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WO2018068357A1 - 一类新型sirt2蛋白抑制剂及其在制药中的用途 - Google Patents

一类新型sirt2蛋白抑制剂及其在制药中的用途 Download PDF

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WO2018068357A1
WO2018068357A1 PCT/CN2016/105443 CN2016105443W WO2018068357A1 WO 2018068357 A1 WO2018068357 A1 WO 2018068357A1 CN 2016105443 W CN2016105443 W CN 2016105443W WO 2018068357 A1 WO2018068357 A1 WO 2018068357A1
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group
compound
mmol
substituted
phenyl
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French (fr)
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杨羚羚
王周玉
袁陈
王丽姣
钱珊
赖朋
方莎
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Xihua University
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Xihua University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and 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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/38—One sulfur atom
    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention belongs to the field of compound medicines, and in particular relates to a novel class of SIRT2 protein inhibitors and their use in pharmacy.
  • Histone acetyltransferase catalyzes the acetylation of substrate histones or non-histone lysine residues.
  • HAT histone acetylase
  • HDAC histone deacetylase
  • Deacetylation of acid residues the above-mentioned acetylation/deacetylation protein post-translational modification jointly regulates the functions of various proteins in the body and participates in important physiological processes such as gene expression and cell cycle progression.
  • HDAC1-11 Zn2+-dependent histone deacetylase
  • Sirtuin1-7 NAD+-dependent histone deacetylase
  • SIRT2 is mainly located in the cytoplasm, and it is found that SIRT2 can continuously shuttle into the nucleus and cytoplasm. Therefore, it can catalyze histones and non-histone lysine residues such as ⁇ -tubulin, P53, p65 and FOXO1. Deacetylation regulates gene expression, microtubule stability and cell cycle progression. Due to the involvement of SIRT2 in many important biological processes, recent studies have revealed abnormal expression of SIRT2 and various diseases including neurodegenerative diseases (Parkinson, Alzheimer's disease, Huntington, etc.), tumors (lung cancer, breast cancer, liver cancer). Etc. etc. are closely related, therefore, SIRT2 is considered to be a potential therapeutic target for these diseases.
  • neurodegenerative diseases Parkinson, Alzheimer's disease, Huntington, etc.
  • tumors lung cancer, breast cancer, liver cancer.
  • Etc. etc. are closely related, therefore, SIRT2 is considered to be a potential therapeutic target for these diseases.
  • SIRT2 inhibitors in vitro and in vivo for the treatment of related diseases are still an urgent task.
  • the number of existing SIRT2 inhibitors is still small, it is difficult to meet the needs of the majority of patients, and a new class of inventions needs to be invented.
  • Inhibitors of sir-regulatory factor 2-related proteins provide more medication options for a wide range of patients.
  • R 1 is selected from H or
  • X is selected from
  • R 4 is selected from aryl, heteroaryl, substituted aryl, substituted heteroaryl or
  • the substituents of the substituted aryl group and the substituted heteroaryl group are each independently selected from a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, a C 1 -C 4 haloalkyl group, Halogen, hydroxy, thiol, ether, ester, amino or nitro;
  • R 4a and R 4b are each independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, aryl, heteroaryl or C 3 -C 6 cycloalkyl ;
  • R 2 is selected from
  • R 2a to R 2f are each independently selected from H, a hydroxyl group, a halogen, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, a C 1 -C 4 haloalkyl group or a phenyl group;
  • R 3 is selected from halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or
  • Y is selected from
  • R 5 is selected from aryl, heteroaryl, substituted aryl or substituted heteroaryl, and the substituents of the substituted aryl and substituted heteroaryl are each independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, halogen, hydroxy, decyl, ether, ester, amino, nitro, amido or aminoacyl.
  • the aryl group is a phenyl group or a naphthyl group
  • the heteroaryl group is a pyridyl group, a furyl group, a thienyl group, a quinolyl group, a carbazolyl group or a quinolyl group, the substituted aryl group and the substituent.
  • the substituents of the heteroaryl group are each independently selected from a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, a C 1 -C 4 haloalkyl group,
  • R 4a and R 4b are each independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, phenyl or thienyl;
  • R 2 , R 2a , R 2c and R 2f are each independently selected from H, a hydroxyl group, a halogen, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, a C 1 -C 4 haloalkyl group or a phenyl group.
  • R 2b , R 2d , and R 2e are each H.
  • R 5 is selected from the group consisting of phenyl, pyridyl, furyl, thienyl, substituted phenyl, substituted pyridyl, substituted furyl or substituted thienyl; substituted phenyl, substituted pyridyl, substituted furanyl and substituted thienyl
  • the substituents are each independently selected from a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group or a C 1 -C 4 haloalkyl group.
  • the present invention also provides the use of the above compound, or a pharmaceutically acceptable salt, crystal form, or solvate thereof, for the preparation of an inhibitor of a sirtuin-2 related protein.
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt, crystal form, or solvate thereof for the preparation of a medicament for treating and/or preventing a tumor.
  • the tumor is liver cancer, hepatoblastoma, breast cancer, lung cancer, pancreatic cancer, prostate cancer or leukemia.
  • the present invention also provides a pharmaceutical composition for treating and/or preventing tumors, which comprises the above compound or a pharmaceutically acceptable salt, a crystal form thereof, a solvate thereof as an active ingredient, and a pharmaceutically-acceptable auxiliary ingredient.
  • a pharmaceutical composition for treating and/or preventing tumors which comprises the above compound or a pharmaceutically acceptable salt, a crystal form thereof, a solvate thereof as an active ingredient, and a pharmaceutically-acceptable auxiliary ingredient.
  • the resulting preparation was prepared.
  • the novel compound of the formula I of the present invention not only has good inhibitory activity against SIRT2, but also has a good inhibitory effect on tumors, has good medicinal potential, and provides a new potential choice for clinical use;
  • the preparation method of the novel compound of the invention is simple, the reaction condition is mild, the operation and the control are convenient, the energy consumption is small, the yield is high, the cost is low, and the product can be suitable for industrial production.
  • the compounds and derivatives provided in the present invention may be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.
  • substitution means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
  • C 1 -C 4 alkyl means an alkyl group containing from 1 to 4 carbon atoms, in other words, C 1 -C 4 alkyl includes methyl, ethyl, n-propyl, isopropyl, N-butyl, isobutyl, tert-butyl.
  • pharmaceutically acceptable means that a carrier, carrier, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients that constitute a pharmaceutical dosage form, and is physiologically Compatible with the receptor.
  • salts and “pharmaceutically acceptable salt” refer to the above-mentioned compounds or stereoisomers thereof, acid and/or basic salts formed with inorganic and/or organic acids and bases, and also includes zwitterionic salts (within Salts) also include quaternary ammonium salts such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. It can also be obtained by mixing the above compound, or a stereoisomer thereof, with a certain amount of an acid or a base as appropriate (for example, an equivalent amount).
  • the salt in the present invention may be a hydrochloride, a sulfate, a citrate, a besylate, a hydrobromide, a hydrofluoride, a phosphate, an acetate, a propionate or a dibutyl compound.
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, parenteral (intravenous, intramuscular or subcutaneous) and topical administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorbing accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form can comprise inert diluents conventionally employed in the art, such as water or other solvents.
  • Solubilizers and emulsifiers for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ Oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for the compounds of the invention for topical administration include ointments, powders, patches, propellants and inhalants.
  • the active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, propellants.
  • the pharmaceutically acceptable excipient of the present invention means a substance which is contained in a dosage form in addition to the active ingredient.
  • the pharmaceutically acceptable auxiliary component of the present invention has certain physiological activity, but the addition of the component does not change the dominant position of the above pharmaceutical composition in the course of disease treatment, but only plays an auxiliary effect, and the auxiliary effects are only It is the utilization of the known activity of the component, and is an auxiliary treatment method conventionally used in the medical field. It is still within the scope of the present invention to use the above auxiliary ingredients in combination with the pharmaceutical composition of the present invention.
  • Figure 1 is a 1 H NMR chart of Compound 28 of the present invention.
  • Figure 2 is a 13 C NMR chart of Compound 28 of the present invention.
  • Figure 3 is a 1 H NMR chart of the compound 33 of the present invention.
  • Figure 4 is a 13 C NMR chart of the compound 33 of the present invention.
  • the raw materials and equipment used in the specific embodiments of the present invention are known products and are obtained by purchasing commercially available products.
  • intermediate 1b (1 mmol, 183 mg) and bromoacetic acid (1.2 mmol, 166.8 mg) were dissolved in DCM (16 ml), and stirred at 0 ° C, and then added at 0 ° C, 1-(3-di) Methylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 1.2 mmol, 230.4 mg), 1-hydroxybenzotriazole (HOBT, 1.2 mmol, 162 mg), N,N-diisopropyl Ethylethylamine (DIEA, 2 mmol, 331 ⁇ l) was added and the reaction was taken to room temperature and stirred overnight. After the reaction was completed by TLC (Thin Layer Chromatography), the excess solvent was removed under reduced pressure, and the residue was purified by column chromatography.
  • TLC Thin Layer Chromatography
  • the compound 4,6-dimethyl-2-mercaptopyrimidine (1.2 mmol, 168.2 mg) was dissolved in DMF (3 ml), and potassium t-butoxide (2 mmol, 224.4 mg) was added at room temperature and stirred at room temperature After 30 min, the compound 1c (1 mmol, 302 mg) was dissolved in DMF (1 ml) and slowly added to the reaction. After the reaction was stirred for 4-5 h at room temperature, after the reaction was completed by TLC, ice water (40 ml) was added to the reaction, and acetic acid was used.
  • the target compound 2 was synthesized by the synthesis method of the target compound 1 using the intermediate 2c in a four-step total yield of 26%.
  • 3a was synthesized by the synthesis of 2c intermediate and bromoacetic acid according to 1c, and the target compound 3 was synthesized by the synthesis method of compound 1 using 3a and the starting material methylthiouracil, and the yield was 45%.
  • the target compound 5 was synthesized by the synthesis method of Compound 1 using 5b in a three-step total yield of 46%.
  • LiAlH 4 (5 mmol, 189.8 mg) was added to the reaction flask, and after stirring at 0 ° C for 15 min, a solution of AlCl 3 (5 mmol, 666.7 mg) in diethyl ether (8 ml) was added dropwise to the reaction, and the mixture was Stir at 0 ° C for 5 min. Then, a solution of m-aminobenzophenone (6a, 1 mmol, 197.2 mg) in diethyl ether (8 ml) was added dropwise to the reaction, and then the reaction was allowed to react to room temperature for 3 h, and after the reaction was completed by TLC, the reaction solution was firstly used.
  • m-nitroacetophenone (8a, 1 mmol, 165 mg) and p-methylbenzenesulfonylhydrazide (1 mmol, 185 mg) were dissolved in 10 ml of dioxane, and reacted at 80 ° C for 1.5 hours, and the reaction was detected by TLC. After completion, distillation under reduced pressure gave 8b crude product; then p-methoxyphenylboronic acid (1.5 mmol, 227 mg), K 2 CO 3 (1.5 mmol) and 15 ml of dioxane were added and refluxed at 110 ° C for 5 hours.
  • the raw material 2b (1.0 eq.) is dissolved in DMF and catalytically dehydrogenated with NaH (0.5 eq.) and then reacted with methyl iodide to obtain intermediate 9a.
  • the target compound 9 is synthesized according to the synthesis method of compound 2 using 9a. The rate is 19%.
  • the intermediate 10a was synthesized by the method of the synthesis of the compound 1b, and then 10a (590 mg, 1.85 mmol) was dissolved in DCM (10 mL), and m-chloroperoxybenzoic acid (335 mg, 1.94 mmol) was added with stirring at 0 ° C, and reacted at room temperature. After 45 min, the excess solvent was removed under reduced pressure by TLC. Then, the target compound 10 was synthesized by the synthesis method of the compound 1 using the intermediate 10b in a four-step total yield of 32%.
  • the compound 10a (590 mg, 1.85 mmol) was dissolved in DCM (10 mL). EtOAc (EtOAc m. Column chromatography gave the white intermediate 11a.
  • the target compound 11 was synthesized by the synthesis method of the target compound 1 using 11a. The total yield in two steps was 51%.
  • the synthesis of the above intermediate 12b is carried out by the synthesis method of 1b using 12a, and then the intermediate 12c is synthesized by the synthesis method of the target compound 1 using 12b. Then, benzaldehyde (0.374 mmol, 39.6 mg) and compound 12c (0.34 mmol, 98.1 mg) were dissolved in DCM (6 ml), then dihydropyridyl ester (0.477 mmol, 120.1 mg) was added, and finally trifluoro Acetic acid (0.17 mmol, 12.7 ⁇ l) was refluxed at 45 ° C overnight. After the reaction was completed by TLC, the excess solvent was removed under reduced pressure, and the title compound 12 was obtained by column chromatography.
  • the title compound 13 was obtained by the method of synthesizing compound 12 using the important intermediate 12c and 2-thiophenecarbaldehyde in a yield of 68%.
