TW200413280A

TW200413280A - 1,2,4-triaminobenzene derivatives

Info

Publication number: TW200413280A
Application number: TW092135930A
Authority: TW
Inventors: Mario Rottlander; Andreas Ritzen; Morten Bang Norgaard; Nikolay Khanzhin; Christian Wenzel Tornoe
Original assignee: Lundbeck & Co As H
Priority date: 2002-12-27
Filing date: 2003-12-18
Publication date: 2004-08-01
Also published as: NO20053612D0; CN100448867C; KR20050089862A; ZA200504565B; EA200501053A1; UA79666C2; CN1732162A; TWI325414B; BR0317748A; HK1088317A1; EA008589B1; MY139844A; IS7856A; PE20041015A1; IS2649B; SI1578740T1; CL2003002748A1; NO20053612L; PL377221A1; UY28151A1

Abstract

The present invention concerns 1,2,4-triaminobenzene derivatives of the general formula I or pharmaceutically acceptable salts thereof, and the use thereof.

Description

200413280 狄、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穎 I 2, 4-三胺基苯衍生物。這些化合物可用來預防、治療及 /或抑制中樞神經系統的障礙。【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、氯離子和納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 心2〇〇〇，1，21-30)，而在結構與功能二者方面有很大的差異。神經元鉀離子通道可在大腦中發現’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膜復極化。鉀離子通道基因的一個亞群是KCNQ族。在五個KCNQ 基因中四個的突變已經證實是造成疾病，包括心律不整、耳聾及癲癇的基礎（jentsch yPeF/ews·200413280 D. Description of the invention: [Technical field to which the invention belongs] The present invention relates to a novel I 2,4-triaminobenzene derivative of a KCNQ group potassium ion channel opener. These compounds can be used to prevent, treat and / or inhibit 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, calcium, chloride, and nano ions, into and out of cells. Such channels exist 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 Heart 2000, 1, 21-30), and there are large differences in both structure and function. Neuronal potassium ion channels can be found in the brain. It is mainly responsible for maintaining a negative resting membrane potential and controlling membrane repolarization after the action potential. A subgroup of potassium channel genes is the KCNQ family. Mutations in four of the five KCNQ genes have been shown to be the basis of diseases including arrhythmia, deafness, and epilepsy (jentsch yPeF / ews ·

Wezyroscye/jce 2000，1，21-30)。 KCNQ4基因被認為是編碼與發現在耳蝸外毛感覺上皮細胞及前庭器第一型毛細胞中之鉀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。 200413280 KCNQl(KvLQTl)係與KCNE1 (極小的K( + )-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（R〇bbins 尸77?er 2001，90，1-19)。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貝與海馬（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· ⑽ 赴ade鮮〇/ y s j 2000，97，4914一々gig)。 KCNQ2和KCNQ3是二個當在活體外表現時會形成，，m一電流，’的鉀離子通道亞單位。M—電流是一種在許多神經元細胞 ;負i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，而在控制膜應中佔重要地位（Marrion 1997，59，483-504 ) 。M-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 ^因此，這些KCNQ通道的開啟劑將降低在諸如癲癇發作 ;丙狀及特彳玫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 ; N一（2一胺基一4一 200413280 (4-氟苄基胺基）—苯基）胺基甲酸乙酯）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、藉由伸戊基四唑、印防已毒素（ picrotoxin)及N-曱基咄-天冬胺酸（NMDA)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核式（DBA/2小鼠）的口服和腹膜内投藥之後起作用（Rostock et al·办"邙砂如以以以ι996，23, 21 1 223)。除此之外，瑞提加賓在複雜性局部癲癇發作的 f仁核激動模式中起作用，進一步指出此化合物具有抗痙攣⑺療的潛力。在臨床試驗中，瑞提加賓最近已經證實在 p牛低癲癇患者之癲癇發作發病率方面的效果（Bialer et al·办Wepsy yPesearc/? 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（ heter〇multimer)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 et &1. 户/zar历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 斿2002，454·7)，而鉀離子通道調節體已經被假设在神經病痛和癲癇二者中都可起作用（ 200413280Wezyroscye / jce 2000, 1, 21-30). The KCNQ4 gene is thought to encode a molecule related to potassium ion channels found in cochlear outer hair sensory epithelial cells and vestibular type 1 hair cells, and mutations in it cause a form of hereditary deafness. 200413280 KCNQl (KvLQTl) and KCNE1 (a very small K (+)-channel protein) gene are combined in the heart to form a cardiac-like delayed rectified K (+) current. Mutations in this channel can cause a form of hereditary long QT syndrome type 1 (LQT1), and it is related to a form of deafness (Robbins 77? Er 2001, 90, 1-19). The genes KCNQ2 and KCNQ3 were discovered in 1988 and appear to be mutated in a genetic form of epilepsy known as benign familial neonatal spasm (Rogawski Trends in Neurosciences 2000, 23, 393-398). The proteins encoded by the KCNQ2 and KCNQ3 genes are confined to pyramidal neurons in the human pelvis and hippocampus (that is, regions in the brain that are involved in the production and transmission of seizures) (Cooper et al. 97,4914-gig). KCNQ2 and KCNQ3 are two potassium channel subunits that will form when expressed in vitro, m-current, '. M-current is a type of non-deactivated potassium current found in many neuronal cells; negative i. Among the various cell types, it plays an important role in controlling membrane applications because it is the only continuous current in the initial range of action potentials (Marrion 1997, 59, 483-504). The adjustment of M-current has a dramatic effect on neuron stress. For example, the activation of the current will reduce neuron stress ^ Therefore, these KCNQ channel openers will reduce the effects such as seizures; Mei lies in diseases with excessive neuronal activity such as epilepsy and neuropathic pain. Retigabine (D-231 29; N- (2-Amino-4-200413280 (4-fluorobenzylamino) -phenyl) urethane) and its analogs are disclosed in EP554543. Retigabine is an antispasmodic compound with a broad spectrum and effective antispasmodic properties, both in vitro and in vivo. It is in the range of anti-spasmodic tests that include electrically induced seizures, chemically induced seizures by dextyltetrazole, picrotoxin, and N-fluorenyl-aspartic acid (NMDA), Works in rats and mice, and after oral and intraperitoneal administration in genetic animal nucleus (DBA / 2 mice) (Rostock et al. Office " 邙沙如以以 ι996, 23, 21 1 223) . In addition, retigabine plays a role in the f-nucleolar agitation pattern of complex local seizures, further pointing out that this compound has the potential for antispasmodic therapy. In clinical trials, Retigabine has recently been shown to have an effect on the incidence of seizures in patients with low epilepsy in cattle (Bialer et al. Office Wepsy y Pesearc /? 2002, 51, 31-71). Retigabine has been shown to activate K (+) currents in neuronal cells, and the pharmacology of this induced current has an index of the published M-channel pharmacology 'M-channels have recently been shown to interact with KCNQ2 / 3 κ (+ ) Channel heteromultimer. This means that activation of the KCNQ2 / 3 channel may be responsible for some of the anticonvulsant activity of this agent (Wickenden et & 1. Household / zar calendar 2000, 58, 59, 600), and other agents acting through the same mechanism may have Similar use. KCNQ channels 2 and 3 have been reported to be upregulated in neuropathic pain patterns (Wickenden et al. Society for 斿 2002, 454.7), while potassium channel regulators have been hypothesized in both neuropathic pain and epilepsy Can work (200413280

Schroder et al. Neuropharmacology 2001, 40, 888-898 ;Blackburn一Munro and Jensen European Journal of 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樞神經系統區域中（Goldstein et al. Society for Yei/rosc/eece 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. Sociei，/or Msiracb 2003，53·8) 〇最近的報導證實，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 al.，《Soc/eiy /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•办//epWa 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)。 200413280 已知抗痙攣化合物如苯并二氮罩類（benz〇d iazepines )和氯美噻唾（chlormethiazole)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（ Watson et al. Neuropharmacology 1 997, 36, 1 369-1375 )’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· /⑽尸仰/ 〇/ 2001， 21，4609-4624 )，瑞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· /⑽〇/ 户奸咖处㈣卿/哪2003，17 suppl 3，A28，B16)，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0 W0 2001 96540揭示因KCNQ2和KCNQ3基因表現所形成 M-電流之調節劑對於失眠的用途，而w〇 _1〇92526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㈣預防和、冶療用途。 WO02/049628敘述瑞提加賓對於焦慮症如焦慮、廣泛 1·生焦慮症、恐慌性焦慮、強迫症、社交恐懼症、表現焦慮、創傷後壓力纟、急性壓力反應、適應障礙、疑病性障^ 200413280 、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絲/母默氏症（Alzheimer’s disease)、亨丁頓氏舞蹈症（Huntington’s Ch0rea)、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Schroder et al. Neuropharmacology 2001, 40, 888-898; Blackburn-Munro and Jensen European Journal of 2003, 460, 109-116). In addition, localized KCNQ channel mRNAs have been reported in the brain and other pain-related central nervous system regions (Goldstein et al. Society for Yei / rosc / eece 2003, 53.8). In addition to its role in neuropathic pain, the expression of KCNQ 2-5 mRNA in the trigeminal and dorsal root knots and in the trigeminal nerve tail suggests that the opening of these channels can also affect the sensory management of migraine (Goldstein et al. Sociei / Or Msiracb 2003, 53.8) Recent reports confirm that, in addition to KCNQ2 mRNA, KCNQ 3 and 5 mRNA lines are expressed in astrocytes and glial cells. Therefore, KCNQ channels 2, 3, and 5 can help regulate synaptic activity in the CNS and help the neuroprotective effects of KCNQ channel openers (Noda et al., "Soc / eiy / or 2003, 53.9). Retigabine and other KCNQ modulators can therefore show protection against neurodegeneration in epilepsy, as Retigabine has been shown to prevent marginal neurodegeneration and cells after kainic acid-induced seizure persistence in rats Expression of Apoptotic Markers (Ebert et al. Office // epWa 2002, 43 Suppl 5, 86-95). This may have something to do with preventing the progress of epilepsy in patients, that is, anti-seizures. Retigabine has also been shown to delay hippocampal inflammatory progression in rats, a further model of epilepsy development (Tober et al. European Journal Of Pharmacology 1996, 303, 163-169). 200413280 It is known that antispasmodic compounds such as benzodidazepines and chlormethiazole are clinically used in the treatment of alcohol withdrawal syndrome, while other antispasmodic compounds such as gabapentin are here This syndrome is very effective in animal models (Watson et al. Neuropharmacology 1 997, 36, 1 369-1375). 'We expect other anticonvulsants such as KCNQ opener to be effective in this condition. The mRNAs of KCNQ 2 and 3 subunits are found in some brain regions associated with anxiety and emotional behaviors such as bipolar disorder, such as in the hippocampus and amygdala (Saganich et al. / ⑽ deadly / / 2001, 21, 4609- 4624), Retigarbin was reported to play a role in some animal models of anxiety-like behaviors (Hartz et al · / ⑽〇 / 户奸咖啡处㈣卿 / Ne 2003, 17 suppl 3, A28, B16), and Other clinically used anticonvulsant compounds are used to treat bipolar psychiatric disorders. 0 W0 2001 96540 reveals the use of modulators of M-current formed by the expression of KCNQ2 and KCNQ3 genes for insomnia, and w〇_1〇92526 discloses the use of KCNQ5. Modifiers can be used to treat sleep disorders. > W001 / 022953 describes the use of Retigabine in the prevention and treatment of neuropathic pain such as tactile pain, hyperalgesia, phantom pain, neuropathic pain related to diabetic neuropathy, and neuropathy related to migraine. . WO02 / 049628 describes Retigabine's response to 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 disorders, suspected disease Handicap ^ 200413280, prevention, treatment, suppression and improvement of separation anxiety, aphobia, and specific phobia. W097 / 15300 describes Retigabine for the treatment of neurodegenerative disorders such as Alzheimer's disease, Huntington's Ch0rea, multiple sclerosis, amyotrophic lateral sclerosis, AIDS-induced encephalopathy and other encephalopathy related to infection caused by German measles virus, herpes virus, Borrelia and unknown pathogens

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㈣統的神經退化性障礙如多發隆神經病和多發性神經炎（p〇lyneuritides)等的用途。〆因此’對於是為有效K⑽族鉀離子通道開啟劑之化合物有很大的需求。 Μ㈣㈣疋相對於是為·㈣鉀離子通道開已知化合物，如瑞提加賓而言，具有改良性質：物。下列參數之一或多者之改良是為所求：、Creutzfeld-Jakob disease, Parkinson's disease, trauma-induced neurodegeneration, and overexcitation of neurons such as drug withdrawal or poisoning, neurodegenerative disorders of the peripheral nervous system such as polyneuropathy and Uses such as polyneuritides. 〆 Therefore, there is a great demand for a compound which is an effective K 钾 group potassium ion channel opener. Μ 是 is relatively open for potassium ion channels. Known compounds, such as retigabine, have improved properties: Improvements in one or more of the following parameters are sought:

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，化學穩膜渗透性，溶解度及治療指數。這類參數的如下列的改良： k¥致Half-life 'clearance' selectivity, interaction with other drugs, bioavailability, potency, formulation, chemical stability, membrane permeability, solubility, and therapeutic index. Such parameters are improved as follows: k ¥ 致

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m N 降低的副作用，增大的治療指數， 11 200413280 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。 1，2, 4-三胺基苯衍生物或本發明之化合物為通式I之其醫藥上可接受之鹽： R\ /R2·Improved dosing regimen for reducing the number of required doses per day Reduced side effects, increased therapeutic index, 11 200413280 improved tolerability and / or improved compliance for multiple drug patients. SUMMARY OF THE INVENTION Therefore, an object of the present invention is to provide a novel compound which is an effective KCNQ group potassium ion channel opener. 1,2,4-triaminobenzene derivative or compound of the present invention is a pharmaceutically acceptable salt of the general formula I: R \ / R2 ·

R1、R2、R2’，、x、z、Mq 其用途。R1, R2, R2 ', x, z, Mq and their uses.

