TWI325414B - 1,2,4-triaminobenzene derivatives - Google Patents

1,2,4-triaminobenzene derivatives Download PDF

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TWI325414B
TWI325414B TW092135930A TW92135930A TWI325414B TW I325414 B TWI325414 B TW I325414B TW 092135930 A TW092135930 A TW 092135930A TW 92135930 A TW92135930 A TW 92135930A TW I325414 B TWI325414 B TW I325414B
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amino
alkenyl
phenyl
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TW092135930A
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TW200413280A (en
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Andreas Ritzen
Nikolay Khanzhin
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Lundbeck & Co As H
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/28—Halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/32—Oxygen atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

1325414 玖、發明說明： 【發明所屬之技術領域】 本發明係關於KCNQ族鉀離子通道開啟劑之新賴 1，2, 4-三胺基苯衍生物。這些化合物可用來預防、治療及 /或抑制中枢神經系統的障礙。 【先前技術】 發明背景 離子通道是調節離子，包括鉀離子、鈣離子、氣離子 和鈉離子等進出細胞之流動的細胞蛋白質。這類通道係存 在於所有的動物和人類細胞中且影響各種不同的程序，包 括神經元傳遞、肌肉收縮和細胞分泌。 人類有超過70個鉀離子通道亞單位（Jentsch 印ce2〇〇〇，j，2卜3〇),而在結構與功 月t« —者方面有很大的差異。神經元鉀離子通道可在大腦中 各現，主要是負責維持一個負的靜息膜電位，以及控制在 動作電位之後的臈復極化。 鉀離子通道基因的一個亞群是KCNQ族。在五個KCNQ 土因中四個的大變已經證實是造成疾$，包括心律不整、 及癲痛的基礎（Jentsch yVaii/re 妒5 ’e"/·⑽/e卿 2000，1，2卜30)。 KCNQ4基因被認為是編碼與發現在耳蜗外毛感覺上皮 包及則庭器第-型毛細胞中之_離子通道相關的分子， 其中的突變導致一種形態的遺傳性耳聾。 1325414 KCNQl(KvLQTl)係與KCNE1(極小的Κ( + )-通道蛋白 質）基因的產物在心臟共組合以形成一種似心臟延遲整流 Κ( + )電流。在此通道中的突變可引起一種形態的遺傳性第 1型QT節段延長症侯群（long QT syndrome type 1 (LQT1))，而且係與一種形態的耳聾有關（R0bbins PZ/a/*历aco/ 7V7er 2001，90，1-19) 0 基因KCNQ2和KCNQ3是在1988年被發現且似乎在一種 已知為良性家族性新生兒痙攣的遺傳性形態癲癇中突變（ Rogawski Trends in Neurosciences 2000, 23, 393-398 )。被KCNQ2和KCNQ3基因編碼的蛋白質係局限於人類皮 質與海馬（即大腦中與癲癇發作產生和傳導有關之區域） 的錐體神經元中（Cooper et al.斤WhMa/ Z/ 51 j 2000，97, 4914-4919 ) 〇 KCNQ2和KCNQ3是二個當在活體外表現時會形成，’μ-電 流’’的鉀離子通道亞單位。電流是一種在許多神經元細胞 類型中發現的非去活化鉀電流。在各個細胞類型中，它因 為是動作電位起始範圍中唯一的持續電流，而在控制膜應 激性中佔重要地位（Marrion如刀"a/ iPer/e# 1997，59’ 483-504 ) 。Μ-電流的調整對於神經元應激性有 戲劇性的影響’舉例來說，電流的活化將降低神經元應激 性。因此’這些KCNQ通道的開啟劑將降低在諸如癲癇發作 之病狀及特徵在於過度神經元活動之疾病如癲癇和神經病 痛中的過度神經元活動。 瑞提加賓（Retigabine ) ( D-231 29 ; Ν-(2-胺基-4- 1325414 (4-氟苄基胺基）-苯基）胺基曱酸乙酯）及其類似物係揭示 在EP554543中。瑞提加賓是一種具有廣譜和有效抗痙攣 性質的抗痙攣化合物，在活體外和活體内皆然。它在包括 電誘發癲癇發作、藉由伸戊基四。坐、印防已毒素（ picrotoxin)及N-曱基-D-天冬胺酸以化學方式 誘發之癲癇發作的抗痙攣試驗範圍中，在大鼠和小鼠及在 基因動物模式（DBA/2小鼠）的口服和腹膜内投藥之後起 作用（Rostock et al.办1996， 23, 21 1-223)。除此之外，瑞提加賓在複雜性局部癲癇發作的 杏仁核激動模式中起作用，進一步指出此化合物具有抗痙 攣治療的潛力。在臨床試驗中，瑞提加賓最近已經證實在 降低癲癇患者之癲癇發作發病率方面的效果（Bialer al. 2002，51，31-71)。 瑞提加賓經證實可活化神經元細胞中之K( + )電流，而 此感應電流的藥理學顯示具有已公開Μ_通道藥理學的索引 ，Μ-通道最近顯示與KCNQ2/3 κ( + )通道雜多聚體（ heteromultimer)有關·>此意味著KCNQ2/3通道的活化可 能是此藥劑部分抗痙攣活性的原因（Wickenden Μ 射㈣7a/*户/7卿彻/咐2000，58，59卜600 )，而且其 他藉相同機構發揮作用的藥劑可能有類似用途。 KCNQ 2和3通道經報導在神經病痛模式中是上調的（ upregulated ) ( Wickenden et al. Society for 肋wracis· 2002，454.7)，而鉀離子通道調 節體已經被假設在神經病痛和癲癇二者中都可起作用（ 13254141325414 发明, DESCRIPTION OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to a novel lysine 1,2,4-triaminobenzene derivative of the KCNQ family potassium channel opener. These compounds are useful for preventing, treating and/or inhibiting disorders of the central nervous system. [Prior Art] Background of the Invention Ion channels are cellular proteins that regulate the flow of ions, including potassium ions, calcium ions, gas ions, and sodium ions, into and out of cells. Such channels are present in all animal and human cells and affect a variety of different procedures, including neuronal transmission, muscle contraction, and cell secretion. Humans have more than 70 potassium channel subunits (Jentsch ce2〇〇〇, j, 2 卜 3 〇), and there is a big difference between the structure and the function of the moon. Neuronal potassium channels can occur in the brain, primarily responsible for maintaining a negative resting membrane potential and controlling enthalpy repolarization after the action potential. A subgroup of the potassium channel gene is the KCNQ family. Four major changes in the five KCNQ soil factors have been shown to cause illness, including the basis of arrhythmia and epilepsy (Jentsch yVaii/re 妒5 'e"/·(10)/eqing 2000,1,2 30). The KCNQ4 gene is thought to encode a molecule associated with the ion channel found in the outer hair sensory epithelium of the cochlea and the hair cells of the court type, in which the mutation results in a form of hereditary deafness. 1325414 KCNQl (KvLQTl) is a product of the KCNE1 (very small Κ(+)-channel protein) gene that is co-assembled in the heart to form a cardiac-like delayed rectifying Κ(+) current. Mutations in this pathway can cause a morphological hereditary type 1 QT syndrome type 1 (LQT1), and are associated with a form of deafness (R0bbins PZ/a/* calendar) Aco/ 7V7er 2001,90,1-19) 0 Genes KCNQ2 and KCNQ3 were discovered in 1988 and appear to be mutations in hereditary morphological epilepsy known as benign familial neonatal neonates (Rogawski Trends in Neurosciences 2000, 23 , 393-398). The protein lines encoded by the KCNQ2 and KCNQ3 genes are confined to the pyramidal neurons of the human cortex and the hippocampus (the area associated with seizure production and conduction in the brain) (Cooper et al., WhMa/Z/ 51 j 2000, 97) , 4914-4919 ) 〇KCNQ2 and KCNQ3 are two potassium ion channel subunits that form , 'μ-current' when expressed in vitro. Current is a non-deactivated potassium current found in many neuronal cell types. Among the various cell types, it is the only continuous current in the initial range of action potentials, and it plays an important role in controlling membrane stress (Marrion is like a knife "a/ iPer/e# 1997, 59' 483-504 ) . The Μ-current adjustment has a dramatic effect on neuronal stress. For example, activation of current will reduce neuronal stress. Thus, these KCNQ channel openers will reduce excessive neuronal activity in conditions such as seizures and diseases characterized by excessive neuronal activity such as epilepsy and neuropathic pain. Retigabine (D-231 29; Ν-(2-amino-4- 1325414 (4-fluorobenzylamino)-phenyl)amino decanoic acid ethyl ester) and its analogs reveal In EP554543. Retistatin is an anti-caries compound with broad-spectrum and effective anti-caries properties, both in vitro and in vivo. It includes electro-induced seizures, by stretching pentylene IV. Sitting, imprinted with toxin (picrotoxin) and N-mercapto-D-aspartate in a chemical-induced epileptic seizure of anti-caries test in rats and mice and in the genetic animal model (DBA/2 Oral and intraperitoneal administration of mice) (Rostock et al. 1996, 23, 21 1-223). In addition, Retistatin plays a role in the amygdaloid agonistic mode of complex partial seizures, further indicating that this compound has potential for anti-caries treatment. In clinical trials, ritigatin has recently been shown to reduce the incidence of seizures in patients with epilepsy (Bialer al. 2002, 51, 31-71). Retistatin has been shown to activate K(+) currents in neuronal cells, and the pharmacology of this induced current has been shown to have an open Μ-channel pharmacology index, and the Μ-channel has recently been shown to interact with KCNQ2/3 κ (+ ) Channel heteromultimer (related) · This means that activation of the KCNQ2/3 channel may be responsible for the partial anti-caries activity of this agent (Wickenden ( (4) 7a / * household / 7 Qing 咐 / 咐 2000, 58, 59 Bu 600), and other drugs that work by the same institution may have similar uses. KCNQ 2 and 3 channels have been reported to be upregulated in neuropathic pain patterns (Wickenden et al. Society for rib wracis 2002, 454.7), whereas potassium channel modulators have been hypothesized in both neuropathic pain and epilepsy Can work ( 1325414

Schroder et al. Neuropharmacology 2001, 40, 888-898 ；Blackburn-Munro and Jensen European Journal of 叹/ 2003，460，109-116 )。此外，KCNQ 通道 mRNA的局限化係被報導在大腦及其他與疼痛有關之中柩 神經系統區域中（Goldstein et al. ibc/eiy /or Neuroscience Abstracts 2003，53.8)。 除了在神經病痛中之角色外，KCNQ 2-5之mRNA在三 叉和背根神經結及在三叉神經尾的表現，暗示這些通道的 開啟劑亦可影響偏頭痛的感官處理（Goldstein et al. iS'cOeiy /στ* Msiracis 2003，53.8)。 最近的報導證實，除了 KCNQ2之mRNA外，KCNQ 3和5 之mRNA係在星形細胞和神經膠質細胞中表現。因此KCNQ 2、3和5等通道可幫助調節CNS中的突觸活性，且有助於 KCNQ通道開啟劑的神經保護作用（Noda et a 1.，iS'oc/e /or 2003，53.9)。瑞提加賓及 其他KCNQ調節劑可因此展現出抵抗癲癇神經退化方面的 保護，因為瑞提加賓已經證實可預防邊緣神經退化及在大 鼠中紅藻胺酸誘發的癲癇持續狀態之後的細胞凋亡標記物 的表現（Ebert et al. 2002，43 Suppl 5， 86-95 )。這可能與預防患者癲癇進展狀態有關係，亦即是 抗引致癲癇發作的。瑞提加賓亦已經證實可延緩大鼠的海 馬激動進展狀態，此為癲癇發展的進一步模式 （Tober et al. European Journal Of Pharmacology 1996, 303, 163-169)。 1325414 已头抗痙擎化合物如苯并二氮肇類（benZ〇diaZepines )和氯美噻唑（chi〇rmethiazole)臨床上係用於治療酒精 戒斷症候群，而其他抗痙攣化合物如加巴喷丁 （ gabapentin)在這種症候群的動物模式中是非常有效的（Schroder et al. Neuropharmacology 2001, 40, 888-898; Blackburn-Munro and Jensen European Journal of Sigh/2003, 460, 109-116). In addition, localization of KCNQ channel mRNA has been reported in the brain and other areas of the sacral nervous system associated with pain (Goldstein et al. ibc/eiy /or Neuroscience Abstracts 2003, 53.8). In addition to its role in neuropathic pain, the expression of KCNQ 2-5 mRNA at the trigeminal and dorsal root ganglia and at the trigeminal nerve tail suggests that the opening agents of these channels may also affect the sensory treatment of migraine (Goldstein et al. iS) 'cOeiy /στ* Msiracis 2003, 53.8). Recent reports have confirmed that in addition to KCNQ2 mRNA, KCNQ 3 and 5 mRNA lines are expressed in astrocytes and glial cells. Therefore, channels such as KCNQ 2, 3, and 5 can help regulate synaptic activity in the CNS and contribute to the neuroprotective effects of KCNQ channel openers (Noda et a 1., iS'oc/e / or 2003, 53.9). Retistatin and other KCNQ modulators thus exhibit protection against epileptic neurodegeneration, as ritigatin has been shown to prevent marginal neuronal degeneration and cells after hyperalination-induced seizure persistence in rats Expression of apoptotic markers (Ebert et al. 2002, 43 Suppl 5, 86-95). This may be related to preventing the status of epilepsy in patients, that is, it is caused by seizures. Retistatin has also been shown to delay the progression of hippocampal agonism in rats, a further mode of epilepsy development (Tober et al. European Journal Of Pharmacology 1996, 303, 163-169). 1325414 The first anti-anthraquinone compounds such as benzodiazepines (benZ〇diaZepines) and cimetrazole (chi〇rmethiazole) are clinically used to treat alcohol withdrawal syndrome, while other anti-caries compounds such as gabapentin are in This syndrome is very effective in animal models (

Watson et al. Neuropharmacology 1997, 36, 1369-1375 )，我們預期其他抗痙攣化合物如KCNQ開啟劑在此病狀中 也有效。 KCNQ 2和3亞單位之mRNA係見於與焦慮和情緒性行 為如雙極性精神障礙有關的一些腦區，例如海馬和杏仁核 中（Saganich et al. goo!, 1’ 4609 4624 ) ’知提加賓據報導是在一些似焦慮行為的 動物模式中起作用（Hartz et al. 〇/ 户够細騰〇/聊 2003，17 _ρ1 3, A28 Bi6)，而 其他臨床上使用的抗痙攣化合物係用於治療雙極性精神障 礙。 W0 200196540揭示因KCNQ2和明3基因表現所形成 電流之調節劑對於失眠的用途，而⑽㈣⑽揭示 KCNQ5的調節劑可用來治療睡眠障礙。 W001/022953敘述瑞提加賓對於諸如觸感痛、痛覺過 敏疼痛幻痛之類的神經病痛、與糖尿病神經病變有關之 神經病痛及與偏頭痛有關之神經病痛的預防和㈣用途。 W〇〇2/049628敘述瑞提加賓對於焦慮症如焦慮、廣泛 性焦慮症、恐慌性焦慮、強迫症、社交恐懼症、表現焦慮 創傷後壓力症、急性壓力反應、適應障礙、疑病性障礙 10 1325414 、分離焦慮症、畏曠症及特定恐懼症等之預防、治療、抑 制及改善的用途。 W097/15300敘述瑞提加賓對於治療神經退化性障礙 如阿茲海默氏症（Alzheimer，s disease)、亨丁頓氏舞蹈 症（Huntington’s chorea)、多發性硬化、肌萎縮性脊髓 側索硬化、AIDS誘發的腦病及其他因德國麻疹病毒、疱疹 病毒、疏螺旋體和未知病原體所引起感染有關之腦病、庫 賈氏症（Creutzfeld-Jakob disease )、帕金森氏症、創 傷誘發的神經退化及諸如藥品戒斷中或中毒所致之神經元 過度興奮狀態、周圍神經系統的神經退化性障礙如多發性 神經病和多發性神經炎（p〇lyneuritides )等的用途。 因此，對於是為有效KCNQ族鉀離子通道開啟 化合物有很大的需求。 新穎 同樣需求的是相對於是為KCNQ族鉀離子通道開啟劑之 已知化合物，#瑞提加賓而言’具有改良性質的新穎化合 物。下列參數之一或多者之改良是為所求： 半生期，清除率，選擇性，與其他藥物之交互作用， 生物利用度’效力’調配性’化學穩定性，代謝穩定性， 模渗透性’溶解度及治療指數。這類參數的改良可導致 如下列的改良： 因降低一天所需劑量數而改良的給劑方案， 對多重藥物患者投藥的簡易性， 降低的副作用， 增大的治療指數， 1325414 改良的耐受度及/或 改良的順應性。 【發明内容】 因此’本發明之一個目的是提供新穎化合物，其為有 效的KCNQ族鉀離子通道開啟劑。 本發明之化合物為通式I之1，2, 4-三胺基苯衍生物或 其醫藥上可接受之鹽：Watson et al. Neuropharmacology 1997, 36, 1369-1375), we expect other anti-caries compounds such as KCNQ openers to be effective in this condition as well. The mRNA sequences of the KCNQ 2 and 3 subunits are found in brain regions associated with anxiety and emotional behavior such as bipolar disorder, such as the hippocampus and amygdala (Saganich et al. goo!, 1' 4609 4624 ). It has been reported to play a role in animal models that resemble anxious behaviors (Hartz et al. 〇 / 够 细 2003 聊 聊 聊 聊 聊 聊 聊 聊 聊 聊 聊 聊 聊 聊 聊 聊 聊 聊 聊 聊 聊 聊 聊 聊 聊 聊 聊 聊 聊 聊 聊 2003 2003 2003 2003 2003 2003 2003 2003 Treatment of bipolar disorder. W0 200196540 discloses the use of modulators of current formation by KCNQ2 and Ming3 genes for insomnia, and (10) (iv) (10) reveal that KCNQ5 modulators can be used to treat sleep disorders. W001/022953 describes the use of rititicarbine for neuropathic pains such as tactile pain, hyperalgesia, painful pain, neuropathic pain associated with diabetic neuropathy, and neuropathic pain associated with migraine and (4) use. W〇〇2/049628 describes Ritti Gabin for anxiety disorders such as anxiety, generalized anxiety disorder, panic anxiety, obsessive-compulsive disorder, social phobia, performance anxiety, post-traumatic stress disorder, acute stress response, adaptation disorder, and suspicion Obstacle 10 1325414, the use of prevention, treatment, inhibition, and improvement in separation anxiety, phobia, and specific phobia. W097/15300 describes rititicarbine in the treatment of neurodegenerative disorders such as Alzheimer's disease, Huntington's chorea, multiple sclerosis, amyotrophic lateral sclerosis , AIDS-induced encephalopathy and other encephalopathy related to infections caused by German measles virus, herpes virus, Borrelia and unknown pathogens, Creutzfeld-Jakob disease, Parkinson's disease, trauma-induced neurodegeneration, and drugs such as drugs The use of neuronal hyperexcitability due to withdrawal or poisoning, neurodegenerative disorders of the peripheral nervous system such as polyneuropathy and polyneuritis (p〇lyneuritides). Therefore, there is a great need for opening compounds for effective KCNQ potassium ion channels. Novelty Also desirable is a novel compound having improved properties relative to the known compound which is a KCNQ potassium ion channel opener, #瑞提加宾. Improvements in one or more of the following parameters are required: half-life, clearance, selectivity, interaction with other drugs, bioavailability 'potency' formulation' chemical stability, metabolic stability, mode permeability 'Solubility and therapeutic index. Improvements in such parameters can lead to improvements such as: improved dosage regimens for reducing the number of doses required per day, ease of administration to multiple drug patients, reduced side effects, increased therapeutic index, 1325414 improved tolerance Degree and / or improved compliance. SUMMARY OF THE INVENTION Accordingly, it is an object of the present invention to provide novel compounds which are effective KCNQ potassium ion channel openers. The compound of the present invention is a 1,2,4-triaminobenzene derivative of the formula I or a pharmaceutically acceptable salt thereof:

其中 R1、R2、R2’、R3、X、ζ、γ及q係如以下所定義者。 本發明係進一步關於包含式I化合物之醫藥組成物及 其用途。 【實施方式】 發明說明 本發明係關於新穎的式I之1，2,4-三胺基苯衍生物： 12 1325414Wherein R1, R2, R2', R3, X, ζ, γ and q are as defined below. The invention further relates to pharmaceutical compositions comprising a compound of formula I and uses thereof. [Embodiment] The present invention relates to a novel 1,2,4-triaminobenzene derivative of the formula I: 12 1325414

其中 R1係選自於氫、Cl_6-烷（烯/炔）基、C3_8_環烷（烯 )基、c3_8-環烧（稀）基_c丨6_垸（稀/炔）基、醯基、 羥基-Cy-烷（烯/炔）基及羥基气38 —環烷（烯）基所組 成之群組； R2和R2’係獨立地選自於氫、Ci6_烷（烯/炔）基、 C"-環烧（烯）基、芳基、Ch—環⑥（烯）基_c^「烧（ 烯/炔）基、芳基-Cu-烷（烯/炔）基、醯基、羥基_C1 6烷（烯/炔）基及羥基吒38_環烷（烯）基所組成之群組 V係選自於氫、Cl，烧（稀/炔）基、c38_環烧（稀 匕基、芳基、C"-環烷（烯）基气丨·「烷（烯，炔）基、 :基-C丨{烷（烯/炔）基、羥基气丨「烷（烯，炔）基、 方，-C3_8-環烧（稀）基、NR10Rlo’n (稀/快）基、 NR R -C3_8-環院（稀）基及經基_c3•厂環烧（稀）基所組 成之群組；其中 R10和R1。’係獨立地選自於氫、Ci「烷（稀/快）基、 環烷（稀）基、Cw環烷（稀）基_Ci•「烷（稀/炔 基、經基-Ch-烷（烯/炔）基、__c"_環烷（烯） 13 基羥基C3_8-環烷（烯）基_Ci 6_烧（稀/块）基、齒基、 Ci-6烷（稀/炔）基、_基-(：3·「環烧（稀）基、齒基乂 「環烧（稀）基「燒（稀/炔）基、氰基-C1_6-烧 /炔）基氛基C3_8-環烧（稀）基及氰基_^8_環烷（歸 )基-C〗-6-烷（烯//炔）基所組成之群組，或者 R和R㊣同它們所連接之敗原子一起形成一個視需 要含有1、2或3個其他雜原子之4_8員飽和或不飽和環 X 是 C0 或 S02 ; Z是0或NR4，其中 κ4係選自於氫、Cl_「院（稀/快）基、C3「環烷（稀 )基、（：3_8_環烷（烯）基_Ci e_& (烯/炔）基、羥基—Ια 炔） 基及經基—C3_8_ 環烧 （烯） 基所組成之群組 ;或者 R3和R4連同它們所連接之氮原子一起形成一個視需要 含有1、2或3個其他雜原子之4_8員飽和或不飽和環由 R3和R4及氮原子所形成之環係視需要經一或多個獨立地選 自於Ci_e-烷（烯/炔）基、芳基及芳基_Ci 6_烷（烯/炔 )基的取代基取代； q是0或1 ; 以及 Y代表式II或III之雜芳基： 1325414Wherein R1 is selected from the group consisting of hydrogen, Cl_6-alkane (ene/alkynyl), C3_8-cycloalkane (alkenyl), c3-8-cycloalkyl (thin), _c丨6_垸 (thin/alkyne), fluorenyl a group consisting of a hydroxy-Cy-alkene (alkenyl/alkynyl) group and a hydroxy gas 38-cycloalkane (alkenyl) group; R2 and R2' are independently selected from hydrogen, Ci6-alkane (ene/alkyne) group , C"-cyclic (alkenyl) group, aryl group, Ch-ring 6 (alkenyl) group _c^ "alkene (alkenyl/alkynyl) group, aryl-Cu-alkane (ene/alkyne) group, fluorenyl group, The group V consisting of a hydroxy-C1-6 alkane (alkene/alkynyl) group and a hydroxy hydrazine 38-cycloalkane (alkenyl) group is selected from the group consisting of hydrogen, Cl, calcined (thin/alkyne) group, c38_cyclic burning (thin Sulfhydryl, aryl, C"-cycloalkane (alkenyl) based gas, "alkane (alkenyl), alkyl (alkenyl), alkyl (alkene) ) base, square, -C3_8-cyclic burnt (thin) base, NR10Rlo'n (dilute/fast) base, NR R -C3_8-ring (thin) base and warp group _c3•factory ring-burning (lean) base a group of constituents; wherein R10 and R1. ' are independently selected from hydrogen, Ci" alkane (thin/fast), naphthenic (dilute), Cw cycloalkane (thin), _Ci, "alkane (thin/alkynyl, trans-Ch-alkane (alkenyl/alkynyl) group, __c"_cycloalkane (alkenyl) 13-hydroxyl C3_8-cycloalkane (alkenyl) group _Ci 6_burning (thin/block) group, Tooth base, Ci-6 alkane (thin/alkyne) group, _ group-(:3·"ring-burning (thin) group, dentate group" ring-burning (thin) group "burning (thin/alkyne) group, cyano group -C1_6-burning/alkyne) group consisting of C3_8-cyclic (dilute) group and cyano group _8-8-cycloalkane group-C--6-alkane (alkene//alkyne) group , or R and R together with the atom they are attached to form a 4-8 member of the saturated or unsaturated ring X, which optionally contains 1, 2 or 3 other heteroatoms, is C0 or S02; Z is 0 or NR4, where κ4 It is selected from the group consisting of hydrogen, Cl_"yard (lean/fast) base, C3 "cycloalkane (dilute) group, (:3_8_cycloalkane)-Ci e-& (ene/alkyne) group, hydroxy-Ια alkyne a group consisting of a group consisting of a C3_8_cyclic (alkenyl) group; or R3 and R4 together with the nitrogen atom to which they are attached form a 4-8 member saturated with 1, 2 or 3 other heteroatoms as desired or The ring formed by the R3 and R4 and the nitrogen atom of the unsaturated ring is optionally separated by one or more Substituted with a substituent selected from the group consisting of Ci_e-alkane (alkenyl/alkynyl), aryl and aryl-Ci 6-alkane (alkenyl/alkynyl); q is 0 or 1; and Y represents a heteroaryl of formula II or III Base: 1325414

其中 W是0或s; m 是 0、1、2 或 3 ;Where W is 0 or s; m is 0, 1, 2 or 3;

η是 0、1、2、3 或 4; ρ是Ο或1 ;以及 各個R5係獨立地選自於c^-烷（烯/炔）基、c 環烷（烯）基、芳基、。_8_環烷（烯）基吒卜「烷心 炔）基、芳基-Cm-烷（烯/炔）基、醯基、齒素、南基—η is 0, 1, 2, 3 or 4; ρ is Ο or 1; and each R5 is independently selected from the group consisting of c-alkane (ene/alkynyl), c-cycloalkanoyl, aryl. _8_cycloalkane (alkenyl) azide "alkyl alkyne", aryl-Cm-alkane (alkenyl), thiol, dentate, south base -

Ch-烷（烯/炔）基、Ci「烷（烯，炔）氧基 、氰基、石肖基、曹Rr、_S_R8、_s〇2R8及SMr8所組 群組； '之a group of Ch-alkane (alkenyl/alkynyl) group, Ci "alkane (alkenyl) alkoxy group, cyano group, schlossyl group, Cao Rr, _S_R8, _s〇2R8 and SMr8;

其中 R6和R6係獨立地選自於氫、（^厂烷（烯/块）基、 c3_8-環烷（烯）基、C38-環烷（烯）基_Ci 6_烷（烯/炔 )基及芳基所組成之群組； R和R7係獨立地選自於氫、（：卜6-烷（烯/炔）基、 C3-8-^烷（烯）基、c3 8_環烷（烯）基_Ci 6烷（烯/炔 )基、芳基及醯基所組成之群組；以及 R係選自於c卜厂烷（烯/炔）基、C3 8_環烷（烯）基 15 叫 5414 C3-8-環烷（烯）基-C丨_6-烷（烯/炔）基、芳基及_服9尺9’ 所組成之群組；其中 R9和R9’係獨立地選自於氫、Ci6_烷（烯/炔）基、 C3-8-環院（烯）基及c38一環烷（烯）基乂^烷（烯/炔 )基所組成之群組； 或其醫藥上可接受之鹽。 § q疋0，則R係連接到X，而當q是1，則r3係連 接到Z，其又連接到X。x_(z)q_R3因此可代表X R3、χ 〇_ R3 或 X-NR3R4。 在一個特定的具體實例中，本發明係關於一種式I化 合物，其中 R1、R2、R2’、X和q係如以上所定義者；且 R3係選自於氩、Cl_「烷（稀/炔）基、C3「環烷（稀 )基、芳基、C3_8-環烷（烯）基气丨厂烷（烯/炔）基、 芳基—Cm-烷（烯/炔）基、羥基乂^烷（烯/炔）基及 經基-C3·8-環烷（烯）基所組成之群組；以及 Z係如以上所定義者’但前提是R4係選自於氫、Ci 6_ 院（稀/炔）基、c3_8-環烷（稀）基、c3 8_環烷（烯）基 -C^-烷（烯/炔）基、羥基_Ci 6_烷（烯/炔）基及羥基一 C3·8-環燒（烯）基所組成之群組；且 γ係如以上所定義者，但前提是各個RS係獨立地選自 於Ch-垸（稀/炔）基、c3「環烧（稀）基芳基、c _ 環烷（烯）基-C1_6-烷（烯/炔）基、芳基_。丨6烷（二 炔）基IS基、自素、南基_c丨「烧（婦/块）基' —C〇- 1325414 卿，、氰基、石肖基、_NR7R7,、_S_R8、_s〇2R8 及 s〇2〇 · 組成之群組； 或其醫藥上可接受之酸加成鹽。 在一個具體實例中，R1係選自於醯基、羥基_Ci_6 —烷（ 烯/炔）基及經基-(^广環烧（稀）基所組成之群組。 在另一個具體實例中’本發明係關於其中R1係選自於 氣、Cm-烧（埽/炔）基、C3「環烷（烯）基及C3「環貌 (烯）基烷（烯/炔）基所組成群組之這類化合2 在一個較佳具體實例中，本發明係關於其中R1係選自 於氫及（:卜6-烷（烯/炔）基所組成群組之這類化合物。 在一個特定的具體實例中，本發明係關於其中R1是氫 原子之這類化合物。 - 在另一個特定的具體實例中，本發明係關於其中…是 . Ci-e-炫（烯/炔）基之這類化合物。 在一個具體實例中，R2和R2’中至少一者係選自於芳基 、芳基—Ch-烷（烯/炔）基、醯基、羥基乂丨6_烷（烯/ _ 炔）基及羥基-(：3_8_環烷（烯）基所組成之群組。 在另一個具體實例中，R2和R2’中至少一者係選自於氫 、C丨_e-烷（烯/炔）基、q 8一環烷（烯）基及環烷（ 稀）基-C卜6_烧（稀/炔）基所組成之群組。 在又另一個具體實例中，本發明係關於其中取代基r2 和R2‘中至少一者是氫原子之這類化合物。 在又另一個具體實例中’本發明係關於其中R2和Μ‘ 17 1325414 二者皆是氫原子之這類化合物。 在-個具體實例中，"、選_基_Ci「院（烯/块 )基、芳基-c3_8-環燒（稀）基、nr10r10，_Ch_烧 )基、NR1QR1G’-c3-8-環烷（烯）基及羥基_c 、 & I ^3-8-¼ 烷（烯） 基所組成之群組；其中 Γ ^和R1°’係獨立地選自於氫ϋ (烯/块）基、 :環；二）基、環院（稀……埽/块 二二 (稀/块）基、經基H貌（稀） 基、舍基H貌（稀）基_Ci_6_w块）基 c】-6-烷（烯/炔）基、齒A 鹵基~ 囪基^-厂壌烷（烯）基、鹵基彳 8_裱烷（烯）基-Cl_6_烷（烯/块）基 3- /炔）其、査A π 乳I 貌（烯 A)基氰基(稀）基及氛基n )基-Ch-烷（烯/炔）基所組成之群組；或者 ，Wherein R6 and R6 are independently selected from the group consisting of hydrogen, (i) alkane (alkene), c3-8-cycloalkanoyl, C38-cycloalkanoyl-Ci 6-alkane (alkenyl/alkyne) a group consisting of a group and an aryl group; R and R7 are independently selected from the group consisting of hydrogen, (6-alkane), C3-8-alkane group, c3 8-cycloalkane a group consisting of (alkenyl)-Ci 6 alkene (alkenyl/alkynyl), aryl and fluorenyl; and R is selected from the group consisting of c-alkane (alkenyl/alkyne), C38-cycloalkane a group consisting of 5414 C3-8-cycloalkanoyl-C丨_6-alkane (alkenyl/alkynyl), aryl and -9 9'; wherein R9 and R9' are Individually selected from the group consisting of hydrogen, Ci6-alkane (alkenyl/alkynyl), C3-8-ring (alkenyl), and c38-cycloalkanoyl (alkene). Or a pharmaceutically acceptable salt thereof. § q疋0, then R is connected to X, and when q is 1, r3 is attached to Z, which in turn is connected to X. x_(z)q_R3 may thus represent X R3 χ R _ R 3 or X-NR 3 R 4 . In a specific embodiment, the invention relates to a compound of formula I, wherein R 1 , R 2 , R 2 ', X and q are as defined above And R3 is selected from the group consisting of argon, Cl_"alkane (thin/alkyne) group, C3 "cycloalkane (thin) group, aryl group, C3_8-cycloalkane (alkene) based gas alkane (alkenyl/alkyne) group) a group consisting of an aryl-Cm-alk (alkenyl/alkynyl) group, a hydroxy oxime (alkene/alkynyl) group, and a benzyl-C3·8-cycloalkane (alkenyl) group; and a Z system as described above Definer's but presuppose that R4 is selected from hydrogen, Ci 6_ hospital (thin/alkyne), c3-8-cycloalkane (diluted), c3 8-cycloalkanoyl-C-alkane (alkenyl/alkyne) a group consisting of a hydroxyl group, a hydroxy-Ci 6-alkane (alkenyl/alkynyl) group, and a hydroxy-C3·8-cycloalkylene group; and the γ is as defined above, provided that each RS system is independent It is selected from the group consisting of Ch-垸 (thin/alkyne), c3 "cyclo-(aryl) aryl, c-cycloalkane-C1_6-alkane (ene/alkyne), aryl. Alkane (diacetylene) group IS, self-priming, south base _c丨 "burning (women / block) base" - C〇 - 1325414 qing, cyano, schwitz, _NR7R7, _S_R8, _s〇2R8 and s〇 a group consisting of: or a pharmaceutically acceptable acid addition salt thereof. In one embodiment, R1 is selected from the group consisting of sulfhydryl and hydroxy _Ci_6 - an alkane (alkenyl/alkynyl) group and a group consisting of a thiol (small) group. In another specific example, the present invention relates to the invention wherein R1 is selected from the group consisting of gas and Cm- Such a compound of the group consisting of a (埽/alkyne) group, a C3 "cycloalkane (alkenyl) group, and a C3 "cycloalkenyl (alkenyl) alkane (alkenyl) group). In a preferred embodiment, the present invention It relates to such a compound in which R1 is selected from the group consisting of hydrogen and (: 6-alkane (alkenyl/alkyne) group. In a specific embodiment, the invention relates to such compounds wherein R1 is a hydrogen atom. - In another specific embodiment, the invention relates to such compounds in which ... is a Ci-e-hyun (ene/alkyne) group. In one embodiment, at least one of R2 and R2' is selected from the group consisting of an aryl group, an aryl-Ch-alk(alkene/alkynyl) group, a fluorenyl group, a hydroxy 乂丨6-alkane (alkene/ acetylene) group. And a group consisting of a hydroxy-(:3_8-cycloalkane (alkenyl) group. In another embodiment, at least one of R2 and R2' is selected from the group consisting of hydrogen, C丨_e-alkane (alkenyl/alkyne) a group consisting of a q8-cycloalkane (alkenyl) group and a cycloalkane (thin) group-Cb6-sinter (thin/alkyne) group. In yet another specific example, the invention relates to At least one of the radicals r2 and R2' is a compound of the hydrogen atom. In yet another embodiment, the invention relates to such compounds wherein both R2 and Μ'17 1325414 are hydrogen atoms. In a specific example, ", select_基_Ci "院(烯/块) base, aryl-c3_8-cyclic (dilute) base, nr10r10, _Ch_) base, NR1QR1G'-c3-8-cycloalkane a group consisting of (alkenyl) and hydroxy-c, & I^3-8-1⁄4 alk(en)yl; wherein Γ^ and R1°' are independently selected from hydroquinone (ene/block) , : ring; 2) base, ring hospital (rare... 埽 / block 2 (thin/block) radical, transbasic H-form (dilute) radical, base-based H-form (dilute) radical _Ci_6_w block) c]-6-alkane (ene/alkyne) group, tooth A halo group ~ chiral group ^ - plant decane (alkenyl) group, halo fluorene 8 decane (alkenyl)-Cl_6-alkane (alkene / block) group 3- / alkyne), check A π milk I appearance (ene A) cyano group a group of (thin) groups and an aryl group n)-Ch-alkane (alkenyl/alkyne) group; or

要二和R1°’連同它們所連接之氮原子-起形成一個視需 要含有卜2或3個其他雜原子之4_8員飽和或不飽而 T又另一個具體實例中，本發丫。 是膨且R3是氳原子之這類化合物。 中…、Z 在具时財，本發縣騎其巾r 原子之這類化合物。 个马虱 )A在Γ另广具體實例中，…係選自於W烧（烯/块 )基、⑷基、芳基、‘_環院(稀)块 組。 土方基Ί規（烯/块）基所組成之群 選 在又另-個具體實例中，本發明係關於其中尺3係 18 1325414 :CH-烷（烯，炔）基及芳基_Ci_6_烷 成群組之這類化合物。 炔）基所組 在又另一個具體實例令，本發明係關於其 r烷（烯/炔）基之這類化合物。 疋Ch 在又另-個具體實例中，R3 A c3 8_環 6、烷（烯/炔）基。 ）基-C】· 在又另一個具體實例申’本發明係關於其中^The second and R1°' together with the nitrogen atom to which they are attached form a 4-8 member that satisfies 2 or 3 other heteroatoms, either saturated or not, and another specific example, the present invention. It is a compound of this type which is expanded and R3 is a halogen atom. In the middle of ..., Z is in the possession of time, this county is riding this kind of compound of the towel r atom. In the other specific examples, A is selected from the group consisting of W (alkene/block), (4), aryl, and ‘_ ring (thin) blocks. The group consisting of earthy bases (alkenes/blocks) is selected in yet another specific example, and the present invention relates to the rule 3 series 18 1325414: CH-alkane (alkenyl), and aryl_Ci_6_ Alkane groups of such compounds. Groups of alkyne groups In yet another embodiment, the invention relates to such compounds of the alkane (alkenyl/alkyne) group. Further, in another specific example, R3 A c3 8_ring 6, an alkane (alkenyl/alkyne) group. )基-C]· In yet another specific example, the invention is related to

Cu-炫（烯/炔）基之這類化合物。 土 在一個具體實例中，本發明係關於 類化合物。 〒x疋S02之這 在又另一個具體實例中 這類化合物》 ’本發明係關於其中X是C0之 在一個具體實例中，q是〇。 在又另一個具體實例中 q是〇之這類化合物。 本發明係關於其中 X是co且 在又另一個具體實財，本發明係關於其巾χ q是〇且R3不為芳基之這類化合物。 在另一個具體實例中，q是1 ^ 在-個具體實例中，本發明係關於其 NR4之這類化合物。 且&疋 在-個具體實例中，q是卜2是_且^和^連 們所連接之氮原子-起形成-個視需要含有1、2或3個立 他雜原子t 4-8員飽和或不飽和環’由R3 # r4及氮_ 所形成之環係視需要經一或多個獨立地 。 ㈡％匕1-6_規C烯 1325414 :块)基'芳基及芳基-c-貌(烯/幻基的取代基取 氣、广個具體實例中，…、2是肥且"選自於 :法 (稀，块）基、。3-「環烧（烯）基、W環烧 及基-k-烧（稀/炔）基、經基^ 6烧（歸/块） 暴及翹基-Cm-環烷（烯）基所組成之群組。 在又另一個具體實例中，（1是丨、2是NR4a Μ是氫原 子。 ’、Cu-Hyun (ene/alkyne) based compounds of this type. Soil In one embodiment, the invention relates to a class of compounds. 〒x疋S02 This is another compound in the present invention. The present invention relates to wherein X is C0. In one embodiment, q is hydrazine. In yet another embodiment, q is a compound of this type. The present invention relates to compounds wherein X is co and in another particular embodiment, the invention relates to compounds of this type wherein x is 〇 and R3 is not aryl. In another embodiment, q is 1 ^ In a specific example, the invention relates to such compounds of NR4. And & 疋 in a specific example, q is 卜 2 is _ and ^ and ^ connected to the nitrogen atom - formed - one if necessary, contains 1, 2 or 3 standing hetero atoms t 4-8 The ring formed by R3 #r4 and nitrogen_ of the saturated or unsaturated ring is optionally one or more independently. (b) % 匕 1-6 _ C ene 1325414: block) base 'aryl and aryl-c-morphology (the olefin / phantom substituents take gas, a wide specific example, ..., 2 is fat and " Selected from: method (thin, block) base, 3-"cycloalkyl (alkenyl) group, W ring-burning and ki-k-burning (thin/alkyne) group, base group 6 (burning / block) And a group consisting of a fluorenyl-Cm-cycloalkane (alkenyl) group. In still another specific example, (1 is 丨, 2 is NR4a Μ is a hydrogen atom.

