TW202031644A - Benzimidazole derivative - Google Patents
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Abstract
Description
本發明係關於具有血清素5A受體(以下有時記載為5-HT5A受體)調節作用的化合物或其藥學上容許的鹽。又，本發明係關於使用前述化合物之預防或治療睡眠障礙、認知功能不全、及思覺失調症等疾病的方法。The present invention relates to a compound having a serotonin 5A receptor (hereinafter sometimes referred to as 5-HT5A receptor) modulating effect or a pharmaceutically acceptable salt thereof. In addition, the present invention relates to a method for preventing or treating diseases such as sleep disorders, cognitive insufficiency, and schizophrenia using the aforementioned compounds.
1990年代初期，作為同源性篩選的結果，已有報告：新的血清素(5-HT)受體亞科，亦即5-HT5(非專利文獻1)。已有報告：此5-HT受體亞科中有被命名為5-HT5A及5-HT5B的二個亞型。然而，在人類身上，5-HT5B受體基因係會被產生功能不活性蛋白質的停止密碼子中斷，因此被報告為不會產生5-HT5B受體(非專利文獻2、3)。In the early 1990s, as a result of homology screening, there have been reports: a new subfamily of serotonin (5-HT) receptors, namely 5-HT5 (Non-Patent Document 1). It has been reported that there are two subtypes named 5-HT5A and 5-HT5B in this 5-HT receptor subfamily. However, in humans, the 5-HT5B receptor gene system is interrupted by a stop codon that produces a functionally inactive protein, so it is reported that the 5-HT5B receptor is not produced (Non-Patent Documents 2 and 3).
5-HT5A受體，已透過使用放射性及免疫標誌物的研究而被報告為其在腦中係局部存在於神經系統的成分中(非專利文獻4、5)。基於在人類身上5-HT5A受體係被報告為與複數的訊息傳導路徑偶聯，暗示了透過5-HT5A受體而可進行腦功能的精巧的細胞調節。然而，5-HT5A受體未被解明的部分多，從2005年報告SB-699551(非專利文獻6)作為選擇性拮抗藥至今，已有報告複數的拮抗藥(非專利文獻7、8)，研究仍正進行中。The 5-HT5A receptor has been reported to be locally present in the components of the nervous system in the brain through research using radioactive and immunological markers (Non-Patent Documents 4 and 5). Based on the fact that 5-HT5A receptor system in humans is reported to be coupled to multiple signal transmission pathways, it is implied that through 5-HT5A receptors, the delicate cellular regulation of brain function can be carried out. However, there are many unexplained parts of 5-HT5A receptor. Since SB-699551 (Non-Patent Document 6) was reported as a selective antagonist in 2005, multiple antagonists have been reported (Non-Patent Documents 7 and 8). Research is still in progress.
透過健康正常自願者的關於基因變異之人類5-HT5A受體基因的分析，已清楚得知：人類5-HT5A受體基因中在密碼子區域與非密碼子區域兩者有多數的單鹼基多型(SNP)(非專利文獻9)。結果，開始有人研究5-HT5A受體基因的序列變化在病態生理學上的功用，並報告5-HT5A與酒精依賴症(非專利文獻10)、躁鬱症及重度憂鬱症(非專利文獻11、12)、以及思覺失調症(非專利文獻13)的關聯。Through the analysis of the human 5-HT5A receptor gene of genetic mutations by healthy volunteers, it is clear that the human 5-HT5A receptor gene has most single bases in both the codon region and the non-codon region. Polytype (SNP) (Non-Patent Document 9). As a result, people began to study the function of 5-HT5A receptor gene sequence changes in pathological physiology, and reported 5-HT5A and alcohol dependence (Non-Patent Document 10), bipolar disorder and severe depression (Non-Patent Document 11, 12), and the association of schizophrenia (Non-Patent Document 13).
作為5-HT5A受體的功用，由初期的研究暗示有協調運動，還有學習、記憶、感情行為等(非專利文獻1、14、15)。再者，藉由利用組織化學性探討所進行之表現部位的特定，暗示了5-HT5A受體在前腦中負責感情狀態、認知、不安、感覺知覺及神經內分泌功能的調節等複數的功用(非專利文獻16)。As the function of 5-HT5A receptor, initial research suggests that there are coordinated exercises, as well as learning, memory, and emotional behavior (Non-Patent Documents 1, 14, 15). Furthermore, the identification of the expression site by histochemical study suggests that 5-HT5A receptors are responsible for complex functions such as emotional state, cognition, anxiety, sensory perception, and regulation of neuroendocrine functions in the forebrain ( Non-Patent Document 16).
已知5-HT在人類的腦中主要係透過G-蛋白偶聯型受體(以下有時記載為GPCR)而調整睡眠覺醒週期與晝夜節律(非專利文獻17、18)。5-HT5A受體係依結構特徵等而被推測為Gi偶聯型GPCR(非專利文獻19、20)，並已有使用5-HT(5-羥基色胺)和5-CT(5-羧醯胺色胺(5-Carboxamidotryptamine))之cAMP抑制活性的報告例(非專利文獻21、22)。It is known that 5-HT mainly regulates sleep-wake cycle and circadian rhythm through G-protein coupled receptors (hereinafter sometimes referred to as GPCR) in the human brain (Non-Patent Documents 17, 18). The 5-HT5A receptor system is presumed to be a Gi-coupled GPCR based on its structural characteristics (Non-Patent Documents 19 and 20), and 5-HT (5-hydroxytryptamine) and 5-CT (5-carboxylic acid) have been used. Reported examples of cAMP inhibitory activity of 5-Carboxamidotryptamine (Non-Patent Documents 21 and 22).
大鼠的視上核(已知作為發送晝夜節律的神經核)中顯示高濃度的類5-HT5A的免疫反應性，故確認到5-HT5A受體在控制晝夜節律上的潛在功用(非專利文獻16)。再者，在敘利亞倉鼠身上亦發現，在被認為對晝夜節律形成是重要的四個腦部位(視上核、膝狀體間小葉(intergeniculate leaflet)、內中縫核(median raphe nucleus)、背中縫核(dorsal raphe nucleus))中，存在5-HT5A受體的高密度免疫反應性。5-HT促效物已知會引起非光同調性的晝夜節律相位變化，且為了在倉鼠身上進行利用血清素促效劑例如(R)-(＋)-8-OH-DPAT之相位變化，在背中縫核中需要進行利用cAMP之cAMP依賴性激酶的活化(非專利文獻23)。The supraoptic nucleus (known as the nerve nucleus that sends circadian rhythms) of rats shows high concentrations of 5-HT5A-like immunoreactivity, so the potential function of 5-HT5A receptors in controlling circadian rhythms has been confirmed (non-patented Literature 16). Furthermore, it has also been found in Syrian hamsters that four brain parts (supraoptic nucleus, intergeniculate leaflet, median raphe nucleus), and intermediate raphe nucleus are important for the formation of circadian rhythms. In the dorsal raphe nucleus, there is a high density of 5-HT5A receptor immunoreactivity. 5-HT agonists are known to cause phase changes in the circadian rhythm that are not optically coherent, and in order to perform phase changes in hamsters using serotonin agonists such as (R)-(+)-8-OH-DPAT, In the dorsal raphe nucleus, cAMP-dependent kinase activation using cAMP is required (Non-Patent Document 23).
如上所述，5-HT5A受體與認知功能不全、睡眠障礙、及思覺失調症等相關，故調整5-HT5A受體的化合物，被期待作為治療該等疾病的新藥劑。As described above, 5-HT5A receptors are associated with cognitive insufficiency, sleep disorders, schizophrenia, etc. Therefore, compounds that modulate 5-HT5A receptors are expected as new agents for the treatment of these diseases.
至今關於對5-HT5A受體具有選擇性拮抗活性的化合物，有以下的報告。There have been the following reports about compounds having selective antagonistic activity against 5-HT5A receptors.
專利文獻1中有關於對5-HT5A受體具有選擇性拮抗活性的4H-3,1-苯并
專利文獻2中有關於對5-HT5A受體具有選擇性拮抗活性的異喹啉-7-羧醯胺(isoquinoline-7-carboxamide)衍生物的報告。Patent Document 2 has a report on isoquinoline-7-carboxamide derivatives which have selective antagonistic activity against 5-HT5A receptors.
專利文獻3中有關於對5-HT5A受體具有選擇性拮抗活性的胍衍生物的報告。Patent Document 3 has a report on guanidine derivatives having selective antagonistic activity against 5-HT5A receptors.
專利文獻4中有關於對5-HT5A受體具有選擇性拮抗活性的聯芳基衍生物的報告。Patent Document 4 reports on biaryl derivatives having selective antagonistic activity against 5-HT5A receptors.
專利文獻5中有關於對5-HT5A受體具有選擇性拮抗活性的喹唑啉衍生物的報告。Patent Document 5 reports about quinazoline derivatives having selective antagonistic activity against 5-HT5A receptors.
如上述，至今雖有關於對5-HT5A受體的抗拮劑的報告，但並無關於如本發明所揭示般的具有苯并咪唑骨架之對5-HT5A受體的促效物的報告。 [先前技術文獻] [專利文獻]As mentioned above, although there have been reports on 5-HT5A receptor antagonists, there are no reports on 5-HT5A receptor agonists having a benzimidazole skeleton as disclosed in the present invention. [Prior Technical Literature] [Patent Literature]
[專利文獻1]美國專利申請公開第2010/0063042號說明書 [專利文獻2]國際公開第2012/108490號 [專利文獻3]美國專利申請公開第2010/0184787號說明書 [專利文獻4]國際公開第2004/096771號 [專利文獻5]日本特開2015-124211號公報 [非專利文獻][Patent Document 1] Specification of U.S. Patent Application Publication No. 2010/0063042 [Patent Document 2] International Publication No. 2012/108490 [Patent Document 3] Specification of U.S. Patent Application Publication No. 2010/0184787 [Patent Document 4] International Publication No. 2004/096771 [Patent Document 5] Japanese Patent Application Publication No. 2015-124211 [Non-Patent Literature]
[非專利文獻1]Plassat,J.L.et al. The mouse 5HT5 receptor reveals a remarkable heterogeneity within the 5HT1D receptor family. EMBO J.,1992,11,4779-4786. [非專利文獻2]Rees,S.et al. Cloning and characterisation of the human 5-HT5A serotonin receptor. FEBS Lett.,1994,355,242-246. [非專利文獻3]Grailhe,R.et al. Human 5-HT5 receptors: the 5-HT5A is functional but the 5-HT5B was lost during mammalian evolution. Eur.J.Pharmacol., 2001,418,157-167. [非專利文獻4]Wang,Z.Y.et al. 5-HT5A receptors in the carotid body chemoreception pathway of rat. Neurosci.Lett.,2000,278,9-12. [非專利文獻5]Nelson,D.L. 5-HT5 receptors. Curr.Drug Targ.CNS Neurol.Disord.,2004,3,53-58. [非專利文獻6]Heightman,T.D.et al. Discovery of potent and selective 5-ht5A receptor antagonist by high-throughput chemistry. Bioorg.Med.Chem.,2005,15,4014-4018. [非專利文獻7]Garcia-Ladona,F.et al. First potent and highly selective antagonists for the human 5-HT5A receptor. Program No 331.B73 2006 Society for Neuroscience Meeting. [非專利文獻8]Yamazaki,M.et al. Functional mechanism of ASP5736, a selective serotonin 5-HT5A receptor antagonist with potential utility for the treatment of cognitive dysfunction in schizophrenia. Eur. Neuropsychopharmacol.,2014,24,1698-1708. [非專利文獻9]Shimron-Abarbanell,D.et al. Human 5-HT5A receptor gene: systematic screening for DNA sequence variation and linkage mapping on chromosome 7q34-q36 using a polymorphism in the 5´ untranslated region. Biochem.Biophys.Res.Commun.,1997,233,6-9. [非專利文獻10]Iwata,N.et al. Identification of a naturally occurring Pro15-Ser15 substitution in the serotonin5A receptor gene in alcoholics and healthy volunteers. Mol.Brain Res.,1998,58,217-220. [非專利文獻11]Birkett,J.T.et al. Association analysis of the 5-HT5A gene in depression, psychosis and antipsychotic response. Neuroreport,2000,11,2017-2020. [非專利文獻12]Arias,B.et al. Genetic variation in the 5-HT5A receptor gene in patients with bipolar disorder and major depression. Neurosci.Lett.,2001,303,111-114. [非專利文獻13]Dubertret,C.et al. Family-based association studies between 5-HT5A receptor gene and schizophrenia. J.Psychiatr.Res.,2004,38,371-376. [非專利文獻14]Erlander,M.G.et al. Two members of a distinct subfamily of 5-hydroxytryptamine receptors differentially expressed in rat brain. Proc.Nat.Acad.Sci.USA,1993,90,3452-3456. [非專利文獻15]Pasqualetti,M.et al. Distribution of the 5-HT5A serotonin receptor mRNA in the human brain. Mol.Brain Res.,1998,56,1-8. [非專利文獻16]Oliver,K.R.et al. Localization of 5-ht5A receptor-like immunoreactivity in the rat brain. Brain Res.,2000,867,131-142. [非專利文獻17]Jouvet,M. Sleep and serotonin: an unfinished story. Neuropsychopharmacology,1999,21,24S-27S. [非專利文獻18]Lustberg,L.et al. Depression and insomnia: questions of cause and effect. Sleep Med.Rev.,2000,4,253-262. [非專利文獻19]Noda,M.et al. Multiple signal transduction pathways mediated by 5-HT receptors. Mol Neurobiol.,2004,29,31-39. [非專利文獻20]Francken,B.J.et al. The human 5-ht5A receptor couples to Gi/Go proteins and inhibits adenylate cyclase in HEK 293 cells. Eur.J.Pharmacol. 1998,361,299-309. [非專利文獻21]Carson, M.J.et al. The 5HT5A serotonin receptor is expressed predominantly by astrocytes in which it inhibits cAMP accumulation: a mechanism for neuronal suppression of reactive astrocytes. Glia. 1996,17,317-326. [非專利文獻22]Noda, M.et al. Recombinant human serotonin 5A receptors stably expressed in C6 glioma cells couple to multiple signal transduction pathways. J.Neurochem.,2003,84,222-232. [非專利文獻23]Duncan,M.J.et al. Cyclic AMP mediates circadian phase shifts induced by microinjection of serotonergic drugs in the hamster dorsal raphe nucleus. Brain Res.,2005,1058,10-16.[Non-Patent Document 1] Plassat, J.L. et al. The mouse 5HT5 receptor reveals a remarkable heterogeneity within the 5HT1D receptor family. EMBO J., 1992,11,4779-4786. [Non-Patent Document 2] Rees, S. et al. Cloning and characterisation of the human 5-HT5A serotonin receptor. FEBS Lett., 1994,355,242-246. [Non-Patent Document 3] Grailhe, R. et al. Human 5-HT5 receptors: the 5-HT5A is functional but the 5-HT5B was lost during mammalian evolution. Eur. J. Pharmacol., 2001,418,157-167. [Non-Patent Document 4] Wang, Z.Y.et al. 5-HT5A receptors in the carotid body chemoreception pathway of rat. Neurosci. Lett., 2000,278,9-12. [Non-Patent Document 5] Nelson, D.L. 5-HT5 receptors. Curr. Drug Targ. CNS Neurol. Disord., 2004, 3, 53-58. [Non-Patent Document 6] Heightman, T.D. et al. Discovery of potent and selective 5-ht5A receptor antagonist by high-throughput chemistry. Bioorg.Med.Chem., 2005, 15, 4014-4018. [Non-Patent Document 7] Garcia-Ladona, F.et al. First potent and highly selective antagonists for the human 5-HT5A receptor. Program No 331.B73 2006 Society for Neuroscience Meeting. [Non-Patent Document 8] Yamazaki, M. et al. Functional mechanism of ASP5736, a selective serotonin 5-HT5A receptor antagonist with potential utility for the treatment of cognitive dysfunction in schizophrenia. Eur. Neuropsychopharmacol., 2014,24,1698-1708 . [Non-Patent Document 9] Shimron-Abarbanell, D. et al. Human 5-HT5A receptor gene: systematic screening for DNA sequence variation and linkage mapping on chromosome 7q34-q36 using a polymorphism in the 5´ untranslated region. Biochem. Biophys. Res. Commun., 1997, 233, 6-9. [Non-Patent Document 10] Iwata, N. et al. Identification of a naturally occurring Pro15-Ser15 substitution in the serotonin5A receptor gene in alcoholics and healthy volunteers. Mol. Brain Res., 1998, 58, 217-220. [Non-Patent Document 11] Birkett, J.T. et al. Association analysis of the 5-HT5A gene in depression, psychosis and antipsychotic response. Neuroreport, 2000, 11, 2017-2020. [Non-Patent Document 12] Arias, B. et al. Genetic variation in the 5-HT5A receptor gene in patients with bipolar disorder and major depression. Neurosci. Lett., 2001,303,111-114. [Non-Patent Literature 13] Dubertret, C.et al. Family-based association studies between 5-HT5A receptor gene and schizophrenia. J.Psychiatr.Res.,2004,38,371-376. [Non-Patent Document 14] Erlander, M.G. et al. Two members of a distinct subfamily of 5-hydroxytryptamine receptors differentially expressed in rat brain. Proc.Nat.Acad.Sci.USA,1993,90,3452-3456. [Non-Patent Document 15] Pasqualetti, M. et al. Distribution of the 5-HT5A serotonin receptor mRNA in the human brain. Mol. Brain Res., 1998, 56, 1-8. [Non-Patent Document 16] Oliver, K.R. et al. Localization of 5-ht5A receptor-like immunoreactivity in the rat brain. Brain Res., 2000,867,131-142. [Non-Patent Document 17] Jouvet, M. Sleep and serotonin: an unfinished story. Neuropsychopharmacology, 1999, 21, 24S-27S. [Non-Patent Document 18] Lustberg, L. et al. Depression and insomnia: questions of cause and effect. Sleep Med. Rev., 2000, 4,253-262. [Non-Patent Document 19] Noda, M. et al. Multiple signal transduction pathways mediated by 5-HT receptors. Mol Neurobiol., 2004, 29, 31-39. [Non-Patent Document 20] Francen, B.J.et al. The human 5-ht5A receptor couples to Gi/Go proteins and inhibits adenylate cyclase in HEK 293 cells. Eur.J.Pharmacol. 1998,361,299-309. [Non-Patent Document 21] Carson, M.J.et al. The 5HT5A serotonin receptor is expressed predominantly by astrocytes in which it inhibits cAMP accumulation: a mechanism for neuronal suppression of reactive astrocytes. Glia. 1996,17,317-326. [Non-Patent Document 22] Noda, M.et al. Recombinant human serotonin 5A receptors stably expressed in C6 glioma cells couple to multiple signal transduction pathways. J. Neurochem., 2003,84,222-232. [Non-Patent Literature 23] Duncan, M.J.et al. Cyclic AMP mediates circadian phase shifts induced by microinjection of serotonergic drugs in the hamster dorsal raphe nucleus. Brain Res., 2005,1058,10-16.
[發明概要] [發明欲解決之課題][Summary of the invention] [The problem to be solved by the invention]
本發明的課題係提供具有5-HT5A受體調節作用的新穎化合物。又，提供一種化合物，其具有5-HT5A受體調節作用，且預防或治療睡醒相位後移症(DSPS，Delayed Sleep Phase Syndrome)、不規則睡醒模式(irregular sleep-wake pattern)、非二十四小時睡醒節律症(non-24-hour sleep-wake rhythm disorder)、輪班工作症(shift worksleep disorder)、時差症(jet lag disorder)、非特定的晝夜節律性睡眠障礙(unspecified circadian rhythm sleep disorder)、情感疾病、認知功能不全、失眠症、及思覺失調症。 [用以解決課題之手段]The subject of the present invention is to provide novel compounds with 5-HT5A receptor modulating effects. Furthermore, a compound is provided, which has a 5-HT5A receptor modulating effect, and prevents or treats Delayed Sleep Phase Syndrome (DSPS), irregular sleep-wake pattern, and non-two Fourteen-hour sleep-wake rhythm disorder (non-24-hour sleep-wake rhythm disorder), shift work sleep disorder, jet lag disorder, unspecified circadian rhythm sleep disorder (unspecified circadian rhythm sleep) disorder), affective disorders, cognitive insufficiency, insomnia, and psychosis. [Means to solve the problem]
本發明人等進行專心致志地探討的結果，發現由通式(I)所表示之化合物或其藥學上容許的鹽具有5-HT5A受體調節作用(較佳為5-HT5A受體選擇性的促效物作用)，且能提供透過5-HT5A受體而預防或治療前述疾病之方法，進而完成本發明。As a result of intensive investigations by the present inventors, they found that the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof has a 5-HT5A receptor modulating effect (preferably 5-HT5A receptor selective promoting Effect), and can provide a method for preventing or treating the aforementioned diseases through 5-HT5A receptors, thereby completing the present invention.
亦即，本發明係關於以下所說明的[1]～[26]。That is, the present invention relates to [1] to [26] described below.
[1]一種化合物或其藥學上容許的鹽，其係由通式(I)所表示：
本發明的由通式(I)所表示之化合物或其藥學上容許的鹽具有顯著的5-HT5A受體調節作用。尤其，本發明的化合物或其藥學上容許的鹽因具有5-HT5A受體選擇性的促效物活性，故有用於治療或預防睡醒相位後移症(DSPS)、不規則睡醒模式、非二十四小時睡醒節律症、輪班工作症、時差症、非特定的晝夜節律性睡眠障礙、情感疾病、認知功能不全、失眠症、或思覺失調症。又，本發明的由通式(I)所表示之化合物或其藥學上容許的鹽在溶解性、細胞膜穿透性、經口吸收性、血中濃度、代謝穩定性、組織移動性、生體可用率、in vitro活性、in vivo活性、藥效表現的速度、藥效的持續性、物理的穩定性、藥物相互作用、安全性等的點具有優異性質，有用於作為用於治療或預防上述疾病的醫藥。The compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof has a significant 5-HT5A receptor modulating effect. In particular, the compound of the present invention or a pharmaceutically acceptable salt thereof has 5-HT5A receptor-selective agonist activity, so it is useful for the treatment or prevention of phase shifting sleep-wake syndrome (DSPS), irregular wake patterns, Non-24-hour wake rhythm disorder, shift work disorder, jet lag, non-specific circadian rhythm sleep disorder, affective disorder, cognitive dysfunction, insomnia, or schizophrenia. In addition, the compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof has solubility, cell membrane penetration, oral absorbability, blood concentration, metabolic stability, tissue mobility, and biological Availability, in vitro activity, in vivo activity, speed of pharmacodynamic performance, continuity of pharmacodynamics, physical stability, drug interactions, safety and other points have excellent properties, and are useful for treating or preventing the above Disease medicine.
[用以實施發明的形態][Form to implement the invention]
以下針對本發明進行詳細地說明。The present invention will be described in detail below.
本說明書中使用以下所說明的用語。In this manual, the terms explained below are used.
「5-HT5A受體調節作用」：表示化合物藉由在內生性配體與5-HT5A受體進行拮抗而阻礙5-HT5A受體活化的作用、或化合物藉由與5-HT5A受體結合而活化前述受體的作用。較佳為活化5-HT5A受體的作用。"5-HT5A receptor modulating effect": It means that the compound inhibits the activation of 5-HT5A receptor by antagonizing the endogenous ligand and 5-HT5A receptor, or the compound binds to 5-HT5A receptor. Activate the effect of the aforementioned receptors. Preferably, it activates the 5-HT5A receptor.
「C1-C6伸烷基」：碳數1～6個的直鏈或分支鏈狀的二價烴基，具體而言例如，亞甲基、伸乙基[-(CH2 )2 -]、三亞甲基[-(CH2 )3 -]、四亞甲基[-(CH2 )4 -]、五亞甲基[-(CH2 )5 -]、六亞甲基[-(CH2 )6 -]、甲基亞甲基[-CH(CH3 )-]、甲基伸乙基[-CH(CH3 )CH2 -或-CH2 CH(CH3 )-]、1,2-二甲基伸乙基[-CH(CH3 )CH(CH3 )-]、1,1,2,2-四甲基伸乙基[-C(CH3 )2 C(CH3 )2 -]。"C1-C6 alkylene": a linear or branched divalent hydrocarbon group having 1 to 6 carbon atoms, specifically, for example, methylene, ethylene [-(CH 2 ) 2 -], Sanya Methyl [-(CH 2 ) 3 -], Tetramethylene [-(CH 2 ) 4 -], Pentamethylene [-(CH 2 ) 5 -], Hexamethylene [-(CH 2 ) 6 -], methyl methylene [-CH(CH 3 )-], methyl ethylene [-CH(CH 3 )CH 2 -or -CH 2 CH(CH 3 )-], 1,2- Dimethylethylene [-CH(CH 3 )CH(CH 3 )-], 1,1,2,2-tetramethylethylene [-C(CH 3 ) 2 C(CH 3 ) 2- ].
「5或6員雜芳基」：包含藉由碳還有自氮、氧、硫獨立選出之1～4的雜原子所構成之5或6員芳香族環而成之一價基，可列舉例如，呋喃基、吡咯基、噻吩基、
「5或6員伸雜芳基」：從前述雜芳基去除任意的一個氫原子之二價基，可列舉例如，呋喃二基、吡咯二基、噻吩二基、
「C3-C6環烷」：碳數3～6的環狀烷烴，具體而言例如，環丙烷、環丁烷、環戊烷、或環己烷。"C3-C6 cycloalkane": A cyclic alkane having 3 to 6 carbon atoms, specifically, for example, cyclopropane, cyclobutane, cyclopentane, or cyclohexane.
「C3-C6環烷基」：從前述C3-C6環烷去除任意的一個氫之一價基，具體而言例如，環丙基、環丁基、環戊基、或環己基。"C3-C6 cycloalkyl": Any one hydrogen monovalent group is removed from the aforementioned C3-C6 cycloalkane, specifically, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
「C3-C6伸環烷基」：從前述C3-C6環烷基去除任意的一個氫原子之二價基，具體而言例如，環丙烯(環丙烷二基)、環丁烯(環丁烷二基)、環戊烯(環戊烷二基)、環己烯(環己烷二基)。"C3-C6 cycloalkylene": A divalent group in which any one hydrogen atom is removed from the aforementioned C3-C6 cycloalkyl group, specifically, for example, cyclopropene (cyclopropane diyl), cyclobutene (cyclobutane Diyl), cyclopentene (cyclopentanediyl), cyclohexene (cyclohexanediyl).
「C2-C6伸炔基」：具有至少一個碳-碳三鍵之直鏈狀或分支鏈狀的碳數2～6的二價基，具體而言例如，伸乙炔基[-C≡C-]、伸丙炔基(propynylene)[-C≡C-CH2 -或-CH2 -C≡C-]、伸丁炔基(butynylene)、1,3-伸丁二烯基(1,3-butadienylene)[-C≡C-C≡C-]、3-甲基伸丙炔基[-C≡C-CH(CH3 )-]、伸戊炔基(pentynylene)、或伸己炔基(hexynylene)。"C2-C6 alkynylene group": a linear or branched divalent group with 2 to 6 carbon atoms having at least one carbon-carbon triple bond, specifically, for example, an ethynylene group [-C≡C- ], propynylene [-C≡C-CH 2 -or -CH 2 -C≡C-], butynylene, 1,3-butadienyl (1,3 -butadienylene)[-C≡CC≡C-], 3-methylpropynylene [-C≡C-CH(CH 3 )-], pentynylene, or hexynylene ).
「3～6員雜環基」：藉由碳還有自氮、氧、硫獨立選出之1～4的雜原子所構成之3～6員環的非芳香族的基，可為飽和或不飽和，亦可藉由伸烷基而被交聯。具體而言，可列舉例如，吖丙啶基(aziridinyl)、吖呾基(azetidinyl)、吡咯啶基、咪唑啶基、二氫咪唑基、
「含有至少一個氮原子之3～6員雜環基或5或6員雜芳基」：包含至少一個氮原子作為環的構成原子，且可進一步包含碳還有自氮、氧、硫獨立選出之1～3的雜原子之3～6員雜環基或5或6員雜芳基，且為結合在前述氮原子上之一價基。具體而言例如，吖丙啶基、吖呾基、吡咯啶基、咪唑啶基、二氫咪唑基、
「鹵素原子」：例如為氟原子、氯原子、溴原子、或碘原子。"Halogen atom": For example, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
「C1-C6烷基」：碳數1～6個的直鏈或分支鏈之一價烴基，具體而言例如，甲基、乙基、丙基、異丙基、丁基、異丁基、sec-丁基、tert-丁基、戊基、異戊基、2-甲基丁基、新戊基、1-乙基丙基、己基、異己基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、或1,2-二甲基丁基。"C1-C6 alkyl group": a linear or branched monovalent hydrocarbon group with 1 to 6 carbons, specifically, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 3-methylpentyl, 2-methyl 1-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, or 1,2-dimethylbutyl base.
「C1-C6烷氧基」：氧原子與前述C1-C6烷基結合的基，具體而言例如，甲氧基、乙氧基、n-丙氧基、異丙氧基、n-丁氧基、sec-丁氧基、異丁氧基、tert-丁氧基、戊氧基、異戊氧基、新戊氧基、己氧基、或異己氧基。"C1-C6 alkoxy": A group in which an oxygen atom is bonded to the aforementioned C1-C6 alkyl group, specifically, for example, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy Group, sec-butoxy, isobutoxy, tert-butoxy, pentoxy, isopentoxy, neopentyloxy, hexoxy, or isohexoxy.
「鹵C1-C6烷基」：前述C1-C6烷基經1～7個鹵素原子取代的基，具體而言例如，三氟甲基、二氟甲基、1,1-二氟乙基、2,2-二氟乙基、或2,2,2-三氟乙基。"Halo C1-C6 alkyl group": The aforementioned C1-C6 alkyl group is substituted with 1 to 7 halogen atoms, specifically, for example, trifluoromethyl, difluoromethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, or 2,2,2-trifluoroethyl.
「鹵C1-C6烷氧基」：前述C1-C6烷氧基被1～7個前述鹵素原子取代的基，具體而言例如，氟甲氧基、二氟甲氧基、二氯甲氧基、二溴甲氧基、三氟甲氧基、三氯甲氧基、2-氟乙氧基、2-溴乙氧基、2-氯乙氧基、2-碘乙氧基、2,2-二氟乙氧基、2,2,2-三氟乙氧基、2,2,2-三氯乙氧基、五氟乙氧基、3-氟丙氧基、3-氯丙氧基、4-氟丁氧基、5-氟戊基氧基、或6-氟己基氧基。"Halo C1-C6 alkoxy group": A group in which the aforementioned C1-C6 alkoxy group is substituted with 1 to 7 aforementioned halogen atoms, specifically, for example, fluoromethoxy, difluoromethoxy, and dichloromethoxy , Dibromomethoxy, trifluoromethoxy, trichloromethoxy, 2-fluoroethoxy, 2-bromoethoxy, 2-chloroethoxy, 2-iodoethoxy, 2,2 -Difluoroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy, 3-fluoropropoxy, 3-chloropropoxy , 4-fluorobutoxy, 5-fluoropentyloxy, or 6-fluorohexyloxy.
「C6-C10芳基」：碳數6～10的單環或雙環性的芳香族碳環，且可與非芳香族雜環或者環烷縮合。具體而言例如，苯基、萘基、四氫萘基(tetralinyl)、二氫茚基、
「6或7員非芳香族雜環」：藉由除了碳以外獨自選自氮、氧、硫之1～4的雜原子所構成之6或7員環的非芳香族的環狀基，且可為飽和或不飽和。具體而言例如，哌啶、四氫吡啶、
「5～7員非芳香族環狀烴」：碳數5～7的非芳香族的環烷，且可為飽和或不飽和。具體而言例如，環戊烷、環戊烯、環己烷、環己烯、環庚烷、或環庚烯。"5- to 7-membered non-aromatic cyclic hydrocarbon": a non-aromatic cycloalkane having 5 to 7 carbon atoms, which may be saturated or unsaturated. Specifically, for example, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cycloheptane, or cycloheptene.
「5～7員非芳香族雜環」：藉由除了碳以外獨自選自氮、氧、硫之1～4的雜原子所構成之5～7員非芳香族的環，且可為飽和或不飽和。具體而言例如，吡咯啶、二氫吡咯、哌啶、四氫吡啶、氮
「側氧基」：表示具有雙鍵的氧原子(=O)。"Pendant oxy group": represents an oxygen atom (=O) having a double bond.
「C1-C3烷基」：碳數1～3個的直鏈或分支鏈之一價烴基，具體而言例如，甲基、乙基、丙基、異丙基。"C1-C3 alkyl group": a linear or branched monovalent hydrocarbon group having 1 to 3 carbon atoms, specifically, for example, methyl, ethyl, propyl, and isopropyl.
以下針對本發明中之由通式(I)所表示之化合物的較佳態樣進行說明。The following describes the preferred aspects of the compound represented by the general formula (I) in the present invention.
本發明中之A係可被自取代基群組α獨立選出的一個以上的基取代之C1-C6伸烷基、可被自取代基群組α獨立選出的一個以上的基取代之伸苯基、可被自取代基群組α獨立選出的一個以上的基取代之5或6員伸雜芳基、可被自取代基群組α獨立選出的一個以上的基取代之C3-C6伸環烷基、或C2-C6伸炔基。In the present invention, A is a C1-C6 alkylene group which may be substituted by one or more groups independently selected from the substituent group α, and a phenylene group which may be substituted by one or more groups independently selected from the substituent group α , 5- or 6-membered heteroaryl groups that may be substituted by more than one group independently selected from substituent group α, C3-C6 cycloalkylene groups that may be substituted by more than one group independently selected from substituent group α Group, or C2-C6 alkynylene group.
較佳為，A係可被自取代基群組α獨立選出的一個以上的基取代之伸苯基(較佳為1,4-伸苯基)、或可被自取代基群組α獨立選出的一個以上的基取代之5或6員伸雜芳基(較佳為1,4-伸雜芳基)，更佳為，A係可被自取代基群組α獨立選出的一個以上的基取代之伸苯基(較佳為1,4-伸苯基)、可被自取代基群組α獨立選出的一個以上的基取代之吡啶二基(較佳為吡啶-1,4-二基)、可被自取代基群組α獨立選出的一個以上的基取代之嘧啶二基(較佳為嘧啶-1,4-二基)、可被自取代基群組α獨立選出的一個以上的基取代之嗒
取代基群組α為包含鹵素原子、氰基、C1-C6烷基、及C1-C6烷氧基之群組，較佳為包含鹵素原子、甲基及甲氧基之群組。The substituent group α is a group including a halogen atom, a cyano group, a C1-C6 alkyl group, and a C1-C6 alkoxy group, and preferably a group including a halogen atom, a methyl group, and a methoxy group.
本發明中之L係含有至少一個氮原子之3～6員雜環基或5或6員雜芳基(前述氮原子係與R6
及R7
所結合之碳原子直接結合)，於此，L亦可被自取代基群組β獨立選出的一個以上的基取代。自取代基群組β獨立選出側氧基之情形，前述3～6員雜環基及前述5或6員雜芳基係側氧基吖呾基、側氧基吡咯啶基、側氧基咪唑啶基、二氧咪唑啶基、側氧基
L1：
於此，選自L1群組的環亦可被自取代基群組β獨立選出的一個以上的基取代。Here, the ring selected from the L1 group may be substituted with one or more groups independently selected from the substituent group β.
取代基群組β較佳為包含鹵素原子、側氧基、及C1-C6烷基之群組，更佳為包含溴原子、側氧基、甲基及乙基之群組。L為選自L1群組的雜環基或雜芳基之情形，取代基群組β係包含鹵素原子、側氧基、及C1-C6之群組，較佳係包含鹵素原子、及C1-C6之群組，更佳係包含溴原子、甲基及乙基之群組。再更佳係甲基。The substituent group β is preferably a group including a halogen atom, a pendant oxy group, and a C1-C6 alkyl group, and more preferably a group including a bromine atom, a pendant oxy group, a methyl group, and an ethyl group. When L is a heterocyclic group or heteroaryl group selected from the group L1, the substituent group β includes a halogen atom, a pendant oxy group, and a group of C1-C6, and preferably includes a halogen atom and C1- The group C6 is more preferably a group containing a bromine atom, a methyl group, and an ethyl group. Methyl is even more preferred.
作為L及取代基β的組合，較佳為選自以下L2群組之3～6員雜環基或5或6員雜芳基，L2群組的環上的碳原子亦可進一步被取代基β取代。The combination of L and the substituent β is preferably a 3- to 6-membered heterocyclic group or a 5- or 6-membered heteroaryl group selected from the following L2 group. The carbon atom on the ring of the L2 group may be further substituted β substitution.
L2：
作為L及取代基β的組合，特佳為由以下的式所表示之N-甲基咪唑啶-2-酮，前述N-甲基咪唑啶-2-酮的環上的碳原子亦可進一步被取代基β取代。The combination of L and the substituent β is particularly preferably N-methylimidazolidin-2-one represented by the following formula, and the carbon atom on the ring of the aforementioned N-methylimidazolidin-2-one may be further Substituted by the substituent β.
R1 、R2 、R3 及R4 係各自獨立為氫原子、鹵素原子、氰基、C1-C6烷基、C1-C6烷氧基、鹵C1-C6烷基、鹵C1-C6烷氧基、可被自取代基群組γ獨立選出之一個以上的基取代之C6-C10芳基、可被自取代基群組γ獨立選出之一個以上的基取代之5或6員雜芳基、可被自取代基群組γ獨立選出之一個以上的基取代之C3-C6環烷基、或可被自取代基群組γ獨立選出之一個以上的基取代之3～6員雜環基；較佳為R1 為氫原子、鹵素原子、C1-C6烷基、C1-C6烷氧基、鹵C1-C6烷氧基、可被自取代基群組γ獨立選出之一個以上的基取代之苯基、可被自取代基群組γ獨立選出之一個以上的基取代之5或6員雜芳基、可被自取代基群組γ獨立選出之一個以上的基取代之C3-C6環烷基、或可被自取代基群組γ獨立選出之一個以上的基取代之3～6員雜環基，R2 、R3 及R4 係各自獨立為氫原子、鹵素原子、氰基、C1-C6烷基、或C1-C6烷氧基；更佳為，R1 為氫原子、氟原子、氯原子、溴原子、C1-C6烷基、C1-C6烷氧基、鹵C1-C6烷氧基、C3-C6環烷基、3～6員雜環基、可被自取代基群組γ獨立選出之一個以上的基取代之苯基、或可被自取代基群組γ獨立選出之一個以上的基取代之5或6員雜芳基，R2 、R3 及R4 係各自獨立為氫原子、氟原子、氰基、C1-C6烷基、或C1-C6烷氧基。R 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom, a halogen atom, a cyano group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen C1-C6 alkyl group, and a halogen C1-C6 alkoxy group Group, C6-C10 aryl group which may be substituted by one or more groups independently selected from substituent group γ, 5- or 6-membered heteroaryl group which may be substituted by one or more groups independently selected from substituent group γ, A C3-C6 cycloalkyl group that may be substituted by one or more groups independently selected from the substituent group γ, or a 3-6 member heterocyclic group that may be substituted by one or more groups independently selected from the substituent group γ; Preferably, R 1 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen C1-C6 alkoxy group, which may be substituted by one or more groups independently selected from the substituent group γ Phenyl, 5- or 6-membered heteroaryl which may be substituted by more than one group independently selected from substituent group γ, C3-C6 cycloalkane which may be substituted by more than one group independently selected from substituent group γ A group, or a 3- to 6-membered heterocyclic group which may be substituted by one or more groups independently selected from the substituent group γ, R 2 , R 3 and R 4 are each independently a hydrogen atom, a halogen atom, a cyano group, and C1 -C6 alkyl, or C1-C6 alkoxy; more preferably, R 1 is a hydrogen atom, fluorine atom, chlorine atom, bromine atom, C1-C6 alkyl, C1-C6 alkoxy, halogen C1-C6 alkane An oxy group, a C3-C6 cycloalkyl group, a 3-6 membered heterocyclic group, a phenyl group which may be substituted by one or more groups independently selected from the substituent group γ, or a phenyl group which may be independently selected from the substituent group γ In a 5- or 6-membered heteroaryl group substituted by more than one group, R 2 , R 3 and R 4 are each independently a hydrogen atom, a fluorine atom, a cyano group, a C1-C6 alkyl group, or a C1-C6 alkoxy group.
取代基群組γ係包含鹵素原子、C1-C6烷基、及C1-C6烷氧基之群組，較佳為包含鹵素原子、及C1-C6烷基之群組，更佳為包含氟原子、氯原子、及C1-C3烷基之群組。Substituent group γ is a group containing a halogen atom, a C1-C6 alkyl group, and a C1-C6 alkoxy group, preferably a group containing a halogen atom and a C1-C6 alkyl group, and more preferably a fluorine atom , Chlorine atom, and C1-C3 alkyl group.
R5 為氫原子、C1-C6烷基、或鹵C1-C6烷基，較佳為氫原子、或C1-C6烷基，更佳為甲基、或乙基。R 5 is a hydrogen atom, a C1-C6 alkyl group, or a halogen C1-C6 alkyl group, preferably a hydrogen atom or a C1-C6 alkyl group, more preferably a methyl group or an ethyl group.
R6 及R7 係各自獨立為氫原子、或C1-C6烷基，較佳為氫原子、或甲基。R 6 and R 7 are each independently a hydrogen atom or a C1-C6 alkyl group, preferably a hydrogen atom or a methyl group.
在一態樣中，R4 與R5 可與其等所結合的原子一起形成與式(I)的結構的一部分進行縮合之6或7員非芳香族雜環。包含前述6或7員非芳香族雜環之本發明的化合物，較佳為以下所示之結構。In one aspect, R 4 and R 5 may form a 6- or 7-membered non-aromatic heterocyclic ring condensed with a part of the structure of formula (I) together with the atoms to which they are bonded. The compound of the present invention containing the aforementioned 6- or 7-membered non-aromatic heterocyclic ring preferably has the structure shown below.
在一態樣中，A為伸苯基或5或6員伸雜芳基之情形，R6 係可與A及其等所結合之原子一起形成縮合成A之5～7員非芳香族環狀烴或5～7員非芳香族雜環。包含前述5～7員非芳香族環狀烴或5～7員非芳香族雜環之結構，較佳為以下所示之結構。In one aspect, when A is a phenylene group or a 5- or 6-membered heteroaryl group, R 6 can be condensed into a 5- to 7-membered non-aromatic ring with A and its bonded atoms Shape hydrocarbon or 5-7 member non-aromatic heterocyclic ring. The structure containing the aforementioned 5- to 7-membered non-aromatic cyclic hydrocarbon or 5- to 7-membered non-aromatic heterocyclic ring is preferably the structure shown below.
在一態樣中，R6 及R7 可與其等所結合之原子一起形成C3-C6環烷。包含前述C3-C6環烷之結構造係以下所示之結構。In one aspect, R 6 and R 7 can form a C3-C6 cycloalkane together with the atoms to which they are bonded. The structure containing the aforementioned C3-C6 cycloalkane is the structure shown below.
作為具有通式(I)的化合物，較佳為實施例所記載的化合物，更佳為以下的化合物。 (E)-1-(4-(2-(1-乙基-1H-苯并[d]咪唑2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮 (E)-1-(4-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)-2-氟苄基)-3-甲基咪唑啶-2-酮 (E)-1-(4-(2-(1-乙基-7-氟-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮 (E)-1-((5-(2-(1-乙基-4-氟-1H-苯并[d]咪唑2-基)乙烯基)吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮 (E)-1-((5-(2-(1-乙基-5-氟-1H-苯并[d]咪唑2-基)乙烯基)吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮As the compound having the general formula (I), the compounds described in the examples are preferred, and the following compounds are more preferred. (E)-1-(4-(2-(1-Ethyl-1H-benzo(d)imidazol-2-yl)vinyl)benzyl)-3-methylimidazolidin-2-one (E)-1-(4-(2-(1-Ethyl-1H-benzo(d)imidazol-2-yl)vinyl)-2-fluorobenzyl)-3-methylimidazolidine-2 -ketone (E)-1-(4-(2-(1-Ethyl-7-fluoro-1H-benzo(d)imidazol-2-yl)vinyl)benzyl)-3-methylimidazolidine-2 -ketone (E)-1-((5-(2-(1-ethyl-4-fluoro-1H-benzo(d)imidazol-2-yl)vinyl)pyridin-2-yl)methyl)-3- Methylimidazolidin-2-one (E)-1-((5-(2-(1-ethyl-5-fluoro-1H-benzo(d)imidazol-2-yl)vinyl)pyridin-2-yl)methyl)-3- Methylimidazolidin-2-one
此外，其結構如同以下的式所示。In addition, its structure is as shown in the following formula.
(藥學上容許的鹽) 所謂「其藥學上容許的鹽」，在化合物中，具有酸性基或鹼性基之情形，因可藉由與鹼或酸進行反應而成為「與鹼的鹽」或「酸加成鹽」，故表示為其鹽。又，所謂「其藥學上容許的鹽」，亦包含其水合物等。(Pharmaceutically acceptable salt) The so-called "pharmaceutically acceptable salt" refers to a compound that has an acidic group or a basic group, which can become a "salt with a base" or an "acid addition salt" by reacting with a base or acid. Therefore, it is expressed as its salt. In addition, the "pharmaceutically acceptable salt thereof" also includes its hydrate and the like.
作為化合物的「與鹼的鹽」，較佳為如鈉鹽、鉀鹽、鋰鹽般的鹼金屬鹽；如鎂鹽、鈣鹽般的鹼土類金屬鹽；如N-甲基
作為化合物的「酸加成鹽」，較佳為如氫氟酸鹽、鹽酸鹽、氫溴酸鹽、氫碘酸鹽般的氫鹵酸鹽、硝酸鹽、過氯酸鹽、硫酸鹽、磷酸鹽等無機酸鹽；如甲磺酸鹽、三氟甲磺酸鹽、乙烷磺酸鹽般的低級烷烴磺酸鹽；如苯磺酸鹽、p-甲苯磺酸鹽般的芳基磺酸鹽；乙酸鹽、蘋果酸鹽、反丁烯二酸鹽、丁二酸鹽、檸檬酸鹽、抗壞血酸鹽、酒石酸鹽、草酸鹽、順丁烯二酸鹽等有機酸鹽；及如甘胺酸鹽、離胺酸鹽、精胺酸鹽、鳥胺酸鹽、麩醯胺酸鹽、天冬醯胺酸鹽般的胺基酸鹽。The "acid addition salt" of the compound is preferably hydrohalide, nitrate, perchlorate, sulfate, such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide, Inorganic acid salts such as phosphate; lower alkane sulfonate such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate; arylsulfonate such as benzenesulfonate and p-toluenesulfonate Acid salts; acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate and other organic acid salts; and such as glycerol Amino acid salt, lysine acid salt, arginine acid salt, ornithine acid salt, glutamine acid salt, aspartic acid salt of amino acid salt.
(水合物等) 本發明的化合物或其鹽，藉由在大氣中放置或再結晶而吸收水分，有附著吸附水、成為水合物之情形，本發明中亦包含此種各種的水合物、溶劑合物及多晶型(crystal polymorphism)的化合物。(Hydrate etc.) The compound of the present invention or its salt absorbs water by being placed in the atmosphere or recrystallized, and may adhere to adsorb water and become a hydrate. The present invention also includes such various hydrates, solvates, and polycrystals. Type (crystal polymorphism) compound.
(異構物) 本發明的化合物中，依據取代基的種類，會存在互變異構物、幾何異構物。本說明書中，雖有時僅以異構物的一形態記載本發明的化合物，但本發明亦包含其以外的異構物，且亦包含異構物經分離者、或者其等之混合物。 本發明的化合物中，有具有不齊碳原子或軸不齊之情形，基於此，會存在光學異構物。本發明亦包含光學異構物經分離者、或者其等之混合物。(Isomers) In the compound of the present invention, tautomers and geometric isomers may exist depending on the types of substituents. In this specification, although the compound of the present invention may be described as only one form of isomer, the present invention also includes other isomers, and also includes separated isomers or mixtures thereof. In the compound of the present invention, there are cases where there are irregular carbon atoms or axial irregularities. Based on this, optical isomers may exist. The present invention also includes separated optical isomers or mixtures thereof.
(同位素) 本發明的化合物中，亦包含標誌物(label body)，亦即，化合物的一或二個以上的原子經同位元素(例如，2 H、3 H、13 C、14 C、35 S等)取代之化合物。(Isotopes) The compound of the present invention also includes a label body, that is, one or two or more atoms of the compound have isotopic elements (for example, 2 H, 3 H, 13 C, 14 C, 35 S). Etc.) Substituted compounds.
(前驅藥) 本發明中，亦包含本發明的化合物的藥學上容許之前驅藥。所謂藥學上容許之前驅藥，係指藉由加溶劑分解或在生理學的條件下，具有會轉變成胺基、羥基、羧基等的基之化合物。作為形成前驅藥的基，可列舉例如，Prog.Med,5,2157-2161(1985)所記載的基。(Prodrug) In the present invention, pharmaceutically acceptable prodrugs of the compound of the present invention are also included. The so-called pharmaceutically acceptable prodrug refers to a compound that has a group that can be converted into an amino group, a hydroxyl group, a carboxyl group, etc. by solubilization or under physiological conditions. Examples of the base forming the prodrug include the base described in Prog. Med, 5, 2157-2161 (1985).
作為該前驅藥，更具體而言，在化合物中存在胺基之情形，可列舉該胺基經醯化、磷酸化的化合物(例如為，該胺基經二十烷醯基(eicosanoyl)化、丙胺醯基化、戊基胺基羰基化、(5-甲基-2-側氧基-1,3-二氧雜環戊烯-4-基)甲氧羰基化、四氫呋喃基化、吡咯啶基甲基化、三甲基乙醯基氧基甲基化的化合物等)等。As the prodrug, more specifically, when there is an amine group in the compound, a compound in which the amine group is acylated or phosphorylated (for example, the amine group is eicosanoylized, Alanine, pentylamino carbonylation, (5-methyl-2-oxo-1,3-dioxol-4-yl) methoxycarbonylation, tetrahydrofurylation, pyrrolidine Methylated compounds, trimethylacetoxymethylated compounds, etc.).
在化合物中存在羥基之情形，可列舉該羥基經醯化、烷基化、磷酸化、硼酸化的化合物(例如為，該羥基經乙醯基化、棕櫚醯基化、丙醯基化、三甲基乙醯基化、琥珀醯基化、富馬醯基化、丙胺醯基化、二甲基胺基甲基羰基化的化合物等)等。In the case of the presence of a hydroxyl group in the compound, examples include compounds in which the hydroxyl group is acylated, alkylated, phosphorylated, or borated (for example, the hydroxy group is acetylated, palmitoylated, propionated, three Methyl acetylation, succinylation, fumaracylation, propylamine acylation, dimethylaminomethyl carbonylation compounds, etc.).
在化合物中存在羧基之情形，可列舉該羧基經酯化、醯胺化的化合物(例如為，該羧基經乙基酯化、苯基酯化、羧甲基酯化、二甲基胺基甲基酯化、三甲基乙醯基氧基甲基酯化、乙氧基羰基氧基乙基酯化、醯胺化或甲基醯胺化的化合物等)等。In the case of the presence of a carboxyl group in the compound, compounds in which the carboxyl group is esterified or aminated (for example, the carboxyl group is esterified with ethyl, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl Group esterification, trimethylacetoxymethyl esterification, ethoxycarbonyloxyethyl esterification, amination or methyl amination compounds, etc.).
(製造方法) 本發明的化合物及其藥學上容許的鹽，可遵循以下記載的方法進行合成。又，亦可利用基於其基本結構或取代基種類所致的特徵，而應用各種公知的合成法進行製造。合成本發明的化合物之際，依據官能基的種類，有時在製造技術上較有效的是在從原料獲致中間體的階段以適當的保護基(能輕易轉換成該官能基的基)保護官能基。作為此種保護基，可列舉例如Wuts (P.G.M.Wuts)及Greene (T.W.Greene)著之Greene’s Protective Groups in Organic Synthesis(第3版，1999年)中所記載的保護基等，只要適當選擇並使用此等反應條件即可。(Production method) The compound of the present invention and its pharmaceutically acceptable salt can be synthesized according to the method described below. Moreover, it is also possible to use the characteristics based on the basic structure or the kind of substituent, and to apply various well-known synthesis methods for manufacture. When synthesizing the compound of the present invention, depending on the type of functional group, it is sometimes more effective in manufacturing technology to protect the functional group with an appropriate protective group (a group that can be easily converted into the functional group) at the stage of obtaining intermediates from the raw materials. base. Examples of such protecting groups include those described in Greene's Protective Groups in Organic Synthesis (3rd edition, 1999) by Wuts (PGMWuts) and Greene (TWGreene), etc., as long as they are appropriately selected and used. Wait for the reaction conditions.
在此種方法中，可在導入該保護基並進行反應後，因應需要去除保護基，藉此獲得所期望的化合物。又，本發明的化合物的前驅藥，可與上述保護基同樣，在從原料獲致中間體的階段，導入特定的基或者使用所得之化合物，並進一步進行反應，而藉此製造。反應可藉由應用通常的酯化、醯胺化、脫水等方法而進行。In this method, after the protective group is introduced and reacted, the protective group can be removed as necessary to obtain the desired compound. In addition, the prodrug of the compound of the present invention can be produced by introducing a specific group or using the obtained compound at the stage of obtaining an intermediate from the raw material in the same manner as the above-mentioned protecting group, and further reacting. The reaction can be carried out by applying ordinary methods such as esterification, amination and dehydration.
合成本發明的化合物之際所使用的中間體可藉由公知的方法或其修飾方法而合成。The intermediate used when synthesizing the compound of the present invention can be synthesized by a known method or its modification method.
在下述方法的各步驟的反應中所使用的溶劑，只要為不阻礙反應且溶解部分起始原料者則無特別限定，例如選自下述溶劑群組。溶劑群組包含如己烷、戊烷、石油醚、環己烷般的脂肪族烴類；如苯、甲苯、二甲苯般的芳香族烴類；如二氯甲烷(氯甲烷)、氯仿、四氯化碳、二氯乙烷、氯苯、二氯苯般的鹵化烴類；如二乙基醚、二異丙基醚、四氫呋喃、二
在下述方法的各步驟的反應中所使用的酸，只要為不阻礙反應者則無特別限定，選自下述酸群組。酸群組包含如鹽酸、氫溴酸、氫碘酸、磷酸、硫酸、硝酸般的無機酸；如乙酸、丙酸、三氟乙酸、五氟丙酸般的有機酸；及如甲磺酸、三氟甲磺酸、p-甲苯磺酸、樟腦磺酸般的有機磺酸。The acid used in the reaction of each step of the following method is not particularly limited as long as it does not hinder the reaction, and is selected from the following acid group. The acid group includes inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, and nitric acid; organic acids such as acetic acid, propionic acid, trifluoroacetic acid, and pentafluoropropionic acid; and organic acids such as methanesulfonic acid, Trifluoromethanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid like organic sulfonic acid.
