CN115745963A - 基于nampt靶蛋白的蛋白降解化合物及其应用 - Google Patents
基于nampt靶蛋白的蛋白降解化合物及其应用 Download PDFInfo
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- piperidin
- butyl
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- acrylamide
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Abstract
本公开涉及式(I)的化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物及其应用。本公开还涉及包含作为活性成分的式(I)的化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物的药物组合物及其应用。本公开设计合成的一系列化合物能有效地预防和/或治疗与NAMPT相关的疾病或病症。
Description
技术领域
本公开涉及一种基于烟酰胺磷酸核糖转移酶(NMPRTase;NAMPT)靶蛋白设计的式(I) 的蛋白降解化合物或其盐、对映异构体、立体异构体、溶剂化物、前药或多晶型物,以及其在治疗或预防与NAMPT相关的疾病或病症的用途。
背景技术
烟酰胺腺嘌呤二核苷酸(nicotinamide adenine dinucleotide,NAD+)是一种传递氢离子的辅酶,参与能量合成、细胞物质代谢、DNA修复等多种生理功能[1],并且作为重要小分子代谢物广泛参与了氧化磷酸化、糖酵解以及脂肪酸氧化等一系列细胞能量代谢中的生化反应,因此,NAD+对于人类健康至关重要[2]。
NAD+生物合成途径共有三种[3]:
1、从头合成途径。从头合成途径是由吲哚胺2,3-二加氧酶(IDO)或色氨酸2,3-二加氧酶(TDO)启动的,它们将色氨酸转化为N-甲酰基尿氨酸。然后通过甲酰胺酶(KFase),将N-甲酰基犬尿氨酸转化为犬尿氨酸,并通过犬尿氨酸3-羟化酶(K3H)向其中加入羟基。产物3-羟基-犬尿氨酸被转化为3-羟基邻氨基苯甲酸,然后通过犬尿氨酸酶(Kyase)和3-羟基邻氨基苯甲酸酯-3,4-二加氧酶转化为2-氨基-3-羧基粘康酸半醛(ACMS)[4]。然后ACMS环化形成喹啉酸(QA),并与喹啉酸酯磷酸核糖基转移酶(QPRT)参与NAMN生物合成[5,6]。
2、Preiss–Handler pathway(烟酸补救途径)。该途径开始于通过烟酸磷酸核糖基转移酶(NAPRT)将NA转化为烟酸单核苷酸(NAMN)之后[7],NAMN通过烟酰胺/烟酸单核苷酸腺苷酸转移酶(NMNAT)用于烟酸腺嘌呤二核苷酸(NAAD)的生物合成。最后,NAD+合成酶(NADS)通过氨和ATP的作用将NAAD转化为NAD+[8,9]。
3、Salvage pathway(补救合成途径)。大多数NAD+不是从头产生,而是在salvagepathway中从NAM、NR和NMN中回收,以维持细胞NAD+水平。因此salvage pathway是哺乳动物细胞中NAD+的主要来源。NAD+消耗反应(包括NAD+依赖的脱乙酰化和ADP-核糖基化) 中,NAM可以通过NAMPT循环转化为NMN,催化回收途径中的限速反应[10]。前体NR由 NRK1/2转化为NMN,NMN被NMNAT腺苷化最终生成NAD+[2]。
烟酰胺磷酸核糖转移酶(NAMPT)是催化烟酰胺腺嘌呤二核苷酸(NAD+)合成的限速酶。
癌细胞已经改变了代谢需求,与正常细胞相比,烟酰胺腺嘌呤二核苷酸(NAD+)循环速度加快[11],因此salvage pathway这一途径对癌细胞至关重要。事实上,许多类型的癌细胞已被证明高表达NAMPT,这反映了由于NAD+的高利用率,以及在某些情况下,其他关键NAD+生物合成酶的表达缺失,潜在地增加了对这一途径的依赖[12-15]。据报道具有高NAMPT表达的癌症类型包括但不限于结直肠癌、乳腺癌、骨肉瘤、软骨肉瘤、胰腺导管腺癌、口腔鳞状细胞癌、前列腺癌、横纹肌肉瘤、平滑肌肉瘤、食管胃交界处腺癌、甲状腺癌、白血病、淋巴瘤、卵巢癌和一些肾癌,在其中许多癌症中,较高的NAMPT表达与较差的预后相关[16-32]。NMN也可以通过烟酰胺核苷激酶从烟酰胺核苷中产生[13],然而,目前NAMPT是唯一一种在临床上被靶向的NAD+生产酶。
NAMPT在哺乳动物中以两种形式存在,即细胞质和细胞核中的细胞内NAMPT(iNAMPT)和血浆或细胞外空间中的细胞外NAMPT(eNAMPT)。
NAMPT在结直肠癌、卵巢癌、乳腺癌、胃癌、前列腺癌、子宫内膜癌、黑色素瘤、多发性骨髓瘤、星形细胞瘤、肝癌、甲状腺癌、恶性淋巴瘤等若干种人类恶性肿瘤中过表达,结合其促进恶性表型的许多方面,表明抑制NAMPT可能发挥抗癌作用。NAMPT抑制也会导致ATP耗竭,降低PARP-1和SirT1活性,并最终导致细胞死亡[34-36]。由于NAD+和ATP分解代谢的增加,肿瘤细胞对于iNAMPT的抑制比正常细胞更敏感[37]。高度特异性的NAMPT抑制剂FK866可以诱导人肝癌细胞HepG2凋亡,该过程涉及NAD+的耗尽,可以通过添加NAM 或烟酸来部分逆转[33]。NAMPT抑制剂可用于治疗三阴性乳腺癌、肝癌,胃癌、具有表皮生长因子受体基因突变的非小细胞肺癌、胶质母细胞瘤、黑色素瘤等。
eNAMPT可由多种类型细胞释放,并作为细胞因子作用于多种细胞。它能够通过刺激其他细胞因子的后续释放激活细胞内的下游途径。
血浆eNAMPT在多种人类恶性肿瘤中升高,包括星形细胞瘤、骨髓瘤和男性口腔鳞状细胞癌、胃癌、子宫内膜癌、肝细胞癌、结肠直肠癌、以及侵袭性乳腺癌等[38-46]。在星形细胞瘤中,随着星形细胞瘤分级的增加,血浆eNAMPT升高,其被认为是一种预后标志物。同样,在男性口腔鳞状细胞癌、肝细胞癌、子宫内膜癌和浸润性乳腺癌中,eNAMPT在肿瘤高分期时均升高。在子宫内膜癌患者中,较高的eNAMPT水平与子宫内膜浸润和较短的患者生存期相关。浸润性乳腺癌中较高的eNAMPT水平与淋巴结转移和雌激素和孕激素受体的缺失相关。小鼠心脏特异性的eNAMPT过表达通过激活JNK1、p38和ERK激酶导致心脏和心肌细胞肥大,用H2O2或血清饥饿培养的心肌细胞会分泌eNAMPT[47]。用eNAMPT预处理人软骨细胞可以抑制IGF-1刺激的蛋白聚糖合成和AKT和胰岛素受体底物-1磷酸化,同时激活 ERK[48]。研究人员发现,eNAMPT处理迅速诱导小鼠巨噬细胞产生IL-6,随后IL-6介导 STAT3激活。有趣的是,IL-1β、TNF-α和IL-6可诱导巨噬细胞中eNAMPT的表达[49-51]。这些数据表明,血浆eNAMPT可能有助于致癌和肿瘤生长。
NAMPT还与多种疾病的发生发展密切相关。
糖尿病肾病是糖尿病最严重的微血管并发症之一,是糖尿病患者死亡的危险因素之一,严重威胁人类健康。糖尿病肾病的发病机制复杂多样,肾脏的炎症-纤维化是最重要的原因。研究表明,肾脏的炎症-纤维化过程与NAMPT密切相关。1、在肾小球系膜细胞中,NAMPT 可以通过促进细胞膜上GLUT-1的表达和易位,从而介导葡萄糖的胞内转运过程,机体糖代谢增加,细胞外基质合成增多,引起肾脏实质损伤[52,53]。2、糖尿病患者体内处于明显的氧化应激失衡状态,通过检测患者血清发现,NAMPT与脂质过氧化代谢产物水平成正比,与抗氧化酶SOD水平成反比,提示NAMPT与体内氧化应激密切相关[54]。两者相互作用共同促进糖尿病肾病的发生。
NAMPT与心脑血管疾病的发生发展密切相关。在冠状动脉不稳定粥样硬化患者的颈动脉斑块和急性心肌梗死病人破裂斑块中NAMPT表达明显增加[55,56]。研究发现NAMPT能够增强MMP-2和MMP-9的酶活性,而MMP可以降解细胞外基质,使纤维帽变薄,导致斑块破裂,提示NAMPT在动脉粥样硬化斑块不稳定中起重要作用57。NAMPT抑制剂可以减少心肌梗死面积、中性粒细胞浸润和在心肌缺血再灌注损伤小鼠模型体内活性氧的产生[58],因此,NAMPT药理抑制剂作为一种有效的治疗药物,可以减少心肌梗死氧化介导的组织损伤。
NAMPT在妊娠高血压综合征产妇胎盘组织中高表达,且二者的表达水平呈明显正相关,提示其与妊娠期高血压密切相关。
临床研究显示NAMPT的浓度在慢性炎症性疾病中明显增加。NAMPT作为一种促炎症脂肪因子,促进单核细胞趋化因子-1和细胞间黏附分子-1蛋白的表达[59]。NAMPT能诱导CD14+单核细胞产生白细胞介素-1β、肿瘤坏死因子-α和白细胞介素-6等炎性因子,增加共刺激分子CD54、CD40和CD80的表面表达[60]。eNAMPT可激活NF-κB,引起诱导型一氧化氮合酶表达上调并促进炎症反应[61]。
NAMPT还起到免疫调节细胞因子的作用,T淋巴细胞和B淋巴细胞的发育和功能几乎完全依赖于NAMPT,淋巴细胞中NAMPT基因的条件敲除导致胸腺细胞数量显著减少,外周血T淋巴细胞和B淋巴细胞几乎完全丧失[62]。类风湿性关节炎、自身免疫性脑炎等自身免疫性疾病患者血清中均可检测到高水平的NAMPT[63,64]。
血液和胃部脂肪组织中表达的大量NAMPT与超重或者肥胖正相关。NAMPT是超重或者肥胖的必要因子,如果在脂肪组织中下调NAMPT,将有助于改善肥胖[65]。
目前处于临床阶段的NAMPT抑制剂有FK866,其在细胞模型、动物模型中都能发挥抗肿瘤功效,尤其是在血液系统肿瘤中,FK866清除肿瘤细胞至低于可检测的水平,导致80%小鼠的长期存活[66]。但是FK866存在一些问题,临床试验结果显示,FK866治疗会引起剂量限制性毒性血小板减少症以及腹泻、便秘等胃肠道反应[67],这也是FK866在临床二期试验后一直处于停滞状态的原因。此外,NAMPT存在酶活和非酶活形式,FK866作为一个酶活抑制剂,不能抑制血浆和细胞外的非酶活NAMPT(eNAMPT),而eNAMPT已被证明有助于致癌和肿瘤生长,这导致FK866的治疗效果受到影响。因此,需要对现有的抑制剂进行改进或开发新的药物以克服现有抑制剂的缺陷。
设计具有靶向特定蛋白的降解剂是药物开发的新模式,我们利用蛋白降解靶向药物 (Proteolysis Targeting Drug,PROTAD)技术平台并用于抗肿瘤药物的开发。PROTAD通过特殊设计的双特异性蛋白调节剂,可对靶蛋白进行“降解”标记,通过激活细胞内部的蛋白降解途径对靶蛋白进行定向降解。因此,我们希望利用蛋白降解技术平台开发可以降解与疾病相关的致病蛋白的蛋白调节剂,从而可以治疗肿瘤病人并延长肿瘤病人的生存期。
因此,迫切需要一系列新颖的基于NAMPT靶蛋白设计的蛋白降解剂,以用于治疗和/ 或预防与NAMPT相关的疾病或病症。
发明概述
本公开提供了一系列新颖的基于NAMPT靶蛋白设计的蛋白降解的化合物或其盐、溶剂化物、同位素富集类似物、多晶型物、前药、立体异构体(包括对映异构体)、或立体异构体的混合物,所述化合物可以靶向并降解NAMPT蛋白,从而有效地治疗和/或预防与 NAMPT相关的疾病或病症。与NAMPT相关的疾病或病症包括但不限于肿瘤、自身免疫性疾病、炎性疾病、妊娠高血压综合征、心脑血管疾病、肥胖症和糖尿病肾病。
在一些实施方案中,本公开提供一种式(I)化合物或其盐、溶剂化物、同位素富集类似物、多晶型物、前药、立体异构体(包括对映异构体)、或立体异构体的混合物:
其中ULM为E3泛素连接酶配体部分,LIN为连接部分,式(I)分子的剩余部分是烟酰胺磷酸核糖转移酶(NAMPT)配体,ULM通过LIN共价连接NAMPT配体;
其中环A是以下基团:
(Ra)m1表示环A可选地被m1个Ra基团取代,各Ra独立地为羟基、氨基、卤素或氰基,和m1表示整数0、1、2、3、4或5;
R1和R2相同或不同且彼此独立地为H、氰基或甲基;
L1表示取代或未取代的直链C3-6亚烷基、或取代或未取代的直链C3-6亚烯基,所述直链C3-6亚烷基和直链C3-6亚烯基的可选的取代基选自C1-3烷基、卤素、C1-3烷氧基、卤代C1-3烷基、 C1-3烷基-NHC(O)-、C1-3烷基-C(O)NH-、氰基或其任意组合;
环B是5元至11元亚杂环基,(Rb)m2表示环B可选地被m2个Rb基团取代,各Rb独立地为C1-3烷基、羟基、氨基、巯基、卤素、C1-3烷氧基、C1-3烷基氨基、卤代C1-3烷基、氨基取代的C1-3亚烷基、C1-3烷基-NHC(O)-、C1-3烷基-C(O)NH-或氰基,和m2表示整数0、1、2、3、4 或5;
环C是5元至10元亚杂芳基、或6元亚芳基,(Rc)m3表示环C可选地被m3个Rc基团取代,各Rc独立地为C1-3烷基、C3-5环烷基、羟基、氨基、巯基、卤素、C1-3烷氧基、C1-3烷基氨基、卤代C1-3烷基、氨基取代的C1-3亚烷基、C1-3烷基-NHC(O)-、C1-3烷基-C(O)NH-或氰基,和m3表示整数0、1、2、3、4或5;
m表示整数0或1;以及
Y表示-N(R3)-,其中R3是氢或C1-3烷基;或
Y表示-O-;或
Y是由以下结构式表示的n个相连的环D:
各环D独立地是5元至11元亚杂环基,(Rd)m4表示各环D可选地独立地被m4个Rd基团取代,各Rd独立地为C1-3烷基、C3-6环烷基、羟基、氨基、巯基、卤素、氧代基、C1-3烷氧基、 C1-3烷基氨基、卤代C1-3烷基、氨基取代的C1-3亚烷基、C1-3烷基-NHC(O)-、C1-3烷基-C(O)NH- 或氰基,和m4表示整数0、1、2、3、4或5;
n是整数0、1、2或3,其中当n表示整数2或3时,各环D可相同或不同,以及
其中m和n不同时为0;
条件是不包括以下化合物:
所述烟酰胺磷酸核糖转移酶(NAMPT)配体表示以下结构:
并且ULM表示式(IV)的结构:
其中Z1表示C(O)或Z1表示键,以及Z2表示H或CH3。
在一些实施方案中,本公开提供一种药物组合物,其包含作为活性成分的所述的式(I) 化合物或其药学上可接受的盐、溶剂化物、同位素富集类似物、多晶型物、前药、立体异构体(包括对映异构体)、或立体异构体的混合物,及至少一种药学上可接受的载体。
在一些实施方案中,本公开提供一种试剂盒或药盒,其包含本发明所述的式(I)化合物或其药学上可接受的盐、溶剂化物、同位素富集类似物、多晶型物、前药、立体异构体(包括对映异构体)、或立体异构体的混合物,或者本发明所述的药物组合物。
在一些实施方案中,本公开提供所述的式(I)化合物,或其药学上可接受的盐、溶剂化物、同位素富集类似物、多晶型物、前药、立体异构体(包括对映异构体)、或立体异构体的混合物,其是用作药物。
在一些实施方案中,本公开进一步提供所述的式(I)化合物,或其药学上可接受的盐、溶剂化物、同位素富集类似物、多晶型物、前药、立体异构体(包括对映异构体)、或立体异构体的混合物或本公开所述的药物组合物,其用于治疗或预防与烟酰胺磷酸核糖转移酶(NAMPT)相关的疾病或病症。
在一些实施方案中,本公开提供所述的式(I)化合物或其药学上可接受的盐、溶剂化物、同位素富集类似物、多晶型物、前药、立体异构体(包括对映异构体)、或立体异构体的混合物或本公开所述的药物组合物用于制备用以治疗或预防与烟酰胺磷酸核糖转移酶(NAMPT) 相关的疾病或病症的药物的用途。
在一些实施方案中,本公开提供一种治疗或预防受试者的与烟酰胺磷酸核糖转移酶 (NAMPT)相关的疾病或病症的方法,其包括向所述受试者施用治疗有效量的所述的式(I)化合物,或其药学上可接受的盐、溶剂化物、同位素富集类似物、多晶型物、前药、立体异构体 (包括对映异构体)、或立体异构体的混合物,或本公开所述的药物组合物。
附图简要说明
图1显示了本发明化合物SIAIS630120和SIAIS630121在SW620、HT29细胞系中对NAMPT蛋白的降解活性。
图2显示了本发明化合物SIAIS630120和SIAIS630121在MCF-7细胞系中对NAMPT蛋白的降解活性。
图3显示了本发明化合物SIAIS630120和SIAIS630121在BEL7404细胞系中对NAMPT蛋白的降解活性。
图4显示了本发明化合物SIAIS630120和SIAIS630121在MOLT4、Jurkat、HL60细胞系中对NAMPT蛋白的降解活性。
图5显示了本发明化合物SIAIS630120和SIAIS630121以及母本抑制剂FK866在HL60、 MOLT4细胞系中对eNAMPT蛋白的降解活性。
图6-7显示了本发明化合物SIAIS630120和SIAIS630121以及母本抑制剂FK866对于 HL60、MOLT4细胞系的体外杀伤效果。
发明详述
提供以下详细描述作为示例性具体实施方案,以帮助本领域普通技术人员理解和实施本公开内容。然而,应当认识到,这样的描述并不旨在限制本公开的范围,在不脱离本公开精神和范围的前提下,本公开描述的具体实施方案还可进行各种修饰和变化,这些变化和改进都落入要求保护的本公开范围内。
I.化合物
本公开提供一种式(I)化合物或其盐(包括药学上可接受的盐)、溶剂化物、同位素富集类似物、多晶型物、前药、立体异构体(包括对映异构体)、或立体异构体的混合物:
其中ULM为E3泛素连接酶配体部分,LIN为连接部分,式(I)分子的剩余部分是烟酰胺磷酸核糖转移酶(NAMPT)配体,ULM通过LIN共价连接NAMPT配体;
其中环A是以下基团:
(Ra)m1表示环A可选地被m1个Ra基团取代,各Ra独立地为羟基、氨基、卤素或氰基,和m1表示整数0、1、2、3、4或5;
R1和R2相同或不同且彼此独立地为H、氰基或甲基;
L1表示取代或未取代的直链C3-6亚烷基、或取代或未取代的直链C3-6亚烯基,所述直链C3-6亚烷基和直链C3-6亚烯基的可选的取代基选自C1-3烷基、卤素、C1-3烷氧基、卤代C1-3烷基、 C1-3烷基-NHC(O)-、C1-3烷基-C(O)NH-、氰基或其任意组合;
环B是5元至11元亚杂环基,(Rb)m2表示环B可选地被m2个Rb基团取代,各Rb独立地为C1-3烷基、羟基、氨基、巯基、卤素、C1-3烷氧基、C1-3烷基氨基、卤代C1-3烷基、氨基取代的C1-3亚烷基、C1-3烷基-NHC(O)-、C1-3烷基-C(O)NH-或氰基,和m2表示整数0、1、2、3、4 或5;
环C是5元至10元亚杂芳基、或6元亚芳基,(Rc)m3表示环C可选地被m3个Rc基团取代,各Rc独立地为C1-3烷基、C3-5环烷基、羟基、氨基、巯基、卤素、C1-3烷氧基、C1-3烷基氨基、卤代C1-3烷基、氨基取代的C1-3亚烷基、C1-3烷基-NHC(O)-、C1-3烷基-C(O)NH-或氰基,和m3表示整数0、1、2、3、4或5;
m表示整数0或1;以及
Y表示-N(R3)-,其中R3是氢或C1-3烷基;或
Y表示-O-;或
Y是由以下结构式表示的n个相连的环D:
各环D独立地是5元至11元亚杂环基,(Rd)m4表示各环D可选地独立地被m4个Rd基团取代,各Rd独立地为C1-3烷基、C3-6环烷基、羟基、氨基、巯基、卤素、氧代基、C1-3烷氧基、 C1-3烷基氨基、卤代C1-3烷基、氨基取代的C1-3亚烷基、C1-3烷基-NHC(O)-、C1-3烷基-C(O)NH- 或氰基,和m4表示整数0、1、2、3、4或5;
n是整数0、1、2或3,其中当n表示整数2或3时,各环D可相同或不同,以及
其中m和n不同时为0;
条件是不包括以下化合物:
所述烟酰胺磷酸核糖转移酶(NAMPT)配体表示以下结构:
并且ULM表示式(IV)的结构:
其中Z1表示C(O)或Z1表示键,以及Z2表示H或CH3。
在一些实施方案中,L1表示取代或未取代的直链C3-6亚烷基。直链C3-6亚烷基的示例性实例包括但不限于亚丙基、亚丁基、亚戊基和亚己基。所述直链C3-6亚烷基可选地进一步被一或多个选自C1-3烷基(例如甲基、乙基或丙基)、卤素(例如氟、氯、溴或碘)、C1-3烷氧基(例如甲氧基、乙氧基或丙氧基)、卤代C1-3烷基(例如-CF3、-CH2F、-CHF2、-CH2Cl、- CHCl2、-CF2CF3、-CHFCF3、-CF2CHF2、-CHFCHF2、-CH2CF3和-CH2CH2Cl)、C1-3烷基- NHC(O)-(例如CH3-NHC(O)-、CH3CH2-NHC(O)-、和CH3CH2CH2-NHC(O)-)、C1-3烷基- C(O)NH-(例如CH3-C(O)NH-、CH3CH2-C(O)NH-、和CH3CH2CH2-C(O)NH-)、氰基或其任意组合的取代基取代。取代基的数量原则上不受任何限制或自动受构建单元的大小限制。
在一些实施方案中,L1表示取代或未取代的直链C3-6亚烯基。直链C3-6亚烯基的示例性实例包括但不限于 所述直链C3-6亚烯基可选地进一步被一或多个选自C1-3烷基(例如甲基、乙基或丙基)、卤素(例如氟、氯、溴或碘)、C1-3烷氧基(例如甲氧基、乙氧基或丙氧基)、卤代C1-3烷基(例如-CF3、- CH2F、-CHF2、-CH2Cl、-CHCl2、-CF2CF3、-CHFCF3、-CF2CHF2、-CHFCHF2、-CH2CF3和- CH2CH2Cl)、C1-3烷基-NHC(O)-(例如CH3-NHC(O)-、CH3CH2-NHC(O)-、和CH3CH2CH2- NHC(O)-)、C1-3烷基-C(O)NH-(例如CH3-C(O)NH-、CH3CH2-C(O)NH-、和CH3CH2CH2- C(O)NH-)、氰基或其任意组合的取代基取代。取代基的数量原则上不受任何限制或自动受构建单元的大小限制。
在一些实施方案中,环B是含有1至3个独立地选自氮、氧和硫的杂原子的5元至11元亚杂环基。
在一些实施方案中,环B是含有1个氮原子并且可选地进一步含有1至2个独立地选自氮、氧和硫的杂原子的5元至11元亚杂环基。
在一些实施方案中,环B的示例性实例包括但不限于以下基团:亚哌啶基、亚哌嗪基、亚吗啉基、亚氮杂环丁基、亚氧杂环丁基、亚吡咯烷基、亚咪唑烷基、亚吡唑烷基、亚四氢呋喃基、亚四氢吡喃基、亚四氢噻吩基、亚四氢噻喃基、亚噁唑烷基、亚噻唑烷基、亚硫代吗啉基、亚二氧杂环己基、亚二氮杂环庚基或C7-11螺杂环亚基。
在一些实施方案中,当环B表示C7-11螺杂环亚基时,所述C7-11螺杂环亚基可以是以下基团:
其中符号*表示与基团L1的连接点(该连接点可以是螺杂环上可以连接基团L1的任意环原子),X表示O、N(Re)、S或CH2或X表示键,Re表示氢或甲基,以及n1、n2和n3各自独立地是整数1或2。
在本文中,用语“……表示键”意指其是键连接体(即表示其不存在)。例如用语“X表示键”意指X是键连接体。换言之,当X为键时,在X两侧的相邻的两个碳原子直接互相连接。
在一些实施方案中,当环B表示C7-11螺杂环亚基时,所述C7-11螺杂环亚基可以是以下基团:
其中符号*表示与基团L1的连接点。
在一些实施方案中,环B可选地进一步被m2个Rb基团取代,其中m2表示整数0、1、2、3、4或5,以及各Rb独立地为C1-3烷基(例如甲基、乙基或丙基)、羟基、氨基、巯基、卤素(例如氟、氯、溴或碘)、C1-3烷氧基(例如甲氧基、乙氧基或丙氧基)、C1-3烷基氨基 (例如C1-3烷基NH-,例如CH3NH-、CH3CH2NH-或CH3CH2CH2NH-)、卤代C1-3烷基(例如 -CF3、-CH2F、-CHF2、-CH2Cl、-CHCl2、-CF2CF3、-CHFCF3、-CF2CHF2、-CHFCHF2、- CH2CF3和-CH2CH2Cl)、氨基取代的C1-3亚烷基(NH2-C1-3亚烷基-,例如NH2CH2-、 NH2CH2CH2-和NH2CH2CH2CH2-)、C1-3烷基-NHC(O)-(例如CH3-NHC(O)-、CH3CH2- NHC(O)-、和CH3CH2CH2-NHC(O)-)、C1-3烷基-C(O)NH-(例如CH3-C(O)NH-、CH3CH2- C(O)NH-、和CH3CH2CH2-C(O)NH-)或氰基。
其中符号*表示与基团L1的连接点。
在一些实施方案中,环C是5元至10元亚杂芳基、或6元亚芳基。环C的示例性实例包括但不限于以下基团:亚苯基、亚吡啶基、亚嘧啶基、亚吡嗪基、亚哒嗪基、1,2,4-亚三嗪基、1,3,5-亚三嗪基、亚三氮唑基、亚呋喃基、亚噁唑基、亚异噁唑基、亚噁二唑基、亚噻吩基、亚噻唑基、亚异噻唑基、亚噻二唑基、亚吡咯基、亚咪唑基、亚吡唑基、亚吲哚基、亚异吲哚基、亚苯并呋喃基、亚异苯并呋喃基、亚苯并噻吩基、亚吲唑基、亚苯并咪唑基、亚苯并噁唑基、亚苯并异噁唑基、亚苯并噻唑基、亚苯并异噻唑基、亚苯并三唑基、亚苯并 [2,1,3]噁二唑基、亚苯并[2,1,3]噻二唑基、亚苯并[1,2,3]噻二唑基、亚喹啉基、亚异喹啉基、亚萘啶基、亚噌啉基、亚喹唑啉基、亚喹喔啉基、亚酞嗪基、吡唑并[1,5-a]吡啶亚基、吡唑并 [1,5-a]嘧啶亚基、咪唑并[1,2-a]吡啶亚基、1H-吡咯并[3,2-b]吡啶亚基、1H-吡咯并[2,3-b]吡啶亚基、4H-氟[3,2-b]吡咯亚基、吡咯并[2,1-b]噻唑亚基、或咪唑并[2,1-b]噻唑亚基。
在一些实施方案中,环C可选地进一步被m3个Rc基团取代,其中m3表示整数0、1、2、3、4或5,以及各Rc独立地为C1-3烷基(例如甲基、乙基或丙基)、C3-5环烷基(例如环丙基、环丁基或环戊基)、羟基、氨基、巯基、卤素(例如氟、氯、溴或碘)、C1-3烷氧基 (例如甲氧基、乙氧基或丙氧基)、C1-3烷基氨基(例如C1-3烷基NH-,例如CH3NH-、 CH3CH2NH-或CH3CH2CH2NH-)、卤代C1-3烷基(例如-CF3、-CH2F、-CHF2、-CH2Cl、- CHCl2、-CF2CF3、-CHFCF3、-CF2CHF2、-CHFCHF2、-CH2CF3和-CH2CH2Cl)、氨基取代的 C1-3亚烷基(NH2-C1-3亚烷基-,例如NH2CH2-、NH2CH2CH2-和NH2CH2CH2CH2-)、C1-3烷基- NHC(O)-(例如CH3-NHC(O)-、CH3CH2-NHC(O)-、和CH3CH2CH2-NHC(O)-)、C1-3烷基- C(O)NH-(例如CH3-C(O)NH-、CH3CH2-C(O)NH-、和CH3CH2CH2-C(O)NH-)或氰基。
其中符号***表示与基团Y的连接点,或者符号***表示与羰基的连接点。
在一些实施方案中,Y表示-N(R3)-,其中R3是氢或C1-3烷基。
在一些实施方案中,Y表示-O-。
在一些实施方案中,Y是由以下结构式表示的n个相连的环D:
其中n是整数0、1、2或3,其中当n表示整数2或3时,各环D可相同或不同,各环D独立地是5元至11元亚杂环基,(Rd)m4表示各环D可选地独立地被m4个Rd基团取代,m4表示整数0、1、2、3、4或5,以及各Rd独立地为C1-3烷基、C3-6环烷基、羟基、氨基、巯基、卤素、氧代基、C1-3烷氧基、C1-3烷基氨基、卤代C1-3烷基、氨基取代的C1-3亚烷基、C1-3烷基- NHC(O)-、C1-3烷基-C(O)NH-或氰基。
在一些实施方案中,环D的示例性实例包括但不限于以下基团:亚哌啶基、亚哌嗪基、亚吗啉基、亚氮杂环丁基、亚氧杂环丁基、亚吡咯烷基、亚咪唑烷基、亚吡唑烷基、亚四氢呋喃基、亚四氢吡喃基、亚四氢噻吩基、亚四氢噻喃基、亚噁唑烷基、亚噻唑烷基、亚硫代吗啉基、亚二氧杂环己基、亚二氮杂环庚基或C7-11螺杂环亚基。
在一些实施方案中,当环D表示C7-11螺杂环亚基时,所述C7-11螺杂环亚基可以是以下基团:
其中符号**表示与环C的连接点,X表示O、N(Re)、S或CH2或X表示键,其中Re表示氢或甲基,以及n1、n2和n3各自独立地是整数1或2。
在一些实施方案中,当环D表示C7-11螺杂环亚基时,所述C7-11螺杂环亚基可以是以下基团:
其中符号**表示与环C的连接点。
在一些实施方案中,环D可选地进一步被m4个Rd基团取代,其中m4表示整数0、1、2、3、4或5,各Rd独立地为C1-3烷基(例如甲基、乙基或丙基)、C3-6环烷基(例如环丙基、环丁基、环戊基或环己基)、羟基、氨基、巯基、卤素(例如氟、氯、溴或碘)、氧代基、 C1-3烷氧基(例如甲氧基、乙氧基或丙氧基)、C1-3烷基氨基(例如C1-3烷基NH-,例如 CH3NH-、CH3CH2NH-或CH3CH2CH2NH-)、卤代C1-3烷基(例如-CF3、-CH2F、-CHF2、- CH2Cl、-CHCl2、-CF2CF3、-CHFCF3、-CF2CHF2、-CHFCHF2、-CH2CF3和-CH2CH2Cl)、氨基取代的C1-3亚烷基(NH2-C1-3亚烷基-,例如NH2CH2-、NH2CH2CH2-和NH2CH2CH2CH2-)、 C1-3烷基-NHC(O)-(例如CH3-NHC(O)-、CH3CH2-NHC(O)-、和CH3CH2CH2-NHC(O)-)、C1-3烷基-C(O)NH-(例如CH3-C(O)NH-、CH3CH2-C(O)NH-、和CH3CH2CH2-C(O)NH-)或氰基。
其中符号**表示与环C的连接点。替代地,在一些实施方案中,所述基团中的符号**还可以表示与基团LIN的连接点。
在一些实施方案中,m为0,n为1。在一些实施方案中,m为0,n为2。在一些实施方案中,m为0,n为3。在一些实施方案中,m为1,n为0。在一些实施方案中,m为1,n 为1。在一些实施方案中,m为1,n为2。在一些实施方案中,m为1,n为3。
其中符号##表示与基团LIN的连接点。
在一些实施方案中,ULM表示式(III)的结构:
其中R表示O、N(R4)、S、亚炔基、亚烯基、或可选取代的亚三唑基,其中R4表示H或C1-3烷基,或R表示键,以及W表示可选取代的亚苯基或W表示键,其中当R表示键时,W 表示键;以及
(Rf)m5表示式(III)的苯环可选地被m5个Rf基团取代,各Rf独立地为卤素,m5表示整数0、 1、2或3;以及
Z表示C(O)或CH2。
在一些实施方案中,式(III)的结构也可以是以下式的结构:
其中Z表示CH2或C(O);
(Rf)m5表示式(III)的苯环可选地被m5个Rf基团取代,各Rf独立地为卤素,m5表示整数0、1、 2或3;以及
R表示O、N(R4)、S、亚炔基、亚烯基、或可选取代的亚三唑基,其中R4表示H或C1-3烷基,或R表示键,以及W表示可选取代的亚苯基或W表示键,其中当R表示键时,W表示键。
在一些实施方案中,Z表示C(O)。
在一些实施方案中,Z表示CH2。
在一些实施方案中,R表示O。
在一些实施方案中,R表示N(R4),其中R4表示H或C1-3烷基(例如甲基、乙基或丙基)。
在一些实施方案中,R表示键。在一些实施方案中,当R表示键时,W表示键。
在一些实施方案中,R表示S。
在一些实施方案中,R表示亚三唑基。
在一些实施方案中,W表示可选取代的亚苯基,示例性的取代基包括但不限于卤素(例如氟、氯、溴或碘)。取代基的个数可以是0、1、2或3个。
在一些实施方案中,W表示键。
在一些实施方案中,ULM表示以下式的结构:
其中R4表示H或C1-3烷基(例如甲基、乙基或丙基);(Rf)m5表示所述苯环可选地被m5个Rf基团取代,各Rf独立地为卤素(例如氟、氯、溴或碘),以及m5表示整数0、1、2或 3。
在一些实施方案中,ULM表示式(IV)的结构:
其中Z1表示C(O)或Z1表示键,以及Z2表示H或CH3。
在一些实施方案中,ULM表示以下式的结构:
其中Z1表示C(O)或Z1表示键。
在一些实施方案中,LIN表示以下式:
#-U-亚烷基,
其中U表示C(O)或U表示键,以及符号#表示与基团Y的连接点;和
所述亚烷基是取代或未取代的亚甲基、或取代或未取代的直链或支链C2-60亚烷基,其中所述直链或支链C2-60亚烷基的主碳链中可选地插入有一或多个基团R5和/或一或多个基团R6或者一或多个基团R5与R6的任意组合。换言之,当所述直链或支链C2-60亚烷基的主碳链中插入有一或多个基团R5和/或一或多个基团R6或者一或多个基团R5与R6的任意组合时,所述基团 R5、R6或者基团R5与R6的组合将所述主碳链的一或多对相邻碳原子之间的碳-碳键间断开。在一些实施方案中,各基团R5独立地选自O、N(R7)、C(O)、C(O)O、OC(O)、C(O)N(R7)、 N(R7)C(O)、或N(R7)C(O)N(R7),其中各R7独立地表示H或C1-3烷基(例如甲基、乙基或丙基),以及当所述直链或支链C2-60亚烷基的主碳链中插入有两个以上基团R5时,各基团R5彼此不直接相连接。在一些实施方案中,各基团R6独立地选自亚环烷基、亚芳基、亚杂环基、亚杂芳基、亚炔基(例如亚乙炔基或亚丁炔基)、亚烯基(例如亚乙烯基)或其任意组合,其中所述亚环烷基、所述亚芳基、所述亚杂环基和所述亚杂芳基彼此独立地可选地进一步被选自C1-3烷基(例如甲基、乙基或丙基)、C3-6环烷基 (例如环丙基、环丁基、环戊基或环己基)、羟基、氨基、巯基、卤素(例如氟、氯、溴或碘)、C1-3烷氧基(例如甲氧基、乙氧基或丙氧基)、C1-3烷基氨基(例如C1-3烷基NH-,例如CH3NH-、CH3CH2NH-或CH3CH2CH2NH-)、卤代C1-3烷基(例如-CF3、-CH2F、-CHF2、- CH2Cl、-CHCl2、-CF2CF3、-CHFCF3、-CF2CHF2、-CHFCHF2、-CH2CF3和-CH2CH2Cl)、氨基取代的C1-3亚烷基(NH2-C1-3亚烷基-,例如NH2CH2-、NH2CH2CH2-和NH2CH2CH2CH2-)、 C1-3烷基-NHC(O)-(例如CH3-NHC(O)-、CH3CH2-NHC(O)-、和CH3CH2CH2-NHC(O)-)、C1-3烷基-C(O)NH-(例如CH3-C(O)NH-、CH3CH2-C(O)NH-、和CH3CH2CH2-C(O)NH-)、氰基或其任意组合的取代基取代。在一些子实施方案中,所述亚烷基链(例如取代或未取代的直链或支链C2-60亚烷基)的主碳链中可选地含有一或多个(例如1-30、1-20、1-15、1-10、1-8、1- 7、1-6、1-5、1-4、1-3、1-2或1个)“-CH2-R5-CH2-”片段和/或一或多个(例如1-30、1-20、1- 15、1-10、1-8、1-7、1-6、1-5、1-4、1-3、1-2或1个)“-CH2-R6-CH2-”片段和/或一或多个(例如1-30、1-20、1-15、1-10、1-8、1-7、1-6、1-5、1-4、1-3、1-2或1个)“-CH2-R5-R6-CH2-”片段。各R5相同或不同,各R6相同或不同,并且如本文中所定义。
在一些实施方案中,LIN表示以下式:
#-U-亚烷基,
其中U表示C(O)或U表示键,以及符号#表示与基团Y的连接点;和
所述亚烷基是未取代或取代的直链或支链的C1-60亚烷基(例如C1-55亚烷基链、C1-50亚烷基链、 C1-45亚烷基链、C1-40亚烷基链、C1-35亚烷基链、C1-30亚烷基链、C1-25亚烷基链、C1-23亚烷基链、C1-22亚烷基链、C1-21亚烷基链、C1-20亚烷基链、C2-20亚烷基链、C1-19亚烷基链、C2-19亚烷基链、 C1-18亚烷基链、C2-18亚烷基链、C1-17亚烷基链、C2-17亚烷基链、C1-16亚烷基链、C2-16亚烷基链、 C1-15亚烷基链、C2-15亚烷基链、C1-14亚烷基链、C2-14亚烷基链、C1-13亚烷基链、C2-13亚烷基链、 C1-12亚烷基链、C2-12亚烷基链、C1-11亚烷基链、C2-11亚烷基链、C1-10亚烷基链、C2-10亚烷基链、 C3-10亚烷基链、C1-9亚烷基链、C2-9亚烷基链、C3-9亚烷基链、C1-8亚烷基链、C2-8亚烷基链、 C3-8亚烷基链、C1-7亚烷基链、C2-7亚烷基链、C3-7亚烷基链、C1-6亚烷基链、C2-6亚烷基链、C3-6亚烷基链、C1-5亚烷基链、C2-5亚烷基链、C3-5亚烷基链、C1-4亚烷基链、C1-3亚烷基链、C1-2亚烷基链、亚甲基)。当所述亚烷基是取代的直链或支链的C1-60亚烷基时,其取代基的实例可选地选自C1-C3烷基(例如甲基、乙基或丙基)、C3-6环烷基(例如环丙基、环丁基、环戊基或环己基)、羟基、氨基、巯基、卤素(例如氟、氯、溴或碘)、C1-C3烷氧基(例如甲氧基、乙氧基或丙氧基)、C1-C3烷基氨基(C1-3烷基NH-,例如CH3NH-、CH3CH2NH-或 CH3CH2CH2NH-)、卤代C1-C3烷基(例如F3C-、FCH2-、F2CH-、ClCH2-、Cl2CH-、CF3CF2-、 CF3CHF-、CHF2CF2-、CHF2CHF-、CF3CH2-和CH2ClCH2-)、氨基C1-3亚烷基(NH2-C1-3亚烷基-,例如NH2CH2-、NH2CH2CH2-和NH2CH2CH2CH2-)、C1-3烷基-NHC(O)-(例如CH3- NHC(O)-、CH3CH2-NHC(O)-、和CH3CH2CH2-NHC(O)-)、C1-3烷基-C(O)NH-(例如CH3- C(O)NH-、CH3CH2-C(O)NH-、和CH3CH2CH2-C(O)NH-)、氰基或其任意组合。
在一些实施方案中,LIN的所述亚烷基可以是取代的直链或支链的C1-60亚烷基,例如携带一或多个相同或不同取代基的直链或支链的C1-60亚烷基(例如C1-55亚烷基链、C1-50亚烷基链、C1-45亚烷基链、C1-40亚烷基链、C1-35亚烷基链、C1-30亚烷基链、C1-25亚烷基链、C1-23亚烷基链、C1-22亚烷基链、C1-21亚烷基链、C1-20亚烷基链、C2-20亚烷基链、C1-19亚烷基链、C2-19亚烷基链、C1-18亚烷基链、C2-18亚烷基链、C1-17亚烷基链、C2-17亚烷基链、C1-16亚烷基链、C2-16亚烷基链、C1-15亚烷基链、C2-15亚烷基链、C1-14亚烷基链、C2-14亚烷基链、C1-13亚烷基链、C2-13亚烷基链、C1-12亚烷基链、C2-12亚烷基链、C1-11亚烷基链、C2-11亚烷基链、C1-10亚烷基链、 C2-10亚烷基链、C3-10亚烷基链、C1-9亚烷基链、C2-9亚烷基链、C3-9亚烷基链、C1-8亚烷基链、 C2-8亚烷基链、C3-8亚烷基链、C1-7亚烷基链、C2-7亚烷基链、C3-7亚烷基链、C1-6亚烷基链、C2-6亚烷基链、C3-6亚烷基链、C1-5亚烷基链、C2-5亚烷基链、C3-5亚烷基链、C1-4亚烷基链、C1-3亚烷基链、C1-2亚烷基链、亚甲基),取代基可选地选自C1-C3烷基(例如甲基、乙基或丙基)、C3-6环烷基(例如环丙基、环丁基、环戊基或环己基)、羟基、氨基、巯基、卤素(例如氟、氯、溴或碘)、C1-C3烷氧基(例如甲氧基、乙氧基或丙氧基)、C1-C3烷基氨基(C1-3烷基NH-,例如CH3NH-、CH3CH2NH-或CH3CH2CH2NH-)、卤代C1-C3烷基(例如F3C-、 FCH2-、F2CH-、ClCH2-、Cl2CH-、CF3CF2-、CF3CHF-、CHF2CF2-、CHF2CHF-、CF3CH2-和 CH2ClCH2-)、氨基C1-3亚烷基(NH2-C1-3亚烷基-,例如NH2CH2-、NH2CH2CH2-和 NH2CH2CH2CH2-)、C1-3烷基-NHC(O)-(例如CH3-NHC(O)-、CH3CH2-NHC(O)-、和CH3CH2CH2-NHC(O)-)、C1-3烷基-C(O)NH-(例如CH3-C(O)NH-、CH3CH2-C(O)NH-、和 CH3CH2CH2-C(O)NH-)、氰基或其任意组合。在本公开的一子实施方案中,所述直链或支链的C1-60亚烷基可选地携带一或多个相同或不同取代基,例如1-30个,1-25个,1-20个,或者 1-15,1-10,1-9,1-8,1-7,1-6,1-5,1-4,1-3,或1-2个,或是20、19、18、17、16、15、 14、13、12、11、10、9、8、7、6、5、4、3、2、或1个取代基。取代基的数量原则上不受任何限制或自动受构建单元的大小限制。
在一些实施方案中,LIN表示以下基团:#-U-CH2-、#-U-(CH2)2-、#-U-(CH2)3-、#-U-(CH2)4-、#-U-(CH2)5-、#-U-(CH2)6-、#-U-(CH2)7-、#-U-(CH2)8-、#-U-(CH2)9-、#-U-(CH2)10-、#- U-(CH2)11-、#-U-(CH2)12-、#-U-(CH2)13-、#-U-(CH2)14-、#-U-(CH2)15-、#-U-(CH2)16-、#-U- (CH2)17-、#-U-(CH2)18-、#-U-(CH2)19-、#-U-(CH2)20-、#-U-(CH2)21-、#-U-(CH2)22-、#-U-(CH2)25-、#-U-(CH2)30-、#-U-(CH2)35-、#-U-(CH2)40-、#-U-(CH2)45-、#-U-(CH2)50-、#-U-(CH2)55-、或#-U- (CH2)60-;其中所述基团的一或多个CH2的氢可选地进一步被选自以下的取代基替代:C1-C3烷基(例如甲基、乙基或丙基)、C3-6环烷基(例如环丙基、环丁基、环戊基或环己基)、羟基、氨基、巯基、卤素(例如氟、氯、溴或碘)、C1-C3烷氧基(例如甲氧基、乙氧基或丙氧基)、 C1-C3烷基氨基(C1-3烷基NH-,例如CH3NH-、CH3CH2NH-或CH3CH2CH2NH-)、卤代C1-C3烷基(例如F3C-、FCH2-、F2CH-、ClCH2-、Cl2CH-、CF3CF2-、CF3CHF-、CHF2CF2-、 CHF2CHF-、CF3CH2-和CH2ClCH2-)、氨基取代的C1-3亚烷基(NH2-C1-3亚烷基-,例如NH2CH2-、NH2CH2CH2-和NH2CH2CH2CH2-)、C1-3烷基-NHC(O)-(例如CH3-NHC(O)-、 CH3CH2-NHC(O)-、和CH3CH2CH2-NHC(O)-)、C1-3烷基-C(O)NH-(例如CH3-C(O)NH-、 CH3CH2-C(O)NH-、和CH3CH2CH2-C(O)NH-)、氰基或其任意组合,以及U表示C(O)或U表示键,且符号#表示与基团Y的连接点。
在一些实施方案中,LIN表示以下式:
#-U-亚烷基,
其中U表示C(O)或U表示键,且符号#表示与基团Y的连接点;和
所述亚烷基是未取代或取代的直链或支链的C2-60亚烷基,所述直链或支链的C2-60亚烷基的主碳链中可选地插入有一或多个基团R5和/或一或多个基团R6或者一或多个基团R5与R6的任意组合。换言之,当所述直链或支链C2-60亚烷基的主碳链中插入有一或多个基团R5和/或一或多个基团R6或者一或多个基团R5与R6的任意组合时,所述基团R5、R6或者基团R5与R6的任意组合将所述主碳链的一或多对相邻碳原子之间的碳-碳键间断开。在一些实施方案中,各基团R5彼此独立地选自O、N(R7)、C(O)、C(O)O、OC(O)、C(O)N(R7)、N(R7)C(O)、或 N(R7)C(O)N(R7),其中各R7独立地表示H或C1-3烷基(例如甲基、乙基或丙基),以及当所述直链或支链C2-60亚烷基的主碳链中插入有两个以上基团R5时,各基团R5彼此不直接相连接。在一些实施方案中,各基团R6彼此独立地选自亚环烷基、亚芳基、亚杂环基、亚杂芳基、亚炔基、亚烯基或其任意组合,其中所述亚环烷基、所述亚芳基、所述亚杂环基和所述亚杂芳基彼此独立地可选地进一步被一或多个(例如1-4、1-3、1-2或1个)选自C1-3烷基(例如甲基、乙基或丙基)、C3-6环烷基(例如环丙基、环丁基、环戊基或环己基)、羟基、氨基、巯基、卤素(例如氟、氯、溴或碘)、C1-3烷氧基(例如甲氧基、乙氧基或丙氧基)、C1-3烷基氨基(例如C1-3烷基NH-,例如CH3NH-、CH3CH2NH-或CH3CH2CH2NH-)、卤代C1-3烷基 (例如-CF3、-CH2F、-CHF2、-CH2Cl、-CHCl2、-CF2CF3、-CHFCF3、-CF2CHF2、-CHFCHF2、 -CH2CF3和-CH2CH2Cl)、氨基取代的C1-3亚烷基(NH2-C1-3亚烷基-,例如NH2CH2-、 NH2CH2CH2-和NH2CH2CH2CH2-)、C1-3烷基-NHC(O)-(例如CH3-NHC(O)-、CH3CH2- NHC(O)-、和CH3CH2CH2-NHC(O)-)、C1-3烷基-C(O)NH-(例如CH3-C(O)NH-、CH3CH2- C(O)NH-、和CH3CH2CH2-C(O)NH-)、氰基或其任意组合的取代基取代。在一些实施方案中,基团R5的数量、R6的数量或者基团R5与R6的任意组合的数量可以分别独立是例如1-30、1- 20、1-15、1-10、1-8、1-7、1-6、1-5、1-4、1-3、1-2或1个。基团R5、R6的数量或者基团R5与R6的任意组合的数量原则上不受任何限制或自动受构建单元的大小限制。在一些子实施方案中,所述直链或支链的C2-60亚烷基的主碳链中可选地含有一或多个(例如1-30、1-20、1-15、 1-10、1-8、1-7、1-6、1-5、1-4、1-3、1-2或1个)“-CH2-R5-CH2-”片段和/或一或多个(例如 1-30、1-20、1-15、1-10、1-8、1-7、1-6、1-5、1-4、1-3、1-2或1个)“-CH2-R6-CH2-”片段和/或一或多个(例如1-30、1-20、1-15、1-10、1-8、1-7、1-6、1-5、1-4、1-3、1-2或1个)“- CH2-R5-R6-CH2-”片段。各R5相同或不同,各R6相同或不同,并且如本文中所定义。
在本文中,当所述直链或支链的C2-60亚烷基的主碳链中插入有一或多个基团R5和/或一或多个基团R6或者一或多个基团R5与R6的任意组合时,所形成的主链基团符合共价键理论并且可以含有一或多个(例如1-30、1-20、1-15、1-10、1-8、1-7、1-6、1-5、1-4、1-3、1-2或1 个)“-CH2-R5-CH2-”片段和/或一或多个(例如1-30、1-20、1-15、1-10、1-8、1-7、1-6、1-5、1-4、1-3、1-2或1个)“-CH2-R6-CH2-”片段和/或一或多个(例如1-30、1-20、1-15、1-10、1-8、1-7、1-6、1-5、1-4、1-3、1-2或1个)“-CH2-R5-R6-CH2-”片段。各R5相同或不同,各R6相同或不同,并且如本文中所定义。
在一些实施方案中,LIN可以表示以下式:
#-U-(C(Ra1)(Ra2))n4-(R5(C(Ra3)(Ra4))n5)m6-;
#-U-(C(Ra1)(Ra2))n4-(R5(C(Ra3)(Ra4))n5)m6-(R5(C(Ra5)(Ra6))n6)m7-;
#-U-(C(Ra1)(Ra2))n4-(R5(C(Ra3)(Ra4))n5)m6-(R5(C(Ra5)(Ra6))n6)m7-(R5(C(Ra7)(Ra8))n7)m8-;
#-U-(C(Ra1)(Ra2))n4-(R6(C(Ra3)(Ra4))n5)m6-;
#-U-(C(Ra1)(Ra2))n4-(R6(C(Ra3)(Ra4))n5)m6-(R6(C(Ra5)(Ra6))n6)m7-;
#-U-(C(Ra1)(Ra2))n4-(R6(C(Ra3)(Ra4))n5)m6-(R6(C(Ra5)(Ra6))n6)m7-(R6(C(Ra7)(Ra8))n7)m8-;
#-U-(C(Ra1)(Ra2))n4-(R5-R6-(C(Ra3)(Ra4))n5)m6-;
#-U-(C(Ra1)(Ra2))n4-(R5(C(Ra3)(Ra4))n5)m6-(R6(C(Ra5)(Ra6))n6)m7-;
#-U-(C(Ra1)(Ra2))n4-(R6-R5-(C(Ra3)(Ra4))n5)m6-;或
#-U-(C(Ra1)(Ra2))n4-(R6(C(Ra3)(Ra4))n5)m6-(R5(C(Ra5)(Ra6))n6)m7-;
其中,各基团R5独立地选自O、N(R7)、C(O)、C(O)O、OC(O)、C(O)N(R7)、N(R7)C(O)、或N(R7)C(O)N(R7),其中各R7独立地表示H或C1-3烷基(例如甲基、乙基或丙基),以及当所述直链或支链C2-60亚烷基的主碳链中插入有两个以上基团R5时,各基团R5彼此不直接相连接;各基团R6独立地选自亚环烷基、亚芳基、亚杂环基、亚杂芳基、亚炔基、亚烯基或其任意组合,其中所述亚环烷基、所述亚芳基、所述亚杂环基和所述亚杂芳基彼此独立地可选地被一或多个(例如1-4、1-3、1-2或1个)选自C1-C3烷基(例如甲基、乙基或丙基)、C3-6环烷基(例如环丙基、环丁基、环戊基或环己基)、羟基、氨基、巯基、卤素(例如氟、氯、溴或碘)、C1-C3烷氧基(例如甲氧基、乙氧基或丙氧基)、C1-C3烷基氨基(C1-3烷基NH-,例如CH3NH-、CH3CH2NH-或CH3CH2CH2NH-)、卤代C1-C3烷基(例如F3C-、FCH2-、F2CH-、 ClCH2-、Cl2CH-、CF3CF2-、CF3CHF-、CHF2CF2-、CHF2CHF-、CF3CH2-和CH2ClCH2-)、氨基取代的C1-3亚烷基(NH2-C1-3亚烷基-,例如NH2CH2-、NH2CH2CH2-和NH2CH2CH2CH2-)、C1-3烷基-NHC(O)-(例如CH3-NHC(O)-、CH3CH2-NHC(O)-、和CH3CH2CH2-NHC(O)-)、C1-3烷基-C(O)NH-(例如CH3-C(O)NH-、CH3CH2-C(O)NH-、和CH3CH2CH2-C(O)NH-)、氰基或其任意组合的取代基取代;
Ra1、Ra2、Ra3、Ra4、Ra5、Ra6、Ra7和Ra8分别独立地表示H、C1-C3烷基(例如甲基、乙基或丙基)、C3-6环烷基(例如环丙基、环丁基、环戊基或环己基)、羟基、氨基、巯基、卤素(例如氟、氯、溴或碘)、C1-C3烷氧基(例如甲氧基、乙氧基或丙氧基)、C1-C3烷基氨基 (C1-3烷基NH-,例如CH3NH-、CH3CH2NH-或CH3CH2CH2NH-)、氨基取代的C1-3亚烷基 (NH2-C1-3亚烷基-,例如NH2CH2-、NH2CH2CH2-和NH2CH2CH2CH2-)、卤代C1-C3烷基(例如F3C-、FCH2-、F2CH-、ClCH2-、Cl2CH-、CF3CF2-、CF3CHF-、CHF2CF2-、CHF2CHF-、 CF3CH2-和CH2ClCH2-)或氰基,
