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WO2018184585A1 - 一种能抑制ido的化合物、其制备方法及其用途 - Google Patents

一种能抑制ido的化合物、其制备方法及其用途 Download PDF

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Publication number
WO2018184585A1
WO2018184585A1 PCT/CN2018/082062 CN2018082062W WO2018184585A1 WO 2018184585 A1 WO2018184585 A1 WO 2018184585A1 CN 2018082062 W CN2018082062 W CN 2018082062W WO 2018184585 A1 WO2018184585 A1 WO 2018184585A1
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compound
ido
cancer
group
inhibiting
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French (fr)
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钟燕
曹西蓉
王永临
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Shanghai Joyu Pharmatech Ltd
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Shanghai Joyu Pharmatech Ltd
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Priority to US16/498,832 priority Critical patent/US10981882B1/en
Priority to JP2020500954A priority patent/JP2020512399A/ja
Publication of WO2018184585A1 publication Critical patent/WO2018184585A1/zh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/04—1,2,3-Oxadiazoles; Hydrogenated 1,2,3-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/08—1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles

Definitions

  • the invention belongs to the field of medicine and relates to a compound capable of inhibiting IDO, a preparation method thereof and a medicament thereof for treating diseases having pathological characteristics of an IDO-mediated tryptophan metabolism pathway, the diseases including Cancer, Alzheimer's disease, autoimmune diseases, depression, anxiety, cataracts, psychological disorders, AIDS, etc.
  • Cancer is one of the major diseases that seriously endanger human life, and more than half of them occur in developing countries.
  • the incidence of cancer in China is generally on the rise, and the incidence rate is increasing at an average annual rate of 3%-5%. It is estimated that by 2020, 4 million people will develop cancer in China and 3 million will die of cancer. The main reason is: old age Changes, urbanization, industrialization and changes in living habits.
  • the sales scale of drugs used to treat cancer has been growing steadily in recent years. In 2012, it reached 66.42 billion yuan, an increase of 13.07% year-on-year. It is expected that by 2017, the market size of anticancer drugs will reach 1055.7. 100 million yuan, an increase of 7.57%.
  • Tumor immunotherapy is a new treatment for cancer prevention and treatment using modern biotechnology and related products. Because of its safety, effectiveness, and low adverse reactions, it has become the fourth mode of cancer treatment after surgery, radiotherapy and chemotherapy.
  • the host's natural defense mechanisms such as inhibition of IDO-mediated tumor immune escape mechanisms) or the naturally occurring highly targeted substances to achieve anti-tumor effects.
  • Indoleamine 2,3-dioxygenase is a monomeric protein containing intracellular heme, consisting of 403 amino acid residues, including two folded alfa a helix domain, the large domain comprising a catalytic pocket, the substrate being capable of hydrophobic interaction with the IDO in the catalytic pocket.
  • IDO is an enzyme that catalyzes the conversion of tryptophan to formyl kynurenine. It is widely distributed in tissues other than the liver of humans and other mammals (rabbits, mice) and is the only restriction outside the liver that catalyzes the catabolism of tryptophan.
  • Fast enzyme which is an essential amino acid for cells to maintain activation and proliferation, is also an indispensable component of protein.
  • IDO interferon
  • IL interleukin
  • tumor necrosis factor tumor necrosis factor
  • IDO is highly expressed in leukemia cells, inhibiting local T-cell proliferation, inhibiting T-cell-mediated immune responses, and blocking T-cell activation signal transduction, thereby mediating tumor cell escape immune system. s attack. Most human tumors have been found to constitutively express IDO. Therefore, IDO is a potential target for cancer immunotherapy.
  • IDO neurotoxin quinolinic acid
  • KP kynurenine pathway
  • IDO and KP play a crucial role in the pathogenesis of Alzheimer's disease and depression.
  • IDO also has an immune tolerance function, and IDO on tumor cells and antigen presenting cells can induce immune tolerance of T cells to tumor antigens.
  • IDO has been proved to be an important drug discovery target. As a new drug target and a new mechanism, IDO inhibitors can be used to treat cancer, Alzheimer's disease, depression, cataract and other major diseases. The economic benefits have broad prospects. The development of foreign IDO inhibitor drugs is in full swing.
  • Inhibitors of the disclosed selective inhibitors of IDO include WO2004094409, WO2006122150, WO2007075598, WO20IDO05958 and WO2014066834, and the like.
  • IDO inhibitors have good application prospects in the pharmaceutical industry as a drug, but no good IDO inhibitors have been found as marketable drugs. In order to better achieve cancer treatment and better meet market demand, we hope to develop A new generation of highly efficient and low toxicity selective IDO inhibitors.
  • the present invention will provide a novel structure of selective IDO inhibitors and find that compounds having such structures exhibit excellent effects and effects.
  • IDO indoleamine 2,3-dioxygenase
  • the present invention provides a compound capable of inhibiting IDO, which has the following structural formula:
  • R 1 and R 2 are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group or a halogenated alkyl group.
  • R 3 is selected from any one of cyclopentyl, cyclohexyl, piperazinyl and piperidinyl, and the substitution position of R 3 is 1, 2, 1, 3 or 1, 4; m, n Take an integer from 0 to 5, respectively.
  • the position of substitution described herein means that the R 3 (cyclopentyl, cyclohexyl, piperazinyl, piperidinyl)-attached group (group containing 1,2,5-oxadiazolylamino group) And, the position of the aminosulfonylamino group-containing group.
  • the halogen is selected from fluorine, chlorine or bromine
  • the alkyl group means an alkyl group of C1-5
  • the alkoxy group is selected from an alkoxy group of C1-5
  • the halogenated alkyl group is selected from C1. a haloalkyl group of -5.
  • the alkyl group selects a methyl group
  • the alkoxy group selects a methoxy group
  • the haloalkyl group selects a trifluoromethyl group
  • R 3 is a cyclohexyl group, and the substitution position is 1, 4 positions; , 1 or 2; n takes 0, 1, or 2.
  • R 1 is fluorine
  • R 2 is bromine
  • R 3 is cyclohexyl, the substitution position is 1,4
  • m is 0, and n is 0.
  • the compound comprises the following compounds:
  • the present invention also provides a process for the preparation of the above-mentioned IDO-inhibiting compound which is prepared by the following route:
  • the present invention also provides the use of a compound capable of inhibiting IDO as described above, wherein the compound can be used for the preparation of a pharmaceutical composition for preventing and/or treating a disease having a pathological characteristic of an IDO-mediated tryptophan metabolism pathway. .
