CN117088864A - 一种苯并[d]异恶唑类化合物及其应用 - Google Patents
一种苯并[d]异恶唑类化合物及其应用 Download PDFInfo
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- CN117088864A CN117088864A CN202210522716.2A CN202210522716A CN117088864A CN 117088864 A CN117088864 A CN 117088864A CN 202210522716 A CN202210522716 A CN 202210522716A CN 117088864 A CN117088864 A CN 117088864A
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Abstract
本发明提供一种苯并[d]异恶唑类化合物及其应用。所述化合物具有如下式Ⅰ所示结构。本发明所述苯并[d]异恶唑类化合物可诱导BET蛋白和/或GSPT1蛋白的降解,对癌细胞具有抗增殖作用。因此,本发明提供的化合物及组合物可用于制备治疗或预防肿瘤形成、炎症、病毒感染、细胞增殖性紊乱、自身免疫性疾病、败血症等疾病的药物。
Description
技术领域
本发明属于化学医药技术领域,具体涉及一种苯并[d]异恶唑类化合物及其应用。
背景技术
表观遗传学是研究没有DNA序列变化的可遗传的基因表达的改变。表观遗传学主要通过DNA的甲基化、组蛋白修饰、染色质重塑和非编码RNA调控等方式控制基因的表达。其中,组蛋白是染色质的核心,参与转录后修饰,主要包括乙酰化、甲基化、磷酸化和泛素化等。溴结构域(BRD)超家族蛋白的溴结构域和额外末端结构域(BET)蛋白是重要的表观遗传“阅读器”。BET家族蛋白包含BRD2、BRD3、BRD4和BRDT四个成员,且蛋白中包含两个串联的N-末端溴结构域(BD1和BD2)。N-末端溴结构域由4个α螺旋(αZ,αA,αB和αC)、ZA环和BC环组成。这类蛋白依赖于溴结构域的疏水口袋识别乙酰化的组蛋白赖氨酸残基来发挥功能。BET蛋白影响着细胞生长、增殖分化、凋亡和坏死等过程。多项研究表明,BET功能异常与癌症、细胞增殖性紊乱、炎症、自身免疫性疾病、败血症或病毒感染(如新型冠状病毒)等的发生发展相关。
GSPT1是一种翻译终止因子,通过结合eRF1,介导终止密码子识别并促进新生肽自核糖体释放。GSPT1也参与若干其他关键的细胞过程,如细胞周期调节、细胞骨架组织、细胞凋亡和转录。因此,GSPT1水平的下调可损害细胞增殖的控制,并促进细胞迁移和瘢痕形成。GSPT1牵涉若干不同癌症类型(包括乳腺癌、肝细胞癌、胃癌和前列腺癌)的致瘤驱动。
BET蛋白和GSPT1蛋白异常表达与疾病相关,研究发现,靶向蛋白降解剂不仅能抑制靶蛋白活性,还可以利用体内的泛素-蛋白酶体系统清除靶蛋白,从而达到治疗目的。现已开发出数个BET或GSPT1降解剂。
CN109311890A公开了一种BET蛋白降解剂,该发明公开的化合物降解BET溴结构域蛋白并且可用于各种疾病和病况的治疗,特别地,本公开的化合物可用于治疗其中BET溴结构域蛋白降解提供有益效果的疾病或病况的方法,所述疾病或病况例如,癌症和增殖性疾病。
CN110062759A公开了一种作为BET蛋白降解剂的稠合的1,4-氧氮杂环化合物。该发明公开的化合物是BET溴结构域蛋白降解剂,因此可用于治疗或预防其中BET溴结构域(例如BRD2、BRD3、BRD4、BRD-t或其同种型或突变体)的降解提供有益效果的疾病或病况。
CN112543764A公开了一种化合物,其在对癌细胞的细胞毒性作用、诱导癌细胞中BET蛋白降解的作用和对BET蛋白与乙酰化组蛋白的结合的抑制作用方面是优异的,并且可用作抗癌剂、BET蛋白降解诱导剂或BET蛋白抑制剂。
CN111032043A公开了一种2-(4-氯苯基)-N-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)甲基)-2,2-二氟乙酰胺的组合物和使用方法,该化合物作为单一剂测试或与依维莫司组合测试时,其对来自骨髓增生异常综合征患者的骨髓单核细胞中的半胱天冬酶-3活化和GSPT1降解的作用。
目前,多个公布的BET或GSPT1降解剂在体内或体外都具有较好的临床前抗肿瘤活性,但其研究仍处于早期阶段。因此,亟待开发一种新型的、高效的可诱导BET家族蛋白和/或GSPT1蛋白降解的化合物。
综上所述,靶向BET蛋白和/或GSPT1蛋白的降解剂对于发展靶向癌症、炎性疾病、细胞增殖性紊乱、自身免疫疾病、败血症和病毒感染等在内疾病的治疗策略可能是有益的。
发明内容
针对现有技术的不足,本发明的目的在于提供一类苯并[d]异恶唑类化合物,这类苯并[d]异恶唑类化合物可调节BET蛋白水平和/或功能,和/或调节GSPT1蛋白水平和/或功能,具有对癌细胞的细胞毒性作用。这将为治疗包括癌症、炎性疾病、细胞增殖性紊乱、自身免疫疾病、败血症和病毒感染等在内的疾病提供了一类新型的具有治疗前景的药物。
为达到此发明目的,本发明采用以下技术方案:
第一方面,本发明提供一种苯并[d]异恶唑类化合物,所述苯并[d]异恶唑类化合物具有如下式Ⅰ所示结构:
其中,
X选自O或S;
R1选自H、羟基、取代或未取代的C1-C5(例如C1、C2、C3、C4、C5)烷基、取代或未取代的C1-C5(例如C1、C2、C3、C4、C5)烷氧基;
R2和R3各自独立地选自如下(i)或(ii)组中的任一基团:
(i)H、卤素、氨基、硝基、羧基、氰基、羟基、取代或未取代的C1-C5(例如C1、C2、C3、C4、C5)烷基、取代或未取代的C1-C6(例如C1、C2、C3、C4、C5、C6)烷氧基、取代或未取代的C3-C10(例如C3、C4、C5、C6、C7、C8、C9、C10)环烷基、取代或未取代的C3-C10(例如C3、C4、C5、C6、C7、C8、C9、C10)杂环烷基、取代或未取代的C6-C20(例如C6、C10、C12、C14、C16、C18、C20等)芳基、取代或未取代的C4-C20(例如C4、C5、C6、C10、C12、C14、C16、C18、C20等)杂芳基;
(ii)-N(Ra)SO2Rb、-SO2N(Ra)Rb、-N(Ra)CORb、-CON(Ra)Rb-、-N(Ra)CH2Rb、-NHCH(Ra)Rb、-N(Ra)Rb、-CH(Ra)Rb、-CORb、-COORb、-OCORb、-SRb或-ORb;
Ra选自H、取代或未取代的C1-C6(例如C1、C2、C3、C4、C5、C6)烷基、取代或未取代的C3-C10(例如C3、C4、C5、C6、C7、C8、C9、C10)环烷基、取代或未取代的C3-C10(例如C3、C4、C5、C6、C7、C8、C9、C10)环烯基、取代或未取代的C1-C10(例如C1、C2、C3、C4、C5、C6、C7、C8、C9、C10)杂环烷基;
Rb选自如下(v)、(vi)、(vii)或(viii)组中的任一基团:
(v)取代或未取代的C6-C20(例如C6、C10、C12、C14、C16、C18、C20等)芳基、取代或未取代的C4-C20(例如C4、C5、C6、C10、C12、C14、C16、C18、C20等)杂芳基;
(vi)取代或未取代的C3-C10(例如C3、C4、C5、C6、C7、C8、C9、C10)环烷基、取代或未取代的C3-C10(例如C3、C4、C5、C6、C7、C8、C9、C10)环烯基、取代或未取代的C3-C10(例如C3、C4、C5、C6、C7、C8、C9、C10)杂环烷基;
(vii)取代或未取代的C1-C5(例如C1、C2、C3、C4、C5)烷基、取代或未取代的C2-C10(例如C2、C3、C4、C5、C6、C7、C8、C9、C10)烯基、取代或未取代的C2-C10(例如C2、C3、C4、C5、C6、C7、C8、C9、C10)炔基;
Y1选自-NH(CH2)nCON(Rc)-、-O(CH2)nCON(Rc)-、-S(CH2)nCON(Rc)-、-(CH2)nCON(Rc)-或单键,n为1-8(例如1、2、3、4、5、6、7、8);
Rc选自H、取代或未取代的C3-C10(例如C3、C4、C5、C6、C7、C8、C9、C10)环烷基、取代或未取代的C3-C10(例如C3、C4、C5、C6、C7、C8、C9、C10)环烯基、取代或未取代的C3-C10(例如C3、C4、C5、C6、C7、C8、C9、C10)杂环烷基、取代或未取代的C6-C20(例如C6、C10、C12、C14、C16、C18、C20等)芳基、取代或未取代的C4-C20(例如C4、C6、C10、C12、C14、C16、C18、C20等)杂芳基、取代或未取代的C2-C10(例如C2、C3、C4、C5、C6、C7、C8、C9、C10)烯基;
Y2选自-O-、-NH-、-CH2-或单键;
L选自单键、亚烷基、亚烯基、亚炔基、醚基、硫醚基、酯基、胺基、酰胺基、氨基甲酸酯基、脲基、砜基、芳基、杂芳基、羰基、环烷基、杂芳基中的任意一种或至少两种的组合;
E具有式Ⅱ所示的结构,其中为基团连接位置;
其中,
Y3选自-O-、-S-、-CHRd-、-C(=O)-、-SO2-、-NRe-;
Rd和Re各自独立地选自H、取代或未取代的C1-C10(例如C1、C2、C3、C4、C5、C6、C7、C8、C9、C10等)烷基、取代或未取代的C3-C8(例如C3、C4、C5、C6、C7、C8等)环烷基、取代或未取代的C3-C8(例如C3、C4、C5、C6、C7、C8等)杂环基;
Y4、Y5、Y6、Y7各自独立地选自CH或N;
T1、T2、T3各自独立地选自选自Ο或S;
R4和R5各自独立选自-H、羟基、取代或未取代的C1-C10(例如C1、C2、C3、C4、C5、C6、C7、C8、C9、C10等)烷基、取代或未取代的C3-C10(例如C3、C4、C5、C6、C7、C8、C9、C10等)环烷基、取代或未取代的C1-C10(例如C1、C2、C3、C4、C5、C6、C7、C8、C9、C10等)含Ο杂环烷基、取代或未取代的C1-C10(例如C1、C2、C3、C4、C5、C6、C7、C8、C9、C10等)含Ν杂环烷基、取代或未取代的C1-C10(例如C1、C2、C3、C4、C5、C6、C7、C8、C9、C10等)含S杂环烷基。
优选地,所述Y4、Y5、Y6、Y7独立地选自CH。
优选地,所述Y4、Y5、Y6、Y7中任一基团为CH,另外三个基团至少一个为N。
优选地,所述Y4、Y5、Y6、Y7中任一基团为CH,所述基团连接位置位于该CH上。
优选地,所述L选自以下组中的任意一种:
其中,m、n和o独立地选自1-8之间的正整数;Y8选自取代或未取代的C1-C10烷基、取代或未取代的C3-C10环烷基、取代或未取代的C1-C10含O杂环烷基、取代或未取代的C1-C10含N杂环烷基、取代或未取代的C1-C10含S杂环烷基;
优选地,所述Y3选自-CH-或-C(=O)-;
优选地,所述T1、T2、T3选自O。
优选地,所述苯并[d]异恶唑类化合物具有如下式Ⅲ所示结构:
其中,R1、R2、R3、R4、R5、X、Y1、Y2、L、Y3、Y4、Y5、Y6、Y7、T1、T2、T3基团的定义与上述相同。
优选地,所述苯并[d]异恶唑类化合物具有如下式Ⅳ所示结构:
其中,R1、R2、R3、R4、R5、X、Y1、Y2、L、Y3基团的定义与上述相同。
优选地,所述苯并[d]异恶唑类化合物具有如下式Ⅴ或Ⅵ所示结构:
其中,R1、R2、R3、R4、R5、X、Y1、Y2、L基团的定义与上述相同。
优选地,所述R1选自取代或未取代的C1-C5烷基,优选为未取代的C1-C5烷基,进一步优选为未取代的C1-C3烷基;
优选地,所述R2和R3中任一基团选自(ii)组中的任一基团,而另一基团选自(i)组中的任一基团,优选为所述R2和R3中任一基团选自-N(Ra)SO2Rb或-SO2N(Ra)Rb中的任一基团,而另一基团选自H;
优选地,所述Ra选自H、取代或未取代的C1-C6烷基,优选为H;
优选地,所述Rb选自(v)组中的任一基团,优选为取代或未取代的C6-C20芳基,进一步优选为取代的C6-C10芳基;
优选地,所述Rb选自取代的苯基,所述苯基的取代基为C1-C3烷氧基和/或卤素;
优选地,所述Y1选自-O(CH2)nCON(Rc)-或单键;
优选地,所述n为1-3,Rc选自H;
优选地,所述Y2选自-O-、-NH-、-CH2-或单键;
优选地,所述L选自以下组中的任意一种:
其中,m、n和o独立地选自1-6之间的正整数,Y8选自未取代的C1-C6烷基;
优选地,所述苯并[d]异恶唑类化合物具有如下式ⅤII示结构:
其中,
Y1选自-O(CH2)nCON(Rc)-或单键,n为1-3,Rc选自H;
L选自以下组中的任意一种:
其中,m、n和o独立地选自1-6之间的正整数,Y8选自未取代的C1-C6烷基;
