CN116848099A - 细胞周期蛋白k降解剂 - Google Patents
细胞周期蛋白k降解剂 Download PDFInfo
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- CN116848099A CN116848099A CN202280013621.6A CN202280013621A CN116848099A CN 116848099 A CN116848099 A CN 116848099A CN 202280013621 A CN202280013621 A CN 202280013621A CN 116848099 A CN116848099 A CN 116848099A
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- alkylene
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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Abstract
提供了一种式(I)化合物及其药物组合物。式(I)化合物可用作细胞周期蛋白K(CyclinK蛋白)的降解剂,可以用于预防或治疗与CyclinK蛋白相关的疾病。
Description
本申请要求于2021年8月27日提交到中国国家知识产权局的发明名称为“细胞周期蛋白K降解剂”的中国专利申请202110994191.8的优先权,其内容通过引用以整体并入本文。
本发明涉及一种降解细胞周期蛋白K的化合物,以及使用其治疗/预防细胞周期蛋白K相关病症的方法。
肿瘤是威胁人类健康的第二大杀手,全世界每年有约1000万人死于肿瘤。细胞蛋白质的异常表达被认为是导致肿瘤发生发展的重要因素,因此大多数药物所针对的靶点都是这些表达异常的蛋白质。相较于传统的基于抑制剂的药物开发,药物诱导的蛋白质降解是针对这些肿瘤相关蛋白的新策略。根据作用机制,可以将蛋白降解子分为3类,即蛋白质水解靶向嵌合体(PROTAC),单价降解子以及分子胶水降解子(Burslem,G.M.&Crews,C.M.Chem.Rev.117,11269–11301(2017).)。近年来,基于蛋白质降解的技术被成功运用到抗肿瘤药物研发上,预计在2021年底将会有至少15个蛋白降解药物进入临床。
PROTAC是目前使用最为广泛的蛋白降解技术,通常由蛋白靶向结合区,E3泛素连接酶募集区以及连接子组成。PROTAC分子通过结合靶蛋白并募集E3连接酶,使得靶蛋白泛素化并最终导致靶蛋白的降解。由于PROTAC分子量较大(通常700-1200之间),使得它们的透膜能力与口服生物利用度较差。单价降解子和分子胶水的分子量要远小于PROTAC,更契合Lipinski五原则(den Besten,W.etal.Nat Chem Biol 16,1157–1158(2020))。单价降解子通过与蛋白结合改变其构象或者其他变化来诱导其降解。分子胶水则是通过诱导Culin-RING E3连接酶与靶蛋白的相互作用最终导致靶蛋白的降解。分子胶水介导的靶蛋白的降解可以不依赖于靶蛋白的配体口袋,如目前已经报道的沙利度胺类似物(Simonetta,K.R.etal.Nat Commun 10,1402(2019))以及芳基磺胺类似物(Baek,K.etal.Nat Chem Biol 16,2–3(2020))等都是按照此类机制开发。因此,分子胶水能够为之前因为缺少合适的配体口袋而难以成药的靶点带来的新的希望。
CCNK即细胞周期蛋白K,也称Cyclin K,是细胞周期蛋白依赖性激酶12/13(CDK12/13)最为主要的细胞周期蛋白(
eral.Int J Mol Sci.2021Mar;22(6):2935)。它能通过与CDK12/13形成复合物参与调控转录,转录后修饰,细胞周期,细胞增殖等多个生物学过程。早期的研究表明,CDK12/13通过与Cyclin K形成复合物,磷酸化RNA聚合酶II的C端结构域来调控其活性,进而调控DNA损伤修复基因的表达,如BRCA1,ATR,FANC1等(Malgorzata Krajewska etal.Nat Commun.2019 Apr 15;10(1):1757.)。CDK12/13被认为是一个潜在的肿瘤治疗靶点(Cells 2020,9(6),1483;),通过设计针对Cyclin K的降解子来影 响CDK12/13与Cyclin K蛋白复合物的形成,为抑制CDK12/13的功能提供了新的思路。2020年Benjamin L.Ebert等人报道(Nature 2020,585,293–297.),CDK抑制剂CR8是以分子胶水降解剂的机制诱导Cyclin K蛋白的降解。然而,目前针对Cyclin K的分子胶水类降解剂还很少且不能让人满意,急需发现对Cyclin K具有良好降解活性的化合物。
发明内容
本发明提供了一类具有良好Cyclin K降解活性的化合物,及所述化合物与其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物或其代谢产物、包含该化合物的药物组合物在治疗或者预防细胞周期蛋白K相关病症中的应用。
本发明的一个方面中,提供了具有式(I)结构的化合物或其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物或其代谢产物:
其中,Cy
1和Cy
2各自独立地代表6元芳环或6元杂芳环;
其中,R
L和R
L’各自独立地表示氢、C
1-C
6烷基或者C
3-C
6环烷基,R
L和R
L’可以与与之相连的碳原子一起形成3-6元环
其中,W
1各自独立地选自CR
0或者N;
其中,R
0表示氢、卤素、硝基、氰基、-R
a、-OR
a、-SR
a、-NR
aR
b、-C(O)R
a、-C(O)OR
a、-C(O)NR
aR
b、-S(O)
2R
a、-NR
a C(O)R
b、-S(O)
2NR
a、-S(O)R
a、-P(O)R
aR
b;
其中,W
2各自独立地选自CR
1或者N;
其中,R
1各自独立地表示氢、卤素、硝基、氰基、-R
a、-OR
a、-SR
a、-NR
aR
b、-C(O)R
a、-C(O)OR
a、-C(O)NR
aR
b、-NR
a C(O)R
b、-S(O)
2R
a、-S(O)R
a、-S(O)
2NR
aR
b、-P(O)R
aR
b,以及由0、1、2、3个取代基任意取代的C
1-C
6烷基、(C
2-C
6)烯基、(C
2-C
6)炔基,所述取代基选自OR
a、SR
a、NR
aR
b、NR
a C(O)R
b、C(O)R
a、C(O)OR
a、C(O)NR
aR
b、S(O)
2R
a、S(O)R
a、S(O)
2NR
aR
b、P(O)R
aR
b;
其中,R
2表示卤素、-R
a、-OR
a、-SR
a、硝基、氰基、-NR
aR
b、-NR
a C(O)R
b、-C(O)R
a、-C(O)OR
a、-C(O)NR
aR
b、-S(O)
2R
a、-S(O)R
a、-S(O)
2NR
aR
b、-P(O)R
aR
b;、(C
2-C
6)烯基、(C
2-C
6)炔基;
其中,R
3表示C
1-C
6烷基、C
1-C
6烯基、C
1-C
6炔基、C
3-C
10环烷基、3-10元杂环烷基、C
6-C
10元芳基、5-10元杂芳基、-NR
MR
N、-NHR
M、-OR
M;
当R
3表示C
1-C
6烷基、C
1-C
6烯基、C
1-C
6炔基、C
3-C
10环烷基、3-10元杂环烷基时,其任选地可被0、1、2、3个以下取代基取代:氧代、硝基、卤素、氰基、-R
a、-(C
0-C
6亚烷基)OR
a、-(C
0-C
6亚烷基)SR
a、-(C
0-C
6亚烷基)NR
aR
b、-(C
0-C
6亚烷基)NR
a C(O)R
b、-(C
0-C
6亚烷基)C(O)R
a、-(C
0-C
6亚烷基)C(O)OR
a、-(C
0-C
6亚烷基)C(O)NR
aR
b、-(C
0-C
6亚烷基)S(O)
2R
a、-(C
0-C
6亚烷基)S(O)R
a、-(C
0-C
6亚烷基)S(O)
2NR
aR
b、-(C
0-C
6亚烷基)P(O)R
aR
b;
当R
3表示C
6-C
10元芳基或者5-10元杂芳基时,其任选地可被0、1、2、3个以下取代基取代:硝基、卤素、氰基、-R
a、-(C
0-C
6亚烷基)OR
a、-(C
0-C
6亚烷基)SR
a、-(C
0-C
6亚烷基)NR
aR
b、-(C
0-C
6亚烷基)NR
a C(O)R
b、-(C
0-C
6亚烷基)C(O)R
a、-(C
0-C
6亚烷基)C(O)OR
a、-(C
0-C
6亚烷基)C(O)NR
aR
b、-(C
0-C
6亚烷基)S(O)
2R
a、-(C
0-C
6亚烷基)S(O)R
a、-(C
0-C
6亚烷基)S(O)
2NR
aR
b、-(C
0-C
6亚烷基)P(O)R
aR
b;
当R
3表示-NR
MR
N、-NHR
M、-OR
M时,R
M和R
N各自独立地表示C
1-C
6烷基、-(C
0-C
6亚烷基)(C
3-C
10环烷基)、-(C
0-C
6亚烷基)(3-10元杂环烷基)、-(C
0-C
6亚烷基)(C
6-C
10元芳基)、-(C
0-C
6亚烷基)(5-10元杂芳基);
其中,R
M和R
N任选地可被0、1、2、3个以下取代基取代:氧代、硝基、卤素、氰基、-R
a、-(C
0-C
6亚烷基)OR
a、-(C
0-C
6亚烷基)SR
a、-(C
0-C
6亚烷基)NR
aR
b、-(C
0-C
6亚烷基)NR
aC(O)R
b、-(C
0-C
6亚烷基)C(O)R
a、-(C
0-C
6亚烷基)C(O)OR
a、-(C
0-C
6亚烷基)C(O)NR
aR
b、-(C
0-C
6亚烷基)S(O)
2R
a、-(C
0-C
6亚烷基)S(O)R
a、-(C
0-C
6亚烷基)S(O)
2NR
aR
b、-(C
0-C
6亚烷基)P(O)R
aR
b;
其中,R
a、R
b各自独立地表示氢、C
1-C
6烷基或者C
3-C
8环烷基,其任选地可被0、1、2、3个卤素原子取代;
前提是式(I)化合物不包括
在另一个实施方案中,R
2为卤素、三氟甲基或者氰基。
在另一个实施方案中,Cy1选自:
优选地Cy1选自:
其中波浪线表示Cy1连接到式(I)中的位点;其中,所述Cy1任选地被0、1、2或者3个R0取代;优选地所述Cy1被0个R0取代。
在另一个实施方案中,Cy2选自:
优选地Cy2选自
其中波浪线表示Cy2连接到式(I)中的位点;其中,所述Cy2任选地被0、1、2或者3个R1取代;优选地,所述Cy2被0个R1取代;优选地,所述Cy2被1或者2个R
1取代。
在又一个实施方案中,R
0为氢、卤素、-R
a、-OR
a、-SR
a。
在另一个实施方案中,R
1各自独立地表示氢、卤素、-R
a、-OR
a、-NR
aR
b、-C(O)R
a、-C(O)OR
a、-C(O)NR
aR
b、-NR
a C(O)R
b、-S(O)
2R
a、-S(O)R
a、-P(O)R
aR
b、-(C
2-C
6)烯基、-(C
2-C
6)炔基、-(C
1-C
6亚烷基)OR
a、-(C
1-C
6亚烷基)NR
aR
b、-(C
1-C
6亚烷基)NR
a C(O)R
b、-(C
1-C
6亚烷基)C(O)R
a、-(C
1-C
6亚烷基)C(O)OR
a、-(C
1-C
6亚烷基)C(O)NR
aR
b、-(C
1-C
6亚烷基)S(O)
2R
a、-(C
1-C
6亚烷基)S(O)R
a、-(C
1-C
6亚烷基)P(O)R
aR
b。
在又一个实施方案中,R
3为C
1-C
6烷基、C
1-C
6烯基、C
1-C
6炔基、C
3-C
10环烷基、3-10元杂环烷基,其任选地可被0、1、2、3个以下取代基取代:硝基、卤素、氰基、-R
a、-(C
0-C
6亚烷基)OR
a、-(C
0-C
6亚烷基)SR
a、-(C
0-C
6亚烷基)NR
aR
b、-NR
a C(O)R
b、-C(O)R
a、-C(O)OR
a、-C(O)NR
aR
b、-S(O)
2R
a、-S(O)R
a、-S(O)
2NR
aR
b、-P(O)R
aR
b;优选地,该R
3任选地可被0、1、2、3个以下取代基取代:卤素、-R
a、-(C
0-C
6亚烷基)OR
a或者-(C
0-C
6亚烷基)SR
a、-(C
0-C
6亚烷基)NR
aR
b。
在另一个实施方案中,R
3为C
6-C
10元芳基或者5-10元杂芳基,其任选地可被0、1、2、3个以下取代基取代:硝基、卤素、氰基、-R
a、-(C
0-C
6亚烷基)OR
a、-(C
0-C
6亚烷基)SR
a、-(C
0-C
6亚烷基)NR
aR
b、-NR
a C(O)R
b、-C(O)R
a、-C(O)OR
a、-C(O)NR
aR
b、-S(O)
2R
a、-S(O)R
a、-S(O)
2NR
aR
b、-P(O)R
aR
b;优选地,该R
3任选地可被0、1、2、3个以下取代基取代:卤素、-R
a、-(C
0-C
6亚烷基)OR
a、-(C
0-C
6亚烷基)SR
a、-(C
0-C
6亚烷基)NR
aR
b、-NR
a C(O)R
b、-C(O)R
a、-C(O)OR
a、-C(O)NR
aR
b、-S(O)
2R
a、-S(O)R
a、-S(O)
2NR
aR
b或者-P(O)R
aR
b。
在又一个实施方案中,R
3为-NR
MR
N、-NHR
M、-OR
M,R
M和R
N各自独立地表示C
1-C
6烷基、-(C
0-C
6亚烷基)(C
3-C
10环烷基)、-(C
0-C
6亚烷基)(3-10元杂环烷基)、-(C
0-C
6亚烷基)(C
6-C
10元芳基)、-(C
0-C
6亚烷基)(5-10元杂芳基);其中,R
M和R
N任选地可被0、1、2、3个以下取代基取代:氧代、硝基、卤素、氰基、-R
a、-OR
a、-SR
a、-NR
aR
b、-NR
a C(O)R
b、-C(O)R
a、-C(O)OR
a、-C(O)NR
aR
b、-S(O)
2R
a、-S(O)R
a、-S(O)
2NR
aR
b、-P(O)R
aR
b;更优选地,该R
M和R
N任选地可被0、1、2、3个以下取代基取代:氧代、-R
a、-OR
a、-SR
a、-NR
aR
b、-NR
a C(O)R
b、-C(O)R
a、-C(O)OR
a、-C(O)NR
aR
b、-S(O)
2R
a、-S(O)R
a、-S(O)
2NR
aR
b或者-P(O)R
aR
b。
在一个实施方案中,R
a、R
b各自独立地表示氢、C
1-C
3烷基或者C
3-C
6环烷基,其任选地可被0、1、2、3个卤素原子取代。
在一个实施方案中,R
a、R
b各自独立地表示氢、C
1-C
3烷基,其任选地可被0、1、2、3个卤素原子取代。优选地,上述任一实施方案所述的化合物选自以下结构:
本发明的另一个实施方案提供了一种药物组合物,该组合物包含如本发明所述的化合物或其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物或其代谢产物,及任选地药学上可接受的载体。
本发明的另一个实施方案提供了一种前述本发明所述的化合物或其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物或其代谢产物,或者本发明所述的药物组合物在制备用于预防或治疗与CyclinK蛋白相关的疾病或病症的药物中的应用。特别地,所述疾病或病症选自肿瘤、癌症、病毒感染、炎症相关疾病和自身免疫性疾病。
本发明的另一个实施方案提供了一种治疗与CyclinK蛋白相关的疾病或病症的方法,其包括向有此需要的哺乳动物施用本发明所述的化合物或其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物或其代谢产物,或者本发明所述的药物组合物。
图1:本发明的化合物1对Cyclin K的降解的诱导作用。
图2:本发明的多个化合物对Cyclin K的降解的诱导作用。
本发明的化合物或其前药在生物体中可具有优异的Cyclin K降解活性,且可用作癌症的预防或治疗药物、癌症增殖抑制剂或癌症转移抑制剂。本发明的化合物表现出Cyclin K降解活性,且本发明的化合物在功效表达、药代动力学(例如,吸收性、分布、代谢、排泄)、溶解度(例如,水溶性)以及与其它药用产品的相互作用(例如,药物代谢酶的抑制作用)、稳定性(例如,化学稳定性、对酶的稳定性)的方面也有望表现优异,因此该化合物可用作药物。
本发明的化合物可预期具有低毒性(例如,急性毒性、慢性毒性、遗传毒性、生殖毒性、心脏毒性、致癌性、中枢神经系统毒性),且可用于向哺乳动物(例如、小鼠、大鼠、仓鼠、兔、猫、狗、牛、绵羊、猴子、人)给药。
本发明的化合物可用作Cyclin K引起的病理或疾病的预防或治疗药剂。此外,本发明的化合物在降解Cyclin蛋白亚家族中的Cyclin K的选择性方面可为优越的,并且预期具有低毒性。
本发明的化合物有望用于预防或治疗例如癌症[例如,直结肠癌(例如,结肠癌、直肠癌、肛门癌、家族性直结肠癌、遗传性非息肉病性直结肠癌、胃肠道间质瘤)、肺癌(例如,非小细胞肺癌、小细胞肺癌、恶性间皮细胞瘤)、间皮细胞瘤、胰腺癌(例如,胰管癌、胰腺内分泌肿瘤)、咽癌、喉癌、食道癌、胃癌(例如,乳头状腺癌、粘液性腺癌、腺鳞癌)、十二指肠癌、小肠癌、乳腺癌(例如,浸润性导管癌、原位导管癌、炎症性乳腺癌)、卵巢癌(例如,卵巢上皮癌、性腺外生殖细胞肿瘤、卵巢生殖细胞肿瘤、卵巢低恶性潜在肿瘤)、睾丸癌、前列腺癌(例如,激素依赖性前列腺癌、非激素依赖性前列腺癌、去势抵抗性前列腺癌)、肝癌(例如,肝细胞瘤、原发性肝癌、肝外胆管癌)、甲状腺癌(例如,甲状腺髓样癌)、肾癌(例如,肾细胞癌(例如,透明细胞型肾细胞癌)、肾盂和输尿管中的移行细胞癌)、子宫癌(例如,子宫颈癌、子宫体癌、子宫肉瘤)、妊娠绒毛膜癌、脑肿瘤(例如,成神经管细胞瘤、神经胶质瘤、松果体星形细胞瘤、纤维性星形细胞瘤、弥漫性星形细胞瘤、间变性星形细胞瘤、垂体腺瘤)、成神经细胞瘤、视网膜胚细胞瘤、皮肤癌(例如,基底肉瘤、恶性黑色素瘤(黑素瘤))、肉瘤(例如,横纹肌肉瘤、平滑肌肉瘤、软组织肉瘤、梭形细胞肉瘤、 骨肉瘤)、恶性骨肿瘤、膀胱癌、血液癌(例如,多发性骨髓瘤、白血病(例如,急性髓细胞性白血病、急性淋巴细胞性白血病)、恶性淋巴瘤、霍奇金病、慢性骨髓增殖性疾病)、原发性未知的癌症]、抑制癌症的扩散、抑制转移、促进细胞凋亡或预防或治疗癌前病变(例如,骨髓增生异常综合征)。此外,预期本发明的化合物可用于预防或治疗硬皮病、肝硬化、特发性肺纤维化、炎性肠病或肌营养不良。
本发明的化合物可以原样或作为与药物理学上可接受的载体混合的药物经向哺乳动物(优选人)给药。适合的给药途径包括但不限于,口服、静脉注射、直肠、气雾剂、非肠道给药、眼部给药、肺部给药、经皮给药、阴道给药、耳道给药、鼻腔给药及局部给药。此外,仅作举例说明,肠道外给药,包括肌肉注射、皮下注射、静脉注射、髓内注射、心室注射、腹膜内注射、淋巴管内注射、及鼻内注射。下面详细描述包含本发明的化合物的药物(有时简称为“本发明的药物”)。本发明的药物的剂型的实例包括口服制剂,例如片剂(例如,糖衣片、薄膜衣片、舌下片、口含片、口服速溶片)、丸剂、颗粒剂、粉剂、胶囊剂(例如,软胶囊、微胶囊)、糖浆、乳剂、悬浮液、薄膜(例如,口腔崩解膜、口腔粘膜贴膜)等。另外,本发明药物的剂型的实例包括注射剂、滴注剂、透皮剂(例如,离子电渗疗法透皮制剂)、栓剂、软膏剂、鼻腔制剂、肺制剂、滴眼剂等肠道外药剂。
本发明的化合物可与其它药物同时使用。具体而言,本发明的化合物可以与诸如激素治疗剂、化学治疗剂、免疫治疗剂、抑制细胞生长因子或细胞生长因子受体的作用的药物等药物一起使用。在下文中,可与本发明的化合物组合使用的药物简称为伴用药物。
作为“激素治疗剂”,可使用例如磷雌酚、己烯雌酚、氯烯雌醚、乙酸甲羟孕酮、甲地孕酮、氯地孕酮、乙酸赛普龙、达那唑、烯丙雌醇、孕三烯酮(gestrinone)、美帕曲星、雷诺昔酚、奥美昔芬(ormeloxifene)、左美洛昔芬、抗雌激素(例如,柠檬酸它莫西芬、柠檬酸托瑞米芬)、丸剂、美雄烷、睾内酯(testrolactone)、氨鲁米特、LH-RH激动剂(例如,乙酸性瑞林、布舍瑞林、乙酸亮丙瑞林)、屈洛昔芬、环硫雄醇、乙炔雌二醇磺酸酯、芳族酶抑制剂(例如,盐酸法屈唑、阿那曲唑、Retrozole、依西美坦、伏氯唑、福美坦)、抗雄激素(例如,氟他胺、Bicartamide、尼鲁米特、恩杂鲁胺(enzalutamido))、5α-还原酶抑制剂(例如,非那雄胺、依立雄胺、度他雄胺(dutas teride))、肾上腺皮质激素药物(例如,地塞米松、泼尼松龙(predonisolone)、倍他米松、氟羟脱氢皮醇)、雄激素合成抑制剂(例如,阿比特龙)、类视黄醇和延迟类视黄醇代谢的药物(例如,利阿唑)、甲状腺激素及其DDS(药物递送体系)制剂。
作为“化学治疗剂”,可以使用烷基化剂、抗代谢物、抗癌抗生素和植物-衍生的抗癌剂。
作为“烷基化剂”,可使用例如氮芥、氮芥-N-氧化物盐酸盐、Chlorambutyl、环磷酰胺、异环磷酰胺、硫替派、卡波醌、对甲苯磺酸英丙舒凡(Improsulfan)、白消安、盐酸嘧啶亚硝脲、二溴甘露醇、苯丙氨酸氮芥、达卡巴嗪、雷莫司汀(Ranimustine)、雌莫司汀磷酸钠、 曲他胺、卡莫司汀、环己亚硝脲、链脲霉素、双溴丙基哌嗪、依托格鲁、卡铂、顺铂、米铂、奈达铂、奥沙利铂、六甲蜜胺、氨莫司汀、二溴螺氯铵(dibrospidium hydrochloride)、福莫司汀、松龙苯芥、嘌嘧替派(Pumitepa)、苯达莫司汀(Ribomustin)、替莫唑胺、曲奥舒凡(treosulfan)、氯乙环磷酰胺、净司他丁斯酯、阿多来新、半胱胺亚硝脲(cystemustine)、比折来新(bizelesin)及其DDS制剂。
作为“抗代谢物”,可使用例如巯基嘌呤、6-巯基嘌呤核糖核苷、硫肌苷、氨甲喋呤、培美曲唑(Pemetrexed)、依诺他滨、阿糖胞苷、阿糖胞苷十八烷基磷酸钠、安西他滨盐酸盐、5-FU药物(例如,氟尿嘧啶、替加氟、UFT、去氧氟尿苷、卡莫氟、Gallocitabine、乙嘧替氟、卡培他滨)、氨基蝶呤、奈拉滨(nelzarabine)、亚叶酸钙、Tabloid、甘氨硫嘌呤(butocine)、亚叶酸钙、左亚叶酸钙、克拉屈滨、乙嘧替氟、氟达拉滨、吉西他滨、羟基脲、喷司他丁、吡曲克辛、碘苷、丙脒腙、噻唑呋啉、氨莫司汀、苯达莫司汀及其DDS制剂。
作为“抗肿瘤抗生素”,可使用例如放线菌素D、放线菌素C、丝裂霉素C、色霉素A3、盐酸博来霉素、硫酸博来霉素、硫酸培洛霉素、盐酸柔红霉素、盐酸多柔比星、盐酸阿柔比星、盐酸吡柔比星、盐酸表柔比星、新制癌菌素、光神霉素、肉瘤霉素、嗜癌霉素、米托坦、盐酸佐柔比星、盐酸米托蒽醌、盐酸伊达比星及其DDS制剂(例如,包封多柔比星的PEG核糖体)。
作为“植物-衍生的抗肿瘤药剂”,可使用例如依托泊苷、磷酸依托泊苷、硫酸长春碱、硫酸醛基长春碱、硫酸去乙酰长春酰胺、表鬼臼毒噻吩糖苷、太平洋紫杉醇、多西他赛、卡巴他赛(cabazitaxel)、长春瑞宾以及其DDS制剂。
作为“免疫治疗剂”,可使用例如溶链菌制剂(picibanil)、云芝多糖K(krestin)、裂裥菌素、蘑菇多糖、乌苯美司、干扰素、白介素、巨噬细胞菌落-刺激因子、粒细胞菌落-刺激因子、红细胞生成素、淋巴细胞毒素、BCG疫苗、小棒状杆菌、左旋四咪唑、多醣K、苯咪唑丙酸(procodazol)、抗CTLA4抗体(例如,易普利姆玛(ipilimumab)、(tremelimumab)、抗PD-1抗体(例如,纳武单抗、派姆单抗)和抗PD-L1抗体。
“抑制细胞生长因子及其受体的作用的药物”中的“细胞生长因子”可以是任何能促进细胞增殖的物质,其通常是分子量不超过20000的肽,并能够通过与受体结合而在低浓度表达活性,且具体地可使用
(1)EGF(表皮生长因子)或具有与EGF基本相同活性的物质(例如,TGFα);
(2)胰岛素或具有与胰岛素基本相同活性的物质(例如,胰岛素、IGF(胰岛素样生长因子)-1、IGF-2);
(3)FGF(成纤维细胞生长因子)或具有与FGF基本相同活性的物质(例如,酸性FGF、碱性FGF、KGF(角质形成细胞生长因子)、FGF-10);
(4)其它细胞生长因子(例如,CSF(克隆刺激因子)、EPO(红细胞生成素)、IL-2(白细胞介素-2)、NGF(神经生长因子)、PDGF(血小板生长因子)、TGFβ(转化生长因子β)、HGF(肝细胞生长因子)、VEGF(血管内皮生长因子)、调节蛋白、血管生成素)。
“细胞生长因子受体”可为能够与上述任何细胞生长因子结合的任何受体,并且具体可使用:EGF受体、heregulin受体(例如,HER3)、胰岛素受体、IGF受体-1、IGF受体-2、FGF受体-1或FGF受体-2、VEGF受体、血管生成素(angiopoietin)受体(例如,Tie2)、PDGF受体等。
