WO2023236926A1 - 4-carbonylamino isoindolin-1-one derivative, composition comprising same, and use method thereof - Google Patents

4-carbonylamino isoindolin-1-one derivative, composition comprising same, and use method thereof Download PDF

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WO2023236926A1
WO2023236926A1 PCT/CN2023/098489 CN2023098489W WO2023236926A1 WO 2023236926 A1 WO2023236926 A1 WO 2023236926A1 CN 2023098489 W CN2023098489 W CN 2023098489W WO 2023236926 A1 WO2023236926 A1 WO 2023236926A1
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formula
acid
optionally
group
compound
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PCT/CN2023/098489
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French (fr)
Chinese (zh)
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高清志
刘胜男
高香倩
张顺杰
张祥瑞
杜金平
杨柳
李扬
朱晓玲
韩建斌
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天津谷堆生物医药科技有限公司
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Publication of WO2023236926A1 publication Critical patent/WO2023236926A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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 present invention relates to a class of 4-carbonylaminoisoindolin-1-one compounds, their preparation methods, pharmaceutical compositions containing them and their uses.
  • Targeted therapy and immunotherapy are new methods for treating cancer that have been proposed in recent years, bringing hope to patients with drug-resistant tumors and advanced tumors.
  • Molecular targeted drugs and immunotherapy drugs have been upgraded to become the main treatment methods for patients with hematological malignancies, completely changing the treatment model of the entire hematological disease. Therefore, developing more and more precise targeted therapies and immunotherapy methods is an essential way to prevent, treat and manage cancer and other diseases.
  • MM malignant hematopathy
  • Common clinical diseases include acute leukemia, lymphoma, multiple myeloma, myelodysplastic syndrome, etc.
  • multiple myeloma MM is a malignant disease characterized by abnormal proliferation of clonal plasma cells. Due to the malignant proliferation, extensive infiltration, and secretion of large amounts of monoclonal immunoglobulins by monoclonal plasma cells, a series of clinical symptoms such as extensive bone destruction, recurrent infections, anemia, hypercalcemia, and renal insufficiency are caused. At present, this disease mostly occurs in middle-aged and elderly people and is the second largest hematological malignant tumor.
  • MM is still incurable, and almost all patients will experience relapse, drug resistance and other problems throughout the course of the disease. Therefore, how to diagnose, treat and improve the efficacy and prognosis of patients with relapsed MM is a matter of great concern.
  • Newly diagnosed MM is usually sensitive to many cytotoxic drugs. Treatment is mainly induction chemotherapy followed by autologous hematopoietic stem cell transplantation (ASCT). The curative effect can usually be sustained, but most of them cannot escape the fate of relapse and progression. However, the emergence of new drugs such as thalidomide, bortezomib, and lenalidomide has changed the treatment options for multiple myeloma.
  • the main treatment options are bortezomib/lenalidomide/dexamethasone (VRD), bortezomib/cyclophosphamide/dexamethasone (VCD), bortezomib/thalidomide/dexamethasone (VTD) )wait.
  • VRD bortezomib/lenalidomide/dexamethasone
  • VCD bortezomib/cyclophosphamide/dexamethasone
  • VTD bortezomib/thalidomide/dexamethasone
  • MDS Myelodysplastic syndromes
  • AML acute myeloid leukemia
  • the immunomodulators thalidomide and lenalidomide are both glutamic acid derivatives, which mainly achieve targeted treatment of tumors through direct anti-tumor effects, immunomodulatory effects, anti-angiogenesis and other mechanisms.
  • Thalidomide was recalled by the FDA in the 1960s because it caused serious congenital malformations in infants. However, it is still used to treat multiple myeloma and other blood cancers. Of course, the drug is safe and serious. The side effects are still an unavoidable fact.
  • Lenalidomide a thalidomide derivative
  • Lenalidomide has been approved for the treatment of myelodysplastic syndrome, multiple myeloma, mantle cell lymphoma, and follicular lymphoma since it was developed and marketed by the American company Celegene in 2005. or diseases such as marginal zone lymphoma.
  • the FDA has added a black box warning to lenalidomide, which includes embryofetal toxicity, hematological toxicity (including significant neutropenia and thrombocytopenia), and venous and arterial thromboembolism.
  • LAT1 is the L-amino group A transmembrane transporter necessary for acid uptake into cells is abnormally highly expressed in a variety of malignant tumors (Reference: The L-Type Amino Acid Transporter LAT1-An Emerging Target in Cancer, International Journal of Molecular Science (2019) .), therefore LAT1 is considered an important drug target for cancer treatment.
  • lenalidomide has poor solubility in water, low bioavailability, and high toxic and side effects, which are also the main problems that have been plaguing this drug. Therefore, the research goals of a new generation of immunomodulatory inhibitors are to develop reduced toxic and side effects, improve solubility, improve bioavailability, improve drug targeting, and increase drug concentration in tumor cells.
  • the invention provides a 4-carbonylaminoisoindoline-1-one compound, a compound represented by 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. It has good anti-multiple myeloma activity and can effectively treat and/or prevent the growth and reproduction of multiple myeloma. Preparation methods, pharmaceutical compositions and uses comprising the compounds are also provided.
  • A is selected from -O-, -S-, -NH-, or A does not exist;
  • 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 base, aryl, arylalkylene, heteroaryl, heteroarylalkylene;
  • R 3 is selected from -H, hydroxyl, alkyl, alkenyl, alkenylalkylene, alkynyl, alkynylalkylene, aryl, arylalkylene, heteroaryl, 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 ;
  • R 4 and R 4 ' are the same or different, and each is independently selected from hydrogen, alkyl, alkenyl, alkenyl alkyl, alkynyl, alkynylalkyl, optionally substituted aryl, optionally substituted heteroaryl group, optionally substituted alicyclic group, optionally substituted alicyclic heterocyclic group, optionally substituted arylalkylene or optionally substituted heteroarylalkylene; or R 4 and R 4 ' form optionally Substituted 3-7 membered rings;
  • the “optionally substituted” refers to unsubstituted or substituted by one or more substituents, wherein the "optionally substituted alkylene", “optionally substituted alicyclic group”, “optionally substituted Aliphatic heterocyclyl”, “optionally substituted aryl”, “optionally substituted heteroaryl”, “optionally substituted arylalkylene” and “optionally substituted heteroarylalkylene”
  • Each substituent is independently selected from hydroxy, amino, carboxyl, halogen, nitro, cyano, alkyl, alkoxy, aryl, heteroaryl, arylalkylene, heteroarylalkylene, aryl Oxygen, heteroaryloxy, cycloalkyl, alicyclic, cycloalkyloxy, heterocycloalkyloxy, arylalkoxy, heteroarylalkoxy, alkanoyloxymethyl , alkanoyloxy, alkoxyacyloxy or alkoxyacyl.
  • alkyl as well as “alkoxy”, “arylalkoxy”, “heteroarylalkoxy”, “alkanoyloxymethyl”, “alkoxyacyloxy”
  • alkyl part in “, “alkanoyloxy” and “alkoxyacyl” is each independently a C 1-20 linear or branched alkyl group, optionally, a C 1-17 linear or branched alkyl group.
  • the base optionally, is a C 1-10 linear or branched alkyl group, optionally, is a C 1-7 linear or branched alkyl group, optionally, is a methyl, ethyl, n-propyl group , isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, heptyl, n-octyl, n-nonyl, n-decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, or hexadecyl;
  • alkylene is each independently a C 1-20 linear or branched alkylene group, optionally, a C 1-17 linear or branched alkylene group , optionally, a C 1-10 linear or branched alkylene group, optionally, a C 1-8 linear or branched alkylene group, optionally, a C 1-6 linear or branched alkylene group Chain alkylene, optionally, C 1-3 straight Chain or branched alkylene, optionally methylene, ethylene, n-propylene, isopropylene, n-buty
  • 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, optionally, a C 2 -C 15 linear or branched alkenyl group.
  • alkynyl part in the "alkynyl” and “alkynyl alkylene” is each independently a C 2 -C 20 linear or branched alkenyl group, optionally, a C 2 -C 15 linear or branched alkenyl group.
  • Branched chain alkynyl optionally, C 2 -C 10 linear or branched alkynyl, optionally, C 2 -C 8 linear or branched alkynyl, optionally, C 2 -C 6 straight chain or branched chain alkynyl, optionally, C 2 -C 4 straight chain or branched chain alkynyl;
  • 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;
  • heteroaryl groups in the "heteroaryl”, “heteroarylalkylene”, “heteroaryloxy” and “heteroarylalkoxy” are each independently selected from O , N, S, SO or SO 2 5-10 membered monocyclic or bicyclic fused heteroaromatic ring groups with 1-3 heteroatoms, optionally, pyrrolyl, pyrazolyl, pyridyl, furyl , imidazolyl, thiazolyl, oxazolyl, oxazolyl, thiazolyl, 1H-azepinyl, quinolyl, isoquinolyl, indolyl, pyrimidinyl or pyrazinyl, or tris Azolyl.
  • R 2 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, starch, pregelatinized starch, mannitol, sorbitol, calcium hydrogen phosphate, calcium sulfate, calcium carbonate, microcrystalline
  • the binder includes sucrose, starch, povidone, sodium carboxymethylcellulose, hypromellose, hydroxypropylcellulose, methylcellulose, One or more combinations of polyethylene glycol, medicinal ethanol, and water
  • the disintegrant includes starch, crospovidone, croscarmellose sodium, and low-substituted hydroxypropyl fiber
  • cellulose sodium carboxymethyl cellulose, 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, lymphoma, Kaposi's sarcoma, 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 Methods for preparing racemates thereof, or isotope markers thereof, or nitrogen oxides thereof;
  • the method includes passing the compound of formula (A) and the compound of formula (B) through step A to obtain the compound of formula (C):
  • Step A Prepare formula (C) by substitution reaction of formula (A) and formula (B);
  • formula (A) and formula (B) are catalyzed by a base (such as potassium carbonate, cesium carbonate, sodium hydride, lithium bistrimethylsilylamide, etc.) in a suitable solvent (such as N, N-dimethylformamide, N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, etc.), formula (C) is prepared through a substitution reaction at a temperature of 0°C to 25°C. .
  • a base such as potassium carbonate, cesium carbonate, sodium hydride, lithium bistrimethylsilylamide, etc.
  • a suitable solvent such as N, N-dimethylformamide, N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, etc.
  • R3 is as described in formula (I), but is not H, OR4;
  • B is selected from Cl, Br, I, OTs, OMs;
  • formula (B) can adopt one of the following methods 1-8, but is not limited to the following methods:
  • 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. Then S4 and S5 are substituted and ammonolyzed to methyl ester under alkali catalysis to obtain LN-S5, which is reduced by iron powder to obtain formula (C ).
  • Step B Perform acylation reaction between formula (C) and formula (D) to obtain formula (E).
  • formula (C) and p-nitrophenyl chloroformate are dissolved in (such as tetrahydrofuran, N, N-dimethylformamide, N-methylpyrrolidone, etc.) and reacted under reflux conditions to obtain Formula (E);
  • Step C Prepare formula (G) by acylation reaction of formula (C) and formula (F);
  • formula (G) slowly drop formula (C) into a dichloromethane or acetonitrile solution of triphosgene at low temperature (preferably 0°C), and slowly raise the temperature to 30°C-60°C (preferably 45°C), wait until the reaction is completed, and concentrate under reduced pressure to obtain formula (G).
  • Step D Condensation reaction of formula (C) and formula (H) to obtain formula (J);
  • formula (C) and N, N'-carbonyldiimidazole are dispersed in tetrahydrofuran and reacted under reflux conditions. After the reaction is completed, concentrate under reduced pressure, add ethyl acetate and stir evenly to obtain a suspension, and reduce the pressure. Filter and wash or spin dry directly to get formula (J).
  • W is selected from any one of -OH, -SH and -NH 2 groups
  • R 5 is Cl, or
  • R 3 is as shown in formula (I);
  • 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 such as ethyl acetate or dioxane
  • a suitable solvent such as ethyl acetate or dioxane
  • hydrogen chloride gas or add other acids
  • react at room temperature or 40°C and precipitate a solid.
  • Add ether if there is no solid.
  • a solid precipitates and is filtered to obtain formula (N) in the form of a salt.
  • 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 (O) in a suitable solvent such as methanol or ethanol
  • a suitable solvent such as methanol or ethanol
  • the free compound can also be obtained by dispersing the salt form of formula (N) in a suitable solvent (such as methanol or ethanol) and adding an equivalent amount of base.
  • the present invention provides the compound of formula (I) or its optical isomer, or its pharmaceutically acceptable salt, or its solvate, or its clathrate, or its racemate, or its Isotopic markers, or their nitrogen oxides or their pharmaceutical compositions are used in combination with one or more other active drugs ("second active compounds") in the preparation of drugs for the prevention and/or treatment of hematological diseases
  • second active compounds active drugs
  • the disease is selected from blood cancer and bone marrow cancer, lymphoma, Kaposi's sarcoma or myelodysplasia syndrome
  • the other active drug is dexamethasone and/or pentezomib.
  • the disease is selected from blood cancers and bone marrow cancers, such as acute and chronic leukemias and multiple myeloma, such as lymphoblastic leukemia, chronic myelogenous leukemia, myelogenous 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.
  • Examples of the second active ingredient of the present invention may include one or more of the following substances: melphalan, vincristine, cyclophosphamide, etoposide, doxorubicin, bendamustine, orbibin Tocilizumab, protease body inhibitors (e.g., bortezomib, carfilzomib, elsazomib, opozomib, or marezomib), histone deacetylase inhibitors (e.g., panobinostat, ACY241), BET inhibitors (eg GSK778).
  • protease body inhibitors e.g., bortezomib, carfilzomib, elsazomib, opozomib, or marezomib
  • histone deacetylase inhibitors e.g., panobinostat, ACY241
  • BET inhibitors eg 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
  • HATU 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate
  • 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 protected amino acid (1.0 equivalent), cesium carbonate (0.5 equivalent) and ethyl iodide, or 1-iodobutane, or 1-iodohexane, or isopropyl iodide , or TBS-protected hydroxyethyl iodide, or 4-(iodomethyl)-2,2-dimethyl-1,3-dioxolane (1.1 equivalent) was dispersed in DMF, stirred at room temperature overnight, and extracted. , column chromatography yields product formula (L).
  • Step A Synthesize using Step A, Step C (or Step D) and Step E.
  • Example 95 Disperse the product of Example 95 in methanol, then add palladium carbon, and react at room temperature in a hydrogen environment. After the reaction is completed, filter out the palladium carbon, add the reaction liquid dropwise to tert-butyl methyl ether, and precipitate a solid to obtain a salt.
  • the acid acid product was a white solid with a yield of 55.31%.
  • Test method Use a 5 mL centrifuge tube to take about 0.5 mL of distilled water, and slowly add the dry compound until it cannot be dissolved (it will shake at 25°C and remain turbid). Filter the solution into another 5 mL clean weighed EP tube, weigh it again, and calculate the weight of the solution. Lyophilize the filtrate, weigh and calculate the solute mass of the remaining solid, calculate the mass of the solvent, and then calculate the solubility of the compound in water. The results are listed in Table 1.
  • Test 2 In vitro anti-multiple myeloma activity test
  • Test method Collect MM.1S cells in the logarithmic phase, seed them in a 96-well plate at a density of 2 ⁇ 10 4 cells/well, incubate them in a 37°C, 5% CO 2 incubator for 2 hours, and then add them to a final concentration of 0.0001 to 50 ⁇ M of compound, 4 duplicate wells of each compound, and incubated for 72 h in a 37°C, 5% CO2 incubator. After the incubation, 20 ⁇ L of 5 mg/mL MTT solution was added to the cell wells. After 4 hours, the supernatant was discarded, 150 ⁇ L of DMSO was added, and the absorbance value at 570 nm wavelength was measured .
  • the absorbance value measured in the blank well without cells is A blank
  • the absorbance value measured in the cell well without drug treatment is A control
  • the IC 50 value is less than 0.05 ⁇ M for A; the IC 50 value is greater than 0.05 ⁇ M and less than 0.1 ⁇ M for B; the IC 50 value is greater than 0.1 ⁇ M and less than 0.5 ⁇ M for C; the IC 50 value is greater than 0.5 ⁇ M and less than 1 ⁇ M for D.
  • Test Method This test evaluates the effect of dexamethasone as a single agent in combination with a compound of the invention or lenalidomide on the proliferation inhibition of lenalidomide-resistant multiple myeloma NCI-H929 cells.
  • the test uses MTT colorimetric method to detect cell survival rate, the method is as in test 2.
  • the compound of the present invention has strong cell proliferation inhibitory activity on lenalidomide-resistant NCI-H929 cells, and when used in combination with the second active component dexamethasone, it can achieve synergistic inhibition of NCI-H929 cell proliferation. Effect.
  • the results are shown in Table 3. Among them, 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 evenly spread into a 6-em 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 preincubated 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 compound of the present invention in the lysate of 293T cells that highly express LAT1 was significantly higher than that of ordinary 293T cells, indicating that the compound of the present invention has significant LAT1 targeting.
  • NOD/SCID female mice aged 6 to 8 weeks were used, and the experimental animals were purchased from Beijing Vitong Lihua 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 calculation formula of tumor volume is: long diameter ⁇ short diameter 2 /2.
  • This test is divided into 9 groups, namely, physiological saline group, compound 73 administration group, compound 82 administration group, compound 90 administration group, compound 109 administration group, compound 169 administration group, compound 174 administration group, Compound 176 administration group, lenalidomide administration group, 7 animals in each group.
  • Oral administration once a day, the dose of lenalidomide is 100 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.
  • the compound of the present invention has a superior tumor inhibitory effect, which fully demonstrates the selective accumulation and selective accumulation of the compound of the present invention in tumor cells and tumor tissues. Targeting.
  • Test 6 In vivo anti-tumor efficacy test II
  • NCI-H929 cells 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. The calculation formula of tumor volume is: long diameter ⁇ short diameter 2 /2.
  • This test is divided into 9 groups, namely the normal saline group, the compound 73 administration group, the compound 82 administration group, the compound 90 administration group, the compound 109 administration group, the compound 169 administration group, and the compound 174 administration group. , compound 176 administration group, lenalidomide group, 7 animals in each group.
  • Oral administration once a day, the dose of lenalidomide is 100 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 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.
  • the results are shown in Table 5 and Figure 3.
  • the compounds provided by the present invention have superior tumor inhibitory effects compared with the clinical control drug lenalidomide, which fully demonstrates the selectivity of the compounds of the present invention in tumor cells and tumor tissues. Accumulation and targeting.

Abstract

A 4-carbonylamino isoindolin-1-one compound represented by formula (I), or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate (such as a hydrate) thereof, or an inclusion compound thereof, or a racemate thereof, or an isotope marker thereof, or a nitrogen oxide thereof, and a pharmaceutical composition and use thereof. The compound has good anti-multiple myeloma activity, and can effectively treat and/or prevent the growth and reproduction of multiple myeloma.

Description

4-羰基氨基异吲哚啉-1-酮衍生物、包括其的组合物及使用方法4-Carbonylaminoisoindolin-1-one derivatives, compositions including the same and methods of use 技术领域Technical field
本发明涉及一类4-羰基氨基异吲哚啉-1-酮化合物、其制备方法、包含其的药物组合物及用途。The present invention relates to a class of 4-carbonylaminoisoindolin-1-one compounds, their preparation methods, pharmaceutical compositions containing them and their uses.
背景技术Background technique
由于人口结构、生态环境及生活方式的持续改变，癌症逐渐成为威胁人类健康的最主要疾病之一。手术、放疗、化疗是目前用于癌症治疗的最常见方法。对于身体某部位的实体肿瘤，外科手术是治疗癌症的一线治疗方法。在接受手术之后，结合高能量的粒子射线摧残剩余的癌细胞-放疗，防止癌症复发，也是目前常规的治疗方法。在肿瘤体积较小，或针对不能使用手术疗法的癌症如血液瘤，可直接进行放疗或化疗。化疗药物通常通过结合细胞DNA来阻止分裂增殖、杀死正在分裂的细胞来起作用，目前已经有超过100种不同类型的化疗药物。但由于放疗和化疗都缺乏选择性，往往会带来严重的副作用。此外，化疗药物的耐药性也是癌症治疗的主要障碍之一。靶向治疗和免疫治疗是近年来提出的治疗癌症的新方法，给肿瘤耐药及肿瘤晚期患者带来了希望。分子靶向药物和免疫治疗药物已升级成为血液恶性肿瘤患者主要治疗手段，彻底改变了整个血液病的治疗模式。因此，开发更多、更精准的靶向治疗和免疫治疗方法，是预防、治疗和管理癌症及其他疾病必要途径。Due to the continuous changes in population structure, ecological environment and lifestyle, cancer has gradually become one of the most important diseases threatening human health. Surgery, radiotherapy, and chemotherapy are the most common methods currently used for cancer treatment. For solid tumors somewhere in the body, surgery is the first line of treatment for cancer. After surgery, high-energy particle rays are combined with radiotherapy to destroy remaining cancer cells to prevent cancer recurrence, which is also a conventional treatment method. When the tumor size is small, or for cancers that cannot be treated with surgery, such as hematomas, radiotherapy or chemotherapy can be used directly. Chemotherapy drugs usually work by binding to cellular DNA to prevent division and proliferation and kill dividing cells. There are currently more than 100 different types of chemotherapy drugs. However, due to the lack of selectivity of radiotherapy and chemotherapy, they often cause serious side effects. In addition, resistance to chemotherapy drugs is also one of the major obstacles to cancer treatment. Targeted therapy and immunotherapy are new methods for treating cancer that have been proposed in recent years, bringing hope to patients with drug-resistant tumors and advanced tumors. Molecular targeted drugs and immunotherapy drugs have been upgraded to become the main treatment methods for patients with hematological malignancies, completely changing the treatment model of the entire hematological disease. Therefore, developing more and more precise targeted therapies and immunotherapy methods is an essential way to prevent, treat and manage cancer and other diseases.
血液系统病，尤其是恶性血液病(malignant hematopathy，MH)，已严重威胁到人类的生命健康，临床上常见包括急性白血病、淋巴瘤、多发性骨髓瘤、骨髓增生异常综合征等。其中，多发性骨髓瘤(multiple myeloma，MM)是一种克隆性浆细胞异常增殖的恶性疾病。由于单克隆浆细胞恶性增生、广泛浸润并分泌大量单克隆免疫球蛋白，从而导致广泛的骨质破坏、反复感染、贫血、高钙血症及肾功能不全等一系列临床症状。目前该疾病多发于中老年群体，是第二大血液系统恶性肿瘤。然而MM仍无法治愈，几乎所有的患者在整个病程中都要经历复发、耐药等问题，因此如何诊治和提高复发MM患者的疗效和预后是备受关注的问题。 Hematological diseases, especially malignant hematopathy (MH), have seriously threatened human life and health. Common clinical diseases include acute leukemia, lymphoma, multiple myeloma, myelodysplastic syndrome, etc. Among them, multiple myeloma (MM) is a malignant disease characterized by abnormal proliferation of clonal plasma cells. Due to the malignant proliferation, extensive infiltration, and secretion of large amounts of monoclonal immunoglobulins by monoclonal plasma cells, a series of clinical symptoms such as extensive bone destruction, recurrent infections, anemia, hypercalcemia, and renal insufficiency are caused. At present, this disease mostly occurs in middle-aged and elderly people and is the second largest hematological malignant tumor. However, MM is still incurable, and almost all patients will experience relapse, drug resistance and other problems throughout the course of the disease. Therefore, how to diagnose, treat and improve the efficacy and prognosis of patients with relapsed MM is a matter of great concern.
新确诊的MM通常对很多细胞毒性药物敏感，治疗以诱导化疗后序贯自体造血干细胞移植(ASCT)为主，疗效通常可以持续，但绝大多数难逃复发、进展的命运。然而，沙利度胺、硼替佐米、来那度胺等新药的产生更改了多发性骨髓瘤的治疗方案。其中，主要治疗方案硼替佐米/来那度胺/地塞米松(VRD)、硼替佐米/环磷酰胺/地塞米松(VCD)、硼替佐米/沙利度胺/地塞米松(VTD)等。Newly diagnosed MM is usually sensitive to many cytotoxic drugs. Treatment is mainly induction chemotherapy followed by autologous hematopoietic stem cell transplantation (ASCT). The curative effect can usually be sustained, but most of them cannot escape the fate of relapse and progression. However, the emergence of new drugs such as thalidomide, bortezomib, and lenalidomide has changed the treatment options for multiple myeloma. Among them, the main treatment options are bortezomib/lenalidomide/dexamethasone (VRD), bortezomib/cyclophosphamide/dexamethasone (VCD), bortezomib/thalidomide/dexamethasone (VTD) )wait.
骨髓增生异常综合征(myelodysplastic syndromes，MDS)是一组起源于造血干细胞的异质性髓系克隆性疾病，其特点是髓系细胞发育异常，表现为无效造血、难治性血细胞减少，高风险向急性髓系白血病(AML)转化，因此被称为白血病前期的恶性肿瘤。MDS的风险随年龄增长而升高。新近统计MDS年发病率为4/10万，在80岁以上人群达50/10万。多数MDS患者需要长期反复输血，统计发现超过90％MDS患者患病期间需要输血，其中30％-45％患者会有输血依赖，患者长期输血会导致铁过载的出现，若不进行适当的治疗，将导致严重的器官功能异常或死亡。尽管通过地西他滨、阿扎胞苷(AZA)、沙利度胺、来那度胺、造血干细胞移植(HSCT)等方法治疗MDS已经改善了患者的生命质量，但仍无法消灭MDS的恶性克隆作用。Myelodysplastic syndromes (MDS) are a group of heterogeneous myeloid clonal diseases originating from hematopoietic stem cells. They are characterized by abnormal development of myeloid cells, manifested by ineffective hematopoiesis, refractory cytopenias, and high risk. It transforms into acute myeloid leukemia (AML) and is therefore called a preleukemic malignant tumor. The risk of MDS increases with age. According to recent statistics, the annual incidence rate of MDS is 4/100,000, reaching 50/100,000 in people over 80 years old. Most MDS patients require long-term repeated blood transfusions. Statistics show that more than 90% of MDS patients require blood transfusions during their illness, and 30%-45% of them are dependent on blood transfusions. Long-term blood transfusions in patients can lead to iron overload. Without appropriate treatment, Severe organ dysfunction or death will result. Although the treatment of MDS through decitabine, azacitidine (AZA), thalidomide, lenalidomide, hematopoietic stem cell transplantation (HSCT) and other methods has improved the quality of life of patients, the malignancy of MDS still cannot be eliminated. Cloning effect.
其中，免疫调节剂沙利度胺、来那度胺均为谷氨酸衍生物，其主要通过直接的抗肿瘤作用、免疫调节作用及抗血管生成等机制实现对肿瘤的靶向治疗。(参考文献：N.Ferrara，R.S.Kerbel，Angiogenesis as a therapeutic target，Nature，438(2005)967-974.)。沙利度胺由于其引发婴儿产生严重的先天畸形于20世纪60年代曾被FDA召回，但目前，沙利度胺仍被用于治疗多发性骨髓瘤和其他血液癌症，当然药物安全性和严重的副作用仍是其无法回避的事实。来那度胺作为沙利度胺衍生物，自2005年由美国Celegene公司开发上市后，分别被批准用于治疗骨髓增生异常综合征、多发性骨髓瘤、套细胞淋巴瘤、滤泡性淋巴瘤或边缘区淋巴瘤等疾病。但FDA对来那度胺加了黑框警告，黑框警告内容包括胚胎胎儿毒性，血液学毒性(包括显著的中性粒细胞减少和血小板减少症)和静脉和动脉血栓栓塞。Among them, the immunomodulators thalidomide and lenalidomide are both glutamic acid derivatives, which mainly achieve targeted treatment of tumors through direct anti-tumor effects, immunomodulatory effects, anti-angiogenesis and other mechanisms. (Reference: N. Ferrara, R.S. Kerbel, Angiogenesis as a therapeutic target, Nature, 438 (2005) 967-974.). Thalidomide was recalled by the FDA in the 1960s because it caused serious congenital malformations in infants. However, it is still used to treat multiple myeloma and other blood cancers. Of course, the drug is safe and serious. The side effects are still an unavoidable fact. Lenalidomide, a thalidomide derivative, has been approved for the treatment of myelodysplastic syndrome, multiple myeloma, mantle cell lymphoma, and follicular lymphoma since it was developed and marketed by the American company Celegene in 2005. or diseases such as marginal zone lymphoma. However, the FDA has added a black box warning to lenalidomide, which includes embryofetal toxicity, hematological toxicity (including significant neutropenia and thrombocytopenia), and venous and arterial thromboembolism.
此外，在多发性骨髓瘤中，由于癌细胞对氨基酸等营养物质的需求特别高，因此L型氨基酸转运体1(LAT1/SLC7A5)表达量异常升高。LAT1是L型氨基 酸的摄入细胞内必须借助的跨膜转运体，在多种恶性肿瘤中异常高表达(参考文献：The L-Type Amino Acid Transporter LAT1-An Emerging Target in Cancer，International Journal of Molecular Science(2019).)，因此LAT1被认为是癌症治疗的重要药物靶标。In addition, in multiple myeloma, because cancer cells have particularly high demand for nutrients such as amino acids, the expression of L-type amino acid transporter 1 (LAT1/SLC7A5) is abnormally increased. LAT1 is the L-amino group A transmembrane transporter necessary for acid uptake into cells is abnormally highly expressed in a variety of malignant tumors (Reference: The L-Type Amino Acid Transporter LAT1-An Emerging Target in Cancer, International Journal of Molecular Science (2019) .), therefore LAT1 is considered an important drug target for cancer treatment.
除此之外，来那度胺在水中溶解度差、生物利用度低，毒副作用高也是一直困扰该药物的主要问题。因此，开发降低毒副作用、提高溶解度、提高生物利用度、提高药物靶向性、增加肿瘤细胞中的药物浓度等是新一代免疫调节抑制剂的研究目标。In addition, lenalidomide has poor solubility in water, low bioavailability, and high toxic and side effects, which are also the main problems that have been plaguing this drug. Therefore, the research goals of a new generation of immunomodulatory inhibitors are to develop reduced toxic and side effects, improve solubility, improve bioavailability, improve drug targeting, and increase drug concentration in tumor cells.
发明内容Contents of the invention
本发明提供一种4-羰基氨基异吲哚啉-1-酮类化合物，如下式(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(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。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繁殖。还提供了包含所述化合物的制备方法、药物组合物和用途。The invention provides a 4-carbonylaminoisoindoline-1-one compound, a compound represented by 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. It has good anti-multiple myeloma activity and can effectively treat and/or prevent the growth and reproduction of multiple myeloma. Preparation methods, pharmaceutical compositions and uses comprising the compounds are also provided.
一种式(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(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，
A compound represented by 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 markers, or its nitrogen oxides,
其中：in:
A选自-O-，-S-，-NH-，或者A不存在；A is selected from -O-, -S-, -NH-, or A does not exist;
Q选自任选取代的亚烷基，或亚烷基亚芳基；Q is selected from optionally substituted alkylene, or alkylene arylene;
R1选自-H、烷基、-C(O)R4、-C(S)R4、-C(O)OR4、-C(O)NHR4、-C(O)NR4R4’；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 ';
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；R 2 is selected from -H, optionally substituted alkyl, alkenyl, alkenyl alkylene, alkynyl, alkynyl alkylene base, aryl, arylalkylene, heteroaryl, heteroarylalkylene;
R3选自-H、羟基、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、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；R 3 is selected from -H, hydroxyl, alkyl, alkenyl, alkenylalkylene, alkynyl, alkynylalkylene, aryl, arylalkylene, heteroaryl, 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 ;
各个R4和R4’相同或者不同，各自独立地选自氢、烷基、烯基、烯基烷基、炔基、炔基烷基、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；Each R 4 and R 4 ' are the same or different, and each is independently selected from hydrogen, alkyl, alkenyl, alkenyl alkyl, alkynyl, alkynylalkyl, optionally substituted aryl, optionally substituted heteroaryl group, optionally substituted alicyclic group, optionally substituted alicyclic heterocyclic group, optionally substituted arylalkylene or optionally substituted heteroarylalkylene; or R 4 and R 4 ' form optionally Substituted 3-7 membered rings;
所述“任选取代的”是指未取代或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”、“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、芳基亚烷基、杂芳基亚烷基、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、烷酰氧基甲基、烷酰氧基、烷氧酰氧基或烷氧酰基。The "optionally substituted" refers to unsubstituted or substituted by one or more substituents, wherein the "optionally substituted alkylene", "optionally substituted alicyclic group", "optionally substituted Aliphatic heterocyclyl", "optionally substituted aryl", "optionally substituted heteroaryl", "optionally substituted arylalkylene" and "optionally substituted heteroarylalkylene" Each substituent is independently selected from hydroxy, amino, carboxyl, halogen, nitro, cyano, alkyl, alkoxy, aryl, heteroaryl, arylalkylene, heteroarylalkylene, aryl Oxygen, heteroaryloxy, cycloalkyl, alicyclic, cycloalkyloxy, heterocycloalkyloxy, arylalkoxy, heteroarylalkoxy, alkanoyloxymethyl , alkanoyloxy, alkoxyacyloxy or alkoxyacyl.
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”、“烷氧酰基”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C1-7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、十一烷基、十二烷基、十三烷基、十四烷基、十五烷基、或十六烷基；Alternatively, the "alkyl", as well as "alkoxy", "arylalkoxy", "heteroarylalkoxy", "alkanoyloxymethyl", "alkoxyacyloxy" The alkyl part in ", "alkanoyloxy" and "alkoxyacyl" is each independently a C 1-20 linear or branched alkyl group, optionally, a C 1-17 linear or branched alkyl group. The base, optionally, is a C 1-10 linear or branched alkyl group, optionally, is a C 1-7 linear or branched alkyl group, optionally, is a methyl, ethyl, n-propyl group , isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, heptyl, n-octyl, n-nonyl, n-decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, or hexadecyl;
可选地，所述“亚烷基”、“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’”或“亚烷基亚芳基”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；Alternatively, the "alkylene", "alkenylalkylene", "alkynylalkylene", "arylalkylene", "heteroarylalkylene", "alkylene- OC(O)R 4 ”, “alkylene-OC(O)OR 4 ”, “alkylene-OC(O)NHR 4 ”, or “alkylene-OC(O)NR 4 R 4 ‘” Or the alkylene part in "alkylene arylene" is each independently a C 1-20 linear or branched alkylene group, optionally, a C 1-17 linear or branched alkylene group , optionally, a C 1-10 linear or branched alkylene group, optionally, a C 1-8 linear or branched alkylene group, optionally, a C 1-6 linear or branched alkylene group Chain alkylene, optionally, C 1-3 straight Chain or branched alkylene, optionally methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, tert-butylene, sec-butylene , n-pentylene, isopentylene, neopentylene, tert-pentylene, n-hexylene, isohexylene, hepterylene, n-octanylene, n-nonyl, n-decylene, n-tenylene Monoalkyl, dodecyl, tridecyl, tetradecyl, pentadecyl, or hexadecyl;
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；Optionally, the cycloalkyl part in the "cycloalkyloxy" and "cycloalkyl" is C 3-8 cycloalkyl, optionally, it is cyclopropyl, cyclobutyl, or cyclopentyl or cyclohexyl;
所述“烯基”、“烯基亚烷基”中的烯基部分各自独立地为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；The alkenyl part in the "alkenyl" and "alkenyl alkylene" is each independently a C 2 -C 20 linear or branched alkenyl group, optionally, a C 2 -C 15 linear or branched alkenyl group. Alkenyl, optionally, C 2 -C 10 straight chain or branched alkenyl, optionally, C 2 -C 8 straight chain or branched alkenyl, optionally, C 2 -C 6 Straight-chain or branched alkenyl, optionally, C 2 -C 4 straight-chain or branched alkenyl;
所述“炔基”、“炔基亚烷基”中的炔基部分各自独立地为为C2-C20直链或支链烯基，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；The alkynyl part in the "alkynyl" and "alkynyl alkylene" is each independently a C 2 -C 20 linear or branched alkenyl group, optionally, a C 2 -C 15 linear or branched alkenyl group. Branched chain alkynyl, optionally, C 2 -C 10 linear or branched alkynyl, optionally, C 2 -C 8 linear or branched alkynyl, optionally, C 2 -C 6 straight chain or branched chain alkynyl, optionally, C 2 -C 4 straight chain or branched chain alkynyl;
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；Alternatively, 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;
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；Optionally, the 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;
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；Optionally, 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;
可选地，所述“杂芳基”、“杂芳基亚烷基”、“杂芳基氧基”、“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。 Optionally, the heteroaryl groups in the "heteroaryl", "heteroarylalkylene", "heteroaryloxy" and "heteroarylalkoxy" are each independently selected from O , N, S, SO or SO 2 5-10 membered monocyclic or bicyclic fused heteroaromatic ring groups with 1-3 heteroatoms, optionally, pyrrolyl, pyrazolyl, pyridyl, furyl , imidazolyl, thiazolyl, oxazolyl, oxazolyl, thiazolyl, 1H-azepinyl, quinolyl, isoquinolyl, indolyl, pyrimidinyl or pyrazinyl, or tris Azolyl.
可选地，R1选自-H，或-(C＝O)CH3，-(C＝O)OC(CH3)3；Alternatively, R 1 is selected from -H, or -(C=O)CH 3 , -(C=O)OC(CH 3 ) 3 ;
可选地，R2选自-H，甲基、乙基、叔丁基、烯丙基、炔丙基或苄基；Alternatively, R 2 is selected from -H, methyl, ethyl, tert-butyl, allyl, propargyl or benzyl;
可选地，R3选自-H，-OH， Optionally, R 3 is selected from -H, -OH,
可选地，式(I)化合物的氨基酸部分为D构型或L构型。Alternatively, the amino acid moiety of the compound of formula (I) is in D configuration or L configuration.
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、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：

















