CN117285524A - 一类取代的4-氨基异吲哚啉类化合物、其制备方法、药物组合物及应用 - Google Patents
一类取代的4-氨基异吲哚啉类化合物、其制备方法、药物组合物及应用 Download PDFInfo
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- CN117285524A CN117285524A CN202310751982.7A CN202310751982A CN117285524A CN 117285524 A CN117285524 A CN 117285524A CN 202310751982 A CN202310751982 A CN 202310751982A CN 117285524 A CN117285524 A CN 117285524A
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Abstract
本发明涉及一种取代的4‑氨基异吲哚啉类化合物、其制备方法、药物组合物及应用,所述化合物具有式(Ⅰ)所示的结构。具体地,本发明提供的取代的4‑氨基异吲哚啉类化合物作为CRL4CRBNE3泛素连接酶调节剂具有很好的的抗肿瘤活性,可以用于制备治疗与CRL4CRBN E3泛素连接酶相关的疾病的药物。
Description
技术领域
本发明涉及药物化学领域,具体地,涉及一类取代的4-氨基异吲哚啉类化合物、其制备方法、药物组合物及应用。
背景技术
针对小分子抑制剂存在的耐药性问题和针对“不可成药性”靶点蛋白的开发有效的药物分子,近年来发展了一种调节蛋白质功能的策略——靶向蛋白降解技术。靶向蛋白降解技术是药物研发中快速发展的技术,该技术通过利用生物体内泛素-蛋白酶体(UPS)介导的蛋白降解途径,来对疾病相关的蛋白进行降解,从而达到治疗疾病的效果。靶向蛋白降解技术已经成为药物研发领域的研究热点,该技术在药物研发和生物医学领域具有广阔的应用前景。目前,基于泛素化蛋白酶体系统(UPS)的靶向蛋白降解技术主要包含蛋白质水解靶向嵌合体(Proteolysis Targeting Chimera,PROTAC)和分子胶(Molecular Glue)。尽管PROTAC领域正在蓬勃发展,也有存在诸多挑战:1)PROTAC的分子量大部分大于1000Da,这使得它的生物利用度和透膜性差,不符合Lipinski法则,生物利用度低,药代动力学性质差;2)PROTAC分子合成较复杂,合成成本高;3)PROTAC发挥作用是催化循环,因此传统方法无法准确评估PROTAC的PK和PD性质,针对PROTAC分子,目前尚无成熟的PK和PD评价体系。
分子胶是一种诱导蛋白质-蛋白质相互作用的小分子,可以对各种生物过程进行精确的时间控制。分子胶是作用于蛋白质界面并形成新的蛋白质-蛋白质相互作用的小分子。经过将靶蛋白带入调节蛋白的物理附近,分子胶减轻了对靶蛋白上活性连接口袋的需求,因此有可能极大地扩展可成药蛋白质组。分子胶的分子胶介导邻近诱导的蛋白质降解,相比PROTAC具有内在优势:1)分子胶相比PROTAC,分子量小,有利于优化理化性质,更符合“类药五项原则”;2)分子胶相比PROTAC,更容易提高生物利用度和改善药代动力学性质;3)分子胶合成相对更简单;4)从功能的角度来看,目标蛋白和PROTAC的机制通常是明确的,而分子胶的发现往往伴随着发现新的作用方式和新的药物靶点。
沙利度胺、来那度胺和泊马度胺等,统称为免疫调节药物(IMiDs)。最近研究表明这类免疫调节药物作为临床中的治疗策略是一种分子胶的机制,它们直接作用靶点是CRBN(Science,2010,327,1345;Science,2014,343,301;Science,2014,343,305;Nature,2015,523,183.)。免疫调节药物靶向CRL4CRBNE3泛素连接酶,与CEBN结合导致蛋白结合界面的构象发生微调,从而招募不同的底物蛋白,对底物蛋白进行泛素化,被泛素标记的底物蛋白随后被蛋白酶体降解。这些蛋白降解的下游影响介导来免疫调节药物的抗肿瘤增殖和免疫调节活性。这些研究结果表明:不同度胺类药物分子与靶点CRBN相互作用后,具有不同底物蛋白降解特异性,即化合物具有不同的药理活性和完全不同的治疗效果,进而在临床上可用于治疗不同的适应症。例如来那度胺通过降解IKZF1和IKZF3,应用于治疗多发性骨髓瘤;而治疗5q缺失型骨髓异常性增生综合征(MDS)通过降解CK1α来达到疗效。随着新的度胺类化合物开发,度胺类化合物的适应症不断扩大,目前有多类分子胶降解剂处于临床阶段。
来那度胺目前主要用于治疗多发性骨髓瘤和骨髓增生异常综合征,但针对其他适应症的疗效不是很理想;而其类似物如CC-122、CC-220、CC-92480、CC-90009等目前尚处于临床研究阶段。因此,开发一类结构新颖的CRL4CRBNE3泛素连接酶分子胶类降解剂,通过结构的改变和调整,增强配体相互作用和与连接酶的亲和力来提高底物降解率的策略,进一步提高肿瘤的治疗效果和拓宽分子胶类降解剂的适应症。从分子胶类降解剂的分子机制上研究,度胺类药物结构上改变,引起CRBN构象的改变,往往伴随着发现新的作用方式和新的药物靶点。因此,开发新的CRL4CRBNE3泛素连接酶分子胶类降解剂能够实现新的底物蛋白的招募降解,可以进一步探索用于治疗新的适应症。综上,开发新的CRL4CRBNE3泛素连接酶分子胶类降解剂,提高对肿瘤的治疗效果和拓宽新适应症,可以用于进一步解决未满足的医疗需求,具有重要的研究价值和现实意义。
发明内容
本发明目的是提供一种结构新颖的CRL4CRBNE3泛素连接酶分子胶类降解剂,其提高肿瘤的治疗效果和拓宽分子胶类降解剂的适应症。
本发明的第一方面,提供一种式(I)化合物、或其药学上可接受的盐、互变异构体、立体异构体、前药:
其中,n为0或1;
X、Y各自独立地选自:CH或N,且X、Y不同时为CH;
Z选自:O、S或NH;
选自:C6-C10芳基、C4-C10环烷基、4-10元杂环基、5-10元杂芳基,其中,所述C6-C10芳基、C4-C10环烷基、4-10元杂环基、5-10元杂芳基任选地被选自以下一个或多个基团所取代:氢、氘、卤素、氰基、硝基、羟基、羧基、氨基羰基、4-10元杂环基、C1-C6烷基、C1-C6烷氧基、卤素取代C1-C6的烷基、卤素取代C1-C6的烷氧基、取代或未取代的苯基、C2-C6烯基、C3-C8杂环基氧基、C3-C8环烷基氧基、羟基取代的C1-C6烷氧基、C1-C6烷氧基取代的C1-C6烷氧基、–C(O)-R1、-(CH2)m-R2;其中,所述取代或未取代的苯基任选地被选自以下一个或多个基团所取代:氢、卤素、氰基、硝基、羟基、羧基、4-10元杂环基、C1-C6烷基、C1-C6烷氧基、卤素取代C1-C6的烷基、卤素取代C1-C6的烷氧基;
R1选自:卤素取代或未取代的C1-C6烷基、C4-C12环烷基、C6-C10芳基、4-10元杂环基、-CH2-(C4-C12环烷基),并且所述C4-C12环烷基、C6-C10芳基、4-10元杂环基、-CH2-(C4-C12环烷基)任选地被选自以下一个或多个基团所取代:氢、氘、卤素、氰基、硝基、羟基、羧基、4-10元杂环基、C1-C6烷基、C1-C6烷氧基、卤素取代C1-C6的烷基、卤素取代C1-C6的烷氧基、卤素取代或未取代的苯基;
R2为C6-C10芳基,并且所述C6-C10芳基任选地被选自以下一个或多个基团所取代:氢、卤素、氰基、硝基、羟基、羧基、4-10元杂环基、C1-C6烷基、C1-C6烷氧基、卤素取代C1-C6的烷基、卤素取代C1-C6的烷氧基;
m为0或1;
R3为氢或卤素;
R4为氢、氘或氟。
在另一优选例中,n为0。
在另一优选例中,Z选自O或S。
在另一优选例中,X为N,Y为C,且Z为O;或者X为N,Y为C,Z为S。
在另一优选例中,选自:/>
在另一优选例中,为/>其中,A1选自:苯基、C4-C6环烷基、4-6元杂环基、5-6元杂芳基;
L为无、CO或CH2;
A2选自:无、C1-C6烷基、卤素取代C1-C6的烷基、苯基、C4-C6环烷基、4-6元杂环基、5-6元杂芳基;
Ra1和Ra2各自独立地选自:氢、氘、卤素、氰基、硝基、羟基、羧基、氨基羰基、4-10元杂环基、C1-C6烷基、C1-C6烷氧基、卤素取代C1-C6的烷基、卤素取代C1-C6的烷氧基、取代或未取代的苯基、C2-C6烯基、C3-C8杂环基氧基、C3-C8环烷基氧基、羟基取代的C1-C6烷氧基、C1-C6烷氧基取代的C1-C6烷氧基;其中,所述取代或未取代的苯基任选地被选自以下一个或多个基团所取代:氢、卤素、氰基、硝基、羟基、羧基、4-10元杂环基、C1-C6烷基、C1-C6烷氧基、卤素取代C1-C6的烷基、卤素取代C1-C6的烷氧基;
p和q各自独立地为0、1、2、3、4或5。
在另一优选例中,选自:苯基、5-6元杂芳基、含氮4或6元杂环基,并且所述苯基、5-6元杂芳基、含氮4元或6元杂环基任选地被选自以下一个或多个基团所取代:氢、氘、卤素、氰基、吗啉基、C1-C6烷基、C1-C6烷氧基、卤素取代C1-C6的烷基、卤素取代C1-C6的烷氧基、取代或未取代的苯基、C2-C6烯基、C3-C8杂环基氧基、C3-C8环烷基氧基、羟基取代的C1-C6烷氧基、C1-C6烷氧基取代的C1-C6烷氧基、–C(O)-R1、-(CH2)-R2,其中,所述取代或未取代的苯基任选地被选自以下一个或多个基团所取代:氢、卤素、氰基、硝基、羟基、羧基、4-10元杂环基、C1-C6烷基、C1-C6烷氧基、卤素取代C1-C6的烷基、卤素取代C1-C6的烷氧基;R1和R2的定义如上所述;优选地,R1选自:卤素取代或未取代的C1-C6烷基、C4-C12环烷基、苯基、-CH2-(C4-C12环烷基),并且所述C4-C12环烷基、苯基、-CH2-(C4-C12环烷基)任选地被选自以下一个或多个基团所取代:氢、氘、卤素、氰基、C1-C6烷基、C1-C6烷氧基、卤素取代的C1-C6烷基、卤素取代的C1-C6烷氧基、卤素取代或未取代的苯基;
R2为苯基,并且所述苯基任选地被选自以下一个或多个基团所取代:卤素、氰基、C1-C6烷基、C1-C6烷氧基、卤素取代C1-C6的烷基、卤素取代C1-C6的烷氧基。
在另一优选例中,所述化合物具有式II所示的结构
其中,n为0或1;
X、Y各自独立地选自:CH或N,且X、Y不同时为CH;
Z选自:O、S或NH;
R3为氢或卤素;
R4为氢、氘或氟;
A1选自:苯基、C4-C6环烷基、4-6元杂环基、5-6元杂芳基;
L为无、CO或CH2;
A2选自:无、C1-C6烷基、苯基、C4-C10环烷基、4-6元杂环基、5-6元杂芳基;
Ra1和Ra2各自独立地选自:氢、氘、卤素、氰基、硝基、羟基、羧基、氨基羰基、4-10元杂环基、C1-C6烷基、C1-C6烷氧基、卤素取代C1-C6的烷基、卤素取代C1-C6的烷氧基、取代或未取代的苯基、C2-C6烯基、C3-C8杂环基氧基、C3-C8环烷基氧基、羟基取代的C1-C6烷氧基、C1-C6烷氧基取代的C1-C6烷氧基;其中,所述取代或未取代的苯基任选地被选自以下一个或多个基团所取代:氢、卤素、氰基、硝基、羟基、羧基、4-10元杂环基、C1-C6烷基、C1-C6烷氧基、卤素取代C1-C6的烷基、卤素取代C1-C6的烷氧基;
p和q各自独立地为0、1、2、3、4或5。
在另一优选例中,A1选自:苯基、吡啶基、哌啶基、环己基、哌嗪基、吖丁啶基。
在另一优选例中,L和A2同时为无。
在另一优选例中,所述化合物具有式(I-1)-(I-4)所示的结构:
其中,选自:/>
R3为氢或卤素;
R4为氢、氘或氟;
R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21各自独立地选自:氢、氘、卤素、氰基、C1-C6烷基、C1-C6烷氧基、卤素取代C1-C6的烷基、卤素取代C1-C6的烷氧基、苯基、乙烯基、C3-C8杂环基氧基、C3-C8环烷基氧基、羟基取代的C1-C6烷氧基、C1-C6烷氧基取代的C1-C6烷氧基。
在另一优选例中,R5、R6、R7、R8和R9都为H或氘,或有一个不为氢或氘,或有两个不为H或氘。
在另一优选例中,所述化合物具有(I-5)或式(I-6)所示的结构:
其中,选自:/>
R1选自:叔丁基、环丁基、环己基、苯基、并且所述环丁基、环己基、苯基任选地被选自以下一个或多个基团所取代:卤素、氰基、C1-C3烷基、三氟甲基、三氟甲氧基、卤素取代或未取代的苯基;
R2为苯基,并且所述苯基任选地被选自以下一个或多个基团所取代:氟、氰基、三氟甲氧基。
R3为氢或卤素;
R4为氢、氘或氟。
在另一优选例中,式(I-5)中,R1选自:叔丁基、环丁基、环己基、苯基、并且所述环丁基、苯基任选地被选自以下一个或多个基团所取代:卤素、氰基、三氟甲基、三氟甲氧基、卤素取代或未取代的苯基。
在另一优选例中,所述前药具有式III所示的结构
其中,
Rp为CH2OCOC(CH3)3;
R3为氢或卤素;
R4为氢、氘或氟;
X、Y、Z、A、n的定义如上所述。
在另一优选例中,选自:/>
在另一优选例中,所述化合物为下列化合物:
本发明第二方面,提供一种制备权第一方面所述化合物的方法,其中,所述方法选自如下方法之一:
合成方法一:
X、Y各自选自CH或N,且X、Y不能同时为CH;
Z选自O、S或NH;
R3、R4、R5、R6、R7、R8、R9的定义如上所述;
步骤1-1:化合物1A与化合物1B在苯基硅烷和二氯二丁基锡存在下反应,得到化合物1C;或化合物1A与化合物1B在乙酸和硼氢化钠存在下反应,得到化合物1C;
合成方法2:
X为N,Y为CH;
Z为O;
R1、R3、R4的定义如上所述;
步骤2-1:化合物2A与1,2-二碘乙烷反应,得到化合物2B;
步骤2-2:化合物2B与化合物2C偶联反应,得到化合物2D;
步骤2-3:化合物2D氢化还原,得到化合物2F;
步骤2-4:化合物2F经硼氢化钠还原,得到化合物2G;
步骤2-5:化合物2G与氧化剂反应,得到化合物2H;
步骤2-6:化合物2H和1B在苯基硅烷和二氯二丁基锡存在下反应,得到化合物化合物2I;
步骤2-7:化合物2I在盐酸存在下,得到化合物2J;
步骤2-8:化合物2K和化合物2J在HATU和N,N-二异丙基乙胺反存在下反应,得到化合物2L;
合成方法3:
X为N,Y为CH;
Z为O;
R2、R3、R4的定义如上所述;
步骤3-1:化合物3A和化合物2J在氯化锌、三乙胺和氰基硼氢化钠的存在下反应,得到化合物3B;
合成方法4:
X为N,Y为CH;
Z为O;
的定义如上所述,优选地,/>为含氮4或6元杂环基;
步骤4-1:化合物4A与四氢铝锂反应,得到化合物4B;
步骤4-2:化合物4B与叔丁基二苯基氯硅烷反应,得到化合物4C;
步骤4-3:在硼烷四氢呋喃络合物、正丁基锂存在下,化合物4C与和4-甲酰吗啉反应,得到化合物4D;
步骤4-4:化合物4D经Dess-Martin氧化剂氧化,得到化合物4E;
步骤4-5:化合物4E与在醋酸硼氢化钠存在下,通过还原胺化反应,得到化合物4F;
步骤4-6:在四丁基氟化铵的四氢呋喃溶液存在下,化合物4F脱保护基,得到化合物4G;
步骤4-7:化合物4G经Dess-Martin氧化剂氧化,得到化合物4H;
步骤4-8:在乙酸和硼氢化钠存在下,化合物4H与化合物1B反应,得到化合物4I;
合成方法5:
X、Y各自选自CH或N,且X、Y不能同时为CH;
Z选自O、S或NH;
R3、R4、Ra2和q的定义如上所述;
步骤5-1:在钯催化剂存在下,化合物5A与化合物5B发生Buchwald-Hartwig胺化反应,得到化合物5C;
步骤5-2:在醋酸和硼氢化钠存在下,化合物5C与化合物1B发生还原胺化反应,得到化合物5D。
本发明第三方面,提供一种药物组合物,其中,所述的药物组合物包含治疗有效剂量的第一方面所述的化合物、其药学上可接受的盐、互变异构体、立体异构体、前药、其可药用的盐和药学上可接受的载体。
在另一优选例中,所述的药物组合物进一步包含另一种或多种具有医药学治疗活性的成分,在预防或治疗特定疾病或功能紊乱过程中产生协同作用;或者减轻或消除另外一种或多种具有医药学治疗活性成分在预防或治疗特定疾病或功能紊乱过程中所产生的毒副作用。
在另一优选例中,所述的药物组合物进一步包含选自地塞米松、利妥昔单抗、曲妥珠单抗、PD-1抑制剂、PDL-1抑制剂、培美曲塞、托泊替康、阿霉素、硼替佐米、吉西他滨、达卡巴嗪、克拉霉素、长春新碱、阿糖胞苷、泼尼松、多西他赛、氯法拉滨注射液、HDAC抑制剂、激酶靶向抑制剂、雄激素受体抑制剂、雄激素生物合成抑制剂、红血球生长激素、米诺四环素、Elotuzumab、Palbociclib、Nivolumab、Pembrolizumab、Panobinostat、Ublituximab、Romidepsin、Eltrombopag、CAR-T和美法仑中的一种或多种。
本发明第四方面,提供一种如第一方面所述的化合物、其药学上可接受的盐、互变异构体、立体异构体、前药、或其可药用的盐在制备用于预防或治疗与CRL4CRBN E3泛素连接酶相关的疾病的药物中的用途,优选地,所述与CRL4CRBN E3泛素连接酶相关的疾病为癌症、疼痛、中枢神经系统疾病或免疫系统疾病。
在另一优选例中,所述的疾病为实体瘤、血液瘤,优选地,所述的疾病选自:骨髓增生异常综合征、多发性骨髓瘤、套细胞淋巴瘤、非霍奇金淋巴瘤、慢性淋巴细胞白血病、慢性粒单核细胞白血病、骨髓纤维化、伯基特淋巴瘤、霍奇金淋巴瘤、弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、睫状体和慢性黑色素瘤、虹膜黑色素瘤、复发性两眼间黑色素瘤、T细胞淋巴瘤、红系淋巴瘤、成单核细胞和单核细胞白血病、髓性白血病、中枢神经系统淋巴瘤、脑膜瘤、脊髓肿瘤、非小细胞肺癌、卵巢癌、皮肤癌、肾细胞癌、星状细胞瘤、淀粉样变性、I型复杂性局部疼痛综合征、恶性黑色素瘤、神经根病、成胶质细胞瘤、胶质肉瘤、恶性胶质瘤、难治性浆细胞瘤、眼外延伸黑色素瘤、乳头状和滤泡状甲状腺癌、乳腺癌、前列腺癌、肝细胞癌或原发性巨球蛋白血症。
本发明第五方面,提供了一种预防或治疗与CRL4CRBN E3泛素连接酶相关的疾病的方法,包括步骤:给予有需要的受试者如本发明第一方面所述的化合物、其药学上可接受的盐、互变异构体、立体异构体、或其前药,或本发明第三方面所述的药物组合物,从而预防或治疗所述疾病。
在另一优选例中,所述受试者为人或非人哺乳动物,如大鼠、小鼠。
在另一优选例中,所述的疾病为实体瘤、血液瘤等。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
附图说明
图1示出了本发明化合物可形成分子内氢键并通过亚烷基与五元杂芳环形成特别的二面角的结构图和立体构象图。
具体实施方式
本发明人经过广泛而深入的研究,意外地开发了一种结构新颖的CRL4CRBNE3泛素连接酶分子胶类降解剂,其由于分子内氢键的形成,在多发性骨髓瘤MM.1S细胞、套细胞淋巴瘤Mino细胞、急性髓性白血病细胞系(MV-4-11)的细胞等细胞上的活性上优于上市药物、已经临床在研药物,以及现有技术中结构上具有可比较性的度胺类、没有形成分子内氢键或特定二面角的化合物。在此基础上,发明人完成了本发明。
术语
当通过从左向右书写的常规化学式描述取代基时,该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言,-CH2O-等同于-OCH2-。
本领域技术人员应理解,本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。本发明中相关结构上的取代,包括取代和未取代,如“可选地”或“任选地”被某种取代基取代,是指包括被某种取代基取代或者未取代的含义。
本发明中提到的当取代基数>1时,R取代基可以为相同或不同的取代基,指当某一种结构中取代基数为多个时,R的取代基组合可以为选自多种不同类型的取代基。
术语“取代”只适用于能够被取代基所取代的位点,不包括在现有的化学知识上不能实现的取代。术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中有相应描述的取代基,或各实施例中所出现的取代基。除非特别说明,某个任意取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基,所述的取代基在各个位置上可以是相同或不同的。环状取代基,例如杂环烷基,可以与另一个环相连,例如环烷基,从而形成螺二环系,例如,两个环共用一个碳原子。
术语“卤素”是指氟、氯、溴或碘。
术语“C1-C6烷基”是指链上具有1至6个碳原子的直链或支链饱和烃基,非限制性地包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基等。
术语“C1-C6烷氧基”是指具有1至6个碳原子的直链或支链烷氧基,非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。
术语“芳基”是指具有共轭的p电子体系的6-14元全碳单环或稠合多环基团,优选为6至10元环(即C6-C10芳基),更优选苯基和萘基,最优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为芳基环。
术语“卤素取代的C1-C6烷氧基”是指由单个或者多个卤素取代的直链或支链C1-C6烷氧基,非限制性地包括-OCH2F、-OCHF2、-OCF3。
术语“卤素取代的C1-C6烷基”是指由单个或者多个卤素取代的直链、支链C1-C6烷基,非限制性地包括2-溴乙基、2-溴丙基等。
术语“环烷基”是指饱和或部分不饱和单环或者多环环状烃取代基。环烷基包括C4-C12环烷基,优选地为C4-C10环烷基,C4-C6环烷基或C10-C12环烷基。单环环烷基非限制性包括环丙基、环丁基、环戊烯基、环己基,多环环烷基包括螺环、稠环和桥环的环烷基,如
术语“4-10元杂环基”是指含有一个或多个饱和和/或部分饱和环,其包括4至10个环原子,其中一个或多个(如2、3)环原子选自氮、氧、硫或S(O)m(其中m是0至2的整数)的杂原子,其余环原子为碳,4-10元杂环基优选地为4-6元杂环基,例如,环氧丙烷、四氢呋喃基、吡咯烷基、四氢吡喃基、哌啶基、哌嗪基、吗啉基、硫代吗啉基。术语“C3-C8杂环基”指含有3-8个环碳原子的饱和和/或部分饱和环,其中,还包括一个或多个(如2、3)选自氮、氧、硫或S(O)m(其中m是0至2的整数)的杂原子,C3-C8杂环基包括含有3-5个环碳原子的杂环基,其还包括一个或多个(如2、3)选自氮、氧、硫的杂原子,例如,氧杂环丁基、四氢呋喃基、吡咯烷基、四氢吡喃基、哌啶基、哌嗪基、吗啉基、硫代吗啉基。
术语“C2-C6烯基”意指仅由碳原子和氢原子组成、含有至少一个双键、具有2至6个碳原子且通过1个或多个单键与分子的其余部分连接的直链或支链的烃链基团,例如但不限于乙烯基、丙烯基、丁烯基、苯乙烯基、苯丙烯基。
术语“杂芳基”是指具有1至4个杂原子作为环原子,其余的环原子为碳的5-14元芳基,其中杂原子包括氧、硫和氮,优选为5-10元,更优选为5元或6元,如噻吩基、呋喃基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。
“水合物”是指含有水的化合物。
“药学上可接受的盐”是指药物分子与对应的有机酸、无机酸或者有机碱、无机碱形成相应的盐的,例如盐酸、甲酸、三氟乙酸、琥珀酸、甲磺酸盐等。
在本发明中,除非特别指出,所用术语具有本领域技术人员公知的一般含义。
活性成分
如本文所用,“本发明化合物”或“活性成分”指式I所示的化合物,并且还包含其药学上可接受的盐、互变异构体、立体异构体、前药。
式(I)所示的化合物还可以以不同互变异构体形式存在,所有这些形式均包括在本发明范围内。
术语“互变异构体”是指经由低能垒相互转化的具有不同能量的构造异构体,反应一般导致伴随单键和相邻双键转变的氢原子或质子的形式移动。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想的所有这类化合物,包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对应异构体及外消旋体和其他混合物,所有这些混合物都属于本发明专利的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有的这些异构体以及它们的混合物,均包括在本发明的范围内。
式(I)所示的化合物可以含有一个或多个不对称或手性中心,因此可以以不同立体异构体形式存在。本发明化合物包括所有立体异构体形式,包括但不限于非对映异构体、对映异构体和阻转异构体以及它们的混合物(如外消旋体),均包括在本发明的范围内。
除非另有说明,术语“对映异构体”是指互为镜像关系的立体异构体。
除非另有说明,术语“非对映异构体”是指分子具有两个或多个手性中心,并且分子间为非镜像的关系的立体异构体。
“消旋体”是指两个互为镜像的立体异构体,旋光性相反,互相抵消了旋光性。
本发明中的通式及实施例化合物中存在手性中心,因此,本发明化合物的单一构型或消旋体也是在本申请的范围内的。此外,现有技术中已经有相应证据表明,具有度胺类结构的化合物,其R构型、S构型、消旋体在体外细胞实验中的细胞上进入体内均会转化为1:1的消旋体,因此,本领域技术人员可以预期本发明化合物的对映体或消旋体所对应的技术方案均能实现相当的技术效果。本发明中如需获得单一构型的实施例化合物,可以通过单一构型的中间体1B,通过化合物制备方法中的合成方法1获得单一构型的实施例化合物,因此,可获得对映异构体。另外通过单一构型的中间体1B制备可以获得非对映异构体的实施例化合物,因此本发明中也可以获得非对映异构体,如化合物48和化合物54可形成非对映异构体。这些不同的异构体形式,都属于立体异构体。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如,可以放射性同位素标记化合物,比如氘(D)、氚(T)、12C、13C和14C等。又例如,可以重氢取代氢形成氘代药物,氘与碳构成的键比普通氢与碳构成的键更坚固,相比于未氘代药物,氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物所有的同位素组成的变换,无论放射性与否,都包括在本发明的范围之内。
