CN115956080A - 双环化合物,包含其的组合物及其应用 - Google Patents
双环化合物,包含其的组合物及其应用 Download PDFInfo
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- CN115956080A CN115956080A CN202180050625.7A CN202180050625A CN115956080A CN 115956080 A CN115956080 A CN 115956080A CN 202180050625 A CN202180050625 A CN 202180050625A CN 115956080 A CN115956080 A CN 115956080A
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- China
- Prior art keywords
- trifluoromethyl
- phenyl
- pyridin
- pyrazolo
- azetidin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
提供了式(I)所示化合物,包含其的药用组合物和其应用。所述化合物可用于治疗,预防或改善诸如癌症之类的疾病或障碍。
Description
技术领域
本发明涉及式(I)所示的新化合物。本发明还涉及包含此类化合物的药物组合物及将所述化合物用于疾病的治疗和预防的方法,尤其是癌症,癌前综合征、先天性疾病和过度增殖性疾病。
背景技术
在正常环境下,细胞增殖和凋亡之间的动态平衡维持了组织器官的正常大小和体内环境的稳定。当细胞的增殖或凋亡失控时,就会发生细胞恶性转化。Hippo信号通路是一种细胞抑制生长通路,它由多种抑癌因子组成,通过一系列激酶级联反应调节细胞增殖和凋亡之间的平衡。Hippo信号通路在早期胚胎发育、器官大小和再生等方面起着关键作用。
Hippo通路最初是在果蝇中发现的,是一种控制器官大小的重要发育通路,随后也在哺乳动物体内发现。在哺乳动物体内,Hippo通路可以分为三类:上游调控元件(Merlin/NF2、GPCRS等)、核心激酶级联(MST1/2、LATS1/2和调控蛋白SAV1和MOB)和下游效应分子(YAP/TAZ)。肿瘤抑制蛋白2型神经纤维瘤抗原(NF2/merlin)或其他上游调控信号激活的MST1/2激酶和支架蛋白SAV1。激活的MST1/2促进LATS1/2和MOB的磷酸化。然后,磷酸化的LATS1/2能够进一步磷酸化YAP/TAZ来实现Hippo信号通路的调节。磷酸化的YAP/TAZ与介导细胞质滞留的14-3-3和蛋白酶体降解的β-TrCP连接最终被降解。
细胞质中未磷酸化的YAP/TAZ穿过核膜进入细胞核并作为TEAD1-4的转录共激活因子。各种细胞因子包括结缔组织生长因子(CTGF)、富含半胱氨酸的血管生成诱导剂61(CYR61)、锚蛋白重复结构域1(ANKRD1)、杆状病毒IAP重复蛋白5(BIRC5)、脑源性神经营养因子和成纤维细胞生长因子1是YAP/TAZ刺激的下游底物。作为YAP/TAZ的直接靶向基因,CTGF可以促进细胞增殖并支持细胞独立生长。
人类YAP基因位于染色体11q13,广泛表达于除了外周血细胞的各种组织。YAP包括了多个结构域和特定的氨基酸序列,包括一个TEAD结合区域,两个WW结构域,一个富含脯氨酸的N-末端结构域,一个C-末端的PDZ结合基序,一个SH3结合的基序的,一个卷曲螺旋结构域和一个转录激活结构域。YAP有两个亚型:YAP1和YAP2。YAP1包括1个WW结构域,YAP2包括2个WW结构域。WW结构域特异性识别PPXY基序来介导转录复合物的形成。YAP2是YAP的主要形态,并且具有比YAP1更强的转录调控活性。另外,TAZ与YAP同源,具有与YAP相似的结构域和功能,但缺少富含胞脯氨酸的结构域和第二个WW结构域。
TEAD家族是YAP和TAZ最重要的转录因子。TEAD关键位置的点突变,尤其是与YAP和TEAD结合域相关的突变,显著抑制了YAP诱导基因的表达和功能。人类TEAD家族转录因子包括四个成员TEAD1/2/3/4,具有高度同源性。TEADs包括在N-端的TEA结合结构域,作为与DNA转录启动子结合的位点,以及在C-端的YAP/TAZ结合结构域。YAP/TAZ的N-端结构域包裹TEAD的C-端结构域,形成球形结构。YAP/TAZ和TEAD的绑定区域分为三个界面。界面1由YAPβ1和TEADβ7的肽骨架之间的七个分子间氢键介导,形成反平行的β折叠。界面2由靠近由TEADα3和α4形成的凹槽的YAPα1螺旋产生。在界面3中,YAP的Ω环与由TEAD的β4、β11、β12、α1和α4形成的深入口袋相互作用。
通常,YAP/TAZ仅在特定组织和特定条件下(例如发育,伤口愈合等)被诱导。在其他组织中的表达水平较低。Hippo通路原件的突变触发了YAP/TAZ的过度激活,导致正常细胞的增殖。研究表明,在Hippo通路失调后,YAP/TAZ的过度激活在肺癌、肝癌、胰腺癌、乳腺癌等癌症中很普遍。
在多种实体瘤的癌症干细胞中,YAP/TAZ可以促进癌症干细胞的存活,并且与癌细胞转移和耐药性关系密切,促进多种肿瘤的发生和发展。在化疗药物治疗期间,抗微管药物、抗代谢药物和DNA损伤剂等可影响Hippo信号通路,导致YAP/TAZ激活和转录,从而产生耐药性。YAP/TAZ的过度激活会引起多种药物转运蛋白的高度表达,其可以将药物转移至胞外,导致抗凋亡蛋白如Bcl和survivin的上调,从而抑制细胞凋亡。许多研究表明PD-L1是YAP/TAZ的直接转录靶点。活化的YAP/TAZ可以增加PD-L1的表达。同时,其还可以诱导细胞因子IL-6,CSF1-3,TNFA,IL-3,CXCL1/2,CCL2等的表达来促进髓源性抑制细胞(MDSC)的募集和极化,灭活T细胞或诱导T细胞凋亡。更多的研究表明,解除Hippo通路的下调引起YAP/TAZ的激活,这也是多种靶向耐药的主要机制。YAP/TAZ激活的转录可以通过多种机理克服EGFR耐药。例如,AXL的高表达介导NSCLC对EGFR抑制剂的耐药性;抑制促凋亡蛋白BMF介导EGFR/MEK抑制剂的耐药性;激活PI3K/AKT信号通路以逃避靶向治疗。YAP激活的转录也可以介导对BRAF,KRAS和MAPK抑制剂的抗性。YAP/TAZ的激活不仅与耐药性有关,研究表明YAP基因扩增与结肠癌和胰腺癌的复发相关。
因此,Hippo通路在控制组织器官的形态上具有重要作用。其与肿瘤发生的许多方面相关,包括细胞增殖,分化,凋亡,竞争,组织再生,癌症转移和癌症疗法抗性。解除Hippo通路的管控可导致细胞质和细胞核中YAP/TAZ的高表达和激活,从而诱导肿瘤的发展和转移甚至产生耐药性。YAP/TAZ-TEAD相互作用的破坏可以消除YAP/TAZ的致癌特性。因此YAP/TAZ和TEAD的蛋白-蛋白相互作用抑制剂治疗这些癌症提供了理论依据。
发明内容
本发明涉及式(I)所示的化合物,或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,
其中,
A1和A2分别选自C或N;
环B选自C5-6芳基,C5-6环烷基,5-6元杂环基和5-6元杂芳基,其中5-6元杂环基和5-6元杂芳基包含1,2,3或4个独立选自N,S和O的杂原子;
环A选自C5-6芳基,5-6元杂芳基,5-6元杂环基,5-6元杂芳基和5-6元杂环基包含1-4个独立选自N,S和O的杂原子,其中C5-6芳基,5-6元杂芳基和5-6元杂环基可分别任选地被0-3个独立选自氧代基,=NH,羟基,卤素,CN,-NH(C1-6烷基),-NH(C1-6烷基),-N-(C1-6烷基)2,C1-6烷基,C2-6烯基,C2-6炔基,C1-6卤代烷基,C1-6烷氧基,C1-6卤代烷氧基,-OC(=O)Ra,-C(=O)NRaRb,-C(=O)ORa,-C(=O)Rc,-S(=O)Rb,-S(=O)2Rb,-S(=O)NRaRb,-S(=O)2NRaRb;
L1是键,-O-,-S-,-NRa-,-(CH2)t-,-(CH2)t-NRa-,-NRa-(CH2)t-,-(CH2)t-O-,-O-(CH2)t-,-C(=O)-,-C(=O)NRa-或-NRa-C(=O)-;
环E是C5-6芳基,5-10元杂芳基,C3-8环烷基或4-8元杂环基,其中5-10元杂芳基4-8元杂环基包含1-4个独立选自N,S和O的杂原子;
L2是键,-O-,-S-,-NH-,-(CH2)t-O-,-O-(CH2)t-,-C(=O)-,-C1-4亚烷基,-C2-4亚烯基,或-C2-4亚炔基;
环D是C5-10芳基,5-10元杂芳基,C3-10环烷基或4-10元杂环基,其中5-10元杂芳基或4-10元杂环基包含1,2,3或4个独立选自N,S和O的杂原子;
R1为H,氧代基,羟基,卤素,CN,-NO2,-NRdRe,C1-6烷基,C2-6烯基,C2-6炔基,C1-6卤代烷基,C1-6烷氧基,-C(=O)NRaRb,-C(=O)ORa,-C(=O)Rc,-S(=O)Rb,-S(=O)2Rb,-S(=O)NRaRb,-S(=O)2NRaRb,-O-(C=O)-Ra,-O-(C=O)-NRaRb,C1-6卤代烷氧基,C3-6环烷基,3-6元杂环基,C5-6芳基或5-6元杂芳基,其中C1-6烷基,C2-6烯基,C2-6炔基,C1-6卤代烷基,C1-6烷氧基,C1-6卤代烷氧基,C3-6环烷基,3-6元杂环基,C5-6芳基和5-6元杂芳基可分别任选地被0-3个独立选自OH,CN,卤素,C1-6烷基,C2-4烯基,C2-4炔基,C1-4卤代烷基,C1-4烷氧基,-NRaRb,-C(=O)NRaRb,-OC(=O)Ra,-C(=O)ORa,-C(=O)Ra,-S(=O)Rb,-S(=O)2Rb,-S(=O)NRaRb,-S(=O)2NRaRb,-NRaC(=O)Rb,C1-4卤代烷氧基,C3-6环烷基,3-6元杂环烷基,C5-6芳基和5-6元杂芳基的取代基取代;其中5-6元杂芳基,3-6元杂环烷基和3-6元杂环基任选地包含1,2或3个独立选自N,S和O的杂原子;
R2为H,羟基,卤素,CN,-NO2,-NRaRb,氧代基,-C(=O)NRaRb,-C(=O)ORa,-C(=O)Ra,-S(=O)Rb,-S(=O)2Rb,-S(=O)NRaRb,-S(=O)2NRaRb,-NRaC(=O)Rb,SF5,C1-6烷基,C2-6烯基,C2-6炔基,C1-6烷氧基,C1-6卤代烷基,C3-6环烷基或包含1,2或3个独立选自N,S和O的杂原子的3-6元杂环基;其中C1-6烷基,C2-6烯基,C2-6炔基,C1-6烷氧基,C3-6环烷基和3-6元杂环基分别任选地被0-3个独立选自-ORa,卤素,CN,C1-4烷基,C1-6卤代烷基,-NRaRb,氧代基,-OC(=O)Ra,-C(=O)NRaRb,-C(=O)ORa,-C(=O)Ra,-S(=O)Rb,-S(=O)2Rb,-S(=O)NRaRb,-S(=O)2NRaRb和-NRaC(=O)Rb的取代基取代;
R3为H,氧代基,卤素,-ORa,CN,-NO2,-NRaRb,-NRaC(=O)Rb,-C1-4亚烷基-NRaRb,-C1-4亚烷基-NRaC(=O)Rb,-C(=O)Rb,-OC(=O)Ra,-C(=O)ORa,-C(=O)NRaRb,-S(=O)Rb,-S(=O)2Rb,-S(=O)NRaRb,-S(=O)2NRaRb,-C1-4亚烷基-C(=O)NRaRb,C1-6烷基,C2-6烯基,C2-6炔基,C1-6烷氧基,C1-6卤代烷基,C1-6卤代烷氧基,3-6元杂环基,C3-6环烷基,C5-6芳基或5-6元杂芳基,其中5-6元杂芳基和3-6元杂环基任选地包含1,2或3个独立选自N,S和O的杂原子;其中C1-6烷基,C2-6烯基,C2-6炔基,C1-6卤代烷基,C1-6烷氧基,C1-6卤代烷氧基,C3-6环烷基,3-6元杂环基,C5-6芳基和5-6元杂芳基分别任选地被0-3个独立选自氧代基,羟基,卤素,CN,-NO2,C1-6烷基,-C1-4亚烷基-OH,C1-6卤代烷基,C1-6烷氧基,-S(=O)Rb,-S(=O)2Rb,-NRaRb,-C(=O)Rb,-OC(=O)Ra,-C(=O)ORa,-NRaC(=O)Rb,-C(=O)NRaRb,-NRaC(=O)Rb,-C1-4亚烷基-NRaRb,-C1-4亚烷基-NRaC(=O)Rb,C1-4亚烷基-C(=O)NRaRb,-C1-4亚烷基-OH,C3-6环烷基,3-6元杂环烷基,C5-6芳基和5-6元杂芳基的取代基取代;
L3为键,-NRa-,-(CH2)t-NRa-,-C4-6杂环基或-C4-6环烷基-NRa-;
R5,R6,R7和R8分别独立选自H,卤素,-ORa,CN,-NRaRb,-C1-6亚烷基-NRaRb,-C1-6亚烷基-Rc,C1-6烷基,C2-6烯基,C2-6炔基,C1-6卤代烷基,C1-6卤代烷基,C1-6烷氧基,C3-6环烷基,3-6元杂环基,C5-6芳基和5-6元杂芳基,其中C1-6烷基,C2-6烯基,C2-6炔基,C1-6卤代烷基,C1-6烷氧基,C1-6卤代烷氧基,C3-6环烷基,3-6元杂环基,C5-6芳基和5-6元杂芳基分别任选地被0-4个独立选自OH,CN,卤素,C1-6烷基,C2-4烯基,C2-4炔基,C1-4卤代烷基,C1-4烷氧基,-NRaRb,C3-6环烷基,3-6元杂环基,C5-6芳基和5-6元杂芳基的取代基取代,其中5-6元杂芳基和3-6元杂环基任选地包含1,2或3个独立选自N,S和O的杂原子;
Ra和Rb分别独立选自H,CN,羟基,卤素,C1-6烷基,C1-6卤代烷基,C1-4烷氧基,C3-6环烷基,3-6元杂环烷基,C5-6芳基和5-6元杂芳基,其中C1-6烷基,C1-4烷氧基,C3-6环烷基,3-6元杂环烷基,C5-6芳基和5-6元杂芳基分别任选地被0-4个独立选自卤素,CN,-OH,氧代基,C1-6烷基,C2-6烯基,C2-6炔基,C1-6卤代烷基,C1-3烷氧基,C1-3卤代烷氧基和C5-6芳基;其中5-6元杂芳基和3-6元杂环烷基任选地包含1,2或3个独立选自N,S和O的杂原子;
Rc为3-6元杂环基任选地被0-4个独立选自卤素,CN,-OH,氧代基,C1-6烷基,C2-6烯基,C2-6炔基,C1-6卤代烷基,C1-3烷氧基和C1-3卤代烷氧基;
Rd和Re分别独立选自C1-6烷基,C2-6烯基,C2-6炔基,C1-6卤代烷基,C1-6烷氧基,-C(=O)NRfRf,-C(=O)ORf,-O-C(=O)Rf,-C(=O)Rf,-S(=O)Rf,-S(=O)2Rf,-S(=O)NRfRf,-S(=O)2NRfRf,-C1-4亚烷基-NRfRf,-C1-4亚烷基-NRfC(=O)Rf,-C1-4亚烷基-C(=O)NRfRf;
Rf为H,C1-6烷基,C2-6炔基,C1-6卤代烷基,C1-6卤代烷氧基或C1-6烷氧基;
t为1,2,3或4;
x,y和m分别独立选自0,1,2,3,4或5。
一些实施方式中,式(I-1)所示的化合物,或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,
其中,
A1和A2分别选自C或N;
环B选自C5-6芳基,包含1,2,3或4个独立选自N,S和O的杂原子的5-6元杂芳基;
环A选自C5-6芳基,5-6元杂芳基,5-6元杂环基,5-6元杂芳基和5-6元杂环基包含1-4个独立选自N,S和O的杂原子,所述5-6元杂环基和5-6元杂芳基分别独立任选地被一个或多个和/或取代基取代;
L1为键,-O-,-S-,-NH-,-(CH2)t-,-(CH2)t-O-,-O-(CH2)t-,-C(=O)-,-C(=O)NH-或-NH-C(=O)-;
环E为C5-6芳基,5-10元杂芳基,C3-8环烷基或4-8元杂环基,其中5-10元杂芳基和4-8元杂环基包含1-4个独立选自N,S和O的杂原子;
L2为键,-O-,-S-,-NH-,-(CH2)t-O-,-O-(CH2)t-,-C(=O)-,-C1-4亚烷基,-C2-4亚烯基,或-C2-4亚炔基;
环D为C5-10芳基,5-10元杂芳基,C3-10环烷基或4-10元杂环基,其中5-10元杂芳基或4-10元杂环基包含1,2,3或4个独立选自N,S和O的杂原子;
R1为H,氧代基,羟基,卤素,CN,-NH(C1-6烷基),-N-(C1-6烷基)2,C1-6烷基,C2-4烯基,C2-4炔基,C1-4卤代烷基,C1-4烷氧基,-C(=O)NRaRb,-C(=O)ORa,-OC(=O)Ra,-C(=O)Rc,-S(=O)Rb,-S(=O)2Rb,-S(=O)NRaRb,-S(=O)2NRaRb,C1-4卤代烷氧基,C3-6环烷基,3-6元杂环基,C5-6芳基或5-6元杂芳基,其中C1-6烷基,C2-4烯基,C2-4炔基,C1-4卤代烷基,C1-4烷氧基,C1-4卤代烷氧基,C3-6环烷基,3-6元杂环基,C5-6芳基和5-6元杂芳基可分别任选地被0-3个独立选自OH,CN,卤素,C1-6烷基,C2-4烯基,C2-4炔基,C1-4卤代烷基,C1-4烷氧基,-NRaRb,-C(=O)NRaRb,-S(=O)Rb,-S(=O)2Rb,-S(=O)NRaRb,-S(=O)2NRaRb,-NRaC(=O)Rb,C1-4卤代烷氧基,C3-6环烷基,3-6元杂环烷基,C5-6芳基和5-6元杂芳基的取代基取代;其中5-6元杂芳基和3-6元杂环基任选地包含1,2或3个独立选自N,S和O的杂原子;
R2为H,羟基,卤素,CN,C1-6烷基,C2-6烯基,C2-6炔基,C1-6烷氧基,C1-6卤代烷基,C3-6环烷基或包含1,2或3个独立选自N,S和O的杂原子的3-6元杂环烷基;其中C1-4烷基,C2-4烯基,C2-4炔基,C1-4烷氧基,C3-6环烷基和3-6元杂环烷基分别任选地被0-3个独立选自羟基,卤素,CN和C1-4烷基;
R3为H,氧代基,卤素,CN,-NO2,-NRaRb,-NRaC(=O)Rb,-C1-4亚烷基-NRaRb,-C1-4亚烷基-NRaC(=O)Rb,-C(=O)Rb,-OC(=O)Ra,-C(=O)ORa,-C(=O)NRaRb,-S(=O)Rb,-S(=O)2Rb,-S(=O)NRaRb,-S(=O)2NRaRb,-C1-4亚烷基-C(=O)NRaRb,C1-6烷基,C2-6烯基,C2-6炔基,C1-6烷氧基,C1-6卤代烷基,C1-4卤代烷氧基,3-6元杂环烷基,C3-6环烷基,C5-6芳基或5-6元杂芳基,其中5-6元杂芳基和3-6元杂环烷基任选地包含1,2或3个独立选自N,S和O的杂原子;其中C1-6烷基,C2-6烯基,C2-6炔基,C1-4卤代烷基,C1-4烷氧基,C1-4卤代烷氧基,C3-6环烷基,3-6元杂环烷基,C5-6芳基和5-6元杂芳基分别任选地被0-3个独立选自氧代基,羟基,卤素,CN,-NO2,C1-6烷基,-C1-4亚烷基-OH,C1-6卤代烷基,C1-6烷氧基,-S(=O)Rb,-S(=O)2Rb,-NRaRb,-C(=O)Rb,-OC(=O)Ra,-C(=O)ORa,-NRaC(=O)Rb,-C(=O)NRaRb,-NRaC(=O)Rb,-C1-4亚烷基-NRaRb,-C1-4亚烷基-NRaC(=O)Rb,C1-4亚烷基-C(=O)NRaRb,-C1-4亚烷基-OH,C3-6环烷基,3-6元杂环烷基,C5-6芳基和5-6元杂芳基的取代基取代;
L3为键,-NH-,-(CH2)t-NH-,-C4-6杂环基或-C4-6环烷基-NH-;
R5,R6,R7和R8分别独立选自H,卤素,CN,-NRaRb,-C1-6亚烷基-NRaRb,-C1-6亚烷基-Rc,C1-4烷基,C2-4烯基,C2-4炔基,C1-4烷氧基,C3-6环烷基,3-6元杂环烷基,C5-6芳基和5-6元杂芳基,其中C1-6烷基,C2-4烯基,C2-4炔基,C1-4卤代烷基,C1-4烷氧基,C1-4卤代烷氧基,C3-6环烷基,3-6元杂环烷基,C5-6芳基和5-6元杂芳基分别任选地被0-4个独立选自OH,CN,卤素,C1-6烷基,C2-4烯基,C2-4炔基,C1-4卤代烷基,C1-4烷氧基,-NRaRb,C3-6环烷基,3-6元杂环烷基,C5-6芳基和5-6元杂芳基的取代基取代,其中5-6元杂芳基和3-6元杂环烷基任选地包含1,2或3个独立选自N,S和O的杂原子;
Ra和Rb分别独立选自H,CN,羟基,卤素,C1-6烷基,C1-6卤代烷基,C1-4烷氧基,C3-6环烷基,3-6元杂环烷基,C5-6芳基和5-6元杂芳基,其中C1-6烷基,C1-4烷氧基,C3-6环烷基,3-6元杂环烷基,C5-6芳基和5-6元杂芳基分别任选地被0-4个独立选自卤素,CN,-OH,氧代基,C1-6烷基,C2-6烯基,C2-6炔基,C1-6卤代烷基,C1-3烷氧基,C1-3卤代烷氧基和C5-6芳基;其中5-6元杂芳基和3-6元杂环烷基任选地包含1,2或3个独立选自N,S和O的杂原子;
Rc为3-6元杂环烷基,其可任选地被0-4个独立选自卤素,CN,-OH,氧代基,C1-6烷基,C2-6烯基,C2-6炔基,C1-6卤代烷基,C1-3烷氧基或C1-3卤代烷氧基的取代基取代;
t为1,2,3或4;
x,y和m分别独立选自0,1,2,3,4或5。
一些实施方式中,环B选自C5-6芳基,C5-6环烷基,包含1,2,3或4个N杂原子的5-6元杂芳基,或包含1,2,3或4个独立选自N,S,O的杂原子的5-6元杂环基。
一些实施方式中,环B选自C5-6芳基,C5-6环烷基,包含1或2个N杂原子的5-6元杂芳基,或包含1或2个O杂原子的5-6元杂环基,其中5-6元杂芳基和5-6元杂环基分别独立任选地被一个或多个取代基取代。
一些实施方式中,环B选自苯基,环己基,包含1或2个N杂原子的6元杂芳基,或包含1或2个O杂原子的6元杂环基。
一些实施方式中,环B是C5-6芳基,氧代基取代或未取代的5-6元杂芳基,所述5-6元杂芳基包含1,2,3或4个N杂原子。
一些实施方式中,环B是C5-6芳基,氧代基取代或未取代的5-6元杂芳基,,所述5-6元杂芳基包含1或2个N杂原子。
一些实施方式中,环B为苯基或包含1或2个N原子的6元杂芳基。
一些实施方式中,环A选自C5-6芳基,5-6元杂芳基,5-6元杂环基,所述5-6元杂芳基和5-6元杂环基包含1-4个独立选自N,S和O的杂原子,其中5-6元杂环基和5-6元杂芳基任选独立地被一个或多个或取代基取代。
一些实施方式中,环A是C5-6芳基,5-6元杂芳基或5-6元杂环基,其中5-6元杂芳基和5-6元杂环基包含1,2或3个N杂原子,其中5-6元杂芳基和5-6元杂环基分别独立任选地被一个或多个取代基取代。
一些实施方式中,环A为C6苯基或包含1或2个N杂原子的5-6元杂芳基。
一些实施方式中,环E为C5-6芳基,5-6元杂芳基,C3-8环烷基或4-8元杂环基,其中5-6元杂芳基和4-8元杂环基包含1,2或3个独立选自N,S和O的杂原子。
一些实施方式中,环E为C3-8环烷基,C5-6芳基或包含1,2或3个独立选自N,S和O的杂原子的5-6元杂芳基。
一些实施方式中,环E为C3-6环烷基,苯基或包含1,2或3个独立选自N,S和O的杂原子的5-6元杂芳基。
一些实施方式中,环E为C3-6环烷基,苯基或包含1,2或3个独立选自N和S的杂原子的5-6元杂芳基。
一些实施方式中,L1和L2均与环A相连。
一些实施方式中,L1为键,-O-,-S-,-NRa-,-(CH2)t-,-(CH2)t-O-,-O-(CH2)t-,-C(=O)-,-C(=O)NRa-或-NRa-C(=O)-。
一些实施方式中,L1为键,-O-,-S-,-NH-,-(CH2)t-,-(CH2)t-O-,-C(=O)-或-C(=O)NH-。
一些实施方式中,L1为键,-NH-,-O-,-S-,-N-C1-3亚烷基-,-(CH2)t-或-C(=O)-。
一些实施方式中,L1为键,-NH-,-N-C1-3亚烷基-,-(CH2)t-或-C(=O)-。
一些实施方式中,L1为键,-NH-,-(CH2)t-或-C(=O)-。
一些实施方式中,L1为键,-NH-,-N-C1-3亚烷基-,-CH2-或-C(=O)-。
一些实施方式中,L1为键,-NH-,-CH2-或-C(=O)-。
一些实施方式中,L1为键,-NH-或-C(=O)-。
优选地,L1为键。
一些实施方式中,L2为键,-O-,-S-,-NH-,-C(=O)-,-C2-4亚烯基,或-C2-4亚炔基。
一些实施方式中,L2为键,-O-,C2-4亚烯基,或C2-4亚炔基。
一些实施方式中,L2为键,C2-4亚烯基或C2-4亚炔基。
一些实施方式中,L2为键或-O-。
一些实施方式中,L2为C2-4亚烯基或C2-4亚炔基。
一些实施方式中,环E为苯基或包含1或2个N杂原子的5-6元杂芳基时,L2为键,C2-4亚烯基,C2-4亚炔基;当环E为C3-6环烷基时,L2为C2-4亚烯基或C2-4亚炔基。
一些实施方式中,环E为苯基或包含1或2个N杂原子的6元杂芳基时,L2为键,C2-4亚烯基,C2-4亚炔基;当环E为C3-6环烷基或包含1或2个N杂原子独立选自N,S和O的5元杂芳基时,L2为C2-4亚烯基或C2-4亚炔基。
一些实施方式中,L2为键。
一些实施方式中,环D为C5-6芳基,C5-10杂芳基,C4-6环烷基或C4-10杂环基,其中C5-10杂芳基和C4-10杂环基任选地包含1,2或3个独立选自N,S,或O的杂原子。
一些实施方式中,环D为C5-10芳基,5-10元杂芳基,C3-10环烷基或4-10元杂环基,其中5-10元杂芳基和4-10元杂环基包含1,2或3个独立选自N和O的杂原子。
一些实施方式中,环D为C5-6芳基,5-6元杂芳基,3-6元单环烷基,4-6元单杂环基,6-10元稠合或螺双环杂芳基,6-10元稠合或螺双环杂环基,其中5-6元杂芳基,4-6元杂环基,6-10元杂芳基,6-10元杂环基包含1,2或3个独立选自N和O的杂原子。
一些实施方式中,环D为C5-6芳基,5-6元杂芳基,C3-6环烷基,4-6元杂环基,其中5-6元杂芳基和4-6元杂环基包含1,2或3个独立选自N,S和O的杂原子。
一些实施方式中,环D为苯基,C3-6环烷基或包含1或2个独立选自N和O的杂原子的4-6元杂环基。
一些实施方式中,环D为苯基或包含1或2个N杂原子的4-5元杂环基。
一些实施方式中,R1为H,氧代基,羟基,卤素,CN,-NO2,-NRdRe,C1-6烷基,C2-6烯基,C2-6炔基,C1-6卤代烷基,C1-6烷氧基,-C(=O)NRaRb,-C(=O)ORa,-C(=O)Rc,-S(=O)Rb,-S(=O)2Rb,-S(=O)NRaRb,-S(=O)2NRaRb,-O-(C=O)-Ra,-O-(C=O)-NRaRb,C1-6卤代烷氧基,C3-5环烷基,3-5元杂环基,其中C1-6烷基,C2-6烯基,C2-6炔基,C1-6卤代烷基,C1-6烷氧基,C1-6卤代烷氧基,C3-5环烷基,3-5元杂环基可分别任选地被0-3个独立选自OH,CN,卤素,C1-6烷基,C2-4烯基,C2-4炔基,C1-4卤代烷基,C1-4烷氧基,-NRaRb,-C(=O)NRaRb,-C(=O)ORa,-OC(=O)Ra,-C(=O)Ra,-S(=O)Rb,-S(=O)2Rb,-S(=O)NRaRb,-S(=O)2NRaRb,-NRaC(=O)Rb,C1-4卤代烷氧基的取代基取代。
一些实施方式中,R1为H,氧代基,羟基,卤素,CN,-NRaRb,-NRaC(=O)Rb,-NO2,C1-6烷基,C2-4烯基,C2-4炔基,C1-4卤代烷基,C1-4烷氧基,-C(=O)NRaRb,-S(=O)Rb,-S(=O)2Rb,-S(=O)NRaRb,-S(=O)2NRaRb,C1-4卤代烷氧基,C3-6环烷基,C3-6杂环烷基,C5-6芳基或C5-6杂芳基,其中C5-6杂芳基和C3-6杂环烷基任选地包含1,2或3个独立选自N,S,或O的杂原子;C1-6烷基,C2-4烯基,C2-4炔基,C1-4卤代烷基,C1-4烷氧基,C1-4卤代烷氧基,C3-6环烷基,C3-6杂环烷基,C5-6芳基和C5-6杂芳基分别任选地被一个或多个独立选自OH,CN,卤素,C1-6烷基,C2-4烯基,C2-4炔基,C1-4卤代烷基,C1-4烷氧基,-NRaRb,-C(=O)NRaRb,-S(=O)Rb,-S(=O)2Rb,-S(=O)NRaRb,-S(=O)2NRaRb,-NRaC(=O)Rb,C1-4卤代烷氧基,C3-6环烷基,C3-6杂环烷基,C5-6芳基或C5-6杂芳基的取代基取代,其中C5-6杂芳基和C3-6杂环烷基任选地包含1,2或3个独立选自N,S,或O的杂原子。
一些实施方式中,R1为H,氧代基,羟基,卤素,CN,-NO2,-NRdRe,C1-6烷基,C2-6烯基,C2-6炔基,C1-6卤代烷基,C1-6烷氧基,-C(=O)NRaRb,-C(=O)ORa,-C(=O)Rc,-S(=O)Rb,-S(=O)2Rb,-S(=O)NRaRb,-S(=O)2NRaRb,-O-(C=O)-Ra,-O-(C=O)-NRaRb,C1-6卤代烷氧基,C3-5环烷基,包含1或2个独立选自N,S和O的N杂原子的3-5元杂环烷基。
一些实施方式中,R1为H,氧代基,羟基,卤素,CN,-NRdRe,C1-6烷基,C1-6卤代烷基,C1-6烷氧基,-C(=O)NRaRb,-C(=O)ORa,-C(=O)Rc,-S(=O)2NRaRb。
一些实施方式中,R1为H,氧代基,羟基,卤素,CN,-N-(C1-6烷基)2,C1-6烷基,C1-4卤代烷基,C1-4烷氧基,-C(=O)NRaRb,-C(=O)ORa或-C(=O)Rc。
一些实施方式中,R1为H,氧代基,卤素,CN,-N-(C1-6烷基)2,C1-6烷基,C1-4卤代烷基,C1-4烷氧基,-C(=O)O-C1-4烷基,或-C(=O)Rc。
一些实施方式中,R1为H,氧代基,卤素,-N-(C1-3烷基)2,C1-6烷基,C1-4卤代烷基,C1-4烷氧基,-C(=O)O-C1-4烷基,或-C(=O)Rc。
一些实施方式中,R1为H,氧代基,卤素,-N-(CH3)2,C1-6烷基,C1-4卤代烷基,或C1-4烷氧基。
一些实施方式中,R1为H,氧代基,卤素,-NRaRb或C1-6烷基,其中Ra为H或C1-6烷基,Rb为C1-6烷基。
一些实施方式中,R1为H,氧代基,C1-6烷基。
一些实施方式中,R1为H,氧代基,C1-3烷基。
一些实施方式中,R2为H,羟基,卤素,CN,-NO2,-NRaRb,氧代基,-C(=O)NRaRb,-C(=O)ORa,-C(=O)Ra,-S(=O)Rb,-S(=O)2Rb,-S(=O)NRaRb,-S(=O)2NRaRb,-NRaC(=O)Rb,-SF5,C1-6烷基,C2-6烯基,C2-6炔基,C1-6烷氧基,C1-6卤代烷基;其中C1-6烷基,C2-6烯基,C2-6炔基,C1-6烷氧基,C3-6环烷基分别任选地被0-3个独立选自-ORa,-NH2,卤素,CN,C1-4烷基,C1-6卤代烷基,-NRaRb,氧代基,-C(=O)NRaRb,-C(=O)ORa,-OC(=O)Ra,-C(=O)Ra,-S(=O)Rb,-S(=O)2Rb,-S(=O)NRaRb,-S(=O)2NRaRb和-NRaC(=O)Rb的取代基取代。
一些实施方式中,R2为H,羟基,卤素,CN,-NRaRb,-NO2,C1-4烷基,C2-4烯基,C2-4炔基,C1-4烷氧基,C3-6环烷基,或C3-6杂环烷基,其中C3-6杂环烷基任选地包含1,2或3个独立选自N,S,或O的杂原子;其中C1-4烷基,C2-4烯基,C2-4炔基,C1-4烷氧基,C3-6环烷基和C3-6杂环烷基分别任选地被一个或多个独立选自羟基,卤素,CN,-NH2或C1-4烷基的取代基取代。
一些实施方式中,R2为H,羟基,卤素,CN,C1-6烷基,C2-6烯基,C2-6炔基,C1-6烷氧基,-SF5,其中C1-6烷基,C2-6烯基,C2-6炔基和C1-6烷氧基分别任选地被0-3个独立选自-ORa,卤素,CN,C1-4烷基,C1-6卤代烷基,-NRaRb,氧代基,-C(=O)NRaRb,-C(=O)ORa,-OC(=O)Ra,-C(=O)Ra,-S(=O)Rb,-S(=O)2Rb,-S(=O)NRaRb,-S(=O)2NRaRb和-NRaC(=O)Rb的取代基取代。
一些实施方式中,R2为羟基,卤素,CN,C1-6烷基,C2-6烯基,C2-6炔基,C1-6烷氧基,-SF5,其中C1-6烷基,C2-6烯基,C2-6炔基和C1-6烷氧基分别任选地被0-3个独立选自ORa,卤素,CN,C1-4烷基,C1-6卤代烷基,-NRaRb,氧代基,-C(=O)NRaRb,-C(=O)ORa,-C(=O)Ra,-S(=O)Rb,-S(=O)2Rb,-S(=O)NRaRb,-S(=O)2NRaRb和-NRaC(=O)Rb的取代基取代;其中Ra和Rb分别独立选自H,CN,羟基,卤素,C1-6烷基。
一些实施方式中,R2为H,羟基,卤素,CN,C1-6烷基,C2-6烯基,C2-6炔基,C1-6烷氧基,C1-6卤代烷基;其中C1-4烷基,C2-4烯基,C2-4炔基,C1-4烷氧基分别任选地被0-3个独立选自羟基,卤素,CN和C1-4烷基的取代基取代。
一些实施方式中,R2为H,CN,卤素,C1-6烷基,C1-6卤代烷基,C1-6卤代烷氧基。
一些实施方式中,R2为H,CN,卤素,C1-6烷基,C1-6卤代烷基。
一些实施方式中,R2为H,CN,卤素,C1-3烷基,C1-3卤代烷基。
一些实施方式中,R2为H,卤素,C1-4烷基,C1-4卤代烷基。
一些实施方式中,R2为H,C1-3卤代烷基。
优选地,R2为H或-CF3。
优选地,R2为H。
一些实施方式中,R3为H,卤素,-ORa,CN,-NRaRb,-C1-4亚烷基-NRaRb,-C1-4亚烷基-NRaC(=O)Rb,-C(=O)Rb,-OC(=O)Ra,-C(=O)ORa,-C(=O)NRaRb,-S(=O)Rb,-S(=O)2Rb,-S(=O)NRaRb,-S(=O)2NRaRb,-C1-4亚烷基-C(=O)NRaRb,C1-6烷基,C1-6烷氧基,C1-6卤代烷基,C1-6卤代烷氧基,3-6元杂环基,C3-6环烷基,C5-6芳基或5-6元杂芳基,其中5-6元杂芳基和3-6元杂环基任选地包含1,2或3个独立选自N,S和O的杂原子;其中C1-6烷基,C1-6卤代烷基,C1-6烷氧基,C1-6卤代烷氧基,C3-6环烷基,3-6元杂环基,C5-6芳基和5-6元杂芳基分别任选地被0-3个独立选自氧代基,羟基,卤素,CN,C1-6烷基,-C(=O)Rb,-NRaRb,-C(=O)Rb,-C(=O)ORa,-C(=O)NRaRb的取代基取代。
一些实施方式中,R3为H,氧代基,卤素,-ORa,CN,-NO2,-NRaRb,-NRaC(=O)Rb,-C1-4亚烷基-NRaRb,-C1-4亚烷基-NRaC(=O)Rb,-C(=O)Rb,-C(=O)ORa,-C(=O)NRaRb,-S(=O)Rb,-S(=O)2Rb,-S(=O)NRaRb,-S(=O)2NRaRb,-C1-4亚烷基-C(=O)NRaRb,C1-6烷基,C2-6烯基,C2-6炔基,C1-6烷氧基,C1-4卤代烷基,C1-4卤代烷氧基,C3-6杂环烷基,C3-6环烷基,C5-6芳基或C5-6杂芳基,其中C5-6杂芳基和C3-6杂环烷基任选地包含1,2或3个独立选自N,S,或O的杂原子;其中C1-6烷基,C2-6烯基,C2-6炔基,C1-4卤代烷基,C1-4烷氧基,C1-4卤代烷氧基,C3-6环烷基,C3-6杂环烷基,C5-6芳基和C5-6杂芳基分别任选地被一个或多个独立选自氧代基,羟基,卤素,CN,-NO2,C1-6烷基,-C1-4亚烷基-OH,C1-4卤代烷基,C1-4烷氧基,-S(=O)2Rb,-C(=O)Rb,-NRaRb,-C(=O)Rb,-C(=O)ORa,-NRaC(=O)Rb,-C(=O)NRaRb,-NRaC(=O)Rb,-C1-4亚烷基-NRaRb,-C1-4亚烷基-NRaC(=O)Rb,C1-4亚烷基-C(=O)NRaRb,-C1-4亚烷基-OH,C3-6环烷基,C3-6杂环烷基,C5-6芳基或C5-6杂芳基的取代基取代。
一些实施方式中,R3为H,卤素,-ORa,CN,-C1-4亚烷基-NRaRb,-C1-4亚烷基-C(=O)NRaRb,C1-6烷基,C1-6烷氧基,C1-6卤代烷基,C1-6卤代烷氧基,3-6元杂环基,C3-6环烷基,C5-6芳基或5-6元杂芳基,其中5-6元杂芳基和3-6元杂环基任选地包含1,2或3个独立选自N,S和O的杂原子;其中C1-6烷基,C3-6环烷基,3-6元杂环基,C5-6芳基和5-6元杂芳基分别任选地被0-3个独立选自卤素,CN,C1-6烷基,C1-6卤代烷基,-NRaRb,-C(=O)ORa,-C(=O)NRaRb的取代基取代。
一些实施方式中,R3为H,卤素,-ORa,CN,-C1-4亚烷基-NRaRb,-C1-4亚烷基-C(=O)NRaRb,C1-6烷基,C1-6烷氧基,C1-6卤代烷基,3-6元杂环基,C3-6环烷基或5-6元杂芳基,其中5-6元杂芳基和3-6元杂环基任选地包含1,2或3个独立选自N,S和O的杂原子;其中C1-6烷基,C3-6环烷基,3-6元杂环基和5-6元杂芳基分别任选地被0-3个独立选自卤素,CN,C1-6烷基,-NRaRb,-C(=O)ORa,-C(=O)NRaRb的取代基取代。
一些实施方式中,R3为H,卤素,-ORa,CN,-C1-4亚烷基-NRaRb,-C1-4亚烷基-C(=O)NRaRb,C1-6烷基,C1-6烷氧基,C1-6卤代烷基,3-6元杂环基,C3-6环烷基或5-6元杂芳基,其中5-6元杂芳基和3-6元杂环基任选地包含1,2或3个独立选自N,S和O的杂原子;其中C1-6烷基,C3-6环烷基,3-6元杂环基和5-6元杂芳基分别任选地被0-3个独立选自卤素,CN,C1-6烷基,-NRaRb,-C(=O)ORa,-C(=O)NRaRb的取代基取代;其中Ra和Rb分别独立选自H和C1-6烷基。
一些实施方式中,R3为H,卤素,CN,-ORa,C1-6烷基,C1-6卤代烷基,C3-6环烷基,3-6元杂环烷基或5-6元杂芳基,其中5-6元杂芳基和3-6元杂环烷基任选地包含1,2或3个独立选自N和O的杂原子;其中C1-6烷基,C3-6环烷基,3-6元杂环烷基和5-6元杂芳基分别任选地被下述取代基取代:C1-6烷基,C1-4卤代烷基或卤素。
一些实施方式中,R3为H,卤素,CN,-ORa,C1-6烷基,C1-6卤代烷基,C3-6环烷基,3-6元杂环烷基或5-6元杂芳基,其中5-6元杂芳基和3-6元杂环烷基任选地包含1,2或3个独立选自N和O的杂原子;其中C1-6烷基,C3-6环烷基,3-6元杂环烷基和5-6元杂芳基分别任选地被C1-6烷基,C1-4卤代烷基或卤素取代;其中Ra和Rb分别独立选自H和C1-6烷基。
一些实施方式中,R3为H,卤素,CN,C1-6烷基,C1-4卤代烷基,C1-6烷氧基,C1-4卤代烷基,-NRaRb,C3-6杂环烷基,C3-6环烷基或C5-6杂芳基;其中C3-6环烷基,C3-6杂环烷基和C5-6杂芳基分别任选地被一个或多个独立选自H,卤素或C1-6烷基的取代基取代。
一些实施方式中,R3为H,卤素,CN,-O-C1-3烷基,C1-3烷基,C1-3卤代烷基,C3-5环烷基,5-6元杂芳基或4-6元杂环烷基,其中5-6元杂芳基和4-6元杂环烷基分别任选地被C1-6烷基或卤素取代。
优选地,R3为H,卤素,CN,C1-3烷基,-ORa。
优选地,R3为H。
一些实施方式中,L3为键,-NH-,-N-C1-3烷基-,-(CH2)t-NH-,-C4-6杂环基。
一些实施方式中,L3为键或-NH-。
一些实施方式中,R5,R6和R7分别独立选自H,卤素,-ORa,CN,-NRaRb,-C1-6亚烷基-NRaRb,-C1-6亚烷基-Rc,C1-6烷基,C1-6烷氧基,C3-6环烷基,3-6元杂环基,其中C1-6烷基,C1-6烷氧基,C3-6环烷基,3-6元杂环基分别任选地被0-4个独立选自CN,卤素,C1-6烷基,C1-4卤代烷基,-NRaRb,C3-6环烷基,3-6元杂环基的取代基取代,其中5-6元杂芳基和3-6元杂环基任选地包含1,2或3个独立选自N,S和O的杂原子。
一些实施方式中,R5,R6和R7分别独立选自H,卤素,CN,-C1-6亚烷基-NRaRb,-C1-6亚烷基-Rc,C1-6烷基,C1-6烷氧基,C3-6环烷基,包含1,2或3个独立选自N,S和O的杂原子的3-6元杂环基。
一些实施方式中,R5,R6和R7分别独立选自H,卤素,CN,-C1-6亚烷基-NRaRb,-C1-6亚烷基-Rc,C1-6烷基,C1-6烷氧基,C3-6环烷基,包含1,2或3个独立选自N,S和O的杂原子的3-6元杂环基;其中Ra和Rb分别独立选自H和C1-6烷基。
一些实施方式中,R5,R6和R7分别独立选自H,卤素,CN,C1-6烷基,-C1-6亚烷基-NRaRb,和-C1-6亚烷基-Rc。
一些实施方式中,R5,R6和R7分别独立选自H,卤素,CN,C1-6烷基,-C1-6亚烷基-NRaRb,和-C1-6亚烷基-Rc;其中Ra和Rb分别独立选自H和C1-6烷基。
一些实施方式中,R5,R6和R7分别独立选自H,卤素,CN,C1-4烷基,和-C1-4亚烷基-NRaRb。
一些实施方式中,其中,
R5为H,CN,C1-4烷基或卤素;
R6和R7其中一个为H,另一个为H,卤素,C1-4烷基或-C1-4亚烷基-N(C1-3烷基)2。
R5为H,C1-4烷基或卤素;
R6和R7其中一个为H,另一个为H,卤素,C1-4烷基或-C1-4亚烷基-N(C1-3烷基)2。
一些实施方式中,其中,
R5为H,C1-4烷基或卤素;
R6和R7其中一个为H,另一个为H,C1-4烷基或卤素。
一些实施方式中,R8为H,卤素,CN,C1-4烷基或-C1-4亚烷基-NRaRb。
一些实施方式中,R8为H,卤素或C1-4烷基。
一些实施方式中,R8为H或C1-4烷基。
一些实施方式中,R8为卤素。
一些实施方式中,R8为C1-4烷基。
一些实施方式中,Ra和Rb分别独立选自H,C1-6烷基,C3-6环烷基,3-6元杂环烷基,C5-6芳基和5-6元杂芳基,其中C1-6烷基,C3-6环烷基,3-6元杂环烷基,C5-6芳基和5-6元杂芳基可任选地被卤素,C1-6卤代烷基或C5-6芳基取代,其中5-6元杂芳基和3-6元杂环烷基任选地包含1,2或3个独立选自N,S和O的杂原子。
一些实施方式中,Ra选自H,CN,C1-6烷基,C2-6烯基,C2-6炔基,C3-6环烷基或C3-6杂环基。
一些实施方式中,Ra为H或C1-6烷基。
一些实施方式中,Rb为H,羟基,卤素,CN,C1-6烷基,-O-C1-6烷基,C2-6烯基,C2-6炔基,C1-3卤代烷基,C1-6烷氧基,C1-6卤代烷氧基,C3-4环烷基,C3-4杂环烷基,C5-6芳基或C5-6杂芳基。
一些实施方式中,Rb选自H,C1-6烷基,C3-6环烷基,卤素取代的C3-6环烷基,3-6元杂环基和卤素或C1-4卤代烷基取代的3-6元杂环基。
一些实施方式中,Rb为H,C1-6烷基或C3-6杂环基。
一些实施方式中,Ra和Rb分别独立选自H和C1-6烷基。
一些实施方式中,Rd为H,C1-6烷基。
一些实施方式中,Re为C1-6烷基,-C(=O)Rc,S(=O)2Rb。
一些实施方式中,Rc为可被卤素或C1-6卤代烷基取代的3-6元杂环烷基。
一些实施方式中,t为1。
一些实施方式中,y为1或2。
一些实施方式中,m为1或2。
一些实施方式中,x为1。
一些实施方式中,式(II-1)或式(II-2)所示的化合物,
或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中,
A1,A2,A4和A6分别独立为C或N;
A3为不存在,CH,CH2,C=O或N;
A5为CH,CH2,C=O,C=NH或N;
B1,B2,B3和B4分别独立选自C,CH,CH2,C=O,NH或N;
环E,环D,L1,L2,R1,R2,R3,R4,m,y和x分别在实施例的类和子类中有所定义。
一些实施方式中,式(III)所示的化合物,
或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中,
A1,A2,A4和A6分别为C或N;
A5为CH,CH2,N,C=O或C=NH;
B1,B2,B3和B4分别独立选自C,CH,CH2,C=O,NH或N;
环E,环D,L1,L2,R1,R2,R3,R4,m,y和x分别如本文实施例的类和子类中所定义。
在式(III)的一些实施方式中,A1,A2,A4,A5和A6至少有一个为N。
一些实施方式中,式(IV-1)或式(IV-2)所示的化合物,
或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中,
A1,A2,A4和A6分别为C或N;
A3为不存在,CH2,CH,C=O或N;
A5为CH,CH2,C=O,C=NH或N;
B1,B2,B3和B4分别独立选自C,CH,CH2,C=O,NH或N;
M1,M2,M3,M4,M5和M6分别独立选自C,CH或N;
环D,L1,R1,R2,R3,R4,m,y和x分别如本文实施例的类和子类中所定义。
一些实施方式中,式(VI)所示的化合物,
或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中,
A1,A2,A3,A4,A5,A6,B1,B2,B3,B4,M1,M2,M3,M4,M5,M6,环D,L1,R1,R2,R3,R4,m,y和x分别如本文实施例的类和子类中所定义。
一些实施方式中,式V所示的化合物,或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,
其中,
A3为CR11或NR11;
A1,A2,A4和A6分别独立选自C或N;
A5 is CR15或NR15;
B1,B2,B3和B4分别独立选自C或N;
M1,M2,M3,M4,M5和M6分别独立选自C或N;
k为0或1;当k为0时,A1,A2,A4,A5或A6至少有一个为N;
R11为不存在,H,氧代基,羟基,卤素,CN,-NH2,-NO2,=NH,C1-6烷基,C1-4卤代烷基,C1-4烷氧基或C1-4卤代烷氧基;
R15为不存在,H,氧代基,羟基,卤素,CN,-NO2,-NH2,=NH,C1-3烷基,C2-4烯基,C2-4炔基,C1-3卤代烷基,C1-3烷氧基,C1-3卤代烷氧基,C3-4环烷基或C3-4杂环烷基;
R10为卤素,C1-3烷基,C2-6烯基,C2-6炔基,C3-6环烷基,C3-6卤代环烷基,或C5-6芳基;其中C1-3烷基,C2-6烯基,C2-6炔基,C3-6环烷基和C5-6芳基分别任选地被卤素取代;
R14为-NRaC(=O)Rz,-C1-4亚烷基-NRaC(=O)Rz,-C(=O)Rz,C1-4亚烷基-C(=O)Rz,C3-6杂环烷基-C(=O)Rz,C3-6杂环烷基-NRaC(=O)Rz,C3-6环烷基-NRaC(=O)Rz,C5-6芳基-NRaC(=O)Rz或C5-6杂芳基-NRaC(=O)Rz或C3-6环烷基-C(=O)Rz,其中C5-6杂芳基和C3-6杂环烷基任选地包含1,2或3个独立选自N,S,或O的杂原子;其中C3-6环烷基,C3-6杂环烷基,C5-6芳基和C5-6杂芳基分别任选地被一个或多个独立选自氧代基,羟基,卤素,CN,-NO2,C1-6烷基,C2-6烯基,C2-6炔基,-C1-4亚烷基-OH,C1-4卤代烷基,C1-4烷氧基,-S(=O)2Rb,-NRaRb,-C(=O)ORa,-C(=O)NRaRb,-C1-4亚烷基-NRaRb,-C1-4亚烷基-NRaC(=O)Rb,C1-4亚烷基-C(=O)NRaRb,C3-6环烷基,C3-6杂环烷基,C5-6芳基或C5-6杂芳基的取代基取代;
Rz为C2-6烯基或C2-6炔基,其中C2-6烯基和C2-6炔基分别任选地被一个或多个独立选自H,氧代基,CN,卤素,-ORa,-NO2,-NRaRb,-S(=O)Rb,-S(=O)2Rb,-S(=O)NRaRb,-S(=O)2NRaRb,C1-6卤代烷基,C1-6卤代烷氧基,C3-6环烷基,C3-6杂环烷基,C5-6芳基或C5-6杂芳基的取代基取代;
t和n分别独立选自1,2,3或4;
y,m和x分别独立选自0,1,2,3,4或5;并且
环D,L1,R1,R2,R3分别如本文的实施例和类和子类中所定义。
一些实施方式中,当A3为不存在时,A1,A2,A4,A5和A6至少一个为N。
一些实施方式中,R14为-NRaC(=O)Rz,-C1-4亚烷基-NRaC(=O)Rz,-C(=O)Rz或C3-6杂环烷基-C(=O)Rz,其中C3-6杂环烷基任选地包含1,2或3个独立选自N,S,或O的杂原子.
一些实施方式中,R15为不存在,H,氧代基或=NH。
一些实施方式中,Rz为C2-6烯基或C2-6炔基,其中C2-6烯基和C2-6炔基分别任选地被一个或多个独立选自H,CN,卤素,-ORa,C3-6环烷基或-NRaRb的取代基取代。
一些实施方式中,Rz为C2-6烯基或C2-6炔基,其中C2-6烯基和C2-6炔基分别任选地被一个或多个独立选自H,卤素或-NRaRb的取代基取代。
一些实施方式中,Rz为C2-6烯基或C2-6炔基,其中C2-6烯基和C2-6炔基分别任选地被-NRaRb取代。
一些实施方式中,R10为C1-3卤代烷基。
一些实施方式中,R10为-CF3。
一些实施方式中,R11为H,氧代基,C1-3烷基。
一些实施方式中,R11为H。
一些实施方式中,式(VI)所示的化合物,
或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中,
A1,A2,A4,A5,A6,B1,B2,B3,B4,M1,M2,M3,M4,M5,M6,环D,L1,R1,R2,R3,R10,R14,m,y和x分别如本文的实施例和类和子类中所定义。
一些实施方式中,下述通式所示的化合物:
或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中环A,环B,环E,环D,L1,L2,L3,R1,R2,R3,R5,R6,R7,R8,m,y和x分别如本文的实施例的类和子类中所定义。
一些实施方式中,下列通式所示的化合物:
或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中环A,环B,环D,L1,L2,L3,R1,R2,R3,R5,R6,R7,y和x分别如本文的实施例和类和子类中所定义。
一些实施方式中,下列通式所示的化合物:
或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中环A,环B,环D,L1,L2,L3,R1,R2,R3,R8,y和x分别如本文的实施例和类和子类中所定义。
一些实施方式中,下列通式所示的化合物:
或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中环A,环B,环E,环D,L1,L3,R1,R2,R3,R5,R6,R7,R8,m,y和x分别如本文的实施例和类和子类中所定义。
或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中环A,环B,环D,L1,L3,R1,R2,R3,R5,R6,R7,R8,m,y和x分别如本文的实施例和类和子类中所定义。
一些实施方式中,下列通式所示的化合物:
或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中环A,环B,环D,L1,L3,R1,R2,R3,R5,R6,R7,R8,m,y和x分别如本文的实施例和类和子类中所定义。
一些实施方式中,下列通式所示的化合物:
或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,
其中J1为1,2,3或4,环A,环B,环D,L1,L3,R1,R2,R3,R5,R6,R7,R8,m,y和x分别如本文的实施例和类和子类中所定义。
一些实施方式中,下列通式所示的化合物:
或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,
其中J2和J3分别独立为1或2,环A,环B,环E,L1,L2,R1,R2,R3,R5,R6,R7,R8,m,y和x分别如本文的实施例的类和子类中所定义。
一些实施方式中,下列通式所示的化合物:
或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中,
J2和J3分别独立为1或2;
E1,E2,E3和E4分别独立为CH或N,并且至少一个或两个为N;
环A,环B,L1,L2,R1,R2,R3,R5,R6,R7,R8,m,y和x分别如本文的实施例的类和子类中所定义。
一些实施方式中,下列通式所示的化合物:
或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中,环B,环E,环D,L1,L2,L3,R1,R2,R3,R5,R6,R7,m,y和x分别如本文的实施例的类和子类中所定义。
一些实施方式中,下列通式所示的化合物:
或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中,环B,环E,环D,L1,L2,L3,R1,R2,R3,R8,m,y和x分别如本文的实施例和类和子类中所定义。
一些实施方式中,下列通式所示的化合物:
或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中,环B,L1,L2,R1,R2,R3,R5,R6,R7,R8,m,y和x分别如本文的实施例和类和子类中所定义。.
在式(I)的一些实施例中,其中化合物为:
1)1-(1-丙烯酰吡咯烷-3-基)-3-(4-环己基苯基)-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮;
2)1-(1-丙烯酰吡咯烷-3-基)-3-(4-(三氟甲基)苯基)-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮;
3)1-(3-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
4)1-(3-(1-(4-(三氟甲基)苯基)-1H-吲唑-3-基)吡咯烷-1-基)丙-2-烯-1-酮;
5)2-氟-1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
6)2-氟-1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
7)1-(1-丙烯酰吡咯烷-3-基)-6-甲基-3-(4-(三氟甲基)苯基)-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮;
8)2-氟-1-(3-甲基-3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
9)2-氟-1-(2-甲基-3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
10)2-氟-N-(2-甲基-5-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)苯基)丙烯酰胺;
11)2-氟-1-(3-(6-甲基-3-((4-(三氟甲基)苯基)氨基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
12)2-氟-1-(2-羟基-3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
13)N-(1-(3-(4-(三氟甲基)苯基)咪唑并[1,5-a]吡啶-1-基)氮杂环丁烷-3-基)丙烯酰胺;
14)N-(1-(1-丙烯酰氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1H-吲唑-7-基)甲磺酰胺;
15)N-(1-(1-丙烯酰氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1H-吲唑-7-基)乙酰胺;
16)1-(3-(4-氨基-3-(4-环己基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
17)1-(3-(3-(4-环己基苯基)-4-羟基-1H-吡唑并[3,4-d]嘧啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
18)1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡嗪-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
19)1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
20)1-(3-(6-氯-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡嗪-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
21)1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
22)1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
23)1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
24)1-(3,3-二氟-4-(3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
25)1-((3R,4S)-3-氟-4-(3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
26)1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
27)1-(3-(3-(5-(三氟甲基)吡啶-2-基)-1H-吡唑并[3,4-b]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
28)N-(1-(1-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-3-基)吡咯烷-3-基)丁-2-酰胺;
29)1-(3-(3-(2-氟-4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
30)1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
31)1-(3-(3-(4-(三氟甲基)苯氧基)-1H-吡唑并[4,3-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
32)1-(3-(3-(4-(三氟甲基)苯氧基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
33)1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;
34)1-(3-((3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)甲基)吡咯烷-1-基)丙-2-烯-1-酮;
35)N-(1-(1-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-3-基)吡咯烷-3-基)丙烯酰胺;
36)(E)-N-(1-(1-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-3-基)吡咯烷-3-基)丁-2-烯酰胺;
37)N-(3-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)环戊基)丙烯酰胺;
38)1-(3-((3-(4-环己基苯基)-1H-吲唑-1-基)甲基)吡咯烷-1-基)丙-2-烯-1-酮;
39)1-(3-(7-甲基-3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
40)(E)-4-(二甲基氨基)-1-(3-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)吡咯烷-1-基)丁-2-烯-1-酮;
41)(E)-4-(二甲基氨基)-N-(1-(1-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-3-基)吡咯烷-3-基)丁-2-烯酰胺;
42)1-(1-丙烯酰吡咯烷-3-基)-3-(4-(三氟甲基)苯基)-1H-吲唑-7-甲酰胺;
43)1-(4-(1-(4-(三氟甲基)苯基)-1H-吲唑-3-羰基)哌嗪-1-基)丙-2-烯-1-酮;
44)1-(3-(7-甲氧基-3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
45)1-(3-(7-氯-3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
46)1-(3-(7-(三氟甲基)-3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
47)1-(3-(6-甲基-3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
48)1-(1-丙烯酰吡咯烷-3-基)-3-(4-(三氟甲基)苯基)-1H-吲唑-7-腈;
49)1-(7-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)-2-氮杂螺[4,4]壬烷-2-基)丙-2-烯-1-酮;
50)1-(3-(6-氟-3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
51)1-(3-(5,6-二氟-3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
52)1-(3-(1-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)吡咯烷-1-基)丙-2-烯-1-酮;
53)N-(1-(1-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)吡咯烷-3-基)丙烯酰胺;
54)1-(3-(6-甲氧基-3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
55)1-(3-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)吡咯烷-1-基)丁-2-炔-1-酮;
56)(E)-1-(3-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)吡咯烷-1-基)丁-2-烯-1-酮;
57)1-(3-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)吡咯烷-1-基)丙-2-炔-1-酮;
58)1-(3-(3-(5-(三氟甲基)吡啶-2-基)-1H-吲唑-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
59)1-(3-(3-(6-(三氟甲基)吡啶-3-基)-1H-吲唑-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
60)1-(3-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)哌啶-1-基)丙-2-烯-1-酮;
61)1-(3-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
62)N-(4-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)四氢呋喃-3-基)丙烯酰胺;
63)N-((5-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)-1,3,4-恶二唑-2-基)甲基)丙烯酰胺;
64)N-(1-(1-(4-(三氟甲基)苯基)-1H-吲唑-3-羰基)吡咯烷-3-基)丙烯酰胺;
65)1-(3-(1-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-3-基)吡咯烷-1-基)丙-2-烯-1-酮;
66)N-(1-(5-甲氧基-1-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-3-基)吡咯烷-3-基)丙烯酰胺;
67)1-(3-(5-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)-1,3,4-恶二唑-2-基)吡咯烷-1-基)丙-2-烯-1-酮;
68)N-(4-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)四氢-2H-吡喃-3-基)丙烯酰胺;
69)N-(1-(5-氰基-1-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-3-基)吡咯烷-3-基)丙烯酰胺;
70)1-(3-(7-氟-3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
71)2-氟-1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
72)N-(1-(5-氰基-1-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)吡咯烷-3-基)丙烯酰胺;
73)2-甲基-1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
74)N-(1-(5-甲氧基-1-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)吡咯烷-3-基)丙烯酰胺;
75)N-(1-(5-甲基-1-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-3-基)吡咯烷-3-基)丙烯酰胺;
76)5-甲基-2-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-羰基)己二烯腈;
77)1-(1-(2-氟丙烯酰)吡咯烷-3-基)-6-甲基-3-(4-(三氟甲基)苯基)-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮;
78)甲基1-(1-丙烯酰吡咯烷-3-基)-3-(4-(三氟甲基)苯基)-1H-吲唑-7-羧酸;
79)1-(1-丙烯酰氮杂环丁烷-3-基)-6-甲基-3-(4-(三氟甲基)苯基)-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮;
80)1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-6-甲基-3-(4-(三氟甲基)苯基)-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮;
81)N-(1-(6-甲基-1-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-3-基)吡咯烷-3-基)丙烯酰胺;
82)1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
83)N-(1-(5-甲基-1-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)吡咯烷-3-基)丙烯酰胺;
84)N-(1-(5-氯-1-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-3-基)吡咯烷-3-基)丙烯酰胺;
85)N-(1-(5-氯-1-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)吡咯烷-3-基)丙烯酰胺;
86)N-(1-(6-氯-1-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)吡咯烷-3-基)丙烯酰胺;
87)2-甲基-1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
88)4-甲基-4-吗啉-2-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)氮杂环丁烷-1-羰基)戊二烯腈;
89)1-(3-(5-甲氧基-3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
90)N-(1-(1-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)吡咯烷-3-基)丙烯酰胺;
91)N-(1-(1-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-3-基)吡咯烷-3-基)丙吡胺;
92)N-(1-(1-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)吡咯烷-3-基)丙吡胺;
93)1-(1-丙烯酰吡咯烷-3-基)-3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-5-腈;
94)1-(3-(5-甲氧基-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
95)2-氟-1-(3-(5-甲氧基-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
96)1-(3-(5-甲基-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
97)N-(3-(1-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)丙烯酰胺;
98)1-(1-丙烯酰吡咯烷-3-基)-N-异丙基-3-(6-(三氟甲基)吡啶-3-基)-1H-吲唑-7-甲酰胺;
99)N-(1-(3-(4-(三氟甲基)苯基)咪唑并[1,5-a]吡啶-1-基)吡咯烷-3-基)丙烯酰胺;
100)1-(1-丙烯酰吡咯烷-3-基)-N-环丙基-3-(6-(三氟甲基)吡啶-3-基)-1H-吲唑-7-甲酰胺;
101)1-(1-丙烯酰吡咯烷-3-基)-N-(氧杂环丁烷-3-基)-3-(6-(三氟甲基)吡啶-3-基)-1H-吲唑-7-甲酰胺;
102)1-(1-丙烯酰吡咯烷-3-基)-N-甲基-3-(6-(三氟甲基)吡啶-3-基)-1H-吲唑-7-甲酰胺;
103)1-(1-丙烯酰吡咯烷-3-基)-N,N-二甲基-3-(4-(三氟甲基)苯基)-1H-吲唑-7-甲酰胺;
104)1-(1-丙烯酰吡咯烷-3-基)-N-(3,3-二氟环丁基)-3-(6-(三氟甲基)吡啶-3-基)-1H-吲唑-7-甲酰胺;
105)1-(3-(1-(4-(三氟甲基)苯基)咪唑并[1,5-a]吡啶-3-基)吡咯烷-1-基)丙-2-烯-1-酮;
106)N-(1-(6-(4-(三氟甲基)苯基)咪唑并[1,5-a]嘧啶-8-基)吡咯烷-3-基)丙烯酰胺;
107)1-(1-丙烯酰吡咯烷-3-基)-N-苯基-3-(4-(三氟甲基)苯基)-1H-吲唑-7-甲酰胺;
108)1-(3-(5-氯-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
109)1-(3-(8-(4-(三氟甲基)苯基)咪唑并[1,5-a]嘧啶-6-基)吡咯烷-1-基)丙-2-烯-1-酮;
110)1-(3-(3-(4-(三氟甲基)苯基)-7-(4-(三氟甲基)哌啶-1-羰基)-1H-吲唑-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
111)1-(1-丙烯酰吡咯烷-3-基)-N-(4,4-二氟环己基)-3-(4-(三氟甲基)苯基)-1H-吲唑-7-甲酰胺;
112)1-(3-(7-(3,3-二氟吡咯烷-1-羰基)-3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
113)1-(1-丙烯酰吡咯烷-3-基)-N-(3,3-二氟环戊基)-3-(4-(三氟甲基)苯基)-1H-吲唑-7-甲酰胺;
114)1-(1-丙烯酰吡咯烷-3-基)-N-(4-(三氟甲基)环己基)-3-(4-(三氟甲基)苯基)-1H-吲唑-7-甲酰胺;
115)1-(1-丙烯酰吡咯烷-3-基)-N-苄基-3-(4-(三氟甲基)苯基)-1H-吲唑-7-甲酰胺;
116)1-(1-丙烯酰吡咯烷-3-基)-N-(叔丁基)-3-(4-(三氟甲基)苯基)-1H-吲唑-7-甲酰胺;
117)1-(3-甲基-4-(3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
118)1-(7-(3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)-5-氮杂螺[2.4]庚烷-5-基)丙-2-烯-1-酮;
119)N-(2-(3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)环戊基)丙烯酰胺;
120)1-(3-(3-(4-环丙基苯基)-1H-吡唑并[4,3-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
121)1-(3-(6-(二甲基氨基)-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
122)1-(3-(6-(二甲基氨基)-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;
123)1-(3-(3-(6-(三氟甲基)吡啶-3-基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
124)2-氟-1-(3-(3-(6-(三氟甲基)吡啶-3-基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
125)1-(7-(3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)-2-氮杂螺[4.4]壬烷-2-基)丙-2-烯-1-酮;
126)2-氟-1-(7-(3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)-2-氮杂螺[4.4]壬烷-2-基)丙-2-烯-1-酮;
127)1-(3-(3-(2-氟-4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
128)2-氟-1-(3-(3-(2-氟-4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
129)1-(3-(3-(2-氟-4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
130)2-氟-1-(3-(3-(2-氟-4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
131)1-(3-(3-(6-(三氟甲基)吡啶-3-基)-1H-吡唑并[4,3-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
132)2-氟-1-(3-(3-(6-(三氟甲基)吡啶-3-基)-1H-吡唑并[4,3-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
133)N-(3-(4-(三氟甲基)苯基)-1'H-[1,6'-二吲唑]-4'-基)丙烯酰胺;
134)N-(6-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)-[1,2,4]三唑并[4,3-a]吡啶-8-基)丙烯酰胺;
135)N-(3-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)苯基)丙烯酰胺;
136)N-(3-甲基-5-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)苯基)丙烯酰胺;
137)N-(3-甲氧基-5-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)苯基)丙烯酰胺;
138)N-(3-氯-5-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)苯基)丙烯酰胺;
139)1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-炔-1-酮;
140)1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-炔-1-酮;
141)(E)-2-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)氮杂环丁烷-1-羰基)丁-2-腈;
142)1-(1-丙烯酰吡咯烷-3-基)-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-5-腈;
143)1-(3-(5-甲基-3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
144)1-(3-(6-甲基-3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
145)1-(1-丙烯酰吡咯烷-3-基)-N-(吡啶-2-基)-3-(4-(三氟甲基)苯基)-1H-吲唑-7-甲酰胺;
146)1-(3-(5-氯-3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
147)1-(3-(6-氯-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
148)1-(1-丙烯酰吡咯烷-3-基)-3-(4-(三氟甲基)苯基)-N-(5-(三氟甲基)吡啶-2-基)-1H-吲唑-7-甲酰胺;
149)1-丙烯酰-4-(3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)吡咯烷-3-腈;
150)1-(3-(5-甲基-1-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)吡咯烷-1-基)丙-2-烯-1-酮;
151)N-(3-氰基-5-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)苯基)丙烯酰胺;
152)N-(3-氰基-5-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)苯基)丙烯酰胺;
153)N-(3-环丙基-5-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)苯基)丙烯酰胺;
154)N-(3-(3,3-二氟氮杂环丁烷-1-基)-5-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)苯基)丙烯酰胺;
155)N-(3-(3-甲基吡啶-2-基)-5-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)苯基)丙烯酰胺;
156)N-(3-(3-氯吡啶-2-基)-5-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)苯基)丙烯酰胺;
157)N-(3-(1H-吡唑-1-基)-5-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)苯基)丙烯酰胺;
158)N-(3-吗啉-5-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)苯基)丙烯酰胺;
159)N-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)苯基)丙烯酰胺;
160)2-氟-1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡嗪-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
161)1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡嗪-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
162)2-氟-1-(3-氟-3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
163)2-氟-1-(2-氟-3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
164)2-氟-1-(3-羟基-3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
165)1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶7-氧化物;
166)乙基2-(1-(2-氟丙烯酰)-3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-3-基)醋酸;
167)2-(1-(2-氟丙烯酰)-3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-3-基)乙腈;
168)2-氟-1-(3-(氟甲基)-3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
169)2-(1-(2-氟丙烯酰)-3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-3-基)乙酰胺;
170)1-(2-氟丙烯酰)-3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-3-腈;
171)2-氟-1-(3-(3-(4-异丙基苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
172)2-氟-1-(3-(3-(4-(三氟甲氧基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
173)2-氟-1-(3-(3-(4-(五氟-l6-硫烷基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
174)2-甲基-1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
175)(E)-1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丁-2-烯-1-酮;
176)2-氟-1-(3-(3-(3-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
177)5-(1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)-2-(三氟甲基)苄腈;
178)4-(1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)-2-(三氟甲基)苄腈;
179)2-氟-1-(3-(3-(6-(三氟甲基)吡啶-2-基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
180)2-氟-1-(3-(3-(2-(三氟甲基)吡啶-4-基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
181)2-氟-1-(3-(3-(5-甲基-6-(三氟甲基)吡啶-3-基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
182)2-氟-1-(3-(3-(2-甲基-6-(三氟甲基)吡啶-3-基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
183)2-氟-1-(3-(3-(2-(三氟甲基)嘧啶-5-基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
184)2-氟-1-(3-(3-(5-氟-6-(三氟甲基)吡啶-3-基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
185)2-氟-1-(3-(3-(2-氟-6-(三氟甲基)吡啶-3-基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
186)2-氟-1-(3-(6-甲基-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
187)1-(3-(6-氯-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;
188)2-氟-N-(2-甲氧基-5-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)苯基)丙烯酰胺;
189)N-(2-氯-5-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)苯基)丙烯酰胺;
190)N-(2,4-二氟-5-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)苯基)-2-氟丙烯酰胺;
191)2-氟-N-(4-氟-3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)苯基)丙烯酰胺;
192)N-(2,4-二氯-5-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)苯基)-2-氟丙烯酰胺;
193)2-氟-1-(6-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)吲哚啉-1-基)丙-2-烯-1-酮;
194)N-(4-((二甲基氨基)甲基)-3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)苯基)-2-氟丙烯酰胺;
195)N-(2,4-二氟-3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)苯基)-2-氟丙烯酰胺;
196)2-氟-1-(3-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
197)2-氟-1-(3-(3-(6-(三氟甲基)吡啶-3-基)-1H-吲唑-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
198)2-氟-1-(3-(3-(6-(三氟甲基)吡啶-3-基)-1H-吡唑并[3,4-b]吡嗪-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
199)2-氟-1-(3-(6-甲基-3-(6-(三氟甲基)吡啶-3-基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
200)1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-6-腈;
201)1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-N-甲基-3-(4-(三氟甲基)苯基)-1H-吲唑-7-磺胺;
202)2-氟-1-(3-(5-氟-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
203)2-氟-1-(3-(6-氟-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
204)2-氟-1-(3-(6-氟-3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
205)1-(3-(6-(二氟甲基)-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;
206)1-(3-(6-氯-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡嗪-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;
207)2-氟-1-(3-(3-(4-(三氟甲基)苯基)-4,5,6,7-四氢-1H-吲唑-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
208)2-氟-1-(3-(3-(4-(三氟甲基)苯基)-6,7-二氢吡喃并[4,3-c]吡唑-1(4H)-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
209)2-氟-1-(3-(3-(4-(三氟甲基)苯基)-6,7-二氢吡喃并[4,3-c]吡唑-2(4H)-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
210)1-(3-(4,4-二氟-3-(4-(三氟甲基)苯基)-4,5,6,7-四氢-1H-吲唑-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;
211)1-(3-(5-(二氟甲基)-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;
212)1-(3-(5-(二氟甲基)-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;
213)2-氟-1-(3-(5-甲基-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
214)2-氟-1-(3-(5-甲氧基-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
215)2-氟-1-(3-(5-(三氟甲基)-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
216)2-氟-1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-d]嘧啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
217)2-氟-1-(3-(3-(4-(三氟甲基)苯基)-4,5,6,7-四氢-1H-吲唑-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
218)6-乙基-1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮;
219)1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-7-甲基-3-(4-(三氟甲基)苯基)-1,7-二氢-6H-吡唑并[3,4-b]吡啶-6-酮;
220)1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-6-甲基-3-(4-(三氟甲基)苯基)-1,6-二氢-7H-吡唑并[3,4-c]吡啶-7-酮;
221)2-氟-1-(3-(6-甲氧基-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
222)2-氟-1-(3-(7-甲氧基-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-c]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
223)2-氟-1-(3-(6-甲氧基-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡嗪-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
224)1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-7-甲基-3-(4-(三氟甲基)苯基)-1,7-二氢-6H-吡唑并[3,4-b]吡嗪-6-酮;
225)1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-5,6-二甲基-3-(4-(三氟甲基)苯基)-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮;
226)2-氟-1-(3-(7-甲氧基-5-甲基-3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-d]嘧啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
227)2-氟-1-(3-(7-甲氧基-3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-d]嘧啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
228)1-(3-(5-溴-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;
229)1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1,3-二氢-2H-苯并[d]咪唑并l-2-酮;
230)2-氟-1-(3-(4-(4-(三氟甲基)苯基)喹唑啉-2-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
231)1-(3-(2-亚胺-3-(4-(三氟甲基)苯基)-2,3-二氢-1H-苯并[d]咪唑并l-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
232)N-((5-(2-氧代基-3-(4-(三氟甲基)苯基)-2,3-二氢-1H-苯并[d]咪唑并l-1-基)-1,3,4-恶二唑-2-基)甲基)丙烯酰胺;
233)1-(1-丙烯酰吡咯烷-3-基)-3-(4-环己基苯基)-1,3-二氢-2H-苯并[d]咪唑并l-2-酮;
234)1-(1-丙烯酰吡咯烷-3-基)-3-(4-(三氟甲基)苯基)-1,3-二氢-2H-苯并[d]咪唑并l-2-酮;
235)1-(3-(2-亚胺-3-(4-(三氟甲基)苯基)-2,3-二氢-1H-苯并[d]咪唑并l-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
236)1-(1-丙烯酰氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1,3-二氢-2H-苯并[d]咪唑并l-2-酮;
237)1-(1-(2-氟丙烯酰)-3-甲基氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1,3-二氢-2H-苯并[d]咪唑并l-2-酮;
238)3-(1-(2-氟丙烯酰)-3-甲基氮杂环丁烷-3-基)-1-(4-(三氟甲基)苯基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
239)1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
240)1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1,3-二氢-2H-咪唑并[4,5-b]吡嗪-2-酮;
241)1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-3-(6-(三氟甲基)吡啶-3-基)-1,3-二氢-2H-咪唑并[4,5-b]吡嗪-2-酮;
242)3-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-5-甲基-1-(4-(三氟甲基)苯基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
243)3-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-5-甲基-1-(6-(三氟甲基)吡啶-3-基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
244)3-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-6-甲基-1-(4-(三氟甲基)苯基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
245)3-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-6-(三氟甲基)-1-(4-(三氟甲基)苯基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
