WO2017045271A1 - 苯并呋喃类衍生物、其制备方法及其治疗作用 - Google Patents

苯并呋喃类衍生物、其制备方法及其治疗作用 Download PDF

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WO2017045271A1
WO2017045271A1 PCT/CN2015/095735 CN2015095735W WO2017045271A1 WO 2017045271 A1 WO2017045271 A1 WO 2017045271A1 CN 2015095735 W CN2015095735 W CN 2015095735W WO 2017045271 A1 WO2017045271 A1 WO 2017045271A1
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methylbenzofuran
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尤启冬
孙昊鹏
杨英睿
魏金莲
张晓进
郭小可
徐晓莉
姜正羽
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China Pharmaceutical 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans 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 carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2

Definitions

  • the present invention relates to the field of medicinal chemistry, and in particular to a class of benzofuran derivatives having antitumor use and medical therapeutic effects as HIF1 ⁇ inhibitors.
  • benzofuran structure As a kind of important heterocyclic compound, benzofuran structure is widely used in various natural products and clinical medicines, and has a wide range of pharmacological activities, such as anti-tumor, antibacterial, anti-viral, anti-arrhythmia and the like.
  • hypoxic environment is an environmental condition that must be met during the development of solid tumors.
  • radiotherapy combined with nicotinamide and inhaled carbopol gas, biological reducing agent, hypoxia-inducible factor-1 ⁇ (HIF-1 ⁇ ) inhibitor, hypoxia-regulated gene therapy Etc.
  • HIF-l ⁇ inhibitors have become a hot spot in current anti-tumor drug research.
  • HIF-l ⁇ is a key regulatory protein of cells found by Semenza et al. (Semenza, GL Moll Cell Biol. 1992, 12(12): 5447-5454) under hypoxic conditions, which is a key factor for malignant tumors to adapt to hypoxic microenvironment. It can cause anaerobic glycolysis of tumor cells, trigger tumor angiogenesis, promote the proliferation, invasion and migration of tumor cells, so that tumor cells can adapt to hypoxic environment, and its expression level is positively correlated with poor prognosis.
  • HIF-l ⁇ inhibitors are classified into the following categories according to their different characteristics: l) compounds that act on the upstream signaling pathway of HIF-1 ⁇ , such as the mTOR inhibitor rapamycin and its esterified compounds; 2) inhibition of HIF- 1 ⁇ mRNA expression, such as HIF-1 ⁇ antisense oligonucleotide E Z N-2968; 3) inhibition of HIF-1 ⁇ protein synthesis, such as camptothecin Top l inhibitor topotecan; 4) promote HIF -l ⁇ protein degradation, including YC-1; 5) blocking HIF-1 ⁇ DNA binding to target genes, such as doxorubicin; 6) inhibiting H IF-l ⁇ protein by inhibiting HIF-1 ⁇ -p300 protein protein interaction Guided downstream gene transcriptional activation, such as Chetomin, benzopyran derivatives KCN1, etc.; 7) Others such as niacin / isonicotinic acid, ibuprofen and celecoxib.
  • the invention discloses a kind of benzofuran derivative (I), and the pharmacodynamic test proves that the compound of the invention has good anti-tumor proliferative activity, especially various solid solid tumors, including colorectal cancer, liver cancer and gastric cancer. , breast cancer, colon cancer, bone cancer, pancreatic cancer, head or neck cancer, cervical cancer, ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, perianal cancer, fallopian tube cancer, endometrial cancer, cervical cancer, Vaginal cancer, vulvar cancer, Hodgkin's disease, prostate cancer, bladder cancer, kidney cancer, ureteral cancer, renal cell carcinoma, renal pelvic cancer and central nervous system tumors.
  • the benzofuran derivative of the invention can also effectively inhibit the HIF1 ⁇ signaling pathway, thereby inhibiting the transcriptional activation of the downstream gene of HIF1 ⁇ , and has an effect on angiogenesis, drug resistance, proliferation, energy metabolism, etc. of solid solid tumors, thereby inhibiting tumors.
  • HIF inhibitor KCN1 The mechanism was studied to find that the structure of this compound is similar to the HIF inhibitor KCN1. It inhibits the activity of the HIF1 ⁇ signaling pathway, and some of its effects are produced by inhibiting the interaction of HIF1a-p300.
  • HIF inhibitor KCN1 has a good HIF1 ⁇ inhibitory activity, its water solubility is poor, and its benzopyran structure has poor stability in vivo, and its inhibitory effect on tumor cells in vitro cytotoxicity is not strong.
  • the benzofuran structure of the present invention is more stable than the benzopyran structure, and the inhibition effect in the cytotoxicity test is stronger in vitro.
  • the antitumor activity of the derivatives and their effects on the HIF1 ⁇ signaling pathway were tested. Most of these compounds were found to have a good inhibitory activity on the HIF1 ⁇ signaling pathway, and some of them inhibited ⁇ IF1 ⁇ -p300. And they all have good anti-tumor proliferation activity.
  • R 1 represents hydrogen, C 1 -C 3 alkyl, carboxyl, C 1 -C 3 carbamoyl,
  • R 2 represents hydrogen, C 1 -C 3 alkyl, carboxyl or R 5 represents C 1 -C 4 alkyl, C 1 -C 4 alkoxy, phenyl, morpholinyl, piperidinyl, piperazinyl, piperazinone group, N- methylpiperazinyl, NR 6 R 7 or -NH-(CH) 2m -NR 6 R 7 wherein m is 2 or 3; R 6 and R 7 each independently represent hydrogen, C 1 -C 4 alkyl, acetyl or phenyl, or R 6 and R 7 are bonded to a four to six membered heterocyclic ring;
  • R 3 represents a C 3 -C 7 cycloalkyl group or R 8 represents a mono- or di-substituted H, halogen, nitro, carboxyl, hydroxy, cyano, trifluoromethyl, C 1 -C 4 alkyl, methoxy, acetylamino, C 1 -C 3 alkyl group Amine;
  • X represents a bond, -CH 2 -,
  • R 4 represents hydrogen, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl substituted methylene or R 9 is mono or disubstituted H, halogen, carboxyl, hydroxy, cyano, C 1 -C 4 alkyl or methoxy;
  • R 1 preferably represents a C 1 -C 3 alkyl group, a carboxyl group,
  • R 2 preferably represents a carboxyl group or R 5 represents piperazinyl, morpholinyl, piperazinone, N-methylpiperazinyl,
  • R 3 preferably represents X preferably represents -CH 2 - or R 8 preferably represents a mono- or di-substituted halogen, a trifluoromethyl group, a C 1 -C 4 alkyl group, a methoxy group.
  • R 4 represents hydrogen or R 9 preferably represents a mono- or di-substituted halogen, cyano or methoxy group.
  • the preparation method of the compound of the present invention comprises:
  • R 1, R 2, R 3 , R 4, Y is defined as previously.
  • R 1 , R 2 , R 3 , R 4 and Y have the same meanings as defined above.
  • the invention also includes hydrates, stereoisomers, solvates and pharmaceutically acceptable salts of the compounds of formula I. They have the same pharmacological activity as the compounds of formula I.
  • the compound of the present invention may be added into a pharmaceutically acceptable carrier to prepare a common pharmaceutical preparation, such as a tablet, a capsule, a powder, a syrup, a liquid, a suspension, an injection, and may be added to a fragrance, a sweetener, a liquid or Common pharmaceutical excipients such as solid fillers or thinners.
  • a pharmaceutically acceptable carrier such as a tablet, a capsule, a powder, a syrup, a liquid, a suspension, an injection, and may be added to a fragrance, a sweetener, a liquid or Common pharmaceutical excipients such as solid fillers or thinners.
  • the compound of the present invention is used in a clinical dose of 0.01 mg to 1000 mg/day, and may be deviated from this range depending on the severity of the condition or the dosage form.
  • the MCF cells were evenly spotted in a 32-well plate, and pGL2-HRE-luciferase and SV40 luciferase were used.
  • Lipofectamine 2000 was transfected into MCF cells. After incubation for 24 hours, the medium was aspirated, and the medium containing 20 ⁇ M compound was added. After incubating for 24 h at 37 ° C 1% oxygen concentration, the cells were lysed, and the cell lysate was diluted 10 times into 96 wells. In the white plate, firefly luciferase was added and the luminescence value was immediately detected. Then add sea cucumber luciferase and immediately detect the luminescence value. No compound was added to the control wells.
  • a 384-well plate was spiked with a final concentration of 50 nM His-p300 at a final concentration of 100 ⁇ M. After incubation for 1 h, a final concentration of 10 nM FITC-labeled HIF fluorescent probe was added and the fluorescence polarization was measured using an instrument. The blank space is only HIF fluorescent probe, and the negative well is HIF fluorescent probe and p300 protein.
  • MCF7 cells were uniformly spotted in 96-well plates, and after 12 h, the medium was aspirated and the medium containing the compound was added. After 72 h, 20 ⁇ L of MTT was added to each well, and after incubating at 37 ° C for 4 h, the medium was aspirated and DMSO was added to measure the absorbance. The blank is only added to the medium, and the negative is the addition of the medium and the cells.
  • the positive drug KCN1 has a very strong inhibitory activity against the HIF1 ⁇ signaling pathway, but its antitumor activity in vitro is not strong.
  • the analog of the N-(benzofuran-5-yl)-benzenesulfonamide structure has a good HIF1 ⁇ inhibitory activity at a concentration of 20 ⁇ M. Further fluorescence polarization tests against HIF1 ⁇ -p300 inhibition revealed that such compounds exert HIF1 ⁇ inhibitory activity not primarily by inhibiting HIF1 ⁇ -p300 interaction.
  • N-trisubstituted benzenesulfonamide structure also has a good HIF1 ⁇ inhibitory activity, and a compound with better activity is also stronger in inhibiting HIF1 ⁇ -p300 interaction. And after introduction of a suitable hydrophilic group, the antitumor activity is greatly increased.
  • N-(4-Methoxyphenyl)acetamide (3.30 g, 0.02 mol) was dissolved in dichloromethane (100 ml), chloroacetyl chloride (2.7 ml, 0.06 mol), aluminum trichloride (7.98 g). , 0.06 mol), heated to reflux, reacted for 6 h, cooled, quenched with dilute hydrochloric acid, extracted with chloroform, and evaporated under reduced pressure to give a white solid, 2.82 g (yield: about 84.0%)
  • N-(3-carbonyl-2,3-dihydrobenzofuran-5-yl)acetamide (0.33 g, 1.73 mmol) was dissolved in ethanol (30 ml), 5% palladium carbon (183 mg), hydrogen atmosphere After stirring at room temperature overnight, palladium on carbon was filtered off. 3M dilute hydrochloric acid (30 ml) was added directly, and the mixture was heated to reflux for 6 h.
