108mg, 1.26mmol), palladium acetate (19mg, 84umol), tricyclohexylphosphine (47mg, 0.17mmol) and potassium phosphate (534mg, 2.52 mmol), water (2 mL) and toluene (10 mL) were added to a round bottom flask. After the reaction solution was stirred for 16 hours at 80° C. under nitrogen protection, the reaction was monitored by LCMS.
  • the third step the compound 36c (76mg, 0.28mmol) was dissolved in methanol (8mL), followed by reaction Ammonia water (0.8 mL) and Raney nickel (0.8 mL, aqueous suspension) were added to the system, hydrogen was replaced by a hydrogen balloon, and the reaction was carried out under hydrogen atmosphere at room temperature for 3 hours, and the reaction was completed by LCMS monitoring.
  • the reaction solution was diluted with methanol, filtered with suction, and the filtrate was concentrated to obtain a brown oily liquid 36d.
  • ESI-MS (m/z): 276.4 [M+H] + .
  • the fourth step the compound 36d (51mg) obtained in the previous step was dissolved in n-butanol (2mL), and compound Int-1 (45mg, 0.19mmol) and p-toluenesulfonic acid monohydrate (7mg, 37umol) were added to react The solution was stirred at 160° C. for 3 hours under microwave conditions. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by reverse-phase preparative HPLC to obtain 36 as a white solid (10 mg, two-step reaction yield 7%).
  • Comparative Example 1 was obtained by referring to the synthesis method of compound 136 described in patent WO2019209757.
  • ESI-MS (m/z): 447.2[M+H] + ;
  • Comparative Example 2 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, in the exponential growth phase of the cells, the method of transfection with lipo3000 liposomes was transfected with TCF/LEF transcription factors Driven luciferase reporter plasmid (Promega). The plasmid carries a resistance gene for resistance screening. Transfection was carried out in 10 cm culture dishes using conventional complete medium without resistance. After 2 days, the medium with resistance was replaced, and the culture was continued. After that, 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 an adaptive medium.
  • the cells When the cells covered the culture dish, the cells were digested, counted, and passaged in a 96-well plate, so that the average number of cells contained in each well was 1.5/well, and the adaptive medium was used for passage. The rest of the cells were frozen. After subculture, culture 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 were labeled as monoclonal wells. Afterwards, normal culture was performed, and the culture medium was replaced every 2 days, and observed. There are holes where the monoclonal cells continue to grow in the early stage, and they are labeled twice, and can be replaced with normal resistant medium.
  • a monoclonal well When a monoclonal well is overgrown with a 96-well plate, it is digested and passaged to a 24-well culture plate. After the 24-well plate is overgrown, it is passaged to a 96-well plate and a 6-well plate.
  • the cells in a 96-well plate are at least 6 wells, of which 3 wells were added with known Wnt inhibitors, and the other 3 wells were not treated. After 24 hours, the cells in the 96-well plate were added with a fluorescence detection reagent to detect the fluorescence intensity. Cell lines with fluorescent expression when not treated and decreased fluorescent light after inhibition were selected and further cultured.
  • Colo205-LUC-TCF/LEF-M1 cell line is one of the above screened cell lines, its growth curve, cell shape, and cell growth state are similar to those of the original Colo205 cells, and the fluorescence signals of inhibitor treatment and no treatment
  • the ratio is the largest among all cell lines, and the ratio can reach 4-5 times when inhibited at 4 hours, which is completely suitable for the screening of Wnt inhibitors in the later stage.
  • Test Example 2 Detection of compound's inhibitory ability on 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.
  • the ⁇ -catenin Wnt pathway is continuously activated. After adding the inhibitor, the Wnt pathway is inhibited.
  • the expression of firefly luciferase regulated by the TCF/LEF cis-element decreased, and after adding the detection substrate, the detected light signal decreased accordingly, so as to detect the inhibitory effect of the compound.
  • a 96-well cell culture plate To a 96-well cell culture plate, add 100uL of the compound with a maximum concentration of 20uM to each well, and make a 3-fold serial dilution of the compound concentration. Then inoculate 10,000 colo205 cells stably transfected with the reporter gene and 100uL medium into each well, and make corresponding positive and negative control wells at the same time. Put the cells in a 5% CO2 cell incubator, culture at 37°C for 4 hours, remove the culture medium after 4 hours, add 100uL of reagent (Promega) containing the corresponding firefly luciferase substrate to each well, and measure the luciferase reporter gene activity. Luminescence intensities were read with SpectraMax in full wavelength mode.
  • Test Example 3 Proliferation Inhibitory Test of Compounds on Wnt Mutant Cell Lines (Colo205, H929, HepG2 and DU4475) and Non-Wnt Mutant Cell Lines (RKO)
  • the cell lines used in the experiment are Colo205, H929, HepG2 and DU4475 cell lines whose Wnt pathway is continuously activated, and whose proliferation is Wnt pathway-dependent; while the Wnt pathway is not activated under normal circumstances, and the proliferation is independent of Wnt pathway RKO
  • the cell line is used as a control cell line, and it is judged that the inhibitory effect of the compound of the present invention on Wnt-dependent proliferation is not caused by other non-specific toxicity.
  • Colo205, H929, DU4475, HepG2, and RKO cell lines cultured in their respective culture media were treated during the logarithmic growth phase, and the cells were collected to prepare a uniform cell suspension of known concentration, and then transferred to a 96-well cell culture plate Add cell suspension to each well so that each well contains 1000-4000 cells. Put it into a 5% CO2 incubator and incubate at 37°C for 20-24h. On the second day, the fully dissolved, 3-fold serially diluted compound was added to each cell culture well, so that the final maximum concentration in the cell culture well was 10 uM, and the culture was continued for 96 hours. In this test, Promega's cell viability detection test is used for detection.
  • the detection instrument is SpectraMax, full wavelength mode.
  • the wells only added with DMSO were used as positive control wells, and the wells that were not inoculated with cells were used as negative control wells.
  • the IC50 values of each compound for the proliferation inhibition of Wnt sustained activation or proliferation-dependent cells, and for Wnt-inactive or proliferation-independent cells were calculated.
  • the IC50 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 (Table 2).
  • Test Example 4 The tumor growth inhibition test of Compound 1 on the Colo205 mouse Xenograft model
  • mice Female BALB/c Nude nude mice were subcutaneously inoculated with human colon cancer cell Colo205, and the Colo205 BALB/c Nude nude mouse xenograft model was established. After the tumor grew to an average tumor volume of about 80 mm3, the tumor-bearing mice were randomly divided into 3 groups according to the tumor volume: solvent treatment control group, 3 mg/kg compound 1 group and 10 mg/kg control group 1. Compound 1 and Control Example 1 were administered orally, once a day, and the administration cycle was 14 days. The tumor volume was measured every other day, and the body weight and tumor volume were measured on Day 14 (Table 3 and Figure 1).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Provided are a compound possessing the structure of formula (I) and having excellent Wnt pathway inhibitory activity, or a pharmaceutically acceptable salt, an isotope derivative, or a stereoisomer thereof. Further provided are a preparation method for the compound and a use thereof in the prevention and/or treatment of a cancer, a tumor, an inflammatory disease, an autoimmune disease, or an immune-mediated disease.

Description

一种Wnt通路抑制剂化合物A kind of Wnt pathway inhibitor compound
本申请要求于2022年01月29日提交到中国国家知识产权局、申请号为202210114025.9、发明名称为“一种Wnt通路抑制剂化合物”的中国专利申请的优先权，其全部内容均通过引用结合在本申请中。This application claims the priority of the Chinese patent application with the application number 202210114025.9 and the invention title "a Wnt pathway inhibitor compound" submitted to the State Intellectual Property Office of China on January 29, 2022, the entire contents of which are incorporated by reference in this application.
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 invention relates to a heterocyclic compound, in particular to a highly active Wnt pathway inhibitor and its application.
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。Wnt/β-catenin signal transduction pathway is a pathway conserved in biological evolution. In normal somatic cells, β-catenin is only a cytoskeleton protein that forms a complex with E-cadherin at the cell membrane to maintain the adhesion of the same type of cells 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, and GSK3β, thereby initiating the ubiquitin system to degrade β-catenin through the proteasome pathway, so that β-catenin in the cytoplasm was maintained at a low level. When cells are stimulated by Wnt signal, Wnt protein binds to the specific receptor Frizzled protein on the cell membrane, and the activated Frizzled receptor recruits intracellular Dishevelled protein, which inhibits the degradation activity of the β-catenin degradation complex formed by GSK3β and other proteins, stabilizing Free β-catenin protein in the cytoplasm. The stably accumulated β-catenin 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 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 Wnt classic signaling pathway and nuclear accumulation of β-catenin protein widely exist in colorectal cancer, and the proliferation of cancers such as colon cancer can be inhibited by inhibiting the activity of Wnt signaling pathway. APC mutations exist in more than 85% of colorectal cancers, and the mutated APC blocks the phosphorylation and degradation of β-catenin and induces the occurrence of colorectal cancer. In addition, mutations of Axin and β-catenin itself can also cause the 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 inhibition of the Wnt signaling pathway can be effective in preventing and/or treating cancer, tumors, inflammatory diseases, autoimmune diseases, and immune-mediated diseases, satisfactory effective Wnt pathway inhibition is currently lacking in the prior art agent compound. Therefore, it is a need in the prior art to study effective Wnt pathway inhibitor compounds.
发明内容Contents of the invention
本发明人经过研究，意外发现本发明的式(I)结构的化合物或其药学上可接受的盐、同位素衍生物、立体异构体是有效的Wnt通路抑制剂，具有优异的Wnt通路抑制活性。After research, the inventors unexpectedly found that the compound of the formula (I) structure of the present invention or its pharmaceutically acceptable salt, isotopic derivatives, and stereoisomers are effective Wnt pathway inhibitors, and have excellent Wnt pathway inhibitory activity.
基于上述发现，在一方面，本发明提供了一种具有式(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：
Based on the above findings, in one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof:
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、-(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；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 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 are connected to them The carbon atoms together 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, halo (C 1 -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, halo (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;
X表示CR4或者N；X means CR 4 or N;
R4各自独立地表示氢、卤素、氰基、(C1-C3)烷基、卤代(C1-C3)烷基；R 4 each independently represent hydrogen, halogen, cyano, (C 1 -C 3 ) alkyl, halo (C 1 -C 3 ) alkyl;
L表示-O-或者-(CRmRm’)-，其中，Rm、Rm’各自独立地表示氢、(C1-C3)烷基、(C3-C8)环烷基，或者Rm、Rm’与和其相连的碳原子形成3-5元环，该环可以包含0个或1个选自O和S的杂原子；L represents -O- or -(CR m R m ')-, wherein R m and R m ' each independently represent hydrogen, (C 1 -C 3 ) alkyl, (C 3 -C 8 ) cycloalkyl , or R m , R m 'and the carbon atom connected to it form a 3-5 membered ring, and the ring may contain 0 or 1 heteroatom selected from O and S;
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、S；Cy represents a 5-12 membered aromatic heterocycle, which optionally contains 1, 2, 3 or 4 heteroatoms, each of which is independently selected from N, O, S;
R5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；R 5 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 ;
R6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、(C3-C8)杂环烷基、卤代(C3-C8)杂环烷基、(C2-C6)炔基、卤代(C2-C6)炔基、-(C1-C6)亚烷基ORa、-卤代(C1-C6)亚烷基ORa、-(C3-C8)亚环烷基ORa、-卤代(C3-C8)亚环烷基ORa、-(C1-C6)亚烷基SRa、-卤代(C1-C6)亚烷基SRa、-(C3-C8)亚环烷基SRa、-卤代(C3-C8)亚环烷基SRa、-(C1-C6)亚烷基CN、-卤代(C1-C6)亚烷基CN、-(C3-C8)亚环烷基CN、-卤代(C3-C8)亚环烷基CN、-(C1-C6)亚烷基-NRaRa′、-卤代(C1-C6)亚烷基-NRaRa′、-(C3-C8)亚环烷基-NRaRa′、-卤代(C3-C8)亚环烷基-NRaRa′、-CN、-NO2、-ORa、-SRa、-NRaRa′，其中Ra、Ra’可以与它们相连的N原子一起形成3-8元环，所述环还任意可以有0、1或2个选自N、O、S的杂原子，所述环可以是单环、双环、桥环或者螺环；R 6 represents halogen, (C 1 -C 6 ) alkyl, halo (C 1 -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, halo (C 3 -C 8 ) cycloalkane radical, (C 3 -C 8 )heterocycloalkyl, halo(C 3 -C 8 )heterocycloalkyl, (C 2 -C 6 )alkynyl, halo(C 2 -C 6 )alkynyl, -(C 1 -C 6 )alkylene OR a , -halogenated (C 1 -C 6 )alkylene OR a , -(C 3 -C 8 )cycloalkylene OR a , -halogenated (C 3 -C 8 )cycloalkylene OR a , -(C 1 -C 6 )alkylene SR a , -halogenated (C 1 -C 6 )alkylene SR a , -(C 3 -C 8 ) Cycloalkylene SR a , -halogenated (C 3 -C 8 )cycloalkylene SR a , -(C 1 -C 6 )alkylene CN, -halogenated (C 1 -C 6 )alkylene CN, -(C 3 -C 8 )cycloalkylene CN, -halo(C 3 -C 8 )cycloalkylene CN, -(C 1 -C 6 )alkylene-NR a R a ′, -Halo(C 1 -C 6 )alkylene-NR a R a ′, -(C 3 -C 8 )cycloalkylene-NR a R a ′, -halo(C 3 -C 8 )alkylene Cycloalkyl-NR a R a ', -CN, -NO 2 , -OR a , -SR a , -NR a R a ', where R a and R a ' can form 3- 8-membered ring, the ring can optionally have 0, 1 or 2 heteroatoms selected from N, O, S, and the ring can be a monocyclic, bicyclic, bridged or spiro ring;
R7各自独立地表示氢、卤素、(C1-C3)烷基、卤代(C1-C3)烷基；R 7 each independently represent hydrogen, halogen, (C 1 -C 3 ) alkyl, halo (C 1 -C 3 ) alkyl;
m、n各自独立地表示0、1或2；m and n independently represent 0, 1 or 2;
Ra、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 and R a ' 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.
特别地，当R6连接于碳原子时，R6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、(C3-C8)杂环烷基、卤代(C3-C8)杂环烷基、(C2-C6)炔基、卤代(C2-C6)炔基、-(C1-C6)亚烷基ORa、-卤代(C1-C6)亚烷基ORa、-(C3-C8)亚环烷基ORa、-卤代(C3-C8)亚环烷基ORa、-(C1-C6)亚烷基SRa、-卤代(C1-C6)亚烷基SRa、-(C3-C8)亚环烷基SRa、-卤代(C3-C8)亚环烷基SRa、-(C1-C6)亚烷基CN、-卤代(C1-C6)亚烷基CN、-(C3-C8)亚环烷基CN、-卤代(C3-C8)亚环烷基CN、-(C1-C6)亚烷基-NRaRa′、-卤代(C1-C6)亚烷基-NRaRa′、-(C3-C8)亚环烷基-NRaRa′、-卤代(C3-C8)亚环烷基-NRaRa′、-CN、-NO2、-ORa、-SRa、-NRaRa′，其中Ra、Ra’可以与它们相连的N原子一起形成3-8元环，所述环还任意可以有0、1或2个选自N、O和S的杂原子，所述环可以是单环、双环、桥环或者螺环；In particular, when R 6 is attached to a carbon atom, R 6 represents halogen, (C 1 -C 6 ) alkyl, halo (C 1 -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, Halo(C 3 -C 8 )cycloalkyl, (C 3 -C 8 )heterocycloalkyl, halo(C 3 -C 8 )heterocycloalkyl, (C 2 -C 6 )alkynyl, halo Substituted (C 2 -C 6 )alkynyl, -(C 1 -C 6 )alkylene OR a , -halogenated (C 1 -C 6 )alkylene OR a , -(C 3 -C 8 )alkylene OR a , -(C 3 -C 8 )alkylene Cycloalkyl OR a , -Halo(C 3 -C 8 )cycloalkylene OR a , -(C 1 -C 6 )alkylene SR a , -Halo(C 1 -C 6 )alkylene SR a , -(C 3 -C 8 )cycloalkylene SR a , -halo(C 3 -C 8 )cycloalkylene SR a , -(C 1 -C 6 )alkylene CN, -halogen Substituted (C 1 -C 6 )alkylene CN, -(C 3 -C 8 )cycloalkylene CN, -halogenated (C 3 -C 8 )cycloalkylene CN, -(C 1 -C 6 ) alkylene-NR a R a ′, -halo(C 1 -C 6 ) alkylene-NR a R a ′, -(C 3 -C 8 )cycloalkylene-NR a R a ′, -Halo(C 3 -C 8 )cycloalkylene-NR a R a ', -CN, -NO 2 , -OR a , -SR a , -NR a R a ', wherein R a , R a ' It can form a 3-8 membered ring together with the N atoms connected to them, and the ring can also optionally have 0, 1 or 2 heteroatoms selected from N, O and S, and the ring can be a monocyclic ring, a bicyclic ring, a bridge Ring or Spiral;
当R6连接于N原子时，R6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、(C3-C8)杂环烷基、卤代(C3-C8)杂环烷基、(C2-C6)炔基、卤代(C2-C6)炔基、-(C1-C6)亚烷基ORa、-卤代(C1-C6)亚烷基ORa、-(C3-C8)亚环烷基ORa、-卤代(C3-C8)亚环烷基ORa、-(C1-C6)亚烷基SRa、-卤代(C1-C6)亚烷基SRa、-(C3-C8)亚环烷基SRa、-卤代(C3-C8)亚环烷基SRa。When R 6 is connected to the N atom, R 6 represents halogen, (C 1 -C 6 ) alkyl, halo (C 1 -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, halo ( C 3 -C 8 )cycloalkyl, (C 3 -C 8 )heterocycloalkyl, halo(C 3 -C 8 )heterocycloalkyl, (C 2 -C 6 )alkynyl, halo(C 2 -C 6 )alkynyl, -(C 1 -C 6 )alkylene OR a , -halo(C 1 -C 6 )alkylene OR a , -(C 3 -C 8 )cycloalkylene OR a , -halogenated (C 3 -C 8 )cycloalkylene OR a , -(C 1 -C 6 )alkylene SR a , -halogenated (C 1 -C 6 )alkylene SR a , -(C 3 -C 8 )cycloalkylene SR a , -halo(C 3 -C 8 )cycloalkylene SR a .
更优选地，R6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。More preferably, R 6 represents halogen, (C 1 -C 6 ) alkyl, halo (C 1 -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, halo (C 3 -C 8 ) cycloalkyl.
在本发明一个实施方案中，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、-(C1-C6)亚烷基ORa、-(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。In one embodiment of the present invention, R 1 and R 2 each independently represent hydrogen, (C 1 -C 6 ) alkyl, halogenated (C 1 -C 6 ) alkyl, (C 3 -C 8 ) cycloalkane group, halo(C 3 -C 8 )cycloalkyl, -(C 1 -C 6 )alkylene OR a , -(C 1 -C 6 )alkylene SR a ; or R 1 , R 2 and Together with the carbon atoms to which they are attached, they form a 3-8 membered ring which may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O and S.
在本发明一个实施方案中，R3为C1-C6)烷基或卤代(C1-C6)烷基。 In one embodiment of the present invention, R 3 is C 1 -C 6 )alkyl or halo(C 1 -C 6 )alkyl.
在本发明一个优选的实施方案中，R3为(C1-C6)烷基。In a preferred embodiment of the invention, R 3 is (C 1 -C 6 )alkyl.
在本发明一个实施方案中，Cy为5-6元单环芳杂环，或者Cy为9-10元双环芳杂环。In one embodiment of the present invention, Cy is a 5-6 membered monocyclic aromatic heterocycle, or Cy is a 9-10 membered bicyclic aromatic heterocycle.
在本发明一个实施方案中，Cy为吡啶基、嘧啶基、吡唑基、咪唑基或吡咯基。In one embodiment of the invention Cy is pyridyl, pyrimidinyl, pyrazolyl, imidazolyl or pyrrolyl.
在本发明一个实施方案中，R6与L连接于Cy的邻位。In one embodiment of the present invention, R6 and L are connected at the ortho position of Cy.
在本发明一个实施方案中，R5位于R6的间位，且位于L的间位或者对位。In one embodiment of the present invention, R 5 is located at the meta position of R 6 , and is located at the meta or para position of L.
在本发明一个优选实施方案中，X为CR4。In a preferred embodiment of the invention, X is CR 4 .
在本发明另一个优选实施方案中，R4为氢。In another preferred embodiment of the invention R4 is hydrogen.
在本发明一个实施方案中，Cy与R5、R6的连接如下：
In one embodiment of the present invention, the connection of Cy to R 5 and R 6 is as follows:
在本发明一个优选实施方案中，Cy与R5、R6的连接如下：
In a preferred embodiment of the present invention, the connection of Cy to R 5 and R 6 is as follows:
在本发明一个实施方案中，R6选自：
In one embodiment of the invention, R is selected from:
其任选地可以被0、1、2、3或者4个选自卤素、-CN、-ORa、-SRa和-NRaRa′的取代基取代。It may optionally be substituted with 0, 1 , 2, 3 or 4 substituents selected from halogen, -CN, -OR a , -SR a and -NR a R a '.
本发明还提供了一类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：







The present invention also provides a class of compounds or pharmaceutically acceptable salts, isotopic derivatives, and stereoisomers thereof, wherein the compounds have the following structure:







在另一个方面，本发明还提供了药物组合物，其包含前述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。In another aspect, the present invention also provides a pharmaceutical composition, which comprises the aforementioned compound or a pharmaceutically acceptable salt, isotope derivative, stereoisomer, and optionally a pharmaceutically acceptable carrier.
在另一个方面，本发明还提供了前述化合物或其药学上可接受的盐、同位素衍生物、立体异构体或前述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。In another aspect, the present invention also provides the aforementioned compounds or their pharmaceutically acceptable salts, isotope derivatives, stereoisomers, or the aforementioned pharmaceutical compositions used in the prevention and/or treatment of cancer, tumors, and inflammatory diseases , use in medicines for autoimmune diseases or immune-mediated diseases.
特别注意的是，在本文中，当提及式(I)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。It should be noted that in this article, when referring to the "compound" of the structure of formula (I), it generally also covers its stereoisomers, diastereoisomers, enantiomers, and racemic mixtures. and isotopic 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)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 a compound's salt, solvate, and hydrate are alternative forms of the compound, and they can all be converted into the compound under certain conditions. When referring to the compound of the formula (I), it generally includes its pharmaceutically acceptable salt, and further includes its solvate and hydrate.
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, when referring to a compound herein, its prodrugs, metabolites and nitroxides are also generally included.
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。The pharmaceutically acceptable salts of the present invention may be formed using, for example, the following inorganic or organic acids: "Pharmaceutically acceptable salt" means a salt which, within the scope of reasonable medical judgment, is suitable for use in contact with humans and lower other animals tissue, without undue toxicity, irritation, allergic reaction, etc., can be called a reasonable benefit/risk ratio. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or alone by reacting the free base or acid with a suitable reagent, as outlined below. For example, a free base function can be reacted with a suitable acid. Examples of pharmaceutically acceptable inorganic acid addition salts are amino acids with inorganic acids (e.g., hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric) or organic acids (e.g., acetic, oxalic, maleic, tartaric, lemon acid, succinic acid or malonic acid), or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, sodium alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, Camphorsulfonate, Citrate, Cyclopentanepropionate, Digluconate, Lauryl Sulfate, Ethylate, Formate, Fumarate, Glucoheptonate, Glycerin Phosphate, gluconate, hernisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate Salt, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectate Salt, persulfate, 3-phenylpropionate, phosphate, bitter salt, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluene Sulfonate, Undecanoate, Valerate, etc. Representative alkali or alkaline earth metal salts include those 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, for example, halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower Alkylsulfonates and arylsulfonates.
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 compound of the present invention in a water-miscible organic solvent (such as acetone, methanol, ethanol and acetonitrile), adding an excess of organic acid or inorganic Aqueous acid solution, so that the salt is precipitated 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 precursors or metabolites known in the art, as long as the precursors or metabolites are transformed 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 sound medical judgment, are suitable for use in contact with human and lower animal tissues without undue toxicity, irritation, allergic response, etc., Qualified as having a reasonable benefit/risk ratio and valid for its intended use. The term "prodrug" refers to a compound that is rapidly transformed in vivo to yield the parent compound of the above formula, for example by in vivo metabolism, 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 present invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In some cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, solvates will be able to be isolated. Solvent molecules in solvates 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 isolatable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. 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。"Stereoisomerism" described in the present invention is divided into conformational isomerism and configurational isomerism, and configurational isomerism can also be divided into cis-trans isomerism and optical isomerism (i.e. optical isomerism), conformational isomerism refers to having Due to the rotation or twisting of carbon and carbon single bonds in organic molecules of a certain configuration, a stereoisomerism phenomenon in which each atom or atomic group of the molecule has a different arrangement in space, the common structures are alkanes and cycloalkanes. Such as the chair conformation and boat conformation that appear in the structure of cyclohexane. "Stereoisomer" 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 can produce two optical isomers, and the scope of the present invention includes all possible optical isomers and diastereoisomer mixtures and pure or partially pure compounds . The compounds described herein may exist in tautomeric forms having different points of attachment of hydrogens by 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 present invention. Enantiomers, diastereoisomers, racemates, mesoforms, cis-trans isomers, tautomers, geometric isomers of all compounds of formula (I) to formula (III) Isomers, epimers and mixtures thereof are 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 an isotopically labeled molecule of a compound herein. Isotopes commonly used for isotope labeling 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 isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. Especially deuterium 3 H and carbon 13 C are more widely used because of their easy labeling and convenient detection. The substitution of some heavy isotopes, such as deuterium ( 2 H), can enhance the stability of metabolism, prolong the half-life and thus achieve the purpose of reducing the dose and provide therapeutic advantages. Isotopically labeled compounds generally start from labeled starting materials using known synthetic techniques such as the synthesis of non-isotopic Labeled compounds to complete their synthesis.
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 compound of the present invention in the preparation of medicaments for preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease.
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。In addition, the present invention provides a pharmaceutical composition for preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease, neurodegenerative disease, attention-related disease or immune-mediated disease, which comprises the present invention compounds as active ingredients. The pharmaceutical composition may optionally comprise 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、立体异构体或者本发明的药物组合物。In addition, the present invention provides a method of preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease, neurodegenerative disease, attention-related disease or immune-mediated disease, which includes the need for The mammal of the present invention is administered the compound of formula (I) or its pharmaceutically acceptable salt, isotope derivative, stereoisomer or the pharmaceutical composition of the present invention.
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, autoimmune, and immune-mediated diseases may include, but are not limited to, arthritis, rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, juvenile arthritis , Other Arthritis Conditions, Lupus, Systemic Lupus Erythematosus (SLE), Skin Related Disorders, Psoriasis, Eczema, Dermatitis, Atopic Dermatitis, Pain, Pulmonary 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, xenograft, idiopathic thrombocytopenic purpura (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 Lymphocytic Leukemia (ALL), Chronic Lymphocytic Leukemia (CLL), Acute Myelogenous Leukemia (AML), Chronic Myelogenous Leukemia (CML), Hairy Cell Leukemia, He Jie King's disease, non-Hodgkin's lymphoma, multiple myeloma, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (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 cancer or tumor 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 Carcinoma, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine body cancer, endometrium Carcinoma, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral neuroectodermal tumors , Hodgkin's Lymphoma, Non-Hodgkin's Lymphoma, Burkitt's 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, myoma, 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。When the compound of the present invention or a pharmaceutically acceptable salt thereof is administered in combination with another anticancer agent or immune checkpoint inhibitor for the treatment of cancer or tumors, the compound of the present invention or a pharmaceutically acceptable salt thereof can provide enhanced anticancer effects .
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、关法仑、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、曲关替尼、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 anticancer agents useful in the treatment of cancer or tumors may include, but are not limited to, inhibitors of cell signaling, chlorambucil, guanfalan, cyclophosphamide, ifosfamide, busulfan, carbamate, Mustin, lomustine, streptozotocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, 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, ixabepilone, tamoxifen, flutamide, gonadorelin analogs, methadone Progesterone, prednisone, dexamethasone, methylprednisolone, thalidomide, interferon alpha, leucovorin, sirolimus, sirolimus ester, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, britinib, cabozantinib, cediranib, crenolanib, kezhuotinib, dabrafenib, dabrafenib, Cotinib, danucitinib, dasatinib, dovitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib, iniparib, la Patinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motisanib, neratinib, nilotinib, niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib , regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib, saridegib, sorafenib, sunitinib, tiratinib, tivantinib, tivozanib, tofacitinib, Triguantinib, Vandetanib, Veliparib, Vemurafenib, vimodegib, volasertib, alemtuzumab, bevacizumab, berentuzumab vedotin, catumaxomab, cetuximab, denosumab, gemtuximab Zizumab, ipilimumab, nimotuzumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, PI3K inhibitors, CSF1R inhibitors A2A and/or A2B receptor antagonists, 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。Compounds of the present invention, or pharmaceutically acceptable salts thereof, 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、吡关莫司等)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 useful in the treatment of inflammatory, autoimmune, and immune-mediated diseases can include, but are not limited to, steroidal drugs (e.g., prednisone, prednisone, prednisone, methylphenidate, Cortisone, cortisone, hydroxycortisone, betamethasone, dexamethasone, etc.), methotrexate, leflunomide, anti-TNFα agents (eg, etanercept, infliximab, adalib monoclonal antibody, etc.), calcineurin inhibitors (eg, tacrolimus, piguanolimus, etc.), and antihistamines (eg, diphenhydramine, hydroxyzine, loratadine, ebazan Tin, ketotifen, cetirizine, levocetirizine, fexofenadine, etc.), and at least one or more therapeutic agents selected from them can 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 as an active ingredient. The dose of the active ingredient can be adjusted according to 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 the opinion of the physician. In some cases, amounts less than the above dosages may be appropriate. Amounts greater than the above doses may be used if no deleterious side effects are caused and such amounts may be administered in divided doses daily.
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化合物或药物组合物。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 comprises the following A compound of the invention or a compound or 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 dosage forms 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 carriers such as cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, stearic acid, Magnesium stearate, calcium stearate, gelatin, talc, surfactant, suspending agent, emulsifier and diluent.
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 employed in the pharmaceutical composition for injection administration of the present invention may be water, saline solution, glucose solution, glucose-like solution, alcohol, glycol, ether (for example, 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 the description of 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, using the methods described below as well as synthetic methods known in the art of synthetic organic chemistry or by variations thereof known to those skilled in the art Synthesis of compounds of the invention. Preferred methods include, but are not limited to, those described below. Reactions are performed in solvents or solvent mixtures appropriate to the kit materials used and to the transformations effected. Those skilled in the art of organic synthesis will appreciate that the functionality present on the molecule is consistent with the proposed transitions. 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为化合物1在人结肠癌细胞Colo205裸鼠异种移植瘤肿瘤体积的影响。Figure 1 shows the effect of compound 1 on the tumor volume of human colon cancer cell Colo205 xenograft tumor in nude mice.
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 stated, the terms used in the present application, including the specification and claims, are defined as follows. If not stated otherwise, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are used. In this application, the use of "or" or "and" means "and/or" if not 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 specification and claims, a given chemical formula or name shall encompass all stereoisomers and optical isomers thereof and racemates in which such isomers exist. Unless otherwise indicated, all chiral (enantiomers and diastereoisomers) 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 compounds, and all such stable isomers are encompassed by the present invention. The present invention describes cis- and trans- (or E- and Z-) geometric isomers of the compounds of the invention and which may be isolated as a mixture of isomers or as separated isomeric forms. The compounds of the invention may be isolated in optically active or racemic forms. Intermediates used in the preparation of the compounds of the present invention and prepared therein All methods of the subject are considered part of the present invention. When preparing enantiomeric or diastereomeric products, they may be separated by customary methods, for example by chromatography or fractional crystallization. Depending on the process conditions, the end products of the invention are obtained in free (neutral) or salt form. The free forms and salts of these end products are within the scope of the present invention. A compound can be converted from one form to another, if desired. A free base or acid can be converted into a salt; a salt can be converted into the free compound or another salt; a mixture of isomeric compounds of the invention can be separated into the individual isomers. The compounds of the invention, their free forms and salts, may exist in various tautomeric forms in which the hydrogen atoms are transposed to other parts of the molecule and thus 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 within 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 substituents in the present invention are independent and not interrelated, for example (listed but not exhaustive), in one aspect, for R a (or R a ') in the substituent, its are independent of each other in the definitions of the different substituents. Specifically, when one definition is selected for R a (or R a ') in one substituent, it does not mean that the R a (or R a ') has the same definition in other substituents. More specifically, for example (but not exhaustively) 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. In another aspect, when there is more than one R a (or R a ') in a certain substituent, these R a (or R a ') are also independently independent. For example, in the substituent -(CR a R a ')mO-(CR a R a ')n-, in the case where m+n is greater than or equal to 2, the m+n R a (or R a ' ) are independent, they may 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 noted as "optionally substituted", the substituent is selected from, for example, the following substituents, such as alkyl, cycloalkyl, aryl, heterocyclyl, halogen, hydroxy, Alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amino (wherein 2 amino substituents are selected from alkyl radical, aryl or arylalkyl), alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thio, alkylthio , arylthio, arylalkylthio, arylthiocarbonyl, arylalkylthiocarbonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, aminosulfonyl such as -SO 2 NH 2. Substituted sulfonylamino, nitro, cyano, carboxyl, carbamoyl such as -CONH 2 , substituted carbamoyl such as -CONHalkyl, -CONHaryl, -CONHarylalkyl or on nitrogen In the case of having two substituents selected from alkyl, aryl or arylalkyl, alkoxycarbonyl, aryl, substituted aryl, guanidino, heterocyclic group such as indolyl, imidazolyl, furan base, 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、1至4个、更优选具有1至3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 indicated 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, t-butyl), and Pentyl (eg n-pentyl, isopentyl, neopentyl). Herein, the alkyl group is preferably an alkyl group having 1 to 6, 1 to 4, more preferably 1 to 3 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。The term "alkenyl" denotes a straight or branched chain hydrocarbon group containing one or more double bonds and generally 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, eg vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.
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。The term "alkynyl" denotes a straight or branched chain hydrocarbon group containing one or more triple bonds and generally having a length of 2 to 20 carbon atoms. For example, " C2 - C6 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.
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" denotes an alkyl group as defined above having the indicated number of carbon atoms attached through a sulfur bridge; eg 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 (C=O) composed of two atoms, carbon and oxygen, joined by a double bond.
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 group having a total of 5 to 12 ring members Cyclic, bicyclic or tricyclic ring systems, 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 invention, "aryl" refers to an aromatic ring system which includes, but is not limited to, phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthalene 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. A fused aryl group can be attached to another group at a suitable position on the cycloalkyl ring or aromatic ring. Dashed lines drawn from ring systems indicate that bonds may 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，环烷基优选为具有3至8个、更优选具有3至6个碳原子的环烷基。The term "cycloalkyl" refers to a monocyclic or bicyclic cyclic alkyl group. Monocyclic cyclic alkyl refers to C3-C8 cyclic alkyl, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and norbornyl. Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included within the definition of "cycloalkyl". bicyclic cyclic alkyl group Cycloalkyl groups including bridged rings, spiro rings or fused rings. Herein, the cycloalkyl group is preferably a cycloalkyl group having 3 to 8, more preferably 3 to 6 carbon atoms.
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 within the definition of "cycloalkenyl". Bicyclic cyclic alkenyl groups include bridged, spiro, or fused 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”。类似地，“卤代环烷基”意欲包括具有指定碳原子数且取代有1个或多个卤素的支环烷基。"Halo" or "halogen" includes fluoro, chloro, bromo and iodo. "Haloalkyl" is intended to include branched and straight chain saturated aliphatic hydrocarbon groups having the indicated 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, heptafluoro Propyl and Heptachloropropyl. Examples of haloalkyl also include "fluoroalkyl" intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and substituted with 1 or more fluorine atoms. Similarly, "halocycloalkyl" is intended to include branched cycloalkyl groups having the indicated number of carbon atoms substituted with one or more halogens.
“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 indicated number of carbon atoms attached through an oxygen bridge. For example, "haloC 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" denotes a haloalkyl group as defined above having the indicated number of carbon atoms attached through a sulfur bridge; for example trifluoromethyl-S- and pentafluoroethyl -S-.
本文中所述-卤代(C1-C6)亚烷基ORa、-卤代(C1-C6)亚烷基SRa、-卤代(C1-C6)亚烷基NRaRa′、-卤代(C1-C6)亚烷基CN、-卤代(C3-C8)亚环烷基ORa、-卤代(C3-C8)亚环烷基SRa、-卤代(C3-C8)亚环烷基NRaRa′、-卤代(C3-C8)亚环烷基CN等意指被任意卤代的-(C1-C6)亚烷基ORa、-(C1-C6)亚烷基SRa、-(C1-C6)亚烷基NRaRa′、-(C1-C6)亚烷基CN、-(C3-C8)亚环烷基ORa、-(C3-C8)亚环烷基SRa、-(C3-C8)亚环烷基NRaRa′、-(C3-C8)亚环烷基CN。Described herein -halo(C 1 -C 6 )alkylene OR a , -halo(C 1 -C 6 )alkylene SR a , -halo(C 1 -C 6 )alkylene NR a R a ′, -Halo(C 1 -C 6 )alkylene CN, -Halo(C 3 -C 8 )cycloalkylene OR a , -Halo(C 3 -C 8 )cycloalkane The group SR a , -halogenated (C 3 -C 8 )cycloalkylene NR a R a ′, -halogenated (C 3 -C 8 )cycloalkylene CN, etc. mean any halogenated -(C 1 -C 6 )alkylene OR a , -(C 1 -C 6 )alkylene SR a , -(C 1 -C 6 )alkylene NR a R a ′, -(C 1 -C 6 ) Alkylene CN, -(C 3 -C 8 )cycloalkylene OR a , -(C 3 -C 8 )cycloalkylene SR a , -(C 3 -C 8 )cycloalkylene NR a R a ', -(C 3 -C 8 )cycloalkylene CN.
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 the present 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 groups may be from x 1 to x 2 . For example, 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 The group contains 3, 4, 5, 6, 7 or 8 carbon atoms, and 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 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, 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 "x 1 -x 2 -membered ring" is used when referring to cyclic groups (such as aryl, heteroaryl, cycloalkyl and heterocycloalkyl), which means that the group's The number of ring atoms may be x1 to x2 . For example, the 3-12 membered cyclic group may be a 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 membered ring, and the number of ring atoms may be 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; 3-6-membered ring means that the cyclic group can be 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 A 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 A 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; a 5-8-membered ring means that the cyclic group can be 5, 6, 7 or 8-membered ring, the number of ring atoms can be 5, 6, 7 or 8; 5-12 membered ring means that the ring group can be 5, 6, 7, 8, 9, 10, 11 or 12-membered ring, the number of ring atoms can be 5, 6, 7, 8, 9, 10, 11 or 12; 6-12 membered ring means that the ring group can be 6, 7, 8, 9, 10, 11- or 12-membered rings may have 6, 7, 8, 9, 10, 11 or 12 ring atoms. The ring atoms may be carbon atoms or heteroatoms, for example selected from N, O and S. When the ring is heterocyclic, the heterocyclic ring 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 the present disclosure, the one or more halogens may each be independently selected from fluorine, chlorine, bromine and iodine.
术语“杂芳基”意指稳定的指定数目的单环或多环含有杂原子的芳香基团，优选为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。本文中的杂芳基优选为5至12元杂芳基。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 specified number of stable monocyclic or polycyclic aromatic groups containing heteroatoms, preferably 3-membered, 4-membered, 5-membered, 6-membered, or 7-membered aromatic monocyclic or aromatic bicyclic Or 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered aromatic polycyclic heterocycles, which are fully unsaturated or partially unsaturated, and which 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, wherein any heterocycle defined above is fused to a benzene ring. The heteroaryl group herein is preferably a 5- to 12-membered heteroaryl group. Nitrogen and sulfur heteroatoms can be optionally oxidized. The nitrogen atom is substituted or unsubstituted (ie N or NR, where R is H or another substituent if defined). A heterocycle can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclyl groups described herein may be substituted on carbon or nitrogen atoms if the resulting compound is stable. The nitrogen in the heterocycle can 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 more than 1. When the term "heterocycle" is used, it is intended to include heteroaryl. Examples of heteroaryl groups include, but are not limited to, acridinyl, azetidinyl, aziocinyl, benzimidazolyl, benzofuryl, benzothiofuranyl, benzothienyl, benzooxa Azolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2, 3-b] Tetrahydrofuryl, furyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazopyridyl, indolenyl, indolinyl, Indolazinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuryl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoindolyl Quinolinyl, isothiazolyl, isothiazolopyridyl, 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, diazaphenyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl , phenothiazinyl, phenoxathiyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidinyl, 4-piperidinyl, piperonyl, pteridinyl, purinyl, Pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridyl, pyrazolyl, pyridazinyl, pyridoxazolyl, pyridimidazolyl, pyridothiazolyl, pyridyl , pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinazinyl, 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, thianthryl, thiazolyl, thienyl, thiazolopyridyl, thienothiazolyl, thienooxa Azolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4 - Triazolyl and xanthenyl, quinolinyl, isoquinolyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, indolinyl, 1H-indazolyl, benzo Imidazolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydro-quinolinyl, 2,3 - Dihydro-benzofuranyl, chromanyl, 1,2,3,4-tetrahydro-quinoxalinyl and 1,2,3,4-tetrahydro-quinazolinyl. The term "heteroaryl" may also include biaryl structures formed by the above-defined "aryl" and a monocyclic "heteroaryl", such as but not limited to "-phenylbipyridyl-", "- "Phenyl bipyrimidyl", "-pyridyl biphenyl", "-pyridyl bipyrimidyl-", "-pyrimidyl biphenyl-"; wherein the present invention also includes condensed rings containing, for example, the above-mentioned heterocycles and Spiro compound.
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。本发明中，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 a bicyclic heterocycloalkyl system, and also includes spiroheterocycle or bridged heterocycloalkyl. In the present invention, monocyclic heterocycloalkyl means It is a 3-8 membered, saturated or unsaturated but not aromatic cyclic alkyl system containing at least one heteroatom selected from O, N, S and P. The bicyclic heterocycloalkyl system refers to a heterocycloalkyl fused to a phenyl group, or a cycloalkyl group, or a cycloalkenyl group, or a heterocycloalkyl group, or a heteroaryl group formed 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. Can be divided into bicyclic bridged ring hydrocarbons and polycyclic bridged ring hydrocarbons. The former is composed of two alicyclic rings sharing more than two carbon atoms; the latter is a bridged ring 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 in which monocyclic rings share one carbon atom (called a spiro atom).
本文使用的术语“桥环杂基”指的是共用两个或两个以上原子的多环化合物，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 ring heterogroup" as used herein refers to a polycyclic compound sharing two or more atoms, and the ring contains at least one heteroatom selected from O, N and S atoms. It can be divided into bicyclic 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 a polycyclic hydrocarbon that shares one carbon atom (called a spiro atom) between monocyclic 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 valences are maintained and that the substitution results in a stable compound. A ring double bond, as used herein, 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。Where nitrogen atoms (e.g. amines) are present on compounds of the invention, these nitrogen atoms can be converted to N-oxides by treatment with oxidizing agents (e.g. mCPBA and/or hydrogen peroxide) to obtain other compounds of the invention . Accordingly, both shown and claimed nitrogen atoms are considered to cover both the shown nitrogen and its N-oxides to obtain the derivatives of the present 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 one time in any composition or formula of a compound, its definition on each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R, then said group may be optionally substituted with up to three R groups, and R at each occurrence is independently selected from the definition of R. Also, combinations of substituents and/or variables are permissible 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 being treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (eg, murine, ape, monkey, equine, bovine, porcine, canine, feline, 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 that will elicit, for example, the amount sought by a researcher or clinician. The amount of a drug or agent (ie, a compound of the invention) to which a tissue, system, animal or human is biologically or medically responsive. Furthermore, the term "therapeutically effective amount" means an amount which results in improved treatment, cure, prevention or alleviation of a disease, disorder or side effect, or a reduction in the or the rate of disease progression. An effective amount may be given in one or more administrations, applications or doses and is not intended to be limited by a particular formulation or route of administration. The term also includes within its scope amounts effective to enhance normal physiological function.
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。As used herein, the term "treating" includes any effect that results in amelioration of a condition, disease, disorder, etc., such as alleviation, reduction, regulation, amelioration or elimination, or amelioration of the 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: within the scope of sound medical judgment, they are suitable for use in contact with human and animal tissues without excessive toxicity, irritation sex, allergic reactions, and/or other problems or complications, commensurate with 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 involved in the carrying or transport of a subject compound from one organ or body part to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious 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 present invention together with at least one other pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" means 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, fragrances, 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Certain 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 ingredient or active ingredient does not have an undue adverse effect on health for the general purpose 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 cannot be controlled and, under certain conditions, is capable of metastasizing (spreading). Cancers of this type include, but are not limited to, solid tumors (eg, bladder, bowel, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (eg, thyroid), prostate , skin (melanoma), or blood cancer (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 "administration in combination" or similar terms, as used herein, refers to the administration of several selected therapeutic agents to a patient, in the same or different modes of administration 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 "enhancing" or "capable of enhancing", as used herein, means that the desired result can be enhanced in potency or sustained time has been increased or extended. Thus, in relation to enhancing the therapeutic effect of a drug, the term "capable of potentiating" refers to the ability of the drug to increase or prolong its potency or duration in the system. As used herein, "potency value" refers to the ability to maximize the enhancement of another therapeutic drug 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 of an adverse or deleterious reaction to an endogenous or exogenous antigen. The result is usually dysfunction of the cells, or destruction thereof and dysfunction, or destruction of 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, and pigs; domestic animals such as rabbits and dogs; experimental animals include rodents, Such as rats, mice and guinea pigs. Non-mammalian animals include, but are not limited to, birds, fish, and the like. 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 term "treatment", "course of treatment" or "therapy" as used herein includes alleviating, suppressing or ameliorating the symptoms or conditions of a disease; inhibiting the development of complications; ameliorating or preventing the underlying metabolic syndrome; inhibiting the development of diseases or symptoms, Such as controlling the development of a disease or condition; alleviating a disease or a symptom; causing a disease or a symptom to regress; alleviating a complication caused by a disease or a symptom, or preventing and/or treating a sign caused by a disease or a symptom.
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 certain compound or pharmaceutical composition, after administration, can improve a certain disease, symptom or situation, especially improve its severity, delay the onset, slow down the progression of the disease, or reduce the duration of the disease. Circumstances that may be attributable to or related to the administration, whether fixed or episodic, 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, ear canal , nasal administration and topical administration. In addition, by way of example only, parenteral administration includes intramuscular injection, subcutaneous injection, intravenous injection, intramedullary injection, intraventricular 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, the depot formulation is 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 such embodiments, the liposomes are selectively directed to and taken up by specific organs.
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 known products, which can be synthesized according to methods known in the art, or can be obtained by purchasing commercially available products. All commercially available reagents were used without further purification.
室温是指20-30℃。Room temperature means 20-30°C.
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 is no special description in the reaction examples, and the reactions are all carried out under a nitrogen atmosphere. The nitrogen atmosphere refers to a nitrogen balloon of about 1 L connected to the reaction flask.
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 vacuumized and filled with hydrogen, and the operation is repeated 3 times. The hydrogen atmosphere means that the reaction bottle is connected with a hydrogen balloon of about 1L.
微波反应使用Initiator+微波反应器。microwave reaction use 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 AscendTM500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。耦合常数以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 spectroscopy (MS). NMR shifts (δ) are given in units of 10 -6 (ppm). The determination of NMR is to use (Bruker Ascend TM 500 type) nuclear magnetic instrument, and measuring solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol ( CD3OD ), internal standard is Tetramethylsilane (TMS). The following abbreviations are used for the multiplicity of NMR signals: s = singlet, brs = broad, 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。The determination of LC-MS used Thermo liquid mass spectrometer (UltiMate 3000+MSQ PLUS). For HPLC measurement, a Thermo high pressure liquid chromatograph (UltiMate 3000) was used. Reverse-phase preparative chromatography Thermo (UltiMate 3000) reverse-phase preparative chromatography was used. Fast column chromatography uses Agel (FS-9200T) automatic column passing machine, and silica gel prepacked column uses Santai Prepacked columns. Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used for thin-layer chromatography silica gel plates, and the specifications used for thin-layer chromatography separation and purification products are 0.4mm to 0.5mm.
本发明中一些中间体的合成方法如下：The synthetic method of some intermediates in the present invention is as follows:
中间体1
Intermediate 1
中间体1由以下步骤制备：
Intermediate 1 was 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]+。The first step: the compound Int-1a (5.0g, 28.09mmol), Int-1b (5.61g, 36.51mmol) and sodium bicarbonate (7.08g, 84.26mmol) were dissolved 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, suction filtered, 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 was 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]+。The first step: sodium hydrogen (1.59g, 39.64mmol, content 60%) was added to a two-necked flask filled with anhydrous tetrahydrofuran (10mL), placed in an ice-water bath, compound Int-2a (5.0g, 26.43mmol) It was dissolved in anhydrous tetrahydrofuran (30 mL), and slowly added dropwise to the reaction solution. After 30 minutes, the dropwise addition of deuteroiodomethane (4.02 g, 27.75 mmol) was started, and after the dropwise addition was completed, the mixture was slowly raised to room temperature and stirred overnight. LCMS monitoring reaction results After finishing, cool to 0° C., slowly add saturated ammonium chloride aqueous solution dropwise to quench the reaction, extract with ethyl acetate, and dry the organic phase to obtain Int-2b (5.0 g, yield 91%) as a yellow oil. 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]+。The second step: Int-2b (5.0g, 24.24mmol) was dissolved in methanol (50mL), placed in an ice-water bath, slowly added dropwise thionyl chloride (8.65g, 72.73mmol), rose to room temperature, then raised to 60°C for overnight reaction. After the reaction was monitored by LCMS, the reaction solution was concentrated to obtain Int-2c (3.0 g, yield 79%) as a yellow oil. 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]+。The third step: the compound Int-1a (2.0g, 11.23mmol), Int-2c (3.17g, 20.22mmol) and sodium bicarbonate (2.83g, 33.70mmol) were dissolved 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, suction filtered, 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 was prepared by the following steps:
第一步：将化合物Int-3a(10.17g，55.26mmol)溶于乙醇(50mL)，在室温条 件下加入肼盐Int-3b(5.0g，46.05mmol)，反应回流过夜。LCMS监测反应结束后，减压蒸馏除去乙醇，再加入水和乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩有机相并通过硅胶柱层析(石油醚∶乙酸乙酯＝5∶1)纯化得到白色固体Int-3c(4.0g，收率45％)。ESI-MS(m/z)：193.2[M+H]+。The first step: the compound Int-3a (10.17g, 55.26mmol) was dissolved in ethanol (50mL), at room temperature Hydrazine salt Int-3b (5.0 g, 46.05 mmol) was added under conditions, and the reaction was refluxed overnight. After the LCMS monitoring reaction was completed, the ethanol was distilled off under reduced pressure, then water and ethyl acetate were added for extraction, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure and passed through silica gel column chromatography (petroleum ether) : ethyl acetate=5:1) to obtain Int-3c (4.0 g, yield 45%) as a white solid. ESI-MS (m/z): 193.2 [M+H] + .
第二步：将化合物Int-3c(1.0g，5.20mmol)，Int-3d(669mg，5.73mmol)和碳酸铯(2.55g，7.81mmol)加入到N，N-二甲基甲酰胺(10mL)中，在80℃下反应5小时，LCMS监测反应结束。减压蒸馏除去N，N-二甲基甲酰胺，再加入水和乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩有机相得到棕色固体Int-3e(1.1g，收率71％)。ESI-MS(m/z)：295.2[M+H]+。Second step: Compounds Int-3c (1.0 g, 5.20 mmol), Int-3d (669 mg, 5.73 mmol) and cesium carbonate (2.55 g, 7.81 mmol) were added to N,N-dimethylformamide (10 mL) , reacted at 80° C. for 5 hours, and monitored the completion of the reaction by LCMS. N,N-dimethylformamide was distilled off under reduced pressure, then added water and ethyl acetate for extraction, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain a brown solid Int-3e ( 1.1 g, yield 71%). ESI-MS (m/z): 295.2 [M+H] + .
第三步：将化合物Int-3e(1.1g，3.74mmol)溶于甲醇(10mL)，依次向反应体系加入氨水(1mL)和雷尼镍(3mL悬浮液)，通过氢气球置换氢气并在氢气氛围、室温条件下反应16小时，LCMS监测反应结束。反应液用甲醇稀释，抽滤，滤液浓缩后通过硅胶柱层析(二氯甲烷∶甲醇＝9∶1)纯化，得到棕色油状液体Int-3(700mg，收率62％)。ESI-MS(m/z)：299.3[M+H]+。The third step: Dissolve compound Int-3e (1.1g, 3.74mmol) in methanol (10mL), add ammonia water (1mL) and Raney nickel (3mL suspension) to the reaction system in turn, replace hydrogen by hydrogen balloon and The reaction was carried out under atmosphere and room temperature for 16 hours, and the reaction was monitored by LCMS to complete. The reaction solution was diluted with methanol, filtered with suction, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane:methanol=9:1) to obtain a brown oily liquid Int-3 (700 mg, yield 62%). ESI-MS (m/z): 299.3 [M+H] + .
中间体4
Intermediate 4
中间体4由以下步骤制备：
Intermediate 4 was prepared by the following steps:
第一步：将化合物Int-3a(1.0g，5.43mmol)溶于乙醇(20mL)，在室温条件下加入肼盐Int-4a(979mg，6.52mmol)，反应回流过夜。LCMS监测反应结束后，减压蒸馏除去乙醇，再加入水和乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩有机相并通过硅胶柱层析(石油醚∶乙酸乙酯＝5∶1)纯化得到白色固体Int-4b(909mg，收率93％)。ESI-MS(m/z)：181.4[M+H]+。Step 1: Compound Int-3a (1.0 g, 5.43 mmol) was dissolved in ethanol (20 mL), and hydrazine salt Int-4a (979 mg, 6.52 mmol) was added at room temperature, and the reaction was refluxed overnight. After the LCMS monitoring reaction was completed, the ethanol was distilled off under reduced pressure, then water and ethyl acetate were added for extraction, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure and passed through silica gel column chromatography (petroleum ether) :ethyl acetate=5:1) to obtain Int-4b (909 mg, yield 93%) as a white solid. ESI-MS (m/z): 181.4 [M+H] + .
第二步：将化合物Int-4b(606mg，3.36mmol)、Int-3d(411mg，3.36mmol)和碳酸铯(2.19g，6.73mmol)加入到N，N-二甲基甲酰胺(16mL)中，在80℃下反应5小时，LCMS监测反应结束。减压蒸馏除去N，N-二甲基甲酰胺，再加入水和乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩有机相得到棕色固体Int-4c(897mg，收率94％)。ESI-MS(m/z)：283.3[M+H]+。Second step: Compounds Int-4b (606mg, 3.36mmol), Int-3d (411mg, 3.36mmol) and cesium carbonate (2.19g, 6.73mmol) were added to N,N-dimethylformamide (16mL) , reacted at 80° C. for 5 hours, and monitored the completion of the reaction by LCMS. N,N-dimethylformamide was distilled off under reduced pressure, then added water and ethyl acetate for extraction, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain a brown solid Int-4c ( 897 mg, yield 94%). ESI-MS (m/z): 283.3 [M+H] + .
第三步：将化合物Int-4c(897mg，3.18mmol)溶于甲醇(30mL)，依次向反应体系加入氨水(3mL)和雷尼镍(3mL悬浮液)，通过氢气球置换氢气并在氢气氛围、室温条件下反应3小时，LCMS监测反应结束。反应液用甲醇稀释，抽滤，滤液浓缩后通过硅胶柱层析(二氯甲烷∶甲醇＝9∶1)纯化，得到棕色油状液体Int-4(412mg，收率45％)。ESI-MS(m/z)：328.3[M+CH3CN+H]+。The third step: Dissolve the compound Int-4c (897mg, 3.18mmol) in methanol (30mL), add ammonia water (3mL) and Raney nickel (3mL suspension) to the reaction system in turn, replace the hydrogen with a hydrogen balloon and in a hydrogen atmosphere 1. The reaction was carried out at room temperature for 3 hours, and the reaction was monitored by LCMS to complete. The reaction solution was diluted with methanol, filtered with suction, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane:methanol=9:1) to obtain a brown oily liquid Int-4 (412 mg, yield 45%). ESI-MS (m/z): 328.3 [M+CH 3 CN+H] + .
中间体5b
Intermediate 5b
中间体5b由以下步骤制备：
Intermediate 5b was prepared by the following steps:
第一步：第二步：将化合物Int-5a(3.0g，19.73mmol)、Int-3d(2.41g，19.73mmol)和碳酸铯(12.85g，39.45mmol)加入到乙腈(30mL)中，室温搅拌16小时，LCMS监测反应结束。减压蒸馏除去乙腈，残余物加入水和乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩。残余物通过硅胶柱层析(石油醚∶乙酸乙酯＝10∶1)纯化得到白色固体Int-5b(2.17g，收率43％)。ESI-MS(m/z)：255.2[M+H]+。The first step: the second step: the compound Int-5a (3.0g, 19.73mmol), Int-3d (2.41g, 19.73mmol) and cesium carbonate (12.85g, 39.45mmol) were added in acetonitrile (30mL), room temperature Stirred for 16 hours, LCMS monitored the completion of the reaction. Acetonitrile was distilled off under reduced pressure, and the residue was extracted by adding water and ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain Int-5b (2.17 g, yield 43%) as a white solid. ESI-MS (m/z): 255.2 [M+H] + .
中间体6
Intermediate 6
中间体6由以下步骤制备：
Intermediate 6 was prepared by the following steps:
第一步：将钠氢(153mg，4.0mmol，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-2a(500mg，2.09mmol)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(593mg，4.18mmol)，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固体Int-6b(500mg，收率94％)。ESI-MS(m/z)：252.2[M-H]-。The first step: sodium hydrogen (153mg, 4.0mmol, content 60%) was added to anhydrous tetrahydrofuran (5mL) In a two-necked flask placed in an ice-water bath, compound Int-2a (500 mg, 2.09 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and slowly added dropwise to the reaction solution. After 30 minutes, iodomethane (593 mg, 4.18 mmol) was added dropwise, and 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., slowly added dropwise saturated ammonium chloride aqueous solution to quench the reaction, extracted with ethyl acetate, and the organic phase was dried to obtain a yellow solid Int-6b (500 mg, yield 94%). ESI-MS (m/z): 252.2 [MH] - .
第二步：将Int-6b(500mg，1.97mmol)溶解在甲醇(50mL)中，置于冰水浴中，缓慢滴加氯化亚砜(704mg，5.92mmol)，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-6c(300mg，收率60％)。1H NMR(500MHz，DMSO-d6)δ10.45(br s，1H)，9.84(br s，1H)，6.55-6.26(m，1H)，4.25(dd，J＝7.8，4.9Hz，1H)，3.77(s，3H)，2.65-2.52(m，2H)。Step 2: Dissolve Int-6b (500mg, 1.97mmol) in methanol (50mL), place in an ice-water bath, slowly add thionyl chloride (704mg, 5.92mmol) dropwise, and rise to room temperature after the addition is complete, Then rise to 60°C and react overnight. After the reaction was monitored by LCMS, the reaction solution was concentrated to obtain Int-6c (300 mg, yield 60%) as a yellow oil. 1 H NMR (500MHz, DMSO-d6) δ10.45 (br s, 1H), 9.84 (br s, 1H), 6.55-6.26 (m, 1H), 4.25 (dd, J=7.8, 4.9Hz, 1H) , 3.77 (s, 3H), 2.65-2.52 (m, 2H).
第三步：将化合物Int-1a(250mg，1.40mmol)，Int-6c(343mg，1.69mmol)和碳酸氢钠(353mg，4.21mmol)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-6(170mg，收率43％)。ESI-MS(m/z)：277.2[M+H]+。The third step: the compound Int-1a (250mg, 1.40mmol), Int-6c (343mg, 1.69mmol) and sodium bicarbonate (353mg, 4.21mmol) were dissolved in ethanol (20mL) and water (2mL), the reaction solution Reflux overnight. After the reaction was monitored by LCMS, it was cooled to room temperature, filtered with suction, the filter cake was washed with water, and then dried to obtain an off-white solid Int-6 (170 mg, yield 43%). ESI-MS (m/z): 277.2 [M+H] + .
中间体7
Intermediate 7
中间体7由以下步骤制备：
Intermediate 7 was prepared by the following steps:
第一步：将化合物Int-5b(400mg，1.57mmol)和碳酸铯(1.03g，3.15mmol)加入到N，N-二甲基甲酰胺(8mL)中，随后向反应液滴加1，1-二氟-2-碘代乙烷(0.56mL，6.28mmol)。反应液在室温下搅拌24小时后，LCMS监测反应液中仅有少量原料剩余，加入水淬灭反应，乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩有机相得到Int-7a和Int-7a’的混合物。ESI-MS(m/z)：319.1[M+H]+。The first step: compound Int-5b (400mg, 1.57mmol) and cesium carbonate (1.03g, 3.15mmol) were added to N,N-dimethylformamide (8mL), then 1,1 - Difluoro-2-iodoethane (0.56 mL, 6.28 mmol). After the reaction solution was stirred at room temperature for 24 hours, LCMS monitored that only a small amount of raw materials remained in the reaction solution, adding water to quench the reaction, extracting with ethyl acetate, combining the organic phases and washing with saturated brine, drying over anhydrous sodium sulfate, and concentrating under reduced pressure The organic phase yielded a mixture of Int-7a and Int-7a'. ESI-MS (m/z): 319.1 [M+H] + .
第二步：将第一步的产物溶于甲醇(50mL)，依次向反应体系加入氨水(5mL)和雷尼镍悬浮液(5mL)，通过氢气球置换氢气并在氢气氛围、室温条件下反应2小时，LCMS监测反应结束。反应液用甲醇稀释，硅藻土过滤，滤液浓缩后通过硅胶柱层析(二氯甲烷∶甲醇＝20∶1)纯化，得到棕色油状液体Int-7(145mg，两步收率29％)。ESI-MS(m/z)：323.3[M+H]+。The second step: Dissolve the product of the first step in methanol (50mL), add ammonia water (5mL) and Raney nickel suspension (5mL) to the reaction system in turn, replace the hydrogen with a hydrogen balloon and react in a hydrogen atmosphere at room temperature After 2 hours, LCMS monitored the reaction to be complete. The reaction solution was diluted with methanol, filtered with celite, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain a brown oily liquid Int-7 (145mg, two-step yield 29%). ESI-MS (m/z): 323.3 [M+H] + .
中间体8
Intermediate 8
中间体8由以下步骤制备：
Intermediate 8 was prepared by the following steps:
第一步：将化合物Int-8a(2.0g，12.26mmol)，Na2CO3(2.6g，24.52mmol)加入到水(60mL)中，搅拌溶解，将碘单质(3.11g，12.26mmol)加入到反应液中，室温搅拌3小时。LCMS监测原料消失，用稀盐酸调反应液pH至5-6，乙酸乙酯萃取。合并有机相，无水硫酸钠干燥，过滤浓缩，残余物硅胶柱层析(乙酸乙酯/石油醚＝0-30％梯度洗脱)，得到白色固体Int-8b(1.5g，收率42％)。ESI-MS(m/z)：290.2[M+H]+。Step 1: Add compound Int-8a (2.0g, 12.26mmol), Na 2 CO 3 (2.6g, 24.52mmol) into water (60mL), stir to dissolve, add iodine (3.11g, 12.26mmol) into the reaction solution and stirred at room temperature for 3 hours. LCMS monitored the disappearance of the raw materials, adjusted the pH of the reaction solution to 5-6 with dilute hydrochloric acid, and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated by filtration, and the residue was subjected to silica gel column chromatography (ethyl acetate/petroleum ether=0-30% gradient elution) to obtain a white solid Int-8b (1.5 g, yield 42% ). ESI-MS (m/z): 290.2 [M+H] + .
第二步：将化合物Int-8b(0.5g，1.73mmol)，苄溴(337mg，1.98mmol)溶解于DMF(5mL)中，加入K2CO3(364mg，2.64mmol)，50℃搅拌2小时，LCMS监测翻译结束。反应液加水稀释，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤浓缩。残余物硅胶柱层析(乙酸乙酯/石油醚＝0-15％梯度洗脱)，得到白色固体Int-8c(0.5g，收率76％)。ESI-MS(m/z)：380.2[M+H]+。Step 2: Dissolve compound Int-8b (0.5g, 1.73mmol), benzyl bromide (337mg, 1.98mmol) in DMF (5mL), add K 2 CO 3 (364mg, 2.64mmol), and stir at 50°C for 2 hours , LCMS monitors the end of translation. The reaction solution was diluted with water, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate/petroleum ether=0-15% gradient elution) to obtain Int-8c (0.5 g, yield 76%) as a white solid. ESI-MS (m/z): 380.2 [M+H] + .
第三步：将化合物Int-8c(500mg，1.32mmol)，环丙基硼酸(566mg，6.59mmol)，三环己基膦(74mg，263umol)，醋酸钯(29mg，131umol)，磷酸钾(559mg，2.63mmol)加入到二氧六环(30mL)和水(3mL)，反应体系置换氮气后，在氮气氛保护下，90℃搅拌17小时。LCMS监测反应完全。反应液浓缩，残余物通过硅胶柱层析纯化(乙酸乙酯/石油醚＝0-15％梯度洗脱)，得到白色固体 Int-8d(250mg，收率64％)。ESI-MS(m/z)：294.3[M+H]+。The third step: compound Int-8c (500mg, 1.32mmol), cyclopropylboronic acid (566mg, 6.59mmol), tricyclohexylphosphine (74mg, 263umol), palladium acetate (29mg, 131umol), potassium phosphate (559mg, 2.63 mmol) was added to dioxane (30 mL) and water (3 mL), and the reaction system was replaced with nitrogen, then stirred at 90° C. for 17 hours under the protection of nitrogen atmosphere. LCMS monitored the reaction to be complete. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether=0-15% gradient elution) to obtain a white solid Int-8d (250 mg, yield 64%). ESI-MS (m/z): 294.3 [M+H] + .
第四步：将化合物Int-8d(250mg，0.85mmol)溶解于二氯甲烷(20mL)中，冷却至-78℃滴加BBr3(0.25mL)，反应液在-78℃保温搅拌1小时后加水淬灭，升至室温。乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤浓缩。残余物通过硅胶柱层析(乙酸乙酯/石油醚＝0-15％梯度洗脱)，得到白色固体Int-8e(172mg，收率100％)。ESI-MS(m/z)：204.5[M+H]+。Step 4: Dissolve compound Int-8d (250mg, 0.85mmol) in dichloromethane (20mL), cool to -78°C and add BBr 3 (0.25mL) dropwise, and the reaction solution is stirred at -78°C for 1 hour Add water to quench and warm to room temperature. Extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate. The residue was subjected to silica gel column chromatography (gradient elution of ethyl acetate/petroleum ether=0-15%) to obtain Int-8e (172 mg, yield 100%) as a white solid. ESI-MS (m/z): 204.5 [M+H] + .
第五步：将化合物Int-8e(172mg，0.85mmol)，Int-3d(144mg，1.18mmol)，Cs2CO3(0.64g，2.0mmol)加入到DMF(5mL)中，20℃搅拌17小时，LCMS监测反应完全。反应液加入到水(100mL)中，搅拌30分钟，抽滤得到黄色固体Int-8f(170mg，收率65％)。ESI-MS(m/z)：306.2[M+H]+。Step 5: Compounds Int-8e (172mg, 0.85mmol), Int-3d (144mg, 1.18mmol), Cs 2 CO 3 (0.64g, 2.0mmol) were added to DMF (5mL), stirred at 20°C for 17 hours , LCMS monitored the reaction to be complete. The reaction solution was added into water (100 mL), stirred for 30 minutes, and suction filtered to obtain a yellow solid Int-8f (170 mg, yield 65%). ESI-MS (m/z): 306.2 [M+H] + .
第六步：将化合物Int-8f(90mg，295umol)，雷尼镍(0.5mL，水混悬液)加入到甲醇(5mL)中，加入氨水(0.1ml)，反应体系置换氢气后在氢气氛围下室温搅拌2小时，LCMS监测反应完全。反应液用硅藻土抽滤，滤液浓缩得到黄色固体Int-8(85mg)，无需纯化直接用于下一步反应。ESI-MS(m/z)：310.3[M+H]+。Step 6: Add compound Int-8f (90mg, 295umol), Raney nickel (0.5mL, aqueous suspension) into methanol (5mL), add ammonia water (0.1ml), and replace the reaction system with hydrogen in a hydrogen atmosphere Stir at room temperature for 2 hours, and the reaction is complete as monitored by LCMS. The reaction solution was suction-filtered with celite, and the filtrate was concentrated to obtain a yellow solid Int-8 (85 mg), which was directly used in the next reaction without purification. ESI-MS (m/z): 310.3 [M+H] + .
中间体9
Intermediate 9
中间体9由以下步骤制备：
Intermediate 9 was prepared by the following steps:
第一步：将化合物Int-3a(1.84g，10mmol)溶于乙醇(20mL)，在室温条件下加入肼盐Int-9a(1.25g，10mmol)，反应回流过夜。LCMS监测反应结束后，减压蒸馏除去乙醇，再加入水和乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩有机相并通过硅胶柱层析(石油醚∶乙酸乙酯＝5∶1)纯化得到白色固体Int-9b(2.0g，收率97％)。ESI-MS(m/z)：209.4[M+H]+。Step 1: Compound Int-3a (1.84g, 10mmol) was dissolved in ethanol (20mL), hydrazine salt Int-9a (1.25g, 10mmol) was added at room temperature, and the reaction was refluxed overnight. After the LCMS monitoring reaction was completed, the ethanol was distilled off under reduced pressure, then water and ethyl acetate were added for extraction, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure and passed through silica gel column chromatography (petroleum ether) : ethyl acetate = 5: 1) to obtain a white solid Int-9b (2.0 g, yield 97%). ESI-MS (m/z): 209.4 [M+H] + .
第二步：将化合物Int-9b(2.0g，9.61mmol)和化合物Int-3d(1.17g，9.61mmol)溶于N，N-二甲基甲酰胺(10ml)中，加入碳酸铯(6.26g，19.21mmol)。反应在室温下搅拌4小时。LCMS监测反应结束。反应液加水稀释，得到的混悬液过滤，滤饼通过减压旋转蒸发仪干燥，得到棕色固体化合物Int-9c(1.78g，收率59％)。ESI-MS(m/z)：311.1[M+H]+。Second step: dissolve compound Int-9b (2.0g, 9.61mmol) and compound Int-3d (1.17g, 9.61mmol) in N,N-dimethylformamide (10ml), add cesium carbonate (6.26g , 19.21 mmol). The reaction was stirred at room temperature for 4 hours. LCMS monitored the completion of the reaction. The reaction solution was diluted with water, the resulting suspension was filtered, and the filter cake was dried by a vacuum rotary evaporator to obtain a brown solid compound Int-9c (1.78 g, yield 59%). ESI-MS (m/z): 311.1 [M+H] + .
第三步：将化合物Int-9c(1.78g，5.74mmol)溶于甲醇(20mL)和氨水(1mL)中，加入Raney Nickel(0.5mL，水混悬液)。反应体系置换氢气后在室温下搅拌12小时。反应液硅藻土过滤，滤液浓缩。残余物通过硅胶柱层析纯化(二氯甲烷/甲醇＝10/1)得到无色油状液体Int-9(1.3g，收率72％)。ESI-MS(m/z)：315.3[M+H]+。The third step: Compound Int-9c (1.78 g, 5.74 mmol) was dissolved in methanol (20 mL) and ammonia water (1 mL), and Raney Nickel (0.5 mL, aqueous suspension) was added. The reaction system was stirred at room temperature for 12 hours after hydrogen was replaced. The reaction solution was filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol=10/1) to obtain Int-9 (1.3 g, yield 72%) as a colorless oily liquid. ESI-MS (m/z): 315.3 [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：在氮气氛围下，将化合物Int-5b(500mg，1.97mmol)和碳酸铯(1.28g，3.93mmol)加入到N，N-二甲基甲酰胺(10mL)中，随后向反应液滴加2，2，2-三氟乙基三氟甲烷磺酸酯(0.58mL，3.93mmol)。反应液在室温下搅拌16小时后，LCMS监测反应结束，加入水淬灭反应，乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩有机相得到化合物Int-10a和Int-10a’的混合物。ESI-MS(m/z)：328.5[M+H]+。The first step: under a nitrogen atmosphere, compound Int-5b (500mg, 1.97mmol) and cesium carbonate (1.28g, 3.93mmol) were added to N,N-dimethylformamide (10mL), and then added to the reaction solution 2,2,2-Trifluoroethyl trifluoromethanesulfonate (0.58 mL, 3.93 mmol) was added dropwise. After the reaction solution was stirred at room temperature for 16 hours, LCMS monitored the completion of the reaction, adding water to quench the reaction, extracting with ethyl acetate, combining the organic phases and washing with saturated brine, drying over anhydrous sodium sulfate, and concentrating the organic phase under reduced pressure to obtain the compound Int- Mixture of 10a and Int-10a'. ESI-MS (m/z): 328.5 [M+H] + .
第二步：将第一步的产物溶于甲醇(60mL)，依次向反应体系加入氨水(6mL)和雷尼镍悬浮液(6mL)，通过氢气球置换氢气并在氢气氛围、室温条件下反应2小时，LCMS监测反应结束。反应液用甲醇稀释，硅藻土过滤，滤液浓缩后通过硅胶柱层析(二氯甲烷∶甲醇＝20∶1)纯化，得到棕色油状液体Int-10(287mg，两步收率43％)。ESI-MS(m/z)：382.3[M+CH3CN+H]+。The second step: Dissolve the product of the first step in methanol (60mL), add ammonia water (6mL) and Raney nickel suspension (6mL) to the reaction system in turn, replace the hydrogen with a hydrogen balloon and react in a hydrogen atmosphere at room temperature After 2 hours, LCMS monitored the reaction to be complete. The reaction solution was diluted with methanol, filtered through celite, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain a brown oily liquid Int-10 (287mg, two-step yield 43%). ESI-MS (m/z): 382.3 [M+CH 3 CN+H] + .
中间体11
Intermediate 11
中间体11由以下步骤制备：
Intermediate 11 was prepared by the following steps:
第一步：将化合物Int-5b(400mg，1.57mmol)和碳酸铯(1.03g，3.15mmol)加入到N，N-二甲基甲酰胺(8mL)中，随后向反应液滴加1-氟-2-碘乙烷(548mg，3.15mmol)。反应液在室温下搅拌16小时后，LCMS监测反应结束，加入水淬灭反应，乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩有机相得到化合物Int-11a和Int-11a’的混合物。ESI-MS(m/z)：301.2[M+H]+。The first step: compound Int-5b (400mg, 1.57mmol) and cesium carbonate (1.03g, 3.15mmol) were added to N,N-dimethylformamide (8mL), and then 1-fluoro - 2-iodoethane (548 mg, 3.15 mmol). After the reaction solution was stirred at room temperature for 16 hours, LCMS monitored the completion of the reaction, adding water to quench the reaction, extracting with ethyl acetate, combining the organic phases and washing with saturated brine, drying over anhydrous sodium sulfate, and concentrating the organic phase under reduced pressure to obtain the compound Int- Mixture of 11a and Int-11a'. ESI-MS (m/z): 301.2 [M+H] + .
第二步：将第一步的产物溶于甲醇(50mL)，依次向反应体系加入氨水(5mL)和雷尼镍悬浮液(5mL)，通过氢气球置换氢气并在氢气氛围、室温条件下反应2小时，LCMS监测反应结束。反应液用甲醇稀释，硅藻土过滤，滤液浓缩后通过硅胶柱层析(二氯甲烷∶甲醇＝20∶1)纯化，得到棕色油状液体Int-11(228mg，两步收率48％)。ESI-MS(m/z)：305.1[M+H]+。The second step: Dissolve the product of the first step in methanol (50mL), add ammonia water (5mL) and Raney nickel suspension (5mL) to the reaction system in turn, replace the hydrogen with a hydrogen balloon and react in a hydrogen atmosphere at room temperature After 2 hours, LCMS monitored the reaction to be complete. The reaction solution was diluted with methanol, filtered with celite, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain a brown oily liquid Int-11 (228mg, two-step yield 48%). ESI-MS (m/z): 305.1 [M+H] + .
中间体12
Intermediate 12
中间体12由以下步骤制备：
Intermediate 12 was prepared by the following steps:
第一步：将化合物Int-3d(120mg，0.1mmol)和化合物Int-12a(200mg，0.1mmol)溶于N，N-二甲基甲酰胺(5mL)中，加入碳酸铯(383mg，1.2mmol)。反应在室温下搅拌4小时。LCMS监测原料反应完全。反应液中加入水稀释，得到的混悬液过滤，滤饼减压干燥，得到白色固体Int-12b(265mg，收率88％)。ESI-MS(m/z)：307.1[M+H]+。The first step: Dissolve compound Int-3d (120mg, 0.1mmol) and compound Int-12a (200mg, 0.1mmol) in N,N-dimethylformamide (5mL), add cesium carbonate (383mg, 1.2mmol ). The reaction was stirred at room temperature for 4 hours. LCMS monitored the complete reaction of starting material. The reaction solution was diluted with water, the obtained suspension was filtered, and the filter cake was dried under reduced pressure to obtain a white solid Int-12b (265 mg, yield 88%). ESI-MS (m/z): 307.1 [M+H] + .
第二步：将化合物Int-12b(150mg，0.5mmol)和氟磺酰基二氟乙酸甲酯(189mg，0.1mmol)溶于N，N-二甲基甲酰胺(5mL)中，加入碘化亚铜(373mg，2mmol)。反应在130℃下搅拌13小时。LCMS监测原料反应完全。反应液通过硅藻土过滤，滤液减压浓缩，残余物通过硅胶柱层析纯化(石油醚/乙酸乙酯＝10/3)得到化合物Int-12c(140mg，收率96％)。ESI-MS(m/z)：296.1[M+H]+。The second step: the compound Int-12b (150mg, 0.5mmol) and methyl fluorosulfonyl difluoroacetate (189mg, 0.1mmol) were dissolved in N,N-dimethylformamide (5mL), and ethylene iodide was added Copper (373 mg, 2 mmol). The reaction was stirred at 130°C for 13 hours. LCMS monitored the complete reaction of starting material. The reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/3) to obtain compound Int-12c (140 mg, yield 96%). ESI-MS (m/z): 296.1 [M+H] + .
第三步：将化合物Int-12c(140mg，0.48mmol)溶于甲醇(9mL)和氨水(1mL)中，加入Raney Nickel(1mL，水混悬液)，反应体系置换氢气后在室温下搅拌12小时。反应液硅藻土过滤，滤液浓缩。残余物通过硅胶柱层析纯化(二氯甲烷/甲醇＝10/1)得到无色油状液体Int-12(80mg，收率57％)。ESI-MS(m/z)：300.2 [M+H]+。Step 3: Dissolve compound Int-12c (140mg, 0.48mmol) in methanol (9mL) and ammonia water (1mL), add Raney Nickel (1mL, aqueous suspension), and stir the reaction system at room temperature for 12 Hour. The reaction solution was filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol=10/1) to obtain Int-12 (80 mg, yield 57%) as a colorless oily liquid. ESI-MS (m/z): 300.2 [M+H] + .
中间体13
Intermediate 13
中间体13由以下步骤制备：
Intermediate 13 was prepared by the following steps:
第一步：将化合物Int-13a(700mg，3.54mmol)、Int-3d(433mg，3.54mmol)和碳酸铯(2.31g，7.09mmol)加入到N，N-二甲基甲酰胺(10mL)中，在50℃下反应16小时，LCMS监测反应结束。减压蒸馏除去N，N-二甲基甲酰胺，再加入水和乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩有机相得到白色固体Int-13b(711mg，收率67％)。The first step: compound Int-13a (700mg, 3.54mmol), Int-3d (433mg, 3.54mmol) and cesium carbonate (2.31g, 7.09mmol) were added in N,N-dimethylformamide (10mL) , reacted at 50° C. for 16 hours, and monitored the completion of the reaction by LCMS. N,N-dimethylformamide was distilled off under reduced pressure, then added with water and ethyl acetate for extraction, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain a white solid Int-13b ( 711 mg, yield 67%).
第二步：将化合物Int-13b(355mg，1.18mmol)溶于甲醇(35mL)，依次向反应体系加入氨水(3.5mL)()和雷尼镍(3.5mL悬浮液)，通过氢气球置换氢气并在氢气氛围、室温条件下反应3小时，LCMS监测反应结束。反应液用甲醇稀释，抽滤，滤液浓缩后通过硅胶柱层析(二氯甲烷∶甲醇＝9∶1)纯化，得到棕色油状液体Int-13(199mg，收率55％)。ESI-MS(m/z)：304.2[M+H]+。Step 2: Dissolve compound Int-13b (355mg, 1.18mmol) in methanol (35mL), add ammonia (3.5mL) () and Raney nickel (3.5mL suspension) to the reaction system in turn, and replace the hydrogen with a hydrogen balloon The reaction was carried out under hydrogen atmosphere and room temperature for 3 hours, and the reaction was monitored by LCMS. The reaction solution was diluted with methanol, filtered with suction, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane:methanol=9:1) to obtain brown oily liquid Int-13 (199 mg, yield 55%). ESI-MS (m/z): 304.2 [M+H] + .
中间体14
Intermediate 14
中间体14由以下步骤制备：
Intermediate 14 was prepared by the following steps:
第一步：将化合物Int-3a(450.22mg，2.45mmol)溶于乙醇(5mL)，在室温条件下加入肼盐Int-14a(200mg，2.04mmol)，反应回流过夜。LCMS监测反应结束后，减压蒸馏除去乙醇，再加入水和乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩有机相并通过硅胶柱层析(石油醚∶乙酸乙酯＝5∶1)纯化得到黄色色固体Int-14b(300mg，收率67％)。ESI-MS(m/z)：219.2[M+H]+。Step 1: Compound Int-3a (450.22 mg, 2.45 mmol) was dissolved in ethanol (5 mL), and hydrazine salt Int-14a (200 mg, 2.04 mmol) was added at room temperature, and the reaction was refluxed overnight. After the LCMS monitoring reaction was completed, the ethanol was distilled off under reduced pressure, then water and ethyl acetate were added for extraction, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure and passed through silica gel column chromatography (petroleum ether) : ethyl acetate=5:1) to obtain Int-14b (300 mg, yield 67%) as a yellow solid. ESI-MS (m/z): 219.2 [M+H] + .
第二步：将化合物Int-14b(300mg，1.38mmol)，Int-3d(184mg，1.51mmol)和碳酸铯(672mg，2.06mmol)加入到乙腈(5mL)中，在80℃下反应5小时，LCMS监测反应结束。减压蒸馏除去乙腈，再加入水和乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩有机相得到棕色固体Int-14c(250mg，收率56％)。ESI-MS(m/z)：321.2[M+H]+。The second step: compound Int-14b (300mg, 1.38mmol), Int-3d (184mg, 1.51mmol) and cesium carbonate (672mg, 2.06mmol) were added in acetonitrile (5mL), reacted at 80°C for 5 hours, LCMS monitored the completion of the reaction. Acetonitrile was distilled off under reduced pressure, and water and ethyl acetate were added for extraction. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a brown solid Int-14c (250 mg, yield 56%). ESI-MS (m/z): 321.2 [M+H] + .
第三步：将化合物Int-14c(250mg，0.78mmol)溶于甲醇(5mL)，依次向反应体系加入氨水(1mL)和雷尼镍(3mL悬浮液)，通过氢气球置换氢气并在氢气氛围、室温条件下反应16小时，LCMS监测反应结束。反应液用甲醇稀释，抽 滤，滤液浓缩后通过硅胶柱层析(二氯甲烷∶甲醇＝9∶1)纯化，得到棕色油状液体Int-14(150mg，收率59％)。ESI-MS(m/z)：325.3[M+H]+。The third step: Dissolve the compound Int-14c (250mg, 0.78mmol) in methanol (5mL), add ammonia water (1mL) and Raney nickel (3mL suspension) to the reaction system in turn, replace the hydrogen with a hydrogen balloon and in a hydrogen atmosphere 1. The reaction was carried out at room temperature for 16 hours, and the reaction was monitored by LCMS. The reaction solution was diluted with methanol, After filtration, the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane:methanol=9:1) to obtain brown oily liquid Int-14 (150 mg, yield 59%). ESI-MS (m/z): 325.3 [M+H] + .
中间体15
Intermediate 15
中间体15由以下步骤制备：
Intermediate 15 was prepared by the following steps:
第一步：将化合物Int-15a(500mg，4.23mmol)、N-溴代丁二酰亚胺(829mg，4.66mmol)和偶氮二异丁腈(209mg，1.27mmol)加入到1，2-二氯乙烷(10mL)中。反应在氮气氛围、85℃条件下搅拌16小时。反应结束后，减压蒸馏除去溶剂，残余物通过硅胶柱层析(石油醚∶乙酸乙酯＝5∶1)纯化，得到黄色油状液体Int-15b(244mg，收率29％)。The first step: compound Int-15a (500mg, 4.23mmol), N-bromosuccinimide (829mg, 4.66mmol) and azobisisobutyronitrile (209mg, 1.27mmol) were added to 1,2- in dichloroethane (10 mL). The reaction was stirred under nitrogen atmosphere at 85°C for 16 hours. After the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain Int-15b (244 mg, yield 29%) as a yellow oily liquid.
第二步：将化合物Int-15c(200mg，0.98mmol)，Int-15b(290mg，1.47mmol)和碳酸铯(639mg，1.96mmol)加入到N，N-二甲基甲酰胺(6mL)中。反应液在室温条件下搅拌16小时。LCMS监测反应结束后，加入水淬灭反应，乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩有机相并通过硅胶柱层析(石油醚∶乙酸乙酯＝5∶1)纯化得到白色固体Int-15d(213mg，收率68％)。 Second step: Compounds Int-15c (200 mg, 0.98 mmol), Int-15b (290 mg, 1.47 mmol) and cesium carbonate (639 mg, 1.96 mmol) were added into N,N-dimethylformamide (6 mL). The reaction solution was stirred at room temperature for 16 hours. After the reaction was monitored by LCMS, water was added to quench the reaction, extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure and passed through silica gel column chromatography (petroleum ether: ethyl acetate =5:1) to obtain white solid Int-15d (213 mg, yield 68%).
第三步：将化合物Int-15d(213mg，0.67mmol)溶于甲醇(22mL)，依次向反应体系加入氨水(2.2mL)和雷尼镍(2.2mL，水混悬液)，通过氢气球置换氢气并在氢气氛围、室温条件下反应16小时，LCMS监测反应结束。反应液用甲醇稀释，抽滤，滤液浓缩后得到粗产品Int-15。ESI-MS(m/z)：325.2[M+H]+。Step 3: Dissolve compound Int-15d (213mg, 0.67mmol) in methanol (22mL), add ammonia water (2.2mL) and Raney nickel (2.2mL, aqueous suspension) to the reaction system in turn, and replace by hydrogen balloon Hydrogen was reacted for 16 hours under a hydrogen atmosphere at room temperature, and the reaction was completed by LCMS monitoring. The reaction solution was diluted with methanol, filtered with suction, and the filtrate was concentrated to obtain the crude product Int-15. ESI-MS (m/z): 325.2 [M+H] + .
中间体16
Intermediate 16
中间体16由以下步骤制备：
Intermediate 16 was prepared by the following steps:
第一步：依次将化合物Int-16a(1.00g，11.89mmol)、Int-16b(3.38g，23.78mmol)和乙醇钠(1.62g，23.78mmol)加入到二甲基亚砜(10mL)中。反应液在60℃条件下搅拌16小时。反应结束后，加入6N盐酸淬灭反应，乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩有机相得到粗产品Int-16c。 Step 1: Compounds Int-16a (1.00 g, 11.89 mmol), Int-16b (3.38 g, 23.78 mmol) and sodium ethoxide (1.62 g, 23.78 mmol) were sequentially added to dimethyl sulfoxide (10 mL). The reaction solution was stirred at 60° C. for 16 hours. After the reaction was completed, 6N hydrochloric acid was added to quench the reaction, extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain the crude product Int-16c.
第二步：将化合物Int-16c(1.94g)、水合肼(673mg，10.75mmol，80％)和乙酸(5mL)加入到甲醇(35mL)中，反应液在氮气氛围条件下回流16小时。LCMS监测反应结束后，减压蒸馏除去溶剂，随后加入水稀释并加入碳酸钠(固体)至pH为9，乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩有机相得到棕色固体Int-16d(1.73g，两步收率82％)。ESI-MS(m/z)：177.5[M+H]+。Step 2: Compound Int-16c (1.94g), hydrazine hydrate (673mg, 10.75mmol, 80%) and acetic acid (5mL) were added to methanol (35mL), and the reaction solution was refluxed under nitrogen atmosphere for 16 hours. After the reaction was monitored by LCMS, the solvent was distilled off under reduced pressure, then diluted with water and sodium carbonate (solid) was added to pH 9, extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and reduced pressure Concentration of the organic phase afforded Int-16d as a brown solid (1.73 g, 82% for two steps). ESI-MS (m/z): 177.5 [M+H] + .
第三步：将化合物Int-16d(200mg，1.14mmol)，Int-15b(336mg，1.70mmol)和碳酸钾(314mg，2.27mmol)加入到乙腈(10mL)中。反应液在80℃下搅拌16小时。LCMS监测反应结束后，加入水淬灭反应，乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩有机相并通过硅胶柱层析(石油醚∶乙酸乙酯＝5∶1)纯化得到油状液体Int-16e(250mg，收率75％)和油状液体Int-16e’(80mg，收率24％)。ESI-MS(m/z)：293.2[M+H]+。The third step: Compounds Int-16d (200 mg, 1.14 mmol), Int-15b (336 mg, 1.70 mmol) and potassium carbonate (314 mg, 2.27 mmol) were added into acetonitrile (10 mL). The reaction solution was stirred at 80°C for 16 hours. After the reaction was monitored by LCMS, water was added to quench the reaction, extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure and passed through silica gel column chromatography (petroleum ether: ethyl acetate =5:1) Purification gave oily liquid Int-16e (250 mg, yield 75%) and oily liquid Int-16e' (80 mg, yield 24%). ESI-MS (m/z): 293.2 [M+H] + .
第四步：将化合物Int-16e(228mg，0.78mmol)溶于甲醇(23mL)，依次向反应体系加入氨水(2.3mL)和雷尼镍(2.3mL，水混悬液)，通过氢气球置换氢气并在氢气氛围、室温条件下反应3小时，LCMS监测反应结束。反应液用甲醇稀释，抽滤，滤液浓缩后得到粗产品Int-16。ESI-MS(m/z)：297.3[M+H]+。Step 4: Dissolve compound Int-16e (228mg, 0.78mmol) in methanol (23mL), add ammonia water (2.3mL) and Raney nickel (2.3mL, aqueous suspension) to the reaction system in turn, and replace by hydrogen balloon hydrogen and reacted for 3 hours under a hydrogen atmosphere at room temperature, and LCMS monitored the completion of the reaction. The reaction solution was diluted with methanol, filtered with suction, and the filtrate was concentrated to obtain the crude product Int-16. ESI-MS (m/z): 297.3 [M+H] + .
中间体17
Intermediate 17
中间体17由以下步骤制备：
Intermediate 17 was prepared by the following steps:
第一步：将化合物Int-16e’(80mg，0.27mmol)溶于甲醇(8mL)，依次向反应体系加入氨水(0.8mL)和雷尼镍(0.8mL，水混悬液)，通过氢气球置换氢气并在氢气氛围、室温条件下反应3小时，LCMS监测反应结束。反应液用甲醇稀释，抽滤，滤液浓缩后得到粗产品Int-17。ESI-MS(m/z)：297.2[M+H]+。Step 1: Dissolve compound Int-16e' (80mg, 0.27mmol) in methanol (8mL), add ammonia (0.8mL) and Raney nickel (0.8mL, aqueous suspension) to the reaction system in turn, and pass through a hydrogen balloon The hydrogen gas was replaced and reacted for 3 hours under a hydrogen atmosphere at room temperature, and the reaction was completed by LCMS monitoring. The reaction solution was diluted with methanol, filtered with suction, and the filtrate was concentrated to obtain the crude product Int-17. ESI-MS (m/z): 297.2 [M+H] + .
中间体18
Intermediate 18
中间体18由以下步骤制备：
Intermediate 18 was prepared by the following steps:
第一步：将化合物Int-18a(2.03g，10mmol)溶于无水二甲基亚砜(10mL)中，加入氢氧化钾(1.68g，30mmol)和氘代碘甲烷(2.17g，15mmol)。反应液在室温下搅拌12小时。LCMS检测反应结束。反应液加水淬灭，二氯甲烷萃取，合并有机相并用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩得到化合物Int-18b(2.3g)的粗品。ESI-MS(m/z)：238.3[M+H]+。The first step: Dissolve compound Int-18a (2.03g, 10mmol) in anhydrous dimethyl sulfoxide (10mL), add potassium hydroxide (1.68g, 30mmol) and deuteroiodomethane (2.17g, 15mmol) . The reaction was stirred at room temperature for 12 hours. LCMS detects that the reaction is complete. The reaction solution was quenched with water, extracted with dichloromethane, the combined organic phases were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product of compound Int-18b (2.3 g). ESI-MS (m/z): 238.3 [M+H] + .
第二步：将化合物Int-18b(2.3g，10mmol)溶于盐酸二氧六环溶液(5mL，4M)中。反应液在室温下搅拌1小时。LCMS检测反应结束。反应液浓缩，残余物用饱和碳酸氢钠水溶液调节pH至弱碱性，二氯甲烷萃取，合并有机相并用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩得到化合物Int-18c(1.3g)的粗品。 Second step: compound Int-18b (2.3 g, 10 mmol) was dissolved in dioxane hydrochloride solution (5 mL, 4M). The reaction was stirred at room temperature for 1 hour. LCMS detects that the reaction is complete. The reaction solution was concentrated, the residue was adjusted to weakly alkaline with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, the organic phases were combined and washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound Int-18c ( 1.3 g) of crude product.
第三步：将化合物Int-18c(450mg，3mmol)和Int-18d(539mg，3mmol)溶于四氢呋喃(3mL)中，加入N，N-二异丙基乙胺(1g，7.78mmol)。反应液在室温下搅拌4小时。LCMS检测反应结束。反应液加水淬灭，乙酸乙酯萃取，合并有机相并用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，浓缩，残余液用硅胶柱层析(石油醚/乙酸乙酯＝10/1)纯化得到化合物Int-18e(459mg，收率58％)。ESI-MS(m/z)：309.3[M+H]+。Step 3: Compounds Int-18c (450 mg, 3 mmol) and Int-18d (539 mg, 3 mmol) were dissolved in tetrahydrofuran (3 mL), and N,N-diisopropylethylamine (1 g, 7.78 mmol) was added. The reaction was stirred at room temperature for 4 hours. LCMS detects that the reaction is complete. The reaction solution was quenched with water, extracted with ethyl acetate, the organic phases were combined and washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) Compound Int-18e (459 mg, yield 58%) was obtained. ESI-MS (m/z): 309.3 [M+H] + .
第四步：将化合物Int-18e(400mg，1.30mmol)溶于甲醇(5mL)中，加入碳酸钾(269mg，1.94mmol)，随后加入连二亚硫酸钠(677mg，3.89mmol)。反应液在室温下搅拌30分钟。随后加入盐酸水溶液(2mL，4M)。反应液在室温下继续搅拌8小时。LCMS检测反应结束。反应液用氨甲醇溶液调节pH至9，加水稀释，二氯甲烷萃取，合并有机相并用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，残余液用硅胶柱层析(二氯甲烷/甲醇＝20/1)纯化得到化合物Int-18(230mg，收率60％)。ESI-MS(m/z)：244.4[M+H]+。Step 4: Compound Int-18e (400 mg, 1.30 mmol) was dissolved in methanol (5 mL), potassium carbonate (269 mg, 1.94 mmol) was added, followed by sodium dithionite (677 mg, 3.89 mmol). The reaction was stirred at room temperature for 30 minutes. Aqueous hydrochloric acid (2 mL, 4M) was then added. The reaction was stirred at room temperature for 8 hours. LCMS detects that the reaction is complete. The reaction solution was adjusted to pH 9 with ammonia methanol solution, diluted with water, extracted with dichloromethane, the organic phases were combined and washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane Methane/methanol=20/1) was purified to obtain compound Int-18 (230 mg, yield 60%). ESI-MS (m/z): 244.4 [M+H] + .
本发明中实施例化合物的合成方法如下：The synthetic method of embodiment compound among the present invention is as follows:
实施例1Example 1
(S)-2-(((6-((1-环丙基-3-(三氟甲基)-1H-吡唑-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-((1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxo)pyridin-3-yl)methyl)amino )-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one
实施例1由以下步骤制备：
Embodiment 1 is prepared by the following steps:
第一步：将化合物Int-1(1.0g，4.41mmol)和化合物Int-3(1.71g，5.74mmol)溶于正丁醇(6mL)中，加入对甲苯磺酸一水合物(83mg，0.44mmol)，反应液 在微波条件下，160℃搅拌4小时。待反应液冷却至室温，反应液减压浓缩，残余物直接用反向制备HPLC纯化得到白色固体1(987mg，收率45％)。ESI-MS(m/z)：489.2[M+H]+；1H NMR(500MHz，DMSO-d6)δ9.83(s，1H)，8.16(d，J＝2.4Hz，1H)，7.91(dd，J＝8.5，2.4Hz，1H)，7.20(d，J＝8.4Hz，1H)，6.99(t，J＝6.2Hz，1H)，6.53(s，1H)，4.37(qt，J＝11.5，6.4Hz，2H)，3.99(q，J＝6.8Hz，1H)，3.50-3.41(m，1H)，2.91(s，3H)，2.12(s，3H)，1.18(d，J＝6.8Hz，3H)，1.03(dt，J＝7.5，4.6Hz，2H)，0.92(dt，J＝7.3，3.8Hz，2H)。The first step: Dissolve compound Int-1 (1.0g, 4.41mmol) and compound Int-3 (1.71g, 5.74mmol) in n-butanol (6mL), add p-toluenesulfonic acid monohydrate (83mg, 0.44 mmol), reaction solution Stir at 160° C. for 4 hours under microwave conditions. After the reaction liquid was cooled to room temperature, the reaction liquid was concentrated under reduced pressure, and the residue was directly purified by reverse preparative HPLC to obtain white solid 1 (987 mg, yield 45%). ESI-MS (m/z): 489.2[M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.83 (s, 1H), 8.16 (d, J=2.4Hz, 1H), 7.91 ( dd, J=8.5, 2.4Hz, 1H), 7.20(d, J=8.4Hz, 1H), 6.99(t, J=6.2Hz, 1H), 6.53(s, 1H), 4.37(qt, J=11.5 , 6.4Hz, 2H), 3.99(q, J=6.8Hz, 1H), 3.50-3.41(m, 1H), 2.91(s, 3H), 2.12(s, 3H), 1.18(d, J=6.8Hz , 3H), 1.03 (dt, J=7.5, 4.6Hz, 2H), 0.92 (dt, J=7.3, 3.8Hz, 2H).
实施例2Example 2
(S)-2-(((6-((1-环丙基-3-(三氟甲基)-1H-吡唑-5-基)氧代)吡啶-3-基)甲基)氨基)-4，7-二甲基-8-(甲基-d3)-7，8-二氢蝶啶-6(5H)-酮
(S)-2-(((6-((1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxo)pyridin-3-yl)methyl)amino )-4,7-dimethyl-8-(methyl-d3)-7,8-dihydropteridin-6(5H)-one
实施例2由以下步骤制备：
Embodiment 2 is prepared by the following steps:
第一步：将化合物Int-2(50mg，0.22mmol)和化合物Int-3(84mg，0.28mmol)溶于正丁醇(2mL)中，加入对甲苯磺酸一水合物(4mg，0.02mmol)，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，残余物用反向制备HPLC纯化得到白色固体2(36mg，收率34％)。ESI-MS(m/z)：492.2[M+H]+；1H NMR(500MHz，DMSO-d6)δ9.86(s，1H)，8.16(d，J＝2.3Hz，1H)，7.91(dd，J＝8.4，2.4Hz，1H)，7.21(d，J＝8.4Hz，1H)，7.03(t，J＝6.0Hz，1H)，6.55(s，1H)，4.46-4.29(m，2H)，3.99(q，J＝6.8Hz，1H)，3.46(tt，J＝7.4，3.8Hz，1H)， 2.11(s，3H)，1.17(d，J＝6.8Hz，3H)，1.02(p，J＝4.7，4.2Hz，2H)，0.92(dt，J＝7.2，3.5Hz，2H)。The first step: Dissolve compound Int-2 (50mg, 0.22mmol) and compound Int-3 (84mg, 0.28mmol) in n-butanol (2mL), add p-toluenesulfonic acid monohydrate (4mg, 0.02mmol) , 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 reverse preparative HPLC to obtain a white solid 2 (36 mg, yield 34%). ESI-MS (m/z): 492.2[M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.86 (s, 1H), 8.16 (d, J=2.3Hz, 1H), 7.91 ( dd, J=8.4, 2.4Hz, 1H), 7.21(d, J=8.4Hz, 1H), 7.03(t, J=6.0Hz, 1H), 6.55(s, 1H), 4.46-4.29(m, 2H ), 3.99(q, J=6.8Hz, 1H), 3.46(tt, J=7.4, 3.8Hz, 1H), 2.11 (s, 3H), 1.17 (d, J=6.8Hz, 3H), 1.02 (p, J=4.7, 4.2Hz, 2H), 0.92 (dt, J=7.2, 3.5Hz, 2H).
实施例3Example 3
(S)-2-(((6-((1-(乙基-d5)-3-(三氟甲基)-1H-吡唑-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-((1-(ethyl-d5)-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxo)pyridin-3-yl)methyl Base) amino) -4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one
实施例3’Example 3'
(S)-2-(((6-((1-(乙基-d5)-5-(三氟甲基)-1H-吡唑-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-((1-(ethyl-d5)-5-(trifluoromethyl)-1H-pyrazol-3-yl)oxo)pyridin-3-yl)methyl Base) amino) -4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one
实施例3和3’由以下步骤制备：
Examples 3 and 3' were prepared by the following steps:
第一步：将化合物Int-5b(500mg，1.97mmol)溶于N，N-二甲基甲酰胺(10mL)中，随后加入碳酸铯(1.28g，3.93mmol)和氘代碘乙烷(633mg，3.93mmol)。反应液在室温下搅拌4小时。LCMS监测反应结束。反应液用饱和氯化钠水溶液稀释，乙酸乙酯萃取。有机相用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，过滤浓缩，得到化合物3a和3a’的混合物。ESI-MS(m/z)：288.9[M+H]+。The first step: Dissolve compound Int-5b (500mg, 1.97mmol) in N,N-dimethylformamide (10mL), then add cesium carbonate (1.28g, 3.93mmol) and deuterated iodoethane (633mg , 3.93 mmol). The reaction was stirred at room temperature for 4 hours. LCMS monitored the completion of the reaction. The reaction solution was diluted with saturated aqueous sodium chloride and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a mixture of compounds 3a and 3a'. ESI-MS (m/z): 288.9 [M+H] + .
第二步：将上一步得到的产物3a和3a’溶于甲醇(15mL)和氨水(1mL)中，加入Raney Nickel(1mL，水混悬液)，反应体系置换氢气后在室温下搅拌12小时。反应液硅藻土过滤，滤液浓缩。残余物通过硅胶柱层析纯化(二氯甲烷/甲醇＝5/1)得到无色油状液体3b(186mg，收率33％)，ESI-MS(m/z)：292.2[M+H]+；和无色油状液体3b’(182mg，收率32％)，ESI-MS(m/z)：292.2[M+H]+。Step 2: Dissolve the products 3a and 3a' obtained in the previous step in methanol (15mL) and ammonia water (1mL), add Raney Nickel (1mL, aqueous suspension), and stir the reaction system at room temperature for 12 hours after replacing hydrogen . The reaction solution was filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol=5/1) to obtain colorless oily liquid 3b (186 mg, yield 33%), ESI-MS (m/z): 292.2 [M+H] + and colorless oily liquid 3b' (182 mg, yield 32%), ESI-MS (m/z): 292.2 [M+H] + .
第三步：将化合物3b(60mg，0.21mmol)、溶于正丁醇(3mL)中，加入化合物Int-1(31mg，0.14mmol)和对甲苯磺酸一水合物(3mg，0.02mmol)，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，残余物用反向制备HPLC纯化得到白色固体3(29mg，收率29％)。ESI-MS(m/z)：482.1[M+H]+；1H NMR(500MHz，DMSO)δ9.84(s，1H)，8.15(d，J＝2.1Hz，1H)，7.90(dd，J＝8.4，2.3Hz，1H)，7.19(d，J＝8.4Hz，1H)，7.01(t，J＝5.8Hz，1H)，6.53(s，1H)，4.36(qd，J＝15.2，6.3Hz，2H)，3.99(q，J＝6.8Hz，1H)，2.90(s，3H)，2.11(s，3H)，1.17(d，J＝6.8Hz，3H)。Step 3: Dissolve compound 3b (60mg, 0.21mmol) in n-butanol (3mL), add compound Int-1 (31mg, 0.14mmol) and p-toluenesulfonic acid monohydrate (3mg, 0.02mmol), The reaction solution Stir 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 reverse preparative HPLC to obtain a white solid 3 (29 mg, yield 29%). ESI-MS (m/z): 482.1[M+H] + ; 1 H NMR (500MHz, DMSO) δ9.84 (s, 1H), 8.15 (d, J=2.1Hz, 1H), 7.90 (dd, J=8.4, 2.3Hz, 1H), 7.19(d, J=8.4Hz, 1H), 7.01(t, J=5.8Hz, 1H), 6.53(s, 1H), 4.36(qd, J=15.2, 6.3 Hz, 2H), 3.99 (q, J = 6.8Hz, 1H), 2.90 (s, 3H), 2.11 (s, 3H), 1.17 (d, J = 6.8Hz, 3H).
第四步：从化合物3b’(60mg，0.21mmo)出发，用类似第三步的方法，得到白色固体3’(20mg，收率18％)。ESI-MS(m/z)：482.2[M+H]+；1H NMR(500MHz，DMSO)δ9.83(s，1H)，8.12(d，J＝2.1Hz，1H)，7.82(dd，J＝8.4，2.3Hz，1H)，7.04(d，J＝8.4Hz，1H)，6.97(t，J＝5.8Hz，1H)，6.68(s，1H)，4.34(qd，J＝15.2，6.4Hz，2H)，3.99(q，J＝6.8Hz，1H)，2.91(s，3H)，2.11(s，3H)，1.17(d，J＝6.8Hz，3H)。Step 4: Starting from compound 3b' (60 mg, 0.21 mmol), a white solid 3' (20 mg, yield 18%) was obtained by a method similar to the third step. ESI-MS (m/z): 482.2[M+H] + ; 1 H NMR (500MHz, DMSO) δ9.83 (s, 1H), 8.12 (d, J=2.1Hz, 1H), 7.82 (dd, J=8.4, 2.3Hz, 1H), 7.04(d, J=8.4Hz, 1H), 6.97(t, J=5.8Hz, 1H), 6.68(s, 1H), 4.34(qd, J=15.2, 6.4 Hz, 2H), 3.99 (q, J=6.8Hz, 1H), 2.91 (s, 3H), 2.11 (s, 3H), 1.17 (d, J=6.8Hz, 3H).
实施例4Example 4
(S)-2-(((6-((1-异丙基-3-(三氟甲基)-1H-吡唑-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-((1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxo)pyridin-3-yl)methyl)amino )-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one
实施例4’Example 4'
(S)-2-(((6-((1-异丙基-5-(三氟甲基)-1H-吡唑-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-((1-isopropyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)oxo)pyridin-3-yl)methyl)amino )-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one
实施例4和4’由以下步骤制备：
Examples 4 and 4' were prepared by the following steps:
第一步：将化合物Int-5b(200mg，0.79mmol)溶于N，N-二甲基甲酰胺(5mL)中，随后加入碳酸铯(513mg，1.57mmol)和2-碘代丙烷(268mg，1.57mmol)。反应液在室温下搅拌4小时。LCMS监测反应结束。反应液用饱和氯化钠水溶液稀释，乙酸乙酯萃取。有机相用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，过滤浓缩，得到化合物4a和4a’的混合物。ESI-MS(m/z)：297.2[M+H]+。The first step: Dissolve compound Int-5b (200mg, 0.79mmol) in N,N-dimethylformamide (5mL), then add cesium carbonate (513mg, 1.57mmol) and 2-iodopropane (268mg, 1.57 mmol). The reaction was stirred at room temperature for 4 hours. LCMS monitored the completion of the reaction. The reaction solution was diluted with saturated aqueous sodium chloride and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a mixture of compounds 4a and 4a'. ESI-MS (m/z): 297.2 [M+H] + .
第二步：将上一步得到的产物4a和4a’溶于甲醇(9mL)和氨水(1mL)中，加入Raney Nickel(0.5mL，水混悬液)，反应体系置换氢气后在室温下搅拌12小时。反应液硅藻土过滤，滤液浓缩。残余物通过硅胶柱层析纯化(二氯甲烷/甲醇＝5/1)得到无色油状液体4b(62mg，收率26％)，ESI-MS(m/z)：301.3[M+H]+；和无色油状液体4b’(60mg，收率25％)，ESI-MS(m/z)：301.3[M+H]+。The second step: the products 4a and 4a' obtained in the previous step were dissolved in methanol (9mL) and ammonia water (1mL), and Raney Nickel (0.5mL, aqueous suspension) was added, and the reaction system was stirred at room temperature for 12 Hour. The reaction solution was filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol=5/1) to obtain colorless oily liquid 4b (62 mg, yield 26%), ESI-MS (m/z): 301.3 [M+H] + and colorless oily liquid 4b' (60 mg, yield 25%), ESI-MS (m/z): 301.3 [M+H] + .
第三步：将化合物4b(62mg，0.21mmol)溶于正丁醇(3mL)中，加入化合物Int-1(31mg，0.14mmol)和对甲苯磺酸一水合物(3mg，0.02mmol)，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，残余物用反向制备HPLC纯化得到白色固体4(13mg，收率13％)。ESI-MS(m/z)：491.2[M+H]+；1H NMR(500MHz，DMSO-d6)δ9.83(s，1H)，8.15(d，J＝2.2Hz，1H)，7.90(dd，J＝8.4，2.4Hz，1H)，7.19(d，J＝8.4Hz，1H)，7.03-6.97(m，1H)，6.50(s，1H)，4.49(dt，J＝13.3，6.6Hz，1H)，4.41-4.31(m，2H)，3.99(q，J＝6.8Hz，1H)，2.90(s，3H)，2.11(s，3H)，1.35(d，J＝6.6Hz，6H)，1.17(d，J＝6.8Hz，3H)。The third step: Dissolve compound 4b (62mg, 0.21mmol) in n-butanol (3mL), add compound Int-1 (31mg, 0.14mmol) and p-toluenesulfonic acid monohydrate (3mg, 0.02mmol), react liquid in Stir at 160°C for 3 hours under microwave conditions. After the reaction liquid was cooled to room temperature, the reaction liquid was concentrated under reduced pressure, and the residue was purified by reverse preparative HPLC to obtain white solid 4 (13 mg, yield 13%). ESI-MS (m/z): 491.2[M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.83 (s, 1H), 8.15 (d, J=2.2Hz, 1H), 7.90 ( dd, J=8.4, 2.4Hz, 1H), 7.19(d, J=8.4Hz, 1H), 7.03-6.97(m, 1H), 6.50(s, 1H), 4.49(dt, J=13.3, 6.6Hz , 1H), 4.41-4.31(m, 2H), 3.99(q, J=6.8Hz, 1H), 2.90(s, 3H), 2.11(s, 3H), 1.35(d, J=6.6Hz, 6H) , 1.17 (d, J=6.8Hz, 3H).