作为“抑制细胞生长因子及其受体的作用的药物”,例如,可使用EGF抑制剂、TGFα抑制剂、调节蛋白抑制剂、胰岛素抑制剂、IGF抑制剂、FGF抑制剂、KGF抑制剂、CSF抑制剂、EPO抑制剂、IL-2抑制剂、NGF抑制剂、PDGF抑制剂、TGFβ抑制剂、HGF抑制剂、VEGF抑制剂、血管生成素抑制剂、EGF受体抑制剂、HER2抑制剂、HER4抑制剂、胰岛素受体抑制剂、IGF-1受体抑制剂、IGF-2受体抑制剂、FGF受体-1抑制剂、FGF受体-2抑制剂、FGF受体-3抑制剂、FGF受体-4抑制剂、VEGF受体抑制剂、Tie-2抑制剂、PDGF受体抑制剂、Abl抑制剂、Raf抑制剂、FLT3抑制剂、c-Kit抑制剂、Src抑制剂、PKC抑制剂、Smo抑制剂、ALK抑制剂、ROR1抑制剂、Trk抑制剂、Ret抑制剂、mTOR抑制剂、Aurora抑制剂、PLK抑制剂、MEK(MEK1/2)抑制剂、MET抑制剂、CDK抑制剂、Akt抑制剂、ERK抑制剂、PI3K抑制剂等。更具体地,可使用抗VEGF抗体(例如,贝伐单抗(Bevacizumab)、雷莫芦单抗(Ramucirumab))、抗HER2抗体(例如,曲妥珠单抗(Trastuzumab)、帕妥珠单抗(Pertuzumab))、抗EGFR抗体(例如,西妥昔单抗(Cetuximab)、帕尼单抗(Panitumumab)、马妥珠单抗(Matuzumab)、尼妥珠单抗(Nimotuzumab))、抗HGF抗体、伊马替尼(Imatinib)、埃洛替尼(Erlotini b)、吉非替尼(Gefitinib)、索拉非尼(Sorafenib)、舒尼替尼(Sunitinib)、达沙替尼(Dasatinib)、拉帕替尼(Lapatinib)、瓦他拉尼(Vatalanib)、依鲁替尼(Ibrutinib)、博舒替尼(Bosutinib)、卡博替尼(Cabozantinib)、克唑替尼(Crizotinib)、阿雷替尼(Alectinib)、维莫德吉(Vismodegib)、阿西替尼(Axitinib)、莫特塞尼(Motesanib)、尼洛替尼(Nilotinib)、6-[4-(4-乙基哌嗪-1-基甲基)苯基]-N-[1(R)-苯基乙基]-7H-吡咯并[2,3-D]嘧啶-4-胺(AEE-788)、凡德他尼(Vandetanib)、西罗莫司(Temsirolimus)、依维莫司(Everolimus)、Enzastaurin、陶扎色替(Tozasertib)、磷酸2-[N-[3-[4-[5-[N-(3-氟苯基)氨基甲酰基甲基]-1H-吡唑-3-基氨基]喹唑啉-7-基氧基]丙基]-N-乙基氨基]乙基酯(AZD-1152)、4-[9-氯-7-(2,6-二氟苯基)-5H-嘧啶并[5,4-D][2]苯并氮杂-2-基氨基]苯甲酸、N-[2-甲氧基-5-[(E)-2-(2,4,6-三甲氧基苯基)乙烯基磺酰基甲基]苯基]甘氨酸钠盐(ON-1910Na)、Volasertib、司美替尼(Selumetinib)、曲美替尼(Trametinib)、N-[2(R),3-二羟基丙氧基]-3,4-二氟-2-(2-氟-4-碘苯基氨基)苯甲酰胺(PD-0325901)、博舒替尼(Bosutinib)、瑞戈非尼(Regorafenib)、阿法替尼(Afatinib)、Idelalisib、Ceritinib、达拉非尼(Dabrafenib)等。
除上述药物之外,还可使用天冬酰胺酶、醋葡醛内酯、盐酸甲基苄肼、原卟啉-钴络合盐、汞血卟啉-钠、拓扑异构酶I抑制剂(例如,依立替康、托泊替康、Indotecan、Indimitecan)、拓扑异构酶II抑制剂(例如,索布佐生)、分化诱导性银子(例如,类视黄醇、维生素D)、其它血管生成抑制剂(例如,烟曲霉素、鲨鱼提取物、COX-2抑制剂)、α-阻断剂(例如,盐酸坦洛新)、二膦酸(例如,帕米膦酸盐、唑来膦酸盐)、沙利度胺、来那度胺(lenalidomide)、泊马度胺(Pomalidomide)、5-氮胞苷、地西他滨、蛋白酶体抑制剂(例如,硼替佐米(Bortezomib)、卡非佐米(carfilzomib)、(ixazomib)、NEDD8抑制剂(例如,pevonedistat)、UAE抑制剂、PARP抑制剂(例如,奥拉帕尼(Olaparib)、尼拉帕尼(Niraparib)、维利帕尼(Veliparib)、卢卡帕尼(Rucaparib))、抗肿瘤抗体,例如,抗CD20抗体(例如,利妥昔单抗、Obinutuzumab)、抗CCR4抗体(例如,Mogamulizumab)等、抗体-药物配合物(例如,曲妥珠单抗-美坦新(trastuzumabemtansine)、(brentuximabvedotin)等作为伴用药物。
在下文中,组合使用的本发明化合物和伴用药物称为“本发明的组合药剂”。作为本发明的化合物及伴用药物的给药方式,可提及以下方法:(1)同时配制本发明的化合物和伴用药物,制成给药的单一制剂。(2)分别配制本发明的化合物和伴用药物,制成两种制剂,以相同的给药途径将其同时给药。(3)分别配制本发明的化合物和伴用药物,得到两种制剂,以相同的给药途径、以交错的时间给药。(4)分别配制本发明的化合物和伴用药物,得到两种制剂,通过不同的给药途径同时给药。(5)分别配制本发明的化合物和伴用药物,得到两种制剂,分别以不同的给药途径、以交错的时间给药(例如,本发明的化合物和并用药物按此顺序或相反的顺序给药)等。
本发明的化合物或本发明的组合药剂可进一步与非药物疗法组合使用。具体而言,本发明的化合物或本发明的组合药剂可与非药物疗法组合使用,例如,(1)手术,(2)加压化学治疗,(3)基因治疗,(4)热疗,(5)冷疗,(6)激光烧灼,(7)放疗。
例如,在进行上述手术等之前或之后,或在将两种或三种以上的药物组合治疗之前或之后,使用本发明的化合物或本发明的组合药剂,可达到如预防耐药性表达、延长疾病等、延长无疾病期(无疾病生存期)、抑制癌症转移或复发、延长寿命等效果。
此外,本发明的化合物或本发明的组合药剂可与以下支持性的疗法组合:(i)给药多种抗生素(例如,β-内酰胺类如头孢替安(Pansporin)等,大环内酯类如克拉霉素等)以治疗传染病的组合,(ii)静脉内给药静脉输入营养液、氨基酸制剂、一般维生素制剂用于改善营养不良,(iii)给药吗啡以减轻疼痛,(iv)给药可改善副作用的药物,所述副作用例如恶心、呕吐、厌食、腹泻、白细胞减少症,血小板减少症、血红蛋白浓度降低、脱发、肝病、肾病、DIC、发热等(v)给药抑制癌症对多种药物耐药性的药物。
术语定义
下列定义用于更好地理解本发明。
在本文中,当提及具有特定结构式的“化合物”时,一般地还涵盖其立体异构体、非对映异构体、对映异构体、外消旋混合物和同位素衍生物,以及作为其替代性存在形式的可药用盐、溶剂合物、水合物等形式。本领域技术人员公知,一种化合物的盐、溶剂合物、水合物是化合物的替代性存在形式,它们都可以在一定条件下转化为所述化合物,因此,特别注意的是在本文中当提到一种化合物时,一般地还包括它的可药用盐,进而还包括其溶剂合物和水合物。
相似地,在本文中当提到一种化合物时,一般地还包括其前药、代谢产物和氮氧化物。
本发明所述的可药用盐或药学上可接受的盐可使用无机酸或有机酸而形成,所述的“可药用盐”或“药学上可接受的盐”是指这样的盐:在合理的医学判断范围内,其适用于接触人和较低等动物的组织,而没有不适当的毒性、刺激性、过敏反应等,称得上合理的受益/风险比。可以在本发明化合物的最终分离和纯化期间原位制备所述盐,或单独通过将游离碱或游离酸与合适的试剂反应制备所述盐,如下概述。例如,游离碱可以与合适的酸反应。此外,当本发明的化合物带有酸性部分时,其合适的可药用盐可包括金属盐,例如碱金属盐(如钠盐或钾盐)和碱土金属盐(如钙盐或镁盐)。可药用的无毒酸加成盐的示例是氨基与无机酸(例如,盐酸、氢溴酸、磷酸、硫酸和高氯酸)或有机酸(例如,醋酸、草酸、马来酸、酒石酸、柠檬酸、琥珀酸或丙二酸)形成的盐,或通过使用现有技术中的其他方法如离子交换形成的盐。其他可药用盐包括己二酸盐、海藻酸钠、抗坏血酸盐、天门冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯丙酸盐、磷酸盐、苦味盐、新戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐等。代表性碱金属或碱土金属盐包括钠盐、锂盐、钾盐、钙盐、镁盐等。其他可药用盐包括(适当时)无毒铵盐、季铵盐和用反离子形成的铵阳离子,例如,卤化物、氢氧化物、羧酸盐、硫酸盐、磷酸盐、硝酸盐、低级烷基磺酸盐和芳基磺酸盐。
本发明的可药用盐可通过常规方法制备,例如通过将本发明的化合物溶解于与水可混溶的有机溶剂(例如丙酮、甲醇、乙醇和乙腈)中,向其中添加过量的有机酸或无机酸水溶液,以使得盐从所得混合物中沉淀,从中除去溶剂和剩余的游离酸,然后分离所沉淀的盐。
本发明所述的前体或代谢物可以为本领域公知的前体或代谢物,只要所述的前体或代谢物通过体内代谢转化形成化合物即可。例如“前药”是指本发明化合物的那些前药,在合 理的医学判断范围内,其适用于接触人和更低等动物的组织,而没有不适当的毒性、刺激性、过敏反应等,称得上合理的受益/风险比并且对其预期用途有效。术语“前药”是指在体内迅速经转化产生上述式的母体化合物的化合物,例如通过在体内代谢,或本发明化合物的N-去甲基化。
本发明所述的“溶剂合物”意指本发明化合物与一个或更多个溶剂分子(无论有机的还是无机的)的物理缔合。该物理缔合包括氢键。在某些情形中,例如当一个或更多个溶剂分子纳入结晶固体的晶格中时,溶剂合物将能够被分离。溶剂合物中的溶剂分子可按规则排列和/或无序排列存在。溶剂合物可包含化学计量或非化学计量的溶剂分子。“溶剂合物”涵盖溶液相和可分离的溶剂合物。示例性溶剂合物包括但不限于水合物、乙醇合物、甲醇合物和异丙醇合物。溶剂化方法是本领域公知的。
本发明所述的“立体异构”分为构象异构和构型异构,构型异构还可分为顺反异构和旋光异构(即光学异构)。构象异构是指具有一定构型的有机物分子由于碳、碳单键的旋转或扭曲而使得分子各原子或原子团在空间产生不同的排列方式的一种立体异构现象,常见的有烷烃和环烷烃类化合物的结构,如环己烷结构中出现的椅式构象和船式构象。“立体异构体”是指当本发明化合物含有一个或更多个不对称中心,因而可作为外消旋体和外消旋混合物、单一对映异构体、非对映异构体混合物和单一非对映异构体。本发明化合物可以有不对称中心,每个不对称中心会产生两个光学异构体,本发明的范围包括所有可能的光学异构体和非对映异构体混合物和纯的或部分纯的化合物。本发明所述的化合物可以以互变异构体形式存在,其通过一个或更多个双键位移而具有不同的氢的连接点。例如,酮和它的烯醇形式是酮-烯醇互变异构体。各互变异构体及其混合物都包括在本发明的化合物中。所有式(I)化合物的对映异构体、非对映异构体、外消旋体、内消旋体、顺反异构体、互变异构体、几何异构体、差向异构体及其混合物等,均包括在本发明范围中。
本发明的“同位素衍生物”是指在本专利中化合物被同位素标记的分子。通常用作同位素标记的同位素是:氢同位素:
2H和
3H;碳同位素:
11C,
13C和
14C;氯同位素:
35Cl和
37Cl;氟同位素:
18F;碘同位素:
123I和
125I;氮同位素:
13N和
15N;氧同位素:
15O,
17O和
18O和硫同位素
35S。这些同位素标记化合物可以用来研究药用分子在组织中的分布情况。尤其是氘
2H和碳
13C,由于它们容易标记且方便检测,运用更为广泛。某些重同位素,比如重氢(
2H),的取代能增强代谢的稳定性,延长半衰期从而达到减少剂量的目而提供疗效优势的。同位素标记的化合物一般从已被标记的起始物开始,用已知的合成技术象合成非同位素标记的化合物一样来完成其合成。
本发明描述示例性实施方案的过程中,本发明的其它特征将变得显而易见,给出所述实施方案用于说明本发明而不意欲成为其限制,以下实施例使用本发明所公开的方法制备、分离和表征。
如果无另外说明,用于本发明申请(包括说明书和权利要求书)中的术语定义如下。必须注意,在说明书和所附的权利要求书中,如果文中无另外清楚指示,单数形式“一个”包括复数意义。如果无另外说明,使用质谱、核磁、HPLC、蛋白化学、生物化学、重组DNA技术和药理的常规方法。在本申请中,如果无另外说明,使用“或”或“和”指“和/或”。
在说明书和权利要求书中,给定化学式或名称应涵盖所有立体和光学异构体及其中存在上述异构体的外消旋物。除非另外指明,否则所有手性(对映异构体和非对映异构体)和外消旋形式均在本发明范围内。所述化合物中还可存在C=C双键、C=N双键、环系统等的许多几何异构体,且所有上述稳定异构体均涵盖于本发明内。本发明描述了本发明化合物的顺式-和反式-(或E-和Z-)几何异构体,且其可分离成异构体的混合物或分开的异构体形式。本发明化合物可以光学活性或外消旋形式加以分离。用于制备本发明化合物和其中制备的中间体的所有方法均视为本发明的部分。在制备对映异构体或非对映异构体产物时,其可通过常规方法(例如通过色谱或分段结晶)进行分离。取决于方法条件,以游离(中性)或盐形式获得本发明的终产物。这些终产物的游离形式和盐均在本发明的范围内。如果需要的话,则可将化合物的一种形式转化成另一种形式。可将游离碱或酸转化成盐;可将盐转化成游离化合物或另一种盐;可将本发明异构体化合物的混合物分离成单独的异构体。本发明化合物、其游离形式和盐可以多种互变异构体形式存在,其中氢原子转置到分子的其它部分上且由此分子的原子之间的化学键发生重排。应当理解的是,可存在的所有互变异构体形式均包括在本发明内。
除非另有定义,本发明的取代基的定义是各自独立而非互相关联的,例如对于取代基中R
a(或者R
b)而言,其在不同的取代基的定义中是各自独立的。具体而言,对于R
a(或者R
b)在一种取代基中选择一种定义时,并不意味着该R
a(或者R
b)在其他取代基中都具有该相同的定义。更具体而言,例如(仅列举非穷举)对于NR
aR
b中,当R
a(或者R
b)的定义选自氢时,其并不意味着在-C(O)-NR
aR
b中,R
a(或者R
b)必然为氢。在另一个方面,当某一个取代基中存在多于一个R
a(或者R
b)时,这些R
a(或者R
b)也是各自独立的。例如,在取代基-(CR
aR
b)
m-O-(CR
aR
b)
n-中,在m+n大于等于2的情况下,其中的m+n个R
a(或者R
b)是各自独立的,它们可以具有相同或者不同的含义。
除非另有定义,否则当取代基被标注为“任选取代的”时,所述取代基选自例如以下取代基,诸如烷基、环烷基、芳基、杂环基、卤素、羟基、烷氧基、氧代、烷酰基、芳基氧基、烷酰基氧基、氨基、烷基氨基、芳基氨基、芳基烷基氨基、二取代的胺基团(其中两个氨基取代基选自烷基、芳基或芳基烷基)、烷酰基氨基、芳酰基氨基、芳烷酰基氨基、取代的烷酰基氨基、取代的芳基氨基、取代的芳烷酰基氨基、硫基、烷基硫基、芳基硫基、芳 基烷基硫基、芳基硫羰基、芳基烷基硫羰基、烷基磺酰基、芳基磺酰基、芳基烷基磺酰基、磺酰氨基例如-SO
2NH
2、取代的磺酰氨基、硝基、氰基、羧基、氨基甲酰基例如-CONH
2、取代的氨基甲酰基例如-CONH烷基、-CONH芳基、-CONH芳基烷基或在氮上具有两个选自烷基、芳基或芳基烷基的取代基的情况、烷氧基羰基、芳基、取代的芳基、胍基、杂环基,例如吲哚基、咪唑基、呋喃基、噻吩基、噻唑基、吡咯烷基、吡啶基、嘧啶基、吡咯烷基、哌啶基、吗啉基、哌嗪基、高哌嗪基等和取代的杂环基。
本文使用的术语“烷基”或“亚烷基”意欲包括具有指定碳原子数的支链和直链饱和脂族烃基团。例如,“C
1-C
6烷基”表示具有1个至6个碳原子的烷基。烷基的实例包括但不限于甲基(Me)、乙基(Et)、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基。本发明优选的烷基包括C
1-C
6烷基或C
1-C
4烷基。
术语“烯基”表示含一个或更多个双键且通常长度为2至20个碳原子的直链或支链的烃基。例如,“C
2-C
6烯基”含有两个至六个碳原子。烯基包括但不限于例如乙烯基、丙烯基、丁烯基、1-甲基-2-丁烯-1-基等。本发明优选的烯基包括C
2-C
6烯基。
术语“炔基”表示含一个或更多个三键且通常长度为2至20个碳原子的直链或支链的烃基。例如,“C
2-C
6炔基”含有两个至六个碳原子。代表性炔基包括但不限于例如乙炔基、1-丙炔基、1-丁炔基等。本发明优选的炔基包括C
2-C
6炔基。术语“烷氧基”或“烷基氧基”是指-O-烷基。“C
1-C
6烷氧基”(或烷基氧基)意欲包括C
1、C
2、C
3、C
4、C
5、C
6烷氧基。烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(例如正丙氧基和异丙氧基)和叔丁氧基。类似地,“烷基硫基”或“硫代烷氧基”表示具有指定数量碳原子的经硫桥连接的如上文所定义的烷基;例如甲基-S-和乙基-S-。本发明优选的烷氧基包括C
1-C
6烷氧基或C
1-C
4烷氧基。
术语“羰基”是指由碳和氧两种原子通过双键连接而成的有机官能团(C=O)。
术语“芳基”,单独或作为较大部分诸如“芳烷基”、“芳烷氧基”或“芳基氧基烷基”的部分,是指具有总计5至12个环成员的单环、二环或三环的环系统,其中所述系统中的至少一个环为芳族的且其中所述系统中的每个环含有3至7个环成员。在本发明的某些实施方案中,“芳基”是指芳族环系统,其包括但不限于苯基、联苯基、茚满基、1-萘基、2-萘基和四氢萘基。术语“芳烷基”或“芳基烷基”是指连接至芳基环的烷基残基。非限制性实例包括苄基、苯乙基等。稠合的芳基可在环烷基环或芳族环的合适位置上连接至另一基团。例从环系统中画出的虚线表明键可连接至任意合适的环原子。
术语“环烷基”是指单环或二环的环状烷基。单环的环状烷基指非支化或者支化的的环状烷基,包括但不限于环丙基、环丁基、环戊基、环己基、降莰烷基、1-甲基环丙基和2-甲基环丙基。二环的环状烷基包括桥环、螺环或融合环的环烷基。本发明优选的环烷基包括C
3-C
6环烷基。
术语“环烯基”是指单环或二环的环状烯基。单环的环状烯基指非支化或者支化的环状烯基,包括但不限于环丙烯基、环丁烯基、环戊烯基、环己烯基和降莰烯基、1-甲基环丙烯基和2-甲基环丙烯基。二环的环状烯基包括桥环、螺环或稠合环的环状烯基。本发明优选的环烯基包括C
3-C
6环烯基。
“卤代”或“卤素”包括氟、氯、溴和碘。“卤代烷基”意欲包括具有指定碳原子数且取代有1个或多个卤素的支链和直链饱和脂族烃基团。卤代烷基的实例包括但不限于氟甲基、二氟甲基、三氟甲基、三氯甲基、五氟乙基、五氯乙基、2,2,2-三氟乙基、七氟丙基和七氯丙基。卤代烷基的实例还包括意欲包括具有指定碳原子数且取代有1个或多个氟原子的支链和直链饱和脂族烃基团的“氟烷基”。
“卤代烷氧基”或“卤代烷基氧基”表示具有指定数量碳原子的经氧桥连接的如上文所定义的卤代烷基。例如,“C
1-C
6卤代烷氧基”意欲包括C
1、C
2、C
3、C
4、C
5、C
6卤代烷氧基。卤代烷氧基的实例包括但不限于三氟甲氧基、2,2,2-三氟乙氧基和五氟乙氧基。类似地,“卤代烷基硫基”或“硫代卤代烷氧基”表示具有指定数量碳原子的经硫桥连接的如上文所定义的卤代烷基;例如三氟甲基-S-和五氟乙基-S-。
本公开内容中,当提到一些取代基团时使用C
x1-C
x2的表述,这表示所述取代基团中的碳原子数可以是
x1至
x2个。例如,C
0-C
8表示所述基团含有0、1、2、3、4、5、6、7或8个碳原子,C
1-C
8表示所述基团含有1、2、3、4、5、6、7或8个碳原子,C
2-C
8表示所述基团含有2、3、4、5、6、7或8个碳原子,C
3-C
8表示所述基团含有3、4、5、6、7或8个碳原子,C
4-C
8表示所述基团含有4、5、6、7或8个碳原子,C
0-C
6表示所述基团含有0、1、2、3、4、5或6个碳原子,C
1-C
6表示所述基团含有1、2、3、4、5或6个碳原子,C
2-C
6表示所述基团含有2、3、4、5或6个碳原子,C
3-C
6表示所述基团含有3、4、5或6个碳原子。
本公开内容中,当提到环状基团(例如芳基、杂芳基、环烷基和杂环烷基)时使用“x1-x2元环”的表述,这表示该基团的环原子数可以是x1至x2个。例如,所述3-12元环状基团可以是3、4、5、6、7、8、9、10、11或12元环,其环原子数可以是3、4、5、6、7、8、9、10、11或12个;3-6元环表示该环状基团可以是3、4、5或6元环,其环原子数可以是3、4、5或6个;3-8元环表示该环状基团可以是3、4、5、6、7或8元环,其环原子数可以是3、4、5、6、7或8个;3-9元环表示该环状基团可以是3、4、5、6、7、8或9元环,其环原子数可以是3、4、5、6、7、8或9个;4-7元环表示该环状基团可以是4、5、6或7元环,其环原子数可以是4、5、6或7个;5-8元环表示该环状基团可以是5、6、7或8元环,其环原子数可以是5、6、7或8个;5-12元环表示该环状基团可以是5、6、7、8、9、10、11或12元环,其环原子数可以是5、6、7、8、9、10、11或12个;6-12元环表示该环状基团可以是6、7、8、9、10、11或12元环,其环原子数可以是6、7、8、9、10、11或12个。所述环原子可以是碳原子或杂原子,例如选自N、O和S的杂原子。当 所述环是杂环时,所述杂环可以含有1、2、3、4、5、6、7、8、9、10或更多个环杂原子,例如选自N、O和S的杂原子。
本发明内容中,一个或更多个卤素可以各自独立地选自氟、氯、溴和碘。
术语“杂芳基”意指稳定的5元、6元、或7元芳香单环或芳香二环或7元、8元、9元、10元、11元、12元芳香多环杂环,其为完全不饱和的、部分不饱和的,且其含有碳原子和1个、2个、3个或4个独立地选自N、O和S的杂原子;且包括任何以下多环基团,其中上文所定义的任意杂环与苯环稠合。氮和硫杂原子可任选地被氧化。氮原子为取代的或未取代的(即N或NR,其中R为H或如果被定义,则为另一取代基)。杂环可在得到稳定结构的任何杂原子或碳原子处连接至其侧基。如果所得化合物是稳定的,则本文所述的杂环基可在碳或氮原子上被取代。杂环中的氮可任选地被季铵化。优选地,当杂环中S和O原子的总数超过1时,则这些杂原子彼此不相邻。优选地,杂环中S和O原子的总数不大于1。当使用术语“杂环”时,其意欲包括杂芳基。芳杂基的实施例包括但不限于吖啶基、氮杂环丁基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并硫代呋喃基、苯并噻吩基、苯并噁唑基、苯并噁唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异噁唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、色满基、色烯基、噌啉基、十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、咪唑并吡啶基、假吲哚基(indolenyl)、二氢吲哚基、吲嗪基、吲哚基、3H-吲哚基、靛红酰基(isatinoyl)、异苯并呋喃基、异色满基、异吲唑基、异二氢吲哚基、异吲哚基、异喹啉基、异噻唑基、异噻唑并吡啶基、异噁唑基、异噁唑并吡啶基、亚甲基二氧基苯基、吗啉基、二氮杂萘基、八氢异喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑烷基、噁唑基、噁唑并吡啶基、噁唑烷基、萘嵌间二氮杂苯基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪基、吩噻嗪基、吩噁噻基、吩噁嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、喋啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑并吡啶基、吡唑基、哒嗪基、吡啶并噁唑基、吡啶并咪唑基、吡啶并噻唑基、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2-吡咯烷酮基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四唑基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、噻吩基、噻唑并吡啶基、噻吩并噻唑基、噻吩并噁唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基和呫吨基、喹啉基、异喹啉基、酞嗪基、喹唑啉基、吲哚基、异吲哚基、二氢吲哚基、1H-吲唑基、苯并咪唑基、1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基、5,6,7,8-四氢-喹啉基、2,3-二氢-苯并呋喃基、色满基、1,2,3,4-四氢-喹喔啉基和1,2,3,4-四氢-喹唑啉基。术语“杂芳基”还可以包括由上述所定义的“芳基”与单环“杂芳基”所形成的联芳基结构,例如但不限于“-苯基联吡啶基-”、“-苯基联嘧啶基”、 “-吡啶基联苯基”、“-吡啶基联嘧啶基-”、“-嘧啶基联苯基-”;其中本发明还包括含有例如上述杂环的稠环和螺环化合物。
本文使用的术语“杂环烷基”或“杂环”指的是一个单环杂环烷基体系,或为一个二环杂环烷基体系,同时还包括螺杂环或桥杂环烷基。单环的杂环烷基指的是至少含一个选自O、N、S、P的杂原子的饱和或不饱和但不为芳香性的环状烷基体系。二环杂环烷基体系指的是一个杂环烷基与一个苯基、或一个环烷基、或一个环烯基、或一个杂环烷基、或一个杂芳基稠合而成的二环体系。优选地,所述“杂环烷基”或“杂环”中包含至少一个或两个选自O、N、S的杂原子。
