WO2019085808A1 - 一种含三氮唑的ido抑制剂、其制备方法及其医药用途 - Google Patents

一种含三氮唑的ido抑制剂、其制备方法及其医药用途 Download PDF

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WO2019085808A1
WO2019085808A1 PCT/CN2018/111791 CN2018111791W WO2019085808A1 WO 2019085808 A1 WO2019085808 A1 WO 2019085808A1 CN 2018111791 W CN2018111791 W CN 2018111791W WO 2019085808 A1 WO2019085808 A1 WO 2019085808A1
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acid
compound
pharmaceutically acceptable
acceptable salt
ethyl
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French (fr)
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徐云根
朱启华
贺新
何广卫
储昭兴
何光超
王俊杰
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中国药科大学
合肥医工医药有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • 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
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • the invention belongs to the field of medicinal chemistry, and in particular relates to a class of IDO inhibitors (I) containing triazole groups, including preparation methods thereof, and pharmaceutical compositions containing the same and their use in the treatment of malignant tumors.
  • I IDO inhibitors
  • Cancer is the leading cause of morbidity and mortality worldwide. According to the latest data, more than 1.6 million patients were diagnosed with cancer in the United States in 2016, and nearly 600,000 people died from cancer. In 2015, the number of new cancer patients reached 4.3 million, and the number of cancer deaths reached 2.8 million people. The high incidence of cancer and high mortality make people talk about "cancer" discoloration in their lives. Especially with the advent of the problem of population aging, this problem will become more prominent. Therefore, it is extremely urgent to find new cancer treatment methods. After entering the 21st century, with the deepening of oncology and immunology research, the human immune system has become a hot field in the development of new drugs. In 2013, Science magazine ranked tumor immunotherapy as the top of the top ten scientific breakthroughs.
  • IDO Indoleamine 2,3-dioxygenase
  • IDO1 is an important enzyme that decomposes tryptophan.
  • IDO2 is an important enzyme that decomposes tryptophan.
  • IDO1 is expressed in a variety of tumor cells and mediates tumor-induced immunosuppression. This enzyme can locally degrade tryptophan, inactivate the tumor surveillance of the immune system and prevent tumor rejection.
  • IDO affects immunosuppressive molecules associated with the body's immune system in a number of ways, ultimately leading to immune escape of tumor cells, which is further transformed into cancer. Therefore, the role of IDO in tumor immune escape has been paid more and more attention, making IDO the most important small molecular regulation target for anti-tumor immunotherapy.
  • the invention discloses a novel antitumor candidate compound with novel structure, high activity and small side effects. These compounds have good anti-tumor activity, and these compounds can also be combined with other anti-tumor drugs to improve the efficacy of existing anti-tumor drugs and reduce the dose and toxicity.
  • the present invention discloses a compound of the formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention discloses a compound of the formula (I):
  • R 1 is a C 3 -C 6 cycloalkyl group, -COOCH 3 , -CONH 2 , -C(CH 3 ) 2 NH 2 , -CH 2 N(CH 3 ) 2 , -CH 2 N(CH 2 CH 3 ) 2 , among them
  • X CH 2 or O
  • R 2 is H, F, Cl, Br, CH 3 , OH, NH 2 , -N(CH 3 ) 2 or -N(CH 2 CH 3 ) 2 ;
  • R 3 is H or CH 3 ;
  • R 4 is H, CH 3 , CH 2 CH 3 , CH 2 OH, CH 2 CH 2 OH, CH 2 CH 2 CH 2 OH, CH 2 CONH 2 , CH 2 CONHCH 3 , CH 2 COOH or CH 2 COOCH 3 ;
  • R 5 is optionally substituted H, F, Cl, Br, CH 3 , CN, NO 2 , OH, OCH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , COOH, COOCH 3 , COOCH 2 CH 3 , CONH 2 or CONHCH 3 .
  • R 1 preferably represents cyclopropyl, 4-methoxyphenyl, 3-aminophenyl, CONH 2 , COOCH 3 ,
  • m 0 to 2
  • X CH 2 or O
  • R 2 is preferably H, CH 3 , OH or NH 2
  • R 3 is H or CH 3
  • R 4 is preferably H, CH 3 , CH 2 CH 2 OH , CH 2 CH 2 CH 2 OH, CH 2 CONH 2 or CH 2 CONHCH 3 .
  • Preferred partial compounds of the invention are as follows:
  • the compounds of the formula of the invention are preferably prepared by the following methods:
  • the process for preparing compound III by hydrolysis of compound II is sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate or sodium acetate, preferably sodium hydroxide.
  • the solvent to be used is tetrahydrofuran, 1,4-dioxane, acetonitrile or a mixed solvent of N,N-dimethylformamide and water, and a mixed solvent of tetrahydrofuran and water is preferred.
  • the catalyst used is copper sulfate, copper chloride, copper bromide, cuprous chloride, cuprous bromide, cuprous iodide or copper. Powder, preferably cuprous bromide.
  • the solvent used is tetrahydrofuran, 1,4-dioxane, acetonitrile, ethanol, methanol, ethylene glycol dimethyl ether, dichloromethane, N,N-dimethylformamide or N,N-dimethyl
  • the amide or a mixed solvent of the above solvent and water is preferably a mixed solvent of acetonitrile and water.
  • the compounds of the invention are preferably prepared by the following methods:
  • the catalyst used is copper sulfate, copper chloride, copper bromide, cuprous chloride, cuprous bromide, cuprous iodide or copper. Powder, preferably cuprous bromide.
  • the solvent used is tetrahydrofuran, 1,4-dioxane, acetonitrile, ethanol, methanol, ethylene glycol dimethyl ether, dichloromethane, N,N-dimethylformamide or N,N-dimethyl
  • the amide or a mixed solvent of the above solvent and water is preferably a mixed solvent of acetonitrile and water.
  • the process for preparing compound I by hydrolysis of compound V is sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate or sodium acetate, preferably sodium hydroxide.
  • the solvent to be used is tetrahydrofuran, 1,4-dioxane, acetonitrile or a mixed solvent of N,N-dimethylformamide and water, and a mixed solvent of tetrahydrofuran and water is preferred.
  • the reactant (A) is hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, horse
  • the solvent is preferably methanol, ethanol, dichloromethane, acetone, ethyl acetate, toluene or tetrahydrofuran, or a mixed solvent of any of several.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of the present invention or a salt thereof and a pharmaceutically acceptable carrier.
  • 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 can be administered in a clinical manner by oral administration or injection.
  • a human dosage will range from 1 mg to 1000 mg per day. Dosages outside the range may also vary depending on the dosage form and the severity of the disease.
  • IDO1 molecular sieving activity inhibition model positive control drug Epacadostat detecting inhibition and IC 50 values of inhibition ratio on this model, similar to the results reported in many documents, described successful assay development.
  • the IDO enzyme catalyzes the oxidative cleavage of pyrrole on tryptophan to produce N'-formylkynurenine.
  • 40 nM IDO enzyme and 900 ⁇ M L-tryptophan were mixed at room temperature, and added to the reaction buffer (20 mM ascorbate, 3.5 ⁇ M methylene blue and 0.2 mg/mL catalase in 50 mM potassium phosphate buffer pH 6.5) at room temperature.
  • Activity percentage (%) (OD value of the delivery opening - OD value of background) / (OD value of the background control wells -OD value) ⁇ 100%, and then fit IC 50 values calculated using Prism GraphPad sofeware software.
  • the inhibitory activity of the target compound against IDO1 was stronger than that of the positive control drug Epacadostat at a concentration of 100 nM, and the inhibitory activities of the compounds I-3 and I-17 were significantly stronger than those of the positive control drug Epacadostat.
  • the experimental results showed that the IC 50 of the tested compound against IDO1 was smaller than that of the positive control drug Epacadostat, indicating that the compound had strong inhibitory activity against IDO1, and the inhibitory activity of compound I-17 was the strongest; the IC 50 of the compound to IDO2 was less than The positive control drug Epacadostat showed that the compound had strong inhibitory activity against IDO2, and the compound I-17 had the strongest inhibitory activity.
  • the compound (I) of the present invention has not only a strong inhibitory activity against IDO1 but also a good inhibitory activity against IDO2 with respect to the positive control drug Epacadostat, and therefore, the compound (I) of the present invention inhibits IDO1 and The balance of IDO2 activity was better than that of the positive control drug Epacadostat.