係如以下所定義者。化合物之醫藥組成物及【實施方式】發明說明 h 2, 4-三胺基苯衍生物：本發明係關於新I員的式 12 200413280 200413280It is as defined below. Pharmaceutical composition of the compound and [Embodiment] Description of the invention h 2,4-triaminobenzene derivative: The present invention relates to a new member of the formula 12 200413280 200413280

R1係選自於氫、C,-栌r p / )美Γ -产P r 6 炔）基、C3-8-環烷（烯 m (婦）基—ch'貌（婦/炔）基、醯基、羥基-Ch-烷（烯/炔）基及 iffi 土成之群組；基一，烷（烯）基所組其中 C =厂係獨立地選自於氯、w烧（物）基、 3-81烧（烯）基、芳基、^_環烯/炔）基、若其Γ ^ (R1 is selected from the group consisting of hydrogen, C,-栌 rp /) -Pr 6 alkynyl), C3-8-cycloalkane (alkene) (ch) group (ch / alkynyl), and fluorene Group, hydroxy-Ch-alkane (alkene / alkynyl) group and iffi soil; group I, alk (en) group where C = plant is independently selected from chlorine, w 3-81 (alkenyl), aryl, ^ _cycloolefin / alkynyl), if its Γ ^ (

土 C卜6一烷（烯/炔）基、醯基、羥基—C (稀〜基及經基-一(稀)基所組成之群: )基、芳：自於虱、Cl_「烷（烯/炔）基、C3-「環烷（烯芳其Γ 環烧（稀）[Ch-烧（烯/炔）基、方基C1-6-燒（嫌/ 芳美、、）基、羥基-Ch-烷（烯/炔；）基、烯）基'NR1°n烧（稀/快）基、成之群組?:中燒(烯)基及經基-C3_「環烷(烯)基所組 R10 和 pi〇，# 一環燒（稀1選自於氫u(烯/快）基、 )基、羥基、W環烷（烯）基-Ch-烷（烯/炔土 H —烷（烯/炔）基、羥基—Ch一環烷（烯） 13 基、輕基—C3 -環妓；f、膝、 )基-Cy-貌（婦/伊）其鹵其 Ch-燒（稀/块）基 π邱/块）基齒基〜 iS ^ ^ ^ 15 基-C3-8-^ 烷（烯）基、齒基-C3_Soil C: 6-alkane (alkene / alkynyl) group, fluorenyl group, hydroxy-C (group consisting of di- and di- (di) groups:) group, aromatic: from lice, Cl_ "alkane ( Alkenyl / alkynyl, C3- "cycloalkane (alkenyl and its Γ ring-burned (diluted) [Ch-burned (ene / alkynyl), squared C1-6-burned (anthyl / aromatic ,,), hydroxyl- Ch-alk (en / alkyn) group, alkenyl) group 'NR1 ° n (alkene / quick) group, into groups ?: Medium-fired (en) group and mesyl-C3_ "cycloalkene (en) group The group R10 and pi〇, # monocyclic (dilute 1 selected from hydrogen u (ene / fast) group,) group, hydroxyl, W naphthenic (en) yl-Ch-alkane (ene / acetylene H-alkane ( Alkenyl / alkynyl), hydroxy-Ch monocycloalkene (alkene) 13-based, light-based-C3-cycloprostitute; f, knee,) yl-Cy-morphology (Fu / I) its halogen-ch (burned / diluted) ) Base π Qiu / Block) Atodonyl ~ iS ^ ^ ^ 15-Alkyl-C3-8- ^ alk (en) yl-C3_

8-%坑C烯）基—C 栌 J y ^ ) a ^ μ ^ 、炔）基、氰基-Ch-烷（烯 c\ 貌（婦）基及氛基-C-環炫（稀貌（烯/炔）基所組成之群組，或者 R10和R1Q’連同它們〗連接之氮原子一起形成一個視需要3有1、2或3個其他雜原 • 尽于之4一8貝飽和或不飽和環 j X 是 C0 或 S02 ; z是0或NR4，其中 R4係選自於氫、p ^ ^ 1—6一烷（烯/炔）基、C3_8-環烷（烯 )基、C3_8-環烷（烯）基 ^ r ^ / 丞烧（烯/炔）基、羥基— 6-烷（烯/炔）基及羥基—Γ h-8-ί哀燒（烯）基所組成之群組 :或者 R3和^連同它們所連接之氮原子-起形成-個視需要 3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及氮原子所形成夕衣係視萬要經一或多個獨立地選自於Cu-烧（稀/炔）其丹）基、方基及芳基-CV6-烷（烯/炔 )基的取代基取代； q是0或1 ; 以及 Y代表式II或ΙΠ之雜芳基： 14 2004132808-% pit C alkenyl) -C 栌 J y ^) a ^ μ ^, alkynyl), cyano-Ch-alkene (alkene), and cyano-C-cyclohexyl (rare appearance (Ene / alkyne) group, or R10 and R1Q 'together with the nitrogen atom they are connected to form a 3, 1, 2 or 3 other heterogens as required • 4 to 8 saturates or Unsaturated ring j X is C0 or S02; z is 0 or NR4, where R4 is selected from the group consisting of hydrogen, p ^^ 6-alkane (alkynyl), C3_8-cycloalk (en) yl, C3_8- The group consisting of cycloalkene (en) yl ^ r ^ / fluoren (en / alkynyl) group, hydroxy-6-alk (en / alkynyl) group and hydroxy-Γ h-8-ί alkyn (ene) group : Or R3 and ^ together with the nitrogen atom to which they are connected-form a 4-8 member saturated or unsaturated ring with 1, 2 or 3 other heteroatoms as required, formed by R3 and R4 and nitrogen atom It depends on being substituted by one or more substituents independently selected from the group consisting of Cu-alkyl (diluted / alkynyl) yl, square and aryl-CV6-alk (alkynyl); q is 0 Or 1; and Y represents a heteroaryl group of formula II or III: 14 200413280

π m 其中 W是0或s; m 是 0、1、2 或 3 ; _ η 是 0、1、2、3 或 4; ρ是0或1 ;以及各個R5係獨立地選自於（V6-烷（烯/炔）基、C3_8-環烷（烯）基、芳基、C3_8-環烷（烯）基-CV6-烷（烯/ 炔）基、芳基-(V6-烧（烯/炔）基、驢基、鹵素、鹵基-Ch-烷（烯/炔）基、Ch-烷（烯/炔）氧基、-CO-NR6R6’ 、氰基、硝基、-NR7R7’、-S-R8、-S02R8 及 S020R8 所組成之群組； ® 其中 R6和R6’係獨立地選自於氫、（V6-烷（烯/炔）基、 C3_8 -環烧（稀）基、C3_8-環烧（稀）基-Ci_6-烧（婦/炔 )基及芳基所組成之群組； R7和R7’係獨立地選自於氫、（V6-烷（烯/炔）基、 C3_8-環烷（烯）基、C3_8-環烷（烯）基-Cu-烷（烯/炔 )基、芳基及醯基所組成之群組；以及 R8係選自於CV6-烷（烯/炔）基、C3_8-環烷（烯）基 15 200413280 、c3_8-%烷（烯）基-ci-6-烷（烯/炔）基、芳基及_nr9r9, 所組成之群組；其中 R和R9係獨立地選自於氫、Ch-烧（烯/炔）基、π m where W is 0 or s; m is 0, 1, 2, or 3; _η is 0, 1, 2, 3, or 4; ρ is 0 or 1; and each R5 series is independently selected from (V6- Alk (en / alkynyl), C3_8-cycloalk (en) yl, aryl, C3_8-cycloalk (en) yl-CV6-alk (en / alkynyl), aryl- (V6-alkyl (en / alkyn) ), Donkey, halogen, halo-Ch-alk (en / alkynyl), Ch-alk (en / alkynyl) oxy, -CO-NR6R6 ', cyano, nitro, -NR7R7', -S The group consisting of -R8, -S02R8 and S020R8; ® where R6 and R6 'are independently selected from hydrogen, (V6-alk (ene / alkynyl) group, C3_8-cycloalkyl (dilute) group, C3_8-ring A group consisting of alkynyl-Ci_6-alkynyl and aryl; R7 and R7 'are independently selected from hydrogen, (V6-alk (ene / alkynyl), and C3_8-ring A group consisting of alk (en) yl, C3_8-cycloalk (en) yl-Cu-alk (ene / alkynyl), aryl, and fluorenyl; and R8 is selected from CV6-alk (ene / alkyn) Group consisting of C3_8-cycloalkene (en) yl 15 200413280, c3_8-% alk (en) yl-ci-6-alk (en / alkynyl), aryl and _nr9r9, where R and R9 Department of Independence Selected from hydrogen, burning Ch- (en / yn) yl,

Ch-環貌（婦）基及C"—環烷（烯）基—CH —烷（烯/炔 )基所組成之群組；或其醫藥上可接受之鹽。田q疋0 ’貝R3係連接到X，而當Q是i，則r3係連接到Z，其又連接到χ。χ一（z)rR3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丨化合物，其中 R1、R2、R2、X和q係如以上所定義者；且 R，自於氫、Cl-「烧（烯/快）基、C3_8-環烷（稀 ^基、芳基、c3_「環院（烯）基_Ci「炫（稀/快）基、芳基'6-烷（烯/炔）基、羥基々「烷（烯，炔）基及羥基-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、一烷（稀/炔）基、C3—8-環烧（烯）基、c3_8-環烧（婦）基 _Cl-6:烧（烯/炔）基、羥基-C"-烷（烯/炔）基及羥基二 C3_8-%烷（烯）基所組成之群組；且、Y係如以上所定義者，但前提是各個R5係獨立地選自；1-6心（烯/块）基、c3-8-環烧（婦）基、芳基、c — %烷（烯）基烷（烯/炔）基、芳基—Ch 一烷（烯/ 快基醯基、齒素、齒基-Cif烧（婦/块）基…. 16 200413280 _6’、氰基、石肖基、侧7，、抑、__8及_“ 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—c -产烯/快）基及經基-c3_8-環炫（稀）基所組成之土群组一在另-個具體實例中，本發明係關於其中選自於虱、Ww快）基、c3 8_環院（婦）基及c"_環烷 (細）基烧（烯/块）基所組成群組之這類化合物 Ο 在—個較佳具體實例中，本發明係關於其+ri係選自、虱及16-炫（烯/块）基所組成群組之這類化合物。在一個特定的具體實例中，本發明係關於其中原子之這類化合物。 & ^ 在另—個特定的具體實例中，本發明係關於其中 C!-6-烷（烯/炔）基之這類化合物。 47固具體實例中’以和r2,中至少-者係選自於芳基丄及;:Γ (稀/炔）基、醯基、經基-c-烧（稀/ 、土工基環烷（烯）基所組成之群組。在另一個具體實例中，^和R2 者、Γ -栌,β 了王少考係選自於氫 ρ<、卜6 70 、/炔）基、C3-8—環烷（烯）基及C3 8-環烧（繼Ά烯/块）基所組成之群組。一（和r2‘中至另I、一個㈣實例中，本發明係關於其中取代基r2 夕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R2‘ 17 200413280 二者皆是氫原子之這類化合物。在一個具體實例+，R3係選自絲基一^「烧（稀/块 )基、芳基-c3_8-環烷（烯）基、nr1Qr1()’—Ci 6—烷（稀/炔 )基、”、-「環烷（烯）基及羥基-c3_8-環烷（烯）基所組成之群組；其中 R和R1°係獨立地選自於氫、Ch-烷（烯/快）基、 C3-8衣烷（烯）基、c3 —「環烷（烯）基-C卜6—烷（烯/炔 )基、He"—烧（烯/快）基、經基-C3_8-㈣（稀）、基、經基〜(V8-環烧（烯）基—c"—烧（稀/快）基、鹵基〜（稀/快）基、自基—C3-8-環烧（烯）基、鹵基-C3 8/ it (烯t基—燒（稀/炔）基、氰基H (埽 /其、氛基—W環燒（烯）基及氰基一 C3-8-環烷（烯 6烷（烯/炔）基所組成之群組；或者 R:和—連同它們所連接之氮原子一起形成一個視需 3 、2或3個其他雜原子之4_8 M飽和或不飽和環。是肥且又二：Γ實例中，本發明係關於其中…、z 疋風原子之這類化合物。在又另-個具體實例中，本發明原子之這類化合物。一 T K不為氧在：另-個具體實例中’"選自於；卷、Cl8-環烷（嬌）其^ 「燒（稀/块）二 η，（烯）基' 組。 ▲及方基烷（烯/炔）基所組成之群選在又另—個具體實例巾，本發明係關於其中R3係 18 200413280 j & (稀/块）基及芳基烧（烯/炔）基所組烕群組之這類化合物。在又另一個具體實例中，本發明係關於其中y是I 6一烷（烯/炔）基之這類化合物。 1 在又另一個具體實例中，R3是C3厂環烧（稀）基 6 —燒（烯/炔）基。在又另一個具體實例中，本發明係關於其中Μ是芳基 — Cl~6-烧（烯/炔）基之這類化合物。A group consisting of Ch-Cyclomethyl and C " -cycloalk (en) yl-CH-alk (ene / alkynyl); or a pharmaceutically acceptable salt thereof. Tian q 疋 0 'is connected to X, and when Q is i, r3 is connected to Z, which in turn is connected to χ. χ- (z) rR3 can therefore represent X-R3, χ-〇-R3 or X-NR3R4. In a specific specific example, the present invention relates to a compound of formula 丨 wherein R1, R2, R2, X and q are as defined above; and R, from hydrogen, Cl- "burn (ene / fast) Radical, C3_8-cycloalkane (diluted, aryl, c3_ "cyclo (en) yl" _Ci "(hyun (diluted / quick)), aryl'6-alkane (alkene / alkynyl), hydroxy" alkane (Alkene, alkynyl) group and hydroxy-C3-8-cycloalkane (alkene) group; and Z is as defined above, provided that R4 is selected from hydrogen, monoalkane (diluted / alkyne) ) Group, C3-8-cycloalkyl (alkene) group, c3_8-cycloalkyl (alkene) group_Cl-6: alkyl (alkene / alkynyl) group, hydroxy-C " -alkane (alkene / alkynyl) group and hydroxydi A group consisting of C3_8-% alk (en) yl groups; and, Y is as defined above, but provided that each R5 is independently selected from; 1-6 core (ene / block) group, c3-8- Cycloalkyl (aryl), aryl, c —% alk (alkenyl) alkyl (ene / alkynyl), aryl —Ch monoalkane (ene / acryloyl, haloyl, haloyl-Cif / Block) group ... 16 200413280 Group consisting of _6 ', cyano, Shi Xiaoji, side 7, 7, __8 and _ " Or a pharmaceutically acceptable acid addition salt thereof. In a specific example, R1 is selected from the group consisting of fluorenyl, hydroxy-c-olefin-producing / quick), and mesogen-c3_8-cyclohexyl (dilute) radical. Composition of the soil group I In another specific example, the present invention relates to a group selected from the group consisting of lice, Ww fast), c3 8_circle (female), and c " _naphthenic (fine) radical ( In a preferred embodiment, the present invention relates to a compound whose + ri group is selected from the group consisting of 虱 and 16-xan (ene / block) groups. Such compounds. In a specific embodiment, the present invention relates to such compounds in which atoms are present. & ^ In another specific embodiment, the present invention relates to such compounds in which a C! -6-alk (ene / alkynyl) group is mentioned. In the specific example of 47, at least one of the following is selected from the group consisting of aryl and: Γ (diluted / alkynyl) group, fluorenyl group, via group -c-burned (diluted /, geocyclic naphthene ( In another specific example, the group of ^ and R2, Γ-, β is selected from the group of Wang Shaokao, which is selected from the group consisting of hydrogen ρ <, BU 6 70, / alkyne), and C3-8-ring. A group consisting of alk (en) yl group and C3 8-cycloalkyl (sublimene / block) group. In one (1 and r2 ') to another (1) and (1), the present invention relates to compounds in which the substituent r2 is a hydrogen atom. In yet another specific example, the present invention relates to compounds in which R2 and R2' 17 200413280 Both of these compounds are hydrogen atoms. In a specific example +, R3 is selected from the group consisting of a silk group (a dilute (dilute / block) group, an aryl-c3_8-cycloalkene (en) group, nr1Qr1 ( ) '-Ci 6-alkane (diluted / alkynyl), ",-" cycloalkene (alkene) and hydroxy-c3_8-cycloalkene (ene) group; where R and R1 ° are independently selected From hydrogen, Ch-alkane (alkene / quick) group, C3-8 ethene (en) group, c3 — "Cycloalkene (en) yl -C 6 -alkane (alkene / alkynyl) group, He "-burning (Ene / quick) group, mesogen-C3_8-fluorene (diluted), group, meridian group ~ (V8-Cycloalkyl (en) yl-c " -burned (diluted / quick) group, halogen group ~ (diluted / quick ) Group, self-group—C3-8-cycloalkyl (alkenyl) group, halo-C3 8 / it (alkyl group—alkyl (diluted / alkynyl) group, cyano H (fluorene / its, aryl group—W ring) A group consisting of an alkenyl group and a cyano-C3-8-cycloalkane (ene-6 alkene / ene) group; or R: and-together with the nitrogen atom to which they are attached, forms a 4-8 M saturated or unsaturated ring, optionally 3, 2 or 3 other heteroatoms. It is fat and yet another: In the example, the present invention is about which ... , Z such a compound of the wind atom. In yet another specific example, such a compound of the atom of the present invention.-TK is not oxygen. In another specific example, "" is selected from: Vol., Cl8. -Cycloalkane (Jiao) its ^ "burned (diluted / block) di η, (ene) group 'group. ▲ and the group consisting of square alkyl (ene / alkynyl) group is selected in another specific example, The present invention relates to compounds of this group in which R3 is 18 200413280 j & (dilute / block) and aryl (ene / alkynyl) groups. In yet another embodiment, the present invention relates to Where y is a compound of the type I 6 -alkane (alkene / alkynyl). 1 In yet another specific example, R3 is a C3 plant ring ring (lean) group 6-alkene (alkene / alkyne) group. In a specific example, the invention relates to compounds of this type in which M is aryl-Cl ~ 6-alk (en / alkynyl).

