CN104861063A - HER2 positive tumor targeting compound and composition thereof - Google Patents

HER2 positive tumor targeting compound and composition thereof Download PDF

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CN104861063A
CN104861063A CN 201410011262 CN201410011262A CN104861063A CN 104861063 A CN104861063 A CN 104861063A CN 201410011262 CN201410011262 CN 201410011262 CN 201410011262 A CN201410011262 A CN 201410011262A CN 104861063 A CN104861063 A CN 104861063A
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compound
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positive
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李立新
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博笛生物科技有限公司
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Abstract

The present invention provides a HER2 positive tumor targeting compound and a composition thereof, and relates to a compound used for the targeting immunotherapy method, and a composition containing the compound. The present invention further relates to applications of the compound in treatment of HER2-positive tumors/cancers.

Description

靶向HER2阳性肿瘤的化合物和组合物 HER2-positive tumor targeting compounds and compositions

技术领域 FIELD

[0001] 本发明涉及用于靶向免疫疗法的化合物以及含有该化合物的组合物。 [0001] The present invention relates to compositions comprising a compound for targeted immune therapy and containing the compound. 本发明还涉及所述化合物在治疗诸如癌症之类的疾病中的应用。 The present invention further relates to the use of the compounds in the treatment of diseases such as cancer in.

背景技术 Background technique

[0002] 治疗性抗体已用于临床应用二十多年。 [0002] Therapeutic antibodies have been used in clinical applications twenty years. 目前已有十五种抗肿瘤抗体药物用于临床,这些药物包括:Rituxan (1997),Herceptin (1998),Mylotarg (2000),Campath (20 01), Zeval in(2002), Bexxer(2003), Avastin (2004),Erbitux (2004),Vectibix (2006); Arzerra(2009);Benlysta(2011);Yervoy(2011);Adcetris(2011) ;Perjeta(2012);和Kadcyla(2013)。 There are fifteen kinds of drugs used in clinical anti-tumor antibodies, these drugs include: Rituxan (1997), Herceptin (1998), Mylotarg (2000), Campath (20 01), Zeval in (2002), Bexxer (2003), Avastin (2004), Erbitux (2004), Vectibix (2006); Arzerra (2009); Benlysta (2011); Yervoy (2011); Adcetris (2011); Perjeta (2012); and Kadcyla (2013). 这些抗体主要靶定四种分子:EGFR、Her2、CD20和VEGF。 These four kinds of antibodies are mainly targeted molecules: EGFR, Her2, CD20, and VEGF.

[0003] 总体而言,治疗性抗体通过三种机制(Scott AM, Wolchok JD, Old LJ. Antibody therapy of cancer.Nat Rev Cancer. (2012), 12:278-87)杀伤肿瘤细胞:(1)抗体直接作用,也就是阻断或激动配体/受体信号转导活性,诱导细胞凋亡并递送药物或细胞毒素剂。 [0003] In general, therapeutic antibodies by three mechanisms (Scott AM, Wolchok JD, Old LJ Antibody therapy of cancer.Nat Rev Cancer (2012), 12:.. 278-87) to kill tumor cells: (1) antibodies direct effect, i.e. to block or agonistic ligand / receptor signaling activity, induction of apoptosis and deliver the drug or cytotoxic agent. 抗体受体活化活性可产生直接杀伤肿瘤细胞的作用。 Antibodies receptor activation activity may have a direct role in tumor cell killing. 例如,一些抗体可与肿瘤细胞表面的受体结合,活化受体,导致细胞凋亡(例如,在线粒体中)。 For example, some antibodies may bind to tumor cell surface receptors, receptor activation, leading to apoptosis (e.g., in the mitochondria). 抗体还可通过受体拮抗活性介导肿瘤细胞杀伤。 Antagonistic activity of antibodies can also mediate tumor cell killing by receptor. 例如,一些抗体可与细胞表面受体结合并阻断二聚化作用、激酶活化以及下游信号转导,从而抑制增殖并促进细胞凋亡。 For example, some antibodies may bind to cell surface receptors and block dimerization, kinase activation, and downstream signaling, thereby inhibiting proliferation and promote apoptosis. 抗体与酶的结合可导致中和作用、信号阻断以及细胞死亡。 Binding of antibodies to the enzyme may lead to neutralization, and the signal blocking cell death. (2)免疫介导的细胞杀伤机制,该机制包括补体依赖性细胞毒性(CDC)、抗体依赖性细胞介导的细胞毒性(ADCC)、T细胞功能调节,等等。 (2) anti-cell-mediated immune mechanisms, which mechanisms include complement dependent cytotoxicity (the CDC), antibody-dependent cellular cytotoxicity mediated by cells (ADCC), T cell function regulation, and the like. 免疫介导的肿瘤细胞杀伤可通过如下方式完成:诱导吞噬作用、活化补体、抗体依赖性细胞介导的细胞毒性、通过单链可变片段(scFv)使基因修饰的T细胞祀定肿瘤,通过树突细胞的抗体介导的抗原交叉呈递活化T细胞、抑制T细胞抑制性受体(例如,细胞毒性T淋巴细胞相关抗原4 (CTLA4))。 Immune-mediated tumor cell killing can be accomplished by: inducing phagocytosis, complement activation, antibody dependent cell-mediated cytotoxicity of cells, a single chain variable fragment (scFv) of gene-modified T cell tumor Si given by antibody-mediated antigen cross-presentation dendritic cells activated T cells, suppressor T cell inhibitory receptor (e.g., cytotoxic T lymphocyte associated antigen 4 (CTLA4)). 其中,抗体的Fc部分的特性对于CDC和ADCC介导的肿瘤细胞杀伤作用特别重要。 Wherein the characteristics of the Fc portion of the antibody is particularly important for cytotoxicity CDC and ADCC mediated tumor cell. (3)抗体对肿瘤脉管系统和基质的特异性效应,通过捕获血管受体拮抗剂或配体诱导血管和基质细胞消融,包括:抑制基质细胞、将毒素递送至基质细胞以及将毒素递送至脉管系统(Scott AM, Wolchok JD, Old LJ. Antibody therapy of cancer.Nat Rev Cancer. 2012, 12(4):278-87)〇 (3) Effect of antibodies specific for the tumor vasculature and stroma, blood vessels by capturing receptor antagonist or ligand-induced ablation of blood vessels and stromal cells, including: inhibition of stromal cells, stromal cells delivered to the toxin, and the toxin is delivered to the vasculature (Scott AM, Wolchok JD, Old LJ Antibody therapy of cancer.Nat Rev Cancer 2012, 12 (4):.. 278-87) square

[0004] 治疗性单克隆抗体药物推进了抗癌药物的研宄和开发。 [0004] therapeutic monoclonal antibody drug development and to promote the study based anti-cancer drugs. 然而,仍然存在一些问题需要进一步研宄解决,例如,抗体的免疫原性、长期使用肿瘤靶标的耐受性以及单纯地单一阻断信号转导通路的长期作用。 However, there are still some problems to be solved for further study based on, for example, immunogenicity of the antibody, the use of long-term tolerance of tumor targets as well as long term effect simply a single block signal transduction pathways. 简言之,大多数抗体难以实现对肿瘤细胞长期有效的抑制和杀伤作用。 In short, most of the antibody difficult to achieve long-term effective inhibition of tumor cells and in vitro.

[0005] 1964年,"自然(Nature)"杂志发表了抗体-药物偶联(ADC)技术这一新观点,该观点近年来得到突破性发展。 [0005] 1964, "Nature (Nature)" magazine published an antibody - drug conjugates (ADC) technology in this new view, the breakthrough point of view in recent years. ADC使抗体与高毒性药物(毒素)通过化学连接体(连接体)共价连接。 ADC antibody with highly toxic drugs (toxins) linker (linker) covalently linked by a chemical. 抗体识别癌细胞表面抗原分子,内吞作用将ADC带入细胞质内,具体而言,连接体水解之后释放的细胞内环境毒素杀伤细胞。 Antibody recognizes a cancer cell surface antigen molecules, endocytosis into the cytoplasm of the ADC, specifically, after the release of the connector body hydrolysis environmental toxins killer cells.

[0006] Seattle Genetics 已研发了Brentuximab Vedotin (商品名为Adcetris)这种药物,其已被FDA批准上市。 [0006] Seattle Genetics has developed Brentuximab Vedotin (trade name Adcetris) drug that has been approved for marketing FDA. 其为单甲基auristatin E(MMAE),一种合成的毒性抗癌药物,其与靶向淋巴瘤细胞特异性CD30分子的抗体连接,具有改进的杀伤肿瘤细胞的效用。 Thereof, a synthetic cytotoxic anticancer drugs, for antibody targeting of lymphoma cells specific for the CD30 molecule to monomethyl auristatin E (MMAE), have improved tumor cell killing effect.

[0007] 目前,已对几十种这样的ADC药物开展了临床试验。 [0007] At present, the ADC of dozens of such drugs to carry out clinical trials. 其中,Genentech和Immunogen 联合开发了用于治疗乳腺癌的与美登素(maytansine)偶联的曲妥珠单抗,一种名为ado-曲安珠单抗emtansine的药物(Kadcyla),其也被称为T-DM1。2013年2月,FDA已批准T-DMl用于人表皮生长因子受体2 (Her2)-阳性转移性乳腺癌。 Which, Genentech and Immunogen jointly developed with maytansine (maytansine) coupled trastuzumab for the treatment of breast cancer, a ado- triamcinolone drug trastuzumab emtansine (Kadcyla) is named, which is also is referred to as T-DM1 2013 dated 2 years, FDA has approved T-DMl for human epidermal growth factor receptor 2 (Her2) -. positive metastatic breast cancer. 美登素是一种小分子毒素,其可与微管蛋白结合并可通过形成非还原性双-马来酰亚胺-丙二醇复合物防止微管形成。 Maytansine is a small molecule toxins, which can bind to tubulin and by forming a non-reducing-bis - maleimide - propanediol composite prevent microtubule formation. 曲妥珠单抗通过靶向人Her2对乳腺癌和胃癌起作用。 Trastuzumab works with breast cancer and stomach cancer by targeting people Her2. 曲妥珠单抗已被批准用于Her2-阳性癌症。 Trastuzumab has been approved for Her2- positive cancer. 然而,曲妥珠单抗无法促进所有的Her2-阳性细胞的细胞凋亡。 However, trastuzumab can not promote apoptosis all Her2- positive cells. T-DMl使选择性靶向Her2受体的曲妥珠单抗与有效的细胞毒性剂美登素结合,从而杀伤肿瘤细胞。 Selective targeting of T-DMl so Her2 receptor trastuzumab in combination with an effective cytotoxic agent maytansinoid to kill tumor cells. T-DMl抗体结合Her2受体,导致从偶联物中释放的美登素产生细胞内在化作用,从而杀伤肿瘤细胞。 T-DMl Her2 antibody binding receptors, resulting in the release of the maytansinoid conjugate internalization effect generated cells to kill tumor cells. T-DMl具有更好的整体疗效、药代动力学性质以及较低的毒性。 T-DMl with better overall efficacy, pharmacokinetic properties and low toxicity.

[0008] 传统的小分子化疗药物具有很强的毒性和药代动力学优势,但是在治疗肿瘤的过程中传统的小分子化疗药物可影响其他生理靶标,产生严重的副作用。 [0008] The traditional small molecule chemotherapeutic drugs are highly toxic and pharmacokinetic advantages, but in the treatment of tumors in a conventional small molecule chemotherapeutic drugs can affect other physiological targets, serious side effects. 抗体-药物偶联物使靶向作用和具有特定的药代动力学的小分子药物结合。 Antibody - that the targeting of drug conjugates having specific pharmacokinetic binding of a small molecule drug. 抗体-药物偶联物的结构为具有靶向功能的单克隆抗体与具有特定的药理学性质的化合物的连接。 Antibody - drug conjugates having the structure of a monoclonal antibody targeting function connected to a particular compound having a pharmacological properties. 这种技术需要治疗性抗体与靶标特异性结合,与诸如细胞毒素之类的具有治疗作用或其他功能的分子偶联。 This technique requires therapeutic antibody specifically binding to a target, such as a cytotoxic effect or the like having a therapeutic or other functional molecules are coupled. 诸如偶联的抗体的内吞作用、偶联的稳定性以及毒素的释放和杀伤活性之类的许多因素影响这种类型的抗体的作用。 Endocytosis such conjugated antibodies, the stability of a number of factors and the release of toxins conjugated to cytotoxic activity and antibody-like effect of this type.

[0009] 目前正在使用的毒素分子包括微管蛋白抑制剂Auristatin类似物单甲基auristatin E、单甲基auristatin F和美登素。 [0009] Toxin molecules currently in use include microtubule inhibitors Auristatin analogs monomethyl auristatin E, monomethyl auristatin F maytansine. 单甲基auristatin E为合成的微管聚合物抑制剂,其可抑制微管聚集,干扰肿瘤细胞有丝分裂并且可诱导细胞凋亡(Naumovski L and Junutula JR. Glembatumumab vedotin, a conjugate of an anti-glycoprotein non-metastatic melanoma protein B mAb and monomethyl auristatin E for treatment of melanoma and breast cancer. Curr Opin Mol Ther2003;12(2):248-57. Francisco JA, Cerveny CG 等人,cAClO-vcMMAE, an anti-CD30_monomethyl auristatin E conjugate with potent and selective antitumor activity. Bloodl02 (4):1458-65)。 Monomethyl auristatin E is a synthetic polymer microtubule inhibitors, which inhibit microtubule aggregation, tumor interfere with cellular mitosis and may induce apoptosis (Naumovski L and Junutula JR. Glembatumumab vedotin, a conjugate of an anti-glycoprotein non . -metastatic melanoma protein B mAb and monomethyl auristatin E for treatment of melanoma and breast cancer Curr Opin Mol Ther2003; 12 (2):. 248-57 Francisco JA, Cerveny CG et al., cAClO-vcMMAE, an anti-CD30_monomethyl auristatin E conjugate with potent and selective antitumor activity Bloodl02 (4):. 1458-65). 单甲基auristatin F为抗有丝分裂Auristatin衍生物,在C末端具有带电荷的苯丙氨酸残基。 Monomethyl auristatin F as antimitotic Auristatin derivative, having a phenylalanine residue at the C-terminal charged. 与不带电荷的MMAE相比,单甲基auristatin F最小化对细胞信号通路的破坏并且最小化细胞毒性。 Compared with uncharged MMAE, monomethyl auristatin F to minimize damage to the intracellular signaling pathways and to minimize cytotoxicity. 大量CD30细胞测试发现mAb-马来酰亚胺己酰基-缬氨酸-瓜氨酸-P-氨基苄氧基羰基-MMAF (mAb-Ll-MMAF)的毒性比单独的MMAF的毒性强2, 200倍(Doronina SO 等人,Enhanced activity of monomethyl auristatin F through monoclonal antibody delivery: effects of I inker technology on efficacy and toxicity. Bioconjug Chem,2006; 17(1) :pll4-24)。 Testing a large number of CD30 cells was found mAb- maleimidocaproyl- - valine - citrulline amino -P- benzyloxycarbonyl -MMAF (mAb-Ll-MMAF) is stronger than the individual toxic toxic 2 MMAF, 200 times (Doronina SO et al., Enhanced activity of monomethyl auristatin F through monoclonal antibody delivery: effects of I inker technology on efficacy and toxicity Bioconjug Chem, 2006; 17 (1):. pll4-24). 美登素是一种抗有丝分裂剂,其充当微管蛋白聚合的抑制剂, 干扰细胞核内的微管的形成。 Maytansine is an antimitotic agent which acts as an inhibitor of tubulin polymerization, interfere with microtubule formation in the nucleus. 美登素还抑制DNA、RNA和蛋白质合成,已经发现美登素对于DNA合成的影响最大。 Maytansinoid also inhibit DNA, RNA and protein synthesis, it has been found that the greatest impact maytansinoid DNA synthesis.

[0010] 抗体-药物偶联物具有直接和间接抗癌作用。 [0010] Antibody - drug conjugate having direct and indirect anti-cancer effect. 抗体阻断或活化配体/受体信号转导,诱导细胞凋亡,并且同时抗体可直接或间接地向肿瘤细胞呈递或递送有效载荷药物(例如,药物、毒素、小干扰RNA或放射性同位素)。 Or activating antibody blocks ligand / receptor signaling, induces apoptosis, and at the same antibody may be presented or delivered to the tumor cells directly or indirectly payload drugs (e.g., drugs, toxins, radioisotopes or small interfering RNA) . 治疗性抗体药物偶联物使用抗体和偶联的药物的双重特性,第一为与靶标分子特异性结合的结合功能,第二为抗体自身的肿瘤细胞杀伤功能,以及第三为偶联的药物的特定作用。 Dual characteristics therapeutic antibody drug conjugates using antibody and conjugated drug, as a first specific binding to a target molecule binding functions, the second is an antibody own tumor cell killing function, and a third drug is conjugated the specific role. 目前使用的抗体-药物偶联药物限于如何直接杀伤肿瘤细胞。 Currently used antibody - drug conjugates limited to how drugs kill tumor cells directly. 然而,由于在抗体、连接体分子、毒素分子、偶联方面的严格的技术要求以及能够将毒素带入肿瘤微环境内的分子有限,在实际的临床研宄中仍然存在一些难题。 However, due to the stringent technical requirements in the antibody, linker molecule, toxin molecule, and can be coupled aspects of toxins into finite elements within the tumor microenvironment, there are still some problems in actual clinical study based on in.

发明内容 SUMMARY

[0011] -方面,本发明提供一种具有通式(Ia)的结构的化合物或其药学上可接受的盐或其溶剂化物: [0011] - aspect, the present invention provides pharmaceutically having formula (Ia) compound of structure or a pharmaceutically acceptable salt or solvate thereof:

[0012] TM-L-AM (Ia), [0012] TM-L-AM (Ia),

[0013] 其中,TM是与Her2/Neu特异性结合的抗体或其功能片段(例如,抗-Her2的抗体), AM为由下述通式(I)的结构表示的活化部分: [0013] where, TM is specifically binding to Her2 / Neu antibody or functional fragment thereof (e.g., antibodies against the -Her2), AM by the following formula (I) represented by the structure of the activated portion:

[0014] [0014]

Figure CN104861063AD00141

[0015] 其中,虚线表示存在化学键或不存在化学键,~为待与连接体连接的点; [0015] wherein the dotted line represents presence of a bond or absence of a bond, - to be connected to the connecting point of the body;

[0016] X 是S 或-NR1,札是-W〇-W1-W2-W3-W 4; [0016] X is S or -NR1, Sapporo is -W〇-W1-W2-W3-W 4;

[0017] Wtl是化学键,烷基,烯基,炔基,烷氧基或-烷基-S-烷基一, [0017] Wtl is a bond, alkyl, alkenyl, alkynyl, alkoxy, or - an alkyl group -S-,

[0018] W1是化学键,一0 -,或-NR 2-,其中,R2是氛,烷基或條基, [0018] W1 is a bond, 10 - or -NR 2-, wherein, R2 is the atmosphere, an alkyl group or strip,

[0019] W2是化学键,一0-,一C (0) ―,一C (S)-或-S (0) 2-, [0019] W2 is a bond, a 0-, a C (0) -, a C (S) - or -S (0) 2-,

[0020] W3是化学键,一NR 3一,其中,R3是氛,烷基或條基, [0020] W3 is a bond, a NR 3 a, wherein, R3 is the atmosphere, an alkyl group or strip,

[0021] W4是氣,烷基,條基,炔基,烷氧基,环烷基,芳基,芳氧基,杂芳基或杂环基,它们中的每一个被一个或一个以上选自下列基团的取代基任选地取代:羟基,烷氧基,烷基,烯基,炔基,环烷基,芳基,杂芳基,杂环基,一NH 2,硝基,一烷基-羟基,一烷基-芳基,一烧基-杂芳基,一烷基-杂环基,一O-R4^ 一〇_烷基-I,一烷基-O-R4,一C(0)-R4,-烧基-C (0) -R4,一烷基-C (0) -O-R4,一C (0) -O-R4,一S-R4,一S (0) 2-R4,一NH-S (0) 2-R4,一烧基-S-R4,一烷基-S (0) 2_R4, 一NHR4, -NR4R4^ -NH-烷基-R4,卤素,一CN,一腸2和-SH,其中,R4独立地为氢,烷基,烯基,一烷基-羟基,芳基,杂芳基,杂环基或卤代烷基; [0021] W4 is air, alkyl, article, alkynyl, alkoxy, cycloalkyl, aryl, aryloxy, heteroaryl or heterocyclyl, each of them with one or more selected from optionally substituted by substituents from the group consisting of: hydroxy, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, a heterocyclic group, a NH 2, nitro, a alkyl - hydroxy, an alkyl - aryl group, a burn-yl - heteroaryl group, an alkyl - heterocyclic group, a O-R4 ^ a 〇_ alkyl -I, a group -O-R4, a C (0) -R4, - burning group -C (0) -R4, a group -C (0) -O-R4, a C (0) -O-R4, a S-R4, a S (0 ) 2-R4, a NH-S (0) 2-R4, a group burn -S-R4, a group -S (0) 2_R4, a NHR4, -NR4R4 ^ -NH- group -R4, halo, a CN, and a bowel 2 -SH, wherein, R4 is independently hydrogen, an alkyl group, an alkenyl group, an alkyl - hydroxy, aryl, heteroaryl, heterocyclyl, or haloalkyl;

[0022] Z是氣,烷基,條基,炔基,烷氧基,芳基,卤代烷基,杂芳基,杂环基,它们中的每一个可被一个或一个以上选自下列基团的取代基任选地取代:羟基,烷氧基,烷基,烯基, 炔基,芳基,杂芳基,杂环基,卤素,氛基,硝基,一N(R 5) 2,一烷氧基-烷基,一烷氧基_稀基,一C (O)-烷基,一C (0) -〇-烷基,一OC (0)-烷基,一C (0) -N(R5) 2,芳基,杂芳基,一CO-芳基和-CO-杂芳基,其中,馬分别独立地为氢,烷基,卤代烷基,一烷基-芳基或-烷基-杂芳基; [0022] Z is a gas, alkyl, article group, an alkynyl group, an alkoxy group, an aryl group, haloalkyl, heteroaryl, heterocyclyl, each of which may be substituted with one or more groups selected from optionally substituted with substituents: hydroxy, alkoxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halo, atmosphere group, a nitro group, a N (R 5) 2, an alkoxy - alkyl group, an alkoxy group dilute _, a C (O) - alkyl, a C (0) -〇- alkyl group, a OC (0) - alkyl, a C (0) -N (R5) 2, aryl, heteroaryl, aryl-CO- and -CO- a heteroaryl, wherein Ma is independently hydrogen, alkyl, haloalkyl, an alkyl - or aryl - alkyl - heteroaryl;

[0023] R为氣,烷基,烷氧基,[if代烷基,[if素,芳基,杂芳基,杂环基,它们中的每被一个或一个以上选自下列基团的取代基任选地取代:羟基,烷氧基,烷基,烯基,炔基,环烷基, 芳基,杂芳基,杂环基,一NH 2,硝基,一烷基-羟基,一烷基-芳基,一烷基-杂芳基,一烧基-杂环基,一O-R4,一0_ 烷基-R4, 一烷基-O-R4,一C (0) -R4,一C (0) -NH-R4,一C (0) -NR4R4,-_ 烷基-C (0) -R4,一烷基-C (0) -O-R4,一C (0) -O-R4,一0-C (0) -R4,一S-R4,一C (0) -S-R4,一SC ( 0) -R4»一S (0) 2_R4, 一NH-S (0) 2_R4,一烷基-S-R4,一烷基-S (0) 2-R4, 一NHR4,一NR4 R4,一NH-烧基-R4,卤素,一CN和-SH,其中,R4独立地为氢,烷基,烯基,烷氧基,一烷基-羟基,芳基, 杂芳基,杂环基,或卤代烷基; [0023] R is the gas, an alkyl group, an alkoxy group, [IF-substituted alkyl, [IF prime, aryl, heteroaryl, heterocyclyl, each of them with one or more groups selected from optionally substituted with substituents: hydroxy, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, a heterocyclic group, a NH 2, nitro, a group - hydroxy, an alkyl - aryl group, an alkyl - aryl, heteroaryl, a group burn - a heterocyclic group, a O-R4, a group -R4 0_, a group -O-R4, a C (0) -R4 , a C (0) -NH-R4, a C (0) -NR4R4, -_ group -C (0) -R4, a group -C (0) -O-R4, a C (0) - O-R4, a 0-C (0) -R4, a S-R4, a C (0) -S-R4, a SC (0) -R4 »a S (0) 2_R4, a NH-S (0 ) 2_R4, a group -S-R4, a group -S (0) 2-R4, a NHR4, a NR4 R4, a group -R4 burn NH-, halogen, a CN and -SH, wherein, R4 independently are is hydrogen, an alkyl group, an alkenyl group, an alkoxy group, an alkyl - hydroxy, aryl, heteroaryl, heterocyclyl, or haloalkyl;

[0024] η 为0,1,2,3 或4; [0024] η 3, or 4;

[0025] Y为- NR6R7,-CR6R7Ri^ -烷基-NH2,它们中的每一个可被一个或一个以上选自下列基团的取代基任选地取代:羟基,烷氧基,烷基,烯基,炔基,一NH 2,卤素,一N(R5)2,-烧氧基_烷基,一烷氧基_條基,一C(O)-烷基,一C (0)-〇-烷基,一C (0)-N(R5) 2,芳基,杂芳基,一CO-芳基和-CO-杂芳基, [0025] Y is - NR6R7, -CR6R7Ri ^ - alkyl -NH2, each of which may be one of them or more substituents selected from the following group optionally substituted groups: hydroxy, alkoxy, alkyl, alkenyl group, an alkynyl group, an NH 2, a halogen, a N (R5) 2, - burning _ alkyl group, an alkoxy group _ bars, a C (O) - alkyl, a C (0) - 〇- alkyl group, a C (0) -N (R5) 2, aryl, heteroaryl, aryl-CO- and -CO- a heteroaryl group,

[0026] 其中,R6,1?7和R 8独立地为氣,烷基,條基,烷氧基,烷基氣基,^烷基氣基,烧硫基, 芳硫基,一烷基-羟基,一烷基-C (0) -O-R9,一烷基-C (0) -R9或-烷基-〇_C (0) -R 9,其中, 1?5分别独立地为氢,烷基,卤代烷基,一烷基-芳基或一烷基-杂芳基,其中,R 9为氢,烷基, 烯基,卤素或卤代烷基; [0026] wherein, R6,1? 7 and R 8 are independently air, alkyl, article group, an alkoxy group, an alkyl group gas, gas ^ alkyl group, burning arylthio group, an alkyl group - a hydroxyl group, a group -C (0) -O-R9, a group -C (0) -R9 or -? alkyl -〇_C (0) -R 9, wherein 15 each independently hydrogen, alkyl, haloalkyl, monoalkylamino - an aryl group or an alkyl - heteroaryl, wherein, R 9 is hydrogen, alkyl, alkenyl, halo or haloalkyl;

[0027] 任选地,X和Z-同可形成5至9元环。 [0027] Optionally, X may be formed with the Z- and 5-9 yuan ring.

[0028] 在一些实施方式中,AM是通式(I)的化合物,其选自:2_丙基噻唑并[4, 5-c]喹啉-4-胺,1-(2-甲基丙基)-1Η-咪唑并[4, 5-c]喹啉-4-胺,4-氨基-2-(乙氧基甲基)-a, a-二-甲基-IH-咪唑并[4, 5-c]喹啉-1-乙醇,1-(4-氨基-2-乙基氨基甲基咪唑并-[4, 5-c]喹啉-1-基)-2-甲基丙-2-醇,N-[4-(4-氨基-2-乙基-IH-咪唑并[4, 5-c] 喹啉-1-基)丁基-]甲磺酰胺,4-氨基-2-乙氧基甲基-aa-二甲基-6, 7, 8, 9-四氢-IH-咪唑并[4, 5-c]喹啉-1-乙醇,4-氨基-aa-二甲基-2-甲氧基乙基-IH-咪唑并[4, 5-c]喹啉-1-乙醇,1-{2-[3-(苄氧基)丙氧基]乙基}-2-(乙氧基甲基)-IH-咪唑并[4, 5-c]喹啉-4-胺,N-[4-(4-氨基-2-丁基-IH-咪唑并[4, 5-c] [1,5]萘啶-1-基)丁基]-n'_ 丁基脲,Nl-[2-(4-氨基-2-丁基-IH-咪唑并[4, 5-c] [1,5]萘啶-1-基)乙基]-2-氨基-4-甲基戊酰胺,N-(2-{2-[4-氨基-2-(2-甲氧基乙基)-IH-咪唑并[4, 5-c]喹啉-1-基]乙氧基}乙基)-η' -苯基 [0028] In some embodiments, AM is a compound of formula (I) is selected from: propyl 2_ thiazolo [4, 5-c] quinolin-4-amine, 1- (2-methyl propyl) -1Η- imidazo [4, 5-c] quinolin-4-amine, 4-amino-2- (ethoxymethyl) -a, a- two - methyl -IH- imidazo [ 4, 5-c] quinoline-1-ethanol, 1- (4-aminomethyl-2-ethyl imidazo - [4, 5-c] quinolin-1-yl) -2-methyl-propyl 2-ol, N-[4- (4-amino-2-ethyl -IH- imidazo [4, 5-c] quinolin-1-yl) butyl -] methanesulfonamide, 4-amino - -aa- 2-ethoxymethyl-dimethyl-6, 7, 8, 9-tetrahydro -IH- imidazo [4, 5-c] quinoline-1-ethanol, 4-amino -aa- two methyl-2-methoxyethyl -IH- imidazo [4, 5-c] quinoline-1-ethanol, 1- {2- [3- (benzyloxy) propoxy] ethyl} - 2- (ethoxymethyl) -IH- imidazo [4, 5-c] quinolin-4-amine, N- [4- (4- amino-2-butyl -IH- imidazo [4, 5-c] [1,5] naphthyridin-1-yl) butyl] -n'_ butyl urea, nl- [2- (4- amino-2-butyl -IH- imidazo [4, 5 -c] [1,5] naphthyridin-1-yl) ethyl] -2-amino-4-methyl-pentanamide, N- (2- {2- [4- amino-2- (2-methoxy yl ethyl) -IH- imidazo [4, 5-c] quinolin-1-yl] ethoxy} ethyl) -η '- phenyl 脲,1- (2-氨基-2-甲基丙基)-2-(乙氧基甲基)-IH-咪唑并[4, 5-c] 喹啉-4-胺,1-{4-[(3,5_二氯苯基)磺酰基]丁基}-2_乙基-IH-咪唑并[4,5-c]喹啉-4-胺,N-(2-{2-[4-氨基-2-(乙氧基甲基)-1Η-咪唑并[4,5-c]喹啉-1-基]乙氧基}乙基)-n'_环己基脲,N-{3-[4-氨基-2-(乙氧基甲基)-1Η-咪唑并[4,5-c]喹啉-1-基]丙基} -η' - (3-氰基苯基)硫脲,N- [3- (4-氨基-2- 丁基-IH-咪唑并[4, 5-c] 喹啉-1-基)-2, 2-二甲基丙基]苯甲酰胺,2-丁基-1-[3-(甲基磺酰基)丙基]-IH-咪唑并[4, 5-c]喹啉-4-胺,N- {2- [4-氨基-2-(乙氧基甲基)-IH-咪唑并[4, 5-c]喹啉-1-基]-1,1-二甲基乙基}-2-乙氧基乙酰胺,1-[4_氨基-2-乙氧基甲基-7-(吡啶-4-基)-IH-咪唑并[4, 5-c]喹啉-1-基]-2-甲基丙-2-醇,I-[4-氨基-2-(乙氧基甲基)-7-(吡啶-3-基)-IH-咪唑并[4, 5-c]喹啉-1-基]-2-甲基丙-2-醇,N-{3-[4-氨基-1-(2-羟基-2-甲基丙基)-2-(甲氧基乙基)-IH-咪唑并[4, 5-c]喹 Urea, 1- (2-amino-2-methylpropyl) -2- (ethoxymethyl) -IH- imidazo [4, 5-c] quinolin-4-amine, 1- {4- [(3,5_-dichlorophenyl) sulfonyl] butyl} ethyl -2_ -IH- imidazo [4,5-c] quinolin-4-amine, N- (2- {2- [ 4-amino-2- (ethoxymethyl) -1Η- imidazo [4,5-c] quinolin-1-yl] ethoxy} ethyl) -n'_ cyclohexylurea, N- { 3- [4-amino-2- (ethoxymethyl) -1Η- imidazo [4,5-c] quinolin-1-yl] propyl} -η '- (3- cyanophenyl) thiourea, N- [3- (4- amino-2-butyl -IH- imidazo [4, 5-c] quinolin-1-yl) -2,2-dimethylpropyl] benzamide , 2-butyl-1- [3- (methylsulfonyl) propyl] -IH- imidazo [4, 5-c] quinolin-4-amine, N- {2- [4- amino-2 - (ethoxymethyl) -IH- imidazo [4, 5-c] quinolin-1-yl] -1,1-dimethylethyl} -2-ethoxy-acetamide, 1- [ 4_ amino-2-ethoxymethyl-7- (pyridin-4-yl) -IH- imidazo [4, 5-c] quinolin-1-yl] -2-methyl-propan-2-ol , I- [4- amino-2- (ethoxymethyl) -7- (pyridin-3-yl) -IH- imidazo [4, 5-c] quinolin-1-yl] -2- yl-2-ol, N- {3- [4- amino-1- (2-hydroxy-2-methylpropyl) -2- (methoxyethyl) -IH- imidazo [4, 5 -c] quinoline 啉-7-基]苯基}甲磺酰胺,1- [4-氨基-7- (5-羟基甲基吡啶-3-基)-2- (2-甲氧基乙基)-IH-咪唑并[4, 5-c] 喹啉-1-基]-2-甲基丙-2-醇,3-[4-氨基-2-(乙氧基甲基)-7-(吡啶-3-基)-IH-咪唑并[4,5-c]喹啉-1-基]丙-1,2-二醇,1-[2-(4_氨基-2-乙氧基甲基-IH-咪唑并[4,5-c]喹啉-1-基)-1,1-二甲基乙基]-3-丙基脲,1-[2-(4_氨基-2-乙氧基甲基-IH-咪唑并[4,5-c]喹啉-1-基)-1,1-二甲基乙基]-3-环戊基脲,1-[(2,2_二甲基-1,3-二氧戊环-4-基)甲基]-2-(乙氧基甲基)-7- (4-羟基甲基苯基)-IH-咪唑并[4, 5-c]喹啉-4-胺,4-[4_氨基-2-乙氧基甲基-1-(2-羟基-2-甲基丙基)-1Η-咪唑并[4,5-c] 喹啉-7-基]-N-甲氧基-N-甲基苯甲酰胺,2-乙氧基甲基-NI-异丙基-6, 7, 8, 9-四氢-IH-咪唑并[4, 5-c]喹啉-1,4-二胺,1-[4-氨基-2-乙基-7-(吡啶-4-基)-IH-咪唑并[4, 5-c]喹啉-1-基]-2-甲基丙-2-醇,N-[4-(4-氨基-2-乙基-IH-咪唑并[4, 5-c] 喹啉-1-基)丁基]甲磺 7-yl] phenyl} methanesulfonamide, 1- [4-amino-7- (5-hydroxymethyl-pyridin-3-yl) -2- (2-methoxyethyl) -IH- imidazole and [4, 5-c] quinolin-1-yl] -2-methyl-propan-2-ol, 3- [4-amino-2- (ethoxymethyl) -7- (pyridin-3 yl) -IH- imidazo [4,5-c] quinolin-1-yl] propan-1,2-diol, 1- [2- (4_ amino-2-ethoxymethyl -IH- imidazo [4,5-c] quinolin-1-yl) -1,1-dimethyl-ethyl] -3-propyl-urea, 1- [2- (2-ethoxy-methyl-amino 4_ yl -IH- imidazo [4,5-c] quinolin-1-yl) -1,1-dimethylethyl] -3-cyclopentyl-urea, 1 - [(dimethylamino 2,2_ 1,3-dioxolan-4-yl) methyl] -2- (ethoxymethyl) -7- (4-hydroxy-methylphenyl) -IH- imidazo [4, 5-c ] quinolin-4-amine, 4- [4_ amino-2-ethoxymethyl-1- (2-hydroxy-2-methylpropyl) -1Η- imidazo [4,5-c] quinolin -7-yl] -N- methoxy -N- methyl-benzamide, 2-ethoxymethyl -NI- isopropyl-6, 7, 8, 9-tetrahydro-imidazo -IH- [4, 5-c] quinoline-1,4-diamine, 1- [4-amino-2-ethyl-7- (pyridin-4-yl) -IH- imidazo [4, 5-c] quinolin-1-yl] -2-methyl-propan-2-ol, N- [4- (4- ethyl--IH- imidazo [4, 5-c] quinolin-1-yl ) butyl] methanesulfonamide 胺,或N-[4-(4-氨基-2- 丁基-IH-咪唑并[4, 5-c] [1,5]萘啶-1-基)丁基]-η'-环己基脲。 Amine, or N- [4- (4- amino-2-butyl -IH- imidazo [4, 5-c] [1,5] naphthyridin-1-yl) butyl] -η'- cyclohexyl urea. 在一些实施方式中,L由下述通式(II)的结构表示: In some embodiments, L is represented by the following structural formula (II) is:

Figure CN104861063AD00161

[0029] m为1,2,3,4,5或6,b分别独立地为0或1,并且D由下述通式(III)的结构独立地表示: [0029] m is 1,2,3,4,5 or 6, b are independently 0 or 1, and D is independently represented by the following structural formula (III) is:

Figure CN104861063AD00162

[0030] 其中,i分别独立地为0或I ;j分别独立地为0,1,2,3,4,5或6 ; [0030] where, i are independently 0 or I; j each independently 0,1,2,3,4,5 or 6;

[0031] A分别独立地为S,0或N-Ra,其中,Ra为氢,烷基,烯基或烷氧基; [0031] A is independently S, 0 or N-Ra, wherein, Ra of the hydrogen, alkyl, alkenyl or alkoxy;

[0032] B分别独立地为烷基,條基,一O-烷基一,一烷基-0 -,一S-烷基一,一烷基-S-, 芳基,杂芳基,杂环基或肽,它们中的每一个被一个或一个以上选自下列基团的取代基任选地取代:羟基,烷氧基,烷基,烯基,炔基,环烷基,一烷基-芳基,一烷基-杂芳基,一烷基-杂环基,一O-R4,一〇_ 烷基-Rp -C(O) -R4^ 一C (0) -O-R4,一S-R4,一S (0) 2-R4, 一NHR4,一NH -烷基-R4,卤素,一CN,一NO2,和-SH,其中,R4为烷基,烯基,一烷基-羟基,芳基,杂芳基, 杂环基或卤代烷基。 [0032] B is independently an alkyl group, article group, an O- alkyl mono, monoalkylamino -0--, a S- group a, a group -S-, aryl, heteroaryl, heteroaryl group or a cyclic peptide, each of them with one or more groups selected from substituent group is optionally substituted with: hydroxy, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, monoalkylamino - an aryl group, an alkyl - aryl, heteroaryl, a group - a heterocyclic group, a O-R4, an alkyl 〇_ -Rp -C (O) -R4 ^ a C (0) -O-R4, a S-R4, a S (0) 2-R4, a NHR4, an NH - group -R4, halogen, a CN, an NO2, and -SH, wherein, R4 is an alkyl group, an alkenyl group, an alkyl group - hydroxy, aryl, heteroaryl, heterocyclyl or haloalkyl.

[0033] 在一些实施方式中,连接体由下述通式(V)至通式(VII)的结构表示: [0033] In some embodiments, the linker is represented by the following structural formula (V) to formula (VII) is:

[0034] [0034]

Figure CN104861063AD00171

[0035] A、B、i和j为上文中所界定的。 [0035] A, B, i and j are as defined above.

[0036] 在一些实施方式中,所述连接体选自:SI, S2, S3, S4,S5, S6,S7, -Gly-Phe-Leu-G Iy-, -Ala-Leu-Ala-Leu-, -Phe-Arg-, -Phe-Lys-, -Val-Lys-, -Val-Ala-,或Val-Cit-,其中,SI至S7由下述结构表示: [0036] In some embodiments, the linker is selected from: SI, S2, S3, S4, S5, S6, S7, -Gly-Phe-Leu-G Iy-, -Ala-Leu-Ala-Leu- , -Phe-Arg-, -Phe-Lys-, -Val-Lys-, -Val-Ala-, or Val-Cit-, wherein, SI to S7 represented by the following structure:

[0037] [0037]

Figure CN104861063AD00172

[0038] [0038]

Figure CN104861063AD00181

[0039] [0039]

Figure CN104861063AD00191

[0040] 其中,m分别独立地为1至20。 [0040] wherein, m are each independently 1 to 20.

[0041] 在一些实施方式中,抗体为曲妥珠单抗(赫赛汀),帕妥珠单抗或margetuximab (MGAH22)〇 [0041] In some embodiments, the antibody is trastuzumab (Herceptin), pertuzumab or margetuximab (MGAH22) square

[0042] 在一些实施方式中,了11是抗-册1?2抗体,1^选自:31,32,33,34,35,36,37,-61 y-Phe-Leu-Gly-,-Ala-Leu-Ala-Leu-,-Phe-Arg-,-Phe-Lys-,-Val-Lys-,-Val-Ala-,或Val-Cit-;AM是通式(I)的化合物,其选自:2-丙基噻唑并[4, 5-c]喹啉-4-胺,I-(2-甲基丙基)-1Η-咪唑并[4, 5-c]喹啉-4-胺,4-氨基-2-(乙氧基甲基)-a,a-二-甲基-IH-咪唑并[4, 5-c]喹啉-1-乙醇,1-(4-氨基-2-乙基氨基甲基咪唑并-[4, 5-c]喹啉-1-基)-2-甲基丙-2-醇,N-[4-(4-氨基-2-乙基-IH-咪唑并[4, 5-c]喹啉-1-基) 丁基-]甲磺酰胺,4-氨基-2-乙氧基甲基-aa-二甲基-6, 7, 8, 9-四氢-IH-咪唑并[4, 5-c]喹啉-1-乙醇,4-氨基-aa-二甲基-2-甲氧基乙基-IH-咪唑并[4, 5-c]喹啉-1-乙醇,1-{2-[3-(苄氧基)丙氧基]乙基}-2-(乙氧基甲基)-IH-咪唑并[4, 5-c]喹啉-4-胺,N-[4-(4-氨基-2-丁基-IH-咪唑并[4, 5-c] [1,5]萘啶-1-基)丁基]-n'_ 丁基脲,Nl-[2-(4-氨基-2-丁基-IH-咪唑并[4, 5-c] [0042] In some embodiments, the anti-11 - Antibody Volume 12, 1 ^ is selected from: 31,32,33,34,35,36,37, -61 y-Phe-Leu-Gly-,? -Ala-Leu-Ala-Leu -, - Phe-Arg -, - Phe-Lys -, - Val-Lys -, - Val-Ala-, or Val-Cit-; AM is a compound of formula (I), and selected from: 2-propyl-thiazolo [4, 5-c] quinolin-4-amine, I- (2- methylpropyl) -1Η- imidazo [4, 5-c] quinolin-4 - amine, 4-amino-2- (ethoxymethyl) -a, a- two - methyl -IH- imidazo [4, 5-c] quinoline-1-ethanol, 1- (4- -2-ethylamino-methylimidazo - [4, 5-c] quinolin-1-yl) -2-methyl-propan-2-ol, N- [4- (4- amino-2-ethyl -IH- imidazo [4, 5-c] quinolin-1-yl) butyl -] methanesulfonamide, 4-amino-2-ethoxymethyl--aa- dimethyl-6, 7, 8 -tetrahydro -IH- imidazo [4, 5-c] quinoline-1-ethanol, 4-amino -aa--dimethyl-2-methoxyethyl -IH- imidazo [4, 5 -C] quinoline-1-ethanol, 1- {2- [3- (benzyloxy) propoxy] ethyl} -2- (ethoxymethyl) -IH- imidazo [4, 5- c] quinolin-4-amine, N- [4- (4- amino-2-butyl -IH- imidazo [4, 5-c] [1,5] naphthyridin-1-yl) butyl] -n'_ butyl urea, nl- [2- (4- amino-2-butyl -IH- imidazo [4, 5-c] [1,5]萘啶-1-基)乙基]-2-氨基-4-甲基戊酰胺,N-(2-{2-[4-氨基-2-(2-甲氧基乙基)-IH-咪唑并[4, 5-c]喹啉-1-基]乙氧基}乙基)-η' -苯基脲,1- (2-氨基-2-甲基丙基)-2-(乙氧基甲基)-IH-咪唑并[4, 5-c] 喹啉-4-胺,1-{4-[(3,5_二氯苯基)磺酰基]丁基}-2_乙基-IH-咪唑并[4,5-c]喹啉-4-胺,N-(2-{2-[4-氨基-2-(乙氧基甲基)-1Η-咪唑并[4,5-c]喹啉-1-基]乙氧基}乙基)-n'_环己基脲,N-{3-[4_氨基-2-(乙氧基甲基)-IH-咪唑并[4, 5-c]喹啉-1-基]丙基} -η' - (3-氰基苯基)硫脲,N- [3- (4-氨基-2- 丁基-IH-咪唑并[4, 5-c] 喹啉-1-基)-2, 2-二甲基丙基]苯甲酰胺,2-丁基-1-[3-(甲基磺酰基)丙基]-IH-咪唑并[4, 5-c]喹啉-4-胺,N- {2- [4-氨基-2-(乙氧基甲基)-IH-咪唑并[4, 5-c]喹啉-1-基]-1,1-二甲基乙基}-2-乙氧基乙酰胺,1-[4_氨基-2-乙氧基甲基-7-(吡啶-4-基)-IH-咪唑并[4, 5-c]喹啉-1-基]-2-甲基丙-2-醇,1-[4-氨基-2-(乙氧基甲基 [1,5] naphthyridin-1-yl) ethyl] -2-amino-4-methyl-pentanamide, N- (2- {2- [4- amino-2- (2-methoxyethyl ) -IH- imidazo [4, 5-c] quinolin-1-yl] ethoxy} ethyl) -η '- phenyl urea, 1- (2-amino-2-methylpropyl) - 2- (ethoxymethyl) -IH- imidazo [4, 5-c] quinolin-4-amine, 1- {4 - [(3,5_-dichlorophenyl) sulfonyl] butyl} -2_ ethyl -IH- imidazo [4,5-c] quinolin-4-amine, N- (2- {2- [4- amino-2- (ethoxymethyl) -1Η- imidazole and [4,5-c] quinolin-1-yl] ethoxy} ethyl) -n'_ cyclohexylurea, N- {3- [4_-amino-2- (ethoxymethyl) - IH- imidazo [4, 5-c] quinolin-1-yl] propyl} -η '- (3- cyanophenyl) thiourea, N- [3- (4- amino-2-butyl -IH- imidazo [4, 5-c] quinolin-1-yl) -2,2-dimethylpropyl] benzamide, 2-butyl-1- [3- (methylsulfonyl) propyl] -IH- imidazo [4, 5-c] quinolin-4-amine, N- {2- [4- amino-2- (ethoxymethyl) -IH- imidazo [4, 5 -C] quinolin-1-yl] -1,1-dimethylethyl} -2-ethoxy acetamide, l- [4_ amino-2-ethoxymethyl-7- (pyridin - 4- yl) -IH- imidazo [4, 5-c] quinolin-1-yl] -2-methyl-propan-2-ol, 1- [4-amino-2- (ethoxymethyl -7-(吡啶-3-基)-IH-咪唑并[4, 5-c]喹啉-1-基]-2-甲基丙-2-醇,N-{3-[4-氨基-I-(2-羟基-2-甲基丙基)-2-(甲氧基乙基)-IH-咪唑并[4, 5-C]喹啉-7-基]苯基}甲磺酰胺,1- [4-氨基-7- (5-羟基甲基吡啶-3-基)-2- (2-甲氧基乙基)-IH-咪唑并[4, 5-c] 喹啉-1-基]-2-甲基丙-2-醇,3-[4-氨基-2-(乙氧基甲基)-7-(吡啶-3-基)-IH-咪唑并[4,5-c]喹啉-1-基]丙-1,2-二醇,1-[2-(4_氨基-2-乙氧基甲基-IH-咪唑并[4,5-c]喹啉-1-基)-1,1-二甲基乙基]-3-丙基脲,1-[2-(4_氨基-2-乙氧基甲基-IH-咪唑并[4,5-c]喹啉-1-基)-1,1-二甲基乙基]-3-环戊基脲,1-[(2,2_二甲基-1,3-二氧戊环-4-基)甲基]-2-(乙氧基甲基)-7- (4-羟基甲基苯基)-IH-咪唑并[4, 5-c]喹啉-4-胺,4-[4_氨基-2-乙氧基甲基-1-(2-羟基-2-甲基丙基)-1Η-咪唑并[4,5-c] 喹啉-7-基]-N-甲氧基-N-甲基苯甲酰胺,2-乙氧基甲基-NI-异丙基-6, 7, 8, 9-四氢-IH-咪唑并[4, 5-c]喹啉-1,4-二胺,1-[4 7- (pyridin-3-yl) -IH- imidazo [4, 5-c] quinolin-1-yl] -2-methyl-propan-2-ol, N- {3- [4- amino - I- (2- hydroxy-2-methylpropyl) -2- (methoxyethyl) -IH- imidazo [4, 5-C] quinolin-7-yl] phenyl} methanesulfonamide, 1- [4-amino-7- (5-hydroxymethyl-pyridin-3-yl) -2- (2-methoxyethyl) -IH- imidazo [4, 5-c] quinolin-1 yl] -2-methyl-propan-2-ol, 3- [4-amino-2- (ethoxymethyl) -7- (pyridin-3-yl) -IH- imidazo [4,5-c ] quinolin-1-yl] propan-1,2-diol, 1- [2- (4_-amino-2-ethoxymethyl--IH- imidazo [4,5-c] quinolin-l - yl) -1,1-dimethyl-ethyl] -3-propyl-urea, 1- [2- (4_-amino-2-ethoxymethyl--IH- imidazo [4,5-c] quinolin-1-yl) -1,1-dimethylethyl] -3-cyclopentyl-urea, 1 - [(2,2_-dimethyl-1,3-dioxolan-4-yl ) methyl] -2- (ethoxymethyl) -7- (4-hydroxy-methylphenyl) -IH- imidazo [4, 5-c] quinolin-4-amine, 4- [4 _ amino-2-ethoxymethyl-1- (2-hydroxy-2-methylpropyl) -1Η- imidazo [4,5-c] quinolin-7-yl] -N- methoxy - N- methylbenzamide, 2- ethoxymethyl -NI- isopropyl-6, 7, 8, 9-tetrahydro -IH- imidazo [4, 5-c] quinolin-1,4 - diamine, l- [4 -氨基-2-乙基-7-(吡啶-4-基)-IH-咪唑并[4, 5-c]喹啉-1-基]-2-甲基丙-2-醇,N-[4-(4-氨基-2-乙基-IH-咪唑并[4, 5-c] 喹啉-1-基)丁基]甲磺酰胺,或N-[4-(4-氨基-2- 丁基-IH-咪唑并[4, 5-c] [1,5]萘啶-1-基)丁基]-n'_环己基脲,其中,喹啉环上的胺基团为与连接体连接的点。 - 2-ethyl-7- (pyridin-4-yl) -IH- imidazo [4, 5-c] quinolin-1-yl] -2-methyl-propan-2-ol, N- [ 4- (4-amino-2-ethyl -IH- imidazo [4, 5-c] quinolin-1-yl) butyl] methanesulfonamide, N-or [4- (4-amino-2- butyl -IH- imidazo [4, 5-c] [1,5] naphthyridin-1-yl) butyl] -n'_ cyclohexylurea, wherein the amine group on the quinoline ring is connected body connection point. 优选地, 抗-HER2抗体为曲妥珠单抗(赫赛汀)、帕妥珠单抗或margetuximab (MGAH22) ;L为Sl,S2 或S3。 Preferably, the anti -HER2 antibody is trastuzumab (Herceptin), pertuzumab or margetuximab (MGAH22); L is a Sl, S2 or S3. 同样优选地,抗-HER2抗体为曲妥珠单抗(赫赛汀);AM为瑞喹莫德或咪喹莫特,其中, 喹啉环上的胺基团为与连接体连接的点。 Also preferably, the antibody is an anti--HER2 trastuzumab (Herceptin); AM is resiquimod or imiquimod, wherein the amine group on the quinoline ring is connected to the connecting point thereof.