  • HeLa cells were added to each well of a 96-well plate. After overnight growth, human IFN- ⁇ (final concentration 10-50 ng/mL) was added to each well, and different concentrations of the drug containing 15 ⁇ g/mL L-tryptophan were added in a gradient to make a final volume of 200 ⁇ L per well. After 48 hours, 140 ⁇ L of the supernatant was taken, 10 ⁇ L of trichloroacetic acid was added, and the mixture was incubated at 50 ° C for 30 minutes. The resulting mixture was centrifuged at 2500 rpm for 10 minutes.
  • test compound IC of INF- ⁇ induced IDO1 Hela cells 50 is less than the positive control Epacadostat, it indicates that the inhibitory activity of the compounds have a strong IDO1.
  • the CT-26 colon cancer cells grown to log phase were routinely cultured, routinely digested under sterile conditions, and the cells were collected, and the cell concentration was adjusted to 5 ⁇ 10 6 with sterile physiological saline.
  • a 1 mL syringe was used to inoculate the right subcutaneous skin of BALB/C mice after alcohol disinfection, each 0.2 mL, and the whole process of inoculation was completed within 1 hour.
  • the tumor volume was about 100 mm 3 (about 7-14 days), and BALB/C nude mice were randomly divided into 4 groups, 10 in each group.
  • Each group was administered according to the experimental protocol set in Table 4, which was model control group, compound I-3 group, compound I-17 group, and positive control group Epacadostat twice daily for 28 days.
  • the body weight of the rats and the volume of the transplanted tumor were measured for 3 days. After 30 days, the mice were sacrificed and the tumor pieces were surgically removed and weighed.
  • the experimental results are shown in Figure 1.
  • Figure 1 shows the inhibitory effect of compound I-3 and compound I-17 on the growth of mouse colon cancer cell line CT-26 xenograft tumor.
  • the solvent was evaporated under reduced pressure at 30 ° C or less, and 20 mL of water and ethyl acetate were added. (75 mL ⁇ 3) was extracted three times, and water (50 mL ⁇ 2) was washed twice, washed with brine (50 mL) and evaporated to dryness.
  • I-17 (4.84 g, 10.0 mmol) was added to 20 ml of acetone and stirred to dissolve.
  • a saturated solution of ethyl acetate in hydrogen chloride was added dropwise to an ice-water bath to pH 1-2, and a large amount of solid was precipitated and washed with acetone to give 5.05 g of a white solid.

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Abstract

本发明属于药物化学领域，具体涉及一类含三氮唑基团的IDO抑制剂(I)，它们的制备方法，以及含有这些化合物的药物组合物，药效学试验证明，本发明的化合物具有IDO抑制剂活性，具有治疗恶性肿瘤的功效。

Description

一种含三氮唑的IDO抑制剂、其制备方法及其医药用途 技术领域
本发明属于药物化学领域，具体涉及一类含三氮唑基团的IDO抑制剂(I)，包括其制备方法，以及含有这些化合物的药物组合物及其在治疗恶性肿瘤方面的用途。
背景技术
癌症是全球发病与死亡的主要原因。最新的数据显示，2016年美国被诊断为癌症的患者达到了160多万人，而由于癌症死亡的患者接近60万人；我国2015年新增癌症患者达到了430万，因癌症死亡的人数达到了280万人。癌症的高发率和高死亡率让人们在生活中谈“癌”色变。特别是随着人口老年化问题的到来，这一问题将会更加突出，因此，寻找新的癌症治疗方法迫在眉睫。进入21世纪以后，随着肿瘤学与免疫学研究的不断深入，人体免疫系统已成为新药研发的热门领域。2013年《科学》杂志将肿瘤免疫治疗列为十大科学突破的首位。
吲哚胺-2,3-双加氧酶(indoleamine2,3-dioxygenase,IDO)是一种分解色氨酸(tryptophan)的重要酶，IDO存在三种亚型，分别为IDO1、IDO2和TDO。IDO在多种肿瘤细胞中表达，介导肿瘤诱导的免疫抑制。这种酶可局部降解色氨酸，钝化免疫系统的肿瘤监视作用及防止肿瘤排斥。IDO通过多种途径影响与机体免疫系统相关的免疫抑制性分子，最终导致肿瘤细胞的免疫逃逸，进一步转化成癌症。因此，IDO在肿瘤免疫逃逸方面的作用越来越被重视，使得IDO成为抗肿瘤免疫疗法最重要的小分子调控靶点。
发明内容
本发明公开了结构新颖、活性高以及副作用小的一类抗肿瘤候选化合物。这些化合物具有良好的抗肿瘤活性，同时这些化合物还可以与其他抗肿瘤药物联用，从而达到提高现有抗肿瘤药物疗效并降低剂量和毒性的作用。
本发明公开了通式(I)的化合物或其药学上可接受的盐。
本发明公开了通式(I)的化合物：
Figure PCTCN2018111791-appb-000001
其中R 1为C 3～C 6的环烷基、-COOCH 3、-CONH 2、-C(CH 3) 2NH 2、-CH 2N(CH 3) 2、-CH 2N(CH 2CH 3) 2、
Figure PCTCN2018111791-appb-000002
Figure PCTCN2018111791-appb-000003
其中
m＝0～3；
X＝CH 2或O；
R 2为H、F、Cl、Br、CH 3、OH、NH 2、-N(CH 3) 2或-N(CH 2CH 3) 2；
R 3为H或CH 3；
R 4为H、CH 3、CH 2CH 3、CH 2OH、CH 2CH 2OH、CH 2CH 2CH 2OH、CH 2CONH 2、CH 2CONHCH 3、 CH 2COOH或CH 2COOCH 3；
R 5为任意取代的H、F、Cl、Br、CH 3、CN、NO 2、OH、OCH 3、NH 2、NHCH 3、N(CH 3) 2、COOH、COOCH 3、COOCH 2CH 3、CONH 2或CONHCH 3。
其中R 1优选代表环丙基、4-甲氧基苯基、3-氨基苯基、CONH 2、COOCH 3、
Figure PCTCN2018111791-appb-000004
Figure PCTCN2018111791-appb-000005
其中m＝0～2，X＝CH 2或O，R 2优选为H、CH 3、OH或NH 2，R 3为H或CH 3，R 4优选为H、CH 3、CH 2CH 2OH、CH 2CH 2CH 2OH、CH 2CONH 2或CH 2CONHCH 3。
R 1更优选代表CONH 2或
Figure PCTCN2018111791-appb-000006
其中m优选＝0～1，X＝CH 2或O，R 2更优选为H、CH 3、OH或NH 2，R 3为H或CH 3，R 4更优选为H、CH 3、CH 2CH 2OH、CH 2CH 2CH 2OH或CH 2CONH 2。
本发明优选的部分化合物如下：
Figure PCTCN2018111791-appb-000007