U表示C(O)或U表示键,且符号#表示与基团Y的连接点;和
n4、n5、n6、n7、m6、m7、m8分别独立地选自整数1、2、3、4、5、6、7、8、9、10、 11、12、13、14、15、16、17、18、19或20。
在一些实施方案中,LIN可以表示以下式:
#-U-(C(Ra1)(Ra2))n4-(O(C(Ra3)(Ra4))n5)m6-;
#-U-(C(Ra1)(Ra2))n4-(O(C(Ra3)(Ra4))n5)m6-(O(C(Ra5)(Ra6))n6)m7-;
#-U-(C(Ra1)(Ra2))n4-(O(C(Ra3)(Ra4))n5)m6-(O(C(Ra5)(Ra6))n6)m7-(O(C(Ra7)(Ra8))n7)m8-;
#-U-(C(Ra1)(Ra2))n4-(N(R7)(C(Ra3)(Ra4))n5)m6-;
#-U-(C(Ra1)(Ra2))n4-(N(R7)(C(Ra3)(Ra4))n5)m6-(N(R7)(C(Ra5)(Ra6))n6)m7-;
#-U-(C(Ra1)(Ra2))n4-(N(R7)(C(Ra3)(Ra4))n5)m6-(N(R7)(C(Ra5)(Ra6))n6)m7-(N(R7)(C(Ra7)(Ra8))n7)m8-;
#-U-(C(Ra1)(Ra2))n4-(C(O)N(R7)-(C(Ra3)(Ra4))n5)m6-;
#-U-(C(Ra1)(Ra2))n4-(C(O)N(R7)-(C(Ra3)(Ra4))n5)m6-(C(O)N(R7)-(C(Ra5)(Ra6))n6)m7-;
#-U-(C(Ra1)(Ra2))n4-(C(O)N(R7)-(C(Ra3)(Ra4))n5)m6-(C(O)N(R7)-(C(Ra5)(Ra6))n6)m7-(C(O)N(R7)- (C(Ra7)(Ra8))n7)m8-;
#-U-(C(Ra1)(Ra2))n4-(C(O)N(R7)-(C(Ra3)(Ra4))n5)m6-(O-(C(Ra5)(Ra6))n6)m7-;
#-U-(C(Ra1)(Ra2))n4-C(O)N(R7)-(C(Ra3)(Ra4))n5-(O(C(Ra5)(Ra6))n6)m6-;
#-U-(C(Ra1)(Ra2))n4-(N(R7)C(O)-(C(Ra3)(Ra4))n5)m6-;
#-U-(C(Ra1)(Ra2))n4-(N(R7)C(O)-(C(Ra3)(Ra4))n5)m6-(O-(C(Ra5)(Ra6))n6)m7-;
#-U-(C(Ra1)(Ra2))n4-(N(R7)C(O)-(C(Ra3)(Ra4))n5)m6-(O-(C(Ra5)(Ra6))n6)m7-(O-(C(Ra7)(Ra8))n7)m8-;
#-U-(C(Ra1)(Ra2))n4-N(R7)C(O)-(C(Ra3)(Ra4))n5-(O(C(Ra5)(Ra6))n6)m6-;
#-U-(C(Ra1)(Ra2))n4-N(R7)C(O)N(R7)-(C(Ra3)(Ra4))n5-;
#-U-(C(Ra1)(Ra2))n4-C(O)-(C(Ra3)(Ra4))n5-;
#-U-(C(Ra1)(Ra2))n4-CH=CH-(C(Ra3)(Ra4))n5-;
#-U-(C(Ra1)(Ra2))n4-C≡C-(C(Ra3)(Ra4))n5-;
#-U-(C(Ra1)(Ra2))n4-C≡C-C≡C-(C(Ra3)(Ra4))n5-;
#-U-(C(Ra1)(Ra2))n4-(亚芳基-(C(Ra3)(Ra4))n5)m6-;
#-U-(C(Ra1)(Ra2))n4-(亚芳基-(C(Ra3)(Ra4))n5)m6-亚芳基-(C(Ra5)(Ra6))n6-;
#-U-(C(Ra1)(Ra2))n4-(亚杂环基-(C(Ra3)(Ra4))n5)m6-;
#-U-(C(Ra1)(Ra2))n4-(亚杂环基-(C(Ra3)(Ra4))n5)m6-(亚杂环基-(C(Ra5)(Ra6))n6)m7-;
#-U-(C(Ra1)(Ra2))n4-(亚杂芳基-(C(Ra3)(Ra4))n5)m6-;
#-U-(C(Ra1)(Ra2))n4-(亚杂芳基-(C(Ra3)(Ra4))n5)m6-(亚杂芳基-(C(Ra5)(Ra6))n6)m7-;
#-U-(C(Ra1)(Ra2))n4-(亚环烷基-(C(Ra3)(Ra4))n5)m6-;或
#-U-(C(Ra1)(Ra2))n4-(亚环烷基-(C(Ra3)(Ra4))n5)m6-(亚环烷基-(C(Ra5)(Ra6))n6)m7-;
其中,所述亚环烷基、所述亚芳基、所述亚杂环基和所述亚杂芳基彼此独立地可选地被一或多个(例如1-4、1-3、1-2或1个)选自C1-C3烷基(例如甲基、乙基或丙基)、C3-6环烷基(例如环丙基、环丁基、环戊基或环己基)、羟基、氨基、巯基、卤素(例如氟、氯、溴或碘)、C1-C3烷氧基(例如甲氧基、乙氧基或丙氧基)、C1-C3烷基氨基(C1-3烷基NH-,例如CH3NH-、CH3CH2NH-或CH3CH2CH2NH-)、卤代C1-C3烷基(例如F3C-、FCH2-、F2CH-、 ClCH2-、Cl2CH-、CF3CF2-、CF3CHF-、CHF2CF2-、CHF2CHF-、CF3CH2-和CH2ClCH2-)、氨基取代的C1-3亚烷基(NH2-C1-3亚烷基-,例如NH2CH2-、NH2CH2CH2-和NH2CH2CH2CH2-)、 C1-3烷基-NHC(O)-(例如CH3-NHC(O)-、CH3CH2-NHC(O)-、和CH3CH2CH2-NHC(O)-)、C1-3烷基-C(O)NH-(例如CH3-C(O)NH-、CH3CH2-C(O)NH-、和CH3CH2CH2-C(O)NH-)、氰基或其任意组合的取代基取代;
各R7独立地表示H或C1-3烷基(例如甲基、乙基或丙基);
Ra1、Ra2、Ra3、Ra4、Ra5、Ra6、Ra7和Ra8分别独立地表示H、C1-C3烷基(例如甲基、乙基或丙基)、C3-6环烷基(例如环丙基、环丁基、环戊基或环己基)、羟基、氨基、巯基、卤素(例如氟、氯、溴或碘)、C1-C3烷氧基(例如甲氧基、乙氧基或丙氧基)、C1-C3烷基氨基 (C1-3烷基NH-,例如CH3NH-、CH3CH2NH-或CH3CH2CH2NH-)、氨基取代的C1-3亚烷基 (NH2-C1-3亚烷基-,例如NH2CH2-、NH2CH2CH2-和NH2CH2CH2CH2-)、卤代C1-C3烷基(例如F3C-、FCH2-、F2CH-、ClCH2-、Cl2CH-、CF3CF2-、CF3CHF-、CHF2CF2-、CHF2CHF-、 CF3CH2-和CH2ClCH2-)或氰基;
U表示C(O)或U表示键,且符号#表示与基团Y的连接点;和
n4、n5、n6、n7、n8、m6、m7、m8分别独立地表示整数1、2、3、4、5、6、7、8、9、 10、11、12、13、14、15、16、17、18、19或20。
在一些实施方案中,LIN的所述亚环烷基可选地选自以下基团:
亚环丙基、亚环丁基、亚环戊基、亚环戊烯基、亚环己基、亚环己烯基、亚环庚基、亚环辛基、亚十氢萘基、八氢并环戊二烯亚基、八氢-1H-茚亚基、C5-15亚螺环基、亚金刚烷基、亚降金刚烷基、亚冰片基、二环[2.2.1]庚烷亚基、或二环[2.2.1]庚烯亚基,
其中所述亚环烷基可选地被一或多个(例如1-4、1-3、1-2或1个)选自C1-C3烷基(例如甲基、乙基或丙基)、C3-6环烷基(例如环丙基、环丁基、环戊基或环己基)、羟基、氨基、巯基、卤素(例如氟、氯、溴或碘)、C1-C3烷氧基(例如甲氧基、乙氧基或丙氧基)、C1-C3烷基氨基(C1-3烷基NH-,例如CH3NH-、CH3CH2NH-或CH3CH2CH2NH-)、卤代C1-C3烷基 (例如F3C-、FCH2-、F2CH-、ClCH2-、Cl2CH-、CF3CF2-、CF3CHF-、CHF2CF2-、CHF2CHF-、 CF3CH2-和CH2ClCH2-)、氨基取代的C1-3亚烷基(NH2-C1-3亚烷基-,例如NH2CH2-、 NH2CH2CH2-和NH2CH2CH2CH2-)、C1-3烷基-NHC(O)-(例如CH3-NHC(O)-、CH3CH2- NHC(O)-、和CH3CH2CH2-NHC(O)-)、C1-3烷基-C(O)NH-(例如CH3-C(O)NH-、CH3CH2- C(O)NH-、和CH3CH2CH2-C(O)NH-)、氰基或其任意组合的取代基取代。
在一些实施方案中,LIN的所述亚芳基可选地选自以下基团:苯基或萘基,其中所述亚芳基可选地被一或多个(例如1-4、1-3、1-2或1个)选自C1-C3烷基(例如甲基、乙基或丙基)、C3-6环烷基(例如环丙基、环丁基、环戊基或环己基)、羟基、氨基、巯基、卤素(例如氟、氯、溴或碘)、C1-C3烷氧基(例如甲氧基、乙氧基或丙氧基)、C1-C3烷基氨基(C1-3烷基NH-,例如CH3NH-、CH3CH2NH-或CH3CH2CH2NH-)、卤代C1-C3烷基(例如F3C-、 FCH2-、F2CH-、ClCH2-、Cl2CH-、CF3CF2-、CF3CHF-、CHF2CF2-、CHF2CHF-、CF3CH2-和 CH2ClCH2-)、氨基取代的C1-3亚烷基(NH2-C1-3亚烷基-,例如NH2CH2-、NH2CH2CH2-和 NH2CH2CH2CH2-)、C1-3烷基-NHC(O)-(例如CH3-NHC(O)-、CH3CH2-NHC(O)-、和 CH3CH2CH2-NHC(O)-)、C1-3烷基-C(O)NH-(例如CH3-C(O)NH-、CH3CH2-C(O)NH-、和 CH3CH2CH2-C(O)NH-)、氰基或其任意组合的取代基取代。
在一些实施方案中,LIN的所述亚杂环基可选地选自以下基团:
亚氮杂环丁基、亚氧杂环丁基、亚吡咯烷基、亚咪唑烷基、亚吡唑烷基、亚四氢呋喃基、亚四氢吡喃基、亚四氢噻吩基、亚四氢噻喃基、亚噁唑烷基、亚噻唑烷基、亚哌啶基、亚哌嗪基、亚吗啉基、亚硫代吗啉基、亚二氧杂环己基或亚二氮杂环庚基,
其中所述亚杂环基可选地被一或多个(例如1-4、1-3、1-2或1个)选自C1-C3烷基(例如甲基、乙基或丙基)、C3-6环烷基(例如环丙基、环丁基、环戊基或环己基)、羟基、氨基、巯基、卤素(例如氟、氯、溴或碘)、C1-C3烷氧基(例如甲氧基、乙氧基或丙氧基)、C1-C3烷基氨基(C1-3烷基NH-,例如CH3NH-、CH3CH2NH-或CH3CH2CH2NH-)、卤代C1-C3烷基 (例如F3C-、FCH2-、F2CH-、ClCH2-、Cl2CH-、CF3CF2-、CF3CHF-、CHF2CF2-、CHF2CHF-、 CF3CH2-和CH2ClCH2-)、氨基取代的C1-3亚烷基(NH2-C1-3亚烷基-,例如NH2CH2-、 NH2CH2CH2-和NH2CH2CH2CH2-)、C1-3烷基-NHC(O)-(例如CH3-NHC(O)-、CH3CH2- NHC(O)-、和CH3CH2CH2-NHC(O)-)、C1-3烷基-C(O)NH-(例如CH3-C(O)NH-、CH3CH2- C(O)NH-、和CH3CH2CH2-C(O)NH-)、氰基或其任意组合的取代基取代。
在一些实施方案中,LIN的所述亚杂芳基可选地选自以下基团:
亚呋喃基、亚噁唑基、亚异噁唑基、亚噁二唑基、亚噻吩基、亚噻唑基、亚异噻唑基、亚噻二唑基、亚吡咯基、亚咪唑基、亚吡唑基、亚三唑基、亚吡啶基、亚嘧啶基、亚哒嗪基、亚吡嗪基、亚吲哚基、亚异吲哚基、亚苯并呋喃基、亚异苯并呋喃基、亚苯并噻吩基、亚吲唑基、亚苯并咪唑基、亚苯并噁唑基、亚苯并异噁唑基、亚苯并噻唑基、亚苯并异噻唑基、亚苯并三唑基、亚苯并[2,1,3]噁二唑基、亚苯并[2,1,3]噻二唑基、亚苯并[1,2,3]噻二唑基、亚喹啉基、亚异喹啉基、亚萘啶基、亚噌啉基、亚喹唑啉基、亚喹喔啉基、亚酞嗪基、吡唑并 [1,5-a]吡啶亚基、吡唑并[1,5-a]嘧啶亚基、咪唑并[1,2-a]吡啶亚基、1H-吡咯并[3,2-b]吡啶亚基、 1H-吡咯并[2,3-b]吡啶亚基、4H-氟[3,2-b]吡咯亚基、吡咯并[2,1-b]噻唑亚基、或咪唑并[2,1-b] 噻唑亚基,
其中所述亚杂芳基可选地被一或多个(例如1-4、1-3、1-2或1个)选自C1-C3烷基(例如甲基、乙基或丙基)、C3-6环烷基(例如环丙基、环丁基、环戊基或环己基)、羟基、氨基、巯基、卤素(例如氟、氯、溴或碘)、C1-C3烷氧基(例如甲氧基、乙氧基或丙氧基)、C1-C3烷基氨基(C1-3烷基NH-,例如CH3NH-、CH3CH2NH-或CH3CH2CH2NH-)、卤代C1-C3烷基 (例如F3C-、FCH2-、F2CH-、ClCH2-、Cl2CH-、CF3CF2-、CF3CHF-、CHF2CF2-、CHF2CHF-、 CF3CH2-和CH2ClCH2-)、氨基取代的C1-3亚烷基(NH2-C1-3亚烷基-,例如NH2CH2-、 NH2CH2CH2-和NH2CH2CH2CH2-)、C1-3烷基-NHC(O)-(例如CH3-NHC(O)-、CH3CH2- NHC(O)-、和CH3CH2CH2-NHC(O)-)、C1-3烷基-C(O)NH-(例如CH3-C(O)NH-、CH3CH2- C(O)NH-、和CH3CH2CH2-C(O)NH-)、氰基或其任意组合的取代基取代。
在一些实施方案中,LIN表示以下式的结构:
#-U-CH2-O-CH2-、#-U-CH2-O-(CH2)2-、#-U-(CH2)1-O-(CH2)3-、#-U-(CH2)1-O-(CH2)4-、#- U-(CH2)1-O-(CH2)5-、#-U-(CH2)1-O-(CH2)6-、#-U-(CH2)1-O-(CH2)7-、#-U-(CH2)1-O-(CH2)8-、#- U-(CH2)1-O-(CH2)9-、#-U-(CH2)1-O-(CH2)10-、#-U-(CH2)2-O-(CH2)1-、#-U-(CH2)2-O-(CH2)2-、#- U-(CH2)2-O-(CH2)3-、#-U-(CH2)2-O-(CH2)4-、#-U-(CH2)2-O-(CH2)5-、#-U-(CH2)2-O-(CH2)6-、#- U-(CH2)2-O-(CH2)7-、#-U-(CH2)2-O-(CH2)8-、#-U-(CH2)2-O-(CH2)9-、#-U-(CH2)2-O-(CH2)10-、#- U-(CH2)2-O-(CH2)11-、#-U-(CH2)2-O-(CH2)12-、#-U-(CH2)3-O-(CH2)1-、#-U-(CH2)3-O-(CH2)2-、#- U-(CH2)3-O-(CH2)3-、#-U-(CH2)3-O-(CH2)4-、#-U-(CH2)3-O-(CH2)5-、#-U-(CH2)3-O-(CH2)6-、#- U-(CH2)3-O-(CH2)7-、#-U-(CH2)4-O-(CH2)1-、#-U-(CH2)4-O-(CH2)2-、#-U-(CH2)4-O-(CH2)3-、#-U-(CH2)4-O-(CH2)4-、#-U-(CH2)4-O-(CH2)5-、#-U-(CH2)4-O-(CH2)6-、#-U-(CH2)5-O-(CH2)1-、#- U-(CH2)5-O-(CH2)2-、#-U-(CH2)5-O-(CH2)3-、#-U-(CH2)5-O-(CH2)4-、#-U-(CH2)5-O-(CH2)5-、#- U-(CH2)6-O-(CH2)1-、#-U-(CH2)6-O-(CH2)2-、#-U-(CH2)6-O-(CH2)3-、#-U-(CH2)6-O-(CH2)4-、#- U-(CH2)7-O-(CH2)1-、#-U-(CH2)7-O-(CH2)2-、#-U-(CH2)7-O-(CH2)3-、#-U-(CH2)8-O-(CH2)1-、#- U-(CH2)8-O-(CH2)2-、#-U-CH(CH3)-O-(CH2)1-、#-U-CH(CH3)-O-(CH2)2-、#-U-CH(CH3)-O- (CH2)3-、#-U-CH(CH3)-O-(CH2)4-、#-U-CH(CH3)-O-(CH2)5-、#-U-CH(CH3)-O-(CH2)6-、#-U- CH(CH3)-O-(CH2)7-、#-U-CH(CH3)-O-(CH2)8-、#-U-CH(CH3)-O-(CH2)9-、#-U-CH(CH3)-O- (CH2)10-、#-U-CH2-(O(CH2)2)2-、#-U-CH2-(O(CH2)2)3-、#-U-CH2-(O(CH2)2)4-、#-U-CH2- (O(CH2)2)5-、#-U-CH2-(O(CH2)2)6-、#-U-CH2-(O(CH2)2)7-、#-U-CH2-(O(CH2)2)8-、#-U-CH2- (O(CH2)2)9-、#-U-CH2-(O(CH2)2)10-、#-U-CH2-(O(CH2)2)1-OCH2-、#-U-CH2-(O(CH2)2)2-OCH2-、 #-U-CH2-(O(CH2)2)3-OCH2-、#-U-CH2-(O(CH2)2)4-OCH2-、#-U-CH2-(O(CH2)2)5-OCH2-、#-U- CH2-(O(CH2)2)6-OCH2-、#-U-CH2-(O(CH2)2)7-OCH2-、#-U-CH2-(O(CH2)2)8-OCH2-、#-U-CH2- (O(CH2)2)9-OCH2-、#-U-CH2-(O(CH2)2)10-OCH2-、#-U-(CH2)2-(O(CH2)2)2-、#-U-(CH2)2- (O(CH2)2)3-、#-U-(CH2)2-(O(CH2)2)4-、#-U-(CH2)2-(O(CH2)2)5-、#-U-(CH2)2-(O(CH2)2)6-、#-U- (CH2)2-(O(CH2)2)7-、#-U-(CH2)2-(O(CH2)2)8-、#-U-(CH2)2-(O(CH2)2)9-、#-U-(CH2)2-(O(CH2)2)10-、 #-U-(CH2)3-(O(CH2)2)2-、#-U-(CH2)3-(O(CH2)2)3-、#-U-(CH2)3-(O(CH2)2)4-、#-U-(CH2)3- (O(CH2)2)5-、#-U-(CH2)3-(O(CH2)2)6-、#-U-(CH2)3-(O(CH2)2)7-、#-U-(CH2)3-(O(CH2)2)8-、#-U- (CH2)3-(O(CH2)2)9-、#-U-(CH2)3-(O(CH2)2)10-、#-U-(CH2)4-(O(CH2)2)2-、#-U-(CH2)4-(O(CH2)2)3-、 #-U-(CH2)4-(O(CH2)2)4-、#-U-(CH2)4-(O(CH2)2)5-、#-U-(CH2)4-(O(CH2)2)6-、#-U-(CH2)4- (O(CH2)2)7-、#-U-(CH2)4-(O(CH2)2)8-、#-U-(CH2)4-(O(CH2)2)9-、#-U-(CH2)4-(O(CH2)2)10-、#-U- CH2-(O(CH2)3)2-、#-U-CH2-(O(CH2)3)3-、#-U-CH2-(O(CH2)3)4-、#-U-CH2-(O(CH2)3)5-、#-U-CH2- (O(CH2)3)6-、#-U-CH2-(O(CH2)3)7-、#-U-CH2-(O(CH2)3)8-、#-U-CH2-(O(CH2)3)9-、#-U-CH2- (O(CH2)3)10-、#-U-(CH2)2-(O(CH2)3)2-、#-U-(CH2)2-(O(CH2)3)3-、#-U-(CH2)2-(O(CH2)3)4-、#-U- (CH2)2-(O(CH2)3)5-、#-U-(CH2)2-(O(CH2)3)6-、#-U-(CH2)2-(O(CH2)3)7-、#-U-(CH2)2-(O(CH2)3)8-、 #-U-(CH2)2-(O(CH2)3)9-、#-U-(CH2)2-(O(CH2)3)10-、#-U-(CH2)3-(O(CH2)3)2-、#-U-(CH2)3- (O(CH2)3)3-、#-U-(CH2)3-(O(CH2)3)4-、#-U-(CH2)3-(O(CH2)3)5-、#-U-(CH2)3-(O(CH2)3)6-、#-U- (CH2)3-(O(CH2)3)7-、#-U-(CH2)3-(O(CH2)3)8-、#-U-(CH2)3-(O(CH2)3)9-、#-U-(CH2)3-(O(CH2)3)10-、 #-U-CH2-O-(CH2)2-O-(CH2)3-、#-U-CH2-(O(CH2)2)2-(O(CH2)3)2-、#-U-CH2-(O(CH2)2)3- (O(CH2)3)3-、#-U-CH2-(O(CH2)2)4-(O(CH2)3)4-、#-U-CH2-(O(CH2)2)5-(O(CH2)3)5-、#-U-CH2- (O(CH2)2)6-(O(CH2)3)6-、#-U-(CH2)2-O-(CH2)2-O-(CH2)3-、#-U-(CH2)2-(O(CH2)2)2-(O(CH2)3)2-、#- U-(CH2)2-(O(CH2)2)3-(O(CH2)3)3-、#-U-(CH2)2-(O(CH2)2)4-(O(CH2)3)4-、#-U-(CH2)2-(O(CH2)2)5- (O(CH2)3)5-、#-U-(CH2)2-(O(CH2)2)6-(O(CH2)3)6-、#-U-(CH2)3-O-(CH2)2-O-(CH2)3-、#-U-(CH2)3- (O(CH2)2)2-(O(CH2)3)2-、#-U-(CH2)3-(O(CH2)2)3-(O(CH2)3)3-、#-U-(CH2)3-(O(CH2)2)4-(O(CH2)3)4-、 #-U-(CH2)3-(O(CH2)2)5-(O(CH2)3)5-、#-U-(CH2)3-(O(CH2)2)6-(O(CH2)3)6-、#-U-CH2-O-(CH2)3-O-(CH2)2-、#-U-CH2-(O(CH2)3)2-(O(CH2)2)2-、#-U-CH2-(O(CH2)3)3-(O(CH2)2)3-、#-U-CH2- (O(CH2)3)4-(O(CH2)2)4-、#-U-CH2-(O(CH2)3)5-(O(CH2)2)5-、#-U-CH2-(O(CH2)3)6-(O(CH2)2)6-、#- U-(CH2)2-O-(CH2)3-O-(CH2)2-、#-U-(CH2)2-(O(CH2)3)2-(O(CH2)2)2-、#-U-(CH2)2-(O(CH2)3)3- (O(CH2)2)3-、#-U-(CH2)2-(O(CH2)3)4-(O(CH2)2)4-、#-U-(CH2)2-(O(CH2)3)5-(O(CH2)2)5-、#-U- (CH2)2-(O(CH2)3)6-(O(CH2)2)6-、#-U-(CH2)3-O-(CH2)3-O-(CH2)2-、#-U-(CH2)3-(O(CH2)3)2- (O(CH2)2)2-、#-U-(CH2)3-(O(CH2)3)3-(O(CH2)2)3-、#-U-(CH2)3-(O(CH2)3)4-(O(CH2)2)4-、#-U- (CH2)3-(O(CH2)3)5-(O(CH2)2)5-、#-U-(CH2)3-(O(CH2)3)6-(O(CH2)2)6-、#-U-CH2-O-(CH2)2-O-CH2-、 #-U-(CH2)2-O-(CH2)2-O-CH2-、#-U-(CH2)2-(O(CH2)2)2-O-(CH2)3-、#-U-(CH2)2-(O(CH2)2)3-O- (CH2)3-、#-U-(CH2)2-(O(CH2)2)4-O-(CH2)3-、#-U-(CH2)5-(O(CH2)2)2-O-(CH2)5-、#-U-(CH2)5- (O(CH2)2)2-O-(CH2)6-、#-U-(CH2)1-N(R7)-(CH2)1-、#-U-(CH2)1-N(R7)-(CH2)2-、#-U-(CH2)1-N(R7)- (CH2)3-、#-U-(CH2)1-N(R7)-(CH2)4-、#-U-(CH2)1-N(R7)-(CH2)5-、#-U-(CH2)1-N(R7)-(CH2)6-、#- U-(CH2)1-N(R7)-(CH2)7-、#-U-(CH2)1-N(R7)-(CH2)8-、#-U-(CH2)1-N(R7)-(CH2)9-、#-U-(CH2)1- N(R7)-(CH2)10-、#-U-(CH2)2-N(R7)-(CH2)1-、#-U-(CH2)2-N(R7)-(CH2)2-、#-U-(CH2)2-N(R7)-(CH2)3-、#-U-(CH2)2-N(R7)-(CH2)4-、#-U-(CH2)2-N(R7)-(CH2)5-、#-U-(CH2)2-N(R7)-(CH2)6-、#- U-(CH2)2-N(R7)-(CH2)7-、#-U-(CH2)2-N(R7)-(CH2)8-、#-U-(CH2)2-N(R7)-(CH2)9-、#-U-(CH2)2- N(R7)-(CH2)10-、#-U-(CH2)2-N(R7)-(CH2)11-、#-U-(CH2)2-N(R7)-(CH2)12-、#-U-(CH2)3-N(R7)- (CH2)1-、#-U-(CH2)3-N(R7)-(CH2)2-、#-U-(CH2)3-N(R7)-(CH2)3-、#-U-(CH2)4-N(R7)-(CH2)1-、#- U-(CH2)4-N(R7)-(CH2)2-、#-U-(CH2)4-N(R7)-(CH2)3-、#-U-(CH2)4-N(R7)-(CH2)4-、#-U-(CH2)5- N(R7)-(CH2)1-、#-U-(CH2)5-N(R7)-(CH2)2-、#-U-(CH2)5-N(R7)-(CH2)3-、#-U-(CH2)5-N(R7)-(CH2)4-、 #-U-(CH2)5-N(R7)-(CH2)5-、#-U-(CH2)6-N(R7)-(CH2)1-、#-U-(CH2)6-N(R7)-(CH2)2-、#-U-(CH2)6- N(R7)-(CH2)3-、#-U-(CH2)7-N(R7)-(CH2)1-、#-U-(CH2)7-N(R7)-(CH2)2-、#-U-(CH2)7-N(R7)-(CH2)3-、#-U-(CH2)8-N(R7)-(CH2)1-、#-U-(CH2)8-N(R7)-(CH2)2-、#-U-(CH2)8-N(R7)-(CH2)3-、#-U- CH(CH3)-N(R7)-(CH2)1-、#-U-CH(CH3)-N(R7)-(CH2)2-、#-U-CH(CH3)-N(R7)-(CH2)3-、#-U- CH(CH3)-N(R7)-(CH2)4-、#-U-CH(CH3)-N(R7)-(CH2)5-、#-U-CH(CH3)-N(R7)-(CH2)6-、#-U- CH(CH3)-N(R7)-(CH2)7-、#-U-CH(CH3)-N(R7)-(CH2)8-、#-U-CH(CH3)-N(R7)-(CH2)9-、#-U- CH(CH3)-N(R7)-(CH2)10-、#-U-CH2C(O)NHCH2-、#-U-(CH2)2C(O)NH(CH2)2-、#-U- (CH2)2C(O)NH(CH2)3-、#-U-(CH2)2C(O)NH(CH2)4-、#-U-(CH2)2C(O)NH(CH2)5-、#-U- (CH2)3C(O)NH(CH2)3-、#-U-(CH2)3C(O)NH(CH2)4-、#-U-(CH2)4C(O)NH(CH2)4-、#-U- (CH2)5C(O)NH(CH2)5-、#-U-(CH2)6C(O)NH(CH2)7-、#-U-(CH2)6C(O)NH(CH2)6-、#-U- (CH2)7C(O)NH(CH2)7-、#-U-(CH2)8C(O)NH(CH2)8、U-(CH2)9C(O)NH(CH2)9-、#-U- (CH2)10C(O)NH(CH2)10-、#-U-(CH2)2C(O)NH(CH2)2-O-(CH2)2-、#-U-CH2NHC(O)CH2-、#-U- (CH2)2NHC(O)(CH2)2-、#-U-(CH2)2NHC(O)(CH2)3-、#-U-(CH2)2NHC(O)(CH2)4-、#-U- (CH2)2NHC(O)(CH2)5-、#-U-(CH2)3NHC(O)(CH2)3-、#-U-(CH2)3NHC(O)(CH2)4-、#-U- (CH2)4NHC(O)(CH2)4-、#-U-(CH2)5NHC(O)(CH2)5-、#-U-(CH2)6NHC(O)(CH2)7-、#-U- (CH2)6NHC(O)(CH2)6-、#-U-(CH2)7NHC(O)(CH2)7-、#-U-(CH2)8NHC(O)(CH2)8、#-U- (CH2)9NHC(O)(CH2)9-、#-U-(CH2)10NHC(O)(CH2)10-、#-U-(CH2)4NHC(O)(CH2)8-、#-U- (CH2)2NHC(O)(CH2)2-O-(CH2)2-、#-U-(CH2)4NHC(O)CH2-、#-U-CH2-亚苯基-CH2-、#-U-CH2-亚苯基-(CH2)2-、#-U-CH2-亚苯基-(CH2)3-、#-U-CH2-亚苯基-(CH2)4-、#-U-CH2-亚苯基-(CH2)5-、 #-U-CH2-亚苯基-(CH2)6-、#-U-CH2-亚苯基-(CH2)7-、#-U-CH2-亚苯基-(CH2)8-、#-U-(CH2)2-亚苯基-(CH2)1-、#-U-(CH2)2-亚苯基-(CH2)2-、#-U-(CH2)2-亚苯基-(CH2)3-、#-U-(CH2)2-亚苯基- (CH2)4-、#-U-(CH2)2-亚苯基-(CH2)5-、#-U-(CH2)2-亚苯基-(CH2)6-、#-U-(CH2)2-亚苯基-(CH2)7-、 #-U-(CH2)2-亚苯基-(CH2)8-、#-U-(CH2)3-亚苯基-CH2-、#-U-(CH2)3-亚苯基-(CH2)2-、#-U-(CH2)3- 亚苯基-(CH2)3-、#-U-(CH2)3-亚苯基-(CH2)4-、#-U-(CH2)3-亚苯基-(CH2)5-、#-U-(CH2)3-亚苯基-(CH2)6-、#-U-(CH2)3-亚苯基-(CH2)7-、#-U-(CH2)3-亚苯基-(CH2)8-、#-U-(CH2)4-亚苯基-CH2-、#- U-(CH2)4-亚苯基-(CH2)2-、#-U-(CH2)4-亚苯基-(CH2)3-、#-U-(CH2)4-亚苯基-(CH2)4-、#-U- (CH2)4-亚苯基-(CH2)5-、#-U-(CH2)4-亚苯基-(CH2)6-、#-U-(CH2)4-亚苯基-(CH2)7-、#-U-(CH2)4- 亚苯基-(CH2)8-、#-U-(CH2)5-亚苯基-(CH2)1-、#-U-(CH2)5-亚苯基-(CH2)2-、#-U-(CH2)5-亚苯基- (CH2)3-、#-U-(CH2)5-亚苯基-(CH2)4-、#-U-(CH2)5-亚苯基-(CH2)5-、#-U-(CH2)5-亚苯基-(CH2)6-、#-U-(CH2)5-亚苯基-(CH2)7-、#-U-(CH2)5-亚苯基-(CH2)8-、#-U-(CH2)6-亚苯基-(CH2)1-、#-U- (CH2)6-亚苯基-(CH2)2-、#-U-(CH2)6-亚苯基-(CH2)3-、#-U-(CH2)6-亚苯基-(CH2)4-、#-U-(CH2)6- 亚苯基-(CH2)5-、#-U-(CH2)6-亚苯基-(CH2)6-、#-U-(CH2)6-亚苯基-(CH2)7-、#-U-(CH2)6-亚苯基- (CH2)8-、#-U-(CH2)7-亚苯基-(CH2)1-、#-U-(CH2)7-亚苯基-(CH2)2-、#-U-(CH2)7-亚苯基-(CH2)3-、 #-U-(CH2)7-亚苯基-(CH2)4-、#-U-(CH2)7-亚苯基-(CH2)8-、#-U-(CH2)8-亚苯基-CH2-、#-U-(CH2)8- 亚苯基-(CH2)2-、#-U-(CH2)8-亚苯基-(CH2)3-、#-U-(CH2)8-亚苯基-(CH2)4-、#-U-(CH2)8-亚苯基-(CH2)5-、#-U-(CH2)8-亚苯基-(CH2)6-、#-U-(CH2)8-亚苯基-(CH2)7-、#-U-(CH2)8-亚苯基-(CH2)8-、 #-U-CH2-N(R7)-CH2-亚苯基-CH2-、#-U-CH2-N(R7)-CH2-亚苯基-(CH2)2-、#-U-CH2-N(R7)-CH2-亚苯基-(CH2)3-、#-U-CH2-N(R7)-CH2-亚苯基-(CH2)4-、#-U-CH2-N(R7)-CH2-亚苯基-(CH2)5-、#-U- CH2-N(R7)-CH2-亚苯基-(CH2)6-、#-U-CH2-N(R7)-CH2-亚苯基-(CH2)7-、#-U-CH2-N(R7)-CH2-亚苯基-(CH2)8-、#-U-CH2-N(R7)-(CH2)2-亚苯基-CH2-、#-U-CH2-N(R7)-(CH2)2-亚苯基-(CH2)2-、#- U-CH2-N(R7)-(CH2)2-亚苯基-(CH2)3-、#-U-CH2-N(R7)-(CH2)2-亚苯基-(CH2)4-、#-U-CH2-N(R7)- (CH2)2-亚苯基-(CH2)5-、#-U-CH2-N(R7)-(CH2)2-亚苯基-(CH2)6-、#-U-CH2-N(R7)-(CH2)2-亚苯基- (CH2)7-、#-U-CH2-N(R7)-(CH2)2-亚苯基-(CH2)8-、#-U-(CH2)2-N(R7)-CH2-亚苯基-CH2-、#-U- (CH2)2-N(R7)-CH2-亚苯基-(CH2)2-、#-U-(CH2)2-N(R7)-CH2-亚苯基-(CH2)3-、#-U-(CH2)2-N(R7)- CH2-亚苯基-(CH2)4-、#-U-(CH2)2-N(R7)-CH2-亚苯基-(CH2)5-、#-U-(CH2)2-N(R7)-CH2-亚苯基- (CH2)6-、#-U-(CH2)2-N(R7)-CH2-亚苯基-(CH2)7-、#-U-(CH2)2-N(R7)-CH2-亚苯基-(CH2)8-、#-U- (CH2)3-N(R7)-CH2-亚苯基-CH2-、#-U-(CH2)3-N(R7)-CH2-亚苯基-(CH2)2-、#-U-(CH2)3-N(R7)- CH2-亚苯基-(CH2)3-、#-U-(CH2)3-N(R7)-CH2-亚苯基-(CH2)8-、#-U-(CH2)4-N(R7)-CH2-亚苯基- CH2-、#-U-(CH2)4-N(R7)-CH2-亚苯基-(CH2)2-、#-U-(CH2)4-N(R7)-CH2-亚苯基-(CH2)3-、#-U- (CH2)4-N(R7)-CH2-亚苯基-(CH2)8-、#-U-(CH2)5-N(R7)-CH2-亚苯基-(CH2)3-、#-U-(CH2)5-N(R7)-CH2-亚苯基-(CH2)8-、#-U-(CH2)6-N(R7)-CH2-亚苯基-(CH2)3-、#-U-(CH2)6-N(R7)-CH2-亚苯基- (CH2)8-、#-U-(CH2)7-N(R7)-CH2-亚苯基-(CH2)3-、#-U-(CH2)7-N(R7)-CH2-亚苯基-(CH2)8-、#-U- (CH2)8-N(R7)-CH2-亚苯基-CH2-、#-U-(CH2)8-N(R7)-CH2-亚苯基-(CH2)2-、#-U-(CH2)8-N(R7)- CH2-亚苯基-(CH2)3-、#-U-(CH2)8-N(R7)-CH2-亚苯基-(CH2)4-、#-U-(CH2)8-N(R7)-CH2-亚苯基- (CH2)5-、#-U-(CH2)8-N(R7)-CH2-亚苯基-(CH2)6-、#-U-(CH2)8-N(R7)-CH2-亚苯基-(CH2)7-、#-U- (CH2)8-N(R7)-CH2-亚苯基-(CH2)8-、#-U-CH2-亚哌嗪基-CH2-、#-U-CH2-亚哌嗪基-(CH2)2-、#-U- CH2-亚哌嗪基-(CH2)3-、#-U-CH2-亚哌嗪基-(CH2)4-、#-U-CH2-亚哌嗪基-(CH2)5-、#-U-CH2-亚哌嗪基-(CH2)6-、#-U-CH2-亚哌嗪基-(CH2)7-、#-U-CH2-亚哌嗪基-(CH2)8-、#-U-(CH2)2-亚哌嗪基 -(CH2)1-、#-U-(CH2)2-亚哌嗪基-(CH2)2-、#-U-(CH2)2-亚哌嗪基-(CH2)3-、#-U-(CH2)2-亚哌嗪基- (CH2)4-、#-U-(CH2)2-亚哌嗪基-(CH2)5-、#-U-(CH2)2-亚哌嗪基-(CH2)6-、#-U-(CH2)2-亚哌嗪基- (CH2)7-、#-U-(CH2)2-亚哌嗪基-(CH2)8-、#-U-(CH2)3-亚哌嗪基-CH2-、#-U-(CH2)3-亚哌嗪基- (CH2)2-、#-U-(CH2)3-亚哌嗪基-(CH2)3-、#-U-(CH2)3-亚哌嗪基-(CH2)4-、#-U-(CH2)3-亚哌嗪基- (CH2)5-、#-U-(CH2)3-亚哌嗪基-(CH2)6-、#-U-(CH2)3-亚哌嗪基-(CH2)7-、#-U-(CH2)3-亚哌嗪基-(CH2)8-、#-U-(CH2)4-亚哌嗪基-CH2-、#-U-(CH2)4-亚哌嗪基-(CH2)2-、#-U-(CH2)4-亚哌嗪基-(CH2)3-、#-U-(CH2)4-亚哌嗪基-(CH2)4-、#-U-(CH2)4-亚哌嗪基-(CH2)5-、#-U-(CH2)4-亚哌嗪基- (CH2)6-、#-U-(CH2)4-亚哌嗪基-(CH2)7-、#-U-(CH2)4-亚哌嗪基-(CH2)8-、#-U-(CH2)5-亚哌嗪基- (CH2)1-、#-U-(CH2)5-亚哌嗪基-(CH2)2-、#-U-(CH2)5-亚哌嗪基-(CH2)3-、#-U-(CH2)5-亚哌嗪基- (CH2)4-、#-U-(CH2)5-亚哌嗪基-(CH2)5-、#-U-(CH2)5-亚哌嗪基-(CH2)6-、#-U-(CH2)5-亚哌嗪基- (CH2)7-、#-U-(CH2)5-亚哌嗪基-(CH2)8-、#-U-(CH2)6-亚哌嗪基-(CH2)1-、#-U-(CH2)6-亚哌嗪基- (CH2)2-、#-U-(CH2)6-亚哌嗪基-(CH2)3-、#-U-(CH2)6-亚哌嗪基-(CH2)4-、#-U-(CH2)6-亚哌嗪基- (CH2)5-、#-U-(CH2)6-亚哌嗪基-(CH2)6-、#-U-(CH2)6-亚哌嗪基-(CH2)7-、#-U-(CH2)6-亚哌嗪基- (CH2)8-、#-U-(CH2)7-亚哌嗪基-(CH2)1-、#-U-(CH2)7-亚哌嗪基-(CH2)2-、#-U-(CH2)7-亚哌嗪基- (CH2)3-、#-U-(CH2)7-亚哌嗪基-(CH2)4-、#-U-(CH2)7-亚哌嗪基-(CH2)8-、#-U-(CH2)8-亚哌嗪基- CH2-、#-U-(CH2)8-亚哌嗪基-(CH2)2-、#-U-(CH2)8-亚哌嗪基-(CH2)3-、#-U-(CH2)8-亚哌嗪基- (CH2)4-、#-U-(CH2)8-亚哌嗪基-(CH2)5-、#-U-(CH2)8-亚哌嗪基-(CH2)6-、#-U-(CH2)8-亚哌嗪基- (CH2)7-、或#-U-(CH2)8-亚哌嗪基-(CH2)8-;
其中,U表示C(O)或U表示键,且符号#表示与基团Y的连接点;
各R7独立地表示H或C1-3烷基(例如甲基、乙基或丙基);和
所述亚苯基和所述亚哌嗪基彼此独立地可选地被一或多个(例如1-4、1-3、1-2或1个)选自 C1-C3烷基(例如甲基、乙基或丙基)、C3-6环烷基(例如环丙基、环丁基、环戊基或环己基)、羟基、氨基、巯基、卤素(例如氟、氯、溴或碘)、C1-C3烷氧基(例如甲氧基、乙氧基或丙氧基)、C1-C3烷基氨基(C1-3烷基NH-,例如CH3NH-、CH3CH2NH-或 CH3CH2CH2NH-)、卤代C1-C3烷基(例如F3C-、FCH2-、F2CH-、ClCH2-、Cl2CH-、CF3CF2-、 CF3CHF-、CHF2CF2-、CHF2CHF-、CF3CH2-和CH2ClCH2-)、氨基取代的C1-3亚烷基(NH2- C1-3亚烷基-,例如NH2CH2-、NH2CH2CH2-和NH2CH2CH2CH2-)、C1-3烷基-NHC(O)-(例如 CH3-NHC(O)-、CH3CH2-NHC(O)-、和CH3CH2CH2-NHC(O)-)、C1-3烷基-C(O)NH-(例如CH3- C(O)NH-、CH3CH2-C(O)NH-、和CH3CH2CH2-C(O)NH-)、氰基或其任意组合的取代基取代。
在一些实施方案中,本公开的式(I)化合物亦为式(II)化合物或其盐(包括药学上可接受的盐)、溶剂化物、同位素富集类似物、多晶型物、前药、立体异构体(包括对映异构体)、或立体异构体的混合物:
其中,ULM为E3泛素连接酶配体部分,LIN为连接部分,式(I)分子的剩余部分是烟酰胺磷酸核糖转移酶(NAMPT)配体,ULM通过LIN共价连接NAMPT配体;
其中环B是含有1个氮原子并且可选地进一步含有1至2个独立地选自氮、氧和硫的杂原子的5元至11元亚杂环基,(Rb)m2表示环B可选地被m2个Rb基团取代,各Rb独立地为C1-3烷基、羟基、氨基、巯基、卤素、C1-3烷氧基、C1-3烷基氨基、卤代C1-3烷基、氨基取代的C1-3亚烷基、C1-3烷基-NHC(O)-、C1-3烷基-C(O)NH-或氰基,和m2表示整数0、1、2、3、4或5;
环A是以下基团:
(Ra)m1表示环A可选地被m1个Ra基团取代,各Ra独立地为羟基、氨基、卤素或氰基,和m1表示整数0、1、2、3、4或5;
R1和R2相同或不同且彼此独立地为H、氰基或甲基;
L1表示取代或未取代的直链C3-6亚烷基、或取代或未取代的直链C3-6亚烯基,所述直链C3-6亚烷基和直链C3-6亚烯基的可选的取代基选自C1-3烷基、卤素、C1-3烷氧基、卤代C1-3烷基、 C1-3烷基-NHC(O)-、C1-3烷基-C(O)NH-、氰基或其任意组合;
环C是5元至10元亚杂芳基、或6元亚芳基,(Rc)m3表示环C可选地被m3个Rc基团取代,各Rc独立地为C1-3烷基、C3-5环烷基、羟基、氨基、巯基、卤素、C1-3烷氧基、C1-3烷基氨基、卤代C1-3烷基、氨基取代的C1-3亚烷基、C1-3烷基-NHC(O)-、C1-3烷基-C(O)NH-或氰基,和m3表示整数0、1、2、3、4或5;
m表示整数0或1;以及
Y表示-N(R3)-,其中R3是氢或C1-3烷基;或
Y表示-O-;或
Y是由以下结构式表示的n个相连的环D:
各环D独立地是5元至11元亚杂环基,(Rd)m4表示各环D可选地独立地被m4个Rd基团取代,各Rd独立地为C1-3烷基、C3-6环烷基、羟基、氨基、巯基、卤素、氧代基、C1-3烷氧基、C1-3烷基氨基、卤代C1-3烷基、氨基取代的C1-3亚烷基、C1-3烷基-NHC(O)-、C1-3烷基-C(O)NH-或氰基,和m4表示整数0、1、2、3、4或5;
n是整数0、1、2或3,其中当n表示整数2或3时,各环D可相同或不同,以及
其中m和n不同时为0;
条件是不包括以下化合物:
所述烟酰胺磷酸核糖转移酶(NAMPT)配体表示以下结构:
并且ULM表示式(IV)的结构:
其中Z1表示C(O)或Z1表示键,以及Z2表示H或CH3。
在一些实施方案中,式(II)化合物的L1表示取代或未取代的直链C3-6亚烷基。直链C3-6亚烷基的示例性实例包括但不限于亚丙基、亚丁基、亚戊基和亚己基。所述直链C3-6亚烷基可选地进一步被一或多个选自C1-3烷基(例如甲基、乙基或丙基)、卤素(例如氟、氯、溴或碘)、C1-3烷氧基(例如甲氧基、乙氧基或丙氧基)、卤代C1-3烷基(例如-CF3、-CH2F、- CHF2、-CH2Cl、-CHCl2、-CF2CF3、-CHFCF3、-CF2CHF2、-CHFCHF2、-CH2CF3和- CH2CH2Cl)、C1-3烷基-NHC(O)-(例如CH3-NHC(O)-、CH3CH2-NHC(O)-、和CH3CH2CH2- NHC(O)-)、C1-3烷基-C(O)NH-(例如CH3-C(O)NH-、CH3CH2-C(O)NH-、和CH3CH2CH2- C(O)NH-)、氰基或其任意组合的取代基取代。取代基的数量原则上不受任何限制或自动受构建单元的大小限制。
在一些实施方案中,式(II)化合物的L1表示取代或未取代的直链C3-6亚烯基。直链C3-6亚烯基的示例性实例包括但不限于 所述直链C3-6亚烯基可选地进一步被一或多个选自C1-3烷基(例如甲基、乙基或丙基)、卤素(例如氟、氯、溴或碘)、C1-3烷氧基(例如甲氧基、乙氧基或丙氧基)、卤代C1-3烷基(例如-CF3、-CH2F、-CHF2、-CH2Cl、-CHCl2、-CF2CF3、-CHFCF3、-CF2CHF2、 -CHFCHF2、-CH2CF3和-CH2CH2Cl)、C1-3烷基-NHC(O)-(例如CH3-NHC(O)-、CH3CH2- NHC(O)-、和CH3CH2CH2-NHC(O)-)、C1-3烷基-C(O)NH-(例如CH3-C(O)NH-、CH3CH2- C(O)NH-、和CH3CH2CH2-C(O)NH-)、氰基或其任意组合的取代基取代。取代基的数量原则上不受任何限制或自动受构建单元的大小限制。
在一些实施方案中,式(II)化合物的环B是含有1至3个氮原子的5元至11元亚杂环基。
在一些实施方案中,式(II)化合物的环B是亚哌啶基、亚哌嗪基、亚吗啉基、亚氮杂环丁基、亚吡咯烷基、亚咪唑烷基、亚吡唑烷基、亚噁唑烷基、亚噻唑烷基、亚硫代吗啉基、亚二氮杂环庚基、或含有1个氮原子并且可选地进一步含有1至2个独立地选自氮、氧和硫的杂原子的C7-11螺杂环亚基。
在一些实施方案中,当式(II)化合物的环B表示含有1个氮原子并且可选地进一步含有1 至2个独立地选自氮、氧和硫的杂原子的C7-11螺杂环亚基时,所述C7-11螺杂环亚基是以下基团:
其中,符号*表示与基团L1的连接点,X表示O、N(Re)、S或CH2或X表示键,Re表示氢或甲基,以及n1、n2和n3各自独立地是整数1或2。
在一些实施方案中,当式(II)化合物的环B表示含有1个氮原子并且可选地进一步含有1 至2个独立地选自氮、氧和硫的杂原子的C7-11螺杂环亚基时,所述C7-11螺杂环亚基是以下基团:
其中符号*表示与基团L1的连接点。
在一些实施方案中,式(II)化合物的环B可选地进一步被m2个Rb基团取代,其中m2表示整数0、1、2、3、4或5,以及各Rb独立地为C1-3烷基(例如甲基、乙基或丙基)、羟基、氨基、巯基、卤素(例如氟、氯、溴或碘)、C1-3烷氧基(例如甲氧基、乙氧基或丙氧基)、 C1-3烷基氨基(例如C1-3烷基NH-,例如CH3NH-、CH3CH2NH-或CH3CH2CH2NH-)、卤代C1-3烷基(例如-CF3、-CH2F、-CHF2、-CH2Cl、-CHCl2、-CF2CF3、-CHFCF3、-CF2CHF2、- CHFCHF2、-CH2CF3和-CH2CH2Cl)、氨基取代的C1-3亚烷基(NH2-C1-3亚烷基-,例如 NH2CH2-、NH2CH2CH2-和NH2CH2CH2CH2-)、C1-3烷基-NHC(O)-(例如CH3-NHC(O)-、 CH3CH2-NHC(O)-、和CH3CH2CH2-NHC(O)-)、C1-3烷基-C(O)NH-(例如CH3-C(O)NH-、 CH3CH2-C(O)NH-、和CH3CH2CH2-C(O)NH-)或氰基。
其中符号*表示与基团L1的连接点。
在一些实施方案中,式(II)化合物的环C是5元至10元亚杂芳基、或6元亚芳基。环C的示例性实例包括但不限于以下基团:亚苯基、亚吡啶基、亚嘧啶基、亚吡嗪基、亚哒嗪基、1,2,4-亚三嗪基、1,3,5-亚三嗪基、亚三氮唑基、亚呋喃基、亚噁唑基、亚异噁唑基、亚噁二唑基、亚噻吩基、亚噻唑基、亚异噻唑基、亚噻二唑基、亚吡咯基、亚咪唑基、亚吡唑基、亚吲哚基、亚异吲哚基、亚苯并呋喃基、亚异苯并呋喃基、亚苯并噻吩基、亚吲唑基、亚苯并咪唑基、亚苯并噁唑基、亚苯并异噁唑基、亚苯并噻唑基、亚苯并异噻唑基、亚苯并三唑基、亚苯并[2,1,3]噁二唑基、亚苯并[2,1,3]噻二唑基、亚苯并[1,2,3]噻二唑基、亚喹啉基、亚异喹啉基、亚萘啶基、亚噌啉基、亚喹唑啉基、亚喹喔啉基、亚酞嗪基、吡唑并[1,5-a]吡啶亚基、吡唑并[1,5-a]嘧啶亚基、咪唑并[1,2-a]吡啶亚基、1H-吡咯并[3,2-b]吡啶亚基、1H-吡咯并[2,3-b] 吡啶亚基、4H-氟[3,2-b]吡咯亚基、吡咯并[2,1-b]噻唑亚基、或咪唑并[2,1-b]噻唑亚基。
在一些实施方案中,式(II)化合物的环C可选地进一步被m3个Rc基团取代,其中m3表示整数0、1、2、3、4或5,以及各Rc独立地为C1-3烷基(例如甲基、乙基或丙基)、C3-5环烷基(例如环丙基、环丁基或环戊基)、羟基、氨基、巯基、卤素(例如氟、氯、溴或碘)、C1-3烷氧基(例如甲氧基、乙氧基或丙氧基)、C1-3烷基氨基(例如C1-3烷基NH-,例如CH3NH-、CH3CH2NH-或CH3CH2CH2NH-)、卤代C1-3烷基(例如-CF3、-CH2F、-CHF2、- CH2Cl、-CHCl2、-CF2CF3、-CHFCF3、-CF2CHF2、-CHFCHF2、-CH2CF3和-CH2CH2Cl)、氨基取代的C1-3亚烷基(NH2-C1-3亚烷基-,例如NH2CH2-、NH2CH2CH2-和NH2CH2CH2CH2-)、 C1-3烷基-NHC(O)-(例如CH3-NHC(O)-、CH3CH2-NHC(O)-、和CH3CH2CH2-NHC(O)-)、C1-3烷基-C(O)NH-(例如CH3-C(O)NH-、CH3CH2-C(O)NH-、和CH3CH2CH2-C(O)NH-)或氰基。
在一些实施方案中,式(II)化合物的基团Y表示-N(R3)-,其中R3是氢或C1-3烷基。
在一些实施方案中,式(II)化合物的基团Y表示-O-。
在一些实施方案中,式(II)化合物的基团Y是由以下结构式表示的n个相连的环D:
其中n是整数0、1、2或3,其中当n表示整数2或3时,各环D可相同或不同,各环D独立地是5元至11元亚杂环基,(Rd)m4表示各环D可选地独立地被m4个Rd基团取代,m4表示整数0、1、2、3、4或5,以及各Rd独立地为C1-3烷基、C3-6环烷基、羟基、氨基、巯基、卤素、氧代基、C1-3烷氧基、C1-3烷基氨基、卤代C1-3烷基、氨基取代的C1-3亚烷基、C1-3烷基- NHC(O)-、C1-3烷基-C(O)NH-或氰基。
在一些实施方案中,式(II)化合物的环D的示例性实例包括但不限于以下基团:亚哌啶基、亚哌嗪基、亚吗啉基、亚氮杂环丁基、亚氧杂环丁基、亚吡咯烷基、亚咪唑烷基、亚吡唑烷基、亚四氢呋喃基、亚四氢吡喃基、亚四氢噻吩基、亚四氢噻喃基、亚噁唑烷基、亚噻唑烷基、亚硫代吗啉基、亚二氧杂环己基、亚二氮杂环庚基或C7-11螺杂环亚基。
在一些实施方案中,当式(II)化合物的环D表示C7-11螺杂环亚基时,所述C7-11螺杂环亚基可以是以下基团:
其中符号**表示与环C的连接点,X表示O、N(Re)、S或CH2或X表示键,其中Re表示氢或甲基,以及n1、n2和n3各自独立地是整数1或2。
在一些实施方案中,当式(II)化合物的环D表示C7-11螺杂环亚基时,所述C7-11螺杂环亚基可以是以下基团:
其中符号**表示与环C的连接点。
在一些实施方案中,式(II)化合物的环D可选地进一步被m4个Rd基团取代,其中m4表示整数0、1、2、3、4或5,各Rd独立地为C1-3烷基(例如甲基、乙基或丙基)、C3-6环烷基(例如环丙基、环丁基、环戊基或环己基)、羟基、氨基、巯基、卤素(例如氟、氯、溴或碘)、氧代基、C1-3烷氧基(例如甲氧基、乙氧基或丙氧基)、C1-3烷基氨基(例如C1-3烷基NH-,例如CH3NH-、CH3CH2NH-或CH3CH2CH2NH-)、卤代C1-3烷基(例如-CF3、-CH2F、 -CHF2、-CH2Cl、-CHCl2、-CF2CF3、-CHFCF3、-CF2CHF2、-CHFCHF2、-CH2CF3和- CH2CH2Cl)、氨基取代的C1-3亚烷基(NH2-C1-3亚烷基-,例如NH2CH2-、NH2CH2CH2-和 NH2CH2CH2CH2-)、C1-3烷基-NHC(O)-(例如CH3-NHC(O)-、CH3CH2-NHC(O)-、和 CH3CH2CH2-NHC(O)-)、C1-3烷基-C(O)NH-(例如CH3-C(O)NH-、CH3CH2-C(O)NH-、和 CH3CH2CH2-C(O)NH-)或氰基。
其中符号##表示与基团LIN的连接点。
本公开的式(II)化合物的ULM和LIN如本文中式(I)化合物的实施方案及其子实施方案中所定义。
在一些实施方案中,本公开的式(I)化合物亦为式(V)化合物或其盐(包括药学上可接受的盐)、溶剂化物、同位素富集类似物、多晶型物、前药、立体异构体(包括对映异构体)、或立体异构体的混合物:
其中X1、X2、X3和X4中的任意1个、2个或3个表示N,剩余的表示CH;以及 ULM、LIN、Y、环C、(Rc)m3、m、环B、(Rb)m2、L1、R1、R2、(Ra)m1如本文中式(I)化合物的实施方案及其子实施方案中任一项中所定义。
在一些实施方案中,本公开的的式(I)化合物亦为式(VI)化合物或其盐(包括药学上可接受的盐)、溶剂化物、同位素富集类似物、多晶型物、前药、立体异构体(包括对映异构体)、或立体异构体的混合物:
其中X5和X6相同或不同且分别独立地表示CH或N;以及
ULM、LIN、Y、环C、(Rc)m3、m、环B、(Rb)m2、L1、R1、R2、(Ra)m1如本文中式(I)化合物的实施方案及其子实施方案中任一项中所定义。
在一些实施方案中,本公开的的式(I)化合物亦为式(VII)化合物或其盐(包括药学上可接受的盐)、溶剂化物、同位素富集类似物、多晶型物、前药、立体异构体(包括对映异构体)、或立体异构体的混合物:
其中X7和X8中的任意一个表示CH,且另一个表示N,或者X7和X8表示CH;以及
ULM、LIN、Y、环C、(Rc)m3、m、环B、(Rb)m2、L1、R1、R2、(Ra)m1如本文中式(I)化合物的实施方案及其子实施方案中任一项中所定义。
在一些实施方案中,本公开的的式(I)化合物亦为式(VIII)化合物或其盐(包括药学上可接受的盐)、溶剂化物、同位素富集类似物、多晶型物、前药、立体异构体(包括对映异构体)、或立体异构体的混合物:
其中ULM、LIN、Y、环C、(Rc)m3、m、环B、(Rb)m2、L1、R1、R2、(Ra)m1如本文中式(I)化合物的实施方案及其子实施方案中任一项中所定义。
本领域技术人员应当理解,本发明涵盖针对各个实施方案进行任意组合所得的化合物。由一个实施方案中的技术特征或优选技术特征与另外的实施方案的技术特征或优选技术特征组合得到的实施方案也涵盖于本发明的范围内。
在一些实施方案中,提供了以下表1的化合物及其盐(包括药学上可接受的盐,例如它们的盐酸盐)、前药、溶剂化物、同位素富集类似物、多晶型物、立体异构体(包括对映异构体和非对映异构体)、或立体异构体的混合物:
表1本公开的化合物
II.化合物的其它形式(包括化合物的盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物)
本公开的化合物具有式(I)、式(II)、式(V)、式(VI)、式(VII)、或式(VIII)中任一个的结构。除非另有说明,否则当提及本公开的化合物时,是指包括式(I)、式(II)、式(V)、式(VI)、式(VII)、或式(VIII)中任一个的化合物以及落入这些通式范围内的具体化合物。
应认识到本公开的化合物(包括式(I)、式(II)、式(V)、式(VI)、式(VII)、和式(VIII)的化合物)可具有立体构型,因此能以一种以上的立体异构体形式存在。本公开还涉及光学富集的具有立体构型的化合物,如约大于90%ee,如约95%ee或97%ee,或大于99%ee,以及其混合物,包括外消旋混合物。本文使用的“光学富集的”意指对映异构体的混合物由显著更大比例的一种对映体组成,并且可通过对映体过量(ee%)描述。异构体的纯化和异构体混合物的分离可以通过本领域已知的标准技术(例如,柱色谱、制备型TLC、制备型HPLC、不对称合成 (例如,通过使用手性中间体)和/或手性拆分等)来实现。
在一些实施方案中,还提供本公开化合物的多晶型形式或本公开化合物的盐。本公开的化合物的盐可以是药学上可接受的盐,包括但不限于盐酸盐、硫酸盐、枸橼酸盐、马来酸盐、磺酸盐、柠檬酸盐、乳酸盐、酒石酸盐、富马酸盐、磷酸盐、二氢磷酸盐、焦磷酸盐、偏磷酸盐、草酸盐、丙二酸盐、苯甲酸盐、扁桃酸盐、琥珀酸盐、三氟乙酸盐、羟乙酸盐或对甲苯磺酸盐等。本公开的化合物能以非溶剂化物或溶剂化物的形式存在于药学上可接受的溶剂如水、乙醇等中。在一些实施方案中,本公开化合物可以制备成前体药物或前药。前体药物在机体内能转化成母体药物而发挥作用。在一些实施方案中,还提供经同位素标记的本公开化合物,同位素的实例包括氘(D或2H)。
III.药物组合物/制剂
在一些实施方案中,本公开提供一种药物组合物,其包含作为活性成分的本公开的化合物或其药学上可接受的盐、溶剂化物、同位素富集类似物、多晶型物、前药、立体异构体 (包括对映异构体)、或立体异构体的混合物,及至少一种药学上可接受的载体。
在一些实施方案中,药学上可接受的载体包括但不限于填充剂、稳定剂、分散剂、悬浮剂、稀释剂、赋形剂、增稠剂、着色剂、溶剂或包封材料。载体与制剂的其他成分(包括本公开中有用的化合物)相容并且对患者无害,载体必须是“可接受的”。药学上可接受的载体的材料的一些实例包括:糖,如乳糖,葡萄糖和蔗糖;淀粉,如玉米淀粉和马铃薯淀粉;纤维素及其衍生物,例如羧甲基纤维素钠,乙基纤维素和乙酸纤维素;粉状黄蓍胶;麦芽;明胶;滑石;赋形剂,如可可脂和栓剂蜡;油,如花生油,棉籽油,红花油,芝麻油,橄榄油,玉米油和大豆油;二醇,如丙二醇;多元醇,如甘油,山梨糖醇,甘露醇和聚乙二醇;酯类,如油酸乙酯和月桂酸乙酯;琼脂;缓冲剂,如氢氧化镁和氢氧化铝;表面活性剂磷酸盐缓冲溶液;聚氧乙烯,聚乙烯吡咯烷酮,聚丙烯酰胺,泊洛沙姆;和药物制剂中使用的其他无毒相容物质。
本公开所述的药物组合物,进一步包括至少一种治疗或预防与烟酰胺磷酸核糖转移酶 (NAMPT)相关的疾病或病症的第二治疗剂。第二治疗剂可与本公开所述式(I)化合物联合治疗与烟酰胺磷酸核糖转移酶(NAMPT)相关的疾病或病症,其包括但不限于化疗剂、免疫治疗剂、基因治疗剂等。在一些实施方案中,所述与烟酰胺磷酸核糖转移酶(NAMPT)相关的疾病或病症包括肿瘤、自身免疫性疾病、炎性疾病、妊娠高血压综合征、心脑血管疾病、肥胖症和糖尿病肾病。
在一些实施方案中,所述与NAMPT相关的疾病或病症包括:
结直肠癌;乳腺癌(包括三阴性乳腺癌,侵袭性乳腺癌,浸润性乳腺癌);星形细胞瘤;胰腺癌;胃癌;前列腺癌;黑色素瘤;白血病(例如急性髓系白血病、急性淋巴细胞性白血病);卵巢癌;肝癌;肺癌(例如非小细胞肺癌和小细胞肺癌);胶质母细胞瘤;多发性骨髓瘤;食管癌;膀胱癌;甲状腺癌;子宫内膜癌;淋巴瘤(例如弥漫性大B细胞瘤,滤泡性B 细胞淋巴瘤,霍奇金淋巴瘤,外周T细胞淋巴瘤);神经内分泌肿瘤;肾癌(例如肾嗜酸细胞瘤,肾透明细胞癌,肾尿路上皮癌);小儿胶质瘤;横纹肌肉瘤;平滑肌肉瘤;尿路上皮癌;基底细胞癌;口腔鳞状细胞癌;胆管癌;骨癌;宫颈癌;皮肤癌;口腔鳞状细胞癌;自身免疫性疾病(例如类风湿性关节炎,自身免疫性脑炎);心脑血管疾病(包括冠状动脉粥样硬化,急性心肌梗死,心肌缺血再灌注损伤,缺血性中风);炎性疾病;妊娠高血压综合征;肥胖症和糖尿病肾病。
本公开所述的包含作为活性成分的如本公开所述的式(I)化合物或其药学上可接受的盐的药物组合物可根据合适的给药途径(包括但不限于鼻腔给药、吸入给药、局部给药、口服给药、口腔粘膜给药、直肠给药、胸膜腔给药、腹膜给药、阴道给药、肌内给药、皮下给药、经皮给药、硬膜外腔给药、鞘内给药和静脉给药)被制备成合适的制剂形式,例如喷雾制剂、贴剂、片剂(例如常规片剂、分散片、口腔崩解片)、胶囊(例如软胶囊、硬胶囊、肠溶胶囊)、糖衣丸、含片、散剂、颗粒剂、粉针剂、栓剂,或液体制剂(例如混悬剂(例如水性或油性混悬剂)、溶液、乳剂或糖浆剂),或常规注射剂型例如可注射的溶液剂(例如根据本领域已知方法采用水、林格氏溶液或等渗氯化钠溶液等作为载体或溶剂来配制的无菌注射溶液)或冻干组合物。本领域技术人员还可根据需要将所述的式(I)化合物制备成常规的、可分散的、可咀嚼的、口腔速崩解的或快速溶解的制剂,或缓释胶囊或控释胶囊。
IV.药盒(kit)/包装制品
本公开所述的式(I)化合物,或其药学上可接受的盐、溶剂化物、同位素富集类似物、多晶型物、前药、立体异构体(包括对映异构体)、或立体异构体的混合物,其是用作药剂。本公开的药剂或本公开的药物组合物可以存在于药盒/包装制品中。药盒/包装制品可以包括包装或容器。包装或容器包括但不限于安瓶(ampoule)、泡罩包装、药用塑料瓶、小瓶、药用玻璃瓶、容器、注射器、层压软包装、共挤膜输液容器、试管和分配装置等。药盒/包装制品可以包含产品使用说明书。
V.方法和用途
本公开所述的式(I)化合物,或其药学上可接受的盐、溶剂化物、同位素富集类似物、多晶型物、前药、立体异构体(包括对映异构体)、或立体异构体的混合物,可以用作药剂。尤其是,本公开所述的式(I)化合物,或其药学上可接受的盐、溶剂化物、同位素富集类似物、多晶型物、前药、立体异构体(包括对映异构体)、或立体异构体的混合物可以用于制备用于预防及/或治疗与NAMPT相关的疾病或病症的药物。
用于治疗或预防受试者的与NAMPT相关的疾病或病症的方法,包括向所述受试者施用治疗有效量的本公开所述的式(I)化合物,或其药学上可接受的盐,或本公开所述的药物组合物。在一些实施方案中,所述与NAMPT相关的疾病或病症包括肿瘤、自身免疫性疾病、炎性疾病、妊娠高血压综合征、心脑血管疾病、肥胖症和糖尿病肾病。在一些实施方案中,所述与NAMPT相关的疾病或病症包括但不限于:结直肠癌;乳腺癌(包括三阴性乳腺癌,侵袭性乳腺癌,浸润性乳腺癌);星形细胞瘤;胰腺癌;胃癌;前列腺癌;黑色素瘤;白血病 (例如急性髓系白血病、急性淋巴细胞性白血病);卵巢癌;肝癌;肺癌(例如非小细胞肺癌和小细胞肺癌);胶质母细胞瘤;多发性骨髓瘤;食管癌;膀胱癌;甲状腺癌;子宫内膜癌;淋巴瘤(例如弥漫性大B细胞瘤,滤泡性B细胞淋巴瘤,霍奇金淋巴瘤,外周T细胞淋巴瘤);神经内分泌肿瘤;肾癌(例如肾嗜酸细胞瘤,肾透明细胞癌,肾尿路上皮癌);小儿胶质瘤;横纹肌肉瘤;平滑肌肉瘤;尿路上皮癌;基底细胞癌;口腔鳞状细胞癌;胆管癌;骨癌;宫颈癌;皮肤癌;口腔鳞状细胞癌;自身免疫性疾病(例如类风湿性关节炎,自身免疫性脑炎);心脑血管疾病(包括冠状动脉粥样硬化,急性心肌梗死,心肌缺血再灌注损伤,缺血性中风);炎性疾病;妊娠高血压综合征;肥胖症和糖尿病肾病。
在用于治疗或预防受试者的与NAMPT相关的疾病或病症的方法中,通过至少一种选自鼻腔给药、吸入给药、局部给药、口服给药、口腔粘膜给药、直肠给药、胸膜腔给药、腹膜给药、阴道给药、肌内给药、皮下给药、经皮给药、硬膜外腔给药、鞘内给药和静脉给药的给药方式将治疗有效量的本公开所述的式(I)化合物或本公开所述的药物组合物施用至所述受试者。
术语“治疗”或“处理”是指向受试者施用本公开所述的式(I)化合物或其药学上可接受的盐,或包含作为活性成分的式I化合物或其药学上可接受的盐的药物组合物,以减缓(减轻) 不希望发生的疾病或病症(例如肿瘤)的发展。本公开的有益的或期望的临床结果包括但不限于:减轻症状,减轻疾病的严重程度,稳定疾病的状态,延迟或延缓疾病进展,改善或缓和病情,以及缓解疾病。
本公开化合物的“治疗有效量”取决于多种因素,包括所用特定化合物的活性、该化合物的代谢稳定性和作用时间长度、患者的年龄、性别和体重,患者的总体医学状况,给药方式和时间,排泄率,联合用药,以及所治疗患者的疾病或病症进展情况。本领域技术人员能够根据这些和其它因素来确定合适的剂量。
应当理解的是,使用一种或多种活性化合物和/或组合物及其剂量的选择取决于个体的基本情况(通常应该使个人情况达到最佳的效果)。给药和给药方案应该在本领域技术人员的能力范围内,并且合适的剂量取决于许多因素包括普通技术医生,兽医或研究者知识能力水平(见例如李俊主编,“临床药理学”,第4版,人民卫生出版社(2008))。
上述治疗的患者或受试者是指动物,例如哺乳动物,包括但不限于灵长类动物(如人类)、牛、绵羊、山羊、马、狗、猫、兔、豚鼠、大鼠、小鼠等。
VI.定义
除非另有说明,否则本说明书中所使用的下列词语、短语和符号通用地具有如下所述的含义。
通常,本文所用的命名法(包括IUPAC命名法)和下文描述的实验室程序(包括用于细胞培养、有机化学、分析化学和药理学等)是本领域众所周知的并且通常使用的那些。除非另有定义,否则结合本文描述的本公开内容的本文使用的所有科学和技术术语具有本领域技术人员通常理解的相同含义。另外,在权利要求书和/或说明书中,用语“一”或“一个”与术语“包含”或名词结合使用时,其含义可能是“一个”,但也与“一个或多个”,“至少一个”和“一个或多于一个”的含义一致。类似地,用语“另一个”或“其它”可以表示至少第二个或更多。
应该理解的是,每当本文用术语“包括”或“包含”描述各个方面时,还提供了其他由“由…组成”和/或“基本上由…组成”描述的类似方面。
术语“约”在本文中用于意指近似、大致、大约或在…左右。当术语“约”与数值范围联合使用时,它通过使边界延伸高于和低于阐述的数值来修饰那个范围。一般来说,术语“约”可通过向上或向下(增高或降低)变化例如10%、5%、2%或1%来修饰数值高于和低于所述的值。
在本文中,用语“……表示键”意指其是键连接体(即表示其不存在)。例如用语“R表示键”意指R是键连接体。换言之,当R为键时,式(III)结构的基团W直接连接至式(III)结构的苯环。
如本文中所使用,单独或组合使用的用语“直链或支链C2-60亚烷基的主碳链中插入有一或多个基团R5和/或一或多个基团R6或者一或多个基团R5与R6的任意组合”中的“插入”具有本领域已知的定义,即可以指基团R5、R6或者基团R5与R6的任意组合将所述主碳链的一或多对相邻碳原子之间的碳-碳键间断开。在本文中,上述用语“插入有一或多个”的示例可包括但不限于在所述主碳链中插入有一或多个(1-30、1-20、或1-15、1-10、1-9、1-8、1-7、1-6、1- 5、1-4、1-3或1-2个,或1个)如本文所定义的基团R5和/或一或多个(1-30、1-20、或1-15、 1-10、1-9、1-8、1-7、1-6、1-5、1-4、1-3或1-2个,或1个)基团R6和/或一或多个(1-30、1-20、或1-15、1-10、1-9、1-8、1-7、1-6、1-5、1-4、1-3或1-2个,或1个)基团R5与R6的任意组合,由此所形成的主链基团符合共价键理论。例如,表述“直链或支链C2-60亚烷基的主碳链中插入有一或多个基团R5和/或一或多个基团R6或者一或多个基团R5与R6的任意组合”是指直链或支链C2-60亚烷基链的主碳链中的一对或多对任何两个相邻的碳原子之间插入有一或多个(例如1-30、1-20、1-15、1-10、1-8、1-7、1-6、1-5、1-4、1-3、1-2或1个)R5和/或 R6和/或一或多个基团R5与R6的任意组合,以形成含有一个或多个(例如1-30、1-20、1-15、1-10、1-8、1-7、1-6、1-5、1-4、1-3、1-2或1个)“-CH2-R5-CH2-”片段和/或一或多个(例如 1-30、1-20、1-15、1-10、1-8、1-7、1-6、1-5、1-4、1-3、1-2或1个)“-CH2-R6-CH2-”片段和/ 或一或多个(例如1-30、1-20、1-15、1-10、1-8、1-7、1-6、1-5、1-4、1-3、1-2或1个)“- CH2-R5-R6-CH2-”片段,其中各R5相同或不同,各R6相同或不同,并且如本文中所定义。
在本公开的上下文中,应理解,表述“所述直链或支链C2-60亚烷基的主碳链中可选地插入有一或多个基团R5和/或一或多个基团R6或者一或多个基团R5与R6的任意组合”包括“所述直链或支链C2-60亚烷基的主碳链中插入有一或多个基团R5和/或一或多个基团R6或者一或多个基团R5与R6的任意组合”的实施方案,和“所述直链或支链C2-60亚烷基的主碳链中未插入有一或多个基团R5和/或一或多个基团R6或者一或多个基团R5与R6的任意组合”的实施方案。
在本文中,由波形线断裂的键显示所绘示基团与分子的其他部分的连接点。例如,下文所绘示的ULM表示的基团
表示所述基团的Z1与式(I)化合物的基团LIN中的亚烷基连接。
在本文中,单独或组合使用的术语“所述直链或支链Cx-y亚烷基的一或多个CH2的氢被…替代”表示直链或支链Cx-y亚烷基中的任意一或多个CH2中的氢被如本文中所定义的取代基替代。在本文中,“基团#-U-CH2-、#-U-(CH2)2-、#-U-(CH2)3-、#-U-(CH2)4-、#-U-(CH2)5-、#- U-(CH2)6-、#-U-(CH2)7-、#-U-(CH2)8-、#-U-(CH2)9-、#-U-(CH2)10-、#-U-(CH2)11-、#-U-(CH2)12-、 #-U-(CH2)13-、#-U-(CH2)14-、#-U-(CH2)15-、#-U-(CH2)16-、#-U-(CH2)17-、#-U-(CH2)18-、#-U- (CH2)19-、#-U-(CH2)20-、#-U-(CH2)21-、#-U-(CH2)22-、#-U-(CH2)25-、#-U-(CH2)30-、#-U-(CH2)35-、 #-U-(CH2)40-、#-U-(CH2)45-、#-U-(CH2)50-、#-U-(CH2)55-、或#-U-(CH2)60-的一或多个CH2的氢”中的用语“一或多个”可以是指所提及的各亚烷基基团的部分或全部的氢,包括但不限于1-80 个氢。在一些实施方案中,所述用语“一或多个CH2的氢”可以是指所提及的亚烷基的部分或全部的氢,包括但不限于1-30个,例如1-25个,1-20个,1-15个,1-10个,1-5个,1-4个, 1-3个,1-2个或1个氢。在一些实施方案中,所述用语“一或多个CH2的氢”可以是指所提及的亚烷基的多个氢中的1-3个。该数量原则上不受任何限制或自动受构建单元的大小限制。
在本文中,用语“可选地被……取代”与“未取代或取代的”可以互换使用。术语“取代的”通常表示所提及结构中的一或多个氢原子被相同或不同的具体取代基取代。
在本文中,术语“氧代”或“氧代基”指=O。
在本文中,单独或组合使用的术语“C(O)”或“C(=O)”或“C=O”指羰基。
在本文中,单独或组合使用的术语“卤素原子”或“卤素”是指氟、氯、溴或碘。
在本文中,单独或组合使用的术语“烷基”是指直链或支链的烷基。术语“Cx-Cy烷基”或“Cx-y烷基”(x及y各自为整数)是指含有x至y个碳原子的直链或支链烷基。本发明中单独或组合使用的术语“C1-10烷基”是指含有1至10个碳原子的直链或支链烷基。本公开的C1-10烷基的实例包括C1-9烷基,C1-8烷基,C2-8烷基,C1-7烷基,C1-6烷基,C1-5烷基,和C1-4烷基。代表性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、特戊基、己基、庚基、辛基、壬基及癸基。本公开的术语“C1-3烷基”或“C1-C3烷基”是指含有1至3个碳原子的烷基,其代表性实例包括甲基、乙基、正丙基及异丙基。在本公开中,所述“烷基”是可选地经取代的,取代基可选是一或多个选自卤素、羟基、氰基、C1-3烷基、C1-3烷氧基、三氟甲基、杂环基或其组合的取代基。
在本文中,单独或组合使用的术语“卤代烷基”是指被一或多个卤素取代的直链或支链的烷基,其中所述烷基中的一或多个氢被卤素取代。术语“卤代Cx-Cy烷基”或“卤代Cx-y烷基”(x 及y各自为整数)是指被一或多个卤素取代的含有x至y个碳原子的直链或支链烷基。本公开中单独或组合使用的术语“卤代C1-10烷基”是指被一或多个卤素取代的含有1至10个碳原子的直链或支链烷基。本公开的卤代C1-10烷基的实例包括卤代C1-9烷基,例如卤代C1-8烷基,卤代 C2-8烷基,卤代C1-7烷基,卤代C1-6烷基,卤代C1-5烷基,或卤代C1-4烷基。代表性实例包括卤代甲基、卤代乙基、卤代正丙基、卤代异丙基、卤代正丁基、卤代异丁基、卤代仲丁基、卤代叔丁基、卤代戊基、卤代异戊基、卤代新戊基、卤代特戊基、卤代己基、卤代庚基、卤代辛基、卤代壬基及卤代癸基。本公开的术语“卤代C1-3烷基”或“卤代C1-C3烷基”是指被一或多个卤素取代的含有1至3个碳原子的烷基,其代表性实例包括卤代甲基、卤代乙基、卤代正丙基及卤代异丙基。
在本文中,单独或组合使用的术语“亚烷基”(其与“亚烷基链”可互换使用)是指由碳和氢原子组成的直链或支链的二价饱和烃基团。术语“Cx-Cy亚烷基”或“Cx-y亚烷基”(x及y各自为整数)是指含有x至y个碳原子的直链或支链的亚烷基。本公开的C1-C60亚烷基的实例包括C1-C55亚烷基,C1-C50亚烷基,C1-C45亚烷基,C1-C40亚烷基,C1-C35亚烷基,C1-C30亚烷基,C1-C29亚烷基,C1-C28亚烷基,C1-C27亚烷基,C1-C26亚烷基,C1-C25亚烷基,C1-C24亚烷基, C1-C23亚烷基,C1-C22亚烷基,C1-C21亚烷基,C1-C20亚烷基,C1-C19亚烷基,C1-C18亚烷基, C1-C17亚烷基,C1-C16亚烷基,C1-C15亚烷基,C1-C14亚烷基,C1-C13亚烷基,C1-C12亚烷基, C1-C11亚烷基,C1-C10亚烷基,C1-C9亚烷基,C1-C8亚烷基,C1-C7亚烷基,C1-C6亚烷基,C1- C5亚烷基,C1-C4亚烷基,C1-C3亚烷基,或C1-C2亚烷基。代表性实例包括但不限于亚甲基、亚乙基、亚丙基、亚异丙基、亚丁基、亚异丁基、亚仲丁基、亚叔丁基、亚戊基、亚异戊基、亚新戊基、亚特戊基、亚己基、亚庚基、亚辛基、亚壬基、亚癸基、亚十一烷基、亚十二烷基、亚十三烷基、亚十四烷基、亚十五烷基、亚十六烷基、亚十七烷基、亚十八烷基、亚十九烷基、亚二十烷基、亚二十一烷基、亚二十二烷基、亚二十三烷基、亚二十四烷基、亚二十五烷基、亚二十六烷基、亚二十七烷基、亚二十八烷基、亚二十九烷基、和亚三十烷基。在本公开中,所述“亚烷基”是可选地经取代的,取代基可选是一或多个选自C1-C3烷基、C3-6环烷基、羟基、氨基、巯基、卤素、C1-C3烷氧基、C1-C3烷基氨基、卤代C1-C3烷基、氨基C1-3亚烷基、C1-3烷基-NHC(O)-、C1-3烷基-C(O)NH-、氰基或其任意组合的取代基。
在本文中,单独或组合使用的术语“烷氧基”是指直链或支链烷氧基,其结构式为烷基- O-。可选地,烷氧基的烷基部分可包含1-10个碳原子。“烷氧基”的代表性实例包括但不限于甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊氧基、2-戊氧基、异戊氧基、新戊氧基、己氧基、2-己氧基、3-己氧基、3-甲基戊氧基等。术语“C1-C3烷氧基”或“C1-3烷氧基”是指含有1至3个碳原子的直链或支链烷氧基。C1-3烷氧基的代表性实例包括但不限于甲氧基、乙氧基、正丙氧基及异丙氧基。
在本文中,单独或组合使用的术语“烷基氨基”是指直链或支链烷基氨基,其结构式为烷基-NH-。可选地,烷基氨基的烷基部分可包含1-10个碳原子。“烷基氨基”的代表性实例包括但不限于甲基-NH-、乙基-NH-、丙基-NH-、异丙基-NH-、正丁基-NH-、异丁基-NH-、叔丁基-NH-、戊基-NH-、己基-NH-等。术语“C1-C3烷基-NH-”或“C1-3烷基-NH-”是指含有1至3个碳原子的直链或支链烷基-NH-。C1-3烷基-NH-的代表性实例包括但不限于甲基-NH-、乙基-NH-、正丙基-NH-及异丙基-NH-。
在本文中,单独或组合使用的术语“氨基取代的亚烷基”是指氨基取代的直链或支链亚烷基,其结构式为NH2-亚烷基-。可选地,氨基取代的亚烷基的亚烷基部分可包含1-10个碳原子。术语“氨基取代的C1-3亚烷基”或“氨基-C1-3烷基-”是指氨基取代的含有1至3个碳原子的直链或支链亚烷基。氨基取代的C1-3亚烷基的代表性实例包括但不限于NH2-CH2-、NH2-CH2CH2-、及NH2-CH2CH2CH2-。
在本文中,单独或组合使用的术语“烷基-NHC(O)-”是指直链或支链烷基-NHC(O)-,其结构式为烷基-NHC(O)-。可选地,烷基-NHC(O)-的烷基部分可包含1-10个碳原子。术语“C1- C3烷基-NHC(O)-”或“C1-3烷基-NHC(O)-”是指含有1至3个碳原子的直链或支链烷基-NHC(O)-。 C1-3烷基-NHC(O)-的代表性实例包括但不限于CH3-NHC(O)-、CH3CH2-NHC(O)-、及 CH3CH2CH2-NHC(O)-。
在本文中,单独或组合使用的术语“烷基-C(O)NH-”是指直链或支链烷基-C(O)NH-,其结构式为烷基-C(O)NH-。可选地,烷基-C(O)NH-的烷基部分可包含1-10个碳原子。术语“C1- C3烷基-C(O)NH-”或“C1-3烷基-C(O)NH-”是指含有1至3个碳原子的直链或支链烷基-C(O)NH-。 C1-3烷基-C(O)NH-的代表性实例包括但不限于CH3-C(O)NH-、CH3CH2-C(O)NH-、及CH3CH2CH2-C(O)NH-。
在本发明中,单独或组合使用的术语“杂芳基”是指含有至少一个具有1个或多个(例如1至6个、或者1至5个、或者1至4个、或者1至3个)独立选自氧、氮和硫的杂原子的芳香族环的5-至20-元(可选地为5至15元、5至12元、5至11元、5至10元、5至9元、5 至8元、5至7元、5至6元、6至15元或6元至9元)单环或二环或多环的芳香环基团。二环或多环杂芳基包括双环、三环或四环杂芳基,其中一个环是具有一或多个独立地选自O、S 和N的杂原子的芳香族环,并且其它环可为饱和、部分不饱和或芳香族环并且可为碳环或含有一或多个独立地选自O、S和N的杂原子。单环杂芳基的实例包括(但不限于)呋喃基、噁唑基、异噁唑基、噁二唑基、噻吩基、噻唑基、异噻唑基、噻二唑基、吡咯基、咪唑基、吡唑基、三唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、四唑基、和三嗪基。双环杂芳基的实例包括(但不限于)吲哚基、异吲哚基、异吲哚啉基、苯并呋喃基、异苯并呋喃基、苯并噻吩基、吲唑基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、苯并异噻唑基、苯并三唑基、苯并[2,1,3]噁二唑基、苯并[2,1,3]噻二唑基、苯并[1,2,3]噻二唑基、喹啉基、异喹啉基、萘啶基、噌啉基、喹唑啉基、喹喔啉基、酞嗪基、噁唑并吡啶基、呋喃并吡啶基、喋啶基、嘌呤基、吡啶并吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-a]吡啶基、1H-吡咯并[3,2-b]吡啶基、1H-吡咯并[2,3-b]吡啶基、吡咯并[2,1-b]噻唑基和咪唑并[2,1-b]噻唑基。三环杂芳基的实例包括(但不限于)吖啶基、苯并吲哚基、咔唑基、二苯并呋喃基、和呫吨基。所述杂芳基基团可未被取代或被取代。经取代的杂芳基是指经取代基取代一或多次(例如1-4、1-3次或1-2次)的杂芳基,其中取代基可选地选自C1-C3烷基、C3-6环烷基、羟基、氨基、巯基、卤素、C1-C3烷氧基、C1-C3烷基氨基、卤代C1-C3烷基、氨基C1-3亚烷基、C1-3烷基- NHC(O)-、C1-3烷基-C(O)NH-、氰基或其任意组合。
在本发明中,单独或组合使用的术语“亚杂芳基”是指含有至少一个具有1个或多个 (例如1至6个、或者1至5个、或者1至4个、或者1至3个)独立选自氧、氮和硫的杂原子的芳香族环的5-至20-元(可选地为5至15元、5至12元、5至11元、5至10元、5至9 元、5至8元、5至7元、5至6元、6至15元或6元至9元)单环或二环或多环的二价芳香环基团。二环或多环亚杂芳基包括双环、三环或四环亚杂芳基,其中一个环是具有一或多个独立地选自O、S和N的杂原子的芳香族环,并且其它环可为饱和、部分不饱和或芳香族环并且可为碳环或含有一或多个独立地选自O、S和N的杂原子。单环亚杂芳基的实例包括(但不限于)亚呋喃基、亚噁唑基、亚异噁唑基、亚噁二唑基、亚噻吩基、亚噻唑基、亚异噻唑基、亚噻二唑基、亚吡咯基、亚咪唑基、亚吡唑基、亚三唑基、亚吡啶基、亚嘧啶基、亚哒嗪基、亚吡嗪基、亚四唑基、和亚三嗪基。双环亚杂芳基的实例包括(但不限于)亚吲哚基、亚异吲哚基、亚异吲哚啉基、亚苯并呋喃基、亚异苯并呋喃基、亚苯并噻吩基、亚吲唑基、亚苯并咪唑基、亚苯并噁唑基、亚苯并异噁唑基、亚苯并噻唑基、亚苯并异噻唑基、亚苯并三唑基、亚苯并[2,1,3]噁二唑基、亚苯并[2,1,3]噻二唑基、亚苯并[1,2,3]噻二唑基、亚喹啉基、亚异喹啉基、亚萘啶基、亚噌啉基、亚喹唑啉基、亚喹喔啉基、亚酞嗪基、亚噁唑并吡啶基、亚呋喃并吡啶基、亚喋啶基、亚嘌呤基、亚吡啶并吡啶基、吡唑并[1,5-a]吡啶亚基、吡唑并[1,5-a] 嘧啶亚基、咪唑并[1,2-a]吡啶亚基、1H-吡咯并[3,2-b]吡啶亚基、1H-吡咯并[2,3-b]吡啶亚基、吡咯并[2,1-b]噻唑亚基和咪唑并[2,1-b]噻唑亚基。三环亚杂芳基的实例包括(但不限于)亚吖啶基、亚苯并吲哚基、亚咔唑基、亚二苯并呋喃基、和亚呫吨基。经取代的亚杂芳基是指经取代基取代一或多次(例如1-4、1-3次或1-2次)的亚杂芳基,其中取代基可选地选自C1-C3烷基、C3-6环烷基、羟基、氨基、巯基、卤素、C1-C3烷氧基、C1-C3烷基氨基、卤代C1-C3烷基、氨基取代的C1-3亚烷基、C1-3烷基-NHC(O)-、C1-3烷基-C(O)NH-、氰基或其任意组合。
在本文中,单独或组合使用的术语“芳基”是指包含5至14个碳原子并且可选地包含一个或多个稠合环的一价芳香烃基团,例如苯基或萘基或芴基。在本公开中,所述“芳基”是可选地经取代的芳基。经取代的芳基是指经取代基取代一或多次(例如1-4、1-3次或1-2次)的芳基,例如芳基被取代基单取代、双取代或三取代,其中取代基可选地例如选自C1-C3烷基、C3-6环烷基、羟基、氨基、巯基、卤素、C1-C3烷氧基、C1-C3烷基氨基、卤代C1-C3烷基、氨基取代的C1-3亚烷基、C1-3烷基-NHC(O)-、C1-3烷基-C(O)NH-、氰基或其任意组合。
在本公开中,单独或组合使用的术语“亚芳基”是指包含5至14个碳原子并且可选地包含一个或多个稠合环的二价芳香烃基团,例如亚苯基或亚萘基或亚芴基。在本公开中,所述“亚芳基”是可选地经取代的亚芳基。经取代的亚芳基是指经取代基取代一或多次(例如1-4、 1-3次或1-2次)的亚芳基,例如亚芳基被取代基单取代、双取代或三取代,其中取代基可选地例如选自C1-C3烷基、C3-6环烷基、羟基、氨基、巯基、卤素、C1-C3烷氧基、C1-C3烷基氨基、卤代C1-C3烷基、氨基取代的C1-3亚烷基、C1-3烷基-NHC(O)-、C1-3烷基-C(O)NH-、氰基或其任意组合。
在本文中,单独或组合使用的术语“环烷基”是指饱和或部分不饱和(即具有一个或多个双键,但不是完全共轭)的单环或双环或多环环烃基,其在一些实施方案中具有3至20个碳原子(即C3-20环烷基),或者3至15个碳原子(即C3-15环烷基),3至12个碳原子(即 C3-12环烷基),或者3至11个碳原子(即C3-11环烷基),或者3至10个碳原子(即C3-10环烷基),或者3至8个碳原子(即C3-8环烷基),或者3至7个碳原子(即C3-7环烷基),或者3至6个碳原子(即C3-6环烷基)。术语“环烷基”包括单环、双环或三环环烷基,其具有3 至20个碳原子。单环环烷基的代表性实例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环庚基和环辛基。双环和三环环烷基包括桥环烷基、稠环和螺环烷基,例如但不限于十氢萘基、八氢并环戊二烯基、八氢-1H-茚基、螺环烷基、金刚烷基、降金刚烷基、冰片基、降冰片烷基(IUPAC系统命名为二环[2.2.1]庚烷基)。在本文中,所述“环烷基”是可选地经单取代的或多取代的,例如但不限于,2,2-,2,3-,2,4-,2,5-,或2,6-二取代的环己基。所述经取代的“环烷基”的取代基可选地是一或多个(例如1-5、1-4、1-3、1-2、或1个) 选自C1-C3烷基、C3-6环烷基、羟基、氨基、巯基、卤素、C1-C3烷氧基、C1-C3烷基氨基、卤代C1-C3烷基、氨基取代的C1-3亚烷基、C1-3烷基-NHC(O)-、C1-3烷基-C(O)NH-、氰基或其任意组合的取代基。术语“C3-6环烷基”的实例包括但不限于环丙基、环丁基、环戊基、环戊烯基、和环己基。
在本发明中,单独或组合使用的术语“亚环烷基”是指具有3至12个碳原子(例如3-12 个、3-11个、3-10个、3-8个、3-7个、3-6个碳原子)的饱和及部分不饱和(即具有一个或多个双键,但不是完全共轭)的单环或双环或多环环烃二价基团。术语“亚环烷基”包括单环、双环或三环烃二价基团,其具有3至12个碳原子。单环亚环烷基的代表性实例包括但不限于亚环丙基、亚环丁基、亚环戊基、亚环戊烯基、亚环己基、亚环己烯基、亚环庚基、和亚环辛基。双环和三环亚环烷基包括亚桥环烷基、亚稠环基和亚螺环烷基,例如但不限于亚十氢萘基、八氢并环戊二烯亚基、八氢-1H-茚亚基、2,3-二氢-1H-茚亚基、亚螺环基、亚金刚烷基、亚降金刚烷基、亚降冰片烷基(系统命名为双环[2.2.1]庚烷亚基)。在本公开中,所述“亚环烷基”是可选地经单取代的或多取代的,例如但不限于,2,2-,2,3-,2,4-,2,5-,或2,6-二取代的环己基。所述经取代的“亚环烷基”的取代基可选地是一或多个选自C1-C3烷基、C3-6环烷基、羟基、氨基、巯基、卤素、C1-C3烷氧基、C1-C3烷基氨基、卤代C1-C3烷基、氨基取代的C1-3亚烷基、C1-3烷基-NHC(O)-、C1-3烷基-C(O)NH-、氰基或其任意组合的取代基。
在本文中,单独或组合使用的术语“Cx-y亚螺环烷基”或“Cx-y亚螺环基”(x及y各自为整数)是指含有x至y个碳原子的亚螺环烷基。本发明中单独或组合使用的术语“C7-11亚螺环烷基”是指含有7至11个(例如7-10,7-9个)碳原子的亚螺环烷基。术语“C7-11亚螺环烷基”的代表性实例包括但不限于螺[3.3]庚烷亚基、螺[2.5]辛烷亚基、螺[3.5]壬烷亚基、螺[4.4]壬烷亚基、螺[4.5]癸烷亚基或螺[5.5]十一烷亚基。所述“C7-11亚螺环烷基”可选地进一步经一个或多个选自 C1-C3烷基、C3-6环烷基、羟基、氨基、巯基、卤素、C1-C3烷氧基、C1-C3烷基氨基、卤代C1- C3烷基、氨基取代的C1-3亚烷基、C1-3烷基-NHC(O)-、C1-3烷基-C(O)NH-、氰基或其任意组合的取代基取代。
在本文中,单独或组合使用的术语“Cx-y螺杂环亚基”或“Cx-y亚螺杂环基”(x及y各自为整数)是指含有一个或多个(例如含有1至3个、1至2个或1个)独立地选自硫、氧和氮的杂原子以及含有x至y个碳原子的亚螺杂环基。本发明中单独或组合使用的术语“C7-11螺杂环亚基”是指含有7至11个(例如7-10,或7-9个)碳原子以及含有一个或多个(例如含有1至3个、1至2个或1个)独立地选自硫、氧和氮的杂原子的亚螺杂环基。术语“C7-11螺杂环亚基”的代表性实例包括但不限于:
所述“C7-11螺杂环亚基”可选地进一步经一个或多个选自C1-C3烷基、C3-6环烷基、羟基、氨基、巯基、卤素、C1-C3烷氧基、C1-C3烷基氨基、卤代C1-C3烷基、氨基取代的C1-3亚烷基、C1-3烷基-NHC(O)-、C1-3烷基-C(O)NH-、氰基或其任意组合的取代基取代。
在本文中,单独或组合使用的术语“杂环基”或“杂环烷基”是指含有一个或多个(例如含有1至5个、1至4个、1至3个、1至2个或1个)独立地选自硫、氧和氮的杂原子的3至 20元单环、双环或三环的饱和或部分不饱和的(即具有一个或多个双键,但不完全共轭)环烃基。在一些实施方式中,“杂环基”可以是指含有一个或多个(例如含有1至5个或、1至4 个、1至3个、1至2个或1个)独立地选自硫、氧和氮的杂原子的3至15元(可选地为3至 14元、3至12元、3至11元、3至10元、3至9元、3至8元、3至7元、3至6元或3至5 元)单环的饱和或部分不饱和的(即具有一个或多个双键,但不完全共轭)环烃基。单环杂环基的代表性实例包括但不限于氮杂环丁基、氧杂环丁基、吡咯烷基、咪唑烷基、吡唑烷基、四氢呋喃基、四氢吡喃基、四氢噻吩基、四氢噻喃基、噁唑烷基、噻唑烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、二氧杂环己基、氮杂环庚烷基、氮杂环辛烷基、二氮杂环庚烷基 (例如1,4-二氮杂环庚烷-1-基)和二氮杂环辛烷基。双环和三环杂环基包括桥杂环基、稠杂环基和螺杂环基,例如但不限于代表性实例包括但不限于6-氮杂双环[3.1.1]庚烷-3-基、2,5-二氮杂双环[2.2.1]庚烷-2-基、3,6-二氮杂双环[3.1.1]庚烷-3-基、3-氮杂双环[3.2.1]辛烷-8-基、3,8-二氮杂双环[3.2.1]辛烷-8-基、3,8-二氮杂双环[3.2.1]辛烷-3-基、2,5-二氮杂双环[2.2.2]辛烷-2-基、和氮杂螺环基(例如3-氮杂螺[5.5]十一烷-3-基)。所述杂环基可以是未取代的或如明确定义的取代的(例如被单-、双-、三-、或多取代),其中取代基可选地选自C1-C3烷基、C3-6环烷基、羟基、氨基、巯基、卤素、C1-C3烷氧基、C1-C3烷基氨基、卤代C1-C3烷基、氨基取代的 C1-3亚烷基、C1-3烷基-NHC(O)-、C1-3烷基-C(O)NH-、氰基或其任意组合。
在本文中,单独或组合使用的术语“亚杂环基”或“亚杂环烷基”是指含有一个或多个 (例如含有1至5个、1至4个、1至3个、1至2个或1个)独立地选自硫、氧和氮的杂原子的3至20元单环、双环或三环的饱和或部分不饱和的(即具有一个或多个双键,但不完全共轭)二价环烃基。在一些实施方式中,“亚杂环基”可以例如是指含有一个或多个(例如含有1 至5个或、1至4个、1至3个、1至2个或1个)独立地选自硫、氧和氮的杂原子的3至15元 (可选地为3至14元、3至12元、3至11元、3至10元、3至9元、3至8元、3至7元、3 至6元或3至5元)单环的饱和或部分不饱和的(即具有一个或多个双键,但不完全共轭)二价环烃基。单环亚杂环基的代表性实例包括但不限于亚氮杂环丁基、亚氧杂环丁基、亚吡咯烷基、亚咪唑烷基、亚吡唑烷基、亚四氢呋喃基、亚四氢吡喃基、亚四氢噻吩基、亚四氢噻喃基、亚噁唑烷基、亚噻唑烷基、亚哌啶基、亚哌嗪基、亚吗啉基、亚硫代吗啉基、亚二氧杂环己基和二氮杂环庚烷亚基(例如1,4-二氮杂环庚烷亚基,4,5-二氮杂环庚烷亚基,1,3-二氮杂环庚烷亚基)。双环亚杂环基和三环亚杂环基包括亚桥杂环基、亚稠杂环基和亚螺杂环基,例如但不限于代表性实例包括但不限于6-氮杂双环[3.1.1]庚烷亚基、2,5-二氮杂双环[2.2.1]庚烷亚基、3,6-二氮杂双环[3.1.1]庚烷亚基、3-氮杂双环[3.2.1]辛烷亚基、3,8-二氮杂双环[3.2.1]辛烷亚基、3,8-二氮杂双环[3.2.1]辛烷亚基、2,5-二氮杂双环[2.2.2]辛烷亚基、和亚氮杂螺环基(例如3-氮杂螺[5.5]十一烷亚基)。所述亚杂环基可以是未取代的或如明确定义的取代的(例如被单-、双-、三-、或多取代),其中取代基可选选自C1-C3烷基、C3-6环烷基、羟基、氨基、巯基、卤素、C1-C3烷氧基、C1-C3烷基氨基、卤代C1-C3烷基、氨基取代的C1-3亚烷基、C1-3烷基-NHC(O)-、C1-3烷基-C(O)NH-、氰基或其任意组合。
在本文中,单独或组合使用的术语“亚炔基”是指具有一个或多个(例如1至3个、1至 2个或1个)碳碳叁键的包含2至8个(例如2至6个、2至5个、2至4个、较优选2个)碳原子的直链或支链二价烃基。亚炔基的实例包括但不限于亚乙炔基、1-丙炔亚基、1-丁炔亚基和1,3-二炔亚基。
在本文中,单独或组合使用的术语“亚烯基”是指具有一个或多个(例如1至3个、1至 2个或1个)碳碳双键的包含2至8个碳原子(例如2至6个、2至5个碳原子,或2至4个、 2至3个或2个碳原子)的直链或支链二价烃基。亚烯基的实例包括但不限于亚乙烯基(例如- CH=CH-)、1-丙烯亚基、亚烯丙基、1-丁烯亚基、2-丁烯亚基、3-丁烯亚基、异丁烯亚基、戊烯亚基、正-戊-2,4-二烯亚基、1-甲基-丁-1-烯亚基、2-甲基-丁-1-烯亚基、3-甲基-丁-1-烯亚基、1-甲基-丁-2-烯亚基、2-甲基-丁-2-烯亚基、3-甲基-丁-2-烯亚基、1-甲基-丁-3-烯亚基、2- 甲基-丁-3-烯亚基、3-甲基-丁-3-烯亚基、和亚己烯基。
在本文中,术语“冰片”或“冰片烷”(又称1,7,7-trimethylbicyclo[2.2.1]heptane; camphane;bornylane)具有本领域技术人员已知的定义。在本文中,术语“冰片烷基”或“冰片基”是指冰片烷的一价基团,即冰片烷中的任意一个氢去掉后剩余的基团。“冰片基”的代表性实例包括但不限于1,7,7-三甲基二环[2.2.1]庚烷-2-基、1,7,7-三甲基二环[2.2.1]庚烷-3-基、1,7,7- 三甲基二环[2.2.1]庚烷-4-基、1,7,7-三甲基二环[2.2.1]庚烷-5-基、或1,7,7-三甲基二环[2.2.1]庚烷-6-基、
在本文中,术语“二环[2.2.1]庚烷”(又称bicyclo[2.2.1]heptane)或“降冰片烷”,具有本领域技术人员已知的定义。在本文中,“二环[2.2.1]庚烷基”或“降冰片(烷)基”是指二环[2.2.1]庚烷的一价基团,即二环[2.2.1]庚烷中的任意一个氢去掉后剩余的基团。“二环[2.2.1]庚烷基”的代表性实例包括但不限于二环[2.2.1]庚烷-2-基、二环[2.2.1]庚烷-3-基、二环[2.2.1]庚烷-4-基、二环[2.2.1]庚烷-5-基或二环[2.2.1]庚烷-6-基。
在本文中,术语“二环[2.2.1]庚烯”又称bicyclo[2.2.1]heptene),具有本领域技术人员已知的定义。在本文中,“二环[2.2.1]庚烯基”是指二环[2.2.1]庚烯的一价基团,即二环[2.2.1]庚烯中的任意一个氢去掉后剩余的基团。“二环[2.2.1]庚烯基”的代表性实例包括但不限于二环[2.2.1] 庚-5-烯-2-基、二环[2.2.1]庚-5-烯-3-基、或二环[2.2.1]庚-5-烯-7-基。
在本文中,术语“金刚烷”(又称Tricyclo[3.3.1.13,7]decane)具有本领域技术人员已知的定义,其结构式例如如下所示:在本文中,“金刚烷基”是指金刚烷的一价基团,即金刚烷中的任意一个氢去掉后剩余的基团。“金刚烷基”的代表性实例包括但不限于1-金刚烷基、 2-金刚烷基、3-金刚烷基、4-金刚烷基、5-金刚烷基、6-金刚烷基、7-金刚烷基、8-金刚烷基、 9-金刚烷基或10-金刚烷基。
在本文中,术语“降金刚烷”(又称为noradamantane,或octahydro-2,5-methanopentalene(译文:八氢-2,5-甲桥并环戊二烯))具有本领域技术人员已知的定义,其结构式例如如下所示:在本文中,“降金刚烷基”是指降金刚烷的一价基团,即降金刚烷中的任意一个氢去掉后剩余的基团。“降金刚烷基”的代表性实例包括但不限于1-降金刚烷基、2-降金刚烷基、3-降金刚烷基、4-降金刚烷基、5-降金刚烷基、6-降金刚烷基、7-降金刚烷基、8-降金刚烷基或9-降金刚烷基。
在本文中,术语“金刚烷胺”具有本领域技术人员已知的定义,即是指具有氨基取代基的金刚烷,其中氨基可以取代在金刚烷任意位置的碳上的氢。“金刚烷胺”的一实施例可以是金刚烷-1-胺(其对应英文化学名称为adamantan-1-amine或Tricyclo[3.3.1.13,7]decan-1-amine; CAS:768-94-5),具有以下结构式
本公开所述式(I)化合物的盐或药学上可接受的盐、对映异构体、立体异构体、溶剂化物、多晶型物亦涵盖于本公开范围内。
在本公开的所有实施方式中,所述式(I)化合物的盐或药学上可接受的盐是指无毒无机的或有机的酸和/或碱加成盐。示例包括:硫酸盐、盐酸盐、枸橼酸盐、马来酸盐、磺酸盐、柠檬酸盐、乳酸盐、酒石酸盐、富马酸盐、磷酸盐、二氢磷酸盐、焦磷酸盐、偏磷酸盐、草酸盐、丙二酸盐、苯甲酸盐、扁桃酸盐、琥珀酸盐、羟乙酸盐或对甲苯磺酸盐等。
“药学上可接受的载体”是指药学上可接受的材料,例如填充剂、稳定剂、分散剂、悬浮剂、稀释剂、赋形剂、增稠剂、溶剂或包封材料,将本公开中有用的化合物携带或运输到患者体内或给予患者,使得其可以执行其预期功能。通常,这样的构建体从一个器官或身体的一部分携带或运输到另一个器官或身体的一部分。载体与制剂的其他成分(包括本公开中有用的化合物)相容并且对患者无害,载体必须是“可接受的”。可用作药学上可接受的载体的材料的一些实例包括:糖,如乳糖,葡萄糖和蔗糖;淀粉,如玉米淀粉和马铃薯淀粉;纤维素及其衍生物,例如羧甲基纤维素钠,乙基纤维素和乙酸纤维素;粉状黄蓍胶;麦芽;明胶;滑石;赋形剂,如可可脂和栓剂蜡;油,如花生油,棉籽油,红花油,芝麻油,橄榄油,玉米油和大豆油;二醇,如丙二醇;多元醇,如甘油,山梨糖醇,甘露醇和聚乙二醇;酯类,如油酸乙酯和月桂酸乙酯;琼脂;缓冲剂,如氢氧化镁和氢氧化铝;表面活性剂磷酸盐缓冲溶液;和药物制剂中使用的其他无毒相容物质。
本公开的术语“室温”是指周围环境温度,例如20-30℃的温度。
在本文中,“立体异构体”是指具有相同化学构造,但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体,等等。
在本文中,术语“溶剂化物”是指一种或多种溶剂分子和本发明化合物的缔合物或络合物。溶剂的实例包括水、异丙醇、乙醇、甲醇、DMSO、乙酸乙酯、乙酸和乙醇胺。术语“水合物”是指溶剂分子是水的络合物。
在本文中,术语“手性”是具有与其镜像不能重叠性质的分子;而“非手性”是指与其镜像可以重叠的分子。
在本文中,术语“对映异构体”是指一个化合物的两个不能重叠但互成镜像关系的异构体。
在本文中,术语“非对映异构体”是指有两个或多个手性中心并且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质,如熔点、沸点、光谱性质和反应性。非对映异构体混合物可通过高分辨分析操作如电泳和色谱,例如HPLC来分离。
实施例
在下列说明中,为了提供对本发明的彻底了解而提出许多具体细节。本发明可在不具有部分或所有这些具体细节的情况下实施。在其他情况下,为了不对本发明造成不必要的混淆,不详述众所周知的过程操作。虽然本发明将结合具体实施例来进行说明,但应当理解的是,这并非旨在将本发明限制于这些实施例。
整个说明书及实施例中使用下列缩写:
Bipy 联吡啶
Boc 叔丁氧基羰基
BnCl 氯化苄
(COCl)2 草酰氯
Con. 浓度
DCM 二氯甲烷
DMF N,N-二甲基甲酰胺
DMSO 二甲基亚砜
DIPEA N,N-二异丙基乙胺
(COCl)2 草酰氯
EDCI 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐
ESI 电喷雾离子化
equiv 当量
EtOH 乙醇
HATU 2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐
HOAT N-羟基-7-氮杂苯并三氮唑
HPLC 高效液相层析
HRMS 高分辨率质谱
LC-MS 液相色谱-质谱联用
LRMS 低分辨率质谱
LC 液相层析
Me 甲基
MeCN 乙腈
MeOH 甲醇
MS 质谱
MsCl 甲磺酰氯
MsO- 甲磺酸酯基