  • the "pharmaceutical composition” means a mixture containing one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof and other chemical components, as well as other components such as physiology/drug Carrier and excipients used.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • the pharmaceutical composition contains a therapeutically effective amount according to claim 1
  • the disease having the pathological characteristics of the IDO-mediated tryptophan metabolism pathway comprises cancer, myelodysplastic syndrome, Alzheimer's disease, autoimmune disease, depression, anxiety, cataract, psychological disorder And AIDS.
  • the cancer is selected from the group consisting of hepatocellular carcinoma, cholangiocarcinoma, nasopharyngeal carcinoma, breast cancer, cervical cancer, non-small cell lung cancer, small cell lung cancer, gastric cancer, esophageal cancer, colorectal cancer, pancreatic cancer, melanoma, oral cavity.
  • the IDO-inhibiting compound provided by the present invention has strong inhibitory activity against IDO and can be used for preparing an IDO inhibitor to prevent and/or treat a disease having a pathological characteristic of an IDO-mediated tryptophan metabolism pathway, Very good application prospects.
  • the compound for inhibiting IDO provided by the present invention has the following structural formula:
  • R 1 and R 2 are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group or a halogenated alkyl group.
  • R 3 is selected from any one of cyclopentyl, cyclohexyl, piperazinyl and piperidinyl, and the substitution position of R 3 is 1, 2, 1, 3 or 1, 4, preferably 1, 4 bits; m and n each take an integer of 0-5, preferably 0, 1 or 2.
  • the IDO-inhibiting compound provided by the present invention further comprises a tautomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, of the compound of the above formula (I). Or a pharmaceutically acceptable salt thereof.
  • the "pharmaceutically acceptable salt” refers to a salt of a compound of the present invention which is safe and effective for use in a mammal and which has the desired biological activity.
  • the method for preparing the compound of the formula (I) or a salt thereof of the present invention comprises the following steps:
  • the compound of the formula (Ia) is oxidized to a compound of the formula (Ib) under acidic conditions; the compound of the formula (Ib) is reacted with a compound of the formula (Ic) under basic conditions to give a compound of the formula (Id);
  • the compound of the formula (Id) is ring-formed under heating and basic conditions, and the base is preferably N,N'-carbonyldiimidazole to give a compound of the formula (Ie); the compound of the formula (Ie) after ring formation is acidic
  • the protecting group on the amino group is removed under the conditions to obtain a compound of the formula (If) or a salt thereof; an alkali solution of the compound of the formula (If) or a salt thereof is reacted with an alcohol solution of chlorosulfonyl isocyanate at a low temperature to obtain a formula (Ig).
  • the alcohol solution is preferably a t-butanol solution
  • the compound of the formula (Ig) is deprotected under acidic conditions to give a compound of the formula (II); the obtained compound of the formula (II) is obtained under basic conditions.
  • the lower ring is opened to give the compound of the formula (I).
  • the reagents providing basic conditions include organic bases and inorganic bases including, but not limited to, sodium hexamethyldisilazide, triethylamine, N,N-diisopropylethylamine, n-butyl Base lithium, potassium t-butoxide, tetrabutylammonium bromide, said inorganic bases include, but are not limited to, sodium hydride, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate or cesium carbonate.
  • the oxidizing agents used include, but are not limited to, hydrogen peroxide, potassium permanganate, and manganese dioxide.
  • Solvents used include, but are not limited to, N,N-dimethylformamide, toluene, acetic acid, methanol, ethanol, tetrahydrofuran, dichloromethane, dimethyl sulfoxide, 1,4-dioxane or water.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry.
  • the known starting materials of the present invention can be synthesized by or according to methods known in the art or commercially available from a number of reagent companies.
  • the solution in the reaction means an aqueous solution unless otherwise specified.
  • reaction temperature is room temperature, and the temperature range is 20 ° C. 30 ° C.
  • the progress of the reaction in the examples was monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And the ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted depending on the polarity of the compound.
  • the system for the eluent of the column chromatography and the system for the thin layer chromatography of the developer used for the purification of the compound include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: n-hexane, acetic acid Ethyl ester and dichloromethane system, D: petroleum ether and ethyl acetate system, E: ethyl acetate, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine and acid or alkali may be added. The reagents and the like are adjusted.
  • the starting compound la (500 mg, 1.46 mmol, prepared by the method disclosed in P53 Example 3 step A of the patent application "WO2010005958”) was added to 7 mL of trifluoroacetic acid, and 6 mL of hydrogen peroxide (30%) was added thereto, and the reaction was carried out at 45 ° C. hour. After completion of the reaction, the reaction was quenched with EtOAc EtOAc EtOAc (EtOAc m. Compound lb (410 mg, yellow oil) was obtained in a yield of 75%. MS m/z (LC-MS): 373.4 [M+l] + .
  • the crude compound 1d (500 mg, 0.95 mmol) was dissolved in 40 mL of tetrahydrofuran, and N,N'-carbonyldiimidazole (185 mg, 1.14 mmol) was added and reacted at 70 ° C for 1 hour. After the completion of the reaction, the reaction mixture was evaporated to dryness crystals. The crude compound 1e (486 mg) was taken to the next step without purification. MS m/z (LC-MS): 554.3 [M+l] + .
  • Chlorosulfonyl isocyanate (0.793 g, 5.6 mmol) was dissolved in 10 mL of dichloromethane, cooled to 0 ° C, tert-butanol (0.43 g, 5.8 mmol) was added, and the reaction mixture was reacted at 0 ° C for 1 hour.
  • Reaction liquid A The crude compound 1f (550 mg, 1.0 mmol) was dissolved in 20 mL of dichloromethane, and 0.75 mL of triethylamine was added to obtain a reaction liquid B. The reaction liquid A was added to the reaction liquid B at 0 ° C, and reacted at 0 ° C for 1 hour.
  • the human IDO1 protease activity in vitro was tested by the following method. This method is used to determine the inhibitory effect of the compounds of the invention on the activity of human IDO1 protease.
  • the correctly sequenced recombinant expression plasmid PET28a-hIDO1 was transformed into BL21 competent cells, cultured in liquid LB (Luria-Bertani) medium at 37 ° C, and the cells were collected, sonicated, centrifuged at 4 ° C, and the supernatant was collected. Purified rhIDO1 protease was eluted by a Ni column.
  • protease inhibitory activity of the compound of the present invention against human IDO1 was measured by the above test, and the obtained IC 50 value is shown in Table 1.