[0043] 另一方面,本发明提供具有下述通式A至通式C的结构的化合物或其药学上可接受的盐或其溶剂化物: [0043] another aspect, the present invention provides a compound of the structure or a pharmaceutically acceptable salt or solvate thereof having the following general formula A to C are:

[0044] [0044]

Figure CN104861063AD00211

[0045] 在通式A至通式C的一种实施方式中,抗-HER2抗体是曲妥珠单抗(赫赛汀),帕妥珠单抗或margetuximab (MGAH22);通式(I)的化合物选自:2_丙基噻挫并[4,5_c]喹啉-4-胺,1-(2-甲基丙基)-1Η-咪唑并[4, 5-c]喹啉-4-胺,4-氨基-2-(乙氧基甲基)-a, a-二-甲基-IH-咪唑并[4, 5-c]喹啉-1-乙醇,1-(4-氨基-2-乙基氨基甲基咪唑并-[4, 5-c]喹啉-1-基)-2-甲基丙-2-醇,N-[4-(4-氨基-2-乙基-IH-咪唑并[4, 5-c] 喹啉-1-基)丁基-]甲磺酰胺,4-氨基-2-乙氧基甲基-aa-二甲基-6, 7, 8, 9-四氢-IH-咪唑并[4, 5-c]喹啉-1-乙醇,4-氨基-aa-二甲基-2-甲氧基乙基-IH-咪唑并[4, 5-c]喹啉-1-乙醇,1-{2-[3-(苄氧基)丙氧基]乙基}-2-(乙氧基甲基)-IH-咪唑并[4, 5-c]喹啉-4-胺,N-[4-(4-氨基-2-丁基-IH-咪唑并[4, 5-c] [1,5]萘啶-1-基)丁基]-n'_ 丁基脲,Nl-[2-(4-氨基-2-丁基-IH-咪唑并[4,5-c] [1,5]萘啶-1-基)乙基]-2-氨基-4-甲基戊酰胺,N-(2-{2-[4- [0045] In Formula A Formula C to one embodiment, the antibody is an anti--HER2 trastuzumab (Herceptin), pertuzumab or margetuximab (MGAH22); formula (I) compound selected from: propyl-thiazol setback and 2_ [4,5_c] quinolin-4-amine, 1- (2-methylpropyl) -1Η- imidazo [4, 5-c] quinolin-4 - amine, 4-amino-2- (ethoxymethyl) -a, a- two - methyl -IH- imidazo [4, 5-c] quinoline-1-ethanol, 1- (4- -2-ethylamino-methylimidazo - [4, 5-c] quinolin-1-yl) -2-methyl-propan-2-ol, N- [4- (4- amino-2-ethyl -IH- imidazo [4, 5-c] quinolin-1-yl) butyl -] methanesulfonamide, 4-amino-2-ethoxymethyl--aa- dimethyl-6, 7, 8 -tetrahydro -IH- imidazo [4, 5-c] quinoline-1-ethanol, 4-amino -aa--dimethyl-2-methoxyethyl -IH- imidazo [4, 5 -C] quinoline-1-ethanol, 1- {2- [3- (benzyloxy) propoxy] ethyl} -2- (ethoxymethyl) -IH- imidazo [4, 5- c] quinolin-4-amine, N- [4- (4- amino-2-butyl -IH- imidazo [4, 5-c] [1,5] naphthyridin-1-yl) butyl] -n'_ butyl urea, nl- [2- (4- amino-2-butyl -IH- imidazo [4,5-c] [1,5] naphthyridin-1-yl) ethyl] - 2-amino-4-methyl-pentanamide, N- (2- {2- [4- 基-2-(2-甲氧基乙基)-IH-咪唑并[4, 5-c]喹啉-1-基]乙氧基}乙基)-η' -苯基脲,1- (2-氨基-2-甲基丙基)-2-(乙氧基甲基)-IH-咪唑并[4, 5-c] 喹啉-4-胺,1-{4-[(3,5_二氯苯基)磺酰基]丁基}-2_乙基-IH-咪唑并[4,5-c]喹啉-4-胺,N-(2-{2-[4-氨基-2-(乙氧基甲基)-1Η-咪唑并[4,5-c]喹啉-1-基]乙氧基}乙基)-n'_环己基脲,N-{3-[4-氨基-2-(乙氧基甲基)-1Η-咪唑并[4,5-c]喹啉-1-基]丙基} -η' - (3-氰基苯基)硫脲,N- [3- (4-氨基-2- 丁基-IH-咪唑并[4, 5-C] 喹啉-1-基)-2, 2-二甲基丙基]苯甲酰胺,2-丁基-1-[3-(甲基磺酰基)丙基]-IH-咪唑并[4, 5-c]喹啉-4-胺,N- {2- [4-氨基-2-(乙氧基甲基)-IH-咪唑并[4, 5-c]喹啉-1-基]-1,1-二甲基乙基}-2-乙氧基乙酰胺,1-[4_氨基-2-乙氧基甲基-7-(吡啶-4-基)-IH-咪唑并[4, 5-c]喹啉-1-基]-2-甲基丙-2-醇,1-[4-氨基-2-(乙氧基甲基)-7-(吡啶-3-基)-IH-咪唑并[4, 5-c]喹啉-1-基]-2-甲基丙-2-醇 -2- (2-methoxyethyl) -IH- imidazo [4, 5-c] quinolin-1-yl] ethoxy} ethyl) -η '- phenyl urea, 1- ( amino-2-methylpropyl) -2- (ethoxymethyl) -IH- imidazo [4, 5-c] quinolin-4-amine, 1- {4 - [(3,5 _ dichlorophenyl) sulfonyl] butyl} ethyl -2_ -IH- imidazo [4,5-c] quinolin-4-amine, N- (2- {2- [4- amino-2 - (ethoxymethyl) -1Η- imidazo [4,5-c] quinolin-1-yl] ethoxy} ethyl) -n'_ cyclohexylurea, N- {3- [4- amino-2- (ethoxymethyl) -1Η- imidazo [4,5-c] quinolin-1-yl] propyl} -η '- (3- cyanophenyl) thiourea, N- [3- (4-amino-2-butyl -IH- imidazo [4, 5-C] quinolin-1-yl) -2,2-dimethylpropyl] benzamide, 2-butyl 1- [3- (methylsulfonyl) propyl] -IH- imidazo [4, 5-c] quinolin-4-amine, N- {2- [4- amino-2- (ethoxymethyl methyl) -IH- imidazo [4, 5-c] quinolin-1-yl] -1,1-dimethylethyl} -2-ethoxy acetamide, l- [4_-amino-2 - ethoxymethyl-7- (pyridin-4-yl) -IH- imidazo [4, 5-c] quinolin-1-yl] -2-methyl-propan-2-ol, 1- [4 - amino-2- (ethoxymethyl) -7- (pyridin-3-yl) -IH- imidazo [4, 5-c] quinolin-1-yl] -2-methyl-2 alcohol ,N-{3-[4-氨基-1-(2-羟基-2-甲基丙基)-2-(甲氧基乙基)-IH-咪唑并[4, 5-c]喹啉-7-基]苯基}甲磺酰胺,1- [4-氨基-7- (5-羟基甲基吡啶-3-基)-2- (2-甲氧基乙基)-IH-咪唑并[4, 5-c] 喹啉-1-基]-2-甲基丙-2-醇,3-[4-氨基-2-(乙氧基甲基)-7-(吡啶-3-基)-IH-咪唑并[4,5-c]喹啉-1-基]丙-1,2-二醇,1-[2-(4_氨基-2-乙氧基甲基-IH-咪唑并[4,5-c]喹啉-1-基)-1,1-二甲基乙基]-3-丙基脲,1-[2-(4_氨基-2-乙氧基甲基-IH-咪唑并[4,5-c]喹啉-1-基)-1,1-二甲基乙基]-3-环戊基脲,1-[(2,2_二甲基-1,3-二氧戊环-4-基)甲基]-2-(乙氧基甲基)-7- (4-羟基甲基苯基)-IH-咪唑并[4, 5-c]喹啉-4-胺,4-[4_氨基-2-乙氧基甲基-1-(2-羟基-2-甲基丙基)-1Η-咪唑并[4,5-c] 喹啉-7-基]-N-甲氧基-N-甲基苯甲酰胺,2-乙氧基甲基-NI-异丙基-6, 7, 8, 9-四氢-IH-咪唑并[4, 5-c]喹啉-1,4-二胺,1-[4-氨基-2-乙基-7-(吡啶-4-基)-IH-咪唑并[4, 5-c]喹啉-1-基]-2- , N- {3- [4- amino-1- (2-hydroxy-2-methylpropyl) -2- (methoxyethyl) -IH- imidazo [4, 5-c] quinoline - 7- yl] phenyl} methanesulfonamide, 1- [4-amino-7- (5-hydroxymethyl-pyridin-3-yl) -2- (2-methoxyethyl) -IH- imidazo [ 4, 5-c] quinolin-1-yl] -2-methyl-propan-2-ol, 3- [4-amino-2- (ethoxymethyl) -7- (pyridin-3-yl) -IH- imidazo [4,5-c] quinolin-1-yl] propan-1,2-diol, 1- [2- (4_-amino-2-ethoxymethyl-imidazo -IH- [4,5-c] quinolin-1-yl) -1,1-dimethyl-ethyl] -3-propyl-urea, 1- [2- (4_ amino-2-ethoxymethyl - IH- imidazo [4,5-c] quinolin-1-yl) -1,1-dimethylethyl] -3-cyclopentyl-urea, 1 - [(2,2_-dimethyl-1 , 3-dioxolan-4-yl) methyl] -2- (ethoxymethyl) -7- (4-hydroxy-methylphenyl) -IH- imidazo [4, 5-c] quinolin 4-amine, 4- [4_ amino-2-ethoxymethyl-1- (2-hydroxy-2-methylpropyl) -1Η- imidazo [4,5-c] quinoline - 7- yl] -N- methoxy -N- methyl-benzamide, 2-ethoxymethyl -NI- isopropyl-6, 7, 8, 9-tetrahydro -IH- imidazo [4 , 5-c] quinoline-1,4-diamine, 1- [4-amino-2-ethyl-7- (pyridin-4-yl) -IH- imidazo [4, 5-c] quinoline 1-yl] -2- 甲基丙-2-醇,N-[4-(4-氨基-2-乙基-IH-咪唑并[4, 5-c] 喹啉-1-基)丁基]甲磺酰胺,或N-[4-(4-氨基-2-丁基-IH-咪唑并[4,5-c][l,5] 萘啶-1-基)丁基]-n'_环己基脲,其中,喹啉环上的胺基团是与连接体连接的点。 Methylpropan-2-ol, N- [4- (4- ethyl--IH- imidazo [4, 5-c] quinolin-1-yl) butyl] methanesulfonamide, or N - [4- (4-amino-2-butyl -IH- imidazo [4,5-c] [l, 5] naphthyridin-1-yl) butyl] -n'_ cyclohexylurea, wherein a quinoline ring group is the point of attachment to the amine linker. 在通式A至通式C的另一实施方式中,抗-HER2抗体是曲妥珠单抗(赫赛汀),帕妥珠单抗或margetuximab (MGAH22);通式(I)的化合物是瑞喹莫德或咪喹莫特,其中,喹啉环上的胺基团是与连接体连接的点。 In another embodiment of Formula A to Formula C, the anti -HER2 antibody is trastuzumab (Herceptin), pertuzumab or margetuximab (MGAH22); a compound of formula (I) is resiquimod or imiquimod, wherein the amine group on the quinoline ring is a point of attachment to the linker. 在通式A至通式C的另一实施方式中,抗-HER2抗体是曲妥珠单抗(赫赛汀);AM是瑞喹莫德或咪喹莫特,其中,喹啉环上的胺基团是与连接体连接的点。 In the general formula A to another embodiment of Formula C, the anti -HER2 antibody is trastuzumab (Herceptin); AM is resiquimod or imiquimod, wherein, on the quinoline ring amine group is the point of attachment to the linker.

[0046] 在一些实施方式中,本发明提供一种药物组合物,所述药物组合物包含本文所述的化合物或其药学上可接受的盐,和/或一种或一种以上药学上可接受的载体。 [0046] In certain embodiments, the present invention provides a pharmaceutical composition, said pharmaceutical composition comprising a pharmaceutically on the compounds described herein or a pharmaceutically acceptable salt thereof, and / or one or more pharmaceutically acceptable carrier.

[0047] 在一些实施方式中,所述药物组合物还包含其他治疗剂。 [0047] In some embodiments, the pharmaceutical composition further comprising additional therapeutic agent. 在一些实施方式中, 所述其他治疗剂是抗癌药剂。 In some embodiments, the additional therapeutic agent is an anticancer agent. 在一些实施方式中,所述其他治疗剂是抗代谢药物、拓扑异构酶I和拓扑异构酶II的抑制剂、烷基化剂、微管抑制剂、抗雄性激素剂、GNRh调节剂或者它们的混合物。 In some embodiments, the additional therapeutic agent is an anti-metabolite, a topoisomerase I and topoisomerase II inhibitors, alkylating agents, microtubule inhibitors, anti-androgen agents, modifiers or GnRH mixtures thereof. 在一些实施方式中,所述其他治疗剂选自:它莫西芬(tamoxifen)、 雷洛昔芬(raloxifene)、阿那曲挫(anastrozole)、依西美坦(exemestane)、来曲挫(letrozole)、imatanib、紫杉醇、环磷酰胺、洛伐他汀(lovastatin)、minosine、吉西他滨(gemcitabine)、阿糖胞苷(cytarabine)、5_氟尿喃啶、甲氨蝶呤、多西他赛(docetaxel)、 戈舍瑞林(goserelin)、长春新碱、长春碱、噻氨醋挫(nocodazole)、替尼泊苷(teniposide)、依托泊苷(etoposide)、吉西他滨、埃博霉素、长春瑞滨(vinorelbine)、喜树碱、道诺霉素(daunorubicin)、放线菌素D、米托蒽醌、吖啶、阿霉素、表柔比星或去甲氧基柔红霉素。 In some embodiments, the other therapeutic agent is selected from: tamoxifen (tamoxifen), raloxifene (raloxifene), anastrozole frustration (anastrozole), exemestane (exemestane), letrozole frustration (letrozole ), imatanib, paclitaxel, cyclophosphamide, lovastatin (lovastatin), minosine, gemcitabine (gemcitabine), Ara-C (cytarabine), 5_ furans pyridine fluorouracil, methotrexate, docetaxel (docetaxel ), goserelin (of goserelin), vincristine, vinblastine, ammonia, vinegar thiazol setback (Nocodazole), teniposide (teniposide), etoposide (etoposide), gemcitabine, epothilone, vinorelbine (vinorelbine), camptothecin, daunomycin (daunorubicin), actinomycin D, mitoxantrone, acridine, doxorubicin, epirubicin or demethoxy-daunorubicin.

[0048] 又一方面,本发明提供一种抑制HER2阳性肿瘤细胞增殖的方法,所述方法包括将本发明的化合物给药于所述肿瘤细胞。 [0048] In yet another aspect, the present invention provides a method of HER2-positive tumor cell proliferation inhibition, said method comprising administering a compound of the present invention to the tumor cells.

[0049] 在一些实施方式中,本发明提供一种治疗受治者体内的HER2阳性肿瘤/癌症的方法,所述方法包括将本发明的化合物给药于所述受治者。 [0049] In certain embodiments, the present invention provides a method of treating a subject's body HER2-positive tumors / cancer, said method comprising the compounds of the invention are administered to the subject is. 在一些实施方式中,所述肿瘤/癌症选自:食管癌、胃癌、结肠癌、直肠癌、胰腺癌、肺癌、乳腺癌、子宫颈癌、子宫体癌、卵巢癌、 膀胱癌、头颈癌、子宫内膜癌、骨肉瘤、前列腺癌、神经母细胞瘤。 In some embodiments, the tumor / cancer is selected from: esophageal cancer, stomach cancer, colon cancer, colorectal cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, uterine body cancer, ovarian cancer, bladder cancer, head and neck cancer, endometrial cancer, osteosarcoma, prostate cancer, neuroblastoma.

附图说明 BRIEF DESCRIPTION

[0050] 本发明的新特点在所附的权利要求书中具体说明。 [0050] The novel features of the invention are described in detail in the book appended claims. 通过结合后面列举的对示例性的实施方式的详细描述可更好地对本发明的特点和优势加以理解,其中,使用了本发明的原理,并且具有如下附图: By could be better understanding of the nature and advantages of the invention in conjunction with the detailed description of exemplary embodiments of the recited later, which use the principles of the invention and having the following drawings:

[0051] 图1表示偶联的化合物的特性。 [0051] FIG. 1 shows the characteristics of the compound coupled. 如通过FACS分析所确定的,将曲妥珠单抗MC-VC-瑞喹莫德和曲妥珠单抗-瑞喹莫德偶联物与表达Her2的L细胞的结合与未偶联的曲妥珠单抗(作为参比)、对照人IgG和不相关人IgGl抗体比较。 As determined by FACS analysis, trastuzumab MC-VC- resiquimod and trastuzumab - resiquimod conjugate bound L cells expressing Her2 with unconjugated Qu trastuzumab (as reference), control human IgG antibody and irrelevant human IgGl comparison.

[0052] 图2表示曲妥珠单抗、曲妥珠单抗MC-vc-Toll样受体的配体(TLRL)和曲妥珠单抗MC-Toll样受体的配体(TLRL)偶联物的体外抗体依赖性细胞毒性(ADCC)分析。 [0052] FIG. 2 shows trastuzumab, trastuzumab-MC-vc-Toll-like receptor ligands (TLRL) and trastuzumab-MC-Toll-like receptor ligands (TLRL) even analysis of antibody dependent cellular cytotoxicity in vitro-linked (ADCC). PBMC(效应细胞)与SKBR3细胞(靶细胞)一同加至含有不同浓度的对照人IgGU曲妥珠单抗或曲妥珠单抗MC-vc-TLRL和曲妥珠单抗MC-TLRL偶联物的96孔平板(祀标/效应物比例为1/60) 中持续17小时。 PBMC (effector cells) and SKBR3 cells (target cells) was added to a control human with different concentrations IgGU trastuzumab or trastuzumab and MC-vc-TLRL trastuzumab-MC-TLRL conjugate 96-well plates (subscript Si / effector ratio 1/60) in 17 h. 所有实验一式两份进行。 All experiments were performed in duplicate. 分析基于阴性SKBR3群测定。 SKBR3 negative determination based analysis group. 用LDH对死细胞进行染色。 Dead cells were stained with LDH.

[0053] 图3A表示富集前后的DC百分数。 [0053] FIG 3A shows the percentage of DC before and after enrichment. 上部的两个图中的数字表示谱系消减前后总细胞中的DC (HLA-DR+Lin-)百分数。 FIG upper two figures represents the reduction of the total longitudinal lineage cells DC (HLA-DR + Lin-) percent. 下部图中的数字表示谱系消减前后总DC中的mDC (CD11C+CD123-)和pDC (CD123+CD11C-)的百分数。 A lower number indicates the figure before and after the DC lineage percent of total reduction of mDC (CD11C + CD123-) and pDC (CD123 + CD11C-) a. 图3B至图3C表示纯化的人DC的细胞因子产量分析。 Analysis of cytokine production 3B-3C show purified human DC's. 纯化的人DC被接种在96孔平板中并且与异基因的未处理的(培养基)或处理的不同浓度的TLRL或曲妥珠单抗MC-vc-TLRL和曲妥珠单抗MC-TLRL在37 °C下的孵育箱中直接培养20小时至22小时。 Purified human DC were seeded in 96-well plates and allogeneic untreated with different concentrations TLRL (medium) or treated or trastuzumab-MC-vc-TLRL trastuzumab and MC-TLRL direct culture 20 to 22 hours in an incubator at 37 ° C in. 收集上清液,通过ELISA分析人IFN-a,IL-6, IL-12 (ρ70)和TNF-α。 Supernatant was collected and analyzed by ELISA for human IFN-a, IL-6, IL-12 (ρ70), and TNF-α. 数据表示为一式三份的培养物的平均值土SD并且数据代表来自三个健康供体中的两个的独立的实验。 Data are expressed as mean soil culture SD triplicate and the data representative of three independent experiments from two healthy donors. FIG.

[0054] 图4A至图4C表示Η)Χ胃肿瘤模型中曲妥珠单抗MC-vc-TLRL和曲妥珠单抗MC-TLRL的治疗效果。 [0054] FIGS. 4A to 4C show [eta]) Χ treatment of gastric tumor model trastuzumab and MC-vc-TLRL trastuzumab-MC-TLRL of. 皮下带有来源于患者的胃肿瘤的6至8周龄的雌性BALB/c裸鼠(nu/ nu)通过静脉注射10mg/kg曲妥珠单抗MC-vc-TLRL,曲妥珠单抗MC-TLRL或未偶联的曲妥珠单抗或盐水进行治疗(每组12只小鼠)。 6 to 8 week old female BALB subcutaneous tumors derived from a patient with a gastric / c nude mice (nu / nu) by intravenous injection of 10mg / kg trastuzumab-MC-vc-TLRL, trastuzumab-MC -TLRL or unconjugated trastuzumab or saline treatment (12 mice per group). 每周进行治疗持续45天的周期。 Periodic weekly for 45 days of treatment. 当肿瘤达到平均尺寸为170mm 3时开始治疗。 When the tumors reached an average size of 170mm 3 start of treatment. 图4A:数据表示平均肿瘤体积(平均值土SD)。 FIG. 4A: Data represents mean tumor volume (mean soil SD). 当肿瘤达到尺寸为2000mm3时肿瘤生长曲线停止。 When the tumors reached a size of 2000mm3 stop tumor growth curve. 图4B:治疗过程中和治疗后小鼠体重的变化。 Figure 4B: Mouse body weight change after the course of treatment and therapy. 没有观察到可检测的失重。 No detectable weight loss was observed. 图4C :治疗组和对照组的存活曲线;接受曲妥珠单抗MC-vc-TLRL或未偶联的曲妥珠单抗的小鼠的寿命大幅度延长。 FIG. 4C: Survival curves of treated and control groups; receiving trastuzumab MC-vc-TLRL or unconjugated trastuzumab significantly extend the lifespan of mice.

具体实施方式 detailed description

[0055] 通过结合用于举例说明的示例性应用,在下文中对本发明的多个方面进行描述。 [0055], a plurality of the described aspects of the invention in conjunction with an exemplary application illustrated hereinafter. 应当理解的是,列举出许多具体的细节、关系以及方法来全面理解本发明。 It should be understood, it includes numerous specific details, relationships, and methods for a comprehensive understanding of the invention. 然而,本领域普通技术人员可容易地意识到本发明可不按照具体细节中的一种或一种以上来实施或者可以其他方法来实施。 However, one of ordinary skill in the art can readily appreciate that specific details may not be in accordance with one or more embodiments or may be other methods of implementing the present invention. 本发明不受举例说明的操作顺序或事件的限制,因为,一些操作可以不同的顺序进行和/或可同时与其他操作或事件一同进行。 Sequence of operations or events of the present invention is not limiting illustration, since some of the operations may be performed in a different order and / or concurrently with other acts or events.

[0056] 进一步地,不是所有举例说明的操作或事件都需要根据本发明的方法来实施。 [0056] Furthermore, not all illustrated acts or events are required to implement the method according to the present invention.

[0057] 本文使用的术语是仅仅是为了说明具体实施方式,而无意限定本发明。 [0057] The terminology used herein is used only to illustrate particular embodiments, and not intended to limit the present invention. 除非另有明确说明,如本文使用的不指明具体数目的冠词("a","an"和"the")意在包括复数形式。 Unless expressly stated otherwise, if not specifically indicated herein, the number of used articles ( "a", "an" and "the") are intended to include the plural forms. 此外,在具体实施方式部分和/或权利要求中使用的术语"包括("including","include")、 具有("having","has","with")或其变体意在包括与术语"包含(comprising)"类似的方式。 In addition, in the detailed description and / or claims, the terms "comprise (" including "," include "), having a (" having "," has "," with "), or variants thereof is intended to include the term "comprising (comprising,)" in a similar manner.

[0058] 术语"约"或"大约"是指由本领域普通技术人员测定的特定值在可接受的误差范围内,该误差范围部分取决于该值如何测量或确定,即,测量系统的限制。 [0058] The term "about" or "approximately" means that a particular value as determined by one of ordinary skill in the acceptable error range, the error range depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. 例如,"约"可意味着在本领域中每一操作在1个标准偏差范围内或超过一个标准偏差。 For example, "about" can mean that each operation in the present art in one or more than one standard deviation standard deviation. 可选地,"约"可意味着高达给定值的20%的范围,优选地高达给定值的10%的范围,更优选地高达给定值的5% 的范围并且更优选地高达给定值的1%的范围。 Alternatively, "about" can mean a range of up to 20% of a given value, and preferably up to 10% of a given value, and more preferably up to 5% of a given value, and more preferably up to 1% of a given range of values. 可选地,尤其对于生物系统或过程而言,该术语可意味着在某个值的某个数量级范围内,优选地在某个值的5倍范围内,更优选地在某个值的2倍范围内。 Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude of a certain value, preferably in the range of a value of 5 times, more preferably a value of 2 within the fold range. 在本申请和权利要求书中描述特定值的条件下,除非另有说明,应当假定术语"约"意味着在特定值的可接受的误差范围内。 Under the conditions used in this application and claims describing particular value, unless otherwise indicated, it shall be assumed that the term "about" means an acceptable error range at a particular value.

[0059] 释义和缩写 [0059] DEFINITIONS AND ABBREVIATIONS

[0060] 除非另有说明,本文使用的所有技术术语和科学术语通常具有与本发明所属技术领域的普通技术人员通常理解的含义相同的含义。 [0060] Unless otherwise indicated, all technical and scientific terms used herein generally have the same meaning as the art to which this invention belongs commonly understood by one of ordinary skill. 一般而言,本文使用的命名系统和细胞培养、分子遗传学、有机化学和核酸化学以及杂交中的实验操作是本领域熟知的且普遍使用的那些命名系统和实验操作。 In general, the nomenclature used herein and in cell culture, molecular genetics, organic chemistry and nucleic acid chemistry and hybridization experiments are those operating system naming and experimental procedures known in the art and commonly used. 标准技术用于核酸和肽的合成。 Standard techniques for the synthesis of nucleic acids and peptides. 所述技术和操作通常根据本领域的常规方法和各种不同的常规参考文献进行,本领域的常规方法和各种不同的常规参考文献在本文中提供。 The techniques and procedures generally in accordance with conventional methods in the art and various general references literature, conventional methods in the art and various conventional references provided herein. 本文使用的命名系统和下面描述的分析化学和有机合成中的实验操作是本领域熟知的且普遍使用的命名系统和实验操作。 Nomenclature system used herein, experimental procedures and analytical chemistry, and organic synthesis following description are known in the art and naming system and commonly used experimental manipulation. 标准技术或其改良用于化学合成和化学分析。 Chemical syntheses and chemical analyzes, or standard techniques for improvement.

[0061] 除非另有说明,术语"烷基"其自身或作为另一取代基的一部分是指含有指定数目的碳原子(即,C1-Cltl是指1至10个碳原子)的直链或支链或环状烃自由基或者其组合,所述直链或支链或环状烃自由基或者其组合可为完全饱和的、单不饱和的或多不饱和的并且可包括二价和多价自由基。 [0061] Unless otherwise indicated, the term "alkyl" by itself or as part of another substituent refers to a straight chain containing the specified number of carbon atoms (i.e., C1-Cltl refers to 1-10 carbon atoms) or branched chain or cyclic hydrocarbon radical, or combinations thereof, a straight or branched chain or cyclic hydrocarbon radical, or combination thereof may be fully saturated, monounsaturated or polyunsaturated and can include di- and multivalent price radicals. 饱和的烃自由基的实例包括但不限于如下基团,例如,甲基、乙基、η-丙基、异丙基、η-丁基、叔丁基、异丁基、仲丁基、环己基、(环己基)甲基、环丙基甲基、 它们的同系物或异构体,例如,η-戊基、η-己基、η-庚基、η-辛基等等。 Examples of saturated hydrocarbon radicals include, but are not limited to groups such as methyl, ethyl, eta-propyl, isopropyl, eta-butyl, t-butyl, isobutyl, sec-butyl, ring hexyl group, (cyclohexyl) methyl, cyclopropylmethyl, homologs or isomers thereof, e.g., eta-pentyl, eta-hexyl group, eta-heptyl group, eta-octyl and the like. 不饱和烷基为具有一个或一个以上双键或三键的烷基。 Unsaturated alkyl is an alkyl having one or more double bonds or triple bonds. 不饱和烷基的实例包括但不限于:乙烯基、2-丙烯基、 巴豆基、2-异戊烯基、2-( 丁二烯基)、2, 4-戊二烯基、3-(1,4-戊二烯基)、乙炔基、1-丙炔基和3-丙炔基、3-丁炔基以及高级同系物和异构体。 Examples of unsaturated alkyl groups include, but are not limited to: ethenyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2,4-pentadienyl, 3- ( 1,4-pentadienyl), ethynyl, 1-propynyl and 3-propynyl, 3-butynyl and higher homologs and isomers. 除非另有说明,术语"烷基"还意在包括下面更加详细定义的那些烷基衍生物,例如,"杂烷基"。 Unless otherwise indicated, the term "alkyl" is also meant those derivatives of alkyl defined in more detail below include, for example, "heteroalkyl." 限定为烃基的烷基基团被称为"均烷基(homoalkyl )"。 Hydrocarbon is defined as an alkyl group is referred to as "average alkyl (homoalkyl)."

[0062] 术语"烯烃"其自身或作为另一取代基的一部分是指从烷烃衍生得到的二价自由基,例如,但不限于:-ch2ch2ch2ch2-,并且还包括下面如"杂烯烃"所描述的那些基团。 The "heteroolefinic" described -CH2CH2CH2CH2-, and further comprising the following: [0062] The term "olefin" by itself or as part of another substituent refers to a group derived from a divalent radical derived from an alkane, such as, but not limited to, those groups. 通常, 烷基(或烯烃)基团可具有1至24个碳原子,本发明中优选地为具有10个或更少的碳原子的那些基团。 Typically, alkyl (or alkylene) group may have 1 to 24 carbon atoms, the present invention preferably has 10 or fewer carbon atoms, with those groups. "低级烷基"或"低级烯烃"是较短链烷基或烯烃基团,通常具有8个或更少的碳原子。 "Lower alkyl" or "lower olefins" is a shorter chain alkyl or olefinic group, generally having eight or fewer carbon atoms.

[0063] 术语"烷氧基"、"烷基氨基"和"烷硫基"(或硫代烷氧基)以其常规含义使用,并且分别是指通过氧原子、氨基基团或硫原子与分子的剩余部分连接的那些烷基基团。 [0063] The term "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy) are used in their conventional sense, and refer to through an oxygen atom, a sulfur atom or an amino group and remainder of the molecule those alkyl groups attached.

[0064] 除非另有说明,术语"杂烷基"其自身或与另一术语结合是指由规定数目的碳原子和至少一个选自0、N、Si和S的杂原子构成的、稳定的直链或支链或环状烃自由基或者其组合,并且,其中,氮和硫原子可被任选地氧化并且氮杂原子可被任选地季铵化。 [0064] Unless otherwise indicated, the term "heteroalkyl" by itself or in combination with another term, refers to a specified number of carbon atoms and at least one group selected from 0, heteroatoms N, Si and S configuration, stable straight or branched chain or cyclic hydrocarbon radical, or combinations thereof, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. 杂原子0、N和S以及Si可位于杂烷基的任何内部位置或者位于烷基与分子的剩余部分连接的位置。 0, N and S at any interior position and Si may be placed heteroalkyl group or the position at which the alkyl remainder of the molecule attached heteroatom. 实例包括但不限于:-CH 2-CH2-〇-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH 2- CH3, -CH2-CH2, -S (0) -CH3, -CH2-CH2-S (0) 2-CH3, -CH=CH-O-CH3, -Si (CH3) 3, -CH2-CH=N-OCH3, 和-CH=CH-N(CH3) -CH3。 Examples include, but are not limited to: -CH 2-CH2-square-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N (CH3) -CH3, -CH2-S-CH 2- CH3, -CH2- CH2, -S (0) -CH3, -CH2-CH2-S (0) 2-CH3, -CH = CH-OCH3, -Si (CH3) 3, -CH2-CH = N-OCH3, and - CH = CH-N (CH3) -CH3. 最多两个杂原子可以连续,例如,-CH2-NH-OCHjP -CH 2-〇-Si (CH3) 3。 Up to two heteroatoms may be consecutive, for example, -CH2-NH-OCHjP -CH 2-billion-Si (CH3) 3. 类似地,术语"杂烯烃"其自身或作为另一取代基的一部分是指从杂烷基衍生得到的二价自由基,例如但不限于:-CH 2-CH2-S-CH2-CH2-和-CH2-S-CH 2-CH2-NH-CH2-。 Similarly, the term "heteroolefinic" by itself or as part of another substituent refers to a radical derived from heteroalkyl divalent such as, but not limited to: -CH 2-CH2-S-CH2-CH2- and -CH2-S-CH 2-CH2-NH-CH2-. 对于杂烯烃基团而言,杂原子还可占据链端中的一个末端或者链端的两个末端(例如,烯烃氧、烯烃二氧、烯烃氨基、烯烃二氨基,等等)。 For heteroaryl olefinic groups, heteroatoms can also occupy two terminal (e.g., an olefin oxide, olefin-dioxo, amino olefins, alkenes diamino, etc.) or a terminal chain ends of the chain end. 而且,对于烯烃和杂烯烃的连接基团而言,所写的连接基团的分子式中的方向并不暗示连接基团的方向。 Further, olefin and for an olefin heteroaryl linking groups, in the direction of formula written linking group does not imply a direction linking group. 例如,分子式-c(o) 2r' -代表-C(0)2R' -和-R' c(0)2-。 For example, the formula -c (o) 2r '- Representative -C (0) 2R' - and -R 'c (0) 2-.

[0065] 一般而言,"酰基取代基"也选自上面列举的基团。 [0065] Generally, "acyl substituent" is also selected from the group enumerated above. 如本文使用的术语"酰基取代基"是指连接至本发明的化合物的多环核心的基团且该基团满足直接或间接地连接至本发明的化合物的多环核心的羰基碳的化合价。 As used herein, the term "acyl substituent" refers to a polycyclic core of the group of compounds of the present invention is connected to and the group satisfy the valences compounds of the present invention is connected directly or indirectly to the polycyclic core of the carbonyl carbon.

[0066] 除非另有说明,术语"环烷基"和"杂环烷基"其自身或者与其他术语的组合分别表示"烷基"和"杂烷基"的环状形式。 [0066] Unless otherwise indicated, the term "cycloalkyl" and "heterocycloalkyl" itself or in combination with other terms, represent "alkyl" and "heteroalkyl" cyclic form. 此外,对于杂环烷基而言,杂原子可占据杂环与分子的剩余部分连接的位置。 Additionally, for heterocycloalkyl, a heteroatom can occupy the position of the remainder of the molecule linked heterocycle. 环烷基的实例包括但不限于:环戊基、环己基、1-环己烯基、3-环己烯基、环庚基,等等。 Examples of cycloalkyl groups include, but are not limited to: cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. 杂环烷基的实例包括但不限于2, 5, 6-四氢吡啶基)、1_哌啶基、2-哌啶基、3-哌啶基、4-吗啉基、3-吗啉基、四氢呋喃-2-基、四氢呋喃-3-基、四氢噻吩-2-基、四氢噻吩-3-基、1 -哌嗪基、2-哌嗪基,等等。 Examples of heterocycloalkyl include, but are not limited to 2, 5, 6-tetrahydropyridyl), 1_ piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydro-thiophen-2-yl, tetrahydro-thiophen-3-yl of 1 - piperazinyl, 2-piperazinyl, and the like.

[0067] 除非另有说明,术语"卤代"或"卤素"其自身或作为另一取代基的一部分是指氟、 氯、溴或碘原子。 [0067] Unless otherwise indicated, the term "halo" or "halogen" by themselves or as part of another substituent refers to fluorine, chlorine, bromine or iodine atom. 此外,诸如"卤代烷基"之类的术语意在包括单卤代烷基和多卤代烷基。 In addition, terms such as "haloalkyl" or the like terms are intended to include monohaloalkyl and polyhaloalkyl. 例如,术语"卤代(C1-C4)烷基"意在包括但不限于:三氟甲基、2, 2, 2-三氟乙基、4-氯代丁基、 3- 漠代丙基,等等。 For example, the term "halo (C1-C4) alkyl" is meant to include, but not limited to: trifluoromethyl, 2, 2, 2-trifluoroethyl, 4-chlorobutyl, 3-oxopropyl desert ,and many more.

[0068] 本文使用的术语"卤代烷基"是指被一个或一个以上本文所定义的卤素基团取代的本文定义的烷基。 [0068] As used herein, the term "haloalkyl" means a halogen group substituted with one or more substituents as defined herein, alkyl as defined herein. 卤代烷基优选地可为单卤代烷基、二卤代烷基或多卤代烷基(包括全卤代烷基)。 Haloalkyl can preferably be monohaloalkyl, dihaloalkyl or polyhaloalkyl (including perhaloalkyl). 单卤代烷基在烷基基团中可具有一个碘、溴、氯或氟。 Monohaloalkyl in the alkyl group may have one iodo, bromo, chloro or fluoro. 二卤代烷基和多卤代烷基在烷基基团中可具有两个或两个以上相同的卤素原子或不同的卤素基团的组合。 Dihaloalkyl and polyhaloalkyl groups in the alkyl group may have a combination of two or more identical or different halogen atoms, halogen groups. 优选地,多卤代烷基包含多达12个,10个或8个,或6个,或4个,或3个,或2个卤素基团。 Preferably, the polyhaloalkyl contains up to 12, 10 or 8, or 6, or 4, or 3, or 2 halo groups. 卤代烷基的非限定性实例包括氟代甲基、二氟代甲基、三氟代甲基、氯代甲基、二氯代甲基、三氯代甲基、五氟代乙基、七氟代丙基、二氟代氯代甲基、二氯代氟代甲基、二氟代乙基、二氟代丙基、 二氯代乙基和二氯代丙基。 Non-limiting examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl oxopropyl, chloromethyl-difluoro, dichloro fluoromethyl, difluoro ethyl, propyl difluoro, dichloro ethyl and dichloropropyl. 全卤代烷基是指所有的氢原子均被卤素原子取代的烷基。 Perhaloalkyl refers to all hydrogen atoms are substituted with a halogen atom an alkyl group.

[0069] 本文使用的术语"杂芳基"是指具有1至8个选自N、0、S或Se的杂原子的5元至14元单环或双环或稠合的多环系统。 [0069] As used herein, the term "heteroaryl" refers to a 1-8 selected from N, 0, 5 membered to 14- membered heteroaryl atom is S or Se, or a monocyclic or bicyclic fused polycyclic system. 优选地,杂芳基为5元至10元环系统。 Preferably, heteroaryl 5-membered to 10-membered ring system. 典型的杂芳基基团包括2-噻吩基或3-噻吩基,2-呋喃基或3-呋喃基,2-吡咯基或3-吡咯基,2-咪唑基、4-咪唑基或5-咪唑基,3-吡唑基、4-吡唑基或5-吡唑基,2-噻唑基、4-噻唑基或5-噻唑基,3-异噻唑基、4-异噻唑基或5-异噻唑基,2-恶唑基、4-恶唑基或5-恶唑基,3-异恶唑基、4-异恶唑基或5-异恶唑基,3-1,2, 4-三唑基或5-1,2, 4-三唑基,4-1,2, 3-三唑基或5-1,2, 3-三唑基,四唑基,2-吡啶基、3-吡啶基或4-吡啶基,3-哒嗪基或4-哒嗪基,3-吡嗪基、4-吡嗪基或5-吡嗪基,2-吡嗪基,2-嘧啶基、4-嘧啶基或5-嘧啶基。 Typical heteroaryl groups include 2-thienyl or 3-thienyl, 2-furyl or 3-furyl, 2-pyrrolyl or 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl or 5- imidazolyl, 3-pyrazolyl, 4-pyrazolyl or 5-pyrazolyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl or 5 isothiazolyl, 2-oxazolyl, 4-oxazolyl or 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl or 5-isoxazolyl group, 3-1,2, 4 - 5-1, 5-2 or triazolyl, 4-triazolyl, 4-1,2, 3-triazolyl or 5-1, 5-2, 3-triazolyl, tetrazolyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, 3-pyridazinyl or 4-pyridazinyl, 3-pyrazinyl, 2-pyrazinyl or 5-pyrazinyl, 2-pyrazinyl, 2-pyrimidinyl , 4-pyrimidinyl or 5-pyrimidinyl.

[0070] 术语"杂芳基"还指杂芳香族环与一个或一个以上芳基环、环状脂肪族环或杂环烷基环稠合的基团,其中,自由基或连接点位于杂芳香族环上。 [0070] The term "heteroaryl" also refers to heteroaromatic ring with one or more aryl ring, a cyclic aliphatic ring or heterocycloalkyl ring fused radical, wherein the radical or point of attachment is heteroaryl aromatic ring. 非限定性实例包括但不限于: 1- 中氮茚基(indolizinyl),2-中氮茚基,3-中氮茚基,5-中氮茚基,6-中氮茚基,7-中氮茚基或8-中氮茚基,1-异吲哚基,3-异吲哚基,4-异吲哚基,5-异吲哚基,6-异吲哚基或7-异吲哚基,2-吲哚基,3-吲哚基,4-吲哚基,5-吲哚基,6-吲哚基或7-吲哚基,2-吲唑基,3-吲唑基,4-吲唑基,5-吲唑基,6-吲唑基或7-吲唑基,2-嘌呤基,4-嘌呤基,5-嘌呤基,6-嘌呤基,7-嘌呤基或8-嘌呤基,1-喹嗪基,2-喹嗪基,3-喹嗪基,4-喹嗪基,6-喹嗪基,7-喹嗪基,8-喹嗪基或9-喹嗪基,2-喹啉基,3-喹啉基,4-喹啉基,5-喹啉基,6-喹啉基,7-喹啉基或8-喹啉基,1-异喹啉基,3-异喹啉基,4-异喹啉基,5-异喹啉基,6-异喹啉基,7-异喹啉基或8-异喹啉基,1-2, 3-二氮杂萘基,4-2, 3-二氮杂萘基,5-2, 3-二氣杂蔡基,6_2, 3_二氣杂蔡基,7_2, 3_二氣杂蔡基或8_2, 3_二氣杂 Non-limiting examples include, but are not limited to: l-indolizinyl (indolizinyl), 2- indolizinyl, 3-indolizinyl, 5-indolizinyl, 6-indolizinyl, 7 in indolizinyl or 8-indolizinyl, 1-isoindolyl, 3-isoindolyl, 4-isoindolyl, 5-isoindolyl, 6-isoindolyl, or 7-isoindolyl indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl or 7-indolyl, 2-indazolyl, 3-indazolyl 4-indazolyl, 5-indazolyl, 6-indazolyl or 7-indazolyl, 2-purinyl, 4-purinyl, 5-purinyl, 6-purinyl, 7-purinyl or 8- purinyl, quinolizinyl 1-, 2- quinolizinyl, 3-quinolizinyl, quinolizinyl 4-, 6- quinolizinyl, quinolizinyl 7-, 8- or 9-quinolizinyl quinolin piperazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl group, 5-quinolyl, 6-quinolyl, 7-quinolyl or 8-quinolyl, 1-isoquinolyl group, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl or 8-isoquinolinyl group, 1-2, 3- naphthyridinyl, 4-2, 3-naphthyridinyl, 5-2, 3-Cai gas heteroaryl group, 6_2, two gas 3_ Cai heteroaryl group, 7_2, two gas 3_ or heteroaryl group Cai 8_2, heteroaryl two gas 3_ 基,2_1,5_二氣杂萘基,3-1,5-二氮杂萘基,4-1,5-二氮杂萘基,5-1,5-二氮杂萘基或6-1,5-二氮杂萘基, 2- 喹唑啉基,3-喹唑啉基,5-喹唑啉基,6-喹唑啉基,7-喹唑啉基或8-喹唑啉基,3-噌啉基,4-噌啉基,5-噌啉基,6-噌啉基,7-噌啉基或8-噌啉基,2-蝶啶基,4-蝶啶基,6-蝶啶基或7-蝶啶基,l-4aH咔唑基,2-4aH咔唑基,3-4aH咔唑基,4-4aH咔唑基,5-4aH咔唑基,6-4aH咔唑基,7-4aH咔唑基或8-4aH咔唑基,1-咔唑基,2-咔唑基,3-咔唑基,4-咔唑基,5-咔唑基,6-咔唑基,7-咔唑基或8-咔唑基,1-咔啉基,3-咔啉基,4-咔啉基,5-咔啉基,6-咔啉基,7-咔啉基,8-咔啉基或9-咔啉基,1-菲啶基,2-菲啶基,3-菲啶基,4-菲啶基,6-菲啶基,7-菲啶基,8-菲啶基,9-菲啶基或10-菲啶基,1-吖啶基,2-吖啶基,3-吖啶基,4-吖啶基,5-吖啶基,6-吖啶基,7-吖啶基,8-吖啶基或9-吖啶基,1-萘 Group, a naphthyl group 2_1,5_ two gas heteroaryl, 3-1,5- naphthyridinyl, 4-1,5- naphthyridinyl, 5-1,5- naphthyridinyl or 6 1,5-naphthyridinyl, 2-quinazolinyl, 3-quinazolinyl, 5-quinazolinyl, 6- quinazolinyl, 7-quinazolinyl or 8-quinazolinyl group, 3-cinnolinyl, 4-cinnolinyl, 5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl or 8-cinnolinyl, 2-pteridinyl, 4-pteridinyl, 6- or 7-pteridinyl pteridinyl, l-4aH-carbazolyl, 2-4aH carbazolyl, 3-4aH carbazolyl, 4-4aH carbazolyl, 5-4aH carbazolyl, 6-4aH carbazolyl, 7-4aH carbazolyl or 8-4aH carbazolyl, 1- carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl, carbazolyl 5-, 6- carbazolyl, carbazolyl 7- or 8-carbazolyl, 1- carboline-yl, 3-carboline, 4-carboline-yl, 5-carboline, 6-carboline-yl, 7-carboline group, 8- or 9-carbolinyl carboline, 1-phenanthridinyl, 2- phenanthridinyl, 3-phenanthridinyl, 4-phenanthridinyl, 6-phenanthridinyl, 7-phenanthridinyl, 8- phenanthridinyl, 9-phenanthridinyl, or 10- phenanthridinyl, 1-acridinyl, 2- acridinyl, 3-acridinyl, 4-acridinyl group, 5-acridinyl, 6- acridinyl, acridinyl 7-, 8- or 9-acridinyl acridinyl group, 1-naphthyl 嵌二氮杂苯基,2-萘嵌二氮杂苯基,4-萘嵌二氮杂苯基,5-萘嵌二氮杂苯基,6-萘嵌二氮杂苯基,7-萘嵌二氮杂苯基,8-萘嵌二氮杂苯基或9-萘嵌二氮杂苯基(perimidinyl ),2-菲略啉基,3-菲咯啉基,4-菲咯啉基,5-菲咯啉基,6-菲咯啉基,8-菲咯啉基,9-菲咯啉基或10-菲咯啉基,1-吩嗪基,2-吩嗪基,3-吩嗪基,4-吩嗪基,6-吩嗪基,7-吩嗪基,8-吩嗪基或9-吩嗪基,1-噻吩嗪基,2-噻吩嗪基,3-噻吩嗪基,4-噻吩嗪基,6-噻吩嗪基,7-噻吩嗪基,8-噻吩嗪基,9-噻吩嗪基或10-噻吩嗪基,1-吩恶嗪基,2-吩恶嗪基,3-吩恶嗪基,4-吩恶嗪基,6-吩恶嗪基,7-吩恶嗪基,8-吩恶嗪基,9-吩恶嗪基或10-吩恶嗪基,1-苯并异喹啉基,3-苯并异喹啉基,4-苯并异喹啉基,5-苯并异喹啉基,6-苯并异喹啉基,7-苯并异喹啉基,8-苯并异喹啉基,9-苯并异喹啉基或10-苯并异喹啉基,2-噻吩并[2, 3 Diazepine embedded phenyl, 2-perimidine phenyl, 4-phenyl perimidine, 5-phenyl perimidine, 6 perimidine phenyl, naphthyl 7- diazepine embedded phenyl, phenyl perimidine 8- or 9-perimidine phenyl (perimidinyl), 2- Filho quinolinyl, 3-phenanthrolinyl, 4-phenanthrolinyl , 5-phenanthrolinyl, 6-phenanthrolinyl, 8-phenanthrolinyl, 9-or 10-phenanthroline, phenanthroline-yl group, a 1-phenazine group, a 2-phenoxazinyl, 3 phenazine group, 4-phenoxazinyl, 6- yl phenazine, phenazine 7-, 8-or 9-phenoxazinyl phenazine group, a phenothiazine 1- yl, piperazinyl 2-thienyl, 3-thienyl piperazine , 4-phenothiazine group, a phenothiazine group 6-, 7- phenothiazine group, a phenothiazine group 8-, 9- or 10-phenothiazine-yl phenothiazine group, phenoxazine group 1-, 2- phenoxazine group, 3-phenoxazine group, a 4-phenoxazine group, phenoxazine group 6-, 7- phenoxazine group, phenoxazine group 8-, 9- or 10-phenoxazine phenoxazine-yl group , 1-isoquinolinyl, 3-benzo-isoquinolinyl, 4-benzo isoquinolinyl, 5-benzo isoquinolinyl, benzo-6- isoquinolinyl, 7-benzo isoquinolinyl, 8-benzo isoquinolinyl, isoquinolinyl-benzo 9- or 10-benzo-isoquinolinyl, 2-thieno [2, 3 -b]呋喃基,3-噻吩并[2, 3-b]呋喃基,4-噻吩并[2, 3-b]呋喃基或5-噻吩并[2, 3-b]呋喃基,2-7H-吡嗪并[2, 3-c]咔唑基,3-7H-吡嗪并[2, 3-c]咔唑基,5-7H-吡嗪并[2, 3-c]咔唑基,6-7H-吡嗪并[2, 3-c]咔唑基,7-7H-吡嗪并[2, 3-c]咔唑基,8-7H-吡嗪并[2, 3-c]咔唑基,9-7H-吡嗪并[2, 3-c]咔唑基,10-7H-吡嗪并[2, 3-c]咔唑基或11-7H-吡嗪并[2, 3-c]咔唑基,2-2H-呋喃并[3, 2-b]_吡喃基,3-2H-呋喃并[3, 2-b]_吡喃基,5-2H-呋喃并[3, 2-b]-吡喃基,6-2H-呋喃并[3, 2-b]-吡喃基或7-2H-呋喃并[3, 2-b]-吡喃基,2-5H-吡啶并[2, 3-d] -〇-恶嗪基,3-5H-吡啶并[2, 3-d] -〇-恶嗪基,4-5H-吡啶并[2, 3-d] 恶嗪基,5-5H-吡啶并[2, 3-d] 恶嗪基,7-5H-吡啶并[2, 3-d]-〇-恶嗪基或8-5H-吡啶并[2, 3-d]-〇-恶嗪基,1-1H-吡唑并[4, 3-d]_恶唑基,3-1H-吡唑并[4, 3-d]-恶唑基或5-1H-吡唑并[4, 3-d]-恶唑基,2-4H-咪唑并[4, 5-d] 噻唑基,4-4H-咪唑并[4, 5-d]噻唑基或5-4H- -b] furyl, 3-thieno [2, 3-b] furanyl, 4-thieno [2, 3-b] furan-5- yl or thieno [2, 3-b] furanyl, 2- 7H- pyrazino [2, 3-c] carbazolyl, 3-7H- pyrazino [2, 3-c] carbazolyl, 5-7H- pyrazino [2, 3-c] carbazole group, 6-7H- pyrazino [2, 3-c] carbazolyl, 7-7H- pyrazino [2, 3-c] carbazolyl, 8-7H- pyrazino [2, 3- c] carbazolyl, 9-7H- pyrazino [2, 3-c] carbazolyl, 10-7H- pyrazino [2, 3-c] carbazole group or 11-7H- pyrazino [ 2, 3-c] carbazolyl, 2-2H- furo [3, 2-b] _ pyranyl, 3-2H- furo [3, 2-b] _ pyranyl, 5-2H- furo [3, 2-b] - pyranyl, 6-2H- furo [3, 2-b] - pyran group, or 7-2H- furo [3, 2-b] - pyranyl, 2-5H- pyrido [2, 3-d] -〇- oxazinyl, 3-5H- pyrido [2, 3-d] -〇- oxazinyl, 4-5H- pyrido [2, 3 -d] oxazinyl, 5-5H- pyrido [2, 3-d] oxazine-yl, 7-5H- pyrido [2, 3-d] oxazin-yl -〇- or 8-5H- pyrido [2, 3-d] -〇- oxazinyl, 1-1H- pyrazolo [4, 3-d] _ oxazolyl, 3-1H-pyrazolo [4, 3-d] - oxazole group or 5-1H- pyrazolo [4, 3-d] - oxazolyl, 2-4H- imidazo [4, 5-d] thiazolyl, 4-4H- imidazo [4, 5-d] thiazolyl or 5-4H- 唑并[4, 5-d]噻唑基,3-吡嗪并[2, 3-d] 哒嗪基,5-吡嗪并[2, 3-d]哒嗪基或8-吡嗪并[2, 3-d]哒嗪基,2-咪唑并[2, 1-b]噻唑基,3-咪唑并[2, Ι-b]噻唑基,5-咪唑并[2, Ι-b]噻唑基或6-咪唑并[2, Ι-b]噻唑基, I- 呋喃并[3, 4-c]噌啉基,3-呋喃并[3, 4-c]噌啉基,6-呋喃并[3, 4-c]噌啉基,7-呋喃并[3, 4-c]噌啉基,8-呋喃并[3, 4-c]噌啉基或9-呋喃并[3, 4-c]噌啉基,1-4H-吡啶并[2, 3-c]咔唑基,2-4H-吡啶并[2, 3-c]咔唑基,3-4H-吡啶并[2, 3-c]咔唑基,4-4H-吡啶并[2, 3-c]咔唑基,5-4H-吡啶并[2, 3-c]咔唑基,6-4H-吡啶并[2, 3-c]咔唑基,8-4H-吡啶并[2, 3-c]咔唑基,9-4H-吡啶并[2, 3-c]咔唑基,10-4H-吡啶并[2, 3-c]咔唑基或II- 4H-吡啶并[2,3-c]咔唑基,2-咪唑并[l,2-b][l,2,4]三嗪基,3-咪唑并[l,2-b] [1,2, 4]三嗪基,6-咪唑并[1,2-b] [1,2, 4]三嗪基或7-咪唑并[1,2-b] [1,2, 4]三嗪基, 7_苯并[b]噻吩基,2-苯并恶唑基,4-苯并 Oxazolo [4, 5-d] thiazolyl, 3- pyrazino [2, 3-d] pyridazin-yl, 5-pyrazino [2, 3-d] pyridazin-yl or 8-pyrazino [ 2, 3-d] pyridazin-yl, 2-imidazo [2, 1-b] thiazolyl, 3- imidazo [2, Ι-b] thiazolyl, 5-imidazo [2, Ι-b] thiazole yl or 6-imidazo [2, Ι-b] thiazolyl, I- furo [3, 4-c] cinnolinyl, 3-furo [3, 4-c] cinnolinyl, 6- furo [3, 4-c] cinnolinyl, 7-furo [3, 4-c] cinnolinyl, 8-furo [3, 4-c] cinnolinyl or 9-furo [3, 4- c] cinnolinyl, 1-4H- pyrido [2, 3-c] carbazolyl, 2-4H- pyrido [2, 3-c] carbazolyl, 3-4H- pyrido [2, 3 -C] carbazolyl, 4-4H- pyrido [2, 3-c] carbazolyl, 5-4H- pyrido [2, 3-c] carbazolyl, 6-4H- pyrido [2, 3-c] carbazolyl, 8-4H- pyrido [2, 3-c] carbazolyl, 9-4H- pyrido [2, 3-c] carbazolyl, 10-4H- pyrido [2 , 3-c] carbazole group or II- 4H- pyrido [2,3-c] carbazole-yl, 2-imidazo [l, 2-b] [l, 2,4] triazinyl, 3 imidazo [l, 2-b] [1,2, 4] triazinyl, 6-imidazo [1,2-b] [1,2, 4] triazinyl, or 7-imidazo [1,2 -b] [1,2, 4] triazinyl, 7_ benzo [b] thienyl, 2-benzoxazolyl, 4-benzo 恶唑基,5-苯并恶唑基,6-苯并恶唑基或7-苯并恶唑基,2-苯并咪唑基,4-苯并咪唑基,5-苯并咪唑基,6-苯并咪唑基或7-苯并咪唑基,2-苯并噻唑基,4-苯并噻唑基,4-苯并噻唑基,5-苯并噻唑基,6-苯并噻唑基或7-苯并噻唑基,1-苯并氧杂革基,2-苯并氧杂革基,4-苯并氧杂革基,5-苯并氧杂革基,6-苯并氧杂革基,7-苯并氧杂革基,8-苯并氧杂革基或9-苯并氧杂革基(benzoxapinyl ),2-苯并恶嗪基,4-苯并恶嗪基,5-苯并恶嗪基,6-苯并恶嗪基,7-苯并恶嗪基或8-苯并恶嗪基, 1-1H-吡咯并[1,2-b] [2]苯并氮杂革基,2-1H-吡咯并[1,2-b] [2]苯并氮杂革基,3-1H-吡咯并[1,2-b] [2]苯并氮杂革基,5-1H-吡咯并[1,2-b] [2]苯并氮杂革基,6-1H-吡咯并[1,2-b] [2]苯并氮杂革基,7-1H-吡咯并[1,2-b] [2]苯并氮杂革基,8-1H-吡咯并[1,2-b] [2]苯并氮杂革基,9-1H-吡咯并[1,2-b] [2]苯并氮杂革基,10 Oxazolyl, 5-benzoxazolyl, 6-benzoxazolyl or 7-benzoxazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6 - benzimidazolyl or 7-benzimidazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl or 7 benzothiazolyl, 1-oxa leather-yl, 2-benzo oxa leather, 4-oxa-benzo leather-yl, 5-benzoxazepine leather-yl, 6-oxa-benzo leather group, 7-benzo-oxa leather-yl, 8-oxa-benzo leather or 9-oxa-benzo leather-yl (benzoxapinyl), 2- benzoxazine, 4-benzoxazine-yl, 5-benzo oxazin-yl, 6-benzoxazin-yl, 7- or 8-benzoxazin-benzoxazin-yl group, 1-1H- pyrrolo [1,2-b] [2] benzazepine-yl leather , 2-1H-pyrrolo [1,2-b] [2] benzazepine leather-yl, 3-1H-pyrrolo [1,2-b] [2] benzazepine leather-yl, 5-1H - pyrrolo [1,2-b] [2] benzazepine-yl leather, 6-1H- pyrrolo [1,2-b] [2] benzazepine-yl leather, 7-1H- pyrrolo [ 1,2-b] [2] benzazepine-yl leather, 8-1H- pyrrolo [1,2-b] [2] benzazepine-yl leather, 9-1H- pyrrolo [1,2- b] [2] benzazepine leather group, 10 -1H-吡咯并[1,2-b] [2]苯并氮杂革基或11-1H-吡略并[1,2-b] [2]苯并氮杂革基(benzazapinyl)。 -1H- pyrrolo [1,2-b] [2] benzazepine-yl or leather and slightly 11-1H- pyrazol [1,2-b] [2] benzazepine-yl leather (benzazapinyl). 典型的稠合杂芳基基团包括但不限于:2_喹啉基,3-喹啉基,4-喹啉基,5-喹啉基,6-喹啉基,7-喹啉基或8-喹啉基,1-异喹啉基,3-异喹啉基,4-异喹啉基,5-异喹啉基,6-异喹啉基,7-异喹啉基或8-异喹啉基,2-吲哚基,3-吲哚基,4-吲哚基,5-吲哚基,6-吲哚基或7-吲哚基, 2_苯并[b]噻吩基,3-苯并[b]噻吩基,4-苯并[b]噻吩基,5-苯并[b]噻吩基,6-苯并 Typical fused heteroaryl groups include but are not limited to: 2_ quinolyl, 3-quinolyl, 4-quinolyl group, 5-quinolyl, 6-quinolyl, 7-quinolyl or 8-quinolinyl, 1-isoquinolinyl, 3-isoquinolinyl, 4-isoquinolinyl, 5-isoquinolinyl, 6-isoquinolinyl, 7- or 8-isoquinolinyl isoquinolinyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl or 7-indolyl, 2_ benzo [b] thienyl , 3-benzo [b] thienyl, 4-benzo [b] thienyl, 5-benzo [b] thienyl, 6-benzo

[b]噻吩基或7-苯并[b]噻吩基,2-苯并恶唑基,4-苯并恶唑基,5-苯并恶唑基,6-苯并恶唑基或7-苯并恶唑基,2-苯并咪唑基,4-苯并咪唑基,5-苯并咪唑基,6-苯并咪唑基或7-苯并咪唑基,2-苯并噻唑基,4-苯并噻唑基,5-苯并噻唑基,6-苯并噻唑基或7-苯并噻唑基。 [B] thienyl or 7-benzo [b] thienyl, 2-benzoxazolyl, 4- benzoxazolyl, 5-benzoxazolyl, 6-benzoxazolyl or 7 -benzoxazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl or 7-benzimidazolyl, 2-benzothiazolyl, 4- benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl or 7-benzothiazolyl.