第四步：从化合物4b’(60mg，0.21mmo)出发，用类似第三步的方法，可以得到白色固体4’(5mg，收率5％)。ESI-MS(m/z)：491.1[M+H]+；1H NMR(500MHz，DMSO-d6)δ9.85(s，1H)，8.13(d，J＝2.2Hz，1H)，7.83(dd，J＝8.4，2.4Hz，1H)，7.02(t，J＝8.9Hz，2H)，6.65(s，1H)，4.55(dt，J＝13.0，6.4Hz，1H)，4.35(qd，J＝15.2，6.4Hz，2H)，3.99(q，J＝6.7Hz，1H)，2.91(s，3H)，2.11(s，3H)，1.46-1.39(m，6H)，1.17(d，J＝6.8Hz，3H)。Step 4: Starting from compound 4b' (60 mg, 0.21 mmol), a white solid 4' (5 mg, yield 5%) can be obtained by a method similar to the third step. ESI-MS (m/z): 491.1[M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.85 (s, 1H), 8.13 (d, J=2.2Hz, 1H), 7.83 ( dd, J=8.4, 2.4Hz, 1H), 7.02(t, J=8.9Hz, 2H), 6.65(s, 1H), 4.55(dt, J=13.0, 6.4Hz, 1H), 4.35(qd, J =15.2, 6.4Hz, 2H), 3.99(q, J=6.7Hz, 1H), 2.91(s, 3H), 2.11(s, 3H), 1.46-1.39(m, 6H), 1.17(d, J= 6.8Hz, 3H).
实施例5Example 5
(S)-2-(((6-((1-(叔-丁基)-3-(三氟甲基)-1H-吡唑-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-((1-(tert-butyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxo)pyridin-3-yl)methyl Base) amino) -4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one
实施例5由以下步骤制备：
Embodiment 5 is prepared by the following steps:
第一步：将化合物Int-9(100mg，0.32mmol)和化合物Int-1(48mg，0.21mmol)溶于正丁醇(3mL)中，加入对甲苯磺酸一水合物(6mg，0.03mmol)，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，残余物用反向制备HPLC纯化得到白色固体5(20mg，收率13％)。ESI-MS(m/z)：505.1[M+H]+；1H NMR(500MHz，DMSO)δ9.85(s，1H)，8.18(d，J＝1.8Hz，1H)，7.89(dd，J＝8.4，2.1Hz，1H)，7.19(d，J＝8.4Hz，1H)，7.02(t，J＝4.7Hz，1H)，6.49(s，1H)，4.37(qd，J＝15.3，6.3Hz，2H)，3.99(q，J＝6.7Hz，1H)，2.90(s，3H)，2.11(s，3H)，1.54(s，9H)，1.17(d，J＝6.8Hz，3H)。The first step: Dissolve compound Int-9 (100mg, 0.32mmol) and compound Int-1 (48mg, 0.21mmol) in n-butanol (3mL), add p-toluenesulfonic acid monohydrate (6mg, 0.03mmol) , 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 reverse preparative HPLC to obtain white solid 5 (20 mg, yield 13%). ESI-MS (m/z): 505.1[M+H] + ; 1 H NMR (500MHz, DMSO) δ9.85 (s, 1H), 8.18 (d, J=1.8Hz, 1H), 7.89 (dd, J=8.4, 2.1Hz, 1H), 7.19(d, J=8.4Hz, 1H), 7.02(t, J=4.7Hz, 1H), 6.49(s, 1H), 4.37(qd, J=15.3, 6.3 Hz, 2H), 3.99(q, J=6.7Hz, 1H), 2.90(s, 3H), 2.11(s, 3H), 1.54(s, 9H), 1.17(d, J=6.8Hz, 3H).
实施例6Example 6
(S)-2-(((6-((1-(2-氟乙基)-3-(三氟甲基)-1H-吡唑-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-((1-(2-fluoroethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxo)pyridin-3-yl) Methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one
实施例6由以下步骤制备：
Embodiment 6 is prepared by the following steps:
第一步：将中间体Int-1(37mg，0.16mmol)，中间体Int-11(55mg，0.18mmol)和三氟乙酸(2mg，0.02mmol)溶解在正丁醇(2mL)中，在微波160℃的条件下反应4小时。LCMS监测反应结束。反应液通过反相制备HPLC纯化，得到白色固体6(21mg，收率26％)。ESI-MS(m/z)：495.2[M+H]+；1H NMR(500MHz，DMSO-d6)δ9.93(s，1H)，8.18(d，J＝2.3Hz，1H)，7.91(dd，J＝8.4，2.4Hz，1H)， 7.20(d，J＝8.4Hz，1H)，6.60(s，1H)，4.74(dt，J＝47.1，4.7Hz，2H)，4.46-4.33(m，4H)，4.03(q，J＝6.8Hz，1H)，2.93(s，3H)，2.13(s，3H)，1.20(d，J＝6.8Hz，3H)。The first step: intermediate Int-1 (37mg, 0.16mmol), intermediate Int-11 (55mg, 0.18mmol) and trifluoroacetic acid (2mg, 0.02mmol) were dissolved in n-butanol (2mL), and the The reaction was carried out at 160° C. for 4 hours. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain a white solid 6 (21 mg, yield 26%). ESI-MS (m/z): 495.2[M+H] + ; 1 H NMR (500MHz, DMSO-d 6 ) δ9.93 (s, 1H), 8.18 (d, J=2.3Hz, 1H), 7.91 (dd, J=8.4, 2.4Hz, 1H), 7.20(d, J=8.4Hz, 1H), 6.60(s, 1H), 4.74(dt, J=47.1, 4.7Hz, 2H), 4.46-4.33(m, 4H), 4.03(q, J=6.8Hz , 1H), 2.93 (s, 3H), 2.13 (s, 3H), 1.20 (d, J=6.8Hz, 3H).
实施例7Example 7
(S)-4，7，8-三甲基-2-(((6-((1-(2，2，2-三氟乙基)-3-(三氟甲基)-1H-吡唑-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-((1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-1H-pyridine Azol-5-yl)oxo)pyridin-3-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one
实施例7由以下步骤制备：
Embodiment 7 is prepared by the following steps:
第一步：将中间体Int-1(39mg，0.17mmol)，中间体Int-10(65mg，0.19mmol)和三氟乙酸(2mg，0.02mmol)溶解在正丁醇(2mL)中，在微波160℃的条件下反应4小时。LCMS监测反应结束。反应液通过反相制备HPLC纯化，得到白色固体7(24mg，收率26％)。ESI-MS(m/z)：503.9[M+H]+；1H NMR(500MHz，DMSO-d6)δ9.85(s，1H)，8.19(d，J＝2.4Hz，1H)，7.92(dd，J＝8.4，2.4Hz，1H)，7.22(d，J＝8.4Hz，1H)，7.03(t，J＝6.4Hz，1H)，6.71(s，1H)，5.21(q，J＝9.0Hz，2H)，4.50-4.30(m，2H)，3.99(q，J＝6.8Hz，1H)，2.91(s，3H)，2.12(s，3H)，1.17(d，J＝6.8Hz，3H)。The first step: intermediate Int-1 (39mg, 0.17mmol), intermediate Int-10 (65mg, 0.19mmol) and trifluoroacetic acid (2mg, 0.02mmol) were dissolved in n-butanol (2mL), and the The reaction was carried out at 160° C. for 4 hours. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain 7 (24 mg, yield 26%) as a white solid. ESI-MS (m/z): 503.9[M+H] + ; 1 H NMR (500MHz, DMSO-d 6 ) δ9.85 (s, 1H), 8.19 (d, J=2.4Hz, 1H), 7.92 (dd, J=8.4, 2.4Hz, 1H), 7.22(d, J=8.4Hz, 1H), 7.03(t, J=6.4Hz, 1H), 6.71(s, 1H), 5.21(q, J= 9.0Hz, 2H), 4.50-4.30(m, 2H), 3.99(q, J=6.8Hz, 1H), 2.91(s, 3H), 2.12(s, 3H), 1.17(d, J=6.8Hz, 3H).
实施例8 Example 8
(S)-2-(((6-((1-(2，2-二氟乙基)-3-(三氟甲基)-1H-吡唑-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-((1-(2,2-difluoroethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxo)pyridine-3 -yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one
实施例8由以下步骤制备：
Embodiment 8 is prepared by the following steps:
第一步：将中间体Int-1(38mg，0.17mmol)，中间体Int-7(60mg，0.19mmol)和三氟乙酸(2mg，0.02mmol)溶解在正丁醇(2mL)中，在微波160℃的条件下反应4小时。LCMS监测反应结束。反应液通过反相制备HPLC纯化，得到白色固体8(24mg，收率27％)。ESI-MS(m/z)：513.9[M+H]+；1H NMR(500MHz，DMSO-d6)δ9.78(s，1H)，8.11(d，J＝2.3Hz，1H)，7.84(dd，J＝8.4，2.3Hz，1H)，7.13(d，J＝8.4Hz，1H)，6.96(t，J＝6.3Hz，1H)，6.59(s，1H)，6.33(tt，J＝54.3，3.6Hz，1H)，4.56(td，J＝15.2，3.5Hz，2H)，4.40-4.23(m，2H)，3.92(q，J＝6.7Hz，1H)，2.84(s，3H)，2.05(s，3H)，1.11(d，J＝6.8Hz，3H)。The first step: intermediate Int-1 (38mg, 0.17mmol), intermediate Int-7 (60mg, 0.19mmol) and trifluoroacetic acid (2mg, 0.02mmol) were dissolved in n-butanol (2mL), and the The reaction was carried out at 160° C. for 4 hours. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain 8 (24 mg, yield 27%) as a white solid. ESI-MS (m/z): 513.9[M+H] + ; 1 H NMR (500MHz, DMSO-d 6 ) δ9.78 (s, 1H), 8.11 (d, J=2.3Hz, 1H), 7.84 (dd, J=8.4, 2.3Hz, 1H), 7.13(d, J=8.4Hz, 1H), 6.96(t, J=6.3Hz, 1H), 6.59(s, 1H), 6.33(tt, J= 54.3, 3.6Hz, 1H), 4.56(td, J=15.2, 3.5Hz, 2H), 4.40-4.23(m, 2H), 3.92(q, J=6.7Hz, 1H), 2.84(s, 3H), 2.05 (s, 3H), 1.11 (d, J=6.8Hz, 3H).
实施例9Example 9
(S)-2-(((6-((2-环丙基-6-(三氟甲基)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-((2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)oxo)pyridin-3-yl)methyl)amino)-4, 7,8-trimethyl-7,8-dihydropteridin-6(5H)-one
实施例9由以下步骤制备：
Embodiment 9 is prepared by the following steps:
第一步：将中间体Int-1(34mg，0.15mmol)，中间体Int-8(51mg，0.16mmol)和三氟乙酸(2mg，0.02mmol)溶解在正丁醇(2mL)中，在微波160℃的条件下反应4小时。LCMS监测反应结束。反应液通过反相制备HPLC纯化，得到白色固体9(16mg，收率21％)。ESI-MS(m/z)：500.0[M+H]+；1H NMR(500MHz，DMSO-d6)δ9.82(s，1H)，8.08(d，J＝2.3Hz，1H)，7.88(dd，J＝8.4，2.4Hz，1H)，7.75-7.64(m，2H)，7.17(d，J＝8.4Hz，1H)，6.97(t，J＝6.3Hz，1H)，4.44-4.27(m，2H)，3.99(q，J＝6.8Hz，1H)，2.91(s，3H)，2.23-2.16(m，1H)，2.12(s，3H)，1.18(d，J＝6.8Hz，3H)，0.98-0.90(m，4H)。The first step: intermediate Int-1 (34mg, 0.15mmol), intermediate Int-8 (51mg, 0.16mmol) and trifluoroacetic acid (2mg, 0.02mmol) were dissolved in n-butanol (2mL), and the The reaction was carried out at 160° C. for 4 hours. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain white solid 9 (16 mg, yield 21%). ESI-MS (m/z): 500.0[M+H] + ; 1 H NMR (500MHz, DMSO-d 6 ) δ9.82 (s, 1H), 8.08 (d, J=2.3Hz, 1H), 7.88 (dd, J=8.4, 2.4Hz, 1H), 7.75-7.64(m, 2H), 7.17(d, J=8.4Hz, 1H), 6.97(t, J=6.3Hz, 1H), 4.44-4.27( m, 2H), 3.99(q, J=6.8Hz, 1H), 2.91(s, 3H), 2.23-2.16(m, 1H), 2.12(s, 3H), 1.18(d, J=6.8Hz, 3H ), 0.98-0.90 (m, 4H).
实施例10Example 10
(S)-2-(((6-((2-氯-6-(三氟甲基)吡啶-3-基)氧代)吡啶-3-基)甲基)氨基)-4，7-二甲基-8-(甲基-d3)-7，8-二氢蝶啶-6(5H)-酮
(S)-2-(((6-((2-Chloro-6-(trifluoromethyl)pyridin-3-yl)oxo)pyridin-3-yl)methyl)amino)-4,7- Dimethyl-8-(methyl-d3)-7,8-dihydropteridin-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：将中间体Int-2(50mg，0.22mmol)，中间体Int-13(85mg，0.28mmol)和对甲苯磺酸一水合物(4mg，0.02mmol)溶解在正丁醇(2mL)中，在微波160℃的条件下反应3小时。LCMS监测反应结束。反应液通过反相制备HPLC纯化，得到白色固体10(23mg，收率21％)。ESI-MS(m/z)：499.2[M+H]+；1H NMR(500MHz，DMSO-d6)δ9.86(s，1H)，8.14-8.01(m，3H)，7.91(dd，J＝8.5，2.4Hz，1H)，7.23(d，J＝8.4Hz，1H)，7.02(t，J＝6.2Hz，1H)，4.35(qd，J＝15.2，6.3Hz，2H)，3.99(q，J＝6.8Hz，1H)，2.12(s，3H)，1.17(d，J＝6.9Hz，3H)。The first step: intermediate Int-2 (50mg, 0.22mmol), intermediate Int-13 (85mg, 0.28mmol) and p-toluenesulfonic acid monohydrate (4mg, 0.02mmol) were dissolved in n-butanol (2mL) In the microwave, the reaction was carried out at 160°C for 3 hours. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain white solid 10 (23 mg, yield 21%). ESI-MS (m/z): 499.2[M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.86 (s, 1H), 8.14-8.01 (m, 3H), 7.91 (dd, J =8.5, 2.4Hz, 1H), 7.23(d, J=8.4Hz, 1H), 7.02(t, J=6.2Hz, 1H), 4.35(qd, J=15.2, 6.3Hz, 2H), 3.99(q , J=6.8Hz, 1H), 2.12(s, 3H), 1.17(d, J=6.9Hz, 3H).
实施例11Example 11
(S)-2-(((6-((2-甲氧基-6-(三氟甲基)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-((2-methoxy-6-(trifluoromethyl)pyridin-3-yl)oxo)pyridin-3-yl)methyl)amino)-4, 7,8-trimethyl-7,8-dihydropteridin-6(5H)-one
实施例11由以下步骤制备：
Example 11 was prepared by the following steps:
第一步：将化合物Int-12(100mg，0.34mmol)和化合物Int-1(75mg，0.34mmol)溶于正丁醇(3mL)中，加入对甲苯磺酸一水合物(6mg，0.03mmol)，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，残余物用反向制备HPLC纯化得到白色固体11(80mg，收率48％)。ESI-MS(m/z)：490.2[M+H]+；1H NMR(500MHz，DMSO)δ9.81(s，1H)，8.01(d，J＝1.9Hz，1H)，7.83(dd，J＝8.4，2.3Hz，1H)，7.77(d，J＝7.9Hz，1H)，7.55(d，J＝7.9Hz，1H)，7.08(d，J＝8.4Hz，1H)，6.94(t，J＝5.7Hz，1H)，4.33(qd，J＝15.1，6.3Hz，2H)，3.98(q，J＝6.8Hz，1H)，3.83(s，3H)，2.90(s，3H)，2.11(s，3H)，1.17(d，J＝6.8Hz，3H)。The first step: Dissolve compound Int-12 (100mg, 0.34mmol) and compound Int-1 (75mg, 0.34mmol) in n-butanol (3mL), add p-toluenesulfonic acid monohydrate (6mg, 0.03mmol) ,The reaction solution Stir 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 reverse preparative HPLC to obtain white solid 11 (80 mg, yield 48%). ESI-MS (m/z): 490.2[M+H] + ; 1 H NMR (500MHz, DMSO) δ9.81 (s, 1H), 8.01 (d, J=1.9Hz, 1H), 7.83 (dd, J=8.4, 2.3Hz, 1H), 7.77(d, J=7.9Hz, 1H), 7.55(d, J=7.9Hz, 1H), 7.08(d, J=8.4Hz, 1H), 6.94(t, J=5.7Hz, 1H), 4.33(qd, J=15.1, 6.3Hz, 2H), 3.98(q, J=6.8Hz, 1H), 3.83(s, 3H), 2.90(s, 3H), 2.11( s, 3H), 1.17 (d, J = 6.8 Hz, 3H).
实施例12Example 12
(S)-2-(((6-((1-(二环[1.1.1]戊烷-1-基)-3-(三氟甲基)-1H-吡唑-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-((1-(bicyclo[1.1.1]pentane-1-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxy Substitute) pyridin-3-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one
实施例12由以下步骤制备：
Example 12 was prepared by the following steps:
第一步：将化合物Int-1(50mg，0.22mmol)和化合物Int-14(93mg，0.29mmol)溶于正丁醇(2mL)中，加入对甲苯磺酸一水合物(4mg，0.02mmol)，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，残余物用反向制备HPLC纯化得到白色固体12(36mg，收率30％)。ESI-MS(m/z)：515.2[M+H]+；1H NMR(500MHz，DMSO-d6)δ9.82(s，1H)，8.15(d，J＝2.4Hz，1H)，7.90(dd，J＝8.5，2.4Hz，1H)，7.18(d，J＝8.4Hz，1H)，7.00(t，J＝6.2Hz，1H)，6.58(s，1H)，4.52-4.31(m，2H)，3.99(q，J＝6.8Hz，1H)，2.91(s，3H)，2.55(s，1H)，2.16(s，6H)，2.11(s，3H)，1.17(d，J＝6.8Hz，3H)。 The first step: Dissolve compound Int-1 (50mg, 0.22mmol) and compound Int-14 (93mg, 0.29mmol) in n-butanol (2mL), add p-toluenesulfonic acid monohydrate (4mg, 0.02mmol) , 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 reverse preparative HPLC to obtain white solid 12 (36 mg, yield 30%). ESI-MS (m/z): 515.2[M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.82 (s, 1H), 8.15 (d, J=2.4Hz, 1H), 7.90 ( dd, J=8.5, 2.4Hz, 1H), 7.18(d, J=8.4Hz, 1H), 7.00(t, J=6.2Hz, 1H), 6.58(s, 1H), 4.52-4.31(m, 2H ), 3.99(q, J=6.8Hz, 1H), 2.91(s, 3H), 2.55(s, 1H), 2.16(s, 6H), 2.11(s, 3H), 1.17(d, J=6.8Hz , 3H).
实施例13Example 13
(S)-2-(((6-((3，5-二(三氟甲基)-1H-吡唑-1-基)甲基)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-((3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)methyl)pyridin-3-yl)methyl)amino)-4 , 7,8-trimethyl-7,8-dihydropteridin-6(5H)-one
实施例13由以下步骤制备：
Example 13 was prepared by the following steps:
第一步：将中间体Int-1(40mg，0.18mmol)，中间体Int-15(69mg，0.21mmol)和三氟乙酸(2mg，0.02mmol)溶解在正丁醇(2mL)中，在微波160℃的条件下反应3小时。LCMS监测反应结束。反应液通过反相制备HPLC纯化，得到白色固体13(37mg，收率41％)。ESI-MS(m/z)：515.2[M+H]+；1H NMR(500MHz，DMSO-d6)δ9.81(s，1H)，8.43(d，J＝2.2Hz，1H)，7.74(dd，J＝8.0，2.2Hz，1H)，7.62(s，1H)，7.18(d，J＝8.0Hz，1H)，7.09-6.92(m，1H)，5.67(s，2H)，4.46-4.31(m，2H)，3.98(q，J＝6.8Hz，1H)，2.87(s，3H)，2.10(s，3H)，1.16(d，J＝6.9Hz，3H)。The first step: intermediate Int-1 (40mg, 0.18mmol), intermediate Int-15 (69mg, 0.21mmol) and trifluoroacetic acid (2mg, 0.02mmol) were dissolved in n-butanol (2mL), and the The reaction was carried out at 160° C. for 3 hours. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain white solid 13 (37 mg, yield 41%). ESI-MS (m/z): 515.2[M+H] + ; 1 H NMR (500MHz, DMSO-d 6 ) δ9.81 (s, 1H), 8.43 (d, J=2.2Hz, 1H), 7.74 (dd, J=8.0, 2.2Hz, 1H), 7.62(s, 1H), 7.18(d, J=8.0Hz, 1H), 7.09-6.92(m, 1H), 5.67(s, 2H), 4.46- 4.31 (m, 2H), 3.98 (q, J = 6.8Hz, 1H), 2.87 (s, 3H), 2.10 (s, 3H), 1.16 (d, J = 6.9Hz, 3H).
实施例14Example 14
(S)-2-(((6-((1-环丙基-3-(三氟甲基)-1H-吡唑-5-基)氧代)吡啶-3-基)甲基)氨基)-4-甲基-6a，7，8，9-四氢吡咯并[2，1-h]蝶啶-6(5H)-酮
(S)-2-(((6-((1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxo)pyridin-3-yl)methyl)amino )-4-methyl-6a,7,8,9-tetrahydropyrrolo[2,1-h]pteridin-6(5H)-one
实施例14由以下步骤制备：
Example 14 was prepared by the following steps:
第一步：将化合物Int-1a(500mg，2.81mmol)和化合物14a(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14b(385mg，收率57％)，ESI-MS(m/z)：239.4[M+H]+。The first step: Dissolve compound Int-1a (500mg, 2.81mmol) and compound 14a (602mg, 3.65mmol) in ethanol (20mL) and water (2mL), then add sodium bicarbonate (707mg, 8.34mmol), and The temperature of the reaction liquid was raised to 80° C. and stirred for 16 hours. After the reaction solution was cooled to room temperature, water (12 mL) was added to the reaction solution, and after filtration, off-white solid 14b (385 mg, yield 57%) was obtained, ESI-MS (m/z): 239.4 [M+H] + .
第二步：将化合物14b(42mg，0.17mmol)和化合物Int-3(68mg，0.23mmol)溶于正丁醇(2mL)中，加入对甲苯磺酸一水合物(3mg，0.01mmol)，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，残余物用反向制备HPLC纯化得到白色固体14(15mg，收率17％)。ESI-MS(m/z)：501.3[M+H]+；1H NMR(500MHz，DMSO-d6)δ9.69(s，1H)，8.09(d，J＝2.4Hz，1H)，7.83(dd，J＝8.4，2.4Hz，1H)，7.12(d，J＝8.4Hz，1H)，6.92(t，J＝6.3Hz，1H)，6.46(s，1H)，4.39-4.22(m，2H)，3.90(dd，J＝9.1，6.2Hz，1H)，3.47(dt，J＝11.1，7.5Hz，1H)，3.40(tt，J＝7.5，3.8Hz，1H)，2.19-2.08(m，1H)，2.04(s，3H)，1.84(tq，J＝14.0，5.9，5.3Hz，3H)，0.96(p，J＝4.8，4.3Hz，2H)，0.86(dt，J＝7.3，3.6Hz，2H)。Second step: Dissolve compound 14b (42mg, 0.17mmol) and compound Int-3 (68mg, 0.23mmol) in n-butanol (2mL), add p-toluenesulfonic acid monohydrate (3mg, 0.01mmol), react The 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 reverse preparative HPLC to obtain white solid 14 (15 mg, yield 17%). ESI-MS (m/z): 501.3[M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.69 (s, 1H), 8.09 (d, J=2.4Hz, 1H), 7.83 ( dd, J=8.4, 2.4Hz, 1H), 7.12(d, J=8.4Hz, 1H), 6.92(t, J=6.3Hz, 1H), 6.46(s, 1H), 4.39-4.22(m, 2H ), 3.90(dd, J=9.1, 6.2Hz, 1H), 3.47(dt, J=11.1, 7.5Hz, 1H), 3.40(tt, J=7.5, 3.8Hz, 1H), 2.19-2.08(m, 1H), 2.04(s, 3H), 1.84(tq, J=14.0, 5.9, 5.3Hz, 3H), 0.96(p, J=4.8, 4.3Hz, 2H), 0.86(dt, J=7.3, 3.6Hz , 2H).
实施例15Example 15
(S)-4，7，8-三甲基-2-(((6-((4-甲基-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-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)oxo)pyridin-3-yl ) methyl) ammonia base)-7,8-dihydropteridin-6(5H)-one
实施例15由以下步骤制备：
Example 15 was prepared by the following steps:
第一步：将甲酸乙酯(3.17g，42.73mmol)固体乙醇钠(3.49g，50.50mmol)依次加入到干燥四氢呋喃(140mL)中。在5-10℃温度下加入化合物15a(7g，38.85mmol)后，反应液升温至50℃保温搅拌2小时，HPLC监测原料消失。减压蒸出四氢呋喃，得到黄色油状物15b，直接用于下一步。The first step: Ethyl formate (3.17g, 42.73mmol) and solid sodium ethoxide (3.49g, 50.50mmol) were sequentially added into dry tetrahydrofuran (140mL). After compound 15a (7 g, 38.85 mmol) was added at a temperature of 5-10° C., the reaction solution was heated to 50° C. and kept stirring for 2 hours, and the disappearance of the raw material was monitored by HPLC. Tetrahydrofuran was distilled off under reduced pressure to obtain yellow oil 15b, which was directly used in the next step.
第二步：将上一步得到的油状物15b加入150ml无水乙醇，室温搅拌溶解，滴加三氟乙脒(4.35g，33.01mmol，纯度85％)，在30℃条件下保温搅拌5小时，然后升温至80℃继续搅拌2小时，HPLC监测原料消失。反应液降温后减压蒸出约100ml乙醇，剩余残液加入到300ml冰水中，浓盐酸调pH到3，搅拌0.5小时，抽滤，滤饼干燥，得到黄色固体化合物15c(4.37g，收率41％，纯度99％)。ESI-MS(m/z)：271.4[M+H]+。 Step 2: add 150ml of absolute ethanol to the oil 15b obtained in the previous step, stir and dissolve at room temperature, add trifluoroacetamidine (4.35g, 33.01mmol, purity 85%) dropwise, and keep stirring at 30°C for 5 hours, Then the temperature was raised to 80° C. and stirring was continued for 2 hours, and the disappearance of the raw material was monitored by HPLC. After the reaction solution cooled down, about 100ml of ethanol was evaporated under reduced pressure, and the remaining residue was added to 300ml of ice water, adjusted to pH 3 with concentrated hydrochloric acid, stirred for 0.5 hours, filtered with suction, and the filter cake was dried to obtain yellow solid compound 15c (4.37g, yield 41%, purity 99%). ESI-MS (m/z): 271.4 [M+H] + .
第三步：将化合物15c(4.0g，14.80mmol)加入到60ml乙腈中，滴加三氯氧磷(6.81g，44.41mmol)，滴加完毕后搅拌10分钟，升温至80℃，保温搅拌2小时，HPLC监测原料转化完全。减压除去乙腈，残余液加入到200mL冰水中，搅拌0.5小时，抽滤，得到黄色固体15d(3.9g，收率86％，纯度95％)。Step 3: Add compound 15c (4.0g, 14.80mmol) to 60ml of acetonitrile, dropwise add phosphorus oxychloride (6.81g, 44.41mmol), stir for 10 minutes after the addition, heat up to 80°C, keep stirring for 2 Hours, HPLC monitoring raw material conversion is complete. Acetonitrile was removed under reduced pressure, and the residue was added to 200 mL of ice water, stirred for 0.5 hours, and filtered with suction to obtain a yellow solid 15d (3.9 g, yield 86%, purity 95%).
第四步：将化合物15d(2.0g，6.93mmol)，三甲基环三硼氧烷(2.61g，20.79mmol)，醋酸钯(155mg，0.69mol)，磷酸钾(2.94g，13.86mmol)依次加入到1，4-二氧六环(150mL)中，加入水(15mL)，氮气保护条件下，90℃保温搅拌17小时，HPLC监测原料转化完全，滤液浓缩。残余物通过硅胶柱层析纯化(石油醚/乙酸乙酯＝1/9)得到白色固体15e(1.86g，收率50％，纯度99％)。ESI-MS(m/z)：269.1[M+H]+。The fourth step: Compound 15d (2.0g, 6.93mmol), trimethylboroxane (2.61g, 20.79mmol), palladium acetate (155mg, 0.69mol), potassium phosphate (2.94g, 13.86mmol) in sequence Add it to 1,4-dioxane (150 mL), add water (15 mL), under nitrogen protection, keep stirring at 90° C. for 17 hours, HPLC monitors that the conversion of the raw material is complete, and the filtrate is concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/9) to obtain white solid 15e (1.86 g, yield 50%, purity 99%). ESI-MS (m/z): 269.1 [M+H] + .
第五步：将化合物15e(1.0g，3.73mmol)加入到20mL甲醇中，加入10％钯炭(100mg)，反应体系置换氢气后在室温下搅拌过夜。反应液硅藻土过滤，滤液浓缩，得到化合物15f(630mg，收率92％，纯度97％)。ESI-MS(m/z)：177.1[M-H]-。Step 5: Compound 15e (1.0 g, 3.73 mmol) was added to 20 mL of methanol, 10% palladium on carbon (100 mg) was added, and the reaction system was replaced with hydrogen and stirred overnight at room temperature. The reaction liquid was filtered with celite, and the filtrate was concentrated to obtain compound 15f (630 mg, yield 92%, purity 97%). ESI-MS (m/z): 177.1 [MH] - .
第六步：将化合物15f(0.5g，2.81mmol)，Cs2CO3(1.83g，5.61mmol)，Int-3d(514mg，4.21mmol)依次加入到N，N-二甲基甲酰胺(10mL)中，20℃搅拌过夜，HPLC监测原料消失，反应液加到50ml冰水中，搅拌0.5小时，抽滤，得到黄色固体15g(510mg，收率64％，纯度99％)。ESI-MS(m/z)：281.3[M+H]+。Step 6: Add compound 15f (0.5g, 2.81mmol), Cs 2 CO 3 (1.83g, 5.61mmol), Int-3d (514mg, 4.21mmol) to N,N-dimethylformamide (10mL ), stirred overnight at 20°C, HPLC monitored the disappearance of the raw materials, the reaction solution was added to 50ml of ice water, stirred for 0.5 hours, and filtered with suction to obtain 15g of a yellow solid (510mg, yield 64%, purity 99%). ESI-MS (m/z): 281.3 [M+H] + .
第七步：将化合物15g(100mg，0.36mmol)溶于甲醇(5mL)中，加入氨水(0.2mL)中，加入RaneyNickel(0.5mL，水混悬液)，反应体系置换氢气后在室温下搅拌2小时。反应液硅藻土过滤，滤液浓缩，得到化合物15h(95mg，收率93％，纯度90％)，ESI-MS(m/z)：284.9[M+H]+。Step 7: Dissolve compound 15g (100mg, 0.36mmol) in methanol (5mL), add ammonia water (0.2mL), add RaneyNickel (0.5mL, water suspension), and stir the reaction system at room temperature after replacing hydrogen 2 hours. The reaction liquid was filtered with celite, and the filtrate was concentrated to obtain compound 15h (95 mg, yield 93%, purity 90%), ESI-MS (m/z): 284.9 [M+H] + .
第八步：将化合物15h(95mg，0.33mmol)溶于正丁醇(3mL)中，加入化合物Int-1(79mg，0.35mmol)和对甲苯磺酸一水合物(3mg，0.02mmol)，反应 液在微波条件下，160℃搅拌3小时。待反应液冷却至室温，减压浓缩，残余物用反向制备HPLC纯化得到白色固体15(31mg，收率21％，纯度99％)。ESI-MS(m/z)：475.2[M+H]+；1H NMR(500MHz，DMSO-d6)δ9.82(s，1H)，8.86(s，1H)，8.07(d，J＝2.4Hz，1H)，7.91(dd，J＝8.4，2.4Hz，1H)，7.23(d，J＝8.4Hz，1H)，6.98(s，1H)，4.45-4.25(m，2H)，3.99(q，J＝6.8Hz，1H)，2.91(s，3H)，2.42(s，3H)，2.11(s，3H)，1.18(d，J＝6.9Hz，3H)。Step 8: Dissolve compound 15h (95 mg, 0.33 mmol) in n-butanol (3 mL), add compound Int-1 (79 mg, 0.35 mmol) and p-toluenesulfonic acid monohydrate (3 mg, 0.02 mmol), and react The solution was stirred at 160° C. for 3 hours under microwave conditions. After the reaction liquid was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by reverse preparative HPLC to obtain white solid 15 (31 mg, yield 21%, purity 99%). ESI-MS (m/z): 475.2[M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.82(s, 1H), 8.86(s, 1H), 8.07(d, J=2.4 Hz, 1H), 7.91(dd, J=8.4, 2.4Hz, 1H), 7.23(d, J=8.4Hz, 1H), 6.98(s, 1H), 4.45-4.25(m, 2H), 3.99(q , J=6.8Hz, 1H), 2.91(s, 3H), 2.42(s, 3H), 2.11(s, 3H), 1.18(d, J=6.9Hz, 3H).
实施例16Example 16
(S)-2-(((6-((5-环丙基-3-(三氟甲基)-1H-吡唑-1-基)甲基)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-((5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)pyridin-3-yl)methyl)amino )-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one
实施例16由以下步骤制备：
Example 16 was prepared by the following steps:
将中间体Int-1(40mg，0.18mmol)，中间体Int-16(63mg，0.21mmol)和三氟乙酸(2mg，0.02mmol)溶解在正丁醇(2mL)中，在微波160℃的条件下反应3小时。LCMS监测反应结束。反应液通过反相制备HPLC纯化，得到白色固体16(33mg，收率38％)。ESI-MS(m/z)：487.3[M+H]+；1H NMR(500MHz，DMSO-d6)δ9.81(s，1H)，8.48(d，J＝2.1Hz，1H)，7.71(dd，J＝8.0，2.3Hz，1H)，7.02(d，J＝8.1Hz，1H)，6.98(t，J＝6.4Hz，1H)，6.42(s，1H)，5.54(s，2H)，4.43-4.31(m，2H)，3.98(q，J＝6.8Hz，1H)，2.89(s，3H)，2.10(s，3H)，1.96-1.89(m，1H)，1.17(d，J＝6.8Hz，3H)，0.92-0.84(m，2H)，0.70-0.63(m，2H)。 Dissolve intermediate Int-1 (40mg, 0.18mmol), intermediate Int-16 (63mg, 0.21mmol) and trifluoroacetic acid (2mg, 0.02mmol) in n-butanol (2mL), and microwave at 160°C The reaction was carried out for 3 hours. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain white solid 16 (33 mg, yield 38%). ESI-MS (m/z): 487.3[M+H] + ; 1 H NMR (500MHz, DMSO-d 6 ) δ9.81 (s, 1H), 8.48 (d, J=2.1Hz, 1H), 7.71 (dd, J=8.0, 2.3Hz, 1H), 7.02(d, J=8.1Hz, 1H), 6.98(t, J=6.4Hz, 1H), 6.42(s, 1H), 5.54(s, 2H) , 4.43-4.31(m, 2H), 3.98(q, J=6.8Hz, 1H), 2.89(s, 3H), 2.10(s, 3H), 1.96-1.89(m, 1H), 1.17(d, J =6.8Hz, 3H), 0.92-0.84(m, 2H), 0.70-0.63(m, 2H).
实施例17Example 17
(S)-2-(((6-((3-环丙基-5-(三氟甲基)-1H-吡唑-1-基)甲基)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-((3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)pyridin-3-yl)methyl)amino )-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one
实施例17由以下步骤制备：
Example 17 was prepared by the following steps:
将中间体Int-1(35mg，0.15mmol)，中间体Int-17(50mg，0.17mmol)和三氟乙酸(2mg，0.02mmol)溶解在正丁醇(2mL)中，在微波160℃的条件下反应3小时。LCMS监测反应结束。反应液通过反相制备HPLC纯化，得到白色固体17(15mg，收率20％)。ESI-MS(m/z)：487.2[M+H]+；1H NMR(500MHz，DMSO-d6)δ9.96(s，1H)，8.46(s，1H)，7.70(dd，J＝8.2，2.2Hz，1H)，6.90(d，J＝8.0Hz，1H)，6.67(s，1H)，5.41(s，2H)，4.39(s，2H)，4.15-3.91(m，1H)，2.91(s，3H)，2.13(s，3H)，1.96-1.87(m，1H)，1.20(d，J＝6.8Hz，3H)，0.92-0.83(m，2H)，0.72-0.63(m，2H)。Dissolve intermediate Int-1 (35mg, 0.15mmol), intermediate Int-17 (50mg, 0.17mmol) and trifluoroacetic acid (2mg, 0.02mmol) in n-butanol (2mL), and microwave under the condition of 160°C The reaction was carried out for 3 hours. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain white solid 17 (15 mg, yield 20%). ESI-MS (m/z): 487.2[M+H] + ; 1 H NMR (500MHz, DMSO-d 6 ) δ9.96(s, 1H), 8.46(s, 1H), 7.70(dd, J= 8.2, 2.2Hz, 1H), 6.90(d, J=8.0Hz, 1H), 6.67(s, 1H), 5.41(s, 2H), 4.39(s, 2H), 4.15-3.91(m, 1H), 2.91(s, 3H), 2.13(s, 3H), 1.96-1.87(m, 1H), 1.20(d, J=6.8Hz, 3H), 0.92-0.83(m, 2H), 0.72-0.63(m, 2H).
实施例18Example 18
2′-(((6-((1-环丙基-3-(三氟甲基)-1H-吡唑-5-基)氧代)吡啶-3-基)甲基)氨基)-4′-甲基-8′-(甲基-d3)-5′，8′-二氢-6′H-螺[环丙烷-1，7′-蝶啶]-6′-酮
2'-(((6-((1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxo)pyridin-3-yl)methyl)amino)-4 '-Methyl-8'-(methyl-d3)-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pteridine]-6'-one
实施例18由以下步骤制备：
Example 18 was prepared by the following steps:
第一步：将化合物18a(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18b(1.0g，收率84％)的粗品。ESI-MS(m/z)：236.3[M+H]+。The first step: compound 18a (1.01g, 5mmol) and potassium hydroxide (842mg, 15mmol) were dissolved in anhydrous dimethyl sulfoxide (10mL), then deuteroiodomethane (1.59g, 11mmol) was added dropwise into the reaction solution. The reaction solution was stirred at room temperature for 8 hours. LCMS monitored the completion of the reaction. The reaction solution was diluted with water, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude compound 18b (1.0 g, yield 84%). ESI-MS (m/z): 236.3 [M+H] + .
第二步：将化合物18b(1.0g)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18c(720mg)的粗品。ESI-MS(m/z)：136.1[M+H]+。Second step: Compound 18b (1.0 g) was dissolved in dioxane hydrochloride solution (4M, 10 mL). The reaction was stirred at room temperature for 4 hours. LCMS monitored the completion of the reaction. The reaction solution was concentrated under reduced pressure to obtain a crude product of Compound 18c (720 mg). ESI-MS (m/z): 136.1 [M+H] + .
第三步：将化合物18c(720mg)和化合物18d(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18d(993mg，，两步反应收率77％)。ESI-MS(m/z)：307.2 [M+H]+。The third step: Compound 18c (720 mg) and compound 18d (872 mg, 4.19 mmol) were dissolved in tetrahydrofuran (10 mL), and N,N-diisopropylpropylamine (1.62 g, 12.57 mmol) was added. The reaction solution was stirred at room temperature for 8 hours. LCMS monitored the completion of the reaction. The reaction solution was diluted with water, filtered, the filter cake was washed with water, and dried to obtain off-white solid 18d (993 mg, yield 77% in two steps). ESI-MS (m/z): 307.2 [M+H] + .
第四步：将化合物18d(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18e(30mg，收率13％)。ESI-MS(m/z)：242.3[M+H]+。Step 4: Dissolve compound 18d (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 was stirred at room temperature for 15 minutes. LCMS monitored the complete reaction of starting material. Dioxane hydrochloride solution (4M, 1.25 mL) was added to the reaction solution. The reaction 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 18e (30 mg, yield 13%). ESI-MS (m/z): 242.3 [M+H] + .
第五步：将Int-3(35mg，0.12mmol)和化合物18e(28mg，0.12mmol)溶于正丁醇(3mL)中，加入对甲苯磺酸一水合物(2mg，0.01mmol)，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，残余物用反向制备HPLC纯化得到白色固体18(10mg，收率17％)。ESI-MS(m/z)：504.3[M+H]+；1H NMR(500MHz，DMSO)δ8.14(d，J＝2.1Hz，1H)，7.89(dd，J＝8.4，2.3Hz，1H)，7.20(d，J＝8.4Hz，1H)，7.06-6.98(m，1H)，6.54(s，1H)，4.36(d，J＝6.2Hz，2H)，3.46(ddd，J＝11.4，7.5，3.9Hz，1H)，2.11(s，3H)，1.27(dd，J＝7.5，5.1Hz，2H)，1.11(dd，J＝7.5，5.1Hz，2H)，1.06-0.99(m，2H)，0.91(dt，J＝7.7，5.3Hz，2H)。Step 5: Dissolve Int-3 (35mg, 0.12mmol) and compound 18e (28mg, 0.12mmol) in n-butanol (3mL), add p-toluenesulfonic acid monohydrate (2mg, 0.01mmol), and the reaction solution Stir 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 reverse preparative HPLC to obtain white solid 18 (10 mg, yield 17%). ESI-MS (m/z): 504.3[M+H] + ; 1 H NMR (500MHz, DMSO) δ8.14 (d, J=2.1Hz, 1H), 7.89 (dd, J=8.4, 2.3Hz, 1H), 7.20(d, J=8.4Hz, 1H), 7.06-6.98(m, 1H), 6.54(s, 1H), 4.36(d, J=6.2Hz, 2H), 3.46(ddd, J=11.4 , 7.5, 3.9Hz, 1H), 2.11(s, 3H), 1.27(dd, J=7.5, 5.1Hz, 2H), 1.11(dd, J=7.5, 5.1Hz, 2H), 1.06-0.99(m, 2H), 0.91 (dt, J=7.7, 5.3 Hz, 2H).
实施例19Example 19
(S)-2-(((6-((1-(3，3-二氟环丁基)-3-(三氟甲基)-1H-吡唑-5-基)氧代)吡啶-3-基)甲基)氨基)-4，7-二甲基-8-(甲基-d3)-7，8-二氢蝶啶-6(5H)-酮
(S)-2-(((6-((1-(3,3-difluorocyclobutyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxo)pyridine- 3-yl)methyl)amino)-4,7-dimethyl-8-(methyl-d3)-7,8-dihydropteridin-6(5H)-one
实施例19’ Example 19'
(S)-2-(((6-((1-(3，3-二氟环丁基)-5-(三氟甲基)-1H-吡唑-3-基)氧代)吡啶-3-基)甲基)氨基)-4，7-二甲基-8-(甲基-d3)-7，8-二氢蝶啶-6(5H)-酮
(S)-2-(((6-((1-(3,3-difluorocyclobutyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)oxo)pyridine- 3-yl)methyl)amino)-4,7-dimethyl-8-(methyl-d3)-7,8-dihydropteridin-6(5H)-one
实施例19和19’由以下步骤制备：
Examples 19 and 19' were prepared by the following steps:
第一步：在冰浴条件下，将三氟甲磺酸酐(1.25g，4.44mmol)加入到化合物19a(400mg，3.70mmol)和4-二甲氨基吡啶(543mg，4.44mmol)的二氯甲烷溶液(10mL)中。在室温条件下反应16小时后，加入饱和氯化铵水溶液淬灭反应，二氯甲烷萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩有机相得到化合物19b的粗产品，直接用于下一步反应。The first step: trifluoromethanesulfonic anhydride (1.25 g, 4.44 mmol) was added to compound 19a (400 mg, 3.70 mmol) and 4-dimethylaminopyridine (543 mg, 4.44 mmol) in dichloromethane under ice bath conditions solution (10 mL). After reacting at room temperature for 16 hours, the reaction was quenched by adding saturated aqueous ammonium chloride solution, extracted with dichloromethane, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain the crude product of compound 19b , used directly in the next reaction.
第二步：将化合物Int-5b(150mg，0.59mmol)和碳酸铯(385mg，1.18mmol)溶解于N，N-二甲基甲酰胺(5mL)中，随后向反应液滴加化合物19b粗品(284mg)。反应液在室温下搅拌16小时后，LCMS监测反应结束，加入水淬灭反应，乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩有 机相得到19c和19c’的混合物(170mg，84％)。ESI-MS(m/z)：345.2[M+H]+。The second step: compound Int-5b (150mg, 0.59mmol) and cesium carbonate (385mg, 1.18mmol) were dissolved in N,N-dimethylformamide (5mL), then the crude product of compound 19b was added dropwise to the reaction solution ( 284mg). After the reaction solution was stirred at room temperature for 16 hours, LCMS monitored the completion of the reaction, adding water to quench the reaction, extraction with ethyl acetate, combined organic phases and washing with saturated brine, drying over anhydrous sodium sulfate, and concentrating under reduced pressure to obtain The organic phase gave a mixture of 19c and 19c' (170 mg, 84%). ESI-MS (m/z): 345.2 [M+H] + .
第三步：将19c和19c’的混合物(283mg，0.82mmol)溶于甲醇(30mL)中，依次向反应体系加入氨水(3mL)和雷尼镍(3mL，水混悬液)，通过氢气球置换氢气并在氢气氛围、室温条件下反应2小时，LCMS监测反应结束。反应液用甲醇稀释，硅藻土过滤，滤液浓缩后得到19d和19d’的混合物，直接用于下一步反应。ESI-MS(m/z)：349.3[M+H]+。Step 3: Dissolve the mixture of 19c and 19c' (283mg, 0.82mmol) in methanol (30mL), add ammonia water (3mL) and Raney nickel (3mL, aqueous suspension) to the reaction system in turn, and pass through the hydrogen balloon The hydrogen was replaced and reacted for 2 hours under a hydrogen atmosphere at room temperature, and the reaction was completed by LCMS monitoring. The reaction solution was diluted with methanol, filtered through celite, and the filtrate was concentrated to obtain a mixture of 19d and 19d', which was directly used in the next reaction. ESI-MS (m/z): 349.3 [M+H] + .
第四步：将Int-2(80mg，0.35mmol)，19d和19d’的混合物(146mg，粗品)和一水对甲苯磺酸(4mg，0.03mmol)溶解在正丁醇(2mL)中，在微波160℃的条件下反应3小时。LCMS监测反应结束。反应液通过反相制备HPLC纯化，分别得到白色固体19(28mg，收率15％)和19’(17mg，收率9％)。The fourth step: Int-2 (80mg, 0.35mmol), the mixture of 19d and 19d' (146mg, crude product) and p-toluenesulfonic acid monohydrate (4mg, 0.03mmol) were dissolved in n-butanol (2mL), in React under the condition of microwave at 160° C. for 3 hours. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain white solids 19 (28 mg, yield 15%) and 19' (17 mg, yield 9%), respectively.
实施例19：ESI-MS(m/z)：542.3[M+H]+；1H NMR(500MHz，DMSO-d6)δ9.82(s，1H)，8.14(d，J＝2.3Hz，1H)，7.91(dd，J＝8.4，2.4Hz，1H)，7.21(d，J＝8.4Hz，1H)，6.99(t，J＝6.2Hz，1H)，6.62(s，1H)，4.97-4.79(m，1H)，4.48-4.29(m，2H)，3.99(q，J＝6.8Hz，1H)，3.20-3.03(m，4H)，2.11(s，3H)，1.17(d，J＝6.9Hz，3H)。Example 19: ESI-MS (m/z): 542.3[M+H] + ; 1 H NMR (500MHz, DMSO-d 6 ) δ9.82(s, 1H), 8.14(d, J=2.3Hz, 1H), 7.91(dd, J=8.4, 2.4Hz, 1H), 7.21(d, J=8.4Hz, 1H), 6.99(t, J=6.2Hz, 1H), 6.62(s, 1H), 4.97- 4.79(m, 1H), 4.48-4.29(m, 2H), 3.99(q, J=6.8Hz, 1H), 3.20-3.03(m, 4H), 2.11(s, 3H), 1.17(d, J= 6.9Hz, 3H).
实施例19’：ESI-MS(m/z)：542.2[M+H]+；1H NMR(500MHz，DMSO-d6)δ9.82(s，1H)，8.13(d，J＝2.4Hz，1H)，7.84(dd，J＝8.4，2.4Hz，1H)，7.08(d，J＝8.4Hz，1H)，6.96(t，J＝6.3Hz，1H)，6.81(s，1H)，5.00-4.86(m，1H)，4.47-4.28(m，2H)，3.99(q，J＝6.8Hz，1H)，3.28-3.11(m，4H)，2.12(s，3H)，1.18(d，J＝6.8Hz，3H)。Example 19': ESI-MS (m/z): 542.2[M+H] + ; 1 H NMR (500MHz, DMSO-d 6 ) δ9.82(s, 1H), 8.13(d, J=2.4Hz , 1H), 7.84(dd, J=8.4, 2.4Hz, 1H), 7.08(d, J=8.4Hz, 1H), 6.96(t, J=6.3Hz, 1H), 6.81(s, 1H), 5.00 -4.86(m, 1H), 4.47-4.28(m, 2H), 3.99(q, J=6.8Hz, 1H), 3.28-3.11(m, 4H), 2.12(s, 3H), 1.18(d, J = 6.8Hz, 3H).
实施例20Example 20
(S)-2-(((6-((1-环丙基-3-(三氟甲基)-1H-吡唑-5-基)氧代)吡啶-3-基)甲基)氨基)-7-(2，2-二氟乙基)-4，8-二甲基-7，8-二氢蝶啶-6(5H)-酮
(S)-2-(((6-((1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxo)pyridin-3-yl)methyl)amino )-7-(2,2-difluoroethyl)-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one
实施例20由以下步骤制备：
Example 20 was prepared by the following steps:
第一步：将化合物Int-6(50mg，0.18mmol)和化合物Int-3(70mg，0.23mmol)溶于正丁醇(6mL)中，加入对甲苯磺酸一水合物(3mg，18umol)，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，残余物用反向制备HPLC纯化得到白色固体20(3.9mg，收率4％)。ESI-MS(m/z)：539.3[M+H]+；1H NMR(500MHz，DMSO-d6)δ8.16(d，J＝2.3Hz，1H)，7.91(dd，J＝8.4，2.5Hz，1H)，7.20(d，J＝8.4Hz，1H)，7.06(s，1H)，6.54(s，1H)，6.21-5.90(m，1H)，4.42-4.29(m，2H)，4.26-4.17(m，1H)，3.51-3.46(m，1H)，2.96(s，3H)，2.32-2.21(m，2H)，2.13(s，3H)，1.06-1.01(m，2H)，0.96-0.91(m，2H)。The first step: Dissolve compound Int-6 (50mg, 0.18mmol) and compound Int-3 (70mg, 0.23mmol) in n-butanol (6mL), add p-toluenesulfonic acid monohydrate (3mg, 18umol), 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 reverse preparative HPLC to obtain a white solid 20 (3.9 mg, yield 4%). ESI-MS (m/z): 539.3[M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ8.16 (d, J=2.3Hz, 1H), 7.91 (dd, J=8.4, 2.5 Hz, 1H), 7.20(d, J=8.4Hz, 1H), 7.06(s, 1H), 6.54(s, 1H), 6.21-5.90(m, 1H), 4.42-4.29(m, 2H), 4.26 -4.17(m, 1H), 3.51-3.46(m, 1H), 2.96(s, 3H), 2.32-2.21(m, 2H), 2.13(s, 3H), 1.06-1.01(m, 2H), 0.96 -0.91 (m, 2H).
实施例21Example 21
(S)-2-(((6-((4-环丙基-2-(三氟甲基)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-((4-cyclopropyl-2-(trifluoromethyl)pyrimidin-5-yl)oxo)pyridin-3-yl)methyl)amino)-4, 7,8-trimethyl-7,8-dihydropteridin-6(5H)-one
实施例21由以下步骤制备：
Example 21 was prepared by the following steps:
第一步：将化合物15d(550mg，1.91mmol)、环丙基硼酸(818mg，9.53mmol)、醋酸钯(42mg，0.19mmol)、三环己基膦(106mg，0.38mmol)和磷酸钾(1.21g，5.72mmol)加入到1，4-二氧六环(50mL)和水(5mL)混合溶液中，反应体系置换氮气后，在氮气氛围下110℃下反应16小时，LCMS监测反应结束。减压蒸馏除去溶剂，再加入水和乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，有机相浓缩后通过硅胶柱层析(石油醚∶乙酸乙酯＝5∶1)纯化得到白色固体21a(530mg，收率94％)。ESI-MS(m/z)：295.3[M+H]+。The first step: Compound 15d (550mg, 1.91mmol), cyclopropylboronic acid (818mg, 9.53mmol), palladium acetate (42mg, 0.19mmol), tricyclohexylphosphine (106mg, 0.38mmol) and potassium phosphate (1.21g , 5.72mmol) was added to the mixed solution of 1,4-dioxane (50mL) and water (5mL). After the reaction system was replaced with nitrogen, it was reacted at 110°C under nitrogen atmosphere for 16 hours, and the reaction was monitored by LCMS. The solvent was distilled off under reduced pressure, then water and ethyl acetate were added for extraction, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, the organic phase was concentrated and subjected to silica gel column chromatography (petroleum ether:ethyl acetate=5:1 ) to obtain white solid 21a (530 mg, yield 94%). ESI-MS (m/z): 295.3 [M+H] + .
第二步：将化合物21a(530mg，1.80mmol)溶于甲醇(10mL)，向反应体系加入钯碳(10％，21mg)，通过氢气球置换氢气并在氢气氛围、室温条件下反应16小时，LCMS监测反应结束。反应液用甲醇稀释，抽滤，滤液浓缩后得到棕色油状液体21b(330mg，收率89％)。ESI-MS(m/z)：203.3[M-H]-。The second step: Dissolving compound 21a (530mg, 1.80mmol) in methanol (10mL), adding palladium carbon (10%, 21mg) to the reaction system, displacing hydrogen through a hydrogen balloon and reacting under hydrogen atmosphere and room temperature for 16 hours, LCMS monitored the completion of the reaction. The reaction solution was diluted with methanol, suction filtered, and the filtrate was concentrated to obtain brown oily liquid 21b (330 mg, yield 89%). ESI-MS (m/z): 203.3 [MH] - .
第三步：将化合物21b(330mg，1.62mmol)、Int-3d(236mg，1.94mmol)和碳酸铯(1.05g，3.23mmol)加入到乙腈(10mL)中，在室温下反应16小时， LCMS监测反应结束。减压蒸馏除去乙腈，再加入水和乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，有机相浓缩后通过硅胶柱层析(石油醚∶乙酸乙酯＝3∶1)纯化得到白色固体21c(450mg，收率90％)。ESI-MS(m/z)：307.1[M+H]+。The third step: compound 21b (330mg, 1.62mmol), Int-3d (236mg, 1.94mmol) and cesium carbonate (1.05g, 3.23mmol) were added to acetonitrile (10mL), reacted at room temperature for 16 hours, LCMS monitored the completion of the reaction. Acetonitrile was distilled off under reduced pressure, then water and ethyl acetate were added for extraction, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, the organic phase was concentrated and then subjected to silica gel column chromatography (petroleum ether:ethyl acetate=3:1 ) to obtain white solid 21c (450 mg, yield 90%). ESI-MS (m/z): 307.1 [M+H] + .
第四步：将化合物21c(350mg，1.14mmol)溶于甲醇(20mL)，依次向反应体系加入氨水(3.5mL)和雷尼镍(3.5mL，水混悬液)，通过氢气球置换氢气并在氢气氛围、室温条件下反应16小时，LCMS监测反应结束。反应液用甲醇稀释，硅藻土抽滤，滤液浓缩后通过硅胶柱层析(二氯甲烷∶甲醇＝9∶1)纯化，得到黄色油状液体21d(300mg，收率84％)。ESI-MS(m/z)：311.2[M+H]+。Step 4: Dissolve compound 21c (350mg, 1.14mmol) in methanol (20mL), add ammonia water (3.5mL) and Raney nickel (3.5mL, aqueous suspension) to the reaction system in turn, replace the hydrogen with a hydrogen balloon and The reaction was carried out under hydrogen atmosphere and room temperature for 16 hours, and the reaction was monitored by LCMS to complete. The reaction solution was diluted with methanol, suction-filtered with celite, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane:methanol=9:1) to obtain 21d (300 mg, yield 84%) as a yellow oily liquid. ESI-MS (m/z): 311.2 [M+H] + .
第五步：将化合物Int-1(50mg，0.22mmol)和化合物21d(82.13mg，0.26mmol)溶于正丁醇(2mL)中，加入对甲苯磺酸一水合物(4.19mg，22umol)，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，残余物用反向制备HPLC纯化得到白色固体21(48.18mg，收率43％)。ESI-MS(m/z)：501.3[M+H]+；1H NMR(500MHz，DMSO-d6)δ9.87(S，1H)，8.78(s，1H)，8.08(d，J＝2.3Hz，1H)，7.91(dd，J＝8.5，2.4Hz，1H)，7.26(d，J＝8.4Hz，1H)，7.04(d，J＝6.5Hz，1H)，4.35(qd，J＝15.1，6.3Hz，2H)，4.00(q，J＝6.8Hz，1H)，2.91(s，3H)，2.27-2.17(m，1H)，2.12(s，3H)，1.17(d，J＝6.8Hz，3H)，1.15-1.07(m，4H).Step 5: Dissolve compound Int-1 (50mg, 0.22mmol) and compound 21d (82.13mg, 0.26mmol) in n-butanol (2mL), add p-toluenesulfonic acid monohydrate (4.19mg, 22umol), 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 reverse preparative HPLC to obtain a white solid 21 (48.18 mg, yield 43%). ESI-MS (m/z): 501.3[M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.87(S, 1H), 8.78(s, 1H), 8.08(d, J=2.3 Hz, 1H), 7.91(dd, J=8.5, 2.4Hz, 1H), 7.26(d, J=8.4Hz, 1H), 7.04(d, J=6.5Hz, 1H), 4.35(qd, J=15.1 , 6.3Hz, 2H), 4.00(q, J=6.8Hz, 1H), 2.91(s, 3H), 2.27-2.17(m, 1H), 2.12(s, 3H), 1.17(d, J=6.8Hz , 3H), 1.15-1.07(m, 4H).
实施例22Example 22
2-(((6-((1-环丙基-3-(三氟甲基)-1H-吡唑-5-基)氧代)吡啶-3-基)甲基)氨基)-4，7，7-三甲基-8-(甲基-d3)-7，8-二氢蝶啶-6(5H)-酮
2-(((6-((1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxo)pyridin-3-yl)methyl)amino)-4, 7,7-trimethyl-8-(methyl-d3)-7,8-dihydropteridin-6(5H)-one
实施例22由以下步骤制备：
Example 22 was prepared by the following steps:
第一步：将化合物Int-18(50mg，0.17mmol)和化合物Int-3(40.85mg，0.17mmol)溶于正丁醇(2mL)中，加入对甲苯磺酸一水合物(2.89mg，17umol)，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，残余物用反向制备HPLC纯化得到白色固体22(20mg，收率23％)。ESI-MS(m/z)：506.3[M+H]+；1H NMR(500MHz，DMSO-d6)δ9.85(s，1H)，8.15(d，J＝2.0Hz，1H)，7.90(dd，J＝8.4，2.3Hz，1H)，7.20(d，J＝8.4Hz，1H)，7.08-6.98(m，1H)，6.55(s，1H)，4.37(d，J＝6.2Hz，2H)，3.49-3.44(m，1H)，2.12(s，3H)，1.31(s，6H)，1.06-1.00(m，2H)，0.91(td，J＝7.2，5.1Hz，2H).The first step: Dissolve compound Int-18 (50mg, 0.17mmol) and compound Int-3 (40.85mg, 0.17mmol) in n-butanol (2mL), add p-toluenesulfonic acid monohydrate (2.89mg, 17umol ), 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 reverse preparative HPLC to obtain a white solid 22 (20 mg, yield 23%). ESI-MS (m/z): 506.3[M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.85 (s, 1H), 8.15 (d, J=2.0Hz, 1H), 7.90 ( dd, J=8.4, 2.3Hz, 1H), 7.20(d, J=8.4Hz, 1H), 7.08-6.98(m, 1H), 6.55(s, 1H), 4.37(d, J=6.2Hz, 2H ), 3.49-3.44(m, 1H), 2.12(s, 3H), 1.31(s, 6H), 1.06-1.00(m, 2H), 0.91(td, J=7.2, 5.1Hz, 2H).
实施例23Example 23
(S)-2-(((6-((4-乙基-2-(三氟甲基)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-((4-Ethyl-2-(trifluoromethyl)pyrimidin-5-yl)oxo)pyridin-3-yl)methyl)amino)-4,7 ,8-Trimethyl-7,8-dihydropteridin-6(5H)-one
实施例23由以下步骤制备：
Example 23 was prepared by the following steps:
第一步：将化合物15d(2.0g，6.93mmol)，乙烯基硼酸频哪醇酯(3.20g，20.79mmol)，醋酸钯(155mg，0.69mol)，磷酸钾(2.94g，13.86mmol)依次加入到1，4-二氧六环(150mL)中，加入水(15mL)，氮气保护条件下，90℃保温搅拌17小时，HPLC监测原料转化完全，滤液浓缩。残余物通过硅胶柱层析纯化(石油醚/乙酸乙酯＝1/9)得到白色固体23a(1.18g，收率60％，纯度61％)。ESI-MS(m/z)：281.1[M+H]+。The first step: compound 15d (2.0g, 6.93mmol), vinyl borate pinacol ester (3.20g, 20.79mmol), palladium acetate (155mg, 0.69mol), potassium phosphate (2.94g, 13.86mmol) were added in sequence To 1,4-dioxane (150 mL), water (15 mL) was added, under the condition of nitrogen protection, the mixture was stirred at 90° C. for 17 hours, the complete conversion of the raw material was monitored by HPLC, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/9) to obtain white solid 23a (1.18 g, yield 60%, purity 61%). ESI-MS (m/z): 281.1 [M+H] + .
第二步：将化合物23a(1.0g，3.73mmol)加入到20ml甲醇中，加入钯炭(10％，100mg)，反应体系置换氢气后在室温下搅拌过夜，反应液硅藻土过滤，滤液浓缩，得到化合物23b(677mg，收率94％，纯度97％)。ESI-MS(m/z)：191.3[M-H]-。Step 2: Add compound 23a (1.0g, 3.73mmol) to 20ml of methanol, add palladium carbon (10%, 100mg), replace hydrogen in the reaction system and stir at room temperature overnight, filter the reaction solution with diatomaceous earth, and concentrate the filtrate , to obtain compound 23b (677 mg, yield 94%, purity 97%). ESI-MS (m/z): 191.3 [MH] - .
第三步：将化合物23b(0.5g，2.81mmol)，Cs2CO3(1.83g，5.61mmol)，Int-3d(514mg，4.21mmol)依次加入到N，N-二甲基甲酰胺(10mL)中，20℃搅拌过夜，HPLC监测原料消失。反应液加到50ml冰水中，搅拌0.5小时，抽滤，得到黄色固体23c(530mg，收率64％，纯度99％)。ESI-MS(m/z)：294.3[M+H]+。 Step 3: Add compound 23b (0.5g, 2.81mmol), Cs 2 CO 3 (1.83g, 5.61mmol), Int-3d (514mg, 4.21mmol) to N,N-dimethylformamide (10mL ), stirred overnight at 20°C, and the disappearance of raw materials was monitored by HPLC. The reaction solution was added to 50 ml of ice water, stirred for 0.5 hours, and filtered with suction to obtain a yellow solid 23c (530 mg, yield 64%, purity 99%). ESI-MS (m/z): 294.3 [M+H] + .
第四步：将化合物23c(100mg，0.36mmol)溶于甲醇(5mL)中，加入氨水(0.2mL)中，加入Raney Nickel(0.5mL，水混悬液)，反应体系置换氢气后在室温下搅拌2小时。反应液硅藻土过滤，滤液浓缩，得到化合物23d(97mg，收率93％，纯度90％)，ESI-MS(m/z)：298.5[M+H]+。Step 4: Dissolve compound 23c (100mg, 0.36mmol) in methanol (5mL), add ammonia water (0.2mL), add Raney Nickel (0.5mL, aqueous suspension), and replace hydrogen in the reaction system at room temperature Stir for 2 hours. The reaction liquid was filtered with celite, and the filtrate was concentrated to obtain compound 23d (97 mg, yield 93%, purity 90%), ESI-MS (m/z): 298.5 [M+H] + .
