CN105732643A - Conjugate and preparation method thereof and application to preparation of IDO enzyme inhibitor and non-steroidal anti-inflammatory drugs - Google Patents

Conjugate and preparation method thereof and application to preparation of IDO enzyme inhibitor and non-steroidal anti-inflammatory drugs Download PDF

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CN105732643A
CN105732643A CN201610240215.XA CN201610240215A CN105732643A CN 105732643 A CN105732643 A CN 105732643A CN 201610240215 A CN201610240215 A CN 201610240215A CN 105732643 A CN105732643 A CN 105732643A
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conjugate
conjugates
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张士磊
钱彭飞
胡延维
陈韶华
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苏州大学
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract

The invention discloses a conjugate and a preparation method thereof and application to preparation of an IDO enzyme inhibitor and non-steroidal anti-inflammatory drugs.The conjugate or pharmaceutically acceptable salt thereof or an enantiomer, a diastereoisomer, a tautomer, solvate and polymorphic substances thereof or pro-drugs have excellent IDO enzyme activity inhibition, have an anti-inflammatory-immunity synergistic effect, and have good application prospects in serving as anti-tumor drugs.

Description

一种偶联物、其制备方法及在制备I DO酶抑制剂和非甾体抗炎药物中的应用 One kind of a conjugate, their preparation and in the preparation of I DO inhibitors and non-steroidal anti-inflammatory drugs

技术领域 FIELD

[0001] 本发明属于药物化学领域,具体涉及一类具有ID0酶抑制活性以及非留体抗炎作用的偶联物、其制备方法和应用。 [0001] their preparation and applications of the present invention belongs to the field of pharmaceutical chemistry, specifically relates to a class of conjugate has ID0 inhibiting activity as well as non-steroidal anti-inflammatory effect.

背景技术 Background technique

[0002] 肿瘤免疫治疗近来备受关注,是肿瘤治疗领域的焦点,肿瘤免疫治疗由于其卓越的疗效和创新性,在2013年被《科学》杂志评为年度最重要的科学突破。 [0002] tumor immunotherapy recent concern is the focus of the field of cancer treatment, cancer immunotherapy because of its superior efficacy and innovation, in 2013 was named the most important scientific breakthroughs journal "Science." 目前已在一些肿瘤类型如黑色素瘤,非小细胞肺癌等的治疗中展示出了强大的抗肿瘤活性,并已有肿瘤免疫治疗药物获得美国FDA批准临床应用。 As has been the treatment of melanoma, non-small cell lung cancer in demonstrating the potent antitumor activity in a number of tumor types and tumor immunotherapy drugs have received US FDA approval for clinical application. 肿瘤免疫治疗有望成为继手术,化疗,放疗,靶向治疗后肿瘤治疗领域的一场革新。 Cancer immunotherapy is expected to become the surgery, chemotherapy, radiotherapy, an innovation in the field of cancer treatment after targeted therapy.

[0003] 肿瘤微环境中有许多免疫抑制分子存在,通过调节这些抑制分子的功能进而改善肿瘤免疫微环境的免疫治疗策略是目前肿瘤免疫治疗的小分子药物研究的重要策略。 [0003] Many tumor microenvironment immunosuppressive molecule is present, by regulating the function of these inhibitory molecules and thus improve immunotherapeutic strategies tumor immune microenvironment is an important strategy for small molecule drug research tumor immunotherapy. 吲哚胺-(2,3)_双加氧酶(Indoleamine 2,3-dioxygenase,ID0)是由ID01基因编码的酶类,是将人体内色氨酸降解为犬尿氨酸的限速酶,犬尿氨酸可直接抑制效应T细胞的功能,同时微环境中色氨酸耗竭也会抑制T细胞增殖,从而通过多途径发挥免疫抑制的作用。 Indoleamine - (2,3) _ dioxygenase (Indoleamine 2,3-dioxygenase, ID0) is encoded by a gene ID01 enzymes, the human body is the degradation of tryptophan to kynurenine rate-limiting enzyme , kynurenine can directly inhibit the function of effector T cells, while microenvironment tryptophan depletion also inhibit T cell proliferation, and thus play a role in immune suppression by multiple routes. 很多肿瘤高表达ID0从而逃避T细胞的攻击。 Many tumors express high ID0 thus avoid T cell attack. 因此,ID0抑制剂能调节肿瘤微环境的色氨酸含量,避免肿瘤微环境中T细胞增殖受抑制,成为潜在的免疫治疗靶点。 Therefore, an inhibitor capable of modulating the ID0 tryptophan tumor microenvironment, to avoid inhibition of T cell proliferation by the tumor microenvironment, as a potential target for immunotherapy. 目前,已有ID0抑制剂在1/ Π 期临床研究在进行中,评估其在晚期癌症中的疗效和安全性。 Currently, there are ID0 inhibitors in clinical studies during the 1 / Π phase, the evaluation of its efficacy and safety in advanced cancer.

[0004] 同时,科学研究表明,肿瘤细胞经常会产生大量炎症因子如前列腺素等,这些炎症因子不仅能引发全身淋巴管炎症和扩张导致肿瘤细胞的扩散,而且还能削弱免疫系统对肿瘤细胞的正常应答,帮助癌细胞进行隐藏,进而快速增殖和生长。 [0004] Meanwhile, scientific studies suggest that tumor cells often produce large amounts of inflammatory cytokines such as prostaglandins, these inflammatory factors not only lead to expansion and systemic lymphatic inflammation lead to the spread of tumor cells, but also weakens the immune system against tumor cells normal response to help cancer cells hide, and then rapid proliferation and growth. 非留体抗炎药如C0X抑制剂等,除了具有抗炎、镇痛等传统功效,认为对肿瘤的发生、发展和转移均有抑制作用,它们通过抑制前列腺素的合成达到抑制淋巴管的扩张,重新唤起免疫系统的效果,诱导肿瘤细胞的凋亡。 Non-steroidal anti-inflammatory drugs such as C0X inhibitors, in addition to having anti-inflammatory, analgesic and other traditional functions, that are inhibited, development and metastasis, to inhibit expansion which lymphatic vessels by inhibiting prostaglandin synthesis , renewed effect the immune system, inducing apoptosis of tumor cells.

[0005]由于目前已有的ID 0抑制剂及非留体抗炎药作为肿瘤防治药物使用在临床上还存在单药疗效不佳或者副作用较大等缺点,因此发现和寻找低毒高效、具有多重协同作用机制的全新抗肿瘤药物分子具有重要的科学意义和临床应用价值。 [0005] Since the current ID 0 existing inhibitors and non-steroidal anti-inflammatory drug used as a pharmaceutical in clinical PREVENTION there poor efficacy or side effects of monotherapy and other shortcomings, and was thus found to find efficient and low toxicity, having the new anti-tumor drug molecule multiple mechanisms of synergy has important scientific significance and clinical application.

发明内容 SUMMARY

[0006] 本发明的发明目的是提供一种偶联物及其制备方法;制备的偶联物可用于ID0酶抑制剂以及非留体抗炎,从而成为用于肿瘤治疗或预防的药物。 [0006] The invention object of the present invention is to provide a preparation method and a conjugate; preparing conjugates may be used ID0 inhibitor and non-steroidal anti-inflammatory, thus becoming a medicament for the treatment or prevention of cancer.

[0007] 为达到上述发明目的,本发明采用的技术方案为: 一种如式I所示的偶联物; [0007] In order to achieve the above object, the technical solution adopted by the invention is: A conjugate of formula I as shown;

Figure CN105732643AD00061

式中:R选自氢、卤素、氰基、取代或未取代的C1-C6烷基、烷氧基、取代或未取代的氨基中的一种;R1为非留体抗炎药母核结构,如阿司匹林、对乙酰氨基酚、吲哚美辛、萘普生、萘普酮、双氯芬酸、布洛芬、尼美舒利、罗非昔布、塞来昔布等母核结构;L为链接基团,选自选自-(CH2CH2) 、- (CH2CH2OCH2CH2) OF、- (CH2CH2NR7CH2CH2) OF、- (CH2CH2 SCH2CH2) 、- (CH2CH2SSCH2CH2)mM-中的一种,其中m为0-6,R7为氢或烷基;当m为0时,Μ不存在,即-0-L-C0R1为-0C0R1;当m为1-6时,Μ为0,N,S等原子。 Formula: one R is selected from hydrogen, halo, cyano, a substituted or unsubstituted C1-C6 alkyl, alkoxy, substituted or unsubstituted amino group; Rl non-steroidal anti-inflammatory drug core structure , such as aspirin, acetaminophen, indomethacin, naproxen, nabumetone, diclofenac, ibuprofen, nimesulide, rofecoxib, celecoxib like core structure; L is linked group selected from selected from - (CH2CH2), - (CH2CH2OCH2CH2) oF, - (CH2CH2NR7CH2CH2) oF, - (CH2CH2 SCH2CH2), - one kind (CH2CH2SSCH2CH2) mM-, wherein m is 0-6, R7 is hydrogen or alkyl; and when m is 0, [mu] is not present, i.e., -0-L-C0R1 to -0C0R1; when m is 1-6, [mu] is the atom 0, N, S and the like.