[0071] 如本文使用的术语"杂环基"或"杂环"是指被任选地取代的完全饱和的或不饱和的、芳香族的或非芳香族的环基团,例如,其为4元至7元单环系统,7元至12元双环系统或者10元至15元三环系统,其在至少一个含有碳原子的环中具有至少一个杂原子。 [0071] As used herein, the term "heterocyclyl" or "heterocycle" refers to an optionally substituted fully saturated or unsaturated, aromatic or non-aromatic cyclic group, for example, which is 4-7 yuan monocyclic ring system, 7-12 yuan bicyclic ring system, or 10-15 yuan tricyclic ring system, having at least one hetero atom in the ring containing at least one carbon atom. 含有杂原子的杂环基团中的每一个环可具有选自氮原子、氧原子和硫原子的1个,2个或3个杂原子,其中,氮原子和硫原子还可被任选地氧化。 Heterocyclic group containing a heteroatom in each ring selected from a nitrogen atom, an oxygen atom and a sulfur atom, 1, 2 or 3 heteroatoms, wherein the nitrogen and sulfur atoms may be optionally oxidation. 杂环基团可在杂原子或碳原子处连接。 Heterocyclic group may be attached at a heteroatom or a carbon atom.

[0072] 示例性的单环杂环基团包括:吡咯烷基、吡咯基、吡唑基、氧杂环丁烷基、吡唑啉基、咪唑基、咪唑啉基、咪唑烷基、三唑基、恶唑基、恶唑烷基、异恶唑啉基、异恶唑基、噻唑基、噻二唑基、噻唑烷基、异噻唑基、异噻唑烷基、呋喃基、四氢呋喃基、噻吩基、恶二唑基、哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、2-氧代氮杂卓基(2-oxoazepinyl )、氮杂卓基(azepinyl )、4_哌啶酮基、吡啶基、吡嘆基、喃啶基、llJi嘆基、 四氢吡喃基、吗啉基、噻吗啉基、噻吗啉基亚砜、噻吗啉基砜、1,3-二氧戊环和四氢-1,1-二氧代噻吩基、1,1,4-三氧代-1,2, 5-噻二唑烷-2-基,等等。 [0072] Exemplary monocyclic heterocyclic groups include: pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, triazolyl , oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazole alkyl, furanyl, tetrahydrofuranyl, thienyl group, oxadiazolyl, piperidinyl, piperazinyl, 2-oxo-piperazinyl, 2-oxo-piperidinyl, 2-oxo-pyrrolidinyl, 2-oxo-azepinyl (2- oxoazepinyl), azepinyl (azepinyl), 4_ piperidone, pyridyl, pyrazolyl group sigh, furans piperidinyl, llJi sigh-yl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, timolol morpholine sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxo-thienyl, 1,1,4 oxo -1,2,5-thiazole oxadiazol-2-yl, and the like.

[0073] 示例性的双环杂环基团包括:剛哚基、二氢吲哚基、苯并噻唑基、苯并恶嗪基、苯并恶唑基、苯并噻吩基、苯并噻嗪基、奎宁环基、喹啉基、四氢喹啉基、十氢喹啉基、异喹啉基、四氢异喹啉基、十氢异喹啉基、苯并咪唑基、苯并吡喃基、中氮茚基、苯并呋喃基、色酮基(chromony 1 )、香豆素基、苯并吡喃基、噌啉基、喹喔啉基、吲唑基、吡咯并吡啶基、呋喃并吡啶基(例如,呋喃并[2, 3-c]吡啶基、呋喃并[3, 2-b]吡啶基或呋喃并[2, 3-b]吡啶基)、二氢异吲哚基、1,3-二氧-1,3-二氢异吲哚-2-基、二氢喹唑啉基(例如,3, 4-二氢-4-氧代-喹唑啉基)、2, 3-二氮杂萘基,等等。 [0073] Exemplary bicyclic heterocyclic groups include: just indolyl, indolinyl, benzothiazolyl, benzoxazinyl, benzoxazolyl, benzothienyl, benzo-thiazin-yl , quinuclidinyl, quinolinyl, tetrahydroquinolinyl, decahydro-quinolinyl, isoquinolinyl, tetrahydro-isoquinolinyl, decahydro-isoquinolinyl, benzimidazolyl, benzopyranyl group, indolizinyl, benzofuranyl, chromone group (chromony 1), coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furan and pyridyl (e.g., furo [2, 3-c] pyridinyl, furo [3, 2-b] pyridinyl or furo [2, 3-b] pyridin-yl), dihydro-isoindolyl, 1,3-dioxo-1,3-dihydro-isoindol-2-yl, dihydro-quinazolinyl (e.g., 3, 4-dihydro-4-oxo - quinazolinyl), 2, 3- naphthyridinyl, and the like.

[0074] 示例性的三环杂环基团包括:咔唑基、二苯并氮杂卓基、二噻吩并氮杂卓基、苯并吲哚基、菲咯啉基、叮啶基、菲啶基、吩恶嗪基、吩噻嗪基、咕吨基、咔啉基,等等。 [0074] Exemplary tricyclic heterocyclic groups include: carbazolyl, dibenzo azepinyl, di-azepinyl thieno, benzindolyl, phenanthrolinyl, piperidinyl bite, phenanthrene piperidinyl, phenoxazine group, a phenothiazine group, a xanthene group, carboline-yl, and the like.

[0075] 术语"杂环基"进一步是指被1个、2个或3个选自下列基团的取代基取代的如上所定义的杂环基团: [0075] The term "heterocyclyl" further refers to heterocyclic groups, as defined above substituted with one, two or three substituents selected from the group consisting of:

[0076] (a)烷基; [0076] (a) alkyl;

[0077] (b)羟基(或者被保护的羟基); [0077] (b) hydroxy (or protected hydroxy);

[0078] (C)卤素; [0078] (C) halogen;

[0079] (d)氧,即,=0; [0079] (d) oxo, i.e., = 0;

[0080] (e)氨基,烷基氨基或二烷基氨基; [0080] (e) amino, alkylamino or dialkylamino;

[0081] (f)烷氧基; [0081] (f) alkoxy;

[0082] (g)环烷基; [0082] (g) cycloalkyl;

[0083] (h)羧基; [0083] (h) carboxy;

[0084] (i)杂环氧基,其中,杂环氧基是指通过氧桥键连接的杂环基团; [0084] (i) a heterocyclic group, wherein the heterocyclic group means a heterocyclic group attached through an oxygen bridge;

[0085] (j)烷基_0_C(0)-; [0085] (j) alkyl _0_C (0) -;

[0086] (k)巯基; [0086] (k) mercapto;

[0087] (1)硝基; [0087] (1) a nitro group;

[0088] (m)氰基; [0088] (m) cyano;

[0089] (η)氨磺酰基或亚磺酰氨基; [0089] (η) sulfamoyl or sulfonamido;

[0090] (〇)芳基; [0090] (square) aryl;

[0091] (P)烷基-C (0)-0-; [0091] (P) alkyl -C (0) -0-;

[0092] (q)芳基-C (0) -0-; [0092] (q) aryl, -C (0) -0-;

[0093] (r)芳基-S-; [0093] (r) aryl group -S-;

[0094] (S)芳氧基; [0094] (S) aryloxy;

[0095] (t)烷基-S -; [0095] (t) alkyl -S -;

[0096] (u)甲酰基,即,HC(0)-; [0096] (u) formyl, i.e., HC (0) -;

[0097] (V)氨基甲酰基; [0097] (V) carbamoyl;

[0098] (W)芳基-烷基一;以及 [0098] (W) aryl - a group; and

[0099] (X)被烷基、环烷基、烷氧基、羟基、氛基、烷基-C (0)-NH -、烷基氛基、二烷基氛基或卤素取代的芳基。 [0099] (X) is alkyl, cycloalkyl, alkoxy, hydroxy, atmosphere, alkyl -C (0) -NH - substituted alkyl group atmosphere, an atmosphere of a dialkyl aryl group or a halogen .

[0100] 本文使用的术语"烯基"是指具有2个至20个碳原子且含有至少一个双键的直链或支链烃基。 [0100] As used herein, the term "alkenyl" refers to having 2-20 carbon atoms and containing a straight-chain or branched-chain hydrocarbon group of at least one double bond. 所述烯基优选地具有约2个至8个碳原子。 The alkenyl group preferably having from about 2-8 carbon atoms.

[0101] 除非另有说明,术语"芳基"是指多不饱和芳香族烃取代基,其可为单环或多环(优选地为1个环至3个环),其可为稠合的或共价连接的。 [0101] Unless otherwise indicated, the term "aryl" refers to a polyunsaturated, aromatic, hydrocarbon substituent, which may (preferably 1 to 3 rings rings), which may be monocyclic or fused ring or covalently linked. 术语"杂芳基"是指含有1个至4个选自N、0和S的杂原子的芳基基团(或芳环),其中,氮原子和硫原子可被任选地氧化并且氮原子可被任选地季铵化。 The term "heteroaryl" refers to a 1-4 selected from N, an aryl group of 0 and S heteroatoms (or aromatic ring), wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may be optionally quaternized. 杂芳基基团可通过杂原子连接至分子的剩余部分。 Heteroaryl group may be attached to the remainder of the molecule through a heteroatom. 芳基和杂芳基的非限定性实例包括:苯基、1-萘基、2-萘基、4-联苯基、1-吡咯基、2-吡咯基、3-吡咯基、 3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-恶唑基、4-恶唑基、2-苯基-4-恶唑基、5-恶唑基、3-异恶唑基、4-异恶唑基、5-异恶唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、 3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、 5-苯并噻唑基、嘌呤基、2-苯并咪唑基、5-吲哚基、1-异喹啉基、5-异喹啉基、2-喹喔啉基、 5-喹喔啉基、3-喹啉基和6-喹啉基。 Non-limiting examples of aryl and heteroaryl groups include: phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl thiazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl thiazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl group, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl group, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolyl. 上述芳基和杂芳基环系统的每一个的取代基选自下述可接受的取代基基团。 Each of the above noted aryl and heteroaryl ring system substituents are selected from the following group of acceptable substituents.

[0102] 为了简洁起见,当与其他术语(例如,芳氧基、芳硫氧基、芳基烷基)组合使用时,术语"芳基"包括上述芳环和杂芳环。 [0102] For brevity, as with other terms (e.g., aryloxy group, arylthio group, arylalkyl) when used in combination, the term "aryl" includes the above-described aromatic ring and a heteroaromatic ring. 因此,术语"芳基烷基"意在包括其中芳基连接至烷基的那些自由基(例如,苄基、苯乙基、吡啶甲基,等等),所述烷基包括碳原子(例如,亚甲基)被例如氧原子取代的那些烷基(例如,苯氧基甲基、2-吡啶基氧甲基、3-(1-萘基氧)丙基,等等)。 Thus, the term "arylalkyl" is meant to include those in which the aryl radical attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like), the alkyl group comprising carbon atoms (e.g. , methylene) is substituted with an oxygen atom, for example, those alkyl groups (e.g., phenoxymethyl, 2- pyridyloxy methyl, 3- (1-naphthyl) propyl, and the like).

[0103] 上述术语(例如"烷基"、"杂烷基"、"芳基"和"杂芳基")的每一个包括所指定的自由基的取代形式和未取代形式这两者。 [0103] The term (e.g., "alkyl," "heteroalkyl," "aryl" and "heteroaryl") include each a radical of the designated both substituted and unsubstituted forms. 每种类型的自由基的优选的取代基在下文提供。 Each type of preferred substituents of radical are provided below.

[0104] 烷基和杂烷基自由基(包括通常称为條径、條基、杂條径、杂條基、炔基、环烷基、 杂环烷基、环烯基和杂环烯基的那些基团)的取代基通常分别被称为"烷基取代基"和"杂烷基取代基",并且它们可为选自下列多种基团中的一种或一种以上,但不限于下列基团:-0R',=0, =NR',=N-〇R',-NR' R",-SR',-卤素,-SiR' R"R"',-0C(0)R',-C(O) R',-C02R',-C0NR' R",-OC(O) NR' R",-NR"C(O) R',-NR' -C(O) NR"R"',-NR"C(O) 2R',-NR-C (NR,R,,R,,,)=NR,,,,,-NR-C (NR,R")=NR,,,,-S (0) R,,-S (0) 2R,,-S (0) 2NR,R",-NRS02R,,-CN 和-NO2,数量为0至(2m' +1),其中,m'为该自由基的碳原子总数。R',R'',R'''和R'''' 优选地分别独立地指氢、取代或未取代的杂烷基、取代或未取代的芳基(例如,被1个至3个卤素取代的芳基),取代或未取代的烷基、烷氧基或硫代烷氧基,或者芳基烷基 [0104] alkyl and heteroalkyl radicals (including path commonly referred to as bar, strip, heteroaryl bar diameter, bar heteroaryl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl those groups) substituents commonly referred to as "alkyl substituents" and "heteroalkyl substituents," and they may be a plurality of the following group of one or more selected from, but not limited to the following group: -0R ', = 0, = NR', = N-〇R ', - NR' R ", - SR ', - halogen, -SiR' R" R " ', - 0C (0) R ', - C (O) R', - C02R ', - C0NR' R ", - OC (O) NR 'R", - NR "C (O) R', - NR '-C (O) NR "R" ', - NR "C (O) 2R', - NR-C (NR, R ,, R ,,,) = NR ,,,,, - NR-C (NR, R") = NR, ,,, - S (0) R ,, - S (0) 2R ,, - S (0) 2NR, R ", - NRS02R ,, - CN and -NO2, in an amount of 0 to (2m '+1), wherein, m 'for the total number of carbon atoms of the radical .R', R '', R '' 'and R' '' 'each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted substituted aryl (e.g., substituted with 1-3 halogens aryl group), a substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl 基团。例如, 当本发明的化合物包括一个以上R基团时,R基团中的每一个独立地选自各R',R'',R''' 和R' '''基团(当存在这些基团中的一个以上时)。当R'和R' '连接至相同的氮原子时,它们可与氮原子结合形成5元环、6元环或7元环。例如,-NR'R''意在包括但不限于:1_吡咯烷基和4-吗啉基。通过以上对取代基的讨论,本领域技术人员会理解的是,术语"烷基"意在包括如下基团:该基团包括连接至除了氢基团以外的基团的碳原子,例如,卤代烷基(例如,-CF#P -CH 2CF3)和酰基(例如,-C (O) CH3, -C (O) CF3, -C (O) CH2OCH3,等等)。 Groups. For example, when a compound of the invention includes more than one R group, the R groups are each independently selected from R ', R' ', R' '' and R '' '' group ( when one of these groups is present in the above). when R 'and R' 'is connected to the same nitrogen atom, they can be combined with the nitrogen atom form a 5-membered ring, 6-membered ring or 7-membered ring. For example, -NR 'R' 'is intended to include, but not limited to: 1_ pyrrolidinyl and 4-morpholinyl by the above discussion of substituents, one of skill in the art will appreciate that the term "alkyl" is meant to include the following groups group: the group is connected to a carbon atom include a group other than hydrogen groups, e.g., haloalkyl (e.g., -CF # P -CH 2CF3) and acyl (e.g., -C (O) CH3, -C ( O) CF3, -C (O) CH2OCH3, and the like).

[0105] 类似于对于烷基自由基的取代基的描述,芳基取代基和杂芳基取代基通常被分别称为"芳基取代基"和"杂芳基取代基",并且为不同的,选自例如,卤素,-0R',=〇, =NR', =N-〇R',-NR' R",-SR',-卤素,-SiR' R"R"',-OC(O) R',-C(O) R',-C02R',-C0NR' R",-OC(O) NR' R",-NR" C (0) R',-NR' -C (0) NR" R"',-NR" C (0) 2R',-NR-C (NR,R")=NR' ",-S (0) R',-S (0)2R',-S(0)2NR' R",-NRSO2R',-CN 和-NO2,-R',-N3 ,-CH(Ph)2,氟代(C「C4)烷氧基和氟代(C1-C 4)烷基,数量为0至芳香族环系统上开放的化合价的总数,并且其中,R',R",R"'和R""优选地独立地选自:氢、(C1-C8)烷基和杂烷基、未取代的芳基和杂芳基,(未取代的芳基P(C 1-C4)烷基以及(未取代的芳基)氧-(C1-C4)烷基。例如,当本发明的化合物包含一个以上R基团时,R基团中的每一个独立地选自各R',R",R"'和R""基团(当存在这些基团中的一 [0105] similar to that described for the substituted alkyl group radicals, aryl substituents and heteroaryl substituents are generally referred to as "aryl substituents" and "heteroaryl group substituent", and different , selected, for example, halogen, -0R ', = square, = NR', = N-〇R ', - NR' R ", - SR ', - halogen, -SiR' R" R " ', - OC ( O) R ', - C (O) R', - C02R ', - C0NR' R ", - OC (O) NR 'R", - NR "C (0) R', - NR '-C (0 ) NR "R" ', - NR "C (0) 2R', - NR-C (NR, R") = NR ' ", -S (0) R', - S (0) 2R ', - S (0) 2NR 'R ", - NRSO2R', - CN and -NO2, -R ', - N3, -CH (Ph) 2, fluoro (C" C4) alkoxy and fluoro (C1-C 4 ) alkyl, the number of the total number of open valences on the aromatic ring system to 0, and wherein, R ', R ", R"' and R "" are preferably independently selected from: hydrogen, (C1-C8) alkoxy group and heteroalkyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl group P (C 1-C4) alkyl and (unsubstituted aryl) oxy -. (C1-C4) alkyl e.g. when the compound of the present invention contains more than one R group, the R groups are each independently selected from R ', R ", R"' and R "" groups (when these groups are present in a 以上时)。 Over time).

[0106] 芳环或杂芳环的相邻原子上的芳基取代基中的两个可任选地被通式-TC (0) - (CRR')qU-的取代基取代,其中,T和U独立地为-NR-,-0-,-CRR' -或单个化学键, 并且q为0至3的整数。 [0106] an aryl ring on adjacent atoms of the aryl or heteroaryl ring substituents may optionally be two of the formula -TC (0) - (CRR ') qU- substituents, wherein, T and U are independently -NR -, - 0 -, - CRR '- or a single bond, and q is an integer of 0 to 3. 可选地,芳环或杂芳环的相邻原子上的取代基中的两个可任选地被通式-A- (CH丄-B-的取代基取代,其中,A和B独立地为-CRR' -,-0-,-NR-,-S-,-S (0)-, -S (0) 2_,-S (0) 2NR' -或单个化学键,并且r为1至4的整数。由此形成的新环中的单个化学键中的一个可被双键任选地取代。可选地,芳基环或杂芳基环的相邻原子上的取代基中的两个可任选地被通式-(CRR') sX-(CR"R'")d-的取代基取代,其中,s和d独立地为0至3 的整数,并且X 为-0_,-NR' -,-S-,-S (0) -,-S (0) 2_,或-S (0) 2NR' _。取代基R,R',R' ' 和R'''优选地独立地选自氢或者取代或未取代的(C1-C6)烷基。 Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be of the general formula -A- (CH Shang -B- substituents, wherein, A and B are independently is -CRR '-, - 0 -, - NR -, - S -, - S (0) -, -S (0) 2 _, - S (0) 2NR' - or a single bond, and r is 1 to 4 integer of single chemical bonds of the new ring thus formed in a double bond may be optionally substituted. Alternatively, the group may be substituted on two adjacent ring atoms of the aryl or heteroaryl ring optionally substituted with the formula - (CRR ') sX- (CR "R'") d- substituent, where, s and d are independently an integer of 0 to 3, and X is -0 _, - NR ' -, - S -, - S (0) -, - S (0) 2_, or -S (0) 2NR '. _ substituents R, R', R '' and R '' 'are preferably independently selected from from hydrogen or a substituted or unsubstituted (C1-C6) alkyl.

[0107] 本文使用的术语"杂原子"包括氧(0)、氮(N)、硫(S)、磷(P)和硅(Si )。 [0107] As used herein, the term "heteroatom" includes oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0108] 本文使用的术语"芳氧基"是指-0-芳基和-0-杂芳基这两者,其中,芳基和杂芳基是本文所定义的。 [0108] As used herein, the term "aryloxy" refers to -0- -0- aryl and heteroaryl both of which aryl and heteroaryl are as defined herein.

[0109] 本文使用的术语"药学上可接受的盐"是指保持本发明的化合物的生物功效和性质的盐,其不是生物学上不理想的也不是其他不理想的。 [0109] As used herein, the term "pharmaceutically acceptable salts" refers to salts retaining the biological effectiveness and properties of the compounds of the present invention, on which undesirable not biologically nor otherwise undesirable. 在许多情况下,本发明的化合物能够通过存在的氨基和/或羧基或类似基团(例如,苯酷或异轻M亏酸(hydroxyamic acid))形成酸式盐和/或碱式盐。 In many cases, the compounds of the present invention can be prepared by the presence of amino and / or carboxyl groups or the like (e.g., benzene or isobutyl cool light M Deficit acid (hydroxyamic acid)) of forming acid and / or base salts. 药学上可接受的酸加成盐可通过无机酸和有机酸形成。 Pharmaceutically acceptable acid addition salts may be formed by inorganic and organic acids. 可衍生形成盐的无机酸包括,例如,盐酸、氢溴酸、硫酸、硝酸、磷酸,等等。 Inorganic acids may be derivatized to form salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. 可衍生形成盐的有机酸包括,例如,醋酸、丙酸、乙醇酸、丙酮酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸,等等。 Organic acids may be derivatized to form salts include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. 药学上可接受的碱加成盐可通过无机碱和有机碱形成。 Pharmaceutically acceptable base addition salts may be formed by an inorganic and organic bases. 可衍生形成盐的无机碱包括,例如,钠盐、钾盐、 锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐,等等,特别优选地为铵盐、钾盐、钠盐、 钙盐和镁盐。 Inorganic bases may be derivatized to form salts include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like, particularly preferably ammonium, potassium, sodium, calcium and magnesium salts. 可衍生形成盐的有机碱包括,例如,伯胺、仲胺和叔胺、取代的胺(包括天然生成的取代的胺)、环胺、碱性离子交换树脂,等等,尤其例如,异丙基胺、三甲胺、二乙胺、三乙胺、三丙胺和乙醇胺。 May be derivatized to form salts of organic bases include, for example, primary amines, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and the like, in particular, for example, isopropyl amine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. 本发明的药学上可接受的盐可通过常规化学方法由母体化合物, 碱性基团或酸性基团合成。 Pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound, a basic group or acidic moiety by conventional chemical methods. 一般而言,这种盐可通过这些化合物的游离酸形式与化学计量量的合适的碱(例如,氢氧化钠,氢氧化钙,氢氧化镁或氢氧化钾,碳酸盐,碳酸氢盐,等等) 的反应来制备或者可通过这些化合物的游离碱形式与化学计量量的合适的酸的反应来制备。 Generally, such salts can be obtained by the free acid forms of these compounds with an appropriate stoichiometric amount of base (e.g., sodium hydroxide, calcium hydroxide, magnesium hydroxide or potassium hydroxide, carbonate, bicarbonate, etc.) or may be prepared by reacting the free base form prepared by the reaction of a suitable acid compounds with a stoichiometric amount. 这些反应通常在水或有机溶剂中进行,或者在水和有机溶剂的混合物中进行。 These reactions are typically carried out in water or an organic solvent, or in a mixture of water and an organic solvent. 通常,在实际应用中,非水性介质(例如,醚、乙酸乙酯、乙醇、异丙醇或乙腈)为优选的。 Typically, in practical applications, non-aqueous vehicles (e.g., ether, ethyl acetate, ethanol, isopropanol, or acetonitrile) are preferred. 其他合适的盐的列表可在例如,Remington's Pharmaceutical Sciences,第20 版,Mack Publishing Company, Easton, Pa.,(1985)中找到,该参考文献通过引用并入本文。 Other suitable salts are found in, for example, a list, Remington's Pharmaceutical Sciences, 20th Edition, Mack Publishing Company, Easton, Pa., (1985) found in the references incorporated by reference herein.

[0110] 本文使用的术语"药学上可接受的载体/赋形剂"包括本领域普通技术人员已知的任何和所有溶剂、分散介质、包衣、表面活性剂、抗氧化剂、防腐剂(例如,抗菌剂、抗真菌剂)、等渗剂、吸收延迟剂、盐、药物、药物稳定剂、结合剂、赋形剂、崩解剂、润滑剂、甜味剂、调味剂、染料,等等,以及它们的组合(参见,例如,Remington's Pharmaceutical Sciences,第18 版,Mack Printing Company, 1990, ρρ· 1289-1329,该参考文献通过引用并入本文)。 [0110] The term used herein "pharmaceutically acceptable carrier / excipient" includes those of ordinary skill in the art that any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g. , antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, drugs, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, etc. , and combinations thereof (see, e.g., Remington's Pharmaceutical Sciences, 18th Ed., Mack Printing Company, 1990, ρρ · 1289-1329, which references are incorporated herein by reference). 除了迄今已知的与活性成分不相容的任何常规载体之外,上述药学上可接受的载体/赋形剂可用于治疗组合物或药物组合物。 In addition to the heretofore known any conventional carrier is incompatible with the active ingredient, the above-mentioned pharmaceutically acceptable carriers / excipients can be used in therapeutic compositions or pharmaceutical compositions.

[0111] 本文使用的术语"受治者"是指动物。 [0111] As used herein, the term "subject" refers to animals. 优选地,所述动物为哺乳动物。 Preferably, the animal is a mammal. 受治者还指例如,灵长类动物(例如,人类),牛、绵羊、山羊、马、狗、猫、兔子、大鼠、小鼠、鱼、鸟,等等。 A subject who also refers to for example, primates (eg, humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and so on. 在优选的实施方式中,所述受治者为人类。 In a preferred embodiment, the subject is a human person.

[0112] 化合物和组合物 [0112] The compounds and compositions

[0113] 一方面,本发明提供一种具有通式(Ia)的结构的化合物: [0113] In one aspect, the present invention provides a compound having the formula (Ia) of the structure:

[0114] TM-L-AM(Ia), [0114] TM-L-AM (Ia),

[0115] 其中,TM为与Her2/Neu特异性结合的靶向部分,例如,抗体或其片段(例如, 抗-Her2抗体),AM为活化树突细胞、自然杀伤细胞或肿瘤细胞或者它们的组合的活化部分,L为连接体。 [0115] where, TM is the targeting moiety specifically binds to Her2 / Neu, e.g., antibody or fragment (e.g., an anti-antibody -Her2), AM is an activated dendritic cells, natural killer cells or tumor cells or their activated partial composition, L is a linker.

[0116] 本文中的"活化部分"是指能够刺激或增强个体的免疫系统或肿瘤细胞的分子或药剂。 [0116] As used herein the "activating moiety" refers to a molecule capable of stimulating or enhancing the immune system of an individual or an agent or tumor cells. 总体而言,活化部分直接或间接地作用于toll样受体、核苷酸-寡聚结构域样受体、 RIG-I样受体、c型植物凝集素受体或细胞溶质DNA传感器,或者它们的组合。 Overall, the effect of activating moiety directly or indirectly to a toll-like receptor, a nucleotide - like receptor oligomerization domain, RIG-I-like receptor, c-type lectin receptor or cytosolic DNA sensor, or a combination thereof.

[0117] 在一些实施方式中,所述活化部分活化人免疫细胞或肿瘤细胞,或者它们的组合, 所述人免疫细胞包括但不限于:树突细胞、巨噬细胞、单核细胞、骨髓衍生的抑制细胞、NK 细胞、B细胞、T细胞。 [0117] In some embodiments, the activation of the partially activated human immune cells or tumor cells, or a combination thereof, the human immune cells include, but are not limited to: dendritic cells, macrophages, monocytes, bone marrow-derived suppressor cells, NK cells, B cells, T cells.

[0118] 树突细胞为最强的抗原呈递细胞。 [0118] Dendritic cells are the most powerful antigen presenting cells. 树突细胞在启动先天性免疫反应和获得性免疫反应中发挥主要作用。 Dendritic cells play a major role in the initiation of the innate immune response is obtained and immune responses. 树突细胞还在诱导和维持免疫耐受方面发挥关键作用。 Dendritic cells also induction and maintenance of immune tolerance play a key role.

[0119] 本文中的"树突细胞(DC)"是指异质细胞群,其包括两个主要的亚型,即髓样DC (mDC)和衆细胞样DC (pDC) (Steinman 等人,1979, J. Exp. Med.,149, 1-16)。 [0119] As used herein the "dendritic cell (the DC)" refers to a heterogeneous population of cells, comprising two major subtypes, i.e., myeloid DC (mDC) and all the cell-like DC (pDC) (Steinman et al., 1979, J. Exp. Med., 149, 1-16). 这两种血液DC亚组最初通过它们的⑶Ilc (整合素补体受体)和⑶123 (IL-3Ra)的表达来区分。 Both the first blood DC subsets by their ⑶Ilc (integrin complement receptor) and expression ⑶123 (IL-3Ra) to distinguish. PDC 和mDC群中的每一种构成人体内PBMC群的约0. 2%至约0. 6%。 From about 0.2% to about 0.6% of each group constituting the body PBMC mDC and PDC cluster.

[0120] 本文中的"pDC"是指浆细胞样树突细胞,并且它们代表了在血液和外周淋巴器官中发现的树突细胞的亚型。 [0120] As used herein the "pDC" refers to a plasmacytoid dendritic cell, and they represent subtypes found in the blood and in peripheral lymphoid organs, dendritic cells. 这些细胞表达表面标记物⑶123、BDCA-2(⑶303)和80〇4-4(0)304)和!11^-〇1?,但是不表达0)11(3,0)14,0)3,0)20或0)56,这使口0(:与一般树突细胞、单核细胞、T细胞、B细胞和NK细胞得以区分。作为先天性免疫系统的成分,这些细胞表达细胞内Toll样受体7和9,这使病毒和细菌核酸能够得到检测,所述病毒和细菌核酸例如,ssRNA或CpG DNA基序。在刺激和随后的活化之后,这些细胞产生大量I型干扰素(主要为IFN-a和IFN-β )和III型干扰素(例如,IFN-λ ),这两种干扰素是介导多种作用的重要的多效性抗病毒化合物。通过产生大量I型干扰素、细胞因子和趋化因子,浆细胞样树突细胞广泛参与人体先天性免疫反应和获得性免疫反应。它们可调节NK细胞、T细胞、B细胞和其他涉及免疫反应强度、持续期和反应模式的细胞,因此,它们在肿瘤、感染和自体免疫疾病中发挥非常重要的作用(L These cells express surface markers ⑶123, BDCA-2 (⑶303) and 80〇4-4 (0) 304) and! ^ 11 ?, but not expressing -〇1 0) 11 (3,0) 14,0) 3 , 0) 20 or 0) 56, which makes the port 0 (: general dendritic cells, monocytes, T cells, B cells and NK cells can be distinguished as a component of the innate immune system, these cells express intracellular Toll like receptors 7 and 9, this virus can be obtained and detecting bacterial nucleic acids, the nucleic acids such as viruses and bacteria, or the ssRNA CpG DNA motifs. after stimulation and subsequent activation of these cells produce large amounts of type I interferons (mainly of IFN-a and IFN-β) and type III interferon (e.g., IFN-λ), the two interferons are mediated by a variety of important pleiotropic effect of antiviral compounds produce large amounts of type I interferon by , cytokines and chemokines, plasmacytoid dendritic cells are widely involved in human innate immune response and acquired immune response. they can be adjusted NK cells, T cells, B cells and other immune response directed to strength, and duration of response mode cells, therefore, they play a very important role in cancer, infections and autoimmune diseases (L iu YJ.IPC:professional typelinterferon-producing cells and plasmacytoid dendritic cell precursors. Annu Rev Immunol. 2005;23:275-306. Gilliet M,Cao Wj Liu YJ. Plasmacytoid dendritic cells:sensing nucleic acids in viral infection and autoimmune diseases. Nat Rev Immunol.2008Aug;8(8):594-606)〇 iu YJ.IPC: professional typelinterferon-producing cells and plasmacytoid dendritic cell precursors Annu Rev Immunol 2005; 23:.... 275-306 Gilliet M, Cao Wj Liu YJ Plasmacytoid dendritic cells: sensing nucleic acids in viral infection and autoimmune diseases. Nat Rev Immunol.2008Aug; 8 (8): 594-606) square

[0121] 本文中的"mDC"是指髓样树突细胞,并且它们表示血液和外周淋巴器官中发现的循环树突细胞的亚型。 [0121] As used herein the "mDC" refers to myeloid dendritic cells, and they are expressed in blood and peripheral lymphoid organs, dendritic cells circulating subtypes found. 这些细胞表达表面标记物⑶11c,⑶la,HLA-DR以及BDCA-I (⑶Ic) 和BDCA-3(⑶141)中的任一种。 These cells express surface markers ⑶11c, ⑶la, HLA-DR and BDCA-I (⑶Ic) and any one of (⑶141) BDCA-3. 它们不表达BDCA-2或⑶123,这使mDC与pDC得以区分。 They do not express BDCA-2 or ⑶123, which makes mDC and pDC be distinguished. mDC也不表达⑶3,⑶20或⑶56。 mDC not express ⑶3, ⑶20 or ⑶56. 作为先天性免疫系统的成分,mDC表达Toll样受体(TLR), 该受体包括TLR2、TLR3、TLR4、TLR5、TLR6和TLR8,其使细菌和病毒成分能够得到检测。 As a component of the innate immune system, mDC expressing Toll-like receptor (TLR), including the receptors TLR2, TLR3, TLR4, TLR5, TLR6 and TLR8, which bacteria can be detected and viral components. 在刺激和随后的活化之后,这些细胞为最有效的抗原呈递细胞,从而活化抗原特异性CD4和⑶8T细胞。 After stimulation and subsequent activation of these cells are the most potent antigen presenting cells, thereby activating the antigen-specific CD4 cells and ⑶8T. 此外,mDC具有产生大量IL-12和IL23的能力,这种能力对于诱导Thl介导的或Thl7细胞介导的免疫非常重要。 In addition, having the ability to produce a large number of mDCs IL-12 and IL23, which is very important for the ability or Thl7 cell mediated immunity induction mediated Thl.

[0122] 研究发现许多实体瘤(例如,乳腺癌和头颈癌,卵巢癌)具有pDC浸润(Treilleux I, Blay JYj Bendriss-Vermare N 等人,Dendritic cell infiltration and prognosis of early stage breast cancer.Clin Cancer Res2004;10:7466-7474,Hartmann E,Wollenberg B,Rothenfusser S 等人,Identification and functional analysis of tumor-infiltrating plasmacytoid dendritic cells in head and neck cancer. Cancer Res2003;63:6478-6487. Zou WP,Machelon V,Coulomb_L'Hermin A,等人, Stromal-derived factor-lin human tumors recruits and alters the function of plasmacytoid precursor dendritic cells. Nat Med2001; 7:1339-1346)和由肿瘤细胞分泌的因子抑制DC 成熟(Gabrilovich DI,Corak J,Ciernik IF 等人,Decreased antigen presentation by dendritic cells in patients with breast cancer. Clin Cancer Resl997; 3:483-490. Bell D,Chomarat P,Broyles D 等人,In breast carcinoma tissue, immature dendritic cells reside within the tumor,whereas mature dendritic cel [0122] found in many solid tumors (e.g., breast, and head and neck cancer, ovarian cancer) have pDC infiltration (Treilleux I, Blay JYj Bendriss-Vermare N et al., Dendritic cell infiltration and prognosis of early stage breast cancer.Clin Cancer Res2004 ; 10:. 7466-7474, Hartmann E, Wollenberg B, Rothenfusser S et al., Identification and functional analysis of tumor-infiltrating plasmacytoid dendritic cells in head and neck cancer Cancer Res2003; 63:. 6478-6487 Zou WP, Machelon V, Coulomb_L'Hermin a, et al., Stromal-derived factor-lin human tumors recruits and alters the function of plasmacytoid precursor dendritic cells Nat Med2001; 7:. 1339-1346) secreted by tumor cells and inhibition of DC maturation factor (Gabrilovich DI, Corak J, Ciernik IF et al., Decreased antigen presentation by dendritic cells in patients with breast cancer Clin Cancer Resl997; 3:.. 483-490 Bell D, Chomarat P, Broyles D et al., in breast carcinoma tissue, immature dendritic cells reside within the tumor, whereas mature dendritic cel ls are located in peritumoral areas. J Exp Medl999;190:1417-1425. Menetrier-Caux C,Montmain G,Dieu MC 等人,Inhibition of the differentiation of dendritic cells from CD34(+)progenitors by tumor cells:role of interleukin_6and macrophage colony-stimulating factor. Bloodl998;92:4778-4791)。 ls are located in peritumoral areas J Exp Medl999; 190:.. 1417-1425 Menetrier-Caux C, Montmain G, Dieu MC, et al., Inhibition of the differentiation of dendritic cells from CD34 (+) progenitors by tumor cells: role of interleukin_6and macrophage colony-stimulating factor Bloodl998; 92:. 4778-4791). 这些未成熟的DC细胞无法在提高抗肿瘤免疫方面发挥作用。 These immature DC cells can not play a role in enhancing the anti-tumor immunity. 相比之下,肿瘤微环境中的DC通过抑制抗肿瘤免疫和促进血管生成而促进肿瘤生长。 In contrast, the tumor microenvironment suppressing anti-tumor immunity by DC promote angiogenesis and promote tumor growth. 有证据表明Toll样受体7激动剂咪喹莫特和Toll样受体9激动剂CpG药物可刺激肿瘤微环境中的pDC,从而抑制肿瘤发展(Dummer R,Urosevic M,Kempf W等人,Imiquimod in basal cell carcinoma:how does it work?Br J Dermatol2003; 149:57-58. MiIIer RL,Gerster JF,Owens ML 等人,Imiquimod applied topically:a novel immune response modifier and new class of drug. Int J Immunopharmacol 1999; 21:1-14. Hofmann MAj Kors Cj Audring H 等人,Phaselevaluation of intralesionally injected TLR9_agonist PF_3512676in patients with basal cell carcinoma or metastatic melanoma. J Immunother2008;31:52〇-527)〇 There is evidence that Toll-like receptor 7 agonist, imiquimod and Toll like receptor 9 agonist CpG drugs can stimulate tumor microenvironment pDC, thereby inhibiting tumor development (Dummer R, Urosevic M, Kempf W et al., Imiquimod in basal cell carcinoma: how does it work Br J Dermatol2003; 149:? 57-58 MiIIer RL, Gerster JF, Owens ML, et al., Imiquimod applied topically: a novel immune response modifier and new class of drug Int J Immunopharmacol 1999.. ; 21:. 1-14 Hofmann MAj Kors Cj Audring H et al., Phaselevaluation of intralesionally injected TLR9_agonist PF_3512676in patients with basal cell carcinoma or metastatic melanoma J Immunother2008; 31:. 52〇-527) square

[0123] 自然杀伤(NK)细胞为一类细胞毒性淋巴细胞,其构成免疫系统的主要成分。 [0123] Natural killer (NK) cells are a class of cytotoxic lymphocytes that constitute a major component of the immune system. NK 细胞为由⑶56或⑶16的表达和T细胞受体(⑶3)的缺乏界定的外周血液淋巴细胞的一个亚型。 NK cells or by ⑶56 ⑶16 expression and T cell receptor (⑶3) the lack of a defined subtype of peripheral blood lymphocytes. 所述自然杀伤细胞在不引发MHC非限制性方式的条件下识别并杀伤转化的细胞系。 Natural killer cell recognition and killing transformed cell lines without a non-limiting embodiment of MHC initiator. NK细胞在抑制肿瘤和防止细胞受到病毒感染方面发挥重要作用。 NK cells play an important role in the inhibition of tumor cells and prevent infection by the virus. NK细胞识别靶细胞并递送足够的信号以触发靶标溶解的过程由细胞表面上的大量抑制性受体和活化受体确定。 NK cells recognize the target cell and deliver sufficient signal to trigger the process of dissolution of the target is determined by a large number of inhibitory receptors and the activation of receptors on the cell surface. 将NK自身与改变的NK自身区分开涉及抑制性受体对MHC-I分子和诸如CD48和Clr-Ib之类的非MHC配体的识别。 The NK NK itself and change their region directed inhibitory receptor recognition of non-MHC-I and MHC molecules such as CD48 ligand and Clr-Ib or the like separately. 感染的或损伤的细胞(改变的自身)的NK识别通过由各种活化受体(包括,NKG2D,Ly49H和NKp46/Ncrl)识别的应激诱导的配体(例如,MICA,MICB,Rael,H60, Multi)或病毒编码的配体(例如,ml57,血凝素)调节。 Or infected cells (altered itself) is identified by the damage of various NK activating receptors (including, NKG2D, Ly49H and NKp46 / Ncrl) identifying the stress-induced ligand (e.g., MICA, MICB, Rael, H60 , Multi) or virus encoding a ligand (e.g., ml57, hemagglutinin) adjustment.

[0124] NK细胞代表异体或自体干细胞移植之后数月外周血液中的主要淋巴样细胞,并且它们在这个时间段对病原体免疫发挥主要作用(Reittie等人(1989) Blood73:1351_1358;Lowdell 等人(1998)Bone Marrow Transplant21:679_686)。 [0124] cells represent allogeneic NK or autologous after stem cell transplantation for several months in the peripheral blood primary lymphoid cells, and they play a major role (Reittie et al. (1989) Blood73 pathogen immunity in this period: 1351_1358; Lowdell et al ( 1998) Bone Marrow Transplant21: 679_686). NK 细胞在移植、移植物抗宿主疾病、抗白血病活性和移植后感染方面的作用在如下文献中回顾: Lowdell(2003)Transfusion Medicinel3:399-404〇 NK cells versus host disease, transplantation antileukemic activity and the role of infections in the following review of the literature in transplantation, graft: Lowdell (2003) Transfusion Medicinel3: 399-404〇

[0125] 人NK细胞通过天然细胞毒性和抗体依赖性细胞毒性(ADCC)介导肿瘤细胞的溶解和病毒感染的细胞的溶解。 NK cell-mediated tumor cell lysis and viral infections by natural cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC) was dissolved [0125] in human cells.

[0126] 人NK细胞由阳性和阴性细胞溶解信号控制。 [0126] Human NK cells were lysed by the control signal is positive and negative cells. 阴性(抑制性)信号通过包含受体⑶94/NKG2A的C-植物凝集素结构域和一些杀伤免疫球蛋白样受体(KIR)转导。 Negative (inhibiting) signal C- lectin domain ⑶94 / NKG2A and some killer immunoglobulin-like receptors (KIR) comprise transduced by receptors. 通过抑制性信号对NK溶解的调节被称为"自我缺失"假说,其中,特异性HLA (在靶细胞表面表达的I 类等位基因)与NK细胞上的抑制性受体结合。 By inhibitory signal to NK dissolved adjustment is called "missing self" hypothesis, wherein the inhibitory receptor specific HLA (class I alleles expressed in the target cell surface) on binding to NK cells. 肿瘤细胞和一些病毒感染的细胞(例如,CMV) 上的HLA分子的下调使这种抑制降低至目标阈值以下并且如果靶细胞还携带NK引发和活化分子,那么靶细胞可变得易受NK细胞介导的溶解影响。 Down HLA molecules on tumor cells, and some virus-infected cells (e.g., the CMV) such inhibition decreased to make certain threshold and if the target cells induced NK and also carry activated molecules, it may become susceptible to NK cell target cells Effects mediated dissolved guide. TLR7、TLR8或TLR9激动剂可活化mDC和pDC这两者,从而生成I型IFN并表达诸如GITR配体之类的共刺激分子,随后活化NK细胞,从而生成IFN-g并有效促进NK细胞杀伤功能。 TLR7, TLR8 or TLR9 agonist activatable the pDC and mDC both, thereby generating the type I IFN and express GITR ligand such as costimulatory molecules, followed by activated NK cells, and IFN-g to generate effective to promote NK cell Features.

[0127] 抑制性受体归为两组,一组为称为杀伤免疫球蛋白样受体(KIR)的Ig-超家族,另一组为植物凝集素家族(NKG2,在细胞表面与⑶94形成二聚体)。 [0127] Inhibitory Receptor classified into two groups, a group referred to as killer immunoglobulin-like receptors (KIR) the Ig- superfamily, another group of plant lectin family (the NKG2, is formed on the cell surface and ⑶94 dimer). KIR具有2个结构域的细胞外结构或3个结构域的细胞外结构并且与HLA-A、HLA-B或HLA-C结合。 KIR structure having an outer structure of three intracellular or extracellular domains of the two domains of the cell and bind to HLA-A, HLA-B or HLA-C. NKG2/CD94复合物结合HLA-E。 NKG2 / CD94 complex binds to HLA-E.

[0128] 抑制性KIR具有多达4个细胞内结构域,所述结构域包含ITIM并且被表征得最好的抑制性KIR为已知与HLA-C分子结合的KIR2DL1、KIR2DL2和KIR2DL3。 [0128] inhibitory KIR having up to four cells within the domain, the domain comprises a table and is ITIM inhibitory KIR obtain best known to bind to KIR2DL1 and HLA-C molecules, the KIR2DL2 and KIR2DL3. KIR2DL2和KIR2DL3结合第一组HLA-C等位基因,而KIR2DL1结合第二组等位基因。 KIR2DL2 KIR2DL3 and HLA-C binding a first set of alleles, whereas KIR2DL1 binding to a second allele. 一些白血病/淋巴瘤细胞表达第一组HLA-C等位基因和第二组HLA-C等位基因这两者并且已知这些白血病/ 淋巴瘤细胞为抗NK介导的细胞溶解的。 Some of leukemia / lymphoma cells express both the first set of HLA-C alleles and the second set of known HLA-C alleles and the leukemia / lymphoma cells is an anti-NK cell-mediated cytolysis.

[0129] 关于阳性活化信号,ADCC被认为是通过⑶16介导的,并且已识别了大量导致天然细胞毒性的触发受体,包括CD2, CD38, CD69, NKRP-I,CD40, B7-2, NK-TR,NKp46, N Kp30和NKp44。 [0129] For positive activation signal, the ADCC is thought to be mediated by ⑶16, and have identified a large number of leads to natural cytotoxicity triggering receptor, including CD2, CD38, CD69, NKRP-I, CD40, B7-2, NK -TR, NKp46, N Kp30 and NKp44. 此外,带有短胞浆内尾部的几种KIR分子也为刺激性的。 In addition, several KIR molecules with a short cytoplasmic tail is also irritating. 已知这些KIR (KIR2DS1,KIR2DS2和KIR2DS4)与HLA-C结合,它们的细胞外结构域与它们的相关抑制性KIR相同。 These known KIR (KIR2DS1, KIR2DS2, and to KIR2DS4) binding to HLA-C, they have the same extracellular domain associated with their inhibitory KIR. 活化KIR缺乏ITIM,反而与导致NK细胞活化的DAP12结合。 Activating KIR lack ITIM, instead of leading to activation of NK cells DAP12 combination. 控制抑制性KIR和活化KIR的表达的机制仍然还不清楚。 Mechanisms controlling expression and activation of inhibitory KIR KIR is still unclear.

[0130] 一些报道已描述了TLR在小鼠或人癌症或癌症细胞系中的表达。 [0130] Several reports have described the expression of TLR in mouse or human cancer or cancer cell lines. 例如,TLRl至TLR6通过结肠、肺、前列腺和黑色素瘤小鼠肿瘤细胞系表达(Huang B等人,Toll-Iike receptors on tumor cells facilitate evasion of immune surveillance. Cancer Res. 2005; 65 (12) : 5009 - 5014),TLR3在人乳腺癌细胞中表达(Salaun B,Coste I,Rissoan MC,Lebecque SJ,Renno T. TLR3can directly trigger apoptosis in human cancer cells. J Immunol. 2006; 176(8) :4894 - 4901),肝癌和胃癌细胞表达TLR2 和TLR4 (Huang B 等人,Listeria monocytogenes promotes tumor growth via tumor cell toll-like receptor2signaling.Cancer Res.2007;67(9):4346 _ 4352),并且TLR9 (Droemann D 等A, Human lung cancer cells express functionally active Toll-like receptor9. Respir Res. 2005:6:1)和TLR4 (He W,Liu Q,Wang L,Chen W,Li N,Cao X.TLR4signaling promotes immune escape of human lung cancer cells by inducing immunosuppressive cytokines and apoptosis resistance. Mol Immunol. 2007; 44 (11) : 2850 - 2859)通过人肺癌细胞表达。 For example, to tlrl TLR6 through the colon, lung, prostate tumor cell lines expressing murine melanoma and (Huang B, et al., Toll-Iike receptors on tumor cells facilitate evasion of immune surveillance Cancer Res 2005; 65 (12):.. 5009 - 5014), TLR3 expression in human breast cancer cells (Salaun B, Coste I, Rissoan MC, Lebecque SJ, Renno T. TLR3can directly trigger apoptosis in human cancer cells J Immunol 2006; 176 (8..): 4894 - 4901 ), gastric cancer, and liver cancer cells expressing TLR2 and TLR4 (Huang B et al., growth via Listeria monocytogenes promotes tumor tumor cell toll-like receptor2signaling.Cancer Res.2007; 67 (9): 4346 _ 4352), and TLR9 (Droemann D et . A, Human lung cancer cells express functionally active Toll-like receptor9 Respir Res 2005:. 6: 1) and TLR4 (He W, Liu Q, Wang L, Chen W, Li N, Cao X.TLR4signaling promotes immune escape of human . lung cancer cells by inducing immunosuppressive cytokines and apoptosis resistance Mol Immunol 2007; 44 (11): 2850 - 2859) expressed by human lung cancer cells. 在人肺癌肿瘤细胞中发现TLR7和TLR8 (Cherfils-Vicini J,Platonova S,Gillard M,Laurans Lj Validire P,Caliandro R,Magdeleinat Pj Mami-Chouaib F,Dieu-Nosjean MC,Fridman WHj Damotte Dj Sautes-Fridman C,Cremer IJ Clin Invest. 2010;120(4):1285 - 1297)〇 Found TLR7 and TLR8 (Cherfils-Vicini J, Platonova S, Gillard M, Laurans Lj Validire P, Caliandro R, Magdeleinat Pj Mami-Chouaib F, Dieu-Nosjean MC, Fridman WHj Damotte Dj Sautes-Fridman C in human lung cancer cells , Cremer IJ Clin Invest 2010; 120 (4):. 1285 - 1297) square

[0131] TLR为感应微生物产物和/或启动获得性免疫反应的蛋白质家族。 [0131] TLR induction microbial products and / or to initiate adaptive immune response of the protein family. TLR活化树突细胞(DC)。 TLR activation of dendritic cells (DC). TLR为含有富含亮氨酸的重复单元胞外结构域、跨膜结构域和细胞内TIR (Toll/ 白介素受体)结构域的保守跨膜分子。 TLR containing leucine-rich repeat units extracellular domain, a transmembrane molecule conserved transmembrane domain and an intracellular TIR (Toll / interleukin receptor) domains. TLR识别微生物中的不同结构,通常称为"PAMP"(病原体相关分子模式)。 TLR recognition microorganisms of different structures, commonly referred to as "PAMP" (pathogen associated molecular pattern). 与TLR结合的配体引起细胞内信号通路的级联反应,该级联反应诱导参与炎症和免疫的因子的生成。 Binding to the TLR ligands induced cascade of intracellular signaling pathways, induction of the cascade involved in generating inflammation and immune factors.