本文使用的术语“桥环烷基”指的是共用两个或两个以上碳原子的多环化合物。可分为二环桥环烃及多环桥环烃。前者由两个脂环共用两个以上碳原子所构成;后者是由三个以上的环组成的桥环烃。
本文使用的术语“螺环烷基”指的是单环之间共用一个碳原子(称螺原子)的多环烃。
本文使用的术语“桥环杂基”指的是共用两个或两个以上碳原子的多环化合物,该环中至少含一个选自O、N、S原子。可分为二环桥环杂环及多环桥杂环。
本文使用的术语“杂螺环基”指的是单环之间共用一个碳原子(称螺原子)的多环烃,该环中至少含一个选自O、N、S的杂原子。
本文中所用的术语“取代”意指至少一个氢原子被非氢基团替代,条件是维持正常化合价且所述取代得到稳定的化合物。本文所用的环双键为在两个相邻环原子之间形成的双键(例如C=C、C=N或N=N)。
在本发明化合物上存在氮原子(例如胺)的情形下,可通过使用氧化剂(例如mCPBA和/或过氧化氢)进行处理来将这些氮原子转化成N-氧化物以获得本发明的其它化合物。因此,所显示和要求保护的氮原子视为均涵盖所显示氮及其N-氧化物以获得本发明衍生物。
当任何变量在化合物的任何组成或式中出现一次以上时,其每次出现时的定义均独立于其在其它每种情况下出现时的定义。因此,例如如果显示基团取代有0-3个R,则所述基团可任选地取代有至多三个R基团,且在每次出现时R独立地选自R的定义。此外,取代基和/或变量的组合仅在上述组合可产生稳定的化合物时才容许存在。
本文使用的术语“患者”是指通过本发明的方法进行治疗的有机体。这类有机体优选包括但不限于哺乳动物(例如鼠类、猿/猴、马、牛、猪、犬、猫等)且最优选是指人类。
本文使用的术语“有效量”意指将会引起例如研究人员或临床医师所寻求的组织、系统、动物或人的生物学或医学响应的药物或药剂(即本发明化合物)的量。此外,术语“治疗有效量”意指这样的量:与未接受上述量的相应受试者相比,所述量导致改善的治疗、治愈、预防或减轻疾病、病症或副作用,或降低在疾病或病症的进展速度。有效量可以一个或更多个给药、施用或剂量给予且不意欲被特定的制剂或给药途径限制。该术语还包括在其范围内的增强正常生理机能的有效量。
本文使用的术语“治疗”包括其广义上的含义,涵盖对对象的治疗性处理和/或预防性处理。具体而言,所述“治疗”包括导致病症、疾病、障碍等的缓和、抑制、消除和改善和/或预防的任何处理,例如减轻、减少、调节、改善、消除、预防、防止或改善其症状。所述治疗性处理包括缓和、抑制或改善疾病的症状或状况;抑制并发症的产生;改善潜在代谢综合征;抑制疾病或症状的产生,如控制疾病或情况的发展;减轻疾病或症状;使疾病或症状减退;减轻由疾病或症状引起的并发症,或治疗由疾病或症状引起的征兆。所述预防性处理包括事先处理以防止、阻断或延迟、减缓疾病或病症的发生或发展或者减弱疾病或病症的严重程度。
同样,“治疗剂”也包括对对象具有治疗性处理和/或预防性处理的药剂或试剂。
术语“药用”或“药学上可接受的”在本文中用于指如下那些化合物、物质、组合物和/或剂型:在合理医学判断的范围内,其适于与人类和动物的组织接触使用而无过高毒性、刺激性、过敏反应和/或其它问题或并发症,并与合理的益处/风险比相称。
本文使用的短语“药学上可接受的载体”意指药用物质、组合物或媒介物,诸如液体或固体填充剂、稀释剂、赋形剂、制造助剂(例如润滑剂、滑石、硬脂酸镁、硬脂酸钙或硬脂酸锌或硬脂酸)或溶剂包囊物质,其涉及将主题化合物从一个器官或身体的部分携带或运送至另一个器官或身体的部分。每种载体在与制剂的其它成分相容和对患者无害的意义上必须是“可接受的”。
术语“药物组合物”意指包含本发明化合物与至少一种其它药学上可接受的载体的组合物。“药学上可接受的载体”是指本领域中通常接受用于将生物活性剂递送至动物(具体为哺乳动物)的介质,包括(即)佐剂、赋形剂或媒介物,诸如稀释剂、防腐剂、填充剂、流动调控剂、崩解剂、润湿剂、乳化剂、悬浮剂、增甜剂、矫味剂、芳香剂、抗细菌剂、抗真菌剂、润滑剂和分散剂,这取决于给药模式和剂型的性质。
特定药学及医学术语
术语“可接受的”,如本文所用,指一个处方组分或活性成分对一般治疗目标的健康没有过分的有害影响。
术语“癌症”,如本文所用,指一种不能控制的细胞的异常生长,并且在某种条件下能够转移(传播)。这种类型的癌症包括但不限于,实体肿瘤(如膀胱、肠、脑、胸、子宫、心脏、肾、肺、淋巴组织(淋巴瘤)、卵巢、胰腺或其它内分泌器官(如甲状腺)、前列腺、皮肤(黑色素瘤)或血液瘤(如非白血性白血病)。
术语“联合给药”或其类似术语,如本文所用,指将几种所选的治疗药物给一个病人用药,以相同或不同的给药方式在相同或不同的时间给药。
术语“增强”或“能增强”,如本文所用,指预期的结果能够在效价或是持续时间方面都有增加或延长。因此,在增强药物的治疗效果方面,术语“能增强”指药物在系统中有提高 或延长效价或持续时间的能力。本文所用的“增效值”,指在理想的系统中,能够最大限度地的增强另外一个治疗药物的能力。
术语“免疫性疾病”指对内源性或外源性抗原产生的不良或有害反应的疾病或症状。结果通常会造成细胞的功能障碍、或因此而破坏并造成机能障碍、或破坏可能产生免疫症状的器官或组织。
术语“试剂盒”与“产品包装”是同义词。
术语“对象”、“受试者”或“病人”包括哺乳动物和非哺乳动物。哺乳动物包括但不限于,哺乳类:人、非人灵长类如猩猩、猿及猴类;农业动物如牛、马、山羊、绵羊、猪;家畜如兔、狗;实验动物包括啮齿类,如大鼠、小鼠及豚鼠等。非哺乳类动物包括但不限于,鸟、鱼等。在一优选例中,所选哺乳动物是人。
如本文所用,某一化合物或药物组合物,给药后,可以使某一疾病、症状或情况得到改善,尤指其严重度得到改善,延迟发病,减缓病情进展,或减少病情持续时间。无论固定给药或临时给药、持续给药或断续给药,可以归因于或与给药有关的情况。
具体实施例
本发明可以参考下列具体实施例得到更好的理解,所述实施例只是用于说明而非限定本发明。
原料
当未提及制备途径时,相关中间体是市售的(例如来自Sigma Aldrich,Alfa)。
通用过程
使用市售试剂而不需进一步纯化。
1H-NMR谱在Bruker仪器上于500MHz记录。化学位移值以百万分率表示,即δ值。以下简写用于NMR信号的多重性:s=单峰,brs=宽峰,d=二重峰,t=三重峰,m=多重峰。耦合常数以J值列出,以Hz测量。NMR和质谱结果根据背景峰校正。色谱是指使用100筛目硅胶进行并在氮气压力(快速色谱)条件下完成的柱色谱。用于监测反应的TLC指使用特定流动相和来自Merck的硅胶F254作为固定相进行的TLC。
LC-MS实验在以下条件下测量:
仪器:Thermo U3000,ALLtech ELSD,MSQ,UV检测器结合ELSD和MSD(流出比为4:1)。柱:Waters X-Bridge C-18,3.5μm,4.6x50mm;柱温:30℃。梯度【时间(min)/溶剂B在A中(%)】:0.00/5.0,1.40/95,2.80/95,2.82/5,3.00/5。(溶剂A=0.01%三氟 乙酸在水中;溶剂B=0.01%三氟乙酸在乙腈中)。UV检测:214/254/280/300nm;DAD检测:210-350nm;流速:2mL/min;MS:ESI,100-1500m/z
制备型HPLC通常使用碱性方法(乙腈和水的梯度,水中含有10mM碳酸氢铵);用Thermo U3000 AFC-3000;柱:Globalsil C-18 12nm,250x 20mm,10μm,或相当;流速:20mL/min,进行分离。
实施例1:
将3-氧杂环丁醇(1.26g,17.0mmol)和2,4-二氯-5-三氟甲基嘧啶(3.50g,16.1mmol)溶于四氢呋喃(50mL),0℃下缓慢滴加双(三甲基硅基)氨基锂(1M in THF,17.7mL)。混合物在0℃下搅拌3小时后,向反应体系中加入50mL氯化铵溶液,用100mL乙酸乙酯萃取两次。合并后的有机相用水洗三次,饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物通过柱层析色谱纯化得到化合物1-a(1.10g,4.33mmol),白色固体,收率26.9%。
将4-(2-吡啶基)苯甲醛(10.0g,54.6mmol)溶于乙醇(25mL)和水(10mL)的混合物,加入盐酸羟胺(4.17g,60.0mmol)和三水合醋酸钠(8.17g,60.0mmol)。混合物在室温下搅拌12小时。浓缩反应液,残留物用2mL水洗涤2次,2mL乙醇洗涤1次,过滤干燥得到化合物1-b(10.5g,53.0mmol),白色固体,收率97.0%。MS(ESI):m/z 199.4(M+H)
+.
将化合物1-b(10.5g,53.0mmol)溶于乙醇(210mL),加入钯/碳(10%w/w,1.05g)。混合物在氢气气氛下室温搅拌12小时。反应液经硅藻土过滤,浓缩。残留物用柱层析色谱纯化得到1-c(6.10g,33.1mmol),黄色油状液体,收率62.5%。MS(ESI):m/z 185.5(M+H)
+.
将化合物1-c(30.0mg,163μmol)和化合物1-a(41.5mg,163μmol)溶于N,N-二甲基甲酰胺(2mL),加入二异丙基乙基胺(63.1mg,488μmol)。混合物在80℃下搅拌2小时。 将反应液冷却至室温后,通过制备液相色谱纯化得到化合物1(10.0mg,24.8μmol),白色固体,收率15.3%。
1H NMR(500MHz,DMSO-d
6)δ8.71–8.38(m,3H),8.09–8.01(m,2H),7.93(t,J=7.0Hz,1H),7.86(td,J=7.7,1.9Hz,1H),7.41(d,J=8.0Hz,2H),7.36–7.31(m,1H),5.67–5.52(m,1H),4.92–4.70(m,2H),4.62–4.41(m,4H);MS(ESI):m/z 403.4(M+H)
+.
实施例2:
将化合物2-a(200mg,664μmol)和2,4,5-三氯嘧啶(122mg,664μmol)溶于乙腈(3mL)和水(3mL)的混合物,加入碳酸钠(141mg,1.33mmol)和四三苯基膦钯(38.2mg,33.1μmol)。混合物在氮气气氛和90℃条件下搅拌16小时。将反应液冷却至室温,加入30mL乙酸乙酯,用硅藻土过滤,滤液用水洗三次,饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物通过柱层析色谱纯化得到化合物2-b(150mg,371μmol),白色固体,收率55.9%。
将化合物2-b(50.0mg,124μmol)和化合物1-c(27.3mg,148μmol)溶于N,N-二甲基甲酰胺(2mL),加入碳酸钠(32.8mg,309μmol)。混合物在80℃下搅拌8小时。将反应液冷却至室温,加入30mL乙酸乙酯,用水洗三次,饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物通过柱层析色谱纯化得到化合物2-c(50.0mg,90.6μmol),淡黄色固体,收率73.2%。
将化合物2-c(50.0mg,90.6μmol)溶于1,4-二氧六环(2mL),加入氢氧化钠溶液(1N,0.5mL)。混合物在40℃下搅拌4小时。将反应液冷却至室温,用1N的盐酸将pH调至7后浓缩至干。残留物通过制备液相色谱纯化得到化合物2(6.0mg,14.6μmol),白色固体,收率16.1%。
1H NMR(500MHz,DMSO-d
6)δ11.79(s,1H),8.64–8.60(m,1H),8.41(s,1H), 8.27(s,1H),8.19–8.01(m,3H),7.96–7.88(m,2H),7.86–7.80(m,1H),7.51–7.39(m,3H),7.33–7.27(m,1H),7.27–6.77(m,2H),4.65(s,2H);MS(ESI):m/z 412.3(M+H)
+.
实施例3:
将3-氧杂环丁醇(242mg,3.27mmol)溶于四氢呋喃(10mL),0℃下缓慢加入氢化钠(60%w/w,131mg,3.27mmol)。混合物在0℃下搅拌1小时后,将2,4,5-三氯嘧啶(500mg,2.73mmol)的四氢呋喃(5mL)溶液缓慢滴加至反应体系,之后升至室温搅拌1小时。向反应体系中加入15mL氯化铵溶液,用50mL乙酸乙酯分两次萃取。合并后的有机相用水洗三次,饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物通过柱层析色谱纯化得到化合物3-a(600mg,2.71mmol),白色固体,收率99.6%。
将化合物3-a(50.0mg,226μmol)和化合物1-c(41.7mg,226μmol)溶于1,4-二氧六环(3mL),加入Pd(dba)
2(20.7mg,22.6μmol),Xantphos(13.1mg,22.6μmol),碳酸铯(147mg,452μmol)。混合物在氮气气氛和100℃下搅拌16小时后,将反应液冷却至室温后浓缩。残留物通过制备液相色谱纯化得到化合物3(13.0mg,35.2μmol),白色固体,收率15.6%。
1H NMR(500MHz,Chloroform-d)δ8.76–8.67(m,1H),8.08(s,1H),8.01–7.96(m,2H),7.80–7.70(m,2H),7.41(d,J=7.9Hz,2H),7.30–7.28(m,1H),7.26–7.23(m,1H),5.61–5.51(m,1H),4.96–4.82(m,2H),4.79–4.70(m,2H),4.66–4.56(m,2H);MS(ESI):m/z 369.4(M+H)
+.
实施例4:
将(6-氰基吡啶-3-基)硼酸(1.00g,6.76mmol)和2-溴吡啶(1.07g,6.76mmol)溶于二氧六环(10mL)和水(1mL)的混合溶剂,加入碳酸钾(1.87g,13.5mmol)和1,1'-二(二苯膦基)二茂铁二氯化钯(II)(495mg,676μmol)。混合物在氮气保护和95℃下搅拌6小时。将反应液冷却至室温,加入50mL乙酸乙酯,经硅藻土过滤。滤液用水洗三次,饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物通过柱层析色谱纯化得到化合物4-a(760mg,4.19mmol),白色固体,收率62.0%。
将化合物4-a(760mg,4.19mmol)溶于乙醇(10mL),加入钯/碳(10%w/w,76.0mg)。混合物在氢气气氛下室温搅拌12小时。反应液经硅藻土过滤,浓缩。残留物用柱层析色谱纯化得到化合物4-b(300mg,1.62mmol),黄色油状液体,收率38.6%。
将化合物4-b(36.4mg,196μmol)和化合物1-a(50.0mg,196μmol)溶于N,N-二甲基甲酰胺(2mL),加入二异丙基乙基胺(76.2mg,589μmol)。混合物在80℃下搅拌2小时。将反应液冷却至室温后,通过制备液相色谱纯化得到化合物4(20.0mg,49.6μmol),白色固体,收率25.2%。
1H NMR(500MHz,DMSO-d
6)δ9.24–9.17(m,1H),8.73–8.36(m,4H),8.06–8.00(m,1H),7.94–7.90(m,1H),7.43–7.37(m,2H),5.69–5.40(m,1H),4.94–4.32(m,6H);MS(ESI):m/z 404.4(M+H)
+.
实施例5:
从4-(3-吡啶基)苯甲醛起,参照化合物1的合成得到化合物5。
1H NMR(500MHz,DMSO-d
6)δ8.91–8.84(m,1H),8.74–8.37(m,3H),8.09–8.03(m,1H),7.75–7.66(m,2H), 7.50–7.39(m,3H),5.68–5.53(m,1H),4.92–4.72(m,2H),4.61–4.43(m,4H);MS(ESI):m/z 403.4(M+H)
+.
实施例6:
从4-(4-吡啶基)苯甲醛起,参照化合物1的合成得到化合物6。
1H NMR(500MHz,DMSO-d
6)δ8.73–8.39(m,4H),7.81–7.74(m,2H),7.72–7.67(m,2H),7.47–7.42(m,2H),5.67–5.51(m,1H),4.92–4.70(m,2H),4.62–4.41(m,4H);MS(ESI):m/z 403.4(M+H)
+.
实施例7:
从4-联苯甲醛起,参照化合物1的合成得到化合物7。
1H NMR(500MHz,DMSO-d
6)δ8.72–8.37(m,2H),7.69–7.58(m,4H),7.49–7.42(m,2H),7.41–7.33(m,3H),5.67–5.53(m,1H),4.91–4.71(m,2H),4.61–4.42(m,4H);MS(ESI):m/z 402.4(M+H)
+.
实施例8:
从3-氧杂环丁胺起,参照化合物1的合成得到化合物8。
1H NMR(500MHz,Chloroform-d)δ8.74–8.68(m,1H),8.23–8.06(m,1H),8.03–7.95(m,2H),7.80–7.71(m,2H),7.48–7.37(m,2H),7.31–7.29(m,1H),7.27–7.23(m,1H),5.60–5.34(m,1H),5.19–5.02(m,1H),5.00–4.82(m,2H),4.71–4.51(m,4H);MS(ESI):m/z 402.3(M+H)
+.
实施例9:
从2,4-二氯-5-氰基嘧啶起,参照化合物1的合成得到化合物9。
1H NMR(500MHz,Chloroform-d)δ8.73(d,J=4.6Hz,1H),8.48–8.29(m,1H),8.02(dd,J=8.3,2.1Hz,2H),7.87–7.79(m,1H),7.79–7.72(m,1H),7.48–7.37(m,2H),7.32–7.29(m,1H),6.34–5.72(m,1H),5.66–5.56(m,1H),4.99–4.57(m,6H);MS(ESI):m/z 360.4(M+H)
+.
实施例10:
从2,5-二氯-4-甲氧基嘧啶起,参照化合物2的合成得到化合物10。
1H NMR(500MHz,DMSO-d
6)δ8.69–8.63(m,1H),8.10(s,1H),8.06–8.01(m,2H),7.95–7.91(m,1H),7.91–7.84(m,1H),7.48–7.32(m,4H),4.52(d,J=6.3Hz,2H),3.90(s,3H);MS(ESI):m/z 327.3(M+H)
+.
实施例11:
将2,4-二氯-5-三氟甲基嘧啶(300mg,1.38mmol),三乙胺(251mg,2.49mmol),氯化锌(565mg,4.15mmol)溶于叔丁醇(4mL)和1,2-二氯乙烷(4mL)的混合物。混合物在冰浴下搅拌30分钟,加入化合物1-c(254mg,1.38mmol),之后在50℃下搅拌16小时。将混合物冷却至室温,加入20mL水,用1N盐酸将pH调至4,用20mL二氯甲烷萃取三次。 合并有机相,用水洗三次,饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物通过柱层析色谱纯化得到化合物11-a(210mg,575μmol),白色固体,收率41.64%。
将化合物11-a(30mg,82.3μmol)和(1-甲基-1H-吡唑-3-基)硼酸(20.7mg,164μmol)溶于1,4-二氧六环(3mL)和水(0.3mL)的混合物,加入碳酸钾(34.1mg,246μmol)和1,1'-二(二苯膦基)二茂铁二氯化钯(II)(3.0mg,4.11μmol)。混合物在氮气气氛95℃下搅拌3小时。将反应液冷却至室温,加入20mL乙酸乙酯,用硅藻土过滤,滤液用水洗三次,饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物通过制备液相色谱纯化得到化合物11(10.0mg,24.4μmol),白色固体,收率29.6%。
1H NMR(500MHz,Chloroform-d)δ8.81–8.52(m,2H),8.06–7.89(m,2H),7.81–7.69(m,2H),7.52–7.44(m,2H),7.41(s,1H),7.25–7.23(m,1H),6.78(s,1H),6.16–5.75(m,1H),4.78(d,J=5.4Hz,2H),4.10–3.95(m,3H);MS(ESI):m/z 411.4(M+H)
+.
实施例12:
将N-BOC-4-溴苄胺(3.00g,10.5mmol)和双联硼酸频那醇酯(2.93g,11.5mmol)溶于1,4-二氧六环(45mL),加入1,1'-二(二苯膦基)二茂铁二氯化钯(II)(383mg,524μmol)和醋酸钾(3.09g,31.5mmol)。混合物在氮气气氛95℃下搅拌16小时。将反应液冷却至室温,加入50mL乙酸乙酯,用硅藻土过滤,滤液浓缩。残留物通过柱层析色谱纯化得到化合物12-a(3.30g,9.90mmol),无色油状液体,收率94.5%。
将化合物12-a(100mg,300μmol)和2-溴苯甲醚(56.1mg,300μmol)溶于1,4-二氧六环(3mL)和水(0.3mL)的混合物,加入碳酸钾(124mg,900μmol)和1,1'-二(二苯膦基) 二茂铁二氯化钯(II)(11.0mg,15.0μmol)。混合物在氮气气氛95℃下搅拌3小时。将反应液冷却至室温,加入20mL乙酸乙酯,用硅藻土过滤,滤液用水洗三次,饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物通过柱层析色谱纯化得到化合物12-b(80.0mg,255μmol),无色油状液体,收率85.1%。
将化合物12-b(80mg,255μmol)溶于二氯甲烷(2mL),加入氯化氢二氧六环溶液(4N,1mL)。混合物在室温下搅拌2小时。将反应液直接浓缩得到化合物12-c(63.8mg,255μmol),盐酸盐,白色固体,收率100%。
将化合物12-c(29.4mg,118μmol)和化合物1-a(30mg,118μmol)溶于N,N-二甲基甲酰胺(2mL),加入二异丙基乙基胺(45.7mg,354μmol)。混合物在80℃下搅拌2小时。将反应液冷却至室温,通过制备液相色谱纯化得到化合物12(15.0mg,34.8μmol),白色固体,收率29.5%。
1H NMR(400MHz,DMSO-d
6)δ8.70–8.38(m,2H),7.44–7.30(m,5H),7.29–7.20(m,1H),7.15–6.94(m,2H),5.66–5.56(m,1H),4.91–4.73(m,2H),4.67–4.35(m,4H),3.88–3.61(m,3H);MS(ESI):m/z 432.4(M+H)
+.
实施例13:
从3-溴-5-(甲基磺酰基)吡啶起,参照化合物12-a的合成得到化合物13-a。从13-a起,参照化合物11的合成得到化合物13。
1H NMR(500MHz,DMSO-d
6)δ9.27–9.18(m,1H),9.05–8.88(m,2H),8.82–8.72(m,1H),8.68–8.61(m,1H),8.53–8.39(m,1H),8.07–8.00(m,2H),7.98–7.82(m,2H),7.50–7.41(m,2H),7.39–7.28(m,1H),4.72–4.56(m,2H),3.40–3.37(m,3H);MS(ESI):m/z 486.3(M+H)
+.
实施例14:
从苯酚起,参照化合物9的合成得到化合物14。
1H NMR(400MHz,DMSO-d
6)δ9.05–8.72(m,1H),8.72–8.61(m,2H),8.05–7.85(m,4H),7.55–7.44(m,2H),7.41–7.27(m,4H),7.26–7.21(m,1H),6.99–6.95(m,1H),4.63–4.06(m,2H);MS(ESI):m/z 380.4(M+H)
+.
实施例15:
从2-溴-6-甲基吡啶起,参照化合物12的合成得到化合物15。
1H NMR(400MHz,DMSO-d
6)δ8.74–8.39(m,2H),8.09–7.98(m,2H),7.78–7.69(m,2H),7.40(d,J=8.0Hz,2H),7.20(dd,J=6.8,1.5Hz,1H),5.68–5.50(m,1H),4.93–4.68(m,2H),4.61–4.39(m,4H),2.53(s,3H);MS(ESI):m/z 417.4(M+H)
+.
实施例16:
从2-溴-6-三氟甲基吡啶起,参照化合物12的合成得到化合物16。
1H NMR(400MHz,DMSO-d
6)δ8.76–8.45(m,1H),8.44–8.39(m,1H),8.30–8.23(m,1H),8.20–8.14(m,1H),8.13–8.06(m,2H),7.85(d,J=7.6Hz,1H),7.50–7.43(m,2H),5.69–5.49(m,1H),4.93–4.68(m,2H),4.64–4.40(m,4H).;MS(ESI):m/z 471.1(M+H)
+.