Y2选自-O-、-NH-、-CH2-或单键;
Y3选自-CH-或-C(=O)-。
优选地,所述芳基选自苯基或萘基。
优选地,所述杂芳基具有芳族的5-8(例如5、6、7、8)元单环、8-12(例如8、9、10、11、12)元双环或11-14(例如11、12、13、14)元三环系统;所述单环具有1-4(例如1、2、3、4)个杂原子,所述双环具有1-6(例如1、2、3、4、5、6)个杂原子,所述三环具有1-9(例如1、2、3、4、5、6、7、8、9)个杂原子;所述杂原子选自O、N或S。
优选地,所述烷基、烷氧基、环烷基、杂环烷基、芳基、杂芳基、烯基、环烯基、炔基具有取代基,所述取代基选自卤素、羟基、甲氧基、乙氧基、氨基、硝基、醚基、硫醚基、酯基、酰胺基、氨基甲酸酯基、脲基或砜基中的任意一种。
优选地,所述杂芳基选自哒嗪基、吲哚基、喹唑啉基、吡咯基、噻吩基、吲唑基、吡唑基、喹啉基、吡啶基、呋喃基、咪唑基、吡嗪基、嘧啶基、噻唑基、异喹啉基、苯并噻唑基或二氮杂萘基中任意一种。
优选地,所述苯并[d]异恶唑类化合物包括如下化合物1-19中的任意一种:
第二方面,本发明提供一种如第一方面所述化合物的药学上可接受的盐、立体异构体、N-氧化物、前药分子、溶剂化物、氘代化合物。
第三方面,本发明提供一种药物组合物,所述药物组合物包括活性成分和药学上可接受的辅料;
其中,所述活性成分包括至少一种第一方面所述化合物和/或至少一种如第二方面所述药学上可接受的盐、立体异构体、N-氧化物、前药分子、溶剂化物、氘代化合物。
第四方面,本发明提供一种如第一方面所述化合物、第二方面所述药学上可接受的盐、立体异构体、N-氧化物、前药分子、溶剂化物、氘代化合物、第三方面所述药物组合物在制备降解BET和/或GSPT1蛋白制剂中的应用。
第五方面,本发明提供一种如第一方面所述化合物、第二方面所述药学上可接受的盐、立体异构体、N-氧化物、前药分子、溶剂化物、氘代化合物、第三方面所述药物组合物在制备用于预防或治疗癌症、细胞增殖性紊乱、炎症、自身免疫性疾病、败血症或病毒感染的药物中的应用。
优选地,所述癌症选自急性单核细胞白血病、急性骨髓性白血病、慢性骨髓性白血病、慢性淋巴细胞性白血病混合谱系白血病、NUT-中线癌、多发性骨髓瘤、胶质瘤、肺癌、神经母细胞瘤、伯基特淋巴瘤、宫颈癌、食道癌、鼻咽癌、卵巢癌、胰腺癌、结直肠癌、前列腺癌或乳腺癌。所述炎症、自身免疫性疾病选自炎症盆腔疾病、尿道炎、肺炎、脑膜炎、心肌炎、溃疡性结肠炎、器官移植排斥、哮喘、过敏性鼻炎、慢性阻塞性肺疾病、自身免疫性疾病、自身免疫性脱发、贫血、自身免疫性溶血性和系统性红斑狼疮、类风湿性关节炎、桥本甲状腺炎或过敏性皮肤炎。所述病毒感染选自脊髓灰质炎病毒、甲型肝炎病毒、风疹病毒、乙型脑炎病毒、丙型肝炎病毒、人类乳头瘤病毒、狂犬病病毒、疱疹病毒、巴尔病毒或人类免疫缺陷病毒、新型冠状病毒或感染。
在本发明中,适用本发明的化合物所治疗的示例性癌症包括,但并不局限于,白血病(例如,急性白血病、急性淋巴细胞性白血病、急性髓细胞性白血病、急性成髓细胞性白血病、急性前髓细胞性白血病、急性骨髓单核细胞性白血病、急性单核细胞性白血病、急性红白血病、混合性白血病、慢性白血病、慢性髓细胞性白血病、慢性淋巴细胞性白血病)、多发性骨髓瘤、真性红细胞增多、皮肤T淋巴细胞瘤、淋巴瘤(霍奇金病、非霍奇金病)、沃尔丹斯特伦氏巨球蛋白血症、重链病、以及实体瘤,如肉瘤和癌(例如,纤维肉瘤、粘液肉瘤、脂肉瘤、软骨肉瘤、骨肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、淋巴管肉瘤、淋巴管内皮肉瘤、滑膜瘤、间皮瘤、尤文氏瘤、平滑肌肉瘤、横纹肌肉瘤、结肠瘤、结肠直肠癌、胰腺癌、乳腺癌、卵巢癌、前列腺癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊腺癌、髓样癌、支气管癌、肾细胞癌、肝癌、胆管癌、绒毛膜癌、精原细胞瘤、胚胎性癌、肾母细胞所述癌症为:肾上腺肿瘤、听神经瘤、肢端黑色素瘤、肢端汗腺瘤、急性嗜酸性白血病、急性红色的白血病、急性淋巴母细胞性白血病、急性巨核细胞白血病、急性单核细胞的白血病、急性早幼粒细胞性白血病、腺癌、腺样囊性癌、脂肪组织肿瘤、肾上腺皮质癌、成人T细胞白血病/淋巴瘤、艾滋病相关淋巴瘤、肺泡横纹肌肉瘤、肺泡软肉瘤、成釉细胞的纤维瘤、间变性大细胞淋巴瘤、未分化甲状腺癌、血管肌脂肪瘤、血管肉瘤、星形细胞瘤、非典型畸形杆状的肿瘤、B细胞慢性淋巴细胞白血病、B细胞前淋巴细胞白血病、B细胞淋巴瘤、基底细胞癌、胆道癌、膀胱癌、胚细胞瘤、骨肿瘤、棕色肿瘤、伯基特淋巴瘤、乳腺癌、脑癌、原位癌、软骨瘤、牙骨质瘤、髓系肉瘤、软骨瘤、脊索瘤、绒毛膜癌、脉络丛乳头状瘤、肾透明细胞肉瘤、颅咽管瘤、皮肤t细胞淋巴瘤、宫颈癌、结肠癌、小圆细胞肿瘤、细胞弥漫型B细胞淋巴瘤、神经上皮的肿瘤、无性细胞瘤、胚胎性癌内分泌腺肿瘤、内胚层窦肿瘤、食道癌、纤维瘤、纤维肉瘤、滤泡淋巴瘤、滤泡星形胶质细胞瘤、甲状腺癌胃肠道癌症、生殖细胞肿瘤、妊娠期绒毛膜癌、巨细胞成纤维细胞瘤、骨巨细胞瘤、神经胶质细胞瘤、多形性胶质母细胞瘤、神经胶质瘤、颗粒细胞瘤、男性细胞瘤、胆囊癌症、胃癌、成血管细胞瘤、头部和颈部癌症、血管外皮细胞瘤恶性肿瘤、肝母细胞癌、细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、浸润性小叶癌、肠道癌症、肾癌、喉癌、致命的中线癌、白血病、睾丸间质细胞瘤、脂肪肉瘤、肺癌、淋巴管瘤、淋巴上皮瘤、淋巴瘤、急性淋巴管肉瘤,淋巴细胞性白血病、慢性淋巴细胞白血病、肝癌,小细胞肺癌、非小细胞肺癌、麦芽淋巴瘤、恶性纤维组织细胞瘤、恶性周围神经鞘瘤、边缘区b细胞淋巴瘤、肥大细胞白血病、纵隔生殖细胞肿瘤、乳腺髓样癌、髓样甲状腺癌、成神经管细胞瘤、黑色素瘤、脑膜瘤、默克尔细胞癌症、间皮瘤、转移性细胞癌、混合缪氏肿瘤、粘液性肿瘤、多发性骨髓瘤、肌肉组织肿瘤、蕈样黏液样脂肪肉瘤、粘液瘤、粘液肉瘤、鼻咽癌、神经母细胞瘤、神经纤维瘤、神经瘤、眼部癌症、嗜酸性、视神经鞘脑膜瘤、肿瘤、口腔癌、骨肉瘤、卵巢癌、乳头状甲状腺癌、肿瘤副神经节瘤、成松果体细胞瘤、垂体细胞瘤、前体T-淋巴母细胞性淋巴瘤、原发性中枢神经系统淋巴瘤,腹膜癌、前列腺癌、胰腺癌、咽癌、肾细胞癌、肾髓样癌、成视网膜细胞瘤、横纹肌瘤、横纹肌肉瘤、直肠癌、肉瘤、精原细胞瘤、滋养细胞肿瘤、皮肤癌、小圆细胞肿瘤、小细胞癌、软组织肉瘤、生长抑素瘤、脊髓肿瘤、脾边缘带淋巴瘤、鳞状细胞癌、滑膜肉瘤、小肠癌症、鳞状细胞癌、胃癌、T细胞淋巴瘤、睾丸癌、甲状腺癌症、移行细胞癌、喉癌、脐尿管癌、泌尿生殖癌症、子宫癌症、疣状癌、视觉途径神经胶质瘤、外阴癌或阴道癌。
在本发明中,所述细胞增殖性紊乱疾病包括:良性软组织肿瘤、脑和脊髓肿瘤、眼睑和轨道肿瘤、肉芽肿、脂肪瘤、脑膜瘤、多发性内分泌瘤、鼻息肉、垂体肿瘤、泌乳素瘤、脂溢性角质的、胃息肉、甲状腺结节、肝血管瘤、声带结节、息肉、囊肿、藏毛病、皮肤纤维瘤、皮拉尔囊肿或化脓性肉芽肿。
在本发明中,所述炎症疾病包括:炎症盆腔疾病、尿道炎、皮肤晒伤、鼻窦炎、肺炎、脑炎、脑膜炎、心肌炎、肾炎、骨髓炎、肌炎、肝炎、胃炎、肠炎、皮炎、牙龈炎、胰腺炎、牛皮癣、过敏、克罗恩氏病、肠道综合症、溃疡性结肠炎、组织移植排斥、器官移植排斥、哮喘、过敏性鼻炎、慢性阻塞性肺疾病、自身免疫性疾病、自身免疫性脱发、贫血、肾小球肾炎、皮肌炎、多发性硬化症、硬皮病、血管炎、自身免疫性溶血性和血小板减少、肺出血肾炎综合征、动脉粥样硬化、阿狄森氏病、帕金森氏症、阿尔茨海默氏症、糖尿病、感染性休克、系统性红斑狼疮、类风湿性关节炎、银屑病关节炎、骨关节炎、慢性特发性血小板减少性紫癜、重症肌无力、桥本甲状腺炎、过敏性皮肤炎、退化性关节疾病、格林-巴利综合征、蕈样真菌病或急性炎症反应。
在本发明中,所述病毒感染包括:脊髓灰质炎病毒、甲型肝炎病毒、风疹病毒、乙型脑炎病毒、丙型肝炎病毒、人类乳头瘤病毒、狂犬病病毒、疱疹病毒、巴尔病毒或人类免疫缺陷病毒、新型冠状病毒或感染。
【术语解释】
下面对本发明的各个方面和特点作进一步的描述。
本发明使用的各种术语和短语具有本领域技术人员公知的一般含义,即便如此,本发明仍然希望在此对这些术语和短语作更详尽的说明和解释,提及的术语和短语如有与公知含义不一致的,以本发明所表述的含义为准。下面是本发明所用多种术语的定义,这些定义适用于本申请整个说明书中所用的术语,除非在具体情况中另作说明。以下提供本发明化合物各种基团的定义,除另行定义外,它们在说明书和权利要求书中统一使用。
如本发明所提及的,术语“卤”、“卤素”、“卤素原子”、“卤代”等表示氟、氯、溴或碘,特别是表示氟、氯或溴。
如本发明所提及的,术语“烷基”是指具有指定数目碳原子数的烷基,其可以为直链的烷基或支链的烷基,例如所述“C1-C20烷基”时,是指碳原子数为1-20的直链的烷基或支链的烷基,具体基团例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基等,以及类似基团。
如本发明所提及的,术语“环烷基”是指具有指定数目环碳原子数的环状烷基,例如提及的“C3-C10环烷基”时,其指碳原子数为3-10的环烷基,具体基团例如环丙基、环丁基、环戊基、环己基、环庚基等,以及类似基团。
如本发明所提及的,术语“烯基”是指具有指定数目碳原子数的烯基(具有一个或多个C=C双键的烃基基团),其可以为直链的烷基或支链的烯基,例如所述“C2-C20烯基”时,是指碳原子数为2-20的直链的烷基或支链的烯基,具体基团例如乙烯基、丙烯基、烯丙基、1-丁烯基、2-丁烯基、1,3-丁二烯基、1-戊烯基、2-戊烯基、1,3-戊二烯基、1-己烯基、2-己烯基等,以及类似基团。
如本发明所提及的,术语"环烯基”是指具有指定数目碳原子数的环状烯基(具有一个或多个C=C双键的烃基基团),例如所述“C3-C10环烯基”,是指碳原子数为3-10的环状烯基,具体基团例如环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基等,以及类似基团。
如本发明所提及的,术语“炔基”是指具有指定数目碳原子数的炔基(具有一个或多个C≡C三键的烃基基团),其可以为直链的烷基或支链的炔基,例如所述“C2-C20炔基”时,是指碳原子数为2-20的直链的烷基或支链的炔基,具体基团例如乙炔基、丙炔基、1-丁炔基、2-丁炔基、1-戊炔基、2-己炔基等,以及类似基团。
如本发明所提及的,术语“杂环烷基”是指其中一个或多个形成环的原子是如O、N或S这样的杂原子的非芳香杂环。杂环基基团可以包括单环或多环(如具有2、3或4个稠合环)的环系统以及螺环。优选的“杂环烷基”基团的实例包括但不限于:氮杂环丙烷基、氮杂环丁烷基、四氢呋喃基、四氢噻吩基、吡咯烷基、恶唑烷基、噻唑烷基、咪唑烷基、异恶唑烷基、异噻唑烷基、吡唑烷基、吗啉基、硫代吗啉基、哌嗪基、哌啶基,以及类似基团。同时被包括在杂环烷基的定义中还有那些具有一个或多个稠合于非芳香杂环烷基环的芳香环(例如具有共用的键)的部分,例如2,3-二氢苯并呋喃基、1,3-苯并二氧杂环戊烯基、苯并-1,4-二氧杂环己基、邻苯二甲酰亚胺基、萘二甲酰亚胺基,以及类似基团。具有一个或多个稠合芳环的杂环烷基基团可以通过芳香部分或非芳香部分连接。
如本发明所提及的,术语“芳基”是指单环或多环(例如具有2、3或4个稠合环)的芳烃,例如苯基、萘基、蒽基、菲基、茚基,以及类似基团。
如本发明所提及的,术语“杂芳基”是指具有至少一个如O、N或S这样的杂原子环成员的芳香杂环。杂芳基基团包括单环或多环(如具有2、3或4个稠合环)的环系统。任何在杂环基团中成环的N原子也可以被氧化以形成N-氧化物。优选的“杂芳基”基团的实例包括但不限于:吡啶基、嘧啶基、吡嗪基、哒嗪基、三嗪基、呋喃基、噻吩基、咪唑基、三唑基、四唑基、噻唑基、异噻唑基、1,2,4-噻二唑基、吡咯基,吡唑基、恶唑基、异恶唑基、恶二唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、吲哚基、吲唑基、喹啉基、异喹啉基、嘌呤基、咔唑基、苯并咪唑基、吡咯并吡啶基、吡咯并嘧啶基、吡唑并吡啶基、吡唑并嘧啶基,以及类似基团。
如本发明所提及的,术语“单键”指的是与该位置相连的两基团直接相连接;例如当Y1为单键时,L直接连接在苯环上,所述式Ⅰ所示结构可表示为:当Y2为单键时,基团Y1与E直接连接,所述式Ⅰ所示结构可表示为:/>更为具体地例举一例Y2为单键的情况,即本发明提供的化合物18。
如本发明所提及的,术语“化合物”,如在本文中所使用,是指包括所有的立体异构体、几何异构体、互变异构体、同位素。
本发明的化合物可以是非对称的,例如具有一个或多个立体中心。除非有另外的限定,所有的立体异构体,可以是对映异构体和非对映异构体。含有非对称取代的碳原子的本发明的化合物可以被分离成光学纯或外消旋形式。光学纯形式可以通过外消旋体的拆分来制备,或者通过使用手性合成子(synthon)或手性试剂来制备。