  • N-phenylbenzofuran-5-amine (0.31 g, 1.48 mmol) and then 4-(bromomethyl)-1,2-dimethoxybenzene (0.68 g. 2.96 mmol), potassium carbonate (0.41 g) , 2.96 mmol), according to the reaction of Step 5 in Example 1, N-(3,4-dimethoxybenzyl)-N-phenylbenzofuran-5-amine 0.38 g (yield 71.4%)
  • N-isopropylbenzofuran-5-amine (0.2 g, 1.14 mmol) was dissolved in acetone, potassium carbonate (0.32 g, 2.28 mmol), p-hydroxybenzyl chloride (0.33 g, 2.28 mmol). The mixture was refluxed, reacted for 2 h, and the insoluble material was filtered. Column chromatography separated 0.21 g (yield 65.4%)
  • N-(4-methoxyphenyl)acetamide (10.1 g, 0.065 mol) was reacted with acetyl chloride (20.5 g, 0.26 mol) of aluminum trichloride (34.9 g, 0.26 mol), and worked up in the same manner as in Example 1. step 1. 8.1 g of solid was formed (yield 64.1%)
  • N-(3-Acetyl-4-hydroxyphenyl)acetamide (4.4 g, 0.022 mol) was dissolved in 25 ml of N,N-dimethylformamide, and potassium carbonate (6.3 g, 0.046 mol) was added, bromoacetic acid Ethyl ester (7.6 g, 0.046 mol).
  • the tube is heated to 150 degrees. Reaction 4h. After cooling to room temperature, it was poured into water, suction-filtered, and the solid on the filter cake was washed with water several times to obtain a crude product, which was purified by column chromatography to yield white solid (2.1 g, yield: 35.3%)
  • step 3 in Example 5 ethyl 5-amino-3-methylbenzofuran-2-carboxylate (0.8 g, 3.65 mmol) was obtained according to the conditions of step 4 in Example 5 and 4-trifluoromethylsulfonyl chloride (1.07 g, 4.38 mmol), potassium carbonate (1.01 g, 7.30 mmol), The product ethyl 3-methyl-5-(4-(trifluoromethyl)benzenesulfonyl)benzofuran-2-carboxylate 0.78 g (yield 50.0%)
  • Step 2 Ethyl 5-(N-(4-bromobenzyl)-4-trifluoromethyl)benzenesulfonamide)-3-methylbenzofuran-2-carboxylate
  • Step 3 5-(N-(4-Bromophenyl)-4-(trifluoromethyl)benzenesulfonamido)-3-methylbenzofuran-2-carboxylic acid
  • Example 5 The intermediate ethyl 5-amino-3-methylbenzofuran-2-carboxylate (0.8 g, 3.65 mmol) of Example 5 was used as a starting material, and reacted with 4-bromobenzenesulfonyl chloride according to the conditions in Step 4 of Example 5. A solid of 1.2 g (yield 75.0%) was obtained.
  • Example 8 Ethyl 5-(4-bromobenzenesulfonamide)-3-methylbenzofuran-2-carboxylate (0.20 g, 0.46 mmol) was used as material and potassium carbonate (0.126 mg, 0.91 mmol). Bromomethylcyclopentane (0.149 g, 0.91 mmol), anhydrous tetrahydrofuran as a solvent, and reacted at 60 ° overnight. Column chromatography separated 0.101 g of solid (yield 42.1%)
  • Example 11 The product of Example 11 was used as the starting material ethyl 3-methyl-5-(4-methylbenzenesulfonamide)benzofuran-2-carboxylate (0.2 g, 0.62 mmol), and p-bromo bromide (0.31) g, 1.24 mmol) under sodium hydrogen (0.11 g, 4.94 mmol) as a solvent under THF (20 mL). Add water to extract. The organic layer was combined and dried over anhydrous sodium sulfate and then purified by column chromatography to yield 0.1 g (yield: 33.8%)
  • Step 2 (0.5 g, 1.22 mmol) was added to thionyl chloride (10 ml), and heated to reflux. After completion of the reaction, the obtained acid chloride was dissolved in dichloromethane and added to a 10% aqueous solution of piperazine (20 ml). . The reaction was overnight. Direct filtration to obtain the product 0.44 g (yield 77.5%)
  • step 13 of Example 13 5-(4-bromobenzenesulfonamide)-3-methylbenzofuran 2-carboxylic acid (0.5 g, 1.22 mmol) was dissolved in 10 ml of thionyl chloride solution and heated to reflux. The resulting acid chloride was then added to dichloromethane dissolved in N-methylpropanediamine (0.50 g, 4.88 mmol) and allowed to react overnight. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to yield 0.34 g (yield 56.4%)
  • Step 1 Using the product of the step 3 in Example 5, ethyl 5-amino-3-methylbenzofuran-2-carboxylate (0.8 g, 3.65 mmol) as a starting material, according to the conditions of step 4 of Example 5 and p-chloro The reaction of benzenesulfonyl chloride yielded 0.67 g (yield 45.3%)
  • Step 2 Ethyl 5-(4-chlorobenzenesulfonamide)-3-methylbenzofuran-2-carboxylate (0.6 g, 1.58 mmol) and p-chlorobenzyl chloride (0.51 g, 3.16 mmol), Potassium (0.44 g, 3.16 mmol), KI (0.26 g, 1.58 mmol) was refluxed in acetone for 2h, and insolubles were filtered. The mixture was evaporated to dryness under reduced pressure, and purified by column chromatography to yield 0.69 g of solid (yield 86.6%)
  • Step 3 Ethyl 5-((4-chloro-N-(4-chlorobenzyl)phenyl)sulfonamide)benzofuran-2-carboxylate (0.6 g, 1.19 mmol) in sodium hydroxide The solution was refluxed for 1 h. After the reaction, the pH is adjusted to be acidic. Ethanol was distilled off under reduced pressure, and a large amount of solid was precipitated, and filtered to give 0.44 g of solid (yield: 75.43%)