  • m-aminophenol (15a, 0.5 mmol, 54.6 mg) was dissolved in dichloromethane (5 ml), triethylamine (1.5 mmol, 208 ⁇ l) was added, then acetic anhydride (0.55 mmol, 51.9 ⁇ l) was added at room temperature. The reaction was carried out overnight. The reaction was completely confirmed by TLC, and concentrated under reduced pressure.
  • the compound 15c (0.26 mmol, 63.2 mg) was dissolved in methanol (2 ml), chlorosulfoxide (0.64 mmol, 45.3 ⁇ l) was added, and the reaction was stirred under reflux for 3 h. The reaction was completed by TLC, and then saturated NaHCO 3 solution was added to adjust the pH to basicity. Methanol was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate. The organic phase was combined, dried over anhydrous Na 2 SO 4 and concentrated. Important intermediate 15d. Finally, the target compound 15 was synthesized by the synthesis method of the compound 1 using 15d, and the total yield of the five steps was 18%.
  • the reductive amination product 16b (1.89 mmol, 427 mg) was dissolved in a mixed solvent of ethanol (10 ml) and water (5 ml), and then iron powder (9.44 mmol, 528.4 mg) and NH 4 Cl (0.945 mmol, 50.6 mg) were added to the reaction. The mixture was refluxed at 80 ° C for 30 min, and the reaction was completed by TLC. After filtration, the insoluble material was removed by filtration. NaHCO 3 was added to adjust the pH to basicity. Ethanol was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate and concentrated. Compound 16, the total yield in four steps was 45%.
  • the imine reduction product (19c, 0.5 mmol, 127 mg) was dissolved in methanol (2 ml), dichloromethane (1.2 mmol, 87 ⁇ l) was added, and refluxed at 65 ° C for 3-4 h. After the reaction was completely confirmed by TLC, an appropriate amount of saturated NaHCO 3 was added to adjust the pH to basicity, and methanol was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate, and concentrated to give an intermediate 19d. Finally, the target compound 19 was synthesized according to the synthesis method of the compound 1 using 19d; the total yield of the five steps was 28%.
  • the title compound 20 was synthesized according to the synthesis method of the compound 19 using 19a and m-trifluoromethylaniline in a five-step total yield of 30%.
  • 21b (1 mmol, 229 mg) was dissolved in a mixed solvent of ethanol (3 ml) and water (1.5 ml), and NH 4 Cl (0.5 mmol, 26.8 mg) and Fe (5 mmol, 280 mg) were reacted at 80 ° C After 30 min, the reaction was completed by TLC, and the insoluble material was removed by hot filtration. Then, NaHCO 3 was added to adjust the pH to basicity. The ethanol was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate and concentrated. Finally, the target compound 21 was synthesized by the synthesis method of Compound 1 using 21c, and the total yield in four steps was 35%.
  • the target compound 24 was synthesized by the synthesis method of the compound 21 using 1-naphthol, and the yield in four steps was 33%.
  • the target compound 25 was synthesized according to the synthesis method of the compound 21 using 2-naphthol, and the yield in four steps was 35%.
  • the title compound 26 was synthesized according to the synthesis method of the compound 21 using 8-hydroxyquinoline in a four-step yield of 25%.
  • the intermediate 22a (1.0 mmol, 286 mg) was dissolved in 5 ml of methanol, and then 0.5 ml of thionyl chloride was added dropwise thereto, followed by reflux for 0.5 hour, and then the solvent was distilled off under reduced pressure, and then NaHCO 3 was added to adjust the pH to 7-8 and then added. After extraction with water and ethyl acetate, the organic layer was dried over Na 2 SO 4 and then evaporated on a rotary evaporator. After condensing with thiophene-2-carbonyl chloride, the nitro group was reduced by iron powder to obtain intermediate 27b; Synthesis of Compound 1 The title compound 27 was synthesized in a five-step total yield of 28%.
  • the target compound 29 was synthesized according to the synthesis method of the compound 27 using 27a and benzenesulfonyl chloride, and the total yield of the four steps was 30%.
  • the title compound 31 was synthesized by the synthesis method of the compound 15 using 5-amino-2-fluorophenol (31a, 0.5 mmol, 65 mg). The five-step total yield was 26%.
  • the title compound 32 was synthesized by the synthesis method of the compound 15 using 5-amino-2-methylphenol (32a, 0.5 mmol, 62 mg). The total yield of the five steps was 27%.
  • the compound 34a (1 mmol, 185 mg) and bromoacetic acid (1.2 mmol, 166.8 mg) were dissolved in DCM (16 ml), and dissolved at 0 ° C, and then added at 0 ° C, 1-(3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride (EDCI, 1.2 mmol, 230.4 mg), 1-hydroxybenzotriazole (HOBT, 1.2 mmol, 162 mg), N,N-diisopropylethylamine (DIEA, 2 mmol, 331 ⁇ l), after completion, the reaction was taken to room temperature and stirred overnight.
  • EDCI 1-(3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride
  • HOBT 1-hydroxybenzotriazole
  • DIEA N,N-diisopropylethylamine
  • LiAlH 4 (5 mmol, 189.8 mg) was added to the reaction flask, and the mixture was stirred at 0 ° C for 15 min, then a solution of AlCl 3 (5 mmol, 666.7 mg) in diethyl ether (8 ml) was added dropwise to the reaction mixture at 0 ° C. Stir for 5 min. Then, a solution of p-aminobenzophenone (37a, 1 mmol, 197.2 mg) in diethyl ether (8 ml) was added dropwise to the reaction, then the reaction was allowed to react to room temperature for 3 h, and after completion of the reaction by TLC, the reaction solution was firstly taken with 6 M HCl.
  • the intermediate 40b was synthesized by the method of the synthesis of the intermediate 34b of Example 34 using 40a, and then the intermediate 40c was synthesized by the synthesis of the title compound 34 of Example 34 using 40b. Then benzaldehyde (0.374 mmol, 39.6 mg) and compound 40c (0.34 mmol, 98.1 mg) were dissolved in DCM (6 ml), then 2,6-dimethyl-1,4-dihydropyridine-3,5 Ethyl dicarboxylate (Hans, 0.477 mmol, 120.1 mg) was added, and finally trifluoroacetic acid (0.17 mmol, 12.7 ⁇ l) was added dropwise and refluxed at 45 ° C overnight.
  • 45b (0.45 mmol, 103.5 mg) was dissolved in a mixed solvent of ethanol (3 ml) and water (1.5 ml), and NH 4 Cl (0.225 mmol, 12 mg) and Fe (2.25 mmol, 126 mg) were added and reacted at 80 ° C. After 30 min, the reaction was complete by TLC, and then filtered to remove insoluble materials. NaHCO 3 was added to adjust pH to basicity, and then ethanol was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate and concentrated to afford intermediate 45c.
  • the title compound 45 was synthesized by a similar synthetic procedure to the compound 34 of Example 34 using 45c, with a four-step total yield of 41%.
  • Phenol (46a, 1 mmol, 94 mg) was added to a reaction flask and dissolved with 2 ml of DMF, followed by potassium carbonate (5 mmol, 690 mg) and p-nitrobenzyl bromide (1 mmol, 216 mg) was dissolved in 2 ml of DMF and added dropwise. In the reaction bottle. The reaction was stirred at room temperature for 2 hours. After completion of the reaction by TLC, the compound 46b was obtained by distillation under reduced pressure.
  • the reductive amination product 47b (1.89 mmol, 427 mg) was dissolved in a mixed solvent of ethanol (10 ml) and water (5 ml), and then iron powder (9.44 mmol, 528.4 mg) and NH 4 Cl (0.945 mmol, 50.6 mg) were added to the reaction. The mixture was refluxed at 80 ° C for 30 min, and the reaction was completed by TLC. After filtration, the insoluble material was removed by filtration. NaHCO 3 was added to adjust the pH to basicity. Ethanol was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate and concentrated. Compound 47c.
  • the compound 50b was oxidized by m-CPBA using the compound 49b according to the method of the synthesis of the objective compound 35 of Example 35. Then, the title compound 50 was synthesized by the method of synthesizing the compound 34 of Example 34 using Compound 50a, with a three-step total yield of 41%.
  • Compound 49b was oxidized by m-CPBA according to the synthesis of the title compound 36 of Example 36 to give Compound 51a.
  • the title compound 51 was synthesized by the method for the synthesis of the compound 34 of the compound of Example 34, using compound 51a.
  • the test method is as follows:
  • a tris-hydroxymethane buffer was prepared; then, all test compounds and the positive control compound Suramin were dissolved in 100% DMSO to prepare test solutions of different concentrations and transferred to the test wells; then SIRT2 was dissolved.
  • the test plate was incubated at room temperature for 15 minutes; 10 ⁇ L of the substrate buffer was added to each well for 4 hours; after the reaction was completed, the trypsin solution was added to each well for 1.5 hours;
  • the Synergy MX plate reader measures the luminescence intensity of the above reaction solution at excitation light wavelengths of 360 nM and 460 nM to determine the inhibitory activity of the compound on SIRT2.
  • the inhibitory activity of the compound of the present invention against SIRT2 was tested by the above experimental methods.
  • the inhibitory activity of the specific compound at a concentration of 5 ⁇ M and 50 ⁇ M and the effective inhibitory concentration (IC 50 ) of some compounds against SIRT2 are shown in Table 1, wherein "-" Indicates not tested.
  • the compound of the present invention has a good inhibitory activity against SIRT2 and can be used for the preparation of an inhibitor of a sirtuin-2-related protein.
  • Example 54 Inhibitory effect of the compound of the present invention on proliferation of various tumor cell lines
  • RPMI-1640 fetal calf serum, trypsin, etc. were purchased from Gibco BRL (Invitrogen Corporation, USA), and IMDM medium was purchased from ATCC (American Type Culture Collection). Tetramethylazozolium salt (MTT) and dimethyl sulfoxide (DMSO) are products of Sigma (USA).
  • a cell suspension having a cell concentration of 1 to 2 ⁇ 10 4 /mL was adjusted with a complete cell culture solution, and seeded in a 96-well plate, and 200 ⁇ l of a cell suspension per well was cultured overnight. On the next day, the supernatant was aspirated (the supernatant was aspirated after centrifugation), and then the cells were treated with a gradient concentration of the test compound. At the same time, a drug-free negative control group and an equal volume of solvent control group were used, and the DMSO concentration was 0.1%. Three doses of each well were set in each dose group, and cultured at 37 ° C, 5% CO 2 .
  • the compounds 1, 13, 19, 20, 21, 49 of the present invention were tested against human hepatoma cell line (HUH7), human hepatoma cell line (SMMC7721), hepatoblastoma cell line (HepG2), human breast cancer.
  • the leukemia cell line (K562), human prostate cancer cell (DU-145), and the like were tested for proliferation inhibitory activity, specifically, the inhibitory activity of the compound at a concentration of 50 ⁇ M and 100 ⁇ M, as shown in Table 2.
  • the compound of the present invention has a good inhibitory effect on cell proliferation of liver cancer, hepatoblastoma, breast cancer, lung cancer, pancreatic cancer, prostate cancer and leukemia, and can be used for preparing a medicament for treating and/or preventing tumors. .
  • the novel compound of the formula I of the present invention not only has good inhibitory activity against SIRT2, but also has a good inhibitory effect on tumors, has good medicinal potential, and provides a new drug for clinical use.
  • the novel compound of the invention has simple preparation method, mild reaction condition, convenient operation and control, low energy consumption, high yield and low cost, and is suitable for industrial production.