在一個具體實例中，本發明係關於其中χ 〇類化合物。 _ 在又另一個具體實例中，本發明係關於其中又是c〇之這類化合物。在一個具體實例中，q是〇。在又另一個具體實例中，本發明係關於其中χ是⑶且 Q是0之這類化合物。In a specific example, the invention relates to compounds of the x 0 class. In yet another specific embodiment, the invention relates to compounds of this type which are again co. In a specific example, q is 0. In yet another specific example, the invention relates to compounds of this type where χ is ⑶ and Q is 0.

口在又另一個具體實例中，本發明係關於其中χ是⑶， q疋〇且r3不為芳基之這類化合物。在另一個具體實例中，q是1。在一個具體實例中，本發明係關於農 w么具中q是1且Z是 NR4之這類化合物。在-個具體實例中，q是卜z是，連同它們所連接之氮原子-起形成-個視需要含有卜2或3個其他雜原子《4-8員飽和或不飽和環’由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Ch一烧（稀 19 200413280 块）基、芳基及芳基—ci 6—烧（烯/快）基的取代基取代。在另〆個具體貫例中，q是！、z是，且r4係選自於氫、C"-炫（烯/块）基、c3 8 —環燒（稀）基、Ch —環烷 (烯）基-Ch-烷（烯/炔）基、羥基I 一烷（烯，炔）基及羥基-C3—8-環烷（烯）基所組成之群組。在又另一個具體實例中，q是1、Z是州且Μ是氫原子。在一個具體實例中，q是1、z是NR4且R3和R4中至少 ⑩ 一者不為氫原子。在又另一個具體實例中，本發明係關於其中q是丨且 z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Z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ν’ 是氫原子、X是CO、q是1且Z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w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w是硫原子之這類化合物。在又另一個具體實例中，本發明係關於其中W是硫原孑真X是co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是硫原手真q是Q之這類化合物。、 20 200413280 在又另一個具體實例中，本發明係關於其中w是硫原子、X是C0且q是〇之這類化合物。在又另一個具體實例中，本發明係關於其中w是硫原子、q是1且Z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W是硫原子、X是C0、q是1且z是氧原子之這類化合物。在又另一個具體實例中，m是0。在又另一個具體實例中，m是1。在又另一個具體實例中，m是2。在一個具體實例中，m是3。在又另一個具體實例中，η是0。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。在另一個具體實例中，Ρ是1。、-C0-In yet another specific example, the invention relates to compounds of this type where χ is ⑶, q 疋〇 and r3 are not aryl. In another specific example, q is 1. In a specific example, the present invention relates to compounds in which q is 1 and Z is NR4. In a specific example, q is Bu and z is, together with the nitrogen atom to which they are attached, together form-one or two Bu, if necessary, containing 4 or 8 other heteroatoms. The ring formed by the nitrogen atom is optionally substituted with one or more substituents independently selected from the group consisting of Ch 1 (diluted 19 200413280), aryl, and aryl-ci 6-carbon (ene / quick) groups. . In another concrete example, q is! , Z is, and r4 is selected from the group consisting of hydrogen, C " -xen (ene / block) group, c3 8-cycloalkyl (diluted) group, Ch-cycloalkane (en) yl-Ch-alkane (ene / alkyne) A group consisting of a hydroxy group, a hydroxy I monoalkene group, and a hydroxy-C3-8-cycloalkane group. In yet another specific example, q is 1, Z is a state, and M is a hydrogen atom. In a specific example, q is 1, z is NR4, and at least one of R3 and R4 is not a hydrogen atom. In yet another embodiment, the present invention relates to compounds of this type in which q is z and z is an oxygen atom. In yet another specific example, the invention relates to compounds of this type where χ is co, q is 1, and Z is an oxygen atom. In yet another specific example, the present invention relates to compounds of this type in which R2 and v 'are hydrogen atoms, X is CO, q is 1, and Z is an oxygen atom. In yet another embodiment, the invention relates to compounds of this type in which w is an oxygen atom. In yet another embodiment, the present invention relates to compounds of this type in which w is a sulfur atom. In yet another embodiment, the present invention is directed to compounds of this type in which W is thiogen, and X is co. In yet another embodiment, the present invention is directed to compounds of this type in which W is a sulfur atom and real q is Q. 20 200413280 In yet another embodiment, the present invention relates to compounds of this type in which w is a sulfur atom, X is CO and q is 0. In yet another specific example, the invention relates to compounds of this type in which w is a sulfur atom, q is 1 and Z is an oxygen atom. In yet another specific example, the invention relates to compounds of this type in which W is a sulfur atom, X is CO, q is 1 and z is an oxygen atom. In yet another specific example, m is 0. 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 specific example, n is 0. In yet another specific example, n is 1. In a specific example, n is 2, 3, or 4; in a specific example, p is 0. In another specific example, P is 1. , -C0-

在一個具體實例中’至少一個R5係選自於 NR，’、硕基、_S-R8&s〇2〇R8所組成之群組。、土隹另一個具體實例中In a specific example, 'at least one R5 is selected from the group consisting of NR,', Shuo Ji, _S-R8 & s〇2〇R8. 、土隹 In another specific example

，，儿吧2¾目於（；烷（稀/炔）基、c38_環烷（烯）基猶烯）基-c"-烧（烯/炔）基、芳二王“ 、鹵素、鹵基靖/块）基炔) ^ A ^ ^ 烷（烯/你虱基、氰基、—NR7R7’及—S〇2R8所組成之群缸。 21 200413280 、-NR7R7’及-s〇2R8所組成之群組。一在又另一個具體實例中，本發明係關於其中各個p係獨立地選自於Ch-烧（烯/炔）基、鹵素及一 s〇j8 (其中 R8是芳基）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π是c 烷（烯/炔）基。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是c 烷（烯/炔）氧基。 16 _ 在又另一個具體實例中，至少一個取代基RS是〜s〇〇 2 、、在又另一個具體實例中，至少一個取代基R5是一個甴在又另一個具體實例中，至少一個取代基h 'ir JS jr +4. ^ 畜原子’其係選自於氣、溴和碘所組成之群組。在又另一個具體實例中，至少一個取代基R5是氟。在又另一個具體實例中，至少一個取代基R5是氯。鲁在又另一個具體實例中，至少一個取代基R5是溴。在又另一個具體實例中，至少一個取代基R5是— 〇在一個具體實例中，至少一個取代基R5是一NR7R7, · R7和R7’中至少一者是芳基或醯基。在一個具體實例中，至少一個取代基R5是—NR7R?，·且彳R中至少一者係選自於氣、Cu-烧（浠/块）美、 22 200413280 C3-8環燒（烯）基及C3_8-環烷（烯）基—Cp6-烷（烯/炔 )基所組成之群組。在另一個具體實例中，至少一個取代基R5是-NW，；且R7和R7,中至少一者係選自於氫及Ci 6 —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R5是〜NR7R7, :且R7和R7’中至少一者是c“-烷（烯，炔）基。,, the children 2¾ mesh (alkane (diluted / alkynyl) group, c38_ cycloalkene (alkenyl) heptenyl) -c " -burned (ene / alkynyl) group, fang diwang ", halogen, halo / Block) alkyne) ^ A ^ ^ alkane (alkene / yl, cyano, -NR7R7 'and -SO2R8 group of tanks. 21 200413280, -NR7R7' and -s〇2R8 group of groups In yet another specific example, the present invention relates to a group in which each p is independently selected from the group consisting of a Ch-alkyl (alkene / alkynyl) group, a halogen, and a soj8 (wherein R8 is an aryl group). Compounds of this type. ^ In yet another specific example, at least one of the substituents π is c alk (ene / alkynyl). In yet another specific example, at least one of the substituents R5 is Fangmei in yet another specific example. In an example, at least one substituent R5 is c alk (ene / alkyne) oxy. 16_ In yet another specific example, at least one substituent RS is ~ s002, In yet another specific example, At least one substituent R5 is a 甴 In yet another specific example, at least one substituent h'ir JS jr +4. ^ Animal atom 'which is selected from the group consisting of A group of bromine and iodine. In yet another specific example, at least one substituent R5 is fluorine. In yet another specific example, at least one substituent R5 is chlorine. In yet another specific example, At least one substituent R5 is bromine. In yet another specific example, at least one substituent R5 is-. In a specific example, at least one substituent R5 is NR7R7, and at least one of R7 and R7 'is aromatic. In a specific example, at least one substituent R5 is -NR7R ?, and at least one of 彳 R is selected from the group consisting of gas, Cu-fired (fluorene / block), 22 200413280 C3-8 A group consisting of a cycloalkene group and a C3_8-cycloalk (en) yl group-Cp6-alk (en / alkynyl) group. In another specific example, at least one substituent R5 is -NW; and R7 And R7, at least one of them is selected from the group consisting of hydrogen and Ci 6 -alk (ene / alkynyl) groups. In yet another specific example, at least one substituent R5 is ~ NR7R7, and R7 and At least one of R7 'is a c "-alk (en, alkynyl) group.

在又另一個具體實例中，至少一個取代基R5是—NR?R7, 且R和R7二者皆為C卜6-烷（烯/炔）基。 8 B在一個具體實例中，至少一個取代基R5是-S〇2R8;而 /疋NR R ,其中R9和R9’係獨立地選自於氫、（卜6一烷（稀/块）基、c3_8-環烧（烯）基及c3 8-環烷（烯）基一c卜 6一烷（烯/炔）基所組成之群組。 8 乂 , 一個具體實例中，至少一個取代基R5是一s〇2R8 ;而 ^係邊自於Ch-烧（烯/快）基、CH —環烧（稀）基、一In yet another specific example, at least one of the substituents R5 is —NR? R7, and both R and R7 are C6-alkane (alkene / alkynyl) groups. 8 B In a specific example, at least one substituent R5 is -SO2R8; and /; NR R, wherein R9 and R9 'are independently selected from hydrogen, (6-dioxane (dilute / block) group, A group consisting of c3_8-cycloalkyl (en) yl and c3 8-cycloalkyl (en) yl-c6-alkyl (alkynyl). 8 乂, In a specific example, at least one substituent R5 is A s〇2R8; and ^ system edge from the Ch-alkyl (ene / fast) group, CH-cycloalkyl (dilute) group, a

衣烧（烯）基-Ch-燒（烯/快）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R5是一S02R8 ;而κ8是芳基。在又另一個具體實例中，本發明係關於其中γ具有式 11之這類化合物。 ’、在又另一個具體實例中 111之這類化合物。在又另一個具體實例中 1 lb或nib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 23 200413280 (R\A group consisting of isen (en) yl-Ch- (en / quick) and aryl. In yet another specific example, at least one substituent R5 is -S02R8; and κ8 is aryl. In yet another specific example, the invention relates to compounds of this type wherein γ has formula 11. ', In yet another embodiment, such compounds of 111. In yet another specific example, 1 lb or nib of this type of compound ... The present invention relates to the formula wherein γ has the formula The present invention relates to the formula wherein γ has the formula 23 200413280 (R \

nbnb

其中W、m、n、p及R5係如以上所定義者。 Y具有式在又另一個具體實例中，本發明係 IIb<這類化合物。、/、中W, m, n, p and R5 are as defined above. Y has the formula In yet another embodiment, the invention is a compound of the type IIb < ,/,in

在又另一個具體實例中 Y具有式lib之這類化合物。在又另一個具體實例中 111 b之运類化合物。本發明係關於其中m是〇且本發明係關於其中γ具有式 Υ具有式Illb之這類化合物在又另-個具體實例中，本發明係關於其中〇 γ具有式nib之這類化合物。In yet another specific example Y has a compound of the formula lib. In yet another specific example, this compound is 111b. The present invention pertains to compounds of this type in which m is 0 and the present invention pertains to formulas VII and llb in another embodiment.