Alternatively, the compound of formula (I), or its optical isomer, or its pharmaceutically acceptable salt, or its solvate, or its clathrate, or its racemate, or its isotope label , or nitrogen oxides thereof, selected from the following compounds:

















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。 Alternatively, 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.
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。Optionally, the pharmaceutically acceptable excipients are selected from: fillers, disintegrants, lubricants, glidants, effervescent agents, flavoring agents, preservatives, coating materials or other excipients.
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。Optionally, the fillers of the pharmaceutically acceptable excipients include lactose, sucrose, dextrin, starch, pregelatinized starch, mannitol, sorbitol, calcium hydrogen phosphate, calcium sulfate, calcium carbonate, microcrystalline One or more combinations of cellulose; the binder includes sucrose, starch, povidone, sodium carboxymethylcellulose, hypromellose, hydroxypropylcellulose, methylcellulose, One or more combinations of polyethylene glycol, medicinal ethanol, and water; the disintegrant includes starch, crospovidone, croscarmellose sodium, and low-substituted hydroxypropyl fiber One or more combinations of cellulose, sodium carboxymethyl cellulose, and effervescent disintegrant.
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。Optionally, 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.
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。Alternatively, 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.
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、淋巴瘤、卡波西肉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。In another aspect, 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, lymphoma, Kaposi's sarcoma, or myelodysplastic syndrome. The compounds provided by the present invention can be used to treat, prevent or manage primary or metastatic tumors.
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、或其氮氧化物的制备方法；In another aspect, 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 Methods for preparing racemates thereof, or isotope markers thereof, or nitrogen oxides thereof;
包括将式(A)化合物和式(B)化合物通过步骤A得到式(C)化合物： The method includes passing the compound of formula (A) and the compound of formula (B) through step A to obtain the compound of formula (C):
步骤A：将式(A)和式(B)通过取代反应制得式(C)；Step A: Prepare formula (C) by substitution reaction of formula (A) and formula (B);
可选地，将式(A)和式(B)在碱(例如碳酸钾，碳酸铯，氢化钠，双三甲基硅基胺基锂等)催化下，在适合的溶剂中(例如N，N-二甲基甲酰胺，N，N-二甲基甲酰胺，二甲亚砜，N-甲基吡咯烷酮等)，于0℃至25℃温度条件下，通过取代反应制得式(C)。
Alternatively, formula (A) and formula (B) are catalyzed by a base (such as potassium carbonate, cesium carbonate, sodium hydride, lithium bistrimethylsilylamide, etc.) in a suitable solvent (such as N, N-dimethylformamide, N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, etc.), formula (C) is prepared through a substitution reaction at a temperature of 0°C to 25°C. .
其中，in,
式(B)和式(C)中R3如式(I)中所述，但不为H，OR4；In formula (B) and formula (C), R3 is as described in formula (I), but is not H, OR4;
式(B)中，B选自Cl，Br，I，OTs，OMs；In formula (B), B is selected from Cl, Br, I, OTs, OMs;
可选地，式(B)可以采用如下方法1-8中的一种，但并不限于以下方法：Alternatively, formula (B) can adopt one of the following methods 1-8, but is not limited to the following methods:
方法1：
method 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)化合物；1) React the carboxyl group with thionyl chloride under reflux conditions to obtain the acid chloride; 2) Prepare the compound of formula (B) by reacting the acid chloride and paraformaldehyde under zinc chloride catalyst conditions;
或方法2：
or method 2:
在室温下，向剧烈搅拌的酸的二氯甲烷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)化合物。At room temperature, add saturated sodium bicarbonate solution and a catalytic amount of tetrabutylammonium bisulfate to the vigorously stirring dichloromethane solution of the acid, and then add chloromethyl chlorosulfonate. After the reaction is completed, separate the layers and collect the organic phase. , dried over anhydrous sodium sulfate, spun to dryness under reduced pressure, and purified by column chromatography to obtain the compound of formula (B).
或方法3：
or method 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)化合物。At 0°C, add the corresponding secondary amine to the dichloromethane solution of chloromethyl chloroformate. After the reaction is completed, filter, wash the organic phase with 1N hydrochloric acid, dry over anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain formula (B ) compound.
或方法4：
or method 4:
0℃下，向氯甲酸氯甲酯的二氯甲烷溶液中加入吡啶，然后加入相应的醇，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)化合物。At 0°C, add pyridine to the dichloromethane solution of chloromethyl chloroformate, and then add the corresponding alcohol. After the reaction is completed, filter, wash the organic phase with 1N hydrochloric acid, dry over anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain Compounds of formula (B).
或方法5：
or method 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)化合物。Reflux the chloromethyl reagent and sodium bromide (or potassium bromide) in acetonitrile (or acetone). After the reaction is completed, remove the solvent under reduced pressure, add the organic solvent and water, separate the layers, collect the organic phase, and anhydrous sodium sulfate. Dry and remove the solvent under reduced pressure to obtain the corresponding brominated compound of formula (B).
或方法6：
or method 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)化合物。Reflux the chloromethyl reagent and sodium iodide (or potassium iodide) in acetonitrile (or acetone). After the reaction is completed, remove the solvent under reduced pressure, add organic solvent and water, separate layers, collect the organic phase, and dry over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain the corresponding iodo compound of formula (B).
或方法7：
or method 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)化合物。Reflux the chloromethyl reagent and silver methanesulfonate in acetonitrile. After the reaction is completed, remove the solvent under reduced pressure, add the organic solvent and water, separate the layers, collect the organic phase, dry over anhydrous sodium sulfate, remove the solvent under reduced pressure, and obtain the corresponding Methanesulfonyloxy-substituted compounds of formula (B).
或方法8：
or method 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)化合物。Reflux the chloromethyl reagent and silver p-toluenesulfonate in acetonitrile. After the reaction is completed, remove the solvent under reduced pressure, add the organic solvent and water, separate the layers, collect the organic phase, dry over anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain The corresponding p-benzenesulfooxy-substituted compound of formula (B).
各个Y选自-R4、-OR4、-NHR4、NR4R4’，其中R4、R4’如式(I)中所述。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).
或者，通过以下步骤A’的反应得到式(C)：Or, formula (C) can be obtained through the reaction of the following step A':
步骤A’：将S1和S2通过缩合条件得到S3，再将S3经过脱保护得到S4，然后S4和S5在碱催化下通过取代和氨解甲酯得到LN-S5经铁粉还原得到式(C)。
Step A': S1 and S2 are subjected to condensation conditions to obtain S3, and then S3 is deprotected to obtain S4. Then S4 and S5 are substituted and ammonolyzed to methyl ester under alkali catalysis to obtain LN-S5, which is reduced by iron powder to obtain formula (C ).
还包括将式(C)和式(D)通过步骤B，It also includes passing formula (C) and formula (D) through step B,
步骤B：将式(C)和式(D)通过酰化反应得式(E)。Step B: Perform acylation reaction between formula (C) and formula (D) to obtain formula (E).
优选地，将式(C)和对硝基苯基氯甲酸酯溶于(如四氢呋喃、N，N-二甲基甲酰胺、N-甲基吡咯烷酮等)中，在回流条件下反应，得到式(E)；Preferably, formula (C) and p-nitrophenyl chloroformate are dissolved in (such as tetrahydrofuran, N, N-dimethylformamide, N-methylpyrrolidone, etc.) and reacted under reflux conditions to obtain Formula (E);
可选地，所述回流反应结束后，减压浓缩，加入乙酸乙酯、或二氯甲烷或石油醚搅拌均匀得到混悬液，减压过滤并洗涤或直接旋干，得到式(E)。
Optionally, after the reflux reaction is completed, concentrate under reduced pressure, add ethyl acetate, dichloromethane or petroleum ether and stir evenly to obtain a suspension, filter and wash under reduced pressure or directly spin to dryness to obtain formula (E).
其中，式(C)和式(E)中，R3定义同上式(I)中所述；Among them, in formula (C) and formula (E), the definition of R 3 is the same as that described in formula (I) above;
或者，还包括将式(C)和式(F)通过步骤C得到式(G)：Or, it also includes passing formula (C) and formula (F) through step C to obtain formula (G):
步骤C：将式(C)和式(F)通过酰化反应制得式(G)；Step C: Prepare formula (G) by acylation reaction of formula (C) and formula (F);
可选地，式(G)的合成方法：低温下(优选0℃)将式(C)缓慢滴加至三光气的二氯甲烷或乙腈溶液中，缓慢升温至30℃-60℃(优选为45℃)，待反应结束，减压浓缩，得式(G)。
Alternatively, the synthesis method of formula (G): slowly drop formula (C) into a dichloromethane or acetonitrile solution of triphosgene at low temperature (preferably 0°C), and slowly raise the temperature to 30°C-60°C (preferably 45°C), wait until the reaction is completed, and concentrate under reduced pressure to obtain formula (G).
其中，式(C)和式(G)中，R3定义同式(I)中所述；Among them, in formula (C) and formula (G), the definition of R 3 is the same as that described in formula (I);
或者，还包括将式(C)和式(H)通过步骤D得到式(J)：Or, it also includes passing formula (C) and formula (H) through step D to obtain formula (J):
步骤D：将式(C)和式(H)通过缩合反应得式(J)；Step D: Condensation reaction of formula (C) and formula (H) to obtain formula (J);
可选地，将式(C)和N，N′-羰基二咪唑分散在四氢呋喃中，在回流条件下反应，待反应结束，减压浓缩，加入乙酸乙酯搅拌均匀得到混悬液，减压过滤并洗涤或直接旋干，得式(J)。
Alternatively, the formula (C) and N, N'-carbonyldiimidazole are dispersed in tetrahydrofuran and reacted under reflux conditions. After the reaction is completed, concentrate under reduced pressure, add ethyl acetate and stir evenly to obtain a suspension, and reduce the pressure. Filter and wash or spin dry directly to get formula (J).
其中，式(C)和式(J)中，R3定义同式(I)中所述； Among them, in formula (C) and formula (J), the definition of R 3 is the same as that described in formula (I);
当式(I)中A选自-O-，-S-，-NH-时，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：When A in formula (I) is selected from -O-, -S-, -NH-, formula (E) or formula (G) or formula (J) and formula (L) are nucleophilically substituted under base catalysis The reaction and optional deprotection reaction give formula (I), as shown in the following synthesis step E:
步骤E：
Step E:
式(L)中，W选自-OH，-SH，-NH2中的任意一个基团；In formula (L), W is selected from any one of -OH, -SH and -NH 2 groups;
R5为Cl，或 R 5 is Cl, or
式(E，或G或J)中，R3如式(I)所示；In formula (E, or G or J), R 3 is as shown in formula (I);
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：
Alternatively, when R 1 is Boc, 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 2 CH 3 , - CH(CH 3 ) 2 , -CH 2 CH 2 OH, or -CH 2 CHOHCH 2 OH, optionally deprotected using the following method:
将式(M)分散在适合的溶剂中(例如乙酸乙酯或二氧六环)，然后通入氯化氢气体(或加入其他酸)脱保护，室温或40℃反应，析出固体，无固体加入乙醚后析出固体，过滤，得式(N)为盐的形式。Disperse formula (M) in a suitable solvent (such as ethyl acetate or dioxane), then pass in hydrogen chloride gas (or add other acids) for deprotection, react at room temperature or 40°C, and precipitate a solid. Add ether if there is no solid. Afterwards, a solid precipitates and is filtered to obtain formula (N) in the form of a salt.
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。
When 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 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 OH, or -CH 2 CHOHCH 2 OH, optionally deprotected using the following method.
将式(O)分散在合适溶剂中(例如甲醇或乙醇)，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)的盐形式分散在合适溶剂中(例如甲醇或乙醇)，加等当量碱游离得到。Disperse formula (O) in a suitable solvent (such as methanol or ethanol), and then reduce it with palladium hydrocarbon to obtain formula (N) in a free state. The free compound can also be obtained by dispersing the salt form of formula (N) in a suitable solvent (such as methanol or ethanol) and adding an equivalent amount of base.
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、或其氮氧化物的制备方法，还包括将式(C)化合物和式(Q)化合物通过合成方法二得到式(R)化合物：The compound of the above 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 the preparation method of nitrogen oxides thereof, also includes the compound of formula (C) and the compound of formula (Q) through synthesis method two to obtain the compound of formula (R):
当式(I)中A不存在时，采用合成步骤F制备：将式(A)或式(C)与式(P)经适合的缩合剂(例如HATU或TBTU)缩合和任选的脱保护反应得式(R)When A in formula (I) does not exist, synthetic step F is used to prepare: formula (A) or formula (C) and formula (P) are condensed with a suitable condensing agent (such as HATU or TBTU) and optionally deprotected. Reaction formula (R)
步骤F：
Step F:
式(P)中，Q定义如上式(I)中所述。In formula (P), Q is defined as described in formula (I) above.
本发明另一方面，提供所述式(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活性药物(“第二活性化合物”)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、淋巴瘤、卡波西肉瘤或骨髓增生异常 综合征；优选地，所述其他活性药物为地塞米松和/或朋替佐米。In another aspect, the present invention provides the compound of formula (I) or its optical isomer, or its pharmaceutically acceptable salt, or its solvate, or its clathrate, or its racemate, or its Isotopic markers, or their nitrogen oxides or their pharmaceutical compositions are used in combination with one or more other active drugs ("second active compounds") in the preparation of drugs for the prevention and/or treatment of hematological diseases The use; preferably, the disease is selected from blood cancer and bone marrow cancer, lymphoma, Kaposi's sarcoma or myelodysplasia syndrome; preferably, the other active drug is dexamethasone and/or pentezomib.
优选地，所述的疾病选自血癌和骨髓癌，如急性、慢性白血病以及多发性骨髓瘤，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。Preferably, the disease is selected from blood cancers and bone marrow cancers, such as acute and chronic leukemias and multiple myeloma, such as lymphoblastic leukemia, chronic myelogenous leukemia, myelogenous 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.
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))。Among them, "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; immunoglobulin D myeloma; immunoglobulin E myeloma; and multiple myeloma characterized by genetic abnormalities such as Myeloma: cyclin D translocation (eg, t(11;14)(q13;q32); t(6;14)(q21;q32); t(12;14)(p13;q32) or t (6;20);); MMSET translocation (e.g., t(4;14)(p16;q32)); MAF translocation (e.g., t(14;16)(q32;q32); t(20;22) ); t(16;22)(q11;q13) or t(14;20)(q32;q11)); or other chromosomal factors (e.g., deletion of chromosome 17p13 or chromosome 13; del(17/17p), non- Hyperdiploidy and gain(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。As used herein, unless otherwise indicated, 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.
本发明所述第二活性成分实例可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)。Examples of the second active ingredient of the present invention may include one or more of the following substances: melphalan, vincristine, cyclophosphamide, etoposide, doxorubicin, bendamustine, orbibin Tocilizumab, protease body inhibitors (e.g., bortezomib, carfilzomib, elsazomib, opozomib, or marezomib), histone deacetylase inhibitors (e.g., panobinostat, ACY241), BET inhibitors (eg 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。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.
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。The term "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.
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。The term "pharmaceutically acceptable salts" as used herein refers to salts prepared from pharmaceutically acceptable non-toxic acids, including inorganic acid salts and organic acid salts. For example, but not limited to hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid, carbonic acid, nitric acid, hydrogen sulfate acid, methanesulfonic acid, glycolic acid, tartaric acid, formic acid, acetic acid, propionic acid , butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, trifluoroacetic acid, pyruvic acid, cinnamic acid, lauric acid, salicylic acid, citric acid, succinic acid, fumaric acid, benzoic acid, anthranilic acid, 2-(4-Hydroxybenzoyl)benzoic acid, benzenesulfonic acid, ethanesulfonic acid, p-aminobenzenesulfonic acid, p-toluenesulfonic acid, phenylacetic acid, ascorbic acid, alginic acid, furoic acid, stearic acid, mucinic acid, Mandelic acid, malic acid, parapic acid, pantothenic acid, camphorsulfonic acid, gluconic acid, glutamic acid, glucuronic acid, galacturonic acid, glycidic acid, lactic acid, malic acid, maleic acid, aspartic acid, sulfur Cyanic acid, glucoheptanoic acid, glycerophosphate, sulfosalicylic acid, hemi-sulfuric acid, oxalic acid, malonic acid, picric acid, etc.
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。The term "solvate" as used herein refers to a compound that is further bound by non-covalent intermolecular forces to a stoichiometric or non-stoichiometric amount of a solvent. For example, when the solvent is water, the solvate is a hydrate.
缩略语 abbreviation
DCM：二氯甲烷DCM: dichloromethane
DCE：二氯乙烷DCE: dichloroethane
THF：四氢呋喃THF: Tetrahydrofuran
TFA：三氟乙酸TFA: trifluoroacetic acid
2-MeTHF：2-甲基四氢呋喃2-MeTHF: 2-methyltetrahydrofuran
DMSO：二甲亚砜DMSO: dimethyl sulfoxide
DMF：N，N-二甲基甲酰胺DMF: N,N-dimethylformamide
DIPEA：N，N-二异丙基乙胺DIPEA: N,N-diisopropylethylamine
HATU：2-(7-氮杂苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯HATU: 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate
TBTU：O-苯并三氮唑-N，N，N′，N′-四甲基脲四氟硼酸TBTU: O-benzotriazole-N, N, N′, N′-tetramethylurea tetrafluoroborate
NMP：N-甲基吡咯烷酮NMP: N-methylpyrrolidone
DMAC：N，N-二甲基乙酰胺DMAC: N,N-dimethylacetamide
LiHMDS：双三甲基硅基胺基锂TBS：叔丁基二甲基硅基LiHMDS: lithium bistrimethylsilylamide TBS: tert-butyldimethylsilyl
LAT1：L型氨基酸转体1LAT1: L-amino acid transposer 1
RPMI-8226：人多发性骨髓瘤细胞RPMI-8226: human multiple myeloma cells
NCI-H929：人骨髓瘤细胞NCI-H929: human myeloma cells
附图说明Description of the drawings
图1为不同细胞中LAT1的表达情况。Figure 1 shows the expression of LAT1 in different cells.
图2为RPMI-8226模型中小鼠肿瘤体积变化趋势(n＝7)。Figure 2 shows the change trend of mouse tumor volume in the RPMI-8226 model (n=7).
图3为NCI-H929模型中小鼠肿瘤体积变化趋势(n＝7)。Figure 3 shows the change trend of mouse tumor volume in the NCI-H929 model (n=7).
具体实施方式Detailed ways
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。Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. If a term in this article has multiple definitions, this section shall prevail unless otherwise stated.
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。 The embodiments of the present invention are described in detail below, but the provided examples do not limit the present invention in any way.
实施例Example
通用合成方法1：General synthesis method 1:
采用步骤F合成。Synthesize using step F.
将式(A)(1.0当量)、式(P)(1.0当量)、三乙胺(1.0当量)和TBTU(1.0当量)溶于DMF当中，在室温条件下搅拌12h。Dissolve formula (A) (1.0 equivalent), formula (P) (1.0 equivalent), triethylamine (1.0 equivalent) and TBTU (1.0 equivalent) in DMF, and stir at room temperature for 12 hours.
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，减压蒸干，用硅胶柱层析进行纯化后，加入TFA和DCM，室温搅拌1h，将反应液减压蒸干得白色固体。Add ethyl acetate, and then wash the organic phase with saturated aqueous ammonium chloride solution, water, and saturated aqueous sodium chloride solution in sequence. Collect the organic phase and dry it over anhydrous sodium sulfate, evaporate to dryness under reduced pressure, purify with silica gel column chromatography, and add TFA. and DCM, stirred at room temperature for 1 h, and evaporated the reaction solution to dryness under reduced pressure to obtain a white solid.
上述产物溶解在甲醇中，加入Pd/C，在氢气环境下室温搅拌1h。过滤并收集滤液，减压蒸干，得终产物。The above product was dissolved in methanol, Pd/C was added, and stirred at room temperature for 1 h in a hydrogen atmosphere. Filter and collect the filtrate, and evaporate to dryness under reduced pressure to obtain the final product.
实施例1：化合物43的制备
Example 1: Preparation of compound 43
采用通用合成方法1制备，得白色固体产物，收率83％。Prepared by general synthesis method 1, a white solid product was obtained with a yield of 83%.
1H NMR(400MHz，DMSO-d6)δ11.16(s，1H)，11.03(s，1H)，8.10-7.52(m，4H)，7.50(d，J＝4.3Hz，2H)，5.15(dd，J＝13.4，5.1Hz，1H)，4.39(m，2H)，3.69(s，1H)，3.08-2.89(m，2H)，2.73-2.60(m，2H)，2.36-2.28(m，1H)，2.06-2.03(m，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 11.16 (s, 1H), 11.03 (s, 1H), 8.10-7.52 (m, 4H), 7.50 (d, J=4.3Hz, 2H), 5.15 ( dd, J=13.4, 5.1Hz, 1H), 4.39 (m, 2H), 3.69 (s, 1H), 3.08-2.89 (m, 2H), 2.73-2.60 (m, 2H), 2.36-2.28 (m, 1H), 2.06-2.03(m, 1H).
通用合成方法2：General synthesis method 2:
采用步骤B和步骤E合成。Synthesize using steps B and E.
将式(C)(1.0当量)与式(D)(1.5当量)溶于THF中，在回流条件下搅拌2h。减压浓缩，加入乙酸乙酯搅拌均匀得到混悬液，减压过滤并乙酸乙酯洗涤或直接旋干，得式(E)。Dissolve formula (C) (1.0 equivalent) and formula (D) (1.5 equivalent) in THF, and stir under reflux conditions for 2 hours. Concentrate under reduced pressure, add ethyl acetate and stir evenly to obtain a suspension, filter under reduced pressure and wash with ethyl acetate or directly spin to dryness to obtain formula (E).
将式(E)和式(L)(1.1当量)溶于DMF中，在常温搅拌下滴加DIPEA(1.5当量)，继续室温搅拌至原料消失，加入酸水调节pH至3-4，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，过滤得滤液减压蒸干，用硅胶柱层析纯化后，脱保护或不脱保护得式(I)。Dissolve formula (E) and formula (L) (1.1 equivalent) in DMF, add DIPEA (1.5 equivalent) dropwise under stirring at room temperature, continue stirring at room temperature until the raw materials disappear, add acid water to adjust the pH to 3-4, and add acetic acid ethyl ester, and then wash the organic phase with saturated aqueous ammonium chloride solution, water, and saturated aqueous sodium chloride solution, and collect the organic phase. The phase is dried over anhydrous sodium sulfate, filtered and the filtrate obtained is evaporated to dryness under reduced pressure, purified by silica gel column chromatography, and then deprotected or not to obtain formula (I).
