WO2023005894A1 - 一种Wnt通路抑制剂化合物 - Google Patents

一种Wnt通路抑制剂化合物 Download PDF

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WO2023005894A1
WO2023005894A1 PCT/CN2022/107727 CN2022107727W WO2023005894A1 WO 2023005894 A1 WO2023005894 A1 WO 2023005894A1 CN 2022107727 W CN2022107727 W CN 2022107727W WO 2023005894 A1 WO2023005894 A1 WO 2023005894A1
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alkyl
compound
cycloalkyl
pharmaceutically acceptable
stereoisomer
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PCT/CN2022/107727
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English (en)
French (fr)
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陈宇锋
武朋
吕萌
刘灿丰
陈凯旋
杨寒
程万里
李非凡
金超凡
孙钊
王友平
陈可可
路萍萍
何南海
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杭州阿诺生物医药科技有限公司
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Priority to CN202311337012.9A priority Critical patent/CN117384170A/zh
Priority to CN202280013624.XA priority patent/CN116806220A/zh
Priority to CN202311341770.8A priority patent/CN117402159A/zh
Priority to CN202311335039.4A priority patent/CN117384158A/zh
Priority to CN202311342585.0A priority patent/CN117402160A/zh
Publication of WO2023005894A1 publication Critical patent/WO2023005894A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • C07D471/12—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 three hetero rings
    • C07D471/16—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/16—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

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 stable 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 canonical 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 present invention provides a compound having a structure of formula (I) for inhibiting Wnt pathway activity or pharmaceutically acceptable salts, isotopic derivatives, and stereoisomers thereof:
  • R1 represents C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, and said R1 can be Optionally 0, 1, 2, 3 selected from: hydrogen, halogen, OR a , nitro, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) Haloalkyl, (C 3 -C 6 ) cycloalkyl, halo (C 3 -C 6 ) cycloalkyl, 3-6 membered heterocycloalkyl, halogenated 3-6 membered heterocycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, cyano, S R a , halo(C 1 -C 6 )alkoxy, halo(C 3 -C 6 )cycloalkoxy,
  • X represents a covalent bond or -(CR a R a' ) m -, -(CR a Ra') m -O-(CR a R a' ) n -, -(CR a R a' ) m -N( R b )-(CR a R a' ) n -, -(CR a R a' ) m -S-(CR a R a' ) n -, -(CR a R a' ) m C(O)( CR a R a' ) n -, -(CR a R a' ) m S(O) 2 (CR a R a' ) n -, -(CR a R a' ) m C(O)N(R b )(CR a R a' ) n -, -(CR a R a' ) m S(O)
  • Cy represents C 3 -C 5 cycloalkyl or 4-5 membered cycloheteroalkyl, and it can be arbitrarily replaced by 0, 1 or 2 selected from hydrogen, halogen, -OR a , (C 1 -C 6 ) alkane Substituents of radical, (C 1 -C 6 ) haloalkyl, (C 3 -C 6 ) cycloalkyl, cyano and hydroxy (C 1 -C 6 ) alkyl;
  • R 2 represents hydrogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 3 -C 6 ) cycloalkyl or hydroxy (C 1 -C 6 ) alkyl;
  • R 3 and R 3' each independently represent hydrogen, halogen, OR a , (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, hydroxy C 1 -C 6 alkyl or (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl;
  • R 3 and R 3' form a 3-6 membered saturated or unsaturated ring together with the carbon atom connected to it, and the ring can also optionally contain 1 or 2 heteroatoms selected from O, S and N, And the ring can be optionally substituted by 0, 1 or 2 substituents selected from halogen, hydroxyl and C 1 -C 6 alkyl;
  • R 2 , R 3 or R 2 , R 3' together form a 4-6 membered saturated or unsaturated ring with the atoms connected to it, and the ring can also optionally contain 1 or 2 members selected from O, S and N heteroatoms, and the ring can also be optionally substituted by 0, 1, 2 halogens, hydroxyl, C 1 -C 6 alkyl;
  • R 4 and R 4' each independently represent hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, hydroxyl C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl;
  • RT and RT ' each independently represent hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halogen, OR a ;
  • RT and RT ' together form a 3-6 membered ring with the atom attached to it;
  • A represents (CR L R L' ) p , wherein RL and RL' each independently represent hydrogen, C 1 -C 6 alkyl, C 1 -C 6 Haloalkyl, hydroxy C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halogen, OR a , or RL and RL' together form a 3-6 membered ring with the carbon atom connected to it, in which Can optionally contain 0, 1 or 2 heteroatoms selected from O, S and N, and the ring can also be optionally substituted by 0, 1 or 2 substituents selected from halogen and hydroxyl;
  • A indicates CR H , wherein R H indicates hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, hydroxyl C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halogen, OR a ;
  • R a , R a' , R b , R b' each independently represent hydrogen or C 1 -C 6 alkyl
  • n, and p represent 0, 1 or 2 each independently.
  • R 1 , R 2 , R 3 , R 3' , R 4 , R 4' , X, Cy have the above definitions.
  • the present invention also provides a compound having the following formula (III) and pharmaceutically acceptable salts, isotopic derivatives, and stereoisomers:
  • R 1 , R 2 , R 3 , R 3′ , R 4 , R 4′ , RT, RT ′ , RL , RL′ , X , and Cy are as defined above.
  • R 2 represents hydrogen, C 1 -C 6 alkyl, hydroxyl (C 1 -C 6 alkyl) or C 3 -C 6 cycloalkyl.
  • R 3 , R 3' each independently represent hydrogen, C 1 -C 6 alkyl, hydroxyl (C 1 -C 6 alkyl) or C 3 -C 6 cycloalkyl .
  • Cy represents C 3 -C 5 cycloalkyl or 4-5 membered cycloheteroalkyl; preferably, Cy represents
  • X represents a covalent bond or -(CR a R a' ) m -, -(CR a R a' ) m -O-(CR a R a' ) n -, -( CR a R a' ) m -N(R b )-(CR a R a' ) n -, -(CR a R a' ) m -S-(CR a R a' ) n -, -(CR a R a' ) m C(O)N(R b )(CR a R a' ) n -, -(CR a R a' ) m S(O) 2 N(R b )(CR a R a' ) n -, -(CR a R a' ) m N(R b )C(O)(CR a R a' )
  • X represents -O-, -NR b -, -CR a R a' -, -OCR a R a' -, -CR a R a' O-, -C(O) -, -C(O)NR b -, -NR b C(O)-, -NR b -C(O)-NR b -, -CR a R a' -C(O)NR b -, -CR a R a' -NR b C(O)-, -S-, -NR b S(O) 2 -, -SO 2 NR b , -OC(O)NR b -, -S(O) 2 , - C(O)NR b -, -C(O)CR a R a' -, -CR a R a' C(O)NR b -, -NR b C(O) 2 , -
  • X represents -(CR a R a' ) m -O-(CR a R a' ) n -, preferably -O-, -OCR a R a' -, -CR a R a' O-, more preferably -O- or -O-CH 2 -.
  • RT and RT ' represent hydrogen.
  • RL and RL' represent hydrogen.
  • R H represents hydrogen
  • R 1 represents C 3 -C 6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6 -C 10 aryl substituted by 0, 1, 2 or 3 substituents , 5-10 membered heteroaryl, wherein the substituent is selected from halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 3 -C 6 ) cycloalkyl, Halogenated (C 3 -C 6 )cycloalkyl, 3-6 membered heterocycloalkyl, halogenated 3-6 membered heterocycloalkyl, C 6 -C 10 aryl and 5-10 membered heteroaryl.
  • R 1 represents C 3 -C 6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, and said R 1 can be optionally 0, 1, 2, 3 selected from: hydrogen, halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 3 -C 6 ) cycloalkane Substituents of groups, halo(C 3 -C 6 )cycloalkyl groups.
  • R is selected from:
  • R is selected from:
  • the present invention provides a compound having the following structure:
  • the present invention also provides a pharmaceutical composition, comprising the compound of the present invention or its pharmaceutically acceptable salt, isotope derivative or stereoisomer.
  • the present invention also provides the compounds described in the present invention or their pharmaceutically acceptable salts, isotope derivatives, stereoisomers or the pharmaceutical compositions described in the present invention for the prevention and/or treatment of cancer , tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases in medicine.
  • cancer cancer , tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases in medicine.
  • compound when referring to the "compound” of the structure of formula (I) to formula (III), it generally also covers its stereoisomers, diastereomers and enantiomers. , racemic mixtures and isotopic derivatives.
  • the present invention provides a method for preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease, comprising administering the compound described in the present invention or its pharmaceutically acceptable Accepted salts, isotopic derivatives, stereoisomers or pharmaceutical compositions of the present invention.
  • 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 Such animal tissues, 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 tissues of humans and lower animals 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 isotopic 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.
  • 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 are generally synthesized starting from labeled starting materials and carried out in the same way as non-isotopically labeled compounds using known synthetic techniques.
  • 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 mammals administered a compound of the 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, esophagus cancer, lip cancer, larynx cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, medullary thyroid cancer, Papillary thyroid cancer, renal cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine body cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary cancer, melanoma, brain tumors such as Glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectoderma
  • 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, melphalan, 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 agents (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, pimecrolimus, 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 orally or parenterally as an active ingredient, and its effective amount ranges from 0.1 to 2,000 mg/kg body weight/day in the case of mammals including humans (about 70 kg body weight), Preferably 1 to 1,000 mg/kg body weight/day, and administered in single or 4 divided doses per day, or with or without a scheduled time.
  • 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 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 understand that the functionality present on the molecule is consistent with the proposed transformation. This sometimes requires judgment to alter the order of synthetic steps or starting materials to obtain the desired compound of the invention.
  • 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.
  • All methods used to prepare the compounds of the invention and intermediates prepared therein are considered part of the invention.
  • they may be separated by customary methods, for example by chromatography or fractional crystallization.
  • 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 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.
  • the definitions of the 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, more preferably 1 to 4 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. In this context, alkenyl is preferably C 2 -C 6 alkenyl.
  • 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. In this context, alkynyl is preferably C 2 -C 6 alkynyl.
  • 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 C 3 -C 8 cyclic alkyl, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and norbornyl.
  • Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included within the definition of "cycloalkyl”.
  • Bicyclic cyclic alkyl groups include bridged, spiro or fused cycloalkyl groups.
  • cycloalkyl is preferably C 3 -C 6 cycloalkyl.
  • cycloalkenyl refers to a monocyclic or bicyclic cyclic alkenyl group.
  • Monocyclic cyclic alkenyl refers to C 3 -C 8 cyclic alkenyl, including but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and norbornenyl.
  • Branched cycloalkenyl groups such as 1-methylcyclopropenyl and 2-methylcyclopropenyl are included 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.
  • 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.
  • 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-.
  • 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 x1 to x2.
  • C 0 -C 8 means that the group contains 0, 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms
  • C 1 -C 8 means that the group contains 1, 2, 3 , 4, 5, 6, 7 or 8 carbon atoms
  • C 2 -C 8 means that the group contains 2, 3, 4, 5, 6, 7 or 8 carbon atoms
  • C 3 -C 8 means that the 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 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
  • x1-x2 membered ring is used when referring to cyclic groups (such as aryl, heteroaryl, cycloalkyl, and heterocycloalkyl), which means that the ring atoms of the group The number can be x1 to x2.
  • the 3-12 membered cyclic group 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
  • 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 stable 3-membered, 4-membered, 5-membered, 6-membered, or 7-membered aromatic monocyclic or aromatic bicyclic ring or 7-, 8-, 9-, 10-, 11-, 12-membered
  • An aromatic polycyclic heterocycle which is fully unsaturated or partially unsaturated and which contains carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; and includes Any of the following polycyclic groups in which any heterocyclic ring as defined above is fused to a benzene ring. 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.
  • the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to each other.
  • the total number of S and O atoms in the heterocycle is not greater than one.
  • heterocycle it 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] Tetrahydrofuryl, furyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazopyr
  • 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 refers to a 3-8 membered, saturated or unsaturated but non-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 carbon 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.
  • an effective amount means an amount of a drug or agent (ie, a compound of the invention) that will elicit a biological or medical response in a tissue, system, animal or human being sought, eg, by a researcher or clinician.
  • a 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 (ie) 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 a desired result is capable of being increased or prolonged, either in potency or duration.
  • 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 present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of one or more compounds of the present invention formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents, and optionally a One or more of the other therapeutic agents described above.
  • the compounds of the present invention may be administered for any of the above uses by any suitable means, for example orally, such as tablets, pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups and emulsions; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion techniques (e.g., as sterile injectable aqueous or nonaqueous solutions or suspensions liquid form); nasally, including to the nasal membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally, such as in the form of a suppository; or by intratumoral injection.
  • suitable means for example orally, such as tablets, pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, micro
  • Pharmaceutical carriers are formulated according to a number of factors within the purview of those skilled in the art. These factors include, but are not limited to: the type and nature of the active agent being formulated; the subject to whom the composition containing the active agent is to be administered; the intended route of administration of the composition; and the therapeutic indication being targeted. Pharmaceutical carriers include aqueous and non-aqueous liquid media and various solid and semisolid pharmaceutical carriers.
  • Such carriers may include many different ingredients and additives besides the active agent, which are included in the formulation for various reasons known to those skilled in the art, such as stabilizers, binders, and the like.
  • suitable pharmaceutical carriers and the factors involved in carrier selection can be found in several readily available sources, such as Allen L.V.Jr. et al. Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition (2012 ), Pharmaceutical Press.
  • Dosage regimens for the compounds of the present invention will of course vary depending on known factors such as the pharmacodynamic properties of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition and weight of the recipient ; nature and extent of symptoms; type of concomitant therapy; frequency of therapy; route of administration, patient's renal and hepatic function, and desired effects.
  • the daily oral dosage of each active ingredient should be from about 0.001 mg/day to about 10-5000 mg/day, preferably from about 0.01 mg/day to about 1000 mg/day, and most preferably From about 0.1 mg/day to about 250 mg/day.
  • the most preferred dose intravenously will be about 0.01 mg/kg/minute to about 10 mg/kg/minute during a constant rate infusion.
  • the compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses of two, three or four times daily.
  • the compounds are usually formulated with a suitable pharmaceutical diluent, excipient or carrier (herein collectively referred to as drug carriers) in the form of mixtures for administration.
  • a suitable pharmaceutical diluent, excipient or carrier herein collectively referred to as drug carriers
  • Dosage forms suitable for administration may contain from about 1 milligram to about 2000 milligrams of active ingredient per dosage unit.
  • the active ingredient will generally be present in an amount of about 0.1-95% by weight, based on the total weight of the composition.
  • a typical capsule for oral administration contains at least one compound of the invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture was passed through a 60 mesh screen and packed into size 1 gelatin capsules.
  • a typical injectable formulation can be prepared by aseptically placing at least one compound of the present invention (250 mg) in a vial, lyophilizing in a sterile manner and sealing. For use, the vial contents are mixed with 2 mL of normal saline to produce an injectable formulation.
  • compositions comprising (alone or in combination with a pharmaceutical carrier) a therapeutically effective amount of at least one compound of the present invention as an active ingredient.
  • compounds of the invention may be used alone, in combination with other compounds of the invention, or in combination with one or more other therapeutic agents (eg, anticancer agents or other pharmaceutically active substances).
  • the compounds of the invention (which may be used in suitably hydrated form) and/or the pharmaceutical compositions of the invention are formulated into pharmaceutical dosage forms by conventional methods known to those skilled in the art.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of the invention can be varied to obtain an amount of active ingredient that is effective to achieve the desired therapeutic response, composition, and mode of administration for a particular patient without being toxic to the patient.
  • the selected dosage level will depend on a variety of factors, including the activity of the particular compound of the invention employed, or its ester, salt or amide; the route of administration; the time of administration; the rate of excretion of the particular compound employed; and the rate and extent of absorption. ; duration of treatment; other drugs, compounds and/or substances used in combination with the particular compound used; factors well known in the medical art such as age, sex, weight, condition, general health and prior medical history of the patient being treated.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the physician or veterinarian can start the doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a compound of the invention will be that amount of the compound at the lowest dose effective to produce a therapeutic effect.
  • Such effective dosage will generally depend on the factors mentioned above.
  • oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of this invention to patients range from about 0.01 to about 50 mg/kg body weight/day.
  • an effective daily dose of the active compound may be administered in two, three, four, five, six or more sub-doses at appropriate intervals throughout the day, optionally in unit dosage form. In certain aspects of the invention, the administration is once daily.
  • kits for the compounds of the present invention may be administered alone, it is preferred to administer the compounds in the form of pharmaceutical formulations (compositions). Kit/Product Packaging
  • Kits/product packaging are also described herein for use in the treatment of the above indications. These kits may consist of transporters, packs, or container boxes, which may be divided into compartments to accommodate one or more types of containers, such as vials, test tubes, and the like, each container containing the A single component in the method described above. Suitable containers include bottles, vials, syringes, test tubes and the like. Containers are made of acceptable materials such as glass or plastic.
  • a container may contain one or more compounds described herein, either as a pharmaceutical compound or in admixture with other ingredients described herein.
  • the container can have a sterile outlet (eg, the container can be an IV bag or bottle, the stopper of which can be pierced by a hypodermic needle).
  • a kit may contain a compound, together with instructions for use, labels or instructions for the methods described herein.
  • a typical kit may include one or more containers, each containing one or more materials (such as reagents, concentrated stock solutions, and/or or equipment). These materials include, but are not limited to, buffers, diluents, filters, needles, syringes, transporters, bags, containers, bottles and/or test tubes, accompanied by a list of contents and/or instructions for use, and inner packaging also accompanied by instructions. Instructions for the entire set are to be included.
  • Labels can be displayed on or closely associated with the container.
  • the appearance of the label on the container means that the label letters, numbers or other features are pasted, molded, or engraved on the container; the label can also appear in the container box or shipping box containing various containers, such as in the product insert.
  • a label may be used to indicate a specific therapeutic use of the contents.
  • the label may also bear instructions for use of the contents, such as described in the methods above.