[0132] 在一些实施方式中,所述活化部分为TLR7和/或TLR8激动剂。 [0132] In some embodiments, the activated portion of TLR7 and / or TLR8 agonist. TLR7和TLR8在系统发育和结构上相关。 TLR7 and TLR8 related phylogenetically and structures. TLR7由人pDC和B细胞选择性表达。 TLR7 is expressed by human pDC and B cell selectivity. TLR8主要由mDC、单核细胞、巨噬细胞和骨髓抑制细胞表达。 TLR8 mainly mDCs, monocytes, macrophages, and suppression of bone marrow cells. TLR7特异性激动剂活化浆细胞样DC (pDC),从而生成大量1 型IFN并且表达高水平的共刺激分子,所述共刺激分子促进T细胞、NK细胞、B细胞和mDC 的活化。 TLR7-specific agonist activation of plasmacytoid DC (pDC), thereby generating a large number of type 1 IFN and express high levels of costimulatory molecules, a costimulatory molecule to promote T cells, NK cells, B cells, and activation of mDC. TLR8特异性激动剂活化髓样DC、单核细胞、巨噬细胞或骨髓衍生的抑制细胞,从而生成大量1型IFN、IL-12和IL-23,并且表达高水平的MHC I类分子、MHC II类分子和共刺激分子,所述MHC I类分子、MHC II类分子和共刺激分子促进抗原特异性CD4和CD8+T细胞的活化。 TLR8 agonist-specific activation of the DC myeloid, monocytes, macrophages or bone marrow-derived suppressor cells, thereby generating a large number of type 1 IFN, IL-12 and IL-23, and high levels of expression of MHC I class molecules, of MHC class II molecules and costimulatory molecules, the MHC class I molecules, MHC class II molecules and costimulatory molecules activation of antigen-specific CD4 and CD8 + T cells promoted.

[0133] 在一些实施方式中,活化部分是TLR7和/或TLR8激动剂或其药学上接受的盐或其溶剂化物,其由下述通式(I)的结构表示: [0133] In some embodiments, the activated moiety is TLR7 and / or TLR8 agonist or a pharmaceutically acceptable salt or solvate thereof, which is represented by the following structural formula (I) is:

[0134] [0134]

Figure CN104861063AD00351

[0135] 其中,虚线表示存在化学键或不存在化学键,~为待与连接体连接的点; [0135] wherein the dotted line represents presence of a bond or absence of a bond, - to be connected to the connecting point of the body;

[0136] X 是S 或-NR1, 1^是-W。 [0136] X is S or -NR1, 1 ^ is -W. 一W1 一W2一W3一W4; W1 W2 a a a a W3 W4 of the;

[0137] W。 [0137] W. 是化学键,烷基,烯基,炔基,烷氧基或-烷基-S-烷基一, Is a bond, alkyl, alkenyl, alkynyl, alkoxy, or - an alkyl group -S-,

[0138] W1是化学键,一0一,或-NR 2-,其中,R2是氛,烷基或烯基, [0138] W1 is a bond, 101, or -NR 2-, wherein, R2 is the atmosphere, alkyl or alkenyl,

[0139] W2是化学键,一0-,一C(0)-,一C(S) -或-S(O) 2-, [0139] W2 is a bond, a 0-, a C (0) -, a C (S) - or -S (O) 2-,

[0140] W3是化学键,一NR 3一,其中,R3是氛,烷基或烯基, [0140] W3 is a bond, a NR 3 a, wherein, R3 is the atmosphere, alkyl or alkenyl,

[0141] W4是氣,烷基,烯基,炔基,烷氧基,环烷基,芳基,芳氧基,杂芳基或杂环基,它们中的每一个被一个或一个以上选自下列基团的取代基任选地取代:羟基,烷氧基,烷基,烯基,炔基,环烷基,芳基,杂芳基,杂环基,一NH 2,硝基,一烷基-羟基,--烷基-芳基,一焼基-杂芳基,一烷基-杂环基,一〇_R4,一〇_烷基-R 4,一烷基-O-R4,一C(0) -R4?-焼基-C (O)-R4,一烷基-C (0)-O-R4,一C(O)-O-R4,一S-R4,一S (O)2-R4,一NH-S (O)2-R4,一焼基-S-R4,一烷基-S (0) 2-R4, 一NHR4? -NR4R4? -NH-烷基-R4,卤素,一CN,一NO2和-SH,其中,R4独立地为氢,烷基,烯基,一烷基-羟基,芳基,杂芳基,杂环基或卤代烷基; [0141] W4 is a gas, an alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, aryl group, aryloxy group, heteroaryl or heterocyclyl, each of them with one or more selected from optionally substituted by substituents from the group consisting of: hydroxy, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, a heterocyclic group, a NH 2, nitro, a alkyl - hydroxy, - alkyl - aryl group, a group firing - heteroaryl group, an alkyl - heterocyclic group, a 〇_R4, a 〇_ group -R 4, a group -O-R4 , a C (0) -R4 -? firing group -C (O) -R4, a group -C (0) -O-R4, a C (O) -O-R4, a S-R4, a S ?? (O) 2-R4, a NH-S (O) 2-R4, firing a group -S-R4, a group -S (0) 2-R4, a group NHR4 -NR4R4 -NH- - R4, halogen, a CN, an NO2, and -SH, wherein, R4 is independently hydrogen, an alkyl group, an alkenyl group, an alkyl - hydroxy, aryl, heteroaryl, heterocyclyl, or haloalkyl;

[0142] Z是氣,烷基,烯基,炔基,烷氧基,芳基,卤代烷基,杂芳基,杂环基,它们中的每一个可被一个或一个以上选自下列基团的取代基任选地取代:羟基,烷氧基,烷基,烯基, 炔基,芳基,杂芳基,杂环基,卤素,氛基,硝基, __N(R5)2?-烷氧基-烷基,一烷氧基_稀基,一C (0)-烷基,一C (0) -〇-烷基,一OC (0)-烷基,一C (0) -N(R5) 2,芳基,杂芳基,一CO-芳基和-CO-杂芳基,其中,仏分别独立地为氢,烷基,卤代烷基,一烷基-芳基或-烷基-杂芳基; [0142] Z is a gas, an alkyl group, alkenyl group, alkynyl group, alkoxy group, aryl group, haloalkyl, heteroaryl, heterocyclyl, each of which may be substituted with one or more groups selected from optionally substituted with substituents: hydroxy, alkoxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halo, atmosphere, nitro, __N (R5) 2 - alkyl? alkoxy - alkyl group, an alkoxy group dilute _, a C (0) - alkyl, a C (0) -〇- alkyl group, a OC (0) - alkyl, a C (0) -N (R5) 2, aryl, heteroaryl, aryl-CO- and -CO- a heteroaryl, wherein Fo are each independently hydrogen, alkyl, haloalkyl, an alkyl - or aryl - alkyl - heteroaryl;

[0143] R为氣,烷基,烷氧基,1¾代烷基,1¾素,芳基,杂芳基,杂环基,它们中的每一个被一个或一个以上选自下列基团的取代基任选地取代:羟基,烷氧基,烷基,烯基,炔基,环烷基, 芳基,杂芳基,杂环基,一NH 2,硝基,一烷基-羟基,--烷基-芳基,一烷基-杂芳基,一焼基-杂环基,一O-R4? 一〇_ 烷基-R4, 一烷基_〇_R4, 一C (0) -R4? -C (0) -NH-R4? -C (0) -NR4R4?_ _ 烷基-C (0) -R4,一烷基-C (0) -O-R4,一C (0) -O-R4? 一OC (0) -R4,一S-R4,一C(O) -S-R4? 一SC ( 0) -R4? 一S (0) 2-R4, 一NH-S (0) 2-R4,一烷基-S-R4,一烷基-S (0) 2-R4, 一NHR4,一NR4 R4,一NH-焼基-R4,卤素,一CN和-SH,其中,R4独立地为氢,烷基,烯基,烷氧基,一烷基-羟基,芳基, 杂芳基,杂环基,或卤代烷基; [0143] R is a gas, substituted alkyl, alkoxy, substituted alkyl 1¾, 1¾ element, aryl, heteroaryl, heterocyclyl, each of them with one or more groups selected from group optionally substituted by: hydroxy, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, a heterocyclic group, a NH 2, nitro, a group - hydroxy, - - alkyl - aryl group, an alkyl - aryl, heteroaryl, a group firing -? a heterocyclic group, a O-R4 〇_ a -R4 group, an alkyl group _〇_R4, a C (0) - R4? -C (0) -NH-R4? -C (0) -NR4R4? _ _ group -C (0) -R4, a group -C (0) -O-R4, a C (0) -O-R4? a OC (0) -R4, a S-R4, a C (O) -S-R4? a SC (0) -R4? a S (0) 2-R4, a NH-S ( 0) 2-R4, a group -S-R4, a group -S (0) 2-R4, a NHR4, a NR4 R4, a group -R4 firing NH-, a halogen, a CN, and -SH, wherein , R4 is independently hydrogen, an alkyl group, an alkenyl group, an alkoxy group, an alkyl - hydroxy, aryl, heteroaryl, heterocyclyl, or haloalkyl;

[0144] η 为0,1,2,3 或4; [0144] η 3, or 4;

[0145] Y为- NR6R7,-CR6R7Ri^ -烷基-NH2,它们中的每一个可被一个或一个以上选自下列基团的取代基任选地取代:羟基,烷氧基,烷基,烯基,炔基,一NH 2,卤素,一N(R5)2,-烧氧基_烷基,一烷氧基_條基,一C(O)-烷基,一C (0)-〇-烷基,一C (0)-N(R5) 2,芳基,杂芳基,一CO-芳基和-CO-杂芳基, [0145] Y is - NR6R7, -CR6R7Ri ^ - alkyl -NH2, each of which may be one of them or more substituents selected from the following group optionally substituted groups: hydroxy, alkoxy, alkyl, alkenyl group, an alkynyl group, an NH 2, a halogen, a N (R5) 2, - burning _ alkyl group, an alkoxy group _ bars, a C (O) - alkyl, a C (0) - 〇- alkyl group, a C (0) -N (R5) 2, aryl, heteroaryl, aryl-CO- and -CO- a heteroaryl group,

[0146] 其中,R6,1?7和R 8独立地为氣,烷基,條基,烷氧基,烷基氣基,^烷基氣基,烧硫基, 芳硫基,一烷基-羟基,一烷基-C (0) -O-R9,一烷基-C (0) -R9或-烷基-〇_C (0) -R 9,其中, 1?5分别独立地为氢,烷基,卤代烷基,一烷基-芳基或一烷基-杂芳基,其中,R 9为氢,烷基, 烯基,卤素或卤代烷基; [0146] wherein, R6,1? 7 and R 8 are independently air, alkyl, article group, an alkoxy group, an alkyl group gas, gas ^ alkyl group, burning arylthio group, an alkyl group - a hydroxyl group, a group -C (0) -O-R9, a group -C (0) -R9 or -? alkyl -〇_C (0) -R 9, wherein 15 each independently hydrogen, alkyl, haloalkyl, monoalkylamino - an aryl group or an alkyl - heteroaryl, wherein, R 9 is hydrogen, alkyl, alkenyl, halo or haloalkyl;

[0147] 任选地,X和Z-同可形成5至9元环。 [0147] Optionally, X may be formed with the Z- and 5-9 yuan ring.

[0148] 在一些实施方式中,通式(I)中的X为S。 [0148] In some embodiments, the formula (I) wherein X is S.

[0149] 在一些实施方式中,通式(I)中的X为-NR1, R1为烷基,一烷基-W4,一烷基-O-W4,一烷基-NH-C (0) -W4,一烷氧基-NH-C (0) -W4,一烷基-NH-C (0) -NH-W4,一烷氧基-NH-C (0) -NH-W4,一烷基-S (0) 2-W4,或一烷基-NH-C (S) -W4,其中,W4为上面所定义的。 [0149] In some embodiments, the formula (I) wherein X is -NR1, R1 is an alkyl group, an alkyl group -W4, a group -O-W4, a group -NH-C (0) -W4, an alkoxy group -NH-C (0) -W4, a group -NH-C (0) -NH-W4, an alkoxy group -NH-C (0) -NH-W4, an alkoxy group -S (0) 2-W4, or a group -NH-C (S) -W4, wherein, W4 is as defined above.

[0150] 在一些实施方式中,通式(I)中的Z为氢、烷基、烷氧基、芳基、杂芳基、卤代烷基, 它们中的每一个被一个至三个选自下列基团的取代基任选地取代:羟基、烷基、芳基、杂芳基、杂环基、氰基、一烷氧基-烷基、硝基和一N(R 5)2,其中,馬分别独立地为氢、烷基、卤代烷基、一烷基-芳基或_烷基-杂芳基。 [0150] In some embodiments, the formula (I) wherein Z is hydrogen, alkyl, alkoxy, aryl, heteroaryl, haloalkyl, each of them with one to three substituents selected from the following substituent group is optionally substituted with: a hydroxyl group, an alkyl group, an aryl group, a heteroaryl group, a heterocyclic group, a cyano group, an alkoxy - alkyl group, a nitro group and a N (R 5) 2, wherein Ma each independently hydrogen, alkyl, haloalkyl, a group - _ alkyl or aryl group - heteroaryl.

[0151] 在一些实施方式中,通式(I)中的Y为一NH2,-烷基-NH2,它们中的每一个被一个至三个选自烷基、烷氧基、烯基和炔基的取代基任选地取代。 [0151] In some embodiments, the formula (I) in which Y is an NH2, - alkyl -NH2, each of them with one to three substituents selected from alkyl, alkoxy, alkenyl and alkynyl group optionally substituted with a substituent group.

[0152] 在一些实施方式中,通式(I)中的η为1或2。 [0152] In some embodiments, the formula (I) in η is 1 or 2.

[0153] 在一些实施方式中,通式(I)中的R为芳基或杂芳基,它们中的每一个被一个至二个选自下列基团的取代基任选地取代:羟基,烷氧基,一烷基-羟基,一O-R4, 一〇_烧基-R4, - 烷基_〇_R4, -C (0) -R4, -C (0) -NH-R4, -C (0) -NR4R4, 一烷基-C (0) -R4,-烷基-C (O)-O-R4, -C (0) -O-R4, 一OC (0) -R4, 一S-R4, 一C (0) -S-R4, 一SC (0) -R4, 一S (0) 2_R4, -NH-S (O)2-R4, - 烷基-S-R4,-烷基-S (0) 2_R4, -NHR4, -NR4R4, 一NH-烷基-R4,卤素,一CP^Pl-SH,其中,R4独立地为氢,烷基,烯基,烷氧基,一烷基-羟基,芳基,杂芳基,杂环基或卤代烷基。 [0153] In some embodiments, the formula (I) wherein R is an aryl or heteroaryl group, each of which is a one to two substituents selected from the group group optionally substituted with: a hydroxyl group, alkoxy group, a group - a hydroxyl group, a O-R4, a group -R4 〇_ burn, - _〇_R4 alkyl, -C (0) -R4, -C (0) -NH-R4, - C (0) -NR4R4, a group -C (0) -R4, - alkyl -C (O) -O-R4, -C (0) -O-R4, a OC (0) -R4, a S-R4, a C (0) -S-R4, a SC (0) -R4, a S (0) 2_R4, -NH-S (O) 2-R4, - alkyl -S-R4, - alkoxy group -S (0) 2_R4, -NHR4, -NR4R4, a group -R4 NH-, a halogen, a CP ^ Pl-SH, where, R4 is independently hydrogen, an alkyl group, an alkenyl group, an alkoxy group, a alkyl - hydroxy, aryl, heteroaryl, heterocyclyl or haloalkyl.

[0154] 在一些实施方式中,活化部分是选自表1的TLR7和/或TLR8激动剂。 [0154] In some embodiments, the activated moiety is TLR7 1 and / or TLR8 agonist is selected from the table. 表1中的化合物在下列专利文献中更加详细地描述和表征:US4, 689, 338, US5, 389, 640, US5, 226, 57 5, US6, HO, 929, US6, 194, 425, US5, 352, 784, US6, 331, 539, US5, 482, 936, US6, 451810, W020 02/46192, W02002/46193, W02002/46194, US2004/0014779 以及US2004/0162309。 Table 1 The compounds described in the following patent documents in more detail and characterized by: US4, 689, 338, US5, 389, 640, US5, 226, 57 5, US6, HO, 929, US6, 194, 425, US5, 352, 784, US6, 331, 539, US5, 482, 936, US6, 451810, W020 02/46192, W02002 / 46193, W02002 / 46194, US2004 / 0014779 and US2004 / 0162309.

[0155] 表1 :代表性的TLR7和/或TLR8激动剂 [0155] Table 1: Representative TLR7 and / or TLR8 agonist

[0156] [0156]

Figure CN104861063AD00371

[0157] [0157]

Figure CN104861063AD00381

[0158] [0158]

Figure CN104861063AD00391

[0159] [0159]

Figure CN104861063AD00401

[0160] [0160]

Figure CN104861063AD00411

[0161] [0161]

Figure CN104861063AD00421

[0162] [0162]

Figure CN104861063AD00431

[0163] [0163]

Figure CN104861063AD00441

[0164] [0164]

Figure CN104861063AD00451

[0165] 优选地,AM为瑞喹莫德或咪喹莫特。 [0165] Preferably, AM is resiquimod or imiquimod.

[0166] 靶向部分 [0166] a targeting moiety

[0167] 总体而言,本发明的化合物包含靶向部分。 [0167] In general, compounds of the invention comprises a targeting moiety.

[0168] 本文中的"靶向部分(TM)"或"靶向剂"是指特异性地或选择性地与目标分子、细胞、颗粒、组织或聚集体结合的分子、复合物或聚集体,所述目标分子、细胞、颗粒、组织或聚集体通常称为"靶标"或"标记物"并且本文将进一步详细讨论这些目标分子、细胞、颗粒、 组织或聚集体。 [0168] As used herein the "targeting moiety ((TM))" or "targeting agent" refers specifically or selectively to target molecules, cells, particles, or aggregates tissue binding molecule complex or aggregate the target molecules, cells, particles, or aggregates tissue commonly referred to as "target" or "label" and will be discussed in further detail herein, these target molecules, cells, particles, or aggregates tissue.

[0169] 在一些实施方式中,靶向部分包含免疫球蛋白、蛋白质、肽、小分子、纳米颗粒或核酸。 [0169] In some embodiments, the targeting moiety comprises an immunoglobulin, proteins, peptides, small molecules, nanoparticles or a nucleic acid.

[0170] 诸如抗体(例如,嵌合抗体、人源化抗体和人抗体)、受体的配体、植物凝集素和糖类以及一些酶的底物之类的示例性的靶向剂在本领域中被识别并且不受限制地用于实施本发明。 [0170] such as antibodies (e.g., chimeric antibodies, humanized and human antibodies), ligand receptors, lectins and carbohydrates as well as some enzyme substrates or the like Exemplary targeting agents in the present It is recognized in the art, and without limitation for practicing the invention. 其他靶向剂包括一类如下化合物:该化合物不包括特异性分子识别基序,该化合物包括将分子量加至活化部分的纳米颗粒、诸如聚(乙二醇)之类的大分子、多糖,以及聚氨基酸。 Other targeting agents include a class of the following compounds: the compound does not include specific molecular recognition motifs, including the molecular weight of the compound was added to the activated portion of the nanoparticle, such as macromolecules, polysaccharides, poly (ethylene glycol) or the like, and poly acids. 额外的分子量影响活化部分的药代动力学,例如血清半衰期。 Additional portions of the molecular weight on the activation pharmacokinetics, such as serum half-life.

[0171] 在一些实施方式中,靶向部分为抗体,抗体片段,双特异性抗体或其他基于抗体的分子或化合物。 [0171] In some embodiments, the targeting moiety is an antibody, an antibody fragment, bispecific antibody or other antibody-based molecules or compounds. 然而,靶向部分的其他实例为本领域已知的并且可使用靶向部分的其他实例,例如,适体、avimer、受体结合配体、核酸、生物素-亲和素结合对、结合肽或蛋白质,等等。 However, other examples of targeting moieties known in the art and may use other examples of targeting moiety, e.g., an aptamer, avimers, receptor binding ligand, a nucleic acid, biotin - avidin binding pair, binding peptides or proteins, and so on. 术语"靶向部分"和"结合部分"在本文中同义使用。 The term "targeting moiety" and "binding moiety" are used synonymously herein.

[0172] 本文中的"靶标"或"标记物"是指能够特异性结合特定的靶向部分的任何实体, 例如,Her2/Neu〇 [0172] As used herein the "target" or "label" refers to any entity capable of specifically binding a specific targeting moiety, e.g., Her2 / Neu〇

[0173] 在一些实施方式中,靶向部分能够特异性结合Her2/Neu或者相对于非靶向部分能够优先结合Her2/Neu。 [0173] In some embodiments, the targeting moiety capable of specifically binding Her2 / Neu or a non-targeting moiety capable of binding with respect to preferentially Her2 / Neu.

[0174] 本文中的"特异性结合"或"优先结合"是指在两个结合搭档之间(例如,在靶向部分及其结合搭档之间)的结合对两个结合搭档具有选择性并且可从不想要的或非特异性相互作用中区分出来。 [0174] herein, "specific binding" or "preferential binding" refers to binding between two partners (e.g., between the targeting moiety and its binding partner) for selective binding of two binding partners and non-specific interaction may be distinguished from unwanted out. 例如,抗原结合部分结合特异性抗原决定簇的能力可通过酶联免疫吸附分析法(ELISA)或其他本领域技术人员熟悉的技术(例如,表面等离子共振技术(在BIAcore仪器上分析)(Liljeblad等人,Glyco J17, 323-329 (2000))和传统的结合分析(Heeley,Endocr Res28,217-229(2002)))测量。 For example, the ability to bind a specific antigen binding portion of the antigenic determinants by enzyme-linked immunosorbent assay (ELISA) familiar to others skilled in the art or the art (e.g., surface plasmon resonance technique (analyzed on a BIAcore instrument) (like Liljeblad people, Glyco J17, 323-329 (2000)) and traditional binding assays (Heeley, Endocr Res28,217-229 (2002))) measured. 术语"抗-[抗原]抗体"和"与[抗原] 结合的抗体"是指能够通过足够的亲合力结合各自的抗原的抗体,这样,所述抗体用作靶向抗原的诊断剂和/或治疗剂。 The term "anti - [antigen] antibody" and "with [antigen] binding antibody" refers to an antibody capable of binding together the respective antigen with sufficient affinity such that the antibody is used as an antigen targeted diagnostic and / or therapeutic agent. 在一些实施方式中,抗-[抗原]抗体结合不相关的蛋白质的程度小于所测量(例如,通过放射性免疫分析(RIA))的抗体抗原结合程度的约10%。 In some embodiments, the anti - [antigen] extent of protein binding of the antibody is not smaller than the associated measured (e.g., by radioimmunoassays (RIA)) is about 10% of the extent of binding of the antibody-antigen. 在一些实施方式中,结合[抗原]的抗体的解离常数(KD)小于1 μM、小于ΙΟΟηΜ、小于ΙΟηΜ、小于InM、小于0.1 nM、小于0.0 lnM或小于0.0 OlnM (例如,KT8M或更小,例如,KT8M至KT13M,例如,KT 9M至10-13Μ)。 In some embodiments, the binding solution antibody [antigen] dissociation constant (KD) of less than 1 μM, less than ΙΟΟηΜ, less than ΙΟηΜ, less than INM, less than 0.1 nM, less than 0.0 lnM, or less than 0.0 OlnM (e.g., KT8M or less , e.g., KT8M to KT13M, e.g., KT 9M to 10-13Μ). 应当理解的是,上述定义还可应用于与抗原结合的抗原结合部分。 It should be understood that the above definitions are also applicable to the antigen binding portion binds to the antigen.

[0175] 在一些实施方式中,靶向部分包含抗体或其功能片段。 [0175] In some embodiments, the targeting moiety comprises an antibody or functional fragment thereof.

[0176] 本文使用的"免疫球蛋白"或"抗体"是指全长(即,天然生成的或通过正常免疫球蛋白基因片段重组过程形成的)免疫球蛋白分子(例如,IgG抗体)或免疫球蛋白分子的免疫活性(即,特异性结合)部分,例如抗体片段。 [0176] "immunoglobulin" or "antibody" as used herein refers to a full-length (i.e., naturally occurring or formed by normal immunoglobulin gene segment recombination immunoglobulin) immunoglobulin molecule (e.g., IgG antibodies) or immune immunoglobulin molecule immunologically active (i.e., specifically binding) portion, such as an antibody fragment. 在本发明要求保护的范围内,抗体或抗体片段可被偶联或衍生。 Within the scope of the claimed invention, an antibody or antibody fragment may be conjugated or derivatized. 这些抗体包括IgGl,lgG2a,IgG3, IgG4 (以及IgG4亚型)和IgA同种型。 Such antibodies include IgGl, lgG2a, IgG3, IgG4 (and IgG4 subtypes) and IgA isotypes.

[0177] 本文的术语"抗体"以其广义使用并包含各种不同的抗体结构,包括但不限于:单克隆抗体、多克隆抗体、多特异性抗体(例如,双特异性抗体)和抗体片段,只要它们表现出期望的抗原结合活性并且包含免疫球蛋白的Fc区域或等同于该Fc区域的区域。 [0177] The term "antibody" in its broadest sense and includes a variety of different antibody structures, including but not limited to: monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments , so long as they exhibit the desired antigen-binding activity and comprising an immunoglobulin Fc region or a region equivalent to the Fc region. 本文中可互换使用的术语"全长抗体"、"完整抗体"和"整个抗体"是指具有与天然抗体结构基本类似的结构的抗体或者具有含本文定义的Fc区域的重链的抗体。 The term used interchangeably herein, "full length antibody," "intact antibody" and "whole antibody" refers to an antibody having an antibody heavy chain substantially similar to native antibody structure or a structure containing the Fc region as defined herein.

[0178] 本文的"天然抗体"是指具有不同结构的天然生成的免疫球蛋白分子。 [0178] "Native antibodies" as used herein refers to naturally have a different structure to generate immunoglobulin molecule. 例如,天然IgG抗体为约150, 000道尔顿的异源四聚体糖蛋白,其由被二硫键连接的两个相同的轻链和两个相同的重链构成。 For example, native IgG antibody is about 150, 000 daltons heterotetrameric glycoproteins, composed of two identical light chains connected by disulfide bonds and two identical heavy chains. 从N端至C端,每一重链具有可变区(VH),也称为可变重链结构域或重链可变结构域,重链之后为三个恒定结构域(CH1、CH2和CH3),也称为重链恒定区。 From N-terminal to C-terminus of each heavy chain has a variable region (the VH), also called after a variable heavy domain or heavy chain variable domain, heavy chain constant domains three (CH1, CH2 and CH3 ), also known as the heavy chain constant region. 类似地,从N端至C端,每一轻链具有可变区(VL),也称为可变轻链结构域或轻链可变结构域, 轻链之后为恒定轻链结构域(CL),也称为轻链恒定区。 Similarly, from the N-terminal to C-terminal, each having a light chain variable region (the VL), also known as variable light chain domain or after a light chain variable domain of the light chain is the light chain constant domain (CL ), also known as the light chain constant region. 基于抗体恒定结构域的氨基酸序列, 抗体的轻链可指定为两种类型(称为κ和λ)中的一种。 The amino acid sequence of the antibody constant domain based light chains of antibodies can be assigned to two types (referred to as κ and [lambda]) of a medium.

[0179] 本文中的"抗体片段"是指不同于完整抗体的分子,所述分子包含结合抗原的完整抗体的一部分,所述抗原与完整抗体结合。 [0179] As used herein "antibody fragment" refers to an intact antibody molecules is different from a portion of an intact antibody molecule comprises an antigen binding, binding the antigen with the intact antibody. 抗体片段的实例包括但不限于:Fv, Fab, Fab',Fab' -SH, F (ab')2,双体抗体,线性抗体,单链抗体分子(例如, scFv),单结构域抗体和由抗体片段形成的多特异性抗体。 Examples of antibody fragments include but are not limited to: Fv, Fab, Fab ', Fab' -SH, F (ab ') 2, diabody, linear antibody, single chain antibody molecules (e.g., the scFv), single domain antibodies, and multispecific antibodies formed from antibody fragments. 关于一些抗体片段的综述请参见,Hudson等人,Nat Med9, 129-134(2003)。 For a review of some of antibody fragments, see, Hudson et al., Nat Med9, 129-134 (2003). 关于scFv片段的综述请参见例如, Pliickthun, in The Pharmacology of Monoclonal Antibodies, vol. 113,Rosenburg 和Moore 编辑,Springer-Verlag, New York, pp. 269-315(1994);以及W093/16185;和美国专利第5, 571,894号和第5, 587, 458号。 For a review of scFv fragments, see e.g., Pliickthun, in The Pharmacology of Monoclonal Antibodies, vol 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp 269-315 (1994);.. And W093 / 16185; and U.S. Patent 5, 571,894 and No. 5, 587, 458. 关于含有挽救受体结合表位残基且具有提高的体内半衰期的Fab和F(ab')2片段的讨论,请参见美国专利第5, 869, 046号。 2 fragment containing the discussion salvage receptor binding epitope residues and having an increased half-life in vivo Fab and F (ab '), see U.S. Patent No. 5, 869, 046. 双体抗体为可为二价的或双特异性的具有两个抗原结合位点的抗体片段。 Diabodies may be bivalent to or with two antigen-binding sites of the bispecific antibody fragments. 请参见例如, EP404,097;TO1993/01161;Hudson 等人,Nat Med9, 129-134(2003);和Hollinger 等人,Proc Natl Acad Sci USA90, 6444-6448 (1993)。 See for example, EP404,097; TO1993 / 01161; Hudson et al., Nat Med9, 129-134 (2003); and Hollinger et al., Proc Natl Acad Sci USA90, 6444-6448 (1993). 三体抗体和四体抗体也在Hudson 等人,Nat Med9, 129-134 (2003)中描述。 Three and four-antibodies are antibodies Hudson et al., Nat Med9, 129-134 (2003) described. 单结构域抗体为含有抗体的所有或一部分重链可变结构域或者含有抗体的所有或一部分轻链可变结构域的抗体片段。 Single domain antibodies to all or a portion of the heavy chain variable domain or all or a portion of an antibody fragment of the light chain variable domain containing the antibody-containing antibody. 在一些实施方式中,单结构域抗体为人单结构域抗体(Domantis, Inc.,Waltham, MA;参见例如,美国专利No. 6, 248, 516B1)。 In some embodiments, the single domain antibody is a single domain antibody (Domantis, Inc., Waltham, MA; see, e.g., U.S. Pat. No. 6, 248, 516B1). 抗体片段可通过各种不同的技术制备,所述技术包括但不限于:如本文描述的,完整抗体的蛋白水解消化以及通过重组宿主细胞(例如,大肠杆菌或噬菌体)生成。 Antibody fragments may be prepared by a variety of techniques, including but not limited to: As described herein, proteolytic digestion of intact antibodies, and produced by recombinant host cells (e.g., E. coli or phage).

[0180] 本文中的"抗原结合结构域"是指包含与抗原的全部或一部分特异性结合且互补的区域的抗体的一部分。 [0180] As used herein "antigen-binding domain" refers to a portion comprising an antibody-binding region and all or part of an antigen-specific and complementary. 抗原结合结构域可通过例如,一个或一个以上抗体可变结构域(也称为抗体可变区)来提供。 Antigen binding domain by, for example, one or more antibody variable domains (also referred to as antibody variable region) is provided. 具体而言,抗原结合结构域包含抗体轻链可变区(VL)和抗体重链可变区(VH)。 More specifically, the antigen binding domain comprises an antibody light chain variable region (VL) and an antibody heavy chain variable region (VH).

[0181] 本文中的"可变区"或"可变结构域"是指涉及使抗体与抗原结合的抗体重链结构域或轻链结构域。 [0181] As used herein "variable region" or "variable domain" refers to an antibody relates to an antibody to the antigen binding domain of a heavy chain or light chain domain. 天然抗体的重链和轻链的可变结构域(分别为VH和VL)通常具有类似的结构,其中,每一结构域包含四个保守的框架区(FR)和三个高变区(HVR)。 Antibody variable domains of native heavy and light chains (respectively VH and VL) generally have similar structures, wherein each domain comprises four conserved framework regions (FR) and three hypervariable regions (HVR ). 参见例如,Kindt 等人,Kuby Immunology,第六版,WH Freeman and Co.,第91 页(2007)。 See, for example, Kindt et al, Kuby Immunology, Sixth Edition, WH Freeman and Co., p. 91 (2007). 单个VH 或VL 结构域可足以带来抗原结合特异性。 Single VH or VL domain may be enough to bring antigen-binding specificity.

[0182] 本文中的"高变区"或"HVR"是指序列高度可变和/或形成结构限定的环("高变环")的抗体可变结构域的各个区域。 [0182] As used herein the "hypervariable region" or "the HVR" means a highly variable sequence of the respective regions and / or form a ring structure defined ( "hypervariable loop") antibody variable domains. 一般而言,天然四链抗体包含六个HVR,三个在VH(H1、 H2、H3)中,三个在VL (LU L2、L3)中。 Generally, a natural four-chain antibody comprising the HVR six, three in the VH (H1, H2, H3), three in the VL (LU L2, L3). HVR通常包含来自高变环的氨基酸残基和/或来自互补决定区(CDR)的氣基酸残基,后者具有最尚的序列可变性和/或涉及抗原识别。 HVR generally comprise amino acid residues and / or acid gas residues from a complementarity determining region (CDR) derived from hypervariable loops, the latter still having the most sequence variability and / or involved in antigen recognition. 除了VH中的⑶R1,⑶R通常包含形成高变环的氨基酸残基。 In addition to the VH ⑶R1, ⑶R generally comprise the amino acid residues of the hypervariable loops. 高变区(HVR)也被称为"互补决定区(CDR)"并且与形成抗原结合区的可变区部分有关的这些术语在本文中互换使用。 Hypervariable regions (the HVR) also known as "complementarity determining regions (CDRs of)" and related terms with some of these variable regions form an antigen binding regions are used interchangeably herein. 该特定区域已由Kabat 等人,US Dept, of Health and Human Services, Sequences of Proteins of Immunological Interest(1983)和Chothia 等人,J Mol Bioll96:901_917(1987)描述,其中,当彼此比较时,定义包括氨基酸残基的重叠或子集。 This particular region has been Kabat et al., US Dept, of Health and Human Services, Sequences of Proteins of Immunological Interest (1983) and Chothia et al., J Mol Bioll96: 901_917 (1987) described, in which, when compared with each other, defined include overlapping or subsets of amino acid residues. 然而,关于抗体的CDR或其变体的任何定义的应用意在本文定义的和本文使用的术语的范围内。 However, regarding the CDR of an antibody, or any variant as defined application intended to be within the range defined herein and the terms used herein. 包含特定CDR的确切的残基数目随CDR的序列和尺寸的不同而不同。 The exact number of residues comprise a particular CDR sequences with different sizes and different from the CDR. 在给出抗体的可变区氨基酸序列的条件下, 本领域技术人员可常规确定哪些残基包含特定CDR。 Under the conditions given antibody variable region amino acid sequence, those skilled in the art may routinely determine which residues comprise a particular CDR.

[0183] 本发明的抗体可为嵌合抗体、人源化抗体、人抗体或抗体融合蛋白。 [0183] Antibodies of the invention may be a chimeric antibody, a humanized antibody, a human antibody or antibody fusion proteins.

[0184] 本文中的"嵌合抗体"是指包含抗体重链和轻链这两者的可变结构域的重组蛋白质,所述可变结构域包括来源于一个物种的抗体(优选地为啮齿动物抗体,更优选地为鼠科动物抗体)的互补决定区(CDR),而抗体分子的恒定结构域来源于人抗体的恒定结构域。 [0184] As used herein, "chimeric antibody" refers to a recombinant protein comprising an antibody which heavy and light chain variable domains of both the variable domain comprises an antibody derived from one species (preferably rodents animal antibody, more preferably complementarity determining region (CDR) of a murine antibody), and the constant domains of an antibody molecule is derived from a human antibody constant domains. 对于兽医应用而言,嵌合抗体的恒定结构域可来源于其它物种的恒定结构域,所述其它物种例如,类人类灵长类动物、猫或狗。 For veterinary applications, the constant domains of the chimeric antibody may be derived from the constant domains of other species, the other species, e.g., class-human primate, a cat or a dog.

[0185] 本文中的"人源化抗体"是指如下重组蛋白:在该重组蛋白中,来自于一个物种的抗体(例如,啮齿动物抗体)的CDR从啮齿动物抗体的可变重链和可变轻链转移至人重链可变结构域和人轻链可变结构域中。 [0185] herein, "humanized antibody" refers to recombinant proteins: the recombinant protein, an antibody of one species (e.g., a rodent antibody) is derived from the variable heavy chain CDR from a rodent antibody and transferred to the human light chain variable heavy chain variable domain and a human light chain variable domain. 抗体分子的恒定结构域来源于人抗体的恒定结构域。 The constant domain of the antibody molecule is derived from a human antibody constant domains. 在一些实施方式中,人源化抗体的框架区的特定残基,尤其是接触或靠近CDR序列的那些特定残基,可被修饰,例如可被来自于原始啮齿动物、类人类灵长类动物的相应残基或其他抗体代替。 In some embodiments, the specific residues in the humanized antibody framework regions, especially those in contact with or close to the CDR sequences of particular residues may be modified, for example, the original may be derived from rodents, primates humanoid the corresponding residues in place of, or other antibodies.

[0186] 本文中的"人抗体"是指例如从转基因小鼠中获得的抗体,所述转基因小鼠已被"改造"为响应抗原刺激生成特定的人抗体。 [0186] As used herein "human antibody" refers to, for example, an antibody obtained from transgenic mice, the transgenic mice have been "transform" in response to antigenic stimulation generation of human specific antibodies. 在该技术中,人重链基因座和人轻链基因座的元件被引入来源于胚胎干细胞系的小鼠品系中,所述胚胎干细胞系包含内源性重链基因座和轻链基因座的靶向断裂。 In this technique, the human heavy chain locus and the human light chain locus are introduced into the element strains of mice derived from embryonic stem cell lines, the embryonic stem cell line containing endogenous heavy chain locus and light chain loci targeted disruption. 转基因小鼠可合成对人抗原具有特异性的人抗体, 并且小鼠可用于生成分泌人抗体的杂交瘤。 Transgenic mice can synthesize human antibodies specific for human antigens, and the mice can be used to generate hybridomas secreting human antibodies. 从转基因小鼠中获得人抗体的方法由Green 等人,Nature Genet. 7:13(1994),Lonberg 等人,Nature368:856(1994),Taylor 等人,Int.Immun. 6:579(1994)描述。 A method for obtaining human antibodies from transgenic mice by Green et al., Nature Genet 7:13 (1994), Lonberg et al., Nature368:. 856 (1994), Taylor et al., Int.Immun 6:. 579 (1994) description. 完全人抗体还可通过基因转染法或染色体转染法以及噬菌体展示技术来构建,所有这些方法为本领域已知的。 Fully human antibodies can also be transfected by the gene or chromosomal transfection methods, and to construct phage display technology, all of these methods are known in the art. 请参见例如,McCafferty等人,Nature348:552-553 (1990),其中描述了通过来自于未免疫的供体的免疫球蛋白可变结构域基因谱系体外生成人抗体及其片段。 See for example, McCafferty et al., Nature348: 552-553 (1990), which describes a from immunoglobulin variable domain gene repertoire of human antibodies and fragments thereof in vitro unimmunized donors. 在该技术中,抗体可变结构域基因框内克隆至丝状噬菌体的主要或次要外壳蛋白基因中,并且在噬菌体颗粒的表面上展示为功能抗体片段。 In this technique, antibody variable domain genes are cloned in frame into a major or minor coat protein gene of a filamentous bacteriophage, and displayed as functional antibody fragments on the surface of the phage particle. 因为丝状颗粒包含噬菌体基因组的单链DNA拷贝,基于抗体的功能性质的选择还导致对编码表现出那些性质的抗体的基因的选择。 Because the filamentous particle contains a single-stranded DNA copy of the phage genome, selected based on the functional properties of the antibody also result in selection of the gene encoding the antibody exhibiting those properties. 通过该方式,噬菌体模仿B细胞的一些性质。 By this way, the phage mimics some of the properties of the B cell. 噬菌体展示可以多种形式进行,关于噬菌体展示的综述请参见例如,Johnson和Chiswell, Current Opinion in Structural Biology3:5564_571 (1993)。 Phage display can be in various forms, review of phage display, see for example, Johnson and Chiswell, Current Opinion in Structural Biology3: 5564_571 (1993). 人抗体还可通过体外活化B细胞产生。 Human antibodies can also be generated by in vitro activated B cells. 请参见美国专利第5, 567, 610号和第5, 229, 275号,该美国专利的全部内容通过引用并入本文。 See US Patent No. 5, 567, 610 and 5, 229, 275, the entire contents of the US patent is incorporated herein by reference.

[0187] 本文中的"抗体融合蛋白"是指通过重组产生的抗原结合分子,其中,连接相同或不同的天然抗体、具有相同或不同特异性的单链抗体或抗体片段中的两个或两个以上。 [0187] As used herein "antibody fusion protein" refers to a recombinantly produced antigen-binding molecules, wherein the connection of the same or different natural antibody, having two identical or different specificity or two single-chain antibody or antibody fragment of or more. 融合蛋白包含至少一个特异性结合位点。 Fusion protein comprises at least one specific binding site. 融合蛋白的化合价表示融合蛋白具有的与抗原或表位结合的结合臂或结合位点的总数,即,单价的、二价的、三价的或多价的。 Fusion protein indicates the total valency of protein binding to the antigen binding or epitope binding arms or sites, i.e., monovalent, bivalent, trivalent or multivalent fusion. 多价的抗体融合蛋白是指该抗体融合蛋白可利用多种与抗原结合的相互作用,因此增加与抗原或不同抗原结合的亲合力。 Multivalent antibody fusion protein means that the antibody fusion protein can bind to the antigen using a variety of interactions, thus increasing the binding to an antigen or a different antigen affinity. 特异性表示抗体融合蛋白能够与多少种不同类型的抗原或表位结合,即,单特异性、双特异性、三特异性、多特异性。 Specificity antibody fusion protein capable of binding indicates how many different types of antigen or epitope, i.e., monospecific, bispecific, trispecific, multispecific. 使用这些定义,天然抗体(例如,IgG)为二价的,因为其具有两个结合臂,但是其为单特异性的,因为其结合一种类型的抗原或表位。 Using these definitions, a natural antibody (e.g., IgG) is bivalent because it has two binding arms but is monospecific because it binds to one type of antigen or epitope. 单特异性多价融合蛋白具有一个以上用于相同抗原或表位的结合位点。 Monospecific, multivalent fusion protein has more than one binding site for the same antigen or epitope. 例如,单特异性双体抗体为具有两个与相同的抗原反应的结合位点的融合蛋白。 For example, a monospecific diabody is a fusion protein having two antigen-binding sites of the same reaction. 融合蛋白可包含不同抗体成分的多价或多特异性组合或同一抗体成分的多个拷贝。 An antibody fusion protein may contain different ingredients, or multivalent or multispecific combination of multiple copies of the same antibody component. 融合蛋白还可包含治疗剂。 The fusion protein may further comprise a therapeutic agent.

[0188] 在一些实施方式中,TM是单克隆抗-HER2抗体。 [0188] In some embodiments, TM is a monoclonal antibody anti -HER2. HER2是由neu原癌基因编码的跨膜酪氨酸激酶受体。 HER2 kinase receptor is encoded by the protooncogene neu transmembrane tyrosine. HER2与HERl、HER3或HER4发生杂合二聚化(heterodimerize),并且传导导致细胞增殖和存活的信号。 HER2 and HERl, HER3 or HER4 occurs hybrid dimerization (heterodimerize), and signal transduction leading to cell proliferation and survival. 细胞表面HER2的过表达与肿瘤或癌症相关。 HER2 overexpressing cell surface associated with a tumor or cancer. 因此,针对HER2的治疗对于患有HER2阳性癌症或肿瘤的患者而言是有用的。 Therefore, for the treatment of HER2 it is useful for patients with HER2-positive cancer or tumors. 这些治疗性抗-HER2抗体通过下列作用机制的组合介导这些抗体对HER2阳性肿瘤/癌症的抗肿瘤/抗癌活性,所述作用机制包括:促进受体的调节(内在化和/或"脱落")、诱导细胞凋亡、抗体介导的细胞毒性(ADCC)以及调理的细胞的抗原决定簇呈递至抗原呈递细胞。 The anti-therapeutic antibodies by a combination of the following -HER2 mediated mechanisms such antibody / anti-tumor activity in HER2-positive tumors / cancer, anti-tumor, the mechanism of action comprising: adjusting promoting receptors (intrinsic and / or "off "), induce apoptosis, antibody-mediated cytotoxicity (ADCC) and conditioning cell epitopes presented to antigen presenting cells.

[0189] 在一些实施方式中,抗-HER2抗体为曲妥珠单抗(赫赛汀),帕妥珠单抗或margetuximab (MGAH22)。 [0189] In some embodiments, the antibody is an anti--HER2 trastuzumab (Herceptin), pertuzumab or margetuximab (MGAH22). 曲妥珠单抗和帕妥珠单抗均为单克隆抗体,它们对HER2阳性肿瘤细胞或HER2阳性癌细胞具有抗肿瘤活性。 Trastuzumab and pertuzumab are monoclonal antibodies, which have anti-tumor activity in HER2-positive tumor cells or HER2 positive cancer. margetuximab (或MGAH22)是新一代Fc-优化的单克隆抗体(mAb),其革El向HER2。 margetuximab (or MGAH22) is a new generation Fc- optimized monoclonal antibody (mAb), its leather El to HER2. 临床试验已说明margetuximab对表达中等水平的HER2 的肿瘤细胞或癌细胞有效。 Clinical trials have described margetuximab HER2 expression on tumor cells or cancer cells effectively intermediate levels.

[0190] 赫赛汀(曲妥珠单抗)为作用于Her2人表皮生长因子受体细胞外结构域的人源化单克隆抗体,Her2在25%至30%的乳腺癌中表达。 [0190] Herceptin (trastuzumab) acting on the human Her2 human epidermal growth factor receptor extracellular domain of a humanized monoclonal antibody, Her2 expression in 25-30% of breast cancer. 曲妥珠单抗被认为具有以下三方面的抗肿瘤作用:(1)下调Her2受体,抑制Her2细胞内信号转导通路以及诱导细胞凋亡;(2)使抗体依赖性ADCC和CDC与杀伤肿瘤细胞相关联的免疫机制;(3)提高化疗效果。 Trastuzumab is believed to have anti-tumor effects of the following three aspects: (1) Her2 receptor down-regulation, inhibition of cellular signal transduction pathways Her2 and induce apoptosis; (2) antibody-dependent killing and ADCC and CDC immune mechanisms associated with tumor cells; (3) improve the effect of chemotherapy.

[0191] 在一些实施方式中,革巴向部分包含Fab,Fab',F(ab')2,单结构域抗体,T和Abs 二聚物,Fv,scFv,dsFv,ds-scFv,Fd,线性抗体,微小抗体、双体抗体、双特异性抗体片段、 bibody、tribody、sc-双体抗体、κ ( λ ) body,BiTE,DVD-Ig,SIP,SMIP,DART,或者含有一个或一个以上⑶R的抗体类似物。 [0191] In some embodiments, the moiety comprises Gerba Fab, Fab ', F (ab') 2, single domain antibodies, T and Abs dimer, Fv, scFv, dsFv, ds-scFv, Fd, linear antibodies, minibodies, diabodies, bispecific antibody fragments, bibody, tribody, sc- diabodies, κ (λ) body, BiTE, DVD-Ig, SIP, SMIP, DART, or that contains one or more ⑶R antibody analogs.

[0192] 在一些实施方式中,靶向部分包含细胞外结构域化^)或^)-1,(:1'1^4,^47,81'1^ ,KIR,HM3,4-1BB和LAG3的可溶形式,全长的部分表面配体双调蛋白,β动物纤维素,EGF, 肝配蛋白,Epigen,上皮调节蛋白,IGF,神经调节蛋白,TGF,TRAIL或VEGF。 [0192] In some embodiments, the targeting moiety comprises an extracellular domain of cell ^), or ^) - 1, (: 1'1 ^ 4, ^ 47,81'1 ^, KIR, HM3,4-1BB and LAG3 soluble form of the full length of the portion of the surface amphiregulin, animal cellulose beta], EGF, ephrin, Epigen, epiregulin, IGF, neuregulin, TGF, TRAIL ligand or VEGF.

[0193] 在一些实施方式中,靶向部分包含颗粒(靶向颗粒),优选地为纳米颗粒,任选地, 为连接至靶向分子的靶向纳米颗粒,所述靶向分子可特异性结合或优先结合靶标。 [0193] In some embodiments, the targeting moiety comprises particles (particle targeting), preferably nanoparticles, optionally, a targeting molecule is coupled to the targeted nanoparticles, the targeting molecule can specifically binding or preferentially binds to a target. 在一些实施方式中,靶向颗粒其自身引导本发明的化合物(例如,通过在肿瘤细胞或肿瘤组织中的富集),而无需与其连接额外的靶向分子。 In some embodiments, the targeting compound particles having a self-priming of the invention (e.g., by enrichment of the tumor cell or tumor tissue) without additional targeting molecule attached thereto.

[0194] 本文中的"纳米颗粒"是指直径小于1000 nm的任何颗粒。 [0194] herein, "nanoparticle" refers to any particle diameter of less than 1000 nm. 在一些实施方式中,治疗剂和/或靶向分子可与聚合物基体结合。 In some embodiments, the therapeutic agent and / or targeting molecules may be bound to the polymer matrix. 在一些实施方式中,靶向分子可与聚合物基体的表面共价结合。 In some embodiments, the targeting molecule can be covalently bonded to the surface of the polymer matrix. 在一些实施方式中,共价结合由连接体介导。 In some embodiments, the covalent binding is mediated by a linker. 在一些实施方式中,治疗剂可与聚合物基体表面结合,封装在聚合物基体内,被聚合物基体包围,和/或分散于整个聚合物基体。 In some embodiments, the therapeutic agent may be combined with the surface of the polymer matrix, encapsulated in a polymer matrix, surrounded by the polymer matrix, and / or dispersed throughout the polymer matrix. 美国专利第8, 246, 968号,该美国专利的全部内容在此通过引用并入本文。 U.S. Patent Nos. 8, 246, 968, the entire contents of which are incorporated herein U.S. Pat herein by reference.

[0195] 总体而言,本发明的纳米颗粒包含任何类型的颗粒。 [0195] In general, the nano particles of the present invention include any type of particle. 根据本发明可使用任何颗粒。 According to the present invention may be any particle used. 在一些实施方式中,颗粒为可生物降解的且生物相容的。 In some embodiments, the particles are biodegradable and biocompatible. 总体而言,生物相容性物质对细胞无毒。 Overall, biocompatible materials toxic to cells. 在一些实施方式中,如果将某种物质加至细胞中产生小于细胞死亡的某一阈值的结果,那么认为该物质为生物相容的。 In some embodiments, if a certain threshold will produce the result of cell death is less than a substance added to the cells, then the substance is considered biocompatible. 在一些实施方式中,如果将某种物质加至细胞中不诱导副作用,那么认为该物质为生物相容的。 In some embodiments, if a substance added to the cells does not induce side effects, it is considered that the material is biocompatible. 总体而言,可生物降解的物质为经过治疗相关时间段(例如,数周、数月或者数年)在生理学条件下发生分解的物质。 In general, a biodegradable substance is associated with treatment period (e.g., several weeks, months or years) under physiological conditions occurs decomposed substance. 在一些实施方式中,可生物降解的物质为可通过细胞机制进行分解的物质。 In some embodiments, the biodegradable substance is a substance can be decomposed by cellular mechanisms. 在一些实施方式中,可生物降解的物质为可通过化学过程分解的物质。 In some embodiments, the biodegradable material to be decomposed by a chemical process material. 在一些实施方式中,颗粒为生物相容且可生物降解的物质。 In some embodiments, the particles are biocompatible and biodegradable material. 在一些实施方式中,颗粒为生物相容物质,但不为可生物降解的物质。 In some embodiments, the particulate material is biologically compatible, but not to be degraded biomass. 在一些实施方式中, 颗粒为可生物降解的物质,但不为生物相容物质。 In some embodiments, the particles are biodegradable substance, but not biologically compatible material.

[0196] 在一些实施方式中,颗粒的粒度大于肾排泄极限(例如,直径大于6nm的颗粒)。 [0196] In some embodiments, the size of the particles is greater than the renal excretion limit (e.g., particle diameter larger than 6nm). 在一些实施方式中,颗粒尺寸为足以避免通过肝脏从血流中清除的大小(例如,直径小于1000 nm的颗粒)。 In some embodiments, the particle size sufficient to avoid clearance from the bloodstream by the liver size (e.g., particle diameter of less than 1000 nm). 总体而言,颗粒的生理化学特性应当允许靶向颗粒通过降低肾排泄和肝脏清除在血浆中长期循环。 In general, the physiochemical properties should allow targeting of the particles in the particle-removing long circulating plasma and liver by reducing the renal excretion.