实施例17:
从2-溴-6-甲氧基吡啶起,参照化合物12的合成得到化合物17。
1H NMR(400MHz,DMSO-d
6)δ8.75–8.37(m,2H),8.11–8.00(m,2H),7.81–7.73(m,1H),7.57–7.50(m,1H),7.44–7.37(m,2H),6.80–6.73(m,1H),5.68–5.50(m,1H),4.92–4.68(m,2H),4.61–4.40(m,4H),3.99–3.92(m,3H);MS(ESI):m/z 433.4(M+H)
+.
实施例18:
从2-溴-6-羟甲基吡啶起,参照化合物12的合成得到化合物18。
1H NMR(400MHz,DMSO-d
6)δ8.74–8.39(m,2H),8.08–8.00(m,2H),7.90–7.84(m,1H),7.81–7.76(m,1H),7.44–7.38(m,3H),5.68–5.50(m,1H),5.49–5.43(m,1H),4.91–4.69(m,2H),4.65–4.61(m,2H),4.61–4.41(m,4H);MS(ESI):m/z 433.4(M+H)
+.
实施例19:
从2-溴嘧啶起,参照化合物12的合成得到化合物19。
1H NMR(400MHz,DMSO-d
6)δ8.92–8.87(m,2H),8.75–8.44(m,1H),8.44–8.40(m,1H),8.39–8.32(m,2H),7.47–7.42(m,3H),5.68–5.49(m,1H),4.92–4.66(m,2H),4.64–4.39(m,4H);MS(ESI):m/z 403.9(M+H)
+.
实施例20:
将4-羟基-3-甲氧基苯甲腈(2.00g,13.4mmol)溶于乙腈(30mL)和N,N-二甲基甲酰胺(5mL),加入N-苯基双(三氟甲烷磺酰)亚胺(5.74g,14.8mmol)和碳酸铯(6.55g,20.1mmol)。混合物在室温下搅拌16小时。向反应液加入50mL乙酸乙酯,用2N氢氧化钠洗涤三次,用水洗三次,饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩得到化合物20-a(3.40g,12.1mmol),棕色油状化合物,收率90.2%。
将化合物20-a(1.00g,3.56mmol)和(2-吡啶基)三丁基锡烷(1.44g,3.91mmol)溶于N,N-二甲基甲酰胺(20mL),加入氯化锂(196mg,4.62mmol)和四三苯基膦钯(411mg,356μmol)。混合物在氮气气氛95℃下搅拌5小时。将反应液冷却至室温,加入50mL乙酸乙酯和100mL 1N氟化钾溶液,搅拌1小时。混合物用硅藻土过滤,有机相用水洗三次,饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物通过柱层析色谱纯化得到化合物20-b(450mg,2.14mmol),白色固体,收率60.2%。
将氢化锂铝(158mg,4.16mmol)与四氢呋喃(10mL)加热至70℃,在10分钟内缓慢滴加化合物20-b(350mg,1.66mmol)的四氢呋喃(5mL)溶液。混合物在70℃下继续搅拌10分钟。将反应液冷却至室温,加入0.16mL水和0.16mL的10%氢氧化钠溶液,搅拌30分钟。混合物经硅藻土过滤,滤液加入20mL乙酸乙酯,用水洗三次,饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩得到20-c(320mg,1.49mmol),淡黄色油状化合物,收率90.1%。
将化合物20-c(25.2mg,118μmol)和化合物1-a(30.0mg,118μmol)溶于N,N-二甲基甲酰胺(2mL),加入二异丙基乙基胺(45.7mg,354μmol)。混合物在80℃下搅拌2小时。将反应液冷却至室温后,通过制备液相色谱纯化得到化合物20(8.5mg,19.7μmol),白色固体,收率16.7%。
1H NMR(400MHz,DMSO-d
6)δ8.73–8.39(m,3H),7.87–7.75(m,2H),7.74–7.65(m,1H),7.35–7.26(m,1H),7.12(s,1H),7.03–6.95(m,1H),5.69–5.54(m,1H),4.93–4.74(m,2H),4.62–4.42(m,4H),3.90–3.77(m,3H);MS(ESI):m/z 433.4(M+H)
+.
实施例21:
从2-溴吡嗪起,参照化合物12的合成得到化合物21。
1H NMR(500MHz,DMSO-d
6)δ9.28–9.21(m,1H),8.75–8.38(m,4H),8.16–8.07(m,2H),7.51–7.44(m,2H),5.71–5.49(m,1H),4.95–4.42(m,6H);MS(ESI):m/z 404.2(M+H)
+.
实施例22:
从2,4-二氯-5-氟嘧啶起,参照化合物3的合成得到化合物22。
1H NMR(500MHz,DMSO-d
6)δ8.70–8.62(m,1H),8.17(d,J=3.2Hz,1H),8.04(d,J=8.3Hz,2H),7.93(dd,J=8.0,1.2Hz,1H),7.87(td,J=7.7,1.9Hz,1H),7.81(s,2H),7.41(d,J=8.2Hz,2H),5.65–5.45(m,1H),4.91–4.66(m,2H),4.64–4.34(m,4H);MS(ESI):m/z 353.3(M+H)
+.
实施例23:
从2,4-二氯-5-氰基嘧啶和咪唑并[1,2-a]吡啶-6-硼酸起,参照化合物11的合成得到化合物23。
1H NMR(500MHz,DMSO-d
6)δ9.23(s,1H),9.10–8.99(m,1H),8.90–8.79(m,1H),8.65(t,J=5.2Hz,1H),8.22–8.14(m,1H),8.06(dd,J=8.2,4.2Hz,2H),7.98–7.84(m,2H),7.83–7.59(m,3H),7.58–7.40(m,2H),7.40–7.29(m,1H),4.79–4.66(m,2H);MS(ESI):m/z 404.2(M+H)
+.
实施例24:
将化合物11-a(30.0mg,82.2μmol)和吗啉(14.3mg,164μmol)溶于N,N-二甲基甲酰胺(2mL),加入二异丙基乙基胺(45.7mg,353μmol)。混合物在80℃下搅拌2小时。将反应液冷却至室温后,通过制备液相色谱纯化得到化合物24(10mg,24.07μmol),白色固体,收率29.27%。
1H NMR(500MHz,DMSO-d
6)δ8.68–8.60(m,1H),8.32–8.23(m,1H),8.23–8.00(m,3H),7.95–7.90(m,1H),7.89–7.84(m,1H),7.46–7.37(m,2H),7.36–7.30(m,1H),4.62–4.45(m,2H),3.70–3.53(m,4H),3.52–3.41(m,4H);MS(ESI):m/z 416.4(M+H)
+.
实施例25:
从(R)-2-氨基丁醇起,参照化合物24的合成得到化合物25。
1H NMR(500MHz,DMSO-d
6)δ8.68–8.62(m,1H),8.08–7.76(m,6H),7.45–7.37(m,2H),7.37–7.30(m,1H),5.94–5.81(m,1H),4.82–4.71(m,1H),4.61–4.41(m,2H),4.27–4.04(m,1H),3.54–3.35(m,2H),1.68–1.40(m,2H),0.91–0.65(m,3H);MS(ESI):m/z 418.4(M+H)
+.
实施例26:
将化合物11-a(30.0mg,82.3μmol)和氧杂环丁烷-3-基甲醇(10.9mg,123μmol)溶于四氢呋喃(4mL),加入叔丁醇钾(18.5mg,164μmol)。混合物在80℃下搅拌16小时。将反应液冷却至室温后,加入10mL氯化铵,用20mL乙酸乙酯萃取。有机相用水洗三次,饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物通过制备液相色谱纯化得到化合物26(15.0mg,36.0μmol),白色固体,收率43.8%。
1H NMR(500MHz,DMSO-d
6)δ8.70–8.45(m,2H),8.39–8.32(m,1H),8.08–8.01(m,2H),7.95–7.90(m,1H),7.90–7.84(m,1H),7.48–7.39(m,2H),7.36–7.31(m,1H),4.70–4.64(m,1H),4.61–4.32(m,7H),3.30–3.23(m,1H);MS(ESI):m/z 417.3(M+H)
+.
实施例27:
从3-溴吡啶起,参照化合物4的合成得到化合物27。
1H NMR(500MHz,DMSO-d
6)δ8.99–8.86(m,2H),8.72–8.38(m,3H),8.19–8.07(m,2H),7.59–7.48(m,1H),7.47–7.37(m,1H),5.73–5.39(m,1H),4.95–4.54(m,5H),4.41–4.35(m,1H);MS(ESI):m/z 404.3(M+H)
+.
实施例28:
从苯甲醇起,参照化合物26的合成得到化合物28。
1H NMR(500MHz,DMSO-d
6)δ8.68–8.48(m,2H),8.42–8.34(m,1H),8.06–8.01(m,2H),7.95–7.89(m,1H),7.90–7.84(m,1H),7.49–7.25(m,8H),5.52–5.43(m,2H),4.66–4.55(m,2H);MS(ESI):m/z 437.5(M+H)
+.
实施例29:
从苯硼酸起,参照化合物11的合成得到化合物29。
1H NMR(500MHz,DMSO-d
6)δ8.79–8.57(m,3H),8.10–7.98(m,2H),7.97–7.91(m,1H),7.90–7.81(m,1H),7.55–7.40(m,7H),7.38–7.28(m,1H),4.71–4.57(m,2H);MS(ESI):m/z 407.2(M+H)
+.
实施例30:
从吡啶-3-基硼酸起,参照化合物11的合成得到化合物30。
1H NMR(500MHz,DMSO-d
6)δ8.86–8.78(m,1H),8.78–8.57(m,4H),8.08–8.02(m,2H),7.96–7.84(m,3H),7.58–7.51(m,1H),7.49–7.40(m,2H),7.37–7.30(m,1H),4.69–4.60(m,2H);MS(ESI):m/z 408.4(M+H)
+.
实施例31:
从吡啶-4-基硼酸起,参照化合物11的合成得到化合物31。
1H NMR(500MHz,DMSO-d
6)δ8.94–8.80(m,1H),8.80–8.68(m,3H),8.68–8.59(m,1H),8.10–8.00(m,2H),7.97–7.91(m,1H),7.91–7.81(m,1H),7.54–7.38(m,4H),7.38–7.28(m,1H),4.72–4.55(m,2H);MS(ESI):m/z 408.3(M+H)
+.
实施例32:
从(5-氟-2-甲氧基苯基)硼酸起,参照化合物11的合成得到化合物32。
1H NMR(500MHz,DMSO-d
6)δ8.78–8.57(m,3H),8.11–7.98(m,2H),7.98–7.91(m,1H),7.91–7.82(m,1H),7.51–7.37(m,2H),7.37–7.22(m,2H),7.21–7.01(m,2H),4.76–4.46(m,2H),3.74–3.61(m,3H);MS(ESI):m/z 455.3(M+H)
+.
实施例33:
从2-溴-6-(甲氧基甲基)吡啶起,参照化合物12的合成得到化合物33。
1H NMR(500MHz,DMSO-d
6)δ8.72–8.38(m,2H),8.09–7.81(m,4H),7.46–7.34(m,3H),5.70–5.52(m,1H),4.92–4.71(m,2H),4.61–4.42(m,6H),3.41(s,3H);MS(ESI):m/z 447.3(M+H)
+.
实施例34:
从四氢吡喃-4-醇起,参照化合物26的合成得到化合物34。
1H NMR(500MHz,DMSO-d
6)δ8.68–8.63(m,1H),8.63–8.40(m,1H),8.39–8.32(m,1H),8.08–8.00(m,2H),7.95–7.90(m,1H),7.90–7.83(m,1H),7.46–7.38(m,2H),7.37–7.29(m,1H),5.45–5.17 (m,1H),4.65–4.46(m,2H),3.85–3.64(m,2H),3.59–3.39(m,2H),2.05–1.73(m,2H),1.71–1.43(m,2H);MS(ESI):m/z 431.3(M+H)
+.
实施例35:
从N-甲基-4-哌啶醇起,参照化合物26的合成得到化合物35。
1H NMR(500MHz,DMSO-d
6)δ8.68–8.63(m,1H),8.62–8.36(m,1H),8.37–8.30(m,1H),8.06–8.00(m,2H),7.95–7.89(m,1H),7.90–7.83(m,1H),7.47–7.38(m,2H),7.37–7.30(m,1H),5.25–4.99(m,1H),4.62–4.47(m,2H),2.46–2.21(m,2H),2.19–2.10(m,4H),1.97–1.51(m,4H);MS(ESI):m/z 444.4(M+H)
+.
实施例36:
从2,4-二氯-5-甲基嘧啶起,参照化合物3的合成得到化合物36。
1H NMR(500MHz,DMSO-d
6)δ8.70–8.61(m,1H),8.03(d,J=8.0Hz,2H),7.93(d,J=9.0Hz,2H),7.86(td,J=7.7,1.8Hz,1H),7.64–7.45(m,1H),7.40(d,J=8.0Hz,2H),7.33(dd,J=7.4,4.8Hz,1H),5.61–5.36(m,1H),4.95–4.62(m,2H),4.61–4.32(m,4H),1.96(s,3H);MS(ESI):m/z 349.3(M+H)
+.
实施例37:
从2,4-二氯-5-溴嘧啶起,参照化合物1的合成得到化合物37。
1H NMR(500MHz,DMSO-d
6)δ8.73–8.58(m,1H),8.22(s,1H),8.19–7.81(m,5H),7.39(d,J=8.0Hz,2H), 7.37–7.29(m,1H),5.65–5.37(m,1H),4.98–4.65(m,2H),4.64–4.35(m,4H);MS(ESI):m/z 413.2(M+H)
+.
实施例38:
从2,4-二氯-5-碘嘧啶起,参照化合物1的合成得到化合物38。
1H NMR(500MHz,DMSO-d
6)δ8.64(d,J=4.8Hz,1H),8.29(s,1H),8.16–7.96(m,3H),7.92(d,J=8.0Hz,1H),7.88–7.83(m,1H),7.39(d,J=8.0Hz,2H),7.33(dd,J=7.3,4.9Hz,1H),5.61–5.36(m,1H),4.96–4.64(m,2H),4.61–4.37(m,4H);MS(ESI):m/z 461.2(M+H)
+.
实施例39:
从2-溴-3-甲基吡啶起,参照化合物12的合成得到化合物39。
1H NMR(500MHz,DMSO-d
6)δ8.74–8.34(m,3H),7.76–7.49(m,3H),7.46–7.24(m,3H),5.71–5.52(m,1H),4.93–4.68(m,2H),4.66–4.42(m,4H),2.34–2.26(m,3H);MS(ESI):m/z 417.4(M+H)
+.
实施例40:
从2-溴-4-甲基吡啶起,参照化合物12的合成得到化合物40。
1H NMR(500MHz,DMSO-d
6)δ8.73–8.36(m,3H),8.13–7.73(m,3H),7.47–7.14(m,3H),5.69–5.51(m,1H),4.93–4.69(m,2H),4.62–4.40(m,4H),2.38(s,3H);MS(ESI):m/z 417.4(M+H)
+.
实施例41:
从2-溴-5-甲基吡啶起,参照化合物12的合成得到化合物41。
1H NMR(500MHz,DMSO-d
6)δ8.69–8.37(m,3H),8.06–7.81(m,3H),7.74–7.38(m,3H),5.70–5.52(m,1H),4.92–4.71(m,2H),4.62–4.49(m,3H),4.46–4.43(m,1H),2.33(s,3H);MS(ESI):m/z 417.6(M+H)
+.
实施例42:
从2-氯-3-吡啶甲醇起,参照化合物12的合成得到化合物42。
1H NMR(500MHz,DMSO-d
6)δ8.72–8.34(m,3H),7.98–7.93(m,1H),7.57–7.52(m,2H),7.43–7.37(m,3H),5.71–5.53(m,1H),5.44–5.32(m,1H),4.94–4.70(m,2H),4.67–4.42(m,6H);MS(ESI):m/z 433.4(M+H)
+.
实施例43:
从(2-氯-4-吡啶基)甲醇起,参照化合物12的合成得到化合物43。
1H NMR(500MHz,DMSO-d
6)δ8.74–8.35(m,3H),8.11–7.83(m,3H),7.48–7.26(m,3H),5.71–5.52(m,1H),5.49–5.43(m,1H),4.95–4.70(m,2H),4.63–4.42(m,6H);MS(ESI):m/z 433.4(M+H)
+.
实施例44:
从(1-(4-溴苯基)乙基)氨基甲酸叔丁酯起,参照化合物12的合成得到化合物44。
1H NMR(500MHz,DMSO-d
6)δ8.75–8.35(m,3H),8.12–8.00(m,2H),7.98–7.83(m,2H),7.57–7.28(m,3H),5.77–5.46(m,1H),5.30–4.18(m,5H),1.55–1.44(m,3H);MS(ESI):m/z 417.4(M+H)
+.
实施例45:
从2-(6-氯吡啶-2-基)丙-2-醇起,参照化合物12的合成得到化合物45。
1H NMR(500MHz,DMSO-d
6)δ8.72–8.39(m,2H),8.11–8.01(m,2H),7.87–7.72(m,2H),7.62–7.39(m,3H),5.68–5.52(m,1H),5.24(s,1H),4.92–4.72(m,2H),4.61–4.44(m,4H),1.51(s,6H);MS(ESI):m/z 461.4(M+H)
+.
实施例46:
从1-(6-氯吡啶-2-基)-N,N-二甲基甲胺起,参照化合物12的合成得到化合物46。
1H NMR(500MHz,DMSO-d
6)δ8.73–8.37(m,2H),8.11–7.75(m,4H),7.46–7.34(m,3H),5.72–5.51(m,1H),4.98–4.67(m,2H),4.63–4.38(m,4H),3.58(s,2H),2.23(s,6H);MS(ESI):m/z 460.4(M+H)
+.
实施例47:
从1-(二氟甲基)-1H-吡唑-3-硼酸频哪醇酯起,参照化合物11的合成得到化合物47。
1H NMR(500MHz,DMSO-d
6)δ8.84–8.68(m,2H),8.68–8.62(m,1H),8.42–8.33(m,1H), 8.05(d,J=8.0Hz,2H),8.03–7.76(m,3H),7.52–7.42(m,2H),7.38–7.29(m,1H),6.96–6.88(m,1H),4.70–4.64(m,2H);MS(ESI):m/z 447.4(M+H)
+.
实施例48:
从((6-氯吡啶-3-基)甲基)氨基甲酸叔丁酯起,参照化合物12的合成得到化合物48。
1H NMR(500MHz,DMSO-d
6)δ9.27–9.22(m,1H),8.72–8.37(m,5H),8.06–7.99(m,1H),7.86–7.80(m,1H),7.55–7.48(m,1H),5.70–5.53(m,1H),4.93–4.74(m,2H),4.63–4.45(m,4H);MS(ESI):m/z 404.3(M+H)
+.
实施例49:
从2-甲氧基乙胺起,参照化合物24的合成得到化合物49。
1H NMR(500MHz,DMSO-d
6)δ8.71–8.56(m,1H),8.07–7.79(m,6H),7.46–7.26(m,3H),6.81–6.51(m,1H),4.63–4.43(m,2H),3.62–3.38(m,3H),3.29–3.24(m,2H),3.17–3.07(m,2H);MS(ESI):m/z 404.3(M+H)
+.
实施例50:
从N,N,N'-三甲基乙二胺起,参照化合物24的合成得到化合物50。
1H NMR(500MHz,DMSO-d
6)δ8.64(d,J=5.0Hz,1H),8.24–8.17(m,1H),8.08–7.95(m,3H),7.94–7.88(m,1H),7.88–7.83(m,1H),7.38(d,J=7.9Hz,2H),7.32(dd,J=7.3,4.9Hz,1H),4.53(d,J=6.4Hz,2H),3.64–3.49(m,2H),3.01(s,3H),2.41–2.28(m,2H),2.20–2.01(m,6H);MS(ESI):m/z 431.5(M+H)
+.
实施例51:
从(S)-2-氨基丁醇起,参照化合物24的合成得到化合物51。
1H NMR(500MHz,DMSO-d
6)δ8.66–8.60(m,1H),8.10–7.99(m,3H),7.99–7.81(m,3H),7.45–7.37(m,2H),7.35–7.29(m,1H),5.94–5.78(m,1H),4.84–4.67(m,1H),4.62–4.35(m,2H),4.23–4.02(m,1H),3.56–3.35(m,2H),1.61–1.37(m,2H),0.88–0.67(m,3H);MS(ESI):m/z 418.4(M+H)
+.
实施例52:
从甘氨酰胺盐酸盐起,参照化合物24的合成得到化合物52。
1H NMR(500MHz,DMSO-d
6)δ8.74–8.57(m,1H),8.12–7.94(m,4H),7.94–7.82(m,2H),7.51–7.29(m,4H),7.17–7.04(m,1H),6.93–6.63(m,1H),4.59–4.45(m,2H),3.98–3.86(m,2H);MS(ESI):m/z 403.2(M+H)
+.
实施例53:
从6-氯吡啶-2-甲酸甲酯起,参照化合物12的合成得到化合物53-a。
将化合物53-a(30.0mg,65.2μmol)溶于四氢呋喃(2mL)和甲醇(1mL)的混合溶剂,加入1N氢氧化钠溶液(1mL)。混合物在室温下搅拌6小时。向反应液中加入1N盐酸溶液至pH=7,浓缩至干。残留物通过制备液相色谱纯化得到化合物53(10.1mg,22.4μmol),白色固体,收率34.4%。
1H NMR(500MHz,DMSO-d
6)δ8.70–8.37(m,2H),8.21–8.02(m, 3H),8.01–7.88(m,2H),7.50–7.40(m,2H),5.72–5.49(m,1H),4.93–4.70(m,2H),4.64–4.38(m,4H);MS(ESI):m/z 447.4(M+H)
+.
实施例54:
从(R)-2-哌啶甲醇起,参照化合物24的合成得到化合物54。
1H NMR(500MHz,DMSO-d
6)δ8.73–8.57(m,1H),8.26–8.14(m,1H),8.12–7.98(m,3H),7.98–7.80(m,2H),7.49–7.28(m,3H),4.68–4.60(m,1H),4.60–4.46(m,2H),4.36–4.24(m,1H),3.73–3.43(m,3H),3.12–2.99(m,1H),1.87–1.74(m,1H),1.64–1.35(m,5H);MS(ESI):m/z 444.5(M+H)
+.
实施例55:
从N,N-二甲基乙醇胺起,参照化合物26的合成得到化合物55。
1H NMR(500MHz,DMSO-d
6)δ8.66–8.62(m,1H),8.61–8.37(m,1H),8.36–8.29(m,1H),8.08–7.99(m,2H),7.96–7.83(m,2H),7.46–7.29(m,3H),4.66–4.51(m,2H),4.51–4.36(m,2H),2.65–2.51(m,2H),2.24–2.06(m,6H);MS(ESI):m/z 418.5(M+H)
+.
实施例56:
从1-(6-溴吡啶-2-基)乙烷-1-醇起,参照化合物12的合成得到化合物56。
1H NMR(500MHz,DMSO-d
6)δ8.72–8.33(m,2H),8.16–7.95(m,2H),7.89–7.68(m,2H),7.49–7.37(m,3H),5.65–5.52(m,1H),5.39–5.31(m,1H),4.96–4.80(m,1H),4.79–4.69(m,2H),4.61–4.41(m,4H),1.48–1.36(m,3H);MS(ESI):m/z 447.5(M+H)
+.
实施例57:
从乙醇胺起,参照化合物24的合成得到化合物57。
1H NMR(500MHz,DMSO-d
6)δ8.67–8.60(m,1H),8.05–7.76(m,6H),7.50–7.28(m,3H),6.67–6.43(m,1H),4.77–4.60(m,1H),4.59–4.45(m,2H),3.49–3.37(m,4H);MS(ESI):m/z 390.4(M+H)
+.
实施例58:
从2-(甲胺基)乙醇起,参照化合物24的合成得到化合物58。
1H NMR(500MHz,DMSO-d
6)δ8.72–8.59(m,1H),8.27–8.12(m,1H),8.10–7.95(m,3H),7.95–7.81(m,2H),7.45–7.36(m,2H),7.36–7.27(m,1H),4.65–4.44(m,2H),3.66–3.47(m,2H),3.03–2.98(m,2H),2.35–2.09(m,3H);MS(ESI):m/z 404.2(M+H)
+.
实施例59:
从N,N-二甲基乙二胺起,参照化合物24的合成得到化合物59。
1H NMR(500MHz,DMSO-d
6)δ8.65–8.59(m,1H),8.27–7.96(m,5H),7.93–7.80(m,2H),7.42–7.30(m,3H),4.82–4.35(m,4H),3.72–3.55(m,2H),3.55–3.49(m,3H),3.07–3.04(m,3H);MS(ESI):m/z 417.7(M+H)
+.
实施例60:
从D-脯氨醇起,参照化合物24的合成得到化合物60。
1H NMR(500MHz,DMSO-d
6)δ8.66–8.62(m,1H),8.21–8.13(m,1H),8.04–7.99(m,2H),7.97–7.80(m,3H),7.46–7.28(m,3H),4.64–4.58(m,1H),4.57–4.41(m,3H),3.62–3.32(m,4H),1.98–1.73(m,4H);MS(ESI):m/z 430.5(M+H)
+.
实施例61:
从乙二醇起,参照化合物26的合成得到化合物61。
1H NMR(500MHz,DMSO-d
6)δ8.70–8.26(m,3H),8.07–7.99(m,2H),7.95–7.82(m,2H),7.48–7.37(m,2H),7.36–7.29(m,1H),4.87–4.73(m,1H),4.65–4.50(m,2H),4.45–4.32(m,2H),3.79–3.58(m,2H);MS(ESI):m/z 391.5(M+H)
+.
实施例62:
从甘氨酸甲酯盐酸盐起,参照化合物24的合成得到化合物62-a。
从化合物62-a起,参照化合物53的合成到化合物62。
1H NMR(500MHz,DMSO-d
6)δ8.66–8.60(m,1H),8.17–7.74(m,6H),7.46–7.29(m,3H),7.16–6.78(m,1H),4.55–4.44(m,2H),4.03–3.78(m,2H);MS(ESI):m/z 404.2(M+H)
+.