  • the unit of weight volume percentage in the present invention is well known to those skilled in the art, for example, it refers to the weight (g) of solute in 100 ml of solution.
  • all professional and scientific terms used herein have the same meanings as are familiar to those skilled in the art.
  • any methods and materials similar or equivalent to those described can be applied to the method of the present invention.
  • the preferred implementation methods and materials described herein are for demonstration purposes only.
  • 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
  • ⁇ NMR shifts ( ⁇ ) are given in units of 10 -6 (ppm).
  • the determination of NMR is to use (Bruker Ascend TM 500 type) nuclear magnetic analyzer, and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), internal standard For tetramethylsilane (TMS).
  • DMSO-d6 deuterated dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS internal standard For tetramethylsilane
  • 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.
  • the flash column chromatography uses Agel (FS-9200T) automatic column passing machine, and the 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 of thin-layer chromatography separation and purification products are 0.4mm to 0.5mm.
  • Compound 1 was prepared by the following steps:
  • the first step cis-3-BOC-aminocyclobutanol 1a (250mg, 1.34mmol), methanesulfonic anhydride (465mg, 2.67mmol) and N,N-diisopropylethylamine (517mg, 4.01mmol ) was dissolved in dichloromethane (2 mL), and stirred overnight at room temperature. The completion of the reaction was monitored by TLC. The reaction solution was diluted with dichloromethane, washed with water and saturated brine successively, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a yellow solid 1b (300 mg, yield 84%).
  • Step 2 Dissolve compound 1b (300mg, 1.13mmol), compound 1c (251mg, 1.70mmol) and cesium carbonate (737mg, 2.26mmol) in N,N-dimethylformamide (2mL) at 80°C Stirring overnight.
  • LCMS monitored the completion of the reaction.
  • Step 3 Dissolve compound 1d (280mg, 882umol) in dichloromethane (2mL), add 1,4-dioxane hydrochloride solution (4M, 1.10mL) dropwise, and stir overnight at room temperature. The completion of the reaction was monitored by LCMS, and the reaction solution was concentrated to obtain a white solid 1e (170 mg, yield 75%).
  • ESI-MS m/z: 218.4 [M+H] + .
  • Step 5 Dissolve compound 1h (1.1g, 3.92mmol) in tetrahydrofuran (20mL), add aqueous hydrochloric acid (6N, 0.65mL) and platinum dioxide (88mg, 0.39mmol), and replace the hydrogen gas with a hydrogen balloon in the reaction system, Stir at room temperature under hydrogen balloon pressure for 48 hours, and monitor the completion of the reaction by LCMS.
  • the reaction solution was diluted with methanol, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain white solid 1i (900 mg, yield 90%).
  • ESI-MS (m/z): 253.2 [M+H] + .
  • Step 6 Dissolve compound 1i (50mg, 197umol), compound 1e (65mg, 257umol) and p-toluenesulfonic acid monohydrate (3.7mg, 19umol) in n-butanol (2mL), and microwave at 160°C React for 2 hours. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain white solid 1 (13 mg, yield 15%).
  • Compound 2 was prepared by the following steps:
  • the first step Dissolve compound 1b (500mg, 1.88mmol), compound 2a (461mg, 2.83mmol) and cesium carbonate (1.23g, 3.77mmol) in N,N-dimethylformamide (2mL) at 80 Stir overnight at °C.
  • ESI-MS (m/z): 333.3 [M+H] + .
  • Step 2 Dissolve compound 2b (500mg, 1.50mmol) in dichloromethane (2mL), add dropwise 1,4-dioxane hydrochloride solution (4M, 1.88mL), and stir overnight at room temperature. The completion of the reaction was monitored by LCMS, and the reaction solution was concentrated to obtain a white solid 2c (300 mg, yield 74%).
  • ESI-MS m/z: 233.5 [M+H] + .
  • Step 3 Dissolve compound 1i (50mg, 197umol), compound 2c (68mg, 256umol) and p-toluenesulfonic acid monohydrate (3.7mg, 19umol) in n-butanol (2mL), and microwave at 160°C React for 2 hours.
  • LCMS monitored the completion of the reaction.
  • the reaction solution was purified by reverse-phase preparative HPLC to obtain white solid 2 (10.1 mg, yield 11%).
  • Compound 3 was prepared by the following steps:
  • Step 2 Dissolve compound 3c (600mg, 1.74mmol) in dichloromethane (2mL), add 1,4-dioxane hydrochloride solution (4M, 2.17mL) dropwise, and stir overnight at room temperature. The completion of the reaction was monitored by LCMS, and the reaction solution was concentrated to obtain a white solid 3d (400 mg, yield 81%).
  • ESI-MS (m/z): 245.3 [M+H] + .
  • Step 4 Dissolve compound 3e (150mg, 718umol), methyl iodide (153mg, 1.08mmol) and cesium carbonate (468mg, 1.44mmol) in N,N-dimethylformamide (2mL) at 80°C Stir overnight.
  • LCMS monitored the completion of the reaction.
  • ESI-MS (m/z): 223.4 [M+H] + .
  • Step 5 Dissolve compound 3f (30mg, 134umol), compound 1e (68mg, 256umol) and trifluoroacetic acid (1.5mg, 13umol) in n-butanol (2mL) and react under microwave conditions at 160°C for 2 hours .
  • LCMS monitored the completion of the reaction.
  • the reaction solution was purified by reverse-phase preparative HPLC to obtain white solid 3 (6.8 mg, yield 12%).
  • Compound 4 was prepared by the following steps:
  • Step 1 Dissolve compound 3f (30mg, 134umol), compound 2b (40mg, 175umol) and trifluoroacetic acid (1.5mg, 13umol) in n-butanol (2mL) and react under microwave conditions at 160°C for 2 hours .
  • LCMS monitored the completion of the reaction.
  • the reaction solution was purified by reverse-phase preparative HPLC to obtain white solid 4 (9.3 mg, yield 16%).
  • Compound 5 was prepared by the following steps:
  • Step 2 Dissolve compound 5b (1.0 g, 2.90 mmol) in dichloromethane (10 mL), add 1,4-dioxane hydrochloride solution (4M, 3.62 mL) dropwise, and stir overnight at room temperature. The completion of the reaction was monitored by LCMS, and the reaction solution was concentrated to obtain a white solid 5c (700 mg, yield 98%).
  • Step 4 Dissolve compound 5d (250mg, 1.20mmol), methyl iodide (153mg, 1.08mmol) and cesium carbonate (468mg, 1.44mmol) in N,N-dimethylformamide (2mL) at 80°C Stirring overnight.
  • LCMS monitored the completion of the reaction.
  • ESI-MS (m/z): 223.4 [M+H] + .
  • Step 5 Dissolve compound 5e (30mg, 134umol), compound 2b (47mg, 175umol) and trifluoroacetic acid (1.5mg, 13umol) in n-butanol (2mL) and react under microwave conditions at 160°C for 2 hours .
  • LCMS monitored the completion of the reaction.
  • the reaction solution was purified by reverse-phase preparative HPLC to obtain white solid 5 (9.2 mg, yield 16%).
  • Compound 6 was prepared by the following steps:
  • Step 1 Dissolve compound 5e (30mg, 134umol), compound 1e (44mg, 175umol) and trifluoroacetic acid (1.5mg, 13umol) in n-butanol (2mL) and react under microwave conditions at 160°C for 2 hours .
  • LCMS monitored the completion of the reaction.
  • the reaction solution was purified by reverse-phase preparative HPLC to obtain white solid 6 (17.84 mg, yield 32%).
  • Compound 7 was prepared by the following steps:
  • the first step 5-bromo-2-trifluoromethylpyridine 7a (452mg, 2.00mmol), cis-3-amino-1-cyclobutylcarbamate tert-butyl ester 7b (372mg, 2.00mmol), Pd2 (dba)3 (91.5mg, 0.10mmol), Xantphos (115.6mg, 0.20mmol) and cesium carbonate (1.3g, 4.00mmol) were dissolved in dioxane (10mL), stirred overnight at 100°C under nitrogen protection.
  • Step 2 Dissolve compound 7c (100 mg, 0.3 mmol) in methanol (5 mL), add hydrogen chloride-dioxane solution (4M, 0.75 mL, 3 mmol) dropwise at room temperature, and stir at room temperature for 2 hours. The completion of the reaction was monitored by TLC, and the reaction solution was spin-dried to obtain a white solid 7d (80 mg, yield 99%).
  • ESI-MS m/z: 232.4 [M+H] + .
  • Step 3 Dissolve compound 1i (76mg, 0.30umol), compound 7d (80mg, 0.30mol) and p-toluenesulfonic acid monohydrate (5.7mg, 0.03mol) in n-butanol (3mL) and heat in microwave at 160°C Under the conditions of reaction for 2 hours. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain white solid 7 (45 mg, yield 33%).
  • Compound 10 was prepared by the following steps:
  • the second step Dissolve compound 10b (90mg, 232umol) in 10mL of dichloromethane, add trifluoroacetic acid (1mL), stir at room temperature for 4 hours, LCMS monitors the complete reaction of raw materials, and concentrate the reaction solution to obtain compound 10c (90mg), yellow The oil was directly used in the next reaction.
  • ESI-MS m/z: 289.4 [M+H] + .
  • Step 3 Compounds 10c (90mg) and 10d (53mg, 269umol) were dissolved in 10mL of acetonitrile, potassium carbonate (93mg, 673umol) was added, and reacted at 60°C for 4 hours. LCMS monitored the complete reaction of the raw materials. The reaction solution was concentrated, and the residue was purified by reverse preparative HPLC to obtain compound 10 (10 mg, yield 10.3%) as a white solid.
  • Compound 11 was prepared by the following steps:
  • the first step cis-3-hydroxymethylcyclobutylcarbamate tert-butyl ester 11a (150mg, 0.745mmol), methanesulfonic anhydride (259mg, 1.49mmol) and N,N-diisopropylethylamine (385mg, 2.98mmol) was dissolved in dichloromethane (5mL) and stirred overnight at room temperature. The completion of the reaction was monitored by TLC. The reaction solution was diluted with dichloromethane, washed with water and saturated brine successively, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a yellow solid 11b (204 mg, yield 98%).
  • Step 2 Dissolve compound 11b (204mg, 731umol), compound 2a (131mg, 0.8mmol) and cesium carbonate (485mg, 1.49mmol) in N,N-dimethylformamide (5mL) at 90°C Stir overnight.
  • ESI-MS (m/z): 347.2 [M+H] + .
  • Step 3 Compound 11c (120mg, 346umol) was dissolved in dichloromethane (5mL), and 4M dioxane hydrochloride solution (0.87mL) was added at 0°C and stirred overnight. The completion of the reaction was monitored by TLC, and the product was directly spin-dried to obtain a white solid 11d (85 mg, yield 99%).
  • Step 4 Dissolve compound 11d (82mg, 336umol), compound 1i (85mg, 336umol) and p-toluenesulfonic acid monohydrate (5.7mg, 33.6umol) in n-butanol (3mL), 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 11 (25 mg, yield 16%).
  • Compound 12 was prepared by the following steps:
  • Step 1 Ethyl trifluoroacetoacetate 12a (1.7g, 9.21mmol) and cyclopropylhydrazine hydrochloride 12b (1.0g, 9.21mmol) were dissolved in 20mL of ethanol and reacted overnight at 80°C. The reaction solution was concentrated, the residue was slurried with petroleum ether, and filtered to obtain brown solid compound 12c (800 mg, yield 45%).
  • ESI-MS (m/z): 193.2 [M+H] + .
  • the second step Dissolve compound 11b (872mg, 3.12mmol), compound 12c (500mg, 2.61mmol) and cesium carbonate (1.70g, 5.22mmol) in N,N-dimethylformamide (20mL) at 90°C Stirring overnight.
  • ESI-MS (m/z): 362.6 [M+H] + .
  • Step 3 Dissolve compound 12d (495 mg, 1.1 mmol) in dichloromethane (30 mL), add 4M dioxane hydrochloride solution (1.37 mL) at 0°C and stir overnight. The completion of the reaction was monitored by TLC, and directly spin-dried to obtain a white solid 12e (231 mg, yield 80%).
  • ESI-MS m/z: 262.6 [M+H] + .
  • Step 4 Dissolve compound 12e (26mg, 95umol), compound 1i (20mg, 79umol) and p-toluenesulfonic acid monohydrate (0.4mg, 7.9umol) in n-butanol (3mL), 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 12 (13 mg, yield 35%).
  • Compound 13 was prepared by the following steps:
  • the first step 2,4-dichloropyrido[3,2-d]pyrimidine 1f (4.0g, 20.0mmol) and 2-methyl-L-serine methyl ester hydrochloride 13a (4.07g, 24.0mmol ) was dissolved in dichloromethane (30 mL), N,N-diisopropylethylamine (7.75 g, 59.99 mmol, 10.45 mL) was added, and stirred overnight at room temperature. The completion of the reaction was monitored by LCMS.
  • the second step Dissolving compound 13b (5.0g, 16.85mmol) in tetrahydrofuran (50mL), adding hydrochloric acid aqueous solution (6M, 5.62mL) and platinum dioxide (382mg, 1.69mmol), the reaction system was replaced by hydrogen balloons, Stir at room temperature under hydrogen balloon pressure for 48 hours, and monitor the completion of the reaction by LCMS. The reaction solution was diluted with methanol, filtered, and the filtrate was concentrated to give white solid 13c (4.0 g, yield 88%). ESI-MS (m/z): 269.3 [M+H] + .
  • the third step Dissolve compound 13c (1.5g, 5.58mmol) and iodomethane (1.58g, 11.16mmol) in acetonitrile (5mL), add cesium carbonate (3.64g, 11.16mmol), and stir the reaction mixture at room temperature 48 hours.
  • LCMS monitored the completion of the reaction.
  • Step 4 Dissolve compound 12e (25mg, 84umol), compound 13d (20mg, 70.7umol) and p-toluenesulfonic acid monohydrate (0.4mg, 7.07umol) in n-butanol (3mL), and microwave at 160°C Under the condition of reaction 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 (13 mg, yield 35%).
  • Compound 14 was prepared by the following steps:
  • the first step Compound 2a (2.0g, 12.26mmol), Na 2 CO 3 (2.6g, 24.52mmol) was added to water (60mL), stirred and dissolved, and iodine (3.11g, 12.26mmol) was added to the reaction solution, 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 14a (0.5g, 1.73mmol), benzyl bromide (337mg, 1.98mmol) in DMF (5mL), add K 2 CO 3 (364mg, 2.64mmol), stir at 50°C for 2 hours, LCMS Monitor translation completion.
  • ESI-MS (m/z): 380.2 [M+H] + .
  • Step 5 Dissolve compound 14d (120mg, 677umol), compound 11b (208mg, 745umol) and cesium carbonate (441mg, 1.35mmol) in N,N-dimethylformamide (5mL), and stir at 90°C overnight.
  • ESI-MS (m/z): 361.4 [M+H] + .
  • Step 6 Dissolve compound 14e (196mg, 543umol) in dichloromethane (10mL), add 4M hydrochloric acid (0.952mL) at 0°C and stir overnight. The completion of the reaction was monitored by TLC, and directly spin-dried to obtain a white solid 14f (112 mg, yield 79%).
  • Step 7 Dissolve compound 14f (27mg, 106umol), compound 13d (20mg, 70.7umol) and p-toluenesulfonic acid monohydrate (0.4mg, 7.07umol) in n-butanol (3mL), and microwave at 160°C Under the condition of reaction for 3 hours. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain white solid 14 (19 mg, yield 52%).
  • Compound 15 was prepared by the following steps:
  • the first step Compound 14b (300mg, 0.791mmol), palladium acetate (18mg, 79umol), cyclopropylboronic acid (339mg, 3.96mmol), tricyclohexylphosphine (152mg, 523umol), tripotassium phosphate (672mg, 3.17 mmol), water (1mL), and 1,4-dioxane (10mL) were added to a 100mL two-necked flask, and after nitrogen replacement, stirred overnight at 90°C, and TLC monitored the completion of the reaction. Filter through celite, extract with ethyl acetate, and finally wash with saturated brine.
  • Step 3 Dissolve compound 15b (122mg, 590umol), compound 11b (211mg, 758umol) and cesium carbonate (449mg, 1.38mmol) in N,N-dimethylformamide (5mL) and stir at 90°C overnight.
  • ESI-MS (m/z): 387.3 [M+H] + .
  • Step 4 Dissolve compound 15c (152mg, 393umol) in dichloromethane (10mL), add 4M hydrochloric acid (0.706mL) at 0°C and stir overnight. The completion of the reaction was monitored by TLC and spin-dried directly to obtain a white solid 15d (92 mg, yield 79%).
  • Step 5 Dissolve compound 15d (46mg, 159umol), compound 13d (30mg, 106umol) and p-toluenesulfonic acid monohydrate (0.5mg, 10.6umol) in n-butanol (3mL), 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 15 (18 mg, yield 32%).
  • Compound 16 was prepared by the following steps:
  • the second step Dissolve compound 16b (2.5g, 8.43mmol) in tetrahydrofuran (30mL), add aqueous hydrochloric acid (6N, 1.40mL) and platinum dioxide (191mg, 0.84mmol), and replace the hydrogen gas with a hydrogen balloon in the reaction system, Stir at room temperature under hydrogen balloon pressure for 48 hours, and monitor the completion of the reaction by LCMS.
  • ESI-MS (m/z): 269.3 [M+H] + .
  • Step 3 Dissolve compound 16c (200mg, 0.74mmol) and deuterated methyl iodide (215mg, 1.49mmol) in acetonitrile (5mL), add cesium carbonate (485mg, 1.49mmol), and react at 50°C for 2 Hour.
  • LCMS monitored the completion of the reaction.
  • ESI-MS (m/z): 286.3 [M+H] + .
  • Step 4 Dissolve compound 16d (25mg, 89umol), compound 11c (32mg, 131umol) and p-toluenesulfonic acid monohydrate (0.45mg, 8.9umol) in n-butanol (3mL), 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 (5 mg, yield 10%).