  • Step 4 5-((4-Chloro-N-(4-chlorobenzyl)phenyl)sulfonyl chloride)-3-methylbenzofuran-2-carboxylic acid (0.3 g, 0.61 mmol). With 1-(2-aminoethyl)-4-methylpiperazine (0.18 g, 1.22 mmol), 0.21 g of solid was obtained (yield 55.8%)
  • Step 2 Ethyl 5-((4-chloro-N-cyclohexylmethyl)-3-fluorophenyl)sulfonamide)-3-methylbenzofuran-2-carboxylate as ethyl 5-(( (4-Chloro-3-fluorophenyl)sulfonamide)-3-methylbenzofuran-2-carboxylate (0.5 g, 1.26 mmol) as a starting material, according to the method of Step 1 of Example 10 and bromomethyl Cyclohexylamine (0.45 g, 2.51 mmol) was reacted to give 0.32 g (yield 50.1%)
  • Step 1 Ethyl 5-(N-cyclobutyl-N-(4-methoxyphenyl)aminesulfonyl)-3-methylbenzofuran-2-carboxylate
  • Example 25 Product ethyl 5-(N-cyclobutylaminesulfonyl)-3-methylbenzofuran-2-carboxylate (0.5 g, 1.48 mmol) was dissolved in 20 mL dichloromethane. Methoxybenzyl bromide (0.59 g, 2.96 mmol), potassium carbonate (0.41 g, 2.96 mmol). Column chromatography separated 0.47 g (yield 69.2%)
  • Step 2 5-(N-Cyclobutyl-N-(4-methoxyphenyl)aminesulfonyl)-3-methylbenzofuran-2-carboxylic acid
  • Step 1 The final product of Example 29, methyl 2-methyl-5-(N-phenylaminesulfonyl)benzofuran-3-carboxylate (0.5 g, 1.45 mmol) was obtained according to step 2 of Example 26 The product obtained 0.42 g (yield 87.6%)
  • Step 2 2-methyl-5--(N-phenylaminesulfonyl)benzofuran-3-carboxylic acid (0.4 g, 1.21 mmol). 64.0%
  • Step 2 5-(N-(4-(tert-butyl)benzyl)-N-phenylsulfonamide)-N-isopropyl-2-methylbenzofuran-3-carboxamide

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Abstract

本发明涉及药物化学领域，具体涉及一类苯并呋喃类衍生物（I），药效学试验证明该类化合物具有抗肿瘤方面的用途以及作为HIF1α抑制剂在医学上的治疗作用。

Description

苯并呋喃类衍生物、其制备方法及其治疗作用 技术领域
本发明涉及药物化学领域，具体涉及一类苯并呋喃类衍生物，该类化合物具有抗肿瘤方面的用途以及作为HIF1α抑制剂在医学上的治疗作用。
背景技术
苯并呋喃结构作为一类重要的杂环化合物，广泛存在于各种天然产物及临床药物中，具有广泛的药理学活性，例如抗肿瘤，抗菌，抗病毒，抗心率失常等。
研究表明,低氧环境是实体瘤在发展过程中必经的环境条件。目前,主要有以下针对肿瘤低氧的治疗策略：放射治疗配合使用烟酰胺和吸入卡波金气体、生物还原剂、低氧诱导因子-lα(HIF-lα)抑制剂、低氧调控的基因治疗等,其中HIF-lα抑制剂己经成为当前抗肿瘤药物研究的热点。HIF-lα是Semenza等(Semenza,G.L.Moll Cell Biol.1992,12(12):5447-5454)发现的细胞在缺氧条件下的关键调控蛋白,它是恶性肿瘤适应低氧微环境的关键因子,能引起肿瘤细胞的无氧糖酵解,引发肿瘤的血管生成,促进肿瘤细胞的增殖、侵袭及迁移等行为，使肿瘤细胞能适应低氧环境,其表达程度与预后不良成正相关。
HIF-lα抑制剂根据作用特点不同将其分为以下几类：l)作用于HIF-lα上游相关信号通路的化合物，如mTOR抑制剂雷巴霉素及其酯化物等；2)抑制HIF-1α mRNA的表达,如HIF-lα的反义寡核苷酸E Z N-2968等；3)抑制HIF-lα蛋白合成，如喜树碱类Top l抑制剂拓扑替康等；4)促进HIF-lα蛋白降解，包括YC-l等；5)阻断HIF-lαDNA与靶基因的结合，如阿霉素等；6)通过抑制HIF-lα-p300蛋白蛋白相互作用，抑制H IF-lα介导的下游基因转录激活，如Chetomin、苯并吡喃类衍生物KCN1等；7)其他如烟酸/异烟酸、布洛芬和塞来昔布等。
Figure PCTCN2015095735-appb-000001
发明内容
本发明公开了一类苯并呋喃类衍生物(I)，药效学试验证明，本发明的化合物具有较好的抗肿瘤增殖活性，尤其是各种固体实体瘤，包括大肠癌、肝癌、胃癌、乳腺癌、结肠癌、骨癌、胰腺癌、头部或颈部癌症、宫颈癌、卵巢癌、直肠癌、食道癌、小肠癌、肛周癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、外阴癌、霍奇金病、前列腺癌、膀肤癌、肾癌、输尿管癌、肾细胞癌、肾盂癌和中枢神经系统肿瘤。
本发明的苯并呋喃衍生物还可以有效的抑制HIF1α信号通路，从而抑制HIF1α下游基因的转录激活，对固体实体瘤的血管生成、耐药、增殖、能量代谢等均有作用，从而达到抑制肿瘤的作用。
研究其机制发现该类化合物结构与HIF抑制剂KCN1相似。其抑制HIF1α信号通路的活性，部分作用是通过抑制HIF1a-p300相互作用产生的。HIF抑制剂KCN1虽然具有很好的HIF1α抑制活性，但其水溶性较差，其包含的苯并吡喃结构体内稳定性较差，且对肿瘤细胞的体外细胞毒实验抑制作用不强。而本发明的苯并呋喃结构较苯并吡喃结构更稳定，且体外细胞毒实验抑制作用更强。为了更好研究该类化合物，测试了其衍生物的抗肿瘤活性及对HIF1α信号通路的影响。发现该类化合物大部分均对HIF1α信号通路有很好的抑制活性，而其中部分化合物对ΗIF1α-p300存在抑制作用。并且都具有较好的抗肿瘤增殖活性。
本发明的化合物(I)结构式如下：
Figure PCTCN2015095735-appb-000002
其中R1代表氢、C1-C3烷基、羧基、C1-C3的氨基甲酰基、
Figure PCTCN2015095735-appb-000003
Figure PCTCN2015095735-appb-000004
R2代表氢、C1-C3烷基、羧基或
Figure PCTCN2015095735-appb-000005
R5代表C1-C4烷基、C1-C4烷氧基、苯基、吗啉基、哌啶基、哌嗪基、哌嗪酮基、N-甲基哌嗪基、
Figure PCTCN2015095735-appb-000006
Figure PCTCN2015095735-appb-000007
Figure PCTCN2015095735-appb-000008
NR6R7或-NH-(CH)2m-NR6R7其中m是2或3；R6、R7各自独立地代表氢、C1-C4烷基、乙酰基或苯基，或者R6和R7连接成四到六元杂环；
R3代表C3-C7的环烷基或
Figure PCTCN2015095735-appb-000009
R8表示单或双取代的H、卤素、硝基、羧基、羟基、氰基、三氟甲基、C1-C4烷基、甲氧基、乙酰氨基、C1-C3的烷基胺；X代表键、-CH2-、
Figure PCTCN2015095735-appb-000010
R4代表氢、C1-C4烷基、C3-C7的环烷基取代的亚甲基或
Figure PCTCN2015095735-appb-000011
R9是单或双取代的H、卤素、羧基、羟基、氰基、C1-C4烷基或甲氧基；
Y代表键或
Figure PCTCN2015095735-appb-000012
R1优选代表C1-C3烷基、羧基、
Figure PCTCN2015095735-appb-000013
R2优选代表羧基或
Figure PCTCN2015095735-appb-000014
R5代表哌嗪基、吗啉基、哌嗪酮基、N-甲基哌嗪基、
Figure PCTCN2015095735-appb-000015
Figure PCTCN2015095735-appb-000016
R3优选代表
Figure PCTCN2015095735-appb-000017
X优选代表-CH2-或
Figure PCTCN2015095735-appb-000018
R8优选代表单或双取代的卤素、三氟甲基、C1-C4烷基、甲氧基。
R4代表氢或
Figure PCTCN2015095735-appb-000019
R9优选代表单或双取代的卤素、氰基或甲氧基。
本发明的化合物制备方法包括：
当Y代表
Figure PCTCN2015095735-appb-000020
时：
Figure PCTCN2015095735-appb-000021
其中R1、R2、R3、R4、Y的定义同前。
当Y代表键时：
其中R1、R2、R3、R4、Y的定义同前。
本发明也包括通式I化合物的水合物、立体异构体、溶剂化物和药学上可接受的盐。它们具有与通式I化合物同样的药理活性。
本发明所述的化合物可以添加药学上可接受的载体制成常见的药用制剂，如片剂、胶囊、粉剂、糖浆、液剂、悬浮剂、针剂，可以加入香料、甜味剂、液体或固体填料或稀释剂等常用药用辅料。
本发明的化合物临床所用剂量为0.01mg～1000mg/天，也可根据病情的轻重或剂型的不同偏离此范围。
下面是本发明部分化合物的药效学试验及结果：
实验一：HRE荧光素酶报告基因
将MCF细胞均匀的点在32孔板中，将pGL2-HRE-荧光素酶及SV40荧光素酶用 lipofectamine 2000转染进入MCF细胞中，孵育24h后，吸出培养基，加入含有20μM浓度化合物的培养基，37℃ 1％氧气浓度下孵育24h后，裂解细胞，将细胞裂解液稀释10倍加入96孔白板中，加入萤火虫荧光素酶，立即检测得发光值。再加入海参荧光素酶，立即检测发光值。对照孔不加化合物。
实验二：HIF-p300荧光偏振实验
384孔板中加入终浓度50nM His-p300，终浓度100μM的化合物，孵育1h后加入终浓度10nM FITC标记的HIF荧光探针，利用仪器检测其荧光偏振值。空白空为只加HIF荧光探针，阴性孔为加HIF荧光探针及p300蛋白。
实验三：细胞毒测试
将MCF7细胞均匀点在96孔板中，12h后吸出培养基，加入含化合物的培养基。72h后每孔加入20μL MTT，37℃下孵育4h后吸出培养基，加入DMSO，检测吸光度。空白为只加培养基，阴性为加入培养基及细胞。
结果见表1。表1中的编号对应于实施例的编号。