在下述方法的各步驟的反應中所使用的鹼，只要為不阻礙反應者則無特別限定，選自下述鹼群組。鹼群組包含如碳酸鋰、碳酸鈉、碳酸鉀、碳酸銫般的鹼金屬碳酸鹽；如碳酸氫鋰、碳酸氫鈉、碳酸氫鉀般的鹼金屬碳酸氫鹽；如氫氧化鋰、氫氧化鈉、氫氧化鉀般的鹼金屬氫氧化物；如氫氧化鈣、氫氧化鋇般的鹼土類金屬氫氧化物；如氫化鋰、氫化鈉、氫化鉀般的鹼金屬氫化物；如鋰醯胺、鈉醯胺、鉀醯胺般的鹼金屬醯胺；如甲氧鋰、甲氧鈉、乙氧鈉、tert-丁氧鈉、tert-丁氧鉀般的鹼金屬烷氧化物；如二異丙胺鋰般的烷基醯胺鋰；如鋰雙三甲基矽基醯胺、鈉雙三甲基矽基醯胺般的矽基醯胺；如n-丁基鋰、sec-丁基鋰、tert-丁基鋰般的烷基鋰；如氯化甲鎂、溴化甲鎂、碘化甲鎂、氯化乙鎂、溴化乙鎂、氯化異丙鎂、溴化異丙鎂、氯化異丁鎂般的鹵化烷鎂；及如三乙胺、三丁胺、二異丙基乙胺、N-甲基哌啶、N-甲基
在下述方法的各步驟的反應中，反應溫度係依據溶劑、起始原料、試藥等而異，反應時間係依據溶劑、起始原料、試藥、反應溫度等而異。In the reaction in each step of the following method, the reaction temperature varies depending on the solvent, starting material, reagent, etc., and the reaction time varies depending on the solvent, starting material, reagent, reaction temperature, etc.
在下述方法的各步驟的反應中，反應結束後，各步驟之目的化合物係遵循通常方法而從反應混合物被分離。目的化合物，例如藉由以下步驟而得：(i)因應需要濾除觸媒等不溶物、(ii)在反應混合物中添加水及不與水混合的溶劑(例如，氯甲烷、二乙基醚、乙酸乙酯等)而萃取目的化合物、(iii)將有機層進行水洗並使用無水硫酸鎂等乾燥劑使其乾燥、(iv)將溶劑進行餾去。所得之目的化合物，可因應需要藉由通常方法，例如再結晶、再沉澱、蒸餾、或使用矽膠或者氧化鋁等的管柱層析法(包含順相及逆相)等而進一步純化。又，各步驟之目的化合物亦可不純化而直接使用於後續反應。In the reaction of each step of the following method, after the reaction is completed, the target compound of each step is separated from the reaction mixture according to the usual method. The target compound is obtained, for example, by the following steps: (i) filtering out insoluble materials such as catalysts as needed, (ii) adding water and a solvent that does not mix with water (for example, methyl chloride, diethyl ether) into the reaction mixture , Ethyl acetate, etc.) to extract the target compound, (iii) wash the organic layer with water and dry it with a desiccant such as anhydrous magnesium sulfate, and (iv) distill off the solvent. The obtained target compound can be further purified by usual methods, such as recrystallization, reprecipitation, distillation, or column chromatography using silica gel or alumina (including the normal phase and the reverse phase) as needed. In addition, the target compound in each step can be used directly in the subsequent reaction without purification.
在下述方法的各步驟中，可藉由使用如(R)或(S)-苯乙胺般的光學活性胺進行分別再結晶、或使用光學活性管柱進行分離，而分離、純化光學異構物。In each step of the following method, optical isomers can be separated and purified by using optically active amines such as (R) or (S)-phenethylamine for recrystallization, or optically active columns for separation. Things.
以下針對本發明的化合物之一般製造方法進行敘述。但是，製造方法完全不受限於下述方法。The general production method of the compound of the present invention will be described below. However, the manufacturing method is not limited to the following method at all.
[A法]A法係由化合物A1及A2製造在通式(I)中R6 與R7 為氫原子之本發明的化合物A3的方法。[Method A] Method A is a method for producing compound A3 of the present invention in which R 6 and R 7 are hydrogen atoms in the general formula (I) from compounds A1 and A2.
(步驟A-1)偶合反應
步驟A-1係對於化合物A1，在鈀觸媒及鹼的存在下，藉由使用等量或者過量的硼酸或者硼酸酯衍生物A2的條件(鈴木-宮浦偶合)而獲得本發明的化合物A3之步驟。作為鈀觸媒，可列舉肆(三苯基膦)鈀、[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(II)二氯甲烷錯合物(1：1)、氯(2-二環己基膦基-2’4’6’-三異丙基-1,1’-聯苯基)[2-(2’-胺基-1,1’-聯苯基)]鈀(II)、參(二亞苄基丙酮)二鈀、乙酸鈀(II)、乙醯基丙酮鈀(II)、或雙(三苯基膦)二氯化鈀(II)等。又，作為鹼，可列舉三乙胺、二異丙基乙胺、1,8-二吖雙環[5.4.0]-7-十一烯(DBU)、或1,5-二吖雙環[4.3.0]-5-壬烯(DBN)等有機鹼、碳酸氫鉀、碳酸氫鈉、碳酸鉀、碳酸鈉、氫氧化鉀、氫氧化鈉、磷酸鉀、或磷酸鈉等無機鹼。作為反應溶劑，只要進行目的反應則未被特別限定，但可列舉甲醇及乙醇等醇類、四氫呋喃、1,2-二甲氧乙烷及1,4-二
[A’法]A’法係由化合物A’1製造在通式(I)中R6 及R7 為氫原子之本發明的化合物A’2的方法。[A' method] A'method is a method for producing compound A'2 of the present invention in which R 6 and R 7 are hydrogen atoms in general formula (I) from compound A'1.
(步驟A’-1)偶合反應 步驟A’-1係對於化合物A’1，在鈀觸媒及鹼基的存在下，藉由使用等量或者過量的硼酸或者硼酸酯衍生物(R1 -B(OH)2 或R1 -B(OR)2 、R表示任意的烷基)的條件(鈴木-宮浦偶合)而獲得本發明的化合物A’2之步驟。本步驟可與步驟A-1同樣地進行。(Step A'-1) Coupling reaction step A'-1 is for compound A'1, in the presence of a palladium catalyst and a base, by using the same amount or excess of boric acid or boric acid ester derivative (R 1 -B(OH) 2 or R 1 -B(OR) 2 , R represents an arbitrary alkyl group) (Suzuki-Miyaura coupling) to obtain the compound A'2 of the present invention. This step can be performed in the same manner as step A-1.
[B法]B法係由化合物B1及B2製造在通式(I)中R6 與R7 為氫原子之本發明的化合物B3的方法。[Method B] Method B is a method for producing compound B3 of the present invention in which R 6 and R 7 are hydrogen atoms in the general formula (I) from compounds B1 and B2.
(步驟B-1)烷基化反應
步驟B-1係使用化合物B1，在鹼存在下，進行化合物B2的氮原子上的烷基化而獲得本發明的化合物B3之步驟。作為鹼，可列舉氫化鈉等鹼金屬氫化物、n-丁基鋰、sec-丁基鋰等烷基鋰、二異丙胺鋰等鹼金屬醯胺類等。作為反應溶劑，只要進行目的反應則未被特別限定，但可列舉四氫呋喃、1,2-二甲氧乙烷及1,4-二
[C法]C法係由化合物C1及C2製造在通式(I)中L為咪唑啶-2-酮衍生物之本發明的化合物C3的方法。[Method C] Method C is a method for producing compound C3 of the present invention in which L is an imidazolidin-2-one derivative in the general formula (I) from compounds C1 and C2.
(步驟C-1)偶合反應 步驟C-1係對於化合物C1，在鈀觸媒及鹼的存在下，藉由使用等量或者過量的硼酸或者硼酸酯衍生物C2的條件(鈴木-宮浦偶合)而獲得本發明的化合物C3之步驟。本步驟可與步驟A-1同樣地進行。(Step C-1) Coupling reaction Step C-1 For compound C1, in the presence of a palladium catalyst and a base, the compound C3 of the present invention is obtained by using the same amount or excess of boric acid or boric acid ester derivative C2 (Suzuki-Miyaura coupling)的步。 The steps. This step can be performed in the same manner as step A-1.
[D法]D法係由化合物D1製造在通式(I)中R6 與R7 為氫原子且L為咪唑啶-2-酮衍生物之本發明的化合物D4的方法。[Method D] Method D is a method for producing compound D4 of the present invention in which R 6 and R 7 are hydrogen atoms in general formula (I) and L is an imidazolidin-2-one derivative from compound D1.
(步驟D-1)氧化反應 步驟D-1係對於化合物D1，藉由使等量或稍微過量的氧化劑作用而獲得化合物D2之步驟。作為氧化劑，可使用草醯氯與二甲亞碸的組合(Swern氧化)、或1,1,1-三乙醯氧基-1,1-二氫-1,2-苯碘醯(benziodoxol)-3(1H)-酮(Dess-Martin氧化)等。作為反應溶劑，只要進行目的反應則未被特別限定，但較佳為二氯甲烷、1,2-二氯乙烷等鹵化烴。反應溫度係配合所使用的氧化劑而適當選擇，但較佳為-78～20℃左右。反應時間通常為30分鐘～24小時。(Step D-1) Oxidation reaction Step D-1 is a step for compound D1 to obtain compound D2 by using an equal amount or a slight excess of oxidizing agent. As an oxidizing agent, a combination of oxalic chloride and dimethyl sulfoxide (Swern oxidation), or 1,1,1-triacetyloxy-1,1-dihydro-1,2-phenyliodoxol (benziodoxol) can be used -3(1H)-ketone (Dess-Martin oxidation) and so on. The reaction solvent is not particularly limited as long as the intended reaction is performed, but halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane are preferred. The reaction temperature is appropriately selected according to the oxidizing agent used, but it is preferably about -78 to 20°C. The reaction time is usually 30 minutes to 24 hours.
(步驟D-2)還原性胺基化反應 步驟D-2係對於化合物D2與乙烯二胺衍生物藉由使還原劑作用而進行還原性胺基化以獲得化合物D3之步驟。作為還原劑，可列舉氰基硼氫化鈉或氫化三乙醯氧基硼鈉等。反應系統中若添加乙酸或三氟乙酸等酸則反應會順暢地進行。作為反應溶劑，較佳為二氯甲烷或1,2-二氯乙烷等鹵化烴。反應溫度通常為0～80℃左右。反應時間通常為30分鐘～2日左右。(Step D-2) Reductive amination reaction Step D-2 is a step of reductive amination of compound D2 and ethylene diamine derivative by using a reducing agent to obtain compound D3. As a reducing agent, sodium cyanoborohydride, sodium triacetoxyborohydride, etc. are mentioned. If an acid such as acetic acid or trifluoroacetic acid is added to the reaction system, the reaction proceeds smoothly. The reaction solvent is preferably a halogenated hydrocarbon such as dichloromethane or 1,2-dichloroethane. The reaction temperature is usually about 0 to 80°C. The reaction time is usually about 30 minutes to 2 days.
(步驟D-3)保護基的去除與環化反應
步驟D-3係對於化合物D3使過量的酸作用並去除tert-丁氧羰(Boc)基後，在鹼存在下，使用羰基二咪唑(carbonyldiimidazole)進行環化反應而獲得化合物D4之步驟。作為去除Boc基所使用的酸，較佳為4mol/L之氯化氫的乙酸乙酯溶液或1,4-二
關於用於製造本發明的化合物之方法A～D所使用的原料，其一般的製法例示於以下的E法～K法。Regarding the raw materials used in methods A to D for producing the compound of the present invention, general production methods are exemplified in the following E method to K method.
[E法]E法係製造相當於A法的化合物A1及C法的化合物C1之化合物E8的方法。[Method E] Method E is a method for producing compound E8 corresponding to compound A1 of Method A and compound C1 of Method C.
(步驟E-1、及E-4)偶合反應
步驟E-1、及E-4係對於化合物E1或E3的苯環上的取代基X，在鈀觸媒存在下，藉由使用等量或者過量的硼酸或者硼酸酯(R1
-B(OH)2
或R1
-B(OR)2
；R表示任意的烷基)的條件(鈴木-宮浦偶合)；使用等量或者過量的有機錫試藥(R1
-SnR3
)的條件(Stille偶合)；或使用等量或者過量的有機鋅試藥(R1
-ZnX；X表示鹵素原子)的條件(根岸偶合)等，而進行取代基R1
的導入以獲得化合物E2或E4之步驟。上述反應中，依據需要可添加鹼。作為鈀觸媒，可列舉肆(三苯基膦)鈀、[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(II)二氯甲烷錯合物(1：1)、氯(2-二環己基膦基-2’4’6’-三異丙基-1,1’-聯苯基)[2-(2’-胺基-1,1’-聯苯基)]鈀(II)、參(二亞苄基丙酮)二鈀、乙酸鈀(II)、乙醯基丙酮鈀(II)、或雙(三苯基膦)二氯化鈀(II)等。又，作為鹼，可列舉三乙胺、二異丙基乙胺、1,8-二吖雙環[5.4.0]-7-十一烯(DBU)、或1,5-二吖雙環[4.3.0]-5-壬烯(DBN)等有機鹼、碳酸氫鉀、碳酸氫鈉、碳酸鉀、碳酸鈉、氫氧化鉀、氫氧化鈉、磷酸鉀、或磷酸鈉等無機鹼。作為反應溶劑，只要進行目的反應則未被特別限定，但可列舉甲醇、乙醇、四氫呋喃、1,2-二甲氧乙烷、1,4-二
(步驟E-2、及E-3)本位(ipso)取代反應 步驟E-2、及E-3係對於化合物E1或E2，在鹼基存在下，使等量或者過量的對應胺化合物(R5 -NH2 )進行反應而獲得化合物E3或E4之步驟。作為反應溶劑，只要進行目的反應則未被特別限定，但可使用甲醇、乙醇等醇溶劑等。反應溫度通常為20～80℃左右。反應時間通常為6小時～2日左右。(Steps E-2, and E-3) In situ (ipso) substitution reaction Steps E-2 and E-3 are for compound E1 or E2, in the presence of a base, the equivalent or excess corresponding amine compound (R 5 -NH 2 ) A step of reacting to obtain compound E3 or E4. The reaction solvent is not particularly limited as long as the intended reaction is performed, but alcohol solvents such as methanol and ethanol can be used. The reaction temperature is usually about 20 to 80°C. The reaction time is usually about 6 hours to 2 days.
(步驟E-5)還原反應
步驟E-5係將化合物E4在氫氣體環境下以金屬觸媒進行處理而還原硝基以獲得化合物E5之步驟。作為金屬觸媒，可列舉鈀碳、鈀黒、氫氧化鈀等鈀觸媒、鉑板、氧化鉑等鉑觸媒、還原鎳、雷氏鎳等鎳觸媒、參三苯基膦氯銠等銠觸媒、還原鐵等鐵觸媒等。作為反應溶劑，可列舉甲醇、乙醇、2-丙醇等醇類、二乙基醚、四氫呋喃、二
(步驟E-6)環化反應
步驟E-6係使化合物E5與羰基二咪唑作用而獲得化合物E6之步驟。作為反應溶劑，只要進行目的反應則未被特別限定，但較佳為四氫呋喃、1,2-二甲氧乙烷及1,4-二
(步驟E-7)環化反應 步驟E-7係對於化合物E5在酸存在下使原甲酸三甲酯作用而獲得化合物E7之步驟。作為酸，可使用p-甲苯磺酸一水合物等。作為反應溶劑，只要進行目的反應則未被特別限定，但較佳為四氫呋喃等醚類。反應溫度通常為20～80℃左右，使用四氫呋喃之際較佳為在加熱回流條件下進行反應。反應時間通常為1小時～2日左右。(Step E-7) Cyclization reaction Step E-7 is a step in which compound E5 is reacted with trimethyl orthoformate in the presence of acid to obtain compound E7. As the acid, p-toluenesulfonic acid monohydrate or the like can be used. The reaction solvent is not particularly limited as long as the intended reaction is performed, but ethers such as tetrahydrofuran are preferred. The reaction temperature is usually about 20 to 80°C. When tetrahydrofuran is used, it is preferable to perform the reaction under heating under reflux conditions. The reaction time is usually about 1 hour to 2 days.
(步驟E-8)鹵化反應 步驟E-8係對於化合物E6使溶劑量的三氯一氧化磷、或者三溴一氧化磷作用而獲得目的化合物E5之步驟。亦可將如苯、甲苯、二甲苯般的芳香族烴類作為溶劑，使用過量的三氯一氧化磷、或者三溴一氧化磷進行反應。反應溫度通常為60～190℃左右。反應時間通常為30分鐘～24小時左右。(Step E-8) Halogenation reaction Step E-8 is a step for compound E6 with a solvent amount of phosphorous monoxide or tribromophosphorus monoxide to obtain the target compound E5. It is also possible to use aromatic hydrocarbons such as benzene, toluene, and xylene as the solvent, and use excess phosphorus monoxide or tribromophosphorus monoxide for the reaction. The reaction temperature is usually about 60 to 190°C. The reaction time is usually about 30 minutes to 24 hours.
(步驟E-9)鹵化反應 步驟E-9係對於化合物E7使二異丙胺鋰作用後，使鹵化劑作用，藉此獲得化合物E8之步驟。作為鹵化劑，可使用六氯化乙烷、四溴化碳、碘等。作為反應溶劑，只要進行目的反應則未被特別限定，但較佳為四氫呋喃等醚類。反應溫度通常在將二異丙胺鋰添加至化合物E7之際為-78℃，在其後添加鹵化劑後為-78～30℃左右。反應時間通常在添加鹵化劑後為30分鐘～6小時左右。(Step E-9) Halogenation reaction Step E-9 is a step in which compound E7 is treated with lithium diisopropylamide and then a halogenating agent is used to obtain compound E8. As the halogenating agent, ethane hexachloride, carbon tetrabromide, iodine, etc. can be used. The reaction solvent is not particularly limited as long as the intended reaction is performed, but ethers such as tetrahydrofuran are preferred. The reaction temperature is usually -78°C when adding lithium diisopropylamine to compound E7, and is about -78 to 30°C after adding a halogenating agent. The reaction time is usually about 30 minutes to 6 hours after adding the halogenating agent.
[E’法]E’法係製造相當於A法的化合物A1及C法的化合物C1之化合物E’6的方法。[E' method] The E'method is a method for producing compound E'6 corresponding to compound A1 of method A and compound C1 of method C.
(步驟E’-1)本位取代反應 步驟E’-1係對於化合物E’1在鹼存在下使等量或者過量的對應胺化合物(R5 -NH2 )進行反應而獲得化合物E’2之步驟。本步驟可與步驟E-2同樣地進行。(Step E'-1) In-situ substitution reaction Step E'-1 is to react the equivalent or excess corresponding amine compound (R 5 -NH 2 ) to compound E'1 in the presence of a base to obtain compound E'2 step. This step can be performed in the same manner as step E-2.
(步驟E’-2)還原反應 步驟E’-2係對於化合物E’2在氫氣體環境下使金屬觸媒作用而還原硝基以獲得化合物E’3之步驟。本步驟可與步驟E-5同樣地進行。(Step E’-2) Reduction reaction Step E'-2 is a step of reducing the nitro group of compound E'2 by the action of a metal catalyst in a hydrogen atmosphere to obtain compound E'3. This step can be performed in the same manner as step E-5.
(步驟E’-3)環化反應 步驟E’-3係使化合物E’3與羰基二咪唑作用而獲得化合物E’4之步驟。本步驟可與步驟E-6同樣地進行。(Step E’-3) Cyclization reaction Step E'-3 is a step of reacting compound E'3 with carbonyldiimidazole to obtain compound E'4. This step can be performed in the same manner as step E-6.
(步驟E’-4)偶合反應 步驟E’-4係對於化合物E’4，在鈀觸媒存在下，藉由使用等量或者過量的硼酸或者硼酸酯(R1 -B(OH)2 或R1 -B(OR)2 ，R表示任意的烷基)的條件(鈴木-宮浦偶合)；使用等量或者過量的有機錫試藥(R1 -SnR3 )的條件(Stille偶合)；或使用等量或者過量的有機鋅試藥(R1 -ZnX；X表示鹵素原子)的條件(根岸偶合)等，而進行取代基R1 的導入以獲得化合物E’5之步驟。本步驟可與步驟E-1同樣地進行。(Step E'-4) Coupling reaction step E'-4 is for compound E'4, in the presence of a palladium catalyst, by using the same amount or excess of boric acid or boric acid ester (R 1 -B(OH) 2 Or R 1 -B(OR) 2 , R represents an arbitrary alkyl group) (Suzuki-Miyaura coupling); using the same amount or excess of organotin reagent (R 1 -SnR 3 ) (Stille coupling); Or use the same amount or excess of the organozinc reagent (R 1 -ZnX; X represents a halogen atom) conditions (Negishi coupling), etc., and carry out the step of introducing the substituent R 1 to obtain the compound E'5. This step can be performed in the same manner as step E-1.
(步驟E’-5)鹵化反應 步驟E’-5係對於化合物E’5使三氯一氧化磷、或者三溴一氧化磷作用而獲得目的化合物E’6之步驟。本步驟可與步驟E-8同樣地進行。(Step E’-5) Halogenation reaction Step E'-5 is a step for compound E'5 with phosphorous trichloride monoxide or tribromophosphorus monoxide to obtain the target compound E'6. This step can be performed in the same manner as step E-8.
[F法]F法係製造A法的化合物A1及C法的化合物C1中R1 =R4 、R2 =R3 的化合物F2之方法。[Method F] Method F is a method for producing compound A1 of Method A and compound C1 of Method C, wherein R 1 =R 4 and R 2 =R 3 are used.
(步驟F-1)烷基化反應
步驟F-1係將化合物F1在鹼存在下使用鹵化烷基(R5
-X)或者烷基磺酸酯(R5
-OSO2
R；R為任意的烷基或芳基)進行烷基化而獲得化合物F2之步驟。作為鹼，較佳為氫化鈉等鹼金屬氫化物。作為鹵化烷基，可使用碘化烷基(R5
-I)、溴化烷基(R5
-Br)等，作為烷基磺酸酯，可使用甲磺酸烷基(R5
-OSO2
CH3
)、p-甲苯磺酸烷基(R5
-OSO2
-C6
H4
CH3
)等。作為反應溶劑，只要進行目的反應則未被特別限定，但較佳為四氫呋喃、1,2-二甲氧乙烷及1,4-二
[G法]G法係製造相當於A法的化合物A2之化合物G5的方法。[Method G] Method G is a method for producing compound G5 corresponding to compound A2 of Method A.
(步驟G-1)鹵化反應、或磺醯基化反應 步驟G-1係使化合物G1在鹵化劑、或鹼存在下與磺醯基化劑作用而獲得化合物G3之步驟。作為鹵化劑，可列舉溴化氫乙酸溶液、亞硫醯氯等。作為鹼，可列舉三乙胺、吡啶等。作為磺醯基化劑，可列舉甲烷磺醯基氯、p-甲苯磺醯基氯等。作為反應溶劑，只要進行目的反應則未被特別限定，但在鹵化反應中較佳為二氯甲烷、1,2-二氯乙烷、氯仿等鹵化烴。又，在磺醯基化反應中較佳為二氯甲烷、1,2-二氯乙烷、氯仿等鹵化烴。反應溫度通常為0～60℃左右。反應時間為30～6小時左右。(Step G-1) Halogenation reaction or sulfonylation reaction Step G-1 is a step in which compound G1 is reacted with a sulfonating agent in the presence of a halogenating agent or a base to obtain compound G3. Examples of the halogenating agent include hydrogen bromide acetic acid solution, sulfite chloride, and the like. As a base, triethylamine, pyridine, etc. are mentioned. Examples of the sulfonating agent include methanesulfonyl chloride, p-toluenesulfonyl chloride, and the like. The reaction solvent is not particularly limited as long as the intended reaction is carried out, but halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform are preferred in the halogenation reaction. Furthermore, in the sulfonylation reaction, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform are preferred. The reaction temperature is usually about 0 to 60°C. The reaction time is about 30 to 6 hours.
(步驟G-2)鹵化反應 步驟G-2係使化合物G2與鹵化劑及自由基反應起始劑作用而獲得化合物G3之步驟。作為鹵化劑，較佳為N-溴琥珀醯亞胺等。作為自由基反應起始劑，較佳為2,2’-偶氮雙異丁腈等。作為反應溶劑，只要進行目的反應則未被特別限定，但較佳為四氯化碳等。反應溫度通常為40～80℃左右，使用四氯化碳之情形，通常在加熱回流下進行反應。反應時間通常為30分鐘～24小時左右。(Step G-2) Halogenation reaction Step G-2 is a step of reacting compound G2 with a halogenating agent and a radical reaction initiator to obtain compound G3. As the halogenating agent, N-bromosuccinimide and the like are preferred. As the radical reaction initiator, 2,2'-azobisisobutyronitrile and the like are preferred. The reaction solvent is not particularly limited as long as the intended reaction is performed, but carbon tetrachloride or the like is preferred. The reaction temperature is usually about 40 to 80°C. When carbon tetrachloride is used, the reaction is usually carried out under heating under reflux. The reaction time is usually about 30 minutes to 24 hours.
(步驟G-3)取代反應
步驟G-3係在鹼存在下，以L的氮原子取代化合物G3的X部分而獲得化合物G4之步驟。作為鹼，較佳為氫化鈉等鹼金屬氫化物。作為反應溶劑，只要進行目的反應則未被特別限定，但可列舉四氫呋喃、1,2-二甲氧乙烷及1,4-二
(步驟G-4)Heck反應 步驟G-4係在鹼基存在下，使用鈀觸媒，對於化合物G4使乙烯基硼酸酯進行反應，藉此獲得化合物G5之步驟。作為所使用的鹼基，較佳為三乙胺等有機鹼。作為鈀觸媒，較佳為雙(三-tert-丁基膦)鈀(0)等。作為乙烯基硼酸酯，較佳為4,4,5,5-四甲基-2-乙烯基-1,3,2-二氧硼戊環(dioxaborolane)。作為反應溶劑，只要進行目的反應則未被特別限定，但較佳為甲苯等芳香族烴類。反應溫度通常為60～150℃左右。反應時間為1小時～1日左右。(Step G-4) Heck reaction Step G-4 is a step in which compound G4 is reacted with vinyl borate in the presence of a base using a palladium catalyst to obtain compound G5. The base used is preferably an organic base such as triethylamine. As the palladium catalyst, bis(tri-tert-butylphosphine)palladium(0) or the like is preferred. As the vinyl borate, 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane is preferred. The reaction solvent is not particularly limited as long as it performs the desired reaction, but it is preferably aromatic hydrocarbons such as toluene. The reaction temperature is usually about 60 to 150°C. The reaction time is about 1 hour to 1 day.
[H法]H法係製造相當於B法的化合物B1之化合物H5、及相當於D法的化合物D1之化合物H4的方法。[H method] The H method is a method for producing compound H5 corresponding to the compound B1 of the B method, and compound H4 corresponding to the compound D1 of the D method.
(步驟H-1)Heck反應 步驟H-1係藉由使用鈀觸媒的Heck反應，而對於化合物H1導入乙烯基硼酸、或乙烯基硼酸酯部位，藉此獲得化合物H2之步驟。本步驟可與步驟G-4同樣地進行。(Step H-1) Heck reaction Step H-1 is a step of introducing vinyl boronic acid or vinyl boronic acid ester sites into compound H1 by Heck reaction using a palladium catalyst, thereby obtaining compound H2. This step can be performed in the same manner as step G-4.
(步驟H-2)偶合反應 步驟H-2係對於等量或者過量的化合物H2，在鈀觸媒及鹼基的存在下，藉由使對應的鹵化物、烷基磺酸酯、或芳基磺酸酯進行反應的條件(鈴木-宮浦偶合)而獲得化合物H3之步驟。本步驟可與步驟A-1同樣地進行。(Step H-2) Coupling reaction Step H-2 is a condition for reacting the corresponding halide, alkyl sulfonate, or aryl sulfonate in the presence of a palladium catalyst and a base in the presence of an equal or excess amount of compound H2 ( Suzuki-Miyaura coupling) to obtain compound H3. This step can be performed in the same manner as step A-1.
(步驟H-3)還原反應 步驟H-3係使用還原劑而還原化合物H3的酯部分以獲得醇H4之步驟。作為還原劑，可使用鋁氫化鋰、二異丁基氫化鋁等。作為反應溶劑，只要進行目的反應則未被特別限定，但較佳為四氫呋喃、二乙基醚等醚類。反應溫度通常為-78～80℃左右。反應時間通常為30分鐘～24小時左右。(Step H-3) Reduction reaction Step H-3 is a step of reducing the ester portion of compound H3 using a reducing agent to obtain alcohol H4. As the reducing agent, lithium aluminum hydride, diisobutyl aluminum hydride, and the like can be used. The reaction solvent is not particularly limited as long as the intended reaction is performed, but ethers such as tetrahydrofuran and diethyl ether are preferred. The reaction temperature is usually about -78 to 80°C. The reaction time is usually about 30 minutes to 24 hours.
(步驟H-4)鹵化、或磺醯基化 步驟H-4係藉由使醇H4與鹵化劑、或磺醯基化劑作用而獲得化合物H5之步驟。本步驟可利用與步驟G-1同樣的方法進行。(Step H-4) Halogenation or sulfonylation Step H-4 is a step of obtaining compound H5 by reacting alcohol H4 with a halogenating agent or a sulfonating agent. This step can be performed by the same method as step G-1.
[I法]I法係製造C法的化合物C2中R7 為氫的化合物I4之方法。[Method I] Method I is a method for producing compound I4 in which R 7 is hydrogen in compound C2 of Method C.
(步驟I-1)還原性胺基化反應 步驟I-1係對於與化合物I1對應的乙烯二胺衍生物使還原劑作用，藉此進行還原性胺基化而獲得化合物I2之步驟。本步驟可與步驟D-2同樣地進行。(Step I-1) Reductive amination reaction Step I-1 is a step of applying a reducing agent to the ethylene diamine derivative corresponding to compound I1 to perform reductive amination to obtain compound I2. This step can be performed in the same manner as step D-2.
(步驟I-2)保護基的去除與環化反應 步驟I-2係對於化合物I2使過量的酸作用而去除tert-丁氧羰(Boc)基後，在鹼基存在下，使用羰基二咪唑進行環化反應而獲得化合物I3之步驟。本步驟可與步驟D-3同樣地進行。(Step I-2) Removal of protecting group and cyclization reaction Step I-2 is a step of removing the tert-butoxycarbonyl (Boc) group by using excess acid for compound I2, and then performing a cyclization reaction using carbonyldiimidazole in the presence of a base to obtain compound I3. This step can be performed in the same manner as step D-3.
(步驟I-3)Heck反應 步驟I-3係藉由使用鈀觸媒的Heck反應，對化合物I3導入乙烯基硼酸、或乙烯基硼酸酯部位，藉此獲得化合物I4之步驟。本步驟可與步驟G-4同樣地進行。(Step I-3) Heck reaction Step I-3 is a step of introducing vinyl boronic acid or vinyl boronic acid ester sites into compound I3 by Heck reaction using a palladium catalyst to obtain compound I4. This step can be performed in the same manner as step G-4.
[J法]J法係製造相當於C法的化合物C2之化合物J5的方法。[Method J] Method J is a method for producing compound J5 equivalent to compound C2 of Method C.
(步驟J-1)還原性胺基化反應 步驟J-1係對於化合物J1與化合物J2使還原劑作用，藉此進行還原性胺基化而獲得化合物J3之步驟。本步驟可與步驟D-2同樣地進行。(Step J-1) Reductive amination reaction Step J-1 is a step of applying a reducing agent to compound J1 and compound J2 to perform reductive amination to obtain compound J3. This step can be performed in the same manner as step D-2.
(步驟J-2)保護基的去除與環化反應 步驟J-2係對於化合物J3使過量的酸作用而去除tert-丁氧羰(Boc)基後，在鹼基存在下，使用羰基二咪唑進行環化反應而獲得化合物J4之步驟。本步驟可與步驟D-3同樣地進行。(Step J-2) Removal of protecting group and cyclization reaction Step J-2 is a step of removing the tert-butoxycarbonyl (Boc) group of compound J3 by using excess acid, and then performing a cyclization reaction using carbonyldiimidazole in the presence of a base to obtain compound J4. This step can be performed in the same manner as step D-3.
(步驟J-3)Heck反應 步驟J-3係藉由使用鈀觸媒的Heck反應，而對化合物J4導入乙烯基硼酸、或乙烯基硼酸酯部位，藉此獲得化合物J5之步驟。本步驟可與步驟G-4同樣地進行。(Step J-3) Heck reaction Step J-3 is a step of introducing vinyl boronic acid or vinyl boronic acid ester sites into compound J4 by Heck reaction using a palladium catalyst to obtain compound J5. This step can be performed in the same manner as step G-4.
[K法]K法係製造相當於A’法的化合物A’1之化合物K4的方法。[K method] The K method is a method for producing compound K4 corresponding to compound A'1 of A'method.
(步驟K-1)環化反應 步驟K-1係使化合物K1與1,1’-硫代羰基二咪唑作用而獲得化合物K2之步驟。作為反應溶劑，只要進行目的反應則未被特別限定，但較佳為吡啶等吡啶類等。反應溫度通常為20～100℃左右。反應時間通常為12小時～3日左右。(Step K-1) Cyclization reaction Step K-1 is a step of reacting compound K1 with 1,1'-thiocarbonyldiimidazole to obtain compound K2. The reaction solvent is not particularly limited as long as the intended reaction is performed, but pyridines such as pyridine are preferred. The reaction temperature is usually about 20 to 100°C. The reaction time is usually about 12 hours to 3 days.
(步驟K-2)甲基化反應 步驟K-2係在鹼存在下，使化合物K2與碘甲烷作用而獲得化合物K3之步驟。作為鹼，較佳為二異丙基乙胺、三乙胺等有機鹼。作為反應溶劑，只要進行目的反應則並未被特別限定，但較佳為2-丙醇等醇類。反應溫度通常為20～60℃左右。反應時間通常為30分鐘～12小時左右。(Step K-2) Methylation reaction Step K-2 is a step of reacting compound K2 with methyl iodide in the presence of a base to obtain compound K3. As the base, organic bases such as diisopropylethylamine and triethylamine are preferred. The reaction solvent is not particularly limited as long as the target reaction is performed, but alcohols such as 2-propanol are preferred. The reaction temperature is usually about 20 to 60°C. The reaction time is usually about 30 minutes to 12 hours.
(步驟K-3)偶合反應
步驟K-3係對於與化合物K3對應的乙烯基硼酸或乙烯基硼酸酯進行使用鈀觸媒及銅觸媒的偶合反應，藉此獲得化合物K4之步驟。作為鈀觸媒，可列舉參(二亞苄基丙酮)二鈀、肆(三苯基膦)鈀、乙酸鈀等。有時除了鈀觸媒以外會進一步添加三-2-呋喃基膦、亞磷酸三甲酯、亞磷酸三乙酯等磷配位子。作為銅觸媒，可列舉噻吩-2-羧酸銅(I)、碘化銅(I)等。若進一步添加乙酸鋅，則有時會得到良好結果。作為反應溶劑，只要反應進行則未被特別限定，但較佳為四氫呋喃或1,4-二
(投予形態) 投予可為由錠劑、丸劑、膠囊劑、顆粒劑、散劑、液劑等所致之經口投予；或由關節內、靜脈內、肌肉內等注射劑、坐劑、點眼劑、眼軟膏、經皮用液劑、軟膏劑、經皮用貼附劑、經黏膜液劑、經黏膜貼附劑、吸入劑等所致之非經口投予的任一形態。(Investment form) The administration can be oral administration caused by tablets, pills, capsules, granules, powders, liquids, etc.; or by intra-articular, intravenous, intramuscular injections, sitting doses, eye drops, eye drops, etc. Ointment, transdermal liquid, ointment, transdermal patch, transmucosal liquid, transmucosal patch, inhalant, etc., any form of parenteral administration.
作為用於經口投予的固體組合物，能使用錠劑、散劑、顆粒劑等。此種固體組合物中，一種或二種以上的有效成分係與至少一種的不活性賦形劑，例如乳糖、甘露醇、葡萄糖、羥丙纖維素、微結晶纖維素、澱粉、聚乙烯基吡咯啶酮、及/或矽酸鋁鎂(magnesium aluminometasilicate)等進行混合。組合物可遵循通常方法含有不活性添加劑，例如如硬脂酸鎂般的潤滑劑或如羧甲基澱粉鈉(sodium carboxymethyl starch)等般的崩解劑、穩定化劑、溶解佐劑。錠劑或丸劑可依據需要而以糖衣或胃溶性或者腸溶性物質的薄膜進行被膜。As a solid composition for oral administration, tablets, powders, granules, etc. can be used. In this solid composition, one or two or more active ingredients and at least one inactive excipient, such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrole Pyridone, and/or magnesium aluminometasilicate, etc. are mixed. The composition may contain inactive additives following the usual methods, such as lubricants such as magnesium stearate or disintegrating agents, stabilizers, and dissolution adjuvants such as sodium carboxymethyl starch. Tablets or pills can be coated with sugar coating or a film of gastric or enteric substances as required.
用於經口投予的液體組合物，包含藥劑上所容許之乳化劑、溶液劑、懸浮液、糖漿劑或酏劑等，且包含一般所使用的不活性稀釋劑，例如純化水或乙醇。該液體組合物除了含有不活性稀釋劑以外亦可含有可溶化劑、濕潤劑、如懸浮液般的佐劑、甘味劑、風味劑、芳香劑、防腐劑。Liquid compositions for oral administration include emulsifiers, solutions, suspensions, syrups or elixirs that are pharmaceutically acceptable, and include generally used inactive diluents, such as purified water or ethanol. In addition to the inactive diluent, the liquid composition may also contain solubilizers, wetting agents, adjuvants such as suspensions, sweeteners, flavors, fragrances, and preservatives.
用於非經口投予的注射劑，含有無菌的水性或非水性的溶液劑、懸浮液或乳化劑。作為水性的溶劑，包含例如注射用蒸餾水或生理食鹽液。作為非水性的溶劑，有例如丙二醇、聚乙二醇或如橄欖油般的植物油、如乙醇般的醇類、或Polysorbate80等。此種組合物可進一步包含等滲劑(isotonizing agent)、防腐劑、濕潤劑、乳化劑、分散劑、穩定化劑、或溶解佐劑。此等藉由例如通過細菌保留過濾器的過濾、殺菌劑的摻合或照射而被無菌化。又，此等亦可藉由製造無菌的固體組合物，並在使用前溶解或懸浮於無菌水或無菌的注射用溶劑而使用。Injections for parenteral administration contain sterile aqueous or non-aqueous solutions, suspensions or emulsifiers. The aqueous solvent includes, for example, distilled water for injection or physiological salt solution. Examples of non-aqueous solvents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, or Polysorbate 80. Such a composition may further include an isotonizing agent, preservative, wetting agent, emulsifier, dispersant, stabilizer, or dissolution adjuvant. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending of bactericides, or irradiation. Moreover, these can also be used by preparing a sterile solid composition, and dissolving or suspending it in sterile water or a sterile solvent for injection before use.
作為外用劑，包含軟膏劑、硬膏劑、霜劑、膠凍劑、泥敷劑、噴霧劑、乳液劑、點眼劑、眼軟膏等。含有一般能使用的軟膏基劑、乳液基劑、水性或非水性的液劑、懸浮液、乳劑等。例如，作為軟膏或乳液基劑，可列舉聚乙二醇、丙二醇、白凡士林、白蜂蠟(white beeswax)、聚氧乙烯氫化蓖麻油、甘油單硬脂酸酯、硬脂醇、鯨蠟基醇、聚桂醇(lauromacrogol)、去水山梨醇倍半油酸酯(sorbitan sesquioleate)等。The external preparations include ointments, plasters, creams, jellies, poultices, sprays, emulsions, eye drops, eye ointments, and the like. Contains commonly used ointment bases, emulsion bases, aqueous or non-aqueous liquids, suspensions, emulsions, etc. For example, as an ointment or emulsion base, polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polyoxyethylene hydrogenated castor oil, glycerol monostearate, stearyl alcohol, and cetyl alcohol can be cited. , Lauromacrogol, sorbitan sesquioleate, etc.
吸入劑或經鼻劑等經黏膜劑，係使用固體、液體或半固體狀者，可遵循以往公知的方法製造。例如，可適當添加公知的賦形劑、以及pH調整劑、防腐劑、界面活性劑、潤滑劑、穩定劑或增黏劑等。投予可使用用於適當吸入或吹送的裝置。例如，可使用計量投予吸入裝置等公知裝置或噴霧器，將化合物以單獨或經配方的混合物的粉末的形式，或者以與醫藥上可容許之載體組合的溶液或懸浮液的形式進行投予。乾燥粉末吸入器等可為單次或多次投予用者，可使用乾燥粉末或含有粉末的膠囊。或者，亦可為使用適當的噴射劑，例如氯氟烷烴、氫氟烷烴或二氧化碳等較佳氣體的加壓氣溶膠噴霧等的形態。Transmucosal agents such as inhalants or nasal agents are used in solid, liquid or semi-solid form, and can be manufactured according to conventionally known methods. For example, well-known excipients, as well as pH adjusters, preservatives, surfactants, lubricants, stabilizers, or thickeners can be added as appropriate. For administration, a device for proper inhalation or blowing can be used. For example, the compound can be administered in the form of a powder alone or in a formulated mixture, or in the form of a solution or suspension in combination with a pharmaceutically acceptable carrier, using a well-known device such as a metered dose inhalation device or a nebulizer. Dry powder inhalers and the like can be administered for single or multiple times, and dry powder or powder-containing capsules can be used. Alternatively, it may be a form of a pressurized aerosol spray using a suitable propellant, for example, a preferred gas such as chlorofluoroalkane, hydrofluoroalkane, or carbon dioxide.
(投予量) 通常，經口投予之情形，一日的投予量係每單位體重約0.001～100mg/kg，較佳為0.1～30mg/kg，再佳為0.1～10mg/kg為適當，將此一次或分成二次以上進行投予。靜脈內投予之情形，一日的投予量係每單位體重約0.0001～10mg/kg為適當，且一日一次或分成複數次進行投予。又，作為經黏膜劑，將每單位體重約0.001～100mg/kg以一日一次或分成複數次進行投予。投予量係考慮症狀、年齡、性別等並依據個別情形而適當決定。(Injection amount) Generally, in the case of oral administration, the daily dosage is about 0.001-100 mg/kg per unit body weight, preferably 0.1-30 mg/kg, and more preferably 0.1-10 mg/kg. Divide into more than two times to vote. In the case of intravenous administration, it is appropriate that the daily dosage is about 0.0001-10 mg/kg per unit body weight, and the dosage is administered once a day or divided into multiple times. In addition, as a transmucosal agent, about 0.001 to 100 mg/kg per unit body weight is administered once a day or divided into multiple times. The dosage is appropriately determined according to individual circumstances in consideration of symptoms, age, gender, etc.
(併用) 本發明的化合物可與疾病的各種治療劑或預防劑併用，該疾病係被認為該化合物會顯示有效性的疾病。該併用可同時投予、或個別連續、或者在所期望的時間間隔中進行投予。同時投予製劑可為摻合劑，亦可被個別地製劑化。(Use together) The compound of the present invention can be used in combination with various therapeutic or preventive agents for diseases that are considered to be effective for the compound. The combined use may be administered simultaneously, individually consecutively, or administered at a desired time interval. Simultaneously administered preparations can be admixtures or can be formulated individually.
(製劑例1) 散劑 藉由以摻合機混合本發明的化合物5g、乳糖895g及玉米澱粉100g，而獲得散劑。 (製劑例2) 顆粒劑 將本發明的化合物5g、乳糖865g及低取代度羥丙纖維素100g進行混合後，添加10%羥丙纖維素水溶液300g並進行捏合。若將此使用擠壓造粒機進行造粒、乾燥，則獲得顆粒劑。 (製劑例3) 錠劑 將本發明的化合物5g、乳糖90g、玉米澱粉34g、結晶纖維素20g及硬脂酸鎂1g利用摻合機進行混合後，利用打錠機進行打錠，藉此獲得錠劑。 [實施例](Preparation example 1) Powder A powder is obtained by mixing 5 g of the compound of the present invention, 895 g of lactose, and 100 g of corn starch with a blender. (Formulation example 2) Granules After mixing 5 g of the compound of the present invention, 865 g of lactose, and 100 g of low-substituted hydroxypropyl cellulose, 300 g of a 10% hydroxypropyl cellulose aqueous solution was added and kneaded. If this is granulated and dried using an extrusion granulator, granules are obtained. (Preparation Example 3) Tablets After mixing 5 g of the compound of the present invention, 90 g of lactose, 34 g of corn starch, 20 g of crystalline cellulose, and 1 g of magnesium stearate using a blender, a tablet is used for tableting to obtain a tablet. [Example]
以下舉出參考例、實施例及試驗例，進一步詳細地說明本發明，但本發明的範圍不受限於此等。Hereinafter, reference examples, examples, and test examples are given to illustrate the present invention in further detail, but the scope of the present invention is not limited to these.
參考例及實施例的管柱層析法中之溶出係在由TLC(Thin Layer Chromatography，薄層層析法)所致之觀察下進行。在TLC觀察中，採用默克(Merck)公司製的矽膠60F254 作為TLC試片，採用管柱層析法中使用作為溶出溶劑的溶劑作為展開溶劑，並採用UV檢測器作為檢測法。管柱用矽膠同樣使用默克公司製的矽膠SK-85(230～400網目)、或者Fuji Silysia Chemical Chromatorex NH(200-350網目)。除了通常的管柱層析法以外，適當使用SHOKO SCIENTIFIC公司的自動層析法裝置(Purif-α2或者Purif-espoir2等)或Biotage公司的高速自動純化系統(Isolera等)。在此時適當使用由各公司所販售的急速層析法用卡套式管柱(cartridge column)等。溶出溶劑係基於TLC觀察而決定。The dissolution in the column chromatography of the reference example and the example was performed under observation by TLC (Thin Layer Chromatography). In the TLC observation, the silica gel 60F 254 manufactured by Merck was used as the TLC test piece, the solvent used as the dissolution solvent in the column chromatography method was used as the developing solvent, and the UV detector was used as the detection method. The silica gel for the column also uses the silica gel SK-85 (230-400 mesh) manufactured by Merck, or Fuji Silysia Chemical Chromatorex NH (200-350 mesh). In addition to the usual column chromatography, an automatic chromatography device (Purif-α2 or Purif-espoir2, etc.) of SHOKO SCIENTIFIC or a high-speed automatic purification system (Isolera, etc.) of Biotage is suitably used. At this time, cartridge columns for rapid chromatography sold by various companies, etc. are appropriately used. The dissolution solvent is determined based on TLC observation.
此外，以下的參考例、實施例及試驗例所使用的簡略符號具有如下述的意義。mg：毫克，g：公克，μL：微升，mL：毫升，L：公升，mmol：毫莫耳，μmol：微莫耳，nmol：奈米莫耳，M：mol/L，mM：mmol/L，μM：μmol/L，nM：nmol/L，μm：微米，mm：毫米，MHz：百萬赫In addition, the abbreviations used in the following reference examples, examples, and test examples have the following meanings. mg: milligrams, g: grams, μL: microliters, mL: milliliters, L: liters, mmol: millimoles, μmol: micromoles, nmol: nanomoles, M: mol/L, mM: mmol/ L, μM: μmol/L, nM: nmol/L, μm: micrometer, mm: millimeter, MHz: megahertz
在以下的參考例及實施例，核磁共振(以下為1 H NMR)光譜係將四甲矽烷作為標準物質，將化學位移値記載為δ値(ppm)。***圖案係將一重線表示為s、將二重線表示為d、將三重線表示為t、將四重線表現為q、將五重線表示為quin、將六重線表示為sext、將七重線表示為sep、將多重線表示為m、將寬峰(broad)表示為br。質量分析(以下為MS)係以EI(Electron Ionization，電子游離)法、ESI(Electrospray Ionization，電灑游離)法、APCI(Atmospheric pressure chemical ionization，大氣壓化學游離)法、或FAB(Fast Atom Bombardment，快速原子撞擊)法進行。In the following reference examples and examples, nuclear magnetic resonance ( 1 H NMR) spectroscopy system uses tetramethylsilane as a standard substance, and the chemical shift value is described as δ value (ppm). The split pattern system represents the single line as s, the double line as d, the triple line as t, the quadruple line as q, the five-fold line as quin, the six-fold line as sex, and the The seven-fold line is represented as sep, the multiple line is represented as m, and the broad peak is represented as br. Mass analysis (hereafter MS) is based on EI (Electron Ionization) method, ESI (Electrospray Ionization) method, APCI (Atmospheric pressure chemical ionization, atmospheric pressure chemical ionization) method, or FAB (Fast Atom Bombardment, Fast atom impact) method.
參考例1：(E)-1-甲基-3-(4-(2-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)乙烯基)苄基)咪唑啶-2-酮Reference example 1: (E)-1-methyl-3-(4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) (Vinyl)benzyl)imidazolidin-2-one
步驟1 (4-碘苯基)甲基甲磺酸酯 冰冷下，在(4-碘苯基)甲醇(40.0g)及三乙胺(31mL)的氯仿(300mL)溶液中，滴下甲磺醯氯(14.7mL)。滴下結束後，在相同溫度攪拌30分鐘後，在反應混合液中添加飽和氯化銨水溶液，進行攪拌。以氯仿進行萃取，以飽和食鹽水清洗萃取液後，以硫酸鎂進行乾燥。在減壓下餾去溶劑，獲得標記化合物(53.4g)。1 H NMR (400MHz, CDCl3 ) δ: 2.95 (3H, s), 5.18 (2H, s), 7.16 (2H, d, J=8.5 Hz), 7.75 (2H, d, J=8.5 Hz).Step 1 (4-Iodophenyl) methyl methanesulfonate is added dropwise to a chloroform (300 mL) solution of (4-iodophenyl) methanol (40.0 g) and triethylamine (31 mL) under ice cooling Chlorine (14.7 mL). After completion of the dropping, after stirring for 30 minutes at the same temperature, a saturated aqueous ammonium chloride solution was added to the reaction mixture and stirred. After extraction with chloroform, the extract was washed with saturated brine, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (53.4 g). 1 H NMR (400MHz, CDCl 3 ) δ: 2.95 (3H, s), 5.18 (2H, s), 7.16 (2H, d, J=8.5 Hz), 7.75 (2H, d, J=8.5 Hz).
步驟2 1-(4-碘苄基)-3-甲基咪唑啶-2-酮 冰冷下，在由上述步驟1所得之(4-碘苯基)甲基甲磺酸酯(53.4g)與1-甲基咪唑啶-2-酮(20.6g)的N,N-二甲基甲醯胺(340mL)溶液中，添加氫化鈉(11.4g，55%油性)，在室溫攪拌19小時。在反應混合液中添加飽和氯化銨水溶液，將反應液進行矽藻土過濾，在濾液中添加水並以乙酸乙酯進行萃取。以飽和食鹽水清洗萃取液後，以硫酸鎂進行乾燥。餾去溶劑後，將殘渣以矽膠管柱層析法(n-己烷/乙酸乙酯)進行純化，獲得標記化合物(39.0g)。1 H NMR (400MHz, CDCl3 ) δ: 2.83 (3H, s), 3.12-3.19 (2H, m), 3.24-3.31 (2H, m), 4.30 (2H, s), 7.02 (2H, d, J=8.4 Hz), 7.65 (2H, d, J=8.4 Hz). MS (ESI) m/z 317 (M+H)+ .Step 2 Under ice-cooling, 1-(4-iodobenzyl)-3-methylimidazolidin-2-one is mixed with the (4-iodophenyl)methanesulfonate (53.4g) obtained in step 1 above and To the N,N-dimethylformamide (340 mL) solution of 1-methylimidazolidin-2-one (20.6 g), sodium hydride (11.4 g, 55% oily) was added, and the mixture was stirred at room temperature for 19 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, the reaction solution was filtered through Celite, water was added to the filtrate, and extraction was performed with ethyl acetate. After washing the extract with saturated brine, it was dried with magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (39.0 g). 1 H NMR (400MHz, CDCl 3 ) δ: 2.83 (3H, s), 3.12-3.19 (2H, m), 3.24-3.31 (2H, m), 4.30 (2H, s), 7.02 (2H, d, J =8.4 Hz), 7.65 (2H, d, J=8.4 Hz). MS (ESI) m/z 317 (M+H) + .
步驟3 (E)-1-甲基-3-(4-(2-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)乙烯基)苄基)咪唑啶-2-酮 在由上述步驟2所得之1-(4-碘苄基)-3-甲基咪唑啶-2-酮(56.0g)的甲苯(300mL)溶液中，添加三乙胺(74.1mL)、4,4,5,5-四甲基-2-乙烯基-1,3,2-二氧硼戊環(33.3mL)及雙(三-tert-丁基膦)鈀(0)(6.34g)，氮氣體環境下，在100℃加熱攪拌18小時。放置冷卻後，藉由抽氣過濾去除不溶物後，將濾液進行減壓濃縮。將殘渣以矽膠管柱層析法(n-己烷/乙酸乙酯)進行純化，獲得標記化合物(37.9g)。1 H NMR (400MHz, CDCl3 ) δ: 1.31 (12H, s), 2.83 (3H, s), 3.13-3.20 (2H, m), 3.23-3.30 (2H, m), 4.36 (2H, s), 6.14 (1H, d, J=18.4 Hz), 7.23 (2H, d, J=8.2 Hz), 7.38 (1H, d, J=18.4 Hz), 7.44 (2H, d, J=8.0 Hz).Step 3 (E)-1-methyl-3-(4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl )Benzyl)imidazolidin-2-one is added to the toluene (300mL) solution of 1-(4-iodobenzyl)-3-methylimidazolidin-2-one (56.0g) obtained in step 2 above Triethylamine (74.1mL), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (33.3mL) and bis(tri-tert-butylphosphine) ) Palladium (0) (6.34g), heated and stirred at 100°C for 18 hours in a nitrogen atmosphere. After being left to cool, the insoluble matter was removed by suction filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (37.9 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.31 (12H, s), 2.83 (3H, s), 3.13-3.20 (2H, m), 3.23-3.30 (2H, m), 4.36 (2H, s), 6.14 (1H, d, J=18.4 Hz), 7.23 (2H, d, J=8.2 Hz), 7.38 (1H, d, J=18.4 Hz), 7.44 (2H, d, J=8.0 Hz).