NMM N-甲基吗啉
NMP N-甲基吡咯烷酮
1H NMR 核磁共振氢谱
-OTs 对甲苯磺酸酯基
PEG 聚乙二醇链
rt 室温
tBu 叔丁基
t-BuONO 亚硝酸叔丁酯
TEA 三乙胺
TFA 三氟乙酸
TLC 薄层层析
TMS 三甲基硅烷基
在本发明中,1H NMR谱采用Bruker-500MHz型核磁共振仪测定,用含0.1%TMS(作为内标)的CD3OD(δ=3.31ppm)做溶剂;或用含0.1%TMS(作为内标)的CDCl3(δ=7.26 ppm)做溶剂;或使用含0.03%TMS(作为内标)的DMSO-d6(δ=2.50ppm)做溶剂;LRMS谱在ABTriple 4600型质谱仪上测定,HPLC制备在SHIMADZU LC-20AP型仪器上测定,HPLC 纯度在SHIMADZU LC-30AP或Waters 1525型仪器上测定。所有反应未作特别说明均在空气氛围下进行;反应用TLC或LC-MS跟踪。
溶剂及试剂处理如下:
反应所用溶剂DCM、DMF、无水EtOH、无水MeOH等均购自国药集团;
HPLC制备所用的是制备级CH3CN及去离子水;
除非另有说明,达珀利奈以及各种不同长度碳链链接单元linker(即,用于形成LIN所表示的基团的化合物)、以及其他反应底物、试剂和药品均可通过市售渠道直接购买获得。
下述实施例中所用的材料、试剂,如无特别说明,均可从商业途径购买来直接使用,或者可以采用或按照本领域已知的方法合成得到。
通用合成方法
本公开所述的化合物和/或其药学上可接受的盐,可以使用市售原料通过本领域已知的合成技术合成得到。下文描述的合成方案举例说明了大部分化合物的制备方法。各方案中使用的起始原料或试剂均可从商购途径购买得到或者通过本领域技术人员已知的方法制备得到。本领域技术人员可根据本领域常规技术制备本公开式(I)化合物的盐、外消旋体、对映异构体、磷酸盐、硫酸盐、盐酸盐和前药形式。
达珀利奈衍生物(Nampt抑制剂)的通用制备方法:
中间体LM的通用合成方法
中间体LM(泊马度胺-N-Linker-COOH)的通用制备方法:
在步骤1中,将2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚-1,3-二酮(1equiv;CAS登录号835616-60-9),相应的原料胺(1.2equiv)和N,N-二异丙基乙胺(5equiv)一起加入30mL的微波反应管中,随后加入NMP(8mL)。反应混合物在室温下搅拌10分钟。然后缓慢向微波反应管中鼓入氩气,将反应管放入微波反应器上,升温至110℃,并搅拌反应混合物2h。将反应液降至室温,倾入90%食盐水中,用乙酸乙酯萃取(4x50mL)。将有机相合并,水洗(2x30mL),饱和食盐水洗(50mL),无水Na2SO4干燥,减压蒸去溶剂,所得粗品经柱层析(洗脱剂(v/v):石油醚/乙酸乙酯=1:1)纯化得到Boc保护的中间体。
在步骤2中,向50mL单口瓶中加入Boc保护的中间体,20mL的88%甲酸。反应混合物在室温下搅拌12h,减压蒸去反应溶剂。所得残留物加水冻干得到相应最终的目标化合物。
中间体LM(来那度胺-N-Linker-COOH)的通用制备方法:
将来那度胺(1equiv)、NMP(8mL)、相应的原料溴代叔丁酯(1.2equiv)和N,N-二异丙基乙胺(3equiv)一起加入单口瓶中,110℃反应12h。将反应液降至室温后经C18反相柱(洗脱剂(v/v):乙腈/(水+0.1%TFA)=10%–100%)制备和纯化,得到相应的叔丁醇酯中间体化合物。
将第一步骤得到的叔丁醇酯中间体化合物加入单口瓶中,再加入DCM(6mL)和TFA(2 mL),在室温搅拌1h,减压蒸去反应溶剂,所得残留物加水冻干得到相应的最终的目标化合物。
中间体LM(泊马度胺-N-亚烷基链-I)的通用制备方法:
步骤1:
将2-(2,6-二氧代基哌啶-3-基)-4-氟异吲哚啉-1,3-二酮(1equiv)溶于25mL NMP中,依次加入相应的叔丁基二甲基硅氧基保护的伯胺(1.0equiv)和N,N-二异丙基乙胺(1.5equiv),100℃加热反应4h。反应完全后,将反应液降至室温,倾入饱和食盐水中,乙酸乙酯萃取(4x50mL)。将有机相合并,水洗(2x30mL),饱和食盐水洗(50mL),无水Na2SO4干燥,减压蒸去溶剂。所得粗品经柱层析(洗脱剂(v/v):石油醚/乙酸乙酯=1:1)纯化得到中间体。将中间体溶于50 mL四氢呋喃中,加入四丁基氟化铵(1equiv),室温下搅拌2h,反应完全。加入饱和食盐水 200mL,乙酸乙酯萃取(4x50mL),合并有机相,水洗(2x30mL),饱和食盐水洗(50mL),无水 Na2SO4干燥,减压蒸去溶剂,得到粗品直接进行下一步。
步骤2:
向步骤1所得的粗品溶于40mL混合溶剂(DCM/吡啶=3/1)的溶液中冰浴条件下依次加入三乙胺(3.0equiv)和甲烷磺酰氯(1.5equiv),室温反应12h。反应完全后,将反应液用饱和食盐水洗涤,减压蒸去溶剂。所得残留物经柱层析纯化得到相应的磺酸酯中间体。
步骤3:向步骤2的相应的磺酸酯中间体溶于丙酮中的溶液中加入NaI,加热到60℃,反应过夜得到目标化合物。
中间体LM(来那度胺/泊马度胺-炔基-linker-OMs)的通用制备方法:
步骤1:
将3-(4-溴-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮或4-溴-2-(2,6-二氧代哌啶-3-基)异吲哚啉 -1,3-二酮(1equiv)溶于5mL DMF中,Ar气鼓泡5min,依次加入相应的炔醇(2equiv)、 Pd(PPh3)2Cl2(0.1equiv)和CuI(0.2equiv)。反应混合物搅拌5min,加入2.5mL三乙胺,加热到 80℃,反应过夜。混合物冷却到室温,用50mL水淬灭反应,用乙酸乙酯萃取(3x50mL)。将有机相合并,水洗(2x30mL),饱和食盐水洗(50mL),无水Na2SO4干燥,减压蒸去溶剂。所得粗品经柱层析(洗脱剂(v/v):DCM/MeOH=5/1)得到相应醇中间体。
步骤2:
将步骤1所得的醇中间体溶于15mL DCM中,依次加入三乙胺(3equiv)和甲基磺酰氯(1.5equiv),体系变澄清,反应过夜。将反应液用饱和食盐水洗涤,减压蒸去溶剂。所得残留物经柱层析(洗脱剂(v/v):DCM/MeOH=5/1)纯化,得到相应目标化合物。
中间体LM(来那度胺/泊马度胺-亚烷基链-OMs)的通用制备方法:
在步骤1中,将相应的来那度胺/泊马度胺4位取代的炔醇类化合物(1equiv)溶于10mL 乙醇中,加入10%Pd/C(5mg)和PtO2(5mg)作为催化剂,在氢气氛围下,常压50℃反应12 h。反应混合物过滤,滤液减压蒸去溶剂,得到的粗品直接投入下一步。
在步骤2中,将步骤1得到的还原产物溶于15mL DCM中,依次加入三乙胺(3equiv)和甲基磺酰氯(1.5equiv),体系变澄清,反应过夜。将反应液用饱和食盐水洗涤,减压蒸去溶剂。所得残留物经柱层析(洗脱剂(v/v):DCM/MeOH=5/1)纯化,得到相应目标化合物。
中间体LM(泊马度胺-S-亚烷基链-COOH)的通用制备方法:
步骤1:
将化合物2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮(20g,72.4mmol)加入一个 250mL的蛋形瓶中,随后加入无水N,N-二甲基甲酰胺(150mL),室温搅拌下,分批加入九水硫化钠(28g,108.6mmol)。加完后反应液在室温下搅拌6h。随后将反应液缓慢倾入400 mL的冰水混合物中,搅拌下用6N的盐酸水溶液缓慢调至反应液的pH=2–3,溶液颜色由血红色逐渐变为淡黄色,并有大量灰白色固体析出。反应混合物在室温下搅拌0.5h,抽滤,滤饼用水洗涤3次;随后将滤饼用100mL的无水丙酮打浆,抽滤,滤饼用丙酮洗涤3次,减压干燥得中间体化合物2-(2,6-二氧代哌啶-3-基)-4-巯基异吲哚啉-1,3-二酮(SIAIS151014)。
步骤2:
将步骤1得到的中间体化合物2-(2,6-二氧代哌啶-3-基)-4-巯基异吲哚啉-1,3-二酮 (SIAIS151014)(1equiv)加入一个100mL的蛋形瓶中,随后加入无水N,N-二甲基甲酰胺 (10mL)和无水碳酸钾(2equiv),室温搅拌下缓慢滴入相应溴取代的叔丁基保护的烷基链酸(1.2equiv),滴完室温搅拌0.5h。原料反应完后,向反应混合物中倾入50mL的水,乙酸乙酯萃取(2x50mL)。将有机相合并,水洗(3x20mL),饱和食盐水洗(50mL),无水硫酸钠干燥,减压蒸去溶剂。所得残留物经柱层析(洗脱剂(v/v):二氯甲烷/乙酸乙酯=20:1)纯化,得相应的叔丁酯中间体产物。将该相应的叔丁酯中间体产物加入25mL的蛋形瓶中,随后加入88%的甲酸(10mL),反应混合物在室温下搅拌12h,减压蒸去溶剂,所得残留物加水冻干得相应目标化合物。
中间体LM(泊马度胺-S-PEGn-COOH)的通用制备方法:
将化合物2-(2,6-二氧代哌啶-3-基)-4-巯基异吲哚啉-1,3-二酮(SIAIS151014)(1equiv) 加入一个100mL的蛋形瓶中,随后加入无水N,N-二甲基甲酰胺(10mL)和无水碳酸钾(2 equiv),室温搅拌下缓慢滴入溴取代的OTs保护的不同长度的PEG链酸(1.2equiv)。滴完,反应混合物在室温搅拌0.5h。原料反应完后,向反应混合物中倾入50mL的水,乙酸乙酯萃取 (2x50mL)。合并有机相,水洗(3x20mL),饱和食盐水洗(50mL),无水硫酸钠干燥,减压蒸去溶剂,所得粗品经柱层析(洗脱剂(v/v):二氯甲烷/乙酸乙酯=20:1)纯化,得相应的叔丁酯中间产物。将该相应的叔丁酯中间化合物加入25mL的蛋形瓶中,随后加入DCM和TFA,所得混合物在室温搅拌1h,减压蒸去溶剂,所得残留物加水冻干得目标化合物。
中间体LM(来那度胺-S-亚烷基链-COOH)的通用制备方法:
步骤1:将五水硫代硫酸钠(53.7g,216.3mmol),氯化苄(27.4g,216.3mmol),五水硫酸铜(77.4mg,0.31mmol)及联吡啶(0.72g,4.6mmol)一起加入装有甲醇(120mL)和水(120mL)的500mL的蛋形瓶中,随后缓慢升温至80℃并搅拌2h。随后将反应液降至室温,加入3-(4-氨基-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(即来那度胺)(8.0g,30.9mmol),最后缓慢滴加亚硝酸叔丁酯(4.78g,46.4mmol),滴毕,再次升温至80℃并搅拌8h。反应结束后,将反应液降至室温,加水(200mL),乙酸乙酯萃取(2x200mL),合并有机相,水洗 (2x50mL),饱和食盐水洗(50mL),无水硫酸钠干燥,减压蒸去溶剂。所得粗品经柱层析(洗脱剂(v/v):石油醚/乙酸乙酯=1:2)纯化得化合物SIAIS171088。
步骤2:将无水三氯化铝(2.61g,19.6mmol)及无水甲苯(70mL)加到250mL的蛋形瓶中,搅拌下缓慢加入化合物(SIAIS171088)(1.8g,4.9mmol),加毕,35℃下搅拌过夜。反应结束后,在搅拌下向反应混合物中缓慢加入20%的柠檬酸水溶液,有大量的固体析出,随后抽滤,滤饼分别用水和乙酸乙酯洗涤,滤饼干燥得化合物(SIAIS171095)。
步骤3:将中间体化合物SIAIS171095(1equiv)加入一个100mL的蛋形瓶中,随后加入无水N,N-二甲基甲酰胺(10mL)和无水碳酸钾(2equiv),室温搅拌下缓慢滴入相应的溴取代的叔丁基保护的烷基链酸(1.2equiv),滴完室温搅拌0.5h。原料反应完后,向反应混合物中倾入50mL的水,乙酸乙酯萃取(2x50mL)。合并有机相,水洗(3x20mL),饱和食盐水洗(50mL),无水硫酸钠干燥,减压蒸去溶剂,所得粗品经柱层析(洗脱剂(v/v):二氯甲烷/乙酸乙酯=20:1)纯化,得相应的叔丁酯中间产物。将该相应的叔丁酯中间产物加入25mL 的蛋形瓶中,随后加入88%的甲酸(10mL),室温搅拌12h。减压蒸去溶剂。所得残留物加水冻干得目标化合物。
中间体LM(来那度胺-S-PEGn-COOH)的通用制备方法:
将中间体化合物SIAIS171095(1equiv)加入一个100mL的蛋形瓶中,随后加入无水N,N-二甲基甲酰胺(10mL)和无水碳酸钾(2equiv),室温搅拌下缓慢滴入相应的溴取代的OTs保护的PEG链酸(1.2equiv),滴完室温搅拌0.5h。原料反应完后,向反应混合物中倾入50mL的水,乙酸乙酯萃取(2x50mL)。将有机相合并,水洗(3x20mL),饱和食盐水洗 (50mL),无水硫酸钠干燥,减压蒸去溶剂,所得粗品经柱层析(洗脱剂(v/v):二氯甲烷/乙酸乙酯=20:1)纯化,得相应的叔丁酯中间产物。将该相应的叔丁酯中间产物加入25mL的蛋形瓶中,随后加入TFA(5mL),DCM(10mL)。反应混合物室温搅拌12h,减压蒸去溶剂,所得残留物加水冻干得目标化合物。
中间体LM(来那度胺/泊马度胺-S-亚烷基链-Br)的通用制备方法:
将3-(4-巯基-1-羰基异二氢吲哚-2-基)哌啶-2,6-二酮或2-(2,6-二氧代哌啶-3-基)-4-巯基异二氢吲哚-1,3-二酮(1equiv)溶于20mL DMF中,加入K2CO3(3equiv),搅拌15min,加入相应的二溴化物(3equiv),室温反应12h。将反应液倒入50mL水中,二氯甲烷萃取2次。合并有机相,饱和食盐水洗涤有机相,减压蒸馏除去溶剂。所得残留物经硅胶柱层析(洗脱剂 (v/v):DCM至DCM/MeOH(10/1))纯化,得到目标化合物。
中间体LM(来那度胺-O-亚烷基链-Br)的通用制备方法:
将3-(4-羟基-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(1equiv)溶于20mL DMF中,加入 K2CO3(3equiv),搅拌15min,加入相应的二溴化物(3equiv),加热至80℃,反应12h。将反应液倒入50mL水中,二氯甲烷萃取2次。合并有机相,饱和食盐水洗涤有机相,减压蒸馏除去溶剂。所得残留物经硅胶柱层析(洗脱剂(v/v):DCM至DCM/MeOH(10/1))纯化,得到目标化合物。
中间体LM(泊马度胺-O-亚烷基链-COOH)的通用制备方法:
步骤1:将2-(2,6-二氧代哌啶-3-基)-4-羟基异吲哚啉-1,3-二酮(1equiv)溶于20mL DMF中,加入K2CO3(3equiv),加入相应的溴取代的叔丁基保护的烷基链酸(1.2equiv),室温反应2h。将反应液倒入50mL水中,二氯甲烷萃取2次。合并有机相,饱和食盐水洗涤有机相,减压蒸馏除去溶剂。所得残留物经硅胶柱层析(洗脱剂(v/v):DCM至DCM/MeOH (10/1))纯化,得到叔丁酯中间体化合物。
步骤2:将该相应的叔丁酯中间体化合物加入25mL的蛋形瓶中,随后加入TFA(5mL),DCM(10mL)。反应混合物在室温搅拌12h,减压蒸去溶剂。所得残留物加水冻干得目标化合物。
中间体LM(VHL-CO-Linker-COOH)的通用制备方法:
将相应的原料二酸(2.5equiv)加入250mL的三口瓶中,随后加入无水DMF(10mL)和无水二氯甲烷(150mL),冰水浴搅拌下分别加入DIPEA(10.0mmol,5equiv),VHL-1(2mmol,1equiv),HOAT(2.4mmol,1.2equiv)和EDCI(2.4mmol,1.2equiv)。加完,反应混合物在冰水浴下搅拌5h,随后升至室温搅拌过夜。反应完全后加入1mL的去离子水淬灭,减压蒸去二氯甲烷,所得残留物随后利用C18反相柱(洗脱剂(v/v):乙腈/(水+0.1%TFA)=10%–100%)制备和纯化。收集的组分减压蒸去乙腈,残留物经冻干后得到相应目标化合物。
本发明化合物通用的合成方法:
中间体通用的合成方法:
根据目标化合物,上述各方案以及其反应底物、反应条件(包括反应用量、温度、时间等)、后处理等可通过本领域技术人员熟知的技术和方法进行适当修改和调整以获得所需的目标化合物,并且所得的目标化合物可根据本领域技术人员熟知的方法,进一步通过取代基等进行修饰而获得其他目标化合物。
中间体制备实施例
中间体制备实施例1:达珀利奈衍生物1(SIAIS630006)的制备
根据方案1制备达珀利奈衍生物1(SIAIS630006)。
步骤1:制备(E)-N-(4-(哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS524135)
室温下,在50ml圆底反应瓶中,依次加入(E)-3-(吡啶-3-基)丙烯酸(1g,1.5equiv),10 mL DCM,冰浴下,滴加0.7mL草酰氯(1.8equiv)。滴加完毕后,向反应混合物中加入2滴 DMF引发反应,60℃反应3h后。取少量反应液加入甲醇溶解后,经LC-MS检测到相应甲酯生成后,旋干DCM待用。另取50mL圆底反应瓶中加入4-(4-氨基丁基)哌啶-1-甲酸叔丁酯 (860mg,0.75equiv),10mL DCM,1mL TEA(1.5equiv),冰浴下,向体系中缓慢滴加DCM溶解的酰氯溶液。滴毕,反应混合物在室温反应1h。经LC-MS检测反应完毕后,加水淬灭反应。向混合物中加入硅胶,经5%CH3OH/DCM体系进行柱层析洗脱,得到黄色油状化合物,直接进行下一步的反应。向该黄色油状液体溶于10mL DCM中的溶液中加入2mL TFA,室温反应2h。LC-MS检测反应结束后,将反应液旋蒸除去反应溶剂。向所得残留物中加入饱和碳酸氢钠水溶液调节pH至碱性,二氯甲烷/甲醇(10:1)萃取3次。有机相合并,饱和NaCl水溶液洗涤2次,无水硫酸钠干燥,过滤。滤液旋干,所得残留物经C18反相柱分离,洗脱剂为CH3CN 和水。将收集的组分旋干除去CH3CN,残留物冻干得白色固体(SIAIS524135,823mg,两步总收率为64%)。1H NMR(500MHz,CD3OD)δ9.12(s,1H),8.85-8.80(m,2H),8.12–7.98(m,1H),7.63(d,J=15.8Hz,1H),7.02(d,J=15.9Hz,1H),3.44–3.27(m,5H),3.05-2.95(m,2H),1.95(dd, J=13.6,3.4Hz,2H),1.60(p,J=7.1Hz,3H),1.45–1.27(m,7H).HRMS(ESI)C17H26N3O+[M+H]+, 计算值288.2070;实测值,288.2074.
步骤2:制备(E)-N-(4-(1-(4-(哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS630006)
室温下,向50mL圆底反应瓶中依次加入SIAIS524135(860mg,1equiv),4-(4-(叔丁氧羰基)哌嗪-1-基)苯甲酸(881mg,1equiv),HATU(1.36.g,1.2equiv),5mL DMF,1.6mLDIPEA(3equiv),60℃反应过夜。LC-MS检测反应完毕后,反应混合物过滤,滤液经C18反相柱分离,洗脱溶剂为CH3CN和水。收集的组分旋干除去CH3CN,残留物冻干得黄色固体直接进行下一步反应。向该黄色固体溶于10mL DCM中的溶液中加入2mL TFA,室温反应2h。 LC-MS检测反应结束后,将反应液旋蒸除去反应溶剂。向所得残留物中加入饱和碳酸氢钠水溶液调节pH至碱性。有机相合并,二氯甲烷/甲醇(10:1)萃取3次,饱和NaCl水溶液洗涤2次,无水硫酸钠干燥,过滤。滤液旋干,所得残留物经C18反相柱分离,洗脱剂为CH3CN和水。将收集的组分旋干除去CH3CN,残留物冻干得黄色固体(SIAIS630006,1.1g,两步总收率为 64%)。1HNMR(500MHz,CD3OD)δ9.13(s,1H),8.87(dd,J=18.8,6.9Hz,2H),8.15(dd,J=8.2, 5.7Hz,1H),7.64(d,J=15.8Hz,1H),7.50-7.42(m,2H),7.26-7.16(m,2H),7.05(d,J=15.8Hz,1H),4.98(br,4H),3.63(s,4H),3.43(s,4H),3.34(t,J=7.0Hz,2H),1.94–1.75(m,2H),1.70-1.56 (m,3H),1.49-1.40(m,2H),1.40–1.32(m,2H),1.31–1.19(m,2H).HRMS(ESI)C28H38N5O2 + [M+H]+,计算值476.3020;实测值,476.3024.
中间体制备实施例2:达珀利奈衍生物2(SIAIS630020)的制备
采用与中间体制备实施例1的达珀利奈衍生物1相似的方法,根据方案1制备得到达珀利奈衍生物2,其中间体合成数据以及结构表征数据如下:
(E)-N-(4-(4-(4-(哌嗪-1-基)苯甲酰基)哌嗪-1-基)丁基)-3-(吡啶-3-基)丙烯酰胺 (SIAIS630020)。(白色固体,258mg,两步总收率63%)。1H NMR(500MHz,CD3OD)δ9.07(s, 1H),8.82–8.77(m,2H),8.08(dd,J=8.3,5.6Hz,1H),7.94(d,J=9.0Hz,2H),7.66(d,J=15.9Hz, 1H),7.06(d,J=9.0Hz,2H),6.99(d,J=15.9Hz,1H),3.65(br,3H),3.61–3.56(m,4H),3.56–3.51 (m,1H),3.44–3.36(m,7H),3.42-3.36(m,5H),1.91-1.86(m,2H),1.73-1.68(m,2H).HRMS (ESI)C27H37N6O2 +[M+H]+:计算值477.2973,实测值477.2975.
中间体制备实施例3:达珀利奈衍生物3(SIAIS631127)的制备
采用与中间体制备实施例1的达珀利奈衍生物1相似的方法,根据方案1制备得到达珀利奈衍生物3,其中间体合成数据以及结构表征数据如下:
(E)-N-(4-(1-(4-(哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺 (SIAIS631127)。(黄色油状液体,359mg,收率73%)。1H NMR(500MHz,CD3OD)δ9.12(s,1H),8.92-8.83(m,2H),8.15(dd,J=8.2,5.6Hz,1H),7.64(d,J=15.8Hz,1H),7.44–7.30(m,4H), 7.03(d,J=15.9Hz,1H),4.60(d,J=12.9Hz,1H),3.71(d,J=13.3Hz,1H),3.52(d,J=13.1Hz, 2H),3.34(t,J=7.1Hz,2H),3.20-3.10(m,3H),3.02–2.94(m,1H),2.85(t,J=12.8Hz,1H),2.11 –2.04(m,2H),2.03–1.91(m,2H),1.88–1.82(m,1H),1.73–1.67(m,1H),1.64-1.56(m,3H), 1.48-1.40(m,2H),1.38-1.32(m,2H),1.25–1.06(m,2H).HRMS(ESI)C29H39N4O2 +[M+H]+:计算值475.3068,实测值475.3072.
中间体制备实施例4:达珀利奈衍生物4(SIAIS632004)的制备
采用与中间体制备实施例1的达珀利奈衍生物1相似的方法,根据方案1制备得到达珀利奈衍生物4,其中间体合成数据以及结构表征数据如下:
(E)-N-(4-(1-(6-(哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺 (SIAIS632004)。(黄色油状液体,359mg,收率73%)。1H NMR(500MHz,CD3OD)δ8.77(s, 1H),8.57(d,J=5.0Hz,1H),8.18(d,J=8.0Hz,1H),7.64(d,J=9.5Hz,1H),7.60–7.52(m,2H), 7.43(d,J=9.5Hz,1H),6.76(d,J=15.8Hz,1H),4.63(d,J=12.9Hz,1H),3.99(t,J=5.3Hz,3H), 3.94(d,J=14.3Hz,1H),3.44(p,J=1.6Hz,1H),3.39–3.36(m,4H),3.33(br,3H),3.16(p,J=1.7 Hz,2H),1.88(d,J=13.8Hz,1H),1.72(d,J=13.5Hz,1H),1.60-1.56(m,3H),1.48-1.43(m,2H), 1.37-1.33(m,2H),1.25-1.22(m,2H).HRMS(ESI)C26H36N7O2 +[M+H]+:计算值478.2925,实测值478.2928.
中间体制备实施例5:达珀利奈衍生物5(SIAIS631135)的制备
步骤1:6-(4-(4-(叔-丁氧基羰基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羧酸(SIAIS631145)的制备
根据方案17制备6-(4-(4-(叔-丁氧基羰基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羧酸(SIAIS631145).
将6-氯哒嗪-3-羧酸(1equiv)溶于20mL DMF中,加入DIPEA(5equiv),加入叔-丁基4-(哌啶-4-基)哌嗪-1-羧酸酯(2equiv),130℃反应3h。将反应液倒入50mL水中,二氯甲烷萃取2次。合并有机相,饱和食盐水洗涤有机相,减压蒸馏除去溶剂。所得残留物经硅胶柱层析(洗脱剂(v/v):DCM至DCM/MeOH(10/1))纯化,得到中间体化合物SIAIS631145, ESI[M+H]+392。
步骤2:(E)-N-(4-(1-(6-(4-(哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3- 基)丙烯酰胺(SIAIS631135)的制备
采用与中间体制备实施例1的达珀利奈衍生物1相似的方法,根据方案1,采用步骤1 制备得到的中间体SIAIS631145制备得到达珀利奈衍生物5((E)-N-(4-(1-(6-(4-(哌嗪-1-基)哌啶- 1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;SIAIS631135)(黄色油状液体,359 mg,收率73%)。1H NMR(500MHz,CD3OD)δ9.11(s,1H),8.95-8.80(m,2H),8.17–7.97(m, 3H),7.64(d,J=15.8Hz,1H),7.01(dd,J=15.8,5.5Hz,1H),4.60-4.53(m,2H),4.02(d,J=13.3 Hz,1H),3.87(s,1H),3.72(s,7H),3.46(t,J=12.5Hz,2H),3.34(t,J=7.1Hz,3H),3.20(t,J=12.2 Hz,1H),3.02-2.85(m,1H),2.48(d,J=12.1Hz,2H),2.19–2.01(m,2H),1.98–1.85(m,1H),1.79 (d,J=13.0Hz,1H),1.69–1.55(m,3H),1.50–1.32(m,4H),1.30–1.17(m,2H).HRMS(ESI) C31H45N8O2 +[M+H]+:计算值561.3660,实测值561.3665.
中间体制备实施例6:达珀利奈衍生物6(SIAIS632025)的制备
采用与中间体制备实施例1的达珀利奈衍生物1相似的方法,根据方案1制备得到达珀利奈衍生物6,其中间体合成数据以及结构表征数据如下:
(E)-N-(4-(1-(6-(哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺 (SIAIS632025)。(黄色油状液体,241mg,收率74%)。1H NMR(500MHz,CD3OD)δ9.14(s,1H),8.92(s,1H),8.73(d,J=8.2Hz,1H),8.25(d,J=2.1Hz,1H),8.09(s,1H),7.73–7.59(m,2H), 7.00(d,J=9.0Hz,1H),6.92(d,J=15.8Hz,1H),3.97–3.90(m,4H),3.84(s,2H),3.35–3.32(m, 8H),1.80(br,2H),1.63-1.56(m,3H),1.46-1.40(m,2H),1.39–1.28(m,2H),1.19(br,2H).HRMS (ESI)C27H37N6O2 +[M+H]+:计算值477.2973,实测值477.2976.
中间体制备实施例7:达珀利奈衍生物7(SIAIS632044)的制备
步骤1:6-(4-(4-(叔-丁氧基羰基)哌嗪-1-基)哌啶-1-基)尼古丁酸(SIAIS631147)的制备
根据方案17制备6-(4-(4-(叔-丁氧基羰基)哌嗪-1-基)哌啶-1-基)尼古丁酸(SIAIS631147)。
将6-氯尼古丁酸(1equiv)溶于20mL DMF中,加入DIPEA(5equiv),加入叔-丁基 4-(哌啶-4-基)哌嗪-1-羧酸酯(2equiv),130℃反应3h。将反应液倒入50mL水中,二氯甲烷萃取2次。合并有机相,饱和食盐水洗涤有机相,减压蒸馏除去溶剂。所得残留物经硅胶柱层析(洗脱剂(v/v):DCM至DCM/MeOH(10/1))纯化,得到中间体化合物SIAIS631147, ESI[M+H]+391。
步骤2:(E)-N-(4-(1-(6-(4-(哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS632044)的制备
采用与中间体制备实施例1的达珀利奈衍生物1相似的方法,根据方案1,采用步骤1 制备得到的中间体SIAIS631147制备得到达珀利奈衍生物7((E)-N-(4-(1-(6-(4-(哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺)(SIAIS632044)。(白色固体,132mg,收率30%)。1H NMR(500MHz,CD3OD)δ9.04(s,1H),8.80(s,1H),8.70(d,J=8.2Hz,1H),8.13 (d,J=2.2Hz,1H),8.04–7.94(m,1H),7.86(dd,J=9.2,2.4Hz,1H),7.63(d,J=15.8Hz,1H),7.23 (d,J=9.2Hz,1H),6.91(d,J=15.9Hz,1H),4.48(d,J=14.1Hz,4H),3.54-3.49(m,6H),3.34(d,J =7.2Hz,2H),3.26–3.16(m,3H),2.25(d,J=11.6Hz,4H),1.87-1.76(m,5H),1.62-1.58(m,4H), 1.46-1.41(m,2H),1.38–1.28(m,2H),1.23–1.13(m,2H).HRMS(ESI)C32H46N7O2 +[M+H]+:计算值560.3708,实测值560.3711.
中间体制备实施例8:(3-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-3-氧代丙酸(SIAIS352066)的制备
根据方案14的方法、在本领域可理解的适当条件下制备得到化合物(SIAIS352066),不同之处在于采用的原料二酸是丙二酸。得到的化合物(SIAIS352066)为白色固体,0.82g,收率 68%。ESI[M+H]+517.
中间体制备实施例9:16-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲硫基唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁烷-2-基)氨基)-16-氧代十六烷酸(SIAIS164189)的制备
根据方案14的方法、在本领域可理解的适当条件下制备得到化合物(SIAIS164189),不同之处在于采用的原料二酸是十六碳二酸。得到化合物(SIAIS164189)为白色固体,0.88g,收率67%,ESI[M+H]+699。
中间体制备实施例10:3-(4-((8-溴辛基)氧代)-1-羰基异二氢吲哚-2-基)哌啶-2,6-二酮 (SIAIS1222063)的制备
参考方案12,将3-(4-羟基-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(1.0g,3.8mmol)溶于 20mL DMF中,加入K2CO3(0.27g,1.9mmol),搅拌15min,加入1,8-二溴辛烷(2.0g,7.6 mmol),加热至80℃,反应12h,将反应液倒入50mL水中,二氯甲烷萃取2次,饱和食盐水洗涤有机相,减压蒸馏除去溶剂,硅胶柱层析(洗脱剂(v/v):DCM至DCM/MeOH(10/1)),得到SIAIS1222063(白色粉末,产率32%)。ESI[M+H]+451。
中间体制备实施例11:4-((8-溴辛基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮 (SIAIS1224003)的制备
根据方案11的方法、在本领域可理解的适当条件下制备得到化合物(SIAIS1224003),不同之处在于采用的起始化合物为2-(2,6-二氧代哌啶-3-基)-4-巯基异吲哚啉-1,3-二酮和1,8-二溴辛烷。得到的化合物(SIAIS1224003)为白色固体,0.92g,收率71%。ESI[M+H]+481。
本发明化合物制备实施例
实施例1:(E)-N-(4-(1-(4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丙酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS630009)的制备
根据方案15,室温条件下,在反应瓶中依次加入Nampt抑制剂,即达珀利奈衍生物1(SIAIS630006)(0.02mmol,1equiv),中间体LM(SIAIS151026;3-((2-(2,6-二氧代哌啶-3-基)- 1,3-二氧代异吲哚啉-4-基)氨基)丙酸;CAS登录号2225940-46-3)(0.02mmol,1equiv), HATU(0.024mmol,1.2equiv),2mL DMF,DIPEA(0.06mmol,3equiv),室温反应过夜。LC- MS检测反应结束后,反应混合物过滤,滤液经HPLC制备分离,收集的组分旋蒸除去乙腈,残留物冻干后得到最终目标化合物(SIAIS630009)。(黄色固体,6.3mg,收率46%)。1HNMR (500MHz,DMSO-d6)δ11.09(s,1H),9.00(s,1H),8.80-8.75(m,1H),8.48(d,J=8.4Hz,1H),8.33 (t,J=5.7Hz,1H),7.88(dd,J=8.2,5.4Hz,1H),7.62–7.49(m,2H),7.26(d,J=8.7Hz,2H),7.16 (d,J=8.6Hz,1H),7.03(d,J=7.1Hz,1H),6.96(d,J=8.3Hz,2H),6.89(d,J=15.9Hz,1H),6.79 (s,1H),5.04(dd,J=12.8,5.4Hz,1H),3.67–3.50(m,9H),3.30–3.13(m,6H),2.92-2.83(m,2H), 2.72(t,J=6.4Hz,2H),2.63–2.55(m,1H),2.49-2.44(m,1H),2.01-1.96(m,1H),1.67(d,J=12.5 Hz,2H),1.49-1.42(m,2H),1.36–1.18(m,4H),1.09-1.00(m,2H).。HRMS(ESI)C44H51N8O7 + [M+H]+,计算值803.3875;实测值,803.3879.
实施例2:(E)-N-(4-(1-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丁酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS630010)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(SIAIS151019;4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丁酸;CAS登录号2225940-47-4)制备得到目标化合物(SIAIS630010)(黄色固体,6.8mg,收率49%)。1H NMR (500MHz,DMSO-d6)δ11.09(s,1H),8.99(s,1H),8.76(d,J=5.3Hz,1H),8.46(d,J=8.2Hz,1H), 8.37–8.27(m,1H),7.86(dd,J=8.2,5.3Hz,1H),7.58(dd,J=8.6,7.0Hz,1H),7.53(d,J=15.9Hz, 1H),7.26(d,J=8.5Hz,2H),7.18(d,J=8.6Hz,1H),7.01(d,J=7.0Hz,1H),6.98–6.94(m,2H), 6.88(d,J=15.9Hz,1H),6.67(s,1H),5.05(dd,J=12.7,5.4Hz,1H),3.63–3.57(m,6H),3.34(t,J =7.2Hz,3H),3.27–3.14(m,6H),2.93-2.85(m,2H),2.63–2.53(m,1H),2.54-2.50(m,1H),2.46 (t,J=7.1Hz,2H),2.07–1.97(m,1H),1.82(p,J=7.1Hz,2H),1.66(d,J=12.5Hz,2H),1.53–1.41 (m,3H),1.31-1.20(m,4H),1.11-1.00(m,2H).。HRMS(ESI)C45H53N8O7 +[M+H]+,计算值 817.4032;实测值,817.4038.
实施例3:(E)-N-(4-(1-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)戊酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS630011)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(SIAIS151020;5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)戊酸;CAS登录号2225940-48-5)制备得到目标化合物(SIAIS630011)(黄色固体,6.0mg,收率43%)。1H NMR (500MHz,CD3OD)δ8.85(s,1H),8.63(d,J=5.1Hz,1H),8.36(d,J=8.1Hz,1H),7.77–7.70(m, 1H),7.63–7.48(m,2H),7.31(d,J=8.8Hz,2H),7.07(d,J=8.5Hz,1H),6.99(dd,J=17.8,7.9Hz, 3H),6.81(d,J=15.8Hz,1H),5.03(dd,J=12.6,5.5Hz,1H),3.70(dt,J=16.9,5.3Hz,4H),3.41– 3.35(m,2H),3.35-3.33(m,2H),3.24-3.21(m,6H),2.88-2.81(m,1H),2.77–2.71(m,1H),2.52 -2.51(m,2H),2.13–2.02(m,1H),1.75(t,J=3.3Hz,5H),1.59(p,J=6.9Hz,4H),1.43(br,2H), 1.37-1.32(m,2H),1.29(br,2H),.18(br,2H).HRMS(ESI)C46H55N8O7 +[M+H]+,计算值831.4188;实测值,831.4190.
实施例4:(E)-N-(4-(1-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基乙酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS632014)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(SIAIS1204057;(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基乙酸;CAS登录号 2103656-92-2)制备得到目标化合物(SIAIS632014)(白色固体,5.2mg,收率17%)。1HNMR (500MHz,CD3OD)δ8.96(d,J=9.8Hz,1H),8.73(dd,J=7.5,5.6Hz,1H),8.60(dd,J=23.2,8.3 Hz,1H),7.96-7.90(m,1H),7.61(dd,J=15.8,2.7Hz,1H),7.38–7.26(m,3H),7.12–6.98(m,3H), 6.88(dd,J=15.8,4.2Hz,2H),5.17(dd,J=13.3,5.1Hz,1H),4.39(d,J=16.9Hz,1H),4.35(d,J= 16.8Hz,1H),3.78(br,2H),3.54–3.47(m,2H),3.40–3.32(m,12H),2.97–2.86(m,1H),2.83– 2.77(m,1H),2.54–2.44(m,1H),2.25–2.17(m,1H),1.75(br,1H),1.58(q,J=7.3Hz,3H),1.43 (br,2H),1.37–1.25(m,3H),1.16(br,2H).HRMS(ESI)C43H51N8O6 +[M+H]+,计算值775.3926;实测值,775.3928.
实施例5:(E)-N-(4-(1-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)丁酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS632015)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(SIAIS1204085;4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)丁酸;CAS登录号 1781226-49-0)制备得到目标化合物(SIAIS632015)(白色固体,4.7mg,收率15%)。1H NMR (500MHz,CD3OD)δ9.00(s,1H),8.77(d,J=5.1Hz,1H),8.69(d,J=8.2Hz,1H),8.00(dd,J=8.2, 5.6Hz,1H),7.64(d,J=15.8Hz,1H),7.37–7.29(m,3H),7.10(d,J=7.5Hz,1H),6.99(d,J=8.8 Hz,2H),6.95–6.89(m,2H),5.18(dd,J=13.3,5.1Hz,1H),4.36(d,J=16.8Hz,1H),4.30(d,J= 16.9Hz,1H),3.71(dt,J=32.4,5.3Hz,4H),3.39–3.35(m,7H),3.24-3.17(m,5H),3.03–2.89(m, 1H),2.84-2.79(m,1H),2.61(t,J=7.1Hz,2H),2.56–2.40(m,1H),2.24–2.17(m,1H),2.02(t,J =6.9Hz,2H),1.79(br,1H),1.61(t,J=7.4Hz,4H),1.48-1.45(m,2H),1.39-1.34(m,2H),1.18(br, 2H).HRMS(ESI)C45H55N8O6 +[M+H]+,计算值803.4239;实测值,803.4240.
实施例6:(E)-N-(4-(1-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)戊酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS632016)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(SIAIS1210133;5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)戊酸;CAS登录号 2338824-29-4)制备得到目标化合物(SIAIS632016)(白色固体,4.1mg,收率14%)。1H NMR (500MHz,CD3OD)δ9.07(d,J=2.0Hz,1H),8.87–8.75(m,2H),8.12(dd,J=8.2,5.8Hz,1H), 7.64(d,J=15.8Hz,1H),7.48(t,J=7.8Hz,1H),7.37(dd,J=15.3,8.1Hz,3H),7.19(d,J=7.9Hz, 1H),7.07(d,J=8.8Hz,2H),6.95(d,J=15.8Hz,1H),5.17(dd,J=13.3,5.1Hz,1H),4.48(d,J= 17.0Hz,1H),4.43(d,J=17.1Hz,1H),3.81-3.68(m,4H),3.42-3.35(m,10H),3.27(t,J=5.2Hz, 3H),3.00-2.89(m,1H),2.83-2.75(m,1H),2.58–2.42(m,3H),2.23-2.13(m,1H),1.82–1.70(m, 5H),1.59(q,J=7.3Hz,3H),1.47-1.40(m,2H),1.38-1.30(m,2H),1.17(br,2H).HRMS(ESI) C46H57N8O6 +[M+H]+,计算值817.4396;实测值,817.4398.
实施例7:(E)-N-(4-(1-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)己酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS632017)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(SIAIS1204061;6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)己酸:CAS登录号 2338824-30-7)制备得到目标化合物(SIAIS632017)(白色固体,5.3mg,收率16%)。1H NMR (500MHz,DMSO-d6)δ11.01(s,1H),9.00(d,J=26.7Hz,1H),8.79(s,1H),8.53(s,1H),8.33(s, 1H),7.92(s,1H),7.54(d,J=15.8Hz,1H),7.32–7.23(m,3H),7.00–6.75(m,5H),5.11(dd,J= 13.3,5.1Hz,1H),4.26(d,J=17.4Hz,1H),4.16(d,J=17.4Hz,1H),3.58(br,6H),3.28–3.07(m, 9H),2.95-2.86(m,3H),2.65–2.58(m,1H),2.36(dd,J=8.3,6.5Hz,2H),2.31–2.22(m,1H),2.07 –1.95(m,1H),1.71–1.52(m,5H),1.49-1.35(m,5H),1.32(br,2H),1.25(t,J=7.6Hz,2H),1.11– 0.99(m,2H).HRMS(ESI)C47H59N8O6 +[M+H]+,计算值831.4552;实测值,831.4554.
实施例8:(E)-N-(4-(1-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)庚酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS632018)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(SIAIS1204063;7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)庚酸;CAS登录号 22338824-32-9)制备得到目标化合物(SIAIS632018)(白色固体,5.7mg,收率17%)。1H NMR (500MHz,CD3OD)δ9.00(s,1H),8.76(d,J=5.6Hz,1H),8.70(dt,J=8.2,1.8Hz,1H),8.01(dd,J =8.3,5.6Hz,1H),7.62(d,J=15.8Hz,1H),7.41–7.29(m,3H),7.13(d,J=7.5Hz,1H),7.00(d,J =8.8Hz,2H),6.94–6.85(m,2H),5.15(dd,J=13.3,5.1Hz,1H),4.34(d,J=16.9Hz,1H),4.29(d, J=16.9Hz,1H),3.70(dt,J=22.2,5.3Hz,4H),3.34(d,J=7.0Hz,5H),3.29–3.21(m,7H),2.95- 2.88(m,1H),2.81-2.76(m,1H),2.52–2.38(m,3H),2.20-2.16(m,1H),1.72-1.64(m,4H),1.59 (p,J=7.4Hz,4H),1.52–1.38(m,6H),1.36-1.32(m,3H),1.16(br,2H).HRMS(ESI)C48H61N8O6 + [M+H]+,计算值845.4709;实测值,845.4711.