  • Compound 21 was prepared by the following steps:
  • Step 1 Dissolve compound 21a (290mg, 1.46mmol), compound 11b (451mg, 1.61mmol) and cesium carbonate (191mg, 2.92mmol) in N,N-dimethylformamide (5mL) at 90°C Stir overnight.
  • ESI-MS (m/z): 381.3 [M+H] + .
  • the second step Compound 21b (158mg, 414umol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (30mg, 41.4umol), phenylboronic acid ( 101mg, 829umol), cesium carbonate (405mg, 1.24mmol), water (1mL), and dioxane (10mL) were added to a 25mL two-necked flask, and after nitrogen replacement, stirred overnight at 90°C, and TLC monitored the end of the reaction.
  • Step 3 Compound 21c (78mg, 164umol) was dissolved in dichloromethane (5mL), and 4M dioxane hydrochloride solution (0.1mL) was added at 0°C and stirred overnight. The completion of the reaction was monitored by TLC, and directly spin-dried to obtain a white solid 21d (43 mg, yield 72%).
  • Step 4 Dissolve compound 21d (43mg, 133umol), compound 13d (25mg, 88.4umol) and p-toluenesulfonic acid monohydrate (1.31mg, 13.3umol) in n-butanol (3mL), and microwave at 160°C Under the condition of reaction for 3 hours. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain white solid 21 (14 mg, yield 27%).
  • Compound 22 was prepared by the following steps:
  • the first step Compound 14b (210mg, 554umol), Pd 2 (dba) 3 (50.7mg, 55.4umol), tetrahydropyrrole (89mg, 830umol), potassium tert-butoxide (310mg, 2.77mmol), 2-di Cyclohexaphosphino-2'-(N,N-dimethylamine)-biphenyl (65mg, 166umol) and toluene (8mL) were added to a 50mL one-necked flask, and the reaction system was replaced with nitrogen and stirred overnight at 80°C, LCMS The reaction was shown to be completely converted.
  • Step 3 Dissolve compound 22b (65mg, 279umol), compound 11b (86mg, 307umol) and cesium carbonate (189mg, 560umol) in N,N-dimethylformamide (5mL) and stir overnight at 90°C .
  • ESI-MS (m/z): 416.5 [M+H] + .
  • Step 4 Dissolve compound 22c (78mg, 187umol) in dichloromethane (5mL), add 4M dioxane hydrochloride solution (0.1mL) at 0°C and stir overnight. The completion of the reaction was monitored by TLC, and directly spin-dried to obtain a white solid 22d (45 mg, yield 76%).
  • Step 5 Dissolve compound 22d (40mg, 114umol), compound 13d (25mg, 88.4umol) and p-toluenesulfonic acid monohydrate (1.52mg, 8.82umol) in n-butanol (3mL), and microwave at 160°C Under the condition of reaction for 3 hours. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain white solid 22 (5 mg, yield 10%).
  • Compound 24 was prepared by the following steps:
  • Step 1 Dissolve compound 16c (500mg, 1.86mmol) and iodomethane (343mg, 2.42mmol) in acetonitrile (10mL), add cesium carbonate (1.21g, 372mmol), and react at 50°C for 2 hours.
  • LCMS monitored the completion of the reaction.
  • ESI-MS (m/z): 283.3 [M+H] + .
  • Step 2 Dissolve 24a (250mg, 0.88mmol) in dichloromethane (2mL), and then add boron tribromide (2.21g, 8.84mmol, 0.85mL) dropwise at 0°C, React for two hours.
  • LCMS monitored the completion of the reaction.
  • ESI-MS (m/z): 269.3 [M+H] + .
  • Step 3 Dissolve compound 24b (30mg, 111umol), compound 1e (42mg, 167umol) and p-toluenesulfonic acid monohydrate (1.92mg, 11.1umol) in n-butanol (3mL), 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 24 (16 mg, yield 32%) as a white solid.
  • Compound 26 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 26a (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 26b, which was directly used in the next step.
  • Step 2 Add 150ml of absolute ethanol to the oil 26b 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 26c (4.37g, yield 41%, purity 99%).
  • ESI-MS (m/z): 271.4 [M+H] + .
  • Step 3 Add compound 26c (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 26d (3.9 g, yield 86%, purity 95%).
  • the fifth step Dissolve compound 26e (280mg, 1.04mmol) in methanol (10mL), then add palladium carbon (13mg, 104umol), and replace the reaction system with hydrogen, react for 5 hours, TLC monitors the end of the reaction, and the reaction solution is used Celite was filtered, and the filtrate was concentrated to obtain yellow liquid 26f (170 mg, yield 91%).
  • ESI-MS m/z: 177.5 [MH] - .
  • Step 7 Dissolve compound 26g (148mg, 340umol) in dichloromethane (5mL), add 4M hydrochloric acid (0.4mL) at 0°C and stir overnight. The end of the reaction was monitored by TLC, and directly spin-dried to obtain a white solid 26h (84 mg, yield 86%).
  • Step 8 Dissolve compound 26h (30mg, 118umol), compound 1i (35mg, 142umol) and p-toluenesulfonic acid monohydrate (2mg, 11.8umol) in n-butanol (3mL), and microwave at 160°C React for 3 hours.
  • LCMS monitored the completion of the reaction.
  • the reaction solution was purified by reverse-phase preparative HPLC to obtain a white solid 26 (14 mg, yield 25%).
  • 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.
  • the cells in the monoclonal wells are full of 96-well plates, they are digested and subcultured to 24-well culture plates.
  • the cells of the orifice plate were subcultured to at least 6 wells, 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.
  • the Colo205-LUC-TCF/LEF-M1 cell line is one of the cell lines screened above.
  • Test Example 2 Detection of Compounds’ Inhibitory Ability to 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, and its ⁇ -catenin Wnt pathway is continuously activated.
  • 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.
  • the light signal intensity of cells treated only with DMSO was used as a positive control, and the light signal intensity of wells without cells was used as a negative control, and the concentration of IC 50 of each compound was calculated.
  • the Colo 205 reporter gene detection data are summarized in Table 1 below.
  • Test Example 3 Anti-proliferation test of compounds on Wnt mutant cell lines (Colo205, DU4475, NCI-H929 and HepG2) and non-Wnt mutant cell lines (Hela and RKO)
  • the cell lines used in the experiment are Colo205, DU4475, NCI-H929 and HepG2 cell lines whose Wnt pathway is continuously activated, and whose proliferation is Wnt pathway-dependent; under normal circumstances, the Wnt pathway is not activated, and the proliferation is not dependent on the Wnt pathway HELA and RKO cell lines were used as control cell lines, and it was judged that the inhibitory effect of the compound of the present invention on Wnt-dependent proliferation was not caused by other non-specific toxicity.
  • Colo205, Du4475, NCI-H929, HepG2, HELA, and RKO cell lines cultured in their respective culture media were treated during the logarithmic growth phase, and the cells were collected and prepared into a uniform cell suspension of known concentration, and then transferred to 96-well Add the cell suspension to the cell culture plate so that each well contains 1000 cells. Put it into a 5% CO 2 cell incubator, and cultivate 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 20 ⁇ M, 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 without inoculated cells were used as negative control wells.
  • the IC50 values of each compound for the inhibition of proliferation of Wnt sustained activation or proliferation-dependent cells, and Wnt-inactivated or proliferation-independent cells were calculated.
  • the IC 50 value of the inhibition of cell proliferation was used to evaluate the inhibitory effect of the compound on the Wnt pathway and the toxic effect on normal cells. The results are shown in Table 2 below.

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Abstract

一种式(I)所示的Wnt通路抑制剂化合物以及包含所述化合物的药物组合物，以及式(I)化合物用于预防和/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用途。

Description

一种Wnt通路抑制剂化合物
本申请要求于2021年7月26日提交到中国国家知识产权局的发明名称为“一种Wnt通路抑制剂化合物”的中国专利申请202110847130.9的优先权，其内容通过引用以整体并入本文。
技术领域
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。
背景技术
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。
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。
发明内容
本发明提供了一种具有式(I)结构的抑制Wnt通路活性的化合物或其药学上可接受的盐、同位素衍生物、立体异构体：
Figure PCTCN2022107727-appb-000001
其中：
---表示单键的存在或者不存在；
R1表示C 1-C 6烷基、C 3-C 6环烷基、3-6元杂环烷基、C 6-C 10芳基、5-10元杂芳基，并且所述的R1可以任意地被0、1、2、3个选自：氢、卤素、OR a、硝基、(C 1-C 6)烷基、(C 1-C 6)烷氧基、(C 1-C 6)卤代烷基、(C 3-C 6)环烷基、卤代(C 3-C 6)环烷基、3-6元杂环烷基、卤代3-6元杂环烷基、C 6-C 10芳基、5-10元杂芳基、氰基、SR a、卤代(C 1-C 6)烷氧基、卤代(C 3-C 6)环烷氧基、卤代(C 1-C 6)烷基硫基、(C 3-C 6)环烷基氧基、(C 3-C 6)环烷基硫基、卤代(C 3-C 6)环烷硫基的取代基所取代；
X表示共价键或者-(CR aR a’) m-、-(CR aRa’) m-O-(CR aR a’) n-、-(CR aR a’) m-N(R b)-(CR aR a’) n-、-(CR aR a’) m-S-(CR aR a’) n-、-(CR aR a’) mC(O)(CR aR a’) n-、-(CR aR a’) mS(O) 2(CR aR a’) n-、-(CR aR a’) mC(O)N(R b)(CR aR a’) n-、-(CR aR a’) mS(O) 2N(R b)(CR aR a’) n-、-(CR aR a’) mN(R b)C(O)(CR aR a’) n-、-(CR aR a’) mN(R b)S(O) 2(CR aR a’) n-、-(CR aR a’) mOC(O)N(R b)(CR aR a’) n-、-(CR aR a’) mN(R b)C(O)O(CR aR a’) n-、-(CR aR a’) mN(R b)C(O)N(R b’)(CR aR a’) n-、-(CR aR a’) m N(R b)S(O) 2N(R b’)(CR aR a’) n-；
Cy表示C 3-C 5环烷基或者4-5元环杂烷基，并且其可以任意地被0、1或2个选自氢、卤素、-OR a、(C 1-C 6)烷基、(C 1-C 6)卤代烷基、(C 3-C 6)环烷基、氰基和羟基(C 1-C 6)烷基的取代基所取代；
R 2表示氢、(C 1-C 6)烷基、(C 1-C 6)卤代烷基、(C 3-C 6)环烷基或羟基(C 1-C 6)烷基；
R 3和R 3’各自独立地表示氢，卤素、OR a、(C 1-C 6)烷基、(C 3-C 6)环烷基、羟 基C 1-C 6烷基或(C 1-C 6)烷氧基(C 1-C 6)烷基；
或者R 3和R 3’一起与与之相连的碳原子形成3-6元饱和或者不饱和的环，该环中还可以任意地含有1或2个选自O、S和N的杂原子，并且该环还可以任意地被0、1或2个选自卤素、羟基和C 1-C 6烷基的取代基所取代；
或者R 2、R 3或者R 2、R 3’一起与与其相连的原子形成4-6元饱和或者不饱和的环，该环中还可以任意地含有1或2个选自O、S和N的杂原子，并且该环还可以任意地被0、1、2个卤素、羟基、C 1-C 6烷基所取代；
R 4和R 4’各自独立地表示氢、C 1-C 6烷基、C 3-C 6环烷基、羟基C 1-C 6烷基、卤代C 1-C 6烷基、(C 1-C 6)烷氧基(C 1-C 6)烷基；
或者R 4与R 4’一起形成＝O；
R T和R T’各自独立地表示氢、C 1-C 6烷基、C 1-C 6卤代烷基、羟基C 1-C 6烷基、C 3-C 6环烷基、卤素、OR a；
或者R T和R T’一起与与其相连的原子形成3-6元环；
其中，当---表示单键不存在时，A表示(CR LR L’) p，其中R L和R L’各自独立地表示氢、C 1-C 6烷基、C 1-C 6卤代烷基、羟基C 1-C 6烷基、C 3-C 6环烷基、卤素、OR a、或者R L和R L’一起与与其相连的碳原子形成3-6元环，该环中可以任意地含有0、1或2个选自O、S和N的杂原子，并且该环还可以任意地被0、1或2个选自卤素和羟基的取代基所取代；