如本文所用并且除非另有规定,术语“前药”是指包含生物反应官能团的化合物的衍生物,使得在生物条件下(体外或体内),生物反应官能团可从化合物上裂解或以其他方式发生反应以提供所述化合物。通常,前药无活性,或者至少比化合物本身活性低,使得直到将所述化合物从生物反应官能团上裂解后才能发挥其活性。生物反应官能团可在生物条件下水解或氧化以提供所述化合物。例如,前药可包含可生物水解的基团。可生物水解的基团实例包括但不限于可生物水解的磷酸盐、可生物水解的酯、可生物水解的酰胺、可生物水解的碳酸酯、可生物水解的氨基甲酸酯和可生物水解的酰脲。有关前药的综述参见,例如J.Rautioetal.,Nature Reviews Drug Discovery 2008,7,255-270and Prodrugs:Challenges和Rewards(V.Stellaetal.ed.,Springer,2007)。
本发明化合物中含有碱性基团时可以制备成药学上可接受的盐,包括无机酸盐和有机酸盐。适合形成盐的酸非限制性包括:盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸,甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸,苯磺酸等有机酸;以及天冬氨酸、谷氨酸等酸性氨基酸等。
本发明也包含这里公布的任何一种新的中间体。
药物组合物和施用方法
在本申请中,“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药,利于活性成分的吸收进而发挥生物活性。
式(I)所述化合物可以与已知的治疗或改进相似病状的其他药物联用。联合给药时,原来药物的给药方式和剂量可以保持不变,而同时或随后服用式I的化合物。当式I化合物与其它一种或几种药物同时服用时,可以优选使用同时含有一种或几种已知药物和式I化合物的药用组合物。药物联用也包括在重叠的时间段服用式I化合物与其它一种或几种已知药物。当式I化合物与其它一种或几种药物进行药物联用时,式I化合物或已知药物的剂量可能比它们单独用药的剂量低。
本文所用术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂),并且相对无毒,即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
在本申请中,“药学上可接受的载体”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
可以与通式(I)所述化合物进行药物联用的药物或活性成分包括但不局限为地塞米松、利妥昔单抗、曲妥珠单抗、PD-1抑制剂、PDL-1抑制剂、培美曲塞、托泊替康、阿霉素、硼替佐米、吉西他滨、达卡巴嗪、克拉霉素、长春新碱、阿糖胞苷、泼尼松、多西他赛、氯法拉滨注射液、HDAC抑制剂、激酶靶向抑制剂、雄激素受体抑制剂、雄激素生物合成抑制剂、红血球生长激素、米诺四环素、Elotuzumab、Palbociclib、Nivolumab、Pembrolizumab、Panobinostat、Ublituximab、Romidepsin、Eltrombopag、CAR-T和美法仑中的一种或多种。
典型的配方是通过混合本发明的通式(I)表示的化合物及载体、稀释剂或赋形剂制备而成。适宜的载体、稀释剂或赋形剂是本领域技术人员所熟知的,包括诸如碳水化合物、蜡、水溶性及/或可膨胀性聚合物、亲水性或疏水性物质、明胶、油、溶剂、水等物质。所用的特定载体、稀释剂或赋形剂,将根据本发明的化合物的使用方式和目的而定。一般以本领域技术人员认为可安全有效地给药至哺乳类动物的溶剂为基础而选择溶剂。一般而言,安全的溶剂是无毒性含水溶剂诸如制药用水,以及其他可溶于水或与水混溶的无毒性溶剂。适宜的含水溶剂包括水、乙醇、丙二醇、聚乙二醇(如PEG400、PEG300)等中的一种或多种。该配方也可包括一种或多种缓冲剂、安定剂、表面活性剂、润湿剂、润滑剂、乳化剂、悬浮剂、防腐剂、抗氧化剂、遮光剂、助流剂、加工助剂、着色剂、增甜剂、香料剂、调味剂或其它已知的添加剂,使式(I)表示的化合物以可被接受的形式制造或使用。
本发明如式(I)的化合物与至少一种其它药物组合使用时,两种药物或多种药物可以分开使用也可以组合使用,优选以药学组合物的形式给药。本发明的如式(I)的化合物或药物组合物能以任一已知的口服、静脉注射、直肠给药、阴道给药、透皮吸收、其它局部或全身给药形式,分开或一起给药至受试者。
这些药物组合物亦可含有一种或多种缓冲剂、安定剂、表面活性剂、润湿剂、润滑剂、乳化剂、悬浮剂、防腐剂、抗氧化剂、遮光剂、助流剂、加工助剂、着色剂、增甜剂、香料剂、调味剂或其它已知的添加剂,使该药物组合物以可被接受的形式制造或使用。
本发明药物优选口服给药途径。用于口服给药的固态剂型可包括胶囊、片剂、粉末或颗粒制剂。在固态剂型中,本发明的化合物或药物组合物与至少一种惰性赋形剂、稀释剂或载剂混合。适宜的赋形剂、稀释剂或载剂包括诸如柠檬酸钠或磷酸二钙的物质,或淀粉、乳糖、蔗糖、甘露糖醇、硅酸等;粘合剂如羧甲基纤维素、褐藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖、阿拉伯胶等;湿润剂如甘油等;崩解剂如琼脂、碳酸钙、马铃薯或木薯淀粉、褐藻酸、特定的络合硅酸盐、碳酸钠等;溶液阻滞剂如石蜡等;吸收促进剂如季铵化合物等;吸附剂如高岭土、膨润土等;润滑剂如滑石、硬脂酸钙、硬脂酸镁、固态聚乙二醇、月桂基硫酸钠等。在胶囊与片剂的情况下,该剂型亦可包括缓冲剂。类似类型的固态组合物亦可作为软式与硬式填充明胶胶囊中的填料,其使用乳糖以及高分子量聚乙二醇等作为赋形剂。
用于口服给药的液态剂型包括药学上可接受的乳化液、溶液、悬浮液、糖浆液与酏剂。除了本发明的化合物或其组合物之外,该液态剂型可含有本领域中常用的惰性稀释剂,诸如水或其他溶剂;增溶剂及乳化剂诸如乙醇、异丙基醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄基酯、丙二醇、1,3-丁二醇、二甲基甲酰胺;油类(如棉籽油、落花生油、玉米胚芽油、橄榄油、蓖麻油、芝麻油等);甘油;四氢糠基醇;聚乙二醇与脱水山梨糖醇的脂肪酸酯;或这些物质中的几种的混合物等。
除了这些惰性稀释剂之外,该组合物也可包括赋形剂,诸如润湿剂、乳化剂、悬浮剂、增甜剂、调味剂与香料剂中的一种或多种。
就悬浮液而言,除了本发明的化合物或组合之外,可进一步含有载剂诸如悬浮剂,如乙氧基化异硬脂醇、聚氧乙烯山梨醣醇、脱水山梨醣醇酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂及黄耆胶,或这些物质中几种的混合物等。
用于直肠或阴道投药之组合物优选栓剂,可通过将本发明的化合物或组合与适宜的非刺激性赋形剂或载剂混合而制备,赋形剂或载剂诸如可可豆脂、聚乙二醇或栓剂蜡,其在一般室温为固态而在体温为液态,可在直肠或阴道中熔化而释出活性化合物。
本发明化合物或药物组合物可采用其它局部给药剂型给药,包括膏、粉末、喷剂及吸入剂。该药物可在无菌条件下与药学上可接受的赋形剂、稀释剂或载剂以及所需要的任一防腐剂、缓冲剂或推进剂混合。眼用配方、眼用油膏、粉末与溶液,亦意欲涵盖于本发明的范围内。
本发明所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术,例如在Goodman and Gilman,The Pharmacological Basis of Therapeutics,current ed.;Pergamon;and Remington’s,Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa中讨论的那些。在优选的实施方案中,本文讨论的化合物和组合物通过口服施用。
本发明所使用术语“药物组合”、“药物联用”、“联合用药”、“施用其它治疗”、“施用其它治疗剂”等是指通过混合或组合不止一种活性成分而获得的药物治疗,其包括活性成分的固定和不固定组合。术语“固定组合”是指以单个实体或单个剂型的形式向患者同时施用至少一种本文所述的化合物和至少一种协同药剂。术语“不固定组合”是指以单独实体的形式向患者同时施用、合用或以可变的间隔时间顺次施用至少一种本文所述的化合物和至少一种协同制剂。这些也应用到鸡尾酒疗法中,例如施用三种或更多种活性成分。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg本发明化合物/剂,更佳地,含有10-1000mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
本发明的化合物或药物组合物可用于制备治疗或预防CRL4CRBNE3泛素连接酶参与的疾病的药物。本发明阐述的由CRL4CRBNE3泛素连接酶参与的相关疾病非限制性包括肿瘤、中枢系统疾病和免疫性疾病。
在一优选例中,所述的疾病包括但不限于:癌症、疼痛(包括但不限于复杂性局部疼痛综合症)、皮肤疾病、免疫缺陷型疾病、中枢神经系统的损伤及功能紊乱。
在另一优选例中,所述的癌症包括(但不限于):皮肤癌症(如黑色素瘤)、淋巴系统癌症、乳腺癌、宫颈癌、子宫癌、消化道癌症、肺癌、卵巢癌、前列腺癌、结肠癌、直肠癌、口腔癌、脑瘤、头颈部癌、咽喉癌、睾丸癌、肾癌、胰腺癌、脾癌、肝癌、膀胱癌,喉癌以及与艾滋病相关的癌症。本发明所提供的化合物同样对血液瘤和骨髓瘤有效,如能用于治疗多发性骨髓瘤、淋巴瘤和急慢性白血病。本发明所提供的化合物也可用于预防或治疗原发肿瘤和转移性肿瘤。
本发明的药物分子的用途,包括但不限于所述的疾病选自:骨髓增生异常综合征、多发性骨髓瘤、套细胞淋巴瘤、非霍奇金淋巴瘤、慢性淋巴细胞白血病、慢性粒单核细胞白血病、骨髓纤维化、伯基特淋巴瘤、霍奇金淋巴瘤、弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、睫状体和慢性黑色素瘤、虹膜黑色素瘤、复发性两眼间黑色素瘤、T细胞淋巴瘤、红系淋巴瘤、成单核细胞和单核细胞白血病、髓性白血病、中枢神经系统淋巴瘤、脑膜瘤、脊髓肿瘤、非小细胞肺癌、卵巢癌、皮肤癌、肾细胞癌、星状细胞瘤、淀粉样变性、I型复杂性局部疼痛综合征、恶性黑色素瘤、神经根病、成胶质细胞瘤、胶质肉瘤、恶性胶质瘤、难治性浆细胞瘤、眼外延伸黑色素瘤、乳头状和滤泡状甲状腺癌、乳腺癌、前列腺癌、肝细胞癌或原发性巨球蛋白血症。
化合物的制备方法
以下方案中描述了制备式I所示化合物的方法。在某些情况下,可以改变执行反应方案的步骤的顺序,以促进反应或避免不需要的副反应产物。本发明的化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得,这样的组合可由本发明所属领域的技术人员容易的进行。
通常,在制备流程中,各反应通常在惰性溶剂中,在室温至回流温度(如0℃-150℃,优选10℃-100℃)下进行。反应时间通常为0.1小时-60小时,较佳地为0.5-48小时。
优选地,所述方法选自如下方法之一:
起始化合物,1A、2B、2D、2F的合成参考文献CN111285850A、WO2017193063 A1;
合成方法一:
X、Y各自选自CH或N,且X、Y不能同时为CH;
Z选自O、S或NH;
R3、R4、R5、R6、R7、R8、R9的定义如上所述;
步骤1-1:化合物1A与化合物1B在苯基硅烷和二氯二丁基锡存在下反应,得到化合物1C;或化合物1A与化合物1B在乙酸和硼氢化钠存在下反应,得到化合物1C;
合成方法2:
X为N,Y为CH;
Z为O;
R1、R3、R4的定义如上所述;
步骤2-1:化合物2A与1,2-二碘乙烷反应,得到化合物2B;
步骤2-2:化合物2B与化合物2C偶联反应,得到化合物2D;
步骤2-3:化合物2D氢化还原,得到化合物2F;
步骤2-4:化合物2F经硼氢化钠还原,得到化合物2G;
步骤2-5:化合物2G与氧化剂反应,得到化合物2H;
步骤2-6:化合物2H和1B在苯基硅烷和二氯二丁基锡存在下反应,得到化合物化合物2I;
步骤2-7:化合物2I在盐酸存在下,得到化合物2J;
步骤2-8:化合物2K和化合物2J在HATU和N,N-二异丙基乙胺反存在下反应,得到化合物2L;
合成方法3:
X为N,Y为CH;
Z为O;
R2、R3、R4的定义如上所述;
步骤3-1:化合物3A和化合物2J在氯化锌、三乙胺和氰基硼氢化钠的存在下反应,得到化合物3B;
合成方法4:
X为N,Y为CH;
Z为O;
的定义如上所述,优选地,/>为含氮4或6元杂环基;
步骤4-1:化合物4A与四氢铝锂反应,得到化合物4B;
步骤4-2:化合物4B与叔丁基二苯基氯硅烷反应,得到化合物4C;
步骤4-3:在硼烷四氢呋喃络合物、正丁基锂存在下,化合物4C与和4-甲酰吗啉反应,得到化合物4D;
步骤4-4:化合物4D经Dess-Martin氧化剂氧化,得到化合物4E;
步骤4-5:化合物4E与在醋酸硼氢化钠存在下,通过还原胺化反应,得到化合物4F;
步骤4-6:在四丁基氟化铵的四氢呋喃溶液存在下,化合物4F脱保护基,得到化合物4G;
步骤4-7:化合物4G经Dess-Martin氧化剂氧化,得到化合物4H;
步骤4-8:在乙酸和硼氢化钠存在下,化合物4H与化合物1B反应,得到化合物4I;
合成方法5:
X、Y各自选自CH或N,且X、Y不能同时为CH;
Z选自O、S或NH;
R3、R4、Ra2和q的定义如上所述;
步骤5-1:在钯催化剂存在下,化合物5A与化合物5B发生Buchwald-Hartwig胺化反应,得到化合物5C;
步骤5-2:在醋酸和硼氢化钠存在下,化合物5C与化合物1B发生还原胺化反应,得到化合物5D。
本发明主要优点:
1.本发明中的化合物具有优异的细胞活性,尤其是在多发性骨髓瘤MM.1S细胞、套细胞淋巴瘤Mino细胞、急性髓性白血病细胞系(MV-4-11)的细胞等细胞上的活性,优于上市药物、以及临床在研药物,以及现有技术公开的结构上可比较、而不存在分子内氢键或特定二面角的化合物。
2.本发明化合物具有更好的药代动力学和药效,通过小鼠的药代动力学实验和药效学实验发现,本发明中已有测试结果的化合物,优于现有技术公开的结构上可比较、而不存在分子内氢键的化合物。这些实施例用于说明本发明中的形成分子内氢键或特定二面角的优点,并不限于本发明中其他化合物也有相同的优点。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
所有实施例中,1H NMR谱测试仪器为400MHz Bruker和500MHz Bruker核磁共振仪,化学位移以δ(ppm)表示;质谱由MS质谱UPLC-MS(ESI)测定;其中UPLC型号是WatersHPLC H-CLASS,MS(ESI)的型号是Waters SQ Detector 2;无水四氢呋喃由二苯甲酮/金属钠回流干燥除氧制得,无水甲苯和无水二氯甲烷由氯化钙回流干燥制得;石油醚、乙酸乙酯、二氯甲烷等用于柱层析流动相的溶剂均购置于国药集团化学试剂有限公司;反应检测中使用的薄层层析硅胶板(HSGF254)来自国药集团化学试剂有限公司;化合物分离选用国药集团化学试剂有限公司的200-300目硅胶。本发明中原料可以从商业途径获得,如主要试剂购买于国药集团化学试剂有限公司,或者通过本领域抑制的方法制备,或者根据本发明中所述方法制备。
实施例
关键中间体的合成:
中间体1:2-(1-(叔丁氧基羰基)-1,2,3,6-四氢吡啶-4-基)恶唑-5-羧酸乙酯
将化合物2-碘恶唑-5-羧酸乙酯(500mg,1.87mmol)、N-Boc-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯(636mg,2.06mmol)和四三苯基膦钯(216mg,0.187mml)溶于16mL二氧六环中,加入4mL Na2CO3(396mg,3.74mmol)的水溶液,反应体系用氮气抽换气3次后,在氮气保护的条件下,加热至90℃反应4小时,反应完全后,冷却至室温,反应体系用乙酸乙酯稀释,依次用水和饱和氯化钠溶液洗涤,分液,有机相用无水硫酸钠干燥,过滤,滤液减压浓酸,经硅胶柱层析得到棕色油状物424mg,产率70%;1H NMR(400MHz,CDCl3)δ7.73(s,1H),6.91(s,1H),4.43–4.33(m,2H),4.15(s,2H),3.61(t,J=4.8Hz,2H),2.64(s,2H),1.48(s,9H),1.38(t,J=6.7Hz,3H).
中间体2:2-(1-(叔丁氧基羰基)哌啶-4-基)恶唑-5-羧酸乙酯
将420mg 2-(1-(叔丁氧基羰基)-1,2,3,6-四氢吡啶-4-基)恶唑-5-羧酸乙酯溶于5mL四氢呋喃中,加入催化量的雷尼镍,用氮气抽换气后,用氢气抽换气3次,反应体系在室温常压氢化反应过夜,反应完全后,经硅藻土过滤,滤渣用30mL四氢呋喃洗涤,滤液减压浓缩得到产物,直接投下一步。
中间体3:4-(5-(羟甲基)恶唑-2-基)哌啶-1-羧酸叔丁酯
将化合物2-(1-(叔丁氧基羰基)哌啶-4-基)恶唑-5-羧酸乙酯(437mg,1.67mmol),溶于10mL无水乙醇中,加入硼氢化钠(256mg,6.68mmol),室温反应4小时后,加水淬灭反应,用乙酸乙酯萃取,分液,有机相用无水硫酸钠干燥,过滤,滤液减压浓酸,经硅胶柱层析得到无色油状物300mg,产率64%。1H NMR(500MHz,CDCl3)δ6.90(s,1H),4.64(s,2H),4.12(dd,J=14.3,7.1Hz,2H),2.98-2.85(m,3H),2.04-1.95(m,2H),1.81–1.72(m,2H),1.46(s,9H).
中间体4:4-(5-甲酰基恶唑-2-基)哌啶-1-羧酸叔丁酯
将化合物4-(5-(羟甲基)恶唑-2-基)哌啶-1-羧酸叔丁酯(300mg,1.06mmol)溶于8mL干燥的二氯甲烷溶液,冰浴条件下,加入戴斯-马丁氧化剂(541mg,1.28mmol),加完后,升至室温反应3小时,反应完全后加入硫代硫酸钠溶液淬灭反应,过滤,滤液用二氯甲烷萃取,分液,有机层依次用硫代硫酸钠和饱和碳酸氢钠溶液洗涤,干燥,减压浓缩,经硅胶柱层析得到290mg白色固体,收率98%。1H NMR(400MHz,CDCl3)δ9.74(s,1H),7.78(s,1H),4.11(s,2H),3.00(dt,J=23.4,11.2Hz,3H),2.08(d,J=12.9Hz,2H),1.83(dd,J=22.3,10.3Hz,2H),1.47(s,9H).
中间体5:4-(5-(((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)氨基)甲基)恶唑-2-基)哌啶-1-羧酸叔丁酯
将4-(5-甲酰基恶唑-2-基)哌啶-1-羧酸叔丁酯(300mg,1.07mmol)和消旋的泊马度胺(292mg,1.07mmol),苯基硅烷(132μL,1.07mmol),二氯二丁基锡(232μL,1.07mmol)溶于8mL干燥的四氢呋喃,反应体系升温至80℃反应过夜,反应完全后,减压浓缩,经硅胶柱层析得到黄色固体262mg,产率46%。1H NMR(400MHz,DMSO)δ11.10(s,1H),7.59(t,J=7.6Hz,1H),7.21(d,J=8.4Hz,1H),7.08(d,J=6.9Hz,1H),7.02(d,J=5.8Hz,1H),6.97(s,1H),5.06(dd,J=12.5,4.8Hz,1H),4.60(d,J=5.7Hz,2H),3.85(d,J=12.6Hz,2H),2.93(dt,J=24.9,11.5Hz,4H),2.64-2.53(m,1H),2.08–1.98(m,1H),1.91(d,J=12.6Hz,2H),1.49(dd,J=23.5,11.9Hz,2H),1.39(s,9H).
中间体6:2-(2,6-二氧哌啶-3-基)-4-((2-(哌啶-4-基)恶唑-5-基)甲基)氨基)异吲哚-1,3-二酮盐酸盐
将化合物4-(5-(((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)氨基)甲基)恶唑-2-基)哌啶-1-羧酸叔丁酯(178mg)溶于6mL盐酸二氧六环,室温反应5小时,监测反应完全后,减压浓缩得产物。
中间体7:N-(丙-2-烯-1-基)-4-(三氟甲氧基)苯甲酰胺
将对三氟甲氧基苯甲酸(2g,9.7mmol)、炔丙胺(445mg,8.1mmol)、HATU(3.7g,9.7mmol)溶于30mL DMF中,室温搅拌加入N,N-二异丙基乙胺(8mL,48.6mmol)反应约0.5小时后,TLC监测反应完全后,加水淬灭反应,用乙酸乙酯萃取,有机相用饱和氯化钠溶液水洗数次,干燥浓缩,柱层析得产物1.6g,产率68%。
中间体8:2-(4-(三氟甲氧基)苯基)恶唑-5-甲醛
将N-(丙-2-烯-1-基)-4-(三氟甲氧基)苯甲酰胺(671mg,2.76mmol)、碘(140mg,0.55mol)加入到100mL圆底烧瓶中,用氧气抽换气三次,将反应置于420nm LED光照10小时,TLC监测反应完全后,减压浓缩柱层析,得到黄色固体488mg,产率69%。1H NMR(500MHz,DMSO)δ9.80(s,1H),8.32(s,1H),8.20(d,J=8.9Hz,2H),7.57(d,J=8.1Hz,2H).
中间体9:2-([1,1'-联苯]-3-基)恶唑-5-甲醛
以N-(1-基-2-丙二醇)-[1,1'-联苯]-3-甲酰胺(300mg,1.28mmol)为原料合成方法同中间体8,得到黄色固体93mg,产率31%。1H NMR(400MHz,CDCl3)δ9.84(s,1H),8.42(s,1H),8.17(d,J=7.7Hz,1H),7.98(s,1H),7.79(d,J=7.7Hz,1H),7.67(s,2H),7.60(t,J=7.8Hz,1H),7.49(t,J=7.5Hz,2H),7.41(t,J=7.3Hz,1H).
中间体10:2-(对甲苯基)恶唑-5-甲醛
以4-甲基-N-(1-基-2-丙二醇)苯甲酰胺(500mg,2.89mmol)为原料合成方法同中间体8,得到黄色固体0.255g,产率51%。1H NMR(400MHz,DMSO)δ9.79(s,1H),8.32(s,1H),7.99(d,J=7.6Hz,2H),7.42(d,J=7.7Hz,2H).
中间体11:2-(4-甲氧基苯基)恶唑-5-甲醛
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以4-甲氧基-N-(1-基-2-丙二醇)苯甲酰胺(500mg,2.46mmol)为原料合成方法同中间体8,得到淡黄色固体0.402g,产率51%。UPLC-MS(ESI)理论值为C11H9NO3[M+H]+:204.20,实测值:204.06
中间体12:2-(4-氯苯基)恶唑-5-甲醛
以4-氯-N-(丙-2-炔-1-基)苯甲酰胺(500mg,2.58mmol)为原料,合成方法同中间体8,得到淡黄色固体289mg,产率52%。
1H NMR(400MHz,DMSO)δ9.82(s,1H),8.35(s,1H),8.10(d,J=7.5Hz,2H),7.68(d,J=7.6Hz,2H).
中间体13:2-(4-氟苯基)恶唑-5-甲醛
以4-氟-N-(1-基-2-丙二醇)苯甲酰胺(1g,5.64mmol)为原料,合成方法同中间体8,得到淡黄色固体647mg,产率60%。1H NMR(400MHz,DMSO)δ9.81(s,1H),8.34(s,1H),8.15(d,J=6.0Hz,2H),7.45(s,2H).:
中间体14:2-(2-氯苯基)恶唑-5-甲醛
以2-氯-N-(丙-2-炔-1-基)苯甲酰胺(500mg,2.58mmol)为原料,合成方法同中间体8,得到淡黄色固体230mg,产率43%。UPLC-MS(ESI)理论值为C10H6ClNO2[M+H]+:208.61,实测值:[M+H]+:208.12
中间体15:5-(对甲苯基)恶唑-2-甲醛
将对甲基苯甲醛(3g,24.97mmol)和对甲基苯磺酰甲基异腈(5.12g,26.22mmol)溶于50mL甲醇中,加入碳酸钾(4.14g,29.96mmol),回流反应1.5小时,TLC监测反应完全后,冷却至室温,加水淬灭,用乙酸乙酯萃取,有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,减压浓缩,柱层析得产物2.5g,产率63%。
将5-(对甲苯基)恶唑(1g,6.28mmol)溶于20mL乙醚中,在-78℃,氮气保护的条件下,缓慢滴加2.4mol/L正丁基锂(2.88mL,6.91mmol)己烷溶液,反应30分钟后,逐滴加入DMF(535μL,6.91mmol)的乙醚溶液(2mL),相同温度反应30分钟后,恢复至室温反应1.5小时。TLC监测反应完全后,加入2M HCl调PH至5~6左右,用二氯甲烷萃取,分液,有机相干燥减压浓缩,柱层析得到黄色固体650mg,产率:55%。UPLC-MS(ESI)理论值为C11H9NO2[M+H]+:188.20,实测值:188.16.
中间体16:5-(4-氟苯基)噻唑-2-甲醛
将对氟苯硼酸、5-溴噻唑、四三苯基膦钯加入到100mL两口瓶中,加入24mL二氧六环和6mL碳酸钾(2.79g,20.13mmol)水溶液,氮气抽换三次后,在氮气的保护条件下,100℃回流反应2小时,反应完全后,冷却至室温,加水淬灭反应,用乙酸乙酯(2ⅹ50mL)萃取,合并有机层,用饱和氯化钠洗涤,干燥浓缩,柱层析得到棕红色油状物1.19g。
将5-(4-氟苯基)噻唑(1.19g,6.64mmol)溶于25mL超干的四氢呋喃中,在-78℃,氮气保护的条件下,缓慢滴加2.5mol/L正丁基锂(2.92mL,7.3mmol)己烷溶液,反应30分钟后,逐滴加入DMF(568μL,7.30mmol)的四氢呋喃溶液(5mL),相同温度反应2小时后,2MHCl调PH至5~6左右,用二氯甲烷萃取,分液,有机相干燥减压浓缩,柱层析得到黄色固体743mg,收率54%。1H NMR(400MHz,CDCl3)δ9.96(s,1H),8.21(s,1H),7.64(dd,J=8.7,5.1Hz,2H),7.17(t,J=8.5Hz,2H).