  • Table 1 Inhibitory activity of compounds prepared in Examples 1-19 of human IDO1 embodiment of protease (IC 50)
  • Example number IC 50 (nM) Example number IC 50 (nM) 1 16 11 43 2 46 12 60 3 38 13 72 4 twenty two 14 108 5 45 15 83 6 48 16 63 7 74 17 15 8 51 18 6 9 64 19 12 10 59
  • HEK293 cells were seeded in 96-well plates at a density of 2.5 ⁇ 10 4 /well.
  • Culture medium containing 10% fetal bovine serum, 50 U/mL penicillin, 50 mg/mL streptomycin
  • the liposome Lipofectamin 2000 was used to promote the transfection of pcDNA3.1(+)-hIDO plasmid, which made it highly express IDO.
  • the test compound was added.
  • the IDO protease inhibitory activity of the compounds prepared in Examples 1-19 of the present invention against HEK293 cells was measured by the above test, and the IC 50 values measured are shown in Table 2.
  • Table 2 Inhibitory activity of compounds prepared in Examples 1-19 of the embodiment of IDO proteases HEK293 cells (IC 50)
  • Example number IC 50 (nM) Example number IC 50 (nM) 1 8 11 18 2 36 12 twenty three 3 13 13 32 4 36 14 48 5 14 15 37 6 39 16 42 7 twenty one 17 10 8 45 18 3 9 27 19 5 10 52
  • compounds 14, 15, 16, 17, 19, 20, 21, 22, 23, 24, 26, 27, 28, 30, 31 are synthesized using the methods of Examples 1-19 above.
  • 32 and 33 by the above biological evaluation method, also have a biological activity inhibitory effect on the IDO protease.
  • the compound of the general formula (I) provided by the present invention has a significant inhibitory effect on IDO protease activity and can be used for preparing a disease for treating or preventing pathological features having an IDO-mediated tryptophan metabolism pathway.
  • Pharmaceutical composition provided by the present invention.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

本发明公开了一种能抑制IDO的化合物、其制备方法及其用途，其结构通式如（Ｉ）。其中，（ＩＩ）选自顺式异构体、反式异构体或顺反异构体的混合物；R1和R2各自独立地选自氢原子、卤素、烷基、烷氧基或卤代烷基中的任意一种；R3选自环戊基、环己基、哌嗪基、哌啶基中的任意一种，R3的取代位置为1，2位、1，3位或1，4位；m、n分别取0-5的整数。本发明提供的能抑制IDO的化合物对IDO具有较强的抑制活性，能用于制备IDO抑制剂，以预防和/或治疗具有IDO介导的色氨酸代谢途径的病理学特征的疾病，具有非常好的应用前景。

Description

一种能抑制IDO的化合物、其制备方法及其用途 技术领域
本发明属于医药领域，涉及一种能抑制IDO的化合物、其制备方法及其在医药上的应用，用于治疗具有IDO介导的色氨酸代谢途径病理学特征的疾病，所述的疾病包括癌症、阿尔茨海默病、自身免疫性疾病、抑郁症、焦虑症、白内障、心理障碍、艾滋病等。
背景技术
癌症是严重危害人类生命的重大疾病之一，一半以上发生在发展中国家。我国癌症发病率总体呈上升趋势，发病率以年均3％-5％的速度递增，预计到2020年，我国将有400万人发生癌症，300万人死于癌症，其主要原因是：老龄化、城镇化、工业化及生活习惯改变。在中国医院用药市场，用于治疗癌症的药物的销售规模近几年来一直稳步增长，2012年达到了664.2亿元，同比增长了13.07％，预计到2017年，抗癌药物的市场规模将达到1055.7亿元，同比增长7.57％。
由于恶性肿瘤的无限制生长与浸润、转移，现今临床采用的三大常规治疗方法(手术、放疗和化疗)无法完全切除或彻底杀灭肿瘤细胞，因此常出现肿瘤转移或复发。肿瘤免疫治疗是应用现代生物技术及其相关产品进行肿瘤防治的新疗法，因其安全、有效、不良反应低等特点，成为继手术、放疗、化疗之后癌症治疗的第四种模式，其通过调动宿主的天然防御机制(比如抑制IDO介导的肿瘤免疫逃逸机制)或给予天然产生的靶向性很强的物质来获得抗肿瘤的效应。
吲哚胺2,3-双加氧酶(Indoleamine 2,3-dioxygenase,IDO)是一种细胞内含亚铁血红素的单体蛋白，由403个氨基酸残基组成，包括两个折叠的alfa-螺旋结构域，大结构域包含催化口袋，底物可在催化口袋内与IDO发生疏水等作用。IDO是催化色氨酸转化为甲酰犬尿氨酸的酶，广泛分布在人和其他哺 乳动物(兔、鼠)除肝脏以外的组织中，是肝脏以外唯一可催化色氨酸分解代谢的限速酶，而色氨酸是细胞维持活化和增殖所必需的氨基酸，也是构成蛋白质不可缺少的重要成分。IDO与干扰素(IFN)，白细胞介素(IL)、肿瘤坏死因子等多种细胞因子关系密切，它们在一定条件下可激活IDO。而T-细胞的细胞周期中存在一个对色氨酸水平非常敏感的调节点，一方面，IDO使局部色氨酸耗竭，致使T-细胞停滞于G1期中期，从而抑制了T-细胞的增殖；另一方面，IDO催化色氨酸代谢产生的主要产物犬尿素由氧自由基介导引起细胞内氧化剂和抗氧化剂改变而诱导T-细胞凋亡，这是存在于机体的固有的免疫抑制机制。目前大量研究表明IDO在白血病细胞中较高表达，使局部T-细胞增殖受抑，抑制T-细胞介导的免疫反应，使T-细胞活化信号转导受阻，从而介导肿瘤细胞逃逸免疫系统的攻击。已经发现大多数人类肿瘤组成性地表达IDO。因此，IDO是一个具潜力的癌症免疫治疗的靶标。