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Abstract

本发明公开了式Ⅰ所示的化合物或其药学上可接受的盐、晶型、溶剂合物：其中，Z选自（II）、（III）、（IV）或（V）；R1选自H或（VI）；R2选自（VII）或（VIII）；R3选自卤素、C1～C4烷基、C1～C4烷氧基或（IX）。本发明式Ⅰ所示的新化合物，不仅对SIRT2具有良好的抑制活性，而且对肿瘤具有很好的抑制作用，具有很好的药用潜力，为临床用药提供了一种新的潜在选择；同时，本发明新化合物的制备方法简便，反应条件温和，便于操作和控制，能耗小，产率高，成本低，可适合产业化生产。

Description

一类新型SIRT2蛋白抑制剂及其在制药中的用途 技术领域
本发明属于化合物药物领域，具体涉及一类新型SIRT2蛋白抑制剂及其在制药中的用途。
背景技术
蛋白翻译后的可逆乙酰化修饰是蛋白功能调控的重要手段之一。组蛋白乙酰基转移酶(HAT)可催化底物组蛋白或非组蛋白赖氨酸残基的乙酰化修饰，与此相反，组蛋白去乙酰转移酶(HDAC)可催化相应底物蛋白赖氨酸残基的去乙酰化作用，以上乙酰化/去乙酰化蛋白翻译后修饰共同调控着体内多种蛋白的功能从而参与了基因表达、细胞周期进程等重要生理过程。截止目前共研究发现18种HDAC，按照其催化机制分为两类，即Zn2+依赖型组蛋白去乙酰化酶(HDAC1-11)和NAD+依赖型组蛋白去乙酰化酶(Sirtuin1-7,SIRT1-7)。SIRT从细菌到人类具有高度保守性，并存在于多种组织和器官中，如肝脏、心脏、脑和胰腺等。SIRT1-7因其位于不同的亚细胞结构和作用于不完全相同的底物蛋白从而具有各异的生理功能。
在SIRT1-7当中SIRT2主要位于细胞质中，同时研究发现SIRT2可不断穿梭于细胞核和细胞质中，因此，其可催化组蛋白及α-tubulin、P53、p65、FOXO1等非组蛋白赖氨酸残基的去乙酰化作用从而调控基因的表达，微管的稳定和细胞周期进程等。由于SIRT2参与诸多重要的生物学过程，近些年研究发现SIRT2的异常表达与多种疾病包括神经退行性疾病(帕金森、阿尔兹海默病、亨廷顿等)、肿瘤(肺癌、乳腺癌、肝癌等)等密切相关，因此，SIRT2被认为是这些疾病的潜在治疗靶点。
鉴于此，开发新型选择性高活性SIRT2抑制剂是目前药物研究的一个热点，受到国内外学者、研究机构和医药公司的高度关注。
截止目前已有大量新型SIRT2抑制剂相继被报道，其中包括Sirtinol(IC50＝46μM)、Salermide(IC50＝25μM)、EX-527(IC50＝20μM)、AK-7(IC50＝15.5μM)、AGK2(IC50＝3.5μM)等，它们对SIRT2蛋白的抑制活性及选择性各异，且仅极少数抑制剂表现出了一定的体内抗肿瘤或神经退行性疾病的效果，除此之外几乎暂无SIRT2的抑制剂用于相关疾病治疗的临床研究。
因此，开发真正体内外有效的SIRT2抑制剂用于相关疾病的治疗仍然是十分迫切的任务，特别是，现有SIRT2抑制剂的数量仍然较少，难以满足广大患者的需求，需要发明一类新的沉默信息调节因子2相关蛋白的抑制剂，为广大患者提供更多的用药选择。
发明内容
本发明的目的在于提供一类新的具有药用价值的化合物：式Ⅰ所示的化合物。
本发明提供的式Ⅰ所示的化合物或其药学上可接受的盐、晶型、溶剂合物：
Figure PCTCN2016105443-appb-000001
其中，
Z选自
Figure PCTCN2016105443-appb-000002
R1选自H或
Figure PCTCN2016105443-appb-000003
X选自
Figure PCTCN2016105443-appb-000004
Figure PCTCN2016105443-appb-000005
R4选自芳基、杂芳基、取代芳基、取代杂芳基或
Figure PCTCN2016105443-appb-000006
所述取代芳基和取代杂芳基的取代基分别独立地选自C1～C4烷基、C1～C4烷氧基、C1～C4卤代烷基、
Figure PCTCN2016105443-appb-000007
Figure PCTCN2016105443-appb-000008
卤素、羟基、巯基、醚基、酯基、氨基或硝基；
R4a、R4b分别独立地选自C1～C4烷基、C1～C4烷氧基、C1～C4卤代烷基、芳基、杂芳基或C3～C6环烷基；
R2选自
Figure PCTCN2016105443-appb-000009
R2a～R2f分别独立地选自H、羟基、卤素、C1～C4烷基、C1～C4烷氧基、C1～C4卤代烷基或苯基；
R3选自卤素、C1～C4烷基、C1～C4烷氧基或
Figure PCTCN2016105443-appb-000010
Y选自
Figure PCTCN2016105443-appb-000011
Figure PCTCN2016105443-appb-000012
R5选自芳基、杂芳基、取代芳基或取代杂芳基，所述取代芳基和取代杂芳基的取代基分别独立地选自C1～C4烷基、C1～C4烷氧基、C1～C4卤代烷基、卤素、羟基、巯基、醚基、酯基、氨基、硝基、酰胺基或氨酰基。
进一步的，所述的化合物为
Figure PCTCN2016105443-appb-000013
进一步的，
R4中，所述芳基为苯基或萘基，所述的杂芳基为吡啶基、呋喃基、噻吩基、喹啉基、吲唑基或喹啉基，所述取代芳基和取代杂芳基的取代基分别独立地选自C1～C4烷基、C1～C4烷氧基、C1～C4卤代烷基、
Figure PCTCN2016105443-appb-000014
R4a、R4b分别独立地选自C1～C4烷基、C1～C4烷氧基、C1～C4卤代烷基、C3～C6环烷基、苯基或噻吩基；
R2中，R2a、R2c、R2f分别独立地选自H、羟基、卤素、C1～C4烷基、C1～C4烷氧基、C1～C4卤代烷基或苯基，R2b、R2d、R2e分别为H。
进一步的，
R5选自苯基、吡啶基、呋喃基、噻吩基、取代苯基、取代吡啶基、取代呋喃基或取代噻吩基；所述取代苯基、取代吡啶基、取代呋喃基和取代噻吩基的取代基分别独立地选自C1～C4烷基、C1～C4烷氧基或C1～C4卤代烷基。
进一步的，所述的化合物为
Figure PCTCN2016105443-appb-000015
Figure PCTCN2016105443-appb-000016
Figure PCTCN2016105443-appb-000017
本发明还提供了上述的化合物或其药学上可接受的盐、晶型、溶剂合物在制备沉默信息调节因子2相关蛋白的抑制剂中的用途。
本发明还提供了上述的化合物或其药学上可接受的盐、晶型、溶剂合物在制备治疗和/或预防肿瘤的药物中的用途。
进一步的，所述的肿瘤为肝癌、肝母细胞瘤、乳腺癌、肺癌、胰腺癌、前列腺癌或白血病。
本发明还提供了一种治疗和/或预防肿瘤的药物组合物，它是以上述的化合物或其药学上可接受的盐、晶型、溶剂合物为活性成分，加上药学上常用的辅料制备得到的制剂。
本发明式Ⅰ所示的新化合物，不仅对SIRT2具有良好的抑制活性，而且对肿瘤具有很好的抑制作用，具有很好的药用潜力，为临床用药提供了一种新的潜在选择；同时，本发明新化合物的制备方法简便，反应条件温和，便于操作和控制，能耗小，产率高，成本低，可适合产业化生产。
本发明中提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社，Columbus，OH)命名系统命名。
关于本发明的使用术语的定义：除非另有说明，本文中基团或者术语提供的初始定义 适用于整篇说明书的该基团或者术语；对于本文没有具体定义的术语，应该根据公开内容和上下文，给出本领域技术人员能够给予它们的含义。
“取代”是指分子中的氢原子被其它不同的原子或分子所替换。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示，例如，前缀Ca～Cb烷基表明任何包含“a”至“b”个碳原子的烷基。因此，例如，C1～C4烷基是指包含1～4个碳原子的烷基，换句话说，C1～C4烷基包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基。
术语“药学上可接受的”是指某载体、运载物、稀释剂、辅料，和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容，并在生理上与受体相兼容。
术语“盐”和“可药用的盐”是指上述化合物或其立体异构体，与无机和/或有机酸和碱形成的酸式和/或碱式盐，也包括两性离子盐(内盐)，还包括季铵盐，例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将上述化合物，或其立体异构体，与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集，或在溶剂蒸发后回收而得到，或在水介质中反应后冷冻干燥制得。本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、肠胃外(静脉内、肌肉内或皮下)和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂， 增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明所述药学上可接受的辅料，是指除活性成分以外包含在剂型中的物质。
本发明所述药学上可接受的辅助性成分，它具有一定生理活性，但该成分的加入不会改变上述药物组合物在疾病治疗过程中的主导地位，而仅仅发挥辅助功效，这些辅助功效仅仅是对该成分已知活性的利用，是医药领域惯用的辅助治疗方式。若将上述辅助性成分与本发明药物组合物配合使用，仍然属于本发明保护的范围。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1为本发明化合物28的1H NMR图。
图2为本发明化合物28的13C NMR图。
图3为本发明化合物33的1H NMR图。
图4为本发明化合物33的13C NMR图。
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品，通过购买市售产品获得。
实施例1、N-(3-苄基苯基)-2-((4,6-二甲基嘧啶-2-基)硫代)乙酰胺(化合物1)的合成
Figure PCTCN2016105443-appb-000018
首先，将LiAlH4(10mmol,379.5mg)加入到反应瓶中后置于0℃下约15min后，将 AlCl3(10mmol,1333mg)的乙醚(15ml)溶液滴加到反应中，混合液在0℃搅拌5min。接着将间氨基二苯甲酮(1a,1mmol,197.2mg)的乙醚(15ml)溶液滴加到反应中，并将反应移至室温反应3h,经TLC检测反应完全后，反应液先用6M HCl稀释，后用饱和NaHCO3中和，水层经乙酸乙酯(20ml×3)萃取，合并有机层，无水Na2SO4干燥，浓缩，柱层析得中间体1b。
然后，将中间体1b(1mmol,183mg)和溴乙酸(1.2mmol,166.8mg)溶于DCM(16ml)中，并置于0℃搅拌溶解后，在0℃下依次加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI,1.2mmol,230.4mg),1-羟基苯并三唑(HOBT,1.2mmol,162mg),N,N-二异丙基乙胺(DIEA,2mmol,331μl),加毕，将反应移至室温搅拌反应过夜。经TLC(薄层色谱，Thin Layer Chromatography)检测反应完全后减压除去多余的溶剂，柱层析得中间体1c。
再将化合物4,6-二甲基-2-巯基嘧啶(1.2mmol,168.2mg)溶于DMF(3ml)中，室温条件下加入叔丁醇钾(2mmol,224.4mg)并在室温下搅拌反应30min后将化合物1c(1mmol,302mg)溶于DMF(1ml)中缓慢加入到反应中，室温搅拌反应4-5h后，经TLC检测反应完全后，往反应中加入冰水(40ml)，并用乙酸乙酯萃取(20ml×3。最后有机层经无水MgSO4干燥，浓缩后经柱层析得到化合物1(168mg,三步总产率38％)。1H NMR(400MHz,DMSO):δ10.17(s,1H),7.43-7.41(m,2H),7.31-7.27(m,2H),7.24-7.19(m,4H),7.00-6.94(m,2H),4.01(s,2H),3.91(s,2H),2.32(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.4,166.9,142.3,141.5,139.6,129.2,129.1,128.8,125.5,124.2,119.9,117.4,116.5,41.6,35.9,23.8ppm。
实施例2、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(3-(苯氨基)苯基)乙酰胺(化合物2)的合成
Figure PCTCN2016105443-appb-000019
首先，将间硝基苯胺(2mmol,276.3mg)、苯硼酸(1mmol,121.9mg)、NiCl2.6H2O(0.2mmol,47.5mg)、2,2-二联吡啶(0.2mmol,31.2mg)和1,5-二氮杂二环[5.4.0]十一-5-烯(DBU,2mmol,304.4mg)溶于乙腈(10ml)中，并于室温搅拌反应28h，经TLC检测反应完全后向反应液中加入乙酸乙酯(10ml)和水(10ml)，水层经乙酸乙酯(10ml×3)萃取，合并有机层，无水Na2SO4干燥，浓缩，柱层析得中间体2b。然后，将2b(0.2mmol,42mg)溶于EtOH(2ml)/H2O(1ml)中，加入NH4Cl(0.1mmol,5.4mg)和Fe(1mmol,56mg)后于80℃反应30min，经TLC检测反应完全后趁热过滤除去不溶物质，接着加入NaHCO3调节pH至碱性，减压除去乙醇，水层经乙酸乙酯萃取，浓缩，柱层析得中间体2c。最后，利用中间体2c按照目标化合物1的合成方法合成目标化合物2，四步总产率26％。1H NMR(400MHz,DMSO):δ10.12(s,1H),8.18(s,1H),7.46(s,1H),7.24(t,J＝8.0Hz,2H),7.14(t,J＝8.0Hz,1H),7.08(d,J＝7.6Hz,2H),7.01(d,J＝8.8Hz,1H),6.98(s,1H),6.83(t,J＝7.2Hz,1H),6.74(dd,J＝1.6Hz,J＝5.6Hz,1H),4.02(s,2H),2.35(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.4,167.2,140.8,135.9,134.9,131.4,130.3,130.1,128.0,125.7,121.1, 118.5,116.5,36.0,23.8ppm。
实施例3、2-((4-甲基-6-羰基-1,6-二氢嘧啶-2-基)硫代)-N-(3-(苯胺基)苯基)乙酰胺(化合物3)的合成
Figure PCTCN2016105443-appb-000020