[0197] 通常,理想的是使用尺寸、形状和/或组成相对均匀的颗粒群,这样,每一颗粒具有类似的性质。 [0197] Generally, it is desirable to use a size, shape and / or composition of the particles is relatively uniform, so that, each particle having similar properties. 例如,至少80%的颗粒,至少90%的颗粒或至少95%的颗粒的直径或最大尺寸为平均直径或最大尺寸加减5%,10%或20%。 For example, at least 80% of the particles, at least 90% of the particles, or at least 95% of the diameter or maximum dimension of the particles have an average diameter or maximum dimension plus or minus 5%, 10% or 20%. 在一些实施方式中,颗粒群的尺寸、形状和/ 或组成可为不均一的。 In some embodiments, the size of the particles, the shape and / or composition may be non-uniform.

[0198] 根据本发明可使用多种不同的颗粒。 [0198] According to the present invention may use a variety of different particles. 在一些实施方式中,颗粒为球形或类球形。 In some embodiments, the particles are spherical or spheroidal. 在一些实施方式中,颗粒为球形或类球形。 In some embodiments, the particles are spherical or spheroidal. 在一些实施方式中,颗粒为扁平的或板状的。 In some embodiments, the particles are flat or plate-like. 在一些实施方式中,颗粒为立方体或类立方体。 In some embodiments, the particles are cubic or cubic type. 在一些实施方式中,颗粒为卵形或椭圆形。 In some embodiments, the particles are oval or elliptical. 在一些实施方式中,颗粒为圆柱形、圆锥形或金字塔形。 In some embodiments, the particles are cylindrical, conical or pyramidal.

[0199] 在一些实施方式中,颗粒为微颗粒(例如,微球)。 [0199] In some embodiments, the particles are microparticles (e.g., microspheres). 总体而言,"微颗粒"是指直径小于1000 μLΉ的任何颗粒。 In general, "microparticles" refers to any particle diameter of less than 1000 μLΉ. 在一些实施方式中,颗粒为微微型颗粒(picoparticle)(例如,微微球体)。 In some embodiments, the particles are slightly granular (picoparticle) (e.g., a pico spheres). 总体而言,"微微型颗粒"是指直径小于Inm的任何颗粒。 In general, "slightly granular" refers to any particle diameter of less than Inm. 在一些实施方式中,颗粒为脂质体。 In some embodiments, the particle is a liposome. 在一些实施方式中,颗粒为胶束。 In some embodiments, the particles are micelles.

[0200] 颗粒可为实心的或中空的并且可包含一个或一个以上层(例如,纳米壳,纳米环)。 [0200] The particles may be solid or hollow and may include one or more layers (e.g., nanoshells, ring). 在一些实施方式中,每层相对于其他各层具有独特的组成和独特的性质。 In some embodiments, each relative to the other layers having a unique composition and unique properties. 例如,颗粒可具有核/壳结构,其中,核为一层,壳为另一层。 For example, the particles may have a core / shell structure, wherein the core is a layer, another layer of the shell. 颗粒可包含多个不同的层。 Particles may comprise a plurality of different layers. 在一些实施方式中, 一层可为充分交联的,另一层不充分交联,等等。 In some embodiments, the layer can be sufficiently cross-linked, cross-linked further layer is insufficient, and the like. 在一些实施方式中,不同层中的一层,几层或所有层可包含一种或一种以上待递送的治疗剂或诊断剂。 In some embodiments, the different layers in a layer, layers, or all layers may contain one or more agents to be delivered therapeutic or diagnostic agent. 在一些实施方式中,一层包含待递送的药剂,另一层不含待递送的药剂,等等。 In some embodiments, a layer comprising an agent to be delivered, the other layer free of the drug to be delivered, and the like. 在一些实施方式中,每个单独的层包含不同的待递送的药剂或药剂的集合。 In some embodiments, the individual layers each comprising a different set of agent to be delivered or drug.

[0201] 在一些实施方式中,颗粒为多孔的,其是指颗粒包含孔或通道,所述孔或通道通常比颗粒的尺寸小。 [0201] In some embodiments, the particles are porous, which means that the particles comprise pores or channels, the holes or passages typically smaller than the size of the particles. 例如,颗粒可为多孔二氧化硅颗粒,例如,介孔二氧化硅纳米颗粒,或者颗粒可具有介孔二氧化娃涂层(Lin等人,2005, J. Am. Chem. Soc.,17:4570)。 For example, silica particles may be porous particles, e.g., silica nanoparticles mesoporous, or mesoporous particles may have baby dioxide coating (Lin et al., 2005, J. Am Chem Soc, 17...: 4570). 颗粒可具有直径为约Inm至约50nm的孔,例如,直径为约Inm至20nm的孔。 Particles may have a pore diameter of from about Inm to about 50nm, for example, pores having a diameter of from about Inm to 20nm. 颗粒体积的约10%至95%可由孔或通道内的空隙构成。 Voids within about 10 to 95% by volume of the pores or channels of the particle configuration.

[0202] 颗粒可具有涂层。 [0202] particles may have a coating. 例如,如果颗粒包含对细胞具有毒性的物质,那么生物相容性涂层的使用可为有优势的。 For example, if the particles comprising a substance toxic to cells, then the use of biocompatible coatings may be advantageous. 合适的涂层物质包括但不限于:诸如牛血清白蛋白(BSA)之类的天然蛋白质、诸如聚乙二醇(PEG)或PEG衍生物之类的生物相容性亲水聚合物、磷脂-(PEG)、二氧化硅、脂质、聚合物、诸如葡萄聚糖之类的碳水化合物、可与本发明的纳米颗粒结合的其他纳米颗粒,等等。 Suitable coating materials include, but are not limited to: the native protein bovine serum albumin (BSA) or the like such as a biocompatible hydrophilic polymer polyethylene glycol (PEG) or PEG derivative and the like, a phospholipid - (PEG), silica, a lipid, a polymer, a carbohydrate such as dextran or the like, can be combined with other nanoparticles of the invention nanoparticles, and the like. 涂层可通过诸如浸蘸、使用层-层技术、自组装、共轭作用等的多种方式涂敷或组装。 Such as dip coating by using a layer - layer technology, self-assembly, conjugation or the like is applied or assembled in various ways. 自组装是指自发地组装成高级结构的过程,该过程依赖于高级结构的成分(例如,分子)彼此之间的自然吸引作用。 It refers to a self-assembly process spontaneously assemble into higher order structures, high-level components of the process depends on the structure (e.g., molecules) of natural attraction between each other. 该过程通常基于尺寸、形状、组成或化学性质通过分子的随机运动和键的形成而发生。 The process is usually based on the size, shape, chemical composition or properties by forming a molecular bond and random movement occurs.

[0203] 聚合物的实例包括聚烯烃(例如,聚乙烯),聚碳酸酯(例如,聚(1,3-二氧杂环己烷-2酮)),聚酐(例如,聚(癸二酸酐)),聚羟基酸(例如,聚(β-羟基链烷酸酯)),聚延胡索酸酯,聚己酸内酯,聚酰胺(例如,聚己内酰胺),聚缩醛树脂,聚醚,聚酯(例如,聚乳酸, 聚乙醇酸交酯),聚(原酸酯),聚乙烯醇,聚氨酯,聚磷腈,聚丙烯酸酯,聚甲基丙烯酸酯, 聚氰基丙烯酸酯,聚脲,聚苯乙烯和聚胺。 Examples [0203] polymers include polyolefins (e.g., polyethylene), polycarbonates (e.g., poly (1,3-dioxan-2-one)), polyanhydrides (e.g., poly (sebacic acid anhydride)), poly-hydroxy acids (e.g., poly (hydroxy alkanoates [beta])), poly fumarate, polycaprolactone, polyamides (e.g., polycaprolactam), polyacetal resins, polyethers, esters (e.g., polylactic acid, polyglycolic acid lactide), poly (ortho esters), polyvinyl alcohols, polyurethanes, polyphosphazenes, polyacrylates, polymethacrylates, polycyanoacrylates, polyurea, polystyrene and polyamines. 在一些实施方式中,根据本发明的聚合物包括已由美国食品药品管理局(FDA)根据21C. FR § 177. 2600批准用于人体的聚合物,包括但不限于:聚酯(例如,聚乳酸,聚乙醇酸,聚(乳酸-C0-乙醇酸),聚己酸内醋,聚戊内醋,聚(1,3-二氧杂环己烷-2酮)),聚酐(例如,聚(癸二酸酐)),聚醚(例如,聚乙二醇),聚氨酯, 聚甲基丙烯酸酯,聚丙烯酸酯和聚氰基丙烯酸酯。 In some embodiments, the polymer according to the present invention comprises by the U.S. Food and Drug Administration (FDA) for human polymer according 21C FR § 177. 2600 approval, including but not limited to: polyesters (e.g., poly lactic acid, the polyglycolic acid, poly (lactic -C0- glycolic acid), polycaprolactone vinegar, vinegar amyl cohesive, poly (1,3-dioxan-2-one)), polyanhydrides (e.g., poly (sebacic anhydride)), polyethers (e.g., polyethylene glycol), polyurethanes, polymethacrylates, polyacrylates and polymethacrylates cyanoacrylate.

[0204] 在一些实施方式中,颗粒可为非聚合颗粒(例如,金属颗粒,量子点,陶瓷颗粒,含有无机材料的聚合物,骨衍生的材料,骨代用品,病毒颗粒,等等)。 [0204] In some embodiments, the particles may be non-polymeric particles (e.g., metal particles, quantum dots, ceramic particles, a polymer comprising an inorganic material, a bone-derived material, bone substitute, viral particles, etc.). 在一些实施方式中,待递送的治疗剂或诊断剂可与这样的非聚合颗粒的表面结合。 In some embodiments, the therapeutic or diagnostic agent to be delivered may be combined with the surface of such non-polymeric particles. 在一些实施方式中,非聚合颗粒为非聚合成分的聚集体,例如,金属原子(例如,金原子)的聚集体。 In some embodiments, the non-polymeric particles non-polymeric component aggregates, e.g., metal atoms (e.g. gold atoms) aggregates. 在一些实施方式中,待递送的治疗剂或诊断剂可与非聚合成分的聚集体的表面结合和/或封装在非聚合成分的聚集体内、被非聚合成分的聚集体围绕和/或分散于整个非聚合成分的聚集体。 In some embodiments, the therapeutic or diagnostic agent to be delivered may be surface bound and / or encapsulated within the aggregates in non polymeric component and a non-polymeric component aggregates, is surrounded by aggregate non-polymeric component and / or dispersed in aggregates entire non-polymeric component.

[0205] 颗粒(例如,纳米颗粒,微颗粒)可使用本领域已知的任何方法制备。 [0205] particles (e.g., nanoparticles, microparticles) prepared by any method known in the art may be used. 例如,颗粒剂型可通过下列方法以及本领域普通技术人员熟知的其他方法形成:例如纳米沉淀,流动聚焦流体通道,喷雾干燥,单乳液和双乳液溶剂蒸发,溶剂萃取,相分离,研磨,微乳液操作, 微制造,纳米制造,牺牲层,简单和复合凝聚。 For example, the dosage form may be formed by the following methods, and others of ordinary skill in the art well known: e.g. nanoprecipitation, flow focusing fluid passage, spray drying, single emulsions and double emulsion solvent evaporation, solvent extraction, phase separation, grinding, microemulsions operation, micro-fabrication, nano-fabrication, the sacrificial layer, simple and complex coacervation. 可选地或额外地,已经描述了用于单分散半导体纳米颗粒,导电性纳米颗粒,磁性纳米颗粒,有机纳米颗粒和其他纳米颗粒的水性和有机溶剂合成方法(Pellegrino 等人,2005, Small, 1:48;Murray 等人,2000, Ann. Rev. Mat. Sci.,30:545;以及Trindade 等人,2001,Chem. Mat.,13:3843)。 Alternatively or additionally, have been described for monodisperse semiconductor nanoparticles, electrically conductive nanoparticles, magnetic nanoparticles, organic nanoparticles and other aqueous nanoparticle synthesis methods and an organic solvent (Pellegrino et al., 2005, Small, 1:.. 48; Murray et al., 2000, Ann Rev. Mat Sci, 30:.. 545; and Trindade et al., 2001, Chem Mat, 13: 3843)..

[0206] 制备用于递送封装的药剂的微颗粒的方法在文献中描述(参见,例如,Doubrow, 编辑,"Microcapsules and Nanoparticles in Medicine and Pharmacy, " CRC Press, Boca Raton, 1992;Mathiowitz 等人,1987, J. Control. Release, 5:13;Mathiowitz 等人,1987, Reactive Polymers, δ:275;以及Mathiowitz 等人,1988, J.Appl. Polymer Sci. , 35:755)。 Preparation Method [0206] for the delivery of the encapsulated drug microparticles described in the literature (see, e.g., Doubrow, editor, "Microcapsules and Nanoparticles in Medicine and Pharmacy," CRC Press, Boca Raton, 1992; Mathiowitz et al., 1987, J. Control Release, 5:. 13; Mathiowitz et al., 1987, Reactive Polymers, δ:. 275; and Mathiowitz et al., 1988, J.Appl Polymer Sci, 35: 755)..

[0207] 在一些实施方式中,靶向部分包含核酸靶向部分。 [0207] In some embodiments, the targeting moiety comprising a nucleic acid targeting moiety.

[0208] 总体而言,核酸靶向部分为结合与器官、组织、细胞、细胞外基质成分和/或细胞内腔室有关的成分(靶标)的任何多核苷酸。 [0208] In general, the targeting moiety is a nucleic acid binding organs, tissues, cells, extracellular matrix components and / or component associated intracellular compartments (target) of any polynucleotide.

[0209] 在一些实施方式中,核酸靶向部分为适体。 [0209] In some embodiments, the nucleic acid targeting moiety is an aptamer.

[0210] 适体通常为与特定目标结构结合的多核苷酸,所述特定目标结构与特定器官、 组织、细胞、细胞外基质成分和/或细胞内腔室有关。 [0210] Aptamers typically bind to a particular target polynucleotide of the structure, the structure and the specific target specific organs, tissues, cells, extracellular matrix components and / or related intracellular compartments. 总体而言,适体的靶向功能基于适体的三维结构。 Overall, the targeting function aptamer-based three-dimensional structure of the aptamer. 在一些实施方式中,适体与靶标的结合通常由适体和靶标这两者的二维和/或三维结构之间的相互作用介导。 In some embodiments, the aptamer binding to the target is usually mediated by the interaction between the two-dimensional target and aptamer, and / or three-dimensional structure by the. 在一些实施方式中,适体与靶标的结合不仅仅基于适体的基本序列,还取决于适体和/或靶标的三维结构。 In some embodiments, the aptamer binding to the target base sequence of the aptamer based not only on, but also on the aptamer and / or a three-dimensional structure of a target. 在一些实施方式中,适体通过Watson-Crick互补碱基配对与其祀标结合,所述Watson-Crick碱基配对被破坏碱基配对的结构(例如,发夹环)阻碍。 In some embodiments, the aptamer by Watson-Crick base pairing to its complementary labeled binding worship, the Watson-Crick base pairing structure is destroyed base pairing (e.g., a hairpin loop) hindered.

[0211] 在一些实施方式中,核酸革巴向部分为spiegelmers (PCT公布W098/08856, W002/100442 和W006/117217)。 [0211] In some embodiments, the nucleic acid moiety is to Gerba spiegelmers (PCT Publication W098 / 08856, W002 / 100442 and W006 / 117217). 总体而言,spiegelmers 为合成的镜像核酸, 其可特异性结合祀标(即,镜像适体)。 In general, a synthetic image Spiegelmers nucleic acid, which can specifically bind Si standard (i.e., mirror aptamers). spiegelmers通过如下结构特征表征:所述结构特征使得它们不易受外切-核酸酶和内切-核酸酶的影响。 spiegelmers structural features characterized as follows: the structural characteristics make them susceptible to exo - Effect of nuclease - and endo-nucleases.

[0212] 本领域普通技术人员会意识到的是,根据本发明可使用任何能够特异性结合靶标的核酸靶向部分(例如,适体或spiegelmers)。 [0212] Those of ordinary skill in the art will appreciate that, any nucleic acid capable of specifically targeting moiety binds a target (e.g., aptamers or Spiegelmers) according to the present invention. 在一些实施方式中,根据本发明待使用的核酸靶向部分可靶定与疾病、失调和/或病症有关的标记物。 In some embodiments, the nucleic acid according to the present invention, a targeting moiety may be used to target marker with a disease, disorder, and / or related disorders. 在一些实施方式中,根据本发明待使用的核酸靶向部分可靶定癌相关靶标。 In some embodiments, the nucleic acid according to the present invention, a targeting moiety may be used to target cancer-related targets. 在一些实施方式中,根据本发明待使用的核酸靶向部分可靶定肿瘤标记物。 In some embodiments, the nucleic acid according to the present invention, a targeting moiety may be used to target tumor marker. 使用根据本发明的核酸靶向部分可靶定任何类型的癌症标记物和/或任何肿瘤标记物。 The use of a nucleic acid targeting moiety of the present invention may be any type of cancer targeted markers and / or any of tumor markers. 举例而言,核酸靶向部分可靶定与前列腺癌、肺癌、乳腺癌、直肠结肠癌、膀胱癌、胰腺癌、子宫内膜癌、卵巢癌、骨癌、食管癌、肝癌、胃癌、脑肿瘤、皮肤黑色素瘤和/或白血病有关的标记物。 For example, the nucleic acid targeting moiety may be targeted to prostate cancer, lung cancer, breast cancer, colorectal cancer, bladder cancer, pancreatic cancer, endometrial cancer, ovarian cancer, bone cancer, esophageal cancer, liver cancer, stomach cancer, brain tumors , cutaneous melanoma, and / or markers associated leukemia.

[0213] 本发明的核酸(包括核酸靶向部分和/或待递送的功能性RNA,例如,RNAi-诱导实体,核酶,tRNA,等等,下面进一步详细描述)可根据任何可获得的技术制备,包括但不限于:化学合成、酶合成、较长的前体的酶裂解或化学裂解,等等。 [0213] The inventive nucleic acids (including nucleic acid targeting moiety and / or functional RNA to be delivered, for example, RNAi-inducing entity, a ribozyme, tRNA, etc., described in further detail below) according to any available technique preparation, including but not limited to: chemical synthesis, enzymatic synthesis, enzymatic cleavage of a longer precursor or chemical cleavage, and the like. 合成RNA的方法为本领域已知的(参见例如,Gait, MJ·(编辑)01igonucleotide synthesis:a practical app roach,Oxford[Oxfordshire],Washington,DC :IRL Press, 1984;和Herdewijn,P.(编辑)Oligonucleotide synthesis!methods and applications, Methods in molecular biology, v. 288 (Clifton, NJ) Totowa, NJ :Humana Press, 2005)〇 RNA synthesis method known in the art (see, e.g., Gait, MJ · (Editor) 01igonucleotide synthesis: a practical app roach, Oxford [Oxfordshire], Washington, DC: IRL Press, 1984; and Herdewijn, P (ed. !) Oligonucleotide synthesis methods and applications, Methods in molecular biology, v 288 (Clifton, NJ) Totowa, NJ:. Humana Press, 2005) billion

[0214] 形成核酸靶向部分的核酸可包含天然生成的核苷,修饰的核苷,具有在一个或一个以上核苷之间插入的烃连接体(例如,烯烃)或聚醚连接体(例如,PEG连接体)的天然生成的核苷,具有在一个或一个以上核苷之间插入的烃连接体或PEG连接体的修饰的核苷,或它们的组合。 [0214] form a nucleic acid targeting moiety may comprise a nucleic acid naturally occurring nucleosides, modified nucleosides, having between one or more hydrocarbon linkers inserted nucleotide (e.g., olefin) or a polyether linker (e.g. naturally occurring nucleosides, PEG linker) having a combination between one or more nucleotides inserted or modified nucleosides hydrocarbon linking PEG linker or thereof. 在一些实施方式中,核酸靶向部分的核苷酸或修饰的核苷酸可被烃连接体或聚醚连接体取代,只要核酸靶向部分的结合亲合力和选择性基本不会由于取代(例如,核酸靶向部分对靶标的解离常数不应大于约IX I(T3M)而降低。 In some embodiments, the nucleotides or modified nucleotides a nucleic acid targeting moiety may be substituted with a hydrocarbon linker or a polyether linker, so long as binding affinity and selectivity of the targeting moiety is not a nucleic acid base substitutions ( for example, a nucleic acid targeting moiety for the target and decreases the dissociation constant not greater than about IX I (T3M).

[0215] 本领域普通技术人员已知,根据本发明的核酸可包含天然生成的核酸中发现的全部类型的核苷酸或者可包括一种或一种以上核苷酸类似物或具有与天然生成的核酸的结构不同的结构。 [0215] to those of ordinary skill in the art, the nucleic acid according to the present invention may comprise all types of naturally occurring nucleotides found in nucleic acids or may comprise one or more nucleotide analogs or has a naturally occurring a different structure of the nucleic acid structure. 美国专利第6, 403, 779号、第6, 399, 754号、第6, 225, 460号、第6, 127, 533 号、第6, 031,086号、第6, 005, 087号、第5, 977, 089号,这些美国专利中的参考文献公开了多种不同的具体核苷类似物和可使用的修饰。 U.S. Patent No. 6, 403, 779, 6, 399, 754, 6, 225, 460, 6, 127, 533, 6, No. 031,086, No. 6, 005, 087, 5, 977, 089, these references are U.S. Patent discloses a number of different specific nucleoside analogues and modifications may be employed. 参见Crooke, S.(编辑)Antisense Drug Technology!Principles, Strategies, and Applications (第一版),Marcel Dekker;ISBN:0824705661;第一版(2001)以及其中的参考文献。 ! See also Crooke, S. (Editor) Antisense Drug Technology Principles, Strategies, and Applications (first edition), Marcel Dekker; ISBN: 0824705661; first edition (2001) and references therein. 例如,2'-修饰包括卤代、 烷氧基和烯丙氧基。 For example, modifications include 2'-halo, alkoxy and allyloxy. 在一些实施方式中,2'-OH基团被选自下列的基团取代:H,0R,R,卤素, SH,SR,NH2, NHR,NR2或CN,其中,R为C1-C6烷基,烯基,或炔基,并且卤素为F,Cl,Br或I。 In some embodiments, 2'-OH group is substituted with a group selected from: H, 0R, R, halo, SH, SR, NH2, NHR, NR2 or CN, wherein, R is C1-C6 alkyl group , alkenyl, or alkynyl group, and halogen is F, Cl, Br or I. 修饰的连接键的实例包括硫代磷酸酯和5' -N-亚磷酰胺连接键。 Examples of modified linkages include phosphorothioates and 5 '-N- phosphoramidite linkages.

[0216] 根据本发明可使用包含多种不同的核苷酸类似物、修饰的骨架或非天然生成的核苷间连接键的核酸。 [0216] According to the present invention can be used comprise a variety of different nucleotide analogs, modified backbones or internucleoside linkages of naturally occurring nucleic acids. 本发明的核酸可包括天然核苷(即,腺苷、胸苷、鸟苷、胞苷、尿苷、脱氧腺苷、脱氧胸苷、脱氧鸟苷、脱氧胞苷)或修饰的核苷。 A nucleic acid of the present invention may include natural nucleosides (i.e., adenosine, thymidine, guanosine, cytidine, uridine, deoxyadenosine, deoxythymidine, deoxyguanosine, deoxycytidine) or modified nucleosides. 修饰的核苷酸的实例包括碱基修饰的核苷(例如,阿糖胞苷(3^〇5^1^(1;[116)、肌核苷、异鸟苷、水粉荤素(1161311131';[116)、假尿苷、 2, 6_二氛基嗓吟、2_氛基嗓吟、2_硫代胸昔、3_脱氣_5_氣杂胞昔、2' -脱氧尿昔、3_硝基吡咯、4-甲基吲哚、4-硫代尿苷、4-硫代胸苷、2-氨基腺苷、2-硫代胸苷、2-硫代尿苷、5-溴代胞苷、5-碘代尿苷、肌核苷、6-氮尿苷、6-氯代嘌呤、7-脱氮腺苷、7-脱氮鸟苷、8-氮杂腺苷、8-叠氮腺苷、苯并咪唑、Ml-甲基腺苷、吡咯并嘧啶、2-氨基-6-氯代嘌呤、3-甲基腺苷、5-丙炔基胞苷、5-丙炔基尿苷、5-溴代尿苷、5-氟代尿苷、5-甲基胞苷、7-脱氮腺苷、 7-脱氮鸟苷、8-氧腺苷、8-氧鸟苷、0(6)-甲基鸟嘌呤和2-硫代胞苷),化学或生物修饰的碱基(例如,甲基化的碱基),修饰的糖类(例如,2'-氟代核糖、2'-氨基核糖、2'-叠氮核糖、 2' -0-甲基核糖、L-对 Examples of modified nucleotides include base modified nucleoside (e.g., cytarabine (^ 1 ^ 3 ^ 〇5 (1; [116), muscle nucleosides, isoguanosine, watercolor meat and vegetables (1,161,311,131 ' ; [116), pseudouridine, 2, 6_ two voice group atmosphere Yin, Yin 2_ atmosphere voice group, thio thymidine 2_, 3_ degassed _5_ gas hybrid cells Xi, 2 '- deoxyuridine Xi, 3_ nitropyrrole, 4-methylindole, 4-thiouridine, 4-thiothymidine, 2-aminoadenosine, 2-thiothymidine, 2-thiouridine, 5 - cytidine bromo, 5-iodo-uridine, nucleosides muscle, 6- azauridine, 6-chloropurine, 7-deazaadenosine, 7-deazaguanosine, 8-adenosine, 8-azido adenosine, benzimidazole, of ML-methyladenosine, pyrrolo-pyrimidine, 2-amino-6-chloropurine, 3-methyl adenosine, 5-propynyl cytidine, 5- alkynyl uridine, 5-bromo uridine, 5-fluoro uridine, 5-methylcytidine, 7-deazaadenosine, 7-deazaguanosine, 8-adenosine, 8-birds glycosides, 0 (6) - methylguanine, and 2-thiocytidine), chemically or biologically modified bases (e.g., methylated bases), modified sugars (e.g., 2'-fluoro ribose, 2'-amino ribose, 2'-azido-ribose, 2 '-O-methyl-ribose, L- on 异构体核苷阿糖和己糖),修饰的磷酸酯基团(例如,硫代磷酸酯和5' -N-亚磷酰胺连接键)以及它们的组合。用于核酸的化学合成的天然核苷酸单体和修饰的核苷酸单体易于获得。在一些情况下,含有这些修饰的核酸相对于仅由天然生成的核苷酸构成的核酸表现出改善的性质。在一些实施方式中,本文所述的核酸修饰被用于降低和/或防止核酸酶(例如,核酸外切酶,核酸内切酶,等等)消化。例如,核酸的结构可通过在一条链或两条链的3'端包括核苷酸类似物以降低消化来稳定。 Nucleoside isomers A and hexose), modified phosphate groups (e.g., phosphorothioates and 5 '-N- phosphoramidite linkages), and combinations thereof. Chemically synthesized nucleic acids for natural nucleus nucleotide monomers and modified nucleotide monomers are readily available. in some cases, these modified nucleic acids containing properties with respect to nucleic acids generated only by the natural nucleotides constituted exhibit improved. in some embodiments, the modified nucleic acid described herein is used to reduce and / or prevent nuclease (e.g., an exonuclease, endonuclease, etc.) digestion. for example, the structure of nucleic acids by one or both strands of the 3 'end comprises nucleotide analogs stabilized to reduce digestion.

[0217] 修饰的核酸不需要沿着分子的全长进行一致性修饰。 [0217] The modified nucleic acid need not be modified consistent along the full length molecule. 不同的核苷酸修饰和/或骨架结构可存在于核酸的各个不同位置。 And / or various positions may be present in the nucleic acid backbone structures different nucleotide modifications. 本领域普通技术人员可理解的是,核苷酸类似物或其他修饰可位于使核酸的功能基本不受影响的核酸的任何位置。 One of ordinary skill will appreciate that other nucleotide analogs or modified nucleic acid may be located substantially unaffected the functional nucleic acid at any position. 举例而言,修饰可位于使核酸靶向部分特异性结合靶标的能力基本不受影响的核酸靶向部分的任何位置。 For example, modified nucleic acids may be located anywhere in the target portion that specifically binds to the nucleic acid targeting capability substantially unaffected targeting moiety. 修饰的区域可位于一条链或两条链的5'端和/或3'端。 The modified region may be located in one or both strands of the 5 'end and / or 3' end. 例如,已使用如下修饰的核酸靶向部分: 位于该修饰的核酸靶向部分中的两条链中的任一条链的5'端和/或3'端处的大约1至5 个残基为核苷酸类似物和/或具有骨架修饰。 For example, modified nucleic acid has been used as targeting moieties: at the 5 'end and / or 3' to any portion of one strand of the modified nucleic acid targeting in both strands at the end of about 1 to 5 residues nucleotide analogs and / or having a modified backbone. 所述修饰可为5'或3'末端修饰。 The modification may be the 5 'or 3' terminal modification. 一条或两条核酸链可包含至少50%未修饰的核苷酸,至少80%未修饰的核苷酸,至少90%未修饰的核苷酸或100%未修饰的核苷酸。 One or two nucleic acid strands may comprise at least 50% unmodified nucleotides, at least 80% unmodified nucleotides, at least 90% unmodified nucleotides, or 100% unmodified nucleotides.

[0218] 例如,根据本发明的核酸可包含对糖类、核苷或核苷间连接键的修饰,例如,美国专利申请公开第2003/0175950号,第2004/0192626号,第2004/0092470号,第2005/0020525号以及第2005/0032733号中描述的那些。 [0218] For example, a nucleic acid according to the present invention may comprise modifications to the linkages between the sugars, nucleosides or nucleoside, e.g., U.S. Patent Application Publication No. 2003/0175950, No. 2004/0192626, No. 2004/0092470 No. 2005/0020525 and No. 2005/0032733 those described. 本发明包括具有本文所述的修饰中的任何一种或一种以上的任何核酸的应用。 The present invention includes any use of any one or more of said modified nucleic acid described herein. 例如,已报道了多种末端偶联物(例如,脂质(例如,胆固醇)、石胆酸、月桂酸(aluric acid)、长支链烷基)改善细胞摄取。 For example, it has been reported that a variety of conjugates terminal (e.g., a lipid (e.g., cholesterol), lithocholic acid, lauric acid (aluric acid), long-chain branched alkyl) improve cellular uptake. 例如,可使用本领域已知的任何合适的测试方法检测类似物和修饰,从而选择使治疗剂或诊断剂的递送得以改善、使核酸的靶向部分与靶标的特异性结合得以改善等等的那些类似物和修饰。 Targeting moiety to the target, for example, using any suitable test method for detecting modifications and analogs known in the art, so that the selected delivery of therapeutic or diagnostic agent is improved, so that the nucleic acid binding specificity is improved, etc. those analogs and modifications. 在一些实施方式中,根据本发明的核酸可包括一个或一个以上非天然核苷连接键。 In some embodiments, the nucleic acid according to the present invention may comprise one or more non-natural internucleoside linkages. 在一些实施方式中,一个或一个以上位于核酸靶向部分的3'端、5'端或3'端和5'端这两端的内在核苷酸被倒转生成诸如3' -3'连接键或5' -5'连接键之类的连接键。 In some embodiments, the one or more at the 3 'end, 5' end of a nucleic acid targeting moiety or the 3 'and 5' ends of the two ends of the internal nucleotides is reversed, such as to generate a 3 '-3' linkage or 5 '-5' linkage such linkages.

[0219] 在一些实施方式中,根据本发明的核酸不是合成的,其为已从其天然环境中分离出来的天然生成的实体。 [0219] In some embodiments, the nucleic acid is not a compound according to the present invention, which is isolated from its natural environment naturally occurring entity.

[0220] 可使用任何方法来设计新的核酸靶向部分(请参见例如下列美国专利:6, 716, 583 ;6, 465, 189; 6, 482, 594; 6, 458, 543; 6, 458, 539; 6, 376, 190 ; 6, 344, 318; 6, 242, 246; 6, 184, 364;6, 001, 577;5, 958, 691;5, 874, 218;5, 853, 984;5, 843, 732;5, 843, 653; 5, 817, 785;5, 7 89, 163; 5, 763, 177; 5, 696, 249; 5, 660, 985; 5, 595, 877; 5, 567, 588 和5, 270, 163 以及下列美国专利申请公开:2005/0069910, 2004/0072234, 2004/0043923, 2003/0087301, 2003/005 4360和2002/0064780)。 [0220] Any method may be used to design new nucleic acid targeting moiety (see for example the following U.S. Patents: 6, 716, 583; 6, 465, 189; 6, 482, 594; 6, 458, 543; 6, 458 , 539; 6, 376, 190; 6, 344, 318; 6, 242, 246; 6, 184, 364; 6, 001, 577; 5, 958, 691; 5, 874, 218; 5, 853, 984 ; 5, 843, 732; 5, 843, 653; 5, 817, 785; 5, 789, 163; 5, 763, 177; 5, 696, 249; 5, 660, 985; 5, 595, 877; 5, 567, 588 and 5, 270, 163 and the following U.S. Patent application Publication: 2005/0069910, 2004/0072234, 2004/0043923, 2003/0087301, and 2002/0064780 2003/005 4360). 本发明提供一种用于设计新的核酸靶向部分的方法。 The present invention provides a new method for designing a nucleic acid targeting moiety. 本发明还提供一种用于从候选核酸靶向部分的混合物中分离或识别新的核酸靶向部分的方法。 The present invention also provides a method of isolating or identifying a nucleic acid targeting moiety new part of the mixture of nucleic acid from a candidate for targeting.

[0221] 可设计和/或识别与蛋白质、碳水化合物、脂质和/或核酸结合的核酸靶向部分。 [0221] can be designed and / or identify binding proteins, carbohydrates, lipids, and / or a nucleic targeting moiety. 在一些实施方式中,核酸靶向部分可被设计和/或识别为在与蛋白质和/或其特征部分结合的本发明的复合物中使用,所述蛋白质和/或其特征部分例如,肿瘤标记物、整合素、细胞表面受体、跨膜蛋白、细胞间蛋白质、离子通道、膜转运蛋白、酶、抗体、嵌合蛋白,等等。 In some embodiments, the nucleic acid targeting moiety may be designed and / or identified for use in the present invention, the composite part to the protein binding and / or characteristics, the protein and / or characteristic portions thereof, for example, tumor markers was integrins, cell surface receptors, transmembrane proteins, intracellular proteins, ion channels, membrane transport proteins, enzymes, antibodies, chimeric proteins, and the like. 在一些实施方式中,核酸靶向部分可被设计和/或识别为在与碳水化合物和/或其特征部分结合的本发明的复合物中使用,所述碳水化合物和/或其特征部分例如,糖蛋白、糖类(例如,单糖、二糖和多糖)、多糖包被(即,大多数真核细胞的外表面上的碳水化合物富集的外周区域),等等。 In some embodiments, the nucleic acid targeting moiety may be designed and / or carbohydrate for use in identifying and / or characteristic portion thereof bound complex of the present invention, the carbohydrate and / or characteristic portions thereof e.g., glycoproteins, sugars (e.g., monosaccharides, disaccharides and polysaccharides), coated with polysaccharide (i.e., the outer surface of most carbohydrate eukaryotic cells enriched peripheral region), and the like. 在一些实施方式中,核酸靶向部分可被设计和/或识别为在与脂质和/或其特征部分结合的本发明的复合物中使用,所述脂质和/或其特征部分例如,油、饱和脂肪酸、不饱和脂肪酸、甘油酯、激素、类固醇(例如,胆固醇、胆汁酸)、维生素(例如,维生素E)、 磷脂、神经鞘脂、脂蛋白,等等。 In some embodiments, the nucleic acid targeting moiety may be designed and / or identified for use in the complex of the invention in combination with a lipid portion and / or features, the lipid and / or characteristic portions thereof e.g., oils, saturated fatty acids, unsaturated fatty acids, glycerides, hormones, steroids (e.g., cholesterol, bile acids), vitamins (e.g., vitamin E), phospholipids, sphingolipids, lipoproteins, and the like. 在一些实施方式中,核酸靶向部分可被设计和/或识别为在与核酸和/或其特征部分结合的本发明的复合物中使用,所述核酸和/或其特征部分例如, DNA核酸、RNA核酸、修饰的DNA核酸、修饰的RNA核酸和包括DNA、RNA、修饰的DNA和修饰的RNA的任何组合的核酸,等等。 In some embodiments, the nucleic acid targeting moiety may be designed and / or identified for use in the nucleic acid and / or characteristic portion thereof or a bound complex of the present invention, the nucleic acid and / or characteristic portions thereof e.g., DNA nucleic acid , RNA nucleic acids, nucleic acid modified DNA, modified RNA comprises nucleic acids and DNA, RNA, modified DNA and any combination of modified RNA nucleic acids, and the like.

[0222] 可使用任何可获得的方法设计和/识别核酸靶向部分(例如,适体或spiegelmer)。 [0222] can be designed and / or identification of nucleic acid targeting moiety (e.g., aptamer or Spiegelmer) using any available method. 在一些实施方式中,核酸革El向部分通过从候选的核酸混合物中识别核酸革巴向部分来设计和/或识别。 In some embodiments, the nucleic acid portion to the El leather design and / or identify a nucleic acid by identifying the portion of the nucleic acid from the mixture Gerba of the candidate. 指数富集配体系统进化(SELEX)或其改良方法为从候选的核酸混合物中识别与靶标结合的核酸靶向部分的常用方法。 Systematic evolution of ligands by exponential enrichment (the SELEX) is a nucleic acid or a modified method of identifying target binding nucleic acids from a mixture of candidate targeting moiety commonly used method.

[0223] 选择性结合任何靶标的核酸靶向部分可通过SELEX方法或其改良方法分离,条件是所述靶标可用作SELEX方法中的靶标。 [0223] selectively binds any target nucleic acid targeting moiety may be isolated by the SELEX method or an improved method that may be used as a target for SELEX method targets.

[0224] 连接体 [0224] linker

[0225] 总体而言,本发明的化合物包含连接体,所述连接体将靶向部分和活化部分连接。 [0225] In general, the compounds of the present invention comprises a linker, the linker connecting the targeting moiety and the activated portion. 然而,一些化合物不含连接体,活化部分和靶向部分直接连接。 However, some of the compounds contain a linker, targeting moiety and the activated portion are directly connected.

[0226] 本文中的"连接体"是指使第一分子与第二分子通过化学键连接的部分。 [0226] herein, "linker" refers to a portion of the first molecule to a second molecule through chemical bond. 在本发明的连接体中,可割断连接,从而释放第一和/或第二分子的生物活性形式。 In the present invention, a linker, severable connector, thereby releasing the biologically active form of the first and / or second molecules. 连接体的优选实例为包含在中性PH条件下稳定但在较低pH条件下易于发生裂解的化学键的部分。 Preferred examples of linker comprising at neutral PH conditions stable but readily cleavable chemical bond portion occurs at lower pH conditions. 具体而言,优选的连接体的实例为包含在pH为7至8的条件下稳定但在pH为4至6的条件下易于裂解的化学键的部分。 Specifically, examples of preferred linker is stable but comprising at pH conditions at pH 4-6 is readily cleaved under the conditions of a bond portion 7 to 8. 连接体的另一实例为包含在存在酶的条件下易于裂解的化学键的部分。 Another example of a linker portion comprising an enzyme in the presence of a readily cleavable chemical bond. 这些对酶敏感的连接体的优选实例为肽,所述肽包含内涵体肽酶的识别序列。 Preferred examples of these enzyme-sensitive linker is a peptide comprising a recognition sequence endosomes peptidases. 连接体的另一实例为对氧化还原电位敏感的连接体,该连接体在低还原电位(例如,低浓度的硫醇或谷胱甘肽)条件下稳定但在高还原电位(例如,高浓度的硫醇或谷胱甘肽)条件下裂解。 Another example of a linker for the redox potential-sensitive linker, the linker at a low reduction potential (e.g. low concentrations of glutathione or thiol,) but stable under the conditions in the high reduction potential (e.g., high concentrations thiol or cleaved glutathione) conditions. 这些对氧化还原电位敏感的连接体的优选实例包括二硫化物和次磺酰胺。 Preferred examples of such redox potential-sensitive linkers include disulfide and sulfenamide. 具体而言,优选的实例包括取代的芳基-烷基二硫化物,其中,芳基被有空间需求的且吸电子或给电子的取代基取代,从而控制趋于与硫醇反应的二硫键的敏感性。 Specifically, preferred examples include substituted aryl - alkyl disulfide, wherein the aryl group is sterically demanding and electron withdrawing substituents or to electrons, tend to control the reaction with a disulfide thiol sensitive keys. 连接体的另一实例为包含在暴露于辐射之后易于裂解的化学键的部分。 Another example of a linker portion comprising after exposure to radiation readily cleavable chemical bond. 这些对辐射敏感的连接体的优选实例为2-硝基苄基醚,其在暴露于光之后裂解。 These are 2-nitrobenzyl ether, which cleaves the preferred examples of the radiation-sensitive linker after exposure to light. 具体而言,这些连接体的优选实例为如下部分:在连接键被割断之前该部分掩盖两个连接的分子中的一个的生物活性。 Specifically, preferred examples of these linkers is the following parts: a cover portion of the bioactive molecule in the two prior linkages are severed.

[0227] 在一些实施方式中,本发明的化合物包含选自如下基团的连接体:肼基团、多肽、 ^硫化物基团和硫酿基团。 [0227] In certain embodiments, the compounds of the present invention comprises a linker group selected from: a hydrazine group, a polypeptide, a sulfide group and a sulfur ^ brewing group.

[0228] 本文中的"肼基团"或"肼连接体"或"自环化肼连接体"是指在改变条件(例如,pH 改变)之后可发生环化反应并形成一个或一个以上环的连接体部分。 May occur [0228] As used herein the "hydrazino group" or "hydrazine linker" or "self-cyclizing hydrazine linker" refers to changing conditions (e.g., pH change) after the cyclization reaction and form one or more rings the linker moiety. 当连接时,肼基团被转化为腙。 When connected, a hydrazine group is converted to hydrazone. 这种连接可通过例如在L4部分与酮基团反应而发生。 This connection may be, for example, by reacting the ketone group with the L4 portion occurs. 因此,术语肼连接体也可用于描述本发明的连接体,因为这种向腙的转化发生在连接之后。 Thus, the term hydrazine linker may also be used to describe the linker of the present invention, since such conversion to the hydrazone occurs after the connection.

[0229] 本文中的"五元肼连接体"是指含有肼的分子部分,该部分在条件发生改变(例如, pH发生改变)之后会进行环化反应并形成一个或一个以上五元环。 It will cyclization [0229] As used herein the "five- or hydrazine linker" refers to a molecular moiety hydrazine, varying the part occurs in conditions (e.g., pH change) and after forming one or more five-membered ring. 可选地,该五元连接体可被类似地描述为五元肼连接体。 Alternatively, the five yuan linker may similarly be described a five-membered hydrazine linker.

[0230] 本文中的"六元肼连接体"是指含有肼的分子部分,该部分在条件发生改变(例如, pH发生改变)之后会进行环化反应并形成一个或一个以上六元环。 Will cyclization [0230] As used herein the "six yuan hydrazine linker" refers to a molecular moiety containing hydrazine, the portion changes in conditions (e.g., pH changes) and after forming one or more six-membered rings. 该六元连接体可被类似地描述为六元肼连接体。 The six yuan linker may similarly be described a six-membered hydrazine linker.

[0231] 本文中的"环化反应"是指肽、肼或二硫化物连接体的环化,该"环化反应"表示连接体环化形成环并且启动药物配体复合物的分离。 [0231] As used herein the "cyclization" refers to a peptide, hydrazine, or disulfide linker cyclization of the "cyclization" represents a linker cyclization to form a ring and initiates the separation of the drug-ligand complex. 环化速率可异地测量并且当至少90%、 95%或100%的产物形成时完成环化。 Cyclization rate can be measured and remote cyclization when at least 90%, 95%, or 100% of the product formation.

[0232] 在一些实施方式中,本发明的化合物包含位于靶向部分和活化部分之间的连接体区域,并且所述连接体可被存在于细胞内环境(例如,溶酶体或内涵体或小凹内)中的裂解剂裂解。 [0232] In certain embodiments, the compounds of the invention comprise a linker region positioned between the targeting moiety and the activated portion, and the linker may be present in the intracellular environment (e.g., lysosomes or endosomes or cleavage cleavage agent) in a small inner recess. 连接体可为例如,肽基连接体,该肽基连接体由细胞内肽酶或蛋白酶(包括但不限于:溶酶体蛋白酶或内涵体蛋白酶)裂解。 Linker may be, for example, a peptidyl linker, the linker peptidyl peptidase or protease (including but not limited to: a lysosomal protease or an endosomal protease) by the inner cell lysis. 通常,肽基连接体的长度为至少两个氨基酸的长度或至少三个氨基酸的长度。 Typically, the length of the peptidyl linker is at least two amino acids or a length of at least three amino acids in length. 裂解剂可包括组织蛋白酶B、组织蛋白酶D和纤溶酶,已知组织蛋白酶B、组织蛋白酶D和纤溶酶均可水解二肽药物衍生物,导致靶细胞内部的活性药物释放(参见例如,Dubowchik and Walker, 1999, Pharm. Therapeutics83:67_123)。 Lysing agents may include cathepsin B, cathepsin D and plasmin, the known cathepsin B, cathepsin D and plasmin dipeptide drug derivatives may be hydrolyzed, resulting in the interior of the target cells to release the active drug (see, e.g., Dubowchik and Walker, 1999, Pharm Therapeutics83:. 67_123). 最典型的连接体为肽基连接体,其可由存在于靶细胞或组织中的酶裂解。 The most typical linker group is a peptide linker, which may be present in the enzymatic cleavage of a target cell or tissue. 例如,可使用可由硫醇依赖性蛋白酶组织蛋白酶-B裂解的肽基连接体(例如,Phe-Leu或(Gly-Phe-Leu-Gly)连接体),所述硫醇依赖性蛋白酶组织蛋白酶-B在癌组织中高表达。 For example, a thiol-dependent protease cathepsin be -B peptidyl linker cleavable (e.g., Phe-Leu or (Gly-Phe-Leu-Gly) linker), the thiol-dependent protease cathepsin - B is highly expressed in cancer tissues. 其他这类连接体例如在美国专利第6, 214, 345号中描述。 Other such linkers, for example, in U.S. Patent Nos. 6, 214, 345 are described. 在一些实施方式中,可由细胞内蛋白酶裂解的肽基连接体为Val-Cit连接体或Phe-Lys连接体(参见例如,美国专利第6, 214, 345号,该美国专利描述了带有val-cit连接体的阿霉素的合成)。 In some embodiments, the cell may be a protease cleavable linker is a peptidyl Val-Cit linker or a Phe-Lys linker (see, e.g., U.S. Patent No. 6, 214, 345, the U.S. patent describes with val synthesis of doxorubicin connector body -cit). 使用细胞内蛋白水解释放治疗剂的一个优势为所述治疗剂通常在偶联时被弱化并且偶联物的血清稳定性通常较高。 One advantage of using intracellular proteolytic release of the therapeutic agent to the therapeutic agent is typically weakened upon coupling and serum stability of the conjugate are usually higher.

[0233] 在一些实施方式中,可裂解的连接体为pH敏感的,即对某一pH值条件敏感而发生水解。 [0233] In some embodiments, the cleavable linker is pH-sensitive, i.e., sensitive to hydrolysis and certain pH conditions. 通常,pH敏感的连接体在酸性条件下可水解。 Typically, pH-sensitive linker is hydrolyzable under acidic conditions. 例如,可使用在溶酶体中可水解的酸不稳定连接体(例如,腙、缩氨基脲、硫代缩氨基脲、顺式乌头酰胺、原酸酯、缩醛、 缩酮,等等),参见例如,美国专利第5, 122, 368号,第5, 824, 805号,第5, 622, 929号, Dubowchik and Walker, 1999, Pharm. Therapeutics83:67-123;Neville 等人,1989, Biol. Chem. 264:14653-14661。 For example, a hydrolyzable in the lysosome acid-labile linker (e.g., hydrazone, semicarbazone, thiosemicarbazone, cis-aconitic amide, orthoester, acetal, ketal, etc. ), see, e.g., U.S. Patent No. 5, 122, 368, 5, 824, 805, 5, 622, No. 929, Dubowchik and Walker, 1999, Pharm Therapeutics83: 67-123; Neville et al, 1989. ., Biol Chem 264:. 14653-14661. 这些连接体在中性pH条件下相对稳定,例如,在血液中的那些连接体,但是在低于5. 5或5. 0的pH条件(大约为溶酶体的pH)下不稳定。 The connecting body is relatively stable under neutral pH conditions, e.g., those in the blood of the linker, but below 5.5 or 5.0 pH conditions (approximately pH lysosomes) unstable. 在一些实施方式中,可水解的连接体为硫醚连接体(例如,通过酰基腙化学键与治疗剂连接的硫醚,参见例如,美国专利第5, 622, 929号)。 In some embodiments, the hydrolyzable linker is a thioether linker (e.g., hydrazone thioether-linked chemically by acylation with a therapeutic agent, see, e.g., U.S. Patent No. 5, 622, 929).

[0234] 在其他实施方式中,连接体为在还原性条件下可裂解的(例如,二硫化物连接体)。 [0234] In other embodiments, the body is cleavable under reducing conditions (e.g., a disulfide linker) connection. 本领域已知多种二硫化物连接体,包括例如,可使用SATA (N-琥珀酰亚胺基-5-乙酰基硫代乙酸酯),SPDP (N-琥珀酰亚胺基-3-(2-吡啶基二硫代)丙酸酯),SPDB (N-琥珀酰亚胺基-3-(2-吡啶基二硫代)丁酸酯)和SMPT (N-琥珀酰亚胺基-氧羰基-α -甲基-a-(2-吡啶基二硫代)甲苯),SPDB和SMPT (参见例如,Thorpe等人,1987, Cancer Res. 47:5924-5931;Wawrzynczak 等人,In Immunoconjugates:Antibody Conjugates in Radioimagery and Therapy of Cancer (CW Vogel 编辑),Oxford U.出版,1987.还参见美国专利第4, 880, 935号)形成的那些连接体。 Known in the art a variety of disulfide linkers, including, for example, may be used SATA (N- succinimidyl-5-acetyl-thioacetate), SPDP (N-succinimidyl-3- ( 2- pyridyldithio) propionate), SPDB (N- succinimidyl-3- (2-pyridyldithio) butyrate) and SMPT (N- succinimidyl - oxo carbonylation -α - methyl -a- (2- pyridyldithio) toluene), SPDB and SMPT (see, e.g., Thorpe et al., 1987, Cancer Res 47: 5924-5931; Wawrzynczak et al, In Immunoconjugates: Antibody Conjugates in Radioimagery and Therapy of Cancer (CW Vogel editor), Oxford U. Publishing, 1987. see also U.S. Patent linker those of 4, 880, 935) is formed.

[0235] 在其他具体实施方式中,连接体为丙二酸醋连接体(Johnson等人,1995, Anticancer Res. 15:1387-93),马来酰亚胺苯甲酰基连接体(Lau等人,1995, Bi oorg-Med-Chem. 3(10) : 1299-1304)或3' -N-酰胺类似物(Lau 等人,1995, Bioorg-Med-Ch em. 3(10) : 1305-12)。 [0235] In other embodiments, the linker is a malonate linker vinegar (Johnson et al., 1995, Anticancer Res 15:. 1387-93), maleimidobenzoyl-connection (Lau et al body , 1995, Bi oorg-Med-Chem 3 (10):. 1299-1304), or 3 '-N- amide analog (. Lau et al., 1995, Bioorg-Med-Ch em 3 (10): 1305-12 ).

[0236] 通常,连接体对细胞外环境基本不敏感。 [0236] Generally, the linker is not substantially sensitive to the extracellular environment. 本文在连接体的部分使用的"对细胞外环境基本不敏感"是指在本发明的化合物样品中,当本发明的化合物存在于细胞外环境(例如,血浆中)时,不超过约20%的连接体裂解,典型地不超过约15%的连接体裂解,更加典型地不超过约10%连接体裂解,甚至更加典型地不超过约5%的连接体裂解,不超过约3%的连接体裂解,或者不超过约1%的连接体裂解。 In this paper a moiety used, "not substantially sensitive to the extracellular environment" refers to a sample of the compound of the present invention, when the compound of the present invention resides in extracellular environment (e.g., plasma), there are no more than about 20% linker cleavage, typically no more than about 15% of linker cleavage, more typically no more than about 10% of linker cleavage, even more typically no more than about 5% of linker cleavage, no more than about 3% of the linkages lysis, or no more than about 1% of linker cleavage. 例如,可通过将(a)本发明的化合物("化合物样品")和(b)等摩尔量的未偶联的抗体或治疗剂("对照样品")独立地与血浆一同孵育一段预定的时间段(例如,2小时、4小时、8小时、16小时或24小时)并随后比较存在于化合物样品中的未偶联的抗体或治疗剂的量和存在于对照样品中的未偶联的抗体或治疗剂的量(例如通过高效液相色谱测量)来测定连接体是否对细胞外环境基本不敏感。 For example, unconjugated (b) an equimolar amount of an antibody or therapeutic agent (the "control sample") independently of plasma were incubated with a predetermined time by a compound ( "Compound sample") (A) of the present invention, and the amount of antibody or therapeutic agent of segments (e.g., 2 hours, 4 hours, 8 hours, 16 hours or 24 hours) and then comparing the sample compound present in the unconjugated and are present in a control sample unconjugated antibody or the amount of therapeutic agent (e.g., measured by high performance liquid chromatography) to determine whether a linker is not substantially sensitive to the extracellular environment.

[0237] 在其他不相互排斥的实施方式中,连接体促进细胞内在化。 [0237] In another embodiment are not mutually exclusive embodiments, the linker promotes cell internalization. 在一些实施方式中,当连接体偶联于活化部分时,连接体促进细胞内在化。 In some embodiments, when the activating moiety conjugated to the linker, the linker promotes cell internalization. 在其他实施方式中,当连接体偶联于靶向部分和活化部分这两者时,连接体促进细胞内在化。 In other embodiments, when the linker is conjugated to both the targeting moiety and the activated part, the linker promotes cell internalization.

