WO2023236927A1 - 4-羰基氨基异吲哚啉-1,3-二酮类化合物及其制备方法、药物组合及用途 - Google Patents

4-羰基氨基异吲哚啉-1,3-二酮类化合物及其制备方法、药物组合及用途 Download PDF

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WO2023236927A1
WO2023236927A1 PCT/CN2023/098491 CN2023098491W WO2023236927A1 WO 2023236927 A1 WO2023236927 A1 WO 2023236927A1 CN 2023098491 W CN2023098491 W CN 2023098491W WO 2023236927 A1 WO2023236927 A1 WO 2023236927A1
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formula
acid
optionally
alkylene
group
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PCT/CN2023/098491
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English (en)
French (fr)
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高清志
刘胜男
韩建斌
张顺杰
张祥瑞
刘阳
张婷婷
李扬
朱晓玲
高香倩
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天津谷堆生物医药科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention provides a 4-carbonylaminoisoindoline-1,3-dione compound, its preparation method, a pharmaceutical composition containing the same and its use.
  • MM Multiple myeloma
  • Cockayne syndrome is a malignant tumor with abnormal proliferation of plasma cells. It is the second most common blood system disease in many countries. It is still incurable, and the 5-year relative survival rate is only about 40%.
  • the common symptoms of MM are "CRAB", which is related manifestations such as elevated blood calcium (calcium elevation), renal insuficiency, anemia, bone disease, and secondary amyloidosis.
  • PIs Proteasome inhibitors
  • IiDs immunomodulatory drugs
  • Pomalidomide (trade name POMALYST) is the third generation of IMiDs after thalidomide and lenalidomide. Its strength is approximately 100 times that of thalidomide and 10 times that of lenalidomide. The mechanism of action of pomalidomide has not been fully elucidated.
  • CRBN has been shown to be a direct target of pomalidomide. After pomalidomide binds to CRBN, it changes the substrate specificity of CRBN, resulting in the recruitment of IKZF1 and IKZF3 to the CRBN-coupled E3 protein ligase, which is ubiquitin-conjugated.
  • IKZF1/3 downregulation can further induce the downregulation of IRF4 and MYC, which are two important proteins for myeloma proliferation and survival.
  • Pomalidomide can also have direct anti-proliferative and pro-apoptotic effects on plasma cells, and has anti-angiogenic, anti-inflammatory and immunomodulatory effects (increased T and NK cell activity, inhibited regulatory T cells), therefore, pomalidomide Maldomide exerts its antitumor activity through a pleiotropic mechanism of action. In patients with RRMM (relapsed/refractory MM), pomalidomide induced durable remission for 12 months, a population that previously had a median survival of 9 months and a progression-free survival (PFS) of only 5 months.
  • PFS progression-free survival
  • pomalidomide plus low-dose dexamethasone was effective in patients with advanced disease refractory to lenalidomide, bortezomib, or both.
  • pomalidomide was approved for the treatment of Kaposi's sarcoma in 2020, further expanding its application scope.
  • L-type amino acid transfer (LAT1) protein will increase significantly.
  • the LAT1 inhibitor JPH-203 can cause the death of IMiDs-sensitive and drug-resistant MM cell lines (Reference: The IMiD target CRBN determines HSP90 activity toward transmembrane proteins essential in multiple myeloma. Molecular Cell (2021).), which shows that LAT1 It deserves to be used as a therapeutic target for IMiDs-resistant/refractory MM patients.
  • pomalidomide is a poorly soluble drug. Its solubility in purified water, pH 6.8 phosphate buffer, pH 4.5 acetate buffer and 0.1mol/L hydrochloric acid was measured, and the results were 17.8, 17.0, 18.7 and 18.9 ⁇ g/mL respectively.
  • the low solubility of pomalidomide not only increases the difficulty of the formulation process, but also limits the dissolution and absorption process of the active ingredients in the gastrointestinal tract, thereby affecting oral bioavailability.
  • the present invention aims to provide a 4-carbonylaminoisoindoline-1,3-dione compound having the structure shown in the following formula (I), or its optical isomer, or its pharmaceutically acceptable salt , or its solvate (such as hydrate), or its clathrate, or its racemate, or its isotope label, or its nitrogen oxide.
  • the present invention also relates to preparation methods, pharmaceutical combinations and uses of such compounds in medicaments for treating, preventing or managing multiple myeloma.
  • A is selected from -O-, -S-, or -NH-;
  • Q is selected from optionally substituted alkylene, or alkylene arylene
  • R 1 is selected from -H, alkyl, -C(O)R 4 , -C(S)R 4 , -C(O)OR 4 , -C(O)NHR 4 , -C(O)NR 4 R 4 ';
  • R 2 is selected from -H, optionally substituted alkyl, alkenyl, alkenyl alkylene, alkynyl, alkynyl alkylene, aromatic base, arylalkylene, heteroaryl, heteroarylalkylene;
  • R 3 is selected from H, hydroxyl, alkyl, alkenyl, alkenylalkylene, alkynyl, alkynylalkylene, arylalkylene, heteroarylalkylene, alkylene-OC(O) R 4 , alkylene-OC(O)OR 4 , alkylene-OC(O)NHR 4 , alkylene-OC(O)NR 4 R 4 ', or -OR 4 ;
  • Each R 4 and R 4 ' are the same or different, and each is independently selected from hydrogen, alkyl, alkenyl, alkenyl alkylene, alkynyl, alkynyl alkylene, optionally substituted aryl, optionally substituted Heteroaryl, optionally substituted alicyclic, optionally substituted alicyclic, optionally substituted arylalkylene or optionally substituted heteroarylalkylene; or R 4 and R 4 ′ form optionally substituted 3-7 membered ring;
  • the “optionally substituted” refers to being substituted by one or more substituents, wherein the "optionally substituted alkylene group”, “optionally substituted alicyclic group”, “optionally substituted alicyclic heterocyclic group”
  • substituents of “base”, “optionally substituted aryl” and “optionally substituted heteroaryl”, “optionally substituted arylalkylene” and “optionally substituted heteroarylalkylene” Independently selected from hydroxyl, amino, carboxyl, halogen, nitro, cyano, alkyl, alkoxy, aryl, heteroaryl, arylalkyl, heteroarylalkyl, aryloxy, heteroaryl Alkoxy, cycloalkyl, alicyclic, cycloalkyloxy, heterocycloalkyloxy, arylalkoxy, heteroarylalkoxy, alkanoyloxy, alkanoyloxymethyl , alkoxyacyloxy or alkoxyacyl.
  • alkyl is each independently a C 1-20 linear or branched alkyl group, optionally, a C 1-17 linear or branched alkyl group, optionally, It is a C 1-10 linear or branched alkyl group, optionally, it is a C 1-8 linear or branched alkyl group, optionally, it is a C 1-6 linear or branched alkyl group, optionally , is C 1-4 linear or branched alkyl, optionally methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n- Pentyl, isopentyl, neopentyl, tert
  • alkylene is each independently a C 1-20 linear or branched alkylene group, optionally, a C 1-17 linear or branched alkylene group, which can be Alternatively, it is a C 1-10 linear or branched alkylene group, optionally, it is a C 1-8 linear or branched alkylene group, optionally, it is a C 1-6 linear or branched alkylene group.
  • Alkyl group optionally, is C 1-3 linear or branched alkylene group, optionally, is methylene, ethylene, n-propylene, isopropylene, methylene n-butyl, isobutylene, tert-butylene, sec-butylene, n-pentylene, isopentylene, neopentylene, tert-pentylene, n-hexylene, isohexylene, heptylene , n-octylene, n-nonylene, n-decylene, undecylene, dodecylene, tridecylene, tetradecylene, pentadecylene or hexadecylene base;
  • the cycloalkyl part in the "cycloalkyloxy" and “cycloalkyl” is C 3-8 cycloalkyl, optionally, it is cyclopropyl, cyclobutyl, or cyclopentyl or cyclohexyl;
  • alkenyl part in the "alkenyl” and “alkenyl alkylene” is each independently a C 2 -C 20 linear or branched alkenyl group containing one or more double bonds, optionally, C 2 -C 15 linear or branched alkenyl, optionally, C 2 -C 10 linear or branched alkenyl, optionally, C 2 -C 8 linear or branched alkenyl, optional Ground, is a C 2 -C 6 linear or branched alkenyl group, optionally, is a C 2 -C 4 linear or branched alkenyl group;
  • alkynyl part in the "alkynyl” and “alkynyl alkylene” is each independently a C 2 -C 20 linear or branched alkynyl group containing one or more triple bonds, optionally, C 2 -C 15 straight chain or branched chain alkynyl, optionally, C 2 -C 10 straight chain or branched chain alkynyl, optionally, C 2 -C 8 straight chain or branched chain alkynyl, optional Ground, is a C 2 -C 6 straight chain or branched chain alkynyl group, optionally, is a C 2 -C 4 straight chain or branched chain alkynyl group;
  • exemplary alkenyl and alkynyl groups include, but are not limited to, ethylene, propylene, butene, pentene, acetylene, and hexyne.
  • the heterocyclic group in the "aliphatic heterocyclic group” and “heterocycloalkyloxy group” contains 1-3 heteroatoms selected from O, N, S, SO or SO 2 on the ring.
  • C 3-8 (preferably C 4-6 ) alicyclic group, optionally, oxiranyl, thiiranyl, aziridinyl, oxetanyl, thiocyclic group Butyl, azetidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydropyrrolyl, morpholinyl, piperidinyl, or piperazinyl;
  • aryl group in the "aryl”, “arylalkylene”, “arylalkoxy”, and “aryloxy” is a 6-10 membered monocyclic or bicyclic fused aromatic ring Group; optionally phenyl or naphthyl;
  • the arylene group in the "alkylene arylene group” is a 6-10 membered monocyclic or bicyclic fused aromatic ring group; optionally, it is a phenylene group or a naphthylene group;
  • R2 is selected from -H, methyl, ethyl, tert-butyl, allyl, propargyl or benzyl.
  • R 3 is selected from -H, -OH,
  • amino acid moiety of the compound of formula (I) is in D configuration or L configuration.
  • the present invention is a pharmaceutical composition, which includes the compound of the above formula (I), or its optical isomer, or its pharmaceutically acceptable salt, or its solvate (such as hydrate), or its package. compound, or its racemate, or its isotope label, or its nitrogen oxide, and pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients are selected from: fillers, disintegrants, lubricants, glidants, effervescent agents, flavoring agents, preservatives, coating materials or other excipients.
  • the fillers of the pharmaceutically acceptable excipients include lactose, sucrose, dextrin, and starch. powder, pregelatinized starch, mannitol, sorbitol, calcium hydrogen phosphate, calcium sulfate, calcium carbonate, microcrystalline cellulose;
  • the binder includes sucrose, starch, polyvitamin One or more combinations of ketone, sodium carboxymethylcellulose, hypromellose, hydroxypropylcellulose, methylcellulose, polyethylene glycol, medicinal ethanol, and water;
  • the disintegration The agent includes one or more combinations of starch, crospovidone, croscarmellose sodium, low-substituted hydroxypropylcellulose, carboxymethylcellulose sodium, and effervescent disintegrant.
  • the administration mode of the pharmaceutical composition includes: oral administration (for example, buccal cavity), sublingual administration, parenteral administration (for example, intramuscular, intravenous or subcutaneous), rectal administration (for example, by suppository or lotion), transdermally (e.g., skin electroporation), or by inhalation (e.g., aerosol), and in solid, liquid, or gaseous dosage forms, including tablets and suspensions Medication administration, etc.
  • Administration may be given as a single unit dose under continuous treatment, or as an ad hoc single dose treatment.
  • Therapeutic compositions may also be in the form of oil emulsions or dispersions, combined with lipophilic salts such as pamoic acid, or biodegradable sustained release compositions for subcutaneous or intramuscular administration.
  • the pharmaceutical composition can be made into solid oral preparations, liquid oral preparations, injections and other dosage forms.
  • the solid and liquid oral preparations include: tablets, dispersible tablets, sugar-coated agents, granules, dry powders, capsules, syrups and solutions.
  • the injections include: small injections, large infusions, freeze-dried powder injections, etc.
  • the present invention provides a compound of the above formula (I), or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof (such as a hydrate), or a clathrate thereof, or Its racemate, or its isotope label, or its nitrogen oxide, or the use of the above pharmaceutical composition in the preparation of drugs for preventing and/or treating hematological diseases; preferably, the disease is selected from blood cancer and bone marrow cancer, acute leukemia, chronic leukemia, lymphoma, Kaposi's sarcoma, multiple myeloma, or myelodysplastic syndrome.
  • the compounds provided by the present invention can be used to treat, prevent or manage primary or metastatic tumors.
  • the present invention also provides a compound of the above formula (I) or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof (such as a hydrate), or a clathrate thereof, or Preparation method of its racemate, its isotope label, or its nitrogen oxide intermediate:
  • Step A Prepare formula (C) by substitution reaction of formula (A) and formula (B);
  • formula (C) can be prepared by substitution reaction between formula (A) and formula (B) under base catalysis, in a suitable solvent, and at a suitable temperature.
  • the base is potassium carbonate, or cesium carbonate, or sodium hydride, or lithium bistrimethylsilylamide, etc.
  • the solvent is N,N-dimethylformamide, or N,N- Second Class Acetamide, or dimethyl sulfoxide, or N-methylpyrrolidone, etc.; optionally, the temperature is 0°C to 25°C.
  • R 3 in formula (B) and formula (C) is as described in formula (I), but cannot be H, OR 4 ;
  • B is selected from Cl, Br, I, OTs, OMs;
  • the compound of formula (B) can adopt one of the following (but not limited to) methods 1-8:
  • Each Y is selected from -R 4 , -OR 4 , -NHR 4 , NR 4 R 4 ', wherein R 4 and R 4 ' are as described in formula (I).
  • formula (C) can be obtained through the reaction of the following step A':
  • Step A' S1 and S2 are subjected to condensation conditions to obtain S3, and then S3 is deprotected to obtain S4, and then S4 and S5 are ammonolyzed under the catalysis of Lewis base to obtain S6 and are reduced with iron powder to obtain R 3 selected from OR 4 Compounds of formula (C);
  • Step B Perform acylation reaction between formula (C) and formula (D) to obtain formula (E).
  • formula (C) and formula (D) are dissolved in a solvent and reacted under heating conditions to obtain formula (E); optionally, the solvent is tetrahydrofuran, or N,N-dimethylformamide, Or N-methylpyrrolidone, or 2-methyltetrahydrofuran; optionally, the temperature is 45°C-90°C.
  • Step C Prepare formula (G) by acylation reaction of formula (C) and formula (F);
  • the synthesis method of formula (G) react formula (C) and formula (F) in an appropriate solvent. After the reaction is completed, concentrate under reduced pressure to obtain formula (G); optionally, the solvent is dichloro Methane, acetonitrile, tetrahydrofuran, etc.; optionally, the temperature is -20°C to 50°C.
  • Step D Condensation reaction of formula (C) and formula (H) to obtain formula (J);
  • formula (C) and formula (H) are dispersed in an appropriate solvent, reacted under heating conditions, and after the reaction is completed, directly spin to dryness to obtain formula (J);
  • the solvent is dichloromethane, Or acetonitrile, or tetrahydrofuran, or dichloroethane, etc.; optionally, the temperature is 45°C-90°C.
  • the synthesis method of formula (I) react formula (E or G or J) with formula (L) in an appropriate solvent, wait until the reaction is completed, and concentrate under reduced pressure to obtain formula (I); optionally,
  • the solvent is selected from dichloromethane, acetonitrile, N,N-dimethylformamide or tetrahydrofuran; optionally, the temperature is -20°C to 50°C.
  • C is selected from any one of -OH, -SH and -NH 2 groups;
  • R 5 is Cl
  • R 2 is H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 2 CH 3 , - CH(CH 3 ) 2 , -CH 2 CH 2 OH, or -CH 2 CHOHCH 2 OH, optionally deprotected using the following method:
  • Disperse formula (M) in a suitable solvent then deprotect, separate out the solid, and filter to obtain formula (N) in the form of a salt
  • the solvent is ethyl acetate, dioxane, or dichloro Methane, or dichloroethane, etc.
  • the acid used for deprotection is hydrogen chloride, or hydrogen bromide, or sulfuric acid, or trifluoroacetic acid, or nitric acid, or phosphoric acid, or methanesulfonic acid, or p-toluenesulfonic acid, etc.
  • the temperature is 0-50°C.
  • R 2 is H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 2 CH 3 , - CH(CH 3 ) 2 , -CH 2 CH 2 OH, or -CH 2 CHOHCH 2 OH,
  • R 1 is Cbz
  • R 2 is H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 2 CH 3 , - CH(CH 3 ) 2 , -CH 2 CH 2 OH, or -CH 2 CHOHCH 2 OH.
  • the free compound can also be obtained by dispersing the salt form of formula (N) in a suitable solvent (by adding an equivalent amount of a base); optionally, the solvent is methanol, ethanol, isopropyl alcohol, dioxane, etc.
  • the compound of formula (I) or its optical isomer, or its pharmaceutically acceptable salt, or its solvate, or its inclusion complex, or its racemate, or its isotope Markers, or their nitrogen oxides, or their pharmaceutical compositions are used in combination with one or more other pharmacologically active compounds ("second active compounds") for use in medicines for the prevention and/or treatment of hematological diseases or disorders. the use of.
  • second active compounds pharmacologically active compounds
  • the compounds provided by the present invention can be used to treat hematological diseases.
  • the diseases are selected from blood cancers and bone marrow cancers, such as multiple myeloma, and acute and chronic leukemias, such as lymphoblastic leukemia, chronic myelogenous leukemia, bone marrow leukemia, lymphocytic leukemia, myeloid leukemia, adult T-cell leukemia, Kaposi's sarcoma, nuclear acute myeloid leukemia, chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma, non-Hodgkin's lymphoma , cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, diffuse large B-cell tumor, low-grade follicular lymphoma.
  • the compounds provided by the invention can be used to treat, prevent or manage primary, metastatic, refractory or resistant tumors to chemotherapy or radiotherapy.
  • multiple myeloma refers to hematological diseases characterized by malignant plasma cells, including the following conditions: monoclonal gammopathy of undetermined significance (MGUS); low-risk, intermediate-risk and high-risk multiple myeloma ; Newly diagnosed multiple myeloma (including low-risk, intermediate-risk, and high-risk newly diagnosed multiple myeloma); transplant-eligible and transplant-ineligible multiple myeloma; smoldering (indolent) multiple myeloma (including Low-risk, intermediate-risk, and high-risk multiple myeloma); relapsed multiple myeloma; refractory and resistant multiple myeloma; active multiple myeloma; solitary plasmacytoma; extramedullary plasma Cytoma; plasma cell leukemia; central nervous system multiple myeloma; light chain myeloma; nonsecretory myeloma;
  • MGUS mono
  • the term “treating” or “treating” refers to alleviating or reducing the severity of symptoms associated with the disease or condition being treated, such as multiple myeloma.
  • the term “preventing” includes inhibiting the symptoms of a particular disease or condition, such as multiple myeloma.
  • the term “relapse” refers to a situation in which a patient whose multiple myeloma has gone into remission after treatment has a return of myeloma cells and/or a decrease in normal cells in the myeloma.
  • the terms “refractory and resistant” refer to situations in which a patient has residual myeloma cells and/or a decrease in normal cells in the bone marrow, even after intensive treatment.
  • the second active ingredient useful in the methods and compositions described herein can be a macromolecule (e.g., a protein), a small molecule (e.g., a synthetic inorganic, organometallic, or organic molecule), or a cell therapy (e.g., a CAR cell).
  • a macromolecule e.g., a protein
  • a small molecule e.g., a synthetic inorganic, organometallic, or organic molecule
  • a cell therapy e.g., a CAR cell
  • the second active ingredient include one or more of the following: melphalan, vincristine, cyclophosphamide, etoposide, doxorubicin, bendamustine, orbitaluzumab Antibodies, proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib, opozomib, or marezomib), histone deacetylase inhibitors (e.g., panobinostat, ACY241), BET inhibitors (such as GSK778).
  • proteasome inhibitors e.g., bortezomib, carfilzomib, ixazomib, opozomib, or marezomib
  • histone deacetylase inhibitors e.g., panobinostat, ACY241
  • BET inhibitors such as GSK778
  • the compounds of the present invention may exist in isotopically traced or enriched forms, containing one or more atoms having an atomic weight or mass number different from that of the largest number of atoms found in nature.
  • Isotopes may be radioactive or non-radioactive isotopes.
  • Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine and iodine include, but are not limited to: 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 32 P, 35 S, 18 F, 36 Cl and 125 I.
  • Compounds containing other isotopes of these and/or other atoms are within the scope of this invention.
  • optical isomers used in this article refers to substances with identical molecular structures and similar physical and chemical properties, but different optical rotations. Includes optically isomeric mixtures in any ratio.
  • the compounds of formula (I) may contain one or more asymmetric carbon atoms, and may exist in the form of optically pure enantiomers, such as enantiomeric mixtures of racemates, optically pure diastereoisomers isomers, diastereomeric mixtures, diastereomeric racemates, or diastereomeric racemate mixtures.
  • the optically active form can be obtained, for example, by resolution of the racemate, by asymmetric synthesis or asymmetric chromatography (chromatography using chiral adsorbents or eluents). The invention includes all such forms.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic acids, including inorganic acid salts and organic acid salts.
  • pharmaceutically acceptable non-toxic acids including inorganic acid salts and organic acid salts.
  • solvate refers to a compound that is further bound by non-covalent intermolecular forces to a stoichiometric or non-stoichiometric amount of a solvent.
  • the solvent is water
  • the solvate is a hydrate.
  • DIPEA N,N-diisopropylethylamine
  • LiHMDS lithium bistrimethylsilylamide
  • TBS tert-butyldimethylsilyl
  • RPMI-8226 human multiple myeloma cells
  • NCI-H929 human myeloma cells
  • Figure 1 shows the expression of LAT1 in different cells.
  • the synthesis method of formula (L) combine Boc-tyrosine (1.0 equivalent), cesium carbonate (0.5 equivalent) and iodoethane, or 1-iodobutane, or 1-iodohexane, or isopropyl Iodine, or TBS-protected hydroxyethyl iodide, or 4-(iodomethyl)-2,2-dimethyl-1,3-dioxolane (1.1 equivalent) was dispersed in DMF and stirred at room temperature overnight. Extraction and column chromatography yield the product formula (L).
  • formula (A) (1.0 equivalent), formula (B) (1.2 equivalent) (purchased or homemade) and cesium carbonate (1.2 equivalent) to DMF, and stir at 0°C to 25°C for 3 hours.
  • Disperse the above product in ethyl acetate and then pass in hydrogen chloride gas or methanesulfonic acid, sulfuric acid, phosphoric acid, etc. to perform deprotection reaction at room temperature. After the reaction is completed, filter, rinse with ethyl acetate and n-heptane, and dry at 50°C.
  • Dissolve S3 in DCM add trifluoroacetic acid at low temperature, stir at room temperature for 4 hours, and distill under reduced pressure to obtain light pink S4.
  • Disperse S4 (1.0 equivalent), S5 (1.0 equivalent) and sodium acetate (2.0 equivalent) in acetic acid add molecular sieves and stir at 90°C overnight, remove the molecular sieves by hot filtration, cool and precipitate a white solid, rinse with water and dry Dry to get S6.
  • the general synthesis method 2 is used to continue the reaction of formula (C) to obtain the final product.
  • the specific synthesis process is as follows: dissolve the product of Example 60 in methanol, add palladium on carbon, and react at room temperature in a hydrogen environment. After the reaction is completed, filter out the palladium on carbon, evaporate to dryness under reduced pressure, add ethyl acetate to disperse, filter, and rinse with ethyl acetate and n-heptane to obtain the hydrochloride product as a yellow solid with a yield of 83.41%.
  • the synthesis method was the same as in Example 61, and the hydrochloride was obtained as a yellow solid with a yield of 80.12%.
  • the synthesis method is the same as Example 61, and the hydrochloride is obtained as a yellow solid, with a yield of 52.73%.
  • Test 2 In vitro anti-tumor activity test
  • Collect MM.1S cells growing in the logarithmic phase adjust the concentration of cell suspension, and seed them in a 96-well plate at a density of 2 ⁇ 10 4 cells/well. After incubating for 2 hours at 37°C in a 5% CO2 incubator, add Compounds at final concentrations of 50, 10, 1, 0.1, 0.01, 0.001, 0.0005, 0.0001 and 0 ⁇ M, 3 duplicate wells of each compound, DMSO final concentration 0.5%, incubated at 37°C, 5% CO2 incubator 72h. After the incubation, add 20 ⁇ L of 5 mg/mL MTT solution into the cell wells.
  • the IC 50 value is less than 0.01 ⁇ M for A; the IC 50 value is greater than 0.01 ⁇ M and less than 0.05 ⁇ M for B; the IC 50 value is greater than 0.05 ⁇ M and less than 0.1 ⁇ M for C; the IC 50 value is greater than 0.1 ⁇ M and less than 0.5 ⁇ M for D.
  • Test method 293T cells (6 ⁇ 10 5 ) in the logarithmic growth phase were inoculated into a 6-well cell culture plate and cultured overnight in a cell culture incubator. Use PEI reagent to transfect the constructed LAT1-pQCXIP plasmid fused with protein C tag into cells. Place it in a cell culture incubator for 6 hours, discard the supernatant, and add 2 ml of complete culture medium to continue culturing; 48 hours after transfection, observe the expression of green fluorescent protein under a fluorescence microscope, and use puromycin at concentrations of 8 ⁇ g/mL and 5 ⁇ g/mL. After 13 days of screening, 293T cells stably and highly expressing LAT1 were obtained.
  • 293T and LAT1-293T steady-state cell lines were used to conduct this experimental study.
  • the cells were spread evenly into a 6cm culture dish. When the cells were full the next day, 293T and LAT1-293T cells were collected using trypsin digestion.
  • the cells were resuspended in PBS and pre-incubated at 37°C for 2 hours. Adjust the cell concentration to 1 ⁇ 10 7 cells/ml with physiological saline, and dispense into 1.5 mL centrifuge tubes, 200 ⁇ L/tube.
  • Test results As shown in Table 3, the content of the compounds provided by the present invention in the lysate of 293T cells that highly express LAT1 is significantly higher than that of ordinary 293T cells, indicating that these compounds have significant LAT1 targeting. Table 3. Absorption of compounds of the present invention in 293T cells and 293T-LAT1 cells
  • Model preparation 6-8 weeks old NOD/SCID female mice were used, and the experimental animals were purchased from Beijing Vitong Lever Experimental Animal Technology Co., Ltd. Animals were housed in an IVC system in an SPF-grade environment. All experimental animals had free access to food and water, and the room temperature was 20-25°C, the temperature was 40-70%, and the day-night light-dark alternation time was 12h/12h. Human multiple myeloma RPMI-8226 cells were cultured in 1640 culture medium containing 10% fetal calf serum.
  • RPMI-8226 cells Collect RPMI-8226 cells in the exponential growth phase, resuspend them in 1640 culture medium to 1 ⁇ 10 8 cells/mL, add an equal volume of Matrigel, and inoculate 0.2 mL/mouse subcutaneously into the axilla of the mouse to establish tumor-bearing nude mice.
  • Model. When the tumors grow to 150-300mm3 , mice are randomly divided into groups for administration according to tumor size and body weight. The formula for calculating tumor volume is: long diameter ⁇ short diameter Diameter 2/2 .
  • Grouped administration This trial is divided into 7 groups, namely, physiological saline group, compound 06 administration group, compound 11 administration group, compound 24 administration group, compound 29 administration group, compound 101 administration group, poma There are 7 animals in each group administered with doxorubicin. Oral administration, once a day, the dose of pomalidomide is 15 mg per kilogram of body weight, other drugs are at equimolar concentrations compared with lenalidomide, the administration volume is 10 mL/kg, and the dose is continuous for 14 After 5 days, the drug was stopped and observed for 5 days. The tumor diameter was measured twice a week to observe the anti-tumor effect of the test drug and the changes in the animal's weight.
  • Test results The results are shown in Table 4 and Figure 2. Compared with the clinical control drug pomalidomide, the compound of the present invention has a superior tumor inhibitory effect, which fully demonstrates the selection of the compound of the present invention in tumor cells and tumor tissues. sexual accumulation and targeting.
  • weight change rate (%) (body weight on the day of measurement - initial weight of the experiment)/initial weight of the experiment ⁇ 100%.
  • Test 5 In vivo anti-tumor efficacy test II
  • Model preparation Human multiple myeloma NCI-H929 cells were cultured in 1640 culture medium containing 10% fetal calf serum. Collect NCI-H929 cells in the exponential growth phase, resuspend them in 1640 culture medium to 5 ⁇ 10 7 cells/mL, add an equal volume of Matrigel, and inoculate 0.2 mL/mouse subcutaneously into the axilla of the mouse to establish tumor-bearing nude mice. Model. When the tumors grow to 150-300mm3 , mice are randomly divided into groups for administration according to tumor size and body weight. tumor The volume calculation formula is: long diameter ⁇ short diameter 2 /2.
  • Group administration This test is divided into 7 groups, namely, physiological saline group, compound 06 administration group, compound 11 administration group, compound 24 administration group, compound 29 administration group, compound 101 administration group. drug group and pomalidomide administration group, with 7 animals in each group. Oral administration, once a day, the dose of pomalidomide is 10 mg per kilogram of body weight, other drugs are at equimolar concentrations compared with pomalidomide, the administration volume is 10 mL/kg, and the dose is continuous for 14 After 1 day, the drug was stopped and observed for 1 day. The tumor diameter was measured twice a week to observe the anti-tumor effect of the test drug and the changes in the animal's weight.
  • Test results The results are shown in Table 5 and Figure 3. Compared with the clinical control drug pomalidomide, the compound provided by the present invention has a superior tumor inhibitory effect, which fully demonstrates that the compound of the present invention has an inhibitory effect on tumor cells and tumor tissues. selective accumulation and targeting.
  • weight change rate (%) (body weight on the day of measurement - initial weight of the experiment)/initial weight of the experiment ⁇ 100%.