參考例2：2-溴-1-乙基-1H-苯并[d]咪唑Reference example 2: 2-Bromo-1-ethyl-1H-benzo[d]imidazole
步驟1 2-溴-1-乙基-1H-苯并[d]咪唑 冰冷下，在2-溴苯并咪唑(50.0g)及碘乙烷(26.5mL)的N,N-二甲基甲醯胺(200mL)溶液中，添加氫化鈉(11.0g，60%油性)，攪拌1小時。在反應液中添加水，濾取生成的固體，進行濾取、乾燥，獲得標記化合物(56.0g)。1 H NMR (400MHz, CDCl3 ) δ: 1.43 (3H, t, J=7.3 Hz), 4.26 (2H, q, J=7.3 Hz), 7.21-7.31 (2H, m), 7.32-7.37 (1H, m), 7.65-7.76 (1H, m). MS (ESI) m/z 225 (M+H)+ .Step 1 Under ice cooling, 2-bromo-1-ethyl-1H-benzo[d]imidazole was mixed with 2-bromobenzimidazole (50.0g) and iodoethane (26.5mL) in N,N-dimethylformaldehyde. To the amide (200 mL) solution, sodium hydride (11.0 g, 60% oily) was added, and the mixture was stirred for 1 hour. Water was added to the reaction liquid, and the produced solid was filtered, filtered, and dried to obtain the labeled compound (56.0 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.43 (3H, t, J=7.3 Hz), 4.26 (2H, q, J=7.3 Hz), 7.21-7.31 (2H, m), 7.32-7.37 (1H, m), 7.65-7.76 (1H, m). MS (ESI) m/z 225 (M+H) + .
參考例3：4-溴-1-乙基-1H-苯并[d]咪唑-2-酮Reference example 3: 4-Bromo-1-ethyl-1H-benzo[d]imidazol-2-one
步驟1 3-溴-N-乙基-2-硝基苯胺 在1-溴-3-氟-2-硝基苯(34.6g)的乙醇(210mL)溶液中，添加70%乙胺水溶液(45mL)。在50℃攪拌18小時。放置冷卻後，將溶劑進行減壓餾去。將生成的固體進行濾取、乾燥，獲得標記化合物(27.3g)。1 H NMR (400MHz, CDCl3 ) δ: 1.30 (3H, t, J=7.2 Hz), 3.23 (2H, qd, J=7.2, 5.1 Hz), 5.60 (1H, br s), 6.73 (1H, d, J=8.5 Hz), 6.93 (1H, dd, J=7.8, 1.1 Hz), 7.09-7.17 (1H, m). MS (ESI) m/z 245 (M+H)+ .Step 1 3-Bromo-N-ethyl-2-nitroaniline was added to a solution of 1-bromo-3-fluoro-2-nitrobenzene (34.6g) in ethanol (210mL) and 70% ethylamine aqueous solution (45mL ). Stir at 50°C for 18 hours. After leaving to cool, the solvent was distilled off under reduced pressure. The produced solid was collected by filtration and dried to obtain the labeled compound (27.3 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.30 (3H, t, J=7.2 Hz), 3.23 (2H, qd, J=7.2, 5.1 Hz), 5.60 (1H, br s), 6.73 (1H, d , J=8.5 Hz), 6.93 (1H, dd, J=7.8, 1.1 Hz), 7.09-7.17 (1H, m). MS (ESI) m/z 245 (M+H) + .
步驟2 3-溴-N1 -乙基苯-1,2-二胺 室溫下，在由上述步驟1所得之3-溴-N-乙基-2-硝基苯胺(56.7g)的甲醇(800mL)溶液中，添加5%鉑(硫化)碳(15g)，氫氣體環境下，攪拌48小時。再添加5%鉑(硫化)碳(15g)，再在氫氣體環境下，攪拌24小時。將觸媒進行矽藻土濾去後，將濾液進行減壓濃縮，獲得標記化合物(51.0g)。1 H NMR (400MHz, CDCl3 ) δ: 1.30 (3H, t, J=7.2 Hz), 3.14 (2H, q, J=7.2 Hz), 3.21-4.04 (3H, br s), 6.59 (1H, dd, J=8.0, 1.4 Hz), 6.67 (1H, t, J=8.0 Hz), 6.93 (1H, dd, J=8.0, 1.4 Hz). MS (ESI) m/z 215 (M+H)+ .Step 2 3-Bromo-N 1 -ethylbenzene-1,2-diamine at room temperature, in methanol of 3-bromo-N-ethyl-2-nitroaniline (56.7g) obtained in step 1 above Add 5% platinum (sulfide) carbon (15 g) to the solution (800 mL), and stir for 48 hours under a hydrogen atmosphere. Add 5% platinum (sulfide) carbon (15g), and stir for 24 hours in a hydrogen atmosphere. After the catalyst was filtered through Celite, the filtrate was concentrated under reduced pressure to obtain the labeled compound (51.0 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.30 (3H, t, J=7.2 Hz), 3.14 (2H, q, J=7.2 Hz), 3.21-4.04 (3H, br s), 6.59 (1H, dd , J=8.0, 1.4 Hz), 6.67 (1H, t, J=8.0 Hz), 6.93 (1H, dd, J=8.0, 1.4 Hz). MS (ESI) m/z 215 (M+H) + .
步驟3 4-溴-1-乙基-1H-苯并[d]咪唑-2-酮 在由上述步驟2所得之3-溴-N1 -乙基苯-1,2-二胺(56.1g)的四氫呋喃(500mL)溶液中，添加1,1’-羰基二咪唑(46.4g)，攪拌72小時。將溶劑進行減壓餾去，在殘渣中添加乙酸乙酯及水，濾取生成的固體。以水及二乙基醚清洗所得之固體，獲得標記化合物(51.7g)。1 H NMR (400MHz, CDCl3 ) δ: 1.35 (3H, t, J=7.2 Hz), 3.93 (2H, q, J=7.3 Hz), 6.93 (1H, d, J=8.0 Hz), 6.98 (1H, t, J=7.9 Hz), 7.19 (1H, dd, J=7.9, 1.1 Hz), 8.60 (1H, br s). MS (ESI) m/z 241 (M+H)+ .Step 3 4-Bromo-1-ethyl-1H-benzo[d]imidazol-2-one in the 3-bromo-N 1 -ethylbenzene-1,2-diamine (56.1g) obtained from step 2 above ) In tetrahydrofuran (500 mL), add 1,1'-carbonyldiimidazole (46.4 g), and stir for 72 hours. The solvent was distilled off under reduced pressure, ethyl acetate and water were added to the residue, and the produced solid was collected by filtration. The obtained solid was washed with water and diethyl ether to obtain the labeled compound (51.7 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.35 (3H, t, J=7.2 Hz), 3.93 (2H, q, J=7.3 Hz), 6.93 (1H, d, J=8.0 Hz), 6.98 (1H , t, J=7.9 Hz), 7.19 (1H, dd, J=7.9, 1.1 Hz), 8.60 (1H, br s). MS (ESI) m/z 241 (M+H) + .
參考例5：4-溴-2-氯-1-乙基-1H-苯并[d]咪唑Reference Example 5: 4-Bromo-2-chloro-1-ethyl-1H-benzo[d]imidazole
步驟1 4-溴-2-氯-1-乙基-1H-苯并[d]咪唑 將由參考例3的步驟3所得之4-溴-1-乙基-1H-苯并[d]咪唑-2-酮(5.00g)添加至三氯一氧化磷(38.8mL)，在110℃攪拌2小時。將反應液回溫至室溫，在減壓下餾去三氯一氧化磷後，在殘渣中添加乙酸乙酯，以飽和碳酸氫鈉水及飽和食鹽水進行清洗。以硫酸鈉乾燥有機層，將溶劑進行減壓餾去，獲得標記化合物(5.20g)。1 H NMR (400MHz, CDCl3 ) δ: 1.44 (3H, t, J=7.3 Hz), 4.25 (2H, q, J=7.3 Hz), 7.17 (1H, t, J=7.8 Hz), 7.25-7.29 (1H, m), 7.47 (1H, dd, J=7.7, 0.9 Hz). MS (ESI) m/z 259 (M+H)+ .Step 1 4-Bromo-2-chloro-1-ethyl-1H-benzo[d]imidazole The 4-bromo-1-ethyl-1H-benzo[d]imidazole obtained in step 3 of Reference Example 3 2-ketone (5.00 g) was added to phosphorus monoxide (38.8 mL), and stirred at 110°C for 2 hours. The reaction liquid was warmed to room temperature, and after phosphorus monoxide was distilled off under reduced pressure, ethyl acetate was added to the residue, and the residue was washed with saturated sodium bicarbonate water and saturated brine. The organic layer was dried with sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (5.20 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.44 (3H, t, J=7.3 Hz), 4.25 (2H, q, J=7.3 Hz), 7.17 (1H, t, J=7.8 Hz), 7.25-7.29 (1H, m), 7.47 (1H, dd, J=7.7, 0.9 Hz). MS (ESI) m/z 259 (M+H) + .
參考例6：N-乙基苯-1,2-二胺Reference Example 6: N-ethylbenzene-1,2-diamine
步驟1 N-乙基-2-硝基苯胺 使用2-氟硝基苯，而取代1-溴-3-氟-2-硝基苯，與參考例3的步驟1同樣地進行操作，獲得標記化合物(1.17g)。1 H NMR (400MHz, CDCl3 ) δ: 1.38 (3H, t, J=7.2 Hz), 3.36 (2H, qd, J=7.2, 5.0 Hz), 6.63 (1H, ddd, J=8.5, 7.0, 1.3 Hz), 6.85 (1H, dd, J=8.7, 1.1 Hz), 7.43 (1H, dddd, J=8.6, 6.9, 1.6, 0.6 Hz), 7.97 (1H, br s), 8.17 (1H, dd, J=8.6, 1.6 Hz). MS (ESI) m/z 167 (M+H)+ .Step 1 Using 2-fluoronitrobenzene for N-ethyl-2-nitroaniline and substituting 1-bromo-3-fluoro-2-nitrobenzene, proceed as in Step 1 of Reference Example 3 to obtain the label Compound (1.17g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.38 (3H, t, J=7.2 Hz), 3.36 (2H, qd, J=7.2, 5.0 Hz), 6.63 (1H, ddd, J=8.5, 7.0, 1.3 Hz), 6.85 (1H, dd, J=8.7, 1.1 Hz), 7.43 (1H, dddd, J=8.6, 6.9, 1.6, 0.6 Hz), 7.97 (1H, br s), 8.17 (1H, dd, J =8.6, 1.6 Hz). MS (ESI) m/z 167 (M+H) + .
步驟2 N-乙基苯-1,2-二胺 在由上述步驟1所得之N-乙基-2-硝基苯胺(1.17g)的乙醇(10mL)溶液中，添加10%鈀碳，氫氣體環境下，攪拌15小時。將反應液進行矽藻土過濾，在減壓下餾去溶劑，獲得標記化合物(0.94g)。1 H NMR (400MHz, CDCl3 ) δ: 1.30 (1H, t, J=7.2 Hz), 1.30 (3H, t, J=7.2 Hz), 3.15 (2H, q, J=7.2 Hz), 3.20-3.36 (3H, m), 6.64-6.75 (3H, m), 6.78-6.87 (1H, m). MS (ESI) m/z 137 (M+H)+ .Step 2 N-Ethylbenzene-1,2-diamine is added to the ethanol (10mL) solution of N-ethyl-2-nitroaniline (1.17g) obtained in step 1 above, add 10% palladium on carbon, hydrogen Stir for 15 hours in a gas environment. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain the labeled compound (0.94 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.30 (1H, t, J=7.2 Hz), 1.30 (3H, t, J=7.2 Hz), 3.15 (2H, q, J=7.2 Hz), 3.20-3.36 (3H, m), 6.64-6.75 (3H, m), 6.78-6.87 (1H, m). MS (ESI) m/z 137 (M+H) + .
參考例7：(E)-2-(4-(氯甲基)苯乙烯基)-1-乙基-1H-苯并[d]咪唑Reference Example 7: (E)-2-(4-(chloromethyl)styryl)-1-ethyl-1H-benzo[d]imidazole
步驟1 (E)-4-(2-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)乙烯基)苯甲酸甲酯 在4-溴苯甲酸甲酯(4.60g)的甲苯(30mL)溶液中，添加4,4,5,5-四甲基-2-乙烯基-1,3,2-二氧硼戊環(3.60g)、雙(三-tert-丁基膦)鈀(0)(0.10g)及三乙胺(5.9mL)，使用微波反應裝置，在80℃攪拌2小時。放置冷卻後，添加水，以乙酸乙酯進行萃取，以硫酸鈉乾燥萃取液。減壓下，餾去溶劑，獲得標記化合物(5.80g)。1 H NMR (400MHz, CDCl3 ) δ: 1.32 (12H, s), 3.91 (3H, s), 6.27 (1H, d, J=18.4 Hz), 7.41 (1H, d, J=18.4 Hz), 7.53 (2H, d, J=8.3 Hz), 8.00 (2H, d, J=8.3 Hz).Step 1 (E)-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)methyl benzoate in 4- To a solution of methyl bromobenzoate (4.60g) in toluene (30mL), add 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (3.60g) , Bis(tri-tert-butylphosphine)palladium(0) (0.10g) and triethylamine (5.9mL), using a microwave reaction device, stirred at 80°C for 2 hours. After standing to cool, water was added, extraction was performed with ethyl acetate, and the extract was dried with sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (5.80 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.32 (12H, s), 3.91 (3H, s), 6.27 (1H, d, J=18.4 Hz), 7.41 (1H, d, J=18.4 Hz), 7.53 (2H, d, J=8.3 Hz), 8.00 (2H, d, J=8.3 Hz).
步驟2
(E)-4-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)苯甲酸甲酯
在由上述步驟1所得之(E)-4-(2-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)乙烯基)苯甲酸甲酯(5.80g)的1,4-二
步驟3 (E)-(4-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)苯基)甲醇 在由上述步驟2所得之(E)-4-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)苯甲酸甲酯(3.80g)的四氫呋喃(80mL)溶液中，在-60℃添加鋁氫化鋰(0.47g)，一邊攪拌一邊緩慢回溫至室溫為止。在回溫至室溫後攪拌2小時。將反應液冷卻至0℃，添加飽和酒石酸鉀鈉水溶液。以乙酸乙酯進行萃取，以飽和食鹽水清洗萃取液，以硫酸鈉進行乾燥。將溶劑進行減壓餾去，將殘渣以矽膠管柱層析法(n-己烷/乙酸乙酯)進行純化，獲得標記化合物(1.10g)。1 H NMR (400MHz, CDCl3 ) δ: 1.49 (3H, t, J=7.3 Hz), 1.82 (1H, br s), 4.34 (2H, q, J=7.3 Hz), 4.74 (2H, s), 7.08 (1H, d, J=15.8 Hz), 7.26-7.30 (2H, m), 7.33-7.37 (1H, m), 7.41 (2H, d, J=8.2 Hz), 7.61 (2H, d, J=8.2 Hz), 7.75-7.81 (1H, m), 7.99 (1H, d, J=15.8 Hz).Step 3 (E)-(4-(2-(1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl)phenyl)methanol in the (E)-4 obtained from step 2 above -(2-(1-Ethyl-1H-benzo[d]imidazol-2-yl)vinyl)methyl benzoate (3.80g) in tetrahydrofuran (80mL) solution, add lithium aluminum hydride at -60℃ (0.47g), slowly warm up to room temperature while stirring. Stir for 2 hours after warming to room temperature. The reaction liquid was cooled to 0°C, and saturated potassium sodium tartrate aqueous solution was added. Extract with ethyl acetate, wash the extract with saturated brine, and dry with sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (1.10 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.49 (3H, t, J=7.3 Hz), 1.82 (1H, br s), 4.34 (2H, q, J=7.3 Hz), 4.74 (2H, s), 7.08 (1H, d, J=15.8 Hz), 7.26-7.30 (2H, m), 7.33-7.37 (1H, m), 7.41 (2H, d, J=8.2 Hz), 7.61 (2H, d, J= 8.2 Hz), 7.75-7.81 (1H, m), 7.99 (1H, d, J=15.8 Hz).
步驟4 (E)-2-(4-(氯甲基)苯乙烯基)-1-乙基-1H-苯并[d]咪唑 冰冷下，在由上述步驟3所得之(E)-(4-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)苯基)甲醇(1.10g)的二氯甲烷(60mL)溶液中，添加亞硫醯氯(0.35mL)，回溫至室溫並攪拌1小時。冰冷下，添加飽和碳酸氫鈉水，以氯仿進行萃取。以飽和食鹽水清洗萃取液，以硫酸鈉進行乾燥。將溶劑進行減壓餾去，獲得標記化合物(1.30g)。1 H NMR (400MHz, CDCl3 ) δ: 1.46 (3H, t, J=7.3 Hz), 4.30 (2H, q, J=7.2 Hz), 4.60 (2H, s), 7.07 (1H, d, J=15.8 Hz), 7.25-7.29 (2H, m), 7.30-7.36 (1H, m), 7.41 (2H, d, J=8.0 Hz), 7.59 (2H, d, J=8.2 Hz), 7.74-7.82 (1H, m), 7.98 (1H, d, J=15.8 Hz).Step 4 (E)-2-(4-(chloromethyl)styryl)-1-ethyl-1H-benzo[d]imidazole under ice-cooling, the (E)-(4 -(2-(1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl)phenyl)methanol (1.10g) in dichloromethane (60mL) solution, add sulfite chloride ( 0.35mL), warm to room temperature and stir for 1 hour. Under ice cooling, saturated sodium bicarbonate water was added, and extraction was performed with chloroform. The extract was washed with saturated brine and dried with sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (1.30 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.46 (3H, t, J=7.3 Hz), 4.30 (2H, q, J=7.2 Hz), 4.60 (2H, s), 7.07 (1H, d, J= 15.8 Hz), 7.25-7.29 (2H, m), 7.30-7.36 (1H, m), 7.41 (2H, d, J=8.0 Hz), 7.59 (2H, d, J=8.2 Hz), 7.74-7.82 ( 1H, m), 7.98 (1H, d, J=15.8 Hz).
參考例8：(E)-1-甲基-3-((5-(2-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)乙烯基)吡啶-2-基)甲基)咪唑啶-2-酮Reference Example 8: (E)-1-methyl-3-((5-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )Vinyl)pyridin-2-yl)methyl)imidazolidin-2-one
步驟1 (5-溴-2-吡啶基)甲基甲磺酸酯 冰冷下，在5-溴-2-吡啶甲醇(78.6g)及三乙胺(87mL)的氯仿(330mL)溶液中，緩慢添加甲磺醯氯(34.6mL)。攪拌1小時後，在反應液中添加飽和氯化銨水溶液，以氯仿進行萃取。以飽和食鹽水清洗萃取液，以硫酸鎂進行乾燥。將溶劑進行減壓餾去，獲得標記化合物(105g)作為粗產物。 MS (ESI) m/z 266 (M+H)+ .Step 1 (5-Bromo-2-pyridyl) methyl methanesulfonate is slowly added to a solution of 5-bromo-2-pyridinemethanol (78.6g) and triethylamine (87mL) in chloroform (330mL) under ice cooling. Add methanesulfonyl chloride (34.6 mL). After stirring for 1 hour, a saturated aqueous ammonium chloride solution was added to the reaction solution, and extraction was performed with chloroform. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (105 g) as a crude product. MS (ESI) m/z 266 (M+H) + .
步驟2 1-((5-溴吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮 冰冷下，在氫化鈉(20.1g，60%油性)的N,N-二甲基甲醯胺(150mL)懸浮液中，滴下1-甲基咪唑啶-2-酮(50.2g)的N,N-二甲基甲醯胺(150mL)溶液，攪拌30分鐘。接著，滴下由上述步驟1所得之(5-溴-2-吡啶基)甲基甲磺酸酯(105g)的N,N-二甲基甲醯胺(100mL)溶液後，回溫至室溫並攪拌15小時。在反應液中添加水，以氯仿進行萃取。以飽和食鹽水清洗萃取液，以硫酸鎂進行乾燥。在減壓下餾去溶劑，將殘渣以矽膠管柱層析法(n-己烷/乙酸乙酯)進行純化，獲得標記化合物(46.2g)。1 H NMR (400MHz, CDCl3 ) δ: 2.83 (3H, s), 3.32 (4H, s), 4.45 (2H, s), 7.25 (1H, d, J=8.3 Hz), 7.78 (1H, dd, J=8.3, 2.4 Hz), 8.59 (1H, dd, J=2.5, 0.7 Hz). MS (ESI) m/z 270 (M+H)+ .Step 2 1-((5-Bromopyridin-2-yl)methyl)-3-methylimidazolidin-2-one under ice cooling, in sodium hydride (20.1g, 60% oily) N,N-dimethyl A solution of 1-methylimidazolidin-2-one (50.2 g) in N,N-dimethylformamide (150 mL) was dropped into the suspension of methylcarbamide (150 mL) and stirred for 30 minutes. Next, drop the N,N-dimethylformamide (100 mL) solution of (5-bromo-2-pyridyl) methanesulfonate (105 g) obtained in step 1 above, and then warm to room temperature And stirred for 15 hours. Water was added to the reaction liquid, and extraction was performed with chloroform. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (46.2 g). 1 H NMR (400MHz, CDCl 3 ) δ: 2.83 (3H, s), 3.32 (4H, s), 4.45 (2H, s), 7.25 (1H, d, J=8.3 Hz), 7.78 (1H, dd, J=8.3, 2.4 Hz), 8.59 (1H, dd, J=2.5, 0.7 Hz). MS (ESI) m/z 270 (M+H) + .
步驟3 (E)-1-甲基-3-((5-(2-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)乙烯基)吡啶-2-基)甲基)咪唑啶-2-酮 在由上述步驟2所得之1-((5-溴吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮(46.2g)的甲苯(235mL)溶液中，添加三乙胺(71.5mL)及雙(三-tert-丁基膦)鈀(0)(3.0g)，在氬氣體環境下，在140℃加熱3小時。放置冷卻後，藉由抽氣過濾去除不溶物，將濾液進行減壓餾去。將殘渣以矽膠管柱層析法(氯仿/甲醇)進行純化，獲得標記化合物(40.0g)。1 H NMR (400MHz, CDCl3 ) δ: 1.32 (12H, s), 2.83 (3H, s), 3.32 (4H, s), 4.50 (2H, s), 6.22 (1H, d, J=18.6 Hz), 7.30 (1H, d, J=8.2 Hz), 7.36 (1H, d, J=18.4 Hz), 7.78 (1H, dd, J=8.2, 2.3 Hz), 8.60 (1H, d, J=2.1 Hz).Step 3 (E)-1-methyl-3-((5-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethylene (Yl)pyridin-2-yl)methyl)imidazolidin-2-one in the 1-((5-bromopyridin-2-yl)methyl)-3-methylimidazolidine-2-one obtained from step 2 above To the toluene (235mL) solution of ketone (46.2g), add triethylamine (71.5mL) and bis(tri-tert-butylphosphine) palladium(0)(3.0g), under argon atmosphere, at 140℃ Heat for 3 hours. After standing to cool, the insoluble matter was removed by suction filtration, and the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to obtain the title compound (40.0 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.32 (12H, s), 2.83 (3H, s), 3.32 (4H, s), 4.50 (2H, s), 6.22 (1H, d, J=18.6 Hz) , 7.30 (1H, d, J=8.2 Hz), 7.36 (1H, d, J=18.4 Hz), 7.78 (1H, dd, J=8.2, 2.3 Hz), 8.60 (1H, d, J=2.1 Hz) .
參考例9：(E)-1-((5-(2-(4-溴-1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮Reference Example 9: (E)-1-((5-(2-(4-Bromo-1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl)pyridin-2-yl)methyl Yl)-3-methylimidazolidin-2-one
步驟1 4-溴-1-乙基-1H-苯并[d]咪唑-2-硫醇 在參考例3的步驟2所得之3-溴-N1 -乙基苯-1,2-二胺(1.63g)的吡啶(76mL)溶液中，添加1,1’-硫代羰基二咪唑(1.89g)，攪拌15小時。添加水後，以乙酸乙酯萃取反應液，以水及飽和食鹽水清洗萃取液，以硫酸鈉進行乾燥。在減壓下餾去溶劑，將殘渣以胺基矽膠管柱層析法(n-己烷/乙酸乙酯)進行純化，獲得標記化合物(1.62g)。1 H NMR (400MHz, CDCl3 ) δ: 1.41 (3H, t, J=7.2 Hz), 4.33 (2H, q, J=7.3 Hz), 7.07-7.15 (2H, m), 7.33 (1H, dd, J=7.0, 1.9 Hz), 9.37 (1H, br s). MS (ESI) m/z 257 (M+H)+ .Step 1 4-Bromo-1-ethyl-1H-benzo[d]imidazole-2-thiol 3-bromo-N 1 -ethylbenzene-1,2-diamine obtained in step 2 of Reference Example 3 To a solution of (1.63 g) in pyridine (76 mL), 1,1'-thiocarbonyldiimidazole (1.89 g) was added, and the mixture was stirred for 15 hours. After adding water, the reaction solution was extracted with ethyl acetate, the extract was washed with water and saturated brine, and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by amino silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (1.62 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.41 (3H, t, J=7.2 Hz), 4.33 (2H, q, J=7.3 Hz), 7.07-7.15 (2H, m), 7.33 (1H, dd, J=7.0, 1.9 Hz), 9.37 (1H, br s). MS (ESI) m/z 257 (M+H) + .
步驟2 4-溴-1-乙基-2-(甲基硫代)-1H-苯并[d]咪唑 在由上述步驟1所得之4-溴-1-乙基-1H-苯并[d]咪唑-2-硫醇(0.20g)的2-丙醇(2.5mL)溶液中，添加二異丙基乙胺(0.43mL)及碘甲烷(0.15mL)，攪拌1小時。在反應液中添加水，以氯仿進行萃取，以飽和食鹽水清洗萃取液，以硫酸鈉進行乾燥。在減壓下餾去溶劑，將殘渣以矽膠管柱層析法(n-己烷/乙酸乙酯)進行純化，獲得標記化合物(0.12g)。1 H NMR (400MHz, CDCl3 ) δ: 1.39 (3H, t, J=7.2 Hz), 2.86 (3H, s), 4.12 (2H, q, J=7.2 Hz), 7.05 (1H, dd, J=8.0, 7.8 Hz), 7.19 (1H, dd, J=8.0, 0.8 Hz), 7.38 (1H, dd, J=7.8, 0.9 Hz). MS (ESI) m/z 271 (M+H)+ .Step 2 4-Bromo-1-ethyl-2-(methylthio)-1H-benzo[d]imidazole is used in the 4-bromo-1-ethyl-1H-benzo[d] obtained from step 1 above. ] To a 2-propanol (2.5 mL) solution of imidazole-2-thiol (0.20 g), diisopropylethylamine (0.43 mL) and methyl iodide (0.15 mL) were added, and the mixture was stirred for 1 hour. Water was added to the reaction solution, extraction was performed with chloroform, the extract was washed with saturated brine, and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (0.12 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.39 (3H, t, J=7.2 Hz), 2.86 (3H, s), 4.12 (2H, q, J=7.2 Hz), 7.05 (1H, dd, J= 8.0, 7.8 Hz), 7.19 (1H, dd, J=8.0, 0.8 Hz), 7.38 (1H, dd, J=7.8, 0.9 Hz). MS (ESI) m/z 271 (M+H) + .
步驟3 (E)-1-((5-(2-(4-溴-1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮 氬氣體環境下，在步驟2所得之4-溴-1-乙基-2-(甲基硫代)-1H-苯并[d]咪唑(0.30g)的四氫呋喃(10mL)溶液中，添加由參考例8的步驟3所得之(E)-1-甲基-3-((5-(2-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)乙烯基)吡啶-2-基)甲基)咪唑啶-2-酮(0.46g)、參(二亞苄基丙酮)二鈀(0)(0.10g)、三(2-呋喃基)膦(0.11g)、噻吩-2-羧酸銅(I)(0.69g)及乙酸鋅(0.66g)，在60℃攪拌24小時。再添加由參考例8的步驟3所得之(E)-1-甲基-3-((5-(2-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)乙烯基)吡啶-2-基)甲基)咪唑啶-2-酮(0.09g)、噻吩-2-羧酸銅(I)(0.14g)及乙酸鋅(0.14g)並攪拌24小時。將反應液進行矽藻土過濾，以乙酸乙酯進行清洗。以10%氨水溶液、水及飽和食鹽水清洗濾液，以硫酸鈉進行乾燥。在減壓下餾去溶劑，將殘渣以胺基矽膠管柱層析法(n-己烷/乙酸乙酯)進行純化，獲得標記化合物(0.30g)。1 H NMR (400MHz, CDCl3 ) δ: 1.48 (3H, t, J=7.3 Hz), 2.85 (3H, s), 3.33-3.38 (4H, m), 4.32 (2H, q, J=7.1 Hz), 4.54 (2H, s), 7.09 (1H, d, J=15.9 Hz), 7.15 (1H, d, J=7.9 Hz), 7.31 (1H, d, J=7.4 Hz), 7.38 (1H, d, J=8.2 Hz), 7.48 (1H, d, J=7.8 Hz), 7.90 (1H, dd, J=8.1, 2.3 Hz), 8.08 (1H, d, J=15.8 Hz), 8.78 (1H, s). MS (ESI) m/z 440 (M+H)+ .Step 3 (E)-1-((5-(2-(4-Bromo-1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl)pyridin-2-yl)methyl) -3-Methylimidazolidin-2-one under argon atmosphere, the 4-bromo-1-ethyl-2-(methylthio)-1H-benzo[d]imidazole (0.30g) obtained in step 2 ) In tetrahydrofuran (10 mL), add (E)-1-methyl-3-((5-(2-(4,4,5,5-tetramethyl-) obtained in step 3 of Reference Example 8 1,3,2-dioxaborolan-2-yl)vinyl)pyridin-2-yl)methyl)imidazolidin-2-one (0.46g), ginseng (dibenzylideneacetone)dipalladium ( 0) (0.10g), tris(2-furyl)phosphine (0.11g), copper (I) thiophene-2-carboxylate (0.69g) and zinc acetate (0.66g), and stirred at 60°C for 24 hours. Then add (E)-1-methyl-3-((5-(2-(4,4,5,5-tetramethyl-1,3,2-dioxide obtained from step 3 of Reference Example 8 Boronyl-2-yl)vinyl)pyridin-2-yl)methyl)imidazolidin-2-one (0.09g), copper (I) thiophene-2-carboxylate (0.14g) and zinc acetate (0.14 g) and stir for 24 hours. The reaction solution was filtered through Celite and washed with ethyl acetate. The filtrate was washed with 10% ammonia solution, water and saturated brine, and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by amino silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (0.30 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.48 (3H, t, J=7.3 Hz), 2.85 (3H, s), 3.33-3.38 (4H, m), 4.32 (2H, q, J=7.1 Hz) , 4.54 (2H, s), 7.09 (1H, d, J=15.9 Hz), 7.15 (1H, d, J=7.9 Hz), 7.31 (1H, d, J=7.4 Hz), 7.38 (1H, d, J=8.2 Hz), 7.48 (1H, d, J=7.8 Hz), 7.90 (1H, dd, J=8.1, 2.3 Hz), 8.08 (1H, d, J=15.8 Hz), 8.78 (1H, s) . MS (ESI) m/z 440 (M+H) + .
參考例10：1-[1-(4-溴苯基)乙基]-3-甲基咪唑啶-2-酮Reference Example 10: 1-[1-(4-Bromophenyl)ethyl]-3-methylimidazolidin-2-one
步驟1 tert-丁基N-[2-[1-(4-溴苯基)乙胺基]乙基]-N-甲基胺甲酸酯 在實施例42的步驟1中，使用tert-丁基N-甲基-N-(2-側氧基乙基)胺甲酸酯，而取代5-溴-1-二氫茚酮，又，使用1-(4-溴苯基)乙烷胺，而取代tert-丁基-N-(2-胺基乙基)-N-甲基胺甲酸酯，進行同樣的操作，獲得標記化合物(1.59g)。1 H NMR (400MHz, CDCl3 ) δ: 1.29 (3H, d, J=6.5 Hz), 1.44 (9H, s), 2.51-2.67 (2H, m), 2.81 (3H, s), 3.12-3.28 (1H, m), 3.30-3.42 (1H, m), 3.72-3.81 (1H, m), 7.20 (2H, d, J=8.3 Hz), 7.43 (2H, d, J=8.3 Hz). MS (ESI) m/z357, 359 (M+H)+ .Step 1 tert-butyl N-[2-[1-(4-bromophenyl)ethylamino]ethyl]-N-methyl carbamate In step 1 of Example 42, tert-butyl N-methyl-N-(2-side oxyethyl) carbamate instead of 5-bromo-1-indanone, and 1-(4-bromophenyl)ethaneamine , And substituting tert-butyl-N-(2-aminoethyl)-N-methyl carbamate, and performing the same operation to obtain the labeled compound (1.59 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.29 (3H, d, J=6.5 Hz), 1.44 (9H, s), 2.51-2.67 (2H, m), 2.81 (3H, s), 3.12-3.28 ( 1H, m), 3.30-3.42 (1H, m), 3.72-3.81 (1H, m), 7.20 (2H, d, J=8.3 Hz), 7.43 (2H, d, J=8.3 Hz). MS (ESI ) m/z357, 359 (M+H) + .
步驟2 1-[1-(4-溴苯基)乙基]-3-甲基咪唑啶-2-酮 使用由上述步驟1所得之tert-丁基N-[2-[1-(4-溴苯基)乙胺基]乙基]-N-甲基胺甲酸酯，而取代實施例42的步驟1所得之tert-丁基(2-((5-溴-2,3-二氫-1H-茚-1-基)胺基)乙基)(甲基)胺甲酸酯，進行與實施例42的步驟2同樣的操作，獲得標記化合物(902mg)。1 H NMR (400MHz, CDCl3 ) δ: 1.49 (3H, d, J=7.0 Hz), 2.79 (3H, s), 2.84-2.94 (1H, m), 3.16-3.30 (3H, m), 5.22 (1H, q, J=7.0 Hz), 7.20 (2H, d, J=8.5 Hz), 7.45 (2H, d, J=8.5 Hz). MS (ESI) m/z 283, 285 (M+H)+ .Step 2 1-[1-(4-Bromophenyl)ethyl]-3-methylimidazolidin-2-one uses the tert-butyl N-[2-[1-(4- Bromophenyl) ethylamino] ethyl) -N-methyl carbamate, instead of tert-butyl (2-((5-bromo-2,3-dihydro) obtained in step 1 of Example 42 -1H-inden-1-yl)amino)ethyl)(methyl)carbamate, and the same operation as in step 2 of Example 42 was carried out to obtain the labeled compound (902 mg). 1 H NMR (400MHz, CDCl 3 ) δ: 1.49 (3H, d, J=7.0 Hz), 2.79 (3H, s), 2.84-2.94 (1H, m), 3.16-3.30 (3H, m), 5.22 ( 1H, q, J=7.0 Hz), 7.20 (2H, d, J=8.5 Hz), 7.45 (2H, d, J=8.5 Hz). MS (ESI) m/z 283, 285 (M+H) + .
參考例11：1-[1-(4-溴苯基)環丙基]-3-甲基咪唑啶-2-酮Reference Example 11: 1-[1-(4-Bromophenyl)cyclopropyl]-3-methylimidazolidin-2-one
步驟1 tert-丁基N-[2-[[1-(4-溴苯基)環丙基]胺基]乙基]-N-甲基胺甲酸酯 使用tert-丁基N-甲基-N-(2-側氧基乙基)胺甲酸酯，而取代5-溴-1-二氫茚酮，又，使用1-(4-溴苯基)環丙烷胺，而取代tert-丁基-N-(2-胺基乙基)-N-甲基胺甲酸酯，進行與實施例42的步驟1同樣的操作，獲得標記化合物(1.91g)。1 H NMR (400MHz, CDCl3 ) δ: 0.82-0.91 (2H, m), 0.93-1.00 (2H, m), 1.43 (9H, s), 2.66 (2H, t, J=6.5 Hz), 2.79 (3H, s), 3.16-3.31 (2H, m), 7.16 (2H, d, J=8.5 Hz), 7.42 (2H, d, J=8.5 Hz). MS (ESI) m/z369, 371 (M+H)+ .Step 1 Tert-butyl N-[2-[[1-(4-bromophenyl)cyclopropyl]amino]ethyl]-N-methyl carbamate uses tert-butyl N-methyl -N-(2-sided oxyethyl) carbamate, instead of 5-bromo-1-indanone, and using 1-(4-bromophenyl)cyclopropaneamine instead of tert- For butyl-N-(2-aminoethyl)-N-methylcarbamate, the same operation as in step 1 of Example 42 was performed to obtain the labeled compound (1.91 g). 1 H NMR (400MHz, CDCl 3 ) δ: 0.82-0.91 (2H, m), 0.93-1.00 (2H, m), 1.43 (9H, s), 2.66 (2H, t, J=6.5 Hz), 2.79 ( 3H, s), 3.16-3.31 (2H, m), 7.16 (2H, d, J=8.5 Hz), 7.42 (2H, d, J=8.5 Hz). MS (ESI) m/z369, 371 (M+ H) + .
步驟2 1-[1-(4-溴苯基)環丙基]-3-甲基咪唑啶-2-酮 使用由上述步驟1所得之tert-丁基N-[2-[[1-(4-溴苯基)環丙基]胺基]乙基]-N-甲基胺甲酸酯，而取代實施例42的步驟1所得之tert-丁基(2-((5-溴-2,3-二氫-1H-茚-1-基)胺基)乙基)(甲基)胺甲酸酯，進行與實施例42的步驟2同樣的操作，獲得標記化合物(1.12g)。1 H NMR (400MHz, CDCl3 ) δ: 0.87-0.91 (2H, m), 0.93-0.97 (2H, m), 2.78 (2H, t, J=6.3 Hz), 3.01 (3H, s), 3.44 (2H, t, J=6.3 Hz), 7.16 (2H, d, J=8.5 Hz), 7.43 (2H, d, J=8.5 Hz). MS (ESI) m/z295, 297 (M+H)+ .Step 2 1-[1-(4-Bromophenyl)cyclopropyl]-3-methylimidazolidin-2-one uses the tert-butyl N-[2-[[1-( 4-bromophenyl)cyclopropyl]amino]ethyl]-N-methyl carbamate, instead of tert-butyl (2-((5-bromo-2) obtained in step 1 of Example 42 ,3-Dihydro-1H-inden-1-yl)amino)ethyl)(methyl)carbamate, and the same operation as in step 2 of Example 42 was performed to obtain the title compound (1.12 g). 1 H NMR (400MHz, CDCl 3 ) δ: 0.87-0.91 (2H, m), 0.93-0.97 (2H, m), 2.78 (2H, t, J=6.3 Hz), 3.01 (3H, s), 3.44 ( 2H, t, J=6.3 Hz), 7.16 (2H, d, J=8.5 Hz), 7.43 (2H, d, J=8.5 Hz). MS (ESI) m/z295, 297 (M+H) + .
參考例12：2-氯-1-乙基-4-氟-1H-苯并[d]咪唑Reference Example 12: 2-Chloro-1-ethyl-4-fluoro-1H-benzo[d]imidazole
步驟1 2-氯-1-乙基-4-氟-1H-苯并[d]咪唑 將1-乙基-4-氟-1,3-二氫-2H-苯并咪唑-2-酮(Ref. Journal of Medicinal Chemistry, 2009, Vol.52, 5703-5711)(1.14g)添加至三氯一氧化磷(10mL)，在125℃攪拌4小時。將反應液回溫至室溫，在減壓下餾去三氯一氧化磷後，在殘渣中添加氯仿，冰冷下添加飽和碳酸氫鈉水後，以二氯甲烷進行萃取。以飽和食鹽水清洗有機層後，以硫酸鈉進行乾燥，在減壓下餾去溶劑。將殘渣以矽膠管柱層析法(n-己烷/二氯甲烷)進行純化，獲得標記化合物(1.25g)。1 H NMR (400MHz, CDCl3 ) δ: 1.44 (3H, t, J=7.3 Hz), 4.25 (2H, q, J=7.3 Hz), 6.93-7.00 (1H, m), 7.08-7.12 (1H, m), 7.19-7.25 (1H, m). MS (ESI) m/z 199 (M+H)+ .Step 1 2-Chloro-1-ethyl-4-fluoro-1H-benzo[d]imidazole to 1-ethyl-4-fluoro-1,3-dihydro-2H-benzimidazole-2-one ( Ref. Journal of Medicinal Chemistry, 2009, Vol. 52, 5703-5711) (1.14 g) was added to phosphorus monoxide (10 mL), and stirred at 125°C for 4 hours. The reaction solution was warmed to room temperature, and phosphorus monoxide was distilled off under reduced pressure, chloroform was added to the residue, saturated sodium bicarbonate water was added under ice cooling, and extraction was performed with dichloromethane. After washing the organic layer with saturated brine, it was dried with sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/dichloromethane) to obtain the title compound (1.25 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.44 (3H, t, J=7.3 Hz), 4.25 (2H, q, J=7.3 Hz), 6.93-7.00 (1H, m), 7.08-7.12 (1H, m), 7.19-7.25 (1H, m). MS (ESI) m/z 199 (M+H) + .
參考例13：2-氯-1-乙基-5-氟-1H-苯并[d]咪唑Reference Example 13: 2-Chloro-1-ethyl-5-fluoro-1H-benzo[d]imidazole
步驟1 2-氯-1-乙基-5-氟-1H-苯并[d]咪唑 將1-乙基-5-氟-1,3-二氫-2H-苯并咪唑-2-酮(Ref. Journal of Medicinal Chemistry, 2009, 52, 5703-5711)(39.4g)添加至三氯一氧化磷(207Ml)，在125℃攪拌3小時。將反應液回溫至室溫，在減壓下餾去三氯一氧化磷後，在殘渣中添加氯仿，冰冷下以氫氧化鈉水溶液中和後，以氯仿進行萃取。以飽和食鹽水清洗有機層後，以硫酸鈉進行乾燥，在減壓下餾去溶劑。將殘渣以矽膠管柱層析法(n-己烷/氯仿)進行純化，獲得標記化合物(26.4g)。1 H NMR (400MHz, CDCl3 ) δ: 1.44 (3H, t, J=7.3 Hz), 4.24 (2H, q, J=7.3 Hz), 6.93-7.00 (1H, m), 7.08-7.12 (1H, m), 7.19-7.25 (1H, m). MS (ESI) m/z 199 (M+H)+ .Step 1 2-Chloro-1-ethyl-5-fluoro-1H-benzo[d]imidazole is used to add 1-ethyl-5-fluoro-1,3-dihydro-2H-benzimidazole-2-one ( Ref. Journal of Medicinal Chemistry, 2009, 52, 5703-5711) (39.4 g) was added to phosphorus monoxide (207 Ml), and stirred at 125°C for 3 hours. The reaction solution was warmed to room temperature, and phosphorus monoxide was distilled off under reduced pressure, chloroform was added to the residue, and after neutralization with sodium hydroxide aqueous solution under ice cooling, extraction was performed with chloroform. After washing the organic layer with saturated brine, it was dried with sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/chloroform) to obtain the title compound (26.4 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.44 (3H, t, J=7.3 Hz), 4.24 (2H, q, J=7.3 Hz), 6.93-7.00 (1H, m), 7.08-7.12 (1H, m), 7.19-7.25 (1H, m). MS (ESI) m/z 199 (M+H) + .
參考例14：1-乙基-7-氟-2-碘-1H-苯并[d]咪唑Reference Example 14: 1-Ethyl-7-fluoro-2-iodo-1H-benzo[d]imidazole
步驟1 1-乙基-7-氟-1H-苯并[d]咪唑 在N2 -乙基-3-氟苯-1,2-二胺(Ref.WO2008/56150) (1.20g)的四氫呋喃(20mL)溶液中，添加原甲酸三甲酯(1.1mL)及p-甲苯磺酸一水合物(0.30g)，加熱回流1小時。放置冷卻後，在反應混合液中添加乙酸乙酯，以飽和碳酸氫鈉水、水、飽和食鹽水清洗後，以無水硫酸鈉進行乾燥。減壓下，餾去溶劑，將所得之殘渣以矽膠管柱層析法(氯仿/甲醇)進行純化，藉此獲得標記化合物(1.23g)。1 H NMR (400MHz, CDCl3 ) δ: 1.55 (3H, t, J=7.3 Hz), 4.38 (2H, q, J=7.3 Hz), 6.95-7.01 (1H, m), 7.13-7.20 (1H, m), 7.57 (1H, d, J=8.0 Hz), 7.85 (1H, s). MS (ESI) m/z 165 (M+H)+ .Step 1 1-Ethyl-7-fluoro-1H-benzo[d]imidazole in N 2 -ethyl-3-fluorobenzene-1,2-diamine (Ref.WO2008/56150) (1.20g) in tetrahydrofuran To the solution (20 mL), trimethyl orthoformate (1.1 mL) and p-toluenesulfonic acid monohydrate (0.30 g) were added, and the mixture was heated to reflux for 1 hour. After leaving to cool, ethyl acetate was added to the reaction mixture, washed with saturated sodium bicarbonate water, water, and saturated brine, and then dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform/methanol) to obtain the title compound (1.23 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.55 (3H, t, J=7.3 Hz), 4.38 (2H, q, J=7.3 Hz), 6.95-7.01 (1H, m), 7.13-7.20 (1H, m), 7.57 (1H, d, J=8.0 Hz), 7.85 (1H, s). MS (ESI) m/z 165 (M+H) + .
步驟2 1-乙基-7-氟-2-碘-1H-苯并[d]咪唑 在由上述步驟1所得之1-乙基-7-氟-1H-苯并[d]咪唑(1.23g)的四氫呋喃(20mL)溶液中，在-78℃滴下二異丙胺鋰(7.9mL，1.13mol/L、n-己烷及四氫呋喃溶液)並攪拌1小時。添加碘(2.90g)的四氫呋喃(5.0mL)溶液並攪拌30分鐘。添加飽和亞硫酸鈉水溶液及水，以乙酸乙酯進行萃取。以飽和食鹽水清洗萃取液，以硫酸鈉進行乾燥。在減壓下餾去溶劑，將殘渣以矽膠管柱層析法(氯仿/甲醇)進行純化，獲得標記化合物(1.70g)。1 H NMR (400MHz, CDCl3 ) δ: 1.45 (3H, t, J=7.3 Hz), 4.36 (2H, q, J=7.3 Hz), 6.93 (1H, dd, J=11.5, 8.0 Hz), 7.13 (1H, td, J=8.0, 4.9 Hz), 7.48 (1H, d, J=8.0 Hz). MS (ESI) m/z 291 (M+H)+ .Step 2 1-Ethyl-7-fluoro-2-iodo-1H-benzo[d]imidazole is used in the 1-ethyl-7-fluoro-1H-benzo[d]imidazole obtained from step 1 above (1.23g ) In a tetrahydrofuran (20 mL) solution, lithium diisopropylamine (7.9 mL, 1.13 mol/L, n-hexane and tetrahydrofuran solution) was dropped at -78°C and stirred for 1 hour. A solution of iodine (2.90 g) in tetrahydrofuran (5.0 mL) was added and stirred for 30 minutes. A saturated aqueous sodium sulfite solution and water were added, and extraction was performed with ethyl acetate. The extract was washed with saturated brine and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol) to obtain the title compound (1.70 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.45 (3H, t, J=7.3 Hz), 4.36 (2H, q, J=7.3 Hz), 6.93 (1H, dd, J=11.5, 8.0 Hz), 7.13 (1H, td, J=8.0, 4.9 Hz), 7.48 (1H, d, J=8.0 Hz). MS (ESI) m/z 291 (M+H) + .
參考例15：1-乙基-2-碘-1H-苯并[d]咪唑-7-甲腈Reference example 15: 1-ethyl-2-iodo-1H-benzo[d]imidazole-7-carbonitrile
步驟1 2-(乙胺基)-3-硝苯甲腈 使用2-氟-3-硝苯甲腈，而取代1-溴-3-氟-2-硝基苯，進行與參考例3的步驟1同樣的操作，獲得標記化合物(5.70g)。1 H NMR (400MHz, CDCl3 ) δ: 1.41 (3H, t, J=7.2 Hz), 3.86-3.95 (2H, m), 6.71 (1H, dd, J=8.4, 7.7 Hz), 7.72-7.76 (1H, m), 8.32-8.43 (2H, m).Step 1 2-(Ethylamino)-3-nitrobenzonitrile was used as 2-fluoro-3-nitrobenzonitrile instead of 1-bromo-3-fluoro-2-nitrobenzene, and the same as in Reference Example 3 The same operation as in step 1 was performed to obtain the labeled compound (5.70 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.41 (3H, t, J=7.2 Hz), 3.86-3.95 (2H, m), 6.71 (1H, dd, J=8.4, 7.7 Hz), 7.72-7.76 ( 1H, m), 8.32-8.43 (2H, m).
步驟2 3-胺基-2-(乙胺基)苯甲腈 在由上述步驟1所得之2-(乙胺基)-3-硝苯甲腈(2.00g)的乙醇(50mL)懸浮液中，添加鐵粉(2.92g)、飽和氯化銨水溶液(50mL)，在95℃攪拌2小時。放置冷卻後，使用矽藻土濾去不溶物後，以乙酸乙酯萃取濾液。以飽和食鹽水清洗有機層後，以無水硫酸鎂進行乾燥。餾去溶劑後，將殘渣以矽膠管柱層析法(n-己烷/乙酸乙酯)進行純化，獲得標記化合物(1.44g)。1 H NMR (400MHz, CDCl3 ) δ: 1.24 (4H, t, J=7.2 Hz), 3.27 (2H, q, J=7.2 Hz), 6.80-6.88 (2H, m), 6.96 (1H, dd, J=7.3, 2.0 Hz).Step 2 3-Amino-2-(ethylamino)benzonitrile in ethanol (50mL) suspension of 2-(ethylamino)-3-nitrobenzonitrile (2.00g) obtained in step 1 above , Added iron powder (2.92g) and saturated ammonium chloride aqueous solution (50mL), and stirred at 95°C for 2 hours. After allowing to cool, use Celite to filter out the insoluble matter, and then extract the filtrate with ethyl acetate. After washing the organic layer with saturated brine, it was dried with anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (1.44 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.24 (4H, t, J=7.2 Hz), 3.27 (2H, q, J=7.2 Hz), 6.80-6.88 (2H, m), 6.96 (1H, dd, J=7.3, 2.0 Hz).
步驟3 1-乙基-1H-苯并[d]咪唑-7-甲腈 使用由上述步驟2所得之3-胺基-2-(乙胺基)苯甲腈，而取代N2 -乙基-3-氟苯-1,2-二胺，與參考例14的步驟1同樣地進行操作，獲得標記化合物(1.48g)。1 H NMR (400MHz, CDCl3 ) δ: 1.62 (7H, t, J=7.3 Hz), 4.57 (2H, q, J=7.3 Hz), 7.34 (1H, dd, J=8.2, 7.5 Hz), 7.64 (1H, dd, J=7.5, 1.0 Hz), 8.01 (1H, s), 8.04 (1H, dd, J=8.2, 1.0 Hz). MS (ESI) m/z 172 (M+H)+ .Step 3 1-Ethyl-1H-benzo[d]imidazole-7-carbonitrile uses the 3-amino-2-(ethylamino)benzonitrile obtained in step 2 above instead of N 2 -ethyl -3-Fluorobenzene-1,2-diamine was operated in the same manner as in Step 1 of Reference Example 14 to obtain the labeled compound (1.48 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.62 (7H, t, J=7.3 Hz), 4.57 (2H, q, J=7.3 Hz), 7.34 (1H, dd, J=8.2, 7.5 Hz), 7.64 (1H, dd, J=7.5, 1.0 Hz), 8.01 (1H, s), 8.04 (1H, dd, J=8.2, 1.0 Hz). MS (ESI) m/z 172 (M+H) + .
步驟4 1-乙基-2-碘-1H-苯并[d]咪唑-7-甲腈 使用由上述步驟3所得之1-乙基-1H-苯并[d]咪唑-7-甲腈，而取代參考例14的步驟1所得之1-乙基-7-氟-1H-苯并[d]咪唑，與參考例14的步驟2同樣地進行操作，獲得標記化合物(2.30g)。1 H NMR (400MHz, CDCl3 ) δ: 1.52 (3H, t, J=7.2 Hz), 4.57 (2H, q, J=7.2 Hz), 7.29 (1H, dd, J=8.2, 7.5 Hz), 7.58 (1H, dd, J=7.5, 1.0 Hz), 7.95 (1H, dd, J=8.2, 1.0 Hz). MS (ESI) m/z 298 (M+H)+ .Step 4 1-Ethyl-2-iodo-1H-benzo[d]imidazole-7-carbonitrile uses the 1-ethyl-1H-benzo[d]imidazole-7-carbonitrile obtained in step 3 above, Instead of the 1-ethyl-7-fluoro-1H-benzo[d]imidazole obtained in Step 1 of Reference Example 14, the same procedure as in Step 2 of Reference Example 14 was performed to obtain the labeled compound (2.30 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.52 (3H, t, J=7.2 Hz), 4.57 (2H, q, J=7.2 Hz), 7.29 (1H, dd, J=8.2, 7.5 Hz), 7.58 (1H, dd, J=7.5, 1.0 Hz), 7.95 (1H, dd, J=8.2, 1.0 Hz). MS (ESI) m/z 298 (M+H) + .
參考例16：N-[1-乙基-4-(丙烷-2-基)-1H-苯并[d]咪唑-2-基]-4-[(3-甲基-2-側氧基咪唑啶-1-基)甲基]苯甲醯胺Reference Example 16: N-[1-ethyl-4-(propan-2-yl)-1H-benzo[d]imidazol-2-yl]-4-[(3-methyl-2-oxo (Imidazolidine-1-yl)methyl)benzamide
步驟1 1-氟-2-硝基-3-(丙烷-2-基)苯 在1-氟-2-硝基-3-(丙烯-2-基)苯(US2013/203593所記載的化合物)(700mg)的四氫呋喃/tert-丁醇(1/1)(14mL)溶液中，添加Wilkinson觸媒(179mg)，氫氣體環境下，攪拌10小時。將反應液進行減壓濃縮後，將殘渣以矽膠管柱層析法(n-己烷/乙酸乙酯)進行純化，獲得標記化合物(477mg)。1 H NMR (400MHz, CDCl3 ) δ: 1.28 (6H, d, J=7.0 Hz) , 2.96-3.07 (1H, m), 7.04-7.11 (1H, m), 7.20 (1H, d, J=8.2 Hz), 7.43 (1H, td, J=8.2, 5.4 Hz).Step 1 1-fluoro-2-nitro-3-(propan-2-yl)benzene in 1-fluoro-2-nitro-3-(propen-2-yl)benzene (compound described in US2013/203593) To a (700 mg) tetrahydrofuran/tert-butanol (1/1) (14 mL) solution, Wilkinson catalyst (179 mg) was added, and the mixture was stirred for 10 hours under a hydrogen atmosphere. After the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (477 mg). 1 H NMR (400MHz, CDCl 3 ) δ: 1.28 (6H, d, J=7.0 Hz), 2.96-3.07 (1H, m), 7.04-7.11 (1H, m), 7.20 (1H, d, J=8.2 Hz), 7.43 (1H, td, J=8.2, 5.4 Hz).