[0238] 可在本发明的组合物和方法中使用的多种连接体在W02004010957 (名称为"Drug Conjugates and Their Use for Treating Cancer,An Autoimmune Disease or an Infectious Disease")以及US20120141509A1 和US20120288512A1 (其公开的内容通过引用并入本文)中描述。 [0238] variety of linkers may be used in the compositions and methods of the present invention in W02004010957 (entitled "Drug Conjugates and Their Use for Treating Cancer, An Autoimmune Disease or an Infectious Disease") and US20120141509A1 and US20120288512A1 (the disclosure of contents are incorporated herein by reference) are described.

[0239] 在一些实施方式中,连接体单元具有如下通式: [0239] In some embodiments, the linker unit has the formula:

[0240] -Ta-Ww-Yy- [0240] -Ta-Ww-Yy-

[0241] 其中,-T-为支架单元,a为0或1,-W-分别独立地为氨基酸单元,w独立地为2 至12的整数,-Y-为间隔单元,y为0、1或2。 [0241] wherein, -T- is a holder unit, a is 0 or 1, -W- is independently an Amino Acid unit, w is independently an integer from 2 to 12, -Y- is a Spacer unit, y is 0, or 2.

[0242] I架单元 [0242] I frame means

[0243] 当存在支架单元(-T-)时,该支架单元将靶向部分连接至氨基酸单元(-W-)。 [0243] When present bracket unit (-T-), the stent cell targeting moiety coupled to an amino acid unit (-W-). 可天然地或通过化学操作存在于靶向部分(例如,抗体)上的有用的官能团包括但不限于:巯基、 氨基、羟基、碳水化合物的异头羟基和羧基。 It may be naturally or by chemical manipulation present in a targeting moiety (e.g., antibody) useful functional groups include, but are not limited to the: a mercapto group, an amino group, a hydroxyl group, a carbohydrate anomeric hydroxyl and carboxyl groups. 合适的官能团为巯基和氨基。 Suitable functional groups are sulfhydryl and amino. 巯基可通过还原抗体的分子内二硫键生成。 Mercapto may be generated by intramolecular disulfide bonds of reduced antibody. 可选地,巯基可通过抗体的赖氨酸基团的氨基与2-亚氨基硫杂环戊烷(Traut试剂)或其他巯基生成试剂的反应生成。 Alternatively, sulfhydryl groups can be generated by the reaction of a reagent antibody amino group of lysine with 2-iminothiolane (Traut's reagent) or other sulfhydryl. 在一些实施方式中,抗体为重组抗体并且被设计为带有一个或一个以上赖氨酸。 In some embodiments, the antibody is a recombinant antibody and is designed with one or more lysine. 在其他实施方式中,重组抗体被设计为带有额外的巯基基团,例如,额外的半胱氨酸。 In other embodiments, the recombinant antibody is designed with additional sulfhydryl groups, e.g., additional cysteines.

[0244] 在一些实施方式中,支架单元与抗体的硫原子形成化学键。 [0244] In some embodiments, the sulfur atom of the antibody and the bracket unit form a chemical bond. 所述硫原子可来源于还原的抗体(A)的巯基基团(-SH)。 The sulfur atom can be derived from a reducing thiol group antibody (A), (-SH). 这些实施方式的代表性的支架单元在通式(IIa)和(IIb)的方括号中描述,其中,A-、-W-、-Y-、-D、w和y为如上所定义的,并且R 1选自:-C ^Cltl 條径_、-C3-C8-碳环(C1-C8;)^基)-、-亚芳基-、-C ^Cltl條径-亚芳基-、-亚芳基-C1-Cltl-稀径-、-C 1-Cltl-稀径-(C3-C8碳环)-、-(C 3_C8碳环)-C ^cltl稀径-、-C 3_C8-杂环_、-C1-Cltl-條径-(C3-C 8杂环)-、-(C 3_C8杂环)-C ^Cici條径-、-(CH2CH2O) r_ 和-(CH2CH2O) r-CH2-,并且r为1至10的整数。 Representative of these embodiments the stent units and (lib) in square brackets is described in the general formula (Ha), wherein, A -, - W -, - Y -, - D, w and y are as defined above, and R 1 is selected from: -C ^ Cltl article diameter _, - C3-C8- carbocyclic (C1-C8;) ^ yl) -, - arylene -, - C ^ Cltl strip path - arylene -, - arylene -C1-Cltl- dilute diameter -, - C 1-Cltl- dilute diameter - (C3-C8 carbocycle) -, - (C 3_C8 carbocycle) -C ^ cltl dilute diameter -, - C 3_C8- heterocycle _, - C1-Cltl- strip path - (C3-C 8 heterocycle) -, - (C 3_C8 heterocyclyl) -C ^ Cici strip path -, - (CH2CH2O) r_ and - (CH2CH2O) r-CH2 -, and r is an integer from 1 to 10.

[0245] [0245]

Figure CN104861063AD00571

[0246] 示例性的支架单元为R1为-(CH2)5-时的通式(IIa)的支架单元: Holder unit formula (IIa) when (CH2) 5- - [0246] An exemplary stent unit R1 is:

[0247] [0247]

Figure CN104861063AD00572

[0248] 另一示例性的支架单元为R1为-(CH2CH2O) r-CH2-并且r为2时的通式(IIa)的支架单元: [0248] Another exemplary cradle unit R1 is - (CH2CH2O) r-CH2- and r is the formula (IIa) 2 when the holder unit:

[0249] [0249]

Figure CN104861063AD00573

[0250] 另一示例性的支架单元为R1为-(CH2)5-时的通式(IIb)的支架单元: Formula (lib) when the holder unit (CH2) 5- - [0250] Another exemplary cradle unit R1 is:

[0251] [0251]

Figure CN104861063AD00574

[0252] 在一些其他具体实施方式中,支架单元通过抗体单元的硫原子和支架单元的硫原子之间的二硫键连接至抗体单元(A)。 [0252] In some other embodiments, the antibody unit is connected to the bracket unit (A) via a disulfide bond between a sulfur atom and a sulfur atom of the Antibody unit holder unit. 本实施方式的代表性的支架单元在通式(III)的方括号中描述,其中,R 1、A-、-W-、-Y-、-D、w和y是如上所定义的。 Representative of the bracket unit according to the embodiment in square brackets of formula (III) are described, wherein, R 1, A -, - W -, - Y -, - D, w and y are as defined above.

[0253] A-fS-Ri-C(0)_JWw-'Y^-D (in ) [0253] A-fS-Ri-C (0) _JWw-'Y ^ -D (in)

[0254] 在其他具体实施方式中,支架的反应性基团包含可与抗体的氨基基团反应的反应位点。 [0254] In other embodiments, the reactive group of the scaffold comprises a reaction site of the amino groups with reactive antibodies. 氨基基团可为精氨酸或赖氨酸。 Amino group may be arginine or lysine. 合适的胺反应位点包括但不限于:活化的酯(例如, 琥珀酰亚胺酯、4-硝基苯基酯、五氟代苯基酯),酸酐、酰氯、磺酰氯、异氰酸酯和异硫氰酸酯。 Suitable amine reactive sites include, but are not limited to: activated ester (e.g., succinimide ester, 4-nitrophenyl, pentafluorophenyl ester), acid anhydride, acid chloride, sulfonyl chloride, isocyanate and isothiourea diisocyanate. 这些实施方式的代表性的支架单元在通式(IVa)和(IVb)的方括号中描述,其中,R1、 A-、-W-、-Y-、-D、w和y为如上所述的。 Representative of these embodiments the stent units and (IVb) described in square brackets in formula (IVa), wherein, R1, A -, - W -, - Y -, - D, w and y are as described above of.

[0255] [0255]

Figure CN104861063AD00581

[0256] 另一方面,支架的反应性官能团包含与可存在于抗体上的修饰的碳水化合物基团反应的反应位点。 [0256] On the other hand, the reactive functional group of the scaffold comprises a reaction site reactive with carbohydrate groups may be present in the modified antibody. 在一些实施方式中,抗体通过酶的方式被糖基化,从而生成碳水化合物基团。 In some embodiments, the antibody by way of an enzyme is glycosylated, thereby generating carbohydrate groups. 碳水化合物可被诸如高碘酸钠之类的试剂温和地氧化,得到的氧化的碳水化合物的羰基单元可与含有诸如酰肼、肟、反应性胺、肼、硫代氨基脲、肼羧酸酯和芳基酰肼(例如Kaneko等人,1991,Bioconjugate Chem2:133-41中所描述的那些)之类的官能团的支架缩合。 Carbohydrate can be mildly oxidized reagent such as sodium periodate and the like, oxidized carbohydrate carbonyl units obtained may contain as a hydrazide, an oxime, a reactive amine, hydrazine, thiosemicarbazone, hydrazine carboxylate and aryl hydrazide (e.g. Kaneko et al, 1991, Bioconjugate Chem2: those described 133-41) condensing functional groups stent or the like. 本实施方式的代表性的支架单元在通式(Va)至(Vc)的方括号中描述,其中,R 1、 A-、-W-、-Y-、-D、w和y为如上所述的。 Representative of the bracket unit according to the embodiment in square brackets of formula (Va) to (Vc) are described, wherein, R 1, A -, - W -, - Y -, - D, w and y are as above described later.

[0257] [0257]

Figure CN104861063AD00582

[0258] 氨基酸单元 [0258] Amino Acid unit

[0259] 如果间隔单元存在的话,氨基酸单元(-W-)将支架单元(-T-)连接至间隔单元(-Y-),如果间隔单元不存在的话,氨基酸单元将支架单元连接至细胞毒性剂或细胞抑制剂(活化部分,D)。 [0259] If a Spacer unit is present, the amino acid unit (-W-) the holder unit (the -T-) to the Spacer unit is connected (-Y-), if the spacer unit is absent, then the amino acid unit is connected to the bracket unit cytotoxicity or cytostatic agent (activating moiety, D). -Ww-为二肽、三肽、四肽、五肽、六肽、七肽、八肽、九肽、十肽、^^一肽或十二肽单元。 -Ww- dipeptide, tripeptide, tetrapeptide, pentapeptide, hexapeptide, heptapeptide, octapeptide, a nonapeptide, decapeptide, ^^ a peptide or dodecapeptide unit. 每个-W-单元独立地具有如下方括号中所述的通式,并且w为2至12的整数。 Each -W- unit independently has the formula below in the square brackets, and w is an integer from 2 to 12.

[0260] [0260]

Figure CN104861063AD00583

[0261] 其中,R2为氢、甲基、异丙基、异丁基、仲丁基、苄基、对羟基苄基、一CH20H、一CH(0H)CH3> -CH2CH2SCH3> -CH2CONH2, -CH2COOH, -CH2CH2CONH2, -CH2CH2COOH,- (CH2) 3NHC ( = NH) NH2, - (CH2) 3NH2, - (CH2) 3NHCOCH3, - (CH2) 3NHCHO, - (CH2) 4NHC ( = NH) NH2,一(CH2)4NH2、一(CH 2)4NHCOCh3、一(CH2)4NHCHO、一(CH 2)3NHCONh2、一(CH2)4NHCONh 2、一CH2CH2CH (OH) CH2NH2、2-吡啶基甲基-、3-吡啶基甲基-、4-吡啶基甲基-、苯基、环己基、 [0261] wherein, R2 is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, benzyl, p-hydroxybenzyl group, a CH20H, a CH (0H) CH3> -CH2CH2SCH3> -CH2CONH2, -CH2COOH , -CH2CH2CONH2, -CH2CH2COOH, - (CH2) 3NHC (= NH) NH2, - (CH2) 3NH2, - (CH2) 3NHCOCH3, - (CH2) 3NHCHO, - (CH2) 4NHC (= NH) NH2, a (the CH2 ) 4NH2, a (CH 2) 4NHCOCh3, a (CH2) 4NHCHO, a (CH 2) 3NHCONh2, a (CH2) 4NHCONh 2, a CH2CH2CH (OH) CH2NH2,2- pyridylmethyl -, 3-pyridylmethyl yl -, 4-pyridylmethyl -, phenyl, cyclohexyl group,

Figure CN104861063AD00591

[0262] 连接体单元的氨基酸单元可通过酶(包括但不限于:肿瘤相关蛋白酶)的方式被酶裂解,从而释放出活化部分(-D),释放后该活化部分在体内被质子化,从而产生活化分子(D) 0 [0262] Amino Acid unit can be connected by an enzyme unit (including but not limited to: tumor-associated protease) enzymatic cleavage manner to release the activating moiety (-D), the activating moiety is protonated in vivo upon release to generating activation molecule (D) 0

[0263] 示例性的Ww单元由通式(VI)至(VIII)表示: [0263] Exemplary Ww unit represented by the formula (VI) to (VIII):

[0264] [0264]

Figure CN104861063AD00592

[0265] 其中,R3和R 4如下表所示: [0265] wherein, R3 and R 4 in the following table:

[0266] [0266]

Figure CN104861063AD00601

[0271] 其中,R3、R4、R5和R 6如下表所示: [0271] wherein, R3, R4, R5 and R 6 in the following table:

[0272] [0272]

Figure CN104861063AD00611

[0273] 合适的氨基酸单元包括但不限于:通式(VI)单元,其中,R3为苄基,R 4 为-(CH2) 4NH2, R3为异丙基并且R4为-(CH 2) 4NH2,或者R3为异丙基并且R4为-(CH 2) 3NHC0NH2。 [0273] Suitable amino acid units include, but are not limited to: formula (VI) unit, wherein, R3 is benzyl, R 4 is - (CH2) 4NH2, R3 is isopropyl and R4 is - (CH 2) 4NH2, or R3 is isopropyl and R4 is - (CH 2) 3NHC0NH2. 另一合适的氨基酸单元为通式(VII)单元,其中,R3为苄基、R 4为苄基并且R5 为-(CH2)4NH2。 Another suitable amino acid unit of formula (VII) unit, wherein, R3 is benzyl, R 4 is benzyl and R5 is - (CH2) 4NH2. -Ww-单元可在其选择性方面被设计并优化为通过特定的肿瘤相关蛋白酶进行酶裂解。 -Ww- units can be designed and optimized for enzymatic cleavage by a particular tumor-associated protease in their selectivity. 合适的-Ww-单元为那些通过蛋白酶(组织蛋白酶B、组织蛋白酶C和组织蛋白酶D)以及纤溶酶催化其裂解的单元。 Suitable -Ww- units are those units by a protease (cathepsin B, cathepsin C and cathepsin D), and catalyze the cleavage of plasmin.

[0274] -些实施方式中,-Ww-为二肽、三肽或四肽单元。 [0274] - some embodiment, -Ww- is a dipeptide, tripeptide or tetrapeptide unit.

[0275] 在妒、1?3、1?4、1?5或1? 6不为氢的条件下,1?2、1?3、1?4、1?5或1? 6所连接的碳原子为手性的。 [0275] In jealous, 1? 3,1? 4,1? 5 or 1? 6 is not hydrogen under the conditions of 1? 2,1? 3,1? 4,1? 5 or 1? 6 is connected carbon is chiral. 与R2、R3、R4、R 5或R6连接的每个碳原子独立地为(S)构型或(R)构型。 And R2, R3, R4, R 5 or each of the carbon atoms of R6 is independently connected to the (S) configuration or (R) configuration.

[0276] 在一些实施方式中,氨基酸单元为苯基丙氨酸-赖氨酸二肽(Phe-Lys或FK连接体)。 [0276] In some embodiments, the amino acid unit is a phenylalanine - lysine dipeptide (Phe-Lys or FK linker). 在一些实施方式中,氨基酸单元为缬氨酸-瓜氨酸二肽(Val-Cit或VC连接体)。 In some embodiments, the amino acid unit is a valine - citrulline dipeptide (Val-Cit or VC linker). 在一些实施方式中,氨基酸单元为5-氨基戊酸、均苯基丙氨酸赖氨酸、四异喹啉羧酸酯赖氨酸、 环己基丙氨酸赖氨酸、异哌啶酸(ison印ecotic acid)赖氨酸、β-丙氨酸赖氨酸、甘氨酸丝氨酸缬氨酸谷酰胺或异哌啶酸。 In some embodiments, the amino acid unit is a 5-amino acid, phenylalanine lysine are four isoquinoline carboxylate lysine, cyclohexylalanine lysine, isonipecotic acid ( ison printing ecotic acid) lysine, [beta] alanine lysine, glycine serine valine glutamine or isonipecotic acid.

[0277] 氨基酸单元可包含天然氨基酸。 [0277] Amino Acid unit can comprise natural amino acids. 在其他实施方式中,氨基酸单元可包含非天然氨基酸。 In other embodiments, the amino acid unit may comprise an unnatural amino acid.

[0278] 间隔单元 [0278] spacer means

[0279] 当存在间隔单元(-Υ-)时,该间隔单元将氨基酸单元连接至药物单元。 [0279] When there is a separation unit (-Υ-), the spacer amino acid unit to the drug unit is connected unit. 间隔单元为两个大类:自切除的(self-immolative)和非自切除的。 Spacer unit is a two broad categories: self excised (self-immolative) and removal of non-self. 非自切除的间隔单元为在TM-连接体-AM偶联物或药物连接体化合物中的氨基酸单元酶裂解之后间隔单元的一部分或全部仍然连接于活化部分单元的间隔单元。 Spacer unit cell after an interval of a non self-immolative linker drug conjugate or -AM compound TM- amino acid units connected cleavage remain attached to part or all of the Spacer unit cell activating part. 非自切除间隔单元的实例包括但不限于:(甘氨酸-甘氨酸)间隔单元和甘氨酸间隔单元。 Non self-immolative Spacer unit include, but are not limited to :( Gly - glycine) spacer unit and a glycine spacer unit. 当含有甘氨酸-甘氨酸间隔单元或甘氨酸间隔单元的TM-连接体-AM偶联物通过肿瘤细胞相关蛋白酶、癌细胞相关蛋白酶或淋巴细胞相关蛋白酶发生酶裂解时,甘氨酸-甘氨酸-药物部分或甘氨酸-药物部分从AT-Ww-中裂解出来。 When containing Gly - glycine Spacer unit or a glycine spacer TM- -AM linker conjugate by tumor cell associated protease, a cancer-associated protease or a lymphocyte-associated protease enzymatic cleavage, Gly - glycine - drug moiety or a glycine - drug moiety split off from AT-Ww-. 为了释放出AM,应当在靶细胞中进行独立的水解反应,从而使甘氨酸-药物单元化学键裂解。 To release the AM, an independent hydrolysis reaction should be carried out in a target cell, such that glycine - a bond cleavable Drug unit.

[0280] 在典型的实施方式中,-Yy-为可被Qm取代的对氨基苄基醚,其中,Q为-C1-QJI 基,-C1-C8;)^氧基、-卤素、-硝基或-氛基,并且m为0至4的整数。 [0280] In a typical embodiment, -Yy- which may be substituted with Qm p-aminobenzyl ether, wherein, Q is -C1-QJI group, -C1-C8;) ^ alkoxy, - halogen, - nitro or - atmosphere group, and m is an integer from 0 to 4.

[0281] 在一些实施方式中,非自切除间隔单元(-Y-)为-Gly-Gly-。 [0281] In some embodiments, a non self-immolative Spacer unit (-Y-) is -Gly-Gly-.

[0282] 在一些实施方式中,非自切除间隔单元(-Y-)为-Gly-。 [0282] In some embodiments, a non self-immolative Spacer unit (-Y-) is -Gly-.

[0283] 在一种实施方式中,AM-连接体化合物或TM-连接体-AM偶联物缺乏间隔单元(y=〇)° [0283] In one embodiment, AM- TM- linker compound or linker conjugate -AM lack spacer unit (y = square) °

[0284] 可选地,含有自切除间隔单元的TM-连接体-AM偶联物可释放AM(D),无需单独的水解步骤。 [0284] Alternatively, containing a self-immolative Spacer unit TM- -AM linker conjugate releasably AM (D), without a separate hydrolysis step. 在这些实施方式中,-Y-为对氨基苄基醇(PAB)单元,该对氨基苄基醇(PAB)单元通过PAB基团的氮原子与-Ww-连接并且通过碳酸醋基团、氨基甲酸醋基团或醚基团直接连接于-D。 In these embodiments, -Y- is a p-aminobenzyl alcohol (PAB) unit, the p-aminobenzyl alcohol (PAB) unit via a nitrogen atom of the PAB group, and connected by a -Ww- vinegar carbonate group, an amino group vinegar acid group or ether group is attached directly to -D.

[0285] 自切除间隔单元的其他实例包括但不限于:与PAB基团电子等价的芳香族化合物,例如,2-氨基咪唑基-5-甲醇衍生物(参见例如,Hay等人,1999,Bioorg.Med. Chem. Lett. 9:2237)和邻位或对位-氨基苄基缩醛。 [0285] Other examples of self-immolative spacer units include, but are not limited to: the electronic equivalent of the PAB group and an aromatic compound, e.g., 2-amino-imidazole-5-methanol derivatives (see, e.g., Hay et al, 1999, Bioorg.Med Chem Lett 9:... 2237) and ortho or para - aminobenzyl acetal. 可使用酰胺键水解后易于发生环化的间隔单元,例如,取代和未取代的4-氨基丁酸酰胺(Rodrigues等人,1995, Chemistry Biology2:223),适当取代的双环[2·2· 1]和双环[2.2.2]环系统(Storm等人,1972,工Amer. Chem. Soc. 94:5815)以及2-氨基苯基丙酸酰胺(Amsberry 等人,1990,]\0找· Chem. 55:5867)。 Spacer unit can readily cyclized after using amide bond hydrolysis, e.g., substituted and unsubstituted 4-aminobutyric acid amides (Rodrigues et al., 1995, Chemistry Biology2: 223), appropriately substituted bicyclo [2 · 2 · 1 ] and bicyclo [2.2.2] ring systems (Storm et al., 1972, workers Amer Chem Soc 94:... 5815) and 2-amino-phenylpropionic acid amides (Amsberry et al., 1990] \ 0 · Chem find 55: 5867). 甘氨酸的α -位被取代的含胺药物的消除(Kingsbury等人,1984, J. Med Chem. 27:1447)也是自切除间隔单元的策略的实例,该策略可用于TM-连接体-AM偶联物。 Glycine α - position is substituted with an amine-containing drug elimination (Kingsbury et al., 1984, J. Med Chem 27: 1447.) Are examples of self-immolative spacer unit policy, the policy can be used even TM- linker -AM linked product.

[0286] 在可选的实施方式中,间隔单元为支链双(羟甲基)苯乙烯(BHMS)单元,其可用于合并多个部分。 [0286] In an alternative embodiment, the spacer unit is a branched bis (hydroxymethyl) styrene (BHMS) unit, which can be used to combine a plurality of portions.

[0287] 典型的间隔单元(-Yy-)由通式(IX)- (XI)表示: [0287] Typical spacer units (-Yy-) by the general formula (IX) - represented by (XI):

[0288] [0288]

Figure CN104861063AD00621

[0289] 其中,Q为C1-C8烷基、C ^C8烷氧基、卤素、硝基或氰基,并且m为0至4的整数。 [0289] wherein, Q is C1-C8 alkyl, C ^ C8 alkoxy, halogen, nitro or cyano, and m is an integer from 0 to 4.

[0290] [0290]

Figure CN104861063AD00622

[0291] 在一些实施方式中,连接体为酶可裂解的。 [0291] In some embodiments, the linker is enzymatically cleavable. 在一些实施方式中,连接体不为酶可裂解的。 In some embodiments, the linker is not cleavable enzymes.

[0292] 在一些实施方式中,所述连接体由下述通式(III)的结构表示: [0292] In some embodiments, the linker represented by the following structural formula (III) is:

[0293] 其中,L由通式(II)的结构表示: [0293] wherein, L represents by the general formula (II) is:

[0294] [0294]

Figure CN104861063AD00623

[0295] m为1,2,3,4,5或6,b分别独立地为0或1,并且D由下述通式(III)的结构独立地表示: [0295] m is 1,2,3,4,5 or 6, b are independently 0 or 1, and D is independently represented by the following structural formula (III) is:

[0296] [0296]

Figure CN104861063AD00631

[0297] 其中,i分别独立地为0或I ; [0297] where, i are independently 0 or I;

[0298] j分别独立地为0,1,2,3,4,5或6 ; [0298] j are independently 0,1,2,3,4,5 or 6;

[0299] A分别独立地为S,0或N-Ra,其中,Ra为氢,烷基,烯基或烷氧基; [0299] A is independently S, 0 or N-Ra, wherein, Ra of the hydrogen, alkyl, alkenyl or alkoxy;

[0300] B分别独立地为烷基,條基,一O-烷基一,一烷基-0 -,一S-烷基一,一烷基-S-, 芳基,杂芳基,杂环基或肽,它们中的每一个被一个或一个以上选自下列基团的取代基任选地取代:羟基,烷氧基,烷基,烯基,炔基,环烷基,一烷基-芳基,一烷基-杂芳基,一烷基-杂环基,一O-R4,一〇_ 烷基-Rp -C(O) -R4^ 一C (0) -O-R4,一S-R4,一S (0) 2-R4, 一NHR4,一NH -烷基-R4,卤素,一CN,一NO2,和-SH,其中,R4为烷基,烯基,一烷基-羟基,芳基,杂芳基, 杂环基或卤代烷基。 [0300] B is independently an alkyl group, article group, an O- alkyl mono, monoalkylamino -0--, a S- group a, a group -S-, aryl, heteroaryl, heteroaryl group or a cyclic peptide, each of them with one or more groups selected from substituent group is optionally substituted with: hydroxy, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, monoalkylamino - an aryl group, an alkyl - aryl, heteroaryl, a group - a heterocyclic group, a O-R4, an alkyl 〇_ -Rp -C (O) -R4 ^ a C (0) -O-R4, a S-R4, a S (0) 2-R4, a NHR4, an NH - group -R4, halogen, a CN, an NO2, and -SH, wherein, R4 is an alkyl group, an alkenyl group, an alkyl group - hydroxy, aryl, heteroaryl, heterocyclyl or haloalkyl.

[0301] 在一些实施方式中,所述连接体由下述通式(V)至通式(VII)的结构表示: [0301] In some embodiments, the linker represented by the following structural formula (V) to formula (VII) is represented by:

Figure CN104861063AD00632

[0304] A,B,i和j为上面所定义的。 [0304] A, B, i and j are as defined above.

[0305] 在一些实施方式中,连接体选自:31,52,53,54,55,56,57,-617-?1^-1^11-617-,-Ala-Leu-Ala-Leu-, -Phe-Arg-,-Phe-Lys-,-Val-Lys-, -Val-Ala-,或Val-Cit-,其中,Sl 至S7由下述结构表示: [0305] In some embodiments, the linker is selected from:? 31,52,53,54,55,56,57, -617- 1 ^ ^ 11-617 -1 -, - Ala-Leu-Ala-Leu -, -Phe-Arg -, - Phe-Lys -, - Val-Lys-, -Val-Ala-, or Val-Cit-, wherein, Sl to S7 represented by the following structure:

Figure CN104861063AD00641

Figure CN104861063AD00651

[0308] 其中,m分别独立地为1至20。 [0308] wherein, m are each independently 1 to 20. 优选地,m为1至3,1至5,1至10或2至5。 Preferably, m is 1 to 3, 1 to 5, 1 to 10 or 2 to 5.

[0309] 因此,本发明提供一种通式(Ia)的化合物,其中,TM是抗-HER2抗体;L选自: SI,S2, S3, S4, S5, S6, S7, - Gly-Phe-Leu-Gly-,-Ala-Leu-Ala-Leu-,-Phe-Arg-,-Phe-Lys -,-Val-Lys-,-Val-Ala-,或Val-Cit-;AM是通式(I)的化合物。 [0309] Accordingly, the present invention provides a formula (Ia) compound where, TM is an anti-antibody -HER2; L is selected from: SI, S2, S3, S4, S5, S6, S7, - Gly-Phe- Leu-Gly -, - Ala-Leu-Ala-Leu -, - Phe-Arg -, - Phe-Lys -, - Val-Lys -, - Val-Ala-, or Val-Cit-; AM is the formula ( compound I). 在一种实施方式中,TM 是曲妥珠单抗(赫赛汀),帕妥珠单抗或margetuximab (MGAH22) ;AM是选自表1的化合物, 其中,喹啉环上的胺基团是与连接体连接的点。 In one embodiment, TM is trastuzumab (Herceptin), pertuzumab or margetuximab (MGAH22); AM is a compound selected from Table 1, wherein the amine group on the quinoline ring is the point of attachment to the linker. 在另一实施方式中,TM是曲妥珠单抗(赫赛汀),帕妥珠单抗或margetuximab (MGAH22) ;L是Sl,S2或S3 ;AM是选自表1的化合物,其中,喹啉环上的胺基团是与连接体连接的点。 In another embodiment, TM is trastuzumab (Herceptin), pertuzumab or margetuximab (MGAH22); L is Sl, S2 or S3; AM is a compound selected from Table 1, wherein a quinoline ring group is the point of attachment to the amine linker. 在又一实施方式中,TM是曲妥珠单抗(赫赛汀);L是Sl,S2或S3 ;AM是瑞喹莫德或咪喹莫特,其中,喹啉环上的胺基团是与连接体连接的点。 In another embodiment, TM is trastuzumab (Herceptin); L is Sl, S2 or S3; AM is resiquimod or imiquimod, wherein the amine group on the quinoline ring is the point of attachment to the linker.

[0310] 在另一实施方式中,本发明的化合物由下述通式A至通式C的结构表示: [0310] In another embodiment, the compounds of the invention represented by the following general structures A to C of the general formula:

Figure CN104861063AD00661

[0312] 在通式A至通式C的一种实施方式中,抗-HER2抗体是曲妥珠单抗(赫赛汀),帕妥珠单抗或margetuximab (MGAH22);通式(I)的化合物选自表1,其中,喹啉环上的胺基团是与连接体连接的点。 [0312] In Formula A Formula C to one embodiment, the antibody is an anti--HER2 trastuzumab (Herceptin), pertuzumab or margetuximab (MGAH22); formula (I) compound selected from table 1, wherein the amine group on the quinoline ring is a point of attachment to the linker. 在通式A至通式C的另一实施方式中,抗-HER2抗体是曲妥珠单抗(赫赛汀),帕妥珠单抗或margetuximab (MGAH22);通式(I)的化合物是瑞喹莫德或咪喹莫特,其中,喹啉环上的胺基团是与连接体连接的点。 In another embodiment of Formula A to Formula C, the anti -HER2 antibody is trastuzumab (Herceptin), pertuzumab or margetuximab (MGAH22); a compound of formula (I) is resiquimod or imiquimod, wherein the amine group on the quinoline ring is a point of attachment to the linker. 在通式A至通式C的又一实施方式中, 抗-HER2抗体是曲妥珠单抗(赫赛汀);AM是瑞喹莫德或咪喹莫特,其中,喹啉环上的胺基团是与连接体连接的点。 In another embodiment of Formula A to Formula C, the anti -HER2 antibody is trastuzumab (Herceptin); AM is resiquimod or imiquimod, wherein, on the quinoline ring amine group is the point of attachment to the linker.

[0313] 化合物的制各 [0313] Each prepared compound

[0314] 总体而言,通式(I)的结构表示的活化部分可使用下列列出的合成步骤制备。 [0314] In general, activated partial structure of formula (I) is represented by the following can be prepared using the synthetic steps outlined. 在步骤(1)中,通式A的4-氯代-3-硝基喹啉与通式R 1NH2的胺反应生成通式B的3-硝基喹啉-4-胺。 In step (1), the amine reaction of 4-chloro-3-nitroquinoline of Formula A of the general formula R 1NH2 produce 3-nitro-quinolin-4-amine of Formula B. 在步骤2中,通式B的3-硝基喹啉-4-胺被还原,从而生成通式C的喹啉-3-4-二胺。 In step 2, 3-nitro-quinolin-4-amine of general formula B is reduced, thereby generating a quinoline of general formula C -3-4- diamine. 在步骤3中,通式C的喹啉-3-4-二胺与羧酸或其等同物反应,生成通式D的IH-咪唑并[4, 5c]喹啉。 In Step 3, diamines and quinoline carboxylic -3-4- general formula C, or equivalent thereof, to generate formula IH- imidazole and D [4, 5c] quinoline.

[0315] [0315]

Figure CN104861063AD00671

[0316] 可选地,通式(I)的化合物可根据US6, 331,539B1, US6, 451,810B1, US7, 157, 452 和US7, 301027B2中所述的合成方法制备。 [0316] Alternatively, compounds of formula (I) may be prepared 331,539B1 451,810B1 US7 157 US6,, US6,,,, 452 and US7, 301027B2 in the synthesis method.

[0317] 另一方面,通式(Ia)的化合物可通过使用连接体以连接靶向部分和活化部分这两者来制备。 [0317] On the other hand, the compound of formula (Ia) may be prepared by using a linker to connect to prepare both the targeting moiety and the activated portion. 所述连接体使用其反应位点与靶向部分和活化部分结合。 The reaction using the linker binding site of the targeting moiety and the activated portion. 在一些实施方式中, 所述结合通过在连接体与靶向部分和活化部分之间形成共价键进行。 In some embodiments, the binding is formed by a covalent bond between the linker and targeting moiety and the activated part. 在一些实施方式中, 所述反应位点为亲核基团。 In some embodiments, the reaction site is a nucleophilic group. 在一些实施方式中,所述反应位点为亲电基团。 In some embodiments, the reaction site is an electrophilic group. 连接体中有用的亲核基团包括但不限于:酰肼基团、肟基团、氨基基团、肼基团、缩氨基硫脲基团、肼羧酸酯基团和芳基酰肼基团。 Linker useful nucleophilic groups include, but are not limited to: a hydrazide group, oxime group, amino group, hydrazino group, a group thiosemicarbazone, hydrazine carboxylate groups and aryl groups hydrazide group. 有用的亲电基团包括但不限于:马来酰亚胺基团、碳酸酯基团和卤代乙酰胺基团。 Useful electrophilic groups include, but are not limited to: a maleimide group, a carbonate group, and haloacetamide groups.

[0318] 药物剂塑和给药方式 [0318] Drug administration and plasticizing agent

[0319] 本发明还涉及药物组合物,所述药物组合物包含本发明的化合物或其药学上可接受的盐,以及一种或一种以上药学上可接受的载体。 [0319] The present invention further relates to pharmaceutical compositions, a compound comprising the pharmaceutical composition of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable one or more carriers.

[0320] 本文所述的化合物(例如,其加成盐或水合物)以及药学上可接受的载体可使用多种不同的给药模式或途径递送至患者。 [0320] The compounds described herein (e.g., an addition salt or hydrate thereof) and a pharmaceutically acceptable carrier may use a variety of different modes or routes of administration delivered to the patient. 合适的给药途径包括但不限于:吸入给药、透皮给药、口服给药、直肠给药、透过粘膜给药、肠道给药和肠胃外给药(包括肌肉内、皮下和静脉注射)。 Suitable routes of administration include but are not limited to: inhalation, transdermal, oral, rectal, transmucosal administration, parenteral administration and parenteral (including intramuscular, subcutaneous and intravenous injection). 优选地,包含作为靶向部分的抗体或抗体片段的本发明的化合物以肠胃外的方式给药,更优选地,以静脉注射方式给药。 Preferably, a compound comprising a targeting moiety of the antibody or antibody fragment of the present invention in a manner parenterally administered, more preferably, administered intravenously.

[0321] 本文使用的术语"给药"意在包括直接和间接地将化合物递送至期望的作用位点的所有方式。 [0321] As used herein, the term "administration" is intended to include all direct and indirect manner deliver the compound to the desired site of action.

[0322] 本文所述的化合物或其药学上可接受的盐和/或其水合物可单独给药,与本发明的其他化合物联合给药和/或与其他治疗剂联合以混合剂的形式给药。 [0322] The compound described herein, or a pharmaceutically acceptable salt and / or hydrate thereof can be administered alone, with other compounds of the present invention are administered in combination and / or with other therapeutic agents in the form of a mixture of medicine. 当然,对可与本发明的化合物联合给药的治疗剂的选择部分取决于治疗中的病症。 Of course, the selection portion of the therapeutic agent can be administered in combination with the compounds of the present invention depends on the treatment conditions.

[0323] 例如,当向患有由依赖于自诱导物的生物体引起的疾病病症的患者给药时,本发明的化合物可以混合剂的形式给药,所述混合剂含有用于治疗疼痛、感染和其他症状以及通常与疾病有关的副作用的药剂。 [0323] For example, when administered to a patient having a disease condition caused by an organism depends on the autoinducer, the compounds of the present invention may be administered in the form of a mixture, the mixture comprising for the treatment of pain, infection and other symptoms and side effects commonly associated with drug-related diseases. 这些药剂包括例如,镇痛剂、抗生素,等等。 These agents include, for example, analgesics, antibiotics, and the like.

[0324] 当向正在进行癌症治疗的患者给药时,化合物可以混合剂的形式给药,所述混合剂包含抗癌剂和/或补充增效剂。 [0324] When administered to a patient being treated for cancer, the compounds may be administered in the form of a mixture, said mixture comprising an anticancer agent and / or a supplementary builder. 所述化合物还可以含有治疗放疗的副作用的药剂的混合剂的形式给药,所述治疗放疗的副作用的药剂例如,止吐药,防辐射剂,等等。 Administered in the form of the mixture may also contain compounds radiotherapy side effects of the agent, the agent radiotherapy side effects, for example, anti-emetics, radiation protection agent, and the like.

[0325] 可与本发明的化合物联合给药的补充增效剂包括例如,三环类抗抑郁药(例如,米帕明(imipramine)、地昔帕明(desipramine)、阿米替林(amitriptyline)、氯米帕明(clomipramine)、曲米帕明(trimipramine)、多塞平(doxepin)、去甲替林(nortriptyline)、普罗替林(protriptyline)、阿莫沙平(amoxapine)和马普替林(maprotiline)),非三环类抗抑郁药(例如,舍曲林(sertraline)、曲挫酮(trazodone) 和西酞普兰(citalopram)),Ca2+诘抗剂(例如,维拉帕米(verapamil)、硝苯地平(nifedipine)、尼群地平(nitrendipine)和卡罗维林(caroverine)),两性霉素,三苯乙醇类似物(例如,它莫昔芬(〖3111(^1^11)),抗心律失常药物(例如,奎尼丁(911;[111(1;[116)),抗高血压药物(例如,利血平(reserpine)),硫醇消耗物(例如,丁硫氨酸和亚砜亚胺)以及甲酰四氢叶酸钙。 [0325] synergist may be added with the compounds of the present invention is administered in combination include, for example, tricyclic antidepressants (e.g., imipramine (imipramine), desipramine (of desipramine), amitriptyline (amitriptyline ), clomipramine (clomipramine), trimipramine (trimipramine), doxepin (doxepin), nortriptyline (nortriptyline), protriptyline (protriptyline), amoxapine (amoxapine) and the Max-Planck nortriptyline (maprotiline)), non-tricyclic antidepressants (e.g., sertraline (sertraline), frustrated one song (trazodone) and citalopram (citalopram)), Ca2 + interrogate antagonist (e.g., verapamil (verapamil), nifedipine (nifedipine), nitrendipine (nitrendipine) and caroverine (caroverine)), amphotericin, triphenyl ethanol analogues (e.g., tamoxifen (3111 〖(^ 1 ^ 11) ), antiarrhythmic drugs (e.g., quinidine (911; [111 (1; [116)), antihypertensive drugs (e.g., reserpine (reserpine to)), thiol was consumed (e.g., ammonia-butylthio acid and sulfoximine) and calcium folinate.

[0326] 本发明的活性化合物以其自身的形式给药或者以药物组合物的形式给药,在所述药物组合物中,所述活性化合物与一种或一种以上药学上可接受的载体、赋形剂或稀释剂混合。 [0326] The active compounds according to the invention in the form of its own administration or administered in the form of a pharmaceutical composition, the pharmaceutical composition, the active compound together with one or one or more pharmaceutically acceptable carrier , excipient or diluent. 根据本发明使用的药物组合物通常使用一种或一种以上生理学可接受的载体以常规方式配制,所述生理学可接受的载体包含赋形剂和佐剂,所述生理学可接受的载体有利于将活性化合物加工成可在药学上使用的制剂。 The pharmaceutical compositions of the invention typically use either one or more physiologically acceptable carriers formulated in conventional manner, the physiologically acceptable carriers comprising excipients and adjuvants, said physiologically acceptable carriers facilitate active compounds into preparations which can be used pharmaceutically. 合适的剂型取决于所选择的给药途径。 Suitable dosage forms depending on the route of administration chosen.

[0327] 对于透过粘膜给药而言,在剂型中使用适于待穿透的屏障的渗透剂。 [0327] For penetrants, used in the barrier is adapted to be penetrated through transmucosal dosage forms for administration. 这些渗透剂通常为本领域已知的。 Such penetrants are generally known in the art.

[0328] 对于口服给药而言,化合物易于通过将活性化合物与本领域已知的药学上可接受的载体结合配制。 [0328] For oral administration, the compounds readily prepared by admixing the active compound known in the art in conjunction with a pharmaceutically acceptable carrier formulation. 这些载体能够使本发明的化合物配制成由待治疗的患者口服的片剂、药丸、糖衣药丸、胶囊、液体、凝胶、糖浆、浆状物和悬浮液。 Such carriers enable the compounds of the present invention is formulated for oral patient to be treated by the tablets, pills, dragees, capsules, liquids, gels, syrups, suspensions and syrup. 口服的药物制剂可通过如下方式获得:将固体赋形剂与活性剂化合物混合,任选地研磨得到的混合物,并对颗粒混合物进行加工,如果想要得到片剂或糖衣片芯的话,需要在该过程之前加入合适的佐剂。 Oral pharmaceutical formulations can be obtained by: mixing the active compound with a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, if desired to obtain tablets or dragee cores, the need in suitable adjuvants added before the procedure. 具体而言,合适的赋形剂为填充剂(例如,包括乳糖、蔗糖、甘露醇或山梨醇的糖),纤维素制剂(例如,玉米淀粉、小麦淀粉、大米淀粉、土豆淀粉、明胶、黄耆胶、甲基纤维素、羟丙基甲基纤维素、羧乙基纤维素钠)和/或聚乙烯吡咯烷酮(PVP)。 In particular, suitable excipients, fillers (e.g., including lactose, sucrose, mannitol, sorbitol, or sugars), cellulose preparations (e.g., maize starch, wheat starch, rice starch, potato starch, gelatin, gum Society gum, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxyethyl cellulose), and / or polyvinylpyrrolidone (PVP). 如果需要的话,可加入崩解剂,例如,交联的聚乙烯吡咯烷酮、琼脂或海藻酸或其盐(例如,海藻酸钠)。 If desired, disintegrating agents may be added, for example, crosslinked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof (e.g., sodium alginate).

[0329] 向糖衣片芯提供合适的包衣。 [0329] Suitable coatings to provide sugar-coated tablet core. 为了实现这个目的,可使用浓缩的糖溶液,该溶液可任选地含有阿拉伯树胶、滑石粉、聚乙烯吡咯烷酮、卡波姆凝胶、聚乙二醇和/或二氧化钛、 漆用溶液和合适的有机溶剂或溶剂混合物。 For this purpose, concentrated sugar solutions may be used, the solution may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvent or solvent mixture. 可将染料或颜料加至片剂或糖衣药丸包衣中, 用于识别或表征不同的活性化合物剂量组合。 Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0330] 可口服使用的药物制剂包括由明胶制成的推合式胶囊和由明胶和增塑剂(例如, 丙三醇或山梨糖醇)制成的软的密封的胶囊。 [0330] Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin and soft sealed by gelatin and a plasticizer (e.g., glycerol or sorbitol) made of capsules. 推合式胶囊可含有与诸如乳糖之类的填充剂、 诸如淀粉之类的粘合剂和/或诸如滑石粉或硬脂酸镁之类的润滑剂和任选地稳定剂混合的活性成分。 The push-fit capsules can contain fillers such as lactose, binders, such as starch and / or active ingredients, such as talc or magnesium stearate or the like lubricant, and optionally, stabilizers. 在软胶囊中,活性化合物可溶解于或悬浮于合适的液体中,例如,脂肪油、液体石蜡或液体聚乙二醇。 In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. 此外,可加入稳定剂。 In addition, stabilizers may be added. 用于口服给药的所有剂型的剂量应当适于这种给药方式。 All the dosage formulations for oral administration should be suitable for such administration.

[0331] 对于口腔给药而言,组合物可以通过常规方式配制的片剂或含片的形式给药。 [0331] For buccal administration, the compositions may be formulated administered in the form of tablets or lozenges in conventional manner by the.

[0332] 对于吸入给药而言,根据本发明使用的化合物便于通过使用合适的推进剂(例如, 二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其他合适的气体)以由加压包或喷雾器提供的喷雾的形式递送。 [0332] For administration by inhalation, the compounds for use according to the present invention facilitates using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas ) delivered in the form provided by the pressurized packs or a nebuliser spray. 在使用加压喷雾的情况下,剂量单位可通过提供递送计量的量的阀来确定。 In the case of a pressurized spray dosage unit may be determined by providing a valve to deliver a metered amount of. 在吸入器或吹入器中使用的胶囊和药筒(例如,明胶胶囊和药筒)可被配制为含有化合物和合适粉末基体(例如,乳糖或淀粉)的粉末混合物的剂型。 For use in an inhaler or insufflator Capsules and cartridges (e.g., capsules and cartridges of gelatin) may be formulated in a dosage form containing a powder mix of the compound and a suitable powder base (e.g., lactose or starch) a.

[0333] 化合物可被配制为通过注射(例如,快速注射或连续输注)方式肠胃外给药的剂型。 [0333] compounds may be formulated for administration by injection (e.g., continuous infusion or bolus injection) mode parenteral administration dosage forms. 注射为本发明的组合物的优选的给药方法。 The preferred method of administration by injection of the composition of the present invention. 用于注射的剂型可以带有添加的防腐剂的单位剂量形式提供,例如,以安瓶或多剂量容器的形式提供。 Dosage unit dosage form for injection may be provided with an added preservative, for example, provided in the form of ampoules or multi-dose containers. 组合物可采用诸如油性载体或水性载体中的悬浮液、溶液或乳液之类的形式并且可含有诸如悬浮剂、稳定剂和/或分散剂之类的调配剂(formulatory),并且可加入例如交联的聚乙稀吡略烧酮、琼脂或海藻酸或其盐(例如,海藻酸钠)。 The compositions may take such forms as aqueous or oily carrier vehicle suspensions, solutions or emulsions or the like and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents and the like (formulatory), and may be added, such as cross slightly burnt pyrazol-linked polyethylene, agar, or alginic acid or a salt thereof (e.g., sodium alginate).

[0334] 用于肠胃外给药的药物剂型包括水溶性形式的活性化合物的水溶液。 [0334] The pharmaceutical dosage form for parenteral administration include aqueous solutions of the active compounds in water-soluble form. 此外,活性化合物的悬浮液可制备成合适的油性注射悬浮液。 Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. 合适的亲脂性溶剂或载体包括脂肪油(例如,芝麻油)或合成的脂肪酸酯(例如,油酸乙酯或甘油三酯)或脂质体。 Suitable lipophilic solvents or vehicles include fatty oils (e.g., sesame oil), or synthetic fatty acid esters (e.g., ethyl oleate or triglycerides) or liposomes. 水性注射悬浮液可包含如下物质:该物质增加悬浮液的粘度,例如,羧甲基纤维素钠、山梨糖醇或葡聚糖。 Aqueous injection suspensions may contain the following materials: substances which increase the viscosity of the suspension, for example, sodium carboxymethyl cellulose, sorbitol, or dextran. 任选地,悬浮液还可含有合适的稳定剂或药剂,该稳定剂或药剂增加化合物的溶解度,从而制备高度浓缩的溶液。 Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of an agent or stabilizer compounds to the preparation of highly concentrated solutions. 对于注射而言,本发明的药剂可被配制成水性溶液,优选地配制成生理相容性缓冲液(例如,Hanks溶液、林格氏溶液或生理盐水缓冲液)。 For injection, the agents of the invention may be formulated into aqueous solutions, preferably formulated as a physiologically compatible buffer (e.g., as Hanks solution, Ringer's solution, or physiological saline buffer).

[0335] 可选地,活性成分可为使用前溶解于合适的载体中的粉末形式,所述合适的载体例如,无菌无热原水。 [0335] Alternatively, the active ingredient may be in powder form prior to use is dissolved in a suitable carrier, the suitable carrier e.g., sterile pyrogen-free water.

[0336] 化合物还可被配制成直肠用组合物,例如,栓剂或保留灌肠剂型,例如含有常规栓剂基体(例如可可油或其他甘油酯)。 [0336] The compounds may also be formulated in rectal compositions such as suppositories or retention enemas dosage forms, e.g., containing conventional suppository base (e.g. cocoa butter or other glycerides).

[0337] 除了前述剂型之外,化合物还可被配制成长效制剂。 [0337] In addition to the foregoing dosage forms, the compounds may also be formulated as a depot preparation. 这种长期起效的剂型可通过植入或经皮递送(例如,皮下递送或肌肉内递送)、肌肉内注射或透皮贴剂给药。 Such long acting formulations may be administered by implantation or transcutaneous delivery (e.g., intramuscular delivery or subcutaneous delivery), intramuscular injection or a transdermal patch administration. 因此,例如, 化合物可通过合适的聚合材料或疏水性材料(例如,可接受的油中的乳液)或离子交换树脂配制或可将化合物配制成微溶衍生物,例如,配制成微溶的盐。 Thus, for example, the compounds may be formulated or compounds may be formulated as sparingly soluble derivatives exchange resin suitable polymeric or hydrophobic materials (e.g., an emulsion in an acceptable oil) or ion, e.g., a sparingly soluble salt .

[0338] 药物组合物还可包含合适的固体或凝胶相载体或赋形剂。 [0338] The pharmaceutical compositions may also comprise suitable solid or gel phase carriers or excipients. 这些载体或赋形剂的实例包括碳酸钙、磷酸钙、各种糖类、淀粉、纤维素衍生物、明胶和诸如聚乙二醇之类的聚合物。 Examples of such carriers or excipients include calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols and the like.

[0339] 优选的药物组合物为配制成注射剂型的组合物,例如,静脉注射剂型,并且该优选的药物组合物包含基于总的100重量%的药物组合物的约0. 01重量%至约100重量%的本发明的化合物。 [0339] Preferably the pharmaceutical composition is formulated into an injectable dosage form of the composition, e.g., intravenous injection formulation, and preferably the pharmaceutical composition comprises from about 0.01 wt% based on the total 100 weight percent of the pharmaceutical composition to about 100% by weight of the compound of the present invention. 药物-配体偶联物可为抗体-细胞毒素偶联物,其中,选择靶向特定癌症的抗体。 Drug - ligand conjugate may be an antibody - cytotoxin conjugates, wherein selecting particular cancer antibody targeting.

[0340] 在一些实施方式中,本发明的药物组合物还包含其他治疗剂。 [0340] In some embodiments, the pharmaceutical compositions of the invention further comprises other therapeutic agents.

[0341] 在一些实施方式中,所述其他治疗剂为抗癌剂。 [0341] In some embodiments, the additional therapeutic agent is an anticancer agent.

[0342] 在一些实施方式中,其他抗癌剂选自:抗代谢药物、拓扑异构酶I和拓扑异构酶II 的抑制剂、烷基化剂、微管抑制剂、抗雄性激素剂、GNRh调节剂或者它们的混合物。 [0342] In some embodiments, the other anticancer agent is selected from: antimetabolites, topoisomerase I and topoisomerase II inhibitors, alkylating agents, microtubule inhibitors, anti-androgens agent, GNRh modifiers or mixtures thereof.

[0343] 在一些实施方式中,所述其他治疗剂为化疗剂。 [0343] In some embodiments, the additional therapeutic agent is a chemotherapeutic agent.

[0344] 本文中的"化疗剂"是指在治疗癌症中有用的化学化合物。 [0344] herein, "chemotherapeutic agent" refers to a useful chemical compounds in the treatment of cancer. 实例包括但不限于:吉西他滨(Gemcitabine),伊立替康(Irinotecan),阿霉素(Doxorubicin), 5-氟尿喃啶(5-Fluorouracil),阿糖胞苷(Cytosine arabinoside,"Ara_C"),环磷酰胺(Cyclophosphamide),塞替派(Thiotepa),白消安(Busulfan),细胞毒素,紫杉酷,甲氨蝶呤(Methotrexate),顺钼(Cisplatin),美法仑(Melphalan),长春喊(Vinblastine) 和卡钼(Carboplatin)。 Examples include, but are not limited to: gemcitabine (Gemcitabine), irinotecan (Irinotecan), Adriamycin (Doxorubicin), 5- fluorouracil thiopyran piperidine (5-Fluorouracil), cytarabine (Cytosine arabinoside, "Ara_C"), cyclophosphamide (cyclophosphamide), thiotepa (thiotepa), busulfan (busulfan), cytotoxins, yew cool, methotrexate (methotrexate), along molybdenum (Cisplatin), melphalan (melphalan), Changchun call (Vinblastine) card and molybdenum (Carboplatin).

[0345] 在一些实施方式中,第二化疗剂选自:他莫昔芬(tamoxifen),雷洛昔芬(raloxifene),阿那曲挫(anastrozole),依西美坦(exemestane),来曲挫(Ietrozole), 伊马替尼(imatanib),紫杉醇(paclitaxel),环磷酰胺(cyclophosphamide),洛伐他汀(Iovastatin),含羞草素(minosine),吉西他滨(gemcitabine),阿糖胞苷(cytarabine),5_氟尿喃啶,甲氨蝶呤,多西他赛(docetaxel),戈舍瑞林(goserelin), 长春新碱(vincristine),长春碱(vinblastine),诺考达挫(nocodazole),替尼泊苷(teniposide),依托泊苷(etoposide),吉西他滨,埃博霉素(epothilone),长春瑞滨(vinorelbine),喜树喊(camptothecin),柔红霉素(daunorubicin),放线菌素D (actinomycin D),米托蒽酉昆(mitoxantrone),口丫啶(acridine),阿霉素(doxorubicin), 表柔比星(epirubicin)或去甲氧基柔红霉素(idarubicin)。 [0345] In some embodiments, the second chemotherapeutic agent is selected from: tamoxifen (tamoxifen), raloxifene (raloxifene), anastrozole frustration (anastrozole), exemestane (exemestane), letrozole setback (Ietrozole), imatinib (imatanib), taxol (paclitaxel), cyclophosphamide (cyclophosphamide), lovastatin (Iovastatin), mimosine (minosine), gemcitabine (gemcitabine), cytosine arabinoside (cytarabine) , 5_ furans pyridine fluorouracil, methotrexate, docetaxel (docetaxel), goserelin (goserelin), vincristine (vincristine), vinblastine (vinblastine), nocodazole frustration (nocodazole), teniposide (teniposide), etoposide (etoposide), gemcitabine, epothilone (epothilone), vinorelbine (vinorelbine), call acuminata (camptothecin), daunorubicin (daunorubicin), actinomycetes pigment D (actinomycin D), mitoxantrone unitary Queensland (mitoxantrone), acridine port (acridine), adriamycin (doxorubicin), epirubicin (epirubicin) or demethoxy-daunorubicin (idarubicin).

