WO2022057387A1 - 3-(3-芳基/杂芳基-4-噻唑啉酮基)-n-芳基/杂环苯甲酰胺类化合物及其应用 - Google Patents

3-(3-芳基/杂芳基-4-噻唑啉酮基)-n-芳基/杂环苯甲酰胺类化合物及其应用 Download PDF

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WO2022057387A1
WO2022057387A1 PCT/CN2021/104268 CN2021104268W WO2022057387A1 WO 2022057387 A1 WO2022057387 A1 WO 2022057387A1 CN 2021104268 W CN2021104268 W CN 2021104268W WO 2022057387 A1 WO2022057387 A1 WO 2022057387A1
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benzamide
thiazolinone
phenylbutyl
nmr
aryl
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PCT/CN2021/104268
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English (en)
French (fr)
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刘顺英
邓亚琦
牛荔
宋龙龙
倪丹
李子
韩王宇婧
韦清华
董素珍
皮柔
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上海鸿恒生物医药科技有限公司
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Priority claimed from CN202010972804.3A external-priority patent/CN114262307A/zh
Priority claimed from CN202010972702.1A external-priority patent/CN114262325A/zh
Priority claimed from CN202010971434.1A external-priority patent/CN114262305A/zh
Priority claimed from CN202010971435.6A external-priority patent/CN114262306A/zh
Application filed by 上海鸿恒生物医药科技有限公司 filed Critical 上海鸿恒生物医药科技有限公司
Publication of WO2022057387A1 publication Critical patent/WO2022057387A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/14—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention relates to the field of synthetic medicine and chemical industry, and mainly relates to a 3-(3-aryl/heteroaryl-4-thiazolinone)-N-aryl/heterocyclic benzamide compound and a preparation method and application thereof .
  • Osteosarcoma also known as osteosarcoma, is a malignant bone tumor that occurs more commonly in adolescents or children under the age of 20 (Link MP: Osteosarcoma in adolescents and young adults: new developments and controversies. Commentary on the use of presurgical chemotherapy .Cancer Treat Res 62:383-385, 1993.), according to the epidemiological study of osteosarcoma: it is the most common in pediatric bone malignancies, accounting for about 5% of pediatric tumors. Osteosarcoma is still the highest mortality rate of malignant tumors in children and adolescents, second only to lymphoma and brain cancer, but early detection and timely treatment have greatly improved the survival rate of this disease.
  • the treatment methods for different types of osteosarcoma are usually combined after surgery. It is worth noting that the cancer metastasis rate of patients with osteosarcoma is as high as 80%, and 90% of the patients with metastases are lung metastasis. Among them, the recurrence rate is 20-30%, in situ or in situ tissue may recur, and the survival rate after recurrence, in the past few decades, despite the adjustment of increased doses, the number of changes and the combination of multiple chemotherapy drugs and other treatment methods , the survival rate did not improve.
  • the research on the therapeutic targets of osteosarcoma mainly focuses on the family of cell surface receptor tyrosine kinases (PTKs) and intracellular signaling targets.
  • the main therapeutic drugs are divided into three categories: 1) immunomodulators; 2) receptor tyrosine kinase inhibitors; 3) intracellular signaling pathway inhibitors.
  • new targets and treatment options for osteosarcoma include NK-kB ligands, folic acid inhibitors, etc., but they are all in the experimental research stage.
  • this backbone compound may generate a series of new compound molecules with meaningful structure and activity, which may provide a new source of compounds for biological activity screening.
  • the present invention provides a 3-(3-aryl/heteroaryl-4-thiazolinonyl)-N-aryl/heterocyclic benzene represented by formulas (I), (II) and (III)
  • a carboxamide compound or a pharmaceutically acceptable salt the compound is a new compound, and there is no relevant report:
  • Ar is aryl, aromatic heterocycle, alkyl substituted aryl, halogen substituted aryl, alkyl substituted heteroaryl, halogen substituted heteroaryl, trifluoromethyl substituted aryl, nitro substituted Aryl, decalinyl, furanalkyl, alkenyl, alkynyl, diphenylalkyl, bis(4-bromophenyl)alkyl, trifluoromethyl substituted heteroaryl, nitro substituted heteroaryl ;
  • the aromatic heterocycle and heteroaryl are respectively selected from indole, benzotriazole, thiophene, furan, pyrrole, bislactam, piperazine, imidazole, oxazole, pyrazine;
  • R 1 is a mono- or poly-substituted group selected from the group consisting of halogen, alkoxy, alkyl, nitro, cyano, trifluoromethyl, phenyl, hydrogen, aryl, three-membered ring, acetylene base;
  • R 2 is cycloalkyl, alkylene oxide, alkyl or hydrogen
  • R 3 is halogen, alkoxy, alkyl, cycloalkyl, nitro, cyano, trifluoromethyl, phenyl, hydrogen;
  • n 0;1;2;4;5;6.
  • Het is a heterocycle selected from: pyridine, quinoline, tropane, phenothiazine, benzodiazepine, furan, pyrazolone, pyrimidine, halogen-substituted heteroaryl, nitro-substituted heteroaryl, decalinyl, furanalkyl, alkenyl, alkynyl, diphenylalkyl, di(4-bromophenyl)alkyl, trifluoromethyl substituted heteroaryl, nitro substituted heteroaryl;
  • the heteroaryl group is selected from indole, benzotriazole, thiophene, pyrrole, bislactam, piperazine, imidazole, oxazole, and pyrazine.
  • Ar is phenyl, aromatic heterocycle, C1-C6 alkyl substituted phenyl, halogen substituted phenyl, C1-C6 alkyl substituted heteroaryl, halogen substituted heteroaryl, trifluoromethyl substituted benzene phenyl, nitro-substituted phenyl, naphthylmethyl, furylmethyl, allyl, propargyl, benzhydryl, bis(4-bromophenyl)methyl, trifluoromethyl substituted heteroaryl , nitro-substituted heteroaryl; wherein, the aromatic heterocycle and heteroaryl are respectively selected from indole, benzotriazole, thiophene, furan, pyrrole, bislactam, piperazine, imidazole, oxazole, Pyrazine, etc.;
  • R 1 is a mono- or poly-substituted group selected from the group consisting of halogen, C1-C10 alkoxy, methyl, ethyl, isopropyl, nitro, cyano, trifluoromethyl, phenyl, hydrogen;
  • R 2 is C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 epoxy alkyl, hydrogen, etc.;
  • R 3 is halogen, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, nitro, cyano, trifluoromethyl, phenyl, hydrogen;
  • Het is a heterocycle selected from the group consisting of: pyridine, quinoline, tropane, phenothiazine, benzodiazepine, furan, pyrazolone, pyrimidine, halogen substituted heteroaryl, trifluoromethyl substituted aryl , nitro-substituted aryl, naphthalene C1-C6 alkyl, furan C1-C6 alkyl, alkene C1-C6 alkyl, alkyne C1-C6 alkyl, diphenyl C1-C6 alkyl, bis(4-bromobenzene base) C1-C6 alkyl group, trifluoromethyl-substituted heteroaryl group, nitro-substituted heteroaryl group; wherein, the heteroaryl group is selected from indole, benzotriazole, thiophene, pyrrole, bis-indole Amide, piperazine, imidazole
  • Ar is phenyl, aromatic heterocycle, methyl-substituted phenyl, halogen-substituted phenyl, methyl-substituted heteroaryl, halogen-substituted heteroaryl, trifluoromethyl-substituted phenyl, nitro-substituted Phenyl, naphthylmethyl, furylmethyl, allyl, propargyl, benzhydryl, bis(4-bromophenyl)methyl, trifluoromethyl substituted heteroaryl, nitro substituted heteroaryl
  • R 1 is a mono- or poly-substituted group selected from the group consisting of halogen, C1-C10 alkoxy, methyl, ethyl, isopropyl, nitro, cyano, trifluoromethyl, phenyl, hydrogen;
  • R 2 is methyl, ethyl, isopropyl, cyclopropane, glycidyl, hydrogen, etc.;
  • R 3 is F, methoxy, methyl, cyclopropanyl, nitro, cyano, trifluoromethyl, phenyl, hydrogen;
  • Het is a heterocycle selected from the group consisting of: pyridine, quinoline, tropane, phenothiazine, benzodiazepine, furan, pyrazolone, pyrimidine, halogen substituted heteroaryl, trifluoromethyl substituted aryl , nitro-substituted aryl, naphthylmethyl, furylmethyl, allyl, propargyl, benzhydryl, bis(4-bromophenyl)methyl, trifluoromethyl substituted heteroaryl, Nitro-substituted heteroaryl; wherein, the heteroaryl is selected from indole, benzotriazole, thiophene, pyrrole, bislactam, piperazine, imidazole, oxazole, and pyrazine.
  • 3-(3-aryl/heteroaryl-4-thiazolinone)-N-aryl/heterocyclic benzamide compounds or pharmaceutically acceptable salts of the present invention include but are not limited to the following:
  • the present invention also provides the raw materials used in the compounds represented by formula (II) and (III)
  • the synthetic method of the raw material used in the compound shown in the formula (III) specifically includes the following four methods:
  • the crude product obtained in the previous step was placed in a three-necked flask, palladium carbon with a content of 10% was added, methanol was added after nitrogen protection, and the nitrogen was replaced with hydrogen. Soil suction filtration, the filtrate was collected, and the solvent was spin-dried, which was directly used in the next step.
  • the present invention also provides a 3-(3-aryl/heteroaryl-4-thiazolinone)-N-aryl/
  • a method for synthesizing a heterocyclic benzamide compound or a pharmaceutically acceptable salt the specific steps are as follows, including the following (A), (B), (C), (D) as shown: (the compound designed in the present invention is
  • the synthetic routes are all consistent with the following methods, the following methods only describe the synthetic methods of formula (I) and formula (III), and reaction formulas (A)-1, (A)-2 and (A)-3 are synthetic raw materials Step, the synthetic method of formula (II) see formula (I))
  • the m-bromoaniline is coupled with cyclopropaneboronic acid under the catalysis of palladium acetate/cyclohexylphosphorus system to obtain m-cyclopropanylaniline.
  • the ester compound (5mmol, 1.0eq) obtained in the first step was reacted with LiOH (5.25mmol, 1.05eq) in a solvent of methanol:water (4:1) at room temperature for 20 hours, and monitored by spot plate The substrate was completely consumed.
  • the methanol in the solvent was removed by rotary evaporation, and the remaining reaction solution was poured into 50 mL of water, and 3N HCl was added dropwise to acidify, and a large amount of white solids were precipitated.
  • Use pH test paper to monitor until pH 1 .
  • the white solid was filtered off with a Buchner funnel, and the white solid was dissolved in ethyl acetate, dried over anhydrous sodium sulfate, and rotary-evaporated to obtain a carboxylic acid product.
  • the carboxylic acid product (1.5 mmol, 1.0 eq) obtained in the second step and 1-hydroxybenzotriazole (ie, HOBt, 3.0 mmol, 2.0 eq) were dissolved in 20 mL of tetrahydrofuran, and under ice bath conditions, added N,N-diisopropylethylamine (DIPEA, 4.5 mmol, 3.0 eq), after stirring for 20 minutes, the compound long-chain amine was added, and stirring was continued for 10 minutes.
  • DIPEA N,N-diisopropylethylamine
  • the condensing agent 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI, 3 mmol, 2.0 eq) was added in batches, and after the reaction for two hours, the spot plate was monitored, and the raw materials were completely consumed. .
  • An appropriate amount of saturated sodium bicarbonate was sequentially added to the reaction solution, washed with saturated brine, and extracted three times with ethyl acetate.
  • the present invention also provides the 3-(3-(heteroaryl)-4-thiazolinone)-N-arylbenzamide compound represented by the formula (III) or a pharmaceutically acceptable salt thereof.
  • the synthetic method, the solvent used in the method of the present invention includes alkanes, halogenated alkanes, ethers, halogenated ethers, substituted benzenes, alcohols, esters, ketones, halogenated benzenes, heteroaromatic hydrocarbons, One or a combination of amides, sulfoxides and water.
  • the basic synthesis steps of the method are as follows:
  • compound 2 (1.5 mmol, 1.0 eq) and 1-hydroxybenzotriazole (ie, HOBt, 3.0 mmol, 2.0 eq) were dissolved in 20 mL of tetrahydrofuran.
  • propylethylamine DIPEA, 4.5mmol, 3.0eq
  • the compound alkylamine was added, and stirring was continued for 10 minutes.
  • the condensing agent 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI, 3 mmol, 2.0 eq) was added in batches, and after the reaction for two hours, the spot plate was monitored, and the raw materials were completely consumed.
  • the present invention also proposes an acid addition salt formed by the 3-(3-aryl-4-thiazolinone)-N-arylbenzamide compound and an acid; wherein, the acid is hydrochloric acid, sulfuric acid , phosphoric acid, hydrobromic acid, acetic acid, salicylic acid, tartaric acid, lactic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, maleic acid, pyruvic acid or succinic acid, etc.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the 3-(3-aryl-4-thiazolinone)-N-arylbenzamide compound or a pharmaceutically acceptable salt, and A pharmaceutically acceptable carrier.
  • the pharmaceutical composition is formulated into pills, capsules, creams, gels, excipients, injectable fluids, aerosols, syrups or transdermal patches and the like.
  • the present invention also provides the 3-(3-aryl/heteroaryl-4-thiazolinone)-N-aryl/heterocyclic benzamide compounds or pharmaceutically acceptable salts, or pharmaceutical combinations
  • the 3-(3-aryl/heteroaryl-4-thiazolinone)-N-aryl/heterocyclic benzamide compounds are used to inhibit the proliferation, growth, migration, infiltration, Metastasis and recurrence, or promote tumor cell apoptosis.
  • the tumor cells are osteosarcoma cells, colorectal cancer cells, leukemia cells, lung cancer cells, pancreatic cancer cells and the like.
  • the osteosarcoma cells include SJSA-1, U2OS, HOS, MNNG/HOS, MG63, 143b;
  • the pancreatic cancer cells include PANC-1;
  • the lung cancer cells include A549;
  • the colorectal cancer cells include HCT116;
  • the leukemia cells include Jurkat.
  • the present invention discloses a 3-(3-aryl-4-thiazolinone)-N-arylbenzamide compound or a pharmaceutically acceptable salt and a preparation method thereof,
  • the compounds or compositions have inhibitory activity on tumor cells, can be used to treat osteosarcoma, colorectal cancer, pancreatic cancer, leukemia and other related diseases, and are of great significance in the study of tumor diseases.
  • Fig. 1 is a schematic diagram of 1 H NMR and 13 C NMR of the product 1 obtained in Example 1 of the present invention.
  • Fig. 2 is a schematic diagram of 1 H NMR, 13 C NMR and 19 F NMR of the product 2 obtained in Example 2 of the present invention.
  • Fig. 3 is a schematic diagram of 1 H NMR, 13 C NMR and 19 F NMR of the product 3 obtained in Example 3 of the present invention.
  • Figure 4 is a schematic diagram of 1 H NMR and 13 C NMR of the product 4 obtained in Example 4 of the present invention.
  • Example 5 is a schematic diagram of 1 H NMR, 13 C NMR and 19 F NMR of the product 5 obtained in Example 5 of the present invention.
  • FIG. 6 is a schematic diagram of 1 H NMR and 13 C NMR of the product 6 obtained in Example 6 of the present invention.
  • FIG. 7 is a schematic diagram of 1 H NMR, 13 C NMR and 19 F NMR of the product 7 obtained in Example 7 of the present invention.
  • FIG. 8 is a schematic diagram of 1 H NMR, 13 C NMR and 19 F NMR of the product 8 obtained in Example 8 of the present invention.
  • FIG. 9 is a schematic diagram of 1 H NMR and 13 C NMR of the product 9 obtained in Example 9 of the present invention.
  • Example 10 is a schematic diagram of 1 H NMR and 13 C NMR of the product 10 obtained in Example 10 of the present invention.
  • FIG. 11 is a schematic diagram of 1 H NMR and 13 C NMR of the product 11 obtained in Example 11 of the present invention.
  • Figure 12 is a schematic diagram of 1 H NMR and 13 C NMR of the product 12 obtained in Example 12 of the present invention.
  • Figure 13 is a schematic diagram of 1 H NMR and 13 C NMR of the product 13 obtained in Example 13 of the present invention.
  • Figure 14 is a schematic diagram of 1 H NMR and 13 C NMR of the product 14 obtained in Example 14 of the present invention.
  • Example 15 is a schematic diagram of 1 H NMR, 13 C NMR and 19 F NMR of the product 15 obtained in Example 15 of the present invention.
  • Example 16 is a schematic diagram of 1 H NMR and 13 C NMR of the product 16 obtained in Example 16 of the present invention.
  • Example 17 is a schematic diagram of 1 H NMR and 13 C NMR of the product 17 obtained in Example 17 of the present invention.
  • Example 18 is a schematic diagram of 1 H NMR, 13 C NMR and 19 F NMR of the product 18 obtained in Example 18 of the present invention.
  • FIG. 19 is a schematic diagram of 1 H NMR ( FIG. 19A ) and 13 C NMR ( FIG. 19B ) of the product 19 obtained in Example 19.
  • FIG. 19A 1 H NMR
  • FIG. 19B 13 C NMR
  • FIG. 20 is a schematic diagram of 1 H NMR ( FIG. 20A ) and 13 C NMR ( FIG. 20B ) of the product 20 obtained in Example 20.
  • FIG. 20A is a schematic diagram of 1 H NMR ( FIG. 20A ) and 13 C NMR ( FIG. 20B ) of the product 20 obtained in Example 20.
  • FIG. 20B is a schematic diagram of 1 H NMR ( FIG. 20A ) and 13 C NMR ( FIG. 20B ) of the product 20 obtained in Example 20.