其中，当---表示单键存在时，A表示CR H，其中，R H表示氢、C 1-C 6烷基、C 1-C 6卤代烷基、羟基C 1-C 6烷基、C 3-C 6环烷基、卤素、OR a；
其中，R a、R a’、R b、R b’各自独立地表示氢或C 1-C 6烷基；
其中m、n、p各自独立地表示0、1或2。
在上述式(I)结构化合物或其药学上可接受的盐、同位素衍生物、立体异构体中，其优选地为具有以下式(II)结构的化合物或其药学上可接受的盐、同位素衍生物、立体异构体，
Figure PCTCN2022107727-appb-000002
其中R 1、R 2、R 3、R 3’、R 4、R 4’、X、Cy具有如上述定义。
进一步的，本发明还提供了一种具有以下式(III)结构化合物及药学上可接受的盐、同位素衍生物、立体异构体，：
Figure PCTCN2022107727-appb-000003
其中R 1、R 2、R 3、R 3’、R 4、R 4’、R T、R T’、R L、R L’、X、Cy如上述所定义。
在本发明的一些技术方案中，其中，R 2表示氢、C 1-C 6烷基、羟基(C 1-C 6烷基)或C 3-C 6环烷基。
在本发明的一些实施方案中，其中，R 3，R 3’各自独立地表示氢、C 1-C 6烷基、羟基(C 1-C 6烷基)或C 3-C 6环烷基。
在本发明的一些实施方案中，其中，R 4，R 4’各自独立地表示氢、C 1-C 6烷基、C 3-C 6环烷基，或者R 4与R 4’一起形成＝O。
在本发明的一些实施方案中，其中Cy表示C 3-C 5环烷基或者4-5元环杂烷基；优选地，Cy表示
Figure PCTCN2022107727-appb-000004
Figure PCTCN2022107727-appb-000005
在本发明的一些实施方案中，X表示共价键或者-(CR aR a’) m-、-(CR aR a’) m-O-(CR aR a’) n-、-(CR aR a’) m-N(R b)-(CR aR a’) n-、-(CR aR a’) m-S-(CR aR a’) n-、-(CR aR a’) mC(O)N(R b)(CR aR a’) n-、-(CR aR a’) mS(O) 2N(R b)(CR aR a’) n-、-(CR aR a’) mN(R b)C(O)(CR aR a’) n-、-(CR aR a’) mN(R b)S(O) 2(CR aR a’) n-、-(CR aR a’) mOC(O)N(R b)(CR aR a’) n-、-(CR aR a’) mN(R b)C(O)O(CR aR a’) n-、-(CR aR a’) mN(R b)C(O)N(R b’)(CR aR a’) n-、-(CR aR a’) m N(R b)S(O) 2N(R b’)(CR aR a’) n-。
在本发明的一些实施方案中，X表示-O-，-NR b-、-CR aR a’-、-OCR aR a’-、-CR aR a’O-、-C(O)-、-C(O)NR b-、-NR bC(O)-、-NR b-C(O)-NR b-、-CR aR a’-C(O)NR b-、-CR aR a’-NR bC(O)-、-S-、-NR bS(O) 2-、-SO 2NR b、-OC(O)NR b-、-S(O) 2、-C(O)NR b-、-C(O)CR aR a’-、-CR aR a’C(O)NR b-、-NR bC(O)CR aR a’-、-NR bC(O)O-；其中R a、R a’、R b各自独立地表示氢或者C 1-C 6烷基。
在本发明的一些实施方案中，X表示-(CR aR a’) m-O-(CR aR a’) n-，优选为-O-，-OCR aR a’-、-CR aR a’O-，更优选为-O-或者-O-CH 2-。
在本发明的一些实施方案中，R T和R T’表示氢。
在本发明的一些实施方案中，R L和R L’表示氢。
在本发明的一些实施方案中，R H表示氢。
在本发明的一些实施方案中，R 1表示被0、1、2或3个取代基取代的C 3-C 6环烷基、3-6元杂环烷基、C 6-C 10芳基、5-10元杂芳基，其中，所述取代基选自卤素、(C 1-C 6)烷基、(C 1-C 6)卤代烷基、(C 3-C 6)环烷基、卤代(C 3-C 6)环烷基、3-6元杂环烷基、卤代3-6元杂环烷基、C 6-C 10芳基和5-10元杂芳基。
在本发明的一些实施方案中，R 1表示C 3-C 6环烷基、3-6元杂环烷基、C 6-C 10芳基、5-10元杂芳基，并且所述的R 1可以任意地被0、1、2、3个选自：氢、卤素、(C 1-C 6)烷基、(C 1-C 6)卤代烷基、(C 3-C 6)环烷基、卤代(C 3-C 6)环烷基的取代基所取代。
在本发明的一些实施方案中，R 1选自：
Figure PCTCN2022107727-appb-000006
在本发明的一些实施方案中，R 1选自：
Figure PCTCN2022107727-appb-000007
在一些优选的方面，本发明提供了一种化合物，其具有以下结构：
Figure PCTCN2022107727-appb-000008
Figure PCTCN2022107727-appb-000009
Figure PCTCN2022107727-appb-000010
Figure PCTCN2022107727-appb-000011
Figure PCTCN2022107727-appb-000012
Figure PCTCN2022107727-appb-000013
Figure PCTCN2022107727-appb-000014
进一步地，本发明还提供了一种药物组合物，包含本发明所述的化合物或其及药学上可接受的盐、同位素衍生物或立体异构体。
进一步地，本发明还提供了本发明所述的化合物或其药学上可接受的盐、同 位素衍生物、立体异构体或者本发明所述的药物组合物在制备用于预防和/或治疗癌症、肿瘤、炎症性疾病、自身免疫性疾病或免疫介导性疾病的药物中的用途。特别注意的是，在本文中，当提及式(I)至式(III)结构的“化合物”时，一般地还涵盖其立体异构体、非对映异构体、对映异构体、外消旋混合物和同位素衍生物。
相应地，本发明提供了一种预防和/或治疗癌症、肿瘤、炎症性疾病、自身免疫性疾病或免疫介导性疾病的方法，包括向对象给予本发明所述的化合物或其药学上可接受的盐、同位素衍生物、立体异构体或者本发明所述的药物组合物。
本领域技术人员公知，一种化合物的盐、溶剂合物、水合物是化合物的替代性存在形式，它们都可以在一定条件下转化为所述化合物，因此，特别注意的是在本文中当提到式(I)至式(III)结构的化合物时，一般地还包括它的可药用盐，进而还包括其溶剂合物和水合物。
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。
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。
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。
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。
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。
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。
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。
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。
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。
此外，本发明提供了一种预防和/或治疗癌症、肿瘤、炎症性疾病、自身免疫性疾病、神经退行性疾病、注意力相关疾病或免疫介导性疾病的方法，其包括向有此需要的哺乳动物施用本发明化合物。
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。
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。
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。
用于治疗癌症或肿瘤的抗癌剂的代表性实例可包括但不限于细胞信号转导 抑制剂、苯丁酸氮芥、美法仑、环磷酰胺、异环磷酰胺、白消安、卡莫司汀、洛莫司汀、链脲佐菌素、顺铂、卡铂、奥沙利铂、达卡巴嗪、替莫唑胺、丙卡巴肼、甲氨蝶呤、氟尿嘧啶、阿糖胞苷、吉西他滨、巯基嘌呤、氟达拉滨、长春碱、长春新碱、长春瑞滨、紫杉醇、多西紫杉醇、拓扑替康、伊立替康、依托泊苷、曲贝替定、更生霉素、多柔比星、表柔比星、道诺霉素、米托蒽醌、博来霉素、丝裂霉素C、伊沙匹隆、他莫昔芬、氟他胺、戈那瑞林类似物、甲地孕酮、强的松、地塞米松、甲泼尼龙、沙利度胺、干扰素α、亚叶酸钙、西罗莫司、西罗莫司脂化物、依维莫司、阿法替尼、alisertib、amuvatinib、阿帕替尼、阿西替尼、硼替佐米、波舒替尼、布立尼布、卡博替尼、西地尼布、crenolanib、克卓替尼、达拉菲尼、达可替尼、达努塞替、达沙替尼、多维替尼、厄洛替尼、foretinib、ganetespib、吉非替尼、依鲁替尼、埃克替尼、伊马替尼、iniparib、拉帕替尼、lenvatinib、linifanib、linsitinib、马赛替尼、momelotinib、莫替沙尼、来那替尼、尼罗替尼、niraparib、oprozomib、olaparib、帕唑帕尼、pictilisib、普纳替尼、quizartinib、瑞格菲尼、rigosertib、rucaparib、鲁索利替尼、塞卡替尼、saridegib、索拉非尼、舒尼替尼、替拉替尼、tivantinib、替沃扎尼、托法替尼、曲美替尼、凡德他尼、维利帕尼、威罗菲尼、维莫德吉、volasertib、阿仑单抗、贝伐单抗、贝伦妥单抗维多汀、卡妥索单抗、西妥昔单抗、地诺单抗、吉妥珠单抗、伊匹单抗、尼妥珠单抗、奥法木单抗、帕尼单抗、利妥昔单抗、托西莫单抗、曲妥珠单抗、PI3K抑制剂、CSF1R抑制剂、A2A和/或A2B受体拮抗剂、IDO抑制剂、抗PD-1抗体、抗PD-L1抗体、LAG3抗体、TIM-3抗体及抗CTLA-4抗体，或其任意组合。
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。
用于治疗炎症性疾病、自身免疫性疾病和免疫介导性疾病的治疗剂的代表性实例可包括但不限于，甾体药物(例如，强的松、氢化波尼松、甲基氢化波尼松、可的松、羟基可的松、倍他米松、地塞米松等)、甲氨蝶呤、来氟米特、抗TNFα剂(例如，依那西普、英夫利昔单抗、阿达利单抗等)、钙调神经磷酸酶抑制剂(例如，他克莫司、吡美莫司等)和抗组胺药(例如，苯海拉明、羟嗪、氯雷他定、依巴斯汀、酮替芬、西替利嗪、左西替利嗪、非索非那定等)，并且选自其 中的至少一种或多种治疗剂可包含于本发明药物组合物中。
本发明的化合物或其可药用盐可作为活性成分通过口服或肠胃外施用，其有效量的范围为在哺乳动物包括人(体重约70kg)的情况下0.1至2,000mg/kg体重/天、优选1至1,000mg/kg体重/天，并且每天以单次或4次分次剂量，或者遵循/不遵循预定时间施用。活性成分的剂量可根据多个相关因素(例如待治疗对象的情况、疾病类型和严重性、施用速率和医生意见)进行调整。在某些情况下，小于以上剂量的量可能是合适的。如果不引起有害的副作用则可使用大于以上剂量的量并且该量可以每天以分次剂量施用。
除此之外，本发明还提供了一种预防和/或治疗肿瘤、癌症、病毒感染、器官移植排斥、神经退行性疾病、注意力相关疾病或自身免疫性疾病的方法，其包括向有此需要的哺乳动物施用本发明的化合物或本发明的药物组合物。
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。
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。
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。
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。
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。
具体实施方式
术语
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”。
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。
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R a(或者R a’)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R a(或者R a’)在一种取代基中选择一种定义时，并不意味着该R a(或者R a’)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NR aR a’中，当R a(或者R a’)的定义选自氢时，其并不意味着在-C(O)-NR aR a’中，R a(或者R a’)必然为氢。在另一个 方面，当某一个取代基中存在多于一个R a(或者R a’)时，这些R a(或者R a’)也是各自独立的。例如，在取代基-(CR aR a’) m-O-(CR aR a’) n-中，在m+n大于等于2的情况下，其中的m+n个R a(或者R a’)是各自独立的，它们可以具有相同或者不同的含义。
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-SO 2NH 2、取代的磺酰氨基、硝基、氰基、羧基、氨基甲酰基例如-CONH 2、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。
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，“C 1-C 6烷基”表示具有1个至6个碳原子的烷基。烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(例如正丙基和异丙基)、丁基(例如正丁基、异丁基、叔丁基)和戊基(例如正戊基、异戊基、新戊基)。在本文中，烷基优选为具有1至6个、更优选具有1至4个碳原子的烷基。
术语“烯基”表示含一个或多个双键且通常长度为2至20个碳原子的直链或支链的烃基。例如，“C2-C6烯基”含有两个至六个碳原子。烯基包括但不限于例如乙烯基、丙烯基、丁烯基、1-甲基-2-丁烯-1-基等。在本文中，烯基优选C 2-C 6烯基。
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，“C 2-C 6炔基”含有两个至六个碳原子。代表性炔基包括但不限于例如乙炔基、1-丙炔基、1-丁炔基等。在本文中，炔基优选C 2-C 6炔基。
术语“烷氧基”或“烷基氧基”是指-O-烷基。“C 1-C 6烷氧基”(或烷基氧基)意欲包括C 1、C 2、C 3、C 4、C 5、C 6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-。
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)。
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。
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C 3-C 8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C 3-C 6环烷基。
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C 3-C 8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。
“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”。
“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C 1-C 6烷氧基”意欲包括C 1、C 2、C 3、C 4、C 5、C 6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-。
本公开内容中，当提到一些取代基团时使用C x1-C x2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，C 0-C 8表示所述基团含有0、1、2、3、4、5、6、7或8个碳原子，C 1-C 8表示所述基团含有1、2、3、4、5、6、7或8个碳原子，C 2-C 8表示所述基团含有2、3、4、5、6、7或8个碳原子，C 3-C 8表示所述基团含有3、4、5、6、7或8个碳原子，C 4-C 8表示所述基团含有4、5、6、7或8个碳原子，C 0-C 6表示所述基团含有0、1、2、3、4、5或6个碳原子，C 1-C 6表示所述基团含有1、2、3、4、5或6个碳原子，C 2-C 6表示所述基团含有2、3、4、5或6个碳原子，C 3-C 6表示所述基团含有3、4、5或6个碳原子。
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。
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。
术语“杂芳基”意指稳定的3元、4元、5元、6元、或7元芳香单环或芳香二环或7元、8元、9元、10元、11元、12元芳香多环杂环，其为完全不饱和的或部分不饱和的，且其含有碳原子和1个、2个、3个或4个独立地选自N、 O和S的杂原子；且包括任何以下多环基团，其中上文所定义的任意杂环与苯环稠合。氮和硫杂原子可任选地被氧化。氮原子为取代的或未取代的(即N或NR，其中R为H或如果被定义，则为另一取代基)。杂环可在得到稳定结构的任何杂原子或碳原子处连接至其侧基。如果所得化合物是稳定的，则本文所述的杂环基可在碳或氮原子上被取代。杂环中的氮可任选地被季铵化。优选地，当杂环中S和O原子的总数超过1时，则这些杂原子彼此不相邻。优选地，杂环中S和O原子的总数不大于1。当使用术语“杂环”时，其意欲包括杂芳基。芳杂基的实施例包括但不限于吖啶基、氮杂环丁基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并硫代呋喃基、苯并噻吩基、苯并噁唑基、苯并噁唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异噁唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、色满基、色烯基、噌啉基、十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、咪唑并吡啶基、假吲哚基(indolenyl)、二氢吲哚基、吲嗪基、吲哚基、3H-吲哚基、靛红酰基(isatinoyl)、异苯并呋喃基、异色满基、异吲唑基、异二氢吲哚基、异吲哚基、异喹啉基、异噻唑基、异噻唑并吡啶基、异噁唑基、异噁唑并吡啶基、亚甲基二氧基苯基、吗啉基、二氮杂萘基、八氢异喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑烷基、噁唑基、噁唑并吡啶基、噁唑烷基、萘嵌间二氮杂苯基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪基、吩噻嗪基、吩噁噻基、吩噁嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、喋啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑并吡啶基、吡唑基、哒嗪基、吡啶并噁唑基、吡啶并咪唑基、吡啶并噻唑基、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2-吡咯烷酮基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四唑基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、噻吩基、噻唑并吡啶基、噻吩并噻唑基、噻吩并噁唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基和呫吨基、喹啉基、异喹啉基、酞嗪基、喹唑啉基、吲哚基、异吲哚基、二氢吲哚基、1H-吲唑基、苯并咪唑基、1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基、5,6,7,8-四氢-喹啉基、2,3-二氢-苯并呋喃基、色满基、1,2,3,4-四氢-喹喔啉基和1,2,3,4- 四氢-喹唑啉基。术语“杂芳基”还可以包括由上述所定义的“芳基”与单环“杂芳基”所形成的联芳基结构，例如但不限于“-苯基联吡啶基-”、“-苯基联嘧啶基”、“-吡啶基联苯基”、“-吡啶基联嘧啶基-”、“-嘧啶基联苯基-”；其中本发明还包括含有例如上述杂环的稠环和螺环化合物。
本文使用的术语“杂环烷基”指的是一个单环杂环烷基体系，或为一个二环杂环烷基体系，同时还包括螺杂环或桥杂环烷基。单环的杂环烷基指的是3-8元、且至少含一个选自O、N、S和P的杂原子的饱和或不饱和但不为芳香性的环状烷基体系。二环杂环烷基体系指的是一个杂环烷基稠合到一个苯基、或一个环烷基、或一个环烯基、或一个杂环烷基、或一个杂芳基上而形成的二环体系。
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。
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。
本文使用的术语“桥环杂基”指的是共用两个或两个以上碳原子的多环化合物，该环中至少含一个选自O、N和S原子的杂原子。可分为二环桥环杂环及多环桥杂环。
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。