在一個具體實例中，q是1、Z是NR4且R3和R4中至丨、 ，者不為氫原子。 夕 在又另一個具體實例中，本發明係關於i中 τ q疋1且 2是氧原子之這類化合物。 在又另一個具體實例中，本發明係關於其中χ是c〇、 q是1且Ζ是氧原子之這類化合物。 在又另一個具體實例中，本發明係關於其中R2和Μ 粟氫原子、X是CO、《ι是1且2是氧原子之這類化合物。In one embodiment, q is 1, Z is NR4 and R3 and R4 are not 氢, and are not hydrogen atoms. In still another specific example, the present invention relates to such a compound of τ q 疋 1 and 2 is an oxygen atom. In yet another embodiment, the invention is directed to such compounds wherein χ is c 〇, q is 1 and Ζ is an oxygen atom. In yet another embodiment, the invention is directed to compounds of the formula wherein R2 and oxime hydrogen atoms, X is CO, <1>1 and 2 are oxygen atoms.

在又另一個具體實例中，本發明係關於其中w是氧原 f之這類化合物。 在又另一個具體實例中，本發明係關於其中w是硫原 f之這類化合物。 在又另一個具體實例中，本發明係關於其中w θ & π疋硫原 f其X是C0之這類化合物。 在又另一個具雜實例中’本發明係關於其中w是炉原 子真α是〇之這類化合物。 20 1325414 在又另—個具體實例中，本發明係關於其中w是硫原· 子、X是（：〇且（1是〇之這類化合物。 在β又另—個具體實例中，本發明係關於其中w是硫原 子、Q疋1且Ζ是氧原子之這類化合物。 在曰又另—個具體實例中，本發明係關於其中w是硫原 子、X是C〇、q是】且2是氧原子之這類化合物。 在又另—個具體實例中，m是〇。 在又另一個具體實例中，m是1。 在又另—個具體實例中，m是2。 ® 在個具體實例中，m是3。 在又另一個具體實例中，η是〇。 在又另一個具體實例中，η是1。 在一個具體實例中，η是2、3或4 ; 在一個具體實例中，ρ是〇。 ， 在另—個具體實例中，ρ是1。 在一個具體實例中，至少一個RS係選自於醯基、_c〇_ nr6r6、硝基、m s〇2〇R8m組成之群組。 毫鋒 在另一個具體實例中，各個R5係獨立地選自於 院（稀/炔）基、C38一環烧（稀）基、芳基、^「環院（ 烯）基—烷（烯/炔）基、芳基-C丨·6_烷（烯/炔）基 鹵素、鹵基—Ci_6"烷（烯/炔）基、Ου-烷（烯/炔） 氧基、氰基、-NR7R7’及-S〇2R8所組成之群組。 在又另一個具體實例中，各個Rs係獨立地選自於Cl 6烷（烯/炔）基、芳基、鹵素、c卜广烷（烯/炔）氧基 21 1325414In yet another embodiment, the invention pertains to such compounds wherein w is oxygen f. In yet another embodiment, the invention is directed to such compounds wherein w is sulphide f. In yet another embodiment, the invention relates to such compounds wherein w θ & π 疋 sulphurogen f and X is C0. In yet another heterogeneous example, the present invention relates to such compounds wherein w is a furnace atom and true alpha is ruthenium. 20 1325414 In yet another specific embodiment, the invention relates to a compound in which w is a sulphur pro, X is (: 〇 and (1 is 〇 。. In another embodiment of β, the invention The present invention relates to such compounds wherein w is a sulfur atom, Q疋1 and oxime is an oxygen atom. In still another specific example, the present invention relates to wherein w is a sulfur atom, X is C〇, q is 2 is a compound of such an oxygen atom. In yet another specific example, m is 〇. In yet another specific example, m is 1. In yet another specific example, m is 2. In a specific example, m is 3. In yet another embodiment, η is 〇. In yet another embodiment, η is 1. In one embodiment, η is 2, 3, or 4; Where ρ is 〇. In another specific example, ρ is 1. In a specific example, at least one RS is selected from the group consisting of sulfhydryl, _c〇_nr6r6, nitro, ms〇2〇R8m In another embodiment, each R5 is independently selected from a hospital (thin/alkyne) group, a C38 ring-ring (thin) group. Aryl, "cyclohexene" (alkenyl), alkyl-C丨6-alkane (alkene/alkynyl) halogen, halo-Ci_6"alkane (alkenyl/alkynyl) group, a group consisting of a decyl-alkene (alkene/alkyne)oxy group, a cyano group, -NR7R7' and -S〇2R8. In yet another embodiment, each Rs is independently selected from a C6 alkene (alkenyl) Alkynyl, aryl, halogen, c-bulane (alkenyl/alkyne)oxy 21 1325414

t谷個俨係 S〇2R8 (其中 個具體實例中’本發明係關於其中各個 C1 - 6貌（稀/块)基、齒素及― R8疋芳基）所組成群組之這類化合物。 在又另一個具體實例中，至少一個取代基R5 β 烷（烯/炔）基。 疋 κ 在又另一個具體實例中，至少一個取代基R5是芳美 在又另一個具體實例中，至少一個取代基R5 θ 烷（烯/炔）氧基》 疋丨-6~ 在又另一個具體實例中，至少一個取代基RS是—s〇 γ 在又另一個具體實例中，至少一個取代基y 素原子。 疋個鹵 在又另一個具體實例中，至少一個取代基rs 素月；β 夂 個鹵 ^ ，八係選自於氣、溴和碘所組成之群組。 在又另一個具體實例中， 在又另一個具體實例中， 在又另一個具體實例中， 在又另一個具體實例中，至少一個取代基Μ是氟。 至少一個取代基R5是氣。 至少一個取代基R5是漠。 至少一個取代基R5是_NR7R7, 在一個具體實例中， R7和R7’中至少一者是芳: 至少一者是芳基或醯基。 至少一個取代基R5是-NR7y，；t 俨 俨 R R R R ( ( ( ( ( ( R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R In yet another embodiment, at least one substituent R5 beta alkane (ene/alkynyl) group.疋κ In yet another specific example, at least one substituent R5 is aryl in another specific example, at least one substituent R5 θ alk(ene/alkynyloxy) 疋丨-6~ in yet another specific In the examples, at least one substituent RS is -s〇γ. In yet another embodiment, at least one substituent y atom. In another embodiment, at least one substituent rs is a sulphate; β 夂 is a halogen ^ , and the octasystem is selected from the group consisting of gas, bromine and iodine. In yet another embodiment, in yet another embodiment, in yet another embodiment, in yet another embodiment, at least one substituent Μ is fluorine. At least one substituent R5 is a gas. At least one substituent R5 is desert. At least one substituent R5 is _NR7R7, and in one embodiment, at least one of R7 and R7' is aryl: at least one is aryl or fluorenyl. At least one substituent R5 is -NR7y,;

在 R7和 22 1325414At R7 and 22 1325414

Ch-環烷（烯）基及（Vf環烷（烯）基吒卜厂烷（烯/姝 )基所組成之群組。 在另一個具體實例中，至少一個取代基RS是_NR7Rr ; 且R和R中至少一者係選自於氫及Ch_烷（烯/炔）基 所組成之群組》 在又另一個具體實例中，至少一個取代基RS是 :且R7和R7’中至少-者是Ci「统（稀/炔）基。 在又另一個具體實例中，至少一個取代基RS是_NRTRr ，且R和R7二者皆為Ch-烷（烯/炔）基。 在-個具體實例中，至少一個取聽R5LSM8 :而 R8是-NR9。’；其中R”。R9，係獨立地選自於氫、Ch烷（ 烤/炔）基、c3_8-環燒（烯）基及C3「環烧（稀）基一 厂烷（烯/炔）基所組成之群組。 在一個具體實例中，至少一個取代基而 R8係選自於W院（稀/块）基、C3「環统（稀）基、C〆 環烧（稀）基烧（稀/炔）基及芳基所組成之群組。 在又另一個具體實例中，至少一個取代基RS是_s〇2R8 :而R8是芳基。 在又另一個具體實例中，本發明係關於其+ γ具有式 11之這類化合物。 在又另一個具體實例中，本發明係關於其中γ具有式 111之這類化合物。 在又另一個具體實例中，本發明係關於其中Y具有式 lib或Illb之這類化合物： 23 1325414a group consisting of a Ch-cycloalkane (alkenyl) group and a (Vf cycloalkane (alkenyl) azide alkane (alkenyl) group. In another embodiment, at least one substituent RS is _NR7Rr; At least one of R and R is selected from the group consisting of hydrogen and a Ch-alkane (alkenyl/alkyne) group. In yet another embodiment, at least one substituent RS is: and at least R7 and R7' - is Ci "systemic (thin / alkyne) group. In yet another embodiment, at least one substituent RS is _NRTRr, and both R and R7 are Ch-alkane (alkenyl/alkyne) groups. In a specific example, at least one of the listeners R5LSM8: and R8 is -NR9. '; wherein R". R9, independently selected from hydrogen, Ch alkane (bake/alkyne), c3-8-cyclic (alkenyl) And a group consisting of C3 "ring-burning (diluted)-based alkane (alkenyl/alkyne) groups. In one embodiment, at least one substituent and R8 is selected from the group consisting of W (small / block) groups, C3 a group consisting of a ring system (diluted) group, a C ring ring-fired (dilute) group-burning (thin/alkyne) group, and an aryl group. In still another specific example, at least one substituent RS is _s〇2R8 : and R8 is an aryl group. In another embodiment, the invention relates to compounds of the formula 11 wherein + γ. In yet another embodiment, the invention relates to compounds of the formula wherein γ has the formula 111. In yet another embodiment The present invention relates to compounds of the formula wherein Y has the formula lib or 111b: 23 1325414

其中W、m、η、p及R5係如以上所定義者。 在又另一個具體實例中，本發明係關於其中Υ具有式 jib之這類化合物。 在又另一個具體實例中，本發明係關於其中組是〇且 γ具有式11b之這類化合物。 在又另-個具體實例中，本發明係關於其令Y具有式 Illb之這類化合物。 社入力一 γ具有式Illb之這類化合物 在又另-個具體實例中，本發明係關於其 見 Y具有式Illb之這類化合物。 在又另一個具體實例中，本發明係關於其中n是。Μ 是0且Υ具有式nib之這類化合物。 在又另一個具體實例令，太 本發月係關於其中γ且有式 ⑽且…疋1之這類化合物’在其-特定離樣中，〖 是Up是0,而在其另一個特定態樣中， 在又另一個具體實例中， 且p疋1 τ θ 9 本發明係關於其中γ且有式 ⑴……2之這類化合物，在其-特定…，r 是2且P是0;而在其另4樣中 。 特U樣中，n是丨且p是] 24 1325414 在又另一個具體實例中，本發明係關於其中γ具有下 列式111)1、111)2、111»3、1111)1、1111)2、1111)3或1111)4之Wherein W, m, η, p and R5 are as defined above. In yet another embodiment, the invention is directed to compounds of the formula wherein hydrazine has the formula jib. In yet another embodiment, the invention is directed to compounds of the formula wherein group 〇 and γ has formula 11b. In yet another embodiment, the invention relates to compounds of the formula Ilb having the formula Illb. Incorporating a compound of the formula llb of the formula Illb In yet another embodiment, the invention relates to a compound of the formula Illb of the formula Illb. In yet another embodiment, the invention is directed to wherein n is. Μ is 0 and Υ has such a compound of the formula nib. In yet another specific example, the present invention relates to a compound of the formula γ in which γ and formula (10) and ... 疋1 are in its specific exciment, 〖Up is 0, and in another specific state thereof In another example, and in another embodiment, and p 疋 1 τ θ 9 the present invention relates to a compound of the formula γ and having the formula (1)...2, in which - is ..., r is 2 and P is 0; And in its other four. In the U sample, n is 丨 and p is] 24 1325414 In yet another specific example, the invention relates to wherein γ has the following formula 111) 1, 111) 2, 111»3, 1111) 1, 1111) 2 , 1111) 3 or 1111) 4

其中 W係如以上所定義者； r是0、1或2 ; s是0、1、2或3;以及 25 1325414 R5’和R5’’係獨立地如R5所定義者，且各個R5係獨立地 如以上所定義者。 在又另一個具體實例中，本發明係關於這類化合物， 其中： m是〇且Y具有式lib;或 η是0且Y具有式nib;或 p是0且Y具有式Illb;或 η是0、P是〇且Y具有式iiib;或 Y具有式Illb且n + p* !，在其一特定態樣中，n 是1且p是〇,而在其另一個特定態樣中，11是〇且卩是j :或 Y具有式Illb且|1 + 1)是2，在其一特定態樣中η 是2且ρ是0;而在其另一個特定態樣中，以】且。是i ;或 Y 具有式 1 b ’ 或 I lb2 ;或！ Ib3 ;或！ IIt)1 ;或！ ！ Ib2 ;或 IIIb3 ;或 Illb4。 在又另’個具體實例中’本發明係關於其中γ具有式 lib1 ;或1卬2，或1比3 ;或其中m是〇且γ具有式nb之 這類化合物° 在又另’個具體實例中，本發明係關於其中γ具有式 lib1之這類化合物。 在又另〆個具體實例中，本發明係關於其中γ具有式 lib2之這類化合物° 26 1325414 在又另/個具體實例中，本發明係關於其中γ具有式 IIb3之這類化合物。 在又另^個具體實例中，本發明係關於這類化合物， γ 具有式 或 Hlb2’ 或 Illb3;或 nib4;或 n是〇 Y具有式Illb ;或 p是〇且Y具有式Illb;或 11是〇、卩是0且Y具有式Illb;或 γ具有式Illb且n + p是1，在其一特定態樣中，^ 是1且ρ是〇,而在其另一個特定態樣中，11是〇且1)是1 ;或 是Wherein W is as defined above; r is 0, 1 or 2; s is 0, 1, 2 or 3; and 25 1325414 R5' and R5'' are independently defined as R5, and each R5 is independent The ground is as defined above. In yet another embodiment, the invention relates to such compounds, wherein: m is 〇 and Y has the formula lib; or η is 0 and Y has the formula nib; or p is 0 and Y has the formula 111b; or η is 0, P is 〇 and Y has the formula iiib; or Y has the formula 111b and n + p* !, in one particular aspect, n is 1 and p is 〇, and in another specific aspect thereof, 11 Is 〇 and 卩 is j: or Y has the formula 111b and |1 + 1) is 2, η is 2 and ρ is 0 in one particular aspect thereof; and in another specific aspect thereof, 且且。 Is i; or Y has the formula 1 b ’ or I lb2 ; or! Ib3 ; or! IIt) 1 ; or! ! Ib2; or IIIb3; or Illb4. In yet another specific example, the invention relates to a compound of the formula wherein γ has the formula lib1; or 1卬2, or 1 to 3; or wherein m is 〇 and γ has the formula nb In the examples, the present invention relates to compounds of the formula wherein γ has the formula lib1. In still another embodiment, the invention relates to compounds of the formula wherein γ has the formula lib2. 26 1325414 In yet another embodiment, the invention relates to compounds of the formula wherein γ has the formula IIb3. In yet another embodiment, the invention relates to such compounds, γ having the formula or Hlb2' or Illb3; or nib4; or n being 〇Y having the formula 111b; or p being 〇 and Y having the formula 111b; Is 〇, 卩 is 0 and Y has the formula 111b; or γ has the formula 111b and n + p is 1, in one particular aspect, ^ is 1 and ρ is 〇, and in another specific aspect thereof, 11 is 〇 and 1) is 1; or

Υ具有式 且ρ是〇Υ has the formula and ρ is 〇

Illb且11 + 1)是2，在其 ，而在其另一個特定態樣中 一特定態樣中，η ’ η是1且ρ是 在又另一個具體實例中 111 b1之這類化合物。 在又另一個具體實例中 111 b2之這類化合物。 在又另一個具體實例中 Illb3之這類化合物。 在又另一個具體實例中 Illb4之這類化合物。 在又另一個具體實例中 lie或IIIc之這類化合物： 本發明係關於其中γ具有式 本發明係關於其中γ具有式 本發明係關於其中γ具有式 本發明係關於其中γ具有式 本發明係關於其中γ具有式 27 1325414Illb and 11 + 1) are 2, in which, in a particular aspect thereof, η ' η is 1 and ρ is a compound of this type 111 b1 in yet another embodiment. In yet another embodiment, the compound of formula 111 b2. In yet another embodiment, such a compound of Illb3. In yet another embodiment, such a compound of Illb4. In yet another embodiment, a compound of the kind such as lie or IIIc: the invention relates to wherein γ has the formula wherein the γ has the formula, wherein the γ has the formula, wherein the γ has the formula of the invention About γ has the formula 27 1325414

lie > 其中W、m、η、p及RS係如以上所定義者。 在又另-個具體實例中，本發明係關於其巾γ具有式 之這類化合物 在又另一個具體實例中 γ具有式11 c之這類化合物 本發明係關於其中m是〇且 在又另-個具體實例中，本發明係關於其+ Y具有式 之這類化合物 IIIc 在又另一個具體實例中 γ具有式IIIc之這類化合物 在又另一個具體實例中 γ具_有式IIIc之這類化合物。 %又另-個具體實例中，本發明係關於其中η是h 是Υ具有式IUc之這類化合物。 在又另-個具體實例中’本發明係關於其"且有式 ⑴+ 之這類化合物，在其—特定態樣中，n 是UP是〇’而在其另一個特定態樣中， 在又另-個。實例中’本發明係關於其"具有式 Illcj_n + P疋2之這頬化0 2且P是〇,而在h / 一特定態樣中’ n是2 另一個特定態樣中，nh且 本發明係關於其中n是〇且 本發明係關於其中ρ是〇且 28 1325414 在又另一個具體實例中，本發明係關於其中Y具有下 列式11(：1、11。2、11(：3、111(：1、111〇2、111<:3或111。4之 這類化合物：Lie > where W, m, η, p, and RS are as defined above. In still another specific embodiment, the invention relates to a compound of the formula having a formula of γ, and in another embodiment, γ having such a compound of formula 11c, the present invention relates to wherein m is oxime and In a specific example, the present invention relates to a compound of this type IIIc having a formula of + Y. In yet another embodiment, γ has a compound of the formula IIIc. In yet another embodiment, γ has the formula IIIc Class of compounds. In yet another specific embodiment, the invention relates to compounds of the formula wherein η is h and oxime has the formula IUc. In still another specific example, 'the present invention relates to a compound of the formula (1)+, in which the n is UP is 〇' and in another specific aspect thereof, In another one. In the example 'the invention relates to its " having the formula Illcj_n + P疋2 such that 00 2 and P is 〇, and in h / a particular aspect 'n is 2 another specific aspect, nh and The present invention relates to wherein n is 〇 and the present invention relates to wherein ρ is 〇 and 28 1325414. In yet another embodiment, the invention relates to wherein Y has the following formula 11 (: 1, 1, 2. 2, 11 (: 3) , 111 (: 1, 111 〇 2, 111 <: 3 or 111. 4 of these compounds:

(R5)r(R5)r

Π〇3 ^ WΠ〇3 ^ W

R5' w' 其中 W係如以上所定義者； r是0、1或2 ; s是0、1、2或3;以及 29 1325414 R5’和R5’’係獨立地如R5所定義者，且各個r5係獨立地 如以上所定義者。 在又另一個具體實例中’本發明係關於這類化合物， 其中： in是0且Y具有式lie，或 η是0且Y具有式IIIc;或 p是0且Y具有式IIIc;或 η是0、P是〇且Y具有式IIIc;或 γ具有式IIIc且n + p是1，在其一特定態樣中，n 是1且ρ是〇，而在其另一個特定態樣中，η是〇且1)是1 :或 γ具有式IIIc且η + ρ是2,在其一特定態樣中，η 是2且ρ是〇，而在其另一個特定態樣中，nsi且1)是1 ;或 γ 具有式 II。，或 lie2 ;或 nc3 ;或 IUcl ;或 nIc2 ;或 IIIc3 ;或 IIIc4。 在又另個具體實例中，本發明係關於其中γ具有式 IIc丨；或lie2;或lie3;或m是〇且γ具有式nc之這類 化合物。 在又另/個具體實例中，本發明係關於其中γ具有式 lie1之這類彳b合物。 在又另/個八體實例中，本發明係關於其中γ具有式 lie2之這類化合物° 在又另〆個具體實例中’本發明係關於其巾γ具有式 1325414 ilc3之這類化合物。 在又另一個具體實例中，本發明係關於這類化合物， 其中： '、γ 異有式 IIIc1 ;或 IIIc2 ;或 IIIc3 ;或 IIIc4 ;或 n是〇且Y具有式IIIc;或 p是0且γ具有式IIIc;或 0是0、P是〇且Y具有式IIIc;或 Y異有式IIIc且n + p是1，在其一特定態樣中，n 是丨且口是〇,而在其另一個特定態樣中，η是〇且1)是1 ;或 η γ具有式III。且n + Ρ是2,在其一特定態樣中， 是2且ρ是〇’而在其另一個特定態樣中，且ρ是 在又另一個具體實例中 j JJC!之這類化合物。 在又另一個具體實例中 J J Ic2之這類化合物。 在又另一個具體實例中 Illc3之這類化合物。 在又另一個具體實例中 111 c4之這類化合物。 在又另一個具體實例中 這類化合物。 本發明係關於其中γ具有式 本發明係關於其中γ具有式 本發明係關於其中Υ具有式 本發明係關於其中Υ具有式 本發明係關於其中Γ是0之 31 1325414 在又另一個具體實例中 這類化合物。 在又另一個具體實例中 這類化合物。 在又另一個具體實例中 這類化合物。 在又另一個具體實例中 或3之這類化合物。 本發明係關於其中r是1之 本發明係關於其中r β 〇 、丁 Γ疋2之 本發明係關於其中s是〇之 本發明係關於其中s是1、 在又另一個具體實例中，本發明係關於其中式Η 代表下列之這類化合物： 之Υ lib1 ;或 lib2 ;或 lib3 ;或 iici ;或 u 2 ，或 IIc3 ; 或 式lib之基團’其中m是〇;或 式lie之基團，其中m是〇。 在又另一個具體實例中，本發明係關於其中式^R5' w' wherein W is as defined above; r is 0, 1 or 2; s is 0, 1, 2 or 3; and 29 1325414 R5' and R5'' are independently defined as R5, and Each r5 is independently as defined above. In yet another embodiment, the invention relates to such compounds, wherein: in is 0 and Y has the formula lie, or η is 0 and Y has the formula IIIc; or p is 0 and Y has the formula IIIc; or η is 0, P is 〇 and Y has the formula IIIc; or γ has the formula IIIc and n + p is 1, in a particular aspect, n is 1 and ρ is 〇, and in another specific aspect thereof, η Is 〇 and 1) is 1 or γ has the formula IIIc and η + ρ is 2, in a particular aspect thereof, η is 2 and ρ is 〇, and in another specific aspect thereof, nsi and 1) Is 1; or γ has Formula II. , or lie2; or nc3; or IUcl; or nIc2; or IIIc3; or IIIc4. In still another embodiment, the present invention is directed to a compound of the formula wherein γ has the formula IIc丨; or lie2; or lie3; or m is 〇 and γ has the formula nc. In still another specific embodiment, the invention relates to such quinone b compounds wherein γ has the formula lie1. In still another example, the present invention relates to a compound of the formula wherein γ has the formula lie2. In yet another specific embodiment, the present invention relates to a compound of the formula 1325414 ilc3 having a γ. In yet another embodiment, the invention relates to such compounds, wherein: ', γ is of formula IIIc1; or IIIc2; or IIIc3; or IIIc4; or n is 〇 and Y has formula IIIc; or p is 0 and γ has the formula IIIc; or 0 is 0, P is 〇 and Y has the formula IIIc; or Y has the formula IIIc and n + p is 1, in a particular aspect, n is 丨 and the mouth is 〇, and In another specific aspect, η is 〇 and 1) is 1; or η γ has Formula III. And n + Ρ is 2, in one particular aspect thereof, 2 and ρ is 〇' in another specific aspect thereof, and ρ is such a compound of j JJC! in yet another specific example. In yet another embodiment, such a compound of J J Ic2. In yet another embodiment, such a compound of Illc3. In yet another embodiment, such a compound of 111 c4. In yet another embodiment, such a compound. The present invention relates to wherein γ has the formula wherein γ has the formula, wherein the oxime has the formula, wherein the oxime has the formula, wherein the oxime has the formula, the invention relates to the formula wherein the oxime is 0, 13 254 414. In yet another specific example Such compounds. In yet another embodiment, such a compound. In yet another embodiment, such a compound. In yet another embodiment, or a compound of the kind 3. The present invention relates to the invention in which r is 1 with respect to the invention wherein r β 〇, butyl Γ疋 2 is related to the invention wherein s is 〇, wherein s is 1, in yet another specific example, The invention relates to a compound of the formula: lib lib1 ; or lib2 ; or lib3 ; or iici ; or u 2 , or IIc3 ; or a group of the formula lib where m is 〇; or a formula of lie Mission, where m is 〇. In yet another specific example, the present invention relates to

代表下列之這類化合物： Y lib1 ;或 lib2 ;或 lib3 ;或 式lib之基團，其中m是0;或 式lie之基團，其中m是〇。 在又另一個具體實例中，本發明係關於其中式^ ^ 代表下列之這類化合物： < ~Represents the following compounds of this type: Y lib1 ; or lib2 ; or lib3 ; or a group of the formula lib, where m is 0; or a group of the formula lie, where m is deuterium. In yet another embodiment, the invention pertains to compounds of the formula wherein: ^^ represents the following: < ~

Illb1;或 Illb2;或 Illb3;或 Illb4;或 IIIcl. IIIc2 ;或 IIIc3 ;或 IIIc4 ;或 ’或 32 1325414 式HIb之基團，其中1!是〇 .或 式Illb之基團，其中〇是〇或 式Illb之基團’其中^ a 5 ........— & 0且P是Ο ;或 式Illb之基團，其中η ’π疋1且ρ是0’而在其另一 是1 ;或 ρ是1，在其一特定態樣中 個特定態樣中，η是〇且ρ Υ具有式Illb且η 是2且ρ是0，而在其另 ρ是2，在其一特定態樣中， 個特定態樣中，η是丨且ρ是 η 1 式11 Ic之基團 式IIIc之基團 ’其中n是〇 ;或 ，其中P是0 ’·或 式IIIc之基團，其中n 式111 c之基團》其中 ，11是1且卩是〇，而在其另 是1 ;或 是〇且ρ是〇;或 + Ρ是1，在其一 一個特定態樣中， 特定態樣中 η是0且ρ Υ具有式 是2且ρ是0 IIIc 且 η + 而在其另— Ρ疋2,在其一特定態樣中，η 個特定態樣中’ Q i且？是】 在又另一個具體實例中 III之 貝列甲，本發明係關於其中 Y代表下列之這類化合物： 、工Illb1; or Illb2; or Illb3; or Illb4; or IIIcl. IIIc2; or IIIc3; or IIIc4; or 'or 32 1325414 A group of formula HIb, wherein 1! is a group of 〇. or formula 111b, wherein 〇 is 〇 Or a group of the formula 111b' wherein ^ a 5 . . . - & 0 and P is Ο; or a group of the formula 111b, wherein η 'π疋1 and ρ are 0' and in another One is 1; or ρ is 1, in a particular aspect of a particular aspect, η is 〇 and ρ Υ has the formula 111b and η is 2 and ρ is 0, while in another ρ is 2, in In a particular aspect, in a particular aspect, η is 丨 and ρ is η 1 is a group of formula 11 Ic of the formula IIIc where n is 〇; or, where P is 0 '· or a group of formula IIIc a group, wherein n is a group of 111 c, wherein 11 is 1 and 卩 is 〇, and in it is 1; or 〇 and ρ is 〇; or + Ρ is 1, in a particular aspect thereof In the specific aspect, η is 0 and ρ Υ has the formula 2 and ρ is 0 IIIc and η + and in its other Ρ疋2, in a particular aspect thereof, 'Q i in a particular aspect And? Yes] In yet another specific example, III, Benedictine, the present invention relates to compounds in which Y represents the following:

Illb2 ;或 IIIc2 ;或 式Illb之基圏， 121 ”中η是〇且ρ是〇;或 式IIIc之基團，ΐφ 冉千11是0且ρ是〇。 33 1325414 在又另一個具體實例中，本發明係關於其中m是0且 Y具有式II之這類化合物，在其特定態樣中，γ具有式 I lb 或 IIc。 在又另一個具體實例中，m是1，且γ具有式π,在 其一特定態樣中，Y具有式11 b，而在其更多的特定態樣中 ，Y 具有式 lib1、lib2 或 lib3。 在又另一個具體實例中，m是1、R5係選自於c〗_6-垸 (稀/快）基和豳素所組成之群組且Y具有式II,在其— 特定態樣中，Υ具有式lib’而在其更多的特定態樣中，γ 具有式 lib1、lib2 或 lib3。 在又另一個具體實例中，本發明係關於其中m是j、 R5是c】-6-烷（烯/炔）基且γ具有式II之這類化合物， 在其一特定態樣中，Y具有式11 b，而在其更多的特定雜樣 中，Y具有式lib1或lib3。 在又另一個具體實例中，本發明係關於其中m是i、 R5是齒素原子如溴或氯或氟且Y具有式11之這類化合物 ，在其一特定態樣中’Y具有式lib，而在其更多的特定態 樣中，Y具有式lib1、lib2或lib3。 在又另一個具體實例中，本發明係關於其中m是i、 R5是演或氣且Y具有式Π之這類化合物，在其一特定態 樣中’Y具有式lib’而在其更多的特定態樣中，γ具有式 I lb1、I lb2 或 lib3 〇 在又另一個具體實例中’本發明係關於其中m是i、 R3是C^-烷（烯/炔）基且Y具有式Π之這類化合物， 34 1325414 在其一特定態樣中，Y具有式1，而在其更多的特定熊樣 中，Y具有式lib1、lib2或lib3，而在其最特定的態樣中 ，Y具有式lib3。 在又另一個具體實例中，本發明係關於其中是C 6-烷（烯/炔）基、m是1、R5是Cl_厂烷（烯/炔^基或_ 齒素且Y具有式II之這類化合物，在其一特定態樣/ 具有式lib，而在其一更特定態樣中，γ具有式 在又另一個具體實例中，本發明係關於其中η是〇、ρ 是0且Υ具有式III之這類化合物；在其特定態樣中，γ 具有式Illb或IIIc。 在又另-個具體實例中，本發明係關於其中η是丄且 Y具有式III之這類化合物，在其特定態樣中，有式Illb2; or IIIc2; or the base of formula 111b, where η is 〇 and ρ is 〇; or a group of formula IIIc, ΐφ 冉 1111 is 0 and ρ is 〇. 33 1325414 In yet another specific example The present invention relates to a compound of the formula wherein m is 0 and Y has the formula II, in its particular aspect, γ has the formula I lb or IIc. In yet another embodiment, m is 1, and γ has the formula π, in one particular aspect, Y has the formula 11 b, and in its more specific aspects, Y has the formula lib1, lib2 or lib3. In yet another specific example, m is 1, R5 It is selected from the group consisting of c _6-垸 (thin/fast) and 豳 且 and Y has the formula II, in its specific state, Υ has the formula lib' and in its more specific aspects In the other embodiment, γ has the formula lib1, lib2 or lib3. a compound, in one particular aspect thereof, Y has the formula 11 b, and in more specific samples thereof, Y has the formula lib1 or lib3. In yet another specific example, the invention relates to Where m is i, R5 is a dentate atom such as bromine or chlorine or fluorine and Y has such a compound of formula 11, in one particular aspect 'Y has the formula lib, and in more specific aspects thereof, Y has the formula lib1, lib2 or lib3. In yet another embodiment, the invention relates to a compound of the kind in which m is i, R5 is exemplified or gas and Y has the formula ,, in a particular aspect thereof 'Y Having the formula lib' and in its more specific aspects, γ has the formula I lb1 , I lb2 or lib3 又 In yet another specific example, the invention relates to wherein m is i, R 3 is C^-alkane ( Alkene/alkynyl group and Y having such a compound of the formula 34, 34 1325414 In one particular aspect, Y has the formula 1, and in more specific bears, Y has the formula lib1, lib2 or lib3, In its most specific aspect, Y has the formula lib3. In yet another embodiment, the invention relates to a C 6-alkane (ene/alkyne) group, m is 1, and R 5 is a Cl_steam. (alkenyl/alkynyl or dentate and Y having such a compound of formula II in one particular aspect / having the formula lib, and in a more specific aspect thereof, gamma having the formula in yet another In a specific example, the invention relates to a compound of the formula wherein η is 〇, ρ is 0 and Υ has formula III; in its particular aspect, γ has the formula 111b or IIIc. In yet another embodiment, The invention relates to a compound of the formula wherein η is 丄 and Y has the formula III, in its particular aspect,

Illb或IIIc’而在其更多的拉宁能4装山 夕的特疋態樣中’ Y具有式iiib2 、Illb3 或 IIIC2。 在又另一個具體實例中，士欲nn广 』〒本發明係關於其中n + D是 1且Y具有式III之這類化合物；在其 有式II Ic ;而在其一更特定離榫 ’心，中，'、 于疋態樣中，γ具有式IIIc2。 在又另一個具體實例中，夫欢nn〆 Τ本發明係關於其中η + D是 2且Y具有式III之這類化人 、T n + p疋 ...TTTh . m 。物，在其—特定態樣中，Y具 有式Illb，而在其一更牿金 τττκ3 、疋I樣中，Υ具有式Illb2或Illb or IIIc' and in its more characteristic form of the lining of the mountain, Y has the formula iiib2, Illb3 or IIIC2. In yet another embodiment, the invention is directed to a compound of the formula wherein n + D is 1 and Y has the formula III; in the formula IIc; and in a more specific In the heart, the middle, and the 疋, γ has the formula IIIc2. In still another specific example, the present invention relates to a type of human, T n + p疋 ... TTTh . m in which η + D is 2 and Y has the formula III. In its specific state, Y has the formula 111b, and in its more 牿τττκ3, 疋I, Υ has the formula 111b or