其中，式(L)的合成方法：将Boc保护的氨基酸(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)。Among them, the synthesis method of formula (L): combine Boc protected amino acid (1.0 equivalent), cesium carbonate (0.5 equivalent) and ethyl iodide, or 1-iodobutane, or 1-iodohexane, or isopropyl iodide , or TBS-protected hydroxyethyl iodide, or 4-(iodomethyl)-2,2-dimethyl-1,3-dioxolane (1.1 equivalent) was dispersed in DMF, stirred at room temperature overnight, and extracted. , column chromatography yields product formula (L).
实施例2：化合物44的制备
Example 2: Preparation of compound 44
采用通用合成方法2制备，得盐酸盐为白色固体，收率86.36％。Prepared by general synthesis method 2, the hydrochloride was obtained as a white solid with a yield of 86.36%.
1H NMR(600MHz，DMSO-d6)δ11.02(s，1H)，9.70(s，1H)，8.59(s，2H)，7.82-7.70(m，1H)，7.50(dd，J＝6.3，2.5Hz，2H)，5.14(dt，J＝13.3，4.7Hz，1H)，4.63(ddd，J＝12.1，8.7，3.5Hz，1H)，4.51-4.33(m，3H)，4.30(s，1H)，2.99-2.88(m，1H)，2.67-2.59(m，1H)，2.37-2.27(m，1H)，2.08-2.01(m，1H). 1 H NMR (600MHz, DMSO-d 6 ) δ 11.02 (s, 1H), 9.70 (s, 1H), 8.59 (s, 2H), 7.82-7.70 (m, 1H), 7.50 (dd, J=6.3 , 2.5Hz, 2H), 5.14 (dt, J=13.3, 4.7Hz, 1H), 4.63 (ddd, J=12.1, 8.7, 3.5Hz, 1H), 4.51-4.33 (m, 3H), 4.30 (s, 1H), 2.99-2.88(m, 1H), 2.67-2.59(m, 1H), 2.37-2.27(m, 1H), 2.08-2.01(m, 1H).
实施例3：化合物45的制备
Example 3: Preparation of compound 45
采用通用合成方法1制备，得白色固体产物，收率86％。Prepared by general synthesis method 1, a white solid product was obtained with a yield of 86%.
1H NMR(400MHz，DMSO-d6)δ10.68(d，J＝14.6Hz，1H)，7.95-7.93(m，1H)，7.49-7.45(m，2H)，5.13(dd，J＝13.1，4.9Hz，1H)，4.49-4.33(m，2H)，3.46-3.42(m，1H)，3.17(s，1H)，2.94-2.88(m，1H)，2.61-2.55(m，3H)，2.37-2.31(m，1H)，2.03-1.96(m，3H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.68 (d, J=14.6Hz, 1H), 7.95-7.93 (m, 1H), 7.49-7.45 (m, 2H), 5.13 (dd, J=13.1 , 4.9Hz, 1H), 4.49-4.33(m, 2H), 3.46-3.42(m, 1H), 3.17(s, 1H), 2.94-2.88(m, 1H), 2.61-2.55(m, 3H), 2.37-2.31 (m, 1H), 2.03-1.96 (m, 3H).
实施例4：化合物46的制备
Example 4: Preparation of compound 46
采用通用合成方法2制备，得盐酸盐为白色固体，收率33.72％。Prepared by general synthesis method 2, the hydrochloride was obtained as a white solid with a yield of 33.72%.
1H NMR(400MHz，DMSO-d6)δ11.04(s，1H)，10.21(s，1H)，8.76(s，3H)，7.79(dt，J＝8.0，4.0Hz，1H)，7.59-7.50(m，2H)，7.31(d，J＝8.6Hz，2H)，7.22(d，J＝8.6Hz，2H)，5.15(dd，J＝13.3，5.1Hz，1H)，4.53(d，J＝17.6Hz，1H)，4.43(d，J＝17.6Hz，1H)，4.29(t，J＝6.4Hz，1H)，3.70(s，3H)，3.18(ddd，J＝21.2，14.2，6.5Hz，2H)，2.98-2.86(m，1H)，2.62(d，J＝16.8Hz，1H)，2.38(dd，J＝13.1，4.5Hz，1H)，2.11-2.00(m，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 11.04 (s, 1H), 10.21 (s, 1H), 8.76 (s, 3H), 7.79 (dt, J=8.0, 4.0Hz, 1H), 7.59- 7.50 (m, 2H), 7.31 (d, J=8.6Hz, 2H), 7.22 (d, J=8.6Hz, 2H), 5.15 (dd, J=13.3, 5.1Hz, 1H), 4.53 (d, J =17.6Hz, 1H), 4.43 (d, J = 17.6Hz, 1H), 4.29 (t, J = 6.4Hz, 1H), 3.70 (s, 3H), 3.18 (ddd, J = 21.2, 14.2, 6.5Hz , 2H), 2.98-2.86 (m, 1H), 2.62 (d, J=16.8Hz, 1H), 2.38 (dd, J=13.1, 4.5Hz, 1H), 2.11-2.00 (m, 1H).
实施例5：化合物47的制备
Example 5: Preparation of compound 47
采用通用合成方法2制备，得盐酸盐为白色固体，收率55.55％。Prepared by general synthesis method 2, the hydrochloride was obtained as a white solid with a yield of 55.55%.
1H NMR(600MHz，DMSO-d6)δ11.02(s，1H)，9.54(d，J＝15.4Hz，1H)，8.49(s，2H)，7.84-7.69(m，1H)，7.60-7.32(m，2H)，5.23-5.10(m，2H)，4.45(dd，J＝17.4，13.1Hz，1H)，4.34(dd，J＝17.4，8.6Hz，1H)，4.09(s，1H)，3.00-2.86(m，1H)，2.65-2.59(m，1H)，2.31(qd，J＝13.0，5.4Hz，1H)，2.08-2.00(m，1H)，1.41(d，J＝6.6Hz，3H). 1 H NMR (600MHz, DMSO-d 6 ) δ 11.02 (s, 1H), 9.54 (d, J = 15.4Hz, 1H), 8.49 (s, 2H), 7.84-7.69 (m, 1H), 7.60- 7.32 (m, 2H), 5.23-5.10 (m, 2H), 4.45 (dd, J=17.4, 13.1Hz, 1H), 4.34 (dd, J=17.4, 8.6Hz, 1H), 4.09 (s, 1H) , 3.00-2.86 (m, 1H), 2.65-2.59 (m, 1H), 2.31 (qd, J=13.0, 5.4Hz, 1H), 2.08-2.00 (m, 1H), 1.41 (d, J=6.6Hz ,3H).
实施例6：化合物49的制备
Example 6: Preparation of compound 49
采用通用合成方法2制备，得白色固体，收率82.91％。Prepared by general synthesis method 2, a white solid was obtained with a yield of 82.91%.
1H NMR(600MHz，DMSO-d6)δ12.88(s，1H)，10.99(s，1H)，10.32(s，1H)，8.27(d，J＝8.1Hz，1H)，7.75-7.70(m，1H)，7.56-7.49(m，2H)，5.13(dd，J＝12.9， 4.6Hz，1H)，4.46-4.30(m，3H)，3.40(ddd，J＝13.6，7.1，5.1Hz，1H)，3.09(dt，J＝13.7，8.2Hz，1H)，2.96-2.87(m，1H)，2.60(d，J＝16.8Hz，1H)，2.37(td，J＝13.3，8.9Hz，1H)，2.06-1.99(m，1H)，1.85(d，J＝1.9Hz，3H). 1 H NMR (600MHz, DMSO-d 6 ) δ 12.88 (s, 1H), 10.99 (s, 1H), 10.32 (s, 1H), 8.27 (d, J = 8.1Hz, 1H), 7.75-7.70 ( m, 1H), 7.56-7.49 (m, 2H), 5.13 (dd, J=12.9, 4.6Hz, 1H), 4.46-4.30 (m, 3H), 3.40 (ddd, J=13.6, 7.1, 5.1Hz, 1H), 3.09 (dt, J=13.7, 8.2Hz, 1H), 2.96-2.87 (m , 1H), 2.60 (d, J=16.8Hz, 1H), 2.37 (td, J=13.3, 8.9Hz, 1H), 2.06-1.99 (m, 1H), 1.85 (d, J=1.9Hz, 3H) .
实施例7：化合物50的制备
Example 7: Preparation of Compound 50
采用通用合成方法2制备，得白色固体。收率86.36％。Prepared by general synthesis method 2, a white solid was obtained. The yield is 86.36%.
1H NMR(DMSO-d6，600MHz)：δ8.12(s，1H)，7.62(s，1H)，7.37(s，1H)，7.21-7.26(m，2H)，4.75-4.76(m，1H)，4.39-4.57(m，3H)，3.50(s，2H)，3.01(s，2H)，2.67-2.77(m，1H)，2.04-2.33(m，4H)，1.41-1.72(m，3H). 1 H NMR (DMSO-d 6 , 600MHz): δ8.12 (s, 1H), 7.62 (s, 1H), 7.37 (s, 1H), 7.21-7.26 (m, 2H), 4.75-4.76 (m, 1H), 4.39-4.57(m, 3H), 3.50(s, 2H), 3.01(s, 2H), 2.67-2.77(m, 1H), 2.04-2.33(m, 4H), 1.41-1.72(m, 3H).
实施例8：化合物72的制备
Example 8: Preparation of Compound 72
采用通用合成方法2制备，用甲磺酸进行脱保护，，得甲磺酸盐为白色固体，收率27.31％。It was prepared by general synthesis method 2, and deprotected with methanesulfonic acid to obtain the mesylate salt as a white solid, with a yield of 27.31%.
1H NMR(400MHz，DMSO-d6)δ11.03(s，1H)，10.17(s，1H)，8.44(s，3H)，7.82-7.76(m，1H)，7.57-7.51(m，2H)，7.26(dd，J＝23.2，8.6Hz，4H)，5.16(dd，J＝13.3，5.1Hz，1H)，4.51(d，J＝17.6Hz，1H)，4.39(dd，J＝20.0，11.5Hz，2H)，3.72(s，3H)，3.12(d，J＝5.1Hz，2H)，2.99-2.87(m，1H)，2.62(d，J＝16.5Hz，1H)，2.40-2.30(m，4H)，2.09-1.99(m，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ11.03 (s, 1H), 10.17 (s, 1H), 8.44 (s, 3H), 7.82-7.76 (m, 1H), 7.57-7.51 (m, 2H ), 7.26 (dd, J=23.2, 8.6Hz, 4H), 5.16 (dd, J=13.3, 5.1Hz, 1H), 4.51 (d, J=17.6Hz, 1H), 4.39 (dd, J=20.0, 11.5Hz, 2H), 3.72 (s, 3H), 3.12 (d, J=5.1Hz, 2H), 2.99-2.87 (m, 1H), 2.62 (d, J=16.5Hz, 1H), 2.40-2.30 ( m, 4H), 2.09-1.99 (m, 1H).
实施例9：化合物73的制备
Example 9: Preparation of Compound 73
采用通用合成方法2制备，得盐酸盐为白色固体，收率58.84％。Prepared by general synthesis method 2, the hydrochloride was obtained as a white solid with a yield of 58.84%.
1H NMR(400MHz，DMSO-d6)δ11.04(s，1H)，10.20(s，1H)，8.47(s，3H)，7.78(dd，J＝8.9，4.0Hz，1H)，7.57-7.49(m，2H)，7.34(d，J＝8.5Hz，2H)，7.22(d，J＝8.5Hz，2H)，5.15(dd，J＝13.3，5.1Hz，1H)，4.52(d，J＝17.7Hz，1H)，4.42(d，J＝17.7Hz，1H)，4.18(t，J＝6.2Hz，1H)，3.16(d，J＝6.1Hz，2H)，3.02-2.86(m，1H)，2.62(d，J＝16.8Hz，1H)，2.37(dd，J＝13.1，4.4Hz，1H)，2.10-2.00(m，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 11.04 (s, 1H), 10.20 (s, 1H), 8.47 (s, 3H), 7.78 (dd, J=8.9, 4.0Hz, 1H), 7.57- 7.49 (m, 2H), 7.34 (d, J=8.5Hz, 2H), 7.22 (d, J=8.5Hz, 2H), 5.15 (dd, J=13.3, 5.1Hz, 1H), 4.52 (d, J =17.7Hz, 1H), 4.42 (d, J = 17.7Hz, 1H), 4.18 (t, J = 6.2Hz, 1H), 3.16 (d, J = 6.1Hz, 2H), 3.02-2.86 (m, 1H ), 2.62 (d, J=16.8Hz, 1H), 2.37 (dd, J=13.1, 4.4Hz, 1H), 2.10-2.00 (m, 1H).
实施例10：化合物74的制备
Example 10: Preparation of Compound 74
采用通用合成方法2制备，用浓硫酸进行脱保护，得硫酸盐为白色固体，收率54.82％。It was prepared by general synthesis method 2, and deprotected with concentrated sulfuric acid to obtain the sulfate as a white solid, with a yield of 54.82%.
1H NMR(400MHz，DMSO-d6)δ11.03(s，1H)，10.16(s，1H)，8.42(s，3H)，7.82-7.76(m，1H)，7.54(d，J＝3.6Hz，2H)，7.26(dd，J＝21.2，8.4Hz，4H)，5.16(dd，J＝13.2，4.9Hz，1H)，4.53-4.35(m，3H)，3.72(s，3H)，3.11(d，J＝6.6Hz，2H)，2.98-2.89(m，1H)，2.64-2.59(m，1H)，2.38-2.34(m，1H)，2.08-2.01(m，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 11.03 (s, 1H), 10.16 (s, 1H), 8.42 (s, 3H), 7.82-7.76 (m, 1H), 7.54 (d, J=3.6 Hz, 2H), 7.26 (dd, J=21.2, 8.4Hz, 4H), 5.16 (dd, J=13.2, 4.9Hz, 1H), 4.53-4.35 (m, 3H), 3.72 (s, 3H), 3.11 (d, J=6.6Hz, 2H), 2.98-2.89(m, 1H), 2.64-2.59(m, 1H), 2.38-2.34(m, 1H), 2.08-2.01(m, 1H).
通用合成方法3：General synthesis method 3:
采用步骤A、步骤C(或步骤D)和步骤E合成。Synthesize using Step A, Step C (or Step D) and Step E.
第一步：氯甲基试剂的制备Step 1: Preparation of chloromethyl reagent
(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)。(1) At room temperature, add saturated sodium bicarbonate and Tetrabutylammonium bisulfate (0.1 equivalent), chloromethyl chlorosulfonate (1.2 equivalent), after the reaction is completed, separate the layers, collect the organic phase, dry it over anhydrous sodium sulfate, spin dry under reduced pressure, and purify by column chromatography to obtain Formula (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)。(2) Dissolve morpholine, or dimethylamine, or diethylamine (1.0 equivalent), DIPEA and DMAP in DCM, cool to 0°C, slowly add chloromethyl chloroformate (1.1 equivalent) dropwise into DCM, React at room temperature for 1.5 hours, add DCM, extract with 1N hydrochloric acid and saturated brine, dry with anhydrous sodium sulfate, and distill under reduced pressure to obtain formula (B).
第二步： Step two:
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)。Add 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. Add ethyl acetate, and then wash the organic phase with saturated aqueous ammonium chloride solution, water, and saturated aqueous sodium chloride solution in sequence. Collect the organic phase and dry it over anhydrous sodium sulfate. Filter and evaporate the filtrate to dryness under reduced pressure. Purify with silica gel column chromatography to obtain Formula (C).
将式(C)(1.0当量)、式(F)(0.43当量)或式(H)(1.0当量)分散在乙腈中，在40℃搅拌1h，减压蒸干得式(G)或式(J)。Disperse formula (C) (1.0 equivalent), formula (F) (0.43 equivalent) or formula (H) (1.0 equivalent) in acetonitrile, stir at 40°C for 1 hour, and evaporate to dryness under reduced pressure to obtain formula (G) or formula ( J).
第三步：third step:
将式(L)溶解在DCM中，降温至0℃，加入DIPEA和式(G)或式(J)的DCM溶液。低温反应30分钟后用稀酸水淬灭后，有机相用无水硫酸钠干燥后，减压蒸馏、柱层析纯化后得式(M)或式(O)后，脱保护得式(I)。Dissolve formula (L) in DCM, cool the temperature to 0°C, and add DIPEA and the DCM solution of formula (G) or formula (J). After reacting at low temperature for 30 minutes, the reaction mixture was quenched with dilute acid water, and the organic phase was dried with anhydrous sodium sulfate, distilled under reduced pressure, and purified by column chromatography to obtain formula (M) or formula (O), and then deprotected to obtain formula (I). ).
实施例11：化合物75的制备
Example 11: Preparation of Compound 75
采用通用合成方法3制备，得盐酸盐为白色固体，收率92.31％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 92.31%.
1H NMR(600MHz，DMSO-d6)δ10.18(s，1H)，8.55(s，3H)，7.94(d，J＝7.3Hz，2H)，7.81(d，J＝6.6Hz，1H)，7.68(t，J＝7.4Hz，1H)，7.57-7.43(m，4H)，7.25(dd，J＝44.2，8.4Hz，4H)，5.94(d，J＝9.6Hz，1H)，5.87(d，J＝9.6Hz，1H)，5.38(dd，J＝13.4，5.0Hz，1H)，4.56(d，J＝17.6Hz，1H)，4.45(d，J＝17.5Hz，1H)，4.33(s，1H)，3.71(s，3H)，3.20-3.07(m，3H)，2.89(d，J＝16.3Hz，1H)，2.19-2.07(m，1H). 1 H NMR (600MHz, DMSO-d 6 ) δ 10.18 (s, 1H), 8.55 (s, 3H), 7.94 (d, J = 7.3Hz, 2H), 7.81 (d, J = 6.6Hz, 1H) , 7.68 (t, J=7.4Hz, 1H), 7.57-7.43 (m, 4H), 7.25 (dd, J=44.2, 8.4Hz, 4H), 5.94 (d, J=9.6Hz, 1H), 5.87 ( d, J=9.6Hz, 1H), 5.38 (dd, J=13.4, 5.0Hz, 1H), 4.56 (d, J=17.6Hz, 1H), 4.45 (d, J=17.5Hz, 1H), 4.33 ( s, 1H), 3.71 (s, 3H), 3.20-3.07 (m, 3H), 2.89 (d, J=16.3Hz, 1H), 2.19-2.07 (m, 1H).
实施例12：化合物77的制备
Example 12: Preparation of Compound 77
采用通用合成方法2制备，得盐酸盐为白色固体，收率78.42％。Prepared by general synthesis method 2, the hydrochloride was obtained as a white solid with a yield of 78.42%.
1H NMR(400MHz，DMSO-d6)δ11.06(s，1H)，9.49(s，1H)，9.09(s，1H)，8.63- 7.92(m，4H)，7.44(td，J＝16.7，7.3Hz，4H)，7.18(d，J＝8.5Hz，2H)，5.16(dd，J＝13.3，5.1Hz，1H)，4.46(d，J＝17.2Hz，1H)，4.33(d，J＝17.2Hz，1H)，4.13(t，J＝6.1Hz，1H)，3.12-2.99(m，2H)，3.00-2.86(m，1H)，2.63(d，J＝16.9Hz，1H)，2.32(qd，J＝13.1，4.3Hz，1H)，2.11-2.01(m，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ11.06 (s, 1H), 9.49 (s, 1H), 9.09 (s, 1H), 8.63- 7.92 (m, 4H), 7.44 (td, J=16.7, 7.3Hz, 4H), 7.18 (d, J=8.5Hz, 2H), 5.16 (dd, J=13.3, 5.1Hz, 1H), 4.46 (d , J=17.2Hz, 1H), 4.33 (d, J=17.2Hz, 1H), 4.13 (t, J=6.1Hz, 1H), 3.12-2.99 (m, 2H), 3.00-2.86 (m, 1H) , 2.63 (d, J=16.9Hz, 1H), 2.32 (qd, J=13.1, 4.3Hz, 1H), 2.11-2.01 (m, 1H).
实施例13：化合物78的制备
Example 13: Preparation of Compound 78
采用通用合成方法3制备，，得盐酸盐为白色固体，收率85.62％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 85.62%.
1H NMR(400MHz，DMSO-d6)δ13.92(s，1H)，10.20(s，1H)，8.38(s，3H)，8.02-7.90(m，2H)，7.81(dd，J＝6.1，2.8Hz，1H)，7.68(dt，J＝8.7，1.3Hz，1H)，7.62-7.41(m，4H)，7.32(d，J＝8.6Hz，2H)，7.22(d，J＝8.6Hz，2H)，5.94(d，J＝9.7Hz，1H)，5.87(d，J＝9.6Hz，1H)，5.39(dd，J＝13.4，5.0Hz，1H)，4.56(d，J＝17.7Hz，1H)，4.44(d，J＝17.6Hz，1H)，4.21(s，1H)，3.23-3.08(m，3H)，2.95-2.82(m，1H)，2.44(dd，J＝13.3，8.9Hz，1H)，2.18-2.08(m，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ13.92 (s, 1H), 10.20 (s, 1H), 8.38 (s, 3H), 8.02-7.90 (m, 2H), 7.81 (dd, J=6.1 , 2.8Hz, 1H), 7.68 (dt, J=8.7, 1.3Hz, 1H), 7.62-7.41 (m, 4H), 7.32 (d, J=8.6Hz, 2H), 7.22 (d, J=8.6Hz , 2H), 5.94 (d, J=9.7Hz, 1H), 5.87 (d, J=9.6Hz, 1H), 5.39 (dd, J=13.4, 5.0Hz, 1H), 4.56 (d, J=17.7Hz , 1H), 4.44 (d, J=17.6Hz, 1H), 4.21 (s, 1H), 3.23-3.08 (m, 3H), 2.95-2.82 (m, 1H), 2.44 (dd, J=13.3, 8.9 Hz, 1H), 2.18-2.08 (m, 1H).
实施例14：化合物82的制备
Example 14: Preparation of Compound 82
采用通用合成方法2制备，，得盐酸盐为白色固体，收率78.31％。Prepared by general synthesis method 2, the hydrochloride was obtained as a white solid with a yield of 78.31%.
1H NMR(600MHz，DMSO-d6)δ11.02(s，1H)，9.68(s，1H)，8.70(s，3H)，7.71(dd，J＝10.9，4.7Hz，1H)，7.58-7.40(m，2H)，5.15(dd，J＝13.3，5.0Hz，1H)，4.66-4.56(m，1H)，4.50-4.40(m，3H)，4.35(dd，J＝17.5，4.7Hz，1H)，3.79(d，J＝3.6Hz，3H)，2.99-2.85(m，1H)，2.66-2.60(m，1H)，2.31(qd，J＝13.2，4.4Hz，1H)，2.09-2.01(m，1H). 1 H NMR (600MHz, DMSO-d 6 ) δ 11.02 (s, 1H), 9.68 (s, 1H), 8.70 (s, 3H), 7.71 (dd, J=10.9, 4.7Hz, 1H), 7.58- 7.40 (m, 2H), 5.15 (dd, J=13.3, 5.0Hz, 1H), 4.66-4.56 (m, 1H), 4.50-4.40 (m, 3H), 4.35 (dd, J=17.5, 4.7Hz, 1H), 3.79 (d, J=3.6Hz, 3H), 2.99-2.85 (m, 1H), 2.66-2.60 (m, 1H), 2.31 (qd, J=13.2, 4.4Hz, 1H), 2.09-2.01 (m,1H).
实施例15：化合物83的制备
Example 15: Preparation of Compound 83
采用通用合成方法2制备，得盐酸盐为白色固体，收率90.57％。Prepared by general synthesis method 2, the hydrochloride was obtained as a white solid with a yield of 90.57%.
1H NMR(600MHz，DMSO-d6)δ11.03(d，J＝4.3Hz，1H)，9.64(d，J＝3.5Hz，1H)，8.72(s，3H)，7.72(dd，J＝8.9，4.4Hz，1H)，7.52(t，J＝6.3Hz，2H)，5.27-5.06(m，2H)，4.44(dd，J＝17.5，3.6Hz，1H)，4.33(dd，J＝17.5，4.4Hz，2H)，3.77(d，J＝5.0Hz，3H)，2.99-2.87(m，1H)，2.63(d，J＝18.1Hz，1H)，2.36-2.26(m，1H)，2.11-2.02(m，1H)，1.41(d，J＝6.6Hz，3H). 1 H NMR (600MHz, DMSO-d 6 ) δ11.03 (d, J=4.3Hz, 1H), 9.64 (d, J=3.5Hz, 1H), 8.72 (s, 3H), 7.72 (dd, J= 8.9, 4.4Hz, 1H), 7.52 (t, J=6.3Hz, 2H), 5.27-5.06 (m, 2H), 4.44 (dd, J=17.5, 3.6Hz, 1H), 4.33 (dd, J=17.5 , 4.4Hz, 2H), 3.77 (d, J=5.0Hz, 3H), 2.99-2.87 (m, 1H), 2.63 (d, J=18.1Hz, 1H), 2.36-2.26 (m, 1H), 2.11 -2.02(m, 1H), 1.41(d, J=6.6Hz, 3H).
实施例16：化合物84的制备
Example 16: Preparation of Compound 84
采用通用合成方法2制备，，得盐酸盐为白色固体，收率56.93％。Prepared by general synthesis method 2, the hydrochloride was obtained as a white solid with a yield of 56.93%.
1H NMR(400MHz，DMSO-d6)δ11.02(s，1H)，11.58(s，1H)，8.62(s，3H)，7.74-7.70(m，1H)，7.58-7.52(m，2H)，5.15(dd，J＝13.3，5.1Hz，1H)，4.45-4.32(m，3H)，3.75(d，J＝1.76Hz，3H)，3.47-3.40(m，2H)，2.98-2.86(m，1H)，2.62(d，J＝16.8Hz，1H)，2.38(dd，J＝13.1，4.5Hz，1H)，2.11-2.00(m，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ11.02 (s, 1H), 11.58 (s, 1H), 8.62 (s, 3H), 7.74-7.70 (m, 1H), 7.58-7.52 (m, 2H ), 5.15 (dd, J=13.3, 5.1Hz, 1H), 4.45-4.32 (m, 3H), 3.75 (d, J=1.76Hz, 3H), 3.47-3.40 (m, 2H), 2.98-2.86 ( m, 1H), 2.62 (d, J=16.8Hz, 1H), 2.38 (dd, J=13.1, 4.5Hz, 1H), 2.11-2.00 (m, 1H).
实施例17：化合物85的制备
Example 17: Preparation of Compound 85
采用通用合成方法2制备，，得盐酸盐为白色固体，收率54.28％。Prepared by general synthesis method 2, the hydrochloride was obtained as a white solid with a yield of 54.28%.
1H NMR(600MHz，DMSO-d6)δ11.02(s，1H)，8.38(s，2H)，7.73(dd，J＝12.9，7.8Hz，1H)，7.57-7.51(m，2H)，5.15(dd，J＝13.3，3.4Hz，1H)，4.47-4.31(m，2H)，4.13(s，1H)，3.47(dd，J＝14.6，5.0Hz，1H)，3.36(dd，J＝14.8，6.3Hz，1H)，2.97-2.86(m，1H)，2.64-2.59(m，1H)，2.37-2.29(m，1H)，2.04(dd，J＝9.0，3.7Hz，1H). 1 H NMR (600MHz, DMSO-d 6 ) δ11.02 (s, 1H), 8.38 (s, 2H), 7.73 (dd, J=12.9, 7.8Hz, 1H), 7.57-7.51 (m, 2H), 5.15 (dd, J=13.3, 3.4Hz, 1H), 4.47-4.31 (m, 2H), 4.13 (s, 1H), 3.47 (dd, J=14.6, 5.0Hz, 1H), 3.36 (dd, J= 14.8, 6.3Hz, 1H), 2.97-2.86 (m, 1H), 2.64-2.59 (m, 1H), 2.37-2.29 (m, 1H), 2.04 (dd, J=9.0, 3.7Hz, 1H).
实施例18：化合物86的制备
Example 18: Preparation of Compound 86
采用通用合成方法3制备，，得盐酸盐为白色固体，收率82.87％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 82.87%.
1H NMR(600MHz，DMSO-d6)δ9.70(s，1H)，8.75(s，3H)，7.99-7.91(m，2H)，7.75(d，J＝4.8Hz，1H)，7.69(t，J＝7.4Hz，1H)，7.57-7.49(m，4H)，5.93(d，J＝9.7Hz，1H)，5.88(d，J＝9.6Hz，1H)，5.37(dd，J＝13.4，4.9Hz，1H)，4.65-4.55(m，1H)，4.55-4.30(m，4H)，3.78(d，J＝3.5Hz，3H)，3.22-3.09(m，1H)，2.89(dd，J＝13.6，2.5Hz，1H)，2.44-2.38(m，1H)，2.19-2.10(m，1H). 1 H NMR (600MHz, DMSO-d 6 ) δ9.70 (s, 1H), 8.75 (s, 3H), 7.99-7.91 (m, 2H), 7.75 (d, J=4.8Hz, 1H), 7.69 ( t, J=7.4Hz, 1H), 7.57-7.49 (m, 4H), 5.93 (d, J=9.7Hz, 1H), 5.88 (d, J=9.6Hz, 1H), 5.37 (dd, J=13.4 , 4.9Hz, 1H), 4.65-4.55 (m, 1H), 4.55-4.30 (m, 4H), 3.78 (d, J=3.5Hz, 3H), 3.22-3.09 (m, 1H), 2.89 (dd, J＝13.6, 2.5Hz, 1H), 2.44-2.38(m, 1H), 2.19-2.10(m, 1H).
实施例19：化合物87的制备
Example 19: Preparation of Compound 87
采用通用合成方法3制备，，得盐酸盐为白色固体，收率84.25％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 84.25%.
1H NMR(600MHz，DMSO-d6)δ10.65(d，J＝7.8Hz，1H)，8.75(s，3H)，8.00-7.88(m，2H)，7.76(ddd，J＝12.9，7.9，0.8Hz，1H)，7.69(t，J＝7.4Hz，1H)，7.64-7.45(m，4H)，5.93(d，J＝9.6Hz，1H)，5.88(d，J＝9.6Hz，1H)，5.38(dd，J＝13.5，5.0Hz，1H)，4.50(dd，J＝17.5，14.3Hz，1H)，4.42-4.26(m，2H)，3.74(d，J＝3.0Hz，3H)，3.51-3.40(m，2H)，3.21-3.07(m，1H)，2.91-2.84(m，1H)，2.48-2.41(m，1H)，2.17-2.08(m，1H). 1 H NMR (600MHz, DMSO-d 6 ) δ10.65 (d, J=7.8Hz, 1H), 8.75 (s, 3H), 8.00-7.88 (m, 2H), 7.76 (ddd, J=12.9, 7.9 , 0.8Hz, 1H), 7.69 (t, J=7.4Hz, 1H), 7.64-7.45 (m, 4H), 5.93 (d, J=9.6Hz, 1H), 5.88 (d, J=9.6Hz, 1H ), 5.38 (dd, J=13.5, 5.0Hz, 1H), 4.50 (dd, J=17.5, 14.3Hz, 1H), 4.42-4.26 (m, 2H), 3.74 (d, J=3.0Hz, 3H) , 3.51-3.40(m, 2H), 3.21-3.07(m, 1H), 2.91-2.84(m, 1H), 2.48-2.41(m, 1H), 2.17-2.08(m, 1H).
实施例20：化合物88的制备
Example 20: Preparation of Compound 88
采用通用合成方法3制备，得盐酸盐为白色固体，收率56.85％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 56.85%.
1H NMR(600MHz，DMSO-d6)δ9.68(s，1H)，8.78(s，3H)，7.96-7.89(m，2H)，7.80-7.74(m，1H)，7.69(td，J＝7.4，1.3Hz，1H)，7.58-7.49(m，4H)，5.94(dd，J＝9.6，4.2Hz，1H)，5.88(dd，J＝9.6，1.9Hz，1H)，5.37(ddd，J＝13.5，10.9，5.0Hz，1H)，5.23-5.16(m，1H)，4.51(dd，J＝17.4，7.4Hz，1H)，4.42-4.30(m，2H)，3.75(d，J＝10.2Hz，3H)，3.21-3.11(m，1H)，2.93-2.86(m，1H)，2.44-2.35(m，1H)，2.19-2.09(m，1H)，1.41(d，J＝6.6Hz，3H). 1 H NMR (600MHz, DMSO-d 6 ) δ9.68 (s, 1H), 8.78 (s, 3H), 7.96-7.89 (m, 2H), 7.80-7.74 (m, 1H), 7.69 (td, J =7.4, 1.3Hz, 1H), 7.58-7.49 (m, 4H), 5.94 (dd, J = 9.6, 4.2Hz, 1H), 5.88 (dd, J = 9.6, 1.9Hz, 1H), 5.37 (ddd, J＝13.5, 10.9, 5.0Hz, 1H), 5.23-5.16 (m, 1H), 4.51 (dd, J＝17.4, 7.4Hz, 1H), 4.42-4.30 (m, 2H), 3.75 (d, J＝ 10.2Hz, 3H), 3.21-3.11(m, 1H), 2.93-2.86(m, 1H), 2.44-2.35(m, 1H), 2.19-2.09(m, 1H), 1.41(d, J=6.6Hz ,3H).
实施例21：化合物89的制备
Example 21: Preparation of Compound 89
采用通用合成方法3制备，得盐酸盐为白色固体，收率71.08％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 71.08%.
1H NMR(600MHz，DMSO-d6)δ9.65(s，1H)，8.61(s，2H)，7.96-7.91(m，2H)，7.85-7.77(m，1H)，7.68(td，J＝7.5，1.3Hz，1H)，7.60-7.47(m，4H)，5.94(dd，J＝9.7，1.8Hz，1H)，5.87(d，J＝9.6Hz，1H)，5.36(dt，J＝11.4，5.6Hz，1H)，5.26-5.13(m，1H)，4.53(d，J＝17.5Hz，1H)，4.39(dd，J＝17.4，5.6Hz，1H)，4.13(d，J＝4.0Hz，1H)，3.20-3.10(m，1H)，2.90(dd，J＝13.7，2.6Hz，1H)，2.46-2.36(m，1H)，2.18-2.10(m，1H)，1.43-1.39(m，3H). 1 H NMR (600MHz, DMSO-d 6 ) δ9.65 (s, 1H), 8.61 (s, 2H), 7.96-7.91 (m, 2H), 7.85-7.77 (m, 1H), 7.68 (td, J =7.5, 1.3Hz, 1H), 7.60-7.47 (m, 4H), 5.94 (dd, J＝9.7, 1.8Hz, 1H), 5.87 (d, J＝9.6Hz, 1H), 5.36 (dt, J＝ 11.4, 5.6Hz, 1H), 5.26-5.13 (m, 1H), 4.53 (d, J=17.5Hz, 1H), 4.39 (dd, J=17.4, 5.6Hz, 1H), 4.13 (d, J=4.0 Hz, 1H), 3.20-3.10 (m, 1H), 2.90 (dd, J=13.7, 2.6Hz, 1H), 2.46-2.36 (m, 1H), 2.18-2.10 (m, 1H), 1.43-1.39 ( m, 3H).
实施例22：化合物90的制备
Example 22: Preparation of Compound 90
采用通用合成方法3制备，得盐酸盐为白色固体，收率76.65％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 76.65%.
1H NMR(600MHz，DMSO-d6)δ7.96-7.90(m，2H)，7.76(dd，J＝12.6，7.9Hz，1H)，7.69(t，J＝7.4Hz，1H)，7.61-7.50(m，4H)，5.93(d，J＝9.6Hz，1H)，5.88(d，J＝9.7Hz，1H)，5.38(ddd，J＝13.5，4.8，3.3Hz，1H)，4.49(dd，J＝17.5，12.5Hz，1H)，4.38(dd，J＝17.5，11.2Hz，1H)，4.17-4.07(m，1H)，3.50-3.43(m，1H)，3.41-3.36(m，1H)，3.20-3.12(m，1H)，2.88(d，J＝17.6Hz，1H)，2.48-2.39(m，1H)，2.16-2.06(m，1H). 1 H NMR (600MHz, DMSO-d 6 ) δ7.96-7.90 (m, 2H), 7.76 (dd, J=12.6, 7.9Hz, 1H), 7.69 (t, J=7.4Hz, 1H), 7.61- 7.50 (m, 4H), 5.93 (d, J=9.6Hz, 1H), 5.88 (d, J=9.7Hz, 1H), 5.38 (ddd, J=13.5, 4.8, 3.3Hz, 1H), 4.49 (dd , J=17.5, 12.5Hz, 1H), 4.38 (dd, J=17.5, 11.2Hz, 1H), 4.17-4.07 (m, 1H), 3.50-3.43 (m, 1H), 3.41-3.36 (m, 1H) ), 3.20-3.12(m, 1H), 2.88(d, J=17.6Hz, 1H), 2.48-2.39(m, 1H), 2.16-2.06(m, 1H).
实施例23：化合物91的制备
Example 23: Preparation of Compound 91
采用通用合成方法3制备，得盐酸盐为白色固体，收率72.36％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 72.36%.
1H NMR(400MHz，DMSO-d6)δ9.72(s，1H)，8.58(s，3H)，8.02-7.82(m，2H)，7.84-7.72(m，1H)，7.74-7.64(m，1H)，7.62-7.40(m，4H)，5.99-5.79(dd，J＝25.1，9.6Hz，2H)，5.44-5.30(m，1H)，4.67-4.57(m，1H)，4.56-4.35(m，3H)，4.28(t，J＝4.2Hz，1H)，3.22-3.07(m，1H)，2.95-2.83(m，1H)，2.43-2.35(m，1H)，2.20-2.06(m，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ9.72 (s, 1H), 8.58 (s, 3H), 8.02-7.82 (m, 2H), 7.84-7.72 (m, 1H), 7.74-7.64 (m , 1H), 7.62-7.40 (m, 4H), 5.99-5.79 (dd, J=25.1, 9.6Hz, 2H), 5.44-5.30 (m, 1H), 4.67-4.57 (m, 1H), 4.56-4.35 (m, 3H), 4.28 (t, J=4.2Hz, 1H), 3.22-3.07 (m, 1H), 2.95-2.83 (m, 1H), 2.43-2.35 (m, 1H), 2.20-2.06 (m ,1H).
实施例24：化合物93的制备