本发明的化合物也可以包括互变异构体形式。互变异构体新形式由单键和相邻的双键一起伴随质子的迁移而互换所产生的。
本发明的化合物也可以包括存在于中间体或最终化合物中的原子的所有同位素形式。同位素包括具有相同的原子序数但不同的质量数的那些原子。例如,氢的同位素包括氘和氚。
如本发明所提及的,术语“药物组合物”,其还可以是指“组合物”,其可用于在受试者特别是哺乳动物中实现治疗和/或预防本发明所述疾病或病症。
如本发明所提及的,术语“疾病和/或病症”是指所述受试者的一种身体状态,该身体状态与本发明所述疾病和/或病症有关。例如,本发明所述疾病和/或病症既可以指一种身体状态,也可以指一种疾病状态。在本文中对于身体状态和疾病状态不作区分,或者二者可以相互指代。
如本发明所提及的,术语“药学上可接受的盐”表示该盐不但是受试者生理学上可接受,而且还可指在药学上有使用价值的合成物质,例如在为进行手性拆分时所形成的作为中间体的盐,虽然这种中间体的盐并不能直接给予受试者,但该盐可在为获得本发明终产物中起作用。
式I所示化合物的药学上可接受的盐有两种形成形式:一种是与酸形成的盐;另一种是与碱或者碱金属形成的盐。与式I所示化合物形成药学上可接受的盐的酸包括无机酸和有机酸。合适的无机酸包括:盐酸、硫酸和磷酸。合适的有机酸包括脂肪族、环脂肪族、芳香性、杂环羧酸和磺酸类有机酸,其实例包括但不限于:甲酸、乙酸、丙酸、琥珀酸、甘醇酸、葡萄糖酸、乳酸、苹果酸、酒石酸、甘氨酸、精氨酸、柠檬酸、反丁烯二酸、烷基磺酸、芳级磺酸等。与式I所示化合物形成药学上可接受的盐的碱金属包括锂、钠、钾、镁、钙、铝、锌等;与式I所示化合物形成药学上可接受的盐的碱包括胆碱、二乙醇胺、吗啉等。
如本发明所提及的,术语“前药”是一些式I所示化合物的衍生物借助于在体内代谢的方式将其于活体内转化(例如:水解,还原或氧化)成式I所示化合物,这些衍生物就称为前药。例如,可以将式I所示的、含有羟基基团的化合物与酸反应制备成相应的酯,所述制成的酯即为前药,可以在活体内水解母体药物。适合来制备“前药”的酸包括但不限于:乙酸、柠檬酸、乳酸、酒石酸、丙二酸、草酸、水杨酸、琥珀酸、反丁烯二酸、顺丁烯二酸、亚甲基-双-β-羟基萘酸、龙胆酸、羟乙基磺酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸等。
相对于现有技术,本发明具有以下有益效果:
(1)本发明提供了一类结构新颖的化合物及其药学上可接受的盐、立体异构体、互变异构体、N-氧化物或其前药分子,可诱导BET蛋白的降解(优选地,诱导BRD2的降解),或/和有效诱导GSPT1的降解;
(2)本发明提供的化合物及组合物可用于制备治疗或预防肿瘤形成、炎症、病毒感染、细胞增殖性紊乱、自身免疫性疾病、败血症等疾病的药物。
附图说明
图1为不同浓度下化合物7、8和9下调22Rv1细胞内BET蛋白水平图
图2为不同浓度下化合物9下调22Rv1细胞内BET蛋白水平图。
图3为不同浓度下化合物9下调MV4;11细胞内BET蛋白水平图。
图4为不同时间内化合物9下调22Rv1细胞内BET蛋白水平图。
图5为不同时间内化合物9下调MV4;11细胞内BET蛋白水平图。
图6为不同浓度下化合物9下调22Rv1细胞内GSPT1蛋白水平图。
图7为不同浓度下化合物9下调MV4;11细胞内GSPT1蛋白水平图。
图8为不同时间内化合物9下调22Rv1细胞内GSPT1蛋白水平图。
图9为不同时间内化合物9下调MV4;11细胞内GSPT1蛋白水平图。
具体实施方式
下面通过具体实施方式来进一步说明本发明的技术方案。本领域技术人员应该明了,所述实施例仅仅是帮助理解本发明,不应视为对本发明的具体限制。
制备例
本制备例提供所述苯并[d]异恶唑类化合物制备过程所需原料T-1/T-2合成步骤
化合物T-1/T-2的合成路线如下所示:
(a)N-(2,4-二甲氧苯基)乙酰胺(1-1)
将2,4-二甲氧基苯胺(25g,163.21mmol)和三乙胺(36.29mL,104.4mmol)溶于40mL二氯甲烷,冰水浴条件下,滴加醋酸酐(21.6mL,228.49mmol)反应结束后在反应体系中加入10%柠檬酸水溶液。用二氯甲烷溶液萃取,有机层分别用稀盐酸、饱和碳酸氢钠、饱和食盐水萃取,无水硫酸钠干燥。减压浓缩后得到目标产物为深棕色固体(30g,收率94%)。
1H NMR(400MHz,DMSO)δ8.99(s,1H),7.64(d,J=8.7Hz,1H),6.59(s,1H),6.45(d,J=8.8Hz,1H),3.79(s,3H),3.73(s,3H),2.01(s,3H).MS(ESI)m/z[M+H]+理论值:196.09;实际值:196.1。
(b)N-(5-乙酰基-4-羟基-2-甲氧基苯基)乙酰胺(1-2)
将1-1(30g,153.85mmol)溶于50mL二氯甲烷,冰浴下分批缓慢加入三氯化铝(86.98g,652.32mmol)、氩气保护下加入乙酰氯(34.6mL,489.24mmol),43℃下搅拌反应。反应结束后将反应液缓慢倒入冰水中淬灭2h,后用二氯甲烷萃取,有机层分别用水、饱和食盐水萃取,无水硫酸钠干燥。有机层减压浓缩后,粗产物过柱处理(PE:EA=1:1),得目标产物(26.1g,收率76%)。
1H NMR(500MHz,DMSO)δ12.54(s,1H),9.17(s,1H),8.26(s,1H),6.59(s,1H),3.88(s,3H),2.52(s,3H),2.05(s,3H).MS(ESI)m/z[M+H]+理论值:224.08;实际值:224.1。
(c)(E)-N-(4-羟基-5-(1-(羟基亚氨基)乙基)-2-甲氧基苯基)乙酰胺(1-3)
将1-2(26.1g,116.80mmol)溶于200mL乙醇水溶液(无水乙醇:水=3:1,v/v),加入盐酸羟胺(12.99g,186.88mmol)和醋酸钠(15.33g,186.88mmol),80℃回流2h。TLC监测反应。反应结束后减压旋干溶剂,加入水,减压抽滤,将滤饼水洗干燥,得目标产物(24.5g,收率88%)。
1H NMR(500MHz,DMSO)δ11.74(s,1H),11.33(s,1H),9.03(s,1H),7.84(s,1H),6.54(s,1H),3.80(s,3H),2.17(s,3H),2.02(s,3H).MS(ESI)m/z[M+H]+理论值:239.10;实际值:239.1。
(d)N-(6-甲氧基-3-甲基苯并异恶唑-5-基)乙酰胺(1-4)
将1-3(24.5g)溶于200mL 1,4-二氧六环,40-60℃内剧烈搅拌下加入N,N-二甲基甲酰胺二甲基缩醛。待反应体系稳定后,升温至100℃反应7min。冷却至室温,用二氯甲烷溶解,分别用水、饱和食盐水萃取,无水硫酸钠干燥。有机层减压浓缩后,得目标产物(22.2g,收率98%)。
1H NMR(500MHz,DMSO)δ9.26(s,1H),8.24(s,1H),7.36(s,1H),3.94(s,3H),2.47(s,3H),2.11(s,3H).MS(ESI)m/z[M+H]+理论值:221.08;实际值:221.1。
(e)6-甲氧基-3-甲基苯并[d]异恶唑-5-胺(1-5)
将1-4(22.2g,100.64mmol)溶于400mL盐酸(3mol/L),90℃回流3h。TLC监测反应。反应完毕,加入氢氧化钠溶液(3mol/L)调pH至中性(7-9),析出沉淀,减压过滤,少量水洗涤,干燥,得到棕褐色固体(17.1g,收率95%)。
1H NMR(500MHz,DMSO)δ7.14(s,1H),6.80(s,1H),4.80(s,2H),3.88(s,3H),2.39(s,3H)。
(f)5-氨基-3-甲基苯并异恶唑-6-醇(1-6)
将1-5(17.1g,95.96mmol)溶于100mL二氯甲烷,取BBr3溶于100mL二氯甲烷,冰浴下缓慢加入反应体系,常温下过夜反应。反应结束后,缓慢滴加甲醇和氯化胺溶液淬灭。加水,用氢氧化钠溶液调节pH至7,乙酸乙酯萃取。有机层分别用水、饱和食盐水萃取,无水硫酸钠干燥。有机层减压浓缩干燥得目标产物(6g,收率38%)。
(g)5-溴-N-(6-羟基-3-甲基苯并[d]异恶唑-5-基)-2-甲氧基苯磺酰胺(1-7)
将1-6(6g,36.57mmol)和4-氯苯磺酰氯(10.44g,36.57mmol)溶于二氯甲烷中,加入7mL吡啶,常温下反应4h,反应结束后加水萃取,有机层分别用用稀盐酸水溶液,水、饱和食盐水萃取,无水硫酸钠干燥。有机层减压浓缩后粗产物过柱处理(DCM:MeOH=250:1-125:1),得目标产物(2.5g,收率17%)。
1H NMR(500MHz,DMSO)δ10.70(s,1H),9.09(s,1H),7.74(dd,J=8.8,2.5Hz,1H),7.69(d,J=2.5Hz,1H),7.54(s,1H),7.18(d,J=8.9Hz,1H),6.88(s,1H),3.82(s,3H),2.44(s,3H)。
(h)2-(5-(5-溴-2-甲氧基苯基)磺酰氨基)-3-甲基苯并[d]异恶唑-6-基)乙酸叔丁酯(1-8)
将化合物1-7(500mg,1.21mmol)溶于超干DMF中,加入KI(20mg,0.12mmol)、KHCO3(182mg,1.82mmol)。再将溴丁酸叔丁酯(0.21mL,1.21mmol)溶于2mL超干DMF中,冰浴搅拌并在氩气保护下分批加入反应体系,40℃下搅拌反应4h。反应结束后,将二氯甲烷和水加入到反应体系中进行三次萃取,合并有机层并用饱和食盐水萃取。将有机层分离合并后用无水硫酸钠干燥并进行减压浓缩。浓缩后的粗产物通过硅胶柱进行分离纯化(PE:EA=10:1,v/v),得到目标产物为白色固体(300mg,收率47%)。
(i)2-(5-(5-溴-2-甲氧基苯基)磺酰氨基)-3-甲基苯并[d]异恶唑-6-基)乙酸(T-1)
将化合物1-8(300mg,0.59mmol)溶于二氯甲烷溶剂(5mL)中,加入三氟乙酸(1mL),常温下搅拌反应,通过TLC监测反应。反应结束后进行减压旋干溶剂。产物直接用于下一步反应。
(j)4-(5-(5-(5-溴-2-甲氧基苯基)磺酰胺基)-3-甲基苯并[d]异恶唑-6-基)氧基丁酸叔丁酯(1-9)
将化合物1-7(500mg,1.21mmol)溶于超干DMF中,加入KI(20mg,0.12mmol)、KHCO3(182mg,1.82mmol)。再将溴丁酸叔丁酯(0.21mL,1.21mmol)溶于2mL超干DMF中,冰浴搅拌并在氩气保护下分批加入反应体系,40℃下搅拌反应4h,通过TLC进行监测反应。反应结束后,将二氯甲烷和水加入到反应体系中进行三次萃取,合并有机层并用饱和食盐水萃取。将有机层分离合并后用无水硫酸钠干燥并进行减压浓缩。浓缩后的粗产物通过硅胶柱进行分离纯化(PE:EA=10:1,v/v),得到目标产物为白色固体(134mg,收率20%)。
(k)4-(5-(5-溴-2-甲氧基苯基)磺酰胺基)-3-甲基苯并异恶唑-6-基)氧基)丁酸(T-2)
将化合物1-9(134mg,0.24mmol)溶于二氯甲烷溶剂(5mL)中,加入三氟乙酸(1mL),常温下搅拌反应,通过TLC监测反应。反应结束后进行减压旋干溶剂。产物直接用于下一步反应。
实施例1
2-(5-(5-溴-2-甲氧基苯基)磺酰氨基)-3-甲基苯并[d]异恶唑-6-基)-N-(2-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)乙酰胺)乙基)
化合物1的合成路线如下所示:
(a)2-(2,6-二氧哌啶-3-基)-4-羟基异吲哚啉-1,3-二酮(2-1)
将3-羟基苯二甲酸酐(5.00g,30.47mmol)和3-氨基-2,6-哌啶-二酮盐酸盐(5.00g,30.38mmol)溶于甲苯溶剂中,并加入TEA(4.65mL),在115℃下加热回流过夜,通过TLC监测反应。反应结束后进行减压旋干溶剂,粗产物通过硅胶柱进行分离纯化(DCM:MeOH=50:1,v/v),得到目标产物为2-1,墨绿色固体(8.00g,收率96%)。
1H NMR(500MHz,DMSO-d6)δ11.18(brs,1H),11.08(s,1H),7.65(t,J=7.8Hz,1H),7.32(d,J=7.1Hz,1H),7.25(d,J=8.4Hz,1H),5.09-5.04(m,1H),2.92-2.85(m,1H),2.64-2.53(m,2H),2.04-2.00(m,1H)。
(b)2-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)乙酸叔丁酯(2-2)