实施例63:
从1-(4-溴苯基)环丙胺起,参照化合物12的合成得到化合物63。
1H NMR(500MHz,DMSO-d
6)δ9.01–8.67(m,2H),8.65–8.37(m,2H),8.06–7.98(m,1H),7.73–7.53(m,2H),7.52–7.20(m,3H),5.69–5.27(m,1H),4.70–4.27(m,4H),1.40–1.22(m,4H);MS(ESI):m/z 429.5(M+H)
+.
实施例64:
从(2-氯-6-甲基吡啶-4-基)甲醇起,参照化合物12的合成得到化合物64。
1H NMR(500MHz,DMSO-d
6)δ8.67–8.36(m,2H),8.08–7.92(m,2H),7.68–7.60(m,1H),7.46–7.35(m,2H),7.13(s,1H),5.71–5.49(m,1H),5.47–5.34(m,1H),4.90–4.70(m,2H),4.62–4.40(m,6H),2.51–2.50(m,3H);MS(ESI):m/z 447.5(M+H)
+.
实施例65:
从(1S,2S)-2-氨基环戊醇盐酸盐起,参照化合物24的合成得到化合物65。
1H NMR(500MHz,DMSO-d
6)δ8.67–8.61(m,1H),8.07–8.00(m,3H),7.99–7.76(m,3H),7.51–7.29(m,3H),6.33–6.04(m,1H),4.81–4.64(m,1H),4.64–4.37(m,2H),4.31–3.94(m,2H),1.93–1.36(m,6H);MS(ESI):m/z 430.5(M+H)
+.
实施例66:
从3-氨基丙醇起,参照化合物24的合成得到化合物66。
1H NMR(500MHz,DMSO-d
6)δ8.67–8.61(m,1H),8.05–7.73(m,6H),7.47–7.14(m,3H),6.92–6.62(m,1H),4.61–4.45(m,3H),3.49–3.36(m,4H),1.72–1.55(m,2H);MS(ESI):m/z 404.2(M+H)
+.
实施例67:
从2-(6-氯吡啶-2-基)乙烷-1-醇起,参照化合物12的合成得到化合物67。
1H NMR(500MHz,DMSO-d
6)δ8.71–8.36(m,2H),8.08–7.96(m,2H),7.81–7.69(m,2H),7.45–7.37(m,2H),7.24–7.19(m,1H),5.66–5.51(m,1H),4.90–4.70(m,2H),4.65(s,1H),4.59–4.40(m,4H),3.86–3.77(m,2H),2.95–2.90(m,2H);MS(ESI):m/z 447.3(M+H)
+.
实施例68:
从6-氯吡啶酰胺起,参照化合物12的合成得到化合物68。
1H NMR(500MHz,DMSO-d
6)δ8.71–8.38(m,2H),8.29–8.10(m,4H),8.07–7.90(m,2H),7.69(s,1H),7.45–7.38(m,2H),5.69–5.49(m,1H),4.91–4.70(m,2H),4.61–4.42(m,4H);MS(ESI):m/z 446.3(M+H)
+.
实施例69:
从(6-氯-4-甲基吡啶-2-基)甲醇起,参照化合物12的合成得到化合物69。
1H NMR(500MHz,DMSO-d
6)δ8.71–8.36(m,2H),8.11–7.94(m,2H),7.72–7.55(m,1H),7.51–7.33(m,2H),7.31–7.17(m,1H),5.68–5.49(m,1H),5.43–5.28(m,1H),4.93–4.66(m,2H),4.61–4.40(m,6H),2.41–2.36(m,3H);MS(ESI):m/z 447.4(M+H)
+.
实施例70:
从(1R,2R)-2-氨基环戊醇盐酸盐起,参照化合物24的合成得到化合物70。
1H NMR(500MHz,DMSO-d
6)δ8.70–8.61(m,1H),8.09–8.00(m,3H),7.99–7.75(m,3H),7.54–7.27(m,3H),6.24–6.12(m,1H),4.78–4.65(m,1H),4.62–4.40(m,2H),4.28–3.96(m,2H),1.94–1.25(m,6H);MS(ESI):m/z 430.5(M+H)
+.
实施例71:
从(1R,2S)-2-氨基环戊醇盐酸盐起,参照化合物24的合成得到化合物71。
1H NMR(500MHz,DMSO-d
6)δ8.67–8.62(m,1H),8.12–7.99(m,4H),7.97–7.81(m,2H),7.44–7.37(m,2H),7.36–7.29(m,1H),6.01–5.91(m,1H),5.26–5.12(m,1H),4.62–4.39(m,2H),4.23–3.91(m,2H),1.90–1.32(m,6H);MS(ESI):m/z 430.5(M+H)
+.
实施例72:
从(1S,2R)-2-氨基环戊醇盐酸盐起,参照化合物24的合成得到化合物72。
1H NMR(500MHz,DMSO-d
6)δ8.75–8.57(m,1H),8.14–7.94(m,4H),7.92–7.83(m,2H),7.46–7.27(m,3H),6.06–5.91(m,1H),5.31–5.12(m,1H),4.66–4.40(m,2H),4.20–3.88(m,2H),1.86–1.27(m,6H);MS(ESI):m/z 430.5(M+H)
+.
实施例73:
将化合物38(30.0mg,65.2μmol)和乙烯基硼酸频那醇酯(50.2mg,326μmol)溶于1,4-二氧六环(3mL)和水(0.3mL)的混合物,加入碳酸钾(18.0mg,130μmol)和1,1'-二(二苯膦基)二茂铁二氯化钯(II)(4.8mg,6.52μmol)。混合物在氮气气氛95℃下搅拌3小时。将反应液冷却至室温,加入20mL乙酸乙酯,用硅藻土过滤,滤液用水洗三次,饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物通过制备液相色谱纯化得到化合物73(10.0mg,27.8μmol),白色固体,收率42.6%。
1H NMR(500MHz,DMSO-d
6)δ8.63(d,J=4.8Hz,1H),8.26(s,1H),8.15–7.95(m,3H),7.91(d,J=8.0Hz,1H),7.88–7.82(m,1H),7.39(d,J=8.0Hz,2H),7.32(dd,J=7.4,4.9Hz,1H),6.60–6.49(m,1H),5.78–5.66(m,1H),5.65–5.37(m,1H),5.10(d,J=11.5Hz,1H),4.91–4.65(m,2H),4.63–4.38(m,4H);MS(ESI):m/z 361.1(M+H)
+.
实施例74:
从(6-(甲基磺酰基)吡啶-3-基)硼酸起,参照化合物11的合成得到化合物74。
1H NMR(500MHz,DMSO-d
6)δ8.93–8.84(m,2H),8.83–8.76(m,1H),8.68–8.61(m,1H),8.32–8.22(m,1H),8.22–8.16(m,1H),8.08–8.01(m,2H),7.96–7.90(m,1H),7.90–7.82(m,1H), 7.50–7.40(m,2H),7.37–7.28(m,1H),4.70–4.59(m,2H),3.37–3.34(m,3H);MS(ESI):m/z 486.4(M+H)
+.
实施例75:
从环丙基硼酸起,参照化合物73的合成得到化合物75。
1H NMR(500MHz,DMSO-d
6)δ8.63(d,J=4.5Hz,1H),8.01(d,J=7.9Hz,2H),7.91(d,J=7.9Hz,1H),7.88–7.82(m,1H),7.76(s,1H),7.61–7.35(m,3H),7.31(dd,J=7.4,4.8Hz,1H),5.61–5.35(m,1H),4.89–4.62(m,2H),4.57–4.37(m,4H),1.73–1.66(m,1H),0.79–0.73(m,2H),0.60–0.55(m,2H);MS(ESI):m/z 375.4(M+H)
+.
实施例76:
从2-甲基-4-氰基苯硼酸起,参照化合物4的合成得到化合物76。
1H NMR(500MHz,DMSO-d
6)δ8.69–8.35(m,3H),7.90–7.82(m,1H),7.51–7.45(m,1H),7.38–7.30(m,2H),7.26–7.18(m,2H),5.68–5.55(m,1H),4.91–4.74(m,2H),4.59–4.44(m,4H),2.33–2.27(m,3H);MS(ESI):m/z 417.4(M+H)
+.
实施例77:
将化合物38(25.0mg,54.3μmol)和三甲基硅乙炔(16.0mg,163μmol)溶于四氢呋喃(3mL),加入三乙胺(27.5mg,271μmol),碘化亚铜(1.0mg,5.43μmol)和二三苯基膦二氯化钯(3.8mg,5.43μmol)。混合物在氮气气氛50℃下搅拌3小时。将反应液冷却至室温,加入3mL 1M四丁基氟化铵四氢呋喃溶液,搅拌1小时。混合物中加入20mL乙酸乙酯,用硅藻土过滤,滤液用水洗三次,饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残 留物通过制备液相色谱纯化得到化合物77(5.0mg,14.0μmol),白色固体,收率25.7%。
1H NMR(500MHz,DMSO-d
6)δ8.64(d,J=4.8Hz,1H),8.38–8.27(m,1H),8.26–8.21(m,1H),8.06–8.01(m,2H),7.94–7.90(m,1H),7.88–7.83(m,1H),7.42–7.36(m,2H),7.35–7.29(m,1H),5.60–5.41(m,1H),4.91–4.68(m,2H),4.62–4.40(m,4H),4.36–4.29(m,1H);MS(ESI):m/z 359.4(M+H)
+.
实施例78:
将化合物38(30.0mg,65.2μmol)和二甲基氧化膦(6.4mg,81.5μmol)溶于1,4-二氧六环(3mL),加入碳酸铯(42.5mg,130μmol),Pd
2(dba)
3(6.0mg,6.52μmol)和Xantphos(7.5mg,13.0μmol)。混合物在氮气气氛95℃下搅拌3小时。将反应液冷却至室温,加入20mL乙酸乙酯,用硅藻土过滤,滤液用水洗三次,饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物通过制备液相色谱纯化得到化合物78(8.0mg,19.5μmol),白色固体,收率29.9%。
1H NMR(500MHz,DMSO-d
6)δ8.64(d,J=4.9Hz,1H),8.49–8.15(m,2H),8.10–8.00(m,2H),7.99–7.82(m,2H),7.41(d,J=8.0Hz,2H),7.32(dd,J=7.4,4.8Hz,1H),5.66–5.49(m,1H),4.90–4.68(m,2H),4.62–4.43(m,4H),1.67–1.58(m,6H);MS(ESI):m/z 411.3(M+H)
+.
实施例79:
从5-(羟甲基)吡啶-3-硼酸起,参照化合物11的合成得到化合物79。
1H NMR(500MHz,DMSO-d
6)δ8.84–8.78(m,1H),8.77–8.71(m,1H),8.70–8.60(m,2H),8.58–8.49(m,1H),8.09–8.01(m,2H),7.96–7.91(m,1H),7.90–7.79(m,2H),7.50–7.41(m,2H),7.37–7.31(m,1H),5.50–5.41(m,1H),4.71–4.57(m,4H);MS(ESI):m/z 437.7(M+H)
+.
实施例80:
从6-(羟甲基)吡啶-3-硼酸起,参照化合物11的合成得到化合物80。
1H NMR(500MHz,DMSO-d
6)δ8.81–8.76(m,1H),8.75–8.69(m,1H),8.69–8.62(m,1H),8.60–8.52(m,1H),8.06–8.02(m,2H),7.99–7.83(m,3H),7.62–7.56(m,1H),7.49–7.40(m,2H),7.36–7.30(m,1H),5.55–5.47(m,1H),4.67–4.60(m,4H);MS(ESI):m/z 437.7(M+H)
+.
实施例81:
从5-氨基甲酰吡啶-3-硼酸频哪酯起,参照化合物11的合成得到化合物81。
1H NMR(500MHz,DMSO-d
6)δ9.19–9.11(m,1H),8.92–8.72(m,3H),8.68–8.61(m,1H),8.38–8.30(m,1H),8.29–8.19(m,1H),8.07–8.01(m,2H),7.95–7.89(m,1H),7.87(d,J=7.0Hz,1H),7.78–7.66(m,1H),7.49–7.40(m,2H),7.37–7.29(m,1H),4.70–4.59(m,2H);MS(ESI):m/z 451.4(M+H)
+.
实施例82:
将化合物38(30.0mg,65.2μmol)和N,N'-二甲基乙二胺(1.92mg,21.7μmol)溶于1,4-二氧六环(3mL),加入甲基亚磺酸钠(6.4mg,81.5μmol)和三氟甲烷磺酸铜(3.9mg,10.8μmol)。混合物在氮气气氛115℃下搅拌3小时。将反应液冷却至室温,加入20mL乙酸乙酯,用硅藻土过滤,滤液用水洗三次,饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物通过制备液相色谱纯化得到化合物82(15.0mg,36.4μmol),白色固体,收率33.5%。
1H NMR(500MHz,DMSO-d
6)δ8.94–8.61(m,2H),8.45–8.38(m,1H),8.09–8.01(m,2H),7.96–7.90(m,1H),7.89–7.83(m,1H),7.44–7.39(m,2H),7.36–7.29(m,1H), 5.70–5.56(m,1H),4.90–4.71(m,2H),4.66–4.48(m,4H),3.23–3.18(m,3H);MS(ESI):m/z 413.4(M+H)
+.
实施例83:
从4-氰基-3-甲基苯硼酸起,参照化合物4的合成得到化合物83。
1H NMR(500MHz,DMSO-d
6)δ8.64(d,J=4.5Hz,1H),8.60–8.31(m,2H),7.98–7.89(m,2H),7.89–7.82(m,2H),7.36–7.20(m,2H),5.68–5.49(m,1H),4.93–4.34(m,6H),2.44–2.37(m,3H);MS(ESI):m/z 417.4(M+H)
+.
实施例84:
从D-缬氨醇起,参照化合物24的合成得到化合物84。
1H NMR(500MHz,DMSO-d
6)δ8.67–8.61(m,1H),8.12–7.72(m,6H),7.45–7.36(m,2H),7.35–7.27(m,1H),5.81–5.66(m,1H),4.76–4.62(m,1H),4.60–4.38(m,2H),4.17–3.95(m,1H),3.64–3.36(m,2H),2.01–1.80(m,1H),0.95–0.67(m,6H);MS(ESI):m/z 432.5(M+H)
+.
实施例85:
从D-叔亮氨醇起,参照化合物24的合成得到化合物85。
1H NMR(500MHz,DMSO-d
6)δ8.69–8.62(m,1H),8.13–7.77(m,6H),7.40(d,J=7.8Hz,2H),7.34–7.30(m,1H),5.65–5.53(m,1H),4.72–4.60(m,1H),4.60–4.36(m,2H),4.32–4.10(m,1H),3.70–3.44(m,2H),0.96–0.70(m,9H);MS(ESI):m/z 446.5(M+H)
+.
实施例86:
从(5-溴嘧啶-2-基)甲基氨基甲酸叔丁酯起,参照化合物48的合成得到化合物86。
1H NMR(500MHz,DMSO-d
6)δ9.21–9.12(m,2H),9.05–8.98(m,1H),8.70–8.32(m,3H),8.26–8.18(m,1H),7.58–7.51(m,1H),5.69–5.29(m,1H),4.95–4.51(m,5H),4.33–4.30(m,1H);MS(ESI):m/z 405.6(M+H)
+.
实施例87:
从2-溴-5-氰基吡嗪起,参照化合物48的合成得到化合物87。
1H NMR(500MHz,DMSO-d
6)δ9.33–9.22(m,2H),8.74–8.39(m,5H),7.58–7.53(m,1H),5.68–5.43(m,1H),4.91–4.57(m,5H),4.40–4.38(m,1H);MS(ESI):m/z 405.4(M+H)
+.
实施例88:
从(E)-3-(叔丁基二甲基硅氧基)丙烯-1-基-硼酸频哪醇酯起,参照化合物11的合成得到化合物88-a。
将化合物88-a(55.0mg,110μmol)溶于四氢呋喃(3mL),加入四丁基氟化铵(1M,0.33mL)。混合物在室温下搅拌2小时。反应液加入20mL乙酸乙酯,用水洗三次,饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物通过制备液相色谱纯化得到化合物88(15.0mg,38.8μmol),白色固体,收率35.3%。
1H NMR(500MHz,DMSO-d
6)δ8.63(d,J=4.8Hz,1H),8.57–8.50(m,1H),8.49–8.41(m,1H),8.02(d,J=7.9Hz,2H),7.91(d,J=8.0Hz,1H),7.87–7.83(m,1H),7.47–7.39(m,2H),7.36–7.29(m,2H),6.76–6.67(m,1H),4.67–4.57(m,2H),4.28–4.17(m,2H);MS(ESI):m/z 387.3(M+H)
+.
实施例89:
从2,4-二氯-5-硝基嘧啶和(R)-2-氨基丁醇起,参照化合物1的合成得到化合物89。
1H NMR(500MHz,DMSO-d
6)δ8.96–8.58(m,3H),8.55–8.38(m,1H),8.04(d,J=8.1Hz,2H),7.93(d,J=7.9Hz,1H),7.90–7.84(m,1H),7.46–7.38(m,2H),7.37–7.30(m,1H),4.95–4.86(m,1H),4.73–4.49(m,2H),4.24–4.10(m,1H),3.60–3.40(m,2H),1.73–1.43(m,2H),0.93–0.74(m,3H);MS(ESI):m/z 395.5(M+H)
+.
实施例90:
将化合物89(50mg,127μmol)溶于乙醇(5mL),加入钯/碳(10%w/w,10mg)。混合物在氢气气氛下室温搅拌12小时。反应液经硅藻土过滤,浓缩。残留物用制备液相色谱纯化得到化合物90(12.0mg,32.9μmol),白色固体,收率26.0%。
1H NMR(500MHz,DMSO-d
6)δ8.63(d,J=4.8Hz,1H),7.98(d,J=8.0Hz,2H),7.90(d,J=8.0Hz,1H),7.84(td,J=7.7,1.8Hz,1H),7.40(d,J=8.0Hz,2H),7.31(dd,J=7.3,4.9Hz,1H),7.24(s,1H),6.30(t,J=6.4Hz,1H),5.71(d,J=8.1Hz,1H),4.71–4.52(m,1H),4.45–4.35(m,2H),3.96(td,J=7.9,3.6Hz,1H),3.74(s,2H),3.46(dd,J=10.7,4.7Hz,1H),3.40–3.36(m,1H),1.67–1.58(m,1H),1.48–1.39(m,1H),0.83(t,J=7.4Hz,3H);MS(ESI):m/z 365.5(M+H)
+.
实施例91:
从顺式-2-氨基环丁-1-醇盐酸盐起,参照化合物24的合成得到化合物91。
1H NMR(500MHz,DMSO-d
6)δ8.69–8.61(m,1H),8.14–7.97(m,4H),7.95–7.90(m,1H),7.88–7.83(m,1H),7.47–7.36(m,2H),7.36–7.30(m,1H),6.28–6.20(m,1H),5.67–5.55(m,1H),4.58–4.28(m,4H),2.13–1.97(m,2H),1.84–1.69(m,2H);MS(ESI):m/z 416.4(M+H)
+.
实施例92:
从顺式-3-氨基环戊醇盐酸盐起,参照化合物24的合成得到化合物92。
1H NMR(500MHz,DMSO-d
6)δ8.67–8.62(m,1H),8.07–7.99(m,3H),7.98–7.78(m,3H),7.49–7.37(m,2H),7.36–7.30(m,1H),6.29–6.21(m,1H),4.84–4.62(m,1H),4.57–4.44(m,3H),4.24–4.13(m,1H),1.99–1.77(m,3H),1.77–1.67(m,1H),1.52–1.38(m,2H);MS(ESI):m/z 430.4(M+H)
+.
实施例93:
从D-苯丙氨醇起,参照化合物24的合成得到化合物93。
1H NMR(500MHz,DMSO-d
6)δ8.69–8.63(m,1H),8.10–7.99(m,3H),7.99–7.75(m,3H),7.47–7.35(m,2H),7.34–7.04(m,6H),6.04–5.93(m,1H),4.98–4.89(m,1H),4.62–4.31(m,3H),3.48–3.35(m,2H),2.91–2.77(m,2H);MS(ESI):m/z 480.4(M+H)
+.
实施例94:
从3-三甲基硅氧基-1-丙炔起,参照化合物77的合成得到化合物94。
1H NMR(500MHz,DMSO-d
6)δ8.64(d,J=4.8Hz,1H),8.27–7.97(m,4H),7.92(d,J=8.1Hz,1H),7.85(td,J=7.6,1.7Hz,1H),7.39(d,J=8.0Hz,2H),7.32(dd,J=7.3,4.9Hz,1H),5.54–5.45(m,1H),5.25(s,1H),4.87–4.70(m,2H),4.58–4.43(m,4H),4.28(d,J=4.5Hz,2H);MS(ESI):m/z 389.5(M+H)
+.
实施例95:
将化合物88-a(55.0mg,110μmol)溶于乙醇(5mL),加入钯/碳(10%w/w,10.0mg)。混合物在氢气气氛下室温搅拌12小时。反应液经硅藻土过滤,浓缩得到化合物95-a(50.0mg,99.4μmol),白色固体,收率90.5%。
从95-a起,参照化合物88的合成得到化合物95。
1H NMR(500MHz,DMSO-d
6)δ8.63(d,J=4.8Hz,1H),8.56–8.41(m,2H),8.02(d,J=7.9Hz,2H),7.91(d,J=8.0Hz,1H),7.85(t,J=7.7Hz,1H),7.44–7.40(m,7.9Hz,2H),7.32(dd,J=7.3,4.8Hz,1H),4.60(d,J=6.4Hz,2H),4.55–4.47(m,1H),3.48–3.41(m,2H),2.70(t,J=7.8Hz,2H),1.80(d,J=7.6Hz,2H);MS(ESI):m/z 388.9(M+H)
+.
实施例96:
从3-溴吡啶-5-甲醇起,参照化合物12的合成得到化合物96。
1H NMR(500MHz,DMSO-d
6)δ8.78–8.72(m,1H),8.72–8.35(m,3H),7.95(d,J=7.4Hz,1H),7.70–7.65(m,2H),7.42(d,J=7.9Hz,2H),5.64–5.55(m,1H),5.41–5.30(m,1H),4.89–4.72(m,2H),4.61–4.42(m,6H);MS(ESI):m/z 433.4(M+H)
+.
实施例97:
从3-溴-5-(甲基磺酰)吡啶起,参照化合物12的合成得到化合物97。
1H NMR(500MHz,DMSO-d
6)δ9.25–9.19(m,1H),9.08–9.00(m,1H),8.75–8.37(m,3H),7.89–7.78(m,2H),7.52–7.44(m,2H),5.68–5.51(m,1H),4.91–4.72(m,2H),4.63–4.42(m,4H),3.39(s,3H);MS(ESI):m/z 481.3(M+H)
+.
实施例98:
从反式-2-氨基环丁醇盐酸盐起,参照化合物24的合成得到化合物98。
1H NMR(500MHz,DMSO-d
6)δ8.63(d,J=4.8Hz,1H),8.02(d,J=7.8Hz,3H),7.98–7.77(m,3H),7.51–7.36(m,2H),7.36–7.29(m,1H),6.79–6.69(m,1H),5.22–5.12(m,1H),4.60–4.31(m,3H),4.22–4.11(m,1H),2.03–1.87(m,2H),1.49–1.30(m,2H);MS(ESI):m/z 416.5(M+H)
+.
实施例99:
从2,4-二氯-5-甲氧基嘧啶起,参照化合物3的合成得到化合物99。
1H NMR(500MHz,DMSO-d
6)δ8.66–8.62(m,1H),8.01(d,J=8.1Hz,2H),7.97–7.82(m,3H),7.45–7.28(m,4H),5.54–5.41(m,1H),4.75(s,2H),4.49(t,J=6.4Hz,2H),4.42(d,J=6.3Hz,2H),3.70(s,3H);MS(ESI):m/z 365.4(M+H)
+.
实施例100:
从(1R,2R)-2-氨基环己醇盐酸盐起,参照化合物24的合成得到化合物100。
1H NMR(500MHz,DMSO-d
6)δ8.63(d,J=4.8Hz,1H),8.08–7.93(m,4H),7.92–7.89(m,1H),7.87–7.83(m,1H),7.43–7.37(m,2H),7.34–7.30(m,1H),5.88(d,J=6.3Hz,1H),4.65–4.59(m,1H),4.57–4.38(m,2H),3.91–3.59(m,1H),3.50–3.36(m,1H),2.07–1.95(m,1H),1.95– 1.77(m,2H),1.64–1.57(m,1H),1.50–1.42(m,1H),1.19–1.11(m,2H),1.08–0.95(m,1H).;MS(ESI):m/z 444.5(M+H)
+.
实施例101:
从((3R,4R)-4-(氨基甲基)-3-羟基哌啶-1-羧酸叔丁酯起,参照化合物24的合成得到化合物101-a。
将化合物101-a(50.0mg,89.5μmol)溶于二氯甲烷(3mL),加入盐酸二氧六环(4M,0.50mL)。混合物在室温下搅拌2小时。反应液浓缩,残留物通过制备液相色谱纯化得到化合物101(15.0mg,32.7μmol),白色固体,收率36.5%。
1H NMR(500MHz,DMSO-d
6)δ8.63(d,J=4.9Hz,1H),8.05–7.89(m,5H),7.88–7.83(m,1H),7.47–7.36(m,2H),7.35–7.29(m,1H),7.01–6.83(m,1H),5.23–5.01(m,1H),4.56–4.49(m,2H),3.64–3.36(m,3H),2.99–2.92(m,1H),2.90–2.71(m,1H),2.38–2.18(m,2H),1.59–1.40(m,2H),1.12–0.95(m,1H);MS(ESI):m/z 459.4(M+H)
+.
实施例102:
从2,4-二氯-5-甲硫基嘧啶起,参照化合物3的合成得到化合物102。
1H NMR(500MHz,DMSO-d
6)δ8.67–8.61(m,1H),8.11(s,1H),8.06–7.82(m,5H),7.39(d,J=8.0Hz,2H),7.32(dd,J=7.3,4.9Hz,1H),5.65–5.37(m,1H),4.93–4.63(m,2H),4.60–4.38(m,4H),2.27(s,3H);MS(ESI):m/z 381.4(M+H)
+.