在又另-個具體實例中，本發明係是0且Y具有式mb之這類化合物。、中… 在又另-個具體實例中，本發 Illb且n + p是i之這 Ί Y具有是UP是0,而在其另—個特定能揭/、4寺疋悲樣中 μ玄, 特疋悲樣中，η是〇且口是！在又另一個具體實例中 y p疋 ’本么明係關於直中γ且发 Illb且n + p是2之這類 /、甲ϊ /、有是2且Ρ是〇;而在其另一他枯 4寺&祕中。個特定態樣中，η是1且p @ 24 200413280 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屮、11132、111)3、111131、111132、111133或111134之這類化合物： R5"In yet another specific example, the present invention is a compound of the type 0 and Y has the formula mb. , In ... In yet another specific example, the present issue Illb and n + p is i, Ί Y has UP is 0, and in another specific can reveal /, 4 temple sorrow μ μ In the special case, η is 0 and the mouth is! In yet another specific example, yp 疋 'benmemin is about the type of / in the middle of γ and issued Illb and n + p is 2 /, ϊ / / is 2 and P is 0; and in other other Ku 4 Temple & Secret. In a specific aspect, η is 1 and p @ 24 200413280. In yet another specific example, the present invention relates to a class in which Y has the formula 11 屮, 11132, 111) 3, 111131, 111132, 111133, or 111134. Compound: R5 "

nib1nib1

(R5)s(R5) s

nib3nib3

R5.R5.

nib4 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 200413280 R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。在又另一個具體貫例中，本發明係關於這類化合物，其中： m是0且γ具有式IIb;或 π是0且γ具有式nib ;或 P是0且Y具有式Illb ;或 n是〇、P是〇且Y具有式Iiib;或 Y具有式是1且P是0 ;或 nib且η + p是J，在其一特定態樣中，n 而在其另一個特定態樣中，η是〇且ρ是ιnib4 where w is as defined above; r is 0, 1, or 2; s is 0, 1, 2, or 3; and 25 200413280 R and R5 are independently as defined by R5, and each R5 is independently as As defined above. In yet another specific embodiment, the invention relates to compounds of this type, wherein: m is 0 and γ has formula IIb; or π is 0 and γ has formula nib; or P is 0 and Y has formula Illb; or n Yes 〇, P is 〇 and Y has the formula Iiib; or Y has the formula 1 and P is 0; or nib and η + p is J, in one particular aspect, n and in another particular aspect , Η is 0 and ρ is ι

Υ具有式是2且ρ是0 •’或 mb且η + ρ是2，在其一特定態樣中，η •’而在其另—個特定態樣中，η是1且ρ是i Y具有式I lb1 ;或I lb2 •，或 Illb3 ;或 Illb4。或 nb3 ;或 nibi ;或 nib2Υ has the formula 2 and ρ is 0 • 'or mb and η + ρ is 2. In one particular aspect, η •' and in another particular aspect, η is 1 and ρ is i Y Has the formula I lb1; or I lb2 •, or Illb3; or Illb4. Or nb3; or nibi; or nib2

在又另一個具體實例 lib1 ;或 lib2 ;或 lib3 ; 這類化合物。中本發明係關於其中γ具有式或其中m是〇且γ具有式nb之在又另一個具體實例中 11 b1之這類化合物。在又另一個具體實例中 lib2之這類化合物。本务明係關於其中γ具有式本發明係關於其中γ具有式 26 200413280 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 nibl，或 IIIb2 ;或 Illb3 ;或 nib4 ;或 11是0真Y具有式Illb;或In yet another specific example lib1; or lib2; or lib3; such compounds. The present invention relates to compounds of this type in which γ has the formula or wherein m is 0 and γ has the formula nb in yet another embodiment. In yet another specific example, such compounds of lib2. The present invention relates to a compound in which γ has a formula. The present invention relates to a compound in which γ has a formula. In yet another specific embodiment, the present invention relates to such compounds, γ has the formula nibl, or IIIb2; or Illb3; or nib4; or 11 is 0 true Y has formula Illb;

p是0且Y具有式IIIb;或 η是〇、P是0且Y具有式nib;或 p疋1，在其一特定態樣中，n 個特定態樣中，n是0且p是i 是 Y具有式IIIb且n + 1且P是0，而在其另一或p is 0 and Y has formula IIIb; or η is 0, P is 0 and Y has formula nib; or p 疋 1, in one particular aspect, n of 0 are p and i Is Y having formula IIIb and n + 1 and P is 0, and in another or

γ具有式且P是0 n + p是2,在其-特定態樣中，而在其另-個特定態樣中，n是（且p 在又另一個具體實例中 11 lb1之這類化合物。在又另一個具體實例中 I Hb2之這類化合物。在又另一個具體實例中 II lb3之這類化合物。在又另一個具體實例中 11 lb4之這類化合物。在又另一個具體實例中 11 c或π I c之這類化合物：本發明係關於其中γ具有式本Is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具有式本杂明係關於其中Y具有式γ has the formula and P is 0 n + p is 2. In one particular aspect, and in another particular aspect, n is (and p is 11 lb1 in another specific example.) In yet another embodiment, such compounds as I Hb2. In yet another embodiment, these compounds are II lb3. In yet another embodiment, these compounds are 11 lb4. In yet another embodiment 11 c or π I c of this type of compound: The present invention relates to the formula wherein γ has the formula Is, the system relates to the formula wherein γ has the formula The invention relates to the formula wherein γ has the formula Y has formula

27 200413280 (R\27 200413280 (R \

ΠοΠο

其中、m、n、p及R5係如以上所定義者。具有式在又另一個具體實例中，本發明係關於其中 11 c之這類化合物。Among them, m, n, p and R5 are as defined above. In yet another embodiment, the invention relates to compounds of this type.

在又另一個具體實例中 Y具有式lie之這類化合物。在又另一個具體實例中 111 c之运類化合物。本發明係關於其中m是〇且本發明係關於其中γ具有式另—個具體實例中，本發明係關於其中n是〇 Y具有式IIIc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IIIc之這類化合物。In yet another embodiment Y has a compound of the formula lie. In yet another specific example, this compound is 111 c. The present invention pertains to compounds in which m is 0 and the present invention pertains to formulas in which γ has a formula. In another specific example, the present invention pertains to compounds of this type wherein n is 0 and Y has formula IIIc. In yet another specific example, the invention relates to compounds of this type in which γ has formula IIIc.

在又另個具體實例中，本發明係關是。且y具有式me之這類化合物。中… 在又另一個具體實例中， IIIc且n + P是1之㈣/ _其中γ具有是up是〇,而在其另_ /、特义悲樣中 .^ χ 乂特疋恶樣中，η是〇且η菩1 在又另一個具體實例且Ρ疋1 Τ Τ Τ 0 n + e ’本發明係關於其中γ且；^ IIIc且η + ρ是2 /、甲Υ具有 θ Λ 類化合物，在其一牲中…4装山是2且Ρ是〇，而在发2 ^特疋悲樣中。〃另一個特定態樣中，η是…是 28 200413280 在又另一個具體實例中，本發明係關於其中Y具有下列式 lie1、lie2、lie3、IIIc1、IIIc2、IIIc3 或 IIIc4 之這類化合物： Πο1In yet another specific example, the present invention is related. And y has a compound of the formula me. In ... In yet another specific example, IIIc and n + P are 1 of ㈣ / _ where γ has up is 0, and in other _ /, special sadness. ^ Χ 乂特乂 evil , Η is 0 and ηρ1 is yet another specific example and ρ1 Τ Τ Τ Τ 0 n + e 'The present invention is about γ and; ^ IIIc and η + ρ is 2 /, and formazan has θ Λ class The compound, in one of them ... 4 Zhuangshan is 2 and P is 0, and in the case of 2 2 疋疋. 〃 In another specific aspect, η is ... is 28 200413280 In yet another specific example, the present invention relates to compounds in which Y has the formula lie1, lie2, lie3, IIIc1, IIIc2, IIIc3 or IIIc4:

He2He2

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 200413280 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0且Y具有式lie;或 n是0且Y具有式IIIc ;或 p是0且Y具有式IIIc ;或 η是0、P是0且γ具有式IIIc;或Where W is as defined above; r is 0, 1, or 2; s is 0, 1, 2, or 3; and 29 200413280 R5 and R5 '' are independently as defined by R5, and each R5 is independently As defined above. In yet another specific example, the invention relates to compounds of this type, wherein: m is 0 and Y has the formula lie; or n is 0 and Y has the formula IIIc; or p is 0 and Y has the formula IIIc; or η is 0, P is 0 and γ has formula IIIc; or

γ具有式 1且P是0 或 IIIc且n + p是1，在其一特定態樣中，η 而在其另一個特定態樣中，η是0且ρ是1γ has the formula 1 and P is 0 or IIIc and n + p is 1, in one particular aspect, η and in another particular aspect, η is 0 and ρ is 1

Υ具有式是2且Ρ是0 nic且η + ρ是2，在其一特定態樣中，^ 而在其另一個特定態樣中，η是1且ρ是1 ，•或 γ具有式I Ic1 ;或I Ic2 ;或 Illc3 ;或 IIIC4。在又另/個具體實例中 lie1 ;或 iIc2 ;或 IIc3 ;或化合物。在又另 < 個具體實例中 IIci之這類化合物。在又男/個具體實例中 IIc2之這類化合物。在又另/個具體實例中或 lie3;或 nic1;或 IIIc2 本發明係關於其中γ具有式是0且Y具有式IIc之這類本發明係關於其中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Υ has the formula 2 and P is 0 nic and η + ρ is 2. In one particular aspect, ^ and in another particular aspect, η is 1 and ρ is 1, or γ has formula I Ic1; or I Ic2; or Illc3; or IIIC4. In yet another / specific example, lie1; or iIc2; or IIc3; or a compound. In another < other specific example, such compounds of IIci. In yet another specific example, such compounds of IIc2. In yet another / specific example, or lie3; or nic1; or IIIc2, the present invention is about such a type in which γ has a formula of 0 and Y has a formula IIc. The invention relates to the formula in which γ has the formula

30 200413280 11C3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：、° Y 具有式 IIIc1;或 IIIC2;或 IIIc3;或 Ilic4;或 η是0且γ具有式Iiic ;或 P是0且Y具有式IIIc ;或 η是0、p是0且Y具有式nic;或 P是1，在其一特定態樣中，n 個特定態樣中，η是0且0是i30 200413280 11C3. In yet another specific example, the present invention relates to compounds of the type wherein:, Y has formula IIIc1; or IIIC2; or IIIc3; or Ilic4; or η is 0 and γ has formula Iiic; or P is 0 and Y has Formula IIIc; or η is 0, p is 0, and Y has the formula nic; or P is 1, in one particular aspect, n specific aspects, n is 0 and 0 is i

Y具有式Iiic且n + 是1且p是〇，而在其另一 ;或 γ具有式I!Ic且n + 是2且p是〇，而在其另一 P是2，在其一特定態樣中，n 個特定態樣中，Q !且？是i 在又另/個具體實例中 11 Ic1之這類化合物。在又另/個具體實例中 11 Ic2之這類化合物。在又另，個具體實例中 11 Ic3之這類化合物。在又另/個具體實例中 I lie4之這類化合物。在又另/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γ具有式本發明係關於其中γ具有式本發明係關於其中r是0之 31 200413280 之 Γ是2之在又另一個具體實例中，本發明係關於其中這類化合物。 ~ 在又另一個具體實例中，本發明係關於其中這類化合物。 ^ 之在又另一個具體實例中，本發明係關於其中s日這類化合物。、尺在又另一個具體實例中，本發明係關於其中s η 或3之這類化合物。、疋1、之在又另一個具體實例中，本發明係關於其中式11 代表下列之這類化合物：或Y has the formula Iiic and n + is 1 and p is 0, and at its other; or γ has the formula I! Ic and n + is 2 and p is 0, and at its other P is 2, at one particular In the aspect, among the n specific aspects, Q! And? Is i in another / specific example 11 Ic1 of this type. In yet another / specific example 11 Ic2 of this type. In yet another specific example, compounds of this type are Ic3. In yet another / specific example, compounds of this type. In yet another / specific example, such compounds ° The present invention is about where γ has a formula The present invention is about where γ has a formula The invention is about where γ has a formula The invention is about where γ has a formula Yes 0 to 31 200413280 Γ is 2 In yet another embodiment, the present invention relates to such compounds. ~ In yet another embodiment, the present invention relates to such compounds. In another specific embodiment, the present invention relates to compounds of this type. In another specific embodiment, the present invention relates to compounds of this type in which s η or 3. In another specific embodiment, the present invention relates to compounds in which formula 11 represents the following: or