步驟2 N-乙基-2-硝基-3-(丙烷-2-基)苯胺 使用由上述步驟1所得之1-氟-2-硝基-3-(丙烷-2-基)苯(470mg)，而取代參考例3的步驟1所使用之1-溴-3-氟-2-硝基苯，進行與參考例3的步驟1同樣的操作，獲得標記化合物(439mg)。1 H NMR (400MHz, CDCl3 ) δ: 1.25 (6H, d, J=6.8 Hz), 1.29 (3H, t, J=7.3 Hz), 3.05-3.26 (3H, m), 5.22 (1H, br s), 6.61 (1H, dd, J=8.5, 0.8 Hz), 6.68 (1H, dd, J=7.7, 1.1 Hz), 7.27 (4H, td, J=7.7, 0.8 Hz).Step 2 N-Ethyl-2-nitro-3-(propan-2-yl)aniline uses the 1-fluoro-2-nitro-3-(propan-2-yl)benzene (470mg obtained from step 1 above) ), instead of 1-bromo-3-fluoro-2-nitrobenzene used in Step 1 of Reference Example 3, the same operation as Step 1 of Reference Example 3 was performed to obtain the labeled compound (439 mg). 1 H NMR (400MHz, CDCl 3 ) δ: 1.25 (6H, d, J=6.8 Hz), 1.29 (3H, t, J=7.3 Hz), 3.05-3.26 (3H, m), 5.22 (1H, br s) ), 6.61 (1H, dd, J=8.5, 0.8 Hz), 6.68 (1H, dd, J=7.7, 1.1 Hz), 7.27 (4H, td, J=7.7, 0.8 Hz).
步驟3 N1 -乙基-3-(丙烷-2-基)苯-1,2-二胺 使用由上述步驟2所得之N-乙基-2-硝基-3-(丙烷-2-基)苯胺(435mg)，而取代參考例6的步驟1所得之N-乙基-2-硝基苯胺，進行與參考例6的步驟2同樣的操作，獲得標記化合物(369mg)。1 H NMR (400MHz, CDCl3 ) δ: 1.26 (6H, d, J=6.8 Hz), 1.31 (3H, t, J=7.2 Hz), 1.54 (1H, br s), 2.90-3.03 (1H, m), 3.15 (2H, q, J=7.0 Hz), 3.47 (2H, br s), 6.60 (1H, d, J=7.8 Hz), 6.72 (1H, d, J=7.3 Hz), 6.82 (1H, t, J=7.8 Hz).Step 3 N 1 -Ethyl-3-(propan-2-yl)benzene-1,2-diamine uses the N-ethyl-2-nitro-3-(propan-2-yl obtained from step 2 above) ) Aniline (435 mg), instead of N-ethyl-2-nitroaniline obtained in Step 1 of Reference Example 6, the same operation as in Step 2 of Reference Example 6 was performed to obtain the labeled compound (369 mg). 1 H NMR (400MHz, CDCl 3 ) δ: 1.26 (6H, d, J=6.8 Hz), 1.31 (3H, t, J=7.2 Hz), 1.54 (1H, br s), 2.90-3.03 (1H, m ), 3.15 (2H, q, J=7.0 Hz), 3.47 (2H, br s), 6.60 (1H, d, J=7.8 Hz), 6.72 (1H, d, J=7.3 Hz), 6.82 (1H, t, J=7.8 Hz).
步驟4 1-乙基-4-(丙烷-2-基)-1H-苯并[d]咪唑-2-胺 將由上述步驟3所得之N1 -乙基-3-(丙烷-2-基)苯-1,2-二胺(365mg)溶解於乙醇(9mL)及水(3mL)，添加溴化氰(850mg)，在室溫攪拌2小時。在反應液中添加1mol/L氫氧化鈉水溶液，以乙酸乙酯進行萃取。以水、飽和食鹽水清洗有機層後，以無水硫酸鈉進行乾燥。將溶劑進行減壓餾去後，在所得之殘渣中添加二異丙基醚，使析出物進行濾取、乾燥，藉此獲得標記化合物(358mg)。1 H NMR (400MHz, CDCl3 ) δ: 1.36 (6H, d, J=7.0 Hz), 1.40 (3H, t, J=7.3 Hz), 3.53-3.64 (1H, m), 3.97 (2H, q, J=7.3 Hz), 4.87 (2H, br s), 6.96 (1H, dd, J=7.3, 1.8 Hz), 7.01-7.08 (2H, m).Step 4 1-Ethyl-4-(propan-2-yl)-1H-benzo[d]imidazol-2-amine will be N 1 -ethyl-3-(propan-2-yl) obtained from step 3 above Benzene-1,2-diamine (365 mg) was dissolved in ethanol (9 mL) and water (3 mL), cyanogen bromide (850 mg) was added, and the mixture was stirred at room temperature for 2 hours. A 1 mol/L sodium hydroxide aqueous solution was added to the reaction liquid, and extraction was performed with ethyl acetate. After washing the organic layer with water and saturated brine, it was dried with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, diisopropyl ether was added to the residue obtained, and the precipitate was filtered and dried to obtain the labeled compound (358 mg). 1 H NMR (400MHz, CDCl 3 ) δ: 1.36 (6H, d, J=7.0 Hz), 1.40 (3H, t, J=7.3 Hz), 3.53-3.64 (1H, m), 3.97 (2H, q, J=7.3 Hz), 4.87 (2H, br s), 6.96 (1H, dd, J=7.3, 1.8 Hz), 7.01-7.08 (2H, m).
步驟5 4-[(3-甲基-2-側氧基咪唑啶-1-基)甲基]苯甲酸甲酯 使用4-(溴甲基)苯甲酸甲酯，而取代參考例1的步驟1所得之(4-碘苯基)甲基甲磺酸酯，進行與參考例1的步驟2同樣的操作，獲得標記化合物(3.75g)。1 H NMR (400MHz, CDCl3 ) δ: 2.84 (3H, s), 3.15-3.20 (2H, m), 3.27-3.33 (2H, m), 3.91 (3H, s), 4.42 (2H, s), 7.34 (2H, d, J=8.5 Hz), 8.00 (2H, d, J=8.5 Hz). MS (ESI) m/z 249 (M+H)+ .Step 5 Methyl 4-[(3-methyl-2-oxoimidazolidine-1-yl)methyl]benzoate is methyl 4-(bromomethyl)benzoate instead of the step of Reference Example 1. 1. The obtained (4-iodophenyl) methanesulfonate was subjected to the same operation as in Step 2 of Reference Example 1 to obtain the labeled compound (3.75 g). 1 H NMR (400MHz, CDCl 3 ) δ: 2.84 (3H, s), 3.15-3.20 (2H, m), 3.27-3.33 (2H, m), 3.91 (3H, s), 4.42 (2H, s), 7.34 (2H, d, J=8.5 Hz), 8.00 (2H, d, J=8.5 Hz). MS (ESI) m/z 249 (M+H) + .
步驟6 4-[(3-甲基-2-側氧基咪唑啶-1-基)甲基]苯甲酸 室溫下，在由上述步驟5所得之4-[(3-甲基-2-側氧基咪唑啶-1-基)甲基]苯甲酸甲酯(3.75g)的甲醇(75mL)/水(30mL)溶液中，添加氫氧化鋰一水合物(1.27g)，攪拌4小時。將反應混合液進行減壓濃縮後，冰冷下在殘渣中添加1mol/L鹽酸成為酸性後，以乙酸乙酯進行萃取。以飽和食鹽水清洗有機層後，以無水硫酸鈉進行乾燥。餾去溶劑後，將殘渣以二乙基醚/n-己烷漿化後，進行濾取、乾燥，獲得標記化合物(3.35g)。1 H NMR (400MHz, CDCl3 ) δ: 2.86 (3H, s), 3.17-3.24 (2H, m), 3.29-3.36 (2H, m), 4.45 (2H, s), 7.37 (2H, d, J=8.3 Hz), 8.06 (2H, d, J=8.3 Hz).Step 6 4-[(3-Methyl-2-oxoimidazolidine-1-yl)methyl]benzoic acid at room temperature, the 4-[(3-methyl-2- Lithium hydroxide monohydrate (1.27 g) was added to a methanol (75 mL)/water (30 mL) solution of methyl methyl] benzoate (3.75 g) of pendant oxyimidazolidine-1-yl)methyl]benzoate, and stirred for 4 hours. After the reaction mixture was concentrated under reduced pressure, 1 mol/L hydrochloric acid was added to the residue under ice cooling to make it acidic, and then extraction was performed with ethyl acetate. After washing the organic layer with saturated brine, it was dried with anhydrous sodium sulfate. After the solvent was distilled off, the residue was slurried with diethyl ether/n-hexane, then filtered and dried to obtain the title compound (3.35 g). 1 H NMR (400MHz, CDCl 3 ) δ: 2.86 (3H, s), 3.17-3.24 (2H, m), 3.29-3.36 (2H, m), 4.45 (2H, s), 7.37 (2H, d, J =8.3 Hz), 8.06 (2H, d, J=8.3 Hz).
步驟7 N-[1-乙基-4-(丙烷-2-基)-1H-苯并[d]咪唑-2-基]-4-[(3-甲基-2-側氧基咪唑啶-1-基)甲基]苯甲醯胺 在由上述步驟4所得之1-乙基-4-(丙烷-2-基)-1H-苯并[d]咪唑-2-胺(102mg)及由步驟6所得之4-[(3-甲基-2-側氧基咪唑啶-1-基)甲基]苯甲酸(118mg)的N,N-二甲基甲醯胺(3.0mL)溶液中，添加二異丙基乙胺(0.11mL)，冰冷後，添加1-[雙(二甲基胺基)亞甲基]-1H-1,2,3-三偶氮并[4,5-b]吡啶陽離子3-氧化物六氟磷酸酯(HATU)(191mg)。在室溫攪拌24小時後，在反應混合液中添加水，以乙酸乙酯進行萃取。依序以飽和碳酸氫鈉水、飽和食鹽水清洗有機層後，以無水硫酸鈉進行乾燥。餾去溶劑後，將殘渣以矽膠管柱層析法(氯仿/甲醇)進行純化，獲得標記化合物(85mg)。1 H NMR (400MHz, CDCl3 ) δ: 1.39 (6H, d, J=7.0 Hz), 1.47 (3H, t, J=7.2 Hz), 3.14-3.23 (2H, m), 3.23-3.32 (3H, m), 4.32 (2H, q, J=7.2 Hz), 4.44 (2H, s), 7.12 (2H, d, J=7.8 Hz), 7.23 (1H, d, J=7.5 Hz), 7.35 (2H, d, J=8.5 Hz), 8.31 (2H, d, J=8.3 Hz), 12.52 (1H, br s). MS (ESI) m/z 420 (M+H)+ .Step 7 N-[1-Ethyl-4-(propan-2-yl)-1H-benzo[d]imidazol-2-yl]-4-[(3-methyl-2-oxoimidazolidinium -1-yl)methyl)benzamide in the 1-ethyl-4-(propan-2-yl)-1H-benzo[d]imidazol-2-amine (102mg) obtained in step 4 above and A solution of 4-[(3-methyl-2-oxoimidazolidine-1-yl)methyl]benzoic acid (118mg) obtained from step 6 in N,N-dimethylformamide (3.0mL) Add diisopropylethylamine (0.11mL), after ice cooling, add 1-[bis(dimethylamino)methylene]-1H-1,2,3-trisazo[4,5 -b] Pyridine cation 3-oxide hexafluorophosphate (HATU) (191 mg). After stirring at room temperature for 24 hours, water was added to the reaction mixture, and extraction was performed with ethyl acetate. After washing the organic layer with saturated sodium bicarbonate water and saturated brine in this order, it was dried with anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (chloroform/methanol) to obtain the title compound (85 mg). 1 H NMR (400MHz, CDCl 3 ) δ: 1.39 (6H, d, J=7.0 Hz), 1.47 (3H, t, J=7.2 Hz), 3.14-3.23 (2H, m), 3.23-3.32 (3H, m), 4.32 (2H, q, J=7.2 Hz), 4.44 (2H, s), 7.12 (2H, d, J=7.8 Hz), 7.23 (1H, d, J=7.5 Hz), 7.35 (2H, d, J=8.5 Hz), 8.31 (2H, d, J=8.3 Hz), 12.52 (1H, br s). MS (ESI) m/z 420 (M+H) + .
實施例1：(E)-1-(4-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮Example 1: (E)-1-(4-(2-(1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl)benzyl)-3-methylimidazolidine-2 -ketone
步驟1
(E)-1-(4-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮
在由參考例1的步驟3所得之(E)-1-甲基-3-(4-(2-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)乙烯基)苄基)咪唑啶-2-酮(66g)與由參考例2的步驟1所得之2-溴-1-乙基-1H-苯并[d]咪唑(43.4g)的1,4-二
實施例2：(E)-1-(4-(2-(1,4-二乙基-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮Example 2: (E)-1-(4-(2-(1,4-Diethyl-1H-benzo[d]imidazol-2-yl)vinyl)benzyl)-3-methylimidazole Pyridin-2-one
步驟1
N-乙基-2-硝基-3-乙烯基苯胺
在參考例3的步驟1所得之3-溴-N-乙基-2-硝基苯胺(1.59g)的1,4-二
步驟2 N1,3 -二乙基苯-1,2-二胺 在由上述步驟1所得之N-乙基-2-硝基-3-乙烯基苯胺(1.25g)的乙醇(47mL)溶液中，室溫下，添加5%鈀碳(0.37g)，氫氣體環境下，攪拌2小時。將反應液進行矽藻土過濾，減壓下，餾去濾液的溶劑，獲得標記化合物(1.10g)。1 H NMR (400MHz, CDCl3 ) δ: 1.24 (3H, t, J=7.5 Hz), 1.35 (3H, t, J=7.2 Hz), 2.56 (2H, q, J=7.6 Hz), 3.19-3.27 (2H, m), 6.72-6.84 (3H, m). MS (ESI) m/z 165 (M+H)+ .Step 2 A solution of N 1,3 -diethylbenzene-1,2-diamine in ethanol (47 mL) of N-ethyl-2-nitro-3-vinylaniline (1.25g) obtained from step 1 above Add 5% palladium on carbon (0.37 g) at room temperature, and stir for 2 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the solvent of the filtrate was distilled off under reduced pressure to obtain the labeled compound (1.10 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.24 (3H, t, J=7.5 Hz), 1.35 (3H, t, J=7.2 Hz), 2.56 (2H, q, J=7.6 Hz), 3.19-3.27 (2H, m), 6.72-6.84 (3H, m). MS (ESI) m/z 165 (M+H) + .
步驟3 1,4-二乙基-1H-苯并[d]咪唑-2-酮 在由上述步驟2所得之N1,3 -二乙基苯-1,2-二胺(1.1g)的四氫呋喃(12mL)溶液中，室溫下，添加1,1-羰基二咪唑(1.05g)，攪拌72小時。在減壓下餾去反應溶劑，在殘渣中添加飽和食鹽水，以乙酸乙酯進行萃取。以磷酸水溶液及飽和食鹽水清洗萃取液，以硫酸鈉進行乾燥。減壓下，餾去溶劑，將殘渣以矽膠管柱層析法(n-己烷/乙酸乙酯)進行純化，獲得標記化合物(0.78g)。1 H NMR (400MHz, CDCl3 ) δ: 1.29 (3H, t, J=7.6 Hz), 1.35 (3H, t, J=7.2 Hz), 2.69 (2H, q, J=7.6 Hz), 3.93 (2H, q, J=7.2 Hz), 6.86 (1H, d, J=7.8 Hz), 6.91 (1H, d, J=7.7 Hz), 7.02-7.07 (1H, m), 8.07 (1H, br s). MS (ESI) m/z 191 (M+H)+ .Step 3 1,4-Diethyl-1H-benzo[d]imidazol-2-one in the N 1,3 -diethylbenzene-1,2-diamine (1.1g) obtained from step 2 above To the tetrahydrofuran (12 mL) solution, 1,1-carbonyldiimidazole (1.05 g) was added at room temperature, and the mixture was stirred for 72 hours. The reaction solvent was distilled off under reduced pressure, saturated brine was added to the residue, and extraction was performed with ethyl acetate. The extract was washed with aqueous phosphoric acid and saturated brine, and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (0.78 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.29 (3H, t, J=7.6 Hz), 1.35 (3H, t, J=7.2 Hz), 2.69 (2H, q, J=7.6 Hz), 3.93 (2H , q, J=7.2 Hz), 6.86 (1H, d, J=7.8 Hz), 6.91 (1H, d, J=7.7 Hz), 7.02-7.07 (1H, m), 8.07 (1H, br s). MS (ESI) m/z 191 (M+H) + .
步驟4 2-溴-1,4-二乙基-1H-苯并[d]咪唑 室溫下，在由上述步驟3所得之1,4-二乙基-1H-苯并[d]咪唑-2-酮(0.78g)的甲苯(56mL)溶液中，添加三溴一氧化磷(2.82g)，加熱回流19小時。放置冷卻後，在反應液中添加飽和碳酸氫鈉水，以氯仿進行萃取。將萃取液以硫酸鈉進行乾燥，在減壓下餾去溶劑。將殘渣以矽膠管柱層析法(n-己烷/乙酸乙酯)進行純化，獲得標記化合物(0.66g)。1 H NMR (400MHz, CDCl3 ) δ: 1.36 (3H, t, J=7.6 Hz), 1.43 (3H, t, J=7.2 Hz), 3.06 (2H, q, J=7.5 Hz), 4.24 (2H, q, J=7.2 Hz), 7.06-7.11 (1H, m), 7.15-7.24 (2H, m). MS (ESI) m/z 253 (M+H)+ .Step 4 2-Bromo-1,4-diethyl-1H-benzo[d]imidazole at room temperature, in the 1,4-diethyl-1H-benzo[d]imidazole obtained in step 3 above To a toluene (56 mL) solution of 2-ketone (0.78 g), phosphorus tribromomonoxide (2.82 g) was added, and the mixture was heated to reflux for 19 hours. After leaving to cool, saturated sodium bicarbonate water was added to the reaction solution, and extraction was performed with chloroform. The extract was dried with sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (0.66 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.36 (3H, t, J=7.6 Hz), 1.43 (3H, t, J=7.2 Hz), 3.06 (2H, q, J=7.5 Hz), 4.24 (2H , q, J=7.2 Hz), 7.06-7.11 (1H, m), 7.15-7.24 (2H, m). MS (ESI) m/z 253 (M+H) + .
步驟5
(E)-1-(4-(2-(1,4-二乙基-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮
室溫下，在由上述步驟4所得之2-溴-1,4-二乙基-1H-苯并[d]咪唑(0.66g)及由參考例1的步驟3所得之(E)-1-甲基-3-(4-(2-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)乙烯基)苄基)咪唑啶-2-酮(0.98g)的1,4-二
實施例3：(E)-1-(4-(2-(1-乙基-4-異丙基-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮Example 3: (E)-1-(4-(2-(1-ethyl-4-isopropyl-1H-benzo[d]imidazol-2-yl)vinyl)benzyl)-3- Methylimidazolidin-2-one
步驟1
N-乙基-2-硝基-3-(丙烯-2-基)苯胺
室溫下，在參考例3的步驟1所得之3-溴-N-乙基-2-硝基苯胺(1.75g)的1,4-二
步驟2 (E)-1-(4-(2-(1-乙基-4-異丙基-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮 使用由上述步驟1所得之N-乙基-2-硝基-3-(丙烯-2-基)苯胺，而取代由實施例2的步驟1所得之N-乙基-2-硝基-3-乙烯基苯胺，進行與實施例2的步驟2至步驟5同樣的操作，獲得標記化合物(0.85g)。1 H NMR (400MHz, CDCl3 ) δ: 1.42 (6H, d, J=6.9 Hz), 1.47 (3H, t, J=7.3 Hz), 2.85 (3H, s), 3.17-3.23 (2H, m), 3.26-3.33 (2H, m), 3.87 (1H, spt, J=6.9 Hz), 4.30 (2H, q, J=7.3 Hz), 4.39 (2H, s), 7.08 (1H, d, J=15.8 Hz), 7.12-7.25 (3H, m), 7.31 (2H, d, J=8.2 Hz), 7.58 (2H, d, J=8.2 Hz), 7.92 (1H, d, J=15.9 Hz). MS (ESI) m/z 403 (M+H)+ .Step 2 (E)-1-(4-(2-(1-ethyl-4-isopropyl-1H-benzo[d]imidazol-2-yl)vinyl)benzyl)-3-methyl The imidazolidin-2-one uses the N-ethyl-2-nitro-3-(propen-2-yl)aniline obtained in step 1 above instead of the N-ethyl- obtained in step 1 of Example 2. For 2-nitro-3-vinylaniline, the same operations as in step 2 to step 5 of Example 2 were performed to obtain the labeled compound (0.85 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.42 (6H, d, J=6.9 Hz), 1.47 (3H, t, J=7.3 Hz), 2.85 (3H, s), 3.17-3.23 (2H, m) , 3.26-3.33 (2H, m), 3.87 (1H, spt, J=6.9 Hz), 4.30 (2H, q, J=7.3 Hz), 4.39 (2H, s), 7.08 (1H, d, J=15.8 Hz), 7.12-7.25 (3H, m), 7.31 (2H, d, J=8.2 Hz), 7.58 (2H, d, J=8.2 Hz), 7.92 (1H, d, J=15.9 Hz). MS ( ESI) m/z 403 (M+H) + .
實施例4：(E)-1-(4-(2-(1-乙基-4-氟-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮Example 4: (E)-1-(4-(2-(1-ethyl-4-fluoro-1H-benzo[d]imidazol-2-yl)vinyl)benzyl)-3-methyl Imidazolidin-2-one
使用1,3-二氟-2-硝基苯，而取代參考例3的步驟1所使用之1-溴-3-氟-2-硝基苯，進行與參考例3的步驟1至步驟3同樣的操作。使用所得之化合物，而取代參考例5的步驟1所使用之4-溴-1-乙基-1H-苯并[d]咪唑-2-酮，進行與參考例5的步驟1同樣的操作，獲得4-氟-2-氯-1-乙基-1H-苯并[d]咪唑。再使用本化合物，而取代由參考例2的步驟1所得之2-溴-1-乙基-1H-苯并[d]咪唑，進行與實施例1的步驟1同樣的操作，獲得標記化合物(1.26g)。1 H NMR (400MHz, CDCl3 ) δ: 1.48 (3H, t, J=7.3 Hz), 2.84 (3H, s), 3.15-3.23 (2H, m), 3.26-3.32 (2H, m), 4.32 (2H, q, J=7.3 Hz), 4.40 (2H, s), 6.97 (1H, ddd, J=10.5, 7.7, 1.1 Hz), 7.03 (1H, d, J=15.8 Hz), 7.11-7.14 (1H, m), 7.17 (1H, dd, J=7.7, 4.5 Hz), 7.32 (2H, d, J=8.2 Hz), 7.58 (2H, d, J=8.0 Hz), 8.08 (1H, d, J=15.8 Hz). MS (ESI) m/z 379 (M+H)+ .Using 1,3-difluoro-2-nitrobenzene, instead of 1-bromo-3-fluoro-2-nitrobenzene used in step 1 of Reference Example 3, proceed with steps 1 to 3 of Reference Example 3 The same operation. Using the obtained compound instead of 4-bromo-1-ethyl-1H-benzo[d]imidazol-2-one used in Step 1 of Reference Example 5, the same operation as Step 1 of Reference Example 5 was performed. 4-Fluoro-2-chloro-1-ethyl-1H-benzo[d]imidazole is obtained. Using this compound again, instead of the 2-bromo-1-ethyl-1H-benzo[d]imidazole obtained in Step 1 of Reference Example 2, the same operation as in Step 1 of Example 1 was performed to obtain the labeled compound ( 1.26g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.48 (3H, t, J=7.3 Hz), 2.84 (3H, s), 3.15-3.23 (2H, m), 3.26-3.32 (2H, m), 4.32 ( 2H, q, J=7.3 Hz), 4.40 (2H, s), 6.97 (1H, ddd, J=10.5, 7.7, 1.1 Hz), 7.03 (1H, d, J=15.8 Hz), 7.11-7.14 (1H , m), 7.17 (1H, dd, J=7.7, 4.5 Hz), 7.32 (2H, d, J=8.2 Hz), 7.58 (2H, d, J=8.0 Hz), 8.08 (1H, d, J= 15.8 Hz). MS (ESI) m/z 379 (M+H) + .
實施例5：(E)-1-(4-(2-(4-溴-1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮Example 5: (E)-1-(4-(2-(4-Bromo-1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl)benzyl)-3-methyl Imidazolidin-2-one
使用由參考例3的步驟3所得之4-溴-1-乙基-1H-苯并[d]咪唑-2-酮，而取代由實施例2的步驟4所得之1,4-二乙基-1H-苯并[d]咪唑-2-酮，進行與實施例2的步驟4同樣的操作往2,4-二溴-1-乙基-1H-苯并[d]咪唑變換後，使用本化合物，而取代參考例2所得之2-溴-1-乙基-1H-苯并[d]咪唑，進行與實施例1的步驟1同樣的操作，獲得標記化合物(3.11g)。1 H NMR (400MHz, CDCl3 ) δ: 1.47 (3H, t, J=7.3 Hz), 2.85 (3H, s), 3.17-3.23 (2H, m), 3.27-3.34 (2H, m), 4.31 (2H, q, J=7.4 Hz), 4.40 (2H, s), 7.03 (1H, d, J=15.8 Hz), 7.10-7.15 (1H, m), 7.28-7.33 (3H, m), 7.46 (1H, dd, J=7.7, 0.9 Hz), 7.59 (2H, d, J=8.0 Hz), 8.09 (1H, d, J=15.9 Hz). MS (ESI) m/z 439 (M+H)+ .Use 4-bromo-1-ethyl-1H-benzo[d]imidazol-2-one obtained in step 3 of Reference Example 3 instead of 1,4-diethyl obtained in step 4 of Example 2 -1H-Benzo[d]imidazole-2-one, after performing the same operation as step 4 of Example 2 to 2,4-dibromo-1-ethyl-1H-benzo[d]imidazole, use This compound, instead of the 2-bromo-1-ethyl-1H-benzo[d]imidazole obtained in Reference Example 2, was subjected to the same operation as in Step 1 of Example 1 to obtain the title compound (3.11 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.47 (3H, t, J=7.3 Hz), 2.85 (3H, s), 3.17-3.23 (2H, m), 3.27-3.34 (2H, m), 4.31 ( 2H, q, J=7.4 Hz), 4.40 (2H, s), 7.03 (1H, d, J=15.8 Hz), 7.10-7.15 (1H, m), 7.28-7.33 (3H, m), 7.46 (1H , dd, J=7.7, 0.9 Hz), 7.59 (2H, d, J=8.0 Hz), 8.09 (1H, d, J=15.9 Hz). MS (ESI) m/z 439 (M+H) + .
實施例6：(E)-1-(4-(2-(1-乙基-5-氟-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮Example 6: (E)-1-(4-(2-(1-ethyl-5-fluoro-1H-benzo[d]imidazol-2-yl)vinyl)benzyl)-3-methyl Imidazolidin-2-one
使用參考例13的步驟1所得之2-氯-1-乙基-5-氟-1H-苯并[d]咪唑，而取代由參考例2的步驟1所得之2-溴-1-乙基-1H-苯并[d]咪唑，進行與實施例1的步驟1同樣的操作，獲得標記化合物(0.57g)。1 H NMR (400MHz, CDCl3 ) δ: 1.47 (3H, t, J=7.3 Hz), 2.84 (3H, s), 3.16-3.23 (2H, m), 3.26-3.33 (2H, m), 4.31 (2H, q, J=7.3 Hz), 4.40 (2H, s), 6.98-7.06 (2H, m), 7.22-7.26 (1H, m), 7.32 (2H, d, J=8.0 Hz), 7.42 (1H, dd, J=9.5, 2.3 Hz), 7.57 (2H, d, J=8.2 Hz), 7.97 (1H, d, J=15.8 Hz). MS (ESI) m/z 379 (M+H)+ .Use 2-chloro-1-ethyl-5-fluoro-1H-benzo[d]imidazole obtained in Step 1 of Reference Example 13 instead of 2-bromo-1-ethyl obtained in Step 1 of Reference Example 2 -1H-benzo[d]imidazole, the same operation as in step 1 of Example 1 was performed to obtain the labeled compound (0.57 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.47 (3H, t, J=7.3 Hz), 2.84 (3H, s), 3.16-3.23 (2H, m), 3.26-3.33 (2H, m), 4.31 ( 2H, q, J=7.3 Hz), 4.40 (2H, s), 6.98-7.06 (2H, m), 7.22-7.26 (1H, m), 7.32 (2H, d, J=8.0 Hz), 7.42 (1H , dd, J=9.5, 2.3 Hz), 7.57 (2H, d, J=8.2 Hz), 7.97 (1H, d, J=15.8 Hz). MS (ESI) m/z 379 (M+H) + .
實施例7：(E)-1-(4-(2-(4-環己基-1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮Example 7: (E)-1-(4-(2-(4-cyclohexyl-1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl)benzyl)-3-methan Imidazolidin-2-one
步驟1
4-(環己烯-1-基)-1-乙基-1H-苯并[d]咪唑-2-酮
在由參考例3的步驟3所得之4-溴-1-乙基-1H-苯并[d]咪唑-2-酮(0.37g)的1,4-二
步驟2 4-環己基-1-乙基-1H-苯并[d]咪唑-2-酮 在由上述步驟1所得之4-(環己烯-1-基)-1-乙基-1H-苯并[d]咪唑-2-酮(0.30g)的乙醇(16mL)溶液中，添加5%鈀碳(0.60g)，氫氣體環境下，攪拌15小時。將反應液進行矽藻土過濾，減壓下餾去濾液的溶劑，將殘渣以矽膠管柱層析法(n-己烷/乙酸乙酯)進行純化，獲得標記化合物(0.28g)。1 H NMR (400MHz, CDCl3 ) δ: 1.27-1.40 (4H, m), 1.43-1.54 (4H, m), 1.80 (1H, d, J=12.8 Hz), 1.84-1.99 (4H, m), 2.52-2.70 (1H, m), 3.93 (2H, q, J=7.3 Hz), 6.85 (1H, d, J=7.8 Hz), 6.93 (1H, d, J=7.5 Hz), 7.02-7.11 (1H, m), 8.58 (1H, br s). MS (ESI) m/z 245 (M+H)+ .Step 2 4-Cyclohexyl-1-ethyl-1H-benzo[d]imidazol-2-one in the 4-(cyclohexen-1-yl)-1-ethyl-1H- obtained from step 1 above To a solution of benzo[d]imidazol-2-one (0.30 g) in ethanol (16 mL), 5% palladium on carbon (0.60 g) was added, and the mixture was stirred for 15 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, the solvent of the filtrate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (0.28 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.27-1.40 (4H, m), 1.43-1.54 (4H, m), 1.80 (1H, d, J=12.8 Hz), 1.84-1.99 (4H, m), 2.52-2.70 (1H, m), 3.93 (2H, q, J=7.3 Hz), 6.85 (1H, d, J=7.8 Hz), 6.93 (1H, d, J=7.5 Hz), 7.02-7.11 (1H , m), 8.58 (1H, br s). MS (ESI) m/z 245 (M+H) + .
步驟3 2-溴-4-環己基-1-乙基-1H-苯并[d]咪唑 使用由上述步驟2所得之4-環己基-1-乙基-1H-苯并[d]咪唑-2-酮，而取代由實施例2的步驟3所得之1,4-二乙基-1H-苯并[d]咪唑-2-酮，進行與實施例2的步驟4同樣的操作，獲得標記化合物(0.26g)。1 H NMR (400MHz, CDCl3 ) δ: 1.24-1.35 (2H, m), 1.42 (3H, t, J=7.2 Hz), 1.50-1.60 (4H, m), 1.74-1.89 (3H, m), 1.93-2.02 (2H, m), 3.34-3.45 (1H, m), 4.23 (2H, q, J=7.3 Hz), 7.11 (1H, d, J=7.4 Hz), 7.14-7.18 (1H, m), 7.23 (1H, d, J=7.7 Hz). MS (ESI) m/z 307 (M+H)+ .Step 3 2-Bromo-4-cyclohexyl-1-ethyl-1H-benzo[d]imidazole uses the 4-cyclohexyl-1-ethyl-1H-benzo[d]imidazole obtained in step 2 above 2-ketone, instead of 1,4-diethyl-1H-benzo[d]imidazol-2-one obtained in step 3 of Example 2, perform the same operation as step 4 of Example 2 to obtain the label Compound (0.26g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.24-1.35 (2H, m), 1.42 (3H, t, J=7.2 Hz), 1.50-1.60 (4H, m), 1.74-1.89 (3H, m), 1.93-2.02 (2H, m), 3.34-3.45 (1H, m), 4.23 (2H, q, J=7.3 Hz), 7.11 (1H, d, J=7.4 Hz), 7.14-7.18 (1H, m) , 7.23 (1H, d, J=7.7 Hz). MS (ESI) m/z 307 (M+H) + .
步驟4 (E)-1-(4-(2-(4-環己基-1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮 使用由上述步驟3所得之2-溴-4-環己基-1-乙基-1H-苯并[d]咪唑，而取代由參考例2的步驟1所得之2-溴-1-乙基-1H-苯并[d]咪唑，進行與實施例1的步驟1同樣的操作，獲得標記化合物(0.33g)。1 H NMR (400MHz, CDCl3 ) δ: 1.29-1.41 (1H, m), 1.46 (3H, t, J=7.2 Hz), 1.55-1.66 (5H, m), 1.76-1.91 (3H, m), 2.03-2.10 (2H, m), 2.85 (3H, s), 3.16-3.24 (2H, m), 3.26-3.33 (2H, m), 3.46-3.56 (1H, m), 4.30 (2H, q, J=7.3 Hz), 4.39 (2H, s), 7.07 (1H, d, J=15.8 Hz), 7.10-7.15 (1H, m), 7.15-7.18 (1H, m), 7.19-7.25 (1H, m), 7.31 (2H, d, J=8.0 Hz), 7.58 (2H, d, J=8.2 Hz), 7.94 (1H, d, J=15.8 Hz). MS (ESI) m/z 443 (M+H)+ .Step 4 (E)-1-(4-(2-(4-Cyclohexyl-1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl)benzyl)-3-methylimidazole As the pyridin-2-one, 2-bromo-4-cyclohexyl-1-ethyl-1H-benzo[d]imidazole obtained in step 3 above was used instead of 2-bromo- obtained in step 1 of Reference Example 2. 1-Ethyl-1H-benzo[d]imidazole was subjected to the same operation as in Step 1 of Example 1 to obtain the labeled compound (0.33 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.29-1.41 (1H, m), 1.46 (3H, t, J=7.2 Hz), 1.55-1.66 (5H, m), 1.76-1.91 (3H, m), 2.03-2.10 (2H, m), 2.85 (3H, s), 3.16-3.24 (2H, m), 3.26-3.33 (2H, m), 3.46-3.56 (1H, m), 4.30 (2H, q, J =7.3 Hz), 4.39 (2H, s), 7.07 (1H, d, J=15.8 Hz), 7.10-7.15 (1H, m), 7.15-7.18 (1H, m), 7.19-7.25 (1H, m) , 7.31 (2H, d, J=8.0 Hz), 7.58 (2H, d, J=8.2 Hz), 7.94 (1H, d, J=15.8 Hz). MS (ESI) m/z 443 (M+H) + .
實施例8：(E)-1-(4-(2-(1-乙基-4-(四氫呋喃-3-基)-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮Example 8: (E)-1-(4-(2-(1-ethyl-4-(tetrahydrofuran-3-yl)-1H-benzo[d]imidazol-2-yl)vinyl)benzyl )-3-Methylimidazolidin-2-one
使用2-(2,5-二氫呋喃-3-基)-4,4,5,5-四甲基-1,3,2-二氧硼戊環，而取代實施例7的步驟1所使用之2-(環己烯-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼戊環，進行與實施例7的步驟1同樣的操作。使用所得之化合物，而取代4-(環己烯-1-基)-1-乙基-1H-苯并[d]咪唑-2-酮，進行與實施例7的步驟2同樣的操作，獲得1-乙基-4-(四氫呋喃-3-基)-1H-苯并[d]咪唑-2(3H)-酮。使用本化合物，而取代由參考例3的步驟3所得之4-溴-1-乙基-1H-苯并[d]咪唑-2-酮，進行與參考例5的步驟1同樣的操作。使用所得之化合物，而取代由參考例2的步驟1所得之2-溴-1-乙基-1H-苯并[d]咪唑，進行與實施例1的步驟1同樣的操作，獲得標記化合物(53mg)。1 H NMR (400MHz, CDCl3 ) δ: 1.47 (3H, t, J=7.2 Hz), 2.26 (1H, dq, J=12.1, 7.8 Hz), 2.46-2.57 (1H, m), 2.85 (3H, s), 3.17-3.24 (2H, m), 3.26-3.33 (2H, m), 3.92-4.06 (2H, m), 4.17 (1H, td, J=8.2, 4.7 Hz), 4.28-4.38 (4H, m), 4.40 (2H, s), 7.07 (1H, d, J=15.8 Hz), 7.17-7.23 (3H, m), 7.31 (2H, d, J=8.2 Hz), 7.58 (2H, d, J=8.2 Hz), 7.94 (1H, d, J=15.8 Hz). MS (ESI) m/z 443 (M+H)+ .Use 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of the step 1 of Example 7. Using 2-(cyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, the same operation as in step 1 of Example 7 was performed. Using the obtained compound and substituting 4-(cyclohexen-1-yl)-1-ethyl-1H-benzo[d]imidazol-2-one, the same operation as step 2 of Example 7 was performed to obtain 1-Ethyl-4-(tetrahydrofuran-3-yl)-1H-benzo[d]imidazol-2(3H)-one. Using this compound, instead of 4-bromo-1-ethyl-1H-benzo[d]imidazol-2-one obtained in Step 3 of Reference Example 3, the same operation as Step 1 of Reference Example 5 was performed. Using the obtained compound instead of the 2-bromo-1-ethyl-1H-benzo[d]imidazole obtained in Step 1 of Reference Example 2, the same operation as in Step 1 of Example 1 was performed to obtain the labeled compound ( 53mg). 1 H NMR (400MHz, CDCl 3 ) δ: 1.47 (3H, t, J=7.2 Hz), 2.26 (1H, dq, J=12.1, 7.8 Hz), 2.46-2.57 (1H, m), 2.85 (3H, s), 3.17-3.24 (2H, m), 3.26-3.33 (2H, m), 3.92-4.06 (2H, m), 4.17 (1H, td, J=8.2, 4.7 Hz), 4.28-4.38 (4H, m), 4.40 (2H, s), 7.07 (1H, d, J=15.8 Hz), 7.17-7.23 (3H, m), 7.31 (2H, d, J=8.2 Hz), 7.58 (2H, d, J =8.2 Hz), 7.94 (1H, d, J=15.8 Hz). MS (ESI) m/z 443 (M+H) + .
實施例9：(E)-1-(4-(2-(1-乙基-4-(四氫-2H-哌喃-4-基)-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮Example 9: (E)-1-(4-(2-(1-ethyl-4-(tetrahydro-2H-piperan-4-yl)-1H-benzo[d]imidazol-2-yl )Vinyl)benzyl)-3-methylimidazolidin-2-one
使用2-(3,6-二氫-2H-哌喃-4-基)-4,4,5,5-四甲基-1,3,2-二氧硼戊環，而取代實施例7的步驟1所使用之2-(環己烯-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼戊環，進行與實施例7的步驟1同樣的操作。使用所得之化合物，而取代4-(環己烯-1-基)-1-乙基-1H-苯并[d]咪唑-2-酮，進行與實施例7的步驟2同樣的操作，獲得3-乙基-7-(四氫哌喃-4-基)-1H-苯并[d]咪唑-2(3H)-酮。使用本化合物，而取代由參考例3的步驟3所得之4-溴-1-乙基-1H-苯并[d]咪唑-2-酮，進行與參考例5的步驟1同樣的操作。使用所得之化合物，而取代由參考例2的步驟1所得之2-溴-1-乙基-1H-苯并[d]咪唑，進行與實施例1的步驟1同樣的操作，獲得標記化合物(0.36g)。1 H NMR (400MHz, CDCl3 ) δ: 1.47 (3H, t, J=7.3 Hz), 1.94-2.10 (4H, m), 2.85 (3H, s), 3.16-3.23 (2H, m), 3.26-3.33 (2H, m), 3.68-3.81 (3H, m), 4.09-4.17 (2H, m), 4.31 (2H, q, J=7.3 Hz), 4.40 (2H, s), 7.07 (1H, d, J=15.8 Hz), 7.13 (1H, dd, J=7.0, 1.1 Hz), 7.18-7.25 (2H, m), 7.31 (2H, d, J=8.2 Hz), 7.59 (2H, d, J=8.2 Hz), 7.94 (1H, d, J=15.8 Hz). MS (ESI) m/z 445 (M+H)+ .Using 2-(3,6-dihydro-2H-piperan-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of Example 7 For the 2-(cyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane used in step 1, proceed to step 1 of Example 7 The same operation. Using the obtained compound and substituting 4-(cyclohexen-1-yl)-1-ethyl-1H-benzo[d]imidazol-2-one, the same operation as step 2 of Example 7 was performed to obtain 3-Ethyl-7-(tetrahydropiperan-4-yl)-1H-benzo[d]imidazole-2(3H)-one. Using this compound, instead of 4-bromo-1-ethyl-1H-benzo[d]imidazol-2-one obtained in Step 3 of Reference Example 3, the same operation as Step 1 of Reference Example 5 was performed. Using the obtained compound instead of the 2-bromo-1-ethyl-1H-benzo[d]imidazole obtained in Step 1 of Reference Example 2, the same operation as in Step 1 of Example 1 was performed to obtain the labeled compound ( 0.36g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.47 (3H, t, J=7.3 Hz), 1.94-2.10 (4H, m), 2.85 (3H, s), 3.16-3.23 (2H, m), 3.26- 3.33 (2H, m), 3.68-3.81 (3H, m), 4.09-4.17 (2H, m), 4.31 (2H, q, J=7.3 Hz), 4.40 (2H, s), 7.07 (1H, d, J=15.8 Hz), 7.13 (1H, dd, J=7.0, 1.1 Hz), 7.18-7.25 (2H, m), 7.31 (2H, d, J=8.2 Hz), 7.59 (2H, d, J=8.2 Hz), 7.94 (1H, d, J=15.8 Hz). MS (ESI) m/z 445 (M+H) + .
實施例10：(E)-1-(4-(2-(1-乙基-4-(1-甲基-1H-吡唑-5-基)-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮Example 10: (E)-1-(4-(2-(1-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazole-2 -(Yl)vinyl)benzyl)-3-methylimidazolidin-2-one
使用1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑，而取代實施例7的步驟1所使用之2-(環己烯-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼戊環，進行與實施例7的步驟1同樣的操作。使用所得之化合物，而取代4-溴-1-乙基-1H-苯并[d]咪唑-2-酮，進行與參考例5的步驟1同樣的操作。使用所得之化合物，而取代由參考例2的步驟1所得之2-溴-1-乙基-1H-苯并[d]咪唑，進行與實施例1的步驟1同樣的操作，獲得標記化合物(0.87g)。1 H NMR (400MHz, CDCl3 ) δ: 1.51 (3H, t, J=7.3 Hz), 3.14-3.23 (2H, m), 3.26-3.34 (2H, m), 4.00 (3H, s), 4.31-4.43 (4H, m), 6.55 (1H, d, J=1.9 Hz), 7.05 (1H, d, J=15.7 Hz), 7.28-7.34 (4H, m), 7.38-7.41 (1H, m), 7.57 (2H, d, J=8.0 Hz), 7.60 (1H, d, J=1.9 Hz), 7.98 (1H, d, J=15.8 Hz). MS (ESI) m/z 441 (M+H)+ .Use 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole instead of the step of Example 7 1. The used 2-(cyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was carried out in the same manner as in step 1 of Example 7. operating. Using the obtained compound instead of 4-bromo-1-ethyl-1H-benzo[d]imidazol-2-one, the same operation as in Step 1 of Reference Example 5 was performed. Using the obtained compound instead of the 2-bromo-1-ethyl-1H-benzo[d]imidazole obtained in Step 1 of Reference Example 2, the same operation as in Step 1 of Example 1 was performed to obtain the labeled compound ( 0.87g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.51 (3H, t, J=7.3 Hz), 3.14-3.23 (2H, m), 3.26-3.34 (2H, m), 4.00 (3H, s), 4.31- 4.43 (4H, m), 6.55 (1H, d, J=1.9 Hz), 7.05 (1H, d, J=15.7 Hz), 7.28-7.34 (4H, m), 7.38-7.41 (1H, m), 7.57 (2H, d, J=8.0 Hz), 7.60 (1H, d, J=1.9 Hz), 7.98 (1H, d, J=15.8 Hz). MS (ESI) m/z 441 (M+H) + .
實施例11：(E)-1-(4-(2-(4-(1,4-二甲基-1H-吡唑-5-基)-1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮Example 11: (E)-1-(4-(2-(4-(1,4-Dimethyl-1H-pyrazol-5-yl)-1-ethyl-1H-benzo[d] (Imidazol-2-yl)vinyl)benzyl)-3-methylimidazolidin-2-one
使用1,4-二甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環基(dioxoborolane)-2-基)-1H-吡唑，而取代1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑，進行與實施例10同樣的操作，獲得標記化合物(34mg)。1 H NMR (400MHz, CDCl3 ) δ: 1.52 (3H, t, J=7.3 Hz), 2.08 (3H, s), 2.84 (3H, s), 3.16-3.21 (2H, m), 3.26-3.33 (2H, m), 3.86 (3H, s), 4.32-4.41 (4H, m), 7.04 (1H, d, J=15.8 Hz), 7.19 (1H, dd, J=7.3, 1.0 Hz), 7.28-7.32 (2H, m), 7.34 (1H, d, J=7.3 Hz), 7.38-7.42 (1H, m), 7.45 (1H, s), 7.56 (2H, d, J=8.2 Hz), 7.96 (1H, d, J=15.8 Hz). MS (ESI) m/z 455 (M+H)+ .Use 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborolane-2-yl)-1H-pyrazole, The substituted 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was carried out in the same manner as in Example 10. The labeled compound (34 mg) was obtained. 1 H NMR (400MHz, CDCl 3 ) δ: 1.52 (3H, t, J=7.3 Hz), 2.08 (3H, s), 2.84 (3H, s), 3.16-3.21 (2H, m), 3.26-3.33 ( 2H, m), 3.86 (3H, s), 4.32-4.41 (4H, m), 7.04 (1H, d, J=15.8 Hz), 7.19 (1H, dd, J=7.3, 1.0 Hz), 7.28-7.32 (2H, m), 7.34 (1H, d, J=7.3 Hz), 7.38-7.42 (1H, m), 7.45 (1H, s), 7.56 (2H, d, J=8.2 Hz), 7.96 (1H, d, J=15.8 Hz). MS (ESI) m/z 455 (M+H) + .
實施例12：(E)-1-(4-(2-(4-(3,5-二甲基異
使用(3,5-二甲基異
實施例13：(E)-1-(4-(2-(1-乙基-4-(o-甲苯基)-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮Example 13: (E)-1-(4-(2-(1-ethyl-4-(o-tolyl)-1H-benzo[d]imidazol-2-yl)vinyl)benzyl) -3-Methylimidazolidin-2-one
使用2-甲基苯基硼酸，而取代1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑，進行與實施例10同樣的操作，獲得標記化合物(0.37g)。1 H NMR (400MHz, CDCl3 ) δ: 1.51 (3H, t, J=7.3 Hz), 2.31 (3H, s), 2.84 (3H, s), 3.15-3.21 (2H, m), 3.24-3.32 (2H, m), 4.31-4.39 (4H, m), 7.04 (1H, d, J=15.8 Hz), 7.16 (1H, dd, J=6.9, 1.5 Hz), 7.26-7.37 (7H, m), 7.42-7.47 (1H, m), 7.53 (2H, d, J=8.2 Hz), 7.87 (1H, d, J=15.8 Hz). MS (ESI) m/z 451 (M+H)+ .Use 2-methylphenylboronic acid instead of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- For pyrazole, the same operation as in Example 10 was performed to obtain the labeled compound (0.37 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.51 (3H, t, J=7.3 Hz), 2.31 (3H, s), 2.84 (3H, s), 3.15-3.21 (2H, m), 3.24-3.32 ( 2H, m), 4.31-4.39 (4H, m), 7.04 (1H, d, J=15.8 Hz), 7.16 (1H, dd, J=6.9, 1.5 Hz), 7.26-7.37 (7H, m), 7.42 -7.47 (1H, m), 7.53 (2H, d, J=8.2 Hz), 7.87 (1H, d, J=15.8 Hz). MS (ESI) m/z 451 (M+H) + .
實施例14：(E)-1-(4-(2-(4-(2-氯苯基)-1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮Example 14: (E)-1-(4-(2-(4-(2-chlorophenyl)-1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl)benzyl )-3-Methylimidazolidin-2-one
使用2-氯苯基硼酸，而取代1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑，進行與實施例10同樣的操作，獲得標記化合物(0.11g)。1 H NMR (400MHz, CDCl3 ) δ: 1.52 (3H, t, J=7.3 Hz), 2.84 (3H, s), 3.15-3.21 (2H, m), 3.26-3.32 (2H, m), 4.32-4.40 (4H, m), 7.05 (1H, d, J=15.9 Hz), 7.27-7.40 (7H, m), 7.50-7.57 (3H, m), 7.66 (1H, dd, J=7.5, 1.7 Hz), 7.87 (1H, d, J=15.8 Hz). MS (ESI) m/z 471 (M+H)+ .Use 2-chlorophenylboronic acid instead of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyridine For the azole, the same operation as in Example 10 was performed to obtain the labeled compound (0.11 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.52 (3H, t, J=7.3 Hz), 2.84 (3H, s), 3.15-3.21 (2H, m), 3.26-3.32 (2H, m), 4.32- 4.40 (4H, m), 7.05 (1H, d, J=15.9 Hz), 7.27-7.40 (7H, m), 7.50-7.57 (3H, m), 7.66 (1H, dd, J=7.5, 1.7 Hz) , 7.87 (1H, d, J=15.8 Hz). MS (ESI) m/z 471 (M+H) + .
實施例15：(E)-1-(4-(2-(1-乙基-4-(4-甲基吡啶-3-基)-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮Example 15: (E)-1-(4-(2-(1-ethyl-4-(4-methylpyridin-3-yl)-1H-benzo[d]imidazol-2-yl)ethylene (Yl)benzyl)-3-methylimidazolidin-2-one
使用4-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧硼戊環基-2-基)吡啶，而取代1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑，進行與實施例10同樣的操作，獲得標記化合物(42mg)。1 H NMR (400MHz, CDCl3 ) δ: 1.52 (3H, t, J=7.3 Hz), 2.35 (3H, s), 2.84 (3H, s), 3.16-3.21 (2H, m), 3.25-3.31 (2H, m), 4.34-4.39 (4H, m), 7.04 (1H, d, J=15.7 Hz), 7.17 (1H, dd, J=7.2, 1.1 Hz), 7.27-7.41 (5H, m), 7.54 (2H, d, J=8.2 Hz), 7.87 (1H, d, J=15.8 Hz), 8.49 (1H, d, J=5.0 Hz), 8.64 (1H, s). MS (ESI) m/z 452 (M+H)+ .Use 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine instead of 1-methyl-5-( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was performed in the same manner as in Example 10 to obtain the labeled compound (42 mg). 1 H NMR (400MHz, CDCl 3 ) δ: 1.52 (3H, t, J=7.3 Hz), 2.35 (3H, s), 2.84 (3H, s), 3.16-3.21 (2H, m), 3.25-3.31 ( 2H, m), 4.34-4.39 (4H, m), 7.04 (1H, d, J=15.7 Hz), 7.17 (1H, dd, J=7.2, 1.1 Hz), 7.27-7.41 (5H, m), 7.54 (2H, d, J=8.2 Hz), 7.87 (1H, d, J=15.8 Hz), 8.49 (1H, d, J=5.0 Hz), 8.64 (1H, s). MS (ESI) m/z 452 (M+H) + .
實施例16：(E)-1-(4-(2-(1-乙基-4-(2-甲基吡啶-3-基)-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮Example 16: (E)-1-(4-(2-(1-ethyl-4-(2-methylpyridin-3-yl)-1H-benzo[d]imidazol-2-yl)ethylene (Yl)benzyl)-3-methylimidazolidin-2-one
使用2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧硼戊環基-2-基)吡啶，而取代1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑，進行與實施例10同樣的操作，獲得標記化合物(78mg)。1 H NMR (400MHz, CDCl3 ) δ: 1.52 (3H, t, J=7.3 Hz), 2.56 (3H, s), 2.84 (3H, s), 3.15-3.22 (2H, m), 3.25-3.31 (2H, m), 4.31-4.40 (4H, m), 7.04 (1H, d, J=15.8 Hz), 7.17 (1H, dd, J=7.2, 1.1 Hz), 7.24 (1H, dd, J=7.6, 5.1 Hz), 7.27-7.39 (4H, m), 7.54 (2H, d, J=8.2 Hz), 7.78 (1H, dd, J=7.7, 1.8 Hz), 7.88 (1H, d, J=15.8 Hz), 8.56 (1H, dd, J=4.9, 1.8 Hz). MS (ESI) m/z 452 (M+H)+ .Use 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine instead of 1-methyl-5-( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was carried out in the same manner as in Example 10 to obtain the labeled compound (78 mg). 1 H NMR (400MHz, CDCl 3 ) δ: 1.52 (3H, t, J=7.3 Hz), 2.56 (3H, s), 2.84 (3H, s), 3.15-3.22 (2H, m), 3.25-3.31 ( 2H, m), 4.31-4.40 (4H, m), 7.04 (1H, d, J=15.8 Hz), 7.17 (1H, dd, J=7.2, 1.1 Hz), 7.24 (1H, dd, J=7.6, 5.1 Hz), 7.27-7.39 (4H, m), 7.54 (2H, d, J=8.2 Hz), 7.78 (1H, dd, J=7.7, 1.8 Hz), 7.88 (1H, d, J=15.8 Hz) , 8.56 (1H, dd, J=4.9, 1.8 Hz). MS (ESI) m/z 452 (M+H) + .