  • FIG. 20 is a schematic diagram of 1 H NMR ( FIG. 20A ) and 13 C NMR ( FIG. 20B ) of the product 20 obtained in Example 20.
  • FIG. 21 is a schematic diagram of 1 H NMR ( FIG. 21A ) and 13 C NMR ( FIG. 21B ) of the product 21 obtained in Example 21.
  • FIG. 21A is a schematic diagram of 1 H NMR ( FIG. 21A ) and 13 C NMR ( FIG. 21B ) of the product 21 obtained in Example 21.
  • FIG. 21B is a schematic diagram of 1 H NMR ( FIG. 21A ) and 13 C NMR ( FIG. 21B ) of the product 21 obtained in Example 21.
  • FIG. 22 is a schematic diagram of 1 H NMR ( FIG. 22A ) and 13 C NMR ( FIG. 22B ) of the product 22 obtained in Example 22.
  • FIG. 22A 1 H NMR
  • FIG. 22B 13 C NMR
  • FIG. 23 is a schematic diagram of 1 H NMR ( FIG. 23A ) and 13 C NMR ( FIG. 23B ) of the product 23 obtained in Example 23.
  • FIG. 23A 1 H NMR
  • FIG. 23B 13 C NMR
  • Figure 24 is a schematic representation of1H NMR (Figure 24A) and13C NMR ( Figure 24B) of the product 24 obtained in Example 24.
  • Figure 25 is a schematic diagram of1H NMR (Figure 25A) and13C NMR (Figure 25B) of the product 25 obtained in Example 25.
  • Figure 26 is the 1 H NMR of the product 26 obtained in Example 26 ( Figure 26).
  • FIG. 27 is a schematic diagram of1H NMR (FIG. 27A) and13C NMR (FIG. 27B) of the product 27 obtained in Example 27.
  • FIG. 27A is a schematic diagram of1H NMR (FIG. 27A) and13C NMR (FIG. 27B) of the product 27 obtained in Example 27.
  • FIG. 27B is a schematic diagram of1H NMR (FIG. 27A) and13C NMR (FIG. 27B) of the product 27 obtained in Example 27.
  • FIG. 28 is a schematic diagram of1H NMR (FIG. 28A) and13C NMR (FIG. 28B) of the product 28 obtained in Example 28.
  • FIG. 28A is a schematic diagram of1H NMR (FIG. 28A) and13C NMR (FIG. 28B) of the product 28 obtained in Example 28.
  • FIG. 28B is a schematic diagram of1H NMR (FIG. 28A) and13C NMR (FIG. 28B) of the product 28 obtained in Example 28.
  • FIG. 28A 1H NMR
  • FIG. 28B 13C NMR
  • Figure 29 is a schematic diagram of1H NMR (Figure 29A) and13C NMR (Figure 29B) of the product 29 obtained in Example 29.
  • FIG. 30 is a schematic diagram of 1 H NMR ( FIG. 30A ) and 13 C NMR ( FIG. 30B ) of the product 30 obtained in Example 30.
  • FIG. 30A is a schematic diagram of 1 H NMR ( FIG. 30A ) and 13 C NMR ( FIG. 30B ) of the product 30 obtained in Example 30.
  • FIG. 30B is a schematic diagram of 1 H NMR ( FIG. 30A ) and 13 C NMR ( FIG. 30B ) of the product 30 obtained in Example 30.
  • Figure 31 is a schematic diagram of1H NMR (Figure 31A) and13C NMR ( Figure 31B) of the product 31 obtained in Example 31.
  • Figure 32 is a schematic diagram of1H NMR (Figure 32A) and13C NMR ( Figure 32B) of the product 32 obtained in Example 32.
  • FIG. 33 is a schematic diagram of1H NMR (FIG. 33A) and13C NMR (FIG. 33B) of the product 33 obtained in Example 33.
  • FIG. 33A is a schematic diagram of1H NMR (FIG. 33A) and13C NMR (FIG. 33B) of the product 33 obtained in Example 33.
  • FIG. 33B is a schematic diagram of1H NMR (FIG. 33A) and13C NMR (FIG. 33B) of the product 33 obtained in Example 33.
  • FIG. 33A 1H NMR
  • FIG. 33B 13C NMR
  • Figure 34 is a schematic representation of1H NMR (Figure 34A) and13C NMR (Figure 34B) of the product 34 obtained in Example 34.
  • Figure 35 is a schematic representation of1H NMR (Figure 35A) and13C NMR (Figure 35B) of the product 35 obtained in Example 35.
  • FIG. 36 is a schematic diagram of1H NMR (FIG. 36A) and13C NMR (FIG. 36B) of the product 36 obtained in Example 36.
  • FIG. 36A is a schematic diagram of1H NMR (FIG. 36A) and13C NMR (FIG. 36B) of the product 36 obtained in Example 36.
  • FIG. 36B is a schematic diagram of1H NMR (FIG. 36A) and13C NMR (FIG. 36B) of the product 36 obtained in Example 36.
  • FIG. 37 is a schematic diagram of1H NMR (FIG. 37A) and13C NMR (FIG. 37B) of the product 37 obtained in Example 37.
  • FIG. 37A is a schematic diagram of1H NMR (FIG. 37A) and13C NMR (FIG. 37B) of the product 37 obtained in Example 37.
  • FIG. 37B is a schematic diagram of1H NMR (FIG. 37A) and13C NMR (FIG. 37B) of the product 37 obtained in Example 37.
  • Figure 38 is a schematic representation of1H NMR (Figure 38A) and13C NMR (Figure 38B) of the product 38 obtained in Example 38.
  • Figure 39 is a schematic diagram of1H NMR (Figure 39A), 13C NMR ( Figure 39B) and19F NMR (Figure 39C) of the product 39 obtained in Example 39.
  • FIG. 40 is a schematic diagram of 1 H NMR ( FIG. 40A ) and 13 C NMR ( FIG. 40B ) of the product 40 obtained in Example 2.
  • FIG. 40A 1 H NMR
  • FIG. 40B 13 C NMR
  • Figure 41 is a schematic diagram of1H NMR (Figure 41A) and13C NMR ( Figure 41B) of the product 41 obtained in Example 41.
  • Figure 42 is a schematic representation of1H NMR (Figure 42A) and13C NMR ( Figure 42B) of the product 42 obtained in Example 42.
  • Figure 43 is a schematic diagram of1H NMR (Figure 43A), 13C NMR ( Figure 43B) and19F NMR (Figure 43C) of the product 43 obtained in Example 43.
  • Figure 44 is a schematic representation of1H NMR (Figure 44A) and13C NMR (Figure 44B) of the product 44 obtained in Example 44.
  • FIG. 45 is a schematic diagram of1H NMR (FIG. 45A) and13C NMR (FIG. 45B) of the product 45 obtained in Example 7.
  • FIG. 45A is a schematic diagram of1H NMR (FIG. 45A) and13C NMR (FIG. 45B) of the product 45 obtained in Example 7.
  • FIG. 45B is a schematic diagram of1H NMR (FIG. 45A) and13C NMR (FIG. 45B) of the product 45 obtained in Example 7.
  • FIG. 45A 1H NMR
  • FIG. 45B 13C NMR
  • Figure 46 is a schematic representation of1H NMR (Figure 46A) and13C NMR (Figure 46B) of the product 46 obtained in Example 8.
  • Figure 47 is a schematic representation of1H NMR (Figure 47A) and13C NMR (Figure 47B) of the product 47 obtained in Example 47.
  • Figure 48 is a schematic representation of1H NMR (Figure 48A) and13C NMR (Figure 48B) of the product 48 obtained in Example 48.
  • Figure 49 is a schematic representation of1H NMR (Figure 49A) and13C NMR (Figure 49B) of the product 49 obtained in Example 49.
  • Figure 50 is a schematic diagram of1H NMR (Figure 50A) and13C NMR (Figure 50B) of the product 50 obtained in Example 50.
  • FIG. 51 is the 1 H NMR of the product 51 obtained in Example 51.
  • FIG. 51 is the 1 H NMR of the product 51 obtained in Example 51.
  • Figure 52 is a schematic diagram of1H NMR (Figure 52A) and13C NMR ( Figure 52B) of the product 52 obtained in Example 52.
  • Figure 53 is a schematic diagram of1H NMR (Figure 53A) and13C NMR ( Figure 53B) of the product 53 obtained in Example 53.
  • Embodiment 5 is a diagrammatic representation of Embodiment 5:
  • the present invention adopts the CCK-8 method to determine the effect of the 38 compounds 1 to 38 prepared by the present invention on 6 kinds of osteosarcoma cells (SJSA-1, U2OS, HOS, MNNG/HOS, MG63, 143b), 1 kind of pancreatic cancer cells ( The proliferation inhibitory effect of PANC-1), 1 type of lung cancer cell (A549), 1 type of colorectal cancer cell (HCT116) and 1 type of leukemia cell (Jurkat).
  • a single cell suspension was prepared with DMEM medium containing 10% fetal bovine serum, 1% penicillin and streptomycin, and 2500 MNNG/HOS osteosarcoma cells per well were inoculated into a 96-well cell culture plate. Volume 100 ⁇ l.
  • a single cell suspension was prepared with McCoy'5A medium containing 10% fetal bovine serum, 1% penicillin and streptomycin, and 2500 U-2-OS osteosarcoma cells per well were inoculated into 96-well cell culture plate, with a volume of 100 ⁇ l per well.
  • a single cell suspension was prepared with 1640 medium containing 10% fetal bovine serum, 1% penicillin and streptomycin, and 2500 Jurkat leukemia cells per well were inoculated into a 96-well cell culture plate, with a volume of 100 ⁇ l per well.
  • the 38 compounds (1 to 38) prepared by the present invention were dissolved in DMSO, respectively prepared into a drug solution with a final concentration of 1 ⁇ M with the corresponding cell culture medium, and added to ten different cells (100 ⁇ L/well) respectively.
  • the control group was added with 1 ⁇ DMSO, and cultured in a CO 2 incubator for 72 hours;
  • Cell proliferation activity (%) [A (dosing)-A (blank)]/[A (0 dosing)-A (blank)] ⁇ 100.
  • ND stand for not detected.
  • 25 compounds including compound 1 had a good inhibitory effect on MNNG/HOS cells; 24 compounds including compound 3 had a good inhibitory effect on MG63 cells; 15 compounds including compound 1 had a good inhibitory effect on 143b cells 25 compounds including compound 1 have good inhibitory effect on leukemia cell Jurkat; 17 compounds including compound 4 have good inhibitory effect on colorectal cancer cell HCT116; 19 compounds including compound 1 have good inhibitory effect on lung cancer cell A549 It has a good inhibitory effect; 17 compounds including compound 1 have a certain inhibitory effect on pancreatic cancer cell PANC-1. (Bold parts are data with inhibitory activity)
  • the compound 44 of the present invention is effective for SJSA-1, U-2-OS, HOS , 143B, MNNG/HOS and MG63 osteosarcoma cells, A549 lung cancer cells, Jurkat leukemia cells all have a certain inhibitory effect, but the best inhibitory activity is MNNG/HOS and MG63 osteosarcoma cells, so the present invention is used in subsequent experiments.
  • the compounds of the present invention were used to detect the cellular IC50 of two subtypes of osteosarcoma cells, MNNG/HOS and MG63 (Table 3).

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Abstract

一种3-(3-芳基/杂芳基-4-噻唑啉酮基)-N-芳基/杂环苯甲酰胺类化合物或其药学上可接受的盐及其制备方法，该类化合物或者其药物组合物可用于治疗骨肉瘤，结直肠癌，胰腺癌以及白血病等相关疾病。

Description

3-(3-芳基/杂芳基-4-噻唑啉酮基)-N-芳基/杂环苯甲酰胺类化合物及其应用 技术领域
本发明涉及合成医药化工领域，主要涉及一种3-(3-芳基/杂芳基-4-噻唑啉酮基)-N-芳基/杂环苯甲酰胺类化合物及其制备方法和应用。
背景技术
骨肉瘤也叫成骨肉瘤，是较常见的发生在20岁以下的青少年或儿童的一种恶性骨肿瘤(Link MP:Osteosarcoma in adolescents and young adults:new developments and controversies.Commentary on the use of presurgical chemotherapy.Cancer Treat Res 62:383-385,1993.)，根据骨肉瘤流行病学研究显示：在小儿骨恶性肿瘤中最多见，约为小儿肿瘤的5％。骨肉瘤目前仍是儿童和青少年恶性肿瘤死亡率很高的疾病，仅次于淋巴瘤和脑癌，但早期发现和及时治疗已经从很大程度上提高了该病的生存率。
针对不同类型骨肉瘤治疗方法通常采用手术后联合用药，值得注意的是骨肉瘤患者的癌症转移率高达80％，在发生转移的患者中，90％都是肺部转移。其中复发率20-30％，原位或者原位组织都有可能复发，并且复发后生存率，在过去的几十年，尽管通过调整增加剂量，变更次数以及多种化疗药联用等治疗方法，生存率并没有提高。
目前，针对骨肉瘤治疗靶点的研究主要集中在细胞表面受体酪氨酸激酶家族(PTKs)，和细胞内信号靶点。而针对这些靶点，主要的治疗药物分为三类：1)免疫调节剂；2)受体酪氨酸激酶抑制剂；3)细胞内信号通路抑制剂。此外，骨肉瘤的新靶点和治疗方案还有NK-kB配体、叶酸抑制剂等，但均处于试验研究阶段。
发明内容
本发明人注意到，在以往的文献报道中，噻唑琳酮骨架结构的化合物具有多种药理学活性，如式(IV)所示的化合物具有抗炎症活性以及式(V)所示的化合物具有抗艾滋活性：
Figure PCTCN2021104268-appb-000001
在本发明之前未有针对该类骨架关于骨肉瘤细胞活性测试评价的相关报道。本发明人研究发现并提出，该骨架化合物可能会产生一系列在结构和活性上有意义的新化合物分子，可能为 生物活性筛选提供新的化合物来源。
本发明提出了一种如式(I)、(II)和(III)所示的3-(3-芳基/杂芳基-4-噻唑啉酮基)-N-芳基/杂环苯甲酰胺类化合物或药学上可接受的盐，所述化合物为全新化合物，未有相关报道：
Figure PCTCN2021104268-appb-000002
其中，
Ar为芳基、芳杂环、烷基取代的芳基、卤素取代的芳基、烷基取代的杂芳基、卤素取代的杂芳基、三氟甲基取代的芳基、硝基取代的芳基、萘烷基、呋喃烷基、烯基、炔基、二苯烷基、二(4-溴苯基)烷基、三氟甲基取代的杂芳基、硝基取代的杂芳基；其中，所述芳杂环、杂芳基分别选自吲哚、苯并三氮唑、噻吩、呋喃、吡咯、双内酰胺、哌嗪、咪唑、恶唑、吡嗪；
R 1为单取代基或多取代基，选自下列基团：卤素、烷氧基、烷基、硝基、氰基、三氟甲基、苯基、氢、芳基、三元环、乙炔基；
R 2为环烷基，环氧烷基、烷基或氢；
R 3为卤素、烷氧基、烷基、环烷基、硝基、氰基、三氟甲基、苯基、氢；
n＝0；1；2；4；5；6。
Het为杂环，选自：吡啶、喹啉、托烷、吩噻嗪、苯并二氮杂卓、呋喃、吡唑酮、嘧啶、卤素取代的杂芳基、硝基取代的杂芳基、萘烷基、呋喃烷基、烯烷基、炔烷基、二苯烷基、二(4-溴苯基)烷基、三氟甲基取代的杂芳基、硝基取代的杂芳基；其中，所述杂芳基选自吲哚、苯并三氮唑、噻吩、吡咯、双内酰胺、哌嗪、咪唑、恶唑、吡嗪。
优选地，