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Abstract

一种式(I)所示的4-羰基氨基异吲哚啉-1,3-二酮类化合物，或其光学异构体、或其药学上可接受的盐、或其溶剂化物(例如水合物)、或其包合物、或其消旋体、或其同位素标记物、或其氮氧化物；及它们的药物组合物和用途。该化合物具有良好的抗多发性骨髓瘤活性，能够有效治疗和/或预防多发性骨髓瘤的生长。

Description

4-羰基氨基异吲哚啉-1,3-二酮类化合物及其制备方法、药物组合及用途 技术领域
本发明提供一种4-羰基氨基异吲哚啉-1,3-二酮类化合物、其制备方法、包含其的药物组合物及用途。
背景技术
多发性骨髓瘤(Multiple myeloma，MM)是浆细胞异常增生的恶性肿瘤，在很多国家是第二大血液系统疾病，目前仍无法治愈，5年相对生存率仅为40％左右。MM常见的症状是“CRAB”，即血钙增高(calcium elevation)、肾功能损害(renal insuficiency)、贫血(anemia)、骨病(bone disease)，以及继发淀粉样变性等相关表现。在过去十几年中，MM的治疗取得了重大进展，蛋白酶体抑制剂(PIs)，如硼替佐米，以及免疫调节药物(IMiDs)，如沙利度胺或来那度胺，均常用于一线治疗。随着第二代PI(卡非佐米、艾沙佐米)、新型免疫调节药物(泊马度胺)、组蛋白去乙酰化酶抑制剂(帕比司他)、单克隆抗体(埃罗妥珠单抗和达雷妥尤单抗)以及其他组药物的应用，患者的长期生存率和生活质量得到了显著改善，MM的治疗前景变得既复杂又令人鼓舞。
泊马度胺(商品名POMALYST)是继沙利度胺、来那度胺之后的第三代IMiDs，其强度约为沙利度胺的100倍，来那度胺的10倍。泊马度胺的作用机制尚未完全阐明。CRBN已被证明是泊马度胺的直接靶标，泊马度胺与CRBN结合后，改变了CRBN的底物特异性，导致IKZF1和IKZF3被募集至CRBN偶联的E3蛋白连接酶，被泛素化并被蛋白酶体降解，IKZF1/3的下调进一步可诱导IRF4和MYC的下调，而IRF4和MYC是骨髓瘤增殖和存活的两个重要蛋白。泊马度胺还可以对浆细胞产生直接的抗增殖和促凋亡作用，并具有抗血管生成、抗炎以及免疫调节作用(增加T和NK细胞活性、抑制调节性T细胞)，因此，泊马度胺可通过多效性作用机制发挥其抗肿瘤活性。在RRMM(复发/难治性MM)患者中，泊马度胺可诱导12个月的持久缓解，此前，该人群的中位生存期为9个月，无进展生存期(PFS)仅为5个月。在几项II期研究中，泊马度胺加低剂量地塞米松对来那度胺、硼替佐米或两者都难以治疗的晚期疾病患者均有效。此外，泊马度胺在2020年被批准用于治疗卡波西肉瘤，进一步扩大了应用范围。
尽管可使用的治疗方案越来越多，但几乎所有MM患者最终都会复发。与IMiDs耐药性相关的最常见机制是CRBN的缺乏和突变。血液毒性、肺炎和疲劳是泊马度胺最常见的不良事件(参考文献：Dependence on glutamine uptake and glutamine addiction characterize myeloma cells:a new attractive target.Blood,(2016).)。随着MM疾病的进展，L型氨基酸转体(LAT1)蛋白表达水平会明显增高。而且LAT1的抑制剂JPH-203会导致IMiDs敏感和耐药的MM细胞株死亡(参考文献：The IMiD target CRBN determines HSP90 activity toward transmembrane proteins essential in multiple myeloma.Molecular Cell(2021).)，这表明LAT1值得被作为IMiDs耐药/难治性MM患者的治疗靶点。
此外，泊马度胺属于难溶性药物。测定其在纯化水，pH 6.8磷酸盐缓冲液，pH 4.5醋酸盐缓冲液和0.1mol/L盐酸中的溶解度，结果分别是17.8，17.0，18.7和18.9μg/mL。泊马度胺的低溶解度不仅增加了制剂工艺的难度，也限制了活性成分在胃肠道的溶出和吸收过程，进而影响口服生物利用度。
发明内容
本发明旨在提供一种4-羰基氨基异吲哚啉-1，3-二酮类化合物，具有如下式(I)所示结构，或其光学异构体、或其药学上可接受的盐、或其溶剂化物(例如水合物)、或其包合物、或其消旋体、或其同位素标记物、或其氮氧化物。本发明还涉及包含上述化合物的制备方法、药物组合以及使用此类化合物治疗、预防或管控多发性骨髓瘤的药物中的用途。
其中：
A选自-O-，-S-，或-NH-；
Q选自任选取代的亚烷基，或亚烷基亚芳基；
R1选自-H、烷基、-C(O)R4、-C(S)R4、-C(O)OR4、-C(O)NHR4、-C(O)NR4R4’；
R2选自-H、任选取代的烷基、烯基、烯基亚烷基、炔基、炔基亚烷基、芳 基、芳基亚烷基、杂芳基、杂芳基亚烷基；
R3选自H、羟基、烷基、烯基、烯基亚烷基、炔基、炔基亚烷基、芳基亚烷基、杂芳基亚烷基、亚烷基-OC(O)R4、亚烷基-OC(O)OR4、亚烷基-OC(O)NHR4、亚烷基-OC(O)NR4R4’，或-OR4；
各个R4和R4’相同或不同，各自独立地选自氢、烷基、烯基、烯基亚烷基、炔基、炔基亚烷基、任选取代的芳基、任选取代的杂芳基、任选取代的脂环基、任选取代的脂杂环基、任选取代的芳基亚烷基或任选取代的杂芳基亚烷基；或者R4和R4’形成任选取代的3-7元环；
所述“任选取代的”是指被一个或多个取代基取代，其中所述“任选取代的亚烷基”、“任选取代的脂环基”、“任选取代的脂杂环基”、“任选取代的芳基”和“任选取代的杂芳基”、“任选取代的芳基亚烷基”和“任选取代的杂芳基亚烷基”的取代基各自独立地选自羟基、氨基、羧基、卤素、硝基、氰基、烷基、烷氧基、芳基、杂芳基、芳基烷基、杂芳基烷基、芳基氧基、杂芳基氧基、环烷基、脂杂环基、环烷基氧基、杂环烷基氧基、芳基烷氧基、杂芳基烷氧基、烷酰氧基、烷酰氧基甲基、烷氧酰氧基或烷氧酰基。
可选地，所述“烷基”，以及“烷氧基”、“芳基烷氧基”、“杂芳基烷氧基”、“烷酰氧基甲基”、“烷氧酰氧基”、“烷酰氧基”中的烷基部分各自独立地为C1-20直链或支链烷基，可选地，为C1-17直链或支链烷基，可选地，为C1-10直链或支链烷基，可选地，为C1-8直链或支链烷基，可选地，为C1-6直链或支链烷基，可选地，为C1-4直链或支链烷基，可选地，为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基，异戊基、新戊基、叔戊基、正己基、异己基、庚基、正辛基、正壬基、正癸基、十二烷基、十五烷基、或十六烷基；
可选地，所述“亚烷基”、“亚烷基亚芳基”“烯基亚烷基”、“炔基亚烷基”、“芳基亚烷基”、“杂芳基亚烷基”、“亚烷基-OC(O)R4”、“亚烷基-OC(O)OR4”、“亚烷基-OC(O)NHR4”或“亚烷基-OC(O)NR4R4’”中的亚烷基部分各自独立地为为C1-20直链或支链亚烷基，可选地，为C1-17直链或支链亚烷基，可选地，为C1-10直链或支链亚烷基，可选地，为C1-8直链或支链亚烷基，可选地，为C1-6直链或支链亚烷基，可选地，为C1-3直链或支链亚烷基，可选地，为亚甲基、亚乙基、亚正丙基、亚异丙基、亚 正丁基、亚异丁基、亚叔丁基、亚仲丁基、亚正戊基，亚异戊基、亚新戊基、亚叔戊基、亚正己基、亚异己基、亚庚基、亚正辛基、亚正壬基、亚正癸基、亚十一烷基、亚十二烷基、亚十三烷基、亚十四烷基、亚十五烷基或亚十六烷基；
可选地，所述“环烷基氧基”、“环烷基”中的环烷基部分为C 3-8环烷基，可选地，为环丙基、环丁基、环戊基或环己基；
所述“烯基”、“烯基亚烷基”中的烯基部分各自独立地为含有一个或多个双键的C2-C20直链或支链烯基，可选地，为C2-C15直链或支链烯基，可选地，为C2-C10直链或支链烯基，可选地，为C2-C8直链或支链烯基，可选地，为C2-C6直链或支链烯基，可选地，为C2-C4直链或支链烯基；
所述“炔基”、“炔基亚烷基”中的炔基部分各自独立地为含有一个或多个三键的C2-C20直链或支链炔基，可选地，为C2-C15直链或支链炔基，可选地，为C2-C10直链或支链炔基，可选地，为C2-C8直链或支链炔基，可选地，为C2-C6直链或支链炔基，可选地，为C2-C4直链或支链炔基；
可选地，示例性烯基和炔基包括但不限于乙烯、丙烯、丁烯、戊烯、乙炔和己炔。
可选地，所述“脂杂环基”、“杂环烷基氧基”中的杂环基为环上含有选自O、N、S、SO或SO2的1-3个杂原子的C3-8(优选为C4-6)脂杂环基，可选地，为环氧乙烷基、硫杂环丙烷基、氮杂环丙烷基、氧杂环丁烷基、硫杂环丁烷基、氮杂环丁烷基、四氢呋喃基、四氢吡喃基、四氢吡咯基、吗啉基、哌啶基、或哌嗪基；
可选地，所述“芳基”、“芳基亚烷基”、“芳基烷氧基”、“芳基氧基”中的芳基为6-10元单环或双环稠合芳香环基团；可选地为苯基或萘基；
可选地，所述“亚烷基亚芳基”中的亚芳基为6-10元单环或双环稠合亚芳香环基团；可选地为亚苯基或亚萘基；
可选地，所述“杂芳基”、“杂芳基亚烷基”、“杂芳氧基”、“杂芳基烷氧基”、中的杂芳基各自独立地为含有选自O、N、S、SO或SO2的1-3个杂原子的5-10元单环或双环稠合杂芳香环基团，可选地，为吡咯基、吡唑基、吡啶基、呋喃基、咪唑基、噻唑基、噁唑基、氧杂卓基、硫杂卓基，1H-氮杂卓基、喹啉基、异喹啉基、吲哚基、嘧啶基或吡嗪基、或三唑基。
可选地，R1选自-H，或-(C＝O)CH3，-(C＝O)OC(CH3)3，-(C＝O)OBn。
可选地，R2选自-H，甲基、乙基、叔丁基、烯丙基、炔丙基或苄基。
可选地，R3选自-H，-OH，
可选地，式(I)化合物的氨基酸部分为D构型或L构型。
可选地，所述式(I)化合物、或其光学异构体、或其药学上可接受的盐、或其溶剂化物(例如水合物)、或其包合物、或其消旋体、或其同位素标记物、或其氮氧化物，选自以下化合物：



