[0008] 优选的技术方案中,R选自氢或者卤素;R1) [0008] In a preferred aspect, R is selected from hydrogen or halogen; Rl)

Figure CN105732643AD00062

Figure CN105732643AD00063

、,其中R2为氢、乙酰基等;R3为氢、C1-C6的烷基;R6 为氢、C1-C6的烷基;R4为氢、C1-C3的烷基;R5为氢、烷基、卤素等。 ,, wherein R2 is hydrogen, acetyl and the like; R3 is hydrogen, C1-C6 alkyl group; R6 is hydrogen, C1-C6 alkyl group; R4 is hydrogen, C1-C3 alkyl; R5 is hydrogen, an alkyl group and a halogen.

[0009] 上述技术方案中,取代指基团上的一个或多个氢原子被取代基取代;取代的C1-C6 烷基、取代的氨基中取代基独立的选自卤素、0!1、順2、01未取代或卤代的(:1-08烷基、未取代或卤代的C3-C8环烷基、未取代或卤代的C1-C8烷氧基、未取代或卤代的C2-C6烯基、未取代或卤代的C2-C6炔基、未取代或卤代的C2-C6酰基、未取代或卤代的4-8元饱和杂环或碳环中的一种或几种;其中,所述的杂环包含N、0、S中的一种或几种。 [0009] In the above aspect, it refers to a substituent group on one or more hydrogen atoms are substituted with a substituent; substituted C1-C6 alkyl, substituted amino substituents independently selected from halo, 01, cis! 2,01 unsubstituted or halogenated (: 1-08 alkyl, unsubstituted or halogenated C3-C8 cycloalkyl, unsubstituted or halogenated C1-C8 alkoxy, unsubstituted or halogenated C2 -C6 alkenyl group, unsubstituted or halogenated C2-C6 alkynyl group, an unsubstituted or halogenated C2-C6 acyl, unsubstituted or halogenated saturated 4-8 membered heterocyclic or carbocyclic ring of one or several species; wherein said heterocycle containing N, 0, S, one or several.

[0010] 上述技术方案中,偶联物的化学结构式为以下结构式的一种: [0010] In the above technical solution, the chemical structural formula as a conjugate of the following structural formula:

Figure CN105732643AD00064

[0011]优选的,偶联物的化学结构式为以下结构式的一种: [0011] Preferably, the chemical structure of the following Formula conjugate a structural formula:

Figure CN105732643AD00071

本发明还公开了上述偶联物的对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物、前药或药学结构上可接受的盐。 The present invention also discloses a enantiomers, diastereomers of the above conjugate, tautomers, acceptable solvates, polymorphs, pharmaceutically acceptable prodrug or salt structure.

[0012]本发明还公开一种制备上述偶联物的方法,包括以下步骤: 在碱性条件下,于溶剂A中,将化合物1与化合物2进行反应得到化合物3;于溶剂B中,将化合物3与还原试剂发生反应,得到式I所示的偶联物; 所述化合物1的结构式为: [0012] The present invention also discloses a method for preparing the above conjugates, comprising the steps of: under basic conditions, in solvent A, compound 1 with compound 2 to give compound 3; solvent B, the compound 3 occurred with a reducing agent to give a conjugate of formula I; the compound of formula 1 is:

Figure CN105732643AD00072

所述化合物2的结构式为: The compound of formula 2 is:

Figure CN105732643AD00073

其中,LG为离去基团,如羟基、氯、溴、活性酯、酸酐、磺酸酯; 所述化合物3的结构式为: Wherein, LG is a leaving group, such as hydroxyl, chloro, bromo, an active ester, an acid anhydride, sulfonic acid ester; 3, the compound of the formula:

Figure CN105732643AD00074

[0013] 上述制备过程如下: [0013] The preparation process is as follows:

Figure CN105732643AD00075

上述技术方案中,溶剂A、溶剂B独立的选自水、甲醇、乙醇、异丙醇、乙二醇、N-甲基吡咯烷酮、二甲基亚砜,四氢呋喃、甲苯、二氯甲烷、1,2-二氯乙烷、乙腈、N,N-二甲基甲酰胺、N, N-二甲基乙酰胺、二氧六环中的一种或几种。 In the above technical solution, the solvent A, solvent B independently is selected from water, methanol, ethanol, isopropanol, ethylene glycol, N- methylpyrrolidone, dimethylsulfoxide, tetrahydrofuran, toluene, methylene chloride, 1, 1,2-dichloroethane, acetonitrile, N, N- dimethylformamide, N, N- dimethylacetamide, dioxane or a few.

[0014]上述技术方案中,碱为无机碱或有机碱;无机碱选自氢氧化钾、醋酸钠、醋酸钾、叔丁醇钾、叔丁醇钠、氟化钾、氟化铯、磷酸钾、碳酸钾、碳酸氢钾、碳酸钠、碳酸氢钠中的一种或几种;有机碱选自吡啶,三乙胺,N,N-二异丙基乙胺、1,8_二氮杂二环[5.4.0]十一碳-7-烯(DBU)、六甲基二硅基锂、六甲基二硅基钠、二甲基吡啶中的一种或几种。 [0014] In the above aspect, the base is an inorganic or organic base; inorganic base chosen from potassium hydroxide, sodium acetate, potassium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, cesium fluoride, potassium phosphate , one or more of potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate; the organic base selected from pyridine, triethylamine, N, N- diisopropylethylamine, 1,8_-diaza bicyclo [5.4.0] undec-7-ene (DBU), lithium hexamethyldisilazide, sodium hexamethyl disilazide, lutidine one or several.

[0015]上述技术方案中,还原剂选自氢气、硼氢化钠、三乙酰氧基硼氢化钠、氰基硼氢化钠、硼烷、异丙醇铝中的一种或几种。 [0015] In the above technical solution, the reducing agent is selected from hydrogen, sodium borohydride, triacetoxy sodium borohydride, sodium cyanoborohydride, borane, aluminum isopropoxide one or several.

[0016] 本发明还公开了一种ID0酶抑制剂,为式I所示的偶联物、式I所示偶联物的对映异构体、式I所示偶联物的非对映异构体、式I所示偶联物的互变异构体、式I所示偶联物的溶剂化物、式I所示偶联物的多晶型物、式I所示偶联物的前药或式I所示偶联物的药学结构上可接受的盐。 [0016] The present invention also discloses a ID0 enzyme inhibitor conjugate of Formula I, Formula I diastereomeric enantiomer, represented by Formula I conjugates conjugates isomers, tautomers of formula I conjugates thereof, solvates thereof of formula I conjugate, formula I polymorph conjugates, the conjugate of formula I formula I prodrug or a pharmaceutically acceptable salt of a conjugate structure.

[0017] 本发明还公开了一种非留体抗炎药,为式I所示的偶联物、式I所示偶联物的对映异构体、式I所示偶联物的非对映异构体、式I所示偶联物的互变异构体、式I所示偶联物的溶剂化物、式I所示偶联物的多晶型物、式I所示偶联物的前药或式I所示偶联物的药学结构上可接受的盐。 [0017] The present invention also discloses a non-steroidal anti-inflammatory drugs, enantiomer, of formula I is a conjugate of Formula I, Formula I conjugate was shown unconjugated enantiomers, tautomers of formula I conjugates thereof, solvates thereof of formula I conjugate, formula I polymorph conjugate, conjugate of formula I prodrug thereof of formula I or a pharmaceutically acceptable salt of a conjugate structure.

[0018] 本发明进一步公开了一种药物组合物,包括式I所示的偶联物、式I所示偶联物的对映异构体、式I所示偶联物的非对映异构体、式I所示偶联物的互变异构体、式I所示偶联物的溶剂化物、式I所示偶联物的多晶型物、式I所示偶联物的前药或式I所示偶联物的药学结构上可接受的盐;还包括药学上可接受的载体。 [0018] The present invention further discloses a pharmaceutical composition, enantiomers, comprising a conjugate of Formula I represented by Formula I, Formula I to non-conjugate conjugates shown enantiomers iso tautomeric isomers, the conjugate of formula I, formula I conjugates solvate, polymorph front conjugates, the conjugate of formula I as shown in formula I Chemical formula I or a pharmaceutically acceptable salt of a conjugate structure; further comprising a pharmaceutically acceptable carrier.

[0019] 本发明还公开了上述药物组合物在制备治疗或预防肿瘤的药物中的应用。 [0019] The present invention also discloses the use of the above pharmaceutical composition of a medicament for treating or preventing a tumor.

[0020] 上述肿瘤为非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、胃肠道间质瘤、白血病、淋巴癌、鼻咽癌等中的任一种。 [0020] The above-described inter-small cell lung cancer is non-small cell lung carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, squamous cell carcinoma, gastrointestinal stromal tumors, leukemia, any of lymphoma, nasopharyngeal carcinoma and the like.