中间体17:2-(4-(三氟甲氧基)苯基)噻唑-5-甲醛
将对三氟甲氧基苯硼酸(355mg,1.72mmol)、2-溴-5-甲醛基噻唑(300mg,1.56mmol)、四三苯基膦钯(180mg,0.156mmol)加入到100mL两口瓶中,加入10mL二氧六环和3mL碳酸钾(647mg,4.68mmol)水溶液,氮气抽换三次后,在氮气的保护条件下,100℃回流反应2小时,反应完全后,冷却至室温,加水淬灭反应,用乙酸乙酯(2ⅹ50mL)萃取,合并有机层,用饱和氯化钠洗涤,干燥浓缩,柱层析得到黄色固体220mg,收率52%。1HNMR(400MHz,DMSO)δ10.09(s,1H),8.80(s,1H),8.21(d,J=8.7Hz,2H),7.56(d,J=8.4Hz,2H).
中间体18:3-(5-甲酰基噻唑-2-基)苄腈
以(3-氰基苯基)硼酸(253mg,1.72mmol)和2-溴-5-甲醛基噻唑(300mg,1.56mmol)为原料,合成方法同中间体17,得到棕色固体216mg,产率65%。1H NMR(400MHz,DMSO)δ10.07(s,1H),8.79(s,1H),8.48(s,1H),8.36(d,J=8.0Hz,1H),8.02(d,J=7.7Hz,1H),7.74(t,J=7.9Hz,1H).
中间体19:4-(5-甲酰基噻唑-2-基)苄腈
(4-氰基苯基)硼酸(253mg,1.72mmol)和2-溴-5-甲醛基噻唑(300mg,1.56mmol)为原料,合成方法同中间体17,得到棕色固体235mg,产率66%。1H NMR(400MHz,DMSO)δ10.12(s,1H),8.86(s,1H),8.26(d,J=8.3Hz,2H),8.04(d,J=8.3Hz,2H).
中间体20:2-(4-(三氟甲基)苯基)噻唑-5-甲醛
以(4-(三氟甲基)苯基)硼酸(218mg,1.15mmol)和2-溴-5-甲醛基噻唑(200mg,1mmol)为原料,合成方法同中间体17,得到黄色固体162mg,产率40%。1H NMR(400MHz,CDCl3)δ10.08(s,1H),8.48(s,1H),8.15(d,J=6.8Hz,2H),7.75(d,J=6.8Hz,2H).
中间体21:2-(2,4-二甲氧基苯基)噻唑-5-甲醛
以(2,4-二甲氧基苯基)硼酸(313mg,1,72mmo)和2-溴-5-甲醛基噻唑(300mg,1.56mmol)为原料,合成方法同中间体17,得到黄色固体249mg,产率64%。UPLC-MS(ESI)理论值为C12H11NO3S[M+H]+:250.28,实测值:250.52.
中间体22:2-(3-氟苯基)噻唑-5-甲醛
以(3-氟苯基)硼酸(88mg,0.63mmol)和2-溴-5-甲醛基噻唑(110mg,0.57mmol)为原料,合成方法同中间体17,得到淡黄色固体94mg,产率72%。1H NMR(500MHz,DMSO)δ10.10(s,1H),8.81(s,1H),7.95–7.92(m,1H),7.92–7.89(m,1H),7.62(td,J=8.0,5.9Hz,1H),7.50–7.44(m,1H).
中间体23:2-(对甲苯基)噻唑-5-甲醛
以对甲苯基硼酸(156mg,1.14mmol)和2-溴-5-甲醛基噻唑(200mg,1.04mmol)为原料,合成方法同中间体17,得到黄色固体162mg,产率70%。1H NMR(500MHz,DMSO)δ10.07(s,1H),8.75(s,1H),7.99–7.96(m,2H),7.38(d,J=7.9Hz,2H),2.39(s,3H).
中间体24:N-甲基-1-(2-(4-(三氟甲氧基)苯基)恶唑-5-基)甲胺
以2-(4-(三氟甲氧基)苯基)恶唑-5-甲醛(200mg,0.778mmol)为原料,将上一步中间体2-(4-(三氟甲氧基)苯基)恶唑-5-甲醛溶于10ml甲醇中,加入甲胺(40%甲醇溶液),室温下反应一小时,0℃条件下加入硼氢化钠(59mg,1.55mmol),室温下反应30分钟,反应完全后,丙酮(10mL)淬灭,减压浓缩得到白色固体190mg,产率90%。1H NMR(500MHz,DMSO)δ8.06(d,J=8.8Hz,2H),7.52(d,J=8.3Hz,2H),7.17(s,1H),3.76(s,2H),2.30(s,3H).
中间体25:噁唑-5-甲醇
0℃条件下,将化合物噁唑-5-羧酸乙酯(9g,63.78mmol)的10mL THF溶液滴加至LiAlH4(2.548g,63.78mmol)的100mL THF悬浮液中,搅拌反应30分钟,反应完全后,0℃条件下,加水淬灭,过滤,滤渣用乙酸乙酯洗涤,滤液减压浓缩,经硅胶柱层析得到红色油状产物3.039g,产率48.09%;1H NMR(500MHz,DMSO)δ8.28(s,1H),7.04(s,1H),5.37(t,J=5.8Hz,1H),4.47(d,J=5.8Hz,2H).
中间体26:5-((((叔丁基二苯基甲硅烷基)氧基)甲基)噁唑
将化合物噁唑-5-甲醇(1.15g,11.61mmol)和咪唑(1.580g,23.21mmol)溶于20mL干燥的DMF中,加入叔丁基二苯基氯硅烷(3.142mL,12.77mmol),搅拌反应1小时,反应完全后加水淬灭,反应体系用乙酸乙酯萃取,有机相用饱和氯化钠洗涤数次,干燥浓缩,柱层析得无色油状产物3.918g,产率100%;1H NMR(500MHz,DMSO)δ8.33(s,1H),7.66–7.61(m,4H),7.51–7.43(m,6H),7.01(s,1H),4.74(s,2H),0.99(s,9H).
中间体27:(5-(((叔丁基二苯基甲硅烷基)氧基)甲基)噁唑-2-基)甲醇
将化合物5-((((叔丁基二苯基甲硅烷基)氧基)甲基)噁唑(3.918g,11.61mmol)溶于30mL干燥的THF中,用氮气抽换气3次,在0℃下加入硼烷四氢呋喃络合物(15.3mL,15.30mmol),维持0℃反应1小时,后将反应体系冷却至-78℃,滴加正丁基锂的己烷溶液(6.116mL,15.29mmol),维持-78℃反应2小时,再滴加4-甲酰吗啉(1.6mL,15.29mmol)并将反应缓慢升至-25℃,反应完全后用5%v/v醋酸的乙醇溶液35mL淬灭反应,升至室温搅拌反应30分钟,减压浓缩,残余物用乙酸乙酯溶解,依次用饱和碳酸氢钠水溶液和饱和氯化钠水溶液洗涤,有机相用无水硫酸钠干燥,过滤减压浓缩经硅胶柱层析得到无色油状产物2.724g,产率63.84%;1H NMR(500MHz,DMSO)δ7.65–7.62(m,4H),7.50–7.43(m,6H),6.91(s,1H),5.63(t,J=6.2Hz,1H),4.71(s,2H),4.46(d,J=6.2Hz,2H),0.99(d,J=5.0Hz,9H).
中间体28:5-(((叔丁基二苯基甲硅烷基)氧基)甲基)噁唑-2-甲醛
将化合物(5-(((叔丁基二苯基甲硅烷基)氧基)甲基)噁唑-2-基)甲醇(1.254g,3.412mmol)溶于10mL二氯甲烷中,0℃条件下加入Dess-Martin氧化剂(1.592g,3.753mmol),升至室温反应1小时,反应完全后用1N NaOH淬灭反应,用二氯甲烷萃取水相,合并有机相,用饱和氯化钠洗涤,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩,经硅胶柱层析得到无色油状产物500mg,产率40.09%;1H NMR(500MHz,DMSO)δ9.66(s,1H),7.64(dd,J=7.9,1.5Hz,4H),7.49–7.43(m,7H),4.85(s,2H),1.01(s,9H).
中间体29:(2R,6S)-4-((5-(((叔丁基二苯基甲硅烷基)氧基)甲基)噁唑-2-基)甲基)-2,6-二甲基吗啉
将化合物5-(((叔丁基二苯基甲硅烷基)氧基)甲基)噁唑-2-甲醛(500mg,1.368mmol)溶于5mL 1,2-二氯乙烷中,加入顺式2,6-二甲基吗啉(204μL,1.642mmol),0℃条件下,加入醋酸硼氢化钠(580mg,2.736mmol),后升至室温搅拌反应6h,反应完全后,用冰水淬灭反应,用二氯甲烷萃取2次,合并有机相用饱和氯化钠洗涤,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩,经硅胶柱层析得到油状产物527mg,产率82.60%;1H NMR(500MHz,CDCl3)δ7.67(dd,J=8.0,1.4Hz,4H),7.47–7.37(m,6H),6.77(s,1H),4.67(s,2H),3.72(dt,J=13.6,6.9Hz,2H),3.65(s,2H),2.75(d,J=10.8Hz,2H),1.91(t,J=10.6Hz,2H),1.14(d,J=6.3Hz,6H),1.05(s,9H).
中间体30:(2-(((2R,6S)-2,6-二甲基吗啉代)甲基)噁唑-5-基)甲醇
将化合物(2R,6S)-4-((5-(((叔丁基二苯基甲硅烷基)氧基)甲基)噁唑-2-基)甲基)-2,6-二甲基吗啉(527mg,1.13mmol)溶于5mL干燥的四氢呋喃溶液中,将反应体系冷却至0℃,加入四丁基氟化铵的四氢呋喃溶液(1.7mL,1.70mmol),将反应升至室温搅拌反应2小时,反应完全后,加水淬灭,用乙酸乙酯萃取两次,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,经硅胶柱层析得到油状产物170mg;产率66.49%;1H NMR(500MHz,CDCl3)δ6.96(s,1H),4.67(s,2H),3.72(dqd,J=12.5,6.3,2.0Hz,2H),3.66(s,2H),2.76(d,J=10.4Hz,2H),1.94–1.87(m,2H),1.15(d,J=6.3Hz,6H).
中间体31:2-(((2R,6S)-2,6-二甲基吗啉代)甲基)恶唑-5-甲醛
将化合物(2-(((2R,6S)-2,6-二甲基吗啉代)甲基)噁唑-5-基)甲醇(170mg,0.7513mmol)溶于3mL二氯甲烷中,0℃条件下加入Dess-Martin氧化剂(351mg,0.8264mmol),升至室温反应2小时,反应完全后,用1N NaOH淬灭反应,用二氯甲烷萃取水相,合并有机相,用饱和氯化钠洗涤,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩,经硅胶柱层析得到无色油状产物151mg;产率89.62%;1H NMR(500MHz,CDCl3)δ9.79(s,1H),7.82(s,1H),3.79(s,2H),3.73(dqd,J=12.5,6.3,2.1Hz,2H),2.79(d,J=10.2Hz,2H),1.99–1.93(m,2H),1.15(d,J=6.3Hz,6H).
中间体32:3-氟-4-(4-(5-甲酰基噻唑-2-基)哌嗪-1-基)苄腈
将化合物2-溴噻唑-5-甲醛(100mg,0.521mmol)、3-氟-4-(哌嗪-1-基)苄腈(128mg,0.625mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(30mg,0.0521mml)、三(二亚苄基丙酮)二钯(15mg,0.0261mmol)和碳酸铯(238mg,0.729mmol)溶于10mL甲苯中,反应体系用氮气抽换气3次后,在氮气保护的条件下,加热至100℃反应12小时,反应完全后,冷却至室温,反应体系用乙酸乙酯稀释,依次用水和饱和氯化钠溶液洗涤,分液,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩,经硅胶柱层析得到棕色固体102mg,产率62%。
实施例化合物的合成:
合成路线1:
其中,R1与上述定义相同,S-2为上述中间体,反应条件见下具体实施例中。
实施例1:2-(2,6-二氧哌啶-3-基)-4-((((2-(1-(1-甲基环丁烷-1-羰基)哌啶-4-基)恶唑-5-基)甲基)氨基)异二氢吲哚-1,3-二酮
将化合物2-(2,6-二氧哌啶-3-基)-4-((2-(哌啶-4-基)恶唑-5-基)甲基)氨基)异吲哚-1,3-二酮盐酸盐(40mg,0.084mmol),1-甲基环丁烷羧酸(11mg,0.092mmol),N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(35mg,0.092mmol)溶于3mL N,N-二甲基甲酰胺,搅拌条件下加入N,N-二异丙基乙胺(42μL,0.252mmol),室温反应1小时,LC-Mas监测反应完全后,经HPLC纯化得到黄色固体21mg,产率47%。1H NMR(600MHz,DMSO)δ11.10(s,1H),7.62–7.55(m,1H),7.21(d,J=8.6Hz,1H),7.08(d,J=7.1Hz,1H),7.02(t,J=6.1Hz,1H),6.98(s,1H),5.06(dd,J=12.9,5.4Hz,1H),4.61(d,J=6.0Hz,2H),4.19(s,1H),3.51(s,1H),3.05(td,J=10.8,5.4Hz,2H),2.92–2.83(m,1H),2.77(s,1H),2.59(d,J=18.1Hz,1H),2.55–2.51(m,1H),2.37(q,J=9.5Hz,2H),2.06–1.99(m,1H),1.97–1.85(m,3H),1.78(t,J=9.5Hz,2H),1.57(dt,J=69.6,34.8Hz,3H),1.32(s,3H)。UPLC-MS(ESI)理论值为C28H31N5O6[M+H]+:534.23,实测值:534.36。
实施例2:2-(2,6-二氧哌啶-3-基)-4-((((2-(1-(1-(4-氟苯基)环丁烷-1-羰基)哌啶-4-基)恶唑-5-基)甲基)氨基)异二氢吲哚-1,3-二酮
以1-(4-氟苯基)环丁烷-1-羧酸和中间体6为原料,路线同合成路线1及实施例1,得到黄色固体18mg,产率35%。1H NMR(500MHz,DMSO)δ11.11(s,1H),7.61–7.54(m,1H),7.38(dd,J=8.6,5.4Hz,2H),7.23–7.14(m,3H),7.07(d,J=7.1Hz,1H),7.02-6.97(t,1H),6.92(s,1H),5.06(dd,J=12.8,5.4Hz,1H),4.57(d,J=6.2Hz,2H),4.26(d,J=11.6Hz,1H),3.23(d,J=13.1Hz,1H),2.96–2.84(m,2H),2.83-2.73(m,3H),2.68-2.55(m,2H),2.44-2.34(m,2H),2.26-2.15(m,1H),2.05-1.97(m,1H),1.87(dd,J=18.2,9.8Hz,2H),1.76(dt,J=15.3,7.3Hz,1H),1.54(d,J=9.8Hz,1H),1.43-1.33(m,1H).UPLC-MS(ESI)理论值为C33H32FN5O6[M+H]+:614.23,实测值:614.45
实施例3:4-((2-(1-((3r,5r,7r)-金刚烷-1-羰基)哌啶-4-基)恶唑-5-基)甲基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮
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以1-金刚烷甲酸和中间体6为原料,路线同合成路线1及实施例1,得到黄色固体25mg,产率50%。1H NMR(500MHz,DMSO)δ11.11(s,1H),7.59(dd,J=14.0,6.0Hz,1H),7.21(d,J=8.6Hz,1H),7.08(d,J=7.1Hz,1H),7.02(dd,J=12.6,6.4Hz,1H),6.98(s,1H),5.06(dd,J=12.8,5.3Hz,1H),4.61(d,J=6.2Hz,1H),4.25(d,J=13.2Hz,2H),3.12–3.05(m,1H),2.99(t,J=12.2Hz,2H),2.93–2.84(m,1H),2.65-2.52(m,2H),2.06–1.99(m,1H),1.99-1.91(m,5H),1.88(s,5H),1.80(dd,J=18.5,8.2Hz,2H),1.73–1.61(m,7H),1.49(dd,J=21.3,10.9Hz,2H).UPLC-MS(ESI)理论值为C33H37N5O6[M+H]+:600.27实测值:600.41
实施例4:2-(2,6-二氧哌啶-3-基)-4-((((2-(1-(1-(三氟甲氧基)环丁烷-1-羰基)哌啶-4-基)恶唑-5-基)甲基)氨基)异二氢吲哚-1,3-二酮
以2-溴-6-三氟甲基吡啶和中间体6为原料,路线同合成路线1及实施例1,得到黄色固体20.5mg,产率42%。1H NMR(500MHz,DMSO)δ11.11(s,1H),7.62–7.55(m,1H),7.21(d,J=8.6Hz,1H),7.08(d,J=7.1Hz,1H),7.03(t,J=6.1Hz,1H),6.98(s,1H),5.06(dd,J=12.8,5.4Hz,1H),4.61(d,J=6.2Hz,2H),4.26(d,J=12.5Hz,1H),3.50(d,J=12.3Hz,1H),3.17–3.05(m,2H),2.94–2.82(m,2H),2.7-2.53(m,4H),2.46-2.32(m,3H),2.06–1.90(m,5H),1.8-1.71(m,1H),1.63-1.49(m,2H).UPLC-MS(ESI)理论值为C28H28F3N5O7[M+H]+:588.20,实测值:588.41
实施例5:2-(2,6-二氧哌啶-3-基)-4-((2-(1-(4-氟苯甲酰基)哌啶-4-基)恶唑-5-基)甲基)氨基)异吲哚-1,3-二酮
以对氟苯甲酸和中间体6为原料,路线同合成路线1及实施例1,得到黄色固体20mg,产率43%。1H NMR(600MHz,DMSO)δ11.10(s,1H),7.62–7.57(m,1H),7.48–7.43(m,2H),7.26(t,J=8.9Hz,2H),7.21(d,J=8.6Hz,1H),7.08(d,J=7.1Hz,1H),7.02(t,J=6.3Hz,1H),6.99(s,1H),5.06(dd,J=12.9,5.4Hz,1H),4.61(d,J=6.2Hz,2H),4.32(s,1H),3.55(s,1H),3.17–3.01(m,3H),2.88(ddd,J=17.1,13.9,5.4Hz,1H),2.62–2.56(m,1H),2.56–2.52(m,1H),2.07-1.87(m,3H),1.68-1.57(m,2H).UPLC-MS(ESI)理论值为C29H26FN5O6[M+H]+:560.19,实测值:560.73
实施例6:4-(4-(5-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)甲基)恶唑-2-基)哌啶-1-羰基)-3-氟苯腈
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以4-氰基-2-氟苯酸和中间体6为原料,路线同合成路线1及实施例1,得到黄色固体13mg,产率26%。1H NMR(500MHz,DMSO)δ11.11(s,1H),8.00(d,J=9.2Hz,1H),7.79(d,J=7.8Hz,1H),7.63–7.55(m,2H),7.21(d,J=8.6Hz,1H),7.08(d,J=7.1Hz,1H),7.03(t,J=5.9Hz,1H),6.99(s,1H),5.06(dd,J=12.8,5.4Hz,1H),4.61(d,J=6.2Hz,2H),4.37(d,J=13.3Hz,1H),3.36(s,1H),3.22–3.12(m,2H),3.06(dd,J=17.7,7.0Hz,1H),2.93–2.82(m,1H),2.64–2.52(m,2H),2.11–1.86(m,3H),1.56(d,J=10.1Hz,2H).UPLC-MS(ESI)理论值为C30H25FN6O6[M+H]+:585.18,实测值:585.25
实施例7:2-(2,6-二氧哌啶-3-基)-4-((((2-(1-(4-(三氟甲氧基)苯甲酰基)哌啶-4-基)恶唑-5-基)甲基)氨基)异二氢吲哚-1,3-二酮
以对三氟甲氧基苯甲酸和中间体6为原料,路线同合成路线1及实施例1,得到黄色固体20mg,产率38%。1H NMR(500MHz,DMSO)δ11.11(s,1H),7.60(s,1H),7.54(d,J=8.5Hz,2H),7.43(d,J=8.2Hz,2H),7.21(d,J=8.6Hz,1H),7.08(d,J=7.1Hz,1H),7.03(s,1H),6.99(s,1H),5.06(dd,J=12.8,5.4Hz,1H),4.61(d,J=6.1Hz,2H),4.34(s,1H),3.51(s,1H),3.20-2.98(m,3H),2.94–2.81(m,1H),2.63–2.52(m,2H),2.08–1.87(m,3H),1.70-1.55(m,2H).UPLC-MS(ESI)理论值为C30H26F3N5O7[M+H]+:626.18,实测值:626.26
实施例8:4-((2-(1-(2,4-二氯苯甲酰基)哌啶-4-基)恶唑-5-基)甲基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚啉-1,3-二酮
以对2,4-二氯苯甲酸和中间体6为原料,路线同合成路线1及实施例1,得到黄色固体20mg,产率39%。1H NMR(500MHz,DMSO)δ11.11(s,1H),7.72(d,J=1.7Hz,1H),7.66–7.54(m,1H),7.50(ddd,J=8.0,3.8,1.8Hz,1H),7.42(dd,J=27.4,8.2Hz,1H),7.21(d,J=7.8Hz,1H),7.08(d,J=7.1Hz,1H),7.03(t,J=6.2Hz,1H),6.99(s,1H),5.06(dd,J=12.8,5.4Hz,1H),4.61(d,J=6.2Hz,2H),4.37(d,J=13.2Hz,1H),3.27(d,J=14.1Hz,1H),3.10(ddt,J=29.8,21.2,10.3Hz,3H),2.93–2.82(m,1H),2.65-2.55(m,2H),2.10-1.99(m,2H),1.89(t,J=13.4Hz,1H),1.71–1.48(m,2H).UPLC-MS(ESI)理论值为C29H25Cl2N5O6[M+H]+:610.12,实测值:610.28。
实施例9:2-(2,6-二氧哌啶-3-基)-4-((2-(1-新戊酰哌啶-4-基)恶唑-5-基)甲基)氨基)异吲哚-1,3-二酮
以对三甲基乙酸和中间体6为原料,路线同合成路线1及实施例1,得到黄色固体20mg,产率46%。1H NMR(600MHz,DMSO)δ11.10(s,1H),7.59(s,1H),7.21(d,J=8.6Hz,1H),7.08(d,J=7.1Hz,1H),7.02(s,1H),6.98(s,1H),5.06(dd,J=12.9,5.4Hz,1H),4.61(d,J=6.2Hz,2H),4.17(d,J=13.5Hz,2H),3.12–3.04(m,1H),2.99(t,J=12.0Hz,2H),2.92–2.85(m,1H),2.62-2.52(m,2H),2.06–2.00(m,1H),1.95(dd,J=13.1,2.5Hz,2H),1.51(td,J=14.5,3.6Hz,2H),1.18(s,9H).UPLC-MS(ESI)理论值为C27H31N5O6[M+H]+:522.23,实测值:522.44
实施例10:2-(2,6-二氧哌啶-3-基)-4-(((2-(1-(1-甲基环己烷-1-羰基)哌啶-4-基)恶唑-5-基)甲基)氨基)异二氢吲哚-1,3-二酮
以1-甲基-1-环已羧酸和中间体6为原料,路线同合成路线1及实施例1,得到黄色固体18mg,产率38%。1H NMR(500MHz,DMSO)δ11.11(s,1H),7.62–7.57(m,1H),7.21(d,J=8.6Hz,1H),7.08(d,J=7.1Hz,1H),7.03(s,1H),6.97(s,1H),5.06(dd,J=12.8,5.4Hz,1H),4.61(d,J=6.2Hz,2H),4.18(d,J=13.4Hz,2H),3.13–3.04(m,1H),2.98(t,J=12.0Hz,2H),2.92–2.82(m,1H),2.57(ddd,J=17.7,15.6,9.9Hz,2H),2.07–1.99(m,1H),1.94(d,J=10.3Hz,4H),1.54–1.43(m,4H),1.39(dd,J=13.2,6.2Hz,3H),1.32–1.20(m,4H),1.15(s,3H).UPLC-MS(ESI)理论值为C30H35N5O6[M+H]+:562.26,实测值:562.82
实施例11:4-((2-(1-(2-((3r,5r,7r)-金刚烷-1-基)乙酰基)哌啶-4-基)恶唑-5-基)甲基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮
以1-金刚烷乙酸和中间体6为原料,路线同合成路线1及实施例1,得到黄色固体26mg,产率50%。1H NMR(500MHz,DMSO)δ11.11(s,1H),7.62–7.56(m,1H),7.21(d,J=8.6Hz,1H),7.08(d,J=7.1Hz,1H),7.03(t,J=6.3Hz,1H),6.98(s,1H),5.06(dd,J=12.8,5.4Hz,1H),4.61(d,J=6.2Hz,2H),4.30(d,J=13.1Hz,1H),3.93(d,J=14.0Hz,1H),3.15(t,J=11.4Hz,1H),3.08–3.02(m,1H),2.92–2.83(m,1H),2.75(t,J=12.0Hz,1H),2.65–2.52(m,2H),2.13(d,J=13.5Hz,1H),2.04(dd,J=18.4,9.4Hz,2H),1.98–1.88(m,5H),1.64(d,J=11.9Hz,3H),1.61-1.55(m,10H),1.43(d,J=13.1Hz,1H).UPLC-MS(ESI)理论值为C34H39N5O6[M+H]+:614.29,实测值:614.37
实施例12:2-(2,6-二氧哌啶-3-基)-4-((2-(1-(4-氟苄基)哌啶-4-基)恶唑-5-基)甲基)氨基)异吲哚-1,3-二酮
将对氟苯甲醛(9mg,0.076mmol)、中间体6(30mg,0.063mmol)和ZnCl2(1M in THF,66μL)的四氢呋喃溶液在室温搅拌3小时后,加入氰基硼氢化钠(8mg,0.126mmol),反应体系在室温反应过夜,LC-Mass监测反应完全后,用乙酸乙酯稀释,用饱和氯化钠溶液洗涤,分液,有机层用无水硫酸钠干燥,过滤,滤液旋干,得粗品,经HPLC纯化得到黄色固体10mg,产率29%。1H NMR(500MHz,DMSO)δ11.11(s,1H),7.62–7.57(m,1H),7.32(s,2H),7.20(d,J=8.6Hz,1H),7.13(t,J=8.6Hz,2H),7.08(d,J=7.1Hz,1H),7.02(t,J=6.2Hz,1H),6.96(s,1H),5.06(dd,J=12.9,5.4Hz,1H),4.60(d,J=6.2Hz,2H),3.49-3.39(m,2H),2.92–2.83(m,1H),2.81-2.70(m,3H),2.65–2.53(m,2H),2.11–1.97(m,3H),1.91(d,J=11.4Hz,2H),1.70-1.60(m,2H).UPLC-MS(ESI)理论值为C29H28FN5O5[M+H]+:546.21,实测值:546.84
实施例13:4-((4-(5-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异喹啉-4-基)氨基)甲基)恶唑-2-基)哌啶-1-基)甲基)-3-氟苯腈
以4-氰基-2-氟苯甲醛和中间体6为原料,合成路线同实施例12,得到黄色固体13mg,产率38%。1H NMR(500MHz,DMSO)δ11.10(s,1H),7.82(dd,J=9.8,1.3Hz,1H),7.68(dd,J=7.9,1.4Hz,1H),7.66–7.56(m,2H),7.20(d,J=8.6Hz,1H),7.08(d,J=7.1Hz,1H),7.02(t,J=6.2Hz,1H),6.96(s,1H),5.06(dd,J=12.8,5.4Hz,1H),4.60(d,J=6.2Hz,2H),3.58(s,2H),2.88(ddd,J=17.1,14.0,5.4Hz,1H),2.76(dd,J=7.6,3.4Hz,3H),2.65–2.55(m,2H),2.13(t,J=10.4Hz,2H),2.07–1.98(m,1H),1.91(d,J=11.0Hz,2H),1.73–1.61(m,2H).UPLC-MS(ESI)理论值为C30H27FN6O5[M+H]+:571.20,实测值:571.72
实施例14:2-(2,6-二氧哌啶-3-基)-4-((((2-(1-(4-(三氟甲氧基)苄基)哌啶-4-基)恶唑-5-基)甲基)氨基)异二氢吲哚-1,3-二酮
以对三氟甲氧基苯甲醛和中间体6为原料,合成路线同实施例12,得到黄色固体23mg,产率60%。1H NMR(500MHz,DMSO)δ11.11(s,1H),7.62–7.56(m,1H),7.42(d,J=8.5Hz,2H),7.30(d,J=8.2Hz,2H),7.20(d,J=8.6Hz,1H),7.08(d,J=7.1Hz,1H),7.01(d,J=6.5Hz,1H),6.96(s,1H),5.06(dd,J=12.8,5.4Hz,1H),4.60(d,J=6.1Hz,2H),2.93–2.84(m,2H),2.81–2.70(m,3H),2.64–2.56(m,2H),2.11–1.96(m,4H),1.91(d,J=10.7Hz,2H),1.66(dd,J=21.1,11.1Hz,2H).UPLC-MS(ESI)理论值为C30H28F3N5O6[M+H]+:612.20,实测值:612.33
实施例15:2-(2,6-二氧哌啶-3-基)-4-((((2-(4-(三氟甲氧基)苯基)恶唑-5-基)甲基)氨基)异吲哚啉-1,3-二酮
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将2-(4-(三氟甲氧基)苯基)恶唑-5-甲醛(46mg,0.18mmol)和消旋的泊马度胺(50mg,0.18mmol),苯硅烷(22μL,0.18mmol)和二丁基二氯化锡(55mg,0.18mmol)的四氢呋喃(6mL)溶液加热回流反应过夜,LC-Mass监测反应完全后,减压浓缩,经HPLC纯化得到黄色固体12mg,产率13%。1H NMR(500MHz,DMSO)δ11.11(s,1H),8.03(d,J=8.8Hz,2H),7.62(s,1H),7.52(d,J=8.3Hz,2H),7.32–7.25(m,2H),7.15(s,1H),7.10(d,J=7.1Hz,1H),5.07(dd,J=12.8,5.4Hz,1H),4.74(d,J=6.2Hz,2H),2.89(dd,J=22.4,8.8Hz,1H),2.59(d,J=18.3Hz,2H),2.07–1.99(m,1H).UPLC-MS(ESI)理论值为C24H17F3N4O6[M+H]+:515.11,实测值:515.29
实施例16:2-(2,6-二氧哌啶-3-基)-4-((2-(4-甲氧基苯基)恶唑-5-基)甲基)氨基)异吲哚-1,3-二酮
以2-(4-甲氧基苯基)恶唑-5-甲醛和消旋的泊马度胺为原料,合成路线同实施例15,经HPLC纯化得到黄色8mg,产率10%。1H NMR(500MHz,DMSO)δ11.12(s,1H),7.84(d,J=8.9Hz,2H),7.66–7.59(m,1H),7.30(d,J=8.6Hz,1H),7.17(s,1H),7.13(s,1H),7.08(dd,J=14.6,8.0Hz,3H),5.07(dd,J=12.8,5.4Hz,1H),4.71(d,J=6.2Hz,2H),3.81(s,3H),2.95–2.84(m,1H),2.58(d,J=19.4Hz,2H),2.07–1.96(m,1H).UPLC-MS(ESI)
理论值C24H20N4O6[M+H]+:461.45,实测值:461.27.