可选地，本发明一种药物组合物，其包括上述式(I)化合物，或其光学异构体、或其药学上可接受的盐、或其溶剂化物(例如水合物)、或其包合物、或其消旋体、或其同位素标记物、或其氮氧化物，和药学上可接受的辅料。
可选地，所述的药学上可接受辅料选自：填充剂、崩解剂、润滑剂、助流剂、泡腾剂、矫味剂、防腐剂、包衣材料或其它赋形剂。
可选地，所述的药学上可接受的辅料，其填充剂包括乳糖、蔗糖、糊精、淀 粉、预胶化淀粉、甘露醇、山梨醇、磷酸氢钙、硫酸钙、碳酸钙、微晶纤维素的一种或几种的组合物；所述的粘合剂包括蔗糖、淀粉、聚维酮、羧甲基纤维素钠、羟丙甲纤维素、羟丙纤维素、甲基纤维素、聚乙二醇、药用乙醇、水的一种或几种的组合物；所述的崩解剂包括淀粉、交联聚维酮、交联羧甲基纤维素钠、低取代羟丙基纤维素、羧甲基纤维素钠、泡腾崩解剂的一种或几种的组合物。
可选地，所述药物组合物的给药方式包括：经口给药(例如，口腔)、舌下给药、肠胃外给药(例如，肌肉内、静脉内或者皮下)、直肠给药(例如，由栓剂或洗剂)、透皮给药(例如，皮肤电穿孔)或者通过吸入给药(例如，气雾剂)，并且以固体、液体或气态剂量的形式，包括片剂和混悬剂给药等。可以在连续治疗下，以单一单位剂量形式，或以随意的单一剂量治疗，进行给药。治疗组合物还可以为油乳剂或分散剂的形式，其结合有亲脂性盐如双羟萘酸，或者为可生物降解的持续释放组合物的形式，其用于皮下或者肌肉内给药。
可选地，所述药物组合物可以制成固体口服制剂、液体口服制剂、注射剂等剂型。所述固体及液体口服制剂包括：片剂、分散片、糖衣剂、颗粒剂、干粉剂、胶囊剂、糖浆剂和溶液剂。所述的注射剂包括：小针、大输液、冻干粉针等。
又一方面，本发明提供一种上述式(I)的化合物，或其光学异构体、或其药学上可接受的盐、或其溶剂化物(例如水合物)、或其包合物、或其消旋体、或其同位素标记物、或其氮氧化物，或上述药物组合物在制备用于预防和/或治疗血液系统疾病的药物中的用途；优选地，所述的疾病选自血癌和骨髓癌、急性白血病、慢性白血病、淋巴瘤、卡波西肉瘤、多发性骨髓瘤或骨髓增生异常综合征。本发明所提供的化合物可用于治疗、预防或管理原发或转移性肿瘤。
又一方面，本发明还提供一种如上述式(I)化合物或其光学异构体、或其药学上可接受的盐、或其溶剂化物(例如水合物)、或其包合物、或其消旋体、或其同位素标记物、或其氮氧化物中间体的制备方法：
包括将式(A)和式(B)化合物通过步骤A得式(C)：
步骤A：将式(A)和式(B)通过取代反应制得式(C)；
可选地，将式(A)和式(B)在碱催化下，在合适溶剂中，于适当温度下，通过取代反应制得式(C)。可选地，碱为碳酸钾、或碳酸铯、或氢化钠、或双三甲基硅基胺基锂等；可选地，溶剂为N,N-二甲基甲酰胺、或N,N-二甲 基乙酰胺、或二甲亚砜、或N-甲基吡咯烷酮等；可选地，温度为0℃至25℃。
其中，
式(B)和式(C)中R3如式(I)中所述，但不能为H，OR4；
式(B)中，B选自Cl，Br，I，OTs，OMs；
可选地，式(B)化合物可采用如下(但并不限于)方法1-8中的一种：
方法1：
1)将羧基与二氯亚砜在回流条件下反应得到酰氯；2)将酰氯和多聚甲醛在氯化锌催化剂条件下制得式(B)；
或方法2：
在室温下，向剧烈搅拌的二氯甲烷酸溶液中加入饱和碳酸氢钠溶液和催化量四丁基硫酸氢铵，然后加入氯磺酸氯甲酯，反应完成后，分层，收集有机相，无水硫酸钠干燥，减压旋干，柱层析纯化后得式(B)。
方法3：
0℃下，向氯甲酸氯甲酯的二氯甲烷溶液中加入相应的仲胺，反应完成后，过滤，有机相用1N盐酸洗，无水硫酸钠干燥，减压除去溶剂，得式(B)。
或方法4：
0℃下，向氯甲酸氯甲酯的二氯甲烷溶液中加入吡啶，后加入相应的醇，反应完成后，过滤，有机相用1N盐酸洗，无水硫酸钠干燥，减压除去溶剂，得式(B)。
或方法5：
将氯甲基试剂和溴化钠(或溴化钾)在乙腈(或丙酮)中回流，反应完成后，减压除去溶剂，加入有机溶剂和水，分层，收集有机相，无水硫酸钠干燥，减压除去溶剂，得相应的溴代式(B)。
或方法6：
将氯甲基试剂和碘化钠(或碘化钾)在乙腈(或丙酮)中回流，反应完成后，减压除去溶剂，加入有机溶剂和水，分层，收集有机相，无水硫酸钠干燥，减压除去溶剂，得相应的碘代式(B)。
方法7：
将氯甲基试剂和甲磺酸银在乙腈中回流，反应完成后，减压除去溶剂，加入有机溶剂和水，分层，收集有机相，无水硫酸钠干燥，减压除去溶剂，得相应的甲磺基氧基取代的式(B)。
或方法8：
将氯甲基试剂和对甲苯磺酸银在乙腈中回流，反应完成后，减压除去溶剂，加入有机溶剂和水，分层，收集有机相，无水硫酸钠干燥，减压除去溶剂，得相应的对苯磺基氧基取代的式(B)。
各个Y选自-R4、-OR4、-NHR4、NR4R4’，其中R4、R4’如式(I)中所述。
或者，通过以下步骤A’的反应得到式(C)：
步骤A’：将S1和S2通过缩合条件得到S3，再将S3经脱保护得S4，然后S4和S5在路易斯碱催化下通过氨解得到S6经铁粉还原制得R3选自OR4的式(C)化合物；
还包括将式(C)和式(D)化合物通过步骤B得到式(E)：
步骤B：将式(C)和式(D)通过酰化反应得式(E)。
可选地，将式(C)和式(D)溶于溶剂中，在加热条件下反应，得到式(E)；可选地，溶剂为四氢呋喃、或N,N-二甲基甲酰胺、或N-甲基吡咯烷酮、或2-甲基四氢呋喃；可选地，温度为45℃-90℃。
其中，式(C)和式(E)中，R3定义同上式(I)中所述；
或者，还包括将式(C)和式(F)化合物通过步骤C得到式(G)：
步骤C：将式(C)和式(F)通过酰化反应制得式(G)；
可选地，式(G)的合成方法：将式(C)与式(F)于适当溶剂中反应，待反应结束，减压浓缩，得式(G)；可选地，溶剂为二氯甲烷、或乙腈、或四氢呋喃等；可选地，温度为-20℃-50℃。
其中，式(C)和式(G)中，R3定义同式(I)中所述；
或者还包括将式(C)和式(H)化合物通过步骤D得到式(J)：
步骤D：将式(C)和式(H)通过缩合反应得式(J)；
可选地，将式(C)和式(H)分散在适当溶剂中，在加热条件下反应，待反应结束，直接旋干，得式(J)；可选地，溶剂为二氯甲烷、或乙腈、或四氢呋喃、或二氯乙烷等；可选地，温度为45℃-90℃。
其中，式(C)和式(J)中，R3定义同式(I)中所述；
还包括将将式(E)或式(G)或式(J)与式(L)在碱催化下经亲核取代 反应和任选的脱保护反应得到式(I)，如以下合成步骤E：
步骤E：
可选地，式(I)的合成方法：将式(E或G或J)与式(L)于适当溶剂中反应，待反应结束，减压浓缩，得式(I)；可选地，溶剂选自二氯甲烷、乙腈、N,N-二甲基甲酰胺或四氢呋喃；可选地，温度为-20℃-50℃。
其中：
式(L)中，C选自-OH，-SH，-NH2中的任意一个基团；
R5为Cl，
可选地，当R1为Boc，R2为H，-CH3，-CH2CH3，-CH2CH2CH2CH3，-CH2CH2CH2CH2CH2CH3，-CH(CH3)2，-CH2CH2OH，或-CH2CHOHCH2OH，任选地采用以下方法脱保护：
将式(M)分散在合适溶剂中，然后进行脱保护，析出固体，过滤，得式(N)为盐的形式；可选地，溶剂为乙酸乙酯、或二氧六环、或二氯甲烷、或二氯乙烷等；可选地，脱保护所用酸为氯化氢、或溴化氢、或硫酸、或三氟乙酸、或硝酸、或磷酸、或甲磺酸、或对甲苯磺酸等；可选地，温度为0-50℃。
可选地，当R1为Cbz，R2为H，-CH3，-CH2CH3，-CH2CH2CH2CH3，-CH2CH2CH2CH2CH2CH3，-CH(CH3)2，-CH2CH2OH，或-CH2CHOHCH2OH， 任选地采用以下方法脱保护。
将式(O)分散在合适溶剂中，经钯碳氢气还原得式(N)为游离态。游离态化合物也可将式(N)的盐形式分散在适合溶剂中(加等当量碱游离得到；可选地，溶剂为甲醇、或乙醇、或异丙醇、或二氧六环等。
本发明中，可将所述式(I)化合物或其光学异构体、或其药学上可接受的盐、或其溶剂化物、或其包合物或、或其消旋体、或其同位素标记物、或其氮氧化物或它们的药物组合物与其他一种或多种药理活性化合物(“第二活性化合物”)组合使用，用于预防和/或治疗血液系统疾病或病症的药物中的用途。
本发明所提供化合物可用于治疗血液系统疾病，优选地，所述的疾病选自血癌和骨髓癌，如多发性骨髓瘤以及急性、慢性白血病，例如成淋巴细胞性白血病、慢性粒细胞白血病、骨髓性白血病、淋巴细胞性白血病、髓细胞性白血病、成人T细胞白血病、卡波西肉瘤、核型急性髓细胞白血病，慢性淋巴细胞白血病(CLL)、霍奇金淋巴瘤、非霍奇金淋巴瘤、皮肤T细胞淋巴瘤、皮肤B细胞淋巴瘤、弥漫性大B细胞瘤、低级滤泡性淋巴瘤。本发明所提供的化合物可用于治疗、预防或管理原发、转移性、难治性或对化疗、放疗具有耐受性的肿瘤。
其中，“多发性骨髓瘤”是指以恶性浆细胞为特征的血液学病患，包括以下病症：意义未明的单克隆丙种球蛋白病(MGUS)；低危、中危和高危多发性骨髓瘤；新诊断的多发性骨髓瘤(包括低危、中危和高危的新诊断的多发性骨髓瘤)；适合移植和不适合移植的多发性骨髓瘤；郁积型(惰性)多发性骨髓瘤(包括低危、中危和高危的郁积型多发性骨髓瘤)；复发的多发性骨髓瘤；难治性和抗性多发性骨髓瘤；活动性多发性骨髓瘤；孤立性浆细胞瘤；髓外浆细胞瘤；浆细胞白血病；中枢神经系统多发性骨髓瘤；轻链骨髓瘤；非分泌性骨髓瘤；免疫球蛋白D骨髓瘤；免疫球蛋白E骨髓瘤；以及诸如以下的遗传异常为特征的多发性骨髓瘤：细胞周期蛋白D易位(例如，t(11；14)(q13；q32)；t(6；14)(q21；q32)；t(12；14)(p13；q32)或t(6；20)；)；MMSET易位(例如，t(4；14)(p16；q32))；MAF易位(例如，t(14；16)(q32；q32)；t(20；22)；t(16；22)(q11；q13)或t(14；20)(q32；q11))；或其它染色体因子(例如，17p13或13号染色体的缺失；del(17/17p)、非超二倍性和增加(1q))。
如本文中所用，除非另有说明，否则术语“治疗”是指减轻或减少与所治疗的疾病或病患例如多发性骨髓瘤相关的症状的严重性。术语“预防”包括抑制特定疾病或病症例如多发性骨髓瘤的症状。术语“复发”是指治疗后多发性骨髓瘤已缓解的患者在骨髓瘤中有骨髓瘤细胞返回和/或正常细胞减少的情况。术语“难治性和抗性”是指即使经过强化治疗，患者骨髓中仍残留骨髓瘤细胞和/或正常细胞减少的情况。
可用于本文所述的方法和组合物中的第二活性成分可以是大分子(例如，蛋白质)、小分子(例如，合成的无机、有机金属或有机分子)或细胞疗法(例如，CAR 细胞)。具体的第二活性成分实例包括以下物质中的一种或多种：美法仑、长春新碱、环磷酰胺、依托泊苷、多柔比星、苯达莫司汀、澳比妥珠单抗、蛋白酶体抑制剂(例如，硼替佐米、卡非佐米、艾莎佐米、奥泊佐米或玛瑞佐米)、组蛋白脱乙酰基酶抑制剂(例如，帕比司他、ACY241)、BET抑制剂(例如GSK778)。
本发明的化合物可以以同位素示踪或富集形式存在，含有一个或多个原子，这些原子的原子量或质量数不同于自然界中发现的最大量的原子的原子量或质量数。同位素可以是放射性或非放射性的同位素。原子例如氢、碳、磷、硫、氟、氯和碘的同位素包括但不局限于：2H，3H，13C，14C，15N，18O，32P，35S，18F，36Cl和125I。含有这些和/或其它原子的其它同位素的化合物在本发明范围之内。
本文使用的术语“光学异构体”指的是分子结构完全相同，物理化学性质相近，但旋光性不同的物质。包括任意比例光学异构混合物。式(I)化合物可以含有一个或多个不对称碳原子，并且其存在形式可以是旋光纯对映异构体，例如外消旋物的对映异构体混合物、旋光纯非对映异构体、非对映异构体混合物、非对映异构体的外消旋物或非对映异构体的外消旋物的混合物。可以通过例如外消旋物的拆分，通过不对称合成或不对称色谱法(使用手性吸附剂或洗脱剂的色谱法)，获得旋光活性形式。本发明包括所有这些形式。
本文使用的术语“药学上可接受的盐”是指药学上可接受的无毒酸所制备的盐，包括无机酸盐和有机酸盐。例如但不限于盐酸、氢氟酸、氢溴酸、氢碘酸、硫酸、焦硫酸、磷酸、碳酸、硝酸、硫酸氢酸、甲磺酸、羟基乙磺酸、酒石酸、甲酸、乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、三氟乙酸、丙酮酸、肉桂酸、月桂酸、水杨酸、柠檬酸、琥珀酸、富马酸、苯甲酸、邻氨基苯甲酸、2-(4-羟基苯甲酰基)苯甲酸、苯磺酸、乙磺酸、对氨基苯磺酸、对甲苯磺酸、苯乙酸、抗坏血酸、褐藻酸、糠酸、硬脂酸、粘液酸、扁桃酸、苹果酸、扑酸、泛酸、樟脑磺酸、葡萄糖酸、谷氨酸、葡萄糖醛酸、半乳糖醛酸、缩水甘油酸、乳酸、苹果酸、马来酸、天冬氨酸、硫氰酸、葡庚酸、甘油磷酸、磺基水杨酸、半硫酸、草酸、丙二酸、苦味酸等。
本文所使用的术语“溶剂化物”是指进一步通过非共价分子间力结合的化学量或非化学量的溶剂的化合物。例如当溶剂为水时，该溶剂化物为水合物。
缩略语
DCM：二氯甲烷
DCE：二氯乙烷
ACN：乙腈
THF：四氢呋喃
2-MeTHF：2-甲基四氢呋喃
DMSO：二甲亚砜
DMF：N,N-二甲基甲酰胺
DIPEA：N,N-二异丙基乙胺
NMP：N-甲基吡咯烷酮
DMAC：N，N-二甲基乙酰胺
LiHMDS：双三甲基硅基胺基锂TBS：叔丁基二甲基硅基
LAT1：L型氨基酸转体1
RPMI-8226：人多发性骨髓瘤细胞
NCI-H929：人骨髓瘤细胞
附图说明
图1为不同细胞中LAT1的表达情况。
图2为RPMI-8226模型中小鼠肿瘤体积变化趋势(n＝7)。
图3为NCI-H929模型中小鼠肿瘤体积变化趋势(n＝7)。
具体实施方式
除非另有定义，否则本文使用的所有技术和科学术语具有与本领域普通技术人员通常理解的相同的含义。如果本文的术语有多个定义，除非另有说明，否则以本部分为主。
本发明的实施例详细说明如下，但所提供的实施例不以任何方式限制本发明。
实施例
通用合成方法1：采用上述步骤C和步骤E合成。
1、将式(C)(1.0当量)、式(F)(0.33当量)分散在乙腈中，在45℃条件下搅拌1h，冷却至室温后加入甲苯，搅拌1h过滤得灰白色固体。
2、将上述步骤1所得固体和式(L)(1.0当量)(购买或自制)分散在DCM中，在低温搅拌下滴加DIPEA(1.1当量)，搅拌反应至原料消失，加入DCM，再依次用饱和硫酸氢钠水溶液、水、饱和氯化钠水溶液洗涤，收集有机相用无水硫酸钠干燥，过滤后减压蒸干，用硅胶柱层析纯化，得产物。
3、将上述步骤2所得产物溶于DCM和二氧六环中，然后通入氯化氢气体或用甲磺酸、硫酸、磷酸等在室温进行脱保护反应，待反应完成后，过滤，用DCM淋洗后烘干。
其中，式(L)的合成方法：将Boc-酪氨酸(1.0当量)、碳酸铯(0.5当量)和碘乙烷、或1-碘丁烷、或1-碘己烷、或异丙基碘、或TBS保护的羟乙基碘、或4-(碘甲基)-2,2-二甲基-1,3-二氧环戊烷(1.1当量)分散在DMF中，室温搅拌过夜，萃取、柱层析得产物式(L)。
实施例1：化合物6的制备
采用通用合成方法1制备，得盐酸盐为白色固体，收率81.63％。
1H NMR(400MHz,DMSO-d6)δ11.18(s,1H),9.68(s,1H),8.69(s,3H),8.18(d,J＝8.3Hz,1H),7.95–7.83(m,1H),7.68(d,J＝7.1Hz,1H),7.33(d,J＝8.6Hz,2H),7.25(d,J＝8.6Hz,2H),5.17(dd,J＝12.8,5.4Hz,1H),4.31(t,J＝6.5Hz,1H),3.70(s,3H),3.18(qd,J＝14.2,6.5Hz,2H),2.97–2.85(m,1H),2.67–2.52(m,2H),2.08(dd,J＝9.1,3.6Hz,1H).
通用合成方法2：采用步骤B和步骤E合成。
将式(C)(1.0当量)、式(D)(1.5当量)分散在四氢呋喃中，在回流条件下搅拌12h，减压蒸干后，加入DMF溶解的式(L)、DIPEA(1.1当量)，于室温搅拌1h后，加入乙酸乙酯和饱和氯化铵水溶液萃取得粗产物。减压蒸干，用硅胶柱层析纯化。
实施例2：化合物8的制备
采用通用合成方法2制备，得类白色固体，收率75.75％。
1H NMR(600MHz,DMSO-d6)δ12.90(s,1H),11.13(s,1H),10.06(s,1H),8.31(d,J＝8.0Hz,1H),8.16(d,J＝8.4Hz,1H),7.87–7.83(m,1H),7.66(d,J＝7.3Hz,1H),5.14(dd,J＝12.9,5.4Hz,1H),4.43(dt,J＝5.2,3.2Hz,1H),3.44(dd,J＝13.8,5.0Hz,1H),3.15(dd,J＝13.8,8.4Hz,1H),2.94–2.85(m,1H),2.64–2.51(m,2H),2.09–2.02(m,1H),1.85(d,J＝0.8Hz,3H).
实施例3：化合物11的制备
采用通用合成方法1制备，得盐酸盐为白色固体，收率52.13％。
1H NMR(600MHz,DMSO-d6)δ11.16(s,1H),9.66(s,1H),8.29(s,3H),8.18(d,J＝8.4Hz,1H),7.93–7.86(m,1H),7.68(d,J＝7.2Hz,1H),7.34(d,J＝8.6Hz,2H),7.25(d,J＝8.6Hz,2H),5.17(dd,J＝12.9,5.4Hz,1H),4.13(d,J＝6.2Hz,1H),3.16–3.06 (m,2H),2.91(ddd,J＝17.1,14.0,5.4Hz,1H),2.65–2.52(m,2H),2.11–2.01(m,1H).
实施例4：化合物12的制备
采用通用合成方法1制备，得甲磺酸盐为类白色固体，收率51.27％。
1H NMR(400MHz,DMSO-d6)δ11.17(s,1H),9.67(s,1H),8.41(s,3H),8.18(d,J＝8.4Hz,1H),7.99–7.82(m,1H),7.68(d,J＝7.2Hz,1H),7.28(dd,J＝19.7,8.7Hz,4H),5.17(dd,J＝12.7,5.4Hz,1H),4.36(t,J＝6.6Hz,1H),3.71(s,3H),3.22–3.02(m,2H),2.97–2.84(m,1H),2.69–2.52(m,2H),2.31(s,3H),2.13–2.02(m,1H).
实施例5：化合物13的制备
采用通用合成方法1制备，得硫酸盐为白色固体，收率54.72％。
1H NMR(400MHz,DMSO-d6)δ11.17(s,1H),9.67(s,1H),8.53(s,3H),8.18(d,J＝8.3Hz,1H),7.95–7.86(m,1H),7.68(d,J＝7.2Hz,1H),7.28(dd,J＝19.2,8.7Hz,4H),5.17(dd,J＝12.8,5.4Hz,1H),4.33(t,J＝6.6Hz,1H),3.71(s,3H),3.11(d,J＝6.5Hz,2H),2.96–2.86(m,1H),2.66(d,J＝12.1Hz,2H),2.08(dd,J＝9.1,3.7Hz,1H).
实施例6：化合物14的制备
采用通用合成方法1制备，得磷酸盐为白色固体，收率76.58％。
1H NMR(400MHz,DMSO-d6)δ11.17(s,1H),9.67(s,1H),8.53(s,3H),8.18(d,J＝8.3Hz,1H),7.95–7.86(m,1H),7.68(d,J＝7.2Hz,1H),7.28(dd,J＝19.2,8.7Hz,4H),5.17(dd,J＝12.8,5.4Hz,1H),4.33(t,J＝6.6Hz,1H),3.71(s,3H),3.11(d,J＝6.5Hz,2H),2.96–2.86(m,1H),2.66(d,J＝12.1Hz,2H),2.08(dd,J＝9.1,3.7Hz,1H).
通用合成方法3：
采用步骤A、B、E合成。
第一步：氯甲基试剂的制备
(1)在室温下，向剧烈搅拌的苯甲酸、或取代的苯甲酸、或正癸酸、或正十二酸、或正十四酸(1.0当量)的DCM溶液中加入饱和碳酸氢钠和四丁基硫酸氢铵(0.1当量)、氯磺酸氯甲酯(1.2当量)，反应完成后，分层，收集有机相，无水硫酸钠干燥，减压旋干，柱层析纯化后得式(B)。
(2)将吗啉、或二甲胺、或二乙胺(1.0当量)，DIPEA和DMAP溶于DCM中，降温至0℃，缓慢滴加氯甲酸氯甲酯(1.1当量)的DCM中，室温反应1.5h，加入DCM、用1N盐酸、饱和食盐水萃取，无水硫酸钠干燥，减压蒸馏得式(B)。第二步：
将式(A)(1.0当量)、式(B)(1.2当量)(购买或自制)和碳酸铯(1.2当量)加入到DMF中，0℃至25℃搅拌3h。加入乙酸乙酯，再依次用饱和氯化铵水溶液、水、饱和氯化钠水溶液洗涤有机相，收集有机相无水硫酸钠干燥，过滤得到滤 液减压蒸干，用硅胶柱层析进行纯化得式(C)。
将式(C)(1.0当量)、式(D)(1.5当量)分散在四氢呋喃中，在回流条件下搅拌12h，减压蒸干后，加入DMF溶解的式(L)、DIPEA(1.1当量)，于室温搅拌1h后，加入乙酸乙酯和饱和氯化铵水溶液萃取得粗产物。减压蒸干，用硅胶柱层析纯化。
第三步：
将上述产物分散在乙酸乙酯中，然后通入氯化氢气体或甲磺酸、硫酸、磷酸等在室温进行脱保护反应。待反应完成后，过滤，用乙酸乙酯，正庚烷淋洗，50℃烘干。
实施例7：化合物15的制备
采用通用合成方法3制备，得盐酸盐为白色固体，收率52.16％。
1H NMR(600MHz,DMSO-d6)δ9.63(s,1H),8.19(d,J＝8.3Hz,1H),8.01–7.87(m,3H),7.67(dd,J＝12.9,7.2Hz,2H),7.54(t,J＝7.8Hz,2H),7.34(d,J＝8.5Hz,2H),7.22(d,J＝8.5Hz,2H),5.94(dd,J＝26.1,9.6Hz,2H),5.40(dd,J＝13.0,5.4Hz,1H),3.97(s,1H),3.19–3.02(m,3H),2.90(dd,J＝13.6,2.9Hz,1H),2.66(dd,J＝13.3,4.4Hz,1H),2.23–2.10(m,1H).
实施例8：化合物16的制备
采用通用合成方法1制备，得盐酸盐为类白色固体，收率97.53％。
1H NMR(600MHz,DMSO-d6)δ11.16(s,1H),10.09(s,1H),9.10(s,1H),8.62(d,J＝8.6Hz,1H),7.79(t,J＝7.9Hz,1H),7.50(d,J＝7.2Hz,1H),7.45(d,J＝8.4Hz,2H),7.21(d,J＝8.4Hz,2H),5.15(dd,J＝12.8,5.4Hz,1H),3.98(s,1H),3.11–2.87(m,3H),2.66–2.52(m,2H),2.13–2.05(m,1H).
实施例9：化合物17的制备
采用通用合成方法3制备，得盐酸盐为黄色固体，收率78.94％。
1H NMR(600MHz,DMSO-d6)δ9.65(s,1H),8.59(s,3H),8.19(d,J＝8.4Hz,1H),8.00–7.92(m,2H),7.92–7.87(m,1H),7.67(dd,J＝16.5,7.4Hz,2H),7.54(t,J＝7.8Hz,2H),7.32(d,J＝8.5Hz,2H),7.24(d,J＝8.5Hz,2H),5.96(d,J＝9.6Hz,1H),5.92(d,J＝9.6Hz,1H),5.40(dd,J＝13.0,5.4Hz,1H),4.30(t,J＝6.6Hz,1H),3.70(s,3H),3.25–3.03(m,3H),2.90(dd,J＝13.6,3.0Hz,1H),2.67–2.55(m,1H),2.23–2.09(m,1H).
实施例10：化合物19的制备
采用通用合成方法1制备，得盐酸盐为淡黄色固体，收率68.59％。
1H NMR(600MHz,DMSO-d6)δ11.15(s,1H),9.10(s,1H),8.72(s,3H),8.35(d,J＝8.4Hz,1H),7.88(dd,J＝8.4,7.4Hz,1H),7.63(d,J＝7.3Hz,1H),5.15(dd,J＝12.9,5.4Hz,1H),4.64–4.50(m,3H),3.80(s,3H),2.94–2.86(m,1H),2.64–2.51(m,2H),2.11–2.02(m,1H).
实施例11：化合物20的制备
采用通用合成方法1制备，得盐酸盐为白色固体，收率58.71％。
1H NMR(600MHz,DMSO-d6)δ11.16(s,1H),9.07(s,1H),8.88(s,3H),8.37(dd,J＝8.5,3.9Hz,1H),7.90–7.81(m,1H),7.62(dd,J＝7.3,1.5Hz,1H),5.34–5.24(m,1H),5.15(ddd,J＝12.9,5.3,3.5Hz,1H),4.42(t,J＝3.5Hz,1H),3.77(s,3H),2.96–2.84(m,1H),2.65–2.51(m,2H),2.13–2.04(m,1H),1.45(d,J＝6.7Hz,3H).
实施例12：化合物21的制备
采用通用合成方法1制备，得盐酸盐为白色固体，收率68.56％。
1H NMR(600MHz,DMSO-d6)δ11.16(s,1H),9.03(s,1H),8.58(s,2H),8.42–8.37(m,1H),8.04–7.80(m,1H),7.61(dd,J＝7.3,1.1Hz,1H),5.38–5.27(m,1H),5.16–5.11(m,1H),4.22(s,1H),2.94–2.85(m,1H),2.61(d,J＝17.0Hz,1H),2.53–2.46(m,1H),2.08(dd,J＝11.2,6.0Hz,1H),1.44(d,J＝6.6Hz,3H).
实施例13：化合物22的制备
采用通用合成方法1制备，得盐酸盐为淡黄色固体，收率97.71％。
1H NMR(600MHz,DMSO-d6)δ11.14(s,1H),8.12(d,J＝8.4Hz,1H),7.87(dd,J＝8.2,7.4Hz,1H),7.70(d,J＝7.3Hz,1H),5.14(dd,J＝12.9,5.4Hz,1H),4.15(s,1H),3.53–3.49(m,1H),3.42–3.37(m,1H),2.94–2.85(m,1H),2.64–2.53(m,2H),2.09–2.01(m,1H).
实施例14：化合物23的制备