實施例17：(E)-1-(4-(2-(4-(3-氯吡啶-4-基)-1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮Example 17: (E)-1-(4-(2-(4-(3-chloropyridin-4-yl)-1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl )Benzyl)-3-Methylimidazolidin-2-one
使用3-氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環基-2-基)吡啶，而取代1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑，進行與實施例10同樣的操作，獲得標記化合物(38mg)。1 H NMR (400MHz, CDCl3 ) δ: 1.24 (3H, t, J=7.0 Hz), 1.52 (3H, t, J=7.3 Hz), 2.84 (3H, s), 3.14-3.22 (2H, m), 3.25-3.32 (2H, m), 3.47 (2H, s), 3.71 (2H, q, J=7.0 Hz), 4.33-4.40 (4H, m), 7.05 (1H, d, J=15.8 Hz), 7.21-7.44 (5H, m), 7.55 (2H, d, J=8.0 Hz), 7.68 (1H, d, J=5.0 Hz), 7.89 (1H, d, J=15.8 Hz), 8.58 (1H, d, J=5.0 Hz), 8.74 (1H, s). MS (ESI) m/z 472 (M+H)+ .Use 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine instead of 1-methyl-5-(4 ,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, the same operation as in Example 10 was performed to obtain the labeled compound (38 mg). 1 H NMR (400MHz, CDCl 3 ) δ: 1.24 (3H, t, J=7.0 Hz), 1.52 (3H, t, J=7.3 Hz), 2.84 (3H, s), 3.14-3.22 (2H, m) , 3.25-3.32 (2H, m), 3.47 (2H, s), 3.71 (2H, q, J=7.0 Hz), 4.33-4.40 (4H, m), 7.05 (1H, d, J=15.8 Hz), 7.21-7.44 (5H, m), 7.55 (2H, d, J=8.0 Hz), 7.68 (1H, d, J=5.0 Hz), 7.89 (1H, d, J=15.8 Hz), 8.58 (1H, d , J=5.0 Hz), 8.74 (1H, s). MS (ESI) m/z 472 (M+H) + .
實施例18：(E)-1-(4-(2-(1-乙基-4-苯基-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮Example 18: (E)-1-(4-(2-(1-ethyl-4-phenyl-1H-benzo[d]imidazol-2-yl)vinyl)benzyl)-3-methan Imidazolidin-2-one
步驟1
1-乙基-4-苯基-1H-苯并[d]咪唑-2(3H)-酮
在由參考例3的步驟3所得之4-溴-1-乙基-1H-苯并[d]咪唑-2-酮(0.40g)的1,4-二
步驟2 (E)-1-(4-(2-(1-乙基-4-苯基-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮 使用由上述步驟1所得之1-乙基-4-苯基-1H-苯并[d]咪唑-2(3H)-酮，而取代由實施例2的步驟3所得之1,4-二乙基-1H-苯并[d]咪唑-2-酮，進行與實施例2的步驟4至步驟5同樣的操作，獲得標記化合物(0.52g)。1 H NMR (400MHz, CDCl3 ) δ: 1.50 (3H, t, J=7.3 Hz), 2.84 (3H, s), 3.17-3.22 (2H, m), 3.27-3.32 (2H, m), 4.32-4.40 (4H, m), 7.08 (1H, d, J=15.8 Hz), 7.29-7.34 (3H, m), 7.37 (1H, tt, J=7.3, 1.3 Hz), 7.43-7.53 (3H, m), 7.58 (2H, d, J=8.0 Hz), 7.63-7.71 (1H, m), 8.00 (1H, d, J=15.8 Hz), 8.11 (2H, dd, J=8.3, 1.2 Hz). MS (ESI) m/z 437 (M+H)+ .Step 2 (E)-1-(4-(2-(1-ethyl-4-phenyl-1H-benzo[d]imidazol-2-yl)vinyl)benzyl)-3-methylimidazole The pyridin-2-one used 1-ethyl-4-phenyl-1H-benzo[d]imidazole-2(3H)-one obtained in step 1 above instead of 1 obtained in step 3 of Example 2 , 4-Diethyl-1H-benzo[d]imidazol-2-one, and the same operations as steps 4 to 5 of Example 2 were performed to obtain the labeled compound (0.52 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.50 (3H, t, J=7.3 Hz), 2.84 (3H, s), 3.17-3.22 (2H, m), 3.27-3.32 (2H, m), 4.32- 4.40 (4H, m), 7.08 (1H, d, J=15.8 Hz), 7.29-7.34 (3H, m), 7.37 (1H, tt, J=7.3, 1.3 Hz), 7.43-7.53 (3H, m) , 7.58 (2H, d, J=8.0 Hz), 7.63-7.71 (1H, m), 8.00 (1H, d, J=15.8 Hz), 8.11 (2H, dd, J=8.3, 1.2 Hz). MS ( ESI) m/z 437 (M+H) + .
實施例19：(E)-1-(4-(2-(1-乙基-4-(3-甲基吡啶-4-基)-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮Example 19: (E)-1-(4-(2-(1-ethyl-4-(3-methylpyridin-4-yl)-1H-benzo[d]imidazol-2-yl)ethylene (Yl)benzyl)-3-methylimidazolidin-2-one
步驟1
(E)-1-(4-(2-(1-乙基-4-(3-甲基吡啶-4-基)-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮
在由參考例5的步驟1所得之4-溴-2-氯-1-乙基-1H-苯并[d]咪唑(0.25g)的1,4-二
實施例20：(E)-1-(4-(2-(1-乙基-4-(3-甲基噻吩-2-基)-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮Example 20: (E)-1-(4-(2-(1-ethyl-4-(3-methylthiophen-2-yl)-1H-benzo[d]imidazol-2-yl)ethylene (Yl)benzyl)-3-methylimidazolidin-2-one
步驟1
(E)-1-(4-(2-(1-乙基-4-(3-甲基噻吩-2-基)-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮
在由實施例5所得之(E)-1-(4-(2-(4-溴-1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮(0.08g)的1,4-二
實施例21：(E)-1-(4-(2-(4-(2-氯噻吩-3-基)-1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮Example 21: (E)-1-(4-(2-(4-(2-chlorothiophen-3-yl)-1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl )Benzyl)-3-Methylimidazolidin-2-one
使用2-氯-3-噻吩硼酸，而取代實施例20的步驟1所使用之4,4,5,5-四甲基-2-(3-甲基-2-噻吩基)-1,3,2-二氧硼戊環，進行與實施例20的步驟1同樣的操作，獲得標記化合物(98mg)。1 H NMR (400MHz, CDCl3 ) δ: 1.50 (3H, t, J=7.3 Hz), 2.84 (2H, s), 3.17-3.22 (1H, m), 3.27-3.32 (2H, m), 4.35 (2H, q, J=7.3 Hz), 4.39 (1H, s), 7.06 (1H, d, J=15.7 Hz), 7.22 (1H, d, J=5.6 Hz), 7.29-7.34 (3H, m), 7.54-7.61 (2H, m), 7.70 (1H, d, J=5.8 Hz), 7.95 (1H, d, J=15.8 Hz). MS (ESI) m/z 477 (M+H)+ .Use 2-chloro-3-thiophene boronic acid instead of 4,4,5,5-tetramethyl-2-(3-methyl-2-thienyl)-1,3 used in step 1 of Example 20 , 2-Dioxaborolane, and the same operation as in Step 1 of Example 20 was performed to obtain the labeled compound (98 mg). 1 H NMR (400MHz, CDCl 3 ) δ: 1.50 (3H, t, J=7.3 Hz), 2.84 (2H, s), 3.17-3.22 (1H, m), 3.27-3.32 (2H, m), 4.35 ( 2H, q, J=7.3 Hz), 4.39 (1H, s), 7.06 (1H, d, J=15.7 Hz), 7.22 (1H, d, J=5.6 Hz), 7.29-7.34 (3H, m), 7.54-7.61 (2H, m), 7.70 (1H, d, J=5.8 Hz), 7.95 (1H, d, J=15.8 Hz). MS (ESI) m/z 477 (M+H) + .
實施例22：(E)-1-(4-(2-(4-(二氟甲氧基)-1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮Example 22: (E)-1-(4-(2-(4-(Difluoromethoxy)-1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl)benzyl )-3-Methylimidazolidin-2-one
步驟1 1-(二氟甲氧基)-3-氟-2-硝基苯 在3-氟-2-硝基酚的N,N-二甲基乙醯胺(10mL)溶液中，添加碳酸鉀(0.63g)，接著，室溫下，緩緩滴下氯二氟乙酸甲酯(0.49mL)。在90℃攪拌1小時，放置冷卻後，在反應液中添加水、乙酸乙酯並進行萃取。以飽和食鹽水清洗有機層後，以硫酸鈉進行乾燥。在減壓下餾去溶劑，將殘渣以矽膠管柱層析法(n-己烷/乙酸乙酯)進行純化，獲得標記化合物(0.37g)。1 H NMR (400MHz, CDCl3 ) δ: 6.59 (1H, t, J=72.0 Hz), 7.14-7.21 (2H, m), 7.51 (1H, td, J=8.6, 5.9 Hz).Step 1 1-(Difluoromethoxy)-3-fluoro-2-nitrobenzene in 3-fluoro-2-nitrophenol in N,N-dimethylacetamide (10mL) solution, add carbonic acid Potassium (0.63 g), then, at room temperature, methyl chlorodifluoroacetate (0.49 mL) was slowly dropped. After stirring at 90°C for 1 hour and leaving to cool, water and ethyl acetate were added to the reaction solution to perform extraction. After washing the organic layer with saturated brine, it was dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (0.37 g). 1 H NMR (400MHz, CDCl 3 ) δ: 6.59 (1H, t, J=72.0 Hz), 7.14-7.21 (2H, m), 7.51 (1H, td, J=8.6, 5.9 Hz).
步驟2 (E)-1-(4-(2-(4-(二氟甲氧基)-1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮 使用由上述步驟1所得之1-(二氟甲氧基)-3-氟-2-硝基苯，而取代參考例3的步驟1所使用之1-溴-3-氟-2-硝基苯，進行與參考例3的步驟1至步驟3同樣的操作。使用所得之化合物，而取代4-溴-1-乙基-1H-苯并[d]咪唑-2-酮，進行與參考例5的步驟1同樣的操作，獲得2-氯-4-(二氟甲氧基)-1-乙基-1H-苯并[d]咪唑。接著，使用本化合物，而取代由參考例2的步驟1所得之2-溴-1-乙基-1H-苯并[d]咪唑，進行與實施例1的步驟1同樣的操作，獲得標記化合物(0.27g)。1 H NMR (400MHz, CDCl3 ) δ: 1.48 (3H, t, J=7.3 Hz), 2.85 (3H, s), 3.17-3.24 (2H, m), 3.27-3.34 (2H, m), 4.32 (2H, q, J=7.3 Hz), 4.40 (2H, s), 6.99-7.08 (2H, m), 7.15-7.23 (2H, m), 7.32 (2H, d, J=8.0 Hz), 7.48 (1H, t, J=75.0 Hz), 7.58 (2H, d, J=8.2 Hz), 8.02 (1H, d, J=15.7 Hz). MS (ESI) m/z 427 (M+H)+ .Step 2 (E)-1-(4-(2-(4-(Difluoromethoxy)-1-ethyl-1H-benzo(d)imidazol-2-yl)vinyl)benzyl)- 3-Methylimidazolidin-2-one uses the 1-(difluoromethoxy)-3-fluoro-2-nitrobenzene obtained in step 1 above, instead of the 1-(difluoromethoxy)-3-fluoro-2-nitrobenzene used in step 1 of Reference Example 3. For bromo-3-fluoro-2-nitrobenzene, the same operations as steps 1 to 3 of Reference Example 3 were performed. Using the obtained compound instead of 4-bromo-1-ethyl-1H-benzo[d]imidazol-2-one, the same operation as in Step 1 of Reference Example 5 was performed to obtain 2-chloro-4-(二(Fluoromethoxy)-1-ethyl-1H-benzo[d]imidazole. Next, using this compound instead of the 2-bromo-1-ethyl-1H-benzo[d]imidazole obtained in Step 1 of Reference Example 2, the same operation as in Step 1 of Example 1 was performed to obtain the labeled compound (0.27g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.48 (3H, t, J=7.3 Hz), 2.85 (3H, s), 3.17-3.24 (2H, m), 3.27-3.34 (2H, m), 4.32 ( 2H, q, J=7.3 Hz), 4.40 (2H, s), 6.99-7.08 (2H, m), 7.15-7.23 (2H, m), 7.32 (2H, d, J=8.0 Hz), 7.48 (1H , t, J=75.0 Hz), 7.58 (2H, d, J=8.2 Hz), 8.02 (1H, d, J=15.7 Hz). MS (ESI) m/z 427 (M+H) + .
實施例23：(E)-1-(4-(2-(1-乙基-7-甲基-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮Example 23: (E)-1-(4-(2-(1-ethyl-7-methyl-1H-benzo[d]imidazol-2-yl)vinyl)benzyl)-3-methyl Imidazolidin-2-one
步驟1 N-乙基-2-甲基-6-硝基苯胺 使用2-氟-1-甲基-3-硝基苯，而取代參考例3的步驟1所使用之1-溴-3-氟-2-硝基苯，進行與參考例3的步驟1同樣的操作，獲得標記化合物(13.0g)。1 H NMR (400MHz, CDCl3 ) δ: 1.22 (3H, t, J=7.2 Hz), 2.39 (3H, s), 3.29 (2H, q, J=6.4 Hz), 6.76 (1H, dd, J=8.4, 7.4 Hz), 6.81 (1H, br s), 7.27-7.31 (1H, m), 7.91 (1H, dd, J=8.5, 1.6 Hz).Step 1 N-ethyl-2-methyl-6-nitroaniline uses 2-fluoro-1-methyl-3-nitrobenzene instead of 1-bromo-3- used in Step 1 of Reference Example 3. For fluoro-2-nitrobenzene, the same operation as in Step 1 of Reference Example 3 was performed to obtain the labeled compound (13.0 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.22 (3H, t, J=7.2 Hz), 2.39 (3H, s), 3.29 (2H, q, J=6.4 Hz), 6.76 (1H, dd, J= 8.4, 7.4 Hz), 6.81 (1H, br s), 7.27-7.31 (1H, m), 7.91 (1H, dd, J=8.5, 1.6 Hz).
步驟2 1-乙基-7-甲基-1H-苯并[d]咪唑 使用由上述步驟1所得之N-乙基-2-甲基-6-硝基苯胺，而取代3-溴-N-乙基-2-硝基苯胺，進行與參考例3的步驟2同樣的操作，獲得N1 -乙基-6-甲基苯-1,2-二胺。接著，在本化合物(9.05g)的四氫呋喃(100mL)溶液中，添加原甲酸三甲酯(9.0mL)及p-甲苯磺酸一水合物(2.29g)，加熱回流18小時。放置冷卻後，在反應液中添加氫氧化鈉水溶液，以乙酸乙酯進行萃取。以飽和食鹽水清洗萃取液，以硫酸鈉進行乾燥。在減壓下餾去溶劑，將殘渣以胺基矽膠管柱層析法(n-己烷/乙酸乙酯)進行純化，獲得標記化合物(8.74g)。1 H NMR (400MHz, CDCl3 ) δ: 1.52 (3H, t, J=7.2 Hz), 4.41 (2H, q, J=7.2 Hz), 7.02 (1H, d, J=7.2 Hz), 7.15 (1H, t, J=7.7 Hz), 7.64 (1H, d, J=8.2 Hz), 7.84 (1H, s). MS (ESI) m/z 161 (M+H)+ .Step 2 1-Ethyl-7-methyl-1H-benzo[d]imidazole uses the N-ethyl-2-methyl-6-nitroaniline obtained in step 1 above instead of 3-bromo-N -Ethyl-2-nitroaniline, the same operation as in Step 2 of Reference Example 3 was performed to obtain N 1 -ethyl-6-methylbenzene-1,2-diamine. Next, to a tetrahydrofuran (100 mL) solution of this compound (9.05 g), trimethyl orthoformate (9.0 mL) and p-toluenesulfonic acid monohydrate (2.29 g) were added, and the mixture was heated under reflux for 18 hours. After being left to cool, an aqueous sodium hydroxide solution was added to the reaction solution, and extraction was performed with ethyl acetate. The extract was washed with saturated brine and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by amino silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (8.74 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.52 (3H, t, J=7.2 Hz), 4.41 (2H, q, J=7.2 Hz), 7.02 (1H, d, J=7.2 Hz), 7.15 (1H , t, J=7.7 Hz), 7.64 (1H, d, J=8.2 Hz), 7.84 (1H, s). MS (ESI) m/z 161 (M+H) + .
步驟3 2-氯-1-乙基-7-甲基-1H-苯并[d]咪唑 氮氣體環境下，在-78℃，在由上述步驟2所得之1-乙基-7-甲基-1H-苯并[d]咪唑(8.74g)的四氫呋喃(200mL)溶液中，滴下二異丙胺鋰(1mol/L四氫呋喃溶液，54.6mL)並攪拌50分鐘。接著，滴下六氯乙烷(15、5g)的四氫呋喃(20mL)溶液，攪拌30分鐘。在反應液中添加飽和氯化銨水溶液後，將溫度上升直至室溫為止，以乙酸乙酯進行萃取。以飽和食鹽水清洗萃取液，以硫酸鎂進行乾燥。在減壓下餾去溶劑，將殘渣以矽膠管柱層析法(n-己烷/乙酸乙酯)進行純化，獲得標記化合物(10.8g)。1 H NMR (400MHz, CDCl3 ) δ: 1.43 (3H, t, J=7.2 Hz), 2.68 (3H, s), 4.42 (2H, q, J=7.2 Hz), 7.01 (1H, dt, J=7.3, 1.0 Hz), 7.14 (1H, t, J=7.7 Hz), 7.53 (1H, dt, J=8.3, 0.7 Hz). MS (ESI) m/z 195 (M+H)+ .Step 3 2-Chloro-1-ethyl-7-methyl-1H-benzo[d]imidazole under nitrogen atmosphere, at -78℃, in the 1-ethyl-7-methyl obtained from step 2 above In a tetrahydrofuran (200 mL) solution of -1H-benzo[d]imidazole (8.74 g), lithium diisopropylamine (1 mol/L tetrahydrofuran solution, 54.6 mL) was dropped and stirred for 50 minutes. Next, a tetrahydrofuran (20 mL) solution of hexachloroethane (15, 5 g) was dropped and stirred for 30 minutes. After adding a saturated ammonium chloride aqueous solution to the reaction liquid, the temperature was raised to room temperature, and extraction was performed with ethyl acetate. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (10.8 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.43 (3H, t, J=7.2 Hz), 2.68 (3H, s), 4.42 (2H, q, J=7.2 Hz), 7.01 (1H, dt, J= 7.3, 1.0 Hz), 7.14 (1H, t, J=7.7 Hz), 7.53 (1H, dt, J=8.3, 0.7 Hz). MS (ESI) m/z 195 (M+H) + .
步驟4 (E)-1-(4-(2-(1-乙基-7-甲基-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮 使用由上述步驟3所得之2-氯-1-乙基-7-甲基-1H-苯并[d]咪唑，而取代由參考例2的步驟1所得之2-溴-1-乙基-1H-苯并[d]咪唑，進行與實施例1的步驟1同樣的操作，獲得標記化合物(60mg)。1 H NMR (400MHz, CDCl3 ) δ: 1.49 (3H, t, J=7.2 Hz), 2.73 (3H, s), 2.84 (3H, s), 3.14-3.22 (2H, m), 3.25-3.33 (2H, m), 4.39 (2H, s), 4.52 (2H, q, J=7.2 Hz), 6.98 (1H, d, J=7.3 Hz), 7.06 (1H, d, J=15.8 Hz), 7.11-7.17 (1H, m), 7.31 (2H, d, J=8.2 Hz), 7.57 (2H, d, J=8.0 Hz), 7.62 (1H, d, J=7.7 Hz), 7.97 (1H, d, J=15.8 Hz). MS (ESI) m/z 375 (M+H)+ .Step 4 (E)-1-(4-(2-(1-ethyl-7-methyl-1H-benzo[d]imidazol-2-yl)vinyl)benzyl)-3-methylimidazole As the pyridin-2-one, 2-chloro-1-ethyl-7-methyl-1H-benzo[d]imidazole obtained in step 3 above was used instead of 2-bromo- obtained in step 1 of Reference Example 2. 1-Ethyl-1H-benzo[d]imidazole was subjected to the same operation as in Step 1 of Example 1 to obtain the labeled compound (60 mg). 1 H NMR (400MHz, CDCl 3 ) δ: 1.49 (3H, t, J=7.2 Hz), 2.73 (3H, s), 2.84 (3H, s), 3.14-3.22 (2H, m), 3.25-3.33 ( 2H, m), 4.39 (2H, s), 4.52 (2H, q, J=7.2 Hz), 6.98 (1H, d, J=7.3 Hz), 7.06 (1H, d, J=15.8 Hz), 7.11- 7.17 (1H, m), 7.31 (2H, d, J=8.2 Hz), 7.57 (2H, d, J=8.0 Hz), 7.62 (1H, d, J=7.7 Hz), 7.97 (1H, d, J =15.8 Hz). MS (ESI) m/z 375 (M+H) + .
實施例24：(E)-1-(4-(2-(1-乙基-4,7-二甲基-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮Example 24: (E)-1-(4-(2-(1-ethyl-4,7-dimethyl-1H-benzo[d]imidazol-2-yl)vinyl)benzyl)- 3-Methylimidazolidin-2-one
步驟1 1,4-二甲基-2,3-二硝基苯 冰冷下，在p-二甲苯(3.0mL)中添加濃硫酸(13mL)及硝酸(5mL)，以100℃攪拌1小時。放置冷卻後，添加飽和碳酸氫鈉水並以乙酸乙酯進行萃取。以飽和食鹽水清洗萃取液，以硫酸鈉進行乾燥。在減壓下餾去溶劑，將殘渣以矽膠管柱層析法(n-己烷/乙酸乙酯)進行純化，獲得標記化合物(10.8g)。1 H NMR (400MHz, CDCl3 ) δ: 2.43 (6H, s), 7.38 (2H, s).Step 1 Under ice-cooling 1,4-dimethyl-2,3-dinitrobenzene, concentrated sulfuric acid (13 mL) and nitric acid (5 mL) were added to p-xylene (3.0 mL), and the mixture was stirred at 100°C for 1 hour. After standing to cool, saturated sodium bicarbonate water was added and extraction was performed with ethyl acetate. The extract was washed with saturated brine and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (10.8 g). 1 H NMR (400MHz, CDCl 3 ) δ: 2.43 (6H, s), 7.38 (2H, s).
步驟2 1-乙基-4,7-二甲基-1H-苯并[d]咪唑 使用由上述步驟1所得之1,4-二甲基-2,3-二硝基苯，而取代由實施例23的步驟1所得之N-乙基-2-甲基-6-硝基苯胺，進行與實施例23的步驟2同樣的操作，獲得標記化合物(450mg)。1 H NMR (400MHz, CDCl3 ) δ: 1.51 (3H, t, J=7.3 Hz), 2.63 (3H, s), 2.67 (3H, s), 4.41 (2H, q, J=7.2 Hz), 6.87-7.00 (2H, m), 7.83 (1H, s). MS (ESI) m/z 175 (M+H)+ .Step 2 1-Ethyl-4,7-dimethyl-1H-benzo[d]imidazole uses 1,4-dimethyl-2,3-dinitrobenzene obtained from step 1 above, and the substitution is The N-ethyl-2-methyl-6-nitroaniline obtained in Step 1 of Example 23 was subjected to the same operation as Step 2 of Example 23 to obtain the labeled compound (450 mg). 1 H NMR (400MHz, CDCl 3 ) δ: 1.51 (3H, t, J=7.3 Hz), 2.63 (3H, s), 2.67 (3H, s), 4.41 (2H, q, J=7.2 Hz), 6.87 -7.00 (2H, m), 7.83 (1H, s). MS (ESI) m/z 175 (M+H) + .
步驟3 1-乙基-2-碘-4,7-二甲基-1H-苯并[d]咪唑 在由上述步驟2所得之1-乙基-4,7-二甲基-1H-苯并[d]咪唑(0.45g)的四氫呋喃(10mL)溶液中，以-78℃滴下二異丙胺鋰(1.13 mol/L，n-己烷及四氫呋喃溶液)並攪拌1小時。接著，添加碘(1.0g)的四氫呋喃(10mL)溶液並攪拌30分鐘。添加飽和亞硫酸鈉水溶液及水，以乙酸乙酯進行萃取。以飽和食鹽水清洗萃取液，以硫酸鈉進行乾燥。在減壓下餾去溶劑，將殘渣以矽膠管柱層析法(n-己烷/乙酸乙酯)進行純化，獲得標記化合物(0.65g)。1 H NMR (400MHz, CDCl3 ) δ: 1.40 (3H, t, J=7.2 Hz), 2.59 (3H, s), 2.66 (3H, s), 4.41 (2H, q, J=7.2 Hz), 6.83-6.92 (2H, m).Step 3 1-Ethyl-2-iodo-4,7-dimethyl-1H-benzo[d]imidazole in the 1-ethyl-4,7-dimethyl-1H-benzene obtained from step 2 above In a tetrahydrofuran (10 mL) solution of [d]imidazole (0.45 g), lithium diisopropylamine (1.13 mol/L, n-hexane and tetrahydrofuran solution) was dropped at -78°C and stirred for 1 hour. Next, a tetrahydrofuran (10 mL) solution of iodine (1.0 g) was added and stirred for 30 minutes. A saturated aqueous sodium sulfite solution and water were added, and extraction was performed with ethyl acetate. The extract was washed with saturated brine and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (0.65 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.40 (3H, t, J=7.2 Hz), 2.59 (3H, s), 2.66 (3H, s), 4.41 (2H, q, J=7.2 Hz), 6.83 -6.92 (2H, m).
步驟4 (E)-1-(4-(2-(1-乙基-4,7-二甲基-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮 使用由上述步驟3所得之1-乙基-2-碘-4,7-二甲基-1H-苯并[d]咪唑，而取代由參考例2的步驟1所得之2-溴-1-乙基-1H-苯并[d]咪唑，進行與實施例1的步驟1同樣的操作，獲得標記化合物(19mg)。1 H NMR (400MHz, CDCl3 ) δ: 1.46 (3H, t, J=7.2 Hz), 2.67 (3H, s), 2.69 (3H, s), 2.84 (3H, s), 3.16-3.23 (2H, m), 3.25-3.33 (2H, m), 4.39 (2H, s), 4.50 (2H, q, J=7.2 Hz), 6.83-6.90 (1H, m), 6.91-6.98 (1H, m), 7.07 (1H, d, J=15.8 Hz), 7.30 (2H, d, J=8.0 Hz), 7.58 (2H, d, J=8.0 Hz), 7.96 (1H, d, J=15.8 Hz). MS (ESI) m/z 389 (M+H)+ .Step 4 (E)-1-(4-(2-(1-ethyl-4,7-dimethyl-1H-benzo(d)imidazol-2-yl)vinyl)benzyl)-3- Methylimidazolidine-2-one uses 1-ethyl-2-iodo-4,7-dimethyl-1H-benzo[d]imidazole obtained in step 3 above instead of step 1 in Reference Example 2. The obtained 2-bromo-1-ethyl-1H-benzo[d]imidazole was subjected to the same operation as in Step 1 of Example 1 to obtain the labeled compound (19 mg). 1 H NMR (400MHz, CDCl 3 ) δ: 1.46 (3H, t, J=7.2 Hz), 2.67 (3H, s), 2.69 (3H, s), 2.84 (3H, s), 3.16-3.23 (2H, m), 3.25-3.33 (2H, m), 4.39 (2H, s), 4.50 (2H, q, J=7.2 Hz), 6.83-6.90 (1H, m), 6.91-6.98 (1H, m), 7.07 (1H, d, J=15.8 Hz), 7.30 (2H, d, J=8.0 Hz), 7.58 (2H, d, J=8.0 Hz), 7.96 (1H, d, J=15.8 Hz). MS (ESI ) m/z 389 (M+H) + .
實施例25：(E)-1-(4-(2-(1,7-二乙基-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮Example 25: (E)-1-(4-(2-(1,7-Diethyl-1H-benzo[d]imidazol-2-yl)vinyl)benzyl)-3-methylimidazole Pyridin-2-one
使用1-溴-2-氟-3-硝基苯，而取代1-溴-3-氟-2-硝基苯，進行與參考例3的步驟1同樣的操作。使用所得之化合物，而取代3-溴-N-乙基-2-硝基苯胺，進行與實施例2的步驟1同樣的操作，獲得N-乙基-2-硝基-6-乙烯基苯胺。對於本化合物，使用氫氧化鈀而取代5%鈀碳，進行與實施例2的步驟2同樣的操作，獲得N1 ,6-二乙基苯-1,2-二胺。使用本化合物，而取代參考例14的步驟1所使用之N2-乙基-3-氟苯-1,2-二胺，進行參考例14的步驟1至步驟2同樣的操作，獲得1,7-二乙基-2-碘-1H-苯并[d]咪唑。使用本化合物，而取代由參考例2的步驟1所得之2-溴-1-乙基-1H-苯并[d]咪唑，進行與實施例1的步驟1同樣的操作，獲得標記化合物(0.18g)。1 H NMR (400MHz, CDCl3 ) δ: 1.38 (3H, t, J=7.5 Hz), 1.47 (3H, t, J=7.2 Hz), 2.84 (3H, s), 3.05 (2H, q, J=7.5 Hz), 3.17-3.23 (2H, m), 3.26-3.33 (2H, m), 4.40 (2H, s), 4.48 (2H, q, J=7.2 Hz), 7.03-7.11 (2H, m), 7.20 (1H, t, J=7.7 Hz), 7.31 (2H, d, J=8.2 Hz), 7.58 (2H, d, J=8.0 Hz), 7.61-7.65 (1H, m), 7.98 (1H, d, J=15.8 Hz). MS (ESI) m/z 389 (M+H)+ .Using 1-bromo-2-fluoro-3-nitrobenzene instead of 1-bromo-3-fluoro-2-nitrobenzene, the same operation as step 1 of Reference Example 3 was performed. Using the obtained compound instead of 3-bromo-N-ethyl-2-nitroaniline, perform the same operation as step 1 of Example 2 to obtain N-ethyl-2-nitro-6-vinylaniline . For this compound, palladium hydroxide was used instead of 5% palladium on carbon, and the same operation as in step 2 of Example 2 was performed to obtain N 1 ,6-diethylbenzene-1,2-diamine. Using this compound instead of N2-ethyl-3-fluorobenzene-1,2-diamine used in Step 1 of Reference Example 14, the same operations as Step 1 to Step 2 of Reference Example 14 were performed to obtain 1,7 -Diethyl-2-iodo-1H-benzo[d]imidazole. Using this compound instead of the 2-bromo-1-ethyl-1H-benzo[d]imidazole obtained in Step 1 of Reference Example 2, the same operation as in Step 1 of Example 1 was performed to obtain the labeled compound (0.18 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.38 (3H, t, J=7.5 Hz), 1.47 (3H, t, J=7.2 Hz), 2.84 (3H, s), 3.05 (2H, q, J= 7.5 Hz), 3.17-3.23 (2H, m), 3.26-3.33 (2H, m), 4.40 (2H, s), 4.48 (2H, q, J=7.2 Hz), 7.03-7.11 (2H, m), 7.20 (1H, t, J=7.7 Hz), 7.31 (2H, d, J=8.2 Hz), 7.58 (2H, d, J=8.0 Hz), 7.61-7.65 (1H, m), 7.98 (1H, d , J=15.8 Hz). MS (ESI) m/z 389 (M+H) + .
實施例26：(E)-1-(4-(2-(1-乙基-7-氟-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮Example 26: (E)-1-(4-(2-(1-ethyl-7-fluoro-1H-benzo[d]imidazol-2-yl)vinyl)benzyl)-3-methyl Imidazolidin-2-one
在參考例1的步驟3所得之(E)-1-甲基-3-(4-(2-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)乙烯基)苄基)咪唑啶-2-酮(0.35g)與參考例14的步驟2所得之1-乙基-7-氟-2-碘-1H-苯并[d]咪唑(0.60g)的1,4-二
實施例27： (E)-1-乙基-2-(4-(3-甲基-2-側氧基咪唑啶-1-基)甲基)苯乙烯基)-1H-苯并[d]咪唑-7-甲腈Example 27: (E)-1-Ethyl-2-(4-(3-methyl-2-oxoimidazolidine-1-yl)methyl)styryl)-1H-benzo[d ]Imidazole-7-carbonitrile
使用參考例15的步驟4所得之1-乙基-2-碘-1H-苯并[d]咪唑-7-甲腈，而取代2-溴-1-乙基-1H-苯并[d]咪唑，進行與實施例1的步驟1同樣的操作，獲得標記化合物(0.32g)。1 H NMR (400MHz, CDCl3 ) δ: 1.57 (3H, t, J=7.2 Hz), 2.85 (3H, s), 3.16-3.24 (2H, m), 3.27-3.33 (2H, m), 4.41 (2H, s), 4.67 (2H, q, J=7.3 Hz), 7.07 (1H, d, J=15.7 Hz), 7.29-7.37 (3H, m), 7.54-7.62 (3H, m), 7.97 (1H, dd, J=8.2, 1.0 Hz), 8.03 (1H, d, J=15.8 Hz). MS (ESI) m/z 386 (M+H)+ .Use 1-ethyl-2-iodo-1H-benzo[d]imidazole-7-carbonitrile obtained in step 4 of Reference Example 15 instead of 2-bromo-1-ethyl-1H-benzo[d] For imidazole, the same operation as in step 1 of Example 1 was performed to obtain the labeled compound (0.32 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.57 (3H, t, J=7.2 Hz), 2.85 (3H, s), 3.16-3.24 (2H, m), 3.27-3.33 (2H, m), 4.41 ( 2H, s), 4.67 (2H, q, J=7.3 Hz), 7.07 (1H, d, J=15.7 Hz), 7.29-7.37 (3H, m), 7.54-7.62 (3H, m), 7.97 (1H , dd, J=8.2, 1.0 Hz), 8.03 (1H, d, J=15.8 Hz). MS (ESI) m/z 386 (M+H) + .
實施例28：(E)-1-(4-(2-(5,6-二氫-4H-咪唑并[4,5,1-ij]喹啉-2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮Example 28: (E)-1-(4-(2-(5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2-yl)vinyl)benzyl) -3-Methylimidazolidin-2-one
步驟1 1,2,3,4-四氫喹啉-8-胺 在8-硝基喹啉(2.00g)的乙酸乙酯(5.0mL)溶液中，添加乙酸(2.0mL)及氧化鉑(0.20g)，在氫氣體環境下，以60℃攪拌24小時。放置冷卻後，使用矽藻土濾去觸媒，減壓下餾去濾液的溶劑，將殘渣以矽膠管柱層析法(n-己烷/乙酸乙酯)進行純化，獲得標記化合物(1.40g)。1 H NMR (400MHz, CDCl3 ) δ: 1.87-1.95 (2H, m), 2.77 (2H, t, J=6.4 Hz), 3.15-3.40 (5H, m), 6.53-6.60 (3H, m). MS (ESI) m/z 149 (M+H)+ .Step 1 1,2,3,4-Tetrahydroquinoline-8-amine is in the ethyl acetate (5.0mL) solution of 8-nitroquinoline (2.00g), add acetic acid (2.0mL) and platinum oxide ( 0.20g), stirred at 60°C for 24 hours in a hydrogen atmosphere. After being left to cool, the catalyst was filtered using Celite, the solvent of the filtrate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the labeled compound (1.40 g) ). 1 H NMR (400MHz, CDCl 3 ) δ: 1.87-1.95 (2H, m), 2.77 (2H, t, J=6.4 Hz), 3.15-3.40 (5H, m), 6.53-6.60 (3H, m). MS (ESI) m/z 149 (M+H) + .
步驟2 5,6-二氫-4H-咪唑并[4,5,1-ij]喹啉 使用由上述步驟1所得之1,2,3,4-四氫喹啉-8-胺(1.35g)，而取代參考例14的步驟1所使用之N2-乙基-3-氟苯-1,2-二胺，進行與參考例14的步驟1同樣的操作，獲得標記化合物(1.22g)。1 H NMR (400MHz, DMSO-d6 ) δ: 2.13 (2H, quin, J=5.9 Hz), 2.94 (2H, t, J=6.0 Hz), 4.21-4.31 (2H, m), 6.98 (1H, d, J=7.0 Hz), 7.09 (1H, t, J=7.6 Hz), 7.42 (1H, d, J=8.2 Hz), 8.15 (1H, s). MS (ESI) m/z 159 (M+H)+ .Step 2 5,6-Dihydro-4H-imidazo[4,5,1-ij]quinoline uses the 1,2,3,4-tetrahydroquinoline-8-amine (1.35g) obtained from step 1 above ), instead of N2-ethyl-3-fluorobenzene-1,2-diamine used in Step 1 of Reference Example 14, the same operation as Step 1 of Reference Example 14 was performed to obtain the labeled compound (1.22 g). 1 H NMR (400MHz, DMSO-d 6 ) δ: 2.13 (2H, quin, J=5.9 Hz), 2.94 (2H, t, J=6.0 Hz), 4.21-4.31 (2H, m), 6.98 (1H, d, J=7.0 Hz), 7.09 (1H, t, J=7.6 Hz), 7.42 (1H, d, J=8.2 Hz), 8.15 (1H, s). MS (ESI) m/z 159 (M+ H) + .
步驟3 2-碘-5,6-二氫-4H-咪唑并[4,5,1-ij]喹啉 使用由上述步驟2所得之5,6-二氫-4H-咪唑并[4,5,1-ij]喹啉(1.00g)，而取代實施例24的步驟2所得之1-乙基-4,7-二甲基-1H-苯并[d]咪唑，進行同樣的操作，獲得標記化合物(1.04g)。1 H NMR (400MHz, CDCl3 ) δ: 2.28 (2H, quin, J=5.9 Hz), 2.98 (2H, t, J=6.1 Hz), 4.09 (2H, t, J=6.0 Hz), 6.98 (1H, d, J=7.3 Hz), 7.10-7.16 (1H, m), 7.52 (1H, dd, J=8.2, 0.6 Hz). MS (ESI) m/z 285 (M+H)+ .Step 3 2-Iodo-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline uses the 5,6-dihydro-4H-imidazo[4,5 ,1-ij]quinoline (1.00g), instead of 1-ethyl-4,7-dimethyl-1H-benzo[d]imidazole obtained in step 2 of Example 24, the same operation was performed to obtain The labeled compound (1.04 g). 1 H NMR (400MHz, CDCl 3 ) δ: 2.28 (2H, quin, J=5.9 Hz), 2.98 (2H, t, J=6.1 Hz), 4.09 (2H, t, J=6.0 Hz), 6.98 (1H , d, J=7.3 Hz), 7.10-7.16 (1H, m), 7.52 (1H, dd, J=8.2, 0.6 Hz). MS (ESI) m/z 285 (M+H) + .
步驟4 (E)-1-(4-(2-(5,6-二氫-4H-咪唑并[4,5,1-ij]喹啉-2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮 使用由上述步驟3所得之2-碘-5,6-二氫-4H-咪唑并[4,5,1-ij]喹啉，而取代由參考例2的步驟1所得之2-溴-1-乙基-1H-苯并[d]咪唑，進行與實施例1的步驟1同樣的操作，獲得標記化合物(0.57g)。1 H NMR (400MHz, CDCl3 ) δ: 2.27-2.35 (2H, m), 2.84 (3H, s), 3.02 (2H, t, J=5.8 Hz), 3.16-3.23 (2H, m), 3.26-3.32 (2H, m), 4.30 (2H, t, J=5.8 Hz), 4.39 (2H, s), 6.99 (1H, d, J=7.3 Hz), 7.05 (1H, d, J=15.9 Hz), 7.18 (1H, t, J=7.7 Hz), 7.31 (2H, d, J=8.0 Hz), 7.56 (3H, d, J=8.2 Hz), 7.90 (1H, d, J=16.1 Hz). MS (ESI) m/z 373 (M+H)+ .Step 4 (E)-1-(4-(2-(5,6-Dihydro-4H-imidazo[4,5,1-ij]quinolin-2-yl)vinyl)benzyl)-3 -Methylimidazolidin-2-one uses the 2-iodo-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline obtained from the above step 3 instead of the reference example 2 The 2-bromo-1-ethyl-1H-benzo[d]imidazole obtained in step 1 was subjected to the same operation as in step 1 of Example 1 to obtain the labeled compound (0.57 g). 1 H NMR (400MHz, CDCl 3 ) δ: 2.27-2.35 (2H, m), 2.84 (3H, s), 3.02 (2H, t, J=5.8 Hz), 3.16-3.23 (2H, m), 3.26- 3.32 (2H, m), 4.30 (2H, t, J=5.8 Hz), 4.39 (2H, s), 6.99 (1H, d, J=7.3 Hz), 7.05 (1H, d, J=15.9 Hz), 7.18 (1H, t, J=7.7 Hz), 7.31 (2H, d, J=8.0 Hz), 7.56 (3H, d, J=8.2 Hz), 7.90 (1H, d, J=16.1 Hz). MS ( ESI) m/z 373 (M+H) + .
實施例29：(E)-1-甲基-(4-(2-(9-甲基-5,6-二氫-4H-咪唑并[4,5,1-ij]喹啉-2-基)乙烯基)苄基)咪唑啶-2-酮Example 29: (E)-1-Methyl-(4-(2-(9-methyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2- (Yl)vinyl)benzyl)imidazolidin-2-one
使用8-胺基-7-甲基喹啉，而取代8-硝基喹啉，進行與實施例28的步驟1至步驟4同樣的操作，獲得標記化合物(0.45g)。1 H NMR (400MHz, CDCl3 ) δ: 2.27 (2H, quin, J=5.9 Hz), 2.67 (3H, s), 2.84 (3H, s), 2.98 (2H, t, J=6.1 Hz), 3.17-3.23 (2H, m), 3.26-3.32 (2H, m), 4.26-4.31 (2H, m), 4.39 (2H, s), 6.86-6.92 (1H, m), 6.94-6.99 (1H, m), 7.08 (1H, d, J=16.1 Hz), 7.30 (2H, d, J=8.0 Hz), 7.56 (2H, d, J=8.0 Hz), 7.84 (1H, d, J=16.2 Hz). MS (ESI) m/z 387 (M+H)+ .Using 8-amino-7-methylquinoline instead of 8-nitroquinoline, the same operation as in step 1 to step 4 of Example 28 was performed to obtain the labeled compound (0.45 g). 1 H NMR (400MHz, CDCl 3 ) δ: 2.27 (2H, quin, J=5.9 Hz), 2.67 (3H, s), 2.84 (3H, s), 2.98 (2H, t, J=6.1 Hz), 3.17 -3.23 (2H, m), 3.26-3.32 (2H, m), 4.26-4.31 (2H, m), 4.39 (2H, s), 6.86-6.92 (1H, m), 6.94-6.99 (1H, m) , 7.08 (1H, d, J=16.1 Hz), 7.30 (2H, d, J=8.0 Hz), 7.56 (2H, d, J=8.0 Hz), 7.84 (1H, d, J=16.2 Hz). MS (ESI) m/z 387 (M+H) + .
實施例30：(E)-1-(4-(2-(3,4-二氫-5-氧代-1,2a-二吖乙烯合萘-2-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮Example 30: (E)-1-(4-(2-(3,4-Dihydro-5-oxo-1,2a-diethylenenaphthalene-2-yl)vinyl)benzyl)- 3-Methylimidazolidin-2-one
使用5-硝基-3,4-二氫-2H-苯并[b][1,4]
實施例31：(E)-1-(4-(2-(8,9-二氫-7H-6-氧代-2,9a-二吖苯并[cd]薁-1-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮Example 31: (E)-1-(4-(2-(8,9-dihydro-7H-6-oxo-2,9a-diazylbenzo[cd]azulene-1-yl)vinyl )Benzyl)-3-Methylimidazolidin-2-one
步驟1 6-硝基-2,3,4,5-四氫苯并[b][1,4]氧雜吖庚因 冰冷下，在2-胺基-3-硝基酚(1.00g)的N,N-二甲基甲醯胺(20mL)溶液中，添加氫化鈉(0.85g，55%油性)，再添加1,3-二溴丙烷(1.0mL)後，在室溫攪拌17小時。在反應液中添加水，以乙酸乙酯進行萃取。以飽和食鹽水清洗萃取液，以硫酸鈉進行乾燥。減壓下，餾去溶劑，將殘渣以矽膠管柱層析法(n-己烷/乙酸乙酯)進行純化，獲得標記化合物(0.75g)。1 H NMR (400MHz, CDCl3 ) δ: 2.14-2.22 (2H, m), 3.67-3.74 (2H, m), 4.33 (2H, t, J=6.5 Hz), 6.56 (1H, dd, J=8.7, 7.7 Hz), 7.05 (1H, ddd, J=7.6, 1.6, 0.7 Hz), 7.84 (1H, dd, J=8.8, 1.6 Hz), 7.96 (1H, br s). MS (ESI) m/z 195 (M+H)+ .Step 1 6-Nitro-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine under ice cooling, in 2-amino-3-nitrophenol (1.00g) Add sodium hydride (0.85g, 55% oily) to the N,N-dimethylformamide (20mL) solution, then add 1,3-dibromopropane (1.0mL), and stir at room temperature for 17 hours . Water was added to the reaction liquid, and extraction was performed with ethyl acetate. The extract was washed with saturated brine and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (0.75 g). 1 H NMR (400MHz, CDCl 3 ) δ: 2.14-2.22 (2H, m), 3.67-3.74 (2H, m), 4.33 (2H, t, J=6.5 Hz), 6.56 (1H, dd, J=8.7 , 7.7 Hz), 7.05 (1H, ddd, J=7.6, 1.6, 0.7 Hz), 7.84 (1H, dd, J=8.8, 1.6 Hz), 7.96 (1H, br s). MS (ESI) m/z 195 (M+H) + .
步驟2 (E)-1-(4-(2-(8,9-二氫-7H-6-氧代-2,9a-二吖苯并[cd]薁-1-基)乙烯基)苄基)-3-甲基咪唑啶-2-酮 使用由上述步驟1所得之6-硝基-2,3,4,5-四氫苯并[b][1,4]氧雜吖庚因，而取代參考例3的步驟1所得之3-溴-N-乙基-2-硝基苯胺，進行與參考例3的步驟2同樣的操作。使用所得之化合物，而取代實施例28的步驟1所得之1,2,3,4-四氫喹啉-8-胺，進行與實施例28的步驟2至4同樣的操作，獲得標記化合物(0.31g)。1 H NMR (400MHz, CDCl3 ) δ: 2.46-2.52 (2H, m), 2.84 (3H, s), 3.16-3.23 (2H, m), 3.27-3.33 (2H, m), 4.35-4.43 (6H, m), 6.83 (1H, dd, J=7.8, 0.9 Hz), 7.08 (1H, d, J=15.8 Hz), 7.16 (1H, t, J=8.0 Hz), 7.31 (2H, d, J=8.0 Hz), 7.41 (1H, dd, J=8.0, 0.9 Hz), 7.56 (2H, d, J=8.2 Hz), 7.95 (1H, d, J=15.8 Hz). MS (ESI) m/z 389 (M+H)+ .Step 2 (E)-1-(4-(2-(8,9-dihydro-7H-6-oxo-2,9a-diazylbenzo[cd]azulene-1-yl)vinyl)benzyl Yl)-3-methylimidazolidin-2-one uses the 6-nitro-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin obtained from step 1 above , Instead of the 3-bromo-N-ethyl-2-nitroaniline obtained in Step 1 of Reference Example 3, the same operation as Step 2 of Reference Example 3 was performed. Using the obtained compound instead of the 1,2,3,4-tetrahydroquinoline-8-amine obtained in step 1 of Example 28, the same operations as steps 2 to 4 of Example 28 were performed to obtain the labeled compound ( 0.31g). 1 H NMR (400MHz, CDCl 3 ) δ: 2.46-2.52 (2H, m), 2.84 (3H, s), 3.16-3.23 (2H, m), 3.27-3.33 (2H, m), 4.35-4.43 (6H , m), 6.83 (1H, dd, J=7.8, 0.9 Hz), 7.08 (1H, d, J=15.8 Hz), 7.16 (1H, t, J=8.0 Hz), 7.31 (2H, d, J= 8.0 Hz), 7.41 (1H, dd, J=8.0, 0.9 Hz), 7.56 (2H, d, J=8.2 Hz), 7.95 (1H, d, J=15.8 Hz). MS (ESI) m/z 389 (M+H) + .
實施例32：(E)-1-甲基-3-(4-(2-(1-甲基-1H-苯并[d]咪唑-2-基)乙烯基)苄基)咪唑啶-2-酮Example 32: (E)-1-Methyl-3-(4-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)vinyl)benzyl)imidazolidine-2 -ketone
步驟1 2-溴-1-甲基-1H-苯并[d]咪唑 在2-溴苯并咪唑(2.00g)的N,N-二甲基甲醯胺(20mL)溶液中，冰冷下，添加碘甲烷(0.70mL)及氫化鈉(0.47g，60%油性)，在室溫攪拌1小時。添加水，以乙酸乙酯進行萃取。以水及飽和食鹽水清洗萃取液，以硫酸鈉進行乾燥。在減壓下餾去溶劑，獲得標記化合物(2.10g)。1 H NMR (400MHz, CDCl3 ) δ: 3.80 (3H, s), 7.23-7.34 (3H, m), 7.71 (1H, dt, J=7.7, 1.1 Hz). MS (ESI) m/z 211 (M+H)+ .Step 1 2-Bromo-1-methyl-1H-benzo[d]imidazole in 2-bromobenzimidazole (2.00g) in N,N-dimethylformamide (20mL) solution, under ice cooling, Add methyl iodide (0.70 mL) and sodium hydride (0.47 g, 60% oily), and stir at room temperature for 1 hour. Water was added, and extraction was performed with ethyl acetate. The extract was washed with water and saturated brine, and dried with sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (2.10 g). 1 H NMR (400MHz, CDCl 3 ) δ: 3.80 (3H, s), 7.23-7.34 (3H, m), 7.71 (1H, dt, J=7.7, 1.1 Hz). MS (ESI) m/z 211 ( M+H) + .
步驟2 (E)-1-甲基-3-(4-(2-(1-甲基-1H-苯并[d]咪唑-2-基)乙烯基)苄基)咪唑啶-2-酮 使用由上述步驟1所得之2-溴-1-甲基-1H-苯并[d]咪唑(0.60g)，而取代由參考例2的步驟1所得之2-溴-1-乙基-1H-苯并[d]咪唑，進行與實施例1的步驟1同樣的操作，獲得標記化合物(0.78g)。1 H NMR (400MHz, CDCl3 ) δ: 2.84 (3H, s), 3.17-3.22 (2H, m), 3.26-3.32 (2H, m), 3.88 (3H, s), 4.40 (2H, s), 7.10 (1H, d, J=15.8 Hz), 7.27-7.37 (5H, m), 7.58 (2H, d, J=8.2 Hz), 7.74-7.80 (1H, m), 7.96 (1H, d, J=15.9 Hz). MS (ESI) m/z 347 (M+H)+ .Step 2 (E)-1-Methyl-3-(4-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)vinyl)benzyl)imidazolidine-2-one Use 2-bromo-1-methyl-1H-benzo[d]imidazole (0.60g) obtained in step 1 above instead of 2-bromo-1-ethyl-1H obtained in step 1 of Reference Example 2 -Benzo[d]imidazole, the same operation as in step 1 of Example 1 was performed to obtain the labeled compound (0.78 g). 1 H NMR (400MHz, CDCl 3 ) δ: 2.84 (3H, s), 3.17-3.22 (2H, m), 3.26-3.32 (2H, m), 3.88 (3H, s), 4.40 (2H, s), 7.10 (1H, d, J=15.8 Hz), 7.27-7.37 (5H, m), 7.58 (2H, d, J=8.2 Hz), 7.74-7.80 (1H, m), 7.96 (1H, d, J= 15.9 Hz). MS (ESI) m/z 347 (M+H) + .
實施例33：(E)-1-(4-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)-2-甲基苄基)-3-甲基咪唑啶-2-酮Example 33: (E)-1-(4-(2-(1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl)-2-methylbenzyl)-3-methan Imidazolidin-2-one
步驟1 1-(4-溴-2-甲基苄基)-3-甲基咪唑啶-2-酮 冰冷下，在4-溴-2-甲基苄基溴(1.00g)的N,N-二甲基甲醯胺(15mL)溶液中，添加1-甲基咪唑啶-2-酮(0.42g)與氫化鈉(0.17g，60%油性)，在室溫攪拌18小時。在添加飽和氯化銨水溶液及水後，以乙酸乙酯進行萃取。以硫酸鈉乾燥萃取液。減壓下，餾去溶劑，將殘渣以矽膠管柱層析法(氯仿/甲醇)進行純化，獲得標記化合物(1.05g)。1 H NMR (400MHz, CDCl3 ) δ: 2.30 (3H, s), 2.83 (3H, s), 3.11-3.15 (2H, m), 3.25-3.30 (2H, m), 4.31 (2H, s), 7.06 (1H, d, J=8.2 Hz), 7.27-7.33 (2H, m). MS (ESI) m/z 283 (M+H)+ .Step 1 Under ice-cooling, 1-(4-bromo-2-methylbenzyl)-3-methylimidazolidin-2-one was mixed with 4-bromo-2-methylbenzyl bromide (1.00g) in N,N -To the dimethylformamide (15 mL) solution, add 1-methylimidazolidin-2-one (0.42 g) and sodium hydride (0.17 g, 60% oily), and stir at room temperature for 18 hours. After adding saturated ammonium chloride aqueous solution and water, extraction was performed with ethyl acetate. The extract was dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol) to obtain the title compound (1.05 g). 1 H NMR (400MHz, CDCl 3 ) δ: 2.30 (3H, s), 2.83 (3H, s), 3.11-3.15 (2H, m), 3.25-3.30 (2H, m), 4.31 (2H, s), 7.06 (1H, d, J=8.2 Hz), 7.27-7.33 (2H, m). MS (ESI) m/z 283 (M+H) + .
步驟2 (E)-1-甲基-3-(2-甲基-4-(2-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)乙烯基)苄基)咪唑啶-2-酮 使用由上述步驟1所得之1-(4-溴-2-甲基苄基)-3-甲基咪唑啶-2-酮(1.05g)，而取代參考例1的步驟2所得之1-(4-碘苄基)-3-甲基咪唑啶-2-酮，進行與參考例1的步驟3同樣的操作，獲得標記化合物(1.11g)。1 H NMR (400MHz, CDCl3 ) δ: 1.31 (12H, s), 2.33 (3H, m), 2.83 (3H, s), 3.11-3.16 (2H, m), 3.25-3.30 (2H, m), 4.36 (2H, s), 6.13 (1H, d, J=18.3 Hz), 7.16 (1H, d, J=8.4 Hz), 7.26-7.30 (2H, m), 7.35 (1H, d, J=18.4 Hz). MS (ESI) m/z 357 (M+H)+ .Step 2 (E)-1-Methyl-3-(2-methyl-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -(Yl)vinyl)benzyl)imidazolidin-2-one using the 1-(4-bromo-2-methylbenzyl)-3-methylimidazolidin-2-one (1.05g) obtained from step 1 above ), instead of 1-(4-iodobenzyl)-3-methylimidazolidin-2-one obtained in Step 2 of Reference Example 1, the same operation as Step 3 of Reference Example 1 was performed to obtain the labeled compound (1.11 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.31 (12H, s), 2.33 (3H, m), 2.83 (3H, s), 3.11-3.16 (2H, m), 3.25-3.30 (2H, m), 4.36 (2H, s), 6.13 (1H, d, J=18.3 Hz), 7.16 (1H, d, J=8.4 Hz), 7.26-7.30 (2H, m), 7.35 (1H, d, J=18.4 Hz) ). MS (ESI) m/z 357 (M+H) + .