Figure PCTCN2018111791-appb-000008
Figure PCTCN2018111791-appb-000009
Figure PCTCN2018111791-appb-000010
Figure PCTCN2018111791-appb-000011
本发明通式化合物优选下列方法制备：
Figure PCTCN2018111791-appb-000012
其中：
由化合物II经水解制备化合物III的过程，所用的碱为氢氧化钠、氢氧化钾、碳酸钾、碳酸钠或乙酸钠，优选氢氧化钠。所用的溶剂为四氢呋喃、1,4-二氧六环、乙腈或N,N-二甲基甲酰胺与水的混合溶剂，优选四氢呋喃与水的混合溶剂。
由化合物III与相应的炔衍生物IV通过Click反应制备化合物I的过程，所用的催化剂为硫酸铜、氯化铜、溴化铜、氯化亚铜、溴化亚铜、碘化亚铜或铜粉，优选溴化亚铜。所用的溶剂为四氢呋喃、1,4-二氧六环、乙腈、乙醇、甲醇、乙二醇二甲醚、二氯甲烷、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺、或上述溶剂与水组成的混合溶剂，优选乙腈与水的混合溶剂。
本发明的化合物优选下列方法制备：
Figure PCTCN2018111791-appb-000013
其中：
由化合物II与相应的炔衍生物IV通过Click反应制备化合物V的过程，所用的催化剂为硫酸铜、氯化铜、溴化铜、氯化亚铜、溴化亚铜、碘化亚铜或铜粉，优选溴化亚铜。所用的溶剂为四氢呋喃、1,4-二氧六环、乙腈、乙醇、甲醇、乙二醇二甲醚、二氯甲烷、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺、或上述溶剂与水组成的混合溶剂，优选乙腈与水的混合溶剂。
由化合物V经水解制备化合物I的过程，所用的碱为氢氧化钠、氢氧化钾、碳酸钾、碳酸钠或乙酸钠，优选氢氧化钠。所用的溶剂为四氢呋喃、1,4-二氧六环、乙腈或N,N-二甲基甲酰胺与水的混合溶剂，优选四氢呋喃与水的混合溶剂。
由化合物I经成盐制备化合物I·A的过程，反应物(A)为氯化氢、溴化氢、硫酸、磷酸、碳酸、草酸、柠檬酸、琥珀酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸或阿魏酸；溶剂优选为甲醇、乙醇、二氯甲烷、丙酮、乙酸乙酯、甲苯或四氢呋喃，或任意几种的混合溶剂。
本发明的另一目的在于提供一种药物组合物，其包括药物有效剂量的本发明的化合物或其盐和药学上可接受的载体。
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。
本发明所述的化合物在临床上的给药方式可以采用口服、注射等方式。
一般地，本发明的化合物用于治疗时，人用剂量范围为1mg～1000mg/天。也可根据剂型的不同和疾病严重程度，使用剂量超出该范围。
本发明部分化合物的药理学实验及结果如下：
(1)检测部分目标化合物在酶水平抑制IDO1的活性
实验方法
建立IDO1酶活性抑制分子筛选模型，检测阳性对照药Epacadostat在此模型上的抑制IC 50值及抑制率，结果与多篇文献报道相近，说明筛选模型构建成功。IDO酶可以催化色氨酸上的吡咯环氧化裂解产生N’-甲酰犬尿氨酸(N’-formylkynurenine)。在室温环境下，将40nM的IDO酶及900μM的L-色氨酸混合，并加入反应缓冲液(20mM ascorbate,3.5μM methylene blue and 0.2mg/mL catalase in 50mM potassium phosphate buffer pH 6.5)，在室温反应3小时，然后在酶标仪上进行紫外测定，检测波长为321nm。酶活性百分率(％)＝(OD值给药孔－ OD值本底)/(OD值对照孔－OD值本底)×100％，然后用Prism GraphPad sofeware软件拟合计算IC 50值。
实验结果见表1
表1.部分目标化合物在酶水平对IDO1的抑制率
Figure PCTCN2018111791-appb-000014
由表1可知，在100nM浓度下，所测定的目标化合物对IDO1的抑制活性均强于阳性对照药Epacadostat，其中化合物I-3和I-17的抑制活性明显强于阳性对照药Epacadostat。我们选择抑制率大于50％的化合物测定了它们对IDO1和IDO2的IC 50(半数抑制浓度)，结果见表2。
表2.部分目标化合物在酶水平对IDO1和IDO2的抑制活性
Figure PCTCN2018111791-appb-000015
实验结果显示，所测化合物对IDO1的IC 50均小于阳性对照药Epacadostat，表明化合物对IDO1均有较强的抑制活性，其中化合物I-17的抑制活性最强；化合物对IDO2的IC 50均小于阳性对照药Epacadostat，表明化合物对IDO2均有较强的抑制活性，其中化合物I-17的抑制活性最强。从以上结果可知，相对于阳性对照药Epacadostat，本发明的化合物(I)不仅对IDO1具有较强的抑制活性，而且对IDO2也有较好的抑制活性，因此，本发明化合物(I)抑制IDO1和IDO2活性的平衡性好于阳性对照药Epacadostat。
(2)检测部分目标化合物对细胞内IDO1的抑制活性
96孔板中每孔加入5000-10000个Hela细胞。生长过夜后，于每孔中加入人源IFN-γ(终浓度为10-50ng/mL)，并梯度加入含15μg/mL L-色氨酸的不同浓度药物，使每孔终体积为200μL。48小时后，取140μL上清，加入10μL三氯乙酸，混匀后50℃孵育30分钟。所得混合液2500rpm离心10分钟。取100μL上清于96孔板中，加入100μL含有2％的对二甲基氨基苯甲醛的醋酸。酶标仪480nm测定。酶标仪检测各孔OD值(检测波长：515nm)；记录结果；按下列公式计算抑制率：抑制率(％)＝(OD对照－OD给药)/OD对照×100％，并计算IC 50，结果见表3。
表3.部分目标化合物对INF-γ诱导的Hela细胞IDO1的抑制活性
Figure PCTCN2018111791-appb-000016
实验结果显示，所测化合物对INF-γ诱导的Hela细胞IDO1的IC 50均小于阳性对照药Epacadostat，表明化合物对IDO1均有较强的抑制活性。
(3)化合物I-3和I-17对小鼠结肠癌细胞CT-26异种移植瘤生长的抑制实验
选择常规培养生长至对数期的CT-26结肠癌细胞，在无菌条件下常规消化，收集细胞，用无菌生理盐水将细胞浓度调整为5×10 6。用1mL注射器接种于酒精消毒后的BALB/C小鼠右腋皮下，每只0.2mL，接种全过程在1小时内完成。待肿瘤体积达100mm 3左右(7-14天左右)，将BALB/C裸鼠随机分为4组，每组10只。各组按表4设定的实验方案给药，分别为模型对照组、化合物I-3组、化合物I-17组、阳性对照组Epacadostat，每日两次，给药28天，给药期间每3天测量鼠体重及移植瘤体积，30天后，小鼠处死，手术剥取瘤块称重。实验结果见图1。
表4受试化合物对小鼠结肠癌细胞CT-26异种移植瘤生长的抑制活性
Figure PCTCN2018111791-appb-000017
化合物I-3和化合物I-17对肿瘤生长的抑制效果如图1所示。
由图1结果表明，化合物I-3和化合物I-17对小鼠结肠癌细胞CT-26异种移植瘤生长的抑制作用强于阳性对照药Epacadostat。
附图说明
图1是化合物I-3和化合物I-17对小鼠结肠癌细胞CT-26异种移植瘤生长的抑制效果
具体实施方式
实施例1
N-(3-溴-4-氟苯基)-Nˊ-羟基-4-((2-(4-苯基-1H-1,2,3-三氮唑-1-基)乙基)氨基)-1,2,5-噁二唑-3-甲脒(I-1)的制备
4-((2-叠氮基乙基)-N-(3-溴-4-氟苯基)-N'-羟基-1,2,5-噁二唑-3-甲脒(III)的制备
将THF(2mL)和3-{4-[(2-叠氮基乙基)氨基]-1,2,5-噁二唑-3-基}-4-(3-溴-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮(II)(411mg,1.0mmol)投入25mL三颈瓶中，搅拌溶解。10℃以下滴加2mol/L的氢氧化钠(1mL)，滴完升温至25℃保温反应2小时左右，TLC监测原料反应完全，30℃以下减压蒸除溶剂，加入5mL水，乙酸乙酯(5mL×3)萃取三次，水(5mL×2)洗涤两次，饱和食盐水(5mL)洗涤，减压蒸干得浅棕色油状物(III)0.39g。
N-(3-溴-4-氟苯基)-Nˊ-羟基-4-((2-(4-苯基-1H-1,2,3-三氮唑-1-基)乙基)氨基)-1,2,5-噁二唑-3-甲脒(I-1)的制备
将乙腈(4mL)，水(1mL)和上步制备的油状物III(0.39g,1.0mmol)投入25mL三颈瓶，搅拌溶解。加入苯乙炔(IV-1)(250μL，2.3mmol)和溴化亚铜(15mg,0.1mmol)搅拌反应5小时左右。待TLC监测原料反应完全后，40℃以下减压蒸除溶剂，加入乙酸乙酯(5mL)和水(5mL)，过滤，静止分层，水层用乙酸乙酯(5mL×3)萃取三次，合并有机层，分别用水(5mL×2)洗涤两次，饱和食盐水(5mL)洗涤，无水硫酸镁干燥，减压蒸干得浅棕色油状物，柱层析分离(洗脱剂：石油醚：乙酸乙酯＝1：2～1：4)，得白色固体250mg，熔点：208-210℃，两步收率51.3％。
1H NMR(300MHz,DMSO-d 6)δ(ppm):11.46(s,1H),8.94(s,1H),8.62(s,1H),7.85(d,J＝7.1Hz,2H),7.47(t,J＝7.3Hz,2H),7.35(t,J＝7.4Hz,1H),7.22-7.09(m,2H),6.75-6.70(m,1H),6.46(d,J＝5.8Hz,1H),4.68(t,J＝5.7Hz,2H),3.78(t,J＝5.9Hz,2H).HRMS(ESI):m/z[M+H] +Calcd for C 19H 17BrFN 8O 2:487.0636；Found:487.0624.