Ar为苯基、芳杂环、C1-C6烷基取代的苯基、卤素取代的苯基、C1-C6烷基取代的杂芳基、卤素取代的杂芳基、三氟甲基取代的苯基、硝基取代的苯基、萘甲基、呋喃甲基、烯丙基、炔丙基、二苯甲基、二(4-溴苯基)甲基、三氟甲基取代的杂芳基、硝基取代的杂芳基；其中，所述芳杂环、杂芳基分别选自吲哚、苯并三氮唑、噻吩、呋喃、吡咯、双内酰胺、哌嗪、咪唑、恶唑、吡嗪等；
R 1为单取代基或多取代基，选自下列基团：卤素、C1-C10烷氧基、甲基、乙基、异丙基、硝基、氰基、三氟甲基、苯基、氢；
R 2为C1-C6烷基、C3-C6环烷基，C1-C6环氧烷基、氢等；
R 3为卤素、C1-C6烷氧基、C1-C6烷基、C3-C6环烷基、硝基、氰基、三氟甲基、苯基、氢；
Het为杂环，选自：吡啶、喹啉、托烷、吩噻嗪、苯并二氮杂卓、呋喃、吡唑酮、嘧啶、卤素取代的杂芳基、三氟甲基取代的芳基、硝基取代的芳基、萘C1-C6烷基、呋喃C1-C6烷基、烯C1-C6烷基、炔C1-C6烷基、二苯C1-C6烷基、二(4-溴苯基)C1-C6烷基、三氟甲基取代的杂芳基、硝基取代的杂芳基；其中，所述杂芳基选自吲哚、苯并三氮唑、噻吩、吡咯、双内酰胺，哌嗪、咪唑、恶唑、吡嗪。
进一步优选地，
Ar为苯基、芳杂环、甲基取代的苯基、卤素取代的苯基、甲基取代的杂芳基、卤素取代的杂芳基、三氟甲基取代的苯基、硝基取代的苯基、萘甲基、呋喃甲基、烯丙基、炔丙基、二苯甲基、二(4-溴苯基)甲基、三氟甲基取代的杂芳基、硝基取代的杂芳基、吲哚、苯并三氮唑、噻吩、呋喃、吡咯、双内酰胺、哌嗪、咪唑、恶唑、吡嗪等；
R 1为单取代基或多取代基，选自下列基团：卤素、C1-C10烷氧基、甲基、乙基、异丙基、硝基、氰基、三氟甲基、苯基、氢；
R 2为甲基、乙基、异丙基、环丙烷基，环氧丙基、氢等；
R 3为F、甲氧基、甲基、环丙烷基、硝基、氰基、三氟甲基、苯基、氢；
Het为杂环，选自：吡啶、喹啉、托烷、吩噻嗪、苯并二氮杂卓、呋喃、吡唑酮、嘧啶、卤素取代的杂芳基、三氟甲基取代的芳基、硝基取代的芳基、萘甲基、呋喃甲基、烯丙基、炔丙基、二苯甲基、二(4-溴苯基)甲基、三氟甲基取代的杂芳基、硝基取代的杂芳基；其中，所述杂芳基选自吲哚、苯并三氮唑、噻吩、吡咯、双内酰胺，哌嗪、咪唑、恶唑、吡嗪。
本发明所述3-(3-芳基/杂芳基-4-噻唑啉酮基)-N-芳基/杂环苯甲酰胺类化合物或药学上可接受的盐，包括但不限于以下：
3-(3-(2-甲氧基苯基)-4-噻唑啉酮基)-5-甲基-N-(4-苯基丁基)苯甲酰胺；
3-(3-(2-甲氧基苯基)-4-噻唑啉酮基)-5-氟-N-(4-苯基丁基)苯甲酰胺；
3-(3-(2-氟苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
4-(3-(2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-N-吡唑丁基)苯甲酰胺；
3-(3-(3-甲氧基苯基)-4-噻唑啉酮基)-N-(4-N-吡唑丁基)苯甲酰胺；
3-(3-(4-甲氧基苯基)-4-噻唑啉酮基)-N-(4-N-吡唑丁基)苯甲酰胺；
3-(3-(2,5-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-N-吡唑丁基)苯甲酰胺；
3-(3-(2，3-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-N-吡唑丁基)苯甲酰胺；
3-(3-(2，4-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-N-吡唑丁基)苯甲酰胺；
3-(3-(5-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-N-吡唑丁基)苯甲酰胺；
3-(3-(4-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-N-吡唑丁基)苯甲酰胺；
3-(3-(3-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-N-吡唑丁基)苯甲酰胺；
3-(3-(5-甲基-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-N-吡唑丁基)苯甲酰胺；
3-(3-(4-甲基-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-N-吡唑丁基)苯甲酰胺；
3-(3-(3-甲基-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-N-吡唑丁基)苯甲酰胺；
3-(3-(2-氟苯基)-4-噻唑啉酮基)-N-(4-N-吡唑丁基)苯甲酰胺；
3-(3-(3-氟苯基)-4-噻唑啉酮基)-N-(4-N-吡唑丁基)苯甲酰胺；
3-(3-(4-氟苯基)-4-噻唑啉酮基)-N-(4-N-吡唑丁基)苯甲酰胺；
3-(3-(2-氯苯基)-4-噻唑啉酮基)-N-(4-N-吡唑丁基)苯甲酰胺；
3-(3-(3-氯苯基)-4-噻唑啉酮基)-N-(4-N-吡唑丁基)苯甲酰胺；
3-(3-(4-氯苯基)-4-噻唑啉酮基)-N-(4-N-吡唑丁基)苯甲酰胺；
3-(3-(2-甲基苯基)-4-噻唑啉酮基)-N-(4-N-吡唑丁基)苯甲酰胺；
3-(3-(3-甲基苯基)-4-噻唑啉酮基)-N-(4-N-吡唑丁基)苯甲酰胺；
3-(3-(4-甲基苯基)-4-噻唑啉酮基)-N-(4-N-吡唑丁基)苯甲酰胺；
3-(3-(2-三氟甲基苯基)-4-噻唑啉酮基)-N-(4-N-吡唑丁基)苯甲酰胺；
3-(3-(3-三氟甲基苯基)-4-噻唑啉酮基)-N-(4-N-吡唑丁基)苯甲酰胺；
3-(3-(4-三氟甲基苯基)-4-噻唑啉酮基)-N-(4-N-吡唑丁基)苯甲酰胺；
3-(3-(3-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(4-氟)苯基丁基)苯甲酰胺；
3-(3-(4-甲氧基苯基)-4-噻唑啉酮基)-N-(4-苯(4-氟)基丁基)苯甲酰胺；
3-(3-(2,5-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-(4-氟)苯基丁基)苯甲酰胺；
3-(3-(2，3-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-(4-氟)苯基丁基)苯甲酰胺；
3-(3-(2，4-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-(4-氟)苯基丁基)苯甲酰胺；
3-(3-(5-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(4-氟)苯基丁基)苯甲酰胺；
3-(3-(4-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(4-氟)苯基丁基)苯甲酰胺；
3-(3-(3-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(4-氟)苯基丁基)苯甲酰胺；
3-(3-(5-甲基-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(4-氟)苯基丁基)苯甲酰胺；
3-(3-(4-甲基-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(4-氟)苯基丁基)苯甲酰胺；
3-(3-(3-甲基-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(4-氟)苯基丁基)苯甲酰胺；
3-(3-(2-氟苯基)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺；
3-(3-(3-氟苯基)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺；
3-(3-(4-氟苯基)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺；
3-(3-(2-氯苯基)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺；
3-(3-(3-氯苯基)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺；
3-(3-(4-氯苯基)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺；
3-(3-(2-甲基苯基)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺；
3-(3-(3-甲基苯基)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺；
3-(3-(4-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺；
3-(3-(2,5-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺；
3-(3-(2，3-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺；
3-(3-(2，4-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺；
3-(3-(5-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺；
3-(3-(4-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺；
3-(3-(3-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺；
3-(3-(5-甲基-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺；
3-(3-(4-甲基-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺；
3-(3-(3-甲基-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺；
3-(3-(2-氟苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(3-氟苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(4-氟苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(2-氯苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(3-氯苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(4-氯苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(2-甲基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(3-甲基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(4-甲基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(2-三氟甲基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(3-三氟甲基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(4-三氟甲基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(3-甲氧基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(4-甲氧基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(2,5-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(2，3-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(2，4-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(5-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(4-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(3-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(5-甲基-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(4-甲基-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(3-甲基-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-N-吲哚丁基)苯甲酰胺；
3-(3-(3-甲氧基苯基)-4-噻唑啉酮基)-N-(4-N-吲哚丁基)苯甲酰胺；
3-(3-(4-甲氧基苯基)-4-噻唑啉酮基)-N-(4-N-吲哚丁基)苯甲酰胺；
3-(3-(2,5-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-N-吲哚丁基)苯甲酰胺；
3-(3-(2，3-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-N-吲哚丁基)苯甲酰胺；
3-(3-(2，4-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-N-吲哚丁基)苯甲酰胺；
3-(3-(5-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-N-吲哚丁基)苯甲酰胺；
3-(3-(2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-N-苯并三氮唑基丁基)苯甲酰胺；
3-(3-(2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-Boc-哌嗪丁基)苯甲酰胺；
3-(3-(3-甲氧基苯基)-4-噻唑啉酮基)-N-(4-Boc-哌嗪丁基)苯甲酰胺；
3-(3-(4-甲氧基苯基)-4-噻唑啉酮基)-N-(4-Boc-哌嗪丁基)苯甲酰胺；
3-(3-(2,5-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-Boc-哌嗪丁基)苯甲酰胺；
3-(3-(2，3-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-Boc-哌嗪丁基)苯甲酰胺；
3-(3-(2，4-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-Boc-哌嗪丁基)苯甲酰胺；
(E)-3-(3-(2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁-3-烯-1-基)苯甲酰；
(E)-3-(3-(2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(苯基)丁-3-烯-1-基)苯甲酰；
(E)-3-(3-(5-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁-3-烯-1-基)苯甲酰胺；
(Z)-3-(3-(2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁-3-烯-1-基)苯甲酰；
(Z)-3-(3-(2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(苯基)丁-3-烯-1-基)苯甲酰；
(Z)-3-(3-(5-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁-3-烯-1-基)苯甲酰胺；
3-(3-(2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺；
3-(3-(2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(2,5-二氧-2,5-二氢-1H-吡咯-1-基)丁基)苯甲酰胺；
3-(3-(5-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺。
3-(3-(3-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺；
3-(3-(4-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺；
3-(3-(2,5-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺；
3-(3-(2，3-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺；
3-(3-(2，4-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺；
3-(3-(4-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺；
3-(3-(3-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺；
3-(3-(5-甲基-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺；
3-(3-(4-甲基-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺；
3-(3-(3-甲基-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺；
3-(3-(2-氟苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺；
3-(3-(3-氟苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺；
3-(3-(4-氟苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺；
3-(3-(2-氯苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺；
3-(3-(3-氯苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺；
3-(3-(4-氯苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺；
3-(3-(2-甲基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺；
3-(3-(3-甲基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺；
3-(3-(4-甲基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁基)苯甲酰胺；
3-(3-(2-甲氧基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺
3-(3-(3-甲氧基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(4-甲氧基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(2-乙氧基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(3-乙氧基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(4-乙氧基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(2,5-二甲氧基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(2，3-二甲氧基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(2，4-二甲氧基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(5-氟-2-甲氧基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(4-氟-2-甲氧基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(3-氟-2-甲氧基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(5-甲基-2-甲氧基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(4-甲基-2-甲氧基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(3-甲基-2-甲氧基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(2-氟苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(3-氟苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(4-氟苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(2-氯苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(3-氯苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(4-氯苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(2-甲基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(3-甲基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(4-甲基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(2-三氟甲基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(3-三氟甲基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(4-三氟甲基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(4-环丙烷基苯)-4-噻唑啉酮基)-N-(4-苯基乙基)苯甲酰胺；
3-(3-(4-环丙烷基苯)-4-噻唑啉酮基)-N-(4-苯基丙基)苯甲酰胺；
3-(3-(2-环丙烷基苯)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(2-环丙烷基苯)-4-噻唑啉酮基)-5-氟-N-(4-苯基丁基)苯甲酰胺；
3-(3-(2-环丙烷基苯)-4-噻唑啉酮基)-5-甲基-N-(4-苯基丁基)苯甲酰胺；
3-(3-(2-环丙烷基苯)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺；
3-(3-(2-环丙烷基苯)-4-噻唑啉酮基)-N-(4-(4-氟)苯基丁基)苯甲酰胺；
3-(3-(2-环丙烷基苯)-4-噻唑啉酮基)-5-甲基-N-(4-(4-氯)-苯基丁基)苯甲酰胺；
3-(3-(3-环丙烷基苯)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(3-环丙烷基苯)-4-噻唑啉酮基)-5-氟-N-(4-苯基丁基)苯甲酰胺；
3-(3-(3-环丙烷基苯)-4-噻唑啉酮基)-5-甲基-N-(4-苯基丁基)苯甲酰胺；
3-(3-(3-环丙烷基苯)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺；
3-(3-(3-环丙烷基苯)-4-噻唑啉酮基)-N-(4-(4-氟)苯基丁基)苯甲酰胺；
3-(3-(3-环丙烷基苯)-4-噻唑啉酮基)-5-甲基-N-(4-(4-氯)-苯基丁基)苯甲酰胺；
3-(3-(4-环丙烷基苯)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(4-环丙烷基苯)-4-噻唑啉酮基)-5-氟-N-(4-苯基丁基)苯甲酰胺；