首先，利用2c中间体与溴乙酸按照1c的合成方法合成3a，再利用3a与原料甲基硫脲嘧啶按照化合物1的合成方法合成目标化化合物3，两产率45％。1H NMR(400MHz,DMSO):δ12.56(br s,1H),10.16(s,1H),8.20(s,1H),7.46(s,1H),7.24(t,J＝8.0Hz,2H),7.15(t,J＝8.0Hz,1H),7.09(d,J＝7.6Hz,2H),7.01(d,J＝8.0Hz,1H),6.84(t,J＝7.6Hz,1H),6.75(dd,J＝1.6Hz,J＝7.6Hz,2H),6.01(br s,1H),4.06(s,2H),2.15(s,3H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.5,167.1,160.5，150.2,140.5,135.9,134.9,131.4,130.3,130.1,128.0,125.7,121.1,118.5,116.5,35.9,22.6ppm。
实施例4、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(3-(苯氧基)苯基)乙酰胺(化合物4)的合成
Figure PCTCN2016105443-appb-000021
利用化合物4a,按照目标化合物1的合成方法合成化合物4，两步总产率为58％。1H NMR(400MHz,CDCl3):δ9.60(s,1H),7.35(t,J＝8.0Hz,2H),7.27-7.25(m,2H),7.14(t,J＝7.2Hz,1H),7.09(s,1H),7.03(d,J＝7.6Hz,2H),6.82(s,1H),6.76-6.73(m,1H),3.88(s,2H),2.46(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.7,167.3,167.0,140.5,135.9,134.9,131.4,130.3,130.1,128.0,125.7,121.1,118.5,116.5,36.0,23.8ppm。
实施例5、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(3-(苯硫基)苯基)乙酰胺(化合物5)的合成
Figure PCTCN2016105443-appb-000022
首先，向反应瓶中加入间碘苯胺(5a,2mmol,438mg)、CuSO4.5H2O(0.1mmol,25mg)、KOH(10mmol,561mg)和DMSO(4ml)/H2O(0.4ml),接着加入1,2-乙二硫醇(2mmol,180μl)并于100-110℃反应8h，然后将反应液冷却至室温后，将碘苯(2.6mmol,530.4mg)溶于DMF(2ml)中后加入到反应中，于120℃继续反应18h。经TLC检测反应完全后，将反应冷却至室温，加入水和乙酸乙酯，经乙酸乙酯(10ml×3)萃取，合并有机相，无水Na2SO4干燥，浓缩，柱层析得中间体5b。利用5b按照化合物1的合成方法合成目标化合物5，三步总产率46％。1H NMR(400MHz,DMSO):δ10.32(s,1H),7.92(s,1H),7.61(s,1H),7.52(d,J＝8.0Hz,1H),7.46-7.30(m,6H),7.02(d,J＝8.0Hz,1H),6.96(s,1H),4.02(s,2H),2.32(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.7,167.4,167.2,140.5,135.9,134.9,131.4, 130.3,130.1,128.0,125.7,121.1,118.5,116.5,35.9,23.8ppm。
实施例6、N-(3-苯甲酰苯基)-2-((4,6-二甲基嘧啶-2-基)硫代)乙酰胺(化合物6)的合成
Figure PCTCN2016105443-appb-000023
目标化合物6的合成按照化合物1的合成方法获得，两步总产率46％。1H NMR(400MHz,CDCl3):δ9.84(s,1H),8.02(t,J＝8.0Hz,1H),7.80(d,J＝8.4Hz,2H),7.66(s,1H),7.62(t,J＝7.2Hz,1H),7.52-7.43(m,4H),6.85(s,1H),3.91(s,2H),2.50(s,6H)ppm；13C NMR(100MHz,DMSO):δ196.0,169.7,167.4,139.6,138.0,137.5,133.1,130.0,129.6,129.0,124.9,123.5,120.6,116.5,35.9,23.8ppm。
实施例7、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(3-(羟基(苯基)甲基)苯基)乙酰胺(化合物7)的合成
Figure PCTCN2016105443-appb-000024
首先，将LiAlH4(5mmol,189.8mg)加入到反应瓶中，置于0℃下搅拌15min后将AlCl3(5mmol,666.7mg)的乙醚(8ml)溶液滴加到反应后，将混合液在0℃搅拌5min。接着将间氨基二苯甲酮(6a,1mmol,197.2mg)的乙醚(8ml)溶液滴加到反应中，然后将反应移至室温反应3h,经TLC检测反应完全后，将反应液先用6M HCl稀释，再用饱和NaHCO3中和，水层经乙酸乙酯(10ml×3)萃取，合并有机层，无水Na2SO4干燥，浓缩，柱层析得到化合物中间体7a。最后利用7a按照目标化合物1的合成方法获得化合物7，三步总产率35％。1H NMR(400MHz,DMSO):δ10.20(s,1H),7.57(s,1H),7.47(d,J＝8.0Hz,1H),7.36(d,J＝7.6Hz,2H),7.30(t,J＝7.6Hz,2H),7.20(q,J＝8.0Hz,J＝8.0Hz,2H),7.07(d,J＝7.6Hz,1H),6.97(s,1H),5.90(d,J＝4.0Hz,1H),5.65(d,J＝4.0Hz,1H),4.01(s,2H),2.31(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.4,166.9,146.9,146.0,139.3,128.8,128.5,127.2,125.7,121.8,118.1,117.6,116.5,74.7,35.9,23.8ppm。
实施例8、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(3-(1-苯乙基)苯基)乙酰胺(化合物8)的合成
Figure PCTCN2016105443-appb-000025
首先，将间硝基苯乙酮(8a,1mmol,165mg)和对甲基苯磺酰肼(1mmol,185mg)溶于10ml二氧六环中，并于80℃反应1.5小时，经TLC检测反应完全后，减压蒸馏得8b粗产品；然后加入对甲氧基苯硼酸(1.5mmol,227mg)，K2CO3(1.5mmol)和15ml二氧六环后于110℃回流反应5小时，经TLC检测反应完全后，减压蒸馏除去溶剂后加入水和乙酸乙酯萃取(10ml×3),合并有机层，无水Na2SO4干燥，浓缩，柱层析得到化合物 中间体8c；利用8c按照化合物2的合成方法合成目标化合物8，五步总产率23％。：1H NMR(400MHz,DMSO):δ10.18(s,1H),7.42(d,J＝7.6Hz,2H),7.30-7.28(m,2H),7.24-7.19(m,4H),7.00-6.94(m,2H),4.01(s,2H),3.93(t,J＝7.6Hz,1H),3.87(s,3H),2.32(s,6H),1.58(d,J＝7.6Hz,3H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.4,166.9,142.3,141.5,139.6,129.2,129.1,128.8,125.5,124.2,119.9,117.4,116.5,56.3,41.6,35.9,23.8,20.6ppm。
实施例9、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(3-(甲基(苯基)氨基)苯基)乙酰胺(化合物9)的合成
Figure PCTCN2016105443-appb-000026
首先，将原料2b(1.0当量)溶于DMF中用NaH(0.5当量)催化脱氢后与碘甲烷反应获得中间体9a，利用9a，按照化合物2的合成方法合成目标化合物9，四步总产率19％。1H NMR(400MHz,DMSO):δ10.13(s,1H),7.45(s,1H),7.23(t,J＝8.0Hz,2H),7.12(t,J＝8.0Hz,1H),7.06(d,J＝7.6Hz,2H),7.01(d,J＝8.8Hz,1H),6.98(s,1H),6.83(t,J＝7.2Hz,1H),6.74(dd,J＝1.6Hz,J＝5.6Hz,1H),4.02(s,2H),3.02(s,3H),2.35(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.4,167.1,140.5,135.9,134.9,131.4,130.3,130.1,128.0,125.7,121.1,118.5,116.5,42.5,35.9,23.8ppm。
实施例10、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(3-(苯亚磺酰基)苯基)乙酰胺(化合物10)的合成
Figure PCTCN2016105443-appb-000027
利用化合物5b按照化合物1c的合成方法合成中间体10a,接着将10a(590mg,1.85mmol)用DCM(10mL)溶解，0℃搅拌下加入间氯过氧苯甲酸(335mg,1.94mmol)，室温反应45min，经TLC检测反应完全后减压除去多余的溶剂，柱层析得白色中间体10b。然后，利用中间体10b按照化合物1的合成方法合成目标化合物10，四步总产率32％。1H NMR(400MHz,DMSO):δ10.32(s,1H),7.92(s,1H),7.61(s,1H),7.52(d,J＝8.0Hz,1H),7.46-7.30(m,6H),7.02(d,J＝8.0Hz,1H),6.96(s,1H),4.02(s,2H),2.32(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.7,167.4,167.2,140.5,135.9,134.9,131.4,130.3,130.1,128.0,125.7,121.1,118.5,116.5,35.9,23.8ppm。
实施例11、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(3-(苯磺酰基)苯基)乙酰胺(化合物11)的合成
Figure PCTCN2016105443-appb-000028
将化合物10a(590mg,1.85mmol)用DCM(10mL)溶解，0℃搅拌下加入间氯过氧 苯甲酸(956mg,5.54mmol)，室温反应3h，经TLC检测反应完全后减压除去多余的溶剂，柱层析得白色中间体11a。利用11a按照目标化合物1的合成方法合成目标化合物11。两步总产率51％。1H NMR(400MHz,DMSO):δ10.33(s,1H),7.98(s,1H),7.60(s,1H),7.55(d,J＝8.0Hz,1H),7.46-7.31(m,6H),7.02(d,J＝8.0Hz,1H),6.96(s,1H),4.02(s,2H),2.32(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.4,167.2,142.5,135.9,134.9,131.4,130.3,130.1,128.0,125.7,121.1,118.5,116.5,36.0,23.8ppm。
实施例12、N-(3-(苄胺基)苯基)-2-((4,6-二甲基嘧啶-2-基)硫代)乙酰胺(化合物12)的合成
Figure PCTCN2016105443-appb-000029
上述中间体12b的合成利用12a按照1b的合成方法合成，接着利用12b按照目标化合物1的合成方法合成中间体12c。然后，将苯甲醛(0.374mmol,39.6mg)和化合物12c(0.34mmol,98.1mg)溶于DCM(6ml)中，再将二氢吡啶酯(0.477mmol,120.1mg)加入，最后滴入三氟乙酸(0.17mmol,12.7μl)并置于45℃回流反应过夜。经TLC检测反应完全后减压除去多余的溶剂，柱层析得目标化合物12，三步反应总产率为29％。1H NMR(400MHz,DMSO):δ9.93(s,1H),7.35-7.29(m,4H),7.22(t,J＝6.8Hz,1H),6.97-6.91(m,3H),6.75(d,J＝8.0Hz,1H),6.32-6.27(m,2H),4.23(d,J＝6.0Hz,2H),3.99(s,2H),2.33(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.4,166.7,149.3,141.6,139.6,129.3,129.1,122.6,118.2,118.0,116.5,116.2,112.7,48.0,36.0,23.8ppm。
实施例13、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(3-((噻吩-2-基甲基)氨基)苯基)乙酰胺(化合物13)的合成
Figure PCTCN2016105443-appb-000030
利用重要中间体12c与2-噻吩甲醛按照化合物12的合成方法获得目标化合物13，产率68％。1H NMR(400MHz,DMSO):δ9.95(s,1H),7.36(dd,J＝0.8Hz,J＝4.0Hz,1H),7.03(d,J＝2.4Hz,1H),6.99-6.95(m,4H),6.77(d,J＝8.8Hz,1H),6.35-6.31(m,2H),4.41(d,J＝6.4Hz,2H),4.00(s,2H),2.34(s,6H)ppm。
实施例14、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(3-((1-苯乙基)氨基)苯基)乙酰胺(化合物14)的合成
Figure PCTCN2016105443-appb-000031
利用重要中间体12c与苯乙酮按照化合物12的合成方法获得目标化合物14，产率 53％。1H NMR(400MHz,DMSO):δ9.92(s,1H),7.35-7.29(m,4H),7.22(t,J＝7.2Hz,1H),6.97-6.91(m,3H),6.75(d,J＝7.2Hz,1H),6.32-6.27(m,2H),4.20(m,1H),3.99(s,2H),2.33(s,6H),1.38(d,J＝6.0Hz,3H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.4,166.7,149.3,141.6,139.6,129.3,129.1,122.6,118.2,118.0,116.5,116.2,112.7,48.0,36.0,23.8ppm。
实施例15、N-(3-(苯氧基)苯基)-2-((4,6-二甲基嘧啶-2-基)硫代)乙酰胺(化合物15)的合成
Figure PCTCN2016105443-appb-000032