采用通用合成方法1制备，得盐酸盐为黄色固体，收率86.59％。
1H NMR(600MHz,DMSO-d6)δ11.15(s,1H),9.07(s,1H),8.56(s,2H),8.37(dd,J＝8.5,3.3Hz,1H),7.88(dd,J＝8.3,7.5Hz,1H),7.62(d,J＝7.3Hz,1H),5.14(dd,J＝12.9,5.4Hz,1H),4.64–4.48(m,2H),4.38(s,1H),2.93–2.86(m,1H),2.64–2.59(m,1H),2.52–2.51(m,1H),2.08(dd,J＝7.2,5.3Hz,1H).
实施例15：化合物24的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率33.83％。
1H NMR(600MHz,DMSO-d6)δ9.09(s,1H),8.81(s,3H),8.36(d,J＝8.5Hz,1H),7.93(d,J＝7.2Hz,2H),7.91–7.86(m,1H),7.70(t,J＝7.4Hz,1H),7.64(d,J＝7.3Hz,1H),7.55(t,J＝7.5Hz,2H),6.00–5.83(m,2H),5.39(ddd,J＝13.1,5.3,1.6Hz,1H),4.64–4.52(m,3H),3.79(d,J＝4.3Hz,3H),3.19–3.01(m,1H),2.90(dd,J＝14.2,3.4Hz,1H),2.70–2.57(m,1H),2.16(dd,J＝13.2,7.7Hz,1H).
实施例16：化合物25的制备
采用通用合成方法1制备，得盐酸盐为白色固体，收率52.74％。
1H NMR(400MHz,DMSO-d6)δ11.16(s,1H),8.77(s,3H),8.09(d,J＝8.3Hz,1H),7.94–7.77(m,1H),7.71(d,J＝7.3Hz,1H),5.15(dd,J＝12.8,5.4Hz,1H),4.34(t,J＝5.6Hz,1H),3.75(s,3H),3.49(t,J＝5.2Hz,2H),2.98–2.81(m,1H),2.63(dt,J＝27.1,5.4Hz,2H),2.10–2.00(m,1H).
实施例17：化合物26的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率76.72％。
1H NMR(400MHz,DMSO-d6)δ9.05(s,1H),8.69(s,3H),8.38(dd,J＝8.4,2.2Hz,1H),7.96–7.91(m,2H),7.91–7.85(m,1H),7.72–7.66(m,1H),7.64(d,J＝6.9Hz,1H),7.56(t,J＝7.7Hz,2H),5.98–5.88(m,2H),5.42–5.24(m,2H),4.43(t,J＝3.5Hz,1H),3.77(d,J＝2.0Hz,3H),3.17–3.04(m,1H),2.90(d,J＝17.5Hz,1H),2.62(dd,J＝13.3,4.3Hz,1H),2.25–2.10(m,1H),1.43(d,J＝6.6Hz,3H).
实施例18：化合物28的制备

采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率70.65％。
1H NMR(600MHz,DMSO-d6)δ9.03(s,1H),8.41(d,J＝8.5Hz,1H),7.98–7.91(m,2H),7.91–7.84(m,1H),7.73–7.67(m,1H),7.62(dd,J＝7.2,2.0Hz,1H),7.56(t,J＝7.8Hz,2H),6.03–5.75(m,2H),5.57–5.34(m,1H),5.36–5.28(m,1H),4.17(d,J＝3.4Hz,1H),3.15–3.04(m,1H),2.97–2.85(m,1H),2.73–2.56(m,1H),2.21–2.12(m,1H),1.45(d,J＝6.6Hz,3H).
实施例19：化合物29的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率64.56％。
1H NMR(600MHz,DMSO-d6)δ8.14(d,J＝8.3Hz,1H),7.97–7.91(m,2H),7.90–7.86(m,1H),7.73–7.65(m,2H),7.56(t,J＝7.7Hz,2H),5.96–5.86(m,2H),5.39(ddd,J＝13.0,5.4,1.3Hz,1H),4.09(t,J＝5.3Hz,1H),3.56–3.46(m,1H),3.41(ddd,J＝14.5,6.3,2.9Hz,1H),3.11(ddd,J＝17.6,14.0,5.4Hz,1H),2.95–2.85(m,1H),2.63(qd,J＝13.3,4.4Hz,1H),2.20–2.12(m,1H).
实施例20：化合物30的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率56.64％。
1H NMR(600MHz,DMSO-d6)δ9.06(s,1H),8.62(s,2H),8.38(dd,J＝8.4,3.2Hz,1H),7.93(d,J＝8.1Hz,2H),7.91–7.86(m,1H),7.70(t,J＝7.4Hz,1H),7.63(d,J＝7.3Hz,1H),7.55(t,J＝7.2Hz,2H),6.01–5.77(m,2H),5.39(ddd,J＝13.1,5.2,2.8Hz,1H),4.62(dt,J＝11.5,3.6Hz,1H),4.56–4.46(m,1H),4.29(s,1H),3.15–3.02(m,1H),2.95–2.82(m,1H),2.69–2.57(m,1H),2.20–2.12(m,1H).
实施例21：化合物31的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率64.32％。1H NMR(600MHz,DMSO-d6)δ9.65(s,1H),8.61(s,3H),8.20(d,J＝8.4Hz,1H),7.93–7.88(m,1H),7.69(d,J＝7.3Hz,1H),7.32(d,J＝8.5Hz,2H),7.25(d,J＝8.5Hz,2H),5.68(dd,J＝27.8,9.4Hz,2H),5.36(dd,J＝13.1,5.4Hz,1H),4.78(m,1H),4.32(s,1H),3.70(s,3H),3.22–3.03(m,3H),2.86(dd,J＝13.7,2.8Hz,1H),2.62(m,1H),2.17–2.11(m, 1H),1.22(dd,J＝6.2,1.6Hz,6H).
实施例22：化合物32的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率57.84％。
1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.57(s,3H),8.10(d,J＝8.2Hz,1H),7.92–7.86(m,1H),7.72(d,J＝7.4Hz,1H),5.67(dd,J＝21.2,9.4Hz,2H),5.34(dd,J＝13.1,5.3Hz,1H),4.78(dt,J＝12.5,6.2Hz,1H),4.38(t,J＝5.4Hz,1H),3.76(s,3H),3.47(m,2H),3.05(dd,J＝13.9,5.0Hz,1H),2.85(d,J＝16.7Hz,1H),2.59(dd,J＝13.3,4.1Hz,1H),2.15–2.08(m,1H),1.22(d,J＝6.2Hz,6H).
实施例23：化合物33的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率65.41％。
1H NMR(400MHz,DMSO-d6)δ9.06(s,1H),8.50(s,3H),8.39(dd,J＝8.5,3.1Hz,1H),7.93–7.86(m,1H),7.63(d,J＝7.3Hz,1H),5.66(m,2H),5.35(dd,J＝13.1,4.1 Hz,1H),4.82–4.72(m,1H),4.63–4.45(m,2H),4.30(s,1H),3.11–3.01(m,1H),2.85(d,J＝16.5Hz,1H),2.57(d,J＝14.1Hz,1H),2.17–2.10(m,1H),1.23(d,J＝6.2Hz,6H).
实施例24：化合物34的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率57.26％。
1H NMR(400MHz,DMSO-d6)δ9.10(s,1H),8.84(s,3H),8.37(d,J＝8.5Hz,1H),7.93–7.86(m,1H),7.64(d,J＝7.3Hz,1H),5.70(d,J＝9.4Hz,1H),5.64(dd,J＝9.4,1.7Hz,1H),5.36(dd,J＝13.0,5.2Hz,1H),4.83–4.73(m,1H),4.64–4.53(m,3H),3.80(s,3H),3.13–3.02(m,1H),2.89–2.81(m,1H),2.57(dd,J＝13.5,3.4Hz,1H),2.19–2.09(m,1H),1.23(d,J＝6.2Hz,6H).
实施例25：化合物35的制备