表1本发明化合物荧光素酶活性及HIF1α-p300荧光偏振测试结果
Figure PCTCN2015095735-appb-000023
Figure PCTCN2015095735-appb-000024
ND表示未测
从表1可见阳性药KCN1具有非常强的HIF1α信号通路的抑制活性，但其体外抗肿瘤活性并不强。N-(苯并呋喃-5-基)-苯磺酰胺结构的类似物在20μM浓度下均具有较好的对HIF1α抑制活性。而进一步的针对HIF1α-p300抑制的荧光偏振测试发现，这类化合物发挥HIF1α抑制活性不是主要通过抑制HIF1α-p300相互作用产生的。另一类N三取代苯磺酰胺结构也具有很好的HIF1α抑制活性，而其中活性较好的化合物对抑制HIF1α-p300相互作用也较强。并且引入合适的亲水基团后，抗肿瘤活性大大增加。
具体实施方式
实施例1
N-苄基-N-苯并呋喃-5-胺
Figure PCTCN2015095735-appb-000025
步骤1：N-(3-(2-氯乙酰基)-4-羟基苯基)乙酰胺
将N-(4-甲氧基苯基)乙酰胺(3.30g,0.02mol)溶于二氯甲烷(100ml)中，加入氯乙酰氯(2.7ml,0.06mol)，三氯化铝(7.98g,0.06mol)，加热至回流，反应6h，冷却，用稀盐酸猝灭，氯仿萃取，减压旋转蒸发得黄色固体2.82g(产率约为84.0％)
1H-NMR(300MHz,DMSO):δ10.83(s,1H,-OH),9.90(s,1H,-NHAc),7.93(s,1H,Ar-H),7.70(d,1H,Ar-H),6.95(d,1H,Ar-H),5.04(s,2H,-COCH 2Cl),2.06(s,3H，-NHCOCH 3)EI-MS:m/z 227.0
步骤2：N-(3-羰基-2,3-二氢苯并呋喃-5-基)乙酰胺
将N-(3-(2-氯乙酰基)-4-羟基苯基)乙酰胺(1.14g.0.005mol)溶于DCM中，加入碳酸钾(1.38g,0.01mol),加热至回流，1h后停止反应。抽滤，硅胶柱层析分离，得到0.66g固体(产率68.9％)
1H-NMR(300MHz,DMSO):δ9.98(s,1H,-NHAc),8.13(s,1H,Ar-H),7.89(d,1H,Ar-H),7.14(d,1H,Ar-H),5.20(s,2H,-COCH 2-),2.14(s,3H-NHCOCH 3)EI-MS:m/z 191.1
步骤3：苯并呋喃-5-胺
将N-(3-羰基-2,3-二氢苯并呋喃-5-基)乙酰胺(0.33g,1.73mmol)溶于乙醇(30ml)中，加入5％钯碳(183mg),氢气氛围下室温搅拌过夜，滤除钯碳。直接加入3M稀盐酸(30ml)，加热至回流6h后，减压蒸发下除去溶剂，重结晶得固体0.21g(产率为91.3％)
1H-NMR(300MHz,DMSO):δ11.13(brs,2H,-NH 2),8.16(s,1H,Ar-H),7.86(d,1H,Ar-H),7.53(d,1H,Ar-H),7.17(d,1H,Ar-H),6.69(d,1H,Ar-H)EI-MS:m/z 133.1
步骤4：N-环己基苯并呋喃-5-胺
将苯并呋喃-5-胺(0.2g.1.5mmol)加入二氯甲烷中，加入碳酸钾(0.42g,3mmol),溴代环己烷(0.49g,3mmol)，加热至回流，反应2h后，滤除碳酸钾，柱层析分离得油状物0.23g(产率71.1％)
1H-NMR(300MHz,DMSO):δ7.82(s,1H,Ar-H),7.73(d,1H,Ar-H),7.51(d,1H,Ar-H),7.14(d,1H,Ar-H),6.89(d,1H,Ar-H),6.77(d,1H,Ar-H),2.47-2.53(m,1H,环己烷-H),2.02-2.15(m,4H环己烷-H),1.11-1.54(m,5H环己烷-H)EI-MS:m/z 215.2
步骤5：N-苄基-N-苯并呋喃-5-胺
将N-环己基苯并呋喃-5-胺(0.21g,1mmol)加入无水二氯甲烷中，加入溴苄(0.34g,2mmol)，碳酸钾(0.28g,2mmol),加热至回流。反应6h后，滤除碳酸钾，柱层析分离得油状物0.23g(产率75.3％)
1H-NMR(300MHz,DMSO):δ7.78(s,1H,Ar-H),7.42-7.45(m,2H,Ar-H),7.13-7.30(m,6H,Ar-H),7.01-7.10(m,1H,Ar-H),7.00(d,1H,Ar-H),4.85(s,2H,-CH 2Ph),2.52-2.64(m,1H,环己烷-H),2.07-2.18(m,4H,环己烷-H),1.01-1.78(m,5H环己烷-H)EI-MS:m/z 305.2
实施例2
N-(3,4-二甲氧基苄基)-N-苯基苯并呋喃-5-胺
Figure PCTCN2015095735-appb-000026
步骤1：N-苯基苯并呋喃-5-胺
由实施例1中步骤3制备得得产物苯并呋喃-5-胺(0.5g,3.76mmol)，按照实施例1中步骤4与溴苯(1.18g,7.51mmol)，钠氢(0.45g,18.8mmol)反应得到中间体N-苯基苯并呋喃-5-胺0.31g(产率39.4％)
1H-NMR(300MHz,DMSO):δ7.82(s,1H,Ar-H),7.74(d,1H,Ar-H),7.52(d,1H,Ar-H),6.92-7.28(m,6H,Ar-H),6.86(d,1H,Ar-H),EI-MS:m/z 209.2
步骤2：N-(3,4-二甲氧基苄基)-N-苯基苯并呋喃-5-胺
N-苯基苯并呋喃-5-胺(0.31g，1.48mmol)再与4-(溴甲基)-1,2-二甲氧基苯(0.68g.2.96mmol),碳酸钾(0.41g,2.96mmol)按照实施例1中步骤5反应得N-(3,4-二甲氧基苄基)-N-苯基苯并呋喃-5-胺0.38g(产率71.4％)
1H-NMR(300MHz,CDCl3):δδ7.72(s,1H,Ar-H),7.40(d,1H,Ar-H),7.25-7.39(m,8H,Ar-H),6.93-7.02(m,2H,Ar-H),6.94(d,1H,Ar-H)4.85(s,2H,-CH 2Ph),3.92(s,3H,-OCH3 ),3.72(s,3H,-OCH3 )EI-MS:m/z 359.1
实施例3
4-((苯并呋喃-5-基(异丙基)氨基)甲基)苯酚
Figure PCTCN2015095735-appb-000027
步骤1：N-异丙基苯并呋喃-5-胺
以实施例1中步骤3制备得得产物苯并呋喃-5-胺(0.5g,3.76mmol)按照实施例1步骤4方法与溴代异丙基(0.92g,7.51mmol)反应得0.23g油状物(产率35.0％)
1H NMR(300MHz,CDCL3)δ7.59(d,1H,Ar-H),7.27(d,1H,Ar-H),6.64-6.72(m,1H,Ar-H),6.50-6.63(m,2H,Ar-H),3.41-3.56(m,1H,-CH(CH3)2),1.24(d,6H,-CH(CH3)2 ).EI-MS:m/z 175.1
步骤2：4-((苯并呋喃-5-基(异丙基)氨基)甲基)苯酚
将N-异丙基苯并呋喃-5-胺(0.2g,1.14mmol)溶于丙酮中，加入碳酸钾(0.32g,2.28mmol)、对羟基氯苄(0.33g,2.28mmol),加热至回流，反应2h，滤除不溶物。柱层析分离得到0.21g(产率65.4％)
1H NMR(300MHz,DMSO)δ9.18(s,1H,-OH),8.11(d,1H,Ar-H),7.49(s,1H,Ar-H),7.42(d,1H,Ar-H),7.09-7.31(m,4H,Ar-H),6.84-6.92(m,2H,Ar-H),5.22(s,2H,-CH 2Ph),4.28-4.48(m,1H,-CH(CH3)2),1.18(d,6H,-CH(CH3)2 ).EI-MS:m/z 281.1
实施例4
N-(苯并呋喃-5-基)-3,4-二甲氧基苯磺酰胺
Figure PCTCN2015095735-appb-000028
由实施例1中步骤3制备得得产物苯并呋喃-5-胺(0.5g,3.76mmol)，按照实施例1中步骤4与3,4-二甲氧基苯磺酰氯(1.1g,4.51mmol)反应生成。
1H-NMR(300MHz,DMSO):δ10.1(s,1H,Ar-H)7.56(d,1H,Ar-H),7.48(d,1H,Ar-H),7.12-7.30(m,10H,Ar-H),6.96-6.99(m,1H,Ar-H),3.86(s,3H,-OCH3),3.69(s,3H,-OCH3)EI-MS:m/z 333.0
实施例5
N-(苯并呋喃-5-基)萘-2-磺酰胺
Figure PCTCN2015095735-appb-000029
步骤1：N-(3-乙酰基-4-羟基苯基)乙酰胺
N-(4-甲氧基苯基)乙酰胺(10.1g,0.065mol)与乙酰氯(20.5g,0.26mol)三氯化铝(34.9g,0.26mol)反应,后处理同实施例1中步骤1。生成固体8.1g(产率64.1％)
1H-NMR(300MHz,DMSO):δ11.54(s,1H,-OH),9.93(s,1H,-NHAc),8.04(d,1H,Ar-H),7.64-7.69(m,1H,Ar-H),6.92(d,1H,Ar-H),2.51(s,3H,ArCH 3),2.02((s,3H,NHCOCH 3)EI-MS: m/z 193.1
步骤2：乙基5-乙酰胺基-3-甲基苯并呋喃-2-甲酸酯
将N-(3-乙酰基-4-羟基苯基)乙酰胺(4.4g,0.022mol)溶于25ml N,N-二甲基甲酰胺，加入碳酸钾(6.3g，0.046mol)，溴乙酸乙酯(7.6g,0.046mol)。封管加热至150度。反应4h。冷却至室温后倒入水中，抽滤，滤饼上固体用水洗多次后，得到粗品，粗品柱层析纯化得白色固体2.1g(产率35.3％)
1H-NMR(300MHz,DMSO):δ10.03(s,1H,-NHAc),8.04(d,1H,Ar-H)7.64-7.69(m,1H,Ar-H),6.92(d,1H,Ar-H),4.32(q,2H,-CH 2CH3),2.51(s,3H,ArCH 3),2.05((s,3H,NHCOCH 3),1.32(t,3H,-CH2CH 3)EI-MS:m/z 261.1
步骤3：乙基5-氨基-3-甲基苯并呋喃-2-甲酸酯
将乙基5-乙酰胺基-3-甲基苯并呋喃-2-甲酸酯(2.1g，8.04mmol)加入50ml 3M HCl与50ml乙醇中，加热至回流，反应6h后，减压蒸除溶剂，乙醇重结晶得1.1g固体(产率62.4％)
1H-NMR(300MHz,DMSO):δ12.01(brs,2H,NH 2)10.02(s,1H,-NHAc),8.06(d,1H,Ar-H),7.64-7.69(m,1H,Ar-H),6.90(d,1H,Ar-H),4.36(q,2H,-CH 2CH3),2.51(s,3H,ArCH 3),1.32(t,3H,-CH2CH 3)EI-MS:m/z 219.1
步骤4：N-(苯并呋喃-5-基)萘-2-磺酰胺
将乙基5-氨基-3-甲基苯并呋喃-2-甲酸酯(0.8g,3.65mmol)，2-萘磺酰氯(1.24g,5.47mmol),碳酸钾(1.01g,7.30mmol)依次加入二氯甲烷30ml中，室温搅拌过夜，滤除碳酸钾，柱层析分离得固体1.49g(产率31.46％)