此外，IDO广泛分布于人和动物的许多组织和细胞中，催化色氨酸沿犬尿氨酸途径(KP)分解代谢生成包括神经毒素喹啉酸(QUIN)在内的一些代谢产物。IDO和KP在阿尔茨海默病和抑郁症的发病机制中发挥着至关重要的作用。IDO还具有免疫耐受功能，肿瘤细胞、抗原呈递细胞上的IDO均可诱导T细胞对肿瘤抗原的免疫耐受。目前，IDO已被证实是一个重要的药物发现靶标，IDO抑制剂作为具有新药靶、新机制的药物，可应用于治疗癌症、阿尔茨海默病、抑郁症、白内障等多种重大疾病，社会、经济效益前景广阔。国外IDO抑制剂药物的研发正在如火如荼地进行。
公开的选择性抑制IDO的抑制剂专利申请包括WO2004094409、WO2006122150、WO2007075598、WO20IDO05958和WO2014066834等。
IDO抑制剂作为药物在医药行业具有良好的应用前景，但是目前尚未找到很好的IDO抑制剂可作为上市药物，为了达到更好的癌症治疗效果，更好地满足市场需求，我们希望能开发出新一代的高效低毒的选择性IDO抑制剂。本发明将提供一种新型结构的选择性IDO抑制剂，并发现具有此类结构的化合物表现出优异的效果和作用。
发明的公开
本发明的目的是提供一种高效低毒的能选择性地抑制吲哚胺2,3-双加氧酶(Indoleamine 2,3-dioxygenase,IDO)的化合物。
为了达到上述目的，本发明提供了一种能抑制IDO的化合物，其结构通式如下：
Figure PCTCN2018082062-appb-000001
其中，
Figure PCTCN2018082062-appb-000002
选自顺式异构体、反式异构体或顺反异构体的混合物；R 1和R 2各自独立地选自氢原子、卤素、烷基、烷氧基或卤代烷基中的任意一种；R 3选自环戊基、环己基、哌嗪基、哌啶基中的任意一种，R 3的取代位置为1，2位、1，3位或1，4位；m、n分别取0-5的整数。此处所述的取代位置是指所述的R 3(环戊基、环己基、哌嗪基、哌啶基)连接两端基团(含1,2,5-噁二唑氨基的基团，及，含氨基磺酰氨基的基团)的位置。
优选地，所述的卤素选择氟、氯或溴，所述的烷基是指C1-5的烷基，所述的烷氧基选择C1-5的烷氧基，所述的卤代烷基选择C1-5的的卤代烷基。
优选地，所述的烷基选择甲基，所述的烷氧基选择甲氧基，所述卤代烷基选择三氟甲基；R 3为环己基，取代位置为1，4位；m取0、1或2；n取0、1或2。
优选地，R 1为氟，R 2为溴；R 3为环己基，取代位置为1，4位；m为0，且n为0。
优选地，该化合物包含以下化合物：
Figure PCTCN2018082062-appb-000003
本发明还提供了一种上述的能抑制IDO的化合物的制备方法，该化合物通过以下路线制备：
Figure PCTCN2018082062-appb-000004
本发明还提供了一种上述的能抑制IDO的化合物的用途，其中，该化合物能用于制备预防和/或治疗具有IDO介导的色氨酸代谢途径的病理学特征的疾病的药物组合物。
所述的“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
优选地，所述的药物组合物含有治疗有效量的根据权利要求1
Figure PCTCN2018082062-appb-000005
5中任意一项所述的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
优选地，所述具有IDO介导的色氨酸代谢途径病理学特征的疾病包含癌症、骨髓增生异常综合征、阿尔茨海默病、自身免疫性疾病、抑郁症、焦虑症、白内障、心理障碍和艾滋病。
优选地，所述癌症选自肝细胞肝癌、胆管癌、鼻咽癌、乳腺癌、宫颈癌、非小细胞肺癌、小细胞肺癌、胃癌、食道癌、结直肠癌、胰腺癌、黑色素瘤、口腔癌、肾癌、膀胱癌、前列腺癌、骨肉瘤、卵巢癌、输卵管癌症、胃肠间质瘤、神经胶质瘤、头颈部癌症、白血病、淋巴瘤、多发性骨髓瘤、骨髓增生异常综合症。
本发明提供的能抑制IDO的化合物对IDO具有较强的抑制活性，能用 于制备IDO抑制剂，以预防和/或治疗具有IDO介导的色氨酸代谢途径的病理学特征的疾病，具有非常好的应用前景。
实现本发明的最佳方式
本发明提供的能抑制IDO的化合物，其结构通式如下：
Figure PCTCN2018082062-appb-000006
其中，
Figure PCTCN2018082062-appb-000007
选自顺式异构体、反式异构体或顺反异构体的混合物；R 1和R 2各自独立地选自氢原子、卤素、烷基、烷氧基或卤代烷基中的任意一种；R 3选自环戊基、环己基、哌嗪基、哌啶基中的任意一种，R 3的取代位置为1，2位、1，3位或1，4位，优选1，4位；m、n分别取0-5的整数，优选地选择0、1或2。
本发明提供的能抑制IDO的化合物还包含具有上述通式(I)的化合物的互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐。
所述的“可药用盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。
本发明化合物的合成方法
本发明通式(I)所示的化合物或其盐的制备方法，包括以下步骤：
Figure PCTCN2018082062-appb-000008
在酸性条件下，通式(Ia)化合物被氧化成通式(Ib)化合物；通式(Ib)化合物在碱性条件下与通式(Ic)化合物反应，得到通式(Id)化合物；通式(Id)化合物在加热、碱性条件下成环，该条件下的碱优选N,N'-羰基二咪唑，得到通式(Ie)化合物；成环后的通式(Ie)化合物在酸性条件下脱去氨基上的保护基，得到通式(If)化合物或其盐；通式(If)化合物或其盐的碱溶液与氯磺酰异氰酸酯的醇溶液在低温下反应得到通式(Ig)化合物，该醇溶液优选叔丁醇溶液；通式(Ig)化合物在酸性条件下脱去氨基上的保护基，得到通式(II)化合物；得到的通式(II)化合物在碱性条件下开环得到目标通式(I)化合物。
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于六甲基二硅基氨基钠、三乙胺、N,N-二异丙基乙胺、正丁基锂、叔丁醇钾，四丁基溴化铵，所述的无机碱类包括但不限于氢化钠、碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾或碳酸铯。
所用的氧化剂包括但不限于：双氧水、高锰酸钾和二氧化锰。
所用溶剂包括但不限于：N,N-二甲基甲酰胺、甲苯、醋酸、甲醇、乙醇、四氢呋喃、二氯甲烷、二甲基亚砜、1,4二氧六环或水。
以下结合实施例进一步描述本发明，但这些实施例并非限制着本发明的范围。
化合物的结构是通过核磁共振(NMR)和/或质谱来确定的。
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或购自于多个试剂公司的市售品。
实施例中如无特殊说明，反应均在氩气氛或氮气氛下进行。
实施例中如无特殊说明，反应中的溶液是指水溶液。
实施例中如无特殊说明，反应的温度为室温，温度范围是20℃
Figure PCTCN2018082062-appb-000009
30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂的体系有：A：二氯甲烷和甲醇体系，B：正己烷和乙酸乙酯体系，C:石油醚和乙酸乙酯体系，D：丙酮，溶剂的体积比根据化合物的极性不同而进行调节。
纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂的体系包括：A：二氯甲烷和甲醇体系，B：正己烷和乙酸乙酯体系，C:正己烷、乙酸乙酯和二氯甲烷体系，D：石油醚和乙酸乙酯体系，E：乙酸乙酯，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和酸性或碱性试剂等进行调节。
实施例1：