实施例2
N-(3-溴-4-氟苯基)-Nˊ-羟基-4-((2-(4-环丙基-1H-1,2,3-三氮唑-1-基)乙基)氨基)-1,2,5-噁二唑-3-甲脒(I-2)的制备
以III(0.39g,1.0mmol)和环丙基乙炔(IV-2)(250μL，3.0mmol)为原料，操作同I-1，柱层析分离(洗脱剂：石油醚：乙酸乙酯＝1：2)，得白色固体263mg，熔点：154-158℃，收率58.3％。
1H NMR(300MHz,DMSO-d 6)δ(ppm):11.48(s,1H),8.93(s,1H),7.82(s,1H),7.24-7.08(m,2H),6.78-6.69(m,1H),6.38(t,J＝5.7Hz,1H),4.52(t,J＝5.5Hz,2H),3.67(d,J＝5.7Hz,2H),1.96-1.85(m,1H),0.88(d,J＝8.1Hz,2H),0.69(d,J＝4.6Hz,2H). 13C NMR(75MHz,DMSO)δ155.40,152.13,148.92,139.90,139.05,137.92,124.82,121.50,121.03,116.07,115.76,107.19,106.90,47.51,44.06,7.58,6.50.
实施例3
N-(3-溴-4-氟苯基)-N'-羟基-4-((2-(4-(1-羟基乙基)-1H-1,2,3-三氮唑-1-基)乙基)氨基)-1,2,5-噁二唑-3-甲脒(I-3)的制备
将THF(70mL)和3-{4-[(2-叠氮基乙基)氨基]-1,2,5-噁二唑-3-基}-4-(3-溴-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮(II)(15g,36.5mmol)投入250mL反应瓶，搅拌溶解。控制10℃以下滴加2mol/L氢氧化钠(66mL)，滴完升温至25℃保温反应3小时左右，TLC监测原料反应完全，30℃以下减压蒸除溶剂，加入20mL水，乙酸乙酯(75mL×3)萃取三次，水(50mL×2)洗涤两次，饱和食盐水(50mL)洗涤，减压蒸干得浅棕色油状物(III)14.07g。
将乙腈(100mL)，水(20mL)和上步制备的油状物III(14.07g)投入250mL三颈瓶， 搅拌溶解。加入3-丁炔-2-醇(IV-3)(4mL，50mmol)和溴化亚铜(0.53g,3.7mmol)搅拌反应12小时左右。待TLC监测原料反应完全后，40℃以下减压蒸除溶剂，加入乙酸乙酯(75mL)和水(30mL)，过滤，静止分层，水层用乙酸乙酯(50mL×3)萃取三次，合并有机层，分别用水(50mL×2)洗涤两次，饱和食盐水(50mL)洗涤，无水硫酸镁干燥2小时，过滤，滤液减压蒸干得浅棕色油状物，柱层析分离(洗脱剂：石油醚：乙酸乙酯＝1：2～1：4)，得白色固体9.30g，熔点：176-177℃，收率56.0％。
1H NMR(300MHz,DMSO-d 6)δ(ppm):9.00(br,1H),7.95(s,1H),7.24-7.18(t,J＝8.7Hz,1H),7.15-7.12(dd,J＝2.7,6.12Hz,1H)6.80-6.70(m,1H),6.44(t,J＝5.6Hz,1H),4.83(dd,J＝13.0,6.3Hz,1H),4.59(t,J＝6.0Hz,2H),3.71(d,J＝5.8Hz,2H),1.40(d,J＝6.5Hz,3H).HRMS(ESI):m/z[M+H] +Calcd for C 15H 17BrFN 8O 3:455.0586；Found:455.0576.
实施例4
N-(3-溴-4-氟苯基)-N'-羟基-4-((2-(4-(p-甲苯基)-1H-1,2,3-三氮唑-1-基)乙基)氨基)-1,2,5-噁二唑-3-甲脒(I-4)的制备
以III(0.39g,1.0mmol)和4-甲基苯基乙炔(IV-4)(250μL，2.0mmol)为原料，操作同I-1，柱层析分离(洗脱剂：石油醚：乙酸乙酯＝1：2)，得白色固体274mg，熔点：217-220℃，收率54.7％。
1H NMR(300MHz,DMSO-d 6)δ(ppm):11.47(s,1H),8.94(s,1H),8.55(s,1H),7.74(d,J＝7.9Hz,2H),7.27(d,J＝7.5Hz,2H),7.22-7.09(m,2H),6.74-6.71(m,1H),6.47(t,J＝6.0Hz,1H),4.66(t,J＝5.5Hz,2H),3.78(m,2H),2.34(s,3H).HRMS(ESI):m/z[M+H] +Calcd for C 20H 19BrFN 8O 2:501.0793；Found:501.0800.
实施例5
N-(3-溴-4-氟苯基)-N'-羟基-4-((2-(4-(3-氨基苯基)-1H-1,2,3-三氮唑-1-基)乙基)氨基)-1,2,5-噁二唑-3-甲脒(I-5)的制备
以III(0.39g,1.0mmol)和3-氨基苯基乙炔(IV-5)(250μL，2.2mmol)为原料，操作同I-1，柱层析分离(洗脱剂：石油醚：乙酸乙酯＝1：2～1：4)，得白色固体300mg，熔点：202-206℃，收率59.8％。
1H NMR(300MHz,DMSO-d 6)δ(ppm):11.47(s,1H),8.94(s,1H),8.44(s,1H),7.20-7.05(m,4H),6.94(d,J＝7.6Hz,1H),6.75-6.70(m,1H),6.53(d,J＝6.9Hz,1H),6.45(t,J＝5.6Hz,1H),5.21(s,2H),4.64(d,J＝5.5Hz,2H),3.77(d,J＝5.4Hz,2H).HRMS(ESI):m/z[M+H] +Calcd for C 19H 18BrFN 9O 2:502.0745；Found:502.0760.
实施例6
N-(3-溴-4-氟苯基)-N'-羟基-4-((2-(4-(4-甲氧基苯基)-1H-1,2,3-三氮唑-1-基)乙基)氨基)-1,2,5-噁二唑-3-甲脒(I-6)的制备
以III(0.39g,1.0mmol)和4-甲氧基苯基乙炔(IV-6)(250μL，1.9mmol)为原料，操作同I-1，柱层析分离(洗脱剂：石油醚：乙酸乙酯＝1：2)，得白色固体232mg，熔点：225-227℃，收率44.9％。
1H NMR(300MHz,DMSO-d 6)δ(ppm):11.47(s,1H),8.92(s,1H),8.48(s,1H),7.77(d,J＝8.7Hz,2H),7.22-7.10(m,2H),7.03(d,J＝8.7Hz,2H),6.76-6.71(m,1H),6.46(t,J＝5.8Hz,1H),4.65(t,J＝5.6Hz,2H),3.78(m,5H).HRMS(ESI):m/z[M+H] +Calcd for C 20H 19BrFN 8O 3:517.0742；Found:517.0754.
实施例7
N-(3-溴-4-氟苯基)-N'-羟基-4-((2-(4-(4-叔丁基苯基)-1H-1,2,3-三氮唑-1-基)乙基)氨基)-1,2,5-噁 二唑-3-甲脒(I-7)的制备
以III(0.39g,1.0mmol)和4-叔丁基苯基乙炔(IV-7)(250μL，1.4mmol)为原料，操作同I-1，柱层析分离(洗脱剂：石油醚：乙酸乙酯＝1：2)，得白色固体165mg，熔点：210-212℃，收率30.4％。
1H NMR(300MHz,DMSO-d 6)δ(ppm):11.48(s,1H),8.92(s,1H),7.86(s,1H),7.78(d,J＝8.7Hz,2H),7.20(t,J＝8.8Hz,1H),7.15(t,J＝2.6Hz,6.0Hz,1H),7.04(d,J＝8.7Hz,1H),6.83-6.70(m,1H),6.39(t,J＝5.9Hz,1H),4.55(t,J＝5.9Hz,2H),3.71(q,J＝5.9Hz,11.5Hz,2H),1.27(s,9H).HRMS(ESI):m/z[M+H] +Calcd for C 17H 21BrFN 8O 2:467.0949；Found:467.0954.