246)3-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-6-甲氧基-1-(4-(三氟甲基)苯基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
247)1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮;
248)3-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-1-(4-(三氟甲基)苯基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮;
249)6-氯-3-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-1-(4-(三氟甲基)苯基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
250)9-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-7-(4-(三氟甲基)苯基)-7,9-二氢-8H-嘌呤-8-酮;
251)3-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-5-甲氧基-1-(4-(三氟甲基)苯基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
252)5-氯-3-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-1-(4-(三氟甲基)苯基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
253)6-氟-3-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-1-(4-(三氟甲基)苯基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
254)N-(1-(2-(4-(三氟甲基)苯基)喹唑啉-4-基)吡咯烷-3-基)丙烯酰胺;
255)2-氟-1-(3-((2-(4-(三氟甲基)苯基)喹唑啉-4-基)氨基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
256)2-氟-1-(3-(2-(4-(三氟甲基)苯基)喹唑啉-4-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
257)2-氟-1-(3-(4-(4-(三氟甲基)苯基)喹唑啉-2-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
258)N-(1-(1-(4-(三氟甲基)苯基)异喹啉-3-基)吡咯烷-3-基)丙烯酰胺;
259)N-(3-(1-(4-(三氟甲基)苯基)异喹啉-3-基)苯基)丙烯酰胺;
260)1-(3-(4-(4-(三氟甲基)苯基)喹啉-2-基)吡咯烷-1-基)丙-2-烯-1-酮;
261)1-(3-(4-(4-(三氟甲基)苯基)喹唑啉-2-基)吡咯烷-1-基)丙-2-烯-1-酮;
262)3-(1-丙烯酰吡咯烷-3-基)-1-(4-(三氟甲基)苯基)喹唑啉-2,4(1H,3H)-二酮;
263)2-(1-丙烯酰吡咯烷-3-基)-4-(4-(三氟甲基)苯基)酞嗪-1(2H)-酮;
264)2-(1-丙烯酰哌啶-3-基)-4-(4-(三氟甲基)苯基)酞嗪-1(2H)-酮;
265)3-(1-丙烯酰吡咯烷-3-基)-1-(4-(三氟甲基)苯基)-3,4-二氢喹唑啉-2(1H)-酮;
266)3-(5-(1-丙烯酰吡咯烷-3-基)-1,3,4-恶二唑-2-基)-1-(4-(三氟甲基)苯基)喹啉-2(1H)-酮;
267)1-(3-(5-(4-(4-(三氟甲基)苯基)喹唑啉-2-基)-1,3,4-恶二唑-2-基)吡咯烷-1-基)丙-2-烯-1-酮;
268)N-(1-(2-(4-(三氟甲基)苯基)喹唑啉-4-基)氮杂环丁烷-3-基)丙烯酰胺;
269)2-氟-N-(1-(2-(4-(三氟甲基)苯基)喹唑啉-4-基)氮杂环丁烷-3-基)丙烯酰胺;
270)2-氟-N-(1-(2-(4-(三氟甲基)苯基)喹唑啉-4-基)吡咯烷-3-基)丙烯酰胺;
271)N-(1-(2-(4-(三氟甲基)苯基)吡啶并[2,3-d]嘧啶-4-基)吡咯烷-3-基)丙烯酰胺;
272)N-(1-(2-(4-(三氟甲基)苯基)吡啶并[3,4-d]嘧啶-4-基)吡咯烷-3-基)丙烯酰胺;
273)1-(4-(2-(4-(三氟甲基)苯基)吡啶并[3,4-d]嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮;
274)N-(5-甲基-1-(2-(4-(三氟甲基)苯基)吡啶并[3,4-d]嘧啶-4-基)吡咯烷-3-基)丙烯酰胺;
275)N-(1-(2-(4-(三氟甲基)苯基)吡啶并[2,3-d]嘧啶-4-基)氮杂环丁烷-3-基)丙烯酰胺;
276)2-氟-N-(1-(2-(4-(三氟甲基)苯基)吡啶并[2,3-d]嘧啶-4-基)氮杂环丁烷-3-基)丙烯酰胺;
277)2-氟-N-(1-(2-(4-(三氟甲基)苯基)吡啶并[2,3-d]嘧啶-4-基)吡咯烷-3-基)丙烯酰胺;
278)2-氟-N-(1-(2-(4-(三氟甲基)苯基)吡啶并[3,4-d]嘧啶-4-基)吡咯烷-3-基)丙烯酰胺;
279)N-(1-(2-(4-(三氟甲基)苯基)吡啶并[3,4-d]嘧啶-4-基)氮杂环丁烷-3-基)丙烯酰胺;
280)2-氟-N-(1-(2-(4-(三氟甲基)苯基)吡啶并[3,4-d]嘧啶-4-基)氮杂环丁烷-3-基)丙烯酰胺;
281)N-(1-(2-(4-(三氟甲基)苯基)吡啶并[3,2-d]嘧啶-4-基)氮杂环丁烷-3-基)丙烯酰胺;
282)2-氟-N-(1-(2-(4-(三氟甲基)苯基)吡啶并[3,2-d]嘧啶-4-基)氮杂环丁烷-3-基)丙烯酰胺;
283)1-(3-((2-(4-(三氟甲基)苯基)喹唑啉-4-基)氨基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
284)N-(3-(4-(4-(三氟甲基)苯氧基)萘-2-基)苯基)丙烯酰胺;
285)1-(3-(2-(4-(三氟甲基)苯基)喹啉-4-基)吡咯烷-1-基)丙-2-烯-1-酮;
286)1-(3-(6-(4-(三氟甲基)苯基)喹啉-8-基)吡咯烷-1-基)丙-2-烯-1-酮;
287)N-(1-(2-(4-(三氟甲基)苯基)吡啶并[3,2-d]嘧啶-4-基)吡咯烷-3-基)丙烯酰胺;
288)2-氟-N-(1-(2-(4-(三氟甲基)苯基)吡啶并[3,2-d]嘧啶-4-基)吡咯烷-3-基)丙烯酰胺;
289)3-(1-丙烯酰吡咯烷-3-基)-1-(4-(三氟甲基)苯基)-4a,8a-二氢喹啉-2(1H)-酮;
290)2-(1-丙烯酰吡咯烷-3-基)-4-(4-(三氟甲基)苯基)-4a,8a-二氢异喹啉-1(2H)-酮;
291)2-(1-丙烯酰氮杂环丁烷-3-基)-4-(4-(三氟甲基)苯基)酞嗪-1(2H)-酮;
292)3-(1-丙烯酰氮杂环丁烷-3-基)-1-(4-(三氟甲基)苯基)喹唑啉-2,4(1H,3H)-二酮;
293)2-(1-丙烯酰氮杂环丁烷-3-基)-4-(4-(三氟甲基)苯基)异喹啉-1(2H)-酮;
294)1-(3-(4-(4-(三氟甲基)苯基)喹唑啉-2-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
295)2-氟-N-(1-(3-(4-(三氟甲基)苯基)萘-1-基)氮杂环丁烷-3-基)丙烯酰胺;
296)2-氟-N-(1-(6-(4-(三氟甲基)苯基)喹啉-8-基)氮杂环丁烷-3-基)丙烯酰胺;
297)1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)喹啉-2(1H)-酮;
298)1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1,8-萘啶-2(1H)-酮;
299)1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)喹喔啉-2(1H)-酮;
300)4-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-2-(4-(三氟甲基)苯基)吡啶并[2,3-b]吡嗪-3(4H)-酮;
301)2-氟-N-(1-(2-(4-(三氟甲基)苯基)蝶呤-4-基)氮杂环丁烷-3-基)丙烯酰胺;
302)2-氟-N-甲基-N-(1-(2-(4-(三氟甲基)苯基)喹唑啉-4-基)氮杂环丁烷-3-基)丙烯酰胺;
303)2-氟-N-(1-(7-甲氧基-2-(4-(三氟甲基)苯基)喹唑啉-4-基)氮杂环丁烷-3-基)丙烯酰胺;
304)2-氟-N-(1-(5-(三氟甲基)-2-(4-(三氟甲基)苯基)喹唑啉-4-基)氮杂环丁烷-3-基)丙烯酰胺;
305)2-氟-N-(1-(2-(4-(三氟甲基)苯基)吡啶并[4,3-d]嘧啶-4-基)氮杂环丁烷-3-基)丙烯酰胺;
306)2-氟-N-(1-(2-(6-(三氟甲基)吡啶-3-基)吡啶并[3,2-d]嘧啶-4-基)氮杂环丁烷-3-基)丙烯酰胺;
307)2-氟-1-(3-(3-(苯基乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
308)(E)-2-氟-1-(3-(3-苯乙烯-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
309)1-(3-(3-((3,3-二氟环丁基)乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
310)N-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)苯基)丙烯酰胺;
311)1-(3-(3-(环戊基乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
312)1-(3-(3-(环戊基乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;
313)1-(3-(3-(嘧啶-2-基乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
314)2-氟-1-(3-(3-(嘧啶-2-基乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
315)1-(3-(3-(环丙基乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
316)1-(3-(3-(噻吩-3-基乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
317)2-氟-1-(3-(3-(噻吩-3-基乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
318)1-(3-(3-((1-甲基-1H-咪唑并l-5-基)乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
319)1-(3-(3-(苯基乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
320)1-(3-(3-(环丁基乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
321)1-(3-(3-(环丁基乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;
322)1-(3-(3-(环丙基乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;
323)2-氟-1-(3-(3-((1-甲基-1H-咪唑并l-5-基)乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
324)1-(3-(3-(环己基乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
325)1-(3-(3-(环己基乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;
326)1-(3-(3-((3,3-二氟环丁基)乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;
327)(E)-1-(3-(3-苯乙烯-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
328)1-(3-(3-((3,3-二氟环戊基)乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
329)1-(3-(3-((3,3-二氟环戊基)乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;
330)(E)-1-(3-(3-(2-环己基乙烯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
331)(E)-1-(3-(3-(2-环己基乙烯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;
332)(E)-1-(3-(3-(2-环丙基乙烯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
333)(E)-1-(3-(3-(2-环丙基乙烯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;
334)2-氟-1-(3-(3-((4-氟苯基)乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
335)2-氟-1-(3-(3-((3-氟苯基)乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
336)2-氟-1-(3-(3-((2-氟苯基)乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
337)1-(3-(3-((3-氯苯基)乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;
338)1-(3-(3-((3-((二氟-l3-甲基)-l2-氟烷基)苯基)乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;
339)(E)-2-氟-1-(3-(3-(4-氟苯乙烯)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
340)(E)-2-氟-1-(3-(3-(3-氟苯乙烯)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
341)(E)-2-氟-1-(3-(3-(2-氟苯乙烯)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
342)(E)-1-(3-(3-(4-氯苯乙烯)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;
343)(E)-2-氟-1-(3-(3-(4-(三氟甲基)苯乙烯)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
344)(E)-4-(2-(1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)乙烯基)苄腈;
345)(E)-2-氟-1-(3-(3-(3-(三氟甲基)苯乙烯)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
346)1-(3-(3-((2,3-二氟苯基)乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;
347)2-氟-1-(3-(3-((2-氟苯基)乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
348)1-(3-(3-((2-氯苯基)乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;or
349)2-氟-1-(3-(3-((2-(三氟甲基)苯基)乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮。
本发明还提供一种药物组合物,其包含本发明任一化合物和药学上可接受的辅料,例如,羟基丙基甲基纤维素。在组合物中,所述化合物与所述辅料的重量比在约0.0001至约10之间。
本发明还提供了式I药物组合物在制备用于治疗受试者疾病的药物中的用途。
本发明还提供了关于上述用途的一些优选技术解决方案。
在一些实施方式中,按此方法制备的药物可用于治疗或预防、或用于延迟或预防癌症、癌症转移。所述癌症为结肠癌、胃癌、甲状腺癌、肺癌、白血病、胰腺癌、黑色素瘤、多发性黑色素瘤、脑癌、肾癌、肝癌、鳞癌、胃肠癌、间皮瘤、前列腺癌、卵巢癌或乳腺癌。
本发明还提供了一种治疗受试者疾病的方法,所述方法包括向有需要的受试者施用有效量的本发明化合物或其药学上可接受的盐或其立体异构体,所述疾病为结肠癌、胃癌、甲状腺癌、肺癌、白血病、胰腺癌、黑色素瘤、多发性黑色素瘤、脑癌、肾癌、肝癌、鳞癌、胃肠癌、间皮瘤、前列腺癌、卵巢癌或乳腺癌。
本发明还提供了本发明化合物或其药物组合物用于制备药物的用途。
在一些实施方式中,所述药物用于治疗,预防癌症或增殖性疾病。
在一些实施方式中,所述癌症为结肠癌、胃癌、甲状腺癌、肺癌、白血病、胰腺癌、黑色素瘤、多发性黑色素瘤、脑癌、肾癌、肝癌、鳞癌、胃肠癌、间皮瘤、前列腺癌、卵巢癌或乳腺癌。
在一些实施方式中,所述药物可用作YAP/TAZ-TEAD相互作用的抑制剂。
上述结构通式中使用的一般化学术语具有通常的含义。例如,除非另有说明,本文使用的术语“卤素”是指氟、氯、溴或碘。优选的卤素基团包括F、Cl和Br。
如本文所用,除非另有说明,烷基包括包括具有直链、支链或环状部分的饱和单价烃基。例如,烷基自由基包括甲基、乙基、丙基、异丙基、环丙基、正丁基、异丁基、仲丁基、叔丁基、环丁基、正戊基、3-(2-甲基)丁基、2-戊基、2-甲基丁基、新戊基、环戊基、正己基、2-己基、2-甲基戊基和环己基。类似地,如C1-4烷基中的C1-4,被定义为识别在直链或支链排列中具有1、2、3或4个碳原子的基团。
烯基和炔基包括直链、支链或环状烯烃和炔烃。同样地,“C2-8烯基”和“C2-8炔基”是指具有2、3、4、5、6、7或8个碳原子的线性或支化排列的烯基或炔基。
烷氧基是由前述直链、支链或环状烷基形成的氧醚。
除非另有说明,本文使用的术语“芳基”是指未经取代或取代的含有碳环原子的单环或多环体系。首选芳基为单环或双环6-10元芳香环体系。苯基和萘基是首选芳基。最优选的芳基是苯基。
除非另有说明,本文使用的术语“杂环基”代表未经取代或取代的稳定的3至10元饱和单环、螺环、桥连双环或稠合双环体系,其由碳原子和1至3个选自N、O和S的杂原子组成。N或S杂原子可以任选地被氧化,N杂原子可以任选地被季铵化。杂环基可以连接在任何杂原子或碳原子上,从而产生稳定的结构。此类杂环基的实例包括但不限于氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、氧代哌嗪基、氧代哌啶基、氧代氮杂吡啶基、氮杂吡啶基、四氢呋喃基、二氧戊环基、四氢咪唑基、四氢噻唑基、四氢噁唑基、四氢吡喃基、吗啉基、硫吗啉基、噻吗啉亚砜、噻吗啉基砜和恶二唑基。
除非另有说明,本文所用的术语“杂芳基”代表未取代或取代的稳定的五或六元单环芳香环体系或未取代或取代的八元至十元苯并稠合杂芳香环体系或双环杂芳香环体系,其由碳原子和1-4个选自N、O或S的杂原子组成,其中N或S杂原子可以地任选被氧化,N杂原子可以任选地被季铵化。杂芳基可以连接在任何杂原子或碳原子上,从而产生稳定的结构。杂芳基的实例包括但不限于噻吩基、呋喃基、咪唑基、异噁唑基、唑基、吡唑基、吡咯基、噻唑基、噻二唑基、三唑基、吡啶基、哒嗪基、吲哚基、氮杂吲哚基、吲哚唑基、苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并异噁唑基、苯并噁唑基、苯并吡唑基、苯并噻唑基、苯并噻唑基、苯并三唑腺嘌呤基、喹啉基或异喹啉基。
术语“烯氧基”是指基团-O-烯基,其中烯基的定义如上所述。
术语“炔氧基”是指基团-O-炔基,其中炔基的定义如上所述。
术语“环烷基”是指具有3至12个碳原子的环状饱和烷基,例如环丙基、环丁基、环丁基、环丁基。
术语“杂环烷基”指的是包含碳原子和1-3个选自N,O或S的杂原子的饱和环烷基,所述N或S杂原子可以地任选被氧化,N杂原子可以任选地被季铵化。例如氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、氧代哌嗪基、氧代哌啶基、氧氮杂吡啶基。
术语“取代的”是指基团中的一个或多个氢原子分别被相同的或者不同的取代基所取代。常见的取代基包括但不限于卤素(F、Cl、Br或I)、C1-8烷基、C3-12环烷基、-OR1、SR1、=O、=S、-C(O)R1、-C(S)R1、=NR1、-C(O)OR1、-C(S)OR1、-NR1R2、-C(O)NR1R2、氰基、硝基、-S(O)2R1、-OS(O2)OR1、-OS(O)2R1、-OP(O)(OR1)(OR2);其中,R1和R2独立地选自-H、低级烷基、低级卤代烷基。在一些实施方案中,取代基独立地选自-F、-Cl、-Br、-I、-OH、三氟甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、-SCH3、-SC2H5、甲醛基团、-C(OCH3)、氰基、硝基、CF3、-OCF3、氨基、二甲氨基、甲硫基、磺酰基和乙酰基。
本文所用的术语“组合物”旨在包括包含特定量的特定成分的产品,以及由特定量的特定成分的组合直接或间接产生的产品。因此,包含本发明化合物作为活性成分的药物组合物以及制备本发明化合物的方法也是本发明的一部分。此外,化合物的一些结晶形式可以多晶型存在,并且此多晶型包括在本发明中。另外,一些化合物可以与水(即水合物)或常见的有机溶剂形成溶剂化物,并且此类溶剂化物也包括在本发明的范围内。
取代烷基的实施例包括但不限于2-氨基乙基、2-羟乙基、五氯乙基、三氟甲基、甲氧基甲基、五氟乙基和哌嗪基甲基。
取代的烷氧基的实施例包括但不限于氨基甲氧基、三氟甲氧基、2-二乙基氨基乙氧基、2-乙氧基羰基乙氧基、3-羟基丙氧基。
本发明的化合物也可以药学上可接受的盐的形式存在。对于医药用途,本发明化合物的盐是指无毒的“药学上可接受的盐”。药学上可接受的盐的形式包括药学上可接受的酸/阴离子或碱/阳离子盐。药学上可接受的酸/阴离子盐一般以碱性氮与无机酸或有机酸质子化的形式存在。典型的有机或无机酸包括盐酸、氢溴酸、氢碘酸、高氯酸、硫酸、硝酸、磷酸、乙酸、丙酸、乙醇酸、乳酸、琥珀酸、马来酸、富马酸、苹果酸、酒石酸、柠檬酸、苯甲酸、扁桃酸、甲磺酸、羟基乙磺酸、苯磺酸、草酸、聚酰胺酸、2-萘磺酸、对甲苯磺酸、环己烷磺酸、水杨酸、糖酸或三氟乙酸。药学上可接受的碱/阳离子盐,包括但不限于,铝盐、钙盐、氯普鲁卡因盐、胆碱、二乙醇胺盐、乙二胺、锂盐、镁盐、钾盐、钠盐和锌盐。
本发明化合物的药物前体包含在本发明的保护范围内。通常,所述药物前体是指很容易在体内转化成所需化合物的功能性衍生物。因此,本发明提供的治疗方法中的术语“给药”是指施用能治疗不同疾病的本发明公开的化合物,或虽未明确公开但对受试者给药后能够在体内转化为本发明公开的化合物的化合物。有关选择和制备合适药物前体衍生物的常规方法,已记载在例如《药物前体设计》(Design of Prodrugs,ed.H.Bundgaard,Elsevier,1985)这类书中。
分子中特定位置的任何取代基或变量的定义独立于该分子中其它位置的定义。应当理解,本领域技术人员可以通过现有技术手段及本发明中所述的方法来选择本发明中的化合物的取代基或取代形式,以获得化学上稳定且易于合成的化合物。
本发明所述化合物可能含有一个或多个不对称中心,并可能由此产生非对映异构体和光学异构体。本发明包括所有可能的非对映异构体及其外消旋混合物、其基本上纯的拆分对映异构体、所有可能的几何异构体及其药学上可接受的盐。
上述式I没有确切定义该化合物某一位置的立体结构。本发明包括式I所示化合物的所有立体异构体及其药学上可接受的盐。进一步地,立体异构体的混合物及分离出的特定的立体异构体也包括在本发明中。制备此类化合物的合成过程中,或使用本领域普通技术人员本领域技术人员公知的外消旋化或差向异构化的过程中,制得的产品可以是立体异构体的混合物。
当式I所示化合物存在互变异构体时,除非特别声明,本发明包括任何可能的互变异构体和其药学上可接受的盐,及它们的混合物。
当式I所示化合物及其药学上可接受的盐存在溶剂化物或多晶型时,本发明包括任何可能的溶剂化物和多晶型。形成溶剂化物的溶剂类型没有特别的限定,只要该溶剂是药理学上可以接受的。例如,水、乙醇、丙醇、丙酮等类似的溶剂都可以采用。
术语“药学上可接受的盐”是指从药学上可接受的无毒的碱或酸制备的盐。本发明提供的化合物是酸时,可以从药学上可接受的无毒的碱,包括无机碱和有机碱,方便地制得其相应的盐。从无机碱衍生的盐包括铝、铵、钙、铜(高价和低价)、三价铁、亚铁、锂、镁、锰(高价和低价)、钾、钠、锌之类的盐。特别优选铵、钙、镁、钾和钠的盐。药学上可接受的能够衍生成盐的无毒有机碱包括伯胺、仲胺和叔胺,也包括环胺及含有取代基的胺,如天然存在的和合成的含取代基的胺。能够成盐的其他药学上可接受的无毒有机碱,包括离子交换树脂以及精氨酸、甜菜碱、咖啡因、胆碱、N',N'-二苄乙二胺、二乙胺、2-二乙氨基乙醇、2-二甲胺基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、还原葡萄糖胺、氨基葡萄糖、组氨酸、哈胺、异丙胺、赖氨酸,甲基葡萄糖胺、吗啉、哌嗪、哌啶、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等。
当本发明提供的化合物是碱时,可以从药学上可接受的无毒的酸,包括无机酸和有机酸,方便制得其相应的盐。这样的酸包括,如,醋酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、甲酸、富马酸、葡萄糖酸、谷氨酸、氢溴酸、盐酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、黏酸、硝酸、扑酸、泛酸、磷酸、琥珀酸、硫酸、酒石酸和对甲苯磺酸等。较优地,柠檬酸、氢溴酸、甲酸、盐酸、马来酸、磷酸、硫酸和酒石酸。更优地,甲酸和盐酸。由于式(I)所示化合物将作为药物应用,较优地优选地,使用一定纯度,例如,至少为60%纯度,比较合适的纯度为至少75%,特别合适地纯度为至少98%(%是重量比)。
本发明提供的药物组合物包括作为活性组分的式(I)所示化合物(或其药学上可接受的盐)、一种药学上可接受的赋形剂及其他可选的治疗组分或辅料。本发明的药物组合物包括适于口腔、直肠、局部和不经肠道(包括皮下给药、肌肉注射、静脉给药)给药的药物组合物,尽管任何给定的情况下,最适合的活性组分给药方式取决于接受给药的特定的主体、主体性质和病情严重程度。本发明的药物组合物可以方便地以本领域公知的单位剂型存在和药学领域公知的任何制备方法制备。
在实践中,根据常规的药物混合技术,本发明式(I)所示化合物,或药物前体,或代谢物,或药学上可接受的盐,可以作为活性组分,与药物载体按照常规药物混合技术紧密混合成药物组合物。所述药物载体可以采取各种各样的形式,这取决于期望采用的给药方式,例如,口服或注射(包括静脉注射)。因此,本发明的药物组合物可以采用适于口服给药的独立单元单位,如包含预定剂量的活性组分的胶囊剂、扁囊剂或片剂。进一步地,本发明的药物组合物可采用粉末、颗粒、溶液、水性悬浮液、非水液体、水包油型乳液,或油包水型乳液形式。另外,除了上述提到的常见的剂型,式I所示化合物或其药学上可接受的盐,也可以通过控释的方式和/或输送装置给药。本发明的药物组合物可以采用任何制药学上的方法制备。一般情况下,这种方法包括使活性组分和组成一个或多个必要成分的载体缔合的步骤。一般情况下,所述药物组合物经由活性组分与液体载体或精细分割的固体载体或两者的混合物经过统一均匀的密切和紧密的混合制得。另外,该产品可以方便地制备成所需要的外观。
因此,本发明的药物组合物可以包括药学上可接受的载体和式I所示化合物或其药学上可接受的盐。式I所示化合物或其药学上可接受的盐,与其他一种或多种具有治疗活性的化合物的联合用药也包括在本发明的药物组合物中。
本发明采用的药物载体可以是,例如,固体载体、液体载体或气体载体。固体载体,包括乳糖、石膏粉、蔗糖、滑石粉、明胶、琼脂、果胶、阿拉伯胶、硬脂酸镁、硬脂酸。液体载体,包括糖浆、花生油、橄榄油和水。气体载体,包括二氧化碳和氮气。制备药物口服制剂时,可以使用任何制药学上方便的介质。例如,水、乙二醇、油类、醇类、增味剂、防腐剂、着色剂等可用于口服的液体制剂如悬浮剂、酏剂和溶液剂;而载体,如淀粉类、糖类、微晶纤维素、稀释剂、造粒剂、润滑剂、粘合剂、崩解剂等可用于口服的固体制剂如散剂、胶囊剂和片剂。考虑到易于施用,口服制剂首选片剂和胶囊,在此应用固体药学载体。可选地,片剂包衣可使用标准的水制剂或非水制剂技术。
含有本发明化合物或药物组合物的片剂可通过压制压缩或模塑模制成型,可选地,可以与一种或多种辅助组分或辅药一起制成片剂。活性组分以自由流动的形式如粉末或颗粒,与粘合剂、润滑剂、惰性稀释剂、表面活性剂或分散剂混合,在适当的机器中,通过压缩可以制得压缩片。用一种惰性液体稀释剂浸湿粉末状的化合物或药物组合物,然后在适当的机器中,通过模塑可以制得模塑片。较优地优选地,每个片剂含有大约0.05mg到5g的活性组分,每个扁囊剂或胶囊剂含有大约0.05mg到5g的活性组分。例如,拟用于人类口服给药的配方包含约0.5mg到约5g的活性组分,与合适且方便计量的辅助材料复合,该辅助材料约占药物组合物总量的5%至95%。单位剂型一般包含约1mg到约2g的活性组分,典型的是25mg、50mg、100mg、200mg、300mg、400mg、500mg、600mg、800mg或1000mg。
本发明提供的适用于胃肠外给药的药物组合物可将活性组分加入水中制备成水溶液或悬浮液。可以包含适当的表面活性剂如羟丙基纤维素。在甘油、液态聚乙二醇,及其在油中的混合物,也可以制得分散体系。进一步地,防腐剂也可以包含在本发明的药物组合物中用于防止有害的微生物生长。
本发明提供适用于注射的药物组合物,包括无菌水溶液或分散体系。进一步地,上述药物组合物可以制备成无菌粉末形式以用于即时配制无菌注射液或分散液。无论如何,最终的注射形式必须是无菌的,且为了易于注射,必须是易于流动的。此外,所述药物组合物在制备和储存过程中必须稳定。因此,优选地,所述药物组合物要在抗微生物如细菌和真菌污染的条件下保存。载体可以是溶剂或分散介质,例如,水、乙醇、多元醇(如甘油、丙二醇、液态聚乙二醇)、植物油及其适当的混合物。
本发明提供的药物组合物可以是适于局部用药的形式,例如,气溶胶、乳剂、软膏、洗液、撒粉或其他类似的剂型。进一步地,本发明提供的药物组合物可以采用适于经皮给药设备使用的形式。利用本发明式(I)所示化合物,或其药学上可接受的盐,通过常规的加工方法,可以制备这些制剂。作为一个例子,乳剂或软膏通过加入约5wt%到10wt%的亲水性材料和水,制得具有预期一致性的乳剂或软膏。
本发明提供的药物组合物,可以以固体为载体,适用于直肠给药的形式。单位剂量的栓剂是最典型常见的剂型。适当的辅料包括本领域常用的可可脂和其他材料。栓剂可以方便地制备,首先将药物组合物与软化或熔化的辅料混合,然后冷却和模具成型而制得。
除了上述提到的辅料组分外,上述制剂配方还可以包括,适当的,一种或多种附加的辅料组分,如稀释剂、缓冲剂、调味剂、粘合剂、表面活性剂、增稠剂、润滑剂和防腐剂(包括抗氧化剂)等。进一步地,其他的辅药还可以包括调节药物与预期接受者血液等渗压的促渗剂。包含式(I)所示化合物,或其药学上可接受的盐的药物组合物,可以制备成粉剂或浓缩液的形式。
一般情况下,治疗上述所示的状况或不适,药物的剂量水平约为每天0.01mg/kg体重到150mg/kg体重,或者每个病人每天0.5mg到7g。例如,结肠癌,直肠癌,套细胞淋巴瘤,多发性骨髓瘤,乳腺癌,前列腺癌,胶质母细胞瘤,鳞状细胞食管癌,脂肪肉瘤,T细胞淋巴瘤黑素瘤,胰腺癌,恶性胶质瘤或肺癌,有效治疗的药物剂量水平为每天0.01mg/kg体重到50mg/kg体重,或者每个病人每天0.5mg到3.5g。
但是,可以理解的是,可能需要比上述那些更低或更高的剂量。任何特定病人的具体剂量水平和治疗方案将取决于多种因素,包括所用具体化合物的活性、年龄、体重、综合健康状况、性别、饮食、给药时间、给药途径、排泄率、药物联用的情况和接受治疗的特定疾病的严重程度。
通过下面对本发明的书面描述,这些和其他方面将变得显而易见。
提供以下实施例以更好地说明本发明。除非另有明确说明,否则所有份数和百分比均按重量计算,所有温度均为摄氏度。
将通过具体实施例更详细地描述本发明。提供以下实施例用于说明性目的,并不旨在以任何方式限制本发明。本领域技术人员将容易地认识到可以改变或修改以产生基本相同结果的各种非关键参数。根据本文所述的至少一种测定方法,发现实施例化合物可抑制YAP/TAZ和TEAD蛋白/蛋白相互作用的转录活性。
具体实施方式
图1:Brdu试验中化合物5对NCI-H226细胞系的抑制曲线。
图2:Brdu试验中化合物6对NCI-H226细胞系的抑制曲线。
图3:Brdu试验中化合物30对NCI-H226细胞系的抑制曲线。
图4:Brdu试验中化合物73对NCI-H226细胞系的抑制曲线。
图5:Brdu试验中化合物80对NCI-H226细胞系的抑制曲线。
图6:Brdu试验中化合物124对NCI-H226细胞系的抑制曲线。
图7:Brdu试验中化合物132对NCI-H226细胞系的抑制曲线。
图8:荷NCI-H226肿瘤的Balb/c裸鼠不同治疗组的肿瘤生长曲线。
图9:荷NCI-H226肿瘤的Balb/c裸鼠在不同治疗组的体重变化百分比。
实施例
本文所述化合物可从商业来源获得或通过如下所示的常规方法使用商业上可获得的起始原料和试剂合成。实施例中使用了以下缩略语:
BOP:六氟磷酸苯并三唑-1-氧基三(二甲氨基)磷;
Cu(OAc)2:醋酸铜;
DMA:二甲基乙酰胺;
DMF:N,N-二甲基甲酰胺;
DIAD:偶氮二甲酸二异丙酯;
DEAD:偶氮二甲酸二乙酯;
DIEA或DIPEA:N,N-二异丙基乙胺;
DMSO:二甲基亚砜;
DCM:二氯甲烷;
EA:乙酸乙酯;
EDTA:乙二胺四乙酸;
HATU:1-[双(二甲氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐;
TMB:3,3',5,5'-四甲基联苯胺;
TBAF:四丁基氟化铵;
TBDPSCl:叔丁基二苯基氯硅烷;
THF:四氢呋喃;
TFA:三氟乙酸;
TEA:三乙胺;
Mscl:甲基磺酰氯;
NIS:N-碘代琥珀酰亚胺;
NMP:N-甲基吡咯烷酮;
PBS:磷酸盐缓冲溶液;
HRP:辣根过氧化物酶;
h或hrs:小时;
Hex:己烷;
HATU:1-[双(二甲氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐;
LCMS:液相色谱质谱;
MeOH:甲醇;
min:分钟;
NIS:N-碘代琥珀酰亚胺;
Pd/C:钯碳;
PE:石油醚;
PPh3:三苯基膦;
Pd(PPh3)4:四(三苯基膦)钯;
Pd(dppf)Cl2.CH2Cl2:[1,1′-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物;
Rt or r.t or RT:室温。
实施例1化合物1(1-(1-丙烯酰吡咯烷-3-基)-3-(4-环己基苯基)-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮)的合成
步骤1:3-碘-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮的制备
向1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮(1.00g,7.35mmol)在DMF(20mL)中的混合物中加入NIS(2,48g,11.02mmol)。室温下搅拌该混合物1小时后60℃下搅拌4小时。冷却至室温后,混合物倒入冰水中,搅拌过滤。将滤饼悬浮在甲苯中并真空浓缩,得到题述化合物1-1(1.90g)。LCMS[M+H]+=262.94。
步骤2:3-(3-碘-7-氧代-6,7-二氢-1H-吡唑并[4,3-d]嘧啶-1-基)吡咯烷-1-羧酸叔丁基酯的制备
向化合物1-1(250mg,954.17umol)和3-羟基吡咯烷-1-羧酸叔丁基酯(250mg,1.34mmol)在THF(5mL)中的混合物中加入PPh3(501mg,1.91mmol),然后在0℃下逐滴加入DIAD(386mg,1.91mmol)。将混合物自然升温至室温后搅拌16小时。混合物经真空浓缩后得到残余物,残余物进一步通过硅胶柱(Hex:EA=0%-50%)纯化得到题述化合物1-2(450mg)。LCMS[M+H]+=432.05。
步骤3:3-(3-(4-环己基苯基)-7-氧代-6,7-二氢-1H-吡唑并[4,3-d]嘧啶-1-基)吡咯烷-1-羧酸叔丁基酯的制备
向化合物1-2(450mg,1.04mmol)和2-(4-环己基苯基)-4,4,5,5-四甲基-1,3,2-二氧硼烷(213mg,1.04mmol)在1,4-二氧六环(10mL)和水(1mL)中的混合物中加入Pd(dppf)Cl2.CH2Cl2(76mg,103umol),K2CO3(432mg,3.13mmol)。在氮气条件下反应混合物在100℃下搅拌6小时。反应混合物真空浓缩后得到残余物,残余物经硅胶柱(Hex:EA=0%-50%)纯化后得到题述化合物1-3(450mg)。LCMS[M+H]+=464.26。
步骤4:3-(4-环己基苯基)-1-(吡咯烷-3-基)-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮的制备
将化合物1-3(340mg,733mol)在HCl/1,4-二氧六环(4.0N,10ml)中的混合物室温下搅拌4小时。将反应混合物真空浓缩后得到题述化合物1-4(400mg),不经纯化可直接用于下一步骤。LCMS[M+H]+=400.18。
步骤5:1-(1-丙烯酰吡咯烷-3-基)-3-(4-环己基苯基)-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮(化合物1)的制备
向化合物1-4(200mg,550umol)在THF/H2O(v:v=1:1,10mL)中的混合物中加入NaHCO3(139mg,1。65mmol),然后0℃时在氮气保护下逐滴加入丙烯酰氯(50mg,552umol)。将混合物0℃下搅拌0.5小时,然后使用EA稀释,用水洗涤,无水硫酸钠干燥后真空浓缩获得残余物。残余物经硅胶柱(DCM:MeOH=20:1)纯化后得到题述化合物1(31.9mg)。LCMS[M+H]+=418.22。
实施例2化合物2(1-(1-丙烯酰吡咯烷-3-基)-3-(4-(三氟甲基)苯基)-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮)的合成
步骤1:3-(7-氧代-3-(4-(三氟甲基)苯基)-6,7-二氢-1H-吡唑并[4,3-d]嘧啶-1-基)吡咯烷-1-羧酸叔丁基酯的制备
向Pd(dppf)Cl2.CH2Cl2(60mg,81umol)和K2CO3(336mg,2.43mmol)在1,4-二氧六环(10mL)和水(1mL)的混合物中加入化合物1-2(350mg,811umol)和4,4,5,5-四甲基-2-(4-(三氟甲基)苯基)-1,3,2-二氧硼烷(231mg,1.22mmol)。100℃时反应混合物在氮气条件下搅拌6小时,减压浓缩后得到残余物。残余物经硅胶柱(Hex:EA=0%-50%)纯化得到题述化合物2-1(350mg)。LCMS[M+H]+=450.17。
步骤2:1-(吡咯烷-3-基)-3-(4-(三氟甲基)苯基)-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮的制备
室温下将化合物2-1(350mg,733umol)在HCl/1,4-二氧六环(4.0N,10ml)中的混合物搅拌过夜,减压浓缩后得到化合物2-2(400mg)。LCMS[M+H]+=400.18。
步骤3:1-(1-丙烯酰吡咯烷-3-基)-3-(4-(三氟甲基)苯基)-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮的制备
向化合物2-2(200mg,518umol)在THF/H2O(v:v=1:1,10mL)的混合物中加入NaHCO3(130mg,1.56mmol),然后0℃下逐滴加入丙烯酰氯(47mg,518umol)。0℃下搅拌混合物0.5小时。使用EA稀释,然后用水洗涤,MgSO4干燥后真空浓缩得到残余物。残余物使用制备型薄层色谱(DCM:MeOH=20:1)纯化得到化合物2(10mg)。LCMS[M+H]+=404.13。
实施例3化合物3(1-(3-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)吡咯烷-1-基)丙基-2-烯-1-酮)的合成
步骤1 3-(3-碘-1H-吲唑-1-基)吡咯烷-1-羧酸叔丁基酯的制备
在0℃氮气条件下在搅拌中将甲磺酰氯(140mg,1.23mmol)逐滴加入至3-羟基吡咯烷-1-羧酸叔丁基酯(184mg,0.98mmol),TEA(248mg,0.34mL)和DCM(5.00mL)的混合液中。反应混合物在0℃下搅拌0.5小时。反应混合物中加水淬灭,二氯甲烷萃取,水洗涤,无水硫酸钠干燥后过滤。滤液真空浓缩后得到中间体1(200mg)。
在0℃氮气条件下向3-碘-1H-吲唑(200mg,819umol)的DMF(5.00mL)溶液中分批加入NaH(19.67mg)。室温下搅拌混合物30分钟后,将上述中间体1加入至反应混合物中,在60℃下搅拌过夜。反应混合物冷却至室温,乙酸乙酯稀释,水洗涤,干燥后,真空浓缩后得到残余物。残余物经硅胶柱(Hex:EA=1:1)纯化后得到化合物3-1(100mg)。LCMS[M+H]+=414.06。
步骤2:3-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)吡咯烷-1-羧酸叔丁基酯的制备
氮气条件下,将化合物3-1(100mg,0.24mmol),4,4,5,5-四甲基-2-(4-(三氟甲基)苯基)-1,3,2-二氧硼烷(45mg,0.24mmol),碳酸钾(100mg,0.73mmol),Pd(dppf)Cl2.CH2Cl2(17mg,0.024mmol),1,4-二氧六环(5mL)和水(0.5mL)的混合物在100℃搅拌6小时。混合物经真空浓缩后得残余物,残余物经硅胶柱(Hex:EA=0%-50%)纯化后得化合物3-2(120mg)。LCMS[M+H]+=432.18。
步骤3:1-(吡咯烷-3-基)-3-(4-(三氟甲基)苯基)-1H-吲唑的制备
化合物3-2(100mg,231umol)在HCl/1,4-二氧六环(4.0N,10ml)中的混合物室温下搅拌过夜。反应混合物真空下浓缩得到题述化合物3-3(100mg),不经过进一步纯化用于下一步骤。LCMS[M+H]+=332.13。
步骤4:1-(3-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)吡咯烷-1-基)丙基-2-烯-1-酮的制备
向化合物3-3(300mg,905umol)在THF/H2O(v:v=1:1,20mL)的混合物中加入NaHCO3(130mg,1.56mmol),然后0℃氮气保护条件下逐滴加入丙烯酰氯(81mg,905umol)。反应混合物在0℃下搅拌10分钟,EA稀释,水洗涤,无水硫酸钠干燥,真空浓缩得到残余物。残余物经硅胶柱(DCM:MeOH=30:1)纯化得到化合物3(44.1mg)。
LCMS[M+H]+=386.14。
1H NMR(500MHz,DMSO-d6)δ8.21(d,J=3.2Hz,1H),8.19(d,J=3.2Hz,1H),8.15(d,J=8.2Hz,1H),7.88(d,J=3.4Hz,1H),7.87(s,1H),7.86(d,J=3.7Hz,1H),7.53(dd,J=8.4,6.8Hz,1H),7.33(t,J=7.5Hz,1H),6.65(ddd,J=38.9,16.8,10.3Hz,1H),6.18(ddd,J=16.7,5.7,2.4Hz,1H),5.75–5.51(m,2H),4.21–3.95(m,2H),3.91–3.83(m,1H),3.81–3.58(m,1H),2.56(dt,J=13.4,6.5Hz,1H),2.46(q,J=6.9Hz,1H)。
实施例4化合物4(1-(3-(1-(4-(三氟甲基)苯基)-1H-吲唑-3-基)吡咯烷-1-基)丙基-2-烯-1-酮)的合成
步骤1:3-(1H-吲唑-3-基)-2,5-二氢-1H-吡咯-1-羧酸叔丁基酯的制备
氮气保护下,将3-碘-1H-吲唑(200mg,0.82mmol),3-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-2,5-二氢-1H-吡咯-1-羧酸叔丁基酯(290mg,0.98mmol),Pd(dppf)Cl2.CH2Cl2(67mg,0.082mmol),碳酸钾(339mg,2.46mmol),1,4-二氧六环(10mL)和水(1mL)的混合物在90℃搅拌6小时。LCMS监控反应。将反应混合物冷却至室温。混合物经乙酸乙酯稀释,水洗涤,无水硫酸钠干燥,然后过滤。滤液在真空下浓缩。残余物经硅胶柱(DCM:MeOH=20:1)纯化得到题述化合物4-1(210mg)。LCMS[M+H]+=286.15。
步骤2:3-(1H-吲唑-3-基)吡咯烷-1-羧酸叔丁基酯的制备
在氢气条件下将化合物4-1(210mg,0.74mmol),Pd/C(10mg)和甲醇(20mL)的混合物室温搅拌6小时。LCMS监控反应。过滤反应混合物,滤液真空下浓缩后得到题述化合物4-2(200mg)。LCMS[M+H]+=288.16。
步骤3:3-(1-(4-(三氟甲基)苯基)-1H-吲唑-3-基)吡咯烷-1-羧酸叔丁基酯的制备
将化合物4-2(200mg,0.70mmol),4,4,5,5-四甲基-2-(4-(三氟甲基)苯基)-1,3,2-二氧硼戊环(132mg,0.70mmol),TEA(211mg,2.09mmol),Cu(OAc)2(63mg,0.35mmol)和二氯甲烷(20mL)的混合物在室温下搅拌14小时。反应混合物经二氯甲烷稀释,水洗涤,无水硫酸钠干燥,然后过滤。滤液真空下浓缩。残余物经硅胶柱(DCM:MeOH=30:1)纯化得到题述化合物4-3(210mg)。LCMS[M+H]+=432.18。
步骤4:3-(吡咯烷-3-基)-1-(4-(三氟甲基)苯基)-1H-吲唑盐酸盐的制备
将化合物4-3(210mg,0.49mmol)和HCl/1,4-二氧六环的混合物室温下搅拌1.5小时。反应混合物真空下浓缩得到化合物4-4(200mg),不经进一步纯化直接用于下一步骤。LCMS[M+H]+=332.13。
步骤5:1-(3-(1-(4-(三氟甲基)苯基)-1H-吲唑-3-基)吡咯烷-1-基)丙基-2-烯-1-酮的制备
0℃氮气条件下,向化合物4-4(100mg,0.30mmol),碳酸氢钠(76mg,0.90mmol),THF(10mL)和水(5mL)的混合物中一边搅拌一边逐滴加入丙烯酰氯(35mg,0.37mmol)。混合物0℃下搅拌1小时。反应混合物经乙酸乙酯稀释,水洗涤,无水硫酸钠干燥,然后过滤。滤液真空下浓缩。残余物经硅胶柱(DCM:MeOH=20:1)纯化得到题述化合物4(33mg)。LCMS[M+H]+=386.14。
1H NMR(500MHz,DMSO-d6)δ8.04(s,1H),8.04–7.96(m,3H),7.93(dd,J=8.8,2.2Hz,2H),7.66–7.54(m,1H),7.34(t,J=7.5Hz,1H),6.66(ddd,J=16.5,10.3,5.9Hz,1H),6.17(dt,J=16.8,2.7Hz,1H),5.69(ddd,J=12.4,10.4,2.4Hz,1H),4.24–3.98(m,2H),3.98–3.75(m,2H),3.72(ddd,J=11.9,8.5,3.9Hz,1H),2.48–2.20(m,2H).