1H-NMR(300MHz,DMSO):δ10.42(s,1H，-NH-),8.41(s,1H,Ar-H),8.08-8.13(m,1H,Ar-H),8.03(d,1H,Ar-H),7.78(d,1H,Ar-H),7.58-7.73(m,2H,Ar-H),7.47-7.53(m,2H,Ar-H),7.20(d,1H,Ar-H),4.34(q,2H,-CH2CH3),1.25(t,3H,-CH2CH3)EI-MS:m/z 409.2
实施例6
5-(N-(4-溴苯基)-4-(三氟甲基)苯磺酰胺基)-3-甲基苯并呋喃-2-甲酸
Figure PCTCN2015095735-appb-000030
步骤1：乙基3-甲基-5-(4-(三氟甲基)苯磺酰基)苯并呋喃-2-甲酸酯
实施例5中步骤3产物乙基5-氨基-3-甲基苯并呋喃-2-甲酸酯(0.8g,3.65mmol)按照实施例5中步骤4条件与4-三氟甲基磺酰氯(1.07g,4.38mmol),碳酸钾(1.01g,7.30mmol)反应， 得产物乙基3-甲基-5-(4-(三氟甲基)苯磺酰基)苯并呋喃-2-甲酸酯0.78g(产率50.0％)
1H-NMR(300MHz,DMSO):δ10.38(s,1H,NH),7.61-7.77(m,4H,Ar-H),7.55-7.58(m,1H,Ar-H),7.42-7.43(m,1H,Ar-H),7.16(dd,1H,Ar-H),4.33(q,2H,-CH 2CH3),2.46(s,3H,Ar-CH3 ),1.31(t,3H,-CH2CH 3)EI-MS:m/z 427.1
步骤2：乙基5-(N-(4-溴苄基)-4-三氟甲基)苯磺酰胺)-3-甲基苯并呋喃-2-甲酸酯
乙基3-甲基-5-(4-(三氟甲基)苯磺酰基)苯并呋喃-2-甲酸酯(0.45g,1.05mmol),与4溴溴苄(0.52g,2.11mmol),碳酸钾(0.29g,2.11mmol)在二氯甲烷中回流反应6h,柱层析分离得乙基5-(N-(4-溴苄基)-4-三氟甲基)苯磺酰胺)-3-甲基苯并呋喃-2-甲酸酯固体0.51g(产率81.2％)
1H-NMR(300MHz,DMSO):δ7.63-7.79(m,4H,Ar-H),7.51-7.58(m,3H,Ar-H),7.39-7.41(m,1H,Ar-H),7.03-7.11(m,3H,Ar-H),4.26(q,2H,-CH 2CH3),2.52(s,3H,Ar-CH3 ),1.30(t,3H,-CH2CH 3)EI-MS:m/z 595.0
步骤3：5-(N-(4-溴苯基)-4-(三氟甲基)苯磺酰胺基)-3-甲基苯并呋喃-2-甲酸
乙基5-(N-(4-溴苄基)-4-三氟甲基)苯磺酰胺)-3-甲基苯并呋喃-2-甲酸酯(0.2g,0.33mmol)与1M氢氧化钠4ml，乙醇20ml加热至回流，反应生成5-(N-(4-溴苄基)-4-三氟甲基)苯磺酰胺)-3-甲基苯并呋喃-2-甲酸0.11g(产率57.7％)
1H-NMR(300MHz,DMSO):δ13.12(brs,1H,-COOH)7.67-7.87(m,4H,Ar-H),7.52-7.58(m,3H,Ar-H),7.39-7.40(m,1H,Ar-H),7.00-7.15(m,3H,Ar-H)4.65(s,2H,-CH 2Ph),2.48(s,3H,Ar-CH3 )EI-MS:m/z 567.0
实施例7
乙基5-(3-异丙基苯磺酰胺)-3-甲基苯并呋喃-2-甲酸酯
Figure PCTCN2015095735-appb-000031
以实施例5中步骤3产物乙基5-氨基-3-甲基苯并呋喃-2-甲酸酯(0.8g,3.65mmol)为原料，按照实施例5步骤4条件与3-异丙基苯磺酰氯(0.96g,4.38mmol)反应生成固体0.73g(产率49.83％)
1H-NMR(300MHz,DMSO):δ10.48(s,1H,NH),7.84(s,1H,Ar-H),7.64-7.77(m,3H,Ar-H),7.42-7.43(m,1H,Ar-H),7.10-7.18(m,2H,Ar-H)4.34(q,2H,-CH 2CH3),2.77-2.89(m,1H,-CH(CH3)2)2.55(s,3H,Ar-CH3 ),1.27(t,3H,-CH2CH 3)，1.22(d,6H,-CH(CH 3)2) EI-MS:m/z 401.1
实施例8
乙基5-(4-溴苯磺酰胺)-3-甲基苯并呋喃-2-甲酸酯
Figure PCTCN2015095735-appb-000032
以实施例5中间体乙基5-氨基-3-甲基苯并呋喃-2-甲酸酯(0.8g,3.65mmol)为原料，按照实施例5步骤4条件与4-溴苯磺酰氯反应得固体1.2g(产率75.0％)。
1H-NMR(300MHz,DMSO):δ10.40(s,1H，-NH),7.56-7.74(m,5H，Ar-H),7.44(d,1H,Ar-H),7.17(dd,1H,Ar-H)4.34(q,2H,-CH 2CH3),2.46(s,3H，Ar-CH3 ),1.32(t,3H,-CH2CH 3).EI-MS:m/z 437.0,439.0
实施例9
乙基3-甲基-5-((4-氰基苯基)磺酰胺)苯并呋喃-2-甲酸酯
以实施例5中步骤3产物乙基5-氨基-3-甲基苯并呋喃-2-甲酸酯(0.8g,3.65mmol)为原料，按照实施例5步骤4条件与对氰基苯磺酰氯反应得固体1.3g(产率88.1％)
1H NMR(300MHz,DMSO)δ10.64(s,1H，-NH),8.35(d,2H,Ar-H),7.95(d,2H，Ar-H),7.58(d,1H),7.46(d,1H，Ar-H),7.16-7.19(m,1H，Ar-H),4.33(q,2H,-CH 2CH3),2.45(s,3H，Ar-CH3 ),1.32(t,3H-CH2CH 3).EI-MS:m/z 384.1
实施例10
乙基5-(4-溴-N-(环戊甲基)苯基胺磺酰基)-3-甲基苯并呋喃-2-甲酸酯
以实施例8乙基5-(4-溴苯磺酰胺)-3-甲基苯并呋喃-2-甲酸酯(0.20g,0.46mmol)为原料与碳酸钾(0.126mg,0.91mmol)，溴甲基环戊烷(0.149g,0.91mmol)，无水四氢呋喃为溶剂，60度反应过夜。柱层析分离得固体0.101g(产率42.1％)
Figure PCTCN2015095735-appb-000033
1H-NMR(300MHz,DMSO):δ7.54-7.72(m,5H，Ar-H),7.41(d,1H,Ar-H),7.14(dd,1H,Ar-H),4.34(q,2H,-CH 2CH3),3.13(d,2H,-N-CH 2-)2.51(s,3H，Ar-CH3 ),1.14-1.39(m,12H,-CH2CH 3,环戊基-H).EI-MS:m/z 519.1
实施例11
乙基3-甲基-5-(4-甲基苯磺酰胺)苯并呋喃-2-甲酸酯
Figure PCTCN2015095735-appb-000034
以实施例5中步骤3产物乙基5-氨基-3-甲基苯并呋喃-2-甲酸酯(0.8g,3.65mmol)为原料，与对甲基苯甲酰氯(1.13g,7.30mmol),三乙胺(1.48g,14.6mmol)，以无水二氯甲烷(30ml)为溶剂，室温反应30min。减压蒸馏除去溶剂得到粗品，柱层析分离得0.9g(73.1％)
1H-NMR(300MHz,DMSO):δ10.40(s,1H,NH),7.34-7.65(m,4H,Ar-H),7.06-7.27(m,3H,Ar-H),4.43(q,2H,-CH 2CH3),2.45(s,3H,Ar-CH 3),2.31(s,3H,Ar-CH 3),1.32(t,3H,-CH2CH 3).EI-MS:m/z 337.1
实施例12
5-(N-(4-溴苄基)-4-甲基苯甲酰胺)-3-甲基苯并呋喃-2-甲酸
Figure PCTCN2015095735-appb-000035
以实施例11步骤产物乙基3-甲基-5-(4-甲基苯磺酰胺)苯并呋喃-2-甲酸酯(0.2g,0.62mmol)为原料，与对溴溴苄(0.31g,1.24mmol)在钠氢(0.11g，4.94mmol)做碱条件下四氢呋喃(20ml)做溶剂下，加热回流反应12h。加水萃灭。二氯甲烷萃，合并有机层，无水硫酸钠干燥,柱层析分离得0.1g产物(产率33.8％)
1H NMR(300MHz,DMSO)δ8.06(d,1H,Ar-H),7.53-7.62(m,2H,Ar-H),7.28(dd,2H,Ar-H),5.03(s,1H),2.54(s,2H),2.41(s,2H).EI-MS:m/z 477.1
实施例13
4-溴-N-(3-甲基-2-(哌嗪-1-羰基)苯并呋喃-5-基)苯磺酰胺
步骤1：5-(4-溴苯磺酰胺)-3-甲基苯并呋喃2-甲酸
实施例8乙基5-(4-溴苯磺酰胺)-3-甲基苯并呋喃-2-甲酸酯(1.2g,2.74mmol)与1M NaOH/乙醇溶液中，加热至回流。反应1h后，乙酸乙酯萃取，减压蒸馏除去溶剂得到固体0.87g,(产率75.5％)
1H-NMR(300MHz,DMSO):δ13.01(brs,1H,-COOH),10.04(s,1H,-NH-)7.56-7.74(m,5H，Ar-H),7.44(d,1H,Ar-H),7.18(dd,1H,Ar-H),2.46(s,3H，Ar-CH3),EI-MS:m/z 411.0,409.0
步骤2：将(0.5g，1.22mmol)加入氯化亚砜(10ml)中，加热至回流，反应完毕后将制得的酰氯溶于二氯甲烷中，加入10％哌嗪水溶液(20ml)中。反应过夜。抽滤直接得到产物0.44g(产率77.5％)
1H-NMR(300MHz,DMSO):δ10.04(s,1H,-NH-)7.56-7.74(m,5H，Ar-H),7.44(d,1H,Ar-H),7.18(dd,1H,Ar-H),3.18(t,4H,
Figure PCTCN2015095735-appb-000037
),2.84(t,4H,
Figure PCTCN2015095735-appb-000038
),2.46(s,3H,Ar-CH3),EI-MS:m/z 479，477
实施例14
5-(4-溴苯磺酰胺)-N-(3-(二甲基氨基)丙基)-3-甲基苯并呋喃-2-甲酰胺
Figure PCTCN2015095735-appb-000039
将实施例13步骤1产物5-(4-溴苯磺酰胺)-3-甲基苯并呋喃2-甲酸(0.5g,1.22mmol)溶于10ml氯化亚砜溶液中加热至回流，反应完毕后将制得的酰氯加入溶有N-甲基丙二胺(0.50g,4.88mmol)的二氯甲烷中，反应过夜。减压蒸馏去除溶剂，柱层析分离得到0.34g(产率56.4％)
1H-NMR(300MHz,DMSO):δ12.01(s,1H,-CONH),9.94(s,1H,-SO2NH-)7.58-7.76(m,5H,Ar-H),7.43(d,1H,Ar-H),7.15(dd,1H,Ar-H),3.14(t,2H),2.42-2.51(m,5H),2.26(s,6H,-N(CH3)2),1.75-1.87(m,2H)EI-MS:m/z 495.1，493.1
实施例15
5-(4-溴苯磺酰胺)-N,N-二乙基-3-甲基苯并呋喃-2-甲酰胺
Figure PCTCN2015095735-appb-000040
按照实施例14方法将5-(4-溴苯磺酰胺)-3-甲基苯并呋喃2-甲酸(0.5g,1.22mmol)与二乙胺(1ml)反应得到0.46g(产率81.1％)