trans-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-((4-((sulfamoylamino)methyl)cyclohexyl)amino)-1,2,5-oxadiazole-3-carboximidamide，即化合物1的制备，其中化合物1的结构式如下:
Figure PCTCN2018082062-appb-000010
第一步，制备化合物lb：
将原料化合物la(500mg,1.46mmol，参考专利申请“WO2010005958”中P53 Example 3 stepA公开的方法制备而得)加入到7mL三氟乙酸中，再加入6mL双氧水(30％)，于45℃反应20小时。反应结束后，加入饱和亚硫酸钠溶液淬灭反应，用乙酸乙酯萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到化合物lb(410mg，黄色油状物)，产率75％。MS m/z(LC-MS):373.4[M+l] +。
第二步，制备化合物1d：
将化合物lb(400mg,1.1mmol)溶于25mL四氢呋喃中，加入化合物1c(502mg，2.2mmol)，加入3mL 2N的氢氧化钠溶液，于室温下反应40分钟。反应结束后，加入1N的盐酸调节反应液pH至2，用乙酸乙酯萃取三次，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品化合物1d(510mg)，产物不经纯化直接进行下一步反应。MS m/z(LC-MS):528.2[M+l] +。
第三步，制备化合物1e：
将粗品化合物1d(500mg,0.95mmol)溶于40mL四氢呋喃中，加入N,N’-羰基二咪唑(185mg，1.14mmol)，于70℃反应1小时。反应结束后，将反应液减压浓缩，用乙酸乙酯溶解残留物，依次用1N盐酸、水、饱和氯化钠溶液洗涤，用无水硫酸钠干燥有机相，过滤，滤液减压浓缩，得到粗品化合物1e(486mg)，产物不经纯化直接进行下一步反应。MS m/z(LC-MS):554.3[M+l] +。
第四步，制备化合物1f：
将粗品化合物1e(470mg,0.85mmol)溶于40mL二氯甲烷中，加入3mL三氟乙酸，于室温下反应1小时。反应结束后，将反应液减压浓缩，得到粗品化合物1f(586mg)，产品不经纯化直接进行下一步反应。MS m/z(LC-MS):552.4[M+l] +。
第五步，制备化合物1g：
将氯磺酰异氰酸酯(0.793g，5.6mmol)，溶于10mL二氯甲烷中，冷却至0℃，加入叔丁醇(0.43g，5.8mmol),反应液在0℃下反应1小时，制得反应液A。将粗品化合物1f(550mg,1.0mmol)溶于20mL二氯甲烷中，加入0.75mL三乙胺，制得反应液B。于0℃下，将反应液A加入反应液B中，于0℃ 反应1小时。反应结束后，加入饱和碳酸氢钠溶液将反应液淬灭，分液，有机相依次用水洗涤，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得到化合物1g(217mg，白色固体)，收率34％。MS m/z(LC-MS):633.5[M+l] +。
第六步，制备化合物1h：
将化合物1g(200mg，0.3mmol)溶于25mL二氯甲烧中，加入4mL三氟乙酸，于室温下反应1小时。反应结束后，将反应液减压浓缩，得到粗品化合物1h(210mg)，产品不经纯化直接进行下一步反应。MS m/z(LC-MS):533.4[M+l] +。
第七步，制备化合物1：
将粗品化合物1h(200mg，0.38mmol)溶于20mL甲醇中，加入碳酸钾(230mg，1.67mmol)，于50℃反应1小时。反应结束后，加入饱和氯化钠溶液中和反应，分液，水相用乙酸乙酯萃取三次，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得到化合物1(45mg，白色固体)，收率24％。
MS m/z(ESI):507.2[M+1] +,
1HNMR(400MHz,DMSO-d6)δ11.54(s,1H),8.89(s,1H),7.1l-7.25(m,3H),6.78-6.79(m,1H),6.68(s,2H),6.23(t,1H),2.43(m,H),1.21-1.82(m,9H),3.24(d,2H)。
实施例2：
trans-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-((4-(2-(sulfamoylamino)ethyl)cyclohexyl)amino)-1,2,5-oxadiazole-3-carboximidamide，即化合物2的制备，其中化合物2的结构式如下:
Figure PCTCN2018082062-appb-000011
采用实施例1的合成方法，将第二步原料化合物1c替换为
Figure PCTCN2018082062-appb-000012
(市售)，制得化合物2(73mg，白色固体)，收率45％。MS m/z(ESI):521.4[M+1] +, 1HNMR(400MHz,DMSO-d6)δ11.52(s,1H),8.87(s, 1H),7.09-7.27(m,3H),6.76-6.79(m,1H),6.67(s,2H),6.21(t,1H),2.41(m,1H),1.20-1.83(m,11H),3.55(d,2H)。
实施例3：
trans-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-(((4-(sulfamoylamino)cyclohexyl)methyl)amino)-1,2,5-oxadiazole-3-carboximidamide，即化合物3的制备，其中，化合物3的结构式如下：
Figure PCTCN2018082062-appb-000013
采用实施例1的合成方法，将第二步原料1c替换为
Figure PCTCN2018082062-appb-000014
制得化合物3(47mg，白色固体)，收率38％。MSm/z(ESI):507.2[M+1] +, 1HNMR(400MHz,DMSO-d6)δ11.50(s,1H),8.85(s,1H),7.09-7.27(m,3H),6.76-6.79(m,1H),6.67(s,2H),6.21(t,1H),3.01(m,1H),1.19-1.86(m,9H),3.42(d,2H)。
实施例4：
N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-((2-(4-(sulfamoylamino)cyclohexyl)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide，即化合物4的制备，其中，化合物4的结构式如下：
Figure PCTCN2018082062-appb-000015
采用实施例1的合成方法，将第二步原料1c替换为
Figure PCTCN2018082062-appb-000016
制得化合物4(36mg，白色固体)，收率34％。MS m/z(ESI):521.4[M+1] +, 1HNMR(400MHz,DMSO-d6)δ11.49(s,1H),8.87(s,1H),7.11-7.29(m,3H),6.75-6.80(m,1H),6.68(s,2H),6.23(t,1H),3.05(m,H),1.20-1.91(m,11H),3.81(d,2H)。
实施例5：
N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-(((4-((sulfamoylamino) methyl)cyclohexyl)methyl)amino)-1,2,5-oxadiazole-3-carboximidamide，即化合物5的制备，其中，化合物5的结构式如下：