3-(3-(4-环丙烷基苯)-4-噻唑啉酮基)-5-甲基-N-(4-苯基丁基)苯甲酰胺；
3-(3-(4-环丙烷基苯)-4-噻唑啉酮基)-5-甲基-N-(4-(4-氯)-苯基丁基)苯甲酰胺；
3-(3-(4-环丙烷基苯)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺；
3-(3-(4-环丙烷基苯)-4-噻唑啉酮基)-N-(4-(4-氟)苯基丁基)苯甲酰胺；
3-(3-苯基-4-噻唑啉酮基)-5-环丙烷基-N-(4-苯基丁基)苯甲酰胺；
3-(3-(3-环丙基苯基)-4-噻唑琳酮基)-N-(4-(N-吡唑)丁基)-苯甲酰胺；
3-(3-(3-环丙基苯基)-4-噻唑琳酮基)-N-(4-(N-吲哚)丁基)-苯甲酰胺；
3-(3-(4-环丙烷基苯)-4-噻唑啉酮基)-N-5-甲基-(4-(N-吡唑)丁基)苯甲酰胺；
3-环丙基-5-(3-(2-甲氧基苯基)-4-噻唑琳酮基)-N-(4-苯基丁基)苯甲酰胺；
3-环丙基-5-(3-(3-甲氧基苯基)-4-噻唑琳酮基)-N-(4-苯基丁基)苯甲酰胺；
3-环丙基-5-(3-(4-甲氧基苯基)-4-噻唑琳酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(3-乙炔基苯)-4-噻唑啉酮基)-N-(4-N-吡唑丁基)苯甲酰胺；
3-(3-(3-乙炔基苯)-4-噻唑啉酮基)-N-(4-N-苯基丙基)苯甲酰胺；
3-(3-(3-乙炔基苯)-4-噻唑啉酮基)-N-(4-N-苯基乙基)苯甲酰胺；
3-(3-(2-甲氧基-5-乙炔基苯)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(2-甲基-4-乙炔基苯)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(2-甲基-4-乙炔基苯)-4-噻唑啉酮基)-N-(4-N-吲哚丁基)苯甲酰胺；
3-(3-(2-甲基-4-乙炔基苯)-4-噻唑啉酮基)-N-(4-N-吡唑丁基)苯甲酰胺；
3-(3-(2-甲基-5-乙炔基苯)-4(5-甲基)-噻唑啉酮基)-N-(4-N-吲哚丁基)苯甲酰胺；
3-(3-(2-甲氧基苯)-4-噻唑啉酮基)-5-乙炔基-N-(4-苯基丁基)苯甲酰胺；
3-(3-(2-乙炔基苯)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(2-乙炔基苯)-4-噻唑啉酮基)-5-氟-N-(4-苯基丁基)苯甲酰胺；
3-(3-(2-乙炔基苯)-4-噻唑啉酮基)-5-甲基-N-(4-苯基丁基)苯甲酰胺；
3-(3-(2-乙炔基苯)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺；
3-(3-(2-乙炔基苯)-4-噻唑啉酮基)-N-(4-(4-氟)苯基丁基)苯甲酰胺；
3-(3-(3-乙炔基苯)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(3-乙炔基苯)-4-噻唑啉酮基)-5-氟-N-(4-苯基丁基)苯甲酰胺；
3-(3-(3-乙炔基苯)-4-噻唑啉酮基)-5-甲基-N-(4-苯基丁基)苯甲酰胺；
3-(3-(3-乙炔基苯)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺；
3-(3-(3-乙炔基苯)-4-噻唑啉酮基)-N-(4-(4-氟)苯基丁基)苯甲酰胺；
3-(3-(4-乙炔基苯)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(4-乙炔基苯)-4-噻唑啉酮基)-5-氟-N-(4-苯基丁基)苯甲酰胺；
3-(3-(4-乙炔基苯)-4-噻唑啉酮基)-5-甲基-N-(4-苯基丁基)苯甲酰胺；
3-(3-(4-乙炔基苯)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺；
3-(3-(4-乙炔基苯)-4-噻唑啉酮基)-N-(4-(4-氟)苯基丁基)苯甲酰胺；
3-(3-(2-甲基-4-乙炔基苯)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(2-甲基-4-乙炔基苯)-4-噻唑啉酮基)-N-(4-苯并吡咯基丁基)苯甲酰胺；
3-(3-(2-甲基-4-乙炔基苯)-4-噻唑啉酮基)-N-(4-咔唑基丁基)苯甲酰胺；
3-(3-(2-甲基-5-乙炔基苯)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(2-甲氧基-5-乙炔基苯)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(2-甲氧基-5-乙炔基苯)-4-噻唑啉酮基)-5-氟-N-(4-苯基丁基)苯甲酰胺；
3-(3-(2-甲氧基-5-乙炔基苯)-4-噻唑啉酮基)-5-甲基-N-(4-苯基丁基)苯甲酰胺；
3-(3-(2-甲氧基-5-乙炔基苯)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺；
3-(3-(2-甲氧基-5-乙炔基苯)-4-噻唑啉酮基)-N-(4-(4-氟)苯基丁基)苯甲酰胺；
3-(3-苯基-4-噻唑啉酮基)-5-乙炔基-N-(4-苯基丁基)苯甲酰胺；
3-(3-苯基-4-噻唑啉酮基)-5-乙炔基-N-(4-(4-氯)苯基丁基)苯甲酰胺；
3-(3-苯基-4-噻唑啉酮基)-5-乙炔基-N-(4-(4-氟)苯基丁基)苯甲酰胺；
3-(3-(2-甲氧基苯)-4-噻唑啉酮基)-5-乙炔基-N-(4-(4-氯)苯基丁基)苯甲酰胺；
3-(3-(2-甲氧基苯)-4-噻唑啉酮基)-5-乙炔基-N-(4-(4-氟)苯基丁基)苯甲酰胺；
3-(3-(2-吡啶基)-4-噻唑啉酮基)-N-(4-吡唑丁基)苯甲酰胺；
3-(3-(2-(4-溴)吡啶基)-4-噻唑啉酮基)-N-(4-吡唑丁基)苯甲酰胺；
3-(3-(2-(4-氯)吡啶基)-4-噻唑啉酮基)-N-(4-吡唑丁基)苯甲酰胺；
3-(3-(2-(4-氟)吡啶基)-4-噻唑啉酮基)-N-(4-吡唑丁基)苯甲酰胺；
3-(3-(2-(4-甲基)吡啶基)-4-噻唑啉酮基)-N-(4-吡唑丁基)苯甲酰胺；
N-(4-(1H-吡唑啉-1-基)丁基)-3-(3-(4-(3-乙基-2,6-二氧哌啶-3-基)苯基)-4-恶噻唑烷-2-基)苯甲酰胺；
2-(2-(3-((4-(1H-吡唑啉-1-基)丁基)氨甲酰基)苯基)-4-恶噻唑烷-3-基)-4-甲基噻唑-5-羧酸乙酯；
3-(3-(3-吡啶基)-4-噻唑啉酮基)-N-(4-吡唑丁基)苯甲酰胺；
3-(3-(4-吡啶基)-4-噻唑啉酮基)-N-(4-吡唑丁基)苯甲酰胺；
3-氟-5-(4-氧代-3-(吡啶-2-基)噻唑烷-2-基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(2-吡啶基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(2-吡嗪基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(2-吡嗪基)-4-噻唑啉酮基)-5-氟-N-(4-苯基丁基)苯甲酰胺；
3-(3-(2-吡啶基)-4-噻唑啉酮基)--5-甲基-N-(4-苯基丁基)苯甲酰胺；
3-(3-(2-噻唑基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(3-叔丁基2-异恶唑基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-(2-吡嗪基)-4-噻唑啉酮基)-N-(4-1,2,4-三氮唑基丁基)苯甲酰胺；
3-(3-(2-吡啶基)-4-噻唑啉酮基)-N-(4-N-吲哚丁基)苯甲酰胺；
3-(3-(2-吡啶基)-4-噻唑啉酮基)-N-(4-N-苯并三氮唑基丁基)苯甲酰胺；
3-(3-(2-吡啶基)-4-噻唑啉酮基)-N-(4-N-吡唑丁基)苯甲酰胺；
3-(3-(2-吡啶基)-4-噻唑啉酮基)-N-(4-Boc-哌嗪丁基)苯甲酰胺；
3-(3-(2-吡啶基)-4-噻唑啉酮基)-N-(4-马来酰亚胺丁基)苯甲酰胺；
3-(3-(2-吡啶基)-4-噻唑啉酮基)-N-(4-噻吩丁基)苯甲酰胺；
3-(3-(4-(叔丁基)异恶唑-3-基)-4-恶噻唑烷-2-基)-N-(4-苯基丁基)苯甲酰胺；
3-(3-([1,1'-联苯]-4-基)-4-恶噻唑烷-2-基)-N-(4-苯基丁基)苯甲酰胺。
本发明还提供了式(II)和(III)所示化合物中所用到的原料
Figure PCTCN2021104268-appb-000003
的合成方法。
在一个具体的实施方式中，所述如式(III)所示化合物中所用到的原料的合成方法，具体包括步骤如下四种方法：
方法一：
Figure PCTCN2021104268-appb-000004
在干燥的三颈烧瓶中加入S1、氢化钠，进行氮气保护，随后加入干燥的DMSO或者DMF，于110℃下搅拌10min，然后将N-(6-溴己基)邻苯二甲酰亚胺和催化量的KI溶于干燥的DMSO或DMF溶液中加入到反应液中，于110℃下继续搅拌，薄层色谱法监测反应。反应完全后加入饱和氯化钠，用二氯甲烷萃取三次，收集有机相，无水硫酸钠干燥，浓缩后通过柱层分析法分离纯化(石油醚/乙酸乙酯＝9:1)。
向上述分离纯化得到的产物加入甲醇、肼，65℃下反应15h，薄层色谱法监测反应，反应完全后加入1M氢氧化钠溶液，用二氯甲烷萃取三次，收集有机相，无水硫酸钠干燥，浓缩后无需纯化直接用于反应。
方法二：
Figure PCTCN2021104268-appb-000005
在干燥的三颈烧瓶中加入S1、碳酸钾，N-(6-溴己基)邻苯二甲酰亚胺和催化量的KI，随后加入干燥的乙腈，于回流条件反应，薄层色谱法监测反应。反应完全后加入饱和氯化钠，用二氯甲烷萃取三次，收集有机相，无水硫酸钠干燥，浓缩后通过柱层分析法分离纯化(石油醚/乙酸乙酯＝10:1～1:1)。
向上述分离纯化得到的产物加入甲醇、肼，65℃下反应15h，薄层色谱法监测反应，反应完全后加入1M氢氧化钠溶液，用二氯甲烷萃取三次，收集有机相，无水硫酸钠干燥，浓缩后无需纯化直接用于反应。
方法三：
Figure PCTCN2021104268-appb-000006
在干燥的三颈烧瓶中加入N-(3-溴丙基)苯二胺和S1以及THF。氮气保护后降温到-55℃，加入叔丁醇钾。加完后将反应混合物升至10℃，反应4小时后，倒入水中。用乙酸乙酯萃取，合并有机相，用水洗涤，硫酸镁干燥。减压浓缩，得到油状粗产物，柱层析纯化，用于下一步；
将上述产物溶解在乙醇中，加入水合肼，回流过夜，滤出白色不溶物，减压除去溶剂。将所得油状物溶解在乙酸乙酯中，用2M NaOH洗涤；再将水相用乙酸乙酯萃取，合并有机相后用硫酸镁干燥。减压除去溶剂，无需纯化直接用于反应。
方法四：
Figure PCTCN2021104268-appb-000007
在干燥的三颈烧瓶中加入N-(3-溴丙基)苯二胺和S1以及THF。氮气保护后降温到-55℃，加入叔丁醇钾。加完后将反应混合物升至10℃，反应4小时后，倒入水中。用乙酸乙酯萃取，合并有机相，用水洗涤，硫酸镁干燥。减压浓缩，得到油状粗产物，柱层析纯化，用于下一步；
将上述产物溶解在乙醇中，加入水合肼，回流过夜，滤出白色不溶物，减压除去溶剂。将所得油状物溶解在乙酸乙酯中，用2M NaOH洗涤；再将水相用乙酸乙酯萃取，合并有机相后用硫酸镁干燥。减压除去溶剂，无需纯化直接用于反应。
将上步所得粗产品放置于三口瓶中，加入含量10％的钯碳，氮气保护之后加入甲醇，再用氢气置换氮气，整个反应体系在氢气氛围和室温下反应16h之后，反应液用硅藻土抽滤，收集滤液，旋干溶剂，直接用于下步反应。
本发明还提出了一种如式(I)或式(II)或式(III)所示的3-(3-芳基/杂芳基-4-噻唑啉酮基)-N-芳基/杂环苯甲酰胺类化合物或药学上可接受的盐的合成方法，具体包括步骤如下，包含如下(A)、(B)、(C)、(D)所示：(本发明中所设计化合物合成路线均与下述方法一致，下述方法仅描述式(I)和式(III)的合成方法，反应式(A)-1、(A)-2和(A)-3均为合成原料的步骤，式(II)的合成方法参见式(I))
Figure PCTCN2021104268-appb-000008
用间溴苯胺与环丙硼酸在醋酸钯/环己基磷体系催化下进行偶联，得到间环丙烷基苯胺。
Figure PCTCN2021104268-appb-000009
Figure PCTCN2021104268-appb-000010
用对碘苯胺与三甲基硅基乙炔进行Sonogashira偶联反应，得到对三甲基硅基乙炔基苯胺，随后用碳酸钾脱去三甲基硅基，得到产物对乙炔基苯胺。
Figure PCTCN2021104268-appb-000011
用硼氢化钠将取代的间苯二甲酸甲酯中的一个甲酯基团还原为醇，再在二氧化锰条件下将醇氧化为醛。当R 3为碘原子时，得到的化合物与三甲基硅基乙炔进行Sonogashira偶联反应，生成3-甲醛-5-三甲基硅基乙炔基苯甲酸甲酯，随后用碳酸钾脱去三甲基硅基，得到产物3-甲醛-5-乙炔基苯甲酸甲酯。
Figure PCTCN2021104268-appb-000012
第一步，用含有取代基的苯胺(10mmol，1.0eq)与取代的3-甲醛苯甲酸甲酯(10mmo，1.0eq)在甲苯回流条件下反应30分钟，此时会生成相应的亚胺化合物。随后冷却至室温，再向反应体系中加入硫代乙醇酸(10mmol，1.0eq)继续回流，反应5h后冷却至室温，点板监测反应结束，再通过柱层析(石油醚：乙酸乙酯＝3:1～1:1)分离纯化得到酯类化合物。
Figure PCTCN2021104268-appb-000013
第二步，将第一步所得酯类化合物(5mmol，1.0eq)与LiOH(5.25mmol，1.05eq)在甲醇：水(4:1)的溶剂中，室温条件下反应20小时，点板监测到底物消耗完全，反应结束后， 将溶剂中的甲醇旋蒸除去，再将剩下的反应液倒入50mL水中，滴加3N HCl酸化，有大量白色固体析出，用pH试纸监测直至pH＝1。用布氏漏斗将白色固体抽滤出来，用乙酸乙酯溶解白色固体，无水硫酸钠干燥之后，旋蒸得羧酸类产物。
Figure PCTCN2021104268-appb-000014
第三步，将第二步所得羧酸类产物(1.5mmol，1.0eq)与1-羟基苯并三唑(即HOBt，3.0mmol，2.0eq)溶于20mL四氢呋喃中，冰浴条件下，加入N,N-二异丙基乙胺(DIPEA，4.5mmol，3.0eq)，搅拌20分钟后，加入化合物长链胺，继续搅拌10分钟。随后，分批加入缩合剂1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDCI，3mmol，2.0eq)，反应两小时后，点板监测，原料消耗完全。往反应液中依次加入适量饱和碳酸氢钠，用饱和食盐水洗涤，再用乙酸乙酯萃取三次，旋蒸得到的粗产物通过柱层析(石油醚：乙酸乙酯＝3:1～1:1)最终得到目标产物。
其中，反应式(A)、(B)(C)及反应式(D)中，R 1、R 2、R 3和Ar的定义同式(I),n＝1,2,3,4,5,6。
本发明还提供了所述式(III)所示的3-(3-(杂芳基)-4-噻唑啉酮基)-N-芳基苯甲酰胺类化合物或药学上可接受的盐的合成方法，本发明所述方法中所用到的溶剂包括烷烃类、卤代烷烃类、醚类、卤代醚类、取代苯类、醇类、酯类、酮类、卤代苯、杂芳烃类、酰胺类、亚砜类、水之一种或几种的组合。所述方法基本合成步骤如下：
Figure PCTCN2021104268-appb-000015
第一步，将化合物1(5mmol，1.0eq)与LiOH(5.25mmol，1.05eq)在甲醇：水(4:1)的溶剂中，室温下条件下反应20小时，点板监测到底物消耗完全，反应结束后，将溶剂中的甲醇旋蒸除去，再将剩下的反应液倒入50mL水中，滴加3N HCl酸化，有大量白色固体析出，用pH试纸监测直至pH＝1。用布氏漏斗将白色固体抽滤出来，用乙酸乙酯溶解白色固体，无水硫酸钠干燥之后，旋蒸得产物2。
第二步，将化合物2(1.5mmol，1.0eq)与1-羟基苯并三唑(即HOBt，3.0mmol，2.0eq)溶于20mL四氢呋喃中，冰浴条件下，加入N，N-二异丙基乙胺(DIPEA，4.5mmol，3.0eq)，搅拌20分钟后，加入化合物烷基胺，继续搅拌10分钟。随后，分批加入缩合剂1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDCI，3mmol，2.0eq)，反应两小时后，点板监测，原料消耗完全。往反应液中依次加入适量饱和碳酸氢钠，用饱和食盐水洗涤，再用乙酸乙酯萃取三次，旋蒸得到的粗产物通过柱层析(石油醚：乙酸乙酯＝3:1-1:1)得到化合物3。
第三步，用杂环的氨4(5mmol，1.0eq)与硫代乙醇酸5(5mmol，1.0eq)在甲苯/1，4-二氧六环混合溶液回流条件下反应30分钟，此时会生成相应的酰胺化合物。随后冷却至室温，再向反应体系中加入3(10mmol，1.0eq)继续回流，反应5h后冷却至室温，点板监测反应结束，再通过柱层析(石油醚：乙酸乙酯＝3:1～1:1)分离纯化得到白色泡沫状固体1。
其中，反应式(A)、(B)(C)及反应式(D)中，R 1、R 2、R 3、Ar、Het的定义同式(I)。
本发明还提出了所述3-(3-芳基-4-噻唑啉酮基)-N-芳基苯甲酰胺类化合物与酸形成的酸加成盐；其中，所述酸是盐酸、硫酸、磷酸、氢溴酸、乙酸、水杨酸、酒石酸、乳酸、柠檬酸、甲磺酸、对甲苯磺酸、马来酸、丙酮酸或琥珀酸等。
本发明还提出了一种药物组合物，其包含所述的3-(3-芳基-4-噻唑啉酮基)-N-芳基苯甲酰胺类化合物或药学上可接受的盐，以及药学上可接受的载体。
其中，所述药物组合物被配制成丸剂、胶囊剂、乳膏、凝胶剂、赋形剂、可注射流体、气雾剂、糖浆剂或透皮贴剂等。
本发明还提出了所述3-(3-芳基/杂芳基-4-噻唑啉酮基)-N-芳基/杂环苯甲酰胺类化合物或药学上可接受的盐，或药物组合物在制备预防和/或治疗肿瘤的药物中的应用。
其中，所述3-(3-芳基/杂芳基-4-噻唑啉酮基)-N-芳基/杂环苯甲酰胺类化合物用于抑制肿瘤细胞的增殖、生长、迁移、浸润、转移和复发，或促进肿瘤细胞的凋亡。
其中，所述肿瘤细胞为骨肉瘤细胞、结直肠癌细胞、白血病细胞、肺癌细胞、胰腺癌细胞等。
所述骨肉瘤细胞包括SJSA-1、U2OS、HOS、MNNG/HOS、MG63、143b；
所述胰腺癌细胞包括PANC-1；
所述肺癌细胞包括A549；
所述结直肠癌细胞包括HCT116；
所述白血病细胞包括Jurkat。
本发明的有益效果在于：本发明公开了一种3-(3-芳基-4-噻唑啉酮基)-N-芳基苯甲酰胺类化合物或药学上可接受的盐及其制备方法，该类化合物或者组合物对肿瘤细胞有抑制活性的作用，可用于治疗骨肉瘤，结直肠癌，胰腺癌以及白血病等相关疾病，在肿瘤疾病的研究上具有重要意义。
附图说明
图1为本发明实施例1所得产物1的 1H NMR和 13C NMR示意图。
图2为本发明实施例2所得产物2的 1H NMR、 13C NMR和 19F NMR示意图。
图3为本发明实施例3所得产物3的 1H NMR、 13C NMR和 19F NMR示意图。
图4为本发明实施例4所得产物4的 1H NMR和 13C NMR示意图。
图5为本发明实施例5所得产物5的 1H NMR、 13C NMR和 19F NMR示意图。
图6为本发明实施例6所得产物6的 1H NMR和 13C NMR示意图。
图7为本发明实施例7所得产物7的 1H NMR、 13C NMR和 19F NMR示意图。
图8为本发明实施例8所得产物8的 1H NMR、 13C NMR和 19F NMR示意图。
图9为本发明实施例9所得产物9的 1H NMR和 13C NMR示意图。
图10为本发明实施例10所得产物10的 1H NMR和 13C NMR示意图。
图11为本发明实施例11所得产物11的 1H NMR和 13C NMR示意图。
图12为本发明实施例12所得产物12的 1H NMR和 13C NMR示意图。
图13为本发明实施例13所得产物13的 1H NMR和 13C NMR示意图。
图14为本发明实施例14所得产物14的 1H NMR和 13C NMR示意图。
图15为本发明实施例15所得产物15的 1H NMR、 13C NMR和 19F NMR示意图。
图16为本发明实施例16所得产物16的 1H NMR和 13C NMR示意图。
图17为本发明实施例17所得产物17的 1H NMR和 13C NMR示意图。
图18为本发明实施例18所得产物18的 1H NMR、 13C NMR和 19F NMR示意图。
图19为实施例19所得产物19的 1H NMR(图19A)和 13C NMR(图19B)示意图。
图20为实施例20所得产物20的 1H NMR(图20A)和 13C NMR(图20B)示意图。
图21为实施例21所得产物21的 1H NMR(图21A)和 13C NMR(图21B)示意图。
图22为实施例22所得产物22的 1H NMR(图22A)和 13C NMR(图22B)示意图。
图23为实施例23所得产物23的 1H NMR(图23A)和 13C NMR(图23B)示意图。
图24为实施例24所得产物24的 1H NMR(图24A)和 13C NMR(图24B)示意图。
图25为实施例25所得产物25的 1H NMR(图25A)和 13C NMR(图25B)示意图。
图26为实施例26所得产物26的 1H NMR(图26)。
图27为实施例27所得产物27的 1H NMR(图27A)和 13C NMR(图27B)示意图。
图28为实施例28所得产物28的 1H NMR(图28A)和 13C NMR(图28B)示意图。
图29为实施例29所得产物29的 1H NMR(图29A)和 13C NMR(图29B)示意图。
图30为实施例30所得产物30的 1H NMR(图30A)和 13C NMR(图30B)示意图。
图31为实施例31所得产物31的 1H NMR(图31A)和 13C NMR(图31B)示意图。
图32为实施例32所得产物32的 1H NMR(图32A)和 13C NMR(图32B)示意图。
图33为实施例33所得产物33的 1H NMR(图33A)和 13C NMR(图33B)示意图。
图34为实施例34所得产物34的 1H NMR(图34A)和 13C NMR(图34B)示意图。
图35为实施例35所得产物35的 1H NMR(图35A)和 13C NMR(图35B)示意图。
图36为实施例36所得产物36的 1H NMR(图36A)和 13C NMR(图36B)示意图。
图37为实施例37所得产物37的 1H NMR(图37A)和 13C NMR(图37B)示意图。
图38为实施例38所得产物38的 1H NMR(图38A)和 13C NMR(图38B)示意图。
图39为实施例39所得产物39的 1H NMR(图39A)、 13C NMR(图39B)和 19F NMR(图39C)示意图。
图40为实施例2所得产物40的 1H NMR(图40A)和 13C NMR(图40B)示意图。
图41为实施例41所得产物41的 1H NMR(图41A)和 13C NMR(图41B)示意图。
图42为实施例42所得产物42的 1H NMR(图42A)和 13C NMR(图42B)示意图。
图43为实施例43所得产物43的 1H NMR(图43A)和 13C NMR(图43B)示意图和 19F NMR(图43C)示意图。
图44为实施例44所得产物44的 1H NMR(图44A)和 13C NMR(图44B)示意图。
图45为实施例7所得产物45的 1H NMR(图45A)和 13C NMR(图45B)示意图。
图46为实施例8所得产物46的 1H NMR(图46A)和 13C NMR(图46B)示意图。
图47为实施例47所得产物47的 1H NMR(图47A)和 13C NMR(图47B)示意图。
图48为实施例48所得产物48的 1H NMR(图48A)和 13C NMR(图48B)示意图。
图49为实施例49所得产物49的 1H NMR(图49A)和 13C NMR(图49B)示意图。
图50为实施例50所得产物50的 1H NMR(图50A)和 13C NMR(图50B)示意图。
图51为实施例51所得产物51的 1H NMR。
图52为实施例52所得产物52的 1H NMR(图52A)和 13C NMR(图52B)示意图。
图53为实施例53所得产物53的 1H NMR(图53A)和 13C NMR(图53B)示意图。
具体实施方式
结合以下具体实施例和附图，对本发明作进一步的详细说明，本发明的保护内容不局限于以下实施例。在不背离发明构思的精神和范围下，本领域技术人员能够想到的变化和优点都被包括在本发明中，并且以所附的权利要求书为保护范围。
本发明以下实施例中关于化合物的制备方法参考上文中提到的式(I)所示化合物的制备。测定方法：低分辨质谱(分子量)以及核磁仪器(氢谱、碳谱以及氟谱)。
实施例1
Figure PCTCN2021104268-appb-000016
1H NMR(400MHz,Chloroform-d)δ7.68(d,J＝12.4Hz,1H),7.58(d,J＝7.6Hz,1H),7.48(d,J＝7.4Hz,1H),7.31(dd,J＝16.3Hz,8.2Hz,3H),7.18(q,J＝6.2Hz,5.7Hz,3H),3.92(t,J＝9.1Hz,2H),3.82(s,2H),3.53(s,0H),3.44(q,J＝6.3Hz,2H),2.67(t,J＝7.0Hz,2H),1.31–1.22(m,5H).