实施例9:(E)-N-(4-(1-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)庚酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS630012)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(SIAIS151086;7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)庚酸:CAS登录号2225940-50-9)制备得到目标化合物(SIAIS630012)(黄色固体,6.1mg,收率44%)。1H NMR (500MHz,DMSO-d6)δ11.09(s,1H),8.96(d,J=26.7Hz,1H),8.74(d,J=20.1Hz,1H),8.39(d,J =69.3Hz,2H),7.82(d,J=44.1Hz,1H),7.58(dd,J=8.6,7.1Hz,1H),7.52(dd,J=15.9,9.1Hz, 1H),7.26(d,J=8.3Hz,2H),7.10(d,J=8.6Hz,1H),7.02(d,J=7.0Hz,1H),6.96(dd,J=9.2,4.5 Hz,2H),6.92–6.80(m,1H),6.54(s,1H),5.05(dd,J=12.8,5.4Hz,1H),3.62–3.53(m,6H),3.30 (t,J=7.1Hz,3H),3.25-3.15(m,6H),2.93-2.85(m,2H),2.62–2.54(m,1H),2.53–2.52(m,1H), 2.35(t,J=7.4Hz,2H),2.07–1.98(m,1H),1.72-1.63(m,2H),1.61–1.43(m,7H),1.39-1.30(m, 6H),1.25(t,J=7.5Hz,2H),1.10-0.99(m,2H).HRMS(ESI)C48H59N8O7 +[M+H]+,计算值859.4501;实测值,859.4505.
实施例10:(E)-N-(4-(1-(4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基) 乙酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS630013)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(SIAIS171090;2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙酸;CAS登录号 2378582-40-0)制备得到目标化合物(SIAIS630013)(白色固体,3.1mg,收率24%)。1H NMR (500MHz,CD3OD)δ8.94(d,J=17.6Hz,1H),8.73(d,J=6.4Hz,1H),8.61(s,1H),7.93(s,1H),7.80 (d,J=7.7Hz,1H),7.73(d,J=7.5Hz,1H),7.66–7.52(m,2H),7.32(d,J=8.8Hz,2H),6.99(d,J= 8.9Hz,2H),6.87(t,J=14.0Hz,1H),5.16(dd,J=13.4,5.2Hz,1H),4.56(d,J=17.4Hz,1H),4.49 (d,J=17.3Hz,1H),4.00(s,2H),3.69(t,J=9.4Hz,5H),3.35–3.33(m,3H),3.22(t,J=5.3Hz,6H), 2.95-2.85(m,1H),2.83–2.72(m,1H),2.54–2.42(m,1H),2.21-2.15(m,1H),1.77(br,2H),1.67 –1.50(m,5H),1.47-1.40(m,2H),1.39–1.27(m,2H),1.18(br,2H).HRMS(ESI)C43H50N7O6S+ [M+H]+,计算值792.3538;实测值,792.3540.
实施例11:(E)-N-(4-(1-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基) 戊酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS630014)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(SIAIS171079;5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)戊酸;CAS登录号 2378582-43-3)制备得到目标化合物(SIAIS630014)(白色固体,4.0mg,收率29%)。1H NMR (500MHz,DMSO-d6)δ10.98(s,1H),8.92(d,J=45.5Hz,1H),8.70(d,J=38.9Hz,1H),8.50–8.18 (m,2H),7.82(s,1H),7.64(dd,J=7.5,1.2Hz,1H),7.59–7.46(m,3H),7.26(d,J=8.3Hz,2H),6.99 –6.92(m,2H),6.89–6.76(m,1H),5.12(dd,J=13.3,5.1Hz,1H),4.36(d,J=17.4Hz,1H),4.22(d, J=17.4Hz,1H),3.60-3.55(m,10H),3.24-3.16(m,5H),3.11(t,J=6.5Hz,2H),2.95-2.85(m, 2H),2.65–2.54(m,1H),2.49–2.44(m,1H),2.41–2.36(m,2H),2.05-1.95(m,1H),1.68–1.62 (m,5H),1.52-1.40(m,2H),1.35-1.20(m,4H),1.13–0.96(m,2H).HRMS(ESI)C46H56N7O6S+ [M+H]+,计算值834.4007;实测值,834.4011.
实施例12:(E)-N-(4-(1-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基) 己酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS630037)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(SIAIS171091;6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)己酸;CAS登录号 2378582-44-4)制备得到目标化合物(SIAIS6320037)(白色固体,4.6mg,收率33%)。1H NMR (500MHz,CD3OD)δ8.77(s,1H),8.56(d,J=5.1Hz,1H),8.18(d,J=8.1Hz,1H),7.69–7.59(m, 2H),7.59-7.57(m,1H),7.52(dd,J=14.7,7.1Hz,2H),7.32(d,J=8.6Hz,2H),7.00(d,J=8.7Hz, 2H),6.76(d,J=15.8Hz,1H),5.16(dd,J=13.3,5.2Hz,1H),4.45(d,J=17.3Hz,1H),4.40(d,J= 17.3Hz,1H),3.69(dt,J=25.7,5.2Hz,5H),3.35(br,3H),3.29-3.22(m,5H),3.08(td,J=7.1,2.4 Hz,3H),2.95–2.85(m,1H),2.82–2.74(m,1H),2.43(t,J=7.4Hz,2H),2.21–2.10(m,1H),1.72 -1.55(m,10H),1.45-1.40(m,2H),1.36-1.30(m,4H),1.16(br,2H).HRMS(ESI)C47H58N7O6S+ [M+H]+,计算值848.4164;实测值,848.4168.
实施例13:(E)-N-(4-(1-(4-(4-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS630038) 的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙酸;CAS登录号 2378582-21-7)制备得到目标化合物(SIAIS630038)(白色固体,4.3mg,收率31%)。1HNMR (500MHz,CD3OD)δ8.84(s,1H),8.63(d,J=5.2Hz,1H),8.34(d,J=8.2Hz,1H),7.74–7.69(m, 2H),7.64(d,J=6.7Hz,1H),7.58(d,J=15.9Hz,1H),7.51(t,J=7.6Hz,1H),7.32(d,J=8.7Hz, 2H),6.97(d,J=8.8Hz,2H),6.81(d,J=15.9Hz,1H),5.14(dd,J=13.4,5.1Hz,1H),4.49(d,J= 17.3Hz,1H),4.43(d,J=17.3Hz,1H),4.23(s,2H),3.74(td,J=6.2,2.1Hz,2H),3.68(br,2H),3.59 (t,J=5.3Hz,2H),3.33(d,J=7.2Hz,2H),3.29(d,J=6.2Hz,2H),3.21(br,4H),3.08(br,1H),2.95 -2.85(m,1H),2.83-2.73(m,1H),2.55-2.45(m,1H),2.20-2.10(m,1H),1.77(br,2H),1.59(p,J =7.1Hz,3H),1.47-1.40(m,2H),1.39-1.27(m,4H),1.21–1.13(m,2H).HRMS(ESI) C45H54N7O7S+[M+H]+,计算值836.3800;实测值,836.3805.
实施例14:(E)-N-(4-(1-(4-(4-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基) 硫基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺 (SIAIS630039)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(SIAIS1213131;2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙酸;CAS登录号2378582-22-8)制备得到目标化合物(SIAIS630039)(白色固体,4.2mg,收率31%)。1H NMR(500MHz,CD3OD)δ8.89(s,1H),8.67(s,1H),8.43(d,J=8.1Hz,1H),7.81 –7.77(m,1H),7.70-7.64(m,2H),7.59(d,J=15.9Hz,1H),7.52(t,J=7.7Hz,1H),7.29(d,J=8.9 Hz,2H),6.97(d,J=8.9Hz,2H),6.84(d,J=15.8Hz,1H),5.14(dd,J=13.4,5.2Hz,1H),4.46(d,J =17.4Hz,1H),4.41(d,J=17.3Hz,1H),4.25(s,2H),3.72–3.60(m,11H),3.35–3.33(m,2H),3.29 –3.21(m,5H),3.05(br,1H),2.93-2.84(m,1H),2.81-2.74(m,1H),2.54-2.45(m,1H),2.18-2.10 (m,1H),1.75(br,2H),1.59(p,J=7.1Hz,3H),1.47–1.39(m,2H),1.37–1.26(m,4H),1.21–1.11 (m,2H).HRMS(ESI)C47H58N7O8S+[M+H]+,计算值880.4062;实测值,880.4065.
实施例15:(E)-N-(4-(1-(4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基) 乙基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS630130)的制备
根据方案16,室温条件下,在反应瓶中依次加入Nampt抑制剂,即达珀利奈衍生物1(SIAIS630006)(0.04mmol,1equiv),中间体LM(SIAIS213137;3-(4-(2-溴乙基硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;CAS登录号2378582-57-9)(0.048mmol,1.2equiv),2mLDMF, DIPEA(0.12mmol,3equiv),60℃反应8h。LC-MS检测反应结束后,反应混合物过滤,滤液经HPLC制备分离。收集的组分旋蒸除去乙腈,残留物冻干后得到最终目标化合物(SIAIS630130)(白色固体,6.2mg,收率20%)。1H NMR(500MHz,CD3OD)δ8.92(s,1H),8.70(d,J=5.3Hz,1H),8.50(dt,J=8.2,1.8Hz,1H),7.92–7.74(m,3H),7.67–7.56(m,2H),7.35(d,J =8.7Hz,2H),7.06(d,J=8.8Hz,2H),6.86(d,J=15.8Hz,1H),5.19(dd,J=13.5,5.3Hz,1H),4.56 (d,J=17.5Hz,1H),4.49(d,J=17.7Hz,1H),3.81(br,1H),3.72(t,J=6.6Hz,1H),3.54–3.40(m, 6H),3.33(d,J=7.2Hz,4H),3.17(t,J=6.6Hz,1H),2.98–2.85(m,1H),2.84–2.75(m,1H),2.60- 2.56(m,1H),2.25-2.15(m,1H),1.76(d,J=54.3Hz,2H),1.65-1.54(m,4H),1.45-1.27(m,1H), 1.38–1.27(m,2H),1.15(br,2H).HRMS(ESI)C43H52N7O5S+[M+H]+,计算值778.3745;实测值, 778.3748.
实施例16:(E)-N-(4-(1-(4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基) 丙基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS630131)的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物1(SIAIS630006)和中间体 LM(SIAIS213132;3-(4-(3-溴丙基硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;CAS登录号 2378582-58-0)制备得到目标化合物(SIAIS630131)(白色固体,6.4mg,收率21%)。1HNMR (500MHz,CD3OD)δ8.78(d,J=2.1Hz,1H),8.56(d,J=3.9Hz,1H),8.33(d,J=8.2Hz,1H),7.72 –7.57(m,3H),7.52–7.43(m,2H),7.25(d,J=8.8Hz,2H),6.95(d,J=8.9Hz,2H),6.75(d,J=15.9 Hz,1H),5.09(dd,J=13.4,5.2Hz,1H),4.42(d,J=17.4Hz,1H),4.36(d,J=17.4Hz,1H),3.77(d, J=65.1Hz,3H),3.54(br,2H),3.25(dd,J=16.0,7.7Hz,4H),3.15–3.00(m,7H),2.86-2.79(m, 1H),2.72-2.68(m,1H),2.48-2.40(m,1H),2.13-2.09(m,1H),2.06–1.94(m,2H),1.81–1.58(m, 2H),1.49(p,J=7.1Hz,4H),1.37–1.27(m,2H),1.27–1.16(m,3H),1.06(br,2H).HRMS(ESI) C44H54N7O5S+[M+H]+,计算值792.3902;实测值,792.3905.
实施例17:(E)-N-(4-(1-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基) 丁基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS630123)的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物1(SIAIS630006)和中间体 LM(SIAIS213134;3-(4-(4-溴丁基硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;CAS登录号 2378582-59-1)制备得到目标化合物(SIAIS630123)(白色固体,5.6mg,收率23%)。1HNMR (500MHz,CD3OD)δ8.88(d,J=2.2Hz,1H),8.66(dd,J=5.3,1.5Hz,1H),8.39(dt,J=8.1,1.8Hz, 1H),7.79–7.65(m,3H),7.63–7.55(m,2H),7.37(d,J=8.8Hz,2H),7.08(d,J=8.9Hz,2H),6.85 (d,J=15.8Hz,1H),5.20(dd,J=13.4,5.2Hz,1H),4.52(d,J=17.3Hz,1H),4.45(d,J=17.4Hz, 1H),3.90(d,J=68.5Hz,3H),3.65(br,2H),3.35(d,J=7.1Hz,4H),3.26–3.11(m,9H),2.98-2.91 (m,1H),2.84-2.79(m,1H),2.60-2.51(m,1H),2.24-2.19(m,1H),2.01-1.94(m,2H),1.84-1.73 (m,3H),1.61(p,J=7.3Hz,3H),1.48-1.42(m,2H),1.40–1.28(m,3H),1.18(br,2H).HRMS(ESI) C45H56N7O5S+[M+H]+,计算值806.4058;实测值,806.4061.
实施例18:(E)-N-(4-(1-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基) 戊基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS630132)的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物1(SIAIS630006)和中间体 LM(SIAIS1216049;3-(4-((5-溴戊基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;CAS登录号 2378582-60-4)制备得到目标化合物(SIAIS630132)(白色固体,6.1mg,收率19%)。1H NMR (500MHz,CD3OD)δ8.89(d,J=2.1Hz,1H),8.67(dd,J=5.4,1.5Hz,1H),8.45(dt,J=8.2,1.8Hz, 1H),7.80(dd,J=8.2,5.3Hz,1H),7.66(ddd,J=7.5,6.5,1.0Hz,2H),7.55(dd,J=15.7,8.1Hz,2H), 7.35(d,J=8.8Hz,2H),7.06(d,J=8.9Hz,2H),6.86(d,J=15.9Hz,1H),5.17(dd,J=13.3,5.1Hz, 1H),4.47(d,J=17.3Hz,1H),4.41(d,J=17.4Hz,1H),3.94-3.74(m,3H),3.64(br,2H),3.33(d,J =7.1Hz,4H),3.24–3.05(m,9H),2.95-2.88(m,1H),2.84-2.75(m,1H),2.58-2.49(m,1H),2.22 -2.16(m,1H),1.86–1.67(m,6H),1.64–1.52(m,5H),1.45-1.39(m,2H),1.36–1.26(m,2H),1.16 (br,2H).HRMS(ESI)C46H58N7O5S+[M+H]+,计算值820.4215;实测值,820.4217.
实施例19:(E)-N-(4-(1-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基) 己基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS630133)的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物1(SIAIS630006)和中间体 LM(SIAIS1216133;3-(4-(6-溴己基硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮:CAS登录号 2378582-61-5)制备得到目标化合物(SIAIS630133)(白色固体,6.4mg,收率19%)。1H NMR (500MHz,CD3OD)δ8.88(d,J=2.1Hz,1H),8.65(dd,J=5.3,1.5Hz,1H),8.41(dt,J=8.1,1.8Hz, 1H),7.77(dd,J=8.1,5.3Hz,1H),7.67–7.63(m,2H),7.61–7.52(m,2H),7.35(d,J=8.8Hz,2H), 7.06(d,J=8.8Hz,2H),6.85(d,J=15.9Hz,1H),5.17(dd,J=13.3,5.2Hz,1H),4.47(d,J=17.3 Hz,1H),4.41(d,J=17.3Hz,1H),3.98–3.77(m,3H),3.64(br,2H),3.33(d,J=7.0Hz,3H),3.19– 3.03(m,10H),2.95-2.86(m,1H),2.82-2.77(m,1H),2.58-2.49(m,1H),2.21-2.16(m,1H),1.81 –1.67(m,6H),1.62-1.51(m,5H),1.46-1.38(m,4H),1.36-1.30(m,2H),1.16(br,2H).HRMS (ESI)C47H60N7O5S+[M+H]+,计算值834.4371;实测值,834.4375.
实施例20:(E)-N-(4-(1-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基) 庚基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS630134)的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物1(SIAIS630006)和中间体 LM(SIAIS1216135:3-(4-(7-溴庚基硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;CAS登录号 2378582-62-6)制备得到目标化合物(SIAIS630134)(白色固体,6.7mg,收率20%)。1H NMR (500MHz,CD3OD)δ8.86(d,J=2.2Hz,1H),8.64(dd,J=5.3,1.5Hz,1H),8.39(dt,J=8.2,1.8Hz, 1H),7.75(dd,J=8.1,5.3Hz,1H),7.65(dt,J=7.0,1.3Hz,2H),7.62–7.47(m,2H),7.35(d,J=8.8 Hz,2H),7.06(d,J=8.9Hz,2H),6.84(d,J=15.8Hz,1H),5.16(dd,J=13.3,5.2Hz,1H),4.46(d,J =17.3Hz,1H),4.40(d,J=17.3Hz,1H),3.98–3.79(m,3H),3.64(br,2H),3.33(d,J=7.1Hz,3H), 3.26–3.00(m,10H),2.93-2.87(m,1H),2.82-2.76(m,1H),2.58-2.49(m,1H),2.21-2.16(m,1H), 1.82–1.74(m,3H),1.72–1.65(m,2H),1.61-1.56(m,3H),1.51-1.47(m,2H),1.46–1.28(m,9H), 1.16(br,2H).HRMS(ESI)C48H62N7O5S+[M+H]+,计算值848.4528;实测值,848.4531.
实施例21:(E)-N-(4-(1-(4-(4-(8-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基) 辛基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS630135)的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物1(SIAIS630006)和中间体 LM(SIAIS1216137;3-(4-((8-溴辛基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;CAS登录号 2378582-63-7)制备得到目标化合物(SIAIS630135)(白色固体,6.9mg,收率20%)。1H NMR (500MHz,CD3OD)δ8.84(d,J=14.4Hz,1H),8.63(dd,J=11.6,5.1Hz,1H),8.40–8.29(m,1H), 7.77–7.68(m,1H),7.69–7.62(m,2H),7.62–7.50(m,2H),7.36(d,J=8.8Hz,2H),7.07(d,J=8.9 Hz,2H),6.82(t,J=14.1Hz,1H),5.17(dd,J=13.3,5.2Hz,1H),4.46(d,J=17.3Hz,1H),4.40(d, J=17.3Hz,1H),3.96(d,J=13.4Hz,2H),3.65(d,J=12.0Hz,2H),3.33(d,J=5.1Hz,6H),3.24– 3.02(m,8H),2.95-2.85(m,1H),2.83-2.75(m,1H),2.58-2.49(m,1H),2.21-2.16(m,1H),1.75 (br,3H),1.68(q,J=7.4Hz,2H),1.59(p,J=7.3Hz,3H),1.53–1.28(m,12H),1.18(br,2H).HRMS (ESI)C49H64N7O5S+[M+H]+,计算值862.4684;实测值,862.4689.
实施例22:(E)-N-(4-(1-(4-(4-(11-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基) 十一烷基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS630136)的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物1(SIAIS630006)和中间体 LM(SIAIS1220015;3-(4-((11-溴十一烷基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;CAS登录号2378582-66-0)制备得到目标化合物(SIAIS630136)(白色固体,7.0mg,收率20%)。1H NMR(500MHz,CD3OD)δ8.83(d,J=2.3Hz,1H),8.62(dd,J=5.2,1.6Hz,1H),8.33(dt,J=8.2, 1.8Hz,1H),7.70(dd,J=8.1,5.2Hz,1H),7.66–7.59(m,2H),7.59–7.50(m,2H),7.35(d,J=8.8 Hz,2H),7.06(d,J=8.8Hz,2H),5.15(dd,J=13.3,5.2Hz,1H),4.44(d,J=17.3Hz,1H),4.39(d,J =17.3Hz,1H),3.95-3.78(m,3H),3.67(br,2H),3.33(d,J=7.1Hz,3H),3.24–3.02(m,10H),2.94 -2.86(m,1H),2.81-2.76(m,1H),2.57-2.48(m,1H),2.21-2.15(m,1H),1.84–1.72(m,3H),1.69 -1.63(m,2H),1.60-1.55(m,2H),1.50–1.24(m,20H),1.15(br,3H).。HRMS(ESI)C52H70N7O5S+ [M+H]+,计算值904.5154;实测值,904.5155.
实施例23:(E)-N-(4-(1-(4-(4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊-4-炔 -1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS630129)的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物1(SIAIS630006)和中间体 LM(SIAIS255121;5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊-4-炔-1-基甲磺酸酯; CAS登录号2138441-31-1)制备得到目标化合物(SIAIS630129)(白色固体,5.3mg,收率17%)。1H NMR(500MHz,CD3OD)δ8.75(d,J=2.1Hz,1H),8.53(dd,J=5.2,1.5Hz,1H),8.25(d,J=8.3 Hz,1H),7.68(d,J=7.7Hz,1H),7.63(dd,J=8.1,5.2Hz,1H),7.57(dd,J=7.8,1.0Hz,1H),7.48 (d,J=15.9Hz,1H),7.43(t,J=7.7Hz,1H),7.26(d,J=8.8Hz,2H),6.98(d,J=8.8Hz,2H),6.72 (d,J=15.9Hz,1H),5.10(dd,J=13.3,5.2Hz,1H),4.48(d,J=17.5Hz,1H),4.41(d,J=17.5Hz, 1H),3.88(br,2H),3.61(br,3H),3.33–3.25(m,2H),3.24-3.22(m,5H),3.14-2.99(m,2H),2.86- 2.79(m,1H),2.72-2.67(m,1H),2.60(t,J=6.9Hz,2H),2.48-2.40(m,1H),2.14–1.99(m,3H), 1.67(d,J=53.2Hz,2H),1.52-1.46(m,3H),1.38–1.27(m,2H),1.28–1.18(m,3H),1.07(br,3H). HRMS(ESI)C46H54N7O5 +[M+H]+,计算值784.4181;实测值,784.4183.
实施例24:(E)-N-(4-(1-(4-(4-(6-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)己-5-炔 -1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS630119)的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物1(SIAIS630006)和中间体 LM(SIAIS255119;6-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)己-5-炔-1-基甲磺酸酯; CAS登录号2570254-40-7)制备得到目标化合物(SIAIS630119)(白色固体,5.6mg,收率24%)。1H NMR(500MHz,CD3OD)δ8.88(s,1H),8.70–8.61(m,1H),8.41(d,J=8.2Hz,1H),7.81–7.74 (m,2H),7.68–7.55(m,2H),7.51(t,J=7.6Hz,1H),7.35(d,J=8.7Hz,2H),7.07(d,J=8.9Hz, 2H),6.84(d,J=15.9Hz,1H),5.19(dd,J=13.3,5.2Hz,1H),4.56(d,J=17.5Hz,1H),4.50(d,J= 17.5Hz,1H),3.95(br,1H),3.70(br,3H),3.33(d,J=7.1Hz,5H),3.29–3.26(m,7H),2.95-2.88 (m,1H),2.81-2.76(m,1H),2.63(t,J=6.9Hz,2H),2.57-2.50(m,1H),2.25-2.15(m,1H),2.03- 1.97(m,2H),1.85-1.70(m,4H),1.59(p,J=7.1Hz,3H),1.45-1.39(m,2H),1.36-1.31(m,2H), 1.16(br,2H).HRMS(ESI)C47H56N7O5 +[M+H]+,计算值798.4337;实测值,798.4339.
实施例25:(E)-N-(4-(1-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔 -1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS630120)的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物1(SIAIS630006)和中间体 LM(SIAIS292017;7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基甲磺酸酯; CAS登录号2570254-41-8)制备得到目标化合物(SIAIS630120)(白色固体,5.8mg,收率25%)。1H NMR(500MHz,DMSO-d6)δ11.00(s,1H),8.89(s,1H),8.72–8.61(m,1H),8.26(t,J=5.3Hz, 2H),7.71(t,J=8.2Hz,2H),7.65(d,J=7.5Hz,1H),7.57–7.46(m,2H),7.28(d,J=8.5Hz,2H), 7.01(d,J=8.4Hz,2H),6.82(d,J=15.9Hz,2H),5.16(dd,J=13.3,5.1Hz,1H),4.47(d,J=17.7Hz, 1H),4.33(d,J=17.7Hz,1H),3.89(d,J=13.0Hz,2H),3.55(br,4H),3.25-3.15(m,3H),3.15– 3.05(m,5H),2.95-2.87(m,1H),2.68–2.57(m,1H),2.56-2.53(m,1H),2.47–2.39(m,1H),2.06 -1.97(m,1H),1.84–1.75(m,2H),1.72-1.60(m,4H),1.52-1.43(m,5H),1.36-1.26(m,2H),1.25 -1.20(m,2H),1.09–0.98(m,2H).HRMS(ESI)C48H58N7O5 +[M+H]+,计算值812.4494;实测值, 812.4496.
实施例26:(E)-N-(4-(1-(4-(4-(8-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)辛-7-炔 -1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS630121)的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物1(SIAIS630006)和中间体 LM(SIAIS292020;8-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)辛-7-炔-1-基甲磺酸酯; CAS登录号2570254-42-9)制备得到目标化合物(SIAIS630121)(白色固体,5.7mg,收率24%)。1H NMR(500MHz,CD3OD)δ8.84(d,J=2.2Hz,1H),8.63(dd,J=5.2,1.5Hz,1H),8.37-8.32(m, 1H),7.75(d,J=6.6Hz,1H),7.71(dd,J=8.1,5.2Hz,1H),7.63–7.55(m,2H),7.51(t,J=7.6Hz, 1H),7.36(d,J=8.7Hz,2H),7.07(d,J=8.9Hz,2H),6.81(d,J=15.9Hz,1H),5.19(dd,J=13.3,5.2 Hz,1H),4.53(d,J=17.4Hz,1H),4.47(d,J=17.4Hz,1H),3.95(br,1H),3.67(br,2H),3.39-3.32 (m,6H),3.25–3.19(m,4H),3.18–3.11(m,2H),2.95-2.86(m,1H),2.84-2.75(m,1H),2.57–2.49 (m,3H),2.24-2.15(m,1H),1.86-1.80(m,2H),1.70(p,J=6.9Hz,3H),1.65–1.55(m,5H),1.53– 1.39(m,4H),1.37–1.27(m,3H),1.24-1.07(m,2H).HRMS(ESI)C49H60N7O5 +[M+H]+,计算值 826.4650;实测值,826.4655.
实施例27:(E)-N-(4-(1-(4-(4-(9-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)壬-8-炔 -1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS630122)的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物1(SIAIS630006)和中间体 LM(SIAIS255127;9-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)壬-8-炔-1-基甲磺酸酯; CAS登录号2600734-35-6)制备得到目标化合物(SIAIS630122)(白色固体,6.3mg,收率25%)。1H NMR(500MHz,CD3OD)δ8.75(s,1H),8.55(s,1H),8.13(d,J=8.0Hz,1H),7.75(dd,J=7.6, 1.0Hz,1H),7.61(dd,J=7.7,1.0Hz,1H),7.58–7.49(m,3H),7.36(dd,J=8.8,1.8Hz,2H),7.06 (dd,J=9.0,2.5Hz,2H),6.75(d,J=15.9Hz,1H),5.19(dd,J=13.4,5.2Hz,1H),4.53(d,J=17.4 Hz,1H),4.46(d,J=17.5Hz,1H),3.94(d,J=13.6Hz,2H),3.83(br,1H),3.64(d,J=11.9Hz,2H), 3.35–3.32(m,2H),3.25–3.16(m,4H),3.11(br,2H),2.98(s,2H),2.96–2.86(m,2H),2.84-2.76 (m,1H),2.61–2.48(m,2H),2.25-2.16(m,1H),1.83-1.75(m,3H),1.67(p,J=6.9Hz,3H),1.62- 1.53(m,4H),1.50–1.38(m,6H),1.37–1.27(m,4H),1.21–1.13(m,2H).HRMS(ESI)C50H62N7O5 + [M+H]+,计算值840.4807;实测值,840.4809.
实施例28:(2S,4R)-1-((S)-3,3-二甲基-2-(3-氧代-3-(4-(4-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)苯基)哌嗪-1-基)丙酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基) 吡咯烷-2-甲酰胺(SIAIS631001)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM:SIAIS352066制备得到目标化合物(SIAIS631001)(白色固体,11.9mg,收率31%)。1HNMR(500MHz,DMSO-d6)δ9.05(d,J=6.4Hz,2H),8.82(d,J=4.2Hz,1H),8.61(d,J=6.2Hz,2H),8.39(t,J=5.5Hz,1H),8.25(d,J=9.4Hz,1H),8.03–7.94(m,1H),7.55(d,J=15.9Hz,1H), 7.41(q,J=8.4Hz,4H),7.27(dd,J=8.6,5.2Hz,2H),7.02–6.91(m,3H),4.54(d,J=9.4Hz,1H), 4.47–4.39(m,3H),4.37-4.34(m,1H),4.25–4.19(m,1H),3.68(dd,J=10.6,4.1Hz,2H),3.64- 3.57(m,5H),3.54(d,J=15.5Hz,1H),3.49–3.42(m,2H),3.30–3.14(m,6H),3.13-3.07(m,1H), 2.94-2.67(m,2H),2.45(s,3H),2.07-2.00(m,1H),1.95-1.85(m1H),1.70-1.64(m,1H),1.46(p, J=7.1Hz,3H),1.35-1.28(m,2H),1.29–1.22(m,2H),1.09-0.99(m,2H),0.95(s,9H).。HRMS (ESI)C53H68N9O7S+[M+H]+,计算值974.4957;实测值,974.4959.
实施例29:(2S,4R)-1-((S)-3,3-二甲基-2-(4-氧代-4-(4-(4-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)苯基)哌嗪-1-基)丁酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基) 吡咯烷-2-甲酰胺(SIAIS631002)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(SIAIS074011;4-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷- 1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-4-氧代丁酸;CAS登录号2172819-72-4)制备得到目标化合物(SIAIS631002)(白色固体,11.5mg,收率30%)。1H NMR(500MHz,DMSO-d6)δ9.08(d, J=5.9Hz,2H),8.84(d,J=4.3Hz,1H),8.65(d,J=8.4Hz,1H),8.59(t,J=6.1Hz,1H),8.41(t,J= 5.5Hz,1H),8.02(dd,J=8.1,5.5Hz,1H),7.93(d,J=9.3Hz,1H),7.56(d,J=15.9Hz,1H),7.41(q, J=8.3Hz,4H),7.30–7.23(m,2H),7.06–6.92(m,3H),4.52(d,J=9.3Hz,1H),4.46–4.38(m,3H), 4.36–4.33(m,1H),4.26–4.18(m,1H),3.71–3.57(m,6H),3.45(t,J=5.3Hz,1H),3.28(t,J=5.3 Hz,1H),3.19(p,J=6.6,6.0Hz,5H),2.65–2.53(m,3H),2.45(s,3H),2.44–2.35(m,2H),2.06–2.00 (m,1H),1.95-1.85(m,1H),1.66(d,J=12.4Hz,2H),1.51–1.42(m,3H),1.36–1.28(m,2H),1.26 -1.21(m,2H),1.09–1.00(m,2H),0.93(s,9H).HRMS(ESI)C54H70N9O7S+[M+H]+,计算值988.5113;实测值,988.5116.
实施例30:(2S,4R)-1-((S)-3,3-二甲基-2-(5-氧代-5-(4-(4-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)苯基)哌嗪-1-基)戊酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基) 吡咯烷-2-甲酰胺(SIAIS631003)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(SIAIS074012;5-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷- 1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-5-氧代戊酸;CAS登录号2172819-73-5)制备得到目标化合物(SIAIS631003)(白色固体,12.8mg,收率33%)。1H NMR(500MHz,CD3OD)δ9.66(d,J= 19.2Hz,1H),9.08(d,J=2.0Hz,1H),8.86–8.77(m,2H),8.13(dd,J=8.2,5.8Hz,1H),7.64(d,J= 15.9Hz,1H),7.57–7.46(m,4H),7.36(d,J=8.9Hz,2H),7.12(d,J=8.3Hz,1H),7.08(d,J=8.8 Hz,1H),6.97(dd,J=15.9,1.0Hz,1H),4.62(d,J=1.8Hz,1H),4.59–4.52(m,2H),4.52–4.47(m, 1H),4.38(dd,J=15.7,3.6Hz,1H),3.97–3.88(m,1H),3.84–3.72(m,3H),3.54–3.48(m,3H), 3.41–3.32(m,12H),2.57(s,3H),2.48(t,J=7.5Hz,1H),2.40–2.34(m,2H),2.34–2.28(m,1H), 2.26–2.20(m,1H),2.11-2.04(m,1H),1.91(dt,J=17.0,7.5Hz,2H),1.60(p,J=6.8Hz,3H),1.47 –1.29(m,5H),1.21–1.11(m,2H),1.04(s,9H).HRMS(ESI)C55H72N9O7S+[M+H]+,计算值 1002.5270;实测值,1002.5273.
实施例31:(2S,4R)-1-((S)-3,3-二甲基-2-(6-氧代-6-(4-(4-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)苯基)哌嗪-1-基)己酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基) 吡咯烷-2-甲酰胺(SIAIS630007)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(SIAIS074013;6-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷- 1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-6-氧代己酸;CAS登录号2172819-74-6)制备得到目标化合物(SIAIS630007)(白色固体,13.4mg,收率34%)。1H NMR(500MHz,DMSO-d6)δ9.04- 8.98(m,2H),8.79–8.74(m,1H),8.57(t,J=6.1Hz,1H),8.53–8.42(m,1H),8.31(d,J=6.1Hz, 1H),7.86(d,J=9.4Hz,2H),7.53(dd,J=15.9,2.6Hz,1H),7.44–7.35(m,4H),7.27(dd,J=11.5, 8.6Hz,2H),7.02–6.94(m,2H),6.88(dd,J=15.9,7.5Hz,1H),4.54(d,J=9.4Hz,1H),4.47–4.39 (m,2H),4.38-4.32(m,1H),4.21(dd,J=15.9,5.5Hz,1H),3.65–3.57(m,10H),3.43(d,J=5.6Hz, 2H),3.25–3.14(m,6H),2.44(s,3H),2.37–2.33(m,1H),2.31–2.25(m,1H),2.20-2.11(m,1H), 2.06–2.00(m,1H),1.93-1.88(m,1H),1.69-1.61(m,2H),1.53-1.42m,7H),1.35-1.20(m,4H), 1.09-1.02(m,2H),0.93(s,9H).HRMS(ESI)C56H74N9O7S+[M+H]+,计算值1016.5426;实测值, 1016.5428.
实施例32:(2S,4R)-1-((S)-3,3-二甲基-2-(7-氧代-7-(4-(4-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)苯基)哌嗪-1-基)庚酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基) 吡咯烷-2-甲酰胺(SIAIS631004)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(SIAIS074014;7-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷- 1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-7-氧代庚酸;CAS登录号2162120-87-6)制备得到目标化合物(SIAIS631004)(白色固体,12.1mg,收率30%)。1H NMR(500MHz,DMSO-d6)δ9.08(d, J=2.0Hz,1H),9.06(d,J=3.2Hz,1H),8.83(d,J=4.3Hz,1H),8.64(d,J=8.3Hz,1H),8.58(t,J= 6.1Hz,1H),8.40(q,J=5.4Hz,1H),8.01(dd,J=8.2,5.5Hz,1H),7.85(dd,J=9.4,2.7Hz,1H),7.56 (d,J=15.9Hz,1H),7.44–7.34(m,4H),7.27(dd,J=8.8,2.5Hz,2H),7.05–6.91(m,3H),4.53(d, J=9.3Hz,1H),4.45–4.40(m,3H),4.36–4.32(m,1H),4.21(dd,J=15.9,5.5Hz,1H),3.71-3.56 (m,6H),3.45(dd,J=6.5,4.0Hz,1H),3.25(t,J=5.2Hz,1H),3.23-3.15(m,5H),2.95-2.65(m, 2H),2.44(s,3H),2.33(t,J=7.5Hz,1H),2.26-2.21(m,1H),2.19–2.08(m,1H),2.06–1.99(m, 1H),1.94-1.90(m,1H),1.72–1.62(m,2H),1.54–1.40(m,7H),1.35–1.20(m,7H),1.08-1.00(m, 2H),0.93(s,9H)..HRMS(ESI)C57H76N9O7S+[M+H]+,计算值1030.5583;实测值,1030.5585.
实施例33:(2S,4R)-1-((S)-3,3-二甲基-2-(8-氧代-8-(4-(4-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)苯基)哌嗪-1-基)辛酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基) 吡咯烷-2-甲酰胺(SIAIS631005)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(SIAIS074015;8-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷- 1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-8-氧代辛酸;CAS登录号2172819-75-7)制备得到目标化合物(SIAIS631005)(白色固体,14.8mg,收率36%)。1H NMR(500MHz,CD3OD)δ9.17(d,J= 23.5Hz,1H),9.03(d,J=2.0Hz,1H),8.84–8.70(m,2H),8.14–7.96(m,1H),7.63(d,J=15.8Hz, 1H),7.52–7.47(m,2H),7.46–7.43(m,2H),7.38–7.30(m,2H),7.05(dd,J=26.6,8.8Hz,2H), 6.92(d,J=15.8Hz,1H),4.64(s,1H),4.61–4.53(m,2H),4.50(s,1H),4.42–4.33(m,1H),3.91(d, J=11.0Hz,1H),3.80(dd,J=10.9,3.9Hz,1H),3.75-3.69(m,3H),3.53–3.47(m,1H),3.40–3.33 (m,12H),3.25(t,J=5.4Hz,1H),2.50(s,3H),2.45(t,J=7.6Hz,1H),2.34–2.26(m,2H),2.25– 2.19(m,1H),2.10-2.05(m,1H),1.67–1.55(m,8H),1.47–1.29(m,9H),1.20–1.12(m,2H),1.03 (s,9H).HRMS(ESI)C58H78N9O7S+[M+H]+,计算值1044.5739;实测值,1044.5741.
实施例34:(2S,4R)-1-((S)-3,3-二甲基-2-(9-氧代-9-(4-(4-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)苯基)哌嗪-1-基)壬酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基) 吡咯烷-2-甲酰胺(SIAIS631006)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(SIAIS074016;9-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷- 1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-9-氧代壬酸;CAS登录号2172819-76-8)制备得到目标化合物(SIAIS631006)(白色固体,18mg,收率43%)。1H NMR(500MHz,CD3OD)δ8.93(d,J= 7.1Hz,1H),8.90(d,J=2.1Hz,1H),8.68(dd,J=5.3,1.4Hz,1H),8.47(d,J=8.2Hz,1H),7.82(dd, J=8.1,5.4Hz,1H),7.60(d,J=15.9Hz,1H),7.47(d,J=8.1Hz,2H),7.42(d,J=8.3Hz,2H),7.32 (d,J=8.8Hz,2H),7.00(d,J=8.7Hz,2H),6.84(d,J=15.9Hz,1H),4.63(s,1H),4.58(d,J=8.7Hz, 1H),4.54(d,J=15.8Hz,1H),4.50(d,J=4.1Hz,1H),4.36(d,J=15.4Hz,1H),3.91(d,J=11.0Hz, 1H),3.80(dd,J=11.0,3.9Hz,1H),3.74-3.68(m,4H),3.40–3.33(m,12H),3.23(t,J=5.4Hz,1H), 2.48(s,3H),2.44(t,J=7.6Hz,1H),2.32-2.26(m,2H),2.26-2.19(m,1H),2.11-2.05(m,1H),1.65 -1.56(m,8H),1.41-1.31(m,11H),1.22–1.11(m,2H),1.03(s,9H).HRMS(ESI)C59H80N9O7S+ [M+H]+,计算值1058.5896;实测值,1058.5898.
实施例35:(2S,4R)-1-((S)-3,3-二甲基-2-(10-氧代-10-(4-(4-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)苯基)哌嗪-1-基)癸酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(SIAIS631007)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(SIAIS074019;10-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷- 1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-10-氧代癸酸;CAS登录号2172819-77-9)制备得到目标化合物(SIAIS631007)(白色固体,18.3mg,收率43%)。1H NMR(500MHz,DMSO-d6)δ9.11 –9.00(m,2H),8.84–8.73(m,1H),8.64–8.51(m,2H),8.36(t,J=5.6Hz,1H),7.96(dd,J=8.2,5.4 Hz,1H),7.83(d,J=9.3Hz,1H),7.55(d,J=15.9Hz,1H),7.45–7.36(m,4H),7.26(d,J=8.5Hz, 2H),6.99(dd,J=8.9,3.7Hz,2H),6.92(d,J=15.9Hz,1H),4.54(d,J=9.4Hz,1H),4.46–4.38(m, 3H),4.35(dd,J=4.8,2.5Hz,1H),4.21(dd,J=15.9,5.5Hz,1H),3.68–3.62(m,2H),3.59(d,J= 5.4Hz,4H),3.44(dd,J=6.6,3.9Hz,1H),3.26–3.14(m,6H),2.95-2.70(m,2H),2.44(s,3H),2.33 (t,J=7.5Hz,2H),2.28-2.20(m,1H),2.13-2.05(m,1H),2.07-2.00(m,1H),1.95-1.86(m,1H), 1.69-1.62(m,2H),1.52-1.42(m,7H),1.36–1.20(m,13H),1.10–0.98(m,2H),0.93(s,9H).HRMS (ESI)C60H82N9O7S+[M+H]+,计算值1072.6052;实测值,1072.6055.
实施例36:(2S,4R)-1-((S)-3,3-二甲基-2-(11-氧代-11-(4-(4-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)苯基)哌嗪-1-基)十一烷酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基) 苄基)吡咯烷-2-甲酰胺(SIAIS631008)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(SIAIS074020;11-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷- 1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-11-氧代十一烷酸;CAS登录号2172819-78-0)制备得到目标化合物(SIAIS631008)(白色固体,21mg,收率49%)。1H NMR(500MHz,DMSO-d6)δ9.10 –9.01(m,2H),8.83(dd,J=5.5,1.3Hz,1H),8.65–8.51(m,2H),8.38(t,J=5.6Hz,1H),8.00(dd,J =8.2,5.5Hz,1H),7.84(d,J=9.3Hz,1H),7.56(d,J=15.9Hz,1H),7.45–7.37(m,4H),7.28(d,J =8.6Hz,2H),7.01(d,J=8.8Hz,2H),6.94(d,J=15.9Hz,1H),4.54(d,J=9.4Hz,1H),4.48–4.40 (m,3H),4.38–4.33(m,1H),4.22(dd,J=15.9,5.6Hz,1H),3.68-3.59(m,6H),3.34–3.12(m,7H), 2.95-2.70(m,2H),2.45(s,3H),2.34(t,J=7.5Hz,2H),2.28-2.23(m,1H),2.13-2.08(m,1H),2.07 -2.00(m,1H),1.93-1.88(m,1H),1.67(d,J=12.8Hz,2H),1.55-1.43(m,8H),1.36–1.30(m,2H), 1.28-1.20(m,12H),1.08-0.99(m,2H),0.93(s,9H).HRMS(ESI)C61H84N9O7S+[M+H]+,计算值 1086.6209;实测值,1086.6211.
实施例37:(2S,4R)-1-((S)-3,3-二甲基-2-(2-(2-(2-氧代-2-(4-(4-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)苯基)哌嗪-1-基)乙氧基)乙氧基)乙酰氨基)丁酰基)-4-羟基-N-(4-(4- 甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(SIAIS631010)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(SIAIS151010;2-(2-(2-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-2-氧代乙氧基)乙氧基)乙酸;CAS登录号2172820- 08-3)制备得到目标化合物(SIAIS631010)(白色固体,14.1mg,收率34%)。1H NMR(500MHz, CD3OD)δ9.18(d,J=38.0Hz,1H),9.03(d,J=2.0Hz,1H),8.79(d,J=5.5Hz,1H),8.81-8.74(m, 1H),8.09-8.04(m,1H),7.63(d,J=15.9Hz,1H),7.53–7.39(m,4H),7.36(d,J=8.8Hz,1H),7.31 (d,J=8.8Hz,1H),7.08(d,J=8.9Hz,1H),6.99(d,J=8.9Hz,1H),6.93(dd,J=15.9,1.6Hz,1H), 4.70(d,J=8.3Hz,1H),4.61–4.54(m,2H),4.50(t,J=7.7Hz,1H),4.37(s,1H),4.06(dd,J=6.8, 2.2Hz,2H),3.88(d,J=10.8Hz,1H),3.81(dd,J=11.1,3.7Hz,1H),3.77–3.73(m,4H),3.73-3.69 (m,1H),3.53–3.49(m,2H),3.38(dd,J=6.6,3.9Hz,2H),3.35–3.32(m,11H),3.28–3.22(m,1H), 2.52(s,3H),2.24(dd,J=13.2,7.7Hz,1H),2.13-2.07(m,1H),1.78-1.70(m,1H),1.62–1.55(m, 3H),1.47-1.40(m,2H),1.38-1.30(m,2H),1.22–1.10(m,2H),1.04(s,9H).HRMS(ESI)C56H74N9O9S+[M+H]+,计算值1048.5325;实测值,1048.5327.
实施例38:(2S,4R)-1-((S)-3,3-二甲基-2-(3-(2-(3-氧代-3-(4-(4-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)苯基)哌嗪-1-基)丙氧基)乙氧基)丙酰氨基)丁酰基)-4-羟基-N-(4-(4- 甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(SIAIS631011)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(SIAIS151002;3-(2-(3-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-3-氧代丙氧基)乙氧基)丙酸;CAS登录号2172820- 09-4)制备得到目标化合物(SIAIS631011)(白色固体,14.2mg,收率33%)。1H NMR(500MHz, CD3OD)δ9.45(d,J=34.6Hz,1H),9.06(d,J=1.9Hz,1H),8.86-8.80(m,2H),8.11(dd,J=8.2, 5.8Hz,1H),7.64(d,J=15.8Hz,1H),7.55–7.44(m,4H),7.35(t,J=9.2Hz,2H),7.07(dd,J=11.4, 8.8Hz,2H),6.95(dd,J=15.8,1.8Hz,1H),4.65(s,1H),4.60–4.53(m,2H),4.52–4.47(m,1H), 4.37(d,J=15.7Hz,1H),3.89(d,J=10.9Hz,1H),3.84–3.67(m,9H),3.63–3.57(m,4H),3.51(dd, J=6.6,3.9Hz,1H),3.42–3.33(m,11H),3.27(d,J=5.3Hz,1H),2.71(t,J=6.3Hz,1H),2.53(s, 3H),2.48-2.42(m,1H),2.26-2.20(m,1H),2.12-2.04(m,1H),1.85-1.70(m,1H),1.59(p,J=7.2 Hz,3H),1.47-1.40(m,2H),1.38-1.30(m,2H),1.22–1.11(m,2H),1.03(s,9H).HRMS(ESI)C58H78N9O9S+[M+H]+,计算值1076.5638;实测值,1076.5641.
实施例39:(2S,4R)-1-((S)-2-(叔丁基)-4,16-二氧代-16-(4-(4-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)苯基)哌嗪-1-基)-7,10,13-三氧杂-3-氮杂十六烷酰基)-4-羟基-N-(4-(4- 甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(SIAIS631012)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(SIAIS151003;(S)-15-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1- 羰基)-16,16-二甲基-13-氧代-4,7,10-三氧杂-14-氮杂十七烷酸;CAS登录号2140807-42-5)制备得到目标化合物(SIAIS631012)(白色固体,14.8mg,收率34%)。1H NMR(500MHz,CD3OD)δ 9.52(d,J=11.8Hz,1H),9.00(d,J=2.0Hz,1H),8.74(dd,J=12.9,7.0Hz,2H),8.03(dd,J=8.2, 5.7Hz,1H),7.54(d,J=15.8Hz,1H),7.46–7.34(m,4H),7.31–7.23(m,2H),7.07(d,J=8.7Hz, 2H),7.00–6.95(m,1H),6.92(d,J=15.9Hz,1H),4.55(d,J=5.1Hz,1H),4.50–4.46(m,1H),4.45 –4.39(m,2H),4.28(d,J=15.8Hz,1H),3.81(d,J=11.1Hz,1H),3.75–3.59(m,8H),3.57–3.48 (m,10H),3.44–3.39(m,2H),3.34–3.23(m,7H),2.67(t,J=6.1Hz,1H),2.53–2.36(m,6H),2.17 –2.12(m,1H),2.01-1.95(m,1H),1.67(d,J=43.4Hz,2H),1.52-1.46(m,3H),1.34-1.30(m,2H), 1.27–1.20(m,2H),1.04(br,2H),0.94(s,9H).HRMS(ESI)C60H82N9O10S+[M+H]+,计算值 1120.5900;实测值,1120.5905.
实施例40:(2S,4R)-1-((S)-2-(叔丁基)-4,19-二氧代-19-(4-(4-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)苯基)哌嗪-1-基)-7,10,13,16-四氧杂-3-氮杂十九烷酰基)-4-羟基-N-(4- (4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(SIAIS631013)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(SIAIS151008;(S)-18-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1- 羰基)-19,19-二甲基-16-氧代-4,7,10,13-四氧杂-17-氮杂二十烷酸;CAS登录号2172820-12-9)制备得到目标化合物(SIAIS631013)(白色固体,15.2mg,收率33%)。1HNMR(500MHz,CD3OD) δ9.59(d,J=1.6Hz,1H),9.09(d,J=2.1Hz,1H),8.86-8.82(m,2H),8.17–8.09(m,1H),7.64(d, J=16.0Hz,1H),7.56–7.47(m,4H),7.39–7.29(m,2H),7.08(d,J=8.9Hz,2H),7.00(d,J=15.8 Hz,1H),4.65(s,1H),4.61–4.54(m,2H),4.52–4.50(m,1H),4.38(d,J=15.7Hz,1H),3.90(d,J= 12.1Hz,1H),3.84–3.78(m,2H),3.77-3.70(m,4H),3.67–3.59(m,12H),3.55–3.49(m,3H),3.40 –3.36(m,4H),3.36–3.28(m,6H),2.64–2.46(m,7H),2.28-2.20(m,1H),2.11-2.05(m,1H),1.81 (br,2H),1.60(p,J=6.9Hz,3H),1.46-1.40(m,2H),1.36-1.32(m,2H),1.20–1.10(m,2H),1.04 (s,9H).HRMS(ESI)C62H86N9O11S+[M+H]+,计算值1164.6162;实测值,1164.6165.
实施例41:(2S,4R)-1-((S)-2-(叔丁基)-4,22-二氧代-22-(4-(4-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)苯基)哌嗪-1-基)-7,10,13,16,19-五氧杂-3-氮杂二十二烷酰基)-4-羟基- N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(SIAIS631014)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(SIAIS151009;(S)-21-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1- 羰基)-22,22-二甲基-19-氧代-4,7,10,13,16-五氧杂-20-氮杂二十三烷酸;CAS登录号2172820-14- 1)制备得到目标化合物(SIAIS631014)(白色固体,17.6mg,收率36%)。1H NMR(500MHz, CD3OD)δ9.10(d,J=12.4Hz,1H),8.96(s,1H),8.75–8.61(m,2H),7.98(dd,J=8.2,5.7Hz,1H), 7.53(d,J=15.8Hz,1H),7.42–7.30(m,4H),7.25(dd,J=10.0,8.7Hz,2H),6.96(dd,J=15.0,8.8 Hz,2H),6.87(dd,J=15.9,2.0Hz,1H),4.55(s,1H),4.50–4.46(m,1H),4.45–4.39(m,2H),4.27 (d,J=15.6Hz,1H),3.83–3.75(m,1H),3.73–3.60(m,10H),3.55-3.50(m,18H),3.42-3.41(m, 1H),3.31–3.22(m,5H),3.18(t,J=5.3Hz,1H),2.63(t,J=6.1Hz,1H),2.53–2.43(m,2H),2.41- 2.37(m,4H),2.16-2.11(m,1H),2.05–1.95(m,1H),1.66(br,2H),1.52-1.46(m,3H),1.36-1.28 (m,2H),1.24-1.22(m,2H),1.10–1.02(m,2H),0.94(s,9H).HRMS(ESI)C64H90N9O12S+[M+H]+, 计算值1208.6424;实测值,1208.6427.