Figure PCTCN2018082062-appb-000017
采用实施例1的合成方法，将第二步原料1c替换为
Figure PCTCN2018082062-appb-000018
制得化合物5(47mg，白色固体)，收率39％。MS m/z(ESI):521.4[M+1] +, 1HNMR(400MHz,DMSO-d6)δ11.52(s,1H),8.88(s,1H),7.11-7.30(m,3H),6.77-6.81(m,1H),6.69(s,2H),6.22(t,1H),1.21-2.05(m,10H),3.51(d,2H),3.23(d,2H)。
实施例6：
N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-((2-(4-((sulfamoylamino)methyl)cyclohexyl)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide，即化合物6的制备，其中，化合物6的结构式如下：
Figure PCTCN2018082062-appb-000019
采用实施例1的合成方法，将第二步原料1c替换为
Figure PCTCN2018082062-appb-000020
制得化合物6(27mg，白色固体)，收率32％。MSm/z(ESI):535.4[M+1] +, 1HNMR(400MHz,DMSO-d6)δ11.52(s,1H),8.87(s,1H),7.10-7.29(m,3H),6.77-6.82(m,1H),6.71(s,2H),6.23(t,1H),1.19-2.15(m,12H),3.82(d,2H),3.29(d,2H)。
实施例7：
N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-(((4-(2-(sulfamoylamino)ethyl)cyclohexyl)methyl)amino)-1,2,5-oxadiazole-3-carboximidamide，即化合物7的制备，其中，化合物7的结构式如下：
Figure PCTCN2018082062-appb-000021
采用实施例1的合成方法，将第二步原料1c替换为
Figure PCTCN2018082062-appb-000022
制得化合物7(38mg，白色固体)，收率32％。MS m/z(ESI):535.4[M+1] +, 1HNMR(400MHz,DMSO-d6)δ11.50(s,1H),8.86(s,1H),7.11-7.28(m,3H),6.79-6.84(m,1H),6.70(s,2H),6.25(t,1H),1.24-2.11(m,12H),3.84(d,2H),3.54(d,2H)。
实施例8：
N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-((2-(4-(2-(sulfamoylamino)ethyl)cyclohexyl)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide，即化合物8的制备，其中，化合物8的结构式如下：
Figure PCTCN2018082062-appb-000023
采用实施例1的合成方法，将第二步原料1c替换为
Figure PCTCN2018082062-appb-000024
制得化合物8(42mg，白色固体)，收率39％。MS m/z(ESI):549.3[M+1] +, 1HNMR(400MHz,DMSO-d6)δ11.53(s,1H),8.88(s,1H),7.10-7.26(m,3H),6.80-6.86(m,1H),6.71(s,2H),6.26(t,1H),1.24-2.11(m,14H),4.04(d,2H),3.52(d,2H)。
实施例9：
N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-((3-((sulfamoylamino)methyl)cyclohexyl)amino)-1,2,5-oxadiazole-3-carboximidamide，即化合物9的制备，其中，化合物9的结构式如下：
Figure PCTCN2018082062-appb-000025
采用实施例1的合成方法，将第二步原料1c替换为
Figure PCTCN2018082062-appb-000026
制得化合物9(52mg，白色固体)，收率47％。MS m/z(ESI):507.2[M+1] +, 1HNMR(400MHz,DMSO-d6)δ11.51(s,1H),8.88(s,1H),7.11-7.26(m,3H),6.81-6.88(m,1H),6.70(s,2H),6.25(t,1H),1.23-2.15(m,9H),2.43(d,1H),3.12(d,2H)。
实施例10：
N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-((3-(2-(sulfamoylamino)ethyl)cyclohexyl)amino)-1,2,5-oxadiazole-3-carboximidamide，即化合物10的制备，其中，化合物10的结构式如下：
Figure PCTCN2018082062-appb-000027
采用实施例1的合成方法，将第二步原料1c替换为
Figure PCTCN2018082062-appb-000028
制得化合物10(39mg，白色固体)，收率31％。MS m/z(ESI):521.4[M+1] +, 1HNMR(400MHz,DMSO-d6)δ11.52(s,1H),8.86(s,1H),7.10-7.27(m,3H),6.80-6.89(m,1H),6.71(s,2H),6.23(t,1H),1.23-2.21(m,11H),2.41(d,1H),3.42(d,2H)。
实施例11：
N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-(((3-(sulfamoylamino)cyclohexyl)methyl)amino)-1,2,5-oxadiazole-3-carboximidamide，即化合物11的制备，其中，化合物11的结构式如下：
Figure PCTCN2018082062-appb-000029
采用实施例1的合成方法，将第二步原料1c替换为
Figure PCTCN2018082062-appb-000030
制得 化合物11(27mg，白色固体，收率15％。MS m/z(ESI):507.2[M+1] +, 1HNMR(400MHz,DMSO-d6)δ11.50(s,1H),8.86(s,1H),7.11-7.28(m,3H),6.81-6.91(m,1H),6.73(s,2H),6.25(t,1H),1.21-2.23(m,9H),3.76(d,2H),3.82(d,2H)。
实施例12：
N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-((2-(3-(sulfamoylamino)cyclohexyl)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide，即化合物12的制备，其中，化合物12的结构式如下：
Figure PCTCN2018082062-appb-000031