[0021] 本发明还公开了式I所示的偶联物、式I所示偶联物的对映异构体、式I所示偶联物的非对映异构体、式I所示偶联物的互变异构体、式I所示偶联物的溶剂化物、式I所示偶联物的多晶型物、式I所示偶联物的前药或式I所示偶联物的药学结构上可接受的盐在制备药物中的应用。 [0021] The present invention also discloses a conjugate of Formula I, Formula I diastereomeric enantiomers thereof, as shown in Formula I conjugates conjugates, of formula I tautomers conjugates of formula I in solvate conjugates of formula I polymorph conjugate, a prodrug of formula I or a conjugate of formula I coupling application of a pharmaceutically acceptable salt thereof linked structure in the manufacture of a medicament. 药物包括ID0酶抑制剂、非留体抗炎药、治疗或预防肿瘤药物。 ID0 agents include inhibitors, non-steroidal anti-inflammatory drugs, treatment or prevention of cancer drugs.

[0022] 本发明进一步公开了一种中间体,其结构式为: [0022] The present invention further discloses an intermediate having the formula:

Figure CN105732643AD00081

[0023] 本发明公开的具有式I结构的偶联物,可以抑制多种肿瘤细胞的增殖,尤其是在体内能释放出非留体抗炎药分子,与ID0抑制剂协同发挥作用,通过调节免疫系统,达到预防或治疗癌症的作用,可以作为一类全新作用机制的多靶点抗肿瘤治疗或预防的药物。 [0023] The present invention discloses a conjugate of Formula I having the structure, can inhibit the proliferation of various tumor cells, especially in vivo release of a non-steroidal antiinflammatory drug molecules, act synergistically with inhibitors ID0, by adjusting the the immune system to achieve the prevention or treatment of cancer, can be used as a new class of multi-target mechanism of action of anti-tumor therapy or drug prevention.

具体实施方式 Detailed ways

[0024] 本发明公开了一类具有式I所示结构的ID0酶抑制剂-非留体抗炎药偶联物,其具有较好的抑制ID0酶的活性,且该偶联物在体内能转变成ID 0抑制剂和非留体抗炎药,发挥协同作用,抑瘤活性相当优异,因而可以用于制备治疗或预防肿瘤的药物,或者用于癌症病人并发症的辅助治疗。 [0024] The present invention discloses a class of enzyme inhibitors ID0 having the structure shown in the formula I - a non-steroidal antiinflammatory drug conjugate having better inhibitory activity ID0 enzyme, and the conjugate in vivo can ID 0 is converted into a non-steroidal inhibitors and anti-inflammatory drugs, synergy, very excellent antitumor activity, and thus may be used in preparation of a medicament for the treatment or prevention of a tumor, or cancer patients for the adjuvant treatment of complications.

[0025] 可在参考文献中找到对本发明记载的标准化学术语的定义。 [0025] can be found in the definition of standard chemistry terms of the present invention is described in the literature. 除非另有说明,否则采用本领域技术范围内的常规方法,如质谱、NMR、IR和UV/VIS光谱法和药理学方法。 Unless otherwise indicated, conventional methods within the skill in the art, such as mass spectrometry, NMR, IR, and UV / VIS spectroscopy and pharmacological approaches. 除非提出具体定义,否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。 Unless specific definitions proposed otherwise described herein in terms related to the analysis of chemical, pharmaceutical and synthetic organic chemistry and pharmaceutical chemistry are employed known in the art. 可在化学合成、化学分析、药物制备、制剂和递送,以及对患者的治疗中使用标准技术。 It may be chemical syntheses, chemical analyzes, pharmaceutical preparation, formulation, and delivery, and using standard techniques for treatment of patients. 例如,可利用厂商对试剂盒的使用说明,或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。 For example, using the manufacturer's instructions for using the kit, or in accordance with the description of the invention, or known in the art way to implement the reaction and purification. 通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述,按照本领域熟知的常规方法实施上述技术和方法。 Summary and description of a plurality of more specific literature cited and discussed generally in accordance with the present specification, the above-described methods and techniques in a conventional manner known in the art. 在本说明书中, 可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。 In the present specification, by one skilled in the art to select groups and substituents thereof to provide stable moieties and compounds. 当通过从左向右书写的常规化学式描述取代基时,该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。 When the substituent by conventional chemical formulas, written from left to right description, the substituent also include the right to left in chemical equivalent substituents writing structural formula obtained. 举例而言,-CH 2〇-等同于-〇CH2-。 For example, -CH 2〇- equivalent to -〇CH2-. 在本文中定义的某些化学基团前面通过简化符号来表示该基团中存在的碳原子总数。 In front of certain chemical groups defined herein to refer to the total number of carbon atoms present in the group by a shorthand notation. 例如,C1-6烷基是指具有总共1至6个碳原子的如下文所定义的烷基。 For example, C1-6 alkyl refers to an alkyl group having a total of from 1 to 6 carbon atoms as defined below. 简化符号中的碳原子总数不包括可能存在于所述基团的取代基中的碳。 The total number of carbons in the shorthand notation does not include the substituent groups may be present in the carbon.

[0026] 在本发明中,卤素是指氟、氯、溴或碘;羟基是指-OH基团;羟基烷基是指被羟基(_ 0H)取代的烷基;羰基是指-C(=0)_基团;硝基是指-N0 2;氰基是指-CN;氨基是指-NH2;羧基是指-C00H。 [0026] In the present invention, halogen means fluorine, chlorine, bromine or iodine; refers to a -OH group; hydroxyalkyl refers to an alkyl hydroxy (_ 0H) substituted; refers to a carbonyl group -C (= 0) _ group; a nitro group refers -N0 2; refers to a cyano group -CN; amino refers to -NH2; refers to a carboxyl group -C00H.