IlbM 或 lib2;或 Iib3 ;或 IIch 或 Ilc2; ;或 lie3 ; 式lib之基團，其中m是〇;或式lie之基團，其中m是〇。 II之γ 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： $ I lb1 ;或 I lb2 ;或 lib3 ;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U 代表下列之這類化合物：之γ jllb1 ;或 Illb2 ;或 Illb3 ;或 IIIb4 ;或 nici •口 IIIc2 ;或 IIIc3 ;或 my ;或 c ’ 或 32 200413280 式IIIb之基團，其中η是〇;戋式Illb之基團，其中p是〇·戈式II lb之基團，其中η是〇 ^ T U且Ρ是〇 ;或式Illb之基團，其中n+ ^ ，n是i且D是〇， Ρ是1，在其一特定態樣今 η疋1且ρ疋〇，而在其另一是1;或個特定態樣中，…且 Υ具有式Illb且η + ρ是是2且Ρ是0,而在其另― /其-特定態樣中，】 ; 特疋態樣中，η是！且ρ是: 式〗IIc之基團，其中η是〇;戋IlbM or lib2; or Iib3; or IIch or Ilc2 ;; or lie3; a group of formula lib, where m is 0; or a group of formula lie, where m is 0. Γ of II In yet another embodiment, the present invention relates to compounds in which the formula represents the following: $ I lb1; or I lb2; or lib3; or a group of formula lib, where m is 0; or formula lie A group in which m is 0. In yet another specific example, the invention relates to compounds in which formula U represents the following: γ jllb1; or Illb2; or Illb3; or IIIb4; or nici • IIIc2; or IIIc3; or my; or c ' Or 32 200413280 a group of formula IIIb where η is 0; a group of formula Illb where p is a group of formula II lb where n is 〇 TU and P is 0; or a group of formula Illb A group, where n + ^, n is i and D is 0, and P is 1, in one particular aspect η 疋 1 and ρ 疋〇, and in the other aspect 1; or in a particular aspect, ... and Υ has the formula Illb and η + ρ is 2 and P is 0, and in its other-/-specific aspect,]; in the special aspect, η is! And ρ is: a group of the formula IIc, where η is 0; 戋

式IIIc之基團，其中？是式IIIc之基團，其中式IIIc之基團，其中η + ，11是1且ρ是0，而在其另一是1 ;或〇 ;或 0且Ρ是0 ;或 Ρ是1，在其一個特定態樣中，特定態樣中 η是0且ρ Υ具有式IIIc且η + 是2且ρ是〇，而在其另_ Ρ疋2，在其一特定態樣中，η 個特定態樣中，η是1且ρ是iA group of formula IIIc, in which? Is a group of formula IIIc, wherein the group of formula IIIc, where n +, 11 is 1 and ρ is 0, and the other is 1; or 0; or 0 and P is 0; or P is 1, In one particular aspect, in the particular aspect, η is 0 and ρ Υ has the formula IIIc and η + is 2 and ρ is 0. In another specific aspect, in its specific aspect, η specific In the aspect, η is 1 and ρ is i

在又另一個具體實例中 Y代表下列之這類化合物： 11 lb2 ;或 11 Ic2 ;或本奄明係關於其中式111之式11 lb之基團，其中式111 c之基團’其中 η是0且ρ是〇 ; η是0且ρ是〇。或 33 200413280 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11之這類化合物’在其特定態樣中，γ具有式 lib 或 lie 〇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，Υ具有式nb，而在其更多的特定態樣中，Y 具有式 lib1、lib2 或 lib3 °In yet another specific example, Y represents the following compounds: 11 lb2; or 11 Ic2; or this compound is a group of formula 11 lb with respect to formula 111, wherein the group of formula 111 c 'wherein η is 0 and p are 0; n is 0 and p is 0. Or 33 200413280 In yet another specific embodiment, the present invention pertains to compounds of this type in which m is 0 and Y has formula 11 In its particular aspect, γ has formula lib or lie. In yet another specific embodiment, , M is 1, and γ has the formula π, in one particular aspect, Υ has the formula nb, and in more specific aspects, Y has the formula lib1, lib2, or lib3 °

在又另一個具體實例中，m是1、R5係選自於一烷 (稀/快）基和_素所組成之群組且Y具有式11，在其一特定悲樣中’ Y具有式IIb ’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i、 R5是Ch-烧（烯/炔）基且γ具有式π之這類化合物，在其一特定態樣中’ Y具有式11 b ’而在其更多的特定離、樣中，Y具有式I lb1或lib3。In yet another specific example, m is 1, and R5 is selected from the group consisting of a monoalkane (diluted / quick) group and _ prime, and Y has formula 11, in one particular example, 'Y has formula IIb 'and in its more specific form, γ has the formula lib1, lib2 or lib3. In yet another specific example, the present invention relates to compounds in which m is i, R5 is a Ch-alkyl (alkene / alkynyl) group, and γ has a formula π. In a particular aspect, 'Y has a formula 11 b 'and in more specific cases, Y has the formula I lb1 or lib3.

在又另一個具體實例中，本發明係關於苴φ H /、τ Π1 疋 1、In yet another specific example, the present invention relates to 苴 φ H /, τ Π1 疋 1,

R5是鹵素原子如溴或氯或氟且Y具有式11之這類化人物，在其一特定態樣中，Y具有式I lb，而在其更多的特定能樣中，Y具有式lib1、lib2或lib3。 “ 在又另一個具體實例中，本發明係關於i申 /、丁 K1 疋 1、 R5是溴或氯且Y具有式11之這類化合物，在政一、一一特定態樣中，Y具有式I lb，而在其更多的特定態樣中，γ且 lib1、lib2 或 lib3。，、式在又另一個具體實例中，本發明係關於其中班是 R3是烷（烯/炔）基且Y具有式π之這類化：物1 : 34 200413280 特定悲樣中，Y具有式在其 ........... …识夕 ”文夕的特定態樣中，Υ具有式lib1、lib2或nb3，而在士 /、破特定的態樣中，Y具有式Π b3。R5 is a halogen atom such as bromine or chlorine or fluorine and Y has a formula such as Y. In one particular aspect, Y has the formula I lb, and in more specific energy forms, Y has the formula lib1 , Lib2, or lib3. "In yet another embodiment, the present invention relates to a compound of the type i //, D1, K1, R1, R5 is bromine or chlorine, and Y has formula 11. In a specific aspect, Y has Formula I lb, and in its more specific aspect, γ and lib1, lib2, or lib3. In a further specific embodiment, the present invention relates to a group in which R3 is an alk (alkynyl) group And Y has this kind of transformation of the formula π: thing 1: 34 200413280 In the specific sadness, Y has the formula In its particular aspect of Wen Xi, Wen Xi, Υ has Formula lib1, lib2, or nb3, and in a particular aspect, Y has formula Π b3.

在又另一個具體實例中，本發明係關於其中βΐ是C 6-烷（烯/炔）基、m是1、R5是（:丨焓r泣/ 疋卜 μ沉（烯/炔）基或鹵素且Υ具有式II之這類化合物，在直_ 牧丹特定態樣中，Υ 具有式nb，而在其一更特定態樣中，γ具有式iib3。在又另一個具體實例中，本發明係關於其"中η是〇、In yet another specific example, the present invention relates to wherein βΐ is a C 6-alkane (alkene / alkynyl) group, m is 1, R5 is (: Halogens and compounds of formula II in which Υ has a formula nb in a particular form of _ Moutan, and γ has a formula iib3 in a more specific form. In yet another specific example, this The invention is about its " where n is 0,

是0且γ具有式m之這類化合物；在其特定=、具有式Illb或IIIc。在又另-個具體實例中，本發明係關於其中且 γ具有式III之這類化合物，在其特定態樣+，Y具有式 111 b或111C，而在其更多的轉# /、夕的特疋悲樣中，Y具有式nib2 、Illb3 或 IIIc2。 ρ Ά Υ Ά ρ是 Υ β 在又另-個具體實例中，本發明係關於其中η 具有式m之這類化合物；在其一特定態樣中Is 0 and γ has a compound of the formula m; at its specific =, it has the formula Illb or IIIc. In yet another specific example, the present invention pertains to compounds of this type in which γ has formula III, in its specific form +, Y has formula 111 b or 111C, and in more of its transitions In particular, Y has the formula nib2, Illb3, or IIIc2. ρ Ά Υ Ά ρ is Υ β In yet another specific example, the invention relates to compounds of this type in which η has the formula m; in one particular aspect

有式111C ;而在其一更特定能# 疋您板中，Y具有式IIIc2 在又另一個具體貫例中士』中’本發明係關於其中η - 2且Υ具有式ΙΠ之這類化入舲· — * ^ ^ ϋ物，在其一特定態樣中，ϊ 有式Illb;而在其一更特定能好疋怨樣中，γ具有式nib2There is a formula 111C; and in one of its more specific capabilities, #Y has a formula IIIc2 In yet another specific embodiment, “The present invention is about such a type in which η-2 and舲 · — * ^ ^ In a particular aspect, ϊ has the formula Illb; and in a more specific aspect, γ has the formula nib2