Example 24: Preparation of Compound 93

采用通用合成方法3制备，得盐酸盐为白色固体，收率90.57％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 90.57%.
1H NMR(600MHz，DMSO-d6)δ10.16(s，1H)，8.55(s，3H)，7.83-7.78(m，1H)，7.58-7.52(m，2H)，7.29(d，J＝8.5Hz，2H)，7.22(d，J＝8.5Hz，2H)，5.69(d，J＝9.4Hz，1H)，5.61(d，J＝9.4Hz，1H)，5.33(dd，J＝13.5，5.0Hz，1H)，4.77(m，J＝6.3Hz，1H)，4.48(dd，J＝67.0，17.6Hz，2H)，4.32(t，J＝6.6Hz，1H)，3.71(s，3H)，3.19-3.07(m，3H)，2.86(dd，J＝17.1，14.3Hz，1H)，2.41(dd，J＝13.2，4.4Hz，1H)，2.15-2.04(m，1H)，1.22(d，J＝6.2Hz，6H). 1 H NMR (600MHz, DMSO-d 6 ) δ10.16 (s, 1H), 8.55 (s, 3H), 7.83-7.78 (m, 1H), 7.58-7.52 (m, 2H), 7.29 (d, J =8.5Hz, 2H), 7.22 (d, J = 8.5Hz, 2H), 5.69 (d, J = 9.4Hz, 1H), 5.61 (d, J = 9.4Hz, 1H), 5.33 (dd, J = 13.5 , 5.0Hz, 1H), 4.77 (m, J=6.3Hz, 1H), 4.48 (dd, J=67.0, 17.6Hz, 2H), 4.32 (t, J=6.6Hz, 1H), 3.71 (s, 3H ), 3.19-3.07(m, 3H), 2.86(dd, J＝17.1, 14.3Hz, 1H), 2.41(dd, J＝13.2, 4.4Hz, 1H), 2.15-2.04(m, 1H), 1.22( d, J=6.2Hz, 6H).
实施例25：化合物94的制备
Example 25: Preparation of Compound 94
采用通用合成方法3制备，得盐酸盐为白色固体，收率90.57％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 90.57%.
1H NMR(600MHz，DMSO-d6)δ10.57(s，1H)，8.59(s，3H)，7.75(dd，J＝15.8，8.0Hz，1H)，7.56(m，J＝15.4，7.7Hz，2H)，5.65(dd，J＝54.0，9.4Hz，2H)，5.34(dd，J＝13.5，5.0Hz，1H)，4.77(m，J＝12.5，6.2Hz，1H)，4.38(m，J＝26.0，22.9，13.9Hz，3H)，3.75(d，J＝2.5Hz，3H)，3.50-3.38(m，2H)，3.16-3.06(m，1H)，2.85(d，J＝16.1Hz，1H)，2.44-2.39(m，1H)，2.13-2.07(m，1H)，1.22(d，J＝6.2，1.8Hz，6H). 1 H NMR (600MHz, DMSO-d 6 ) δ 10.57 (s, 1H), 8.59 (s, 3H), 7.75 (dd, J=15.8, 8.0Hz, 1H), 7.56 (m, J=15.4, 7.7 Hz, 2H), 5.65 (dd, J=54.0, 9.4Hz, 2H), 5.34 (dd, J=13.5, 5.0Hz, 1H), 4.77 (m, J=12.5, 6.2Hz, 1H), 4.38 (m , J=26.0, 22.9, 13.9Hz, 3H), 3.75 (d, J=2.5Hz, 3H), 3.50-3.38 (m, 2H), 3.16-3.06 (m, 1H), 2.85 (d, J=16.1 Hz, 1H), 2.44-2.39 (m, 1H), 2.13-2.07 (m, 1H), 1.22 (d, J=6.2, 1.8Hz, 6H).
实施例26：化合物95的制备
Example 26: Preparation of Compound 95
采用通用合成方法3制备，得盐酸盐为白色固体，收率59.68％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 59.68%.
1H NMR(600MHz，DMSO-d6)δ10.57(s，1H)，8.45(s，3H)，7.80-7.72(m，1H)，7.56(m，J＝15.4，7.6Hz，2H)，5.70(d，J＝9.4Hz，1H)，5.61(d，J＝9.4Hz，1H)，5.33(m，J＝13.5，5.0，2.9Hz，1H)，4.77(m，J＝6.2Hz，1H)，4.46(dd，J＝17.5，13.1Hz， 1H)，4.35(dd，J＝17.5，11.1Hz，1H)，4.18(d，J＝4.9Hz，1H)，3.50-3.40(m，2H)，3.16-3.07(m，1H)，2.85(d，J＝17.4Hz，1H)，2.42(d，J＝4.4Hz，1H)，2.13-2.06(m，1H)，1.22(d，J＝6.2，1.8Hz，6H). 1 H NMR (600MHz, DMSO-d 6 ) δ10.57 (s, 1H), 8.45 (s, 3H), 7.80-7.72 (m, 1H), 7.56 (m, J=15.4, 7.6Hz, 2H), 5.70 (d, J=9.4Hz, 1H), 5.61 (d, J=9.4Hz, 1H), 5.33 (m, J=13.5, 5.0, 2.9Hz, 1H), 4.77 (m, J=6.2Hz, 1H ), 4.46 (dd, J=17.5, 13.1Hz, 1H), 4.35 (dd, J=17.5, 11.1Hz, 1H), 4.18 (d, J=4.9Hz, 1H), 3.50-3.40 (m, 2H), 3.16-3.07 (m, 1H), 2.85 (d , J=17.4Hz, 1H), 2.42 (d, J=4.4Hz, 1H), 2.13-2.06 (m, 1H), 1.22 (d, J=6.2, 1.8Hz, 6H).
实施例27：化合物96的制备
Example 27: Preparation of Compound 96
采用通用合成方法3制备，得盐酸盐为白色固体，收率65.42％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 65.42%.
1H NMR(600MHz，DMSO-d6)δ13.85(s，1H)，10.16(s，1H)，8.37(s，3H)，7.80(dd，J＝6.3，2.4Hz，1H)，7.58-7.52(m，2H)，7.33(d，J＝8.5Hz，2H)，7.22(d，J＝8.5Hz，2H)，5.65(dd，J＝47.4，9.4Hz，2H)，5.33(dd，J＝13.4，5.0Hz，1H)，4.77(dt，J＝12.5，6.2Hz，1H)，4.48(dd，J＝66.4，17.5Hz，2H)，4.20(s，1H)，3.18-3.06(m，3H)，2.91-2.80(m，2H)，2.14-2.06(m，1H)，1.22(d，J＝6.2Hz，6H). 1 H NMR (600MHz, DMSO-d 6 ) δ 13.85 (s, 1H), 10.16 (s, 1H), 8.37 (s, 3H), 7.80 (dd, J=6.3, 2.4Hz, 1H), 7.58- 7.52 (m, 2H), 7.33 (d, J=8.5Hz, 2H), 7.22 (d, J=8.5Hz, 2H), 5.65 (dd, J=47.4, 9.4Hz, 2H), 5.33 (dd, J =13.4, 5.0Hz, 1H), 4.77 (dt, J = 12.5, 6.2Hz, 1H), 4.48 (dd, J = 66.4, 17.5Hz, 2H), 4.20 (s, 1H), 3.18-3.06 (m, 3H), 2.91-2.80 (m, 2H), 2.14-2.06 (m, 1H), 1.22 (d, J=6.2Hz, 6H).
实施例28：化合物97的制备
Example 28: Preparation of Compound 97
采用通用合成方法3制备，得盐酸盐为白色固体，收率67.24％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 67.24%.
1H NMR(400MHz，DMSO-d6)δ9.72(d，J＝5.3Hz，1H)，8.77(s，3H)，7.79-7.70(m，1H)，7.56-7.49(m，2H)，5.65(dd，J＝36.3，9.4Hz，2H)，5.33(dd，J＝13.5，5.0Hz，1H)，4.84-4.71(m，1H)，4.62(td，J＝11.7，3.3Hz，1H)，4.45(dt，J＝15.3，6.1Hz，3H)，4.35(dd，J＝17.5，4.1Hz，1H)，3.79(d，J＝2.6Hz，3H)，3.18-3.04(m，1H)，2.89-2.81(m，1H)，2.43-2.34(m，1H)，2.15-2.06(m，1H)，1.22(d，J＝6.2Hz，6H). 1 H NMR (400MHz, DMSO-d 6 ) δ9.72 (d, J=5.3Hz, 1H), 8.77 (s, 3H), 7.79-7.70 (m, 1H), 7.56-7.49 (m, 2H), 5.65 (dd, J=36.3, 9.4Hz, 2H), 5.33 (dd, J=13.5, 5.0Hz, 1H), 4.84-4.71 (m, 1H), 4.62 (td, J=11.7, 3.3Hz, 1H) , 4.45 (dt, J=15.3, 6.1Hz, 3H), 4.35 (dd, J=17.5, 4.1Hz, 1H), 3.79 (d, J=2.6Hz, 3H), 3.18-3.04 (m, 1H), 2.89-2.81(m, 1H), 2.43-2.34(m, 1H), 2.15-2.06(m, 1H), 1.22(d, J=6.2Hz, 6H).
实施例29：化合物98的制备
Example 29: Preparation of Compound 98
采用通用合成方法3制备，得盐酸盐为白色固体，收率37.95％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 37.95%.
1H NMR(400MHz，DMSO-d6)δ10.59(s，1H)，8.62(s，3H)，7.75(t，J＝8.1Hz，1H)，7.63-7.51(m，2H)，5.63(dd，J＝27.7，9.4Hz，2H)，5.32(dd，J＝13.4，4.9Hz，1H)，4.51-4.30(m，3H)，3.75(s，3H)，3.54(s，4H)，3.44(d，J＝5.0Hz，2H)，3.32(d，J＝4.6Hz，4H)，3.16-3.06(m，1H)，2.84(d，J＝17.1Hz，1H)，2.42-2.32(m，1H)，2.10(d，J＝5.5Hz，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.59 (s, 1H), 8.62 (s, 3H), 7.75 (t, J = 8.1Hz, 1H), 7.63-7.51 (m, 2H), 5.63 ( dd, J=27.7, 9.4Hz, 2H), 5.32 (dd, J=13.4, 4.9Hz, 1H), 4.51-4.30 (m, 3H), 3.75 (s, 3H), 3.54 (s, 4H), 3.44 (d, J=5.0Hz, 2H), 3.32 (d, J=4.6Hz, 4H), 3.16-3.06 (m, 1H), 2.84 (d, J=17.1Hz, 1H), 2.42-2.32 (m, 1H), 2.10 (d, J=5.5Hz, 1H).
实施例30：化合物99的制备
Example 30: Preparation of Compound 99
采用通用合成方法3制备，得盐酸盐为白色固体，收率26.70％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 26.70%.
1H NMR(400MHz，DMSO-d6)δ10.18(s，1H)，8.54(s，3H)，7.80(dd，J＝5.9，3.1Hz，1H)，7.59-7.53(m，2H)，7.26(m，J＝30.4，8.6Hz，4H)，5.63(dd，J＝34.2，9.3Hz，2H)，5.31(dd，J＝13.4，5.0Hz，1H)，4.47(dd，J＝52.7，17.5Hz，2H)，4.33(s，1H)，3.71(s，3H)，3.52(s，4H)，3.32-3.26(m，4H)，3.11(m，J＝13.3，6.6Hz，3H)，2.84(d，J＝16.6Hz，1H)，2.40(dd，J＝13.0，4.4Hz，1H)，2.15-2.06(m，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.18 (s, 1H), 8.54 (s, 3H), 7.80 (dd, J=5.9, 3.1Hz, 1H), 7.59-7.53 (m, 2H), 7.26 (m, J=30.4, 8.6Hz, 4H), 5.63 (dd, J=34.2, 9.3Hz, 2H), 5.31 (dd, J=13.4, 5.0Hz, 1H), 4.47 (dd, J=52.7, 17.5Hz, 2H), 4.33 (s, 1H), 3.71 (s, 3H), 3.52 (s, 4H), 3.32-3.26 (m, 4H), 3.11 (m, J=13.3, 6.6Hz, 3H), 2.84 (d, J=16.6Hz, 1H), 2.40 (dd, J=13.0, 4.4Hz, 1H), 2.15-2.06 (m, 1H).
实施例31：化合物100的制备
Example 31: Preparation of Compound 100
采用通用合成方法3制备，得盐酸盐为白色固体，收率61.23％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 61.23%.
1H NMR(400MHz，DMSO-d6)δ9.70(s，1H)，8.67(s，3H)，7.74(d，J＝4.3Hz，1H)，7.56-7.51(m，2H)，5.62(dd，J＝29.7，9.3Hz，2H)，5.31(dd，J＝13.4，5.0Hz，1H)，4.66-4.58(m，1H)，4.53-4.30(m，4H)，3.79(s，3H)，3.54(s，4H)，3.31(m，J＝4.7Hz，4H)，3.14-3.04(m，1H)，2.84(d，J＝16.0Hz，1H)，2.39-2.31(m，1H)，2.11(d，J＝5.4Hz，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ9.70 (s, 1H), 8.67 (s, 3H), 7.74 (d, J=4.3Hz, 1H), 7.56-7.51 (m, 2H), 5.62 ( dd, J=29.7, 9.3Hz, 2H), 5.31 (dd, J=13.4, 5.0Hz, 1H), 4.66-4.58 (m, 1H), 4.53-4.30 (m, 4H), 3.79 (s, 3H) , 3.54 (s, 4H), 3.31 (m, J=4.7Hz, 4H), 3.14-3.04 (m, 1H), 2.84 (d, J=16.0Hz, 1H), 2.39-2.31 (m, 1H), 2.11 (d, J=5.4Hz, 1H).
实施例32：化合物101的制备
Example 32: Preparation of Compound 101
采用通用合成方法3制备，氯甲基试剂是购买所得，得盐酸盐为白色固体，收率69.55％。It was prepared by general synthesis method 3. The chloromethyl reagent was purchased. The hydrochloride was obtained as a white solid with a yield of 69.55%.
1H NMR(400MHz，DMSO-d6)δ9.72(s，1H)，8.43(s，3H)，7.84-7.72(m，1H)，7.50(m，J＝6.3Hz，2H)，5.69(dd，J＝9.4，1.7Hz，1H)，5.61(d，J＝9.4Hz，1H)，5.39-5.25(m，1H)，4.83-4.71(m，1H)，4.65-4.55(m，1H)，4.53-4.32(m，3H)，4.13(s，1H)，3.18-3.04(m，2H)，2.85(d，J＝16.9Hz，1H)，2.41-2.30(m，1H)，2.14-2.05(m，1H)，1.22(d，J＝6.2Hz，6H). 1 H NMR (400MHz, DMSO-d 6 ) δ9.72 (s, 1H), 8.43 (s, 3H), 7.84-7.72 (m, 1H), 7.50 (m, J=6.3Hz, 2H), 5.69 ( dd, J=9.4, 1.7Hz, 1H), 5.61 (d, J=9.4Hz, 1H), 5.39-5.25 (m, 1H), 4.83-4.71 (m, 1H), 4.65-4.55 (m, 1H) , 4.53-4.32 (m, 3H), 4.13 (s, 1H), 3.18-3.04 (m, 2H), 2.85 (d, J=16.9Hz, 1H), 2.41-2.30 (m, 1H), 2.14-2.05 (m, 1H), 1.22 (d, J=6.2Hz, 6H).
实施例33：化合物102的制备

Example 33: Preparation of Compound 102

采用通用合成方法3制备，得盐酸盐为白色固体，收率52.86％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 52.86%.
1H NMR(400MHz，DMSO-d6)δ10.18(s，1H)，7.84-7.77(m，1H)，7.57-7.51(m，2H)，7.33(d，J＝8.2Hz，2H)，7.19(d，J＝8.3Hz，2H)，5.63(dd，J＝34.7，9.3Hz，2H)，5.31(dd，J＝13.5，5.0Hz，1H)，4.48(dd，J＝53.3，17.6Hz，2H)，3.90(s，1H)，3.81-3.75(m，1H)，3.50(s，4H)，3.31-3.29(m，4H)，3.09(dd，J＝19.3，14.5Hz，3H)，2.84(d，J＝16.6Hz，1H)，2.40(d，J＝9.1Hz，1H)，2.11(d，J＝5.9Hz，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.18 (s, 1H), 7.84-7.77 (m, 1H), 7.57-7.51 (m, 2H), 7.33 (d, J=8.2Hz, 2H), 7.19 (d, J=8.3Hz, 2H), 5.63 (dd, J=34.7, 9.3Hz, 2H), 5.31 (dd, J=13.5, 5.0Hz, 1H), 4.48 (dd, J=53.3, 17.6Hz , 2H), 3.90 (s, 1H), 3.81-3.75 (m, 1H), 3.50 (s, 4H), 3.31-3.29 (m, 4H), 3.09 (dd, J=19.3, 14.5Hz, 3H), 2.84 (d, J=16.6Hz, 1H), 2.40 (d, J=9.1Hz, 1H), 2.11 (d, J=5.9Hz, 1H).
实施例34：化合物103制备
Example 34: Preparation of Compound 103
采用通用合成方法3制备，得盐酸盐为白色固体，收率37.44％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 37.44%.
1H NMR(400MHz，DMSO-d6)δ10.56(d，J＝4.3Hz，1H)，8.43(s，3H)，7.75(t，J＝7.9Hz，1H)，7.56(dt，J＝15.1，7.5Hz，2H)，5.63(dd，J＝28.7，9.4Hz，2H)，5.31(dd，J＝13.4，3.1Hz，1H)，4.46(dd，J＝17.6，8.4Hz，1H)，4.34(dd，J＝17.5，6.9Hz，1H)，4.23(s，1H)，3.54(s，4H)，3.47(d，J＝9.5Hz，2H)，3.34-3.29(m，4H)，3.12-3.04(m，1H)，2.84(d，J＝16.8Hz，1H)，2.39(dd，J＝13.2，4.4Hz，1H)，2.10(d，J＝5.3Hz，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.56 (d, J=4.3Hz, 1H), 8.43 (s, 3H), 7.75 (t, J=7.9Hz, 1H), 7.56 (dt, J= 15.1, 7.5Hz, 2H), 5.63 (dd, J=28.7, 9.4Hz, 2H), 5.31 (dd, J=13.4, 3.1Hz, 1H), 4.46 (dd, J=17.6, 8.4Hz, 1H), 4.34 (dd, J=17.5, 6.9Hz, 1H), 4.23 (s, 1H), 3.54 (s, 4H), 3.47 (d, J=9.5Hz, 2H), 3.34-3.29 (m, 4H), 3.12 -3.04 (m, 1H), 2.84 (d, J=16.8Hz, 1H), 2.39 (dd, J=13.2, 4.4Hz, 1H), 2.10 (d, J=5.3Hz, 1H).
实施例35：化合物104的制备
Example 35: Preparation of Compound 104
采用通用合成方法3制备，得盐酸盐为白色固体，收率42.45％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 42.45%.
1H NMR(400MHz，DMSO-d6)δ10.19(s，1H)，8.62(s，3H)，7.80(dd，J＝5.9，2.9Hz，1H)，7.57-7.50(m，2H)，7.30(d，J＝8.6Hz，2H)，7.21(d，J＝8.6Hz，2H)， 5.63(dd，J＝20.3，9.6Hz，2H)，5.34(dd，J＝13.4，5.0Hz，1H)，4.47(dd，J＝59.4，17.6Hz，2H)，4.31(t，1H)，3.70(s，3H)，3.23-3.08(m，3H)，2.90-2.81(m，1H)，2.42-2.31(m，1H)，2.19-2.05(m，1H)，1.11(s，9H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.19 (s, 1H), 8.62 (s, 3H), 7.80 (dd, J=5.9, 2.9Hz, 1H), 7.57-7.50 (m, 2H), 7.30(d, J＝8.6Hz, 2H), 7.21(d, J＝8.6Hz, 2H), 5.63 (dd, J=20.3, 9.6Hz, 2H), 5.34 (dd, J=13.4, 5.0Hz, 1H), 4.47 (dd, J=59.4, 17.6Hz, 2H), 4.31 (t, 1H), 3.70 (s, 3H), 3.23-3.08 (m, 3H), 2.90-2.81 (m, 1H), 2.42-2.31 (m, 1H), 2.19-2.05 (m, 1H), 1.11 (s, 9H).
实施例36：化合物105的制备
Example 36: Preparation of Compound 105
采用通用合成方法3制备，得盐酸盐为白色固体，收率48.97％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 48.97%.
1H NMR(400MHz，DMSO-d6)δ9.70(s，1H)，8.52(s，3H)，7.82-7.73(m，1H)，7.52(d，J＝4.3Hz，2H)，5.62(dd，J＝31.8，9.3Hz，2H)，5.30(d，J＝8.4Hz，1H)，4.63(d，J＝8.5Hz，1H)，4.54-4.24(m，4H)，3.54(s，4H)，3.31-3.28(m，4H)，3.09(d，J＝12.3Hz，1H)，2.84(d，J＝17.1Hz，1H)，2.39(s，1H)，2.10(dd，J＝9.8，4.3Hz，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ9.70 (s, 1H), 8.52 (s, 3H), 7.82-7.73 (m, 1H), 7.52 (d, J=4.3Hz, 2H), 5.62 ( dd, J=31.8, 9.3Hz, 2H), 5.30 (d, J=8.4Hz, 1H), 4.63 (d, J=8.5Hz, 1H), 4.54-4.24 (m, 4H), 3.54 (s, 4H ), 3.31-3.28 (m, 4H), 3.09 (d, J = 12.3Hz, 1H), 2.84 (d, J = 17.1Hz, 1H), 2.39 (s, 1H), 2.10 (dd, J = 9.8, 4.3Hz, 1H).
实施例37：化合物106的制备
Example 37: Preparation of Compound 106
采用通用合成方法3制备，得盐酸盐为白色固体，收率68.45％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 68.45%.
1H NMR(400MHz，DMSO-d6)δ10.63(s，1H)，8.70(s，3H)，7.78-7.71(m，1H)，7.56(m，J＝15.2，7.5Hz，2H)，5.63(dd，J＝21.5，9.6Hz，2H)，5.34(dd，J＝13.4，5.0Hz，1H)，4.47(dd，J＝17.6，9.2Hz，1H)，4.37-4.29(m，2H)，3.74(s，3H)，3.44(t，J＝5.4Hz，2H)，3.13(m，J＝18.1，13.5，4.8Hz，1H)，2.90-2.80(m，1H)，2.38(dd，J＝13.2，4.4Hz，1H)，2.15-2.06(m，1H)，1.11(s，9H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.63 (s, 1H), 8.70 (s, 3H), 7.78-7.71 (m, 1H), 7.56 (m, J=15.2, 7.5Hz, 2H), 5.63 (dd, J=21.5, 9.6Hz, 2H), 5.34 (dd, J=13.4, 5.0Hz, 1H), 4.47 (dd, J=17.6, 9.2Hz, 1H), 4.37-4.29 (m, 2H) , 3.74 (s, 3H), 3.44 (t, J=5.4Hz, 2H), 3.13 (m, J=18.1, 13.5, 4.8Hz, 1H), 2.90-2.80 (m, 1H), 2.38 (dd, J =13.2, 4.4Hz, 1H), 2.15-2.06 (m, 1H), 1.11 (s, 9H).
实施例38：化合物107的制备
Example 38: Preparation of Compound 107
采用通用合成方法3制备，得盐酸盐为白色固体，收率57.36％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 57.36%.
1H NMR(400MHz，DMSO-d6)δ10.19(s，1H)，8.59(s，3H)，7.80(dd，J＝5.8，2.9Hz，1H)，7.54(dd，J＝8.2，5.3Hz，2H)，7.30(d，J＝8.5Hz，2H)，7.21(d，J＝8.5Hz，2H)，5.59(dd，J＝25.2，9.3Hz，2H)，5.32(dd，J＝13.3，5.0Hz，1H)，4.47(dd，J＝59.1，17.6Hz，2H)，4.32(s，1H)，3.70(s，3H)，3.24-3.07(m，6H)，2.84(d，J＝16.5Hz，1H)，2.38(dd，J＝13.2，4.1Hz，1H)，2.15-2.06(m，1H)，1.01(s，6H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.19 (s, 1H), 8.59 (s, 3H), 7.80 (dd, J=5.8, 2.9Hz, 1H), 7.54 (dd, J=8.2, 5.3 Hz, 2H), 7.30 (d, J=8.5Hz, 2H), 7.21 (d, J=8.5Hz, 2H), 5.59 (dd, J=25.2, 9.3Hz, 2H), 5.32 (dd, J=13.3 , 5.0Hz, 1H), 4.47 (dd, J=59.1, 17.6Hz, 2H), 4.32 (s, 1H), 3.70 (s, 3H), 3.24-3.07 (m, 6H), 2.84 (d, J= 16.5Hz, 1H), 2.38 (dd, J=13.2, 4.1Hz, 1H), 2.15-2.06 (m, 1H), 1.01 (s, 6H).
实施例39：化合物108的制备
Example 39: Preparation of Compound 108
采用通用合成方法3制备，得盐酸盐为白色固体，收率58.41％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 58.41%.
1H NMR(400MHz，DMSO-d6)δ9.71(s，1H)，8.70(s，3H)，7.74(s，1H)，7.53(s，2H)，5.63(dd，J＝20.0，9.3Hz，2H)，5.33(d，J＝9.4Hz，1H)，4.68-4.27(m，5H)，3.79(s，3H)，3.11(d，J＝12.1Hz，1H)，2.86(d，J＝23.9Hz，1H)，2.36(d，J＝12.8Hz，1H)，2.12(s，1H)，1.11(s，9H). 1 H NMR (400MHz, DMSO-d 6 ) δ9.71 (s, 1H), 8.70 (s, 3H), 7.74 (s, 1H), 7.53 (s, 2H), 5.63 (dd, J=20.0, 9.3 Hz, 2H), 5.33 (d, J=9.4Hz, 1H), 4.68-4.27 (m, 5H), 3.79 (s, 3H), 3.11 (d, J=12.1Hz, 1H), 2.86 (d, J =23.9Hz, 1H), 2.36 (d, J = 12.8Hz, 1H), 2.12 (s, 1H), 1.11 (s, 9H).
实施例40：109的制备
Example 40: Preparation of 109
采用通用合成方法3制备，得盐酸盐为白色固体，收率51.78％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 51.78%.
1H NMR(400MHz，DMSO-d6)δ10.18(s，1H)，8.17(s，2H)，7.80(dd，J＝5.9，3.0Hz，1H)，7.54(dd，J＝8.3，5.2Hz，2H)，7.31(d，J＝8.5Hz，2H)，7.21(d，J＝8.5Hz，2H)，5.63(dd，J＝20.5，9.6Hz，2H)，5.34(dd，J＝13.3，5.0Hz，1H)，4.46(dd，J＝58.1，17.6Hz，2H)，4.07(s，1H)，3.12(ddd，J＝18.1，13.4，7.0Hz，3H)，2.85(d，J＝16.4Hz，1H)，2.45-2.31(m，2H)，2.15-2.05(m，1H)，1.11(s，9H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.18 (s, 1H), 8.17 (s, 2H), 7.80 (dd, J=5.9, 3.0Hz, 1H), 7.54 (dd, J=8.3, 5.2 Hz, 2H), 7.31 (d, J=8.5Hz, 2H), 7.21 (d, J=8.5Hz, 2H), 5.63 (dd, J=20.5, 9.6Hz, 2H), 5.34 (dd, J=13.3 , 5.0Hz, 1H), 4.46 (dd, J=58.1, 17.6Hz, 2H), 4.07 (s, 1H), 3.12 (ddd, J=18.1, 13.4, 7.0Hz, 3H), 2.85 (d, J= 16.4Hz, 1H), 2.45-2.31(m, 2H), 2.15-2.05(m, 1H), 1.11(s, 9H).
实施例41：化合物110的制备
Example 41: Preparation of Compound 110
采用通用合成方法3制备，得盐酸盐为白色固体，收率28.51％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 28.51%.
1H NMR(400MHz，DMSO-d6)δ10.58(s，1H)，8.45(s，2H)，7.75(m，1H)，7.56(m，2H)，5.63(dd，J＝21.1，9.6Hz，2H)，5.34(dd，J＝12.6，4.1Hz，1H)，4.40(m，2H)，4.20(d，J＝2.8Hz，1H)，3.48(dd，J＝14.7，5.1Hz，2H)，3.40(d，J＝6.1Hz，2H)，3.13(m，2H)，2.84(d，J＝17.4Hz，1H)，2.39(dd，J＝13.1，4.3Hz，1H)，1.11(s，9H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.58 (s, 1H), 8.45 (s, 2H), 7.75 (m, 1H), 7.56 (m, 2H), 5.63 (dd, J=21.1, 9.6 Hz, 2H), 5.34 (dd, J=12.6, 4.1Hz, 1H), 4.40 (m, 2H), 4.20 (d, J=2.8Hz, 1H), 3.48 (dd, J=14.7, 5.1Hz, 2H ), 3.40 (d, J=6.1Hz, 2H), 3.13 (m, 2H), 2.84 (d, J=17.4Hz, 1H), 2.39 (dd, J=13.1, 4.3Hz, 1H), 1.11 (s , 9H).
实施例42：化合物111的制备
Example 42: Preparation of Compound 111
采用通用合成方法3制备，得盐酸盐为白色固体，收率23.09％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 23.09%.
1H NMR(400MHz，DMSO-d6)δ9.69(s，1H)，8.32(s，3H)，7.81-7.71(m，1H)，7.55-7.48(m，2H)，5.63(dd，J＝19.7，9.6Hz，2H)，5.38-5.28(m，1H)，4.60(d，J＝12.0Hz，1H)，4.48(dd，J＝17.5，6.0Hz，1H)，4.34(dd，J＝17.4，4.1Hz，2H)，4.13(s，1H)，3.12(dd，J＝23.4，10.2Hz，2H)，2.85(d，J＝16.8Hz，1H)，2.37(s，1H)，2.14-2.06(m，1H)，1.12(d，J＝9.2Hz，9H). 1 H NMR (400MHz, DMSO-d 6 ) δ9.69 (s, 1H), 8.32 (s, 3H), 7.81-7.71 (m, 1H), 7.55-7.48 (m, 2H), 5.63 (dd, J =19.7, 9.6Hz, 2H), 5.38-5.28 (m, 1H), 4.60 (d, J＝12.0Hz, 1H), 4.48 (dd, J＝17.5, 6.0Hz, 1H), 4.34 (dd, J＝ 17.4, 4.1Hz, 2H), 4.13 (s, 1H), 3.12 (dd, J=23.4, 10.2Hz, 2H), 2.85 (d, J=16.8Hz, 1H), 2.37 (s, 1H), 2.14- 2.06 (m, 1H), 1.12 (d, J=9.2Hz, 9H).
实施例43：化合物112的制备
Example 43: Preparation of Compound 112
采用通用合成方法3制备，得盐酸盐为白色固体，收率61.94％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 61.94%.
1H NMR(400MHz，DMSO-d6)δ10.19(s，1H)，8.33(s，2H)，7.90(dd，J＝7.8，1.5Hz，1H)，7.80(dd，J＝6.3，2.6Hz，1H)，7.73-7.66(m，1H)，7.60-7.52(m，2H)，7.41(t，J＝7.7Hz，1H)，7.33(d，J＝8.5Hz，2H)，7.23(dd，J＝16.2，8.0Hz，3H)，5.84(dd，J＝24.0，9.7Hz，2H)，5.76(s，1H)，5.36(dd，J＝13.3，5.0Hz，1H)，4.50(dd，J＝51.1，17.6Hz，2H)，4.13(s，1H)，3.21-3.04(m，4H)，2.89(d，J＝17.0Hz，1H)，2.44(dd，J＝13.2，4.4Hz，1H)，2.25(s，3H)，2.18-2.08(m，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.19 (s, 1H), 8.33 (s, 2H), 7.90 (dd, J=7.8, 1.5Hz, 1H), 7.80 (dd, J=6.3, 2.6 Hz, 1H), 7.73-7.66 (m, 1H), 7.60-7.52 (m, 2H), 7.41 (t, J=7.7Hz, 1H), 7.33 (d, J=8.5Hz, 2H), 7.23 (dd , J=16.2, 8.0Hz, 3H), 5.84 (dd, J=24.0, 9.7Hz, 2H), 5.76 (s, 1H), 5.36 (dd, J=13.3, 5.0Hz, 1H), 4.50 (dd, J=51.1, 17.6Hz, 2H), 4.13 (s, 1H), 3.21-3.04 (m, 4H), 2.89 (d, J=17.0Hz, 1H), 2.44 (dd, J=13.2, 4.4Hz, 1H ), 2.25(s, 3H), 2.18-2.08(m, 1H).
实施例44：化合物113的制备
Example 44: Preparation of Compound 113
采用通用合成方法3制备，得盐酸盐为白色固体，收率49.26％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 49.26%.
1H NMR(400MHz，DMSO-d6)δ10.53(s，1H)，8.34(s，2H)，7.76(t，J＝6.7Hz，1H)，7.56(dt，J＝15.1，7.4Hz，2H)，5.63(dd，J＝30.2，9.6Hz，2H)，5.32(d，J＝8.2Hz，1H)，4.40(m，2H)，4.21(s，1H)，3.47(dd，J＝14.7，4.8Hz，2H)，3.17-3.04(m，1H)，2.84(d，J＝17.1Hz，1H)，2.40(d，J＝13.0Hz，1H)，2.28(t，J＝7.3Hz，2H)，2.10(s，1H)，1.49(s，2H)，1.23(s，10H)，0.84(t，J＝6.7Hz，3H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.53 (s, 1H), 8.34 (s, 2H), 7.76 (t, J = 6.7Hz, 1H), 7.56 (dt, J = 15.1, 7.4Hz, 2H), 5.63 (dd, J=30.2, 9.6Hz, 2H), 5.32 (d, J=8.2Hz, 1H), 4.40 (m, 2H), 4.21 (s, 1H), 3.47 (dd, J=14.7 , 4.8Hz, 2H), 3.17-3.04 (m, 1H), 2.84 (d, J=17.1Hz, 1H), 2.40 (d, J=13.0Hz, 1H), 2.28 (t, J=7.3Hz, 2H ), 2.10(s, 1H), 1.49(s, 2H), 1.23(s, 10H), 0.84(t, J=6.7Hz, 3H).
实施例45：化合物114的制备
Example 45: Preparation of Compound 114
采用通用合成方法3制备，得盐酸盐为白色固体，收率65.29％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 65.29%.
1H NMR(400MHz，DMSO-d6)δ10.53(s，1H)，8.32(s，3H)，7.90(dd，J＝7.8，1.6Hz，1H)，7.79-7.68(m，2H)，7.56(dt，J＝15.2，7.5Hz，2H)，7.42(td，J＝7.6，1.1Hz，1H)，7.25(dd，J＝8.1，1.0Hz，1H)，5.84(dd，J＝22.4，10.0Hz，2H)，5.37(d，J＝13.5Hz，1H)，4.42(m，3H)，4.20(s，1H)，3.47(m，2H)，3.21-3.11(m，2H)，2.89(d，J＝17.3Hz，1H)，2.42(s，1H)，2.26(s，3H)，2.16-2.09(m，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.53 (s, 1H), 8.32 (s, 3H), 7.90 (dd, J=7.8, 1.6Hz, 1H), 7.79-7.68 (m, 2H), 7.56 (dt, J=15.2, 7.5Hz, 2H), 7.42 (td, J=7.6, 1.1Hz, 1H), 7.25 (dd, J=8.1, 1.0Hz, 1H), 5.84 (dd, J=22.4, 10.0Hz, 2H), 5.37 (d, J=13.5Hz, 1H), 4.42 (m, 3H), 4.20 (s, 1H), 3.47 (m, 2H), 3.21-3.11 (m, 2H), 2.89 ( d, J=17.3Hz, 1H), 2.42 (s, 1H), 2.26 (s, 3H), 2.16-2.09 (m, 1H).
实施例46：化合物115的制备
Example 46: Preparation of Compound 115
采用通用合成方法3制备，得盐酸盐为白色固体，收率56.50％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 56.50%.
1H NMR(400MHz，DMSO-d6)δ9.67(s，1H)，8.47(s，3H)，7.90(dd，J＝7.8，1.6Hz，1H)，7.73(m，2H)，7.52(dd，J＝8.2，5.3Hz，2H)，7.42(t，J＝7.6Hz，1H)，7.25(d，J＝8.1Hz，1H)，5.84(dd，J＝20.3，9.7Hz，2H)，5.41-5.31(m，1H)，4.64(m，1H)，4.50(dd，J＝17.5，6.6Hz，1H)，4.43-4.33(m，2H)，4.29(s，1H)，3.22-3.09(m，2H)，2.89(d，J＝16.8Hz，1H)，2.44-2.37(m，1H)，2.26(s，3H)，2.18-2.09(m，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ9.67 (s, 1H), 8.47 (s, 3H), 7.90 (dd, J=7.8, 1.6Hz, 1H), 7.73 (m, 2H), 7.52 ( dd, J=8.2, 5.3Hz, 2H), 7.42 (t, J=7.6Hz, 1H), 7.25 (d, J=8.1Hz, 1H), 5.84 (dd, J=20.3, 9.7Hz, 2H), 5.41-5.31(m, 1H), 4.64(m, 1H), 4.50(dd, J=17.5, 6.6Hz, 1H), 4.43-4.33(m, 2H), 4.29(s, 1H), 3.22-3.09( m, 2H), 2.89 (d, J=16.8Hz, 1H), 2.44-2.37 (m, 1H), 2.26 (s, 3H), 2.18-2.09 (m, 1H).
实施例47：化合物116的制备
Example 47: Preparation of Compound 116
采用通用合成方法3制备，得盐酸盐为白色固体，收率37.55％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 37.55%.
1H NMR(400MHz，DMSO-d6)δ10.56(s，1H)，8.55(s，2H)，7.90(dd，J＝7.8，1.5Hz，1H)，7.72(m，2H)，7.56(dt，J＝15.2，7.6Hz，2H)，7.45-7.40(m，1H)，7.25(d，J＝8.1Hz，1H)，5.84(dd，J＝20.1，9.8Hz，2H)，5.37(dd，J＝13.2，5.2Hz，1H)，4.46(m，1H)，4.40-4.32(m，2H)，3.75(s，3H)，3.48-3.40(m，2H)，3.20-3.12(m，1H)，2.89(d，J＝17.2Hz，1H)，2.26(s，3H)，2.14(d，J＝5.4Hz，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.56 (s, 1H), 8.55 (s, 2H), 7.90 (dd, J=7.8, 1.5Hz, 1H), 7.72 (m, 2H), 7.56 ( dt, J=15.2, 7.6Hz, 2H), 7.45-7.40 (m, 1H), 7.25 (d, J=8.1Hz, 1H), 5.84 (dd, J=20.1, 9.8Hz, 2H), 5.37 (dd , J=13.2, 5.2Hz, 1H), 4.46 (m, 1H), 4.40-4.32 (m, 2H), 3.75 (s, 3H), 3.48-3.40 (m, 2H), 3.20-3.12 (m, 1H) ), 2.89 (d, J = 17.2Hz, 1H), 2.26 (s, 3H), 2.14 (d, J = 5.4Hz, 1H).
实施例48：化合物117的制备
Example 48: Preparation of Compound 117
采用通用合成方法3制备，得盐酸盐为白色固体，收率45.95％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 45.95%.
1H NMR(600MHz，DMSO-d6)δ9.75(s，1H)，8.84(s，3H)，7.91(d，J＝7.7Hz，1H)，7.82-7.66(m，2H)，7.52(dd，J＝8.1，5.3Hz，2H)，7.43(t，J＝7.6Hz，1H)，7.25(d，J＝8.0Hz，1H)，5.91-5.76(m，2H)，5.36(dd，J＝13.4，4.9Hz，1H)，4.62(td，J＝12.0，3.4Hz，1H)，4.55-4.30(m，4H)，4.03(q，J＝7.1Hz，1H)，3.41(s，2H)，3.16(ddd，J＝18.2，11.9，5.4Hz，1H)，2.90(dd，J＝14.0，2.6Hz，1H)，2.48-2.34(m，1H)，2.13(dd，J＝18.8，13.7Hz，1H)，1.99(s，1H)，1.17(t，J＝7.1Hz，1H). 1 H NMR (600MHz, DMSO-d 6 ) δ9.75 (s, 1H), 8.84 (s, 3H), 7.91 (d, J = 7.7Hz, 1H), 7.82-7.66 (m, 2H), 7.52 ( dd, J=8.1, 5.3Hz, 2H), 7.43 (t, J=7.6Hz, 1H), 7.25 (d, J=8.0Hz, 1H), 5.91-5.76 (m, 2H), 5.36 (dd, J =13.4, 4.9Hz, 1H), 4.62 (td, J = 12.0, 3.4Hz, 1H), 4.55-4.30 (m, 4H), 4.03 (q, J = 7.1Hz, 1H), 3.41 (s, 2H) , 3.16 (ddd, J=18.2, 11.9, 5.4Hz, 1H), 2.90 (dd, J=14.0, 2.6Hz, 1H), 2.48-2.34 (m, 1H), 2.13 (dd, J=18.8, 13.7Hz , 1H), 1.99 (s, 1H), 1.17 (t, J=7.1Hz, 1H).
实施例49：化合物118的制备
Example 49: Preparation of Compound 118
采用通用合成方法3制备，得盐酸盐为白色固体，收率50.98％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 50.98%.
1H NMR(400MHz，DMSO-d6)δ10.71(d，J＝4.2Hz，1H)，8.82(s，3H)，7.83-7.68(m，1H)，7.55(dt，J＝15.1，7.4Hz，2H)，5.63(dd，J＝30.1，9.6Hz，2H)，5.53-5.28(m，1H)，4.49(dd，J＝17.6，9.3Hz，1H)，4.41-4.26(m，2H)，3.75(d，J＝11.8Hz，3H)，3.54-3.40(m，2H)，3.22-3.03(m，1H)，2.85(d，J＝16.7Hz，1H)，2.40(qd， J＝13.2，4.1Hz，1H)，2.28(t，J＝7.3Hz，2H)，2.15-2.05(m，1H)，1.60-1.42(m，2H)，1.33-1.14(m，8H)，0.84(t，J＝6.8Hz，3H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.71 (d, J=4.2Hz, 1H), 8.82 (s, 3H), 7.83-7.68 (m, 1H), 7.55 (dt, J=15.1, 7.4 Hz, 2H), 5.63 (dd, J=30.1, 9.6Hz, 2H), 5.53-5.28 (m, 1H), 4.49 (dd, J=17.6, 9.3Hz, 1H), 4.41-4.26 (m, 2H) , 3.75 (d, J=11.8Hz, 3H), 3.54-3.40 (m, 2H), 3.22-3.03 (m, 1H), 2.85 (d, J=16.7Hz, 1H), 2.40 (qd, J=13.2, 4.1Hz, 1H), 2.28 (t, J=7.3Hz, 2H), 2.15-2.05 (m, 1H), 1.60-1.42 (m, 2H), 1.33-1.14 (m, 8H), 0.84 (t, J=6.8Hz, 3H).
实施例50：化合物119的制备
Example 50: Preparation of Compound 119
采用通用合成方法3制备，得盐酸盐为白色固体，收率31.28％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 31.28%.
1H NMR(600MHz，DMSO-d6)δ10.59(s，1H)，8.49(s，3H)，7.75(dd，J＝13.0，7.9Hz，1H)，7.56(dt，J＝15.3，7.5Hz，2H)，5.58(tt，J＝19.2，5.6Hz，2H)，5.32(ddd，J＝13.4，4.8，2.8Hz，1H)，4.47(dd，J＝17.5，13.0Hz，1H)，4.35(dd，J＝17.5，10.8Hz，1H)，4.21(d，J＝4.2Hz，1H)，3.523.44(m，1H)，3.433.29(m，4H)，3.183.07(m，1H)，2.80(d，J＝2.7Hz，6H)，2.452.34(m，1H)，2.162.07(m，1H). 1 H NMR (600MHz, DMSO-d 6 ) δ 10.59 (s, 1H), 8.49 (s, 3H), 7.75 (dd, J=13.0, 7.9Hz, 1H), 7.56 (dt, J=15.3, 7.5 Hz, 2H), 5.58 (tt, J=19.2, 5.6Hz, 2H), 5.32 (ddd, J=13.4, 4.8, 2.8Hz, 1H), 4.47 (dd, J=17.5, 13.0Hz, 1H), 4.35 (dd, J=17.5, 10.8Hz, 1H), 4.21 (d, J=4.2Hz, 1H), 3.523.44 (m, 1H), 3.433.29 (m, 4H), 3.183.07 (m, 1H ), 2.80 (d, J=2.7Hz, 6H), 2.452.34 (m, 1H), 2.162.07 (m, 1H).
实施例51：化合物120的制备
Example 51: Preparation of Compound 120
采用通用合成方法3制备，得盐酸盐为白色固体，收率43.77％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 43.77%.
1H NMR(600MHz，DMSO-d6)δ9.71(s，1H)，8.60(s，3H)，7.90-7.64(m，1H)，7.64-7.40(m，2H)，5.68-5.50(m，2H)，5.31(dt，J＝13.4，4.3Hz，1H)，4.63(ddd，J＝12.0，8.6，3.5Hz，1H)，4.57-4.28(m，4H)，3.43(dt，J＝21.3，10.7Hz，1H)，3.18-3.05(m，1H)，2.80(d，J＝3.7Hz，6H)，2.36(qd，J＝13.2，4.3Hz，1H)，2.16-2.04(m，1H). 1 H NMR (600MHz, DMSO-d 6 ) δ9.71 (s, 1H), 8.60 (s, 3H), 7.90-7.64 (m, 1H), 7.64-7.40 (m, 2H), 5.68-5.50 (m , 2H), 5.31 (dt, J=13.4, 4.3Hz, 1H), 4.63 (ddd, J=12.0, 8.6, 3.5Hz, 1H), 4.57-4.28 (m, 4H), 3.43 (dt, J=21.3 , 10.7Hz, 1H), 3.18-3.05 (m, 1H), 2.80 (d, J=3.7Hz, 6H), 2.36 (qd, J=13.2, 4.3Hz, 1H), 2.16-2.04 (m, 1H) .
实施例52：化合物121的制备
Example 52: Preparation of Compound 121
采用通用合成方法3制备，得盐酸盐为白色固体，收率60.30％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 60.30%.
1H NMR(400MHz，DMSO-d6)δ9.74(s，1H)，8.82(s，1H)，7.75(dd，J＝9.8，5.0Hz，1H)，7.55-7.49(m，1H)，5.63(dd，J＝28.7，9.6Hz，1H)，5.32(dd，J＝13.5，5.0Hz，1H)，4.62(ddd，J＝10.3，7.0，3.3Hz，1H)，4.53-4.40(m，1H)，3.78(d，J＝1.0Hz，1H)，3.17-3.06(m，1H)，2.89-2.81(m，1H)，2.37(dd，J＝13.1，4.4Hz，1H)，2.28(t，J＝7.3Hz，1H)，2.14-2.07(m，1H)，1.53-1.44(m，1H)，1.21(d，J＝15.0Hz，4H)，0.84(t，J＝6.7Hz，2H). 1 H NMR (400MHz, DMSO-d 6 ) δ9.74 (s, 1H), 8.82 (s, 1H), 7.75 (dd, J=9.8, 5.0Hz, 1H), 7.55-7.49 (m, 1H), 5.63 (dd, J=28.7, 9.6Hz, 1H), 5.32 (dd, J=13.5, 5.0Hz, 1H), 4.62 (ddd, J=10.3, 7.0, 3.3Hz, 1H), 4.53-4.40 (m, 1H), 3.78 (d, J=1.0Hz, 1H), 3.17-3.06 (m, 1H), 2.89-2.81 (m, 1H), 2.37 (dd, J=13.1, 4.4Hz, 1H), 2.28 (t , J=7.3Hz, 1H), 2.14-2.07 (m, 1H), 1.53-1.44 (m, 1H), 1.21 (d, J=15.0Hz, 4H), 0.84 (t, J=6.7Hz, 2H) .
实施例53：化合物122的制备
Example 53: Preparation of Compound 122
采用通用合成方法3制备，得盐酸盐为白色固体，收率57.39％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 57.39%.
1H NMR(600MHz，DMSO-d6)δ10.19(s，1H)，7.81(dd，J＝5.5，3.2Hz，1H)，7.56-7.48(m，2H)，7.34(d，J＝8.4Hz，2H)，7.20(d，J＝8.5Hz，2H)，5.72-5.52(m，2H)，5.35-5.24(m，1H)，4.55(d，J＝17.5Hz，1H)，4.41(d，J＝17.5Hz，1H)，4.03(s，1H)，3.17(s，2H)，2.88-2.81(m，1H)，2.46-2.35(m，1H)，2.27(t，J＝7.3Hz，2H)，2.14-2.07(m，1H)，1.54-1.45(m，2H)，1.24(d，J＝9.0Hz，8H)，0.84(dt，J＝14.0，6.9Hz，3H). 1 H NMR (600MHz, DMSO-d 6 ) δ10.19 (s, 1H), 7.81 (dd, J=5.5, 3.2Hz, 1H), 7.56-7.48 (m, 2H), 7.34 (d, J=8.4 Hz, 2H), 7.20 (d, J=8.5Hz, 2H), 5.72-5.52 (m, 2H), 5.35-5.24 (m, 1H), 4.55 (d, J=17.5Hz, 1H), 4.41 (d , J=17.5Hz, 1H), 4.03 (s, 1H), 3.17 (s, 2H), 2.88-2.81 (m, 1H), 2.46-2.35 (m, 1H), 2.27 (t, J=7.3Hz, 2H), 2.14-2.07 (m, 1H), 1.54-1.45 (m, 2H), 1.24 (d, J=9.0Hz, 8H), 0.84 (dt, J=14.0, 6.9Hz, 3H).
实施例54：123的制备