[0027] 在本申请中,作为基团或是其它基团的一部分(例如用在卤素取代的烷基等基团中),烷基意指仅由碳原子和氢原子组成、不含不饱和键、具有例如1至12个碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团,比如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-甲基丁基、2,2_二甲基丙基、正己基、庚基、2-甲基己基、3-甲基己基、辛基、壬基和癸基等;烯基意指仅由碳原子和氢原子组成、含有至少一个双键、具有例如2至14个碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团, 比如乙烯基、丙烯基、稀丙基、丁-1-烯基、丁-2-烯基、戊-1-烯基、戊-1,4-二烯基等;炔基意指仅由碳原子和氢原子组成、含有至少一个三键和任选的一个或多个双键、具有例如2至14 个碳原子且通过单键与分子的其余部 [0027] In the present application, a group or as part of other groups (e.g., halogen-substituted with an alkyl group and the like), alkyl means solely of carbon and hydrogen atoms, containing no unsaturation bond, for example having 1 to 12 carbon atoms and a linear hydrocarbon chain group or branched-chain linked by a single bond and the remainder of the molecule, such as methyl, ethyl, n-propyl, isopropyl, n-butyl , iso-butyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2_-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methyl hexyl, octyl, nonyl and decyl and the like; means an alkenyl group consisting solely of carbon and hydrogen atoms, containing at least one double bond, for example, having 2 to 14 carbon atoms and attached to the rest of the molecule by a single bond hydrocarbon chain radical straight or branched chain, such as ethenyl, propenyl, dilute propyl, 1-enyl, but-2-enyl, pent-1-enyl, pent-1,4- alkenyl group; an alkynyl group means consisting solely of carbon and hydrogen atoms, containing at least one triple bond and optionally one or more double bonds, for example having 2 to 14 carbon atoms and a single bond to the rest of the molecule of section 连接的直链或支链的烃链基团,例如但不限于乙炔基、丙-1-炔基、丁-1-炔基、戊-1-烯-4-炔基等;环烷基意指仅由碳原子和氢原子组成的稳定的非芳香族单环或多环烃基,其可包括稠合环体系、桥环体系或螺环体系,具有3至15个碳原子,优选具有3至10个碳原子,更优选具有3至8个碳原子,且其为饱和或不饱和并可经由任何适宜的碳原子通过单键与分子的其余部分连接,除非本说明书中另外特别指明,环烷基中的碳原子可以任选地被氧化,比如环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环辛基、1H-茚基、2,3_二氢化茚基、1,2,3,4_四氢-萘基、5,6,7, 8_四氢-萘基、8,9-二氢-7H-苯并环庚烯-6-基、6,7,8,9-四氢-5H-苯并环庚烯基、5,6,7,8, 9,10-六氢-苯并环辛烯基、芴基、二环[2.2.1]庚基、7,7_二甲基-二环[2.2.1]庚基、二 Hydrocarbon chain radical straight or branched chain linked such as, but not limited to, ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-en-4-ynyl and the like; cycloalkyl intended refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms which may comprise a fused ring system, or spiro ring systems bridged ring systems, having from 3 to 15 carbon atoms, preferably having from 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, and which may be connected through a single bond and the remainder of the molecule is a saturated or unsaturated, via any suitable carbon atom, the present specification unless otherwise specifically indicated, cycloalkoxy carbon atom may optionally be oxidized, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctadiene yl, 1H- indenyl, indanyl 2,3_, 1,2,3,4_ tetrahydro - naphthyl, 5,6,7,8-tetrahydro 8_ - naphthyl, 8,9-dihydro- -7H- benzocyclohepten-6-yl, 6,7,8,9-tetrahydro-benzo -5H- cycloheptenyl, 5,6,7,8, 9,10-hexahydro - benzo cyclooctenyl group, fluorenyl, bicyclo [2.2.1] heptyl, 7,7_ dimethyl - bicyclo [2.2.1] heptyl, di [2.2.1]庚烯基、二环[2.2.2]辛基、二环[3.1.1]庚基、二环[3.2.1]辛基、二环[2.2.2]辛烯基、二环[3.2.1]辛烯基、金刚烷基、八氢-4,7-亚甲基-1!1-茚基和八氢-2,5-亚甲基-并环戊二烯基等;杂环基意指由2至14个碳原子以及1至6个选自氮、磷、氧和硫的杂原子组成的稳定的3元至20元非芳香族环状基团,除非本说明书中另外特别指明,否则杂环基可以为单环、双环、三环或更多环的环体系,其可包括稠合环体系、桥环体系或螺环体系,其杂环基中的氮、碳或硫原子可任选地被氧化,氮原子可任选地被季铵化,且杂环基可为部分或完全饱和,杂环基可以经由碳原子或者杂原子并通过单键与分子其余部分连接,在包含稠环的杂环基中,一个或多个环可以是下文所定义的芳基或杂芳基,条件是与分子其余部分的连接点为非芳香族环原子,本发明中杂环基优选为包含1至3个选 [2.2.1] heptenyl, bicyclo [2.2.2] octyl, bicyclo [3.1.1] heptyl, bicyclo [3.2.1] octyl, bicyclo [2.2.2] octenyl, ! bicyclo [3.2.1] octenyl, adamantanyl, octahydro-4,7-methyl-1 1-indenyl and octahydro-2,5-methano - cyclopentadienyl and and the like; heterocyclic group means a stable 3-20 yuan non-aromatic cyclic radical of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur, unless the present Further specification otherwise specified, the heterocyclic group may be a monocyclic ring system, bicyclic, tricyclic or more rings, which may include fused ring systems or bridged ring system spiro ring system of a nitrogen heterocyclic group, , carbon or sulfur atoms may optionally be oxidized, the nitrogen atoms may optionally be quaternized, and the heterocyclic group may be partially or fully saturated heterocyclic group via a carbon atom or a hetero atom of the molecule by a single bond and attachment to the rest, the fused heterocyclyl ring containing one or more rings can be aryl or heteroaryl group, as defined below conditions is the point of attachment to the rest of the molecule are non-aromatic ring atoms, the present invention the heterocyclic group is preferably 1 to 3 substituents selected from the group comprising 氮、氧和硫的杂原子的稳定的4元至11元非芳香性单环、双环、桥环或螺环基团,更优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至8元非芳香性单环、双环、桥环或螺环基团,比如吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、硫代吗啉基、2,7-二氮杂-螺[3.5 ]壬烷-7-基、2-氧杂-6-氮杂-螺[3.3]庚烷-6-基、2,5-二氮杂-双环[2.2.1]庚烷-2-基、氮杂环丁烷基、吡喃基、四氢吡喃基、噻喃基、四氢呋喃基、噁嗪基、二氧环戊基、四氢异喹啉基、十氢异喹啉基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、邻苯二甲酰亚氨基等;芳基意指具有6至18个碳原子的共辄烃环体系基团,芳基可以为单环、双环、三环或更多环的环体系,还可以与环烷基或杂环基稠合,条件是 Stable 4-11 yuan nonaromatic monocyclic hetero atoms nitrogen, oxygen and sulfur, bicyclic, bridged or spiro ring group, more preferably containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur heteroatoms stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged or spiro ring group, such as pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholine yl, 2,7-diaza - spiro [3.5] nonan-7-yl, 2-oxa-6-aza - spiro [3.3] heptane-6-yl, 2,5-diaza - bicyclo [2.2.1] heptan-2-yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazine group, dioxolanyl, tetrahydroisoquinoline quinolinyl, decahydro-isoquinolinyl, imidazolinyl, imidazolidinyl, quinolyl, piperazinyl, thiazolidinyl, isothiazolyl group, isoxazolyl group, indolinyl, octahydro-indolyl, octahydro-isoindolyl, pyrrolidinyl, pyrazolidinyl, phthalimido imino group; an aryl group means a hydrocarbon ring system having a total Noir group having 6 to 18 carbon atoms, an aryl group may be a single rings, bicyclic, tricyclic or more cyclic ring systems, and can also be cycloalkyl or heterocyclyl is fused with the proviso that 芳基经由芳香环上的原子通过单键与分子的其余部分连接。 Aryl group is attached via atom on the aromatic ring to the rest of the molecule by a single bond. 比如苯基、萘基、蒽基、菲基、芴基、2,3-二氢-1H-异吲哚基、2-苯并噁唑啉酮、2H-1,4-苯并噁嗪-3 (4H)-酮-7-基等; 芳基烷基是指被芳基所取代的烷基;杂芳基意指环内具有1至15个碳原子和1至6个选自氮、 氧和硫的杂原子的5元至16元共辄环系基团,除非本说明书中另外特别指明,否则杂芳基可为单环、双环、三环或更多环的环体系,还可以与上文所定义的环烷基或杂环基稠合,条件是杂芳基经由芳香环上的原子通过单键与分子的其余部分连接,杂芳基中的氮、碳或硫原子可任选地被氧化;氮原子可任选地被季铵化,本发明杂芳基优选为包含1至5个选自氮、氧和硫的杂原子的稳定的5元至12元芳香性基团,更优选为包含1至4个选自氮、氧和硫的杂原子的稳定的5元至10元芳香性基团或者包含1至3个选自氮、氧和硫的杂原子的5元至6元芳香性基团比如噻吩基、咪唑 Such as phenyl, naphthyl, anthryl, phenanthryl, fluorenyl, 2,3-dihydro -1H- isoindolyl, 2- benzoxazolinone, 2H-1,4- benzoxazine - 3 (4H) - one-7-yl and the like; arylalkyl refers to an alkyl group substituted with an aryl group; having 1 to 15 carbon atoms and 1-6 heteroatoms selected from nitrogen within the meaning aryl ring, oxygen and 5-16 yuan total sulfur heteroatom ring system radical Noir, the present specification unless otherwise specifically indicated otherwise, the heteroaryl ring system may be monocyclic, bicyclic, tricyclic or more rings, and can also be cycloalkyl or heterocyclyl fused to the conditions defined above is heteroaryl connected to the rest of the molecule through a single bond, aromatic ring atoms, heteroaryl group nitrogen, carbon or sulfur atoms may be optionally oxidized; the nitrogen atom may optionally be quaternized, the present invention is preferably a heteroaryl group comprising a stable 5-12 yuan aromatic group 1 to 5 hetero atoms selected from nitrogen, oxygen and sulfur, more preferably from 1 to 4 comprises a stable 5-10 yuan aromatic group selected from nitrogen, oxygen and sulfur atoms or containing from 1 to 3 heteroatoms selected from nitrogen, 5-membered heteroaryl and sulfur atoms to oxygen 6-membered aromatic groups such as thienyl, imidazolyl, 基、吡唑基、噻唑基、噁唑基、噁二唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并咪唑基、苯并吡唑基、剛噪基、呋喃基、吡咯基、三唑基、四唑基、三嗪基、吲嗪基、异吲哚基、吲唑基、异吲唑基、嘌呤基、喹啉基、异喹啉基、二氮萘基、萘啶基、 喹噁啉基、蝶啶基、咔唑基、咔啉基、菲啶基、菲咯啉基、吖啶基、吩嗪基、异噻唑基、苯并噻唑基、苯并噻吩基、噁三唑基、噌啉基、喹唑啉基、苯硫基、中氮茚基、邻二氮杂菲基、异噁唑基、 吩噁嗪基、吩噻嗪基、4,5,6,7-四氢苯并[b]噻吩基、萘并吡啶基、[1,2,4]三唑并[4,3-b]哒嗪、[1,2,4]三唑并[4,3-a]吡嗪、[1,2,4]三唑并[4,3-c]嘧啶、[1,2,4]三唑并[4,3-a]吡啶、咪唑并[1,2-a ]吡啶、咪唑并[1,2-b ]哒嗪、咪唑并[1,2-a]吡嗪等;杂芳基烷基是指被杂芳基所取代的烷基。 Group, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzo pyrazolyl, just noise , furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoindolyl, indazolyl, iso-indazolyl, purinyl, quinolinyl, isoquinolinyl, naphthyridin-yl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazine group, isothiazolyl group, benzothiazolyl group, benzothienyl, oxatriazolyl, cinnolinyl, quinazolinyl, thiophenyl, indolizinyl, o-phenanthroline, isoxazolyl, phenoxazine group, a phenothiazine yl, 4,5,6,7-tetrahydro-benzo [b] thienyl, naphthyl and pyridyl, [1,2,4] triazolo [4,3-b] pyridazine, [1,2, 4] triazolo [4,3-a] pyrazine, [1,2,4] triazolo [4,3-c] pyrimidine, [1,2,4] triazolo [4,3-a ] pyridine, imidazo [1,2-a] pyridine, imidazo [1,2-b] pyridazine, imidazo [1,2-a] pyrazine; heteroarylalkyl, it refers to a heteroaryl group substituted alkyl.