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)。
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。
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。
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。
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。
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。
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。
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”。
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。
特定药学及医学术语
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。
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)。
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。
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。
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。
术语“试剂盒”与“产品包装”是同义词。
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。
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。
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。
给药途径
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。
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。
药物组合物和剂量
本发明还提供药用组合物，其包含治疗有效量的与一种或多种药用载体(添加剂)和/或稀释剂一起配制的一种或多种本发明的化合物，和任选的一种或多种上述其它治疗剂。可通过任意合适方式给予本发明化合物以用于任意上述用途，例如口服，诸如片剂、丸剂、粉剂、颗粒剂、酏剂、酊剂、悬浮液(包括纳米悬浮液、微悬浮液、喷雾干燥的分散液)、糖浆和乳液；经舌下；含服；经肠胃外，诸如通过皮下、静脉内、肌内或胸骨内注射或输注技术(例如以无菌可注射水性或非水性溶液或悬浮液形式)；经鼻，包括向鼻膜给药，诸如通过吸入喷雾；局部，诸如以乳膏剂或软膏剂形式；或经直肠，诸如以栓剂形式；或经瘤内注射。它们可单独给药，但通常使用基于所选给药途径和标准药学实践选择的药物载体给药。
根据本领域技术人员认识范围内的诸多因素来调配药用载体。这些因素包括但不限于：所调配活性剂的类型和性质；含有活性剂的组合物所要给予的受试者；组合物的预期给药途径；及所靶向的治疗适应症。药用载体包括水性和非水性液体介质及各种固体和半固体的药用载体。
上述载体可包括除活性剂外的诸多不同成分和添加剂，上述其它成分出于本领域技术人员公知的各种原因包括于制剂中，例如稳定剂、粘合剂等。关于合适的药用载体和载体选择中所涉及的因素的描述可参见多个容易获得的来源，例如Allen L.V.Jr.et al.Remington:The Science and Practice of Pharmacy(2 Volumes),22nd Edition(2012),Pharmaceutical Press。
当然，本发明化合物的剂量方案取决于已知因素而有所变化，诸如具体药剂的药效学特性及其给药模式和途径；接受者的物种、年龄、性别、健康状况、医学病状和重量；症状的性质和程度；同时治疗的种类；治疗频率；给药途径、患者的肾和肝功能及期望效应。根据一般指导，当用于指定效应时，各活性成分的日口服剂量应为约0.001mg/天至约10-5000mg/天，优选地为约0.01mg/天至约 1000mg/天，且最优选地为约0.1mg/天至约250mg/天。在恒速输注期间，静脉内最优选剂量应为约0.01mg/kg/分钟至约10mg/kg/分钟。本发明化合物可以单一日剂量给药，或可以每日两次、三次或四次的分开剂量给药总日剂量。
所述化合物通常以与根据预期给药形式(例如口服片剂、胶囊剂、酏剂和糖浆剂)适当地选择且与常规药学实践相符合的合适药物稀释剂、赋形剂或载体(在本文中统称为药物载体)的混合物形式进行给药。
适于给药的剂型(药物组合物)可含有约1毫克至约2000毫克活性成分/剂量单位。在这些医药组合物中，以组合物的总重量计，活性成分通常将以约0.1-95重量％的量存在。
用于口服给药的典型胶囊剂含有至少一种本发明化合物(250mg)、乳糖(75mg)和硬脂酸镁(15mg)。使该混合物通过60目网筛，并包装成1号明胶胶囊。
典型的可注射制剂可如下制备：以无菌方式将至少一种本发明化合物(250mg)置于瓶中、以无菌方式冻干并密封。为进行使用，将瓶内容物与2mL生理盐水混合，以产生可注射制剂。
本发明范围包括(单独或与药物载体组合)包含治疗有效量的至少一种本发明化合物作为活性成分的药物组合物。任选地，本发明化合物可单独使用、与本发明其它化合物组合使用或与一种或多种其它治疗剂(例如抗癌剂或其它药学活性物质)组合使用。
不考虑所选择的给药路径，通过本领域技术人员已知的常规方法来将本发明的化合物(其可以合适的水合形式使用)和/或本发明的药物组合物配制成药用剂量形式。
可改变活性成分在本发明的药物组合物中的实际剂量水平，从而获得对于实现特定患者的期望的治疗响应、组成和给药模式有效的而对患者无毒的活性成分量。
选定的剂量水平会取决于多种因素，包括所用的本发明的特定化合物或其酯、盐或酰胺的活性；给药路径；给药时间；所用的特定化合物的排泄速率；吸收速率和程度；治疗的持续时间；与所用的特定化合物组合使用的其它药物、化合物和/或物质；所治疗的患者的年龄、性别、重量、状况、一般健康和先前的医学史等医学领域公知的因素。
具有本领域普通技术的医生或兽医可容易地确定并开出有效量的所需药物 组合物。例如，为了达到所期望的治疗效果，医师或兽医可在低于所需的水平开始药物组合物中所用的本发明化合物的较量，并逐步增加剂量直至实现所期望的效果。通常，合适日剂量的本发明化合物将是有效产生治疗效果的最低剂量的化合物的量。此种有效剂量通常取决于上述因素。通常，口服、静脉内、脑室内和皮下剂量的用于患者的本发明化合物的范围为约0.01至约50mg/kg体重/天。如果需要的话，有效日剂量的活性化合物可以两个、三个、四个、五个、六个或更多个亚剂量在一天当中的适当的间隔分别给药，任选地呈单位剂型形式。在本发明的某些方面中，服药为每天一次给药。
虽然本发明化合物可单独给药，但优选以药物制剂(组合物)形式给予化合物。试剂盒/产品包装
为了用于上述适应症的治疗，试剂盒/产品包装也在此进行描述。这些试剂盒可以由输送器、药包或容器盒组成，容器盒可被划分成多格，以容纳一种或多种容器，如管形瓶、试管及类似物等，每个容器中包含所述方法中的单独一种成分。合适的容器包括瓶子，管形瓶，注射器和试管等。容器由可接受的玻璃或塑料等材料制作而成。
举例来讲，容器可容纳有一种或多种在此所述的化合物，所述化合物可能以药物化合物形式存在，也可能与在本文中所述的其它成分组成混合物的形式存在。容器可有一个无菌输出口(例如容器可为静脉输液包或瓶，瓶塞可被皮下注射器针头刺破)。这样的试剂盒可容纳有一种化合物，及本文中所述的使用方法的说明、标签或操作说明。
一个典型的试剂盒可包括一种或多种容器，为适应商业推广和使用者对化合物使用的需求，每个容器装有一种或多种材料(如试剂，也可以是浓缩的母液，和/或器械)。这些材料包括但不局限于缓冲液，稀释液，滤器，针头，注射器，输送器，包，容器，瓶和/或试管，附有内容清单和/或使用说明书，内置包装也附有说明书。整套的说明都要包括在内。
标签可显示在容器上或与容器紧密相关。标签出现在容器上即指标签字母、数字或其它特征被粘贴、铸模、刻在容器上；标签也可出现在装有多种容器的容器盒或运输盒内，如在产品插页中。一个标签可用来提示内容物的某种特定治疗用途。标签也可标示内容物使用说明，诸如在上述方法中描述的。
在本说明书中被描述的所有特征(包括任何所述的权利要求、摘要和附图), 和/或任何方法或过程中涉及的所有步骤，均有可能以任意一种组合存在，除非某些特征或步骤在同一组合中是相互排斥的。
本发明提到的上述特征，或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以任何可提供相同、等同或相似目的的替代性特征取代。因此除有特别说明，所揭示的特征仅为等同或相似特征的一般性例子。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。除非另外说明，否则所有的百分数、比率、比例、或份数按重量计。
本发明中的重量体积百分比中的单位是本领域技术人员所熟知的，例如是指在100毫升的溶液中溶质的重量(g)。除非另行定义，文中所使用的所有专业与科学用语与本领域技术人员所熟悉的意义相同。此外，任何与所记载内容相似或等同的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
实施例
通用过程
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。
室温是指20-30℃。
反应实施例中无特殊说明，反应均在氮气氛下进行。氮气氛是指反应瓶连接一个约1L的氮气气球。
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。
微波反应使用
Figure PCTCN2022107727-appb-000015
Initiator+微波反应器。
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 Ascend TM 500 型)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl 3),氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。以下简写用于NMR信号的多重性：s＝单峰，brs＝宽峰，d＝二重峰，t＝三重峰，m＝多重峰。偶合常数以J值列出，以Hz测量。
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
Figure PCTCN2022107727-appb-000016
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。
实施例1
(S)-4,5-二甲基-2-((反-3-(3,4,5-三氟苯氧基)环丁基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
Figure PCTCN2022107727-appb-000017
化合物1由以下步骤制备：
Figure PCTCN2022107727-appb-000018
第一步：将顺式-3-BOC-氨基环丁醇1a(250mg,1.34mmol)，甲基磺酸酐(465mg,2.67mmol)和N,N-二异丙基乙胺(517mg,4.01mmol)溶解于二氯甲烷(2mL)中，在室温条件下搅拌过夜。TLC监测反应结束，反应液用二氯甲烷稀释，依次用水和饱和食盐水洗涤，有机相通过无水硫酸钠干燥，过滤浓缩得到黄色固体1b(300mg,收率84％)。 1H NMR(500MHz,DMSO-d6)δ7.23(d,J＝8.3Hz,1H),4.69-4.64(m,1H),3.63-3.60(m,1H),3.13(s,3H),2.70-2.62(m,2H),2.16-2.09(m,2H),1.37(s,9H)。
第二步：将化合物1b(300mg,1.13mmol)，化合物1c(251mg,1.70mmol)和碳酸铯(737mg,2.26mmol)溶解于N,N-二甲基甲酰胺(2mL)中，在80℃条件下搅拌过夜。LCMS监测反应结束，反应液用乙酸乙酯稀释，依次用水和饱和食盐水洗涤，有机相通过无水硫酸钠干燥，过滤浓缩，残余物通过硅胶柱层析纯化(二氯甲烷/甲醇＝20/1)得到白色固体1d(280mg,收率78％)。ESI-MS(m/z):318.6[M+H] +。
第三步：将化合物1d(280mg,882umol)溶解在二氯甲烷(2mL)中，滴加盐酸1，4-二氧六环溶液(4M,1.10mL)，在室温条件下搅拌过夜。LCMS监测反应结束，反应液浓缩得到白色固体1e(170mg,收率75％)。ESI-MS(m/z):218.4[M+H] +。
第四步：将2,4-二氯吡啶并[3,2-d]嘧啶1f(1.7g，8.50mmol)和(S)-2-(甲基氨基)丙酸甲酯盐酸盐1g(1.70g，11.05mmol)溶解于四氢呋喃(40mL)中，加入三乙胺(2.58g，25.50mmol，3.53mL)，在室温条件下搅拌过夜。LCMS监测反应结束，反应液浓缩，残余物通过硅胶柱层析纯化，得到黄色油状物1h(1.1g，收率46％)。ESI-MS(m/z):281.2[M+H] +。
第五步：将化合物1h(1.1g，3.92mmol)溶解于四氢呋喃(20mL)中，加入盐酸水溶液(6N，0.65mL)和二氧化铂(88mg，0.39mmol)，反应体系用氢气球置换氢气，在室温氢气球压力下搅拌48小时，LCMS监测反应结束。反应液用甲醇稀释，过滤，滤液浓缩后通过硅胶柱层析纯化，得到白色固体1i(900mg，收率90％)。ESI-MS(m/z):253.2[M+H] +。
第六步：将化合物1i(50mg,197umol)，化合物1e(65mg,257umol)和一水对甲苯磺酸(3.7mg,19umol)溶解在正丁醇(2mL)中，在微波160℃的条件下反应2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1(13mg,收率15％)。ESI-MS(m/z):434.3[M+H] +； 1H NMR(500MHz,DMSO-d6)δ6.90-6.82(m,3H),4.86-4.81(m,1H),4.42-4.36(m,1H),4.12(q,J＝6.8Hz,1H),4.05-4.00(m,1H),3.30-3.24(m,1H),2.94(s,3H),2.55-2.52(m,2H),2.48-2.38(m,2H),2.36-2.28(m,2H),1.97-1.88(m,1H),1.85-1.76(m,1H),1.23(d,J＝6.8Hz,3H)。
实施例2
(S)-4,5-二甲基-2-((反-3-((6-(三氟甲基)吡啶-3-基)氧代)环丁基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
Figure PCTCN2022107727-appb-000019
化合物2由以下步骤制备：
Figure PCTCN2022107727-appb-000020
第一步：将化合物1b(500mg,1.88mmol)，化合物2a(461mg,2.83mmol)和碳酸铯(1.23g,3.77mmol)溶解于N,N-二甲基甲酰胺(2mL)中，在80℃条件下搅拌过夜。LCMS监测反应结束，反应液用乙酸乙酯稀释，依次用水和饱和食盐水洗涤，有机相通过无水硫酸钠干燥，反应液浓缩，残余物通过硅胶柱层析纯化(二氯甲烷/甲醇＝20/1)得到白色固体2b(500mg,收率79％)。ESI-MS(m/z):333.3[M+H] +。
第二步：将化合物2b(500mg,1.50mmol)溶解在二氯甲烷(2mL)中，滴加盐酸1，4-二氧六环溶液(4M,1.88mL)，在室温条件下搅拌过夜。LCMS监测反应结束，反应液浓缩得到白色固体2c(300mg,收率74％)。ESI-MS(m/z):233.5[M+H] +。
第三步：将化合物1i(50mg,197umol)，化合物2c(68mg,256umol)和一水对甲苯磺酸(3.7mg,19umol)溶解在正丁醇(2mL)中，在微波160℃的条件下反应2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2(10.1mg,收率11％)。ESI-MS(m/z):449.2[M+H] +； 1H NMR(500MHz,DMSO-d6)δ8.38(d,J＝2.8Hz,1H),7.83(d,J＝8.7Hz,1H),7.46(dd,J＝8.7,2.9Hz,1H),6.91(d,J＝6.9Hz,1H),5.05-5.00(m,1H),4.46-4.42(m,1H),4.12(q,J＝6.9Hz,1H),4.03-3.99(m,2H),3.28-3.25(m,1H),2.95(s,3H),2.50-2.38(m,4H),1.97-1.87(m,1H),1.84-1.77(m,1H),1.23(d,J＝6.7Hz,3H)。
实施例3
(R)-4,6-二甲基-N-(反-3-(3,4,5-三氟苯氧基)环丁基)-5,6-二氢-4H-吡咯并[3,2,1-脱]蝶啶-2-胺
Figure PCTCN2022107727-appb-000021
化合物3由以下步骤制备：
Figure PCTCN2022107727-appb-000022
第一步：将化合物3a(500mg,2.66mmol)，化合物3b(946mg,3.99mmol)，碳酸钾(1.47g,10.64mmol)和18-冠-6(351mg,1.33mmol)溶解于1，4-二氧六环(10mL)中，在80℃条件下搅拌过夜。LCMS监测反应结束，反应液用乙酸乙酯稀释，依次用水和饱和食盐水洗涤，有机相通过无水硫酸钠干燥，过滤浓缩，残余物通过硅胶柱层析纯化(石油醚/乙酸乙酯＝1/1)得到黄色固体3c(600mg,收率65％)。ESI-MS(m/z):345.3[M+H] +。
第二步：将化合物3c(600mg,1.74mmol)溶解在二氯甲烷(2mL)中，滴加盐酸1，4-二氧六环溶液(4M,2.17mL)，在室温条件下搅拌过夜。LCMS监测反应结束，反应液浓缩得到白色固体3d(400mg,收率81％)。ESI-MS(m/z):245.3[M+H] +。
第三步：将化合物3d(400mg,1.63mmol)和N,N-二异丙基乙胺(632mg,4.90mmol)溶解于1，4-二氧六环(5mL)中，在100℃条件下搅拌过夜。LCMS监测反应结束，反应液浓缩，残余物通过硅胶柱层析纯化(二氯甲烷/甲醇＝10/1)得到黄色固体3e(150mg,收率44％)。ESI-MS(m/z):209.4[M+H] +。
第四步：将化合物3e(150mg,718umol)，碘甲烷(153mg,1.08mmol)和碳酸铯(468mg,1.44mmol)溶解于N,N-二甲基甲酰胺(2mL)中，在80℃条件下搅拌过夜。LCMS监测反应结束，反应液用乙酸乙酯稀释，依次用水和饱和食盐水洗涤，有机相通过无水硫酸钠干燥，过滤浓缩，残余物通过硅胶柱层析纯化(二氯甲烷/甲醇＝20/1)得到黄色固体3f(100mg,收率62％)。ESI-MS(m/z):223.4[M+H] +。
第五步：将化合物3f(30mg,134umol)，化合物1e(68mg,256umol)和三氟乙酸(1.5mg,13umol)溶解在正丁醇(2mL)中，在微波160℃的条件下反应2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3(6.8mg,收率12％)。ESI-MS(m/z):404.2[M+H] +； 1H NMR(500MHz,DMSO-d6)δ8.19(s,1H),7.30(d,J＝2.8Hz,1H),6.92-6.82(m,2H),6.04(d,J＝2.8Hz,1H),4.93-4.81(m,1H),4.46-4.41(m,1H),4.37-4.24(m,1H),3.64(dd,J＝12.4,3.9Hz,1H),3.35-3.30(m,1H),3.05(s,3H),2.48-2.42(m,2H),2.38-2.33(m,2H),1.42(d,J＝6.4Hz,3H)。
实施例4
(R)-4,6-二甲基-N-(反-3-((6-(三氟甲基)吡啶-3-基)氧代)环丁基)-5,6-二氢-4H-吡咯并[3,2,1-脱]蝶啶-2-胺
Figure PCTCN2022107727-appb-000023
化合物4由以下步骤制备：
Figure PCTCN2022107727-appb-000024
第一步：将化合物3f(30mg,134umol)，化合物2b(40mg,175umol)和三氟乙酸(1.5mg,13umol)溶解在正丁醇(2mL)中，在微波160℃的条件下反应2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4(9.3mg,收率16％)。ESI-MS(m/z):419.5[M+H] +； 1H NMR(400MHz,DMSO-d6)δ8.39(d,J＝2.8Hz,1H),8.20(s,1H),7.84(d,J＝8.7Hz,1H),7.47(dd,J＝8.7,2.9Hz,1H),7.30(d,J＝2.8Hz,1H),6.69(br s,1H),6.04(d,J＝2.8Hz,1H),5.08-5.02(m,1H),4.53-4.45(m,1H),4.35-4.25(m,1H),3.64(dd,J＝12.3,3.9Hz,2H),3.05(s,3H),2.50-2.40(m,4H),1.42(d,J＝6.4Hz,3H)。
实施例5
(S)-4,6-二甲基-N-(反-3-((6-(三氟甲基)吡啶-3-基)氧代)环丁基)-5,6-二氢-4H-吡咯并[3,2,1-脱]蝶啶-2-胺
Figure PCTCN2022107727-appb-000025
化合物5由以下步骤制备：
Figure PCTCN2022107727-appb-000026