实施例8
N-(3-溴-4-氟苯基)-N'-羟基-4-((2-(4-(2-羟基乙基)-1H-1,2,3-三氮唑-1-基)乙基)氨基)-1,2,5-噁二唑-3-甲脒(I-8)的制备
以III(0.39g,1.0mmol)和3-丁炔-1-醇(IV-8)(250μL，3.3mmol)为原料，操作同I-1，柱层析分离(洗脱剂：石油醚：乙酸乙酯＝1：2～1：4)，得白色固体186mg，熔点：175-177℃，收率40.9％。
1H NMR(300MHz,DMSO-d 6)δ(ppm):11.48(s,1H),8,92(s,1H),7.88(s,1H),7.20(t,J＝8.8Hz,1H),7.15(dd,J＝2.6,6.0Hz,1H),6.77-6.73(m,1H),6.38(t,J＝5.7Hz,1H),4.74(t,J＝5.2Hz,1H),4.57(t,J＝5.8Hz,2H),3.70(q,J＝5.4Hz,11.2Hz,2H),3.62(q,J＝7.0Hz,12.4Hz,2H),2.78(t,J＝6.9Hz,2H).HRMS(ESI):m/z[M+H] +Calcd for C 15H 16BrFN 8O 3:456.0580；Found:456.0575.
实施例9
N-(3-溴-4-氟苯基)-N'-羟基-4-((2-(4-(2-羟基丙基-2-基)-1H-1,2,3-三氮唑-1-基)乙基)氨基)-1,2,5-噁二唑-3-甲脒(I-9)的制备
以III(0.39g,1.0mmol)和2-甲基-3-丁炔-2-醇(IV-9)(250μL，2.6mmol)为原料，操作同I-1，柱层析分离(洗脱剂：石油醚：乙酸乙酯＝1：2～1：4)，得白色固体172mg，熔点：182-183℃，收率36.7％。
1H NMR(300MHz,DMSO-d 6)δ(ppm):11.50(s,1H),8.92(s,1H),7.90(s,1H),7.20(t,J＝8.8Hz,1H),7.15(dd,J＝2.6,6.0Hz,1H),6.78-6.74(m,1H),6.39(t,J＝5.8Hz,1H),5.13(s,1H),4.58(t,J＝5.8Hz,2H),3.72(q,J＝5.9,11.6Hz,2H),1.46(s,6H).HRMS(ESI):m/z[M+H] +Calcd for C 16H 18BrFN 8O 3:469.0745；Found:469.0745.
实施例10
N-(3-溴-4-氟苯基)-4-((2-(4-((2-乙胺基)甲基)-1H-1,2,3-三氮唑-1-基)乙基)氨基)-N'-羟基-1,2,5-噁二唑-3-甲脒(I-10)的制备
以III(0.39g,1.0mmol)和N,N-二乙基丙炔胺(IV-10)(250μL，2.2mmol)为原料，操作同I-1，柱层析分离(洗脱剂：石油醚：乙酸乙酯＝1：2～1：4)，得白色固体195mg，熔点：161-163℃，收率39.3％。
1H NMR(300MHz,DMSO-d 6)δ(ppm):11.52(s,1H),8.87(s,1H),7.94(s,1H),7.19(t,J＝8.7Hz,1H),7.12(dd,J＝2.1,5.6Hz,1H),6.80-6.68(m,1H),6.30(t,J＝5.5Hz,1H),4.58(t,J＝5.4Hz,2H),3.71(q,J＝5.8,11.2Hz,2H),3.65(s,2H),2.39(q,J＝6.9,13.9Hz,4H),0.97(t,J＝6.9Hz,6H).
实施例11
N-(3-溴-4-氟苯基)-4-((2-(4-(2-(二甲氨基)甲基)-1H-1,2,3-三氮唑-1-基)乙基)氨基)-N'-羟基 -1,2,5-噁二唑-3-甲脒(I-11)的制备
以III(0.39g,1.0mmol)和N,N-二甲基-3-丁炔-1-胺(IV-11)(250μL，2.2mmol)为原料，操作同I-1，柱层析分离(洗脱剂：石油醚：乙酸乙酯＝1：2～1：4)，得白色固体181mg，熔点：184-188℃，收率37.6％。
1H NMR(300MHz,DMSO-d 6)δ(ppm):11.58(s,1H),8.85(s,1H),7.95(s,1H),7.22-7.07(m,2H),6.73(dd,J＝7.9,3.8Hz,1H),6.29(t,J＝5.9Hz,1H),4.58(t,J＝5.6Hz,2H),3.69(d,J＝5.6Hz,2H),3.46(s,2H),2.11(s,6H).
实施例12
N-(3-溴-4-氟苯基)-N'-羟基-4-((2-(4-(2-羟基丙基)-1H-1,2,3-三氮唑-1-基)乙基)氨基)-1,2,5-噁二唑-3-甲脒(I-12)的制备
以III(0.39g,1.0mmol)和4-戊炔-2-醇(IV-12)(250μL，2.6mmol)为原料，操作同I-1，柱层析分离(洗脱剂：石油醚：乙酸乙酯＝1：2～1：4)，得白色固体205mg，熔点：151-153℃，收率43.7％。
1H NMR(300MHz,DMSO-d 6)δ(ppm):11.45(br,1H),8.88(s,1H),7.85(s,1H),7.20(t,J＝8.7Hz,1H),7.15(dd,J＝2.2,5.7Hz,1H),6.78-6.75(m,1H),6.36(t,J＝5.6Hz,1H),4.65(s,1H),4.57(d,J＝5.6Hz,2H),3.87(q,J＝5.3Hz,11.5Hz,1H),3.71(q,J＝5.3Hz,11.0Hz,2H),2.69(m,2H),1.06(d,J＝5.9Hz,3H).
实施例13
N-(3-溴-4-氟苯基)-Nˊ-羟基-4-((2-(4-(6-羟基己基)-1H-1,2,3-三氮唑-1-基)乙基)氨基)-1,2,5-噁二唑-3-甲脒(I-13)的制备
以III(0.39g,1.0mmol)和5-己炔-1-醇(IV-13)(250μL，2.3mmol)为原料，操作同I-1，柱层析分离(洗脱剂：石油醚：乙酸乙酯＝1：2～1：4)，得白色固体190mg，熔点：153-155℃，收率39.3％。
1H NMR(300MHz,DMSO-d 6)δ(ppm):11.50(br,1H),8.91(s,1H),7.86(s,1H),7.20(t,J＝8.9Hz,1H),714(dd,J＝2.6,5.9Hz,1H),6.78-6.73(m,1H),6.38(t,J＝5.8Hz,1H),4.55(t,J＝5.7Hz,2H),3.70(q,J＝5.6,11.3Hz,2H),3.44(t,J＝5.9Hz,4H),2.65(t,J＝7.6Hz,2H),1.78-1.71(m,2H).
实施例14
N-(3-溴-4-氟苯基)-N'-羟基-4-((2-(4-异丁基)-1H-1,2,3-三氮唑-1-基)乙基)氨基)-1,2,5-噁二唑-3-甲脒(I-14)的制备
以III(0.39g,1.0mmol)和3,3-二甲基-1-丁炔(IV-14)(250μL，2mmol)为原料，操作同I-1，柱层析分离(洗脱剂：石油醚：乙酸乙酯＝1：2)，得白色固体188mg，熔点：154-158℃，收率40.2％。
1H NMR(300MHz,DMSO-d 6)δ(ppm):11.44(s,1H),8.88(s,1H),8.09(s,1H),7.16(dd,J＝20.8,6.2Hz,2H),6.76(s,1H),6.36(s,1H),4.61(s,2H),4.44(s,2H),3.72(d,J＝4.5Hz,2H),3.25(s,3H).
实施例15
N-(3-溴-4-氟苯基)-N'-羟基-4-((2-(4-甲氧基甲基)-1H-1,2,3-三氮唑-1-基)乙基)氨基)-1,2,5-噁二唑-3-甲脒(I-15)的制备
以III(0.39g,1.0mmol)和3-甲氧基-1-丙炔(IV-15)(250μL，3.0mmol)为原料，操作同I-1，柱层析分离(洗脱剂：石油醚：乙酸乙酯＝1：2)，得白色固体225mg，熔点：159-161℃，收率49.5％。
1H NMR(300MHz,DMSO-d 6)δ(ppm):11.44(s,1H),8.88(s,1H),8.09(s,1H),7.18(t,J＝8.6Hz,1H),7.14-712(m,1H),6.85-6.66(m,1H),6.36(s,1H),4.61(s,2H),4.44(s,2H),3.72(d,J＝4.5Hz,2H),3.25(s,3H).