[0028] 立体异构体是指由相同原子组成,通过相同的键键合,但具有不同三维结构的化合物。 [0028] Stereoisomers are defined by the same atoms, bonded by the same bonds but compounds having different three-dimensional structures. 本发明将涵盖各种立体异构体及其混合物。 The present invention contemplates various stereoisomers and mixtures thereof. 互变异构体是指质子从分子的一个原子转移至相同分子的另一个原子而形成的异构体。 Tautomer refers to a proton shift from one atom of a molecule to another atom of the same molecule to form isomers. 本发明的化合物的所有互变异构形式也将包含在本发明的范围内。 All tautomeric forms of the compounds of the present invention will be included within the scope of the present invention. 当本发明的化合物中含有烯双键时,除非另有说明,否则本发明的化合物旨在包含E-和Z-几何异构体。 When the compounds of the present invention contain olefinic double bonds, unless otherwise indicated, the compounds of the present invention is intended to encompass E- and Z- geometric isomers.

[0029] 本发明的化合物或其药学上可接受的盐可能含有一个或多个手性碳原子,且因此可产生对映异构体、非对映异构体及其它立体异构形式。 [0029] The compounds of the present invention or pharmaceutically acceptable salts may contain one or more chiral carbon atoms and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms thereof. 每个手性碳原子可以基于立体化学而被定义为(R)_或(S)-。 Each chiral carbon atoms and may be based on the stereochemistry is defined as (R & lt) _ or (S) -. 本发明公开了所有可能的异构体,以及其外消旋体和光学纯形式。 The present invention disclosed all the possible isomers, as well as racemic and optically pure forms. 本发明的化合物的制备可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。 Preparation of compounds of the invention may be selected racemates, diastereomers or enantiomers as starting materials or intermediates. 光学活性的异构体可以使用手性合成子或手性试剂来制备,或者使用常规技术进行拆分,例如采用结晶以及手性色谱等方法。 The optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example using chiral chromatography methods crystallinity and the like. 制备/分离个别异构体的常规技术包括由合适的光学纯前体的手性合成,或者使用例如手性高效液相色谱法拆分外消旋体(或盐或衍生物的外消旋体)。 Conventional techniques for the preparation / isolation of individual isomers include chiral synthesis from a suitable optically pure precursor, for example an outer or as chiral HPLC racemate (or the racemate of a salt or derivative thereof ).

[0030] 在本申请中,药学上可接受的盐包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。 [0030] In the present application, the pharmaceutically acceptable salts including pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. 药学上可接受的酸加成盐是指能够保留游离碱的生物有效性而无其它副作用的,与无机酸或有机酸所形成的盐。 Pharmaceutically acceptable acid addition salts of the free base refers to the ability to retain the biological effectiveness and no other side effects, inorganic or organic acid salts formed with. 无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等;有机酸盐包括但不限于甲酸盐、乙酸盐、2,2_二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、萘二磺酸盐等。 Inorganic acid salts include but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate and the like; organic acid salts including but not limited to formate, acetate, dichloroacetate 2,2_ , trifluoroacetate, propionate, hexanoate, octanoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, adipic , glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate , alginate, ascorbate, salicylate, 4-amino-salicylate, naphthalene sulfonate. 这些盐可通过本专业已知的方法制备。 These salts may be prepared by methods known in the art. 药学上可接受的碱加成盐是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。 Pharmaceutically acceptable base addition salts refers to the ability to maintain the salts with inorganic or organic bases biological effectiveness of the free acids no other side effects. 衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。 Salts derived from inorganic bases include but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. 优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。 Preferred inorganic salts are the ammonium, sodium, potassium, calcium and magnesium salts. 衍生自有机碱的盐包括但不限于以下的盐:伯胺类、仲胺类及叔胺类,被取代的胺类,包括天然的被取代胺类、环状胺类及碱性离子交换树脂,例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、 哌啶、N-乙基哌啶、聚胺树脂等。 Salts derived from organic bases include, but are not limited to, salts of: primary amines, secondary amines and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins , such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclic hexyl amine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N- ethylpiperidine, polyamine resins and the like. 优选的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱及咖啡因。 Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. 这些盐可通过本专业已知的方法制备。 These salts may be prepared by methods known in the art.

[0031] 多晶型物是指本发明的化合物在固体状态下由于存在两种或两种以上不同分子排列而产生的不同固体结晶相。 [0031] The polymorph of the present invention means a compound in the solid state due to the presence of two or more different molecular arrangement or produced in different solid crystalline phase. 本发明的某些化合物可以存在多于一种晶型,本发明公开了各种晶型及其混合物。 Certain compounds of the present invention may exist in more than one crystal form, the present invention discloses various crystalline forms, and mixtures thereof. 通常,结晶化作用会产生本发明化合物的溶剂化物。 Typically, crystallization of action will produce a solvate of the compound of the present invention.

[0032] 溶剂化物是指包含一个或多个本发明化合物分子与一个或多个溶剂分子的聚集体。 [0032] A solvate refers to a molecule containing one or more compounds of the present invention with one or more solvent molecules aggregate. 溶剂可以是水,该情况下的溶剂化物为水合物。 The solvent may be water, the solvate is a hydrate in this case. 或者,溶剂可以是有机溶剂。 Alternatively, the solvent may be an organic solvent. 因此,本发明的化合物可以以水合物存在,包括单水合物、二水合物、半水合物、倍半水合物、三水合物、四水合物等,以及相应的溶剂化形式。 Accordingly, the compounds of the present invention may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms. 本发明化合物可形成真实的溶剂化物,但在某些情况下,也可以仅保留不定的水或者水加上部分不定溶剂的混合物。 The compounds of this invention may form solvates true, but in some cases, adventitious water or a mixture of water plus solvent may remain uncertain part only. 本发明的化合物可以在溶剂中反应或者从溶剂中沉淀析出或结晶出来。 Compounds of the invention may be reacted in a solvent or crystallization from a solvent or precipitated out.

[0033]本发明还包括偶联物的前药,前药表示可在生理学条件下或通过溶剂分解而被转化成本发明的生物活性化合物的化合物。 [0033] The present invention also encompasses prodrugs of the conjugate, a prodrug can be expressed under physiological conditions or by solvolysis biologically active compound is a compound of the invention, the cost of conversion. 因此,本发明的前药是指化合物的药学上可接受的代谢前体。 Thus, the prodrugs of the invention refers to a precursor compound a pharmaceutically acceptable metabolic precursor. 当被给予有需要的个体时,前药可以不具有活性,但在体内被转化成本发明的活性化合物。 When administered to an individual in need thereof, prodrugs may not be active, but is converted to an active compound of the invention in vivo. 前药通常在体内迅速转化,而产生本发明的母体化合物,例如通过在血液中水解来实现。 Prodrugs are typically rapidly transformed in vivo to yield the parent compound of the present invention, for example by hydrolysis in blood. 前药化合物通常在哺乳动物生物体内提供溶解度、组织相容性或缓释的优点。 The prodrug compound often offers a mammalian organism solubility, tissue compatibility or delayed release of advantages. 前药包括已知的氨基保护基和羧基保护基,具体的前药制备方法属于现有技术。 Prodrugs include known amino-protecting groups and carboxy-protecting groups, specific Prodrugs prior art.

[0034]在本申请中,药物组合物是指本发明偶联物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。 [0034] In the present application, it refers to a formulation of a pharmaceutical composition conjugates of the invention generally accepted in the art for delivering bioactive compounds to a mammal (e.g. human) medium. 该介质包括药学上可接受的载体。 The medium comprises a pharmaceutically acceptable carrier. 药物组合物的目的是促进生物体的给药,利于活性成分的吸收进而发挥生物活性。 Purpose of a pharmaceutical composition is administered to promote organism, facilitates the absorption of the active ingredient and thus exert a biological activity.

[0035] 药学上可接受的是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂),并且相对无毒,即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。 [0035] Pharmaceutically acceptable refers to not affect the biological activity or properties of the compounds of the present invention, a substance (such as a carrier or diluent), and is relatively nontoxic, i.e., the material may be administered to an individual without causing undesirable biological reactions or interact in any way defective component included in the composition. 药学上可接受的载体包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。 Pharmaceutically acceptable carriers include, but are not limited to any government authorities are associated license for acceptable adjuvant, carrier, excipient, glidant human or animal use, sweetening agent, diluent, preservative, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agent, solvent, or emulsifier.

[0036] 肿瘤,细胞增殖异常相关疾病等包括但不限于白血病、胃肠间质瘤、组织细胞性淋巴瘤、非小细胞肺癌、小细胞肺癌、胰腺癌、肺鳞癌、肺腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、宫颈癌、卵巢癌、肠癌、鼻咽癌、脑癌、骨癌、食道癌、黑色素瘤、肾癌、口腔癌等疾病。 [0036] tumor, and other diseases related to abnormal cell proliferation include, but are not limited to leukemia, gastrointestinal stromal tumors, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, lung squamous carcinoma, adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, squamous cell carcinoma, cervical cancer, ovarian cancer, colorectal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, renal cancer, oral cancer and other diseases.