实施例5化合物5(2-氟-1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙基-2-烯-1-酮)的合成
步骤1:3-(3-碘-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-羧酸叔丁基酯的制备
0℃时在搅拌下将DEAD(8.53g,48.98mmol)逐滴加入至含有3-碘-1H-吡唑并[3,4-b]吡啶(4.00g,16.33mmol),3-羟基氮杂环丁烷-1-羧酸叔丁酯(4.24g,24.49mmol),三苯基膦(12.85g,48.98mmol)和无水THF(80mL)的混合物中。0℃时搅拌反应混合物10分钟,升温至室温。反应搅拌过夜。使用LCMS监控反应。反应混合物真空下浓缩残余物经硅胶柱(PE:EA=3:1)纯化得到题述化合物(7.83g)。LCMS[M+H]+=401.04。
步骤2:3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-羧酸叔丁基酯的制备
在氮气条件下将3-(3-碘-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-羧酸叔丁基酯(4.00g,10mmol),(4-(三氟甲基)苯基)硼酸(2.85g,15mmol),Cs2CO3(9.77g,30mmol),Pd(dppf)Cl2CH2Cl2(0.82g,1mmol),1,4-二氧六环(40mL)和水(8mL)的混合物100℃搅拌6小时。真空条件下浓缩混合物。残余物通过硅胶柱用DCM洗脱得到题述化合物(4.62g)。LCMS[M+H]+=419.16。
步骤3:1-(氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶的制备
将3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-羧酸叔丁基酯(4.62g,11.04mmol),TFA(15mL)和DCM(20mL)的混合物室温搅拌1小时。反应真空条件下浓缩混合物后得到题述化合物(3.18g)为淡黄色固体,可以不经纯化用于下一步骤。LCMS[M+H]+=319.11。
步骤4:2-氟-1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙基-2-烯-1-酮的制备
将1-(氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶(3.18g,10mmol),2-氟丙烯酸(1.35g,15mmol),HATU(7.60g,20mmol),DIEA(8.07mL,50mmol),DCM(100mL)和DMF(2mL)的混合物室温搅拌5小时。反应混合物用水和盐水洗涤,无水硫酸钠干燥后过滤。滤液在真空下干燥。残余物通过硅胶柱(Hex:EA=1.5:1)洗脱纯化得到题述化合物(0.94g)为淡黄色固体。LCMS[M+H]+=391.11。
1H NMR(500MHz,CDCl3)δ8.58(d,J=3.4Hz,1H),8.36(dd,J=8.05,0.9Hz,1H),8.11(d,J=8.1Hz,2H),7.78(d,J=8.2Hz,2H),7.28(dd,J=8.1,4.5Hz,1H),6.07–5.97(m,1H),5.71(dd,J=46.65,3.0Hz,1H),5.15(dd,J=15.65,3.0Hz,1H),5.09-5.02(m,1H),5.00–4.92(m,1H),4.83–4.75(m,1H),4.73–4.64(m,1H).
1H),5.00–4.92(m,1H),4.83–4.75(m,1H),4.73–4.64(m,1H)。
实施例6化合物6(2-氟-1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)氮杂环丁烷-1-基)丙基-2-烯-1-酮)的合成
步骤1:3-((甲基磺酰基)氧代基)氮杂环丁烷-1-羧酸叔丁基酯的制备
0℃下在搅拌中将甲磺酰氯(7.94g,69.28mmol)加入至含有3-羟基氮杂环丁烷-1-羧酸叔丁基酯(10.00g,57.73mmol),TEA(16.05mL,115.47mmol)和DCM(30mL)的混合物中。0℃下搅拌混合物1.5小时。向反应混合物中加水以淬灭反应,二氯甲烷萃取,水洗涤,无水硫酸钠干燥后过滤。滤液在真空下干燥得到题述化合物(14.67g),可以不经过纯化用于下一步骤。
步骤2:3-(3-溴-1H-吡唑并[4,3-b]吡啶-1-基)氮杂环丁烷-1-羧酸叔丁基酯的制备
0℃时在氮气条件下向3-溴-1H-吡唑并[4,3-b]吡啶(1.60g,8.08mmol)在DMF(20mL)的混合物中分批加入NaH(60%悬浮于矿物油,0.97g,24.24mmol)。室温下搅拌混合物30分钟后,向反应混合物中加入3-((甲基磺酰基)氧代基)氮杂环丁烷-1-羧酸叔丁基酯(6.09g,24.24mmol)。90℃反应搅拌过夜。反应混合物冷却至室温后使用DCM稀释,水洗,无水硫酸钠干燥后过滤。滤液在真空下浓缩。残余物经硅胶柱(DCM:CH3OH=30:1)洗脱纯化得到题述化合物(3.17g)为淡黄色固体。LCMS[M+H]+=353.05。
步骤3:3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)氮杂环丁烷-1-羧酸叔丁基酯的制备
在氮气条件下将含有3-(3-溴-1H-吡唑并[4,3-b]吡啶-1-基)氮杂环丁烷-1-羧酸叔丁基酯(2.85g,8.07mmol),(4-(三氟甲基)苯基)硼酸(2.30g,12.10mmol),Cs2CO3(7.89g,24.21mmol),Pd(dppf)Cl2CH2Cl2(0.66g,0.81mmol),1,4-二氧六环(30mL)和水(6mL)的混合物120℃搅拌4小时。真空条件下浓缩混合物。残余物经硅胶柱用DCM洗脱纯化得到题述化合物(1.80g)为淡黄色固体。LCMS[M+H]+=419.16。
步骤4:1-(氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶的制备
将含有3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)氮杂环丁烷-1-羧酸叔丁基酯(1.80g,4.30mmol),TFA(10mL)和DCM(20mL)的混合物室温搅拌1小时。反应混合物真空下浓缩后得到题述化合物,可以不经过纯化用于下一步骤。LCMS[M+H]+=319.11。
步骤5:2-氟-1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)氮杂环丁烷-1-基)丙基-2-烯-1-酮的制备
将1-(氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶(1.22g,3.83mmol),2-氟丙烯酸(0.52g,5.75mmol),HATU(2.91g,7.67mmol),DIEA(3.16mL,19.15mmol),DCM(100mL)和DMF(2mL)的混合物室温搅拌1小时。反应混合物使用水和盐水洗涤,无水硫酸钠干燥后过滤。滤液在真空下浓缩。残余物经硅胶柱Hex:EA=1.5:1洗脱纯化得到题述化合物(0.60g)为类白色固体。
LCMS[M+H]+=391.11。
1H NMR(500MHz,CDCl3)δ8.73(d,J=3.4Hz,1H),8.70(d,J=8.1Hz,2H),7.81(d,J=8.0Hz,1H),7.76(d,J=8.3Hz,2H),7.39(dd,J=8.6,4.3Hz,1H),5.73(dd,J=46.7,3.0Hz,1H),5.58–5.47(m,1H),5.18(dd,J=15.6,3.0Hz,1H),5.10–5.01(m,1H),5.00–4.90(m,1H),4.84–4.75(m,1H),4.73–4.65(m,1H)。
实施例7化合物7(1-(1-丙烯酰吡咯烷-3-基)-6-甲基-3-(4-(三氟甲基)苯基)-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮)的合成
步骤1:3-碘-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮的制备
将1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮(2.00g,14.69mmol),DMF(20mL)和N-碘代琥珀酰亚胺(4.96g,22.04mmol)的混合物在室温下搅拌1小时后在60℃搅拌4小时。使用LCMS监控反应。反应冷却至室温倒入冰水中。所得混合物过滤后用EA洗涤。滤饼悬浮在甲苯中,后在真空下浓缩得到题述化合物(2.75g)为类白色固体。LCMS[M+H]+=262.94。
步骤2:叔丁基3-(3-碘-7-氧代-6,7-二氢-1H-吡唑并[4,3-d]嘧啶-1-基)吡咯烷-1-羧酸盐的制备
0℃时在氮气保护下将氢化钠(60%悬浮于矿物油中,330mg,13.74mmol)分批加入含有3-碘-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮(1.20g,4.58mmol)和DMF(10mL)的混合物中。反应自然升温至室温并搅拌1小时。室温下向反应混合物中加入3-((甲基磺酰基)氧代基)吡咯烷-1-羧酸叔丁基酯(2.43g,9.16mmol),然后在60℃下搅拌16小时。使用LCMS监控反应。反应冷却至室温,乙酸乙酯稀释后倒入冰水。分离有机层用无水硫酸钠干燥后过滤。真空条件下浓缩滤液。残余物用正己烷(20ml×3)洗涤后过滤。滤饼在真空下浓缩得到题述化合物(1.52g)为类白色固体。LCMS[M+H]+=376.23。
步骤3:3-(7-氧代-3-(4-(三氟甲基)苯基)-6,7-二氢-1H-吡唑并[4,3-d]嘧啶-1-基)吡咯烷-1-羧酸叔丁基酯的制备
在氮气条件下将含有3-(3-碘-7-氧代-6,7-二氢-1H-吡唑并[4,3-d]嘧啶-1-基)吡咯烷-1-羧酸叔丁基酯(1.20g,2.78mmol),(4-(三氟甲基)苯基)硼酸(0.79g,4.17mmol),Pd(dppf)Cl2.CH2Cl2(227mg,0.28mmol),碳酸钾(1.15g,8.35mmol),1,4-二氧六环(20mL)和水(2.0mL)的混合物100℃搅拌6小时。使用LCMS监控反应。反应冷却至室温后。混合物在真空条件下浓缩。残余物经硅胶柱(Hex:EA=0%-40%)洗脱纯化得到题述化合物(1.52g)为淡黄色固体。LCMS[M+H]+=394.42。
步骤4:3-(6-甲基-7-氧代-3-(4-(三氟甲基)苯基)-6,7-二氢-1H-吡唑并[4,3-d]嘧啶-1-基)吡咯烷-1-羧酸叔丁基酯的制备
0℃将碘甲烷(0.24g,1.67mmol)加入含有3-(7-氧代-3-(4-(三氟甲基)苯基)-6,7-二氢-1H-吡唑并[4,3-d]嘧啶-1-基)吡咯烷-1-羧酸盐叔丁基酯(0.50g,1.11mmol),碳酸铯(1.09g,3.34mmol)和DMF(5mL)的混合物中。反应升至室温后搅拌2小时。使用LCMS监控反应。反应使用乙酸乙酯稀释,倒入冰水中。分离有机相,无水硫酸钠干燥,过滤。滤液在真空下浓缩得到题述化合物(0.42g)为黄色固体,可以不经过纯化用于下一步骤。LCMS[M+H]+=408.45。
步骤5:6-甲基-1-(吡咯烷-3-基)-3-(4-(三氟甲基)苯基)-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮盐酸盐的制备
将3-(6-甲基-7-氧代-3-(4-(三氟甲基)苯基)-6,7-二氢-1H-吡唑并[4,3-d]嘧啶-1-基)吡咯烷-1-羧酸叔丁基酯(420mg,0.91mmol)和HCl/1,4-二氧六环(4.0M,10mL)中的混合物室温搅拌4小时。使用LCMS监控反应。反应混合物真空下浓缩得到题述化合物(290mg)为黄色油状物体,可以不经过纯化用于下一步骤。LCMS[M+H]+=364.35。
步骤6:1-(1-丙烯酰吡咯烷-3-基)-6-甲基-3-(4-(三氟甲基)苯基)-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮的制备
0℃时在氮气保护下在搅拌中将丙烯酰氯(99mg,1.09mmol)加入到含有6-甲基-1-(吡咯烷-3-基)-3-(4-(三氟甲基)苯基)-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮盐酸盐(290mg,0.73mmol),碳酸氢钠(310mg,3.69mmol),DCM(20mL)和水(10mL)的混合物中。0℃下搅拌混合物30分钟。使用LCMS监控反应。二氯甲烷稀释,水洗,无水硫酸钠干燥后过滤。滤液在真空下浓缩。残余物经硅胶柱(DCM:MeOH=95:5)洗脱纯化得到题述化合物(148mg)为白色固体。
LCMS[M+H]+=418.22。
1H NMR(500MHz,DMSO-d6)δ8.48–8.41(m,2H),8.37(d,J=3.6Hz,1H),7.87(dd,J=8.5,3.9Hz,2H),6.63(ddd,J=51.4,16.7,10.3Hz,1H),6.17(ddd,J=16.8,7.9,2.4Hz,1H),5.90(dp,J=30.5,5.2,4.5Hz,1H),5.69(ddd,J=27.3,10.4,2.4Hz,1H),4.16–3.99(m,1H),3.97–3.81(m,2H),3.81–3.60(m,1H),3.56(s,3H),2.55(d,J=5.6Hz,1H),2.44(dd,J=7.7,5.7Hz,1H)。
实施例8化合物8(2-氟-1-(3-甲基-3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮)的合成
步骤1:3-甲基-3-((甲基磺酰基)甲氧基)氮杂环丁烷-1-羧酸叔丁基甲酯的制备
0℃时在氮气条件下将甲烷磺酰基氯(0.99mL,12.82mmol)逐滴加入含有3-羟基-3-甲基氮杂环丁烷-1-羧酸叔丁基酯(2.00g,10.68mmol),TEA(2.97mL,21.36mmol),和二氯甲烷(25mL)的混合物中。反应自然升温至室温后搅拌2小时。向混合物中加入水淬灭反应,用二氯甲烷萃取。有机相用盐水洗涤,无水硫酸钠干燥后过滤。滤液在真空条件下浓缩得到题述化合物(2.81g)为黄色油状液体,不用纯化可直接用于下一步。
步骤2:3-(3-溴-1H-吡唑并[3,4-b]吡啶-1-基)-3-甲基氮杂环丁烷-1-羧酸叔丁基酯的制备
将3-甲基-3-((甲基磺酰基)甲氧基)氮杂环丁烷-1-羧酸叔丁基酯(2.81g,10.61mmol),3-溴-1H-吡唑并[3,4-b]吡啶(0.3g,1.51mmol),碳酸铯(2.47g,7.58mmol),和DMF(20mL)的混合物在125℃搅拌12小时。反应混合物冷却至室温后倒入冰水中,乙酸乙酯萃取混合物,盐水洗涤,无水硫酸钠干燥后过滤。真空下浓缩滤液。残余物经硅胶柱(EA:Hex=0%-30%)洗脱纯化得到题述化合物(0.2g)为淡黄色固体。LCMS[M+H]+=367.07。
步骤3:3-甲基-3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-羧酸叔丁基酯的制备
在氮气条件下将3-(3-溴-1H-吡唑并[3,4-b]吡啶-1-基)-3-甲基氮杂环丁烷-1-羧酸叔丁基酯(0.2g,0.54mmol),(4-(三氟甲基)苯基)硼酸(0.15g,0.82mmol),碳酸钾(0.15g,1.09mmol),[PdCl2(dppf)]CH2Cl2(0.04g,0.05mmol),1,4-二氧六环(10mL)和水(2mL)的混合物100℃搅拌4小时。反应混合物冷却至室温后用水稀释,乙酸乙酯萃取。混合的有机相用盐水洗涤,无水硫酸钠干燥后过滤。滤液在真空条件下浓缩。残余物经硅胶柱(EA:Hex=0%-10%)洗脱纯化的得到题述化合物(0.15g)为类白色固体。LCMS[M+H]+=433.18。
步骤4:1-(3-甲基氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶的制备
将3-甲基-3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-羧酸叔丁基酯(0.15g,0.35mmol),二氯甲烷(10mL),和盐酸在1,4-二氧六环(1.77mL,4M,7.08mmol)中的混合物室温搅拌1小时。真空下浓缩该混合物。残余物悬浮在水中并使用饱和碳酸氢钠调节pH为8-9,乙酸乙酯萃取混合物。有机相用盐水洗涤,无水硫酸钠干燥后过滤。真空下浓缩滤液得到题述化合物(0.10g)为淡黄色固体,其不用纯化可直接用于下一步。LCMS[M+H]+=333.12。
步骤5:2-氟-1-(3-甲基-3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮的制备
将2-氟丙烯酸(0.03g,0.37mmol),DMF(5.00mL),DIEA(0.15mL,0.93mmol),HATU(0.17g,0.46mmol),1-(3-甲基氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶(0.1g,0.31mmol)的混合物室温下搅拌过夜。混合物用乙酸乙酯稀释,盐水洗涤,无水硫酸钠干燥后过滤。真空条件下浓缩滤液。残余物经硅胶柱(EA:Hex=0%-10%)洗脱纯化得到题述化合物(20mg)为白色固体。
LCMS[M+H]+=405.13.。
1H NMR(500MHz,DMSO)δ8.68(dd,J=12.7,6.0Hz,1H),8.28(d,J=7.9Hz,1H),7.89(d,J=8.0Hz,1H),7.43(dd,J=8.0,4.5Hz,1H),5.53(dd,J=48.4,3.2Hz,1H),5.39–5.20(m,1H),4.95(d,J=10.6Hz,1H),4.78(d,J=6.8Hz,1H),4.39(d,J=10.5Hz,1H),1.88(s,1H)。
实施例9化合物9(2-氟-1-(2-甲基-3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮)的合成
步骤1:3-羟基-2-甲基氮杂环丁烷-1-羧酸叔丁基酯的制备
0℃时在氮气条件下将硼氢化钠(0.28g,7.29mmol)分批加入含有2-甲基-3-氧代基氮杂环丁烷-1-羧酸叔丁基酯(0.90g,4.86mmol)和甲醇的溶液中(20mL)。反应自然升温直至室温后搅拌3小时。向反应混合物中加入水来淬灭反应,后在真空条件下浓缩以除去甲醇。残余物用水稀释后用乙酸乙酯存取。混合有机相用盐水洗涤,无水硫酸钠干燥后过滤。真空条件下浓缩滤液得到题述化合物(0.80g)为白色固体,其不用纯化可直接用于下一步。LCMS[M+H]+=188.12.
步骤2:3-((甲基磺酰基)甲氧基)氮杂环丁烷-1-羧酸2-甲酯的制备
0℃时在氮气条件下将甲烷磺酰氯(0.73g,6.41mmol)逐滴加入到含有3-羟基-2-甲基氮杂环丁烷-1-羧酸叔丁基酯(0.80g,4.27mmol),TEA(1.2mL)和二氯甲烷(20mL)的混合物中。相同温度下将混合物搅拌2小时。0℃时向反应中加水以淬灭反应,二氯甲烷萃取。混合有机相用盐水洗涤,无水硫酸钠干燥后过滤。真空条件下浓缩滤液得到题述化合物(1.00g)为白色固体,其不用纯化可直接用于下一步。
步骤3:3-(3-溴-1H-吡唑并[3,4-b]吡啶-1-基)-2-甲基氮杂环丁烷-1-羧酸叔丁基酯的制备
将2-甲基-3-((甲基磺酰基)甲氧基)氮杂环丁烷-1-羧酸叔丁基酯(1.0g,3.78mmol),3-溴-1H-吡唑并[3,4-b]吡啶(0.60g,3.03mmol),碳酸铯(1.97g,6.06mmol)和DMF(20mL)的混合物在100℃下搅拌3小时。反应冷却至室温,用水稀释。使用乙酸乙酯萃取混合物。混合的有机相用盐水洗涤,无水硫酸钠干燥后过滤。真空条件下浓缩滤液。残余物通过硅胶柱(EA:Hex=0%-20%)纯化得到题述化合物(0.38g)为黄色固体。LCMS[M+H]+=367.07。
步骤4:2-甲基-3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-羧酸叔丁基酯的制备
在氮气条件下将3-(3-溴-1H-吡唑并[3,4-b]吡啶-1-基)-2-甲基氮杂环丁烷-1-羧酸叔丁基酯(0.36g,0.98mmol),(4-(三氟甲基)苯基)硼酸(0.23g,1.17mmol),碳酸钾(0.41g,2.93mmol),Pd(dppf)Cl2CH2Cl2(0.072g,0.10mmol),1,4-二氧六环(20mL)和水(4mL)的混合物90℃搅拌过夜。混合物冷却至室温,用水稀释。乙酸乙酯萃取混合物。合并的有机相用盐水洗涤,无水硫酸钠干燥,过滤。真空条件下浓缩滤液。残余物通过硅胶色谱(EA:Hex=0%-50%)洗脱纯化得到题述化合物(0.35g)为黄色固体。LCMS[M+H]+=433.18。
步骤5:1-(2-甲基氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶的制备
将2-甲基-3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-羧酸叔丁基酯(0.35g,0.69mmol),二氯甲烷(20mL),和三氟乙酸(0.77mL)的混合物室温下搅拌2小时。用饱和碳酸氢钠溶液(50mL)调节反应混合物的pH值。使用乙酸乙酯萃取混合物,合并的有机相用盐水洗涤,无水硫酸钠干燥,过滤。真空条件下浓缩滤液得到题述化合物(0.20g)为黄色固体,其不用纯化可直接用于下一步。LCMS[M+H]+=333.12。
步骤6:2-氟-1-(2-甲基-3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮的制备
将2-氟丙烯酸(0.11g,1.26mmol),DMF(5.00mL),DIEA(0.42mL,2.52mmol),HATU(0.48g,1.26mmol),1-(2-甲基氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶(0.20g,0.84mmol)的混合物在室温下搅拌2小时。混合物用乙酸乙酯稀释,盐水洗涤,无水硫酸钠干燥后过滤。真空条件下浓缩滤液。残余物通过硅胶色谱(MeOH:DCM=0%-3%)洗脱纯化得到题述化合物(0.18g)为白色固体。
LCMS[M+H]+=405.13。
1H NMR(500MHz,CDCl3-d3)δ8.59–8.58(m,1H),8.37–8.35(m,1H),8.12–8.10(m,2H),7.78–7.77(m,2H),7.28–7.26(m,1H),5.75–5.65(m,1H),5.53–5.52(m,1H),5.16–5.13(m,2H),2.81(s,2H),1.73–1.72(m,3H)。
实施例10化合物10(2-氟-N-(2-甲基-5-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)苯基)丙烯酰胺)的合成
步骤1:3-溴-1-(4-甲基-3-硝基苯基)-1H-吡唑并[3,4-b]吡啶的制备
在氮气条件下将3-溴-1H-吡唑并[3,4-b]吡啶(0.50g,2.52mmol),(4-甲基-3-硝基-苯基)硼酸(685.36mg,3.79mmol),吡啶(0.50g,2.52mmol),Cu(OAc)2(0.92g,5.05mmol),和DMF(20mL)的混合物80℃搅拌8小时。混合物用乙酸乙酯稀释后硅藻土过滤。滤液用盐水洗涤,无水硫酸钠干燥后过滤,真空条件下浓缩滤液。残余物通过硅胶色谱(EA:Hex=0%-20%)洗脱纯化得到题述化合物(0.65g)为白色固体。LCMS[M+H]+=332.99。
步骤2:1-(4-甲基-3-硝基苯基)-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶的制备
在氮气条件下将3-溴-1-(4-甲基-3-硝基苯基)-1H-吡唑并[3,4-b]吡啶(0.35g,1.05mmol),(4-(三氟甲基)苯基)硼酸(0.30g,1.58mmol),碳酸钾(0.44g,3.15mmol),Pd(dppf)Cl2CH2Cl2(0.085g,0.11mmol),1,4-二氧六环(20mL),和水(4mL)在90℃搅拌4小时。混合物冷却至室温后用水稀释,乙酸乙酯萃取混合物。合并的有机相用盐水洗涤,无水硫酸钠干燥,过滤。真空条件下浓缩滤液。残余物通过硅胶色谱(EA:Hex=0%-50%)洗脱纯化得到题述化合物(0.26g)为黄色固体。LCMS[M+H]+=399.10。
步骤3:2-甲基-5-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)苯胺的制备将1-(4-甲基-3-硝基苯基)-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶(0.26g,0.88mmol),EtOH(30mL),H2O(10mL),氯化铵(0.47g,8.79mmol),和铁粉(0.25g,4.39mmol)的混合物在75℃下搅拌2小时。反应混合物冷却至室温后用硅藻土过滤。真空条件下浓缩滤液。残余物用乙酸乙酯稀释,盐水洗涤,无水硫酸钠干燥后过滤。真空条件下浓缩滤液得到题述化合物(0.20g)为棕色固体,不用纯化可直接用于下一步。LCMS[M+H]+=369.12。
步骤4:2-氟-N-(2-甲基-5-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)苯基)丙烯酰胺的制备
将2-氟丙烯酸(0.058g,0.65mmol),DMF(20mL),DIEA(0.27mL,1.63mmol),HATU(0.27g,0.71mmol),2-甲基-5-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)苯胺(0.20g,0.54mmol)的混合物在室温下搅拌2小时。混合物用乙酸乙酯稀释,盐水洗涤,无水硫酸钠干燥后过滤。真空条件下浓缩滤液。残余物通过硅胶色谱(MeOH:DCM=0%-3%)洗脱纯化得到题述化合物(0.10g)为白色固体。
LCMS[M+H]+=441.13。
1H NMR(500MHz,CDCl3-d3)δ8.99–8.98(m,1H),8.71–8.70(m,1H),8.42–8.40(m,1H),8.18–8.17(m,2H),8.13–8.11(m,1H),7.97(s,1H),7.80–7.78(m,2H),7.41–7.39(m,1H),7.33–7.31(m,1H),5.93–5.83(m,1H),5.32–5.28(m,1H),2.38(s,3H)。
实施例11化合物11(2-氟-1-(3-(6-甲基-3-((4-(三氟甲基)苯基)氨基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮)的合成
步骤1:3-(3-碘-6-甲基-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-羧酸叔丁基酯的制备
将3-碘-6-甲基-1H-吡唑并[3,4-b]吡啶(0.4g,1.54mmol),3-碘氮杂环丁烷-1-羧酸叔丁基酯(0.7g,2.47mmol),碳酸铯(1.1g,3.4mmol),和DMSO(20ml)的混合物在80s下搅拌2小时。反应混合物冷却至室温后倒入冰水中,用乙酸乙酯萃取混合物。合并的有机相用水洗涤,无水硫酸钠干燥,过滤。真空条件下浓缩滤液。残余物经过硅胶色谱(EA:Hex=0%-15%)洗脱纯化得到题述化合物(0.57g)为白色固体。LCMS[M+H]+=415.06。
步骤2:3-(6-甲基-3-((4-(三氟甲基)苯基)氨基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-羧酸叔丁基酯的制备
在氮气条件下将3-(3-碘-6-甲基-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-羧酸叔丁基酯(0.25g,0.6mmol),4-(三氟甲基)苯胺(0.29g,1.8mmol),磷酸钾(0.38g,1.8mmol),XpHos(0.057g,0.12mmol),Pd2dba3(0.055g,0.06mmol),和1,4-二氧六环(20mL)的混合物100℃搅拌8小时。反应混合物冷却至室温在真空下浓缩。残余物通过硅胶色谱(EA:Hex=0%-30%)洗脱纯化得到标题所述化合物(0.19g)为白色固体。LCMS[M+H]+=448.46。
步骤3:1-(氮杂环丁烷-3-基)-6-甲基-N-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-胺的制备
将3-(6-甲基-3-((4-(三氟甲基)苯基)氨基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-羧酸叔丁基酯(0.19g,0.43mmol),二氯甲烷(10mL),和三氟乙酸(0.3mL,4.29mmol)的混合物在室温下搅拌2小时。真空条件下浓缩反应混合物,残余物中加入饱和碳酸钠溶液,用乙酸乙酯萃取混合物。合并的有机相用盐水洗涤,无水硫酸钠干燥,过滤。真空条件下浓缩滤液得到题述化合物(0.15g)为黄色固体,不用纯化可直接用于下一步。LCMS[M+H]+=348.14。
步骤4:2-氟-1-(3-(6-甲基-3-((4-(三氟甲基)苯基)氨基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮的制备
将2-氟丙烯酸(0.05g,0.56mmol),DMF(10mL),DIEA(0.21mL,1.3mmol),HATU(0.24g,0.65mmol),1-(氮杂环丁烷-3-基)-6-甲基-N-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-胺(0.15g,0.43mmol)的混合物在室温下搅拌2小时。混合物用乙酸乙酯稀释,盐水洗涤,无水硫酸钠干燥后过滤。真空条件下浓缩滤液。残余物通过硅胶色谱(EA:Hex=0%-20%)洗脱纯化得到题述化合物(10mg)为白色固体。
LCMS[M+H]+=420.14。
1H NMR(500MHz,DMSO)δ9.75(s,1H),8.29(d,J=8.2Hz,1H),7.83(d,J=8.6Hz,2H),7.63(d,J=8.7Hz,2H),7.10(d,J=8.2Hz,1H),5.80(s,1H),5.56(dd,J=48.4,3.5Hz,1H),5.37(dd,J=16.5,3.5Hz,1H),4.89(d,J=7.5Hz,1H),4.76(d,J=4.7Hz,1H),4.54(s,1H),4.45(d,J=5.2Hz,1H),2.59(s,3H)。
实施例12化合物12(2-氟-1-(2-羟基-3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮)的合成
步骤1:(3-((叔丁基二苯基甲硅烷基)甲氧基)-2-羟基丙基)氨基甲酸叔丁基酯
室温下将叔丁基氯二苯基硅烷(1.58g,5.75mmol)加入至含有(2,3-二羟基丙基)氨基甲酸叔丁基酯(1.00g,5.23mmol)和咪唑(0.78g,11.50mmol)在DMF(30mL)中的混合物中。反应在室温下搅拌过夜。通过LCMS监测反应。反应液加水淬灭反应。用乙酸乙酯萃取混合物,合并的有机相用盐水洗涤,无水硫酸钠干燥,过滤。真空条件下浓缩滤液。残余物通过硅胶色谱(EA:Hex=0%-30%)洗脱纯化得到题述化合物(2.1g,93%)。LCMS[M+H]+=430.23。
步骤2:(3-((叔丁基二苯基硅烷基)甲氧基)-2-(3-碘-1H-吡唑并[3,4-b]吡啶-1-基)丙基)氨基甲酸叔丁基酯的制备
0℃时在氮气条件下将DEAD(2.56g,14.69mmol)逐滴加入至含有(3-((叔丁基二苯基硅烷基)甲氧基)-2-羟基丙基)氨基甲酸叔丁基酯(2.1g,4.9mmol),PPh3(3.85g,14.69mmol),3-碘-1H-吡唑并[3,4-b]吡啶(1.20g,4.90mmol),和THF(20mL)的混合物中。反应混合物升至室温后搅拌过夜。通过LCMS监测反应。将反应物倒入冰水中并用乙酸乙酯萃取。合并的有机相用盐水洗涤,无水硫酸钠干燥,过滤。真空条件下浓缩滤液。粗品通过硅胶色谱(EA:Hex=0-30%)洗脱纯化得到题述化合物(2.22g,69%)为红色油状物体。LCMS[M+H]+=657.17。
步骤3:(3-((叔丁基二苯基硅烷基)甲氧基)-2-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)丙基)氨基甲酸叔丁基酯的制备
在氮气条件下将(3-((叔丁基二苯基硅烷基)甲氧基)-2-(3-碘-1H-吡唑并[3,4-b]吡啶-1-基)丙基)氨基甲酸叔丁基酯(1g,1.52mmol),(4-(三氟甲基)苯基)硼酸(0.40g,2.13mmol),K2CO3(0.63g,4.57mmol),Pd(dppf)Cl2(0.1g,0.23mmol)在1,4-二氧六环(20mL)和水(4mL)中的混合物90℃搅拌6小时。真空条件下浓缩混合物。残余物进一步通过硅胶色谱(EA:Hex=0-20%)洗脱纯化得到题述化合物(0.65g,63%)。LCMS[M+H]+=675.29。
步骤4:3-((叔丁基二苯基硅烷基)甲氧基)-2-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)丙烷-1-胺的制备
将(3-((叔丁基二苯基硅烷基)甲氧基)-2-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)丙基)氨基甲酸叔丁基酯(651mg,0.96mmol),DCM(10mL),和TFA(1mL,13.51mmol)的混合物室温搅拌4小时。通过LCMS监测反应。真空条件下浓缩混合物。残余物用二氯甲烷稀释,碳酸钾溶液调节溶液pH值至10。混合物用二氯甲烷萃取,盐水洗涤,无水硫酸钠干燥,过滤。真空条件下浓缩滤液得到题述化合物(542mg,98%),不用纯化可直接用于下一步。LCMS[M+H]+=575.24。
步骤5:N-(3-((叔丁基二苯基硅烷基)甲氧基)-2-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)丙基)-2-氟丙烯酰胺的制备
将2-氟丙烯酸(115mg,1.27mmol),DIEA(0.42mL,2.55mmol),HATU(387mg,1.02mmol),DCM(20mL),DMF(4mL),和3-((叔丁基二苯基硅烷基)甲氧基)-2-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)丙烷-1-胺(488mg,0.85mmol)的混合物室温搅拌3小时。反应混合物用水淬灭。乙酸乙酯萃取混合物,盐水洗涤,无水硫酸钠干燥,过滤。真空条件下浓缩滤液。残余物通过硅胶色谱(EA:Hex=0-20%)洗脱纯化得到题述化合物(300mg)。LCMS[M+H]+=647.24。
步骤6:2-氟-N-(3-羟基-2-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)丙基)丙烯酰胺的制备
向搅拌中的N-(3-((叔丁基二苯基硅烷基)甲氧基)-2-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)丙基)-2-氟丙烯酰胺(300mg,0.46mmol)的THF(8mL)溶液中加入TBAF(0.7mL,1M in THF)。反应在室温下搅拌2小时。通过LCMS监测反应。将反应物倒入冰水中并用乙酸乙酯萃取,分离有机相,水相用乙酸乙酯萃取。合并的有机相用盐水洗涤,无水硫酸钠干燥,过滤。真空条件下浓缩滤液。残余物通过硅胶色谱(EA:Hex=0%-100%)洗脱纯化得到题述化合物(162mg,86%)为白色固体。
LCMS[M+H]+=409.12。
1H NMR(500MHz,DMSO)δ8.70–8.58(m,3H),8.27(d,J=6.0Hz,2H),7.89(d,J=6.0Hz,2H),7.35(m,1H),5.49–5.33(m,1H),5.32–5.23(m,1H),5.15(m,1H),5.04–4.91(m,1H),4.05–3.97(m,1H),3.96–3.88(m,1H),3.84–3.76(m,1H),3.71–3.62(m,1H).