13C NMR(101MHz,CDCl 3)δ171.45,166.80,154.81,142.00,139.78,134.97,129.72,128.76,128.41,127.25,126.51,125.88,120.92,112.15,64.35,55.78,39.97,35.47,33.17,29.18,28.70.
实施例2：
Figure PCTCN2021104268-appb-000017
1H NMR(400MHz,Chloroform-d)δ7.73(s,1H),7.61(d,J＝7.4Hz,1H),7.48(d,J＝7.3Hz,1H),7.40–7.25(m,4H),7.18(d,J＝6.9Hz,5H),7.08–6.97(m,5H),6.12(s,1H),4.15–3.76(m,2H),3.40(d,J＝22.2Hz,2H),2.65(d,J＝7.1Hz,3H),1.66(dd,J＝19.2Hz,11.2Hz,8H).
13C NMR(101MHz,CDCl 3)δ170.99,166.62,142.00,139.12,135.25,130.40,129.90,129.42,128.41,127.65,126.13,125.89,124.71,116.82,116.62,64.61,39.99,35.47,33.11,29.14,28.69.
19F NMR(376MHz,CDCl 3)δ-118.96.
实施例3：
Figure PCTCN2021104268-appb-000018
1H NMR(400MHz,Chloroform-d)δ7.73(s,1H),7.58(d,J＝7.3Hz,1H),7.49(s,1H),7.38(dd,J＝17.1Hz,8.6Hz,7H),7.27(d,J＝6.8Hz,3H),7.17(d,J＝6.9Hz,4H),6.17(s,1H),6.12(s,1H),3.99(d,J＝16.0Hz,1H),3.88(d,J＝15.9Hz,1H),3.43(d,J＝5.6Hz,2H),2.64(d,J＝6.8Hz,3H),1.83–1.52(m,8H).
13C NMR(101MHz,CDCl 3)δ171.04,166.52,141.98,139.60,137.84,135.58,129.79,129.62,129.34,128.65,128.37,127.21,126.01,125.88,123.71,122.13,64.86,40.03,35.46,33.37,29.13,28.68.
19F NMR(376MHz,CDCl 3)δ-62.73.
实施例4：
Figure PCTCN2021104268-appb-000019
1H NMR(400MHz,Chloroform-d)δ7.81(s,1H),7.59(d,J＝6.7Hz,1H),7.47(d,J＝6.6Hz,1H),7.25(d,J＝6.3Hz,3H),7.16(s,5H),7.05(t,J＝8.0Hz,2H),6.52(s,1H),6.42(d,J＝8.0Hz,1H),6.30(d,J＝8.0Hz,1H),6.16(s,1H),3.94–3.81(m,2H),3.78(s,3H),3.51(s,3H),3.39–3.26(m,4H),2.61(s,3H),1.67–1.48(m,7H).
13C NMR(101MHz,CDCl 3)δ170.75,166.98,156.62,156.13,141.99,139.19,134.52,131.09,129.90,128.41,128.11,127.50,126.50,125.89,113.80,105.14,104.23,63.57,56.08,56.00,39.94,35.48,33.16,29.26,28.72.
实施例5:
Figure PCTCN2021104268-appb-000020
1H NMR(400MHz,Chloroform-d)δ7.72(s,1H),7.58(d,J＝7.6Hz,1H),7.39(dd,J＝20.6Hz,7.3Hz,3H),7.31–7.26(m,4H),7.18(t,J＝8.1Hz,7H),6.98(dd,J＝23.9Hz,9.0Hz,3H),6.85(t,J＝8.1Hz,2H),6.15(d,J＝12.9Hz,3H),3.97(d,J＝16.0Hz,1H),3.85(d,J＝16.0Hz,1H),3.43(d,J＝6.0Hz,3H),2.65(t,J＝6.6Hz,4H),1.78–1.47(m,5H).
13C NMR(101MHz,CDCl 3)δ170.97,166.59,142.66,139.94,135.51,130.24,129.44,129.30,128.41,127.11,125.88,125.84,120.64,114.19,113.98,112.85,112.61,64.87,40.03,35.46,33.40,29.14,28.69.
19F NMR(376MHz,CDCl 3)δ-110.67.
实施例6：
Figure PCTCN2021104268-appb-000021
1H NMR(400MHz,Chloroform-d)δ7.74(s,1H),7.59(d,J＝7.1Hz,1H),7.39(d,J＝6.9Hz,1H),7.30–7.21(m,5H),7.15(t,J＝8.9Hz,5H),7.07(t,J＝7.5Hz,2H),6.97(s,1H),6.89(dd,J＝17.9Hz,7.2Hz,3H),6.56(s,1H),6.07(s,1H),3.92(d,J＝15.7Hz,1H),3.78(d,J＝15.7Hz,1H),3.39–3.27(m,3H),2.61(s,3H),2.19(s,3H),1.70–1.49(m,7H).
13C NMR(101MHz,CDCl 3)δ171.14,166.74,142.19,140.08,137.10,135.26,129.70,128.96,128.44,128.38,126.45,125.86,122.79,65.34,39.98,35.53,33.50,29.08,28.77,21.35.
实施例7：
Figure PCTCN2021104268-appb-000022
1H NMR(400MHz,Chloroform-d)δ7.73(s,1H),7.57(d,J＝7.8Hz,1H),7.47(d,J＝7.8Hz,1H),7.38–7.27(m,3H),7.22–7.15(m,3H),6.83(t,J＝7.4Hz,1H),6.58(d,J＝10.3Hz,1H),6.48(t,J＝8.6Hz,1H),6.04(d,J＝10.6Hz,2H),3.90(dd,2H),3.80(s,3H),3.45(q,J＝6.7Hz,2H),2.67(t,J＝7.4Hz,2H),1.76–1.62(m,4H).
13C NMR(101MHz,CDCl 3)δ171.55,166.69,164.28,161.82,141.99,139.64,135.06,131.20,131.10,128.78,128.38,127.22,126.78,125.89,121.18,107.56,107.34,100.63,100.36,64.32,56.07,39.99,35.47,33.03,29.17,28.71.
19F NMR(376MHz,CDCl 3)δ-109.07.
实施例8：
Figure PCTCN2021104268-appb-000023
1H NMR(400MHz,Chloroform-d)δ7.44(s,1H),7.31–7.25(m,4H),7.23–7.15(m,4H),6.93(d,J＝7.9Hz,1H),6.90–6.78(m,2H),6.11(s,1H),5.96(s,1H),3.92(d,J＝816.0Hz,2H),3.83(s,3H),3.47–3.37(m,2H),2.66(t,J＝7.4Hz,2H),1.74–1.60(m,4H).
13C NMR(101MHz,CDCl 3)δ165.49,154.76,142.47,141.96,137.12,129.87,128.40,125.91,125.00,121.96,121.04,117.56,117.33,114.87,114.64,112.25,63.84,55.78,40.05,35.45,33.02,29.06,28.67.
19F NMR(376MHz,CDCl 3)δ-110.98.
实施例9：
Figure PCTCN2021104268-appb-000024
1H NMR(400MHz,Chloroform-d)δ7.45(s,1H),7.40(s,1H),7.29(d,J＝4.7Hz,3H),7.18(t,J＝7.3Hz,5H),6.90(d,J＝7.8Hz,1H),6.86(d,J＝8.3Hz,1H),6.79(t,J＝7.8Hz,1H),6.08(s,1H),5.96(d,J＝7.7Hz,1H),3.96(d,J＝15.7Hz,1H),3.89(d,J＝15.6Hz,1H),3.82(s,3H),3.43(q,J＝6.7Hz,2H),2.66(t,J＝7.5Hz,2H),2.33(s,3H),1.75–1.58(m,4H).
13C NMR(101MHz,CDCl 3)δ171.46,167.00,154.84,142.02,139.78,138.79,131.14,129.99,129.70,128.41,128.14,125.88,123.44,120.91,112.17,64.36,55.78,39.92,35.48,33.16,29.20,28.69,21.31.
实施例10：
Figure PCTCN2021104268-appb-000025
1H NMR(400MHz,CDCl 3)δ7.87(s,1H),7.80(d,J＝7.3Hz,2H),7.42(t,J＝7.4Hz,2H),7.34(t,J＝7.3Hz,1H),6.34(d,J＝5.0Hz,1H),4.20(dd,J＝14.2Hz,7.4Hz,1H),4.05(dd,J＝14.0Hz,7.3Hz,1H),2.75–2.64(m,1H),2.42(dd,J＝23.9Hz,12.0Hz,2H),2.14–2.03(m,1H).
13C NMR(101MHz,CDCl 3)δ148.08,131.29,130.20,128.84,128.52,126.05,92.25,69.59,31.37,24.50.HRMS(ESI)C 12H 13N 3O Calcd.for(M+H) +,216.1137,Found:216.1124
实施例11：
Figure PCTCN2021104268-appb-000026
1H NMR(400MHz,Chloroform-d)δ7.63(s,1H),7.49(dd,J＝12.9Hz,7.9Hz,1H),7.41(dd,J＝15.8Hz,7.6Hz,1H),7.22–7.17(m,5H),7.09(q,J＝10.6Hz,9.4Hz,6H),6.83–6.60(m,4H),6.17(s,0H),5.99(d,J＝13.4Hz,1H),4.24–3.91(m,1H),3.71(s,3H),3.31(s,2H),2.56(d,J＝5.9Hz,3H),1.63(dt,J＝18.3Hz,9.1Hz,7H),1.52(s,3H).
13C NMR(101MHz,CDCl 3)δ174.76,174.35,166.82,154.24,142.04,140.08,139.17,134.99,134.85,131.05,130.57,130.44,129.61,129.43,128.77,128.64,128.41,127.18,127.04,126.51,126.02,125.87,125.72,120.70,112.86,64.12,62.51,42.24,39.94,35.49,29.17,28.72,20.59,19.68,14.96.
实施例12：
Figure PCTCN2021104268-appb-000027
1H NMR(400MHz,Chloroform-d)δ7.72(s,1H),7.59(d,J＝6.8Hz,1H),7.48–7.35(m,2H),7.32(s,1H),7.29–7.17(m,2H),7.13–7.02(m,2H),6.80(dd,J＝18.2Hz,6.7Hz,5H),6.71(d,J＝6.7Hz,2H),6.18(s,1H),6.05(s,1H),4.11(s,2H),3.84(q,J＝15.7Hz,3H),3.73(s,3H),3.32(s,2H),1.86(s,2H),1.50(s,2H).
13C NMR(101MHz,CDCl 3)δ170.49,165.87,153.74,138.71,138.18,133.76,129.66,129.12,128.71,128.29,127.68,126.48,125.61,124.17,119.87,111.07,104.52,63.36,54.72,50.24,38.51,32.13,26.96,25.04.
实施例13：
Figure PCTCN2021104268-appb-000028
1H NMR(400MHz,Methanol-d 4)δ7.79(s,1H),7.60(d,J＝7.5Hz,1H),7.46(s,1H),7.26(d,J＝14.6Hz,1H),7.12(t,J＝7.8Hz,1H),6.87(t,J＝7.4Hz,2H),6.69(t,J＝7.7Hz,1H),6.15(s,1H),3.93(d,J＝15.8Hz,1H),3.83(d,J＝15.9Hz,1H),3.73(s,3H),3.42(s,4H),3.30(s,2H),2.62(s,6H),1.55(s,4H),1.36(s,8H).
13C NMR(101MHz,CDCl 3)δ176.34,171.96,159.01,158.54,143.67,138.38,134.95,133.53,132.26,131.27,130.61,129.00,124.16,115.77,84.24,68.55,61.15,58.77,56.05,42.93,36.33,31.10,30.63,26.50.
实施例14：
Figure PCTCN2021104268-appb-000029
1H NMR(400MHz,Chloroform-d)δ7.71(s,1H),7.58(d,J＝7.4Hz,1H),7.48(d,J＝7.3Hz,1H),7.33(t,J＝7.5Hz,1H),7.25(d,J＝11.1Hz,3H),7.18(t,J＝7.1Hz,2H),7.10(d,J＝7.3Hz,2H),6.88(dd,J＝18.3Hz,7.8Hz,2H),6.78(t,J＝7.6Hz,1H),4.00–3.86(m,2H),3.82(s,3H),3.43(d,J＝5.8Hz,2H),1.66(d,J＝8.3Hz,3H).
13C NMR(101MHz,CDCl 3)δ171.45,166.79,154.82,140.41,139.84,134.92,131.57,130.70,130.10,129.75,128.76,128.45,127.23,126.50,125.23,120.91,112.14,64.33,55.77,39.87,34.78,33.16,29.12,28.58.
实施例15：
Figure PCTCN2021104268-appb-000030
1H NMR(400MHz,Chloroform-d)δ7.80(s,1H),7.63(d,J＝7.4Hz,1H),7.40(d,J＝7.4Hz,1H),7.26(t,J＝7.4Hz,4H),7.16(t,J＝7.6Hz,4H),6.96–6.86(m,1H),6.79(q,J＝7.8Hz,2H),6.70(d,J＝7.7Hz,1H),6.58(s,1H),6.08(s,1H),3.94(s,3H),3.86(t,J＝14.3Hz,2H),3.40–3.35(m,2H),2.62(t,J＝6.9Hz,3H),1.72–1.51(m,7H).
13C NMR(101MHz,CDCl 3)δ171.47,166.73,156.92,154.45,144.09,143.98,142.06,139.09,135.23,130.73,130.41,128.82,128.36,127.81,126.26,125.85,124.60,123.17,117.35,117.16,64.82,61.48,61.41,39.99,35.49,33.17,29.12,28.72.
19F NMR(376MHz,CDCl 3)δ-127.80.
实施例16：
Figure PCTCN2021104268-appb-000031
1H NMR(400MHz,Chloroform-d)δ7.71(s,1H),7.56(d,J＝7.6Hz,1H),7.39(d,J＝7.5Hz,1H),7.23(dd,J＝16.6Hz,8.9Hz,1H),7.11(s,1H),6.81(dd,J＝16.9Hz,8.0Hz,2H),6.71(t,J＝7.6Hz,1H),6.63(s,1H),6.34(s,1H),6.06(s,1H),3.86(q,J＝15.6Hz,2H),3.75(s,2H),3.49(t,J＝6.8Hz,2H),3.36(q,J＝6.4Hz,3H),1.59(q,J＝7.2Hz,3H),1.52(q,J＝5.7Hz,4.8Hz,2H).
13C NMR(101MHz,CDCl 3)δ171.46,170.90,166.82,154.83,139.87,134.81,134.15,130.74,130.13,129.73,128.75,127.36,126.51,125.22,120.92,112.13,64.34,55.77,39.49,37.28,33.16,26.55,26.11.
实施例17：
Figure PCTCN2021104268-appb-000032
1H NMR(400MHz,Chloroform-d)δ7.71(s,1H),7.57(d,J＝7.2Hz,1H),7.42(d,J＝7.0Hz,1H),7.37–7.31(m,2H),7.23(d,J＝7.3Hz,3H),7.21–7.09(m,8H),6.19(s,1H),6.13(s,1H),3.97(d,J＝15.8Hz,1H),3.86(d,J＝15.8Hz,1H),3.48–3.30(m,4H),2.64(d,J＝6.8Hz,4H),1.64(dd,J＝23.6Hz,6.7Hz,6H).