[0346] 试齐I丨盒 [0346] Test I Shu Qi cartridge

[0347] 另一方面,本发明提供一种试剂盒,所述试剂盒包含本发明的化合物或组合物中的一种或一种以上以及使用所述化合物或组合物的说明书。 [0347] another aspect, the present invention provides a kit, the reagent A cartridge comprising a compound of the invention or a composition or one or more instructions and using the compound or composition. 在示例性的实施方式中,本发明提供用于将本发明的连接体臂与另一分子偶联的试剂盒。 In an exemplary embodiment, the present invention provides a linker arm for the present invention is conjugated with another molecule of a kit. 所述试剂盒包括连接体和用于使连接体与特定的官能团连接的说明书。 The kit comprises a linker and linker for the description of the specific functional group. 所述试剂盒还包括细胞毒性药物、靶向剂、可检测的标记、药学上可接受的盐或缓冲剂中的一种或一种以上。 The kit further comprises a cytotoxic drug, a targeting agent, a detectable label may be a pharmaceutically acceptable salt or of one or more buffers. 所述试剂盒还可包括容器和任选地一种或一种以上小瓶、测试管、烧瓶、瓶子或注射器。 The kit may also include a container and optionally one or more vial, test tube, flask, bottle, or syringe. 其他形式的试剂盒对于本领域技术人员而言是显而易见的并且在本发明的范围内。 Other forms of the kit to those skilled in the art and will be apparent within the scope of the present invention.

[0348] 医疗用涂 [0348] Medical coated

[0349] 本发明的化合物包含抗-HER2抗体,连接体以及作为TLR7/8激动剂的且由通式(I)表示的细胞毒素试剂。 [0349] Compounds of the invention comprises an anti--HER2 antibody, linker and cytotoxic agent and represented by the general formula (I) as a TLR7 / 8 agonist. 在现有技术中,只有几种主要化学类型的细胞素试剂被开发用于抗体药物偶联物。 In the prior art, only a few main types of chemical agents have been developed for cytokine antibody drug conjugates. 它们分为两类:DNA损伤剂和微管干扰剂。 They fall into two categories: DNA damaging agents and microtubule interfering agent. 本发明提供了一类新的用于抗体药物偶联物的化学细胞素试剂一TLR7/8激动剂,其调节免疫反应,随后活化树突细胞和自然杀伤细胞并且促进抗肿瘤活性。 The present invention provides a new class of chemical agents for cytokine antibody drug conjugate of a TLR7 / 8 agonists which modulate immune responses, dendritic cells and subsequent activation of natural killer cells and promotes anti-tumor activity. 本发明的发明人出于意料地发现本发明的化合物表现出非常好的抗肿瘤活性。 The inventors of the present invention surprisingly found that for the compounds of the present invention exhibit excellent anti-tumor activity. 在用本发明的化合物进行典型治疗的过程中,像导弹那样起作用的抗体部分将细胞毒素试剂部分递送至表达HER2的肿瘤细胞/癌细胞,在该肿瘤细胞/ 癌细胞中,所述细胞毒素试剂部分直接或间接地对抗肿瘤细胞/癌细胞。 In a typical process of the treatment of the compound of the present invention, as the missile to function as part of the antibody portion of the cytotoxic agent is delivered to tumor cells expressing HER2 / cancer cells, the cancer cells / cancer cells, the cytotoxic reagent section directly or indirectly, against tumor cells / cancer cells. 这种治疗方法得益于毒性副作用的降低以及药代动力学特性的改善。 Thanks to this treatment to reduce toxic side effects and improved pharmacokinetics dynamics. 而且,细胞毒素试剂(药物)从载体抗体中缓慢释放使活性细胞毒素试剂的肿瘤内浓度维持在较高水平并且使活性细胞毒素试剂的血药浓度维持在较低水平。 Moreover, a cytotoxic agent (drug) is released from the carrier slowly so that the antibody activity of the toxin in the tumor cell concentration agent at a higher level and the blood concentration of the active agent toxin cells were maintained at a low level.

[0350] 因此,另一方面,本发明提供一种抑制HER2阳性肿瘤细胞/癌细胞增殖的方法,所述方法包括将本发明的化合物给药于所述肿瘤细胞。 [0350] Accordingly, another aspect, the present invention provides a method of HER2-positive tumor cells / cancer cell line, said method comprising administering a compound of the present invention to the tumor cells. 在一些实施方式中,肿瘤可以是转移的或非转移的。 In some embodiments, the tumor can be transferred or transferred.

[0351] 本文中的"癌症"或"肿瘤"是指人体内的病理状态,其特征为不受控制的细胞增殖。 [0351] As used herein "cancer" or "tumor" refers to a pathological state of the human body, characterized by uncontrolled cellular proliferation. 实例包括但不限于:癌症、淋巴瘤、母细胞瘤和白血病。 Examples include, but are not limited to: cancer, lymphoma, blastoma, and leukemia. 癌症的更加具体的实例包括但不限于:肺(小细胞和非小细胞)癌、乳腺癌、前列腺癌、类癌性癌症、膀胱癌、胃癌、胰腺癌、 肝癌(肝细胞癌)、肝母细胞瘤、结肠直肠癌、头颈部鳞状细胞癌、食管癌、卵巢癌、子宫颈癌、 子宫内膜癌、间皮瘤、黑色素瘤、肉瘤、骨肉瘤、脂肪肉瘤、甲状腺癌、硬纤维瘤、急性髓细胞白血病(AML)和慢性髓细胞白血病(CML)。 More specific examples of cancers include, but are not limited to: lung (small cell and non-small cell) cancer, breast cancer, prostate cancer, carcinoid cancer, bladder cancer, stomach cancer, pancreatic cancer, liver cancer (hepatocellular), hepatoblastoma cell tumor, colorectal cancer, head and neck squamous cell cancer, esophageal cancer, ovarian cancer, cervical cancer, endometrial cancer, mesothelioma, melanoma, sarcoma, osteosarcoma, liposarcoma, thyroid cancer, desmoid tumor, acute myeloid leukemia (AML) and chronic myeloid leukemia (CML).

[0352] 本文中的"抑制"或"治疗"是指降低、治疗性和预防性治疗,其中,目的是降低或预防指定的病理性失调或病症。 [0352] herein, "inhibit" or "treating" means reducing, therapeutic and prophylactic treatment, wherein the designated purpose of reducing or preventing pathological condition or disorder. 在一个实施例中,给药本发明的化合物之后,癌症患者可经历肿瘤尺寸减小。 In one embodiment, after administration of the compounds of the present invention, a cancer patient can be subjected to reduction in tumor size. "治疗"包括(1)抑制患有或表现出疾病的病理或症状的受治者体内的疾病;(2)缓解患有或表现出疾病的病理或症状的受治者体内的疾病;和/或(3)影响患有或表现出疾病的病理或症状的受治者或患者体内的疾病的任何可测量的降低。 "Treatment" includes (1) inhibiting the disease in vivo by a subject having or displaying the pathology or symptomatology of the disease; a subject's disease (2) to alleviate suffering from or displaying the pathology or symptomatology of the disease in vivo; and / or (3) reducing the impact of having or exhibiting any measurable disease in a subject or patient pathology or symptoms of the disease. 本发明的化合物在一定程度上可防止癌细胞生长和/或杀死癌细胞,在该程度上的本发明的化合物可为抑制细胞生长的和/或细胞毒性的。 The compounds of this invention can prevent growth of cancer cells to a certain extent and / or kill cancer cells, the compounds of the invention may inhibit the extent and / or cytotoxic cell growth.

[0353] 本文中的"治疗有效量"是指有效"治疗"受治者或哺乳动物体内的失调的本文提供的化合物的量。 [0353] herein, "therapeutically effective amount" refers to the effective "therapeutic" amount of a compound of the disorders described herein a subject or mammal is provided. 在治疗癌症的情况下,治疗有效量的药物可降低癌细胞的数目,使肿瘤尺寸减小,抑制癌细胞浸润进入外周器官,抑制肿瘤转移,抑制肿瘤生长至某一程度,和/ 或一定程度地减轻与癌症相关的症状中的一种或一种以上。 In the case of the treatment of cancer, the therapeutically effective amount of the drug may reduce the number of cancer cells, reducing tumor size, inhibiting cancer cell infiltration into peripheral organs, inhibition of tumor metastasis, inhibition of tumor growth to a certain degree, and / or to a certain extent relieve one symptom associated with cancer or more than one.

[0354] 另一方面,本发明提供一种治疗受治者体内的HER2阳性肿瘤/癌症的方法,所述方法包括将治疗有效量的本发明的化合物给药于所述受治者。 [0354] another aspect, the present invention provides a method of treating HER2 positive tumors a subject's body / cancer, comprising a therapeutically effective amount of the compound of the present invention is administered to a subject by. 在一些实施方式中,肿瘤或癌症可以是处于任何阶段的肿瘤或癌症,例如,早期或晚期肿瘤或癌症,例如,I期、II期、 III期、IV期或V期肿瘤或癌症。 In some embodiments, the tumor or cancer may be at any stage of the tumor or cancer, e.g., early or late tumors or cancers, e.g., I phase, II, III,, IV or V of the tumor or cancer. 在一些实施方式中,肿瘤或癌症可为转移的或非转移的。 In some embodiments, the tumor or cancer or the transfer may be transferred. 在转移性肿瘤或癌症的情况下,本发明的方法可减缓或抑制原发性肿瘤或癌症向其他位点转移,或者减缓或抑制在远离原发性肿瘤或癌症治疗的其他位点形成或产生转移性肿瘤或癌症。 In the metastatic tumor or cancer, the methods of the invention may slow or inhibit the metastasis of the primary tumor or cancer to other sites, or formation or slow or inhibit generation in other sites distant from the primary tumor or cancer treatment metastatic tumor or cancer. 因此,本发明的方法还包括:1)减缓或抑制可能发生转移或已经发生转移的肿瘤细胞或癌细胞(例如,播散性肿瘤细胞,DTC)的生长、增殖、迀移或入侵;2)减缓或抑制原发性肿瘤或癌症向一个或一个以上不同于原发性肿瘤或癌症的其他位点、位置或区域形成转移或建立转移;3)在转移已形成或已建立之后,减缓或抑制一个或一个以上不同于原发性肿瘤或癌症的其他位点、位置或区域的转移的生长或增殖;以及4)在转移已形成或已建立之后,减缓或抑制额外的转移的形成或建立。 Thus, the method of the present invention further comprises: 1) slow or inhibit the growth of tumor cells or cancer cells (e.g., disseminated tumor cells, the DTC) of the transfer may have occurred, or metastasis, proliferation, invasion or shift Gan; 2) slow or inhibit primary tumor or cancer to one or more different from the other sites of the primary tumor or cancer, or metastasis formation location or area to establish metastasis; 3) after the transfer has been formed or established, slow or inhibit one or more different from the growth or proliferation of primary tumor or metastasis of cancer at other sites, locations or regions; and 4) after the transfer has been formed or established, slowing or inhibiting formation or establishment of additional metastasis.

[0355] 在一些实施方式中,肿瘤或癌症为实体或液体细胞团块。 [0355] In some embodiments, the cancer is a solid tumor or a liquid or a cell pellet. "实体"瘤是指通常聚集在一起并形成团块的癌症、瘤或转移。 "Entity" refers to tumors usually come together and form a cancer, tumor or metastasis lumps. 具体的非限定性实例包括:乳腺肿瘤/乳腺癌、卵巢肿瘤/卵巢癌、子宫肿瘤/子宫癌、子宫颈肿瘤/子宫颈癌、胃肿瘤/胃癌、肺肿瘤/肺癌、 胃肿瘤/胃癌、结肠肿瘤/结肠癌、膀胱肿瘤/膀胱癌、胶质肿瘤/胶质癌和子宫内膜肿瘤/ 子宫内膜癌等。 Specific non-limiting examples include: breast cancer / breast, ovary tumors / ovarian cancer, uterine cancer / uterine cancer, cervical cancer / cervical cancer, stomach tumors / cancer, lung tumors / cancer, stomach tumors / cancer, colon tumor / colon, bladder tumors / bladder cancer, glial tumors / cancer and endometrial tumors gum / endometrial cancer. "液体肿瘤"是指自然分散或扩散的瘤,其通常不会形成实体团块。 "Liquid tumor" refers to tumors or dispersible natural diffusion, which will generally not form solid clumps. 具体的实例包括:网状内皮系统瘤或造血系统瘤,例如,淋巴瘤、骨髓瘤和白血病。 Specific examples include: tumor of the reticuloendothelial system or hematopoietic tumors, e.g., lymphoma, myeloma and leukemia. 白血病的非限定性实例包括:急性和慢性淋巴母细胞性白血病、成髓细胞白血病和多发性骨髓瘤。 Non-limiting examples of leukemias include: acute and chronic lymphoblastic leukemia, myeloblastic leukemia, and multiple myeloma. 通常,这些疾病由低分化急性白血病(例如,成红细胞白血病和急性巨核细胞白血病)引起。 Typically, these diseases (e.g., erythroblastic leukemia and acute megakaryocytic leukemia) caused by poorly differentiated acute leukemias. 具体的骨髓性疾病包括,但不限于:急性早幼粒细胞白血病(APML)、急性粒细胞白血病(AML)和慢性粒细胞白血病(CML)。 Specific myeloid disorders include, but are not limited to: acute promyelocytic leukemia (APML), acute myeloid leukemia (AML) and chronic myelogenous leukemia (CML). 淋巴系统恶性肿瘤包括,但不限于:急性淋巴细胞性白血病(ALL), 其包括B细胞系ALL (B-ALL)和T细胞系ALL (T-ALL),慢性淋巴细胞性白血病(CLL), 幼淋巴细胞白血病(PLL),多毛细胞白血病(HLL)和Waldenstroem巨球蛋白血症(WM)。 Lymphoid malignancies include, but are not limited to: acute lymphoblastic leukemia (ALL), which includes B cell lines ALL (B-ALL), and T-cell lines ALL (T-ALL), chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), hairy cell leukemia (HLL) and Waldenstroem macroglobulinemia (WM). 具体的恶性淋巴瘤包括:非霍奇金淋巴瘤及其变体,外周T细胞淋巴瘤,成人T细胞白血病/淋巴瘤(ATL),皮肤T细胞淋巴瘤(CTCL),大颗粒淋巴细胞白血病(LGF),霍奇金疾病和Reed-Sternberg 疾病。 Specific malignant lymphomas include: non-Hodgkin lymphoma and variants thereof, peripheral T cell lymphomas, adult T-cell leukemia / lymphoma (the ATL), cutaneous T-cell lymphoma (of CTCL), large granular lymphocytic leukemia ( LGF), Hodgkin's disease and Reed-Sternberg disease.

[0356] 在一些实施方式中,本发明的方法可与其他治疗方法或疗法(例如,手术切除术、 放疗、离子或化学辐射疗法、化疗、免疫疗法、局部或区域热疗(过高热)或接种疫苗)一同实施。 [0356] In some embodiments, the methods of the invention may be combined with other treatments or therapies (e.g., surgical excision, radiation, ion radiation or chemical therapy, chemotherapy, immunotherapy, local or regional hyperthermia (hyperthermia) or vaccination) together embodiment. 这些其他治疗方法或疗法可在本发明的化合物的给药之前、基本同时(分开或以混合物的形式)或之后给予。 These other treatments or therapies can be administered before the compounds of the present invention, substantially at the same time (separately or as a mixture) or after administration.

[0357] 在一些实施方式中,本发明的方法包括治疗有效量的本发明的化合物与其他治疗剂联合给药。 [0357] In certain embodiments, the compounds of the present invention comprises a method of therapeutically effective amount of the present invention is administered in combination with other therapeutic agents. 在一些实施方式中,所述其他治疗剂是抗癌剂/抗肿瘤剂。 In some embodiments, the additional therapeutic agent is an anticancer / antitumor agents. 在一些实施方式中,所述其他治疗剂是抗代谢物、拓扑异构酶I和拓扑异构酶II的抑制剂、烷基化剂、微管抑制剂、抗雄性激素剂、GNRh调节剂或者它们的混合物。 In some embodiments, the additional therapeutic agent is an anti-metabolite, a topoisomerase I and topoisomerase II inhibitors, alkylating agents, microtubule inhibitors, anti-androgen agents, modifiers or GnRH mixtures thereof. 在一些实施方式中,所述其他治疗剂选自:它莫西芬(tamoxifen)、雷洛昔芬(raloxifene)、阿那曲挫(anastrozole)、 依西美坦(exemestane)、来曲挫(letrozole)、imatanib、紫杉醇、环磷酰胺、洛伐他汀(1〇¥38七&1:;[11)、111;[1108;[116、吉西他滨(86111(3;^313;[116)、阿糖胞苷(05^3四13;[116)、5-氟尿喃啶、 甲氨蝶呤、多西他赛(docetaxel)、戈舍瑞林(goserelin)、长春新碱、长春碱、噻氨醋挫(nocodazole)、替尼泊苷(teniposide)、依托泊苷(etoposide)、吉西他滨、埃博霉素、长春瑞滨(vinorelbine)、喜树碱、道诺霉素(daunorubicin)、放线菌素D、米托蒽醌、P丫啶、阿霉素、表柔比星或去甲氧基柔红霉素。 In some embodiments, the other therapeutic agent is selected from: tamoxifen (tamoxifen), raloxifene (raloxifene), anastrozole frustration (anastrozole), exemestane (exemestane), letrozole frustration (letrozole ), imatanib, paclitaxel, cyclophosphamide, lovastatin (1 & seven 1〇 ¥ 38:; [11), 111; [1108; [116, gemcitabine (86 111 (3; 313 ^; [116), Ara glycoside (05 ^ 13 3 IV; [116), 5-fluorouracil thiopyran, piperidine, methotrexate, docetaxel (docetaxel), goserelin (of goserelin), vincristine, vinblastine, ammonia, vinegar thiophene setback (Nocodazole), teniposide (teniposide), etoposide (etoposide), gemcitabine, epothilone, vinorelbine (vinorelbine), camptothecin, daunomycin (daunorubicin), actinomycin D, mitoxantrone, P acridine, doxorubicin, epirubicin or demethoxy-daunorubicin.

[0358] 与一种或一种以上其他治疗剂"联合"给药包括同时给药和以任何顺序连续给药。 [0358] with one or one or more other therapeutic agents "in combination" includes simultaneous administration and administration consecutive administration in any order. 本文使用的术语"药物组合"是指通过混合活性成分或组合活性成分得到的产品,并且包括活性成分的固定组合和非固定组合这两者。 As used herein, the term "pharmaceutical composition" refers to mixing the active ingredient or a combination of the active ingredient and includes both fixed and non-fixed combinations of the active ingredients of the combination. 术语"固定组合"是指活性成分(例如通式(1) 的化合物)和联合药剂以单个实体或剂量同时给药于患者。 The term "fixed combination" means that the active ingredients (e.g. Formula (1) compound) and the combined agents simultaneously in a single entity or dosage administered to a patient. 术语"非固定组合"是指活性成分(例如通式(1)的化合物)和联合药剂作为分开的实体同时或按顺序(没有特定的时间限制)给药于患者,这种给药向患者体内提供治疗有效量的活性成分。 The term "non-fixed combination" means that the active ingredients (e.g. Formula (1) compound) and the combined agents as separate entities either simultaneously or sequentially (no specific time limits) administered to the patient, such administration to a patient providing a therapeutically effective amount of the active ingredient. 后者还用于混合剂治疗,例如,给药三种或三种以上活性成分。 The latter mixture for further treatment, e.g., the administration of three or more active ingredients.

[0359] 有效剂量 [0359] Effective dose

[0360] 适用于本发明的药物组合物包括包含治疗有效量的活性成分的组合物,所述治疗有效量即为有效实现期望目的的量。 [0360] The pharmaceutical compositions suitable for the present invention include a therapeutically effective amount of the active ingredient in the composition, the therapeutically effective amount is the amount effective to achieve the desired purpose. 对特定应用有效的实际量将(尤其)取决于治疗中的病症。 The actual effective amount for a particular application (among others) depending on the treatment conditions. 有效量的确定恰好在本领域技术人员的能力范围内(尤其是根据本文具体公开的内容)。 Determining the effective amount is well within the purview of one skilled in the art (in particular, based on the contents disclosed herein specifically).

[0361] 对于本文所述的任何化合物而言,治疗有效量可最先通过细胞培养检测法确定。 [0361] For any compound described herein the therapeutically effective amount may be determined by the first cell culture assay. 目标血药浓度为能够抑制细胞生长或分裂的活性化合物的浓度。 Target blood concentration capable of inhibiting cell growth or division concentration of the active compound. 在优选的实施方式中,细胞活性的至少25%被抑制。 In a preferred embodiment, at least 25% of the cell activity is inhibited. 能够诱导至少约30%、50%、75%或甚至90%或者更高的细胞活性抑制的活性化合物的目标血药浓度为目前优选的。 Capable of inducing at least about 30%, the target plasma concentration of 50%, 75% or even 90% or higher inhibition of cellular activity of the active compound is presently preferred. 可监测患者体内的细胞活性抑制的百分数,从而评估所达到的血药浓度的适当性,并且可上调或下调剂量以实现期望的抑制百分数。 Monitoring the patient can be a percentage inhibition of cellular activity, so as to achieve an appropriate assessment of the percent inhibition of plasma concentration, and may be upregulated or downregulated to achieve the desired dose.

[0362] 如本领域已知的,用于人体的治疗有效量还可通过动物模型来确定。 [0362] As known in the art, the therapeutically effective amount for use in humans can also be determined by animal models. 例如,用于人体的剂量可被配制成实现已在动物体内发现的有效循环浓度。 For example, a dose for humans can be formulated to achieve effective circulating concentrations that have been found in animals. 如上所述,人体内的剂量可通过监测细胞抑制和上调或下调剂量来调节。 As described above, doses in humans can be adjusted by monitoring cellular inhibition and upregulation or downregulation dose.

[0363] 治疗有效剂量还可通过已知的表现出类似药理学活性的化合物的人体数据来确定。 [0363] A therapeutically effective dose can also be determined by known human data exhibit similar pharmacological activity of the compound. 所使用的剂量可基于与已知化合物比较的所给药的化合物的相对生物利用度和效力来调节。 Dose used may be based on the relative bioavailability and potency of the compounds compared to known compounds administered adjusted.

[0364] 基于上述方法和本领域熟知的其他方法为实现人体内的最大效力对剂量进行调节恰好在本领域普通技术人员的能力范围内。 [0364] The dose will be adjusted to achieve maximal efficacy in humans based on the methods described above and other methods known in the art is well within the purview of one of ordinary skill in the art.

[0365] 在局部给药的情况下,所给药的化合物的全身循环浓度不是特别重要。 [0365] In cases of local administration, the systemic circulating concentration of administered compound is not particularly important. 在这种情况下,给药化合物以达到在局部区域有效实现期望的结果的浓度。 In this case, the compound is administered to achieve a concentration effective to achieve a desired result in a localized area.

[0366] 对于预防和/或治疗与异常细胞增殖有关的疾病方面的应用而言,优选的是,所给药的化合物的循环浓度为约0. 001 μ M至20 μ M,优选地约0. 01 μ M至5 μ M。 [0366] Applications for the prevention and / or treatment of abnormal cell proliferation associated with diseases, it is preferable that the circulating concentration of administered compound of about 0. 001 μ M to 20 μ M, preferably about 0 . 01 μ M to 5 μ M.

[0367] 本文所述的化合物的口服给药的患者剂量典型地为约lmg/天至约10, OOOmg/天, 更加典型地为约IOmg/天至约1,OOOmg/天,最典型地为约50mg/天至约500mg/天。 [0367] patient doses for oral administration the compounds described herein is typically from about lmg / day to about 10, OOOmg / day, more typically about IOmg / day to about 1, OOOmg / day, and most typically from from about 50mg / day to about 500mg / day. 按照患者体重而言,典型的剂量为约〇· Olmg/kg/天至约150mg/kg/天,更加典型地为约0· lmg/ kg/天至约15mg/kg/天,最典型地为约lmg/kg/天至约10mg/kg/天,例如,5mg/kg/天或3mg/kg/ 天。 According to the patient body weight, typical dosages range from about billion · Olmg / kg / day to about 150mg / kg / day, more typically about 0 · lmg / kg / day to about 15mg / kg / day, and most typically from from about lmg / kg / day to about 10mg / kg / day, e.g., 5mg / kg / day or 3mg / kg / day.

[0368] 在至少一些实施方式中,延迟或抑制肿瘤生长的患者剂量可为1 μπιοΐ/kg/天或更少。 [0368] In at least some embodiments, patient doses retard or inhibit tumor growth can be 1 μπιοΐ / kg / day or less. 例如,患者剂量可为〇· 9 μ mol/kg/天、0· 6 μ mol/kg/天、0· 5 μ mol/kg/天、 0· 45 μ mol/kg/ 天、0· 3 μ mol/kg/ 天、0· 2 μ mol/kg/ 天、0· 15 μ mol/kg/ 天或0· I μ mol/kg/ 天或更少(参考药物的摩尔数)。 For example, patient dose may be square · 9 μ mol / kg / day, 0 · 6 μ mol / kg / day, 0 · 5 μ mol / kg / day, 0 · 45 μ mol / kg / day, 0 · 3 μ mol / kg / day, 0 · 2 μ mol / kg / day, 0 · 15 μ mol / kg / day, or 0 · I μ mol / kg / day or less (refer to moles of the drug). 优选地,当以每日剂量给药持续至少五天的时间段时,抗体药物偶联物延迟肿瘤生长。 Preferably, daily doses when a time period for at least five days, an antibody drug conjugate tumor growth delay.

[0369] 对于其他给药模式而言,剂量和间隔可分开调节,从而提供对于治疗中的特定临床适应症有效的给药的化合物的血药浓度。 [0369] For other modes of administration, dosage and interval can be adjusted separately, thereby providing effective blood concentration of the administered compound for specific clinical indications of the treatment. 例如,在一种实施方式中,根据本发明的化合物可以相对高的浓度每天多次给药。 For example, in one embodiment, it can be administered in relatively high concentrations multiple times per day the compounds according to the invention. 可选地,更加理想的是,以最小有效浓度给药本发明的化合物并且使用较低频率的给药方案。 Alternatively, it is more desirable that the minimum effective concentration to the compound of the present invention is administered and less frequent dosing regimen used. 这会提供与个体的疾病的严重程度相称的治疗方案。 This program will provide treatment and severity of the disease individuals proportionate.

[0370] 使用本文的教导可安排有效的治疗方案,而不导致较大的毒性,并且还完全有效地治疗特定患者表现出的临床症状。 [0370] Using the teachings herein, effective treatment can be arranged, without causing more toxic, and is also entirely effective to treat the clinical symptoms exhibited by the particular patient. 这种安排应当包括通过考虑多种因素仔细选择活性化合物,所述多种因素例如,化合物效力、相对生物利用度、患者体重、存在的不良副作用及其严重性、优选的给药模式和所选择的药剂的毒性特征。 This arrangement should include the active compounds selected by carefully considering a variety of factors, various factors such as the compound potency, relative bioavailability, patient body weight, presence and severity of adverse side effects, preferred mode of administration selected and the toxicity profile of medicament.

[0371] 虽然本文描述并显示了本发明的优选的实施方式,但是对于本领域技术人员而言显而易见的是,这些实施方式仅仅是举例说明。 [0371] While the herein described and shown a preferred embodiment of the present invention, but those skilled in the art will be apparent that these embodiments are merely illustrative. 本领域技术人员可对这些实施方式作出多种改变、修改和替换,而不背离本发明。 Those skilled in the art can make various changes, modifications and alterations to these embodiments without departing from the present invention. 应当理解的是,本文所述的本发明的可选实施方式可用于实践本发明。 It should be appreciated that alternative embodiments of the invention described herein may be used in the practice of the present invention. 通过所附的权利要求来限定本发明的范围,并且这些权利要求范围内的方法和结构及其等同物也被所附的权利要求涵盖。 By the appended claims to define the scope of the present invention, and equivalents are also encompassed by the appended claims methods and structures within the scope of these claims and their.

[0372] 实施例 [0372] Example

[0373] 本发明进一步通过下述实施例举例说明,但本发明不限于此,下述实施例举例说明本发明的化合物的制备方法。 [0373] Example embodiments of the present invention is further illustrated by the following, but the present invention is not limited thereto, examples illustrate the preparation of compounds of the present invention described below.

[0374] 实施例1 [0374] Example 1

[0375] her2转染的L细朐系的牛成 [0375] her2 L transfected into bovine-based thin Qu

[0376] 试剂:来自ATCC (Manassas, VA; Cat No. CRL2648)的L 细胞,购自GeneCopoeia, (Cat No. Z2866)的Her2/pEZ-Lvl05cDNA,葡萄糖DMEM, L-谷酰胺,Lipofect amine2000(Invitrogen;Carlsbad, CA)〇 [0376] Reagents: from ATCC (Manassas, VA; Cat No. CRL2648) L cell available from GeneCopoeia, (Cat No. Z2866) of Her2 / pEZ-Lvl05cDNA, glucose DMEM, L- glutamine, Lipofect amine2000 (Invitrogen ; Carlsbad, CA) billion

[0377] 为了制备用于筛选偶联的曲妥珠单抗的细胞系,生成表达标记的Her2的L细胞。 [0377] To prepare the screening of cell lines conjugated trastuzumab for generating L cells expressing Her2 marker. Her2/pEZ_Lvl05构建体通过标准Lipofectamine2000操作规程转染至L细胞(该细胞在高浓度葡萄糖DMEM+10%FBS+2mM L-谷酰胺中生长)。 Her2 / pEZ_Lvl05 construct by standard procedures Lipofectamine2000 transfected into L cells (the cells in high glucose DMEM + 10% FBS + 2mM L- glutamine grown).

[0378] 结合分析(FACS分析) [0378] binding analysis (FACS analysis)

[0379] 为了确定偶联的曲妥珠单抗的结合能力,对表达人her2的L细胞进行FACS分析。 [0379] In order to determine trastuzumab binding capacity coupling of L cells expressing human her2 FACS analysis. 简言之,将100 μ 1大约IO6个带有瞬时转染的her2的L细胞与不同量的曲妥珠单抗偶联的抗体一同孵育,使用PBS或单独的二抗或不相关huIgG作为阴性对照。 Briefly, 100 μ 1 of about IO6 with different amounts of L cells transiently transfected with her2 of trastuzumab were incubated with conjugated antibodies, or PBS using the secondary antibody alone served as negative or unrelated huIgG control. 洗涤之后,将细胞重悬于FACS缓冲液中并在100 μ L反应体积中在室温下与偶联至藻红蛋白(Mu抗人I3E)二抗的20 μ L小鼠抗人IgG -同孵育30分钟。 After washing, cells were resuspended in FACS buffer and 100 μ L reaction volume with conjugated to phycoerythrin (Mu anti-human i3e) 20 μ L of the secondary antibody anti-human mouse IgG at room temperature - incubation with 30 minutes. 洗涤之后,将细胞固定在200 μ L2%多聚甲醛/PBS中,随后进行流式细胞仪分析。 After washing, the cells were fixed in 200 μ L2% paraformaldehyde / PBS, followed by flow cytometric analysis. 将相同的步骤用于作为同种型对照的不相关人IgG抗体以设定基线PMT/细胞系。 The same procedure is used as irrelevant human IgG isotype control antibodies to set the baseline PMT / cell lines. 在BD FACSCalibur®上进行流式细胞仪分析并且记录每个样品的几何平均荧光强度。 Flow cytometric analysis was performed on BD FACSCalibur® and recording the geometric mean fluorescence intensity of each sample. 使用Flowjo软件分析记录的数据。 Analysis of the recorded data using Flowjo software. 结果在图1中显示。 The results are shown in FIG.

[0380] 抗体toll样#体配体偶联物的牛成 [0380] Antibody # toll-like ligand conjugate to bovine

[0381] 试剂:曲妥珠单抗(Roche/Genentech Corporation, South San Francisco, CA)、 与瑞喹莫德连接的MC-val-c i t-PAB (MC-vc-PAB-TLRL )或与瑞喹莫德连接的MC- (MC-TLRL ) (在Contract Research Organization, China 合成)、硼酸钠、氯化钠、二硫苏糖醇(DTT)、 Sephadex G25、DTPA、DTNB 和马来酰亚胺基己酰基-单甲基(Sigma-Aldrich, Milwaukee, Wi sconsin)。 [0381] Reagents: trastuzumab (Roche / Genentech Corporation, South San Francisco, CA), and connected resiquimod MC-val-c i t-PAB (MC-vc-PAB-TLRL) or resiquimod connected MC- (MC-TLRL) (in the Contract Research Organization, China synthesis), sodium borate, sodium chloride, dithiothreitol (DTT), Sephadex G25, DTPA, DTNB and maleimido amino hexanoyl - monomethyl (Sigma-Aldrich, Milwaukee, Wi sconsin).

[0382] 用于生成抗体TLR配体偶联物的药物包括曲妥珠单抗和瑞喹莫德(TLRL)。 [0382] TLR ligands for the production of antibody drug conjugates include trastuzumab and resiquimod (TLRL). 用于生成TLAC的连接体为可裂解的连接体MC-vc-PAB或非可裂解的连接体MC。 TLAC for generating the linker is a cleavable linker MC-vc-PAB linker may be cleavable or non-MC.

[0383] 曲妥珠单抗MC-TLRL的制各 [0383] trastuzumab-MC-TLRL each braking

[0384] 曲妥珠单抗通过20mg/mL浓度下的缓冲液交换从HERCEPTIN®中纯化出来,在pH为8. 0的条件下溶解于500mM硼酸钠和500mM氯化钠的抗体用过量的IOOmM二硫苏糖醇(DTT)处理。 [0384] Trastuzumab was purified from HERCEPTIN® by buffer exchange at 20mg / mL concentration, at a pH of 8.0 was dissolved in a condition 500mM sodium borate and 500mM sodium chloride with an excess of an antibody IOOmM dithiothreitol (DTT) process. 在37°C孵育约30分钟之后,通过在S印hadex G25树脂上的洗脱交换缓冲液并用含有ImM DTPA的PBS进行洗脱。 After 37 ° C for about 30 minutes, by elution on a printed hadex G25 S buffer exchange resin and eluted with PBS with ImM DTPA is. 硫醇/Ab值通过测定还原的抗体的浓度和硫醇浓度来检测,所述还原的抗体的浓度通过溶液在280nm的吸光度来检测,所述硫醇浓度通过与DTNB (Sigma-Aldrich, Milwaukee, Wisconsin)反应以及在412nm处的吸光度来确定。 Thiol / Ab value is detected by measuring the concentration and the thiol reduced antibody concentration, the concentration of the reduced antibody is detected by absorbance at 280nm in a solution of the thiol concentration by DTNB (Sigma-Aldrich, Milwaukee, wisconsin) the reaction and the absorbance determined at 412nm. 溶解于PBS中的还原的抗体在冰上冷冻。 Was dissolved in PBS was chilled on ice reduced antibody. 在已知浓度下在乙腈和水中稀释溶解于DMSO的药物连接体试剂(与瑞喹莫德连接的Mc-),并且将其加至PBS中的冷冻的还原抗体中。 At a known concentration diluted in acetonitrile and water are dissolved in DMSO drug-linker reagent (Mc- resiquimod and connection), and it was added to the chilled reduced antibody in PBS. 约1小时后,加入过量的马来酰亚胺淬灭反应并遮盖任何未反应的抗体硫醇基团。 After about one hour, an excess of maleimide is added to quench the reaction and covers any antibody thiol groups unreacted. 在一些情况下,通过标准步骤与免疫球蛋白的赖氨酸进行偶联。 In some cases, by standard procedures and immune globulin lysine coupling. 反应混合物通过离心超滤浓缩,偶联的抗体通过PBS中的G25树脂的洗脱进行纯化和脱盐,在无菌条件下通过0. 2 μ m的过滤器过滤, 并冷冻储存。 The reaction mixture was concentrated by centrifugal ultrafiltration and, conjugated antibody is purified and desalted by elution G25 resin in PBS, filtered under sterile conditions through a filter of 0. 2 μ m, and stored frozen.

[0385] 曲妥珠单抗MC-vc-TLRL的制各 [0385] trastuzumab-MC-vc-TLRL each braking

[0386] 抗体通过半胱氨酸由马来酰亚胺基己酰基-缬氨酸-瓜氨酸(vc)-p-氨基苄氧基羰基(MC-vc-PAB)连接至TLRL。 [0386] Antibody cysteine ​​by a maleimido-caproyl - TLRL connected to citrulline (vc) -p- aminobenzyloxycarbonyl group (MC-vc-PAB) - valine. MC-vc-PAB连接体可通过诸如组织蛋白酶B之类的细胞间蛋白酶裂解,当裂解时,释放游离药物(Doronina等人,Nat. Biotechnol.,21:778-784 (2003)),而MC连接体为抗细胞间蛋白酶裂解的。 MC-vc-PAB linker may be a protease or the like between B cells lysed by proteases such as tissue, when cleaved, releases free drug (Doronina, et al., Nat Biotechnol, 21:.. 778-784 (2003)), and MC anti-cell linker between the protease cleavage. 纯化的曲妥珠单抗在pH为8.0的条件下溶解于500mM硼酸钠和500mM氯化钠中,并且进一步用过量的IOOmM二硫苏糖醇(DTT)处理。 Purified trastuzumab conditions at a pH of 8.0 was dissolved in 500mM sodium borate and 500mM sodium chloride and further treated with excess IOOmM dithiothreitol (DTT). 在37°C下孵育约30分钟后,通过S印hadex G25树脂上的洗脱交换缓冲液并且用含有ImM DTPA的PBS洗脱。 After about 30 minutes incubation at 37 ° C, the buffer is exchanged by elution on a printed hadex G25 S with PBS containing resin and eluting the ImM DTPA. 硫醇/Ab值通过测定还原的抗体的浓度和硫醇浓度来检测,所述还原的抗体的浓度通过溶液在280nm处的吸光度来检测,所述硫醇浓度通过与DTNB (Sigma-Aldrich, Milwaukee, Wisconsin)反应以及在412nm处的吸光度(消光系数=13600(31^1¾^)来检测。溶解于PBS中的还原的抗体在冰上冷冻。DMSO中的与瑞喹莫德连接的MC-val-cit-PAB-PNP溶解于乙腈和水中,并将其加至PBS中的冷冻的还原的抗体中。孵育1小时后,加入过量的马来酰亚胺淬灭反应并遮盖任何未反应的抗体硫醇基团。在一些情况下,通过标准步骤与免疫球蛋白的赖氨酸进行偶联。通过离心超滤浓缩反应混合物,抗体药物偶联物通过PBS中的G25树脂的洗脱进行纯化和脱盐,在无菌条件下通过0. 2 μπι的过滤器过滤,并冷冻储存。 Thiol / Ab value is detected by measuring the concentration and the thiol reduced antibody concentration, the concentration of the reduced antibody is detected by absorbance at 280nm of the solution, the thiol concentration by DTNB (Sigma-Aldrich, Milwaukee , Wisconsin) and the reaction absorbance (extinction coefficient = 13600 (31 ^ 1¾ ^) 412nm to detect at. MC-val dissolved in PBS was chilled on ice reduced antibody .DMSO is connected to resiquimod -cit-PAB-PNP was dissolved in acetonitrile and water, and add it to the reduced antibody in PBS frozen in. after 1 hour incubation, an excess of maleimide is added to quench the reaction and any unreacted antibody was covered thiol group. in some cases, standard procedures lysine by immunoglobulin G. the reaction mixture was concentrated by centrifugal ultrafiltration and the antibody drug conjugate was purified by elution G25 resin in PBS and desalted, filtered under sterile conditions through a filter of 0. 2 μπι, and stored frozen.

[0387] 通常,抗体与MC-TLRL或MC-vc-TLRL的偶联反应生成非均一混合物,该混合物包含与不同数量的TLRL药物连接的、偶联的抗体,即,药物分配为1至约8的药物装载。 [0387] Generally, the coupling reaction with the antibody or MC-TLRL MC-vc-TLRL generating a non-homogeneous mixture which comprises, connected to different conjugated antibody TLRL number of drugs, i.e., drug dispensing from 1 to about 8 Drug loading. 因此,抗体MC-TLRL或抗体MC-vc-TLRL包括分离的纯化的物种分子和平均药物装载为1至8的混合物。 Thus, the antibody or antibody MC-TLRL MC-vc-TLRL comprising an isolated and purified molecular species of the mixture the average drug loading from 1 to 8. 通过控制加工过程,药物装载为3至5。 By controlling the process, the drug loading is 3 to 5. 通过偶联反应得到的化合物制剂中, 每个抗体中TLRL药物部分的平均数目可由常规方式表征,例如质谱法、ELISA分析法、电泳分离法和HPLC。 Compound preparation obtained by the coupling reaction of each antibody TLRL average number of drug moieties may be characterized by conventional means, such as mass spectrometry, ELISA, assay, separation and electrophoresis HPLC. 也可确定根据药物的抗体MC-TLRL或抗体MC-vc-TLRL的量分配。 It may be determined according to the amount of allocation of the MC-TLRL an antibody drug or antibody MC-vc-TLRL of. 通过ELISA,可确定抗体与TLRL偶联的特定制剂中的药物有效装载数目的平均值(Hamblett等人(2004)Clinical Cancer Res. 10:7063_7070;Sanderson 等人(2005)Clinical Cancer Res. 11:843-852)。 By ELISA, the antibody may be determined TLRL conjugated particular formulation in pharmaceutically effective average number of loading (Hamblett et al (2004) Clinical Cancer Res 10:. 7063_7070; Sanderson et al (2005) Clinical Cancer Res 11: 843. -852). 然而,药物的分配值不能通过抗体-抗原结合和ELISA检测限辨别。 However, the value of the drug can not be assigned an antibody - antigen binding ELISA detection limit and discrimination. 而且,用于检测抗体药物偶联物的ELISA分析不能确定药物部分与抗体在哪个位置连接,例如,重链或轻链片段或特定的氨基酸残基。 Further, ELISA for the detection of antibody drug conjugates analysis can not determine the drug moiety to the antibody in which position the connection, e.g., heavy or light chain or a fragment of a particular amino acid residue. 在一些情况下,均一的曲妥珠单抗MC-TLRL或曲妥珠单抗MC-vc-TLRL的分离、纯化和表征(其中,具有其他药物装载的曲妥珠单抗MC-TLRL 或曲妥珠单抗MC-vc-TLRL中的药物为特定值)可通过诸如反相HPLC或电泳分离之类的方式实现。 In some instances, separation, purification and characterization of trastuzumab-MC-TLRL trastuzumab or MC-vc-TLRL a uniform (wherein, with trastuzumab MC-TLRL curved or other drug loading of the trastuzumab MC-vc-TLRL drugs a certain value) can be achieved by means such as reverse phase HPLC or electrophoresis the like.

[0388] 抗体依赖件细朐介导的细朐毒件分析(ADCC) [0388] Antibody-dependent element fine fine Qu Qu mediated cytotoxic element analysis (ADCC)

[0389] 试剂:SKBR3 细胞(ATCC, Cat No. HTB-30),McCoy' s5A (Invitrogen, Cat No. 22400, Lot No. 747809), RPMI-1640 (Invitrogen1Cat No.11835, Lot No. 764956), FCS (Hyclone, Cat No.SH30084. 03, Lot No. GRH0054), Ficoll-Hypaque (Amersham No. 3916),台盼蓝(Invitrogen Cat N〇15250_061),LDH 试剂盒(Promega, Cat No. G7891), ELISA 测读仪MD5 (Molecule device)。 [0389] Reagents: SKBR3 cells (ATCC, Cat No. HTB-30), McCoy 's5A (Invitrogen, Cat No. 22400, Lot No. 747809), RPMI-1640 (Invitrogen1Cat No.11835, Lot No. 764956), FCS (Hyclone, Cat No.SH30084. 03, Lot No. GRH0054), Ficoll-Hypaque (Amersham No. 3916), trypan blue (Invitrogen Cat N〇15250_061), LDH kit (Promega, Cat No. G7891), ELISA readings instrument MD5 (Molecule device). 人源化抗体·Herceptin® (Genentech Corporation, South San Francisco, CA;商品名曲妥珠单抗)在使用前复溶于水中以制成lOmg/ml 原液。 Humanized antibodies · Herceptin® (Genentech Corporation, South San Francisco, CA; trade music trastuzumab) complex dissolved in water prior to use to prepare a lOmg / ml stock solution.

[0390] 为了确定与高效负载的TLRL偶联的曲妥珠单抗是否仍然具有效应功能,检测几种不同偶联形式的抗体依赖性细胞介导的细胞毒性(ADCC)活性并且与已显示出具有显著提高的ADCC活性的曲妥珠单抗参比材料相比。 [0390] In order to determine whether efficient load TLRL conjugated trastuzumab still effector function, detection of several different forms of conjugated antibody-dependent cellular cytotoxicity mediated by cells (ADCC) activity and has been shown to significantly increased ADCC activity of trastuzumab compared to a reference material. 使用来自于健康供体的外周血单核细胞(PBMC)作为效应细胞、使用人SKBR3细胞系作为靶细胞进行ADCC分析。 From using peripheral blood mononuclear cells (PBMC) from healthy donors as effector cells used as target cells for human ADCC assay cell line SKBR3. 第一天,将IX 104/100 μ L SKBR3细胞接种于96孔平板上,随后在37°C、5%C02条件下,孵育48小时。 The first day, the IX 104/100 μ L SKBR3 cells were seeded in 96-well plates, and then at 37 ° C, 5% C02 condition for 48 hours.

[0391] 在第三天,由从健康自愿供体获得的人血液制备新鲜的人PBMC。 [0391] On the third day, by voluntary donor human blood obtained from healthy body prepared fresh human PBMC. 人静脉血样品收集在柠檬酸铵(ACD-A)管中。 Human venous blood samples were collected in ammonium citrate (ACD-A) tubes. 将管颠倒数次,将全部血液转移至一个50ml圆锥管中。 The tube was inverted several times, the whole blood was transferred to a 50ml conical tube. 用2%FBS中的PBS以1:3稀释血液。 With 2% FBS in PBS at 1: 3 dilution of the blood. 将Ficoll-Hypaque缓慢分配至血液/PBS混合物底部。 The Ficoll-Hypaque slowly assigned to blood / PBS mixture bottom. 在室温下以2400rpm的速度对样品进行离心分离持续30分钟,随后通过抽吸除去上层(血浆/PBS)。 The samples were centrifuged at 2400rpm at room temperature for 30 min separation, followed by removal of the upper layer (plasma / PBS) by aspiration. 血沉层(Buffy coat)用无菌移液管收集并汇集在50ml圆锥管中。 Buffy layer (Buffy coat) was collected with sterile pipettes and pooled in a 50ml conical tube. 如果在血沉层下仍然可见WBC块,那么收集所有WBC物质,小心不要除去过多的Ficol I-Hypaque。 If you are still visible in buffy layer WBC block, then collect all the WBC substance, being careful not to remove too much Ficol I-Hypaque. 加入无菌PBS-2%FBS并通过倒置混合。 Add Sterile PBS-2% FBS and mixed by inversion. 在室温、250Xg的条件下对稀释的PBMC悬浮液进行离心分离持续20分钟,收集细胞小粒。 Centrifuging the diluted PBMC suspension at room temperature, the separation conditions 250Xg for 20 minutes, the cell pellets were collected. PBMC小粒悬浮于具有2%热灭活的FBS的RPMI-1640 培养基,洗涤并通过台盼蓝排除法检查活细胞数。 PBMC pellets were suspended in RPMI-1640 medium with 2% heat-inactivated FBS, and washed and method for detecting the number of viable cells by trypan blue exclusion. 制备I. 2 X IO7细胞/mL的密度待用。 Preparation I. 2 X IO7 cells / mL density stand. 同时,在RPMI-1640 中制备抗体的最终浓度为从12 μ g/mL、4 μ g/mL、l. 2 μ g/mL、0. 4 μ g/mL、 0· 12 μ g/mL、0. 04 μ g/mL、0. 012 μ g/mL、0. 004 μ g/mL 至0 μ g/mL。 At the same time, the final concentration of the preparation of antibodies in RPMI-1640 of from 12 μ g / mL, 4 μ g / mL, l. 2 μ g / mL, 0. 4 μ g / mL, 0 · 12 μ g / mL, 0. 04 μ g / mL, 0. 012 μ g / mL, 0. 004 μ g / mL to 0 μ g / mL.

[0392] 随后将一系列测试抗体和对照抗体的稀释液加至含有靶细胞的孔中,将50 μ L RPMI-1640培养基中的PBMC效应细胞加至每个孔中(效应细胞与靶细胞的比例为60:1 ),并且再孵育17小时。 [0392] The subsequent dilution series of test and control antibodies were added to wells containing target cells, effector cells PBMC were 50 μ L RPMI-1640 medium was added to each well (effector cells to target cells ratio of 60: 1), and incubated for 17 hours. 在孵育结束时对平板进行离心处理并使用LDH测量试剂盒分析上清液中的乳酸盐脱氢酶(LDH)活性。 Plates were centrifuged at the end of the incubation and analysis using LDH measurement kit supernatant lactate dehydrogenase (LDH) activity. 细胞溶解使用酶标仪通过490nm处的吸光度定量。 Cells were lysed using a microplate reader quantified by absorbance at 490nm. 仅含有靶细胞的孔的吸光度作为背景对照,而含有用Triton-XlOO溶解的靶细胞的孔提供最大可获得信号。 The absorbance hole containing only target cells as a background control, while providing maximum achievable signal containing Triton-XlOO hole solubilized target cell. 非抗体依赖性细胞毒性在含有靶细胞和效应细胞而未加入抗体的孔中测量。 Non-antibody dependent cellular cytotoxicity wells containing target and effector cells without addition of the antibody was measured. 细胞毒性根据下列方程计算: Cytotoxicity is calculated according to the following equation:

[0393] %细胞毒性=100%x [A490nm (样品)-A490 (靶细胞)-A490 (效应细胞]/ [A490nm (溶解的靶细胞)-A490nm (靶细胞)] [0393]% cytotoxicity = 100% x [A490nm (sample) -A490 -A490 (effector cells (target cells)] / [A490nm (dissolved target cells) -A490nm (target cells)]

[0394] 相对于抗体浓度绘制一式两份样品稀释液中的平均ADCC值,并且通过拟合至Prism5 (GraphPad)得到EC50 值和ADCC (%)最大程度。 [0394] The antibody concentration plotted with respect to the mean value of two samples ADCC dilution of a type, and by fitting to Prism5 (GraphPad) to obtain EC50 values ​​and ADCC (%) maximum extent.

[0395] 从PBMC中富集人树突细朐(DC) [0395] Qu enriched human dendritic (DC) from PBMC

[0396] 通过Ficoll离心,由从健康的自愿者供体中获得的血沉层制备人PBMC。 [0396] by Ficoll centrifugation, prepared from human buffy layer is obtained from a healthy volunteer donor PBMC. 通过使用负向消减,由具有来自人PBMC的抗CD3抗体、抗CD 19抗体、抗CD20抗体、抗CD 14抗体和抗⑶16抗体的混合物的磁珠(Miltenyi Biotec)富集树突细胞。 By using negative abatement, having anti-CD3 antibodies derived from human PBMC, the CD 19 antibody anti, anti-CD20 antibody, anti-CD 14 beads and anti-antibody mixture ⑶16 antibody (Miltenyi Biotec) enriched dendritic cells. 用山羊抗小鼠FITC (谱系)、HLA-DR-APCCy7、CD123-BV421和CD11C-APC对富集的DC进行染色。 With goat anti-mouse FITC (lineage), HLA-DR-APCCy7, CD123-BV421 and CD11C-APC staining of DC enriched. 染色的细胞在BD LSR Fortessa上进行分析。 The stained cells were analyzed on BD LSR Fortessa. 抗⑶3单克隆抗体、抗⑶4单克隆抗体、抗⑶IlC单克隆抗体、 抗CD19单克隆抗体、抗CD14单克隆抗体、抗CD16单克隆抗体、抗CD123单克隆抗体购自BD Biosciences 或Biolgend0 Anti-⑶3 monoclonal antibody, anti-⑶4 monoclonal antibody, anti-⑶IlC monoclonal antibody, anti-CD19 monoclonal antibody, anti-CD14 monoclonal antibody, anti-CD16 monoclonal antibody, anti-CD123 monoclonal antibody was purchased from BD Biosciences or Biolgend0

[0397] 图3A表示富集前后DC的百分数。 [0397] Figure 3A represents the percentage of DC before and after enrichment. 上部的两个图中的数字表示谱系消减前后总细胞的DC (HLA-DR+Lin-)百分数。 FIG upper two figures represents the total cells before and after reduction lineage DC (HLA-DR + Lin-) percent. 下部图中的数字表示谱系消减前后总DC的mDC (CD11C+CD123-)和pDC (CD123+CD11C-)的百分数。 A lower number represents the percentage figure of the total DC mDC (CD11C + CD123-) and pDC (CD123 + CD11C-) before and after reduction lineage.

[0398] 对富集的人DC的刺激以及细朐闵子表汰 [0398] stimulation of the human DC-enriched and eliminating fine Qu Min subtable

[0399] 将1-2X IO5富集的DC接种于100 μ 1培养基中的96孔平板中,将100 μ 1稀释的刺激剂加至平板中并在37°C的孵育器中培养20至22小时。 [0399] The DC enriched 1-2X IO5 inoculated in 100 μ 1 of medium in 96-well plates, diluted 1 to 100 μ stimulating agent added to the plate and incubated at 37 ° C in the incubator 20 to 22 hours. 收集上清液并通过ELISA (Mabtech AB)分析人IFN-a,IL-6, IL_12(p70)和TNF-α。 The supernatant was collected by ELISA (Mabtech AB) analysis of human IFN-a, IL-6, IL_12 (p70) and TNF-α.

[0400] 统计学分析 [0400] Statistical analysis

[0401] 所有比较的显著性使用Student双尾t检测计算,假设模拟组和样品组之间的方差不相等,当P〈〇. 05时认为结果是显著的。 [0401] variance between all the significant comparison using Student's two-tailed t-test calculation, assuming analog group and the sample are not equal, when P <square. 05 Results were considered significant. 参数之间的相关性使用斯皮尔曼秩相关测试评价,P值〈0. 05被认为是统计学上显著的。 The correlation between the parameters using Spearman rank correlation evaluation test, P value <0.05 was considered statistically significant.