将化合物2-1(2.00g,7.33mmol)溶于超干DMF中,加入KI(122mg,0.733mmol)、KHCO3(1.10g,11.00mmol)。再将溴乙酸叔丁酯(1.28mL,8.80mmol)溶于5mL超干DMF中,并在氩气保护下分批加入反应体系中,在60℃下搅拌过夜,通过TLC监测反应。反应结束后将二氯甲烷和水加入到反应体系中进行萃取,萃取步骤重复三次,合并有机层并用饱和食盐水萃取。将有机层分离合并后用无水硫酸钠干燥,并进行减压浓缩。粗产物通过硅胶柱进行分离纯化(DCM:MeOH=100:1,v/v),得到目标产物为2-2,白色固体(2.15g,收率76%)。
1H NMR(400MHz,DMSO-d6)δ11.11(s,1H),7.80(dd,J=8.3,7.5Hz,1H),7.48(d,J=7.2Hz,1H),7.38(d,J=8.6Hz,1H),5.10(dd,J=12.8,5.3Hz,1H),4.97(s,2H),2.93-2.85(m,1H),2.61-2.53(m,2H),2.06-2.01(m,1H),1.43(s,9H)。
(c)2-(2-(2,6-二氧阿哌啶-3-基)-1,3-二氧异吲哚-4-基)乙酸(2-3)
将化合物2-2(2.05g,5.20mmol)溶于二氯甲烷(100mL)中,加入三氟乙酸(5mL),常温下搅拌反应,通过TLC监测反应。反应结束后通过减压旋干溶剂。得到目标产物为2-3,白色固体(1.40g,收率81%),产物直接用于下一步反应。
1H NMR(400MHz,DMSO-d6)δ11.11(s,1H),7.79(dd,J=8.4,7.4Hz,1H),7.48(d,J=7.2Hz,1H),7.39(d,J=8.6Hz,1H),5.10(dd,J=12.8,5.3Hz,1H),4.99(s,2H),2.94-2.90(m,1H),2.61-2.53(m,2H),2.06-2.01(m,1H)。
(d)(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)乙酰氨基)乙基)氨基甲酸叔丁酯(2-4)
取化合物2-3(300mg,0.90mmol)溶于超干DMF中,加入HATU(411mg,1.08mmol),氩气保护下加入DIPEA(0.5mL,2.70mmol),常温下搅拌反应0.5h,再加入N-BOC-乙二胺(173mg,1.08mmol),常温下搅拌反应,通过TLC监测反应。反应结束后,将二氯甲烷和水加入到反应体系中进行三次萃取,合并有机层并用饱和食盐水萃取一次。将有机层分离合并后用无水硫酸钠干燥,并进行减压浓缩。粗产物通过硅胶柱进行分离纯化(DCM:MeOH=100:1,v/v),得到目标产物为2-4,淡黄绿色固体(136mg,收率23%)。
1H NMR(400MHz,DMSO-d6)δ11.11(s,1H),8.03(t,J=5.1Hz,1H),7.81(t,J=8.0Hz,1H),7.50(d,J=7.2Hz,1H),7.39(d,J=8.5Hz,1H),6.84(t,J=5.2Hz,1H),5.15-5.09(m,1H),4.76(s,2H),3.19-3.15(m,2H),3.03-2.99(m,2H),2.90-2.85(m,1H),2.62-2.50(m,2H),2.05-2.00(m,1H),1.36(s,9H)。
(e)N-(2-氨基乙基)-2-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异喹啉-4-基)氧基)乙酰胺(2-5)
将化合物2-4(136mg,0.36mmol)溶于二氯甲烷(10mL)中,加入三氟乙酸(1mL),常温下搅拌反应,TLC监测反应。反应结束后进行减压旋干溶剂。产物为2-5,直接用于下一步反应。
(f)2-(5-(5-溴-2-甲氧基苯基)磺酰氨基)-3-甲基苯并[d]异恶唑-6-基)-N-(2-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)乙酰胺)乙基)(实施例1)
将化合物T1(50mg,0.11mmol)和HATU(46mg,0.12mmol)溶于DMF中,加入DIPEA(0.1mL,0.53mmol),搅拌反应0.5h。再向反应体系中加入2-5(44mg,0.12mmol),常温下搅拌反应,TLC监测反应。反应结束后,将二氯甲烷和水加入到反应体系中进行萃取,重复三次,合并有机层并用饱和食盐水萃取。将有机层分离后用无水硫酸钠干燥,并减压浓缩。粗产物通过硅胶色谱柱进行纯化(DCM:MeOH=100:1,v/v),得到目标产物为化合物1,白色固体(33mg,收率38%)。
1H NMR(500MHz,DMSO-d6)δ11.12(s,1H),9.67(s,1H),8.21(s,1H),8.17(s,1H),7.77(t,J=7.8Hz,1H),7.71-7.69(m,3H),7.45(d,J=7.2Hz,1H),7.36(d,J=8.5Hz,1H),7.31(s,1H),7.08(d,J=8.5Hz,1H),5.13-5.10(m,1H),4.79(s,2H),4.36(s,2H),3.53(s,3H),3.24-3.20(m,4H),2.93-2.86(m,1H),2.62-2.55(m,2H),2.47(s,3H),2.04-2.03(m,1H);13C NMR(126MHz,DMSO-d6)δ172.71,169.82,167.36,166.67,166.66,165.37,161.14,155.92,154.99,153.31,137.13,136.84,133.01,131.36,129.50,123.12,120.32,118.53,116.80,115.99,115.00,114.85,110.61,93.49,67.67,67.55,56.18,48.79,38.03,30.92,21.98,9.43;MS(ESI)m/z[M-H]-理论值:825.09和827.09,实际值:825.8和827.5;HPLC分析:MeOH-H2O(85:15),9.26min,98.26%纯度。
实施例2
2-((5-((5-溴-2-甲氧基苯基)磺酰胺)-3-甲基苯并[d]异恶唑-6-基)氧基)-N-(3-(2-((2-(2,6))-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)乙酰氨基)丙基)乙酰胺
合成方法参照实施例1的合成路线。
区别仅在于:将N-BOC-乙二胺原料替换为等摩尔量的N-叔丁氧羰基-1,3-丙二胺原料。
化合物2为白色固体,收率28%。
1H NMR(500MHz,DMSO-d6)δ11.11(s,1H),9.74(s,1H),8.25-8.23(m,1H),8.12-8.11(m,1H),7.80(t,J=7.6Hz,1H),7.71-7.68(m,3H),7.48(d,J=7.0Hz,1H),7.40(d,J=8.3Hz,1H),7.29(s,1H),7.07(d,J=8.6Hz,1H),5.13-5.10(m,1H),4.80(s,2H),4.38(s,2H),3.55(s,3H),3.22-3.06(m,4H),2.97-2.81(m,1H),2.67-2.53(m,2H),2.49-2.44(m,3H),2.09-1.98(m,1H),1.65-1.53(m,2H);13C NMR(126MHz,DMSO-d6)δ172.74,169.84,166.85,166.71,166.42,165.42,155.91,155.06,154.96,153.53,137.03,136.91,133.03,131.28,120.41,116.81,116.02,114.99,114.85,110.58,93.55,67.75,67.64,56.17,48.80,36.20,36.10,30.93,29.21,21.99,9.43;MS(ESI)m/z[M-H]-理论值:839.11和841.11;实际值:839.5和841.8;HPLC分析:MeOH-H2O(85:15),11.20min,97.32%纯度。
实施例3
2-((5-((5-溴-2-甲氧基苯基)磺酰胺)-3-甲基苯并[d]异恶唑-6-基)氧基)-N-(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)乙酰胺基)丁基)乙酰胺
合成方法参照实施例1的合成路线。
区别仅在于:将N-BOC-乙二胺原料替换为等摩尔量的N-叔丁氧羰基-1,4-丁二胺原料。
化合物3为白色固体,收率25%。
1H NMR(500MHz,DMSO-d6)δ11.12(s,1H),9.70(s,1H),8.06(t,J=5.4Hz,1H),7.96(t,J=5.4Hz,1H),7.80(t,J=7.9Hz,1H),7.72-7.70(m,3H),7.49(d,J=7.2Hz,1H),7.38(d,J=8.5Hz,1H),7.30(s,1H),7.08(d,J=9.5Hz,1H),5.15-5.10(m,1H),4.77(s,2H),4.38(s,2H),3.54(s,3H),3.15-3.10(m,4H),2.93-2.85(m,1H),2.61-2.54(m,2H),2.49-2.48(m,3H),2.05-2.01(m,1H),1.48-1.37(m,4H);13C NMR(126MHz,DMSO-d6)δ172.72,169.83,166.69(2×C),166.23,165.48,161.14,155.91,155.04,154.99,153.43,137.14,136.90,133.01,131.26,129.58,123.19,120.40,118.60,116.81,116.03,115.00,114.83,110.58,93.50,67.71,67.65,56.17,48.80,38.01(2×C),30.93,26.54,26.49,21.97,9.42;MS(ESI)m/z[M-H]-理论值:853.12和855.12;实际值:853.4和855.5;HPLC分析:MeOH-H2O(85:15),9.40min,95.21%纯度。
实施例4
2-(5-(5-溴-2-甲氧基苯基)磺酰氨基)-3-甲基苯并[d]异恶唑-6-基)-N-(5-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)乙酰胺)戊酰胺
合成方法参照实施例1的合成路线。
区别仅在于:将N-BOC-乙二胺原料替换为等摩尔量的单BOC-戊二胺原料。
化合物4为白色固体,收率29%。
1H NMR(500MHz,DMSO-d6)δ11.11(s,1H),9.77(s,1H),8.03(brs,1H),7.92(brs,1H),7.80(t,J=7.8Hz,1H),7.72-7.70(m,3H),7.48(d,J=7.2Hz,1H),7.39(d,J=8.5Hz,1H),7.29(s,1H),7.08(d,J=8.8Hz,1H),5.15-5.12(m,1H),4.78(s,2H),4.39(s,2H),3.55(s,3H),3.13-3.08(m,4H),2.94-2.87(m,1H),2.63-2.56(m,2H),2.49(s,3H),2.06-2.04(m,1H),1.39-1.36(m,4H),1.30-1.21(m,2H).13C NMR(126MHz,DMSO-d6)δ172.76,169.86,166.73,166.65,166.26,165.51,161.09,155.92,155.07,154.97,153.59,137.03,136.90,133.02,131.26,129.85,120.39,116.79,116.01,114.99,114.84,110.59,93.49,67.77,67.64,56.18,48.83,38.27,38.26,30.95,28.79,28.66,23.69,22.00,9.44.MS(ESI)m/z[M-H]-理论值:867.14和869.14;实际值:867.5和869.2.HPLC分析:MeOH-H2O(85:15),9.44min,98.43%纯度。
实施例5
2-(5-(5-溴-2-甲氧基苯基)磺酰氨基)-3-甲基苯并[d]异恶唑-6-基)-N-(6-(2-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)乙酰氨基)己酰胺)
合成方法参照实施例1的合成路线。
区别仅在于:将N-BOC-乙二胺原料替换为等摩尔量的N-(6-氨基己基)氨基甲酸叔丁酯原料。
化合物5为白色固体,收率69%。