第五步：将化合物Int-1(79.74mg，0.35mmol)和化合物23d(104.93mg，0.35mmol)溶于正丁醇(2mL)中，加入对甲苯磺酸一水合物(6.68mg，0.35umol)，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，残余物用反向制备HPLC纯化得到白色固体23(33mg，收率19％)。ESI-MS(m/z)：489.3[M+H]+；1H NMR(500MHz，DMSO-d6)δ9.85(s，1H)，8.87(s，1H)，8.07(s，1H)，7.91(d，J＝8.1Hz，1H)，7.24(d，J＝8.4Hz，1H)，7.01(s，1H)，4.35(s，2H)，4.08-3.91(m，1H)，2.90(s，3H)，2.82-2.68(m，2H)，2.11(s，3H)，1.32-0.96(m，6H).Step 5: Dissolve compound Int-1 (79.74mg, 0.35mmol) and compound 23d (104.93mg, 0.35mmol) in n-butanol (2mL), add p-toluenesulfonic acid monohydrate (6.68mg, 0.35umol ), 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 reverse preparative HPLC to obtain a white solid 23 (33 mg, yield 19%). ESI-MS (m/z): 489.3[M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.85 (s, 1H), 8.87 (s, 1H), 8.07 (s, 1H), 7.91(d, J=8.1Hz, 1H), 7.24(d, J=8.4Hz, 1H), 7.01(s, 1H), 4.35(s, 2H), 4.08-3.91(m, 1H), 2.90(s , 3H), 2.82-2.68(m, 2H), 2.11(s, 3H), 1.32-0.96(m, 6H).
实施例24Example 24
(S)-2-(((6-((4-乙基-2-(三氟甲基)嘧啶-5-基)氧代)吡啶-3-基)甲基)氨基)-4，7-二甲基-8-(甲基-d3)-7，8-二氢蝶啶-6(5H)-酮
(S)-2-(((6-((4-Ethyl-2-(trifluoromethyl)pyrimidin-5-yl)oxo)pyridin-3-yl)methyl)amino)-4,7 -Dimethyl-8-(methyl-d3)-7,8-dihydropteridin-6(5H)-one
用Int-2替换实施例23中第五步的Int-1，用类似的方法和反应步骤，得到化合物24。ESI-MS(m/z)：492.3[M+H]+；1H NMR(500MHz，DMSO-d6)δ9.82(s，1H)，8.87(s，1H)，8.08(d，J＝2.4Hz，1H)，7.92(dd，J＝8.5，2.4Hz，1H)，7.24(d，J＝8.4Hz，1H)，7.02-6.95(m，1H)，4.36(dd，J＝8.7，6.3Hz，2H)，4.00(t，J＝6.8Hz，1H)，2.76(q，J＝7.5Hz，2H)，2.12(s，3H)，1.20-1.16(m，6H). Compound 24 was obtained by replacing Int-1 in the fifth step in Example 23 with Int-2 and using a similar method and reaction steps. ESI-MS (m/z): 492.3[M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.82(s, 1H), 8.87(s, 1H), 8.08(d, J=2.4 Hz, 1H), 7.92(dd, J=8.5, 2.4Hz, 1H), 7.24(d, J=8.4Hz, 1H), 7.02-6.95(m, 1H), 4.36(dd, J=8.7, 6.3Hz , 2H), 4.00(t, J=6.8Hz, 1H), 2.76(q, J=7.5Hz, 2H), 2.12(s, 3H), 1.20-1.16(m, 6H).
实施例25Example 25
(S)-2-(((6-((2-(二氟甲基)-6-(三氟甲基)吡啶-3-基)氧代)吡啶-3-基)甲基)氨基)-4，7-二甲基-8-(甲基-d3)-7，8-二氢蝶啶-6(5H)-酮
(S)-2-(((6-((2-(difluoromethyl)-6-(trifluoromethyl)pyridin-3-yl)oxo)pyridin-3-yl)methyl)amino) -4,7-Dimethyl-8-(methyl-d3)-7,8-dihydropteridin-6(5H)-one
实施例25由以下步骤制备：
Example 25 was prepared by the following steps:
第一步：将化合物Int-8c(930mg，2.45mmol)溶于四氢呋喃(10mL)中，在-78℃下将正丁基锂(1.5mL，2M in hexane)缓慢滴加至溶液中。反应液继续在-78℃下搅拌10分钟。随后将N，N-二甲基甲酰胺(359mg，4.91mmol)缓慢滴加至反应液中，反应液在-78℃下搅拌1小时。LCMS检测反应结束。加饱和氯化铵水溶液淬灭反应，二氯甲烷萃取，合并有机相并用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，残余液通过硅胶柱层析(石油醚/乙酸乙酯＝10/3)纯化得到化合物25a(281mg，收率41％)。ESI-MS(m/z)：282.2[M+H]+。 Step 1: Compound Int-8c (930 mg, 2.45 mmol) was dissolved in tetrahydrofuran (10 mL), and n-butyllithium (1.5 mL, 2M in hexane) was slowly added dropwise to the solution at -78°C. The reaction solution was further stirred at -78°C for 10 minutes. Then N,N-dimethylformamide (359mg, 4.91mmol) was slowly added dropwise to the reaction solution, and the reaction solution was stirred at -78°C for 1 hour. LCMS detects that the reaction is complete. Add saturated aqueous ammonium chloride solution to quench the reaction, extract with dichloromethane, combine the organic phases and wash with saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and the residue is subjected to silica gel column chromatography (petroleum ether/ethyl acetate =10/3) was purified to obtain compound 25a (281 mg, yield 41%). ESI-MS (m/z): 282.2 [M+H] + .
第二步：将化合物25a(230mg，0.82mmol)溶于二氯甲烷(5mL)中，在0℃下将二乙胺基三氟化硫(264mg，1.64mmol)缓慢滴加至溶液中，反应在0℃继续搅拌2小时。LCMS检测反应结束。加饱和碳酸氢钠水溶液淬灭反应，二氯甲烷萃取，合并有机相并用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩得到化合物25b(247mg)的粗品。ESI-MS(m/z)：304.1[M+H]+。The second step: compound 25a (230mg, 0.82mmol) was dissolved in dichloromethane (5mL), and diethylaminosulfur trifluoride (264mg, 1.64mmol) was slowly added dropwise to the solution at 0°C, and the reaction Stirring was continued for 2 hours at 0°C. LCMS detects that the reaction is complete. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, the combined organic phases were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product of compound 25b (247 mg). ESI-MS (m/z): 304.1 [M+H] + .
第三步：将化合物25b(247mg，粗品)溶于二氯甲烷(5mL)中，在-78℃下将三溴化硼(308mg，1.23mmol)缓慢滴加至溶液中，反应在-78℃继续搅拌30分钟。LCMS检测反应结束。加饱和碳酸氢钠水溶液淬灭反应，二氯甲烷洗涤，水相用盐酸水溶液(4M)调节pH至2，二氯甲烷萃取，合并有机相并用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩得到化合物25c(82mg，两步反应收率47％)。ESI-MS(m/z)：212.3[M-H]+。Step 3: Dissolve compound 25b (247mg, crude product) in dichloromethane (5mL), slowly add boron tribromide (308mg, 1.23mmol) into the solution at -78°C, and react at -78°C Stirring was continued for 30 minutes. LCMS detects that the reaction is complete. Add saturated aqueous sodium bicarbonate solution to quench the reaction, wash with dichloromethane, adjust the pH of the aqueous phase to 2 with aqueous hydrochloric acid (4M), extract with dichloromethane, combine the organic phases and wash with saturated aqueous sodium chloride, and dry over anhydrous sodium sulfate. Concentration under reduced pressure gave compound 25c (82 mg, yield 47% in two steps). ESI-MS (m/z): 212.3 [MH] + .
第四步：将化合物25c(82mg，0.39mmol)和化合物Int-2(47mg，0.39mmol)溶于N，N-二甲基甲酰胺(3mL)中，加入碳酸铯(251mg，0.77mmol)，反应液在50℃搅拌12小时。LCMS检测反应结束。反应液加水稀释，减压抽滤得到化合物25d(98mg，收率80％)。Step 4: Dissolve compound 25c (82mg, 0.39mmol) and compound Int-2 (47mg, 0.39mmol) in N,N-dimethylformamide (3mL), add cesium carbonate (251mg, 0.77mmol), The reaction solution was stirred at 50°C for 12 hours. LCMS detects that the reaction is complete. The reaction solution was diluted with water, and filtered under reduced pressure to obtain compound 25d (98 mg, yield 80%).
第五步：将化合物25d(98mg，0.32mmol)溶于甲醇(3mL)和氨水(0.5mL)中，加入Raney Nickel(0.5mL，水混悬液)，反应体系置换氢气后在室温下搅拌12小时，LC-MS监测反应已完全。反应液硅藻土过滤，滤液浓缩。残余物通过硅胶柱层析纯化(二氯甲烷/甲醇＝10/1)得到无色油状液体化合物25e(40mg，收率40％)。ESI-MS(m/z)：320.2[M+H]+。Step 5: Dissolve compound 25d (98mg, 0.32mmol) in methanol (3mL) and ammonia water (0.5mL), add Raney Nickel (0.5mL, aqueous suspension), and stir the reaction system at room temperature for 12 Hours, LC-MS monitoring reaction is complete. The reaction solution was filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol=10/1) to obtain colorless oily liquid compound 25e (40 mg, yield 40%). ESI-MS (m/z): 320.2 [M+H] + .
第六步：将化合物25e(20mg，0.06mmol)和Int-2(15mg，0.06mmol)溶于正丁醇(3mL)中，加入对甲苯磺酸一水合物(2mg，0.01mmol)，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，残余物通过Prep-HPLC纯化得到白色固体化合物25(7mg，收率22％)。ESI-MS(m/z)： 513.2[M+H]+；1H NMR(500MHz，DMSO-d6)δ9.89(s，1H)，8.16(d，J＝8.7Hz，1H)，8.12(d，J＝1.5Hz，1H)，8.06(d，J＝8.9Hz，1H)，7.94-7.88(m，1H)，7.23(d，J＝8.4Hz，1H)，7.22-7.18(m，1H)，6.58(s，1H)，4.41-4.33(m，2H)，4.03-3.98(m，1H)，2.12(s，3H)，1.18(d，J＝5.8Hz，3H).Step 6: Dissolve compound 25e (20mg, 0.06mmol) and Int-2 (15mg, 0.06mmol) in n-butanol (3mL), add p-toluenesulfonic acid monohydrate (2mg, 0.01mmol), and the reaction solution Stir 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 compound 25 (7 mg, yield 22%) as a white solid. ESI-MS(m/z): 513.2[M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.89(s, 1H), 8.16(d, J=8.7Hz, 1H), 8.12(d, J=1.5Hz, 1H) , 8.06(d, J=8.9Hz, 1H), 7.94-7.88(m, 1H), 7.23(d, J=8.4Hz, 1H), 7.22-7.18(m, 1H), 6.58(s, 1H), 4.41-4.33(m, 2H), 4.03-3.98(m, 1H), 2.12(s, 3H), 1.18(d, J=5.8Hz, 3H).
实施例26Example 26
(S)-2-(((6-((2，6-二(三氟甲基)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-((2,6-bis(trifluoromethyl)pyridin-3-yl)oxo)pyridin-3-yl)methyl)amino)-4,7,8 -Trimethyl-7,8-dihydropteridin-6(5H)-one
实施例26由以下步骤制备：
Example 26 was prepared by the following steps:
第一步：将化合物26a(1.0g，4.65mmol)溶于无水四氢呋喃(20mL)中，氮气保护下，降温至-78℃，开始缓慢滴加正丁基锂(3.05mL，4.88mmol)，一小时后，开始滴加硼酸三异丙酯(0.79mL，6.97mmol)，两小时后LCMS监测反应结束。缓慢滴加水淬灭反应，当体系升温至0℃时开始滴加氢氧化钠水溶液(4M，3.49mL，13.95mmol)和双氧水(1mL)，在室温条件下反应16小时。 反应液用盐酸(2M)酸化，用二氯甲烷萃取三次，浓缩，残余物通过硅胶柱层析纯化(二氯甲烷∶甲醇＝10∶1)得到黄色固体混合物26b和26b’(400mg，收率37％)。MS(m/z)：230.5[M-H]-。Step 1: Dissolve compound 26a (1.0g, 4.65mmol) in anhydrous tetrahydrofuran (20mL), under the protection of nitrogen, cool down to -78°C, and slowly add n-butyllithium (3.05mL, 4.88mmol) dropwise, After one hour, dropwise addition of triisopropyl borate (0.79 mL, 6.97 mmol) was started, and the reaction was completed after two hours by LCMS. Water was slowly added dropwise to quench the reaction. When the temperature of the system was raised to 0°C, sodium hydroxide aqueous solution (4M, 3.49mL, 13.95mmol) and hydrogen peroxide (1mL) were added dropwise, and the reaction was carried out at room temperature for 16 hours. The reaction solution was acidified with hydrochloric acid (2M), extracted three times with dichloromethane, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain yellow solid mixture 26b and 26b' (400mg, yield 37%). MS (m/z): 230.5 [MH] - .
第二步：将化合物26b和26b’(400mg，1.73mmol)、Int-3d(232.48mg，1.90mmol)和N，N-二异丙基乙胺(671.1mg，5.19mmol)加入到乙腈(10mL)中，在120℃下反应4小时，LCMS监测反应结束。减压蒸馏除去乙腈，再加入水和乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，有机相浓缩后通过硅胶柱层析(石油醚∶乙酸乙酯＝10∶1)纯化得到黄色固体26c(180mg，收率31％)。ESI-MS(m/z)：334.4[M+H]+。Second step: Compounds 26b and 26b' (400mg, 1.73mmol), Int-3d (232.48mg, 1.90mmol) and N,N-diisopropylethylamine (671.1mg, 5.19mmol) were added to acetonitrile (10mL ), reacted at 120° C. for 4 hours, and LCMS monitored the end of the reaction. Acetonitrile was distilled off under reduced pressure, then water and ethyl acetate were added for extraction, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, the organic phase was concentrated and subjected to silica gel column chromatography (petroleum ether:ethyl acetate=10:1 ) to obtain yellow solid 26c (180 mg, yield 31%). ESI-MS (m/z): 334.4 [M+H] + .
第三步：将化合物26c(180mg，0.54mmol)溶于甲醇(30mL)，依次向反应体系加入氨水(5mL)和雷尼镍(3.5mL，水混悬液)，通过氢气球置换氢气并在氢气氛围、室温条件下反应3小时，LCMS监测反应结束。反应液用甲醇稀释，抽滤，滤液浓缩得到棕色油状液体26d(150mg，收率82％)。ESI-MS(m/z)：338.5[M+H]+。The third step: Dissolve compound 26c (180mg, 0.54mmol) in methanol (30mL), add ammonia water (5mL) and Raney nickel (3.5mL, aqueous suspension) to the reaction system in turn, replace hydrogen by hydrogen balloon and in The reaction was carried out under hydrogen atmosphere and room temperature for 3 hours, and the reaction was monitored by LCMS to complete. The reaction solution was diluted with methanol, filtered with suction, and the filtrate was concentrated to obtain a brown oily liquid 26d (150 mg, yield 82%). ESI-MS (m/z): 338.5 [M+H] + .
第四步：将化合物26d(74.39mg，0.22mmol)溶于正丁醇(2mL)中，加入化合物Int-1(50mg，0.22mmol)和对甲苯磺酸一水合物(4.19mg，22umol)，反应液在微波条件下，160℃搅拌3小时。待反应液冷却至室温，减压浓缩，残余物用反相制备HPLC纯化得到白色固体26(38.57mg，收率33％)。ESI-MS(m/z)：528.5[M+H]+；1H NMR(500MHz，DMSO-d6)δ9.83(s，1H)，8.31(d，J＝8.7Hz，1H)，8.21(d，J＝8.7Hz，1H)，8.13(d，J＝2.4Hz，1H)，7.93(dd，J＝8.4，2.4Hz，1H)，7.25(d，J＝8.4Hz，1H)，7.01(t，J＝6.3Hz，1H)，4.49-4.30(m，2H)，4.00(q，J＝6.8Hz，1H)，2.92(s，3H)，2.13(s，3H)，1.19(d，J＝6.8Hz，3H).Step 4: Dissolve compound 26d (74.39mg, 0.22mmol) in n-butanol (2mL), add compound Int-1 (50mg, 0.22mmol) and p-toluenesulfonic acid monohydrate (4.19mg, 22umol), The reaction solution was stirred at 160° C. for 3 hours under microwave conditions. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by reverse-phase preparative HPLC to obtain 26 (38.57 mg, yield 33%) as a white solid. ESI-MS (m/z): 528.5[M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.83 (s, 1H), 8.31 (d, J=8.7Hz, 1H), 8.21 ( d, J=8.7Hz, 1H), 8.13(d, J=2.4Hz, 1H), 7.93(dd, J=8.4, 2.4Hz, 1H), 7.25(d, J=8.4Hz, 1H), 7.01( t, J=6.3Hz, 1H), 4.49-4.30(m, 2H), 4.00(q, J=6.8Hz, 1H), 2.92(s, 3H), 2.13(s, 3H), 1.19(d, J =6.8Hz, 3H).
实施例27Example 27
(S)-3-((5-(((4，7-二甲基-8-(甲基-d3)-6-羰基-5，6，7，8-四氢蝶啶-2-基)氨基)甲基)吡啶-2-基)氧代)-6-(三氟甲基)氰基吡啶
(S)-3-((5-(((4,7-dimethyl-8-(methyl-d3)-6-carbonyl-5,6,7,8-tetrahydropteridin-2-yl )amino)methyl)pyridin-2-yl)oxo)-6-(trifluoromethyl)cyanopyridine
实施例27由以下步骤制备：
Example 27 was prepared by the following steps:
第一步：冰水浴条件下，将碳酸酐二叔丁酯(1.75g，8.02mmol)滴加到Int-13(2.03g，6.68mmol)和三乙胺(1.39mL，10.02mmol)的二氯甲烷(40mL)溶液中。反应液在室温条件下搅拌16小时后，加入水淬灭反应。二氯甲烷萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，有机相浓缩后通过硅胶柱层析(石油醚∶乙酸乙酯＝3∶1)纯化得到白色固体27a(1.95g，收率72％)。ESI-MS(m/z)：403.9[M+H]+。The first step: under ice-water bath conditions, di-tert-butyl carbonic anhydride (1.75g, 8.02mmol) was added dropwise to a dichloromethane solution of Int-13 (2.03g, 6.68mmol) and triethylamine (1.39mL, 10.02mmol). methane (40mL) solution. After the reaction solution was stirred at room temperature for 16 hours, water was added to quench the reaction. Extracted with dichloromethane, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, the organic phase was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=3:1) to obtain a white solid 27a (1.95g, Yield 72%). ESI-MS (m/z): 403.9 [M+H] + .
第二步：将化合物27a(300mg，0.74mmol)，氰化锌(174mg，1.49mmol)，四三苯基膦钯(172mg，0.15mol)和N，N-二甲基甲酰胺(10mL)加入到圆底烧瓶中。反应液在120℃、氮气保护条件下搅拌24小时后，LCMS监测反应结束。减压蒸馏除去溶剂，加入水和乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，有机相浓缩后通过硅胶柱层析(石油醚∶乙酸乙酯＝3∶1)纯化得到白色固体27b(177mg，收率60％)。ESI-MS(m/z)：395.3[M+H]+。Second step: Compound 27a (300mg, 0.74mmol), zinc cyanide (174mg, 1.49mmol), tetrakistriphenylphosphine palladium (172mg, 0.15mol) and N,N-dimethylformamide (10mL) were added into a round bottom flask. After the reaction solution was stirred at 120° C. for 24 hours under nitrogen protection, the reaction was monitored by LCMS. The solvent was distilled off under reduced pressure, water and ethyl acetate were added for extraction, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, the organic phase was concentrated and then subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) Purification afforded 27b as a white solid (177 mg, 60% yield). ESI-MS (m/z): 395.3 [M+H] + .
第三步：将三氟乙酸(0.5mL)滴加到化合物27b的二氯甲烷(6mL)溶液中。反应液在室温条件下搅拌5小时后，LCMS监测反应结束。减压蒸馏浓缩反 应液，加入氢氧化钠水溶液至pH为8，乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，有机相浓缩后得到粗产品27c。ESI-MS(m/z)：295.3[M+H]+。Step 3: Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of compound 27b in dichloromethane (6 mL). After the reaction solution was stirred at room temperature for 5 hours, the reaction was monitored by LCMS to complete. Concentrated by vacuum distillation To the reaction solution, an aqueous sodium hydroxide solution was added to pH 8, extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated to obtain the crude product 27c. ESI-MS (m/z): 295.3 [M+H] + .
第四步：将化合物Int-2(45mg，0.20mmol)溶于正丁醇(3mL)中，加入化合物27c(64mg，0.22mmol)和对甲苯磺酸一水合物(8mg，44umol)，反应液在微波条件下，160℃搅拌3小时。LCMS监测反应结束。反应液通过反相制备HPLC纯化得到白色固体27(16mg，收率8％)。ESI-MS(m/z)：499.0[M+H]+；1H NMR(500MHz，DMSO-d6)δ9.92(s，1H)，8.25(d，J＝8.9Hz，1H)，8.15(d，J＝8.8Hz，1H)，8.11(d，J＝2.4Hz，1H)，7.91(dd，J＝8.4，2.4Hz，1H)，7.27(d，J＝8.4Hz，1H)，4.43-4.32(m，2H)，4.06-3.96(m，1H)，2.08(s，3H)，1.16(d，J＝7.0Hz，3H).Step 4: Dissolve compound Int-2 (45mg, 0.20mmol) in n-butanol (3mL), add compound 27c (64mg, 0.22mmol) and p-toluenesulfonic acid monohydrate (8mg, 44umol), and the reaction solution Stir at 160° C. for 3 hours under microwave conditions. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain a white solid 27 (16 mg, yield 8%). ESI-MS (m/z): 499.0[M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.92 (s, 1H), 8.25 (d, J=8.9Hz, 1H), 8.15( d, J=8.8Hz, 1H), 8.11(d, J=2.4Hz, 1H), 7.91(dd, J=8.4, 2.4Hz, 1H), 7.27(d, J=8.4Hz, 1H), 4.43- 4.32(m, 2H), 4.06-3.96(m, 1H), 2.08(s, 3H), 1.16(d, J=7.0Hz, 3H).
实施例28Example 28
(S)-2-((4-环丙基-2-(三氟甲基)嘧啶-5-基)氧代)-5-(((4，7，8-三甲基-6-羰基-5，6，7，8-四氢蝶啶-2-基)氨基)甲基)尼古丁腈
(S)-2-((4-cyclopropyl-2-(trifluoromethyl)pyrimidin-5-yl)oxo)-5-(((4,7,8-trimethyl-6-carbonyl -5,6,7,8-tetrahydropteridin-2-yl)amino)methyl)nicotine nitrile
实施例28由以下步骤制备：
Example 28 was prepared by the following steps:
第一步：将21b(400mg，1.96mmol)，28a(639mg，2.94mmol)，DIPEA(759mg，5.88mmol)加入到DMF中(5mL)，120℃条件下，搅拌2小时，分别加入50mL乙酸乙酯，50mL水，硅藻土抽滤，分液，残液硅胶柱层析(石油醚∶乙酸乙酯＝7∶1)，得到28b(483mg，收率64％)。ESI-MS(m/z)：385.1[M+H]+。Step 1: Add 21b (400mg, 1.96mmol), 28a (639mg, 2.94mmol), DIPEA (759mg, 5.88mmol) into DMF (5mL), stir at 120°C for 2 hours, then add 50mL ethyl acetate Esters, 50 mL of water, suction filtration with celite, liquid separation, silica gel column chromatography (petroleum ether: ethyl acetate = 7: 1) of the residue to obtain 28b (483 mg, yield 64%). ESI-MS (m/z): 385.1 [M+H] + .
第二步：将28b(400mg，1.04mmol)，正丁基二(1-金刚烷基)膦(37mg，103umol)，28c(492mg，2.08mmol)，TBAF(56mg，259umol)，醋酸钯(23mg，103umol)，碳酸铯(1.02g，3.12mmol)，水(1mL)加入到正丁醇(7mL)中，氮气保护条件下，110℃搅拌17小时。LCMS显示原料转化完全，分别加入50mL乙酸乙酯，50mL水，硅藻土过滤，萃取分液，有机相浓缩。残余物经石油醚∶乙酸乙酯＝1∶2硅胶柱层析得到28d(273mg，收率60％)。ESI-MS(m/z)：436.1[M+H]+。The second step: 28b (400mg, 1.04mmol), n-butyl bis (1-adamantyl) phosphine (37mg, 103umol), 28c (492mg, 2.08mmol), TBAF (56mg, 259umol), palladium acetate (23mg , 103umol), cesium carbonate (1.02g, 3.12mmol), water (1mL) were added to n-butanol (7mL), and stirred at 110°C for 17 hours under nitrogen protection. LCMS showed that the conversion of the raw materials was complete, and 50 mL of ethyl acetate and 50 mL of water were added, filtered through celite, extracted and separated, and the organic phase was concentrated. The residue was subjected to petroleum ether: ethyl acetate = 1:2 silica gel column chromatography to obtain 28d (273 mg, yield 60%). ESI-MS (m/z): 436.1 [M+H] + .
第三步：将化合物28d(273mg，627umol)加入到二氯甲烷中(3ml)，加入三氟乙酸(1ml)，室温搅拌2小时。LCMS显示原料转化完全，减压蒸馏，残渣依次加入10ml乙酸乙酯，10ml饱和碳酸氢钠水溶液，分液，有机相经水洗，硫酸钠干燥，浓缩得到褐色油状物，直接用于下一步。ESI-MS(m/z)：336.0[M+H]+。Step 3: Add compound 28d (273mg, 627umol) into dichloromethane (3ml), add trifluoroacetic acid (1ml), and stir at room temperature for 2 hours. LCMS showed that the conversion of the raw material was complete. Distilled under reduced pressure, the residue was sequentially added to 10ml of ethyl acetate and 10ml of saturated aqueous sodium bicarbonate solution for liquid separation. The organic phase was washed with water, dried over sodium sulfate, and concentrated to obtain a brown oil, which was directly used in the next step. ESI-MS (m/z): 336.0 [M+H] + .
第四步：将上一步得到的化合物28e，Int-1(79mg，351umol)，对甲苯磺酸(6mg，35umol)加入到正丁醇中(2mL)，微波160℃搅拌3小时。LCMS 显示原料消失。反应液用反相制备HPLC纯化得到白色固体28(20mg，两步反应收率6％)。ESI-MS(m/z)：526.3[M+H]+；1H NMR(500MHz，DMSO-d6)δ9.87(s，1H)，8.95(s，1H)，8.43(d，J＝2.4Hz，1H)，8.36(d，J＝2.3Hz，1H)，7.03(t，J＝6.3Hz，1H)，4.42-4.34(m，2H)，4.03-3.97(m，1H)，2.91(s，3H)，2.28-2.23(m，1H)，2.11(s，3H)，1.19-1.11(m，7H).Step 4: Add compound 28e, Int-1 (79mg, 351umol) and p-toluenesulfonic acid (6mg, 35umol) obtained in the previous step into n-butanol (2mL), stir in microwave at 160°C for 3 hours. LCMS Display ingredients disappear. The reaction solution was purified by reverse-phase preparative HPLC to obtain a white solid 28 (20 mg, yield 6% in two steps). ESI-MS (m/z): 526.3[M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.87(s, 1H), 8.95(s, 1H), 8.43(d, J=2.4 Hz, 1H), 8.36(d, J=2.3Hz, 1H), 7.03(t, J=6.3Hz, 1H), 4.42-4.34(m, 2H), 4.03-3.97(m, 1H), 2.91(s , 3H), 2.28-2.23(m, 1H), 2.11(s, 3H), 1.19-1.11(m, 7H).
实施例29Example 29
(S)-4，7，8-三甲基-2-(((6-((4-甲基-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-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)oxo)pyridin-3-yl )methyl)amino)-7,8-dihydropteridin-6(5H)-one
用4-甲基-6-(三氟甲基)吡啶-3-醇替换实施例15中第六步的15f，用后续类似的方法和反应步骤，得到化合物29。ESI-MS(m/z)：474.3[M+H]+；1H NMR(500MHz，DMSO-d6)δ9.82(s，1H)，8.48(s，1H)，8.04(d，J＝2.3Hz，1H)，7.96(s，1H)，7.87(dd，J＝8.4，2.4Hz，1H)，7.16(d，J＝8.3Hz，1H)，6.98(t，J＝6.2Hz，1H)，4.44-4.26(m，2H)，3.99(q，J＝6.8Hz，1H)，2.91(s，3H)，2.21(s，3H)，2.11(s，3H)，1.17(d，J＝6.8Hz，3H).Substituting 4-methyl-6-(trifluoromethyl)pyridin-3-ol for 15f in the sixth step in Example 15, followed by similar methods and reaction steps to obtain compound 29. ESI-MS (m/z): 474.3[M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.82(s, 1H), 8.48(s, 1H), 8.04(d, J=2.3 Hz, 1H), 7.96(s, 1H), 7.87(dd, J=8.4, 2.4Hz, 1H), 7.16(d, J=8.3Hz, 1H), 6.98(t, J=6.2Hz, 1H), 4.44-4.26(m, 2H), 3.99(q, J=6.8Hz, 1H), 2.91(s, 3H), 2.21(s, 3H), 2.11(s, 3H), 1.17(d, J=6.8Hz , 3H).
实施例30Example 30
(S)-2-(((6-((1-环丙基-3-(三氟甲基)-1H-吡唑-5-基)氧代)吡啶-3-基)甲基)氨基)-7-(甲氧基甲基)-4，8-二甲基-7，8-二氢蝶啶-6(5H)-酮
(S)-2-(((6-((1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxo)pyridin-3-yl)methyl)amino )-7-(methoxymethyl)-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one
实施例30由以下步骤制备：
Example 30 was prepared by the following steps:
第一步：将化合物30a(1.10g，5mmol)溶于无水四氢呋喃(10mL)中，溶液冷却至0℃，在氮气氛围下将氢化钠(478mg，60％dispersion in mineral oil)缓慢加至反应液中。反应液在0℃下搅拌10分钟。随后将碘甲烷(1.42g，10mmol)滴加至反应液中。反应液缓慢升至室温并继续搅拌2小时。LCMS检测反应结束。加饱和氯化铵水溶液淬灭反应，乙酸乙酯萃取，合并有机相并用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩得到化合物30b(1.17g，粗品)。ESI-MS(m/z)：234.4[M+H]+。The first step: Dissolve compound 30a (1.10g, 5mmol) in anhydrous tetrahydrofuran (10mL), cool the solution to 0°C, and slowly add sodium hydride (478mg, 60% dispersion in mineral oil) to the reaction under nitrogen atmosphere in the liquid. The reaction solution was stirred at 0°C for 10 minutes. Then methyl iodide (1.42 g, 10 mmol) was added dropwise to the reaction solution. The reaction solution was slowly warmed to room temperature and stirring was continued for 2 hours. LCMS detects that the reaction is complete. The reaction was quenched by adding saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the combined organic phases were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 30b (1.17 g, crude product). ESI-MS (m/z): 234.4 [M+H] + .
第二步：将化合物30b(1.17g)溶于甲醇(10mL)中，在室温下将二氯亚砜(1.19g，10mmol)缓慢滴加至反应液中，随后反应液升温至70℃并继续在此温度下搅拌2小时。LCMS检测反应结束。待反应液冷却至室温，反应液减压浓缩，得到化合物30c(918mg，粗品)。The second step: Dissolve compound 30b (1.17g) in methanol (10mL), slowly add thionyl chloride (1.19g, 10mmol) dropwise to the reaction solution at room temperature, then the reaction solution is heated to 70°C and continued Stir at this temperature for 2 hours. LCMS detects that the reaction is complete. After the reaction liquid was cooled to room temperature, the reaction liquid was concentrated under reduced pressure to obtain compound 30c (918 mg, crude product).
第三步：将化合物30c(918mg，粗品)和化合物18d(1.04g，5mmol)溶于四氢呋喃(10mL)中，加入N，N-二异丙基乙胺(1.94g，15mmol)。反应在室温下搅拌8小时。LCMS检测反应结束。加水淬灭反应，乙酸乙酯萃取，合并有机相并用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，残余物通过硅胶柱层析(石油醚/乙酸乙酯＝2/1)纯化得到化合物30d(1.27g，三步反应收率 84％)。ESI-MS(m/z)：319.3[M+H]+。The third step: compound 30c (918 mg, crude product) and compound 18d (1.04 g, 5 mmol) were dissolved in tetrahydrofuran (10 mL), and N,N-diisopropylethylamine (1.94 g, 15 mmol) was added. The reaction was stirred at room temperature for 8 hours. LCMS detects that the reaction is complete. Add water to quench the reaction, extract with ethyl acetate, combine the organic phases and wash with saturated aqueous sodium chloride, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and the residue is subjected to silica gel column chromatography (petroleum ether/ethyl acetate=2/1) Purified to obtain compound 30d (1.27g, three-step reaction yield 84%). ESI-MS (m/z): 319.3 [M+H] + .
第四步：将化合物30d(320mg，1mmol)和化合物Int-3(300mg，1mmol)溶于N，N-二甲基甲酰胺(5mL)中，加入N，N-二异丙基乙胺(390mg，3mmol)。反应在室温下搅拌4小时。LCMS检测反应结束。加水淬灭反应，乙酸乙酯萃取，合并有机相并用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，残余物通过硅胶柱层析(石油醚/乙酸乙酯＝5/1)纯化得到化合物30e(430mg，收率74％)。ESI-MS(m/z)：581.3[M+H]+。Step 4: Dissolve compound 30d (320 mg, 1 mmol) and compound Int-3 (300 mg, 1 mmol) in N, N-dimethylformamide (5 mL), add N, N-diisopropylethylamine ( 390 mg, 3 mmol). The reaction was stirred at room temperature for 4 hours. LCMS detects that the reaction is complete. Add water to quench the reaction, extract with ethyl acetate, combine the organic phases and wash with saturated aqueous sodium chloride, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and the residue is subjected to silica gel column chromatography (petroleum ether/ethyl acetate=5/1) Purification afforded compound 30e (430 mg, yield 74%). ESI-MS (m/z): 581.3 [M+H] + .
第五步：将化合物30e(430mg，0.74mmol)溶于甲醇(5mL)中，加入10％钯碳(394mg)，反应体系置换氢气后在室温下搅拌6小时。LCMS检测反应结束。反应液硅藻土过滤，滤液减压浓缩，残余物通过Prep-HPLC纯化得到白色固体化合物30(15mg，收率4％)。ESI-MS(m/z)：519.2[M+H]+；1H NMR(500MHz，DMSO-d6)δ9.89(s，1H)，8.16(s，1H)，7.91(d，J＝8.2Hz，1H)，7.19(d，J＝8.4Hz，1H)，6.91(t，J＝5.4Hz，1H)，6.53(s，1H)，4.42-4.29(m，2H)，4.14(s，1H)，3.66-3.55(m，2H)，3.50-3.42(m，1H)，3.15(s，3H)，2.95(s，3H)，2.08(s，3H)，1.06-0.99(m，2H)，0.95-0.88(m，2H).Step 5: Dissolve compound 30e (430 mg, 0.74 mmol) in methanol (5 mL), add 10% palladium on carbon (394 mg), and stir the reaction system at room temperature for 6 hours after replacing hydrogen. LCMS detects that the reaction is complete. The reaction solution was filtered with celite, the filtrate was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to obtain compound 30 (15 mg, yield 4%) as a white solid. ESI-MS (m/z): 519.2[M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.89(s, 1H), 8.16(s, 1H), 7.91(d, J=8.2 Hz, 1H), 7.19(d, J=8.4Hz, 1H), 6.91(t, J=5.4Hz, 1H), 6.53(s, 1H), 4.42-4.29(m, 2H), 4.14(s, 1H ), 3.66-3.55(m, 2H), 3.50-3.42(m, 1H), 3.15(s, 3H), 2.95(s, 3H), 2.08(s, 3H), 1.06-0.99(m, 2H), 0.95-0.88(m, 2H).
实施例31Example 31
(S)-2-(((6-((1-环丙基-3-(三氟甲基)-1H-吡唑-5-基)氧代)吡啶-3-基)甲基)氨基)-7-(羟甲基)-4，8-二甲基-7，8-二氢蝶啶-6(5H)-酮
(S)-2-(((6-((1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxo)pyridin-3-yl)methyl)amino )-7-(hydroxymethyl)-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one
实施例31由以下步骤制备：
Example 31 was prepared by the following steps:
第一步：将化合物30(10mg，0.02mmol)溶于二氯甲烷(2mL)中，在-78℃下缓慢滴加三溴化硼(10mg，0.04mmol)至反应液。反应继续在-78℃下搅拌30分钟。LCMS检测反应结束。加饱和碳酸氢钠水溶液淬灭反应，二氯甲烷萃取，合并有机相并用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，残余物通过Prep-HPLC纯化得到白色固体化合物31(8mg，收率80％)。ESI-MS(m/z)：505.3[M+H]+；1H NMR(500MHz，DMSO-d6)δ9.85(s，1H)，8.16(s，1H)，7.91(d，J＝8.4Hz，1H)，7.19(d，J＝8.4Hz，1H)，6.86(t，J＝6.1Hz，1H)，6.54(s，1H)，4.98(t，J＝5.2Hz，1H)，4.35-4.29(m，2H)，3.96(s，1H)，3.76-3.61(m，2H)，3.51-3.43(m，1H)，2.96(s，3H)，2.07(s，3H)，1.12-0.99(m，2H)，0.98-0.88(m，2H).Step 1: Compound 30 (10 mg, 0.02 mmol) was dissolved in dichloromethane (2 mL), and boron tribromide (10 mg, 0.04 mmol) was slowly added dropwise to the reaction solution at -78°C. The reaction continued to stir at -78°C for 30 minutes. LCMS detects that the reaction is complete. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, the organic phases were combined and washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by Prep-HPLC to obtain white solid compound 31 (8 mg , yield 80%). ESI-MS (m/z): 505.3[M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.85(s, 1H), 8.16(s, 1H), 7.91(d, J=8.4 Hz, 1H), 7.19(d, J=8.4Hz, 1H), 6.86(t, J=6.1Hz, 1H), 6.54(s, 1H), 4.98(t, J=5.2Hz, 1H), 4.35- 4.29(m, 2H), 3.96(s, 1H), 3.76-3.61(m, 2H), 3.51-3.43(m, 1H), 2.96(s, 3H), 2.07(s, 3H), 1.12-0.99( m, 2H), 0.98-0.88 (m, 2H).
实施例32Example 32
4，7，7-三甲基-8-(甲基-d3)-2-(((6-((4-甲基-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-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)oxo) Pyridin-3-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one
用Int-18替换实施例15中第八步的Int-1，用后续类似的方法和反应步骤，得到化合物32。ESI-MS(m/z)：492.3[M+H]+；1H NMR(500MHz，DMSO-d6)δ9.82(s，1H)，8.86(s，1H)，8.07(s，1H)，7.91(dd，J＝8.4，1.9Hz，1H)，7.23(d，J＝8.4Hz，1H)，6.99(t，J＝5.9Hz，1H)，4.36(d，J＝6.1Hz，2H)，2.42(s，3H)，2.13(s，3H)，1.31(s，6H). Int-1 in the eighth step in Example 15 was replaced with Int-18, and compound 32 was obtained by subsequent similar methods and reaction steps. ESI-MS (m/z): 492.3[M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.82 (s, 1H), 8.86 (s, 1H), 8.07 (s, 1H), 7.91(dd, J=8.4, 1.9Hz, 1H), 7.23(d, J=8.4Hz, 1H), 6.99(t, J=5.9Hz, 1H), 4.36(d, J=6.1Hz, 2H), 2.42(s, 3H), 2.13(s, 3H), 1.31(s, 6H).
实施例33Example 33
4′-甲基-8′-(甲基-d3)-2′-(((6-((4-甲基-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-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)oxo)pyridine- 3-yl)methyl)amino)-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pteridine]-6'-one
用化合物15g替换实施例18中第五步的Int-3，用后续类似的方法和反应步骤，得到化合物33。ESI-MS(m/z)：490.4[M+H]+；1H NMR(500MHz，DMSO-d6)δ9.89(s，1H)，8.86(s，1H)，8.06(s，1H)，7.90(d，J＝8.4Hz，1H)，7.22(d，J＝8.4Hz，1H)，6.99(t，J＝5.9Hz，1H)，4.35(d，J＝6.2Hz，2H)，2.42(s，3H)，2.11(s，3H)，1.31-1.27(m，2H)，1.15-1.08(m，2H).Compound 15g was used to replace Int-3 in the fifth step in Example 18, and compound 33 was obtained by subsequent similar methods and reaction steps. ESI-MS (m/z): 490.4[M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.89 (s, 1H), 8.86 (s, 1H), 8.06 (s, 1H), 7.90(d, J=8.4Hz, 1H), 7.22(d, J=8.4Hz, 1H), 6.99(t, J=5.9Hz, 1H), 4.35(d, J=6.2Hz, 2H), 2.42( s, 3H), 2.11(s, 3H), 1.31-1.27(m, 2H), 1.15-1.08(m, 2H).
实施例34Example 34
(S)-2-(6-(三氟甲基)-3-((5-(((4，7，8-三甲基-6-羰基-5，6，7，8-四氢蝶啶-2-基)氨基)甲基)吡啶-2-基)氧代)吡啶-2-基)乙酰腈
(S)-2-(6-(trifluoromethyl)-3-((5-(((4,7,8-trimethyl-6-carbonyl-5,6,7,8-tetrahydropterene Pyridin-2-yl)amino)methyl)pyridin-2-yl)oxo)pyridin-2-yl)acetonitrile
实施例34由以下步骤制备：
Example 34 was prepared by the following steps:
第一步：将化合物27a(675mg，1.67mmol)，乙烯基硼酸频哪醇酯(1.29g，8.36mmol)，四三苯基膦钯(194mg，0.17mol)，碳酸钠(354mg，3.34mmol)，水(3mL)和1，4-二氧六环(17mL)加入到圆底烧瓶中。反应液在120℃、氮气保护条件下搅拌16小时后，LCMS监测反应结束。减压蒸馏除去溶剂，加入水和乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，有机相浓缩后通过硅胶柱层析(石油醚∶乙酸乙酯＝3∶1)纯化得到白色固体34a(609mg，收率92％)。ESI-MS(m/z)：396.4[M+H]+。The first step: compound 27a (675mg, 1.67mmol), vinylboronic acid pinacol ester (1.29g, 8.36mmol), tetrakistriphenylphosphine palladium (194mg, 0.17mol), sodium carbonate (354mg, 3.34mmol) , water (3 mL) and 1,4-dioxane (17 mL) were added to a round bottom flask. After the reaction solution was stirred for 16 hours at 120° C. under nitrogen protection, the reaction was monitored by LCMS. The solvent was distilled off under reduced pressure, water and ethyl acetate were added for extraction, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, the organic phase was concentrated and then subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) Purification afforded 34a as a white solid (609 mg, 92% yield). ESI-MS (m/z): 396.4 [M+H] + .
第二步：将高碘酸钠(907mg，4.24mmol)加入到34a(559mg，1.41mmol)的四氢呋喃(12mL)和水(3mL)的混合溶液中，反应液在室温下搅拌一分钟后，向其加入锇酸钾(41mg，0.14mmol)。反应液在40℃条件下搅拌2小时后，LCMS监测反应结束。加入水和乙酸乙酯萃取，合并有机相并依次用硫代硫 酸钠水溶液、饱和食盐水洗涤，无水硫酸钠干燥，有机相浓缩后得到粗产品34b。ESI-MS(m/z)：398.3[M+H]+。The second step: sodium periodate (907mg, 4.24mmol) was added to 34a (559mg, 1.41mmol) in the mixed solution of tetrahydrofuran (12mL) and water (3mL), after the reaction solution was stirred at room temperature for one minute, to To this was added potassium osmate (41 mg, 0.14 mmol). After the reaction solution was stirred at 40° C. for 2 hours, the reaction was monitored by LCMS to complete. Add water and ethyl acetate for extraction, combine the organic phases and successively use thiosulfur NaCl aqueous solution and saturated brine were washed, dried over anhydrous sodium sulfate, and the organic phase was concentrated to obtain the crude product 34b. ESI-MS (m/z): 398.3 [M+H] + .
第三步：冰水浴条件下，将硼氢化钠(80mg，2.12mmol)加入到粗产品34b的甲醇(15mL)溶液中。反应液在该温度下继续搅拌两个小时。LCMS监测反应结束后，加入水和乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，有机相浓缩后通过硅胶柱层析(石油醚∶乙酸乙酯＝2∶1)纯化得到白色固体34c(359mg，两步收率64％)。ESI-MS(m/z)：400.3[M+H]+。Step 3: Sodium borohydride (80 mg, 2.12 mmol) was added to a solution of crude product 34b in methanol (15 mL) under ice-water bath conditions. The reaction was continued to stir at this temperature for two hours. After the reaction was monitored by LCMS, water and ethyl acetate were added for extraction, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated and then subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) Purification afforded 34c as a white solid (359 mg, 64% for two steps). ESI-MS (m/z): 400.3 [M+H] + .
第四步：将二氯亚砜(0.13mL，1.80mmol)滴加到34c(359mg，0.90mmol)的二氯甲烷(14mL)溶液中。反应液在室温条件下搅拌2小时后，LCMS监测反应结束。减压蒸馏浓缩反应液得到粗产品34d。ESI-MS(m/z)：418.2[M+H]+。Step 4: Thionyl chloride (0.13 mL, 1.80 mmol) was added dropwise to a solution of 34c (359 mg, 0.90 mmol) in dichloromethane (14 mL). After the reaction solution was stirred at room temperature for 2 hours, the reaction was monitored by LCMS to complete. The reaction solution was concentrated by distillation under reduced pressure to obtain the crude product 34d. ESI-MS (m/z): 418.2 [M+H] + .
第五步：在10℃条件下，将三甲基氰硅烷(178mg，1.80mmol)滴加到氟化铯(119mg，1.80mmol)的乙腈(8mL)溶液中。反应液搅拌30分钟后，向其加入碳酸铯(586mg，1.80mmol)和上述粗产品34d，反应液升温至40℃并在该温度下继续搅拌16小时。LCMS监测反应结束后，加入水和乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，有机相浓缩后得到粗产品34e。ESI-MS(m/z)：409.3[M+H]+。Step 5: Trimethylsilyl cyanide (178 mg, 1.80 mmol) was added dropwise to a solution of cesium fluoride (119 mg, 1.80 mmol) in acetonitrile (8 mL) at 10°C. After the reaction solution was stirred for 30 minutes, cesium carbonate (586 mg, 1.80 mmol) and the above crude product 34d were added thereto, and the reaction solution was heated to 40° C. and continued to stir at this temperature for 16 hours. After the reaction was monitored by LCMS, water and ethyl acetate were added for extraction, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated to obtain the crude product 34e. ESI-MS (m/z): 409.3 [M+H] + .
第六步：将三氟乙酸(2mL)滴加到上述粗产品34e的二氯甲烷(8mL)溶液中。反应液在室温条件下搅拌1.5小时后，LCMS监测反应结束。减压蒸馏浓缩反应液，加入氢氧化钠水溶液至pH为8，乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，有机相浓缩后得到粗产品34f。ESI-MS(m/z)：309.3[M+H]+。Step 6: Trifluoroacetic acid (2 mL) was added dropwise to a solution of the above crude product 34e in dichloromethane (8 mL). After the reaction solution was stirred at room temperature for 1.5 hours, the reaction was monitored by LCMS to complete. The reaction solution was concentrated by distillation under reduced pressure, aqueous sodium hydroxide solution was added to pH 8, extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated to obtain the crude product 34f. ESI-MS (m/z): 309.3 [M+H] + .
第七步：将化合物Int-1(50mg，0.22mmol)溶于正丁醇(2mL)中，加入化合物34f(82mg，粗品)和对甲苯磺酸一水合物(8mg，44umol)，反应液在微波条件下，160℃搅拌3小时。LCMS监测反应结束。反应液通过反相制备HPLC纯化得到白色固体34(20mg，四步反应收率4％)。ESI-MS(m/z)：499.0 [M+H]+；1H NMR(500MHz，DMSO-d6)δ9.83(s，1H)，8.11(d，J＝2.3Hz，1H)，8.02-7.84(m，3H)，7.18(d，J＝8.4Hz，1H)，7.10-6.91(m，1H)，4.42-4.30(m，2H)，4.27(s，2H)，3.98(q，J＝6.8Hz，1H)，2.90(s，3H)，2.10(s，3H)，1.17(d，J＝6.8Hz，3H).Step 7: Dissolve compound Int-1 (50mg, 0.22mmol) in n-butanol (2mL), add compound 34f (82mg, crude product) and p-toluenesulfonic acid monohydrate (8mg, 44umol), and the reaction solution is in Stir at 160°C for 3 hours under microwave conditions. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain 34 (20 mg, 4% yield in four steps) as a white solid. ESI-MS (m/z): 499.0 [M+H] + ; 1 H NMR (500MHz, DMSO-d 6 ) δ9.83(s, 1H), 8.11(d, J=2.3Hz, 1H), 8.02-7.84(m, 3H), 7.18( d, J=8.4Hz, 1H), 7.10-6.91(m, 1H), 4.42-4.30(m, 2H), 4.27(s, 2H), 3.98(q, J=6.8Hz, 1H), 2.90(s , 3H), 2.10(s, 3H), 1.17(d, J=6.8Hz, 3H).
实施例35Example 35
(S)-2-(((6-((2-氟-6-(三氟甲基)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-((2-fluoro-6-(trifluoromethyl)pyridin-3-yl)oxo)pyridin-3-yl)methyl)amino)-4,7, 8-Trimethyl-7,8-dihydropteridin-6(5H)-one
实施例35由以下步骤制备：
Example 35 was prepared by the following steps:
第一步：将化合物35a(300mg，1.82mmol)溶于无水四氢呋喃(5mL)中，氮气保护下，降温至-78℃，开始缓慢滴加正丁基锂(1.19mL，1.91mmol)，一小时后，开始滴加硼酸三异丙酯(0.63mL，2.73mmol)，两小时后LCMS监测反应结束。缓慢滴加水淬灭反应，当体系升温至0℃时开始滴加氢氧化钠水溶液(4M，1.36mL，5.45mmol)和双氧水(1mL)，在室温条件下反应16小时。反应液用盐酸(2M)酸化，用二氯甲烷萃取三次，浓缩，残余物通过硅胶柱层 析纯化(二氯甲烷∶甲醇＝10∶1)得到黄色固体35b(280mg，收率85％)。MS(m/z)：180.5[M-H]-。Step 1: Dissolve compound 35a (300mg, 1.82mmol) in anhydrous tetrahydrofuran (5mL), under the protection of nitrogen, cool down to -78°C, and slowly add n-butyl lithium (1.19mL, 1.91mmol) dropwise. After 1 hour, dropwise addition of triisopropyl borate (0.63 mL, 2.73 mmol) was started, and the reaction was completed after 2 hours by LCMS monitoring. Water was slowly added dropwise to quench the reaction. When the temperature of the system was raised to 0°C, sodium hydroxide aqueous solution (4M, 1.36mL, 5.45mmol) and hydrogen peroxide (1mL) were added dropwise, and reacted at room temperature for 16 hours. The reaction solution was acidified with hydrochloric acid (2M), extracted three times with dichloromethane, concentrated, and the residue was passed through a silica gel column Purification by analysis (dichloromethane:methanol=10:1) gave yellow solid 35b (280 mg, yield 85%). MS (m/z): 180.5 [MH] - .
第二步：将化合物35b(280mg，1.55mmol)、Int-3d(226mg，1.86mmol)和碳酸铯(1.01g，3.09mmol)加入到乙腈(10mL)中，在室温下反应16小时，LCMS监测反应结束。减压蒸馏除去乙腈，再加入水和乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，有机相浓缩后通过硅胶柱层析(石油醚∶乙酸乙酯＝5∶1)纯化得到黄色油状液体35c(270mg，收率61％)。ESI-MS(m/z)：284.4[M+H]+。The second step: compound 35b (280mg, 1.55mmol), Int-3d (226mg, 1.86mmol) and cesium carbonate (1.01g, 3.09mmol) were added in acetonitrile (10mL), reacted at room temperature for 16 hours, LCMS monitoring The reaction is over. Acetonitrile was distilled off under reduced pressure, then water and ethyl acetate were added for extraction, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, the organic phase was concentrated and then subjected to silica gel column chromatography (petroleum ether:ethyl acetate=5:1 ) to obtain yellow oily liquid 35c (270 mg, yield 61%). ESI-MS (m/z): 284.4 [M+H] + .
第三步：将化合物35c(270mg，0.95mmol)溶于甲醇(30mL)，依次向反应体系加入氨水(3.5mL)和雷尼镍(3.5mL，水混悬液)，通过氢气球置换氢气并在氢气氛围、室温条件下反应3小时，LCMS监测反应结束。反应液用甲醇稀释，抽滤，滤液浓缩得到棕色油状液体35d(270mg，收率98％)。ESI-MS(m/z)：271.5[M+H]+。Step 3: Dissolve compound 35c (270mg, 0.95mmol) in methanol (30mL), add ammonia water (3.5mL) and Raney nickel (3.5mL, aqueous suspension) to the reaction system in turn, replace the hydrogen with a hydrogen balloon and The reaction was carried out under a hydrogen atmosphere at room temperature for 3 hours, and the reaction was monitored by LCMS to complete. The reaction solution was diluted with methanol, filtered with suction, and the filtrate was concentrated to obtain a brown oily liquid 35d (270 mg, yield 98%). ESI-MS (m/z): 271.5 [M+H] + .
第四步：将化合物35d(82.36mg，0.29mmol)溶于正丁醇(2mL)中，加入化合物Int-1(50mg，0.22mmol)和对甲苯磺酸一水合物(4.19mg，22umol)，反应液在微波条件下，160℃搅拌3小时。待反应液冷却至室温，减压浓缩，残余物用反相制备HPLC纯化得到白色固体35(1.07mg，收率1％)。ESI-MS(m/z)：478.5[M+H]+；1H NMR(500MHz，DMSO-d6)δ9.80(s，1H)，8.25(s，0H)，8.18(t，J＝8.7Hz，1H)，8.06(s，1H)，7.98(d，J＝8.1Hz，1H)，7.89(dd，J＝8.3，2.2Hz，1H)，7.20(d，J＝8.5Hz，1H)，6.97(d，J＝6.8Hz，1H)，4.35(qd，J＝15.2，6.4Hz，2H)，3.98(q，J＝6.8Hz，1H)，2.90(s，3H)，2.11(s，3H)，1.17(d，J＝6.7Hz，3H).Step 4: Dissolve compound 35d (82.36mg, 0.29mmol) in n-butanol (2mL), add compound Int-1 (50mg, 0.22mmol) and p-toluenesulfonic acid monohydrate (4.19mg, 22umol), The reaction solution was stirred at 160° C. for 3 hours under microwave conditions. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by reverse-phase preparative HPLC to obtain 35 (1.07 mg, yield 1%) as a white solid. ESI-MS (m/z): 478.5[M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.80(s, 1H), 8.25(s, 0H), 8.18(t, J=8.7 Hz, 1H), 8.06(s, 1H), 7.98(d, J=8.1Hz, 1H), 7.89(dd, J=8.3, 2.2Hz, 1H), 7.20(d, J=8.5Hz, 1H), 6.97(d, J=6.8Hz, 1H), 4.35(qd, J=15.2, 6.4Hz, 2H), 3.98(q, J=6.8Hz, 1H), 2.90(s, 3H), 2.11(s, 3H ), 1.17(d, J=6.7Hz, 3H).
实施例36Example 36
(S)-2-(((6-((6-氯-2-环丙基吡啶-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-chloro-2-cyclopropylpyridin-3-yl)oxo)pyridin-3-yl)methyl)amino)-4,7,8-tri Methyl-7,8-dihydropteridin-6(5H)-one
实施例36由以下步骤制备：
Example 36 was prepared by the following steps:
第一步：将化合物36a(1.0g，3.91mmol)、Int-3d(478mg，3.91mmol)和碳酸铯(2.55g，7.83mmol)加入到乙腈(20mL)中，在50℃下反应16小时，LCMS监测反应结束。减压蒸馏除去乙腈，再加入水和乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩有机相得到白色固体36b(1.38g，收率98％)。ESI-MS(m/z)：258.2[M+H]+。The first step: compound 36a (1.0g, 3.91mmol), Int-3d (478mg, 3.91mmol) and cesium carbonate (2.55g, 7.83mmol) were added to acetonitrile (20mL), and reacted at 50°C for 16 hours, LCMS monitored the completion of the reaction. Acetonitrile was distilled off under reduced pressure, and water and ethyl acetate were added for extraction. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a white solid 36b (1.38 g, yield 98%). ESI-MS (m/z): 258.2 [M+H] + .
第二步：将化合物36b(300mg，0.84mmol)，环丙基硼酸(108mg，1.26mmol)，醋酸钯(19mg，84umol)，三环己基膦(47mg，0.17mmol)和磷酸钾(534mg，2.52mmol)，水(2mL)和甲苯(10mL)加入到圆底烧瓶中。反应液在80℃、氮气保护条件下搅拌16小时后，LCMS监测反应结束。减压蒸馏除去溶剂，加入水和乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，有机相浓缩后通过硅胶柱层析(石油醚∶乙酸乙酯＝4∶1)纯化得到白色固体36c(76mg，收率33％)。ESI-MS(m/z)：272.4[M+H]+。The second step: compound 36b (300mg, 0.84mmol), cyclopropylboronic acid (108mg, 1.26mmol), palladium acetate (19mg, 84umol), tricyclohexylphosphine (47mg, 0.17mmol) and potassium phosphate (534mg, 2.52 mmol), water (2 mL) and toluene (10 mL) were added to a round bottom flask. After the reaction solution was stirred for 16 hours at 80° C. under nitrogen protection, the reaction was monitored by LCMS. The solvent was distilled off under reduced pressure, water and ethyl acetate were added for extraction, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, the organic phase was concentrated and then subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) Purification afforded 36c (76 mg, 33% yield) as a white solid. ESI-MS (m/z): 272.4 [M+H] + .
第三步：将化合物36c(76mg，0.28mmol)溶于甲醇(8mL)，依次向反应 体系加入氨水(0.8mL)和雷尼镍(0.8mL，水混悬液)，通过氢气球置换氢气并在氢气氛围、室温条件下反应3小时，LCMS监测反应结束。反应液用甲醇稀释，抽滤，滤液浓缩后得到棕色油状液体36d。ESI-MS(m/z)：276.4[M+H]+。The third step: the compound 36c (76mg, 0.28mmol) was dissolved in methanol (8mL), followed by reaction Ammonia water (0.8 mL) and Raney nickel (0.8 mL, aqueous suspension) were added to the system, hydrogen was replaced by a hydrogen balloon, and the reaction was carried out under hydrogen atmosphere at room temperature for 3 hours, and the reaction was completed by LCMS monitoring. The reaction solution was diluted with methanol, filtered with suction, and the filtrate was concentrated to obtain a brown oily liquid 36d. ESI-MS (m/z): 276.4 [M+H] + .
第四步：将上一步得到的化合物36d(51mg)溶于正丁醇(2mL)中，加入化合物Int-1(45mg，0.19mmol)和对甲苯磺酸一水合物(7mg，37umol)，反应液在微波条件下，160℃搅拌3小时。待反应液冷却至室温，减压浓缩，残余物用反相制备HPLC纯化得到白色固体36(10mg，两步反应收率7％)。ESI-MS(m/z)：466.3[M+H]+；1H NMR(500MHz，DMSO-d6)δ9.82(s，1H)，8.05(d，J＝2.3Hz，1H)，7.83(dd，J＝8.5，2.4Hz，1H)，7.53(d，J＝8.4Hz，1H)，7.26(d，J＝8.4Hz，1H)，7.09(d，J＝8.4Hz，1H)，7.01-6.90(m，1H)，4.40-4.25(m，2H)，3.98(q，J＝6.8Hz，1H)，2.90(s，3H)，2.10(s，3H)，2.05(p，J＝6.4Hz，1H)，1.16(d，J＝6.8Hz，3H)，0.93-0.85(m，4H).The fourth step: the compound 36d (51mg) obtained in the previous step was dissolved in n-butanol (2mL), and compound Int-1 (45mg, 0.19mmol) and p-toluenesulfonic acid monohydrate (7mg, 37umol) were added to react The solution was stirred at 160° C. for 3 hours under microwave conditions. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by reverse-phase preparative HPLC to obtain 36 as a white solid (10 mg, two-step reaction yield 7%). ESI-MS (m/z): 466.3[M+H] + ; 1H NMR (500MHz, DMSO-d6) δ9.82(s, 1H), 8.05(d, J=2.3Hz, 1H), 7.83(dd , J=8.5, 2.4Hz, 1H), 7.53(d, J=8.4Hz, 1H), 7.26(d, J=8.4Hz, 1H), 7.09(d, J=8.4Hz, 1H), 7.01-6.90 (m, 1H), 4.40-4.25(m, 2H), 3.98(q, J=6.8Hz, 1H), 2.90(s, 3H), 2.10(s, 3H), 2.05(p, J=6.4Hz, 1H), 1.16(d, J=6.8Hz, 3H), 0.93-0.85(m, 4H).
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 route and the synthetic method of the intermediate described in the above examples, the following examples can be obtained.