Illb3 。在又另一個具體實例中，田w疋虱原子，Y不具有 11° 在又另一個具體實例中，4 τ ^ ^ 式I化合物含有不多於3 如本文所疋義之方基。 35 200413280 下α單之化合物及其醫藥上可接受之鹽為較佳者： {2月女基4 [(5-氣一噻吩一2一基甲基）一甲基一胺基]一苯基 }-胺基甲酸乙酯； {2-月女基-4-[ (5-氯一噻吩一2一基甲基）一胺基]一苯基卜胺基甲酸乙酯； {2-胺基-4 - [(5—甲基-噻吩—2 一基甲基卜甲基-胺基]一笨基}-胺基曱酸乙酯； {2_胺基-4-[ (5-溴—噻吩—2-基甲基）一胺基]—苯基卜胺基甲酸乙酯； {2-胺基-4-[(6-氣-3-甲氧基-苯并[b]噻吩-2-基甲基 )-胺基]-苯基}-胺基甲酸乙酯； {2_胺基-4-[(苯并[b]暖吩—2-基甲基）-胺基]-苯基}-胺基甲酸乙酯； {2-胺基-4-[(5-甲基吩-2-基甲基）-胺基]-苯基胺基甲酸乙酯； {2-胺基-4-[(4-溴-3-甲氧基-噻吩-2-基甲基）-胺基]-苯基}-胺基曱酸乙酯； {2-胺基-4-[(5-苯基-噻吩-2-基曱基）-胺基]-苯基}-胺基甲酸乙醋； {2-胺基_4-[(3-氣-噻吩-2-基甲基胺基]-苯基卜胺基曱酸乙酯； (2 -胺基-4-{[4-（4-氯-苯石黃酿基）-3-甲基-瞳吩-2-基甲基]-胺基}-苯基）一胺基甲酸乙酯； {2-胺基-4-[(3-甲基-噻吩-2-基曱基）-胺基]-苯基}- 胺基甲酸乙酯； 200413280 {2-胺基-4-[(5-氟-苯并呋喃-3-基甲基）-胺基]一苯基 }-胺基曱酸乙酯； {2-胺基_4-[(噻吩-2-基甲基）-胺基]-苯基}-胺基曱酸乙酉旨； {2-胺基_4-[(4-溴-噻吩-2-基曱基）-胺基]-苯基}-胺基曱酸乙酯； { 2-胺基-4-[(5-乙基-噻吩-2-基曱基胺基]-苯基}-胺基曱酸乙酯； {2-胺基_4-[(噻吩-3-基甲基）-胺基]-苯基}-胺基曱酸乙酯； {2-胺基-4 - [(5 -氣-瞳吩-2-基曱基）-乙基-胺基]-苯基 }-胺基曱酸乙酯； {2-胺基_4-[(苯并[b]噻吩—3 —基曱基）一胺基]一苯基}一胺基曱酸乙酯； {2-胺基-4-[(5-二甲基-胺基—笨并[b;|噻吩—3一基甲基 )-胺基]-苯基} 胺基曱酸乙g旨； {2-胺基-4-[(5-二曱基—胺基_3-曱基—苯并[b]噻吩一2一基曱基）-胺基]-苯基卜胺基甲酸乙酯； U-胺基-4-[(5-氟-噻吩_2-基曱基）一胺基]一苯基卜胺基甲酸乙酯； {2-胺基-4-[(苯并[b]噻吩_2一基甲基）一胺基]一苯基}一胺基曱酸丙酯； {2-胺基-4-[(苯并[b]噻吩_3_基甲基）_胺基]_苯基卜胺基曱酸丙酉旨； 37 200413280 (2月女基一 4—[(5一氣一噻吩-2-基曱基）胺基]-苯基}-2 -(4-氟-苯基）-乙醯胺；及 ^丨2月女基—4—[ (5一氣—噻吩-2-基曱基）胺基]-苯基卜 3，3 -一曱基-丁酿胺。特定心樣中，下清單之化合物及其醫藥上可接受之鹽為較佳者：胺基-4-[(5—氯一瞎吩-2_基甲基）一甲基一胺基]一苯基 } -胺基曱酸乙酯； {2-胺基-4-[(5〜氯_噻吩_2_基甲基）_胺基卜苯基卜胺基甲酸乙酯； {2-胺基-4-[(5〜甲基_噻吩_2_基甲基甲基一胺基]-苯基} -胺基曱酸乙酯； {2月女基4 [(5〜溴一噻吩-2-基甲基）一胺基]一苯基卜胺基甲酸乙酯； {2-胺基一4 一 [(6〜患—q 一田g# 乳一 3-曱乳基—本并[b]噻吩-2-基甲基 )月女基]-本基}-胺基曱酸乙酉旨； &胺&+[(笨并㈤瞳吩—2_基甲基）_胺基卜苯基卜胺基曱酸乙酯； {2月女基4 [(5〜甲基一噻吩一2 —基甲基）一胺基卜苯基卜胺基曱酸乙酯； {2-胺基-4-[(4〜填_3_甲氧基，吩__2_基甲基胺基卜苯基卜胺基曱酸乙酉旨； {2月女基4 [(5〜笨基一噻吩一 2 —基曱基卜胺基]一苯基卜胺基甲酸乙酯； 38 200413280 {2-胺基-4〜[(3-氣-Hi吩-2-基曱基）-胺基]-苯基卜胺基曱酸乙酯； (2-月女基-4〜{[4-(4-氣-苯石黃酿基）-3-曱基-瞳吩-2-基曱基]-胺基}-笨基）一胺基甲酸乙酯； {2-胺基-4〜[(3-曱基-噻吩-2-基甲基）-胺基]-苯基卜胺基曱酸乙酯； {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-[(噻吩—2-基甲基）-胺基]-苯基}-胺基曱酸乙酯； {2-胺基-4-[(4-溴-噻吩-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-基曱基）一胺基]一苯基卜胺基甲酸乙酯； {2-胺基~4-[(噻吩—3-基甲基）一胺基]一苯基} 一胺基曱酸乙酯；及 {2-胺基-4-U5-氯—噻吩一2_基甲基）_乙基—胺基]_苯基 }-胺基曱酸乙酷。 --…小丄W双里；少-種如以上所定義之< ϊ化合物或其醫藥上可接受之鹽及-或多種或醫藥上可接受之載劑或稀釋劑的醫藥組成：〇在-特定態樣中，本發明提供一種包含治療上有效量 39 200413280 之至少一種如以上所定義之式之酸加成鹽及一或多種或醫藥醫藥組成物。 1化合物或其醫藥上可接受上可接受之載劑或稀釋劑的本發明提供一種口服★ 服或非經腸投藥用醫藥組成物，該面樂組成物包含治療上有Illb3. In yet another specific example, the field tick atom, Y does not have 11 °. In yet another specific example, 4τ ^^ The compound of formula I contains no more than 3 square groups as defined herein. 35 200413280 The compounds of the alpha mono and their pharmaceutically acceptable salts are better: {February 4 [(5-Gas-thiophene-2 2-ylmethyl) -methyl-amino]] phenyl } -Ethyl aminoformate; {2-Methynyl-4-[(5-chloro-thiophene-2 2-ylmethyl) -amino] -phenylphenylaminoformate; {2-amino -4-[(5-methyl-thiophene-2 monomethylmethylmethyl-amino] monobenzyl} -aminomethyl ethyl acetate; {2-amino-4- [(5-bromo-thiophene— 2-ylmethyl) monoamino] -phenylphenylaminocarboxylate; {2-amino-4-[(6-gas-3-methoxy-benzo [b] thiophen-2-yl (Methyl) -amino] -phenyl} -urethane; {2-amino-4-[(benzo [b] nuphen-2-ylmethyl) -amino] -phenyl} -Ethylaminoformate; {2-amino-4-[(5-methylphen-2-ylmethyl) -amino] -phenylaminoformate; {2-amino-4- [(4-Bromo-3-methoxy-thien-2-ylmethyl) -amino] -phenyl} -aminophosphonic acid ethyl ester; {2-amino-4-[(5-phenyl -Thien-2-ylfluorenyl) -amino] -phenyl} -aminocarboxylic acid ethyl acetate; {2-amino_4-[(3-gas-thien-2-ylmethylamino) -benzene Ethyl phenylaminophosphonate; (2-amino-4-{[4 -(4-Chloro-benzoxanthenol) -3-methyl-pidophen-2-ylmethyl] -amino} -phenyl) monoaminoformate; {2-amino-4- [(3-methyl-thien-2-ylfluorenyl) -amino] -phenyl} -urethane; 200413280 {2-amino-4-[(5-fluoro-benzofuran-3 -Ylmethyl) -amino] monophenyl} -aminoammonium ethyl ester; {2-amino_4-[(thien-2-ylmethyl) -amino] -phenyl} -amino Ethyl acetate; {2-amino_4-[(4-bromo-thien-2-ylfluorenyl) -amino] -phenyl} -aminoacetic acid ethyl ester; {2-amino-4 -[(5-ethyl-thien-2-ylfluorenylamino] -phenyl} -aminosulfonic acid ethyl ester; {2-amino_4-[(thien-3-ylmethyl) -amine Phenyl] -phenyl} -aminoethyl ethyl; {2-amino-4-[(5 -qi-tidophen-2-ylfluorenyl) -ethyl-amino] -phenyl} -amine Ethyl amidinoacetate; {2-amino_4-[(benzo [b] thiophen-3-ylamino) monoamino] -phenyl} monoaminoethylacetate; {2-amino -4-[(5-Dimethyl-amino-benzyl [b; | thiophene-3-ylmethyl) -amino] -phenyl} amino ethyl acetate; {2-amino- 4-[(5-Difluorenyl-amino_3-fluorenyl-benzo [b] thiophene-2 2-ylfluorenyl) -amino] -phenylimino Ethyl acetate; U-amino-4-[(5-fluoro-thiophen_2-ylfluorenyl) monoamino] -phenylphenylamino aminoformate; {2-amino-4-[(benzene Benzo [b] thiophen_2 monomethyl) monoamino] monophenyl} monoaminopropyl propyl ester; {2-amino-4-[(benzo [b] thiophene-3-ylmethyl] ) _Amino group] _Phenylphenylamino acetic acid propionate; 37 200413280 (February 4-[(5-aqi-thiophen-2-ylfluorenyl) amino] -phenyl} -2- (4-fluoro-phenyl) -acetamidine; and February feminine-4 [(5-monoki-thiophen-2-ylfluorenyl) amino] -phenylbu 3,3-monofluorenyl -Butyramine. In a specific sample, the compounds listed below and their pharmaceutically acceptable salts are preferred: Amino-4-[(5-chloro-benzophen-2-ylmethyl) -methyl-amino]] Phenyl}-Ethyl aminosulfonic acid ethyl ester; {2-Amino-4-[(5 ~ chloro_thiophene_2-ylmethyl) _aminophenylphenylphenylaminocarbamate; {2-amine Methyl-4-[(5 ~ methyl_thiophene_2_ylmethylmethylmonoamino] -phenyl} -aminoammonium ethyl ester; {February 4 [(5 ~ bromomonothiophene- 2-ylmethyl) monoamino] ethylphenylphenylaminoformate; {2-amino-4 4-[[6 ~ AI—q 一田 g # 乳一 3- 曱乳基 — 本本 [b ] Thien-2-ylmethyl) Menyl] -benzyl} -Aminoacetic acid ethyl ester; & Amine & + [(Benzopyridin-2-ylmethyl) _Aminophenyl Ethyl phenylamino phosphonium ethyl ester; {February 4 [(5 ~ methyl-thiophene-2-ylmethyl) -amino phenyl phenyl phenyl amino ethyl oxalate; {2-amino- 4-[(4 ~ Fill_3_methoxy, phen__2_ylmethylaminophenyl phenylphenylamino acetic acid ethyl acetate; {February 4 [(5 ~ benzyl-thiophene-2 —Ethylfluorenylethylamine] -phenylphenylaminoethyl ester; 38 200413280 {2-amino-4 ~ [(3-Gas -Hiphen-2-ylfluorenyl) -amino] -phenylphenylaminophosphonic acid ethyl ester; (2-monthlyl-4-4 {{4- (4-Gas-benzoxanthenyl)- 3-fluorenyl-pidophen-2-ylfluorenyl] -amino} -benzyl) monocarbamate; {2-amino-4 ~ [(3-fluorenyl-thien-2-ylmethyl) (Yl) -amino] -phenylphenylaminophosphonic acid ethyl ester; {2-amino-4-[(5-fluoro-benzofuran-3-ylfluorenyl) -amino] -phenyl}- Ethyl aminoformate; {2-Amino-4-[(thiophen-2-ylmethyl) -amino] -phenyl} -aminoacetic acid ethyl ester; {2-Amino-4-[( 4-bromo-thien-2-ylmethyl) -amino] -phenyl-bromide ethylacetate; {2-amino-4-[(5-ethyl-thiophen-2-ylyl) Monoamino] ethylphenylphenylaminoformate; {2-amino ~ 4-[(thiophen-3-ylmethyl) monoamino] monophenyl} monoaminoethylacetate; and { 2-Amino-4-U5-chloro-thiophene-2-ylmethyl) _ethyl-amino] _phenyl} -aminoacetic acid ethyl ester. --... Small acrylamide; less-species The pharmaceutical composition of a hydrazone compound or a pharmaceutically acceptable salt thereof and / or a plurality or a pharmaceutically acceptable carrier or diluent as defined above: In a specific aspect, the present invention provides a A compound comprising a therapeutically effective amount of at least one acid addition salt of the formula 39 200413280 as defined above and one or more or a pharmaceutical or pharmaceutical composition. 1 of a compound or a pharmaceutically acceptable carrier or diluent thereof The present invention provides a medicinal composition for oral administration or parenteral administration.

丄々里之至少一種式I化合物或A 鹽及一或多種或醫藥上可接 " Ώ永上』接文之載劑或稀釋劑。在一個具體實例中，本發 4知Λ之化合物可以唯一治療有效之化合物來投予。 μ至少 at least one compound of formula I or salt A and one or more or pharmaceutically acceptable carriers or diluents. In a specific example, the compounds of the present invention can be administered as the only therapeutically effective compound. μ

在另一個具體實例中，本發明之化合物可以組合治療的-部份來投予，㈣本發明之化合物可與其他具有例如抗痙攣！·生貝之/台療上有效的化合物組合投予。這類具有抗痙攣性質之其他化合物的作用可包括但不限於對於下列之活性：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In another embodiment, the compounds of the present invention can be administered in combination-part of a treatment, and the compounds of the present invention can be combined with others such as anti-spasm! · Compound administration of compounds that are effective on raw shellfish / Taiwan therapy. The effects of such other compounds with anti-spasmodic properties may include, but are not limited to, the following activities: Ion channels, such as sodium, potassium, or calcium channels Excitatory amino acid systems, such as blockade or regulation of receptors

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。目如的抗癌筆樂物包括但不限於··替加賓（t i a g & b i n e )、卡馬西平（carbamazepine )、丙戊酸納、拉莫三啡（ lamotrigine)、加巴噴丁、普利加巴林（pregabalin)、乙琥胺（ethosuximide)、左乙拉西坦（levetiracetam) 、苯妥英（phenytoin )、托D比酯（topiramate )、峻尼沙 40 200413280 胺（zonisamide)及苯并二氮簞和巴比妥酸鹽類的成員。本發明之化合物被任何可用來增加電壓依賴性鉀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/或抑制對鉀離子通道如KCNQ族鉀離子通道中增加的離子流敏感的障礙或病狀。在一怨樣中，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。根據一態樣，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、廣泛性焦慮纟、恐慌性焦慮、強迫症、社交恐懼症1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、畏曠症及特定恐懼症。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、癲癇和癲癇持續狀態；神經病痛’如觸感痛、痛覺過敏疼痛、幻痛、與糖尿病神絰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、畏瞻症、特定恐懼症；神、里退化|±障礙，如阿兹海默氏症、亨丁頓氏舞蹈症 41 200413280 、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、I賈氏症、帕金森氏症、創傷誘發的神經退化，及 4如藥。口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。、口此，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。二據特疋怨樣，本發明之化合物被認為可用來預防、治療及/或抑制諸如驚厥、癲癇及癲癇持續狀態之類的癲癇發作症。、㈣付疋恶樣，本發Inhibitory neurotransmitter systems, such as GABA-enhanced release or blockage of GABA uptake, and / or membrane stabilization. Examples of anti-cancer pen music include, but are not limited to, tiag & bine, carbamazepine, sodium valproate, lamotrigine, gabapentin, pregabalin ( pregabalin), ethosuximide, levetiracetam, phenytoin, topiramate, zonisamide 40 200413280 and benzodiazepine and barbi Member of the Tartrate class. The compounds of the invention are used to increase the ion current in the voltage-dependent potassium channel. The compounds of the present invention are believed to be useful in preventing, treating and / or inhibiting disorders or conditions that are sensitive to increased ion currents in potassium channels such as the KCNQ family potassium channels. In one complaint, the compounds of the present invention have been found to have an effect on potassium ion channels of the KCNQ family, especially on the KCNQ2 subunit. According to one aspect, the compounds of the present invention are believed to be useful in preventing, treating, and / or inhibiting various disorders of the central nervous system, such as: seizures such as convulsions, epilepsy, and status epilepticus; anxiety disorders such as anxiety, generality Anxiety, panic anxiety, obsessive-compulsive disorder, social phobia1 present anxiety, post-traumatic stress disorder, acute stress response, adaptation disorder, suspected disorder, separation anxiety disorder, aphobia and specific phobia. Therefore, 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; neuropathic pain such as tenderness, hyperalgesia Pain, phantom pain, neuropathy related to diabetic neuropathy and neuropathy related to migraine; Anxiety disorders such as anxiety, generalized anxiety, 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; degeneracy, degeneration | ± disorders, such as Alzheimer's disease, Huntington's disease 41 200413280, 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, IJ syndrome, Parkinson's disease, trauma Induced neurodegeneration, and 4 as medicine. Neuronal hyperexcitability caused by oral withdrawal or poisoning, neurodegenerative disorders of the peripheral nervous system such as polyneuropathy and polyneuritis. As such, the compounds of the present invention are believed to be useful in preventing, treating, and / or inhibiting disorders or conditions such as seizures, neurological and migraine disorders, anxiety, and neurodegenerative disorders. According to particular complaints, the compounds of the present invention are believed to be useful in preventing, treating, and / or inhibiting seizures such as convulsions, epilepsy, and the state of epilepsy. , ㈣付疋 wicked, this hair

今、奴％ < 貧籾被認為可月Today, slavery < poverty

、防、治療及/或抑制諸如觸感痛、痛覺過敏疼痛、么尿病神經病變有關之神經病痛及與偏頭痛有關3 經病痛之類的神經病和偏頭痛障礙。本發明之化合物進—步被認為可用來預防及或抑制諸如隹虐、良、< u ’、 _ '、、、慮|泛性焦慮症、恐慌性焦慮、強迫症適m U、創傷制力症、急性a力反應、應JV礙、疑病性障礙、焦慮症、畏曠症、一般醫病狀所致之焦慮症及物的焦慮症。、料的焦慮症及特定恐懼症之 42 200413280 —步被認為可用來預防、治療及/Prevent, treat, and / or inhibit neuropathy and migraine disorders such as tactile pain, hyperalgesia, neuropathy associated with urinary neuropathy, and migraine related 3-menstrual pain. The compounds of the present invention are further believed to be useful in the prevention and / or inhibition of factors such as maltreatment, goodness, < u ', _' ,,, and general anxiety, panic anxiety, obsessive-compulsive disorder, trauma Dysfunction, acute dysfunction, response to JV, suspected disorder, anxiety, aphobia, anxiety related to common medical conditions. Anxiety Disorders and Specific Phobia 42 200413280 — Steps are considered to be used for prevention, treatment and /

元過度興奮狀態。本發明之化合物進_ 或抑制神經退化性障礙，蹈症、多發性硬化、肌蓋在另一態樣中，本發明提供在下列試驗之一或多者中顯不效用的化合物：經過KCNQ2通道之相對外流（relative efflux广，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 “毛果芸香鹼（Pilocarpine)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“抗藥性癲癇發作”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，此模式中之癲癇發作隨該動物接收進一步刺激而變得更為嚴重。 200413280 根據本發明之一特定離揭又心樣，該化合物係以小於 1 5000ΠΜ 之 EC5()而對 KCNQ2 匁双，如下文所述之“經過 KCNQ2通道之相對外流”試驗所測者。根據本發明之一特定態樣，Yuan is over excited. The compound of the present invention inhibits or inhibits neurodegenerative disorders, chorea, multiple sclerosis, and muscle caps. In another aspect, the present invention provides compounds that are not effective in one or more of the following tests: Via the KCNQ2 channel Relative efflux (relative efflux is broad, this is a measure of the compound's effectiveness in the target channel "maximum electrical shock" This is a measure of seizures induced by non-specific CNS stimulation caused by electrical methods "Pilocarpine-induced seizures Seizures induced by pilocarpine are often difficult to treat with many existing anti-seizure medications' and therefore reflect a pattern of "drug-resistant seizures." "Electrical seizure threshold test" and "chemical seizure threshold test, These modes measure the threshold of seizure initiation and are therefore a model for detecting whether compounds can delay the onset of seizures. "Amygdala activation" This is used as a measure of disease progression. In normal animals, epilepsy in this mode The seizures became more severe as the animal received further stimuli. 20041328 0 According to a specific release of the present invention, the compound is doubled to KCNQ2 with an EC5 () of less than 15,000 μM, as measured by the “relative outflow through the KCNQ2 channel” test described below. One particular aspect of the invention,

^ 4化合物係以小於1 500nM 之EC5Q而對KNQ2有效，如下々轿、+、—〜卜文所述之‘經過KCNQ2通道之相對外流”試驗所測者。^ 4 compounds are effective against KNQ2 with an EC5Q of less than 1,500 nM, as measured by the “relative outflow through the KCNQ2 channel” test described in the following text, +, — ~.