13C NMR(101MHz,CDCl 3)δ171.01,166.68,142.01,140.22,137.22,135.36,129.73,129.23,129.14,128.38,127.28,127.12,125.93,125.88,125.64,65.21,40.00,35.47,33.48,29.15,28.70.
实施例18：
Figure PCTCN2021104268-appb-000033
1H NMR(400MHz,Chloroform-d)δ7.76(s,1H),7.58(d,J＝6.6Hz,1H),7.45(d,J＝6.6Hz,1H),7.29–7.23(m,6H),7.16(s,4H),6.84(s,1H),6.78–6.62(m,3H),6.49(s,1H),6.12(s,1H),3.94–3.80(m,3H),3.75(s,3H),3.44–3.27(m,4H),2.62(s,3H),1.69–1.50(m,8H).
13C NMR(101MHz,CDCl 3)δ171.41,166.64,157.32,154.93,151.30,142.09,139.24,135.05,130.49,128.78,128.42,128.36,127.48,126.78,125.85,117.36,117.12,116.03,115.80,112.68,64.19,56.23,39.96,35.48,33.10,29.12,28.72.
19F NMR(376MHz,CDCl 3)δ-121.95.
实施例19：
Figure PCTCN2021104268-appb-000034
核磁共振 1H NMR、 13C NMR图谱如图19所示：
1H NMR(400MHz,Chloroform-d)δ7.78(d,J＝6.4Hz,1H),7.57(d,J＝7.8Hz,1H),7.42(t,J＝6.2Hz,1H),7.29–7.05(m,9H),6.71–6.60(m,1H),6.08(s,1H),3.92–3.75(m,3H),3.73–3.59(m,3H),3.40–3.20(m,2H),2.91(s,1H),2.57(q,J＝7.0Hz,2H),1.56(dt,J＝24.2Hz,7.6Hz,4H).
13C NMR(101MHz,CDCl 3)δ171.04,169.55,166.73,145.51,141.98,140.35,137.18,135.30,129.81,129.14,128.41,127.10,124.75,123.28,122.76,65.36,40.02,35.47,33.47,29.17,28.68,15.29,9.42.
实施例20:
Figure PCTCN2021104268-appb-000035
核磁共振 1H NMR、 13C NMR图谱如图20所示：
1H NMR(400MHz,Chloroform-d)δ7.70(s,1H),7.62(d,J＝7.2Hz,1H),7.43(s,1H),7.39–7.17(m,5H),7.04(t,J＝7.7Hz,1H),6.79(d,J＝16.8Hz,4H),6.18(s,1H),6.02(s,1H),4.12(t,J＝6.2Hz,3H),3.91(d,J＝15.9Hz,1H),3.79(d,J＝15.7Hz,1H),3.35(d,J＝5.6Hz,3H),1.94–1.79(m,4H),1.57–1.46(m,4H),0.81(d,J＝7.8Hz,3H),0.51–0.43(m,2H).
13C NMR(100MHz,Chloroform-d)δ170.02,165.74,144.46,139.27,138.18,136.18,134.13,128.79,128.29,128.06,127.99,126.35,124.99,123.70,122.27,121.76,104.55,64.37,50.22,38.58,32.44,28.68,27.00,24.98,14.26,8.46,8.40.
实施例21:
Figure PCTCN2021104268-appb-000036
核磁共振 1H NMR、 13C NMR图谱如图21所示：
1H NMR(400MHz,Chloroform-d)δ7.70(t,J＝1.8Hz,1H),7.59(dt,J＝7.6Hz,1.5Hz,1H),7.40(dt,J＝7.8Hz,1.4Hz,1H),7.34–7.24(m,4H),7.18(td,J＝7.4Hz,6.8Hz,1.7Hz,4H),6.99(d,J＝8.5Hz,2H),6.91(d,J＝8.6Hz,2H),6.31(t,J＝5.8Hz,1H),6.06(d,J＝1.6Hz,1H),3.95(dd,J＝15.8Hz,1.7Hz,1H),3.83(d,J＝15.8Hz,1H),3.48–3.32(m,2H),2.64(t,J＝7.4Hz,3H),1.91(s,1H),0.98–0.80(m,2H),0.58(dd,J＝4.8Hz,1.9Hz,2H).
13C NMR(101MHz,CDCl 3)δ171.05,166.72,143.41,142.04,140.35,135.33,134.38,129.76,129.11,128.38,127.21,126.41,125.93,125.88,125.65,65.29,40.00,35.49,33.43,29.15,28.72,15.04,9.46,9.36.
实施例22:
Figure PCTCN2021104268-appb-000037
核磁共振 1H NMR、 13C NMR图谱如图22所示：
1H NMR(400MHz,Chloroform-d)δ7.64(d,J＝3.7Hz,1H),7.49(dd,J＝22.7Hz,7.6Hz,1H),7.32(dd,J＝20.4Hz,7.7Hz,2H),7.13(d,J＝8.1Hz,3H),6.98(d,J＝8.1Hz,4H),6.81(s,1H),5.99(s,1H),4.11(d,J＝6.9Hz,0H),3.99(d,J＝6.9Hz,1H),3.27(d,J＝6.0Hz,3H),2.49(t,J＝6.6Hz,5H),1.62(d,J＝6.9Hz,2H),1.17(s,1H),0.77(d,J＝7.5Hz,3H).
13C NMR(101MHz,CDCl 3)δ173.82,166.74,145.41,140.50,137.64,135.31,135.00,131.47,130.38,129.77,129.33,128.94,128.41,127.10,124.60,123.36,122.83,122.28,63.29,42.72,41.80,39.87,34.78,29.06,28.57,19.98,19.22,15.32,9.51.
实施例23:
Figure PCTCN2021104268-appb-000038
核磁共振 1H NMR、 13C NMR图谱如图23所示：
1H NMR(400MHz,Chloroform-d)δ7.67(s,1H),7.56(dd,J＝17.1Hz,7.5Hz,1H),7.42(d,J＝23.8Hz,1H),7.17(d,J＝7.4Hz,3H),7.04(d,J＝8.1Hz,1H),6.99(d,J＝8.1Hz,1H),6.92(t,J ＝9.0Hz,2H),6.13(s,1H),4.20(d,J＝6.9Hz,0H),4.10(d,J＝6.9Hz,0H),3.42(d,J＝6.1Hz,2H),2.65(t,J＝7.0Hz,2H),1.73(d,J＝7.1Hz,3H),1.27(d,J＝10.3Hz,1H),0.89(s,2H).
13C NMR(101MHz,CDCl 3)δ173.78,166.74,143.11,142.01,130.35,129.32,129.17,129.02,128.41,126.99,126.88,126.56,126.35,125.88,125.71,125.52,125.20,42.68,41.78,39.98,35.48,29.17,28.70,20.15,19.31,15.02,9.41,9.30.
实施例24:
Figure PCTCN2021104268-appb-000039
核磁共振 1H NMR、 13C NMR图谱如图24所示：
1H NMR(400MHz,Chloroform-d)δ7.70(s,1H),7.57(d,J＝27.7Hz,1H),7.41(dd,J＝18.6,7.7Hz,1H),7.16(d,J＝7.0Hz,4H),7.07(d,J＝8.1Hz,1H),6.90(s,1H),6.80(d,J＝12.1Hz,2H),6.00(s,0H),4.19(d,J＝6.9Hz,0H),4.09(d,J＝6.9Hz,0H),3.39(d,J＝5.9Hz,2H),2.62(d,J＝7.0Hz,3H),1.72(s,1H),1.33(s,1H),0.86(s,2H).
13C NMR(101MHz,CDCl 3)δ173.81,166.75,145.42,142.04,140.81,139.56,137.66,135.38,130.37,129.30,128.96,126.71,125.87,124.62,123.38,122.84,122.28,63.29,41.82,39.98,35.49,29.72,29.16,28.71,20.00,19.24,15.33,9.48.
实施例25:
Figure PCTCN2021104268-appb-000040
核磁共振 1H NMR、 13C NMR图谱如图25所示：
1H NMR(400MHz,Chloroform-d)δ7.64(d,J＝3.7Hz,1H),7.49(dd,J＝22.7Hz,7.6Hz,1H),7.32(dd,J＝20.4Hz,7.7Hz,2H),7.13(d,J＝8.1Hz,3H),6.98(d,J＝8.1Hz,4H),6.81(s, 1H),5.99(s,1H),4.11(d,J＝6.9Hz,0H),3.99(d,J＝6.9Hz,1H),3.27(d,J＝6.0Hz,3H),2.49(t,J＝6.6Hz,5H),1.62(d,J＝6.9Hz,2H),1.17(s,1H),0.77(d,J＝7.5Hz,3H).
13C NMR(101MHz,CDCl 3)δ173.82,166.74,145.41,140.50,137.64,135.31,135.00,131.47,130.38,129.77,129.33,128.94,128.41,127.10,124.60,123.36,122.83,122.28,63.29,42.72,41.80,39.87,34.78,29.06,28.57,19.98,19.22,15.32,9.51.
实施例26:
Figure PCTCN2021104268-appb-000041
核磁共振 1H NMR图谱如图26所示：
1H NMR(400MHz,Chloroform-d)δ7.95(dd,J＝3.2Hz,1.6Hz,1H),7.94–7.84(m,1H),7.69(s,1H),7.64–7.53(m,2H),7.50–7.40(m,3H),7.40–7.22(m,6H),7.19(s,1H),7.10–6.98(m,2H),6.92–6.73(m,3H),6.19(s,0H),6.04(d,J＝7.0Hz,1H),5.96(d,J＝11.9Hz,0H),4.23–3.85(m,3H),3.49–3.19(m,1H),2.00–1.76(m,2H),1.79–1.56(m,4H),1.52(dd,J＝14.3Hz,7.5Hz,3H),1.18(s,3H),0.82(dd,J＝7.7Hz,4.7Hz,3H),0.60–0.40(m,4H).
实施例27:
Figure PCTCN2021104268-appb-000042
核磁共振 1H NMR、 13C NMR图谱如图27所示：
1H NMR(400MHz,Chloroform-d)δ7.61(s,1H),7.46(d,J＝7.4Hz,1H),7.37(d,J＝7.3Hz,1H),7.22(dd,J＝16.0Hz,7.7Hz,6H),7.14(d,J＝7.1Hz,3H),7.08(d,J＝7.9Hz,1H),6.77(dd,J＝12.5Hz,8.7Hz,3H),6.69(t,J＝7.4Hz,1H),6.17(s,1H),6.04(s,1H),3.91–3.76(m,2H),3.71(s,3H),3.59(d,J＝6.1Hz,2H),2.83(t,J＝6.2Hz,3H).
13C NMR(101MHz,CDCl 3)δ170.39,165.75,153.76,138.76,137.81,133.86,129.71,129.09,128.68,127.78,127.70,126.24,125.61,125.49,124.13,119.86,111.07,63.29,54.69,40.16,34.58,32.11.
实施例28:
Figure PCTCN2021104268-appb-000043
核磁共振 1H NMR、 13C NMR图谱如图28所示：
1H NMR(400MHz,Chloroform-d)δ7.61(s,1H),7.42(d,J＝7.5Hz,1H),7.37(d,J＝7.5Hz,1H),7.18(d,J＝5.0Hz,4H),7.13–7.03(m,5H),6.80(d,J＝7.6Hz,1H),6.74(d,J＝8.2Hz,1H),6.66(t,J＝7.4Hz,1H),6.32(s,1H),6.03(s,1H),3.81(q,J＝15.6Hz,4H),3.70(s,3H),3.32(d,J＝6.0Hz,3H),2.59(t,J＝7.2Hz,3H),1.89–1.74(m,3H).
13C NMR(101MHz,CDCl 3)δ171.52,166.72,154.80,141.47,139.72,134.86,130.60,130.14,129.74,128.68,128.54,128.39,127.30,126.61,126.07,125.18,120.87,112.09,64.37,55.74,39.87,33.48,33.16,31.01.
实施例29：
Figure PCTCN2021104268-appb-000044
核磁共振 1H NMR、 13C NMR图谱如图29所示：
1H NMR(400MHz,Chloroform-d)δ7.78(d,J＝6.4Hz,1H),7.57(d,J＝7.8Hz,1H),7.42(t,J＝6.2Hz,1H),7.29–7.05(m,9H),6.71–6.60(m,1H),6.08(s,1H),3.92–3.75(m,3H),3.73– 3.59(m,3H),3.40–3.20(m,2H),2.91(s,1H),2.57(q,J＝7.0Hz,2H),1.56(dt,J＝24.2Hz,7.6Hz,4H). 13C NMR(100MHz,CDCl 3)δ171.43,166.73,155.35,142.12,139.21,134.96,133.76,133.67,130.47,128.79,128.44,128.36,127.49,126.77,125.84,125.29,114.66,112.16,82.41,77.60,77.28,77.03,76.96,64.30,55.92,39.97,35.49,33.13,29.11,28.71.
实施例30：
Figure PCTCN2021104268-appb-000045
核磁共振 1H NMR、 13C NMR图谱如图30所示：
1H NMR(400MHz,Chloroform-d)δ7.65(s,1H),7.52(s,1H),7.39(d,J＝7.5Hz,1H),7.31–7.16(m,7H),7.11(t,J＝7.2Hz,5H),3.95(d,J＝15.7Hz,1H),3.82(d,J＝15.9Hz,1H),3.36(d,J＝6.1Hz,2H),2.96(s,1H),2.59(t,J＝6.9Hz,3H),1.68–1.51(m,8H),1.26(s,2H).
13C NMR(101MHz,CDCl 3)δ166.55,142.00,135.07,130.49,128.98,128.39,127.42,125.89,82.64,78.13,40.02,35.47,31.44,30.20,29.71,29.16,28.70.
实施例31：
Figure PCTCN2021104268-appb-000046
核磁共振 1H NMR、 13C NMR图谱如图31所示：
1H NMR(400MHz,Chloroform-d)δ7.65(s,1H),7.52(d,1H),7.39(d,J＝7.5Hz,1H),7.32–7.17(m,7H),7.10(q,J＝12.3Hz,9.7Hz,6H),5.99(s,1H),3.95(d,J＝15.7Hz,1H),3.82(d,J＝15.9Hz,1H),3.36(d,J＝6.1Hz,2H),2.96(s,1H),2.59(t,J＝6.9Hz,3H),1.68–1.49(m,8H),1.26(s,2H),0.81(s,1H).
13C NMR(101MHz,CDCl 3)δ169.35,135.89,134.45,130.13,128.59,128.27,127.79,121.46,121.01,119.31,109.37,101.15,45.82,39.42,27.46,26.81.
实施例32：
Figure PCTCN2021104268-appb-000047
核磁共振 1H NMR、 13C NMR图谱如图32所示：
1H NMR(400MHz,Chloroform-d)δ7.63(s,1H),7.55(d,J＝7.8Hz,1H),7.43(d,J＝7.5Hz,1H),7.38(d,J＝7.5Hz,1H),7.22(dt,J＝15.5Hz,8.1Hz,3H),7.11(t,J＝7.4Hz,2H),7.06–6.97(m,3H),6.77(t,J＝8.3Hz,2H),6.70–6.50(m,3H),4.07(t,J＝6.4Hz,3H),3.90–3.72(m,3H),3.67(s,3H),3.27(q,J＝6.1Hz,3H),1.83–1.75(m,3H),1.56–1.34(m,3H).
13C NMR(101MHz,CDCl3)δ170.37,165.69,156.32,153.80,150.25,138.39,134.93,133.80,129.48,127.86,127.47,126.69,126.30,125.61,124.88,124.78,120.46,120.01,118.30,116.28,116.04,115.03,114.80,111.76,111.68,108.32,100.14,63.10,55.23,44.81,38.43,32.07,26.43,26.04.
实施例33：
Figure PCTCN2021104268-appb-000048
核磁共振 1H NMR、 13C NMR图谱如图33所示：
1H NMR(400MHz,Chloroform-d)δ7.64(d,J＝12.8Hz,1H),7.53(d,J＝7.4Hz,0H),7.36(d,J＝7.9Hz,1H),7.18(d,J＝7.6Hz,3H),7.08(d,J＝8.0Hz,4H),5.99(s,0H),4.18(q,J＝7.4 Hz,1H),4.02(q,J＝7.2Hz,1H),3.29(d,J＝7.0Hz,2H),2.55(t,J＝7.6Hz,2H),2.19–2.07(m,1H),1.93(d,J＝10.2Hz,1H),1.67(d,J＝6.9Hz,1H),0.79(q,J＝10.0Hz,8.3Hz,1H).
13C NMR(101MHz,CDCl 3)δ166.65,142.05,131.49,131.46,128.43,128.37,125.87,120.72,39.99,35.49,29.71,29.14,28.69,20.16,19.90.
实施例34：
Figure PCTCN2021104268-appb-000049
核磁共振 1H NMR、 13C NMR图谱如图34所示：
1H NMR(400MHz,Chloroform-d)δ7.66(d,J＝9.4Hz,2H),7.62(s,1H),7.32–7.28(m,2H),7.22–7.16(m,4H),6.93(d,J＝7.7Hz,1H),6.88–6.79(m,2H),6.09(s,1H),5.95(d,J＝12.7Hz,1H),3.97(d,J＝15.5Hz,1H),3.90(d,J＝15.7Hz,1H),3.82(s,3H),3.43(q,J＝6.8Hz,2H),3.12(s,1H),2.66(t,J＝7.4Hz,2H),1.71–1.61(m,4H).
13C NMR(101MHz,CDCl3)δ171.32,165.84,154.80,141.95,140.50,135.25,133.89,130.60,129.89,128.39,126.94,125.91,125.03,122.87,121.04,112.22,82.15,78.73,63.97,55.79,40.03,35.44,33.08,29.10,28.66.