1H-NMR(300MHz,DMSO):δ10.04(s,1H,-NH-)7.56-7.74(m,5H，Ar-H),7.44(d,1H,Ar-H),7.16(dd,1H,Ar-H),3.72(q,4H,-CH 2CH3),2.52(s,3H，Ar-CH3),1.34(t,6H,-CH2CH3 )EI-MS:m/z 466.0，464.0
实施例16
N-(2-乙酰胺乙基)-5-(4-溴苯磺酰胺)-3-甲基苯并呋喃-2-甲酰胺
Figure PCTCN2015095735-appb-000041
按照实施例14方法将5-(4-溴苯磺酰胺)-3-甲基苯并呋喃2-甲酸(0.5g,1.22mmol)与N-乙酰基乙二胺(0.5g,4.88mmol)反应得到0.34g(产率56.4％)
1H-NMR(300MHz,DMSO):δ12.01(s,1H,-CONH),9.94(s,1H,-SO2NH-)7.58-7.76(m,5H，Ar-H),7.42(d,1H,Ar-H),7.15(dd,1H,Ar-H),3.66(t,2H,-CH 2CH2-)3.45(t,2H,-CH 2CH2-),2.51(s,3H,Ar-CH3),1.84(s,3H,-COCH 3)EI-MS:m/z 495.0，493.0
实施例17
5-(4-氯-N-(4-氯苄基)苯磺酰胺基)-3-甲基-N-(2-(4-甲基哌嗪-1-基)乙基)苯并呋喃-2-甲酰胺
Figure PCTCN2015095735-appb-000042
步骤1：以实施例5中步骤3产物乙基5-氨基-3-甲基苯并呋喃-2-甲酸酯(0.8g,3.65mmol)为原料，按照实施例5步骤4条件与对氯苯磺酰氯反应得0.67g(产率45.3％)
1H-NMR(300MHz,DMSO):δ10.40(s,1H,-NH-),7.56-7.74(m,5H,Ar-H),7.44(d,1H,Ar-H),7.17(dd,1H,Ar-H)4.34(q,2H,-CH 2CH3),2.46(s,3H,Ar-CH3),1.33(t,3H-CH2CH3 ).EI-MS:m/z 393.0,395.0
步骤2：乙基5-(4-氯苯磺酰胺)-3-甲基苯并呋喃-2-甲酸酯(0.6g,1.58mmol)与对氯氯苄(0.51g,3.16mmol)，碳酸钾(0.44g,3.16mmol)，KI(0.26g,1.58mmol)在丙酮中回流反应2h,滤除不溶物。减压蒸馏旋干，柱层析分离得0.69g固体(产率86.6％)
1H NMR(300MHz,DMSO)δ7.61-7.77(m,4H,Ar-H),7.59(d,1H,Ar-H),7.52(d,1H,Ar-H),7.31(m,4H，,Ar-H),7.18(dd,1H,Ar-H),4.86(s,2H,-CH 2Ph),4.35(q,2H,-CH 2CH3),2.45(s,3H,Ar-CH3),1.34(t,3H,-CH2CH3 ).EI-MS:m/z 503.04
步骤3：乙基5-((4-氯-N-(4-氯苄基)苯基)磺酰胺)苯并呋喃-2-甲酸酯(0.6g,1.19mmol),在氢氧化钠乙醇溶液中回流1h。反应完调节PH至酸性。减压蒸馏去除乙醇，大量固体析出，抽滤得0.44g固体(产率为75.43％)
1H NMR(300MHz,DMSO-d6)δ7.61-7.77(m,4H,Ar-H),7.55(d,1H,Ar-H),7.49(s,1H,Ar-H),7.24-7.37(m,4H,Ar-H),4.86(s,2H,-CH 2Ph),2.43(s,3H,Ar-CH 3).EI-MS:.m/z 489.02
步骤4：按照实施例14方法将5-((4-氯-N-(4-氯苄基)苯基)磺酰氯)-3-甲基苯并呋喃-2-甲酸(0.3g,0.61mmol)与1-(2-氨乙基)-4-甲基哌嗪(0.18g,1.22mmol)，反应得0.21g固体(产率55.8％)
1H NMR(300MHz,CDCl3)δ7.46-7.68(m,4H,Ar-H),7.29-7.41(m,3H,Ar-H),7.18(d,1H,Ar-H),7.04-7.15(m,3H,Ar-H),6.91(dd,1H,Ar-H),4.72(s,2H,-CH 2Ph),3.55(q,2H,-NHCH 2CH2),2.40-2.71(m,13H,
Figure PCTCN2015095735-appb-000043
Ar-CH 3),2.33(s,3H,N-CH 3).EI-MS:m/z 614.2
实施例18
5-(4-氯-N-(4-氯苄基)苯磺酰胺基)-3-甲基-N-(2-(吡咯烷-1-基)乙基)苯并呋喃-2-甲酰胺
Figure PCTCN2015095735-appb-000044
按照实施例14方法将5-((4-氯-N-(4-氯苄基)苯基)磺酰氯)-3-甲基苯并呋喃-2-甲酸(0.3g,0.61mmol)与氨乙基吡咯烷(0.14g,1.22mmol)反应，得0.24g固体(产率66.9％)
1H NMR(300MHz,CDCL3)δ7.47-7.69(m,4H,Ar-H),7.29-7.41(m,3H,Ar-H),7.19(d,1H,Ar-H),7.14-7.04(m,2H,Ar-H),6.89(dd,1H,Ar-H),4.72(s,2H,-CH 2Ph),3.59-3.67(m,2H,-NHCH 2CH2),2.79-2.87(m,2H,-NHCH2CH2 ),2.61-2.78(m,4H,吡咯烷-H),2.50(s,3H,Ar-CH 3),1.70-2.01(m,6H,吡咯烷-H). EI-MS:m/z 585.1
实施例19
5-(4-氯-N-(4-氯苄基)苯磺酰胺基)-3-甲基-N-(2-(苯胺)乙基)苯并呋喃-2-甲酰胺
Figure PCTCN2015095735-appb-000045
按照实施例14方法将5-((4-氯-N-(4-氯苄基)苯基)磺酰氯)-3-甲基苯并呋喃-2-甲酸(0.3g,0.61mmol)与N-苯基乙二胺(0.17g,1.22mmol)反应，得0.31g固体(产率83.3％)
1H NMR(300MHz,DMSO-d6)δ8.63-8.67(t,1H,Ar-H),7.79-7.88(m,2H,Ar-H),7.50-7.59(m,2H,Ar-H),7.37-7.50(m,4H,Ar-H),7.21(d,2H,Ar-H),7.00-7.15(m,3H,Ar-H),6.59(d,2H,Ar-H),6.51(t,1H,Ar-H),5.71(t,1H,Ar-H),4.82(s,2H,-CH 2Ph),3.36-3.45(m,2H-NHCH 2CH2),3.12-3.23(m,2H-NHCH2CH2 ),2.41(s,3H,Ar-CH 3).EI-MS:m/z 607.1
实施例20
5-(4-氯-N-(4-氯苄基)苯磺酰胺基)-3-甲基-N-(2-吗啡啉乙基)苯并呋喃-2-甲酰胺
Figure PCTCN2015095735-appb-000046
按照实施例14方法将5-((4-氯-N-(4-氯苄基)苯基)磺酰氯)-3-甲基苯并呋喃-2-甲酸(0.3g,0.61mmol)与氨乙基吗啉(0.16g,1.22mmol)反应，得0.19g固体(产率51.6％)
1H NMR(300MHz,CDCL3)δ7.48-7.70(m,4H,Ar-H),7.29-7.41(m,3H,Ar-H),7.15-7.21(d,1H,Ar-H),7.08-7.15(d,3H,Ar-H),6.91-6.95(m,1H,Ar-H),4.72(s,2H,-CH 2Ph),3.71-3.78(m,4H,吗啉-H),3.52-3.61(m,2H,-NHCH 2CH2),2.62-2.70(m,2H,-NHCH2CH2 ),2.44-2.57(m,7H,吗啉-H,Ar-CH 3).EI-MS:m/z 601.1
实施例21
5-(4-氯-N-(4-氯苄基)苯磺酰胺基)-3-甲基-N-(2-(甲磺酰基)乙基)苯并呋喃-2-甲酰胺
Figure PCTCN2015095735-appb-000047
按照实施例14方法将5-((4-氯-N-(4-氯苄基)苯基)磺酰氯)-3-甲基苯并呋喃-2-甲酸(0.3g,0.61mmol)与2-(甲磺酰基)乙胺(0.20g,1.22mmol)反应，得0.23g固体(产率63.1％)
1H NMR(300MHz,CDCL3)δ7.46-7.69(m,4H,Ar-H),7.28-7.41(m,4H,Ar-H),7.22(d,1H,Ar-H),7.10(d,2H,Ar-H),6.89(dd,1H,Ar-H),4.72(s,2H,-CH 2Ph),4.00(m,2H,-NHCH 2CH2),3.31-3.42(m,2H,-NHCH2CH 2),3.00(s,3H,-SO2CH 3),2.51(s,3H,Ar-CH 3).EI-MS:m/z 594.1
实施例22
5-(4-氯-N-(4-氯苄基)苯磺酰胺基)--3-甲基-N-(2-(甲基氨基)乙基)苯并呋喃-2-甲酰胺
Figure PCTCN2015095735-appb-000048
按照实施例14方法将5-((4-氯-N-(4-氯苄基)苯基)磺酰氯)-3-甲基苯并呋喃-2-甲酸(0.3g,0.61mmol)与N-甲基乙二胺(0.18g,2.45mmol)反应，生成固体0.11g(产率32.9％)
1H-NMR(300MHz,DMSO):δ8.35-8.38(m,1H,Ar-H),7.61-7.71(m,4H,Ar-H),7.45-7.48(d,1H,Ar-H),7.38-7.39(d,1H,Ar-H),7.26-7.32(m,4H,Ar-H),7.06-7.10(dd,1H,Ar-H),4.83(s,2H，PhCH2 ),3.34(t,2H,CH2CH2 )2.59(t,2H,CH2CH2 ),2.39(s,3H,Ar-CH3),2.26(s,3H,NHCH3 )EI-MS:m/z 545.1
实施例23
乙基5-((4-氯-N-环己基甲基)-3-氟苯基)磺酰胺)-3-甲基苯并呋喃-2-甲酸酯
Figure PCTCN2015095735-appb-000049
步骤1：乙基5-((4-氯-3-氟苯基)磺酰胺)-3-甲基苯并呋喃-2-甲酸酯
以实施例5中步骤3产物乙基5-氨基-3-甲基苯并呋喃-2-甲酸酯(0.4g,1.82mmol)为原料，与4-氯-3-氟磺酰氯(0.5g,2.19mmol)按照实施例5步骤4方法，得0.41g(产率54.6％)
1H NMR(300MHz,DMSO)δ9.43(s,1H,NH),7.84(d,1H,Ar-H),7.44-7.67(m,4H,Ar-H),6.54-6.62(m,1H,Ar-H),4.37(q,2H,-CH 2CH3),2.54(s,3H,Ar-CH3),1.31(t,3H,-CH2CH3 ).EI-MS:m/z 411.0
步骤2：乙基5-((4-氯-N-环己基甲基)-3-氟苯基)磺酰胺)-3-甲基苯并呋喃-2-甲酸酯以乙基5-((4-氯-3-氟苯基)磺酰胺)-3-甲基苯并呋喃-2-甲酸酯(0.5g,1.26mmol)为原料，按照实施例10步骤1的方法与溴甲基环己胺(0.45g,2.51mmol)反应得0.32g(产率50.1％)
1H NMR(300MHz,DMSO-d6)δ7.64-7.74(m,2H,Ar-H),7.48-7.62(m,2H,Ar-H),6.41-6.51(m,1H,Ar-H),4.38(q,2H,-CH 2CH3),3.08(d,2H,-CH 2CH),2.53(s,3H Ar-CH3),1.42-1.89(m,6H,环己基-H),1.10-1.42(m,8H,环己基-H).