Example 54: Preparation of 123

采用通用合成方法3制备，得盐酸盐为白色固体，收率23.59％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 23.59%.
1H NMR(400MHz，DMSO-d6)δ9.73(s，1H)，8.62(s，3H)，7.77(dd，J＝9.6，4.9Hz，1H)，7.57-7.48(m，2H)，5.63(dd，J＝27.9，9.6Hz，2H)，5.40-5.24(m，1H)，4.64(dt，J＝11.9，3.3Hz，1H)，4.56-4.29(m，4H)，3.21-3.01(m，1H)，2.91-2.77(m，1H)，2.42-2.31(m，1H)，2.28(t，J＝7.3Hz，2H)，2.16-2.06(m，1H)，1.48(dd，J＝13.8，6.9Hz，2H)，0.84(t，J＝6.8Hz，3H). 1 H NMR (400MHz, DMSO-d 6 ) δ9.73 (s, 1H), 8.62 (s, 3H), 7.77 (dd, J=9.6, 4.9Hz, 1H), 7.57-7.48 (m, 2H), 5.63 (dd, J=27.9, 9.6Hz, 2H), 5.40-5.24 (m, 1H), 4.64 (dt, J=11.9, 3.3Hz, 1H), 4.56-4.29 (m, 4H), 3.21-3.01 ( m, 1H), 2.91-2.77 (m, 1H), 2.42-2.31 (m, 1H), 2.28 (t, J＝7.3Hz, 2H), 2.16-2.06 (m, 1H), 1.48 (dd, J＝ 13.8, 6.9Hz, 2H), 0.84 (t, J=6.8Hz, 3H).
实施例55：化合物124的制备
Example 55: Preparation of Compound 124
采用通用合成方法3制备，得盐酸盐为白色固体，收率62.13％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 62.13%.
1H NMR(600MHz，DMSO-d6)δ9.71(s，1H)，8.58(s，2H)，7.86-7.71(m，1H)，7.64-7.49(m，4H)，7.15(d，J＝8.4Hz，1H)，7.02(t，J＝7.5Hz，1H)，5.81(dt，J＝27.2，13.6Hz，2H)，5.35(dt，J＝13.4，4.4Hz，1H)，4.62(tt，J＝39.6，19.8Hz，1H)，4.51(dd，J＝17.4，7.6Hz，1H)，4.48-4.32(m，2H)，4.32(d，J＝36.4Hz，1H)，4.11(s，1H)，3.80(d，J＝7.8Hz，3H)，3.41-3.25(m，1H)，2.88(d，J＝17.5Hz，1H)，2.40(qd，J＝13.1，4.0Hz，1H)，2.21-2.02(m，1H). 1 H NMR (600MHz, DMSO-d 6 ) δ9.71 (s, 1H), 8.58 (s, 2H), 7.86-7.71 (m, 1H), 7.64-7.49 (m, 4H), 7.15 (d, J =8.4Hz, 1H), 7.02 (t, J = 7.5Hz, 1H), 5.81 (dt, J = 27.2, 13.6Hz, 2H), 5.35 (dt, J = 13.4, 4.4Hz, 1H), 4.62 (tt , J=39.6, 19.8Hz, 1H), 4.51 (dd, J=17.4, 7.6Hz, 1H), 4.48-4.32 (m, 2H), 4.32 (d, J=36.4Hz, 1H), 4.11 (s, 1H), 3.80 (d, J=7.8Hz, 3H), 3.41-3.25 (m, 1H), 2.88 (d, J=17.5Hz, 1H), 2.40 (qd, J=13.1, 4.0Hz, 1H), 2.21-2.02(m,1H).
实施例56：化合物125的制备
Example 56: Preparation of Compound 125
采用通用合成方法3制备，得盐酸盐为白色固体，收率33.38％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 33.38%.
1H NMR(400MHz，DMSO-d6)δ9.74(s，1H)，8.80(s，3H)，7.88(d，J＝8.9Hz，2H)，7.75(dd，J＝10.3，6.1Hz，1H)，7.52(dd，J＝7.1，5.8Hz，2H)，7.06(d，J＝8.9Hz， 2H)，5.86(dd，J＝23.3，9.6Hz，2H)，5.37(dd，J＝13.4，4.9Hz，1H)，4.72-4.32(m，5H)，3.84(s，3H)，3.78(d，J＝2.8Hz，3H)，3.24-3.07(m，1H)，3.01-2.84(m，1H)，2.47-2.36(m，1H)，2.22-2.06(m，1H)，1.99(s，1H)，1.25-1.12(m，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 9.74 (s, 1H), 8.80 (s, 3H), 7.88 (d, J = 8.9Hz, 2H), 7.75 (dd, J = 10.3, 6.1Hz, 1H), 7.52 (dd, J=7.1, 5.8Hz, 2H), 7.06 (d, J=8.9Hz, 2H), 5.86 (dd, J=23.3, 9.6Hz, 2H), 5.37 (dd, J=13.4, 4.9Hz, 1H), 4.72-4.32 (m, 5H), 3.84 (s, 3H), 3.78 (d , J=2.8Hz, 3H), 3.24-3.07(m, 1H), 3.01-2.84(m, 1H), 2.47-2.36(m, 1H), 2.22-2.06(m, 1H), 1.99(s, 1H ), 1.25-1.12(m, 1H).
实施例57：化合物126的制备
Example 57: Preparation of Compound 126
采用通用合成方法3制备，得盐酸盐为白色固体，收率48.86％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 48.86%.
1H NMR(400MHz，DMSO-d6)δ14.09(s，1H)，10.58(d，J＝3.9Hz，1H)，8.46(s，3H)，7.76(t，J＝8.2Hz，1H)，7.59-7.39(m，4H)，7.27(d，J＝7.9Hz，1H)，5.89(dd，J＝28.4，9.6Hz，2H)，5.38(d，J＝10.4Hz，1H)，4.49(dd，J＝17.5，8.5Hz，1H)，4.38(dd，J＝17.6，6.9Hz，1H)，4.23(s，1H)，4.03(dd，J＝14.3，7.2Hz，1H)，3.82(s，3H)，3.55-3.40(m，3H)，3.25-3.08(m，1H)，2.87(d，J＝13.7Hz，1H)，2.47-2.32(m，1H)，2.19-2.06(m，1H)，1.99(s，1H)，1.19(dd，J＝20.9，13.8Hz，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ14.09 (s, 1H), 10.58 (d, J=3.9Hz, 1H), 8.46 (s, 3H), 7.76 (t, J=8.2Hz, 1H) , 7.59-7.39 (m, 4H), 7.27 (d, J = 7.9Hz, 1H), 5.89 (dd, J = 28.4, 9.6Hz, 2H), 5.38 (d, J = 10.4Hz, 1H), 4.49 ( dd, J=17.5, 8.5Hz, 1H), 4.38 (dd, J=17.6, 6.9Hz, 1H), 4.23 (s, 1H), 4.03 (dd, J=14.3, 7.2Hz, 1H), 3.82 (s , 3H), 3.55-3.40 (m, 3H), 3.25-3.08 (m, 1H), 2.87 (d, J=13.7Hz, 1H), 2.47-2.32 (m, 1H), 2.19-2.06 (m, 1H) ), 1.99 (s, 1H), 1.19 (dd, J=20.9, 13.8Hz, 1H).
实施例58：化合物127的制备
Example 58: Preparation of Compound 127
采用通用合成方法3制备，得盐酸盐为白色固体，收率41.67％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 41.67%.
1H NMR(600MHz，DMSO-d6)δ9.71(s，1H)，8.61(s，3H)，7.77(d，J＝10.5Hz，1H)，7.57-7.38(m，5H)，7.26(d，J＝8.1Hz，1H)，5.89(dd，J＝40.7，9.6Hz，2H)，5.36(dd，J＝13.3，4.5Hz，1H)，4.63(dd，J＝15.0，6.0Hz，1H)，4.51(dd，J＝17.4，7.5Hz，1H)，4.46-4.36(m，2H)，4.34(s，1H)，3.26-3.09(m，1H)，2.97-2.81(m，1H)，2.43(qd，J＝13.2，4.2Hz，1H)，2.18-2.08(m，1H). 1 H NMR (600MHz, DMSO-d 6 ) δ9.71 (s, 1H), 8.61 (s, 3H), 7.77 (d, J=10.5Hz, 1H), 7.57-7.38 (m, 5H), 7.26 ( d, J=8.1Hz, 1H), 5.89 (dd, J=40.7, 9.6Hz, 2H), 5.36 (dd, J=13.3, 4.5Hz, 1H), 4.63 (dd, J=15.0, 6.0Hz, 1H ), 4.51 (dd, J=17.4, 7.5Hz, 1H), 4.46-4.36 (m, 2H), 4.34 (s, 1H), 3.26-3.09 (m, 1H), 2.97-2.81 (m, 1H), 2.43(qd, J=13.2, 4.2Hz, 1H), 2.18-2.08(m, 1H).
实施例59：化合物128的制备
Example 59: Preparation of Compound 128
采用通用合成方法3制备，得盐酸盐为白色固体，收率35.98％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 35.98%.
1H NMR(400MHz，DMSO-d6)δ13.90(s，1H)，10.20(s，1H)，8.44(s，2H)，7.81(dd，J＝5.5，3.5Hz，1H)，7.58-7.53(m，2H)，7.51(d，J＝7.6Hz，1H)，7.48-7.40(m，2H)，7.33(d，J＝8.5Hz，2H)，7.28-7.24(m，1H)，7.22(d，J＝8.5Hz，2H)，5.90(dd，J＝31.9，9.6Hz，2H)，5.38(dd，J＝13.4，5.0Hz，1H)，4.51(dd，J＝48.7，17.6Hz，2H)，4.20(s，1H)，3.81(s，3H)，3.38(s，3H)，2.89(d，J＝16.7Hz，1H)，2.21-2.06(m，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 13.90 (s, 1H), 10.20 (s, 1H), 8.44 (s, 2H), 7.81 (dd, J=5.5, 3.5Hz, 1H), 7.58- 7.53 (m, 2H), 7.51 (d, J=7.6Hz, 1H), 7.48-7.40 (m, 2H), 7.33 (d, J=8.5Hz, 2H), 7.28-7.24 (m, 1H), 7.22 (d, J=8.5Hz, 2H), 5.90 (dd, J=31.9, 9.6Hz, 2H), 5.38 (dd, J=13.4, 5.0Hz, 1H), 4.51 (dd, J=48.7, 17.6Hz, 2H), 4.20(s, 1H), 3.81(s, 3H), 3.38(s, 3H), 2.89(d, J=16.7Hz, 1H), 2.21-2.06(m, 1H).
实施例60：化合物129的制备
Example 60: Preparation of Compound 129
采用通用合成方法3制备，得盐酸盐为白色固体，收率55.52％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 55.52%.
1H NMR(600MHz，DMSO-d6)δ10.61(d，J＝9.0Hz，1H)，8.51(s，3H)，7.89(d，J＝8.9Hz，2H)，7.76(dd，J＝12.3，7.7Hz，1H)，7.56(dt，J＝15.3，7.6Hz，2H)，7.06(d，J＝8.9Hz，2H)，5.86(dd，J＝35.7，9.8Hz，2H)，5.37(ddd，J＝13.5，4.8，2.8Hz，1H)，4.50(dd，J＝17.5，11.3Hz，1H)，4.43-4.29(m，1H)，4.21(s，1H)，3.84(s，3H)，3.40(ddd，J＝14.6，5.9，2.6Hz，3H)，3.23-3.09(m，1H)，2.88(d，J＝10.5Hz，1H)，2.48-2.39(m，1H)，2.17-2.08(m，1H). 1 H NMR (600MHz, DMSO-d 6 ) δ10.61 (d, J=9.0Hz, 1H), 8.51 (s, 3H), 7.89 (d, J=8.9Hz, 2H), 7.76 (dd, J= 12.3, 7.7Hz, 1H), 7.56 (dt, J=15.3, 7.6Hz, 2H), 7.06 (d, J=8.9Hz, 2H), 5.86 (dd, J=35.7, 9.8Hz, 2H), 5.37 ( ddd, J=13.5, 4.8, 2.8Hz, 1H), 4.50 (dd, J=17.5, 11.3Hz, 1H), 4.43-4.29 (m, 1H), 4.21 (s, 1H), 3.84 (s, 3H) , 3.40 (ddd, J=14.6, 5.9, 2.6Hz, 3H), 3.23-3.09 (m, 1H), 2.88 (d, J=10.5Hz, 1H), 2.48-2.39 (m, 1H), 2.17-2.08 (m,1H).
实施例61：化合物130的制备
Example 61: Preparation of Compound 130
采用通用合成方法3制备，得盐酸盐为白色固体，收率48.59％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 48.59%.
1H NMR(600MHz，DMSO-d6)δ9.73(s，1H)，8.65(s，3H)，7.89(d，J＝8.8Hz，2H)，7.83-7.71(m，1H)，7.62-7.40(m，2H)，7.06(d，J＝8.8Hz，2H)，5.86(dd，J＝36.6，9.6Hz，2H)，5.43-5.32(m，1H)，4.64(ddd，J＝12.2，9.0，3.5Hz，1H)，4.52(dd，J＝17.5，6.0Hz，1H)，4.48-4.29(m，4H)，3.84(s，3H)，3.20-3.11(m，1H)，2.93-2.85(m，1H)，2.12(dd，J＝17.3，10.5Hz，1H)，1.91(s，1H). 1 H NMR (600MHz, DMSO-d 6 ) δ9.73 (s, 1H), 8.65 (s, 3H), 7.89 (d, J=8.8Hz, 2H), 7.83-7.71 (m, 1H), 7.62- 7.40 (m, 2H), 7.06 (d, J=8.8Hz, 2H), 5.86 (dd, J=36.6, 9.6Hz, 2H), 5.43-5.32 (m, 1H), 4.64 (ddd, J=12.2, 9.0, 3.5Hz, 1H), 4.52 (dd, J=17.5, 6.0Hz, 1H), 4.48-4.29 (m, 4H), 3.84 (s, 3H), 3.20-3.11 (m, 1H), 2.93-2.85 (m, 1H), 2.12 (dd, J=17.3, 10.5Hz, 1H), 1.91 (s, 1H).
实施例62：化合物131的制备
Example 62: Preparation of Compound 131
采用通用合成方法3制备，得盐酸盐为白色固体，收率47.64％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 47.64%.
1H NMR(400MHz，DMSO-d6)δ13.89(s，1H)，10.22(s，1H)，8.50(s，3H)，7.96-7.84(m，2H)，7.81(dt，J＝7.4，3.7Hz，1H)，7.61-7.53(m，2H)，7.33(t，J＝11.3Hz，2H)，7.22(d，J＝8.5Hz，2H)，7.05(d，J＝8.9Hz，2H)，5.87(dd，J＝27.6，9.6Hz，2H)，5.38(dd，J＝13.4，5.0Hz，1H)，4.51(dd，J＝50.1，17.6Hz，2H)，4.19(s，1H)，3.83(s，3H)，3.17(t，J＝8.5Hz，2H)，2.89(dd，J＝10.2，6.5Hz，1H)，2.50-2.36(m，2H)，2.14(dd，J＝8.7，3.4Hz，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ13.89 (s, 1H), 10.22 (s, 1H), 8.50 (s, 3H), 7.96-7.84 (m, 2H), 7.81 (dt, J=7.4 , 3.7Hz, 1H), 7.61-7.53 (m, 2H), 7.33 (t, J=11.3Hz, 2H), 7.22 (d, J=8.5Hz, 2H), 7.05 (d, J=8.9Hz, 2H ), 5.87 (dd, J=27.6, 9.6Hz, 2H), 5.38 (dd, J=13.4, 5.0Hz, 1H), 4.51 (dd, J=50.1, 17.6Hz, 2H), 4.19 (s, 1H) , 3.83 (s, 3H), 3.17 (t, J=8.5Hz, 2H), 2.89 (dd, J=10.2, 6.5Hz, 1H), 2.50-2.36 (m, 2H), 2.14 (dd, J=8.7 ,3.4Hz,1H).
实施例63：化合物132的制备
Example 63: Preparation of Compound 132
采用通用合成方法3制备，得盐酸盐为白色固体，收率48.95％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 48.95%.
1H NMR(400MHz，DMSO-d6)δ10.58(d，J＝67.0Hz，1H)，8.75(d，J＝148.3Hz，3H)，7.76(dt，J＝7.6，5.1Hz，1H)，7.56(dt，J＝15.2，7.4Hz，2H)，5.59(dd，J＝24.0，9.5Hz，2H)，5.33(dd，J＝13.3，3.9Hz，1H)，4.49(dd，J＝17.6，7.0Hz，1H)，4.34(dd，J＝17.6，5.4Hz，1H)，4.17(dd，J＝8.2，5.5Hz，1H)，3.45(ddd，J＝20.6，14.6，5.6Hz，3H)，3.24-3.05(m，5H)，2.87(dd，J＝22.4，11.9Hz，1H)，2.39(qd，J＝13.2，4.2Hz，1H)，2.15-2.04(m，1H)，1.01(s，6H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.58 (d, J = 67.0Hz, 1H), 8.75 (d, J = 148.3Hz, 3H), 7.76 (dt, J = 7.6, 5.1Hz, 1H) , 7.56 (dt, J=15.2, 7.4Hz, 2H), 5.59 (dd, J=24.0, 9.5Hz, 2H), 5.33 (dd, J=13.3, 3.9Hz, 1H), 4.49 (dd, J=17.6 , 7.0Hz, 1H), 4.34 (dd, J=17.6, 5.4Hz, 1H), 4.17 (dd, J=8.2, 5.5Hz, 1H), 3.45 (ddd, J=20.6, 14.6, 5.6Hz, 3H) , 3.24-3.05(m, 5H), 2.87(dd, J＝22.4, 11.9Hz, 1H), 2.39(qd, J＝13.2, 4.2Hz, 1H), 2.15-2.04(m, 1H), 1.01(s , 6H).
实施例64：化合物133的制备
Example 64: Preparation of Compound 133
采用通用合成方法3制备，得盐酸盐为白色固体，收率53.83％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 53.83%.
1H NMR(600MHz，DMSO-d6)δ9.72(s，1H)，8.62(s，3H)，7.82-7.67(m，1H)，7.58-7.44(m，2H)，5.58(dt，J＝21.6，10.8Hz，2H)，5.32(ddd，J＝13.4，11.0，4.4Hz，1H)，4.63(ddd，J＝11.8，6.3，3.6Hz，1H)，4.50(dd，J＝17.4，6.7Hz，1H)，4.46-4.30(m，3H)，3.26-3.05(m，5H)，2.90-2.77(m，1H)，2.35(qd，J＝13.2，4.3Hz，1H)，2.16-2.06(m，1H)，1.11-0.83(m，6H). 1 H NMR (600MHz, DMSO-d 6 ) δ9.72 (s, 1H), 8.62 (s, 3H), 7.82-7.67 (m, 1H), 7.58-7.44 (m, 2H), 5.58 (dt, J =21.6, 10.8Hz, 2H), 5.32 (ddd, J = 13.4, 11.0, 4.4Hz, 1H), 4.63 (ddd, J = 11.8, 6.3, 3.6Hz, 1H), 4.50 (ddd, J = 17.4, 6.7 Hz, 1H), 4.46-4.30 (m, 3H), 3.26-3.05 (m, 5H), 2.90-2.77 (m, 1H), 2.35 (qd, J=13.2, 4.3Hz, 1H), 2.16-2.06 ( m, 1H), 1.11-0.83 (m, 6H).
实施例65：化合物134制备
Example 65: Preparation of Compound 134
采用通用合成方法3制备，得盐酸盐为白色固体，收率49.29％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 49.29%.
1H NMR(600MHz，DMSO-d6)δ13.87(s，1H)，10.21(s，1H)，8.46(s，3H)，7.80(dd，J＝6.4，2.2Hz，1H)，7.63-7.50(m，2H)，7.34(d，J＝8.4Hz，2H)，7.21(d，J＝8.4Hz，2H)，5.58(dt，J＝20.8，10.4Hz，2H)，5.37-5.25(m，1H)，4.55(d，J＝17.5Hz，1H)，4.42(t，J＝17.9Hz，1H)，4.16(d，J＝38.4Hz，1H)，3.42(d，J＝30.7Hz，4H)，3.16(dd，J＝13.2，8.0Hz，4H)，2.87(dt，J＝17.0，11.6Hz，1H)，2.38(qd，J＝13.2，4.3Hz，1H)，2.16-2.06(m，1H)，1.09-0.93(m，6H). 1 H NMR (600MHz, DMSO-d 6 ) δ 13.87 (s, 1H), 10.21 (s, 1H), 8.46 (s, 3H), 7.80 (dd, J=6.4, 2.2Hz, 1H), 7.63- 7.50 (m, 2H), 7.34 (d, J = 8.4Hz, 2H), 7.21 (d, J = 8.4Hz, 2H), 5.58 (dt, J = 20.8, 10.4Hz, 2H), 5.37-5.25 (m , 1H), 4.55 (d, J=17.5Hz, 1H), 4.42 (t, J=17.9Hz, 1H), 4.16 (d, J=38.4Hz, 1H), 3.42 (d, J=30.7Hz, 4H ), 3.16 (dd, J=13.2, 8.0Hz, 4H), 2.87 (dt, J=17.0, 11.6Hz, 1H), 2.38 (qd, J=13.2, 4.3Hz, 1H), 2.16-2.06 (m, 1H), 1.09-0.93(m, 6H).
实施例66：化合物135的制备
Example 66: Preparation of Compound 135
采用通用合成方法3制备，得盐酸盐为白色固体，收率48.46％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 48.46%.
1H NMR(600MHz，DMSO-d6)δ10.24(d，J＝54.4Hz，1H)，8.63(s，3H)，7.90(dd，J＝7.8，1.6Hz，1H)，7.80(d，J＝6.9Hz，1H)，7.70(td，J＝7.9，1.7Hz，1H)，7.59-7.51(m，2H)，7.40(dd，J＝11.8，4.3Hz，1H)，7.30(d，J＝8.5Hz，2H)，7.23(dd，J＝21.0，8.3Hz，3H)，5.85(dd，J＝34.3，9.7Hz，2H)，5.36(dd，J＝13.4，5.0Hz，1H)，4.56(d，J＝17.6Hz，1H)，4.44(d，J＝17.3Hz，1H)，4.32(t，J＝6.4Hz，1H)，3.70(s，3H)，3.22-3.09(m，3H)，2.95-2.84(m，1H)，2.48-2.38(m，1H)，2.25(s，3H)，2.13(dd，J＝17.9，12.7Hz，1H). 1 H NMR (600MHz, DMSO-d 6 ) δ 10.24 (d, J=54.4Hz, 1H), 8.63 (s, 3H), 7.90 (dd, J=7.8, 1.6Hz, 1H), 7.80 (d, J=6.9Hz, 1H), 7.70 (td, J=7.9, 1.7Hz, 1H), 7.59-7.51 (m, 2H), 7.40 (dd, J=11.8, 4.3Hz, 1H), 7.30 (d, J =8.5Hz, 2H), 7.23 (dd, J=21.0, 8.3Hz, 3H), 5.85 (dd, J=34.3, 9.7Hz, 2H), 5.36 (dd, J=13.4, 5.0Hz, 1H), 4.56 (d, J=17.6Hz, 1H), 4.44 (d, J=17.3Hz, 1H), 4.32 (t, J=6.4Hz, 1H), 3.70 (s, 3H), 3.22-3.09 (m, 3H) , 2.95-2.84 (m, 1H), 2.48-2.38 (m, 1H), 2.25 (s, 3H), 2.13 (dd, J=17.9, 12.7Hz, 1H).
实施例67：化合物136的制备
Example 67: Preparation of Compound 136
采用通用合成方法3制备，得盐酸盐为白色固体，收率34.39％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 34.39%.
1H NMR(600MHz，DMSO-d6)δ10.21(s，1H)，8.50(s，3H)，7.88-7.74(m，1H)，7.62-7.48(m，2H)，7.34(d，J＝8.4Hz，2H)，7.21(d，J＝8.4Hz，2H)，5.58(dt，J＝16.2，8.1Hz，2H)，5.37-5.23(m，1H)，4.53(t，J＝17.0Hz，1H)，4.42(d，J＝17.5Hz，1H)，4.18(t，J＝6.1Hz，1H)，3.21-3.05(m，3H)，2.90-2.74(m，7H)，2.40(qd，J＝13.2，4.2Hz，1H)，2.16-2.04(m，1H). 1 H NMR (600MHz, DMSO-d 6 ) δ10.21 (s, 1H), 8.50 (s, 3H), 7.88-7.74 (m, 1H), 7.62-7.48 (m, 2H), 7.34 (d, J =8.4Hz, 2H), 7.21 (d, J = 8.4Hz, 2H), 5.58 (dt, J = 16.2, 8.1Hz, 2H), 5.37-5.23 (m, 1H), 4.53 (t, J = 17.0Hz , 1H), 4.42 (d, J=17.5Hz, 1H), 4.18 (t, J=6.1Hz, 1H), 3.21-3.05 (m, 3H), 2.90-2.74 (m, 7H), 2.40 (qd, J=13.2, 4.2Hz, 1H), 2.16-2.04 (m, 1H).
实施例68：化合物137的制备
Example 68: Preparation of Compound 137
采用通用合成方法3制备，得盐酸盐为白色固体，收率17.41％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 17.41%.
1H NMR(600MHz，DMSO-d6)δ10.63(s，1H)，8.71(s，3H)，7.75(dd，J＝13.1，7.8Hz，1H)，7.68-7.51(m，2H)，5.58(dt，J＝21.3，10.6Hz，2H)，5.41-5.18(m，1H)，4.46(t，J＝16.3Hz，1H)，4.34(dd，J＝17.5，10.0Hz，2H)，3.76(d，J＝16.9Hz，3H)，3.47(s，1H)，3.19-3.02(m，1H)，2.88-2.82(m，1H)，2.80(d，J＝4.1Hz，6H)，2.38(qd，J＝13.3，4.4Hz，1H)，2.16-2.01(m，1H). 1 H NMR (600MHz, DMSO-d 6 ) δ10.63 (s, 1H), 8.71 (s, 3H), 7.75 (dd, J=13.1, 7.8Hz, 1H), 7.68-7.51 (m, 2H), 5.58 (dt, J=21.3, 10.6Hz, 2H), 5.41-5.18 (m, 1H), 4.46 (t, J=16.3Hz, 1H), 4.34 (dd, J=17.5, 10.0Hz, 2H), 3.76 (d, J=16.9Hz, 3H), 3.47 (s, 1H), 3.19-3.02 (m, 1H), 2.88-2.82 (m, 1H), 2.80 (d, J=4.1Hz, 6H), 2.38 ( qd, J＝13.3, 4.4Hz, 1H), 2.16-2.01(m, 1H).
实施例69：化合物138的制备
Example 69: Preparation of Compound 138
采用通用合成方法3制备，得盐酸盐为白色固体，收率69.45％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 69.45%.
1H NMR(600MHz，DMSO-d6)δ9.74(s，1H)，8.82(s，3H)，7.76(d，J＝4.9Hz，1H)，7.60-7.43(m，2H)，5.65-5.52(m，2H)，5.33(ddd，J＝18.7，13.5，5.0Hz，1H)，4.62(td，J＝11.4，3.4Hz，1H)，4.54-4.41(m，3H)，4.36(dd，J＝17.4，6.7Hz，1H)，3.78(s，3H)，3.15-3.06(m，1H)，2.82(dd，J＝29.6，10.5Hz，6H)，2.41-2.31(m，1H)，2.15-2.07(m，1H). 1 H NMR (600MHz, DMSO-d 6 ) δ9.74 (s, 1H), 8.82 (s, 3H), 7.76 (d, J=4.9Hz, 1H), 7.60-7.43 (m, 2H), 5.65- 5.52 (m, 2H), 5.33 (ddd, J=18.7, 13.5, 5.0Hz, 1H), 4.62 (td, J=11.4, 3.4Hz, 1H), 4.54-4.41 (m, 3H), 4.36 (dd, J=17.4, 6.7Hz, 1H), 3.78 (s, 3H), 3.15-3.06 (m, 1H), 2.82 (dd, J=29.6, 10.5Hz, 6H), 2.41-2.31 (m, 1H), 2.15 -2.07(m,1H).
实施例70：化合物139的制备
Example 70: Preparation of Compound 139
采用通用合成方法3制备，得盐酸盐为白色固体，收率24.88％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 24.88%.
1H NMR(600MHz，DMSO-d6)δ9.77(s，1H)，8.91(s，3H)，7.76(d，J＝3.4Hz，1H)，7.58-7.48(m，2H)，5.67(d，J＝9.6Hz，1H)，5.60(d，J＝9.6Hz，1H)，5.31(dd，J＝13.5，5.0Hz，1H)，4.67-4.57(m，1H)，4.56-4.43(m，3H)，4.36(dd，J＝17.4，1.6Hz，1H)，3.78(s，3H)，3.21-3.04(m，1H)，2.85(d，J＝17.4Hz，1H)，2.38(qd，J＝13.0，3.7Hz，1H)，2.28(t，J＝7.3Hz，2H)，2.16-2.07(m，1H)，1.55-1.44(m，2H)，1.26(dd，J＝20.7，6.6Hz，9H)，1.18(t，J＝7.1Hz，3H). 1 H NMR (600MHz, DMSO-d 6 ) δ9.77 (s, 1H), 8.91 (s, 3H), 7.76 (d, J=3.4Hz, 1H), 7.58-7.48 (m, 2H), 5.67 ( d, J＝9.6Hz, 1H), 5.60 (d, J＝9.6Hz, 1H), 5.31 (dd, J＝13.5, 5.0Hz, 1H), 4.67-4.57(m, 1H), 4.56-4.43(m , 3H), 4.36 (dd, J=17.4, 1.6Hz, 1H), 3.78 (s, 3H), 3.21-3.04 (m, 1H), 2.85 (d, J=17.4Hz, 1H), 2.38 (qd, J=13.0, 3.7Hz, 1H), 2.28 (t, J=7.3Hz, 2H), 2.16-2.07 (m, 1H), 1.55-1.44 (m, 2H), 1.26 (dd, J=20.7, 6.6Hz , 9H), 1.18 (t, J=7.1Hz, 3H).
实施例71：化合物140的制备
Example 71: Preparation of Compound 140
采用通用合成方法3制备，得盐酸盐为白色固体，收率52.74％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 52.74%.
1H NMR(400MHz，DMSO-d6)δ10.18(s，1H)，8.52(s，3H)，7.81(s，1H)，7.55(s，2H)，7.26(d，J＝21.7Hz，3H)，5.64(d，J＝16.9Hz，2H)，5.33(s，2H)，4.65-4.27(m，4H)，3.71(s，3H)，3.13(s，3H)，2.73(s，2H)，2.21(d，J＝54.3Hz，3H)，1.49(s，2H)，1.23(s，6H)，0.84(s，3H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.18 (s, 1H), 8.52 (s, 3H), 7.81 (s, 1H), 7.55 (s, 2H), 7.26 (d, J=21.7Hz, 3H), 5.64 (d, J=16.9Hz, 2H), 5.33 (s, 2H), 4.65-4.27 (m, 4H), 3.71 (s, 3H), 3.13 (s, 3H), 2.73 (s, 2H) ), 2.21 (d, J=54.3Hz, 3H), 1.49 (s, 2H), 1.23 (s, 6H), 0.84 (s, 3H).
实施例72：化合物141的制备
Example 72: Preparation of Compound 141
采用通用合成方法3制备，得盐酸盐为白色固体，收率74.75％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 74.75%.
1H NMR(400MHz，DMSO-d6)δ10.63(d，J＝6.4Hz，1H)，8.69(s，3H)，7.84-7.70(m，1H)，7.56(dt，J＝15.4，7.8Hz，4H)，7.15(d，J＝8.4Hz，1H)，7.02(t，J＝7.5Hz，1H)，5.81(dt，J＝17.3，8.6Hz，2H)，5.37(dd，J＝13.4，5.0Hz，1H)，4.48(dd，J＝17.6，10.9Hz，1H)，4.35(dd，J＝17.3，6.6Hz，2H)，3.81(s，3H)，3.75(t，J＝8.0Hz，3H)，3.56(t，J＝27.0Hz，2H)，3.22-3.09(m，1H)，2.88(t，J＝8.2Hz，1H)，2.49-2.34(m，1H)，2.18-2.05(m，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.63 (d, J=6.4Hz, 1H), 8.69 (s, 3H), 7.84-7.70 (m, 1H), 7.56 (dt, J=15.4, 7.8 Hz, 4H), 7.15 (d, J=8.4Hz, 1H), 7.02 (t, J=7.5Hz, 1H), 5.81 (dt, J=17.3, 8.6Hz, 2H), 5.37 (dd, J=13.4 , 5.0Hz, 1H), 4.48 (dd, J=17.6, 10.9Hz, 1H), 4.35 (dd, J=17.3, 6.6Hz, 2H), 3.81 (s, 3H), 3.75 (t, J=8.0Hz , 3H), 3.56 (t, J=27.0Hz, 2H), 3.22-3.09 (m, 1H), 2.88 (t, J=8.2Hz, 1H), 2.49-2.34 (m, 1H), 2.18-2.05 ( m, 1H).
实施例73：化合物142的制备
Example 73: Preparation of Compound 142
采用通用合成方法3制备，得盐酸盐为白色固体，收率62.59％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 62.59%.
1H NMR(400MHz，DMSO-d6)δ9.72(s，1H)，8.75(s，3H)，7.83-7.68(m，1H)，7.66-7.42(m，4H)，7.15(d，J＝8.3Hz，1H)，7.02(td，J＝7.6，0.9Hz，1H)，5.81(dt，J＝17.7，8.9Hz，2H)，5.36(dd，J＝13.4，4.8Hz，1H)，4.62(td，J＝11.7，3.5Hz，1H)，4.55-4.33(m，4H)，3.88-3.64(m，6H)，3.22-3.08(m，1H)，2.94-2.83(m，1H)，2.46-2.31(m，1H)，2.14(dd，J＝9.1，3.7Hz，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ9.72 (s, 1H), 8.75 (s, 3H), 7.83-7.68 (m, 1H), 7.66-7.42 (m, 4H), 7.15 (d, J =8.3Hz, 1H), 7.02 (td, J = 7.6, 0.9Hz, 1H), 5.81 (dt, J = 17.7, 8.9Hz, 2H), 5.36 (dd, J = 13.4, 4.8Hz, 1H), 4.62 (td, J=11.7, 3.5Hz, 1H), 4.55-4.33 (m, 4H), 3.88-3.64 (m, 6H), 3.22-3.08 (m, 1H), 2.94-2.83 (m, 1H), 2.46 -2.31 (m, 1H), 2.14 (dd, J=9.1, 3.7Hz, 1H).
实施例74：化合物143的制备
Example 74: Preparation of Compound 143
采用通用合成方法3制备，得盐酸盐为白色固体，收率70.57％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 70.57%.
1H NMR(400MHz，DMSO-d6)δ10.20(s，1H)，8.61(s，3H)，7.80(dd，J＝6.2，2.7Hz，1H)，7.56(tdd，J＝11.1，5.9，2.0Hz，4H)，7.30(d，J＝8.6Hz，2H)，7.26-7.18(m，2H)，7.14(d，J＝8.2Hz，1H)，7.00(td，J＝7.6，0.9Hz，1H)，5.83(dd，J＝24.4，9.6Hz，2H)，5.37(dd，J＝13.4，5.0Hz，1H)，4.47(dt，J＝35.9，17.9Hz，2H)，4.33(s，1H)，3.80(s，3H)，3.70(s，3H)，3.23-3.08(m，3H)，2.96-2.79(m，1H)，2.48-2.35(m，1H)，2.21-2.09(m，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.20 (s, 1H), 8.61 (s, 3H), 7.80 (dd, J=6.2, 2.7Hz, 1H), 7.56 (tdd, J=11.1, 5.9 , 2.0Hz, 4H), 7.30 (d, J=8.6Hz, 2H), 7.26-7.18 (m, 2H), 7.14 (d, J=8.2Hz, 1H), 7.00 (td, J=7.6, 0.9Hz , 1H), 5.83 (dd, J=24.4, 9.6Hz, 2H), 5.37 (dd, J=13.4, 5.0Hz, 1H), 4.47 (dt, J=35.9, 17.9Hz, 2H), 4.33 (s, 1H), 3.80(s, 3H), 3.70(s, 3H), 3.23-3.08(m, 3H), 2.96-2.79(m, 1H), 2.48-2.35(m, 1H), 2.21-2.09(m, 1H).
实施例75：化合物144的制备
Example 75: Preparation of Compound 144
采用通用合成方法3制备，得盐酸盐为白色固体，收率70.38％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 70.38%.
1H NMR(400MHz，DMSO-d6)δ10.61(d，J＝5.3Hz，1H)，8.66(s，3H)，7.76(ddd，J＝9.2，7.7，1.2Hz，1H)，7.63-7.40(m，5H)，7.27(ddd，J＝8.1，2.7，1.2Hz，1H)，5.89(dd，J＝26.9，9.7Hz，2H)，5.38(dd，J＝13.4，5.0Hz，1H)，4.56-4.29(m，3H)，3.82(s，3H)，3.75(t，J＝7.0Hz，3H)，3.52-3.42(m，2H)，3.24-3.09(m，1H)，2.98-2.82(m，1H)，2.48-2.38(m，1H)，2.19-2.08(m，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.61 (d, J=5.3Hz, 1H), 8.66 (s, 3H), 7.76 (ddd, J=9.2, 7.7, 1.2Hz, 1H), 7.63- 7.40 (m, 5H), 7.27 (ddd, J=8.1, 2.7, 1.2Hz, 1H), 5.89 (dd, J=26.9, 9.7Hz, 2H), 5.38 (dd, J=13.4, 5.0Hz, 1H) , 4.56-4.29 (m, 3H), 3.82 (s, 3H), 3.75 (t, J=7.0Hz, 3H), 3.52-3.42 (m, 2H), 3.24-3.09 (m, 1H), 2.98-2.82 (m, 1H), 2.48-2.38 (m, 1H), 2.19-2.08 (m, 1H).
实施例76：化合物145的制备