实施例17:2-(2,6-二氧哌啶-3-基)-4-((2-(3-甲氧基苯基)恶唑-5-基)甲基)氨基)异吲哚-1,3-二酮
将2-(3-甲氧基苯基)恶唑-5-甲醛(74mg,0.37mmol)和消旋的泊马度胺(100mg,0.37mmol),苯硅烷(45μL,0.37mmol)和二丁基二氯化锡(112mg,0.27mmol)的四氢呋喃(6mL)溶液加热回流反应过夜,LC-Mass监测反应完全后,减压浓缩,经HPLC纯化得到黄色40mg,产率23%。1H NMR(500MHz,DMSO)δ11.12(s,1H),7.63(dd,J=8.4,7.2Hz,1H),7.49(dd,J=7.7,1.1Hz,1H),7.44(d,J=8.0Hz,1H),7.41–7.39(m,1H),7.31(d,J=8.6Hz,1H),7.23(s,1H),7.16(t,J=6.3Hz,1H),7.08(ddd,J=5.9,4.0,3.5Hz,2H),5.07(dd,J=12.8,5.4Hz,1H),4.73(d,J=6.1Hz,2H),3.81(s,3H),2.88(ddd,J=17.0,13.9,5.4Hz,1H),2.61–2.53(m,2H),2.06–1.99(m,1H).UPLC-MS(ESI)理论值为C24H20N4O6[M+H]+:461.45,实测值:461.38.
实施例18:4-((2-([1,1'-联苯基]-3-基)恶唑-5-基)甲基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮
以2-([1,1'-联苯]-3-基)恶唑-5-甲醛和消旋的泊马度胺为原料,合成路线同实施例17,经HPLC纯化得到黄色28mg,产率15%。1H NMR(500MHz,DMSO)δ11.12(s,1H),8.13(t,J=1.5Hz,1H),7.91(d,J=7.8Hz,1H),7.84–7.78(m,1H),7.73–7.67(m,2H),7.62(q,J=8.3Hz,2H),7.51(t,J=7.7Hz,2H),7.43(d,J=7.4Hz,1H),7.33(d,J=8.7Hz,1H),7.27(s,1H),7.18(s,1H),7.10(d,J=7.1Hz,1H),5.07(dd,J=12.8,5.4Hz,1H),4.76(d,J=6.3Hz,2H),2.88(ddd,J=17.0,13.9,5.4Hz,1H),2.62–2.52(m,2H),2.07–1.96(m,1H).UPLC-MS(ESI)理论值为C29H22N4O5[M+H]+:507.52,实测值:507.28.
实施例19:2-(2,6-二氧哌啶-3-基)-4-((2-(对甲苯基)恶唑-5-基)甲基)氨基)异吲哚啉-1,3-二酮
以2-(对甲苯基)恶唑-5-甲醛和消旋的泊马度胺为原料,合成路线同实施例17,经HPLC纯化得到黄色42mg,产率26%。1H NMR(500MHz,DMSO)δ11.12(s,1H),7.80(d,J=8.2Hz,2H),7.62(dd,J=8.5,7.2Hz,1H),7.31(dd,J=12.2,8.3Hz,3H),7.20(s,1H),7.14(s,1H),7.09(d,J=7.1Hz,1H),5.07(dd,J=12.8,5.4Hz,1H),4.72(s,2H),2.88(ddd,J=17.0,14.0,5.4Hz,1H),2.57(dd,J=25.6,10.1Hz,2H),2.35(s,3H),2.06–1.98(m,1H).UPLC-MS(ESI)理论值为C24H20N4O5[M+H]+:445.45,实测值:445.33.
实施例20:2-(2,6-二氧哌啶-3-基)-4-((2-(间甲苯基)恶唑-5-基)甲基)氨基)异吲哚-1,3-二酮
以2-(间甲苯基)恶唑-5-甲醛和消旋的泊马度胺为原料,合成路线同实施例17,经HPLC纯化得到黄色32mg,产率20%。1H NMR(500MHz,DMSO)δ11.12(s,1H),7.73(s,1H),7.70(d,J=7.7Hz,1H),7.65–7.59(m,1H),7.39(t,J=7.7Hz,1H),7.30(t,J=8.7Hz,2H),7.22(s,1H),7.15(t,J=6.2Hz,1H),7.09(d,J=7.1Hz,1H),5.07(dd,J=12.8,5.4Hz,1H),4.73(d,J=6.2Hz,2H),2.93–2.82(m,1H),2.58(d,J=19.8Hz,2H),2.36(s,3H),2.07–1.97(m,1H).UPLC-MS(ESI)理论值为C24H20N4O5[M+H]+:445.45,实测值:445.22
实施例21:2-(2,6-二氧哌啶-3-基)-4-((2-(邻甲苯基)恶唑-5-基)甲基)氨基)异吲哚啉-1,3-二酮
以2-(邻甲苯基)恶唑-5-甲醛和消旋的泊马度胺为原料,成路线同实施例17,经HPLC纯化得到黄色25mg,产率15%.1H NMR(500MHz,DMSO)δ11.12(s,1H),7.85(d,J=7.7Hz,1H),7.65–7.58(m,1H),7.35(dt,J=16.6,8.0Hz,4H),7.26(s,1H),7.15(t,J=6.3Hz,1H),7.09(d,J=7.0Hz,1H),5.07(dd,J=12.8,5.4Hz,1H),4.75(d,J=6.2Hz,2H),2.94–2.81(m,1H),2.62-2.53(m,5H),2.06–1.95(m,1H).
UPLC-MS(ESI)理论值为C24H20N4O5[M+H]+:445.45,实测值:445.29.
实施例22:2-(2,6-二氧哌啶-3-基)-4-((2-苯基恶唑-5-基)甲基)氨基)异吲哚-1,3-二酮
以2-苯基恶唑-5-甲醛和消旋的泊马度胺为原料,合成路线同实施例15,经HPLC纯化得到黄色31mg,产率20%。1H NMR(500MHz,DMSO)δ11.12(s,1H),7.94–7.89(m,2H),7.63(dd,J=8.4,7.3Hz,1H),7.55–7.48(m,3H),7.30(d,J=8.6Hz,1H),7.24(s,1H),7.15(t,J=6.3Hz,1H),7.10(d,J=7.1Hz,1H),5.07(dd,J=12.8,5.4Hz,1H),4.74(d,J=6.2Hz,2H),2.88(ddd,J=17.0,13.9,5.4Hz,1H),2.65–2.52(m,2H),2.03(ddd,J=10.5,5.4,3.1Hz,1H).UPLC-MS(ESI)理论值为C23H18N4O5[M+H]+:431.42,实测值:431.28.
实施例23:4-((2-(4-溴苯基)恶唑-5-基)甲基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚啉-1,3-二酮
以2-(4-溴苯基)恶唑-5-甲醛和消旋的泊马度胺为原料,合成路线同实施例15,经HPLC纯化得到黄色21mg,产率11%.1H NMR(400MHz,DMSO)δ11.10(s,1H),7.84(d,J=8.4Hz,2H),7.73(d,J=8.5Hz,2H),7.66–7.59(m,1H),7.33–7.23(m,2H),7.18–7.06(m,2H),5.07(dd,J=12.8,5.3Hz,1H),4.73(d,J=4.7Hz,2H),2.94–2.79(m,1H),2.69–2.55(m,2H),2.08–1.97(m,1H).UPLC-MS(ESI)理论值为C23H17BrN4O5[M+H]+:510.32,实测值:510.07.
实施例24:2-(2,6-二氧哌啶-3-基)-4-((5-(对甲苯基)恶唑-2-基)甲基)氨基)异吲哚啉-1,3-二酮
以5-(对甲苯基)恶唑-2-甲醛(55mg,0.294mmol)和泊马度胺(80mg,0.294mmol)为原料,合成路线同实施例15,经HPLC纯化得到黄色14mg,产率11%。1H NMR(500MHz,DMSO)δ11.13(s,1H),7.61(dd,J=8.3,7.3Hz,1H),7.55(t,J=4.1Hz,3H),7.30–7.20(m,4H),7.10(d,J=7.1Hz,1H),5.09(dd,J=12.7,5.5Hz,1H),4.78(d,J=6.2Hz,2H),2.95–2.82(m,1H),2.66–2.53(m,2H),2.32(s,3H),2.08–2.01(m,1H).UPLC-MS(ESI)理论值为C24H20N4O5[M+H]+:445.45,实测值:445.22.
实施例25:4-((2-(4-氯苯基)恶唑-5-基)甲基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚啉-1,3-二酮
以2-(4-氯苯基)恶唑-5-甲醛和消旋的泊马度胺为原料,合成路线同实施例17,经HPLC纯化得到黄色93mg,产率55%。1H NMR(500MHz,DMSO)δ11.14(s,1H),7.96–7.87(m,2H),7.67–7.59(m,3H),7.31(d,J=8.6Hz,1H),7.27(s,1H),7.17(t,J=6.2Hz,1H),7.11(d,J=7.1Hz,1H),5.08(dd,J=12.8,5.5Hz,1H),4.75(d,J=6.3Hz,2H),2.90(ddd,J=16.9,14.0,5.4Hz,1H),2.68–2.57(m,2H),2.04(dd,J=10.7,5.7Hz,1H).UPLC-MS(ESI)理论值为C23H17ClN4O5[M+H]+:465.86,实测值:465.37.
实施例26:2-(2,6-二氧哌啶-3-基)-4-((2-(4-氟苯基)恶唑-5-基)甲基)氨基)异吲哚-1,3-二酮
以2-(4-氟苯基)恶唑-5-甲醛和消旋的泊马度胺为原料,合成路线同实施例17,经HPLC纯化得到黄色92mg,产率56%。1H NMR(500MHz,DMSO)δ11.12(s,1H),8.00–7.91(m,2H),7.62(dd,J=8.4,7.2Hz,1H),7.41–7.33(m,2H),7.30(d,J=8.6Hz,1H),7.23(s,1H),7.15(t,J=6.4Hz,1H),7.10(d,J=7.0Hz,1H),5.07(dd,J=12.8,5.4Hz,1H),4.73(d,J=6.3Hz,2H),2.88(ddd,J=17.0,13.9,5.4Hz,1H),2.60(dd,J=17.5,14.6Hz,2H),2.06–1.98(m,1H).UPLC-MS(ESI)理论值为C23H17FN4O5[M+H]+:449.41,实测值:449.54.
实施例27:4-((2-(2-氯苯基)恶唑-5-基)甲基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚啉-1,3-二酮
以2-(2-氯苯基)恶唑-5-甲醛和消旋的泊马度胺为原料,合成路线同实施例17,经HPLC纯化得到黄色144mg,产率86%。1H NMR(500MHz,DMSO)δ11.10(s,1H),7.92(dd,J=7.6,1.9Hz,1H),7.64–7.59(m,2H),7.50(dtd,J=18.4,7.4,1.6Hz,2H),7.31(t,J=4.3Hz,2H),7.14(d,J=6.4Hz,1H),7.10(d,J=7.0Hz,1H),5.07(dd,J=12.8,5.4Hz,1H),4.76(d,J=6.2Hz,2H),2.88(ddd,J=17.0,14.0,5.4Hz,1H),2.65–2.54(m,2H),2.06–1.96(m,1H).UPLC-MS(ESI)理论值为C23H17ClN4O5[M+H]+:465.86,实测值:465.30.
实施例28:2-(2,6-二氧哌啶-3-基)-4-((2-(3-氟苯基)噻唑-5-基)甲基)氨基)异吲哚-1,3-二酮
将2-(3-氟苯基)噻唑-5-甲醛(45mg,0.22mmol)和消旋的泊马度胺(59mg,0.22mmol)的乙酸悬浊液(4mL)加热回流过夜,将反应冷却室温,加入硼氢化钠(9mg,0.22mmol),室温反应两小时后,减压浓缩,用乙酸乙酯稀释,依次用饱和碳酸氢钠溶液和饱和氯化钠溶液洗涤,有机相干燥浓缩,经HPLC纯化得到黄色5.5mg,产率15.4%。1H NMR(500MHz,DMSO)δ11.13(s,1H),7.94(s,1H),7.74–7.66(m,2H),7.61–7.55(m,1H),7.51(dt,J=14.0,7.0Hz,1H),7.38(t,J=6.3Hz,1H),7.30(td,J=8.4,2.1Hz,1H),7.21(d,J=8.6Hz,1H),7.07(d,J=7.1Hz,1H),5.07(dd,J=12.8,5.4Hz,1H),4.85(d,J=6.3Hz,2H),2.93–2.84(m,1H),2.65–2.55(m,2H),2.03(ddd,J=7.5,6.8,3.9Hz,1H).UPLC-MS(ESI)理论值为C23H17FN4O4S[M+H]+:465.47,实测值:465.19.
实施例29:2-(2,6-二氧哌啶-3-基)-4-((2-(对甲苯基)噻唑-5-基)甲基)氨基)异吲哚-1,3-二酮
以2-(对甲苯基)噻唑-5-甲醛(80mg,0.39mmol)和消旋的泊马度胺(108mg,0.39mmol)为原料,合成路线同实施例28,经HPLC纯化得到黄色25.4mg,产率14%。1H NMR(500MHz,DMSO)δ11.13(s,1H),7.86(s,1H),7.77(d,J=8.2Hz,2H),7.58(dd,J=8.5,7.2Hz,1H),7.33(t,J=6.2Hz,1H),7.27(d,J=8.0Hz,2H),7.22(d,J=8.6Hz,1H),7.07(d,J=7.1Hz,1H),5.07(dd,J=12.8,5.4Hz,1H),4.82(d,J=6.1Hz,2H),2.89(ddd,J=16.9,13.9,5.5Hz,1H),2.59(dd,J=34.3,14.6Hz,2H),2.33(s,3H),2.07–2.00(m,1H).UPLC-MS(ESI)理论值为C24H20N4O4S[M+H]+:461.51,实测值:461.23.
实施例30:3-(5-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异喹啉-4-基)氨基)甲基)噻唑-2-基)苯甲腈
以3-(5-甲酰基噻唑-2-基)苄腈(62mg,0.29mmol)和消旋的泊马度胺(80mg,0.29mmol)为原料,合成路线同实施例28,经HPLC纯化得到黄色9mg,产率7%。1H NMR(500MHz,DMSO)δ11.13(s,1H),8.31(s,1H),8.21(d,J=8.4Hz,1H),7.98(s,1H),7.91(d,J=7.8Hz,1H),7.67(t,J=7.9Hz,1H),7.62–7.55(m,1H),7.40(t,J=6.4Hz,1H),7.22(d,J=8.6Hz,1H),7.08(d,J=7.1Hz,1H),5.07(dd,J=12.8,5.4Hz,1H),4.87(d,J=6.1Hz,2H),2.94–2.83(m,1H),2.65–2.55(m,2H),2.07–1.99(m,1H).UPLC-MS(ESI)理论值为C24H17N5O4S[M+H]+:472.49,实测值:472.20.
实施例31:2-(2,6-二氧哌啶-3-基)-4-(2-(4-乙烯基苯基)噻唑-5-基)甲基)氨基)异吲哚-1,3-二酮
以2-(4-乙烯基苯基)噻唑-5-甲醛(63mg,0.29mmol)和消旋的泊马度胺(80mg,0.29mmol)为原料,合成路线同实施例28,经HPLC纯化得到黄色10mg,产率7%。1H NMR(500MHz,DMSO)δ11.13(s,1H),7.90(s,1H),7.86(d,J=8.3Hz,2H),7.57(t,J=8.2Hz,3H),7.35(t,J=6.3Hz,1H),7.22(d,J=8.6Hz,1H),7.07(d,J=7.1Hz,1H),6.77(dd,J=17.6,11.0Hz,1H),5.92(d,J=17.7Hz,1H),5.34(d,J=11.2Hz,1H),5.07(dd,J=12.8,5.4Hz,1H),4.84(d,J=6.3Hz,2H),2.96–2.80(m,1H),2.65–2.53(m,2H),2.10–2.00(m,1H).UPLC-MS(ESI)理论值为C25H20N4O4S[M+H]+:473.52,实测值:473.19.
实施例32:4-((2-(4-氯苯基)噻唑-5-基)甲基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚啉-1,3-二酮
2-(4-氯苯基)噻唑-5-甲醛(66mg,0.29mmol)和消旋的泊马度胺(80mg,0.29mmol)为原料,合成路线同实施例28,经HPLC纯化得到黄色12mg,产率9%。1H NMR(500MHz,DMSO)δ11.13(s,1H),7.96–7.85(m,3H),7.58(dd,J=8.5,7.2Hz,1H),7.54–7.49(m,2H),7.36(t,J=6.1Hz,1H),7.21(d,J=8.6Hz,1H),7.07(d,J=7.1Hz,1H),5.07(dd,J=12.8,5.4Hz,1H),4.84(d,J=5.6Hz,2H),2.89(ddd,J=17.1,13.9,5.4Hz,1H),2.65–2.52(m,2H),2.07–1.99(m,1H).UPLC-MS(ESI)理论值为C23H17ClN4O4S[M+H]+:481.92,实测值:481.13.
实施例33:4-(5-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异喹啉-4-基)氨基)甲基)噻唑-2-基)苯甲腈
以4-(5-甲酰基噻唑-2-基)苄腈(70mg,0.33mmol)和消旋的泊马度胺(90mg,0.33mmol)为原料,合成路线同实施例28,经HPLC纯化得到黄色28mg,产率18%。1H NMR(400MHz,DMSO)δ11.11(s,1H),8.07(d,J=8.3Hz,2H),8.01(s,1H),7.92(d,J=8.3Hz,2H),7.62–7.55(m,1H),7.39(t,J=6.2Hz,1H),7.22(d,J=8.6Hz,1H),7.08(d,J=7.1Hz,1H),5.07(dd,J=12.9,5.3Hz,1H),4.87(d,J=6.2Hz,2H),2.95–2.83(m,1H),2.70–2.57(m,2H),2.09–1.98(m,1H).UPLC-MS(ESI)理论值为C24H17N5O4S[M+H]+:472.49,实测值:472.19.
实施例34:2-(2,6-二氧哌啶-3-基)-4-((5-(4-氟苯基)噻唑-2-基)甲基)氨基)异吲哚-1,3-二酮
以5-(4-氟苯基)噻唑-2-甲醛(72mg,0,348mmol)和消旋的泊马度胺(80mg,0.29mmol)为原料,合成路线同实施例28,经HPLC纯化得到黄色10.5mg,产率8%。1H NMR(500MHz,DMSO)δ11.14(s,1H),8.12(s,1H),7.68(dd,J=8.6,5.3Hz,2H),7.56(dt,J=12.1,7.0Hz,2H),7.25(t,J=8.8Hz,2H),7.10(dd,J=7.5,5.6Hz,2H),5.10(dd,J=12.7,5.3Hz,1H),4.88(d,J=6.1Hz,2H),2.94–2.86(m,1H),2.60(dd,J=28.6,10.3Hz,2H),2.10–2.02(m,1H).UPLC-MS(ESI)理论值为C23H17FN4O4S[M+H]+:465.47,实测值:465.22.
实施例35:2-(2,6-二氧哌啶-3-基)-4-(2-(4-(三氟甲氧基)苯基)噻唑-5-基)甲基)氨基)异吲哚-1,3-二酮
以2-(4-(三氟甲氧基)苯基)噻唑-5-甲醛(80mg,0.29mmol)和消旋的泊马度胺(80mg,0.29mmol)为原料,合成路线同实施例28,经HPLC纯化得到黄色20mg,产率13%。1HNMR(500MHz,DMSO)δ11.13(s,1H),8.01(dd,J=8.7,1.8Hz,2H),7.94(s,1H),7.59(t,J=7.8Hz,1H),7.46(d,J=8.0Hz,2H),7.37(d,J=5.8Hz,1H),7.22(d,J=8.6Hz,1H),7.07(d,J=7.1Hz,1H),5.07(dd,J=12.3,4.8Hz,1H),4.85(d,J=6.0Hz,2H),2.94–2.83(m,1H),2.57(d,J=35.0Hz,2H),2.09–1.98(m,1H).UPLC-MS(ESI)理论值为C24H17F3N4O5S[M+H]+:531.48,实测值:531.19.
实施例36:4-((2-(2,4-二甲氧基苯基)噻唑-5-基)甲基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮
以2-(2,4-二甲氧基苯基)噻唑-5-甲醛(72mg,0.29mmol)和消旋的泊马度胺(80mg,0.29mmol)为原料,合成路线同实施例28,经HPLC纯化得到黄色19mg,产率13%。1HNMR(500MHz,DMSO)δ11.12(s,1H),8.14(d,J=8.8Hz,1H),7.83(s,1H),7.60–7.55(m,1H),7.26(t,J=5.7Hz,1H),7.21(d,J=8.6Hz,1H),7.07(t,J=7.1Hz,1H),6.74(d,J=2.3Hz,1H),6.68(dd,J=8.8,2.4Hz,1H),5.07(dd,J=12.8,5.4Hz,1H),4.80(d,J=5.0Hz,2H),3.96(s,3H),3.83(s,3H),2.88(ddd,J=16.9,13.9,5.3Hz,1H),2.58(dd,J=21.8,4.3Hz,2H),2.07–1.95(m,1H).UPLC-MS(ESI)理论值为C25H22N4O6S[M+H]+:507.53,实测值:507.61.
实施例37:2-(2,6-二氧哌啶-3-基)-4-(2-(4-(三氟甲基)苯基)噻唑-5-基)甲基)氨基)异吲哚-1,3-二酮
以2-(4-(三氟甲基)苯基)噻唑-5-甲醛(75mg,0.29mmol)和泊马度胺(80mg,0.29mmol)为原料,合成路线同实施例28,经HPLC纯化得到黄色6mg,产率4%。1H NMR(500MHz,DMSO)δ11.11(s,1H),8.10(d,J=8.2Hz,2H),8.00(s,1H),7.82(d,J=8.4Hz,2H),7.63–7.56(m,1H),7.39(t,J=6.3Hz,1H),7.23(d,J=8.6Hz,1H),7.08(d,J=7.1Hz,1H),5.07(dd,J=12.8,5.3Hz,1H),4.87(d,J=6.3Hz,2H),2.94–2.82(m,1H),2.59(d,J=20.0Hz,2H),2.10–1.96(m,1H).UPLC-MS(ESI)理论值为C24H17F3N4O4S[M+H]+:515.48,实测值:515.11.