实施例35：
Figure PCTCN2021104268-appb-000050
Figure PCTCN2021104268-appb-000051
核磁共振 1H NMR. 13C NMR图谱如图35所示：
1H NMR(400MHz,Chloroform-d)δ7.70(s,1H),7.58(d,J＝7.6Hz,1H),7.43(d,J＝7.8Hz,1H),7.36(t,2H),7.32–7.26(m,3H),7.24–7.12(m,5H),6.14(s,1H),6.02(t,J＝5.7Hz,1H),3.98(d,J＝15.9Hz,1H),3.88(d,J＝15.8Hz,1H),3.45(q,J＝6.7Hz,2H),3.04(s,1H),2.67(t,J＝7.3Hz,2H),1.75–1.62(m,4H).
13C NMR(101MHz,CDCl 3)δ171.32,165.84,154.80,141.95,140.50,135.25,133.89,130.60,129.89,128.39,126.94,125.91,125.03,122.87,121.04,112.22,82.15,78.73,63.97,55.79,40.03,35.44,33.08,29.10,28.66.
实施例36：
Figure PCTCN2021104268-appb-000052
核磁共振 1H NMR. 13C NMR图谱如图36所示：
1H NMR(400MHz,Chloroform-d)δ7.74(s,1H),7.61(d,J＝7.1Hz,1H),7.42(s,1H),7.32(s,2H),7.26(s,2H),7.21–7.15(m,2H),7.14–7.01(m,3H),6.95(s,1H),6.17(s,1H),6.06(s,1H),4.13–4.05(m,3H),3.88(d,J＝15.8Hz,1H),3.76(d,J＝15.8Hz,1H),3.37–3.20(m,3H),2.99(s,1H),1.90–1.67(m,3H),1.56–1.42(m,3H).
13C NMR(101MHz,CDCl3)δ171.00,166.65,139.71,139.14,137.34,135.25,130.82,129.63,129.32,129.21,128.95,127.53,126.08,126.00,123.20,105.57,82.49,78.40,64.95,51.26,39.65,33.43,28.06,25.99.
实施例37：
Figure PCTCN2021104268-appb-000053
核磁共振 1H NMR. 13C NMR图谱如图37所示：
1H NMR(400MHz,Chloroform-d)δ7.66(t,J＝1.5Hz,1H),7.53(dt,J＝7.6Hz,1.3Hz,1H),7.40(dt,J＝7.6Hz,1.3Hz,1H),7.36–7.29(m,3H),7.29–7.24(m,2H),7.25–7.16(m,3H),7.12(ddd,J＝8.0Hz,2.0Hz,1.3Hz,1H),6.22(s,1H),6.11(s,1H),3.96(dd,J＝15.9Hz,1.5Hz,1H),3.85(d,J＝15.9Hz,1H),3.75–3.64(m,2H),3.06(s,1H),2.91(t,J＝6.9Hz,1H).
13C NMR(101MHz,CDCl3)δ170.94,166.63,139.89,138.81,137.35,135.42,130.85,129.73,129.22,128.75,127.21,126.68,126.06,125.82,123.27,82.48,78.35,64.92,58.41,41.20,35.59,33.37,18.41.
实施例38：
Figure PCTCN2021104268-appb-000054
核磁共振 1H NMR. 13C NMR图谱如图38所示：
1H NMR(400MHz,Chloroform-d)δ7.65(s,1H),7.49(d,J＝7.7Hz,1H),7.39(d,J＝7.8Hz,1H),7.35–7.22(m,5H),7.23–7.14(m,4H),7.12(d,J＝8.1Hz,1H),6.27(s,1H),6.10(s,1H),3.96(s,0H),3.81(s,0H),3.43(q,J＝6.6Hz,2H),3.03(s,1H),2.68(t,J＝7.5Hz,2H),1.92(p,J＝7.2Hz,3H).
13C NMR(101MHz,CDCl 3)δ170.99,166.54,141.48,139.81,137.38,135.37,130.84,129.57,129.22,128.93,128.57,128.41,127.25,126.09,125.87,123.26,82.49,78.43,64.92,39.97,33.54,33.39,30.97.
实施例39：
Figure PCTCN2021104268-appb-000055
核磁共振 1H NMR. 13C NMR图谱如图39所示：
39为泡沫状白色固体，产率92％。 1H NMR(400MHz,Chloroform-d)δ8.20(s,1H),8.12(d,J＝8.3Hz,1H),7.69(t,J＝6.9Hz,1H),7.48(s,1H),7.29(s,3H),7.18(d,J＝7.1Hz,3H),7.10(d,J＝8.6Hz,1H),7.02(d,J＝4.6Hz,1H),6.85(s,1H),6.05(s,1H),4.02(d,J＝16.1Hz,1H),3.81(d,J＝16.1Hz,1H),3.43(d,J＝5.7Hz,2H),2.65(d,J＝7.2Hz,3H),1.79–1.50(m,6H).
13C NMR(101MHz,CDCl 3)δ171.04,165.71,163.94,150.37,147.69,144.79,141.94,137.98,137.38,128.40,125.91,120.92,120.31,116.82,115.87,115.64,113.98,113.74,62.08,40.07,35.45,34.02,29.10,28.66.
19F NMR(376MHz,CDCl 3)δ-110.94.
实施例40：
Figure PCTCN2021104268-appb-000056
核磁共振 1H NMR. 13C NMR图谱如图40所示：
1H NMR(400MHz,Chloroform-d)δ8.31(s,1H),7.90(s,1H),7.73(s,1H),7.67–7.55(m,3H),7.42(s,1H),7.31(s,2H),7.26–7.20(m,2H),7.05(s,2H),6.74(s,1H),6.68(s,2H),6.17(s,1H),4.09(s,3H),3.93(d,J＝16.1Hz,1H),3.69(d,J＝16.0Hz,1H),3.33(s,2H),1.85(s,2H),1.50(s,3H).
13C NMR(101MHz,CDCl 3)δ171.35,167.05,158.46,151.16,148.06,145.39,141.66,139.12,135.15,133.89,129.35,128.89,128.55,126.77,125.02,124.01,119.56,116.59,112.65,105.54,62.57,51.27,39.58,33.97,30.32,27.98,26.08.
实施例41：
Figure PCTCN2021104268-appb-000057
核磁共振 1H NMR. 13C NMR图谱如图41所示：
1H NMR(400MHz,Chloroform-d)δ8.16(s,1H),7.98(s,1H),7.73(s,1H),7.58(d,J＝6.3Hz,1H),7.43(s,1H),7.36–7.16(m,4H),6.90(s,2H),6.75(s,1H),6.17(s,1H),4.10(s,2H),3.93(d,J＝16.2Hz,1H),3.70(d,J＝16.2Hz,1H),3.35–3.24(m,3H),1.86(s,2H),1.50(s,2H).
13C NMR(101MHz,CDCl 3)δ171.34,166.98,151.35,148.17,145.35,141.72,139.18,135.18,129.30,128.51,126.70,125.01,121.10,116.63,105.54,62.58,51.26,39.59,33.98,30.32,29.69,28.01,26.05.
实施例42：
Figure PCTCN2021104268-appb-000058
核磁共振 1H NMR. 13C NMR图谱如图42所示：
1H NMR(400MHz,Chloroform-d)δ8.05(s,1H),7.83(s,2H),7.59(d,J＝45.3Hz,2H),7.35(d,J＝41.1Hz,2H),6.84(d,J＝20.1Hz,3H),6.27(s,1H),4.16(s,2H),4.00(s,1H),3.80(s,1H),3.41(s,2H),2.31(s,2H),1.93(s,2H),1.58(s,2H).
13C NMR(101MHz,CDCl 3)δ171.20,167.09,150.53,149.32,147.28,141.83,135.04,128.87,126.75,125.14,122.18,117.95,105.70,62.79,51.31,39.53,34.17,27.94,26.15,21.27.
实施例43：
Figure PCTCN2021104268-appb-000059
核磁共振 1H NMR. 13C NMR图谱如图43所示：
1H NMR(400MHz,Chloroform-d)δ8.12(s,1H),8.01(d,J＝10.7Hz,1H),7.80(s,1H),7.65(s,1H),7.51(s,1H),7.44–7.29(m,3H),6.86(s,1H),6.74(s,1H),6.25(s,1H),4.18(s,2H),4.01(d,J＝16.2Hz,1H),3.78(d,J＝16.2Hz,1H),3.42(s,2H),1.94(s,2H),1.59(s,2H).
13C NMR(101MHz,CDCl 3)δ171.40,170.70,168.11,166.99,152.57,149.46,141.91,139.17,135.18,129.30,128.87,128.42,126.60,124.94,109.06,108.89,105.54,104.35,104.12,62.64,51.26,39.61,33.99,28.01,26.08.
19F NMR(376MHz,CDCl 3)δ-99.62.
实施例44：
Figure PCTCN2021104268-appb-000060
Figure PCTCN2021104268-appb-000061
核磁共振 1H NMR. 13C NMR图谱如图44所示：
1H NMR(400MHz,Chloroform-d)δ8.19(s,1H),8.07(d,J＝8.3Hz,1H),7.73(s,1H),7.64(d,J＝7.5Hz,1H),7.56(d,J＝7.0Hz,1H),7.40(d,J＝6.8Hz,1H),7.33–7.24(m,4H),7.17(d,J＝7.0Hz,3H),6.97(s,1H),6.88(s,1H),6.16(s,1H),4.01(d,J＝16.0Hz,1H),3.80(d,J＝16.1Hz,1H),3.51–3.27(m,3H),2.64(d,J＝7.1Hz,3H),1.74–1.41(m,6H).
13C NMR(101MHz,CDCl 3)δ171.23,166.94,150.53,147.72,142.02,137.84,135.29,128.87,128.37,126.47,125.87,124.99,120.82,117.16,77.37,62.65,39.96,35.48,34.11,29.19,28.70.
实施例45：
Figure PCTCN2021104268-appb-000062
核磁共振 1H NMR. 13C NMR图谱如图45所示：
1H NMR(400MHz,Chloroform-d)δ8.41(d,J＝30.1Hz,1H),7.83(s,1H),7.70(d,J＝6.9Hz,1H),7.63(d,J＝7.4Hz,1H),7.51(s,1H),7.40(dt,J＝16.7Hz,7.4Hz,2H),7.27(s,0H),6.95(s,1H),6.27(s,1H),6.20(s,1H),4.20(s,1H),3.99(d,J＝16.0Hz,1H),3.90(d,J＝15.9Hz,1H),3.52–3.33(m,2H),1.96(s,1H),1.59(d,J＝6.0Hz,1H).
13C NMR(101MHz,CDCl 3)δ171.21,166.58,147.50,145.88,139.25,135.50,132.99,129.65,129.40,127.69,126.19,123.84,105.62,64.60,51.24,39.70,33.29,28.12,25.93.
实施例46：
Figure PCTCN2021104268-appb-000063
核磁共振 1H NMR. 13C NMR图谱如图46所示：
1H NMR(400MHz,Chloroform-d)δ8.12(s,1H),7.99(d,J＝8.3Hz,1H),7.73(s,1H),7.66–7.51(m,2H),7.45(s,1H),7.33(s,2H),7.24(d,J＝7.6Hz,1H),6.91(s,1H),6.81(s,1H),6.71(s,1H),6.19(s,1H),4.11(s,2H),3.95(d,J＝16.1Hz,1H),3.73(d,J＝16.1Hz,1H),3.34(d,J＝5.7Hz,2H),1.90–1.80(m,3H),1.58–1.42(m,3H).
13C NMR(101MHz,CDCl 3)δ171.26,167.07,150.51,147.71,141.86,137.84,135.07,128.79,126.67,125.12,120.83,117.22,62.68,51.31,39.56,34.12,29.70,27.98,26.12.
实施例47：
Figure PCTCN2021104268-appb-000064
核磁共振 1H NMR. 13C NMR图谱如图47所示：
1H NMR(400MHz,Chloroform-d)δ8.39(s,1H),7.77(s,1H),7.63(s,1H),7.43(s,1H),7.31(d,J＝12.0Hz,2H),7.20(s,1H),6.88(s,1H),6.19(s,1H),4.13(s,1H),3.89(d,J＝16.1Hz,1H),3.75(d,J＝16.1Hz,1H),3.37(s,1H),1.90(s,2H).
13C NMR(101MHz,CDCl 3)δ171.31,166.52,150.60,144.76,139.67,139.18,135.68,129.50,129.35,128.48,127.26,125.46,116.78,105.62,63.58,51.21,39.72,33.32,29.70,29.32,28.12,25.86.
实施例48：
Figure PCTCN2021104268-appb-000065
核磁共振 1H NMR. 13C NMR图谱如图48所示：
1H NMR(400MHz,Chloroform-d)δ7.76(s,1H),7.58(d,J＝7.0Hz,1H),7.46(d,J＝6.8Hz,6H),7.41–7.35(m,6H),7.32(d,J＝7.5Hz,1H),7.23(d,J＝10.5Hz,6H),7.16(d,J＝6.8Hz,4H),6.16(d,J＝13.4Hz,2H),4.01(d,J＝15.7Hz,1H),3.89(d,J＝15.7Hz,1H),3.52–3.36(m,3H),2.63(d,J＝6.5Hz,3H),1.74–1.56(m,6H).
13C NMR(101MHz,CDCl 3)δ170.37,165.69,156.32,153.80,150.25,138.39,134.93,133.80,129.48,127.86,127.47,126.69,126.30,125.61,124.88,124.78,120.46,120.01,118.30,116.28,116.04,115.03,114.80,111.76,111.68,108.32,100.14,63.10,55.23,44.81,38.43,32.07,26.43,26.04.
实施例49：
Figure PCTCN2021104268-appb-000066
核磁共振 1H NMR. 13C NMR图谱如图49所示：
1H NMR(400MHz,Chloroform-d)δ9.41(d,J＝1.3Hz,1H),8.19(d,J＝2.5Hz,1H),8.11–8.03(m,1H),7.68(d,J＝1.6Hz,1H),7.49(d,J＝8.9Hz,1H),7.32(d,J＝7.8Hz,1H),7.21–7.17(m,2H),7.14–7.05(m,4H),6.66(s,1H),6.16(s,1H),3.98(d,J＝17.4Hz,1H),3.74(d,J＝16.3Hz,1H),3.36(q,J＝6.8Hz,2H),2.57(t,J＝7.3Hz,2H),1.72–1.37(m,5H).
13C NMR(101MHz,CDCl 3)δ171.37,166.91,147.45,142.00,141.82,141.25,140.60,138.98,135.41,129.05,128.65,128.41,128.37,126.61,125.87,125.19,61.94,40.04,35.46,33.64,29.15,28.69.
实施例50：
Figure PCTCN2021104268-appb-000067
核磁共振 1H NMR. 13C NMR图谱如图50所示：
1H NMR(400MHz,DMSO-d 6)δ8.52(t,J＝5.5Hz,1H),7.74(t,2H),7.47(d,J＝7.9Hz,1H),7.43–7.33(m,3H),7.27(t,J＝7.4Hz,2H),7.17(dd,J＝15.4Hz,7.2Hz,3H),6.79(s,1H),4.28(d,J＝16.5Hz,1H),4.00(d,J＝16.5Hz,1H),3.26(q,J＝7.6Hz,7.1Hz,2H),2.59(t,J＝7.3Hz,2H),1.56(dt,J＝24.8Hz,7.3Hz,4H).
13C NMR(101MHz,DMSO)δ170.68,165.52,156.16,142.08,141.74,137.63,135.05,128.67,128.26,128.19,127.97,126.66,125.60,124.00,114.99,62.42,34.79,31.80,28.77,28.47.
实施例51：
Figure PCTCN2021104268-appb-000068
核磁共振 1H NMR. 13C NMR图谱如图51所示：
1H NMR(400MHz,Chloroform-d)δ7.64(s,1H),7.54(d,J＝6.1Hz,1H),7.29(t,J＝7.8Hz,2H),7.20(t,J＝6.3Hz,3H),7.09(d,J＝7.2Hz,3H),6.73(s,1H),6.22(s,1H),6.18(s,1H),3.91 (d,J＝16.3Hz,1H),3.62(d,J＝16.3Hz,1H),3.35(d,J＝6.0Hz,2H),2.57(t,J＝6.9Hz,3H),1.73–1.48(m,7H),1.36(s,1H),1.21(s,10H).
实施例52：
Figure PCTCN2021104268-appb-000069
核磁共振 1H NMR. 13C NMR图谱如图52所示：
1H NMR(400MHz,Chloroform-d)δ7.77(s,1H),7.64(d,J＝7.0Hz,1H),7.53(d,J＝5.6Hz,1H),7.40(s,2H),7.38–7.31(m,1H),7.26(s,2H),7.18(s,3H),6.73(s,1H),6.26(s,1H),6.15(s,1H),4.22(s,2H),3.98(d,J＝16.1Hz,1H),3.87(d,J＝16.0Hz,1H),3.49–3.32(m,3H),2.58–2.46(m,1H),2.20(dq,J＝24.1,12.4,11.0Hz,4H),1.97(s,4H),1.88–1.76(m,1H),1.64–1.56(m,3H),0.80(q,J＝6.8Hz,4H).
13C NMR(101MHz,CDCl 3)δ174.67,172.02,171.41,170.99,166.77,154.82,141.99,140.12,139.80,139.19,137.52,136.72,135.36,134.98,130.65,130.08,129.70,129.43,128.75,128.37,127.23,127.01,126.50,125.88,125.59,125.25,120.91,112.15,105.56,64.98,64.34,55.77,51.30,50.80,50.76,39.96,39.66,35.47,33.41,33.17,32.74,29.19,28.70,28.10,26.91,26.02,9.02.