首先，将间氨基苯酚(15a,0.5mmol，54.6mg)溶于二氯甲烷(5ml)中，加入三乙胺(1.5mmol,208μl)，后加入醋酸酐(0.55mmol,51.9μl)并在室温下反应过夜。经TLC检测反应完全，减压浓缩，柱层析得化合物15b。接着，将化合物15b(0.54mmol,81.6mg)和叔丁醇钾(0.81mmol,90.9mg)溶于DMF(5ml)中，在室温下搅拌反应30min后将苄溴(0.59mmol,70.6μl)缓慢加入，且在室温反应过夜。经TLC检测反应完全，加入适量水，水层经乙酸乙酯萃取，合并有机相，无水Na2SO4干燥，浓缩后经柱层析得中间体15c。然后，将化合物15c(0.26mmol,63.2mg)溶于甲醇(2ml)中，加入二氯亚砜(0.64mmol,45.3μl)，回流搅拌反应3h。经TLC检测反应完全，加入饱和NaHCO3溶液，调pH至碱性，减压除去甲醇，水层经乙酸乙酯萃取，合并有机相，无水Na2SO4干燥，浓缩后经柱层析得重要中间体15d。最后利用15d按照化合物1的合成方法合成目标化合物15，五步总产率18％。1H NMR(400MHz,DMSO):δ10.22(s,1H),7.46-7.33(m,6H),7.21(d,J＝8.4Hz,1H),7.12(d,J＝8.4Hz,1H),6.98(s,1H),6.72(dd,J＝2.4Hz,J＝5.6Hz,1H),5.07(s,2H),4.04(s,2H),2.34(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.4,166.7,149.3,141.6,139.6,129.3,129.1,122.6,118.2,118.0,116.5,116.2,112.7,48.0,36.0,23.8ppm。
实施例16、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(3-((苯胺基)甲基)苯基)乙酰胺(化合物16)的合成
Figure PCTCN2016105443-appb-000033
将间硝基苯甲醛(16a,2mmol,302.2mg)和苯胺(2.2mmol,201μl)溶于DCM(16ml)中，接着将二氢吡啶酯(2.8mmol,708.4mg)加入，最后滴入三氟乙酸(1mmol,74.6μl)并置于45℃回流反应过夜。经TLC检测反应完全后减压除去多余的溶剂，柱层析得到还原胺化产物16b。将还原胺化产物16b(1.89mmol,427mg)溶于乙醇(10ml)和水(5ml)的混合溶剂后加入铁粉(9.44mmol,528.4mg)和NH4Cl(0.945mmol,50.6mg)至反应中并置于80℃回流反应30min，经TLC检测反应完全后过滤除去不溶物质，加入NaHCO3调节pH至碱性，减压除去乙 醇，水层经乙酸乙酯萃取，浓缩，柱层析得目标化合物16，四步总产率45％。1H NMR(400MHz,DMSO):δ10.21(s,1H),7.55(s,1H),7.48(d,J＝8.4Hz,1H),7.25(t,J＝8.0Hz,1H),7.06-7.01(m,3H),6.96(s,1H),6.55-6.49(m,3H),6.24(d,J＝6.0Hz,1H),4.22(d,J＝6.0Hz,2H),4.02(s,2H),2.32(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.4,166.9,149.1,141.6,139.6,129.3,129.1,122.6,118.2,118.0,116.5,116.2,112.7,47.0,35.9,23.8ppm。
实施例17、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(3-(((4-甲氧基苯基)氨基)甲基)苯基)乙酰胺(化合物17)的合成
Figure PCTCN2016105443-appb-000034
利用16a将苯胺换做4-甲氧基苯胺，按照化合物16的合成方法合成目标化合物17，四步总产率46％。1H NMR(400MHz,DMSO):δ10.23(s,1H),7.54(s,1H),7.46(d,J＝8.0Hz,1H),7.26(t,J＝8.0Hz,1H),7.06-7.00(m,3H),6.96(s,1H),6.55-6.49(m,3H),6.24(d,J＝6.0Hz,1H),4.22(d,J＝6.0Hz,2H),4.02(s,2H),3.83(s,1H),2.32(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.4,166.9,149.1,141.6,139.6,129.3,129.1,122.6,118.2,118.0,116.5,116.2,112.7,47.0,58.0,35.9,23.8ppm。
实施例18、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(3-(((3-(三氟甲基)苯基)氨基)甲基)苯基)乙酰胺(化合物18)的合成
Figure PCTCN2016105443-appb-000035
使用16a和间三氟甲基苯胺，按照化合物16的合成方法合成目标化合物18，四步总产率38％。1H NMR(400MHz,DMSO):δ10.22(s,1H),7.56(s,1H),7.50(d,J＝8.0Hz,1H),7.29-7.22(m,2H),7.06(d,J＝7.6Hz,1H),6.96(s,1H),6.84(s,1H),6.79(t,J＝7.6Hz,3H),4.29(d,J＝6.0Hz,2H),4.02(s,2H),2.31(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.5,166.9,146.9,146.1,139.3,133.3,129.3,128.8,128.5,127.2,125.7,121.8,119.4,118.1,117.6,116.5,74.7,35.9,23.8ppm。
实施例19、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(3-(1-(苯胺基)乙基)苯基)乙酰胺(化合物19)的合成
Figure PCTCN2016105443-appb-000036
将间乙酰氨基苯乙酮(19a,2mmol,354.4mg)和苯胺(2.4mmol,219.2μl)溶于甲苯(30ml)中，随后加入NaHCO3(10mmol,840mg)和适量的分子筛并置于120℃回流反应过夜。经TLC检测反应完全后过滤除去不溶物质，减压浓缩，柱层析得亚胺化合物19b。然后，将化合物19b溶于DCM(5ml)中，再加入催化量的DMF(0.2mmol,384μl)，反应液置于0℃，并在0℃下加入HSiCl3(2mmol,200μl)的DCM(5ml)溶液，加毕于0℃反应过夜。经TLC检测反应完全后加入适量水淬灭多余的HSiCl3，室温搅拌10min后用NaHCO3调pH至碱性，减压除去DCM，水层经乙酸乙酯萃取，浓缩，柱层析得到亚胺还原产物19c。接着将上步亚胺还原产物(19c,0.5mmol,127mg)溶于甲醇(2ml)中，加入二氯亚砜(1.2mmol,87μl)，65℃回流反应3-4h。经TLC检测反应完全后加入适量饱和NaHCO3调pH至碱性，减压除去甲醇，水层经乙酸乙酯萃取，浓缩，柱层析得到重要中间体19d。最后利用19d,按照化合物1的合成方法合成目标化合物19；五步总产率为28％。1H NMR(400MHz,DMSO):δ10.19(s,1H),7.56(s,1H),7.43(d,J＝8.0Hz,1H),7.23(t,J＝7.6Hz,1H),7.07(d,J＝7.6Hz,1H),6.99-6.95(m,3H),6.48-6.44(m,3H),6.13(d,J＝6.0Hz,1H),4.40-4.34(m,1H),4.02(s,2H),2.32(s,6H),1.40(d,J＝6.8Hz,3H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.4,166.8 149.1,141.6,139.6,129.3,129.1,122.6,118.2,118.0,116.5,116.2,112.7,55.8,35.9,23.8,21.0ppm。
实施例20、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(3-(1-((3-(三氟甲基)苯基)氨基)乙基)苯基)乙酰胺(化合物20)的合成
Figure PCTCN2016105443-appb-000037
使用19a和间三氟甲基苯胺，按照化合物19的合成方法合成目标化合物20，五步总产率30％。1H NMR(400MHz,DMSO):δ10.20(s,1H),7.57(s,1H),7.45(d,J＝8.0Hz,1H),7.25(t,J＝7.6Hz,1H),7.18(t,J＝8.0Hz,1H),7.08(d,J＝7.6Hz,1H),6.95(s,1H),6.80(s,1H),6.76-6.66(m,3H),4.49-4.42(m,1H),4.01(s,2H),2.31(s,6H),1.42(d,J＝6.8Hz,3H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.4,166.9,146.9,146.0,139.3,133.3,129.9,128.8,128.5,127.2,125.7,121.8,118.6,118.1,117.6,116.5,74.7,35.9,23.8ppm。
实施例21、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(3-(苯氧甲基)苯基)乙酰胺(化合物21)的合成
Figure PCTCN2016105443-appb-000038
首先，将苯酚(1.0当量)溶于DMF中，加入K2CO3(3.0当量)，后将间硝基苄溴的DMF溶液加入到反应液中，室温搅拌反应过夜。经TLC检测反应完全后加入适量水，水层经乙酸乙酯萃取，合并有机相，无水Na2SO4干燥，浓缩后经柱层析得亲核取代产物21b。 然后，将21b(1mmol,229mg)溶于乙醇(3ml)和水(1.5ml)的混合溶剂中，加入NH4Cl(0.5mmol,26.8mg)，和Fe(5mmol,280mg)，于80℃反应30min，经TLC检测反应完全后趁热过滤除去不溶物质，再加入NaHCO3调节pH至碱性，减压除去乙醇，水层经乙酸乙酯萃取，浓缩，柱层析得到重要中间体21c。最后利用21c按照化合物1的合成方法合成目标化合物21，四步总产率35％。：1H NMR(400MHz,DMSO):δ10.29(s,1H),7.69(s,1H),7.54(d,J＝8.4Hz,1H),7.35-7.28(m,3H),7.14(d,J＝7.6Hz,1H),7.01-6.93(m,4H),5.08(s,2H),4.04(s,2H),2.33(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.4,167.1,158.7,139.7,138.3,130.0,129.3,122.9,121.2,119.0,118.5,116.5,115.2,69.5,35.9,23.8ppm。
实施例22、N-(3-((4-乙酰氨基苯氧基)甲基)苯基)-2-((4,6-二甲基嘧啶-2-基)硫代)乙酰胺(化合物22)的合成
Figure PCTCN2016105443-appb-000039
使用对乙酰氨基酚替换苯酚，按照化合物21的合成方法合成目标化合物22，四步产率为28％。1H NMR(400MHz,DMSO):δ10.29(s,1H),9.78(s,1H),7.68(s,1H),7.54(d,J＝8.0Hz,1H),7.48(d,J＝8.8Hz,2H),7.32(t,J＝7.6Hz,1H),7.12(d,J＝7.6Hz,2H),6.97(s,1H),6.93(d,J＝8.8Hz,2H),5.04(s,2H),4.05(s,2H),2.34(s,6H),2.01(s,3H),ppm；13C NMR(100MHz,DMSO):δ169.8,168.0,167.4,167.1,158.7,139.7,138.3,130.0,129.3,122.9,121.2,119.0,118.5,116.5,115.2,69.5,35.9,23.8,22.9ppm。
实施例23、N-(3-((3-乙酰氨基苯氧基)甲基)苯基)-2-((4,6-二甲基嘧啶-2-基)硫代)乙酰胺(化合物23)的合成
Figure PCTCN2016105443-appb-000040
使用间乙酰氨基酚替换苯酚，按照化合物21的合成方法合成目标化合物23，四步产率为29％。1H NMR(400MHz,DMSO):δ10.30(s,1H),9.92(s,1H),7.68(s,1H),7.56(d,J＝7.6Hz,1H),7.37-7.32(m,2H),7.20(t,J＝7.6Hz,1H),7.12(t,J＝7.6Hz,2H),6.98(s,1H),6.69(d,J＝7.6Hz,1H),5.05(s,2H),4.05(s,2H),2.34(s,6H),2.04(s,3H),ppm；13C NMR(100MHz,DMSO):δ169.8,168.0,167.4,167.1,154.1,139.8,138.3,134.6,129.4,128.0,127.6,127.0,126.7,125.9,125.5,122.7,122.0,120.7,119.0,118.7,118.3,116.5,106.3,69.8,36.0,23.8,22.9ppm。
实施例24、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(3-((萘基-1-氧基)甲基)苯基)乙酰胺(化合物24)的合成
Figure PCTCN2016105443-appb-000041
使用1-萘酚，按照化合物21的合成方法合成目标化合物24，四步产率为33％。1H NMR(400MHz,DMSO):δ10.33(s,1H),8.24(d,J＝8.4Hz,1H),7.90(d,J＝8.4Hz,1H),7.81(s,1H),7.61(d,J＝8.0Hz,1H),7.58-7.49(m,3H),7.45-7.36(m,2H),7.24(d,J＝7.6Hz,1H),7.06(d,J＝7.6Hz,1H),6.95(s,1H),5.30(s,2H),4.06(s,2H),2.33(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.4,167.1,154.1,139.8,138.3,134.6,129.4,128.0,127.0,126.7,125.9,125.5,122.7,122.0,120.7,119.0,118.3,116.5,106.3,69.8,36.0,23.8ppm。
实施例25、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(3-((萘基-2-氧基)甲基)苯基)乙酰胺(化合物25)的合成
Figure PCTCN2016105443-appb-000042