步骤7:2-氟-1-(2-羟基-3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮的制备
向搅拌中的2-氟-N-(3-羟基-2-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)丙基)丙烯酰胺(40mg,0.10mmol)的DCM(10mL)溶液加入戴斯-马丁试剂(54mg,0.13mmol)。反应在室温下搅拌2小时。通过LCMS监测反应。使用碳酸氢钠和硫代硫酸钠溶液淬灭反应。混合物用二氯甲烷萃取,盐水洗涤,无水硫酸钠干燥,过滤。真空条件下浓缩滤液。残余物通过制备型薄层色谱(Hex:EA=1:1)纯化得到题述化合物(28mg,70%)。
LCMS[M+H]+=407.11。
1H NMR(500MHz,DMSO)δ8.65–8.54(m,2H),8.39(m,1H),8.26(d,J=8.1Hz,2H),7.90(m,2H),7.34(m,1H),5.37–5.24(m,1H),5.16(m,1H),5.07(dd,J=15.7,3.3Hz,1H),4.09(q,J=5.2Hz,1H),3.96–3.84(m,2H)。
实施例13化合物13(N-(1-(3-(4-(三氟甲基)苯基)咪唑并[1,5-a]吡啶-1-基)氮杂环丁烷-3-基)丙烯酰胺)的合成
步骤1:7-溴-9-[4-(三氟甲基)苯基]-1,8-二氮杂双环[4.3.0]壬烷-2,4,6,8-四烯的制备
在氮气条件下将7,9-二溴-1,8-二氮杂双环[4.3.0]壬烷-2,4,6,8-四烯(0.70g,2.54mmol),[4-(三氟甲基)苯基]硼酸(0.48g,2.54mmol),Pd(PpH3)4(0.15g,0.13mmol),K2CO3(0.70g,5.07mmol),1,4-二氧六环(4mL),和水(1mL)的混合物85℃搅拌2小时。将反应冷却至室温,用水稀释,乙酸乙酯萃取。合并的有机相用盐水洗涤,无水硫酸钠干燥后过滤。真空条件下浓缩滤液。残余物通过硅胶色谱(正己烷/乙基醋酸=5/1)洗脱纯化得到题述化合物(0.50g,57.78%)为棕色固体。LCMS[M+H]+=342.13。
步骤2:N-[1-[9-[4-(三氟甲基)苯基]-1,8-二氮杂双环[4.3.0]壬烷-2,4,6,8-四烯-7-基]氮杂环丁烷-3-基]氨基甲酸叔丁基酯的制备
将7-溴-9-[4-(三氟甲基)苯基]-1,8-二氮杂双环[4.3.0]壬烷-2,4,6,8-四烯(0.50g,1.47mmol),N-(氮杂环丁烷-3-基)氨基甲酸叔丁基酯(0.25g,1.47mmol),XantpHos(0.08g,0.15mmol),Pd2(dba)3(0.13g,0.15mmol)和Cs2CO3(0.96g,2.93mmol)在1,4-二氧六环(5.00mL)中的混合物用氮气脱气并在80℃时搅拌过夜。完成后,反应冷却至室温,用EA萃取3次。减压条件下浓缩有机相。残余物通过硅胶色谱(己烷/EA=10/1)洗脱纯化得到题述化合物(0.40g,63.11%)为黄色固体。
LCMS[M+H]+=433.45。
步骤3:1-[9-[4-(三氟甲基)苯基]-1,8-二氮杂双环[4.3.0]壬烷-2,4,6,8-四烯-7-基]氮杂环丁烷-3-胺的制备
向N-[1-[9-[4-(三氟甲基)苯基]-1,8-二氮杂双环[4.3.0]壬烷-2,4,6,8-四烯-7-基]氮杂环丁烷-3-基]氨基甲酸叔丁基酯(0.20g,0.46mmol)的DCM(2.00mL)溶液中逐滴加入TFA(0.03mL,0.46mmol)并且在室温下搅拌2小时。完成后,反应的pH值调节至7并用DCM萃取,浓缩。残余物不经纯化可直接用于下一步。LCMS[M+H]+=333.33。
步骤4:N-[1-[9-[4-(三氟甲基)苯基]-1,8-二氮杂双环[4.3.0]壬烷-2,4,6,8-四烯-7-基]氮杂环丁烷-3-基]丙-2-烯酰胺的制备
0℃时向1-[9-[4-(三氟甲基)苯基]-1,8-二氮杂双环[4.3.0]壬烷-2,4,6,8-四烯-7-基]氮杂环丁烷-3-胺(0.10g,0.30mmol)和TEA(0.08mL,0.60mmol)的DCM(3mL)溶液加入丙-2-烯酰氯(0.03g,0.30mmol)并在室温下搅拌0.5小时。完成后,反应用水淬灭,用DCM萃取。在减压条件下浓缩合并的有机相。残余物用制备型薄层色谱纯化得到题述化合物(10mg,8.6%)为类白色固体。
LCMS[M+H]+=387.38。
实施例14化合物14(N-(1-(1-丙烯酰氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1H-吲唑-7-基)甲磺酰胺)的合成
步骤1:3-碘-7-硝基-1H-吲唑的制备
将7-硝基-1H-吲唑(2.00g,12.26mmol),KOH(2.75g,49.04mmol)和I2(1.56g,12.26mmol)在DMF(10.00mL)中的混合物室温搅拌过夜。完成后,向反应物中加水稀释,EA萃取3次,合并有机相并进行浓缩。残余物经过硅胶色谱洗脱纯化得到题述化合物(2.50g,70.55%)为棕色固体。LCMS[M+H]+=290.03。
步骤2:3-(3-碘-7-硝基-1H-吲唑-1-基)氮杂环丁烷-1-乙酸叔丁基酯的制备
将3-碘-7-硝基-1H-吲唑(1.00g,3.46mmol),3-溴氮杂环丁烷-1-乙酸叔丁基酯(0.98g,4.15mmol),Cs2CO3(2.25g,6.92mmol)在DMF(10.00mL)中的混合物100℃搅拌3小时。完成后,反应冷却至室温,向反应中加水稀释,EA萃取3次。减压条件下浓缩有机相。残余物通过硅胶色谱(己烷/EA=10/1)洗脱纯化得到题述化合物(1.00g,65.07%)为棕色固体。LCMS[M+H]+=445.23。
步骤3:3-(7-硝基-3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)氮杂环丁烷-1-乙酸叔丁基酯的制备
将-3-(3-碘-7-硝基-吲唑-1-基)氮杂环丁烷-1-乙酸叔丁基酯(1.00g,2.25mmol),[4-(三氟甲基)苯基]硼酸(0.43g,2.25mmol),Pd(PpH3)4(0.13g,0.11mmol),K2CO3(0.62g,4.50mmol)在二氧六环(5.00mL)和水(1.00mL)中的混合物用氮气脱气并在80℃搅拌过夜。反应完成后,反应冷却至室温,EA萃取3次。减压条件下浓缩有机相。残余物通过硅胶色谱(己烷/EA=3/1)洗脱纯化得到题述化合物(0.40g,38.42%)为黄色固体。LCMS[M+H]+=463.43。
步骤4:1-(氮杂环丁烷-3-基)-7-硝基-3-[4-(三氟甲基)苯基]吲唑的制备
向3-[7-硝基-3-[4-(三氟甲基)苯基]吲唑-1-基]氮杂环丁烷-1-乙酸叔丁基酯的DCM(4.00mL)溶液加入TFA(0.32mL,4.33mmol)并室温搅拌2小时。完成后,调节反应物pH值至7并用DCM萃取,浓缩。残余物(0.25g,79.77%)不经纯化可直接用于下一步。LCMS[M+H]+=363.31。
步骤5:1-[3-[7-硝基-3-[4-(三氟甲基)苯基]吲唑-1-基]氮杂环丁烷-1-基]丙-2-烯-1-酮的制备
0℃向1-(氮杂环丁烷-3-基)-7-硝基-3-[4-(三氟甲基)苯基]吲唑(0.25g,0.69mmol)和TEA(0.19mL,1.38mmol)的DCM(4mL)溶液逐滴加入丙-2-烯酰氯(0.07g,0.76mmol)并在室温下搅拌0.5小时。完成后,反应加入水淬灭反应,DCM萃取。减压条件下浓缩合并的有机相。残余物可不经纯化用于下一步。LCMS[M+H]+=417.36。
步骤6:1-[3-[7-氨基-3-[4-(三氟甲基)苯基]吲唑-1-基]氮杂环丁烷-1-基]丙-2-烯-1-酮的制备
将1-[3-[7-硝基-3-[4-(三氟甲基)苯基]吲唑-1-基]氮杂环丁烷-1-基]丙-2-烯-1-酮(0.20g,0.48mmol),Fe(0.08g,1.44mmol),NH4Cl(0.03g,0.58mmol)在EtOH/H2O(4/1mL)中的混合物80℃搅拌1小时。完成后,反应冷却至室温,过滤。滤液减压浓缩。残余物通过硅胶色谱(PE/EA=3/1)洗脱纯化得到题述产品(0.17g,91.59%)为棕色固体。LCMS[M+H]+=387.38。
步骤7:N-(1-(1-丙烯酰氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1H-吲唑-7-基)甲磺酰胺的制备
向1-[3-[7-氨基-3-[4-(三氟甲基)苯基]吲唑-1-基]氮杂环丁烷-1-基]丙-2-烯-1-酮(0.05g,0.13mmol)和TEA(0.06g,0.26mmol)的DCM(3mL)溶液中加入甲磺酰氯(0.02g,0.17mmol)并搅拌1小时。完成后,向反应物中加入水,分离有机相并浓缩。残余物经制备型薄层色谱纯化得到题述产物(5.8mg,9%)为固体。LCMS[M+H]+=465.46。
实施例15化合物15(N-(1-(1-丙烯酰氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1H-吲唑-7-基)乙酰胺)的合成
步骤1:N-(1-(1-丙烯酰氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1H-吲唑-7-基)乙酰胺的制备
将1-[3-[7-氨基-3-[4-(三氟甲基)苯基]吲唑-1-基]氮杂环丁烷-1-基]丙-2-烯-1-酮(170.00mg,0.44mmol),Ac2O(0.04mL,0.44mmol)在DCM(2.00mL)中的混合物室温搅拌1小时,加水至反应物,分离有机相并浓缩。残余物通过制备型薄层色谱纯化得到题述产物(3.00mg,1.59%)为白色固体。LCMS[M+H]+=429.42。
使用不同的反应起始物和合适的试剂通过与实施例1-15类似的方法制备表1中的化合物。
表1
实施例229化合物229(1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1,3-二氢-2H-苯并[d]咪唑并l-2-酮)的合成
步骤1:3-((2-硝基苯基)氨基)氮杂环丁烷-1-乙酸叔丁基酯的制备
将1-氟-2-硝基苯(10.0g,70.87mmol),3-氨基氮杂环丁烷-1-乙酸叔丁基酯(24.41g,141.74mmol),碳酸钾(29.39g,212.62mmol),和DMF(200mL)的混合物室温搅拌3小时。通过LCMS监测反应。反应物倒入冰水中。过滤混合物。滤饼用水洗涤并在真空下干燥得到题述化合物(18.12g)为黄色固体,不用进一步纯化可直接用于下一步。LCMS[M+H]+=238.32。
步骤2:3-((2-氨基苯基)氨基)氮杂环丁烷-1-乙酸叔丁基酯的制备
在氢气条件下将3-((2-硝基苯基)氨基)氮杂环丁烷-1-乙酸叔丁基酯(8.00g,27.27mmol),Pd/C(1.0g,10%),和MeOH(100mL)的混合物室温下搅拌过夜。通过LCMS监测反应。过滤混合物。真空条件下浓缩滤液得到题述化合物(10.50g)为类白色固体,不用进一步纯化可直接用于下一步。LCMS[M+H]+=264.42。
步骤3:3-(2-氧代基-2,3-二氢-1H-苯并[d]咪唑并l-1-基)氮杂环丁烷-1-乙酸叔丁基酯的制备
将3-((2-氨基苯基)氨基)氮杂环丁烷-1-乙酸叔丁基酯(10.00g,37.97mmol),DMF(50mL),和1,1'-羰基二咪唑(12.31g,75.95mmol)的混合物100℃时搅拌2小时。通过LCMS监测反应。将反应冷却至室温。反应混合物乙酸乙酯稀释,水洗涤,无水硫酸钠干燥,过滤。真空条件下浓缩滤液。残余物通过硅胶色谱(己烷:乙酸乙酯=2:1)洗脱纯化得到题述化合物(6.10g)为类白色固体。LCMS[M+H]+=234.34。
步骤4:3-(2-氧代基-3-(4-(三氟甲基)苯基)-2,3-二氢-1H-苯并[d]咪唑并l-1-基)氮杂环丁烷-1-乙酸叔丁基酯的制备
氧气条件下将3-(2-氧代基-2,3-二氢-1H-苯并[d]咪唑并l-1-基)氮杂环丁烷-1-乙酸叔丁基酯(6.00g,20.74mmol),(4-(三氟甲基)苯基)硼酸(5.91g,31.11mmol),DIPEA(8.04g,62.21mmol),Cu(OAc)2(3.77g,20.74mmol),和DCM(60mL)的混合物室温下搅拌8小时。通过LCMS监测反应。混合物通过硅藻土过滤。滤液用盐水洗涤,无水硫酸钠干燥,然后过滤。真空条件下浓缩滤液。残余物通过硅胶色谱(己烷:乙酸乙酯=3:1)洗脱纯化得到题述化合物(7.65g)为蓝色油状液体。LCMS[M+H]+=378.42。
步骤5:1-(氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1,3-二氢-2H-苯并[d]咪唑并l-2-酮的制备
将3-(2-氧代基-3-(4-(三氟甲基)苯基)-2,3-二氢-1H-苯并[d]咪唑并l-1-基)氮杂环丁烷-1-乙酸叔丁基酯(7.65g,17.65mmol),TFA(38.0mL),和DCM(75mL)的混合物室温下搅拌8小时。使用LCMS监控反应。真空条件下浓缩反应混合物。残余物用二氯甲烷稀释,饱和碳酸钠溶液调节pH值至10。混合物用二氯甲烷萃取,无水硫酸钠干燥,过滤。真空条件下浓缩滤液得到题述化合物(4.25g)为类白色固体,不用进一步纯化可直接用于下一步。LCMS[M+H]+=334.31。
步骤6:1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1,3-二氢-2H-苯并[d]咪唑-2-酮的制备
将1-(氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1,3-二氢-2H-苯并[d]咪唑-2-酮(2.80g,8.40mmol),DIPEA 3.26g,25.20mmol),DCM(20mL),2-氟丙烯酸(1.13g,12.60mmol),和HATU(3.19g,8.40mmol)室温下搅拌2小时。使用LCMS监控反应。混合物二氯甲烷稀释,水洗涤,无水硫酸钠干燥,过滤。真空条件下浓缩滤液。残余物通过硅胶色谱(正己烷:乙酸乙酯=2:1)洗脱纯化得到题述化合物(1.32g)为白色固体。
LCMS[M+H]+=406.46。
1H NMR(500MHz,DMSO-d6)δ7.96(d,J=8.4Hz,2H),7.84(d,J=8.3Hz,2H),7.39(d,J=7.8Hz,1H),7.27–7.18(m,2H),7.14(td,J=7.7,1.1Hz,1H),5.55(dd,J=48.4,3.5Hz,1H),5.43(tt,J=8.7,5.7Hz,1H),5.36(dd,J=16.5,3.5Hz,1H),5.03–4.69(m,2H),4.65–4.40(m,2H)。
实施例230化合物230(2-氟-1-(3-(4-(4-(三氟甲基)苯基)喹唑啉-2-基)氮杂环丁烷-1-基)丙-2-烯-1-酮)的合成
步骤1:3-((3-硝基吡啶-2-基)氨基)氮杂环丁烷-1-乙酸叔丁基酯的制备
将3-氨基氮杂环丁烷-1-乙酸叔丁基酯(5.45g,31.76mmol),2-氟-3-硝基吡啶(3.0g,21.11mmol),碳酸钾(8.75g,63.34mmol),和DMF(20mL)20℃下搅拌2小时。通过LCMS监测反应。反应液乙酸乙酯稀释,水洗涤,无水硫酸钠干燥,过滤。真空条件下浓缩滤液得到题述化合物(9.25g)为黄色油状液体,不用进一步纯化可直接用于下一步。LCMS[M+H]+=239.42。
步骤2:3-((3-氨基吡啶-2-基)氨基)氮杂环丁烷-1-乙酸叔丁基酯的制备
在氢气条件下将3-((3-硝基吡啶-2-基)氨基)氮杂环丁烷-1-乙酸叔丁基酯(9.25g,31.43mmol),Pd/C(1.50g,10%),MeOH(100mL)的混合物室温下搅拌过夜。通过LCMS监测反应。过滤混合物后真空条件下浓缩滤液得到题述化合物(6.50g)为棕色固体,不用进一步纯化可直接用于下一步。LCMS[M+H]+=265.42。
步骤3:3-(2-氧代基-1,2-二氢-3H-咪唑并[4,5-b]吡啶-3-基)氮杂环丁烷-1-乙酸叔丁基酯的制备
将3-((3-氨基吡啶-2-基)氨基)氮杂环丁烷-1-乙酸叔丁基酯(5.20g,19.67mmol),DMF(25mL),和1,1'-羰基二咪唑(9.57g,59.02mmol)的混合物65℃下搅拌过夜。使用LCMS监控反应。将反应冷却至室温。反应混合物乙酸乙酯稀释,水洗涤,无水硫酸钠干燥,过滤。真空条件下浓缩滤液。残余物通过硅胶色谱(己烷:乙酸乙酯=2:1)洗脱纯化得到题述化合物(4.25g)为棕色泡沫。LCMS[M+H]+=235.34。
步骤4:3-(2-氧代基-1-(4-(三氟甲基)苯基)-1,2-二氢-3H-咪唑并[4,5-b]吡啶-3-基)氮杂环丁烷-1-乙酸叔丁基酯的制备
在氧气条件下3-(2-氧代基-1,2-二氢-3H-咪唑并[4,5-b]吡啶-3-基)氮杂环丁烷-1-乙酸叔丁基酯(3.52g,12.12mmol),(4-(三氟甲基)苯基)硼酸(4.61g,24.25mmol),TEA(6.13g,60.62mmol),Cu(OAc)2(2.20g,12.12mmol),4A粉状分子筛(7.0g)和DCM(40mL)室温下搅拌8小时。通过LCMS监测反应。混合物通过硅藻土过滤,滤饼用DCM洗涤。滤液用盐水洗涤,无水硫酸钠干燥后过滤。真空条件下浓缩滤液。残余物通过硅胶色谱(己烷:乙酸乙酯=2:1)洗脱纯化得到题述化合物(5.50g)为黄色固体。LCMS[M+H]+=379.42。
步骤5:3-(氮杂环丁烷-3-基)-1-(4-(三氟甲基)苯基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮的制备
将3-(2-氧代基-1-(4-(三氟甲基)苯基)-1,2-二氢-3H-咪唑并[4,5-b]吡啶-3-基)氮杂环丁烷-1-乙酸叔丁基酯酯(5.50,12.66mmol),TFA(28.0mL)和DCM(60mL)的混合物室温下搅拌8小时。使用LCMS监控反应。真空条件下浓缩反应混合物。残余物溶解在二氯甲烷中,用饱和碳酸钠溶液调节pH值至10。混合物用二氯甲烷萃取,盐水洗涤,无水硫酸钠干燥,过滤。真空条件下浓缩滤液得到题述化合物(4.50g)为黄色固体,不用进一步纯化可直接用于下一步。LCMS[M+H]+=335.31。
步骤6:1 3-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-1-(4-(三氟甲基)苯基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮的制备
将2-氟丙烯酸(1.82g,20.19mmol),DCM(45mL),DIPEA(5.22g,40.38mmol),HATU(4.50g,40.38mmol),和3-(氮杂环丁烷-3-基)-1-(4-(三氟甲基)苯基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮(4.50g,13.46mmol)的混合物室温下搅拌2小时。使用LCMS监控反应。混合物用二氯甲烷稀释,水洗涤,无水硫酸钠干燥,过滤。真空条件下浓缩滤液。残余物通过硅胶色谱(己烷:乙酸乙酯=2:1)洗脱纯化得到题述化合物(3.40g)为白色固体。
LCMS[M+H]+=407.46。
1H NMR(500MHz,DMSO-d6)δ8.13(dd,J=5.2,1.4Hz,1H),7.96(d,J=8.7Hz,2H),7.86(d,J=8.3Hz,2H),7.58(dd,J=7.8,1.4Hz,1H),7.21–7.11(m,1H),5.62–5.43(m,2H),5.34(dd,J=16.5,3.4Hz,1H),5.10–5.01(m,1H),4.83–4.67(m,2H),4.47–4.35(m,1H)。
实施例231化合物231(1-(3-(2-亚胺-3-(4-(三氟甲基)苯基)-2,3-二氢-1H-苯并[d]咪唑并l-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮)的合成
步骤1:1-(4-(三氟甲基)苯基)-1,3-二氢-2H-苯并[d]咪唑并l-2-亚胺的制备
将3H-苯并咪唑并l-2-胺(1.00g,7.51mmol),4[4-(三氟甲基)苯基]硼酸(1.71g,9.01mmol),Cu(OAc)2(0.27g,1.50mmol),TEA(3.13mL,22.53mmol)在DCM(10mL)中的混合物室温下搅拌4小时。过滤反应混合物。真空条件下浓缩滤液。残余物通过硅胶色谱使用乙酸乙酯的正己烷溶液(0%-50%)洗脱纯化得到题述产品(1.50g,72%)为棕色固体。LCMS[M+H]+=278.25。
步骤2:3-(2-亚胺-3-(4-(三氟甲基)苯基)-2,3-二氢-1H-苯并[d]咪唑并l-1-基)氮杂环丁烷-1-乙酸叔丁基酯的制备
将1-(4-(三氟甲基)苯基)-1,3-二氢-2H-苯并[d]咪唑并l-2-亚胺(0.10g,0.36mmol),叔丁基-3-碘氮杂环丁烷-1-乙酸叔丁基酯(0.12g,0.43mmol),Cs2CO3(0.23g,0.72mmol)在DMF(3mL)中的混合物100℃时搅拌4小时。反应冷却至室温加水淬灭反应。使用乙酸乙酯萃取混合物,盐水洗涤,无水硫酸钠干燥后过滤。真空条件下浓缩滤液。残余物通过硅胶色谱使用乙酸乙酯的正己烷溶液(0%-30%)洗脱纯化得到题述化合物(80mg,51%)为棕色固体。LCMS[M+H]+=433.45。
步骤3:1-(氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1,3-二氢-2H-苯并[d]咪唑并l-2-亚胺的制备
将3-(2-亚胺-3-(4-(三氟甲基)苯基)-2,3-二氢-1H-苯并[d]咪唑并l-1-基)氮杂环丁烷-1-乙酸叔丁基酯(80mg,0.18mmol),DCM(5mL),和TFA(0.14mL,1.85mmol)的混合物室温下搅拌1小时。用碳酸钠水溶液调节pH值,用二氯甲烷萃取,盐水洗涤,无水硫酸钠干燥后过滤。真空条件下浓缩滤液得到题述化合物(50mg)为黄色固体,不用进一步纯化可直接用于下一步。LCMS[M+H]+=333.33。
步骤4:1-(3-(2-亚胺-3-(4-(三氟甲基)苯基)-2,3-二氢-1H-苯并[d]咪唑并l-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮的制备
0℃时在氮气条件下将丙烯酰氯(16.30mg,0.18mmol)逐滴加入至含有1-(氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1,3-二氢-2H-苯并[d]咪唑并l-2-亚胺(50.00mg,0.15mmol),TEA(0.04mL,0.30mmol),和DCM(4mL)的溶液中。反应液在室温下搅拌0.5小时。加水淬灭反应。混合物用二氯甲烷萃取。有机相用盐水洗涤,无水硫酸钠干燥后过滤。真空条件下浓缩滤液。残余物通过制备型薄层色谱(己烷/EA=2/1)纯化得到题述产物(3.00mg,5%)为类白色固体。LCMS[M+H]+=387.38。
使用不同的反应起始物和合适的试剂通过与实施例1-235类似的方法制备得到表2中的化合物。
表2
实施例254化合物254(N-(1-(2-(4-(三氟甲基)苯基)喹唑啉-4-基)吡咯烷-3-基)丙烯酰胺)的合成
步骤1:(1-(2-氯喹唑啉-4-基)吡咯烷-3-基)氨基甲酸叔丁基酯的制备
将2,4-二氯喹唑啉(1.00g,5.02mmol)和3-氨基氮杂环丁烷-1-羧酸叔丁基酯(0.65g,3.77mmol),碳酸盐(1.40g,7.54mmol)和DMF(10mL)的混合物45℃搅拌3小时。使用LCMS监控反应。反应物通过乙酸乙酯稀释,倒入冰水中。分离有机相,无水硫酸钠干燥后,过滤。滤液在真空下浓缩得到题述化合物(1.30g)为黄色固体。LCMS[M+H]+=293.12。
步骤2:(1-(2-(4-(三氟甲基)苯基)喹唑啉-4-基)吡咯烷-3-基)氨基甲酸叔丁基酯的制备
氮气条件下将(1-(2-氯喹唑啉-4-基)吡咯烷-3-基)氨基甲酸叔丁基酯(1.30g,3.73mmol),(4-(三氟甲基)苯基)硼酸(1.06g,5.59mmol),Pd(dppf)Cl2.CH2Cl2(303mg,0.37mmol),碳酸铯(3.64g,11.18mmol),1,4-二氧六环(20mL)和水(2.0mL)的混合物100℃搅拌6小时。使用LCMS监控反应。反应冷却至室温。真空条件下浓缩混合物。残余物通过硅胶柱(Hex:EA=0%-30%)洗脱纯化得到题述化合物(1.30g)为类白色固体。LCMS[M+H]+=403.42。
步骤3:1-(2-(4-(三氟甲基)苯基)喹唑啉-4-基)吡咯烷-3-胺的制备
将(1-(2-(4-(三氟甲基)苯基)喹唑啉-4-基)吡咯烷-3-基)氨基甲酸叔丁基酯(500mg,1.09mmol),TFA(5mL)和DCM(20mL)的混合物室温搅拌4小时。使用LCMS监控反应。反应混合物真空下浓缩得到题述化合物(600mg)为类白色固体,可不经进一步纯化用于下一步骤。LCMS[M+H]+=359.26。
步骤4:N-(1-(2-(4-(三氟甲基)苯基)喹唑啉-4-基)吡咯烷-3-基)丙烯酰胺的制备
0℃时在氮气条件下在搅拌中将丙烯酰氯(76mg,0.83mmol)加入含有1-(2-(4-(三氟甲基)苯基)喹唑啉-4-基)吡咯烷-3-胺(300mg,0.83mmol),碳酸氢钠(350mg,4.19mmol),DCM(20mL)和水(10mL)的混合物中。混合物在0℃搅拌30分钟。使用LCMS监控反应。反应混合物用二氯甲烷洗涤,水洗,无水硫酸钠干燥,过滤。滤液在真空下浓缩。残余物通过硅胶柱(正己烷:乙酸乙酯=2:1)洗脱纯化得到题述化合物(113mg)为类白色固体。
LCMS[M+H]+=413.33。
1H NMR(500MHz,DMSO-d6)δ8.68(d,J=8.1Hz,2H),8.50(d,J=6.6Hz,1H),8.31(d,J=8.4Hz,1H),7.90–7.84(m,3H),7.81(t,J=7.6Hz,1H),7.51(ddd,J=8.5,6.7,1.6Hz,1H),6.23(dd,J=17.1,9.9Hz,1H),6.13(dd,J=17.1,2.4Hz,1H),5.62(dd,J=10.0,2.5Hz,1H),4.52(p,J=5.5Hz,1H),4.26(dd,J=11.8,6.0Hz,1H),4.15(q,J=7.7,5.8Hz,1H),4.12–4.03(m,1H),3.89(dd,J=11.6,4.0Hz,1H),2.27(pd,J=9.2,8.4,5.5Hz,1H),2.06(dq,J=11.8,5.5Hz,1H)。
实施例255化合物255(2-氟-1-(3-((2-(4-(三氟甲基)苯基)喹唑啉-4-基)氨基)氮杂环丁烷-1-基)丙-2-烯-1-酮)的合成
步骤1:3-((2-氯喹唑啉-4-基)氨基)氮杂环丁烷-1-羧酸叔丁基酯的制备
将2,4-二氯喹唑啉(500mg,2.51mmol)和吡咯烷-3-基氨基甲酸叔丁基酯(4.91g,15.07mmol),碳酸钾(1.04g,7.54mmol)和DMF(10mL)的混合物室温搅拌3小时。使用LCMS监控反应。反应用乙酸乙酯洗涤后,倒入冰水中。分离有机相,无水硫酸钠干燥后,过滤。滤液在真空下浓缩得到题述化合物(0.80g)为黄色固体。LCMS[M+H]+=335.54。
步骤2:3-((2-(4-(三氟甲基)苯基)喹唑啉-4-基)氨基)氮杂环丁烷-1-羧酸叔丁基酯的制备
在氮气条件下将3-((2-氯喹唑啉-4-基)氨基)氮杂环丁烷-1-羧酸叔丁基酯(0.80g,2.39mmol),(4-(三氟甲基)苯基)硼酸(0.68g,3.58mmol),Pd(dppf)Cl2.CH2Cl2(0.20mg,0.24mmol),碳酸钾(0.99g,7.17mmol),1,4-二氧六环(20mL)和水(2.0mL)的混合物100℃搅拌6小时。使用LCMS监控反应。反应冷却至室温。真空条件下浓缩混合物。残余物通过硅胶柱(Hex:EA=0%-30%)洗脱纯化得到题述化合物(0.75g)为类白色固体。LCMS[M+H]+=445.43。
步骤3:N-(氮杂环丁烷-3-基)-2-(4-(三氟甲基)苯基)喹唑啉-4-胺的制备
将3-((2-(4-(三氟甲基)苯基)喹唑啉-4-基)氨基)氮杂环丁烷-1-羧酸叔丁基酯(750mg,1.69mmol),TFA(5mL)和DCM(20mL)的混合物室温搅拌4小时。使用LCMS监控反应。反应混合物真空下浓缩得到题述化合物(600mg)为黄色油状物质,不经进一步纯化直接用于下一步骤。LCMS[M+H]+=345.35。
步骤4:2-氟-1-(3-((2-(4-(三氟甲基)苯基)喹唑啉-4-基)氨基)氮杂环丁烷-1-基)丙基-2-烯-1-酮的制备
向N-(氮杂环丁烷-3-基)-2-(4-(三氟甲基)苯基)喹唑啉-4-胺(300mg,0.87mmol),N,N-二异丙基乙胺(563mg,4.36mmol),2-氟丙烯酸(118mg,1.31mmol)和DMF(5mL)的混合物中搅拌加入HATU(663mg,1.74mmol),反应液室温搅拌2小时。使用LCMS监控反应。反应混合物用乙酸乙酯稀释,水洗,无水硫酸钠干燥,过滤。真空下浓缩滤液。残余物经硅胶柱(正己烷:乙酸乙酯=1.5:1)洗脱纯化得到题述化合物(57mg)为类白色固体。
LCMS[M+H]+=417.43。
1H NMR(500MHz,CDCl3)δ8.62(d,J=8.1Hz,2H),7.98–7.96(m,1H),7.92(d,J=8.2Hz,1H),7.82–7.79(m,1H),7.74(d,J=8.2Hz,2H),7.52(t,J=7.6Hz,1H),6.62(m,1H),5.71–5.41(m,1H),5.22–5.10(m,1H),5.00–4.86(m,1H),4.69–4.45(m,2H),4.31–3.97(m,1H),3.67–3.31(m,1H)。
实施例256化合物256(2-氟-1-(3-(2-(4-(三氟甲基)苯基)喹唑啉-4-基)氮杂环丁烷-1-基)丙-2-烯-1-酮)的合成
步骤1:3-(羟基(2-硝基苯基)甲基)氮杂环丁烷-1-乙酸叔丁基酯的制备
-60℃时在氮气条件下向1-碘-2-硝基苯(3.00g,12.05mmol)的THF(50mL)溶液逐滴加入pHMgCl(7.23mL,2.00mol/L,14.46mmol)。反应在-60℃时搅拌30分钟。然后将3-甲酰基氮杂环丁烷-1-羧酸叔丁基酯(2.68g,14.46mmol)的THF(6mL)溶液加入至反应中。混合物升温至室温后继续搅拌1小时。通过LCMS监测反应。加入饱和NH4Cl溶液以淬灭反应。用乙酸乙酯萃取混合物,盐水洗涤,无水硫酸钠干燥,过滤。真空条件下浓缩滤液。残余物通过硅胶色谱(EA:Hex=0-50%)洗脱纯化得到题述化合物(3.65g,98%)为黄色固体。LCMS[M+H]+=309.14。
步骤2:3-(2-硝基苯甲酰)氮杂环丁烷-1-羧酸叔丁基酯的制备
0℃在氮气条件下将戴斯-马丁试剂(6.62g,15.60mmol)加入正在搅拌中的3-(羟基(2-硝基苯基)甲基)氮杂环丁烷-1-羧酸叔丁基酯(3.7g,2.00mmol)的DCM(50mL)溶液中。反应在室温下搅拌2小时。通过LCMS监测反应。加入饱和碳酸氢钠水溶液和饱和硫代硫酸钠水溶液来淬灭反应。混合物用二氯甲烷萃取,盐水洗涤,无水硫酸钠干燥,过滤。真空条件下浓缩滤液。残余物通过硅胶色谱(EA:Hex=0-30%)洗脱纯化得到题述化合物(3.4g,92.5%)为为黄色油状物体。LCMS[M+H]+=307.12。
步骤3:3-(2-氨氨基苯甲酰基)氮杂环丁烷-1-羧酸叔丁基酯的制备
将3-(2-硝基苯甲酰)氮杂环丁烷-1-羧酸叔丁基酯(3.40g,11.10mmol),铁粉(3.10g,55.50mmol),和NH4Cl(2.97g,55.50mmol)在EtOH(20mL)和水(5mL)中的混合物80℃时搅拌3小时。通过LCMS监测反应。反应混合物冷却至室温后通过硅藻土垫过滤。真空条件下浓缩滤液。残余物通过硅胶柱色谱(EA:Hex=0-70%)洗脱纯化得到题述化合物(2.2g,72%)为黄色油状物体。LCMS[M+H]+=277.15。
步骤4:3-(2-(4-(三氟甲基)苯基)喹唑啉-4-基)氮杂环丁烷-1-羧酸叔丁基酯的制备
将3-(2-氨基苯并yl)氮杂环丁烷-1-羧酸叔丁基酯(600mg,2.17mmol),2-氨基-2-(4-(三氟甲基)苯基)醋酸(714mg,3.26mmol),I2(138mg,1.09mmol),和2-氢过氧甲氧基-2-甲基丙烷(TBHP)(391mg,4.34mmol)在DMA(15mL)中的混合物80℃下搅拌14小时。通过LCMS监测反应。加入水和乙酸乙酯淬灭反应。合并的有机相用盐水洗涤,无水硫酸钠干燥,过滤。真空条件下浓缩滤液。残余物通过硅胶色谱(EA:Hex=0-30%)洗脱纯化得到题述化合物(610mg,65%)为为黄色油状物体。LCMS[M+H]+=430.17。
步骤5:4-(氮杂环丁烷-3-基)-2-(4-(三氟甲基)苯基)喹唑啉的制备
将3-(2-(4-(三氟甲基)苯基)喹唑啉-4-基)氮杂环丁烷-1-羧酸叔丁基酯(610mg,1.42mmol),二氯甲烷(5mL),和TFA(1mL,14.21mmol)的混合物室温下搅拌6小时。真空条件下浓缩混合物。残余物溶解在二氯甲烷中。用碳酸钾水溶液调节溶液pH值至10。混合物用二氯甲烷萃取,盐水洗涤,无水硫酸钠干燥后过滤。真空条件下浓缩滤液得到题述化合物(460mg)为黄色固体,其不用纯化可直接用于下一步。LCMS[M+H]+=330.11。
步骤6:2-氟-1-(3-(2-(4-(三氟甲基)苯基)喹唑啉-4-基)氮杂环丁烷-1-基)丙-2-烯-1-酮的制备
将4-(氮杂环丁烷-3-基)-2-(4-(三氟甲基)苯基)喹唑啉(460mg,1.40mmol),2-氟丙烯酸(377mg,4.19mmol),DIEA(1.39mL,8.38mmol),二氯甲烷(10mL),DMF(2mL),和1H-苯并三唑-1-基甲氧基三(二甲基氨基)六氟磷酸鏻(BOP)(741mg,1.68mmol)的混合物室温下搅拌3小时。通过LCMS监测反应。反应液中加入水和乙酸乙酯淬灭反应。合并的有机相用盐水洗涤,无水硫酸钠干燥,过滤。真空条件下浓缩滤液。残余物通过硅胶色谱(EA:Hex=0–100%)洗脱纯化得到题述化合物(124mg,22%)为白色固体。
LCMS[M+H]+=402.12。
1H NMR(500MHz,DMSO-d6)δ8.80(d,J=8.0Hz,2H),8.15(d,J=9.7Hz,2H),8.07(t,J=7.6Hz,1H),7.97(d,J=8.4Hz,2H),7.79(t,J=7.6Hz,1H),5.53(dd,J=48.5,3.5Hz,1H),5.34(dd,J=16.6,3.5Hz,1H),5.03–4.95(m,2H),4.87(s,1H),4.68–4.51(m,2H)。
实施例257化合物257(2-氟-1-(3-(4-(4-(三氟甲基)苯基)喹唑啉-2-基)氮杂环丁烷-1-基)丙-2-烯-1-酮)的合成
步骤1:3-((2-氨基甲酰基苯基)氨基甲酰基)氮杂环丁烷-1-羧酸叔丁基酯的制备
10℃条件下向2-氨基苯甲酰胺(4.05g,33.05mmol),DIPEA(8.54g,66.10mmol),1-(叔丁基甲氧基羰基)氮杂环丁烷-3-羧酸(4.66g,23.14mmol),和DCM(20mL)的混合物中一边搅拌一边加入HATU(12.57g,33.05mmol)。混合物在室温下搅拌1小时。通过LCMS监测反应。反应液二氯甲烷稀释,倒入冰水中分离有机相,无水硫酸钠干燥,过滤。真空条件下浓缩滤液。残余物通过硅胶色谱(己烷:EA=3:1)洗脱纯化得到题述化合物(7.82g)为白色固体。LCMS[M+H]+=320.45。
步骤2:3-(4-氧代基-3,4-二氢喹唑啉-2-基)氮杂环丁烷-1-羧酸叔丁基酯的制备
氮气条件下将3-((2-氨基甲酰基苯基)氨基甲酰基)氮杂环丁烷-1-羧酸叔丁基酯(3.00g,9.39mmol),碳酸钾(12.98g,93.94mmol),和EtOH(20mL)的混合物60℃搅拌6小时。通过LCMS监测反应。将反应冷却至室温。真空条件下浓缩混合物。残余物中加入冰水后用稀盐酸调节pH值为4~5,然后过滤。滤饼水洗后真空干燥得到题述化合物(2.32g)为白色固体,不用进一步纯化可直接用于下一步。LCMS[M+H]+=246.42。
步骤3:3-(4-(((三氟甲基)磺酰基)甲氧基)喹唑啉-2-基)氮杂环丁烷-1-羧酸叔丁基酯的制备
0℃在氮气条件下向3-(4-氧代基-3,4-二氢喹唑啉-2-基)氮杂环丁烷-1-羧酸叔丁基酯(1.50g,4.98mmol),碳酸钾(1.93g,14.93mmol),和NMP(5.0mL)的混合物中一边搅拌一边加入1,1,1-三氟-N-苯基-N-((三氟甲基)磺酰基)甲磺酰胺(2.67g,7.74mmol)。混合物室温下搅拌2小时。使用LCMS监控反应。反应混合物乙酸乙酯稀释,水洗涤,无水硫酸钠干燥,过滤。真空条件下浓缩滤液。残余物通过硅胶色谱(己烷:EA=4:1)洗脱纯化得到题述化合物(1.60g)为黄色油状物体。LCMS[M+H]+=378.26。
步骤4:3-(4-(4-(三氟甲基)苯基)喹唑啉-2-基)氮杂环丁烷-1-羧酸叔丁基酯的制备
100℃在氮气条件下将3-(4-(((三氟甲基)磺酰基)甲氧基)喹唑啉-2-基)氮杂环丁烷-1-羧酸叔丁基酯(1.60g,3.69mmol),(4-(三氟甲基)苯基)硼酸(1.05g,5.54mmol),Pd(dppf)Cl2.CH2Cl2(300mg,0.37mmol),碳酸钾(1.53g,11.08mmol),1,4-二氧六环(20mL),和水(2.0mL)的混合物搅拌6小时。通过LCMS监测反应。将反应冷却至室温。真空条件下浓缩混合物。残余物通过硅胶色谱洗脱纯化(正己烷:EA=3:1)得到题述化合物(1.40g)为无色油状物质。LCMS[M+H]+=374.44。
步骤5:2-(氮杂环丁烷-3-基)-4-(4-(三氟甲基)苯基)喹唑啉的制备
将3-(4-(4-(三氟甲基)苯基)喹唑啉-2-基)氮杂环丁烷-1-羧酸叔丁基酯(1.40g,3.26mmol),TFA(7.0mL),和DCM(28mL)的混合物室温下搅拌8小时。使用LCMS监控反应。真空下浓缩反应混合物。残余物用二氯甲烷溶解,并用饱和碳酸钠水溶液调节溶液pH值为10。混合物用二氯甲烷萃取,盐水洗涤,无水硫酸钠干燥,过滤。真空条件下浓缩滤液得到题述化合物(0.92g)为无色油状物质,不用进一步纯化可直接用于下一步。LCMS[M+H]+=330.23。
步骤6:2-氟-1-(3-(4-(4-(三氟甲基)苯基)喹唑啉-2-基)氮杂环丁烷-1-基)丙-2-烯-1-酮的制备
将2-(氮杂环丁烷-3-基)-4-(4-(三氟甲基)苯基)喹唑啉(900mg,2.73mmol),DIPEA(1.06g,8.20mmol),DCM(20mL),2-氟丙烯酸(370mg,4.10mmol),和HATU(1.04g,2.73mmol)的混合物室温下搅拌1小时。使用LCMS监控反应。反应混合物乙酸乙酯稀释,水洗涤,无水硫酸钠干燥,过滤。真空条件下浓缩滤液。残余物通过硅胶色谱(Hex:EA=2:1)洗脱纯化得到题述化合物(55mg)为白色固体。
LCMS[M+H]+=402.43。
1H NMR(500MHz,DMSO-d6)δ8.27–7.86(m,7H),7.75(ddd,J=8.3,6.7,1.4Hz,1H),5.50(dd,J=48.5,3.5Hz,1H),5.32(dd,J=16.6,3.5Hz,1H),4.86(td,J=8.9,8.5,4.0Hz,1H),4.81–4.69(m,1H),4.47(t,J=9.3Hz,1H),4.44–4.29(m,2H)。
使用不同的反应起始物料和合适的试剂通过与实施例1-257类似的方法制备表3中的化合物。
表3
实施例307化合物307(2-氟-1-(3-(3-(苯基乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮)的合成
步骤1:3-(3-(苯基乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-羧酸叔丁基酯的制备
在氮气条件下将3-(3-碘-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-羧酸叔丁基酯(0.40g,1mmol),苯乙炔(0.20g,2mmol),DIEA(0.50mL,3mmol),Pd(PpH3)4(0.12g,0.1mmol),CuI(0.08g,0.4mmol),1,4-二氧六环(40mL)的混合物100℃搅拌4小时。真空条件下浓缩混合物得到残余物,残余物水洗3次,盐水洗涤1次,有机相在真空下浓缩。残余物经硅胶柱(DCM:MeOH=30:1)洗脱纯化得到题述化合物(0.50g)为淡黄色固体。LCMS[M+H]+=375.17。
步骤2:1-(氮杂环丁烷-3-基)-3-(苯基乙炔基)-1H-吡唑并[3,4-b]吡啶的制备
将3-(3-(苯基乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-羧酸叔丁基酯(0.37g,1mmol),TFA(5mL)和DCM(10mL)的混合物室温搅拌1小时。反应混合物真空下浓缩得到题述化合物,不经过进一步纯化直接用于下一步骤。LCMS[M+H]+=275.12。
步骤3:2-氟-1-(3-(3-(苯基乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙基-2-烯-1-酮的制备
将1-(氮杂环丁烷-3-基)-3-(苯基乙炔基)-1H-吡唑并[3,4-b]吡啶(0.18g,0.66mmol),2-氟丙烯酸(0.09g,1mmol),HATU(0.50g,1.32mmol),DIEA(0.55mL,3.3mmol),DCM(20mL)和DMF(1mL)的混合物室温搅拌过夜。反应混合物经水和盐水洗涤,无水硫酸钠干燥,过滤。滤液在真空下浓缩。残余物经硅胶柱用乙酸乙酯洗脱纯化得到题述化合物(0.08g)为类白色固体。
LCMS[M+H]+=347.12。
1H NMR(500MHz,CDCl3)δ8.58(dd,J=4.5,1.5Hz,1H),8.22(dd,J=8.0,1.5Hz,1H),7.68–7.62(m,2H),7.43–7.36(m,3H),7.27(dd,J=8.0,4.5Hz,1H),6.04–5.95(m,1H),5.69(dd,J=46.7,3.1Hz,1H),5.13(dd,J=15.6,3.1Hz,1H),5.10–5.03(m,1H),4.97–4.88(m,1H),4.76-4.70(m,1H),4.70–4.63(m,1H)。
实施例308化合物308((E)-2-氟-1-(3-(3-苯乙烯-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮)的合成
步骤1:(E)-3-(3-苯乙烯-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-羧酸叔丁基酯的制备
氮气条件下将3-(3-碘-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-羧酸叔丁基酯(0.50g,1.25mmol),(E)-4,4,5,5-四甲基-2-苯乙烯-1,3,2-二氧硼烷(0.43g,1.87mmol),Cs2CO3(1.22g,3.75mmol),Pd(dppf)Cl2CH2Cl2(0.10g,0.12mmol),1,4-二氧六环(20mL)和水(4mL)的混合物在10℃搅拌过夜。真空条件下浓缩混合物。残余物经硅胶柱(DCM:MeOH=30:1)洗脱纯化得到题述化合物(0.50g)。LCMS[M+H]+=377.19。
步骤2:(E)-1-(氮杂环丁烷-3-基)-3-苯乙烯-1H-吡唑并[3,4-b]吡啶的制备
将(E)-3-(3-苯乙烯-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-羧酸叔丁基酯(0.50g,1.33mmol),TFA(5mL)和DCM(10mL)的混合物室温搅拌1小时。反应混合物真空下浓缩得到题述化合物,不经进一步纯化直接用于下一步骤。LCMS[M+H]+=277.14。
步骤3:(E)-2-氟-1-(3-(3-苯乙烯-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙基-2-烯-1-酮的制备
室温下将含有(E)-1-(氮杂环丁烷-3-基)-3-苯乙烯-1H-吡唑并[3,4-b]吡啶(0.18g,0.66mmol),2-氟丙烯酸(0.09g,1mmol),HATU(0.50g,1.32mmol),DIEA(0.55mL,3.3mmol),DCM(20mL)和DMF(1mL)的混合物搅拌过夜。反应混合物经水和盐水洗涤,无水硫酸钠干燥,过滤。滤液在真空下浓缩。残余物经硅胶柱用乙酸乙酯洗脱纯化得到题述化合物(0.12g)为类白色固体。
LCMS[M+H]+=349.14。