实施例16
1-(2-((4-(N-(3-溴-4-氟苯基)-N'-羟基甲脒基)-1,2,5-噁二唑-3-基)氨基)乙基)-1H-1,2,3-三氮唑-4-甲酸酯(I-16)的制备
以III(0.39g,1.0mmol)和丙炔酸甲酯(IV-16)(250μL，2.8mmol)为原料，操作同I-1，柱层析分离(洗脱剂：石油醚：乙酸乙酯＝1：2～1：4)，得白色固体155mg，收率33.0％。 1H NMR(300MHz,DMSO-d 6)δ(ppm):11.42(s,1H),8.89(s,1H),8.81(s,1H),7.30-7.03(m,2H),6.74-6.70(m,1H),6.40(t,J＝5.1Hz,1H),4.70(s,2H),3.85(s,3H),3.78(s,2H).
实施例17
N-(3-溴-4-氟苯基)-N'-羟基-4-((2-(4-((2-羟基乙氧基)甲基)-1H-1,2,3-三氮唑-1-基)乙基)氨基)-1,2,5-噁二唑-3-甲脒(I-17)的制备
将THF(70mL)和3-{4-[(2-叠氮基乙基)氨基]-1,2,5-噁二唑-3-基}-4-(3-溴-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮(15g,36.5mmol)投入250mL三颈瓶中，搅拌溶解。控制内温10℃以下滴加2mol/L氢氧化钠(66mL)，滴完升温至25℃保温反应3小时左右，TLC监测原料反应完全后，于30℃以下减压蒸除溶剂，加入20mL水，乙酸乙酯(75mL×3)萃取三次，水(50mL×2)洗涤两次，饱和食盐水(50mL)洗涤，减压浓缩至干得浅棕色油状物(III)14.31g。
将乙腈(100mL)，水(20mL)和上步制备的油状物III(14.31g)投入250mL三颈瓶，搅拌溶解。加入2-(丙-2-炔-1-基氧基)乙醇(IV-17)(4.9mL，50mmol)和溴化亚铜(0.53g,3.7mmol)，搅拌反应16小时左右。待TLC监测原料反应完全后，40℃以下减压蒸除溶剂，加入乙酸乙酯(75mL)和水(30mL)，过滤，静止分层，水层用乙酸乙酯(75mL×3)萃取三次，合并有机层，分别用水(50mL×2)洗涤两次，饱和食盐水(50mL)洗涤，无水硫酸镁干燥2小时，过滤，滤液减压蒸干得浅棕色油状物，柱层析分离(洗脱剂：石油醚：乙酸乙酯＝1：2～1：4)，得白色固体10.76g，熔点：125-126℃，收率60.8％。
1H NMR(300MHz,MeOD)δ(ppm):7.94(s,1H),7.08(m,2H),6.83(s,1H),4.65(d,J＝11.2Hz,4H),3.80(s,2H),3.66(s,2H),3.57(s,2H).HRMS(ESI):m/z[M+H] +Calcd for C 16H 19BrFN 8O 4:485.0695；Found:485.0692
实施例18
N-(3-溴-4-氟苯基)-4-((2-(4-丁基-1H-1,2,3-三氮唑-1-基)乙基)氨基)-N'-羟基-1,2,5-噁二唑-3-甲脒(I-18)的制备
以III(0.39g,1.0mmol)和1-己炔(IV-18)(250μL，2.2mmol)为原料，操作同I-1，柱层析分离(洗脱剂：石油醚：乙酸乙酯＝1：2)，得白色固体165mg，熔点：204-208℃，收率35.3％。
1H NMR(300MHz,DMSO-d 6)δ(ppm):7.79(s,1H),7.30(t,J＝8.8Hz,1H),7.18(dd,J＝6.3,2.4Hz,1H),7.05(s,2H),6.94-6.84(m,2H),4.54(t,J＝5.6Hz,2H),3.68(q,J＝5.8,11.3Hz,2H),2.53(d,J＝7.4Hz,2H),1.46(dt,J＝15.1,7.4Hz,2H),1.28–1.21(m,2H),0.83(t,J＝7.3Hz,3H).
实施例19
4-((2-(4-(氨基甲基)-1H-1,2,3-三氮唑-1-基)乙基)氨基)-N-(3-溴-4-氟苯基)-N'-羟基-1,2,5-噁二唑-3-甲脒(I-19)的制备
以III(0.39g,1.0mmol)和炔丙胺(IV-19)(250μL，3.6mmol)为原料，操作同I-1， 柱层析分离(洗脱剂：石油醚：乙酸乙酯＝1：2～1：4)，得白色固体185mg，熔点：167-172℃，收率42.0％。
MS(ESI):m/z[M+H] +439.1，441.1。
实施例20
2-(1-(1-(2-((4-(N-(3-溴-4-氟苯基)-N'-羟基甲脒)-1,2,5-噁二唑-3-基)氨基)乙基)-1H-1,2,3-三氮唑-4-基)乙氧基)乙酰胺(I-20)的制备
(Z)-2-(1-(1-(2-((4-(N-(3-bromo-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-1,2,5-oxadiazol-3-yl)a mino)ethyl)-1H-1,2,3-triazol-4-yl)ethoxy)acetamide
以III(0.39g,1.0mmol)和2-(丁-3-炔-2-基氧基)乙酰胺(IV-20)(250μL，2.0mmol)为原料，操作同I-1，柱层析分离(洗脱剂：石油醚：乙酸乙酯＝1：2～1：4)，得白色固体154mg，熔点：164-168℃，收率30.0％。
1H NMR(300MHz,DMSO-d 6)δ(ppm):11.50(s,1H),8.91(s,1H),8.15(s,1H),7.36(s,1H),7.20(t,J＝8.8Hz,1H),7.15(q,J＝2.6,6.0Hz,1H),6.78-6.72(m,1H),6.40(t,J＝5.8Hz,1H),4.69(q,J＝6.4,12.9Hz,1H),4.61(t,J＝5.6Hz,2H),3.78(d,J＝3.0Hz,2H),3.74(d,J＝5.7Hz,2H),1.50(d,J＝6.5Hz,3H).
实施例21
N-(3-溴-4-氟苯基)-N'-羟基-4-((2-(4-((2-羟基乙氧基)乙基)-1H-1,2,3-三氮唑-1-基)乙基)氨基)-1,2,5-噁二唑-3-甲脒(I-21)的制备
以III(0.39g,1.0mmol)和2-(丁-3-炔-2-基氧基)乙醇(IV-21)(250μL，2.0mmol)为原料，操作同I-1，柱层析分离(洗脱剂：石油醚：乙酸乙酯＝1：2～1：4)，得白色固体205mg，熔点：144-148℃，收率41.1％。
1H NMR(300MHz,MeOD)δ(ppm):8.15(s,1H),7.16(dd,J＝2.6,6.0Hz,1H),7.08(t,J＝8.6Hz,1H),6.87-6.82(m,1H),4.75-4.69(m,3H),4.19-4.12(m,2H),3.84(t,J＝5.6Hz,2H),3.67-3.52(m,2H),1.53(d,J＝6.6Hz,3H).
实施例22
N-(3-溴-4-氟苯基)-N'-羟基-4-((2-(4-(2-(2-羟基乙氧基)丙基-2-基)-1H-1,2,3-三氮唑-1-基)乙基)氨基)-1,2,5-噁二唑-3-甲脒(I-22)的制备
以III(0.39g,1.0mmol)和2-((2-甲基丁-3-炔-2-基)氧基)乙醇(IV-22)(250μL，2.0mmol)为原料，操作同I-1，柱层析分离(洗脱剂：石油醚：乙酸乙酯＝1：2～1：4)，得白色固体225mg，熔点：143-145℃，收率43.8％。
1H NMR(300MHz,DMSO-d 6)δ(ppm):11.48(s,1H),8.92(s,1H),8.08(s,1H),7.21(m,2H),6.80(s,1H),6.41(s,1H),4.63(s,2H),4.52(s,1H),3.77(s,2H),3.42(s,2H),3.21(s,2H),1.53(s,6H).