对照例1Comparative example 1
(S)-4，7，8-三甲基-2-(((1-((6-(三氟甲基)吡啶-3-基)甲基)-1H-吡唑-4-基)甲基)氨基)-7，8-二氢蝶啶-6(5H)-酮
(S)-4,7,8-Trimethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl) Methyl)amino)-7,8-dihydropteridin-6(5H)-one
对照例1参照专利WO2019209757中描述的compound 136的合成方法得到。ESI-MS(m/z)：447.2[M+H]+；1H NMR(500MHz，DMSO-d6)δ9.81(s，1H)，8.63(s，1H)，7.88(d，J＝8.1Hz，1H)，7.84(d，J＝8.3Hz，1H)，7.76(s，1H)，7.43(d，J＝1.3Hz，1H)，6.61-6.56(m，1H)，5.45(s，2H)，4.28-4.20(m，2H)，3.99(q，J＝6.8Hz，1H)，2.93(s，3H)，2.13(s，3H)，1.18(d，J＝6.9Hz，3H)。Comparative Example 1 was obtained by referring to the synthesis method of compound 136 described in patent WO2019209757. ESI-MS (m/z): 447.2[M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.81 (s, 1H), 8.63 (s, 1H), 7.88 (d, J=8.1 Hz, 1H), 7.84(d, J=8.3Hz, 1H), 7.76(s, 1H), 7.43(d, J=1.3Hz, 1H), 6.61-6.56(m, 1H), 5.45(s, 2H ), 4.28-4.20 (m, 2H), 3.99 (q, J = 6.8Hz, 1H), 2.93 (s, 3H), 2.13 (s, 3H), 1.18 (d, J = 6.9Hz, 3H).
对照例2Comparative example 2
(S)-2-(((6-(4-氟苯氧基)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-(4-fluorophenoxy)pyridin-3-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridine- 6(5H)-keto
对照例2参照专利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 2 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).
Wnt通路抑制剂生物学筛选和结果Biological Screening and Results of Wnt Pathway Inhibitors
试验例1：Colo205-LUC-TCF/LEF-M1报告细胞系构建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，96孔板细胞至少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时抑制时可达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, in the exponential growth phase of the cells, the method of transfection with lipo3000 liposomes was transfected with TCF/LEF transcription factors Driven luciferase reporter plasmid (Promega). The plasmid carries a resistance gene for resistance screening. Transfection was carried out in 10 cm culture dishes using conventional complete medium without resistance. After 2 days, the medium with resistance was replaced, and the culture was continued. After that, 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 an adaptive medium. When the cells covered the culture dish, the cells were digested, counted, and passaged in a 96-well plate, so that the average number of cells contained in each well was 1.5/well, and the adaptive medium was used for passage. The rest of the cells were frozen. After subculture, culture 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 were labeled as monoclonal wells. Afterwards, normal culture was performed, and the culture medium was replaced every 2 days, and observed. There are holes where the monoclonal cells continue to grow in the early stage, and they are labeled twice, and can be replaced with normal resistant medium. When a monoclonal well is overgrown with a 96-well plate, it is digested and passaged to a 24-well culture plate. After the 24-well plate is overgrown, it is passaged to a 96-well plate and a 6-well plate. The cells in a 96-well plate are at least 6 wells, of which 3 wells were added with known Wnt inhibitors, and the other 3 wells were not treated. After 24 hours, the cells in the 96-well plate were added with a fluorescence detection reagent to detect the fluorescence intensity. Cell lines with fluorescent expression when not treated and decreased fluorescent light after inhibition were selected and further cultured. Colo205-LUC-TCF/LEF-M1 cell line is one of the above screened cell lines, its growth curve, cell shape, and cell growth state are similar to those of the original Colo205 cells, and the fluorescence signals of inhibitor treatment and no treatment The ratio is the largest among all cell lines, and the ratio can reach 4-5 times when inhibited 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报告细胞系上抑制能力的检测Test Example 2: Detection of compound's inhibitory ability on Colo205-LUC-TCF/LEF-M1 reporter cell line
Colo205-LUC-TCF/LEF-M1细胞株为稳定转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. The β-catenin Wnt pathway is continuously activated. After adding the inhibitor, the Wnt pathway is inhibited. The expression of firefly luciferase regulated by the TCF/LEF cis-element decreased, and after adding the detection substrate, the detected light signal decreased accordingly, so as to detect the inhibitory effect of the compound.
向96孔的细胞培养板，每孔中加入100uL，最高浓度20uM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100uL培养基，同时做相应的阳性、阴性对照孔。将细胞放入细5％CO2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)100uL，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ICS0的浓度。Colo 205报告基因检测数据汇总于表1。To a 96-well cell culture plate, add 100uL of the compound with a maximum concentration of 20uM to each well, and make a 3-fold serial dilution of the compound concentration. Then inoculate 10,000 colo205 cells stably transfected with the reporter gene and 100uL medium into each well, and make corresponding positive and negative control wells at the same time. Put the cells in a 5% CO2 cell incubator, culture at 37°C for 4 hours, remove the culture medium after 4 hours, add 100uL of reagent (Promega) containing the corresponding firefly luciferase substrate to each well, and measure the luciferase reporter gene activity. Luminescence intensities were read with SpectraMax in full wavelength mode. The light signal intensity of the cells treated with DMSO alone was used as a positive control, and the light signal intensity of cells without cells was used as a negative control, and the concentration of ICSO of each compound was calculated. Colo 205 reporter gene detection data are summarized in Table 1.
表1、化合物对Colo205-LUC-TCF/LEF报告基因抑制的IC50值
Table 1. IC50 values of compounds for Colo205-LUC-TCF/LEF reporter gene inhibition
试验例3：化合物对Wnt突变细胞株(Colo205、H929、HepG2和DU4475)和非Wnt突变细胞株(RKO)的增殖抑制试验 Test Example 3: Proliferation Inhibitory Test of Compounds on Wnt Mutant Cell Lines (Colo205, H929, HepG2 and DU4475) and Non-Wnt Mutant Cell Lines (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、H929、HepG2和DU4475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, H929, HepG2 and DU4475 cell lines whose Wnt pathway is continuously activated, and whose proliferation is Wnt pathway-dependent; while the Wnt pathway is not activated under normal circumstances, and the proliferation is independent of Wnt pathway RKO The cell line is used as a control cell line, and it is judged that the inhibitory effect of the compound of the present invention on Wnt-dependent proliferation is not caused by other non-specific toxicity.
将培养于各自的培养基中的Colo205、H929、DU4475、HepG2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1000-4000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10uM，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(表2)。Colo205, H929, DU4475, HepG2, and RKO cell lines cultured in their respective culture media were treated during the logarithmic growth phase, and the cells were collected to prepare a uniform cell suspension of known concentration, and then transferred to a 96-well cell culture plate Add cell suspension to each well so that each well contains 1000-4000 cells. Put it into a 5% CO2 incubator and incubate at 37°C for 20-24h. On the second day, the fully dissolved, 3-fold serially diluted compound was added to each cell culture well, so that the final maximum concentration in the cell culture well was 10 uM, and the culture was continued for 96 hours. In this test, Promega's cell viability detection test is used for detection. The more the cells proliferate, the stronger the final signal intensity will be. The detection instrument is SpectraMax, full wavelength mode. The wells only added with DMSO were used as positive control wells, and the wells that were not inoculated with cells were used as negative control wells. The IC50 values of each compound for the proliferation inhibition of Wnt sustained activation or proliferation-dependent cells, and for Wnt-inactive or proliferation-independent cells were calculated. The IC50 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 (Table 2).
表2、化合物对Wnt突变细胞株的增殖抑制的IC50值