实施例38:2-(2,6-二氧哌啶-3-基)-4-(5-(苯基-d5)-1,3,4-噻二唑-2-基)甲基)氨基)异吲哚-1,3-二酮
参考实施例32合成路线,获得实施例化合物38。
实施例39:(3-(1,3-二氧基-4-((2-(4-(三氟甲基)苯基)噻唑-5-基)甲基)氨基)异吲哚-2-基)-2,6-二氧哌啶-1-基)新戊酸甲酯
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将实施例化合物37,2-(2,6-二氧哌啶-3-基)-4-(2-(4-(三氟甲基)苯基)噻唑-5-基)甲基)氨基)异吲哚-1,3-二酮(70mg,0.11mmol)于2mL N,N-二甲基甲酰胺中,室温条件下,加入特戊酸氯甲酯(16μL,0.11mmol)和碳酸铯(43mg,0.13mmol),反应体系升温至50℃反应一小时,TLC监测反应完全后,冷却至室温,加水淬灭反应,用乙酸乙酯萃取,分液,有机层用饱和氯化钠溶液洗涤数次,干燥过滤浓缩,粗品经HPLC纯化得到黄色固体7.6mg,产率11%。1H NMR(500MHz,DMSO)δ8.10(d,J=8.2Hz,2H),7.99(s,1H),7.82(d,J=8.4Hz,2H),7.60(dd,J=8.5,7.2Hz,1H),7.36(t,J=6.3Hz,1H),7.24(d,J=8.6Hz,1H),7.09(d,J=7.1Hz,1H),5.65(s,2H),5.26(dd,J=13.0,5.4Hz,1H),4.88(d,J=6.2Hz,2H),3.07(ddd,J=17.4,14.0,5.4Hz,1H),2.87–2.80(m,1H),2.65–2.51(m,1H),2.11(tdd,J=7.6,5.0,2.6Hz,1H).13C NMR(126MHz,DMSO)δ176.44,171.12,169.37,168.42,167.07,164.71,145.34,142.47,139.59,136.59,136.30,132.25,129.69,126.65,126.19,126.17,117.72,111.41,110.06,63.18,49.05,38.46,38.22,31.05,26.62,21.07.UPLC-MS(ESI)理论值为C30H27F3N4O6S[M+H]+:629.62,实测值:629.28.
实施例40:(3-(4-(((2-(4-氯苯基)恶唑-5-基)甲基)氨基)-1,3-二氧代异吲哚啉-2-基)-2,6-二氧代哌啶-1-基)甲基新戊酸酯
参考实施例25合成路线及实施例39的合成路线,获得实施例化合物40为黄色固体(50mg,26.7%)。1H NMR(500MHz,DMSO)δ7.91(d,J=8.6Hz,2H),7.63(dd,J=8.4,7.3Hz,1H),7.61–7.57(m,2H),7.30(d,J=8.6Hz,1H),7.26(s,1H),7.13(d,J=5.7Hz,1H),7.11(d,J=7.1Hz,1H),5.64(s,2H),5.26(dd,J=13.0,5.4Hz,1H),4.74(d,J=5.8Hz,2H),3.06(ddd,J=17.5,14.0,5.3Hz,1H),2.83(dd,J=13.6,2.8Hz,1H),2.56(dd,J=13.4,4.3Hz,1H),2.12–2.04(m,1H),1.09(s,9H).UPLC-MS(ESI)理论值为C29H27ClN4O7[M+H]+:579.16,实测值:579.36.
实施例41:(3-(1,3-二氧基-4-((2-(1-丙戊酰哌啶-4-基)恶唑-5-基)甲基)氨基)异吲哚-2-基)-2,6-二氧哌啶-1-基)丙戊酸甲酯
参考实施例38合成路线及实施例39的合成路线,获得实施例化合物41。得到黄色固体56.9mg,产率38%。1H NMR(500MHz,DMSO)δ7.60(dd,J=8.5,7.2Hz,1H),7.22(d,J=8.6Hz,1H),7.09(d,J=7.1Hz,1H),7.02(s,1H),6.98(s,1H),5.64(s,2H),5.26(dd,J=13.0,5.4Hz,1H),4.61(d,J=3.5Hz,2H),4.17(d,J=13.5Hz,2H),3.06(ddd,J=22.2,12.9,6.0Hz,2H),2.99(dd,J=13.1,10.8Hz,2H),2.83(dd,J=13.6,2.8Hz,1H),2.62–2.54(m,1H),2.09(ddd,J=14.9,7.4,4.9Hz,1H),1.95(dd,J=13.4,3.0Hz,2H),1.55–1.46(m,2H),1.17(s,9H),1.10(s,9H).13C NMR(201MHz,DMSO)δ176.45,174.84,171.11,169.36,168.53,167.08,165.57,148.77,145.69,136.20,132.11,123.98,117.74,111.36,109.90,63.17,49.05,43.80,40.43,39.99,38.23,38.12,36.82,34.56,31.04,29.62,28.07,26.62,21.08.UPLC-MS(ESI)理论值为C33H41N5O8[M+H]+:636.72,实测值:636.36.
实施例42:2-(2,6-二氧哌啶-3-基)-4-((2-(4-(4-氟苄基)环己基)恶唑-5-基)甲基)氨基)异吲哚-1,3-二酮
参考实施例12合成路线,获得实施例化合物42。化合物42为实施例化合物105和实施例化合物106未分离前的混合物,核磁及质谱数据对应于相应的实施例化合物105和106。
实施例43:4-((2-(5-氯吡啶-2-基)噻唑-5-基)甲基)氨基)-2-(2,6-二氧吡啶-3-基)异吲哚-1,3-二酮
参考实施例32合成路线,获得实施例化合物43,经HPLC纯化得到黄色58mg,产率33%。1H NMR(600MHz,DMSO)δ11.10(s,1H),8.65(d,J=0.9Hz,1H),8.09–8.02(m,2H),7.97(s,1H),7.59(t,J=7.8Hz,1H),7.35(t,J=6.3Hz,1H),7.22(d,J=8.6Hz,1H),7.07(d,J=7.1Hz,1H),5.07(dd,J=12.8,5.4Hz,1H),4.85(d,J=6.4Hz,2H),2.93–2.84(m,1H),2.62–2.51(m,2H),2.08–2.00(m,1H).UPLC-MS(ESI)理论值为C22H16ClN5O4S[M+H]+:482.06,实测值:482.25.
实施例44:4-((2-(6-氯吡啶-3-基)恶唑-5-基)甲基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮
参考实施例25合成路线,获得实施例化合物44。得到黄色固体49.3mg,产率53%。1H NMR(500MHz,DMSO)δ11.10(s,1H),8.91(d,J=2.0Hz,1H),8.29(dd,J=8.4,2.5Hz,1H),7.69(d,J=8.4Hz,1H),7.62(dd,J=8.4,7.2Hz,1H),7.32(s,1H),7.29(d,J=8.6Hz,1H),7.16(t,J=6.3Hz,1H),7.10(d,J=7.1Hz,1H),5.07(dd,J=12.8,5.4Hz,1H),4.75(d,J=6.2Hz,2H),2.88(ddd,J=17.0,13.9,5.4Hz,1H),2.65–2.52(m,2H),2.03(ddd,J=10.5,5.4,3.1Hz,1H).13C NMR(126MHz,DMSO)δ172.82,170.07,168.64,167.22,157.37,151.58,150.94,146.91,145.52,136.60,136.19,132.21,126.17,124.97,122.54,117.72,111.41,110.16,48.59,36.94,30.97,22.12.UPLC-MS(ESI)理论值为C22H16ClN5O5[M+H]+:466.85,实测值:466.23.实施例45:2-(2,6-二氧哌啶-3-基)-4-((2-(苯基-d5)恶唑-5-基)甲基)氨基)异吲哚啉-1,3-二酮
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参考实施例22合成路线,获得实施例化合物45,黄色固体(110mg,69%)。1H NMR(400MHz,DMSO)δ11.10(s,1H),7.63(s,1H),7.30(d,J=7.4Hz,1H),7.23(s,1H),7.10(s,2H),5.07(d,J=8.0Hz,1H),4.74(s,2H),2.86(d,J=12.4Hz,1H),2.59(d,J=17.8Hz,2H),2.04(s,1H).UPLC-MS(ESI)理论值为C23H13D5N4O5[M+H]+:436.16,实测值:436.28.
实施例46:2-(2,6-二氧哌啶-3-基)-4-((2-(苯基-d5)噻唑-5-基)甲基)氨基)异吲哚-1,3-二酮
参考实施例32合成路线,获得实施例化合物46。以2-(苯基-d5)噻唑-5-甲醛(134mg,0.69mmol)和消旋的泊马度胺(188mg,0.69mmol)为原料获得实施例化合物46,经HPLC纯化得到黄色固体88mg,产率28%。1H NMR(600MHz,DMSO)δ11.11(s,1H),7.90(s,1H),7.59(t,J=7.8Hz,1H),7.33(t,J=6.2Hz,1H),7.22(d,J=8.6Hz,1H),7.07(d,J=7.1Hz,1H),5.07(dd,J=12.9,5.4Hz,1H),4.84(d,J=6.2Hz,2H),2.89(ddd,J=17.3,14.1,5.3Hz,1H),2.62–2.51(m,2H),2.07–2.01(m,1H).UPLC-MS(ESI)理论值为C23H13D5N4O4S[M+H]+:452.14,实测值:452.31.
实施例47:2-(2,6-二氧哌啶-3-基)-4-(5-(苯基-d5)-1,3,4-恶二唑-2-基)甲基)氨基)异吲哚-1,3-二酮
参考实施例32合成路线,获得实施例化合物47。
实施例48:2-(2,6-二氧代哌啶-3-基)-4-(((2-(4-(((S)-四氢呋喃-3-基)氧基)苯基)恶唑-5-基)甲基)氨基)异二氢吲哚-1,3-二酮
参考实施例22合成路线,获得实施例化合物48。得到黄色固体65.3mg,产率55%。1HNMR(500MHz,DMSO)δ11.08(s,1H),7.83(d,J=8.9Hz,2H),7.65–7.60(m,1H),7.30(d,J=8.6Hz,1H),7.17(s,1H),7.10(t,J=6.5Hz,2H),7.05(d,J=8.9Hz,2H),5.12–5.08(m,1H),5.06(dd,J=12.9,5.5Hz,1H),4.71(d,J=6.3Hz,2H),3.90(dd,J=10.2,4.5Hz,1H),3.84(dd,J=15.4,8.0Hz,1H),3.79(d,J=10.3Hz,1H),3.78–3.72(m,1H),2.93–2.83(m,1H),2.58(dt,J=18.0,9.6Hz,2H),2.25(td,J=14.3,8.1Hz,1H),2.06–2.00(m,1H),1.99–1.94(m,1H).13CNMR(126MHz,DMSO)δ172.77,170.02,168.66,167.20,160.35,158.89,149.12,145.61,136.11,132.18,127.48,125.53,119.65,117.72,115.78,111.30,110.05,77.40,72.20,66.39,48.57,36.90,32.40,30.95,22.09.UPLC-MS(ESI)理论值为C27H24N4O7[M+H]+:517.51,实测值:517.41.
实施例49:2-(2,6-二氧哌啶-3-基)-4-(2-(4-(oxetan-3-氧基)苯基)恶唑-5-基)甲基)氨基)异吲哚-1,3-二酮
参考实施例22合成路线,获得实施例化合物49。得到黄色固体14.3mg,产率23%。1HNMR(500MHz,DMSO)δ11.09(s,1H),7.83(d,J=8.9Hz,2H),7.62(dd,J=8.3,7.3Hz,1H),7.29(d,J=8.6Hz,1H),7.17(s,1H),7.10(t,J=6.0Hz,2H),6.92(d,J=8.9Hz,2H),5.37–5.30(m,1H),5.06(dd,J=12.8,5.4Hz,1H),4.94(t,J=6.8Hz,2H),4.71(d,J=6.2Hz,2H),4.55(dd,J=7.4,5.1Hz,2H),2.88(ddd,J=17.0,13.8,5.4Hz,1H),2.57(dt,J=12.8,9.4Hz,2H),2.02(ddd,J=7.4,5.2,2.7Hz,1H).UPLC-MS(ESI)理论值为C26H22N4O7[M+H]+:503.48,实测值:503.39.
实施例50:2-(2,6-二氧哌啶-3-基)-4-(2-(4-(2-羟基乙氧基)苯基)恶唑-5-基)甲基)氨基)异吲哚-1,3-二酮
参考实施例22合成路线,获得实施例化合物50。得到黄色固体47mg,产率37%。1HNMR(500MHz,DMSO)δ11.09(s,1H),7.83(d,J=8.9Hz,2H),7.62(dd,J=8.4,7.2Hz,1H),7.30(d,J=8.6Hz,1H),7.16(s,1H),7.09(d,J=7.0Hz,2H),7.06(d,J=8.9Hz,2H),5.06(dd,J=12.8,5.4Hz,1H),4.71(d,J=5.8Hz,2H),4.04(t,J=4.9Hz,2H),3.72(t,J=4.9Hz,2H),2.88(ddd,J=17.0,13.9,5.4Hz,1H),2.57(ddd,J=19.7,14.6,9.2Hz,2H),2.06–2.00(m,1H).13C NMR(126MHz,DMSO)δ172.82,170.07,168.68,167.23,160.46,160.44,149.06,145.62,136.14,132.20,127.43,125.54,119.46,117.74,115.05,111.31,110.04,69.75,59.44,48.58,36.91,30.97,22.11.UPLC-MS(ESI)理论值为C25H22N4O7[M+H]+:491.15,实测值:491.41.
实施例51:4-((2-(4-环丙氧基苯基)恶唑-5-基)甲基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮
参考实施例22合成路线,获得实施例化合物51。得到黄色固体82.3mg,产率45%。1HNMR(500MHz,DMSO)δ11.08(s,1H),7.85(d,J=8.9Hz,2H),7.63(dd,J=8.4,7.2Hz,1H),7.30(d,J=8.6Hz,1H),7.19–7.15(m,3H),7.09(d,J=7.0Hz,2H),5.06(dd,J=12.8,5.4Hz,1H),4.71(d,J=5.2Hz,2H),3.90(tt,J=6.0,2.9Hz,1H),2.88(ddd,J=17.1,13.9,5.4Hz,1H),2.65–2.51(m,2H),2.06–1.99(m,1H),0.84–0.78(m,2H),0.70–0.65(m,2H).13CNMR(126MHz,DMSO)δ172.82,170.06,168.68,167.23,160.41,160.40,149.15,145.62,136.14,132.19,127.38,125.55,119.95,117.75,115.50,111.32,110.05,51.06,48.58,36.92,30.97,22.11,5.94.UPLC-MS(ESI)理论值为C26H22N4O6[M+H]+:487.48,实测值:487.39.
实施例52:2-(2,6-二氧哌啶-3-基)-4-(2-(4-(2-甲氧基乙氧基)苯基)恶唑-5-基)甲基)氨基)异吲哚-1,3-二酮
参考实施例22合成路线,获得实施例化合物52。得到黄色固体72.4mg,收率59%;1H NMR(600MHz,DMSO)δ11.10(s,1H),7.83(d,J=8.9Hz,2H),7.62(dd,J=8.5,7.2Hz,1H),7.30(d,J=8.6Hz,1H),7.16(s,1H),7.13–7.03(m,4H),5.06(dd,J=12.9,5.4Hz,1H),4.71(d,J=5.6Hz,2H),4.16–4.12(m,2H),3.69–3.64(m,2H),3.30(s,3H),2.88(ddd,J=17.1,13.9,5.4Hz,1H),2.59(dd,J=17.2,2.4Hz,1H),2.56–2.51(m,1H),2.03(ddd,J=10.4,5.4,3.0Hz,1H).13CNMR(151MHz,DMSO)δ172.86,170.09,168.71,167.26,160.45,160.26,149.12,145.65,136.18,132.22,127.47,125.57,119.61,117.77,115.06,111.36,110.07,70.25,67.16,58.20,48.61,36.93,30.99,22.14.UPLC-MS(ESI)理论值为C26H24N4O7[M+H]+:505.50,实测值:505.41.
实施例53:2-(2,6-二氧哌啶-3-基)-4-(2-(4-(四氢-2H-吡喃-4-基)氧基)苯基)恶唑-5-基)甲基)氨基)异吲哚-1,3-二酮
参考实施例22合成路线,获得实施例化合物53。得到黄色固体70mg,产率60%。1HNMR(500MHz,DMSO)δ11.09(s,1H),7.82(d,J=8.8Hz,2H),7.62(dd,J=8.4,7.3Hz,1H),7.29(d,J=8.6Hz,1H),7.16(s,1H),7.12–7.06(m,4H),5.06(dd,J=12.8,5.4Hz,1H),4.71(d,J=4.6Hz,2H),4.68–4.62(m,1H),3.85(dt,J=11.4,4.3Hz,2H),3.51–3.47(m,2H),2.88(ddd,J=17.1,13.9,5.4Hz,1H),2.59(dd,J=17.7,1.9Hz,1H),2.53(d,J=4.4Hz,1H),2.05–2.00(m,1H),2.00–1.95(m,2H),1.64–1.53(m,2H).13C NMR(126MHz,DMSO)δ172.82,170.06,168.70,167.24,160.44,158.76,149.09,145.64,136.15,132.20,127.51,125.54,119.54,117.75,116.14,111.34,110.07,71.55,64.51,48.61,36.93,31.66,30.98,22.13.UPLC-MS(ESI)理论值为C28H26N4O7[M+H]+:531.54,实测值:531.40.
实施例54:2-(2,6-二氧哌啶-3-基)-4-(2-(4-((R)-四氢呋喃-3-基)氧基)苯基)恶唑-5-基)甲基)氨基)异吲哚-1,3-二酮
参考实施例22合成路线,获得实施例化合物54。得到黄色固体77.5mg,产率65%。1HNMR(600MHz,DMSO)δ11.10(s,1H),7.83(d,J=8.9Hz,2H),7.62(dd,J=8.5,7.1Hz,1H),7.30(d,J=8.6Hz,1H),7.17(s,1H),7.10(dd,J=10.4,6.4Hz,2H),7.05(d,J=8.9Hz,2H),5.10–5.08(m,1H),5.08–5.04(m,1H),4.71(d,J=5.4Hz,2H),3.89(dd,J=10.2,4.5Hz,1H),3.84(dd,J=15.3,8.1Hz,1H),3.79(d,J=10.2Hz,1H),3.75(td,J=8.4,4.6Hz,1H),2.88(ddd,J=17.1,13.9,5.4Hz,1H),2.62–2.56(m,1H),2.53(ddd,J=9.8,6.7,3.2Hz,1H),2.25(dtd,J=14.4,8.2,6.3Hz,1H),2.06–2.00(m,1H),1.96(dt,J=12.1,5.7Hz,1H).13C NMR(151MHz,DMSO)δ172.86,170.10,168.72,167.26,160.40,158.93,149.16,145.65,136.18,132.22,127.54,125.58,119.68,117.77,115.83,111.36,110.07,77.44,72.25,66.45,48.61,36.93,32.45,30.99,22.14.UPLC-MS(ESI)理论值为C27H26N4O6[M+H]+:517.51,实测值:517.26.
实施例55:2-(2,6-二氧哌啶-3-基)-4-(2-(3-(三氟甲氧基)苯基)恶唑-5-基)甲基)氨基)异吲哚-1,3-二酮
参考实施例22合成路线,获得实施例化合物55。得到黄色固体64.4mg,产率64%。1HNMR(500MHz,DMSO)δ11.08(s,1H),7.94(d,J=7.9Hz,1H),7.79(s,1H),7.68(t,J=8.0Hz,1H),7.62(dd,J=8.4,7.3Hz,1H),7.53(d,J=8.3Hz,1H),7.30(d,J=8.6Hz,1H),7.29(s,1H),7.15(t,J=6.1Hz,1H),7.10(d,J=7.1Hz,1H),5.06(dd,J=12.7,5.4Hz,1H),4.75(d,J=5.6Hz,2H),2.88(ddd,J=17.0,13.9,5.4Hz,1H),2.64–2.52(m,2H),2.03(ddd,J=10.4,5.4,3.2Hz,1H).13C NMR(126MHz,DMSO)δ172.77,170.02,168.63,167.19,158.80,150.65,148.74,145.55,136.11,132.19,131.62,128.82,126.03,124.68,122.97,117.73,111.37,110.15,48.58,36.95,30.95,22.09.UPLC-MS(ESI)理论值为C24H17F3N4O6[M+H]+:515.42,实测值:515.33.
实施例56:2-(2,6-二氧哌啶-3-基)-4-(2-(2-(三氟甲氧基)苯基)恶唑-5-基)甲基)氨基)异吲哚-1,3-二酮
参考实施例22合成路线,获得实施例化合物56。得到黄色固体66.4mg,产率66%。1HNMR(500MHz,DMSO)δ11.08(s,1H),8.04(dd,J=7.8,1.6Hz,1H),7.65(td,J=8.0,1.6Hz,1H),7.62–7.58(m,1H),7.58–7.51(m,2H),7.33(s,1H),7.26(d,J=8.6Hz,1H),7.12(d,J=6.3Hz,1H),7.09(d,J=7.1Hz,1H),5.07(dd,J=12.7,5.4Hz,1H),4.75(d,J=6.3Hz,2H),2.89(ddd,J=17.0,13.8,5.4Hz,1H),2.64–2.51(m,2H),2.02(ddd,J=7.4,5.4,2.7Hz,1H).13CNMR(126MHz,DMSO)δ172.76,169.98,168.61,167.21,156.80,150.52,145.53,144.89,136.09,132.28,132.16,129.96,128.30,125.92,122.96,120.82,117.55,111.33,110.12,48.56,36.88,30.94,22.10.UPLC-MS(ESI)理论值为C24H17F3N4O6[M+H]+:515.42,实测值:515.34.
实施例57:2-(2,6-二氧哌啶-3-基)-4-(2-(4-(三氟甲基)苯基)恶唑-5-基)甲基)氨基)异吲哚-1,3-二酮
参考实施例22合成路线,获得实施例化合物57。得到黄色固体46.5mg,产率37%。1HNMR(500MHz,DMSO)δ11.11(s,1H),8.11(d,J=8.0Hz,2H),7.89(d,J=7.9Hz,2H),7.62(t,J=7.7Hz,1H),7.32(s,1H),7.30(d,J=8.6Hz,1H),7.17(t,J=5.9Hz,1H),7.10(d,J=6.9Hz,1H),5.06(dd,J=12.8,5.0Hz,1H),4.76(d,J=5.5Hz,2H),2.92–2.83(m,1H),2.65–2.53(m,2H),2.07–1.99(m,1H).13C NMR(151MHz,DMSO)δ172.88,170.11,168.69,167.27,159.06,150.94,145.59,136.25,132.25,130.40,130.15,126.47,126.30,126.26,124.86,123.06,117.76,111.47,110.18,48.63,37.02,31.00,22.16.UPLC-MS(ESI)理论值为C24H17F3N4O5[M+H]+:499.42,实测值:499.35.
实施例58:2-(2,6-二氧哌啶-3-基)-4-(2-(3-(三氟甲基)苯基)恶唑-5-基)甲基)氨基)异吲哚-1,3-二酮
参考实施例22合成路线,获得实施例化合物58。得到黄色固体58.9mg,产率57%。1HNMR(500MHz,DMSO)δ11.08(s,1H),8.20(d,J=7.8Hz,1H),8.15(s,1H),7.89(d,J=7.9Hz,1H),7.78(t,J=7.8Hz,1H),7.62(dd,J=8.3,7.3Hz,1H),7.31(t,J=4.3Hz,2H),7.17(t,J=6.2Hz,1H),7.10(d,J=7.1Hz,1H),5.07(dd,J=12.7,5.4Hz,1H),4.76(d,J=6.1Hz,2H),2.88(ddd,J=16.9,14.3,5.4Hz,1H),2.65–2.52(m,2H),2.06–2.00(m,1H).13CNMR(126MHz,DMSO)δ172.77,170.02,168.62,167.19,158.88,150.70,145.54,136.10,132.20,130.65,129.52,127.73,126.98,126.07,124.83,122.66,121.92,121.89,117.74,111.37,110.16,48.58,36.96,30.95,22.10.UPLC-MS(ESI)理论值为C24H17F3N4O5[M+H]+:499.42,实测值:499.18.
实施例59:2-(2,6-二氧哌啶-3-基)-4-(2-(2-(三氟甲基)苯基)恶唑-5-基)甲基)氨基)异吲哚-1,3-二酮
参考实施例22合成路线,获得实施例化合物59。得到黄色固体42.6mg,产率45%。1HNMR(500MHz,DMSO)δ11.08(s,1H),7.97(d,J=7.7Hz,1H),7.91(d,J=7.8Hz,1H),7.82(t,J=7.5Hz,1H),7.75(t,J=7.6Hz,1H),7.63–7.58(m,1H),7.32(s,1H),7.25(d,J=8.6Hz,1H),7.10(t,J=6.7Hz,2H),5.07(dd,J=12.7,5.4Hz,1H),4.75(d,J=6.0Hz,2H),2.89(ddd,J=16.9,13.8,5.3Hz,1H),2.65–2.52(m,2H),2.06–1.99(m,1H).13C NMR(126MHz,DMSO)δ172.81,170.03,168.63,167.23,158.02,151.05,145.58,136.10,132.93,132.16,131.30,131.05,127.08,127.03,126.99,126.95,125.90,117.71,111.38,110.15,48.57,36.87,30.96,22.12.UPLC-MS(ESI)理论值为C24H17F3N4O5[M+H]+:499.42,实测值:499.34.
实施例60:2-(2,6-二氧哌啶-3-基)-4-(5-(4-(三氟甲基)苯基)恶唑-2-基)甲基)氨基)异吲哚-1,3-二酮
参考实施例24合成路线,获得实施例化合物60。得到黄色固体17.6mg,产率17%。1HNMR(500MHz,DMSO)δ11.10(s,1H),7.88(d,J=8.4Hz,2H),7.83(t,J=4.2Hz,3H),7.61(dd,J=8.1,7.5Hz,1H),7.25(d,J=6.1Hz,1H),7.22(d,J=8.6Hz,1H),7.11(d,J=7.1Hz,1H),5.08(dd,J=12.8,5.4Hz,1H),4.83(d,J=6.2Hz,2H),2.94–2.85(m,1H),2.63–2.58(m,1H),2.57–2.51(m,1H),2.06–2.01(m,1H).13C NMR(126MHz,DMSO)δ172.78,170.03,168.65,167.21,162.01,149.46,145.71,136.16,132.10,131.09,130.09,128.43,128.17,126.14,126.11,125.11,124.81,124.34,122.95,117.84,111.50,110.19,48.62,30.97,22.11.UPLC-MS(ESI)理论值为C24H17F3N4O5[M+H]+:499.42,实测值:499.35.