Illb3。 在又另一個具體實例中，告 田ff疋氧原子，γ不具有式 11 ° 在又另一個具體實例中，4 τ 7人 丄 ^ - Ιέ ^ Α 式1化合物含有不多於3個 如本文所定義之方基。 35 下清單之化合物 {2-胺基-4—[(5_ -胺基曱酸乙酯； 及其醫藥上可接受之鹽為較佳者： 氣-噻吩-2-基甲基）一曱基—胺基]一苯基 {2-胺基-4_[(5_氯__吩 基甲酸乙酯； 2-基甲基）一胺基]-苯基丨-胺 {2胺基4-[(5-甲基-噻吩_2_基曱基曱基一胺基卜苯 基}-胺基甲酸乙酯； {2胺基-4一[(5_溴_噻吩_2_基曱基）_胺基]-苯基卜胺 基甲酸乙酯； {2胺基-4-[(6~氯_3_甲氧基_苯并[b]噻吩_2_基甲基 )-胺基]-苯基}-胺基曱酸乙酯； {2-胺基-4-[(苯并[b]噻吩_2_基甲基）_胺基]_苯基卜 胺基甲酸乙酯； {2-胺基-4-[(5-甲基-噻吩_2_基甲基）_胺基]_苯基卜 胺基甲酸乙酯； {2-胺基-4-[(4~溴-3_甲氧基一噻吩-2_基甲基）_胺基]_ 苯基}-胺基曱酸乙酯； {2-胺基-4-[(5-笨基-噻吩-2-基甲基）-胺基]-苯基}-胺基甲酸乙酯； {2-胺基-4-[(3·•氯-噻吩-2-基甲基）-胺基]_苯基卜胺 基曱酸乙酯； (2-胺基-4-{ [4-(4-氯-苯磺醯基）-3-甲基吩-2-基 曱基]-胺基}-苯基）-胺基甲酸乙酯； {2-胺基-4-[(3-甲基-噻吩-2-基甲基）-胺基]-苯基}-胺基曱酸乙酯； 36 1325414 {2-胺基-4-[(5-氟-苯并呋喃-3-基曱基）-胺基]-苯基 }-胺基甲酸乙酯； {2_胺基-4-[(_吩-2-基甲基）-胺基]-苯基}-胺基曱酸 乙酷； {2-胺基-4-[(4-溴-_吩-2-基曱基）-胺基]-苯基卜胺 基曱酸乙醋； {2-胺基-4-[(5-乙基-噻吩-2-基甲基）-胺基]-苯基}_ 胺基曱酸乙酯； {2-胺基-4-[(噻吩-3-基曱基）-胺基]一苯基卜胺基曱酸 乙酯； {2-胺基-4-[(5-氯吩-2-基甲基）-乙基-胺基]-苯基 }-胺基曱酸乙酯； {2-胺基-4-[(笨并[b]噻吩_3_基曱基胺基卜苯基卜 胺基甲酸乙酯； {2-胺基-4-[(5-二曱基-胺基-苯并[b]噻吩_3_基甲基 )-胺基]-苯基}-胺基甲酸乙酯； {2-胺基_4-[(5-二曱基-胺基-3-曱基_笨并[b]噻吩_2_ 基甲基）-胺基]-笨基卜胺基甲酸乙酯； {2-胺基-4-[(5-氟-噻吩-2-基甲基）一胺基卜苯基卜胺 基曱酸乙酯； {2-胺基_4-[(笨并噻吩_2_基甲基）_胺基]_苯基卜 胺基曱酸丙酯； {2 —胺基_4_[(笨并[b]噻吩-3-基甲基）-胺基]-苯基}-胺基甲酸丙酯； 37 1325414 N-{2-胺基-4-[(5-氯-噻吩-2-基甲基）胺基]_苯基卜2_ (4 -氟-苯基）-乙酿胺；及 1^{2-胺基_4-[(5-氯-噻吩_2-基甲基）胺基]-苯基卜 3, 3-二甲基-丁醯胺。 在一特定態樣中，下清單之化合物及其醫藥上可接受 之鹽為較佳者： {2-胺基-4-[(5_氯-噻吩-2-基曱基）-曱基-胺基]-苯基 }-胺基曱酸乙酯； {2-胺基-4-[(5-氯-噻吩—2-基曱基）_胺基]—苯基卜胺 基甲酸乙酯； {2-胺基-4-[(5-甲基-噻吩-2-基甲基）_甲基-胺基]-苯 基}_胺基甲酸乙醋； {2-胺基-4-[(5-溴-噻吩-2-基甲基）-胺基]-苯基卜胺 基曱酸乙酯； {2-胺基-4-[(6-氣-3-曱氧基-苯并[b]噻吩_2_基甲基 )-胺基]-苯基}-胺基甲酸乙酿； {2_胺基''4-[(笨并[乜]_吩-2-基甲基）-胺基]-笨基}-胺基甲酸乙酯； {2-胺基-4-[ (5-曱基-噻吩_2_基曱基）_胺基]_苯基卜 胺基甲酸乙酯； {2-胺基-4-[(4-溴-3-曱氧基_噻吩-2_基甲基）一胺基]一 苯基}-胺基甲酸乙酯； {2-胺基-4-[(5-笨基-噻吩-2一基曱基）_胺基]_苯基卜 胺基曱酸乙酯； 1325414 {2-胺基-4-[(3_氯-噻吩-2-基甲基）-胺基]-苯基卜胺 基甲酸乙酯； (2-胺基-4-{[4-(4-氯-苯續醯基）_3 -甲基吩-2-基 曱基]-胺基}-苯基）-胺基甲酸乙酯； {2-胺基-4-[(3-曱基-噬吩-2-基甲基）-胺基]-苯基}_ 胺基曱酸乙酯； {2 -胺基- 4- [(5 -亂-苯并肤喃-3-基甲基）-胺基]-苯基 }-胺基甲酸乙酯； {2-胺基-4-[ (_吩-2-基曱基）-胺基]-苯基卜胺基曱酸 乙酯； {2-胺基-4-[(4-漠-瞳吩-2-基甲基）-胺基]-苯基卜胺 基曱酸乙酯； {2-胺基-4-[(5-乙基-噻吩-2-基甲基）-胺基]-苯基}-胺基甲酸乙酯； {2-胺基-4-[(噻吩-3-基甲基）-胺基]-苯基}-胺基甲酸 乙酯；及 {2-胺基-4-[(5-氯吩-2-基甲基）-乙基-胺基]-苯基 }-胺基曱酸乙S旨。 在一態樣中，本發明提供一種包含治療上有效量之至 少一種如以上所定義之式I化合物或其醫藥上可接受之鹽 及一或多種或醫藥上可接受之載劑或豨釋劑的醫藥組成物 〇 在一特定態樣中，本發明提供一種包含治療上有效量 39 1325414 化合物或其醫藥上可接受 可接受之載劑或稀釋劑的 之至少一種如以上所定義之式j 之酸加成鹽及一或多種或醫藥上 醫藥組成物。 本發明提供一種口 醫藥組成物包含治療上 鹽及一或多種或醫藥上 在一個具體實例中 有效之化合物來投予。 在另一個具體實例 的一部份來投予，亦即 抗痙攣性質之治療上有 痙攣性質之其他化合物 活性： 服取非經腸投藥用醫藥組成物，节 有效量之至少-種< I化合物或‘ 可接受之载劑或稀釋劑。 ，本發明之化合物可以唯一治療上 中本發明之化合物可以組合治療 本發明之化合物可與其他具有例如 效的化合物組合投予。這類具有抗 的作用可包括但不限於對於下列之 離子通道，例如鈉離子、鉀離子或鈣離子通道 興奮性胺基酸系統，例如受體的阻斷或調節 抑制性神經遞質系統，例如GABA_攝取之GABA釋放或 阻斷的增強，及/或 膜穩定作用。 目前的抗痙攣藥物包括但不限於：替加賓（tiagabine )、卡馬西平（carbamazepine )、丙戊酸納、拉莫三明：（ lamotrigine)、加巴噴丁、普利加巴林（pregabaiin)、 乙琥胺（ethosuximide )、左乙拉西坦（ievetiracetam ) 、本妥英（phenytoin)、托 Utg旨（topi ramate ) 、°坐尼沙 1325414 胺（z〇msamide)及苯并二氮簞和巴比妥酸鹽類的成員。 本發明之化合物独何可用來增力口電壓依賴性钟離子 通道中的離子流。 本發明之化合物被認為可用來預防、治療及/或抑制 對奸離子it道如K⑽族鉀料料巾增加的料流敏感的 障礙或病狀。 在嘘樣中，本發明之化合物已經發現對KCNQ族之鉀 離子通道，尤其是對KCNQ2亞單位有作用。 根據態樣，本發明之化合物被認為可用來預防、治 療及/或抑制中樞神經系統的各種障礙，例如：癲癇發作 症，如驚厥、癲癇和癲癇持續狀態；焦慮症，如焦慮、廣 “、、慮症恐慌性焦慮、強迫症、社交恐懼症、表現焦 慮、創傷後壓力症、急性壓力反應、適應障礙、疑病性障 礙刀離焦慮症、畏曠症及特定恐懼症❶ 因此本發明之化合物被認為可用來預防、治療及/ 或抑制中樞神經系統的各種障礙，例如： 癲癇發作症’如驚厥、癲癎和癲癎持續狀態； 、神經病痛’如觸感痛、痛覺過敏疼痛、幻痛、與糖尿 病神經病變有關之神經病痛及與偏頭痛有關之神經病痛； :焦慮症’如焦慮、廣泛性焦慮症、恐慌性焦慮、強迫 ；社交心懼症、表現焦慮、創傷後壓力症、急性壓力反 應 '適應障礙' 疑病性障礙、分離焦慮症、畏曠症、特定 恐懼症； 神經退化性障礙，如阿兹海默氏症亨丁頓氏舞蹈症 1325414 、多發性硬化、肌萎縮性脊髓側索硬化、AIDS誘發的腦病 及其他因德國麻疹病毒、疱疹病毒、疏螺旋體和未知病原 體所引起感染有關之腦病、冑賈氏症、帕金森氏症、創傷 誘發的神經退化，及 諸如藥。。戒斷中或中毒所致之神經元過度興奮狀態、 周圍神經系統的神經退化性障礙如多發性神經病和多發性 神經炎。 本發明之化合物被認為可用來預防、治療及/ 或抑制諸如癲癇發作症、神經病與偏頭痛障礙、焦慮症及 神經退化性障礙等之類的障礙或病狀。 么根據n態樣，本發明之化合物被認為可用來預防 /口療及/或抑制諸如驚厥、癲癎及癲癇持續狀態之類的 癲癇發作症。 根據另-個特定態樣，本發明之化合物被認為可用來 療及/或抑制諸如觸感痛、痛覺過敏疼痛、幻痛 〃糖尿病神經病變有關之神經病痛及與偏頭痛有關之神 經病痛之類的神經病和偏頭痛障礙。 本發月之化合物進一步被認為可用來預防、治療及/ 或：制諸如焦慮、廣泛性焦慮症、恐慌性焦慮、強迫症' 、。灌症表現焦慮、創傷後壓力症、急性壓力反應、 適應障礙、疑病彳生陸饱^ Λ *A- Α ^ 性障礙、刀離焦慮症、畏曠症、一般醫療 病狀所致之焦慮症及物質誘發的焦慮症及特定恐懼症之類 的焦慮症。 42 1325414 本發月之化。物進—步被認為可用來預防、治療及/ 騎制神經退化性障礙，例如阿兹海默氏症、亨丁頓氏舞 蹈症、多發性硬化、肌萎縮性脊髓側索硬化、應誘發的 腦病及其他因德國歸病毒、财病毒、疏螺旋體和未知 病原體所引起感染有關之腦病、冑賈氏症、帕金森氏症、 創傷誘發的神經退化及钱^磁σ斗 次。t如樂品戒斷中或中毒所致之神經 元過度興奮狀態。 在另一態樣中，本發明提供在下列試驗之一或多者中 顯示效用的化合物： “經過KCNQ2通道之相對外流（relative efflux )，， 此為化合物在目標通道之效力的度量 “最大電休克” 此為由電方法所致非特定CNS刺激所誘發之癲癇發作 的度量 f毛果芸香鹼（Pil〇carpine)誘發的癲癇發作，， 由毛果芸香鹼所誘發之癲癇發作通常難以用許多現有 的抗癲癇發作藥物治療，而因此反映出一種“抗藥性癲癎發 作”的模式。 電癲癇發作閾試驗”和“化學癲癇發作閾試驗” 這些模式係測量引發癲癇發作之閾值，因此是檢測化 合物可否延緩癲癇發作引發作用之模式。 “杏仁核激動’’ 此係用作疾病進展的度量’以正常動物中而言，此模 式中之_癇發作隨該動物接收進一步刺激而變得更為嚴重。 43 1325414 根據本發明之-特定態樣，該化合物係以小於 15〇〇〇詣之E^而對_2有效，如下文所述之“經過 KCNQ2通道之相對外流，，試驗所測者。Illb3. In yet another specific example, the gamma 疋 oxygen atom, γ does not have the formula 11 °. In yet another specific example, 4 τ 7 human 丄 ^ - Ιέ ^ Α the compound of formula 1 contains no more than 3 as herein The square base defined. 35 The compound of the following list {2-Amino-4-[(5--amino decanoic acid ethyl ester; and its pharmaceutically acceptable salt is preferred: gas-thiophen-2-ylmethyl)-indenyl) —amino]phenyl-phenyl{2-amino-4_[(5-chloro-methyl phenyl); 2-ylmethyl)-amino]-phenylindole-amine {2 amine 4-[ (5-Methyl-thiophene-2-ylindenyl-monoaminophenylphenyl}-carbamic acid ethyl ester; {2amino-4-[(5-bromo-thiophene-2-ylindenyl) _Amino]-phenylethyl carbamic acid ethyl ester; {2amino-4-[(6-chloro-3-yl-methoxy-benzo[b]thiophen-2-ylmethyl)-amino] -phenyl}-amino decanoic acid ethyl ester; {2-amino-4-[(benzo[b]thiophen-2-ylmethyl)-amino]-phenyl- phenylaminocarbamate; Ethyl 2-amino-4-[(5-methyl-thiophen-2-ylmethyl)-amino]-phenyl-p-propylcarbamate; {2-amino-4-[(4~bromo-) 3-methoxy-thiophen-2-ylmethyl)-amino]-phenyl}-amino decanoic acid ethyl ester; {2-amino-4-[(5-phenyl-thiophen-2-yl) Methyl)-amino]-phenyl}-carbamic acid ethyl ester; {2-amino-4-[(3·•chloro-thiophen-2-ylmethyl)-amino]-phenylphenamine Ethyl phthalate; (2-amino-4-{[4-(4-chloro-phenylsulfonyl)-3-) Phen-2-ylindenyl]-amino}-phenyl)-carbamic acid ethyl ester; {2-amino-4-[(3-methyl-thiophen-2-ylmethyl)-amino] -phenyl}-aminoethyl decanoate; 36 1325414 {2-Amino-4-[(5-fluoro-benzofuran-3-ylindenyl)-amino]-phenyl}-aminocarboxylic acid Ethyl ester; {2_amino-4-[(_phen-2-ylmethyl)-amino]-phenyl}-amino decanoic acid; {2-amino-4-[(4- Bromo-{phen-2-ylindenyl)-amino]-phenyl-amino-aminoacetic acid ethyl acetate; {2-amino-4-[(5-ethyl-thiophen-2-ylmethyl)- Ethyl]-phenyl}-amino decanoic acid ethyl ester; {2-amino-4-[(thiophen-3-ylindenyl)-amino]phenylphenylamino decanoic acid ethyl ester; {2 -Amino-4-[(5-chlorophen-2-ylmethyl)-ethyl-amino]-phenyl}-amino decanoic acid ethyl ester; {2-Amino-4-[(stupid [b] thiophene-3-ylhydrazinyl phenyl phenylaminocarbamate; {2-amino-4-[(5-diamidino-amino-benzo[b]thiophene_3_ Ethylmethyl)-amino]-phenyl}-carbamic acid ethyl ester; {2-amino-4-[[5-diamidino-amino-3-indolyl] benzo[b]thiophene 2_ylmethyl)-amino]-p-butyryl carbamate; {2-amino-4-[(5-fluoro-thiophen-2-ylmethyl)-amine bromide Ethyl ruthenium hydride; {2-amino-4-[(p- and thiophene-2-ylmethyl)-amino]-phenyl-phenylamino decanoate; {2 - amine _4_[( Stupid [b]thiophen-3-ylmethyl)-amino]-phenyl}-carbamic acid propyl ester; 37 1325414 N-{2-amino-4-[(5-chloro-thiophene-2- Methyl)amino]-phenyl b-2-(4-fluoro-phenyl)-ethinamide; and 1^{2-amino-4-[[5-chloro-thiophen-2-ylmethyl) Amino]-phenyl b 3,3-dimethyl-butanamine. In a particular aspect, the compounds of the following list and their pharmaceutically acceptable salts are preferred: {2-Amino-4-[(5-chloro-thiophen-2-ylindenyl)-indenyl- Ethyl]-phenyl}-amino decanoic acid ethyl ester; {2-amino-4-[(5-chloro-thiophene-2-ylindenyl)-amino]-phenyl- propylaminocarbamate {2-Amino-4-[(5-methyl-thiophen-2-ylmethyl)-methyl-amino]-phenyl}-carbamic acid ethyl acetate; {2-Amino-4- [(5-Bromo-thiophen-2-ylmethyl)-amino]-phenylethylamino decanoate; {2-Amino-4-[(6-Ga-3-methoxy-benzene) And [b]thiophene-2-ylmethyl)-amino]-phenyl}-carbamic acid ethyl; {2_amino"'4-[(stupid [乜]_ phen-2-yl) Ethyl)-amino]-phenyl]ethyl urethane; {2-amino-4-[(5-fluorenyl-thiophene-2-ylindolyl)-amino]-phenyl- phenylamino Ethyl formate; {2-amino-4-[(4-bromo-3-indolyl-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic acid ethyl ester; {2- Amino-4-[(5-phenyl-thiophen-2-ylindenyl)-amino]-phenyl-phenylamino decanoic acid ethyl ester; 1325414 {2-Amino-4-[(3-chloro- Ethyl thiophen-2-ylmethyl)-amino]-phenyl-p-aminocarboxylate; (2-amino-4-{[4-( 4-chloro-benzene hydrazino)_3-methylphen-2-ylindenyl]-amino}-phenyl)-carbamic acid ethyl ester; {2-amino-4-[(3-indolyl) - phenophen-2-ylmethyl)-amino]-phenyl}-amino decanoic acid ethyl ester; {2-amino- 4- [(5-disorgan-benzo-pyran-3-ylmethyl) Ethylamino]-phenyl}-carbamic acid ethyl ester; {2-amino-4-[(_phen-2-ylindenyl)-amino]-phenyl-aminoglycolic acid ethyl ester; {2-Amino-4-[(4-oxa-瞳-phen-2-ylmethyl)-amino]-phenyl-amino-carbamic acid ethyl ester; {2-Amino-4-[(5- Ethyl-thienyl-2-ylmethyl)-amino]-phenyl}-carbamic acid ethyl ester; {2-amino-4-[(thiophen-3-ylmethyl)-amino]-benzene Ethyl}-urethane; and {2-amino-4-[(5-chlorophen-2-ylmethyl)-ethyl-amino]-phenyl}-amino decanoic acid . In one aspect, the invention provides a therapeutically effective amount of at least one compound of formula I as defined above, or a pharmaceutically acceptable salt thereof, and one or more or a pharmaceutically acceptable carrier or release agent Pharmaceutical composition 〇 In a particular aspect, the invention provides at least one formula J as defined above comprising a therapeutically effective amount of a compound 13 1325414 or a pharmaceutically acceptable acceptable carrier or diluent thereof An acid addition salt and one or more or a medicinal pharmaceutical composition. The present invention provides a pharmaceutical composition comprising a therapeutically superior salt and one or more compounds which are pharmaceutically effective in one embodiment for administration. In another part of the specific embodiment, that is, the anti-caries property of the other compound having the properties of anthraquinone: the administration of a parenterally-administered pharmaceutical composition, at least an effective amount of a < I Compound or 'acceptable carrier or diluent. The compound of the present invention may be the only one of the compounds of the present invention which can be administered in combination. The compound of the present invention can be administered in combination with other compounds having, for example, efficacy. Such anti-effects may include, but are not limited to, ion channels for the following, such as sodium ion, potassium ion or calcium channel excitatory amino acid systems, such as receptor blockade or modulation of inhibitory neurotransmitter systems, for example Enhancement of GABA release or blockade by GABA_ uptake, and/or membrane stabilization. Current anti-caries drugs include, but are not limited to, tiagabine, carbamazepine, sodium valproate, lamotrigine, gabapentin, pregabaiin, ethosuxamine (pregabaiin) Ethosuximide ), levetiracetam (ievetiracetam), phenytoin, totuk (topi ramate), sinisha 1325414 amine (z〇msamide) and benzodiazepine and barbiturate Member of the class. The compounds of the present invention can be used alone to increase the ion current in the voltage-dependent clock ion channel. The compounds of the present invention are believed to be useful in the prevention, treatment, and/or inhibition of a flow-sensitive disorder or condition that is additive to the K-type (K) family of potassium batters. In the case of the compounds of the present invention, it has been found that the potassium channel of the KCNQ group, especially the KCNQ2 subunit, has an effect. Depending on the aspect, the compounds of the present invention are believed to be useful in the prevention, treatment, and/or inhibition of various disorders of the central nervous system, such as: seizures such as convulsions, epilepsy, and status epilepticus; anxiety disorders such as anxiety, broadness, , panic anxiety, obsessive-compulsive disorder, social phobia, performance anxiety, post-traumatic stress disorder, acute stress response, adaptation disorder, suspected disability, knife anxiety disorder, phobia and specific phobia Compounds are believed to be useful in the prevention, treatment, and/or inhibition of various disorders of the central nervous system, such as: seizures such as convulsions, epilepsy, and epilepticus; neuropathic pains such as tactile pain, hyperalgesia, pain, and illusion Pain, neuropathic pain associated with diabetic neuropathy and neuropathic pain associated with migraine; : anxiety disorders such as anxiety, generalized anxiety disorder, panic anxiety, compulsion; social distress, performance anxiety, post-traumatic stress disorder, Acute stress response 'adaptive disorder' suspicion disorder, separation anxiety disorder, phobia, specific phobia; neurodegenerative disorder Such as Alzheimer's disease, Huntington's disease 1325414, multiple sclerosis, amyotrophic lateral sclerosis, AIDS-induced encephalopathy and other infections caused by German measles virus, herpes virus, Borrelia and unknown pathogens Related encephalopathy, Jay's disease, Parkinson's disease, trauma-induced neurodegeneration, and drugs such as drugs. Excessive state of neuron caused by withdrawal or poisoning, neurodegenerative disorders of the peripheral nervous system such as polyneuropathy And polyneuritis. The compounds of the present invention are believed to be useful for preventing, treating, and/or inhibiting disorders or conditions such as seizures, neuropathy and migraine disorders, anxiety disorders, and neurodegenerative disorders. In the n-state, the compounds of the invention are believed to be useful for preventing/oral therapy and/or inhibiting seizures such as convulsions, epilepsy, and status epilepticus. According to another particular aspect, the compounds of the invention are considered It can be used to treat and/or inhibit neuropathic pains such as tactile pain, hyperalgesia pain, phantom pain, diabetic neuropathy and Neuropathy and migraine disorders such as pain-related neuropathic pain. Compounds of this month are further considered to be useful in the prevention, treatment, and/or treatment of such as anxiety, generalized anxiety disorder, panic anxiety, obsessive-compulsive disorder. Symptoms of anxiety, post-traumatic stress disorder, acute stress response, adaptation disorder, suspected twins and sputum *A- Α ^ sexual disorders, knife-away anxiety, phobia, general medical conditions caused by anxiety And substance-induced anxiety disorders and anxiety disorders such as specific phobias. 42 1325414 This month's metamorphosis. The disease is considered to be used to prevent, treat and/or ride neurodegenerative disorders such as Alzheimer's Symptoms, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, encephalopathy that should be induced, and other encephalopathy related to infection caused by German virus, viral, Borrelia and unknown pathogens , Parkinson's disease, trauma-induced neurodegeneration, and money. t If the hormone is absent or poisoned, the neuron is overexcited. In another aspect, the invention provides a compound that exhibits utility in one or more of the following assays: "relative efflux through the KCNQ2 channel, which is a measure of the efficacy of the compound in the target channel" maximal electricity Shock" This is a measure of seizures induced by non-specific CNS stimulation caused by electrical methods. Pil〇carpine-induced seizures, seizures induced by pilocarpine are often difficult to use with many existing anti-epileptic drugs. Treatment, and thus reflects a pattern of “drug-resistant epileptic seizures.” Electro-seizure threshold test” and “Chemical seizure threshold test” These patterns measure the threshold of seizures, so whether the test compound delays seizures Mode of action. "Amygdaloid agonism" This line is used as a measure of disease progression. In normal animals, the seizures in this pattern become more severe as the animal receives further stimulation. 43 1325414 -Specific according to the invention In the aspect, the compound is effective for _2 with less than 15 E E^, as described below, "relative outflow through the KCNQ2 channel, as measured by the test.

根據本發明之一特定態樣，該化合物係以小於15_M 之仏❶而對_2有效，如下文所述之“經過_2通道之 相對外流”試驗所測者。 :艮據本發明之另一個特定態樣，該化合物係以小於 n之此50而對KCNQ2有效，如下文所述之“經過謂2 通道之相對外流，，試驗所測者。 根據本發明之另一個特定態樣，該化合物在下文所述 之最大電休克，，試驗中具有小於15毫克/公斤之I。 根據本發明之又另一個 、f θ “I 4· # 1 f ^ I樣，該化合物在下文所 边之最大電休克，，試驗中具有小於5毫克/公斤之 根據本發明之一特定態 5〇 1 4化合物在下女所iifc之“ 電癲癇發作閾試驗，，及/或 文斤述之 有小於5毫克/公斤H ㈣痛發作間試驗，，中具 有些化合物有少許或臨床上 些化合物令有些係於化合物相要鎮=作用。因此這 失調作用模式中受測試。 静U共濟 有些化合物有適當的半生 者只需要-天吃藥例如一次或二二除率，表示患 記得，所以有助於對荜物 &對〜、者而言很容易 丁樂物/σ療的順應性。 這些化合物中有些在抗痙 能力或共濟失調作用之缺損’由0副作用（例如活動 藉由在旋轉柱上表現所測 44 1325414 表示這些化合物預期在 胃齊1量之患者充分耐受。 量者）之間有很大的治療指數。 見到副作用之前將可為允許使用 因此對於此治療之順應性預期將會是良好的，且可允許高 劑量之投藥，使得治療在可能對其他藥物有副作用的患者 中更為有效。 定義 雜原子一詞係指氮、氧或硫原子。 鹵素意指氟、氯、溴或碘。According to a particular aspect of the invention, the compound is effective against _2 with less than 15 mm and is tested as described in the "Extra-flow through the _2 channel" test as described below. According to another particular aspect of the invention, the compound is effective for KCNQ2 with less than n of 50, as described below, "through relative outflow of the 2 channel, the test is performed. According to the invention In another specific aspect, the compound has a maximum electrical shock as described below, and has an I of less than 15 mg/kg in the test. According to yet another aspect of the invention, f θ "I 4 · # 1 f ^ I, The compound has a maximum electroshock, hereinafter, having less than 5 mg/kg of a specific state of the invention according to one aspect of the invention. The compound is in the electric seizure threshold test, and/or It is said that there are less than 5 mg / kg H (four) pain interstitial test, there are some compounds in the compound or some of the compounds in the clinical phase, some of which are in the phase of the compound phase. Therefore, this mode of imbalance is tested. Some compounds with appropriate half-life need only take a day-to-day medication such as one or two or two removal rates, which means that the patient remembers, so it is easy for the sputum & Compliance. These Some of the defects in the anti-spasmodic or ataxia effect are caused by 0 side effects (for example, activity is measured by the performance of the spin column. 44 1325414 indicates that these compounds are expected to be well tolerated in patients with a dose of stomach.) There is a large therapeutic index between them. It will be acceptable to see the side effects before the side effects are expected, so the compliance with this treatment is expected to be good, and high doses of the drug may be allowed to be administered, so that the treatment may have side effects on other drugs. More effective in patients. The definition of a hetero atom refers to a nitrogen, oxygen or sulfur atom. Halogen means fluorine, chlorine, bromine or iodine.

Ch-烷（烯/炔）基一詞意指Ci e_烷基、c2 6_烯基或 〇2-6_炔基。 C!-6-烷基一詞係指具有一至六個（含）碳原子之分支 或未分支烷基，包括但不限於：甲基、乙基 '卜丙基、2_ 丙基、1-丁基、2-丁基、2一曱基_2一丙基、2_2二甲基_卜 丙基及2-甲基-1-丙基。 類似地，（：2_6~烯基和q厂炔基分別表示具有二至六個 碳原子，分別包含一個雙鍵和一個參鍵的這類基團，包括 但不限於：乙烯基、丙烯基、丁烯基、乙炔基、丙炔基及 丁炔基。 C3-8-環烷（烯）基一詞意指C3_8-環烷基或環烯基。 〇3-8_環烧基一詞表示具有三至八個c原子之單環族或 雙環族碳環，包括但不限於：環丙基、環戊基、環己基等 等》 C3_8_環稀基一詞表示具有三至八個C原子且包含一個 1325414 雙鍵之單環族或雙環族碳環。 —當二個取代基連同它們所連接之氮原子一起形成一個 視&要3有卜2或3個其他雜原子之員飽和或不飽和 環時，則單環族環系統係由4至8個選自於氮原子、卜7 個碳科㈣-3個選自於N、S4k雜原子的原子所形成 者。圾類環系統的例子有：氮雜環丁烷、卜内醯胺、毗咯 燒飛咬顿啡、嗎咐、® ；洛、聘嗤燒、噻嗤烧、咪。坐烧 、四σ坐及卩比唾。 方基一詞係指諸如毗啶 '噻唑、腭唑、苯基、笼基、 暖吩及呋喃之類的芳族系統，其係視需要經—或多個獨立 為下列各基之取代基取代：歸、_素、U (稀/快 )基、W環烷（稀）基、c3-8-環烷（婦）基H ( 烯/炔）基、齒基-Cl_「烷（烯，炔）基、Ci_「烷氧基、 c3-8-烷氧基、酿基、石肖基或氰基，r烷（烯/块 )α/炔）基）2, .Ci 6 炫（稀/ 炔）基、-叫_6-烧（稀/炔）基）2, __s_u⑽/快 )基、-so2-Cl_6-统（稀 / 块）基、一δ〇2〇ϋ (稀 / 快 )基、-μη2、-SM(Cl_6i (稀 / 块）基）2 或為NH C"_ 烷（烯/炔）基；或者 二個相鄰取代基可連同它們所連接之芳職團一起形 成-個4-8員環，其視需要含有一或二個雜原子。 當二個相鄰取代基連同它們所連接之芳族基團一起形 成-個視需要含有-或二個雜原子之4_8員環時，則環系 統係由4-8個選自於4-8個選自於3_8個碳原子和〇 2個 46 1325414 選自於N、S武 ' 5 0之雜原子的原子所形成者。這種的二個相 鄰取代基可一起形成： -（CH2)n，‘、ch 2~ 、 -CH=CH-(CH2)m，‘- 、 -CH2-CH=CH- (ch2)p，‘、普Ch、ch=ch…(cH2)n _G_、+(c +、_ CH2-〇-(CH2)D，‘〜ο οτι 2或3，n’‘是 或4，而 p ' -ch2-〇-ch2-o-ch2- ' -(CH2)n..-S- > -S-(CH2)ffl..-S- > 'CH2-S-(CH2)p,.-S- ' -CH2-S-CH2-S-CH2- > -(CH2)n’‘-NH-'’-(CH2)m,‘—NH-、-CH2-NH-(CH2)p，.-NH-、-CH_CH_NH_、〜〇 —(CH2)m，‘-NH-、_CH2-〇-(CH2)p,‘-NH-或_〇_ (CH2)p..-NH-CH2- , -S-(CH2)n..-NH- ' -N=CH-NH- ^ -N = CH-0-或-N=CH-S- ’其中m，‘是 p ’ ‘是1或2。 當用於本文時，醯基-詞係指甲醯基、Ch-烷（烯/ 炔）基羰基、C3-广環烷（烯）基羰基、芳基羰基、芳基_ Cy-烷（烯/炔）基羰基或C3 8_環烷（烯）基义厂烷（ 稀/炔）基-幾基，其+ u (烤/炔）基、w環烧 (婦）基及芳基係如以上所定義者。 鹵基-C!—6-烷（烯/炔）基一詞表示被一或多個鹵素原 子取代之C丨_6-炫（稀/炔）基，包括但不限於：三氟甲基 。類似地，處基-c^-環烷（烯）基表示被一或多個齒素 原子取代之〇3_8_環烷（烯）基，而鹵基_CM_環炫（婦） 基丨_6~·炫（烯/块）基表示被一或多個鹵素原子取代之 C3-8-環烷（烯）基~C!_6-烷（烯/炔）基。 在〇3-8_ί衣烧（稀）基-C!_6-统（稀/块）基一詞中， C3-s-環烷（烯）基及Ci_e-烷（烯/炔）基係如以上所定義 47 1325414 者0 此外，諸如羥基_(^_6-烷（烯/炔）基、羥基_C3 8一環 烷（烯）基、芳基-Cm-烷（烯/炔）基、(：卜6-烷（烯/ 炔）氧基、Cm-環烷（烯）氧基、（^厂烷（烯/炔）基羰 基、C3_8_環烷（烯）基羰基、芳基羰基、芳基气卜广烷（ 烯/炔）基羰基、C3-r環烷（烯）基-Ch-烷（烯/炔） 基羰基、芳基-C3_8_環烷（烯）基、羥基_C3_8_環烷（烯） 基-Ch-烷（烯/炔）基 '羥基_c丨_6_烷（烯/炔）基气^一 環烷（烯）基、氰基-Cl_6_烷（烯/炔）基、氰基_C3厂環 烷（烯）基、氰基-C3_8_環烷（烯）基_Ci 6_烷（烯//炔） 基、NWg’-Ch-烷（烯/炔）基及nr1Qr1〇，_C3厂環烷（烯 )基等之類的名詞表示其中c^-烷（烯/炔）基、C3 8_環 烧（稀）基及芳基係如以上所定義之基團。 本發明之鹽最好是醫藥上可接受之鹽。這類鹽包括醫 藥上可接受之酸加成鹽、醫藥上可接受之金屬鹽、銨鹽及 烷基化銨鹽。 本發明之醫藥上可接受之鹽最好是酸加成鹽。 加成鹽包括無機酸和有機酸的鹽。 本發明之酸加成鹽最好是本發明化合物與無毒酸形成 之醫藥上可接受之鹽。 这類有機鹽的例子為與下列酸所形成者：馬來酸、富 馬酸、苯曱酸、抗壞血酸、琥拍酸、草酸、雙_亞甲基水 楊酸、曱烷磺酸、乙烷二磺酸、醋酸、丙酸、酒石酸、水 楊酸、檸檬酸、葡糖酸、乳酸、蘋果酸、扁桃酸、肉桂酸 48 1325414 、檸康酸、天冬胺酸、硬脂酸、棕櫚酸、衣康酸、乙醇酸 、p-胺基苯甲酸、榖胺酸、苯磺酸和茶鹼醋酸，以及8_鹵 命驗，例如8 -溴茶驗。 這類無機鹽類的例子為與下列酸所形成者：氫氣酸、 氫溴酸、硫酸、胺基磺酸、磷酸及硝酸。這類酸加成鹽可 經由熟習該項技術者所知的方法形成。醫藥上可接受之無 機或有機酸加成鹽之其他例子包括列舉於人 1977，66’ 2 (其係以引用方式納入本文）中之醫藥上可接 受之鹽。 亦意欲作為醫藥上可接受之酸加成鹽者為本發明化合 物所能夠形成之水合物。 ° 此外，當在分子中有雙鍵或有全飽和或部分飽和環系 統存在時’則可形成幾何異構物。所意欲的是，任何幾何 異構物、剛分離、純化或部分純化之幾何異構物或幻昆人 物係包含在本發明之範圍内。同樣地，具有限制旋轉鍵結 的分子可形成幾何異構物。這些也意欲包含在本發 FH r3n 导匕 此外’本發明化合物中有些可以不同的互變異構 二存在’而所意欲的是該化合物所能夠形成的任何互變異 物形式都包含在本發明之範圍内。 、The term Ch-alkane (alkenyl/alkynyl) refers to Ci e-alkyl, c2 6-alkenyl or 〇2-6-alkynyl. The term C!-6-alkyl refers to a branched or unbranched alkyl group having one to six (inclusive) carbon atoms, including but not limited to methyl, ethyl 'propyl, 2-propyl, 1-butyl, 2-butyl, 2-indolyl-2-propyl, 21-2 dimethyl-propyl and 2-methyl-1-propyl. Similarly, (: 2_6-alkenyl and q-acetylene groups respectively represent such groups having two to six carbon atoms, each containing a double bond and a single bond, including but not limited to: vinyl, propenyl, Butenyl, ethynyl, propynyl and butynyl. The term C3-8-cycloalkane (alkenyl) means C3_8-cycloalkyl or cycloalkenyl. The term 〇3-8_cycloalkyl is used. a monocyclic or bicyclic carbon ring having three to eight c atoms, including but not limited to: cyclopropyl, cyclopentyl, cyclohexyl, and the like. The term C3_8_cycloalkyl means having three to eight C atoms. And a monocyclic or bicyclic carbon ring containing a 1325414 double bond. - When two substituents together with the nitrogen atom to which they are attached form a single & 3 or 2 other heteroatoms saturated or In the case of an unsaturated ring, the monocyclic ring system is formed by 4 to 8 atoms selected from nitrogen atoms, 7 carbon families (4)-3 atoms selected from N, S4k hetero atoms. Examples are: azetidine, bupropion, pyrrole, bitumin, 咐, ;; 洛, 嗤 嗤, thiazepine, imi, sitting, four sigma The term "square" refers to an aromatic system such as pyridinium thiazole, carbazole, phenyl, cage, warm phenanthrene and furan, which may be as desired - or Substituent substituent substitution: ruthenium, _ 素, U (lean/fast) group, W cycloalkane (thin) group, c3-8-cycloalkane (indenyl) H (alkenyl/alkyne) group, dentate group - Cl_" Alkane (alkenyl, alkyne) group, Ci_ "alkoxy group, c3-8-alkoxy group, aryl group, schlossyl or cyano group, r alkane (alk) / alkyne)), .Ci 6 Dilute / alkyne base, - _6-burn (thin / alkyne) base 2, __s_u (10) / fast) base, -so2-Cl_6-system (thin / block) base, a δ 〇 2 〇ϋ (lean / fast ), -μη2, -SM(Cl_6i (thin/block) group) 2 or NH C"_alkane (ene/alkyne) group; or two adjacent substituents may be formed together with the aromatic group to which they are attached a 4-8 membered ring which optionally contains one or two heteroatoms. When two adjacent substituents are formed together with the aromatic group to which they are attached - 4_8 optionally containing - or two heteroatoms When the ring is ringed, the ring system is selected from 4-8 and 4-8 are selected from 3-8 carbon atoms and 2 46 1325414 is formed by an atom selected from a hetero atom of N, S wu '50. Two adjacent substituents may be formed together: -(CH2)n, ', ch 2~, -CH=CH -(CH2)m,'-, -CH2-CH=CH-(ch2)p,', PuCh, ch=ch...(cH2)n _G_, +(c +, _ CH2-〇-(CH2)D , '~ο οτι 2 or 3, n'' is or 4, and p ' -ch2-〇-ch2-o-ch2- ' -(CH2)n..-S- > -S-(CH2)ffl ..-S- > 'CH2-S-(CH2)p,.-S- ' -CH2-S-CH2-S-CH2- > -(CH2)n''-NH-''-(CH2 m, '-NH-, -CH2-NH-(CH2)p, .-NH-, -CH_CH_NH_, ~〇-(CH2)m, '-NH-, _CH2-〇-(CH2)p, '- NH- or _〇_ (CH2)p..-NH-CH2-, -S-(CH2)n..-NH- '-N=CH-NH- ^ -N = CH-0- or -N= CH-S- 'where m, ' is p ' 'is 1 or 2. As used herein, thiol-term is nail sulfhydryl, Ch-alkane (alkenyl/alkynyl)carbonyl, C3-polycyclo(alkenyl)carbonyl, arylcarbonyl, aryl-cy-alkane (alkenyl) Alkynylcarbonyl or C3 8 -cycloalkane (n-) alkane (diuret / alkyne)-yl, which has a + u (roast / alkyne) group, a w-ring (female) group and an aryl group such as Defined by. The term halo-C!-6-alkane (alkenyl/alkynyl) refers to a C丨_6-horse (thin/alkyne) group substituted by one or more halogen atoms, including but not limited to: trifluoromethyl. Similarly, the group -c^-cycloalkane (alkenyl) group means a 〇3_8_cycloalkane (alkenyl) group substituted by one or more dentate atoms, and a halogen group _CM_ring 炫 (妇) 丨6~·Hyun(ene/block) group means a C3-8-cycloalkane(ene) group ~C!_6-alkane (ene/alkyne) group substituted by one or more halogen atoms. In the term 〇3-8_ί衣(稀)基-C!_6-统(稀/块)基, the C3-s-cycloalkane (alkenyl) group and the Ci_e-alkane (ene/alkyne) group are as above Defined 47 1325414 0 In addition, such as hydroxy-(^_6-alkane (ene/alkynyl) group, hydroxy-C3 8-cycloalkane (alkenyl) group, aryl-Cm-alkane (ene/alkyne) group, (: Bu 6-alkane (alkenyl/alkynyloxy), Cm-cycloalkane (alkenyloxy), (i-alkane (alkenyl)-carbonyl), C3-8-cycloalkanecarbonyl, arylcarbonyl, aryl Bulkane (alkenyl/alkynyl)carbonyl, C3-r cycloalkanoyl-Ch-alkane (alkenyl/alkynyl)carbonyl, aryl-C3-8-cycloalkanoyl, hydroxy-C3_8-cycloalkane )-Ch-alkane (alkenyl/alkynyl)-hydroxy-cc_6-alkane (alkenyl/alkynyl)-cyclohexane (alkenyl) group, cyano-Cl_6-alkane (ene/alkyne) group, cyanide _C3 plant cycloalkane (alkenyl) group, cyano-C3_8_cycloalkane (alkenyl) group -Ci 6-alkane (ene / / alkyne) group, NWg'-Ch-alkane (ene / alkyne) group and nr1Qr1〇 The term "cycloalkane (alkenyl)" or the like of the _C3 plant means a group wherein c--alkane (alkenyl/alkynyl) group, C3 8-cyclic (slty) group, and aryl group are as defined above. Salt Preferably, it is a pharmaceutically acceptable salt. Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium salts and alkylated ammonium salts. The pharmaceutically acceptable salts of the present invention Preferably, the acid addition salt. The addition salt comprises a salt of an inorganic acid and an organic acid. The acid addition salt of the present invention is preferably a pharmaceutically acceptable salt of the compound of the present invention and a non-toxic acid. Examples are those formed with the following acids: maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, bis-methylene salicylic acid, decane sulfonic acid, ethane disulfonic acid, acetic acid , propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid 48 1325414, citraconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, Glycolic acid, p-aminobenzoic acid, valine acid, benzenesulfonic acid and theophylline acetic acid, and 8-halogen test, such as 8-bromo tea test. Examples of such inorganic salts are those formed with the following acids. Hydrogen acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid and nitric acid. Such acid addition salts can be obtained via Forms are known to those skilled in the art. Other examples of pharmaceutically acceptable inorganic or organic acid addition salts include those pharmaceutically acceptable in humans 1977, 66' 2 (which is incorporated herein by reference) Salts. Also intended as pharmaceutically acceptable acid addition salts, are hydrates which can be formed by the compounds of the invention. ° In addition, when there are double bonds in the molecule or a fully saturated or partially saturated ring system exists, then Geometric isomers may be formed. It is intended that any geometric isomer, freshly isolated, purified or partially purified geometric isomer or magical character is included within the scope of the invention. Likewise, molecules with restricted spin bonds can form geometric isomers. These are also intended to be encompassed by the present FH r3n guides and in addition to the fact that some of the compounds of the invention may have different tautomeric dimers, and it is intended that any tautomeric forms which the compounds are capable of forming are encompassed within the scope of the invention. Inside. ,