1H NMR(500MHz,CDCl3)δ8.55(dd,J=4.5,1.4Hz,1H),8.37(dd,J=8.1,1.4Hz,1H),7.60(d,J=7.3Hz,2H),7.50(d,J=16.7Hz,1H),7.45–7.38(m,3H),7.32(t,J=7.3Hz,1H),7.24(dd,J=8.0,4.5Hz,1H),6.01–5.93(m,1H),5.70(dd,J=46.6,3.0Hz,1H),5.15(dd,J=15.6,3.0Hz,1H),5.08–5.00(m,1H),4.97–4.89(m,1H),4.78–4.71(m,1H),4.69–4.62(m,1H)。
使用不同的反应起始物料和合适的试剂通过与实施例1-308类似的方法制备表4中的化合物。
表4
化合物的1HNMR数据如下所示:
1H NMR(500MHz,CDCl3)δ8.59(dd,J=4.5,1.3Hz,1H),8.37(dd,J=8.1,1.3Hz,1H),8.11(d,J=8.1Hz,2H),7.78(d,J=8.1Hz,2H),7.28(dd,J=8.1,4.5Hz,1H),6.43(dd,J=17.0,1.7Hz,1H),6.30(dd,J=17.0,10.3Hz,1H),6.06–5.98(m,1H),5.76(dd,J=10.3,1.7Hz,1H),4.96–4.88(m,1H),4.83–4.75(m,2H),4.72–4.65(m,1H)。(化合物30)
1H NMR(500MHz,DMSO-d6)δ8.33(d,J=9.2Hz,1H),8.23(dt,J=8.2,1.4Hz,1H),8.17(d,J=8.1Hz,2H),8.00–7.80(m,3H),7.60(dd,J=7.1,2.8Hz,1H),7.35(ddd,J=8.5,7.0,1.6Hz,1H),6.62(ddd,J=41.2,16.8,10.3Hz,1H),6.16(dt,J=16.8,2.7Hz,1H),5.71–5.65(m,1H),4.17–4.03(m,1H),3.98–3.76(m,2H),3.74–3.51(m,1H),3.21–2.83(m,1H),2.61(dd,J=8.5,4.2Hz,1H),2.45–2.34(m,1H)。(化合物42)
1H NMR(500MHz,DMSO-d6)δ8.16(dd,J=8.4,4.1Hz,2H),7.99(dd,J=8.9,1.4Hz,1H),7.84(dd,J=8.4,3.8Hz,2H),7.35(dd,J=12.3,2.2Hz,1H),6.93(dd,J=8.9,2.2Hz,1H),6.18(ddd,J=16.7,5.3,2.5Hz,1H),5.70(ddd,J=28.7,10.3,2.5Hz,1H),5.57(dq,J=38.1,6.2Hz,1H),4.20–3.99(m,1H),3.99–3.93(m,1H),3.90(s,3H),3.86–3.78(m,2H),3.75–3.54(m,1H),2.54(d,J=7.1Hz,1H),2.45(qd,J=6.7,1.9Hz,1H)。(化合物54)
1H NMR(500MHz,CDCl3)δ8.58(dd,J=4.5,1.4Hz,1H),8.36(dd,J=8.1,1.4Hz,1H),8.12(d,J=8.1Hz,2H),7.78(d,J=8.2Hz,2H),7.27(dd,J=8.1,4.5Hz,1H),6.00–5.92(m,1H),5.49–5.42(m,2H),4.95–4.59(m,4H),2.01(s,3H)。(化合物73)
1H NMR(500MHz,DMSO)δ8.52(d,J=8.1Hz,2H),8.38(s,1H),7.89(d,J=8.3Hz,2H),6.08(m,1H),5.55(dd,J=48.4,3.5Hz,1H),5.36(dd,J=16.6,3.5Hz,1H),4.97–4.76(m,2H),4.60–4.43(m,2H),3.55(s,3H)。(化合物80)
1H NMR(500MHz,CDCl3)δ8.73(dd,J=4.3,1.2Hz,1H),8.69(d,J=8.1Hz,2H),7.82(dd,J=8.6,1.2Hz,1H),7.76(d,J=8.2Hz,2H),7.39(dd,J=8.6,4.3Hz,1H),6.45(dd,J=17.0,1.8Hz,1H),6.30(dd,J=17.0,10.3Hz,1H),5.78(dd,J=10.3,1.8Hz,1H),5.56-5.49(m,1H),4.96–4.86(m,1H),4.83–4.72(m,2H),4.72–4.64(m,1H)。(化合物82)
1H NMR(500MHz,CDCl3)δ8.73(dd,J=4.3,1.1Hz,1H),8.69(d,J=8.1Hz,2H),7.82(dd,J=8.6,1.0Hz,1H),7.77(d,J=8.2Hz,2H),7.39(dd,J=8.6,4.3Hz,1H),5.53–5.44(m,3H),4.97–4.83(m,1H),4.82–4.60(m,3H),2.02(s,3H)。(化合物87)
1H NMR(500MHz,DMSO-d6)δ9.13(dd,J=13.9,7.0Hz,1H),8.26(dd,J=8.3,2.3Hz,1H),8.22–8.05(m,2H),7.88(dd,J=8.5,2.6Hz,2H),7.56(dd,J=7.0,3.8Hz,1H),7.37(ddd,J=8.5,7.1,1.8Hz,1H),6.61(ddd,J=42.4,16.8,10.3Hz,1H),6.15(dt,J=16.8,3.0Hz,1H),5.68(ddd,J=12.4,10.2,2.4Hz,1H),5.58–5.40(m,1H),4.25–4.02(m,3H),3.96–3.75(m,2H),3.75–3.52(m,2H),2.59(td,J=16.9,14.5,7.5Hz,2H),2.43–2.31(m,2H),2.26–2.15(m,2H)。(化合物113)
1H NMR(500MHz,CDCl3)δ8.67(dd,J=4.3,1.3Hz,1H),8.65(d,J=8.1Hz,2H),8.17(dd,J=8.6,1.3Hz,1H),7.73(d,J=8.2Hz,2H),7.34(dd,J=8.6,4.3Hz,1H),6.29(dd,J=16.9,1.2Hz,1H),6.05(dd,J=16.9,10.3Hz,1H),5.66(dd,J=10.3,1.2Hz,1H),5.62(d,J=5.4Hz,1H),5.34–5.27(m,1H),4.45–4.35(m,1H),2.64–2.53(m,1H),2.40–2.20(m,3H),2.08–1.96(m,1H),1.95–1.83(m,1H)。(化合物119)
1H NMR(500MHz,CDCl3)δ8.69(dd,J=4.3,1.3Hz,1H),8.40(d,J=8.3Hz,2H),7.77(dd,J=8.6,1.3Hz,1H),7.34(dd,J=8.5,4.4Hz,1H),7.21(d,J=8.3Hz,2H),6.44(dd,J=17.0,1.8Hz,1H),6.29(dd,J=17.0,10.3Hz,1H),5.76(dd,J=10.3,1.8Hz,1H),5.53–5.45(m,1H),4.98–4.87(m,1H),4.80–4.71(m,2H),4.69–4.62(m,1H),2.00–1.93(m,1H),1.04–0.98(m,2H),0.80–0.74(m,2H)。(化合物120)
1H NMR(500MHz,CDCl3)δ8.04(d,J=8.1Hz,2H),8.00(d,J=9.0Hz,1H),7.72(d,J=8.2Hz,2H),6.58(d,J=9.0Hz,1H),6.40(dd,J=17.0,2.0Hz,1H),6.29(dd,J=17.0,10.2Hz,1H),5.79–5.73(m,1H),5.72(dd,J=10.2,1.9Hz,1H),4.99–4.92(m,1H),4.85–4.78(m,1H),4.74–4.67(m,1H),4.64–4.57(m,1H),3.19(s,6H)。(化合物121)
1H NMR(500MHz,CDCl3)δ9.34(d,J=1.3Hz,1H),8.63(dd,J=4.5,1.4Hz,1H),8.52(dd,J=8.1,1.5Hz,1H),8.36(dd,J=8.2,1.4Hz,1H),7.84(d,J=8.2Hz,1H),7.33(dd,J=8.2,4.5Hz,1H),6.44(dd,J=17.0,1.8Hz,1H),6.30(dd,J=17.0,10.3Hz,1H),6.07–5.99(m,1H),5.76(dd,J=10.3,1.8Hz,1H),4.95–4.85(m,1H),4.84–4.73(m,2H),4.72–4.65(m,1H)。(化合物123)
1H NMR(500MHz,CDCl3)δ8.58(dd,J=4.5,1.4Hz,1H),8.26(ddd,J=8.2,3.6,1.5Hz,1H),8.10(t,J=7.6Hz,1H),7.57(d,J=8.1Hz,1H),7.52(d,J=10.5Hz,1H),7.28–7.24(m,1H),6.42(dd,J=17.0,1.9Hz,1H),6.29(dd,J=17.0,10.3Hz,1H),6.03(dq,J=8.2,5.7Hz,1H),5.74(dd,J=10.3,1.9Hz,1H),4.93–4.87(m,1H),4.82–4.73(m,2H),4.71–4.64(m,1H)。(化合物127)
1H NMR(500MHz,CDCl3)δ8.73(dd,J=4.3,1.1Hz,1H),8.41(t,J=7.5Hz,1H),7.87(dd,J=8.6,1.1Hz,1H),7.59(d,J=8.1Hz,1H),7.52(d,J=10.1Hz,1H),7.41(dd,J=8.6,4.3Hz,1H),6.43(dd,J=17.0,1.8Hz,1H),6.29(dd,J=17.0,10.3Hz,1H),5.77(dd,J=10.3,1.8Hz,1H),5.61–5.53(m,1H),5.00–4.89(m,1H),4.84–4.76(m,1H),4.75–4.65(m,2H)。(化合物129)
1H NMR(500MHz,CDCl3)δ8.72(d,J=4.0Hz,1H),8.40(t,J=7.5Hz,1H),7.86(d,J=8.4Hz,1H),7.59(d,J=8.0Hz,1H),7.52(d,J=10.1Hz,1H),7.42(dd,J=8.5,4.3Hz,1H),5.71(dd,J=46.7,3.1Hz,1H),5.62–5.52(m,1H),5.17(dd,J=15.6,3.1Hz,1H),5.12–5.04(m,1H),5.03–4.93(m,1H),4.81–4.65(m,2H)。(化合物130)
1H NMR(500MHz,CDCl3)δ9.85(d,J=1.6Hz,1H),9.06(dd,J=8.2,1.5Hz,1H),8.74(dd,J=4.3,1.0Hz,1H),7.85(dd,J=8.6,0.9Hz,1H),7.81(d,J=8.1Hz,1H),7.42(dd,J=8.6,4.3Hz,1H),6.45(dd,J=17.0,1.8Hz,1H),6.30(dd,J=17.0,10.3Hz,1H),5.79(dd,J=10.3,1.8Hz,1H),5.59–5.50(m,1H),4.97–4.87(m,1H),4.86–4.77(m,1H),4.75–4.65(m,2H)。(化合物131)
1H NMR(500MHz,CDCl3)δ9.86(d,J=1.4Hz,1H),9.07(dd,J=8.2,1.4Hz,1H),8.74(dd,J=4.3,0.9Hz,1H),7.87–7.78(m,2H),7.42(dd,J=8.6,4.3Hz,1H),5.74(dd,J=46.7,3.1Hz,1H),5.61–5.50(m,1H),5.19(dd,J=15.6,3.1Hz,1H),5.10–4.94(m,2H),4.81–4.66(m,2H)。(化合物132)
1H NMR(500MHz,DMSO-d6)δ8.84(d,J=2.2Hz,1H),8.74(d,J=2.2Hz,1H),8.65(d,J=8.0Hz,2H),7.93(d,J=8.1Hz,2H),6.45(dd,J=16.9,10.3Hz,1H),6.21(dd,J=17.0,2.3Hz,1H),5.96(ddd,J=13.6,8.2,5.5Hz,1H),5.76(dd,J=10.3,2.3Hz,1H),5.00–4.65(m,2H),4.64–4.37(m,2H)。(化合物161)
1H NMR(500MHz,DMSO-d6)δ8.78–8.56(m,2H),8.27(d,J=8.1Hz,2H),7.89(d,J=8.2Hz,2H),7.43(dd,J=8.2,4.4Hz,2H),6.88(d,J=2.3Hz,1H),5.51(dd,J=48.5,3.6Hz,1H),5.36–5.21(m,2H),5.11–4.83(m,2H),4.63(d,J=11.0Hz,1H),3.20(d,J=3.9Hz,2H)。(化合物169)
1H NMR(500MHz,DMSO-d6)δ8.67–8.55(m,2H),8.00–7.91(m,2H),7.45–7.39(m,2H),7.36(dd,J=8.1,4.4Hz,1H),5.99(tt,J=8.2,5.5Hz,1H),5.57(dd,J=48.4,3.5Hz,1H),5.37(dd,J=16.6,3.5Hz,1H),5.02–4.80(m,2H),4.72–4.41(m,2H),3.05–2.81(m,1H),1.26(d,J=6.9Hz,6H)。(化合物171)
1H NMR(500MHz,DMSO-d6)δ8.98(s,1H),8.72–8.55(m,2H),8.22–8.17(m,1H),7.63–7.46(m,2H),7.40(dd,J=8.0,4.6Hz,1H),6.01(tt,J=8.3,5.5Hz,1H),5.57(dd,J=48.4,3.5Hz,1H),5.37(dd,J=16.6,3.5Hz,1H),5.02–4.81(m,2H),4.70–4.43(m,2H)。(化合物172)
1H NMR(500MHz,DMSO-d6)δ8.75–8.59(m,2H),8.31(d,J=8.4Hz,2H),8.20–8.00(m,2H),7.45(dd,J=8.0,4.5Hz,1H),6.07–6.00(m,1H),5.57(dd,J=48.4,3.5Hz,1H),5.37(dd,J=16.6,3.6Hz,1H),4.93(d,J=49.3Hz,2H),4.68–4.47(m,2H)。(化合物173)
1H NMR(500MHz,DMSO-d6)δ8.69–8.53(m,2H),8.43–8.24(m,2H),7.90–7.69(m,2H),7.41(dd,J=8.1,4.5Hz,1H),4.70–4.32(m,4H),4.07(dq,J=26.8,7.1Hz,3H)。(化合物176)
1H NMR(500MHz,DMSO-d6)δ8.74(dd,J=8.3,1.6Hz,1H),8.70(dd,J=4.5,1.5Hz,1H),8.59(dd,J=8.1,1.8Hz,1H),8.52(d,J=1.6Hz,1H),8.33(d,J=8.1Hz,1H),7.47(ddd,J=8.5,4.6,1.4Hz,1H),6.04(tt,J=8.4,5.5Hz,1H),5.57(dd,J=48.4,3.6Hz,1H),5.37(dd,J=16.4,3.6Hz,1H),5.08–4.80(m,2H),4.69–4.48(m,2H)。(化合物177)
1H NMR(500MHz,DMSO-d6)δ8.85–8.74(m,2H),8.69(dd,J=4.5,1.6Hz,1H),8.59(d,J=8.5Hz,1H),8.13(d,J=8.2Hz,1H),7.45(m 1.5Hz,1H),6.04(tt,J=8.5,5.4Hz,1H),5.58(m,1.4Hz,1H),5.38(m,1.4Hz,1H),5.08–4.77(m,2H),4.77–4.44(m,2H)。(化合物178)
1H NMR(500MHz,DMSO-d6)δ9.21(d,J=2.0Hz,1H),8.79(dd,J=8.2,1.5Hz,1H),8.68(dd,J=4.4,1.5Hz,1H),8.54(d,J=2.0Hz,1H),7.43(dd,J=8.2,4.5Hz,1H),5.97(tt,J=8.2,5.6Hz,1H),4.75–4.33(m,4H),4.10(q,J=7.0Hz,2H),1.22(t,J=7.0Hz,3H)。(化合物181)
1H NMR(500MHz,DMSO)δ8.69(d,J=3.9Hz,1H),8.35(dd,J=24.0,8.0Hz,2H),7.90(d,J=7.9Hz,1H),7.40(dd,J=7.8,4.5Hz,1H),6.04(s,1H),5.55(d,J=48.3Hz,1H),5.36(dd,J=16.5,2.9Hz,1H),5.00(s,1H),4.84(s,1H),4.64(t,J=9.4Hz,1H),4.51(s,1H),2.73(s,3H)。(化合物182)
1H NMR(500MHz,CDCl3-d3)δ9.13(s,1H),8.65–8.64(m,1H),8.36–8.35(m,1H),8.27–8.25(m,1H),7.36–7.34(m,1H),6.07–6.01(m,1H),5.77-5.67(m,1H),5.19–5.15(m,1H),5.06–5.50(m,2H),4.78–4.68(m,2H)。(化合物184)
1H NMR(500MHz,CDCl3-d3)δ8.22–8.21(m,1H),8.11–8.10(m,2H),7.77–7.76(m,2H),7.14–7.13(m,1H),6.04–5.98(m,1H),5.76–5.66(m,1H),5.17–5.13(m,1H),5.06–5.02(m,1H),4.96–4.92(m,1H),4.79–4.76(m,1H),4.70–4.66(m,1H),2.70(s,3H)。(化合物186)
1H NMR(500MHz,DMSO)δ9.49(d,J=2.2Hz,1H),8.75(ddd,J=14.9,9.3,2.0Hz,3H),8.35(d,J=8.2Hz,2H),8.16(dd,J=8.9,2.7Hz,1H),7.95(t,J=14.2Hz,2H),7.55–7.46(m,1H),7.34(d,J=9.0Hz,1H),5.89–5.66(m,1H),5.49(dd,J=15.8,3.8Hz,1H),3.94(s,3H)。(化合物188)
1H NMR(500MHz,DMSO-d6)δ9.96(s,1H),8.88–8.87(m,1H),8.79–8.78(m,2H),8.37–8.35(m,2H),8.32–8.30(m,1H),7.95–7.94(m,2H),7.77–7.75(m,1H),7.55–7.52(m,1H),6.72–6.66(m,1H),6.35-6.32(m,1H),5.86–5.84(m,1H)。(化合物189)
1H NMR(500MHz,DMSO)δ9.75(s,1H),9.02(d,J=8.3Hz,1H),8.89(d,J=2.2Hz,1H),8.80(d,J=2.2Hz,1H),8.13(d,J=8.2Hz,1H),6.00(dq,J=8.2,5.5Hz,1H),5.58(dd,J=48.4,3.5Hz,1H),5.38(dd,J=16.6,3.5Hz,1H),5.08–4.87(m,2H),4.70–4.54(m,2H)。(化合物298)
1H NMR(500MHz,DMSO)δ9.44(s,1H),8.71(d,J=8.2Hz,1H),8.62(d,J=8.3Hz,1H),8.04(d,J=8.2Hz,1H),7.33(d,J=8.3Hz,1H),6.12–5.92(m,1H),5.57(dd,J=48.4,3.4Hz,1H),5.37(dd,J=16.5,3.4Hz,1H),4.98(s,1H),4.86(s,1H),4.62(t,J=9.5Hz,1H),4.51(dd,J=10.5,5.2Hz,1H),2.66(s,3H)。(化合物199)
1H NMR(500MHz,DMSO-d6)δ8.75(s,1H),8.66–8.64(m,1H),8.31–8.30(m,2H),7.90–7.88(m,2H),6.02–6.00(m,1H),5.62–5.51(m,1H),5.39–5.35(m,1H),5.00–4.86(m,2H),4.64–4.51(m,2H)。(化合物202)
1H NMR(500MHz,DMSO-d6)δ7.79(q,J=8.4Hz,4H),5.55(d,J=45Hz,1H),5.37(d,J=15Hz,1H),5.32–5.25(m,1H),4.86–4.79(m,3H),4.71(q,J=6.1,5.4Hz,1H),4.48(t,J=9.4Hz,1H),4.37(dd,J=10.7,5.3Hz,1H),3.88(t,J=5.5Hz,2H),2.78(dt,J=7.0,3.3Hz,2H)。(化合物208)
1H NMR(500MHz,DMSO-d6)δ9.09(d,J=2.0Hz,1H),9.05(d,J=2.0Hz,1H),8.37(d,J=8.1Hz,2H),7.92(d,J=8.2Hz,2H),6.06(tt,J=8.3,5.4Hz,1H),5.58(d,J=45Hz,1H),5.38(dd,J=16.6,3.5Hz,1H),5.00(td,J=9.5,9.0,4.2Hz,1H),4.90(q,J=8.1,6.0Hz,1H),4.64(t,J=9.6Hz,1H),4.56(dd,J=10.9,5.4Hz,1H)。(化合物215)
1H NMR(500MHz,DMSO)δ8.54(m,2H),8.42(s,1H),7.89(d,J=8.2Hz,2H),6.11(m,1H),5.55(dd,J=48.4,3.5Hz,1H),5.36(dd,J=16.6,3.5Hz,1H),4.88(m,2H),4.52(m,2H),4.08(q,J=7.1Hz,2H),1.31(t,J=7.1Hz,3H)。(化合物218)
1H NMR(500MHz,DMSO-d6)δ8.57(d,J=8.2Hz,2H),8.42(s,1H),7.90(d,J=8.2Hz,2H),5.77(ddd,J=8.1,5.3,2.9Hz,1H),5.57(dd,J=48.4,3.6Hz,1H),5.38(dd,J=16.6,3.5Hz,1H),4.93(ddt,J=40.9,9.7,5.3Hz,2H),4.67–4.48(m,2H),4.03(s,3H)。(化合物223)
1H NMR(500MHz,DMSO-d6)δ8.53(d,J=8.1Hz,2H),7.88(d,J=8.2Hz,2H),6.07(ddd,J=8.1,5.3,2.8Hz,1H),5.55(dd,J=48.4,3.5Hz,1H),5.35(dd,J=16.6,3.6Hz,1H),4.99–4.72(m,2H),4.64–4.40(m,2H),3.56(s,3H),2.64(s,3H)。(化合物225)
1H NMR(400MHz,CDCl3)δ7.83-7.81(m,2H),7.70-7.68(m,2H),7.32(d,J=6MHz,1H),7.23-7.20(m,1H),7.17-7.16(m,2H),6.47(dd,J=1.4MHz,J=13.5MHz,1H),6.33-6.27(m,1H),5.78(dd,J=1.4MHz,J=8.3MHz,1H),5.54-5.48(m,1H),4.87-4.83(m,1H),4.71-4.68(m,2H),4.62-4.59(m,1H)。(化合物236)
1H NMR(500MHz,CDCl3)δ8.11-8.09(dd,J=1.0MHz,J=4.2MHz,1H),7.83-7.81(m,2H),7.71-7.69(m,2H),7.37(dd,J=1.0MHz,J=6.3MHz,1H),7.07-7.04(m,1H),5.69-5.60(m,1H),5.27-5.25(m,1H),5.13(dd,J=4.0MHz,J=12.0MHz,1H),4.98-4.96(m,1H),4.66-4.63(m,1H),4.41-4.38(m,1H),1.86(s,3H)。(化合物238)
1H NMR(500MHz,DMSO)δ8.16–8.11(m,1H),8.05(d,J=3.2Hz,1H),7.99(q,J=8.7Hz,4H),5.54(dd,J=48.5,3.5Hz,1H),5.45(dq,J=8.7,5.8Hz,1H),5.35(dd,J=16.6,3.5Hz,1H),5.05-4.97(m,1H),4.79(td,J=9.3,4.2Hz,1H),4.67(dd,J=10.6,5.8Hz,1H),4.43(t,J=9.7Hz,1H)。(化合物240)
1H NMR(500MHz,DMSO)δ9.20(d,J=2.2Hz,1H),8.50(dd,J=8.5,2.3Hz,1H),8.12-8.15(m,2H),8.09(d,J=3.3Hz,1H),5.55(dd,J=48.5,3.5Hz,1H),5.48-5.42(m,1H),5.36(dd,J=16.6,3.5Hz,1H),5.01(d,J=3.6Hz,1H),4.81(td,J=9.2,4.2Hz,1H),4.67(dd,J=10.7,5.8Hz,1H),4.45(t,J=9.7Hz,1H)。(化合物241)
1H NMR(500MHz,DMSO)δ8.01–7.93(m,3H),7.85(d,J=8.4Hz,2H),7.45(d,J=1.7Hz,1H),5.53(dd,J=48.5,3.5Hz,1H),5.43(ddd,J=14.7,7.3,4.4Hz,1H),5.34(dd,J=16.6,3.5Hz,1H),5.08–4.99(m,1H),4.76(td,J=9.3,4.2Hz,1H),4.68(dd,J=10.6,6.0Hz,1H),4.43–4.36(m,1H),2.31(s,3H)。(化合物244)
1H NMR(500MHz,DMSO-d6)δ8.55(dd,J=1.9,1.0Hz,1H),7.99(d,J=8.4Hz,2H),7.86(d,J=8.3Hz,2H),7.82(d,J=1.9Hz,1H),5.59–5.48(m,2H),5.35(dd,J=16.5,3.5Hz,1H),5.05(td,J=10.6,9.2,6.0Hz,1H),4.79(td,J=9.4,4.2Hz,1H),4.70(dd,J=10.7,5.9Hz,1H),4.47–4.40(m,1H)。(化合物245)
1H NMR(500MHz,DMSO-d6)δ7.97(d,J=8.7Hz,2H),7.84(d,J=8.3Hz,2H),7.62(d,J=8.1Hz,1H),7.22(dd,J=8.1,1.3Hz,1H),5.53(d,J=75Hz,1H),5.41(tt,J=8.8,5.7Hz,1H),5.34(d,J=20Hz,1H),5.00(dt,J=9.6,4.2Hz,1H),4.77(td,J=9.3,3.9Hz,1H),4.65(dd,J=10.8,5.8Hz,1H),4.45–4.37(m,1H)。(化合物252)
1H NMR(500MHz,DMSO-d6)δ8.32–8.11(m,1H),8.11–7.95(m,4H),7.87–7.67(m,2H),7.57–7.41(m,1H),6.40(dt,J=16.9,10.9Hz,1H),6.15(ddd,J=16.8,13.9,2.2Hz,1H),5.71(ddd,J=12.8,10.3,2.3Hz,1H),4.80–4.53(m,2H),4.50–4.26(m,3H)。(化合物294-310)
1H NMR(500MHz,CDCl3)δ8.56(dd,J=4.5,1.4Hz,1H),8.12(dd,J=8.0,1.4Hz,1H),7.24(dd,J=8.1,4.5Hz,1H),6.39(dd,J=17.0,1.8Hz,1H),6.25(dd,J=17.0,10.3Hz,1H),5.98–5.89(m,1H),5.72(dd,J=10.3,1.7Hz,1H),4.90–4.84(m,1H),4.75–4.68(m,1H),4.66–4.59(m,2H),3.29–3.19(m,1H),3.09–2.97(m,2H),2.95–2.80(m,2H)。(化合物309)
1H NMR(500MHz,CDCl3)δ8.52(dd,J=4.5,1.5Hz,1H),8.11(dd,J=8.0,1.5Hz,1H),7.20(dd,J=8.0,4.5Hz,1H),6.38(dd,J=17.0,1.8Hz,1H),6.24(dd,J=17.0,10.3Hz,1H),5.96–5.87(m,1H),5.71(dd,J=10.3,1.8Hz,1H),4.90–4.82(m,1H),4.73–4.66(m,1H),4.66–4.55(m,2H),1.60–1.52(m,1H),0.99–0.90(m,4H)。(化合物315)
1H NMR(500MHz,CDCl3)δ8.59(dd,J=4.5,1.5Hz,1H),8.18(dd,J=8.0,1.5Hz,1H),7.61(s,1H),7.53(s,1H),7.28(dd,J=8.1,4.5Hz,1H),6.41(dd,J=17.0,1.8Hz,1H),6.27(dd,J=17.0,10.3Hz,1H),6.03–5.94(m,1H),5.74(dd,J=10.3,1.8Hz,1H),4.94–4.84(m,1H),4.79–4.72(m,1H),4.71 4.61(m,2H),3.83(s,3H)。(化合物318)
1H NMR(500MHz,CDCl3)δ8.58(dd,J=4.5,1.4Hz,1H),8.22(dd,J=8.0,1.4Hz,1H),7.69–7.60(m,2H),7.45–7.35(m,3H),7.27(dd,J=8.0,4.5Hz,1H),6.40(dd,J=17.0,1.7Hz,1H),6.27(dd,J=17.0,10.3Hz,1H),6.03–5.92(m,1H),5.73(dd,J=10.3,1.7Hz,1H),4.96–4.87(m,1H),4.79–4.72(m,1H),4.71–4.59(m,2H)。(化合物319)
1H NMR(500MHz,CDCl3)δ8.53(dd,J=4.5,1.5Hz,1H),8.13(dd,J=8.0,1.5Hz,1H),7.21(dd,J=8.0,4.5Hz,1H),5.98-5.91(m,1H),5.67(dd,J=46.6,3.1Hz,1H),5.12(dd,J=15.6,3.1Hz,1H),5.06–4.99(m,1H),4.93–4.82(m,1H),4.71–4.57(m,2H),3.41–3.30(m,1H),2.46–2.28(m,4H),2.08–1.92(m,2H)。(化合物321)
1H NMR(500MHz,CDCl3)δ8.52(dd,J=4.5,1.4Hz,1H),8.11(dd,J=8.0,1.3Hz,1H),7.20(dd,J=8.0,4.5Hz,1H),5.98–5.88(m,1H),5.66(dd,J=46.6,3.0Hz,1H),5.12(dd,J=15.6,3.0Hz,1H),5.06–4.96(m,1H),4.93–4.83(m,1H),4.70–4.56(m,2H),1.61–1.52(m,1H),1.00–0.91(m,4H)。(化合物322)
1H NMR(500MHz,CDCl3)δ8.59(dd,J=4.5,1.5Hz,1H),8.17(dd,J=8.0,1.5Hz,1H),7.65(s,1H),7.53(s,1H),7.28(dd,J=8.1,4.5Hz,1H),6.03–5.95(m,1H),5.69(dd,J=46.7,3.1Hz,1H),5.14(dd,J=15.6,3.1Hz,1H),5.08–5.00(m,1H),4.98–4.88(m,1H),4.75–4.60(m,2H),3.83(s,3H)。(化合物323)
1H NMR(500MHz,CDCl3)δ8.53(dd,J=4.5,1.5Hz,1H),8.11(dd,J=8.0,1.5Hz,1H),7.21(dd,J=8.0,4.5Hz,1H),5.98–5.90(m,1H),5.67(dd,J=46.6,3.1Hz,1H),5.12(dd,J=15.6,3.1Hz,1H),5.07–4.99(m,1H),4.92–4.84(m,1H),4.72–4.65(m,1H),4.65–4.58(m,1H),2.76–2.67(m,1H),2.01–1.91(m,2H),1.86–1.74(m,2H),1.68–1.53(m,4H),1.45–1.34(m,2H)。(化合物325)
1H NMR(500MHz,CDCl3)δ8.56(dd,J=4.5,1.5Hz,1H),8.12(dd,J=8.0,1.5Hz,1H),7.24(dd,J=8.0,4.5Hz,1H),6.00–5.92(m,1H),5.68(dd,J=46.7,3.1Hz,1H),5.13(dd,J=15.6,3.1Hz,1H),5.06–4.98(m,1H),4.94–4.85(m,1H),4.70–4.60(m,2H),3.30–3.19(m,1H),3.10–2.98(m,2H),2.96–2.81(m,2H)。(化合物326)
1H NMR(500MHz,CDCl3)δ8.55(dd,J=4.5,1.3Hz,1H),8.37(dd,J=8.0,1.3Hz,1H),7.60(d,J=7.4Hz,2H),7.50(d,J=16.7Hz,1H),7.44–7.35(m,3H),7.32(t,J=7.3Hz,1H),7.24(dd,J=8.0,4.5Hz,1H),6.42(dd,J=17.0,1.8Hz,1H),6.30(dd,J=17.0,10.3Hz,1H),6.00–5.90(m,1H),5.74(dd,J=10.3,1.8Hz,1H),4.93–4.84(m,1H),4.78–4.68(m,2H),4.67–4.60(m,1H)。(化合物327)
1H NMR(500MHz,CDCl3)δ8.55(dd,J=4.5,1.5Hz,1H),8.10(dd,J=8.0,1.5Hz,1H),7.23(dd,J=8.0,4.5Hz,1H),6.39(dd,J=17.0,1.8Hz,1H),6.25(dd,J=17.0,10.3Hz,1H),5.98–5.89(m,1H),5.72(dd,J=10.3,1.8Hz,1H),4.92–4.83(m,1H),4.76–4.68(m,1H),4.67–4.56(m,2H),3.30–3.20(m,1H),2.64–2.52(m,1H),2.43–2.23(m,3H),2.23–2.04(m,2H)。(化合物328)
1H NMR(500MHz,CDCl3)δ8.55(dd,J=4.5,1.5Hz,1H),8.10(dd,J=8.0,1.5Hz,1H),7.23(dd,J=8.0,4.5Hz,1H),5.99-5.91(m,1H),5.68(dd,J=46.7,3.1Hz,1H),5.13(dd,J=15.6,3.1Hz,1H),5.05–4.98(m,1H),4.93–4.85(m,1H),4.70–4.59(m,2H),3.30–3.21(m,1H),2.64–2.52(m,1H),2.42–2.25(m,3H),2.22–2.03(m,2H)。(化合物329)
1H NMR(500MHz,CDCl3)δ8.50(dd,J=4.5,1.4Hz,1H),8.23(dd,J=8.1,1.4Hz,1H),7.16(dd,J=8.0,4.5Hz,1H),6.69–6.62(m,1H),6.58(dd,J=16.4,6.4Hz,1H),6.40(dd,J=17.0,1.9Hz,1H),6.27(dd,J=17.0,10.3Hz,1H),5.93–5.85(m,1H),5.72(dd,J=10.3,1.9Hz,1H),4.87–4.79(m,1H),4.74–4.55(m,3H),2.28–2.18(m,1H),1.92–1.85(m,2H),1.84–1.76(m,2H),1.75–1.67(m,1H),1.43–1.30(m,2H),1.29–1.19(m,3H)。(化合物330)
1H NMR(500MHz,CDCl3)δ8.49(dd,J=4.5,1.4Hz,1H),8.22(dd,J=8.0,1.4Hz,1H),7.16(dd,J=8.0,4.5Hz,1H),6.66(dd,J=16.5,0.7Hz,1H),6.58(dd,J=16.4,6.4Hz,1H),5.96–5.87(m,1H),5.68(dd,J=46.6,3.0Hz,1H),5.12(dd,J=15.6,3.0Hz,1H),5.04–4.95(m,1H),4.93–4.79(m,1H),4.74–4.66(m,1H),4.65–4.55(m,1H),2.29–2.18(m,1H),1.94–1.85(m,2H),1.84–1.76(m,2H),1.75–1.67(m,1H),1.42–1.31(m,2H),1.30–1.18(m,3H)。(化合物331)
1H NMR(500MHz,CDCl3)δ8.49(dd,J=4.5,1.3Hz,1H),8.15(dd,J=8.0,1.3Hz,1H),7.14(dd,J=8.0,4.5Hz,1H),6.75(d,J=16.1Hz,1H),6.40(dd,J=17.0,1.8Hz,1H),6.27(dd,J=17.0,10.3Hz,1H),6.17(dd,J=16.1,9.0Hz,1H),5.92–5.84(m,1H),5.72(dd,J=10.3,1.8Hz,1H),4.86–4.80(m,1H),4.73–4.63(m,2H),4.63–4.56(m,1H),1.71-1.62(m,1H),0.95–0.88(m,2H),0.66–0.59(m,2H)。(化合物332)
1H NMR(500MHz,CDCl3)δ8.48(dd,J=4.5,1.5Hz,1H),8.15(dd,J=8.1,1.5Hz,1H),7.14(dd,J=8.0,4.5Hz,1H),6.76(d,J=16.1Hz,1H),6.18(dd,J=16.1,9.1Hz,1H),5.94–5.86(m,1H),5.68(dd,J=46.6,3.0Hz,1H),5.12(dd,J=15.6,3.0Hz,1H),5.02–4.94(m,1H),4.92–4.82(m,1H),4.73–4.65(m,1H),4.65–4.57(m,1H),1.74–1.59(m,1H),0.95–0.88(m,2H),0.65–0.59(m,2H)。(化合物333)
1H NMR(500MHz,CDCl3)δ8.58(dd,J=4.5,1.4Hz,1H),8.21(dd,J=8.0,1.3Hz,1H),7.66–7.60(m,2H),7.29–7.24(m,1H),7.13–7.06(m,2H),6.04–5.95(m,1H),5.69(dd,J=46.7,3.1Hz,1H),5.13(dd,J=15.6,3.1Hz,1H),5.10–5.02(m,1H),4.97–4.88(m,1H),4.76–4.62(m,2H)。(化合物334)
1H NMR(500MHz,CDCl3)δ8.59(dd,J=4.5,1.5Hz,1H),8.21(dd,J=8.0,1.5Hz,1H),7.46–7.41(m,1H),7.40–7.32(m,2H),7.28(dd,J=8.0,4.5Hz,1H),7.15–7.09(m,1H),6.04–5.96(m,1H),5.69(dd,J=46.7,3.1Hz,1H),5.14(dd,J=15.6,3.1Hz,1H),5.10–5.03(m,1H),4.97–4.89(m,1H),4.75–4.63(m,2H)。(化合物335)
1H NMR(500MHz,CDCl3)δ8.59(dd,J=4.5,1.4Hz,1H),8.21(dd,J=8.0,1.4Hz,1H),7.64(d,J=1.6Hz,1H),7.53(d,J=7.5Hz,1H),7.39(d,J=8.2Hz,1H),7.33(t,J=7.8Hz,1H),7.28(dd,J=8.0,4.5Hz,1H),6.05–5.95(m,1H),5.69(dd,J=46.7,3.1Hz,1H),5.14(dd,J=15.6,3.0Hz,1H),5.10–5.02(m,1H),4.97–4.89(m,1H),4.75–4.62(m,2H)。(化合物337)
1H NMR(500MHz,CDCl3)δ8.59(dd,J=4.5,1.5Hz,1H),8.23(dd,J=8.0,1.5Hz,1H),7.91(s,1H),7.82(d,J=7.7Hz,1H),7.65(d,J=7.9Hz,1H),7.54(t,J=7.8Hz,1H),7.29(dd,J=8.0,4.5Hz,1H),6.00(dq,J=8.2,5.8Hz,1H),5.69(dd,J=46.7,3.1Hz,1H),5.14(dd,J=15.6,3.1Hz,1H),5.10–5.02(m,1H),4.98–4.88(m,1H),4.76–4.62(m,2H)。(化合物338)
1H NMR(500MHz,CDCl3)δ8.55(dd,J=4.5,1.4Hz,1H),8.34(dd,J=8.1,1.3Hz,1H),7.57(dd,J=8.6,5.4Hz,2H),7.46(d,J=16.6Hz,1H),7.31(d,J=16.6Hz,1H),7.23(dd,J=8.0,4.5Hz,1H),7.10(t,J=8.6Hz,2H),5.96(dq,J=8.3,5.8Hz,1H),5.70(dd,J=46.6,3.0Hz,1H),5.15(dd,J=15.6,3.0Hz,1H),5.06–4.98(d,J=4.5Hz,1H),4.96–4.88(m,1H),4.77–4.70(m,1H),4.69–4.62(m,1H)。(化合物339)
1H NMR(500MHz,CDCl3)δ8.55(dd,J=4.5,1.5Hz,1H),8.34(dd,J=8.1,1.5Hz,1H),7.50–7.43(m,1H),7.42–7.32(m,3H),7.31–7.27(m,1H),7.24(dd,J=8.1,4.5Hz,1H),7.04–6.97(m,1H),5.96(tt,J=8.3,5.8Hz,1H),5.70(dd,J=46.6,3.0Hz,1H),5.14(dd,J=15.6,3.1Hz,1H),5.07–4.99(m,1H),4.96–4.87(m,1H),4.78–4.70(m,1H),4.69–4.61(m,1H)。(化合物340)
1H NMR(500MHz,CDCl3)δ8.54(dd,J=4.5,1.4Hz,1H),8.37(dd,J=8.1,1.4Hz,1H),7.68(td,J=7.7,1.4Hz,1H),7.64(d,J=16.9Hz,1H),7.47(d,J=16.8Hz,1H),7.31–7.26(m,1H),7.24(dd,J=8.1,4.5Hz,1H),7.18(t,J=7.2Hz,1H),7.14–7.08(m,1H),5.96(tt,J=8.3,5.8Hz,1H),5.69(dd,J=46.6,3.0Hz,1H),5.14(dd,J=15.6,3.0Hz,1H),5.06–4.98(m,1H),4.96–4.86(m,1H),4.78–4.70(m,1H),4.69–4.63(m,1H)。(化合物341)
1H NMR(500MHz,DMSO-d6)δ8.82(dd,J=8.1,1.6Hz,1H),8.64(dd,J=4.5,1.5Hz,1H),8.04–7.92(m,2H),7.90–7.75(m,3H),7.71(d,J=16.8Hz,1H),7.41(dd,J=8.0,4.5Hz,1H),5.98(tt,J=8.5,5.3Hz,1H),5.57(dd,J=48.5,3.5Hz,1H),5.46–5.23(m,1H),5.07–4.72(m,2H),4.70–4.34(m,2H)。(化合物344)
1H NMR(500MHz,DMSO-d6)δ8.85(dd,J=8.1,1.7Hz,1H),8.64(dd,J=4.3,1.6Hz,1H),8.24–8.11(m,2H),7.86–7.71(m,2H),7.65(d,J=6.3Hz,2H),7.40(dd,J=8.1,4.5Hz,1H),5.98(tt,J=8.3,5.3Hz,1H),5.65–5.49(m,1H),5.38(dd,J=16.6,3.5Hz,1H),5.01–4.73(m,2H),4.66–4.41(m,2H)。(化合物345)
1H NMR(500MHz,DMSO-d6)δ8.70(dd,J=4.5,1.5Hz,1H),8.38(dd,J=8.1,1.5Hz,1H),7.81(td,J=7.5,1.8Hz,1H),7.64–7.50(m,1H),7.50–7.28(m,3H),6.00(tt,J=8.2,5.2Hz,1H),5.56(dd,J=48.4,3.6Hz,1H),5.37(dd,J=16.5,3.6Hz,1H),5.02–4.69(m,2H),4.69–4.28(m,2H)。(化合物347)
1H NMR(500MHz,DMSO-d6)δ8.70(dd,J=4.5,1.5Hz,1H),8.38(dd,J=8.1,1.4Hz,1H),7.85(dd,J=7.6,1.8Hz,1H),7.67(dd,J=7.9,1.3Hz,1H),7.60–7.29(m,3H),6.01(tt,J=8.3,5.3Hz,1H),5.57(dd,J=48.4,3.6Hz,1H),5.37(dd,J=16.5,3.5Hz,1H),5.06–4.66(m,2H),4.53(ddd,J=74.3,10.9,7.4Hz,2H)。(化合物348)