实施例61:2-(2,6-二氧哌啶-3-基)-4-(5-(3-(三氟甲基)苯基)恶唑-2-基)甲基)氨基)异吲哚-1,3-二酮
参考实施例24合成路线,获得实施例化合物61。得到黄色固体54.6mg,产率53%。1HNMR(500MHz,DMSO)δ11.10(s,1H),7.99(s,1H),7.96(dd,J=4.2,3.1Hz,1H),7.84(s,1H),7.74–7.70(m,2H),7.64–7.59(m,1H),7.24(dd,J=12.9,7.4Hz,2H),7.11(d,J=7.0Hz,1H),5.08(dd,J=12.8,5.4Hz,1H),4.82(d,J=6.3Hz,2H),2.89(ddd,J=16.9,13.8,5.2Hz,1H),2.60(dd,J=15.0,3.3Hz,1H),2.54(dd,J=13.5,4.4Hz,1H),2.04(ddd,J=12.4,5.3,2.2Hz,1H).13CNMR(126MHz,DMSO)δ172.77,170.01,168.64,167.20,161.66,149.36,145.71,136.12,132.09,130.39,128.39,127.56,124.85,124.20,120.21,120.18,117.88,111.48,110.18,48.61,30.96,22.10.UPLC-MS(ESI)理论值为C24H17F3N4O5[M+H]+:499.42,实测值:499.31.
实施例62:2-(2,6-二氧哌啶-3-基)-4-(5-(2-(三氟甲基)苯基)恶唑-2-基)甲基)氨基)异吲哚-1,3-二酮
参考实施例24合成路线,获得实施例化合物62。得到黄色固体20.6mg,产率20%。1HNMR(500MHz,DMSO)δ11.09(s,1H),7.88(d,J=7.9Hz,1H),7.81–7.76(m,2H),7.66(dd,J=10.9,5.1Hz,1H),7.62–7.57(m,1H),7.43(s,1H),7.23(t,J=6.3Hz,1H),7.19(d,J=8.6Hz,1H),7.11(d,J=7.0Hz,1H),5.08(dd,J=12.7,5.4Hz,1H),4.82(d,J=6.3Hz,2H),2.89(ddd,J=16.6,13.7,5.3Hz,1H),2.60(d,J=18.4Hz,1H),2.56–2.51(m,1H),2.07–2.01(m,1H).13CNMR(126MHz,DMSO)δ172.77,169.99,168.62,167.21,162.06,147.66,145.71,136.09,132.97,132.07,130.39,129.73,126.86,126.81,126.77,126.72,126.10,126.08,125.46,124.70,122.53,117.77,111.47,110.21,48.59,30.95,22.11.UPLC-MS(ESI)理论值为C24H17F3N4O5[M+H]+:499.42,实测值:499.24.
实施例63:4-((2-(3-氯苯基)恶唑-5-基)甲基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮
参考实施例22合成路线,获得实施例化合物63。得到黄色固体76.1mg,产率68%.1H NMR(500MHz,DMSO)δ11.08(s,1H),7.89(d,J=1.7Hz,1H),7.87(dt,J=7.0,1.5Hz,1H),7.63(dd,J=8.4,7.2Hz,1H),7.60–7.55(m,2H),7.30(d,J=8.6Hz,1H),7.28(s,1H),7.15(t,J=5.9Hz,1H),7.10(d,J=7.1Hz,1H),5.07(dd,J=12.7,5.4Hz,1H),4.74(d,J=4.8Hz,2H),2.88(ddd,J=16.9,13.9,5.4Hz,1H),2.61(ddd,J=33.5,17.4,7.5Hz,2H),2.03(ddd,J=12.1,6.2,3.9Hz,1H).13C NMR(126MHz,DMSO)δ172.77,170.02,168.63,167.20,158.90,150.48,145.54,136.13,133.84,132.20,131.26,130.33,128.69,126.00,125.18,124.29,117.72,111.37,110.14,48.58,36.95,30.95,22.10.UPLC-MS(ESI)理论值为C23H17ClN4O5[M+H]+:465.86,实测值:465.31.
实施例64:4-((5-(4-氯苯基)恶唑-2-基)甲基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮
参考实施例24合成路线,获得实施例化合物64。得到黄色固体10.2mg,产率9%。1HNMR(500MHz,DMSO)δ11.10(s,1H),7.68(d,J=8.7Hz,2H),7.67(s,1H),7.63–7.59(m,1H),7.53(d,J=8.6Hz,2H),7.25–7.20(m,2H),7.11(d,J=7.0Hz,1H),5.08(dd,J=12.7,5.4Hz,1H),4.80(d,J=6.3Hz,2H),2.89(ddd,J=16.7,13.6,5.3Hz,1H),2.57(ddd,J=18.0,13.9,3.5Hz,2H),2.04(ddd,J=12.8,5.6,2.3Hz,1H).13C NMR(126MHz,DMSO)δ172.78,170.02,168.65,167.21,161.23,149.82,145.72,136.15,132.87,132.09,129.20,126.25,125.53,123.19,117.83,111.47,110.16,48.61,30.96,22.10.UPLC-MS(ESI)理论值为C23H17ClN4O5[M+H]+:465.86,实测值:465.29.
实施例65:4-((5-(3-氯苯基)恶唑-2-基)甲基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮
参考实施例24合成路线,获得实施例化合物65。得到黄色固体5.1mg,产率5%。1HNMR(500MHz,DMSO)δ11.10(s,1H),7.76–7.73(m,2H),7.63–7.60(m,2H),7.49(t,J=7.9Hz,1H),7.42(dd,J=8.0,1.0Hz,1H),7.23(dd,J=11.1,7.4Hz,2H),7.11(d,J=7.1Hz,1H),5.08(dd,J=12.8,5.4Hz,1H),4.80(d,J=6.2Hz,2H),2.95–2.83(m,1H),2.60(dd,J=14.8,3.5Hz,1H),2.57–2.52(m,1H),2.08–2.01(m,1H).13C NMR(126MHz,DMSO)δ172.78,170.02,168.64,167.21,161.48,149.39,145.70,136.14,133.88,132.09,131.10,129.33,128.20,123.88,123.42,122.30,117.85,111.47,110.17,48.61,30.96,22.10.UPLC-MS(ESI)理论值为C23H17ClN4O5[M+H]+:465.86,实测值:465.28.
实施例66:4-((5-(2-氯苯基)恶唑-2-基)甲基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮
参考实施例24合成路线,获得实施例化合物66。得到黄色固体21.6mg,产率19%。1HNMR(500MHz,DMSO)δ11.10(s,1H),7.74(dd,J=7.8,1.5Hz,1H),7.72(s,1H),7.64–7.60(m,1H),7.59(d,J=1.0Hz,1H),7.48(td,J=7.7,1.2Hz,1H),7.40(td,J=7.8,1.6Hz,1H),7.26(d,J=6.3Hz,1H),7.22(s,1H),7.11(d,J=7.1Hz,1H),5.08(dd,J=12.8,5.4Hz,1H),4.83(d,J=6.3Hz,2H),2.89(ddd,J=16.7,13.7,5.2Hz,1H),2.63–2.57(m,1H),2.57–2.52(m,1H),2.06–2.02(m,1H).13C NMR(126MHz,DMSO)δ172.77,170.02,168.64,167.21,161.28,147.37,145.73,136.15,132.09,130.67,129.88,129.44,127.80,126.61,125.87,117.88,111.49,110.20,48.61,30.96,22.10.UPLC-MS(ESI)理论值为C23H17ClN4O5[M+H]+:465.86,实测值:465.32.
实施例67:4-((2-(4-氯苯基)噻唑-5-基)甲基)氨基)-2-(2,6-二氧卟啉-3-基)异吲哚-1,3-二酮
参考实施例32合成路线,获得实施例化合物67。
实施例68:4-((2-(3-氯苯基)噻唑-5-基)甲基)氨基)-2-(2,6-二氧卟啉-3-基)异吲哚-1,3-二酮
参考实施例32合成路线,获得实施例化合物68。得到黄色固体10.8mg,产率55%。1HNMR(500MHz,DMSO)δ11.09(s,1H),7.94(s,1H),7.90(d,J=1.7Hz,1H),7.85–7.81(m,1H),7.62–7.56(m,1H),7.54–7.46(m,2H),7.35(t,J=6.3Hz,1H),7.22(d,J=8.6Hz,1H),7.08(d,J=7.1Hz,1H),5.07(dd,J=12.7,5.4Hz,1H),4.86(d,J=6.3Hz,2H),2.89(ddd,J=17.1,13.8,5.4Hz,1H),2.64–2.52(m,2H),2.04(ddd,J=17.4,7.8,4.8Hz,1H).13C NMR(126MHz,DMSO)δ172.78,170.05,168.57,167.19,164.75,145.30,142.13,138.95,136.20,134.94,133.91,132.28,131.15,129.82,125.20,124.77,117.61,111.30,110.11,48.59,38.45,30.96,22.11.UPLC-MS(ESI)理论值为C23H17ClN4O4S[M+H]+:481.92,实测值:481.15.
实施例69:4-((2-(2-氯苯基)噻唑-5-基)甲基)氨基)-2-(2,6-二氧卟啉-3-基)异吲哚-1,3-二酮
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参考实施例32合成路线,获得实施例化合物69。得到黄色固体20.3mg,产率12%。1HNMR(500MHz,DMSO)δ11.09(s,1H),8.18–8.11(m,1H),8.01(s,1H),7.61(ddd,J=12.4,6.5,5.1Hz,2H),7.50–7.44(m,2H),7.35(t,J=6.2Hz,1H),7.24(d,J=8.6Hz,1H),7.08(d,J=7.0Hz,1H),5.07(dd,J=12.7,5.4Hz,1H),4.88(d,J=5.9Hz,2H),2.89(ddd,J=16.9,13.8,5.4Hz,1H),2.64–2.53(m,2H),2.07–1.99(m,1H).13C NMR(126MHz,DMSO)δ172.78,170.05,168.58,167.20,161.71,145.36,140.97,139.38,136.20,132.30,131.25,131.03,130.72,130.47,130.42,127.71,117.61,111.27,110.08,48.59,38.31,30.96,22.10.UPLC-MS(ESI)理论值为C23H17ClN4O4S[M+H]+:481.92,实测值:481.14.
实施例70:2-(2,6-二氧哌啶-3-基)-4-((2-(3-氟苯基)恶唑-5-基)甲基)氨基)异吲哚-1,3-二酮
参考实施例22合成路线,获得实施例化合物70。得到黄色固体79.1mg,产率73%。1HNMR(500MHz,DMSO)δ11.09(s,1H),7.76(d,J=7.8Hz,1H),7.67–7.61(m,2H),7.58(td,J=8.0,6.0Hz,1H),7.36(td,J=8.4,2.1Hz,1H),7.30(d,J=8.6Hz,1H),7.27(s,1H),7.14(t,J=5.9Hz,1H),7.10(d,J=7.1Hz,1H),5.07(dd,J=12.7,5.4Hz,1H),4.74(d,J=5.5Hz,2H),2.88(ddd,J=16.9,13.8,5.3Hz,1H),2.58(dt,J=17.7,9.4Hz,2H),2.03(ddd,J=10.8,5.6,3.3Hz,1H).13C NMR(126MHz,DMSO)δ172.77,170.02,168.63,167.19,163.25,161.31,159.13,159.11,150.40,145.55,136.14,132.19,131.57,131.50,128.93,128.86,125.96,121.87,117.71,117.53,117.36,112.39,112.20,111.37,110.13,48.58,36.94,30.95,22.10.UPLC-MS(ESI)理论值为C23H17FN4O5[M+H]+:449.41,实测值:449.32.
实施例71:2-(2,6-二氧哌啶-3-基)-4-((2-(2-氟苯基)恶唑-5-基)甲基)氨基)异吲哚-1,3-二酮
参考实施例22合成路线,获得实施例化合物71。得到黄色固体54.6mg,产率51%。1HNMR(500MHz,DMSO)δ11.08(s,1H),7.95(td,J=7.7,1.6Hz,1H),7.62(dd,J=8.4,7.3Hz,1H),7.56(tdd,J=7.1,5.1,1.7Hz,1H),7.42–7.37(m,1H),7.35(dd,J=11.2,3.9Hz,1H),7.29(t,J=4.3Hz,2H),7.13(t,J=5.8Hz,1H),7.10(d,J=7.1Hz,1H),5.06(dd,J=12.7,5.4Hz,1H),4.75(d,J=4.9Hz,2H),2.88(ddd,J=17.0,13.8,5.4Hz,1H),2.65–2.53(m,2H),2.03(ddd,J=7.2,5.3,2.5Hz,1H).13C NMR(126MHz,DMSO)δ172.77,170.02,168.64,167.20,159.99,157.96,156.70,150.24,145.56,136.12,132.65,132.58,132.17,129.19,125.72,125.03,117.72,117.06,116.89,114.98,114.89,111.35,110.09,48.57,36.91,30.95,22.09.UPLC-MS(ESI)理论值为C23H17FN4O5[M+H]+:449.41,实测值:449.27.
实施例72:2-(2,6-二氧哌啶-3-基)-4-((5-(4-氟苯基)恶唑-2-基)甲基)氨基)异吲哚-1,3-二酮
参考实施例24合成路线,获得实施例化合物72。得到黄色固体10.5mg,产率10%。1HNMR(500MHz,DMSO)δ11.10(s,1H),7.73–7.68(m,2H),7.61(dd,J=8.4,7.3Hz,1H),7.59(s,1H),7.31(t,J=8.9Hz,2H),7.22(t,J=6.7Hz,2H),7.11(d,J=7.1Hz,1H),5.08(dd,J=12.7,5.4Hz,1H),4.79(d,J=6.1Hz,2H),2.89(ddd,J=16.8,13.8,5.2Hz,1H),2.64–2.52(m,2H),2.07–2.02(m,1H).13C NMR(126MHz,DMSO)δ172.78,170.03,168.66,167.21,162.90,160.94,160.89,150.03,145.73,136.15,132.09,126.12,126.06,124.08,124.05,122.31,117.83,116.28,116.11,111.46,110.15,48.61,30.97,22.11.UPLC-MS(ESI)理论值为C23H17FN4O5[M+H]+:449.41,实测值:449.38.
实施例73:4-((2-(3,4-二氯苯基)恶唑-5-基)甲基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮
参考实施例22合成路线,获得实施例化合物73。得到黄色固体77mg,产率62%。1HNMR(500MHz,DMSO)δ11.11(s,1H),8.06(d,J=1.9Hz,1H),7.86(dd,J=8.4,2.0Hz,1H),7.80(d,J=8.4Hz,1H),7.65–7.60(m,1H),7.31-7.26(m,2H),7.16(t,J=6.3Hz,1H),7.10(d,J=7.0Hz,1H),5.06(dd,J=12.8,5.4Hz,1H),4.74(d,J=6.1Hz,2H),2.88(ddd,J=17.3,14.0,5.5Hz,1H),2.64–2.53(m,2H),2.02(ddd,J=7.7,6.4,2.1Hz,1H).13C NMR(151MHz,DMSO)δ172.87,170.11,168.68,167.26,158.27,150.80,145.56,136.22,133.19,132.25,132.09,131.70,127.28,127.24,126.22,125.79,117.76,111.46,110.19,48.63,36.98,31.00,22.16.UPLC-MS(ESI)理论值为C23H16Cl2N4O5[M+H]+:499.05实测值:499.25.
实施例74:4-((2-(2,3-二氯苯基)恶唑-5-基)甲基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮
参考实施例22合成路线,获得实施例化合物74。得到黄色固体64.8mg,产率63%。1HNMR(500MHz,DMSO)δ11.08(s,1H),7.89(dd,J=7.9,1.5Hz,1H),7.81(dd,J=8.1,1.5Hz,1H),7.62(dd,J=8.4,7.3Hz,1H),7.51(t,J=8.0Hz,1H),7.34(s,1H),7.30(d,J=8.6Hz,1H),7.14(t,J=6.3Hz,1H),7.10(d,J=7.1Hz,1H),5.07(dd,J=12.7,5.4Hz,1H),4.77(d,J=6.0Hz,2H),2.88(ddd,J=17.0,13.8,5.4Hz,1H),2.58(dt,J=17.9,9.3Hz,2H),2.06–2.00(m,1H).13CNMR(126MHz,DMSO)δ172.77,170.01,168.63,167.19,157.45,150.77,145.56,136.13,133.48,132.28,132.16,129.55,129.31,128.63,127.94,125.73,117.83,111.39,110.14,48.58,36.89,30.95,22.10.UPLC-MS(ESI)理论值为C26H24N4O7[M+H]+:499.05,实测值:499.12.
实施例75:4-((2-(3,5-二氯苯基)恶唑-5-基)甲基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮
参考实施例22合成路线,获得实施例化合物75。得到黄色固体47.2mg,产率38%。1HNMR(500MHz,DMSO)δ11.11(s,1H),7.86(d,J=1.9Hz,2H),7.79(t,J=1.9Hz,1H),7.62(dd,J=8.4,7.3Hz,1H),7.31(s,1H),7.29(d,J=8.6Hz,1H),7.17(t,J=6.3Hz,1H),7.10(d,J=7.1Hz,1H),5.06(dd,J=12.7,5.4Hz,1H),4.74(d,J=6.1Hz,2H),2.88(ddd,J=17.0,14.1,5.5Hz,1H),2.65–2.59(m,1H),2.56(dd,J=13.2,8.2Hz,1H),2.03(ddd,J=10.4,5.5,3.1Hz,1H).13C NMR(151MHz,DMSO)δ172.87,170.11,168.67,167.26,157.76,151.12,145.54,136.21,135.07,132.26,129.91,129.87,126.31,124.15,117.78,111.47,110.22,48.63,36.98,31.00,22.16.UPLC-MS(ESI)理论值为C23H16Cl2N4O5[M+H]+:499.05,实测值:499.28.
实施例76:4-((2-(2,4-二氯苯基)恶唑-5-基)甲基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮
参考实施例22合成路线,获得实施例化合物76。得到黄色固体55.5mg,产率45%。1HNMR(500MHz,DMSO)δ11.11(s,1H),7.94(d,J=8.5Hz,1H),7.80(d,J=2.1Hz,1H),7.63-7.54(m,2H),7.32(s,1H),7.30(d,J=8.6Hz,1H),7.14(t,J=6.5Hz,1H),7.10(d,J=7.1Hz,1H),5.06(dd,J=12.8,5.5Hz,1H),5.06(dd,J=12.8,5.5Hz,1H),4.75(d,J=6.3Hz,2H),2.88(ddd,J=17.0,13.9,5.4Hz,1H),2.64–2.52(m,2H),2.05–2.00(m,1H).13CNMR(151MHz,DMSO)δ172.87,170.09,168.69,167.27,157.34,150.69,145.62,136.20,135.64,132.20,132.04,131.90,130.69,128.02,125.83,124.58,117.91,111.46,110.17,48.63,36.92,31.00,22.16.UPLC-MS(ESI)理论值为C23H16Cl2N4O5[M+H]+:499.05,实测值:499.13.
实施例77:4-((2-(2,5-二氯苯基)恶唑-5-基)甲基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮
参考实施例22合成路线,获得实施例化合物77。得到黄色固体53.1mg,产率51%。1HNMR(500MHz,DMSO)δ11.08(s,1H),7.95(d,J=2.5Hz,1H),7.65(d,J=8.6Hz,1H),7.63–7.58(m,2H),7.34(s,1H),7.30(d,J=8.6Hz,1H),7.15(t,J=6.4Hz,1H),7.10(d,J=7.1Hz,1H),5.06(dd,J=12.7,5.4Hz,1H),4.76(d,J=6.2Hz,2H),2.88(ddd,J=17.0,13.9,5.4Hz,1H),2.62–2.53(m,2H),2.06–2.00(m,1H).13C NMR(126MHz,DMSO)δ172.77,170.01,168.62,167.20,156.79,150.90,145.56,136.09,132.93,132.16,132.08,131.44,129.81,129.72,127.03,125.83,117.87,111.39,110.17,48.58,36.88,30.95,22.10.UPLC-MS(ESI)理论值为C23H16Cl2N4O5[M+H]+:499.05,实测值:499.29.
实施例78:4-((2-(2,6-二氯苯基)恶唑-5-基)甲基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮
参考实施例22合成路线,获得实施例化合物78。
实施例79:4-(((2-(((2R,6S)-2,6-二甲基吗啉)甲基)恶唑-5-基)甲基)氨基)-2-(2,6-二氧代哌啶-3-基)异二氢吲哚-1,3-二酮
将化合物2-(((2R,6S)-2,6-二甲基吗啉代)甲基)噁唑-5-甲醛(30mg,0.1338mmol),泊马度胺(37mg,0.1338mmol)溶于3mL醋酸中,135℃回流过夜,冷却至室温加入硼氢化钠(10mg,0.2675mmol),室温反应1小时,反应完全后,冰浴条件下加水淬灭,减压浓缩,浓缩物用乙酸乙酯溶解,水洗3次,依次用饱和碳酸氢钠水溶液,饱和氯化钠水溶液洗涤,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩;UPLC-MS(ESI)理论值为C24H27N5O6[M+H]+:482.51,实测值:482.20.1H NMR(500MHz,DMSO)δ11.08(s,1H),7.61–7.56(m,1H),7.20(d,J=8.6Hz,1H),7.08(d,J=7.1Hz,1H),7.06–7.02(m,2H),5.06(dd,J=12.8,5.4Hz,1H),4.64(d,J=6.3Hz,2H),3.58(s,2H),3.49(dd,J=13.8,6.6Hz,2H),2.88(ddd,J=17.2,13.9,5.4Hz,1H),2.63(d,J=11.5Hz,2H),2.61–2.51(m,2H),2.05–1.99(m,1H),1.70(td,J=10.7,4.9Hz,2H),0.97(dd,J=6.2,1.9Hz,6H).13C NMR(126MHz,DMSO)δ172.81,170.04,168.66,167.21,160.26,149.55,145.53,136.09,132.16,124.27,117.66,111.26,109.97,70.82,58.15,53.54,48.58,36.74,30.97,22.12,18.86.
实施例80:2-(2,6-二氧哌啶-3-基)-4-((2-((3-吗啉偶氮-1-基)甲基)恶唑-5-基)甲基)氨基)异吲哚-1,3-二酮
参考实施例79合成路线,获得实施例化合物80。得到黄色固体16.8mg,产率6%。1HNMR(500MHz,DMSO)δ11.09(s,1H),7.59(dd,J=8.3,7.4Hz,1H),7.21(d,J=8.6Hz,1H),7.07(d,J=7.0Hz,1H),7.03(t,J=6.4Hz,1H),7.01(s,1H),5.05(dd,J=12.8,5.4Hz,1H),4.62(d,J=6.3Hz,2H),3.61(s,2H),3.54–3.50(m,4H),3.44–3.37(m,2H),2.93(t,J=6.9Hz,2H),2.91–2.85(m,1H),2.83(dd,J=12.9,6.4Hz,1H),2.62–2.56(m,1H),2.56–2.51(m,1H),2.17(s,4H),2.05–1.98(m,1H).13C NMR(126MHz,DMSO)δ172.81,170.03,168.69,167.22,160.53,149.42,145.60,136.11,132.17,124.17,117.67,111.28,109.99,65.86,57.83,55.11,53.79,49.65,48.60,36.71,30.98,22.13.UPLC-MS(ESI)理论值为C25H28N6O6[M+H]+:509.54,实测值:509.85.
实施例81:4-(4-(5-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)甲基)恶唑-2-基)甲基)哌嗪-1-基)-3-氟苯甲腈
参考实施例79合成路线,获得实施例化合物81。得到黄色固体48mg,产率19%。1HNMR(500MHz,DMSO)δ11.09(s,1H),7.66(dd,J=13.4,1.9Hz,1H),7.58(dd,J=8.3,7.4Hz,1H),7.55(dd,J=8.5,1.7Hz,1H),7.20(d,J=8.6Hz,1H),7.11–7.03(m,4H),5.05(dd,J=12.8,5.4Hz,1H),4.65(d,J=6.3Hz,2H),3.67(s,2H),3.16–3.09(m,4H),2.88(ddd,J=17.1,13.9,5.4Hz,1H),2.60(d,J=2.7Hz,1H),2.58–2.55(m,4H),2.52(d,J=4.5Hz,1H),2.05–1.96(m,1H).13C NMR(126MHz,DMSO)δ172.81,170.06,168.66,167.20,160.32,154.11,152.15,149.60,145.56,143.75,143.69,136.10,132.17,129.89,129.87,124.29,119.79,119.59,119.44,119.42,118.40,117.68,111.28,110.02,102.30,102.22,53.58,51.80,49.04,48.58,36.82,30.97,22.12.UPLC-MS(ESI)理论值为C29H26FN7O5[M+H]+:572.57,实测值:572.61.
实施例82:2-(2,6-二氧哌啶-3-基)-4-(2-(吗啉甲基)恶唑-5-基)甲基)氨基)异吲哚-1,3-二酮
参考实施例79合成路线,获得实施例化合物82。得到黄色固体5.4mg,产率7%。1HNMR(600MHz,DMSO)δ11.10(s,1H),7.58(dd,J=8.4,7.2Hz,1H),7.20(d,J=8.6Hz,1H),7.08(d,J=7.0Hz,1H),7.05(d,J=6.5Hz,2H),5.06(dd,J=12.9,5.4Hz,1H),4.64(d,J=6.3Hz,2H),3.78–3.58(m,2H),3.51(dd,J=15.5,12.3Hz,4H),2.88(ddd,J=17.1,13.9,5.4Hz,1H),2.62–2.57(m,1H),2.53(ddd,J=6.0,5.0,3.7Hz,1H),2.45(dd,J=23.4,15.2Hz,4H),2.03(dtd,J=7.5,5.2,2.1Hz,1H).13C NMR(151MHz,DMSO)δ172.86,170.10,168.69,167.25,145.58,136.15,132.19,124.38,117.72,111.35,110.07,69.80,65.76,52.50,48.61,36.83,31.00,22.15.UPLC-MS(ESI)理论值为C22H23N5O6[M+H]+:454.46,实测值:454.67.
实施例83:4-(4-(5-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异辛醇-4-基)氨基)甲基)噻唑-2-基)哌嗪-1-基)-3-氟苯甲腈
将3-氟-4-(4-(5-甲酰基噻唑-2-基)哌嗪-1-基)苄腈(83mg,0.303mmol),消旋的泊马度胺(96mg,0.303mmol)溶于5mL冰醋酸中,130℃回流过夜,冷却至室温加入NaBH4(23mg,0.606mmol)反应两个小时,减压浓缩,经硅胶柱层析得到绿色固体50mg,产率28.7%。UPLC-MS(ESI)理论值为C28H24FN7O4S[M+H]+:574.60,实测值:574.44.