藥上二：：本發明之化合物可以非溶劑化形式以及以經醫 、—接文之溶劑如水、乙醇及諸如此類溶劑化之形 ^般而言，就本發明之目的來說，溶劑 疋等同於非溶劑化形式。 H 49 1325414 本發明化合物中有些含有手性中心，且這類化合物以 異構物形<(例如對映異構物）存在。本發明包括所有的 這類異構物及其任意混合物，包括外消旋混合物。 外消旋體可經由已知方法解析成光學對映體，例如經 由其與光學活性酸所成之非對映異構鹽之分離，然後經由 用鹼處理而釋放出光學活性胺化合物。另一種將外消旋異 構體解析成光學對映體的方法係以在光學活性基質上的層 析法為基礎。本發明之外消旋亦可被解析成它們的光學對 映體，例如經由d-或卜酒石酸鹽、扁桃酸鹽或樟腦磺酸鹽 的分級結晶。本發明之化合物亦可經由非對映異構衍生物 的形成而被解析。 可使用熟習該項技術者所知之其他用於光學異構物解 析之其他方法。這類方法包括j. jaqUes、A. c〇l let和 S. Wilen在“對映異構物、外消旋物及解析，，（ Enantiomers, Racemates, and Resolutions”， John Wiley and Sons，New York (1981))中所討論者。 光學活性化合物亦可自光學活性起始物製備。 本發明亦涵蓋本發明化合物之前驅藥物，其在投藥時 經由代謝過程進行化學轉化，而後變成藥理活性物質。一 般而言，這類前驅藥物將是通式I化合物之官能衍生物， 其在活體内可很容易地轉化成所需的式I化合物。適當前 驅藥物衍生物之選擇和分離所用的轉化程序係敘述於例如 "前驅藥物設計"（"Design of Prodrugs"， ed. Η. Bundgaard， Elsevier， 1985)中。 50 1325414 本發明亦涵蓋本發明化合物之活性代謝物。 每當提及有關於式工化合物時，瘤痛一詞包括在國際 治癲癇聯盟、癲癇發作之修正臨床及腦電圖分類提案（ 國際防治癲癇聯盟之分類與術語考查團，办"印1981 22 : 489-501 )和國際防治癲癇聯盟：癲癇與癲癇症候群之 修正分類提案（國際防治癲癇聯盟之分類與術語考查團， 伽心仏聰3G⑷：389_399 )中所提及之_癇瘤痛 症候群及癲癇發作任一者。 醫藥組成物 本發明之化合物一般係以自由鹼或以其醫藥上可接受 之鹽來使用。代表性實例係提及於上文。 右需要，本發明之醫藥組成物可包含與其他藥理活性 物質（如前述所敘述者）組合之式I化合物。 本醫藥組成物可特別調配以供經由任何適當的途經投 藥，例如口、直腸、鼻、肺、局部（包括口腔和舌下）、 厶皮、腦池内、腹膜内、陰道及非經腸（包括皮下、肌肉 内鞘内、靜脈内和皮内）路徑，以口服途徑較佳。應瞭 解的疋，較佳途徑將取決於所欲治療個體的一般病狀和年 齡、所欲治療病狀的性質及所選擇的活性成分。 本發明之醫藥組成物根據本發明所製備者可經由任何 適每的途徑投予’例如以藥片、膠囊、粉劑、顆粒、丸劑 糖衣片、藥丸或錠劑、在水性或非水性液體中之溶液或 〜'子液、或水包油或油包水液體乳劑、酏劑、糖漿等形式 51 1325414 而以口服方式投予’或是以注射用溶液形式而以非經腸方 式投予。其他非經腸投藥用醫藥組成物包括分散液、懸浮 液或礼劑，以及在使用前才溶在無菌注射用溶液或分散液 復原的無菌粉劑。貯存注射用調配物亦被預想是在本發明 之範圍内。其他適當的投藥形式包括拴劑、喷霧劑、軟膏 、乳霜、凝膠、吸入劑、皮膚貼片、植入片等等。 就製備這類組成物而言，可使用此技藝中眾所周知的 方法，並可使用任何此技藝中普遍使用的醫藥上可接受之 載劑、稀釋劑、賦形劑或其他添加劑。 適當而言，本發明之化合物係以含有該化合物約〇 . 〇1 至100毫克量的單位劑型來投予。總每日劑量通常是在約 0.05 - 500 毫克或甚至 0·05 _ 1500 毫克或 〇 〇5 _ 3〇〇〇 毫克的範圍内’且最佳為約0. i至50毫克的本發明活性化 合物。就非經腸途徑如靜脈内、鞘内、肌肉内及類似投藥 法而言’劑量通常大約是口服投藥所用劑量的約一半。 本發明之化合物可單獨或結合醫藥上可接受之載劑或 賦形劑來投予’以單劑或多劑皆可β根據本發明之醫藥組 成物可與醫藥上可接受之載劑或稀釋劑及任何其他已知的 佐劑和賦形劑依據習知技術調配在一起，例如揭示於雷明 頓：藥物科學與實用第19版（Remington: The Science and Practice of Pharmacy, 19 Edition, Gennaro, Ed.,Pharmacology 2: The compound of the present invention can be in an unsolvated form and in the form of a medicinal, solvent, such as water, ethanol, and the like, for the purposes of the present invention, solvent oxime is equivalent to Unsolvated form. H 49 1325414 Some of the compounds of the invention contain a chiral center and such compounds exist as isomer forms <RTI ID=0.0> The present invention includes all such isomers and any mixtures thereof, including racemic mixtures. The racemate can be resolved into the optical enantiomer by known methods, for example, by separation of its diastereomeric salt with an optically active acid, and then by treatment with a base to liberate the optically active amine compound. Another method for the resolution of racemic isomers into optical enantiomers is based on a chromatography method on an optically active substrate. The racemization of the present invention can also be resolved into their optical enantiomers, e.g., by fractional crystallization via d- or bortartrate, mandelate or camphor sulfonate. The compounds of the invention may also be resolved via the formation of diastereomeric derivatives. Other methods known to those skilled in the art for the resolution of optical isomers may be used. Such methods include j. jaqUes, A. c〇l let, and S. Wilen, in "Enantiomers, Racemates, and Resolutions," John Wiley and Sons, New York. (1981)). Optically active compounds can also be prepared from optically active starting materials. The invention also encompasses prodrugs of the compounds of the invention which are chemically converted via metabolic processes upon administration and then become pharmacologically active. In general, such prodrugs will be functional derivatives of the compounds of formula I which are readily converted in vivo to the desired compounds of formula I. The transformation procedures used for the selection and isolation of appropriate prodrug derivatives are described, for example, in "Precursor Design"("Design of Prodrugs", ed. Η. Bundgaard, Elsevier, 1985). 50 1325414 The present invention also encompasses active metabolites of the compounds of the invention. Whenever there is a reference to formula compound, the term "tumor pain" includes the International Treatment of Epilepsy Alliance, the revision of clinical trials for seizures, and the EEG classification proposal (International Classification and Terminology Research Group for the Prevention and Treatment of Epilepsy, Office "Print 1981 22: 489-501) and the International Alliance for the Prevention and Treatment of Epilepsy: Proposed Classification of Epilepsy and Epilepsy Syndrome (International Classification and Terminology Research Group for Epilepsy, Gynecology, Congcong 3G(4): 389_399) And any of the seizures. Pharmaceutical Compositions The compounds of the present invention are generally employed as a free base or as a pharmaceutically acceptable salt thereof. Representative examples are mentioned above. To the right, the pharmaceutical composition of the present invention may comprise a compound of formula I in combination with other pharmacologically active substances (as described above). The pharmaceutical composition may be specially formulated for administration via any suitable route, such as oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), ecdysis, intracranial, intraperitoneal, vaginal and parenteral (including Subcutaneous, intramuscular, intravascular, and intradermal routes are preferred for oral administration. It will be appreciated that the preferred route will depend on the general condition and age of the individual to be treated, the nature of the condition being treated, and the active ingredient selected. The pharmaceutical compositions of the present invention can be administered according to the present invention by any suitable route, for example, in the form of tablets, capsules, powders, granules, granules, pills or lozenges, solutions in aqueous or non-aqueous liquids. Or ~' liquid, or oil-in-water or water-in-oil liquid emulsion, sputum, syrup, etc., form 51 1325414 and administered orally or as a solution for parenteral administration. Other parenteral pharmaceutical compositions include dispersions, suspensions or remedies, as well as sterile powders which are dissolved in sterile injectable solutions or dispersions before use. Storage injectable formulations are also contemplated as being within the scope of the invention. Other suitable forms of administration include elixirs, sprays, ointments, creams, gels, inhalants, dermal patches, implants and the like. For the preparation of such compositions, methods well known in the art can be used, and any pharmaceutically acceptable carrier, diluent, excipient or other additive commonly used in the art can be used. Suitably, the compound of the present invention is administered in a unit dosage form containing the compound in an amount of from about 1 to 100 mg. The total daily dose is usually in the range of about 0.05 to 500 mg or even 0. 05 _ 1500 mg or 〇〇 5 _ 3 〇〇〇 mg and is preferably from about 0. i to 50 mg of the active compound of the present invention. . For parenteral routes such as intravenous, intrathecal, intramuscular, and the like, the dosage is typically about one-half of the dosage for oral administration. The compound of the present invention can be administered alone or in combination with a pharmaceutically acceptable carrier or excipient. 'A single or multiple doses can be used. The pharmaceutical composition according to the present invention can be combined with a pharmaceutically acceptable carrier or diluent. Agents and any other known adjuvants and excipients are formulated according to conventional techniques, for example, as disclosed in Remington: The Science and Practice of Pharmacy, 19 Edition, Gennaro, Ed .,

Mack Publishing Co.，Easton, PA, 1 995 )中之技術。這 些調配物可方便地經由藥學技藝已知的方法以單位劑型提 出。 52 1325414 任何其他通常為這類目的使用的佐劑或添 料、香料、防腐劑等等，都可使用，但前提是它們要 性成分相容。 Ί 本發明之醫藥冑酉己物可經由此技#中習&的方法 。舉例來說’藥片可經由將活性成分與普通佐劑 ： 釋劑混合，接著在習知㈣機中塵縮混合物而製得。= 或稀釋劑的例子包括：玉米殿粉、馬龄著殺粉、滑石、石 脂酸鎮、明膠、乳糖、樹膠及諸如此類。任何其他通常: =類目的使用的佐劑或添加劑，如色料、香料、防腐劑等 ’都可使用，但前提是它們要與活性成分相容。 適當時，固體劑型可製備根據此技藝中眾所皆知 法製備成具有包衣’例如腸溶包衣，或者它們可調配 供活性成分的控制釋放，例如持續或延長釋放。 若有使用液體載劑，則製劑可為糖毁、乳劑、軟質明 膠膠囊W纽射㈣g水㈣非水性㈣ 液的形式。 次各 就非經腸投藥而言，可使用本發明新穎化合物溶於無 函水溶液、含水丙二醇、含水維生素E或芝麻油或花生油 中之溶液。注射用溶液可製備如下：將活性成分和可能的 添加劑溶解於部分的注射用溶劑，較佳為無菌的水中，調 整溶液至所欲的體積’消毒溶液’然後將之填充於適當安 瓿或管瓶中。可添加任何習用於此技藝中之適當添加劑， 例如張度劑、防腐劑、抗氧化劑等等。因此，必要時這類 溶液應該要適當地經緩衝’且液體稀釋劑先用充足的食踐 53 1325414 糖使之具有等張性。水溶液特別適合靜脈内、肌 肉内：皮下及腹膜内投藥。所用之無菌水性媒質全都是經 由熟習該項技術者已知技術可容易取得者。 、適當醫藥載劑包括惰性固，體稀釋劑或填充劑、無菌水 溶液及各種有機溶劑。液體載劑的例子有：糖漿 '花生、、由 、撖欖油、磷脂、脂肪酸、脂肪酸胺、聚氧乙烯及水。同 樣地’载劑或稀釋劑可包含此技藝中已知的任何持續釋放Mack Publishing Co., Easton, PA, 1 995). These formulations are conveniently presented in unit dosage form by methods known in the art of pharmacy. 52 1325414 Any other adjuvants or additives, fragrances, preservatives, etc., which are normally used for such purposes, may be used provided that they are compatible with the essential ingredients. Ί The medicine of the present invention can be obtained by the method of this technique. For example, a tablet can be prepared by mixing the active ingredient with a conventional adjuvant: an excipient, followed by a dusting mixture in a conventional (four) machine. Examples of = or thinners include: corn house powder, horse age powder, talc, town of stearic acid, gelatin, lactose, gums and the like. Any other commonly used adjuvants or additives such as colorants, perfumes, preservatives, etc., may be used, provided they are compatible with the active ingredient. Where appropriate, solid dosage forms may be prepared as known in the art to have a coating such as an enteric coating, or they may be formulated to provide controlled release, e.g., sustained or extended release, of the active ingredient. If a liquid carrier is used, the preparation may be in the form of a sugar-destroyed, emulsion, soft gelatin capsule W (4) g water (iv) non-aqueous (tetra) liquid. For the parenteral administration, a solution of the novel compound of the present invention in an aqueous solution, aqueous propylene glycol, aqueous vitamin E or sesame oil or peanut oil may be used. The solution for injection can be prepared by dissolving the active ingredient and possible additives in a portion of the injectable solvent, preferably in sterile water, adjusting the solution to the desired volume of 'disinfecting solution' and filling it into a suitable ampoule or vial. in. Any suitable additives conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, and the like. Therefore, such solutions should be suitably buffered if necessary' and the liquid diluent is first rendered isotonic with sufficient sugar. The aqueous solution is particularly suitable for intravenous, intramuscular: subcutaneous and intraperitoneal administration. The sterile aqueous media used are all readily available by techniques known to those skilled in the art. Suitable pharmaceutical carriers include inert solids, body diluents or fillers, sterile aqueous solutions and various organic solvents. Examples of liquid carriers are: syrup 'peanut, y, eucalyptus oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water. Similarly, the carrier or diluent may comprise any sustained release known in the art.

物質’例如單硬脂酸甘油酯或二硬脂酸甘油酯，單獨或與 蠟混合。 本發明調配物配方的典型例子如下： 1)藥片，含有以自由鹼計算之5.0毫克本發明化合物： 式I化合物 5. 0毫克 乳糖 60毫克 玉米澱粉 30毫克 羥丙基纖維素 2. 4毫克The substance 'e.g., glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. Typical examples of formulations of the present invention are as follows: 1) Tablets containing 5.0 mg of the compound of the invention calculated as free base: Compound of formula I 5. 0 mg Lactose 60 mg Corn starch 30 mg Hydroxypropylcellulose 2. 4 mg

微晶纖維素 19.2毫克 交聯羧曱基纖維素鈉A型2.4毫克 硬脂酸鎂 0.84毫克 2)藥片，含有以自由鹼計算之0.5毫克本發明化合物： 式I化合物 0. 5毫克 乳糖 46. 9毫克 玉米澱粉 23. 5毫克 聚乙烯吡咯烷酮 1.8毫克 54 i 1325414 微晶纖維素 14.4毫克 交聯羧曱基纖維素鈉A型1.8毫克 硬脂酸鎂 0. 63毫克 3)糖漿，每毫升含有： 式I化合物 山梨糖醇 羥丙基纖維素 甘油 甲基-對羥基苯甲酸酯 丙基-對羥基苯甲酸酯 乙醇 香料 糖精鈉 水 25毫克 500毫克 15毫克 50毫克 1毫克 0. 1毫克 0. 005毫升 0. 05毫克 0. 5毫克 加至1毫升Microcrystalline cellulose 19.2 mg croscarmellose sodium A type 2.4 mg magnesium stearate 0.84 mg 2) Tablets, containing 0.5 mg of the compound of the invention calculated as a free base: Compound of formula I 0. 5 mg of lactose 46. 9 mg corn starch 23. 5 mg polyvinylpyrrolidone 1.8 mg 54 i 1325414 microcrystalline cellulose 14.4 mg croscarmellose sodium sodium type A 1.8 mg magnesium stearate 0. 63 mg 3) syrup, per ml containing: Compound I of the formula I sorbitol hydroxypropyl cellulose glycerol methyl-p-hydroxybenzoate propyl-p-hydroxybenzoate ethanol perfume saccharin sodium water 25 mg 500 mg 15 mg 50 mg 1 mg 0. 1 mg 0 005 ml 0. 05 mg 0. 5 mg to 1 ml

4)注射用溶液，每毫升含有： 式I化合物 山梨糖醇 醋酸 糖精納 水 0. 5毫克 5. 1毫克 0. 05毫克 0. 5毫克 加至1毫升 本發明化合物之製備 本發明之通式I化合物， 55 1325414 其中R1、R2、R2’、R3、X、Y、Z及q係如以上所定義者， 係以方案中所代表之方法且如以下所述者製備：4) The solution for injection, per ml contains: a compound of the formula I sorbitol acetate saccharin sodium water 0. 5 mg 5. 1 mg 0. 05 mg 0. 5 mg added to 1 ml of the compound of the invention preparation of the general formula of the invention Compound I, 55 1325414 wherein R1, R2, R2', R3, X, Y, Z and q are as defined above, are prepared by the methods represented in the scheme and as described below:

56 132541456 1325414

在下文中，R1、R2、R2’、R3 、尺8、尺9、1?9、尺1()、尺10、叉、7、2、评、111、11、口和〇4中任 一者係如以上所定義者。 通式VII之化合物係根據熟諳此技藝之化學家所熟知 的方法（V. Bebenburg et al. C7?e/Z7il：er 1979,In the following, any of R1, R2, R2', R3, ruler 8, ruler 9, 1?9, ruler 1 (), ruler 10, fork, 7, 2, rating, 111, 11, mouth and 〇4 Is as defined above. The compounds of the formula VII are based on methods well known to those skilled in the art (V. Bebenburg et al. C7?e/Z7il: er 1979,

Sonderdruck 103，3-15)且係如以下所概述者製備： 通式IV化合物係製備如下：4_硝基苯胺與適當親電子 試劑，例如但不限於：醯基氣、醯基溴、醯基碘、磺醯基 氯、異氰酸鹽、碳酸酐、活性酯及烷基鹵甲酸鹽反應，此 係於有或無添加鹼，例如三烷基胺、碳酸鉀或鋰、鈉或鉀 的醇鹽，在適當溶劑如醋酸乙酿、二聘统、四氮肤嗔、乙 ^二乙时，在適當溫度如室溫或經由傳統加熱或微波 二、射下達到之回流溫度下進行，接著用適當還原劑如連二 ^酸鋼、於虱氯酸水溶液錢氣中之鐵粉或鋅粉將硝基 :二此係於適當氫化催化劑如活性炭上纪 备溶劑如甲醇或乙醇中，在適當溫度下進行。 在適 伴二式V化。物係經由通式IV化合物與在苯胺基上形成 保噠基之試劑如鄰苯二甲 上形成 適當π声铁甲馱酐在適备浴劑如冰醋酸中，於 均/皿度下反應而製得。 ％ 57 1325414 通式νι化合物係經由熟諳此技藝之化學家所熟知的石肖 化反應而自通式v化合物製得，例如與發煙硝酸在適當溶 劑如冰醋酸t於適當溫度下反應。 通式VII化合物係經由在適當溶劑如1>2_二聘烷中於 適當溫度下，用水合肼將苯胺官能去保護而自通式VI化 合物製得。 或者，通式VII化合物可以方案中所示且如以下所說 明之3個步驟中製自2_硝基_14_二胺基苯。在第一個^ 驟中，用適當保護基PG 刀以Sonderdruck 103, 3-15) and prepared as outlined below: The compound of formula IV is prepared as follows: 4-nitroaniline with a suitable electrophile such as, but not limited to, mercapto, mercapto bromide, fluorenyl Iodine, sulfonyl chloride, isocyanate, carbonic anhydride, active ester and alkyl haloformate, with or without the addition of a base such as a trialkylamine, potassium carbonate or lithium, sodium or potassium The alkoxide is carried out in a suitable solvent such as acetic acid, brewing, quaternary, tetrazolium, and ethylene, at a suitable temperature such as room temperature or through a conventional heating or microwave, and a reflux temperature of the microwave, followed by a reflux temperature. The nitro group is prepared by using a suitable reducing agent such as iron sulphate or iron powder or zinc powder in a chloric acid aqueous solution, in a suitable hydrogenation catalyst such as activated carbon, such as methanol or ethanol. Perform at temperature. It is suitable for the second type of V. The system is prepared by reacting a compound of the formula IV with a reagent which forms a sulfhydryl group on an anilino group, such as phthalic acid, to form an appropriate π-acoustic iron phthalic anhydride in a suitable bathing agent such as glacial acetic acid at a uniform/dish level. Got it. % 57 1325414 The compound of the formula νι is prepared from a compound of the formula v by a stone scouring reaction well known to those skilled in the art, for example by reaction with fuming nitric acid in a suitable solvent such as glacial acetic acid t at a suitable temperature. The compound of the formula VII is prepared from a compound of the formula VI by deprotecting the aniline function in a suitable solvent such as 1>2-dioxane at a suitable temperature with hydrazine hydrate. Alternatively, the compound of formula VII can be prepared from 2-nitro-14-diaminobenzene as shown in the scheme and in three steps as described below. In the first step, use the appropriate protection PG knife to

Synthesis, 3rd Edition T. W. Greene, P. G. M. Wuts, Wiley lnterscience 1999]如第三丁 氧羰基（B〇c 基）將 較不受阻且較有反應性的苯胺氮保護起來，此係經由在適 當溶劑如乙腈中且於供給通式χι化合物之適當溫度下， 與形成保護基之適當試劑如二碳酸二第三丁酯反應來進行 通式XII化合物係自通式ΧΙ化合物獲得如下：與形成 R3-（Z)q-X基團之適當親電子試劑，例如烷基、芳基或错芳 基氯甲酸鹽或胺基甲醯氣' 醢基氣、酿基漠、酿基蛾、續 醯基氯、異氰酸鹽、碳酸酐、經活性化試劑如碳二亞胺活 性化之碳酸或熟諳此技藝之化學家所熟知之其他者反應， 此係在適當溶劑如乙腈、四氫呋喃、氯乙烷或二氯 甲烷中，⑨適當溫度b室溫或經由傳統加#或在微波照射 下所達到的回流溫度下’有或無添加驗，例如氧化錢、碳 酸舒一烧基胺、班咬或碳酸氫納，如以上對通式ιν化 58 1325414 合物所敘述者。 保護基係經由熟請此技藝之化學家所熟知的方法除去 。尤其，可經由用適當酸如三氣醋酸在無或有溶劑如二氣 甲燒或曱苯存在下於供給通< VII化合物之溫度下處理而 將Boc基裂解。 通式VIII化合物之製備： 5使通式VI1化合物進行與通式Ila或IIIa之醛（其中 R5、W、m、n和p係如以上所敘述者）的還原性烷基化反 應（熟諳此技藝之化學家所熟知者），使用還原劑，例如 硼氫化鈉或氰基硼氫化鈉，在適當溶劑如甲醇、乙醇、四 氫呋喃、水、二腭烷或它們的混合物中，有或無添加催化 量的酸，如醋酸，在適當溫度下進行，以形成通式¥111化 合物，其中R1是氫。 或者，通式vii化合物可與通式IIa或nla之醛反 應，此係在適當溶劑如甲醇、乙醇、四氫呋喃、二聘烷、 二甲苯或它們的混合物中，有或無添加催化量的酸如醋酸 或酸性離子交換樹脂，在適當溫度下進行，以形成亞胺， 其可經由結晶或蒸發溶劑而被離析出來。然後可在適當溶 劑如甲醇、乙醇、四氩呋喃、水、二聘烷或它們的混合物 中’使用還原劑如硼氫化鈉或氰基硼氫化鈉，將該亞胺還 原成通式V111化合物’其中R1是氫。 或者’就R1之變化而言，可使所得通式V〖丨I化合物 進行額外的還原性烷基化步驟，此係使用適當醛和還原劑 59 1325414 如硼氫化鈉或氰基硼氫化鈉，在適當溶劑如曱醇、乙。 四氫呋喃、水、二聘烷或它們的混合物中，， 窃 ’或1無添加催 化S的I ’如醋酸，在適當溫度下進行， ,„ Λ 3以上所敘述者 。此步驟亦可在與通式！ Ia或〗！ Ia搭 心乐 次逛原性烷美 化之後當場進行》 反暴 VIII化合物 醯基氯、醯基 ’有添加驗， ’在適當溶劑 ’在適當溫度 或者，就R1之變化而言，可使所得通式 進行醯化反應，此係使用適當親電子試劑如 溴、醯基碘、磺醯基氯和烷基_基_甲酸鹽 例如二烷基胺、碳酸鉀或鋰、鈉或鉀的醇鹽 如醋酸乙醋、二聘烷、四氫呋喃或二乙醚Ϊ 下進行，如以上所敘述者。 通式IX化合物，係經由通式VIII化合物與適當還原 劑，例如在有機溶劑如四氫肤喃或乙醇不存在或存在下之 溶於氯氯酸或醋酸水溶液中之連m鐵粉或鋅粉反 應，或在適當氫化催化劑如活性炭上把存在下之氣氣，在 :當溶劑如甲醇或乙醇或水/四氫呋。南混合物中，在適當 皿度下反應。所侍化合物和本發明通< ! 4匕合物相同直 …是氣’且其"，，小卜“”係如以上； 定義者。 其中R1不是氫，且其中R2和視需要之R2，不是氮之通 式I化合物，係經由复中ρι R不疋虱之通式IX化合物的反 應獲得，利用下列方法： 弓」入R ’此係、經由一個使用適當醛和還原劑如棚氫化 鈉或氰基硼氫化鈉，為；+ 在適谷劑如曱醇、乙醇、四氫呋喃 60 1325414 、水 '二腭烷或它們的混合物中，有或無添加催化量的酸 如醋酸，在適當溫度下的還原性烷基化步驟進行，如以上 所敛述者。 視需要引入R2’，此係經由一個使用適當醛和還原劑如 硼氫化鈉或氰基硼氫化鈉，在適當溶劑如甲醇、乙醇、四 氯呋喃、水、二聘烧或它們的混合物中，有或無添加催化 量的酸如醋酸，在適當溫度下的額外還原性燒基化步驟進 行’如以上所敘述者。 或者，R2’或R2係經由如以上所敘述之使用適當親電子 試劑如醯基氣、醯基溴、醯基碘、磺醯基氣和烷基鹵基_ 甲酸鹽，有添加驗，例如三燒基胺、碳酸卸或鐘、納或舒 的醇鹽，在適當溶劑如醋酸乙酯、二聘烷、四氫呋喃或二 乙喊中，在適當溫度下之醯化反應被引入。 為獲得其中R1是氫，且其中R2和視需要之r2,不是氫 之通式I化合物，係在硝基的還原反應之前，經由熟諳此 技藝之化學家所熟知的方法，將保護基如第三丁氧羰基引 入作為R1。此保護基係在引入R2和視需要之R2,之後經 由已知方法被裂解。 通式11 a和111 a之化合物係經由熟諳此技藝之化學家 所热知的標準方法製備’如以下所概述者： 羧酸酯與適當還原劑如氫化二異丁基鋁的還原反應， 接著為所得苄基醇與適當氧化劑如過釕酸四丙基鋁/N_甲基 嗎啉氧化物、氯代鉻酸毗錠、二甲亞楓/草醯氣的氧化 反應。或者通式Ila和Ilia之化合物可經由與二氯甲基甲 61 1325414 基醚和四氯化欽的甲醯化反應製備（Gross et al，0/*^·. Synth. Coll, 1973 Vol V, 365 I Fanghaenel et al. /. ❹⑽.1997，％見277)。或者通式na和IIIa 之化合物可經由熟諳此技藝之化學家所熟知的方法製備， 例如經画素取代之雜芳族化合物如溴化物或雄化物的齒素 金屬交換反應，經由與金屬化試劑如烷基鋰或函化烷基鎂 或二烷基鎂的反應。或者通式113和丨〗13之化合物可經由 熟諳此技藝之化學家所熟知的方法製備，例如噻吩與苯并 噻吩與磷醯氣在於甲基-於苯基甲醯胺存在下的反應（ ^1叩6131./.〇^.以故 1949 " 638)或在况於二 曱基曱醯胺存在下的反應（Vilsmeier formylation，Synthesis, 3rd Edition TW Greene, PGM Wuts, Wiley lnterscience 1999] such as the third butoxycarbonyl (B〇c group) will protect the less resistant and more reactive aniline nitrogen, in a suitable solvent such as acetonitrile And reacting with a suitable reagent for forming a protecting group, such as dibutyl succinate, at a suitable temperature for supplying a compound of the formula 获得 to carry out the compound of the formula XII from the general oxime compound as follows: and forming R3-(Z) Suitable electrophiles for the qX group, such as alkyl, aryl or arylaryl chloroformate or amine methyl hydrazine, sulfhydryl, turmeric, turmeric, decyl chloride, isocyanic acid Salt, carbonic anhydride, carbonic acid activated by an activating reagent such as carbodiimide or other reactions well known to those skilled in the art, in a suitable solvent such as acetonitrile, tetrahydrofuran, ethyl chloride or dichloromethane , 9 at a suitable temperature b at room temperature or via conventional addition # or under reflux temperature reached under microwave irradiation 'with or without addition test, such as oxidized money, sulphonate, stalk or sodium bicarbonate, as above For the formula ιν 5 8 1325414 The compound is described. The protecting group is removed by methods well known to those skilled in the art. In particular, the Boc group can be cleaved by treatment with a suitable acid such as tri-glycolic acid in the absence or presence of a solvent such as gas or benzene in the presence of a compound of the <VII compound. Preparation of a compound of the formula VIII: 5 a reductive alkylation reaction of a compound of the formula VI1 with an aldehyde of the formula Ila or IIIa (wherein R5, W, m, n and p are as described above) A skilled chemist, using a reducing agent such as sodium borohydride or sodium cyanoborohydride in a suitable solvent such as methanol, ethanol, tetrahydrofuran, water, dioxane or mixtures thereof, with or without added catalysis An amount of an acid, such as acetic acid, is carried out at a suitable temperature to form a compound of the formula: 111, wherein R1 is hydrogen. Alternatively, the compound of formula vii can be reacted with an aldehyde of formula IIa or nla, in a suitable solvent such as methanol, ethanol, tetrahydrofuran, dioxane, xylene or mixtures thereof, with or without the addition of a catalytic amount of an acid such as Acetic acid or an acidic ion exchange resin is carried out at an appropriate temperature to form an imine which can be isolated by crystallization or evaporation of the solvent. The reducing agent can then be reduced to a compound of the formula V111 using a reducing agent such as sodium borohydride or sodium cyanoborohydride in a suitable solvent such as methanol, ethanol, tetrahydrofuran, water, dioxane or a mixture thereof. Wherein R1 is hydrogen. Or 'in terms of the change of R1, the resulting compound of formula V can be subjected to an additional reductive alkylation step using an appropriate aldehyde and reducing agent 59 1325414 such as sodium borohydride or sodium cyanoborohydride, In a suitable solvent such as decyl alcohol, B. In tetrahydrofuran, water, dioxane or a mixture thereof, thieves or 1 without the addition of a catalytic S I' such as acetic acid, carried out at an appropriate temperature, „ Λ 3 above. The step can also be Ia or 〗! Ia took a look at the original alkalization after the landscaping. "Anti-storm VIII compound thiol chloride, sulfhydryl" has added test, 'in the appropriate solvent' at the appropriate temperature or, on the change of R1 The resulting formula can be subjected to a deuteration reaction using a suitable electrophile such as bromine, mercaptoiodine, sulfonyl chloride and alkyl-based monoformate such as dialkylamine, potassium carbonate or lithium. The alkoxide of sodium or potassium, such as ethyl acetate, dioxane, tetrahydrofuran or diethyl ether, is as described above. The compound of formula IX is via a compound of formula VIII with a suitable reducing agent, for example in an organic solvent. Tetrahydrofuran or ethanol in the absence or presence of a solution of m iron or zinc powder dissolved in chlorochloric acid or aqueous acetic acid, or a gas mixture in the presence of a suitable hydrogenation catalyst such as activated carbon: Such as methanol or ethanol or water / tetrahydrogen In the south mixture, the reaction is carried out under the appropriate degree of the dish. The compound of the present invention is the same as the one of the present invention, which is the same as that of the present invention, and is a gas and its ",, small "" is as above; R1 is not hydrogen, and wherein R2 and, if desired, R2, a compound of formula I which is not nitrogen, is obtained by the reaction of a compound of formula IX which is a complex of ρι R, using the following method: By using an appropriate aldehyde and a reducing agent such as sodium hydride or sodium cyanoborohydride; + in a sterilant such as decyl alcohol, ethanol, tetrahydrofuran 60 1325414, water 'dioxane or a mixture thereof, with or The addition of a catalytic amount of an acid such as acetic acid is carried out at a reductive alkylation step at a suitable temperature, as exemplified above. R2' is introduced as needed, via a suitable aldehyde and a reducing agent such as sodium borohydride or sodium cyanoborohydride in a suitable solvent such as methanol, ethanol, tetrachlorofuran, water, two or a mixture thereof. With or without the addition of a catalytic amount of an acid such as acetic acid, an additional reductive alkylation step at the appropriate temperature is carried out as described above. Alternatively, R2' or R2 is added, for example, by using an appropriate electrophile such as a mercapto group, a mercapto bromide, a mercapto iodide, a sulfonyl group, and an alkyl halo-formate as described above. The trialkylamine, the carbonic acid effluent or the alkoxide of sodium or sulphate is introduced in a suitable solvent such as ethyl acetate, dioxane, tetrahydrofuran or diethyl sulfonate at a suitable temperature. In order to obtain a compound of the formula I in which R1 is hydrogen, and wherein R2 and, if desired, r2, are not hydrogen, the protecting group is as described prior to the reduction reaction of the nitro group by methods well known to those skilled in the art. Tributoxycarbonyl is introduced as R1. This protecting group is introduced into R2 and, if desired, R2, after which it is cleaved by known methods. The compounds of the formulae 11a and 111a are prepared by standard methods well known to those skilled in the art 'as outlined below: reduction of a carboxylic acid ester with a suitable reducing agent such as diisobutylaluminum hydride, followed by The oxidation reaction of the obtained benzyl alcohol with a suitable oxidizing agent such as tetrapropylaluminum hydride/N-methylmorpholine oxide, chlorochromic acid bismuth, dimethyl sulfoxide/grass. Alternatively, a compound of the formula Ila and Ilia can be prepared by a formazanization reaction with dichloromethylmethyl 61 1325414-ether and tetrachlorinated (Gross et al, 0/*^·. Synth. Coll, 1973 Vol V, 365 I Fanghaenel et al. /. ❹ (10). 1997, % see 277). Alternatively, compounds of the formulas na and IIIa can be prepared by methods well known to those skilled in the art, such as the dentate metal exchange reaction of a heteroaromatic compound such as a bromide or an anthracene substituted with a pixel, via a metallization reagent such as A reaction of an alkyl lithium or a functional alkyl magnesium or a dialkyl magnesium. Alternatively, the compounds of the formula 113 and the formula 13 can be prepared by methods well known to those skilled in the art, for example, the reaction of thiophene with benzothiophene and phosphonium in the presence of methyl-p-phenylformamide (^ 1叩6131./.〇^. 1949 " 638) or in the presence of dimercaptoamine (Vilsmeier formylation,