采用通用合成方法3制备，得盐酸盐为白色固体，收率61.46％。
1H NMR(400MHz,DMSO-d6)δ9.64(s,1H),8.19(d,J＝8.3Hz,1H),7.95–7.85(m,1H),7.69(d,J＝7.2Hz,1H),7.25(dd,J＝28.6,8.6Hz,4H),5.66(dd,J＝29.7,9.4Hz,2H),5.34(dd,J＝13.0,5.4Hz,1H),4.01(t,J＝6.4Hz,1H),3.66(s,3H),3.54(s,4H),3.31(s,4H),3.12–2.96(m,3H),2.89–2.80(m,1H),2.56(dd,J＝13.5,4.5Hz,1H),2.19–2.09(m,1H).
实施例26：化合物36的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率63.58％。
1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),8.50(s,3H),8.13(d,J＝8.2Hz,1H),7.92–7.85(m,1H),7.72(d,J＝7.3Hz,1H),5.67(dd,J＝20.8,9.4Hz,2H),5.35(dd,J＝13.1,5.3Hz,1H),4.77(dt,J＝12.4,6.2Hz,1H),4.24(s,1H),3.54(s,4H),3.47–3.38(m,4H),3.13–3.02(m,1H),2.85(d,J＝16.6Hz,1H),2.59(dd,J＝13.2,4.3Hz,1H),2.16–2.08(m,1H),1.22(d,J＝6.2Hz,6H).
实施例27：化合物37的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率59.27％。
1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),8.70(s,2H),8.13–8.07(m,1H),7.91–7.85(m,1H),7.72(d,J＝7.3Hz,1H),5.65(dd,J＝23.9,9.4Hz,2H),5.32(dd,J＝13.0,5.4Hz,1H),4.36(t,J＝5.6Hz,1H),4.03(q,J＝7.1Hz,1H),3.75(s,3H),3.54(s,4H),3.48(t,J＝6.0Hz,2H),3.35–3.29(m,4H),3.06(m,1H),2.84(dd,J＝13.8,2.9Hz,1H),2.58–2.53(m,1H),2.12(dd,J＝9.1,3.8Hz,1H).
实施例28：化合物38的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率69.36％。
1H NMR(400MHz,DMSO-d6)δ8.33(d,J＝8.3Hz,1H),8.02–7.79(m,1H),7.63(d,J＝7.1Hz,1H),5.65(q,J＝8.2,6.7Hz,2H),5.32(d,J＝9.7Hz,1H),4.42(d,J＝58.4Hz,2H),3.76(s,2H),3.54(s,3H),3.05(s,1H),2.84(d,J＝16.4Hz,1H),2.68(m,4H),2.57(m,4H),2.12(s,1H),1.25(d,J＝14.4Hz,2H).
实施例29：化合物39的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率62.36％。
1H NMR(400MHz,DMSO-d6)δ9.66(s,1H),8.33(s,3H),8.19(d,J＝8.4Hz,1H),7.93–7.87(m,1H),7.69(d,J＝7.2Hz,1H),7.29(dd,J＝43.4,8.6Hz,4H),5.66(dd,J＝29.8,9.4Hz,2H),5.34(dd,J＝13.0,5.4Hz,1H),4.15(t,J＝6.3Hz,1H),3.54(s,4H),3.31(s,4H),3.18–3.01(m,3H),2.88–2.80(m,1H),2.60–2.55(m,1H),2.19–2.08(m,1H).
实施例30：化合物40的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率64.15％。
1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.45(s,3H),8.12(d,J＝8.4Hz,1H),7.93–7.85(m,1H),7.72(d,J＝7.3Hz,1H),5.65(m,2H),5.32(dd,J＝12.7,5.0Hz, 1H),4.24(s,1H),3.54(s,4H),3.51–3.41(m,2H),3.30(s,4H),3.13–2.99(m,1H),2.84(m,1H),2.57(m,1H),2.12(m,1H).
实施例31：化合物41的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率58.26％。
1H NMR(400MHz,DMSO-d6)δ9.06(s,1H),8.39(d,J＝8.5Hz,1H),7.93–7.86(m,1H),7.63(d,J＝7.2Hz,1H),5.65(dd,J＝17.2,9.9Hz,2H),5.32(dd,J＝12.5,4.7Hz,1H),4.65–4.45(m,2H),4.25(s,1H),3.81(d,J＝6.6Hz,1H),3.54(s,4H),3.31–3.24(m,4H),3.04(m,1H),2.82(m,1H),2.15(m,1H).
实施例32：化合物42的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率62.52％。
1H NMR(400MHz,DMSO-d6)δ9.68(s,1H),8.45(s,3H),8.19(d,J＝8.4Hz,1H),7.94–7.88(m,1H),7.69(d,J＝7.2Hz,1H),7.36(d,J＝8.6Hz,2H),7.25(d,J＝8.6Hz,2H),5.68(dd,J＝19.9,9.4Hz,2H),5.37(dd,J＝13.1,5.3Hz,1H),4.78(m,1H),4.17(t,J＝6.2Hz,1H),3.16(d,J＝6.1Hz,2H),3.13–3.00(m,1H),2.86(dd,J＝13.7,2.8Hz,1H),2.61(dd,J＝13.3,4.5Hz,1H),2.19–2.10(m,1H),1.22(dd,J＝6.2,0.9Hz,6H).
实施例33：化合物43的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率67.25％。
1H NMR(400MHz,DMSO-d6)δ9.66(s,1H),8.52(s,3H),8.18(d,J＝8.4Hz,1H),7.96–7.87(m,1H),7.69(d,J＝7.1Hz,1H),7.28(dd,J＝25.5,8.6Hz,4H),5.70–5.62(m,2H),5.36(dd,J＝13.0,5.4Hz,1H),4.34(t,J＝6.6Hz,1H),3.71(s,3H),3.20–3.05(m,3H),2.90–2.82(m,1H),2.59(d,J＝4.3Hz,1H),2.18–2.10(m,1H),1.11(s,9H).
实施例34：化合物44的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率58.25％。
1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.70(s,3H),8.10(d,J＝8.3Hz,1H),7.88(t,J＝7.8Hz,1H),7.72(d,J＝7.3Hz,1H),5.65(d,J＝10.0Hz,2H),5.34(dd,J＝13.0,5.3Hz,1H),4.36(t,J＝5.4Hz,1H),3.76(d,J＝9.0Hz,3H),3.54–3.41(m,2H),3.15–3.03(m,1H),2.85(d,J＝16.7Hz,1H),2.61–2.55(m,1H),2.17–2.07(m,1H),1.11(s,9H).
实施例35：化合物45的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率49.25％。
1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),8.66(s,3H),8.10(d,J＝8.3Hz,1H),7.88(t,J＝7.8Hz,1H),7.72(d,J＝7.3Hz,1H),5.66(s,2H),5.34(dd,J＝12.9,5.3Hz,1H),4.38(d,J＝5.3Hz,1H),3.75(s,3H),3.53–3.41(m,2H),3.14–3.03(m,1H),2.85(m,1H),2.59(m 1H),2.17–2.07(m,1H),1.11(s,9H).
实施例36：化合物46的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率52.25％。
1H NMR(400MHz,DMSO-d6)δ9.66(s,1H),8.30(s,3H),8.18(d,J＝8.3Hz,1H),7.93–7.85(m,1H),7.69(d,J＝7.1Hz,1H),7.29(dd,J＝40.7,8.6Hz,4H),5.71–5.63(m,2H),5.36(dd,J＝13.0,5.4Hz,1H),4.14(s,1H),3.20–3.03(m,3H),2.87(dd,J＝12.2,8.9Hz,1H),2.64–2.54(m,1H),2.19–2.08(m,1H),1.11(d,J＝5.9Hz,9H).
实施例37：化合物47的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率52.62％。
1H NMR(400MHz,DMSO-d6)δ8.13(d,J＝8.4Hz,1H),7.91–7.84(m,1H),7.71(d,J＝7.3Hz,1H),5.66(s,2H),5.36–5.30(m,1H),4.19(s,1H),3.45(dd,J＝29.2,5.5Hz,2H),3.14–3.02(m,1H),2.90–2.81(m,1H),2.62–2.55(m,1H),2.13(d,J＝6.8Hz,1H),1.11(s,9H).
实施例38：化合物48的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率59.25％。
1H NMR(400MHz,DMSO-d6)δ8.40(d,J＝8.5Hz,1H),7.88(t,J＝8.0Hz,1H),7.62(d,J＝7.2Hz,1H),5.65(s,2H),5.34(d,J＝12.9Hz,2H),4.58(d,J＝11.4Hz,2H),4.40(s,2H),3.97(s,2H),3.09(t,J＝14.5Hz,2H),2.85(d,J＝17.4Hz,2H),2.14(s,1H),1.17(d,J＝50.1Hz,9H).
实施例39：化合物49的制备
采用通用合成方法2制备，不进行脱保护得黄色固体，收率48.15％。
1H NMR(400MHz,DMSO-d6)δ12.89(s,1H),11.17(s,1H),10.10(s,1H),8.17(d,J＝8.3Hz,1H),7.86(t,J＝7.9Hz,1H),7.67(d,J＝7.3Hz,1H),7.28(d,J＝8.4Hz,1H),5.15(dd,J＝12.8,5.4Hz,1H),4.12(dd,J＝8.9,4.6Hz,1H),4.08(d,J＝4.8Hz,1H),3.46(dd,J＝13.7,4.5Hz,1H),3.09(dd,J＝13.2,10.1Hz,1H),2.90(ddd,J＝16.8,13.9,5.3Hz,1H),2.58(dd,J＝25.0,11.9Hz,2H),2.07(dd,J＝9.2,3.7Hz,1H),1.38(s,9H).
实施例40：化合物50的制备
采用通用合成方法2制备，不进行脱保护，得黄色固体，收率52.57％。
1H NMR(400MHz,DMSO-d6)δ11.16(s,1H),10.14(s,1H),8.14(d,J＝8.2Hz,1H),7.90–7.81(m,1H),7.67(d,J＝7.0Hz,1H),7.44(d,J＝8.2Hz,1H),5.14(dd,J＝12.8,5.5Hz,1H),4.24–4.14(m,1H),3.66(s,3H),3.43(dd,J＝13.9,4.8Hz,2H),3.14–3.06(m,1H),2.95–2.85(m,1H),2.60(m,1H),2.11–2.02(m,1H),1.43–1.29(s,9H).
实施例41：化合物51的制备
采用通用合成方法2制备，不进行脱保护得黄色固体，收率45.14％。
1H NMR(400MHz,DMSO-d6)δ11.17(s,1H),9.64(s,1H),8.19(d,J＝8.3Hz,1H),7.93–7.86(m,1H),7.67(d,J＝6.8Hz,1H),7.30(d,J＝8.5Hz,2H),7.18(d,J＝8.5Hz,2H),5.17(dd,J＝12.8,5.4Hz,1H),4.19(td,J＝8.5,5.1Hz,1H),3.62(s,3H),3.02(m,1H),2.91–2.84(m,1H),2.65–2.51(m,3H),2.08(m,1H),1.30(s,9H).
实施例42：化合物52的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率62.63％。
1H NMR(400MHz,DMSO-d6)δ9.07(s,1H),8.44(s,3H),8.40–8.36(m,1H),7.93–7.85(m,1H),7.64(d,J＝7.3Hz,1H),7.62–7.53(m,2H),7.16(d,J＝8.3Hz,1H),7.02(t,J＝7.6Hz,1H),5.89–5.79(m,2H),5.38(m,1H),4.63–4.46(m,2H),4.34(s,1H),3.81(d,J＝1.1Hz,3H),3.13–3.05(m,1H),2.93–2.85(m,1H),2.61(dd,J＝13.1,4.1Hz,1H),2.20–2.11(m,1H).
实施例43：化合物53的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率35.36％。
1H NMR(400MHz,DMSO-d6)δ8.43(s,3H),8.13(d,J＝8.3Hz,1H),7.93–7.84(m,1H),7.72(d,J＝7.3Hz,1H),7.63–7.54(m,2H),7.16(d,J＝8.4Hz,1H),7.03(t,J＝7.5Hz,1H),5.84(q,J＝9.7Hz,2H),5.37(dd,J＝12.7,5.3Hz,1H),4.21(t,J＝5.3Hz, 1H),3.82(s,3H),3.55–3.41(m,2H),3.10(dd,J＝21.7,9.4Hz,1H),2.88(d,J＝17.5Hz,1H),2.62(dd,J＝13.1,4.3Hz,2H),2.16–2.09(m,1H).
实施例44：化合物54的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率52.37％。
1H NMR(400MHz,DMSO-d6)δ13.92(s,1H),9.68(s,1H),8.40(s,3H),8.19(d,J＝8.3Hz,1H),7.95–7.86(m,1H),7.70(d,J＝7.3Hz,1H),7.61(dd,J＝7.7,1.7Hz,1H),7.58–7.50(m,1H),7.34(d,J＝8.6Hz,2H),7.25(d,J＝8.6Hz,2H),7.15(d,J＝8.4Hz,1H),7.02(t,J＝7.5Hz,1H),5.85(dd,J＝16.6,9.6Hz,2H),5.39(dd,J＝13.0,5.4Hz,1H),4.21(s,1H),3.82(s,3H),3.20–3.06(m,3H),2.89(dd,J＝10.5,6.0Hz,1H),2.72–2.57(m,1H),2.22–2.11(m,1H).
实施例45：化合物55的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率61.25％。
1H NMR(400MHz,DMSO-d6)δ9.67(s,1H),8.51(s,3H),8.19(d,J＝8.4Hz,1H),7.93–7.86(m,1H),7.70(d,J＝7.3Hz,1H),7.62–7.52(m,2H),7.28(dd,J＝22.7,8.7Hz,3H),7.15(d,J＝8.4Hz,1H),7.01(dd,J＝11.2,3.8Hz,2H),5.90–5.82(m,2H),5.39(dd,J＝13.0,5.4Hz,1H),4.35(s,1H),3.81(d,J＝1.3Hz,3H),3.71(s,2H),3.20–3.04(m,3H),2.93–2.85(m,1H),2.69–2.58(m,1H),2.22–2.14(m,1H).
实施例46：化合物56的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率48.61％。
1H NMR(400MHz,DMSO-d6)δ9.09(d,J＝2.9Hz,1H),8.76(s,3H),8.36(d,J＝8.5Hz,1H),7.94–7.80(m,1H),7.65(d,J＝7.3Hz,1H),7.62–7.54(m,2H),7.16(dd,J＝7.9,4.9Hz,1H),7.08–6.99(m,1H),5.92–5.80(m,2H),5.38(dd,J＝13.0,5.1Hz,1H),4.66–4.49(m,3H),3.81(s,3H),3.79(d,J＝1.6Hz,2H),3.16–3.03(m,1H),2.94–2.84(m,1H),2.66–2.57(m,1H),2.20–2.11(m,1H).
实施例47：化合物57的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率66.26％。
1H NMR(400MHz,DMSO-d6)δ10.40(s,1H),8.64(s,3H),8.10(d,J＝8.3Hz,1H),7.92–7.85(m,1H),7.73(d,J＝7.3Hz,1H),7.63–7.54(m,2H),7.16(d,J＝8.3Hz,1H),7.03(dd,J＝9.5,5.6Hz,1H),5.84(q,J＝9.6Hz,2H),5.37(dd,J＝13.0,5.4Hz,1H),4.38(s,1H),3.82(s,3H),3.75(s,2H),3.53–3.46(m,2H),3.18–3.04(m,1H),2.92–2.83(m,1H),2.62(dt,J＝13.8,11.9Hz,1H),2.22–2.10(m,1H).
实施例48：化合物58的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率61.36％。
1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),8.51(s,3H),8.12(d,J＝8.3Hz,1H),7.92–7.85(m,1H),7.71(d,J＝7.3Hz,1H),7.49(dt,J＝15.6,7.7Hz,2H),7.41(s,1H),7.27(d,J＝7.9Hz,1H),5.99–5.86(m,2H),5.39(dd,J＝12.8,5.1Hz,1H),4.25(s,1H),3.83(s,3H),3.58–3.38(m,3H),3.18–3.05(m,1H),2.62(dd,J＝13.2,4.3Hz,1H),2.16(d,J＝6.0Hz,1H).
实施例49：化合物59的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率57.14％。
1H NMR(600MHz,DMSO-d6)δ13.90(s,0H),9.65(s,1H),8.37(s,3H),8.19(d,J＝8.3Hz,1H),7.95(s,0H),7.93–7.87(m,1H),7.69(d,J＝7.3Hz,1H),7.52(d,J＝7.8Hz,1H),7.49–7.40(m,2H),7.34(d,J＝8.5Hz,2H),7.25(d,J＝8.5Hz,3H),5.93(dd,J＝43.6,9.6Hz,1H),5.41(dd,J＝13.0,5.4Hz,1H),4.22(d,J＝5.1Hz,1H),3.82(s,3H),3.20–3.07(m,3H),2.91–2.88(m,1H),2.63(m,1H),2.26–2.09(m,1H).
实施例50：化合物60的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率48.25％。
1H NMR(600MHz,DMSO-d6)δ14.22(s,1H),9.07(s,1H),8.62(s,3H),8.38(dd,J＝8.4,3.4Hz,1H),7.92–7.86(m,1H),7.63(d,J＝7.3Hz,1H),7.48(m,2H),7.41(s,1H),7.30–7.25(m,1H),5.92(m,2H),5.39(m,1H),4.61(dt,J＝11.7,3.6Hz,1H),4.57– 4.48(m,1H),4.37(d,J＝3.6Hz,1H),3.82(s,3H),3.16–3.06(m,1H),2.89(dd,J＝13.7,3.0Hz,1H),2.69–2.55(m,1H),2.17(m,1H).
实施例51：化合物61的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率53.25％。
1H NMR(400MHz,DMSO-d6)δ10.41(s,1H),8.64(s,4H),8.10(d,J＝8.3Hz,1H),7.94–7.83(m,1H),7.72(d,J＝7.3Hz,1H),7.65–7.37(m,3H),7.27(d,J＝8.1Hz,1H),5.92(dd,J＝21.8,9.7Hz,2H),5.39(dd,J＝13.0,5.3Hz,1H),4.37(s,1H),3.47(dd,J＝16.3,9.0Hz,6H),3.18–3.08(m,1H),2.89(d,J＝16.7Hz,1H),2.67–2.56(m,12H),2.20–2.11(m,1H).
实施例52：化合物62的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率62.25％。
1H NMR(600MHz,DMSO-d6)δ9.65(s,1H),8.54(s,3H),8.19(d,J＝8.4Hz,1H),7.93–7.87(m,1H),7.69(d,J＝7.3Hz,1H),7.52(d,J＝7.7Hz,1H),7.49–7.40(m,2H),7.31(d,J＝8.5Hz,2H),7.25(d,J＝8.5Hz,3H),5.93(dd,J＝43.8,9.6Hz,1H),5.41(dd,J＝13.0,5.4Hz,1H),4.33(t,J＝6.6Hz,1H),3.82(s,3H),3.70(s,3H),3.19–3.07(m,3H),2.89(dd,J＝13.6,3.1Hz,1H),2.63(m,1H),2.24–2.07(m,1H).
实施例53：化合物63的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率41.36％。
1H NMR(400MHz,DMSO-d6)δ9.09(s,1H),8.75(s,3H),8.36(d,J＝8.4Hz,1H),7.92–7.86(m,1H),7.64(d,J＝7.3Hz,1H),7.49(dt,J＝15.5,7.6Hz,2H),7.41(s,1H),7.27(d,J＝7.9Hz,1H),5.92(dt,J＝17.7,7.2Hz,2H),5.40(dd,J＝12.8,5.1Hz,1H),4.63–4.51(m,3H),3.82(s,3H),3.80(d,J＝1.7Hz,3H),3.16–3.06(m,1H),2.89(d,J＝16.5Hz,1H),2.68–2.56(m,1H),2.22–2.11(m,1H).
实施例54：化合物64的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率38.15％。
1H NMR(400MHz,DMSO-d6)δ8.56(s,3H),8.17–8.08(m,1H),7.88(ddd,J＝7.5,5.5,3.4Hz,3H),7.72(d,J＝7.4Hz,1H),7.10–7.04(m,2H),5.88(m,2H),5.38(dd,J＝12.6,4.9Hz,1H),4.21(t,J＝5.5Hz,1H),3.84(s,3H),3.55–3.40(m,3H),3.16–3.04(m,1H),2.94–2.85(m,1H),2.62(ddd,J＝17.7,13.0,4.2Hz,1H),2.19–2.10(m,1H).
实施例55：化合物65的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率49.26％。
1H NMR(400MHz,DMSO-d6)δ9.65(s,1H),8.19(d,J＝8.3Hz,1H),7.94–7.82(m,3H),7.68(d,J＝7.3Hz,1H),7.34(d,J＝8.6Hz,2H),7.22(d,J＝8.5Hz,2H),7.15–7.02(m,2H),5.89(dd,J＝20.6,9.6Hz,2H),5.40(dd,J＝13.0,5.4Hz,1H),3.90(t,J＝6.0Hz,1H),3.81(s,3H),3.20–3.00(m,3H),2.95–2.85(m,1H),2.71–2.57(m,1H),2.24–2.06(m,1H).
实施例56：化合物66的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率51.36％。
1H NMR(400MHz,DMSO-d6)δ9.06(s,1H),8.44(s,3H),8.39(dd,J＝8.5,2.7Hz,1H),7.88(t,J＝7.6Hz,3H),7.63(d,J＝7.3Hz,1H),7.07(d,J＝8.8Hz,2H),5.88(s,2H),5.39(dd,J＝13.0,3.5Hz,1H),4.65–4.43(m,2H),4.18(s,1H),3.84(s,3H),3.18–3.04(m,1H),2.88(d,J＝17.2Hz,1H),2.62(dt,J＝13.3,11.7Hz,1H),2.24–2.11(m,1H).
实施例57：化合物67的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率61.25％。
1H NMR(600MHz,DMSO-d6)δ9.04(s,1H),8.99–8.70(s,3H),8.10(m,1H),7.90–7.87(m,3H),7.72(m,1H),7.07(d,J＝8.9Hz,2H),5.88(d,J＝10.5Hz,2H),5.43–5.37(m,1H),4.30(t,J＝5.7Hz,1H),3.84(s,3H),3.52–3.44(m,2H),3.14–3.08(m,1H),2.89(dd,J＝13.8,3.2Hz,1H),2.66–2.59(m,1H),2.18–2.12(m,1H).
实施例58：化合物68的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率62.25％。
1H NMR(400MHz,DMSO-d6)δ9.67(s,1H),8.19(d,J＝8.3Hz,1H),7.89(d,J＝8.9Hz,3H),7.69(d,J＝7.2Hz,1H),7.26(dd,J＝28.6,8.6Hz,4H),7.08–7.03(m,2H),5.89(dd,J＝21.2,9.6Hz,2H),5.40(dd,J＝13.0,5.4Hz,1H),4.17(t,J＝6.6Hz,1H), 3.81(s,3H),3.16–3.04(m,3H),2.93–2.85(m,1H),2.71–2.57(m,1H),2.16(dd,J＝8.9,3.8Hz,1H).
实施例59：化合物69的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率59.25％。
1H NMR(400MHz,DMSO-d6)δ8.34(d,J＝8.5Hz,1H),8.22(s,3H),7.88(d,J＝8.7Hz,3H),7.64(d,J＝7.3Hz,1H),7.07(d,J＝8.9Hz,2H),5.89(d,J＝11.5Hz,2H),5.39(dd,J＝12.8,5.0Hz,1H),4.58–4.48(m,2H),4.44(t,J＝3.8Hz,1H),3.84(s,3H),3.18–3.05(m,1H),2.89(dd,J＝13.7,2.9Hz,1H),2.66–2.57(m,1H),2.21–2.11(m,1H).
通用合成方法4：
采用步骤A’、步骤B和步骤E合成。
将S1(1.0当量)、EDCI(0.5当量)、HOBT(2.5当量)、TEA(5.0当量)分散在干燥的DCM中，室温搅拌下滴加苄氧胺(1.0当量)的DCM溶液，室温搅拌3天，加入DCM、1N HCl、饱和碳酸氢钠、饱和食盐水萃取，用无水Na2SO4干燥有机相，减压浓缩后，室温析晶，过滤。得到S3。
将S3溶于DCM中，低温下加入三氟乙酸，室温搅拌4h，减压蒸馏，得淡粉色S4。将S4(1.0当量)、S5(1.0当量)和乙酸钠(2.0当量)分散在乙酸中，加入分子筛于90℃搅拌过夜，热过滤除去分子筛，冷却，析出白色固体，水冲洗，干 燥得S6。
将S6(1.0当量)置于甲苯和水的混合溶液中，加入铁粉(2.0当量)，催化量的醋酸铵,100℃反应5h，加入乙酸乙酯、水、饱和食盐水萃取，无水硫酸钠干燥，减压蒸馏后，用甲醇分散，过滤，得式(C)。
将式(C)采用通用合成方法2继续进行反应，得终产物。
实施例60：化合物70的制备
采用通用方法4制备，最终得盐酸盐为黄色固体，收率61.25％。
1H NMR(600MHz,DMSO-d6)δ9.09(s,1H),8.66(s,3H),8.39(dd,J＝8.5,3.0Hz,1H),7.90(dd,J＝8.4,7.5Hz,1H),7.65(d,J＝7.3Hz,1H),7.51(dd,J＝7.5,1.8Hz,2H),7.44–7.36(m,3H),5.38(m,1H),4.93(s,2H),4.65–4.52(m,2H),4.39(t,J＝3.7Hz,1H),3.13–2.98(m,1H),2.87–2.78(m,1H),2.59–2.52(m,1H),2.19–2.08(m,1H).
实施例61：化合物71的制备
具体合成过程如下：将实施例60产物溶于甲醇中，加入钯碳，在氢气环境下室温反应。待反应完成后，过滤掉钯碳，减压蒸干，加乙酸乙酯分散，过滤，用乙酸乙酯和正庚烷淋洗，得到盐酸盐产物为黄色固体，收率83.41％。
1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),9.08(s,1H),8.60(s,3H),8.38(dd,J＝8.4,1.6Hz,1H),7.89(dd,J＝8.4,7.4Hz,1H),7.63(d,J＝7.3Hz,1H),5.34(dd,J＝12.9,5.3Hz,1H),4.66–4.47(m,2H),4.32(s,1H),3.09–2.97(m,1H),2.79(dd,J＝13.1,2.7Hz,1H),2.56(dd,J＝13.2,4.5Hz,1H),2.13–2.03(m,1H).
实施例62：化合物72的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率37.51％。
1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),8.47(s,3H),8.15–8.10(m,1H),7.93–7.85(m,2H),7.72(m,2H),7.44(t,J＝7.6Hz,1H),7.26(d,J＝7.7Hz,1H),5.92–5.81(m,2H),5.38(dd,J＝12.6,4.9Hz,1H),4.25(s,1H),3.54–3.43(m,2H),3.16–3.06(m,1H),2.90(d,J＝17.6Hz,1H),2.62(m,1H),2.29–2.22(m,3H),2.20–2.12(m,1H).
实施例63：化合物73的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率42.47％。
1H NMR(400MHz,DMSO-d6)δ13.94(s,1H),9.68(s,1H),8.38(s,3H),8.19(d,J＝8.3Hz,1H),7.90(t,J＝7.7Hz,2H),7.69(t,J＝6.5Hz,2H),7.43(t,J＝7.6Hz,1H),7.34(d,J＝8.5Hz,2H),7.25(d,J＝8.3Hz,2H),5.87(q,J＝9.7Hz,2H),5.40(dd,J＝13.0,5.3Hz,1H),4.21(t,J＝6.1Hz,1H),3.20–3.06(m,3H),2.90(d,J＝16.8Hz,1H),2.72–2.56(m,2H),2.26(s,3H),2.22–2.11(m,1H).
实施例64：化合物74的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率51.46％。
1H NMR(400MHz,DMSO-d6)δ14.24(s,1H),9.08(d,J＝4.7Hz,1H),8.58(s,3H),8.38(dd,J＝8.5,2.4Hz,1H),7.93–7.86(m,2H),7.72(td,J＝7.6,1.4Hz,1H),7.64(d,J＝7.3Hz,1H),7.47–7.41(m,1H),7.26(d,J＝8.1Hz,1H),5.86(s,2H),5.38(m,1H), 4.64–4.50(m,2H),4.44(s,1H),3.16–3.04(m,1H),2.91-2.87(m,1H),2.62(d,J＝10.2Hz,1H),2.26(d,J＝0.8Hz,3H),2.20–2.13(m,1H).
实施例65：化合物75的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率61.25％。
1H NMR(400MHz,DMSO-d6)δ8.68(s,3H),8.09(dd,J＝8.0,4.0Hz,1H),7.93–7.87(m,2H),7.76–7.70(m,2H),7.43(dd,J＝11.0,4.3Hz,1H),7.26(dd,J＝8.1,1.0Hz,1H),5.91–5.83(m,2H),5.38(dd,J＝13.0,5.3Hz,1H),4.37(t,J＝5.5Hz,1H),3.75(d,J＝0.8Hz,3H),3.55–3.42(m,2H),3.17–3.05(m,1H),2.90(dd,J＝12.3,4.3Hz,1H),2.62(m,1H),2.26(s,3H),2.19–2.11(m,1H).
实施例66：化合物76的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率52.47％。
1H NMR(600MHz,DMSO-d6)δ9.66(s,1H),8.58(s,3H),8.19(d,J＝8.4Hz,1H),7.94–7.86(m,2H),7.69(dd,J＝11.6,4.4Hz,2H),7.42(dd,J＝11.0,4.3Hz,1H),7.31(d,J＝8.5Hz,2H),7.25(d,J＝8.4Hz,3H),5.87(dd,J＝22.0,9.7Hz,2H),5.39(dd,J＝13.0,5.4Hz,1H),4.33(s,1H),3.70(s,3H),3.22–3.07(m,3H),2.90(dd,J＝13.6,2.8Hz,1H),2.64(dd,J＝13.4,4.5Hz,1H),2.26(s,3H),2.20–2.13(m,1H).
实施例67：化合物77的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率59.36％。
1H NMR(400MHz,DMSO-d6)δ9.09(d,J＝2.3Hz,1H),8.75(s,3H),8.36(d,J＝8.5Hz,1H),7.96–7.87(m,2H),7.72(t,J＝6.9Hz,1H),7.65(d,J＝7.2Hz,1H),7.48–7.42(m,1H),7.26(d,J＝8.0Hz,1H),5.86(s,2H),5.39(dd,J＝13.2,5.1Hz,1H),4.67–4.51(m,3H),3.79(d,J＝2.1Hz,3H),3.18–3.05(m,1H),2.94–2.88(m,1H),2.69–2.57(m,1H),2.26(s,3H),2.20–2.13(m,1H).
实施例68：化合物78的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率57.25％。
1H NMR(400MHz,DMSO-d6)δ9.67(s,1H),8.18(d,J＝8.4Hz,1H),8.06(s,2H),7.93–7.86(m,1H),7.69(d,J＝7.3Hz,1H),7.27(dd,J＝26.7,8.5Hz,4H),5.61(dd,J＝24.0,9.4Hz,2H),5.35(dd,J＝13.0,5.4Hz,1H),4.25(t,J＝6.5Hz,1H),3.69(s,3H),3.16–3.03(m,3H),2.86(d,J＝3.2Hz,1H),2.80(s,6H),2.65–2.55(m,1H),2.19–2.10(m,1H).
实施例69：化合物79的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率48.25％。
1H NMR(400MHz,DMSO-d6)δ7.48(dd,J＝8.4,7.1Hz,1H),7.19(s,2H),7.02(t,J＝7.3Hz,2H),6.55(s,2H),5.63–5.57(m,2H),5.22(dd,J＝13.0,5.4Hz,1H),4.38(d,J ＝4.0Hz,1H),3.77–3.63(m,3H),3.04(ddd,J＝25.7,15.7,8.7Hz,2H),2.86–2.72(m,9H),2.15–2.05(m,2H).
实施例70：化合物80的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率53.46％。
1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),8.66(s,3H),8.10(d,J＝8.3Hz,1H),7.97–7.82(m,1H),7.72(d,J＝7.3Hz,1H),5.61(dd,J＝20.7,9.6Hz,2H),5.32(dd,J＝13.0,5.4Hz,1H),4.37(t,J＝5.4Hz,1H),3.84–3.68(m,3H),3.47(ddd,J＝22.2,16.2,5.7Hz,2H),3.12–2.99(m,1H),2.80(s,6H),2.68–2.54(m,2H),2.20–2.06(m,1H).
实施例71：化合物81的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率57.15％。
1H NMR(400MHz,DMSO-d6)δ8.57(d,J＝8.9Hz,2H),8.13(d,J＝8.2Hz,1H),7.88(t,J＝7.8Hz,1H),7.72(d,J＝7.3Hz,1H),5.61(dd,J＝20.8,9.5Hz,2H),5.33(dd,J＝ 12.9,5.3Hz,1H),4.19(s,1H),3.58–3.36(m,3H),3.16–2.97(m,2H),2.83(d,J＝23.5Hz,6H),2.66–2.53(m,2H),2.12(d,J＝5.6Hz,1H).
实施例72：化合物82的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率62.36％。
1H NMR(400MHz,DMSO-d6)δ9.07(s,1H),8.58(s,2H),8.38(dd,J＝8.5,1.8Hz,1H),7.89(t,J＝7.9Hz,1H),7.63(d,J＝7.3Hz,1H),5.61(ddd,J＝11.4,9.5,3.1Hz,2H),5.33(ddd,J＝13.0,5.1,2.6Hz,1H),4.57(dtd,J＝18.1,11.6,4.8Hz,2H),4.34(s,1H),3.17(s,1H),3.06(dd,J＝22.1,8.8Hz,1H),2.86(s,1H),2.77(d,J＝27.5Hz,6H),2.66–2.52(m,2H),2.19–2.06(m,1H).
实施例73：化合物83的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率42.47％。
1H NMR(400MHz,DMSO-d6)δ9.67(s,1H),8.18(d,J＝8.3Hz,1H),7.90(t,J＝7.8Hz,1H),7.69(d,J＝7.3Hz,1H),7.29(dd,J＝46.5,8.4Hz,4H),5.61(dd,J＝24.2,9.4Hz,2H),5.34(dd,J＝13.0,5.3Hz,1H),3.99(d,J＝6.1Hz,1H),3.23–2.99(m,4H),2.85(d,J＝14.7Hz,1H),2.80(s,6H),2.69–2.53(m,2H),2.21–2.08(m,1H).
实施例74：化合物84的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率58.47％。
1H NMR(400MHz,DMSO-d6)δ9.66(s,1H),8.29(s,3H),8.18(s,1H),7.95–7.83(m,1H),7.69(d,J＝7.2Hz,1H),7.28(dd,J＝30.8,8.6Hz,4H),5.62(dd,J＝20.0,9.3Hz,2H),5.35(dd,J＝12.9,5.4Hz,1H),4.26(t,J＝6.5Hz,1H),3.69(s,3H),3.24–3.01(m,7H),2.85(dd,J＝13.8,3.1Hz,1H),2.64–2.55(m,1H),2.21–2.07(m,1H),1.02(t,J＝6.5Hz,6H).
实施例75：化合物85的制备