Example 76: Preparation of Compound 145

采用通用合成方法3制备，得盐酸盐为白色固体，收率35.54％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 35.54%.
1H NMR(400MHz，DMSO-d6)δ9.75(s，1H)，8.83(s，3H)，7.76(dd，J＝9.8，5.4Hz，1H)，7.58-7.37(m，5H)，7.32-7.16(m，1H)，5.89(dd，J＝27.0，9.7Hz，2H)，5.37(dd，J＝13.4，5.0Hz，1H)，4.70-4.57(m，1H)，4.55-4.33(m，4H)，3.88-3.71(m，6H)，3.15(ddd，J＝18.1，12.8，5.4Hz，1H)，2.97-2.77(m，1H)，2.43(dt，J＝13.0，9.1Hz，1H)，2.19-2.05(m，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ9.75 (s, 1H), 8.83 (s, 3H), 7.76 (dd, J=9.8, 5.4Hz, 1H), 7.58-7.37 (m, 5H), 7.32-7.16 (m, 1H), 5.89 (dd, J=27.0, 9.7Hz, 2H), 5.37 (dd, J=13.4, 5.0Hz, 1H), 4.70-4.57 (m, 1H), 4.55-4.33 ( m, 4H), 3.88-3.71 (m, 6H), 3.15 (ddd, J=18.1, 12.8, 5.4Hz, 1H), 2.97-2.77 (m, 1H), 2.43 (dt, J=13.0, 9.1Hz, 1H), 2.19-2.05(m, 1H).
实施例77：化合物146的制备
Example 77: Preparation of Compound 146
采用通用合成方法3制备，得盐酸盐为白色固体，收率49.34％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 49.34%.
1H NMR(400MHz，DMSO-d6)δ10.20(s，1H)，8.63(s，3H)，7.81(dt，J＝7.5，3.7Hz，1H)，7.62-7.40(m，5H)，7.35-7.12(m，5H)，5.90(dd，J＝31.7，9.6Hz，2H)，5.38(dd，J＝13.4，5.0Hz，1H)，4.51(dd，J＝48.5，17.6Hz，2H)，4.32(s，1H)，3.81(s，3H)，3.70(s，3H)，3.22-3.04(m，3H)，2.95-2.84(m，1H)，2.48-2.39(m，1H)，2.20-2.07(m，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.20 (s, 1H), 8.63 (s, 3H), 7.81 (dt, J=7.5, 3.7Hz, 1H), 7.62-7.40 (m, 5H), 7.35-7.12 (m, 5H), 5.90 (dd, J=31.7, 9.6Hz, 2H), 5.38 (dd, J=13.4, 5.0Hz, 1H), 4.51 (dd, J=48.5, 17.6Hz, 2H) , 4.32 (s, 1H), 3.81 (s, 3H), 3.70 (s, 3H), 3.22-3.04 (m, 3H), 2.95-2.84 (m, 1H), 2.48-2.39 (m, 1H), 2.20 -2.07(m,1H).
实施例78：化合物147的制备
Example 78: Preparation of Compound 147
采用通用合成方法3制备，得盐酸盐为白色固体，收率67.67％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 67.67%.
1H NMR(400MHz，DMSO-d6)δ10.61(s，1H)，8.65(s，3H)，7.92-7.85(m，2H)，7.75(ddd，J＝16.5，8.8，5.0Hz，1H)，7.56(dt，J＝15.2，7.5Hz，2H)，7.11-7.00(m， 2H)，5.86(dd，J＝23.1，9.6Hz，2H)，5.38(dd，J＝13.4，5.0Hz，1H)，4.56-4.32(m，3H)，3.83(d，J＝6.1Hz，3H)，3.75(t，J＝7.4Hz，3H)，3.43(dd，J＝8.8，3.2Hz，1H)，3.15(ddd，J＝18.1，13.1，5.3Hz，1H)，2.89(s，1H)，2.73(s，1H)，2.47-2.34(m，1H)，2.18-2.06(m，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.61 (s, 1H), 8.65 (s, 3H), 7.92-7.85 (m, 2H), 7.75 (ddd, J=16.5, 8.8, 5.0Hz, 1H ), 7.56 (dt, J=15.2, 7.5Hz, 2H), 7.11-7.00 (m, 2H), 5.86 (dd, J=23.1, 9.6Hz, 2H), 5.38 (dd, J=13.4, 5.0Hz, 1H), 4.56-4.32 (m, 3H), 3.83 (d, J=6.1Hz, 3H ), 3.75 (t, J=7.4Hz, 3H), 3.43 (dd, J=8.8, 3.2Hz, 1H), 3.15 (ddd, J=18.1, 13.1, 5.3Hz, 1H), 2.89 (s, 1H) , 2.73(s, 1H), 2.47-2.34(m, 1H), 2.18-2.06(m, 1H).
实施例79：化合物的制备
Example 79: Preparation of Compounds
采用通用合成方法3制备，得盐酸盐为白色固体，收率72.46％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 72.46%.
1H NMR(600MHz，DMSO-d6)δ9.73(s，1H)，8.80(s，3H)，7.88(d，J＝8.8Hz，2H)，7.76(d，J＝5.0Hz，1H)，7.52(dd，J＝7.5，5.6Hz，2H)，7.06(d，J＝8.9Hz，2H)，5.86(dd，J＝33.1，9.6Hz，2H)，5.37(dd，J＝13.4，4.9Hz，1H)，4.61(tt，J＝37.9，19.1Hz，1H)，4.55-4.35(m，4H)，3.84(s，3H)，3.78(d，J＝4.0Hz，3H)，3.21-3.07(m，1H)，2.94-2.82(m，1H)，2.42(qd，J＝12.7，3.8Hz，1H)，2.13(dd，J＝17.2，12.0Hz，1H). 1 H NMR (600MHz, DMSO-d 6 ) δ9.73 (s, 1H), 8.80 (s, 3H), 7.88 (d, J = 8.8Hz, 2H), 7.76 (d, J = 5.0Hz, 1H) , 7.52 (dd, J=7.5, 5.6Hz, 2H), 7.06 (d, J=8.9Hz, 2H), 5.86 (dd, J=33.1, 9.6Hz, 2H), 5.37 (dd, J=13.4, 4.9 Hz, 1H), 4.61 (tt, J=37.9, 19.1Hz, 1H), 4.55-4.35 (m, 4H), 3.84 (s, 3H), 3.78 (d, J=4.0Hz, 3H), 3.21-3.07 (m, 1H), 2.94-2.82 (m, 1H), 2.42 (qd, J=12.7, 3.8Hz, 1H), 2.13 (dd, J=17.2, 12.0Hz, 1H).
实施例80：化合物149的制备
Example 80: Preparation of Compound 149
采用通用合成方法3制备，得盐酸盐为白色固体，收率57.13％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 57.13%.
1H NMR(600MHz，DMSO-d6)δ10.20(s，1H)，8.67(s，3H)，7.88(d，J＝8.8Hz，3H)，7.56-7.53(m，2H)，7.30(d，J＝8.4Hz，2H)，7.22(d，J＝8.4Hz，2H)，7.05(dd，J＝8.9，2.2Hz，3H)，5.89(t，J＝4.8Hz，1H)，5.83(dd，J＝9.6，3.2Hz，1H)，5.37(dd，J＝13.3，5.0Hz，1H)，4.57(d，J＝17.3Hz，1H)，4.46(t，J＝11.5Hz，1H)，4.31(s，1H)， 4.13(t，J＝6.3Hz，1H)，3.83(s，3H)，3.69(d，J＝6.5Hz，3H)，3.18-3.15(m，1H)，2.92-2.88(m，1H)，2.13(dd，J＝10.9，5.8Hz，1H). 1 H NMR (600MHz, DMSO-d 6 ) δ 10.20 (s, 1H), 8.67 (s, 3H), 7.88 (d, J = 8.8Hz, 3H), 7.56-7.53 (m, 2H), 7.30 ( d, J=8.4Hz, 2H), 7.22 (d, J=8.4Hz, 2H), 7.05 (dd, J=8.9, 2.2Hz, 3H), 5.89 (t, J=4.8Hz, 1H), 5.83 ( dd, J=9.6, 3.2Hz, 1H), 5.37 (dd, J=13.3, 5.0Hz, 1H), 4.57 (d, J=17.3Hz, 1H), 4.46 (t, J=11.5Hz, 1H), 4.31(s,1H), 4.13 (t, J=6.3Hz, 1H), 3.83 (s, 3H), 3.69 (d, J=6.5Hz, 3H), 3.18-3.15 (m, 1H), 2.92-2.88 (m, 1H), 2.13 (dd, J=10.9, 5.8Hz, 1H).
实施例81：化合物150的制备
Example 81: Preparation of Compound 150
采用通用合成方法3制备，得盐酸盐为白色固体，收率63.59％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 63.59%.
1H NMR(600MHz，DMSO-d6)δ10.20(s，1H)，8.67(s，3H)，7.88(d，J＝8.8Hz，3H)，7.56-7.53(m，2H)，7.30(d，J＝8.4Hz，2H)，7.22(d，J＝8.4Hz，2H)，7.05(dd，J＝8.9，2.2Hz，3H)，5.89(t，J＝4.8Hz，1H)，5.83(dd，J＝9.6，3.2Hz，1H)，5.37(dd，J＝13.3，5.0Hz，1H)，4.57(d，J＝17.3Hz，1H)，4.46(t，J＝11.5Hz，1H)，4.31(s，1H)，4.13(t，J＝6.3Hz，1H)，3.83(s，3H)，3.69(d，J＝6.5Hz，3H)，3.18-3.15(m，1H)，2.92-2.88(m，1H)，2.13(dd，J＝10.9，5.8Hz，1H). 1 H NMR (600MHz, DMSO-d 6 ) δ 10.20 (s, 1H), 8.67 (s, 3H), 7.88 (d, J = 8.8Hz, 3H), 7.56-7.53 (m, 2H), 7.30 ( d, J=8.4Hz, 2H), 7.22 (d, J=8.4Hz, 2H), 7.05 (dd, J=8.9, 2.2Hz, 3H), 5.89 (t, J=4.8Hz, 1H), 5.83 ( dd, J=9.6, 3.2Hz, 1H), 5.37 (dd, J=13.3, 5.0Hz, 1H), 4.57 (d, J=17.3Hz, 1H), 4.46 (t, J=11.5Hz, 1H), 4.31 (s, 1H), 4.13 (t, J=6.3Hz, 1H), 3.83 (s, 3H), 3.69 (d, J=6.5Hz, 3H), 3.18-3.15 (m, 1H), 2.92-2.88 (m, 1H), 2.13 (dd, J=10.9, 5.8Hz, 1H).
实施例82：化合物151的制备
Example 82: Preparation of Compound 151
采用通用合成方法3制备，得盐酸盐为白色固体，收率54.86％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 54.86%.
1H NMR(600MHz，DMSO-d6)δ9.77(s，1H)，8.91(s，3H)，7.76(d，J＝3.3Hz，1H)，7.61-7.39(m，2H)，5.71-5.52(m，2H)，5.32(td，J＝13.5，6.8Hz，1H)，4.62(dd，J＝13.2，5.5Hz，1H)，4.50-4.46(m，2H)，4.35(dt，J＝17.4，4.7Hz，1H)，3.78(s，3H)，3.49-3.39(m，1H)，2.93-2.79(m，2H)，2.42-2.32(m，1H)，2.18-2.07(m，1H)，1.91(s，1H)，1.20(tt，J＝14.3，4.9Hz，2H)，1.07-0.96(m，6H). 1 H NMR (600MHz, DMSO-d 6 ) δ9.77 (s, 1H), 8.91 (s, 3H), 7.76 (d, J=3.3Hz, 1H), 7.61-7.39 (m, 2H), 5.71- 5.52 (m, 2H), 5.32 (td, J=13.5, 6.8Hz, 1H), 4.62 (dd, J=13.2, 5.5Hz, 1H), 4.50-4.46 (m, 2H), 4.35 (dt, J= 17.4, 4.7Hz, 1H), 3.78 (s, 3H), 3.49-3.39 (m, 1H), 2.93-2.79 (m, 2H), 2.42-2.32 (m, 1H), 2.18-2.07 (m, 1H) , 1.91 (s, 1H), 1.20 (tt, J=14.3, 4.9Hz, 2H), 1.07-0.96 (m, 6H).
实施例83：化合物152的制备
Example 83: Preparation of Compound 152
采用通用合成方法3制备，得盐酸盐为白色固体，收率59.83％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 59.83%.
1H NMR(400MHz，DMSO-d6)δ10.21(s，1H)，8.67(s，3H)，7.81(s，1H)，7.56(s，2H)，7.26(dd，J＝38.8，8.1Hz，4H)，5.65(dd，J＝32.6，9.3Hz，2H)，5.34(dd，J＝13.3，4.6Hz，1H)，4.77(dt，J＝12.2，6.0Hz，1H)，4.48(dd，J＝50.0，17.6Hz，2H)，4.26(t，J＝6.3Hz，1H)，4.21-4.06(m，2H)，3.35(s，2H)，3.17(ddd，J＝26.7，13.7，5.9Hz，3H)，2.85(d，J＝16.7Hz，1H)，2.47-2.27(m，1H)，2.11(d，J＝5.5Hz，1H)，1.20(t，J＝9.8Hz，6H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.21 (s, 1H), 8.67 (s, 3H), 7.81 (s, 1H), 7.56 (s, 2H), 7.26 (dd, J=38.8, 8.1 Hz, 4H), 5.65 (dd, J=32.6, 9.3Hz, 2H), 5.34 (dd, J=13.3, 4.6Hz, 1H), 4.77 (dt, J=12.2, 6.0Hz, 1H), 4.48 (dd , J=50.0, 17.6Hz, 2H), 4.26 (t, J=6.3Hz, 1H), 4.21-4.06 (m, 2H), 3.35 (s, 2H), 3.17 (ddd, J=26.7, 13.7, 5.9 Hz, 3H), 2.85 (d, J=16.7Hz, 1H), 2.47-2.27 (m, 1H), 2.11 (d, J=5.5Hz, 1H), 1.20 (t, J=9.8Hz, 6H).
实施例84：化合物153的制备
Example 84: Preparation of Compound 153
采用通用合成方法3制备，得盐酸盐为白色固体，收率23.32％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 23.32%.
1H NMR(400MHz，DMSO-d6)δ10.20(s，1H)，8.63(s，3H)，7.81(dd，J＝5.5，3.2Hz，1H)，7.62-7.46(m，2H)，7.30(d，J＝8.5Hz，2H)，7.21(d，J＝8.5Hz，2H)，5.68-5.46(m，2H)，5.32(dd，J＝13.4，5.0Hz，1H)，4.48(dd，J＝51.3，17.6Hz，2H)，4.32(s，1H)，3.70(s，3H)，3.37(s，2H)，3.21-3.11(m，2H)，2.91-2.71(m，6H)，2.40(ddd，J＝17.9，13.5，4.8Hz，1H)，2.16-2.04(m，1H).1H NMR (400MHz, DMSO-d 6 ) δ10.20 (s, 1H), 8.63 (s, 3H), 7.81 (dd, J=5.5, 3.2Hz, 1H), 7.62-7.46 (m, 2H), 7.30 (d, J=8.5Hz, 2H), 7.21 (d, J=8.5Hz, 2H), 5.68-5.46 (m, 2H), 5.32 (dd, J=13.4, 5.0Hz, 1H), 4.48 (dd, J=51.3, 17.6Hz, 2H), 4.32 (s, 1H), 3.70 (s, 3H), 3.37 (s, 2H), 3.21-3.11 (m, 2H), 2.91-2.71 (m, 6H), 2.40 (ddd, J=17.9, 13.5, 4.8Hz, 1H), 2.16-2.04 (m, 1H).
实施例85：化合物154的制备
Example 85: Preparation of Compound 154
采用通用合成方法2制备，得盐酸盐为白色固体，得白色固体，收率70.84％。Prepared by general synthesis method 2, the hydrochloride salt is obtained as a white solid, with a yield of 70.84%.
1H NMR(400MHz，DMSO-d6)δ11.05(s，1H)，10.60(d，J＝7.5Hz，1H)，8.63(s，2H)，7.95(s，1H)，7.72(ddd，J＝11.6，7.6，1.2Hz，1H)，7.63-7.47(m，2H)，5.17(dd，J＝13.3，5.1Hz，1H)，4.38(qd，J＝17.7，8.3Hz，3H)，4.20(qd，J＝7.0，2.6Hz，2H)，3.50-3.38(m，2H)，2.89(s，3H)，2.73(s，2H)，1.24(t，J＝7.1Hz，3H). 1 H NMR (400MHz, DMSO-d 6 ) δ 11.05 (s, 1H), 10.60 (d, J=7.5Hz, 1H), 8.63 (s, 2H), 7.95 (s, 1H), 7.72 (ddd, J=11.6, 7.6, 1.2Hz, 1H), 7.63-7.47 (m, 2H), 5.17 (dd, J=13.3, 5.1Hz, 1H), 4.38 (qd, J=17.7, 8.3Hz, 3H), 4.20 (qd, J=7.0, 2.6Hz, 2H), 3.50-3.38 (m, 2H), 2.89 (s, 3H), 2.73 (s, 2H), 1.24 (t, J=7.1Hz, 3H).
实施例86化合物155的制备
Example 86 Preparation of Compound 155
采用通用合成方法3制备，得盐酸盐为白色固体，收率69.41％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 69.41%.
1H NMR(600MHz，DMSO-d6)δ10.65(s，1H)，8.74(s，3H)，7.94(d，J＝7.8Hz，2H)，7.76(dd，J＝12.6，7.8Hz，1H)，7.69(t，J＝7.4Hz，1H)，7.62-7.50(m，4H)，5.91(dd，J＝33.8，9.6Hz，2H)，5.39(dd，J＝13.4，5.0Hz，1H)，4.50(dd，J＝17.5，13.2Hz，1H)，4.38(dd，J＝17.5，8.0Hz，1H)，4.31(t，J＝5.0Hz，1H)，4.19(q，J＝7.0Hz，2H)，3.52-3.43(m，2H)，3.37(s，1H)，2.95-2.84(m，1H)，2.49-2.38(m，1H)，2.19-2.10(m，1H)，1.22(td，J＝7.1，2.5Hz，3H). 1 H NMR (600MHz, DMSO-d 6 ) δ 10.65 (s, 1H), 8.74 (s, 3H), 7.94 (d, J = 7.8Hz, 2H), 7.76 (dd, J = 12.6, 7.8Hz, 1H), 7.69 (t, J=7.4Hz, 1H), 7.62-7.50 (m, 4H), 5.91 (dd, J=33.8, 9.6Hz, 2H), 5.39 (dd, J=13.4, 5.0Hz, 1H ), 4.50 (dd, J=17.5, 13.2Hz, 1H), 4.38 (dd, J=17.5, 8.0Hz, 1H), 4.31 (t, J=5.0Hz, 1H), 4.19 (q, J=7.0Hz , 2H), 3.52-3.43(m, 2H), 3.37(s, 1H), 2.95-2.84(m, 1H), 2.49-2.38(m, 1H), 2.19-2.10(m, 1H), 1.22(td , J=7.1, 2.5Hz, 3H).
实施例87：化合物156的制备
Example 87: Preparation of Compound 156
采用通用合成方法2制备，得盐酸盐为白色固体，收率68.37％。Prepared by general synthesis method 2, the hydrochloride was obtained as a white solid with a yield of 68.37%.
1H NMR(400MHz，DMSO-d6)δ11.05(s，1H)，9.72(s，1H)，8.79(s，3H)，7.81-7.58(m，1H)，7.60-7.35(m，2H)，5.16(dd，J＝13.3，5.1Hz，1H)，4.70-4.55(m，1H)，4.55-4.17(m，5H)，3.01-2.88(m，1H)，2.62(d，J＝16.9Hz，1H)，2.31(qd，J＝13.2，4.3Hz，1H)，2.10-2.01(m，1H)，1.21(dt，J＝28.6，7.1Hz，3H). 1 H NMR (400MHz, DMSO-d 6 ) δ11.05 (s, 1H), 9.72 (s, 1H), 8.79 (s, 3H), 7.81-7.58 (m, 1H), 7.60-7.35 (m, 2H ), 5.16 (dd, J=13.3, 5.1Hz, 1H), 4.70-4.55 (m, 1H), 4.55-4.17 (m, 5H), 3.01-2.88 (m, 1H), 2.62 (d, J=16.9 Hz, 1H), 2.31 (qd, J=13.2, 4.3Hz, 1H), 2.10-2.01 (m, 1H), 1.21 (dt, J=28.6, 7.1Hz, 3H).
实施例88：化合物157的制备
Example 88: Preparation of Compound 157
采用通用合成方法3制备，得盐酸盐为白色固体，收率54.59％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 54.59%.
1H NMR(600MHz，DMSO-d6)δ9.74(s，1H)，8.83(s，3H)，7.94(d，J＝7.5Hz，2H)，7.76(s，1H)，7.69(t，J＝7.4Hz，1H)，7.58-7.41(m，4H)，5.91(dd，J＝35.1，9.6Hz，2H)，5.38(dd，J＝13.4，5.0Hz，1H)，4.67-4.57(m，1H)，4.56-4.34(m，4H)，4.22(q，J＝6.9Hz，2H)，3.21-3.09(m，1H)，2.90(d，J＝17.1Hz，1H)，2.42(tt，J＝24.3，12.1Hz，1H)，2.20-2.09(m，1H)，1.29-1.20(m，3H). 1 H NMR (600MHz, DMSO-d 6 ) δ9.74 (s, 1H), 8.83 (s, 3H), 7.94 (d, J=7.5Hz, 2H), 7.76 (s, 1H), 7.69 (t, J＝7.4Hz, 1H), 7.58-7.41(m, 4H), 5.91(dd, J＝35.1, 9.6Hz, 2H), 5.38(dd, J＝13.4, 5.0Hz, 1H), 4.67-4.57(m , 1H), 4.56-4.34 (m, 4H), 4.22 (q, J=6.9Hz, 2H), 3.21-3.09 (m, 1H), 2.90 (d, J=17.1Hz, 1H), 2.42 (tt, J=24.3, 12.1Hz, 1H), 2.20-2.09(m, 1H), 1.29-1.20(m, 3H).
实施例89：化合物158的制备
Example 89: Preparation of Compound 158
采用通用合成方法3制备，得盐酸盐为白色固体，收率43.68％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 43.68%.
1H NMR(600MHz，DMSO-d6)δ10.21(s，1H)，8.71(s，3H)，7.94(d，J＝7.4Hz，2H)，7.81(d，J＝6.2Hz，1H)，7.68(t，J＝7.4Hz，1H)，7.54(dd，J＝14.0，6.4Hz，4H)，7.32(d，J＝8.4Hz，2H)，7.21(d，J＝8.4Hz，2H)，5.91(dd，J＝39.5，9.6Hz，2H)，5.38(dd，J＝13.4，5.0Hz，1H)，4.58(d，J＝17.6Hz，1H)，4.46(d，J＝17.4Hz，1H)，4.25(t，J＝6.7Hz，1H)，4.12(qq，J＝10.9，7.1Hz，2H)，3.24(dd，J＝14.0，5.7Hz，1H)，3.20-3.05(m，2H)，2.95-2.86(m，1H)，2.49-2.39(m，1H)，2.20-2.11(m，1H)，1.11(t，J＝7.1Hz，3H). 1 H NMR (600MHz, DMSO-d 6 ) δ 10.21 (s, 1H), 8.71 (s, 3H), 7.94 (d, J = 7.4Hz, 2H), 7.81 (d, J = 6.2Hz, 1H) , 7.68 (t, J=7.4Hz, 1H), 7.54 (dd, J=14.0, 6.4Hz, 4H), 7.32 (d, J=8.4Hz, 2H), 7.21 (d, J=8.4Hz, 2H) , 5.91 (dd, J=39.5, 9.6Hz, 2H), 5.38 (dd, J=13.4, 5.0Hz, 1H), 4.58 (d, J=17.6Hz, 1H), 4.46 (d, J=17.4Hz, 1H), 4.25 (t, J=6.7Hz, 1H), 4.12 (qq, J=10.9, 7.1Hz, 2H), 3.24 (dd, J=14.0, 5.7Hz, 1H), 3.20-3.05 (m, 2H ), 2.95-2.86 (m, 1H), 2.49-2.39 (m, 1H), 2.20-2.11 (m, 1H), 1.11 (t, J=7.1Hz, 3H).
实施例90：化合物159的制备
Example 90: Preparation of Compound 159
采用通用合成方法2制备，得盐酸盐为白色固体，收率57.53％。Prepared by general synthesis method 2, the hydrochloride was obtained as a white solid with a yield of 57.53%.
1H NMR(600MHz，DMSO-d6)δ11.03(s，1H)，10.18(s，1H)，8.66(s，3H)，7.86-7.75(m，1H)，7.53(dd，J＝7.1，5.8Hz，2H)，7.31(d，J＝8.4Hz，2H)，7.22(d，J＝8.4Hz，2H)，5.15(dd，J＝13.3，5.1Hz，1H)，4.47(dd，J＝58.0，17.6Hz，2H)，4.27(s，1H)，4.19-4.05(m，2H)，3.21(dd，J＝14.1，5.9Hz，1H)，3.09(dd，J＝12.6，6.2Hz，1H)，2.98-2.89(m，1H)，2.62(d，J＝17.0Hz，1H)，2.37(qd，J＝13.2，4.3Hz，1H)，2.05(dd，J＝21.8，16.3Hz，1H)，1.12(t，J＝7.1Hz，3H). 1 H NMR (600MHz, DMSO-d 6 ) δ11.03 (s, 1H), 10.18 (s, 1H), 8.66 (s, 3H), 7.86-7.75 (m, 1H), 7.53 (dd, J=7.1 , 5.8Hz, 2H), 7.31 (d, J=8.4Hz, 2H), 7.22 (d, J=8.4Hz, 2H), 5.15 (dd, J=13.3, 5.1Hz, 1H), 4.47 (dd, J =58.0, 17.6Hz, 2H), 4.27 (s, 1H), 4.19-4.05 (m, 2H), 3.21 (dd, J = 14.1, 5.9Hz, 1H), 3.09 (dd, J = 12.6, 6.2Hz, 1H), 2.98-2.89 (m, 1H), 2.62 (d, J=17.0Hz, 1H), 2.37 (qd, J=13.2, 4.3Hz, 1H), 2.05 (dd, J=21.8, 16.3Hz, 1H ), 1.12 (t, J=7.1Hz, 3H).
实施例91：化合物163的制备
Example 91: Preparation of Compound 163
采用通用合成方法3制备，得白色固体产物，收率49.26％。Prepared by general synthesis method 3, a white solid product was obtained with a yield of 49.26%.
1H NMR(400MHz，DMSO-d6)δ10.19(s，1H)，7.80(dt，J＝7.7，3.8Hz，1H)，7.55(dd，J＝6.4，2.9Hz，1H)，7.31(d，J＝8.5Hz，1H)，7.15(d，J＝8.5Hz，1H)，5.63(dd，J＝20.8，9.6Hz，1H)，5.33(dd，J＝13.4，5.0Hz，1H)，4.47(dd，J＝59.3，17.6Hz，1H)，3.42(dd，J＝7.7，4.7Hz，1H)，3.16-3.07(m，1H)，2.93-2.81(m，1H)，2.42-2.33(m，1H)，2.12(dd，J＝14.2，8.9Hz，1H)，1.10(s，4H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.19 (s, 1H), 7.80 (dt, J=7.7, 3.8Hz, 1H), 7.55 (dd, J=6.4, 2.9Hz, 1H), 7.31 ( d, J＝8.5Hz, 1H), 7.15 (d, J＝8.5Hz, 1H), 5.63 (dd, J＝20.8, 9.6Hz, 1H), 5.33 (dd, J＝13.4, 5.0Hz, 1H), 4.47 (dd, J=59.3, 17.6Hz, 1H), 3.42 (dd, J=7.7, 4.7Hz, 1H), 3.16-3.07 (m, 1H), 2.93-2.81 (m, 1H), 2.42-2.33 ( m, 1H), 2.12 (dd, J=14.2, 8.9Hz, 1H), 1.10 (s, 4H).
实施例92：化合物164的制备
Example 92: Preparation of Compound 164
采用通用合成方法3制备，得游离态产物为白色固体，收率42.11％。Prepared by general synthesis method 3, the free product was obtained as a white solid with a yield of 42.11%.
1H NMR(400MHz，DMSO-d6)δ10.45(s，1H)，8.88(s，1H)，8.16-8.01(m，1H)，8.02-7.84(m，2H)，7.81-7.63(m，2H)，7.63-7.44(m，3H)，7.46-7.30(m，1H)，6.02-5.81(m，2H)，5.36(dt，J＝16.8，8.3Hz，1H)，4.59-4.27(m，2H)，3.57-3.23(m，4H)，3.25-3.04(m，2H)，2.98-2.82(m，1H)，2.41(dd，J＝29.9，20.1Hz，1H)，2.22-2.05(m，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.45 (s, 1H), 8.88 (s, 1H), 8.16-8.01 (m, 1H), 8.02-7.84 (m, 2H), 7.81-7.63 (m , 2H), 7.63-7.44(m, 3H), 7.46-7.30(m, 1H), 6.02-5.81(m, 2H), 5.36(dt, J=16.8, 8.3Hz, 1H), 4.59-4.27(m , 2H), 3.57-3.23(m, 4H), 3.25-3.04(m, 2H), 2.98-2.82(m, 1H), 2.41(dd, J=29.9, 20.1Hz, 1H), 2.22-2.05(m ,1H).
实施例93：化合物165的制备
Example 93: Preparation of Compound 165
采用通用合成方法2制备，得到游离态产物为白色固体，收率67.68％。Prepared by general synthesis method 2, the free product was obtained as a white solid with a yield of 67.68%.
1H NMR(400MHz，DMSO-d6)δ11.05(s，1H)，10.21(s，1H)，7.79(dd，J＝8.5，4.1Hz，2H)，7.67-7.42(m，3H)，7.40-7.23(m，2H)，7.23-6.99(m，2H)，5.15(dd，J＝13.3，5.1Hz，1H)，4.47(dd，J＝41.5，17.7Hz，2H)，3.46(dd，J＝7.5，4.8Hz，2H)，3.13(dt，J＝34.8，17.5Hz，1H)，3.05-2.85(m，2H)，2.74-2.60(m，1H)，2.49-2.30(m，1H)，2.15-2.00(m，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ11.05 (s, 1H), 10.21 (s, 1H), 7.79 (dd, J=8.5, 4.1Hz, 2H), 7.67-7.42 (m, 3H), 7.40-7.23 (m, 2H), 7.23-6.99 (m, 2H), 5.15 (dd, J=13.3, 5.1Hz, 1H), 4.47 (dd, J=41.5, 17.7Hz, 2H), 3.46 (dd, J=7.5, 4.8Hz, 2H), 3.13 (dt, J=34.8, 17.5Hz, 1H), 3.05-2.85 (m, 2H), 2.74-2.60 (m, 1H), 2.49-2.30 (m, 1H) ,2.15-2.00(m,1H).
实施例94：化合物166的制备
Example 94: Preparation of Compound 166
采用通用合成方法2制备，得游离态产物为白色固体，收率49.71％。 Prepared by general synthesis method 2, the free product was obtained as a white solid with a yield of 49.71%.
1H NMR(400MHz，DMSO-d6)δ11.02(s，1H)，9.61(s，1H)，7.73(s，1H)，7.55-7.44(m，2H)，5.13(dd，J＝13.2，5.1Hz，1H)，4.52-4.29(m，2H)，4.27-4.14(m，2H)，3.70-3.62(m，3H)，3.00-2.85(m，1H)，2.60(dd，J＝35.8，18.4Hz，2H)，2.35(qd，J＝13.4，4.5Hz，1H)，2.10-1.90(m，3H). 1 H NMR (400MHz, DMSO-d 6 ) δ11.02 (s, 1H), 9.61 (s, 1H), 7.73 (s, 1H), 7.55-7.44 (m, 2H), 5.13 (dd, J=13.2 , 5.1Hz, 1H), 4.52-4.29 (m, 2H), 4.27-4.14 (m, 2H), 3.70-3.62 (m, 3H), 3.00-2.85 (m, 1H), 2.60 (dd, J=35.8 , 18.4Hz, 2H), 2.35 (qd, J=13.4, 4.5Hz, 1H), 2.10-1.90 (m, 3H).
实施例95：化合物167的制备
Example 95: Preparation of Compound 167
具体合成过程如下：The specific synthesis process is as follows:
将Boc-L-谷氨酸(5g)、EDCI(15.51g)、HOBt(10.93g)、TEA(14.05mL)分散在干燥二氯甲烷(100mL)中，室温搅拌下滴加苄氧胺(2.59mL，22.24mmol)的二氯甲烷溶液，室温搅拌3天，加入二氯甲烷，依次用1MHCl洗，饱和碳酸氢钠洗，饱和食盐水洗，合并有机相，无水Na2SO4干燥，减压旋蒸至剩余少量溶剂，室温析晶，过滤。得到3.27g白色固体产物。Disperse Boc-L-glutamic acid (5g), EDCI (15.51g), HOBt (10.93g), and TEA (14.05mL) in dry dichloromethane (100mL), and add benzyloxyamine (2.59) dropwise with stirring at room temperature. mL, 22.24 mmol) of dichloromethane solution, stirred at room temperature for 3 days, added dichloromethane, washed with 1M HCl, saturated sodium bicarbonate, saturated brine, combined organic phases, dried over anhydrous Na2SO4, and evaporated under reduced pressure to A small amount of solvent remains, crystallize at room temperature, and filter. 3.27 g of white solid product were obtained.
将上述产物(4.76g)溶于二氯甲烷(145mL)中，低温下加入三氟乙酸(29mL)，室温搅拌4h，减压旋蒸除去溶剂，得到淡粉色固体产物，直接用于一步。The above product (4.76g) was dissolved in dichloromethane (145mL), trifluoroacetic acid (29mL) was added at low temperature, stirred at room temperature for 4h, and the solvent was evaporated under reduced pressure to obtain a light pink solid product, which was used directly in the first step.
将上述产物(3.98g)和2-溴甲基-3-硝基苯甲酸甲酯(5g)分散在乙腈(75ml)中，低温下加入三乙胺(6ml)，室温搅拌过夜，析出固体，过滤，干燥，得4.9g产物。Disperse the above product (3.98g) and methyl 2-bromomethyl-3-nitrobenzoate (5g) in acetonitrile (75ml). Add triethylamine (6ml) at low temperature and stir at room temperature overnight to precipitate a solid. Filter and dry to obtain 4.9g of product.