[0037] 有效量、治疗有效量或药学有效量是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。 [0037] an effective amount, the therapeutically effective amount or a pharmaceutically effective amount means an amount of at least one agent or compound after taking a sufficient treatment of the disease or relieve to some extent one or more symptoms of a disorder. 其结果可以为迹象、症状或病因的消减和/或缓解,或生物系统的任何其它所需变化。 The result can be a sign of symptoms or causes of a reduction and / or mitigation, or any other desired changes in biological systems. 例如,用于治疗的有效量是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。 For example, for the treatment of an effective amount to provide a significant amount of a composition comprising a disease-modifying compounds disclosed herein the desired clinical results. 可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。 Determination of an effective amount may be adapted to any individual case using techniques such as a dose escalation trial.

[0038]服用、施用、给药等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。 [0038] administration, administration, administration method and the like refers to a compound or composition capable of be delivered to the desired site of biological action. 这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药,本领域技术人员熟知可用于本文所述化合物和方法的施用技术;本发明优选的实施方案中,偶联物和组合物通过口服施用。 These methods include, but are topical, and rectal administration are not limited to, oral routes, by intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), Those skilled in the art may be used for administration techniques are well known compounds and methods described herein; the present preferred embodiment of the invention, the conjugates and compositions are administered orally.

[0039] 药物组合、药物联用、联合用药、施用其它治疗、施用其它治疗剂等是指通过混合或组合不止一种活性成分而获得的药物治疗,其包括活性成分的固定和不固定组合。 [0039] The pharmaceutical compositions, drug combination, combination therapy, administration of the other therapeutic, refers to the administration of other therapeutic drugs and the like obtained by mixing or combining of more than one active ingredient, comprising a fixed and non-fixed combinations of the active ingredient. 术语"固定组合"是指以单个实体或单个剂型的形式向患者同时施用至少一种本文所述的化合物和至少一种协同药剂。 The term "fixed combination" refers to a form of a single entity or a single dosage form is administered at least one compound described herein to a patient at the same time and at least one synergistic agent. 不固定组合是指以单独实体的形式向患者同时施用、合用或以可变的间隔时间顺次施用至少一种本文所述的化合物和至少一种协同制剂。 Refers to a non-fixed combination is administered as a separate entity to a patient simultaneously, or in combination with a variable time interval sequential administration of said at least one compound described herein and at least one synergistic formulation. 这些也应用到鸡尾酒疗法中,例如施用三种或更多种活性成分。 These also apply to cocktail therapy, e.g. the administration of three or more active ingredients.

[0040] 本领域技术人员还应当理解,在本发明实施例中,中间体化合物官能团可能需要由适当的保护基保护。 [0040] Those skilled in the art will also be appreciated that, in embodiments of the present invention, the functional groups of intermediate compounds may need a suitable protecting group. 这样的官能团包括羟基、氨基、巯基及羧酸。 Such functional groups include hydroxy, amino, mercapto and carboxylic acid. 合适的羟基保护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基(例如叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基等。 Suitable hydroxyl protecting groups include trialkylsilyl group or diaryl alkylsilyl (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl group) , tetrahydropyranyl, benzyl and the like. 合适的氨基、脒基及胍基的保护基包括叔丁氧羰基、苄氧羰基等。 Suitable amino, protected amidino group and guanidino include t-butoxycarbonyl group, benzyloxycarbonyl group and the like. 合适的巯基保护基包括-C(0)_R(其中R为烷基、芳基或芳烷基)、对甲氧基苄基、三苯甲基等合适的羧基;保护基包括烷基、芳基或芳烷基酯类;保护基还可为聚合物树脂。 Suitable protecting groups for mercapto include -C (0) _R (where R is alkyl, aryl or aralkyl group), for a suitable carboxyl-methoxybenzyl, trityl and the like; protecting groups include alkyl, aryl alkyl esters or aralkyl group; protective group may also be a polymer resin. 保护基可根据本领域技术人员已知的技术来引入和除去。 Protecting group can be introduced and removed as known to those skilled in the art.

[0041] 下面结合具体实施例、进一步阐述本发明。 [0041] The following embodiments with reference to specific embodiments, further illustrate the present invention. 应理解、这些实施例仅用于说明本发明而不用于限制本发明的范围。 It should be understood that these embodiments are illustrative only and the present invention is not intended to limit the scope of the invention. 下列实施例中未注明具体条件的实验方法、通常按照常规条件、或按照制造厂商所建议的条件;除非另外说明、否则百分比和份数是重量百分比和重量份数。 Experimental methods without specific conditions in the examples below, are performed under routine conditions, or in accordance with the conditions recommended by the manufacturer; Unless otherwise indicated, percentages and parts are parts by weight and percentages by weight.

[0042]实施例制备通用反应式如下: Ιί 锹S' 本实施例涉及的化合物如下。 Preparation Example [0042] The general reaction formula is as follows: Ιί shovel S 'following the compound according to Example of the present embodiment.

[0043] 中间体: W [0043] Intermediate: W

Figure CN105732643AD00131

ΧΗ NMR (DMSO-de) δ (ppm): 7.64(s,0.5H), 7.58(s, 0.5H), 7.32-7.37(m, 2H), 7.14(s,lH),6.88(t,J=8.4Hz,lH),5.70-5.77(m,lH),3.58-3.64(0.5H),3.91-4.03(m, 0.5H),3.49(d,J=18.8Hz,lH),2.82(ddJ=10.8Hz,18.8Hz,lH),2.31-2.44(m,lH)a.87-2.02(m,3H),1.23-1.74(m,6H). MS (ESI+): m/z 315.2 中间体2: ΧΗ NMR (DMSO-de) δ (ppm): 7.64 (s, 0.5H), 7.58 (s, 0.5H), 7.32-7.37 (m, 2H), 7.14 (s, lH), 6.88 (t, J = 8.4Hz, lH), 5.70-5.77 (m, lH), 3.58-3.64 (0.5H), 3.91-4.03 (m, 0.5H), 3.49 (d, J = 18.8Hz, lH), 2.82 (ddJ = 10.8 hz, 18.8Hz, lH), 2.31-2.44 (m, lH) a.87-2.02 (m, 3H), 1.23-1.74 (m, 6H) MS (ESI +):. m / z 315.2 intermediate 2:

Figure CN105732643AD00132

MS (ESI+): m/z 297.1 中间体:: MS (ESI +): m / z 297.1 Intermediate ::

Figure CN105732643AD00133

/ 将中间体2(297mg, lmmol)和阿司匹林(198mg, lmmol)溶解在二氯甲烧(15mL)中,向上述溶液中依次加入DCC(310mg, 1 · 5mmol)和DMAP( 13mg,0 · lmmol),室温搅拌过夜。 / Intermediate 2 (297mg, lmmol) and aspirin (198mg, lmmol) was dissolved in dichloromethane burning (15mL), the sequentially added to the above solution DCC (310mg, 1 · 5mmol) and DMAP (13mg, 0 · lmmol ), stirred at room temperature overnight. 滤去不溶物,有机相用饱和碳酸氢钠溶液,水,饱和食盐水洗涤,干燥,过滤,浓缩,柱层析分离纯化得到中间体3(298mg,白色固体XMS (ESI+): m/z 459.4。 Insolubles were filtered off, the organic phase was washed with saturated sodium bicarbonate solution, water, saturated brine, dried, filtered, concentrated, separated and purified by column chromatography to give Intermediate 3 (298mg, as a white solid XMS (ESI +): m / z 459.4 .

[0044] 中间体4 [0044] Intermediate 4

Figure CN105732643AD00134

采用中间体3相同的合成方法,以中间体1与阿司匹林为原料,得到中间体4(278mg,白色固体XMS (ESI+): m/z 477.3。 Using the same synthetic process of Intermediate 3, Intermediate 1 and aspirin as a raw material, to give the intermediate 4 (278mg, as a white solid XMS (ESI +): m / z 477.3.