EI-MS:m/z 507.1
实施例24
乙基3-甲基-5-(N-(4-硝基苯基)胺磺酰基)苯并呋喃-2-甲酸酯
Figure PCTCN2015095735-appb-000050
步骤1：乙基3-甲基苯并呋喃-2-甲酸酯
将1-(2-羟基苯基)乙酮(2.7g，19.83mmol)及溴乙酸乙酯(4.97g,29.8mmol),碳酸钾(5.48g,39.7mmol)加入N,N-二甲基甲酰胺(20ml)中加热至160度3h后，倒入水中，析出固体(3.1g,产率76.5％)
1H-NMR(300MHz,DMSO):δ7.87(d,1H，Ar-H),7.67(d,1H，Ar-H)7.36(d,1H)4.34(q,2H,-CH 2CH3),2.53(s,3H，Ar-CH3),1.33(t,3H,-CH2CH 3)EI-MS:m/z 204.1
步骤2：乙基5-(氯磺酰)-3-甲基苯并呋喃-2-甲酸酯
将乙基3-甲基苯并呋喃-2-甲酸酯(1.50g.7.34mmol)与氯磺酸(1.48g,14.69mmol)室温反应过夜，反应完毕后加水萃取，有机层减压蒸馏去除溶剂，得1.32g(产率为59.36％)乙基5-(氯磺酰)-3-甲基苯并呋喃-2-甲酸酯
1H-NMR(300MHz,DMSO):δ7.97(s,1H，Ar-H)7.58-7.77(m,2H，Ar-H),4.28(q,2H,-CH 2CH3),2.55(s,3H),1.29(t,3H,-CH2CH 3)EI-MS:m/z 302.0
步骤3：乙基3-甲基-5-(N-(4-硝基苯基)胺磺酰基)苯并呋喃-2-甲酸酯
将苯胺1ml溶于20ml无水二氯甲烷中，加入碳酸钾(0.23g,1.65mmol)，滴加溶于10ml的乙基5-(氯磺酰)-3-甲基苯并呋喃-2-甲酸酯(0.5g,1.65mmol)，室温搅拌过夜,反应完毕后，减压蒸去溶剂，粗品通过柱层析分离。得到0.32g(产率53.9％)
1H-NMR(300MHz,DMSO):δ10.34(s,1H,NH)8.21(s,1H，Ar-H)7.85(d,2H，Ar-H),7.00-7.23(m,4H,Ar-H)4.36(q,2H,-CH 2CH3),2.54(s,3H,Ar-CH 3),1.32(t,3H,-CH2CH 3)EI-MS:m/z 404.1
实施例25
乙基5-(N-环丁基胺磺酰基)-3-甲基苯并呋喃-2-羧酸酯
Figure PCTCN2015095735-appb-000051
按照实施例24步骤3所用方法将胺替换成环丁胺1ml，其余条件均一致。得到固体0.41g(产率73.4％)
1H-NMR(300MHz,DMSO):δ7.96(s,1H，Ar-H)7.54-7.76(m,2H，Ar-H),4.29(q,2H,-CH 2CH3),3.02(m,1H,环丁基-H)2.48(s,3H,Ar-CH 3),2.01-2.31(m,6H,环丁基-H)1.29(t,3H,-CH2CH 3)EI-MS:m/z 337.1
实施例26
5-(N-环丁基-N-(4-甲氧基苯基)胺磺酰基)-3-甲基苯并呋喃-2-甲酸
Figure PCTCN2015095735-appb-000052
步骤1：乙基5-(N-环丁基-N-(4-甲氧基苯基)胺磺酰基)-3-甲基苯并呋喃-2-甲酸酯
实施例25产物乙基5-(N-环丁基胺磺酰基)-3-甲基苯并呋喃-2-羧酸酯(0.5g,1.48mmol)溶于20ml二氯甲烷中，加入4-甲氧基溴苄(0.59g,2.96mmol)，碳酸钾(0.41g,2.96mmol)，加热至回流过夜。柱层析分离得到0.47g(产率69.2％)
1H-NMR(300MHz,DMSO):δ8.01(s,1H，Ar-H)7.86-7.96(m,2H，Ar-H),7.26(d,2H,Ar-H),6.92(d,2H,Ar-H),4.32(q,2H,-CH 2CH3),3.02(m,1H,环丁基-H)2.55(s,3H,Ar-CH 3),2.11-2.39(m,6H,环丁基-H),1.28(t,3H,-CH2CH 3)EI-MS:m/z 457.2
步骤2：5-(N-环丁基-N-(4-甲氧基苯基)胺磺酰基)-3-甲基苯并呋喃-2-甲酸
将乙基5-(N-环丁基-N-(4-甲氧基苯基)胺磺酰基)-3-甲基苯并呋喃-2-甲酸酯(0.2g,0.44mmol)溶于NaOH/乙醇混合溶液中，加热至回流，反应1h。调节PH至酸性。加二氯甲烷萃取，减压蒸馏去除溶剂得到0.11g(产率58.6％)
1H-NMR(300MHz,DMSO):δ13.05(brs,1H,-COOH),8.06(s,1H，Ar-H)7.82-7.94(m,2H，Ar-H),7.24(d,2H,Ar-H),6.93(d,2H,Ar-H),,3.02(m,1H,环丁基-H)2.51(s,3H,Ar-CH 3),2.10-2.38(m,6H,环丁基-H)EI-MS:m/z 429.1
实施例27
5-(N-环丁基-N-(4-甲氧基苄基)胺磺酰基)-N-(2-(二甲氨基)乙基)-3-甲基苯并呋喃-2-甲酰胺
Figure PCTCN2015095735-appb-000053
将实施例26产物5-(N-环丁基-N-(4-甲氧基苯基)胺磺酰基)-3-甲基苯并呋喃-2-甲酸(0.3g,0.70mmol)溶于二氯亚砜(10ml)中，加热至回流，反应1h后，减压蒸除溶剂，加入溶于无水二氯甲烷(10ml)的N,N-二甲基乙二胺(1ml)，反应过夜，柱层析分离得到0.12g固体(产率34.38％)
1H-NMR(300MHz,DMSO):δ8.06(s,1H，Ar-H)7.82-7.94(m,2H，Ar-H),7.25(d,2H,Ar-H),6.93(d,2H,Ar-H),,3.02(m,1H,环丁基-H)2.48-2.57(m,5H,Ar-CH 3,-CH2CH2 N(CH3)2),2.10-2.38(m,12H,环丁基-H,-N(CH 3)2)EI-MS:m/z 499.2
实施例28
2-苯甲酰-3-甲基-N-苯基苯并呋喃-5-磺酰胺
Figure PCTCN2015095735-appb-000054
步骤1：(3-甲基苯并呋喃-2-基)(苯基)甲酮
将1-(2-羟基苯基)乙酮(3.2g，23.50mmol)及溴代苯乙酮(5.61g,28.2mmol),碳酸钾(6.50g,47.01mmol)加入N,N-二甲基甲酰胺(20ml)中加热至120度2h后，倒入水中，析出固体(4.4g,产率79.3％)
1H-NMR(300MHz,DMSO):δ7.86-7.92(m,3H，Ar-H)7.65-7.90(m,4H，Ar-H),7.23-7.43(m,2H,Ar-H)2.54(s,3H,Ar-CH 3)EI-MS:m/z 236.1
步骤2：2-苯甲酰-3-甲基苯并呋喃-5-磺酰氯
按照实施例24步骤2的合成方法将反应物替换为(3-甲基苯并呋喃-2-基)(苯基)甲酮(2.2g)，得到固体1.3g(产率41.7％)
1H-NMR(300MHz,DMSO):δ8.17(s,1H,Ar-H),7.86-7.91(m,4H，Ar-H)7.65-7.83(m,3H，Ar-H)2.55(s,3H,Ar-CH 3)EI-MS:m/z 334.0
步骤3：2-苯甲酰-3-甲基-N-苯基苯并呋喃-5-磺酰胺
按照实施例24步骤3的反应条件，将反应物替换为2-苯甲酰-3-甲基苯并呋喃-5-磺酰氯(1.3g，3.88mmol),得到最终产物1.2g(产率78.9％)
1H-NMR(300MHz,DMSO):δ9.98(s,1H,-NH),8.16(s,1H,Ar-H),7.86-7.94(m,4H，Ar-H)7.67-7.80(m,3H,Ar-H)7.20-7.25(m,2H,Ar-H),6.83-6.92(m,2H,Ar-H)2.55(s,3H,Ar-CH 3)EI-MS:m/z 391.1
实施例29
甲基2-甲基-5-(N-苯基胺磺酰基)苯并呋喃-3-甲酸酯
Figure PCTCN2015095735-appb-000055
步骤1：甲基2-甲基苯并呋喃-3-甲酯
将1-溴-2-碘苯(1.0g.3.53mmol)、乙酰乙酸甲酯(0.82g,7.07mmol)、碳酸钾(0.97g,7.07mmol)、碘化亚铜(0.67g,3.53mmol)加入无水四氢呋喃(15ml)中100度加热封管过夜，滤除碳酸钾，柱层析分离得到0.36g(产率53.5％)
1H NMR(300MHz,DMSO)δ7.62-7.71(m,1H，Ar-H),7.49-7.55(m,1H，Ar-H),7.28-7.37(m,1H，Ar-H),7.22-7.29(m,1H，Ar-H),3.95(s,3H,-OCH 3),2.74(s,3H Ar-CH 3).EI-MS:m/z 190.1
步骤2：甲基5-(氯磺酰基)-2-甲基苯并呋喃-3-甲酸酯
按照实施例24步骤2的合成方法，反应物替换为甲基2-甲基苯并呋喃-3-甲酯(0.36g,1.89mmol),最终得到固体(0.23g,产率42.1％)
1H NMR(300MHz,DMSO)δ8.09-8.15(m,1H,Ar-H),7.68-7.76(m,1H,Ar-H),7.65(d,1H,Ar-H),3.95(s,3H,-OCH 3),2.75(s,3H Ar-CH 3).EI-MS:m/z 288.0
步骤3：甲基2-甲基-5-(N-苯基胺磺酰基)苯并呋喃-3-甲酸酯
将甲基5-(氯磺酰基)-2-甲基苯并呋喃-3-甲酯(0.23g，0.80mmol)按照实施例23步骤3条件反应，最终得到固体0.13g(产率47.25％)
1H-NMR(300MHz,DMSO):δ8.32(s,1H,Ar-H),7.70-7.78(m,2H，Ar-H),7.25-7.32(m,2H,Ar-H),7.04-7.18(m,3H,Ar-H)3.97(s,3H,-OCH3)，2.75(s,3H,Ar-CH 3)EI-MS:m/z 345.1
实施例30
N-(2-(二甲氨基)乙基)-2-甲基-5-(N-苯基磺酰胺)苯并呋喃-3-甲酰胺
Figure PCTCN2015095735-appb-000056
步骤1：将实施例29最终产物甲基2-甲基-5-(N-苯基胺磺酰基)苯并呋喃-3-甲酸酯(0.5g,1.45mmol)按照实施例26步骤2的方法得到产物0.42g(产率87.6％)