将上述产物(500mg)置于10mL甲苯，10mL水的混合溶液中，加入铁粉(284mg)，醋酸铵(390mg)，100℃反应3h，加入乙酸乙酯，依次用水洗，饱和食盐水洗，无水硫酸钠干燥，减压除去溶剂，残留物经硅胶柱层析得产物128mg。Place the above product (500mg) into a mixed solution of 10mL toluene and 10mL water, add iron powder (284mg) and ammonium acetate (390mg), react at 100°C for 3 hours, add ethyl acetate, wash with water and saturated brine in sequence, no Dry over sodium sulfate, remove the solvent under reduced pressure, and subject the residue to silica gel column chromatography to obtain 128 mg of the product.
将上述产物(120mg)、对硝基苯基氯甲酸酯(100mg)溶于四氢呋喃中，在回流条件下搅拌2h。减压浓缩，加入乙酸乙酯搅拌均匀得到混悬液，减压过滤并乙酸乙酯洗涤或直接旋干，得到残留物直接用于下一步。The above product (120 mg) and p-nitrophenyl chloroformate (100 mg) were dissolved in tetrahydrofuran and stirred under reflux conditions for 2 h. Concentrate under reduced pressure, add ethyl acetate and stir evenly to obtain a suspension, filter under reduced pressure and wash with ethyl acetate or spin dry directly, and the residue obtained can be used directly in the next step.
将上述残留物和化合物Boc-L-半胱氨酸(73mg)溶于DMF中，在常温搅拌下滴加DIPEA(85mg)，继续室温搅拌至原料消失，加入酸水调节PH至3-4，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(石油醚∶乙酸乙酯＝1∶2)进行纯化，得130mg泡沫状固体。Dissolve the above residue and the compound Boc-L-cysteine (73 mg) in DMF, add DIPEA (85 mg) dropwise under stirring at room temperature, continue stirring at room temperature until the raw materials disappear, add acid water to adjust the pH to 3-4, Add ethyl acetate, and then wash the organic phase with saturated aqueous ammonium chloride solution, water, and saturated aqueous sodium chloride solution. The organic phase was collected and dried over anhydrous sodium sulfate, filtered and the filtrate obtained was evaporated to dryness under reduced pressure, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:2) to obtain 130 mg of foamy solid.
将上述产物分散在乙酸乙酯中，然后通入氯化氢气体，室温反应，析出固体，待反应完成后，过滤，用乙酸乙酯，正庚烷洗，50℃烘干，得到盐酸盐为白色固体，收率75.32％。Disperse the above product in ethyl acetate, then pass in hydrogen chloride gas, react at room temperature, and precipitate a solid. After the reaction is completed, filter, wash with ethyl acetate and n-heptane, and dry at 50°C to obtain the hydrochloride salt, which is white. Solid, yield 75.32%.
1H NMR(600MHz，DMSO-d6)δ7.96-7.90(m，2H)，7.76(dd，J＝12.6，7.9Hz，1H)，7.69(t，J＝7.4Hz，1H)，7.61-7.50(m，4H)，5.53(d，J＝9.6Hz，1H)，5.48(d，J＝9.7Hz，1H)，5.38(ddd，J＝13.5，4.8，3.3Hz，1H)，4.49(dd，J＝17.5，12.5Hz，1H)，4.38(dd，J＝17.5，11.2Hz，1H)，4.17-4.07(m，1H)，3.50-3.43(m，1H)，3.41-3.36(m，1H)，3.20-3.12(m，1H)，2.88(d，J＝17.6Hz，1H)，2.48-2.39(m，1H)，2.16-2.06(m，1H). 1 H NMR (600MHz, DMSO-d 6 ) δ7.96-7.90 (m, 2H), 7.76 (dd, J=12.6, 7.9Hz, 1H), 7.69 (t, J=7.4Hz, 1H), 7.61- 7.50 (m, 4H), 5.53 (d, J=9.6Hz, 1H), 5.48 (d, J=9.7Hz, 1H), 5.38 (ddd, J=13.5, 4.8, 3.3Hz, 1H), 4.49 (dd , J=17.5, 12.5Hz, 1H), 4.38 (dd, J=17.5, 11.2Hz, 1H), 4.17-4.07 (m, 1H), 3.50-3.43 (m, 1H), 3.41-3.36 (m, 1H) ), 3.20-3.12(m, 1H), 2.88(d, J=17.6Hz, 1H), 2.48-2.39(m, 1H), 2.16-2.06(m, 1H).
实施例96：化合物168的制备
Example 96: Preparation of Compound 168
将实施例95产物分散在甲醇中，然后加入钯碳，在氢气环境下室温反应，，待反应完成后，过滤掉钯碳，将反应液滴加到叔丁基甲基醚中，析出固体，得到盐酸盐产物为白色固体，收率55.31％。Disperse the product of Example 95 in methanol, then add palladium carbon, and react at room temperature in a hydrogen environment. After the reaction is completed, filter out the palladium carbon, add the reaction liquid dropwise to tert-butyl methyl ether, and precipitate a solid to obtain a salt. The acid acid product was a white solid with a yield of 55.31%.
1H NMR(600MHz，DMSO-d6)δ10.12(s，1H)，8.38(s，2H)，7.73(dd，J＝12.9，7.8Hz，1H)，7.57-7.51(m，2H)，5.15(dd，J＝13.3，3.4Hz，1H)，4.47-4.31(m，2H)，4.13(s，1H)，3.47(dd，J＝14.6，5.0Hz，1H)，3.36(dd，J＝14.8，6.3Hz，1H)，2.97-2.86(m，1H)，2.64-2.59(m，1H)，2.37-2.29(m，1H)，2.04(dd，J＝9.0，3.7Hz，1H). 1 H NMR (600MHz, DMSO-d 6 ) δ10.12 (s, 1H), 8.38 (s, 2H), 7.73 (dd, J=12.9, 7.8Hz, 1H), 7.57-7.51 (m, 2H), 5.15 (dd, J=13.3, 3.4Hz, 1H), 4.47-4.31 (m, 2H), 4.13 (s, 1H), 3.47 (dd, J=14.6, 5.0Hz, 1H), 3.36 (dd, J= 14.8, 6.3Hz, 1H), 2.97-2.86 (m, 1H), 2.64-2.59 (m, 1H), 2.37-2.29 (m, 1H), 2.04 (dd, J=9.0, 3.7Hz, 1H).
实施例97：化合物169的制备
Example 97: Preparation of Compound 169
采用通用合成方法3制备，得盐酸盐为白色固体，收率45.71％。 Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 45.71%.
1H NMR(400MHz，DMSO-d6)δ10.20(s，1H)，8.40(s，2H)，7.86-7.74(m，1H)，7.54(dd，J＝7.4，5.6Hz，2H)，7.33(d，J＝8.5Hz，2H)，7.21(d，J＝8.5Hz，2H)，5.63(dd，J＝26.0，9.6Hz，2H)，5.32(dd，J＝13.4，4.9Hz，1H)，4.48(dd，J＝53.5，17.6Hz，2H)，4.14(dd，J＝28.3，22.2Hz，1H)，3.21-3.05(m，3H)，2.84(d，J＝17.2Hz，1H)，2.46-2.33(m，1H)，2.27(t，J＝7.3Hz，2H)，2.17-2.05(m，1H)，1.47(d，J＝6.6Hz，2H)，1.32-1.12(m，20H)，0.85(t，J＝6.8Hz，3H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.20 (s, 1H), 8.40 (s, 2H), 7.86-7.74 (m, 1H), 7.54 (dd, J=7.4, 5.6Hz, 2H), 7.33 (d, J=8.5Hz, 2H), 7.21 (d, J=8.5Hz, 2H), 5.63 (dd, J=26.0, 9.6Hz, 2H), 5.32 (dd, J=13.4, 4.9Hz, 1H ), 4.48 (dd, J=53.5, 17.6Hz, 2H), 4.14 (dd, J=28.3, 22.2Hz, 1H), 3.21-3.05 (m, 3H), 2.84 (d, J=17.2Hz, 1H) , 2.46-2.33 (m, 1H), 2.27 (t, J=7.3Hz, 2H), 2.17-2.05 (m, 1H), 1.47 (d, J=6.6Hz, 2H), 1.32-1.12 (m, 20H ), 0.85 (t, J=6.8Hz, 3H).
实施例98：化合物170的制备
Example 98: Preparation of Compound 170
采用通用合成方法3制备，用浓硫酸条件脱保护，得到硫酸盐为白色固体，收率40.38％。It was prepared by general synthesis method 3 and deprotected with concentrated sulfuric acid to obtain the sulfate as a white solid with a yield of 40.38%.
1H NMR(400MHz，DMSO-d6)δ10.18(s，1H)，8.17(s，1H)，7.80(dd，J＝5.9，3.0Hz，1H)，7.54(dd，J＝8.3，5.2Hz，1H)，7.31(d，J＝8.5Hz，1H)，7.21(d，J＝8.5Hz，1H)，5.63(dd，J＝20.5，9.6Hz，1H)，5.34(dd，J＝13.3，5.0Hz，1H)，4.46(dd，J＝58.1，17.6Hz，1H)，4.07(s，1H)，3.16-3.02(m，2H)，2.85(d，J＝16.4Hz，1H)，2.45-2.31(m，1H)，2.18-2.05(m，1H)，1.11(s，9H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.18 (s, 1H), 8.17 (s, 1H), 7.80 (dd, J=5.9, 3.0Hz, 1H), 7.54 (dd, J=8.3, 5.2 Hz, 1H), 7.31 (d, J=8.5Hz, 1H), 7.21 (d, J=8.5Hz, 1H), 5.63 (dd, J=20.5, 9.6Hz, 1H), 5.34 (dd, J=13.3 , 5.0Hz, 1H), 4.46 (dd, J=58.1, 17.6Hz, 1H), 4.07 (s, 1H), 3.16-3.02 (m, 2H), 2.85 (d, J=16.4Hz, 1H), 2.45 -2.31(m, 1H), 2.18-2.05(m, 1H), 1.11(s, 9H).
实施例99：化合物171的制备
Example 99: Preparation of Compound 171
采用通用合成方法3制备，用浓硝酸条件脱保护，得到硝酸盐为白色固体，收率57.74％。It was prepared by general synthesis method 3 and deprotected with concentrated nitric acid to obtain the nitrate as a white solid with a yield of 57.74%.
1H NMR(400MHz，DMSO-d6)δ10.18(s，1H)，8.17(s，1H)，7.80(dd，J＝5.9，3.0Hz，1H)，7.54(dd，J＝8.3，5.2Hz，1H)，7.31(d，J＝8.5Hz，1H)，7.21(d，J＝8.5 Hz，1H)，5.63(dd，J＝20.5，9.6Hz，1H)，5.34(dd，J＝13.3，5.0Hz，1H)，4.46(dd，J＝58.1，17.6Hz，1H)，4.07(s，1H)，3.16-3.02(m，2H)，2.85(d，J＝16.4Hz，1H)，2.45-2.31(m，1H)，2.18-2.05(m，1H)，1.11(s，9H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.18 (s, 1H), 8.17 (s, 1H), 7.80 (dd, J=5.9, 3.0Hz, 1H), 7.54 (dd, J=8.3, 5.2 Hz, 1H), 7.31 (d, J=8.5Hz, 1H), 7.21 (d, J=8.5 Hz, 1H), 5.63 (dd, J=20.5, 9.6Hz, 1H), 5.34 (dd, J=13.3, 5.0Hz, 1H), 4.46 (dd, J=58.1, 17.6Hz, 1H), 4.07 (s , 1H), 3.16-3.02 (m, 2H), 2.85 (d, J=16.4Hz, 1H), 2.45-2.31 (m, 1H), 2.18-2.05 (m, 1H), 1.11 (s, 9H).
实施例100：化合物172的制备
Example 100: Preparation of Compound 172
采用通用合成方法3制备，用浓硫酸条件脱保护，得到硫酸盐为白色固体，收率53.69％。It was prepared by general synthesis method 3 and deprotected with concentrated sulfuric acid to obtain the sulfate as a white solid with a yield of 53.69%.
1H NMR(400MHz，DMSO-d6)δ10.51(s，1H)，8.34(s，1H)，7.98-7.90(m，1H)，7.80-7.66(m，1H)，7.64-7.49(m，2H)，5.91(dd，J＝24.2，9.8Hz，1H)，5.44-5.36(m，1H)，4.42(ddd，J＝25.9，17.6，9.2Hz，1H)，4.26(s，1H)，3.51-3.33(m，2H)，3.16-3.11(m，1H)，2.88(d，J＝17.1Hz，1H)，2.48-2.40(m，1H)，2.17-2.09(m，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.51 (s, 1H), 8.34 (s, 1H), 7.98-7.90 (m, 1H), 7.80-7.66 (m, 1H), 7.64-7.49 (m , 2H), 5.91 (dd, J=24.2, 9.8Hz, 1H), 5.44-5.36 (m, 1H), 4.42 (ddd, J=25.9, 17.6, 9.2Hz, 1H), 4.26 (s, 1H), 3.51-3.33 (m, 2H), 3.16-3.11 (m, 1H), 2.88 (d, J=17.1Hz, 1H), 2.48-2.40 (m, 1H), 2.17-2.09 (m, 1H).
实施例101：化合物173的制备
Example 101: Preparation of Compound 173
采用通用合成方法3制备，用浓硝酸条件脱保护，得到硝酸盐为白色固体，收率47.46％。It was prepared by general synthesis method 3 and deprotected with concentrated nitric acid to obtain the nitrate as a white solid with a yield of 47.46%.
1H NMR(400MHz，DMSO-d6)δ10.51(s，1H)，8.33(s，1H)，7.97-7.91(m，1H)，7.82-7.73(m，1H)，7.69(t，J＝7.4Hz，1H)，7.56(dt，J＝13.9，7.5Hz，2H)，5.91(dd，J＝24.3，9.7Hz，1H)，5.45-5.35(m，1H)，4.42(ddd，J＝25.8，17.6，9.0Hz，1H)，4.22(s，1H)，3.50-3.37(m，1H)，3.21-3.11(m，1H)，2.88(d，J＝17.5Hz，1H)，2.47-2.39(m，1H)，2.18-2.09(m，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.51 (s, 1H), 8.33 (s, 1H), 7.97-7.91 (m, 1H), 7.82-7.73 (m, 1H), 7.69 (t, J =7.4Hz, 1H), 7.56 (dt, J=13.9, 7.5Hz, 2H), 5.91 (dd, J=24.3, 9.7Hz, 1H), 5.45-5.35 (m, 1H), 4.42 (ddd, J= 25.8, 17.6, 9.0Hz, 1H), 4.22 (s, 1H), 3.50-3.37 (m, 1H), 3.21-3.11 (m, 1H), 2.88 (d, J=17.5Hz, 1H), 2.47-2.39 (m, 1H), 2.18-2.09 (m, 1H).
实施例102：化合物174的制备
Example 102: Preparation of Compound 174
采用通用合成方法3制备，得盐酸盐为白色固体，收率60.36％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 60.36%.
1H NMR(400MHz，DMSO-d6)δ10.58(s，1H)，8.44(s，3H)，7.87-7.70(m，1H)，7.65-7.43(m，2H)，5.63(dd，J＝29.7，9.6Hz，2H)，5.32(dd，J＝13.2，3.8Hz，1H)，4.40(ddd，J＝22.9，17.6，6.4Hz，2H)，4.19(s，1H)，3.47(dd，J＝14.6，5.1Hz，1H)，3.42-3.37(m，2H)，3.20-3.06(m，1H)，2.84(d，J＝17.0Hz，1H)，2.46-2.35(m，1H)，2.27(t，J＝7.3Hz，2H)，2.14-2.03(m，1H)，1.47(d，J＝6.9Hz，2H)，1.22(s，20H)，0.85(t，J＝6.8Hz，3H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.58 (s, 1H), 8.44 (s, 3H), 7.87-7.70 (m, 1H), 7.65-7.43 (m, 2H), 5.63 (dd, J =29.7, 9.6Hz, 2H), 5.32 (dd, J = 13.2, 3.8Hz, 1H), 4.40 (ddd, J = 22.9, 17.6, 6.4Hz, 2H), 4.19 (s, 1H), 3.47 (dd, J=14.6, 5.1Hz, 1H), 3.42-3.37 (m, 2H), 3.20-3.06 (m, 1H), 2.84 (d, J=17.0Hz, 1H), 2.46-2.35 (m, 1H), 2.27 (t, J=7.3Hz, 2H), 2.14-2.03 (m, 1H), 1.47 (d, J=6.9Hz, 2H), 1.22 (s, 20H), 0.85 (t, J=6.8Hz, 3H) .
实施例103：化合物175的制备
Example 103: Preparation of Compound 175
采用通用合成方法3制备，得盐酸盐为白色固体，收率62.47％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 62.47%.
1H NMR(400MHz，DMSO-d6)δ9.70(s，1H)，8.54(s，3H)，7.76(dd，J＝9.9，5.1Hz，1H)，7.58-7.47(m，2H)，5.63(dd，J＝27.4，9.6Hz，2H)，5.31(dd，J＝13.4，2.9Hz，1H)，4.63(dt，J＝11.9，3.4Hz，1H)，4.55-4.26(m，4H)，3.20-3.05(m，1H)，2.84(d，J＝16.8Hz，1H)，2.43-2.30(m，1H)，2.27(t，J＝7.3Hz，2H)，2.16-2.05(m，1H)，1.47(d，J＝6.6Hz，2H)，1.33-1.11(m，20H)，0.85(t，J＝6.8Hz，3H). 1 H NMR (400MHz, DMSO-d 6 ) δ9.70 (s, 1H), 8.54 (s, 3H), 7.76 (dd, J=9.9, 5.1Hz, 1H), 7.58-7.47 (m, 2H), 5.63 (dd, J=27.4, 9.6Hz, 2H), 5.31 (dd, J=13.4, 2.9Hz, 1H), 4.63 (dt, J=11.9, 3.4Hz, 1H), 4.55-4.26 (m, 4H) , 3.20-3.05 (m, 1H), 2.84 (d, J=16.8Hz, 1H), 2.43-2.30 (m, 1H), 2.27 (t, J=7.3Hz, 2H), 2.16-2.05 (m, 1H ), 1.47 (d, J=6.6Hz, 2H), 1.33-1.11 (m, 20H), 0.85 (t, J=6.8Hz, 3H).
实施例104：化合物176的制备

Example 104: Preparation of Compound 176

采用通用合成方法3制备，得盐酸盐为白色固体，收率64.32％。Prepared by general synthesis method 3, the hydrochloride was obtained as a white solid with a yield of 64.32%.
1H NMR(400MHz，DMSO-d6)δ13.88(s，1H)，10.21(s，1H)，8.47(s，3H)，7.80(dt，J＝7.4，3.7Hz，1H)，7.63-7.51(m，2H)，7.34(d，J＝8.5Hz，2H)，7.21(d，J＝8.5Hz，2H)，5.63(dd，J＝20.5，9.6Hz，2H)，5.34(dd，J＝13.4，5.0Hz，1H)，4.47(dd，J＝60.4，17.6Hz，2H)，4.20(s，1H)，3.20-3.07(m，3H)，2.93-2.79(m，1H)，2.39(m，1H)，2.19-2.06(m，1H)，1.11(s，9H). 1 H NMR (400MHz, DMSO-d 6 ) δ 13.88 (s, 1H), 10.21 (s, 1H), 8.47 (s, 3H), 7.80 (dt, J=7.4, 3.7Hz, 1H), 7.63- 7.51 (m, 2H), 7.34 (d, J=8.5Hz, 2H), 7.21 (d, J=8.5Hz, 2H), 5.63 (dd, J=20.5, 9.6Hz, 2H), 5.34 (dd, J =13.4, 5.0Hz, 1H), 4.47(dd, J=60.4, 17.6Hz, 2H), 4.20(s, 1H), 3.20-3.07(m, 3H), 2.93-2.79(m, 1H), 2.39( m, 1H), 2.19-2.06 (m, 1H), 1.11 (s, 9H).
实施例105：化合物177的制备
Example 105: Preparation of Compound 177
采用通用合成方法3制备，得白色固体，收率67.21％。Prepared by general synthesis method 3, a white solid was obtained with a yield of 67.21%.
1H NMR(400MHz，DMSO-d6)δ12.72(s，1H)，10.16(s，1H)，8.24(d，J＝8.1Hz，1H)，7.78(dt，J＝7.5，3.8Hz，1H)，7.58-7.52(m，2H)，7.28(d，J＝8.5Hz，2H)，7.15(d，J＝8.5Hz，2H)，5.63(dd，J＝20.3，9.6Hz，2H)，5.33(dd，J＝13.4，5.0Hz，1H)，4.58-4.34(m，3H)，3.17-3.02(m，2H)，2.90-2.81(m，2H)，2.45-2.33(m，1H)，2.11(dd，J＝14.6，9.4Hz，1H)，1.79(d，J＝7.2Hz，3H)，1.10(s，9H). 1 H NMR (400MHz, DMSO-d 6 ) δ 12.72 (s, 1H), 10.16 (s, 1H), 8.24 (d, J = 8.1Hz, 1H), 7.78 (dt, J = 7.5, 3.8Hz, 1H), 7.58-7.52 (m, 2H), 7.28 (d, J=8.5Hz, 2H), 7.15 (d, J=8.5Hz, 2H), 5.63 (dd, J=20.3, 9.6Hz, 2H), 5.33(dd, J=13.4, 5.0Hz, 1H), 4.58-4.34(m, 3H), 3.17-3.02(m, 2H), 2.90-2.81(m, 2H), 2.45-2.33(m, 1H), 2.11 (dd, J=14.6, 9.4Hz, 1H), 1.79 (d, J=7.2Hz, 3H), 1.10 (s, 9H).
实施例106：化合物184的制备
Example 106: Preparation of Compound 184
采用通用合成方法3制备，得白色固体，收率67.3％。 Prepared by general synthesis method 3, a white solid was obtained with a yield of 67.3%.
1H NMR(400MHz，DMSO)δ10.20(s，1H)，8.48(s，3H)，7.81(dd，J＝5.8，3.0Hz，1H)，7.61-7.50(m，2H)，7.33(d，J＝8.5Hz，2H)，7.21(d，J＝8.5Hz，2H)，5.63(dd，J＝20.3，9.6Hz，2H)，5.34(dd，J＝13.4，5.0Hz，1H)，4.93(t，J＝5.6Hz，1H)，4.54(d，J＝17.6Hz，1H)，4.37(dd，J＝21.4，12.0Hz，2H)，4.14(t，J＝4.9Hz，2H)，3.61-3.52(m，2H)，3.19-3.12(m，2H)，2.85(d，J＝16.5Hz，1H)，2.39(dd，J＝13.2，4.4Hz，1H)，2.16-2.07(m，1H)，1.20-1.02(m，9H)，0.85(dt，J＝9.3，5.8Hz，1H). 1 H NMR (400MHz, DMSO) δ10.20 (s, 1H), 8.48 (s, 3H), 7.81 (dd, J=5.8, 3.0Hz, 1H), 7.61-7.50 (m, 2H), 7.33 (d , J=8.5Hz, 2H), 7.21 (d, J=8.5Hz, 2H), 5.63 (dd, J=20.3, 9.6Hz, 2H), 5.34 (dd, J=13.4, 5.0Hz, 1H), 4.93 (t, J=5.6Hz, 1H), 4.54 (d, J=17.6Hz, 1H), 4.37 (dd, J=21.4, 12.0Hz, 2H), 4.14 (t, J=4.9Hz, 2H), 3.61 -3.52 (m, 2H), 3.19-3.12 (m, 2H), 2.85 (d, J=16.5Hz, 1H), 2.39 (dd, J=13.2, 4.4Hz, 1H), 2.16-2.07 (m, 1H ), 1.20-1.02 (m, 9H), 0.85 (dt, J=9.3, 5.8Hz, 1H).
实施例107：化合物185的制备
Example 107: Preparation of Compound 185
采用通用合成方法3制备，得白色固体，收率62.4％。Prepared by general synthesis method 3, a white solid was obtained with a yield of 62.4%.
1H NMR(400MHz，DMSO)δ10.20(s，1H)，8.49(s，3H)，7.81(s，1H)，7.55(dd，J＝8.3，5.2Hz，2H)，7.33(d，J＝7.0Hz，2H)，7.21(d，J＝8.4Hz，2H)，5.63(dd，J＝20.4，9.5Hz，2H)，5.34(dd，J＝13.3，5.2Hz，1H)，5.05(s，1H)，4.73(s，1H)，4.54(d，J＝17.5Hz，1H)，4.39(d，J＝17.6Hz，2H)，4.24-4.13(m，1H)，4.04(dt，J＝14.0，6.6Hz，1H)，3.67(s，1H)，3.16(d，J＝6.5Hz，2H)，2.85(d，J＝17.4Hz，1H)，2.39(d，J＝12.7Hz，1H)，2.12(s，1H)，1.32-0.97(m，9H)，0.84(dd，J＝9.3，7.0Hz，1H). 1 H NMR (400MHz, DMSO) δ10.20 (s, 1H), 8.49 (s, 3H), 7.81 (s, 1H), 7.55 (dd, J=8.3, 5.2Hz, 2H), 7.33 (d, J =7.0Hz, 2H), 7.21 (d, J = 8.4Hz, 2H), 5.63 (dd, J = 20.4, 9.5Hz, 2H), 5.34 (dd, J = 13.3, 5.2Hz, 1H), 5.05 (s , 1H), 4.73 (s, 1H), 4.54 (d, J=17.5Hz, 1H), 4.39 (d, J=17.6Hz, 2H), 4.24-4.13 (m, 1H), 4.04 (dt, J= 14.0, 6.6Hz, 1H), 3.67 (s, 1H), 3.16 (d, J = 6.5Hz, 2H), 2.85 (d, J = 17.4Hz, 1H), 2.39 (d, J = 12.7Hz, 1H) , 2.12 (s, 1H), 1.32-0.97 (m, 9H), 0.84 (dd, J=9.3, 7.0Hz, 1H).
实施例108：化合物186的制备
Example 108: Preparation of Compound 186
采用通用合成方法3制备，得白色固体，收率64.5％。Prepared by general synthesis method 3, a white solid was obtained with a yield of 64.5%.
1H NMR(400MHz，DMSO)δ10.21(s，1H)，8.66(d，J＝3.6Hz，3H)，7.81(dd，J＝5.4，3.4Hz，1H)，7.60-7.50(m，2H)，7.31(d，J＝8.5Hz，2H)，7.21(d，J＝8.5Hz，2H)，5.63(dd，J＝20.2，9.6Hz，2H)，5.34(dd，J＝13.4，5.0Hz，1H)，4.97-4.83(m，1H)，4.55(d，J＝17.6Hz，1H)，4.39(d，J＝17.6Hz，1H)，4.22(s，1H)，3.27-2.99(m，3H)，2.85(d，J＝16.9Hz，1H)，2.44-2.30(m，1H)，2.11(dd，J＝10.0，5.1Hz，1H)，1.16(d，J＝6.2Hz，3H)，1.11(s，9H)，1.05(t，J＝7.5Hz，3H). 1 H NMR (400MHz, DMSO) δ10.21 (s, 1H), 8.66 (d, J=3.6Hz, 3H), 7.81 (dd, J=5.4, 3.4Hz, 1H), 7.60-7.50 (m, 2H ), 7.31 (d, J=8.5Hz, 2H), 7.21 (d, J=8.5Hz, 2H), 5.63 (dd, J=20.2, 9.6Hz, 2H), 5.34 (dd, J=13.4, 5.0Hz , 1H), 4.97-4.83 (m, 1H), 4.55 (d, J=17.6Hz, 1H), 4.39 (d, J=17.6Hz, 1H), 4.22 (s, 1H), 3.27-2.99 (m, 3H), 2.85 (d, J=16.9Hz, 1H), 2.44-2.30 (m, 1H), 2.11 (dd, J=10.0, 5.1Hz, 1H), 1.16 (d, J=6.2Hz, 3H), 1.11 (s, 9H), 1.05 (t, J=7.5Hz, 3H).
实施例109：化合物187的制备
Example 109: Preparation of Compound 187
采用通用合成方法3制备，得白色固体，收率60.3％。Prepared by general synthesis method 3, a white solid was obtained with a yield of 60.3%.
1H NMR(400MHz，DMSO)δ10.22(s，1H)，8.73(d，J＝3.6Hz，3H)，7.81(dd，J＝5.7，3.1Hz，1H)，7.65-7.44(m，2H)，7.31(d，J＝8.5Hz，2H)，7.21(d，J＝8.5Hz，2H)，5.63(dd，J＝20.2，9.6Hz，2H)，5.34(dd，J＝13.4，5.0Hz，1H)，4.56(d，J＝17.6Hz，1H)，4.40(d，J＝17.6Hz，1H)，4.28(d，J＝5.4Hz，1H)，4.10-3.98(m，2H)，3.16(dtd，J＝22.1，14.2，6.9Hz，3H)，2.91-2.78(m，1H)，2.39(ddd，J＝26.5，13.4，4.0Hz，1H)，2.11(dd，J＝9.9，4.8Hz，1H)，1.52-1.42(m，2H)，1.21(tt，J＝14.2，6.2Hz，3H)，1.09(d，J＝13.1Hz，9H)，0.86-0.81(m，3H). 1 H NMR (400MHz, DMSO) δ10.22 (s, 1H), 8.73 (d, J=3.6Hz, 3H), 7.81 (dd, J=5.7, 3.1Hz, 1H), 7.65-7.44 (m, 2H ), 7.31 (d, J=8.5Hz, 2H), 7.21 (d, J=8.5Hz, 2H), 5.63 (dd, J=20.2, 9.6Hz, 2H), 5.34 (dd, J=13.4, 5.0Hz , 1H), 4.56 (d, J=17.6Hz, 1H), 4.40 (d, J=17.6Hz, 1H), 4.28 (d, J=5.4Hz, 1H), 4.10-3.98 (m, 2H), 3.16 (dtd, J=22.1, 14.2, 6.9Hz, 3H), 2.91-2.78 (m, 1H), 2.39 (ddd, J=26.5, 13.4, 4.0Hz, 1H), 2.11 (dd, J=9.9, 4.8Hz , 1H), 1.52-1.42 (m, 2H), 1.21 (tt, J=14.2, 6.2Hz, 3H), 1.09 (d, J=13.1Hz, 9H), 0.86-0.81 (m, 3H).
实施例110：化合物188的制备
Example 110: Preparation of Compound 188
采用通用合成方法3制备，得白色固体，收率69.5％。Prepared by general synthesis method 3, a white solid was obtained with a yield of 69.5%.
1H NMR(400MHz，DMSO)δ10.22(s，1H)，8.74(d，J＝3.5Hz，3H)，7.81(dd，J＝6.1，2.7Hz，1H)，7.62-7.49(m，2H)，7.31(d，J＝8.5Hz，2H)，7.20(d，J＝8.5Hz，2H)，5.63(dd，J＝20.2，9.6Hz，2H)，5.34(dd，J＝13.4，5.0Hz，1H)，4.56(d，J＝17.6Hz，1H)，4.40(d，J＝17.6Hz，1H)，4.27(d，J＝5.7Hz，1H)，3.16(dtd，J＝21.8，13.9，6.7Hz，3H)，2.90-2.78(m，1H)，2.39(ddd，J＝27.0，13.6，4.6Hz，1H)，2.11(dd，J＝10.1，5.0Hz，1H)，1.56-1.43(m，2H)，1.22(t，J＝10.3Hz，6H)，1.11(s，9H)，0.87-0.84(m，3H). 1 H NMR (400MHz, DMSO) δ10.22 (s, 1H), 8.74 (d, J=3.5Hz, 3H), 7.81 (dd, J=6.1, 2.7Hz, 1H), 7.62-7.49 (m, 2H ), 7.31 (d, J=8.5Hz, 2H), 7.20 (d, J=8.5Hz, 2H), 5.63 (dd, J=20.2, 9.6Hz, 2H), 5.34 (dd, J=13.4, 5.0Hz , 1H), 4.56 (d, J=17.6Hz, 1H), 4.40 (d, J=17.6Hz, 1H), 4.27 (d, J=5.7Hz, 1H), 3.16 (dtd, J=21.8, 13.9, 6.7Hz, 3H), 2.90-2.78 (m, 1H), 2.39 (ddd, J=27.0, 13.6, 4.6Hz, 1H), 2.11 (dd, J=10.1, 5.0Hz, 1H), 1.56-1.43 (m , 2H), 1.22 (t, J=10.3Hz, 6H), 1.11 (s, 9H), 0.87-0.84 (m, 3H).
试验例Test example
试验1：溶解度试验Test 1: Solubility test
试验方法：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。Test method: Use a 5 mL centrifuge tube to take about 0.5 mL of distilled water, and slowly add the dry compound until it cannot be dissolved (it will shake at 25°C and remain turbid). Filter the solution into another 5 mL clean weighed EP tube, weigh it again, and calculate the weight of the solution. Lyophilize the filtrate, weigh and calculate the solute mass of the remaining solid, calculate the mass of the solvent, and then calculate the solubility of the compound in water. The results are listed in Table 1.
表1.本发明化合物的溶解度