Table 2. IC50 values of the compounds on the proliferation inhibition of Wnt mutant cell lines

ND＝未测试ND = not tested
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 is effective for mutant cell lines Colo205, DU4475, NCI-H929 and HepG2 have significant inhibitory activity, but basically have no significant inhibitory activity on Hela and RKO cell lines, which shows that the compound of the present invention has a significant Wnt-dependent proliferation inhibitory effect.
试验例4：化合物1对Colo205小鼠Xenograft模型的肿瘤增长抑制试验Test Example 4: The tumor growth inhibition test of Compound 1 on the Colo205 mouse Xenograft model
本研究用人结肠癌细胞Colo205的BALB/c Nude裸鼠移植瘤模型对对照例l和化合物1的体内抗肿瘤活性进行评价。In this study, the BALB/c Nude nude mouse transplanted tumor model of human colon cancer cell Colo205 was used to evaluate the anti-tumor activity of control example 1 and compound 1 in vivo.
雌性BALB/c Nude裸鼠皮下接种人结肠癌细胞Colo205，建立Colo205BALB/c Nude裸鼠移植瘤模型。待肿瘤生长至平均肿瘤体积为80mm3左右后，根据肿瘤体积大小采用随机分组法将荷瘤鼠分为3组：溶剂处理对照组、3mg/kg化合物1组和10mg/kg对照例1组。化合物1和对照例1口服给药，每天给药一次，给药周期14天，每隔一天测量肿瘤体积，Day 14称量体重和测量肿瘤体积(表3和图1)。Female BALB/c Nude nude mice were subcutaneously inoculated with human colon cancer cell Colo205, and the Colo205 BALB/c Nude nude mouse xenograft model was established. After the tumor grew to an average tumor volume of about 80 mm3, the tumor-bearing mice were randomly divided into 3 groups according to the tumor volume: solvent treatment control group, 3 mg/kg compound 1 group and 10 mg/kg control group 1. Compound 1 and Control Example 1 were administered orally, once a day, and the administration cycle was 14 days. The tumor volume was measured every other day, and the body weight and tumor volume were measured on Day 14 (Table 3 and Figure 1).
表3