1H NMR(500MHz,DMSO-d6)δ11.12(s,1H),9.70(s,1H),8.03(s,1H),7.92(s,1H),7.81(t,J=7.7Hz,1H),7.71(d,J=10.0Hz,3H),7.49(d,J=7.0Hz,1H),7.40(d,J=8.4Hz,1H),7.29(s,1H),7.09(d,J=8.6Hz,1H),5.21-5.05(m,1H),4.77(s,2H),4.40(s,2H),3.56(s,3H),3.22-3.01(m,4H),2.96-2.82(m,1H),2.58(m,2H),2.37(s,3H),2.03(m,1H),1.45-1.32(m,4H),1.22(m,4H).13C NMR(126MHz,DMSO-d6)δ172.74,169.85,166.72,166.62,166.19,165.51,161.17,155.92,155.02,154.99,153.47,137.13,136.90,133.02,131.23,129.66,123.22,120.39,118.67,116.84,116.05,115.00,114.84,110.61,93.45,67.72,67.68,56.18,48.83,38.25,30.95,29.11,28.94,26.04,25.97,22.00,9.43.MS(ESI)m/z[M-H]-理论值:881.15和883.15;实际值:881.6和883.5.HPLC分析:MeOH-H2O(85:15),9.86min,98.60%纯度。
实施例6
2-(5-(5-溴-2-甲氧基苯基)磺酰氨基)-3-甲基苯并[d]异恶唑-6-基)-N-(2-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)乙酰胺)乙酰胺
化合物6的合成路线如下所示:
(a)2-(2,6-二氧哌啶-3-基)-4-氟异吲哚啉-1,3-二酮(3-1)
将3-氟酞酐(5.00g,30.10mmol)、3-氨基-2,6-哌啶-二酮盐酸盐(4.95g,30.10mmol)和醋酸钠(2.95g,36.00mmol)溶于醋酸溶液中,120℃下加热回流过夜,TLC监测反应。反应结束后,加入冰水至固体洗出,并进行抽滤,用水多次洗滤饼,在60℃干燥箱中烘干滤饼。得到目标产物为3-1,灰白色固体(7.32g,收率88%)。
1H NMR(500MHz,DMSO-d6)δ11.15(s,1H),7.95(m,1H),7.79(d,J=7.4Hz,1H),7.73(t,J=8.9Hz,1H),5.18-5.14(m,1H),2.93-2.85(m,1H),2.62-2.52(m,2H),2.09-2.05(m,1H)。
(b)(2-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)叔丁基氨基甲酸乙酯(3-2)
将化合物3-1(100mg,0.36mmol)溶于超干DMF中,氩气保护下加入N-BOC-乙二胺(0.06mL,0.40mmol),80℃下搅拌反应,通过TLC监测反应。反应结束后,将二氯甲烷和水加入到反应体系中进行三次萃取后合并有机层,并用饱和食盐水萃取一次。将有机层分离合并后用无水硫酸钠干燥,并通过减压浓缩。粗产物通过硅胶柱进行纯化分离(DCM:MeOH=100:1,v/v),得到目标产物为3-2,黄色固体(30mg,收率20%)。
1H NMR(400MHz,DMSO-d6)δ11.08(s,1H),7.57(t,J=7.8Hz,1H),7.14(d,J=8.6Hz,1H),7.03-7.00(m,2H),6.70(t,J=5.2Hz,1H),5.05(dd,J=12.7,5.2Hz,1H),3.37-3.32(m,2H),3.12-3.11(m,2H),2.93-2.84(m,1H),2.61-2.54(m,2H),2.03-2.00(m,1H),1.36(s,9H)。
(c)4-((2-氨基乙基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮(3-3)
将化合物3-2(30mg,0.07mmol)溶于二氯甲烷溶剂(5mL)中,加入三氟乙酸(0.5mL),常温下搅拌反应,通过TLC监测反应。反应结束后进行减压旋干溶剂。产物3-3直接用于下一步反应。
(d)2-(5-(5-溴-2-甲氧基苯基)磺酰氨基)-3-甲基苯并[d]异恶唑-6-基)-N-(2-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)乙酰胺)乙酰胺(实施例6)
将化合物T-1(34mg,0.07mmol)和HATU(33mg,0.09mmol)溶于DMF中,加入DIPEA(0.07mL,0.37mmol),搅拌反应0.5h。再向反应体系中加入2-3(23mg,0.07mmol),常温下搅拌反应,TLC监测反应。反应结束后,将二氯甲烷和水加入到反应体系中进行萃取,重复三次,合并有机层并用饱和食盐水萃取。将有机层分离后用无水硫酸钠干燥,并减压浓缩。粗产物通过硅胶色谱柱进行纯化(DCM:MeOH=100:1,v/v),得到目标产物为化合物6,黄色固体(20mg,收率36%)。
1H NMR(400MHz,CDCl3)δ8.40(s,1H),7.90(s,1H),7.63-7.59(m,2H),7.52-7.42(m,3H),7.05-7.04(m,1H),6.91-6.86(m,3H),6.35(t,J=5.0Hz,1H),4.95-4.93(m,1H),4.49(s,2H),3.88(s,3H),3.56-3.55(m,2H),3.46-3.45(m,2H),2.88-2.73(m,3H),2.47(s,3H),2.22-2.15(m,1H),.13C NMR(126MHz,DMSO-d6)δ172.75,170.05,168.66,167.23,167.19,161.09,155.92,154.96,153.32,146.18,137.12,136.18,132.20,131.27,129.48,123.09,118.56,116.95,115.01,114.86,110.59,110.55,109.32,93.48,67.67,56.19,48.53,41.45,37.85,30.96,22.13,9.41.MS(ESI)m/z[M-H]-理论值:767.08和769.08;实际值:767.0和769.5.HPLC分析:MeOH-H2O(70:30),13.75min,97.84%纯度。
实施例7
2-(5-(5-溴-2-甲氧基苯基)磺酰氨基)-3-甲基苯并[d]异恶唑-6-基)-N-(3-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)乙酰胺丙基)
合成方法参照实施例6的合成路线。
区别仅在于:将N-BOC-乙二胺原料替换为等摩尔量的N-叔丁氧羰基-1,3-丙二胺原料。
化合物7为黄色固体,收率46%。
1H NMR(500MHz,DMSO-d6)δ11.10(s,1H),9.70(s,1H),8.17(t,J=4.9Hz,1H),7.71-7.70(m,3H),7.56(t,J=5.8Hz,1H),7.32(s,1H),7.08(d,J=8.7Hz,1H),7.05-6.98(m,2H),6.66(t,J=6.0Hz,1H),5.06-5.02(m,1H),4.41(s,2H),3.54(s,3H),3.33-3.26(m,2H),3.23-3.19(m,2H),2.95-2.78(m,1H),2.63-2.56(m,2H),2.49(s,3H),2.03-2.01(m,1H),1.71-1.65(m,2H).13C NMR(126MHz,DMSO-d6)δ172.74,170.04,168.81,167.25,166.54,161.14,155.91,154.98,153.40,146.20,137.11,136.20,132.23,131.20,129.63,123.16,118.61,117.00,115.03,114.83,110.59,110.44,109.22,93.44,67.68,56.17,48.53,35.94,30.95,28.87,20.73,22.13,9.41.MS(ESI)m/z[M-H]-理论值:781.10和783.10;实际值:781.1和783.0.HPLC分析:MeOH-H2O(85:15),9.10min,95.11%纯度。
实施例8
2-((5-((5-溴-2-甲氧基苯基)磺酰胺)-3-甲基苯并[d]异恶唑-6-基)氧基)-N-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丁基)乙酰胺
合成方法参照实施例6的合成路线。
区别仅在于:将N-BOC-乙二胺原料替换为等摩尔量的N-叔丁氧羰基-1,4-丁二胺原料。
化合物8为黄色固体,收率54%。
1H NMR(500MHz,DMSO-d6)δ11.09(s,1H),9.69(s,1H),8.08(s,1H),7.71-7.69(m,3H),7.56(t,J=7.7Hz,1H),7.30(s,1H),7.09-7.06(m,2H),7.02-7.01(m,1H),6.52(t,J=5.1Hz,1H),5.06-5.03(m,1H),4.39(s,2H),3.54(s,3H),3.32-3.31(m,2H),3.16-3.14(m,2H),2.98-2.80(m,1H),2.67-2.55(m,2H),2.49-2.38(s,3H),2.09-1.97(m,1H),1.63-1.41(m,4H).13C NMR(126MHz,DMSO-d6)δ172.75,170.05,168.91,167.26,166.25,161.12,155.90,154.97,153.43,146.34,137.11,136.24,132.16,131.23,129.64,123.20,118.61,117.14,114.99,114.82,110.58,110.40,109.05,93.47,67.70,56.15,48.53,41.47,38.01,30.95,26.59,26.16,22.13,9.41.MS(ESI)m/z[M-H]-理论值:795.12和797.11;实际值:795.5和797.1.HPLC分析:MeOH-H2O(70:30),18.16min,98.93%纯度。
实施例9
2-((5-((5-溴-2-甲氧基苯基)磺酰胺)-3-甲基苯并[d]异恶唑-6-基)氧基)-N-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)戊基)乙酰胺
合成方法参照实施例6的合成路线。
区别仅在于:将N-BOC-乙二胺原料替换为等摩尔量的单BOC-戊二胺原料。
化合物9为黄色固体,收率81%。
1H NMR(500MHz,DMSO-d6)δ11.08(s,1H),9.70(s,1H),8.04(t,J=5.1Hz,1H),7.72-7.69(m,3H),7.59-7.56(m,1H),7.30(s,1H),7.09-7.01(m,3H),6.50(t,J=5.6Hz,1H),5.06-5.03(m,1H),4.39(s,2H),3.54(s,3H),3.32-3.21(m,2H),3.12-3.09(m,2H),2.91-2.84(m,1H),2.63-2.55(m,2H),2.49(s,3H),2.04-2.01(m,1H),1.59-1.53(m,2H),1.45-1.39(m,2H),1.34-1.26(m,2H).13C NMR(126MHz,DMSO-d6)δ172.74,170.04,168.93,167.26,166.17,161.14,155.90,154.98,153.45,146.36,137.11,136.24,132.16,131.20,129.68,123.22,118.64,117.10,115.01,114.81,110.58,110.39,109.05,93.46,67.72,56.15,48.53,41.76,38.17,30.95,28.86,28.34,23.66,22.13,9.41.MS(ESI)m/z[M-H]-理论值:809.13和811.13;实际值:809.8和811.5.HPLC分析:MeOH-H2O(85:15),5.46min,98.91%纯度。
实施例10
2-((5-((5-溴-2-甲氧基苯基)磺酰胺)-3-甲基苯并[d]异恶唑-6-基)氧基)-N-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)己基)乙酰胺
合成方法参照实施例6的合成路线。
区别仅在于:将N-BOC-乙二胺原料替换为等摩尔量的N-(6-氨基己基)氨基甲酸叔丁酯原料。
化合物10为白色固体,收率71%。