实施例103:
将化合物102(30.0mg,78.8μmol)溶于二氯甲烷(5mL),加入间氯过氧苯甲酸(13.6mg,78.8μmol)。混合物室温搅拌2小时。反应液加入20mL乙酸乙酯,用饱和碳酸氢钠洗涤一次,水洗一次,饱和食盐水系一次,干燥,浓缩。残留物用制备液相色谱纯化得到化合物103(12mg,30.2μmol),白色固体,收率38.4%。
1H NMR(500MHz,DMSO-d
6)δ8.64(d,J=4.8Hz,1H),8.53–8.19(m,2H),8.07–8.00(m,2H),7.95–7.90(m,1H),7.89–7.83(m,1H),7.44–7.39(m,2H),7.35–7.30(m,1H),5.66–5.49(m,1H),4.88–4.69(m,2H),4.62–4.44(m,4H),2.84–2.79(m,3H);MS(ESI):m/z 397.3(M+H)
+.
实施例104:
从丝氨醇起,参照化合物24的合成得到化合物104。
1H NMR(500MHz,DMSO-d
6)δ8.70–8.61(m,1H),8.13–7.80(m,6H),7.53–7.30(m,3H),5.86–5.72(m,1H),4.87–4.72(m,2H),4.58–4.47(m,2H),4.24–4.12(m,1H),3.65–3.54(m,2H),3.55–3.41(m,2H);MS(ESI):m/z 420.5(M+H)
+.
实施例105:
从(R)-1-氨基-2-丙醇起,参照化合物24的合成得到化合物105。
1H NMR(500MHz,DMSO-d
6)δ8.69–8.57(m,1H),8.10–7.76(m,6H),7.49–7.23(m,3H),6.00–5.89(m,1H),4.88–4.76(m,1H),4.60–4.43(m,2H),4.31–4.16(m,1H),3.50–3.35(m,2H),1.18–1.00(m,3H);MS(ESI):m/z 404.2(M+H)
+.
实施例106:
从(R)-1-甲基-3-吡咯烷醇起,参照化合物26的合成得到化合物106。
1H NMR(500MHz,DMSO-d
6)δ8.67–8.30(m,3H),8.12–7.83(m,4H),7.49–7.24(m,3H),5.51–5.25(m,1H),4.68–4.46(m,2H),2.66–2.55(m,2H),2.40–2.34(m,1H),2.31–1.99(m,5H),1.83–1.65(m,1H);MS(ESI):m/z 430.4(M+H)
+.
实施例107:
从(S)-1-甲基-3-吡咯烷醇起,参照化合物26的合成得到化合物107。
1H NMR(500MHz,DMSO-d
6)δ8.67–8.61(m,1H),8.61–8.30(m,2H),8.07–8.00(m,2H),7.94–7.81(m,2H),7.47–7.27(m,3H),5.50–5.24(m,1H),4.70–4.46(m,2H),2.68–2.54(m,2H),2.44–2.10(m,6H),1.86–1.64(m,1H);MS(ESI):m/z 430.4(M+H)
+.
实施例108:
从3-溴苯甲醇起,参照化合物12的合成得到化合物108。
1H NMR(500MHz,DMSO-d
6)δ8.72–8.33(m,2H),7.65–7.56(m,3H),7.52–7.47(m,1H),7.42–7.36(m,3H),7.32–7.28(m,1H),5.66–5.55(m,1H),5.26–5.19(m,1H),4.91–4.72(m,2H),4.59–4.43(m,6H);MS(ESI):m/z 432.3(M+H)
+.
实施例109:
从1-(4-溴苯基)-1-甲基乙胺起,参照化合物12的合成得到化合物109。
1H NMR(500MHz,DMSO-d
6)δ8.79–8.35(m,3H),8.12–7.83(m,4H),7.57–7.23(m,3H),5.04–4.02(m,5H),1.77–1.60(m,6H);MS(ESI):m/z 431.4(M+H)
+.
实施例110:
从[(S)-1-(4-溴苯基)乙基]氨基甲酸叔丁酯起,参照化合物12的合成得到化合物110。
1H NMR(500MHz,DMSO-d
6)δ8.72–8.32(m,3H),8.12–7.80(m,4H),7.60–7.24(m,3H),5.71–5.43(m,1H),5.06–4.87(m,2H),4.64–4.18(m,3H),1.48(d,J=6.9Hz,3H);MS(ESI):m/z 417.4(M+H)
+.
实施例111:
从反式-1,2-环己二醇起,参照化合物26的合成得到化合物111。
1H NMR(500MHz,DMSO-d
6)δ8.67–8.61(m,1H),8.57–8.27(m,2H),8.06–7.99(m,2H),7.94–7.89(m,1H),7.89–7.82(m,1H),7.47–7.38(m,2H),7.36–7.29(m,1H),5.13–4.91(m,1H),4.83–4.72(m,1H),4.63–4.42(m,2H),3.57–3.50(m,1H),2.05–1.92(m,1H),1.88–1.54(m,3H),1.49–1.24(m,4H);MS(ESI):m/z 445.4(M+H)
+.
实施例112:
从4-氰基-3-甲氧基苯硼酸起,参照化合物4的合成得到化合物112。
1H NMR(500MHz,DMSO-d
6)δ8.70–8.64(m,1H),8.56–8.23(m,2H),8.02–7.94(m,1H),7.92–7.84(m,1H),7.78–7.69(m,1H),7.66–7.57(m,1H),7.39–7.32(m,1H),7.28–7.17(m,1H),5.69–5.45(m,1H),4.96–4.39(m,6H),4.03–3.88(m,3H);MS(ESI):m/z 433.3(M+H)
+.
实施例113:
从2,4-二氯嘧啶-5-甲酰胺起,参照化合物89的合成得到化合物113。
1H NMR(500MHz,DMSO-d
6)δ9.08–8.87(m,1H),8.64(d,J=4.9Hz,1H),8.36(s,1H),8.01(d,J=7.9Hz,2H),7.92(d,J=7.9Hz,1H),7.89–7.83(m,1H),7.79–7.63(m,1H),7.61–7.47(m,1H),7.47–7.36(m,2H),7.36–7.29(m,1H),4.79–4.65(m,1H),4.60–4.41(m,2H),4.07–3.93(m,1H),3.53–3.43(m,1H),3.42–3.35(m,1H),3.30–3.29(m,1H),2.05–1.95(m,1H),1.68–1.51(m,1H),1.50–1.25(m,3H);MS(ESI):m/z 393.5(M+H)
+.
实施例114:
从2-溴-4-甲氧基吡啶起,参照化合物12的合成得到化合物114。
1H NMR(500MHz,DMSO-d
6)δ8.70–8.37(m,3H),8.08–7.99(m,2H),7.48–7.42(m,1H),7.41–7.36(m,2H),6.95–6.90(m,1H),5.69–5.49(m,1H),4.90–4.69(m,2H),4.59–4.40(m,4H),3.89(s,3H);MS(ESI):m/z 433.4(M+H)
+.
实施例115:
从反式-1,2-环戊二醇起,参照化合物26的合成得到化合物115。
1H NMR(500MHz,DMSO-d
6)δ8.69–8.61(m,1H),8.61–8.36(m,1H),8.36–8.28(m,1H),8.08–7.98(m,2H),7.97–7.82(m,2H),7.50–7.38(m,2H),7.38–7.28(m,1H),5.24–5.12(m,1H),4.99–4.88(m,1H),4.65–4.47(m,2H),4.11–3.99(m,1H),2.13–1.92(m,1H),1.91–1.75(m,1H),1.75–1.41(m,4H);MS(ESI):m/z 431.3(M+H)
+.
实施例116:
从反式-1,2-环戊二醇起,参照化合物101的合成得到化合物116。
1H NMR(500MHz,DMSO-d
6)δ8.67–8.61(m,1H),8.13–7.77(m,6H),7.50–7.35(m,2H),7.35–7.29(m,1H),6.52–6.24(m,1H),5.32–4.79(m,1H),4.65–4.43(m,2H),4.31–4.02(m,2H),3.20–2.94(m,3H),2.59–2.52(m,1H);MS(ESI):m/z 431.4(M+H)
+.
实施例117:
从2-溴-4-氯吡啶起,参照化合物12的合成得到化合物117。
1H NMR(500MHz,DMSO-d
6)δ8.73–8.37(m,3H),8.13–8.04(m,3H),7.49–7.46(m,1H),7.43–7.38(m,2H),5.67–5.50(m,1H),4.93–4.69(m,2H),4.65–4.38(m,4H);MS(ESI):m/z 437.1(M+H)
+.
实施例118:
从4-氰基-3-三氟甲基苯硼酸起,参照化合物4的合成得到化合物118。
1H NMR(500MHz,DMSO-d
6)δ8.79–8.39(m,4H),8.39–8.27(m,1H),8.11–8.02(m,1H),7.99–7.90(m,1H),7.61–7.50(m,1H),7.46–7.37(m,1H),5.73–5.37(m,1H),4.97–4.28(m,6H);MS(ESI):m/z 471.1(M+H)
+.
实施例119:
从[(R)-1-(4-溴苯基)乙基]氨基甲酸叔丁酯起,参照化合物12的合成得到化合物119。
1H NMR(500MHz,DMSO-d
6)δ8.79–8.27(m,3H),8.14–7.80(m,4H),7.57–7.29(m,3H),5.73–5.39(m,1H),5.10–4.84(m,2H),4.65–4.47(m,2H),4.33–4.15(m,1H),1.53–1.43(m,3H);MS(ESI):m/z 417.4(M+H)
+.
实施例120:
从化合物4-b起,参照化合物70的合成得到化合物120。
1H NMR(500MHz,DMSO-d
6)δ9.20–9.15(m,1H),8.72–8.67(m,1H),8.41–8.35(m,1H),8.03(s,1H),8.02–7.99(m,1H),7.98–7.81(m,2H),7.43–7.37(m,2H),6.25–6.15(m,1H),4.75–4.69(m,1H),4.67–4.53(m,2H),4.24–3.88(m,2H),2.11–1.95(m,1H),1.77–1.61(m,2H),1.51–1.43(m,2H),1.39–1.29(m,1H);MS(ESI):m/z 431.4(M+H)
+.
实施例121:
从(R)-2-氨基丁醇起,参照化合物120的合成得到化合物121。
1H NMR(500MHz,DMSO-d
6)δ9.18–9.15(m,1H),8.70–8.66(m,1H),8.39–8.35(m,1H),8.08–7.73(m,4H),7.41–7.34(m,2H),5.91–5.85(m,1H),4.80–4.49(m,3H),4.24–3.88(m,1H),3.57–3.35(m,2H),1.71–1.33(m,2H),0.86–0.54(m,3H);MS(ESI):m/z 419.4(M+H)
+.
实施例122:
从2-氯-4,6-二甲基吡啶起,参照化合物12的合成得到化合物122。
1H NMR(500MHz,DMSO-d
6)δ8.69–8.37(m,2H),8.06–7.97(m,2H),7.60–7.53(m,1H),7.43–7.35(m,2H), 7.02(s,1H),5.67–5.51(m,1H),4.90–4.69(m,2H),4.61–4.40(m,4H),2.47(s,3H),2.32(s,3H).;MS(ESI):m/z 431.5(M+H)
+.
实施例123:
从2-氨基-2-甲基-1-丙醇起,参照化合物24的合成得到化合物123。
1H NMR(500MHz,DMSO-d
6)δ8.63(d,J=4.8Hz,1H),8.12–7.96(m,4H),7.93–7.89(m,1H),7.87–7.83(m,1H),7.42–7.36(m,2H),7.35–7.29(m,1H),5.74–5.56(m,1H),5.33–5.24(m,1H),4.54(d,J=6.3Hz,2H),3.30–3.25(m,2H),1.28–1.13(m,6H);MS(ESI):m/z 418.5(M+H)
+.
实施例124:
从(R)-3-氨基-2-吡咯烷酮起,参照化合物24的合成得到化合物124。
1H NMR(500MHz,DMSO-d
6)δ8.63(d,J=4.8Hz,1H),8.11–8.09(m,1H),8.01(d,J=7.9Hz,2H),7.99–7.74(m,4H),7.39(d,J=7.8Hz,2H),7.35–7.27(m,1H),6.83–6.62(m,1H),4.83–4.36(m,3H),3.11–2.93(m,2H),2.11–1.95(m,2H);MS(ESI):m/z 429.4(M+H)
+.
实施例125:
从2-氯-4,6-二羟甲基吡啶起,参照化合物12的合成得到化合物125。
1H NMR(500MHz,DMSO-d
6)δ8.70–8.36(m,2H),8.04–7.97(m,2H),7.70–7.66(m,1H),7.41–7.37(m,3H),5.68–5.50(m,1H),5.46–5.43(m,1H),5.43–5.38(m,1H),4.93–4.66(m,2H),4.64–4.54(m,6H),4.53–4.39(m,3H);MS(ESI):m/z 463.6(M+H)
+.
实施例126:
从L-苏氨醇起,参照化合物24的合成得到化合物126。
1H NMR(500MHz,DMSO-d
6)δ8.75–8.54(m,1H),8.20–7.72(m,6H),7.55–7.28(m,3H),5.81–5.63(m,1H),5.13–4.44(m,4H),4.17–3.95(m,2H),3.55–3.43(m,2H),1.09–0.92(m,3H);MS(ESI):m/z 434.4(M+H)
+.
实施例127:
从D-丝氨酰胺盐酸盐起,参照化合物24的合成得到化合物127。
1H NMR(500MHz,DMSO-d
6)δ8.67–8.63(m,1H),8.10–7.99(m,4H),7.94–7.90(m,1H),7.89–7.84(m,1H),7.56–7.41(m,3H),7.35–7.31(m,1H),7.28–7.20(m,1H),6.41–6.09(m,1H),5.04–4.97(m,1H),4.59–4.47(m,3H),3.83–3.61(m,2H);MS(ESI):m/z 433.3(M+H)
+.
实施例128:
从2-氯-4-环丙基吡啶起,参照化合物12的合成得到化合物128。
1H NMR(500MHz,DMSO-d
6)δ8.75–8.36(m,3H),8.09–7.97(m,2H),7.64–7.57(m,1H),7.42–7.34(m,2H),7.03–6.97(m,1H),5.68–5.48(m,1H),4.93–4.37(m,6H),2.04–1.95(m,1H),1.10–1.02(m,2H),0.92–0.86(m,2H);MS(ESI):m/z 443.5(M+H)
+.
实施例129:
从2-氯-4-乙烯基吡啶起,参照化合物12的合成得到化合物129。
1H NMR(500MHz,DMSO-d
6)δ8.75–8.36(m,3H),8.16–8.04(m,2H),8.04–7.93(m,1H),7.48–7.37(m,3H),6.90–6.73(m,1H),6.32–6.18(m,1H),5.67–5.50(m,2H),4.94–4.67(m,2H),4.62–4.41(m,4H);MS(ESI):m/z 429.4(M+H)
+.
实施例130:
从D-苏氨醇起,参照化合物24的合成得到化合物130。
1H NMR(500MHz,DMSO-d
6)δ9.01–8.67(m,2H),8.10–7.99(m,4H),7.65–7.41(m,3H),6.88–6.56(m,1H),4.72–4.60(m,2H),4.18–3.96(m,2H),3.57–3.47(m,2H),1.08–0.93(m,3H);MS(ESI):m/z 434.4(M+H)
+.
实施例131:
从(R,R)-2,3-丁二醇起,参照化合物26的合成得到化合物131。
1H NMR(500MHz,DMSO-d
6)δ8.72–8.66(m,1H),8.59–8.35(m,1H),8.35–8.29(m,1H),8.08–7.97(m,4H),7.54–7.41(m,3H),5.27–5.12(m,1H),4.62–4.48(m,2H),3.79–3.74(m,2H),1.23–1.20(m,1H),1.12–1.04(m,3H),1.03–0.95(m,2H);MS(ESI):m/z 419.4(M+H)
+.
实施例132:
从L-丝氨酰胺盐酸盐起,参照化合物24的合成得到化合物132。
1H NMR(500MHz,DMSO-d
6)δ8.82–8.68(m,2H),8.40–8.30(m,1H),8.10–7.98(m,4H),7.66–7.49(m,3H),7.46–7.35(m,2H),4.69–4.58(m,3H),3.82–3.78(m,2H),3.74–3.70(m,2H);MS(ESI):m/z 433.4(M+H)
+.
实施例133:
从4-氰基-3-氯苯硼酸起,参照化合物4的合成得到化合物133。
1H NMR(500MHz,DMSO-d
6)δ8.68–8.66(m,1H),8.45–8.39(m,1H),8.22–8.14(m,1H),8.06–7.97(m,2H),7.95–7.87(m,1H),7.43–7.35(m,2H),5.74–5.44(m,1H),4.96–4.80(m,1H),4.72–4.32(m,6H);MS(ESI):m/z 437.5(M+H)
+.
实施例134:
从R-2-氨基丁酰胺盐酸盐起,参照化合物24的合成得到化合物134。
1H NMR(500MHz,DMSO-d
6)δ8.67–8.63(m,1H),8.13–7.84(m,6H),7.82–7.50(m,1H),7.49–7.24(m,4H),6.59–6.12(m,1H),4.67–4.16(m,3H),2.02–1.60(m,2H),0.87–0.67(m,3H);MS(ESI):m/z 431.4(M+H)
+.
实施例135:
从2-氯-4-乙基吡啶起,参照化合物12的合成得到化合物135。
1H NMR(500MHz,DMSO-d
6)δ8.75–8.36(m,3H),8.09–7.97(m,2H),7.64–7.57(m,1H),7.42–7.34(m,2H),7.03–6.97(m,1H),5.68–5.48(m,1H),4.93–4.37(m,6H),2.04–1.95(m,1H),1.10–1.02(m,2H),0.92–0.86(m,2H);MS(ESI):m/z 431.5(M+H)
+.
实施例136:
从[(R)-1-(4-溴苯基)-2-甲基丙基]氨基甲酸叔丁酯起,参照化合物12的合成得到化合物136。
1H NMR(500MHz,DMSO-d
6)δ8.72–8.66(m,1H),8.66–8.62(m,1H),8.37–8.33(m,1H),8.07–7.99(m,2H),7.96–7.90(m,1H),7.89–7.83(m,1H),7.54–7.45(m,2H),7.36–7.29(m,1H),5.69–5.58(m,1H),5.05–4.33(m,5H),2.17–2.07(m,1H),1.04–0.96(m,3H),0.79–0.71(m,3H);MS(ESI):m/z 445.4(M+H)
+.
实施例137:
从[(R)-(4-溴苯基)-环丙基甲基]氨基甲酸叔丁酯起,参照化合物12的合成得到化合物137。
1H NMR(500MHz,DMSO-d
6)δ8.88–8.56(m,2H),8.39–8.29(m,1H),8.09–7.98(m,2H),7.92(t,J=7.8Hz,1H),7.86(td,J=7.7,1.9Hz,1H),7.59–7.50(m,2H),7.38–7.29(m,1H),5.70–5.45(m,1H),5.35–4.16(m,5H),2.04–1.92(m,1H),0.61–0.33(m,4H);MS(ESI):m/z 443.4(M+H)
+.
实施例138:
从2-氯-4-氰基吡啶起,参照化合物12的合成得到化合物138。
1H NMR(500MHz,DMSO-d
6)δ8.88(d,J=5.0Hz,1H),8.72–8.36(m,3H),8.18–8.07(m,2H),7.78(dd,J=5.0,1.4Hz,1H),7.43(dd,J=8.5,2.4Hz,2H),5.69–5.47(m,1H),4.90–4.38(m,6H);MS(ESI):m/z 428.5(M+H)
+.
实施例139:
从2-氯-4-二甲氧膦基吡啶起,参照化合物12的合成得到化合物139。
1H NMR(500MHz,DMSO-d
6)δ8.80(t,J=4.4Hz,1H),8.71–8.38(m,2H),8.25–8.16(m,1H),8.16–8.06(m,2H),7.72–7.65(m,1H),7.43(d,J=8.1Hz,2H),5.68–5.51(m,1H),4.91–4.39(m,6H),1.74(d,J=13.6Hz,6H);MS(ESI):m/z 479.4(M+H)
+.
实施例140:
从[(S)-1-(4-溴苯基)-2-甲基丙基]氨基甲酸叔丁酯起,参照化合物12的合成得到化合物140。
1H NMR(500MHz,DMSO-d
6)δ8.73–8.66(m,1H),8.66–8.62(m,1H),8.37–8.33(m,1H),8.07–7.98(m,2H),7.96–7.90(m,1H),7.89–7.83(m,1H),7.54–7.44(m,2H),7.36–7.29(m,1H),5.69–5.58(m,1H),5.05–4.33(m,5H),2.17–2.07(m,1H),1.04–0.96(m,3H),0.79–0.71(m,3H);MS(ESI):m/z 445.4(M+H)
+.
实施例141:
从6-氯-2-氰基吡啶起,参照化合物12的合成得到化合物141。
1H NMR(500MHz,DMSO-d
6)δ8.72–8.39(m,2H),8.34–8.25(m,1H),8.17–8.04(m,3H),7.98(d,J=7.7Hz,1H),7.47(d,J=8.0Hz,2H),5.70–5.51(m,1H),4.95–4.40(m,6H);MS(ESI):m/z 428.4(M+H)
+.
实施例142:
从[(R)-1-(4-溴苯基)丙基]氨基甲酸叔丁酯起,参照化合物12的合成得到化合物142。
1H NMR(500MHz,DMSO-d
6)δ8.73–8.30(m,3H),8.12–8.00(m,2H),7.97–7.91(m,1H),7.91–7.82(m,1H),7.56–7.45(m,2H),7.40–7.29(m,1H),5.75–5.52(m,1H),5.04–4.25(m,5H),1.93–1.74(m,2H),0.98–0.89(m,3H);MS(ESI):m/z 431.4(M+H)
+.
实施例143:
从2-氯-4-三氟甲基吡啶起,参照化合物12的合成得到化合物143。
1H NMR(500MHz,DMSO-d
6)δ8.93(d,J=5.1Hz,1H),8.74–8.37(m,2H),8.31–8.23(m,1H),8.22–8.13(m,2H),7.71(d,J=5.1Hz,1H),7.46(d,J=8.0Hz,2H),5.72–5.50(m,1H),4.96–4.40(m,6H);MS(ESI):m/z 471.4(M+H)
+.
实施例144:
从6-氯-4-甲氧基吡啶-2-甲醇起,参照化合物12的合成得到化合物144。
1H NMR(500MHz,DMSO-d
6)δ8.74–8.38(m,2H),8.09–7.98(m,2H),7.39(d,J=8.1Hz,2H),7.35–7.29(m,1H),6.99(s,1H),5.69–5.52(m,1H),5.43(t,J=5.9Hz,1H),4.97–4.40(m,8H),3.91(s,3H);MS(ESI):m/z 463.4(M+H)
+.
实施例145:
从6-氯-4-甲氧基吡啶-2-甲醇起,参照化合物12的合成得到化合物145。
1H NMR(500MHz,DMSO-d
6)δ8.76–8.38(m,3H),8.11–8.01(m,2H),7.87–7.82(m,1H),7.42(d,J=8.1Hz,2H),7.28(d,J=4.8Hz,1H),5.74–5.53(m,1H),4.91–4.40(m,8H),3.38(s,3H);MS(ESI):m/z 447.4(M+H)
+.
实施例146:
从3-溴苯基甲基砜起,参照化合物13的合成得到化合物146。
1H NMR(500MHz,DMSO-d
6)δ8.89–8.83(m,1H),8.77–8.75(m,1H),8.66(d,J=4.8Hz,1H),8.10–8.05(m,4H),7.98–7.77(m,4H),7.46(dd,J=8.4,2.5Hz,2H),7.34(t,J=6.1Hz,1H),4.69–4.61(m,2H),3.28(d,J=5.0Hz,3H);MS(ESI):m/z 485.4(M+H)
+.
实施例147:
从5-溴吡啶-3-磺酰胺起,参照化合物13的合成得到化合物147。
1H NMR(500MHz,DMSO-d
6)δ9.12(t,J=2.2Hz,1H),8.98–8.77(m,3H),8.66(s,1H),8.36–8.29(m,1H),8.05(dd,J=8.1,4.9Hz,2H),8.00–7.69(m,4H),7.46(t,J=8.4Hz,2H),7.35(t,J=5.9Hz,1H),4.70–4.62(m,2H);MS(ESI):m/z 487.4(M+H)
+.
实施例148:
从4-氯-6-甲氧基嘧啶起,参照化合物12的合成得到化合物148。
1H NMR(500MHz,DMSO-d
6)δ8.93–8.38(m,3H),8.17–8.12(m,2H),7.53–7.41(m,3H),5.67–5.53(m,1H),4.92–4.68(m,2H),4.64–4.40(m,4H),3.98(s,3H);MS(ESI):m/z 434.4(M+H)
+.
实施例149:
从R-1-叔丁基二甲基硅氧基-2-丁醇起,参照化合物26的合成得到化合物149-a,从149-a起,参照化合物88的合成得到化合物149。
1H NMR(500MHz,DMSO-d
6)δ8.68–8.62(m,1H),8.62–8.38(m,1H),8.37–8.28(m,1H),8.08–8.00(m,2H),7.95–7.89(m,1H),7.91–7.82(m,1H),7.48–7.38(m,2H),7.36–7.30(m,1H),5.29–3.44(m,6H),1.80–1.29(m,2H),0.96–0.72(m,3H);MS(ESI):m/z 419.4(M+H)
+.
实施例150:
从顺式-1,2-环已二醇起,参照化合物26的合成得到化合物150。
1H NMR(500MHz,DMSO-d
6)δ8.71–8.62(m,1H),8.54–8.29(m,2H),8.07–8.01(m,2H),7.96–7.89(m,1H),7.89–7.83(m,1H),7.50–7.37(m,2H),7.37–7.29(m,1H),5.48–5.21(m,1H),4.71–4.39(m,3H),3.77–3.65(m,1H),1.94–1.21(m,8H);MS(ESI):m/z 445.5(M+H)
+.
实施例151:
从顺式-四氢呋喃-3,4-二醇起,参照化合物26的合成得到化合物151。
1H NMR(500MHz,DMSO-d
6)δ8.67(d,J=4.9Hz,1H),8.62–8.33(m,2H),8.09–8.01(m,2H),8.00–7.90(m,2H),7.52–7.42(m,2H),7.42–7.35(m,1H),5.54–5.32(m,1H),4.69–4.28(m,3H),4.13–3.94(m,1H),3.93–3.84(m,1H),3.75–3.63(m,1H),3.57–3.50(m,2H);MS(ESI):m/z 433.4(M+H)
+.