***：与Vehicle阴性对照组相比，P＜0.001。 table 3

***: Compared with Vehicle negative control group, P<0.001.

Claims (18)

  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 a structure of formula (I) or a pharmaceutically acceptable salt, isotopic derivative, and 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, 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 , -(C 1 -C 6 ) alkylene SR a , -halogenated (C 1 -C 6 ) alkylene SR a , or R 1 , R 2 and the carbon atom connected to them together 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, halo (C 1 -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, halo (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;
    X表示CR4或者N；X means CR 4 or N;
    R4各自独立地表示氢、卤素、氰基、(C1-C3)烷基、卤代(C1-C3)烷基；R 4 each independently represent hydrogen, halogen, cyano, (C 1 -C 3 ) alkyl, halo (C 1 -C 3 ) alkyl;
    L表示-O-或者-(CRmRm’)-，其中，Rm、Rm’各自独立地表示氢、(C1-C3)烷基、(C3-C8)环烷基，或者Rm、Rm’与和其相连的碳原子形成3-5元环，该环可以包含0个或1个选自O和S的杂原子；L represents -O- or -(CR m R m ')-, wherein R m and R m ' each independently represent hydrogen, (C 1 -C 3 ) alkyl, (C 3 -C 8 ) cycloalkyl , or R m , R m 'and the carbon atom connected to it form a 3-5 membered ring, and the ring may contain 0 or 1 heteroatom selected from O and S;
    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；Cy represents a 5-12 membered aromatic heterocycle, which optionally contains 1, 2, 3 or 4 heteroatoms, each of which is independently selected from N, O and S;
    R5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；R 5 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 ;
    R6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、(C3-C8)杂环烷基、卤代(C3-C8)杂环烷基、(C2-C6)炔基、卤代(C2-C6)炔基、-(C1-C6)亚烷基ORa、-卤代(C1-C6)亚烷基ORa、-(C3-C8)亚环烷基ORa、-卤代(C3-C8)亚环烷基ORa、-(C1-C6)亚烷基SRa、-卤代(C1-C6)亚烷基SRa、-(C3-C8)亚环烷基SRa、-卤代(C3-C8)亚环烷基SRa、-(C1-C6)亚烷基CN、-卤代(C1-C6)亚烷基CN、-(C3-C8) 亚环烷基CN、-卤代(C3-C8)亚环烷基CN、-(C1-C6)亚烷基-NRaRa′、-卤代(C1-C6)亚烷基-NRaRa′、-(C3-C8)亚环烷基-NRaRa′、-卤代(C3-C8)亚环烷基-NRaRa′、-CN、-NO2、-ORa、-SRa、-NRaRa′，其中Ra、Ra’可以与它们相连的N原子一起形成3-8元环，所述环还任意可以有0、1或2个选自N、O和S的杂原子，所述环可以是单环、双环、桥环或者螺环；R 6 represents halogen, (C 1 -C 6 ) alkyl, halo (C 1 -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, halo (C 3 -C 8 ) cycloalkyl , (C 3 -C 8 )heterocycloalkyl, halo(C 3 -C 8 )heterocycloalkyl, (C 2 -C 6 )alkynyl, halo(C 2 -C 6 )alkynyl, - (C 1 -C 6 )alkylene OR a , -halo(C 1 -C 6 )alkylene OR a , -(C 3 -C 8 )cycloalkylene OR a , -halo(C 3 -C 8 )cycloalkylene OR a , -(C 1 -C 6 )alkylene SR a , -halo(C 1 -C 6 )alkylene SR a , -(C 3 -C 8 )alkylene SR a , -(C 3 -C 8 )alkylene CycloalkylSR a , -Halo(C 3 -C 8 )cycloalkylene SR a , -(C 1 -C 6 )alkylene CN, -Halo(C 1 -C 6 )alkylene CN 、-(C 3 -C 8 ) Cycloalkylene CN, -halo(C 3 -C 8 )cycloalkylene CN, -(C 1 -C 6 )alkylene-NR a R a ′, -halo(C 1 -C 6 ) Alkylene-NR a R a ′, -(C 3 -C 8 ) cycloalkylene-NR a R a ′, -halogenated (C 3 -C 8 ) cycloalkylene-NR a R a ′, -CN, -NO 2 , -OR a , -SR a , -NR a R a ′, wherein R a , R a ′ can form a 3-8-membered ring together with their connected N atoms, and the ring can also be arbitrarily There are 0, 1 or 2 heteroatoms selected from N, O and S, and the ring may be monocyclic, bicyclic, bridged or spiro;
    R7各自独立地表示氢、卤素、(C1-C3)烷基、卤代(C1-C3)烷基；R 7 each independently represent hydrogen, halogen, (C 1 -C 3 ) alkyl, halo (C 1 -C 3 ) alkyl;
    m、n各自独立地表示0、1或2；m and n each independently represent 0, 1 or 2;
    Ra、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 and R a ' 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.
  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，The compound with the structure of formula (I) or its pharmaceutically acceptable salt, isotopic derivative, stereoisomer according to claim 1, wherein,
    当R6连接于碳原子时，R6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、(C3-C8)杂环烷基、卤代(C3-C8)杂环烷基、(C2-C6)炔基、卤代(C2-C6)炔基、-(C1-C6)亚烷基ORa、-卤代(C1-C6)亚烷基ORa、-(C3-C8)亚环烷基ORa、-卤代(C3-C8)亚环烷基ORa、-(C1-C6)亚烷基SRa、-卤代(C1-C6)亚烷基SRa、-(C3-C8)亚环烷基SRa、-卤代(C3-C8)亚环烷基SRa、-(C1-C6)亚烷基CN、-卤代(C1-C6)亚烷基CN、-(C3-C8)亚环烷基CN、-卤代(C3-C8)亚环烷基CN、-(C1-C6)亚烷基-NRaRa′、-卤代(C1-C6)亚烷基-NRaRa′、-(C3-C8)亚环烷基-NRaRa′、-卤代(C3-C8)亚环烷基-NRaRa′、-CN、-NO2、-ORa、-SRa、-NRaRa′，其中Ra、Ra’可以与它们相连的N原子一起形成3-8元环，所述环还任意可以有0、1或2个选自N、O和S的杂原子，所述环可以是单环、双环、桥环或者螺环；When R 6 is connected to a carbon atom, R 6 represents halogen, (C 1 -C 6 ) alkyl, halo (C 1 -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, halo ( C 3 -C 8 )cycloalkyl, (C 3 -C 8 )heterocycloalkyl, halo(C 3 -C 8 )heterocycloalkyl, (C 2 -C 6 )alkynyl, halo(C 2 -C 6 )alkynyl, -(C 1 -C 6 )alkylene OR a , -halo(C 1 -C 6 )alkylene OR a , -(C 3 -C 8 )cycloalkylene OR a , -halogenated (C 3 -C 8 )cycloalkylene OR a , -(C 1 -C 6 )alkylene SR a , -halogenated (C 1 -C 6 )alkylene SR a , -(C 3 -C 8 )cycloalkylene SR a , -halogenated (C 3 -C 8 )cycloalkylene SR a , -(C 1 -C 6 )alkylene CN, -halogenated (C 1 -C 6 )alkylene CN, -(C 3 -C 8 )cycloalkylene CN, -halo(C 3 -C 8 )cycloalkylene CN, -(C 1 -C 6 )alkylene -NR a R a ′, -halo(C 1 -C 6 )alkylene-NR a R a ′, -(C 3 -C 8 )cycloalkylene-NR a R a ′, -halo (C 3 -C 8 )cycloalkylene-NR a R a ', -CN, -NO 2 , -OR a , -SR a , -NR a R a ', wherein R a , R a ' can be with their The connected N atoms together form a 3-8 membered ring, and the ring can optionally have 0, 1 or 2 heteroatoms selected from N, O and S, and the ring can be monocyclic, bicyclic, bridged or spiro ring;
    当R6连接于N原子时，R6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、(C3-C8)杂环烷基、卤代(C3-C8)杂环烷基、(C2-C6)炔基、卤代(C2-C6)炔基、-(C1-C6)亚烷基ORa、-卤代(C1-C6)亚烷基ORa、-(C3-C8)亚环烷基ORa、-卤代(C3-C8)亚环烷基ORa、-(C1-C6)亚烷基SRa、-卤代(C1-C6)亚烷基SRa、-(C3-C8)亚环烷基SRa、-卤代(C3-C8)亚环烷基SRa。When R 6 is connected to the N atom, R 6 represents halogen, (C 1 -C 6 ) alkyl, halo (C 1 -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, halo ( C 3 -C 8 )cycloalkyl, (C 3 -C 8 )heterocycloalkyl, halo(C 3 -C 8 )heterocycloalkyl, (C 2 -C 6 )alkynyl, halo(C 2 -C 6 )alkynyl, -(C 1 -C 6 )alkylene OR a , -halo(C 1 -C 6 )alkylene OR a , -(C 3 -C 8 )cycloalkylene OR a , -halogenated (C 3 -C 8 )cycloalkylene OR a , -(C 1 -C 6 )alkylene SR a , -halogenated (C 1 -C 6 )alkylene SR a , -(C 3 -C 8 )cycloalkylene SR a , -halo(C 3 -C 8 )cycloalkylene SR a .
  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，R6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 a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof according to any preceding claim, wherein R 6 represents halogen, (C 1 -C 6 ) alkane radical, halo(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, halo(C 3 -C 8 )cycloalkyl.
  4. 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、-(C1-C6)亚烷基ORa、-(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。The compound having the structure of formula (I) or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof according to any one of the preceding claims, wherein 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, -(C 1 -C 6 ) alkylene OR a , -(C 1 -C 6 ) alkylene SR a ; or R 1 , R 2 form a 3-8 membered ring together with the carbon atoms connected to them, and the ring can be optionally Contains 0, 1, 2 or 3 heteroatoms selected from N, O and S.
  5. 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)烷基或卤代(C1-C6)烷基。According to any one of the preceding claims, the compound having the structure of formula (I) or its pharmaceutically acceptable Salts, isotopic derivatives, and stereoisomers, wherein R 3 is (C 1 -C 6 )alkyl or halogenated (C 1 -C 6 )alkyl.
  6. 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) or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof according to any one of the preceding claims, wherein R 3 is (C 1 -C 6 )alkyl.
  7. 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5-6元单环芳杂环，或者Cy为9-10元双环芳杂环。The compound having the structure of formula (I) or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof according to any one of the preceding claims, wherein Cy is a 5-6 membered monocyclic aromatic heterocycle, or Cy is a 9-10 membered bicyclic aromatic heterocycle.
  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，Cy为吡啶基、嘧啶基、吡唑基、咪唑基或吡咯基。According to any of the preceding claims, the compound having the structure of formula (I) or its pharmaceutically acceptable salt, isotopic derivative, stereoisomer, wherein, Cy is pyridyl, pyrimidyl, pyrazolyl, imidazole base or pyrrolyl.
  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，R6与L连接于Cy的邻位。The compound having the structure of formula (I) or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof according to any one of the preceding claims, wherein R and L are connected at the ortho position of Cy.
  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，R5位于R6的间位，且位于L的间位或者对位。The compound having the structure of formula (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein R is at the meta position of R , and at the position of L Interposition or counterposition.
  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，X为CR4。The compound having the structure of formula (I) or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof according to any one of the preceding claims, wherein X is CR 4 .
  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，R4为氢。The compound having the structure of formula (I) or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof according to any one of the preceding claims, wherein R 4 is hydrogen.
  13. 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与R5、R6的连接如下：
    According to any one of the preceding claims, the compound having the structure of formula (I) or its pharmaceutically acceptable salt, isotopic derivative, or stereoisomer, wherein, the connection of Cy to R 5 and R 6 is as follows:
  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，Cy与R5、R6的连接如下：
    According to any one of the preceding claims, the compound having the structure of formula (I) or its pharmaceutically acceptable salt, isotopic derivative, or stereoisomer, wherein, the connection of Cy to R 5 and R 6 is as follows:
  15. 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选自：
    The compound having the structure of formula (I) or a pharmaceutically acceptable salt , isotopic derivative, or stereoisomer thereof according to any one of the preceding claims, wherein R is selected from:
    其任选地可以被0、1、2、3或者4个选自卤素、-CN、-ORa、-SRa和-NRaRa′的取代基取代。It may optionally be substituted with 0, 1 , 2, 3 or 4 substituents selected from halogen, -CN, -OR a , -SR a and -NR a R a '.
  16. 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:







  17. 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 the compound of any one of the preceding claims or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer, and an optional pharmaceutically acceptable carrier.
  18. 权利要求1-16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17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 described in any one of claims 1-16 or its pharmaceutically acceptable salt, isotope derivative, stereoisomer or the pharmaceutical composition described in claim 17 is used for preventing and/or treating cancer , tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases in medicine.
PCT/CN2023/073533 2022-01-29 2023-01-28 Wnt pathway inhibitor compound WO2023143501A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202380009996.XA CN116964053A (en) 2022-01-29 2023-01-28 Wnt pathway inhibitor compound

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202210114025.9 2022-01-29
CN202210114025 2022-01-29

Publications (1)

Publication Number Publication Date
WO2023143501A1 true WO2023143501A1 (en) 2023-08-03

Family

ID=87470624

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/073533 WO2023143501A1 (en) 2022-01-29 2023-01-28 Wnt pathway inhibitor compound

Country Status (3)

Country Link
CN (1) CN116964053A (en)
TW (1) TW202334157A (en)
WO (1) WO2023143501A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024022365A1 (en) * 2022-07-28 2024-02-01 杭州阿诺生物医药科技有限公司 Wnt pathway inhibitor compound

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013093508A2 (en) * 2011-12-22 2013-06-27 Oslo University Hospital Hf Wnt pathway inhibitors
CN104379583A (en) * 2012-06-15 2015-02-25 广州源生医药科技有限公司 Compound as WNT signaling inhibitor, composition, and use thereof
CN106458983A (en) * 2014-03-20 2017-02-22 拜耳制药股份公司 Novel compounds
CN109310690A (en) * 2016-04-27 2019-02-05 萨穆梅德有限公司 Isoquinolin -3- base benzamide type and its preparation and its purposes
WO2020125759A1 (en) * 2018-12-21 2020-06-25 汇瀚医疗科技有限公司 Compound as wnt signal pathway inhibitor and medical use thereof
CN112218865A (en) * 2018-04-24 2021-01-12 沃泰克斯药物股份有限公司 Pteridinone compounds and uses thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013093508A2 (en) * 2011-12-22 2013-06-27 Oslo University Hospital Hf Wnt pathway inhibitors
CN104379583A (en) * 2012-06-15 2015-02-25 广州源生医药科技有限公司 Compound as WNT signaling inhibitor, composition, and use thereof
CN106458983A (en) * 2014-03-20 2017-02-22 拜耳制药股份公司 Novel compounds
CN109310690A (en) * 2016-04-27 2019-02-05 萨穆梅德有限公司 Isoquinolin -3- base benzamide type and its preparation and its purposes
CN112218865A (en) * 2018-04-24 2021-01-12 沃泰克斯药物股份有限公司 Pteridinone compounds and uses thereof
WO2020125759A1 (en) * 2018-12-21 2020-06-25 汇瀚医疗科技有限公司 Compound as wnt signal pathway inhibitor and medical use thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ASHIHARA EISHI, TAKADA TETSUYA, MAEKAWA TAIRA: "Targeting the canonical Wnt/β‐catenin pathway in hematological malignancies", CANCER SCIENCE, JAPANESE CANCER ASSOCIATION, TOKYO, JP, vol. 106, no. 6, 1 June 2015 (2015-06-01), JP , pages 665 - 671, XP093080992, ISSN: 1347-9032, DOI: 10.1111/cas.12655 *
LIU ZHIQING, WANG PINGYUAN, WOLD ERIC A., SONG QIAOLING, ZHAO CHENYANG, WANG CHANGYUN, ZHOU JIA: "Small-Molecule Inhibitors Targeting the Canonical WNT Signaling Pathway for the Treatment of Cancer", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 64, no. 8, 22 April 2021 (2021-04-22), US , pages 4257 - 4288, XP093080990, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.0c01799 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024022365A1 (en) * 2022-07-28 2024-02-01 杭州阿诺生物医药科技有限公司 Wnt pathway inhibitor compound

Also Published As

Publication number Publication date
TW202334157A (en) 2023-09-01
CN116964053A (en) 2023-10-27

Similar Documents

Publication Publication Date Title
CN107011348B (en) Heteroaryl pyridone and aza-pyridone compounds as inhibitors of BTK activity
TWI723511B (en) Highly active sting protein agonist compound
WO2022089454A1 (en) High-activity wnt pathway inhibitor compound
TWI716976B (en) Highly active sting protein agonist
WO2019158070A1 (en) A2a and/or a2b receptor antagonist
WO2019222521A1 (en) Cdk inhibitors for the treatment of neoplastic disorders
AU2021273744A1 (en) Cyclin-dependent kinase inhibiting compounds for the treatment of medical disorders
WO2023143501A1 (en) Wnt pathway inhibitor compound
WO2022089398A1 (en) High activity hpk1 kinase inhibitor
JP7436630B2 (en) Adenosine receptor antagonist
WO2021129584A1 (en) Pd-l1 antagonist compound
WO2020169058A1 (en) Pd-l1 antagonist compound
WO2024022365A1 (en) Wnt pathway inhibitor compound
WO2023143546A1 (en) Wnt pathway inhibitor compounds
LU505117B1 (en) A pan-KRAS inhibitor compound
WO2023005894A1 (en) Inhibitor compound for wnt pathway
WO2024060966A1 (en) Pan-kras inhibitor compound
WO2023025225A1 (en) Cyclin k degradation agent
TWI810547B (en) Pd-l1 antagonist compound
WO2024104364A1 (en) Pan-kras inhibitor compound
TW202304906A (en) Highly active hpk1 kinase inhibitor
WO2020206034A1 (en) Cell cycle inhibiting compounds for the treatment of medical disorders
WO2022199561A1 (en) Hpk1 kinase inhibitor compound
CN117396482A (en) Wnt pathway inhibitor compound

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 202380009996.X

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23746378

Country of ref document: EP

Kind code of ref document: A1