1H NMR(500MHz,DMSO-d6)δ11.09(s,1H),9.69(s,1H),8.02(brs,1H),7.71-7.69(m,3H),7.57(t,J=7.7Hz,1H),7.29(s,1H),7.09-7.06(m,2H),7.01(d,J=7.0Hz,1H),6.50(t,J=5.0Hz,1H),5.05(dd,J=12.6,5.3Hz,1H),4.39(s,2H),3.55(s,3H),3.32-3.24(m,2H),3.11-3.08(m,2H),2.91-2.84(m,1H),2.61-2.53(m,2H),2.49(s,3H),2.03-2.01(m,1H),1.53-1.50(m,2H),1.39-1.23(m,6H).13C NMR(126MHz,DMSO-d6)δ172.75,170.04,168.94,167.27,166.15,161.15,155.90,154.97,153.47,146.39,137.09,136.23,132.16,131.19,129.69,123.22,118.65,117.11,115.00,114.81,110.59,110.36,109.02,93.45,67.72,56.16,48.53,41.75,38.25,30.96,29.08,28.61,26.09,26.02,22.14,9.40.MS(ESI)m/z[M-H]-理论值:823.15和825.15;实际值:823.5和825.5.HPLC分析:MeOH-H2O(70:30),22.45min,99.55%纯度。
实施例11
2-((5-((5-溴-2-甲氧基苯基)磺胺基)-3-甲基苯并[d]异恶唑-6-基)氧基)-N-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)乙基)乙酰胺
合成方法参照实施例6的合成路线。
区别仅在于:将3-氟酞酐原料替换为等摩尔量的4-氟邻苯二甲酸酐原料。
得到目标产物为化合物11为黄色固体(70mg,收率54%)。
1H NMR(500MHz,DMSO-d6)δ11.06(s,1H),9.63(s,1H),8.30-8.29(m,1H),7.71-7.70(m,3H),7.56(d,J=8.5Hz,1H),7.32(s,1H),7.15(t,J=5.5Hz,1H),7.09(d,J=9.5Hz,1H),6.99(s,1H),6.87(d,J=8.4Hz,1H),5.05-5.01(m,1H),4.39(s,2H),3.56(s,3H),3.27-3.25(m,2H),3.17-3.16(m,1H),2.87-2.85(m,1H),2.64-2.50(m,2H),2.47(s,3H),2.36(brs,1H),2.00-1.99(m,1H).13C NMR(126MHz,DMSO-d6)δ172.68,170.03,167.51,167.01,166.89,161.06,155.87,154.91,154.11,153.27,137.08,134.17,131.22,129.44,124.98,123.05,118.44,116.40,114.99,114.83,110.52,93.49,67.69,56.15,48.59,48.51,41.68,37.50,30.91,22.14,9.35.MS(ESI)m/z[M+H]+理论值:769.08和71.08;实际值:769.11和771.17.HPLC分析:MeOH-H2O(80:20),4.70min,95.15%纯度。
实施例12
2-((5-((5-溴-2-甲氧基苯基)磺酰胺)-3-甲基苯并[d]异恶唑-6-基)氧基)-N-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)丙基)乙酰胺
合成方法参照实施例7的合成路线。
区别仅在于:将3-氟酞酐原料替换为等摩尔量的4-氟邻苯二甲酸酐原料。
化合物12为黄色固体,收率38%。
1H NMR(500MHz,DMSO-d6)δ11.06(s,1H),9.69(s,1H),8.15(t,J=5.6Hz,1H),7.71-7.70(m,3H),7.55(d,J=8.3Hz,1H),7.30(s,1H),7.09-7.08(m,2H),6.92(s,1H),6.80(d,J=8.4Hz,1H),5.05-5.01(m,1H),4.42(s,2H),3.56(s,3H),3.24-3.22(m,2H),3.14-3.12(m,2H),2.89-2.85(m,1H),2.63-2.56(m,2H),2.47(s,3H),2.01-1.98(m,1H),1.72-1.69(m,2H).13C NMR(126MHz,DMSO-d6)δ172.72,170.08,167.62,167.09,166.47,161.10,155.89,154.92,154.26,153.48,137.05,134.13,131.15,129.65,124.98,123.22,118.56,116.00,115.01,114.83,110.57,93.48,67.73,56.15,52.99,48.61,41.39,36.24,30.94,28.29,22.20,9.36.MS(ESI)m/z[M+H]+理论值:783.10和785.10;实际值:783.08和785.13.HPLC分析:MeOH-H2O(80:20),4.70min,98.83%纯度。
实施例13
2-((5-((5-溴-2-甲氧基苯基)磺酰胺)-3-甲基苯并[d]异恶唑-6-基)氧基)-N-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)丁基)乙酰胺
合成方法参照实施例8的合成路线。
区别仅在于:将3-氟酞酐原料替换为等摩尔量的4-氟邻苯二甲酸酐原料。
化合物13为黄色固体,收率49%。
1H NMR(500MHz,DMSO-d6)δ11.05(s,1H),9.69(s,1H),8.08(brs,1H),7.72-7.69(m,3H),7.55(d,J=8.3Hz,1H),7.31(s,1H),7.11-7.07(m,2H),6.94(s,1H),6.83(d,J=8.3Hz,1H),5.04-5.01(m,1H),4.39(s,2H),3.54(s,3H),3.31-3.29(m,2H),3.16-3.13(m,2H),2.91-2.87(m,1H),2.64-2.59(m,2H),2.47(s,3H),2.01-1.97(m,1H),1.55-1.47(m,4H).13C NMR(126MHz,DMSO-d6)δ172.69,170.07,167.63,167.06,166.23,161.09,155.87,154.93,154.35,153.41,137.08,134.16,131.21,129.60,125.01,123.18,118.52,115.85,114.98,114.80,110.55,93.47,67.70,56.12,54.82,48.58,42.08,37.98,30.92,26.74,25.60,22.17,9.36.MS(ESI)m/z[M+H]+理论值:797.12和799.11;实际值:797.23和799.35.HPLC分析:MeOH-H2O(80:20),4.84min,99.59%纯度。
实施例14
2-((5-((5-溴-2-甲氧基苯基)磺酰胺)-3-甲基苯并[d]异恶唑-6-基)氧基)-N-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)戊基)乙酰胺
合成方法参照实施例9的合成路线。
区别仅在于:将3-氟酞酐原料替换为等摩尔量的4-氟邻苯二甲酸酐原料。
化合物14为黄色固体,收率36%。
1H NMR(500MHz,DMSO-d6)δ11.05(s,1H),9.70(s,1H),8.05(brs,1H),7.72-7.69(m,3H),7.55(d,J=8.3Hz,1H),7.30(s,1H),7.09-7.06(m,2H),6.92(s,1H),6.82(d,J=8.4Hz,1H),5.04-5.01(m,1H),4.39(s,2H),3.54(s,3H),3.13-3.08(m,4H),2.88-2.84(m,1H),2.63-2.55(m,2H),2.47(s,3H),2.00-1.97(m,1H),1.58-1.53(m,2H),1.45-1.39(m,2H),1.34-1.30(m,2H).13C NMR(126MHz,DMSO-d6)δ172.70,170.07,167.63,167.07,166.16,161.12,155.87,154.93,154.36,153.44,137.07,134.14,131.17,129.63,125.01,123.17,118.59,115.81,114.99,114.79,110.56,93.45,67.69,56.13,48.58,42.37,38.17,30.92,28.86,27.85,23.83,22.18,9.36.MS(ESI)m/z[M+H]+理论值:811.13和813.13;实际值:811.21和813.17.HPLC分析:MeOH-H2O(80:20),5.06min,97.47%纯度。
实施例15
2-(5-(5-溴-2-甲氧基苯基)磺酰胺基)-3-甲基苯并[d]异恶唑-6-基)-N-(2-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)己基)乙酰胺
合成方法参照实施例10的合成路线。
区别仅在于:将3-氟酞酐原料替换为等摩尔量的4-氟邻苯二甲酸酐原料。
化合物15为黄色固体,收率50%。
1H NMR(500MHz,DMSO-d6)δ11.05(s,1H),9.70(s,1H),8.03(brs,1H),7.71-7.69(m,3H),7.55(d,J=8.4Hz,1H),7.29(s,1H),7.09-7.07(m,2H),6.93(s,1H),6.83(d,J=8.7Hz,1H),5.04-5.01(m,1H),4.39(s,2H),3.54(s,3H),3.14-3.07(m,4H),2.88-2.84(m,1H),2.63-2.55(m,2H),2.49(s,3H),2.00-1.98(m,1H),1.55-1.49(m,2H),1.39-1.31(m,4H),1.27-1.24(m,2H).13C NMR(126MHz,DMSO-d6)δ172.70,170.07,167.63,167.07,166.13,161.12,155.87,154.93,154.38,153.44,137.07,134.15,131.17,129.63,125.02,123.17,118.58,115.77,114.98,114.79,110.56,99.45,93.43,67.70,56.13,48.58,42.35,38.24,30.92,29.08,28.12,26.17,26.09,22.18,9.36.MS(ESI)m/z[M+H]+理论值:825.15和827.15;实际值:825.31和827.36.HPLC分析:MeOH-H2O(80:20),5.28min,98.81%纯度。
实施例16
2-(5-(5-溴-2-甲氧基苯基)磺酰胺基)-3-甲基苯并[d]异恶唑-6-基)氧基)-N-(3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)丙酰基-2-炔-1-基)乙酰胺
化合物16的合成路线如下所示:
(a)叔丁基(3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)丙酸-2-炔-1-基)氨基甲酸酯(4-1)
将化合物3-(4-碘-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(3.0g,9.28mmol),N-Boc-氨基丙炔(4.32g,27.85mmol),Pd(PPh3)2Cl2(652mg,0.93mmol)和CuI(177mg,0.93mmol)加入干燥的双口瓶并密封,加入30mL超干DMF溶解和19.36mL三乙胺后,用氩气换气后在80℃条件下反应12h,TLC监测反应。反应结束后,将二氯甲烷和水加入到反应体系中进行萃取,重复三次,合并有机层并用饱和食盐水萃取。将有机层分离,用无水硫酸钠干燥后进行减压浓缩。粗产物通过硅胶色谱柱进行纯化(DCM:MeOH=100:1,v/v),得到目标产物为4-1,棕色固体(2.4g,收率65%)。
1HNMR(500MHz,DMSO-d6)δ11.02(s,1H),7.74(d,J=7.5Hz,1H),7.66(d,J=7.2Hz,1H),7.55(t,J=7.6Hz,1H),7.40(br,1H),5.17(dd,J=13.3,5.1Hz,1H),4.45(d,J=17.7Hz,1H),4.30(d,J=17.7Hz,1H),4.02(d,J=5.4Hz,2H),2.97-2.90(m,1H),2.65-2.57(m,1H),2.43-2.34(m,1H),2.08-2.00(m,1H),1.40(s,9H).