实施例152:
从(1R,2R)-2-氨基环戊-1-醇盐酸盐起,参照化合物24的合成得到化合物152。
1H NMR(500MHz,DMSO-d
6)δ8.65(d,J=4.8Hz,1H),8.10–8.02(m,3H),8.00–7.81(m,3H),7.50–7.39(m,2H),7.38–7.32(m,1H),6.18(d,J=7.0Hz,1H),4.75–4.70(m,1H),4.61–4.46(m,2H),4.22–4.02(m,2H),2.02–1.82(m,2H),1.69–1.40(m,4H);MS(ESI):m/z 430.5(M+H)
+.
实施例153:
从(1S,2R)-2-氨基环戊-1-醇盐酸盐起,参照化合物24的合成得到化合物153。
1H NMR(500MHz,DMSO-d
6)δ8.65(d,J=4.8Hz,1H),8.15–7.98(m,4H),7.93(d,J=7.9Hz,1H),7.89–7.85(m,1H),7.42(d,J=7.8Hz,2H),7.37–7.31(m,1H),6.02–5.93(m,1H),5.27–5.15(m,1H),4.60–4.44(m,2H),4.21–3.94(m,2H),1.88–1.76(m,2H),1.73–1.52(m,2H),1.47–1.31(m,2H);MS(ESI):m/z 430.5(M+H)
+.
实施例154:
从3-羟基吡啶起,参照化合物24的合成得到化合物154。
1H NMR(500MHz,DMSO-d
6)δ8.84–8.51(m,5H),8.04–7.89(m,4H),7.86–7.68(m,1H),7.62–7.53(m,1H),7.49–7.37(m,2H),7.00(d,J=8.0Hz,1H),4.59–4.13(m,2H);MS(ESI):m/z 424.4(M+H)
+.
实施例155:
从5-羟基吡啶-3-甲砜起,参照化合物24的合成得到化合物155。
1H NMR(500MHz,DMSO-d
6)δ9.09–9.03(m,1H),9.00–8.61(m,3H),8.57(d,J=6.7Hz,1H),8.42–8.35(m,1H),8.01(d,J=8.0Hz,1H),7.94–7.86(m,3H),7.45–7.32(m,2H),6.98(d,J=7.9Hz,1H),4.58–4.16(m,2H),3.42–3.38(m,3H);MS(ESI):m/z 502.4(M+H)
+.
实施例156:
从(1S,2R)-2-氨基环己-1-醇盐酸盐起,参照化合物24的合成得到化合物156。
1H NMR(500MHz,DMSO-d
6)δ8.65(d,J=4.8Hz,1H),8.13–7.99(m,4H),7.92(d,J=7.9Hz,1H),7.87(t,J=7.6Hz,1H),7.41(d,J=7.9Hz,2H),7.35–7.31(m,1H),5.68(d,J=7.6Hz,1H), 5.08–4.91(m,1H),4.55–4.40(m,2H),4.08–3.68(m,2H),1.79–1.58(m,2H),1.51–1.46(m,4H),1.38–1.30(m,2H);MS(ESI):m/z 444.6(M+H)
+.
实施例157:
从顺式-2,6-二甲基哌嗪起,参照化合物24的合成得到化合物157。
1H NMR(500MHz,DMSO-d
6)δ8.69–8.60(m,1H),8.33–7.72(m,6H),7.51–7.17(m,3H),4.65–4.41(m,2H),3.96–3.72(m,2H),2.80–2.57(m,2H),2.44–2.35(m,2H),0.99–0.89(m,6H);MS(ESI):m/z 443.4(M+H)
+.
实施例158:
从(S)-2-氨基-3-甲氧基丙烷-1-醇盐酸盐起,参照化合物24的合成得到化合物158。
1H NMR(500MHz,DMSO-d
6)δ8.74–8.59(m,1H),8.13–7.82(m,6H),7.50–7.31(m,3H),5.94–5.79(m,1H),5.00–4.80(m,1H),4.59–4.26(m,3H),3.59–3.35(m,4H),3.30–3.12(m,3H);MS(ESI):m/z 434.5(M+H)
+.
实施例159:
从(R)-2-氨基-2-环丙乙醇盐酸盐起,参照化合物24的合成得到化合物159。
1H NMR(500MHz,DMSO-d
6)δ8.75–8.49(m,1H),8.12–8.01(m,3H),7.98–7.73(m,3H),7.44–7.36(m,2H),7.36–7.30(m,1H),6.15–5.82(m,1H),4.87–4.70(m,1H),4.61–4.37(m,2H),3.77–3.45(m,3H),1.09–0.97(m,1H),0.52–0.25(m,2H),0.22–0.06(m,2H);MS(ESI):m/z 430.4(M+H)
+.
实施例160:
从(2-氯-6-甲基吡啶-4-基)甲醇起,参照化合物12-c的合成得到化合物160-a。
将2,4-二氯-5-(三氟甲基)嘧啶(20.00g,92.18mmol)溶于四氢呋喃(400mL),0℃下分批加入氯化锌(16.33g,119.8mmol)。混合物在0℃下搅拌0.5小时后,缓慢加入20%甲硫醇钠水溶液(48.45g,138.3mmol),混合物在室温下继续搅拌5小时。向反应体系中加入400mL水和400mL乙酸乙酯,过滤,滤液分液,水相用200mL乙酸乙酯萃取两次,合并有机相,用水洗三次,饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物通过柱层析色谱纯化得到化合物160-b(8.44g,36.9mmol),收率40.0%。
将化合物160-b(100mg,0.437mmol)和(2R,3R)-2-氨基丁烷-1,3-二醇(48.3mg,0.459mmol)溶于N-甲基吡咯烷酮(3mL),加入N,N-二异丙基乙胺(170mg,1.31mmol)。混合物在90℃下搅拌16小时。向反应体系中加入20mL水,用20mL乙酸乙酯萃取两次,合并后的有机相用水洗三次,饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物通过柱层析色谱纯化得到化合物160-c(110mg,0.37mmol),收率84.6%。MS(ESI):m/z 298.4(M+H)
+.
将化合物160-b(100mg,0.437mmol)溶于乙酸乙酯(4mL),冰浴下加入3-氯过氧苯甲酸(192mg,1.11mmol)。混合物在室温下搅拌7小时。向反应体系中加入20mL乙酸乙酯,用5mL饱和硫代硫酸钠和5mL饱和碳酸氢钠洗三次,饱和食盐水洗一次,无水硫酸钠干 燥,过滤,浓缩得到粗产品化合物160-d(100mg,0.304mmol),收率84.6%。MS(ESI):m/z 330.5(M+H)
+.
将化合物160-d(37.31mg,0.113mmol)和160-a(30mg,0.113mmol)溶于N-甲基吡咯烷酮(3mL),加入N,N-二异丙基乙胺(73.2mg,0.567mmol)。混合物在90℃下搅拌3小时。将反应液冷却至室温后,通过制备液相色谱纯化得到化合物160(10mg,20.9μmol),收率18.5%。
1H NMR(500MHz,DMSO-d
6)δ8.15–7.78(m,4H),7.67–7.61(m,1H),7.53–7.35(m,2H),7.20–7.11(m,1H),5.70–5.63(m,1H),5.45–5.39(m,1H),5.03–4.92(m,1H),4.81–4.73(m,1H),4.63–4.45(m,4H),4.11–4.02(m,2H),3.56–3.41(m,2H),2.53–2.51(m,3H),1.09–0.93(m,3H);MS(ESI):m/z 478.5(M+H)
+.
实施例161:
从(2-氯-6-甲基吡啶-4-基)甲醇和R-2-氨基丁酰胺盐酸盐起,参照化合物160的合成得到化合物161。
1H NMR(500MHz,DMSO-d
6)δ8.16–7.98(m,3H),7.87–7.59(m,2H),7.46–7.42(m,1H),7.40–7.29(m,1H),7.27–7.14(m,1H),6.30–6.21(m,1H),5.48–5.32(m,1H),4.62–4.46(m,4H),2.53–2.51(m,3H),2.04–1.90(m,1H),1.90–1.73(m,1H),0.85–0.69(m,3H);MS(ESI):m/z 475.5(M+H)
+.
实施例162:
从(6-氯-4-甲基吡啶-2-基)甲醇和L-苏氨醇盐酸盐起,参照化合物160的合成得到化合物162。
1H NMR(500MHz,DMSO-d
6)δ8.11–7.98(m,4H),7.62(s,1H),7.47–7.36(m,2H),7.25(s,1H),5.66(d,J=7.8Hz,1H),5.41–5.35(m,1H),5.04–4.93(m,1H),4.82–4.72(m,1H),4.62–4.47(m,4H),4.12–4.02(m,2H),3.52–3.39(m,2H),2.39(s,3H),1.09–0.93(m,3H);MS(ESI):m/z 478.4(M+H)
+.
实施例163:
从(6-氯-4-甲基吡啶-2-基)甲醇和R-2-氨基丁酰胺盐酸盐起,参照化合物160的合成得到化合物163。
1H NMR(500MHz,DMSO-d
6)δ8.24–7.97(m,4H),7.70–7.59(m,2H),7.47–7.37(m,2H),7.36–7.28(m,1H),7.25(s,1H),6.34–6.21(m,1H),5.43–5.36(m,1H),4.62–4.46(m,5H),2.40(s,3H),2.06–1.90(m,1H),1.88–1.65(m,1H),0.84–0.69(m,3H);MS(ESI):m/z 475.5(M+H)
+.
实施例164:
从顺式-四氢呋喃-3,4-二醇起,参照化合物26的合成得到化合物164-a。从化合物164-a起,参照化合物101的合成得到化合物164。
1H NMR(500MHz,DMSO-d
6)δ8.65(d,J=4.9Hz,1H),8.58–8.27(m,2H),8.07–8.00(m,2H),7.92(d,J=8.0Hz,1H),7.90–7.83(m,1H),7.48–7.39(m,2H),7.33(dd,J=7.3,4.9Hz,1H),5.50–5.12(m,1H),4.77–4.36(m,3H),4.30–4.04(m,1H),3.24–2.54(m,4H);MS(ESI):m/z 432.5(M+H)
+.
实施例165:
从R-1-叔丁基二甲基硅氧基-2-丙醇起,参照化合物149的合成得到化合物165。
1H NMR(500MHz,DMSO-d
6)δ8.68–8.63(m,1H),8.63–8.40(m,1H),8.38–8.28(m,1H),8.07–8.01(m,2H),7.95–7.84(m,2H),7.48–7.39(m,2H),7.36–7.31(m,1H),5.38–4.21(m,4H),4.19–3.41(m,2H),1.28–1.03(m,3H);MS(ESI):m/z 404.1(M+H)
+.
实施例166:
从(R)-2-羟基丙酰胺起,参照化合物26的合成得到化合物166。
1H NMR(500MHz,DMSO-d
6)δ8.69–8.63(m,1H),8.58–8.26(m,2H),8.08–7.99(m,2H),7.96–7.83(m,2H),7.47–7.44(m,1H),7.43–7.38(m,1H),7.35–7.31(m,1H),7.27–7.14(m,2H),5.39–5.22(m,1H),4.62–4.45(m,2H),1.47–1.40(m,3H);MS(ESI):m/z 418.3(M+H)
+.
实施例167:
从(R)-2-甲基丁烷-2,3-二醇起,参照化合物26的合成得到化合物167。
1H NMR(500MHz,DMSO-d
6)δ8.69–8.62(m,1H),8.60–8.28(m,2H),8.08–7.99(m,2H),7.97–7.90(m,1H),7.90–7.82(m,1H),7.49–7.38(m,2H),7.37–7.29(m,1H),5.14–4.99(m,1H),4.64–4.46(m,3H),1.27–1.05(m,9H);MS(ESI):m/z 433.7(M+H)
+.
实施例168:
从(6-氯吡啶-2,4-基)二甲醇和(2R,3R)-丁烷-2,3-二醇起,参照化合物160的合成得到化合物168。
1H NMR(500MHz,DMSO-d
6)δ8.57–8.27(m,2H),8.04–7.98(m,2H),7.71–7.67(m,1H),7.46–7.37(m,3H),5.45(t,J=5.8Hz,1H),5.41(t,J=5.9Hz,1H),5.32–5.12(m,1H),4.83–4.73(m,1H),4.68–4.45(m,6H),3.84–3.73(m,1H),1.24–0.98(m,6H);MS(ESI):m/z 479.7(M+H)
+.
实施例169:
从(6-氯吡啶-2,4-基)二甲醇和R-2-氨基丁酰胺盐酸盐起,参照化合物160的合成得到化合物169。
1H NMR(500MHz,DMSO-d
6)δ8.20–7.98(m,4H),7.76–7.60(m,2H),7.54–7.28(m,4H),6.38–6.23(m,1H),5.49–5.40(m,2H),4.65–4.45(m,7H),2.09–1.74(m,2H),0.86–0.69(m,3H);MS(ESI):m/z 491.4(M+H)
+.
实施例170:
从(6-氯吡啶-2,4-基)二甲醇和L-苏氨醇盐酸盐起,参照化合物160的合成得到化合物170。
1H NMR(500MHz,DMSO-d
6)δ8.13–7.97(m,4H),7.69(s,1H),7.49–7.39(m,3H),5.72–5.62(m,1H),5.46(t,J=5.7Hz,1H),5.41(t,J=5.8Hz,1H),5.03–4.94(m,1H),4.83–4.74(m,1H),4.72–4.42(m,6H),4.11–4.01(m,2H),3.52–3.41(m,2H),1.11–0.92(m,3H);MS(ESI):m/z 494.4(M+H)
+.
实施例171:
从(6-氯吡啶-2-基)甲醇和L-苏氨醇盐酸盐起,参照化合物160的合成得到化合物171。
1H NMR(500MHz,DMSO-d
6)δ8.08–7.33(m,9H),5.73–5.61(m,1H),5.52–5.33(m,1H),5.02–4.70(m,2H),4.65–4.46(m,4H),4.14–3.97(m,2H),3.52–3.40(m,2H),1.09–0.92(m,3H);MS(ESI):m/z 464.4(M+H)
+.
实施例172:
从(6-氯吡啶-2-基)甲醇和R-2-氨基丁酰胺盐酸盐起,参照化合物160的合成得到化合物172。
1H NMR(500MHz,DMSO-d
6)δ8.14–7.99(m,4H),7.90–7.77(m,2H),7.67–7.60(m,1H),7.47–7.28(m,4H),6.30–6.22(m,1H),5.45–5.37(m,1H),4.64–4.61(m,2H),4.60–4.47(m,3H),1.91–1.64(m,2H),0.82–0.69(m,3H);MS(ESI):m/z 461.4(M+H)
+.
实施例173:
从(6-氯吡啶-2-基)甲醇和(2R,3R)-丁烷-2,3-二醇起,参照化合物160的合成得到化合物173。
1H NMR(500MHz,DMSO-d
6)δ8.59–8.28(m,2H),8.07–7.73(m,4H),7.49–7.38(m,3H),5.45–5.39(m,1H),5.28–5.14(m,1H),4.83–4.74(m,1H),4.65–4.49(m,4H),3.90–3.68(m,1H),1.24–1.00(m,6H);MS(ESI):m/z 449.4(M+H)
+.
实施例174:
从2,4-二氯-5-氰基嘧啶起,参照化合物169的合成得到化合物174。
1H NMR(500MHz,DMSO-d
6)δ8.51–8.10(m,2H),8.00(d,J=8.2Hz,2H),7.76(s,1H),7.60–7.38(m,4H),7.17(s,1H),4.83–4.42(m,8H),2.04–1.70(m,3H),0.88–0.79(m,4H);MS(ESI):m/z 448.3(M+H)
+.
实施例175:
从2,4-二氯-5-氰基嘧啶起,参照化合物170的合成得到化合物175。
1H NMR(500MHz,DMSO-d
6)δ8.34–7.97(m,4H),7.69(s,1H),7.57–7.36(m,3H),5.53–5.39(m,2H),4.90–4.54(m,7H),4.53–4.43(m,1H),4.17–3.80(m,2H),3.54–3.41(m,2H),0.96(d,J=6.7Hz,3H);MS(ESI):m/z 451.3(M+H)
+.
实施例176
从((5-溴吡啶-2-基)甲基)氨基甲酸叔丁酯起,参照化合物169的合成得到化合物176。
1H NMR(500MHz,DMSO-d
6)δ9.19(s,1H),8.45(d,J=8.6Hz,2H),8.25(s,1H),7.84–7.79(m,1H),7.68–7.61(m,1H),7.56–7.46(m,2H),7.40–7.29(m,1H),4.79–4.44(m,8H),2.06–1.44(m,2H),0.85–0.61(m,3H);MS(ESI):m/z 492.3(M+H)
+.
实施例177:
从((5-溴吡啶-2-基)甲基)氨基甲酸叔丁酯起起,参照化合物170的合成得到化合物177。
1H NMR(500MHz,DMSO-d
6)δ9.22(d,J=2.2Hz,1H),8.94–8.51(m,2H),8.38(s,1H),7.87(s,1H),7.67(d,J=8.4Hz,1H),7.56(s,1H),6.78–6.62(m,1H),4.88–4.73(m,3H),4.68–4.64(m,5H),3.98–3.94(m,2H),3.57–3.41(m,4H),0.94–0.88(m,3H);MS(ESI):m/z 495.2(M+H)
+.
实施例178:
从6-氯-4-(羟甲基)吡啶甲腈起,参照化合物12的合成得到化合物178。
1H NMR(500MHz,DMSO-d
6)δ8.72–8.40(m,2H),8.19(d,J=8.7Hz,1H),8.15–7.86(m,3H),7.47(d,J=7.9Hz,2H),5.73–5.52(m,2H),4.92–4.66(m,4H),4.63–4.42(m,4H);MS(ESI):m/z 458.3(M+H)
+.
实施例179:
从2-氯-6-(羟甲基)异烟腈起,参照化合物12的合成得到化合物179。
1H NMR(500MHz,DMSO-d
6)δ8.73–8.39(m,2H),8.35–8.08(m,3H),7.79–7.71(m,1H),7.52–7.41(m,2H),5.74–5.50(m,2H),4.92–4.66(m,4H),4.63–4.40(m,4H):m/z 458.3(M+H)
+.
实施例180:
从2-氯-6-(羟甲基)异烟酰胺起,参照化合物12的合成得到化合物180。
1H NMR(500MHz,DMSO-d
6)δ8.71–8.40(m,2H),8.34(s,1H),8.20–8.06(m,3H),7.91–7.69(m,2H),7.43(d,J=8.1Hz,2H),5.66–5.53(m,2H),4.90–4.66(m,4H),4.61–4.41(m,4H):m/z 476.3(M+H)
+.
实施例181:
从[(R)-1-(4-溴苯基)乙基]氨基甲酸叔丁酯起,参照化合物125的合成得到化合物181。
1H NMR(500MHz,DMSO-d
6)δ8.73–8.33(m,2H),8.06–7.64(m,3H),7.52–7.38(m,3H),5.71–5.33(m,3H),5.26–4.18(m,9H),1.55–1.44(m,3H):m/z 477.3(M+H)
+.
实施例182:
从((5-溴吡啶-2-基)甲基)氨基甲酸叔丁酯起,参照化合物168的合成得到化合物182。
1H NMR(500MHz,DMSO-d
6)δ9.17–8.32(m,3H),7.80–6.96(m,4H),5.60–4.56(m,8H),3.84–3.59(m,1H),1.28–1.24(m,3H),1.01–0.83(m,3H);MS(ESI):m/z 480.2(M+H)
+.
实施例183:
从(5-氯吡啶-3-基)甲醇和(2R,3R)-丁烷-2,3-二醇起,参照化合物160的合成得到化合物183。
1H NMR(500MHz,DMSO-d
6)δ8.78–8.72(m,1H),8.59–8.28(m,3H),7.95(s,1H),7.70–7.65(m,2H),7.49–7.41(m,2H),5.40–5.35(m,1H),5.29–5.13(m,1H),4.83–4.74(m,1H),4.66–4.46(m,4H),3.82–3.72(m,1H),1.24–1.09(m,3H),1.09–1.00(m,3H);MS(ESI):m/z 449.2(M+H)
+.
实施例184:
从[(R)-1-(4-溴苯基)乙基]氨基甲酸叔丁酯起,参照化合物168的合成得到化合物184。
1H NMR(500MHz,DMSO-d
6)δ8.61–8.33(m,1H),8.28(s,1H),8.03–7.94(m,2H),7.67(s,1H),7.54–7.46(m,2H),7.40(s,1H),5.52–5.34(m,2H),5.30–4.98(m,2H),4.86–4.72(m,1H),4.67–4.57(m,4H),3.83–3.74(m,1H),1.54–1.45(m,3H),1.10–1.02(m,3H),0.97–0.87(m,3H);MS(ESI):m/z 493.1(M+H)
+.
实施例185:
从(S)-吡咯烷-2-基甲醇盐酸盐起,参照化合物24的合成得到化合物185。
1H NMR(500MHz,DMSO-d
6)δ8.68–8.12(m,2H),8.06–7.64(m,5H),7.48–7.26(m,3H),4.71–4.37(m,4H),3.56–3.35(m,4H),2.00–1.70(m,4H);MS(ESI):m/z 430.3(M+H)
+.
实施例186:
从(R)-1-氨基丙-2-醇起,参照化合物24的合成得到化合物186。
1H NMR(500MHz,DMSO-d
6)δ8.66–8.63(m,1H),8.11–7.96(m,4H),7.94–7.90(m,1H),7.88–7.84(m,1H),7.44–7.37(m,2H),7.35–7.31(m,1H),6.54–6.33(m,1H),4.85–4.68(m,1H),4.56–4.45(m,2H),3.90–3.70(m,1H),3.47–3.35(m,1H),3.25–3.14(m,1H),1.10–0.92(m,3H);MS(ESI):m/z 403.8(M+H)
+.
实施例187:
从(3R,5S)-5-(羟甲基)吡咯烷-3-醇盐酸盐起,参照化合物24的合成得到化合物187。
11H NMR(500MHz,DMSO-d
6)δ8.70–8.63(m,1H),8.24–8.15(m,1H),8.11–7.90(m,4H),7.89–7.84(m,1H),7.43(d,J=8.2Hz,2H),7.36–7.31(m,1H),4.95–4.84(m,1H),4.64–4.44(m,4H),4.35–4.26(m,1H),3.70–3.42(m,3H),3.31–3.26(m,1H),2.07–1.91(m,2H);MS(ESI):m/z 446.2(M+H)
+.
实施例188:
从R-2-氨基丙酰胺盐酸盐起,参照化合物24的合成得到化合物188。
1H NMR(500MHz,DMSO-d
6)δ8.69–8.60(m,1H),8.17–7.81(m,6H),7.68–7.24(m,5H),6.47–6.33(m,1H),4.66–4.42(m,3H),1.41–1.25(m,3H);MS(ESI):m/z 417.2(M+H)
+.
实施例189:
将化合物179(10mg,21.9μmol)溶于甲醇(2mL),加入浓氨水和雷尼镍(1mg)。混合物在氢气气氛室温下搅拌3小时。混合物经硅藻土过滤,浓缩,残留物通过制备液相色谱纯化得到化合物189(3.0mg,6.5μmol),收率29.7%。
1H NMR(500MHz,DMSO-d
6)δ8.72–8.39(m,2H),8.12–8.00(m,2H),7.85–7.63(m,1H),7.46–7.38(m,3H),5.67–5.52(m,1H),5.50–5.38(m,1H),5.35–4.86(m,1H),4.76–4.56(m,5H),4.55–4.20(m,3H),3.89–3.78(m,2H):m/z 462.4(M+H)
+.
实施例190:
从D-别苏氨醇起,参照化合物24的合成得到化合物190。
1H NMR(500MHz,DMSO-d
6)δ8.67–8.63(m,1H),8.12–8.00(m,4H),7.94–7.90(m,1H),7.88–7.84(m,1H),7.49–7.38(m,2H),7.36–7.31(m,1H),5.67–5.31(m,1H),5.02–4.91(m,1H),4.81–4.72(m,1H),4.59–4.46(m,2H),4.11–4.00(m,2H),3.50–3.42(m,2H),1.07–0.93(m,3H);MS(ESI):m/z 434.4(M+H)
+.
实施例191:
从L-别苏氨醇起,参照化合物24的合成得到化合物191。
1H NMR(500MHz,DMSO-d
6)δ8.72–8.56(m,1H),8.10–7.99(m,4H),7.95–7.91(m,1H),7.89–7.84(m,1H),7.44–7.38(m,2H),7.35–7.31(m,1H),5.93–5.77(m,1H),4.82–4.42(m,4H),4.20–4.06(m,1H),3.83–3.65(m,2H),3.63–3.48(m,1H),1.10–0.96(m,3H);MS(ESI):m/z 434.4(M+H)
+.
实施例192:
从(R)-2-氨基-N,N-二甲基丙酰胺盐酸盐起,参照化合物24的合成得到化合物192。
1H NMR(500MHz,DMSO-d
6)δ8.72–8.56(m,1H),8.14–7.83(m,6H),7.49–7.26(m,3H),6.51–6.35(m,1H),5.07–4.77(m,1H),4.59–4.46(m,2H),3.12–2.90(m,3H),2.90–2.73(m,3H),1.34–1.14(m,3H);MS(ESI):m/z 445.3(M+H)
+.
实施例192:
从(R)-2-氨基-N-甲基丙酰胺起,参照化合物24的合成得到化合物193。
1H NMR(500MHz,DMSO-d
6)δ8.74–8.59(m,1H),8.14–8.00(m,5H),7.94–7.84(m,2H),7.46–7.31(m,3H),6.45–6.30(m,1H),4.61–4.46(m,3H),2.64–2.57(m,3H),1.36–1.20(m,3H);MS(ESI):m/z 431.3(M+H)
+.
实施例194:
从(6-氯吡啶-2,4-二基)二甲醇和(2R,3R)-3-氨基丁-2-醇起,参照化合物160的合成得到化合物194。
1H NMR(500MHz,DMSO-d
6)δ8.11–7.96(m,4H),7.73–7.66(m,1H),7.45–7.36(m,3H),5.79–5.66(m,1H),5.51–5.42(m,2H),5.08–4.98(m,1H),4.66–4.59(m,4H),4.59–4.40(m,2H),4.17–4.00(m,1H),3.80–3.64(m,1H),1.10–0.92(m,6H);MS(ESI):m/z 478.4(M+H)
+.