[0402] 伸用曲妥珠单抗TLRL偶联物讲行体内肿瘤细朐杀伤试骀 [0402] extending TLRL with trastuzumab conjugates fine line speak again spun in vivo tumor killing Qu

[0403] 对于源自患者的胃癌异种移植物(PDX)小鼠模型的研宄而言,将6至8周龄的雌性Balb/c裸鼠(获自SLAC, Shanghai, China)用于肿瘤碎片移植。 [0403] For gastric carcinoma patient-derived xenograft mouse model study based (PDX), the Female Balb 6 to 8 weeks of age / c nude mice (obtained from SLAC, Shanghai, China) for tumor fragments transplant. 根据动物护理和使用委员会(Institutional Animal Care and Use Committee)的实验室动物护理和使用指南和规程,用正常裸鼠饮食饲养动物并且将动物养在SPF动物设施中。 According to animal care and use guidelines and procedures for laboratory animal care and use committee (Institutional Animal Care and Use Committee), the nude mice with normal diet feeding animals and animals kept in SPF animal facility. 将尺寸为约15mm 3至30mm 3 的患者ST0#69胃肿瘤碎片移植(皮下地)到Balb/c裸鼠的右侧。 Patients dimensions of about 15mm 3 to 30mm 3 ST0 # 69 of gastric transplanted tumor fragments (subcutaneously) to the right Balb / c nude mice.

[0404] 通过静脉注射途径给药含有5mg/kg至20mg/kg抗体的药物或参比药物(QWKx3)。 [0404] route of administration by intravenous injection containing 5mg / kg to 20mg / kg of an antibody drug or the reference drugs (QWKx3). 通过卡尺每周测量一次肿瘤以确定其皮下生长。 Once a week by caliper measurements to determine tumor grown subcutaneously. 用卡尺每周测量两次肿瘤的二维尺寸。 Tumor measuring two dimensions with calipers twice a week. 使用如下方程式计算肿瘤体积:肿瘤体积=(长度X宽度2) X0. 5。 Tumor volume was calculated using the following equation: Tumor volume = (length X width 2) X0 5.. 平均肿瘤体积或体重使用画图程序Prism5 (GraphPad)绘制。 Mean tumor volume of body weight or drawing program Prism5 (GraphPad) drawing. 效力研宄的终点设置在第一次治疗后30天至45天或者当肿瘤尺寸达到2000mm3以上时(无论哪个先达到)。 Efficacy endpoint provided a Subsidiary of 30 to 45 days or when the tumor size reached 2000mm3 above (whichever comes first) after the first treatment. 如果小鼠失去超过20%的体重或者病得很重并且无法得到足够的食物或水,那么将其从研宄中除去并实施安乐死。 If the mice lost more than 20% by weight or very ill and can not get enough food or water, and then it is removed from the study based on the euthanized. 在终点收集小鼠的肿瘤,在LN 2中半冷冻并在福尔马林中半固定,用于制备FFPE组织。 Tumor-bearing mice were collected at the end, and semi-fixed in formalin half frozen in LN 2 for the preparation FFPE tissues.

Claims (22)

  1. 1. 一种具有下述通式(Ia)的结构的化合物或其药学上可接受的盐或其溶剂化物: TM-L-AM (Ia), 其中,TM是与Her2/Neu特异性结合的抗体或其功能片段,AM为由下述通式(I)的结构表示的活化部分: CLAIMS 1. A compound of the structure or a pharmaceutically having the following formula (Ia) or a salt of solvate thereof: TM-L-AM (Ia), where, TM is specifically binding to Her2 / Neu in antibody or functional fragment thereof, AM activated partial structure by the following general formula (I) is represented by:
    Figure CN104861063AC00021
    其中,虚线表示存在化学键或不存在化学键,~为待与连接体连接的点; X 是S 或-NR1, 1^是-W。 Wherein the dotted line represents presence of a bond or absence of a bond, - the point to be connected to the connecting member; X is S or -NR1, 1 ^ is -W. 一W1 一W2一W3一W4; Wtl是化学键,烷基,烯基,炔基,烷氧基或-烷基-S-烷基--, W1是化学键,一O -,或-NR 2-,其中,R2是氛,烷基或條基, W2是化学键,一〇-,一C (O) ―,一C (S)-或-S (O) 2-, W3是化学键,一NR3--,其中,R3是氢,烷基或烯基, W4是氣,烷基,條基,炔基,烷氧基,环烷基,芳基,芳氧基,杂芳基或杂环基,它们中的每一个被一个或一个以上选自下列基团的取代基任选地取代:羟基,烷氧基,烷基,烯基, 炔基,环烷基,芳基,杂芳基,杂环基,一NH 2,硝基,一烷基-羟基,一烷基-芳基,一烧基-杂芳基,一烷基-杂环基,一O-R4^ 一〇_烷基-I,一烷基-O-R4,一C(0)-R4,-烧基-C (0) -R4,一烷基-C (0) -O-R4,一C (0) -O-R4,一S-R4,一S (0) 2-R4,一NH-S (0) 2-R4,一烧基-S-R4,一烷基-S (0) 2_R4, 一NHR4, -NR4R4^ -NH-烷基-R4,卤素,一CN,一腸2和-SH,其中,R4独立地为氢, W1 W2 a a a a W3 W4; Wtl is a bond, alkyl, alkenyl, alkynyl, alkoxyalkyl or - -S- alkyl group -, W1 is a bond, a O -, or -NR 2- wherein, R2 is the atmosphere, an alkyl group or strip, W2 is a bond, a 〇-, a C (O) -, a C (S) - or -S (O) 2-, W3 is a bond, a NR3- -, wherein, R3 is hydrogen, alkyl or alkenyl, W4 is a gas, an alkyl group, article, alkynyl, alkoxy, cycloalkyl, aryl, aryloxy, heteroaryl, or heterocyclyl group, each of which is substituted with one or more groups selected from the group thereof optionally substituted with: hydroxy, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroaryl cycloalkyl group, a NH 2, nitro, a group - a hydroxyl group, an alkyl - aryl group, a burn-yl - heteroaryl group, an alkyl - heterocyclic group, a O-R4 ^ 〇_ a group - I, a group -O-R4, a C (0) -R4, - burning group -C (0) -R4, a group -C (0) -O-R4, a C (0) -O- R4, a S-R4, a S (0) 2-R4, a NH-S (0) 2-R4, a group burn -S-R4, a group -S (0) 2_R4, a NHR4, -NR4R4 -R4 ^ -NH- alkyl, halogen, a CN, a gut and 2 -SH, wherein, R4 is independently hydrogen, 基,烯基,一烷基-羟基,芳基,杂芳基,杂环基或卤代烷基; Z是氢,烷基,烯基,炔基,烷氧基,芳基,卤代烷基,杂芳基,杂环基,它们中的每一个可被一个或一个以上选自下列基团的取代基任选地取代:羟基,烷氧基,烷基,烯基,炔基,芳基,杂芳基,杂环基,卤素,氛基,硝基,一N(R 5)2,-烷氧基-烷基,一烷氧基_稀基,一C (0)-烷基,一C (0) -〇-烷基,一OC (0)-烷基,一C (0) -N(R5) 2,芳基,杂芳基,一CO-芳基和-CO-杂芳基,其中,馬分别独立地为氢,烷基,卤代烷基,一烷基-芳基或-烷基-杂芳基; R为氢,烷基,烷氧基,卤代烷基,卤素,芳基,杂芳基,杂环基,它们中的每一个被一个或一个以上选自下列基团的取代基任选地取代:羟基,烷氧基,烷基,烯基,炔基,环烷基,芳基,杂芳基,杂环基,一NH2,硝基,一烷基-羟基,一烷基-芳基 Group, an alkenyl group, an alkyl - hydroxy, aryl, heteroaryl, heterocyclyl or haloalkyl group; Z is hydrogen, an alkyl group, alkenyl group, alkynyl group, alkoxy group, aryl group, haloalkyl, heteroaryl group, a heterocyclic group, each of which may be substituted with one or more substituents selected from the following optionally substituted groups: hydroxy, alkoxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl group, a heterocyclic group, a halogen, atmosphere group, a nitro group, a N (R 5) 2, - alkoxy - alkyl group, an alkoxy group dilute _, a C (0) - alkyl, a C ( 0) -〇- alkyl group, a OC (0) - alkyl, a C (0) -N (R5) 2, aryl, heteroaryl, aryl-CO- and -CO- a heteroaryl, wherein Ma each independently hydrogen, alkyl, haloalkyl, an alkyl - or aryl - alkyl - heteroaryl aryl; R is hydrogen, alkyl, alkoxy, haloalkyl, halo, aryl, heteroaryl group, a heterocyclic group, optionally substituted with substituents each of them with one or more groups selected from: hydroxy, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, aryl , heteroaryl, a heterocyclic group, a NH2, nitro, a group - a hydroxyl group, an alkyl - aryl group 一烷基-杂芳基,一烧基-杂环基,一O -R4,一〇_ 烷基-R4, 一烷基-O-R4,一C (0) -R4,一C (0) -NH-R4,一C (0) -NR4R4,- _ 烷基-C (O) -R4,一烷基-C (0) -O-R4,一C (0) -O-R4,一0-C (0) -R4,一S-R4,一C (0) -S-R4,一SC ( 0) -R4»一S (0) 2_R4, 一NH-S (0) 2_R4,一烷基-S-R4,一烷基-S (0) 2-R4, 一NHR4,一NR4 R4,一NH-烧基-R4,卤素,一CN和-SH,其中,R4独立地为氢,烷基,烯基,烷氧基,一烷基-羟基,芳基, 杂芳基,杂环基,或卤代烷基; η 为0,1,2,3 或4 ; Y为- NR6R7,-CR6R7Ri^ -烷基-NH2,它们中的每一个可被一个或一个以上选自下列基团的取代基任选地取代:羟基,烷氧基,烷基,烯基,炔基,一NH2,卤素,一N(R5) 2,-烷氧基_烷基,一烷氧基_條基,一C(O)-烷基,一C (0)-〇-烷基,一C (0)-N(R5) 2,芳基,杂芳基,一CO-芳基和-CO-杂芳基, 其中,R6,1?7和R 8独立地为氣,烷基,條基,烷氧基,烷基氣 An alkyl - aryl, heteroaryl, a group burn - a heterocyclic group, an O -R4, -R4 a 〇_ group, a group -O-R4, a C (0) -R4, a C (0) -NH-R4, a C (0) -NR4R4, - _ alkyl -C (O) -R4, a group -C (0) -O-R4, a C (0) -O-R4, 10 -C (0) -R4, a S-R4, a C (0) -S-R4, a SC (0) -R4 »a S (0) 2_R4, a NH-S (0) 2_R4, an alkyl group -S-R4, a group -S (0) 2-R4, a NHR4, a NR4 R4, a group -R4 burn NH-, halogen, a CN and -SH, wherein, R4 is independently hydrogen, an alkyl group , an alkenyl group, an alkoxy group, an alkyl - hydroxy, aryl, heteroaryl, heterocyclyl, or haloalkyl; [eta] 3, or 4; Y is - NR6R7, -CR6R7Ri ^ - alkyl -NH2, each of which may be substituted with one or more groups selected from the substituent group thereof optionally substituted with: a hydroxyl group, an alkoxy group, an alkyl group, an alkenyl group, an alkynyl group, an NH2, a halogen, a N (R5) 2, - _ alkoxy group, an alkoxy group _ bars, a C (O) - alkyl, a C (0) -〇- alkyl group, a C (0) -N ( R5) 2, aryl, heteroaryl, aryl-CO- and -CO- a heteroaryl, wherein, R6,1? 7 and R 8 are independently air, alkyl, article group, an alkoxy group, gas-yl ,^烷基氣基,烧硫基,芳硫基,一烷基-羟基,一烷基-C (0) -O-R9,一烷基-C (0) _1?9或-烷基-〇_C (0) -R 9,其中,R5 分别独立地为氢,烷基,卤代烷基,一烷基-芳基或一烷基-杂芳基,其中,R9为氢,烷基,烯基,卤素或卤代烷基; 任选地,X和Z -同可形成5至9元环。 , ^ Alkyl group gas, burning arylthio group, an alkyl - hydroxy, a group -C (0) -O-R9, a group -C (0) _1 9 or? - alkyl - 〇_C (0) -R 9, wherein, R5 are each independently hydrogen, alkyl, haloalkyl, monoalkylamino - an aryl group or an alkyl - heteroaryl, wherein, R9 is hydrogen, alkyl, alkenyl, group, halo or haloalkyl; optionally, X and Z - can be formed with the ring 5-9 yuan.
  2. 2.如权利要求1所述的化合物,其中,AM选自:2_丙基噻唑并[4, 5-c]喹啉-4-胺,1-(2-甲基丙基)-1Η-咪唑并[4, 5-c]喹啉-4-胺,4-氨基-2-(乙氧基甲基)-a, a-二-甲基-IH-咪唑并[4, 5-c]喹啉-1-乙醇,1-(4-氨基-2-乙基氨基甲基咪唑并-[4, 5-c]喹啉-1-基)-2-甲基丙-2-醇,N-[4-(4-氨基-2-乙基-IH-咪唑并[4, 5-c] 喹啉-1-基)丁基-]甲磺酰胺,4-氨基-2-乙氧基甲基-aa-二甲基-6, 7, 8, 9-四氢-IH-咪唑并[4, 5-c]喹啉-1-乙醇,4-氨基-aa-二甲基-2-甲氧基乙基-IH-咪唑并[4, 5-c]喹啉-1-乙醇,1-{2-[3-(苄氧基)丙氧基]乙基}-2-(乙氧基甲基)-IH-咪唑并[4, 5-c]喹啉-4-胺,N-[4-(4-氨基-2-丁基-IH-咪唑并[4, 5-c] [1,5]萘啶-1-基)丁基]-n'_ 丁基脲,Nl-[2-(4-氨基-2-丁基-IH-咪唑并[4, 5-c] [1,5]萘啶-1-基)乙基]-2-氨基-4-甲基戊酰胺,N-(2-{2-[4-氨基-2-(2-甲氧基乙基)-IH-咪唑并[4, 5-c]喹啉-1-基]乙氧基}乙基)-η' -苯基脲,1- (2-氨基 2. The compound according to claim 1, wherein, AM is selected from: propyl 2_ thiazolo [4, 5-c] quinolin-4-amine, 1- (2-methylpropyl) -1Η- imidazo [4, 5-c] quinolin-4-amine, 4-amino-2- (ethoxymethyl) -a, a- two - methyl -IH- imidazo [4, 5-c] quinoline-1-ethanol, 1- (4-aminomethyl-2-ethyl imidazo - [4, 5-c] quinolin-1-yl) -2-methyl-propan-2-ol, N - [4- (4-amino-2-ethyl -IH- imidazo [4, 5-c] quinolin-1-yl) butyl -] methanesulfonamide, 2-ethoxy-4-carboxylic yl -aa- dimethyl-6, 7, 8, 9-tetrahydro -IH- imidazo [4, 5-c] quinoline-1-ethanol, 4-amino-2-dimethyl -aa- oxyethyl -IH- imidazo [4, 5-c] quinoline-1-ethanol, 1- {2- [3- (benzyloxy) propoxy] ethyl} -2- (ethoxymethyl methyl) -IH- imidazo [4, 5-c] quinolin-4-amine, N- [4- (4- amino-2-butyl -IH- imidazo [4, 5-c] [1 , 5] naphthyridin-1-yl) butyl] -n'_ butyl urea, nl- [2- (4- amino-2-butyl -IH- imidazo [4, 5-c] [1, 5] naphthyridine-1-yl) ethyl] -2-amino-4-methyl-pentanamide, N- (2- {2- [4- amino-2- (2-methoxyethyl) at -IH - and imidazo [4, 5-c] quinolin-1-yl] ethoxy} ethyl) -η '- phenyl urea, 1- (2-amino -2-甲基丙基)-2-(乙氧基甲基)-IH-咪唑并[4, 5-c] 喹啉-4-胺,1-{4-[(3,5_二氯苯基)磺酰基]丁基}-2_乙基-IH-咪唑并[4,5-c]喹啉-4-胺,N-(2-{2-[4-氨基-2-(乙氧基甲基)-1Η-咪唑并[4,5-c]喹啉-1-基]乙氧基}乙基)-n'_环己基脲,N-{3-[4-氨基-2-(乙氧基甲基)-1Η-咪唑并[4,5-c]喹啉-1-基]丙基} -η' - (3-氰基苯基)硫脲,N- [3- (4-氨基-2- 丁基-IH-咪唑并[4, 5-c] 喹啉-1-基)-2, 2-二甲基丙基]苯甲酰胺,2-丁基-1-[3-(甲基磺酰基)丙基]-IH-咪唑并[4, 5-c]喹啉-4-胺,N- {2- [4-氨基-2-(乙氧基甲基)-IH-咪唑并[4, 5-c]喹啉-1-基]-1,1-二甲基乙基}-2-乙氧基乙酰胺,1-[4_氨基-2-乙氧基甲基-7-(吡啶-4-基)-IH-咪唑并[4, 5-c]喹啉-1-基]-2-甲基丙-2-醇,1-[4-氨基-2-(乙氧基甲基)-7-(吡啶-3-基)-IH-咪唑并[4, 5-c]喹啉-1-基]-2-甲基丙-2-醇,N-{3-[4-氨基-1-(2-羟基-2-甲基丙基)-2-(甲氧基乙基)-IH-咪唑并[4, 5-c]喹啉-7-基]苯基} 2-methylpropyl) -2- (ethoxymethyl) -IH- imidazo [4, 5-c] quinolin-4-amine, 1- {4 - [(dichloro 3,5_ phenyl) sulfonyl] butyl} ethyl -2_ -IH- imidazo [4,5-c] quinolin-4-amine, N- (2- {2- [4- amino-2- (ethyl oxymethyl) -1Η- imidazo [4,5-c] quinolin-1-yl] ethoxy} ethyl) -n'_ cyclohexylurea, N- {3- [4- amino-2 - (ethoxymethyl) -1Η- imidazo [4,5-c] quinolin-1-yl] propyl} -η '- (3- cyanophenyl) thiourea, N- [3- (4-amino-2-butyl -IH- imidazo [4, 5-c] quinolin-1-yl) -2,2-dimethylpropyl] benzamide, 2-butyl-1 [3- (methylsulfonyl) propyl] -IH- imidazo [4, 5-c] quinolin-4-amine, N- {2- [4- amino-2- (ethoxymethyl) -IH- imidazo [4, 5-c] quinolin-1-yl] -1,1-dimethylethyl} -2-ethoxy acetamide, l- [4_-2-ethoxyphenyl yl-methyl-7- (pyridin-4-yl) -IH- imidazo [4, 5-c] quinolin-1-yl] -2-methyl-propan-2-ol, 1- [4-amino - 2- (ethoxymethyl) -7- (pyridin-3-yl) -IH- imidazo [4, 5-c] quinolin-1-yl] -2-methyl-propan-2-ol, N - {3- [4-amino-1- (2-hydroxy-2-methylpropyl) -2- (methoxyethyl) -IH- imidazo [4, 5-c] quinolin-7 yl] phenyl} 磺酰胺,1- [4-氨基-7- (5-羟基甲基吡啶-3-基)-2- (2-甲氧基乙基)-IH-咪唑并[4, 5-c] 喹啉-1-基]-2-甲基丙-2-醇,3-[4-氨基-2-(乙氧基甲基)-7-(吡啶-3-基)-IH-咪唑并[4,5-c]喹啉-1-基]丙-1,2-二醇,1-[2-(4_氨基-2-乙氧基甲基-IH-咪唑并[4,5-c]喹啉-1-基)-1,1-二甲基乙基]-3-丙基脲,1-[2-(4_氨基-2-乙氧基甲基-IH-咪唑并[4,5-c]喹啉-1-基)-1,1-二甲基乙基]-3-环戊基脲,l-[(2,2-二甲基-1,3-二氧戊环-4-基)甲基]-2-(乙氧基甲基)-7- (4-羟基甲基苯基)-IH-咪唑并[4, 5-c]喹啉-4-胺,4-[4_氨基-2-乙氧基甲基-1-(2-羟基-2-甲基丙基)-1Η-咪唑并[4,5-c] 喹啉-7-基]-N-甲氧基-N-甲基苯甲酰胺,2-乙氧基甲基-NI-异丙基-6, 7, 8, 9-四氢-IH-咪唑并[4, 5-c]喹啉-1,4-二胺,1-[4-氨基-2-乙基-7-(吡啶-4-基)-IH-咪唑并[4, 5-c]喹啉-1-基]-2-甲基丙-2-醇,N-[4-(4-氨基-2-乙基-IH-咪唑并[4, 5-c] 喹啉-1-基)丁基]甲磺酰胺,和N-[4-(4- Sulfonamide, [4-amino-7- (5-hydroxymethyl-pyridin-3-yl) -2- (2-methoxyethyl) -IH- imidazo [4, 5-c] quinoline 1-yl] -2-methyl-propan-2-ol, 3- [4-amino-2- (ethoxymethyl) -7- (pyridin-3-yl) -IH- imidazo [4, 5-c] quinolin-1-yl] propan-1,2-diol, 1- [2- (4_-amino-2-ethoxymethyl--IH- imidazo [4,5-c] quinolin 1-yl) -1,1-dimethyl-ethyl] -3-propyl-urea, 1- [2- (4_-amino-2-ethoxymethyl--IH- imidazo [4,5 -C] quinolin-1-yl) -1,1-dimethylethyl] -3-cyclopentyl-urea, l - [(2,2- dimethyl-1,3-dioxolane - 4- yl) methyl] -2- (ethoxymethyl) -7- (4-hydroxy-methylphenyl) -IH- imidazo [4, 5-c] quinolin-4-amine, 4- [4_ amino-2-ethoxymethyl-1- (2-hydroxy-2-methylpropyl) -1Η- imidazo [4,5-c] quinolin-7-yl] -N- methyl -N- methylbenzamide group, 2-ethoxymethyl -NI- isopropyl-6, 7, 8, 9-tetrahydro -IH- imidazo [4, 5-c] quinoline - 1,4-diamine, 1- [4-amino-2-ethyl-7- (pyridin-4-yl) -IH- imidazo [4, 5-c] quinolin-1-yl] -2- methylpropan-2-ol, N- [4- (4- ethyl--IH- imidazo [4, 5-c] quinolin-1-yl) butyl] methanesulfonamide, and N - [4- (4- 氨基-2- 丁基-IH-咪唑并[4, 5-c] [1,5]萘啶_1_基)丁基]_n'-环己基脈。 Amino-2-butyl -IH- imidazo [4, 5-c] [1,5] naphthyridin-_1_ yl) butyl] _n'- cyclohexyl veins.
  3. 3. 如权利要求1或2所述的化合物,其中,L由下述通式(II)的结构表示: 3. The compound of claim 1 or claim 2, wherein, L is represented by the following structural formula (II) is:
    Figure CN104861063AC00041
    m为1,2, 3,4, 5或6,b分别独立地为O或1,并且D由下述通式(III)的结构独立地表示: m is 1, 2, 3, 4, 5 or 6, b are each independently O or 1, and D is independently represented by the following structural formula (III) is:
    Figure CN104861063AC00042
    其中,i分别独立地为〇或1 ; j分别独立地为〇,1,2,3,4,5或6 ; A分别独立地为S,O或N-Ra,其中,Ra为氢,烷基,烯基或烷氧基; B分别独立地为烷基,條基,一〇-烷基一,一烷基-〇-,一S-烷基一,一烷基-S-,芳基,杂芳基,杂环基或肽,它们中的每一个被一个或一个以上选自下列基团的取代基任选地取代:羟基,烷氧基,烷基,烯基,炔基,环烷基,一烷基-芳基,一烷基-杂芳基,一烷基-杂环基,一O -R4,一〇_ 烷基-R4, 一C (0) -R4,一C (0) -O-R4,一S-R4,一S (0) 2-R4, 一NHR4,一NH-烧基-R4,卤素,一CN,一NO2,和-SH,其中,R 4为烷基,烯基,一烷基-羟基,芳基,杂芳基,杂环基或卤代烷基。 Here, i each independently square or 1; j billion each independently, 1,2,3,4,5 or 6; A is independently S, O or N-Ra, wherein, Ra of the hydrogen, alkyl group, an alkenyl group or an alkoxy group; B is independently an alkyl group, article group, an alkyl group 〇- a, a -〇- alkyl, a group a S-, a group -S-, an aryl group , heteroaryl, heterocyclyl or peptides, each of them with one or more groups selected from substituent group is optionally substituted with: hydroxy, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, alkyl group, an alkyl - aryl group, an alkyl - aryl, heteroaryl, a group - a heterocyclic group, an O -R4, -R4 a 〇_ alkyl, a C (0) -R4, a C ( 0) -O-R4, a S-R4, a S (0) 2-R4, a NHR4, NH- burning a -R4 group, a halogen, a CN, an NO2, and -SH, wherein, R 4 is alkyl group, an alkenyl group, an alkyl - hydroxy, aryl, heteroaryl, heterocyclyl or haloalkyl.
  4. 4. 如权利要求3所述的化合物,其中,L由下述通式(V)至通式(VII)的结构表示: 4. The compound according to claim 3, wherein, L is represented by the following structural formula (V) to formula (VII) is:
    Figure CN104861063AC00051
    A、B、i和j为如上所界定的。 A, B, i and j are as defined above.
  5. 5.如权利要求4所述的化合物,其中,所述连接体选自:51,52,53,54,55,56,57,-61 y-Phe-Leu-Gly-,-Ala-Leu-Ala-Leu-,-Phe-Arg-,-Phe-Lys-,-Val-Lys-,-Val-Ala-,或Val-Cit-,其中,SI至S7由下述结构表示: 5. The compound according to claim 4, wherein said linker is selected from: 51,52,53,54,55,56,57, -61 y-Phe-Leu-Gly -, - Ala-Leu- ala-Leu -, - Phe-Arg -, - Phe-Lys -, - Val-Lys -, - Val-Ala-, or Val-Cit-, wherein, SI to S7 represented by the following structure:
    Figure CN104861063AC00052
    Figure CN104861063AC00061
    其中,m分别独立地为1至20。 Wherein, m are each independently 1 to 20.
    Figure CN104861063AC00071
  6. 6. 如权利要求1至5任一项所述的化合物,其中,所述抗体为曲妥珠单抗(赫赛汀),帕妥珠单抗或margetuximab (MGAH22)。 Compound of any one of claims 1 to 5, as claimed in claim 6, wherein the antibody is trastuzumab (Herceptin), pertuzumab or margetuximab (MGAH22).
  7. 7. 如权利要求1所述的化合物,其中,TM是抗-HER2抗体,L选自: SI,S2, S3, S4, S5, S6, S7, - Gly-Phe-Leu-Gly-,-Ala-Leu-Ala-Leu-,-Phe-Arg-,-Phe-Lys -,-Val-Lys-,-Val-Ala-,或Val-Cit-;AM是通式(I)的化合物,其选自:2_丙基噻唑并[4, 5-c]喹啉-4-胺,1-(2-甲基丙基)-IH-咪唑并[4, 5-c]喹啉-4-胺,4-氨基-2-(乙氧基甲基)-a, a-二-甲基-IH-咪唑并[4, 5-c]喹啉-1-乙醇,1-(4-氨基-2-乙基氨基甲基咪唑并-[4, 5-c]喹啉-1-基)-2-甲基丙-2-醇,N-[4-(4-氨基-2-乙基-IH-咪唑并[4, 5-c]喹啉-1-基)丁基-]甲磺酰胺,4-氨基-2-乙氧基甲基-aa-二甲基-6, 7, 8, 9-四氢-IH-咪唑并[4, 5-c]喹啉-1-乙醇,4-氨基-aa-二甲基-2-甲氧基乙基-IH-咪唑并[4, 5-c]喹啉-1-乙醇,1-{2-[3-(苄氧基)丙氧基]乙基}-2-(乙氧基甲基)-1Η-咪唑并[4, 5-c]喹啉-4-胺,N-[4-(4-氨基-2- 丁基-IH-咪唑并[4, 5-c] [1,5]萘啶-1-基) 丁基]-η' - 丁基脲,Nl- [2- (4-氨基-2- 丁基-IH-咪 7. The compound according to claim 1, wherein, TM antibody is an anti--HER2, L is selected from: SI, S2, S3, S4, S5, S6, S7, - Gly-Phe-Leu-Gly -, - Ala -Leu-Ala-Leu -, - Phe-Arg -, - Phe-Lys -, - Val-Lys -, - Val-Ala-, or Val-Cit-; AM is a compound of formula (I) is selected from the group from: 2_ propyl-thiazolo [4, 5-c] quinolin-4-amine, 1- (2-methylpropyl) -IH- imidazo [4, 5-c] quinolin-4-amine , 4-amino-2- (ethoxymethyl) -a, a- two - methyl -IH- imidazo [4, 5-c] quinoline-1-ethanol, 1- (4-amino-2 - ethylamino methylimidazo - [4, 5-c] quinolin-1-yl) -2-methyl-propan-2-ol, N- [4- (4- amino-2-ethyl -IH - and imidazo [4, 5-c] quinolin-1-yl) butyl -] methanesulfonamide, 4-amino-2-ethoxymethyl--aa- dimethyl-6, 7, 8, 9 - tetrahydro -IH- imidazo [4, 5-c] quinoline-1-ethanol, 4-amino -aa--dimethyl-2-methoxyethyl -IH- imidazo [4, 5-c ] quinoline-1-ethanol, 1- {2- [3- (benzyloxy) propoxy] ethyl} -2- (ethoxymethyl) -1Η- imidazo [4, 5-c] quinolin-4-amine, N- [4- (4- amino-2-butyl -IH- imidazo [4, 5-c] [1,5] naphthyridin-1-yl) butyl] eta '- butyl urea, nl- [2- (4- amino-2-butyl-imidazol -IH- 并[4, 5-c] [1,5]萘啶-1-基) 乙基]-2-氨基-4-甲基戊酰胺,Ν-(2-{2-[4-氨基-2-(2-甲氧基乙基)-1Η-咪唑并[4, 5-c]喹啉-1-基]乙氧基}乙基)-η'_苯基脲,1-(2-氨基-2-甲基丙基)-2-(乙氧基甲基)-IH-咪唑并[4, 5-c]喹啉-4-胺,1-{4-[ (3, 5-二氯苯基)磺酰基]丁基}-2-乙基-IH-咪唑并[4, 5-c]喹啉-4-胺,N- (2- {2- [4-氨基-2-(乙氧基甲基)-IH-咪唑并[4,5-c]喹啉-1-基]乙氧基}乙基)-n'_环己基脲,N-{3-[4-氨基-2-(乙氧基甲基)-IH-咪唑并[4, 5-c]喹啉-1-基]丙基}-η'- (3-氰基苯基)硫脲,N-[3-(4-氨基-2-丁基-IH-咪唑并[4, 5-c]喹啉-1-基)-2,2-二甲基丙基]苯甲酰胺,2-丁基-1-[3-(甲基磺酰基)丙基]-IH-咪唑并[4, 5-c]喹啉-4-胺,N-{2-[4-氨基-2-(乙氧基甲基)-IH-咪唑并[4, 5-c]喹啉-1-基]-1,1-二甲基乙基}-2-乙氧基乙酰胺,1-[4-氨基-2-乙氧基甲基-7-(吡啶-4-基)-IH-咪唑并[4, 5-c]喹啉-1-基]-2-甲基丙-2-醇,1- [4-氨基-2-(乙氧 And [4, 5-c] [1,5] naphthyridin-1-yl) ethyl] -2-amino-4-methyl pentanamide, Ν- (2- {2- [4- amino-2- (2-methoxyethyl) -1Η- imidazo [4, 5-c] quinolin-1-yl] ethoxy} ethyl) -η'_ phenylurea, 1- (2-amino - 2-methylpropyl) -2- (ethoxymethyl) -IH- imidazo [4, 5-c] quinolin-4-amine, 1- {4- [(3, 5-dichlorobenzene yl) sulfonyl] butyl} -2-ethyl -IH- imidazo [4, 5-c] quinolin-4-amine, N- (2- {2- [4- amino-2- (ethoxymethyl ylmethyl) -IH- imidazo [4,5-c] quinolin-1-yl] ethoxy} ethyl) -n'_ cyclohexylurea, N- {3- [4- amino-2- (ethoxymethyl) -IH- imidazo [4, 5-c] quinolin-1-yl] propyl} -η'- (3- cyanophenyl) thiourea, N- [3- ( 4-amino-2-butyl -IH- imidazo [4, 5-c] quinolin-1-yl) -2,2-dimethylpropyl] benzamide, 2-butyl-1- [ 3- (methylsulfonyl) propyl] -IH- imidazo [4, 5-c] quinolin-4-amine, N- {2- [4- amino-2- (ethoxymethyl) - IH- imidazo [4, 5-c] quinolin-1-yl] -1,1-dimethylethyl} -2-ethoxy-acetamide, 1- [4-amino-2-ethoxy methyl-7- (pyridin-4-yl) -IH- imidazo [4, 5-c] quinolin-1-yl] -2-methyl-propan-2-ol, 1- [4-amino-2 - (ethoxycarbonyl 基甲基)-7-(吡啶-3-基)-1Η-咪唑并[4, 5-c]喹啉-1-基]-2-甲基丙-2-醇,N-{3-[4-氨基-1-(2-羟基-2-甲基丙基)-2-(甲氧基乙基)-1Η-咪唑并[4, 5-c]喹啉-7-基]苯基}甲磺酰胺,1-[4-氨基-7-(5-羟基甲基吡啶-3-基)-2-(2-甲氧基乙基)-IH-咪唑并[4, 5-c]喹啉-1-基]-2-甲基丙-2-醇,3-[4-氨基-2-(乙氧基甲基)-7-(吡啶-3-基)-1Η-咪唑并[4,5-c]喹啉-1-基]丙-1,2-二醇,1-[2-(4_氨基-2-乙氧基甲基-IH-咪唑并[4, 5-c]喹啉-1-基)-1,1-二甲基乙基]-3-丙基脲,1-[2-(4_氨基-2-乙氧基甲基-IH-咪唑并[4,5-c]喹啉-1-基)-1,1-二甲基乙基]-3-环戊基脲,1-[ (2, 2-二甲基-1,3-二氧戊环-4-基)甲基]-2-(乙氧基甲基)-7-(4-羟基甲基苯基)-1Η-咪唑并[4,5-c]喹啉-4-胺,4-[4_氨基-2-乙氧基甲基-1-(2-羟基-2-甲基丙基)-IH-咪唑并[4, 5-c]喹啉-7-基]-N-甲氧基-N-甲基苯甲酰胺,2-乙氧基甲基-NI-异丙基-6, 7, 8, 9-四氢-IH-咪唑并[4, 5-c]喹啉-1,4- Ylmethyl) -7- (pyridin-3-yl) -1Η- imidazo [4, 5-c] quinolin-1-yl] -2-methyl-propan-2-ol, N- {3- [ 4-amino-1- (2-hydroxy-2-methylpropyl) -2- (methoxyethyl) -1Η- imidazo [4, 5-c] quinolin-7-yl] phenyl} methanesulfonamide, 1- [4-amino-7- (5-hydroxymethyl-pyridin-3-yl) -2- (2-methoxyethyl) -IH- imidazo [4, 5-c] quinolin -1-yl] -2-methyl-propan-2-ol, 3- [4-amino-2- (ethoxymethyl) -7- (pyridin-3-yl) -1Η- imidazo [4 , 5-c] quinolin-1-yl] propan-1,2-diol, 1- [2- (4_-amino-2-ethoxymethyl--IH- imidazo [4, 5-c] quinolin-1-yl) -1,1-dimethyl-ethyl] -3-propyl-urea, 1- [2- (4_-amino-2-ethoxymethyl--IH- imidazo [4, 5-c] quinolin-1-yl) -1,1-dimethylethyl] -3-cyclopentyl-urea, 1- [(2, 2-dimethyl-1,3-dioxolane 4-yl) methyl] -2- (ethoxymethyl) -7- (4-hydroxy-methylphenyl) -1Η- imidazo [4,5-c] quinolin-4-amine, 4 - [4_ amino-2-ethoxymethyl-1- (2-hydroxy-2-methylpropyl) -IH- imidazo [4, 5-c] quinolin-7-yl] -N- methoxy -N- methyl-benzamide, 2-ethoxymethyl -NI- isopropyl-6, 7, 8, 9-tetrahydro -IH- imidazo [4, 5-c] quinoline 1,4 二胺,1-[4-氨基-2-乙基-7-(吡啶-4-基)-IH-咪唑并[4, 5-c]喹啉-1-基]-2-甲基丙-2-醇,N-[4-(4-氨基-2-乙基-IH-咪唑并[4, 5-c]喹啉-1-基)丁基]甲磺酰胺, 或N-[4-(4-氨基-2-丁基-IH-咪唑并[4,5-c] [1,5]萘啶-1-基)丁基]-n'_环己基脲, 其中,喹啉环上的胺基团为与连接体连接的点。 Diamine, 1- [4-amino-2-ethyl-7- (pyridin-4-yl) -IH- imidazo [4, 5-c] quinolin-1-yl] -2-methyl propyl - 2- ol, N- [4- (2-ethyl-4- -IH- imidazo [4, 5-c] quinolin-1-yl) butyl] methanesulfonamide, or N- [4- (4-amino-2-butyl -IH- imidazo [4,5-c] [1,5] naphthyridin-1-yl) butyl] -n'_ cyclohexylurea, wherein, on the quinoline ring the amine group is connected to the connecting point thereof.
  8. 8. 如权利要求7所述的化合物,其中,所述抗-HER2抗体是曲妥珠单抗(赫赛汀),帕妥珠单抗或margetuximab (MGAH22) ;L 是Sl,S2 或S3。 8. The compound according to claim 7, wherein said antibody is an anti--HER2 trastuzumab (Herceptin), pertuzumab or margetuximab (MGAH22); L is Sl, S2 or S3.
  9. 9. 如权利要求8所述的化合物,其中,所述抗-HER2抗体是曲妥珠单抗(赫赛汀);AM是瑞喹莫德或咪喹莫特,其中,喹啉环上的胺基团是与连接体连接的点。 9. The compound according to claim 8, wherein said antibody is an anti--HER2 trastuzumab (Herceptin); AM is resiquimod or imiquimod, wherein, on the quinoline ring amine group is the point of attachment to the linker.
  10. 10. -种具有通式A至通式C的结构的化合物或其药学上可接受的盐或其溶剂化物: 10. - A compound having the general formula A kind of structure to the general formula C, or a pharmaceutically acceptable salt or solvate thereof:
    Figure CN104861063AC00091
  11. 11.如权利要求10所述的化合物,其中,所述抗-HER2抗体是曲妥珠单抗(赫赛汀), 帕妥珠单抗或margetuximab (MGAH22);通式(I)的化合物选自:2_丙基噻挫并[4,5_c] 喹啉-4-胺,1-(2-甲基丙基)-IH-咪唑并[4, 5-c]喹啉-4-胺,4-氨基-2-(乙氧基甲基)-a, a-二-甲基-IH-咪唑并[4, 5-c]喹啉-1-乙醇,1-(4-氨基-2-乙基氨基甲基咪唑并-[4, 5-c]喹啉-1-基)-2-甲基丙-2-醇,N-[4-(4-氨基-2-乙基-IH-咪唑并[4, 5-c] 喹啉-1-基)丁基-]甲磺酰胺,4-氨基-2-乙氧基甲基-aa-二甲基-6, 7, 8, 9-四氢-IH-咪唑并[4, 5-c]喹啉-1-乙醇,4-氨基-aa-二甲基-2-甲氧基乙基-IH-咪唑并[4, 5-c]喹啉-1-乙醇,1-{2-[3-(苄氧基)丙氧基]乙基}-2-(乙氧基甲基)-IH-咪唑并[4, 5-c]喹啉-4-胺,N-[4-(4-氨基-2-丁基-IH-咪唑并[4, 5-c] [1,5]萘啶-1-基)丁基]-n'_ 丁基脲,Nl-[2-(4-氨基-2-丁基-IH-咪唑并[4, 5-c] [1,5]萘啶-1-基)乙基]-2-氨基-4-甲基戊酰胺,N-(2-{2-[ 11. The compound according to claim 10, wherein said antibody is an anti--HER2 trastuzumab (Herceptin), pertuzumab or margetuximab (MGAH22); compound selected from formula (I) is from: propyl-thiazol setback and 2_ [4,5_c] quinolin-4-amine, 1- (2-methylpropyl) -IH- imidazo [4, 5-c] quinolin-4-amine, 4-amino-2- (ethoxymethyl) -a, a- two - methyl -IH- imidazo [4, 5-c] quinoline-1-ethanol, 1- (4-amino-2- ethylamino methylimidazo - [4, 5-c] quinolin-1-yl) -2-methyl-propan-2-ol, N- [4- (4- amino-2-ethyl -IH- imidazo [4, 5-c] quinolin-1-yl) butyl -] methanesulfonamide, 4-amino-2-ethoxymethyl--aa- dimethyl-6, 7, 8, 9 tetrahydro -IH- imidazo [4, 5-c] quinoline-1-ethanol, 4-amino -aa--dimethyl-2-methoxyethyl -IH- imidazo [4, 5-c] quinoline-1-ethanol, 1- {2- [3- (benzyloxy) propoxy] ethyl} -2- (ethoxymethyl) -IH- imidazo [4, 5-c] quinolin -4-amine, N- [4- (4- amino-2-butyl -IH- imidazo [4, 5-c] [1,5] naphthyridin-1-yl) butyl] -n ' _ butyl urea, nl- [2- (4- amino-2-butyl -IH- imidazo [4, 5-c] [1,5] naphthyridin-1-yl) ethyl] -2-amino -4-methyl-pentanamide, N- (2- {2- [ 4-氨基-2-(2-甲氧基乙基)-IH-咪唑并[4, 5-c]喹啉-1-基]乙氧基}乙基)-η' -苯基脲,1- (2-氨基-2-甲基丙基)-2-(乙氧基甲基)-IH-咪唑并[4, 5-c] 喹啉-4-胺,1-{4-[(3,5_二氯苯基)磺酰基]丁基}-2_乙基-IH-咪唑并[4,5-c]喹啉-4-胺,N-(2-{2-[4-氨基-2-(乙氧基甲基)-1Η-咪唑并[4,5-c]喹啉-1-基]乙氧基}乙基)-n'_环己基脲,N-{3-[4-氨基-2-(乙氧基甲基)-1Η-咪唑并[4,5-c]喹啉-1-基]丙基} -η' - (3-氰基苯基)硫脲,N- [3- (4-氨基-2- 丁基-IH-咪唑并[4, 5-C] 喹啉-1-基)-2, 2-二甲基丙基]苯甲酰胺,2-丁基-1-[3-(甲基磺酰基)丙基]-IH-咪唑并[4, 5-c]喹啉-4-胺,N- {2- [4-氨基-2-(乙氧基甲基)-IH-咪唑并[4, 5-c]喹啉-1-基]-1,1-二甲基乙基}-2-乙氧基乙酰胺,1-[4_氨基-2-乙氧基甲基-7-(吡啶-4-基)-IH-咪唑并[4, 5-c]喹啉-1-基]-2-甲基丙-2-醇,1-[4-氨基-2-(乙氧基甲基)-7-(吡啶-3-基)-IH-咪唑并[4, 5-c]喹啉-1-基]-2-甲基丙-2 4-amino-2- (2-methoxyethyl) -IH- imidazo [4, 5-c] quinolin-1-yl] ethoxy} ethyl) -η '- phenylurea, 1 - (2-amino-2-methylpropyl) -2- (ethoxymethyl) -IH- imidazo [4, 5-c] quinolin-4-amine, 1- {4 - [(3 , 5_ dichlorophenyl) sulfonyl] butyl} ethyl -2_ -IH- imidazo [4,5-c] quinolin-4-amine, N- (2- {2- [4- amino 2- (ethoxymethyl) -1Η- imidazo [4,5-c] quinolin-1-yl] ethoxy} ethyl) -n'_ cyclohexylurea, N- {3- [ 4-amino-2- (ethoxymethyl) -1Η- imidazo [4,5-c] quinolin-1-yl] propyl} -η '- (3- cyanophenyl) thiourea, N- [3- (4- amino-2-butyl -IH- imidazo [4, 5-C] quinolin-1-yl) -2,2-dimethylpropyl] benzamide, 2- butyl-1- [3- (methylsulfonyl) propyl] -IH- imidazo [4, 5-c] quinolin-4-amine, N- {2- [4- amino-2- (ethyl oxymethyl) -IH- imidazo [4, 5-c] quinolin-1-yl] -1,1-dimethylethyl} -2-ethoxy acetamide, l- [4_ amino -2-ethoxy-methyl-7- (pyridin-4-yl) -IH- imidazo [4, 5-c] quinolin-1-yl] -2-methyl-propan-2-ol, 1- [4-amino-2- (ethoxymethyl) -7- (pyridin-3-yl) -IH- imidazo [4, 5-c] quinolin-1-yl] -2-methyl propyl - 2 -醇,N-{3-[4-氨基-1-(2-羟基-2-甲基丙基)-2-(甲氧基乙基)-IH-咪唑并[4, 5-c]喹啉-7-基]苯基}甲磺酰胺,1- [4-氨基-7- (5-羟基甲基吡啶-3-基)-2- (2-甲氧基乙基)-IH-咪唑并[4, 5-c] 喹啉-1-基]-2-甲基丙-2-醇,3-[4-氨基-2-(乙氧基甲基)-7-(吡啶-3-基)-IH-咪唑并[4,5-c]喹啉-1-基]丙-1,2-二醇,1-[2-(4_氨基-2-乙氧基甲基-IH-咪唑并[4,5-c]喹啉-1-基)-1,1-二甲基乙基]-3-丙基脲,1-[2-(4_氨基-2-乙氧基甲基-IH-咪唑并[4,5-c]喹啉-1-基)-1,1-二甲基乙基]-3-环戊基脲,1-[(2,2_二甲基-1,3-二氧戊环-4-基)甲基]-2-(乙氧基甲基)-7- (4-羟基甲基苯基)-IH-咪唑并[4, 5-c]喹啉-4-胺,4-[4_氨基-2-乙氧基甲基-1-(2-羟基-2-甲基丙基)-1Η-咪唑并[4,5-c] 喹啉-7-基]-N-甲氧基-N-甲基苯甲酰胺,2-乙氧基甲基-NI-异丙基-6, 7, 8, 9-四氢-IH-咪唑并[4, 5-c]喹啉-1,4-二胺,1-[4-氨基-2-乙基-7-(吡啶-4-基)-IH-咪唑并[4, 5-c]喹啉-1-基 - alcohol, N- {3- [4- amino-1- (2-hydroxy-2-methylpropyl) -2- (methoxyethyl) -IH- imidazo [4, 5-c] quinolin 7-yl] phenyl} methanesulfonamide, 1- [4-amino-7- (5-hydroxymethyl-pyridin-3-yl) -2- (2-methoxyethyl) -IH- imidazole and [4, 5-c] quinolin-1-yl] -2-methyl-propan-2-ol, 3- [4-amino-2- (ethoxymethyl) -7- (pyridin-3 yl) -IH- imidazo [4,5-c] quinolin-1-yl] propan-1,2-diol, 1- [2- (4_ amino-2-ethoxymethyl -IH- imidazo [4,5-c] quinolin-1-yl) -1,1-dimethyl-ethyl] -3-propyl-urea, 1- [2- (2-ethoxy-methyl-amino 4_ yl -IH- imidazo [4,5-c] quinolin-1-yl) -1,1-dimethylethyl] -3-cyclopentyl-urea, 1 - [(dimethylamino 2,2_ 1,3-dioxolan-4-yl) methyl] -2- (ethoxymethyl) -7- (4-hydroxy-methylphenyl) -IH- imidazo [4, 5-c ] quinolin-4-amine, 4- [4_ amino-2-ethoxymethyl-1- (2-hydroxy-2-methylpropyl) -1Η- imidazo [4,5-c] quinolin -7-yl] -N- methoxy -N- methyl-benzamide, 2-ethoxymethyl -NI- isopropyl-6, 7, 8, 9-tetrahydro-imidazo -IH- [4, 5-c] quinoline-1,4-diamine, 1- [4-amino-2-ethyl-7- (pyridin-4-yl) -IH- imidazo [4, 5-c] quinolin-1-yl ]-2-甲基丙-2-醇,N-[4-(4-氨基-2-乙基-IH-咪唑并[4, 5-c] 喹啉-1-基)丁基]甲磺酰胺,或N-[4-(4-氨基-2- 丁基-IH-咪唑并[4, 5-c] [1,5]萘啶-1-基)丁基]-η' -环己基脲,其中,喹啉环上的胺基团是与所述连接体连接的点。 ] -2-methyl-propan-2-ol, N- [4- (4- ethyl--IH- imidazo [4, 5-c] quinolin-1-yl) butyl] methanesulfonamide amide, or N- [4- (4- amino-2-butyl -IH- imidazo [4, 5-c] [1,5] naphthyridin-1-yl) butyl] -η '- cyclohexyl urea, wherein the amine group on the quinoline ring is connected to the connection point thereof.
  12. 12. 如权利要求11所述的化合物,其中,通式(I)的化合物是瑞喹莫德或咪喹莫特,其中,喹啉环上的胺基团是与所述连接体连接的点。 12. The compound according to claim 11, wherein the compound of formula (I) is resiquimod or imiquimod, wherein the amine group on the quinoline ring is a point of attachment to the connecting body .
  13. 13. 如权利要求10至12中任一项所述的化合物,其中,所述抗-HER2抗体是曲妥珠单抗(赫赛汀)。 10 13. The compound according to claim 12 as claimed in claim, wherein said antibody is an anti--HER2 trastuzumab (Herceptin).
  14. 14. 一种药物组合物,所述药物组合物包含有效量的权利要求1至13任一项所述的化合物,以及一种或一种以上药学上可接受的载体。 14. A pharmaceutical composition, said pharmaceutical composition comprising an effective amount of a compound as claimed in claim any one of claims 1-13, and a pharmaceutically acceptable one or more carriers.
  15. 15. 如权利要求14所述的药物组合物,所述药物组合物还包含有效量的其他治疗剂。 15. A pharmaceutical composition according to claim 14, the pharmaceutical composition further comprises an effective amount of another therapeutic agent.
  16. 16. 如权利要求15所述的药物组合物,其中,所述其他治疗剂是抗癌剂。 16. A pharmaceutical composition according to claim 15, wherein said additional therapeutic agent is an anticancer agent.
  17. 17. 如权利要求16所述的药物组合物,其中,所述抗癌剂是抗代谢药物、拓扑异构酶I 和拓扑异构酶Π 的抑制剂、烷基化剂、微管抑制剂、抗雄性激素剂、GNRh调节剂或者它们的混合物。 17. A pharmaceutical composition according to claim 16, wherein said anticancer agent is an anti-metabolite, a topoisomerase I inhibitor and a topoisomerase Π, alkylating agents, microtubule inhibitors, anti-androgen agents, GNRh modifiers or mixtures thereof.
  18. 18. -种抑制HER2阳性肿瘤细胞增殖的方法,所述方法包括将权利要求1至13任一项所述的化合物给药于所述肿瘤细胞。 18. - The method of HER2-positive tumor cell proliferation inhibiting species, the method comprises administering a compound according to any one of claims 1 to 13, is administered to said tumor cells.
  19. 19. 一种治疗受治者体内HER2阳性肿瘤/癌症的方法,所述方法包括将权利要求1至13任一项所述的化合物给药于所述受治者。 19. A method of treating a subject in vivo HER2 positive tumors / cancer, said method comprising a compound according to any one of claims 1 to 13, said administering to a subject person.
  20. 20. 如权利要求18或19所述的方法,其中,所述肿瘤/癌症选自:食管癌、胃癌、结肠癌、直肠癌、胰腺癌、肺癌、乳腺癌、子宫颈癌、子宫体癌、卵巢癌、膀胱癌、头颈癌、子宫内膜癌、骨肉瘤、前列腺癌、神经母细胞瘤。 20. The method of claim 18 or claim 19, wherein the tumor / cancer is selected from: esophageal cancer, stomach cancer, colon cancer, colorectal cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, uterine cancer, ovarian cancer, bladder cancer, head and neck cancer, endometrial cancer, osteosarcoma, prostate cancer, neuroblastoma.
  21. 21. 权利要求1至13任一项所述的化合物在制备用于治疗受治者体内的HER2阳性肿瘤/癌症的药物中的应用。 21. The process according to any one of claims 1 to 13 in a pharmaceutical compound for the treatment of HER2-positive tumors in vivo treatment of subject / cancer applications.
  22. 22.权利要求14至17任一项所述的药物组合物在制备用于治疗受治者体内的HER2阳性肿瘤/癌症的药物中的应用。 HER2-positive tumor pharmaceutical composition according to any one of claims 14 to 17, 22 in the treatment of for the treatment in vivo by the application / cancer medicament.
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CN 201410011262 CN104861063A (en) 2014-01-10 2014-01-10 HER2 positive tumor targeting compound and composition thereof
EP20150735519 EP3092255A4 (en) 2014-01-10 2015-01-08 Compounds and compositions for treating egfr expressing tumors
CN 201580004156 CN105899537A (en) 2014-01-10 2015-01-08 Compounds and compositions for treating EGFR expressing tumors
JP2016545882A JP2017502068A5 (en) 2015-01-08
US15110690 US20160375148A1 (en) 2014-01-10 2015-01-08 Compounds and Compositions for Treating EGFR Expressing Tumors
JP2016545803A JP2017507912A5 (en) 2015-01-08
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US15110679 US20170028079A1 (en) 2014-01-10 2015-01-08 Compounds and Compositions for Treating HER2 Positive Tumors
PCT/CN2015/070380 WO2015103990A1 (en) 2014-01-10 2015-01-08 Compounds and compositions for treating egfr expressing tumors
CA 2936375 CA2936375A1 (en) 2014-01-10 2015-01-08 Compounds and compositions for treating her2 positive tumors
CN 201580004172 CN105899539A (en) 2014-01-10 2015-01-08 Compounds and compositions for immunotherapy
US15110685 US9827329B2 (en) 2014-01-10 2015-01-08 Compounds and compositions for immunotherapy
EP20150735122 EP3092254A4 (en) 2014-01-10 2015-01-08 Compounds and compositions for treating her2 positive tumors
CA 2936377 CA2936377A1 (en) 2014-01-10 2015-01-08 Compounds and compositions for treating egfr expressing tumors
CA 2936376 CA2936376A1 (en) 2014-01-10 2015-01-08 Compounds and compositions for immunotherapy
PCT/CN2015/070377 WO2015103987A1 (en) 2014-01-10 2015-01-08 Compounds and compositions for treating her2 positive tumors
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