采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率46.25％。
1H NMR(600MHz,DMSO-d6)δ9.08(s,1H),8.82(s,3H),8.36(d,J＝8.5Hz,1H),7.92–7.86(m,1H),7.64(d,J＝7.3Hz,1H),5.66–5.55(m,2H),5.33(ddd,J＝13.0,5.3,3.1Hz,1H),4.66–4.53(m,3H),3.80(s,3H),3.17(d,J＝26.0Hz,4H),3.07(dd,J＝22.0,9.7Hz,1H),2.85(dd,J＝13.8,3.0Hz,1H),2.56(m,1H),2.21–2.05(m,1H),1.02(s,6H).
实施例76：化合物86的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率56.14％。
1H NMR(600MHz,DMSO-d6)δ8.92(s,3H),8.11(dd,J＝8.3,1.4Hz,1H),7.91–7.86(m,1H),7.71(d,J＝7.3Hz,1H),5.66–5.57(m,2H),5.33(dd,J＝13.0,5.4Hz,1H),4.31(t,J＝4.7Hz,1H),3.74(s,3H),3.53–3.43(m,2H),3.17(d,J＝23.0Hz,4H),3.09–3.03(m,1H),2.85(dd,J＝13.8,3.1Hz,1H),2.56(m,1H),2.15–2.08(m,1H),1.02(s,6H).
实施例77：化合物87的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率66.14％。
1H NMR(600MHz,DMSO-d6)δ8.13(d,J＝8.4Hz,1H),7.88(t,J＝7.8Hz,1H),7.71(d,J＝7.2Hz,1H),5.61(m,2H),5.35–5.30(m,1H),4.17(m,1H),3.46(dd,J＝60.7,12.3Hz,2H),3.17(d,J＝23.6Hz,4H),3.11–3.03(m,1H),2.84(d,J＝17.6Hz,1H),2.56(dd,J＝13.5,4.4Hz,1H),2.12(d,J＝7.0Hz,1H),1.02(s,6H).
实施例78：化合物88的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率47.36％。
1H NMR(400MHz,DMSO-d6)δ9.06(s,1H),8.53(s,2H),8.38(d,J＝8.2Hz,1H),7.91–7.84(m,1H),7.63(d,J＝7.2Hz,1H),5.66–5.56(m,2H),5.38–5.28(m,1H),4.55(dd,J＝41.2,11.9Hz,2H),4.34(s,1H),3.23–3.03(m,5H),2.84(d,J＝17.4Hz,1H),2.61–2.53(m,1H),2.14(d,J＝4.5Hz,1H),1.01(s,5H).
实施例79：化合物89的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率57.25％。
1H NMR(600MHz,DMSO-d6)δ9.64(s,1H),8.34(s,2H),8.19(d,J＝8.4Hz,1H),7.90(t,J＝7.8Hz,1H),7.69(d,J＝7.2Hz,1H),7.35(d,J＝7.6Hz,2H),7.24(d,J＝7.2Hz,2H),5.62(dd,J＝28.7,9.3Hz,2H),5.34(dd,J＝12.9,5.4Hz,1H),4.15(s,1H),3.23–3.04(m,7H),2.85(d,J＝16.8Hz,1H),2.57(ddd,J＝26.3,13.1,4.4Hz,1H),2.17–2.08(m,1H),1.02(s,6H).
实施例80：化合物90的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率67.52％。
1H NMR(400MHz,DMSO-d6)δ9.67(s,1H)δ8.49(s,3H),8.20(d,J＝8.4Hz,1H),7.90(t,J＝7.9Hz,1H),7.68(d,J＝7.3Hz,1H),7.36(d,J＝8.2Hz,2H),7.24(d,J＝8.2Hz,2H),5.82–5.54(m,2H),5.36(dd,J＝13.1,5.4Hz,1H),4.18(t,J＝6.3Hz,1H), 3.23–2.96(m,3H),2.85(dt,J＝17.2,3.5Hz,1H),2.60(qd,J＝13.2,4.4Hz,1H),2.28(t,J＝7.2Hz,2H),2.14(tt,J＝7.6,4.3Hz,1H),1.49(t,J＝7.1Hz,2H),1.22(dd,J＝9.6,4.7Hz,12H),0.83(t,J＝6.5Hz,3H).
实施例81：化合物91的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率62.46％。
1H NMR(600MHz,DMSO-d6)δ8.17(td,J＝9.5,8.9,3.2Hz,1H),7.87(dd,J＝8.4,7.3Hz,1H),7.72–7.62(m,1H),5.74–5.56(m,2H),5.40–5.23(m,1H),3.60–3.48(m,2H),3.25(dt,J＝13.6,6.7Hz,2H),3.07(ddt,J＝17.5,12.9,6.4Hz,1H),2.84(dt,J＝17.5,3.7Hz,1H),2.59(qd,J＝13.1,4.2Hz,1H),2.27(t,J＝7.3Hz,2H),2.19–2.04(m,1H),1.49(p,J＝7.3Hz,2H),1.22(q,J＝9.2,7.9Hz,12H),0.96–0.70(m,3H).
实施例82：化合物92的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率71.62％。
1H NMR(400MHz,DMSO-d6)δ9.07(s,1H),8.60(s,3H),8.39(dd,J＝8.6,2.1Hz,1H),7.89(t,J＝7.9Hz,1H),7.62(d,J＝7.4Hz,1H),5.70–5.62(m,2H),5.34(ddd,J＝13.2,5.3,2.2Hz,1H),4.56(ddt,J＝38.7,11.7,3.7Hz,2H),4.32(t,J＝4.1Hz,1H),3.08(ddd,J＝18.1,13.9,5.4Hz,1H),2.84(dt,J＝17.1,3.4Hz,1H),2.59(tt,J＝12.8,6.2Hz,1H),2.27(t,J＝7.3Hz,2H),2.17–2.09(m,1H),1.49(t,J＝7.2Hz,2H),1.23–1.19(m,13H),0.83(t,J＝6.5Hz,3H).
实施例83：化合物93的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率59.25％。
1H NMR(400MHz,DMSO-d6)δ9.68(S,1H),8.29–8.11(m,1H),7.91(s,1H),7.68(s,1H),7.32(d,J＝75.2Hz,2H),5.70(d,J＝28.0Hz,2H),5.52–5.20(m,1H),4.20(s,1H),3.17(s,3H),2.87(s,1H),2.28(s,1H),2.15(s,1H),1.99(s,1H),1.49(s,2H),1.22(d,J＝12.4Hz,14H),0.84(d,J＝7.4Hz,3H).
实施例84：化合物94的制备