Raimundo et al· /. 2002，67’ 205 )。 實施例 分析的 LC-MS數攄将以# I 士 T p ^ t 像你以裝備有IonSpray源與Raimundo et al. /. 2002, 67' 205). Example The LC-MS number analyzed will be # I士 T p ^ t like you are equipped with IonSpray source and

Shimadzu LC-8A/SLC-10A ΤΓ i + 。 ·Shimadzu LC-8A/SLC-10A ΤΓ i + . ·

ιχ 系統之 pE Sciex API 150EX 儀器獲得。管柱·· 30 X 4.6毫米Symmetry n8管 柱，具有3.5微来粒子大小；溶劑系統：A =水/三氟醋酸 (100 0.05)和 B -水 / 乙膳 / 三氣醋酸（5: 95: 〇.〇3); 方法：線性梯度沖提，4分鐘内從9嶋至厲B，流速 為2毫升/分。純度係φ—*㈣描圖的積分 來測定。滯留時間（RT或tR)係以分鐘表示。 製備LC-MS純化係 米YMC 0DS-A，具有The ιχ system's pE Sciex API 150EX instrument is available. Column · · 30 X 4.6 mm Symmetry n8 column with 3.5 micro particle size; solvent system: A = water / trifluoroacetic acid (100 0.05) and B - water / B / triacetic acid (5: 95: 〇.〇3); Method: Linear gradient elution, from 9 嶋 to Li B in 4 minutes, flow rate 2 ml / min. The purity is determined by integrating the φ-*(4) trace. The residence time (RT or tR) is expressed in minutes. Preparation of LC-MS purification system YMC 0DS-A, with

用相同儀器進行。管柱：50 X 20 〕微米粒子大小：方法：線性梯度 62 1325414 沖提’ 7分鐘内從80% A至100% B，流速為22 7毫升/八 。沖提分收集係藉由分流MS偵測來進行。 乃 丨H NMR光譜係以Bruker Avance DRX500儀器於 50 0. 13 MHz 記錄，或以 Bruker AC 250 儀器於 25〇. 13 MHz 記錄。使用氘化氣仿（99.8%D)或二甲亞楓（99 8%d)作 為溶劑。使用TMS作為内參考標準品。化學位移數值係以 ppm值表示。下列縮寫係用於NMR信號的峰裂數：s =單峰 ，d=雙重峰，t=三重峰，q=四重峰，叫丨=五重峰，匕二 七重峰，dd =雙雙重峰，ddd =雙雙二重峰，以=雙三重峰 ，dq =雙四重峰，tt =三重峰的三重峰，m =多重峰，以及 b =寬單峰。在某些例子中，有列出偶合常數/。熔點（ Μ. p.)係以Btichi B-540儀器記錄且未經校正。 中間物之製備 (4 -胺基-苯基）一胺基甲酸乙輯。 將>4-硝基-苯胺（1〇〇克，〇 72莫耳）溶於醋酸乙酉旨 (800毫升）並添加二異丙基乙基胺（89 6毫升，〇 ο% 莫耳）。添加溶於醋酸乙酯（2〇〇毫升）中之氣甲酸乙酯 (252毫升，丨_ 45莫耳）並使溶液在周圍溫度下攪拌μ小 時。將混合物肖2M HC1 ( 300毫升）和食鹽水（3〇〇毫升 )洗條’乾帛（MgS〇4 )及在真空下漢縮至原#體積的—半 。在所得溶液中加入載於活性炭上之纪（1〇克，5%… 5: H20)並在帕爾（parr)裝置（池=3巴）中於周圍 又下將/扣。物氫化12小時。使混合物經過塞里塑料 63 1^^5414Use the same instrument. Column: 50 X 20 〕 Micron particle size: Method: Linear gradient 62 1325414 Rushing 'from 80% A to 100% B in 7 minutes, flow rate is 22 7 ml / 八. The rushing collection is performed by shunt MS detection. The H NMR spectrum was recorded on a Bruker Avance DRX500 instrument at 50.13 MHz or on a Bruker AC 250 instrument at 25 〇. 13 MHz. Use deuterated gas imitation (99.8% D) or dimethyl sulfoxide (99 8% d) as a solvent. TMS was used as an internal reference standard. The chemical shift values are expressed in ppm. The following abbreviations are used for the number of peaks of NMR signals: s = singlet, d = doublet, t = triplet, q = quartet, 丨 = quintuple, 匕 七 重, dd = double Peak, ddd = doublet doublet, = double triplet, dq = double quadruple, tt = triplet of triplet, m = multiplet, and b = broad singlet. In some examples, there are listed coupling constants /. Melting points ( Μ. p.) were recorded on a Btichi B-540 instrument and were uncorrected. Preparation of the intermediate (4-amino-phenyl)-aminoformic acid. > 4-Nitro-aniline (1 g, 〇 72 mol) was dissolved in ethyl acetate (800 ml) and diisopropylethylamine (89 6 ml, ο ο % Mo) was added. Ethyl formate (252 ml, 丨 _ 45 mol) dissolved in ethyl acetate (2 mL) was added and the solution was stirred at ambient temperature for one hour. The mixture was shaken into a mixture of 2M HCl (300 ml) and brine (3 ml), dried (MgS 〇 4) and condensed under vacuum to the original volume. The obtained solution was added to the activated carbon (1 gram, 5% ... 5: H20) and placed in the vicinity of the parr device (pool = 3 bar). The product was hydrogenated for 12 hours. Pass the mixture through the Seri plastic 63 1^^5414

Cel 1 te)過濾並在真空中蒸發溶劑，得到ιι8克（9〇% ) 軚題化合物，為結晶產物。Lc/Ms以々）i8〇 g (MH+);、 =0.60 分。NMR (CDCl3): ! 27 (t，3H) ; 3 42 (b，， 2H，NH2) ’ 4.19 (q, 2H) ; 6.52 (b, 1H NH) ; 6.64 (m， 2H) ； 7.14 (m, 2H). 下列化合物係以類似方式製備·· (4-胺基-笨基）_胺基甲酸丙酯。 鑛 產率：98%。ijj NMR (CDC13): 〇. 96 (t，3H) ; 1. 68 2H) ； 3. 51 (h> 2H) ； 4. 09 (t, 2H) ； 6. 46 (b, 1H)； 6.63 (d，2H) ’· 7.14 (m，2H). (4-苯二甲醯亞胺基-苯基y胺基甲酸乙酯。 - 在敗氣下將（4-胺基-苯基）_胺基曱酸乙酯（118克’ · 〇. 65莫耳）溶於冰醋酸（2. 0升）中，並將混合物加熱到 90 C。將鄰笨二甲酸酐（102. 0克，0. 69莫耳）分成幾部 刀於30分鐘期間加入。並使反應保持在90 °C下2小時。 讓此合物冷;gp到周圍溫度，並將沈澱固體過濾出來。使固 體在過據器上經水（2升），接著經二乙喊㈠升）洗滌 ’然後在真空中乾燥。產率：127克（62% )標題化合物 ’為白色結晶化合物。LC/MS 〇/>) 311· 3 (MH+) ; tR = 2.57 分。1H NMR (dmSO-A): 1.26 (t，3H) ; 4.15 (q， 2H) * 7.34 (dd, 2H) ; 7.58 (dd, 2H) ； 7.90 (ddd, 2H)； 7. 95 (ddd，2H) ; 9. 80 (s，1H，NH)· 64 1325414 下列化合物係以類似方式製備： (4 -笨二甲醯亞胺基-苯基）_胺基甲酸丙醋。 產率：81%。 (2-硝基-4-苯二甲醢亞胺基—苯基）_胺基甲酸乙酯。 將（4-苯二甲醯亞胺基-苯基）_胺基曱酸乙酯（99.0克 ，0. 32莫耳）懸浮於冰醋酸（丨.5升）中並加熱到9〇吒 。在90-95°C下將發煙硝酸（π. 2毫升，〇· 41莫耳）分成 幾部分於30分鐘期間加入。然後使反應混合物在丨〇〇 〇c 下授拌1小時’然後冷卻到周圍溫度。將結晶的固體過濾 出來，並在過濾器上用冰醋酸（50〇毫升）、水（1升）和 二乙趟（1升）洗滌，然後在真空中乾燥，得到1 〇丨克（ 90 % )標題化合物’為黃色固體。lc/MS U/z) 355. 0 (MH+)，tR = 3.34 分。卬 NMR (DMSO-i/6): 1.25 (t，3H); 4.16 (q，2H) ; 7.81 (m，2H) ; 7.93 (ddd，2H) ; 7.99 (ddd, 2H) ； 6. 15 (dd, 1H) ； 9. 99 (s, 1H, NH).Cel 1 te) was filtered and the solvent was evaporated in vacuo to give EtOAc (yield: EtOAc). Lc/Ms is 々) i8〇 g (MH+);, =0.60 points. NMR (CDCl3): ! 27 (t,3H) ; 3 42 (b,, 2H,NH2) ' 4.19 (q, 2H) ; 6.52 (b, 1H NH) ; 6.64 (m, 2H) ; 7.14 (m, 2H). The following compounds were prepared in a similar manner. (4-Amino-phenyl) propyl carbamate. Mine yield: 98%. Ijj NMR (CDC13): 〇. 96 (t, 3H); 1. 68 2H); 3. 51 (h>2H); 4. 09 (t, 2H); 6. 46 (b, 1H); 6.63 ( d,2H) '· 7.14 (m,2H). (4-Benzene dimethyl imino-phenyl ary methacrylate) - (4-Amino-phenyl)-amine under depletion Ethyl phthalate (118 g ' · 〇. 65 mol) was dissolved in glacial acetic acid (2.0 liters), and the mixture was heated to 90 C. O-paraformic acid anhydride (102. 0 g, 0. 69 moles were divided into several knives and added during 30 minutes. The reaction was kept at 90 ° C for 2 hours. The mixture was allowed to cool; gp was applied to ambient temperature, and the precipitated solid was filtered out. The upper water (2 liters), then the second wash (2) liters washed 'then and then dried in a vacuum. Yield: 127 g (62%) of title compound. LC/MS 〇/>) 311· 3 (MH+) ; tR = 2.57 points. 1H NMR (dmSO-A): 1.26 (t,3H); 4.15 (q, 2H) * 7.34 (dd, 2H); 7.58 (dd, 2H); 7.90 (ddd, 2H); 7. 95 (ddd, 2H) 9. 80 (s, 1H, NH)· 64 1325414 The following compounds were prepared in a similar manner: (4-hypoxylene imido-phenyl)-amino propyl acrylate. Yield: 81%. (2-Nitro-4-phenyldimethylimido)-phenyl)-carbamic acid ethyl ester. Ethyl (4-phthalimido-phenyl)-amino decanoate (99.0 g, 0.22 mol) was suspended in glacial acetic acid (5. 5 liters) and heated to 9 Torr. The fuming nitric acid (π. 2 ml, 〇·41 mol) was divided into portions at 90-95 ° C for 30 minutes. The reaction mixture was then allowed to mix for 1 hour under 丨〇〇c and then cooled to ambient temperature. The crystallized solid was filtered off and washed with glacial acetic acid (50 mL), water (1 L) and diethylamine (1 L), and then dried in vacuo to give 1 g (90%) The title compound 'is a yellow solid. Lc/MS U/z) 355. 0 (MH+), tR = 3.34 min.卬NMR (DMSO-i/6): 1.25 (t, 3H); 4.16 (q, 2H); 7.81 (m, 2H); 7.93 (ddd, 2H); 7.99 (ddd, 2H); 6. 15 (dd , 1H) ; 9. 99 (s, 1H, NH).

下列化合物係以類似方式製備： (2-硝基-4-苯二甲醯亞胺基-苯基）—胺基曱酸丙酯。 產率：70%。 (4-胺基-2-硝基-苯基）-胺基曱酸乙酯。 將1，2-二甲氧基乙烷（1.〇升）加到（2一硝基_4、笨二 甲酿亞胺基-苯基）-胺基甲酸乙醋（1〇；[克，〇·28莫耳）中 ’並在回流下加熱混合物。於丨〇分鐘期間逐滴添加單水 合肼（19. 6克，0. 3 9莫耳）’並使混合物於回流下搜摔 65 1325414 1. 5小時。當冷卻到周圍溫度時，將混合物過濾，而固體 係在過遽器上用二曱氧基乙烷（25〇毫升）洗滌。利用蒸 發濃縮濾液’並使紅色結晶產物從曱苯（3 5 〇毫升）再結 晶，將沈澱的產物過遽出來並在真空中乾燥。將母液是濃 縮到原始體積的一半’並讓其靜置1 6小時。將沈澱物質 過濾出來並如先前做再結晶。將再結晶固體合併後得到總 共57.6克（90/6) 冰紅色的標題化合物。lc/MS (ju/z) 225.1 (MH+) ; tR = 2.08 分。1H NMR (CDC13): 1.33 (t， 3H) ; 3.77 (s，2H，NH2) ; 4.23 (q，2H) ; 6.98 (dd，1H) > 7.45 (d, 1H) ； 8.28 (d, 1H) ； 9.39 (s, 1H, NH). 下列化合物係以類似方式製備： (4-胺基-2-硝基-苯基）-胺基甲酸丙酯。 產率：91 %。4 NMR (CDC13): 0· 98 (t，3H) ; 1. 71 (m, 2H) ； 3.78 (b, 2H) ； 4.13 (t, 2H) ； 6.98 (dd, 1H) ;7.44 (d，1H) ; 8.27 (d，1H) ; 9.39 (s，1H). (4-胺基-3-硝基-苯基）_胺基曱酸第三丁酯。 在2-硝基-1,4-二胺基苯（1〇.135克，66.18毫莫耳 )於四氫呋喃（100亳升）中的回流溶液内，在2小時期 間將B〇c20 (二碳酸二第三丁酯，32. 6克，149毫莫耳） 非成幾部分加入。將所得溶液倒入庚烷（2升）中，聲波 振盈15分鐘’過濾及在真空中乾燥，得到13.40克標題化 合物’為紅色固體。產率：8〇 %。LC/MS 〇々）295. 4 ([M + H+MeCN] + ) ; tR = 2.54 (UV，ELSD) 96%，100%。4 66 1325414 NMR (DMS〇-d6): 1. 47 2H, NH2), 7.41 (dd> NH). (s’ 9H) ; 6. 96 (d, 1H) ; 7 24 (s， 1H) ; 8. 20 (s，1H) ; 9. 28 (s，1H， [4_(4-氣-苯㈣基）—3—甲基一瞳吩、2、基卜甲醇。 在N2下使4~(4_氯—苯續酿基）_3_甲基 酯（ 992 毫克，3.00 毫"幡％ 毫莫耳）於無水四氧呋喃（20毫升） 和無水CH/l2 ( 1〇毫升）巾六 开J中之/谷液冷部到〇 〇c，並加入 DIBAL-H (9.0毫升，9〇吝苜π 认田从 9.〇宅莫耳，於曱笨中之1Μ溶液） 。3小時之後’加入另-份DIBAL—Η (4.5毫升，4.5毫莫 耳）’並繼續搜拌丨2小時。藉由添加飽和羅謝爾（ ochel le ) | ’合液（3〇毫升）使反應淬滅，並使混合物在 室溫下攪拌1小時。將相分離，用EtOAc ( 2 X 50毫升） 萃取水相，並將收集的有機層經Na2S04乾燥及在真空中蒸 發。產物係經由在FiashMaster系統中使用庚烷/醋酸乙酯 作為沖提液（從1 : 〇至6 : 4之線性梯度沖提）在矽凝膠 上層析而純化。收集含產物之沖提分並在真空中蒸發而得 到所要的化合物（788毫克，87% ) 。LC-MS: U/y = 285.2 (Μ-Η20 + Η+)，對 C12H1()C102S2 計算值：284.9805， =2.45 分。iH _R (CDC13): 1.84 (t，/= 5.7 Hz，1 H)，2·2〇 (s，3 H)，4.73 (d，/= 5.7 Hz, 2 H)，7.49 (d， / = 8.5 Hz， 2 H)， 7.84 (d， / = 8.5 Hz， 2 H)， 8. 18 (s，1 H)· 67 1325414 下列化合物係以類似方式製備： (3-氯-噻吩-2~基）-甲醇。 產率：73%。M NMR (CDC13): L92 (b，i Η)，4 8ι (S，2 HX 6·91 (dj ^ = 5.2 Hz, 1 H), 7.25 (d, / = 5· 2 Hz, 1 H). (5~二甲基胺基-苯并[b]噻吩—3_基）_f醇。 產率：63%。Μ NMR (CDC13): (b，i H)，3 〇ιThe following compounds were prepared in a similar manner: (2-nitro-4-phenyldimethylimido-phenyl)-propyl propyl citrate. Yield: 70%. (4-Amino-2-nitro-phenyl)-amino decanoic acid ethyl ester. Add 1,2-dimethoxyethane (1. liter) to (2 nitro-4, stupid diphenyl-imino-phenyl)-carbamic acid ethyl vinegar (1 〇; [gram , 〇·28 moles) in 'and heat the mixture under reflux. The monohydrate hydrazine (19.6 g, 0.39 mol) was added dropwise during the minute and the mixture was dropped under reflux 65 1325414 1. 5 hours. When cooled to ambient temperature, the mixture was filtered and the solid was washed with dimethoxy ethane (25 mL) on a filter. The filtrate was concentrated by evaporation and the red crystalline product was recrystallized from toluene (3 5 mL). The precipitated product was taken up and dried in vacuo. The mother liquor was concentrated to half of the original volume' and allowed to stand for 16 hours. The precipitated material was filtered off and recrystallized as before. The recrystallized solids were combined to give a total of 57.6 g (yiel. Lc/MS (ju/z) 225.1 (MH+) ; tR = 2.08 min. 1H NMR (CDC13): 1.33 (t, 3H); 3.77 (s, 2H, NH2); 4.23 (q, 2H); 6.98 (dd, 1H) > 7.45 (d, 1H); 8.28 (d, 1H) 9.39 (s, 1H, NH). The following compounds were prepared in a similar manner: (4-amino-2-nitro-phenyl)- propyl carbamate. Yield: 91%. 4 NMR (CDC13): 0·98 (t, 3H); 1. 71 (m, 2H); 3.78 (b, 2H); 4.13 (t, 2H); 6.98 (dd, 1H); 7.44 (d, 1H) 8.27 (d,1H); 9.39 (s,1H). (4-Amino-3-nitro-phenyl)-aminodecanoic acid tert-butyl ester. In a refluxing solution of 2-nitro-1,4-diaminobenzene (1 〇.135 g, 66.18 mmol) in tetrahydrofuran (100 liters), B 〇c20 (dicarbonic acid) during 2 hours Two third butyl esters, 32.6 grams, 149 millimoles) were added in portions. The resulting solution was poured into heptane (2 liters) and sonicated for 15 min <">> Yield: 8 %. LC/MS 〇々) 295. 4 ([M + H+MeCN] + ); tR = 2.54 (UV, ELSD) 96%, 100%. 4 66 1325414 NMR (DMS〇-d6): 1. 47 2H, NH2), 7.41 (dd> NH). (s' 9H) ; 6. 96 (d, 1H) ; 7 24 (s, 1H) ; 20 (s,1H) ; 9. 28 (s,1H, [4_(4-Gas-Benzyl)]-3-methyl- porphin, 2, benzyl alcohol. 4~(4) under N2 _Chloro-benzoic acid) _3_methyl ester (992 mg, 3.00 mM " 幡% mM) in anhydrous tetrahydrofuran (20 ml) and anhydrous CH/l2 (1 〇 ml) towel six open J In the middle of the liquid / cold liquid to the 〇〇c, and added DIBAL-H (9.0 ml, 9 〇吝苜 π recognised from the 9. 〇 house Moer, in the 曱 中 中 中 1 solution). After 3 hours 'joined Another part of DIBAL-Η (4.5 ml, 4.5 mmol) and continue to mix for 2 hours. The reaction was quenched by the addition of saturated Rochelle (ochel le) | 'liquid (3 mL). The mixture was stirred at room temperature for 1 h. The phases were separated and EtOAc (EtOAc (EtOAc)EtOAc. Alkane/ethyl acetate as extract (linear gradient elution from 1: 〇 to 6: 4) Purification by chromatography on a EtOAc gel. EtOAc (EtOAc: EtOAc: EtOAc) ), for C12H1()C102S2 calculated value: 284.9805, =2.45 min. iH _R (CDC13): 1.84 (t, /= 5.7 Hz, 1 H), 2·2〇(s, 3 H), 4.73 (d, /= 5.7 Hz, 2 H), 7.49 (d, / = 8.5 Hz, 2 H), 7.84 (d, / = 8.5 Hz, 2 H), 8. 18 (s,1 H)· 67 1325414 Prepared in a similar manner: (3-chloro-thiophene-2-yl)-methanol. Yield: 73%. M NMR (CDC13): L92 (b, i Η), 4 8 ι (S, 2 HX 6·91 ( Dj ^ = 5.2 Hz, 1 H), 7.25 (d, / = 5· 2 Hz, 1 H). (5~Dimethylamino-benzo[b]thiophen-3-yl)-f alcohol. :63%.Μ NMR (CDC13): (b,i H),3 〇ι

Cs, 6 H), 4.89 (s, 2 H), 6.96 (dd, 1 H), 7 ll (d i H), 7.34 (s, 1 H), 7.68, (d, / = 9. 0 Hz, i H). ? (5-二甲基胺基-3-曱基-笨并[b]噻吩_2—基）曱醇。 產率：56%。4 NMR (CDC13): 1. 69 (t, / = 5 9 Hz 1 Η), 2.35 (s, 3 Η), 3.00 (s, 6 Η), 4.88 (d, 2 Η), 6.90 (d, 1 Η)，6.93 (dd，1 Η)，7.63，（d，1 Η) (4-溴-3-甲氧基吩-2-基）-甲醇。 將4-溴-3-羥基-噻吩-2-羧酸甲酯（948毫克，4 〇〇 毫莫耳）、硫酸二甲酯（0.57毫升，6.0毫莫耳）和ΚΑΙ (1.11克，8.0毫莫耳）於丙酮（10毫升）中之懸浮液在 回流下加熱4小時。在冷卻到室溫之後，添加水（25毫升 )。用EtOAc ( 2 X 25毫升）萃取混合物，並將萃取物收 集’經Na^O4乾燥及在真空中蒸發。將殘餘物溶於無水四 氫呋喃（20毫升）中，在Nz下將溶液冷卻到〇 ，然後 添加DIBAL-H (12毫升’ 12毫莫耳’於甲苯中之ιΜ溶液 )。2小時之後，加入另一份DIBAL-H ( 6毫升，6毫莫耳 )，並繼續攪拌另2小時。藉由添加飽和羅謝爾鹽溶液（ 68 1325414 30毫升）使反應淬滅，並使混合物在室溫下攪拌i小時 將相分離，用 的有機層經 FlashMaster (2 X 5G毫升）萃取水相，並將收集 ㈣S04乾燥及在真空巾蒸發。產物係經由在 系統中使用庚烧/醋酸乙s旨作為沖提液（從i .〇至2·· i之線性梯度沖提）在矽凝膠上層析而純化。收 集含產物之沖提分並在真空中蒸發而得到所要的化合物（ 482 毫克，54% )。咜 NMR (CDCl3): i 86 化 i 们， 3.90 (s, 3 H), 4.77 (s, 2 H), 7.15 (s, i H)Cs, 6 H), 4.89 (s, 2 H), 6.96 (dd, 1 H), 7 ll (di H), 7.34 (s, 1 H), 7.68, (d, / = 9. 0 Hz, i H). (5-Dimethylamino-3-indenyl- benzo[b]thiophen-2-yl) decyl alcohol. Yield: 56%. 4 NMR (CDC13): 1. 69 (t, / = 5 9 Hz 1 Η), 2.35 (s, 3 Η), 3.00 (s, 6 Η), 4.88 (d, 2 Η), 6.90 (d, 1 Η), 6.93 (dd, 1 Η), 7.63, (d, 1 Η) (4-bromo-3-methoxyphen-2-yl)-methanol. Methyl 4-bromo-3-hydroxy-thiophene-2-carboxylate (948 mg, 4 〇〇 mmol), dimethyl sulfate (0.57 mL, 6.0 mmol) and hydrazine (1.11 g, 8.0 mM) The suspension in MeOH (10 mL) was heated under reflux for 4 h. After cooling to room temperature, water (25 mL) was added. The mixture was extracted with EtOAc (2×25 mL) andEtOAc evaporated. The residue was dissolved in anhydrous tetrahydrofuran (20 mL). EtOAc (EtOAc m. After 2 hours, another portion of DIBAL-H (6 mL, 6 mmol) was added and stirring was continued for another 2 hours. The reaction was quenched by the addition of saturated EtOAc (EtOAc (EtOAc) (EtOAc) And collect (iv) S04 dry and evaporate in a vacuum towel. The product was purified by chromatography on a hydrazine gel using a helium-burning/acetic acid ethyl sate as a solvent (linear gradient elution from i. 〇 to 2·· i) in the system. The product containing fractions were collected and evaporated in vacuo to give the desired compound ( 482 mg, 54%).咜 NMR (CDCl3): i 86 I, 3.90 (s, 3 H), 4.77 (s, 2 H), 7.15 (s, i H)

下列化合物係以類似方式製備： (6-氯-3-甲氧基-苯并[b]噻吩-2-基）、甲醇。 產率：75%。4 NMR (CDC13): h 92 (t，y = 5 9 Hz 1 H)，3." (S，3 H)，4.9° (d，h 5.7 Hz，2 Η; 7-33 (dd, /= 1.9, 8.5 Hz, 1 H), 7.64 (d, J = 8.The following compounds were prepared in a similar manner: (6-chloro-3-methoxy-benzo[b]thiophen-2-yl), methanol. Yield: 75%. 4 NMR (CDC13): h 92 (t, y = 5 9 Hz 1 H), 3." (S, 3 H), 4.9° (d, h 5.7 Hz, 2 Η; 7-33 (dd, / = 1.9, 8.5 Hz, 1 H), 7.64 (d, J = 8.

Hz, 1 H), 7. 73 (d, /=1.9 Hz, 1 H). 通式Ila和Ilia之雜芳基醛類的製備 4-(4-氣-苯磺醯基）-3-甲基-噻吩_2_甲路。 在[4-(4-氯-苯磺醯基）-3-曱基-噻吩、2_基]_甲醇（ 786毫克，2.60毫莫耳）、&quot;基嗎啉^氧化物（〇 克，3.9毫莫耳）與粉末狀4 A分子篩（13克藉由在 真空中短暫加熱使之活化）⑤CH2C12 (7毫升）中的懸浮 液内加入過釕酸四丙基銨（46毫克，0.13毫莫耳）。將所 得混合物授拌i小時’之後使其經過一個用Et〇Ac沖提的 69 丄奶414 氧化石夕（大約2 5克）塞子過滤、。使沖出液在真空中蒸 發，而產物係經由在FlashMaster系統中使用庚烷/醋酸乙 @曰作為沖提液（從1 : 〇至丨：丨之線性梯度沖提）在矽凝 膠上層析而純化。收集含產物之沖提分並在真空中蒸發而 得到標題化合物（644毫克，82% ) 。lH NMR (CDCl3): 2.60 (s’ 3 H)’ 7.53 (d，/ = 9·〇 Hz，2 Η), 7.87 (d， /= 8.5 Hz，2 H)，8.53 (s，1 H)，lo.oi (s, i h). 下列醛類係以類似方式製備： 3- 氯-噻吩-2-甲醛。 產率：94%。卬 NMR (CDC13): 7.07 (d，/ = 5.2 Hz, 1 Η), 7.72 (d, / = 0.5, 4.7 Hz, l R), 10.07 (d, J = 0. 9 Hz, 1 H). 4- 溴-3-曱氧基-噻吩-2-甲醛。 產率：45%。NMR (CDC13): 4.18 (s，3 H)，7 6〇 (d, /= 1.4 Hz, 1 H), 10.08 (d, /= 1.4 Hz, 1 H). 6~氯-3 -曱氧基-本弁[b]瞳吩-2 -曱酸·。 產率：86%。NMR (CDC13): 4.34 (s，3 H)，7 36 (dd, / = 1.7, 8.7 Hz, 1 Η), 7.75 (d, / = 1.4 Hz, 1 Η), 7.82 (d，8.5 Hz, 1 Η), 10.36 (s，1 η). 5- 二甲基胺基-苯并[b]噻吩-3-甲链。 產率：72% » NMR (CDC13): 3.05 (s，6 H)，7.00 (dd, / = 2.4, 9.0 Hz, 1 H), 7.68 (d, / = 9. 0 Hz, 1 H), 7.99 (d, / = 2.8 Hz, 1 H), 8.24 (s, 1 H), 10. n 1325414 (s，1 η). 5-二甲基胺基-3-甲基-苯并[b]噻吩-2-曱醛。 產率：73%。印 NMR (CDC13): 2.74 (s，3 H)，3.03 (s，6 H)，7.00 (d，7&quot; = 2.4 Hz，1 Η)，7.12 (dd，/ ：；；； 2.4，9.0 Hz，1 H)，7.69 (d，/ = 9·0 flz，1 H)，ι〇·3〇 (s，1 H). 5-氟-苯并呋喃-3_甲酿e 在-60 °C的固定溫度下，將二曱炎楓（3. 27克， 41.8毫莫耳）於二氣甲烷（1〇毫升）中么漆液加到草醯氯 (2.65克’20.9毫莫耳）於二氯甲烷（3〇毫升）之溶液 中，並將溶液攪拌15分鐘。於_6〇。(；卞逐滴加入溶於二 氯甲烧（60毫升）之i_(5_氟苯并呋喃-基）甲醇（3 16 克，19. 0毫莫耳）。將混合物攪拌2〇分鐘，接著添加三 乙胺（9.61克’〇.〇95毫莫耳）。在攪拌10分鐘之後，使 反應混合物加熱到周圍溫度並攪拌另外的20分鐘。將有 機部分相繼地用50毫升份的水、in HC1水溶液、飽和碳 酸氫納水溶液及食鹽水洗滌，然後乾燥（MgS〇4)及在真空 下濃縮’而以量產產率製得粗製標題化合物，為米黃色結 晶固體。1H NMR (CDC13): 7. 13 (dt，1H) ; 7.50 (dd, 1H) ；7. 86 (dd, 1H) ; 8. 30 (s, 1H) ； 10. 15 (s, 1H). 5-氟-暖吩-2-曱搭。 於0 °C下，在噻吩（4.8毫升，60毫莫耳）於無水 Et20 ( 200毫升）中之溶液内逐滴加入yj-BuLi ( 70毫升， 66毫莫耳’ 0.95 Μ於己烷中），並於-5 - 0 °C下將溶液 71 1325414 授拌1小時。然後將溫度調整Hz, 1 H), 7. 73 (d, /=1.9 Hz, 1 H). Preparation of Heteroarylaldehydes of the Formula Ila and Ilia 4-(4-Gas-Benzenesulfonyl)-3-A Base-thiophene_2_A road. [4-(4-Chloro-phenylsulfonyl)-3-indolyl-thiophene, 2-yl]-methanol (786 mg, 2.60 mmol), &quot; morpholine^ oxide (〇克, 3.9 mmol, and 4 g of ammonium citrate (46 mg, 0.13 mmol) in a suspension of powdered 4 A molecular sieve (13 g activated by heating in a vacuum) 5CH2C12 (7 ml) ear). The resulting mixture was mixed for 1 hour and then filtered through a plug of 69 丄 milk 414 oxidized stone (about 25 gram) scoured with Et 〇Ac. The eluate was allowed to evaporate in vacuo, and the product was applied to the top layer of the ruthenium gel by using heptane/acetic acid ethyl hydrazine as the extract (from 1 : 〇 to 丨: linear gradient of 丨) in the FlashMaster system. Analyzed and purified. The product-containing fractions were collected and evaporated in vacuo to give the title compound (644 mg, 82%). lH NMR (CDCl3): 2.60 (s' 3 H)' 7.53 (d, / = 9·〇Hz, 2 Η), 7.87 (d, /= 8.5 Hz, 2 H), 8.53 (s, 1 H), Lo.oi (s, ih). The following aldehydes were prepared in a similar manner: 3-chloro-thiophene-2-carbaldehyde. Yield: 94%.卬NMR (CDC13): 7.07 (d, / = 5.2 Hz, 1 Η), 7.72 (d, / = 0.5, 4.7 Hz, l R), 10.07 (d, J = 0. 9 Hz, 1 H). 4 - bromo-3-indolyl-thiophene-2-carbaldehyde. Yield: 45%. NMR (CDC13): 4.18 (s, 3 H), 7 6 〇 (d, / = 1.4 Hz, 1 H), 10.08 (d, / = 1.4 Hz, 1 H). 6~chloro-3-methoxyl - Ben 弁 [b] 瞳 -2 -2 - 曱 acid ·. Yield: 86%. NMR (CDC13): 4.34 (s,3 H),7 36 (dd, / = 1.7, 8.7 Hz, 1 Η), 7.75 (d, / = 1.4 Hz, 1 Η), 7.82 (d, 8.5 Hz, 1 Η), 10.36 (s, 1 η). 5-Dimethylamino-benzo[b]thiophene-3-methyl chain. Yield: 72% » NMR (CDC13): 3.05 (s, 6 H), 7.00 (dd, / = 2.4, 9.0 Hz, 1 H), 7.68 (d, / = 9. 0 Hz, 1 H), 7.99 (d, / = 2.8 Hz, 1 H), 8.24 (s, 1 H), 10. n 1325414 (s,1 η). 5-Dimethylamino-3-methyl-benzo[b]thiophene -2-furfural. Yield: 73%. NMR (CDC13): 2.74 (s, 3 H), 3.03 (s, 6 H), 7.00 (d, 7 &quot; = 2.4 Hz, 1 Η), 7.12 (dd, / :;;; 2.4, 9.0 Hz, 1 H), 7.69 (d, / = 9·0 flz, 1 H), ι〇·3〇(s, 1 H). 5-Fluoro-benzofuran-3_甲乙e at -60 °C At a fixed temperature, dithizone maple (3.77 g, 41.8 mmol) in di-methane (1 ml) was added to the grassy chlorine (2.65 g '20.9 mmol) to dichloro In a solution of methane (3 mL), the solution was stirred for 15 minutes. At _6〇. (*) I_(5-fluorobenzofuran-yl)methanol (3 16 g, 19.0 mmol) dissolved in dichloromethane (60 ml) was added dropwise. The mixture was stirred for 2 min. Triethylamine (9.61 g of '〇.〇95 mmol) was added. After stirring for 10 minutes, the reaction mixture was allowed to warm to ambient temperature and stirred for an additional 20 minutes. The organic portion was taken sequentially with 50 mL portions of water, in The title compound was obtained as a beige crystalline solid. 1H NMR (CDC13): </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 7. 13 (dt, 1H); 7.50 (dd, 1H); 7.86 (dd, 1H); 8. 30 (s, 1H); 10. 15 (s, 1H). 5-Fluor-warm pheno- 2-y 。. At 0 ° C, yj-BuLi (70 ml, 66 mM '0.95 Μ) was added dropwise to a solution of thiophene (4.8 ml, 60 mmol) in anhydrous Et20 (200 mL). In hexane, and mix the solution 71 1325414 for 1 hour at -5 °C. Then adjust the temperature