[0045] 实施例一将中间体3(228mg,0.5mmo 1)溶解在甲醇(15mL)中,冰浴冷却下,分批加入硼氢化钠(37mg,lmmol)固体,搅拌半小时,加入饱和氯化铵淬灭反应,二氯甲烷萃取,萃取液依次用饱和碳酸氢钠、水、饱和食盐水洗涤,干燥,过滤,减压浓缩,柱层析分离纯化得到偶联物(192!^白色固体),]\^"31+) :111/2 461.5;化学结构式如下: [0045] The first embodiment of Intermediate 3 (228mg, 0.5mmo 1) was dissolved in methanol (15mL), the ice-bath cooling, was added portionwise sodium borohydride (37mg, lmmol) a solid, stirred for a half hour, saturated chloride The reaction was quenched with ammonium hydroxide, extracted with dichloromethane, the extract was washed with saturated sodium bicarbonate, water, saturated brine, dried, filtered, and concentrated under reduced pressure, separated and purified by column chromatography to give a conjugate (192! ^ as a white solid ),] \ ^ "31+): 111/2 461.5; the following chemical structure:

Figure CN105732643AD00135

[0046] 实施例二采用实施例一相同的方法合成,以中间体4为原料,得到偶联物(178mg,白色固体),MS 化31+):!11/2 479.5;化学结构式如下: [0046] Synthesis of the second embodiment uses a same manner as in Example, intermediate 4 as a raw material, to obtain a conjugate (178 mg, white solid), MS of 31 +) 479.5 :! 11/2; following chemical structure:

Figure CN105732643AD00141

ί ί

[0047] 采用实施例一、实施例二相同的方法合成,用布洛芬,萘普生,吲哚美辛,双氯芬酸等替换阿司匹林,制备得到实施例三~实施例十的偶联物: [0047] The first embodiment, two methods of synthesis of the same embodiment, replace aspirin ibuprofen, naproxen, indomethacin, diclofenac, etc., prepared in Example 3- to ten conjugates Examples:

Figure CN105732643AD00142

第一步:将中间体1(315 mg, 1 mmol)溶于无水DMF(3 mL)中,冰浴冷却下加入NaH (Aldrich, 60% in mineral oil, 60 mg, 1.5 mmol),揽摔10分钟后加入2_漠乙基_2_乙酰氧基苯甲酸酯(316 mg,1.1 mmol)。 The first step: Intermediate 1 (315 mg, 1 mmol) was dissolved in dry DMF (3 mL) was added under ice cooling NaH (Aldrich, 60% in mineral oil, 60 mg, 1.5 mmol), football fall after 10 minutes, desert 2_ _2_ acetoxy ethyl benzoate (316 mg, 1.1 mmol). 反应液缓慢升至室温,继续搅拌60分钟。 The reaction solution was slowly warmed to room temperature, stirring was continued for 60 minutes. 反应液用乙酸乙酯和饱和氯化铵水溶液稀释,分出有机相,分别用水和饱和氯化钠水溶液洗涤,无水硫酸钠干燥,过滤浓缩,柱层析分离到中间体2-((4-(2-(6-氟-5H-咪唑[5,1-a]异B引哚-5-基) 乙酰基)环己基)氧)乙基-2-乙酰氧基苯甲酸酯,用于下步反应。 The reaction solution was diluted with ethyl acetate and saturated aqueous ammonium chloride solution, the organic phase was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated, isolated by column chromatography to intermediate 2 - ((4 - (2- (6-fluoro -5H- imidazo [5,1-a] indol-5-yl iso B) acetyl) cyclohexyl) oxy) ethyl-2-acetoxy-benzoate with in the next reaction. MS (ESI+): m/z 521.3。 MS (ESI +): m / z 521.3.

[0048] 第二步:以上一步获得的中间体2-( (4-(2-(6-氟-5H-咪唑[5,1-a]异吲哚-5-基) 乙酰基)环己基)氧)乙基-2-乙酰氧基苯甲酸酯为原料,采用实施例一相同的方法还原得到偶联物(58mg,白色固体),MS (ESI+): m/z 523.2。 [0048] Second Step: a step above obtained intermediate 2- ((4- (2- (6-fluoro -5H- imidazo [5,1-a] isoindol-5-yl) acetyl) cyclohexyl ) oxy) ethyl-2-acetoxy-benzoate as starting material, using the same manner as in Example was reduced to give a conjugate (58 mg, white solid), MS (ESI +): m / z 523.2.

[0049] 实施例十二 [0049] The twelfth embodiment

Figure CN105732643AD00151

用2-((2-溴乙基)二硫键)乙基-2-乙酰氧基苯甲酸酯代替原料2-溴乙基-2-乙酰氧基苯甲酸酯,采用实施例十一的方法制备得到偶联物(21mg,白色固体),MS (ESI + ): m/z 615.5〇 With 2 - ((2-bromoethyl) disulfide) ethyl-2-acetoxy-benzoate starting material in place of 2-bromo-ethyl-2-acetoxy benzoate, according to the eleventh embodiment using the method of preparing a conjugate obtained (21mg, white solid), MS (ESI +): m / z 615.5〇

[0050] 实施例十三 [0050] Embodiment 13

Figure CN105732643AD00152

用2-(2-溴乙氧基)乙基-2-乙酰氧基苯甲酸酯代替原料2-溴乙基-2-乙酰氧基苯甲酸酯,采用实施例十一的方法制备得到偶联物(20mg,白色固体),MS (ESI+): m/z 615.5。 2- (2-bromoethoxy) ethyl-2-acetoxy-benzoate starting material in place of 2-bromo-ethyl-2-acetoxy benzoate, obtained using the method according to the eleventh embodiment was prepared conjugate (20mg, white solid), MS (ESI +): m / z 615.5. [0051 ]实施例十四偶联物对rh-IDO酶活性的抑制作用重组人源ID0(大肠杆菌,HEK293细胞)将色氨酸氧化裂解成Ν'-甲酰基犬尿酸⑶'-formylkynurenine)。 [0051] Embodiment 14 conjugates on rh-IDO inhibitory activity the ID0 human recombinant (E. coli, HEK293 cells) oxidative cleavage of tryptophan to kynurenine Ν'- formyl ⑶'-formylkynurenine). 利用这一特点,建立体外筛选评价体系。 Using this feature, the establishment of evaluation system in vitro screening. 甲酰基犬尿酸量的变化可以通过比色方法测定(参考美国R&D公司试剂盒使用指南)。 Formyl kynurenine change amount can be measured (refer to US forego R & D kit Guide) colorimetric method. 底物与酶作用动力学可以参考现有的方法测定(JBC 1980,255,1339-1345)。 Substrate with enzyme kinetics can be measured with reference to a conventional method (JBC 1980,255,1339-1345).

[0052] 材料:缓冲液,50mM MES, pH 6·5;0·405Μ Tris, pH 8.0;重组人-ID0酶(Catalog#6030-A0) ; L-抗坏血酸,配成500mM的去离子水溶液;L-色氨酸配成1 OmM的去离子水溶液;催化酶(Sigma),用缓冲液配成100000u/mL的溶液;甲基蓝, 配成10mM的去离子水溶液;读数仪器:SpectraMax Plus by MolecularDevices。 [0052] Materials: Buffer, 50mM MES, pH 6 · 5; 0 · 405Μ Tris, pH 8.0; -ID0 recombinant human enzyme (Catalog # 6030-A0); L- ascorbic acid formulated in deionized water of 500mM; L - tryptophan formulated in deionized water to 1 OmM; catalase (Sigma), with a buffer 100000u / mL was dubbed; methylene blue, 10mM formulated in deionized water; instrument readings: SpectraMax Plus by MolecularDevices.

[0053] 步骤:1、将L-抗坏血酸溶液用Tris缓冲液稀释至80mM;用缓冲液配置SOOuML-色氨酸,9000u/mL催化酶,40uM甲基蓝的底物混合溶液;待用。 [0053] Step: 1, L- ascorbic acid solution was diluted with Tris buffer to 80mM; Tryptophan arranged SOOuML- buffer, 9000u / mL catalase, 40 uM substrate methylene blue mixed solution; stand.

[0054] 2、将重组人-ID0酶用缓冲液稀释至16 ng/uL。 [0054] 2, the recombinant human -ID0 enzyme was diluted to 16 ng / uL buffer.

[0055] 3、将50uL的16 ng/uL的重组人-ID0酶置于筛选板中,然后加入50uL底物混合液开始反应。 Recombinant human [0055] 3, of the 16 ng 50uL / uL of enzyme -ID0 filter plate was placed, followed by addition of 50uL of substrate to start the reaction mixture.

[0056] 4、加入本发明受试偶联物后孵育后,记录Amax= 321 nm处的读数,与空白对照比对,测算出受试偶联物对ID0酶的抑制活性。 [0056] 4. After incubation after addition of the test conjugates of the invention, the recording Amax = 321 nm at the reading, comparison with the control, measure inhibitory activity of the test ID0 enzyme conjugate.

[0057]上述方法测试表明,本发明实施例偶联物对重组人-ID0酶的抑制活性均小于luM, 优于1-MT的抑制活性。 [0057] The test methods described above show embodiments of the present invention conjugates inhibitory activity on recombinant human enzyme were less than -ID0 Lum, superior inhibitory activity of 1-MT.

[0058]应理解,在阅读了本发明的公开内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所限定的范围。 [0058] It should be understood, after reading the present disclosure, one skilled in the art that various changes or modifications may be made to the present invention, and these equivalents also fall within the range defined herein.