1H-NMR(300MHz,DMSO):δ13.01(brs,1H,-COOH),10.02(s,1H,NH),8.31(s,1H,Ar-H),7.79–7.70(m,2H，Ar-H),7.24-7.33(m,2H,Ar-H),7.02-7.17(m,3H,Ar-H),2.78(s,3H,Ar-CH 3)EI-MS:m/z331.1
步骤2：将2-甲基-5--(N-苯基胺磺酰基)苯并呋喃-3-甲酸(0.4g,1.21mmol)按照实施例27步骤1的方法得到目标产物0.31g产率64.0％
1H NMR(300MHz,DMSO):δ10.04(s,1H,NH),8.31(s,1H,Ar-H),7.79-7.70(m,2H，Ar-H),7.24-7.33(m,2H,Ar-H),7.02-7.17(m,3H,Ar-H),3.54(t,2H,-CH2 CH2N(CH3)2),2.43-2.58(m,5H,-CH2CH 2N(CH3)2,Ar-CH 3),2.20(s,6H,-N(CH3)2).EI-MS:m/z 401.1
实施例31
2-甲基-N-苯基-3-(哌嗪-1-甲酰基)苯并呋喃-5-磺酰胺
Figure PCTCN2015095735-appb-000057
将2-甲基-5--(N-苯基胺磺酰基)苯并呋喃-3-甲酸(0.4g,1.21mmol)按照实施例13步骤2的方法得到目标产物0.33g，产率65.7％
1H NMR(300MHz,DMSO):δ10.02(s,1H,NH),8.11–8.07(m,1H,Ar-H),7.92-8.01(m,1H,Ar-H),7.83–7.72(m,3H，Ar-H)7.24-7.33(m,2H,Ar-H),6.92-7.17(m,3H,Ar-H),3.48(t,4H,
Figure PCTCN2015095735-appb-000058
),2.81(t,4H,
Figure PCTCN2015095735-appb-000059
),2.50(s,3H,Ar-CH3),EI-MS:m/z 399.1
实施例32
5-(N-(4-(叔丁基)苄基)-N-苯基磺酰胺)-N-异丙基-2-甲基苯并呋喃-3-甲酰胺
Figure PCTCN2015095735-appb-000060
步骤1：N-异丙基-2-甲基-5-(N-苯基磺酰胺)苯并呋喃-3-甲酰胺
将2-甲基-5--(N-苯基胺磺酰基)苯并呋喃-3-甲酸(0.5g,1.51mmol)按照实施例27步骤1的方法，与异丙胺(1ml)反应得0.21g(产率37.4％)
1H NMR(300MHz,DMSO)δ8.28(s,1H，NH),7.95-8.04(m,1H,Ar-H),7.83(dd,2H,Ar-H),7.12–7.26(m,4H,Ar-H),6.76-6.89(m,1H.Ar-H),3.84-4.05(m,1H,-CH(CH3)2),2.58(s,3H,Ar-CH3),1.10(d,6H,-CH(CH3)2 )).
EI-MS:m/z 372.1
步骤2：5-(N-(4-(叔丁基)苄基)-N-苯基磺酰胺)-N-异丙基-2-甲基苯并呋喃-3-甲酰胺
将N-异丙基-2-甲基-5-(N-苯基磺酰胺)苯并呋喃-3-甲酰胺(0.3g,0.81mmol)按照实施例25步骤1方法与对叔丁基溴苄反应得0.32g固体(产率76.6％)
1H NMR(300MHz,DMSO-d6)δ7.99(dd,1H Ar-H),7.79-7.91(m,2H Ar-H),7.37(d,2H Ar-H),7.17-7.31(m,4H Ar-H),6.72-6.85(m,1H Ar-H),6.59-6.67(m,2H Ar-H),5.00(s,2H,PhCH 2),2.60(s,3H,Ar-CH3),1.31(s,9H,叔丁基-H),1.10(d,6H,-CH(CH3)2 )).EI-MS:m/z 518.2
实施例33
N-(4-(3-乙酰基-2甲基苯并呋喃-5-磺酰基)苯基)乙酰胺
Figure PCTCN2015095735-appb-000061
步骤1：1-(2-甲基苯并呋喃-3-基)乙酮
按照实施例29的步骤1的方法，将乙酰乙酸甲酯替换为2,4-戊二酮(0.71g,7.07mmol),得到产物0.22g(产率35.7％)
1H-NMR(300MHz,DMSO):δ7.88-7.91(d,1H，Ar-H),7.64-7.68(m,1H，Ar-H)7.32-7.38(m,2H,Ar-H)2.86(s,3H,Ar-CH 3),2.58(s,3H,-COCH 3),EI-MS:m/z 174.1
步骤2：3-乙酰基-2-甲基苯并呋喃-5-磺酰氯
按照实施例25的步骤2的方法，以1-(2-甲基苯并呋喃-3-基)乙酮为原料(0.2g,1.15mmol)，得到产物0.18g(产率57.5％)
1H-NMR(300MHz,DMSO):δ8.18(s,1H,Ar-H),7.87-7.89(m,2H，Ar-H),2.85(s,3H,Ar-CH 3),2.50(s,3H,-COCH 3),EI-MS:m/z 272.0
步骤3:N-(4-(3-乙酰基-2甲基苯并呋喃-5-磺酰基)苯基)乙酰胺
按照实施例24步骤3方法，以3-乙酰基-2-甲基苯并呋喃-5-磺酰氯为原料(0.18g,0.66mmol)，得到最终产物0.17g(产率78.2％)
1H-NMR(300MHz,DMSO):δ11.04(s,1H,-CONH)10.12(s,1H,NH)，8.16(s,1H,Ar-H),7.87-7.94(m,2H，Ar-H),7.21-7.36(m,2H,Ar-H),6.81-6.93(m,2H,Ar-H),2.87(s,3H,Ar-CH 3),2.51(s,3H,-COCH 3),2.01(s,3H,CH 3CONH)EI-MS:m/z 386.1

Claims (10)

  1. 通式(I)的化合物或其药学上可接受的盐：
    Figure PCTCN2015095735-appb-100001
    其中R1代表氢、C1-C3烷基、羧基、C1-C3的氨基甲酰基、
    Figure PCTCN2015095735-appb-100002
    Figure PCTCN2015095735-appb-100003
    R2代表氢、C1-C3烷基、羧基或
    Figure PCTCN2015095735-appb-100004
    R5代表C1-C4烷基、C1-C4烷氧基、苯基、吗啉基、哌啶基、哌嗪基、哌嗪酮基、N-甲基哌嗪基、
    Figure PCTCN2015095735-appb-100005
    Figure PCTCN2015095735-appb-100006
    Figure PCTCN2015095735-appb-100007
    NR6R7或-NH-(CH)2m-NR6R7其中m是2或3；R6、R7各自独立地代表氢、C1-C4烷基、乙酰基或苯基，或者R6和R7连接成四到六元杂环；
    R3代表C3-C7的环烷基或
    Figure PCTCN2015095735-appb-100008
    R8表示单或双取代的H、卤素、硝基、羧基、羟基、氰基、三氟甲基、C1-C4烷基、甲氧基、乙酰氨基、C1-C3的烷基胺；X代表键、-CH2-、
    Figure PCTCN2015095735-appb-100009
    R4代表氢、C1-C4烷基、C3-C7的环烷基取代的亚甲基或
    Figure PCTCN2015095735-appb-100010
    R9是单或双取代的H、卤素、羧基、羟基、氰基、C1-C4烷基或甲氧基；
    Y代表键或
    Figure PCTCN2015095735-appb-100011
  2. 权利要求1的化合物或其药学上可接受的盐，其中R1代表C1-C3烷基、羧基、
    Figure PCTCN2015095735-appb-100012
    Figure PCTCN2015095735-appb-100013
  3. 权利要求1的化合物或其药学上可接受的盐，其中R2代表羧基或
    Figure PCTCN2015095735-appb-100014
    R5代表哌嗪基、吗啉基、哌嗪酮基、N-甲基哌嗪基、
    Figure PCTCN2015095735-appb-100015
    Figure PCTCN2015095735-appb-100016
  4. 权利要求1的化合物或其药学上可接受的盐，其中R3代表
    Figure PCTCN2015095735-appb-100017
    X代表-CH2-或
    Figure PCTCN2015095735-appb-100018
    R8代表单或双取代的卤素、三氟甲基、C1-C4烷基、甲氧基。
  5. 权利要求1的化合物或其药学上可接受的盐，其中R4代表氢或
    Figure PCTCN2015095735-appb-100019
    R9代表单或双取代的卤素、氰基或甲氧基。
  6. 权利要求1的化合物的制备方法，当Y代表
    Figure PCTCN2015095735-appb-100020
    时，包括：
    Figure PCTCN2015095735-appb-100021
    其中R1、R2、R3、R4、Y的定义同权利要求1。
  7. 权利要求1的化合物的制备方法，当Y代表键时，包括：
    Figure PCTCN2015095735-appb-100022
    其中R1、R2、R3、R4、Y的定义同权利要求1。
  8. 一种药物组合物，其中含有权利要求1的化合物或其药学上可接受的盐及药学上可接受的载体。
  9. 权利要求1的化合物或其药学上可接受的盐用于制备HIF1α抑制剂的用途。
  10. 权利要求1的化合物或其药学上可接受的盐用于制备抗肿瘤药物的用途。
PCT/CN2015/095735 2015-09-14 2015-11-27 苯并呋喃类衍生物、其制备方法及其治疗作用 Ceased WO2017045271A1 (zh)

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