采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率69.25％。
1H NMR(400MHz,DMSO-d6)δ8.50(s,3H),8.13(d,J＝8.2Hz,1H),7.88(t,J＝7.9Hz,1H),7.71(d,J＝7.3Hz,1H),5.81–5.56(m,2H),5.34(dd,J＝13.1,5.3Hz,1H),4.34–4.08(m,2H),3.58–3.37(m,5H),3.17–2.91(m,2H),2.93–2.75(m,1H),2.27(t,J＝7.3Hz,2H),2.19–2.06(m,1H),1.57–1.42(m,2H),1.22(d,J＝5.1Hz,12H),0.84(t,J＝6.6Hz,3H).
实施例85：化合物95的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率59.25％。
1H NMR(400MHz,DMSO-d6)δ8.21(d,J＝8.3Hz,1H),7.90(dd,J＝8.4,7.3Hz,1H),7.67(d,J＝7.2Hz,2H),7.34(d,J＝8.6Hz,2H),7.27–7.04(m,2H),5.73–5.55(m,2H),5.35(dd,J＝13.1,5.4Hz,1H),3.46(t,J＝6.0Hz,1H),3.24–2.98(m,3H),2.99–2.77(m,2H),2.60(qd,J＝13.2,4.4Hz,2H),2.28(t,J＝7.2Hz,2H),1.57–1.41(m,2H),1.20(s,14H),0.84(t,J＝6.8Hz,3H).
实施例86：化合物96的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率49.25％。
1H NMR(600MHz,DMSO-d6)δ9.62(s,1H),8.21(d,J＝8.3Hz,1H),7.90(t,J＝7.9Hz,1H),7.67(d,J＝7.2Hz,1H),7.36(d,J＝8.3Hz,2H),7.19(d,J＝8.4Hz,2H),5.66(dd,J＝18.3,9.6Hz,2H),5.35(dd,J＝13.1,5.3Hz,1H),3.62(s,1H),3.20–3.05(m,2H),2.99(dd,J＝14.4,7.4Hz,1H),2.85(d,J＝16.9Hz,1H),2.60(dt,J＝13.4,8.8Hz,1H),2.28(t,J＝7.2Hz,2H),2.20–2.10(m,1H),1.48(d,J＝6.8Hz,2H),1.33–1.10(m,22H),0.84(t,J＝6.9Hz,3H).
实施例87：化合物97的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率71.23％。
1H NMR(600MHz,DMSO-d6)δ9.97(s,1H),8.05(d,J＝8.5Hz,1H),7.79(t,J＝7.9Hz,1H),7.40(d,J＝7.2Hz,1H),5.77–5.53(m,2H),5.57(dd,J＝12.8,4.5Hz,1H),4.61(d,J＝9.9Hz,1H),4.44–4.34(m,1H),3.68(s,1H),3.15–3.05(m,1H), 2.84(d,J＝17.1Hz,1H),2.63–2.55(m,1H),2.34(t,J＝7.2Hz,2H),2.18–2.09(m,1H),1.53–1.45(m,2H),1.33–1.26(m,22H),0.85(t,J＝6.9Hz,3H).
实施例88：化合物98的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率52.62％。
1H NMR(600MHz,DMSO-d6)δ9.02(s,1H),8.41(d,J＝8.5Hz,1H),7.87(t,J＝7.9Hz,1H),7.59(d,J＝7.2Hz,1H),5.77–5.53(m,2H),5.34(dd,J＝12.8,4.5Hz,1H),4.61(d,J＝9.9Hz,1H),4.44–4.34(m,1H),3.80(s,1H),3.15–3.05(m,1H),2.84(d,J＝17.1Hz,1H),2.63–2.55(m,1H),2.27(t,J＝7.2Hz,2H),2.18–2.09(m,1H),1.53–1.45(m,2H),1.32–1.14(m,22H),0.85(t,J＝6.9Hz,3H).
实施例89：化合物99的制备
采用通用合成方法4制备，得盐酸盐为黄色固体，收率60.17％。
1H NMR(600MHz,DMSO-d6)δ9.09(s,1H),8.66(s,3H),8.39(dd,J＝8.5,3.0Hz,1H),7.90(dd,J＝8.4,7.5Hz,1H),7.65(d,J＝7.3Hz,1H),7.51(dd,J＝7.5,1.8Hz,2H),7.44–7.36(m,3H),5.38(m,1H),4.93(s,2H),4.65–4.52(m,2H),4.39(t,J＝3.7Hz,1H),3.13–2.98(m,1H),2.87–2.78(m,1H),2.59–2.52(m,1H),2.19–2.08(m, 1H).
实施例90：化合物100的制备
合成方法同实施例61，得盐酸盐为黄色固体，收率80.12％。
1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),9.08(s,1H),8.60(s,3H),8.38(dd,J＝8.4,1.6Hz,1H),7.89(dd,J＝8.4,7.4Hz,1H),7.63(d,J＝7.3Hz,1H),5.34(dd,J＝12.9,5.3Hz,1H),4.66–4.47(m,2H),4.32(s,1H),3.09–2.97(m,1H),2.79(dd,J＝13.1,2.7Hz,1H),2.56(dd,J＝13.2,4.5Hz,1H),2.13–2.03(m,1H).
实施例91：化合物101的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率58.25％。
1H NMR(600MHz,DMSO-d6)δ9.65(s,1H),8.74(s,3H),8.21(d,J＝8.4Hz,1H),8.03–7.87(m,1H),7.68(d,J＝7.3Hz,1H),7.33(d,J＝8.6Hz,2H),7.24(d,J＝8.4Hz,2H),5.66(dd,J＝18.4,9.6Hz,2H),5.36(dd,J＝13.1,5.4Hz,1H),4.29(t,J＝6.5Hz,1H),3.69(s,3H),3.23(dd,J＝14.1,5.8Hz,1H),3.19–3.03(m,2H),2.85(dd,J＝13.9,3.0Hz,1H),2.60(qd,J＝13.2,4.4Hz,1H),2.32–2.24(m,2H),2.19– 2.08(m,1H),1.49(dd,J＝13.8,6.9Hz,2H),1.27–1.16(m,24H),0.84(t,J＝7.0Hz,3H).
实施例92：化合物102的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率65.53％。
1H NMR(600MHz,DMSO-d6)δ9.14–8.69(m,2H),8.05(S,1H),7.79(S,1H),7.4(S,1H),7.73–7.62(m,1H),5.53–5.49(m,2H),5.37–5.27(m,1H),4.44(S,1H),3.78–3.66(m,3H),3.47(qd,J＝14.6,6.1Hz,2H),3.07(ddd,J＝19.5,12.4,5.5Hz,1H),2.84(dd,J＝13.7,3.0Hz,1H),2.59(qd,J＝13.1,4.6Hz,1H),2.27–2.21(m,2H),2.12(dd,J＝9.1,3.7Hz,1H),1.66(d,J＝6.7Hz,2H),1.26(s,22H),0.88(dd,J＝9.2,4.1Hz,3H).
实施例93：化合物103的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率61.22％。
1H NMR(600MHz,DMSO-d6)δ9.14–8.69(m,2H),8.64–8.39(m,1H),8.19–8.08(m,1H),7.91–7.80(m,1H),7.73–7.62(m,1H),5.70–5.60(m,2H),5.37–5.27(m,1H),4.36–4.24(m,1H),3.78–3.71(m,3H),3.47(qd,J＝14.6,6.1Hz,2H),3.07(ddd,J＝19.5,12.4,5.5Hz,1H),2.84(dd,J＝13.7,3.0Hz,1H),2.59(qd,J＝13.1,4.6Hz,1H),2.28–2.24(m,2H),2.12(dd,J＝9.1,3.7Hz,1H),1.48(d,J＝6.7Hz,2H),1.21(s,22H),0.85(dd,J＝9.2,4.1Hz,3H).
实施例94：化合物111的制备
采用通用合成方法1制备，得盐酸盐为淡黄色固体，收率56.25％。
1H NMR(600MHz,DMSO-d6)δ11.16(s,1H),9.66(s,1H),8.54(s,3H),8.18(d,J＝8.4Hz,1H),7.89(t,J＝7.9Hz,1H),7.68(d,J＝7.3Hz,1H),7.28(dd,J＝35.7,8.5Hz,4H),5.17(dd,J＝12.9,5.4Hz,1H),4.48–4.23(m,1H),3.71(s,3H),3.15(qd,J＝14.2,6.6Hz,2H),3.03–2.81(m,1H),2.69–2.53(m,2H),2.16–2.02(m,1H).
实施例95：化合物S9的制备
采用通用合成方法4制备，得盐酸盐为淡黄固体，收率60.25％。
1H NMR(600MHz,DMSO-d6)δ9.69(s,1H),8.41(s,2H),8.19(d,J＝8.4Hz,1H),7.96–7.87(m,1H),7.71(d,J＝7.3Hz,1H),7.51(dd,J＝7.6,2.0Hz,2H),7.40(q,J＝5.3Hz,3H),7.35(d,J＝8.6Hz,2H),7.25(d,J＝8.5Hz,2H),5.40(dd,J＝12.9,5.3Hz,1H),4.93(s,2H),4.18(t,J＝6.4Hz,1H),3.19–3.10(m,2H),3.07–2.99(m,1H),2.85–2.78(m,1H),2.61–2.53(m,1H),2.12(ddd,J＝7.8,4.3,2.1Hz,1H).
实施例96：化合物S10的制备
合成方法同实施例61，得盐酸盐为黄色固体，收率52.73％
1H NMR(600MHz,DMSO-d6)δ10.33(s,1H),9.67(s,1H),8.32(s,3H),8.18(d,J＝8.4Hz,1H),7.90(t,J＝7.9Hz,1H),7.69(d,J＝7.3Hz,1H),7.34(d,J＝8.6Hz,2H),7.25(d,J＝8.5Hz,1H),5.36(dd,J＝12.9,5.3Hz,1H),4.24–4.16(m,2H),3.16–3.09(m,1H),3.04(ddd,J＝17.2,13.7,5.4Hz,3H),2.80(ddd,J＝17.1,4.5,2.6Hz,6H),2.56(dd,J＝13.3,4.7Hz,20H),2.13–2.03(m,1H).
实施例97：化合物112的制备

采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率62.45％。
1H NMR(600MHz,DMSO-d6)δ9.64(s,1H),8.61(s,3H),8.20(d,J＝8.4Hz,1H),7.90(t,J＝7.9Hz,1H),7.68(d,J＝7.3Hz,1H),7.32(d,J＝8.3Hz,2H),7.24(d,J＝8.4Hz,2H),5.66(q,J＝9.7Hz,2H),5.35(dd,J＝13.1,5.4Hz,1H),4.32(t,J＝6.6Hz,1H),3.70(s,3H),3.21–3.03(m,3H),2.85(dt,J＝17.3,3.6Hz,1H),2.60(qd,J＝13.2,4.4Hz,1H),2.28(t,J＝7.3Hz,2H),1.53–1.45(m,2H),1.21(q,J＝11.0,8.8Hz,12H),0.83(t,J＝7.0Hz,3H).
实施例98：化合物113的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率71.36％。
1H NMR(400MHz,DMSO-d6)δ8.53(dd,J＝22.6,8.4Hz,1H),8.13(t,J＝7.8Hz,1H),7.91–7.61(m,3H),7.46(dd,J＝8.4,5.5Hz,1H),5.71–5.58(m,J＝3.3Hz,3H),5.33(dt,J＝13.3,4.9Hz,1H),3.70(d,J＝7.1Hz,3H),2.85(ddd,J＝14.5,6.6,3.5Hz,1H),2.58(dt,J＝13.9,4.5Hz,1H),2.27(td,J＝7.3,3.5Hz,3H),2.15–2.07(m,1H),1.55–1.39(m,3H),1.21(t,J＝6.4Hz,14H),0.83(q,J＝2.8Hz,3H).
实施例99：化合物114的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率63.45％。
1H NMR(400MHz,DMSO-d6)δ8.27(d,J＝8.4Hz,1H),7.86(dd,J＝8.5,7.3Hz,1H),7.61(d,J＝7.3Hz,1H),5.71–5.57(m,2H),5.32(dd,J＝13.1,5.4Hz,1H),4.26(dd,J＝5.3,1.4Hz,2H),3.65(s,3H),3.07(ddd,J＝17.8,13.7,5.4Hz,1H),2.91–2.78(m,1H),2.67–2.54(m,1H),2.27(t,J＝7.2Hz,2H),2.11(d,J＝12.8Hz,1H),1.49(s,2H),1.21(d,J＝5.6Hz,14H),0.83(td,J＝6.7,3.9Hz,3H).
实施例100：化合物115的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率68.14％。
1H NMR(400MHz,DMSO-d6)δ9.66(s,1H),8.61(s,3H),8.20(d,J＝8.3Hz,1H),7.90(dd,J＝8.4,7.3Hz,1H),7.68(d,J＝7.3Hz,1H),7.36–7.20(m,4H),5.73–5.61(m,2H),5.36(dd,J＝13.0,5.4Hz,1H),4.33(t,J＝6.6Hz,1H),3.70(s,3H),3.23–3.02(m,3H),2.85(dt,J＝16.9,3.6Hz,1H),2.60(qd,J＝13.2,4.4Hz,1H),2.28(t,J＝ 7.2Hz,2H),2.19–2.07(m,1H),1.55–1.43(m,2H),1.21(d,J＝6.6Hz,16H),0.87–0.79(m,3H).
实施例101：化合物116的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率59.25％。
1H NMR(400MHz,DMSO-d6)δ8.53(dd,J＝23.8,8.2Hz,1H),8.14(d,J＝8.3Hz,1H),7.91–7.78(m,1H),7.76–7.64(m,1H),5.64(dd,J＝9.3,5.0Hz,2H),5.32(tt,J＝8.5,4.8Hz,1H),3.69(d,J＝5.9Hz,2H),3.32–3.20(m,2H),3.07(dq,J＝16.1,6.9,4.9Hz,1H),2.84(dd,J＝18.2,4.0Hz,1H),2.59(ddt,J＝13.4,8.8,4.4Hz,1H),2.30–2.24(m,2H),2.16–2.07(m,1H),1.49(t,J＝7.0Hz,2H),1.20(d,J＝5.0Hz,16H),0.84(td,J＝6.7,3.3Hz,3H).
实施例102：化合物117的制备
采用通用合成方法3制备，得盐酸盐为淡黄色固体，收率67.15％。
1H NMR(400MHz,DMSO-d6)δ8.25(t,J＝11.5Hz,1H),7.86(dd,J＝8.5,7.3Hz,1H),7.60(d,J＝7.3Hz,1H),6.54(s,1H),5.68–5.61(m,2H),5.28(ddd,J＝37.7,13.0,5.3Hz,2H),4.26(dd,J＝5.4,1.4Hz,2H),3.65(s,3H),3.14–2.99(m,2H),2.83(d,J＝17.9Hz,1H),2.59(dt,J＝13.2,6.6Hz,1H),1.48(d,J＝6.8Hz,3H),1.21(d,J＝6.3Hz,18H),0.83(dt,J＝7.1,2.8Hz,3H).
实施例103：化合物118的制备
采用通用合成方法1制备，得类白色固体，收率58.35％。
1H NMR(600MHz,DMSO)δ11.14(s,1H),9.64(s,1H),8.61(s,3H),8.18(d,J＝8.4Hz,1H),7.89(t,J＝7.9Hz,1H),7.67(d,J＝7.3Hz,1H),7.29(dd,J＝48.1,8.5Hz,4H),5.16(dd,J＝12.9,5.4Hz,1H),4.27(t,J＝6.8Hz,1H),4.17–4.06(m,2H),3.16(ddd,J＝21.7,14.1,6.8Hz,2H),2.96–2.85(m,1H),2.66–2.53(m,2H),2.12–2.01(m,1H),1.13(t,J＝7.1Hz,3H).
实施例104：化合物119的制备
采用通用合成方法1制备，得类白色固体，收率56.75％。
1H NMR(400MHz,DMSO)δ11.16(s,1H),9.67(s,1H),8.68(s,3H),8.18(d,J＝8.3Hz,1H),7.94–7.85(m,1H),7.68(d,J＝7.0Hz,1H),7.29(dd,J＝35.1,8.6Hz,4H),5.17(dd,J＝12.7,5.4Hz,1H),4.27(t,J＝6.8Hz,1H),4.20–3.98(m,2H),3.23(dd,J＝14.1,5.8Hz,1H),3.11(dd,J＝14.1,7.7Hz,1H),2.91(ddd,J＝16.7,13.7,5.3Hz,1H),2.67–2.52(m,2H),2.20–2.02(m,1H),1.12(t,J＝7.1Hz,3H).
实施例105：化合物120的制备
采用通用合成方法3制备，得白色固体，收率67.4％。
1H NMR(400MHz,DMSO)δ9.10(s,1H),8.91(s,3H),8.36(d,J＝8.4Hz,1H),7.91(dd,J＝21.2,7.8Hz,3H),7.70(t,J＝7.4Hz,1H),7.64(d,J＝7.2Hz,1H),7.56(t,J＝7.6Hz,2H),5.93(s,2H),5.40(dd,J＝13.0,5.1Hz,1H),4.67–4.51(m,3H),3.79(d,J＝3.0Hz,3H),3.20–3.04(m,1H),2.90(d,J＝16.9Hz,1H),2.64(dd,J＝20.6,7.1Hz,1H),2.22–2.11(m,1H).
实施例106：化合物121的制备
采用通用合成方法1制备，得白色固体，收率58.1％。
1H NMR(400MHz,DMSO)δ11.16(s,1H),9.66(s,1H),8.60(s,3H),8.18(d,J＝8.4Hz,1H),7.95–7.83(m,1H),7.68(d,J＝7.2Hz,1H),7.33(d,J＝8.6Hz,2H), 7.25(d,J＝8.5Hz,2H),5.17(dd,J＝12.7,5.4Hz,1H),4.96–4.85(m,1H),4.32–4.16(m,1H),3.22(dd,J＝14.0,5.8Hz,1H),3.06(dd,J＝14.0,8.1Hz,1H),2.97–2.85(m,1H),2.71–2.54(m,2H),2.14–2.02(m,1H),1.19(t,J＝13.7Hz,3H),1.07(d,J＝6.2Hz,3H).
实施例107：化合物122的制备
采用通用合成方法1制备，得白色固体，收率49.3％。
1H NMR(400MHz,DMSO)δ11.16(s,1H),9.63(s,1H),8.19(d,J＝8.5Hz,1H),7.89(t,J＝7.9Hz,1H),7.67(d,J＝7.2Hz,1H),7.34–7.26(m,2H),7.19(d,J＝8.3Hz,2H),5.17(dd,J＝12.9,5.3Hz,1H),4.20(s,1H),4.08(dd,J＝9.6,4.8Hz,2H),3.75(s,2H),3.09–2.83(m,3H),2.69–2.55(m,3H),2.07(d,J＝11.3Hz,1H),1.25(d,J＝11.6Hz,2H).
实施例108：化合物123的制备
采用通用合成方法1制备，得白色固体，收率59.5％。
1H NMR(400MHz,DMSO)δ11.16(s,1H),9.66(s,1H),8.66(s,3H),8.18(d,J＝8.3Hz,1H),7.89(t,J＝7.8Hz,1H),7.68(d,J＝7.2Hz,1H),7.29(dd,J＝32.4,8.3Hz,4H),5.17(dd,J＝12.6,5.2Hz,1H),4.30(t,J＝6.6Hz,1H),4.07(t,J＝6.4Hz,2H), 3.23(dd,J＝14.1,5.6Hz,1H),3.10(dd,J＝14.2,7.8Hz,1H),2.90(d,J＝13.4Hz,1H),2.66–2.56(m,2H),2.13–2.01(m,1H),1.56–1.42(m,2H),1.22(dq,J＝14.8,7.2Hz,2H),0.85(t,J＝7.3Hz,3H).
实施例109：化合物124的制备
采用通用合成方法1制备，得白色固体，收率62.5％。
1H NMR(600MHz,DMSO)δ11.15(s,1H),9.63(s,1H),8.66(s,3H),8.19(d,J＝8.4Hz,1H),7.89(t,J＝7.9Hz,1H),7.67(d,J＝7.3Hz,1H),7.29(dd,J＝49.4,8.5Hz,4H),5.17(dd,J＝12.9,5.4Hz,1H),4.29(s,1H),4.06(t,J＝6.6Hz,2H),3.23(dd,J＝14.1,5.8Hz,1H),3.10(dd,J＝14.1,7.9Hz,1H),2.91(ddd,J＝17.2,14.0,5.4Hz,1H),2.57(ddd,J＝23.2,17.9,10.7Hz,2H),2.14–2.03(m,1H),1.54–1.39(m,2H),1.32–1.16(m,6H),0.85(t,J＝7.0Hz,3H).
实施例110：化合物125的制备
采用通用合成方法1制备，得白色固体，收率69.3％。
1H NMR(400MHz,DMSO)δ11.17(s,1H),9.66(d,J＝17.1Hz,1H),8.63(s,2H),8.45(s,1H),8.18(d,J＝8.3Hz,1H),7.96–7.82(m,1H),7.68(d,J＝7.3Hz,1H),7.37 (ddd,J＝8.9,8.4,6.2Hz,2H),7.25(dd,J＝8.6,2.7Hz,2H),5.17(dd,J＝12.7,5.4Hz,1H),4.34(s,1H),4.19(ddd,J＝10.8,6.8,3.7Hz,1H),4.05(ddd,J＝11.2,6.5,4.9Hz,1H),3.71–3.65(m,2H),3.38(ddd,J＝12.9,11.2,5.4Hz,2H),3.32–3.26(m,1H),3.18(dd,J＝14.2,6.1Hz,2H),2.98–2.83(m,1H),2.71–2.55(m,2H),2.12–2.02(m,1H).
试验例
试验1：溶解度试验
实验方法：用5mL的离心管取约0.5mL的蒸馏水，慢慢加入干燥的的化合物至不能溶解(25℃产生震荡，仍浑浊)。将溶液过滤至另一个5mL的干净已称重的EP管中，再称重，计算出溶液的重量。将滤液冻干，称重并计算出所剩固体的溶质质量，计算溶剂的质量，进而计算化合物在水中的溶解度。结果列于表1。
表1.本发明化合物的溶解度

结论：本发明中的上述化合物在水中的溶解度远远大于已经上市药物泊马度胺，水溶性能够提高几十倍至几百倍。这种高水溶性特点在理论上能够增加和提高药物在肾脏的排泄，减轻泊马度胺存在的肾毒副作用，同时这种高水溶性特性使这些化合物容易制剂化和在临床上的应用更方便。
试验2：体外抗肿瘤活性实验
试验方法：
收集对数期生长的MM.1S细胞，调整细胞悬液浓度，以2×104个/孔的密度接种于96孔板内，37℃，5％CO2培养箱中孵育2h后，分别加入终浓度为50，10，1，0.1，0.01，0.001，0.0005，0.0001和0μM的化合物，每个化合物3个复孔，DMSO终浓度为0.5％，于37℃，5％CO2培养箱中孵育72h。孵育结束后，向细胞孔内加入20μL 5mg/mL的MTT溶液，于37℃条件下继续孵育4h后，小心吸弃上层培养基，加入150μL DMSO，置于Thermo Multiskan GO酶标仪中，震荡5min，检测570nm波长处的吸光度值A测定。以无细胞的空白孔加入DMSO后测得的吸光度值A空白作为空白，以未加药处理的细胞孔同法操作测得的吸光度值A对照作为对照，并按以下公式计算各孔细胞存活率：
细胞存活率(％)＝(A测定-A空白)/(A对照-A空白)×100％。
计算出各药物浓度下的细胞存活率，用GraphPad Prism 8.0软件对细胞存活率和药物浓度作图，计算出IC50值。
对本发明化合物进行了上述活性测定试验，结果表明，本发明化合物均对人源多发性骨髓瘤MM.1S细胞具有较强的细胞增殖抑制活性。结果见下表2。其中，IC50值小于0.01μM为A；IC50值大于0.01μM且小于0.05μM为B；IC50值大于0.05μM且小于0.1μM为C；IC50值大于0.1μM且小于0.5μM为D。
表2.本发明化合物的体外抗肿瘤效果