Claims (10)

1. 一种如式I所示的偶联物; 1. A conjugate of formula I as shown;
Figure CN105732643AC00021
式中:R选自氢、卤素、氰基、取代或未取代的C1-C6烷基、烷氧基、取代或未取代的氨基中的一种;R1为非留体抗炎药母核结构;所述非留体抗炎药为阿司匹林、对乙酰氨基酚、吲哚美辛、萘普生、萘普酮、双氯芬酸、布洛芬、尼美舒利、罗非昔布或者塞来昔布;uag-(CH2CH2) 、- (CH2CH2OCH2CH2) 、- (CH2CH2NR7CH2CH2)mM-、- (CH2CH2SCH2CH2)mM-、- (CH2CH2SSCH2CH2)』-中的一种,其中m为0~6,R7为氢或烷基;当m为0时,M不存在;当m为1~6 时,M为0、N或者S。 Formula: one R is selected from hydrogen, halo, cyano, a substituted or unsubstituted C1-C6 alkyl, alkoxy, substituted or unsubstituted amino group; Rl non-steroidal anti-inflammatory drug core structure ; the non-steroidal anti-inflammatory drugs as aspirin, acetaminophen, indomethacin, naproxen, nabumetone, diclofenac, ibuprofen, nimesulide, rofecoxib or celecoxib ; uag- (CH2CH2), - (CH2CH2OCH2CH2), - (CH2CH2NR7CH2CH2) mM -, - (CH2CH2SCH2CH2) mM -, - (CH2CH2SSCH2CH2) "- a medium, wherein m is 0 ~ 6, R7 is hydrogen or alkyl ; when m is 0, m is not present; and when m is 1 ~ 6, m is 0, N or S.
2. 根据权利要求1所述偶联物,其特征在于:取代的C1-C6烷基、取代的氨基中取代基独立地选自卤素、0!1、順2、01未取代或卤代的(:1-08烷基、未取代或卤代的03-08环烷基、未取代或卤代的C1-C8烷氧基、未取代或卤代的C2-C6烯基、未取代或卤代的C2-C6炔基、未取代或卤代的C2-C6酰基、未取代或卤代的4~8元饱和杂环或碳环中的一种或几种;其中,所述杂环包含N、0或S中的一种或几种。 The conjugate according to claim 1, wherein: the substituted C1-C6 alkyl, substituted amino substituents independently selected from halogen, 01, cis-2,01 unsubstituted or halogenated! (: 1-08 alkyl, unsubstituted or halogenated 03-08 cycloalkyl, unsubstituted or halogenated C1-C8 alkoxy, unsubstituted or halogenated C2-C6 alkenyl group, an unsubstituted or halo substituted C2-C6 alkynyl group, an unsubstituted or halogenated C2-C6 acyl, unsubstituted or substituted 4 to 8-membered saturated carbocyclic or heterocyclic ring of one or several halogenated; wherein said heterocycle comprising N, 0 or S, one or several.
3. 根据权利要求1所述偶联物,其特征在于:R选自氢或者卤素;R1为 3. The conjugate claimed in claim 1, wherein: R is selected from hydrogen or halo; Rl is
Figure CN105732643AC00022
Figure CN105732643AC00023
,其中R2为氢或者乙酰基;R3 为氢或者C1-C6的烷基;R6为氢或者C1-C6的烷基;R4为氢或者C1-C3的烷基;R5为氢、烷基或者卤素。 Wherein R2 is hydrogen or acetyl; R3 is hydrogen or a C1-C6 alkyl; R6 is hydrogen or a C1-C6 alkyl; R4 is hydrogen or C1-C3 alkyl; R5 is hydrogen, alkyl or halo .
4. 根据权利要求1所述偶联物,其特征在于,所述偶联物的化学结构式为以下结构式中的一种: 4. The conjugate according to claim 1, characterized in that the chemical structure of the conjugate is one of the following structural formulas:
Figure CN105732643AC00024
5. -种权利要求1所述偶联物的对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物、前药或药学结构上可接受的盐。 Of the enantiomers, diastereomers thereof, tautomers, solvates, polymorphs, prodrugs or a pharmaceutically acceptable salt thereof of the structure 1 conjugate of claim species - 5 .
6. 权利要求1所述偶联物的制备方法,其特征在于,包括以下步骤: 在碱性条件下,于溶剂A中,将化合物1与化合物2进行反应得到化合物3;于溶剂B中,将化合物3与还原试剂发生反应,得到式I所示的偶联物; The method of preparing the conjugate of claim 1, characterized in that, comprising the steps of: under basic conditions, in solvent A, compound 1 with compound 2 to give compound 3; solvent B, compound 3 reacts with a reducing agent to give a conjugate of formula I;
Figure CN105732643AC00031
所述化合物1的结构式为: 所述化合物2的结构式为: 其中,LG为离去基团; 所述化合物3的结构式为: The compound of formula 1 is: The compound of Formula 2: wherein, LG is a leaving group; the compound of formula 3 is:
Figure CN105732643AC00032
7. 根据权利要求6所述偶联物的制备方法,其特征在于:溶剂A、溶剂B独立的选自水、甲醇、乙醇、异丙醇、乙二醇、N-甲基吡咯烷酮、二甲基亚砜,四氢呋喃、甲苯、二氯甲烷、1,2_二氯乙烷、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二氧六环中的一种或几种;碱选自氢氧化钾、醋酸钠、醋酸钾、叔丁醇钾、叔丁醇钠、氟化钾、氟化铯、磷酸钾、碳酸钾、碳酸氢钾、 碳酸钠、碳酸氢钠、吡啶,三乙胺,N,N-二异丙基乙胺、1,8_二氮杂二环[5.4.0]^碳-7-烯、六甲基二硅基锂、六甲基二硅基钠、二甲基吡啶中的一种或几种;还原剂选自氢气、硼氢化钠、三乙酰氧基硼氢化钠、氰基硼氢化钠、硼烷、异丙醇铝中的一种或几种。 7. The method of preparing the conjugate according to claim 6, characterized in that: the solvent A, solvent B independently is selected from water, methanol, ethanol, isopropanol, ethylene glycol, N- methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, methylene chloride, 1,2_ dichloroethane, acetonitrile, N, N- dimethylformamide, N, N- dimethylacetamide, dioxane in a or more species; base is selected from potassium hydroxide, sodium acetate, potassium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium hydrogencarbonate, pyridine, triethylamine, N, N- diisopropylethylamine, 1,8_-diazabicyclo [5.4.0] undec-7-ene ^, lithium hexamethyldisilazide, six sodium dimethyl silicon, lutidine one or more; the reducing agent is selected from hydrogen, sodium borohydride, triacetoxy sodium borohydride, sodium cyanoborohydride, borane, aluminum isopropoxide of one or more.
8. -种IDO酶抑制剂、非留体抗炎药或者药物组合物,其特征在于:所述IDO酶抑制剂为式I所示的偶联物、式I所示偶联物的对映异构体、式I所示偶联物的非对映异构体、式I所示偶联物的互变异构体、式I所示偶联物的溶剂化物、式I所示偶联物的多晶型物、式I所示偶联物的前药或式I所示偶联物的药学结构上可接受的盐;所述非留体抗炎药为式I所示的偶联物、式I所示偶联物的对映异构体、式I所示偶联物的非对映异构体、式I所示偶联物的互变异构体、式I所示偶联物的溶剂化物、式I所示偶联物的多晶型物、式I所示偶联物的前药或式I所示偶联物的药学结构上可接受的盐;所述药物组合物包括式I所示的偶联物、式I所示偶联物的对映异构体、式I所示偶联物的非对映异构体、式I所示偶联物的互变异构体、式I所示偶联物的溶剂化物、式I所示偶联物的多晶型物、式I 8. - kind of IDO inhibitors, non-steroidal anti-inflammatory drug or a pharmaceutical composition, characterized in that: said IDO inhibitor is a conjugate of Formula I, Formula I enantiomerically conjugate isomer of formula I diastereomers thereof conjugates of formula I as tautomers conjugates of formula I solvates conjugate, conjugate of formula I polymorph thereof, a prodrug of formula I conjugate structure pharmaceutically acceptable salt thereof or a conjugate of formula I; coupling said non-steroidal anti-inflammatory agent is of formula I I was shown even formula I diastereomeric enantiomers thereof, of formula I conjugates conjugate, tautomers shown conjugates of formula I, formula I polymorph solvate thereof linked, the conjugate of formula I, formula I a prodrug conjugate structure pharmaceutically acceptable salt thereof, or conjugate of formula I; the pharmaceutical composition conjugate comprises tautomers of formula I represented by formula I diastereomeric enantiomers thereof, of formula I conjugates conjugates, the conjugate of formula I shown isomer polymorphs, solvates of formula I conjugates, the conjugate of formula I as shown in formula I 示偶联物的前药或式I所示偶联物的药学结构上可接受的盐。 Shown prodrug conjugate of formula I or a pharmaceutically acceptable salt of a conjugate structure.
9. 式I所示的偶联物、式I所示偶联物的对映异构体、式I所示偶联物的非对映异构体、 式I所示偶联物的互变异构体、式I所示偶联物的溶剂化物、式I所示偶联物的多晶型物、式I 所示偶联物的前药或式I所示偶联物的药学结构上可接受的盐在制备药物中的应用;所述药物包括IDO酶抑制剂、非留体抗炎药、治疗或预防肿瘤药物。 Diastereomeric enantiomers thereof, of Formula I shown in FIG 9. The conjugate of Formula I conjugates, the conjugate of Formula I, the conjugate of Formula I as shown interconversion structure acceptable prodrug conjugate shown isomers polymorphs, solvates of formula I conjugate, the conjugate of formula I, formula I or a conjugate of formula I application in the manufacture of a pharmaceutical acceptable salt thereof in the; the IDO inhibitor drugs include non-steroidal anti-inflammatory drugs, treatment or prevention of cancer drugs.
10. -种中间体,其特征在于,所述中间体的结构式为: 10. - intermediate species, which is characterized in that the intermediate of the formula:
Figure CN105732643AC00041
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