(28.4克，90毫莫耳）於鉦卜~ °C，並加入（PhS〇2)2NF 溶液，同時使溫度維持在—5〇四氫咲喃（200毫升）中之 合物緩慢地過夜溫熱到室溫 /下。然後過仪將所得混 、证各 添加2 N NaOH ( 300毫升） ，過濾混合物，將有機層用2 M M 宅幵； ， 2 N N_ ( 2 X 300 毫升）和 飽和NH4C1 ( 300毫升）洗滌，妙 ^ “、 然後經Na2S04乾燥。使用 4〇公分Vigreux管柱蒸餾除去 友太。p分的Et20，最後與庚烷 (50毫升）共蒸餾，得到2〇. 7 宅冥耳2-氟噻吩與4· 6毫 莫耳噻吩（經由使帛200微升_作為内標準品之4麵 於大約loo毫升四氣咲味與庚烧（bp 6〇 _ _ °c)中之溶液。將此溶液冷卻到G %，並逐滴加人心 (44毫升，41毫莫耳’ 0.95 Μ於己烷中）。j小時之後 ，逐滴加入DMF ( 4.8毫升’ 62毫莫耳）於Et2〇 ( 15毫升 )中之溶液，並於〇 °C下繼續攪拌另丨小時。然後用飽 和NH4C1 ( 200毫升）使反應淬滅。並用Et2〇 ( 2 x 2〇〇毫 升）萃取之’然後使萃取液經NaJO4乾燥》經由在大氣壓 力下蒸餾（40公分Vi greux管柱）除去大部分的溶劑，然 後真空蒸德深色殘餘物，而得到大約5 -氟-噻吩-2-曱链與 噻吩-2-甲醛（bp· 78-79 0C，25 mmHg)的 1〇 : 1 混合物 為金黃色油（1.32克’ 44%)。無進一步純化即使用此 混合物》4 NMR (CDC13): 6.65 (d，*/ = 4.2，1 H)，7 50 (d，/= 3.8 Hz，1 H)，9.76 (d，/= 4.2 Hz，1 Η). 通式V11中間物之製備 72 1325414 通式VII中間物係經由以下所敘述之製備丨4-[(5-氟-苯并呋喃-3-基甲基）_胺基]-2-硝基-苯基}-胺基甲酸乙酯 的一般方法製備，或經由以下所敘述之製備N-(4-胺基-2-硝基苯基）-2-(4-氟苯基）乙醯胺的一般方法製備。 {4-[(5~氟-苯并呋喃-3-基甲基）-胺基]-2-硝基-苯基 }-胺基甲酸乙酯。 在一個裝備有Dean-Stark裝置的三頸圓底燒瓶中，將 5-氟-苯并呋喃-3-甲醛（3.59克，21.9毫莫耳）和（4-胺 基-2-硝基-苯基）_胺基甲酸乙酯（4_ μ克，19. 9毫莫耳） 混合於鄰二甲苯（8〇毫升）中，並加入催化量的酸性離子 交換樹脂（Amberlite IRC-84，100毫克）。將混合物加 熱到回流維持5小時，趁溫熱過濾及在真空中濃縮。將此 粗產物溶於二腭烷：甲醇（4 : 1)混合物（90毫升）中， 並將硼氫化鈉（丨.50克，39 8毫莫耳）分成幾份於3〇分 鐘期間加入。使反應混合物於周圍溫度下攪拌過夜，然後 將其倒入水（200毫升）中，並用醋酸乙酯（3 X 75毫升 )萃取。將合併的有機沖提分用食鹽水洗滌，乾燥（MgS〇4 )及蒸發而得到粗製固體，經由在矽凝膠上層析（沖提劑 k乙知.庚燒1: 2)將其純化。此提供4.50克（61 % ) ‘題化合物，為紅色結晶物質。4 NMR (CDC13): U 33 (t，3H) ; 4.07 (t，1H) ; 4.23 (q，2H) ; 4.42 (d， 2H)，6.99 (dd，1H) ; 7.05 (dt，1H) ; 7.25 (dd，1H); 42 (t’ in)，7.44 (d，ih) ; 7.65 (s，1H) ; 8.31 (d, 1H) ; 9. 39 (s，1H). 73 1325414 下列中間物係以類似方式製備： {4-[(5-甲基-噻吩-2-基甲基）_胺基]-2-硝基-苯基}-胺基甲酸乙醋 產率：73%。LC/MS 336 (MH+) ; tR = 3.41 分 〇 {4-[(3-曱基-_吩-2-基甲基）一胺基]-2-硝基-苯基}-胺基曱酸乙酯 產率：89%。LC/MS U/z) ί 4-[(噬吩-2-基甲基）-胺基]-2-硝基-苯基卜胺基甲酸 乙S旨 產率：71%。LC/MS 〇/之）321 (ΜΗ+) ; tR = 3. 24 分 〇 {4-[(睡吩-3-基甲基）-胺基]-2-硝基-苯基}-胺基甲酸 乙醋 產率：69%。LC/MS (历/&gt;) 320 (MH+) ; tR = 3.08 分 〇 {4-(笨并[b]瞳吩-3-基甲基）_胺基]-2 -石肖基-苯基}-胺 基甲酸乙酯 產率：87%。Μ·ρ. 151-152 °C. LC-MS U/z) 371.0 (MH+)，tR = 3. 59 分。 N-(4~胺基-2-硝基苯基）-2-(4-氟苯基）乙醢胺。 在{4-[2-(4 -氟苯基）_乙醯基胺基]确基-苯基}-胺 基甲酸第三丁酯（2. 40克，6. 16毫莫耳）於二氯曱烷（5 毫升）中之經攪拌懸浮液内加入三氟醋酸（5毫升）。15 1325414 刀鐘之後，將二氯甲烷蒸餾除去，然後隨著聲波振盪將殘 餘的溶液轉移到飽和NaHC〇3水溶液（2〇〇亳升）中。將沈 澱物過濾，用水洗滌及在真空中乾燥，而製得1. 70克標題 化合物’為紅棕色固體。產率：96 3 %。Lc/MS ; tR = 2.25(UV，ELSD) 89%, 1〇〇%。iH NMR (DMS〇_d6): 3 59 (s’ 2H) ; 5.65 (b, 2H, p2) ; 6.83 (dd, 1H) ; 7.08 (d， 1H) ； 7.15 (t, 2H), 7.21 (d, 1H) ； 7.32 (dd, 2H)； 9. 91 (s，1H, NH). 下化合物係以類似方式製備： N_(4-胺基-2-硝基苯基）~3, 3-二曱基丁醯胺。 產率：680 毫克，93% 。LC/MS U/z) 293.43 ([M+H+MeCN] + ); tR = 2.29 (UV，ELSD) 99.5%，99· 1%» !H NMR (DMSO-d6)： 1.00 (s, 9H) ； 2.12 (s, 2H) ； 3.45 (b, H20 + NH2) ; 6.84 (dd, 1H) ; 7.06 (d, 1H) ； 7.14 (d, 1H) ; 9. 64 (s, 1H，NH). 通式VIII中間物之製備 N-{4-[(5-氣噻吩-2-基甲基）胺基]一2-硝基苯基}-2- (4-氟苯基）乙醯胺。 使N-(4-胺基-2-硝基苯基）-2-(4-氟苯基）乙醯胺（ 306毫克’ 1. 06毫莫耳）與5-氣-2-噻吩甲醛（186毫克， 1.2當量）於無水乙醇（40毫升）中之溶液於70。(：加熱 3 0分鐘。將所得溶液濃縮到小量體積（大約3毫升），然 75 1325414 後用庚烧（15毫升）淬滅。藉由過渡將棕色結晶產物分離 ，製得350毫克中間亞胺N_{4—[(5一氣瞎吩_2基亞甲基） 胺基]2硝基苯基卜2-(4-氟笨基）乙醯胺。產率：79 2% « ^ NMR (DMSO-d6)： 3.71 (s, 2H) ； 7.17 (t, 2H) ； 7.29 (d, 1H) , 7.36 (dd, 2H) ； 7.62 (d, 1H) ； 7.63 (dd, 1H) ;7·71 (d’ 1H) ; 8· 83 (s，1H) ; 10.44 (s，1H).將此固 體懸汙於曱醇（5毫升）中’加人NaBH3CN ( 2〇〇毫克）， 接著加入醋酸（2毫升）。所得溶液變成懸浮液。15分鐘 之後’用水（50毫升）處理之，經由過濾將產物分離，在_ 真空中乾燥之後製得330毫克紅色固體。產率：μ. 8%。 LC/MS {m/z) 420 ([M+H] + ); tR = 3.34 (UV, ELSD) 97%, 100%。^ NMR (DMS0-d6): 3.60 (s，2H) ; 4.45 (d, 2H) .6.87 (t, 1H, NH) ; 6.93 (dd, 1H) ； 6.94 (d, 1H); 6. 97 (d, 1H) ； 7. 11 (d, 1H) ； 7. 14 (t, 2H) ； 7. 28 (d,. 1H) ·’ 7.32 (dd，2H) ; 9.98 (s，ijj) 下列化合物係以類似方式從對應苯胺製備： N-{4-[(5-氣噻吩-2-基甲基）胺基]一2-硝基苯基}-3, 3~ 二曱基丁醯胺。 如以上所述將粗製中間亞胺藉蒸發分離及還原。然後 ’將反應混合物蒸發到小量體積，用飽和NaHC〇3水溶液和 醋酸乙酯處理’並蒸發有機層。將殘餘物溶於熱的二異丙 喊中’用庚烧沈澱及過濾。產率：880毫克，87· 6%。 LC/MS (历/2〇 382.48 ([M+H] + ); tR = 3.46 (UV，ELSD) 88 76 1325414 %，91%。NMR (DMS0-d6): 0.99 (s，9H) ; 2.12 (s， 2H) ; 4.45 (d，2H) ; 6.84 (t, 1H，NH) ; 6.92 (dd，1H) ;6-94 (d, 1H) ； 6.97 (d, 1H) ； 7.07 (d, 1H) ； 7.19 (d，1H) ; 9. 69 (s，1H). 通式XII中間物之製備 (4~ [2-(4-氟苯基）乙醢基胺基]-3-硝基苯基}胺基甲酸 第三丁酯。 在（4-胺基-3-硝基苯基）-胺基甲酸第三丁酯（1.992 克’ 7· 87毫莫耳）與NaHC03 ( 5. 4克）於乙腈（20毫升） 中之懸浮液内加入（4-氟苯基）乙醯氯（1.8毫升，1.3當量 )。將所得懸浮液聲波振盪5分鐘，然後於周圍溫度攪拌 16小時。將它倒入水（200毫升）中，聲波振盪5分鐘， 過濾’以及用水和庚烷洗滌。將所得殘餘物溶於熱的醋酸 乙酯（30毫升）中，加入飽和NaHC03水溶液（50毫升） 然後用庚烷（2 0 0毫升）淬滅所得混合物。將所得懸浮 液聲波振盪5分鐘及過濾。將殘餘物用水和庚烷洗滌及在 真二中乾燥’製得2.48克棕黃色固體。產率：M g%。 LC/MS (m/z) 412.54 ([M+Na]+), 453.58 ([M+MeCN+Na]+) ，h ~ 3.33 〇JV’ ELSD) 97%，ι〇〇% β iH NMR (DMS〇_ d6): 1.48 (s，9H) ; 3.66 (s，2H) ; 7.16 (t，2H)’ 7.34 (dd, 2H)； 7.54 (d, 1H)； 7.64 (dd, 1H) ; 8.16 (d, 1H) 9.79 (s, 1H, NH), 10.29 (s, 1H, NH) 1325414 下列化合物係使用對應的醯氯以類似方式製備： [4-(3, 3-—曱基丁醢基胺基）-3-硝基苯基]胺基甲酸第 三丁酯。 使反應混合物與過量的第三丁基乙醯氣（3當量）一 起於45 °C攪拌30分鐘。在醋酸乙酯—飽和NaHC〇3水溶液 增濃之後分離出粗產物及經由在Si〇2 ( 50克）上使用10_ 15%醋酸乙酯-庚烷作為沖提液之急驟層析純化之。產率 :2. 20 克（78. 6% ) ’ 黃色固體。LC/MS (历々）415. 58 ([M+MeCN + Na] + ) ； tR = 3.31 (UV, ELSD) 99.5%, 99.9% 。^ NMR (DMSO-d6): 1. 〇l (s，9H) ; 1·49 (s，9H) ; 2 17 (s，2H)，7.43 (d，2H) ; 7.63 (dd，1H) ; 8.11 (d，1H) ;9. 77 (s，1H，NH) ; 10. 〇l (s，ih，NH). 本發明之化合物 本發明化合物之酸加成鹽可經由熟習該項技術者所已 知的方法容易地形成。 _ 實施例1 la {2-胺基-4-[(5-氟-苯并呋喃-3-基甲基）_胺基卜笨 基卜胺基甲酸乙酯。 將丨4-[(5-氟-苯并呋喃-3-基曱基）_胺基]_2_硝基-笨 基}-胺基甲酸乙酯（4. 50克，12. 1毫莫耳）溶於無水乙 醇（140毫升）中，在其中加入6N HC1 (38毫升）水溶液 及鐵粉（5· 70克，〇. 1〇莫耳）。使此紅色混合物於6〇 % 78 1325414 加熱。直到強烈顏色消失（2〇分鐘）。將固體濾出並經由 在真空中蒸發將乙醇從濾液中除去。將氨水（飽和的）加 到殘餘物中，然後用醋酸乙酯（3 X 100毫升）萃取之。 將合併的有機沖提分用食鹽水洗滌，乾燥（MgS04)及在真 玄中濃縮。經由在矽凝膠上層析（沖提劑：醋酸乙酯：庚 院1 : 1)來純化粗產物，製得2.70克（66% )標題化合 物，為固體。Μ· p. 150-151 〇c 對 C18h18FN303 之計算值：c(28.4 g, 90 mmol) at 钲b ~ °C, and add (PhS〇2) 2NF solution while maintaining the temperature in -5 〇 tetrahydrofuran (200 ml). Heat to room temperature / down. Then, the mixture was mixed with 2 N NaOH (300 ml), the mixture was filtered, and the organic layer was washed with 2 MM house; 2 N N_ ( 2 X 300 ml) and saturated NH4C1 (300 ml). ^, then dried over Na2S04. Distilled off the tartar with a 4 〇 Vigreux column. Et20 was then co-distilled with heptane (50 ml) to give 2 〇. 7 冥耳耳 2-fluorothiophene with 4 · 6 mM thiophene (via 200 μl of 帛 as a solution of 4 sides of the internal standard in approximately loo ml of four gas astringent and heptane (bp 6 〇 _ _ °c). Cool this solution to G %, and added to the heart (44 ml, 41 mmoles < 0.95 in hexane). After j hours, DMF (4.8 ml '62 mmol) was added dropwise to Et 2 (15 mL) The solution was stirred for an additional hour at 〇 ° C. The reaction was then quenched with saturated NH 4 C 1 (200 mL) and extracted with Et.sub.2 (2 x 2 mL) and then the extract was dried over NaJO. Remove most of the solvent by distillation at atmospheric pressure (40 cm Vi greux column), then vacuum dry dark Residue, and a mixture of about 5-fluoro-thiophene-2-indole and thiophene-2-carbaldehyde (bp·78-79 0C, 25 mmHg) was obtained: 1 mixture was golden yellow oil (1.32 g '44%) This mixture was used without further purification. 4 NMR (CDC13): 6.65 (d, */ = 4.2, 1 H), 7 50 (d, / = 3.8 Hz, 1 H), 9.76 (d, / = 4.2 Hz , 1 Η). Preparation of intermediate of formula V11 72 1325414 Intermediate of formula VII is prepared by the following description of 丨4-[(5-fluoro-benzofuran-3-ylmethyl)-amino]- Preparation of 2-nitro-phenyl}-carbamic acid ethyl ester by the general method or preparation of N-(4-amino-2-nitrophenyl)-2-(4-fluorophenyl) as described below Preparation of acetamide by the general method. {4-[(5~Fluoro-benzofuran-3-ylmethyl)-amino]-2-nitro-phenyl}-carbamic acid ethyl ester. In a three-necked round bottom flask equipped with a Dean-Stark apparatus, 5-fluoro-benzofuran-3-carbaldehyde (3.59 g, 21.9 mmol) and (4-amino-2-nitro-phenyl) Ethyl urethane (4 μg, 19.9 mmol) was mixed in o-xylene (8 mL) and a catalytic amount of acidic ion exchange resin (Amber) was added. Lite IRC-84, 100 mg). The mixture was heated to reflux for 5 h, warm filtered and concentrated in vacuo. This crude product was dissolved in a mixture of dioxane:methanol (4:1) (90 ml), and sodium borohydride (.50 g, 39 8 mM) was added in portions over 3 Torr. The reaction mixture was stirred at rt EtOAc (EtOAc)EtOAc. The combined organic extracts were washed with brine, dried (MgSO.sub.4) and evaporated to give a crude solid, which was purified by chromatography on hydrazine gel (purifying agent k s. . This provides 4.50 g (61%) of the title compound as a red crystalline material. 4 NMR (CDC13): U 33 (t, 3H); 4.07 (t, 1H); 4.23 (q, 2H); 4.42 (d, 2H), 6.99 (dd, 1H); 7.05 (dt, 1H); (dd,1H); 42 (t' in), 7.44 (d,ih); 7.65 (s,1H) ; 8.31 (d, 1H) ; 9. 39 (s,1H). 73 1325414 The following intermediates are Prepared in a similar manner: {4-[(5-Methyl-thiophen-2-ylmethyl)-amino]-2-nitro-phenyl}-carbamic acid ethyl acetate Yield: 73%. LC/MS 336 (MH+); tR = 3.41 〇{4-[(3-indolyl--phen-2-ylmethyl)-amino]-2-nitro-phenyl}-amino decanoic acid Ethyl ester yield: 89%. LC/MS U/z) 4- 4-[(Phenyphen-2-ylmethyl)-amino]-2-nitro-phenyl-p-aminocarbamic acid B. Yield: 71%. LC/MS 〇/) 321 (ΜΗ+) ; tR = 3. 24 minutes 4-{4-[(sedum-3-ylmethyl)-amino]-2-nitro-phenyl}-amino group Ethyl formate yield: 69%. LC/MS (calendar)&gt; 320 (MH+); tR = 3.08 min. {4-(stupid[b] 瞳--3-ylmethyl)-amino]-2 - Shishoyl-phenyl}- Ethyl urethane yield: 87%. Μ·ρ. 151-152 °C. LC-MS U/z) 371.0 (MH+), tR = 3.59 min. N-(4~Amino-2-nitrophenyl)-2-(4-fluorophenyl)acetamide. In the order of {4-[2-(4-fluorophenyl)-ethinylamino]-decyl-phenyl}-carbamic acid tert-butyl ester (2.40 g, 6.16 mmol) Trifluoroacetic acid (5 ml) was added to a stirred suspension of chlorohexane (5 mL). 15 1325414 After the knives, the dichloromethane was distilled off and the residual solution was transferred to a saturated aqueous solution of NaHC 3 (2 liters) with sonication. The precipitate was filtered, washed with water and dried in vacuo. Yield: 96 3 %. Lc/MS ; tR = 2.25 (UV, ELSD) 89%, 1〇〇%. iH NMR (DMS〇_d6): 3 59 (s' 2H); 5.65 (b, 2H, p2); 6.83 (dd, 1H); 7.08 (d, 1H); 7.15 (t, 2H), 7.21 (d , 1H); 7.32 (dd, 2H); 9. 91 (s, 1H, NH). The lower compound is prepared in a similar manner: N_(4-Amino-2-nitrophenyl)~3, 3- Mercaptobutylamine. Yield: 680 mg, 93%. LC/MS U/z) 293.43 ([M+H+MeCN] + ); tR = 2.29 (UV, ELSD) 99.5%, 99·1%» !H NMR (DMSO-d6): 1.00 (s, 9H) 2.12 (s, 2H); 3.45 (b, H20 + NH2); 6.84 (dd, 1H); 7.06 (d, 1H); 7.14 (d, 1H); 9. 64 (s, 1H, NH). Preparation of the intermediate of formula VIII N-{4-[(5-oxathiophen-2-ylmethyl)amino]- 2-nitrophenyl}-2-(4-fluorophenyl)acetamide. N-(4-Amino-2-nitrophenyl)-2-(4-fluorophenyl)acetamide (306 mg ' 1.06 mmol) with 5-Ga-2-thiophenecarboxaldehyde ( A solution of 186 mg, 1.2 eq. in absolute ethanol (40 mL) was taken at 70. (: heating for 30 minutes. The resulting solution was concentrated to a small volume (about 3 ml), then 75 1325414 and then quenched with heptane (15 ml). The brown crystalline product was separated by the transition to obtain 350 mg of intermediate Amine N_{4-[(5-azepine-2-ylmethylene)amino]2nitrophenyl-2-(4-fluorophenyl)acetamide. Yield: 79 2% « ^ NMR ( DMSO-d6): 3.71 (s, 2H); 7.17 (t, 2H); 7.29 (d, 1H), 7.36 (dd, 2H); 7.62 (d, 1H); 7.63 (dd, 1H) ;7·71 (d' 1H) ; 8· 83 (s, 1H) ; 10.44 (s, 1H). This solid was suspended in sterol (5 ml) and added with NaBH3CN (2 〇〇 mg), followed by acetic acid ( 2 ml). The resulting solution becomes a suspension. After 15 minutes, it is treated with water (50 ml), the product is separated by filtration, and dried in vacuo to yield 330 mg of red solid. Yield: 8%. /MS {m/z) 420 ([M+H] + ); tR = 3.34 (UV, ELSD) 97%, 100%. ^ NMR (DMS0-d6): 3.60 (s, 2H); 4.45 (d, 2H) .6.87 (t, 1H, NH); 6.93 (dd, 1H); 6.94 (d, 1H); 6. 97 (d , 1H); 7. 11 (d, 1H) ; 7. 14 (t, 2H) ; 7. 28 (d,. 1H) ·' 7.32 (dd, 2H) ; 9.98 (s, ijj) The following compounds are Prepared in a similar manner from the corresponding aniline: N-{4-[(5-oxathiophen-2-ylmethyl)amino]- 2-nitrophenyl}-3,3~dimercaptoamine. The crude intermediate imine is separated and reduced by evaporation as described above. Then, the reaction mixture was evaporated to a small volume, which was treated with saturated aqueous NaHCO3 and ethyl acetate. The residue was dissolved in hot diisopropyl hexanes and precipitated with heptane and filtered. Yield: 880 mg, 87.6%. LC/MS (Late/2〇382.48 ([M+H] + ); tR = 3.46 (UV, ELSD) 88 76 1325414 %, 91%. NMR (DMS0-d6): 0.99 (s, 9H); s, 2H); 4.45 (d, 2H); 6.84 (t, 1H, NH); 6.92 (dd, 1H); 6-94 (d, 1H); 6.97 (d, 1H); 7.07 (d, 1H) 7.19 (d,1H); 9. 69 (s,1H). Preparation of intermediate of formula XII (4~[2-(4-fluorophenyl)ethinylamino]-3-nitrophenyl }T-butyl carbamic acid ester. T-butyl (4-amino-3-nitrophenyl)-carbamic acid (1.992 g '7.87 mmol) with NaHC03 (5.4 g) (4-Fluorophenyl)acetamidine chloride (1.8 ml, 1.3 eq.) was added to a suspension in acetonitrile (20 mL). The resulting suspension was sonicated for 5 minutes, then stirred at ambient temperature for 16 hours. In water (200 ml), the mixture was shaken for 5 minutes, filtered and washed with water and heptane. The obtained residue was dissolved in ethyl acetate (30 ml). The resulting mixture was quenched with aq. (200 mL). The resulting suspension was sonicated for 5 min and filtered. The mixture was washed with heptane and dried in EtOAc to yield 2.48 g of a brown solid. Yield: M g. LC/MS (m/z) 412.54 ([M+Na]+), 453.58 ([M+MeCN+ Na]+) ,h ~ 3.33 〇JV' ELSD) 97%, ι〇〇% β iH NMR (DMS〇_d6): 1.48 (s,9H) ; 3.66 (s,2H) ; 7.16 (t,2H) ' 7.34 (dd, 2H); 7.54 (d, 1H); 7.64 (dd, 1H) ; 8.16 (d, 1H) 9.79 (s, 1H, NH), 10.29 (s, 1H, NH) 1325414 The corresponding hydrazine chloride was prepared in a similar manner: [4-(3,3--indolylbutylideneamino)-3-nitrophenyl]carbamic acid tert-butyl ester. The reaction mixture was combined with an excess of butyl. Ethylene gas (3 equivalents) was stirred together at 45 ° C for 30 minutes. The crude product was isolated after enrichment with ethyl acetate-saturated NaHC 3 aqueous solution and 10% 15% acetic acid was used on Si 2 (50 g). The ester-heptane was purified by flash chromatography as a solvent. Yield: 2.20 g (78.6%) LC/MS (calendar) 415. 58 ([M+MeCN + Na] + ); tR = 3.31 (UV, ELSD) 99.5%, 99.9%. ^ NMR (DMSO-d6): 1. 〇l (s, 9H); 1·49 (s, 9H); 2 17 (s, 2H), 7.43 (d, 2H); 7.63 (dd, 1H); 8.11 (d, 1H); 9.77 (s, 1H, NH); 10. 〇l (s, ih, NH). The compound of the present invention The acid addition salt of the compound of the present invention can be obtained by those skilled in the art. Known methods are easily formed. _ Example 1 la {2-Amino-4-[(5-fluoro-benzofuran-3-ylmethyl)-amino-p-phenyl).丨 4-[(5-Fluoro-benzofuran-3-ylindenyl)-amino]_2_nitro-phenyl}-carbamic acid ethyl ester (4. 50 g, 12. 1 mmol) It was dissolved in absolute ethanol (140 ml), and 6N HCl (38 ml) aqueous solution and iron powder (5·70 g, 〇. 1 〇mol) were added thereto. This red mixture was heated at 6 〇 % 78 1325414. Until the strong color disappears (2 〇 minutes). The solid was filtered off and the ethanol was removed from the filtrate by evaporation in vacuo. Ammonia (saturated) was added to the residue and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in EtOAc. The crude product was purified by chromatography EtOAcjjjjjjjjjjj Μ· p. 150-151 〇c Calculated value for C18h18FN303: c

62· 96 ; Η 5· 28 ; N 12. 24。實測值：C 63. 00 ; Η 5. 38 ; N 12. 13. LC/MS 〇/ζ) 344 (MH+) ; tR = 2.00 分。1H NMR (DMSO-i/6)： 1.19 (t, 3H) ； 4.03 (q, 2H) ； 4.26 (d, 2H) ;4.55 (s，2H，NH2) ; 5.79 (t，1H) ; 5.91 (dd，1H); 6.02 (d，1H，NH) ; 6.72 (d，1H) ; 7.13 (dt，1H) ; 7.56 (m, 2H) ； 7. 95 (s, 1H) ； 8. 16 (b, 1H, NH). 下列化合物係以類似方式製備並以其氫氯酸加成鹽離 析出來： lb {2-胺基-4-[(5-甲基-噻吩-2-基甲基）-胺基卜笨基 }_胺基甲酸乙m二鹽酸鹽。 經由添加醚氫氯酸自醋酸乙酯製備粗產物，得到標題 化合物。62· 96 ; Η 5· 28 ; N 12. 24. Found: C 63. 00 ; Η 5. 38 ; N 12. 13. LC/MS 〇/ζ) 344 (MH+) ; tR = 2.00 min. 1H NMR (DMSO-i/6): 1.19 (t, 3H); 4.03 (q, 2H); 4.26 (d, 2H); 4.55 (s, 2H, NH2); 5.79 (t, 1H); 5.91 (dd , 1H); 6.02 (d, 1H, NH); 6.72 (d, 1H); 7.13 (dt, 1H); 7.56 (m, 2H); 7. 95 (s, 1H); 8. 16 (b, 1H , NH). The following compounds were prepared in a similar manner and isolated by their hydrochloric acid addition salt: lb {2-Amino-4-[(5-methyl-thiophen-2-ylmethyl)-amino卜笨基}_Aminocarbamic acid ethyl m dihydrochloride. The crude product was prepared from ethyl acetate by ethyl ether hydrochloride to afford the title compound.

Μ·ρ. 1 90 0C (dec.).對 C15H19N302S，2HC1 之計算值：c 47. 〇〇 ; Η 5. 67 ; N 10. 97。實測值：C 46. 84 ; Η 5. 86 ; N 11.10. LC/MS U/z) 306 (MH+) ; tR = 1.77 分。1H NMR (DMSO-i/6): 1.22 (t, 3H) ； 2.37 (s, 3H) ； 4.08 (q, 2H) 79 1325414 ^ 4.37 (s, 2H) ； 6.64 (m, 1H) ； 6.67 (dd, 1H) ； 6. 72 (d, 1H) ； 6.86 (d, 1H) ； 7.13 (d, iH) ； 8. 93 (b} 1R NH). ’ lc {2-胺基-4 - [(3 一甲基-噻吩一 2—基曱基）胺基]―笨基 }-胺基甲酸乙酯二鹽酸鹽。 經由添加醚氫氯酸自醋酸乙酯製備粗產物，得到標題 化合物。 LC/MS U/z) 306 (MH+) ; tR = 168 分。1H nmr (CDC13) ( : 1.25 (t, 3H) ； 2.23 (s, 3H) ； 3.78 (b, 3H) ； 4.13 (q, 2H) ； 4.32 (s, 2H) ； 6.05-6.10 (m, 2H + NH)； 6.82 (d, IH) ； 6.93 (d&gt; lH) ; 7.11 (d, 1H)/Μ·ρ. 1 90 0C (dec.). For C15H19N302S, 2HC1 calculated value: c 47. 〇〇 ; Η 5. 67 ; N 10. 97. Found: C 46. 84 ; Η 5. 86 ; N 11.10. LC/MS U/z) 306 (MH+); tR = 1.77 min. 1H NMR (DMSO-i/6): 1.22 (t, 3H); 2.37 (s, 3H); 4.08 (q, 2H) 79 1325414^ 4.37 (s, 2H); 6.64 (m, 1H); 6.67 (dd , 1H); 6. 72 (d, 1H); 6.86 (d, 1H); 7.13 (d, iH); 8. 93 (b} 1R NH). ' lc {2-amino-4 - [(3 Monomethyl-thiophene-2-ylindenyl)amino]-stupyl}-carbamic acid ethyl ester dihydrochloride. The crude product was prepared from ethyl acetate by ethyl ether hydrochloride to afford the title compound. LC/MS U/z) 306 (MH+); tR = 168 min. 1H nmr (CDC13) ( : 1.25 (t, 3H) ; 2.23 (s, 3H) ; 3.78 (b, 3H) ; 4.13 (q, 2H) ; 4.32 (s, 2H) ; 6.05-6.10 (m, 2H + NH); 6.82 (d, IH); 6.93 (d&gt;lH); 7.11 (d, 1H)/

Id {2-胺基一4-[(噻吩-2-基甲基）一胺基]_苯基卜胺基 甲酸乙酯二鹽酸鹽。 經由添加醚氫氯酸自乙醇製備粗產物，得到標題化合 物0 M.p. 195 °C.對 C14H17N302S，2HC1 之計算值：C 46.16Id {2-Amino-4-[(thiophen-2-ylmethyl)-amino]phenylphenylaminocarbamate dihydrochloride. The crude product was obtained from ethanol by the addition of etheric hydrochloric acid to give the title compound: M.p. 195 ° C. Calculated for C14H17N302S, 2HC1: C 46.16

;Η 5· 26，N 11. 54。實測值：c 46· 34 ; H 5. 43 ; N;Η 5· 26, N 11. 54. Found: c 46· 34 ; H 5. 43 ; N

11.28. LC/MS 〇/z) 292 (MH+) ; = i 58 分。1H NMR (DMSO-A): 1.22 (t，3Η) ; 4.08 (q，2Η) ; 4· 48 (s，2Η) ^ 6.71 (dd, IH) ; 6.79 (d, IH) ； 6. 97 (dd, IH) ； 7.10 (d，IH) ; 7.16 (d，IH) ; 7·4〇 (d，1H) ; 8.97 (b，1H， NH). le {2-胺基—4-[(噻吩-3一基曱基）胺基]-苯基卜胺基 曱酸乙醋二鹽酸鹽。 80 1325414 經由添加醚氫氣自醋酸乙酯酸製備粗產物，得到標題 化合物。11.28. LC/MS 〇/z) 292 (MH+) ; = i 58 points. 1H NMR (DMSO-A): 1.22 (t, 3 Η); 4.08 (q, 2 Η); 4· 48 (s, 2 Η) ^ 6.71 (dd, IH); 6.79 (d, IH); 6. 97 (dd , IH); 7.10 (d, IH); 7.16 (d, IH); 7·4〇(d,1H); 8.97 (b,1H, NH). le {2-Amino-4-[(thiophene- 3-monomethyl)amino]-phenyl-aminoglycolic acid ethyl acetate dihydrochloride. The crude product was obtained from the ethyl acetate.

M.p. 1 96-197 °C.對 c14Hi7N302S，2HC1 之計算值：C 46.16，Η 5.26，N 11.54。實測值：C 46.23; II 5 47; N 11.30· LC/MS (历々）292 (ΜΗ+) ; tR = 1.54 分。1H NMR (DMSO-i/6): 1.21 (t，3Η) ; 4.08 (q, 2Η) ; 4.29 (s, 2Η) ；6.66 (dd, 1H) ； 6.73 (d, 1H) ； 7. 14 (dd&gt; 1H) ; 7.16 (d, 1H) ； 7.45 (m, 1H) ; 7.51 (dd, iH) ； 8&gt; 86 (b&gt; 1H, NH).M.p. 1 96-197 ° C. For c14Hi7N302S, 2HC1 calculated: C 46.16, Η 5.26, N 11.54. Found: C 46.23; II 5 47; N 11.30· LC/MS (times) 292 (ΜΗ+) ; tR = 1.54 min. 1H NMR (DMSO-i/6): 1.21 (t, 3 Η); 4.08 (q, 2 Η); 4.29 (s, 2 Η); 6.66 (dd, 1H); 6.73 (d, 1H); 7. 14 (dd&gt ; 1H); 7.16 (d, 1H); 7.45 (m, 1H); 7.51 (dd, iH); 8&gt; 86 (b&gt; 1H, NH).