实施例42:(2S,4R)-1-((S)-3,3-二甲基-2-(16-氧代-16-(4-(4-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)苯基)哌嗪-1-基)十六烷酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基) 苄基)吡咯烷-2-甲酰胺(SIAIS630008)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(SIAIS164189)制备得到目标化合物(SIAIS630008)(白色固体,7.0mg,收率37%)。1HNMR(500MHz,CD3OD)δ8.87(s,1H),8.72(s,1H),8.65(s,1H),8.52(d,J=5.0Hz,1H),8.07(d, J=8.2Hz,1H),7.80(d,J=8.7Hz,1H),7.55(d,J=15.8Hz,1H),7.46(d,J=7.8Hz,3H),7.42– 7.39(m,2H),7.32(d,J=8.2Hz,1H),7.00(d,J=8.3Hz,1H),6.73(d,J=15.9Hz,1H),4.64(d,J= 6.1Hz,1H),4.58–4.47(m,3H),4.35(d,J=15.5Hz,1H),3.90(d,J=11.2Hz,1H),3.81-3.78(m, 1H),3.73-3.68(m,3H),3.63(d,J=10.5Hz,1H),3.55(d,J=17.9Hz,2H),3.45-3.44(m,1H),3.35 –3.32(m,6H),3.17-3.16(m,1H),2.47(s,3H),2.31–2.17(m,4H),2.10–2.02(m,2H),1.59(br, 10H),1.28(br,25H),1.03(s,9H).HRMS(ESI)C66H94N9O7S+[M+H]+,计算值1156.6991;实测值, 1156.6995.
实施例43:(E)-N-(4-(1-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基) 丁基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS631020)的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物1(SIAIS630006)和中间体 LM(SIAIS1222171;3-(4-(4-溴丁氧基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;CAS登录号 2641288-70-0)制备得到目标化合物(SIAIS631020)(白色固体,6.8mg,收率22%)。1HNMR (500MHz,CD3OD)δ8.90(d,J=2.2Hz,1H),8.67(dd,J=5.4,1.5Hz,1H),8.46(d,J=8.2Hz,1H), 7.81(dd,J=8.1,5.3Hz,1H),7.59(d,J=15.8Hz,1H),7.50(t,J=7.8Hz,1H),7.40(d,J=7.3Hz, 1H),7.35(d,J=8.8Hz,2H),7.23(d,J=8.1Hz,1H),7.07(d,J=8.9Hz,2H),6.86(d,J=15.8Hz, 1H),5.16(dd,J=13.3,5.2Hz,1H),4.51(d,J=17.3Hz,1H),4.43(d,J=17.3Hz,1H),4.23(t,J= 5.8Hz,2H),4.01-3.79(m,3H),3.70(br,2H),3.35–3.32(m,4H),3.29–3.21(m,6H),2.96-2.86 (m,1H),2.81-2.76(m,1H),2.56-2.47(m,1H),2.24-2.15(m,1H),2.10–2.01(m,2H),2.01–1.92 (m,2H),1.84–1.69(m,2H),1.59(p,J=7.1Hz,3H),1.47–1.39(m,2H),1.38–1.27(m,2H),1.16 (br,2H).HRMS(ESI)C45H56N7O6 +[M+H]+,计算值790.4287;实测值,790.4289.
实施例44:(E)-N-(4-(1-(4-(4-(8-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基) 辛基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS631024)的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物1(SIAIS630006)和中间体 LM(SIAIS1222063)制备得到目标化合物(SIAIS631024)(白色固体,5.4mg,16%)。1HNMR (500MHz,DMSO-d6)δ11.10(s,1H),10.97(s,1H),9.03(s,1H),8.80(d,J=5.4Hz,1H),8.55(d,J =8.1Hz,1H),8.37(t,J=5.6Hz,1H),7.94(t,J=6.9Hz,1H),7.54(d,J=15.9Hz,1H),7.47(t,J= 7.8Hz,1H),7.29(dd,J=10.4,8.0Hz,3H),7.24(d,J=8.2Hz,1H),7.01(d,J=8.6Hz,2H),6.92(d, J=15.9Hz,1H),5.11(dd,J=13.3,5.1Hz,1H),4.37(d,J=17.3Hz,1H),4.22(d,J=17.4Hz,1H), 4.12(t,J=6.4Hz,2H),3.88(d,J=13.0Hz,2H),3.53(d,J=11.8Hz,2H),3.29–3.15(m,5H),3.11 –3.01(m,5H),2.95-2.86(m,2H),2.64–2.52(m,1H),2.48–2.42(m,1H),2.05-1.95(m,1H),1.79 –1.70(m,4H),1.66(br,2H),1.46(p,J=6.9Hz,5H),1.39–1.29(m,9H),1.27–1.19(m,2H),1.10 -1.00(m,2H)..HRMS(ESI)C49H64N7O6 +[M+H]+,计算值846.4913;实测值,846.4915.
实施例45:(E)-N-(4-(4-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔 -1-基)哌嗪-1-基)苯甲酰基)哌嗪-1-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS631045)的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物2(SIAIS630020)和中间体LM(SIAIS292017;7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基甲磺酸酯; CAS登录号2570254-41-8))制备得到目标化合物(SIAIS631045)(白色固体,12.4mg,收率39%)。1H NMR(500MHz,CD3OD)δ9.00(s,1H),8.75(s,1H),8.65(s,1H),7.96(s,1H),7.75(dd,J=7.6, 1.1Hz,1H),7.69–7.58(m,2H),7.51(t,J=7.7Hz,1H),7.47(d,J=8.8Hz,2H),7.10(d,J=8.9Hz, 2H),6.95(d,J=14.5Hz,1H),5.19(dd,J=13.3,5.2Hz,1H),4.54(d,J=17.4Hz,1H),4.48(d,J= 17.5Hz,1H),3.99(d,J=12.8Hz,2H),3.69(d,J=11.4Hz,2H),3.63(br,1H),3.40(t,J=6.9Hz, 3H),3.27-3.23(m,6H),3.21–3.15(m,4H),2.97-2.88(m,1H),2.83-2.75(m,2H),2.57(t,J=6.9 Hz,2H),2.53(dd,J=13.3,4.6Hz,1H),2.22-2.17(m,1H),1.93–1.84(m,5H),1.75-1.60(m,8H), 1.29(br,1H).HRMS(ESI)C47H57N8O5 +[M+H]+,计算值813.4446;实测值,813.4449.
实施例46:(E)-N-(4-(1-(4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS631068)的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物1(SIAIS630006)和中间体 LM(4-((2-溴乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮二氧代哌啶;CAS登录号 2378582-68-2)制备得到目标化合物(SIAIS631068)(黄色固体,11.6mg,收率37%)。1H NMR (500MHz,CD3OD)δ8.75(s,1H),8.56(s,1H),8.14(s,1H),7.84(d,J=5.9Hz,2H),7.78(dd,J=5.7, 2.4Hz,1H),7.56(d,J=14.0Hz,1H),7.36(d,J=8.7Hz,2H),7.08(d,J=8.6Hz,2H),6.75(d,J= 16.6Hz,1H),5.16(dd,J=12.8,5.4Hz,1H),3.63–3.50(m,12H),3.35(br,4H),2.85(br,2H),2.87 -2.85(m,1H),2.25–2.04(m,1H),1.89(br,1H),1.68–1.55(m,4H),1.42(br,2H),1.39–1.27(m, 3H),1.22–1.11(m,2H).HRMS(ESI)C43H50N7O6S+[M+H]+,计算值792.3538;实测值,792.3539.
实施例47:(E)-N-(4-(1-(4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS631069)的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物1(SIAIS630006)和中间体 LM(4-((3-溴丙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;CAS登录号2378582-69-3) 制备得到目标化合物(SIAIS631069)(黄色固体,6.9mg,收率22%)。1H NMR(500MHz, CD3OD)δ8.86(s,1H),8.65(d,J=5.0Hz,1H),8.39(d,J=8.5Hz,1H),7.83–7.77(m,3H),7.72– 7.66(m,1H),7.59(d,J=15.8Hz,1H),7.35(d,J=8.8Hz,2H),7.07(d,J=8.9Hz,2H),6.82(d,J= 15.9Hz,1H),5.14(dd,J=12.8,5.5Hz,1H),3.96(br,2H),3.71–3.61(m,2H),3.47–3.40(m,4H), 3.30-2.28(m,8H),2.92-2.85(m,1H),2.81–2.68(m,1H),2.25-2.20(m,2H),2.19–2.10(m,1H), 1.82(br,1H),1.62-1.57(m,4H),1.47–1.38(m,2H),1.36-1.29(m,4H),1.18(br,2H).HRMS(ESI) C44H52N7O6S+[M+H]+,计算值806.3694;实测值,806.3699.
实施例48:(E)-N-(4-(1-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丁基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS631070)的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物1(SIAIS630006)和中间体 LM(4-((4-溴丁基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;CAS登录号2378582-70-6) 制备得到目标化合物(SIAIS631070)(黄色固体,7.1mg,收率22%)。1H NMR(500MHz, CD3OD)δ8.75(s,1H),8.54(s,1H),8.26(s,1H),7.66(d,J=4.6Hz,3H),7.60–7.53(m,1H),7.48 (d,J=15.8Hz,1H),7.26(d,J=8.8Hz,2H),6.97(d,J=8.9Hz,2H),6.71(d,J=15.8Hz,1H),5.03 (dd,J=12.8,5.5Hz,1H),3.87(br,2H),3.58(br,2H),3.18-3.14(m,6H),3.04(br,3H),2.79–2.74 (m,1H),2.66–2.60(m,1H),2.07–1.98(m,1H),1.96–1.83(m,2H),1.80-1.74(m,5H),1.49(p,J =7.2Hz,4H),1.33-1.30(m,3H),1.28–1.17(m,4H),1.07(br,3H).HRMS(ESI)C45H54N7O6S+ [M+H]+,计算值820.3851;实测值,820.3856.
实施例49:(E)-N-(4-(1-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS631071)的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物1(SIAIS630006)和中间体 LM(4-((5-溴戊基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;CAS登录号2378582-71-7) 制备得到目标化合物(SIAIS631071)(黄色固体,5.9mg,收率18%)。1H NMR(500MHz, CD3OD)δ8.98(s,1H),8.75(s,1H),8.65(s,1H),7.97(s,1H),7.79–7.69(m,2H),7.70–7.55(m, 2H),7.45–7.22(m,2H),7.07(d,J=8.8Hz,2H),6.89(d,J=16.0Hz,1H),5.12(dd,J=12.7,5.5 Hz,1H),3.97(d,J=13.4Hz,2H),3.68(d,J=12.1Hz,2H),3.34(dd,J=8.1,1.6Hz,6H),3.27– 3.06(m,9H),2.88-2.84(m,1H),2.78–2.66(m,1H),2.19–2.06(m,1H),1.86(p,J=7.8Hz,4H), 1.67-1.56(m,4H),1.43(br,2H),1.38–1.26(m,4H),1.16(br,3H).HRMS(ESI)C46H56N7O6S+ [M+H]+,计算值834.4007;实测值,834.4009.
实施例50:(E)-N-(4-(1-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS631072)的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物1(SIAIS630006)和中间体 LM(4-((6-溴己基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;CAS登录号2378586-19-5) 制备得到目标化合物(SIAIS631072)(黄色固体,6.9mg,收率21%)。1H NMR(500MHz, CD3OD)δ8.81(d,J=2.2Hz,1H),8.60(dd,J=5.2,1.5Hz,1H),8.28(dt,J=8.0,1.9Hz,1H),7.76 –7.70(m,3H),7.64–7.53(m,2H),7.36(d,J=8.8Hz,2H),7.07(d,J=8.9Hz,2H),6.80(d,J=15.8 Hz,1H),5.12(dd,J=12.7,5.5Hz,1H),3.98-3.82(m,3H),3.67(br,2H),3.33(d,J=7.3Hz,2H), 3.24–3.15(m,12H),2.91–2.81(m,1H),2.81–2.71(m,1H),2.19–2.08(m,1H),1.86-1.79(m 5H),1.66-1.58(m,4H),1.52-1.48(m,4H),1.44-1.40(m,2H),1.36-1.32(m,2H),1.16(br,2H). HRMS(ESI)C47H58N7O6S+[M+H]+,计算值848.4164;实测值,848.4168.
实施例51:(E)-N-(4-(1-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)庚基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS631078)的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物1(SIAIS630006)和中间体 LM(4-((7-溴庚基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;CAS登录号2378586-22-0) 制备得到目标化合物(SIAIS631078)(黄色固体,7.1mg,收率21%)。1H NMR(500MHz, DMSO-d6)δ11.12(s,1H),10.69(s,1H),8.87(s,1H),8.66(d,J=5.0Hz,1H),8.30–8.17(m,2H), 7.83–7.71(m,2H),7.70-7.61(m,2H),7.48(d,J=15.9Hz,1H),7.28(d,J=8.6Hz,2H),7.01(d,J =8.9Hz,2H),6.81(d,J=16.0Hz,1H),5.11(dd,J=12.9,5.4Hz,1H),3.89(d,J=12.9Hz,2H),3.54 (d,J=12.0Hz,2H),3.25–3.03(m,10H),2.94-2.85(m,1H),2.64-2.56(m 1H),2.55-2.52(m,1H), 2.10-2.02(m,1H),1.79–1.61(m,6H),1.46(h,J=7.5Hz,5H),1.39–1.20(m,9H),1.12–0.98(m, 2H).HRMS(ESI)C48H60N7O6S+[M+H]+,计算值862.4320;实测值,862.4324.
实施例52:(E)-N-(4-(1-(4-(4-(8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)辛基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS631073)的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物1(SIAIS630006)和中间体 LM(SIAIS1224003)制备得到目标化合物(SIAIS631073)(黄色固体,7.7mg,收率22%)。1H NMR(500MHz,CD3OD)δ8.81(d,J=2.3Hz,1H),8.60(dd,J=5.1,1.5Hz,1H),8.27(dt,J=8.0, 1.9Hz,1H),7.77–7.68(m,3H),7.63–7.54(m,2H),7.36(d,J=8.8Hz,2H),7.07(d,J=8.9Hz, 2H),6.80(d,J=15.9Hz,1H),5.12(dd,J=12.7,5.5Hz,1H),3.96-3.82(m,3H),3.67(br,2H),3.33 (d,J=7.4Hz,2H),3.24–3.10(m,11H),2.89-2.84(m,1H),2.77-2.75(m,1H),2.75–2.66(m,1H), 2.16-2.11(m,1H),1.79(q,J=7.3Hz,5H),1.65–1.52(m,6H),1.43(s,8H),1.37–1.26(m,2H), 1.16(br,2H).HRMS(ESI)C49H62N7O6S+[M+H]+,计算值876.4477;实测值,876.4478.
实施例53:(E)-N-(4-(1-(4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS632027)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(SIAIS151045;2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙酸;CAS登录号2378582-26-2)制备得到目标化合物(SIAIS632027)(黄色固体,8.7mg,收率32%)。1H NMR (500MHz,CD3OD)δ9.01(s,1H),8.77(d,J=4.6Hz,1H),8.71(dt,J=8.3,1.7Hz,1H),8.02(dd,J =8.3,5.6Hz,1H),7.85(d,J=8.2Hz,1H),7.77–7.70(m,1H),7.69–7.60(m,2H),7.33(d,J=8.8 Hz,2H),7.02(d,J=8.9Hz,2H),6.91(d,J=15.8Hz,1H),5.12(dd,J=12.7,5.5Hz,1H),4.20(s, 2H),3.79(dt,J=42.2,5.4Hz,5H),3.38(t,J=5.2Hz,2H),3.34(d,J=7.0Hz,3H),3.27(t,J=5.4 Hz,2H),2.93-2.83(m,2H),2.79–2.66(m,3H),2.18-2.10(m,1H),1.76(br,2H),1.59(p,J=7.3 Hz,3H),1.47–1.39(m,2H),1.36-1.31(m,2H),1.21–1.10(m,2H).HRMS(ESI)C43H48N7O7S+ [M+H]+,计算值806.3330;实测值,806.3335.
实施例54:(E)-N-(4-(1-(4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS632028)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(SIAIS151138B;3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙酸;CAS登录号2378582-27-3)制备得到目标化合物(SIAIS632028)(黄色固体,8.6mg,收率27%)。1H NMR (500MHz,DMSO-d6)δ11.12(s,1H),9.03(s,1H),8.79(d,J=5.4Hz,1H),8.53(d,J=7.8Hz,1H), 8.34(s,1H),7.95–7.85(m,1H),7.85–7.76(m,2H),7.64(dd,J=6.3,1.7Hz,1H),7.54(d,J=15.9 Hz,1H),7.26(d,J=8.6Hz,2H),6.96(d,J=8.5Hz,2H),6.90(d,J=15.9Hz,1H),5.11(dd,J=12.9, 5.4Hz,1H),3.60(d,J=25.7Hz,6H),3.35(t,J=7.1Hz,2H),3.25-3.15(m,6H),2.95–2.80(m, 5H),2.63-2.55(m,1H),2.52(br,1H),2.07-1.96(m,1H),1.66(d,J=12.4Hz,2H),1.51-1.40(m, 3H),1.35-1.20(m,4H),1.10-0.95(m,2H).HRMS(ESI)C44H50N7O7S+[M+H]+,计算值820.3487;实测值,820.3489.
实施例55:(E)-N-(4-(1-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS632029)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(SIAIS151140B;5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊酸;CAS登录号2378582-29-5)制备得到目标化合物(SIAIS632029)(黄色固体,9.1mg,收率28%)。1H NMR (500MHz,DMSO-d6)δ11.12(s,1H),8.97(s,1H),8.74(d,J=5.3Hz,1H),8.43(d,J=8.1Hz,1H), 8.29(t,J=5.7Hz,1H),7.83(t,J=6.7Hz,1H),7.80–7.75(m,2H),7.62(dd,J=6.3,1.8Hz,1H), 7.52(d,J=15.8Hz,1H),7.26(d,J=8.5Hz,2H),6.96(d,J=8.7Hz,2H),6.86(d,J=15.9Hz,1H), 5.11(dd,J=12.8,5.4Hz,1H),3.63–3.57(m,5H),3.29–3.12(m,8H),2.96-2.81(m,3H),2.64- 2.67(m,1H),2.54-2.51(m,1H),2.45–2.41(m,2H),2.08-2.00(m,1H),1.73–1.67(m,7H),1.51 -1.43(m,3H),1.36–1.28(m,2H),1.26-1.20(m,2H),1.10-0.98(m,2H).HRMS(ESI)C46H54N7O7S+ [M+H]+,计算值848.3800;实测值,848.3806.
实施例56:(E)-N-(4-(1-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS632030)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(SIAIS151141B;6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己酸;CAS登录号2378582-30-8)制备得到目标化合物(SIAIS632030)(黄色固体,8.8mg,收率26%)。1H NMR (500MHz,DMSO-d6)δ11.12(s,1H),9.01(d,J=9.5Hz,1H),8.78(t,J=5.6Hz,1H),8.55–8.45 (m,1H),8.37–8.29(m,1H),7.97–7.86(m,1H),7.83–7.72(m,2H),7.61(d,J=6.9Hz,1H),7.54 (dd,J=15.9,2.5Hz,1H),7.26(d,J=8.4Hz,2H),6.97(dd,J=8.9,3.1Hz,2H),6.94–6.86(m,1H), 5.11(dd,J=12.9,5.4Hz,1H),3.59(d,J=5.4Hz,5H),3.25-3.17(m,6H),3.13(t,J=7.3Hz,2H), 2.95-2.82(m,3H),2.63-2.57(m,1H),2.53-2.51(m,1H),2.37(t,J=7.3Hz,2H),2.08-2.03(m, 1H),1.75–1.62(m,4H),1.56(q,J=7.4Hz,2H),1.51-1.45(m,5H),1.36–1.18(m,4H),1.08-0.97 (m,2H).HRMS(ESI)C47H56N7O7S+[M+H]+,计算值862.3956;实测值,862.3959.
实施例57:(E)-N-(4-(1-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)庚酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS632031)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(SIAIS151142B;7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)庚酸;CAS登录号2378582-31-9)制备得到目标化合物(SIAIS632031)(黄色固体,10.1mg,收率29%)。1H NMR(500MHz,DMSO-d6)δ11.12(s,1H),9.00(s,1H),8.76(t,J=5.1Hz,1H),8.47(br,1H),8.31 (br,1H),7.87(br,1H),7.76(dt,J=15.9,8.0Hz,2H),7.62(d,J=6.9Hz,1H),7.53(d,J=15.9Hz, 1H),7.26(d,J=8.6Hz,2H),6.96(d,J=7.4Hz,1H),6.91–6.82(m,1H),5.11(dd,J=12.8,5.4Hz, 1H),3.58(d,J=5.5Hz,5H),3.25-3.15(m,6H),3.13(t,J=7.3Hz,2H),2.95–2.79(m,3H),2.62- 2.57(m,1H),2.53(d,J=4.6Hz,1H),2.35(t,J=7.4Hz,2H),2.08-2.04(m,1H),1.66(q,J=7.2 Hz,4H),1.56–1.42(m,8H),1.40–1.28(m,4H),1.26-1.22(m,2H),1.08-1.00(m,2H).HRMS (ESI)C48H58N7O7S+[M+H]+,计算值876.4113;实测值,876.4116.
实施例58:(E)-N-(4-(1-(4-(4-(8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)辛酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS632032)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)辛酸;CAS登录号2378585-62-5) 制备得到目标化合物(SIAIS632032)(黄色固体,10mg,收率28%)。1H NMR(500MHz, DMSO-d6)δ11.12(s,1H),9.03(s,1H),8.80(d,J=5.1Hz,1H),8.55(d,J=8.1Hz,1H),8.34(d,J= 5.3Hz,1H),7.98–7.90(m,1H),7.84–7.69(m,2H),7.62(d,J=6.9Hz,1H),7.54(d,J=15.9Hz, 1H),7.26(d,J=8.7Hz,2H),6.98(d,J=9.2Hz,2H),6.90(d,J=15.9Hz,1H),5.11(dd,J=12.9, 5.4Hz,1H),3.59(t,J=5.2Hz,5H),3.26–3.17(m,5H),3.12(t,J=7.3Hz,2H),2.94–2.79(m,3H), 2.64-2.56(m,1H),2.53(d,J=4.8Hz,1H),2.34(t,J=7.5Hz,2H),2.09-2.00(m,1H),1.72–1.58 (m,4H),1.55-1.41(m,8H),1.37–1.19(m,8H),1.09-1.00(m,2H).HRMS(ESI)C49H60N7O7S+ [M+H]+,计算值890.4269;实测值,890.4275.
实施例59:(E)-N-(4-(1-(4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)乙酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS632033)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)乙酸;CAS登录号1061605-21-7) 制备得到目标化合物(SIAIS632033)(淡黄色固体,7.3mg,收率24%)。1HNMR(500MHz, DMSO-d6)δ11.11(s,1H),9.01(s,1H),8.78(d,J=5.4Hz,1H),8.51(d,J=7.3Hz,1H),8.33(t,J= 5.6Hz,1H),7.90(p,J=4.0Hz,1H),7.78(dd,J=8.6,7.2Hz,1H),7.54(d,J=15.9Hz,1H),7.45(d, J=7.2Hz,1H),7.38(s,1H),7.27(d,J=8.7Hz,2H),6.99(d,J=8.5Hz,2H),6.89(dd,J=15.8,1.9 Hz,1H),5.24(s,2H),5.10(dd,J=12.8,5.5Hz,1H),3.61(d,J=5.1Hz,5H),3.41–3.12(m,7H), 2.95-2.78(m,3H),2.64-2.57(m,1H),2.54(d,J=4.3Hz,1H),2.06-1.99(m,1H),1.67(br,2H), 1.52-1.40(m,3H),1.36-1.28(m,2H),1.28-1.20(q,J=6.9Hz,2H),1.08-1.00(m,2H).。HRMS (ESI)C43H48N7O8 +[M+H]+,计算值790.3559;实测值,790.3562.
实施例60:(E)-N-(4-(1-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)戊酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS632034)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)戊酸;CAS登录号2169266-67-3) 制备得到目标化合物(SIAIS632034)(淡黄色固体,8.7mg,收率26%)。1HNMR(500MHz, CD3OD)δ8.99(d,J=2.0Hz,1H),8.75(d,J=5.5Hz,1H),8.67(dt,J=8.3,1.7Hz,1H),7.98(dd,J =8.2,5.5Hz,1H),7.77(dd,J=8.5,7.3Hz,1H),7.62(d,J=15.8Hz,1H),7.44(dd,J=7.9,6.7Hz, 2H),7.39–7.30(m,2H),6.99(d,J=8.9Hz,2H),6.90(d,J=15.9Hz,1H),5.07(dd,J=12.5,5.5 Hz,1H),4.28(t,J=5.7Hz,2H),3.79–3.60(m,4H),3.35-3.30(m,6H),3.24-3.22(m,4H),2.88– 2.77(m,2H),2.71–2.60(m,3H),2.13–2.05(m,1H),1.98–1.86(m,4H),1.77(br,2H),1.59(p,J =7.2Hz,3H),1.47–1.39(m,2H),1.36-1.32(m,2H),1.16(br,2H).HRMS(ESI)C46H54N7O8 + [M+H]+,计算值832.4028;实测值,832.4029.
实施例61:(E)-N-(4-(1-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)己酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS632035)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)己酸;CAS登录号2087490-48-8) 制备得到目标化合物(SIAIS632035)(淡黄色固体,7.2mg,收率21%)。1HNMR(500MHz, DMSO-d6)δ11.10(s,1H),8.97(d,J=10.8Hz,1H),8.74(q,J=5.5Hz,1H),8.40(s,1H),8.28(d,J =7.5Hz,1H),7.80(dd,J=8.5,7.2Hz,2H),7.56–7.49(m,2H),7.43(d,J=7.2Hz,1H),7.25(d,J =8.4Hz,2H),6.97-6.93(m,2H),6.84(d,J=15.1Hz,1H),5.07(dd,J=12.8,5.5Hz,1H),4.21(t,J =6.3Hz,2H),3.62–3.56(m,7H),3.25-3.15(m,6H),2.90-2.85(m,2H),2.62–2.55(m,1H),2.53 –2.51(m,1H),2.38(t,J=7.4Hz,2H),2.06-1.99(m,1H),1.81-1.76(m,2H),1.71–1.55(m,4H), 1.53-1.42(m,5H),1.35-1.21(m,4H),1.09-1.00(m,2H).HRMS(ESI)C47H56N7O8 +[M+H]+,计算值846.4185;实测值,846.4189.
实施例62:(E)-N-(4-(1-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)庚酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS632036)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)庚酸;CAS登录号2169266-69-5) 制备得到目标化合物(SIAIS632036)(淡黄色固体,9.6mg,收率26%)。1HNMR(500MHz, DMSO-d6)δ11.10(s,1H),8.97(d,J=5.4Hz,1H),8.74(d,J=5.1Hz,1H),8.41(d,J=8.5Hz,1H), 8.33–8.24(m,1H),7.81(dd,J=8.6,7.3Hz,2H),7.60–7.49(m,2H),7.44(d,J=7.3Hz,1H),7.26 (d,J=8.7Hz,2H),6.96(d,J=8.4Hz,2H),6.85(d,J=15.9Hz,1H),5.08(dd,J=12.7,5.4Hz,1H), 4.21(t,J=6.4Hz,2H),3.62-3.57(m,7H),3.26-3.13(m,6H),2.92-2.83(m,1H),2.61–2.55(m, 1H),2.54–2.52(m,1H),2.36(t,J=7.4Hz,2H),2.06-1.98(m,1H),1.80-1.74(m,2H),1.71-1.64 (m,2H),1.57–1.43(m,7H),1.42–1.28(m,4H),1.27-1.21(m,2H),1.11–0.99(m,2H).HRMS (ESI)C48H58N7O8 +[M+H]+,计算值860.4341;实测值,860.4346.
实施例63:(E)-N-(4-(1-(4-(1-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS631139)的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物3(SIAIS631127)和中间体 LM(SIAIS292017;7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基甲磺酸酯; CAS登录号2570254-41-8)制备得到目标化合物(SIAIS631139)(白色固体,7.7mg,收率23%)。1H NMR(500MHz,DMSO-d6)δ11.00(s,1H),10.62(s,1H),8.95(d,J=2.3Hz,1H),8.73(d,J=5.5Hz,1H),8.39(d,J=8.1Hz,1H),8.34–8.27(m,1H),7.80(dd,J=8.2,5.3Hz,1H),7.71(d,J= 7.5Hz,1H),7.65(d,J=7.6Hz,1H),7.57–7.47(m,2H),7.36–7.23(m,4H),6.86(d,J=15.9Hz, 1H),5.16(dd,J=13.3,5.1Hz,1H),4.47(d,J=17.7Hz,1H),4.33(d,J=17.7Hz,1H),3.57-3.52 (m,2H),3.18(q,J=6.6Hz,2H),3.09–2.81(m,8H),2.72(br,1H),2.63–2.55(m,1H),2.53(t,J= 7.1Hz,2H),2.48–2.43(m,1H),2.10(d,J=12.6Hz,1H),2.06-2.00(m,1H),1.99–1.94(m,1H), 1.85–1.76(m,2H),1.62(q,J=7.2Hz,3H),1.53-1.43(m,5H),1.35-1.22(m,4H),1.05(br,2H).。 HRMS(ESI)C49H59N6O5 +[M+H]+,计算值811.4541;实测值,811.4544.
实施例64:(E)-N-(4-(1-(4-(1-(8-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)辛-7-炔 -1-基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS631140)的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物3(SIAIS631127)和中间体 LM(SIAIS292020;8-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)辛-7-炔-1-基甲磺酸酯; CAS登录号2570254-42-9)制备得到目标化合物(SIAIS631140)(白色固体,10.1mg,收率31%)。1H NMR(500MHz,DMSO-d6)δ11.01(s,1H),8.90(s,1H),8.69(s,1H),8.27(s,2H),7.71(d,J= 7.5Hz,2H),7.64(d,J=7.5Hz,1H),7.56–7.47(m,2H),7.36–7.25(m,4H),6.82(d,J=16.2Hz, 1H),5.16(dd,J=13.3,5.1Hz,1H),4.46(d,J=17.7Hz,1H),4.33(d,J=17.7Hz,1H),3.59–3.51 (m,2H),3.18(q,J=6.6Hz,2H),3.09–2.80(m,8H),2.73(br,1H),2.65–2.57(m,1H),2.52(br,2H), 2.49–2.42(m,1H),2.12–2.01(m,2H),1.97(d,J=13.6Hz,1H),1.76(br,2H),1.61(p,J=7.1Hz, 3H),1.53–1.42(m,5H),1.40-1.27(m,4H),1.27-1.21(m,2H),1.05(br,2H).HRMS(ESI) C50H61N6O5 +[M+H]+,计算值825.4698;实测值,825.4702.
实施例65:(E)-N-(4-(1-(4-(1-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基) 丁基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS631141)的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物3(SIAIS631127)和中间体 LM(SIAIS213134;3-(4-(4-溴丁基硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;CAS登录号 2378582-59-1)制备得到目标化合物(SIAIS631141)(白色固体,9.7mg,收率30%)。1HNMR (500MHz,CD3OD)δ8.96(s,1H),8.72(s,1H),8.58(d,J=8.2Hz,1H),7.91(dd,J=8.2,5.4Hz, 1H),7.77–7.64(m,2H),7.63–7.52(m,2H),7.37(s,4H),6.90(d,J=15.9Hz,1H),5.18(dd,J= 13.4,5.2Hz,1H),4.50(d,J=17.4Hz,1H),4.43(d,J=17.4Hz,1H),3.75–3.63(m,4H),3.34(d,J =7.0Hz,2H),3.23–3.04(m,7H),3.02–2.91(m,1H),2.86–2.76(m,1H),2.59–2.51(m,1H),2.25 -2.17(m,1H),2.14–1.93(m,7H),1.87(br,1H),1.78-1.72(m,2H),1.71–1.64(m,1H),1.59(p,J =7.2Hz,4H),1.47–1.38(m,3H),1.37–1.28(m,3H),1.26–1.08(m,2H).HRMS(ESI) C46H57N6O5S++[M+H]+,计算值805.4106;实测值,805.4107.
实施例66:(E)-N-(4-(1-(6-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6- 炔-1-基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS632005) 的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物5(SIAIS631135)和中间体LM(SIAIS292017;7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基甲磺酸酯; CAS登录号2570254-41-8)制备得到目标化合物(SIAIS631139)(白色固体,8.3mg,收率24%)。1H NMR(500MHz,DMSO-d6)δ10.99(s,1H),9.00(s,1H),8.76(s,1H),8.48(s,1H),8.34(s,1H), 7.88(br,1H),7.71(d,J=7.6Hz,1H),7.65(dd,J=7.7,1.1Hz,2H),7.58(br,1H),7.55–7.53(m, 1H),7.51(d,J=7.4Hz,1H),6.90(d,J=15.2Hz,1H),5.15(dd,J=13.3,5.1Hz,1H),4.62(d,J= 13.1Hz,2H),4.47(d,J=17.7Hz,2H),4.33(d,J=17.7Hz,1H),3.94(d,J=13.0Hz,2H),3.72(br, 5H),3.52(br,2H),3.25–2.98(m,8H),2.96-2.87(m,1H),2.78(t,J=12.6Hz,1H),2.67–2.55(m, 1H),2.52(d,J=7.3Hz,2H),2.49–2.46(m,1H),2.23(d,J=11.6Hz,2H),2.05-1.97(m,1H),1.82- 1.72(m,5H),1.67-1.54(m,4H),1.53-1.43(m,4H),1.36-1.29(m,2H),1.28–1.22(m,2H),1.16 -1.05(m,2H).HRMS(ESI)C51H65N10O5 +[M+H]+,计算值897.5134;实测值,897.5138.
实施例67:(E)-N-(4-(1-(6-(4-(4-(8-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)辛-7- 炔-1-基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS632006) 的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物5(SIAIS631135)和中间体 LM(SIAIS292020;8-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)辛-7-炔-1-基甲磺酸酯; CAS登录号2570254-42-9)制备得到目标化合物(SIAIS632006)(白色固体,9.3mg,收率26%)。1H NMR(500MHz,DMSO-d6)δ11.00(s,1H),8.97(s,1H),8.74(s,1H),8.38(d,J=49.8Hz,2H), 7.83(br,1H),7.71(d,J=7.6Hz,1H),7.67–7.59(m,2H),7.56–7.48(m,3H),6.88(d,J=16.3Hz, 1H),5.15(dd,J=13.3,5.1Hz,1H),4.62(d,J=13.1Hz,2H),4.47(dd,J=16.0,10.9Hz,2H),4.32 (d,J=17.6Hz,1H),3.95(d,J=13.5Hz,2H),3.73(br,5H),3.52(br,2H),3.23–2.98(m,8H),2.95- 2.85(m,1H),2.83–2.74(m,1H),2.70–2.58(m,1H),2.49(br,2H),2.47–2.43(m,1H),2.22(br, 2H),2.10-1.96(m,1H),1.83-1.70(m,5H),1.67–1.50(m,4H),1.47(p,J=7.2Hz,4H),1.37-1.29 (m,4H),1.28-1.21(m,2H),1.18-1.05(m,2H).。HRMS(ESI):C52H67N10O5 +[M+H]+,计算值 911.5290;实测值,911.5294.
实施例68:(E)-N-(4-(1-(6-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺 (SIAIS632007)的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物5(SIAIS631135)和中间体 LM(SIAIS213134;3-(4-(4-溴丁基硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;CAS登录号 2378582-59-1)制备得到目标化合物(SIAIS632007)(白色固体,9.7mg,收率28%)。1HNMR (500MHz,DMSO-d6)δ10.99(s,1H),8.99(s,1H),8.76(d,J=5.6Hz,1H),8.46(s,1H),8.34(s,1H), 7.91–7.76(m,1H),7.71–7.61(m,2H),7.62–7.48(m,4H),6.89(d,J=15.9Hz,1H),5.14(dd,J= 13.3,5.2Hz,1H),4.62(d,J=13.1Hz,2H),4.48(d,J=12.9Hz,1H),4.39(d,J=17.4Hz,1H),4.25 (d,J=17.4Hz,1H),3.95(d,J=13.2Hz,2H),3.65(br,7H),3.22-3.12(m,6H),3.03(t,J=13.0 Hz,2H),2.95-2.86(m,1H),2.78(t,J=12.6Hz,1H),2.63–2.56(m,1H),2.55-2.51(m,2H),2.49 -2.43(m,1H),2.23(d,J=11.6Hz,2H),2.05-1.98(m,1H),1.87(t,J=8.0Hz,2H),1.77(br,3H), 1.68-1.62(m,3H),1.54(br,1H),1.46(q,J=7.2Hz,2H),1.38-1.30(m,2H),1.28-1.22(m,2H), 1.16-1.06(m,2H).HRMS(ESI)C48H63N10O5S+[M+H]+,计算值891.4698;实测值,891.4603.
实施例69:(E)-N-(4-(1-(6-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔 -1-基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS632010)的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物4(SIAIS632004)和中间体 LM(SIAIS292017;7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基甲磺酸酯; CAS登录号2570254-41-8)制备得到目标化合物(SIAIS632010)(白色固体,7.7mg,收率24%)。1H NMR(500MHz,CD3OD)δ8.94(s,1H),8.71(s,1H),8.53(d,J=8.2Hz,1H),7.88(d,J=7.2Hz, 1H),7.75(d,J=6.6Hz,1H),7.66(d,J=9.5Hz,1H),7.64–7.57(m,2H),7.51(t,J=7.7Hz,1H), 7.45(d,J=9.5Hz,1H),6.87(d,J=15.8Hz,1H),5.19(dd,J=13.3,5.2Hz,1H),4.63(d,J=13.4Hz, 1H),4.53(d,J=17.5Hz,1H),4.47(d,J=17.5Hz,1H),3.93(d,J=13.2Hz,2H),3.71(s,2H),3.51 –3.37(m,2H),3.34(d,J=7.1Hz,2H),3.27–3.22(m,3H),3.20–3.13(m,2H),2.95-2.87(m,2H), 2.85-2.76(m,1H),2.57(t,J=6.9Hz,2H),2.54–2.47(m,1H),2.25-2.15(m,1H),1.95-1.86(m, 3H),1.79-1.70(m,3H),1.65-1.55(m,5H),1.46-1.40(m,2H),1.39-1.30(m,2H),1.29–1.16(m, 3H).HRMS(ESI)C46H56N9O5 +[M+H]+,计算值814.4399;实测值,814.4403.
实施例70:(E)-N-(4-(1-(6-(4-(8-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)辛-7-炔 -1-基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS632011)的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物4(SIAIS632004)和中间体 LM(SIAIS292020;8-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)辛-7-炔-1-基甲磺酸酯; CAS登录号2570254-42-9)制备得到目标化合物(SIAIS632011)(白色固体,9.2mg,收率28%)。1H NMR(500MHz,CD3OD)δ9.06(d,J=1.8Hz,1H),8.82–8.79(m,2H),8.09(dd,J=7.8,6.0Hz, 1H),7.75(dd,J=7.7,1.0Hz,1H),7.70(d,J=9.5Hz,1H),7.66–7.60(m,2H),7.53–7.49(m,2H), 6.95(d,J=15.8Hz,1H),5.19(dd,J=13.3,5.2Hz,1H),4.63(d,J=12.5Hz,2H),4.53(d,J=17.5 Hz,1H),4.47(d,J=17.4Hz,1H),3.93(d,J=13.3Hz,1H),3.72(s,2H),3.54–3.42(m,2H),3.36- 3.34(m,3H),3.25–3.19(m,3H),3.18-3.14(m,1H),2.96-2.87(m,3H),2.85-2.76(m,1H),2.59 –2.45(m,3H),2.25-2.15(m,1H),1.93-1.81(m,3H),1.78–1.66(m,3H),1.65-1.59(m,5H),1.54 -1.47(m,2H),1.47–1.40(m,2H),1.37-1.31(m,2H),1.31–1.20(m,3H).HRMS(ESI)C47H58N9O5 + [M+H]+,计算值828.4555;实测值,828.4559.
实施例71:(E)-N-(4-(1-(6-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基) 丁基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS632012)的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物4(SIAIS632004)和中间体 LM(SIAIS213134;3-(4-(4-溴丁基硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;CAS登录号 2378582-59-1)制备得到目标化合物(SIAIS632012)(白色固体,8.7mg,收率27%)。1HNMR (500MHz,CD3OD)δ9.04(s,1H),8.81-8.75(m,2H),8.07(dd,J=8.2,5.6Hz,1H),7.73–7.61(m, 4H),7.56(t,J=7.6Hz,1H),7.48(d,J=9.5Hz,1H),6.93(d,J=15.8Hz,1H),5.19(dd,J=13.4,5.2 Hz,1H),4.63(d,J=13.1Hz,2H),4.50(d,J=17.4Hz,1H),4.43(d,J=17.1Hz,1H),3.94(d,J= 13.7Hz,1H),3.67(s,1H),3.48–3.41(m,1H),3.34(d,J=7.7Hz,3H),3.24–3.12(m,6H),2.96- 2.88(m,2H),2.84–2.77(m,1H),2.61-2.49(m,1H),2.22-2.19(m,1H),2.00–1.86(m,3H),1.78 -1.70(m,3H),1.64-1.58(m,3H),1.50-1.41(m,2H),1.40-1.34(m,3H),1.33-1.22(m,4H).HRMS (ESI)C43H54N9O5S+[M+H]+,计算值808.3963;实测值,808.3967.
实施例72:(E)-N-(4-(1-(6-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔 -1-基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS632039)的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物6(SIAIS632025)和中间体 LM(SIAIS292017;7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基甲磺酸酯; CAS登录号2570254-41-8)制备得到目标化合物(SIAIS632039)(白色固体,6.5mg,20%)。1H NMR(500MHz,CD3OD)δ8.93(s,1H),8.70(s,1H),8.52(d,J=8.2Hz,1H),8.25(d,J=2.3Hz, 1H),7.87(dd,J=8.2,5.4Hz,1H),7.75(d,J=7.7Hz,1H),7.69(dd,J=8.8,2.4Hz,1H),7.64–7.58 (m,2H),7.51(t,J=7.7Hz,1H),6.96(d,J=8.8Hz,1H),6.86(d,J=15.8Hz,1H),5.19(dd,J=13.4, 5.2Hz,1H),4.62–4.51(m,3H),4.47(d,J=17.4Hz,1H),3.85-3.60(m,2H),3.34(d,J=7.3Hz, 6H),3.26–3.20(m,3H),3.19-3.13(m,2H),2.96-2.87(m,1H),2.84-2.78(m,1H),2.57(t,J=6.9 Hz,3H),2.26-2.10(m,1H),1.88-1.85(m,3H),1.75(q,J=7.3Hz,2H),1.63-1.59(m,5H),1.50– 1.39(m,2H),1.36-1.32(m,4H),1.32-1.28(m,2H).HRMS(ESI)C47H57N8O5 +[M+H]+,计算值 813.4446;实测值,813.4449.
实施例73:(E)-N-(4-(1-(6-(4-(8-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)辛-7-炔 -1-基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS632040)的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物6(SIAIS632025)和中间体 LM(SIAIS292020;8-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)辛-7-炔-1-基甲磺酸酯; CAS登录号2570254-42-9)制备得到目标化合物(SIAIS632040)(白色固体,7.4mg,22%)。1H NMR(500MHz,CD3OD)δ9.07(s,1H),8.87–8.78(m,2H),8.24(d,J=2.3Hz,1H),8.10(dd,J= 8.1,5.8Hz,1H),7.79-7.72(m,2H),7.67–7.59(m,2H),7.51(t,J=7.7Hz,1H),7.05(d,J=9.0Hz, 1H),6.96(d,J=15.9Hz,1H),5.18(dd,J=13.3,5.2Hz,1H),4.62–4.50(m,3H),4.47(d,J=17.5 Hz,1H),3.75-3.63(m,2H),3.40–3.32(m,6H),3.24–3.16(m,5H),2.97-2.87(m,1H),2.83-2.75 (m,1H),2.53(t,J=6.8Hz,3H),2.24-2.15(m,1H),1.91-1.75(m,4H),1.72-1.68(m,2H),1.65– 1.56(m,5H),1.52-1.40(m,4H),1.39–1.28(m,3H),1.21-1.14(m,2H).HRMS(ESI)C48H59N8O5 + [M+H]+,计算值827.4603;实测值,827.4608.
实施例74:(E)-N-(4-(1-(6-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基) 丁基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS632041)的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物6(SIAIS632025)和中间体 LM(SIAIS213134;3-(4-(4-溴丁基硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;CAS登录号2378582-59-1)制备得到目标化合物(SIAIS632041)(白色固体,7.6mg,24%)。1H NMR(500MHz, CD3OD)δ9.05(s,1H),8.87–8.71(m,2H),8.24(d,J=2.3Hz,1H),8.07(dd,J=8.2,5.7Hz,1H), 7.74–7.66(m,3H),7.63(d,J=15.8Hz,1H),7.55(t,J=7.7Hz,1H),7.01(d,J=8.9Hz,1H),6.95 (d,J=15.9Hz,1H),5.18(dd,J=13.3,5.2Hz,1H),4.59–4.47(m,3H),4.43(d,J=17.4Hz,1H), 3.86(s,1H),3.71–3.56(m,2H),3.34(t,J=7.2Hz,6H),3.24–3.07(m,6H),3.25-3.10(m,1H), 2.97-2.86(m,1H),2.60-2.50(m,1H),2.25-2.15(m,1H),1.96(p,J=7.3Hz,2H),1.83–1.69(m, 4H),1.60(p,J=7.3Hz,3H),1.48–1.27(m,5H),1.23-1.10(m,2H).HRMS(ESI)C44H55N8O5S+ [M+H]+,计算值807.4011;实测值,807.4016.
实施例75:(E)-N-(4-(1-(4-(4-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基) 氨基)乙氧基)丙酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS631079) 的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(SIAIS151001;3-(2-((2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚-4-基)氨基)乙氧基)丙酸; CAS登录号2139348-60-8)制备得到目标化合物(SIAIS631079)(黄色固体,8.9mg,收率27%)。1H NMR(500MHz,CD3OD)δ8.94(s,1H),8.70(d,J=4.1Hz,1H),8.55(dt,J=8.2,1.8Hz,1H), 7.89(dd,J=8.2,5.4Hz,1H),7.60(d,J=15.9Hz,1H),7.51(dd,J=8.6,7.0Hz,1H),7.25(d,J=8.8 Hz,2H),7.02(dd,J=15.3,7.8Hz,2H),6.88(dd,J=12.4,3.5Hz,3H),5.01(dd,J=12.5,5.4Hz, 1H),3.82(t,J=5.9Hz,2H),3.79–3.66(m,6H),3.52-3.43(m,3H),3.40–3.33(m,5H),3.26–3.15 (m,4H),2.81–2.75(m,1H),2.75–2.68(m,3H),2.67–2.59(m,1H),2.07–1.99(m,1H),1.77(br, 2H),1.59(p,J=7.1Hz,3H),1.47–1.39(m,2H),1.36-1.32(m,2H),1.16(br,2H).HRMS(ESI) C43H48N7O7S+[M+H]+,计算值847.4137;实测值,847.4139.
实施例76:(E)-N-(4-(1-(4-(4-(3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4- 基)氨基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺 (SIAIS631109)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(SIAIS151004;3-(2-(2-((2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚-4-基)氨基)乙氧基) 乙氧基)丙酸;CAS登录号2140807-17-4)制备得到目标化合物(SIAIS631109)(黄色固体,9.6mg,收率27%)。1H NMR(500MHz,CD3OD)δ9.02(s,1H),8.76(d,J=21.8Hz,2H),8.04(s,1H),7.63 (d,J=15.6Hz,1H),7.56(dd,J=8.6,7.1Hz,2H),7.36(d,J=8.7Hz,1H),7.28(d,J=8.7Hz,1H), 7.10(d,J=8.6Hz,1H),7.06(d,J=7.3Hz,1H),6.97–6.89(m,2H),5.05(dd,J=12.4,5.5Hz,1H), 3.77–3.69(m,7H),3.67–3.60(m,8H),3.50(t,J=5.3Hz,3H),3.47–3.42(m,1H),3.38(dd,J= 6.6,3.9Hz,2H),3.27-3.20(m,1H),2.88–2.81(m,2H),2.76(dt,J=5.3,2.7Hz,1H),2.75–2.72 (m,1H),2.72–2.68(m,1H),2.54(t,J=6.3Hz,3H),2.18–2.03(m,1H),1.59(p,J=7.1Hz,3H), 1.42(br,2H),1.39–1.28(m,3H),1.25–1.09(m,2H).HRMS(ESI)C48H59N8O9 +[M+H]+,计算值 891.4400;实测值,891.4403.
实施例77:(E)-N-(4-(1-(4-(4-(5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)戊- 4-炔-1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS631119)的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物1(SIAIS630006)和中间体 LM(SIAIS292006;5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)戊-4-炔-1-基甲磺酸酯; CAS登录号2570254-45-2)制备得到目标化合物(SIAIS631119)(白色固体,8.7mg,收率28%)。1H NMR(500MHz,DMSO-d6)δ11.14(s,1H),11.08(s,1H),8.88(d,J=2.2Hz,1H),8.67(dd,J= 5.1,1.5Hz,1H),8.26(q,J=8.2,6.9Hz,2H),8.00–7.88(m,3H),7.68(dd,J=8.1,5.0Hz,1H),7.49 (d,J=15.9Hz,1H),7.29(d,J=8.7Hz,2H),7.02(d,J=8.9Hz,2H),6.82(d,J=15.8Hz,1H),5.16 (dd,J=12.9,5.4Hz,1H),3.92(d,J=12.4Hz,2H),3.62(d,J=11.5Hz,2H),3.34–3.14(m,8H), 2.94-2.85(m,1H),2.67(t,J=6.9Hz,2H),2.63–2.58(m,1H),2.57–2.52(m,1H),2.15-2.01(m, 3H),1.67(br,2H),1.46(q,J=7.3Hz,3H),1.35-1.18(m,5H),1.10-1.00(m,2H).HRMS(ESI) C46H52N7O6 +[M+H]+,计算值798.3974;实测值,798.3977.
实施例78:(E)-N-(4-(1-(4-(4-(6-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)己- 5-炔-1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS631120)的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物1(SIAIS630006)和中间体 LM(SIAIS292007;6-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)己-5-炔-1-基甲磺酸酯; CAS登录号2641288-61-9)制备得到目标化合物(SIAIS631120)(白色固体,8.9mg,收率28%)。1H NMR(500MHz,CD3OD)δ8.72(s,1H),8.51(d,J=3.8Hz,1H),8.19(d,J=8.2Hz,1H),7.78–7.72(m,3H),7.57(dd,J=8.1,5.1Hz,1H),7.47(d,J=15.9Hz,1H),7.26(d,J=8.7Hz,2H),6.97 (d,J=8.7Hz,2H),6.70(d,J=15.9Hz,1H),5.05(dd,J=12.8,5.5Hz,1H),4.46(s,1H),3.87(s,2H), 3.72(s,1H),3.61(s,2H),3.23(d,J=7.2Hz,2H),3.22-3.16(m,4H),3.10-3.02(m,2H),2.82-2.73 (m,2H),2.71–2.60(m,2H),2.54(t,J=6.8Hz,2H),2.09-2.02(m,1H),1.98–1.87(m,2H),1.67 (p,J=7.1Hz,4H),1.49(p,J=7.4Hz,4H),1.35-1.27(m,2H),1.28–1.17(m,2H),1.07(br,2H). HRMS(ESI)C47H54N7O6 +[M+H]+,计算值812.4130;实测值,812.4132.
实施例79:(E)-N-(4-(1-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)庚- 6-炔-1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS631108)的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物1(SIAIS630006)和中间体 LM(SIAIS292016;7-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)庚-6-炔-1-基甲磺酸酯; CAS登录号2641288-62-0)制备得到目标化合物(SIAIS631108)(白色固体,7.7mg,收率23%)。1H NMR(500MHz,DMSO-d6)δ11.14(s,1H),11.10(s,1H),9.00(d,J=2.1Hz,1H),8.77(d,J= 5.3Hz,1H),8.48(d,J=8.1Hz,1H),8.36(t,J=5.6Hz,1H),7.94–7.83(m,4H),7.53(d,J=15.9 Hz,1H),7.29(d,J=8.5Hz,2H),7.01(d,J=8.7Hz,2H),6.91(d,J=15.9Hz,1H),5.16(dd,J=12.9, 5.4Hz,1H),3.90(d,J=13.0Hz,2H),3.56(d,J=11.8Hz,2H),3.27–3.07(m,8H),2.95-2.85(m, 1H),2.65-2.57(m,1H),2.56(t,J=6.9Hz,3H),2.10-2.03(m,1H),1.88-1.75(m,2H),1.70-1.60 (m,4H),1.52-1.43(m,5H),1.35-1.21(m,4H),1.05(m,2H).。HRMS(ESI)C48H56N7O6 +[M+H]+, 计算值862.4287;实测值,862.428.