实施例84:4-(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)甲基)恶唑-2-基)哌嗪-1-基)-3-氟苄腈
参考实施例83合成路线,获得实施例化合物84。
实施例85:2-(2,6-二氧哌啶-3-基)-4-(2-(3-吗啉氮杂丁烷-1-基)恶唑-5-基)甲基)氨基)异吲哚-1,3-二酮
参考实施例83合成路线,获得实施例化合物85。
实施例86:2-(2,6-二氧哌啶-3-基)-4-(2-(3-吗啉氮杂丁烷-1-基)噻唑-5-基)甲基)氨基)异吲哚-1,3-二酮
参考实施例83合成路线,获得实施例化合物86。
实施例87:2-(2,6-二氧哌啶-3-基)-4-(2-((4-吗啉哌啶-1-基)甲基)恶唑-5-基)甲基)氨基)异吲哚-1,3-二酮
参考实施例79合成路线,获得实施例化合物87。得到黄色固体65.8mg,产率23%。1H NMR(500MHz,DMSO)δ11.13(s,1H),7.60(dd,J=8.3,7.3Hz,1H),7.23(s,1H),7.21(d,J=8.6Hz,1H),7.11(t,J=6.6Hz,2H),5.07(dd,J=12.9,5.4Hz,1H),4.68(d,J=6.0Hz,2H),4.35(s,2H),3.98(dd,J=14.9,8.7Hz,2H),3.75–3.59(m,2H),3.53–3.26(m,5H),3.18–3.00(m,2H),2.95–2.79(m,3H),2.63–2.57(m,1H),2.53(s,1H),2.23(d,J=11.6Hz,2H),2.06–2.00(m,1H),1.79(dd,J=24.6,13.0Hz,2H).
13C NMR(201MHz,DMSO)δ172.84,170.13,168.68,167.21,145.47,136.18,132.20,125.03,117.60,117.13,115.66,111.42,110.10,63.54,50.36,48.62,40.43,39.99,36.75,30.98,22.13.UPLC-MS(ESI)理论值为C27H32N6O6[M+H]+:537.59,实测值:537.45.
实施例88:2-(2,6-二氧哌啶-3-基)-6-氟-4-(2-苯基恶唑-5-基)甲基)氨基)异吲哚-1,3-二酮
参考实施例22合成路线,获得实施例化合物88。
实施例89:2-(2,6-二氧哌啶-3-基-3-d)-4-((2-苯基恶唑-5-基)甲基)氨基)异吲哚-1,3-二酮
参考实施例22合成路线,获得实施例化合物89。
实施例90:2-(3-氟-2,6-二氧哌啶-3-基)-4-((2-苯基恶唑-5-基)甲基)氨基)异吲哚-1,3-二酮
参考实施例22合成路线,获得实施例化合物90。
实施例91:2-(2,6-二氧哌啶-3-基)-4-((((2-((4-甲基哌嗪-1-基)甲基)恶唑-5-基)甲基)氨基)异二氢吲哚-1,3-二酮
参考实施例79合成路线,获得实施例化合物91。得到黄色固体21.1mg,产率6%。1HNMR(600MHz,DMSO)δ11.11(s,1H),7.59(dd,J=8.5,7.1Hz,1H),7.20(d,J=8.6Hz,1H),7.09(d,J=7.4Hz,1H),7.08(s,1H),7.05(t,J=6.1Hz,1H),5.06(dd,J=12.9,5.4Hz,1H),4.64(d,J=5.6Hz,2H),3.73(s,2H),3.36(d,J=10.4Hz,2H),2.98(dd,J=13.5,10.0Hz,4H),2.89(ddd,J=17.1,14.0,5.5Hz,1H),2.76(s,3H),2.63–2.57(m,1H),2.56–2.51(m,1H),2.45(t,J=10.4Hz,2H),2.03(dtd,J=7.8,5.3,2.3Hz,1H).13C NMR(151MHz,DMSO)δ172.85,170.11,168.71,167.22,159.73,149.73,145.54,136.18,132.20,124.44,117.60,111.36,110.03,52.61,52.44,48.84,48.61,42.13,36.79,30.99,22.14.UPLC-MS(ESI)理论值为C23H26N6O5[M+H]+:467.50,实测值:467.46
实施例92:4-(((2-(2-氯苯基)恶唑-5-基)甲基)氨基)-2-(2,6-二氧代哌啶-3-基)异二氢吲哚-1,3-二酮
参考实施例22合成路线,获得实施例化合物92。得到黄色固体57.9mg,产率52%。1H NMR(500MHz,DMSO)δ11.08(s,1H),7.92(dd,J=7.6,1.8Hz,1H),7.61(dd,J=12.5,5.0Hz,2H),7.52(td,J=7.7,1.9Hz,1H),7.48(td,J=7.5,1.4Hz,1H),7.31(t,J=4.0Hz,2H),7.13(t,J=6.0Hz,1H),7.10(d,J=7.1Hz,1H),5.06(dd,J=12.7,5.4Hz,1H),4.76(d,J=4.8Hz,2H),2.88(ddd,J=17.0,13.9,5.4Hz,1H),2.64–2.52(m,2H),2.03(ddd,J=10.3,6.1,3.9Hz,1H).13C NMR(126MHz,DMSO)δ172.77,170.01,168.64,167.20,158.10,150.38,145.60,136.11,132.15,131.81,131.08,131.05,130.72,127.60,125.67,125.60,117.85,111.37,110.12,48.57,36.90,30.95,22.10.UPLC-MS(ESI)理论值为C23H17ClN4O5[M+H]+:465.86,实测值:465.33。
实施例93:2-(2,6-二氧哌啶-3-基)-4-(((2-(4-氟苯基)恶唑-5-基)甲基)氨基)异吲哚啉-1,3-二酮
参考实施例22合成路线,获得实施例化合物92。得到黄色固体67.7mg,产率58%。1H NMR(500MHz,DMSO)δ11.09(s,1H),7.98–7.94(m,2H),7.62(dd,J=8.4,7.3Hz,1H),7.36(t,J=8.9Hz,2H),7.30(d,J=8.6Hz,1H),7.23(s,1H),7.12(t,J=4.8Hz,1H),7.10(d,J=7.1Hz,1H),5.06(dd,J=12.7,5.4Hz,1H),4.73(d,J=4.8Hz,2H),2.88(ddd,J=17.0,13.9,5.4Hz,1H),2.57(dt,J=12.7,9.1Hz,2H),2.06–2.00(m,1H).13C NMR(126MHz,DMSO)δ172.77,170.02,168.65,167.20,164.28,162.30,159.53,149.91,145.58,136.14,132.19,129.63,128.20,128.13,125.77,123.56,123.54,117.70,116.40,116.23,111.34,110.10,48.58,36.92,30.95,22.10.UPLC-MS(ESI)理论值为C23H17FN4O5[M+H]+:449.41,实测值:449.35。
实施例94:2-(2,6-二氧哌啶-3-基)-4-(((5-(3-氟苯基)恶唑-2-基)甲基)氨基)异二氢吲哚-1,3-二酮
参考实施例22合成路线,获得实施例化合物94。得到黄色固体10.5mg,产率10%。1H NMR(500MHz,DMSO)δ11.11(s,1H),7.72(s,1H),7.62(dd,J=8.5,7.2Hz,1H),7.54–7.48(m,3H),7.26–7.17(m,3H),7.11(d,J=7.1Hz,1H),5.09(dd,J=12.8,5.4Hz,1H),4.80(d,J=5.9Hz,2H),2.89(ddd,J=16.6,13.7,5.2Hz,1H),2.64–2.52(m,2H),2.08–2.01(m,1H).13C NMR(126MHz,DMSO)δ172.82,170.06,168.66,167.24,161.51,161.43,149.69,149.67,145.72,136.17,132.11,131.44,131.38,129.56,129.49,123.82,119.87,119.86,117.87,115.35,115.18,111.49,110.67,110.48,110.16,48.62,30.99,22.12.UPLC-MS(ESI)理论值为C23H17FN4O5[M+H]+:449.41,实测值:449.31。
实施例95:2-(2,6-二氧哌啶-3-基)-4-(((5-(2-氟苯基)恶唑-2-基)甲基)氨基)异二氢吲哚-1,3-二酮
参考实施例22合成路线,获得实施例化合物95。得到黄色固体20.3mg,产率17%。1H NMR(500MHz,DMSO)δ11.11(s,1H),7.70(td,J=7.7,1.7Hz,1H),7.62(dd,J=8.4,7.2Hz,1H),7.47(d,J=3.6Hz,1H),7.46–7.41(m,1H),7.40–7.31(m,2H),7.25(t,J=6.5Hz,1H),7.23(d,J=8.6Hz,1H),7.11(d,J=7.1Hz,1H),5.09(dd,J=12.8,5.4Hz,1H),4.83(d,J=6.3Hz,2H),2.89(ddd,J=16.7,13.7,5.2Hz,1H),2.63–2.51(m,2H),2.05(ddt,J=12.7,5.4,2.6Hz,1H).13C NMR(126MHz,DMSO)δ172.82,170.07,168.66,167.24,161.21,158.85,156.86,145.74,145.24,145.23,136.17,132.11,130.31,130.25,125.94,125.85,125.27,125.25,117.88,116.33,116.17,115.51,115.41,111.50,110.17,48.62,30.99,22.12.UPLC-MS(ESI)理论值为C23H17FN4O5[M+H]+:449.51,实测值:449.39。
实施例96:4-(((2-(3-环丙氧基苯基)恶唑-5-基)甲基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚啉-1,3-二酮
参考实施例22合成路线,获得实施例化合物96。得到黄色固体64.9mg,产率61%。1H NMR(500MHz,DMSO)δ11.11(s,1H),7.62(dd,J=8.5,7.2Hz,1H),7.57–7.55(m,1H),7.51(d,J=7.8Hz,1H),7.43(t,J=8.0Hz,1H),7.31(d,J=8.6Hz,1H),7.23(s,1H),7.18–7.13(m,2H),7.09(d,J=7.1Hz,1H),5.07(dd,J=12.8,5.4Hz,1H),4.74(d,J=3.3Hz,2H),3.90(ddd,J=8.9,5.9,2.9Hz,1H),2.88(ddd,J=17.0,13.9,5.4Hz,1H),2.62–2.56(m,1H),2.54(dd,J=8.5,4.4Hz,1H),2.06–1.99(m,1H),0.80(dt,J=11.5,5.8Hz,2H),0.70–0.65(m,2H).13C NMR(151MHz,DMSO)δ172.82,170.06,168.68,167.23,160.11,158.98,149.97,145.62,136.14,132.21,130.40,128.04,125.73,118.41,117.78,117.53,111.47,111.36,110.10,50.90,48.59,36.95,30.98,22.12,5.94.UPLC-MS(ESI)理论值为C26H22N4O6[M+H]+:487.48,实测值:487.31。
实施例97:4-(((2-(2-环丙氧基苯基)恶唑-5-基)甲基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚啉-1,3-二酮
参考实施例22合成路线,获得实施例化合物97。得到黄色固体72.3mg,产率68%。1HNMR(500MHz,DMSO)δ11.11(s,1H),7.75(dd,J=7.7,1.5Hz,1H),7.61(dd,J=8.4,7.2Hz,1H),7.51–7.47(m,1H),7.44(d,J=7.7Hz,1H),7.28(d,J=8.6Hz,1H),7.20(s,1H),7.13–7.04(m,3H),5.07(dd,J=12.7,5.4Hz,1H),4.70(d,J=2.3Hz,2H),3.90(dq,J=8.9,2.8Hz,1H),2.89(ddd,J=16.8,13.8,5.3Hz,1H),2.59(dd,J=15.7,3.7Hz,1H),2.52(d,J=9.6Hz,1H),2.03(ddd,J=10.1,5.2,3.1Hz,1H),0.79–0.74(m,2H),0.62–0.58(m,2H).13CNMR(126MHz,DMSO)δ172.84,170.05,168.71,167.26,159.20,156.46,149.47,145.65,136.15,132.19,131.85,129.84,125.25,120.95,117.69,116.14,114.44,111.27,109.94,51.31,48.59,40.43,36.81,30.98,22.15,6.02.UPLC-MS(ESI)理论值为C26H22N4O6[M+H]+:487.48,实测值:487.31
实施例98:2-(2,6-二氧哌啶-3-基)-4-(((5-苯基-1,3,4-恶二唑-2-基)甲基)氨基)异吲哚啉-1,3-二酮
合成路线:
步骤一:将化合物98-1(300mg,1.70mmol)、化合物98-2(501mg,3.4mmol)、三苯基膦(893mg,3.4mmol)溶于10mL干燥的四氢呋喃溶液中,室温条件下加入DIAD(671μL,3.4mmol),在氮气保护条件下,室温反应反应5小时,TLC监测反应完全后,减压浓缩,经硅胶柱层析得到化合物98-3为淡黄色油状物600mg,UPLC-MS(ESI)理论值为C17H11N3O3[M+H]+:306.08,实测值:306.15.
步骤二:将化合物98-3(600mg,1.97mmol)溶于8mL乙醇中,加入80%的水合肼回流反应1小时,LC-Mass监测反应完全,冷却至室温,过滤,滤液减压浓缩得到目标产物化合物98-4为185mg黄色油状物,UPLC-MS(ESI)理论值为C9H9N3O[M+H]+:176.07,实测值:176.15.
步骤三:将化合物98-4(86mg,0.49mmol)、化合物98-5(147mg,0.53mmol)和DIEA(160Μl,0.97mmol)溶于3mL DMF中,升温至90℃反应过夜,TLC监测反应完全后,冷却至室温,加入乙酸乙酯稀释,用饱和氯化钠洗涤多次,有机相用无水硫酸钠干燥,过滤,浓缩,经HPLC纯化得到化合物98为黄色固体13.1mg,收率6%。1H NMR(500MHz,DMSO)δ11.13(s,1H),7.96–7.94(m,2H),7.63(dd,J=9.3,6.6Hz,2H),7.61(dd,J=7.1,4.6Hz,2H),7.31(t,J=6.4Hz,1H),7.27(d,J=8.6Hz,1H),7.14(d,J=7.1Hz,1H),5.09(dd,J=12.7,5.4Hz,1H),4.96(d,J=6.3Hz,2H),2.89(ddd,J=16.8,13.7,5.2Hz,1H),2.60(dd,J=15.5,3.6Hz,1H),2.54(t,J=6.8Hz,1H),2.07–2.01(m,1H).13C NMR(126MHz,DMSO)δ172.84,170.07,168.59,167.22,164.37,145.46,136.24,132.15,132.06,129.60,129.51,126.93,126.47,123.25,117.87,111.74,110.42,48.64,37.41,30.99,22.12.UPLC-MS(ESI)理论值为C22H17N5O5[M+H]+:432.41,实测值:432.21
实施例99:2-(2,6-二氧哌啶-3-基)-4-(((5-苯基-1,3,4-噻二唑-2-基)甲基)氨基)异吲哚啉-1,3-二酮
实施例99的合成路线同实施例98,以(5-苯基-1,3,4-噻二唑-2-基)甲胺(200mg,1.04mmol)、2-(2,6-二氧哌啶-3-基)-4-氟异吲哚啉-1,3-二酮(144mg,0.52mmol)为原料,得到实施例98,经HPLC纯化得到黄色固体5mg,产率2%。1H NMR(500MHz,DMSO)δ11.13(s,1H),7.95(dd,J=7.9,1.4Hz,2H),7.62–7.59(m,3H),7.55–7.53(m,2H),7.17(d,J=8.6Hz,1H),7.12(d,J=7.1Hz,1H),5.09(dd,J=12.8,5.4Hz,1H),5.05(d,J=6.5Hz,2H),2.90(ddd,J=16.8,13.8,5.3Hz,1H),2.60(dd,J=15.5,4.0Hz,1H),2.54(dd,J=8.1,5.5Hz,1H),2.07–2.03(m,1H).13CNMR(126MHz,DMSO)δ172.84,170.02,168.56,167.19,145.11,136.39,132.29,132.06,131.53,131.45,131.35,129.43,128.82,128.72,127.63,117.57,111.76,110.46,48.64,41.44,30.99,22.12.UPLC-MS(ESI)理论值为C22H17N5O4S[M+H]+:448.47,实测值:448.20
实施例100:2-(2,6-二氧代哌啶-3-基)-4-((((2-(3-(氧杂环丁烷-3-基氧基)苯基)恶唑-5-基)甲基)氨基)异二氢吲哚-1,3-二酮
参考实施例22合成路线,获得实施例化合物100。得到黄色固体67.6mg,产率66%。1H NMR(500MHz,DMSO)δ11.11(s,1H),7.63(dd,J=8.4,7.3Hz,1H),7.52(d,J=7.7Hz,1H),7.44(t,J=8.0Hz,1H),7.30(d,J=8.6Hz,1H),7.23(d,J=4.0Hz,2H),7.15(t,J=5.9Hz,1H),7.10(d,J=7.1Hz,1H),6.94(dd,J=8.2,2.3Hz,1H),5.40–5.31(m,1H),5.07(dd,J=12.8,5.4Hz,1H),4.93(t,J=6.7Hz,2H),4.73(d,J=5.5Hz,2H),4.56(dd,J=7.2,5.0Hz,2H),2.88(ddd,J=16.9,13.9,5.3Hz,1H),2.62–2.55(m,1H),2.54–2.51(m,1H),2.02(ddd,J=7.3,5.3,2.9Hz,1H).13C NMR(126MHz,DMSO)δ172.83,170.08,168.68,167.23,159.86,156.66,150.06,145.60,136.15,132.22,130.82,128.35,125.79,118.75,117.77,116.77,111.40,110.12,76.67,70.12,48.60,36.94,30.98,22.12.UPLC-MS(ESI)理论值为C26H22N4O7[M+H]+:503.48,实测值:503.25
实施例101:2-(2,6-二氧代哌啶-3-基)-4-(((2-(2-(氧杂环丁烷-3-基氧基)苯基)恶唑-5-基)甲基)氨基)异二氢吲哚-1,3-二酮
参考实施例22合成路线,获得实施例化合物101。得到黄色固体2.1mg,产率39%。1HNMR(500MHz,DMSO)δ11.13(s,1H),8.22(s,1H),8.09(dd,J=8.2,1.4Hz,1H),7.77–7.72(m,1H),7.70–7.65(m,1H),7.39–7.33(m,3H),7.28(d,J=8.4Hz,1H),7.16(d,J=7.1Hz,1H),5.09(dd,J=12.8,5.4Hz,1H),4.89(d,J=6.5Hz,2H),4.82(d,J=15.1Hz,1H),4.53–4.47(m,1H),4.40(dd,J=15.1,8.3Hz,1H),3.85(dd,J=11.6,4.8Hz,1H),3.78(dd,J=11.6,5.0Hz,1H),2.89(ddd,J=17.2,13.7,5.2Hz,1H),2.65–2.56(m,2H),2.06–2.01(m,1H).13C NMR(201MHz,DMSO)δ172.82,170.07,168.56,167.17,157.99,157.91,151.00,145.06,136.80,136.34,132.24,129.43,123.34,121.53,121.34,117.78,111.87,110.56,109.57,77.64,60.99,52.53,48.65,36.53,30.98,22.13.UPLC-MS(ESI)理论值为C26H22N4O7[M+H]+:503.48,实测值:503.29。
实施例102:2-(2,6-二氧代哌啶-3-基)-4-((((2-(4-(氧杂环丁烷-3-基氧基)苯基)噻唑-5-基)甲基)氨基)异二氢吲哚-1,3-二酮
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参考实施例22合成路线,获得实施例化合物102。得到黄色固体8.6mg,产率8%。1HNMR(500MHz,DMSO)δ11.12(s,1H),7.86–7.79(m,3H),7.60–7.56(m,1H),7.31(t,J=6.2Hz,1H),7.21(d,J=8.6Hz,1H),7.07(d,J=7.1Hz,1H),6.87(d,J=8.8Hz,2H),5.36–5.30(m,1H),5.07(dd,J=12.8,5.4Hz,1H),4.93(t,J=6.7Hz,2H),4.81(d,J=6.2Hz,2H),4.55(dd,J=7.3,5.0Hz,2H),2.88(ddd,J=16.9,13.9,5.4Hz,1H),2.62–2.52(m,2H),2.07–2.00(m,1H).13C NMR(126MHz,DMSO)δ172.84,170.10,168.62,167.23,166.34,157.78,145.40,141.78,136.91,136.20,132.28,127.75,126.68,117.67,115.13,111.26,110.05,76.68,70.15,48.59,38.47,30.98,22.13.UPLC-MS(ESI)理论值为C26H22N4O6S[M+H]+:519.54,实测值:519.22。
实施例103:4-(((2-(4-环丙氧基苯基)噻唑-5-基)甲基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚啉-1,3-二酮
参考实施例22合成路线,获得实施例化合物103。得到黄色固体6.6mg,产率6%。1HNMR(500MHz,DMSO)δ11.12(s,1H),7.83(s,2H),7.81(d,J=2.5Hz,1H),7.59(dd,J=8.3,7.4Hz,1H),7.31(t,J=6.1Hz,1H),7.22(d,J=8.6Hz,1H),7.12(d,J=8.8Hz,2H),7.07(d,J=7.1Hz,1H),5.07(dd,J=12.8,5.4Hz,1H),4.81(d,J=5.9Hz,2H),3.89(ddd,J=8.9,6.0,2.9Hz,1H),2.89(ddd,J=17.0,14.0,5.4Hz,1H),2.61–2.53(m,2H),2.07–2.00(m,1H),0.80(q,J=5.8Hz,2H),0.69–0.64(m,2H).13C NMR(201MHz,DMSO)δ172.83,170.09,168.61,167.23,166.57,160.19,145.40,141.70,136.71,136.19,132.28,128.89,127.48,126.35,117.67,115.46,111.25,110.04,51.02,48.59,38.47,30.98,22.13,5.94.UPLC-MS(ESI)理论值为C26H22N4O5S[M+H]+:503.13,实测值:503.18
实施例104:2-(2,6-二氧代哌啶-3-基)-4-((((2-(4-(2-甲氧基乙氧基)苯基)噻唑-5-基)甲基)氨基)异吲哚啉-1,3-二酮
参考实施例22合成路线,获得实施例化合物104。得到黄色固体3.4mg,产率5%。1HNMR(500MHz,DMSO)δ11.12(s,1H),7.82(s,1H),7.81–7.78(m,2H),7.58(dd,J=8.3,7.3Hz,1H),7.31(t,J=6.2Hz,1H),7.22(d,J=8.6Hz,1H),7.07(d,J=7.0Hz,1H),7.02(t,J=5.8Hz,2H),5.07(dd,J=12.8,5.5Hz,1H),4.81(d,J=6.2Hz,2H),4.13(dd,J=5.3,3.7Hz,2H),3.66(dd,J=5.3,3.7Hz,2H),3.30(s,3H),2.89(ddd,J=17.3,13.8,5.3Hz,1H),2.61–2.53(m,2H),2.06–2.01(m,1H).13C NMR(126MHz,DMSO)δ172.83,170.10,168.61,167.23,166.58,160.01,145.40,141.70,136.64,136.18,132.28,127.52,126.00,117.68,115.00,111.25,110.04,70.25,67.11,58.18,48.59,38.47,30.98,22.13.UPLC-MS(ESI)理论值为C26H24N4O6S[M+H]+:521.14,实测值:521.21。
实施例105:2-(2,6-二氧哌啶-3-基)-4-(((2-((1s,4s)-4-(4-氟苄基)环己基)恶唑-5-基)甲基)氨基)异二氢吲哚-1,3-二酮
参考实施例12合成路线,获得实施例化合物105。得到黄色固体43.6mg,产率51%。1H NMR(500MHz,DMSO)δ11.11(s,1H),7.60(dd,J=8.5,7.2Hz,1H),7.22(d,J=8.6Hz,1H),7.16–7.11(m,2H),7.10–7.02(m,4H),6.98(s,1H),5.07(dd,J=12.7,5.4Hz,1H),4.62(d,J=1.4Hz,2H),3.00(p,J=4.6Hz,1H),2.88(ddd,J=16.9,13.8,5.4Hz,1H),2.61–2.55(m,1H),2.53(d,J=4.5Hz,1H),2.39(d,J=7.4Hz,2H),2.04–1.94(m,3H),1.64–1.56(m,3H),1.47–1.39(m,2H),1.11(td,J=12.7,2.7Hz,2H).
实施例106:2-(2,6-二氧哌啶-3-基)-4-(((2-((1r,4r)-4-(4-氟苄基)环己基)恶唑-5-基)甲基)氨基)异二氢吲哚-1,3-二酮
参考实施例22合成路线,获得实施例化合物106。得到黄色固体10.8mg,产率55%。1HNMR(500MHz,DMSO)δ11.11(s,1H),7.59(dd,J=8.4,7.2Hz,1H),7.18(dd,J=8.3,6.2Hz,3H),7.10–7.05(m,3H),7.01(t,J=6.9Hz,1H),6.93(s,1H),5.06(dd,J=12.8,5.5Hz,1H),4.58(d,J=5.6Hz,2H),2.88(ddd,J=17.2,14.0,5.4Hz,1H),2.70–2.63(m,1H),2.61–2.53(m,2H),2.47(d,J=7.1Hz,2H),2.06–1.94(m,3H),1.67(dd,J=12.7,1.9Hz,2H),1.52–1.43(m,1H),1.35(ddd,J=15.8,13.2,3.4Hz,2H),1.04(ddd,J=15.7,13.1,3.3Hz,2H).UPLC-MS(ESI)理论值为C30H29FN4O5[M+H]+:545.48,实测值:545.32。
实施例Ctrl-1:3-(1-氧代-4-((2-(1-新戊酰哌啶-4-基)恶唑-5-基)甲基)氨基)异吲哚-2-基)哌啶-2,6-二酮
将来那度胺(100mg,0.357mmol)、4-(5-甲酰基恶唑-2-基)哌啶-1-羧酸叔丁酯(92mg,0.357mmol)、苯硅烷(44μL,0.357mmol)、二丁基二氯化锡(108mg,0.357mmol)溶于6mL四氢呋喃中,升温回流反应过夜,TLC监测反应完全后,减压浓缩,柱层析,得到4-(5-((2-(2,6-二氧哌啶-3-基)-1-氧异喹啉-4-基)氨基)甲基)恶唑-2-基)哌啶-1-羧酸叔丁酯为无色油状物90mg,产率48%。
将4-(5-((2-(2,6-二氧哌啶-3-基)-1-氧异喹啉-4-基)氨基)甲基)恶唑-2-基)哌啶-1-羧酸叔丁酯(90mg,0.17mmol)溶于2mL二氯甲烷中,加入1mL三氟乙酸,反应0.5小时后,减压浓缩,真空干燥,将粗品溶于2mL N,N-二甲基甲酰胺中,加入三甲基乙酸(19mg,0.187mmol),2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(71mg,0.187mmol),搅拌条件下,加入N,N-二异丙基乙胺(296μL,1.7mmol),室温反应一小时后,加水淬灭反应,用乙酸乙酯萃取,分液,有机层用饱和氯化钠水洗数次,干燥过滤浓缩,经HPLC纯化得到白色固体:7mg,收率8%。1H NMR(400MHz,DMSO)δ11.01(s,1H),7.28(d,J=7.7Hz,1H),6.98(d,J=10.2Hz,2H),6.88(d,J=8.0Hz,1H),6.21(s,1H),5.11(d,J=8.3Hz,1H),4.40(d,J=5.3Hz,2H),4.29–4.08(m,4H),3.15–2.86(m,5H),2.68–2.57(m,2H),2.37–2.21(m,1H),2.10–1.89(m,4H),1.52(dd,J=21.5,10.8Hz,2H),1.18(s,9H).UPLC-MS(ESI)理论值为C27H33N5O5[M+H]+:508.59,实测值:508.32.