实施例195:
从(2R,3R)-3-氨基戊-2-醇起,参照化合物24的合成得到化合物195。
1H NMR(500MHz,DMSO-d
6)δ8.67–8.63(m,1H),8.10–7.99(m,4H),7.91(d,J=7.9Hz,1H),7.89–7.83(m,1H),7.40(d,J=8.1Hz,2H),7.36–7.31(m,1H),5.69–5.59(m,1H),4.99–4.89(m,1H),4.56–4.41(m,2H),4.05–3.91(m,1H),3.87–3.73(m,1H),1.54–1.38(m,2H),0.93–0.70(m,6H);MS(ESI):m/z 432.3(M+H)
+.
实施例196:
从(1R,2R)-2-氨基-1-环丙基丙-1-醇起,参照化合物24的合成得到化合物196。
1H NMR(500MHz,DMSO-d
6)δ8.72–8.61(m,1H),8.14–7.83(m,6H),7.48–7.28(m,3H),5.81–5.70(m,1H),5.19–5.02(m,1H),4.60–4.45(m,2H),4.35–4.20(m,1H),2.98–2.85(m,1H),1.22–1.07(m,3H),0.87–0.65(m,1H),0.44–0.04(m,4H);MS(ESI):m/z 444.2(M+H)
+.
实施例197:
从(1S,2R)-2-氨基-1-环丙基丙-1-醇起,参照化合物24的合成得到化合物197。
1H NMR(500MHz,DMSO-d
6)δ8.72–8.59(m,1H),8.12–7.83(m,6H),7.55–7.30(m,3H),5.82–5.71(m,1H),5.19–5.00(m,1H),4.70–4.46(m,2H),4.37–4.18(m,1H),2.97–2.85(m,1H),1.20–1.03(m,3H),0.90–0.67(m,1H),0.47–0.08(m,4H);MS(ESI):m/z 444.2(M+H)
+.
实施例198:
从(6-氯吡啶-2,4-二基)二甲醇和(2R,3R)-3-氨基戊-2-醇起,参照化合物160的合成得到化合物198。
1H NMR(500MHz,DMSO-d
6)δ8.12–7.96(m,4H),7.67(s,1H),7.43–7.36(m,3H),5.67–5.59(m,1H),5.47–5.43(m,1H),5.43–5.38(m,1H),5.00–4.87(m,1H),4.63–4.59(m,4H),4.55–4.41(m,2H),4.06–3.90(m,1H),3.90–3.72(m,1H),1.52–1.42(m,2H),0.90–0.71(m,6H);MS(ESI):m/z 492.4(M+H)
+.
实施例199:
从(2R,3S)-2-氨基戊-3-醇起,参照化合物24的合成得到化合物199。
1H NMR(500MHz,DMSO-d
6)δ8.76–8.60(m,1H),8.13–7.97(m,4H),7.93–7.89(m,1H),7.88–7.83(m,1H),7.47–7.28(m,3H),6.03–5.88(m,1H),4.98–4.78(m,1H),4.62–4.46(m,2H),4.31–4.10(m,1H),3.52–3.36(m,1H),1.45–1.21(m,2H),1.12–0.70(m,6H);MS(ESI):m/z 432.2(M+H)
+.
实施例200:
从(2R,3R)-2-氨基戊-3-醇起,参照化合物24的合成得到化合物200。
1H NMR(500MHz,DMSO-d
6)δ8.69–8.62(m,1H),8.14–7.98(m,4H),7.96–7.89(m,1H),7.89–7.82(m,1H),7.46–7.36(m,2H),7.36–7.30(m,1H),5.74–5.62(m,1H),5.15–4.99(m,1H),4.60–4.42(m,2H),4.27–4.09(m,1H),3.45–3.35(m,1H),1.43–1.13(m,3H),1.11–1.00(m,2H),0.92–0.65(m,3H);MS(ESI):m/z 432.2(M+H)
+.
实施例201:
从(2R,3R)-3-氨基-4-(哌啶-1-基)丁-2-醇起,参照化合物24的合成得到化合物201。
1H NMR(500MHz,DMSO-d
6)δ8.58(d,J=4.5Hz,1H),8.08–7.93(m,4H),7.88–7.83(m,1H),7.83–7.68(m,1H),7.35–7.24(m,3H),5.56(d,J=8.0Hz,1H),5.18–4.92(m,1H),4.54–4.37(m,2H),4.12–3.86(m,2H),2.34–1.98(m,6H),1.31–1.21(m,4H),1.21–1.16(m,2H),1.03–0.94(m,1H),0.86–0.82(m,2H);MS(ESI):m/z 501.6(M+H)
+.
实施例202:
从(2R,3R)-3-氨基-4-(吡咯烷-1-基)丁-2-醇起,参照化合物24的合成得到化合物202。
1H NMR(500MHz,DMSO-d
6)δ8.64(s,1H),8.16–7.98(m,4H),7.95–7.83(m,2H),7.46–7.28(m,3H),5.77–5.52(m,1H),5.35–5.00(m,1H),4.63–4.41(m,2H),4.19–3.93(m,2H),3.15(d,J=9.5Hz,2H),2.32–2.19(m,4H),1.71–1.51(m,4H),1.34–1.27(m,3H);MS(ESI):m/z 487.2(M+H)
+.
实施例203:
从(2R,3R)-3-氨基-4-((R)-3-羟基吡咯烷-1-基)丁-2-醇起,参照化合物24的合成得到化合物203。
1H NMR(500MHz,DMSO-d
6)δ8.66–8.53(m,1H),8.13–7.73(m,6H),7.39–7.23(m,3H),5.69–5.57(m,1H),5.21–4.80(m,2H),4.50–4.07(m,5H),3.96–3.81(m,2H),3.12–3.03(m,4H),1.25–1.16(m,5H);MS(ESI):m/z 503.3(M+H)
+.
实施例204:
从(2-氯-6-(羟甲基)异烟腈和R-2-氨基丁酰胺盐酸盐起,参照化合物160的合成得到化合物204-a。从化合物204-a起,参照化合物189的合成得到化合物204。
1H NMR(500MHz,DMSO-d
6)δ8.17–7.98(m,4H),7.78(s,1H),7.62(s,1H),7.51–7.37(m,3H),7.36–7.21(m,1H),6.31–6.21(m,1H),4.65–4.60(m,2H),4.60–4.54(m,2H),4.54–4.45(m,1H),3.95–3.87(m,2H),1.86–1.62(m,2H),0.84–0.64(m,3H);MS(ESI):m/z 490.7(M+H)
+.
实施例205:
从((5-溴吡啶-2-基)甲基)氨基甲酸叔丁酯起,参照化合物204的合成得到化合物205。
1H NMR(500MHz,DMSO-d
6)δ9.21–9.12(m,1H),8.39–8.31(m,1H),8.12–8.09(m,1H),8.09–7.77(m,2H),7.68–7.58(m,1H),7.46(s,1H),7.41–7.38(m,1H),7.31–7.22(m,1H),6.32–6.21(m,1H),5.45–5.38(m,1H),4.74–4.53(m,5H),3.84(s,2H),2.06–1.95(m,2H),0.82–0.57(m,3H);MS(ESI):m/z 491.8(M+H)
+.
实施例206:
从(R)-2-氨基-2-环丙基乙酰胺盐酸盐起,参照化合物24的合成得到化合物206。
1H NMR(500MHz,DMSO-d
6)δ8.69–8.61(m,1H),8.16–7.78(m,6H),7.63–7.24(m,5H),6.28–6.19(m,1H),4.66–4.43(m,2H),4.28–4.17(m,1H),1.22–1.13(m,1H),0.53–0.16(m,4H);MS(ESI):m/z 443.7(M+H)
+.
实施例207:
从(2S,3R)-2-氨基-3-羟基丁酰胺盐酸盐起,参照化合物24的合成得到化合物207。
1H NMR(500MHz,DMSO-d
6)δ8.72–8.60(m,1H),8.18–7.80(m,6H),7.52–7.13(m,5H),6.17–5.97(m,1H),5.28–5.12(m,1H),4.62–4.40(m,3H),4.28–4.10(m,1H),1.10–0.94(m,3H);MS(ESI):m/z 447.7(M+H)
+.
实施例208:
从(R)-2-氨基-2-苯乙烷-1-醇起,参照化合物24的合成得到化合物208。
1H NMR(500MHz,DMSO-d
6)δ8.68–8.62(m,1H),8.13–8.03(m,1H),8.02–7.71(m,5H),7.39–7.14(m,8H),6.63–6.51(m,1H),5.38–5.03(m,2H),4.61–4.24(m,2H),3.85–3.65(m,2H);MS(ESI):m/z 466.7(M+H)
+.
实施例209:
从(2S,3S)-2-氨基-3-羟基丁酰胺盐酸盐起,参照化合物24的合成得到化合物209。
1H NMR(500MHz,DMSO-d
6)δ8.70–8.61(m,1H),8.18–7.80(m,6H),7.52–7.21(m,5H),6.26–6.13(m,1H),5.11–4.98(m,1H),4.66–4.43(m,3H),4.11–3.90(m,1H),1.12–1.04(m,3H);MS(ESI):m/z 447.6(M+H)
+.
实施例210:
从(R)-2-氨基-3-甲基丁酰胺盐酸盐起,参照化合物24的合成得到化合物210。
1H NMR(500MHz,DMSO-d
6)δ8.68–8.61(m,1H),8.18–7.96(m,4H),7.94–7.90(m,1H),7.86(td,J=7.7,1.9Hz,1H),7.61(s,1H),7.49–7.37(m,2H),7.35–7.27(m,2H),6.10–5.90(m,1H), 4.70–4.57(m,2H),4.54–4.40(m,1H),2.11–1.92(m,1H),0.92–0.76(m,6H);MS(ESI):m/z 445.6(M+H)
+.
实施例211:
从(R)-2-氨基-2-环丁基乙酰胺盐酸盐起,参照化合物24的合成得到化合物211。
1H NMR(500MHz,DMSO-d
6)δ8.64(dd,J=5.0,1.6Hz,1H),8.14–7.74(m,6H),7.55(s,1H),7.50–7.36(m,2H),7.36–7.29(m,1H),7.27–7.17(m,1H),6.14–6.02(m,1H),4.70–4.42(m,3H),2.67–2.58(m,1H),1.89–1.50(m,6H);MS(ESI):m/z 457.6(M+H)
+.
实施例212:
从(2R,3S)-2-氨基-3-羟基丁酰胺盐酸盐起,参照化合物24的合成得到化合物212。
1H NMR(500MHz,DMSO-d
6)δ8.64(d,J=4.7Hz,1H),8.22–7.98(m,4H),7.94–7.89(m,1H),7.89–7.83(m,1H),7.49–7.29(m,4H),7.19(s,1H),6.10–6.01(m,1H),5.22–5.16(m,1H),4.57–4.43(m,3H),4.26–4.12(m,1H),1.09–0.98(m,3H);MS(ESI):m/z 447.6(M+H)
+.
实施例213:
从(2R,3R)-2-氨基-3-羟基丁酰胺盐酸盐起,参照化合物24的合成得到化合物213。
1H NMR(500MHz,DMSO-d
6)δ8.68–8.60(m,1H),8.26–7.98(m,4H),7.95–7.89(m,1H),7.89–7.79(m,1H),7.51–7.30(m,4H),7.25–7.13(m,1H),6.11–5.99(m,1H),5.20(s,1H),4.52–4.43(m,3H),4.26–4.13(m,1H),1.09–0.96(m,3H);MS(ESI):m/z 447.6(M+H)
+.
实施例214:
从(R)-(2-氨基丁基)氨基甲酸叔丁酯起,参照化合物101的合成得到化合物214。
1H NMR(500MHz,DMSO-d
6)δ8.67–8.59(m,1H),8.11–7.94(m,4H),7.93–7.89(m,1H),7.88–7.83(m,1H),7.45–7.37(m,2H),7.35–7.30(m,1H),6.32–6.20(m,1H),4.61–4.41(m,2H),4.19–4.09(m,1H),2.89–2.63(m,2H),1.60–1.40(m,2H),0.87–0.65(m,3H);MS(ESI):m/z 417.6(M+H)
+.
测试实施例
HGC27(人胃癌细胞)细胞生长抑制的生物活性检测
本检测方法用于本发明所述化合物的细胞水平生物学活性评价。
收获HGC27细胞(购买自中科院),用完全培养基重悬并调整细胞密度为每毫升0.2x 10
6个细胞。按照100μL每孔,将细胞悬液加入96孔板中,于37℃、5%CO
2培养箱培养过夜。准备待测化合物,加入细胞孔板中,使得化合物的最高浓度为10μM。按照3倍稀释设置8个浓度点。同时设置100%抑制对照孔,即不加入细胞,只有等体积完全培养基的孔;以及0%抑制的对照孔,即加入0.1%DMSO的细胞孔。将上述细胞板于37℃、5%CO
2培养24小时。取出细胞培养板,每孔加入25μl
Luminescent Cell Viability试剂(promega cat#G7573),避光孵育10分钟后转移100μL到白板中使用Molecular Devices SpectraMax i3检测化学发光。数据处理采用如下公式计算抑制率:化合物抑制率=(0%抑制对照孔信号-化合物处理孔信号)/(0%抑制对照孔信号-100%抑制对照孔信号)*100%。计算得到的数据利用graphpad prism软件进行四参数拟合并计算其对应的IC
50。
根据上述检测方法,对本发明所述化合物进行细胞水平生物学活性评价,活性结果见下表。其中CR8为文献化合物,其采购自上海毕得医药,具体结构如下:
由上述结果可见,本发明的化合物具有良好的肿瘤细胞生长抑制活性。
Western blot检测Cyclin K(CCNK)的降解
收获HEK293细胞(ATCC,cat#CRL-1573),调整细胞密度为每毫升1x 10
6个细胞。以每孔1ml细胞悬液铺入6孔板中,过夜贴壁培养。取化合物贮存液,用DMSO将其稀释至合适的浓度。用培养基以1:1000的比例将稀释好的化合物加入细胞孔中,保证每孔DMSO浓度为0.1%。同时设置阴性对照孔,即含有0.1%DMSO的完全培养基。化合物按照图中所示的浓度处理固定以及不同的时间后,用加入PMSF的RIPA细胞裂解液(Beyotime,cat#P0013B)提取细胞总蛋白。使用BCA蛋白定量试剂盒(Thermo Fisher,cat#A53225)进行蛋白定量后,每个样品按照40μg的上样量进行后续的SDS-PAGE以及western blot实验。具体条件为,120V恒压跑胶90分钟后,按照320mA恒流转膜60min。按照抗体推荐的稀释比例以及孵育时间进行抗体孵育。实验中所用抗体信息如下:Anti-GAPDH抗体(abcam,cat#ab9485),Anti-Cyclin K抗体(abcam,cat#ab85854),Goat anti-Rabbit IgG(H+L)Cross-Adsorbed Secondary Antibody,HRP(invitrogen,cat#G-21234)。使用ECL发光液(Thermo Fisher,cat#32209)显色发光。使用凝胶成像系统分析最终结果。
根据上述检测方法,对本发明所述部分化合物进行了评价。
图1显示,化合物1能够显著诱导Cyclin K的降解,并且呈现出较强的时间和剂量依赖性。具体如下,化合物1与HEK293细胞孵育6h,14h和24h后,相对于对照均体现 出Cyclin K的降解,其中高浓度(1μM)的效果最优,其次为中浓度(0.3μM),最后为低浓度(0.1μM)。同时相同浓度的化合物随着孵育时间的延长,降解效果越好。例如用低浓度(0.1μM)化合物1处理24h后Cyclin K的降解效果优于同浓度处理14h和6h后的Cyclin K降解效果。
图2显示,本发明的其他化合物,例如化合物3、4、5、8、13、18在1μM处理HEK293细胞6h后相较于对照均能够显著诱导Cyclin K的降解。
由上述结果可见,本发明的化合物可有效降解Cyclin K。
Claims (19)
- 具有式(I)结构的化合物或其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物或其代谢产物:其中,Cy1和Cy2各自独立地代表6元芳环或6元杂芳环;其中,R L和R L’各自独立地表示氢、C 1-C 6烷基或者C 3-C 6环烷基,R L和R L’可以与与之相连的碳原子一起形成3-6元环;其中,W 1各自独立地表示CR 0或者N;其中,R 0各自独立地表示氢、卤素、硝基、氰基、-R a、-OR a、-SR a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-S(O) 2R a、-NR aC(O)R b、-S(O) 2NR a、-S(O)R a或者-P(O)R aR b;其中,W 2各自独立地表示CR 1或者N;其中,R 1各自独立地表示氢、卤素、硝基、氰基、-R a、-OR a、-SR a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-NR aC(O)R b、-S(O) 2R a、-S(O)R a、-S(O) 2NR aR b、-P(O)R aR b,以及由0、1、2、3个取代基任意取代的C 1-C 6烷基、(C 2-C 6)烯基、(C 2-C 6)炔基,所述取代基选自OR a、SR a、NR aR b、NR aC(O)R b、C(O)R a、C(O)OR a、C(O)NR aR b、S(O) 2R a、S(O)R a、S(O) 2NR aR b或者P(O)R aR b;其中,R 2表示卤素、-R a、-OR a、-SR a、硝基、氰基、-NR aR b、-NR aC(O)R b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-S(O) 2R a、-S(O)R a、-S(O) 2NR aR b、-P(O)R aR b、(C 2-C 6)烯基或者(C 2-C 6)炔基;其中,R 3表示C 1-C 6烷基、C 1-C 6烯基、C 1-C 6炔基、C 3-C 10环烷基、3-10元杂环烷基、C 6-C 10元芳基、5-10元杂芳基、-NR MR N、-NHR M、-OR M或者;当R 3表示C 1-C 6烷基、C 1-C 6烯基、C 1-C 6炔基、C 3-C 10环烷基或者3-10元杂环烷基时,其任选地可被0、1、2、3个以下取代基取代:硝基、卤素、氰基、-R a、-(C 0-C 6亚烷基)OR a、-(C 0-C 6亚烷基)SR a、-(C 0-C 6亚烷基)NR aR b、-(C 0-C 6亚烷基)NR aC(O)R b、-(C 0-C 6亚烷基)C(O)R a、-(C 0-C 6亚烷基)C(O)OR a、-(C 0-C 6亚烷基)C(O)NR aR b、-(C 0-C 6亚烷基)S(O) 2R a、-(C 0-C 6亚烷基)S(O)R a、-(C 0-C 6亚烷基)S(O) 2NR aR b、-(C 0-C 6亚烷基)P(O)R aR b;当R 3表示C 6-C 10元芳基或者5-10元杂芳基时,其任选地可被0、1、2、3个以下取代基取代:硝基、卤素、氰基、-R a、-(C 0-C 6亚烷基)OR a、-(C 0-C 6亚烷基)SR a、-(C 0-C 6亚烷基)NR aR b、-(C 0-C 6亚烷基)NR aC(O)R b、-(C 0-C 6亚烷基)C(O)R a、-(C 0-C 6亚烷基)C(O)OR a、-(C 0-C 6亚烷基)C(O)NR aR b、-(C 0-C 6亚烷基)S(O) 2R a、-(C 0-C 6亚烷基)S(O)R a、-(C 0-C 6亚烷基)S(O) 2NR aR b、-(C 0-C 6亚烷基)P(O)R aR b;当R 3表示-NR MR N、-NHR M、-OR M时,R M和R N各自独立地选自C 1-C 6烷基、-(C 0-C 6亚烷基)(C 3-C 10环烷基)、-(C 0-C 6亚烷基)(3-10元杂环烷基)、-(C 0-C 6亚烷基)(C 6-C 10元芳基)、-(C 0-C 6亚烷基)(5-10元杂芳基);其中,R M和R N任选地可被0、1、2、3个以下取代基取代:氧代、硝基、卤素、氰基、-R a、-(C 0-C 6亚烷基)OR a、-(C 0-C 6亚烷基)SR a、-(C 0-C 6亚烷基)NR aR b、-(C 0-C 6亚烷基)NR aC(O)R b、-(C 0-C 6亚烷基)C(O)R a、-(C 0-C 6亚烷基)C(O)OR a、-(C 0-C 6亚烷基)C(O)NR aR b、-(C 0-C 6亚烷基)S(O) 2R a、-(C 0-C 6亚烷基)S(O)R a、-(C 0-C 6亚烷基)S(O) 2NR aR b、-(C 0-C 6亚烷基)P(O)R aR b;其中,R a、R b各自独立地表示氢、C 1-C 6烷基或者C 3-C 8环烷基,其任选地可被0、1、2、3个卤素原子取代;前提是式(I)化合物不包括
- 如权利要求1所述的化合物或其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物或其代谢产物,其中R 2表示卤素、三氟甲基或氰基。
- 如前述任一权利要求所述的化合物或其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物或其代谢产物,其中Cy1选自:优选地Cy1选自: 其中波浪线表示Cy1连接到式(I)中的位点;其中,所述Cy1任选地被0、1、2或者3个R 0取代;优选地所述Cy1被0个R 0取代。
- 如前述任一权利要求所述的化合物或其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物或其代谢产物,其中Cy2选自:优选地Cy2选自 其中波浪线表示Cy2连接到式(I)中的位点;其中,所述Cy2任选地被0、1、2或者3个R 1取代;优选地,所述Cy2被0个R 1取代;优选地,所述Cy2被1或者2个R 1取代。
- 如前述任一权利要求所述的化合物或其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物或其代谢产物,其中,R 0各自独立地表示氢、卤素、-R a、-OR a或者-SR a。
- 如前述任一权利要求所述的化合物或其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物或其代谢产物,其中,R 1各自独立地表示氢、卤素、-R a、-OR a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-NR aC(O)R b、-S(O) 2R a、-S(O)R a、-P(O)R aR b、-(C 2-C 6)烯基、-(C 2-C 6)炔基、-(C 1-C 6亚烷基)OR a、-(C 1-C 6亚烷基)NR aR b、-(C 1-C 6亚烷基)NR aC(O)R b、-(C 1-C 6亚烷基)C(O)R a、-(C 1-C 6亚烷基)C(O)OR a、-(C 1-C 6亚烷基)C(O)NR aR b、-(C 1-C 6亚烷基)S(O) 2R a、-(C 1-C 6亚烷基)S(O)R a或者-(C 1-C 6亚烷基)P(O)R aR b。
- 如前述任一权利要求所述的化合物或其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物或其代谢产物,其中,R 3表示C 1-C 6烷基、C 1-C 6烯基、C 1-C 6炔基、C 3-C 10环烷基或者3-10元杂环烷基,其任选地可被0、1、2、3个以下取代基取代:硝基、卤素、氰基、-R a、-(C 0-C 6亚烷基)OR a、-(C 0-C 6亚烷基)SR a、-(C 0-C 6亚烷基)NR aR b、-NR aC(O)R b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-S(O) 2R a、-S(O)R a、-S(O) 2NR aR b、-P(O)R aR b。
- 如权利要求7所述的化合物或其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物或其代谢产物,其中,R 3表示C 1-C 6烷基、C 1-C 6烯基、C 1-C 6炔基C 3-C 10环烷基或者3-10元杂环烷基,其任选地可被0、1、2、3个以下取代基取代:卤素、-R a、-(C 0-C 6亚烷基)OR a或者-(C 0-C 6亚烷基)SR a、-(C 0-C 6亚烷基)NR aR b。
- 如前述任一权利要求所述的化合物或其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物或其代谢产物,其中,R 3表示C 6-C 10元芳基或者5-10元杂芳基,其任选 地可被0、1、2、3个以下取代基取代:硝基、卤素、氰基、-R a、-(C 0-C 6亚烷基)OR a、-(C 0-C 6亚烷基)SR a、-(C 0-C 6亚烷基)NR aR b、-NR aC(O)R b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-S(O) 2R a、-S(O)R a、-S(O) 2NR aR b或者-P(O)R aR b。
- 如权利要求9所述的化合物或其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物或其代谢产物,其中,所述R 3任选地可被0、1、2、3个以下取代基取代:卤素、-R a、-(C 0-C 6亚烷基)OR a、-(C 0-C 6亚烷基)SR a、-(C 0-C 6亚烷基)NR aR b、-NR aC(O)R b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-S(O) 2R a、-S(O)R a、-S(O) 2NR aR b或者-P(O)R aR b。
- 如前述任一权利要求所述的化合物或其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物或其代谢产物,其中,R 3表示-NR MR N、-NHR M、-OR M,R M和R N各自独立地表示C 1-C 6烷基、-(C 0-C 6亚烷基)(C 3-C 10环烷基)、-(C 0-C 6亚烷基)(3-10元杂环烷基)、-(C 0-C 6亚烷基)(C 6-C 10元芳基)或者-(C 0-C 6亚烷基)(5-10元杂芳基);其中,R M和R N任选地可被0、1、2、3个以下取代基取代:氧代、硝基、卤素、氰基、-R a、-OR a、-SR a、-NR aR b、-NR aC(O)R b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-S(O) 2R a、-S(O)R a、-S(O) 2NR aR b、-P(O)R aR b。
- 如权利要求11所述的化合物或其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物或其代谢产物,其中,R M和R N任选地可被0、1、2、3个以下取代基取代:氧代、-R a、-OR a、-SR a、-NR aR b、-NR aC(O)R b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-S(O) 2R a、-S(O)R a、-S(O) 2NR aR b或者-P(O)R aR b。
- 如前述任一权利要求所述的化合物或其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物或其代谢产物,其中,R a、R b各自独立地表示氢、C 1-C 3烷基或者C 3-C 6环烷基,其任选地可被0、1、2、3个卤素原子取代。
- 如前述任一权利要求所述的化合物或其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物或其代谢产物,其中,R a、R b各自独立地表示氢、C 1-C 3烷基,其任选地可被0、1、2、3个卤素原子取代。
- 如前述任一权利要求所述的化合物,其选自:
- 药物组合物,其包含如前述权利要求任意一项所述的化合物或其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物或其代谢产物,及任选地药学上可接受的载体。
- 如权利要求1-15任一项所述的化合物或其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物或其代谢产物,或者如权利要求16所述的药物组合物在制备用于预防或治疗与Cyclin K蛋白相关的疾病或病症的药物中的应用。
- 如权利要求17所述的应用,其中所述疾病或病症选自肿瘤、癌症、病毒感染、炎症相关疾病和自身免疫性疾病。
- 一种治疗与Cyclin K蛋白相关的疾病或病症的方法,其包括向有此需要的哺乳动物施用权利要求1-15任一项所述的化合物或其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物或其代谢产物,或者权利要求16所述的药物组合物。
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