使用2-萘酚，按照化合物21的合成方法合成目标化合物25，四步产率为35％。1H NMR(400MHz,DMSO):δ10.31(s,1H),7.87-7.77(m,4H),7.57(d,J＝7.6Hz,1H),7.47(t,J＝7.6Hz,1H),7.42(s,1H),7.36(t,J＝8.0Hz,2H),7.26-7.20(m,2H),6.96(s,1H),5.22(s,2H),4.06(s,2H),2.33(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.4,167.1,156.7,139.7,138.1,134.7,129.9,129.4,129.1,128.0,127.2,125.9,124.1,123.0,119.2,119.1,118.7,116.5,107.8,69.7,36.0,23.8ppm。
实施例26、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(3-((喹啉基-8-氧基)甲基)苯基)乙酰胺(化合物26)的合成
使用8-羟基喹啉，按照化合物21的合成方法合成目标化合物26，四步产率为25％。1H NMR(400MHz,DMSO):δ10.32(s,1H),8.80(dd,J＝1.6Hz,J＝4.0Hz,1H),8.33(dd,J＝1.6Hz,J＝8.0Hz,1H),7.76(s,1H),7.61-7.54(m,2H),7.53-7.48(m,2H),7.37(t,J＝8.0Hz,1H),7.26(t,J＝8.0Hz,2H),6.96(s,1H),5.30(s,2H),4.05(s,2H),2.32(s,6H)ppm。
实施例27、N-(4-((3-(2-((4,6-二甲基嘧啶-2-基)硫代)乙酰胺)苄基)氧基)苯基)噻吩-2-甲酰胺(化合物27)的合成
Figure PCTCN2016105443-appb-000044
将中间体22a(1.0mmol,286mg)溶解于5ml甲醇中，然后滴加0.5ml二氯亚砜后回流0.5小时，然后减压蒸馏出去溶剂后，加入NaHCO3调节pH为7-8后，加入水和乙酸乙酯萃取，有机层经Na2SO4干燥后，旋转蒸发仪旋除溶剂后，与噻吩-2-甲酰氯缩合后，硝基经铁粉还原，得中间体27b；利用27b按照化合物1的合成方法合成目标化合物27，五步总产率为28％。1H NMR(400MHz,DMSO):δ10.30(s,1H),10.13(s,1H),7.99(d,J＝3.2Hz,1H),7.84(dd,J＝0.8Hz,J＝4.0Hz,1H),7.71(s,1H),7.63(d,J＝8.4Hz,2H),7.55(d,J＝8.4Hz,1H),7.34(t,J＝8.0Hz,1H),7.22(t,J＝8.0Hz,1H),7.14(d,J＝8.0Hz,1H),7.02-6.97(m,3H),5.08(s,2H),4.06(s,2H),2.36(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.4,167.1,160.0,155.1,140.7,139.7,138.3,132.4,132.0,129.2,128.5,122.9,122.5,119.0,118.5,116.5,115.3,69.8,36.0,23.8ppm。
实施例28、N-(3((4-(环丙磺酰胺基)苯氧基)甲基)苯基-2-((4,6-二甲基嘧啶-2-基)硫代)乙酰胺(化合物28)的合成
Figure PCTCN2016105443-appb-000045
利用27a和环丙磺酰氯，按照化合物27的合成方法合成目标化合物28，四步总产率29％。1H NMR(400MHz,DMSO):δ10.30(s,1H),9.38(s,1H),7.70(s,1H),7.54(d,J＝8.0Hz,1H),7.33(t,J＝8.0Hz,1H),7.18(d,J＝8.8Hz,2H),7.14(d,J＝7.6Hz,1H),6.98(s,1H),7.00-6.97(m,3H),5.06(s,2H),4.05(s,2H),2.50-2.47(m,1H),2.34(s,6H),0.91-0.86(m,4H),ppm；13C NMR(100MHz,DMSO):δ169.8,167.4,167.1,156.0,139.6,138.2,131.5,129.3,124.2,122.9 119.0,118.6,116.5,115.7,69.8,36.3,36.0,23.8,5.3ppm。
实施例29、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(3-((4-(苯基磺酰胺基)苯氧基)甲基)苯基)乙酰胺(化合物29)的合成
Figure PCTCN2016105443-appb-000046
利用27a和苯磺酰氯，按照化合物27的合成方法合成目标化合物29，四步总产率30％。1H NMR(400MHz,DMSO):δ10.28(s,1H),9.95(s,1H),7.70(d,J＝7.2Hz,2H),7.65 (s,1H),7.61(t,J＝7.2Hz,1H),7.56-7.52(m,3H),7.31(t,J＝8.0Hz,1H),7.09(d,J＝7.6Hz,1H),6.99(s,1H),6.97(d,J＝2.8Hz,2H),6.89(s,1H),6.87(s,1H),4.98(s,2H),4.04(s,2H),2.36(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.4,167.1,156.0,139.9,139.6,138.1,133.2,130.8,129.6,129.3,127.1,123.8,122.9,119.0,118.6,116.5,115.7,69.8,35.9,23.8ppm。
实施例30、N-(3(((1H-吲唑-5-基)氧基)甲基)苯基)-2-((4,6-二甲基嘧啶-2-基)硫代)乙酰胺(化合物30)的合成
Figure PCTCN2016105443-appb-000047
将化合物30a(400mg,2.99mmol)用5mL DMF溶解，搅拌下加入K2CO3(3.19g,23.1mmol),将混合液冷至0℃，将间硝基苄溴(1g,4.62mmol)用5mL DMF溶解，缓慢滴加到化合物30a的混合液中，0℃下反应2h后室温反应3h,TLC监测反应完全，反应液加水，用EA提取，饱和NaCl洗涤，干燥浓缩得粗品，经柱层析纯化(DCM)得30b纯品420mg，收率52％。接着，将化合物30b(200mg,0.74mmol)用4mL乙醇溶解，加入2mL H2O，室温搅拌下加入NH4Cl(20mg,0.37mmol)，铁粉(151mg,3.70mmol)，80℃回流30min。趁热过滤，滤饼用乙醇洗涤，将滤液浓缩，加水，EA提取，饱和NaCl洗涤，干燥浓缩得粗品173mg，为淡黄色固体(化合物30c)，不经纯化直接投下一步。再将化合物30c(170mg,0.71mmol)、8(108mg,0.78mmol)加入反应瓶，用8mL DCM溶解，0℃搅拌下加入EDCI(164mg,0.85mmol)，HOBt(125mg,0.85mmol)，DIEA(235μL,1.42mmol)，然后室温下反应过夜，将反应液旋干，经柱层析(PE:EA＝3:1→PE:EA＝1:1)得30d纯品131mg，收率51％。最后，将化合物30d(130mg,0.36mmol)用2mLDMF溶解，室温搅拌下加入t-BuOK(48mg,0.43mmol)，室温活化30min,然后将10(73mg,0.43mmol)用2mL DMF溶解后滴加入巯基咪唑的混合液中，室温反应过夜，加水，用EA提取，饱和NaCl洗涤，干燥浓缩得粗品，经柱层析(PE:EA＝3:1→PE:EA＝1:1)得淡黄色固体(化合物30)105mg，收率71.9％。1H NMR(400MHz,DMSO):δ12.93(s,1H),10.30(s,1H),7.95(s,1H),7.73(s,1H),7.55(d,J＝8.0Hz,1H),7.47(d,J＝8.8Hz,1H),7.34(t,J＝8.0Hz,1H),7.26(s,1H),7.17(d,J＝8.0Hz,1H),7.08(dd,J＝8.8Hz,J＝2.0Hz,1H),6.96(s,1H),5.11(s,2H),4.05(s,2H),2.32(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.4,167.1,153.2,139.7,138.5,136.3,133.3,129.3,123.5,122.9,118.9,118.8,118.5,116.5,111.6,101.9,70.1,36.0,23.8ppm。
实施例31、N-(3-(苄氧基)-4-氟-苯基)-2-((4,6-二甲基嘧啶-2-基)硫代)乙酰胺(化合物31)的合成
Figure PCTCN2016105443-appb-000048
利用5-氨基-2-氟苯酚(31a,0.5mmol,65mg)按照化合物15的合成方法合成目标化合物31，五步总产率26％。1H NMR(400MHz,DMSO):δ10.21(s,1H),7.44-7.30(m,6H),7.22(d,J＝8.4Hz,1H),7.13(d,J＝8.4Hz,1H),7.11(s,1H),6.98(s,1H),5.06(s,2H),4.03(s,2H),2.34(s,6H)ppm；LC-MS m/z:398.1[M+H]+。
实施例32、N-(3-(苄氧基)-4-甲基-苯基)-2-((4,6-二甲基嘧啶-2-基)硫代)乙酰胺(化合物32)的合成
Figure PCTCN2016105443-appb-000049
利用5-氨基-2-甲基苯酚(32a,0.5mmol,62mg)按照化合物15的合成方法合成目标化合物32，五步总产率27％。1H NMR(400MHz,DMSO):δ10.22(s,1H),7.45-7.31(m,6H),7.24(d,J＝8.4Hz,1H),7.10(d,J＝8.4Hz,1H),7.10(s,1H),6.99(s,1H),5.05(s,2H),4.03(s,2H),2.34(s,6H)，2.08(s,3H)ppm；LC-MS m/z:394.2[M+H]+。
实施例33、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(4-(苯氨基)苯基)乙酰胺(化合物33)的合成
Figure PCTCN2016105443-appb-000050
将化合物33a(1mmol,184mg)溶于二氯甲烷(DCM,3ml)中,加入三乙胺(3mmol,416μl)，后将反应置于0℃搅拌溶解，在0℃下将溴乙酰溴(1.1mmol,96μl)的DCM(1ml)溶液缓慢加入到反应后，将反应移至室温搅拌反应4-5h,经TLC检测反应完全后，减压除去多余的溶剂，柱层析得到中间体33b。然后，将4,6-二甲基-2-巯基嘧啶(1.2mmol,168.2mg)溶于DMF(N,N-二甲基甲酰胺，3ml)中，室温条件下加入叔丁醇钾(2mmol,224.4mg)，接着在室温下搅拌反应30min后，将化合物33b(1mmol,305mg)溶于DMF(1ml)中缓慢加入到反应中，室温搅拌反应4-5h后，经TLC检测反应完全后，往反应中加入冰水(40ml)，并用乙酸乙酯萃取(20ml×3)，有机层经无水MgSO4干燥，浓缩后经柱层析得到化合物33(142mg,产率41％)。1H NMR(400MHz,DMSO):δ10.08(s,1H),8.05(s,1H),7.46(d,J＝8.8Hz,2H),7.20(t,J＝8.0Hz,2H),7.05-6.98(m,5H),6.77(t,J＝7.2Hz,1H),4.02(s,2H),2.35(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.4,166.3,144.5,139.4,132.3,129.6,121.0,119.5,118.3,116.5,116.3,35.9,23.8ppm。
实施例34、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(4-苯氧基苯基)乙酰胺(化合物34)的合成
Figure PCTCN2016105443-appb-000051
将化合34a(1mmol,185mg)和溴乙酸(1.2mmol,166.8mg)溶于DCM(16ml)中，并置于0℃搅拌溶解后，在0℃下依次加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI,1.2mmol,230.4mg),1-羟基苯并三唑(HOBT,1.2mmol,162mg),N,N-二异丙基乙胺(DIEA,2mmol,331μl)，加毕，将反应移至室温搅拌反应过夜。经TLC检测反应完全后减压除去多余的溶剂，柱层析得中间体34b。以中间体34b为原料，按照实施例33化合物33类似的合成方法，得到目标化合物34，产率52％。1H NMR(400MHz,DMSO):δ10.27(s,1H),7.60(d,J＝8.8Hz,2H),7.37(t,J＝8.0Hz,2H),7.11(t,J＝7.6Hz,1H),7.01-6.96(m,5H),4.04(s,2H),2.35(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.4,166.8,157.8,152.3,135.4,130.4,123.5,121.3,119.9,118.4,116.5,35.8,23.8ppm。
实施例35、2-((4,6-二甲基嘧啶-2-基)亚磺酰基)-N-(4-苯氧基苯基)乙酰胺(化合物35)的合成
Figure PCTCN2016105443-appb-000052
将化合物34(70.0mg,0.185mmol)用DCM(4mL)溶解，0℃搅拌下加入间氯过氧苯甲酸(33.5mg,0.194mmol)，室温反应45min，经TLC检测反应完全后，减压除去多余的溶剂，柱层析得白色固体目标化合物35(44mg，产率62％)。1H NMR(400MHz,CDCl3):δ9.32(s,1H),7.47(d,J＝8.8Hz,2H),7.33(t,J＝7.6Hz,2H),7.10(t,J＝8.8Hz,2H),7.00-6.93(m,5H),4.16(d,J＝14.4Hz,1H),3.93(d,J＝14.4Hz,1H),2.55(s,6H)ppm；13C NMR(100MHz,DMSO):δ171.5,168.9,162.9,157.7,152.7,134.9,130.4,123.5,121.9,121.4,119.9,118.4,60.5,23.9ppm。
实施例36、2-((4,6-二甲基嘧啶-2-基)磺酰基)-N-(4-苯氧基苯基)乙酰胺(化合物36)的合成
Figure PCTCN2016105443-appb-000053
将化合物34(70.0mg,0.185mmol)用DCM(4mL)溶解，0℃搅拌下加入间氯过氧苯甲酸(95.6mg,0.554mmol)，室温反应3h，经TLC检测反应完全后减压除去多余的溶剂，柱层析得白色固体目标化合物36(44mg，产率71％)。1H NMR(400MHz,CDCl3):δ9.33(s,1H),7.55(d,J＝8.8Hz,2H),7.46(t,J＝7.6Hz,2H),7.13(t,J＝8.8Hz,2H),7.00-6.95(m,5H),4.16(d,J＝14.4Hz,1H),3.93(d,J＝14.4Hz,1H),2.55(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.3,164.5,159.8,157.6,152.9,134.6,130.5,123.7,123.6,121.4,119.9,118.5,57.9,23.8ppm。