(b)3-(4-(3-氨基丙-1-炔-1-基)-1-氧异喹啉-2-基)哌啶-2,6-二酮(4-2)
将化合物4-1(1.00g,2.52mmol)溶于二氯甲烷溶剂(10mL)中,加入三氟乙酸(2mL),常温下搅拌反应2h,通过TLC监测反应。反应结束后,将二氯甲烷和水加入到反应体系中进行三次萃取,合并有机层并用饱和食盐水萃取。将有机层分离合并后用无水硫酸钠干燥和减压浓缩。粗产物通过硅胶柱进行分离纯化(DCM:MeOH=100:1,v/v),得到目标产物为4-2,棕色固体(730mg,收率98%)。
1H NMR(500MHz,DMSO-d6)δ11.06(s,1H),8.37(s,2H),7.82(d,J=7.5Hz,1H),7.71(d,J=7.2Hz,1H),7.60(t,J=7.6Hz,1H),5.21(dd,J=13.3,5.1Hz,1H),4.49(d,J=17.8Hz,1H),4.35(d,J=17.8Hz,1H),4.06(s,2H),3.00-2.90(m,1H),2.67-2.58(m,1H),2.39-2.29(m,1H),2.12-2.02(m,1H).
(c)2-(5-(5-溴-2-甲氧基苯基)磺酰胺基)-3-甲基苯并[d]异恶唑-6-基)氧基)-N-(3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)丙酰基-2-炔-1-基)乙酰胺(实施例16)
将化合物T-1(80mg,0.17mmol)和HATU(100mg,0.30mmol)溶于DMF中,加入DIPEA(0.10mL,0.51mmol),搅拌反应0.5h。再向反应体系中加入3-2(79mg,0.20mmol),常温下搅拌反应,TLC监测反应。反应结束后,将二氯甲烷和水加入到反应体系中进行萃取,重复三次,合并有机层并用饱和食盐水萃取。将有机层分离后用无水硫酸钠干燥,并减压浓缩。粗产物通过硅胶色谱柱进行纯化(DCM:MeOH=100:1,v/v),得到目标产物为化合物16,白色固体(70mg,收率55%)。
1H NMR(500MHz,DMSO-d6)δ11.00(s,1H),9.76(s,1H),8.81(t,J=5.5Hz,1H),7.76(d,J=7.3Hz,1H),7.72-7.71(m,2H),7.70-7.67(m,1H),7.65(d,J=7.0Hz,1H),7.55(t,J=7.6Hz,1H),7.33(s,1H),7.08(d,J=8.9Hz,1H),5.16-5.13(m,1H),4.48(s,2H),4.31-4.29(m,2H),3.61(s,3H),2.94-2.87(m,1H),2.63-2.57(m,2H),2.47(s,3H),2.44-2.36(m,2H),2.02-1.99(m,1H).13C NMR(126MHz,DMSO-d6)δ172.69,170.88,167.44,166.39,160.96,155.90,154.93,152.96,143.88,137.17,134.20,132.02,131.40,129.10,128.65,123.29,122.99,117.90,117.64,115.03,114.86,110.56,93.60,91.77,77.63,67.65,56.21,51.61,46.85,31.12,28.46,22.35,9.37.HRMS(ESI)m/z[M+H]+理论值:750.51和752.51;实际值:750.0840和752.0827.HPLC分析:MeOH-H2O(80:20),4.92min,96.37%纯度。
实施例17
2-((5-((5-溴-2-甲氧基苯基)磺胺基)-3-甲基苯并[d]异恶唑-6-基)氧基)-N-(3-(2-(2,6-二氧哌啶-3-基)-1-氧异喹啉-4-基)丙基)乙酰胺
化合物17的合成路线如下所示:
步骤(a)、(b)与实施例16相同。
区别仅在于进行步骤(d):3-(4-(3-氨丙基)-1-氧异喹啉-2-基)哌啶-2,6-二酮(4-3)
将化合物4-2(300mg,1.01mmol)溶于20mL甲醇,用氩气置换气体后,加入10%钯碳,再用氢气置换体系3次,并在室温条件下搅拌反应24h,TLC监测反应。反应结束后,抽滤除去钯碳并减压浓缩,粗产物通过硅胶色谱柱进行纯化(DCM:MeOH=100:1-50:1,v/v),得到目标产物为4-3,白色固体(270mg,收率89%),直接进行下一步反应。
步骤(e)合成方法参照实施例16的步骤(c),区别仅在于将原料化合物4-2替换为本实施例制备得到的原料化合物4-3。
化合物17为白色固体,收率39%。
1H NMR(500MHz,DMSO-d6)δ11.00(s,1H),9.70(s,1H),8.81(t,J=5.9Hz,1H),7.71-7.68(m,3H),7.58(d,J=7.3Hz,1H),7.47-7.40(m,2H),7.32(s,1H),7.08(d,J=8.7Hz,1H),5.15-5.11(m,1H),4.46-4.41(m,3H),4.29(d,J=8.6Hz,1H),3.54(s,3H),3.17-3.15(m,3H),2.95-2.90(m,1H),2.64-2.59(m,2H),2.47(s,3H),2.43-2.36(m,2H),2.02-1.99(m,1H),1.74-1.71(m,1H).13C NMR(126MHz,DMSO-d6)δ172.75,170.94,168.25,166.31,161.12,155.87,154.94,153.40,140.46,137.08,136.65,131.57,131.32,131.18,129.60,128.25,123.14,120.72,118.60,115.00,114.81,110.55,93.43,67.69,56.14,51.51,46.14,37.97,31.13,29.13,28.44,22.47,9.37.MS(ESI)m/z[M+H]+理论值:754.11和756.11;实际值:754.09和756.19.HPLC分析:MeOH-H2O(80:20),4.88min,96.98%纯度。
实施例18
4-(5-(5-溴-2-甲氧基苯基)磺酰胺基)-3-甲基苯并[d]异恶唑-6-基)氧基)-N-(3-(2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)丙酰基-2-炔-1-基)丁酰胺
化合物18的合成路线如下所示:
合成方法参照实施例16的合成路线。
区别仅在于:将T-1原料替换为等摩尔量的T-2原料。
化合物为白色固体,收率64%。
1H NMR(500MHz,DMSO-d6)δ11.01(s,1H),9.20(s,1H),8.36(t,J=5.3Hz,1H),7.74-7.70(m,3H),7.61-7.59(m,2H),7.52-7.49(m,1H),7.24(s,1H),7.14(d,J=8.8Hz,1H),5.17-5.14(m,1H),4.43(d,J=17.7Hz,1H),4.30(d,J=17.7Hz,1H),4.19(d,J=5.4Hz,2H),3.90(t,J=6.4Hz,2H),3.72(s,3H),2.95-2.88(m,1H),2.61-2.53(m,1H),2.45(s,3H),2.43-2.36(m,1H),2.22(t,J=7.3Hz,2H),2.03-1.99(m,1H),1.81-1.74(m,2H).13CNMR(126MHz,DMSO-d6)δ172.72,171.47,170.88,167.44,161.32,155.90,154.77,154.57,143.86,136.97,134.05,131.94,131.01,129.87,128.57,123.14,123.03,117.75,117.69,115.16,113.86,110.56,92.56,92.40,77.33,68.09,56.25,51.56,46.81,31.11,28.59,23.97,22.40,9.33.HRMS(ESI)m/z[M+H]+理论值:778.11和780.11;实际值:778.1144和780.1147.HPLC分析:MeOH-H2O(80:20),5.03min,97.71%纯度。
实施例19
4-(5-(5-溴-2-甲氧基苯基)磺酰胺基)-3-甲基苯并[d]异恶唑-6-基)氧基)-N-(2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)丙基)丁酰胺
合成方法参照实施例17的合成路线。
区别仅在于:将T-1原料替换为等摩尔量的T-2原料。
化合物19为白色固体,收率37.59%。
1H NMR(500MHz,DMSO-d6)δ11.01(s,1H),9.76(s,1H),8.80(t,J=5.5Hz,1H),7.74(d,J=7.3Hz,1H),7.72-7.70(m,2H),7.70-7.68(m,1H),7.65(d,J=7.0Hz,1H),7.55(t,J=7.6Hz,1H),7.33(s,1H),7.08(d,J=8.9Hz,1H),5.16-5.13(m,1H),4.48(s,2H),4.31-4.29(m,2H),4.19(d,J=5.4Hz,2H),3.90(t,J=6.4Hz,2H),3.61(s,3H),2.94-2.87(m,1H),2.63-2.57(m,2H),2.47(s,3H),2.44-2.36(m,2H),2.03-1.99(m,1H).13C NMR(126MHz,DMSO-d6)δ172.69,170.88,167.44,166.39,160.96,155.90,154.93,152.96,143.88,137.17,134.20,132.02,131.40,129.10,128.65,123.29,122.99,117.90,117.64,115.03,114.86,110.56,93.60,91.77,77.63,67.65,56.21,51.61,46.85,31.12,28.59,23.97,22.40,9.37.HRMS(ESI)m/z[M+H]+理论值:782.14和784.14;实际值:782.1486和784.1462.HPLC分析:MeOH-H2O(80:20),5.03min,98.76%纯度。
测试例1
细胞增殖抑制实验(CellTiter-Glo)
实验目的:采用CellTiter-Glo检测试剂对本发明化合物抗肿瘤细胞增殖活性进行评价。
实验方法:按每孔500-1500个细胞/20μl接种在384或96孔板中,于恒温培养箱中培养过夜。化合物用对应细胞的培养基(+10%FBS)稀释至指定浓度,将稀释后的化合物按每孔10μl加入到孔板中,继续培养72-120h。再向每孔加入25μL的CellTiter-Glo试剂,利用多功能酶标仪(PerkinElmer)测量荧光信号。
实验结果如下表1所示:
表1
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注:抗癌细胞增殖抑制活性,小于1μM为强活性,以具体数值表示;1-10μM为中等活性;10-20μM为弱活性;大于20μM表示抗细胞增殖抑制活性微弱。