步驟3 (E)-1-(4-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)-2-甲基苄基)-3-甲基咪唑啶-2-酮 使用由上述步驟2所得之(E)-1-甲基-3-(2-甲基-4-(2-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)乙烯基)苄基)咪唑啶-2-酮(1.11g)，而取代由參考例1的步驟3所得之(E)-1-甲基-3-(4-(2-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)乙烯基)苄基)咪唑啶-2-酮，進行與實施例1的步驟1同樣的操作，獲得標記化合物(0.48g)。1 H NMR (400MHz, CDCl3 ) δ: 1.48 (3H, t, J=7.3 Hz), 2.39 (3H, s), 2.84 (3H, s), 3.14-3.21 (2H, m), 3.26-3.33 (2H, m), 4.33 (2H, q, J=7.3 Hz), 4.40 (2H, s), 7.05 (1H, d, J=15.8 Hz), 7.22-7.29 (3H, m), 7.32-7.37 (1H, m), 7.38-7.44 (2H, m), 7.75-7.80 (1H, m), 7.95 (1H, d, J=15.8 Hz). MS (ESI) m/z 375 (M+H)+ .Step 3 (E)-1-(4-(2-(1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl)-2-methylbenzyl)-3-methylimidazole The pyridin-2-one uses (E)-1-methyl-3-(2-methyl-4-(2-(4,4,5,5-tetramethyl-1,3) obtained from step 2 above ,2-dioxaborolan-2-yl)vinyl)benzyl)imidazolidin-2-one (1.11g) instead of (E)-1-methyl- obtained in step 3 of Reference Example 1 3-(4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)benzyl)imidazolidin-2-one, The same operation as in step 1 of Example 1 was performed to obtain the labeled compound (0.48 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.48 (3H, t, J=7.3 Hz), 2.39 (3H, s), 2.84 (3H, s), 3.14-3.21 (2H, m), 3.26-3.33 ( 2H, m), 4.33 (2H, q, J=7.3 Hz), 4.40 (2H, s), 7.05 (1H, d, J=15.8 Hz), 7.22-7.29 (3H, m), 7.32-7.37 (1H , m), 7.38-7.44 (2H, m), 7.75-7.80 (1H, m), 7.95 (1H, d, J=15.8 Hz). MS (ESI) m/z 375 (M+H) + .
實施例34：(E)-1-(4-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)-3-甲基苄基)-3-甲基咪唑啶-2-酮Example 34: (E)-1-(4-(2-(1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl)-3-methylbenzyl)-3-methyl Imidazolidin-2-one
使用4-溴-3-甲基苄基溴，而取代實施例33的步驟1所使用之4-溴-2-甲基苄基溴，進行與實施例33的步驟1至步驟3同樣的操作，獲得標記化合物(0.42g)。1 H NMR (400MHz, CDCl3 ) δ: 1.47 (3H, t, J=7.3 Hz), 2.50 (3H, s), 2.84 (3H, s), 3.17-3.23 (2H, m), 3.26-3.32 (2H, m), 4.29-4.37 (4H, m), 6.98 (1H, d, J=15.6 Hz), 7.13 (1H, s), 7.16 (1H, d, J=7.9 Hz), 7.26-7.29 (2H, m), 7.32-7.37 (1H, m), 7.62 (1H, d, J=7.9 Hz), 7.75-7.81 (1H, m), 8.18 (1H, d, J=15.7 Hz). MS (ESI) m/z 375 (M+H)+ .Use 4-bromo-3-methylbenzyl bromide instead of 4-bromo-2-methylbenzyl bromide used in step 1 of Example 33, and perform the same operations as steps 1 to 3 of Example 33 , The labeled compound (0.42g) was obtained. 1 H NMR (400MHz, CDCl 3 ) δ: 1.47 (3H, t, J=7.3 Hz), 2.50 (3H, s), 2.84 (3H, s), 3.17-3.23 (2H, m), 3.26-3.32 ( 2H, m), 4.29-4.37 (4H, m), 6.98 (1H, d, J=15.6 Hz), 7.13 (1H, s), 7.16 (1H, d, J=7.9 Hz), 7.26-7.29 (2H , m), 7.32-7.37 (1H, m), 7.62 (1H, d, J=7.9 Hz), 7.75-7.81 (1H, m), 8.18 (1H, d, J=15.7 Hz). MS (ESI) m/z 375 (M+H) + .
實施例35：(E)-1-(4-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)-2-氟苄基)-3-甲基咪唑啶-2-酮Example 35: (E)-1-(4-(2-(1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl)-2-fluorobenzyl)-3-methyl Imidazolidin-2-one
步驟1 1-[(4-溴-2-氟苯基)甲基]-3-甲基咪唑啶-2-酮 冰冷下，在4-溴-2-氟苄溴(50.7g)及1-甲基咪唑啶-2-酮(20.8g)的N,N-二甲基甲醯胺(350mL)溶液中，緩緩添加氫化鈉(9.90g，55%油性)。攪拌1小時後，將反應混合液添加至冰水中，以乙酸乙酯進行萃取。以飽和食鹽水清洗有機層後，以硫酸鎂進行乾燥。餾去溶劑後，將殘渣以矽膠管柱層析法(n-己烷/乙酸乙酯)進行純化，獲得標記化合物(53.1 g)。1 H NMR (400MHz, CDCl3 ) δ: 2.81 (3H, s), 3.19-3.32 (4H, m), 4.38 (2H, d, J=1.3 Hz), 7.21-7.27 (4H, m).Step 1 1-[(4-Bromo-2-fluorophenyl)methyl]-3-methylimidazolidin-2-one under ice-cooling, in 4-bromo-2-fluorobenzyl bromide (50.7g) and 1- To the N,N-dimethylformamide (350 mL) solution of methylimidazolidin-2-one (20.8g), sodium hydride (9.90g, 55% oily) was slowly added. After stirring for 1 hour, the reaction mixture was added to ice water and extracted with ethyl acetate. After washing the organic layer with saturated brine, it was dried with magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (53.1 g). 1 H NMR (400MHz, CDCl 3 ) δ: 2.81 (3H, s), 3.19-3.32 (4H, m), 4.38 (2H, d, J=1.3 Hz), 7.21-7.27 (4H, m).
步驟2 1-(｛2-氟-4-[(E)-2-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)乙烯基]苯基｝甲基)-3-甲基咪唑啶-2-酮 在上述步驟1所得之1-[(4-溴-2-氟苯基)甲基]-3-甲基咪唑啶-2-酮(53.1g)的甲苯(400mL)溶液中，添加三乙胺(77.0mL)及4,4,5,5-四甲基-2-乙烯基-1,3,2-二氧硼戊環(34.8mL)，脫氣後添加雙(三-tert-丁基膦)鈀(0)(3.00g)，進行氮置換，加熱回流20小時。放置冷卻後，藉由矽藻土過濾去除不溶物後，將濾液進行減壓濃縮。將殘渣以矽膠管柱層析法(氯仿/甲醇)進行純化，獲得標記化合物 (61.7g)。1 H NMR (400MHz, CDCl3 ) δ: 1.31 (12H, s), 2.81 (3H, s), 3.19-3.33 (4H, m), 4.42 (2H, s), 6.14 (1H, d, J=18.6 Hz), 7.15 (1H, dd, J=11.0, 1.5 Hz), 7.21 (1H, dd, J=7.8, 1.5 Hz), 7.29 (1H, d, J=1.5 Hz), 7.32 (1H, d, J=8.3 Hz).Step 2 1-({2-Fluoro-4-[(E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxboran-2-yl)vinyl] 1-[(4-Bromo-2-fluorophenyl)methyl]-3-methylimidazolidin-2-one obtained in step 1 above To the toluene (400mL) solution of ketone (53.1g), add triethylamine (77.0mL) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (34.8 mL), after degassing, bis(tri-tert-butylphosphine) palladium(0) (3.00 g) was added, nitrogen replacement was performed, and heating was refluxed for 20 hours. After leaving to cool, filtering through Celite to remove insoluble matter, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to obtain the title compound (61.7 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.31 (12H, s), 2.81 (3H, s), 3.19-3.33 (4H, m), 4.42 (2H, s), 6.14 (1H, d, J=18.6 Hz), 7.15 (1H, dd, J=11.0, 1.5 Hz), 7.21 (1H, dd, J=7.8, 1.5 Hz), 7.29 (1H, d, J=1.5 Hz), 7.32 (1H, d, J =8.3 Hz).
步驟3
(E)-1-(4-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)-2-氟苄基)-3-甲基咪唑啶-2-酮
在參考例2的步驟1所得之2-溴-1-乙基-1H-苯并[d]咪唑(6.25g)與上述步驟2所得之1-(｛2-氟-4-[(E)-2-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)乙烯基]苯基｝甲基)-3-甲基咪唑啶-2-酮(10.0g)的1,4-二
實施例36：(E)-1-(4-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)-3-氟苄基)-3-甲基咪唑啶-2-酮Example 36: (E)-1-(4-(2-(1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl)-3-fluorobenzyl)-3-methyl Imidazolidin-2-one
使用4-溴-3-氟苄溴，而取代實施例33的步驟1所使用之4-溴-2-甲基苄基溴，進行與實施例33的步驟1至步驟3同樣的操作，獲得標記化合物(0.43g)。1 H NMR (400MHz, CDCl3 ) δ: 1.47 (3H, t, J=7.3 Hz), 2.85 (3H, s), 3.17-3.25 (2H, m), 3.27-3.34 (2H, m), 4.32 (2H, q, J=7.3 Hz), 4.37 (2H, s), 7.02-7.11 (2H, m), 7.21-7.30 (3H, m), 7.33-7.37 (1H, m), 7.54 (1H, t, J=7.8 Hz), 7.75-7.81 (1H, m), 7.99 (1H, d, J=15.9 Hz). MS (ESI) m/z 379 (M+H)+ .Using 4-bromo-3-fluorobenzyl bromide instead of 4-bromo-2-methylbenzyl bromide used in step 1 of Example 33, the same operations as steps 1 to 3 of Example 33 were performed to obtain Labeled compound (0.43g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.47 (3H, t, J=7.3 Hz), 2.85 (3H, s), 3.17-3.25 (2H, m), 3.27-3.34 (2H, m), 4.32 ( 2H, q, J=7.3 Hz), 4.37 (2H, s), 7.02-7.11 (2H, m), 7.21-7.30 (3H, m), 7.33-7.37 (1H, m), 7.54 (1H, t, J=7.8 Hz), 7.75-7.81 (1H, m), 7.99 (1H, d, J=15.9 Hz). MS (ESI) m/z 379 (M+H) + .
實施例37：(E)-1-(4-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)-2,6-二氟苄基)-3-甲基咪唑啶-2-酮Example 37: (E)-1-(4-(2-(1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl)-2,6-difluorobenzyl)-3 -Methylimidazolidin-2-one
步驟1 5-溴-2-(溴甲基)-1,3-二氟苯 室溫下，在30%溴化氫乙酸溶液(10.1mL)中，少量地持續添加4-溴-2,6-二氟苯甲醇(5.00g)，攪拌2小時。在反應液添加二乙基醚後，添加飽和碳酸氫鈉水，攪拌30分鐘。以二乙基醚進行萃取，以水及飽和食鹽水清洗萃取液，以硫酸鈉進行乾燥。在減壓下餾去溶劑，將殘渣以矽膠管柱層析法(n-己烷/乙酸乙酯)進行純化，獲得標記化合物(4.25g)。1 H NMR (400MHz, CDCl3 ) δ: 4.46 (2H, s), 7.08-7.15 (2H, m).Step 1 5-Bromo-2-(bromomethyl)-1,3-difluorobenzene in 30% hydrogen bromide acetic acid solution (10.1 mL) at room temperature, continuously add 4-bromo-2,6 in small amounts -Difluorobenzyl alcohol (5.00 g), stirred for 2 hours. After adding diethyl ether to the reaction liquid, saturated sodium bicarbonate water was added and stirred for 30 minutes. Extract with diethyl ether, wash the extract with water and saturated brine, and dry with sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (4.25 g). 1 H NMR (400MHz, CDCl 3 ) δ: 4.46 (2H, s), 7.08-7.15 (2H, m).
步驟2 (E)-1-(4-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)-2,6-二氟苄基)-3-甲基咪唑啶-2-酮 使用由上述步驟1所得之5-溴-2-(溴甲基)-1,3-二氟苯，而取代實施例33的步驟1所使用之4-溴-2-甲基苄基溴，進行與實施例33的步驟1至步驟3同樣的操作，獲得標記化合物(0.28g)。1 H NMR (400MHz, CDCl3 ) δ: 1.48 (3H, t, J=7.3 Hz), 2.81 (3H, s), 3.26 (4H, s), 4.34 (2H, q, J=7.3 Hz), 4.51 (2H, s), 7.06 (1H, d, J=15.8 Hz), 7.10-7.17 (2H, m), 7.28-7.32 (2H, m), 7.34-7.40 (1H, m), 7.75-7.81 (1H, m), 7.88 (1H, d, J=15.8 Hz). MS (ESI) m/z 397 (M+H)+ .Step 2 (E)-1-(4-(2-(1-ethyl-1H-benzo(d)imidazol-2-yl)vinyl)-2,6-difluorobenzyl)-3-methyl The 5-bromo-2-(bromomethyl)-1,3-difluorobenzene obtained from step 1 above was used for the imidazolidin-2-one, instead of 4-bromo-2 used in step 1 of Example 33 -Methylbenzyl bromide, the same operation as in step 1 to step 3 of Example 33 was performed to obtain the labeled compound (0.28 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.48 (3H, t, J=7.3 Hz), 2.81 (3H, s), 3.26 (4H, s), 4.34 (2H, q, J=7.3 Hz), 4.51 (2H, s), 7.06 (1H, d, J=15.8 Hz), 7.10-7.17 (2H, m), 7.28-7.32 (2H, m), 7.34-7.40 (1H, m), 7.75-7.81 (1H , m), 7.88 (1H, d, J=15.8 Hz). MS (ESI) m/z 397 (M+H) + .
實施例38：(E)-5-(2-(1-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)-2-((3-甲基-2-側氧基咪唑啶-1-基)甲基)苯甲腈Example 38: (E)-5-(2-(1-(1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl)-2-((3-methyl-2- Pendant oxyimidazolidine-1-yl)methyl)benzonitrile
步驟1 在5-溴-2-甲基苯甲腈(2.00g)的四氯化碳(20mL)溶液中，添加N-溴琥珀醯亞胺(1.80g)及2,2-偶氮雙(異丁腈)(0.08g)，進行6小時加熱回流。放置冷卻後，將反應液進行矽藻土過濾，減壓下，餾去濾液的溶劑，獲得5-溴-2-(溴甲基)苯甲腈。使用上述所得之5-溴-2-(溴甲基)苯甲腈，而取代實施例33的步驟1所使用之4-溴-2-甲基苄基溴，進行與實施例33的步驟1至步驟3同樣的操作，獲得標記化合物(0.91g)。1 H NMR (400MHz, CDCl3 ) δ: 1.50 (3H, t, J=7.3 Hz), 2.85 (3H, s), 3.34 (4H, s), 4.35 (2H, q, J=7.3 Hz), 4.61 (2H, s), 7.11 (1H, d, J=15.8 Hz), 7.28-7.33 (2H, m), 7.34-7.39 (1H, m), 7.58 (1H, d, J=8.2 Hz), 7.74-7.80 (2H, m), 7.87 (1H, d, J=1.8 Hz), 7.94 (1H, d, J=15.8 Hz). MS (ESI) m/z 386 (M+H)+ .Step 1 In a solution of 5-bromo-2-methylbenzonitrile (2.00g) in carbon tetrachloride (20mL), add N-bromosuccinimide (1.80g) and 2,2-azobis( Isobutyronitrile) (0.08g), heated to reflux for 6 hours. After standing to cool, the reaction solution was filtered through Celite, and the solvent of the filtrate was distilled off under reduced pressure to obtain 5-bromo-2-(bromomethyl)benzonitrile. Using the 5-bromo-2-(bromomethyl)benzonitrile obtained above, instead of 4-bromo-2-methylbenzyl bromide used in step 1 of Example 33, proceed with step 1 of Example 33. The same operation as in step 3 was performed to obtain the labeled compound (0.91 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.50 (3H, t, J=7.3 Hz), 2.85 (3H, s), 3.34 (4H, s), 4.35 (2H, q, J=7.3 Hz), 4.61 (2H, s), 7.11 (1H, d, J=15.8 Hz), 7.28-7.33 (2H, m), 7.34-7.39 (1H, m), 7.58 (1H, d, J=8.2 Hz), 7.74- 7.80 (2H, m), 7.87 (1H, d, J=1.8 Hz), 7.94 (1H, d, J=15.8 Hz). MS (ESI) m/z 386 (M+H) + .
實施例39：(E)-1-(4-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)-2-甲氧基苄基)-3-甲基咪唑啶-2-酮Example 39: (E)-1-(4-(2-(1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl)-2-methoxybenzyl)-3- Methylimidazolidin-2-one
使用4-溴-1-(溴甲基)-2-甲氧基苯，而取代實施例33的步驟1所使用之4-溴-2-甲基苄基溴，進行與實施例33的步驟1至步驟3同樣的操作，獲得標記化合物(1.07g)。1 H NMR (400MHz, CDCl3 ) δ: 1.49 (3H, t, J=7.3 Hz), 2.82 (3H, s), 3.23-3.29 (4H, m), 3.89 (3H, s), 4.34 (2H, q, J=7.3 Hz), 4.43 (2H, s), 7.01-7.08 (2H, m), 7.22-7.25 (1H, m), 7.26-7.38 (4H, m), 7.74-7.80 (1H, m), 7.96 (1H, d, J=15.7 Hz). MS (ESI) m/z 391 (M+H)+ .Using 4-bromo-1-(bromomethyl)-2-methoxybenzene instead of 4-bromo-2-methylbenzyl bromide used in step 1 of Example 33, proceed to the same steps as in Example 33 The same operation from 1 to 3 was performed to obtain the labeled compound (1.07 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.49 (3H, t, J=7.3 Hz), 2.82 (3H, s), 3.23-3.29 (4H, m), 3.89 (3H, s), 4.34 (2H, q, J=7.3 Hz), 4.43 (2H, s), 7.01-7.08 (2H, m), 7.22-7.25 (1H, m), 7.26-7.38 (4H, m), 7.74-7.80 (1H, m) , 7.96 (1H, d, J=15.7 Hz). MS (ESI) m/z 391 (M+H) + .
實施例40：(E)-1-((5-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)噻吩-2-基)甲基)-3-甲基咪唑啶-2-酮Example 40: (E)-1-((5-(2-(1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl)thiophen-2-yl)methyl)-3 -Methylimidazolidin-2-one
步驟1 (E)-5-(3-((2-(乙胺基)苯基)胺基)-3-側氧基丙烯-1-基)噻吩-2-羧酸甲酯 冰冷下，在參考例6的步驟2所得之N-乙基苯-1,2-二胺(1.28g)及(E)-3-(5-(甲氧羰基)噻吩-2-基)丙烯酸(Ref.JournalofMedicinalChemistry,2009,52,8,2265-2279)(2.00g)的N,N-二甲基甲醯胺(30mL)溶液中，添加N,N-二異丙基乙胺(4.8mL)及O-(7-氮雜苯并***-1-基)-N,N,N’,N’-四甲基脲六氟磷酸鹽(4.30g)。以室溫攪拌1小時後，在反應液中添加水，以乙酸乙酯進行萃取。以飽和食鹽水清洗萃取液，以硫酸鈉進行乾燥。在減壓下餾去溶劑，獲得標記化合物(2.80g)作為粗產物。 MS (ESI) m/z 331 (M+H)+ .Step 1 (E)-5-(3-((2-(Ethylamino)phenyl)amino)-3-oxopropen-1-yl)thiophene-2-carboxylic acid methyl ester under ice cooling, N-ethylbenzene-1,2-diamine (1.28g) and (E)-3-(5-(methoxycarbonyl)thiophen-2-yl)acrylic acid (Ref.JournalofMedicinalChemistry) obtained in step 2 of Reference Example 6 ,2009,52,8,2265-2279)(2.00g) in N,N-dimethylformamide (30mL) solution, add N,N-diisopropylethylamine (4.8mL) and O- (7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (4.30g). After stirring at room temperature for 1 hour, water was added to the reaction solution, and extraction was performed with ethyl acetate. The extract was washed with saturated brine and dried with sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (2.80 g) as a crude product. MS (ESI) m/z 331 (M+H) + .
步驟2 (E)-5-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)噻吩-2-羧酸甲酯 室溫下，在由上述步驟1所得之(E)-5-(3-((2-(乙胺基)苯基)胺基)-3-側氧基丙烯-1-基)噻吩-2-羧酸甲酯(2.80g)中添加乙酸(20mL)，以80℃攪拌30分鐘。放置冷卻後，減壓下，餾去反應溶劑，將殘渣以胺基矽膠管柱層析法(n-己烷/乙酸乙酯)進行純化，獲得標記化合物(1.60g)。1 H NMR (400MHz, CDCl3 ) δ: 1.48 (3H, t, J=7.3 Hz), 3.91 (3H, s), 4.32 (2H, q, J=7.3 Hz), 7.00 (1H, d, J=15.6 Hz), 7.21 (1H, d, J=3.9 Hz), 7.27-7.32 (2H, m), 7.33-7.38 (1H, m), 7.72 (1H, d, J=3.9 Hz), 7.74-7.79 (1H, m), 8.06 (1H, d, J=15.6 Hz).Step 2 (E)-5-(2-(1-Ethyl-1H-benzo[d]imidazol-2-yl)vinyl)thiophene-2-carboxylic acid methyl ester at room temperature, in step 1 The resulting (E)-5-(3-((2-(ethylamino)phenyl)amino)-3-oxopropen-1-yl)thiophene-2-carboxylic acid methyl ester (2.80g) Acetic acid (20 mL) was added to the mixture, and the mixture was stirred at 80°C for 30 minutes. After leaving to cool, the reaction solvent was distilled off under reduced pressure, and the residue was purified by amino silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (1.60 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.48 (3H, t, J=7.3 Hz), 3.91 (3H, s), 4.32 (2H, q, J=7.3 Hz), 7.00 (1H, d, J= 15.6 Hz), 7.21 (1H, d, J=3.9 Hz), 7.27-7.32 (2H, m), 7.33-7.38 (1H, m), 7.72 (1H, d, J=3.9 Hz), 7.74-7.79 ( 1H, m), 8.06 (1H, d, J=15.6 Hz).
步驟3 (E)-(5-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)噻吩-2-基)甲醇 在-78℃，在由上述步驟2所得之(E)-5-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)噻吩-2-羧酸甲酯(1.50g)的甲苯(40mL)溶液中，添加二異丁基氫化鋁(n-己烷溶液，1.5 mol/L，6.15mL)，攪拌2小時。在反應液中添加甲醇及飽和酒石酸鈉鉀水溶液，攪拌1小時。再添加水並以乙酸乙酯進行萃取。以飽和食鹽水清洗萃取液，以硫酸鈉進行乾燥。在減壓下餾去溶劑，將殘渣以胺基矽膠管柱層析法(n-己烷/乙酸乙酯)進行純化，獲得標記化合物(0.72g)。1 H NMR (400MHz, CDCl3 ) δ: 1.47 (3H, t, J=7.3 Hz), 4.29 (2H, q, J=7.3 Hz), 4.84 (2H, d, J=5.6 Hz), 6.81 (1H, d, J=15.7 Hz), 6.94 (1H, br s), 7.10 (1H, d, J=3.6 Hz), 7.27-7.28 (1H, m), 7.25-7.26 (2H, m), 7.31-7.37 (1H, m), 7.70-7.78 (1H, m), 8.04 (1H, d, J=15.6 Hz). MS (ESI) m/z 285 (M+H)+ .Step 3 (E)-(5-(2-(1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl)thiophen-2-yl)methanol at -78°C, after 2 The obtained (E)-5-(2-(1-ethyl-1H-benzo(d)imidazol-2-yl)vinyl)thiophene-2-carboxylic acid methyl ester (1.50g) in toluene (40mL ) Add diisobutylaluminum hydride (n-hexane solution, 1.5 mol/L, 6.15 mL) to the solution, and stir for 2 hours. Methanol and saturated sodium potassium tartrate aqueous solution were added to the reaction liquid, and stirred for 1 hour. Water was added and extraction was performed with ethyl acetate. The extract was washed with saturated brine and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by amino silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (0.72 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.47 (3H, t, J=7.3 Hz), 4.29 (2H, q, J=7.3 Hz), 4.84 (2H, d, J=5.6 Hz), 6.81 (1H , d, J=15.7 Hz), 6.94 (1H, br s), 7.10 (1H, d, J=3.6 Hz), 7.27-7.28 (1H, m), 7.25-7.26 (2H, m), 7.31-7.37 (1H, m), 7.70-7.78 (1H, m), 8.04 (1H, d, J=15.6 Hz). MS (ESI) m/z 285 (M+H) + .
步驟4 (E)-(5-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)噻吩-2-基)甲醛((E)-(5-(2-(1-ethyl-1H-benzo[d]imidazole-2-ly) vinyl)thiophene-2-ly)carbaldehyde) 室溫下，在由上述步驟3所得之(E)-(5-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)噻吩-2-基)甲醇(0.42g)的二氯甲烷(10mL)溶液中，添加1,1,1-三乙醯氧基-1,1-二氫-1,2-苯碘醯-3(1H)-酮(0.75g)，攪拌30分鐘。在反應液添加飽和碳酸氫鈉水，以乙酸乙酯進行萃取。以飽和食鹽水清洗萃取液，以硫酸鈉進行乾燥。在減壓下餾去溶劑，將殘渣以矽膠管柱層析法(n-己烷/乙酸乙酯)進行純化，獲得標記化合物(0.40g)。1 H NMR (400MHz, CDCl3 ) δ: 1.49 (3H, t, J=7.3 Hz), 4.33 (2H, q, J=7.4 Hz), 7.09 (1H, d, J=15.4 Hz), 7.27-7.32 (3H, m), 7.35-7.40 (1H, m), 7.71 (1H, d, J=4.0 Hz), 7.75-7.80 (1H, m), 8.10 (1H, d, J=15.6 Hz), 9.91 (1H, s). MS (ESI) m/z 283 (M+H)+ .Step 4 (E)-(5-(2-(1-ethyl-1H-benzo(d)imidazol-2-yl)vinyl)thiophen-2-yl)carbaldehyde ((E)-(5-( 2-(1-ethyl-1H-benzo[d]imidazole-2-ly) vinyl)thiophene-2-ly)carbaldehyde) at room temperature, in the (E)-(5-(2- (1-Ethyl-1H-benzo[d]imidazol-2-yl)vinyl)thiophen-2-yl)methanol (0.42g) in dichloromethane (10mL), add 1,1,1- Triacetoxy-1,1-dihydro-1,2-phenyliodonium-3(1H)-one (0.75g), stirred for 30 minutes. Saturated sodium bicarbonate water was added to the reaction liquid, and extraction was performed with ethyl acetate. The extract was washed with saturated brine and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (0.40 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.49 (3H, t, J=7.3 Hz), 4.33 (2H, q, J=7.4 Hz), 7.09 (1H, d, J=15.4 Hz), 7.27-7.32 (3H, m), 7.35-7.40 (1H, m), 7.71 (1H, d, J=4.0 Hz), 7.75-7.80 (1H, m), 8.10 (1H, d, J=15.6 Hz), 9.91 ( 1H, s). MS (ESI) m/z 283 (M+H) + .
步驟5 (E)-tert-丁基(2-(((5-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)噻吩-2-基)甲基)胺基)乙基)(甲基)胺甲酸酯 在由上述步驟4所得之(E)-(5-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)噻吩-2-基)甲醛(0.40g)的二氯甲烷(7.0mL)溶液中，添加N-(tert-丁氧羰基)-N-甲基-1,2-乙烯二胺(0.49g)及氫化三乙醯氧基硼鈉(0.90g)，攪拌18小時。在減壓下餾去反應溶劑，將殘渣以矽膠管柱層析法(氯仿/甲醇)進行純化，獲得標記化合物(0.54g)。 1H NMR (400MHz, CDCl3 ) δ: 1.42-1.51 (12H, m), 2.81-2.94 (7H, m), 4.01 (2H, s), 4.28 (2H, q, J=7.3 Hz), 6.78 (1H, d, J=15.6 Hz), 6.85 (1H, d, J=3.8 Hz), 7.07 (1H, d, J=3.8 Hz), 7.24-7.27 (2H, m), 7.30-7.35 (1H, m), 7.71-7.77 (1H, m), 8.04 (1H, d, J=15.6 Hz). MS (ESI) m/z 441 (M+H)+ .Step 5 (E)-tert-butyl(2-(((5-(2-(1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl)thiophen-2-yl)methan (E)-(5-(2-(1-ethyl-1H-benzo[d]imidazole-2-) obtained from step 4 above. Add N-(tert-butoxycarbonyl)-N-methyl-1,2-ethylene diamine to a dichloromethane (7.0 mL) solution of (methyl) vinyl) thiophen-2-yl) formaldehyde (0.40 g) (0.49g) and sodium triacetoxyborohydride (0.90g), stirred for 18 hours. The reaction solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol) to obtain the title compound (0.54 g). 1H NMR (400MHz, CDCl 3 ) δ: 1.42-1.51 (12H, m), 2.81-2.94 (7H, m), 4.01 (2H, s), 4.28 (2H, q, J=7.3 Hz), 6.78 (1H , d, J=15.6 Hz), 6.85 (1H, d, J=3.8 Hz), 7.07 (1H, d, J=3.8 Hz), 7.24-7.27 (2H, m), 7.30-7.35 (1H, m) , 7.71-7.77 (1H, m), 8.04 (1H, d, J=15.6 Hz). MS (ESI) m/z 441 (M+H) + .
步驟6 (E)-1-((5-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)噻吩-2-基)甲基)-3-甲基咪唑啶-2-酮 對由上述步驟5所得之(E)-tert-丁基(2-(((5-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)噻吩-2-基)甲基)胺基)乙基)(甲基)胺甲酸酯(0.52g)添加氯化氫(4mol/L，乙酸乙酯溶液，10mL)。攪拌30分鐘後，在減壓下餾去溶劑。室溫下，在殘渣中添加四氫呋喃(11.0mL)、三乙胺(0.35mL)及1,1-羰基二咪唑(0.22g)，攪拌1小時。在反應液中添加飽和碳酸氫鈉水並以乙酸乙酯進行萃取。以水及飽和食鹽水清洗萃取液，以硫酸鈉進行乾燥。在減壓下餾去溶劑，將殘渣以胺基矽膠管柱層析法(n-己烷/乙酸乙酯)進行純化，獲得標記化合物(0.29g)。1 H NMR (400MHz, CDCl3 ) δ: 1.46 (3H, t, J=7.3 Hz), 2.85 (3H, s), 3.26-3.33 (4H, m), 4.28 (2H, q, J=7.4 Hz), 4.53 (2H, s), 6.78 (1H, d, J=15.4 Hz), 6.88 (1H, d, J=3.5 Hz), 7.05 (1H, d, J=3.5 Hz), 7.25-7.26 (2H, m), 7.31-7.36 (1H, m), 7.71-7.76 (1H, m), 8.04 (1H, d, J=15.4 Hz). MS (ESI) m/z 367 (M+H)+ .Step 6 (E)-1-((5-(2-(1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl)thiophen-2-yl)methyl)-3-methyl (E)-tert-butyl(2-(((5-(2-(1-ethyl-1H-benzo[d]imidazole-2- (Yl)vinyl)thiophen-2-yl)methyl)amino)ethyl)(methyl)carbamate (0.52g) was added with hydrogen chloride (4mol/L, ethyl acetate solution, 10mL). After stirring for 30 minutes, the solvent was distilled off under reduced pressure. Tetrahydrofuran (11.0 mL), triethylamine (0.35 mL), and 1,1-carbonyldiimidazole (0.22 g) were added to the residue at room temperature, and the mixture was stirred for 1 hour. Saturated sodium bicarbonate water was added to the reaction liquid, and extraction was performed with ethyl acetate. The extract was washed with water and saturated brine, and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by amino silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (0.29 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.46 (3H, t, J=7.3 Hz), 2.85 (3H, s), 3.26-3.33 (4H, m), 4.28 (2H, q, J=7.4 Hz) , 4.53 (2H, s), 6.78 (1H, d, J=15.4 Hz), 6.88 (1H, d, J=3.5 Hz), 7.05 (1H, d, J=3.5 Hz), 7.25-7.26 (2H, m), 7.31-7.36 (1H, m), 7.71-7.76 (1H, m), 8.04 (1H, d, J=15.4 Hz). MS (ESI) m/z 367 (M+H) + .
實施例41：(E)-1-((5-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)噻唑-2-基)甲基)-3-甲基咪唑啶-2-酮Example 41: (E)-1-((5-(2-(1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl)thiazol-2-yl)methyl)-3 -Methylimidazolidin-2-one
步驟1 5-(溴甲基)噻唑-2-羧酸甲酯 在5-甲基噻唑-2-羧酸甲酯(1.00g)的二氯甲烷(20mL)溶液中，添加N-溴琥珀醯亞胺(3.40g)及2,2’-偶氮雙異丁腈(0.11g)，以80℃加熱1小時。放置冷卻後，在反應液中添加水，以乙酸乙酯進行萃取。以飽和食鹽水清洗萃取液，以硫酸鈉進行乾燥。在減壓下餾去溶劑，將殘渣以矽膠管柱層析法(n-己烷/乙酸乙酯)進行純化，獲得標記化合物(0.68g)。1 H NMR (400MHz, CDCl3 ) δ: 4.01 (3H, s), 4.71 (2H, d, J=0.8 Hz), 7.94 (1H, s). MS (ESI) m/z 236 (M+H)+ .Step 1 Methyl 5-(bromomethyl)thiazole-2-carboxylate is added to a solution of methyl 5-methylthiazole-2-carboxylate (1.00g) in dichloromethane (20mL) and N-bromosuccinate Imine (3.40g) and 2,2'-azobisisobutyronitrile (0.11g) were heated at 80°C for 1 hour. After leaving to cool, water was added to the reaction solution, and extraction was performed with ethyl acetate. The extract was washed with saturated brine and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (0.68 g). 1 H NMR (400MHz, CDCl 3 ) δ: 4.01 (3H, s), 4.71 (2H, d, J=0.8 Hz), 7.94 (1H, s). MS (ESI) m/z 236 (M+H) + .
步驟2
5-(羥基甲基)噻唑-2-羧酸甲酯
室溫下，在由上述步驟1所得之5-(溴甲基)噻唑-2-羧酸甲酯(0.90g)的1,4-二
步驟3 5-甲醯基噻唑-2-羧酸甲酯 在由上述步驟2所得之5-(羥基甲基)噻唑-2-羧酸甲酯(0.32g)的二氯甲烷(10mL)溶液中，添加1,1,1-三乙醯氧基-1,1-二氫-1,2-苯并碘醯(benzoiodoxol)-3-(1H)-酮(0.94g)，攪拌2小時。在反應液中添加水，以乙酸乙酯進行萃取。以飽和食鹽水清洗萃取液，以硫酸鈉進行乾燥。在減壓下餾去溶劑，將殘渣以矽膠管柱層析法(n-己烷/乙酸乙酯)進行純化，獲得標記化合物(0.27g)。1 H NMR (400MHz, CDCl3 ) δ: 4.06 (3H, s), 8.56 (1H, s), 10.13 (1H, s). MS (ESI) m/z 172 (M+H)+ .Step 3 5-methylthiazole-2-carboxylic acid methyl ester in dichloromethane (10mL) solution of 5-(hydroxymethyl)thiazole-2-carboxylic acid methyl ester (0.32g) obtained from step 2 above , Add 1,1,1-triacetyloxy-1,1-dihydro-1,2-benzoiodoxol-3-(1H)-one (0.94g), and stir for 2 hours. Water was added to the reaction liquid, and extraction was performed with ethyl acetate. The extract was washed with saturated brine and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (0.27 g). 1 H NMR (400MHz, CDCl 3 ) δ: 4.06 (3H, s), 8.56 (1H, s), 10.13 (1H, s). MS (ESI) m/z 172 (M+H) + .
步驟4 5-[(E)-3-tert-丁氧基-3-側氧基丙烯-1-基]噻唑-2-羧酸甲酯 在由上述步驟3所得之5-甲醯基噻唑-2-羧酸甲酯(0.26g)的四氫呋喃(5.0mL)溶液中，添加(tert-丁氧羰基亞甲基)三苯基正膦(0.74g)，以60℃攪拌1小時。放置冷卻後，在減壓下餾去反應溶劑，將殘渣以矽膠管柱層析法(n-己烷/乙酸乙酯)進行純化，獲得標記化合物(0.38g)。 1H NMR (400MHz, CDCl3 ) δ: 1.53 (9H, s), 4.02 (3H, s), 6.32 (1H, d, J=15.8 Hz), 7.67 (1H, d, J=15.8 Hz), 8.04 (1H, s). MS (ESI) m/z 270 (M+H)+ .Step 4 5-[(E)-3-tert-butoxy-3-oxopropen-1-yl]thiazole-2-carboxylic acid methyl ester is used in the 5-methylthiazole- To a tetrahydrofuran (5.0 mL) solution of methyl 2-carboxylate (0.26 g), (tert-butoxycarbonylmethylene)triphenylphosphorane (0.74 g) was added, and the mixture was stirred at 60°C for 1 hour. After leaving to cool, the reaction solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (0.38 g). 1H NMR (400MHz, CDCl 3 ) δ: 1.53 (9H, s), 4.02 (3H, s), 6.32 (1H, d, J=15.8 Hz), 7.67 (1H, d, J=15.8 Hz), 8.04 ( 1H, s). MS (ESI) m/z 270 (M+H) + .
步驟5 (E)-3-(2-甲氧羰基噻唑-5-基)-2-丙烯酸 在由上述步驟4所得之5-[(E)-3-tert-丁氧基-3-側氧基丙烯-1-基]噻唑-2-羧酸甲酯(0.38g)的二氯甲烷(0.5mL)溶液中，添加三氟乙酸(2.0mL)，攪拌1小時。在減壓下餾去溶劑，獲得標記化合物(0.29g)。 1H-NMR (400MHz, DMSO-d6 ) δ: 3.93 (3H, s), 6.52 (1H, d, J=15.8 Hz), 7.84 (1H, d, J=15.8 Hz), 8.43 (1H, s). MS (ESI) m/z 214 (M+H)+ .Step 5 (E)-3-(2-Methoxycarbonylthiazol-5-yl)-2-acrylic acid is added to the 5-[(E)-3-tert-butoxy-3- pendant oxygen obtained in step 4 above To a solution of methyl propen-1-yl]thiazole-2-carboxylate (0.38 g) in dichloromethane (0.5 mL), trifluoroacetic acid (2.0 mL) was added, and the mixture was stirred for 1 hour. The solvent was distilled off under reduced pressure to obtain the title compound (0.29 g). 1H-NMR (400MHz, DMSO-d 6 ) δ: 3.93 (3H, s), 6.52 (1H, d, J=15.8 Hz), 7.84 (1H, d, J=15.8 Hz), 8.43 (1H, s) . MS (ESI) m/z 214 (M+H) + .
步驟6 5-[(E)-2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基]噻唑-2-羧酸甲酯 在實施例40的步驟1中，使用由上述步驟5所得之(E)-3-(2-甲氧羰基噻唑-5-基)-2-丙烯酸，而取代(E)-3-(5-(甲氧羰基)噻吩-2-基)丙烯酸，進行與實施例40的步驟1同樣的操作。使用所得之化合物，而取代(E)-5-(3-((2-(乙胺基)苯基)胺基)-3-側氧基丙烯-1-基)噻吩-2-羧酸甲酯，進行與實施例40的步驟2同樣的操作，獲得標記化合物(0.31g)。 1H NMR (400MHz, CDCl3 ) δ: 1.49 (3H, t, J=7.3 Hz), 4.04 (3H, s), 4.33 (2H, q, J=7.3 Hz), 7.03 (1H, d, J=15.6 Hz), 7.28-7.33 (2H, m), 7.34-7.40 (1H, m), 7.75-7.81 (1H, m), 8.06 (1H, s), 8.10 (1H, d, J=15.6 Hz). MS (ESI) m/z 314 (M+H)+ .Step 6 5-[(E)-2-(1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl]thiazole-2-carboxylic acid methyl ester In step 1 of Example 40, Use (E)-3-(2-methoxycarbonylthiazol-5-yl)-2-acrylic acid obtained from step 5 above, instead of (E)-3-(5-(methoxycarbonyl)thiophene-2- (Base) acrylic acid, the same operation as in step 1 of Example 40 was performed. Use the obtained compound, and substituted (E)-5-(3-((2-(ethylamino)phenyl)amino)-3-oxopropen-1-yl)thiophene-2-carboxylic acid methyl For the ester, the same operation as in Step 2 of Example 40 was performed to obtain the labeled compound (0.31 g). 1H NMR (400MHz, CDCl 3 ) δ: 1.49 (3H, t, J=7.3 Hz), 4.04 (3H, s), 4.33 (2H, q, J=7.3 Hz), 7.03 (1H, d, J=15.6 Hz), 7.28-7.33 (2H, m), 7.34-7.40 (1H, m), 7.75-7.81 (1H, m), 8.06 (1H, s), 8.10 (1H, d, J=15.6 Hz). MS (ESI) m/z 314 (M+H) + .
步驟7 [5-[(E)-2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基]噻唑-2-基]甲醇 在上述由步驟6所得之5-[(E)-2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基]噻唑-2-羧酸甲酯(0.31g)的甲醇(3.3mL)溶液中，添加硼氫化鈉(40mg)，攪拌30分鐘。在減壓下餾去溶劑，將殘渣以矽膠管柱層析法(氯仿/甲醇)進行純化，獲得標記化合物(0.24g)。 1H NMR (400MHz, CDCl3 ) δ: 1.47 (3H, t, J=7.3 Hz), 2.93 (1H, br s), 4.30 (2H, q, J=7.3 Hz), 4.95 (2H, s), 6.80 (1H, d, J=15.6 Hz), 7.27-7.31 (14H, m), 7.32-7.37 (1H, m), 7.74-7.78 (1H, m), 7.80 (1H, s), 8.04 (1H, d, J=15.6 Hz). MS (ESI) m/z 286 (M+H)+ .Step 7 [5-[(E)-2-(1-Ethyl-1H-benzo[d]imidazol-2-yl)vinyl]thiazol-2-yl]methanol in the 5- [(E)-2-(1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl]thiazole-2-carboxylic acid methyl ester (0.31g) in methanol (3.3mL) solution, Sodium borohydride (40 mg) was added and stirred for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol) to obtain the title compound (0.24 g). 1H NMR (400MHz, CDCl 3 ) δ: 1.47 (3H, t, J=7.3 Hz), 2.93 (1H, br s), 4.30 (2H, q, J=7.3 Hz), 4.95 (2H, s), 6.80 (1H, d, J=15.6 Hz), 7.27-7.31 (14H, m), 7.32-7.37 (1H, m), 7.74-7.78 (1H, m), 7.80 (1H, s), 8.04 (1H, d) , J=15.6 Hz). MS (ESI) m/z 286 (M+H) + .
步驟8 (E)-1-((5-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)噻唑-2-基)甲基)-3-甲基咪唑啶-2-酮 使用上述步驟7所得之[5-[(E)-2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基]噻唑-2-基]甲醇，而取代實施例40的步驟3中所得之(E)-(5-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)噻吩-2-基)甲醇，進行與實施例40的步驟4至步驟6同樣的操作，獲得標記化合物(0.13g)。1 H NMR (400MHz, CDCl3 ) δ: 1.46 (3H, t, J=7.3 Hz), 2.87 (3H, s), 3.34-3.44 (4H, m), 4.29 (2H, q, J=7.3 Hz), 4.68 (2H, s), 6.79 (1H, d, J=15.4 Hz), 7.26-7.31 (2H, m), 7.33-7.37 (1H, m), 7.72-7.78 (2H, m), 8.07 (1H, d, J=15.1 Hz). MS (ESI) m/z 368 (M+H)+ .Step 8 (E)-1-((5-(2-(1-Ethyl-1H-benzo(d)imidazol-2-yl)vinyl)thiazol-2-yl)methyl)-3-methyl [5-[(E)-2-(1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl]thiazol-2-yl obtained from step 7 above ] Methanol instead of (E)-(5-(2-(1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl)thiophene-2- obtained in step 3 of Example 40 Based on methanol, the same operations as in step 4 to step 6 of Example 40 were performed to obtain the labeled compound (0.13 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.46 (3H, t, J=7.3 Hz), 2.87 (3H, s), 3.34-3.44 (4H, m), 4.29 (2H, q, J=7.3 Hz) , 4.68 (2H, s), 6.79 (1H, d, J=15.4 Hz), 7.26-7.31 (2H, m), 7.33-7.37 (1H, m), 7.72-7.78 (2H, m), 8.07 (1H , d, J=15.1 Hz). MS (ESI) m/z 368 (M+H) + .
實施例42：(E)-1-(5-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)-2,3-二氫-1H-茚-1-基)-3-甲基咪唑啶-2-酮Example 42: (E)-1-(5-(2-(1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl)-2,3-dihydro-1H-indene- 1-yl)-3-methylimidazolidin-2-one
步驟1 tert-丁基(2-((5-溴-2,3-二氫-1H-茚-1-基)胺基)乙基)(甲基)胺甲酸酯 在5-溴-1-二氫茚酮(1.50g)的二氯甲烷溶液(15mL)中，添加tert-丁基-N-(2-胺基乙基)-N-甲基胺甲酸酯(1.30g)及氫化三乙醯氧基硼鈉(1.81g)，攪拌26小時。添加水及飽和碳酸氫鈉水，以乙酸乙酯進行萃取。以飽和食鹽水清洗萃取液，以硫酸鈉進行乾燥。在減壓下餾去溶劑，將殘渣以矽膠管柱層析法(氯仿/甲醇)進行純化，獲得標記化合物(0.81g)。 MS (ESI) m/z 369 (M+H)+ .Step 1 tert-butyl(2-((5-bromo-2,3-dihydro-1H-inden-1-yl)amino)ethyl)(methyl)carbamate in 5-bromo-1 -Indanone (1.50g) in dichloromethane solution (15mL), add tert-butyl-N-(2-aminoethyl)-N-methyl carbamate (1.30g) and hydrogenate Sodium triacetoxyboron (1.81 g) was stirred for 26 hours. Add water and saturated sodium bicarbonate water, and extract with ethyl acetate. The extract was washed with saturated brine and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol) to obtain the title compound (0.81 g). MS (ESI) m/z 369 (M+H) + .
步驟2
1-(5-溴-2,3-二氫-1H-茚-1-基)-3-甲基咪唑啶-2-酮
在上述步驟1所得之tert-丁基(2-((5-溴-2,3-二氫-1H-茚-1-基)胺基)乙基)(甲基)胺甲酸酯(0.81g)的甲醇(8mL)溶液中，添加氯化氫(4mol/L，1,4-二
步驟3
(E)-1-(5-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)-2,3-二氫-1H-茚-1-基)-3-甲基咪唑啶-2-酮
在上述步驟2所得之1-(5-溴-2,3-二氫-1H-茚-1-基)-3-甲基咪唑啶-2-酮(0.48g)的甲苯(5mL)溶液中，添加三乙胺(0.57mL)、4,4,5,5-四甲基-2-乙烯基-1,3,2-二氧硼戊環(0.31mL)及雙(三-tert-丁基膦)鈀(0)(0.04g)，以90℃攪拌2小時。在反應液中添加水，以氯仿進行萃取。將萃取液以硫酸鈉進行乾燥，減壓下，餾去溶劑。在殘渣中添加1,4-二
實施例43：(E)-1-(1-(4-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)苯基)乙基)-3-甲基咪唑啶-2-酮Example 43: (E)-1-(1-(4-(2-(1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl)phenyl)ethyl)-3- Methylimidazolidin-2-one
使用參考例10的步驟2所得之1-[1-(4-溴苯基)乙基]-3-甲基咪唑啶-2-酮，而取代實施例42的步驟2所得之1-(5-溴-2,3-二氫-1H-茚-1-基)-3-甲基咪唑啶-2-酮，進行與實施例42的步驟3同樣的操作，獲得標記化合物(0.46g)。1 H NMR (400MHz, CDCl3 ) δ: 1.48 (3H, t, J=7.3 Hz), 1.54 (3H, d, J=7.2 Hz), 2.79-2.82 (1H, m), 2.81 (3H, s), 2.87-2.98 (1H, m), 3.18-3.31 (3H, m), 4.33 (2H, q, J=7.3 Hz), 5.29 (1H, q, J=7.2 Hz), 7.06 (1H, d, J=15.8 Hz), 7.26-7.30 (2H, m), 7.33-7.36 (1H, m), 7.37 (2H, d, J=8.2 Hz), 7.58 (2H, d, J=8.2 Hz), 7.75-7.80 (1H, m), 7.98 (1H, d, J=15.8 Hz). MS (ESI) m/z 375 (M+H)+ .The 1-[1-(4-bromophenyl)ethyl]-3-methylimidazolidin-2-one obtained in Step 2 of Reference Example 10 was used instead of the 1-(5) obtained in Step 2 of Example 42 -Bromo-2,3-dihydro-1H-inden-1-yl)-3-methylimidazolidin-2-one, and the same operation as in step 3 of Example 42 was performed to obtain the labeled compound (0.46 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.48 (3H, t, J=7.3 Hz), 1.54 (3H, d, J=7.2 Hz), 2.79-2.82 (1H, m), 2.81 (3H, s) , 2.87-2.98 (1H, m), 3.18-3.31 (3H, m), 4.33 (2H, q, J=7.3 Hz), 5.29 (1H, q, J=7.2 Hz), 7.06 (1H, d, J =15.8 Hz), 7.26-7.30 (2H, m), 7.33-7.36 (1H, m), 7.37 (2H, d, J=8.2 Hz), 7.58 (2H, d, J=8.2 Hz), 7.75-7.80 (1H, m), 7.98 (1H, d, J=15.8 Hz). MS (ESI) m/z 375 (M+H) + .
實施例44：(E)-1-(1-(4-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)苯基)環丙基)-3-甲基咪唑啶-2-酮Example 44: (E)-1-(1-(4-(2-(1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl)phenyl)cyclopropyl)-3 -Methylimidazolidin-2-one
使用參考例11的步驟2所得之1-[1-(4-溴苯基)環丙基]-3-甲基咪唑啶-2-酮，而取代實施例42的步驟2所得之1-(5-溴-2,3-二氫-1H-茚-1-基)-3-甲基咪唑啶-2-酮，進行與實施例42的步驟3同樣的操作，獲得標記化合物(0.53g)。1 H NMR (400MHz, CDCl3 ) δ: 1.18-1.24 (2H, m), 1.34-1.39 (2H, m), 1.47 (3H, t, J=7.2 Hz), 2.78 (3H, s), 3.23-3.38 (4H, m), 4.31 (2H, q, J=7.3 Hz), 7.03 (1H, d, J=15.8 Hz), 7.25-7.28 (2H, m), 7.28-7.36 (3H, m), 7.54 (2H, d, J=8.3 Hz), 7.74-7.79 (1H, m), 7.96 (1H, d, J=15.8 Hz). MS (ESI) m/z 387 (M+H)+ .The 1-[1-(4-bromophenyl)cyclopropyl]-3-methylimidazolidin-2-one obtained in step 2 of Reference Example 11 was used instead of the 1-( 5-bromo-2,3-dihydro-1H-inden-1-yl)-3-methylimidazolidin-2-one, and the same operation as in step 3 of Example 42 was performed to obtain the labeled compound (0.53 g) . 1 H NMR (400MHz, CDCl 3 ) δ: 1.18-1.24 (2H, m), 1.34-1.39 (2H, m), 1.47 (3H, t, J=7.2 Hz), 2.78 (3H, s), 3.23- 3.38 (4H, m), 4.31 (2H, q, J=7.3 Hz), 7.03 (1H, d, J=15.8 Hz), 7.25-7.28 (2H, m), 7.28-7.36 (3H, m), 7.54 (2H, d, J=8.3 Hz), 7.74-7.79 (1H, m), 7.96 (1H, d, J=15.8 Hz). MS (ESI) m/z 387 (M+H) + .
實施例45：(E)-1-(4-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-3-甲基-1H-咪唑-2(3H)-酮Example 45: (E)-1-(4-(2-(1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl)benzyl)-3-methyl-1H-imidazole -2(3H)-ketone
在參考例7的步驟4所得之(E)-2-(4-(氯甲基)苯乙烯基)-1-乙基-1H-苯并[d]咪唑-(0.25g)的N,N-二甲基甲醯胺(3.0mL)溶液中，添加1-甲基-2,3-二氫-1H-咪唑-2-酮(0.12g)及氫化鈉(0.08g，60%油性)，攪拌3小時。在添加乙酸乙酯後，添加飽和碳酸氫鈉水，以水及飽和食鹽水清洗有機層，以硫酸鈉進行乾燥。在減壓下餾去溶劑，將殘渣以胺基矽膠管柱層析法(n-己烷/乙酸乙酯)進行純化，獲得標記化合物(0.18g)。1 H NMR (400MHz, CDCl3 ) δ: 1.45 (3H, t, J=7.3 Hz), 3.28 (3H, s), 4.30 (2H, q, J=7.3 Hz), 4.80 (2H, s), 6.13 (1H, d, J=3.0 Hz), 6.17 (1H, d, J=3.0 Hz), 7.05 (1H, d, J=15.8 Hz), 7.24-7.27 (2H, m), 7.28 (1H, s), 7.30 (1H, s), 7.32-7.35 (1H, m), 7.57 (2H, d, J=8.2 Hz), 7.75-7.79 (1H, m), 7.96 (1H, d, J=15.8 Hz). MS (ESI) m/z 359 (M+H)+ .(E)-2-(4-(chloromethyl)styryl)-1-ethyl-1H-benzo[d]imidazole-(0.25g) N,N obtained in step 4 of Reference Example 7 -In the dimethylformamide (3.0mL) solution, add 1-methyl-2,3-dihydro-1H-imidazol-2-one (0.12g) and sodium hydride (0.08g, 60% oily), Stir for 3 hours. After adding ethyl acetate, saturated sodium bicarbonate water was added, the organic layer was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by amino silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (0.18 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.45 (3H, t, J=7.3 Hz), 3.28 (3H, s), 4.30 (2H, q, J=7.3 Hz), 4.80 (2H, s), 6.13 (1H, d, J=3.0 Hz), 6.17 (1H, d, J=3.0 Hz), 7.05 (1H, d, J=15.8 Hz), 7.24-7.27 (2H, m), 7.28 (1H, s) , 7.30 (1H, s), 7.32-7.35 (1H, m), 7.57 (2H, d, J=8.2 Hz), 7.75-7.79 (1H, m), 7.96 (1H, d, J=15.8 Hz). MS (ESI) m/z 359 (M+H) + .