根據本發明之另一個特定 _ A 荷疋恶樣，該化合物係以小於 150nM之阢5〇而對KCNQ2有 ^ 如下文所述之“經過KCNq2 通道之相對外流，，試驗所測者。根據本發明之另一個特宏能 _ A t 田符疋匕、樣，该化合物在下文所述之“最大電休克”試驗中具有+ -、令小於15耄克/公斤之ed50。根據本發明之又另一個特定態樣，該化合物在下文所逑之“最大電休克”試驗中具有小於5毫克/公斤之EDs。。根據本發明之一转&能從 ^ ^ ♦疋L樣，該化合物在下文所述之“ 電癲癇發作閾試驗，，及/ iWL ^ ^ ^ /或化學癲癇發作閾試驗，，中具有小於5毫克/公斤之eD5q。此化百物有乂 5午或臨床上不顯著的副作用。因此這 :化σ物中有些係於化合物之不想要的鎮靜、低溫及共濟大调作用模式中受測試。有i化合物有適當的半生期和適當的清除率，表示患二而要一天吃藥例如-次或二次。這對患者而言很容易心寻二所以有助於對藥物治療的順應性。 & &些化合物中有些在抗痙攣功效和副作肖（例如活動月匕力或共濟失調作用用之缺知，如藉由在旋轉柱上表現所測 44 200413280 置者）之間有很大的治療指數。這丄目d -丨a m 衣不廷些化合物預期在見到田彳作用之前將可為允許使用高劑心 , 之患者充分耐受。因此對於此治療之順應性預期將會是良好的，且劑量之投藥，使得治療在可能對其门中更為有效。丰物有副作用的患者定義雜原子一詞係指氮、氧或硫原子。鹵素意指IL、氯、漠或蛾。According to another specific _ A charge of the present invention, the compound has KCNQ2 at a value of less than 150 nM to 50. ^ As described below, "relative outflow through the KCNq2 channel, test the test person. According to this Another special invention of the invention is _________________, this compound has an ed50 of +-, making it less than 15 试验 g / kg in the "maximum electrical shock" test described below. According to the invention In another specific aspect, the compound has EDs of less than 5 mg / kg in the "maximum electrical shock" test described below. According to one aspect of the present invention, the compound can be changed from ^ ^ The "electrical seizure threshold test, and / iWL ^^^ / or chemical seizure threshold test described below, has an eD5q of less than 5 mg / kg. This chemical has side effects that are not significant at 5 o'clock or clinically. So this: some of the compounds are tested in unwanted sedation, low temperature, and ataxia modes of the compound. Compounds with i have a proper half-life and a proper clearance rate, which means that they should take medicine once a day, for example, once or twice. This is easy for the patient to find, so it helps to adapt to medication. & & Some of these compounds have a gap between anti-spasmodic effects and side effects (such as active moon force or ataxia, such as those measured by performance on a rotating column 44 200413280) Great therapeutic index. These compounds are expected to be well tolerated by patients who are allowed to use high doses of cores before seeing the effects of tadpoles. Therefore the compliance with this treatment is expected to be good, and the dose administration makes the treatment more effective in its treatment. Patients with side effects of abundance Definition The term heteroatom refers to nitrogen, oxygen or sulfur atoms. Halogen means IL, chlorine, moth or moth.

Ci_6-烧（浠/坱）基一詞咅相 Γ „ ^ w知Ci—厂烷基、c2_6-烯基或匕2-6-炔基。The term Ci_6-alkenyl (坱 / 坱) radical 咅 Γ ^ ^ ^ ^ ^ Ci Ci-alkyl, c2-6-alkenyl or 2-6-alkynyl.

Cl-6-燒基一詞係指具有一？丄八有至/、個（含）碳原子之分支或未分支烷基，包括但不限於：工* 个限於·甲基、乙基、1-丙基、2- 丙基、1 -丁基、2 -丁基、2 一甲其9工甘n z T基-2一丙基、2-2-二甲基-1 - 丙基及2-甲基-1-丙基。山類似地，c2_6-稀基和C2 6一快基分別表示具有二至六個原子刀別包3 一個雙鍵和一個參鍵的這類基團，包括但不限於：乙烯基、而祕 ^ 丙烯基、丁烯基、乙炔基、丙炔基及丁炔基。 3一8 %烷（烯）基一詞意指c3_8-環烷基或環烯基。 3 8衣烷基周表不具有三至八個C原子之單環族或又環族碳環，包括但不四 Λ ^ π 1艮於· ％丙基、ί哀戊基、環己基等寺0 ◦3-8 一環稀基一詞矣+目士 ^ 表不具有二至八個C原子且包含一個 45 200413280 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—起形成一個視需要含有卜2或3個其他雜原子之[8員飽和或不飽和環時，則單環族㈣、㈣由4至8㈣自於氮原子、卜7 個碳原子和〇 —3個選自於N、S或。之雜原子的原子所形成者。這類環系統的例子有：氮雜環丁烧、β_内酿胺、姐口各 L、呢啡、嗎啉、1各、聘„坐貌、噻嗤炫、㈣烧、四唑及(¾唑。The term Cl-6-alkyl refers to having a?丄 A branched or unbranched alkyl group with up to, (including) carbon atoms, including but not limited to: 工 * Limited to methyl, ethyl, 1-propyl, 2-propyl, 1-butyl , 2-butyl, 2-methyl-9-glycine, T-yl-2-propyl, 2-2-dimethyl-1 -propyl, and 2-methyl-1-propyl. Similarly, c2_6-diluted and C2 6-quick radicals respectively represent such groups with two to six atoms, including a double bond and a parameter bond, including but not limited to: vinyl, and ^ Propenyl, butenyl, ethynyl, propynyl and butynyl. The term 3-8% alk (en) yl means c3-8-cycloalkyl or cycloalkenyl. 3 8-Cycloalkyl groups do not have monocyclic or cyclic carbocyclic rings of three to eight C atoms, including but not four Λ ^ π 1 roots ·% propyl, pentyl, cyclohexyl, etc. 0 ◦3-8 The term “one-ring dilute radical” + headings ^ means a monocyclic or bicyclic carbocyclic ring having two to eight C atoms and containing one 45 200413280 double bond. When two substituents together with the nitrogen atom to which they are attached form an [8-membered saturated or unsaturated ring containing 2 or 3 other heteroatoms as needed, the monocyclic group ㈣, ㈣ from 4 to 8㈣ It is selected from the group consisting of N, S7 carbon atoms and 0-3 selected from N, S or. Formed by the atoms of heteroatoms. Examples of this type of ring system are: azetidine, β-lactam, each of L, morphine, morpholine, 1 each, sit, appearance, thiazine, tertiary, tetrazolium and ( ¾azole.

芳基6司係指諸如毗唆、噻嗤、聘唑、苯基、萘基、睡吩及呋喃之類的芳族系統，其係視需要經一或多個獨立為下列各基之取代基取代：經基、齒素、Cl_6 一烧（烯/快 )基、C"-環烧（浠）基、c38_環烧（稀）基n (The aryl group 6 refers to aromatic systems such as pyridoxine, thiazole, oxazole, phenyl, naphthyl, thiophene, and furan, and is optionally substituted by one or more substituents independently Substitutions: via radicals, dentin, Cl_6 monoalkylene (ene / quick) radical, C " -cycloalkyl (fluorene) radical, c38_cycloalkyl (dilute) radical n (

稀/快）基、_基'6—燒（烯/快）基、kHL基、 c3_8-烧氧基、醢基、石肖基或氰基，普NHU (稀/快 )基 co’Ch-烷（烯^/炔）基)2，_NH_C1—6_烷（烯/ 炔）基、-N(Cl_6-烧（稀/块）基）2, _Su (稀/快 )基、—吨^-燒（烯/块）基、—s〇2〇n (稀/炔 )土 H2 S〇2N(Cb-烷（烯 / 炔）基）2 或一s〇2nH_Ch_ 烧（稀/炔）基；或者、一個相鄰取代基可連同它們所連接之芳族基團一起形成：4 8員娘’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一個視需要含右_十_ ¥ 或—個雜原子之4-8員環時，則環系統係由4-8個選白％」。，口、自於4-8個選自於3 —8個碳原子和〇 — 2個 46 選自於N、S或ο之雜鄰取代基可一起形成.、的原子所形成者。這種的二個相 -(cH2)n，‘-CH?~ 、 „ (ch2)p，‘、—ch=ch 'H=ch~(CH2)»’‘-、-ch2-ch=Ch- CH2-〇-(CH2)pl.〇_ ' -〇-(CH2)_〇- _ (CH2)m，.-S- > ^CH2-S-(CH 'CH2'〇'CH2~ ' -(CH^--S- ' -S-(CH2)n，‘-NH-、，__( ?‘ S—、-CH2~S_Cm、- CH=CH-NH-、—0〜（CH、2 m NH CH2'NH-(CH2)p,.-NH- > -Dilute / quick) group, _yl'6-alkene (quick / quick) group, kHL group, c3_8-carbyloxy, fluorenyl, schottyl or cyano group, NHU (dilute / quick) group co'Ch-alkane ( Alkenyl / alkynyl) 2, _NH_C1-6_alk (alkynyl / alkynyl), -N (Cl_6-alkyn (dilute / block)), 2, _Su (dilute / quick) group, —t ^ (-) Alkenyl / block) group, —s02on (diluted / alkynyl) earth H2 S〇2N (Cb-alk (alkene / alkynyl) yl) 2 or a sol 2nH_Ch_ (alkene / alkynyl) group; or, a Adjacent substituents can be formed together with the aromatic group to which they are attached: 48 members, which contain one or two heteroatoms as needed. When two adjacent substituents together with the aromatic group to which they are attached form a 4- to 8-membered ring containing a right_ten_ ¥ or -heteroatom as required, the ring system is selected from 4-8 White%". Or, formed by 4-8 atoms selected from 3 to 8 carbon atoms and 0 to 2 46 hetero-ortho substituents selected from N, S or ο may be formed together. This two phases-(cH2) n, '-CH? ~,' (Ch2) p, ', --ch = ch' H = ch ~ (CH2) »''-, -ch2-ch = Ch- CH2-〇- (CH2) pl.〇_ '-〇- (CH2) _〇- _ (CH2) m, .-S- > ^ CH2-S- (CH' CH2'〇'CH2 ~ '-( CH ^-S- '-S- (CH2) n,' -NH- ,, __ (? 'S—, -CH2 ~ S_Cm,-CH = CH-NH-, -0 ~ (CH, 2 m NH CH2'NH- (CH2) p, .- NH- >-

(ch2)p,‘_nh-ch2-、j CH2-0—(ch2)p，‘-nh-或-〇- P，‘是U2。爪疋1、2或3，n，‘是2、3或4,而田用山於本文時，酿基一詞係指甲酿基、烧（稀/ 块）基1^基、W環烧（稀）基幾基、芳基幾基、芳基· C"-烷（烯/炔）基羰基或c"_環烷（烯）基——6_烷( 稀/炔）基-幾基，其+ U (烯/块）基、環娱 (烯）基及芳基係如以上所定義者。(ch2) p, ‘_nh-ch2-, j CH2-0— (ch2) p,‘ -nh- or -〇-P, ’is U2. Claw 1, 2, or 3, n, 'is 2, 3, or 4, and Tian Yongshan in this article, the term brewing base refers to nail brewing base, burning (thin / block) base 1 ^ base, W ring burning ( Diluted) alkynyl, aryl, aryl, C " -alk (en / alkynyl) carbonyl or c " -cycloalk (en) yl- 6-alk (di / alkynyl) -chidyl, Its + U (ene / block) group, cycloalkene (alkenyl) group and aryl group are as defined above.