If {2-胺基-4-[(苯并[1)]_吩~3〜基 }-胺基甲酸乙酯二鹽酸鹽 經由添加喊氫氣酸自酷酸乙酯 化合物。 甲基）-胺基]-苯基 製備粗產物 得到襟題 M.P. 213-214 % 冑 Ci8H2lN3Cl2〇2s 之計算值：If {2-Amino-4-[(benzo[1)]-phenoxy~3~yl}-carbamate ethyl ester dihydrochloride salt is added via the addition of hydrogen acid to the ethyl acrylate compound. Methyl)-amino]-phenyl The crude product was obtained. The calculated value of M.P. 213-214 % 胄 Ci8H2lN3Cl2〇2s:

51.68;114.95;1^1〇.〇5。實測值-广[_ C L 51. 88 ； Η 5. 35 · μ 9. 95. LC/MS im/z) 342.2 (M + H+) ； + ^51.68; 114.95; 1^1〇.〇5. Found - wide [_ C L 51. 88 ; Η 5. 35 · μ 9. 95. LC/MS im/z) 342.2 (M + H+) ; + ^

% = 2· 08 分。1H (DMSO-i/e): 1.22 (t, 3H) ； 4.08 (q 9u、 f 、q’ 2H) ; 4. 53 (s， ;6·81 (dd, 1H) ; 6.93 (d，1H) ; 7 i9 (d ih)&quot;% = 2·08 points. 1H (DMSO-i/e): 1.22 (t, 3H); 4.08 (q 9u, f, q' 2H); 4. 53 (s, ;6·81 (dd, 1H); 6.93 (d, 1H) ; 7 i9 (d ih)&quot;

On，2H); 7.70 (s，1H); 7.98 (m，2h); 8 97 (b = NH). 1Hj 實施例2 甲基-噻吩、2 2a (2-胺基-4-{[4-(4-氣-苯續酿基 基曱基]-胺基h苯基）-胺基甲酸乙曄。 81 1325414 在I下，使4-(4-氯-笨磺醯基）_3_曱基_噻吩_2_甲醛 (301毫克，l.oo毫莫耳）與（4胺基_2_硝基苯基）_胺基 甲酸乙酯（293毫克’ UO毫莫耳）於無水乙醇（10毫升 )中之懸斤液在回流下加熱2〇小時。冷卻之後，所形成 之板色至紅色固體亞胺藉過濾收集及真空乾燥，得到粗產 物（312毫克，61%)’將其懸浮於甲醇：醋酸1〇:1(1〇 毫升）中。添加NaBH3CN (0.19克，3 〇毫莫耳），並於室 溫下將混合物授拌丨+時，然後添加另_❾NaBH3CN ( 克3. 0毫莫耳），在另1小時之後，添加飽和碳酸 氯納水溶液（20毫升），將所形成之紅色固體亞胺藉過濾 收集及真空乾燥，得到粗產物（293毫克，94% )，將其 懸汁於無水乙醇（i〇毫升）中。對此加入6 n hci ( 1. 1 毫升，6. 6毫莫耳）和鐵粉（193毫克，3. 46毫莫耳）’ 並將此紅色混合物加熱到6〇 〇c ，直到紅色褪色成黃色， 大約10-20分鐘。將混合物倒入飽和碳酸氫鈉水溶液（5〇 毫升）和EtOAc ( 50毫升）中，將所得混合物過濾，使 相分離，並將水相進一步用Et〇Ac ( 2 χ 5〇毫升）萃取。 將合併的有機相乾燥（Na2S〇4 )並在真空中蒸發溶劑。產 物係經由在FlashMaster系統中使用庚烷/醋酸乙酯作為沖 提液（線性梯度沖提，通常從8 : 2至1 : 1 )在矽凝膠上 層析而純化。收集含產物之沖提分並在真空t蒸發而得到 標題化合物，為淺黃色固體（213毫克，78% ) 。LC-MS: {m/z) = 480.1 (M+H+) ’ 對 C21H23C1N304S2 計算值： 480.0813，tR = 2.35 分，UV 純度=72.4%，ELS 純度== 82 1325414 86.5%。丨H NMR (MSO-i/6): i.19 (b，3 H)，2 16 (s，3 Η), 4.02 (q, /= 6.9 Hz, 2 H), 4.23 (d, / = 6. 1 Hz, 2 H), 4.57 (s, 2 H), 5.81 (dd&gt; j = 2.4, 8.5 Hz, 1 H), 5.91-5.95 (m, 2 H)，6.72 (寬 d, J = 6.6 Hz, 1 H), 7.72 (d, /= 8.5 Hz, 2 H), 7.90 (d, / = 8. 5 Hz, 2 H), 8.15 (b, 1H), 8.31 (s&gt; j R) 下列化合物係以類似方式製備： 2b {2_胺基-4-[(3-氣-噻吩-2_基甲基）_胺基]一苯基 胺基甲酸乙醋 產率：76%。LC-MS:(历/y = 326.0 (M + H+)，對 C14H17CIN3O2S s十算值.326.0725，tR = 1.95 分，UV 純度= 85.8%，ELS 純度=98.1%。4 NMR (DMSO-c/6): 1.19 (b， 3 Η), 4.03 (q, / = 7. 1 Hz, 2 H), 4.30 (d, / = 6. 1On, 2H); 7.70 (s, 1H); 7.98 (m, 2h); 8 97 (b = NH). 1Hj Example 2 Methyl-thiophene, 2 2a (2-amino-4-{[4- (4-Gas-Benzene fluorenyl fluorenyl)-amino hphenyl)-carbamic acid acetonitrile. 81 1325414 Under 4-, 4-(4-chloro- oxasulfonyl)_3_fluorenyl _Thiophene-2-formaldehyde (301 mg, l.oo mmol) and ethyl (4amino-2-nitrophenyl)-carbamate (293 mg 'UO mmol) in absolute ethanol (10 The suspension in liters was heated under reflux for 2 hrs. After cooling, the resulting color of the plated to red solid imamine was collected by filtration and dried in vacuo to afford crude product (312 mg, 61%). Methanol: Acetic acid 1 〇: 1 (1 〇 ml). Add NaBH3CN (0.19 g, 3 〇 millimolar), and mix the mixture at room temperature for 丨+, then add another ❾NaBH3CN (g 3. 0) After a further one hour, a saturated aqueous solution of sodium bicarbonate (20 mL) was added, and the red solid imamine formed was collected by filtration and dried in vacuo to give crude product (293 mg, 94%). Suspended in absolute ethanol (i〇ml). Add 6 to this n hci ( 1. 1 ml, 6.6 mmol) and iron powder (193 mg, 3.46 mmol)' and heat this red mixture to 6〇〇c until the red color fades to yellow, about 10 The mixture was poured into a saturated aqueous solution of sodium bicarbonate (5 mL) and EtOAc (50 mL). The combined organic phase is dried (Na2S〇4) and the solvent is evaporated in vacuo. The product is eluted with heptane/ethyl acetate as a solvent in a FlashMaster system (linear gradient elution, usually from 8:2) Purification by chromatography on a hydrazine gel. EtOAc (EtOAc): /z) = 480.1 (M+H+) ' Calculated for C21H23C1N304S2: 480.0813, tR = 2.35 min, UV purity = 72.4%, ELS purity == 82 1325414 86.5%.丨H NMR (MSO-i/6): i.19 (b,3 H),2 16 (s,3 Η), 4.02 (q, /= 6.9 Hz, 2 H), 4.23 (d, / = 6 1 Hz, 2 H), 4.57 (s, 2 H), 5.81 (dd&gt; j = 2.4, 8.5 Hz, 1 H), 5.91-5.95 (m, 2 H), 6.72 (width d, J = 6.6 Hz , 1 H), 7.72 (d, /= 8.5 Hz, 2 H), 7.90 (d, / = 8. 5 Hz, 2 H), 8.15 (b, 1H), 8.31 (s&gt; j R) Prepared in a similar manner: 2b {2_Amino-4-[(3-carbo-thiophen-2-ylmethyl)-amino]-phenylaminocarbamic acid ethyl acetate Yield: 76%. LC-MS: (L/y = 326.0 (M + H+), calculated for C14H17CIN3O2S s. 326.0725, tR = 1.95 min, UV purity = 85.8%, ELS purity = 98.1%. 4 NMR (DMSO-c/6 ): 1.19 (b, 3 Η), 4.03 (q, / = 7. 1 Hz, 2 H), 4.30 (d, / = 6. 1

Hz, 2 H), 4.57 (s, 2 H), 5.83 (dd, / = 2. 4, 8.5 Hz, 1 H), 5.93-5.97 (m，2 H)，6.73 (寬 d, /= 7.1 Hz, 1 H), 6.99 (d, / = 5.2 Hz, 1 H), 7.48 (d, / = 5. 2 Hz, 1 H), 8. 16 (b, 1 H). 2c {2-胺基-4_[ (4-溴-3-曱氧基-噻吩-2-基甲基）-胺 基]-苯基}-胺基曱酸乙酯。 產率：66%。LC-MS: = 402.0 (M+H+) ’ 對 C15H19BrN303S 計算值：400.0325 (100 % )，402.0310 (97.3%)，tR = 1.97 分 ’ UV 純度=87.9%’ ELS 純度= 98.2%。1 NMR (DMSO-A): 1.20 (b，3 H)，3.83 (s，3 83 1325414 Η), 4.03 (q, /= 6.9 Hz, 2 Η), 4.32 (d, / = 6. 1 Hz, 2 H), 4.58 (s, 2 H), 5.84-5.89 (m, 2 H), 5.97 (d, J =2.4 Hz, 1 H), 6.74 (b, 1 H), 7.46 (s, 1 H), 8.17 (b, 1 H). 2d {2-胺基-4-[ (6-氯-3-曱氧基-苯并[b]噻吩-2-基甲 基）-胺基]-苯基}-胺基曱酸乙酯。 產率：60%。LC-MS: U/z) = 405.3 (M+H+)，對 C19H21C1N303S 計算值：406.0987，tR = 2.39 分，UV 純度= 95.0%，ELS 純度=99.6%。4 NMR (DMS〇-i/6): 1.19 (b， 3 Η), 3.95 (s, 3 Η), 4.02 (q, / = 7. 1 Hz, 2 H), 4.43 (d, / = 6. 1 Hz, 2 H), 4.56 (s, 2 H), 5.90 (dd, J = 2.4, 8.5 Hz, 1 H), 5.96 (t, J = 5.9 Hz, 1 H), 6· 00 (d, / = 2. 8 Hz，1 H), 6· 73 (寬 d, / = 6· 6 Hz, 1 H), 7.39 (dd, J = 1.9, 8.5 Hz, 1 H), 7.68 (d, J = 8.5 Hz, 1 H), 7.98 (d, /= 1.9 Hz, 1 H), 8.15 (b, 1 H). 2e {2-胺基-4-[(5-二曱基-胺基-苯并[b]噻吩-3-基曱 基胺基]-苯基胺基甲酸乙酯。 產率：13%。LC-MS: U/W = 385.0 (M+H+)，對 C20H25N4O2S 計算值：385.1693，tR = 1.29 分，UV 純度= 87.8%，ELS 純度=93.5%。】H NMR (DMSO-A): 1.19 (b， 3 H)， 2.94 (s， 6 H)， 4.02 (q, / = 6.9 Hz, 2 H)， 4.34 (d, J = 5.7 Hz, 2 H), 4.53 (s, 2 H), 5.81 (t, / = 5.9 Hz, 1 H), 5.93 (dd, / = 2. 4, 8.5 Hz, 1 H), 84 1325414 6.03 (d, /= 2.4 Hz, 1 H), 6.72 (b, 1 H), 6.95 (dd, / = 2.4， 9.0 Hz， 1 H)’ 7.08 (d， / = 2.4 Hz， 1 H), 7.38 (s， i H)， 7.71 (d， 8.5 Hz’ 1 H)， 8.15 (b， 1 H). 2f {2-胺基-4_[(5-二甲基-胺基-3-甲基-苯并[b]瞳吩 基甲基）-胺基]-苯基卜胺基甲酸乙酯。 產率：36%。LC-MS:(历/W = 399.2 (M+H+)，對 C21H27N4〇2S 計算值：399.1849，tR = 1.31 分，UV 純度= 98. 4%，ELS 純度=99. 4%。卬 NMR (DMSO-A): 1. 19 (b, · 3 Η), 2.33 (s, 3 Η), 2.93 (s, 6 Η), 4.02 (q, j = 6·9 Hz, 2 Η), 4.37 (d, / = 5. 7 Hz, 2 H), 4.54 (s, 2 5.86 (dd, / = 2.4, 8.5 Hz, 1 H), 5.89 (t, / = 6.6 Hz，1 H)，5.96 (d，/ 二 2·4 Hz，1 H), 6.71 (b, 1 H), 6.84-6.89 (m, 2 H), 7.58 (d, / = 8. 5 Hz, 1 H), 8- 16 (b, 1 H).Hz, 2 H), 4.57 (s, 2 H), 5.83 (dd, / = 2. 4, 8.5 Hz, 1 H), 5.93-5.97 (m, 2 H), 6.73 (width d, /= 7.1 Hz , 1 H), 6.99 (d, / = 5.2 Hz, 1 H), 7.48 (d, / = 5. 2 Hz, 1 H), 8. 16 (b, 1 H). 2c {2-Amino- 4-[(4-Bromo-3-indolyl-thiophen-2-ylmethyl)-amino]-phenyl}-amino decanoic acid ethyl ester. Yield: 66%. LC-MS: = 402.0 (M+H+). calcd. for C15H19BrN303S: 400.0325 (100%), 402.0310 (97.3%), tR = 1.97 min 'UV purity=87.9%' ELS purity = 98.2%. 1 NMR (DMSO-A): 1.20 (b,3 H), 3.83 (s,3 83 1325414 Η), 4.03 (q, /= 6.9 Hz, 2 Η), 4.32 (d, / = 6. 1 Hz, 2 H), 4.58 (s, 2 H), 5.84-5.89 (m, 2 H), 5.97 (d, J = 2.4 Hz, 1 H), 6.74 (b, 1 H), 7.46 (s, 1 H) , 8.17 (b, 1 H). 2d {2-Amino-4-[(6-chloro-3-indolyl-benzo[b]thiophen-2-ylmethyl)-amino]-phenyl }-Aminoethyl decanoate. Yield: 60%. LC-MS: U/z) = 405.3 (M+H+). Calculated for C19H21C1N303S: 406.0987, tR = 2.39, UV purity = 95.0%, ELS purity = 99.6%. 4 NMR (DMS〇-i/6): 1.19 (b, 3 Η), 3.95 (s, 3 Η), 4.02 (q, / = 7. 1 Hz, 2 H), 4.43 (d, / = 6. 1 Hz, 2 H), 4.56 (s, 2 H), 5.90 (dd, J = 2.4, 8.5 Hz, 1 H), 5.96 (t, J = 5.9 Hz, 1 H), 6· 00 (d, / = 2. 8 Hz, 1 H), 6· 73 (width d, / = 6· 6 Hz, 1 H), 7.39 (dd, J = 1.9, 8.5 Hz, 1 H), 7.68 (d, J = 8.5 Hz, 1 H), 7.98 (d, /= 1.9 Hz, 1 H), 8.15 (b, 1 H). 2e {2-Amino-4-[(5-diamidino-amino-benzo[ b] Ethyl thiophen-3-ylhydrazinylamino]-phenylcarbamate. Yield: 13%. LC-MS: U/W = 385.0 (M+H+), for C20H25N4O2S Calculated: 385.1693, tR = 1.29 min, UV purity = 87.8%, ELS purity = 93.5%. H NMR (DMSO-A): 1.19 (b, 3 H), 2.94 (s, 6 H), 4.02 (q, / = 6.9 Hz, 2 H), 4.34 (d, J = 5.7 Hz, 2 H), 4.53 (s, 2 H), 5.81 (t, / = 5.9 Hz, 1 H), 5.93 (dd, / = 2. 4, 8.5 Hz , 1 H), 84 1325414 6.03 (d, /= 2.4 Hz, 1 H), 6.72 (b, 1 H), 6.95 (dd, / = 2.4, 9.0 Hz, 1 H)' 7.08 (d, / = 2.4 Hz, 1 H), 7.38 (s, i H), 7.71 (d, 8.5 Hz' 1 H), 8.15 (b, 1 H). 2f {2-Amino-4_[(5-dimethyl-amine) base- Ethyl 3-methyl-benzo[b]nonenylmethyl)-amino]-phenyl-p-propylcarbamate. Yield: 36%. LC-MS: (L/W = 399.2 (M+H+) , calculated for C21H27N4〇2S: 399.1849, tR = 1.31 min, UV purity = 98. 4%, ELS purity = 99. 4%. NMR (DMSO-A): 1. 19 (b, · 3 Η) , 2.33 (s, 3 Η), 2.93 (s, 6 Η), 4.02 (q, j = 6·9 Hz, 2 Η), 4.37 (d, / = 5. 7 Hz, 2 H), 4.54 (s , 2 5.86 (dd, / = 2.4, 8.5 Hz, 1 H), 5.89 (t, / = 6.6 Hz, 1 H), 5.96 (d, / 2·4 Hz, 1 H), 6.71 (b, 1 H), 6.84-6.89 (m, 2 H), 7.58 (d, / = 8. 5 Hz, 1 H), 8- 16 (b, 1 H).

實施例3 3a {2-胺基-4-[(5-曱基-噻吩_2-基甲基）-(甲基）_胺 基]-苯基}-胺基甲酸乙酯β 在Ar下，使5-曱基-2-_吩甲醛（1〇8微升，1. 〇〇毫 莫耳）、（4-胺基-2-硝基-苯基）-胺基甲酸乙酯（225毫克 ，1. 〇〇 毫莫耳）和 Amberlite IRC_84 ( 1〇 毫克）於鄰二 甲苯（4毫升）中之混合物於回流下加熱5小時。藉由在 真空中蒸發除去揮發物，然後將殘餘物溶於乙腈（5毫升 85 1325414 )中。在所得溶液中加人NaBH3CN(〇 25克，4 〇毫莫耳） 接著力入HOAc ( 5滴）。在授拌5分鐘之後，溶液變成 深紅色。添加甲駿（37%之水溶液，〇 89毫升，12毫莫耳 )，並繼續授拌30分鐘，並偶爾添加舰c。在真空中將 反應混合物蒸發至乾燥，㈣將殘餘物分配於飽和碳酸氣 鈉水溶液（5G毫升）和讓e(5Q毫升）之間。肖E敝 (50毫升）萃取水相’㈣將合併的有機層乾燥（⑻叫 )並在真空中》發溶劑。㉟後將殘餘物溶於乙醇（ι〇毫升 )中。加人6 N HC1水溶液（2.〇毫升，12毫莫耳）和鐵 粕（〇· 34克，6. 0毫莫耳），並將此紅色混合物於6〇 〇c 加熱直到紅色褪色成黃色，大約15 /分鐘。將混合物倒入 飽和碳酸氫鈉水溶液（50毫升）和Et0Ac (5〇毫升）中 ，將所得混合物過濾，使相分離，並將水相進一步用 EtOAc (2 X 50毫升）萃取。將合併的有機層乾燥（¥〇4 )並在真空中蒸發溶劑。產物係經由在FlashMaster系統 中使用庚烷/醋酸乙酯作為沖提液（線性梯度沖提，通常 k 8 . 2至1 . 1 )在矽凝膠上層析而純化❶收集含產物之 沖提分並在真空中蒸發而得到標題化合物，為淺黃色固體 (145 毫克，45% 總率）。LC-MS: = 319. 9 (M+H+) ，對 C16H22N302S 計算值：320.1427，tR = 1.80 分，UV 純 度=98.4%，ELS 純度=97.2%。4 NMR (CDC13): 1.29Example 3 3a {2-Amino-4-[(5-fluorenyl-thiophen-2-ylmethyl)-(methyl)-amino]-phenyl}-carbamic acid ethyl ester β under Ar To give 5-mercapto-2-formaldehyde (1 〇 8 μl, 1. 〇〇 millimol), (4-amino-2-nitro-phenyl)-carbamic acid ethyl ester (225 A mixture of milligrams, 1. 〇〇 mM) and Amberlite IRC_84 (1 mM) in o-xylene (4 mL) was heated under reflux for 5 hours. The volatiles were removed by evaporation in vacuo thenqqqqqqqqqq To the resulting solution was added NaBH3CN (〇 25 g, 4 〇 mmol) followed by HOAc (5 drops). After 5 minutes of mixing, the solution turned dark red. Add a jun (37% aqueous solution, 〇 89 ml, 12 mM) and continue to mix for 30 minutes and occasionally add ship c. The reaction mixture was evaporated to dryness <RTI ID=0.0> Xiao E敝 (50 ml) was extracted from the aqueous phase. (d) The combined organic layers were dried ((8) called) and the solvent was evaporated in vacuo. After 35, the residue was dissolved in ethanol (m.sub.1 mL). Add 6 N HCl solution (2 〇 ml, 12 mmol) and iron 粕 (〇 · 34 g, 6.0 mmol), and heat the red mixture at 6 °c until the red color fades to yellow , about 15 / minute. The mixture was poured into EtOAc (2×50 mL). The combined organic layers were dried (¥4) and evaporated in vacuo. The product was purified by chromatography on a hydrazine gel using heptane/ethyl acetate as a solvent (linear gradient elution, usually k 8.2 to 1.1) in the FlashMaster system. The title compound was obtained as a pale yellow solid (145 mg, 45%). LC-MS: = 319. 9 (M+H+). Calculated for C16H22N302S: 320.1427, tR = 1.80 min, UV purity = 98.4%, ELS purity = 97.2%. 4 NMR (CDC13): 1.29

Ct, / = 7. 1, 3 Η), 2.41 (S, 3 Η), 2.91 (s, 3 Η), 3.76 (b, 2 Η), 4.19 (q, / = 7. 1 Hz, 2 H), 4.52 (s, 2 H), 6.02 (b, 1 H), 6.17 (d, / = 2. 8 Hz, 1 H), 86Ct, / = 7. 1, 3 Η), 2.41 (S, 3 Η), 2.91 (s, 3 Η), 3.76 (b, 2 Η), 4.19 (q, / = 7. 1 Hz, 2 H) , 4.52 (s, 2 H), 6.02 (b, 1 H), 6.17 (d, / = 2. 8 Hz, 1 H), 86

6· 25 (dd, J6· 25 (dd, J

1 H).1 H).

Hz, 1 H), 6.53-6.58 (m, 1 1 H), 6. 98 (d, / = 8. 5 Hz, 方式製備： 一氣吩-2-基甲基）-(甲基胺基 下化合物係以類似 3b {2-胺基 _4_[(5 ]-苯基}-胺基甲酸乙酯 ;34 %。LC-MS:(历/2^ = 340. 0 (M+H+)，對 C15H19CIN3O2S 計算偵· τ 异值· 340.0881，tR = 2·14 分，UV 純度= 8 2 ’ 3 % ’ E L S 純彦=；q 〇 9 〇/ l r 一 $度 90·2%。^ NMR (CDC13): 1.29 (t， =6·8&gt; 3 H), 2.91 (s, 3 H), 3. 78 (b, 2 H), 4.20 (q, J 1Λ HZ， 2 H), 4·49 (s, 2 H), 6.05 (b, 1 H), 6.16 (d, / = 2.4 Hz, 1 H), 6.24 (dd, / = 2.4, 8.5Hz, 1 H), 6.53-6.58 (m, 1 1 H), 6. 98 (d, / = 8. 5 Hz, Preparation by way: mono-phen-2-ylmethyl)-(methylamine-based compound Is similar to 3b {2-amino-4-[(5]-phenyl}-carbamic acid ethyl ester; 34%. LC-MS: (calendar/2^ = 340. 0 (M+H+), for C15H19CIN3O2S Calculate the τ · τ value · 340.0881, tR = 2 · 14 points, UV purity = 8 2 ' 3 % ' ELS pure Yan =; q 〇 9 〇 / lr a $ degree 90 · 2%. ^ NMR (CDC13): 1.29 (t, =6·8&gt; 3 H), 2.91 (s, 3 H), 3. 78 (b, 2 H), 4.20 (q, J 1Λ HZ, 2 H), 4·49 (s, 2 H ), 6.05 (b, 1 H), 6.16 (d, / = 2.4 Hz, 1 H), 6.24 (dd, / = 2.4, 8.5

Hz, 1 H), 6.73 (d, / = 3.8 Hz, 1 H), 6.99 (d, J = 8. 5 Hz, 1 H). 下列化合物係以類似方式製備，但將〒路換成乙路： 3c {2-胺基-4~[(5_氣-噻吩-2-基甲基）-(乙基）-胺基 ]-本基}-胺基甲酸乙黯。 產率.12%。LC-MS: 〇/y = 353.9 (M+H+)，對 Ci6H2iClN302S 計舁值：354. 1038，tR = 2. 02 分，UV 純度= 97·5%，ELS 純度=99.0%。4 NMR (CDC13): 1.16 (t，/ =7.1, 3 Η), 1.29 (t, J = 6.8, 3 H), 3.36 (q, J = 7. 1 Hz, 2 H), 3. 76 (b, 2 H), 4. 19 (q, / = 7. 2 Hz, 2 87 1325414 Η)， 4· 47 (s， 2 Η) 〇 nr ,, ，6. 05 (b，1 η)，6. 13 (d，·/ = 2.4 1 Η), 6. 19 (dd τ = &lt;? a η 5 7 - 2.4, 9. Ο Hz, 1 Η), 6. 73 (d, 3.8ΗΖ，&quot;)，“6U，“8.0Ηζ，1Η). 下列化合物係以類似方式製備，但省略曱醛添加： 3d {2-胺基~4~[(5-患—峨\ η从 敗暖吩-2-基甲基）-胺基]一苯基卜 知基曱酸乙龜 產率.65% (在贺借 製備LC-MS純化以除去未氟化副產物 之後為 25 % ) 。LC-MS. 「/ 、 L MS.(历= 31〇 2 (M+H+)，對 c14h17fn3〇2S 計算值：3101〇2〇, tR=i 76 分，uv 純度= =.6%，ELS 純度=83.4%β1Η 麵⑽cl3) 129(b, 3 ，3.82(b，2Η)，4·19(1 / q.2HZ，2H)，4.31Hz, 1 H), 6.73 (d, / = 3.8 Hz, 1 H), 6.99 (d, J = 8. 5 Hz, 1 H). The following compounds were prepared in a similar manner, but the road was replaced by the road : 3c {2-Amino-4~[(5-gas-thiophen-2-ylmethyl)-(ethyl)-amino]-benyl}-carbamic acid acetamidine. Yield 12.12%. LC-MS: 〇/y = 353.9 (M+H+), for Ci6H2iClN302S: 354. 1038, tR = 2.02 min, UV purity = 97.5%, ELS purity = 99.0%. 4 NMR (CDC13): 1.16 (t, / =7.1, 3 Η), 1.29 (t, J = 6.8, 3 H), 3.36 (q, J = 7. 1 Hz, 2 H), 3. 76 (b , 2 H), 4. 19 (q, / = 7. 2 Hz, 2 87 1325414 Η), 4· 47 (s, 2 Η) 〇nr ,, , 6. 05 (b,1 η), 6. 13 (d,·/ = 2.4 1 Η), 6. 19 (dd τ = &lt;? a η 5 7 - 2.4, 9. Ο Hz, 1 Η), 6. 73 (d, 3.8 ΗΖ, &quot;) , "6U, "8.0Ηζ, 1Η). The following compounds were prepared in a similar manner, but the addition of furfural was omitted: 3d {2-amino-~~~~~~~~~~~~~~ The yield of methyl-)-amino]-phenyl-b-butanoic acid toluene was 6.5% (25% after purification by LC-MS to remove unfluorinated by-products). LC-MS. "/, L MS. (calendar = 31〇2 (M+H+), calculated for c14h17fn3〇2S: 3101〇2〇, tR=i 76 points, uv purity ==.6%, ELS purity =83.4%β1Η face (10)cl3) 129(b, 3,3.82(b,2Η),4·19(1 / q.2HZ,2H), 4.31

Cd, /= 2.0 Hz, 2 H), 6.05 (b, 1 H)&gt; β&gt; 〇g (d&gt; y = 8.0 Hz, 1 H), 6.29 (dd 7 - 1 , 〇 〇 VQQ&gt; J ~ 1.5, 3.8 Hz, 1 H), 6.58 (t，/= 3.5 Hz，i H)，6·94 (d，/= u Hz,丨 h). 實施例4 2-基甲基）一胺基]-苯基} 4a {2-胺基-4-[(5-氣-噻吩— 胺基曱酸乙g旨。 將5-氯噻吩-2-曱醛溶液（24〇微升，iu微莫耳， 463 mM於1，2_二氣乙炫中）加到4_胺基_2_硝基苯基胺基 甲酸乙酿溶液（ 240微升，lu微莫耳，463 mM於12一二 氯乙烷）中。添加三乙醯氧基硼氫化鈉（118毫克，555微 莫耳），錢於4G °C將所得混合物_ 35小時。使混 88 °物冷部到周圍溫度，然後添加水（100微升）。使混合 物經石夕凝膠（500毫克）過攄制12二氯乙烧（3毫升 )沖洗管柱。在真空中將合併的有機相蒸發至乾燥。將所 得固體溶於乙醇（3毫升）中。將鐵（19毫克）加到三分 之的所知洛液（1毫升）巾，接著添加氫氯酸水溶液（ 96微升，6M ) ^將所得混合物置於超聲波浴中丨〇分鐘❹ 然後，添加飽和碳酸氫鈉水溶液（2毫升）。用醋酸乙酯 (3毫升）萃取混合物。將有機相用水（3毫升）和食鹽 水（3毫升）洗滌，經硫酸鎂乾燥，過濾及在真空中蒸發 =乾燥。將所得產物溶於19〇微升二甲亞硼中，並進行 製備Lnm所得溶液在真空中蒸發至乾燥。產率 .(6. 8 毫克，56 % ) 。LC-MS 6z7/&gt;J (M + H)+ 326. 1 RT=1· 90 (UV，ELSD) 92%，99%。 下列化合物係以類似方式製備： 4b {2-胺基-4-[(5-溴-噻吩_2_基甲基胺基卜苯基卜 胺基甲酸乙酯。 LC-MS (ib/z) (M+H)+371.9 RT=l. 94 (UV, ELSD) 89% ，98%。 4〇{2-胺基-4-[(4-溴_瞳吩-2_基甲基）_胺基卜苯基卜 胺基甲酸乙酯。 LC-MS (π,/ζ) (M+H)+ 372.0 RT=i. 96 (UV, ELSD) 76% ，100% 〇 4d (2-胺基-4-[(5-乙基-噻吩_2_基甲基）_胺基]-笨基 89 1325414 }-胺基甲酸乙醋。 LC-MS (m/z) (M+H)+ 320.1 RT=1.90 (UV, ELSD) 72% ，96%。 4e {2-胺基-4-[(苯并[b]噻吩-2-基甲基）-胺基]-苯基 卜胺基甲酸乙酯。 LC-MS (m/z) (M+H)+ 342.1 RT=2. 06 (UV, ELSD) 75% ，100%。 4f {2-胺基-4-[ (5-苯基-噻吩-2-基曱基）-胺基]-苯基 }-胺基甲酸乙酯。 LC-MS (m/z) (M+H)+ 368. 2 RT=2. 21 (UV, ELSD) 90% ，99%。 實施例5 5a丨2_胺基-4-[(苯并[b：j噻吩_2_基f基）_胺基]一笨基 }~胺基甲酸丙醋 將苯并[办]噻吩-2-甲醛（克，8 38毫莫耳）加到 (4-胺基-2-硝基-苯基）-胺基曱酸丙酯（2 〇〇克，8祁毫 莫耳）於乙腈（10毫升）之溶液中。在2〇毫升密封微波 處理管瓶中將混合物加熱到160。〇：維持2分鐘。冷卻時， 添加NaBH3CN(1.06克，16.7毫莫耳）和Ac〇h(48微升， U4毫莫耳），然後於25 %將混合物搜拌3〇分鐘。添 加水/食鹽水（1:丨，100毫升）’然後用醋酸乙醋（3χ 毫升）萃取混σ物。將有機相經硫酸鎂乾燥，過濾及 在真空中濃縮。使粗製中間物經由在矽凝膠上之急驟層析 1325414 (冲提劑.醋酸乙酯：庚烷1: 9 )純化，以及蒸發至乾燥 。然後將此中間物溶於四氫呋喃（2〇毫升）中，並添加溶 於水（50毫升）之Na2S204 ( 3. 67克，21毫莫耳）。在氬 氣下使所得混合物於40°C下攪拌5小時。將所得混合物 用醋酸乙酯（3x 100毫升）萃取，將合併的有機相經硫酸 鎂乾燥，過濾及在真空中濃縮。經由急驟層析（沖提劑： 醋酸乙酯：庚烷1 : 1)純化，製得〇· 3克（丨〇% )標題化 合物’為固體。LC/MS (/s/z) 356 ([M+H] + ) ; RT = 2· 45 分 。4 _ (CDC13): 0.95 (t, 3H) ; 1.67 (m, 2H) ; 4.08 (t, 2H) ； 4.55 (s, 2H) ； 6.08 (d, 1H) ； 6.13 (dd, 1H) ;6.93 (d，1H) ; 7.20 (s，1H) ; 7.27 (dt, 1H) ; 7.32 (dt, 1H) ； 7.68 (d, 1H) ； 7.77 (d, 1H). 下列化合物係以類似方式製備： 5b {2-胺基-4_[(苯并[b]噻吩-3-基甲基胺基]-苯基 }-胺基甲酸丙酯。 產率：16% » LC/MS 〇々）356 ([M+H] + ) ; RT = 2.24 分。1H NMR (CDC13): 〇. 96 (t, 3H) ; 1. 68 (m，2H) ; 4,10 (t, 2H) ； 4.51 (s, 2H) ； 6.12 (d, 1H) ； 6.14 (dd, 1H) ；6.95 (d, 1H) ； 7.36 (s, 1H) ； 7.39 (dt, 1H) ； 7.40 (dt, 1H) ； 7.79 (dd, 1H) ； 7.87 (dd, 1H). 實施例6 6a N-丨2-胺基-4~[(5_氣晴吩-2-基甲基）胺基]苯基h 91 1325414 氟苯基）-乙醯胺。 在N-{ 4-[(5-氯噻吩-2-基曱基）胺基]_2-硝基苯基卜 2-(4-氟苯基）乙醯胺（320毫克，〇.762毫莫耳）於四氫呋 喃（25毫升）與醋酸（8毫升）中之經攪拌紅色溶液_ ’將鋅粉（粒子大小&lt;10微米，10克）分成幾份在3〇分鐘 期間週期性地加入。5分鐘之後溶液變成無色。將所得無 色懸浮液經由S1 〇2 ( 1 〇克）塞子過濾，以醋酸乙酯作為沖 提液’然後使所得溶液在真空中蒸發。將所得固體溶於醋 酸乙酯/丙酮/三氟醋酸（3毫升/3毫升/〇 2毫升）混合物 中，用飽和NaHC〇3水溶液（50毫升）和庚烷（30毫升） 處理，然後藉過濾分離產物，製得28〇毫克淺灰色固體。 產率：94. 2%。LC/MS (m/z) 390. 4 ([M+H] + ) ; RT = 2. 26 (UV, ELSD) 99%，100%。NMR (DMSO-d6): 3.56 (s， 2H) ; 4.28 (d，2H) ; 4.57 (s，2H，NH2) ; 5.87 (dd, 1H) ’ 5.98 (m，2H，NH 和芳族 H) ; 6.74 (d, 1H) ; 6.86 (d， 1H)，6.93 (d，1H) ; 7.13 (t，2H) ; 7.35 (dd，2H); 9. 10 (s, 1H). 下列化合物係以類似方式從對應的硝基化合物製備： 6b N-{2-胺基_4-[(5-氣噻吩-2-基甲基）胺基]苯基卜 3, 3-二甲基丁醯胺。Cd, /= 2.0 Hz, 2 H), 6.05 (b, 1 H)&gt;β&gt; 〇g (d&gt; y = 8.0 Hz, 1 H), 6.29 (dd 7 - 1 , 〇〇VQQ> J ~ 1.5 , 3.8 Hz, 1 H), 6.58 (t, /= 3.5 Hz, i H), 6·94 (d, / = u Hz, 丨h). Example 4 2-Methylmethyl)monoamine]- Phenyl} 4a {2-amino-4-[(5-gas-thiophene-amino decanoic acid). 5-chlorothiophene-2-furaldehyde solution (24 〇 microliter, iu micromolar, 463 mM in 1,2_dioxetane) was added to a solution of 4-amino-2-nitrophenylaminocarbamate (240 μl, lu micromolar, 463 mM in 12-dichloroethane) In alkane), sodium triethoxysulfonate (118 mg, 555 micromolar) was added, and the resulting mixture was _35 hours at 4 ° C. The mixture was allowed to cool to an ambient temperature, then water was added ( 100 μl). The mixture was rinsed through a solution of 12 g of dichloroethene (3 ml) over a solution of stellite (500 mg). The combined organic phases were evaporated to dryness in vacuo. (3 ml). Add iron (19 mg) to a third of the known Lok (1 ml) towel, then add aqueous hydrochloric acid (96 μL, 6 M) ^ The mixture was placed in an ultrasonic bath for a few minutes and then aq. EtOAc (EtOAc) (EtOAc) Drying over magnesium sulfate, filtration and evaporation in vacuo = dryness. The obtained product was dissolved in 19 s of microliters of dimethyl boron, and the solution obtained by the preparation of Lnm was evaporated to dryness in vacuo. Mg, 56%). LC-MS 6z7/&gt;J (M + H)+ 326. 1 RT=1· 90 (UV, ELSD) 92%, 99% The following compounds were prepared in a similar manner: 4b {2 -Amino-4-[(5-bromo-thiophene-2-ylmethylaminophenyl phenyl phenyl) carbamic acid ethyl ester. LC-MS (m/z) (M+H) +371.9 RT=l. 94 (UV, ELSD) 89%, 98%. 4〇{2-Amino-4-[(4-bromo-nonphen-2-ylmethyl)-aminophenylphenylaminocarbamate. LC-MS (π, /ζ) (M+H)+ 372.0 RT=i. 96 (UV, ELSD) 76%, 100% 〇4d (2-amino-4-[(5-ethyl-thiophene) 2_ylmethyl)-amino]-styl 89 1325414 }-amino acetate. LC-MS (m/z) (M+H) + 320.1 RT = 1.90 (UV, ELSD) 72%, 96%. 4e {2-Amino-4-[(benzo[b]thiophen-2-ylmethyl)-amino]-phenylethylaminocarbamate. LC-MS (m/z) (M+H) + 342.1 RT = 2. 06 (UV, ELSD) 75%, 100%. 4f {2-Amino-4-[(5-phenyl-thiophen-2-ylindenyl)-amino]-phenyl}-carbamic acid ethyl ester. LC-MS (m/z) (M+H)+ 368. 2 RT=2. 21 (UV, ELSD) 90%, 99%. Example 5 5a丨2_Amino-4-[(benzo[b:jthiophen-2-yl]yl)-amino]-styl}-amino propyl acetonate benzo[thiophene] 2-formaldehyde (g, 8 38 mmol) was added to (4-amino-2-nitro-phenyl)-amino decanoate (2 g, 8 mM) in acetonitrile ( 10 ml) of the solution. The mixture was heated to 160 in a 2 mL sealed microwave vial. 〇: Maintain for 2 minutes. Upon cooling, NaBH3CN (1.06 g, 16.7 mmol) and Ac〇h (48 μL, U4 mmol) were added, then the mixture was stirred at 25% for 3 min. Water/salt brine (1: 丨, 100 ml) was added, and then the mixture was extracted with ethyl acetate (3 ml). The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The crude intermediate was purified by flash chromatography 1325414 (eluent: ethyl acetate: heptane 1: 9) on hydrazine gel and evaporated to dryness. This intermediate was then dissolved in tetrahydrofuran (2 mL) and Na2S.sub.2 (3. 67 g, 21 mmol) dissolved in water (50 mL). The resulting mixture was stirred at 40 ° C for 5 hours under argon. The mixture was extracted with ethyl acetate (3×100 mL). Purification by flash chromatography (purification: ethyl acetate: heptane 1:1) afforded EtOAc (yield: LC/MS (/s/z) 356 ([M+H] + ); RT = 2 · 45 min. 4 _ (CDC13): 0.95 (t, 3H); 1.67 (m, 2H); 4.08 (t, 2H); 4.55 (s, 2H); 6.08 (d, 1H); 6.13 (dd, 1H); 6.93 ( d,1H); 7.20 (s,1H); 7.27 (dt, 1H); 7.32 (dt, 1H); 7.68 (d, 1H); 7.77 (d, 1H). The following compounds were prepared in a similar manner: 5b { 2-Amino-4_[(benzo[b]thiophen-3-ylmethylamino]-phenyl}-carbamic acid propyl ester. Yield: 16% » LC/MS 〇々) 356 ([M +H] + ) ; RT = 2.24 points. 1H NMR (CDC13): 〇. 96 (t, 3H); 1. 68 (m, 2H); 4,10 (t, 2H); 4.51 (s, 2H); 6.12 (d, 1H); 6.14 (dd , 1H); 6.95 (d, 1H); 7.36 (s, 1H); 7.39 (dt, 1H); 7.40 (dt, 1H); 7.79 (dd, 1H); 7.87 (dd, 1H). Example 6 6a N-丨2-amino-4~[(5-azain-2-ylmethyl)amino]phenyl h 91 1325414 fluorophenyl)-acetamide. N-{4-[(5-Chlorothiophen-2-ylindenyl)amino]_2-nitrophenyl-2-(4-fluorophenyl)acetamide (320 mg, 〇.762 mmol) The ear was stirred in a solution of tetrahydrofuran (25 ml) and acetic acid (8 ml). The zinc powder (particle size &lt; 10 μm, 10 g) was added in portions and periodically added during 3 minutes. The solution became colorless after 5 minutes. The resulting colorless suspension was filtered through a plug of EtOAc (EtOAc), ethyl acetate (eluent) and then evaporated. The obtained solid was dissolved in a mixture of ethyl acetate / EtOAc / EtOAc (EtOAc (EtOAc) The product was isolated to give 28 mg of light gray solid. Yield: 94.2%. LC/MS (m/z) 390. 4 ([M+H] + ); RT = 2. 26 (UV, ELSD) 99%, 100%. NMR (DMSO-d6): 3.56 (s, 2H); 4.28 (d, 2H); 4.57 (s, 2H, NH2); 5.87 (dd, 1H) ' 5.98 (m, 2H, NH and aromatic H); 6.74 (d, 1H); 6.86 (d, 1H), 6.93 (d, 1H); 7.13 (t, 2H); 7.35 (dd, 2H); 9. 10 (s, 1H). The following compounds are in a similar manner Prepared from the corresponding nitro compound: 6b N-{2-amino-4-[(5-athiophen-2-ylmethyl)amino]phenyl b 3,3-dimethylbutanamine.