实施例23
N-(3-溴-4-氟苯基)-N'-羟基-4-((2-(4-(1-羟基环己基)-1H-1,2,3-三氮唑-1-基)乙基)氨基)-1,2,5-噁二唑-3-甲脒(I-23)的制备
以III(0.39g,1.0mmol)和1-乙炔基环己基-1-醇(IV-23)(248mg，2.0mmol)为原料，操作同I-1，柱层析分离(洗脱剂：石油醚：乙酸乙酯＝1：2～1：4)，得白色固体310mg，收率60.9％。
1H NMR(300MHz,DMSO-d 6)δ(ppm):11.48(s,1H),8.92(s,1H),7.90(s,1H),7.24-7.09(m,2H),6.74(d,J＝9.1Hz,1H),6.38(t,J＝5.5Hz,1H),4.87(s,1H),4.57(t,J＝5.5Hz,2H),3.71(d,J＝5.4Hz,2H),1.86(t,J＝10.9Hz,2H),1.56(dd,J＝70.7,16.7Hz,8H). 13C NMR(75MHz, DMSO)δ155.59,152.11,139.82,139.11,137.94,124.81,121.70,116.09,115.77,107.16,106.97,67.95,47.63,44.10,37.74,25.20,21.63.
实施例24
N-(3-溴-4-氟苯基)-4-((2-(4-(溴甲基)-1H-1,2,3-三氮唑-1-基)乙基)氨基)-N'-羟基-1,2,5-噁二唑-3-甲脒(I-24)的制备
以I-15(0.455g,1.0mmol)溶于5ml二氯甲烷，冷却至-80℃,滴加三溴化硼(195μL,2.0mmol)，滴完升至-10℃反应1小时，再升至室温反应半小时，冰水破坏三溴化硼，有机相以水洗后蒸除二氯甲烷得粗品，粗品经柱层析分离(洗脱剂：石油醚：乙酸乙酯＝2：1～1：2)，得白色固体210mg，收率41.7％。
MS(ESI):m/z[M+Na] +525.0,527.0,529.0。
实施例25
N-(3-溴-4-氟苯基)-N'-羟基-4-((2-(4-(1-羟基丙基)-1H-1,2,3-三氮唑-1-基)乙基)氨基)-1,2,5-噁二唑-3-甲脒(I-25)的制备
以III(0.39g,1.0mmol)和1-戊炔-3-醇(IV-25)(250μL，2.7mmol)为原料，操作同I-1，柱层析分离(洗脱剂：石油醚：乙酸乙酯＝1：2～1：4)，得白色固体150mg，收率32.0％。
1H NMR(300MHz,DMSO-d 6)δ(ppm):11.48(s,1H),8.92(s,1H),7.91(d,J＝11.7Hz,1H),7.24-7.09(m,2H),6.80–6.68(m,1H),6.37(t,J＝5.6Hz,1H),5.23(s,1H),4.59(s,3H),3.71(d,J＝5.5Hz,2H),1.71(ddd,J＝20.5,13.5,6.7Hz,2H),0.84(t,J＝7.3Hz,3H). 13C NMR(75MHz,DMSO)δ155.44,152.12,144.03,139.85,139.10,137.93,124.82,121.99,121.52,116.08,115.77,107.18,106.89,66.87,47.61,44.11,30.13,9.79.
实施例26
N-(3-溴-4-氟苯基)-N'-羟基-4-((2-(4-(3-羟基丙基)-1H-1,2,3-三氮唑-1-基)乙基)氨基)-1,2,5-噁二唑-3-甲脒(I-26)的制备
以III(0.39g,1.0mmol)和4-戊炔-1-醇(IV-26)(250μL，2.7mmol)为原料，操作同I-1，柱层析分离(洗脱剂：石油醚：乙酸乙酯＝1：2～1：4)，得白色固体175mg，收率37.3％。
1H NMR(300MHz,DMSO-d 6)δ(ppm):11.48(s,1H),8.92(s,1H),7.84(s,1H),7.23-7.09(m,2H),6.81-6.69(m,1H),6.38(t,J＝5.8Hz,1H),4.54(dd,J＝10.6,5.1Hz,3H),3.69(d,J＝5.5Hz,2H),3.43(d,J＝5.2Hz,2H),2.64(t,J＝7.6Hz,2H),1.78–1.67(m,2H). 13C NMR(75MHz,DMSO)δ155.41,152.01,146.76,139.89,139.06,137.92,124.81,122.10,121.51,116.08,115.78,107.19,106.90,59.99,47.50,44.10,32.23,21.63.
实施例27
N-(3-溴-4-氟苯基)-N'-羟基-4-((2-(4-(2-羟基丁基-2-基)-1H-1,2,3-三氮唑-1-基)乙基)氨基)-1,2,5-噁二唑-3-甲脒(I-27)的制备
以III(0.39g,1.0mmol)和3-甲基-1-戊炔-3-醇(IV-27)(250μL，2.2mmol)为原料，操作同I-1，柱层析分离(洗脱剂：石油醚：乙酸乙酯＝1：2～1：4)，得白色固体180mg，收率37.3％。
1H NMR(300MHz,DMSO-d 6)δ(ppm):11.51(s,1H),8.95(s,1H),7.89(s,1H),7.28-7.12(m,2H),6.81-6.71(m,1H),6.41(t,J＝5.6Hz,1H),4.97(s,1H),4.59(d,J＝5.6Hz,2H),3.74(d,J＝5.7Hz,2H),1.75(q,J＝6.9Hz,2H),1.44(s,3H),0.74(t,J＝7.3Hz,3H). 13C NMR(75MHz,DMSO)δ155.92,155.16,152.59,140.29,139.59,138.42,125.28,122.05,116.57,116.26,107.65,70.23,48.12,44.58,35.90,28.67,8.74.
实施例28
N-(3-溴-4-氟苯基)-N'-羟基-4-((2-(4-(2-羟基-4-甲基戊基-2-基)-1H-1,2,3-三氮唑-1-基)乙基)氨基)-1,2,5-噁二唑-3-甲脒(I-28)的制备
以III(0.39g,1.0mmol)和3，5-二甲基-1-己炔-3-醇(IV-28)(250μL，1.7mmol)为原料，操作同I-1，柱层析分离(洗脱剂：石油醚：乙酸乙酯＝1：2～1：4)，得白色固体180mg，收率35.2％。
1H NMR(300MHz,DMSO-d 6)δ(ppm):11.49(s,1H),8.93(s,1H),7.86(s,1H),7.26-7.10(m,2H),6.82-6.69(m,1H),6.37(s,1H),4.93(s,1H),4.59(s,2H),3.72(d,J＝5.0Hz,2H),1.67(dd,J＝13.4,6.8Hz,2H),1.61-1.52(m,1H),1.44(s,3H),0.80(d,J＝6.2Hz,3H),0.69(d,J＝6.2Hz,3H). 13C NMR(75MHz,DMSO-d 6)δ(ppm):155.42,152.10,139.78,139.11,137.91,124.78,121.49,121.35,116.08,115.77,114.50,107.16,106.87,70.01,51.36,47.60,44.11,29.66,24.39,24.19,23.75.
实施例29
N-(3-溴-4-氟苯基)-N'-羟基-4-((2-(4-(2-氨基丙基-2-基)-1H-1,2,3-三氮唑-1-基)乙基)氨基)-1,2,5-噁二唑-3-甲脒(I-29)的制备
以III(0.39g,1.0mmol)和2-甲基-3-丁炔-2-胺(IV-29)(250μL，2.4mmol)为原料，操作同I-1，柱层析分离(洗脱剂：石油醚：乙酸乙酯＝1：2～1：4)，得白色固体305mg，收率65.2％。
1H NMR(300MHz,DMSO-d 6)δ(ppm):8.85(s,1H),8.01(s,1H),7.24-7.06(m,2H),6.76(d,J＝8.5Hz,1H),6.16(t,J＝5.5Hz,1H),4.59(s,2H),3.67(d,J＝5.3Hz,2H),1.43(s,6H).
实施例30
N-(3-溴-4-氟苯基)-N'-羟基-4-((2-(4-(3-羟基苯基)-1H-1,2,3-三氮唑-1-基)乙基)氨基)-1,2,5-噁二唑-3-甲脒(I-30)的制备
以III(0.39g,1.0mmol)和3-羟基苯乙炔(IV-30)(232mg，2.0mmol)为原料，操作同I-1，柱层析分离(洗脱剂：石油醚：乙酸乙酯＝1：1～1：4)，得白色固体325mg，收率64.6％。
1H NMR(300MHz,DMSO-d 6)δ(ppm):11.45(s,1H),9.56(s,1H),8.92(s,1H),8.53(s,1H),7.29-7.11(m,5H),6.73(s,2H),6.44(d,J＝5.9Hz,1H),4.65(s,2H),3.77(d,J＝5.5Hz,2H). 13C NMR(75MHz,DMSO-d 6)δ(ppm):157.71,155.45,152.16,146.36,139.92,139.03,137.91,131.93,129.92,124.82,121.67,121.50,116.06,115.76,114.82,111.80,107.20,106.91,47.78,44.04.