实施例37、N-(4-苄基苯基)-2-((4,6-二甲基嘧啶-2-基)硫代)乙酰胺(化合物37)的合成
Figure PCTCN2016105443-appb-000054
将LiAlH4(10mmol,379.5mg)加入到反应瓶中后，置于0℃下约15min后将AlCl3(10mmol,1333mg)的乙醚(15ml)溶液滴加到反应中，混合液在0℃搅拌5min。接着将对氨基二苯甲酮(37a,1mmol,197.2mg)的乙醚(15ml)溶液滴加到反应中，并将反应移至室温反应3h,经TLC检测反应完全后，反应液先用6M HCl稀释，后用饱和NaHCO3中和，水层经乙酸乙酯(20ml×3)萃取，合并有机层，无水Na2SO4干燥，浓缩，柱层析得中间体37b。以中间体37b为原料，按照实施例34化合物34类似的合成方法，得到目标化合物37，三步总产率36％。1H NMR(400MHz,DMSO):δ10.17(s,1H),7.49(d,J＝8.4Hz,2H),7.28(t,J＝7.6Hz,2H),7.22-7.15(m,5H),6.97(s,1H),4.02(s,2H),3.89(s,2H),2.34(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.4,166.8,141.9,137.5,136.7,129.4,129.1,128.8,125.4,119.8,116.5,40.0,35.9,23.8ppm。
实施例38、N-(4-苯甲酰基苯基)-2-((4,6-二甲基嘧啶-2-基)硫代)乙酰胺(化合物38)的合成
Figure PCTCN2016105443-appb-000055
以化合物37a为原料，按照实施例34化合物34类似的合成方法，得到目标化合物38，两步总产率45％。1H NMR(400MHz,DMSO):δ10.65(s,1H),7.79-7.74(m,4H),7.72(d,J＝8.0Hz,2H),7.67(t,J＝4.4Hz,1H),7.56(t,J＝8.0Hz,2H),6.98(s,1H),4.10(s,2H),2.34(s,6H)ppm；13C NMR(100MHz,DMSO):δ195.00,169.7,167.7,167.5,143.6,138.0,132.7,131.9,131.7,129.8,128.9,118.8,116.6,36.1,23.8ppm。
实施例39、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(4-(羟基(苯基)甲基)苯基)乙酰胺(化合物39)的合成
Figure PCTCN2016105443-appb-000056
将LiAlH4(5mmol,189.8mg)加入到反应瓶中，置于0℃下搅拌15min后将AlCl3(5mmol,666.7mg)的乙醚(8ml)溶液滴加到反应后，将混合液在0℃搅拌5min。接着将对氨基二苯甲酮(37a,1mmol,197.2mg)的乙醚(8ml)溶液滴加到反应中，然后将反应移至室温反应3h,经TLC检测反应完全后，反应液先用6M HCl稀释，再用饱和NaHCO3中和，水层经乙酸乙酯(10ml×3)萃取，合并有机层，无水Na2SO4干燥，浓缩，柱层析得到化合物中间体39a。以中间体39a为原料，按照实施例34化合物34类似的合成方法，得到化 合物39，三步总产率32％。1H NMR(400MHz,DMSO):δ10.20(s,1H),7.57(s,1H),7.47(d,J＝8.0Hz,1H),7.36(d,J＝7.2Hz,2H),7.30(t,J＝8.0Hz,2H),7.25-7.19(m,2H),7.07(d,J＝7.6Hz,1H),6.97(s,1H),5.89(d,J＝4.0Hz,1H),5.65(d,J＝4.0Hz,1H),4.01(s,2H),2.32(s,6H)ppm。
实施例40、N-(4-(苄胺基)苯基)-2-((4,6-二甲基嘧啶-2-基)硫代)乙酰胺(化合物40)的合成
Figure PCTCN2016105443-appb-000057
利用40a按照实施例34中间体34b的合成方法合成中间体40b，接着利用40b按照实施例34目标化合物34的合成方法合成中间体40c。然后将苯甲醛(0.374mmol,39.6mg)和化合物40c(0.34mmol,98.1mg)溶于DCM(6ml)中，再将2，6-二甲基-1，4-二氢吡啶-3，5-二羧酸乙酯(汉斯酯，0.477mmol,120.1mg)加入，最后滴入三氟乙酸(0.17mmol,12.7μl)并置于45℃回流反应过夜。经TLC检测反应完全后，减压除去多余的溶剂，柱层析得目标化合物40，三步反应总产率为27％。1H NMR(400MHz,DMSO):δ9.85(s,1H),7.37-7.31(m,4H),7.30-7.25(m,4H),6.98(s,1H),6.57(d,J＝8.4Hz,2H),4.26(s,2H),3.97(s,2H),2.35(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.9,167.4,166.0,150.2,149.9,145.1,129.0,122.8,121.4,116.5,112.7,46.1,35.7,23.8ppm。
实施例41、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(4-((3-甲氧基苄基)氨基)苯基)乙酰胺(化合物41)的合成
Figure PCTCN2016105443-appb-000058
利用中间体40c与3-甲氧基苯甲醛，按照实施例40化合物40类似的合成方法获得目标化合物41，产率75％。1H NMR(400MHz,DMSO):δ9.85(s,1H),7.38-7.32(m,3H),7.28-7.24(m,4H),6.98(s,1H),6.57(d,J＝8.4Hz,2H),4.26(s,2H),3.97(s,2H),3.83(s,3H),2.35(s,6H)ppm；13C NMR(100MHz,DMSO):δ170.0,167.6,166.2,159.9,150.3,149.9,145.1,129.0,122.8,121.4,117.0,116.5,112.7,54.2,46.1,35.7,23.8ppm。
实施例42、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(4-((吡啶-4-基-甲基)氨基)苯基)乙酰胺(化合物42)的合成
Figure PCTCN2016105443-appb-000059
利用中间体40c与4-吡啶甲醛，按照实施例40化合物40类似的合成方法获得目标 化合物42，产率78％。1H NMR(400MHz,DMSO):δ9.83(s,1H),8.48(d,J＝5.6Hz,2H),7.33(d,J＝6.0Hz,2H),7.24(d,J＝8.8Hz,2H),6.97(s,1H),6.50(d,J＝8.8Hz,2H),6.29(t,J＝6.0Hz,1H),4.29(d,J＝6.4Hz,2H),3.96(s,2H),2.32(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.9,167.4,166.0,150.2,149.9,145.1,129.0,122.8,121.4,116.5,112.7,46.1,35.7,23.8ppm。
实施例43、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(4-((噻吩-2-基-甲基)氨基)苯基)乙酰胺(化合物43)的合成
Figure PCTCN2016105443-appb-000060
利用重要中间体40c与2-噻吩甲醛，按照实施例40化合物40类似的合成方法获得目标化合物43，产率71％。1H NMR(400MHz,DMSO):δ9.80(s,1H),7.32(d,J＝3.2Hz,1H),7.24(d,J＝5.6Hz,2H),7.01(s,1H),6.93(t,J＝3.2Hz,2H),6.57(d,J＝5.6Hz,2H),6.07(br s,1H,),4.39(s,2H),3.95(s,2H),2.32(s,6H)ppm；13C NMR(100MHz,DMSO):δ170.8,169.9,167.4,165.9,145.1,144.8,129.2,127.2,125.2,124.8,121.3,116.5,113.0,55.4,35.8,23.8ppm。
实施例44、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(4-((呋喃-2-基-甲基)氨基)苯基)乙酰胺(化合物44)的合成
Figure PCTCN2016105443-appb-000061
利用中间体40c与糠醛，按照实施例40化合物40类似的合成方法获得目标化合物44，产率70％。1H NMR(400MHz,DMSO):δ9.89(s,1H),7.58(s,1H),7.30(d,J＝8.8Hz,2H),6.97(s,1H),6.65(d,J＝8.8Hz,2H),6.38(s,1H),6.29(s,1H),4.24(s,2H),3.99(s,2H),2.35(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.9,167.4,166.0,153.4,144.2,142.5,129.8,121.2,116.5,113.5,110.8,107.7,41.0,35.8,24.1ppm。
实施例45、N-(4-(苄氧基)苯基)-2-((4,6-二甲基嘧啶-2-基)硫代)乙酰胺(化合物45)的合成
Figure PCTCN2016105443-appb-000062
将对氟硝基苯(45a,0.5mmol,70.5mg)、苯甲醇(0.75mmol,72mg)溶于二氧六环(5ml)中，加入KOH(1.5mmol,84mg)，室温搅拌反应过夜，经TLC检测反应完全后减压除去溶剂二 氧六环，加适量水和乙酸乙酯，经萃取、干燥、浓缩后柱层析得中间体45b。接着将45b(0.45mmol,103.5mg)溶于乙醇(3ml)和水(1.5ml)的混合溶剂中，加入NH4Cl(0.225mmol,12mg)和Fe(2.25mmol,126mg)，于80℃反应30min，经TLC检测反应完全后过滤除去不溶物质，加入NaHCO3调节PH至碱性，再减压除去乙醇，水层经乙酸乙酯萃取，浓缩，柱层析得到中间体45c。利用45c按照实施例34化合物34类似的合成方法，合成目标化合物45，四步总产率为41％。1H NMR(400MHz,DMSO):δ10.10(s,1H),7.49(d,J＝6.8Hz,2H),7.46-7.44(m,2H),7.41-7.38(m,2H),7.35-7.31(m,1H),7.00-6.95(m,3H),5.07(s,2H),4.01(s,2H),2.34(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.4,166.5,154.8,137.6,132.9,128.9,128.2,128.1,121.1,116.5,115.3,69.8,35.8,23.8ppm。
实施例46、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(4-(苯氧甲基)苯基)乙酰胺(化合物46)的合成
Figure PCTCN2016105443-appb-000063
将苯酚(46a，1mmol,94mg)加到反应瓶中，用2ml DMF溶解，接着加入碳酸钾(5mmol，690mg)后将对硝基苄溴(1mmol,216mg)溶解在2ml DMF中并滴加到反应瓶中。室温搅拌反应2小时。经TLC检测反应完全后，经过萃取减压蒸馏得到化合物46b。然后将化合物46b(1mmol,229mg)溶解在乙醇和水(10ml,乙醇：水＝2：1)的混合溶剂后，加入铁粉(5mmol,280mg)和氯化铵(1mmol,53.5mg)于80℃搅拌回流反应0.5小时，TLC检测反应完全后，用碳酸氢钠调节pH至碱性，抽滤后减压蒸馏除去乙醇，再加少量水，用乙酸乙酯萃取后经过柱层析得到化合物46c。利用46c按照实施例34目标化合物34的合成方法，合成化合物46，四步总产率为24％。1H NMR(400MHz,DMSO):δ10.30(s,1H),7.61(d,J＝8.4Hz,2H),7.40(d,J＝8.4Hz,2H),7.30(t,J＝7.2Hz,2H),7.01-6.98(m,2H),6.94(t,J＝7.2Hz,1H),5.04(s,2H),4.05(s,2H),2.34(s,6H)ppm。
实施例47、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(4-((苯氨基)甲基)苯基)乙酰胺(化合物47)的合成
Figure PCTCN2016105443-appb-000064
将对硝基苯甲醛(47a,2mmol,302.2mg)和苯胺(2.2mmol,201μl)溶于DCM(16ml)中，接着将2，6-二甲基-1，4-二氢吡啶-3，5-二羧酸乙酯(汉斯酯，2.8mmol,708.4mg)加入，最后滴入三氟乙酸(1mmol,74.6μl)并置于45℃回流反应过夜。经TLC检测反应完全后减压除去多余的溶剂，柱层析得到还原胺化产物47b。将还原胺化产物47b(1.89mmol,427mg)溶于乙醇(10ml)和水(5ml)的混合溶剂后加入铁粉(9.44mmol,528.4mg)和NH4Cl(0.945mmol,50.6mg)至反应中并置于80℃回流反应30min，经TLC检测反应完全后 过滤除去不溶物质，加入NaHCO3调节PH至碱性，减压除去乙醇，水层经乙酸乙酯萃取，浓缩，柱层析后得化合物47c.利用47c按照实施例34目标化合物34的合成方法，合成化合物47，四步总产率37％。1H NMR(400MHz,DMSO):δ10.19(s,1H),7.52(d,J＝8.4Hz,2H),7.29(d,J＝8.4Hz,2H),7.03(t,J＝8.4Hz,2H),6.97(s,1H),6.56(d,J＝8.8Hz,2H),6.51(t,J＝7.2Hz,1H),6.14(t,J＝6.0Hz,1H),4.20(d,J＝6.0Hz,2H),4.03(s,2H),2.34(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.4,166.8,149.1,138.0,135.6,129.2,128.0,119.6,116.5,116.2,112.7,46.6,35.9,23.8ppm。
实施例48、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(4-(((3-(三氟甲基)苯基)氨基)甲基)苯基)乙酰胺(化合物48)的合成