第一步：将化合物3a(792mg,4.21mmol)，化合物5a(1g,4.21mmol)，碳酸钾(2.33g,16.86mmol)和18-冠-6(557mg,2.11mmol)溶解于1，4-二氧六环(10mL)中，在80℃条件下搅拌过夜。LCMS监测反应结束，反应液用乙酸乙酯稀释，依次用水和饱和食盐水洗涤，有机相通过无水硫酸钠干燥，过滤浓缩，残余物通过硅胶柱层析纯化(石油醚/乙酸乙酯＝1/1)得到黄色固体5b(1g,收率68％)。ESI-MS(m/z):345.3[M+H] +。
第二步：将化合物5b(1.0g,2.90mmol)溶解在二氯甲烷(10mL)中，滴加盐酸1，4-二氧六环溶液(4M,3.62mL)，在室温条件下搅拌过夜。LCMS监测反应结束，反应液浓缩得到白色固体5c(700mg,收率98％)。ESI-MS(m/z):245.4[M+H] +。
第三步：将化合物5c(700mg,2.86mmol)和N,N-二异丙基乙胺(1.11g,8.57mmol,1.49mL)溶解于1，4-二氧六环(10mL)中，在100℃条件下搅拌过夜。LCMS监测反应结束，反应液浓缩，残余物通过硅胶柱层析纯化(二氯甲烷/甲醇＝10/1)得到黄色固体5d(250mg,收率41％)。ESI-MS(m/z):209.4[M+H] +。
第四步：将化合物5d(250mg,1.20mmol)，碘甲烷(153mg,1.08mmol)和碳酸铯(468mg,1.44mmol)溶解于N,N-二甲基甲酰胺(2mL)中，在80℃条件下搅拌过夜。LCMS监测反应结束，反应液用乙酸乙酯稀释，依次用水和饱和 食盐水洗涤，有机相通过无水硫酸钠干燥，过滤浓缩，残余物通过硅胶柱层析纯化(二氯甲烷/甲醇＝20/1)得到黄色固体5e(150mg,收率56％)。ESI-MS(m/z):223.4[M+H] +。
第五步：将化合物5e(30mg,134umol)，化合物2b(47mg,175umol)和三氟乙酸(1.5mg,13umol)溶解在正丁醇(2mL)中，在微波160℃的条件下反应2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5(9.2mg,收率16％)。ESI-MS(m/z):419.4[M+H] +； 1H NMR(400MHz,DMSO-d6)δ8.39(d,J＝2.8Hz,1H),8.22(s,1H),7.84(d,J＝8.7Hz,1H),7.47(dd,J＝8.7,2.8Hz,1H),7.30(d,J＝2.8Hz,1H),6.74(br s,1H),6.04(d,J＝2.8Hz,1H),5.10-4.99(m,1H),4.51-4.45(m,1H),4.31-4.25(m,1H),3.64(d,J＝8.5Hz,1H),3.34-3.27(m,1H),3.05(s,3H),2.49-2.39(m,4H),1.42(d,J＝6.4Hz,3H)。
实施例6
(S)-4,6-二甲基-N-(反-3-(3,4,5-三氟苯氧基)环丁基)-5,6-二氢-4H-吡咯并[3,2,1-脱]蝶啶-2-胺
Figure PCTCN2022107727-appb-000027
化合物6由以下步骤制备：
Figure PCTCN2022107727-appb-000028
第一步：将化合物5e(30mg,134umol)，化合物1e(44mg,175umol)和三氟乙酸(1.5mg,13umol)溶解在正丁醇(2mL)中，在微波160℃的条件下反应2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(17.84mg,收率32％)。ESI-MS(m/z):404.2[M+H] +； 1H NMR(400MHz, DMSO-d6)δ8.22(s,1H),7.31(d,J＝2.8Hz,1H),6.91-6.84(m,2H),6.05(d,J＝2.8Hz,1H),4.94-4.80(m,1H),4.45-4.40(m,1H),4.31-4.25(m,1H),3.68-3.63(m,1H),3.31(dd,J＝12.4,8.2Hz,1H),3.05(s,3H),2.47-2.29(m,4H),1.42(d,J＝6.4Hz,3H)。
实施例7
(S)-4,5-二甲基-2-((顺-3-((6-(三氟甲基)吡啶-3-基)氨基)环丁基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
Figure PCTCN2022107727-appb-000029
化合物7由以下步骤制备：
Figure PCTCN2022107727-appb-000030
第一步：将5-溴-2-三氟甲基吡啶7a(452mg,2.00mmol)，顺式-3-氨基-1-环丁基氨基甲酸叔丁酯7b(372mg,2.00mmol)，Pd2(dba)3(91.5mg,0.10mmol)，Xantphos(115.6mg,0.20mmol)和碳酸铯(1.3g,4.00mmol)溶解于二氧六环(10mL)中，氮气保护下100度搅拌过夜。TLC监测反应结束，反应液冷却至室温，过滤，滤饼用二氯甲烷洗两次，滤液浓缩，残余物通过硅胶柱层析纯化(二氯甲烷/甲醇＝20/1)纯化得到白色固体7c(580mg,收率87％)。ESI-MS(m/z):332.3[M+H] +。
第二步：将化合物7c(100mg,0.3mmol)溶解于甲醇(5mL)中，室温下滴加氯化氢-二氧六环溶液(4M,0.75mL,3mmol),室温搅拌2小时。TLC监测反应结束，反应液旋干得到白色固体7d(80mg,收率99％)。ESI-MS(m/z):232.4[M+H] +。
第三步：将化合物1i(76mg,0.30umol)，化合物7d(80mg,0.30mol)和一水对甲苯磺酸(5.7mg,0.03mol)溶解在正丁醇(3mL)中，在微波160℃的条件下反应2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(45mg,收率33％)。ESI-MS(m/z):448.5[M+H] +； 1H NMR(400MHz,DMSO-d 6)δ8.01(d,J＝2.7Hz,1H),7.51(d,J＝8.7Hz,1H),6.98-6.90(m,2H),6.81(d,J＝7.5Hz,1H),4.19-3.97(m,3H),3.58(q,J＝7.4Hz,1H),3.32-3.21(m,1H),2.96(s,3H),2.83-2.70(m,2H),2.55-2.52(m,2H),1.98-1.88(m,1H),1.86-1.73(m,3H),1.23(d,J＝6.8Hz,3H)。
实施例8
(S)-4,5-二甲基-2-((反-3-((6-(三氟甲基)吡啶-3-基)氨基)环丁基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
Figure PCTCN2022107727-appb-000031
用(反式-3-氨基环丁基)氨基甲酸叔丁酯替换实施例7中第一步的7b，用类似的方法和反应步骤，得到化合物8。ESI-MS(m/z):448.5[M+H] +； 1H NMR(400MHz,DMSO-d 6)δ7.98(d,J＝2.7Hz,1H),7.53(d,J＝8.6Hz,1H),7.08(d,J＝5.5Hz,1H),6.92-6.80(m,2H),4.44(q,J＝7.3Hz,1H),4.12(q,J＝6.7Hz,1H),4.07-3.98(m,1H),3.96-3.86(m,1H),3.32-3.22(m,1H),2.95(s,3H),2.42-2.28(m,2H),2.25-2.14(m,2H),1.97-1.87(m,1H),1.85-1.72(m,1H),1.23(d,J＝6.8Hz,3H)。
实施例9
(S)-4,5-二甲基-2-((反-3-((6-(三氟甲基)吡啶-3-基)氨基)环戊基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
Figure PCTCN2022107727-appb-000032
用N-[反式-3-氨基环戊基]氨基甲酸叔丁酯替换实施例7中第一步的7b，用类似的方法和反应步骤，得到化合物9。ESI-MS(m/z):462.4[M+H] +； 1H NMR(400MHz,DMSO-d 6)δ8.04(d,J＝2.7Hz,1H),7.51(d,J＝8.7Hz,1H),6.98(dd,J＝8.7,2.8Hz,1H),6.74(d,J＝6.6Hz,1H),6.56(d,J＝7.6Hz,1H),4.29(q,J＝6.9Hz,1H),4.11(q,J＝6.7Hz,1H),4.03(dt,J＝13.0,4.7Hz,1H),3.92(q,J＝6.4Hz,1H),3.30-3.22(m,1H),2.93(s,3H),2.53(d,J＝5.0Hz,2H),2.19-2.02(m,2H),1.91(p,J＝6.9Hz,2H),1.80(dt,J＝12.7,6.7Hz,2H),1.58-1.41(m,2H),1.23(d,J＝6.8Hz,3H)。
实施例10
(S)-4,5-二甲基-2-((1-((6-(三氟甲基)吡啶-3-基)甲基)吖丁啶-3-基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
Figure PCTCN2022107727-appb-000033
化合物10由以下步骤制备：
Figure PCTCN2022107727-appb-000034
第一步：将化合物1i(200mg，791umol)和化合物10a(451mg，1.58mmol)溶于10mL二氧六环中，加入Pd 2dba 3(72mg，79umol)，S-Phos(65mg，158umol)和叔丁醇钠(228mg，2.37mmol)，氮气保护下100℃过夜，LCMS监测原料反应完全。反应液浓缩，残余物通过制备薄层层析(二氯甲烷/甲醇＝20/1)纯化得化合物10b(90mg，收率29％)，黄色油。ESI-MS(m/z):389.5[M+H] +。
第二步：将化合物10b(90mg，232umol)溶于10mL二氯甲烷中，加入三氟乙酸(1mL)，室温搅拌4小时，LCMS监测原料反应完全，反应液浓缩得化合物10c(90mg)，黄色油，直接用于下一步反应。ESI-MS(m/z):289.4[M+H] +。
第三步：将化合物10c(90mg)和10d(53mg，269umol)溶于10mL乙腈中，加入碳酸钾(93mg，673umol)，60℃反应4小时，LCMS监测原料反应完全。反应液浓缩，残余物通过反向制备HPLC纯化得化合物10(10mg，收率10.3％)，白色固体。ESI-MS(m/z):448.5[M+H] +； 1H NMR(500MHz,DMSO-d6)δ8.66(s,1H),7.96(d,J＝8.0Hz,1H),7.85(d,J＝8.0Hz,1H),6.89(d,J＝6.9Hz,1H),4.40(q,J＝7.0Hz,1H),4.12(q,J＝6.8Hz,1H),4.01(dt,J＝13.0,4.9Hz,1H),3.72(s,2H),3.59(t,J＝6.8Hz,2H),3.30-3.23(m,1H),2.95(d,J＝8.0Hz,5H),2.52(s,2H),1.92(d,J＝14.5Hz,1H),1.80(d,J＝3.9Hz,1H),1.23(d,J＝6.7Hz,3H)。
实施例11
(S)-4,5-二甲基-2-(((1s,3R)-3-(((6-(三氟甲基)吡啶-3-基)氧代)甲基)环丁基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
Figure PCTCN2022107727-appb-000035
化合物11由以下步骤制备：
Figure PCTCN2022107727-appb-000036
第一步：将顺式-3-羟甲基环丁基氨基甲酸叔丁酯11a(150mg,0.745mmol)，甲基磺酸酐(259mg,1.49mmol)和N,N-二异丙基乙胺(385mg,2.98mmol)溶解于二氯甲烷(5mL)中，在室温条件下搅拌过夜。TLC监测反应结束，反应液用二氯甲烷稀释，依次用水和饱和食盐水洗涤，有机相通过无水硫酸钠干燥，过滤浓缩得到黄色固体11b(204mg,收率98％)。 1H NMR(500MHz,DMSO-d6)δ7.10(d,J＝8.1Hz,1H),4.11(d,J＝5.2Hz,2H),3.19(d,J＝1.6Hz,1H),3.16(d,J＝1.6Hz,3H),2.26(d,J＝5.9Hz,1H),1.68(d,J＝8.7Hz,2H),1.57-1.47(m,2H),1.37(s,9H)。
第二步：将化合物11b(204mg,731umol)，化合物2a(131mg,0.8mmol) 和碳酸铯(485mg,1.49mmol)溶于N,N-二甲基甲酰胺(5mL)，在90℃条件下搅拌过夜。TLC监测反应结束，反应液用水稀释，用乙酸乙酯萃取，再用饱和食盐水洗涤，有机相通过无水硫酸钠干燥，过滤浓缩，残余物通过硅胶柱层析纯化(石油醚/乙酸乙酯＝3/1)得到黄色固体11c(185mg,收率72％)。ESI-MS(m/z):347.2[M+H] +。
第三步：将化合物11c(120mg,346umol)溶于二氯甲烷(5mL)，在0℃下加入4M盐酸二氧六环溶液(0.87mL)并搅拌过夜。TLC监测反应结束，直接旋干，得到白色固体11d(85mg,收率99％)。ESI-MS(m/z):247.4[M+H] +。
第四步：将化合物11d(82mg,336umol)，化合物1i(85mg,336umol)和一水对甲苯磺酸(5.7mg,33.6umol)溶解在正丁醇(3mL)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11(25mg,收率16％)。ESI-MS(m/z):463.3[M+H] +； 1H NMR(500MHz,DMSO-d6)δ8.47(d,J＝3.0Hz,1H),7.85(d,J＝8.5Hz,1H),7.64(dd,J＝9.0,3.0Hz,1H),6.81(br s,1H),4.32-4.23(m,1H),4.16-4.09(m,3H),4.08-4.01(m,1H),3.30-3.24(m,2H),2.95(s,3H),2.48-2.38(m,3H),1.97-1.88(m,1H),1.86-1.73(m,3H),1.23(d,J＝7.0Hz,3H)。
实施例12
(S)-2-(((1s,3R)-3-(((1-环丙基-3-(三氟甲基)-1H-吡唑-5-基)氧代)甲基)环丁基)氨基)-4,5-二甲基-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
Figure PCTCN2022107727-appb-000037
化合物12由以下步骤制备：
Figure PCTCN2022107727-appb-000038
第一步：将三氟乙酰乙酸乙酯12a(1.7g，9.21mmol)和环丙基肼盐酸盐12b(1.0g，9.21mmol)溶于20mL乙醇中，80℃反应过夜。反应液浓缩，残余物加入石油醚打浆，过滤得棕色固体化合物12c(800mg，收率45％)。ESI-MS(m/z):193.2[M+H] +。
第二步：将化合物11b(872mg,3.12mmol)，化合物12c(500mg,2.61mmol)和碳酸铯(1.70g,5.22mmol)溶于N,N-二甲基甲酰胺(20mL)，在90℃条件下搅拌过夜。TLC监测反应结束，反应液用水稀释，用乙酸乙酯萃取，再用饱和食盐水洗涤，有机相通过无水硫酸钠干燥，过滤浓缩，残余物通过硅胶柱层析纯化(石油醚/乙酸乙酯＝3/1)得到黄色固体12d(495mg,收率52％)。ESI-MS(m/z):362.6[M+H] +。
第三步：将化合物12d(495mg,1.1mmol)溶于二氯甲烷(30mL)，在0℃下加入4M盐酸二氧六环溶液(1.37mL)并搅拌过夜。TLC监测反应结束，直接旋干，得到白色固体12e(231mg,收率80％)。ESI-MS(m/z):262.6[M+H] +。
第四步：将化合物12e(26mg,95umol)，化合物1i(20mg,79umol)和一水对 甲苯磺酸(0.4mg,7.9umol)溶解在正丁醇(3mL)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12(13mg,收率35％)。ESI-MS(m/z):492.4[M+H] +； 1H NMR(500MHz,DMSO-d6)δ6.67(br s,1H),6.17(s,1H),4.26-4.18(m,1H),4.15-4.06(m,2H),4.05-3.97(m,1H),3.54-3.21(m,5H),2.94(s,3H),2.60-2.50(m,2H),2.47-2.35(m,3H),1.96-1.86(m,1H),1.85-1.70(m,3H),1.21(d,J＝6.8Hz,3H),1.05-0.90(m,4H)。
实施例13
(S)-2-(((1s,3R)-3-(((1-环丙基-3-(三氟甲基)-1H-吡唑-5-基)氧代)甲基)环丁基)氨基)-5-(羟甲基)-4,5-二甲基-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
Figure PCTCN2022107727-appb-000039
化合物13由以下步骤制备：
Figure PCTCN2022107727-appb-000040
第一步：将2,4-二氯吡啶并[3,2-d]嘧啶1f(4.0g，20.0mmol)和2-甲基-L-丝氨酸甲酯盐酸盐13a(4.07g，24.0mmol)溶解于二氯甲烷(30mL)中，加入N,N-二异丙基乙胺(7.75g，59.99mmol，10.45mL)，在室温条件下搅拌过夜。LCMS监测反应结束，反应液用二氯甲烷稀释，分别用水和饱和食盐水洗涤，有机相用无水硫酸钠干燥，过滤浓缩得到白色固体13b(5.0g，收率84％)。ESI-MS(m/z):297.3[M+H] +。
第二步：将化合物13b(5.0g，16.85mmol)溶解于四氢呋喃(50mL)中，加入盐酸水溶液(6M，5.62mL)和二氧化铂(382mg，1.69mmol)，反应体系用氢气球置换氢气，在室温氢气球压力下搅拌48小时，LCMS监测反应结束。反应液用甲醇稀释，过滤，滤液浓缩得到白色固体13c(4.0g，收率88％)。ESI-MS(m/z):269.3[M+H] +。
第三步：将化合物13c(1.5g,5.58mmol)和碘甲烷(1.58g,11.16mmol)溶解在乙腈(5mL)中，加入碳酸铯(3.64g,11.16mmol)，反应混合物在室温条件下搅拌48小时。LCMS监测反应结束。反应液用乙酸乙酯稀释，过滤分别用水喝饱和食盐水洗涤，有机相无水硫酸钠干燥，过滤浓缩。残余物通过硅胶柱层析(二氯甲烷/甲醇＝10/1)纯化，得到黄色固体13d(1.1g,收率69％)。ESI-MS(m/z):283.3[M+H] +。
第四步：将化合物12e(25mg,84umol)，化合物13d(20mg,70.7umol)和一水对甲苯磺酸(0.4mg,7.07umol)溶解在正丁醇(3mL)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(13mg,收率35％)。ESI-MS(m/z):522.3[M+H] +； 1H NMR(500MHz,DMSO-d6)δ6.54(br s,1H),6.17(s,1H),5.06(t,J＝5.5Hz,1H),4.29-4.18(m,1H),4.10(d,J＝4.9Hz,2H),3.76-3.67(m,2H),3.65-3.58(m,1H),3.57-3.49(m,2H),2.97(s,3H),2.55-2.45(m,2H),2.44-2.32(m,3H),1.88-1.72(m,4H),1.33(s,3H),0.98(d,J＝7.8Hz,4H)。
实施例14
(S)-5-(羟甲基)-4,5-二甲基-2-(((1s,3R)-3-(((2-甲基-6-(三氟甲基)吡啶-3-基)氧代)甲基)环丁基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
Figure PCTCN2022107727-appb-000041
化合物14由以下步骤制备：
Figure PCTCN2022107727-appb-000042
第一步：将化合物2a(2.0g,12.26mmol)，Na 2CO 3(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14a(1.5g，收率42％)。ESI-MS(m/z):290.2[M+H] +。
第二步：将化合物14a(0.5g，1.73mmol)，苄溴(337mg，1.98mmol)溶解于DMF(5mL)中，加入K 2CO 3(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14b(0.5g，收率76％)。ESI-MS(m/z):380.2[M+H] +。
第三步：将化合物14b(412mg,1.09mmol)，醋酸钯(24mg,109umol)，三甲基环三硼氧烷(682mg,5.43mmol)，三环己基膦(152mg,523umol)，磷酸三钾(922mg,4.35mmol)，水(3mL)，1,4-二氧六环(30mL)加入到100mL的两口烧瓶，置换氮气后，在90℃条件下搅拌过夜，TLC监测反应结束，反应液用水稀释，用硅藻土过滤，再用乙酸乙酯萃取，最后用饱和食盐水洗涤，有机相通过无水硫酸钠干燥，过滤浓缩，残余物通过硅胶柱层析纯化(石油醚/乙酸乙酯＝10/1)得到黄色液体14c(198mg,收率68％)。ESI-MS(m/z):268.2[M+H]+。
第四步：将化合物14c(198mg,741umol)溶于二氯甲烷(10mL),在-78℃条件下滴加三溴化硼(928mg,3.71umol)并搅拌1小时，TLC监测反应结束，反应液用水稀释，再用二氯甲烷萃取，有机相通过无水硫酸钠干燥，过滤浓缩，残余物通过硅胶柱层析纯化(石油醚/乙酸乙酯＝1/1)得到黄色液体14d(143mg,收率91％)。ESI-MS(m/z):178.4[M+H]+。
第五步：将化合物14d(120mg,677umol)，化合物11b(208mg,745umol)和碳酸铯(441mg,1.35mmol)溶于N,N-二甲基甲酰胺(5mL)，在90℃条件下搅拌过夜。TLC监测反应结束，反应液用水稀释，用乙酸乙酯萃取，再用饱和食盐水洗涤，有机相通过无水硫酸钠干燥，过滤浓缩，残余物通过硅胶柱层析纯化(石油醚/乙酸乙酯＝3/1)得到黄色固体14e(196mg,收率80％)。ESI-MS(m/z):361.4[M+H] +。