试验3：氨基酸转运体LAT1/SLC7A5的靶向转运研究
1、稳态细胞株的构建：
本试验自主构建了293T高表达LAT1的稳态细胞株，用于本发明化合物的靶向转运试验研究。
试验方法：将处于对数生长期的293T细胞(6×105)接种于6孔细胞培养板，置于细胞培养箱培养过夜。使用PEI试剂将已经构建好的融合表达protein C标签的LAT1-pQCXIP质粒转染到细胞中。置于细胞培养箱培养6小时，弃上清，加入2ml完全培养基继续培养；转染48小时后，荧光显微镜观察绿色荧光蛋白表达，并使用8μg/mL、5μg/mL浓度的嘌呤霉素进行筛选13天，得到稳定高表达LAT1的293T细胞。
稳态细胞株构建的结果，通过Western-Blotting试验，使用protein C抗体，检测LAT1的蛋白表达情况。检测结果如图1所示。可见，该细胞株构建成功。
2、本发明化合物的靶向细胞吸收试验
试验方法：使用293T和LAT1-293T稳态细胞株进行本试验研究。将细胞均匀铺入6cm培养皿，次日细胞长满后，使用胰蛋白酶消化收集293T和LAT1-293T细胞，用PBS重悬细胞，37℃预孵育2h。用生理盐水调节细胞浓度至1×107个/ml，分装至1.5mL离心管中，200μL/管。化合物DMSO溶解，用生理盐水稀释至20μM(DMSO终浓度0.5％)，加入到相应的离心管中，每管200μL，每个化合物3个复管。离心管颠倒混匀，37℃孵育30min。孵育结束后，8000rpm离心2min，收集 细胞沉淀，用预冷的生理盐水洗细胞2次，小心吸弃上清。每管加入50μL含2％甲酸的纯化水，涡旋2min，细胞裂解完全后，每管加入200μL乙腈甲醇混合液(乙腈：甲醇＝7:3)，等待质谱检测。
试验结果：如表3所示，本发明所提供的化合物在高表达LAT1的293T细胞裂解液中的含量明显高于普通293T细胞，表明这些化合物具有显著的LAT1靶向性。表3.本发明化合物在293T细胞和293T-LAT1细胞中的吸收情况

试验4：体内抗肿瘤药效试验Ⅰ
试验方法：
模型制备：使用6-8周NOD/SCID雌鼠，实验动物购自北京维通利华实验动物技术有限公司。动物饲养于SPF级环境下IVC系统中。所有实验动物自由摄食、饮水，室温20～25℃，温度40～70％，昼夜明暗交替时间12h/12h。将人的多发性骨髓瘤RPMI-8226细胞培养在含10％胎牛血清的1640培养液中。收集指数生长期的RPMI-8226细胞，1640培养液重悬至1×108个/mL，加入等体积Matrigel胶，小鼠皮下接种0.2mL/只注入到鼠的腋部，建立荷瘤裸鼠模型。待肿瘤生长至150～300mm3时，根据小鼠肿瘤大小和体重随机分组给药。肿瘤体积计算公式为：长径×短 径2/2。
分组给药：本试验共分为7组，分别为生理盐水组、化合物06给药组、化合物11给药组、化合物24给药组、化合物29给药组、化合物101给药组、泊马度胺给药组、每组7只。口服给药，每天1次，其中泊马度胺的剂量为15毫克每千克体重，其他药物均按照与来那度胺相比的等摩尔浓度，给药体积为10mL/kg，连续给药14天后，停药观察5天，采用每周2次测量瘤径的方法，观察受试药物的抗肿瘤效果和动物的体重变化。
试验结果：结果如表4和图2所示，本发明所化合物与临床对照药物泊马度胺相比具有更优越的肿瘤抑制效果，充分显示了本发明化合物在肿瘤细胞及肿瘤组织内的选择性蓄积和靶向性。
表4.RPMI-8226模型中的给药剂量、小鼠体重变化率和相对抑瘤率
**p＜0.01，***p＜0.001，vs溶剂对照组；体重变化率(％)＝(测量当天体重-实验初始体重)/实验初始体重×100％。
试验5：体内抗肿瘤药效试验Ⅱ
试验方法：
模型制备：将人的多发性骨髓瘤NCI-H929细胞培养在含10％胎牛血清的1640培养液中。收集指数生长期的NCI-H929细胞，1640培养液重悬至5×107个/mL，加入等体积Matrigel胶，小鼠皮下接种0.2mL/只注入到鼠的腋部，建立荷瘤裸鼠模型。待肿瘤生长至150～300mm3时，根据小鼠肿瘤大小和体重随机分组给药。肿瘤 体积计算公式为：长径×短径2/2。
分组给药:本试验共分为本试验共分为7组，分别为生理盐水组、化合物06给药组、化合物11给药组、化合物24给药组、化合物29给药组、化合物101给药组、泊马度胺给药组、每组7只。口服给药，每天1次，其中泊马度胺的剂量为10毫克每千克体重，其他药物均按照与泊马度胺相比的等摩尔浓度，给药体积为10mL/kg，连续给药14天后，停药观察1天，采用每周2次测量瘤径的方法，观察受试药物的抗肿瘤效果和动物的体重变化。
试验结果:结果如表5和图3所示，本发明所提供的化合物与临床对照药物泊马度胺相比具有更优越的肿瘤抑制效果，充分显示了本发明化合物在肿瘤细胞及肿瘤组织内的选择性蓄积和靶向性。
表5.NCI-H929模型中的给药剂量、小鼠体重变化率和相对抑瘤率
**p＜0.01，***p＜0.001，vs溶剂对照组；体重变化率(％)＝(测量当天体重-实验初始体重)/实验初始体重×100％。

Claims (10)

  1. 一种式(I)所示结构，或其光学异构体、或其药学上可接受的盐、或其溶剂化物(可选地，所述溶剂化物为水合物)、或其包合物、或其消旋体、或其同位素标记物、或其氮氧化物，
    其中：
    A选自-O-，-S-，或-NH-；
    Q选自任选取代的亚烷基，或亚烷基亚芳基；
    R1选自-H、烷基、-C(O)R4、-C(S)R4、-C(O)OR4、-C(O)NHR4、-C(O)NR4R4’；
    R2选自-H、任选取代的烷基、烯基、烯基亚烷基、炔基、炔基亚烷基、芳基、芳基亚烷基、杂芳基、杂芳基亚烷基；
    R3选自H、羟基、烷基、烯基、烯基亚烷基、炔基、炔基亚烷基、芳基亚烷基、杂芳基亚烷基、亚烷基-OC(O)R4、亚烷基-OC(O)OR4、亚烷基-OC(O)NHR4、亚烷基-OC(O)NR4R4’，或-OR4；
    各个R4和R4’相同或不同，各自独立地选自氢、烷基、烯基、烯基亚烷基、炔基、炔基亚烷基、任选取代的芳基、任选取代的杂芳基、任选取代的脂环基、任选取代的脂杂环基、任选取代的芳基亚烷基或任选取代的杂芳基亚烷基；或者R4和R4’形成任选取代的3-7元环；
    所述“任选取代的”是指被一个或多个取代基取代，其中所述“任选取代的亚烷基”、“任选取代的脂环基”、“任选取代的脂杂环基”、“任选取代的芳基”和“任选取代的杂芳基”、“任选取代的芳基亚烷基”和“任选取代的杂芳基亚烷基”的取代基各自独立地选自羟基、氨基、羧基、卤素、硝基、氰基、烷基、烷氧基、芳基、杂芳基、芳基烷基、杂芳基烷基、芳基氧基、杂芳基氧基、环烷基、脂杂环基、环烷基氧基、杂环烷基氧基、芳基烷氧基、杂芳基烷氧基、烷酰氧基、烷酰氧基甲基、烷氧酰氧基或烷氧酰基。
  2. 根据权利要求1所述的式(I)所示的化合物，或其光学异构体、或其药学上可接受的盐、或其溶剂化物、或其包合物、或其消旋体、或其同 位素标记物、或其氮氧化物，其特征在于，
    所述“烷基”，以及“烷氧基”、“芳基烷氧基”、“杂芳基烷氧基”、“烷酰氧基甲基”、“烷氧酰氧基”、“烷酰氧基”中的烷基部分各自独立地为C1-20直链或支链烷基，可选地，为C1-17直链或支链烷基，可选地，为C1-10直链或支链烷基，可选地，为C1-8直链或支链烷基，可选地，为C1-6直链或支链烷基，可选地，为C1-4直链或支链烷基，可选地，为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基，异戊基、新戊基、叔戊基、正己基、异己基、庚基、正辛基、正壬基、正癸基、十二烷基、十五烷基、或十六烷基；
    可选地，所述“亚烷基”、“亚烷基亚芳基”“烯基亚烷基”、“炔基亚烷基”、“芳基亚烷基”、“杂芳基亚烷基”、“亚烷基-OC(O)R4”、“亚烷基-OC(O)OR4”、“亚烷基-OC(O)NHR4”或“亚烷基-OC(O)NR4R4’”中的亚烷基部分各自独立地为为C1-20直链或支链亚烷基，可选地，为C1-17直链或支链亚烷基，可选地，为C1-10直链或支链亚烷基，可选地，为C1-8直链或支链亚烷基，可选地，为C1-6直链或支链亚烷基，可选地，为C1-3直链或支链亚烷基，可选地，为亚甲基、亚乙基、亚正丙基、亚异丙基、亚正丁基、亚异丁基、亚叔丁基、亚仲丁基、亚正戊基，亚异戊基、亚新戊基、亚叔戊基、亚正己基、亚异己基、亚庚基、亚正辛基、亚正壬基、亚正癸基、亚十一烷基、亚十二烷基、亚十三烷基、亚十四烷基、亚十五烷基或亚十六烷基；
    可选地，所述“环烷基氧基”、“环烷基”中的环烷基部分为C3-8环烷基，可选地，为环丙基、环丁基、环戊基或环己基；
    所述“烯基”、“烯基亚烷基”中的烯基部分各自独立地为含有一个或多个双键的C2-C20直链或支链烯基，可选地，为C2-C15直链或支链烯基，可选地，为C2-C10直链或支链烯基，可选地，为C2-C8直链或支链烯基，可选地，为C2-C6直链或支链烯基，可选地，为C2-C4直链或支链烯基；
    所述“炔基”、“炔基亚烷基”中的炔基部分各自独立地为含有一个或多个三键的C2-C20直链或支链炔基，可选地，为C2-C15直链或支链炔基，可选地，为C2-C10直链或支链炔基，可选地，为C2-C8直链或支链炔基，可选地，为C2-C6直链或支链炔基，可选地，为C2-C4直链或支链炔基；
    可选地，示例性烯基和炔基包括但不限于乙烯、丙烯、丁烯、戊烯、乙炔和己炔。
    可选地，所述“脂杂环基”、“杂环烷基氧基”中的杂环基为环上含有选自O、N、S、SO或SO2的1-3个杂原子的C3-8(优选为C4-6)脂杂环基，可选地，为环氧乙烷基、硫杂环丙烷基、氮杂环丙烷基、氧杂环丁烷基、硫杂环丁烷基、氮杂环丁烷基、四氢呋喃基、四氢吡喃基、四氢吡咯基、吗啉基、哌啶基、或哌嗪基；
    可选地，所述“芳基”、“芳基亚烷基”、“芳基烷氧基”、“芳基氧基”中的芳基为6-10元单环或双环稠合芳香环基团；可选地为苯基或萘基；
    可选地，所述“亚烷基亚芳基”中的亚芳基为6-10元单环或双环稠合亚芳香环基团；可选地为亚苯基或亚萘基；
    可选地，所述“杂芳基”、“杂芳基亚烷基”、“杂芳氧基”、“杂芳基烷氧基”、中的杂芳基各自独立地为含有选自O、N、S、SO或SO2的1-3个杂原子的5-10元单环或双环稠合杂芳香环基团，可选地，为吡咯基、吡唑基、吡啶基、呋喃基、咪唑基、噻唑基、噁唑基、氧杂卓基、硫杂卓基，1H-氮杂卓基、喹啉基、异喹啉基、吲哚基、嘧啶基或吡嗪基、或三唑基。
  3. 根据权利要求1或2所述的式(I)所示的化合物，或其光学异构体、或其药学上可接受的盐、或其溶剂化物、或其包合物、或其消旋体、或其同位素标记物、或其氮氧化物，其特征在于，
    可选地，R1选自-H，或-(C＝O)CH3，-(C＝O)OC(CH3)3，-(C＝O)OBn；
    可选地，R2选自-H，甲基、乙基、叔丁基、烯丙基、炔丙基或苄基；
    可选地，R3选自-H，-OH，
  4. 根据权利要求1-3任一项所述的式(I)所示的化合物，或其光学异构体、或其药学上可接受的盐、或其溶剂化物、或其包合物、或其消旋体、或其同位素标记物、或其氮氧化物，其特征在于，式(I)化合物的氨基酸部分为D构型或L构型。
  5. 根据权利要求1-4任一项所述的式(I)所示的化合物，或其光学异构体、或其药学上可接受的盐、或其溶剂化物、或其包合物、或其消旋体、或其同位素标记物、或其氮氧化物，其特征在于，
    所述药学上可接受的盐为无机酸盐或有机酸盐，优选地，选自盐酸、氢氟酸、氢溴酸、氢碘酸、硫酸、焦硫酸、磷酸、碳酸、硝酸、硫酸氢酸、甲磺酸、羟基乙磺酸、酒石酸、甲酸、乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、三氟乙酸、丙酮酸、肉桂酸、月桂酸、水杨酸、柠檬酸、琥珀酸、富马酸、苯甲酸、邻氨基苯甲酸、2-(4-羟基苯甲酰基)苯甲酸、苯磺酸、乙磺酸、对氨基苯磺酸、对甲苯磺酸、苯乙酸、抗坏血酸、褐藻酸、糠酸、硬脂酸、粘液酸、扁桃酸、苹果酸、扑酸、泛酸、樟脑磺酸、葡萄糖酸、谷氨酸、葡萄糖醛酸、半乳糖醛酸、缩水甘油酸、乳酸、苹果酸、马来酸、天冬氨酸、硫氰酸、葡庚酸、甘油磷酸、磺基水杨酸、半硫酸、草酸、丙二酸、或苦味酸。
  6. 根据权利要求1-5任一项所述的式(I)所示的化合物，或其光学异构体、或其药学上可接受的盐、或其溶剂化物、或其包合物、或其消旋体、或其同位素标记物、或其氮氧化物，其特征在于，选自以下化合物：



















  7. 权利要求1-6任一项所述式(I)化合物或其光学异构体、或其药学上可接受的盐、或其溶剂化物(例如水合物)、或其包合物、或其消旋体、或其同位素标记物、或其氮氧化物中间体的制备方法：
    包括将式(A)和式(B)化合物通过步骤A得式(C)：
    步骤A：将式(A)和式(B)通过取代反应制得式(C)；
    可选地，将式(A)和式(B)在碱催化下，在合适溶剂中，于适当温度下，通过取代反应制得式(C)；可选地，碱为碳酸钾、或碳酸铯、或氢化钠、或双三甲基硅基胺基锂等；可选地，溶剂为N,N-二甲基甲酰胺、或N,N-二甲基乙酰胺、或二甲亚砜、或N-甲基吡咯烷酮等；可选地，温度为0℃至25℃；
    其中，
    式(B)和式(C)中R3如式(I)中所述，但不能为H，OR4；
    式(B)中，B选自Cl，Br，I，OTs，OMs；
    或者，通过以下步骤A’的反应得到式(C)：
    步骤A’：将S1和S2通过缩合条件得到S3，再将S3经脱保护得S4，然后S4和S5在路易斯碱催化下通过氨解得到S6经还原制得R3选自OR4的式(C)化合物；
    还包括将式(C)和式(D)化合物通过步骤B得到式(E)：
    步骤B：将式(C)和式(D)通过酰化反应得式(E)；
    可选地，将式(C)和式(D)溶于溶剂中，在加热条件下反应，得到式(E)；可选地，溶剂为四氢呋喃、或N,N-二甲基甲酰胺、或N-甲基吡咯烷酮、或2-甲基四氢呋喃；可选地，温度为45℃-90℃。
    其中，式(C)和式(E)中，R3定义同上式(I)中所述；
    或者，还包括将式(C)和式(F)化合物通过步骤C得到式(G)：
    步骤C：将式(C)和式(F)通过酰化反应制得式(G)；
    可选地，将式(C)与式(F)于适当溶剂中反应，待反应结束，减压浓缩，得式(G)；可选地，溶剂为二氯甲烷、或乙腈、或四氢呋喃等；可选地，温度为-20℃-50℃。
    其中，式(C)和式(G)中，R3定义同式(I)中所述；
    或者，还包括将式(C)和式(H)化合物通过步骤D得到式(J)：
    步骤D：将式(C)和式(H)通过缩合反应得式(J)；
    可选地，将式(C)和式(H)分散在适当溶剂中，在加热条件下反应，待反应结束，直接旋干，得式(J)；可选地，溶剂为二氯甲烷、或乙腈、或四氢呋喃、或二氯乙烷等；可选地，温度为45℃-90℃。
    其中，式(C)和式(J)中，R3定义同式(I)中所述；
    还包括将将式(E)或式(G)或式(J)与式(L)在碱催化下经亲核取代反应和任选的脱保护反应得到式(I)，如以下合成步骤E：
    步骤E：
    可选地，式(I)的合成方法：将式(E)或(G)或(J)与式(L)于适当溶剂中反应，待反应结束，减压浓缩，得式(I)；可选地，溶剂选自二氯甲烷、乙腈、N,N-二甲基甲酰胺或四氢呋喃；可选地，温度为-20℃-50℃。
    其中：
    式(L)中，C选自-OH，-SH，-NH2中的任意一个基团；
    R5为Cl，
  8. 一种药物组合物，其包括权利要求1-6任一项所述的式(I)化合物，或其光学异构体、或其药学上可接受的盐、或其溶剂化物(例如水合物)、或其包合物、或其消旋体、或其同位素标记物、或其氮氧化物，和药学上可接受的辅料；
    可选地，所述的药学上可接受辅料选自：填充剂、崩解剂、润滑剂、助流剂、泡腾剂、矫味剂、防腐剂、包衣材料或其它赋形剂；
    可选地，所述的药学上可接受的辅料，其填充剂包括乳糖、蔗糖、糊精、淀粉、预胶化淀粉、甘露醇、山梨醇、磷酸氢钙、硫酸钙、碳酸钙、微晶纤维素的一种或几种的组合物；所述的粘合剂包括蔗糖、淀粉、聚维酮、羧甲基纤维素钠、羟丙甲纤维素、羟丙纤维素、甲基纤维素、聚乙二醇、药用乙醇、水的一种或几种的组合物；
    可选地，所述的崩解剂包括淀粉、交联聚维酮、交联羧甲基纤维素钠、低取代羟丙基纤维素、羧甲基纤维素钠、泡腾崩解剂的一种或几种的组合物。
    可选地，所述药物组合物可以制成固体口服制剂、液体口服制剂、注射剂等剂型；所述固体及液体口服制剂包括：片剂、分散片、糖衣剂、颗粒剂、干粉剂、胶囊剂、糖浆剂和溶液剂；所述的注射剂包括：小针、大输液、冻干粉针等。
  9. 权利要求1-6任一项所述的式(I)的化合物，或其光学异构体、或 其药学上可接受的盐、或其溶剂化物、或其包合物、或其消旋体、或其同位素标记物、或其氮氧化物，或权利要求8所述的药物组合物在制备用于预防和/或治疗血液系统疾病的药物中的用途；优选地，所述的疾病选自血癌和骨髓癌、急性白血病、慢性白血病、淋巴瘤、卡波西肉瘤、多发性骨髓瘤或骨髓增生异常综合征。
  10. 权利要求1-6任一项所述的式(I)化合物或其光学异构体、或其药学上可接受的盐、或其溶剂化物、或其包合物或、或其消旋体、或其同位素标记物、或其氮氧化物，或者权利要求8所述的药物组合物与其它一种或多种活性药物联合用药，在制备用于预防和/或治疗血液系统疾病的药物中的用途；优选地，所述的疾病选自血癌和骨髓癌、急性白血病、慢性白血病、淋巴瘤、卡波西肉瘤、多发性骨髓瘤或骨髓增生异常综合征；优选地，所述活性药物为大分子(例如，蛋白质)、小分子(例如，合成的无机、有机金属或有机分子)或细胞疗法(例如，CAR细胞)；
    可选地，所述活性药物包括以下物质中的一种或多种：美法仑、长春新碱、环磷酰胺、依托泊苷、多柔比星、苯达莫司汀、澳比妥珠单抗、蛋白酶体抑制剂(例如，硼替佐米、卡非佐米、艾莎佐米、奥泊佐米或玛瑞佐米)、组蛋白脱乙酰基酶抑制剂(例如，帕比司他、ACY241)、BET抑制剂(例如GSK778)。
PCT/CN2023/098491 2022-06-07 2023-06-06 4-羰基氨基异吲哚啉-1,3-二酮类化合物及其制备方法、药物组合及用途 WO2023236927A1 (zh)

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