采用实施例1的合成方法，将第二步原料1c替换为
Figure PCTCN2018082062-appb-000032
制得化合物12(44mg，白色固体)，收率35％。MS m/z(ESI):521.4[M+1] +, 1HNMR(400MHz,DMSO-d6)δ11.48(s,1H),8.84(s,1H),7.09-7.29(m,3H),6.80-6.92(m,1H),6.72(s,2H),6.23(t,1H),1.21-2.23(m,9H),3.76(d,2H),3.82(d,2H)。
实施例13：
N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-(((4-((sulfamoylamino)methyl)cyclohexyl)methyl)amino)-1,2,5-oxadiazole-3-carboximidamide，即化合物13的制备，其中，化合物13的结构式如下：
Figure PCTCN2018082062-appb-000033
采用实施例1的合成方法，将第二步原料1c替换为
Figure PCTCN2018082062-appb-000034
制得化合物13(27mg，白色固体)，收率18％。MS m/z(ESI):521.4[M+1] +, 1HNMR(400MHz,DMSO-d6)δ11.50(s,1H),8.83(s,1H),7.10-7.31(m,3H),6.81-6.95(m,1H),6.71(s,2H),6.22(t,1H),1.20-2.21(m,10H),3.51(d,2H),3.26(d,2H)。
实施例14
N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-((3-((sulfamoylamino)methyl)cyclopentyl)amino)-1,2,5-oxadiazole-3-carboximidamide，即化合物18的制备，其中，化合物18的结构式如下：
Figure PCTCN2018082062-appb-000035
采用实施例1的合成方法，将第二步原料1c替换为
Figure PCTCN2018082062-appb-000036
制得化合物18(42mg，白色固体)，收率34％。MS m/z(ESI):507.7[M+1] +, 1HNMR(400MHz,DMSO-d6)δ11.49(s,1H),8.82(s,1H),7.11-7.29(m,3H),6.81-6.97(m,1H),6.71(s,2H),6.25(t,1H),2.53(m,1H),1.17-2.21(m,7H),3.33(d,2H)。
实施例15
N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-((4-(sulfamoylamino)piperidin-1-yl)amino)-1,2,5-oxadiazole-3-carboximidamide，即化合物25的制备，其中，化合物25的结构式如下：
Figure PCTCN2018082062-appb-000037
采用实施例1的合成方法，将第二步原料1c替换为
Figure PCTCN2018082062-appb-000038
制得化合物25(36mg，白色固体)，收率29％。MS m/z(ESI):494.6[M+1] +, 1HNMR(400MHz,DMSO-d6)δ11.50(s,1H),9.01(s,1H),7.12-7.31(m,3H),6.80-6.94(m,1H),6.72(s,2H),6.26(t,1H),2.56(m,1H),1.70-2.23(m,4H),2.62-2.83(m,4H)。
实施例16
N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-((3-(2-(sulfamoylamino)ethyl)cyclopentyl)amino)-1,2,5-oxadiazole-3-carboximidamide，即化合物29的制备， 其中，化合物29的结构式如下：
Figure PCTCN2018082062-appb-000039
采用实施例1的合成方法，将第二步原料1c替换为
Figure PCTCN2018082062-appb-000040
制得化合物29(26mg，白色固体)，收率19％。MS m/z(ESI):479.3[M+1] +, 1HNMR(400MHz,DMSO-d6)δ11.48(s,1H),8.81(s,1H),7.09-7.30(m,3H),6.80-6.95(m,1H),6.72(s,2H),6.24(t,1H),2.41-2.43(m,2H),1.68-2.19(m,6H)。
实施例17
N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-((4-(sulfamoylamino)cyclohexyl)amino)-1,2,5-oxadiazole-3-carboximidamide，即化合物34的制备，其中，化合物34的结构式如下：
Figure PCTCN2018082062-appb-000041
采用实施例1的合成方法，将第二步原料1c替换为
Figure PCTCN2018082062-appb-000042
(市售)，制得化合物34(51mg，白色固体)，收率42％。MS m/z(ESI):493.5[M+1] +, 1HNMR(400MHz,DMSO-d6)δ11.51(s,1H),8.87(s,1H),7.10-7.28(m,3H),6.79-6.78(m,1H),6.67(s,2H),6.22(t,1H),2.41(m,1H),1.20-1.85(m,8H),3.14(m,1H)。
实施例18
trans-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-(((1r,4r)-4-(sulfamoylamino)cyclohexyl)amino)-1,2,5-oxadiazole-3-carboximidamide，即化合物35的制备，其中，化合物35的结构式如下：
Figure PCTCN2018082062-appb-000043
采用实施例1的合成方法，将第二步原料1c替换为
Figure PCTCN2018082062-appb-000044
(市售)，制得化合物35(43mg，白色固体)，收率37％。MS m/z(ESI):493.5[M+1] +, 1HNMR(400MHz,DMSO-d6)δ11.49(s,1H),8.88(s,1H),7.10-7.27(m,3H),6.81-6.79(m,1H),6.65(s,2H),6.24(t,1H),2.43(m,1H),1.21-1.87(m,8H),3.13(m,1H)。
实施例19
cis-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-(((1s,4s)-4-(sulfamoylamino)cyclohexyl)amino)-1,2,5-oxadiazole-3-carboximidamide，即化合物36的制备，其中，化合物36的结构式如下：
Figure PCTCN2018082062-appb-000045
采用实施例1的合成方法，将第二步原料1c替换为
Figure PCTCN2018082062-appb-000046