第六步：将化合物14e(196mg,543umol)溶于二氯甲烷(10mL)，在0℃下加入4M盐酸(0.952mL)并搅拌过夜。TLC监测反应结束，直接旋干，得到白色固体14f(112mg,收率79％)。ESI-MS(m/z):261.3[M+H] +。
第七步：将化合物14f(27mg,106umol)，化合物13d(20mg,70.7umol)和一水对甲苯磺酸(0.4mg,7.07umol)溶解在正丁醇(3mL)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14(19mg,收率52％)。ESI-MS(m/z):507.3[M+H] +； 1H NMR(500MHz,DMSO-d6)δ7.67(d,J＝8.5Hz,1H),7.48(d,J＝8.5Hz,1H),6.54(br s,1H),5.06(t,J＝5.5Hz,1H),4.29-4.19(m,1H),4.05(d,J＝4.8Hz,2H),3.77-3.66(m,2H),3.65-3.60(m,1H),3.58-3.53(m,1H),2.98(s,3H),2.48-2.35(m,8H),1.90-1.74(m,4H),1.33(s,3H)。
实施例15
(S)-2-(((1s,3R)-3-(((2-环丙基-6-(三氟甲基)吡啶-3-基)氧代)甲基)环丁基)氨基)-5-(羟甲基)-4,5-二甲基-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
Figure PCTCN2022107727-appb-000043
化合物15由以下步骤制备：
Figure PCTCN2022107727-appb-000044
第一步：将化合物14b(300mg,0.791mmol)，醋酸钯(18mg,79umol)，环丙基硼酸(339mg,3.96mmol)，三环己基膦(152mg,523umol)，磷酸三钾(672mg,3.17mmol)，水(1mL)，1,4-二氧六环(10mL)加入到100mL的两口烧瓶，置换氮气后，在90℃条件下搅拌过夜，TLC监测反应结束，反应液用水稀释，用硅藻土过滤，再用乙酸乙酯萃取，最后用饱和食盐水洗涤，有机相通过无水硫酸钠干燥，过滤浓缩，残余物通过硅胶柱层析纯化(石油醚/乙酸乙酯＝10/1)得到黄色液体15a(209mg,收率90％)。ESI-MS(m/z):294.3[M+H]+。
第二步：将化合物15a(209mg,712umol)溶于二氯甲烷(10mL),在-78℃条件下滴加三溴化硼(829mg,3.56umol)并搅拌1小时，TLC监测反应结束，反应液用水稀释，再用二氯甲烷萃取，有机相通过无水硫酸钠干燥，过滤浓缩，残余物通过硅胶柱层析纯化(石油醚/乙酸乙酯＝1/1)得到黄色液体15b(122mg,收率84％)。ESI-MS(m/z):204.4[M+H]+。
第三步：将化合物15b(122mg,590umol)，化合物11b(211mg,758umol)和碳酸铯(449mg,1.38mmol)溶于N,N-二甲基甲酰胺(5mL)，在90℃条件下搅拌过夜。TLC监测反应结束，反应液用水稀释，用乙酸乙酯萃取，再用饱和 食盐水洗涤，有机相通过无水硫酸钠干燥，过滤浓缩，残余物通过硅胶柱层析纯化(石油醚/乙酸乙酯＝3/1)得到黄色固体15c(152mg,收率66％)。ESI-MS(m/z):387.3[M+H] +。
第四步：将化合物15c(152mg,393umol)溶于二氯甲烷(10mL)，在0℃下加入4M盐酸(0.706mL)并搅拌过夜。TLC监测反应结束，直接旋干，得到白色固体15d(92mg,收率79％)。ESI-MS(m/z):287.3[M+H] +。
第五步：将化合物15d(46mg,159umol)，化合物13d(30mg,106umol)和一水对甲苯磺酸(0.5mg,10.6umol)溶解在正丁醇(3mL)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15(18mg,收率32％)。ESI-MS(m/z):533.1[M+H] +； 1H NMR(500MHz,DMSO-d6)δ7.56(dd,J＝8.5,3.8Hz,1H),7.45(d,J＝8.5Hz,1H),6.55(br s,1H),5.06(t,J＝5.7Hz,1H),4.30-4.18(m,1H),4.06(d,J＝5.1Hz,2H),3.77-3.66(m,2H),3.65-3.59(m,1H),3.57-3.52(m,1H),2.98(s,3H),2.52-2.45(m,2H),2.44-2.35(m,3H),1.87-1.75(m,4H),1.33(s,3H),1.02-0.97(m,2H),0.95-0.89(m,2H)。
实施例16
(S)-5-(甲氧基甲基)-4-(甲基-d3)-2-(((1s,3R)-3-(((6-(三氟甲基)吡啶-3-基)氧代)甲基)环丁基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
Figure PCTCN2022107727-appb-000045
化合物16由以下步骤制备：
Figure PCTCN2022107727-appb-000046
第一步：将2,4-二氯吡啶并[3,2-d]嘧啶1f(2g，10.00mmol)和O-甲基-L-丝氨酸甲酯盐酸盐16a(2.45g，15.00mmol)溶解于四氢呋喃(20mL)中，加入N,N-二异丙基乙胺(3.88g，30.00mmol，5.22mL)，在室温条件下搅拌过夜。LCMS监测反应结束，反应液浓缩，残余物通过硅胶柱层析(石油醚/乙酸乙酯＝1/1)纯化，得到黄色油状物16b(2.5g，收率84％)。ESI-MS(m/z):297.2[M+H] +。
第二步：将化合物16b(2.5g，8.43mmol)溶解于四氢呋喃(30mL)中，加入盐酸水溶液(6N，1.40mL)和二氧化铂(191mg，0.84mmol)，反应体系用氢气球置换氢气，在室温氢气球压力下搅拌48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＝10/1)纯化，得到灰色固体16c(2.0g，收率88％)。ESI-MS(m/z):269.3[M+H] +。
第三步：将化合物16c(200mg,0.74mmol)和氘代碘甲烷(215mg,1.49mmol)溶解在乙腈(5mL)中，加入碳酸铯(485mg,1.49mmol)，在50℃的条件下反应2小时。LCMS监测反应结束。反应液用二氯甲烷稀释，过滤，滤液浓缩后通过硅胶柱层析(二氯甲烷/甲醇＝20/1)纯化，得到黄色固体16d(200mg,收率94％)。ESI-MS(m/z):286.3[M+H] +。
第四步：将化合物16d(25mg,89umol)，化合物11c(32mg,131umol)和一水 对甲苯磺酸(0.45mg,8.9umol)溶解在正丁醇(3mL)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(5mg,收率10％)。ESI-MS(m/z):496.4[M+H] +； 1H NMR(500MHz,DMSO-d6)δ8.43(d,J＝2.7Hz,1H),7.82(d,J＝8.7Hz,1H),7.59(dd,J＝8.8,2.8Hz,1H),6.60(br s,1H),4.32-4.20(m,2H),4.09(d,J＝5.0Hz,2H),4.03-3.94(m,1H),3.72-3.60(m,2H),3.16(s,3H),2.52-2.46(m,2H),2.45-2.32(m,3H),1.94-1.85(m,1H),1.84-1.69(m,3H)。
实施例17
(S)-5-(羟甲基)-4,5-二甲基-2-(((1s,3R)-3-(((6-(三氟甲基)吡啶-3-基)氧代)甲基)环丁基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
Figure PCTCN2022107727-appb-000047
用6-(三氟甲基)吡啶-3-醇2a替换实施例14中第五步的原料14d，用类似的方法和反应步骤，得到化合物17。ESI-MS(m/z):493.3[M+H] +； 1H NMR(500MHz,DMSO-d6)δ8.43(d,J＝2.7Hz,1H),7.82(d,J＝8.7Hz,1H),7.59(dd,J＝8.6,2.8Hz,1H),6.53(br s,1H),5.06(t,J＝5.5Hz,1H),4.29-4.18(m,1H),4.10(d,J＝4.9Hz,2H),3.78-3.66(m,2H),3.65-3.58(m,1H),3.57-3.51(m,1H),2.98(s,3H),2.52-2.46(m,2H),2.45-2.34(m,3H),1.90-1.73(m,4H),1.33(s,3H)。
实施例18
(S)-4,5-二甲基-2-(((1s,3R)-3-(((2-(三氟甲基)嘧啶-5-基)氧代)甲基)环丁基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
Figure PCTCN2022107727-appb-000048
用2-(三氟甲基)嘧啶-5-醇替换实施例11中第一步的2a，用类似的方法和反应步骤，得到化合物18。ESI-MS(m/z):464.3[M+H] +； 1H NMR(500MHz,DMSO-d6)δ8.76(s,2H),6.70(s,1H),4.28-4.17(m,3H),4.11(q,J＝6.8Hz,1H),4.11-4.39(m,1H),3.33(s,1H),3.30-3.22(m,2H),2.94(s,3H),2.52-2.46(m,2H),2.45-2.35(m,3H),1.95-1.86(m,1H),1.85-1.72(m,3H),1.21(d,J＝6.7Hz,3H)。
实施例19
(S)-5-(羟甲基)-4,5-二甲基-2-(((1s,3R)-3-((3,4,5-三氟苯氧基)甲基)环丁基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
Figure PCTCN2022107727-appb-000049
用3,4,5-三氟苯酚1c替换实施例14中第五步的原料14d，用类似的方法和反应步骤，得到化合物19。ESI-MS(m/z):478.4[M+H] +； 1H NMR(500MHz,DMSO-d6)δ7.10-6.95(m,2H),6.48(d,J＝7.8Hz,1H),5.06(br s,1H),4.24(q,J＝8.0Hz,1H),3.94(d,J＝5.9Hz,2H),3.81-3.70(m,2H),3.69-3.64(m,1H),3.57(d,J＝11.3Hz,1H),3.00(s,3H),2.52-2.45(m,2H),2.43-2.33(m,3H),1.90-1.80(m,2H),1.79-1.71(m,2H),1.35(s,3H)。
实施例20
(S)-2-(((1s,3R)-3-((4-氟-2-(三氟甲基)苯氧基)甲基)环丁基)氨基)-5-(羟甲基)-4,5-二甲基-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
Figure PCTCN2022107727-appb-000050
用4-氟-2-(三氟甲基)苯酚替换实施例14中第五步的原料14d，用类似的方法和反应步骤，得到化合物20。ESI-MS(m/z):510.4[M+H] +； 1H NMR(500MHz,DMSO-d6)δ7.60-7.50(m,2H),7.34-7.27(m,1H),6.43(br s,1H),5.08(t,J＝5.6Hz,1H),4.22(q,J＝8.2Hz,1H),4.06(d,J＝5.2Hz,2H),3.77-3.68(m,2H),3.67-3.62(m,1H),3.61-3.55(m,1H),2.99(s,3H),2.51-2.45(m,2H),2.43-2.35(m,3H),1.90-1.83(m,2H),1.82-1.71(m,2H),1.34(s,3H)。
实施例21
(S)-5-(羟甲基)-4,5-二甲基-2-(((1s,3R)-3-(((2-苯基-6-(三氟甲基)吡啶-3-基)氧代)甲基)环丁基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
Figure PCTCN2022107727-appb-000051
化合物21由以下步骤制备：
Figure PCTCN2022107727-appb-000052
第一步：将化合物21a(290mg,1.46mmol)，化合物11b(451mg,1.61mmol)和碳酸铯(191mg,2.92mmol)溶于N,N-二甲基甲酰胺(5mL)，在90℃条件下搅拌过夜。TLC监测反应结束，反应液用水稀释，用乙酸乙酯萃取，再用饱和食盐水洗涤，有机相通过无水硫酸钠干燥，过滤浓缩，残余物通过硅胶柱层析纯化(石油醚/乙酸乙酯＝3/1)得到黄色固体21b(445mg,收率79％)。ESI-MS(m/z):381.3[M+H] +。
第二步：将化合物21b(158mg,414umol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(30mg,41.4umol)，苯硼酸(101mg,829umol)，碳酸铯(405mg,1.24mmol)，水(1mL)，二氧六环(10mL)加入到25mL的两口烧瓶，置换氮气后，在90℃条件下搅拌过夜，TLC监测反应结束，反应液用水稀释，用硅藻土过滤，再用乙酸乙酯萃取，最后用饱和食盐水洗涤，有机相通过无水硫酸钠干燥，过滤浓缩，残余物通过硅胶柱层析纯化(石油醚/乙酸乙酯＝10/1)得到黄色液体21c(152mg,收率87％)。ESI-MS(m/z):423.4[M+H] +。
第三步：将化合物21c(78mg,164umol)溶于二氯甲烷(5mL)，在0℃下加入4M盐酸二氧六环溶液(0.1mL)并搅拌过夜。TLC监测反应结束，直接旋 干，得到白色固体21d(43mg,收率72％)。ESI-MS(m/z):323.7[M+H] +。
第四步：将化合物21d(43mg,133umol)，化合物13d(25mg,88.4umol)和一水对甲苯磺酸(1.31mg,13.3umol)溶解在正丁醇(3mL)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21(14mg,收率27％)。ESI-MS(m/z):569.9[M+H] +； 1H NMR(500MHz,DMSO-d6)δ7.92(d,J＝7.7Hz,2H),7.83(d,J＝8.6Hz,1H),7.74(d,J＝8.6Hz,1H),7.60-7.41(m,2H),7.44(d,J＝7.2Hz,1H),6.40(br s,1H),5.06(t,J＝5.6Hz,1H),4.23(p,J＝8.2Hz,1H),4.13(d,J＝5.3Hz,2H),3.79-3.68(m,2H),3.66-3.61(m,1H),3.58-3.52(m,1H),2.98(s,3H),2.52-2.35(m,5H),1.90-1.72(m,4H),1.33(s,2H)。
实施例22
(S)-5-(羟甲基)-4,5-二甲基-2-(((1s,3R)-3-(((2-(吡咯烷-1-基)-6-(三氟甲基)吡啶-3-基)氧代)甲基)环丁基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
Figure PCTCN2022107727-appb-000053
化合物22由以下步骤制备：
Figure PCTCN2022107727-appb-000054
第一步：将化合物14b(210mg,554umol)，Pd 2(dba) 3(50.7mg,55.4umol)，四氢吡咯(89mg,830umol)，叔丁醇钾(310mg,2.77mmol)，2-二环己膦基-2'-(N,N-二甲胺)-联苯(65mg,166umol)和甲苯(8mL)加入到50mL单口烧瓶中，反应体系置换氮气后在80℃下搅拌过夜，LCMS显示反应转化完全。反应液用硅藻土过滤，再用乙酸乙酯和水萃取，用饱和食盐水洗涤，有机相通过无水硫酸钠干燥，过滤浓缩，残余物通过硅胶柱层析纯化(石油醚/乙酸乙酯＝10/1)得到黄色液体22a(132mg,收率73％)。ESI-MS(m/z):323.3[M+H]+。
第二步：将化合物22a(132mg,409umol)溶于二氯甲烷(10mL),在-78℃条件下滴加三溴化硼(474mg,1.89umol)并搅拌1小时，TLC监测反应结束，反应液用水稀释，再用二氯甲烷萃取，有机相通过无水硫酸钠干燥，过滤浓缩，残余物通过硅胶柱层析纯化(石油醚/乙酸乙酯＝1/1)得到黄色液体22b(65mg,收率73％)。ESI-MS(m/z):233.3[M+H]+。
第三步：将化合物22b(65mg,279umol)和化合物11b(86mg,307umol)和碳酸铯(189mg,560umol)溶于N,N-二甲基甲酰胺(5mL)，在90℃条件下搅拌过夜。TLC监测反应结束，反应液用水稀释，用乙酸乙酯萃取，再用饱和食 盐水洗涤，有机相通过无水硫酸钠干燥，过滤浓缩，残余物通过硅胶柱层析纯化(石油醚/乙酸乙酯＝3/1)得到黄色固体22c(78mg,收率67％)。ESI-MS(m/z):416.5[M+H] +。
第四步：将化合物22c(78mg,187umol)溶于二氯甲烷(5mL)，在0℃下加入4M盐酸二氧六环溶液(0.1mL)并搅拌过夜。TLC监测反应结束，直接旋干，得到白色固体22d(45mg,收率76％)。ESI-MS(m/z):316.5[M+H] +。
第五步：将化合物22d(40mg,114umol)，化合物13d(25mg,88.4umol)和一水对甲苯磺酸(1.52mg,8.82umol)溶解在正丁醇(3mL)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22(5mg,收率10％)。ESI-MS(m/z):562.4[M+H] +； 1H NMR(500MHz,DMSO-d6)δ7.12(d,J＝7.9Hz,1H),6.95(d,J＝7.9Hz,1H),6.50(br s,1H),5.07(t,J＝5.4Hz,1H),4.28-4.16(m,1H),3.93(d,J＝5.1Hz,2H),3.76-3.68(m,2H),3.65-3.53(m,6H),2.98(s,3H),2.51-2.45(m,2H),2.43-2.35(m,3H),1.92-1.68(m,8H),1.33(s,3H)。
实施例23
(S)-5-(羟甲基)-4,5-二甲基-2-(((1r,3S)-3-(3,4,5-三氟苯氧基)环丁基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
Figure PCTCN2022107727-appb-000055
用中间体1e替换实施例13中第四步的12e，用类似的方法和反应步骤，得到化合物23。ESI-MS(m/z):464.5[M+H] +； 1H NMR(500MHz,DMSO-d6)δ6.90-6.80(m,2H),6.71(d,J＝6.9Hz,1H),5.07(d,J＝5.0Hz,1H),4.87-4.78(m,1H), 4.45-4.33(m,1H),3.78-3.68(m,2H),3.66-3.58(m,1H),3.57-3.50(m,1H),2.97(s,3H),2.52-2.37(m,4H),2.36-2.28(m,2H),1.90-1.75(m,2H),1.33(s,3H)。
实施例24
(S)-5-(羟甲基)-4-甲基-2-(((1r,3S)-3-(3,4,5-三氟苯氧基)环丁基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
Figure PCTCN2022107727-appb-000056
化合物24由以下步骤制备：
Figure PCTCN2022107727-appb-000057
第一步：将化合物16c(500mg,1.86mmol)和碘甲烷(343mg,2.42mmol)溶解在乙腈(10mL)中，加入碳酸铯(1.21g,372mmol)，在50℃的条件下反应2小时。LCMS监测反应结束。反应液用二氯甲烷稀释，过滤，滤液浓缩后通过硅胶柱层析(二氯甲烷/甲醇＝20/1)纯化，得到白色固体24a(350mg,收率66％)。 ESI-MS(m/z):283.3[M+H] +。
第二步：将24a(250mg，0.88mmol)溶解于二氯甲烷(2mL)中，再0℃滴加三溴化硼(2.21g，8.84mmol,0.85mL)，滴加完成后在0℃下反应两个小时。LCMS监测反应结束。反应液用碳酸氢钠溶液小心淬灭，二氯甲烷萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩，残余物通过硅胶柱层析(二氯甲烷/甲醇＝10/1)纯化，得到白色固体24b(100mg，收率42％)。ESI-MS(m/z):269.3[M+H] +。
第三步：将化合物24b(30mg,111umol)，化合物1e(42mg,167umol)和一水对甲苯磺酸(1.92mg,11.1umol)溶解在正丁醇(3mL)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24(16mg,收率32％)。ESI-MS(m/z):450.3[M+H] +； 1H NMR(500MHz,DMSO-d6)δ6.91-6.79(m,2H),6.76-6.69(m,1H),5.01-4.95(m,1H),4.87-4.81(m,1H),4.45-4.33(m,1H),4.16-3.94(m,2H),3.80-3.63(m,2H),2.97(s,3H),2.51-2.44(m,2H),2.41-2.35(m,2H),1.95-1.85(m,1H),1.81-1.69(m,1H)。
实施例25
(S)-4,5-二甲基-2-(((1r,3S)-3-((2-甲基-6-(三氟甲基)吡啶-3-基)氧代)环丁基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
Figure PCTCN2022107727-appb-000058