实施例53：
Figure PCTCN2021104268-appb-000070
核磁共振 1H NMR. 13C NMR图谱如图53所示：
1H NMR(400MHz,Chloroform-d)δ7.74(s,1H),7.63(s,1H),7.44(s,1H),7.30(d,J＝15.9Hz,4H),6.87(d,J＝28.0Hz,1H),6.60(s,1H),6.18(s,1H),4.31–4.17(m,3H),4.13(s,2H),4.04(d,J＝16.2Hz,1H),3.74(d,J＝16.6Hz,1H),3.37(s,2H),2.40(s,3H),1.89(s,3H),1.64–1.48(m,8H),1.36(s,2H).
13C NMR(101MHz,CDCl 3)δ170.55,167.01,162.60,157.14,156.27,141.13,139.09,135.29,129.45,128.94,128.39,126.95,124.91,116.87,105.61,62.79,60.98,51.24,43.18,39.61,32.57,30.32,29.69,27.98,26.04,17.22,14.34.
实施例54：
抗肿瘤活性测试实验
本发明采用CCK-8法测定了本发明制备的1至38这38个化合物对6种骨肉瘤细胞(SJSA-1、U2OS、HOS、MNNG/HOS、MG63、143b)，1种胰腺癌细胞(PANC-1)，1种肺癌细胞(A549)，1种结直肠癌细胞(HCT116)以及1种白血病细胞(Jurkat)的增殖抑制效果。
1.接种细胞：
1)用含10％胎牛血清、1％青霉素和链霉素的1640培养液配成单个细胞悬液，以每孔2500个SJSA-1型骨肉瘤细胞接种到96孔细胞培养板，每孔体积100μl。
2)用含10％胎牛血清、1％青霉素和链霉素的DMEM培养液配成单个细胞悬液，以每孔2500个MNNG/HOS型骨肉瘤细胞接种到96孔细胞培养板，每孔体积100μl。
3)用含10％胎牛血清、1％青霉素和链霉素的McCoy'5A培养液配成单个细胞悬液，以每孔2500个U-2-OS型骨肉瘤细胞接种到96孔细胞培养板，每孔体积100μl。
4)用含10％胎牛血清、1％青霉素和链霉素的DMEM培养液配成单个细胞悬液，以每孔2500个MG63型骨肉瘤细胞接种到96孔细胞培养板，每孔体积100μl。
5)用含10％胎牛血清、1％青霉素和链霉素的1640培养液配成单个细胞悬液，以每孔2500个HOS型骨肉瘤细胞接种到96孔细胞培养板，每孔体积100μl。
6)用含10％胎牛血清、1％青霉素和链霉素的1640培养液配成单个细胞悬液，以每孔2500个143B型骨肉瘤细胞接种到96孔细胞培养板，每孔体积100μl。
7)用含10％胎牛血清、1％青霉素和链霉素的1640培养液配成单个细胞悬液，以每孔2500个A549型肺癌细胞接种到96孔细胞培养板，每孔体积100μl。
8)用含10％胎牛血清、1％青霉素和链霉素的1640培养液配成单个细胞悬液，以每孔2500个Jurkat白血病细胞接种到96孔细胞培养板，每孔体积100μl。
9)用含10％胎牛血清、1％青霉素和链霉素的1640培养液配成单个细胞悬液，以每孔2500个HCT116结直肠癌细胞接种到96孔细胞培养板，每孔体积100μl。
10)用含10％胎牛血清、1％青霉素和链霉素的1640培养液配成单个细胞悬液，以每孔2500个PANC-1胰腺癌细胞接种到96孔细胞培养板，每孔体积100μl。
2.然后将本发明制备的38个化合物(1至38)用DMSO溶解，分别用对应的细胞培养基配制成终浓度为1μM的药物溶液，分别加入到十种不同细胞(100μL/孔)中，对照组加入1‰DMSO，CO 2培养箱中培养72小时；
3.培养72h后倾去培养液，加入100μL 1:10稀释的CCK-8溶液，37℃孵育2小时后，使用LabServK3型酶标仪测450nm处吸光度A，参考波长620nm，计算对肿瘤细胞及白血病细胞的存活率(见表1)。
4.细胞增殖活力(％)＝[A(加药)-A(空白)]/[A(0加药)-A(空白)]×100。
表1
Figure PCTCN2021104268-appb-000071
Figure PCTCN2021104268-appb-000072
ND stand for not detected.
由表1的数据可以看出，化合物1、3、4、5等20个化合物作用下，骨肉瘤细胞SJSA-1存活率低于30％，说明这14个化合物对骨肉瘤细胞SJSA-1有非常好的抑制作用；化合物17对骨肉瘤细胞U2OS具有一定的抑制作用；化合物1等16个化合物作用下，骨肉瘤细胞HOS存活率低于50％，说明这16个化合物对HOS细胞具有较好的抑制作用；化合物1等25个化 合物对MNNG/HOS细胞具有很好的抑制作用；化合物3等24个化合物对MG63细胞具有很好的抑制作用；化合物1等15个化合物对143b细胞具有很好的抑制作用；化合物1等25个化合物对白血病细胞Jurkat具有很好的抑制作用；化合物4等17个化合物对结直肠癌细胞HCT116具有较好的抑制作用；化合物1等19个化合物对肺癌细胞A549具有很好的抑制作用；化合物1等17个化合物对胰腺癌细胞PANC-1具有一定的抑制作用。(加粗部分为有抑制活性的数据)
在得到3位为杂环以及脂肪族的噻唑酮化合物后，选用表2中五个化合物，通过表2中数据可以看出，本发明的化合物44对SJSA-1、U-2-OS、HOS、143B，MNNG/HOS和MG63骨肉瘤细胞及A549型肺癌细胞、Jurkat白血病细胞都有一定的抑制效果，但抑制活性最好的为MNNG/HOS和MG63骨肉瘤细胞，因而本发明在后续的实验中，仅用本发明化合物检测骨肉瘤细胞中的两个亚型MNNG/HOS和MG63的细胞IC 50(表三)。
表2
Figure PCTCN2021104268-appb-000073
从表3可以看出，化合物39等九个化合物对MNNG/HOS细胞具有优良到中等的IC 50值，化合物39等八个化合物对MG63细胞具有较好的IC 50值，并且可从表中看出，本发明的化合物对不同的细胞系具有较好的选择性。
表3
Figure PCTCN2021104268-appb-000074
a stand for IC 50＞1μM.
上述实施例仅为了说明本发明的技术构思及特点，其目的在于让本领域技术人员能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡是根据本发明内容的实质所作出的等效变化或修饰，都涵盖在本发明保护范围内。

Claims (10)

  1. 一种3-(3-芳基/杂芳基-4-噻唑啉酮基)-N-芳基/杂环苯甲酰胺类化合物或药学上可接受的盐，其特征在于，其结构如式(I)、(II)、(III)所示：
    Figure PCTCN2021104268-appb-100001
    其中，
    Ar为芳基、芳杂环、烷基取代的芳基、卤素取代的芳基、烷基取代的杂芳基、卤素取代的杂芳基、三氟甲基取代的芳基、硝基取代的芳基、萘烷基、呋喃烷基、烯基、炔基、二苯烷基、二(4-溴苯基)烷基、三氟甲基取代的杂芳基、硝基取代的杂芳基；其中，所述芳杂环、杂芳基分别选自吲哚、苯并三氮唑、噻吩、呋喃、吡咯、双内酰胺、哌嗪、咪唑、恶唑、吡嗪；
    R 1为单取代基或多取代基，选自下列基团：氢、卤素、烷氧基、烷基、硝基、氰基、三氟甲基、苯基、氢、芳基、三元环、乙炔基；
    R 2为环烷基，环氧烷基、烷基或氢；
    R 3为卤素、烷氧基、烷基、环烷基、硝基、氰基、三氟甲基、苯基、氢；
    n＝0；1；2；4；5；6。
    Het为杂环，选自：吡啶、喹啉、托烷、吩噻嗪、苯并二氮杂卓、呋喃、吡唑酮、嘧啶、卤素取代的杂芳基、硝基取代的杂芳基、萘烷基、呋喃烷基、烯烷基、炔烷基、二苯烷基、二(4-溴苯基)烷基、三氟甲基取代的杂芳基、硝基取代的杂芳基；其中，所述杂芳基选自吲哚、苯并三氮唑、噻吩、吡咯、双内酰胺、哌嗪、咪唑、恶唑、吡嗪。
  2. 如权利1所述的3-(3-芳基/杂芳基-4-噻唑啉酮基)-N-芳基/杂环苯甲酰胺类化合物或药学上可接受的盐，其特征在于，Ar为苯基、芳杂环、C1-C6烷基取代的苯基、卤素取代的苯基、C1-C6烷基取代的杂芳基、卤素取代的杂芳基、三氟甲基取代的苯基、硝基取代的苯基、萘甲基、呋喃甲基、烯丙基、炔丙基、二苯甲基、二(4-溴苯基)甲基、三氟甲基取代的杂芳基、硝基取代的杂芳基；其中，所述芳杂环、杂芳基分别选自吲哚、苯并三氮唑、噻吩、呋喃、吡咯、双内酰胺、哌嗪、咪唑、恶唑、吡嗪；R 1为单取代基或多取代基，选自下列基团：卤素，C1-C10烷氧基，C1-C10烷基，硝基，氰基，三氟甲基，氢；R 2为C1-C6 烷基、C3-C6环烷基，C1-C6环氧烷基、氢；R 3为卤素、C1-C6烷氧基、C1-C6烷基、C3-C6环烷基、硝基、氰基、三氟甲基、苯基、氢；Het为杂环，选自：吡啶、喹啉、托烷、吩噻嗪、苯并二氮杂卓、呋喃、吡唑酮、嘧啶、卤素取代的杂芳基、三氟甲基取代的芳基、硝基取代的芳基、萘C1-C6烷基、呋喃C1-C6烷基、烯C1-C6烷基、炔C1-C6烷基、二苯C1-C6烷基、二(4-溴苯基)C1-C6烷基、三氟甲基取代的杂芳基、硝基取代的杂芳基；其中，所述杂芳基选自吲哚、苯并三氮唑、噻吩、吡咯、双内酰胺，哌嗪、咪唑、恶唑、吡嗪。
  3. 根据权利要求1或2所述的3-(3-芳基/杂芳基-4-噻唑啉酮基)-N-芳基/杂环苯甲酰胺类化合物或药学上可接受的盐，其特征在于，选自于以下：
    3-(3-(2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(2,5-二氧-2,5-二氢-1H-吡咯-1-基)丁基)苯甲酰胺；
    3-(3-苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
    (Z)-3-(3-(2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁-3-烯-1-基)苯甲酰；
    3-(3-(2-甲氧基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺
    3-(3-(2，4-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
    3-(3-(2-甲基苯基)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺；
    3-(3-(3-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
    3-(3-(5-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
    3-(3-(4-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
    3-(3-(2-甲氧基苯基)-4-噻唑啉酮基)-5-甲基-N-(4-苯基丁基)苯甲酰胺
    3-(3-(2-甲氧基苯基)-噻唑啉酮基)-N-(4-1N-吡唑丁基)苯甲酰胺；
    3-(3-(2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-N-吲哚丁基)苯甲酰胺；
    3-(3-(2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-Boc-哌嗪丁基)苯甲酰胺；
    3-(3-(2-氟-苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
    3-(3-(3-三氟甲基-苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
    3-(3-(3-三氟甲基-苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺。
    3-(3-(3-环丙烷基苯)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
    3-(3-(3-环丙烷基苯)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺；
    3-(3-(4-环丙烷基苯)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
    3-(3-(4-环丙烷基苯)-4-噻唑啉酮基)-N-(4-苯基乙基)苯甲酰胺；
    3-(3-(4-环丙烷基苯)-4-噻唑啉酮基)-N-(4-苯基丙基)苯甲酰胺；
    3-(3-(4-环丙烷基苯)-4-噻唑啉酮基)-N-5-甲基-(4-(4氯)苯基丁基)苯甲酰胺；
    3-(3-(3-环丙烷基苯)-4-噻唑啉酮基)-N-5-甲基-(4-(4氯)苯基丁基)苯甲酰胺；
    3-(3-(4-环丙烷基苯)-4-噻唑啉酮基)-N-5-甲基-(4-苯基丁基)苯甲酰胺；
    3-(3-(3-环丙烷基苯)-4-噻唑啉酮基)-N-5-甲基-(4-苯基丁基)苯甲酰胺；
    3-(3-(3-环丙烷基苯)-4-噻唑啉酮基)-N-5-甲基-(4-(N-吡唑)苯基丁基)苯甲酰胺。
    3-(3-(3-乙炔基苯)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
    3-(3-(2-甲氧基-5-乙炔基苯)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
    3-(3-(2-甲基-4-乙炔基苯)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
    3-(3-(2-甲基-4-乙炔基苯)-4-噻唑啉酮基)-N-(4-N-吲哚丁基)苯甲酰胺；
    3-(3-(2-甲基-4-乙炔基苯)-4-噻唑啉酮基)-N-(4-N-吡唑丁基)苯甲酰胺；
    3-(3-(3-乙炔基苯)-4-噻唑啉酮基)-N-(4-N-吡唑丁基)苯甲酰胺；
    3-(3-(3-乙炔基苯)-4-噻唑啉酮基)-N-(4-N-苯基丙基)苯甲酰胺；
    3-(3-(3-乙炔基苯)-4-噻唑啉酮基)-N-(4-N-苯基乙基)苯甲酰胺；
    3-(3-(2-甲基-5-乙炔基苯)-4(5-甲基)-噻唑啉酮基)-N-(4-N-吲哚丁基)苯甲酰胺；
    3-(3-(2-甲氧基苯)-4-噻唑啉酮基)-5-乙炔基-N-(4-苯基丁基)苯甲酰胺。
    3-(3-(2-吡啶基)-4-噻唑啉酮基)-N-(4-吡唑丁基)苯甲酰胺；
    3-(3-(2-(4-溴)吡啶基)-4-噻唑啉酮基)-N-(4-吡唑丁基)苯甲酰胺；
    3-(3-(2-(4-氯)吡啶基)-4-噻唑啉酮基)-N-(4-吡唑丁基)苯甲酰胺；
    3-(3-(2-(4-氟)吡啶基)-4-噻唑啉酮基)-N-(4-吡唑丁基)苯甲酰胺；
    3-(3-(2-(4-甲基)吡啶基)-4-噻唑啉酮基)-N-(4-吡唑丁基)苯甲酰胺；
    N-(4-(1H-吡唑啉-1-基)丁基)-3-(3-(4-(3-乙基-2,6-二氧哌啶-3-基)苯基)-4-恶噻唑烷-2-基)苯甲酰胺；
    2-(2-(3-((4-(1H-吡唑啉-1-基)丁基)氨甲酰基)苯基)-4-恶噻唑烷-3-基)-4-甲基噻唑-5-羧酸乙酯；
    3-(3-(3-吡啶基)-4-噻唑啉酮基)-N-(4-吡唑丁基)苯甲酰胺；
    3-(3-(4-吡啶基)-4-噻唑啉酮基)-N-(4-吡唑丁基)苯甲酰胺；
    3-氟-5-(4-氧代-3-(吡啶-2-基)噻唑烷-2-基)-N-(4-苯基丁基)苯甲酰胺；
    3-(3-(2-吡啶基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
    3-(3-(2-吡嗪基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺；
    3-(3-(2-吡啶基)-4-噻唑啉酮基)-5-氟-N-(4-苯基丁基)苯甲酰胺；
    3-(3-(4-(叔丁基)异恶唑-3-基)-4-恶噻唑烷-2-基)-N-(4-苯基丁基)苯甲酰胺
    3-(3-([1,1'-联苯]-4-基)-4-恶噻唑烷-2-基)-N-(4-苯基丁基)苯甲酰胺。
  4. 根据权利要求1或2所述的3-(3-芳基/杂芳基-4-噻唑啉酮基)-N-芳基/杂环苯甲酰胺类化合物或药学上可接受的盐，其特征在于，所述化合物与酸形成的酸加成盐；其中，所述酸是盐酸、硫酸、磷酸、氢溴酸、乙酸、水杨酸、酒石酸、乳酸、柠檬酸、甲磺酸、对甲苯磺酸、马来酸、丙酮酸、或琥珀酸。
  5. 一种药物组合物，其特征在于，其包含如权利要求1-3之任一项所述的3-(3-芳基/杂芳基-4-噻唑啉酮基)-N-芳基/杂环苯甲酰胺类化合物或药学上可接受的盐，以及药学上可接受的载体。
  6. 根据权利要求5所述的药物组合物，其特征在于，所述药物组合物被配制成丸剂、胶囊剂、乳膏、凝胶剂、赋形剂、可注射流体、气雾剂、糖浆剂或透皮贴剂。
  7. 根据权利要求1-3之任一项所述的3-(3-芳基/杂芳基-4-噻唑啉酮基)-N-芳基/杂环苯甲酰胺类化合物或药学上可接受的盐在制备预防和/或治疗肿瘤的药物中的应用。
  8. 根据权利要求7所述的应用，其特征在于，所述3-(3-芳基/杂芳基-4-噻唑啉酮基)-N-芳基/杂环苯甲酰胺类化合物或药学上可接受的盐、或药物组合物用于抑制肿瘤细胞的增殖、生长、迁移、浸润、转移和复发，或促进肿瘤细胞凋亡。
  9. 根据权利要求7所述的应用，其特征在于，所述肿瘤包括骨肉瘤、白血病、胰腺癌、肺癌、结直肠癌。
  10. 根据权利要求9所述的应用，其特征在于，所述骨肉瘤细胞包括SJSA-1、U2OS、HOS、MNNG/HOS、MG63、143b；所述胰腺癌细胞包括PANC-1；所述肺癌细胞包括A549；所述结直肠癌细胞包括HCT116；所述白血病细胞包括Jurkat。
PCT/CN2021/104268 2020-09-16 2021-07-02 3-(3-芳基/杂芳基-4-噻唑啉酮基)-n-芳基/杂环苯甲酰胺类化合物及其应用 WO2022057387A1 (zh)

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