实施例80:(E)-N-(4-(1-(4-(4-(8-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)辛- 7-炔-1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS631121)的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物1(SIAIS630006)和中间体 LM(SIAIS292008;8-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)辛-7-炔-1-基甲磺酸酯; CAS登录号2641288-63-1)制备得到目标化合物(SIAIS631121)(白色固体,7.1mg,收率23%)。1H NMR(500MHz,CD3OD)δ8.70(d,J=2.1Hz,1H),8.49(d,J=3.7Hz,1H),8.16(dt,J=8.1,1.9 Hz,1H),7.78–7.66(m,3H),7.54(dd,J=8.1,5.0Hz,1H),7.47(d,J=15.8Hz,1H),7.26(d,J=8.7 Hz,2H),6.97(d,J=8.6Hz,2H),6.70(d,J=15.9Hz,1H),5.04(dd,J=12.8,5.5Hz,1H),4.46(s, 1H),3.86(s,2H),3.72(br,1H),3.58(s,2H),3.23(d,J=7.3Hz,2H),3.16–3.09(m,4H),3.05(br, 2H),2.82-2.73(m,2H),2.69–2.56(m,2H),2.44(t,J=6.9Hz,2H),2.08–2.00(m,1H),1.82–1.69 (m,3H),1.60(p,J=6.9Hz,3H),1.55–1.45(m,6H),1.41(q,J=7.6Hz,2H),1.37–1.29(m,2H), 1.28–1.18(m,2H),1.06(br,2H).HRMS(ESI)C49H58N7O6 +[M+H]+,计算值840.4443;实测值, 840.4447.
实施例81:(E)-N-(4-(1-(4-(4-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基) 硫基)乙氧基)乙酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS631111) 的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(SIAIS1204137;2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙酸; CAS登录号2378582-16-0)制备得到目标化合物(SIAIS631111)(黄色固体,8.0mg,收率24%)。1H NMR(500MHz,CD3OD)δ8.98(s,1H),8.74(d,J=5.6Hz,1H),8.65(d,J=8.4Hz,1H),7.96 (dd,J=8.2,5.5Hz,1H),7.77(d,J=8.0Hz,1H),7.71(t,J=7.8Hz,1H),7.64–7.57(m,2H),7.31 (d,J=8.8Hz,2H),6.98(d,J=8.9Hz,2H),6.91(d,J=15.9Hz,1H),5.08(dd,J=12.8,5.5Hz,1H), 4.29(s,2H),3.86(t,J=6.0Hz,3H),3.71–3.64(m,4H),3.42–3.33(m,6H),3.27-3.23(m,4H), 3.07(br,1H),2.87-2.83(m,1H),2.76–2.73(m,1H),2.71–2.64(m,1H),2.12-2.06(m,1H),1.76 (br,3H),1.59(p,J=7.2Hz,3H),1.46–1.39(m,2H),1.36-1.32(m,2H),1.16(s,2H).HRMS(ESI) C45H52N7O8S+[M+H]+,计算值850.3593;实测值,850.3595.
实施例82:(E)-N-(4-(1-(4-(4-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4- 基)硫基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺 (SIAIS631112)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM (SIAIS1204139;2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙酸;CAS登录号:2378582-17-1)制备得到目标化合物(SIAIS631112)(黄色固体,8.7mg,收率23%)。1H NMR(500MHz,CD3OD)δ8.89(d,J=19.8Hz,1H),8.67(dd,J=16.1,5.2Hz,1H), 8.45(dd,J=47.0,8.4Hz,1H),7.84–7.66(m,3H),7.64–7.54(m,2H),7.35(d,J=8.8Hz,1H),7.26 (d,J=8.7Hz,1H),7.07(d,J=8.9Hz,1H),6.94(d,J=8.8Hz,1H),6.83(dd,J=15.8,10.7Hz,1H), 5.11(dd,J=12.4,5.5Hz,1H),4.30(s,1H),4.10(s,1H),3.83-3.79(m,4H),3.69-1.67(m,8H), 3.54–3.47(m,2H),3.39–3.33(m,8H),2.89–2.83(m,1H),2.80–2.76(m,1H),2.73–2.64(m, 1H),2.15–2.10(m,1H),1.74(br,2H),1.60-1.56(m,3H),1.42(br,2H),1.38–1.30(m,2H),1.15 (br,2H).HRMS(ESI)C47H56N7O9S+[M+H]+,计算值894.3855;实测值,894.3857.
实施例83:(E)-N-(4-(1-(4-(4-(2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉- 4-基)硫基)乙氧基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS631113)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(SIAIS1204141;2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基) 乙氧基)乙氧基)乙酸;CAS登录号:2378582-18-2)制备得到目标化合物(SIAIS631113)(黄色固体,8.4mg,收率22%)。1H NMR(500MHz,CD3OD)δ8.81(s,1H),8.58(d,J=5.4Hz,1H),8.40 (dd,J=8.2,1.8Hz,1H),7.74(dd,J=8.2,5.4Hz,1H),7.67–7.55(m,2H),7.53–7.43(m,2H),7.25 (d,J=8.8Hz,1H),7.18(d,J=8.8Hz,1H),6.85(d,J=8.9Hz,2H),6.76(d,J=15.8Hz,1H),5.00 (dd,J=12.8,5.5Hz,1H),4.19(s,2H),3.74-3.66(m,2H),3.63–3.50(m,12H),3.43–3.38(m,1H), 3.29-3.26(m,1H),3.26–3.21(m,5H),3.21–3.10(m,5H),2.82–2.70(m,1H),2.69–2.63(m,1H), 2.63–2.54(m,1H),2.09-1.95(m,1H),1.64(br,2H),1.52-1.44(m,3H),1.34-1.28(m,2H),1.24 -1.20(m,3H),1.04(br,2H).HRMS(ESI)C49H60N7O10S+[M+H]+,计算值938.4117;实测值, 938.4118.
实施例84:(E)-N-(4-(1-(4-(4-(14-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基) 硫基)-3,6,9,12-四氧杂十四烷酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺 (SIAIS631114)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(SIAIS1204147;14-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-3,6,9,12-四氧杂十四烷酸;CAS登录号:2378582-19-3)制备得到目标化合物(SIAIS631114)(黄色固体,11.3 mg,收率29%)。1H NMR(500MHz,CD3OD)δ9.05(s,1H),8.79(d,J=6.4Hz,2H),8.14–8.01 (m,1H),7.71(q,J=7.8Hz,2H),7.64–7.55(m,2H),7.33(d,J=8.5Hz,2H),7.05(d,J=8.5Hz, 2H),6.96(d,J=15.8Hz,1H),5.09(dd,J=12.9,5.5Hz,1H),4.53(br,1H),4.10(s,2H),3.79(t,J= 6.2Hz,2H),3.70–3.59(m,11H),3.49(dd,J=6.8,3.8Hz,4H),3.39–3.24(m,11H),3.07(br,1H), 2.90-2.80(m,1H),2.76–2.64(m,2H),2.15-2.06(m,1H),1.75(d,J=45.8Hz,2H),1.57(p,J= 7.4Hz,3H),1.48–1.36(m,2H),1.35–1.26(m,2H),1.13(br,2H).HRMS(ESI)C51H64N7O11S+ [M+H]+,计算值982.4379;实测值,982.4381.
实施例85:(E)-N-(4-(1-(4-(4-(17-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基) 硫基)-3,6,9,12,15-五氧杂十七烷酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS631115)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(SIAIS1204149;17-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-3,6,9,12,15-五氧杂十七烷酸;CAS登录号:2378582-20-6)制备得到目标化合物(SIAIS632027)(黄色固体, 12.4mg,收率30%)。1H NMR(500MHz,CD3OD)δ8.90(s,1H),8.68(d,J=5.4Hz,1H),8.50- 8.45(m,1H),7.86-7.80(m,1H),7.77–7.69(m,2H),7.61–7.57(m,2H),7.33(dd,J=23.1,8.7Hz, 2H),7.07(d,J=8.5Hz,1H),7.00–6.95(m,1H),6.86(dt,J=15.8,1.9Hz,1H),5.11(dd,J=12.7, 6.1Hz,1H),4.31(s,1H),4.12(s,1H),3.80(q,J=6.4Hz,2H),3.73–3.59(m,18H),3.54–3.48(m, 2H),3.40–3.23(m,12H),3.08(s,1H),2.93–2.82(m,1H),2.79–2.62(m,1H),2.17-2.08(m,1H), 1.74(br,1H),1.64-1.55(m,3H),1.45-1.35(m,2H),1.35-1.25(m,2H),1.15(br,2H).HRMS(ESI) C53H68N7O12S+[M+H]+,计算值1026.4641;实测值,1026.4646.
实施例86:(E)-N-(4-(1-(4-(4-(17-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-3,6,9,12,15-五氧杂十七烷酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺 (SIAIS631118)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(SIAIS1213137;17-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-3,6,9,12,15-五氧杂十七烷酸;CAS登录号:2378582-25-1)制备得到目标化合物(SIAIS631118)(白色固体,13.1mg,收率32%)。1H NMR(500MHz,CD3OD)δ9.03(d,J=2.1Hz,1H),8.78(d,J=5.5Hz,1H),8.74 (dt,J=8.2,1.7Hz,1H),8.04(dd,J=8.2,5.6Hz,1H),7.71(dd,J=7.8,0.9Hz,1H),7.69–7.59(m, 2H),7.54(t,J=7.6Hz,1H),7.36(d,J=8.8Hz,2H),7.07(d,J=8.8Hz,2H),6.94(d,J=15.9Hz, 1H),5.16(dd,J=13.4,5.3Hz,1H),4.49(d,J=17.3Hz,1H),4.43(d,J=17.4Hz,1H),4.12(s,2H), 3.71–3.63(m,7H),3.62–3.57(m,14H),3.51(dd,J=6.7,3.8Hz,3H),3.38(dd,J=6.6,3.9Hz, 3H),3.35–3.30(m,4H),3.25-3.22(m,3H),2.96-2.87(m,1H),2.82–2.75(m,1H),2.58-2.50(m, 1H),2.22-2.17(m,1H),1.73(br,2H),1.62-1.56(m,3H),1.48–1.39(m,2H),1.36-1.32(m,2H), 1.16(br,2H).HRMS(ESI)C53H70N7O11S+[M+H]+,计算值1012.4849;实测值,1012.4851.
实施例87:(E)-N-(4-(1-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基) 己基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS633097)的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物1(SIAIS630006)和中间体LM(3-(4-((6-溴己基)氧基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;CAS登录号:2413731-77-6)制备得到目标化合物(SIAIS633097)(白色固体,5.7mg,收率17%)。1H NMR(500MHz,DMSO- d6)δ10.98(s,1H),8.80(d,J=2.2Hz,1H),8.59(dd,J=4.9,1.6Hz,1H),8.36(s,1H),8.09(d,J= 8.1Hz,1H),7.53(dd,J=8.0,4.9Hz,1H),7.50–7.44(m,2H),7.39(d,J=8.7Hz,2H),7.31(d,J= 7.5Hz,1H),7.26–7.22(m,1H),7.04(d,J=9.1Hz,2H),6.76(d,J=15.9Hz,1H),5.10(dd,J=13.3, 5.1Hz,1H),4.37(d,J=17.4Hz,1H),4.22(d,J=17.4Hz,1H),4.13(t,J=6.3Hz,2H),3.93(d,J= 11.0Hz,2H),3.36-3.23(m,5H),3.22(q,J=6.6Hz,4H),3.18-3.07(m,12H),2.94–2.80(m,1H), 2.65–2.55(m,1H),2.46–2.42(m,1H),2.00(ddd,J=12.4,6.4,3.8Hz,1H),1.79–1.61(m,6H), 1.49(dt,J=14.1,7.1Hz,4H),1.38(q,J=7.5Hz,2H).HRMS(ESI)C47H60N7O6 +[M+H]+,计算值 818.4600;实测值,818.4607.
实施例88:(E)-N-(4-(1-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基) 庚基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS633098)的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物1(SIAIS630006)和中间体 LM(3-(4-((7-溴庚基)氧基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;CAS登录号:2699962-33-7)制备得到目标化合物(SIAIS633098)(白色固体,6.3mg,收率19%)。1H NMR(500MHz,DMSO- d6)δ10.98(s,1H),8.86(d,J=2.2Hz,1H),8.64(dd,J=5.0,1.5Hz,1H),8.42(t,J=5.7Hz,1H), 8.21(dt,J=8.1,1.9Hz,1H),7.63(dd,J=8.0,5.0Hz,1H),7.52–7.46(m,2H),7.39(d,J=8.5Hz, 2H),7.32(d,J=7.5Hz,1H),7.24(d,J=8.1Hz,1H),7.05(d,J=8.8Hz,2H),6.82(d,J=15.9Hz, 1H),5.10(dd,J=13.3,5.1Hz,1H),4.38(d,J=17.4Hz,1H),4.23(d,J=17.4Hz,1H),4.13(t,J= 6.4Hz,2H),3.93(d,J=12.6Hz,2H),3.27–3.03(m,19H),2.98–2.81(m,1H),2.66–2.57(m,1H), 2.45(dd,J=13.2,4.5Hz,1H),2.01(ddd,J=7.1,5.3,2.3Hz,1H),1.78-1.70(m,8H),1.50(dq,J= 30.1,7.3Hz,4H),1.41–1.30(m,4H).HRMS(ESI)C48H62N7O6 +[M+H]+,计算值832.4756;实测值,832.4758.
实施例89:(E)-N-(4-(1-(6-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6- 炔-1-基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS633093)的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物7(SIAIS632044)和中间体 LM(SIAIS292017;7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基甲磺酸酯; CAS登录号:2570254-41-8)制备得到目标化合物(SIAIS633093)(白色固体,5.8mg,收率18%)。1H NMR(500MHz,DMSO-d6)δ10.99(s,1H),8.88(d,J=2.1Hz,1H),8.65(d,J=5.3Hz,1H), 8.32–8.25(m,1H),8.14(d,J=2.4Hz,1H),7.73–7.64(m,2H),7.64–7.57(m,1H),7.52(t,J=7.6 Hz,1H),7.48(d,J=15.9Hz,1H),6.97(d,J=9.1Hz,1H),6.80(d,J=15.9Hz,1H),5.13(dd,J= 13.3,5.1Hz,1H),4.51(d,J=13.0Hz,2H),4.45(d,J=17.6Hz,1H),4.31(d,J=17.7Hz,1H),3.79 -3.65(m,11H),3.23–3.06(m,5H),2.90(t,J=13.8Hz,4H),2.61(d,J=17.3Hz,1H),2.47-2.35 (m,1H),2.18-2.11(m,1H),2.09-1.98(m,1H),1.74–1.53(m,8H),1.44(d,J=9.0Hz,5H),1.40 –1.27(m,4H),1.28-1.19(m,3H),1.09-1.03(m,2H).HRMS(ESI)C52H66N9O5 +[M+H]+,计算值 896.5181;实测值,896.5186.
实施例90:(E)-N-(4-(1-(6-(4-(4-(8-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)辛-7- 炔-1-基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺(SIAIS633094)的制备
参照实施例15的方法,根据方案16,采用达珀利奈衍生物7(SIAIS632044)和中间体 LM(SIAIS292020;8-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)辛-7-炔-1-基甲磺酸酯; CAS登录号:2570254-42-9)制备得到目标化合物(SIAIS633094)(白色固体,6.1mg,收率19%)。1H NMR(500MHz,DMSO-d6)δ10.99(s,1H),8.95(d,J=2.1Hz,1H),8.72(d,J=5.3Hz,1H), 8.42(d,J=8.1Hz,1H),8.34(t,J=5.7Hz,1H),8.13(d,J=2.3Hz,1H),7.81(dd,J=8.1,5.3Hz, 1H),7.71(s,1H),7.67–7.62(m,2H),7.51(dd,J=16.0,9.0Hz,2H),7.03(d,J=9.1Hz,1H),6.85 (d,J=15.9Hz,1H),5.13(dd,J=13.3,5.1Hz,1H),4.51(d,J=13.2Hz,2H),4.46(d,J=17.7Hz, 1H),4.32(d,J=17.6Hz,1H),3.85-3.66(m,12H),3.20-3.15(m,4H),3.04–2.84(m,4H),2.72(d, J=4.9Hz,1H),2.64-2.53(m,1H),2.59-2.50(m,4H),2.49-2.38(m,1H),2.18(d,J=11.9Hz, 2H),2.06–1.95(m,1H),1.81–1.56(m,7H),1.45(dt,J=15.2,7.9Hz,4H),1.36–1.17(m,5H), 1.07-1.03(m,2H).HRMS(ESI)C53H68N9O5 +[M+H]+,计算值910.5338;实测值,910.5341.
实施例91:(2S,4R)-1-((S)-3,3-二甲基-2-(6-氧代-6-(4-(1-(6-(4-(4-((E)-3-(吡啶-3-基)丙烯酰胺基)丁基)哌啶-1-羰基)哒嗪-3-基)哌啶-4-基)哌嗪-1-基)己酰胺基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯烷-2-甲酰胺(SIAIS633063)的制备
参照实施例1的方法,根据方案15,采用达珀利奈衍生物5(SIAIS631135)和中间体LM(SIAIS074013;6-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷- 1-基)-3,3-二甲基-1-氧代丁烷-2-基)氨基)-6-氧代己酸;CAS登录号:2172819-74-6)制备得到目标化合物(SIAIS633063)(白色固体,9.8mg,收率25%)。1H NMR(500MHz,DMSO-d6)δ9.00 (d,J=1.7Hz,2H),8.76(d,J=5.4Hz,1H),8.60(t,J=6.2Hz,1H),8.52(d,J=8.2Hz,1H),8.38(t, J=5.7Hz,1H),7.95–7.85(m,2H),7.71–7.60(m,1H),7.58–7.47(m,2H),7.44–7.32(m,4H), 6.89(d,J=15.9Hz,1H),4.61–4.50(m,3H),4.48–4.36(m,4H),4.35(s,1H),4.21(dd,J=16.0, 5.5Hz,1H),4.04(s,2H),3.94–3.85(m,3H),3.78-3,72(m,4H),3.19(q,J=6.5Hz,2H),3.03(q, J=14.1,13.1Hz,4H),2.94–2.88(m,1H),2.77(t,J=12.3Hz,1H),2.43(s,3H),2.37-2.30(m,2H), 2.29–2.09(m,4H),2.04(t,J=9.1Hz,1H),1.89(ddd,J=12.9,8.8,4.6Hz,1H),1.80–1.61(m,4H), 1.58–1.35(m,7H),1.35-1.29(m,2H),1.27-1.20(m,3H),1.12-1.05(m,2H),0.92(s,9H).HRMS (ESI)C59H81N12O7S+[M+H]+,计算值1101.6066;实测值,1101.6069.
生物活性检测实验
实验试剂和材料
实验方法:
细胞培养
本公开使用的肿瘤细胞均培养在含5%CO2的37℃培养箱中。细胞培养基补充有10%胎牛血清和终浓度为100U/mL的青霉素和100μg/mL的链霉素。所有细胞在实验前均经STR鉴定为正确细胞并经支原体检测试剂盒检测为支原体阴性。
化合物对肿瘤细胞的半数抑制浓度(IC50)测定:
本公开化合物(包括表1化合物和实施例化合物)的IC50采用Promega公司的CellTiter-Luminescent Cell Viability Assay试剂盒进行测定。具体步骤如下:肿瘤细胞以 20000个细胞/每孔的数量接种在含有100微升的含血清的RPMI 1640培养基中。第二天,将本公开化合物进行系列稀释后加至细胞中。本公开化合物处理细胞72小时后,按照试剂盒的说明书将细胞活性检测试剂加入培养基中进行细胞活性测定。阴性对照为DMSO,阳性对照为FK866抑制剂,均采用与本公开化合物相同的处理方式处理细胞。本公开化合物对细胞的生长抑制通过Prism Graphpad软件进行绘制并从中统计本公开化合物IC50。结果列于以下表2 中。
表2:本公开化合物对于肿瘤细胞增殖抑制活性的IC50值
结果显示,本发明化合物(包括表1化合物和实施例化合物1-91)可以抑制肿瘤细胞的增殖(如表2所示)。部分实施例化合物的IC50与阳性对照药FK866相当,甚至优于阳性对照药FK866,例如SIAIS630010的IC50为0.3506nM。表明本发明化合物对肿瘤细胞生长抑制的效果与阳性药FK866相当,甚至优于阳性对照药FK866。
本公开化合物对肿瘤细胞的体外杀伤试验
MOLT4、HL60肿瘤细胞分别接种在含有1毫升培养基RPMI1640的12孔板里,接种细胞密度为0.5×106个细胞/mL。第二天,分别将母本抑制剂FK866以及本公开化合物SIAIS630120、SIAIS630121溶于DMSO中,得到浓度为10μM的相应化合物的储备液。然后将1微升、浓度为10μM的化合物储备液加入1毫升细胞培养基中,使其终浓度为10nM,连续处理细胞4天,期间每天测量存活细胞数量一次。具体操作为:每天取一次细胞,用细胞染色缓冲液调节细胞浓度为1×106/mL,用4',6二脒基-2-苯吲哚盐酸盐染色液(DAPI)(1:250)进行染色,然后用流式细胞仪分析。首先通过细胞大小的差异对细胞进行门控,然后用DAPI染色对死亡细胞进行门控。最后,计算DAPI正比值来评估杀伤效率。
体外杀伤实验结果如图6-7所示。结果表明:对于HL60细胞,SIAIS630120和SIAIS630121两种PROTAC化合物在第4天对HL60细胞的杀伤效果都达到了95%,而FK866 处理组的HL60细胞死亡不到40%。对于MOLT4细胞,这两种PROTAC化合物在第4天表现出约50%的杀伤效果,这可能是由于MOLT4细胞对两种PROTAC化合物耐受性更高,但仍比FK866强20%。因此,本发明的PROTAC化合物的杀伤效果显著优于FK866。
本公开化合物对靶蛋白半数降解浓度(DC50)测定
蛋白质免疫印迹(Western Blot)
肿瘤细胞以一定的细胞密度接种在含有2毫升培养基RPMI1640/DMEM的6孔板里,其中对于SW620、HT29、MCF-7、BEL7404细胞,接种细胞密度分别为1×106个细胞/孔;对于MOLT4、Jurkat、HL60细胞,接种细胞密度分别为0.5×106个细胞/mL。本公开化合物(包括表1化合物和实施例化合物1-91)分别溶于DMSO中,制备浓度为1μM、5μM、10μM、 100μM的相应化合物的储备液。第二天,以不同浓度的本公开化合物(包括表1化合物和实施例化合物1-91)处理细胞(2微升不同浓度化合物加入2毫升细胞培养基中,终浓度分别为 1nM、5nM、10nM、100nM)。化合物处理24小时后去除上清,用PBS洗涤细胞。将细胞置于冰上,加入含有蛋白酶抑制剂和磷酸酶抑制剂的蛋白裂解液处理细胞。裂解液经过4℃, 12000RPM离心15分钟后,收集上清液。将5×SDS加入等量蛋白中,95℃变性处理5分钟后冻至-20℃或者直接进行蛋白电泳。用等量的蛋白进行SDS-PAGE,在95V和4℃下转移到硝化纤维素膜上90分钟。转膜完成后,用含5%脱脂奶粉的TBST(北京康为世纪生物科技有限公司)在室温下封闭膜1小时。在4℃下用一抗孵育膜过夜。一抗孵育后,用TBST室温下洗3 次膜,每次5分钟。之后的二抗(过氧化物酶标记山羊抗兔IgG(H+L))孵育和显影等操作方法按照JacksonImmunoResearch Laboratories Inc.的抗体说明书进行。
半数降解浓度(蛋白降解至50%所对应的药物浓度,即,DC50)读取方法:对比药物处理后对应Western blotting条带的灰度值与空白DMSO处理后对应Western blotting条带的灰度值,读取灰度值是空白DMSO处理后对应Western blotting条带的灰度值一半时的药物浓度范围。
DC50值的计算可以采用ImageJ软件读取药物处理后对应Western blotting条带的灰度值。拟合药物浓度与灰度值之间的关系曲线推算对应灰度值一半时的药物浓度。
本公开采用Western-blot检测了本公开化合物(包括表1化合物和实施例化合物1-91) 处理肿瘤细胞24小时后的NAMPT蛋白的表达水平。Western-blot检测结果如图1-5所示。实验结果表明本发明的化合物(包括表1化合物和实施例化合物1-91)能够促进细胞内NAMPT (iNAMPT)和细胞外的NAMPT(eNAMPT)蛋白的降解。iNAMPT和eNAMPT都有助于肿瘤的生长。然而商品化母本抑制剂FK866仅是抑制了iNAMPT蛋白活性,而不能像本发明的降解剂化合物那样可以将iNAMPT和eNAMPT蛋白同时降解。单纯抑制iNAMPT蛋白活性,细胞会启动反馈调节,反而生成更多的iNAMPT蛋白,进而促进分泌过程产生更多的 eNAMPT,严重影响治疗效果。这方面已得到了图5的Western-blot检测结果的证实。在图5 中,与DMSO对照组相比,10nM的FK866抑制剂处理MOLT4血液癌细胞后,eNAMPT蛋白含量更高。
以上显示和描述了本发明的基本原理、主要特征和本发明的优点。本领域技术人员应了解,本发明不受上述实施例的限制,在不脱离本发明精神和范围的前提下,本发明还可进行各种变化和改进,这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。
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Claims (31)
1.式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物:
其中ULM为E3泛素连接酶配体部分,LIN为连接部分,式(I)分子的剩余部分是烟酰胺磷酸核糖转移酶(NAMPT)配体,ULM通过LIN共价连接NAMPT配体;
其中环A是以下基团:
(Ra)m1表示环A可选地被m1个Ra基团取代,各Ra独立地为羟基、氨基、卤素或氰基,和m1表示整数0、1、2、3、4或5;
R1和R2相同或不同且彼此独立地为H、氰基或甲基;
L1表示取代或未取代的直链C3-6亚烷基、或取代或未取代的直链C3-6亚烯基,所述直链C3-6亚烷基和直链C3-6亚烯基的可选的取代基选自C1-3烷基、卤素、C1-3烷氧基、卤代C1-3烷基、C1-3烷基-NHC(O)-、C1-3烷基-C(O)NH-、氰基或其任意组合;
环B是5元至11元亚杂环基,(Rb)m2表示环B可选地被m2个Rb基团取代,各Rb独立地为C1-3烷基、羟基、氨基、巯基、卤素、C1-3烷氧基、C1-3烷基氨基、卤代C1-3烷基、氨基取代的C1-3亚烷基、C1-3烷基-NHC(O)-、C1-3烷基-C(O)NH-或氰基,和m2表示整数0、1、2、3、4或5;
环C是5元至10元亚杂芳基、或6元亚芳基,(Rc)m3表示环C可选地被m3个Rc基团取代,各Rc独立地为C1-3烷基、C3-5环烷基、羟基、氨基、巯基、卤素、C1-3烷氧基、C1-3烷基氨基、卤代C1-3烷基、氨基取代的C1-3亚烷基、C1-3烷基-NHC(O)-、C1-3烷基-C(O)NH-或氰基,和m3表示整数0、1、2、3、4或5;
m表示整数0或1;以及
Y表示-N(R3)-,其中R3是氢或C1-3烷基;或
Y表示-O-;或
Y是由以下结构式表示的n个相连的环D:
各环D独立地是5元至11元亚杂环基,(Rd)m4表示各环D可选地独立地被m4个Rd基团取代,各Rd独立地为C1-3烷基、C3-6环烷基、羟基、氨基、巯基、卤素、氧代基、C1-3烷氧基、C1-3烷基氨基、卤代C1-3烷基、氨基取代的C1-3亚烷基、C1-3烷基-NHC(O)-、C1-3烷基-C(O)NH-或氰基,和m4表示整数0、1、2、3、4或5;
n是整数0、1、2或3,其中当n表示整数2或3时,各环D可相同或不同,以及
其中m和n不同时为0;
条件是不包括以下化合物:
所述烟酰胺磷酸核糖转移酶(NAMPT)配体表示以下结构:
并且ULM表示式(IV)的结构:
其中Z1表示C(O)或Z1表示键,以及Z2表示H或CH3。
2.如权利要求1所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其中环B是含有1至3个独立地选自氮、氧和硫的杂原子的5元至11元亚杂环基。
3.如权利要求1所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其中环B是含有1个氮原子并且可选地进一步含有1至2个独立地选自氮、氧和硫的杂原子的5元至11元亚杂环基。
4.如权利要求1所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其中
所述环B表示以下基团:
亚哌啶基、亚哌嗪基、亚吗啉基、亚氮杂环丁基、亚氧杂环丁基、亚吡咯烷基、亚咪唑烷基、亚吡唑烷基、亚四氢呋喃基、亚四氢吡喃基、亚四氢噻吩基、亚四氢噻喃基、亚噁唑烷基、亚噻唑烷基、亚硫代吗啉基、亚二氧杂环己基、亚二氮杂环庚基或C7-11螺杂环亚基;或
所述环C表示以下基团:
亚苯基、亚吡啶基、亚嘧啶基、亚吡嗪基、亚哒嗪基、1,2,4-亚三嗪基、1,3,5-亚三嗪基、亚三氮唑基、亚呋喃基、亚噁唑基、亚异噁唑基、亚噁二唑基、亚噻吩基、亚噻唑基、亚异噻唑基、亚噻二唑基、亚吡咯基、亚咪唑基、亚吡唑基、亚吲哚基、亚异吲哚基、亚苯并呋喃基、亚异苯并呋喃基、亚苯并噻吩基、亚吲唑基、亚苯并咪唑基、亚苯并噁唑基、亚苯并异噁唑基、亚苯并噻唑基、亚苯并异噻唑基、亚苯并三唑基、亚苯并[2,1,3]噁二唑基、亚苯并[2,1,3]噻二唑基、亚苯并[1,2,3]噻二唑基、亚喹啉基、亚异喹啉基、亚萘啶基、亚噌啉基、亚喹唑啉基、亚喹喔啉基、亚酞嗪基、吡唑并[1,5-a]吡啶亚基、吡唑并[1,5-a]嘧啶亚基、咪唑并[1,2-a]吡啶亚基、1H-吡咯并[3,2-b]吡啶亚基、1H-吡咯并[2,3-b]吡啶亚基、4H-氟[3,2-b]吡咯亚基、吡咯并[2,1-b]噻唑亚基、或咪唑并[2,1-b]噻唑亚基;或
各环D独立地表示以下基团:
亚哌啶基、亚哌嗪基、亚吗啉基、亚氮杂环丁基、亚氧杂环丁基、亚吡咯烷基、亚咪唑烷基、亚吡唑烷基、亚四氢呋喃基、亚四氢吡喃基、亚四氢噻吩基、亚四氢噻喃基、亚噁唑烷基、亚噻唑烷基、亚硫代吗啉基、亚二氧杂环己基、亚二氮杂环庚基或C7-11螺杂环亚基。
5.如权利要求1所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其也是式(II)化合物:
其中环B是含有1个氮原子并且可选地进一步含有1至2个独立地选自氮、氧和硫的杂原子的5元至11元亚杂环基,(Rb)m2表示环B可选地被m2个Rb基团取代,各Rb独立地为C1-3烷基、羟基、氨基、巯基、卤素、C1-3烷氧基、C1-3烷基氨基、卤代C1-3烷基、氨基取代的C1-3亚烷基、C1-3烷基-NHC(O)-、C1-3烷基-C(O)NH-或氰基,和m2表示整数0、1、2、3、4或5;以及
ULM、LIN、环A、(Ra)m1、R1、R2、L1、环C、(Rc)m3、m、Y如权利要求1中所定义。
6.如权利要求5所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其中
环B是含有1至3个氮原子的5元至11元亚杂环基;或
环C表示以下基团:
亚苯基、亚吡啶基、亚嘧啶基、亚吡嗪基、亚哒嗪基、1,2,4-亚三嗪基、1,3,5-亚三嗪基、亚三氮唑基、亚呋喃基、亚噁唑基、亚异噁唑基、亚噁二唑基、亚噻吩基、亚噻唑基、亚异噻唑基、亚噻二唑基、亚吡咯基、亚咪唑基、亚吡唑基、亚吲哚基、亚异吲哚基、亚苯并呋喃基、亚异苯并呋喃基、亚苯并噻吩基、亚吲唑基、亚苯并咪唑基、亚苯并噁唑基、亚苯并异噁唑基、亚苯并噻唑基、亚苯并异噻唑基、亚苯并三唑基、亚苯并[2,1,3]噁二唑基、亚苯并[2,1,3]噻二唑基、亚苯并[1,2,3]噻二唑基、亚喹啉基、亚异喹啉基、亚萘啶基、亚噌啉基、亚喹唑啉基、亚喹喔啉基、亚酞嗪基、吡唑并[1,5-a]吡啶亚基、吡唑并[1,5-a]嘧啶亚基、咪唑并[1,2-a]吡啶亚基、1H-吡咯并[3,2-b]吡啶亚基、1H-吡咯并[2,3-b]吡啶亚基、4H-氟[3,2-b]吡咯亚基、吡咯并[2,1-b]噻唑亚基、或咪唑并[2,1-b]噻唑亚基;或
各环D独立地表示以下基团:
亚哌啶基、亚哌嗪基、亚吗啉基、亚氮杂环丁基、亚氧杂环丁基、亚吡咯烷基、亚咪唑烷基、亚吡唑烷基、亚四氢呋喃基、亚四氢吡喃基、亚四氢噻吩基、亚四氢噻喃基、亚噁唑烷基、亚噻唑烷基、亚硫代吗啉基、亚二氧杂环己基、亚二氮杂环庚基或C7-11螺杂环亚基。
7.如权利要求5所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其中环B是亚哌啶基、亚哌嗪基、亚吗啉基、亚氮杂环丁基、亚吡咯烷基、亚咪唑烷基、亚吡唑烷基、亚噁唑烷基、亚噻唑烷基、亚硫代吗啉基、亚二氮杂环庚基、或含有1个氮原子并且可选地进一步含有1至2个独立地选自氮、氧和硫的杂原子的C7-11螺杂环亚基。
15.如权利要求1-14中任一项所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其中LIN表示以下式:
#-U-亚烷基,
其中U表示C(O)或U表示键,以及符号#表示与基团Y的连接点;和
所述亚烷基是取代或未取代的亚甲基、或取代或未取代的直链或支链C2-60亚烷基,其中所述直链或支链C2-60亚烷基的主碳链中可选地插入有一或多个基团R5和/或一或多个基团R6或者一或多个基团R5与R6的任意组合;各基团R5独立地选自O、N(R7)、C(O)、C(O)O、OC(O)、C(O)N(R7)、N(R7)C(O)、或N(R7)C(O)N(R7),其中各R7独立地表示H或C1-3烷基,以及当所述直链或支链C2-60亚烷基的主碳链中插入有两个以上基团R5时,各基团R5彼此不直接相连接;各基团R6选自亚环烷基、亚芳基、亚杂环基、亚杂芳基、亚炔基、亚烯基或其任意组合,其中所述亚环烷基、所述亚芳基、所述亚杂环基和所述亚杂芳基彼此独立地可选地进一步被选自C1-3烷基、C3-6环烷基、羟基、氨基、巯基、卤素、C1-3烷氧基、C1-3烷基氨基、卤代C1-3烷基、氨基取代的C1-3亚烷基、C1-3烷基-NHC(O)-、C1-3烷基-C(O)NH-、氰基或其任意组合的取代基取代。
16.如权利要求15所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其中LIN表示以下式:
#-U-亚烷基,
其中U表示C(O)或U表示键,且符号#表示与基团Y的连接点;和
所述亚烷基是取代或未取代的直链或支链C1-60亚烷基,取代基可选地选自C1-C3烷基、C3-6环烷基、羟基、氨基、巯基、卤素、C1-C3烷氧基、C1-C3烷基氨基、卤代C1-C3烷基、氨基取代的C1-3亚烷基、C1-3烷基-NHC(O)-、C1-3烷基-C(O)NH-、氰基或其任意组合。
17.如权利要求16所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其中LIN表示以下基团:#-U-CH2-、#-U-(CH2)2-、#-U-(CH2)3-、#-U-(CH2)4-、#-U-(CH2)5-、#-U-(CH2)6-、#-U-(CH2)7-、#-U-(CH2)8-、#-U-(CH2)9-、#-U-(CH2)10-、#-U-(CH2)11-、#-U-(CH2)12-、#-U-(CH2)13-、#-U-(CH2)14-、#-U-(CH2)15-、#-U-(CH2)16-、#-U-(CH2)17-、#-U-(CH2)18-、#-U-(CH2)19-、#-U-(CH2)20-、#-U-(CH2)21-、#-U-(CH2)22-、#-U-(CH2)25-、#-U-(CH2)30-、#-U-(CH2)35-、#-U-(CH2)40-、#-U-(CH2)45-、#-U-(CH2)50-、#-U-(CH2)55-、或#-U-(CH2)60-;其中所述基团的一或多个CH2的氢可选地进一步被选自以下的取代基替代:C1-C3烷基、C3-6环烷基、羟基、氨基、巯基、卤素、C1-C3烷氧基、C1-C3烷基氨基、卤代C1-C3烷基、氨基取代的C1-3亚烷基、C1-3烷基-NHC(O)-、C1-3烷基-C(O)NH-、氰基或其任意组合,以及U表示C(O)或U表示键,且符号#表示与基团Y的连接点。
18.如权利要求15所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其中LIN表示以下式:
#-U-亚烷基,
其中U表示C(O)或U表示键,且符号#表示与基团Y的连接点;和
所述亚烷基是未取代或取代的直链或支链的C2-60亚烷基,所述直链或支链的C2-60亚烷基的主碳链中插入有一或多个基团R5和/或一或多个基团R6或者一或多个基团R5与R6的任意组合,所述基团R5、R6或者基团R5与R6的组合将所述主碳链的一或多对相邻碳原子之间的碳-碳键间断开;各基团R5选自O、N(R7)、C(O)、C(O)O、OC(O)、C(O)N(R7)、N(R7)C(O)、或N(R7)C(O)N(R7),其中各R7独立地表示H或C1-3烷基,以及当所述直链或支链C2-60亚烷基的主碳链中插入有两个以上基团R5时,各基团R5彼此不直接相连接;各基团R6选自亚环烷基、亚芳基、亚杂环基、亚杂芳基、亚炔基、亚烯基或其任意组合,其中所述亚环烷基、所述亚芳基、所述亚杂环基和所述亚杂芳基彼此独立地可选地进一步被选自C1-3烷基、C3-6环烷基、羟基、氨基、巯基、卤素、C1-3烷氧基、C1-3烷基氨基、卤代C1-3烷基、氨基取代的C1-3亚烷基、C1-3烷基-NHC(O)-、C1-3烷基-C(O)NH-、氰基或其任意组合的取代基取代。
19.如权利要求1-14中任一项所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其中LIN表示以下式:
#-U-(C(Ra1)(Ra2))n4-(R5(C(Ra3)(Ra4))n5)m6-;
#-U-(C(Ra1)(Ra2))n4-(R5(C(Ra3)(Ra4))n5)m6-(R5(C(Ra5)(Ra6))n6)m7-;
#-U-(C(Ra1)(Ra2))n4-(R5(C(Ra3)(Ra4))n5)m6-(R5(C(Ra5)(Ra6))n6)m7-(R5(C(Ra7)(Ra8))n7)m8-;
#-U-(C(Ra1)(Ra2))n4-(R6(C(Ra3)(Ra4))n5)m6-;
#-U-(C(Ra1)(Ra2))n4-(R6(C(Ra3)(Ra4))n5)m6-(R6(C(Ra5)(Ra6))n6)m7-;
#-U-(C(Ra1)(Ra2))n4-(R6(C(Ra3)(Ra4))n5)m6-(R6(C(Ra5)(Ra6))n6)m7-(R6(C(Ra7)(Ra8))n7)m8-;
#-U-(C(Ra1)(Ra2))n4-(R5-R6-(C(Ra3)(Ra4))n5)m6-;
#-U-(C(Ra1)(Ra2))n4-(R5(C(Ra3)(Ra4))n5)m6-(R6(C(Ra5)(Ra6))n6)m7-;
#-U-(C(Ra1)(Ra2))n4-(R6-R5-(C(Ra3)(Ra4))n5)m6-;或
#-U-(C(Ra1)(Ra2))n4-(R6(C(Ra3)(Ra4))n5)m6-(R5(C(Ra5)(Ra6))n6)m7-;
其中,各基团R5独立地选自O、N(R7)、C(O)、C(O)O、OC(O)、C(O)N(R7)、N(R7)C(O)、或N(R7)C(O)N(R7),其中各R7独立地表示H或C1-3烷基,以及当所述直链或支链C2-60亚烷基的主碳链中插入有两个以上基团R5时,各基团R5彼此不直接相连接;各基团R6独立地选自亚环烷基、亚芳基、亚杂环基、亚杂芳基、亚炔基、亚烯基或其任意组合,其中所述亚环烷基、所述亚芳基、所述亚杂环基和所述亚杂芳基彼此独立地可选地被选自C1-C3烷基、C3-6环烷基、羟基、氨基、巯基、卤素、C1-C3烷氧基、C1-C3烷基氨基、卤代C1-C3烷基、氨基取代的C1-3亚烷基、C1-3烷基-NHC(O)-、C1-3烷基-C(O)NH-、氰基或其任意组合的取代基取代;
Ra1、Ra2、Ra3、Ra4、Ra5、Ra6、Ra7和Ra8分别独立地表示H、C1-C3烷基、C3-6环烷基、羟基、氨基、巯基、卤素、C1-C3烷氧基、C1-C3烷基氨基、氨基取代的C1-3亚烷基、卤代C1-C3烷基或氰基,
U表示C(O)或U表示键,且符号#表示与基团Y的连接点;和
n4、n5、n6、n7、m6、m7、m8分别独立地选自整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20。
20.如权利要求1-14中任一项所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其中LIN表示以下式:
#-U-(C(Ra1)(Ra2))n4-(O(C(Ra3)(Ra4))n5)m6-;
#-U-(C(Ra1)(Ra2))n4-(O(C(Ra3)(Ra4))n5)m6-(O(C(Ra5)(Ra6))n6)m7-;
#-U-(C(Ra1)(Ra2))n4-(O(C(Ra3)(Ra4))n5)m6-(O(C(Ra5)(Ra6))n6)m7-(O(C(Ra7)(Ra8))n7)m8-;
#-U-(C(Ra1)(Ra2))n4-(N(R7)(C(Ra3)(Ra4))n5)m6-;
#-U-(C(Ra1)(Ra2))n4-(N(R7)(C(Ra3)(Ra4))n5)m6-(N(R7)(C(Ra5)(Ra6))n6)m7-;
#-U-(C(Ra1)(Ra2))n4-(N(R7)(C(Ra3)(Ra4))n5)m6-(N(R7)(C(Ra5)(Ra6))n6)m7-(N(R7)(C(Ra7)(Ra8))n7)m8-;
#-U-(C(Ra1)(Ra2))n4-(C(O)N(R7)-(C(Ra3)(Ra4))n5)m6-;
#-U-(C(Ra1)(Ra2))n4-(C(O)N(R7)-(C(Ra3)(Ra4))n5)m6-(C(O)N(R7)-(C(Ra5)(Ra6))n6)m7-;
#-U-(C(Ra1)(Ra2))n4-(C(O)N(R7)-(C(Ra3)(Ra4))n5)m6-(C(O)N(R7)-(C(Ra5)(Ra6))n6)m7-(C(O)N(R7)-
(C(Ra7)(Ra8))n7)m8-;
#-U-(C(Ra1)(Ra2))n4-(C(O)N(R7)-(C(Ra3)(Ra4))n5)m6-(O-(C(Ra5)(Ra6))n6)m7-;
#-U-(C(Ra1)(Ra2))n4-C(O)N(R7)-(C(Ra3)(Ra4))n5-(O(C(Ra5)(Ra6))n6)m6-;
#-U-(C(Ra1)(Ra2))n4-(N(R7)C(O)-(C(Ra3)(Ra4))n5)m6-;
#-U-(C(Ra1)(Ra2))n4-(N(R7)C(O)-(C(Ra3)(Ra4))n5)m6-(O-(C(Ra5)(Ra6))n6)m7-;
#-U-(C(Ra1)(Ra2))n4-(N(R7)C(O)-(C(Ra3)(Ra4))n5)m6-(O-(C(Ra5)(Ra6))n6)m7-(O-(C(Ra7)(Ra8))n7)m8-;
#-U-(C(Ra1)(Ra2))n4-N(R7)C(O)-(C(Ra3)(Ra4))n5-(O(C(Ra5)(Ra6))n6)m6-;
#-U-(C(Ra1)(Ra2))n4-N(R7)C(O)N(R7)-(C(Ra3)(Ra4))n5-;
#-U-(C(Ra1)(Ra2))n4-C(O)-(C(Ra3)(Ra4))n5-;
#-U-(C(Ra1)(Ra2))n4-CH=CH-(C(Ra3)(Ra4))n5-;
#-U-(C(Ra1)(Ra2))n4-C≡C-(C(Ra3)(Ra4))n5-;
#-U-(C(Ra1)(Ra2))n4-C≡C-C≡C-(C(Ra3)(Ra4))n5-;
#-U-(C(Ra1)(Ra2))n4-(亚芳基-(C(Ra3)(Ra4))n5)m6-;
#-U-(C(Ra1)(Ra2))n4-(亚芳基-(C(Ra3)(Ra4))n5)m6-亚芳基-(C(Ra5)(Ra6))n6-;
#-U-(C(Ra1)(Ra2))n4-(亚杂环基-(C(Ra3)(Ra4))n5)m6-;
#-U-(C(Ra1)(Ra2))n4-(亚杂环基-(C(Ra3)(Ra4))n5)m6-(亚杂环基-(C(Ra5)(Ra6))n6)m7-;
#-U-(C(Ra1)(Ra2))n4-(亚杂芳基-(C(Ra3)(Ra4))n5)m6-;
#-U-(C(Ra1)(Ra2))n4-(亚杂芳基-(C(Ra3)(Ra4))n5)m6-(亚杂芳基-(C(Ra5)(Ra6))n6)m7-;
#-U-(C(Ra1)(Ra2))n4-(亚环烷基-(C(Ra3)(Ra4))n5)m6-;或
#-U-(C(Ra1)(Ra2))n4-(亚环烷基-(C(Ra3)(Ra4))n5)m6-(亚环烷基-(C(Ra5)(Ra6))n6)m7-;
其中,所述亚环烷基、所述亚芳基、所述亚杂环基和所述亚杂芳基彼此独立地可选地被选自C1-C3烷基、C3-6环烷基、羟基、氨基、巯基、卤素、C1-C3烷氧基、C1-C3烷基氨基、卤代C1-C3烷基、氨基取代的C1-3亚烷基、C1-3烷基-NHC(O)-、C1-3烷基-C(O)NH-、氰基或其任意组合的取代基取代;
各R7独立地表示H或C1-3烷基;
Ra1、Ra2、Ra3、Ra4、Ra5、Ra6、Ra7和Ra8分别独立地表示H、C1-C3烷基、C3-6环烷基、羟基、氨基、巯基、卤素、C1-C3烷氧基、C1-C3烷基氨基、氨基取代的C1-3亚烷基、卤代C1-C3烷基或氰基;
U表示C(O)或U表示键,且符号#表示与基团Y的连接点;和
n4、n5、n6、n7、n8、m6、m7、m8分别独立地表示整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20。
21.如权利要求15和18-20中任一项所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其中
所述亚环烷基选自以下基团:亚环丙基、亚环丁基、亚环戊基、亚环戊烯基、亚环己基、亚环己烯基、亚环庚基、亚环辛基、亚十氢萘基、八氢并环戊二烯亚基、八氢-1H-茚亚基、C5-15亚螺环基、亚金刚烷基、亚降金刚烷基、亚冰片基、二环[2.2.1]庚烷亚基、或二环[2.2.1]庚烯亚基,以及所述亚环烷基可选地被选自C1-C3烷基、C3-6环烷基、羟基、氨基、巯基、卤素、C1-C3烷氧基、C1-C3烷基氨基、卤代C1-C3烷基、氨基取代的C1-3亚烷基、C1-3烷基-NHC(O)-、C1-3烷基-C(O)NH-、氰基或其任意组合的取代基取代;
所述亚芳基选自以下基团:苯基或萘基,以及所述亚芳基可选地被选自C1-C3烷基、C3-6环烷基、羟基、氨基、巯基、卤素、C1-C3烷氧基、C1-C3烷基氨基、卤代C1-C3烷基、氨基取代的C1-3亚烷基、C1-3烷基-NHC(O)-、C1-3烷基-C(O)NH-、氰基或其任意组合的取代基取代;
所述亚杂环基选自以下基团:亚氮杂环丁基、亚氧杂环丁基、亚吡咯烷基、亚咪唑烷基、亚吡唑烷基、亚四氢呋喃基、亚四氢吡喃基、亚四氢噻吩基、亚四氢噻喃基、亚噁唑烷基、亚噻唑烷基、亚哌啶基、亚哌嗪基、亚吗啉基、亚硫代吗啉基、亚二氧杂环己基或亚二氮杂环庚基,以及所述亚杂环基可选地被选自C1-C3烷基、C3-6环烷基、羟基、氨基、巯基、卤素、C1-C3烷氧基、C1-C3烷基氨基、卤代C1-C3烷基、氨基取代的C1-3亚烷基、C1-3烷基-NHC(O)-、C1-3烷基-C(O)NH-、氰基或其任意组合的取代基取代;或
所述亚杂芳基选自以下基团:亚呋喃基、亚噁唑基、亚异噁唑基、亚噁二唑基、亚噻吩基、亚噻唑基、亚异噻唑基、亚噻二唑基、亚吡咯基、亚咪唑基、亚吡唑基、亚三唑基、亚吡啶基、亚嘧啶基、亚哒嗪基、亚吡嗪基、亚吲哚基、亚异吲哚基、亚苯并呋喃基、亚异苯并呋喃基、亚苯并噻吩基、亚吲唑基、亚苯并咪唑基、亚苯并噁唑基、亚苯并异噁唑基、亚苯并噻唑基、亚苯并异噻唑基、亚苯并三唑基、亚苯并[2,1,3]噁二唑基、亚苯并[2,1,3]噻二唑基、亚苯并[1,2,3]噻二唑基、亚喹啉基、亚异喹啉基、亚萘啶基、亚噌啉基、亚喹唑啉基、亚喹喔啉基、亚酞嗪基、吡唑并[1,5-a]吡啶亚基、吡唑并[1,5-a]嘧啶亚基、咪唑并[1,2-a]吡啶亚基、1H-吡咯并[3,2-b]吡啶亚基、1H-吡咯并[2,3-b]吡啶亚基、4H-氟[3,2-b]吡咯亚基、吡咯并[2,1-b]噻唑亚基、或咪唑并[2,1-b]噻唑亚基,以及所述亚杂芳基可选地被选自C1-C3烷基、C3-6环烷基、羟基、氨基、巯基、卤素、C1-C3烷氧基、C1-C3烷基氨基、卤代C1-C3烷基、氨基取代的C1-3亚烷基、C1-3烷基-NHC(O)-、C1-3烷基-C(O)NH-、氰基或其任意组合的取代基取代。
22.如权利要求1-14中任一项所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其中LIN表示以下式:
#-U-CH2-O-CH2-、#-U-CH2-O-(CH2)2-、#-U-(CH2)1-O-(CH2)3-、#-U-(CH2)1-O-(CH2)4-、#-U-(CH2)1-O-(CH2)5-、#-U-(CH2)1-O-(CH2)6-、#-U-(CH2)1-O-(CH2)7-、#-U-(CH2)1-O-(CH2)8-、#-U-(CH2)1-O-(CH2)9-、#-U-(CH2)1-O-(CH2)10-、#-U-(CH2)2-O-(CH2)1-、#-U-(CH2)2-O-(CH2)2-、#-U-(CH2)2-O-(CH2)3-、#-U-(CH2)2-O-(CH2)4-、#-U-(CH2)2-O-(CH2)5-、#-U-(CH2)2-O-(CH2)6-、#-U-(CH2)2-O-(CH2)7-、#-U-(CH2)2-O-(CH2)8-、#-U-(CH2)2-O-(CH2)9-、#-U-(CH2)2-O-(CH2)10-、#-U-(CH2)2-O-(CH2)11-、#-U-(CH2)2-O-(CH2)12-、#-U-(CH2)3-O-(CH2)1-、#-U-(CH2)3-O-(CH2)2-、#-U-(CH2)3-O-(CH2)3-、#-U-(CH2)3-O-(CH2)4-、#-U-(CH2)3-O-(CH2)5-、#-U-(CH2)3-O-(CH2)6-、#-U-(CH2)3-O-(CH2)7-、#-U-(CH2)4-O-(CH2)1-、#-U-(CH2)4-O-(CH2)2-、#-U-(CH2)4-O-(CH2)3-、#-U-(CH2)4-O-(CH2)4-、#-U-(CH2)4-O-(CH2)5-、#-U-(CH2)4-O-(CH2)6-、#-U-(CH2)5-O-(CH2)1-、#-U-(CH2)5-O-(CH2)2-、#-U-(CH2)5-O-(CH2)3-、#-U-(CH2)5-O-(CH2)4-、#-U-(CH2)5-O-(CH2)5-、#-U-(CH2)6-O-(CH2)1-、#-U-(CH2)6-O-(CH2)2-、#-U-(CH2)6-O-(CH2)3-、#-U-(CH2)6-O-(CH2)4-、#-U-(CH2)7-O-(CH2)1-、#-U-(CH2)7-O-(CH2)2-、#-U-(CH2)7-O-(CH2)3-、#-U-(CH2)8-O-(CH2)1-、#-U-(CH2)8-O-(CH2)2-、#-U-CH(CH3)-O-(CH2)1-、#-U-CH(CH3)-O-(CH2)2-、#-U-CH(CH3)-O-(CH2)3-、#-U-CH(CH3)-O-(CH2)4-、#-U-CH(CH3)-O-(CH2)5-、#-U-CH(CH3)-O-(CH2)6-、#-U-CH(CH3)-O-(CH2)7-、#-U-CH(CH3)-O-(CH2)8-、#-U-CH(CH3)-O-(CH2)9-、#-U-CH(CH3)-O-(CH2)10-、#-U-CH2-(O(CH2)2)2-、#-U-CH2-(O(CH2)2)3-、#-U-CH2-(O(CH2)2)4-、#-U-CH2-(O(CH2)2)5-、#-U-CH2-(O(CH2)2)6-、#-U-CH2-(O(CH2)2)7-、#-U-CH2-(O(CH2)2)8-、#-U-CH2-(O(CH2)2)9-、#-U-CH2-(O(CH2)2)10-、#-U-CH2-(O(CH2)2)1-OCH2-、#-U-CH2-(O(CH2)2)2-OCH2-、#-U-CH2-(O(CH2)2)3-OCH2-、#-U-CH2-(O(CH2)2)4-OCH2-、#-U-CH2-(O(CH2)2)5-OCH2-、#-U-CH2-(O(CH2)2)6-OCH2-、#-U-CH2-(O(CH2)2)7-OCH2-、#-U-CH2-(O(CH2)2)8-OCH2-、#-U-CH2-(O(CH2)2)9-OCH2-、#-U-CH2-(O(CH2)2)10-OCH2-、#-U-(CH2)2-(O(CH2)2)2-、#-U-(CH2)2-(O(CH2)2)3-、#-U-(CH2)2-(O(CH2)2)4-、#-U-(CH2)2-(O(CH2)2)5-、#-U-(CH2)2-(O(CH2)2)6-、#-U-(CH2)2-(O(CH2)2)7-、#-U-(CH2)2-(O(CH2)2)8-、#-U-(CH2)2-(O(CH2)2)9-、#-U-(CH2)2-(O(CH2)2)10-、#-U-(CH2)3-(O(CH2)2)2-、#-U-(CH2)3-(O(CH2)2)3-、#-U-(CH2)3-(O(CH2)2)4-、#-U-(CH2)3-(O(CH2)2)5-、#-U-(CH2)3-(O(CH2)2)6-、#-U-(CH2)3-(O(CH2)2)7-、#-U-(CH2)3-(O(CH2)2)8-、#-U-(CH2)3-(O(CH2)2)9-、#-U-(CH2)3-(O(CH2)2)10-、#-U-(CH2)4-(O(CH2)2)2-、#-U-(CH2)4-(O(CH2)2)3-、#-U-(CH2)4-(O(CH2)2)4-、#-U-(CH2)4-(O(CH2)2)5-、#-U-(CH2)4-(O(CH2)2)6-、#-U-(CH2)4-(O(CH2)2)7-、#-U-(CH2)4-(O(CH2)2)8-、#-U-(CH2)4-(O(CH2)2)9-、#-U-(CH2)4-(O(CH2)2)10-、#-U-CH2-(O(CH2)3)2-、#-U-CH2-(O(CH2)3)3-、#-U-CH2-(O(CH2)3)4-、#-U-CH2-(O(CH2)3)5-、#-U-CH2-(O(CH2)3)6-、#-U-CH2-(O(CH2)3)7-、#-U-CH2-(O(CH2)3)8-、#-U-CH2-(O(CH2)3)9-、#-U-CH2-(O(CH2)3)10-、#-U-(CH2)2-(O(CH2)3)2-、#-U-(CH2)2-(O(CH2)3)3-、#-U-(CH2)2-(O(CH2)3)4-、#-U-(CH2)2-(O(CH2)3)5-、#-U-(CH2)2-(O(CH2)3)6-、#-U-(CH2)2-(O(CH2)3)7-、#-U-(CH2)2-(O(CH2)3)8-、#-U-(CH2)2-(O(CH2)3)9-、#-U-(CH2)2-(O(CH2)3)10-、#-U-(CH2)3-(O(CH2)3)2-、#-U-(CH2)3-(O(CH2)3)3-、#-U-(CH2)3-(O(CH2)3)4-、#-U-(CH2)3-(O(CH2)3)5-、#-U-(CH2)3-(O(CH2)3)6-、#-U-(CH2)3-(O(CH2)3)7-、#-U-(CH2)3-(O(CH2)3)8-、#-U-(CH2)3-(O(CH2)3)9-、#-U-(CH2)3-(O(CH2)3)10-、#-U-CH2-O-(CH2)2-O-(CH2)3-、#-U-CH2-(O(CH2)2)2-(O(CH2)3)2-、#-U-CH2-(O(CH2)2)3-(O(CH2)3)3-、#-U-CH2-(O(CH2)2)4-(O(CH2)3)4-、#-U-CH2-(O(CH2)2)5-(O(CH2)3)5-、#-U-CH2-(O(CH2)2)6-(O(CH2)3)6-、#-U-(CH2)2-O-(CH2)2-O-(CH2)3-、#-U-(CH2)2-(O(CH2)2)2-(O(CH2)3)2-、#-U-(CH2)2-(O(CH2)2)3-(O(CH2)3)3-、#-U-(CH2)2-(O(CH2)2)4-(O(CH2)3)4-、#-U-(CH2)2-(O(CH2)2)5-(O(CH2)3)5-、#-U-(CH2)2-(O(CH2)2)6-(O(CH2)3)6-、#-U-(CH2)3-O-(CH2)2-O-(CH2)3-、#-U-(CH2)3-(O(CH2)2)2-(O(CH2)3)2-、#-U-(CH2)3-(O(CH2)2)3-(O(CH2)3)3-、#-U-(CH2)3-(O(CH2)2)4-(O(CH2)3)4-、#-U-(CH2)3-(O(CH2)2)5-(O(CH2)3)5-、#-U-(CH2)3-(O(CH2)2)6-(O(CH2)3)6-、#-U-CH2-O-(CH2)3-O-(CH2)2-、#-U-CH2-(O(CH2)3)2-(O(CH2)2)2-、#-U-CH2-(O(CH2)3)3-(O(CH2)2)3-、#-U-CH2-(O(CH2)3)4-(O(CH2)2)4-、#-U-CH2-(O(CH2)3)5-(O(CH2)2)5-、#-U-CH2-(O(CH2)3)6-(O(CH2)2)6-、#-U-(CH2)2-O-(CH2)3-O-(CH2)2-、#-U-(CH2)2-(O(CH2)3)2-(O(CH2)2)2-、#-U-(CH2)2-(O(CH2)3)3-(O(CH2)2)3-、#-U-(CH2)2-(O(CH2)3)4-(O(CH2)2)4-、#-U-(CH2)2-(O(CH2)3)5-(O(CH2)2)5-、#-U-(CH2)2-(O(CH2)3)6-(O(CH2)2)6-、#-U-(CH2)3-O-(CH2)3-O-(CH2)2-、#-U-(CH2)3-(O(CH2)3)2-(O(CH2)2)2-、#-U-(CH2)3-(O(CH2)3)3-(O(CH2)2)3-、#-U-(CH2)3-(O(CH2)3)4-(O(CH2)2)4-、#-U-(CH2)3-(O(CH2)3)5-(O(CH2)2)5-、#-U-(CH2)3-(O(CH2)3)6-(O(CH2)2)6-、#-U-CH2-O-(CH2)2-O-CH2-、#-U-(CH2)2-O-(CH2)2-O-CH2-、#-U-(CH2)2-(O(CH2)2)2-O-(CH2)3-、#-U-(CH2)2-(O(CH2)2)3-O-(CH2)3-、#-U-(CH2)2-(O(CH2)2)4-O-(CH2)3-、#-U-(CH2)5-(O(CH2)2)2-O-(CH2)5-、#-U-(CH2)5-(O(CH2)2)2-O-(CH2)6-、#-U-(CH2)1-N(R7)-(CH2)1-、#-U-(CH2)1-N(R7)-(CH2)2-、#-U-(CH2)1-N(R7)-(CH2)3-、#-U-(CH2)1-N(R7)-(CH2)4-、#-U-(CH2)1-N(R7)-(CH2)5-、#-U-(CH2)1-N(R7)-(CH2)6-、#-U-(CH2)1-N(R7)-(CH2)7-、#-U-(CH2)1-N(R7)-(CH2)8-、#-U-(CH2)1-N(R7)-(CH2)9-、#-U-(CH2)1-N(R7)-(CH2)10-、#-U-(CH2)2-N(R7)-(CH2)1-、#-U-(CH2)2-N(R7)-(CH2)2-、#-U-(CH2)2-N(R7)-(CH2)3-、#-U-(CH2)2-N(R7)-(CH2)4-、#-U-(CH2)2-N(R7)-(CH2)5-、#-U-(CH2)2-N(R7)-(CH2)6-、#-U-(CH2)2-N(R7)-(CH2)7-、#-U-(CH2)2-N(R7)-(CH2)8-、#-U-(CH2)2-N(R7)-(CH2)9-、#-U-(CH2)2-N(R7)-(CH2)10-、#-U-(CH2)2-N(R7)-(CH2)11-、#-U-(CH2)2-N(R7)-(CH2)12-、#-U-(CH2)3-N(R7)-(CH2)1-、#-U-(CH2)3-N(R7)-(CH2)2-、#-U-(CH2)3-N(R7)-(CH2)3-、#-U-(CH2)4-N(R7)-(CH2)1-、#-U-(CH2)4-N(R7)-(CH2)2-、#-U-(CH2)4-N(R7)-(CH2)3-、#-U-(CH2)4-N(R7)-(CH2)4-、#-U-(CH2)5-N(R7)-(CH2)1-、#-U-(CH2)5-N(R7)-(CH2)2-、#-U-(CH2)5-N(R7)-(CH2)3-、#-U-(CH2)5-N(R7)-(CH2)4-、#-U-(CH2)5-N(R7)-(CH2)5-、#-U-(CH2)6-N(R7)-(CH2)1-、#-U-(CH2)6-N(R7)-(CH2)2-、#-U-(CH2)6-N(R7)-(CH2)3-、#-U-(CH2)7-N(R7)-(CH2)1-、#-U-(CH2)7-N(R7)-(CH2)2-、#-U-(CH2)7-N(R7)-(CH2)3-、#-U-(CH2)8-N(R7)-(CH2)1-、#-U-(CH2)8-N(R7)-(CH2)2-、#-U-(CH2)8-N(R7)-(CH2)3-、#-U-CH(CH3)-N(R7)-(CH2)1-、#-U-CH(CH3)-N(R7)-(CH2)2-、#-U-CH(CH3)-N(R7)-(CH2)3-、#-U-CH(CH3)-N(R7)-(CH2)4-、#-U-CH(CH3)-N(R7)-(CH2)5-、#-U-CH(CH3)-N(R7)-(CH2)6-、#-U-CH(CH3)-N(R7)-(CH2)7-、#-U-CH(CH3)-N(R7)-(CH2)8-、#-U-CH(CH3)-N(R7)-(CH2)9-、#-U-CH(CH3)-N(R7)-(CH2)10-、#-U-CH2C(O)NHCH2-、#-U-(CH2)2C(O)NH(CH2)2-、#-U-(CH2)2C(O)NH(CH2)3-、#-U-(CH2)2C(O)NH(CH2)4-、#-U-(CH2)2C(O)NH(CH2)5-、#-U-(CH2)3C(O)NH(CH2)3-、#-U-(CH2)3C(O)NH(CH2)4-、#-U-(CH2)4C(O)NH(CH2)4-、#-U-(CH2)5C(O)NH(CH2)5-、#-U-(CH2)6C(O)NH(CH2)7-、#-U-(CH2)6C(O)NH(CH2)6-、#-U-(CH2)7C(O)NH(CH2)7-、#-U-(CH2)8C(O)NH(CH2)8、U-(CH2)9C(O)NH(CH2)9-、#-U-(CH2)10C(O)NH(CH2)10-、#-U-(CH2)2C(O)NH(CH2)2-O-(CH2)2-、#-U-CH2NHC(O)CH2-、#-U-(CH2)2NHC(O)(CH2)2-、#-U-(CH2)2NHC(O)(CH2)3-、#-U-(CH2)2NHC(O)(CH2)4-、#-U-(CH2)2NHC(O)(CH2)5-、#-U-(CH2)3NHC(O)(CH2)3-、#-U-(CH2)3NHC(O)(CH2)4-、#-U-(CH2)4NHC(O)(CH2)4-、#-U-(CH2)5NHC(O)(CH2)5-、#-U-(CH2)6NHC(O)(CH2)7-、#-U-(CH2)6NHC(O)(CH2)6-、#-U-(CH2)7NHC(O)(CH2)7-、#-U-(CH2)8NHC(O)(CH2)8、#-U-(CH2)9NHC(O)(CH2)9-、#-U-(CH2)10NHC(O)(CH2)10-、#-U-(CH2)4NHC(O)(CH2)8-、#-U-(CH2)2NHC(O)(CH2)2-O-(CH2)2-、#-U-(CH2)4NHC(O)CH2-、#-U-CH2-亚苯基-CH2-、#-U-CH2-亚苯基-(CH2)2-、#-U-CH2-亚苯基-(CH2)3-、#-U-CH2-亚苯基-(CH2)4-、#-U-CH2-亚苯基-(CH2)5-、#-U-CH2-亚苯基-(CH2)6-、#-U-CH2-亚苯基-(CH2)7-、#-U-CH2-亚苯基-(CH2)8-、#-U-(CH2)2-亚苯基-(CH2)1-、#-U-(CH2)2-亚苯基-(CH2)2-、#-U-(CH2)2-亚苯基-(CH2)3-、#-U-(CH2)2-亚苯基-(CH2)4-、#-U-(CH2)2-亚苯基-(CH2)5-、#-U-(CH2)2-亚苯基-(CH2)6-、#-U-(CH2)2-亚苯基-(CH2)7-、#-U-(CH2)2-亚苯基-(CH2)8-、#-U-(CH2)3-亚苯基-CH2-、#-U-(CH2)3-亚苯基-(CH2)2-、#-U-(CH2)3-亚苯基-(CH2)3-、#-U-(CH2)3-亚苯基-(CH2)4-、#-U-(CH2)3-亚苯基-(CH2)5-、#-U-(CH2)3-亚苯基-(CH2)6-、#-U-(CH2)3-亚苯基-(CH2)7-、#-U-(CH2)3-亚苯基-(CH2)8-、#-U-(CH2)4-亚苯基-CH2-、#-U-(CH2)4-亚苯基-(CH2)2-、#-U-(CH2)4-亚苯基-(CH2)3-、#-U-(CH2)4-亚苯基-(CH2)4-、#-U-(CH2)4-亚苯基-(CH2)5-、#-U-(CH2)4-亚苯基-(CH2)6-、#-U-(CH2)4-亚苯基-(CH2)7-、#-U-(CH2)4-亚苯基-(CH2)8-、#-U-(CH2)5-亚苯基-(CH2)1-、#-U-(CH2)5-亚苯基-(CH2)2-、#-U-(CH2)5-亚苯基-(CH2)3-、#-U-(CH2)5-亚苯基-(CH2)4-、#-U-(CH2)5-亚苯基-(CH2)5-、#-U-(CH2)5-亚苯基-(CH2)6-、#-U-(CH2)5-亚苯基-(CH2)7-、#-U-(CH2)5-亚苯基-(CH2)8-、#-U-(CH2)6-亚苯基-(CH2)1-、#-U-(CH2)6-亚苯基-(CH2)2-、#-U-(CH2)6-亚苯基-(CH2)3-、#-U-(CH2)6-亚苯基-(CH2)4-、#-U-(CH2)6-亚苯基-(CH2)5-、#-U-(CH2)6-亚苯基-(CH2)6-、#-U-(CH2)6-亚苯基-(CH2)7-、#-U-(CH2)6-亚苯基-(CH2)8-、#-U-(CH2)7-亚苯基-(CH2)1-、#-U-(CH2)7-亚苯基-(CH2)2-、#-U-(CH2)7-亚苯基-(CH2)3-、#-U-(CH2)7-亚苯基-(CH2)4-、#-U-(CH2)7-亚苯基-(CH2)8-、#-U-(CH2)8-亚苯基-CH2-、#-U-(CH2)8-亚苯基-(CH2)2-、#-U-(CH2)8-亚苯基-(CH2)3-、#-U-(CH2)8-亚苯基-(CH2)4-、#-U-(CH2)8-亚苯基-(CH2)5-、#-U-(CH2)8-亚苯基-(CH2)6-、#-U-(CH2)8-亚苯基-(CH2)7-、#-U-(CH2)8-亚苯基-(CH2)8-、#-U-CH2-N(R7)-CH2-亚苯基-CH2-、#-U-CH2-N(R7)-CH2-亚苯基-(CH2)2-、#-U-CH2-N(R7)-CH2-亚苯基-(CH2)3-、#-U-CH2-N(R7)-CH2-亚苯基-(CH2)4-、#-U-CH2-N(R7)-CH2-亚苯基-(CH2)5-、#-U-CH2-N(R7)-CH2-亚苯基-(CH2)6-、#-U-CH2-N(R7)-CH2-亚苯基-(CH2)7-、#-U-CH2-N(R7)-CH2-亚苯基-(CH2)8-、#-U-CH2-N(R7)-(CH2)2-亚苯基-CH2-、#-U-CH2-N(R7)-(CH2)2-亚苯基-(CH2)2-、#-U-CH2-N(R7)-(CH2)2-亚苯基-(CH2)3-、#-U-CH2-N(R7)-(CH2)2-亚苯基-(CH2)4-、#-U-CH2-N(R7)-(CH2)2-亚苯基-(CH2)5-、#-U-CH2-N(R7)-(CH2)2-亚苯基-(CH2)6-、#-U-CH2-N(R7)-(CH2)2-亚苯基-(CH2)7-、#-U-CH2-N(R7)-(CH2)2-亚苯基-(CH2)8-、#-U-(CH2)2-N(R7)-CH2-亚苯基-CH2-、#-U-(CH2)2-N(R7)-CH2-亚苯基-(CH2)2-、#-U-(CH2)2-N(R7)-CH2-亚苯基-(CH2)3-、#-U-(CH2)2-N(R7)-CH2-亚苯基-(CH2)4-、#-U-(CH2)2-N(R7)-CH2-亚苯基-(CH2)5-、#-U-(CH2)2-N(R7)-CH2-亚苯基-(CH2)6-、#-U-(CH2)2-N(R7)-CH2-亚苯基-(CH2)7-、#-U-(CH2)2-N(R7)-CH2-亚苯基-(CH2)8-、#-U-(CH2)3-N(R7)-CH2-亚苯基-CH2-、#-U-(CH2)3-N(R7)-CH2-亚苯基-(CH2)2-、#-U-(CH2)3-N(R7)-CH2-亚苯基-(CH2)3-、#-U-(CH2)3-N(R7)-CH2-亚苯基-(CH2)8-、#-U-(CH2)4-N(R7)-CH2-亚苯基-CH2-、#-U-(CH2)4-N(R7)-CH2-亚苯基-(CH2)2-、#-U-(CH2)4-N(R7)-CH2-亚苯基-(CH2)3-、#-U-(CH2)4-N(R7)-CH2-亚苯基-(CH2)8-、#-U-(CH2)5-N(R7)-CH2-亚苯基-(CH2)3-、#-U-(CH2)5-N(R7)-CH2-亚苯基-(CH2)8-、#-U-(CH2)6-N(R7)-CH2-亚苯基-(CH2)3-、#-U-(CH2)6-N(R7)-CH2-亚苯基-(CH2)8-、#-U-(CH2)7-N(R7)-CH2-亚苯基-(CH2)3-、#-U-(CH2)7-N(R7)-CH2-亚苯基-(CH2)8-、#-U-(CH2)8-N(R7)-CH2-亚苯基-CH2-、#-U-(CH2)8-N(R7)-CH2-亚苯基-(CH2)2-、#-U-(CH2)8-N(R7)-CH2-亚苯基-(CH2)3-、#-U-(CH2)8-N(R7)-CH2-亚苯基-(CH2)4-、#-U-(CH2)8-N(R7)-CH2-亚苯基-(CH2)5-、#-U-(CH2)8-N(R7)-CH2-亚苯基-(CH2)6-、#-U-(CH2)8-N(R7)-CH2-亚苯基-(CH2)7-、#-U-(CH2)8-N(R7)-CH2-亚苯基-(CH2)8-、#-U-CH2-亚哌嗪基-CH2-、#-U-CH2-亚哌嗪基-(CH2)2-、#-U-CH2-亚哌嗪基-(CH2)3-、#-U-CH2-亚哌嗪基-(CH2)4-、#-U-CH2-亚哌嗪基-(CH2)5-、#-U-CH2-亚哌嗪基-(CH2)6-、#-U-CH2-亚哌嗪基-(CH2)7-、#-U-CH2-亚哌嗪基-(CH2)8-、#-U-(CH2)2-亚哌嗪基-(CH2)1-、#-U-(CH2)2-亚哌嗪基-(CH2)2-、#-U-(CH2)2-亚哌嗪基-(CH2)3-、#-U-(CH2)2-亚哌嗪基-(CH2)4-、#-U-(CH2)2-亚哌嗪基-(CH2)5-、#-U-(CH2)2-亚哌嗪基-(CH2)6-、#-U-(CH2)2-亚哌嗪基-(CH2)7-、#-U-(CH2)2-亚哌嗪基-(CH2)8-、#-U-(CH2)3-亚哌嗪基-CH2-、#-U-(CH2)3-亚哌嗪基-(CH2)2-、#-U-(CH2)3-亚哌嗪基-(CH2)3-、#-U-(CH2)3-亚哌嗪基-(CH2)4-、#-U-(CH2)3-亚哌嗪基-(CH2)5-、#-U-(CH2)3-亚哌嗪基-(CH2)6-、#-U-(CH2)3-亚哌嗪基-(CH2)7-、#-U-(CH2)3-亚哌嗪基-(CH2)8-、#-U-(CH2)4-亚哌嗪基-CH2-、#-U-(CH2)4-亚哌嗪基-(CH2)2-、#-U-(CH2)4-亚哌嗪基-(CH2)3-、#-U-(CH2)4-亚哌嗪基-(CH2)4-、#-U-(CH2)4-亚哌嗪基-(CH2)5-、#-U-(CH2)4-亚哌嗪基-(CH2)6-、#-U-(CH2)4-亚哌嗪基-(CH2)7-、#-U-(CH2)4-亚哌嗪基-(CH2)8-、#-U-(CH2)5-亚哌嗪基-(CH2)1-、#-U-(CH2)5-亚哌嗪基-(CH2)2-、#-U-(CH2)5-亚哌嗪基-(CH2)3-、#-U-(CH2)5-亚哌嗪基-(CH2)4-、#-U-(CH2)5-亚哌嗪基-(CH2)5-、#-U-(CH2)5-亚哌嗪基-(CH2)6-、#-U-(CH2)5-亚哌嗪基-(CH2)7-、#-U-(CH2)5-亚哌嗪基-(CH2)8-、#-U-(CH2)6-亚哌嗪基-(CH2)1-、#-U-(CH2)6-亚哌嗪基-(CH2)2-、#-U-(CH2)6-亚哌嗪基-(CH2)3-、#-U-(CH2)6-亚哌嗪基-(CH2)4-、#-U-(CH2)6-亚哌嗪基-(CH2)5-、#-U-(CH2)6-亚哌嗪基-(CH2)6-、#-U-(CH2)6-亚哌嗪基-(CH2)7-、#-U-(CH2)6-亚哌嗪基-(CH2)8-、#-U-(CH2)7-亚哌嗪基-(CH2)1-、#-U-(CH2)7-亚哌嗪基-(CH2)2-、#-U-(CH2)7-亚哌嗪基-(CH2)3-、#-U-(CH2)7-亚哌嗪基-(CH2)4-、#-U-(CH2)7-亚哌嗪基-(CH2)8-、#-U-(CH2)8-亚哌嗪基-CH2-、#-U-(CH2)8-亚哌嗪基-(CH2)2-、#-U-(CH2)8-亚哌嗪基-(CH2)3-、#-U-(CH2)8-亚哌嗪基-(CH2)4-、#-U-(CH2)8-亚哌嗪基-(CH2)5-、#-U-(CH2)8-亚哌嗪基-(CH2)6-、#-U-(CH2)8-亚哌嗪基-(CH2)7-、或#-U-(CH2)8-亚哌嗪基-(CH2)8-;
其中,U表示C(O)或U表示键,且符号#表示与基团Y的连接点;
各R7独立地表示H或C1-3烷基;和
所述亚苯基和所述亚哌嗪基彼此独立地可选地进一步被选自C1-C3烷基、C3-6环烷基、羟基、氨基、巯基、卤素、C1-C3烷氧基、C1-C3烷基氨基、卤代C1-C3烷基、氨基取代的C1-3亚烷基、C1-3烷基-NHC(O)-、C1-3烷基-C(O)NH-、氰基或其任意组合的取代基取代。
23.如权利要求1所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其中
式(I)化合物也是由以下式(V)的结构表示:
其中X1、X2、X3和X4中的任意1个、2个或3个表示N,剩余的表示CH;以及
ULM、LIN、Y、环C、(Rc)m3、m、环B、(Rb)m2、L1、R1、R2、(Ra)m1如权利要求1-22中任一项中所定义;或者
式(I)化合物也是由以下式(VI)的结构表示:
其中X5和X6相同或不同且分别独立地表示CH或N;以及
ULM、LIN、Y、环C、(Rc)m3、m、环B、(Rb)m2、L1、R1、R2、(Ra)m1如权利要求1-22中任一项中所定义;或者
式(I)化合物也是由以下式(VII)的结构表示:
其中X7和X8中的任意一个表示CH,且另一个表示N,或者X7和X8表示CH;以及
ULM、LIN、Y、环C、(Rc)m3、m、环B、(Rb)m2、L1、R1、R2、(Ra)m1如权利要求1-22中任一项中所定义;或者
式(I)化合物也是由以下式(VIII)的结构表示:
其中ULM、LIN、Y、环C、(Rc)m3、m、环B、(Rb)m2、L1、R1、R2、(Ra)m1如权利要求1-22中任一项中所定义。
24.如权利要求1所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其选自:
(E)-N-(4-(1-(4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丙酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丁酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)戊酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基乙酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)丁酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)戊酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)己酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)庚酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)庚酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)戊酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)己酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丙基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)戊基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)己基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)庚基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(8-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)辛基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(11-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)十一烷基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊-4-炔-1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(6-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)己-5-炔-1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(8-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)辛-7-炔-1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(9-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)壬-8-炔-1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(3-氧代-3-(4-(4-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)苯基)哌嗪-1-基)丙酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(4-氧代-4-(4-(4-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)苯基)哌嗪-1-基)丁酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(5-氧代-5-(4-(4-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)苯基)哌嗪-1-基)戊酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(6-氧代-6-(4-(4-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)苯基)哌嗪-1-基)己酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(7-氧代-7-(4-(4-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)苯基)哌嗪-1-基)庚酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(8-氧代-8-(4-(4-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)苯基)哌嗪-1-基)辛酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(9-氧代-9-(4-(4-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)苯基)哌嗪-1-基)壬酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(10-氧代-10-(4-(4-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)苯基)哌嗪-1-基)癸酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(11-氧代-11-(4-(4-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)苯基)哌嗪-1-基)十一烷酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(2-(2-(2-氧代-2-(4-(4-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)苯基)哌嗪-1-基)乙氧基)乙氧基)乙酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(3-(2-(3-氧代-3-(4-(4-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)苯基)哌嗪-1-基)丙氧基)乙氧基)丙酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-2-(叔丁基)-4,16-二氧代-16-(4-(4-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)苯基)哌嗪-1-基)-7,10,13-三氧杂-3-氮杂十六烷酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-2-(叔丁基)-4,19-二氧代-19-(4-(4-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)苯基)哌嗪-1-基)-7,10,13,16-四氧杂-3-氮杂十九烷酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-2-(叔丁基)-4,22-二氧代-22-(4-(4-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)苯基)哌嗪-1-基)-7,10,13,16,19-五氧杂-3-氮杂二十二烷酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(16-氧代-16-(4-(4-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)苯基)哌嗪-1-基)十六烷酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(E)-N-(4-(1-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)丁基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(8-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)辛基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(4-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基)哌嗪-1-基)苯甲酰基)哌嗪-1-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丁基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)庚基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)辛基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)庚酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)辛酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)乙酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)戊酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)己酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)庚酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(8-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)辛-7-炔-1-基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(8-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)辛-7-炔-1-基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(8-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)辛-7-炔-1-基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(8-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)辛-7-炔-1-基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)丙酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)戊-4-炔-1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(6-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)己-5-炔-1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)庚-6-炔-1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(8-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)辛-7-炔-1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)丙酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(3-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(14-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-3,6,9,12-四氧杂十四烷酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(17-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-3,6,9,12,15-五氧杂十七烷酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(17-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-3,6,9,12,15-五氧杂十七烷酰基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丙酰基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丁酰基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)戊酰基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)庚酰基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙酰基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙酰基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊酰基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)庚酰基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)丙酰基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙酰基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)丙酰基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙酰基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(3-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)丙酰基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)乙酰基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(17-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-3,6,9,12,15-五氧杂十七烷酰基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)丙酰基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)丙酰基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)乙酰基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)戊酰基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)庚酰基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基乙酰基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)丁酰基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)戊酰基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)庚酰基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙酰基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)丙酰基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙酰基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)丙酰基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙氧基)乙酰基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(3-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙氧基)丙酰基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(14-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-3,6,9,12-四氧杂十四烷酰基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(1-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-3,6,9,12-四氧杂十五烷-15-酰基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙酰基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)戊酰基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)己酰基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙酰基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙酰基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(17-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-3,6,9,12,15-五氧杂十七烷酰基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊-4-炔-1-基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(6-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)己-5-炔-1-基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(9-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)壬-8-炔-1-基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)戊-4-炔-1-基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(6-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)己-5-炔-1-基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(7-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)庚-6-炔-1-基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丙基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)戊基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)己基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丁基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)辛基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)戊基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)己基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)丙基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)戊基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(3-氧代-3-(4-(4-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)苯基)哌啶-1-基)丙酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(5-氧代-5-(4-(4-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)苯基)哌啶-1-基)戊酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(7-氧代-7-(4-(4-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)苯基)哌啶-1-基)庚酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(10-氧代-10-(4-(4-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)苯基)哌啶-1-基)癸酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(2-(2-(2-氧代-2-(4-(4-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)苯基)哌啶-1-基)乙氧基)乙氧基)乙酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(3-(2-(3-氧代-3-(4-(4-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)苯基)哌啶-1-基)丙氧基)乙氧基)丙酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-2-(叔丁基)-4,16-二氧代-16-(4-(4-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)苯基)哌啶-1-基)-7,10,13-三氧杂-3-氮杂十六烷酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-2-(叔丁基)-4,22-二氧代-22-(4-(4-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)苯基)哌啶-1-基)-7,10,13,16,19-五氧杂-3-氮杂二十二烷酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(E)-N-(4-(1-(6-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丙酰基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)戊酰基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)庚酰基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)丙酰基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙酰基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙酰基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己酰基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)庚酰基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙酰基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)丙酰基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(3-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(14-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-3,6,9,12-四氧杂十四烷酰基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(17-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-3,6,9,12,15-五氧杂十七烷酰基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)乙酰基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)戊酰基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)庚酰基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)戊-4-炔-1-基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(6-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)己-5-炔-1-基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)庚-6-炔-1-基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)丁基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)辛基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(6-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)己基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)庚基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)戊基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基乙酰基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)丁酰基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)己酰基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙酰基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)丙酰基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(14-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-3,6,9,12-四氧杂十四烷酰基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(1-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-3,6,9,12-四氧杂十五烷-15-酰基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)戊酰基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)己酰基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙酰基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(17-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-3,6,9,12,15-五氧杂十七烷酰基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)乙酰基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)戊酰基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)庚酰基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊-4-炔-1-基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(6-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)己-5-炔-1-基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(9-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)壬-8-炔-1-基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丙基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)戊基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(8-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)辛基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)丁基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(8-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)辛基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(2,6-二氧代哌啶-3-基)-3-(6-(4-(5-(4-(4-(3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)吡啶-2-基)哌嗪-1-基)己基)苯甲酰胺;
(E)-N-(4-(1-(6-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(3-氧代-3-(4-(5-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)吡啶-2-基)哌嗪-1-基)丙酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(5-氧代-5-(4-(5-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)吡啶-2-基)哌嗪-1-基)戊酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(7-氧代-7-(4-(5-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)吡啶-2-基)哌嗪-1-基)庚酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(3-(2-(3-氧代-3-(4-(5-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)吡啶-2-基)哌嗪-1-基)丙氧基)乙氧基)丙酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-2-(叔丁基)-4,19-二氧代-19-(4-(5-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)吡啶-2-基)哌嗪-1-基)-7,10,13,16-四氧杂-3-氮杂十九烷酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-2-(叔丁基)-4,22-二氧代-22-(4-(5-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)吡啶-2-基)哌嗪-1-基)-7,10,13,16,19-五氧杂-3-氮杂二十二烷酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(E)-N-(4-(1-(6-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丙酰基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)戊酰基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)庚酰基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)丙酰基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙酰基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙酰基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己酰基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)庚酰基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙酰基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)丙酰基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(3-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(14-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-3,6,9,12-四氧杂十四烷酰基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(17-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-3,6,9,12,15-五氧杂十七烷酰基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)乙酰基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)戊酰基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)庚酰基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)戊-4-炔-1-基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(6-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)己-5-炔-1-基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)庚-6-炔-1-基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)丁基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)辛基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(6-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)己基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)庚基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)戊基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基乙酰基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)丁酰基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)己酰基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙酰基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)丙酰基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺
(E)-N-(4-(1-(6-(4-(3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(14-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-3,6,9,12-四氧杂十四烷酰基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(1-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-3,6,9,12-四氧杂十五烷-15-酰基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)戊酰基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)己酰基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙酰基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(17-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-3,6,9,12,15-五氧杂十七烷酰基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)乙酰基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)戊酰基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)庚酰基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊-4-炔-1-基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(6-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)己-5-炔-1-基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(9-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)壬-8-炔-1-基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丙基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)戊基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(8-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)辛基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)丁基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(8-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)辛基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(2,6-二氧代哌啶-3-基)-3-(6-(4-(6-(4-(4-(3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)哒嗪-3-基)哌嗪-1-基)己基)苯甲酰胺;
(E)-N-(4-(1-(6-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(3-氧代-3-(4-(6-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)哒嗪-3-基)哌嗪-1-基)丙酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(5-氧代-5-(4-(6-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)哒嗪-3-基)哌嗪-1-基)戊酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(7-氧代-7-(4-(6-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)哒嗪-3-基)哌嗪-1-基)庚酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(2-(2-(2-氧代-2-(4-(6-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)哒嗪-3-基)哌嗪-1-基)乙氧基)乙氧基)乙酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(3-(2-(3-氧代-3-(4-(6-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)哒嗪-3-基)哌嗪-1-基)丙氧基)乙氧基)丙酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-2-(叔丁基)-4,19-二氧代-19-(4-(6-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)哒嗪-3-基)哌嗪-1-基)-7,10,13,16-四氧杂-3-氮杂十九烷酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-2-(叔丁基)-4,22-二氧代-22-(4-(6-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)哒嗪-3-基)哌嗪-1-基)-7,10,13,16,19-五氧杂-3-氮杂二十二烷酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(E)-N-(4-(1-(6-(4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丙酰基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)戊酰基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)庚酰基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)丙酰基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙酰基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙酰基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己酰基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)庚酰基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)丙酰基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(3-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(14-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-3,6,9,12-四氧杂十四烷酰基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(17-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-3,6,9,12,15-五氧杂十七烷酰基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)乙酰基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)戊酰基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)庚酰基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)戊-4-炔-1-基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(6-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)己-5-炔-1-基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)庚-6-炔-1-基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)丁基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)辛基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(6-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)己基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)庚基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)戊基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基乙酰基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)丁酰基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)己酰基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)丙酰基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(14-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-3,6,9,12-四氧杂十四烷酰基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(1-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-3,6,9,12-四氧杂十五烷-15-酰基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)戊酰基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)己酰基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(17-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-3,6,9,12,15-五氧杂十七烷酰基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)乙酰基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)戊酰基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)庚酰基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊-4-炔-1-基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(6-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)己-5-炔-1-基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(9-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)壬-8-炔-1-基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丙基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)戊基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(8-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)辛基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)丁基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(8-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)辛基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(6-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)己基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(3-氧代-3-(4-(1-(6-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)哒嗪-3-基)哌啶-4-基)哌嗪-1-基)丙酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(5-氧代-5-(4-(1-(6-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)哒嗪-3-基)哌啶-4-基)哌嗪-1-基)戊酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(7-氧代-7-(4-(1-(6-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)哒嗪-3-基)哌啶-4-基)哌嗪-1-基)庚酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(8-氧代-8-(4-(1-(6-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)哒嗪-3-基)哌啶-4-基)哌嗪-1-基)辛酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(11-氧代-11-(4-(1-(6-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)哒嗪-3-基)哌啶-4-基)哌嗪-1-基)十一烷酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(2-(2-(2-氧代-2-(4-(1-(6-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)哒嗪-3-基)哌啶-4-基)哌嗪-1-基)乙氧基)乙氧基)乙酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(3-(2-(3-氧代-3-(4-(1-(6-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)哒嗪-3-基)哌啶-4-基)哌嗪-1-基)丙氧基)乙氧基)丙酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-2-(叔丁基)-4,19-二氧代-19-(4-(1-(6-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)哒嗪-3-基)哌啶-4-基)哌嗪-1-基)-7,10,13,16-四氧杂-3-氮杂十九烷酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(E)-N-(4-(1-(6-(4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丙酰基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)戊酰基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)庚酰基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)丙酰基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙酰基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙酰基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己酰基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)庚酰基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)丙酰基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(3-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(14-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-3,6,9,12-四氧杂十四烷酰基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(17-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-3,6,9,12,15-五氧杂十七烷酰基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)乙酰基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)戊酰基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)庚酰基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)戊-4-炔-1-基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(6-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)己-5-炔-1-基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)庚-6-炔-1-基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)丁基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)辛基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(6-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)己基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)庚基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)戊基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基乙酰基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)丁酰基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)己酰基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)丙酰基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(14-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-3,6,9,12-四氧杂十四烷酰基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(1-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-3,6,9,12-四氧杂十五烷-15-酰基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)戊酰基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)己酰基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(17-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-3,6,9,12,15-五氧杂十七烷酰基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)乙酰基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)戊酰基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)庚酰基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊-4-炔-1-基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(6-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)己-5-炔-1-基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(9-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)壬-8-炔-1-基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丙基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)戊基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(8-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)辛基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)丁基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(8-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)辛基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(6-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)己基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(3-氧代-3-(4-(1-(5-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)吡啶-2-基)哌啶-4-基)哌嗪-1-基)丙酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(5-氧代-5-(4-(1-(5-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)吡啶-2-基)哌啶-4-基)哌嗪-1-基)戊酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(7-氧代-7-(4-(1-(5-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)吡啶-2-基)哌啶-4-基)哌嗪-1-基)庚酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(8-氧代-8-(4-(1-(5-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)吡啶-2-基)哌啶-4-基)哌嗪-1-基)辛酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(11-氧代-11-(4-(1-(5-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)吡啶-2-基)哌啶-4-基)哌嗪-1-基)十一烷酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(2-(2-(2-氧代-2-(4-(1-(5-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)吡啶-2-基)哌啶-4-基)哌嗪-1-基)乙氧基)乙氧基)乙酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-3,3-二甲基-2-(2-(2-(2-氧代-2-(4-(1-(5-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)吡啶-2-基)哌啶-4-基)哌嗪-1-基)乙氧基)乙氧基)乙酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(2S,4R)-1-((S)-2-(叔丁基)-4,19-二氧代-19-(4-(1-(5-(4-(4-((E)-3-(吡啶-3-基)丙烯酰氨基)丁基)哌啶-1-羰基)吡啶-2-基)哌啶-4-基)哌嗪-1-基)-7,10,13,16-四氧杂-3-氮杂十九烷酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;
(E)-N-(4-(1-(6-(4-(4-(4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)丁-3-炔-1-基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)庚-6-炔-1-基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)硫基)庚基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)硫基)己基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)硫基)戊基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)乙炔基)苄基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(5-(2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-4-基)戊-4-炔-1-基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-4-基)硫基)丁基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-4-基)氨基)丁基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-4-基)氧基)丁基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)丁-3-炔-1-基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)庚-6-炔-1-基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)硫基)庚基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)硫基)己基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)硫基)戊基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)乙炔基)苄基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)丁-3-炔-1-基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)庚-6-炔-1-基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)硫基)庚基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)硫基)戊基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)硫基)戊基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)乙炔基)苄基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(5-(2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-4-基)戊-4-炔-1-基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-4-基)硫基)丁基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-4-基)氨基)丁基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-4-基)氧基)丁基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)丁-3-炔-1-基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)庚-6-炔-1-基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)硫基)庚基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)硫基)己基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)硫基)戊基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)乙炔基)苄基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(8-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)辛-7-炔-1-基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(6-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)己-5-炔-1-基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)硫基)庚基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)硫基)己基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)硫基)戊基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)乙炔基)苄基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(5-(2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-4-基)戊-4-炔-1-基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-((2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-4-基)硫基)丁基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-((2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-4-基)氨基)丁基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-((2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-4-基)氧基)丁基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(8-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)辛-7-炔-1-基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(6-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)己-5-炔-1-基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)硫基)庚基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(6-((2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)硫基)己基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)硫基)戊基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-((2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)乙炔基)苄基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(8-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)辛-7-炔-1-基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(6-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)己-5-炔-1-基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)硫基)庚基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)硫基)己基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)硫基)戊基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)乙炔基)苄基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(5-(2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-4-基)戊-4-炔-1-基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-((2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-4-基)硫基)丁基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-((2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-4-基)氨基)丁基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-((2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-4-基)氧基)丁基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(8-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)辛-7-炔-1-基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(6-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)己-5-炔-1-基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)硫基)庚基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(6-((2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)硫基)己基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)硫基)戊基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-((2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)乙炔基)苄基)哌嗪-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(8-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)辛-7-炔-1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(6-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)己-5-炔-1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)硫基)庚基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)硫基)己基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)硫基)戊基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)乙炔基)苄基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(5-(2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-4-基)戊-4-炔-1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-4-基)硫基)丁基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-4-基)氨基)丁基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-4-基)氧基)丁基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(8-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)辛-7-炔-1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(6-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)己-5-炔-1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)硫基)庚基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)硫基)己基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)硫基)戊基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)乙炔基)苄基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(8-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)辛-7-炔-1-基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(6-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)己-5-炔-1-基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)硫基)庚基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)硫基)己基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)硫基)戊基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)乙炔基)苄基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(5-(2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-4-基)戊-4-炔-1-基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(4-((2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-4-基)硫基)丁基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(4-((2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-4-基)氨基)丁基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(4-((2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-4-基)氧基)丁基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(8-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)辛-7-炔-1-基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(6-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)己-5-炔-1-基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)硫基)庚基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(6-((2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)硫基)己基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)硫基)戊基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-(4-((2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)乙炔基)苄基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(哒嗪-4-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(1,2,3-三嗪-5-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡嗪-2-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(1H-吡咯-3-基)丙烯酰胺;
(E)-3-([1,2,4]三唑并[4,3-a]吡啶-6-基)-N-(4-(1-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(1H-吡唑并[3,4-b]吡啶-5-基)丙烯酰胺;
(E)-N-(4-(4-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基)哌嗪-1-基)苯甲酰基)-1,4-二氮杂环庚-1-基)丁基)-3-(6-氟吡啶-3-基)丙烯酰胺;
(E)-N-(4-(4-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基)哌嗪-1-基)苯甲酰基)-1,4-二氮杂环庚-1-基)丁基)-3-(2-氟吡啶-3-基)丙烯酰胺;
(E)-2-氰基-N-(4-(1-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基)哌嗪-1-基)苯甲酰基)吡咯烷-3-基)丁基)-3-(2-氟吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基)哌嗪-1-基)苯甲酰基)吡咯烷-3-基)丁基)-3-(2-氟吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基)哌嗪-1-基)-2-氟苯甲酰基)吡咯烷-3-基)丁基)-3-(5-氟吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基)哌嗪-1-基)-2-氟苯甲酰基)吡咯烷-3-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基)哌嗪-1-基-2-氟苯甲酰基)吡咯烷-3-基)丁基)-3-(5-甲基吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁基)哌嗪-1-基)-3-甲基苯甲酰基)哌啶-4-基)丁基)-3-(5-甲基吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(3-环丙基-4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(6-甲基吡嗪-2-基)丙烯酰胺;
(Z)-2-氯-N-(4-(1-(5-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁基)哌嗪-1-基)-4-乙基-2-吡啶甲酰基)哌啶-4-基)丁基)-3-(6-甲基吡嗪-2-基)丙烯酰胺;
(E)-N-(4-(1-(5-(3-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁基)咪唑烷-1-基)2-吡啶甲酰基)哌啶-4-基)丁基)-3-(6-甲基吡嗪-2-基)丙烯酰胺;
(E)-N-(4-(1-(5-(3-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁基)-5-甲基咪唑烷-1-基)2-吡啶甲酰基)哌啶-4-基)丁基)-3-(6-甲基吡嗪-2-基)丙烯酰胺;
(E)-2-氰基-N-(4-(1-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(哒嗪-4-基)丙烯酰胺;
(E)-2-氰基-N-(4-(1-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(Z)-3-氰基-N-(3-(1-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丙基)-3-(吡啶-3-基)丙烯酰胺;
(E)-2-氰基-N-(4-(1-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(6-氟吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(6-氟吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(2-氟吡啶-3-基)丙烯酰胺;
(E)-2-氰基-N-(4-(4-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基)哌嗪-1-基)苯甲酰基)-6-甲基-1,4-二氮杂环庚-1-基)丁基)-3-(2-氟吡啶-3-基)丙烯酰胺;
(E)-N-(4-(4-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基)哌嗪-1-基)苯甲酰基)-6-甲基-1,4-二氮杂环庚-1-基)丁基)-3-(2-氟吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基)哌嗪-1-基)苯甲酰基)吡咯烷-3-基)丁基)-3-(6-氟吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基)哌嗪-1-基)苯甲酰基)吡咯烷-3-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基)哌嗪-1-基)-2-氟苯甲酰基)吡咯烷-3-基)丁基)-3-(5-氟吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁基)哌嗪-1-基)-3-羟基苯甲酰基)哌啶-4-基)丁基)-3-(5-氟吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁基)哌嗪-1-基)-3-甲基苯甲酰基)哌啶-4-基)丁基)-3-(5-氟吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁基)哌嗪-1-基)-3-甲基苯甲酰基)哌啶-4-基)丁基)-3-(6-甲基吡嗪-2-基)丙烯酰胺;
(Z)-N-(4-(1-(3-环丙基-4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-氟-3-(6-甲基吡嗪-2-基)丙烯酰胺;
(2S,4R)-1-((S)-2-(6-(4-(5-(4-(4-((Z)-2-氯-3-(6-甲基吡嗪-2-基)丙烯酰氨基)丁基)哌啶-1-羰基)吡啶-2-基)哌嗪-1-基)-6-氧代己酰氨基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺;
(E)-N-(4-(1-(5-(3-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)丁基)咪唑烷-1-基)2-吡啶甲酰基)哌啶-4-基)丁基)-3-(6-甲基吡嗪-2-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁基)-2-甲基哌嗪-1-基)-3-异丙基苯甲酰基)哌啶-4-基)丁基)-3-(吡嗪-2-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)甲基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)甲基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)甲基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(1-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)甲基)哌啶-4-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(5-(4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)哌嗪-1-基)戊基)哌嗪-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)哌嗪-1-基)甲基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)甲基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)甲基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)甲基)哌嗪-1-基)哌啶-1-基)哒嗪-3-羰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-((E)-4-(1-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁-2-烯-1-基)-3-(哒嗪-4-基)丙烯酰胺;
(E)-N-((E)-4-(1-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁-2-烯-1-基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-((E)-4-(1-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁-2-烯-1-基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-((E)-4-(1-(4-(4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊-4-炔-1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁-2-烯-1-基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-((E)-4-(1-(4-(4-(6-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)己-5-炔-1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁-2-烯-1-基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-((E)-4-(1-(4-(4-(8-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)辛-7-炔-1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁-2-烯-1-基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(4-(1-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)-1H-1,2,3-三唑-4-基)丁基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(3-(1-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)-1H-1,2,3-三唑-4-基)丙基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-((2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙基)氨基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-((4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁基)氨基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-((7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基)氨基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(2-氟吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)己基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)庚基)哌嗪-1-基)苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;
(E)-N-(4-(1-(6-(4-(4-(8-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)辛-7-炔-1-基)哌嗪-1-基)哌啶-1-基)烟酰基)哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺;和
(2S,4R)-1-((S)-3,3-二甲基-2-(6-氧代-6-(4-(1-(6-(4-(4-((E)-3-(吡啶-3-基)丙烯酰胺基)丁基)哌啶-1-羰基)哒嗪-3-基)哌啶-4-基)哌嗪-1-基)己酰胺基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯烷-2-甲酰胺。
25.如权利要求1至24中任一项所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物,其是式(I)化合物的盐酸盐、硫酸盐、枸橼酸盐、马来酸盐、磺酸盐、柠檬酸盐、乳酸盐、酒石酸盐、富马酸盐、磷酸盐、二氢磷酸盐、焦磷酸盐、偏磷酸盐、草酸盐、丙二酸盐、苯甲酸盐、扁桃酸盐、琥珀酸盐、三氟乙酸盐、羟乙酸盐或对甲苯磺酸盐。
26.药物组合物,其包含作为活性成分的如权利要求1至25中任一项所述的式(I)化合物或其药学上可接受的盐,及至少一种药学上可接受的载体。
27.如权利要求26所述的药物组合物,进一步包括至少一种额外的治疗剂。
28.一种药盒或试剂盒,其包含如权利要求1至25中任一项所述的式(I)化合物或其药学上可接受的盐或如权利要求26或27所述的药物组合物。
29.如权利要求1至25中任一项所述的式(I)化合物或其药学上可接受的盐或如权利要求26或27所述的药物组合物的用途,其用于制备用以预防及/或治疗与烟酰胺磷酸核糖转移酶(NAMPT)相关的疾病或病症的药物。
30.如权利要求29所述的用途,其中所述与NAMPT相关的疾病或病症包括肿瘤、自身免疫性疾病、炎性疾病、妊娠高血压综合征、心脑血管疾病、肥胖症和糖尿病肾病。
31.如权利要求29所述的用途,其中所述与NAMPT相关的疾病或病症包括:
结直肠癌;乳腺癌(包括三阴性乳腺癌,侵袭性乳腺癌,浸润性乳腺癌);星形细胞瘤;胰腺癌;胃癌;前列腺癌;黑色素瘤;白血病(例如急性髓系白血病、急性淋巴细胞性白血病);卵巢癌;肝癌;肺癌(例如非小细胞肺癌和小细胞肺癌);胶质母细胞瘤;多发性骨髓瘤;食管癌;膀胱癌;甲状腺癌;子宫内膜癌;淋巴瘤(例如弥漫性大B细胞瘤,滤泡性B细胞淋巴瘤,霍奇金淋巴瘤,外周T细胞淋巴瘤);神经内分泌肿瘤;肾癌(例如肾嗜酸细胞瘤,肾透明细胞癌,肾尿路上皮癌);小儿胶质瘤;横纹肌肉瘤;平滑肌肉瘤;尿路上皮癌;基底细胞癌;口腔鳞状细胞癌;胆管癌;骨癌;宫颈癌;皮肤癌;口腔鳞状细胞癌;自身免疫性疾病(例如类风湿性关节炎,自身免疫性脑炎);心脑血管疾病(包括冠状动脉粥样硬化,急性心肌梗死,心肌缺血再灌注损伤,缺血性中风);炎性疾病;妊娠高血压综合征;肥胖症和糖尿病肾病。
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