实施例31
N-(3-溴-4-氟苯基)-Nˊ-羟基-4-((2-(4-(氨基甲酰基)-1H-1,2,3-三氮唑-1-基)乙基)氨基)-1,2,5-噁二唑-3-甲脒(I-31)的制备
以III(0.39g,1.0mmol)和丙炔酰胺(IV-31)(138mg，2.0mmol)为原料，操作同I-1，柱层析分离(洗脱剂：石油醚：乙酸乙酯＝1：1～1：2)，得白色固体160mg，收率35.2％。
1H NMR(300MHz,DMSO-d 6)δ(ppm):11.45(s,1H),8.92(s,1H),8.55(s,1H),7.87(s,1H),7.50(s,1H),7.20(t,J＝8.7Hz,1H),7.13(d,J＝5.9Hz,1H),6.74–6.66(m,1H),6.42(t,J＝5.7Hz,1H),4.67(t,J＝5.1Hz,2H),3.75(dd,J＝10.8,5.7Hz,2H). 13C NMR(75MHz,DMSO-d 6)δ(ppm):161.55,155.43,152.17,142.85,139.88,138.99,137.89,126.87,124.83,121.50,115.83,107.22,47.99,43.98.
实施例32
N-(3-溴-4-氟苯基)-N'-羟基-4-((2-(4-((2-羟基乙氧基)甲基)-1H-1,2,3-三氮唑-1-基)乙基)氨 基)-1,2,5-噁二唑-3-甲脒盐酸盐(I-17A)的制备
将I-17(4.84g,10.0mmol)加入20ml丙酮中，搅拌溶解。冰水浴下滴加乙酸乙酯的氯化氢饱和溶液至pH1-2，析出大量固体，丙酮洗涤，得白色固体5.05g,收率97.1％。
1H NMR(300MHz,DMSO-d 6)δ(ppm):11.48(s,1H),8.91(s,1H),8.11(s,1H),7.24-7.09(m,2H),6.75(s,1H),6.39(s,1H),5.10(s,2H),4.61(t,J＝5.3Hz,2H),4.52(s,2H),3.71(d,J＝4.4Hz,2H),3.48(dd,J＝9.6,3.9Hz,4H).
实施例33
N-(3-溴-4-氟苯基)-N'-羟基-4-((2-(4-((2-羟基乙氧基)甲基)-1H-1,2,3-三氮唑-1-基)乙基)氨基)-1,2,5-噁二唑-3-甲脒(I-17)的制备
4-(3-溴-4-氟苯基)-3-(4-((2-(4-((2-羟基乙氧基)甲基)-1H-1,2,3-三氮唑-1-基)乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(V-17的制备)
将乙腈(12mL)、水(3mL)和3-{4-[(2-叠氮基乙基)氨基]-1,2,5-噁二唑-3-基}-4-(3-溴-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮(II)(1.3g,3.2mmol)投入50ml三颈瓶，搅拌溶解，加入2-(丙-2-炔-1-基氧基)乙醇(IV-17)(750μL，6.0mmol)和溴化亚铜(45mg,0.31mmol)，搅拌反应12小时左右，待TLC监测原料反应完全后，40℃以下减压蒸除溶剂，加入乙酸乙酯(15mL)和水(5mL)，过滤，水相用乙酸乙酯(15mL×3)萃取三次，合并后的有机相用水(15mL×2)洗涤两次，饱和食盐水(15mL)洗涤，无水硫酸镁干燥，过滤，滤液减压蒸干得棕褐色固体，柱层析分离(洗脱剂：石油醚：乙酸乙酯＝3：1)，得白色固体(V-17)915mg，收率56.6％。
1H NMR(300MHz,DMSO-d 6)δ(ppm):8.09(s,2H),7.71-7.57(m,2H),6.73(s,1H),4.62-4.52(m,5H),3.76(s,2H),3.48(d,J＝7.9Hz,4H).
N-(3-溴-4-氟苯基)-N'-羟基-4-((2-(4-((2-羟基乙氧基)甲基)-1H-1,2,3-三氮唑-1-基)乙基)氨基)-1,2,5-噁二唑-3-甲脒(I-17)的制备
将THF(6mL)和上步制得的V-17(915mg，1.79mmol)投入50ml三颈瓶中，搅拌溶解，控制10℃以下滴加2mol/L氢氧化钠(3mL)，滴完升温至25℃保温反应2小时左右，TLC监测原料反应完全，30℃以下减压蒸除溶剂，加入6mL水，乙酸乙酯(15mL×3)萃取三次，合并有机层，用水(15mL×2)洗涤两次，饱和食盐水(15mL)洗涤，减压浓缩至干，残留物柱层析分离(洗脱剂：石油醚：乙酸乙酯＝1：2～1：4)得白色固体765mg，收率88.1％熔点：125-126℃，两步总收率49.9％.

Claims (9)

  1. 通式(I)的化合物或其药学上可接受的盐：
    Figure PCTCN2018111791-appb-100001
    其中R 1为C 3～C 6的环烷基、-COOCH 3、-CONH 2、-C(CH 3) 2NH 2、-CH 2N(CH 3) 2、-CH 2N(CH 2CH 3) 2、
    Figure PCTCN2018111791-appb-100002
    Figure PCTCN2018111791-appb-100003
    其中
    m＝0～3；
    X＝CH 2或O；
    R 2为H、F、Cl、Br、CH 3、OH、NH 2、-N(CH 3) 2或-N(CH 2CH 3) 2；
    R 3为H或CH 3；
    R 4为H、CH 3、CH 2CH 3、CH 2OH、CH 2CH 2OH、CH 2CH 2CH 2OH、CH 2CONH 2、CH 2CONHCH 3、CH 2COOH或CH 2COOCH 3；
    R 5为任意取代的H、F、Cl、Br、CH 3、CN、NO 2、OH、OCH 3、NH 2、NHCH 3、N(CH 3) 2、COOH、COOCH 3、COOCH 2CH 3、CONH 2或CONHCH 3。
  2. 权利要求1的化合物或其药学上可接受的盐，其中R 1为环丙基、4-甲氧基苯基、3-氨基苯基、CONH 2、COOCH 3、
    Figure PCTCN2018111791-appb-100004
    其中m＝0～2，X＝CH 2或O，R 2为H、CH 3、OH或NH 2，R 3为H或CH 3，R 4为H、CH 3、CH 2CH 2OH、CH 2CH 2CH 2OH、CH 2CONH 2或CH 2CONHCH 3。
  3. 权利要求2的化合物或其药学上可接受的盐，其中R 1为CONH 2或
    Figure PCTCN2018111791-appb-100005
    其中m＝0～1，X＝CH 2或O，R 2为H、CH 3、OH或NH 2，R 3为H或CH 3，R 4为H、CH 3、CH 2CH 2OH、CH 2CH 2CH 2OH或CH 2CONH 2。
  4. 一种制备权利要求1的化合物或其药学上可接受的盐的方法，包括：
    Figure PCTCN2018111791-appb-100006
    其中R 1的定义同权利要求1。
  5. 一种制备权利要求1的化合物或其药学上可接受的盐的方法，包括：
    Figure PCTCN2018111791-appb-100007
    其中R 1的定义同权利要求1。
  6. 权利要求1的化合物或其药学上可接受的盐，其中药学上可接受的盐为权利要求1的通式(I)化合物与下列酸形成的酸加成盐：氯化氢、溴化氢、硫酸、碳酸、草酸、柠檬酸、琥珀酸、酒石酸、磷酸、乳酸、丙酮酸、乙酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸或阿魏酸。
  7. 一种药物组合物，其中含有权利要求1的通式(I)化合物或其药学上可接受的盐及药学上可接受的载体。
  8. 权利要求1的化合物或其药学上可接受的盐在制备IDO抑制剂药物中的用途。
  9. 权利要求8的用途，其中IDO抑制剂用于治疗或预防肿瘤。
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