實施例46：(E)-1-(4-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)苄基)吡咯啶-2-酮Example 46: (E)-1-(4-(2-(1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl)benzyl)pyrrolidin-2-one
在實施例45中，使用2-吡咯啶，取代1-甲基-2,3-二氫-1H-咪唑-2-酮，而進行同樣的反應，獲得標記化合物(72mg)。1 H NMR (400MHz, CDCl3 ) δ: 1.46 (3H, t, J=7.3 Hz), 1.96-2.04 (2H, m), 2.45 (2H, t, J=8.1 Hz), 3.28 (2H, t, J=7.0 Hz), 4.31 (2H, q, J=7.3 Hz), 4.47 (2H, s), 7.06 (1H, d, J=15.8 Hz), 7.25-7.29 (4H, m), 7.31-7.36 (1H, m), 7.57 (2H, d, J=8.0 Hz), 7.73-7.80 (1H, m), 7.97 (1H, d, J=15.8 Hz). MS (ESI) m/z 346 (M+H)+ .In Example 45, 2-pyrrolidine was used instead of 1-methyl-2,3-dihydro-1H-imidazol-2-one, and the same reaction was performed to obtain the labeled compound (72 mg). 1 H NMR (400MHz, CDCl 3 ) δ: 1.46 (3H, t, J=7.3 Hz), 1.96-2.04 (2H, m), 2.45 (2H, t, J=8.1 Hz), 3.28 (2H, t, J=7.0 Hz), 4.31 (2H, q, J=7.3 Hz), 4.47 (2H, s), 7.06 (1H, d, J=15.8 Hz), 7.25-7.29 (4H, m), 7.31-7.36 ( 1H, m), 7.57 (2H, d, J=8.0 Hz), 7.73-7.80 (1H, m), 7.97 (1H, d, J=15.8 Hz). MS (ESI) m/z 346 (M+H ) + .
實施例47：(E)-1-(4-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-3-甲基吡咯啶-2-酮Example 47: (E)-1-(4-(2-(1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl)benzyl)-3-methylpyrrolidine-2 -ketone
在實施例45中，使用3-甲基吡咯啶-2-酮，取代1-甲基-2,3-二氫-1H-咪唑-2-酮，而進行同樣的操作，獲得標記化合物(49mg)。1 H NMR (400MHz, CDCl3 ) δ: 1.25 (3H, d, J=7.2 Hz), 1.46 (3H, t, J=7.3 Hz), 1.54-1.67 (1H, m), 2.18-2.27 (1H, m), 2.47-2.59 (1H, m), 3.15-3.24 (2H, m), 4.31 (2H, q, J=7.3 Hz), 4.38-4.54 (2H, m), 7.06 (1H, d, J=15.8 Hz), 7.24-7.29 (4H, m), 7.30-7.37 (1H, m), 7.57 (2H, d, J=8.0 Hz), 7.74-7.82 (1H, m), 7.97 (1H, d, J=15.8 Hz). MS (ESI) m/z 360 (M+H)+ .In Example 45, 3-methylpyrrolidin-2-one was used in place of 1-methyl-2,3-dihydro-1H-imidazol-2-one, and the same operation was performed to obtain the labeled compound (49 mg ). 1 H NMR (400MHz, CDCl 3 ) δ: 1.25 (3H, d, J=7.2 Hz), 1.46 (3H, t, J=7.3 Hz), 1.54-1.67 (1H, m), 2.18-2.27 (1H, m), 2.47-2.59 (1H, m), 3.15-3.24 (2H, m), 4.31 (2H, q, J=7.3 Hz), 4.38-4.54 (2H, m), 7.06 (1H, d, J= 15.8 Hz), 7.24-7.29 (4H, m), 7.30-7.37 (1H, m), 7.57 (2H, d, J=8.0 Hz), 7.74-7.82 (1H, m), 7.97 (1H, d, J =15.8 Hz). MS (ESI) m/z 360 (M+H) + .
實施例48：(E)-1-(4-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)苄基)吡啶-2(1H)-酮Example 48: (E)-1-(4-(2-(1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl)benzyl)pyridine-2(1H)-one
在實施例45中，使用2-羥基吡啶，取代1-甲基-2,3-二氫-1H-咪唑-2-酮，而進行同樣的操作，獲得標記化合物(0.29g)。1 H NMR (400MHz, CDCl3 ) δ: 1.47 (3H, t, J=7.3 Hz), 4.33 (2H, q, J=7.2 Hz), 5.17 (2H, s), 6.17 (1H, td, J=6.7, 1.4 Hz), 6.63 (1H, d, J=9.3 Hz), 7.06 (1H, d, J=15.8 Hz), 7.27-7.37 (7H, m), 7.59 (2H, d, J=8.2 Hz), 7.75-7.79 (1H, m), 7.97 (1H, d, J=15.8 Hz). MS (ESI) m/z 356 (M+H)+ .In Example 45, 2-hydroxypyridine was used in place of 1-methyl-2,3-dihydro-1H-imidazol-2-one, and the same operation was performed to obtain the labeled compound (0.29 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.47 (3H, t, J=7.3 Hz), 4.33 (2H, q, J=7.2 Hz), 5.17 (2H, s), 6.17 (1H, td, J= 6.7, 1.4 Hz), 6.63 (1H, d, J=9.3 Hz), 7.06 (1H, d, J=15.8 Hz), 7.27-7.37 (7H, m), 7.59 (2H, d, J=8.2 Hz) , 7.75-7.79 (1H, m), 7.97 (1H, d, J=15.8 Hz). MS (ESI) m/z 356 (M+H) + .
實施例49：(E)-2-(4-((4-溴-1H-吡唑-1-基)甲基)苯乙烯基)-1-乙基-1H-苯并[d]咪唑Example 49: (E)-2-(4-((4-Bromo-1H-pyrazol-1-yl)methyl)styryl)-1-ethyl-1H-benzo[d]imidazole
在實施例45中，使用4-溴吡唑，取代1-甲基-2,3-二氫-1H-咪唑-2-酮，而進行同樣的操作，獲得標記化合物(0.34g)。1 H NMR (400MHz, CDCl3 ) δ: 1.49 (3H, t, J=7.3 Hz), 3.41-3.51 (2H, m), 4.30-4.38 (4H, m), 4.46 (2H, s), 7.09 (1H, d, J=15.8 Hz), 7.26-7.30 (2H, m), 7.31-7.39 (3H, m), 7.61 (2H, d, J=8.0 Hz), 7.75-7.80 (1H, m), 7.99 (1H, d, J=15.8 Hz). MS (ESI) m/z 407 (M+H)+ .In Example 45, 4-bromopyrazole was used instead of 1-methyl-2,3-dihydro-1H-imidazol-2-one, and the same operation was performed to obtain the labeled compound (0.34 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.49 (3H, t, J=7.3 Hz), 3.41-3.51 (2H, m), 4.30-4.38 (4H, m), 4.46 (2H, s), 7.09 ( 1H, d, J=15.8 Hz), 7.26-7.30 (2H, m), 7.31-7.39 (3H, m), 7.61 (2H, d, J=8.0 Hz), 7.75-7.80 (1H, m), 7.99 (1H, d, J=15.8 Hz). MS (ESI) m/z 407 (M+H) + .
實施例50：(E)-1-(4-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-3-甲基吡啶-2(1H)-酮Example 50: (E)-1-(4-(2-(1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl)benzyl)-3-methylpyridine-2( 1H)-ketone
在實施例45中，使用3-甲基吡啶-2-醇，取代1-甲基-2,3-二氫-1H-咪唑-2-酮，而進行同樣的操作，獲得標記化合物(0.27g)。1 H NMR (400MHz, CDCl3 ) δ: 1.47 (3H, t, J=7.3 Hz), 2.18 (3H, s), 4.32 (2H, q, J=7.3 Hz), 5.17 (2H, s), 6.10 (1H, t, J=6.8 Hz), 7.05 (1H, d, J=15.8 Hz), 7.17-7.23 (2H, m), 7.26-7.29 (2H, m), 7.34 (3H, d, J=8.2 Hz), 7.58 (2H, d, J=8.2 Hz), 7.73-7.80 (1H, m), 7.96 (1H, d, J=15.8 Hz). MS (ESI) m/z 407 (M+H)+ .In Example 45, 3-picoline-2-ol was used in place of 1-methyl-2,3-dihydro-1H-imidazol-2-one, and the same operation was performed to obtain the labeled compound (0.27g ). 1 H NMR (400MHz, CDCl 3 ) δ: 1.47 (3H, t, J=7.3 Hz), 2.18 (3H, s), 4.32 (2H, q, J=7.3 Hz), 5.17 (2H, s), 6.10 (1H, t, J=6.8 Hz), 7.05 (1H, d, J=15.8 Hz), 7.17-7.23 (2H, m), 7.26-7.29 (2H, m), 7.34 (3H, d, J=8.2 Hz), 7.58 (2H, d, J=8.2 Hz), 7.73-7.80 (1H, m), 7.96 (1H, d, J=15.8 Hz). MS (ESI) m/z 407 (M+H) + .
實施例51：(E)-1-(4-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-4-甲基哌
步驟1
1-甲基哌
步驟2
1-(4-溴苄基)-4-甲基哌
步驟3
(E)-1-甲基-4-(4-(2-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)乙烯基)苄基)哌
步驟4
(E)-1-(4-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-4-甲基哌
實施例52：(E)-3-(4-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-1-甲基咪唑啶-2、4-二酮Example 52: (E)-3-(4-(2-(1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl)benzyl)-1-methylimidazolidine-2 , 4-Diketone
使用1-甲基乙內醯脲，而取代1-甲基哌
實施例53：(E)-4-(4-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-1-甲基哌
使用1-甲基哌
實施例54：(E)-1-(4-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-4-甲基-1H-1,2,4-***-5(4H)-酮Example 54: (E)-1-(4-(2-(1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl)benzyl)-4-methyl-1H-1 ,2,4-Triazole-5(4H)-one
使用4-甲基-4,5-二氫-1H-1,2,4-***-5(4H)-酮，而取代實施例51的步驟1所得之1-甲基哌
實施例55：(E)-4-(4-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)苄基)-1-甲基-1H-1,2,4-***-5(4H)-酮Example 55: (E)-4-(4-(2-(1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl)benzyl)-1-methyl-1H-1 ,2,4-Triazole-5(4H)-one
使用1-甲基-4,5-二氫-1H-1,2,4-***-5(4H)-酮，而取代實施例51的步驟1所得之1-甲基哌
實施例56：(E)-1-乙基-4-(4-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)苄基)哌
使用N-乙基乙烯二胺，而取代N-甲基乙烯二胺，進行與實施例51的步驟1至步驟4同樣的操作，獲得標記化合物(0.77g)。1 H NMR (400MHz, CDCl3 ) δ: 1.19 (3H, t, J=7.2 Hz), 1.49 (3H, t, J=7.3 Hz), 3.41-3.50 (4H, m), 3.54 (2H, q, J=7.3 Hz), 4.34 (2H, q, J=7.3 Hz), 4.71 (2H, s), 7.08 (1H, d, J=15.8 Hz), 7.26-7.30 (2H, m), 7.32-7.37 (3H, m), 7.59 (2H, d, J=8.0 Hz), 7.75-7.80 (1H, m), 7.98 (1H, d, J=15.8 Hz). MS (ESI) m/z 403 (M+H)+ .Using N-ethylethylenediamine instead of N-methylethylenediamine, the same operation as in Step 1 to Step 4 of Example 51 was performed to obtain the labeled compound (0.77 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.19 (3H, t, J=7.2 Hz), 1.49 (3H, t, J=7.3 Hz), 3.41-3.50 (4H, m), 3.54 (2H, q, J=7.3 Hz), 4.34 (2H, q, J=7.3 Hz), 4.71 (2H, s), 7.08 (1H, d, J=15.8 Hz), 7.26-7.30 (2H, m), 7.32-7.37 ( 3H, m), 7.59 (2H, d, J=8.0 Hz), 7.75-7.80 (1H, m), 7.98 (1H, d, J=15.8 Hz). MS (ESI) m/z 403 (M+H ) + .
實施例57：(E)-1-(4-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)-2-氟苄基)-4-甲基哌
使用4-溴-2-氟苄溴，而取代4-溴苄氯，進行與實施例51的步驟2至步驟4同樣的操作，獲得標記化合物(0.38g)。1 H NMR (400MHz, CDCl3 ) δ: 1.49 (3H, t, J=7.3 Hz), 3.08 (3H, s), 3.49-3.60 (4H, m), 4.34 (2H, q, J=7.3 Hz), 4.75 (2H, s), 7.08 (1H, d, J=15.7 Hz), 7.27-7.32 (3H, m), 7.33-7.41 (2H, m), 7.44-7.49 (1H, m), 7.74-7.80 (1H, m), 7.92 (1H, d, J=15.7 Hz). MS (ESI) m/z 407 (M+H)+ .Using 4-bromo-2-fluorobenzyl bromide instead of 4-bromobenzyl chloride, the same operations as in step 2 to step 4 of Example 51 were performed to obtain the labeled compound (0.38 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.49 (3H, t, J=7.3 Hz), 3.08 (3H, s), 3.49-3.60 (4H, m), 4.34 (2H, q, J=7.3 Hz) , 4.75 (2H, s), 7.08 (1H, d, J=15.7 Hz), 7.27-7.32 (3H, m), 7.33-7.41 (2H, m), 7.44-7.49 (1H, m), 7.74-7.80 (1H, m), 7.92 (1H, d, J=15.7 Hz). MS (ESI) m/z 407 (M+H) + .
實施例58：(E)-1-(4-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)-3-氟苄基)-4-甲基哌
使用4-溴-3-氟苄溴，而取代4-溴苄氯，進行與實施例51的步驟2至步驟4同樣的操作，獲得標記化合物(0.44g)。1 H NMR (400MHz, CDCl3 ) δ: 1.48 (3H, t, J=7.3 Hz), 3.09 (3H, s), 3.46-3.54 (4H, m), 4.33 (2H, q, J=7.3 Hz), 4.68 (2H, s), 7.05-7.15 (2H, m), 7.23-7.31 (3H, m), 7.33-7.38 (1H, m), 7.56 (1H, t, J=7.8 Hz), 7.75-7.80 (1H, m), 7.98 (1H, d, J=15.9 Hz). MS (ESI) m/z 407 (M+H)+ .Using 4-bromo-3-fluorobenzyl bromide instead of 4-bromobenzyl chloride, the same operations as in step 2 to step 4 of Example 51 were performed to obtain the labeled compound (0.44 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.48 (3H, t, J=7.3 Hz), 3.09 (3H, s), 3.46-3.54 (4H, m), 4.33 (2H, q, J=7.3 Hz) , 4.68 (2H, s), 7.05-7.15 (2H, m), 7.23-7.31 (3H, m), 7.33-7.38 (1H, m), 7.56 (1H, t, J=7.8 Hz), 7.75-7.80 (1H, m), 7.98 (1H, d, J=15.9 Hz). MS (ESI) m/z 407 (M+H) + .
實施例59：(E)-1-((5-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮Example 59: (E)-1-((5-(2-(1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl)pyridin-2-yl)methyl)-3 -Methylimidazolidin-2-one
在參考例2的步驟1所得之2-溴-1-乙基-1H-苯并[d]咪唑(0.30g)與參考例8的步驟3所得之(E)-1-甲基-3-((5-(2-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)乙烯基)吡啶-2-基)甲基)咪唑啶-2-酮(0.46g)的1,4-二
實施例60：(E)-1-((5-(2-(1、4-二乙基-1H-苯并[d]咪唑-2-基)乙烯基)吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮Example 60: (E)-1-((5-(2-(1, 4-Diethyl-1H-benzo[d]imidazol-2-yl)vinyl)pyridin-2-yl)methyl )-3-Methylimidazolidin-2-one
使用由實施例2的步驟4所得之2-溴-1,4-二乙基-1H-苯并[d]咪唑，而取代2-溴-1-乙基-1H-苯并[d]咪唑，進行與實施例59同樣的操作，獲得標記化合物(0.74g)。1 H NMR (400MHz, CDCl3 ) δ: 1.43 (3H, t, J=7.6 Hz), 1.48 (3H, t, J=7.3 Hz), 2.85 (3H, s), 3.17 (2H, q, J=7.8 Hz), 3.35 (4H, quin, J=2.6 Hz), 4.32 (2H, q, J=7.2 Hz), 4.53 (2H, s), 7.09-7.16 (2H, m), 7.18-7.24 (2H, m), 7.37 (1H, d, J=8.2 Hz), 7.88-7.96 (2H, m), 8.76 (1H, d, J=2.0 Hz). MS (ESI) m/z 390 (M+H)+ .The 2-bromo-1,4-diethyl-1H-benzo[d]imidazole obtained in step 4 of Example 2 was used instead of 2-bromo-1-ethyl-1H-benzo[d]imidazole , The same operation as in Example 59 was performed to obtain the labeled compound (0.74 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.43 (3H, t, J=7.6 Hz), 1.48 (3H, t, J=7.3 Hz), 2.85 (3H, s), 3.17 (2H, q, J= 7.8 Hz), 3.35 (4H, quin, J=2.6 Hz), 4.32 (2H, q, J=7.2 Hz), 4.53 (2H, s), 7.09-7.16 (2H, m), 7.18-7.24 (2H, m), 7.37 (1H, d, J=8.2 Hz), 7.88-7.96 (2H, m), 8.76 (1H, d, J=2.0 Hz). MS (ESI) m/z 390 (M+H) + .
實施例61：(E)-1-((5-(2-(1-乙基-4-異丙基-1H-苯并[d]咪唑-2-基)乙烯基)吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮Example 61: (E)-1-((5-(2-(1-ethyl-4-isopropyl-1H-benzo[d]imidazol-2-yl)vinyl)pyridin-2-yl )Methyl)-3-Methylimidazolidin-2-one
使用實施例3的步驟2的合成途中所得之2-溴-1-乙基-4-異丙基-1H-苯并[d]咪唑，而取代2-溴-1-乙基-1H-苯并[d]咪唑，進行與實施例59同樣的操作，獲得標記化合物(0.11g)。1 H NMR (400MHz, CDCl3 ) δ: 1.42 (6H, d, J=6.9 Hz), 1.47 (3H, t, J=7.3 Hz), 2.85 (3H, s), 3.28-3.47 (4H, m), 3.85-3.87 (1H, m), 4.31 (2H, q, J=7.2 Hz), 4.54 (2H, s), 7.11-7.20 (3H, m), 7.23-7.25 (1H, m), 7.37 (1H, d, J=8.4 Hz), 7.88-7.94 (2H, m), 8.76 (1H, d, J=2.1 Hz). MS (ESI) m/z 404 (M+H)+ .The 2-bromo-1-ethyl-4-isopropyl-1H-benzo[d]imidazole obtained during the synthesis of step 2 of Example 3 was used instead of 2-bromo-1-ethyl-1H-benzene And [d]imidazole, the same operation as in Example 59 was performed to obtain the labeled compound (0.11 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.42 (6H, d, J=6.9 Hz), 1.47 (3H, t, J=7.3 Hz), 2.85 (3H, s), 3.28-3.47 (4H, m) , 3.85-3.87 (1H, m), 4.31 (2H, q, J=7.2 Hz), 4.54 (2H, s), 7.11-7.20 (3H, m), 7.23-7.25 (1H, m), 7.37 (1H , d, J=8.4 Hz), 7.88-7.94 (2H, m), 8.76 (1H, d, J=2.1 Hz). MS (ESI) m/z 404 (M+H) + .
實施例62：(E)-1-((5-(2-(1-乙基-4-(四氫-2H-哌喃-4-基)-1H-苯并[d]咪唑-2-基)乙烯基)吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮Example 62: (E)-1-((5-(2-(1-ethyl-4-(tetrahydro-2H-piperan-4-yl)-1H-benzo[d]imidazole-2- (Yl)vinyl)pyridin-2-yl)methyl)-3-methylimidazolidin-2-one
使用實施例9的合成途中所得之2-氯-1-乙基-4-(四氫-2H-哌喃-4-基)-1H-苯并[d]咪唑，而取代2-溴-1-乙基-1H-苯并[d]咪唑，進行與實施例59同樣的操作，獲得標記化合物(0.43g)。1 H NMR (400MHz, CDCl3 ) δ: 1.48 (3H, t, J=7.3 Hz), 1.92-2.11 (4H, m), 2.85 (3H, s), 3.31-3.39 (4H, m), 3.67-3.79 (3H, m), 4.13 (2H, dd, J=10.5, 3.6 Hz), 4.32 (2H, q, J=7.3 Hz), 4.54 (2H, s), 7.08-7.16 (2H, m), 7.20-7.30 (2H, m), 7.38 (1H, d, J=8.2 Hz), 7.88-7.97 (2H, m), 8.77 (1H, d, J=2.3 Hz). MS (ESI) m/z 446 (M+H)+ .Using 2-chloro-1-ethyl-4-(tetrahydro-2H-piperan-4-yl)-1H-benzo[d]imidazole obtained during the synthesis of Example 9 instead of 2-bromo-1 -Ethyl-1H-benzo[d]imidazole, and the same operation as in Example 59 was performed to obtain the labeled compound (0.43 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.48 (3H, t, J=7.3 Hz), 1.92-2.11 (4H, m), 2.85 (3H, s), 3.31-3.39 (4H, m), 3.67- 3.79 (3H, m), 4.13 (2H, dd, J=10.5, 3.6 Hz), 4.32 (2H, q, J=7.3 Hz), 4.54 (2H, s), 7.08-7.16 (2H, m), 7.20 -7.30 (2H, m), 7.38 (1H, d, J=8.2 Hz), 7.88-7.97 (2H, m), 8.77 (1H, d, J=2.3 Hz). MS (ESI) m/z 446 ( M+H) + .
實施例63：(E)-1-((5-(2-(1-乙基-4-(四氫呋喃-3-基)-1H-苯并[d]咪唑-2-基)乙烯基)吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮Example 63: (E)-1-((5-(2-(1-ethyl-4-(tetrahydrofuran-3-yl)-1H-benzo[d]imidazol-2-yl)vinyl)pyridine -2-yl)methyl)-3-methylimidazolidin-2-one
使用實施例8的合成途中所得之2-氯-1-乙基-4-(四氫呋喃-3-基)-1H-苯并[d]咪唑，而取代2-溴-1-乙基-1H-苯并[d]咪唑，進行與實施例59同樣的操作，獲得標記化合物(0.51g)。1 H NMR (400MHz, CDCl3 ) δ: 1.48 (3H, t, J=7.3 Hz), 2.26 (1H, dq, J=12.2, 7.9 Hz), 2.51 (1H, dtd, J=12.1, 7.6, 7.6, 4.8 Hz), 2.85 (3H, s), 3.31-3.40 (4H, m), 3.95 (1H, t, J=7.3 Hz), 4.02 (1H, q, J=7.6 Hz), 4.17 (1H, td, J=8.2, 4.7 Hz), 4.26-4.37 (4H, m), 4.54 (2H, s), 7.12 (1H, d, J=15.8 Hz), 7.18-7.25 (3H, m), 7.38 (1H, d, J=8.0 Hz), 7.86-7.96 (2H, m), 8.76 (1H, d, J=2.1 Hz). MS (ESI) m/z 432 (M+H)+ .The 2-chloro-1-ethyl-4-(tetrahydrofuran-3-yl)-1H-benzo[d]imidazole obtained during the synthesis of Example 8 was used instead of 2-bromo-1-ethyl-1H- For benzo[d]imidazole, the same operation as in Example 59 was carried out to obtain the labeled compound (0.51 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.48 (3H, t, J=7.3 Hz), 2.26 (1H, dq, J=12.2, 7.9 Hz), 2.51 (1H, dtd, J=12.1, 7.6, 7.6 , 4.8 Hz), 2.85 (3H, s), 3.31-3.40 (4H, m), 3.95 (1H, t, J=7.3 Hz), 4.02 (1H, q, J=7.6 Hz), 4.17 (1H, td , J=8.2, 4.7 Hz), 4.26-4.37 (4H, m), 4.54 (2H, s), 7.12 (1H, d, J=15.8 Hz), 7.18-7.25 (3H, m), 7.38 (1H, d, J=8.0 Hz), 7.86-7.96 (2H, m), 8.76 (1H, d, J=2.1 Hz). MS (ESI) m/z 432 (M+H) + .
實施例64：(E)-1-((5-(2-(1-乙基-4-(1-甲基-1H-吡唑-5-基)-1H-苯并[d]咪唑-2-基)乙烯基)吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮Example 64: (E)-1-((5-(2-(1-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazole- 2-yl)vinyl)pyridin-2-yl)methyl)-3-methylimidazolidin-2-one
使用實施例10的合成途中所得之2-氯-1-乙基-4-(1-甲基-1H-吡唑-5-基)-1H-苯并[d]咪唑，而取代2-溴-1-乙基-1H-苯并[d]咪唑，進行與實施例59同樣的操作，獲得標記化合物(0.13g)。1 H NMR (400MHz, CDCl3 ) δ: 1.52 (3H, t, J=7.3 Hz), 2.82-2.87 (3H, m), 3.31-3.38 (4H, m), 3.99 (3H, s), 4.37 (2H, q, J=7.3 Hz), 4.53 (2H, s), 6.56 (1H, d, J=1.9 Hz), 7.10 (1H, d, J=15.8 Hz), 7.27-7.44 (4H, m), 7.61 (1H, d, J=1.9 Hz), 7.88 (1H, dd, J=8.2, 2.3 Hz), 7.97 (1H, d, J=15.8 Hz), 8.75 (1H, d, J=2.1 Hz). MS (ESI) m/z 442 (M+H)+ .The 2-chloro-1-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazole obtained during the synthesis of Example 10 was used instead of 2-bromo -1-ethyl-1H-benzo[d]imidazole, and the same operation as in Example 59 was performed to obtain the title compound (0.13 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.52 (3H, t, J=7.3 Hz), 2.82-2.87 (3H, m), 3.31-3.38 (4H, m), 3.99 (3H, s), 4.37 ( 2H, q, J=7.3 Hz), 4.53 (2H, s), 6.56 (1H, d, J=1.9 Hz), 7.10 (1H, d, J=15.8 Hz), 7.27-7.44 (4H, m), 7.61 (1H, d, J=1.9 Hz), 7.88 (1H, dd, J=8.2, 2.3 Hz), 7.97 (1H, d, J=15.8 Hz), 8.75 (1H, d, J=2.1 Hz). MS (ESI) m/z 442 (M+H) + .
實施例65：(E)-1-((5-(2-(4-(1、4-二甲基-1H-吡唑-5-基)-1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮Example 65: (E)-1-((5-(2-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-1-ethyl-1H-benzo[d ]Imidazol-2-yl)vinyl)pyridin-2-yl)methyl)-3-methylimidazolidin-2-one
使用實施例11的合成途中所得之2-氯-4-(1、4-二甲基-1H-吡唑-5-基)-1-乙基-1H-苯并[d]咪唑，而取代2-溴-1-乙基-1H-苯并[d]咪唑，進行與實施例59同樣的操作，獲得標記化合物(33mg)。1 H NMR (400MHz, CDCl3 ) δ: 1.53 (3H, t, J=7.3 Hz), 2.07 (3H, s), 2.85 (3H, s), 3.31-3.38 (4H, m), 3.85 (3H, s), 4.37 (2H, q, J=7.3 Hz), 4.53 (2H, s), 7.10 (1H, d, J=15.8 Hz), 7.20 (1H, dd, J=7.2, 1.1 Hz), 7.32-7.47 (4H, m), 7.87 (1H, dd, J=8.2, 2.3 Hz), 7.94 (1H, d, J=15.8 Hz), 8.74 (1H, d, J=2.0 Hz). MS (ESI) m/z 456 (M+H)+ .The 2-chloro-4-(1, 4-dimethyl-1H-pyrazol-5-yl)-1-ethyl-1H-benzo[d]imidazole obtained during the synthesis of Example 11 was used instead of 2-Bromo-1-ethyl-1H-benzo[d]imidazole was subjected to the same operation as in Example 59 to obtain the title compound (33 mg). 1 H NMR (400MHz, CDCl 3 ) δ: 1.53 (3H, t, J=7.3 Hz), 2.07 (3H, s), 2.85 (3H, s), 3.31-3.38 (4H, m), 3.85 (3H, s), 4.37 (2H, q, J=7.3 Hz), 4.53 (2H, s), 7.10 (1H, d, J=15.8 Hz), 7.20 (1H, dd, J=7.2, 1.1 Hz), 7.32- 7.47 (4H, m), 7.87 (1H, dd, J=8.2, 2.3 Hz), 7.94 (1H, d, J=15.8 Hz), 8.74 (1H, d, J=2.0 Hz). MS (ESI) m /z 456 (M+H) + .
實施例66：(E)-1-((5-(2-(4-(3,5-二甲基異
使用實施例12的合成途中所得之4-(2-氯-1-乙基-1H-苯并[d]咪唑-4-基)-3,5-二甲基異
實施例67：(E)-1-((5-(2-(1-乙基-4-(o-甲苯基)-1H-苯并[d]咪唑-2-基)乙烯基)吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮Example 67: (E)-1-((5-(2-(1-ethyl-4-(o-tolyl)-1H-benzo[d]imidazol-2-yl)vinyl)pyridine- 2-yl)methyl)-3-methylimidazolidin-2-one
使用實施例13的合成途中所得之2-氯-1-乙基-4-(o-甲苯基)-1H-苯并[d]咪唑，而取代2-溴-1-乙基-1H-苯并[d]咪唑，進行與實施例59同樣的操作，獲得標記化合物(318mg)。1 H NMR (400MHz, CDCl3 ) δ: 0.00-0.00 (1H, m), 1.52 (3H, t, J=7.3 Hz), 2.30 (3H, s), 2.84 (3H, s), 3.31-3.36 (4H, m), 4.36 (2H, q, J=7.3 Hz), 4.52 (2H, s), 7.09 (1H, d, J=15.8 Hz), 7.18 (1H, dd, J=6.7, 1.7 Hz), 7.28-7.38 (6H, m), 7.40-7.46 (1H, m), 7.81-7.91 (2H, m), 8.71 (1H, d, J=2.3 Hz). MS (ESI) m/z 452 (M+H)+ .The 2-chloro-1-ethyl-4-(o-tolyl)-1H-benzo[d]imidazole obtained during the synthesis of Example 13 was used instead of 2-bromo-1-ethyl-1H-benzene And [d]imidazole, the same operation as in Example 59 was performed to obtain the labeled compound (318 mg). 1 H NMR (400MHz, CDCl 3 ) δ: 0.00-0.00 (1H, m), 1.52 (3H, t, J=7.3 Hz), 2.30 (3H, s), 2.84 (3H, s), 3.31-3.36 ( 4H, m), 4.36 (2H, q, J=7.3 Hz), 4.52 (2H, s), 7.09 (1H, d, J=15.8 Hz), 7.18 (1H, dd, J=6.7, 1.7 Hz), 7.28-7.38 (6H, m), 7.40-7.46 (1H, m), 7.81-7.91 (2H, m), 8.71 (1H, d, J=2.3 Hz). MS (ESI) m/z 452 (M+ H) + .
實施例68：(E)-1-((5-(2-(4-(2-氯苯基)-1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮Example 68: (E)-1-((5-(2-(4-(2-chlorophenyl)-1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl)pyridine -2-yl)methyl)-3-methylimidazolidin-2-one
使用實施例14的合成途中所得之2-氯-4-(2-氯苯基)-1-乙基-1H-苯并[d]咪唑，而取代2-溴-1-乙基-1H-苯并[d]咪唑，進行與實施例59同樣的操作，獲得標記化合物(3.04g)。1 H NMR (400MHz, CDCl3 ) δ: 1.52 (3H, t, J=7.3 Hz), 2.84 (3H, s), 3.32-3.35 (4H, m), 4.37 (2H, q, J=7.2 Hz), 4.52 (2H, s), 7.10 (1H, d, J=15.8 Hz), 7.33-7.41 (6H, m), 7.54 (1H, dd, J=7.7, 1.3 Hz), 7.65 (1H, dd, J=7.5, 1.7 Hz), 7.82-7.90 (2H, m), 8.71 (1H, d, J=2.1 Hz). MS (ESI) m/z 472 (M+H)+ .The 2-chloro-4-(2-chlorophenyl)-1-ethyl-1H-benzo[d]imidazole obtained during the synthesis of Example 14 was used instead of 2-bromo-1-ethyl-1H- Benzo[d]imidazole was subjected to the same operation as in Example 59 to obtain the labeled compound (3.04 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.52 (3H, t, J=7.3 Hz), 2.84 (3H, s), 3.32-3.35 (4H, m), 4.37 (2H, q, J=7.2 Hz) , 4.52 (2H, s), 7.10 (1H, d, J=15.8 Hz), 7.33-7.41 (6H, m), 7.54 (1H, dd, J=7.7, 1.3 Hz), 7.65 (1H, dd, J =7.5, 1.7 Hz), 7.82-7.90 (2H, m), 8.71 (1H, d, J=2.1 Hz). MS (ESI) m/z 472 (M+H) + .
實施例69：(E)-1-((5-(2-(1-乙基-4-(2-甲基吡啶-3-基)-1H-苯并[d]咪唑-2-基)乙烯基)吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮Example 69: (E)-1-((5-(2-(1-ethyl-4-(2-methylpyridin-3-yl)-1H-benzo[d]imidazol-2-yl) Vinyl)pyridin-2-yl)methyl)-3-methylimidazolidin-2-one
使用實施例16的合成途中所得之2-氯-1-乙基-4-(2-甲基吡啶-3-基)-1H-苯并[d]咪唑，而取代2-溴-1-乙基-1H-苯并[d]咪唑，進行與實施例59同樣的操作，獲得標記化合物(0.19g)。1 H NMR (400MHz, CDCl3 ) δ: 1.53 (3H, t, J=7.3 Hz), 2.55 (3H, s), 2.84 (3H, s), 3.31-3.36 (4H, m), 4.37 (2H, q, J=7.3 Hz), 4.52 (2H, s), 7.10 (1H, d, J=15.8 Hz), 7.18 (1H, d, J=6.9 Hz), 7.25 (1H, dd, J=7.6, 5.0 Hz), 7.31-7.42 (3H, m), 7.77 (1H, dd, J=7.6, 1.7 Hz), 7.83-7.90 (2H, m), 8.56 (1H, dd, J=4.8, 1.6 Hz), 8.72 (1H, d, J=1.9 Hz). MS (ESI) m/z 453 (M+H)+ .The 2-chloro-1-ethyl-4-(2-methylpyridin-3-yl)-1H-benzo[d]imidazole obtained during the synthesis of Example 16 was used instead of 2-bromo-1-ethyl Yl-1H-benzo[d]imidazole, and the same operation as in Example 59 was performed to obtain the labeled compound (0.19 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.53 (3H, t, J=7.3 Hz), 2.55 (3H, s), 2.84 (3H, s), 3.31-3.36 (4H, m), 4.37 (2H, q, J=7.3 Hz), 4.52 (2H, s), 7.10 (1H, d, J=15.8 Hz), 7.18 (1H, d, J=6.9 Hz), 7.25 (1H, dd, J=7.6, 5.0 Hz), 7.31-7.42 (3H, m), 7.77 (1H, dd, J=7.6, 1.7 Hz), 7.83-7.90 (2H, m), 8.56 (1H, dd, J=4.8, 1.6 Hz), 8.72 (1H, d, J=1.9 Hz). MS (ESI) m/z 453 (M+H) + .
實施例70：(E)-1-((5-(2-(1-乙基-4-(4-甲基吡啶-3-基)-1H-苯并[d]咪唑-2-基)乙烯基)吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮Example 70: (E)-1-((5-(2-(1-ethyl-4-(4-methylpyridin-3-yl)-1H-benzo[d]imidazol-2-yl) Vinyl)pyridin-2-yl)methyl)-3-methylimidazolidin-2-one
使用實施例15的合成途中所得之2-氯-1-乙基-4-(4-甲基吡啶-3-基)-1H-苯并[d]咪唑，而取代2-溴-1-乙基-1H-苯并[d]咪唑，進行與實施例59同樣的操作，獲得標記化合物(0.11g)。1 H NMR (400MHz, CDCl3 ) δ: 1.53 (3H, t, J=7.2 Hz), 2.35 (3H, s), 2.84 (3H, s), 3.32-3.36 (4H, m), 4.37 (2H, q, J=7.3 Hz), 4.52 (2H, s), 7.10 (1H, d, J=15.9 Hz), 7.19 (1H, d, J=7.0 Hz), 7.27 (1H, d, J=5.0 Hz), 7.33-7.43 (3H, m), 7.83-7.90 (2H, m), 8.50 (1H, d, J=5.0 Hz), 8.64 (1H, s), 8.72 (1H, d, J=2.0 Hz). MS (ESI) m/z 453 (M+H)+ .The 2-chloro-1-ethyl-4-(4-methylpyridin-3-yl)-1H-benzo[d]imidazole obtained during the synthesis of Example 15 was used instead of 2-bromo-1-ethyl Yl-1H-benzo[d]imidazole, and the same operation as in Example 59 was performed to obtain the labeled compound (0.11 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.53 (3H, t, J=7.2 Hz), 2.35 (3H, s), 2.84 (3H, s), 3.32-3.36 (4H, m), 4.37 (2H, q, J=7.3 Hz), 4.52 (2H, s), 7.10 (1H, d, J=15.9 Hz), 7.19 (1H, d, J=7.0 Hz), 7.27 (1H, d, J=5.0 Hz) , 7.33-7.43 (3H, m), 7.83-7.90 (2H, m), 8.50 (1H, d, J=5.0 Hz), 8.64 (1H, s), 8.72 (1H, d, J=2.0 Hz). MS (ESI) m/z 453 (M+H) + .
實施例71：(E)-1-((5-(2-(4-(3-氯吡啶-4-基)-1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮Example 71: (E)-1-((5-(2-(4-(3-chloropyridin-4-yl)-1-ethyl-1H-benzo[d]imidazol-2-yl)ethylene (Yl)pyridin-2-yl)methyl)-3-methylimidazolidin-2-one
使用實施例17的合成途中所得之2-氯-4-(3-氯吡啶-4-基)-1-乙基-1H-苯并[d]咪唑，而取代2-溴-1-乙基-1H-苯并[d]咪唑，進行與實施例59同樣的操作，獲得標記化合物(24mg)。1 H NMR (400MHz, CDCl3 ) δ: 1.53 (3H, t, J=7.3 Hz), 2.84 (3H, s), 3.31-3.37 (4H, m), 4.37 (2H, q, J=7.3 Hz), 4.52 (2H, s), 7.10 (1H, d, J=15.8 Hz), 7.34-7.42 (3H, m), 7.43-7.47 (1H, m), 7.66 (1H, d, J=4.9 Hz), 7.84-7.91 (2H, m), 8.59 (1H, d, J=4.9 Hz), 8.73 (1H, d, J=2.1 Hz), 8.74 (1H, s). MS (ESI) m/z 473 (M+H)+ .The 2-chloro-4-(3-chloropyridin-4-yl)-1-ethyl-1H-benzo[d]imidazole obtained during the synthesis of Example 17 was used instead of 2-bromo-1-ethyl -1H-benzo[d]imidazole, the same operation as in Example 59 was carried out to obtain the labeled compound (24 mg). 1 H NMR (400MHz, CDCl 3 ) δ: 1.53 (3H, t, J=7.3 Hz), 2.84 (3H, s), 3.31-3.37 (4H, m), 4.37 (2H, q, J=7.3 Hz) , 4.52 (2H, s), 7.10 (1H, d, J=15.8 Hz), 7.34-7.42 (3H, m), 7.43-7.47 (1H, m), 7.66 (1H, d, J=4.9 Hz), 7.84-7.91 (2H, m), 8.59 (1H, d, J=4.9 Hz), 8.73 (1H, d, J=2.1 Hz), 8.74 (1H, s). MS (ESI) m/z 473 (M +H) + .
實施例72：(E)-1-((5-(2-(4-(二氟甲氧基)-1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮Example 72: (E)-1-((5-(2-(4-(Difluoromethoxy)-1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl)pyridine -2-yl)methyl)-3-methylimidazolidin-2-one
使用實施例22的步驟2的合成途中所得之2-氯-4-(二氟甲氧基)-1-乙基-1H-苯并[d]咪唑，而取代2-溴-1-乙基-1H-苯并[d]咪唑，進行與實施例59同樣的操作，獲得標記化合物(0.33g)。1 H NMR (400MHz, CDCl3 ) δ: 1.49 (3H, t, J=7.3 Hz), 2.85 (3H, s), 3.32-3.38 (4H, m), 4.33 (2H, q, J=7.3 Hz), 4.54 (2H, s), 7.04 (1H, dd, J=7.0, 1.1 Hz), 7.08 (1H, d, J=15.8 Hz), 7.17-7.23 (2H, m), 7.39 (1H, d, J=8.2 Hz), 7.55 (1H, d, J=75.0 Hz), 7.90 (1H, dd, J=8.2, 2.3 Hz), 8.01 (1H, d, J=15.8 Hz), 8.76 (1H, d, J=2.3 Hz). MS (ESI) m/z 428 (M+H)+ .The 2-chloro-4-(difluoromethoxy)-1-ethyl-1H-benzo[d]imidazole obtained during the synthesis of step 2 of Example 22 was used instead of 2-bromo-1-ethyl -1H-benzo[d]imidazole, and the same operation as in Example 59 was performed to obtain the labeled compound (0.33 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.49 (3H, t, J=7.3 Hz), 2.85 (3H, s), 3.32-3.38 (4H, m), 4.33 (2H, q, J=7.3 Hz) , 4.54 (2H, s), 7.04 (1H, dd, J=7.0, 1.1 Hz), 7.08 (1H, d, J=15.8 Hz), 7.17-7.23 (2H, m), 7.39 (1H, d, J =8.2 Hz), 7.55 (1H, d, J=75.0 Hz), 7.90 (1H, dd, J=8.2, 2.3 Hz), 8.01 (1H, d, J=15.8 Hz), 8.76 (1H, d, J =2.3 Hz). MS (ESI) m/z 428 (M+H) + .
實施例73：(E)-1-((5-(2-(1-乙基-4-氟-1H-苯并[d]咪唑-2-基)乙烯基)吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮Example 73: (E)-1-((5-(2-(1-ethyl-4-fluoro-1H-benzo[d]imidazol-2-yl)vinyl)pyridin-2-yl)methan Yl)-3-methylimidazolidin-2-one
在參考例12的步驟1所得之2-氯-1-乙基-4-氟-1H-苯并[d]咪唑(12.1g)與參考例8的步驟3所得之(E)-1-甲基-3-((5-(2-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)乙烯基)吡啶-2-基)甲基)咪唑啶-2-酮(24.1g)的1,4-二
實施例74：(E)-1-((5-(2-(1-乙基-5-氟-1H-苯并[d]咪唑-2-基)乙烯基)吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮Example 74: (E)-1-((5-(2-(1-ethyl-5-fluoro-1H-benzo[d]imidazol-2-yl)vinyl)pyridin-2-yl)methan Yl)-3-methylimidazolidin-2-one
在參考例13的步驟1所得之2-氯-1-乙基-5-氟-1H-苯并[d]咪唑(15.0g)與參考例8的步驟3所得之(E)-1-甲基-3-((5-(2-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)乙烯基)吡啶-2-基)甲基)咪唑啶-2-酮(32.8g)的1,4-二
實施例75：(E)-1-((5-(2-(1-乙基-4,7-二甲基-1H-苯并[d]咪唑-2-基)乙烯基)吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮Example 75: (E)-1-((5-(2-(1-ethyl-4,7-dimethyl-1H-benzo[d]imidazol-2-yl)vinyl)pyridine-2 -(Yl)methyl)-3-methylimidazolidin-2-one
使用實施例24的步驟3所得之1-乙基-2-碘-4,7-二甲基-1H-苯并[d]咪唑，而取代2-溴-1-乙基-1H-苯并[d]咪唑，進行與實施例59同樣的操作，獲得標記化合物(0.42g)。1 H NMR (400MHz, CDCl3 ) δ: 1.47 (3H, t, J=7.2 Hz), 2.67 (3H, s), 2.70 (3H, s), 2.85 (3H, s), 3.33-3.37 (4H, m), 4.47-4.53 (2H, m), 4.53 (2H, s), 6.87-6.92 (1H, m), 6.94-6.98 (1H, m), 7.12 (1H, d, J=15.8 Hz), 7.37 (1H, d, J=8.2 Hz), 7.89 (1H, dd, J=8.2, 2.3 Hz), 7.95 (1H, d, J=15.8 Hz), 8.76 (1H, d, J=2.1 Hz). MS (ESI) m/z 390 (M+H)+ .The 1-ethyl-2-iodo-4,7-dimethyl-1H-benzo[d]imidazole obtained in step 3 of Example 24 was used instead of 2-bromo-1-ethyl-1H-benzo [d] Imidazole, the same operation as in Example 59 was performed to obtain the labeled compound (0.42 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.47 (3H, t, J=7.2 Hz), 2.67 (3H, s), 2.70 (3H, s), 2.85 (3H, s), 3.33-3.37 (4H, m), 4.47-4.53 (2H, m), 4.53 (2H, s), 6.87-6.92 (1H, m), 6.94-6.98 (1H, m), 7.12 (1H, d, J=15.8 Hz), 7.37 (1H, d, J=8.2 Hz), 7.89 (1H, dd, J=8.2, 2.3 Hz), 7.95 (1H, d, J=15.8 Hz), 8.76 (1H, d, J=2.1 Hz). MS (ESI) m/z 390 (M+H) + .
實施例76：(E)-1-((5-(2-(1,7-二乙基-1H-苯并[d]咪唑-2-基)乙烯基)吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮Example 76: (E)-1-((5-(2-(1,7-Diethyl-1H-benzo[d]imidazol-2-yl)vinyl)pyridin-2-yl)methyl )-3-Methylimidazolidin-2-one
使用實施例25的合成途中所得之1,7-二乙基-2-碘-1H-苯并[d]咪唑，而取代2-溴-1-乙基-1H-苯并[d]咪唑，進行與實施例59同樣的操作，獲得標記化合物(0.20g)。1 H NMR (400MHz, CDCl3 ) δ: 1.38 (3H, t, J=7.5 Hz), 1.48 (3H, t, J=7.0 Hz), 2.85 (3H, s), 2.99-3.09 (2H, m), 3.29-3.40 (4H, m), 4.38-4.68 (4H, m), 7.07 (1H, d, J=7.3 Hz), 7.13 (1H, d, J=15.7 Hz), 7.17-7.24 (1H, m), 7.37 (1H, dd, J=8.0, 2.3 Hz), 7.63 (1H, d, J=8.0 Hz), 7.85-7.91 (1H, m), 7.96 (1H, d, J=15.7 Hz), 8.75 (1H, br s). MS (ESI) m/z 390 (M+H)+ .Using 1,7-diethyl-2-iodo-1H-benzo[d]imidazole obtained during the synthesis of Example 25 instead of 2-bromo-1-ethyl-1H-benzo[d]imidazole, The same operation as in Example 59 was performed to obtain the labeled compound (0.20 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.38 (3H, t, J=7.5 Hz), 1.48 (3H, t, J=7.0 Hz), 2.85 (3H, s), 2.99-3.09 (2H, m) , 3.29-3.40 (4H, m), 4.38-4.68 (4H, m), 7.07 (1H, d, J=7.3 Hz), 7.13 (1H, d, J=15.7 Hz), 7.17-7.24 (1H, m) ), 7.37 (1H, dd, J=8.0, 2.3 Hz), 7.63 (1H, d, J=8.0 Hz), 7.85-7.91 (1H, m), 7.96 (1H, d, J=15.7 Hz), 8.75 (1H, br s). MS (ESI) m/z 390 (M+H) + .
實施例77：(E)-1-((5-(2-(1-乙基-7-氟-1H-苯并[d]咪唑-2-基)乙烯基)吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮Example 77: (E)-1-((5-(2-(1-ethyl-7-fluoro-1H-benzo[d]imidazol-2-yl)vinyl)pyridin-2-yl)methan Yl)-3-methylimidazolidin-2-one
使用參考例14的步驟2所得之1-乙基-7-氟-2-碘-1H-苯并[d]咪唑，而取代2-溴-1-乙基-1H-苯并[d]咪唑，進行與實施例59同樣的操作，獲得標記化合物(0.77g)。1 H NMR (400MHz, CDCl3 ) δ: 1.52 (3H, t, J=7.2 Hz), 2.85 (3H, s), 3.35 (4H, quin, J=2.8 Hz), 4.49 (2H, q, J=7.2 Hz), 4.54 (2H, s), 6.95 (1H, dd, J=11.5, 7.8 Hz), 7.09 (1H, d, J=15.8 Hz), 7.17 (1H, td, J=8.1, 5.0 Hz), 7.39 (1H, d, J=8.2 Hz), 7.53 (1H, d, J=8.0 Hz), 7.90 (1H, dd, J=8.2, 2.1 Hz), 7.97 (1H, d, J=15.8 Hz), 8.75 (1H, d, J=2.0 Hz). MS (ESI) m/z 380 (M+H)+ .Use 1-ethyl-7-fluoro-2-iodo-1H-benzo[d]imidazole obtained in step 2 of Reference Example 14 instead of 2-bromo-1-ethyl-1H-benzo[d]imidazole , The same operation as in Example 59 was performed to obtain the labeled compound (0.77 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.52 (3H, t, J=7.2 Hz), 2.85 (3H, s), 3.35 (4H, quin, J=2.8 Hz), 4.49 (2H, q, J= 7.2 Hz), 4.54 (2H, s), 6.95 (1H, dd, J=11.5, 7.8 Hz), 7.09 (1H, d, J=15.8 Hz), 7.17 (1H, td, J=8.1, 5.0 Hz) , 7.39 (1H, d, J=8.2 Hz), 7.53 (1H, d, J=8.0 Hz), 7.90 (1H, dd, J=8.2, 2.1 Hz), 7.97 (1H, d, J=15.8 Hz) , 8.75 (1H, d, J=2.0 Hz). MS (ESI) m/z 380 (M+H) + .
實施例78：(E)-1-((5-(2-(5,6-二氫-4H-咪唑并[4,5,1-ij]喹啉-2-基)乙烯基)吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮Example 78: (E)-1-((5-(2-(5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2-yl)vinyl)pyridine- 2-yl)methyl)-3-methylimidazolidin-2-one
使用實施例28的步驟3所得之2-碘-5,6-二氫-4-咪唑并[4、5、1-ij]喹啉，而取代2-溴-1-乙基-1H-苯并[d]咪唑，進行與實施例59同樣的操作，獲得標記化合物(0.43g)。1 H NMR (400MHz, CDCl3 ) δ: 2.31 (2H, quin, J=5.8 Hz), 3.01 (2H, t, J=5.9 Hz), 3.28-3.38 (4H, m), 4.30 (2H, t, J=5.6 Hz), 4.53 (2H, s), 7.00 (1H, d, J=7.2 Hz), 7.09 (1H, d, J=16.1 Hz), 7.19 (1H, t, J=7.7 Hz), 7.36 (1H, d, J=8.2 Hz), 7.57 (1H, d, J=8.0 Hz), 7.83-7.92 (2H, m), 8.73 (1H, s). MS (ESI) m/z 374 (M+H)+ .Using the 2-iodo-5,6-dihydro-4-imidazo[4,5,1-ij]quinoline obtained in step 3 of Example 28 instead of 2-bromo-1-ethyl-1H-benzene And [d]imidazole, the same operation as in Example 59 was performed to obtain the labeled compound (0.43 g). 1 H NMR (400MHz, CDCl 3 ) δ: 2.31 (2H, quin, J=5.8 Hz), 3.01 (2H, t, J=5.9 Hz), 3.28-3.38 (4H, m), 4.30 (2H, t, J=5.6 Hz), 4.53 (2H, s), 7.00 (1H, d, J=7.2 Hz), 7.09 (1H, d, J=16.1 Hz), 7.19 (1H, t, J=7.7 Hz), 7.36 (1H, d, J=8.2 Hz), 7.57 (1H, d, J=8.0 Hz), 7.83-7.92 (2H, m), 8.73 (1H, s). MS (ESI) m/z 374 (M+ H) + .
實施例79：(E)-1-甲基-3-((5-(2-(9-甲基-5,6-二氫-4H-咪唑并[4,5,1-ij]喹啉-2-基)乙烯基)吡啶-2-基)甲基)咪唑啶-2-酮Example 79: (E)-1-methyl-3-((5-(2-(9-methyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline -2-yl)vinyl)pyridin-2-yl)methyl)imidazolidin-2-one
使用實施例29的合成途中所得之2-碘-9-甲基-5,6-二氫-4-咪唑并[4,5,1-ij]喹啉，而取代2-溴-1-乙基-1H-苯并[d]咪唑，進行與實施例59同樣的操作，獲得標記化合物(0.49g)。1 H NMR (400MHz, CDCl3 ) δ: 2.29 (2H, quin, J=6.0 Hz), 2.67 (3H, s), 2.85 (3H, s), 2.99 (2H, t, J=6.0 Hz), 3.35 (4H, quin, J=2.5 Hz), 4.27-4.33 (2H, m), 4.53 (2H, s), 6.89-6.93 (1H, m), 6.96-7.00 (1H, m), 7.14 (1H, d, J=16.1 Hz), 7.37 (1H, d, J=8.2 Hz), 7.84 (1H, d, J=16.1 Hz), 7.88 (1H, dd, J=8.2, 2.2 Hz), 8.74 (1H, d, J=2.0 Hz). MS (ESI) m/z 388 (M+H)+ .The 2-iodo-9-methyl-5,6-dihydro-4-imidazo[4,5,1-ij]quinoline obtained during the synthesis of Example 29 was used instead of 2-bromo-1-ethyl Yl-1H-benzo[d]imidazole, and the same operation as in Example 59 was performed to obtain the labeled compound (0.49 g). 1 H NMR (400MHz, CDCl 3 ) δ: 2.29 (2H, quin, J=6.0 Hz), 2.67 (3H, s), 2.85 (3H, s), 2.99 (2H, t, J=6.0 Hz), 3.35 (4H, quin, J=2.5 Hz), 4.27-4.33 (2H, m), 4.53 (2H, s), 6.89-6.93 (1H, m), 6.96-7.00 (1H, m), 7.14 (1H, d) , J=16.1 Hz), 7.37 (1H, d, J=8.2 Hz), 7.84 (1H, d, J=16.1 Hz), 7.88 (1H, dd, J=8.2, 2.2 Hz), 8.74 (1H, d , J=2.0 Hz). MS (ESI) m/z 388 (M+H) + .