用中间体14d替换实施例2中第一步的2a，用类似的方法和反应步骤，得到化合物25。ESI-MS(m/z):463.5[M+H] +； 1H NMR(500MHz,DMSO-d6)δ7.66(d,J＝8.5Hz,1H),7.25(d,J＝8.5Hz,1H),6.88(d,J＝6.8Hz,1H),4.97(br s,1H), 4.50-4.36(m,1H),4.11(q,J＝6.8Hz,1H),4.04-3.98(m,1H),3.35-3.29(m,2H),2.94(s,3H),2.60-2.30(m,9H),2.00-1.88(m,1H),1.85-1.75(m,1H),1.23(d,J＝6.6Hz,3H)。
实施例26
(S)-4,5-二甲基-2-(((1r,3S)-3-((4-甲基-2-(三氟甲基)嘧啶-5-基)氧代)环丁基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
Figure PCTCN2022107727-appb-000059
化合物26由以下步骤制备：
Figure PCTCN2022107727-appb-000060
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26a(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26b，直接用于下一步。
第二步：将上一步得到的油状物26b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26c(4.37g，收率41％，纯度99％)。ESI-MS(m/z):271.4[M+H] +。
第三步：将化合物26c(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26d(3.9g，收率86％，纯度95％)。
第四步：将化合物26d(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26e(1.86g，收率50％，纯度99％)。ESI-MS(m/z):269.1[M+H] +。
第五步：将化合物26e(280mg,1.04mmol)溶于甲醇(10mL),再加入钯碳(13mg,104umol)，并将反应体系置换成氢气，反应5小时，TLC监测反应结束，反应液用硅藻土过滤，浓缩滤液，得到黄色液体26f(170mg,收率91％)。ESI-MS(m/z):177.5[M-H] -。
第六步：将化合物26f(120mg,673umol)和化合物1b(268mg,1.01mmol)和碳酸铯(548mg,1.68mmol)溶于N,N-二甲基甲酰胺(5mL)，在90℃条件下搅拌过夜。TLC监测反应结束，反应液用水稀释，用乙酸乙酯萃取，再用饱和食盐水洗涤，有机相通过无水硫酸钠干燥，过滤浓缩，残余物通过硅胶柱层析纯 化(石油醚/乙酸乙酯＝3/1)得到黄色固体26g(148mg,收率62％)。ESI-MS(m/z):348.5[M+H] +。
第七步：将化合物26g(148mg,340umol)溶于二氯甲烷(5mL)，在0℃下加入4M盐酸(0.4mL)并搅拌过夜。TLC监测反应结束，直接旋干，得到白色固体26h(84mg,收率86％)。ESI-MS(m/z):284.4[M+H] +。
第八步：将化合物26h(30mg,118umol)，化合物1i(35mg,142umol)和一水对甲苯磺酸(2mg,11.8umol)溶解在正丁醇(3mL)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26(14mg,收率25％)。ESI-MS(m/z):464.5[M+H] +； 1H NMR(500MHz,DMSO-d6)δ8.34(s,1H),6.87(d,J＝6.9Hz,1H),5.19-5.08(m,1H),4.52-4.41(m,1H),4.12(q,J＝6.9Hz,1H),4.08-3.99(m,1H),3.29-3.24(m,2H),2.95(s,3H),2.58-2.41(m,9H),2.00-1.90(m,1H),1.86-1.73(m,1H),1.23(d,J＝6.8Hz,3H)。
根据以上实施例描述的合成路线和中间体的合成方法，可以得到以下实施例。
Figure PCTCN2022107727-appb-000061
Figure PCTCN2022107727-appb-000062
Wnt通路抑制剂生物学筛选和结果
试验例1：Colo205-LUC-TCF/LEF-M1报告细胞系的构建
Colo205细胞系(中科院细胞库,Cat#TCHu102)购买于中科院细胞库，扩增传代培养后，于细胞的指数生长期，以lipo3000脂质体转染的方法，转染带有TCF/LEF转录因子驱动的萤光素酶报告质粒(Promega)。该质粒带有抗性基因，可以进行抗性筛选。转染在10cm培养皿中进行，使用无抗性的常规完全培养基。2天后，更换带有抗性的培养基，继续培养。之后每2天更换抗性培养基，并将悬浮细胞丢弃，原始培养基离心去除细胞和碎片后保留，作为适应性培养基。当细胞长满培养皿后，将细胞消化下来，计数，传代于96孔板，使每孔中含有的细胞数量平均为1.5个/孔，传代时使用适应培养基。其余细胞进行冻存。传代后培养4小时，让细胞贴壁，然后在显微镜下观察各孔的细胞数量。每孔仅1个细胞的孔进行标记，其为单克隆孔。而后正常培养，每2天更换培养基，并进行观察。前期单克隆细胞有继续生长的孔，进行2次标记，可更换为正常的带抗性培养基。当有单克隆孔中的细胞长满96孔板板孔时，将其消化传代到24孔培养板， 24孔板长满后，传代到1个96孔板和1个6孔板，其中96孔板细胞传代到至少6孔，其中3孔加入已知的Wnt抑制剂，另外3孔不作处理。24h后，96孔板细胞加入萤光检测试剂，检测萤光强度。选择其中不处理时有萤光表达，且抑制后萤之光降低的细胞系，进一步培养。Colo205-LUC-TCF/LEF-M1细胞系为上述筛选出的细胞系之一，其生长曲线、细胞形态、细胞生长状态与原始Colo205细胞相似，且其加抑制剂处理和不处理的萤光信号之比在所有细胞系中属于较大的，比值在4h时抑制可达4-5倍，完全适用于后期的Wnt抑制剂的筛选。
试验例2：化合物对Colo205-LUC-TCF/LEF M1报告细胞系抑制能力的检测
Colo205-LUC-TCF/LEF M1细胞株为稳定转染pGL4.49-LUC2-TCF/LEF载体的报告工具细胞，其β-catenin Wnt通路持续激活，加入抑制剂后，Wnt通路被抑制，载体上TCF/LEF顺式元件调控的萤火虫萤光素酶表达量下降，后续加入检测底物后，检测到的光信号相应下降，从而检测出化合物的抑制效果。
向96孔细胞培养板的每孔中加入100μL，最高浓度20μM的化合物，化合物浓度做3倍梯度稀释。然后向各孔中接种10000个稳定转染过报告基因的colo205细胞和100μL培养基，同时进行相应的处理作为阳性、阴性对照孔。将细胞放入5％CO 2细胞培养箱，37℃培养4h，4小时后，去除培养液，向各孔添加含相应的萤火虫荧光素酶底物的试剂(Promega)100μL，测定荧光素酶报告基因的活性。用SpectraMax在全波长模式下读取发光强度。仅由DMSO处理的细胞的光信号强度为阳性对照，无细胞孔的光信号强度为阴性对照，计算各化合物的IC 50的浓度。Colo 205报告基因检测数据汇总于下表1。
表1化合物对Colo205-LUC-TCF/LEF报告基因抑制的IC 50值
Figure PCTCN2022107727-appb-000063
Figure PCTCN2022107727-appb-000064
试验例3：化合物对Wnt突变细胞株(Colo205、DU4475、NCI-H929和HepG2)和非Wnt突变细胞株(Hela和RKO)的增殖抑制试验
试验中使用的细胞株为Wnt通路持续激活的，且其增殖为Wnt通路依赖型的Colo205、DU4475、NCI-H929和HepG2细胞系；而正常情况下Wnt通路不激活，且增殖不依赖于Wnt通路的HELA和RKO细胞系作为对照细胞系，判断本发明的化合物对于Wnt依赖的增殖的抑制作用不是由于其它非特异毒性造成的。
将培养于各自培养基中的Colo205、Du4475、NCI-H929、HepG2、HELA和RKO细胞株在对数生长期时处理，收集细胞后制备成已知浓度的均匀的细胞悬液，然后向96孔细胞培养板中加入细胞悬液，使每孔中含有1000个细胞。放入5％CO 2胞培养箱，37℃培养20-24h。第二天向各细胞培养孔中加入已经完全溶解的，3倍梯度稀释的化合物，使细胞培养孔中的最终最高浓度为20μM，继续培养96h。本试验使用Promega的细胞活性检测试验进行检测，细胞增殖越多，则最终的信号强度越强。检测仪器为SpectraMax，全波长模式。仅加入DMSO的孔作为阳性对照孔，未接种细胞的孔为阴性对照孔，计算各化合物对于Wnt持续激活或增殖依赖的细胞的增殖抑制的IC 50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IC 50值，评估化合物对于Wnt通路的抑制作用和对于正常细胞的毒性作用。结果如下表2所示。
表2化合物对Wnt突变细胞株的增殖抑制的IC 50值
Figure PCTCN2022107727-appb-000065
27 378.5 NT NT 460.15 NT >10000
28 88.91 NT NT 120.27 NT >10000
29 355.77 NT 1027.91 746.64 NT >10000
30 271.79 NT 431.55 340.16 NT >10000
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且选择性的Wnt通路抑制作用。

Claims (20)

  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：
    Figure PCTCN2022107727-appb-100001
    其中：
    Figure PCTCN2022107727-appb-100002
    表示单键的存在或者不存在；
    R 1表示C 1-C 6烷基、C 3-C 6环烷基、3-6元杂环烷基、C 6-C 10芳基、5-10元杂芳基，并且所述的R1可以任意地被0、1、2、3个选自：氢、卤素、OR a、硝基、(C 1-C 6)烷基、(C 1-C 6)烷氧基、(C 1-C 6)卤代烷基、(C 3-C 6)环烷基、卤代(C 3-C 6)环烷基、3-6元杂环烷基、卤代3-6元杂环烷基、C 6-C 10芳基、5-10元杂芳基、氰基、SR a、卤代(C 1-C 6)烷氧基、卤代(C 3-C 6)环烷氧基、卤代(C 1-C 6)烷基硫基、(C 3-C 6)环烷基氧基、(C 3-C 6)环烷基硫基、卤代(C 3-C 6)环烷硫基的取代基所取代；
    X表示共价键或者-(CR aR a’) m-、-(CR aR a’) m-O-(CR aR a’) n-、-(CR aR a’) m-N(R b)-(CR aR a’) n-、-(CR aR a’) m-S-(CR aR a’) n-、-(CR aR a’) mC(O)(CR aR a’) n-、-(CR aR a’) mS(O) 2(CR aR a’) n-、-(CR aR a’) mC(O)N(R b)(CR aR a’) n-、-(CR aR a’) mS(O) 2N(R b)(CR aR a’) n-、-(CR aR a’) mN(R b)C(O)(CR aR a’) n-、-(CR aR a’) mN(R b)S(O) 2(CR aR a’) n-、-(CR aR a’) mOC(O)N(R b)(CR aR a’) n-、-(CR aR a’) mN(R b)C(O)O(CR aR a’) n-、-(CR aR a’) mN(R b)C(O)N(R b’)(CR aR a’) n-、-(CR aR a’) mN(R b)S(O) 2N(R b’)(CR aR a’) n-；
    Cy表示C 3-C 5环烷基或者4-5元环杂烷基，并且其可以任意地被0、1或2个选自氢、卤素、-OR a、(C 1-C 6)烷基、(C 1-C 6)卤代烷基、(C 3-C 6)环烷基、氰基和羟基(C 1-C 6)烷基的取代基所取代；
    R 2表示氢、(C 1-C 6)烷基、(C 1-C 6)卤代烷基、(C 3-C 6)环烷基或羟基(C 1-C 6)烷 基；
    R 3和R 3’各自独立地表示氢，卤素、OR a、(C 1-C 6)烷基、(C 3-C 6)环烷基、羟基C 1-C 6烷基或(C 1-C 6)烷氧基(C 1-C 6)烷基；
    或者R 3和R 3’一起与与之相连的碳原子形成3-6元饱和或者不饱和的环，该环中还可以任意地含有1或2个选自O、S和N的杂原子，并且该环还可以任意地被0、1或2个选自卤素、羟基和C 1-C 6烷基的取代基所取代；
    或者R 2、R 3或者R 2、R 3’一起与与其相连的原子形成4-6元饱和或者不饱和的环，该环中还可以任意地含有1或2个选自O、S和N的杂原子，并且该环还可以任意地被0、1或2个选自卤素、羟基和C 1-C 6烷基的取代基所取代；
    R 4和R 4’各自独立地表示氢、C 1-C 6烷基、C 3-C 6环烷基、羟基C 1-C 6烷基、卤代C 1-C 6烷基、(C 1-C 6)烷氧基(C 1-C 6)烷基；
    或者R 4与R 4’一起形成＝O；
    R T和R T’各自独立地表示氢、C 1-C 6烷基、C 1-C 6卤代烷基、羟基C 1-C 6烷基、C 3-C 6环烷基、卤素、OR a；
    或者R T和R T’一起与与其相连的原子形成3-6元环；
    其中，当
    Figure PCTCN2022107727-appb-100003
    表示单键不存在时，A表示(CR LR L’) p，其中R L和R L’各自独立地表示氢、C 1-C 6烷基、C 1-C 6卤代烷基、羟基C 1-C 6烷基、C 3-C 6环烷基、卤素、OR a，或者R L和R L’一起与与其相连的碳原子形成3-6元环，该环中可以任意地含有0、1或2个选自O、S和N的杂原子，并且该环还可以任意地被0、1或2个选自卤素和羟基的取代基所取代；
    其中，当
    Figure PCTCN2022107727-appb-100004
    表示单键存在时，A表示CR H，其中，R H表示氢、C 1-C 6烷基、C 1-C 6卤代烷基、羟基C 1-C 6烷基、C 3-C 6环烷基、卤素、OR a；
    其中，R a、R a’、R b、R b’各自独立地表示氢或C 1-C 6烷基；
    其中m、n、p各自独立地表示0、1或2。
  2. 如权利要求1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，具有以下式(II)结构：
    Figure PCTCN2022107727-appb-100005
    其中R 1、R 2、R 3、R 3’、R 4、R 4’、X、Cy具有如权利要求1中的定义。
  3. 如权利要求1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，具有以下式(III)结构：
    Figure PCTCN2022107727-appb-100006
    其中R 1、R 2、R 3、R 3’、R 4、R 4’、R T、R T’、R L、R L’、X、Cy具有如权利要求1中的定义。
  4. 如权利要求1-3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，其中，R 2表示氢、C 1-C 6烷基、羟基(C 1-C 6烷基)或C 3-C 6环烷基。
  5. 如权利要求1-4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，其中，R 3，R 3’各自独立地表示氢、C 1-C 6烷基或羟基(C 1-C 6烷基)。
  6. 如权利要求1-5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，其中，R 4，R 4’各自独立地表示氢、C 1-C 6烷基、C 3-C 6环烷基，或者R 4与R 4’一起形成＝O。
  7. 如权利要求1-6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，其中Cy表示C 3-C 5环烷基或者4-5元环杂烷基，优选地，Cy表示
    Figure PCTCN2022107727-appb-100007
  8. 如权利要求1-7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，其中X表示共价键或者-(CR aR a’) m-、-(CR aR a’) m-O-(CR aR a’) n-、-(CR aR a’) m-N(R b)-(CR aR a’) n-、-(CR aR a’) m-S-(CR aR a’) n-、-(CR aR a’) mC(O)N(R b)(CR aR a’) n-、-(CR aR a’) mS(O) 2N(R b)(CR aR a’) n-、-(CR aR a’) mN(R b)C(O)(CR aR a’) n-、-(CR aR a’) mN(R b)S(O) 2(CR aR a’) n-、-(CR aR a’) mOC(O)N(R b)(CR aR a’) n-、-(CR aR a’) mN(R b)C(O)O(CR aR a’) n-、-(CR aR a’) mN(R b)C(O)N(R b’)(CR aR a’) n-、-(CR aR a’) mN(R b)S(O) 2N(R b’)(CR aR a’) n-。
  9. 如权利要求8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，其中，X表示-O-，-NR b-、-CR aR a’-、-OCR aR a’-、-CR aR a’O-、-C(O)-、-C(O)NR b-、-NR bC(O)-、-NR b-C(O)-NR b-、-CR aR a’-C(O)NR b-、-CR aR a’-NR bC(O)-、-S-、-NR bS(O) 2-、-SO 2NR b、-OC(O)NR b-、-S(O) 2、-C(O)NR b-、-C(O)CR aR a’-、-CR aR a’C(O)NR b-、-NR bC(O)CR aR a’-、-NR bC(O)O-；其中R a、R a’、R b各自独立地表示氢或者C 1-C 6烷基。
  10. 如权利要求9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，其中，X表示-(CR aR a’) m-O-(CR aR a’) n-，优选为-O-，-OCR aR a’-、-CR aR a’O-，更优选为-O-或者-O-CH 2-。
  11. 如权利要求1-10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，其中，R T和R T’表示氢。
  12. 如权利要求1-11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，其中R L和R L’表示氢。
  13. 如权利要求1-12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，其中R H表示氢。
  14. 如权利要求1-13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，其中，R 1表示被0、1、2或3个取代基取代的C 3-C 6环烷基、3-6元杂环烷基、C 6-C 10芳基、5-10元杂芳基，其中所述取代基选自卤素、(C 1-C 6)烷基、(C 1-C 6)卤代烷基、(C 3-C 6)环烷基、卤代(C 3-C 6)环烷基、3-6元杂环烷基、卤代3-6元杂环烷基、C 6-C 10芳基和5-10元杂芳基。
  15. 如权利要求14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，其中，R 1表示C 3-C 6环烷基、3-6元杂环烷基、C 6-C 10芳基、5-10元杂芳基，并且所述的R 1可以任意地被0、1、2、3个选自：氢、卤素、(C 1-C 6)烷基、(C 1-C 6)卤代烷基、(C 3-C 6)环烷基、卤代(C 3-C 6)环烷基的取代基所取代。
  16. 如权利要求14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，其中，R 1选自：
    Figure PCTCN2022107727-appb-100008
  17. 如权利要求15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，其中，R 1选自：
    Figure PCTCN2022107727-appb-100009
  18. 化合物，其具有以下结构：
    Figure PCTCN2022107727-appb-100010
    Figure PCTCN2022107727-appb-100011
    Figure PCTCN2022107727-appb-100012
    Figure PCTCN2022107727-appb-100013
    Figure PCTCN2022107727-appb-100014
    Figure PCTCN2022107727-appb-100015
    Figure PCTCN2022107727-appb-100016
  19. 药物组合物，包括权利要求1-18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。
  20. 权利要求1-18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、立体异构体以及权利要求19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。
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