1H NMR(500MHz,DMSO-d6)δ8.71(dt,J=4.6,1.5Hz,1H),8.28(dd,J=8.0,1.5Hz,1H),8.00(d,J=7.7Hz,1H),7.90(d,J=7.9Hz,1H),7.80(t,J=7.6Hz,1H),7.75–7.61(m,1H),7.48(ddd,J=8.1,4.6,1.2Hz,1H),6.01(tt,J=8.3,5.3Hz,1H),5.64–5.45(m,1H),5.44–5.29(m,1H),5.04–4.74(m,2H),4.53(ddd,J=70.5,10.8,7.5Hz,2H)。(化合物349)
对比实施例
使用不同的反应起始物和合适的试剂通过与实施例1-349类似的方法制备下述对比实施例(如表5所示),
表5
实施例A CTGF检测(ELISA方法)
NCI-H2052细胞(购自ATCC)在RPMI 1640完全培养基(含10%FBS、1%青霉素-链霉素溶液和1mM丙酮酸钠)中培养。处理化合物的前一天,将培养的细胞用FBS洗涤并用胰蛋白酶消化,然后离心收集。除去上清液,将细胞重悬于新鲜的完全培养基中。细胞计数后,以6500个细胞/孔接种在96孔板中。然后将细胞在培养箱(37℃,5%CO2)中培养过夜。
细胞培养过夜后,弃去培养上清液,用PBS溶液洗涤,每孔加入200μl含有化合物的培养基培养细胞。起始浓度为10μM,在DMSO和培养基中进行梯度稀释,最终DMSO浓度为0.5%(最终化合物浓度为10000、2500、625、156、39.1、9.77、2.44,0.61nM,0nM(0.5%DMSO)),然后将细胞在培养箱中培养(37℃,5%CO2)。培养24小时,细胞在4℃下以1500RPM离心5分钟,然后取50μl培养上清液进行CTGF ELISA检测。
人源CTGF ELISA检测试剂盒(Abcam,ab261851)采用亲和标签标记的捕获抗体和报告基因偶联的检测抗体,可免疫捕获溶液中的样品分析物。整个复合物(捕获抗体/分析物/检测器抗体)依次通过包被孔的抗标签抗体的免疫亲和性固定。检测时,将样品或标准品加入孔中,然后加入抗体混合物(捕获抗体/检测抗体)孵育。孵育后,洗涤除去各样品孔中洗涤板孔以除去未被固定的物料。在被HRP催化的培养过程中,加入TMB显影液后呈现蓝色。然后通过添加终止溶液来终止该反应,溶液呈现从蓝色到黄色间的变化。在450nm处测量吸收强度,其信号值的产生与结合分析物的量成正比。首先,按照说明准备所有的试剂,样品和对照品。向检测板的孔中加入50μl标准品或待测细胞上清样品。然后每孔中加入50μl抗体Cocktail。将板密封,室温下在板振荡器上孵育1小时。用洗涤缓冲液将每个孔洗涤3次。每孔中加入100μlTMB显影液,并在摇板机上避光孵育10分钟。然后每孔中加入100μl终止液。在平板振荡器上振摇1分钟以混匀。记录450nm处的OD值。通过标准曲线确定样品中目标CTGF蛋白的浓度。
EC50值使用GraphPad Prism软件拟合浓度响应曲线来计算。通过化合物的CTGF浓度响应曲线来测试本发明化合物对TEAD-YAP/TAZ转录调控功能的抑制活性。
使用上述CTGF ELISA测定法获得的实施例化合物的数据提供于表6中。
表6
实施例B BRDU检测
a)将NCI-H226细胞以1500/孔的密度接种于96孔板。
b)24小时后,每孔中加入化合物和含1%FBS的培养基。待测化合物的最终检测浓度分别为20000,6666.667,2222.222,740.741,246.914,82.305,27.435,9.145,3.048,0.102nM。
c)与化合物孵育的NCI-H226细胞在培养箱中培养72小时。
d)每孔中加入2μL用培养基稀释100倍的BrdU标记试剂,然后将NCI-H226细胞在5%CO2条中在37℃培养箱中培养24小时。
e)按照BrdU试剂盒不转走加入检测试剂,最后在多功能酶标仪Envision上读取各孔的发光信号值。
数据分析:
使用GrapHPad Prism 6软件计算IC50并绘制化合物的效应剂量曲线。
Y=底部+(顶部-底部)/(1+10^((LogIC50-X)×HillSlope)).
Y为抑制率%,
X为化合物浓度的对数值。
抑制率%=(信号值HC-信号值comp)/(信号值HC-信号值LC);
HC(高对照)为DMSO组,
LC(低对照)为10uMStaurosporine组,
Comp为给药组。
得到的实施例化合物的IC50值如表7所示,在NCI-H226细胞中的抑制曲线如图1-7所示,其中X轴为化合物浓度(nm),Y轴为抑制率%。
表7:化合物在NCI-H226细胞中的增殖抑制能力(IC50)
实施例C PO Cassette给药后小鼠血浆中化合物药代动力学研究
成年Balb/C雌性小鼠(6-7周,维通利华)接受测试化合物的盒式给药,其中含有10-20%DMSO,10%Solutol(KollipHor HS 15,北京凤礼精求医药股份有限公司)和80-70%的水作为赋形剂。小鼠(n=3)以5mg/kg的剂量口服给药(灌胃)。采血时间:30min、2h、4h。取眼眶后静脉丛收集全血约0.1mL,置于含EDTA抗凝剂的试管中。样品在4℃、4000rpm离心10min。分析前将血浆转移至离心管中在-20℃保存。采用液相色谱-串联质谱(LC-MS/MS)分析血浆样品中测试化合物的浓度。使用Microsoft Excel 2010分析个体动物的血浆浓度-时间数据。在浓度分析中引入非房室模型。使用WinNonlin(版本4.1;pHarsight)软件计算测试化合物的药代动力学参数。如表8所示,测试化合物显示出良好的药代动力学特征。
表8
实施例D体内药效学和功效研究
化合物5,化合物6,和化合物124在BALB/c裸鼠皮下NCI-H226人肺鳞状细胞癌异种移植模型的体内药效学和功效研究。
方法:
每只小鼠(D000521BALB/c-Nu,集萃药康)在右侧皮下接种NCI-H226肿瘤细胞(ATCC,CRL-5826)(1x107),细胞溶于0.2mL含50%的matrigel基质胶的PBS(Corning,356234)中。当平均肿瘤大小达到大约100-150mm3时开始治疗。从分组之日起,每天给小鼠口服一次试验品,共28天(QD×28天)。定期监测动物的体重变化作为药物安全性的指标。使用卡尺在二维上每周测量两次肿瘤体积,体积以mm3表示,使用公式“V=(L×W^2)/2”,其中V为肿瘤体积,L为肿瘤长度(最长的肿瘤尺寸)和W是肿瘤宽度(垂直于L的最长肿瘤尺寸)。通过肿瘤生长抑制TGI(%)评估治疗效果。TGI(%)=[1-(Ti-T0)/(Vi-V0)]×100;Ti为某一天某治疗组的平均肿瘤体积,T0为治疗组第0天的平均肿瘤体积,Vi为载体对照组与Ti同一天的平均肿瘤体积,V0为赋形剂组第0天的平均肿瘤体积。结果见表9、图8和图9。结果如表9,图8和图9所示。
表9基于第28天肿瘤体积的NCI-H226异种移植模型中的肿瘤生长抑制计算
结果
治疗后第28天,化合物5(2mg/kg)组、化合物5(10mg/kg)组、化合物5(50mg/kg)组、化合物6(2mg/kg)组、化合物6(10mg/kg)组,化合物124(2mg/kg)组在肿瘤体积上与赋形剂组相比产生了显着的抗肿瘤活性。p值分别为0.0111、0.0011、0.0007、0.007、0.0026和0.0284。TGI(%)值分别为76.9%、101.3%、105.9%、77.1%、88.6%和67.3%。在该模型中,如图9所示,在每天服用化合物5、化合物6和化合物124的治疗期间,未观察到显著的体重减轻。
Claims (44)
1.一种式(I)所示化合物,或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,
其中,
A1和A2分别独立选自C或N;
环B选自C5-6芳基,C5-6环烷基,5-6元杂环基和5-6元杂芳基,其中,所述5-6元杂环基和5-6元杂芳基包含1,2,3或4个独立选自N,S和O的杂原子;
环A选自C5-6芳基,5-6元杂芳基,5-6元杂环基,所述5-6元杂芳基和5-6元杂环基包含1-4个独立选自N,S和O的杂原子,其中,所述5-6元杂环基或5-6元杂芳基的1或2个环原子分别独立任选地被-C(=O)和/或-C(=N)所替换;所述C5-6芳基,5-6元杂芳基和5-6元杂环基可分别任选地被0-3个独立选自羟基,卤素,CN,-N-(C1-6烷基)2,C1-6烷基,C2-6烯基,C2-6炔基,C1-6卤代烷基,C1-6烷氧基,-C(=O)NRaRb,-C(=O)ORa,-C(=O)Rc,-S(=O)Rb,-S(=O)2Rb,-S(=O)NRaRb,-S(=O)2NRaRb的取代基取代;
L1为键,-O-,-S-,-NRa-,-(CH2)t-,-(CH2)t-NRa-,-NRa-(CH2)t-,-(CH2)t-O-,-O-(CH2)t-,-C(=O)-,-C(=O)NRa-或-NRa-C(=O)-;
环E为C5-6芳基,5-10元杂芳基,C3-8环烷基或4-8元杂环基,所述5-10元杂芳基和4-8元杂环基包含1-4个独立选自N,S和O的杂原子;
L2为键,-O-,-S-,-NH-,-(CH2)t-O-,-O-(CH2)t-,-C(=O)-,-C1-4亚烷基,-C2-4亚烯基,或-C2-4亚炔基;
环D为C5-10芳基,5-10元杂芳基,C3-10环烷基或4-10元杂环基,所述5-10元杂芳基或4-10元杂环基包含1,2,3或4个独立选自N,S和O的杂原子;
R1为H,氧代基,羟基,卤素,CN,-NO2,-NRdRe,C1-6烷基,C2-6烯基,C2-6炔基,C1-6卤代烷基,C1-6烷氧基,-C(=O)NRaRb,-C(=O)ORa,-C(=O)Rc,-S(=O)Rb,-S(=O)2Rb,-S(=O)NRaRb,-S(=O)2NRaRb,-O-(C=O)-Ra,-O-(C=O)-NRaRb,C1-6卤代烷氧基,C3-6环烷基,3-6元杂环基,C5-6芳基或5-6元杂芳基,其中C1-6烷基,C2-6烯基,C2-6炔基,C1-6卤代烷基,C1-6烷氧基,C1-6卤代烷氧基,C3-6环烷基,3-6元杂环基,C5-6芳基和5-6元杂芳基可分别任选地被0-3个独立选自OH,CN,卤素,C1-6烷基,C2-4烯基,C2-4炔基,C1-4卤代烷基,C1-4烷氧基,-NRaRb,-C(=O)NRaRb,-C(=O)ORa,-C(=O)Ra,-S(=O)Rb,-S(=O)2Rb,-S(=O)NRaRb,-S(=O)2NRaRb,-NRaC(=O)Rb,C1-4卤代烷氧基,C3-6环烷基,3-6元杂环烷基,C5-6芳基和5-6元杂芳基的取代基取代;其中5-6元杂芳基和3-6元杂环基任选地包含1,2或3个独立选自N,S和O的杂原子;
R2为H,羟基,卤素,CN,-NO2,-NRaRb,氧代基,-C(=O)NRaRb,-C(=O)ORa-C(=O)Ra,-S(=O)Rb,-S(=O)2Rb,-S(=O)NRaRb,-S(=O)2NRaRb,-NRaC(=O)Rb,SF5,C1-6烷基,C2-6烯基,C2-6炔基,C1-6烷氧基,C1-6卤代烷基,C3-6环烷基或包含1,2或3个独立选自N,S和O的杂原子的3-6元杂环基;其中C1-6烷基,C2-6烯基,C2-6炔基,C1-6烷氧基,C3-6环烷基和3-6元杂环基分别任选地被0-3个独立选自-ORa,卤素,CN,C1-4烷基,C1-6卤代烷基,-NRaRb,氧代基,-C(=O)NRaRb,-C(=O)ORa,-C(=O)Ra,-S(=O)Rb,-S(=O)2Rb,-S(=O)NRaRb,-S(=O)2NRaRb和-NRaC(=O)Rb的取代基取代;
R3为H,氧代基,卤素,-ORa,CN,-NO2,-NRaRb,-NRaC(=O)Rb,-C1-4亚烷基-NRaRb,-C1-4亚烷基-NRaC(=O)Rb,-C(=O)Rb,-C(=O)ORa,-C(=O)NRaRb,-S(=O)Rb,-S(=O)2Rb,-S(=O)NRaRb,-S(=O)2NRaRb,-C1-4亚烷基-C(=O)NRaRb,C1-6烷基,C2-6烯基,C2-6炔基,C1-6烷氧基,C1-6卤代烷基,C1-6卤代烷氧基,3-6元杂环基,C3-6环烷基,C5-6芳基或5-6元杂芳基,其中5-6元杂芳基和3-6元杂环基任选地包含1,2或3个独立选自N,S和O的杂原子;其中C1-6烷基,C2-6烯基,C2-6炔基,C1-6卤代烷基,C1-6烷氧基,C1-6卤代烷氧基,C3-6环烷基,3-6元杂环基,C5-6芳基和5-6元杂芳基分别任选地被0-3个独立选自氧代基,羟基,卤素,CN,-NO2,C1-6烷基,-C1-4亚烷基-OH,C1-6卤代烷基,C1-6烷氧基,-S(=O)2Rb,-NRaRb,-C(=O)Rb,-C(=O)ORa,-NRaC(=O)Rb,-C(=O)NRaRb,-NRaC(=O)Rb,-C1-4亚烷基-NRaRb,-C1-4亚烷基-NRaC(=O)Rb,C1-4亚烷基-C(=O)NRaRb,-C1-4亚烷基-OH,C3-6环烷基,3-6元杂环烷基,C5-6芳基和5-6元杂芳基的取代基取代;
L3为键,-NRa-,-(CH2)t-NRa-,-C4-6杂环基或-C4-6环烷基-NRa-;
R5,R6,R7和R8分别独立选自H,卤素,-ORa,CN,-NRaRb,-C1-6亚烷基-NRaRb,-C1-6亚烷基-Rc,C1-6烷基,C2-6烯基,C2-6炔基,C1-6烷氧基,C3-6环烷基,3-6元杂环基,C5-6芳基和5-6元杂芳基,其中C1-6烷基,C2-6烯基,C2-6炔基,C1-6卤代烷基,C1-6烷氧基,C1-6卤代烷氧基,C3-6环烷基,3-6元杂环基,C5-6芳基和5-6元杂芳基分别任选地被0-4个独立选自OH,CN,卤素,C1-6烷基,C2-4烯基,C2-4炔基,C1-4卤代烷基,C1-4烷氧基,-NRaRb,C3-6环烷基,3-6元杂环基,C5-6芳基和5-6元杂芳基的取代基取代,其中5-6元杂芳基和3-6元杂环基任选地包含1,2或3个独立选自N,S和O的杂原子;
Ra和Rb分别独立选自H,CN,羟基,卤素,C1-6烷基,C1-6卤代烷基,C1-4烷氧基,C3-6环烷基,3-6元杂环烷基,C5-6芳基和5-6元杂芳基,其中C1-6烷基,C1-4烷氧基,C3-6环烷基,3-6元杂环烷基,C5-6芳基和5-6元杂芳基分别任选地被0-4个独立选自卤素,CN,-OH,氧代基,C1-6烷基,C2-6烯基,C2-6炔基,C1-6卤代烷基,C1-3烷氧基,C1-3卤代烷氧基和C5-6芳基的取代基取代;其中5-6元杂芳基和3-6元杂环烷基任选地包含1,2或3个独立选自N,S和O的杂原子;
Rc为3-6元杂环基,其可任选地被0-4个独立选自卤素,CN,-OH,氧代基,C1-6烷基,C2-6烯基,C2-6炔基,C1-6卤代烷基,C1-3烷氧基和C1-3卤代烷氧基的取代基取代;
Rd和Re分别独立选自C1-6烷基,C2-6烯基,C2-6炔基,C1-6卤代烷基,C1-6烷氧基,-C(=O)NRfRf,-C(=O)ORf,-C(=O)Rf,-S(=O)Rf,-S(=O)2Rf,-S(=O)NRfRf,-S(=O)2NRfRf,-C1-4亚烷基-NRfRf,-C1-4亚烷基-NRfC(=O)Rf,-C1-4亚烷基-C(=O)NRfRf;
Rf为H,C1-6烷基,C2-6炔基,C1-6卤代烷基或C1-6烷氧基;
t为1,2,3或4;
x,y和m独立选自0,1,2,3,4或5。
2.权利要求1所述的化合物,或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中L1为键,-O-,-S-,-NRa-,-(CH2)t-,-(CH2)t-O-,-O-(CH2)t-,-C(=O)-,-C(=O)NRa-或-NRa-C(=O)-。
3.权利要求1或2所述的化合物,或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中L2为键,-O-,-S-,-NH-,-C(=O)-,-C2-4亚烯基,或-C2-4亚炔基。
4.权利要求1-3任一项所述的化合物,或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中L2为键,-O-,C2-4亚烯基,或C2-4亚炔基。
5.权利要求1-4任一项所述的化合物,或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中L1为键,-NH-,-N-C1-3亚烷基-,-CH2-或-C(=O)-。
8.权利要求1-7任一项所述的化合物,或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中环B选自C5-6芳基,C5-6环烷基,包含1,2,3或4个N杂原子的5-6元杂芳基,和包含1,2,3或4个独立选自N,S,O的杂原子的5-6元杂环基。
9.权利要求1-8任一项所述的化合物,或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中环B选自C5-6芳基,C5-6环烷基,包含1或2个N杂原子的5-6元杂芳基,和包含1或2个O杂原子的5-6元杂环基,所述5-6元杂芳基和5-6元杂环基分别独立任选地被一个或多个氧代基取代。
11.权利要求1-10任一项所述的化合物,或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中R1为H,氧代基,羟基,卤素,CN,-NO2,-NRdRe,C1-6烷基,C2-6烯基,C2-6炔基,C1-6卤代烷基,C1-6烷氧基,-C(=O)NRaRb,-C(=O)ORa,-C(=O)Rc,-S(=O)Rb,-S(=O)2Rb,-S(=O)NRaRb,-S(=O)2NRaRb,-O-(C=O)-Ra,-O-(C=O)-NRaRb,C1-6卤代烷氧基,C3-5环烷基,3-5元杂环基,其中C1-6烷基,C2-6烯基,C2-6炔基,C1-6卤代烷基,C1-6烷氧基,C1-6卤代烷氧基,C3-5环烷基,3-5元杂环基可分别任选地被0-3个独立选自OH,CN,卤素,C1-6烷基,C2-4烯基,C2-4炔基,C1-4卤代烷基,C1-4烷氧基,-NRaRb,-C(=O)NRaRb,-C(=O)ORa,-C(=O)Ra,-S(=O)Rb,-S(=O)2Rb,-S(=O)NRaRb,-S(=O)2NRaRb,-NRaC(=O)Rb,C1-4卤代烷氧基的取代基取代。
12.权利要求1-11任一项所述的化合物,或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中R2为羟基,卤素,CN,-NO2,-NRaRb,氧代基,-C(=O)NRaRb,-C(=O)ORa,-C(=O)Ra,-S(=O)Rb,-S(=O)2Rb,-S(=O)NRaRb,-S(=O)2NRaRb,-NRaC(=O)Rb,-SF5,C1-6烷基,C2-6烯基,C2-6炔基,C1-6烷氧基,C1-6卤代烷基;所述C1-6烷基,C2-6烯基,C2-6炔基,C1-6烷氧基,C3-6环烷基分别任选地被0-3个独立选自-ORa,-NH2,卤素,CN,C1-4烷基,C1-6卤代烷基,-NRaRb,氧代基,-C(=O)NRaRb,-C(=O)ORa,-C(=O)Ra,-S(=O)Rb,-S(=O)2Rb,-S(=O)NRaRb,-S(=O)2NRaRb和-NRaC(=O)Rb的取代基取代。
13.权利要求1-12任一项所述的化合物,或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中R2为羟基,卤素,CN,C1-6烷基,C2-6烯基,C2-6炔基,C1-6烷氧基,C1-6卤代烷基;其中C1-4烷基,C2-4烯基,C2-4炔基,C1-4烷氧基分别任选地被0-3个独立选自羟基,卤素,CN和C1-4烷基的取代基取代。
14.权利要求1-13任一项所述的化合物,或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中R1为H,氧代基,羟基,卤素,CN,-NO2,-NRdRe,C1-6烷基,C2-6烯基,C2-6炔基,C1-6卤代烷基,C1-6烷氧基,-C(=O)NRaRb,-C(=O)ORa,-C(=O)Rc,-S(=O)Rb,-S(=O)2Rb,-S(=O)NRaRb,-S(=O)2NRaRb,-O-(C=O)-Ra,-O-(C=O)-NRaRb,C1-6卤代烷氧基,C3-5环烷基,包含1或2个独立选自N,S和O的N杂原子的3-5元杂环基。
15.权利要求1-14任一项所述的化合物,或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中R1为H,氧代基,卤素,-N-(C1-3烷基)2,C1-6烷基,C1-4卤代烷基,C1-4烷氧基,-C(=O)O-C1-4烷基,或-C(=O)Rc。
16.权利要求1-15任一项所述的化合物,或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中环E为C5-6芳基,5-6元杂芳基,C3-8环烷基或4-8元杂环基,所述5-6元杂芳基和4-8元杂环基包含1,2或3个独立选自N,S和O的杂原子。
17.权利要求1-16任一项所述的化合物,或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中环E为C3-6环烷基,苯基或包含1,2或3个独立选自N,S和O的杂原子的5-6元杂芳基。
18.权利要求1-17任一项所述的化合物,或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中环D为C5-10芳基,5-10元杂芳基,C3-10环烷基或4-10元杂环基,所述5-10元杂芳基和4-10元杂环基包含1,2或3个独立选自N和O的杂原子。
19.权利要求1-18任一项所述的化合物,或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中环D为C5-6芳基,5-6元杂芳基,3-6元单-环烷基,4-6元单-杂环基,6-10元稠合-或螺双环杂芳基,6-10元稠合-或螺双环杂环基,所述5-6元杂芳基,4-6元杂环基,6-10元杂芳基,6-10元杂环基包含1,2或3个独立选自N和O的杂原子。
20.权利要求1-19任一项所述的化合物,或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中当环E为苯基或5-6元杂芳基时,L2为键,-C2-4亚烯基,C2-4亚炔基;当环E为C3-6环烷基时,L2为-C2-4亚烯基或C2-4亚炔基。
21.权利要求1-20任一项所述的化合物,或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中R3为H,卤素,-ORa,CN,-NRaRb,-C1-4亚烷基-NRaRb,-C1-4亚烷基-NRaC(=O)Rb,-C(=O)Rb,-C(=O)ORa,-C(=O)NRaRb,-S(=O)Rb,-S(=O)2Rb,-S(=O)NRaRb,-S(=O)2NRaRb,-C1-4亚烷基-C(=O)NRaRb,C1-6烷基,C1-6烷氧基,C1-6卤代烷基,C1-6卤代烷氧基,3-6元杂环基,C3-6环烷基,C5-6芳基或5-6元杂芳基,所述5-6元杂芳基和3-6元杂环基任选地包含1,2或3个独立选自N,S和O的杂原子;其中C1-6烷基,C1-6卤代烷基,C1-6烷氧基,C1-6卤代烷氧基,C3-6环烷基,3-6元杂环基,C5-6芳基和5-6元杂芳基分别任选地被0-3个独立选自氧代基,羟基,卤素,CN,C1-6烷基,-C(=O)Rb,-NRaRb,-C(=O)Rb,-C(=O)ORa,-C(=O)NRaRb的取代基取代。
22.权利要求1-21任一项所述的化合物,或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中R3为H,卤素,CN,-O-C1-3烷基,C1-3烷基,C1-3卤代烷基,C3-5环烷基,5-6元杂芳基或4-6元杂环烷基,所述5-6元杂芳基和4-6元杂环烷基分别任选地被C1-6烷基或卤素所取代。
23.权利要求1-22任一项所述的化合物,或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中L3为键,-NH-,-N-C1-3烷基-,-(CH2)t-NH-,-C4-6杂环基。
24.权利要求1-23任一项所述的化合物,或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中L3为键或-NH-。
25.权利要求1-24任一项所述的化合物,或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中R5,R6和R7分别独立选自H,卤素,CN,C1-6烷基,-C1-6亚烷基-NRaRb,和-C1-6亚烷基-Rc。
26.权利要求1-25任一项所述的化合物,或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中R8为H,卤素,CN,C1-4烷基或-C1-4亚烷基-NRaRb。
27.权利要求1-26任一项所述的化合物,或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中Ra和Rb分别独立选自H,C1-6烷基,C3-6环烷基,3-6元杂环烷基,C5-6芳基和5-6元杂芳基,所述C1-6烷基,C3-6环烷基,3-6元杂环烷基,C5-6芳基和5-6元杂芳基可被卤素,C1-6卤代烷基或C5-6芳基所取代,所述5-6元杂芳基和3-6元杂环烷基任选地包含1,2或3个独立选自N,S和O的杂原子。
28.权利要求1-27任一项所述的化合物,或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中Ra为H或C1-6烷基。
29.权利要求1-28所述的化合物,或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中Rb选自H,C1-6烷基,C3-6环烷基,卤素取代的C3-6环烷基,3-6元杂环基和卤素或C1-4卤代烷基取代的3-6元杂环基。
30.权利要求1-29任一项所述的化合物,或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中Rc为可被卤素或C1-6卤代烷基取代的3-6元杂环烷基。
31.权利要求1-30任一项所述的化合物,或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中Rd为H,C1-6烷基,和Re为C1-6烷基,-C(=O)Rc,S(=O)2Rb。
37.权利要求1所述的化合物,或其立体异构体,互变异构体,药学上可接受的盐,前药,螯合物,非共价复合物或溶剂化物,其中,所述化合物为:
1)1-(1-丙烯酰吡咯烷-3-基)-3-(4-环己基苯基)-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮;
2)1-(1-丙烯酰吡咯烷-3-基)-3-(4-(三氟甲基)苯基)-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮;
3)1-(3-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
4)1-(3-(1-(4-(三氟甲基)苯基)-1H-吲唑-3-基)吡咯烷-1-基)丙-2-烯-1-酮;
5)2-氟-1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
6)2-氟-1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
7)1-(1-丙烯酰吡咯烷-3-基)-6-甲基-3-(4-(三氟甲基)苯基)-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮;
8)2-氟-1-(3-甲基-3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
9)2-氟-1-(2-甲基-3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
10)2-氟-N-(2-甲基-5-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)苯基)丙烯酰胺;
11)2-氟-1-(3-(6-甲基-3-((4-(三氟甲基)苯基)氨基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
12)2-氟-1-(2-羟基-3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
13)N-(1-(3-(4-(三氟甲基)苯基)咪唑并[1,5-a]吡啶-1-基)氮杂环丁烷-3-基)丙烯酰胺;
14)N-(1-(1-丙烯酰氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1H-吲唑-7-基)甲磺酰胺;
15)N-(1-(1-丙烯酰氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1H-吲唑-7-基)乙酰胺;
16)1-(3-(4-氨基-3-(4-环己基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
17)1-(3-(3-(4-环己基苯基)-4-羟基-1H-吡唑并[3,4-d]嘧啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
18)1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡嗪-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
19)1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
20)1-(3-(6-氯-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡嗪-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
21)1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
22)1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
23)1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
24)1-(3,3-二氟-4-(3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
25)1-((3R,4S)-3-氟-4-(3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
26)1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
27)1-(3-(3-(5-(三氟甲基)吡啶-2-基)-1H-吡唑并[3,4-b]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
28)N-(1-(1-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-3-基)吡咯烷-3-基)丁-2-酰胺;
29)1-(3-(3-(2-氟-4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
30)1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
31)1-(3-(3-(4-(三氟甲基)苯氧基)-1H-吡唑并[4,3-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
32)1-(3-(3-(4-(三氟甲基)苯氧基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
33)1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;
34)1-(3-((3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)甲基)吡咯烷-1-基)丙-2-烯-1-酮;
35)N-(1-(1-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-3-基)吡咯烷-3-基)丙烯酰胺;
36)(E)-N-(1-(1-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-3-基)吡咯烷-3-基)丁-2-烯酰胺;
37)N-(3-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)环戊基)丙烯酰胺;
38)1-(3-((3-(4-环己基苯基)-1H-吲唑-1-基)甲基)吡咯烷-1-基)丙-2-烯-1-酮;
39)1-(3-(7-甲基-3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
40)(E)-4-(二甲基氨基)-1-(3-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)吡咯烷-1-基)丁-2-烯-1-酮;
41)(E)-4-(二甲基氨基)-N-(1-(1-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-3-基)吡咯烷-3-基)丁-2-烯酰胺;
42)1-(1-丙烯酰吡咯烷-3-基)-3-(4-(三氟甲基)苯基)-1H-吲唑-7-甲酰胺;
43)1-(4-(1-(4-(三氟甲基)苯基)-1H-吲唑-3-羰基)哌嗪-1-基)丙-2-烯-1-酮;
44)1-(3-(7-甲氧基-3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
45)1-(3-(7-氯-3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
46)1-(3-(7-(三氟甲基)-3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
47)1-(3-(6-甲基-3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
48)1-(1-丙烯酰吡咯烷-3-基)-3-(4-(三氟甲基)苯基)-1H-吲唑-7-腈;
49)1-(7-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)-2-氮杂螺[4.4]壬烷-2-基)丙-2-烯-1-酮;
50)1-(3-(6-氟-3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
51)1-(3-(5,6-二氟-3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
52)1-(3-(1-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)吡咯烷-1-基)丙-2-烯-1-酮;
53)N-(1-(1-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)吡咯烷-3-基)丙烯酰胺;
54)1-(3-(6-甲氧基-3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
55)1-(3-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)吡咯烷-1-基)丁-2-炔-1-酮;
56)(E)-1-(3-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)吡咯烷-1-基)丁-2-烯-1-酮;
57)1-(3-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)吡咯烷-1-基)丙-2-炔-1-酮;
58)1-(3-(3-(5-(三氟甲基)吡啶-2-基)-1H-吲唑-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
59)1-(3-(3-(6-(三氟甲基)吡啶-3-基)-1H-吲唑-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
60)1-(3-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)哌啶-1-基)丙-2-烯-1-酮;
61)1-(3-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
62)N-(4-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)四氢呋喃-3-基)丙烯酰胺;
63)N-((5-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)-1,3,4-恶二唑-2-基)甲基)丙烯酰胺;
64)N-(1-(1-(4-(三氟甲基)苯基)-1H-吲唑-3-羰基)吡咯烷-3-基)丙烯酰胺;
65)1-(3-(1-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-3-基)吡咯烷-1-基)丙-2-烯-1-酮;
66)N-(1-(5-甲氧基-1-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-3-基)吡咯烷-3-基)丙烯酰胺;
67)1-(3-(5-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)-1,3,4-恶二唑-2-基)吡咯烷-1-基)丙-2-烯-1-酮;
68)N-(4-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)四氢-2H-吡喃-3-基)丙烯酰胺;
69)N-(1-(5-氰基-1-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-3-基)吡咯烷-3-基)丙烯酰胺;
70)1-(3-(7-氟-3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
71)2-氟-1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
72)N-(1-(5-氰基-1-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)吡咯烷-3-基)丙烯酰胺;
73)2-甲基-1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
74)N-(1-(5-甲氧基-1-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)吡咯烷-3-基)丙烯酰胺;
75)N-(1-(5-甲基-1-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-3-基)吡咯烷-3-基)丙烯酰胺;
76)5-甲基-2-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-羰基)己二烯腈;
77)1-(1-(2-氟丙烯酰)吡咯烷-3-基)-6-甲基-3-(4-(三氟甲基)苯基)-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮;
78)甲基1-(1-丙烯酰吡咯烷-3-基)-3-(4-(三氟甲基)苯基)-1H-吲唑-7-羧酸;
79)1-(1-丙烯酰氮杂环丁烷-3-基)-6-甲基-3-(4-(三氟甲基)苯基)-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮;
80)1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-6-甲基-3-(4-(三氟甲基)苯基)-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮;
81)N-(1-(6-甲基-1-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-3-基)吡咯烷-3-基)丙烯酰胺;
82)1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
83)N-(1-(5-甲基-1-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)吡咯烷-3-基)丙烯酰胺;
84)N-(1-(5-氯-1-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-3-基)吡咯烷-3-基)丙烯酰胺;
85)N-(1-(5-氯-1-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)吡咯烷-3-基)丙烯酰胺;
86)N-(1-(6-氯-1-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)吡咯烷-3-基)丙烯酰胺;
87)2-甲基-1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
88)4-甲基-4-吗啉-2-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)氮杂环丁烷-1-羰基)戊二烯腈;
89)1-(3-(5-甲氧基-3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
90)N-(1-(1-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)吡咯烷-3-基)丙烯酰胺;
91)N-(1-(1-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-3-基)吡咯烷-3-基)丙吡胺;
92)N-(1-(1-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)吡咯烷-3-基)丙吡胺;
93)1-(1-丙烯酰吡咯烷-3-基)-3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-5-腈;
94)1-(3-(5-甲氧基-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
95)2-氟-1-(3-(5-甲氧基-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
96)1-(3-(5-甲基-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
97)N-(3-(1-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)丙烯酰胺;
98)1-(1-丙烯酰吡咯烷-3-基)-N-异丙基-3-(6-(三氟甲基)吡啶-3-基)-1H-吲唑-7-甲酰胺;
99)N-(1-(3-(4-(三氟甲基)苯基)咪唑并[1,5-a]吡啶-1-基)吡咯烷-3-基)丙烯酰胺;
100)1-(1-丙烯酰吡咯烷-3-基)-N-环丙基-3-(6-(三氟甲基)吡啶-3-基)-1H-吲唑-7-甲酰胺;
101)1-(1-丙烯酰吡咯烷-3-基)-N-(氧杂环丁烷-3-基)-3-(6-(三氟甲基)吡啶-3-基)-1H-吲唑-7-甲酰胺;
102)1-(1-丙烯酰吡咯烷-3-基)-N-甲基-3-(6-(三氟甲基)吡啶-3-基)-1H-吲唑-7-甲酰胺;
103)1-(1-丙烯酰吡咯烷-3-基)-N,N-二甲基-3-(4-(三氟甲基)苯基)-1H-吲唑-7-甲酰胺;
104)1-(1-丙烯酰吡咯烷-3-基)-N-(3,3-二氟环丁基)-3-(6-(三氟甲基)吡啶-3-基)-1H-吲唑-7-甲酰胺;
105)1-(3-(1-(4-(三氟甲基)苯基)咪唑并[1,5-a]吡啶-3-基)吡咯烷-1-基)丙-2-烯-1-酮;
106)N-(1-(6-(4-(三氟甲基)苯基)咪唑并[1,5-a]嘧啶-8-基)吡咯烷-3-基)丙烯酰胺;