根据表1结果发现,本发明化合物实施例7、实施例8、实施例9、实施例16和实施例18对多种肿瘤细胞具有较好的抗增殖抑制活性。
测试例2
蛋白免疫印迹实验
实验目的:蛋白免疫印迹(Western Blot)技术可以用于检测、表征和半定量蛋白质。
实验方法:总蛋白样品收集:收集给药处理后的细胞,将细胞进行充分裂解后取上清进行SDS-PAGE电泳分离。再将SDS-PAGE胶上蛋白进行转膜,转膜完全后将膜放入5%脱脂牛奶中进行封闭。封闭结束后,按照蛋白分子量大小进行切膜。相应的一抗用封闭液稀释至适当浓度,并与PVDF膜在4℃下孵育过夜。一抗孵育结束后,用1×TBST洗膜3-6次,随后与相应的二抗稀释液在室温下孵育1-2h。孵育结束后,用1×TBST洗膜3-6次,每次10min。最后进行化学发光和显影。
实验结果如下图1-9所示:
如图1所示,本发明化合物实施例7、8、9下调细胞内BET家族中BRD2水平具有浓度依赖性;
如图2-3所示,本发明化合物实施例9下调细胞内BRD2蛋白水平具有浓度依赖性;其中,如图2所示,明显能够看出333nM的化合物9在处理22Rv1细胞9h就能显著诱导细胞内BRD2蛋白的降解;如图3所示,37nM的化合物9在处理MV4;11细胞6h就能显著诱导细胞内BRD2蛋白的降解。
如图4-5所示,本发明化合物实施例9下调细胞内BRD2蛋白水平具有时间依赖性;其中,如图4所示,300nM的化合物9处理22Rv1细胞明显能够看出处理12h后就能明显诱导细胞内BRD2蛋白的降解;如图5所示,300nM的化合物9处理MV4;11细胞,明显能够看出处理6h后,就能明显诱导细胞内BRD2蛋白的降解。
如图6-7所示,本发明化合物实施例9可诱导GSPT1蛋白的降解,其中,如图6所示,作用6h条件下,能够看出37nM开始明显诱导22Rv1细胞内GSPT1蛋白的降解;如图7所示,能够看出12nM就能明显的诱导MV4;11细胞GSPT1蛋白的降解。
如图8-9所示,本发明化合物下调GSPT1蛋白水平具有时间依赖性,其中,如图8所示,明显能够看出4h就可诱导22Rv1细胞内GSPT1蛋白的降解;如图9所示,4h内可明显诱导MV4;11细胞内GSPT1蛋白的降解效果。
申请人声明,本发明通过上述实施例来说明本发明所述苯并[d]异恶唑类化合物及其应用,但本发明并不局限于上述工艺步骤,即不意味着本发明必须依赖上述工艺步骤才能实施。所属技术领域的技术人员应该明了,对本发明的任何改进,对本发明所选用原料的等效替换及辅助成分的添加、具体方式的选择等,均落在本发明的保护范围和公开范围之内。
Claims (10)
1.一种苯并[d]异恶唑类化合物,其特征在于,所述苯并[d]异恶唑类化合物具有如下式Ⅰ所示结构:
其中,
X选自O或S;
R1选自H、羟基、取代或未取代的C1-C5烷基、取代或未取代的C1-C5烷氧基;
R2和R3各自独立地选自如下(i)或(ii)组中的任一基团:
(i)H、卤素、氨基、硝基、羧基、氰基、羟基、取代或未取代的C1-C5烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C10环烷基、取代或未取代的C3-C10杂环烷基、取代或未取代的C6-C20芳基、取代或未取代的C4-C20杂芳基;
(ii)-N(Ra)SO2Rb、-SO2N(Ra)Rb、-N(Ra)CORb、-CON(Ra)Rb-、-N(Ra)CH2Rb、-NHCH(Ra)Rb、-N(Ra)Rb、-CH(Ra)Rb、-CORb、-COORb、-OCORb、-SRb或-ORb;
Ra选自H、取代或未取代的C1-C6烷基、取代或未取代的C3-C10环烷基、取代或未取代的C3-C10环烯基、取代或未取代的C1-C10杂环烷基;
Rb选自如下(v)、(vi)、(vii)或(viii)组中的任一基团:
(v)取代或未取代的C6-C20芳基、取代或未取代的C4-C20杂芳基;
(vi)取代或未取代的C3-C10环烷基、取代或未取代的C3-C10环烯基、取代或未取代的C3-C10杂环烷基;
(vii)取代或未取代的C1-C5烷基、取代或未取代的C2-C10烯基、取代或未取代的C2-C10炔基;
Y1选自-NH(CH2)nCON(Rc)-、-O(CH2)nCON(Rc)-、-S(CH2)nCON(Rc)-、-(CH2)nCON(Rc)-或单键,n为1-8;
Rc选自H、取代或未取代的C3-C10环烷基、取代或未取代的C3-C10环烯基、取代或未取代的C3-C10杂环烷基、取代或未取代的C6-C20芳基、取代或未取代的C4-C20杂芳基、取代或未取代的C2-C10烯基;
Y2选自-O-、-NH-、-CH2-或单键;
L选自单键、亚烷基、亚烯基、亚炔基、醚基、硫醚基、酯基、胺基、酰胺基、氨基甲酸酯基、脲基、砜基、芳基、杂芳基、羰基、环烷基、杂芳基中的任意一种或至少两种的组合;
E具有式Ⅱ所示的结构,其中为基团连接位置;
其中,
Y3选自-O-、-S-、-CHRd-、-C(=O)-、-SO2-、-NRe-;
Rd和Re各自独立地选自H、取代或未取代的C1-C10烷基、取代或未取代的C3-C8环烷基、取代或未取代的C3-C8杂环基;
Y4、Y5、Y6、Y7各自独立地选自CH或N;
T1、T2、T3各自独立地选自Ο或S;
R4和R5各自独立选自-H、羟基、取代或未取代的C1-C10烷基、取代或未取代的C3-C10环烷基、取代或未取代的C1-C10含Ο杂环烷基、取代或未取代的C1-C10含Ν杂环烷基、取代或未取代的C1-C10含S杂环烷基。
2.根据权利要求1所述苯并[d]异恶唑类化合物,其特征在于,所述Y4、Y5、Y6、Y7独立地选自CH;
优选地,所述Y4、Y5、Y6、Y7中任一基团为CH,另外三个基团至少一个为N;
优选地,所述Y4、Y5、Y6、Y7中任一基团为CH,所述基团连接位置位于该CH上;
优选地,所述L选自以下组中的任意一种:
其中,m、n和o独立地选自1-8之间的正整数;Y8选自取代或未取代的C1-C10烷基、取代或未取代的C3-C10环烷基、取代或未取代的C1-C10含O杂环烷基、取代或未取代的C1-C10含N杂环烷基、取代或未取代的C1-C10含S杂环烷基;
优选地,所述Y3选自-CH-或-C(=O)-;
优选地,所述T1、T2、T3选自O。
3.根据权利要求1或2所述苯并[d]异恶唑类化合物,其特征在于,所述苯并[d]异恶唑类化合物具有如下式Ⅲ所示结构:
其中,R1、R2、R3、R4、R5、X、Y1、Y2、L、Y3、Y4、Y5、Y6、Y7、T1、T2、T3基团的定义与权利要求1或2相同;
优选地,所述苯并[d]异恶唑类化合物具有如下式Ⅳ所示结构:
其中,R1、R2、R3、R4、R5、X、Y1、Y2、L、Y3基团的定义与权利要求1或2相同;
优选地,所述苯并[d]异恶唑类化合物具有如下式Ⅴ或Ⅵ所示结构:
其中,R1、R2、R3、R4、R5、X、Y1、Y2、L基团的定义与权利要求1或2相同;
优选地,所述R1选自取代或未取代的C1-C5烷基,优选为未取代的C1-C5烷基,进一步优选为未取代的C1-C3烷基;
优选地,所述R2和R3中任一基团选自(ii)组中的任一基团,而另一基团选自(i)组中的任一基团,优选为所述R2和R3中任一基团选自-N(Ra)SO2Rb或-SO2N(Ra)Rb中的任一基团,而另一基团选自H;
优选地,所述Ra选自H、取代或未取代的C1-C6烷基,优选为H;
优选地,所述Rb选自(v)组中的任一基团,优选为取代或未取代的C6-C20芳基,进一步优选为取代的C6-C10芳基;
优选地,所述Rb选自取代的苯基,所述苯基的取代基为C1-C3烷氧基和/或卤素;
优选地,所述Y1选自-O(CH2)nCON(Rc)-或单键;
优选地,所述n为1-3,Rc选自H;
优选地,所述Y2选自-O-、-NH-、-CH2-或单键;
优选地,所述L选自以下组中的任意一种:
其中,m、n和o独立地选自1-6之间的正整数,Y8选自未取代的C1-C6烷基;
优选地,所述苯并[d]异恶唑类化合物具有如下式ⅤII示结构:
其中,
Y1选自-O(CH2)nCON(Rc)-或单键,n为1-3,Rc选自H;
L选自以下组中的任意一种:
其中,m、n和o独立地选自1-6之间的正整数,Y8选自未取代的C1-C6烷基;
Y2选自-O-、-NH-、-CH2-或单键;
Y3选自-CH-或-C(=O)-。
4.根据权利要求1-3中任一项所述苯并[d]异恶唑类化合物,其特征在于,所述芳基选自苯基或萘基;
优选地,所述杂芳基具有芳族的5-8元单环、8-12元双环或11-14元三环系统;所述单环具有1-4个杂原子,所述双环具有1-6个杂原子,所述三环具有1-9个杂原子;所述杂原子选自O、N或S;
优选地,所述杂芳基选自哒嗪基、吲哚基、喹唑啉基、吡咯基、噻吩基、吲唑基、吡唑基、喹啉基、吡啶基、呋喃基、咪唑基、吡嗪基、嘧啶基、噻唑基、异喹啉基、苯并噻唑基或二氮杂萘基中的任意一种;
优选地,所述烷基、烷氧基、环烷基、杂环烷基、芳基、杂芳基、烯基、环烯基、炔基具有取代基,所述取代基选自卤素、羟基、氨基、甲氧基、乙氧基、硝基、醚基、硫醚基、酯基、酰胺基、氨基甲酸酯基、脲基或砜基中的任意一种。
5.根据权利要求1-4中任一项所述苯并[d]异恶唑类化合物,其特征在于,所述苯并[d]异恶唑类化合物包括如下化合物1-19中的任意一种:
6.一种如权利要求1-5任一项所述苯并[d]异恶唑类化合物的药学上可接受的盐、立体异构体、N-氧化物、前药分子、溶剂化物、氘代化合物。
7.一种药物组合物,其特征在于,所述药物组合物包括活性成分和药学上可接受的辅料;
其中,所述活性成分包括至少一种如权利要求1-5任一项所述苯并[d]异恶唑类化合物和/或至少一种如权利要求6所述药学上可接受的盐、立体异构体、N-氧化物、前药分子、溶剂化物、氘代化合物。
8.一种如权利要求1-5任一项所述苯并[d]异恶唑类化合物、权利要求6所述药学上可接受的盐、立体异构体、N-氧化物、前药分子、溶剂化物、氘代化合物、权利要求7所述药物组合物在制备降解BET和/或GSPT1蛋白制剂中的应用。
9.一种如权利要求1-5任一项所述苯并[d]异恶唑类化合物、权利要求6所述药学上可接受的盐、立体异构体、N-氧化物、前药分子、溶剂化物、氘代化合物、权利要求7所述药物组合物在制备用于预防或治疗癌症、细胞增殖性紊乱、炎症、自身免疫性疾病、败血症或病毒感染的药物中的应用。
10.根据权利要求9所述应用,其特征在于,所述癌症选自急性单核细胞白血病、急性骨髓性白血病、慢性骨髓性白血病、慢性淋巴细胞性白血病混合谱系白血病、NUT-中线癌、多发性骨髓瘤、胶质瘤、肺癌、神经母细胞瘤、伯基特淋巴瘤、宫颈癌、食道癌、鼻咽癌、卵巢癌、胰腺癌、结直肠癌、前列腺癌或乳腺癌;
所述炎症、自身免疫性疾病选自炎症盆腔疾病、尿道炎、肺炎、脑膜炎、心肌炎、溃疡性结肠炎、器官移植排斥、哮喘、过敏性鼻炎、慢性阻塞性肺疾病、自身免疫性疾病、自身免疫性脱发、贫血、自身免疫性溶血性和系统性红斑狼疮、类风湿性关节炎、桥本甲状腺炎或过敏性皮肤炎;
所述病毒感染选自脊髓灰质炎病毒、甲型肝炎病毒、风疹病毒、乙型脑炎病毒、丙型肝炎病毒、人类乳头瘤病毒、狂犬病病毒、疱疹病毒、巴尔病毒、人类免疫缺陷病毒、新型冠状病毒或感染。
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