在經過Si〇2過濾及蒸發之後’使產物從醋酸乙酯—飽 和NaHC〇3水溶液（5毫升/20毫升）與庚烷（5〇毫升）之 雙相溶液中沈澱出來。產率：580毫克，71. 5%。LC/MS 92 1325414 (m/z) 352·48 ([M+H]+);RT = 2.16 (UV，ELSD) 96% 99 %。4 m ⑽so-d6): m (s，9H)，2 n (s, 2H); 4.29 (d，2H); 4.54 (s，2H，NH2);5 88 ⑽，1H);5 97 (t’ 1H’ NH); 5·99 (d’ 1H); U2 (d，1H); 6 87 (d, 1H) ; 6. 93 (d，1H) ; 8. 82 (s，1H)· 活體外與活體内試驗 本發明之化合物已經在下列模式夕 .^ ^ ^ 供式之一或多者中受試並 顯示效果： 經過KCNQ2通道之相對外流。 在實驗前一天，將穩定表現電壓選通KCNQ2通道之細 胞接種並裝載[86Rb]。在實驗當天，用含HBS之緩衝液清 洗細胞。使細胞與藥物一起預培養，然後在藥物持續存在 下藉由次極限濃度之15 mM KC1來刺激[86Rb+]。在一段適 當的培養時間之後’將上清液取出並於液體閃煉計數器（ Tricarb)中計數。用2 mM NaOH將細胞溶解，並計算 86Rb+ 的量。計算相對外流（（CPMsu〇er/CPMsuper + CPMcelj)CBpd/ (CPMsuoer/CPMsuper+ CPMce 1 ])]5mj( kci)^1〇〇~10〇 〇 本發明之化合物具有小於20000nM之EC5q，在大部分 情況中係小於2000nM，且在許多情況中係小於200nM。因 此’本發明之化合物被認為可用來治療與KCNQ族鉀離子通 道有關的疾病。 93 1325414 最大電休克 本試驗係在幾組雄小鼠中進行，使用角臈電極並給予 26 mA之方波歷時〇.4秒，以便誘發特徵在於強直性後肢 伸展之驚厥（Wlaz et al. Aesearc》1998，30, 219-229)。 毛果芸香驗誘發之痛痛發作 毛果芸香鹼誘發之癲癇發作係藉由對幾組雄小鼠進行 腹膜内注射毛果芸香驗250毫克/公斤來誘發，並觀察在 30分鐘期間内造成姿勢缺失之癲癇發作活性（Starr· et al. Pharmacology Biochemistry and Behavior 1993, 45， 32卜325)。 電癲癇發作閾試驗 使用一種上下法（Up_and-d〇wn method )之改良（The product was precipitated from a two-phase solution of ethyl acetate-saturated aqueous solution of NaHC 3 (5 mL / 20 mL) and heptane (5 mL) after filtration and evaporation. Yield: 580 mg, 71.5%. LC/MS 92 1325414 (m/z) 352.48 ([M+H]+); RT = 2.16 (UV, ELSD) 96% 99 %. 4 m (10)so-d6): m (s,9H),2 n (s, 2H); 4.29 (d,2H); 4.54 (s,2H,NH2);5 88 (10),1H);5 97 (t' 1H' NH); 5·99 (d' 1H); U2 (d, 1H); 6 87 (d, 1H); 6. 93 (d, 1H); 8. 82 (s, 1H)· In Vivo Tests The compounds of the present invention have been tested in one or more of the following modes and show the effect: relative outflow through the KCNQ2 channel. One day before the experiment, cells stably stabilizing the voltage-gated KCNQ2 channel were inoculated and loaded [86Rb]. On the day of the experiment, the cells were washed with a buffer containing HBS. The cells were pre-incubated with the drug, and then [86Rb+] was stimulated by a submaximal concentration of 15 mM KC1 in the presence of the drug. The supernatant was removed after a suitable incubation time and counted in a liquid flash counter (Tricarb). The cells were lysed with 2 mM NaOH and the amount of 86Rb+ was calculated. Calculate the relative outflow ((CPMsu〇er/CPMsuper + CPMcelj)CBpd/(CPMsuoer/CPMsuper+ CPMce 1 ])]5mj( kci)^1〇〇~10〇〇 The compound of the present invention has EC5q less than 20,000 nM, in most cases The mesage is less than 2000 nM, and in many cases less than 200 nM. Thus the 'inventive compounds are considered to be useful in the treatment of diseases associated with the KCNQ family of potassium channels. 93 1325414 Maximum electroshock test is in several groups of male mice The keratin electrodes were used and a 26 mA square wave was given for 44 seconds to induce convulsions characterized by tonic hind limb extension (Wlaz et al. Aesearc 1998, 30, 219-229). The epileptic seizures induced by pilocarpine were induced by intraperitoneal injection of pilocarpine 250 mg/kg on several groups of male mice, and the seizure activity causing postural loss during 30 minutes was observed (Starr· Et al. Pharmacology Biochemistry and Behavior 1993, 45, 32 325). The electroconvulsive threshold test uses an improvement of the Up_and-d〇wn method (

Kimball et a.，fesearc/? 1957，1-12)來測 定在幾組雄小鼠中誘發回應角膜電休克之強直性後肢伸展 的中間閾值。使各組的第一隻小鼠接受14 mA之電休克（ 0. 4秒’ 5 0赫茲）並觀察癲癇發作活動性。如果觀察到痛 癇發作’則對下一隻小鼠將電流減少1 mA，然而，如果沒 有觀察到癲癇發作，則將電流增加1 mA。在治療組中對所 有的15隻小鼠重複此步驟。 化學癲癇發作閾試驗 94 1325414 誘發陣攣性驚厥所需之伸戊基四唑閾劑量，係藉由伸 戊基四唑（5毫克/毫升，以〇 5毫升/分）進入幾組雄小 鼠側尾靜脈之定時輸注來測量（Nutt et al y户加 户如/·彻1986，38，697-698)。 杏仁核激動 對大鼠進行手術以便將三極電極植入背外侧杏仁核。 手術之後，讓動物恢復，然後使這幾組大鼠接受不同劑量 的e式驗化合物或藥物載體。使這些動物每天經它們放電後 之初閾值+ 25 μΑ刺激，持續3_5週，並於每一次記錄放 電後之癲癇發作嚴重度、癲癇發作持續期間及電持續期間 。ί hcine. Electroencephalography and Clinical Neurophysiology 1972, 32, 281-294) 副作用 中柩神經系統副作用係藉由測量小鼠維持在旋轉裝置 上的時間來測量（Capaci0 et al.知叹a 1992, 15’ 177_201);或藉由利用計算在試 驗籠中交叉的紅外光束數目測量它們的活動能力來測量（ Watson et al. Neuropharmacology 1997^ 36&gt; 1369_1375 )。化合物對於動物核心體溫的低溫作用係、藉由直腸探針 或所植入能夠測量溫度之無線電遙發送器來測量（ et al. Physiology and Behaviour 2001, 74} 177-184) 95 1325414 藥物動力學 化合物之藥物動力學性質係經由對Spraque Daw ley大 鼠之靜脈和經口給劑做測定，之後，在20小時期間抽取 血液樣本。血漿濃度係用LC/MS/MS測定。Kimball et al., Fesearc/? 1957, 1-12) were used to determine the median threshold for inducing tonic hind limb extension in response to corneal electroshock in several groups of male mice. The first mouse of each group received an electric shock of 14 mA (0.4 seconds '50 Hz) and observed seizure activity. If a seizure is observed, the current is reduced by 1 mA for the next mouse, however, if seizures are not observed, the current is increased by 1 mA. This procedure was repeated for all 15 mice in the treatment group. Chemical seizure threshold test 94 1325414 The threshold dose of pentyltetrazole required to induce clonic convulsions was entered into the male mice by pentylenetetrazole (5 mg/ml, 〇5 ml/min) Timed infusion of the tail vein is measured (Nutt et al y households such as / 1986, 38, 697-698). Amygdaloid agonism The rats were operated to implant a tripolar electrode into the dorsolateral amygdala. After the surgery, the animals were allowed to recover and then the rats in each group received different doses of the e test compound or drug carrier. These animals were stimulated daily by their initial threshold + 25 μΑ for 3–5 weeks, and each episode of seizure severity, seizure duration, and duration of electrical discharge were recorded. ί hcine. Electroencephalography and Clinical Neurophysiology 1972, 32, 281-294) Side effects of sacral nervous system are measured by measuring the time the mouse is maintained on a rotating device (Capaci0 et al., a 1992, 15' 177_201) Or by measuring their activity capacity by calculating the number of infrared beams intersecting in the test cage (Watson et al. Neuropharmacology 1997^36&gt; 1369_1375). The low temperature effect of the compound on the core body temperature of the animal is measured by a rectal probe or by a radio teletransmitter capable of measuring temperature (et al. Physiology and Behaviour 2001, 74} 177-184) 95 1325414 Pharmacokinetic compound The pharmacokinetic properties were determined via intravenous and oral administration of Spraque Dawley rats, after which blood samples were taken over a 20 hour period. Plasma concentrations were determined by LC/MS/MS.

9696

Claims (1)

¥、申锖專利範面：刀9曰修(更Μ 種式I之1，2, 4-三胺基苯衍生 物¥,申锖专利范面:刀9曰修(更Μ1,2,4-triaminobenzene derivative of formula I 其中 )/係選自於氫、c-燒（烯/炔）基备環烧（稀 :（稀）基_Ci 6_燒（烯/炔）基、醞基、經 之群組6 ·烷（烯/炔）基及羥基~Ch，烷（烯）基所組成 ,係獨立地選自於氫、c_烧（烯，块）基、ο 炔;二烯）基、芳基、C3-8_環烷（烯）基-Ch-烷（烯/ ' X芳基H (稀/炔）基、酿基'經基H 、基及羥基-C3-8-環烷（烯）基所組成之群組； 係選自於氫、k-院（稀/块）基、C38_環烧（稀 土、方基、C&quot;-環燒（烯）基ϋ (稀/块）基、芳 : 烧（婦/块）基、經基Ί烧（嫦/块）基、芳 :二C…環燒（締）基及經基ϋ燒（稀）基所組 成之群組；其中 …。，係獨立地選自於氣—元（婦/块）基、 97 1325414 c3-8-環烷（烯）基、C3—8_環烷（烯）基_Ci 6_烷（烯/炔） 基、羥基-Cm-烷（烯/炔）基、羥基吒3 8_環烷（烯）基 、羥基-Ch-環烷（烯）基_Ci ^烷（烯/炔）基、鹵基 二烷（烯/炔）基、邊基-C3-8-環烷（烯）基、齒基-C3_8〜 環烷（烯）基-Ch-烷（烯，炔）基、氰基_。6_烷（烯/ 炔）基、氰基-C3-8-環烷（烯）基及氰基气3 8_環烷（烯） 基Cl-6-燒（稀/块）基所組成之群組，或者 和R連同匕們所連接之氮原子一起形成一個視需 要含有卜2 4 3個其他雜原子之4_8員飽和或不飽和環 X 是 co 或 s〇2; z是0或NR4，其中 R4係選自於氫、CH-烧（稀/块）基、C3 8_環燒（稀 )基、c3-8-環烷（烯）基—一_烷（烯/炔）基、經基—Ci •-烷（烯/炔）基及羥基吒&quot;—環烷（烯）基所組成之群組 ;或者Wherein / is selected from hydrogen, c-alkyl (ene/alkyne) based ring-fired (thin: (diluted) group - Ci 6 - burning (ene / alkyne) group, fluorenyl group, group 6 · alkane (alkenyl/alkynyl) group and hydroxy~Ch, alk(en)yl group, independently selected from hydrogen, c-alkyl (alk), acetylene, diene, aryl, C3- 8_cycloalkane(en)yl-Ch-alkane (ene/' X aryl H (lean/alkynyl) group, aryl group' via group H, group and hydroxy-C3-8-cycloalkane (alkenyl) group Group; is selected from the group consisting of hydrogen, k-house (thin/block), C38_cyclic (rare earth, square, C&quot;-cyclic (alkenyl) based oxime (thin/block), aromatic: burned (women/block) group, group consisting of base-burning (嫦/block) base, aromatic: two C... ring-burning (substrate) group and base-burning (thin) group; among them, ... Selected from gas-yuan (female/block) group, 97 1325414 c3-8-cycloalkane (alkenyl) group, C3-8-cycloalkane (alkenyl) group -Ci 6-alkane (ene/alkyne) group, hydroxyl group -Cm-alkane (alkenyl/alkynyl) group, hydroxyindole 38-cycloalkane (alkenyl) group, hydroxy-Ch-cycloalkane (alkenyl) group -Ci ^ alkene (alkenyl/alkyne) group, halodialkyl (alkenyl) /alkyne), side group-C3 -8-cycloalkane (alkenyl) group, dentate group - C3_8~ cycloalkane (alkenyl)-Ch-alkane (alkenyl), cyano-6-alkane (alkenyl) group, cyano-C3 a group consisting of -8-cycloalkane (alkenyl) group and cyano gas 3 8 -cycloalkane (alkenyl) group Cl-6-burning (thin/block) group, or with R together with the nitrogen atom to which we are attached Together form a 4-8-membered saturated or unsaturated ring X which optionally contains 234 other heteroatoms, which is co or s〇2; z is 0 or NR4, wherein R4 is selected from hydrogen, CH-burn (lean/ Block), C3 8_cyclic (diluted), c3-8-cycloalkanoyl-monoalkane (alkenyl/alkynyl), thio-Ci •-alkane (alkenyl/alkynyl) group and hydroxyl group a group consisting of 环&quot;-cycloalkane (alkenyl) groups; or 人R3和r連同它們所連接之氮原子一起形成一個視需 ::卜2或3個其他雜原子之4_8員飽和或不飽和環 和R4及氮原子所形成之環係視m或多個獨立 選自於C卜6_烷（烯/炔）基 Φ 方基及方基-C丨-6-烷（烯 块）基的取代基取代； q是〇或1 ; 以及 Y代表式II或III之雜芳基： 98 1325414Human R3 and r together with the nitrogen atom to which they are attached form an on-demand:: 4 or 8 of the other heteroatoms, 4 or 8 of the saturated or unsaturated ring, and the ring formed by R4 and the nitrogen atom, m or more independent Substituted from a substituent of a C 6 6-alkane (alkenyl/alkyne) group Φ aryl group and a aryl-C 丨-6-alkane (alk) group; q is 〇 or 1; and Y represents Formula II or III Heteroaryl: 98 1325414 其中 w是〇或s ;Where w is 〇 or s; m 是 0、1、2 或 3 ; η是 O'i'2'3 或 4; P是〇或1 ;以及 :個R係獨立地選自於C! 燒（烯 烧（烯）基、关其 r „ ^ A — C3·8—J哀烷（烯）基-C丨-B-烷（烯/炔） 基、方基-cm (稀/炔）基、酿基、函素、m (稀/快）基、Cl-6一烧（烯/ 炔）氧基、-C0-NR6R6’、| 基、確基、’ν’、_S_R8、_s〇2R8、随8所組成之群兔m is 0, 1, 2 or 3; η is O'i'2'3 or 4; P is 〇 or 1; and: R is independently selected from C! (alken (alkenyl) base, off Its r „ ^ A — C3·8—J sane (alkenyl)-C丨-B-alkane (ene/alkyne) group, square group-cm (thin/alkyne) group, brewing group, element, m ( Dilute/fast), Cl-6-burning (ene/alkynyloxy), -C0-NR6R6', | group, exact group, 'ν', _S_R8, _s〇2R8, group of rabbits 其中 R和R係獨立地選自於氫、Ci 6—烷（烯，炔）基、匕 8-環烷（烯）基、C3-8-環烷（烯）基_Cl_6_烷（烯//炔）基 及芳基所組成之群組； R7和R7係獨立地選自於氫、Ci 6_烷（烯^/炔）基、C3 8-環烧（烯）基、C3-8-環烷（烯）基-Ci-6-烷（烯/炔）基 、芳基及醯基所組成之群組；以及 R係選自於Cl-6-烧（稀/炔）基、C3-8-環燒（烯）基 99 1325414 、C3-8-環烧（稀） 所組成之群組；其中 R9和R9’係獨立地選自於氫、c 8_環燒（烯）基及C3·1 2-環烷（烯） 所組成之群組； 基一Cl_6_烷（烯/炔）基、芳基及-NR9R9, μ-烷（烯/炔）基、C3 基-Ci-e-烧（稀/炔）基 或其醫藥上可接受之鹽。 2.申請專利範圍第丨項之化合物 和Cw-烷（烯/炔）基所組成之群組 其中R1係選自於氫Wherein R and R are independently selected from the group consisting of hydrogen, Ci 6-alkane (alkenyl), 匕8-cycloalkanoyl, C3-8-cycloalkanoyl-Cl_6-alkane (alkenyl) a group consisting of an alkynyl group and an aryl group; R7 and R7 are independently selected from the group consisting of hydrogen, Ci 6-alkane (alkenyl), C3 8-ring (alkenyl), C3-8- a group consisting of a cycloalkanoyl-Ci-6-alkane (alkenyl/alkynyl) group, an aryl group and a fluorenyl group; and the R group is selected from the group consisting of Cl-6-sinter (thin/alkyne) group, C3- a group consisting of 8-ring (alkenyl) 99 1325414 and C3-8-cyclic (dilute); wherein R9 and R9' are independently selected from hydrogen, c 8_cyclo(alkenyl) and C3 a group consisting of 1 2-cycloalkane (alkenyl); a base Cl_6-alkane (alkenyl/alkynyl) group, an aryl group and -NR9R9, a μ-alkane (ene/alkyne) group, a C3 group-Ci-e- A burnt (thin/alkyne) group or a pharmaceutically acceptable salt thereof. 2. A group consisting of a compound of the scope of the patent application and a group of Cw-alkane (alkenyl/alkyne) groups wherein R1 is selected from hydrogen 3.根據申請專利範圍第 中取代基R2和R2‘中至少 1和2項中任一項之化合物， 一者是氫原子。3. A compound according to any one of the substituents R2 and R2', wherein at least one of the substituents R2 and R2' is a hydrogen atom. 4.根據申請專利範圍第1 * 2項中任一項之化合物， 其中R和R二者都是氫原子。 5.根據申請專利範圍第J # 2項中任一項之化 其中X是C0。 6. 根據申請專利範圍第1和2項中任一項之化合物， 其中q是0。 100 1 . 根據申請專利範圍第1 # 2項中任-項之化合物，· 其中Q是1且Z是氧原子。 2 ·根據申請專利範圍第1和2項中任一項之化合物， 其中R係選自於Cl.6~烧（稀/快）基和芳基ϋ (烯 /块）基所組成之群組。 9·根據申請專利範圍第8項之化合物其中R3是Gy — 燒（烯/炔）基。 6 1 〇.根據申睛專利範圍第8項之化合物，其中π是芳 1325414 基-C 1 - 6 -烧（稀 /快）基。 11. 根據申請專利範圍第 ，其中W是氧原子。 12. 根據申請專利範圍第 ，其中W是硫原子。 13. 根據申請專利範圍第 ，其中Y具有式II。 14. 根據申請專利範圍第 ，其中Y具有式III。 15. 根據申請專利範圍第 ，其中γ具有式lib或Illb: 1和2項中任一項之化合物 1和2項中任一項之化合物 1和2項中任一項之化合物 1和2項中任一項之化合物 1和2項中任一項之化合物The compound according to any one of claims 1 to 2, wherein both R and R are a hydrogen atom. 5. According to any of the scope of the patent application No. J # 2, where X is C0. 6. The compound according to any one of claims 1 and 2, wherein q is 0. 100 1. A compound according to any one of the claims 1 to 2, wherein Q is 1 and Z is an oxygen atom. The compound according to any one of claims 1 to 2, wherein R is selected from the group consisting of a Cl.6~salt (dilute/fast) group and an arylsulfonium (ene/block) group. . 9. A compound according to item 8 of the patent application wherein R3 is a Gy-burning (alkenyl/alkyne) group. 6 1 〇. A compound according to item 8 of the scope of the patent application, wherein π is an aromatic 1325414-C 1 - 6 -burned (lean/fast) group. 11. According to the scope of the patent application, where W is an oxygen atom. 12. According to the scope of the patent application, where W is a sulfur atom. 13. According to the scope of the patent application, Y has the formula II. 14. According to the scope of the patent application, Y has the formula III. 15. According to the scope of the patent application, wherein γ has the compound 1 and 2 of any one of the compounds 1 and 2 of any one of the compounds 1 and 2 of the formula lib or Illb: 1 and 2 a compound according to any one of the compounds 1 and 2 其中W、m、η、p及R5係如以上所定義者。 16.根據申請專利範圍第1和2項中任一項之化合物 ，其中Υ具有式lie或IIIc:Wherein W, m, η, p and R5 are as defined above. 16. A compound according to any one of claims 1 and 2 wherein Υ has the formula lie or IIIc: 其中W、m、η、p及R5係如以上所定義者。 17.根據申請專利範圍第1和2項中任一項之化合物 101 1325414 ’其中各個R5係獨立地選自於Ck烷（烯/炔）基、芳基 、鹵素、（:1-6-烧（烯/炔）氧基、-NR7R7’、-S〇2R8所組成 之群組。 18.根據申請專利範圍第1和2項中任一項之化合物 ’該化合物係選自於下列各物所組成之群組： {2 -胺基- 4- [(5 -氣-暖吩-2-基甲基）-曱基—胺基]-苯 基}-胺基甲酸乙酯； {2-胺基-4-[(5-氯-噻吩-2-基甲基）-胺基]-苯基卜胺 基曱酸乙酯； {2-胺基-4-[(5-甲基-噻吩-2-基曱基）-甲基-胺基卜 笨基}-胺基甲酸乙酯； {2-胺基-4-[ (5-溴吩-2-基甲基）-胺基]-苯基卜胺 基曱酸乙酯； {2-胺基-4-[(6-氣-3-曱氧基-苯并[b]噻吩-2-基甲基 )-胺基]-苯基}-胺基曱酸乙酯； {2-胺基-4-[(苯并[13]噬吩-2-基甲基）-胺基]-苯基}- 胺基曱酸乙酯； {2-胺基-4-[(5-甲基-噻吩-2-基甲基）-胺基]-苯基}-胺基甲酸乙酯； {2-胺基-4-[(4-溴-3-曱氧基-噻吩-2-基甲基）-胺基 ]_苯基卜胺基甲酸乙酯； {2-胺基-4-[(5-苯基-噻吩-2-基甲基）-胺基]-苯基}-胺基曱酸乙酯； {2-胺基-4-[(3-氣-噻吩-2-基曱基）-胺基]-苯基卜胺 1325414 基曱酸乙酯； (2-胺基-4-{[4-(4-氯-苯磺醯基）-3-甲基-噻吩-2-基 曱基]-胺基}-苯基）-胺基甲酸乙酯； {2-胺基-4-[(3-甲基-噻吩—2-基甲基）-胺基]-苯基}-胺基曱酸乙酯； {2-胺基_4-[(5-氟-苯并呋喃-3-基甲基）-胺基]-苯基 }-胺基甲酸乙酯； {2-胺基-4-[(噻吩-2-基曱基）-胺基]-苯基卜胺基甲 酸乙酯； {2-胺基-4-[(4-溴-噻吩-2-基甲基）-胺基]-苯基卜胺 基甲酸乙酯； {2-胺基-4-[(5-乙基-噻吩-2-基甲基）-胺基]-苯基卜 胺基曱酸乙酯； {2-胺基_4-[(噻吩-3-基甲基）-胺基]-苯基卜胺基甲 酸乙酯； {2-胺基-4-[(5-氣-噻吩-2-基甲基）-乙基-胺基]-苯 基}-胺基甲酸乙酯； {2-胺基_4-[(笨并[b]噻吩-3-基甲基）-胺基]-苯基}-胺基甲酸乙酯； {2-胺基_4-[ (5-二曱基-胺基-苯并[b]噻吩-3-基甲基 )_胺基]_苯基}_胺基甲酸乙醋； {2-胺基-4-[(5-二甲基-胺基-3-甲基-苯并[b]噻吩-2-基曱基）-胺基]-笨基}-胺基曱酸乙酯； {2 -胺基-4_[(5-1_瞻吩-2-基曱基）-胺基]-苯基}-胺 1325414 基甲酸乙醋， {2-胺基_4-[(笨并[b]噻吩_2_基甲基）胺基]苯基卜 胺基曱酸丙酯； {2-胺基-4-[(苯并[b]噻吩_3_基甲基）胺基]苯基卜 胺基甲酸丙酯； N-{2_胺基-4-[(5-氣—噻吩_2_基甲基）胺基]苯基}_2 (4 -敗-苯基）-乙醯胺；及 N-{2-胺基-4-[(5-氣—噻吩_2_基甲基）胺基]苯基}· 3, 3-二甲基-丁醯胺，Wherein W, m, η, p and R5 are as defined above. 17. The compound 101 1325414' according to any one of claims 1 and 2 wherein each R5 is independently selected from the group consisting of Ck alkyne (alkenyl/alkynyl), aryl, halogen, (:1-6-burning) (Alkene/alkyne)oxy, a group of -NR7R7', -S〇2R8. 18. A compound according to any one of claims 1 and 2, which is selected from the following Group consisting of: {2-amino- 4-[(5-a-furophen-2-ylmethyl)-fluorenyl-amino]-phenyl}-carbamic acid ethyl ester; {2-amine Ethyl 4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl-amino-decanoic acid ethyl ester; {2-amino-4-[(5-methyl-thiophene- 2-ylindenyl)-methyl-amino-phenylidene}-carbamic acid ethyl ester; {2-amino-4-[(5-bromophen-2-ylmethyl)-amino]-benzene Ethylaminoethyl decanoate; {2-amino-4-[(6-a-3-methoxy-benzo[b]thiophen-2-ylmethyl)-amino]-phenyl} -Aminoethyl decanoate; {2-Amino-4-[(benzo[13] phen-2-ylmethyl)-amino]-phenyl}-amino decanoate; {2 -Amino-4-[(5-methyl-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic acid ethyl ester; {2-Amino-4-[(4- Ethyl bromo-3-indolyl-thiophen-2-ylmethyl)-amino]-phenyl phenylcarbamate; {2-amino-4-[(5-phenyl-thiophen-2-yl) Methyl)-amino]-phenyl}-amino decanoic acid ethyl ester; {2-amino-4-[(3-a-thiophen-2-ylindenyl)-amino]-phenyl-p-amine 1325414 ethyl decanoate; (2-amino-4-{[4-(4-chloro-phenylsulfonyl)-3-methyl-thiophen-2-ylindenyl]-amino}-phenyl Ethyl urethane; {2-amino-4-[(3-methyl-thiophen-2-ylmethyl)-amino]-phenyl}-amino decanoic acid ethyl ester; {2- Amino 4-[(5-fluoro-benzofuran-3-ylmethyl)-amino]-phenyl}-carbamic acid ethyl ester; {2-amino-4-[(thiophene-2- (2-amino-4-[(4-bromo-thiophen-2-ylmethyl)-amino]-phenyl- phenylamino) Ethyl formate; {2-amino-4-[(5-ethyl-thiophen-2-ylmethyl)-amino]-phenyl-aminoglycolic acid ethyl ester; {2-amino group_4- [(Thiophen-3-ylmethyl)-amino]-phenyl-t-butyl carbamate; {2-amino-4-[(5-a-thiophen-2-ylmethyl)-ethyl- Amino]-phenyl}-carbamic acid ethyl ester; {2-amino-4-[(p- and [b]thiophen-3-ylmethyl)-amine Ethyl]-phenyl}-carbamic acid ethyl ester; {2-amino-4-[(5-diamidino-amino-benzo[b]thiophen-3-ylmethyl)-amino]_ Phenyl}-amino acetate; {2-amino-4-[(5-dimethyl-amino-3-methyl-benzo[b]thiophen-2-ylindenyl)-amino ]-stupyl}-aminoethyl decanoate; {2-amino-4-[(5-1-threo-2-ylindenyl)-amino]-phenyl}-amine 1325414 , {2-amino- 4-[(p- and [b]thiophen-2-ylmethyl)amino]phenyl-phenylamino decanoate; {2-amino-4-[(benzo[ b] thiophene-3-ylmethyl)amino]phenyl phenylcarbamate; N-{2_amino-4-[(5-a-thiophen-2-ylmethyl)amino]benzene }}_2 (4-de-phenyl)-acetamide; and N-{2-amino-4-[(5-a-thiophen-2-ylmethyl)amino]phenyl}· 3, 3-dimethyl-butanamine, 或其醫藥上可接受之鹽。 19_ 一種醫藥組成物，其包含治療上有效量之根據申 請專利範圍第1-18項中任一項之化合物及一或多種醫藥 上可接受之載劑或稀釋劑。 20. —種根據申請專利範圍第卜19項中任一項之化合 物的用途，其係用來製備預防、治療及，或抑制中樞神經 系統障礙之醫藥製劑。Or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 18 and one or more pharmaceutically acceptable carriers or diluents. 20. Use of a compound according to any one of claims 19, for the preparation of a pharmaceutical preparation for preventing, treating and/or inhibiting central nervous system disorders. .根射請專利範圍第2Q項之用途，其特徵在於該 插神經系統之障礙係選自於癲痛發作症如驚厥、痛痛和 癲癇持續狀態所組成之群組。 、 22·根據申請專利範圍帛21項之用途’其特徵在於該 神經糸統之障礙係選自於神經病和偏頭痛障礙，如觸 L病，广痛覺過敏疼痛、幻痛、與糖尿病神經病變有關之神 、-病痛及與偏頭痛有關之神經病痛所組成之群组。 23.根據中請專利範圍第21項之用途，其特徵在於該 104 1325414 中枢神經系統之障礙係選自於焦慮症，如焦慮、廣泛性焦 慮症、恐慌性焦慮、強迫症、社交恐懼症、表現焦慮、創 傷後壓力症、急性壓力反應、適應障礙、疑病性障礙、分 離焦慮症、畏曠症、特定恐懼症、一般醫學病狀所致之焦 慮症及物質誘發之焦慮症所組成之群組。 24.根據申請專利範圍第21項之用途，其特徵在於該 中柩神經系統之障礙係選自於神經退化性障礙，如阿茲海 默氏症、予丁頓氏舞蹈症、多發性硬化、肌萎縮性脊髓側 索硬化、AIDS誘發的腦病及其他因德國麻疹病毒、疱疹病 _ 毒、疏螺旋體和未知病原體所引起感染有關之腦病、庫賈 氏症、帕金森氏症、創傷誘發的神經退化所組成之群組。 25·根據申請專利範圍第21項之用途，其特徵在於該 中樞神經系統之障礙係選自於諸如藥品戒斷中或中毒所致 · 之神經元過度興奮狀態所組成之群組。 — 拾壹、圖式： (無） 蠢、 105The use of the second aspect of the patent application is characterized in that the disorder of the insertional nervous system is selected from the group consisting of epileptic seizures such as convulsions, pain and status epilepticus. 22, according to the scope of the patent application 帛 21, characterized in that the neurological disorder is selected from neurological and migraine disorders, such as touch L disease, widespread pain hyperalgesia pain, phantom pain, and diabetic neuropathy A group of gods, sickness, and neuropathic pain associated with migraine. 23. The use according to item 21 of the scope of the patent application, characterized in that the disorder of the central nervous system of the 104 1325414 is selected from the group consisting of anxiety disorders such as anxiety, generalized anxiety disorder, panic anxiety, obsessive-compulsive disorder, social phobia, Performance anxiety, post-traumatic stress disorder, acute stress response, adaptation disorder, suspected disorder, separation anxiety disorder, phobia, specific phobia, anxiety caused by general medical conditions, and substance-induced anxiety Group. 24. The use according to claim 21, wherein the disorder of the middle sacral nervous system is selected from the group consisting of neurodegenerative disorders such as Alzheimer's disease, Prednisone's disease, multiple sclerosis, Amyotrophic lateral sclerosis, AIDS-induced encephalopathy, and other encephalopathy associated with German measles virus, herpes virus, borreliosis, and unknown pathogens, CJD, Parkinson's disease, trauma-induced neurodegeneration The group formed. 25. Use according to item 21 of the scope of the patent application, characterized in that the disorder of the central nervous system is selected from the group consisting of a state of hyperexcitability of a neuron such as in drug withdrawal or poisoning. — Pick up, pattern: (none) stupid, 105
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