Table 1. Solubility of compounds of the present invention

结论：本发明化合物在水中的溶解度远远大于已经上市药物来那度胺，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，减轻来那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。Conclusion: The solubility of the compound of the present invention in water is much greater than that of the already marketed drug lenalidomide, and the water solubility can be increased dozens to hundreds of times. This high water solubility can theoretically increase and improve the excretion of drugs in the kidneys and reduce the nephrotoxic side effects of lenalidomide. At the same time, this high water solubility makes these compounds easier to formulate and more clinically applicable. convenient.
试验2：体外抗多发性骨髓瘤活性实验Test 2: In vitro anti-multiple myeloma activity test
试验方法：收集对数期的MM.1S细胞，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0.0001至50μM的化合物，每个化合物4个复孔，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，4h后，弃上清，加入150μL DMSO，检测570nm波长处的吸光度值A测定。无细胞的空白孔测得的吸光度值A空白，以未加药处理的细胞孔测得的吸光度值为A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％。Test method: Collect MM.1S cells in the logarithmic phase, seed them in a 96-well plate at a density of 2×10 4 cells/well, incubate them in a 37°C, 5% CO 2 incubator for 2 hours, and then add them to a final concentration of 0.0001 to 50 μM of compound, 4 duplicate wells of each compound, and incubated for 72 h in a 37°C, 5% CO2 incubator. After the incubation, 20 μL of 5 mg/mL MTT solution was added to the cell wells. After 4 hours, the supernatant was discarded, 150 μL of DMSO was added, and the absorbance value at 570 nm wavelength was measured . The absorbance value measured in the blank well without cells is A blank , and the absorbance value measured in the cell well without drug treatment is A control , and the cell survival rate in each well is calculated according to the following formula:
Cell viability (%) = (A measurement - A blank ) / (A control - A blank ) × 100%.
用GraphPad Prism软件对细胞存活率和药物浓度作图，计算出IC50值。Use GraphPad Prism software to plot cell viability and drug concentration, and calculate IC 50 values.
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。结果见表2。其中，IC50值小于0.05μM为A；IC50值大于0.05μM且小于0.1μM为B；IC50值大于0.1μM且小于0.5μM为C；IC50值大于0.5μM且小于1μM为D。The above-mentioned activity measurement test was carried out on the compounds of the present invention, and the results showed that the compounds of the present invention all had strong cell proliferation inhibitory activity on human multiple myeloma MM.1S cells. The results are shown in Table 2. Among them, the IC 50 value is less than 0.05 μM for A; the IC 50 value is greater than 0.05 μM and less than 0.1 μM for B; the IC 50 value is greater than 0.1 μM and less than 0.5 μM for C; the IC 50 value is greater than 0.5 μM and less than 1 μM for D.
表2.本发明化合物的体外抗多发性骨髓瘤效果

Table 2. In vitro anti-multiple myeloma effects of the compounds of the present invention

试验3：单独与地塞米松组合的抗耐药型多发性骨髓瘤细胞活性实验Trial 3: Activity of anti-drug-resistant multiple myeloma cells alone in combination with dexamethasone
试验方法：本试验评估了地塞米松作为单一剂与本发明化合物或来那度胺的组合物对来那度胺耐药型多发性骨髓瘤NCI-H929细胞的增殖抑制的影响。试验采用MTT比色法检测细胞存活率，方法如试验2。Test Method: This test evaluates the effect of dexamethasone as a single agent in combination with a compound of the invention or lenalidomide on the proliferation inhibition of lenalidomide-resistant multiple myeloma NCI-H929 cells. The test uses MTT colorimetric method to detect cell survival rate, the method is as in test 2.
结果显示，本发明化合物对来那度胺耐药型NCI-H929细胞具有较强的细胞增殖抑制活性，且与第二活性组分地塞米松联合使用时，能够达到协同抑制NCI-H929细胞增殖的效果。结果见表3。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。The results show that the compound of the present invention has strong cell proliferation inhibitory activity on lenalidomide-resistant NCI-H929 cells, and when used in combination with the second active component dexamethasone, it can achieve synergistic inhibition of NCI-H929 cell proliferation. Effect. The results are shown in Table 3. Among them, the IC 50 value is less than 0.01 μM for A; the IC 50 value is greater than 0.01 μM and less than 0.05 μM for B; the IC 50 value is greater than 0.05 μM and less than 0.1 μM for C; the IC 50 value is greater than 0.1 μM and less than 0.5 μM for D.
表3.作为单一剂或与地塞米松组合的本发明化合物在抗来那度胺耐药型NCI-H929细胞中的抗增殖活性比较
Table 3. Comparison of antiproliferative activities of compounds of the invention as single agents or in combination with dexamethasone in lenalidomide-resistant NCI-H929 cells
试验4：氨基酸转运体LAT1/SLC7A5的靶向转运研究Experiment 4: Targeted transport study of amino acid transporter LAT1/SLC7A5
1、稳态细胞株的构建：1. Construction of steady-state cell lines:
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。In this experiment, a 293T steady-state cell line with high expression of LAT1 was independently constructed for use in the production of compounds of the present invention. Targeted transport experimental study.
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。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 μg/mL and 5 μg/mL. After 13 days of screening, 293T cells stably and highly expressing LAT1 were obtained.
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。The results of steady-state cell line construction were tested by Western-Blotting using protein C antibody to detect the protein expression of LAT1. The test results are shown in Figure 1. It can be seen that the cell line was successfully constructed.
2、本发明化合物的靶向细胞吸收试验2. Targeted cell absorption test of the compound of the present invention
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6em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。Experimental method: 293T and LAT1-293T steady-state cell lines were used to conduct this experimental study. The cells were evenly spread into a 6-em 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 preincubated 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 μL/tube. Dissolve the compound in DMSO, dilute it to 20 μM with physiological saline (final DMSO concentration: 0.5%), and add it to the corresponding centrifuge tube, 200 μL per tube, and 3 duplicate tubes for each compound. Invert the centrifuge tube to mix, and incubate at 37°C for 30 minutes. After the incubation, centrifuge at 8000 rpm for 2 min, collect the cell pellet, wash the cells twice with pre-cooled physiological saline, and carefully discard the supernatant. Add 50 μL of purified water containing 2% formic acid to each tube and vortex for 2 min. After the cells are completely lysed, add 200 μL of acetonitrile-methanol mixture (acetonitrile:methanol=7:3) to each tube and wait for mass spectrometry detection.
试验结果：如表3所示，本发明化合物在高表达LAT1的293T细胞裂解液中的含量明显高于普通293T细胞，表明本发明化合物具有显著的LAT1靶向性。Test results: As shown in Table 3, the content of the compound of the present invention in the lysate of 293T cells that highly express LAT1 was significantly higher than that of ordinary 293T cells, indicating that the compound of the present invention has significant LAT1 targeting.
表3.本发明化合物在293T细胞和293T-LAT1细胞中的吸收情况


Table 3. Absorption of compounds of the present invention in 293T cells and 293T-LAT1 cells


试验5：体内抗肿瘤药效试验ITest 5: In vivo anti-tumor efficacy test I
试验方法experiment method
(1)模型制备(1) Model preparation
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。NOD/SCID female mice aged 6 to 8 weeks were used, and the experimental animals were purchased from Beijing Vitong Lihua 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. 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 calculation formula of tumor volume is: long diameter × short diameter 2 /2.
(2)分组给药(2)Group administration
本试验共分为9组，分别为生理盐水组、化合物73给药组、化合物82给药组、化合物90给药组、化合物109给药组、化合物169给药组、化合物174给药组、化合物176给药组、来那度胺给药组、每组7只。口服给药，每天1次，其中来那度胺的剂量为100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。This test is divided into 9 groups, namely, physiological saline group, compound 73 administration group, compound 82 administration group, compound 90 administration group, compound 109 administration group, compound 169 administration group, compound 174 administration group, Compound 176 administration group, lenalidomide administration group, 7 animals in each group. Oral administration, once a day, the dose of lenalidomide is 100 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.
(3)试验结果(3)Test results
结果如表4和图2所示，本发明所化合物与临床对照药物来那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。The results are shown in Table 4 and Figure 2. Compared with the clinical control drug lenalidomide, the compound of the present invention has a superior tumor inhibitory effect, which fully demonstrates the selective accumulation and selective accumulation of the compound of the present invention in tumor cells and tumor tissues. Targeting.
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％Table 4. Dosage, mouse body weight change rate and relative tumor inhibition rate in the RPMI-8226 model


**p<0.01, ***p<0.001, vs. solvent control group; weight change rate (%) = (weight on the day of measurement - initial weight of the experiment)/initial weight of the experiment × 100%
试验6：体内抗肿瘤药效试验IITest 6: In vivo anti-tumor efficacy test II
试验方法experiment method
(1)模型制备(1) Model preparation
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。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. The calculation formula of tumor volume is: long diameter × short diameter 2 /2.
(4)分组给药(4)Group administration
本试验共分为9组，分别为生理盐水组、化合物73给药组、化合物82给药组、化合物90给药组、化合物109给药组、化合物169给药组、化合物174给药组组、化合物176给药组、来那度胺组，每组7只。口服给药，每天1次，其中来那度胺的剂量为100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。This test is divided into 9 groups, namely the normal saline group, the compound 73 administration group, the compound 82 administration group, the compound 90 administration group, the compound 109 administration group, the compound 169 administration group, and the compound 174 administration group. , compound 176 administration group, lenalidomide group, 7 animals in each group. Oral administration, once a day, the dose of lenalidomide is 100 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 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.
(5)试验结果(5)Test results
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来那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。The results are shown in Table 5 and Figure 3. The compounds provided by the present invention have superior tumor inhibitory effects compared with the clinical control drug lenalidomide, which fully demonstrates the selectivity of the compounds of the present invention in tumor cells and tumor tissues. Accumulation and targeting.
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％ Table 5. Dosage, mouse body weight change rate and relative tumor inhibition rate in NCI-H929 model


**p<0.01, ***p<0.001, vs. solvent control group; weight change rate (%) = (weight on the day of measurement - initial weight of the experiment)/initial weight of the experiment × 100%

Claims (10)

  1. 一种式(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(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，
    A compound represented by formula (I), or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof (optionally, the solvate is a hydrate), or a clathrate thereof , or its racemate, or its isotope label, or its nitrogen oxide,
    其中：in:
    A选自-O-，-S-，-NH-，或者A不存在；A is selected from -O-, -S-, -NH-, or A does not exist;
    Q选自任选取代的亚烷基，或亚烷基亚芳基；Q is selected from optionally substituted alkylene, or alkylene arylene;
    R1选自-H、烷基、-C(O)R4、-C(S)R4、-C(O)OR4、-C(O)NHR4、-C(O)NR4R4’；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 ';
    R2选自-H、任意取代的烷基、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；R 2 is selected from -H, optionally substituted alkyl, alkenyl, alkenyl alkylene, alkynyl, alkynyl alkylene, aryl, aryl alkylene, heteroaryl, heteroaryl alkylene ;
    R3选自-H、羟基、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、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；R 3 is selected from -H, hydroxyl, alkyl, alkenyl, alkenylalkylene, alkynyl, alkynylalkylene, aryl, arylalkylene, heteroaryl, 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 ;
    各个R4和R4’相同或者不同，各自独立地选自氢、烷基、烯基、烯基烷基、炔基、炔基烷基、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；Each R 4 and R 4 ' are the same or different, and each is independently selected from hydrogen, alkyl, alkenyl, alkenyl alkyl, alkynyl, alkynylalkyl, optionally substituted aryl, optionally substituted heteroaryl group, optionally substituted alicyclic group, optionally substituted alicyclic heterocyclic group, optionally substituted arylalkylene or optionally substituted heteroarylalkylene; or R 4 and R 4 ' form optionally Substituted 3-7 membered rings;
    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”、“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、芳基亚烷基、杂芳基亚烷基、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、烷酰氧基甲基、烷酰氧基、烷氧酰氧基或烷氧酰基。 The "optionally substituted alkylene group", "optionally substituted alicyclic group", "optionally substituted alicyclic heterocyclic group", "optionally substituted aryl group", "optionally substituted heteroaryl group" The substituents of ", "optionally substituted arylalkylene" and "optionally substituted heteroarylalkylene" are each independently selected from the group consisting of hydroxyl, amino, carboxyl, halogen, nitro, cyano, and alkyl , alkoxy, aryl, heteroaryl, arylalkylene, heteroarylalkylene, aryloxy, heteroaryloxy, cycloalkyl, aliphatic heterocyclyl, cycloalkyloxy , heterocycloalkyloxy, arylalkoxy, heteroarylalkoxy, alkanoyloxymethyl, alkanoyloxy, alkoxyacyloxy or alkoxyacyl.
  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，The compound represented by formula (I) according to claim 1, or its optical isomer, or its pharmaceutically acceptable salt, or its solvate, or its clathrate, or its racemate, or Its isotope label, or its nitrogen oxide, is characterized in that,
    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”、“烷氧酰基”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C1-7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、十一烷基、十二烷基、十三烷基、十四烷基、十五烷基、或十六烷基；The "alkyl", as well as "alkoxy", "arylalkoxy", "heteroarylalkoxy", "alkanoyloxymethyl", "alkoxyacyloxy", "alkyl The alkyl part in "acyloxy" and "alkoxyacyl" is each independently a C 1-20 linear or branched alkyl group, optionally, a C 1-17 linear or branched alkyl group, optionally Ground, is a C 1-10 linear or branched alkyl group, optionally, a C 1-7 linear or branched alkyl group, optionally, a methyl, ethyl, n-propyl, or isopropyl group , n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, heptyl, n-octyl, n-nonyl, n-decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, or hexadecyl;
    可选地，所述“亚烷基”、“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’”或“亚烷基亚芳基”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；Alternatively, the "alkylene", "alkenylalkylene", "alkynylalkylene", "arylalkylene", "heteroarylalkylene", "alkylene- OC(O)R 4 ”, “alkylene-OC(O)OR 4 ”, “alkylene-OC(O)NHR 4 ”, or “alkylene-OC(O)NR 4 R 4 ‘” Or the alkylene part in "alkylene arylene" is each independently a C 1-20 linear or branched alkylene group, optionally, a C 1-17 linear or branched alkylene group , optionally, a C 1-10 linear or branched alkylene group, optionally, a C 1-8 linear or branched alkylene group, optionally, a C 1-6 linear or branched alkylene group Chain alkylene, optionally, C 1-3 linear or branched alkylene, optionally, methylene, ethylene, n-propylene, isopropylene, n-butylene , isobutylene, tert-butylene, sec-butylene, n-pentylene, isopentylene, neopentylene, tert-pentylene, n-hexylene, isohexylene, hepterylene, n-pentylene Octyl, n-nonyl, n-decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, or hexadecyl;
    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；Optionally, the cycloalkyl part in the "cycloalkyloxy" and "cycloalkyl" is C 3-8 cycloalkyl, optionally, it is cyclopropyl, cyclobutyl, or cyclopentyl or cyclohexyl;
    可选地，所述“烯基”、“烯基亚烷基”中的烯基部分各自独立地为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；Optionally, the alkenyl part in the "alkenyl" and "alkenyl alkylene" is each independently a C 2 -C 20 linear or branched alkenyl group, optionally, a C 2 -C 15 Straight chain or branched alkenyl, optionally, C 2 -C 10 straight chain or branched alkenyl, optionally, C 2 -C 8 straight chain or branched alkenyl, optionally, C 2 -C 6 linear or branched alkenyl, optionally, C 2 -C 4 linear or branched alkenyl;
    可选地，所述“炔基”、“炔基亚烷基”中的炔基部分各自独立地为为 C2-C20直链或支链烯基，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；Optionally, the alkynyl part in the "alkynyl" and "alkynyl alkylene" is each independently C 2 -C 20 linear or branched alkenyl, optionally, C 2 -C 15 linear or branched alkynyl, optionally, C 2 -C 10 linear or branched alkynyl, can Optionally, it is a C 2 -C 8 linear or branched chain alkynyl group, optionally, it is a C 2 -C 6 linear or branched chain alkynyl group, optionally, it is a C 2 -C 4 linear or branched chain alkynyl group. Alkynyl;
    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；Alternatively, 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;
    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；Optionally, the 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;
    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；Optionally, 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;
    可选地，所述“杂芳基”、“杂芳基亚烷基”、“杂芳基氧基”、“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。Optionally, the heteroaryl groups in the "heteroaryl", "heteroarylalkylene", "heteroaryloxy" and "heteroarylalkoxy" are each independently selected from O , N, S, SO or SO 2 5-10 membered monocyclic or bicyclic fused heteroaromatic ring groups with 1-3 heteroatoms, optionally, pyrrolyl, pyrazolyl, pyridyl, furyl , imidazolyl, thiazolyl, oxazolyl, oxazolyl, thiazolyl, 1H-azepinyl, quinolyl, isoquinolyl, indolyl, pyrimidinyl or pyrazinyl, or tris Azolyl.
  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，The compound represented by formula (I) according to claim 1 or 2, or its optical isomer, or its pharmaceutically acceptable salt, or its solvate, or its clathrate, or its racemate , or its isotope label, or its nitrogen oxide, characterized in that,
    R1选自-H，或-(C＝O)CH3，-(C＝O)OC(CH3)3；R 1 is selected from -H, or -(C＝O)CH 3 , -(C＝O)OC(CH 3 ) 3 ;
    可选地，R2选自-H，甲基、乙基、叔丁基、烯丙基、炔丙基或苄基；Alternatively, R 2 is selected from -H, methyl, ethyl, tert-butyl, allyl, propargyl or benzyl;
    可选地，R3选自-H，-OH， Optionally, R 3 is selected from -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，所述式(I)化合物的氨基酸部分为D构型或L构型。The compound represented by formula (I) according to any one of claims 1 to 3, or its optical isomer, or its pharmaceutically acceptable salt, or its solvate, or its clathrate, or its The racemate, or its isotope label, or its nitrogen oxide, is characterized in that the amino acid part of the compound of formula (I) is in D configuration or L configuration.
  5. 根据权利要求1-4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、或其消旋体、或其同位素标记物、或其氮氧化物，其特征在于，The compound of formula (I) according to any one of claims 1 to 4, or its optical isomer, or its pharmaceutically acceptable salt, or its solvate, or its clathrate, or its racemate , or its isotope label, or its nitrogen oxide, characterized in that,
    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。The pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt, preferably selected from the group consisting of hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid, carbonic acid, nitric acid, and hydrogen sulfate. , Methanesulfonic acid, glycolic acid, tartaric acid, formic acid, acetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, trifluoroacetic acid, pyruvic acid, cinnamic acid, lauric acid, salicylic acid, Citric acid, succinic acid, fumaric acid, benzoic acid, anthranilic acid, 2-(4-hydroxybenzoyl)benzoic acid, benzenesulfonic acid, ethanesulfonic acid, p-aminobenzenesulfonic acid, p-toluenesulfonic acid, Phenylacetic acid, ascorbic acid, alginic acid, furoic acid, stearic acid, mucinic acid, mandelic acid, malic acid, parapeptic acid, pantothenic acid, camphorsulfonic acid, gluconic acid, glutamic acid, glucuronic acid, galacturonic acid, glycerol Glyceric acid, lactic acid, malic acid, maleic acid, aspartic acid, thiocyanic acid, glucoheptanoic acid, glycerophosphate, sulfosalicylic acid, hemisulfate, oxalic acid, malonic acid, or picric acid.
  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：


















    The compound represented by formula (I) according to any one of claims 1 to 5, or its optical isomer, or its pharmaceutically acceptable salt, or its solvate, or its clathrate, or its The racemate, or its isotope label, or its nitrogen oxide, is characterized in that it is selected from the following compounds:


















  7. 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、或其消旋体、或其同位素标记物、或其氮氧化物，其中式(I)化合物的制备方法：The compound of formula (I) according to any one of claims 1 to 6, or its optical isomer, or its pharmaceutically acceptable salt, or its solvate, or its clathrate, or its racemate, Or its isotope label, or its nitrogen oxide, wherein the preparation method of the compound of formula (I):
    包括将式(A)化合物和式(B)化合物通过步骤A得到式(C)：Including passing the compound of formula (A) and the compound of formula (B) through step A to obtain formula (C):
    步骤A：将式(A)和式(B)通过取代反应制得式(C)；Step A: Prepare formula (C) by substitution reaction of formula (A) and formula (B);
    可选地，将式(A)和式(B)在碱(例如碳酸钾，碳酸铯，氢化钠，双三甲基硅基胺基锂等)催化下，在适合的溶剂中(例如N，N-二甲基甲酰胺，N，N-二甲基甲酰胺，二甲亚砜，N-甲基吡咯烷酮等)，于0℃至25℃温度条件下，通过取代反应制得式(C)；
    Alternatively, formula (A) and formula (B) are catalyzed by a base (such as potassium carbonate, cesium carbonate, sodium hydride, lithium bistrimethylsilylamide, etc.) in a suitable solvent (such as N, N-dimethylformamide, N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, etc.), formula (C) is prepared through a substitution reaction at a temperature of 0°C to 25°C. ;
    其中，in,
    式(B)和式(C)中，R3定义同式(I)中所述，但不为H，OR4；In formula (B) and formula (C), R 3 is defined as described in formula (I), but is not H, OR 4 ;
    式(B)中，B选自Cl，Br，I，OTs，OMs；In formula (B), B is selected from Cl, Br, I, OTs, OMs;
    或者，通过以下步骤A’的反应得到式(C)： Alternatively, formula (C) can be obtained through the reaction of step A' below:
    步骤A’：将S1和S2通过缩合条件得到S3，再将S3经过脱保护得到S4，然后S4和S5在碱催化下通过取代和氨解甲酯得到LN-S5，经还原得式(C)；
    Step A': S1 and S2 are subjected to condensation conditions to obtain S3, and then S3 is deprotected to obtain S4. Then S4 and S5 are substituted and ammonolyzed to obtain methyl ester under base catalysis to obtain LN-S5, which is reduced to obtain formula (C) ;
    还包括将式(C)和式(D)通过步骤B得式(E)，It also includes passing formula (C) and formula (D) through step B to obtain formula (E),
    步骤B：将式(C)和式(D)通过酰化反应得式(E)Step B: Acylation reaction of formula (C) and formula (D) to obtain formula (E)
    优选地，将式(C)和对硝基苯基氯甲酸酯溶于溶剂(如四氢呋喃或N，N-二甲基甲酰胺或N-甲基吡咯烷酮)中，在回流条件下反应，得到式(E)；Preferably, formula (C) and p-nitrophenyl chloroformate are dissolved in a solvent (such as tetrahydrofuran or N, N-dimethylformamide or N-methylpyrrolidone), and reacted under reflux conditions to obtain Formula (E);
    可选地，所述回流反应反应结束后，减压浓缩，加入乙酸乙酯或二氯甲烷或石油醚等搅拌均匀得到混悬液，减压过滤并乙酸乙酯洗涤或直接旋干，得到式(E)；
    Optionally, after the reflux reaction is completed, concentrate under reduced pressure, add ethyl acetate, dichloromethane, petroleum ether, etc. and stir evenly to obtain a suspension, filter under reduced pressure and wash with ethyl acetate or spin dry directly to obtain the formula (E);
    其中，式(E)中，R3定义同式(I)中所述；Wherein, in formula (E), R 3 has the same definition as described in formula (I);
    或者，还包括将式(C)和式(F)通过步骤C得到式(G)：Or, it also includes passing formula (C) and formula (F) through step C to obtain formula (G):
    步骤C：将式(C)和式(F)通过酰化反应得到式(G)；Step C: acylation reaction of formula (C) and formula (F) to obtain formula (G);
    优选地，低温下(优选0℃)将式(C)缓慢滴加至三光气的二氯甲烷或乙腈溶液中，缓慢升温至30℃-60℃(优选为45℃)，待反应结束，减压浓缩，得式 (G)；
    Preferably, formula (C) is slowly added dropwise to the dichloromethane or acetonitrile solution of triphosgene at low temperature (preferably 0°C), and the temperature is slowly raised to 30°C-60°C (preferably 45°C). After the reaction is completed, reduce Pressure concentration, formula (G);
    其中，式(G)中，R3定义同式(I)中所述；Wherein, in formula (G), R 3 has the same definition as described in formula (I);
    或者，还包括将式(C)和式(H)通过步骤D得到式(J)：Or, it also includes passing formula (C) and formula (H) through step D to obtain formula (J):
    步骤D：将式(C)和式(D)通过缩合反应得式(J)；Step D: Perform a condensation reaction between formula (C) and formula (D) to obtain formula (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，减压浓缩、过滤并用乙酸乙酯洗涤或直接旋干，得式(J)；可选地，溶剂为DCM、或CAN、或THF、或DCE等；可选地，温度为45℃-90℃。
    Alternatively, formula (C) and formula (H) are dispersed in an appropriate solvent, reacted under heating conditions, and after the reaction is completed, concentrate under reduced pressure, filter and wash with ethyl acetate or directly spin to dryness to obtain formula (J) ; Optionally, the solvent is DCM, or CAN, or THF, or DCE, etc.; Optionally, the temperature is 45°C-90°C.
    其中，式(J)中，R3定义同式(I)中所述；Among them, in formula (J), the definition of R 3 is the same as that described in formula (I);
    当式(I)中A选自-O-，-S-，-NH-时，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得到式(I)，如以下合成步骤E：When A in formula (I) is selected from -O-, -S-, -NH-, formula (E) or formula (G) or formula (J) and formula (L) are nucleophilically substituted under base catalysis Reaction and optional deprotection yield formula (I), as in the following synthesis step E:
    步骤E：
    Step E:
    式(L)中，C选自-OH，-SH，-NH2中的任意一个基团； In formula (L), C is selected from any one of -OH, -SH and -NH 2 groups;
    R5为Cl，或 R 5 is Cl, or
    当式(I)中A不存在时，采用合成步骤F制备：When A in formula (I) does not exist, synthetic step F is used to prepare:
    步骤F：将式(A)或式(C)与式(P)采用缩合剂(例如HATU或TBTU等)缩合和任选的脱保护反应步骤得式(R)，
    Step F: Condensation of formula (A) or formula (C) and formula (P) using a condensing agent (such as HATU or TBTU, etc.) and optional deprotection reaction step to obtain formula (R),
    其中，式(P)中，Q定义同式(I)中所述。Among them, in formula (P), the definition of Q is the same as that described in formula (I).
  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、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；A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1 to 6, or its optical isomer, or its pharmaceutically acceptable salt, or its solvate, or its clathrate substance, or its racemate, or its isotope label, or its nitrogen oxide, and pharmaceutically acceptable excipients;
    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。Optionally, the pharmaceutically acceptable excipients are selected from: fillers, disintegrants, lubricants, glidants, effervescent agents, flavoring agents, preservatives, coating materials or other excipients.
    可选地，所述填充剂包括乳糖、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；Optionally, the filler includes one or more of lactose, sucrose, dextrin, starch, pregelatinized starch, mannitol, sorbitol, calcium hydrogen phosphate, calcium sulfate, calcium carbonate, and microcrystalline cellulose;
    可选地，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；Optionally, the binder includes sucrose, starch, povidone, sodium carboxymethylcellulose, hypromellose, hydroxypropylcellulose, methylcellulose, polyethylene glycol, and medicinal ethanol. , one or more types of water;
    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；Optionally, the disintegrant includes one of starch, crospovidone, croscarmellose sodium, low-substituted hydroxypropylcellulose, carboxymethylcellulose sodium, and effervescent disintegrant. species or species;
    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。Optionally, 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.
  9. 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、淋巴瘤、卡波西肉瘤或骨髓增生异常综合征。The compound of formula (I) according to any one of claims 1 to 6, or its optical isomer, or its pharmaceutically acceptable salt, or its solvate, or its clathrate, or its racemate, Or its isotope label, or its nitrogen oxide, or the pharmaceutical composition according to claim 8 when prepared for the prevention of and/or use in medicines for the treatment of hematological diseases; preferably, the disease is selected from blood cancer and bone marrow cancer, lymphoma, Kaposi's sarcoma or myelodysplastic syndrome.
  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、淋巴瘤、卡波西肉瘤、骨髓增生异常综合征；优选地，所述其他活性药物为地塞米松和/或朋替佐米。 The compound of formula (I) according to any one of claims 1 to 6, or its optical isomer, or its pharmaceutically acceptable salt, or its solvate, or its clathrate or, or its racemate, Or its isotope label, or its nitrogen oxide, or the pharmaceutical composition according to claim 8 is used in combination with one or more other active drugs in the preparation of drugs for preventing and/or treating hematological diseases. Purpose; Preferably, the disease is selected from blood cancer and bone marrow cancer, lymphoma, Kaposi's sarcoma, myelodysplastic syndrome; preferably, the other active drug is dexamethasone and/or pentezomib.
PCT/CN2023/098489 2022-06-07 2023-06-06 4-carbonylamino isoindolin-1-one derivative, composition comprising same, and use method thereof WO2023236926A1 (en)

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