107)1-(1-丙烯酰吡咯烷-3-基)-N-苯基-3-(4-(三氟甲基)苯基)-1H-吲唑-7-甲酰胺;
108)1-(3-(5-氯-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
109)1-(3-(8-(4-(三氟甲基)苯基)咪唑并[1,5-a]嘧啶-6-基)吡咯烷-1-基)丙-2-烯-1-酮;
110)1-(3-(3-(4-(三氟甲基)苯基)-7-(4-(三氟甲基)哌啶e-1-羰基)-1H-吲唑-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
111)1-(1-丙烯酰吡咯烷-3-基)-N-(4,4-二氟环己基)-3-(4-(三氟甲基)苯基)-1H-吲唑-7-甲酰胺;
112)1-(3-(7-(3,3-二氟吡咯烷-1-羰基)-3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
113)1-(1-丙烯酰吡咯烷-3-基)-N-(3,3-二氟环戊基)-3-(4-(三氟甲基)苯基)-1H-吲唑-7-甲酰胺;
114)1-(1-丙烯酰吡咯烷-3-基)-N-(4-(三氟甲基)环己基)-3-(4-(三氟甲基)苯基)-1H-吲唑-7-甲酰胺;
115)1-(1-丙烯酰吡咯烷-3-基)-N-苄基-3-(4-(三氟甲基)苯基)-1H-吲唑-7-甲酰胺;
116)1-(1-丙烯酰吡咯烷-3-基)-N-(叔丁基)-3-(4-(三氟甲基)苯基)-1H-吲唑-7-甲酰胺;
117)1-(3-甲基-4-(3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
118)1-(7-(3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)-5-氮杂螺[2.4]庚烷-5-基)丙-2-烯-1-酮;
119)N-(2-(3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)环戊基)丙烯酰胺;
120)1-(3-(3-(4-环丙基苯基)-1H-吡唑并[4,3-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
121)1-(3-(6-(二甲基氨基)-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
122)1-(3-(6-(二甲基氨基)-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;
123)1-(3-(3-(6-(三氟甲基)吡啶-3-基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
124)2-氟-1-(3-(3-(6-(三氟甲基)吡啶-3-基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
125)1-(7-(3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)-2-氮杂螺[4.4]壬烷-2-基)丙-2-烯-1-酮;
126)2-氟-1-(7-(3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)-2-氮杂螺[4.4]壬烷-2-基)丙-2-烯-1-酮;
127)1-(3-(3-(2-氟-4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
128)2-氟-1-(3-(3-(2-氟-4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
129)1-(3-(3-(2-氟-4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
130)2-氟-1-(3-(3-(2-氟-4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
131)1-(3-(3-(6-(三氟甲基)吡啶-3-基)-1H-吡唑并[4,3-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
132)2-氟-1-(3-(3-(6-(三氟甲基)吡啶-3-基)-1H-吡唑并[4,3-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
133)N-(3-(4-(三氟甲基)苯基)-1'H-[1,6'-bi吲唑]-4'-基)丙烯酰胺;
134)N-(6-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)-[1,2,4]三唑并[4,3-a]吡啶-8-基)丙烯酰胺;
135)N-(3-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)苯基)丙烯酰胺;
136)N-(3-甲基-5-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)苯基)丙烯酰胺;
137)N-(3-甲氧基-5-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)苯基)丙烯酰胺;
138)N-(3-氯-5-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)苯基)丙烯酰胺;
139)1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-炔-1-酮;
140)1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-炔-1-酮;
141)(E)-2-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)氮杂环丁烷-1-羰基)丁-2-腈;
142)1-(1-丙烯酰吡咯烷-3-基)-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-5-腈;
143)1-(3-(5-甲基-3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
144)1-(3-(6-甲基-3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
145)1-(1-丙烯酰吡咯烷-3-基)-N-(吡啶-2-基)-3-(4-(三氟甲基)苯基)-1H-吲唑-7-甲酰胺;
146)1-(3-(5-氯-3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
147)1-(3-(6-氯-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
148)1-(1-丙烯酰吡咯烷-3-基)-3-(4-(三氟甲基)苯基)-N-(5-(三氟甲基)吡啶-2-基)-1H-吲唑-7-甲酰胺;
149)1-丙烯酰-4-(3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)吡咯烷-3-腈;
150)1-(3-(5-甲基-1-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)吡咯烷-1-基)丙-2-烯-1-酮;
151)N-(3-氰基-5-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)苯基)丙烯酰胺;
152)N-(3-氰基-5-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)苯基)丙烯酰胺;
153)N-(3-环丙基-5-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)苯基)丙烯酰胺;
154)N-(3-(3,3-二氟氮杂环丁烷-1-基)-5-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)苯基)丙烯酰胺;
155)N-(3-(3-甲基吡啶-2-基)-5-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)苯基)丙烯酰胺;
156)N-(3-(3-氯吡啶-2-基)-5-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)苯基)丙烯酰胺;
157)N-(3-(1H-吡唑-1-基)-5-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)苯基)丙烯酰胺;
158)N-(3-吗啉-5-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)苯基)丙烯酰胺;
159)N-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)苯基)丙烯酰胺;
160)2-氟-1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡嗪-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
161)1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡嗪-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
162)2-氟-1-(3-氟-3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
163)2-氟-1-(2-氟-3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
164)2-氟-1-(3-羟基-3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
165)1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶7-氧化物;
166)乙基2-(1-(2-氟丙烯酰)-3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-3-基)醋酸;
167)2-(1-(2-氟丙烯酰)-3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-3-基)乙腈;
168)2-氟-1-(3-(氟甲基)-3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
169)2-(1-(2-氟丙烯酰)-3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-3-基)乙酰胺;
170)1-(2-氟丙烯酰)-3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-3-腈;
171)2-氟-1-(3-(3-(4-异丙基苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
172)2-氟-1-(3-(3-(4-(三氟甲氧基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
173)2-氟-1-(3-(3-(4-(五氟-l6-硫烷基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
174)2-甲基-1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
175)(E)-1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丁-2-烯-1-酮;
176)2-氟-1-(3-(3-(3-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
177)5-(1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)-2-(三氟甲基)苄腈;
178)4-(1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)-2-(三氟甲基)苄腈;
179)2-氟-1-(3-(3-(6-(三氟甲基)吡啶-2-基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
180)2-氟-1-(3-(3-(2-(三氟甲基)吡啶-4-基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
181)2-氟-1-(3-(3-(5-甲基-6-(三氟甲基)吡啶-3-基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
182)2-氟-1-(3-(3-(2-甲基-6-(三氟甲基)吡啶-3-基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
183)2-氟-1-(3-(3-(2-(三氟甲基)嘧啶-5-基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
184)2-氟-1-(3-(3-(5-氟-6-(三氟甲基)吡啶-3-基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
185)2-氟-1-(3-(3-(2-氟-6-(三氟甲基)吡啶-3-基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
186)2-氟-1-(3-(6-甲基-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
187)1-(3-(6-氯-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;
188)2-氟-N-(2-甲氧基-5-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)苯基)丙烯酰胺;
189)N-(2-氯-5-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)苯基)丙烯酰胺;
190)N-(2,4-二氟-5-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)苯基)-2-氟丙烯酰胺;
191)2-氟-N-(4-氟-3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)苯基)丙烯酰胺;
192)N-(2,4-二氯-5-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)苯基)-2-氟丙烯酰胺;
193)2-氟-1-(6-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)吲哚啉-1-基)丙-2-烯-1-酮;
194)N-(4-((二甲基氨基)甲基)-3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)苯基)-2-氟丙烯酰胺;
195)N-(2,4-二氟-3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)苯基)-2-氟丙烯酰胺;
196)2-氟-1-(3-(3-(4-(三氟甲基)苯基)-1H-吲唑-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
197)2-氟-1-(3-(3-(6-(三氟甲基)吡啶-3-基)-1H-吲唑-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
198)2-氟-1-(3-(3-(6-(三氟甲基)吡啶-3-基)-1H-吡唑并[3,4-b]吡嗪-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
199)2-氟-1-(3-(6-甲基-3-(6-(三氟甲基)吡啶-3-基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
200)1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-6-腈;
201)1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-N-甲基-3-(4-(三氟甲基)苯基)-1H-吲唑-7-磺胺;
202)2-氟-1-(3-(5-氟-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
203)2-氟-1-(3-(6-氟-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
204)2-氟-1-(3-(6-氟-3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
205)1-(3-(6-(二氟甲基)-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;
206)1-(3-(6-氯-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡嗪-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;
207)2-氟-1-(3-(3-(4-(三氟甲基)苯基)-4,5,6,7-四氢-1H-吲唑-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
208)2-氟-1-(3-(3-(4-(三氟甲基)苯基)-6,7-二氢吡喃并[4,3-c]吡唑-1(4H)-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
209)2-氟-1-(3-(3-(4-(三氟甲基)苯基)-6,7-二氢吡喃并[4,3-c]吡唑-2(4H)-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
210)1-(3-(4,4-二氟-3-(4-(三氟甲基)苯基)-4,5,6,7-四氢-1H-吲唑-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;
211)1-(3-(5-(二氟甲基)-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;
212)1-(3-(5-(二氟甲基)-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;
213)2-氟-1-(3-(5-甲基-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
214)2-氟-1-(3-(5-甲氧基-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
215)2-氟-1-(3-(5-(三氟甲基)-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
216)2-氟-1-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-d]嘧啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
217)2-氟-1-(3-(3-(4-(三氟甲基)苯基)-4,5,6,7-四氢-1H-吲唑-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
218)6-乙基-1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮;
219)1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-7-甲基-3-(4-(三氟甲基)苯基)-1,7-二氢-6H-吡唑并[3,4-b]吡啶-6-酮;
220)1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-6-甲基-3-(4-(三氟甲基)苯基)-1,6-二氢-7H-吡唑并[3,4-c]吡啶-7-酮;
221)2-氟-1-(3-(6-甲氧基-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
222)2-氟-1-(3-(7-甲氧基-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-c]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
223)2-氟-1-(3-(6-甲氧基-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡嗪-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
224)1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-7-甲基-3-(4-(三氟甲基)苯基)-1,7-二氢-6H-吡唑并[3,4-b]吡嗪-6-酮;
225)1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-5,6-二甲基-3-(4-(三氟甲基)苯基)-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮;
226)2-氟-1-(3-(7-甲氧基-5-甲基-3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-d]嘧啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
227)2-氟-1-(3-(7-甲氧基-3-(4-(三氟甲基)苯基)-1H-吡唑并[4,3-d]嘧啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
228)1-(3-(5-溴-3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-
基)-2-氟丙-2-烯-1-酮;
229)1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1,3-二氢-2H-苯并[d]咪唑并l-2-酮;
230)2-氟-1-(3-(4-(4-(三氟甲基)苯基)喹唑啉-2-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
231)1-(3-(2-亚胺-3-(4-(三氟甲基)苯基)-2,3-二氢-1H-苯并[d]咪唑并l-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
232)N-((5-(2-氧代基-3-(4-(三氟甲基)苯基)-2,3-二氢-1H-苯并[d]咪唑并l-1-基)-1,3,4-恶二唑-2-基)甲基)丙烯酰胺;
233)1-(1-丙烯酰吡咯烷-3-基)-3-(4-环己基苯基)-1,3-二氢-2H-苯并[d]咪唑并l-2-酮;
234)1-(1-丙烯酰吡咯烷-3-基)-3-(4-(三氟甲基)苯基)-1,3-二氢-2H-苯并[d]咪唑并l-2-酮;
235)1-(3-(2-亚胺-3-(4-(三氟甲基)苯基)-2,3-二氢-1H-苯并[d]咪唑并l-1-基)吡咯烷-1-基)丙-2-烯-1-酮;
236)1-(1-丙烯酰氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1,3-二氢-2H-苯并[d]咪唑并l-2-酮;
237)1-(1-(2-氟丙烯酰)-3-甲基氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1,3-二氢-2H-苯并[d]咪唑并l-2-酮;
238)3-(1-(2-氟丙烯酰)-3-甲基氮杂环丁烷-3-基)-1-(4-(三氟甲基)苯基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
239)1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
240)1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1,3-二氢-2H-咪唑并[4,5-b]吡嗪-2-酮;
241)1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-3-(6-(三氟甲基)吡啶-3-基)-1,3-二氢-2H-咪唑并[4,5-b]吡嗪-2-酮;
242)3-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-5-甲基-1-(4-(三氟甲基)苯基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
243)3-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-5-甲基-1-(6-(三氟甲基)吡啶-3-基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
244)3-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-6-甲基-1-(4-(三氟甲基)苯基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
245)3-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-6-(三氟甲基)-1-(4-(三氟甲基)苯基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
246)3-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-6-甲氧基-1-(4-(三氟甲基)苯基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
247)1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮;
248)3-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-1-(4-(三氟甲基)苯基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮;
249)6-氯-3-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-1-(4-(三氟甲基)苯基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
250)9-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-7-(4-(三氟甲基)苯基)-7,9-二氢-8H-嘌呤-8-酮;
251)3-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-5-甲氧基-1-(4-(三氟甲基)苯基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
252)5-氯-3-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-1-(4-(三氟甲基)苯基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
253)6-氟-3-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-1-(4-(三氟甲基)苯基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
254)N-(1-(2-(4-(三氟甲基)苯基)喹唑啉-4-基)吡咯烷-3-基)丙烯酰胺;
255)2-氟-1-(3-((2-(4-(三氟甲基)苯基)喹唑啉-4-基)氨基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
256)2-氟-1-(3-(2-(4-(三氟甲基)苯基)喹唑啉-4-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
257)2-氟-1-(3-(4-(4-(三氟甲基)苯基)喹唑啉-2-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
258)N-(1-(1-(4-(三氟甲基)苯基)异喹啉-3-基)吡咯烷-3-基)丙烯酰胺;
259)N-(3-(1-(4-(三氟甲基)苯基)异喹啉-3-基)苯基)丙烯酰胺;
260)1-(3-(4-(4-(三氟甲基)苯基)喹啉-2-基)吡咯烷-1-基)丙-2-烯-1-酮;
261)1-(3-(4-(4-(三氟甲基)苯基)喹唑啉-2-基)吡咯烷-1-基)丙-2-烯-1-酮;
262)3-(1-丙烯酰吡咯烷-3-基)-1-(4-(三氟甲基)苯基)喹唑啉e-2,4(1H,3H)-二酮;
263)2-(1-丙烯酰吡咯烷-3-基)-4-(4-(三氟甲基)苯基)酞嗪-1(2H)-酮;
264)2-(1-丙烯酰哌啶-3-基)-4-(4-(三氟甲基)苯基)酞嗪-1(2H)-酮;
265)3-(1-丙烯酰吡咯烷-3-基)-1-(4-(三氟甲基)苯基)-3,4-二氢喹唑啉-2(1H)-酮;
266)3-(5-(1-丙烯酰吡咯烷-3-基)-1,3,4-恶二唑-2-基)-1-(4-(三氟甲基)苯基)喹啉-2(1H)-酮;
267)1-(3-(5-(4-(4-(三氟甲基)苯基)喹唑啉-2-基)-1,3,4-恶二唑-2-基)吡咯烷-1-基)丙-2-烯-1-酮;
268)N-(1-(2-(4-(三氟甲基)苯基)喹唑啉-4-基)氮杂环丁烷-3-基)丙烯酰胺;
269)2-氟-N-(1-(2-(4-(三氟甲基)苯基)喹唑啉-4-基)氮杂环丁烷-3-基)丙烯酰胺;
270)2-氟-N-(1-(2-(4-(三氟甲基)苯基)喹唑啉-4-基)吡咯烷-3-基)丙烯酰胺;
271)N-(1-(2-(4-(三氟甲基)苯基)吡啶并[2,3-d]嘧啶-4-基)吡咯烷-3-基)丙烯酰胺;
272)N-(1-(2-(4-(三氟甲基)苯基)吡啶并[3,4-d]嘧啶-4-基)吡咯烷-3-基)丙烯酰胺;
273)1-(4-(2-(4-(三氟甲基)苯基)吡啶并[3,4-d]嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮;
274)N-(5-甲基-1-(2-(4-(三氟甲基)苯基)吡啶并[3,4-d]嘧啶-4-基)吡咯烷-3-基)丙烯酰胺;
275)N-(1-(2-(4-(三氟甲基)苯基)吡啶并[2,3-d]嘧啶-4-基)氮杂环丁烷-3-基)丙烯酰胺;
276)2-氟-N-(1-(2-(4-(三氟甲基)苯基)吡啶并[2,3-d]嘧啶-4-基)氮杂环丁烷-3-基)丙烯酰胺;
277)2-氟-N-(1-(2-(4-(三氟甲基)苯基)吡啶并[2,3-d]嘧啶-4-基)吡咯烷-3-基)丙烯酰胺;
278)2-氟-N-(1-(2-(4-(三氟甲基)苯基)吡啶并[3,4-d]嘧啶-4-基)吡咯烷-3-基)丙烯酰胺;
279)N-(1-(2-(4-(三氟甲基)苯基)吡啶并[3,4-d]嘧啶-4-基)氮杂环丁烷-3-基)丙烯酰胺;
280)2-氟-N-(1-(2-(4-(三氟甲基)苯基)吡啶并[3,4-d]嘧啶-4-基)氮杂环丁烷-3-基)丙烯酰胺;
281)N-(1-(2-(4-(三氟甲基)苯基)吡啶并[3,2-d]嘧啶-4-基)氮杂环丁烷-3-基)丙烯酰胺;
282)2-氟-N-(1-(2-(4-(三氟甲基)苯基)吡啶并[3,2-d]嘧啶-4-基)氮杂环丁烷-3-基)丙烯酰胺;
283)1-(3-((2-(4-(三氟甲基)苯基)喹唑啉-4-基)氨基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
284)N-(3-(4-(4-(三氟甲基)苯氧基)萘-2-基)苯基)丙烯酰胺;
285)1-(3-(2-(4-(三氟甲基)苯基)喹啉-4-基)吡咯烷-1-基)丙-2-烯-1-酮;
286)1-(3-(6-(4-(三氟甲基)苯基)喹啉-8-基)吡咯烷-1-基)丙-2-烯-1-酮;
287)N-(1-(2-(4-(三氟甲基)苯基)吡啶并[3,2-d]嘧啶-4-基)吡咯烷-3-基)丙烯酰胺;
288)2-氟-N-(1-(2-(4-(三氟甲基)苯基)吡啶并[3,2-d]嘧啶-4-基)吡咯烷-3-基)丙烯酰胺;
289)3-(1-丙烯酰吡咯烷-3-基)-1-(4-(三氟甲基)苯基)-4a,8a-二氢喹啉-2(1H)-酮;
290)2-(1-丙烯酰吡咯烷-3-基)-4-(4-(三氟甲基)苯基)-4a,8a-二氢异喹啉-1(2H)-酮;
291)2-(1-丙烯酰氮杂环丁烷-3-基)-4-(4-(三氟甲基)苯基)酞嗪-1(2H)-酮;
292)3-(1-丙烯酰氮杂环丁烷-3-基)-1-(4-(三氟甲基)苯基)喹唑啉e-2,4(1H,3H)-二酮;
293)2-(1-丙烯酰氮杂环丁烷-3-基)-4-(4-(三氟甲基)苯基)异喹啉-1(2H)-酮;
294)1-(3-(4-(4-(三氟甲基)苯基)喹唑啉-2-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
295)2-氟-N-(1-(3-(4-(三氟甲基)苯基)萘-1-基)氮杂环丁烷-3-基)丙烯酰胺;
296)2-氟-N-(1-(6-(4-(三氟甲基)苯基)喹啉-8-基)氮杂环丁烷-3-基)丙烯酰胺;
297)1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)喹啉-2(1H)-酮;
298)1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)-1,8-萘啶-2(1H)-酮;
299)1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-3-(4-(三氟甲基)苯基)喹喔啉-2(1H)-酮;
300)4-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-2-(4-(三氟甲基)苯基)吡啶并[2,3-b]吡嗪-3(4H)-酮;
301)2-氟-N-(1-(2-(4-(三氟甲基)苯基)蝶呤-4-基)氮杂环丁烷-3-基)丙烯酰胺;
302)2-氟-N-甲基-N-(1-(2-(4-(三氟甲基)苯基)喹唑啉-4-基)氮杂环丁烷-3-基)丙烯酰胺;
303)2-氟-N-(1-(7-甲氧基-2-(4-(三氟甲基)苯基)喹唑啉-4-基)氮杂环丁烷-3-基)丙烯酰胺;
304)2-氟-N-(1-(5-(三氟甲基)-2-(4-(三氟甲基)苯基)喹唑啉-4-基)氮杂环丁烷-3-基)丙烯酰胺;
305)2-氟-N-(1-(2-(4-(三氟甲基)苯基)吡啶并[4,3-d]嘧啶-4-基)氮杂环丁烷-3-基)丙烯酰胺;
306)2-氟-N-(1-(2-(6-(三氟甲基)吡啶-3-基)吡啶并[3,2-d]嘧啶-4-基)氮杂环丁烷-3-基)丙烯酰胺;
307)2-氟-1-(3-(3-(苯基乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
308)(E)-2-氟-1-(3-(3-苯乙烯-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
309)1-(3-(3-((3,3-二氟环丁基)乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
310)N-(3-(3-(4-(三氟甲基)苯基)-1H-吡唑并[3,4-b]吡啶-1-基)苯基)丙烯酰胺;
311)1-(3-(3-(环戊基乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
312)1-(3-(3-(环戊基乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;
313)1-(3-(3-(嘧啶-2-基乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
314)2-氟-1-(3-(3-(嘧啶-2-基乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
315)1-(3-(3-(环丙基乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
316)1-(3-(3-(噻吩-3-基乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
317)2-氟-1-(3-(3-(噻吩-3-基乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
318)1-(3-(3-((1-甲基-1H-咪唑并l-5-基)乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
319)1-(3-(3-(苯基乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
320)1-(3-(3-(环丁基乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
321)1-(3-(3-(环丁基乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;
322)1-(3-(3-(环丙基乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;
323)2-氟-1-(3-(3-((1-甲基-1H-咪唑并l-5-基)乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
324)1-(3-(3-(环己基乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
325)1-(3-(3-(环己基乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;
326)1-(3-(3-((3,3-二氟环丁基)乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;
327)(E)-1-(3-(3-苯乙烯-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
328)1-(3-(3-((3,3-二氟环戊基)乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
329)1-(3-(3-((3,3-二氟环戊基)乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;
330)(E)-1-(3-(3-(2-环己基乙烯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
331)(E)-1-(3-(3-(2-环己基乙烯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;
332)(E)-1-(3-(3-(2-环丙基乙烯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
333)(E)-1-(3-(3-(2-环丙基乙烯基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;
334)2-氟-1-(3-(3-((4-氟苯基)乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
335)2-氟-1-(3-(3-((3-氟苯基)乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
336)2-氟-1-(3-(3-((2-氟苯基)乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
337)1-(3-(3-((3-氯苯基)乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;
338)1-(3-(3-((3-((二氟-l3-甲基)-l2-氟烷基)苯基)乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;
339)(E)-2-氟-1-(3-(3-(4-氟苯乙烯)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
340)(E)-2-氟-1-(3-(3-(3-氟苯乙烯)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
341)(E)-2-氟-1-(3-(3-(2-氟苯乙烯)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
342)(E)-1-(3-(3-(4-氯苯乙烯)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;
343)(E)-2-氟-1-(3-(3-(4-(三氟甲基)苯乙烯)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
344)(E)-4-(2-(1-(1-(2-氟丙烯酰)氮杂环丁烷-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)乙烯基)苄腈;
345)(E)-2-氟-1-(3-(3-(3-(三氟甲基)苯乙烯)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
346)1-(3-(3-((2,3-二氟苯基)乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;
347)2-氟-1-(3-(3-((2-氟苯基)乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;
348)1-(3-(3-((2-氯苯基)乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)-2-氟丙-2-烯-1-酮;或
349)2-氟-1-(3-(3-((2-(三氟甲基)苯基)乙炔基)-1H-吡唑并[3,4-b]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮。
38.一种药物组合物,其包含权利要求1-37任一项所述的化合物或其药学上可接受的盐或其立体异构体和至少一种药学上可接受的载体或辅料。
39.权利要求1-38任一项所述的化合物或权利要求40所述的组合物在治疗和/或癌症中治疗的应用。
40.权利要求39所述的组合物,或权利要求1-39任一项所述的化合物用于制备药物的应用。
41.权利要求40所述的应用,其中所述药物用于治疗,预防癌症或过度增殖性疾病。
42.权利要求41所述的应用,其中所述癌症为结肠癌、胃癌、甲状腺癌、肺癌、白血病、胰腺癌、黑色素瘤、多发性黑色素瘤、脑癌、肾癌、肝癌、鳞癌、胃肠癌、间皮瘤、前列腺癌、卵巢癌或乳腺癌。
43.一种治疗受试者疾病的方法,所述方法包括向有需要的受试者施用有效量的权利要求1-37任一项所述的化合物,或其药学上可接受的盐或其立体异构体。
44.权利要求43所述的方法,其中所述疾病为结肠癌、胃癌、甲状腺癌、肺癌、白血病、胰腺癌、黑色素瘤、多发性黑色素瘤、脑癌、肾癌、肝癌、鳞癌、胃肠癌、间皮瘤、前列腺癌、卵巢癌或乳腺癌。
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