實施例80：(E)-1-((5-(2-(3,4-二氫-5-氧代-1,2a-二吖乙烯合萘-2-基)乙烯基)吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮Example 80: (E)-1-((5-(2-(3,4-Dihydro-5-oxo-1,2a-diethylenenaphthalene-2-yl)vinyl)pyridine-2 -(Yl)methyl)-3-methylimidazolidin-2-one
使用實施例30的合成途中所得之2-碘-3,4-二氫-5-氧代-1,2a-二吖乙烯合萘，而取代2-溴-1-乙基-1H-苯并[d]咪唑，進行與實施例59同樣的操作，獲得標記化合物(0.37g)。1 H NMR (400MHz, CDCl3 ) δ: 2.84 (3H, s), 3.34 (4H, s), 4.41-4.47 (2H, m), 4.49-4.59 (4H, m), 6.73 (1H, d, J=7.8 Hz), 7.02 (1H, d, J=16.1 Hz), 7.15 (1H, t, J=8.0 Hz), 7.31-7.40 (2H, m), 7.79-7.89 (2H, m), 8.71 (1H, d, J=1.5 Hz). MS (ESI) m/z 376 (M+H)+ .Using the 2-iodo-3,4-dihydro-5-oxo-1,2a-diazene naphthalene obtained during the synthesis of Example 30 instead of 2-bromo-1-ethyl-1H-benzo [d] Imidazole, the same operation as in Example 59 was performed to obtain the labeled compound (0.37 g). 1 H NMR (400MHz, CDCl 3 ) δ: 2.84 (3H, s), 3.34 (4H, s), 4.41-4.47 (2H, m), 4.49-4.59 (4H, m), 6.73 (1H, d, J =7.8 Hz), 7.02 (1H, d, J=16.1 Hz), 7.15 (1H, t, J=8.0 Hz), 7.31-7.40 (2H, m), 7.79-7.89 (2H, m), 8.71 (1H , d, J=1.5 Hz). MS (ESI) m/z 376 (M+H) + .
實施例81：(E)-1-((5-(2-(8,9-二氫-7H-6-氧代-2,9a-二吖苯并[cd]薁-1-基)乙烯基)吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮Example 81: (E)-1-((5-(2-(8,9-dihydro-7H-6-oxo-2,9a-diazylbenzo[cd]azulene-1-yl)ethylene (Yl)pyridin-2-yl)methyl)-3-methylimidazolidin-2-one
使用實施例31的步驟2的合成途中所得之1-碘-8,9-二氫-7H-6-氧代-2,9a-二吖苯并[cd]薁，而取代2-溴-1-乙基-1H-苯并[d]咪唑，進行與實施例59同樣的操作，獲得標記化合物(0.16g)。1 H NMR (400MHz, CDCl3 ) δ: 2.46-2.56 (2H, m), 2.85 (3H, s), 3.30-3.39 (4H, m), 4.35-4.45 (4H, m), 4.53 (2H, s), 6.84 (1H, dd, J=7.9, 0.9 Hz), 7.10-7.20 (2H, m), 7.38 (1H, d, J=8.2 Hz), 7.42 (1H, dd, J=8.1, 0.9 Hz), 7.88 (1H, dd, J=8.2, 2.3 Hz), 7.94 (1H, d, J=15.8 Hz), 8.75 (1H, d, J=2.3 Hz). MS (ESI) m/z 390 (M+H)+ .Using the 1-iodo-8,9-dihydro-7H-6-oxo-2,9a-diaz[cd]azulene obtained during the synthesis of step 2 of Example 31 instead of 2-bromo-1 -Ethyl-1H-benzo[d]imidazole, and the same operation as in Example 59 was performed to obtain the labeled compound (0.16 g). 1 H NMR (400MHz, CDCl 3 ) δ: 2.46-2.56 (2H, m), 2.85 (3H, s), 3.30-3.39 (4H, m), 4.35-4.45 (4H, m), 4.53 (2H, s) ), 6.84 (1H, dd, J=7.9, 0.9 Hz), 7.10-7.20 (2H, m), 7.38 (1H, d, J=8.2 Hz), 7.42 (1H, dd, J=8.1, 0.9 Hz) , 7.88 (1H, dd, J=8.2, 2.3 Hz), 7.94 (1H, d, J=15.8 Hz), 8.75 (1H, d, J=2.3 Hz). MS (ESI) m/z 390 (M+ H) + .
實施例82：(E)-1-甲基-3-((5-(2-(1-甲基-1H-苯并[d]咪唑-2-基)乙烯基)吡啶-2-基)甲基)咪唑啶-2-酮Example 82: (E)-1-methyl-3-((5-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)vinyl)pyridin-2-yl) (Methyl)imidazolidin-2-one
使用實施例32的步驟1所得之2-溴-1-甲基-1H-苯并[d]咪唑，而取代2-溴-1-乙基-1H-苯并[d]咪唑，進行與實施例59同樣的操作，獲得標記化合物(0.17g)。1 H NMR (400MHz, CDCl3 ) δ: 2.85 (3H, s), 3.35 (4H, quin, J=2.6 Hz), 3.90 (3H, s), 4.53 (2H, s), 7.16 (1H, d, J=15.9 Hz), 7.28-7.33 (2H, m), 7.34-7.41 (2H, m), 7.75-7.80 (1H, m), 7.90 (1H, dd, J=8.1, 2.3 Hz), 7.95 (1H, d, J=16.1 Hz), 8.76 (1H, d, J=2.1 Hz). MS (ESI) m/z 348 (M+H)+ .Using 2-bromo-1-methyl-1H-benzo[d]imidazole obtained in step 1 of Example 32 instead of 2-bromo-1-ethyl-1H-benzo[d]imidazole, proceed and implement In the same manner as in Example 59, the labeled compound (0.17 g) was obtained. 1 H NMR (400MHz, CDCl 3 ) δ: 2.85 (3H, s), 3.35 (4H, quin, J=2.6 Hz), 3.90 (3H, s), 4.53 (2H, s), 7.16 (1H, d, J=15.9 Hz), 7.28-7.33 (2H, m), 7.34-7.41 (2H, m), 7.75-7.80 (1H, m), 7.90 (1H, dd, J=8.1, 2.3 Hz), 7.95 (1H , d, J=16.1 Hz), 8.76 (1H, d, J=2.1 Hz). MS (ESI) m/z 348 (M+H) + .
實施例83：(E)-1-((5-(2-(1-乙基-4-(3-甲基噻吩-2-基)-1H-苯并[d]咪唑-2-基)乙烯基)吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮Example 83: (E)-1-((5-(2-(1-ethyl-4-(3-methylthiophen-2-yl)-1H-benzo[d]imidazol-2-yl) Vinyl)pyridin-2-yl)methyl)-3-methylimidazolidin-2-one
在參考例9的步驟3所得之(E)-1-((5-(2-(4-溴-1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮(0.12g)與3-甲基噻吩-2-硼酸[酉品]酯(0.07g)的1,4-二
實施例84：(E)-1-((5-(2-(4-(2-氯噻吩-3-基)-1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮Example 84: (E)-1-((5-(2-(4-(2-chlorothien-3-yl)-1-ethyl-1H-benzo[d]imidazol-2-yl)ethylene (Yl)pyridin-2-yl)methyl)-3-methylimidazolidin-2-one
在參考例9的步驟3所得之(E)-1-((5-(2-(4-溴-1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮(0.09g)與2-氯-3-噻吩噻吩-2-硼酸(0.05g)的1,4-二
實施例85：(E)-1-((5-(2-(1-乙基-4-苯基-1H-苯并[d]咪唑-2-基)乙烯基)吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮Example 85: (E)-1-((5-(2-(1-ethyl-4-phenyl-1H-benzo[d]imidazol-2-yl)vinyl)pyridin-2-yl) (Methyl)-3-Methylimidazolidin-2-one
在由參考例5的步驟1所得之4-溴-2-氯-1-乙基-1H-苯并[d]咪唑(0.12g)與苯基硼酸(0.07g)的1,4-二
實施例86：(E)-1-((5-(2-(1-乙基-4-(3-甲基吡啶-4-基)-1H-苯并[d]咪唑-2-基)乙烯基)吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮Example 86: (E)-1-((5-(2-(1-ethyl-4-(3-methylpyridin-4-yl)-1H-benzo[d]imidazol-2-yl) Vinyl)pyridin-2-yl)methyl)-3-methylimidazolidin-2-one
在由參考例5的步驟1所得之4-溴-2-氯-1-乙基-1H-苯并[d]咪唑(0.25g)與3-甲基-4-吡啶硼酸(0.19g)的1,4-二
實施例87：(E)-1-((5-(2-(4-環己基-1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮Example 87: (E)-1-((5-(2-(4-cyclohexyl-1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl)pyridin-2-yl) (Methyl)-3-Methylimidazolidin-2-one
步驟1 2-氯-4-環己基-1-乙基-1H-苯并[d]咪唑 在由實施例7的步驟2所得之4-環己基-1-乙基-1H-苯并[d]咪唑-2-酮(0.17g)中添加三氯一氧化磷(2.0mL)，加熱至110℃並攪拌1小時。放置冷卻後，在減壓下餾去溶劑，在殘渣中添加乙酸乙酯及飽和碳酸氫鈉水，以硫酸鈉乾燥有機層。在減壓下餾去溶劑，將殘渣以矽膠管柱層析法(n-己烷/乙酸乙酯)進行純化，獲得標記化合物(0.18g)。1 H NMR (400MHz, CDCl3 ) δ: 1.43 (3H, t, J=7.3 Hz), 1.50-1.62 (6H, m), 1.74-1.88 (3H, m), 1.93-2.02 (2H, m), 3.32-3.42 (1H, m), 4.23 (2H, q, J=7.3 Hz), 7.11-7.16 (2H, m), 7.24 (1H, d, J=8.2 Hz). MS (ESI) m/z 263 (M+H)+ .Step 1 2-Chloro-4-cyclohexyl-1-ethyl-1H-benzo[d]imidazole in the 4-cyclohexyl-1-ethyl-1H-benzo[d] obtained from step 2 of Example 7 ] Imidazole-2-one (0.17 g) was added with phosphorus monoxide (2.0 mL), heated to 110°C and stirred for 1 hour. After leaving to cool, the solvent was distilled off under reduced pressure, ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the organic layer was dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (0.18 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.43 (3H, t, J=7.3 Hz), 1.50-1.62 (6H, m), 1.74-1.88 (3H, m), 1.93-2.02 (2H, m), 3.32-3.42 (1H, m), 4.23 (2H, q, J=7.3 Hz), 7.11-7.16 (2H, m), 7.24 (1H, d, J=8.2 Hz). MS (ESI) m/z 263 (M+H) + .
步驟2
(E)-1-((5-(2-(4-環己基-1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮
在由上述步驟1所得之2-氯-4-環己基-1-乙基-1H-苯并[d]咪唑(0.16g)與由參考例8的步驟3所得之(E)-1-甲基-3-((5-(2-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)乙烯基)吡啶-2-基)甲基)咪唑啶-2-酮(0.25g)的1,4-二
實施例88：(E)-1-((5-(2-(1-乙基-7-氟-1H-苯并[d]咪唑-2-基)乙烯基)-3-氟吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮Example 88: (E)-1-((5-(2-(1-ethyl-7-fluoro-1H-benzo[d]imidazol-2-yl)vinyl)-3-fluoropyridine-2 -(Yl)methyl)-3-methylimidazolidin-2-one
步驟1 5-溴-3-氟吡啶甲酸甲酯 在5-溴-3-氟吡啶-2-羧酸(4.00g)與碳酸鉀(3.80g)的N,N-二甲基甲醯胺(18mL)溶液中添加碘甲烷(1.36mL)，以60℃攪拌48小時。放置冷卻後，在反應液中添加水，以乙酸乙酯進行萃取。以飽和食鹽水清洗萃取液，以硫酸鈉進行乾燥。在減壓下餾去溶劑，以矽膠層析法(n-己烷/乙酸乙酯)進行純化，獲得標記化合物(2.90g)。1 H NMR (400MHz, CDCl3 ) δ: 4.02 (3H, s), 7.78 (1H, dd, J=9.3, 1.8 Hz), 8.62 (1H, s). MS (ESI) m/z 234 (M+H)+ .Step 1 Methyl 5-bromo-3-fluoropicolinate in 5-bromo-3-fluoropyridine-2-carboxylic acid (4.00g) and potassium carbonate (3.80g) in N,N-dimethylformamide ( 18 mL) was added with methyl iodide (1.36 mL) and stirred at 60°C for 48 hours. After leaving to cool, water was added to the reaction solution, and extraction was performed with ethyl acetate. The extract was washed with saturated brine and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and purification was performed by silica gel chromatography (n-hexane/ethyl acetate) to obtain the title compound (2.90 g). 1 H NMR (400MHz, CDCl 3 ) δ: 4.02 (3H, s), 7.78 (1H, dd, J=9.3, 1.8 Hz), 8.62 (1H, s). MS (ESI) m/z 234 (M+ H) + .
步驟2 5-溴-3-氟吡啶甲醛 在-78℃，在由上述步驟1所得之5-溴-3-氟吡啶甲酸甲酯(2.8g)的四氫呋喃(30mL)溶液中添加二異丁基氫化鋁(1.0mol/L，n-己烷溶液，22.5mL)，攪拌1小時。添加飽和酒石酸鉀鈉水溶液，以室溫攪拌30分鐘。添加水，以乙酸乙酯進行萃取。以飽和食鹽水清洗萃取液，以硫酸鈉進行乾燥。在減壓下餾去溶劑，以矽膠層析法(n-己烷/乙酸乙酯)進行純化，獲得標記化合物(2.05g)。1 H NMR (400MHz, CDCl3 ) δ: 7.80 (1H, dd, J=9.3, 1.3 Hz), 8.69 (1H, d, J=0.6 Hz), 10.17 (1H, s). MS (ESI) m/z 203 (M+H)+ .Step 2 5-Bromo-3-fluoropicolinaldehyde at -78°C, add diisobutyl to the methyl 5-bromo-3-fluoropicolinate (2.8g) obtained in step 1 above in tetrahydrofuran (30mL) Aluminum hydride (1.0 mol/L, n-hexane solution, 22.5 mL), stirred for 1 hour. A saturated aqueous potassium sodium tartrate solution was added and stirred at room temperature for 30 minutes. Water was added, and extraction was performed with ethyl acetate. The extract was washed with saturated brine and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and purification was performed by silica gel chromatography (n-hexane/ethyl acetate) to obtain the title compound (2.05 g). 1 H NMR (400MHz, CDCl 3 ) δ: 7.80 (1H, dd, J=9.3, 1.3 Hz), 8.69 (1H, d, J=0.6 Hz), 10.17 (1H, s). MS (ESI) m/ z 203 (M+H) + .
步驟3 tert-丁基(2-(((5-溴-3-氟吡啶-2-基)甲基)胺基)乙基)(甲基)胺甲酸酯 室溫下，在由上述步驟2所得之5-溴-3-氟吡啶甲醛(2.00g)與N-(tert-丁氧羰基)-N-甲基-1,2-乙烯二胺(1.8mL)的二氯甲烷(15mL)溶液中添加三乙醯氧基硼氫化鈉(2.40g)，攪拌3小時。添加飽和碳酸氫鈉水並以乙酸乙酯進行萃取。以水及飽和食鹽水清洗萃取液，以硫酸鈉進行乾燥。在減壓下餾去溶劑，以矽膠層析法(n-己烷/乙酸乙酯)進行純化，獲得標記化合物(2.40g)。1 H NMR (400MHz, CDCl3 ) δ: 1.45 (9H, s), 2.80 (2H, t, J=6.5 Hz), 2.87 (3H, s), 3.37 (2H, t, J=6.2 Hz), 3.96 (2H, d, J=2.0 Hz), 7.55 (1H, dd, J=8.5, 1.4 Hz), 8.45 (1H, s). MS (ESI) m/z 362 (M+H)+ .Step 3 tert-butyl(2-(((5-bromo-3-fluoropyridin-2-yl)methyl)amino)ethyl)(methyl)carbamate 2 The resulting 5-bromo-3-fluoropyridinecarbaldehyde (2.00g) and N-(tert-butoxycarbonyl)-N-methyl-1,2-ethylenediamine (1.8mL) in dichloromethane (15mL) Sodium triacetoxyborohydride (2.40 g) was added to the solution and stirred for 3 hours. Add saturated sodium bicarbonate water and extract with ethyl acetate. The extract was washed with water and saturated brine, and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and it was purified by silica gel chromatography (n-hexane/ethyl acetate) to obtain the title compound (2.40 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.45 (9H, s), 2.80 (2H, t, J=6.5 Hz), 2.87 (3H, s), 3.37 (2H, t, J=6.2 Hz), 3.96 (2H, d, J=2.0 Hz), 7.55 (1H, dd, J=8.5, 1.4 Hz), 8.45 (1H, s). MS (ESI) m/z 362 (M+H) + .
步驟4
1-((5-溴-3-氟吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮
在由上述步驟3所得之tert-丁基(2-(((5-溴-3-氟吡啶-2-基)甲基)胺基)乙基)(甲基)胺甲酸酯(2.30g)中添加氯化氫(4mol/L，1,4-二
步驟5 (E)-(2-(5-氟-6-((3-甲基-2-側氧基咪唑啶-1-基)甲基)吡啶-3-基)乙烯基)硼酸 室溫下，在由上述步驟4所得之1-((5-溴-3-氟吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮(3.2g)的甲苯(30mL)溶液中添加4,4,5,5-四甲基-2-乙烯基-1,3,2-二氧硼戊環(2.3mL)、三乙胺(4.7mL)及雙(三-tert-丁基膦)鈀(0),(0.29g)，以120℃攪拌1小時。放置冷卻後，將反應液進行矽藻土過濾，減壓下，餾去濾液的溶劑，以矽膠層析法(氯仿/甲醇)進行純化，獲得標記化合物(1.70g)。1 H NMR (400MHz, CDCl3 ) δ: 2.81-2.89 (3H, m), 3.29-3.44 (4H, m), 3.49 (2H, s), 4.59 (2H, s), 6.20 (1H, d, J=18.3 Hz), 7.19-7.30 (1H, m), 7.45 (1H, d, J=10.3 Hz), 8.40 (1H, s). MS (ESI) m/z 280 (M+H)+ .Step 5 (E)-(2-(5-Fluoro-6-((3-methyl-2-oxoimidazolidine-1-yl)methyl)pyridin-3-yl)vinyl)boronic acid at room temperature Next, in the toluene (30mL) solution of 1-((5-bromo-3-fluoropyridin-2-yl)methyl)-3-methylimidazolidin-2-one (3.2g) obtained from step 4 above Add 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (2.3mL), triethylamine (4.7mL) and bis(tri-tert-butyl) Phosphine) palladium (0), (0.29 g), stirred at 120°C for 1 hour. After standing to cool, the reaction solution was filtered through Celite, and the solvent of the filtrate was distilled off under reduced pressure, and purified by silica gel chromatography (chloroform/methanol) to obtain the labeled compound (1.70 g). 1 H NMR (400MHz, CDCl 3 ) δ: 2.81-2.89 (3H, m), 3.29-3.44 (4H, m), 3.49 (2H, s), 4.59 (2H, s), 6.20 (1H, d, J =18.3 Hz), 7.19-7.30 (1H, m), 7.45 (1H, d, J=10.3 Hz), 8.40 (1H, s). MS (ESI) m/z 280 (M+H) + .
步驟6
(E)-1-((5-(2-(1-乙基-7-氟-1H-苯并[d]咪唑-2-基)乙烯基)-3-氟吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮
在由上述步驟5所得之(E)-(2-(5-氟-6-((3-甲基-2-側氧基咪唑啶-1-基)甲基)吡啶-3-基)乙烯基)硼酸(0.64g)與由參考例14的步驟2所得之1-乙基-7-氟-2-碘-1H-苯并[d]咪唑(0.67g)的1,4-二
實施例89：(E)-1-((5-(2-(5,6-二氫-4H-咪唑并[4、5、1-ij]喹啉-2-基)乙烯基)-3-氟吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮Example 89: (E)-1-((5-(2-(5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2-yl)vinyl)-3 -Fluoropyridin-2-yl)methyl)-3-methylimidazolidin-2-one
使用由實施例88的步驟5所得之(E)-(2-(5-氟-6-((3-甲基-2-側氧基咪唑啶-1-基)甲基)吡啶-3-基)乙烯基)硼酸，而取代(E)-1-甲基-3-((5-(2-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)乙烯基)吡啶-2-基)甲基)咪唑啶-2-酮，並使用由實施例28的步驟3所得之2-碘-5,6-二氫-4H-咪唑并[4,5,1-ij]喹啉，而取代2-溴-1-乙基-1H-苯并[d]咪唑，進行與實施例59同樣的操作，獲得標記化合物(0.15g)。1 H NMR (400MHz, CDCl3 ) δ: 2.27-2.37 (2H, m), 2.84 (3H, s), 2.98-3.07 (2H, m), 3.31-3.37 (2H, m), 3.38-3.44 (2H, m), 4.25-4.34 (2H, m), 4.62 (2H, d, J=2.0 Hz), 7.02 (1H, d, J=7.3 Hz), 7.09 (1H, d, J=15.8 Hz), 7.17-7.23 (1H, m), 7.54-7.61 (2H, m), 7.88 (1H, d, J=15.8 Hz), 8.57 (1H, s). MS (ESI) m/z 392 (M+H)+ .Using the (E)-(2-(5-fluoro-6-((3-methyl-2-oxoimidazolidine-1-yl)methyl)pyridine-3- obtained in step 5 of Example 88 Yl)vinyl)boronic acid, and substituted (E)-1-methyl-3-((5-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane Cyclo-2-yl)vinyl)pyridin-2-yl)methyl)imidazolidin-2-one, using 2-iodo-5,6-dihydro-4H-imidazole obtained in step 3 of Example 28 And [4,5,1-ij]quinoline instead of 2-bromo-1-ethyl-1H-benzo[d]imidazole, the same operation as in Example 59 was performed to obtain the labeled compound (0.15 g). 1 H NMR (400MHz, CDCl 3 ) δ: 2.27-2.37 (2H, m), 2.84 (3H, s), 2.98-3.07 (2H, m), 3.31-3.37 (2H, m), 3.38-3.44 (2H , m), 4.25-4.34 (2H, m), 4.62 (2H, d, J=2.0 Hz), 7.02 (1H, d, J=7.3 Hz), 7.09 (1H, d, J=15.8 Hz), 7.17 -7.23 (1H, m), 7.54-7.61 (2H, m), 7.88 (1H, d, J=15.8 Hz), 8.57 (1H, s). MS (ESI) m/z 392 (M+H) + .
實施例90：(E)-1-((6-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)吡啶-3-基)甲基)-3-甲基咪唑啶-2-酮Example 90: (E)-1-((6-(2-(1-ethyl-1H-benzo[d]imidazol-2-yl)vinyl)pyridin-3-yl)methyl)-3 -Methylimidazolidin-2-one
步驟1 (6-溴-3-吡啶基)甲基甲磺酸鹽(酯) 冰冷下，在2-溴-5-(羥基甲基)吡啶(10.0g)及三乙胺(11.1mL)的氯仿(100mL)溶液中滴下甲磺醯氯(4.6mL)，攪拌30分鐘。在反應液中添加飽和氯化銨水溶液，以氯仿進行萃取。以飽和食鹽水清洗萃取液後，以硫酸鎂進行乾燥。在減壓下餾去溶劑，獲得標記化合物(13.6g)。1 H NMR (400MHz, CDCl3 ) δ: 3.04 (3H, s), 5.22 (2H, s), 7.55 (1H, d, J=8.2 Hz), 7.64 (1H, dd, J=8.2, 2.5 Hz), 8.42 (1H, d, J=2.0 Hz). MS (ESI) m/z 266 (M+H)+ .Step 1 (6-Bromo-3-pyridyl) methyl methanesulfonate (ester) under ice-cooling, in 2-bromo-5-(hydroxymethyl)pyridine (10.0g) and triethylamine (11.1mL) Methanesulfonate chloride (4.6 mL) was dropped into the chloroform (100 mL) solution, and the mixture was stirred for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, and extraction was performed with chloroform. After washing the extract with saturated brine, it was dried with magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (13.6 g). 1 H NMR (400MHz, CDCl 3 ) δ: 3.04 (3H, s), 5.22 (2H, s), 7.55 (1H, d, J=8.2 Hz), 7.64 (1H, dd, J=8.2, 2.5 Hz) , 8.42 (1H, d, J=2.0 Hz). MS (ESI) m/z 266 (M+H) + .
步驟2 1-((6-溴吡啶-3-基)甲基)-3-甲基咪唑啶-2-酮 冰冷下，在氫化鈉(2.68g，55%油性)的N,N-二甲基甲醯胺(50mL)懸浮液中滴下1-甲基咪唑啶-2-酮(6.14g)的N,N-二甲基甲醯胺(30mL)溶液。攪拌30分鐘後，滴下由上述步驟1所得之(6-溴-3-吡啶基)甲基甲磺酸酯(13.6g)的N,N-二甲基甲醯胺(20mL)溶液，再攪拌18小時。在反應液中添加水，以氯仿進行萃取。以飽和食鹽水清洗萃取液，以硫酸鎂進行乾燥。餾去溶劑後，將殘渣以矽膠管柱層析法(n-己烷/乙酸乙酯)進行純化，獲得標記化合物(15.2g)。1 H NMR (400MHz, CDCl3 ) δ: 2.83 (3H, s), 3.15-3.21 (2H, m), 3.28-3.33 (2H, m), 4.34 (2H, s), 7.45 (1H, d, J=8.2 Hz), 7.53 (1H, dd, J=8.2, 2.5 Hz), 8.27 (1H, d, J=2.6 Hz). MS (ESI) m/z 270 (M+H)+ .Step 2 1-((6-Bromopyridin-3-yl)methyl)-3-methylimidazolidin-2-one under ice cooling, in sodium hydride (2.68g, 55% oily) N,N-dimethyl A solution of 1-methylimidazolidin-2-one (6.14g) in N,N-dimethylformamide (30 mL) was dropped into the suspension of methylcarbamide (50 mL). After stirring for 30 minutes, drop the N,N-dimethylformamide (20 mL) solution of (6-bromo-3-pyridyl) methanesulfonate (13.6 g) obtained in step 1 above, and stir again 18 hours. Water was added to the reaction liquid, and extraction was performed with chloroform. The extract was washed with saturated brine and dried with magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (15.2 g). 1 H NMR (400MHz, CDCl 3 ) δ: 2.83 (3H, s), 3.15-3.21 (2H, m), 3.28-3.33 (2H, m), 4.34 (2H, s), 7.45 (1H, d, J =8.2 Hz), 7.53 (1H, dd, J=8.2, 2.5 Hz), 8.27 (1H, d, J=2.6 Hz). MS (ESI) m/z 270 (M+H) + .
步驟3 1-甲基-3-((6-(三甲基矽基)乙炔基)吡啶-3-基)甲基)咪唑啶-2-酮 在由上述步驟2所得之1-((6-溴吡啶-3-基)甲基)-3-甲基咪唑啶-2-酮(7.15g)、三甲基矽基乙炔(5.57mL)的四氫呋喃(100mL)溶液中添加碘化銅(1.00g)及雙(三苯基膦)二氯化鈀(II)(1.86g)後，緩緩添加三乙胺(11.1mL)，攪拌4小時。藉由抽氣過濾去除不溶物，以氨水及飽和食鹽水清洗後，以硫酸鎂乾燥有機層。在減壓下餾去溶劑，獲得為粗產物的標記化合物(7.50g)。1 H NMR (400MHz, CDCl3 ) δ: 0.08 (9H, s), 2.64 (3H, s), 2.94-3.00 (2H, m), 3.08-3.13 (2H, m), 7.24 (1H, dd, J=8.0, 0.8 Hz), 7.41 (1H, dd, J=8.0, 2.3 Hz), 8.27 (1H, dd, J=2.2, 0.7 Hz). MS (ESI) m/z 288 (M+H)+ .Step 3 1-Methyl-3-((6-(trimethylsilyl)ethynyl)pyridin-3-yl)methyl)imidazolidin-2-one in the 1-((6 -Bromopyridin-3-yl)methyl)-3-methylimidazolidin-2-one (7.15g), trimethylsilylacetylene (5.57mL) in tetrahydrofuran (100mL), add copper iodide (1.00 g) and bis(triphenylphosphine) palladium (II) dichloride (1.86 g), then slowly add triethylamine (11.1 mL), and stir for 4 hours. The insoluble matter was removed by suction filtration, washed with ammonia water and saturated brine, and the organic layer was dried with magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (7.50 g) as a crude product. 1 H NMR (400MHz, CDCl 3 ) δ: 0.08 (9H, s), 2.64 (3H, s), 2.94-3.00 (2H, m), 3.08-3.13 (2H, m), 7.24 (1H, dd, J =8.0, 0.8 Hz), 7.41 (1H, dd, J=8.0, 2.3 Hz), 8.27 (1H, dd, J=2.2, 0.7 Hz). MS (ESI) m/z 288 (M+H) + .
步驟4 1-((6-乙炔基吡啶-3-基)甲基)-3-甲基咪唑啶-2-酮 在由上述步驟3所得之1-甲基-3-((6-(三甲基矽基)乙炔基)吡啶-3-基)甲基)咪唑啶-2-酮(7.50g)的四氫呋喃(100mL)溶液中滴下四-N-丁基氟化銨(1moL/L四氫呋喃溶液，26.0mL)，攪拌1小時。以乙酸乙酯稀釋反應液後，以水及飽和食鹽水進行清洗。以硫酸鈉乾燥有機層，在減壓下餾去溶劑。將殘渣以矽膠管柱層析法(氯仿/乙酸乙酯)進行純化，獲得標記化合物(3.73g)。1 H NMR (400MHz, CDCl3 ) δ: 2.84 (3H, s), 3.15 (1H, s), 3.16-3.21 (2H, m), 3.27-3.33 (2H, m), 4.39 (2H, s), 7.46 (1H, d, J=8.0 Hz), 7.63 (1H, dd, J=8.0, 2.1 Hz), 8.49 (1H, d, J=1.6 Hz). MS (ESI) m/z 216 (M+H)+ .Step 4 1-((6-Ethynylpyridin-3-yl)methyl)-3-methylimidazolidin-2-one in the 1-methyl-3-((6-(三) obtained from step 3 above (Methylsilyl)ethynyl)pyridin-3-yl)methyl)imidazolidin-2-one (7.50g) in tetrahydrofuran (100mL) was dripped with tetra-N-butylammonium fluoride (1moL/L tetrahydrofuran solution) , 26.0mL), stirred for 1 hour. After the reaction solution was diluted with ethyl acetate, it was washed with water and saturated brine. The organic layer was dried with sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/ethyl acetate) to obtain the title compound (3.73 g). 1 H NMR (400MHz, CDCl 3 ) δ: 2.84 (3H, s), 3.15 (1H, s), 3.16-3.21 (2H, m), 3.27-3.33 (2H, m), 4.39 (2H, s), 7.46 (1H, d, J=8.0 Hz), 7.63 (1H, dd, J=8.0, 2.1 Hz), 8.49 (1H, d, J=1.6 Hz). MS (ESI) m/z 216 (M+H ) + .
步驟5 (E)-1-甲基-3-((6-(2-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)乙烯基)吡啶-3-基)甲基)咪唑啶-2-酮 冰冷下，在由上述步驟4所得之1-((6-乙炔基吡啶-3-基)甲基)-3-甲基咪唑啶-2-酮(1.00g)的四氫呋喃(25mL)溶液中添加甲醇(0.38mL)及雙聯頻哪醇硼酸酯(bis(pinacolato)diboron)(1.42g)後，添加三級丁醇鈉(0.027g)及4,5-雙二苯基膦-9,9-二甲基氧雜蒽(Xantphos)(0.40g)，氯化銅(I)(0.014g)後，進行氮置換，攪拌24小時。藉由矽藻土過濾去除不溶物後，將濾液進行減壓濃縮。將殘渣以矽膠管柱層析法(氯仿/甲醇)進行純化，獲得標記化合物(0.70g)。1 H NMR (400MHz, CDCl3 ) δ: 1.31 (12H, s), 2.83 (3H, s), 3.13-3.21 (2H, m), 3.25-3.33 (2H, m), 4.37 (2H, s), 6.60 (1H, d, J=18.2 Hz), 7.38 (1H, d, J=8.0 Hz), 7.44 (1H, d, J=18.3 Hz), 7.61 (1H, dd, J=8.0, 2.3 Hz), 8.49 (1H, d, J=1.9 Hz).Step 5 (E)-1-Methyl-3-((6-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)vinyl )Pyridin-3-yl)methyl)imidazolidin-2-one under ice cooling, the 1-((6-ethynylpyridin-3-yl)methyl)-3-methylimidazolidine obtained in step 4 above -2-one (1.00g) in tetrahydrofuran (25mL) was added methanol (0.38mL) and double pinacolato diboron (bis(pinacolato)diboron) (1.42g), then added tertiary butoxide sodium ( 0.027g) and 4,5-bis-diphenylphosphine-9,9-dimethylxanthene (Xantphos) (0.40g), copper (I) chloride (0.014g), followed by nitrogen substitution and stirring for 24 hour. After filtering through Celite to remove the insoluble matter, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to obtain the title compound (0.70 g). 1 H NMR (400MHz, CDCl 3 ) δ: 1.31 (12H, s), 2.83 (3H, s), 3.13-3.21 (2H, m), 3.25-3.33 (2H, m), 4.37 (2H, s), 6.60 (1H, d, J=18.2 Hz), 7.38 (1H, d, J=8.0 Hz), 7.44 (1H, d, J=18.3 Hz), 7.61 (1H, dd, J=8.0, 2.3 Hz), 8.49 (1H, d, J=1.9 Hz).
步驟6
(E)-1-((6-(2-(1-乙基-1H-苯并[d]咪唑-2-基)乙烯基)吡啶-3-基)甲基)-3-甲基咪唑啶-2-酮
在由上述步驟5所得之(E)-1-甲基-3-((6-(2-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)乙烯基)吡啶-3-基)甲基)咪唑啶-2-酮(0.70g)及由參考例2的步驟1所得之2-溴-1-乙基-1H-苯并[d]咪唑(0.46g)的1,4-二
實施例91：(E)-1-((5-(2-(1-乙基-5-氟-1H-苯并[d]咪唑-2-基)乙烯基)吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮鹽酸鹽Example 91: (E)-1-((5-(2-(1-ethyl-5-fluoro-1H-benzo[d]imidazol-2-yl)vinyl)pyridin-2-yl)methan Yl)-3-methylimidazolidin-2-one hydrochloride
在由實施例74所得之(E)-1-((5-(2-(1-乙基-5-氟-1H-苯并[d]咪唑-2-基)乙烯基)吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮(0.073g)中添加2-丙醇(0.34mL)，進行加熱使其完全溶解。添加鹽酸(35%氯化氫，0.01mL)的2-丙醇(0.10mL)溶液，在0℃靜置16小時，將生成的固體進行濾取、乾燥，獲得標記化合物(0.040g)。1 H NMR (400MHz, DMSO-d6 ) δ: 1.40 (3H, t, J=7.2 Hz), 2.71 (3H, s), 3.32 (4H, s), 4.47 (2H, s), 4.65 (2H, q, J=7.2 Hz), 7.31-7.40 (1H, m), 7.47 (1H, d, J=8.2 Hz), 7.59 (1H, dd, J=8.8, 2.4 Hz), 7.74 (1H, d, J=16.1 Hz), 7.86-7.94 (1H, m), 8.18 (1H, d, J=16.1 Hz), 8.43 (1H, dd, J=8.2, 2.0 Hz), 8.97 (1H, d, J=2.0 Hz). MS (ESI) m/z 362 (M+H)+ .(E)-1-((5-(2-(1-ethyl-5-fluoro-1H-benzo[d]imidazol-2-yl)vinyl)pyridine-2- ((Yl)methyl)-3-methylimidazolidin-2-one (0.073g) was added with 2-propanol (0.34mL) and heated to completely dissolve it. A solution of hydrochloric acid (35% hydrogen chloride, 0.01 mL) in 2-propanol (0.10 mL) was added, and the mixture was allowed to stand at 0°C for 16 hours. The resulting solid was filtered and dried to obtain the labeled compound (0.040 g). 1 H NMR (400MHz, DMSO-d 6 ) δ: 1.40 (3H, t, J=7.2 Hz), 2.71 (3H, s), 3.32 (4H, s), 4.47 (2H, s), 4.65 (2H, q, J=7.2 Hz), 7.31-7.40 (1H, m), 7.47 (1H, d, J=8.2 Hz), 7.59 (1H, dd, J=8.8, 2.4 Hz), 7.74 (1H, d, J =16.1 Hz), 7.86-7.94 (1H, m), 8.18 (1H, d, J=16.1 Hz), 8.43 (1H, dd, J=8.2, 2.0 Hz), 8.97 (1H, d, J=2.0 Hz ). MS (ESI) m/z 362 (M+H) + .
實施例92：(E)-1-((5-(2-(1-乙基-5-氟-1H-苯并[d]咪唑-2-基)乙烯基)吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮草酸鹽Example 92: (E)-1-((5-(2-(1-ethyl-5-fluoro-1H-benzo[d]imidazol-2-yl)vinyl)pyridin-2-yl)methan Yl)-3-methylimidazolidin-2-one oxalate
在由實施例74所得之(E)-1-((5-(2-(1-乙基-5-氟-1H-苯并[d]咪唑-2-基)乙烯基)吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮(0.040g)的2-丙醇(0.34mL)溶液中添加草酸二水合物(0，015g)的2-丙醇(0.10mL)溶液，在0℃靜置18小時，將生成的固體進行濾取、乾燥，獲得標記化合物(0.045g)。1 H NMR (400MHz, DMSO-d6 ) δ: 1.33 (3H, t, J=7.2 Hz), 2.70 (3H, s), 3.29 (4H, s), 4.40 (2H, s), 4.49 (2H, q, J=7.2 Hz), 7.07-7.14 (1H, m), 7.34 (1H, d, J=8.2 Hz), 7.41 (1H, dd, J=9.8, 2.4 Hz), 7.55-7.65 (2H, m), 7.88 (1H, d, J=15.8 Hz), 8.27 (1H, dd, J=8.2, 2.1 Hz), 8.90 (1H, d, J=2.1 Hz). MS (ESI) m/z 362 (M+H)+ .(E)-1-((5-(2-(1-ethyl-5-fluoro-1H-benzo[d]imidazol-2-yl)vinyl)pyridine-2- (Yl)methyl)-3-methylimidazolidin-2-one (0.040g) in 2-propanol (0.34mL) was added oxalic acid dihydrate (0,015g) in 2-propanol (0.10mL) The solution was allowed to stand at 0°C for 18 hours, and the generated solid was filtered and dried to obtain the labeled compound (0.045 g). 1 H NMR (400MHz, DMSO-d 6 ) δ: 1.33 (3H, t, J=7.2 Hz), 2.70 (3H, s), 3.29 (4H, s), 4.40 (2H, s), 4.49 (2H, q, J=7.2 Hz), 7.07-7.14 (1H, m), 7.34 (1H, d, J=8.2 Hz), 7.41 (1H, dd, J=9.8, 2.4 Hz), 7.55-7.65 (2H, m ), 7.88 (1H, d, J=15.8 Hz), 8.27 (1H, dd, J=8.2, 2.1 Hz), 8.90 (1H, d, J=2.1 Hz). MS (ESI) m/z 362 (M +H) + .
實施例93：(E)-1-((5-(2-(1-乙基-5-氟-1H-苯并[d]咪唑-2-基)乙烯基)吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮順丁烯二酸鹽Example 93: (E)-1-((5-(2-(1-ethyl-5-fluoro-1H-benzo[d]imidazol-2-yl)vinyl)pyridin-2-yl)methan Yl)-3-methylimidazolidin-2-one maleate
在由實施例74所得之(E)-1-((5-(2-(1-乙基-5-氟-1H-苯并[d]咪唑-2-基)乙烯基)吡啶-2-基)甲基)-3-甲基咪唑啶-2-酮(0.040g)中添加2-丙醇(0.34mL)，進行加熱使其完全溶解。添加順丁烯二酸(0.014g)的2-丙醇(0.10mL)溶液，在0℃靜置18小時，將生成的固體進行濾取、乾燥，獲得標記化合物(0.049g)。1 H NMR (400MHz, DMSO-d6 ) δ: 1.34 (3H, t, J=7.2 Hz), 2.70 (3H, s), 3.30 (4H, s), 4.41 (2H, s), 4.51 (2H, q, J=7.2 Hz), 6.25 (2H, s), 7.10 -7.18 (1H, m), 7.36 (1H, d, J=8.2 Hz), 7.43 (1H, dd, J=9.7, 2.3 Hz), 7.56-7.69 (2H, m), 7.89 (1H, d, J=15.9 Hz), 8.29 (1H, dd, J=8.2, 2.3 Hz), 8.90 (1H, d, J=2.1 Hz). MS (ESI) m/z 362 (M+H)+ .(E)-1-((5-(2-(1-ethyl-5-fluoro-1H-benzo[d]imidazol-2-yl)vinyl)pyridine-2- ((Yl)methyl)-3-methylimidazolidin-2-one (0.040 g) was added with 2-propanol (0.34 mL), and heated to completely dissolve it. A solution of maleic acid (0.014 g) in 2-propanol (0.10 mL) was added, and the mixture was allowed to stand at 0°C for 18 hours. The resulting solid was filtered and dried to obtain the labeled compound (0.049 g). 1 H NMR (400MHz, DMSO-d 6 ) δ: 1.34 (3H, t, J=7.2 Hz), 2.70 (3H, s), 3.30 (4H, s), 4.41 (2H, s), 4.51 (2H, q, J=7.2 Hz), 6.25 (2H, s), 7.10 -7.18 (1H, m), 7.36 (1H, d, J=8.2 Hz), 7.43 (1H, dd, J=9.7, 2.3 Hz), 7.56-7.69 (2H, m), 7.89 (1H, d, J=15.9 Hz), 8.29 (1H, dd, J=8.2, 2.3 Hz), 8.90 (1H, d, J=2.1 Hz). MS (ESI ) m/z 362 (M+H) + .
(試驗例1)待驗化合物的cAMP產生抑制作用的檢測(cAMP Assay) 1)待驗化合物對細胞的處理 將穩定表現人類5-HT5A受體之CHO-K1細胞(cAMP Hunter(註冊商標)CHO-K1 HTR5A Gi Cell Line，DiscoverX，95-0160C2)，使用Assay Complete Cell plating 21 Reagent(DiscoverX，93-0563R21)，在96孔盤播種成1×104 cells/well，並培養一晚。去除上述培養基後，替換成包含1.5μM的isamoltane(nacalai tesque，1963784)與0.15%BSA(Sigma-Aldrich，A8412)之MEM培養基(Thermo Fisher Scientific，51200038)(24μL/well)，在37℃的CO2 培養箱(incubator)進行15分鐘前處理。將用MEM培養基進行系列稀釋後之待驗化合物溶液以6μL/well添加至細胞後，立刻添加48uM的Forskolin(和光純藥工業，067-02191)6μL/well，使其在37℃的CO2 培養箱反應15分鐘。(Test Example 1) Detection of the cAMP production inhibitory effect of the test compound (cAMP Assay) 1) The treatment of the test compound on the cells will stably express the human 5-HT5A receptor CHO-K1 cells (cAMP Hunter (registered trademark) CHO -K1 HTR5A Gi Cell Line, DiscoverX, 95-0160C2), using Assay Complete Cell plating 21 Reagent (DiscoverX, 93-0563R21), sown 1×10 4 cells/well in 96-well plates, and culture overnight. After removing the above medium, it was replaced with MEM medium (Thermo Fisher Scientific, 51200038) (24 μL/well) containing 1.5 μM isamoltane (nacalai tesque, 1963784) and 0.15% BSA (Sigma-Aldrich, A8412) at 37°C in CO 2 Incubator (incubator) for 15 minutes of pretreatment. After adding the test compound solution serially diluted in MEM medium to the cells at 6μL/well, immediately add 48uM Forskolin (Wako Pure Chemical Industries, 067-02191) 6μL/well to incubate at 37°C in CO 2 The box reacts for 15 minutes.
2)cAMP量的測定 將1)所得之細胞的細胞上清液去除後，在冰冷下添加包含內標準物質(cGMP 100ng/mL)的甲醇100 μL/well，使反應停止。靜置10分鐘後，將甲醇全部回收至別的96孔盤後，添加另外製備的校正曲線用cAMP溶液(包含cGMP 100ng/mL)，藉由離心濃縮使其乾固。藉由添加0.1%甲酸水溶液：MeCN=4：1的溶液80μL/well而溶解殘渣，進行過濾器過濾後，以LC-MS/MS(TQ-S)測定通過部分(through fraction)的cAMP濃度。測定後的活性的算出，係遵循下述方法。亦即，將設置在各盤之參考例16所合成之化合物所顯示的最大抑制率，設為Efficacy，將包圍其50%之各待驗化合物的二點的濃度代入下述計算式，而求出IC50。參考例16所合成之化合物係顯示與為陽性對照化合物之5-羧醯胺色胺(以下有時記載為5-CT)相同程度的cAMP產生抑制效果之化合物，5-CT在本cAMP Assay中相對於控制組使cAMP產生量降低了最多60～70%左右。2) Determination of the amount of cAMP After removing the cell supernatant of the cells obtained in 1), 100 μL/well of methanol containing the internal standard substance (cGMP 100ng/mL) was added under ice-cooling to stop the reaction. After standing for 10 minutes, all methanol was recovered to another 96-well plate, and a separately prepared cAMP solution for calibration curve (including cGMP 100ng/mL) was added, and the mixture was concentrated by centrifugation to dry it. The residue was dissolved by adding 0.1% formic acid aqueous solution: 80 μL/well of a MeCN=4:1 solution, filtered through a filter, and measured by LC-MS/MS (TQ-S) to measure the cAMP concentration of the through fraction. The calculation of the activity after the measurement followed the following method. That is, the maximum inhibition rate shown by the compound synthesized in Reference Example 16 set on each plate is set as Efficacy, and the concentration of each test compound surrounding 50% of the two points of each test compound is substituted into the following calculation formula to obtain出IC50. The compound synthesized in Reference Example 16 shows the same level of cAMP production inhibitory effect as 5-carboxamide tryptamine (hereinafter sometimes referred to as 5-CT) which is the positive control compound. 5-CT is included in this cAMP Assay Compared with the control group, the amount of cAMP production was reduced by up to 60 to 70%.
IC50 =10^ (Log(A/B)×(E-C)/(D-C)＋Log(B)) A：顯示比E強的抑制之待驗化合物濃度 B：顯示比E弱的抑制之待驗化合物濃度 C：在B的抑制率% D：在A的抑制率% E：顯示Efficacy的50%之抑制率%IC 50 =10 ^ (Log(A/B)×(EC)/(DC)＋Log(B)) A: Concentration of test compound showing stronger inhibition than E B: Test compound showing weaker inhibition than E Concentration C: Inhibition rate% in B D: Inhibition rate% in A E: Inhibition rate% showing 50% of Efficacy
(試驗例2)待驗化合物對於小鼠血清素5A受體的親和性的探討(5-HT5A Binding Assay) 對於血清素5A(5-HT5A)受體的親和性的測定，係遵循既知報告(JEFFREY SPROUSE et al.,2004)而實施。亦即，從5-HT5A受體表現GripTiteHEK293細胞製備膜部分。以磷酸緩衝生理食鹽水回收細胞，以1500rpm離心分離5分鐘，使細胞沉澱物懸浮在膜部分製備用緩衝液(25mM HEPES、10mM氯化鎂、1mM乙烯二胺四乙酸、0.25mM蔗糖、pH7.4)中。使用超音波均質機將細胞進行破碎。將破碎的細胞懸浮液以1300rpm離心分離5分鐘，獲得上清液。再以100,000g離心分離60分鐘，去除上清液，獲得細胞沉澱物。使細胞沉澱物懸浮在膜部分製備用緩衝液中，獲得膜部分。(Test Example 2) Discussion on the affinity of the test compound for mouse serotonin 5A receptor (5-HT5A Binding Assay) For the determination of the affinity of the serotonin 5A (5-HT5A) receptor, it was implemented in accordance with the known report (JEFFREY SPROUSE et al., 2004). That is, the membrane fraction was prepared from 5-HT5A receptor expressing GripTiteHEK293 cells. The cells were recovered with phosphate buffered saline, centrifuged at 1500 rpm for 5 minutes, and the cell pellet was suspended in the membrane preparation buffer (25 mM HEPES, 10 mM magnesium chloride, 1 mM ethylene diamine tetraacetic acid, 0.25 mM sucrose, pH 7.4) in. Use an ultrasonic homogenizer to break the cells. The broken cell suspension was centrifuged at 1300 rpm for 5 minutes to obtain a supernatant. After centrifugation at 100,000 g for 60 minutes, the supernatant was removed to obtain a cell pellet. The cell pellet is suspended in a buffer for preparing a membrane portion to obtain a membrane portion.
在96孔分析盤中，添加以受體結合試驗用緩衝液(50mM三羥甲基胺基甲烷(Tris)、10mM硫酸鎂、0.5mM乙烯二胺四乙酸、0.1%牛血清白蛋白、pH7.4)所製備之[3H]5-羧醯胺色胺(7.5nM)溶液20μL/well、以成為7μg/well之方式所製備之膜部分30μL/well、以二甲亞碸所製備之試驗化合物溶液50μL/well，並進行混合。在37℃培養60分鐘。利用以0.01%聚乙亞胺前處理過的UniFilter-96的GF/B試片(PerkinElmer公司)，將反應液進行抽氣過濾，以清洗液(50mM三羥甲基胺基甲烷、10mM硫酸鎂、0.5mM乙烯二胺四乙酸、pH7.4)清洗三次，藉此結束反應。以55℃乾燥GF/B試片後，以30μL/well分注MicroScint 0(PerkinElmer公司)，並將試片上部以TOP SEAL A(PerkinElmer公司)進行密栓，利用Top Count NXT(PerkinElmer公司)測定放射活性。各孔的放射活性，係藉由扣除添加5-羥基色胺50μM時的放射活性(非特異性結合)而算出。[3H]5-羧醯胺色胺的結合率%係遵循以下公式而算出。In a 96-well analysis dish, add a buffer for receptor binding assay (50mM Tris (Tris), 10mM magnesium sulfate, 0.5mM ethylenediaminetetraacetic acid, 0.1% bovine serum albumin, pH7. 4) The prepared [3H]5-carboxamide tryptamine (7.5nM) solution 20 μL/well, the membrane part prepared to become 7 μg/well 30 μL/well, and the test compound prepared with dimethyl sulfoxide The solution is 50μL/well and mixed. Incubate at 37°C for 60 minutes. Using the UniFilter-96 GF/B test piece (PerkinElmer) pre-treated with 0.01% polyethyleneimine, the reaction solution was pumped and filtered to clean the solution (50mM tris, 10mM magnesium sulfate). , 0.5 mM ethylene diamine tetraacetic acid, pH 7.4) wash three times to terminate the reaction. After drying the GF/B test piece at 55°C, dispense MicroScint 0 (PerkinElmer) at 30μL/well, seal the upper part of the test piece with TOP SEAL A (PerkinElmer), and measure the radiation with Top Count NXT (PerkinElmer) active. The radioactivity of each well was calculated by subtracting the radioactivity (non-specific binding) when 50 μM of 5-hydroxytryptamine was added. [3H] The binding rate% of 5-carboxamide tryptamine is calculated based on the following formula.
結合率%=(試驗化合物添加組的放射活性)/(介質添加組的放射活性)x100Binding rate% = (radioactivity of test compound added group)/(radioactivity of medium added group) x 100
使用分析軟體GraphPad Prism，將結合率%相對於試驗化合物濃度進行作圖，藉由非線形迴歸進行近似，藉此算出50%抑制濃度IC50。Using the analysis software GraphPad Prism, the binding rate% was plotted against the concentration of the test compound and approximated by nonlinear regression to calculate the 50% inhibitory concentration IC50.
[表1]
[表2]
(試驗例3)使用小鼠之在時差條件下進行的化合物的相位前移作用的評價 對於9～11週齡的雄性C57BL/6J小鼠(Japan SLC股份有限公司)，在麻醉下，將體溫自動記錄器(Thermochron SL型，KN LABORATORIES)埋入腹腔內。體溫自動記錄器係在實驗結束為止前的期間，以可每10分鐘進行經時記綠之方式進行設定。小鼠係在自由攝食攝水下，每一籠各飼育一隻，在手術後經過1週以上的恢復期間後，將飼育室的明暗循環往前調6小時，藉此變更成時差環境。在自變更日起的4個日子，將待驗化合物100mg/kg以10mL/kg的容量進行經口投予。待驗化合物係溶解或懸浮於0.053mol/L鹽酸。對照群組係將0.053mol/L鹽酸以10mL/kg的容量進行經口投予。各群組的實例數設為6～9隻。在投予結束後經過至少2日後，進行安樂死，取出體溫自動記錄器。(Test Example 3) Evaluation of the phase advancement effect of the compound under jet lag conditions using mice For male C57BL/6J mice (Japan SLC Co., Ltd.) aged 9-11 weeks, under anesthesia, an automatic temperature recorder (Thermochron SL type, KN LABORATORIES) was embedded in the abdominal cavity. The automatic body temperature recorder is set in such a way that it can record green every 10 minutes during the period until the end of the experiment. The mice were fed freely with food and water, and each cage was bred one. After a recovery period of more than 1 week after the operation, the light-dark cycle of the feeding room was adjusted forward for 6 hours to change to a jet lag environment. On 4 days from the date of change, 100 mg/kg of the test compound was orally administered in a volume of 10 mL/kg. The test compound is dissolved or suspended in 0.053mol/L hydrochloric acid. In the control group, 0.053 mol/L hydrochloric acid was administered orally at a volume of 10 mL/kg. The number of instances in each group is set to 6-9. At least 2 days after the end of the administration, euthanasia was performed and the automatic temperature recorder was taken out.
將所記錄的體溫數據輸入電腦，對測定値施以單純移動平均處理，將體溫開始上升後出現的最初體溫峰時刻作為體溫節律的基準相位。算出相對於變更成時差環境前的基準相位而言，變更成時差環境後期間第1日至第4日的各日之相位前移時間。算出該4個日子的相位前移時間之和(=累積相位前移時間)，求出對照群組與待驗化合物群組之累積相位前移時間之差。The recorded body temperature data is input into a computer, and the measurement value is subjected to simple moving average processing, and the first body temperature peak time that appears after the body temperature starts to rise is used as the reference phase of the body temperature rhythm. Calculate the phase advance time of each day from the 1st to the 4th day of the period after changing to the time difference environment relative to the reference phase before changing to the time difference environment. Calculate the sum of the phase advance time of the 4 days (=cumulative phase advance time), and obtain the difference between the cumulative phase advance time of the control group and the test compound group.
[表3]
由上述試驗例1～3的結果可知，本發明的化合物對5-HT5A受體具有促效物活性，可用於預防或治療睡醒相位後移症(DSPS)、不規則睡醒模式、非二十四小時睡醒節律症、輪班工作症、時差症、非特定的晝夜節律性睡眠障礙、情感疾病、認知功能不全、失眠症、或思覺失調症用。It can be seen from the results of the above test examples 1 to 3 that the compounds of the present invention have agonist activity on 5-HT5A receptors, and can be used to prevent or treat phase shifting sleep-wake syndrome (DSPS), irregular wake-up patterns, and non-two Fourteen-hour wake rhythm disorder, shift work disorder, jet lag, non-specific circadian rhythm sleep disorder, affective disorder, cognitive insufficiency, insomnia, or schizophrenia.
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