Figure PCTCN2016105443-appb-000065
利用3-三氟甲基苯胺替换苯胺，按照实施例47化合物47的合成方法，合成目标化合物48，四步总产率38％。1H NMR(400MHz,DMSO):δ10.21(s,1H),7.54(d,J＝8.4Hz,2H),7.30(d,J＝8.4Hz,2H),7.24(t,J＝7.6Hz,1H),6.97(s,1H),6.84-6.79(m,3H),6.69(t,J＝6.0Hz,1H),4.26(d,J＝5.6Hz,2H),4.03(s,2H),2.33(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.4,166.9,149.6,138.2,134.7,130.2,128.1,125.4,123.6,119.7,116.5,116.0,112.0,108.6,46.3,35.9,23.8ppm。
实施例49、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(4-(苯硫基)苯基)乙酰胺(化合物49)的合成
Figure PCTCN2016105443-appb-000066
向反应瓶中加入对碘苯胺(49a,2mmol,438mg)、CuSO4.5H2O(0.1mmol,25mg)、KOH(10mmol,561mg)和DMSO(二甲基亚砜，4ml)/H2O(0.4ml),然后加入1,2-乙二硫醇(2mmol,180μl)并于100-110℃反应8h，接着将反应液冷却至室温后将碘苯(2.6mmol,530.4mg)溶于DMF(2ml)中后加入到反应中，于120℃继续反应18h。经TLC检测反应完全后反应冷却至室温，加入水和乙酸乙酯，水层经乙酸乙酯(10ml×3)萃取，合并有机相，无水Na2SO4干燥，浓缩，柱层析得中间体49b。利用49b按照实施例34化合物34的合成方法，合成目标化合物49，三步总产率48％。1H NMR(400MHz,DMSO):δ10.40(s,1H),7.64(d,J＝8.4Hz,2H),7.39(d,J＝8.4Hz,2H),7.33(t,J＝7.6Hz,2H),7.26-7.20(m,3H),6.98(s,1H),4.06(s,2H),2.33(s,6H)ppm。
实施例50、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(4-(苯亚磺酰基)苯基)乙酰胺(化合物50)的合成
Figure PCTCN2016105443-appb-000067
利用化合物49b按照实施例35目标化合物35的合成方法，经m-CPBA氧化生成化合物50a。然后，利用化合物50a按照实施例34化合物34的合成方法，合成目标化合物50，三步总产率为41％。1H NMR(400MHz,DMSO):δ10.46(s,1H),7.80(d,J＝8.4Hz,2H),7.61(d,J＝8.4Hz,2H),7.52(t,J＝7.6Hz,2H),7.27-7.22(m,3H),6.97(s,1H),4.09(s,2H),2.34(s,6H)ppm。
实施例51、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(4-(苯磺酰基)苯基)乙酰胺(化合物51)的合成
Figure PCTCN2016105443-appb-000068
将化合物49b按照实施例36目标化合物36的合成方法，经m-CPBA氧化生成化合物51a。利用化合物51a按照实施例34化合物34的合成方法，合成目标化合物51，三步总产率为41％。1H NMR(400MHz,DMSO):δ10.46(s,1H),7.82(d,J＝8.4Hz,2H),7.64(d,J＝8.4Hz,2H),7.57(t,J＝7.6Hz,2H),7.27-7.20(m,3H),6.97(s,1H),4.08(s,2H),2.33(s,6H)ppm。
实施例52、2-((4-甲基-6-羟基-1,6-二氢嘧啶-2-基)硫代)-N-(4-(苯胺基)苯基)乙酰胺(化合物52)的合成
Figure PCTCN2016105443-appb-000069
利用中间体33b和甲基硫脲嘧啶作为原料，按照实施例33化合物33的合成方法，合成目标化化合物52，产率65％。1H NMR(400MHz,DMSO):δ12.56(br s,1H),10.16(s,1H),8.20(s,1H),7.46(s,1H),7.24(t,J＝8.0Hz,2H),7.15(t,J＝8.0Hz,1H),7.09(d,J＝7.6Hz,2H),7.01(d,J＝8.0Hz,1H),6.84(t,J＝7.6Hz,1H),6.75(dd,J＝1.6Hz,J＝7.6Hz,2H),6.01(br s,1H),4.06(s,2H),2.15(s,3H)ppm。
实施例53、本发明化合物对体外SIRT2蛋白的抑制活性
测试方法如下：
(1)实验材料：
购买于美国BPS Bioscience公司的SIRT2酶(产品编号：50013)；美国Perkin Elmer公司 的384孔板(产品编号：6007279)；Sigma公司的阳性对照产品Suramin(产品编号：S2671)。
(2)实验方法：
首先，制备三羟甲氨基甲烷缓冲液；然后，将所有受试化合物及阳性对照化合物Suramin溶解于100％的DMSO中配制成不同浓度的测试溶液并转移至测试孔板中；随后将SIRT2酶溶于缓冲溶液中配制酶溶液；同时利用烟酰胺腺嘌呤核苷酸(NAD+)和乙酰化的底物肽溶解于缓冲溶液中配制成底物缓冲溶液；接着在测试孔板中分别加入10μL酶溶液或空白对照缓冲溶液后将测试孔板置于室温孵化15分钟；再向每孔中加入10μL底物缓冲液反应4小时；反应完毕后向每孔中加入胰蛋白酶溶液反应1.5小时；最后使用Synergy MX酶标仪在激发光为360nM和460nM发射光波长处测试以上反应液的发光强度，从而确定化合物对SIRT2的抑制活性。
(3)实验结果：
通过以上实验方法，测试了本发明化合物针对SIRT2的抑制活性，具体的化合物在5μM、50μM浓度下的抑制活性及部分化合物对SIRT2的半数抑制有效浓度(IC50)见表1，其中“-”表示未测。
表1.本发明化合物对SIRT2的抑制活性(Inh％)
Figure PCTCN2016105443-appb-000070
Figure PCTCN2016105443-appb-000071
上述结果表明，本发明化合物对SIRT2具有良好的抑制活性，可以用于制备沉默信息调节因子2相关蛋白的抑制剂。
实施例54、本发明化合物对多种肿瘤细胞株的增殖的抑制效果
(1)实验材料：
主要试剂：RPMI-1640、胎牛血清、胰酶等购自Gibco BRL公司(Invitrogen Corporation，USA)，IMDM培养基购自ATCC(American Type Culture Collection)。四甲基偶氮唑盐(MTT)、二甲基亚砜(DMSO)为Sigma公司(USA)产品。人肝癌细胞系(HUH7),人肝癌细胞系(SMMC7721)，肝母细胞瘤细胞系(HepG2),人乳腺癌细胞系(MCF-7)，人肺癌细胞系(NCI-H460),人肺癌细胞系(A549),人胰腺癌细胞系(MIAPACA)，人早幼粒白血病细胞系(HL60),人慢性髓系白血病细胞系(K562),人前列腺癌细胞(DU-145)等均购于美国ATCC(American type culture collection)，由本实验室保存。
(2)实验方法：
用完全细胞培养液调整细胞浓度为1～2×104个/mL的细胞悬液，接种于96孔板，每孔200μl细胞悬液，培养过夜。次日，吸弃上清(悬浮细胞离心后吸取上清)，然后分别用梯度浓度的受试化合物处理细胞。同时设不含药物的阴性对照组和等体积的溶剂对照组，DMSO浓度为0.1％，每个剂量组设3个复孔，在37℃，5％CO2条件下培养。72小时后，每孔加入浓度为5mg/mL的MTT试剂20μl，再培养2-4h后，弃上清，每孔再加入DMSO150μL，振荡混匀15min，用酶标仪(λ＝570nm)测定吸光度(A)值(A值与活细胞数成正比)，取其平均值。相对细胞增殖抑制率＝(阴性对照组A570-实验组A570)/阴性对照组A570×100％。实验至少重复3次。实验数据用均数表示，数据统计资料采用t检验，P<0.05为差异有统计学意义。以下各化合物对细胞增殖抑制作用均用IC50或抑制率表示。
(3)实验结果：
采用以上方法，测试了本发明化合物1、13、19、20、21、49对人肝癌细胞系(HUH7),人肝癌细胞系(SMMC7721)，肝母细胞瘤细胞系(HepG2),人乳腺癌细胞系(MCF-7)，人肺癌细胞系(NCI-H460),人肺癌细胞系(A549),人胰腺癌细胞系(MIAPACA)，人早幼粒白血病细胞系(HL60),人慢性髓系白血病细胞系(K562),人前列腺癌细胞(DU-145)等进行了增殖抑制活性测试，具体的为化合物在50μM、100μM浓度下的抑制活性，见表2。
表2、本发明化合物对不同肿瘤细胞株的增殖抑制活性(Inh％)
Figure PCTCN2016105443-appb-000072
上述结果表明，本发明化合物对肝癌、肝母细胞瘤、乳腺癌、肺癌、胰腺癌、前列腺癌和白血病的细胞增殖，具有很好的抑制作用，可以用于制备治疗和/或预防肿瘤的药物。
综上所述，本发明式Ⅰ所示的新化合物，不仅对SIRT2具有良好的抑制活性，而且对肿瘤具有很好的抑制作用，具有很好的药用潜力，为临床用药提供了一种新的潜在选择；同时，本发明新化合物的制备方法简便，反应条件温和，便于操作和控制，能耗小，产率高，成本低，可适合产业化生产。

Claims (9)

  1. 式Ⅰ所示的化合物或其药学上可接受的盐、晶型、溶剂合物：
    Figure PCTCN2016105443-appb-100001
    其中，
    Z选自
    Figure PCTCN2016105443-appb-100002
    R1选自H或
    Figure PCTCN2016105443-appb-100003
    X选自
    Figure PCTCN2016105443-appb-100004
    Figure PCTCN2016105443-appb-100005
    R4选自芳基、杂芳基、取代芳基、取代杂芳基或
    Figure PCTCN2016105443-appb-100006
    所述取代芳基和取代杂芳基的取代基分别独立地选自C1～C4烷基、C1～C4烷氧基、C1～C4卤代烷基、
    Figure PCTCN2016105443-appb-100007
    Figure PCTCN2016105443-appb-100008
    卤素、羟基、巯基、醚基、酯基、氨基或硝基；
    R4a、R4b分别独立地选自C1～C4烷基、C1～C4烷氧基、C1～C4卤代烷基、芳基、杂芳基或C3～C6环烷基；
    R2选自
    Figure PCTCN2016105443-appb-100009
    或
    Figure PCTCN2016105443-appb-100010
    R2a～R2f分别独立地选自H、羟基、卤素、C1～C4烷基、C1～C4烷氧基、C1～C4卤代烷基或苯基；
    R3选自卤素、C1～C4烷基、C1～C4烷氧基或
    Figure PCTCN2016105443-appb-100011
    Y选自
    Figure PCTCN2016105443-appb-100012
    Figure PCTCN2016105443-appb-100013
    R5选自芳基、杂芳基、取代芳基或取代杂芳基，所述取代芳基和取代杂芳基的取代基分别独立地选自C1～C4烷基、C1～C4烷氧基、C1～C4卤代烷基、卤素、羟基、巯基、醚基、酯基、氨基、硝基、酰胺基或氨酰基。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐、晶型、溶剂合物，其特征在于：所述的化合物为
    Figure PCTCN2016105443-appb-100014
  3. 根据权利要求2所述的化合物或其药学上可接受的盐、晶型、溶剂合物，其特征在于：
    R4中，所述芳基为苯基或萘基，所述的杂芳基为吡啶基、呋喃基、噻吩基、喹啉基、吲唑基或喹啉基，所述取代芳基和取代杂芳基的取代基分别独立地选自C1～C4烷基、C1～C4烷氧基、C1～C4卤代烷基、
    Figure PCTCN2016105443-appb-100015
    R4a、R4b分别独立地选自C1～C4烷基、C1～C4烷氧基、C1～C4卤代烷基、C3～C6环烷基、苯基或噻吩基；
    R2中，R2a、R2c、R2f分别独立地选自H、羟基、卤素、C1～C4烷基、C1～C4烷氧基、C1～C4卤代烷基或苯基，R2b、R2d、R2e分别为H。
  4. 根据权利要求2所述的化合物或其药学上可接受的盐、晶型、溶剂合物，其特征在于：
    R5选自苯基、吡啶基、呋喃基、噻吩基、取代苯基、取代吡啶基、取代呋喃基或取代噻吩基；所述取代苯基、取代吡啶基、取代呋喃基和取代噻吩基的取代基分别独立地选自C1～C4烷基、C1～C4烷氧基或C1～C4卤代烷基。
  5. 根据权利要求2所述的化合物或其药学上可接受的盐、晶型、溶剂合物，其特征在于：所述的化合物为
    Figure PCTCN2016105443-appb-100016
    Figure PCTCN2016105443-appb-100017
    Figure PCTCN2016105443-appb-100018
  6. 权利要求1～5任意一项所述的化合物或其药学上可接受的盐、晶型、溶剂合物在制备沉默信息调节因子2相关蛋白的抑制剂中的用途。
  7. 权利要求1～5任意一项所述的化合物或其药学上可接受的盐、晶型、溶剂合物在制备治疗和/或预防肿瘤的药物中的用途。
  8. 根据权利要求7所述的用途，其特征在于：所述的肿瘤为肝癌、肝母细胞瘤、乳腺癌、肺癌、胰腺癌、前列腺癌或白血病。
  9. 一种治疗和/或预防肿瘤的药物组合物，其特征在于：它是以权利要求1～5任意一项所述的化合物或其药学上可接受的盐、晶型、溶剂合物为活性成分，加上药学上常用的辅料制备得到的制剂。
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US12161639B2 (en) 2018-07-17 2024-12-10 University of Pittsburgh—of the Commonwealth System of Higher Education Methods of treating PACS1 and PACS2 syndromes
US11884647B2 (en) 2019-10-18 2024-01-30 The Regents Of The University Of California Compounds and methods for targeting pathogenic blood vessels
CN112939955A (zh) * 2021-03-05 2021-06-11 朗捷睿(苏州)生物科技有限公司 一种8-(吡啶酰胺)取代香豆素类化合物及其制备方法和应用

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