实施例Ctrl-2:N-((2-(4-氯苯基)恶唑-5-基)甲基)-N-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异喹啉-4-基)甲酰胺
将4-((2-(4-氯苯基)恶唑-5-基)甲基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮(50mg,0.11mmol)溶于1mL甲酸中,加入300μL乙酸酐,反应升至60℃反应1小时。LC-Mass监测反应完全后,冷却至室温经HPLC纯化得到黄色固体14mg,产率26%。1HNMR(400MHz,DMSO)δ11.14(s,1H),8.51(s,1H),7.90(dd,J=16.7,7.2Hz,5H),7.50(d,J=8.0Hz,2H),7.18(s,1H),5.30–5.19(m,2H),5.18–5.06(m,1H),2.94–2.79(m,1H),2.63(d,J=31.6Hz,1H),2.03–1.90(m,1H).UPLC-MS(ESI)理论值为C24H17ClN4O6[M+H]+:493.87,实测值:493.59.
实施例Ctrl-3:4-((2-(4-氯苯基)恶唑-5-基)甲基)(甲基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮
以中间体1-(2-(4-氯苯基)恶唑-5-基)-N-甲基甲胺(100mg,0.45mmol)为原料,将1-(2-(4-氯苯基)恶唑-5-基)-N-甲基甲胺溶于5mL DMSO中,加入2-(2,6-二氧代-哌啶-3-基)-4-氟基-异吲哚-1,3-二酮(101mg,0.367mmol),搅拌下加入N,N-二异丙基乙胺(182ul,0.367mmol),100℃搅拌过夜,反应完全后,用乙酸乙酯稀释,分别用水洗,饱和食盐水洗,无水硫酸钠干燥,旋干,经HPLC纯化得黄绿色固体130mg,产率74%。1H NMR(400MHz,DMSO)δ11.11(s,1H),7.95(d,J=8.4Hz,2H),7.68(t,J=7.7Hz,1H),7.50(d,J=8.1Hz,2H),7.35(t,J=8.2Hz,2H),7.19(s,1H),5.14(dd,J=12.2,4.9Hz,1H),4.96(q,J=16.4Hz,2H),3.06(s,3H),2.89(t,J=13.1Hz,1H),2.60(d,J=16.3Hz,2H),2.18–1.96(m,1H).UPLC-MS(ESI)理论值为C24H19ClN4O5[M+H]+:479.89,实测值:479.63.
实施例Ctrl-4:3-(4-((1-(4-氯苯基)-1H-1,2,3-三唑-4-基)甲基)氨基)-1-氧异喹啉-2-基)哌啶-2,6-二酮
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将1-叠氮-4-氯苯和3-(1-氧基-4-(丙-2-in-1-氧基)异吲哚-2-基)哌啶-2,6-二酮通过Click,反应得到实施例Ctrl-4。1H NMR(400MHz,DMSO)δ11.03(s,1H),8.76(s,1H),7.94(d,J=8.9Hz,2H),7.66(d,J=8.9Hz,2H),7.29(t,J=7.8Hz,1H),6.98(d,J=7.3Hz,1H),6.88(d,J=8.0Hz,1H),6.30(s,1H),5.13(dd,J=13.3,5.1Hz,1H),4.52(s,2H),4.29(d,J=17.2Hz,1H),4.18(d,J=17.2Hz,1H),2.99–2.88(m,1H),2.67–2.58(m,1H),2.30(ddd,J=26.5,13.3,4.4Hz,1H),2.08–1.99(m,1H).UPLC-MS(ESI)理论值为C22H19ClN6O3[M+H]+:451.88,实测值:451.70.
二、试验实施例
本发明还测试了实施例化合多取代异吲哚啉类化合物对三大类血液肿瘤细胞系的活性,代表性的细胞系有:多发性骨髓瘤细胞系(MM.1S)、套细胞淋巴瘤细胞系(Mino)、急性髓系白血病细胞系(MV-4-11)。测试这三类代表性的细胞系的细胞增殖抑制活性。本发明中实施例化合物39,40,41为酯键水解后对应化合物的前药化合物。药理学实验所需要的实验材料除特殊说明外,均为商业购买。
1.化合物对MM.1S细胞增殖的作用
MM.1S细胞用1640加10%胎牛血清培养并收集,按7天的作用时间稀释细胞浓度,在96孔细胞板中每孔加入180ul细胞悬液,使其细胞数为20000个。对照细胞孔加入20ul终浓度为0.2%的DMSO,化合物由10mM母液5倍梯度稀释,同样加20ul到化合物细胞孔(DMSO终浓度为0.2%)。细胞放入37℃,5%CO2培养箱孵育7天。按MTS试剂盒(Promega,G5430)配制反应液后,每孔加入20μL,37℃,5%CO2培养箱孵育3-4小时。用酶标板读取490nm吸收光值,并以690nm吸收光值作为背景值,以OD490-OD690为最终原始数据。化合物的抑制率计算公式为:抑制率=(ODDMSO-OD化合物)/(ODDMSO-O空白)×100%。化合物的增殖抑制IC50由Graph PadPrism 5.0拟合。实验重复三次,每次用三个平行实验计算计算平均数和标准差。
细胞活性测试结果见下表1:A表示细胞活性IC50<15nM,B表示细胞活性15nM<IC50<30nΜ,C表示细胞活性30nM<IC50<150nΜ,D表示细胞活性IC50>150nΜ。
表1.化合物对MM.1S细胞增殖的抑制活性
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基于以上化合物细胞生长抑制活性测试结果,本发明的一些实施例化合物对多发性骨髓瘤MM.1S细胞生长具有很好的抑制活性,绝大部分化合物的活性优于上市药物来那度胺(Lenalidomide)或泊马度胺(Pomalidomide)、与目前临床在研化合物CC-220化合物相当。另一方面,这些结构多样性化合物的开发,为获得更高活性的药物分子和药学性质更佳的分子,提供更多可选择的物质基础和新结构。因此,本发明的化合物可以用于预防和治疗与调节CRBN(CRL4CRBNE3泛素连接酶)活性相关的疾病,如多发性骨髓瘤或非限制性的包括其他潜在的肿瘤疾病、疼痛、神经系统疾病和免疫系统疾病。
2.化合物对Mino细胞增殖的抑制活性
Mino细胞用1640加15%胎牛血清培养并收集,按3天的作用时间稀释细胞浓度,在96孔细胞板中每孔加入90ul细胞悬液,使其细胞数为8000个。对对照细胞孔加入10ul终浓度为0.2%的DMSO,化合物由10mM母液5倍梯度稀释,同样加10ul到化合物细胞孔(DMSO终浓度为0.2%)。细胞放入37℃,5%CO2培养箱孵育3天。按MTS试剂盒(Promega,G5430)配制反应液后,每孔加入20μL,37℃,5%CO2培养箱孵育3-4小时。
用酶标板读取490nm吸收光值,并以690nm吸收光值作为背景值,以OD490-OD690为最终原始数据。化合物的抑制率计算公式为:抑制率=(ODDMSO-OD化合物)/(ODDMSO-O空白)×100%。化合物的增殖抑制IC50由Graph Pad Prism 5.0拟合。实验重复三次,每次用三个平行实验计算计算平均数和标准差。
细胞活性测试结果见下表2:A表示细胞活性IC50<60nM,B表示细胞活性60nM<IC50<120nM,C表示细胞活性IC50>120nΜ。
表2.化合物对Mino细胞增殖的抑制活性
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基于以上部分实施例化合物对细胞生长抑制活性测试结果发现,本发明的一些实施例化合物对套细胞淋巴瘤Mino细胞生长具有很好的抑制活性,绝大部分化合物的活性优于上市药物来那度胺或泊马度胺,且本发明中的大部分化合物优于目前临床在研化合物CC-220化合物。另一方面,这些结构多样性化合物的开发,为获得更高活性的药物分子和药学性质更佳的分子,提供可选择的物质基础和分子来源。因此,本发明的化合物拓宽了度胺类药物在血液瘤疾病治疗中的应用范围,可以用于拓展到血液肿瘤的其他适应症,比如作为套细胞淋巴瘤疾病的活性分子,作为制备预防或治疗该类疾病的药物或诊断试剂的用途。因此本发明的化合物可以作为强效新型的CRBN调节剂,用于预防和治疗与调节CRBN(CRL4CRBNE3泛素连接酶)活性相关的疾病,如多发性骨髓瘤、套细胞淋巴瘤或非限制性的包括其他潜在的肿瘤疾病、疼痛、神经系统疾病和免疫系统疾病。
3.化合物对MV-411细胞增殖的抑制活性
MV-4-11细胞用IMDM加10%胎牛血清培养并收集,按7天的作用时间稀释细胞浓度,在96孔细胞板中每孔加入180ul细胞悬液,使其细胞数为2000个。对照细胞孔加入20ul终浓度为0.2%的DMSO,化合物由10mM母液5倍梯度稀释,同样加20ul到化合物细胞孔(DMSO终浓度为0.2%)。细胞放入37℃,5%CO2培养箱孵育7天。按MTS试剂盒(Promega,G5430)配制反应液后,每孔加入20μL,37℃,5%CO2培养箱孵育3-4小时。用酶标板读取490nm吸收光值,并以690nm吸收光值作为背景值,以OD490-OD690为最终原始数据。化合物的抑制率计算公式为:抑制率=(ODDMSO-OD化合物)/(ODDMSO-O空白)×100%。化合物的增殖抑制IC50由GraphPad Prism 5.0拟合。实验重复三次,每次用三个平行实验计算计算平均数和标准差。
细胞活性测试结果见下表3:A表示细胞活性IC50<1μM,B表示细胞活性1μM≤IC50≤20μM,C表示细胞活性IC50>20μM。
表3.化合物对MV-4-11细胞增殖的抑制活性
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基于以上部分实施例化合物急性髓性白血病细胞系(MV-4-11)的细胞生长抑制活性测试结果发现,本发明的一些实施例化合物对急性白血病细胞MV-4-11细胞具有非常好的抑制活性。部分化合物的IC50处于纳摩尔级别,表中测试的化合物最好的活性IC50可以达到<100nM;然而阳性化合物无论是已经上市的药物来那度胺或泊马度胺,还是目前临床在研的化合物CC-220或者CC-122在急性白血病细胞MV-4-11细胞上的细胞抑制活性(IC50)都是大于20μΜ。因此本发明中的化合物,我们设计在分子内氢键的形成、取代基的筛选与优化,在急性髓性白血病细胞系(MV-4-11)的细胞上获得了意想不到的效果,在该细胞活性上远优于上市药物已经临床在研药物。
4.药代实验
小鼠药代动力学实验方案
ICR小鼠,雌性,18-22g,随机分组,每组4只。灌胃给予被试化合物,给药体积为10mL/kg,口服给药以DMSO/PEG-400/水(5:30:65,v/v/v)配制。试验前禁食12h,自由饮水。给药后2h统一进食。口服给予被试化合物(20mg/kg),4只小鼠,分别在5min,15min,30min,1h,2h,4h,6h,24h时间点眼眶取血50uL(EDTA-K2雾化管),离心后取血浆,12000rpm离心2min,分离血浆,于–20℃冰箱中冷冻,冻存后进行血药浓度测定。
药代动力学的测试结果发现,能够形成分子内氢键化合物(C1类),如本发明实施例化合物22,37,45,51的Cmax(ng/mL)>2000,AUClast(h*ng/mL)>10000,其相关的药代动力学性质显著优于结构上可比较、但不存在分子内氢键的(B1类或B2类)化合物;类似的结果并不仅限于上述这些实施例。
本发明化合物具有更好的药代动力学,通过小鼠的药代动力学实验,本发明中已有测试结果的化合物,优于现有技术公开的结构上可比较、而不存在分子内氢键的化合物。这些实施例用于说明本发明中的形成分子内氢键的优点,并不限于本发明中其他化合物也有相同的优点。
讨论
本发明的发明人在研究过程中意外地发现本发明的式I化合物具有优异的抗细胞增殖活性以及药代动力学性质。通过计算及活性测试发现是由于泊马度胺母核,在4位的氨基上进行取代后,氨基上的氢与异吲哚啉环上的氧原子可以形成很好6元环的分子内氢键作用(C1类型化合物,如化合物25,9等,见图1),该分子内氢键对分子立体结构具有一定的限制作用,进而泊马度胺母核部分与五元杂芳环通过亚烷基,可以形成具有一定角度的二面角(如图1所示)。因此,五元杂芳基与其连接的取代基能够很好地与目标蛋白质的疏水性口袋结合,使得该类化合物的氢键作用对化合物的在细胞活性上有很好的提高作用。此外,通过分子活性测试发现,4位的氨基在没有存在氢键给体(氢原子)的时候(化合物D1-D2,NH上引入甲基或甲酰基),或者五元杂芳环替换为其他基团,如6元芳基、6元杂芳基或环己基的化合物活性并不好(表4)。从表4中可以发现,4位氨基与异吲哚啉环上的氧原子可以形成6元环分子内氢键作用的化合物(实施例9、实施例15、实施例25等)活性比4位氨基无法形成相应分子内氢键的化合物(如实施例Ctrl-1-Ctrl-4等)显著更高类似的例子并不仅仅限于(表4)的实施例。进一步的体内代谢实验验证发现,能够形成分子内氢键的C1类化合物在代谢测试中发现药物代谢性质具有很好的提高。
发明人通过对来那度胺、CC-885、CC-220与CRBN的蛋白复合物晶体结构(PDB ID:4CI2、5HXB、5V3O)进行分析:CC-220和CC-885两个分子的侧链均通过一个凹槽,末端的片段朝向临近的疏水性口袋中。疏水性口袋中的F150位于CC-220和CC-885片段的旁边,通过对比来那度胺与CRBN的晶体结构,发现F150的位置发生了变化,这可能是CRBN蛋白构象的微调产生了不同降解底物的原因。从晶体结构分析可以推测,F150的构象容易改变是由于其所在的β-loop环的自由度比较大,容易受到外界作用力而发生改变。因此,本申请的式I所示的CRL4CRBNE3泛素连接酶分子胶类降解剂,由于具有特定的二面角结构,使得本申请的化合物与CRBN的亲和力大大增强,并且有可能产生新的降解底物,进而可以很大程度地提高对肿瘤的治疗效果及用于新适应症的治疗。
此外,发明人还利用分子动力学模拟方法对模型分子和E3泛素连接酶界面进行结构动态和结合位点分析,结合分子对接和基于复合物的药效团匹配策略,通过打分函数对化合物在E3泛素连接酶活性位点的结合模式、相互作用进行评价及结构设计上的计算模拟和优化,获得新型特异性的CRL4CRBNE3泛素连接酶小分子调节剂。
表4.分子内氢键的形成对化合物活性影响比较
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可以看出,本申请化合物在多发性骨髓瘤细胞系(MM 1S)、套细胞淋巴瘤细胞系(Mino)、急性髓系白血病细胞系(MV-4-11)中测试结果表明,部分新型的小分子调节剂与已上市的或处于临床阶段的来那度胺、泊马度胺和CC-220相比具有更好的细胞抑制活性。尤其是在急性髓系白血病细胞系(MV-4-11)中,来那度胺、泊马度胺和CC-220活性较差,显示微摩尔级别的活性,而我们设计部分化合物的IC50处于纳摩尔级别,细胞活性测试的化合物最好的活性IC50可以达到<100nM;相比较现有技术中的化合物,活性最好的化合物可以提高100倍以上。因此,本发明中的化合物拓宽了在血液瘤疾病治疗中的应用范围,可以作为血液肿瘤的新适应症的治疗的候选药物分子。
综上所述,本发明的化合物拓宽了度胺类药物在血液瘤疾病治疗中的应用范围,可以用于拓展到血液肿瘤的其他适应症,比如作为急性白血病的抑制剂,作为制备治疗该类疾病的药物。因此本发明的化合物可以作为强效新型的CRBN调节剂,用于预防和治疗与调节CRBN(CRL4CRBNE3泛素连接酶)活性相关的疾病,如多发性骨髓瘤、套细胞淋巴瘤、急性白血病或非限制性的包括其他潜在的肿瘤疾病、疼痛、神经系统疾病和免疫系统疾病。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (11)
1.一种式(I)化合物、或其药学上可接受的盐、互变异构体、立体异构体、前药:
其中,n为0或1;
X、Y各自独立地选自:CH或N,且X、Y不同时为CH;
Z选自:O、S或NH;
选自:C6-C10芳基、C4-C10环烷基、4-10元杂环基、5-10元杂芳基,其中,所述C6-C10芳基、C4-C10环烷基、4-10元杂环基、5-10元杂芳基任选地被选自以下一个或多个基团所取代:氢、氘、卤素、氰基、硝基、羟基、羧基、氨基羰基、4-10元杂环基、C1-C6烷基、C1-C6烷氧基、卤素取代C1-C6的烷基、卤素取代C1-C6的烷氧基、取代或未取代的苯基、C2-C6烯基、C3-C8杂环基氧基、C3-C8环烷基氧基、羟基取代的C1-C6烷氧基、C1-C6烷氧基取代的C1-C6烷氧基、–C(O)-R1、-(CH2)m-R2;其中,所述取代或未取代的苯基任选地被选自以下一个或多个基团所取代:氢、卤素、氰基、硝基、羟基、羧基、4-10元杂环基、C1-C6烷基、C1-C6烷氧基、卤素取代C1-C6的烷基、卤素取代C1-C6的烷氧基;
R1选自:卤素取代或未取代的C1-C6烷基、C4-C12环烷基、C6-C10芳基、4-10元杂环基、-CH2-(C4-C12环烷基),并且所述C4-C12环烷基、C6-C10芳基、4-10元杂环基、-CH2-(C4-C12环烷基)任选地被选自以下一个或多个基团所取代:氢、氘、卤素、氰基、硝基、羟基、羧基、4-10元杂环基、C1-C6烷基、C1-C6烷氧基、卤素取代C1-C6的烷基、卤素取代C1-C6的烷氧基、卤素取代或未取代的苯基;
R2为C6-C10芳基,并且所述C6-C10芳基任选地被选自以下一个或多个基团所取代:氢、卤素、氰基、硝基、羟基、羧基、4-10元杂环基、C1-C6烷基、C1-C6烷氧基、卤素取代C1-C6的烷基、卤素取代C1-C6的烷氧基;
m为0或1;
R3为氢或卤素;
R4为氢、氘或氟。
2.如权利要求1所述的化合物、或其药学上可接受的盐、互变异构体、立体异构体、前药,其特征在于,其具有式II所示的结构
其中,n为0或1;
X、Y各自独立地选自:CH或N,且X、Y不同时为CH;
Z选自:O、S或NH;
R3为氢或卤素;
R4为氢、氘或氟;
A1选自:苯基、C4-C6环烷基、4-6元杂环基、5-6元杂芳基;
L为无、CO或CH2;
A2选自:无、C1-C6烷基、苯基、C4-C10环烷基、4-6元杂环基、5-6元杂芳基;
Ra1和Ra2各自独立地选自:氢、氘、卤素、氰基、硝基、羟基、羧基、氨基羰基、4-10元杂环基、C1-C6烷基、C1-C6烷氧基、卤素取代C1-C6的烷基、卤素取代C1-C6的烷氧基、取代或未取代的苯基、C2-C6烯基、C3-C8杂环基氧基、C3-C8环烷基氧基、羟基取代的C1-C6烷氧基、C1-C6烷氧基取代的C1-C6烷氧基;其中,所述取代或未取代的苯基任选地被选自以下一个或多个基团所取代:氢、卤素、氰基、硝基、羟基、羧基、4-10元杂环基、C1-C6烷基、C1-C6烷氧基、卤素取代C1-C6的烷基、卤素取代C1-C6的烷氧基;
p和q各自独立地为0、1、2、3、4或5。
3.如权利要求1所述的化合物、其药学上可接受的盐、互变异构体、立体异构体、前药,其特征在于,所述化合物具有式(I-1)-(I-4)所示的结构:
其中,选自:/>
R3为氢或卤素;
R4为氢、氘或氟;
R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21各自独立地选自:氢、氘、卤素、氰基、C1-C6烷基、C1-C6烷氧基、卤素取代C1-C6的烷基、卤素取代C1-C6的烷氧基、苯基、乙烯基、C3-C8杂环基氧基、C3-C8环烷基氧基、羟基取代的C1-C6烷氧基、C1-C6烷氧基取代的C1-C6烷氧基。
4.如权利要求1所述的化合物、其药学上可接受的盐、互变异构体、立体异构体、前药,其特征在于,所述化合物具有(I-5)或式(I-6)所示的结构:
其中,选自:/>
R1选自:叔丁基、环丁基、环己基、苯基、并且所述环丁基、环己基、苯基任选地被选自以下一个或多个基团所取代:卤素、氰基、C1-C3烷基、三氟甲基、三氟甲氧基、卤素取代或未取代的苯基;
R2为苯基,并且所述苯基任选地被选自以下一个或多个基团所取代:氟、氰基、三氟甲氧基;
R3为氢或卤素;
R4为氢、氘或氟。
5.如权利要求1所述的化合物、其药学上可接受的盐、互变异构体、立体异构体、前药,其特征在于,选自:/>
6.如权利要求1所述的化合物、其药学上可接受的盐、互变异构体、立体异构体、前药,其特征在于,所述化合物为下列化合物:
7.一种制备权利要求1-6中任一项所述化合物的方法,其特征在于,所述方法选自如下方法之一:
合成方法一:
X、Y各自选自CH或N,且X、Y不能同时为CH;
Z选自O、S或NH;
R3、R4、R5、R6、R7、R8、R9的定义与权利要求3中定义相同;
步骤1-1:化合物1A与化合物1B在苯基硅烷和二氯二丁基锡存在下反应,得到化合物1C;或化合物1A与化合物1B在乙酸和硼氢化钠存在下反应,得到化合物1C;
合成方法2:
X为N,Y为CH;
Z为O;
R1、R3、R4的定义与权利要求4中定义相同;
步骤2-1:化合物2A与1,2-二碘乙烷反应,得到化合物2B;
步骤2-2:化合物2B与化合物2C偶联反应,得到化合物2D;
步骤2-3:化合物2D氢化还原,得到化合物2F;
步骤2-4:化合物2F经硼氢化钠还原,得到化合物2G;
步骤2-5:化合物2G与氧化剂反应,得到化合物2H;
步骤2-6:化合物2H和1B在苯基硅烷和二氯二丁基锡存在下反应,得到化合物化合物2I;
步骤2-7:化合物2I在盐酸存在下,得到化合物2J;
步骤2-8:化合物2K和化合物2J在HATU和N,N-二异丙基乙胺反存在下反应,得到化合物2L;
合成方法3:
X为N,Y为CH;
Z为O;
R2、R3、R4的定义与权利要求4中定义相同;
步骤3-1:化合物3A和化合物2J在氯化锌、三乙胺和氰基硼氢化钠的存在下反应,得到化合物3B;
合成方法4:
X为N,Y为CH;
Z为O;
的定义与权利要求1中定义相同,优选地,/>为含氮4或6元杂环基;
步骤4-1:化合物4A与四氢铝锂反应,得到化合物4B;
步骤4-2:化合物4B与叔丁基二苯基氯硅烷反应,得到化合物4C;
步骤4-3:在硼烷四氢呋喃络合物、正丁基锂存在下,化合物4C与和4-甲酰吗啉反应,得到化合物4D;
步骤4-4:化合物4D经Dess-Martin氧化剂氧化,得到化合物4E;
步骤4-5:化合物4E与在醋酸硼氢化钠存在下,通过还原胺化反应,得到化合物4F;
步骤4-6:在四丁基氟化铵的四氢呋喃溶液存在下,化合物4F脱保护基,得到化合物4G;
步骤4-7:化合物4G经Dess-Martin氧化剂氧化,得到化合物4H;
步骤4-8:在乙酸和硼氢化钠存在下,化合物4H与化合物1B反应,得到化合物4I;
合成方法5:
X、Y各自选自CH或N,且X、Y不能同时为CH;
Z选自O、S或NH;
R3、R4、Ra2和q的定义与权利要求2中定义相同;
步骤5-1:在钯催化剂存在下,化合物5A与化合物5B发生Buchwald-Hartwig胺化反应,得到化合物5C;
步骤5-2:在醋酸和硼氢化钠存在下,化合物5C与化合物1B发生还原胺化反应,得到化合物5D。
8.一种药物组合物,其特征在于,所述的药物组合物包含治疗有效剂量的权利要求1-6中任一项所述的化合物、其药学上可接受的盐、互变异构体、立体异构体、前药、其可药用的盐和药学上可接受的载体。
9.如权利要求8所述的药物组合物,其进一步包含选自地塞米松、利妥昔单抗、曲妥珠单抗、PD-1抑制剂、PDL-1抑制剂、培美曲塞、托泊替康、阿霉素、吉西他滨、达卡巴嗪、克拉霉素、长春新碱、阿糖胞苷、泼尼松、多西他赛、氯法拉滨注射液、HDAC抑制剂、雄激素受体抑制剂、雄激素生物合成抑制剂、BTK抑制剂、红血球生长激素、米诺四环素、Elotuzumab、Palbociclib、Nivolumab、Pembrolizumab、Panobinostat、Ublituximab、Romidepsin、Eltrombopag、CAR-T和美法仑中的一种或多种。
10.如权利要求1-6中任一项所述的化合物、其药学上可接受的盐、互变异构体、立体异构体、前药、或其可药用的盐在制备用于预防或治疗与CRL4CRBN E3泛素连接酶相关的疾病的药物中的用途,优选地,所述与CRL4CRBN E3泛素连接酶相关的疾病为癌症、疼痛、中枢神经系统疾病或免疫系统疾病。
11.如权利要求10所述的用途,其特征在于,所述的疾病为实体瘤、血液瘤,优选地,所述的疾病选自:骨髓增生异常综合征、多发性骨髓瘤、套细胞淋巴瘤、非霍奇金淋巴瘤、慢性淋巴细胞白血病、慢性粒单核细胞白血病、骨髓纤维化、伯基特淋巴瘤、霍奇金淋巴瘤、弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、睫状体和慢性黑色素瘤、虹膜黑色素瘤、复发性两眼间黑色素瘤、T细胞淋巴瘤、红系淋巴瘤、成单核细胞和单核细胞白血病、髓性白血病、中枢神经系统淋巴瘤、脑膜瘤、脊髓肿瘤、非小细胞肺癌、卵巢癌、皮肤癌、肾细胞癌、星状细胞瘤、淀粉样变性、I型复杂性局部疼痛综合征、恶性黑色素瘤、神经根病、成胶质细胞瘤、胶质肉瘤、恶性胶质瘤、难治性浆细胞瘤、眼外延伸黑色素瘤、乳头状和滤泡状甲状腺癌、乳腺癌、前列腺癌、肝细胞癌或原发性巨球蛋白血症。
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