(市售)，制得化合物36(38mg，白色固体)，收率30％。MS m/z(ESI):493.5[M+1] +, 1HNMR(400MHz,DMSO-d6)δ11.50(s,1H),8.87(s,1H),7.11-7.29(m,3H),6.79-6.77(m,1H),6.65(s,2H),6.21(t,1H),2.40(m,1H),1.20-1.85(m,8H),3.10(m,1H)。
生物学评价
测试例1:
1、本发明化合物对人源IDO1蛋白酶抑制活性的测定
体外人源IDO1蛋白酶活性通过以下的方法进行测试。该方法用来测定本发明中的化合物对人源IDO1蛋白酶活性的抑制作用。
(1)自制重组人IDO1蛋白酶
将测序正确的重组表达质粒PET28a-hIDO1转化到BL21感受态细胞中，在液态LB(Luria-Bertani)培养基中37℃放大培养，收集菌体，超声破碎， 4℃下离心，收集上清，通过Ni柱，洗脱得到纯化的rhIDO1蛋白酶。
(2)化合物测试实验
在500μL检测体系中，将50mmol/L磷酸钾缓冲液、400μg/mL过氧化氢酶、40mmol/L维生素C、20μmol/mL亚甲基蓝、300mmol/L的L-色氨酸以及待测化合物混合，37℃保温3
Figure PCTCN2018082062-appb-000047
5min，，再向上述混合液内加人IDO1酶，37℃反应30min后，加人质量浓度为30％的三氯乙酸200μL，终止反应。然后将其在65℃水浴锅中加热15min，13800×g离心10min。吸取上清100μL与等体积质量浓度为2％的对二甲氨基苯甲醛的乙酸溶液混合，加入犬尿氨酸与该溶液产生反应，并使溶液变为黄色，使用酶标仪在480nm处检测吸光度(D)值。
本发明中化合物对人源IDO1蛋白酶抑制活性通过以上的试验进行测定，所得的IC 50值见表1。
表1：实施例1-19所制备的化合物对人源IDO1蛋白酶的抑制活性(IC 50)
实施例编号 IC 50(nM) 实施例编号 IC 50(nM)
1 16 11 43
2 46 12 60
3 38 13 72
4 22 14 108
5 45 15 83
6 48 16 63
7 74 17 15
8 51 18 6
9 64 19 12
10 59    
结论：本发明的实施例1-19所制备的化合物对人源IDO1蛋白酶活性具有明显的抑制作用。
2、本发明化合物对HEK293细胞内IDO蛋白酶抑制活性的测定
将HEK293细胞以2.5×10 4/孔的密度接种于96孔板中，培养基培养(含10％胎牛血清、50U/mL青霉素，50mg/mL链霉素)置于37℃培养箱中培养。24h后使用脂质体Lipofectamin2000倡导，pcDNA3.1(+)-hIDO质粒转染，使 其高表达IDO。转染24h后加入待测化合物，孵育5h后，取140μL上清到另一96孔板中，加入10μL30％(W/V)三氯乙酸，65℃加热15min，13000×g离心10min，取等体积2％(WV)对-二甲氨基苯甲醛的乙酸溶液混合显色，采用酶标仪在480nm检测吸光度(D)值。
本发明中实施例1-19所制备的化合物对HEK293细胞内IDO蛋白酶抑制活性通过以上的试验进行测定，测得的IC 50值见表2。
表2：实施例1-19制备的化合物对HEK293细胞内IDO蛋白酶的抑制活性(IC 50)
实施例编号 IC 50(nM) 实施例编号 IC 50(nM)
1 8 11 18
2 36 12 23
3 13 13 32
4 36 14 48
5 14 15 37
6 39 16 42
7 21 17 10
8 45 18 3
9 27 19 5
10 52    
结论：本发明实施例1-19所制备的化合物对HEK293细胞内IDO蛋白酶活性具有明显的抑制作用。
本发明的一些实施例中，采用上述实施例1-19的方法合成了化合物14、15、16、17、19、20、21、22、23、24、26、27、28、30、31、32及33，经上述生物学评价方法，对IDO蛋白酶也具有生物学意义上的活性抑制作用。
综上所述，本发明提供的具有通式(I)的化合物对于IDO蛋白酶活性具有明显的抑制作用，能用于制备治疗或预防具有IDO介导的色氨酸代谢途径的病理学特征的疾病的药物组合物。
尽管本发明的内容已经通过上述优选实施例作了详细介绍，但应当认识到上述的描述不应被认为是对本发明的限制。在本领域技术人员阅读了上述内容后，对于本发明的多种修改和替代都将是显而易见的。因此，本发明的保护范围应由所附的权利要求来限定。

Claims (10)

  1. 一种能抑制IDO的化合物，其特征在于，该化合物的结构通式如下：
    Figure PCTCN2018082062-appb-100001
    其中，
    Figure PCTCN2018082062-appb-100002
    选自顺式异构体、反式异构体或顺反异构体的混合物；R 1和R 2各自独立地选自氢原子、卤素、烷基、烷氧基或卤代烷基中的任意一种；R 3选自环戊基、环己基、哌嗪基、哌啶基中的任意一种，R 3的取代位置为1，2位、1，3位或1，4位；m、n分别取0-5的整数。
  2. 如权利要求1所述的能抑制IDO的化合物，其特征在于，所述的卤素选择氟、氯或溴，所述的烷基是指C1-5的烷基，所述的烷氧基是指C1-5的烷氧基，所述的卤代烷基选择C1-5的卤代烷基。
  3. 如权利要求2所述的能抑制IDO的化合物，其特征在于，所述的烷基选择甲基，所述的烷氧基选择甲氧基，所述卤代烷基选择三氟甲基；R 3为环己基，取代位置为1，4位；m取0、1或2；n取0、1或2。
  4. 如权利要求2所述的能抑制IDO的化合物，其特征在于，R 1和R 2各自独立地选自氟或溴；R 3为环己基，取代位置为1，4位；m为0，且n为0。
  5. 如权利要求1所述的能抑制IDO的化合物，其特征在于，该化合物包含以下化合物：
    Figure PCTCN2018082062-appb-100003
  6. 一种根据权利要求1所述的能抑制IDO的化合物的制备方法，其特征在于，该化合物通过以下路线制备：
    Figure PCTCN2018082062-appb-100004
    其中，
    Figure PCTCN2018082062-appb-100005
    选自顺式异构体、反式异构体或顺反异构体的混合物；R 1和R 2各自独立地选自氢原子、卤素、烷基、烷氧基或卤代烷基中的任意一种；R 3选自环戊基、环己基、哌嗪基、哌啶基中的任意一种，R 3的取代位置为1，2位、1，3位或1，4位；m、n分别取0-5的整数。
  7. 一种根据权利要求1-5所述的能抑制IDO的化合物的用途，其特征在于，该化合物能用于制备预防和/或治疗具有IDO介导的色氨酸代谢途径的病理学特征的疾病的药物组合物。
  8. 如权利要求7所述的能抑制IDO的化合物的用途，其特征在于，所述的药物组合物含有治疗有效量的根据权利要求
    Figure PCTCN2018082062-appb-100006
    中任意一项所述的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
  9. 如权利要求7所述的能抑制IDO的化合物的用途，其特征在于，所述具有IDO介导的色氨酸代谢途径病理学特征的疾病包含癌症、骨髓增生异常综合征、阿尔茨海默病、自身免疫性疾病、抑郁症、焦虑症、白内障、心理障碍和艾滋病。
  10. 如权利要求9所述的能抑制IDO的化合物的用途，其特征在于，所述癌症包含肝细胞肝癌、胆管癌、鼻咽癌、乳腺癌、宫颈癌、非小细胞肺癌、小细胞肺癌、胃癌、食道癌、结直肠癌、胰腺癌、黑色素瘤、口腔癌、肾癌、 膀胱癌、前列腺癌、骨肉瘤、卵巢癌、输卵管癌症、胃肠间质瘤、神经胶质瘤、头颈部癌症、白血病、淋巴瘤、多发性骨髓瘤、骨髓增生异常综合症。
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