鹵基-Ch-烷（烯/炔）基一詞表示被一或多個鹵素原子取代之C卜β-烧（烯/炔）基，包括但不限於：三氟甲基。類似地，鹵基-Ch-環烷（烯）基表示被一或多個鹵素原子取代之C3_8-環烷（烯）基，而鹵基-環烷（烯）基-Cn-烧（烯/快）基表示被一或多個鹵素原子取代之 C3-8-環炫（烯）基-(ν6-烧（烯/块）基。在c3_8-環烧（烯）基-Ch-烧（烯/快）基一詞中， C3_8_環烷（烯）基及Ci_6-烷（烯/炔）基係如以上所定義 47 此外’諸如經盖-「 - ( ^ y ^ r 基C1—6杬（烯/炔）基、羥基-c38-if ：- c,6-.；；；其乳基、W環燒（嫦）氧基、C1「烧（稀/块）基幾二乂3—r:燒（烯）基幾基、芳基幾基、芳基-C1-6-燒（ =夬）基幾基、C3-「環院（稀）基-M (物）二土方基n院（婦）基、經基-C3_8-環燒（稀）土 1-6炫(婦/快)基、經基^^烧(稀/The term halo-Ch-alk (en / alkynyl) group refers to a Cβ beta-alken (en / alkynyl) group substituted with one or more halogen atoms, including, but not limited to, trifluoromethyl. Similarly, halo-Ch-cycloalkyl (en) yl represents a C3_8-cycloalk (en) yl substituted with one or more halogen atoms, while halo-cycloalk (en) yl-Cn-alkyl (ene / The fast group refers to a C3-8-cyclohexen (en) yl- (ν6-halo (en / block) group substituted with one or more halogen atoms. In a c3_8-cycloalken (en) yl-Ch-halo (ene) In the term "quick / quick", C3_8_cycloalkane (en) yl and Ci_6-alkane (alkene / alkynyl) are as defined above. 47 In addition, such as via a cap-"-(^ y ^ r group C1-6 杬(Ene / alkynyl) group, hydroxy-c38-if: -c, 6-. ;;; its lactyl group, W-ring alkoxy (fluorenyl) oxy group, C1 alkynyl (dilute / block) group, oxo 3-r : Burning (alkenyl) aryl, aryl aryl, aryl-C1-6- benzene (= fluorenyl) quinone, C3- "ring (dilute) group -M (physical) two earthwork base n ( Women's base, Jingji-C3_8-ring burn (lean) Soil 1-6xuan (woman / quick) base, Jingji ^^ burn (lean /

環燒⑷基、氮基切（稀/块）基、氛基_c二说（烯）基、氰基_w環烧（烯）基々「炫（稀/块）基、W«rh’-Ci_6_烧（烯/炔）基及 nridriq，_Ch^烧（婦 )基等之類的名詞表示其中Ci「烷（烯，炔）基、c"_環烧（烯）基及芳基係如以上所定義之基^ 、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1、銨鹽及烷基化銨鹽。Cyclofluorenyl, nitrogen-based cleavage (diluted / block), cyano_c two-supplied (en) yl, cyano_w cycloalkyl (en) yl, dazzling (diluted / block), W «rh ' -Ci_6_Alkenyl (alkene / alkynyl) group and nridriq, _Ch ^ alkenyl (alkynyl) group, etc. means that Ci "alk (alkene, alkynyl) group, c " _ cycloalkene (alkenyl) group and aryl system As defined above, the salts of the present invention are preferably pharmaceutically acceptable salts. Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metals 1, ammonium salts and alkylation Ammonium salt.

本發明之醫藥上可接受之鹽最好是酸加成鹽。酸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。攻類有機鹽的例子為與下列酸所形成者：馬來酸、富馬酸、苯甲酸、抗壞血酸、琥珀酸、草酸、雙-亞甲基水楊酸、甲烷磺酸、乙烷二磺酸、醋酸、丙酸、酒石酸、水楊酸、#棣酸、葡糖酸、乳酸、韻果酸、扁桃酸、肉桂酸 48 413280 才丁康&L天冬胺酸、硬脂酸、棕橺酸、衣康酸、乙醇酸 # 土笨甲酉夂榖胺酸、苯石黃酸和茶驗醋酸，以及§ 一函茶鹼，例如8-溴茶鹼。 *、k類無機鹽類的例子為與下列酸所形成者：氫氯酸、氩/臭馱、&馱、胺基磺酸、磷酸及硝酸。這類酸加成鹽可、:由為習4項技術者所知的方法形成。醫藥上可接受之益 1〇„ 攻意之其他例子包括列舉於/·仰打见&/· 1977，66，2 (其係以弓丨士二、、 ^ 、糸乂引用方式納入本文）中之醫藥上可接文之鹽。亦意欲作為醫蕴μ 7 > —枭上了接受之酸加成鹽者為本發明化人物所能夠形成之水合物。月化口此外，當在分子中有雙鍵或有全飽和或部分飽 ===’則可形成幾何異構物。所意欲的是，任何幾何物離、純化或部分純化之幾何異構物或其混合的分：二=:明之範圍内。同樣地，具有限制旋轉鍵結圍内。/、幾何異構物。這些也意欲包含在本發明之範The pharmaceutically acceptable salt of the present invention is preferably an acid addition salt. Acid addition salts include salts of inorganic and organic acids. 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 of organic salts are those formed with the following acids: maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, bis-methylene salicylic acid, methanesulfonic acid, ethanedisulfonic acid , Acetic acid, propionic acid, tartaric acid, salicylic acid, #gallic acid, gluconic acid, lactic acid, rhinoic acid, mandelic acid, cinnamic acid 48 413280 Zetincon & L aspartic acid, stearic acid, palmitic acid Acid, itaconic acid, glycolic acid # succinimidine, benzoic acid and theophylline acetic acid, and § a theophylline, such as 8-bromotheline. *, Examples of k-type inorganic salts are those formed with the following acids: hydrochloric acid, argon / stink, & krypton, aminosulfonic acid, phosphoric acid and nitric acid. Such acid addition salts can be formed by methods known to those skilled in the art. Other examples of medically acceptable benefits include those listed in / · 扬打见 & / · 1977, 66, 2 (which are incorporated herein by reference to Shiji II, ^, 糸乂) A salt that can be used in Chinese medicine. It is also intended as a medical connotation μ 7 > — Those who have accepted the acid addition salt are hydrates that can be formed by the invented characters. Yuehuakou In addition, when in the molecule If there are double bonds or there is full saturation or partial saturation === ', geometric isomers can be formed. It is intended that any geometrical isomers, purified or partially purified geometric isomers or a mixture thereof: two = : Within the scope of the Ming. Similarly, within the bounds of the restricted rotation bond. /, Geometric isomers. These are also intended to be included in the scope of the present invention

式存在…：t明化合物中有些可以不同的互變異構物形子长阳所意欲的是該化人W 構物# + φ δ私所能夠形成的任何互變異構物形式都包含在本發明之範圍内。文，、再者，本發明之化合物藥上可拯^ ^非溶劑化形式以及以經醫在。一知及諸如此類溶劑化之形式存是等门而§ ’就本發明之目的來說，溶劑化形式被辦為疋寺同於非溶劑化形式。飞破㈣為 49 200413280 本^月化&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《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—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φ d-或卜酒石酸鹽、扁桃酉复鹽或樟腦石黃酸鹽的分級結晶。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· CoUet和 S· Wllen在“對映異構物、外消旋物及解析，，（ “Enanti⑽erS， hCemates， and Resolutions», JohnThe formula exists ...: Some of the compounds that can be different tautomers. Changyang intends that the chemical structure W + # φ δ. Any tautomeric forms that can be formed are included in the present invention. Within range. Text, and, furthermore, the compounds of the present invention are medicinally available in unsolvated form as well as in medicine. It is known that such solvated forms exist as equals and for the purposes of the present invention, the solvated form is treated as a temple in the same way as the unsolvated form. Some of these compounds contain chiral centers, and these compounds exist as isomers (e.g., enantiomers). The invention includes all such isomers and any mixtures thereof, including racemic mixtures. Racemates can be resolved by known methods for "optical enantiomers, such as by separation of diastereomeric salts formed from optically active acids thereof, and then by treatment with bases to release optically active amine compounds. Another method of resolving racemic isomers into optical enantiomers is based on a layered method on an optically active matrix. The racemates of the present invention can also be resolved into their optical enantiomers', e.g., by fractional crystallisation of φd- or tartaric acid salt, mandelic acid double salt or camphor luteol salt. The compounds of the present invention can also be resolved by the formation of diastereomeric derivatives. Other methods known to those skilled in the art for the analysis of optical isomers can be used. Such methods include J. Jaques, A. CoUet, and S. Wllen in "Enantiomers, Racemates, and Resolution," ("Enanti⑽erS, hCemates, and Resolutions», John

Wiley and Sons，New Y〇rk (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、、二由代謝過秘進行化學轉化5而後變成藥理活性物質。一般而言，這類前驅藥物將是通式丨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丨化合物。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月,J 驅藥物設計"（"Design of Prodrugs,，， ed. Η· Bundgaard， Elsevier， 1985)中。 50 200413280 本發明亦涵蓋本發明化合物之活性代謝物。Wiley and Sons, New York (1981)). Optically active compounds can also be prepared from optically active starting materials. The present invention also covers the prodrugs of the compounds of the present invention, which are chemically transformed by metabolic processes5, and then become pharmacologically active substances when administered. In general, this type of prodrug will be a functional derivative of a compound of general formula, which can be easily converted into the desired compound of formula in vivo. The transformation procedure used for the selection and isolation of appropriate prodrug derivatives is described in, for example, Design of Prodrugs, (ed., Ed. Η Bundgaard, Elsevier, 1985). 50 200413280 The invention also encompasses active metabolites of the compounds of the invention.

、每當提及有關於式ί化合物時，癲癎一詞包括在國際防治癲癇聯盟：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HU a 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./卿^ 1989 3Q⑷：389_399 )中所提及之癲癇、瘤痛症候群及癲癇發作任一者。醫樂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。若需要’本發明之醫藥組成物可包含與其他藥理活性物貝（如前述所敘述者）組合之式丨化合物。 “本醫藥組成物可特別調配以供經由任何適當的途經投 =，例如口、直腸、鼻、肺、局部（包括口腔和舌下）、 …細池内、腹膜内、陰道及非經腸（包括皮下、肌肉解的Γ内1脈内和皮内）路徑’以口服途徑較佳。應瞭疋’較佳途徑將取決於所欲治療個體的一般病狀和年心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適:的途徑投丨，例如以藥片、夥囊、粉劑、顆粒、丸劑 ^片、樂丸或鍵劑、在水性或非水性液體中之溶液或次、或水包油或油包水液體乳劑、馳劑、糖聚等形式 51 而以口服方式投予，或3 、、式投予。其他非經腸投用溶液形式而以非經腸方液或乳劑，以及在使用樂組成物包括分散液、懸浮復原的在無菌注射用溶液或分散液之範圍内。其他適當的投::=亦被預想是在本發明桌开v式包括栓劑、喷霧劑、軟膏、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2. Whenever reference is made to a compound of formula ί, the term epilepsy is included in the International Alliance for the Prevention of Epilepsy: Proposed Modified Clinical and Electroencephalographic Classification of Seizures Epilepsy, Tumor Syndrome, and Epilepsy mentioned in HU a and the International Alliance for Epilepsy Prevention: Proposed Modified Classification of Epilepsy and Epilepsy Syndrome (Classification and Terminology Review Group of the International Alliance for Epilepsy Prevention, Gal./Qing^ 1989 3Q⑷: 389_399) Any one of them. Medical composition The compound of the present invention is generally used as a free base or a pharmaceutically acceptable salt thereof. Representative examples are mentioned above. If necessary, the pharmaceutical composition of the present invention may be Contains a compound of formula 丨 in combination with other pharmacologically active shellfish (as described above). "This pharmaceutical composition can be specially formulated for administration via any appropriate route, such as oral, rectal, nasal, pulmonary, topical (including Oral and sublingual),… intracranial, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intravascular and intradermal) pathways are compared by the oral route The preferred route will depend on the general condition of the individual to be treated and the nature of the condition to be treated and the active ingredients selected. The pharmaceutical composition of the present invention may be prepared by Appropriate: For example, as tablets, capsules, powders, granules, pills, tablets, or pills, solutions or times in aqueous or non-aqueous liquids, or oil-in-water or water-in-oil liquid emulsions Oral administration 51, oral administration, or 3 ,, or other forms of administration. Other parenteral administration solutions in the form of parenteral solutions or emulsions, and in the use of Le composition including dispersion Liquids and suspensions are reconstituted within the scope of sterile injectable solutions or dispersions. Other suitable injections:: = are also envisioned to be used in the form of a v-tablet in the present invention, including suppositories, sprays, ointments, gels, inhalants, Skin patches, implants, etc., For the preparation of such compositions, the well-known in the art can be used

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。適虽而s，本發明之化合物係以含有該化合物約ο. 至1 〇〇笔克ϊ的單位劑型來投予。總每曰劑量通常是在約〇· 05 500 宅克或甚至〇. 〇5 - 1 500 毫克或 0. 05 - 3000 氅克的範圍内，且最佳為約〇·丨至5〇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。Method ' may also use any pharmaceutically acceptable carrier, diluent, excipient, or other additive commonly used in this art. As appropriate, the compound of the present invention is administered in a unit dosage form containing the compound in the range of about ο. To 100 g. The total daily dosage is usually in the range of about 0.05 500 μg or even 0.005 to 1 500 mg or 0.05 to 3000 μg, and most preferably about 0.05 to 50 mg of this Invention of active compounds. For parenteral routes such as intravenous, intrathecal, intramuscular, and similar administration, the dose is usually about half the dose used for oral administration.

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。根據本發明之醫藥組成物可與醫樂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., 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0 52 200413280 任何其他通常為這類目的使用的佐劑或添加劑，如色料、香料、防腐劑等等，都可使用，但前提是它們要性成分相容。The compounds of the present invention can be administered alone or in combination with a pharmaceutically acceptable carrier or excipient, either in single or multiple doses. The pharmaceutical composition according to the present invention can be formulated with medically acceptable carriers or diluents and any other known adjuvants and excipients according to conventional techniques, such as disclosed in Remington: Pharmaceutical Science and Practical 19th Edition (Remington: The Science and Practice of Pharmacy, 19 Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1 995). These formulations can be conveniently formulated in unit dosage form by methods known in the pharmaceutical art. 0 52 200413280 Any other adjuvants or additives commonly used for such purposes, such as colorants, fragrances, preservatives, etc., can be used, but The premise is that they are sexually compatible.

本發明之醫藥調配物可經由此技藝中習知的方法製備。舉例來說’ t片可經由將活性成分與普通佐劑及/或稀釋劑混合，接著在習知壓片機中壓縮混合物而製得。佐劑或稀釋』的例子包括：叾米澱粉、馬鈴薯澱粉、滑石、硬脂酸鎮、明膠、乳糖、樹膠及諸如此類。任何其他通常為這類目的使用的佐劑或添加劑，&色料、香料、防腐劑等等，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之方法製備成具有包衣，例如腸溶包衣，或者它們可調配成提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，則製劑可為糖漿、乳劑、軟質明膠勝囊或無菌注射用液體如水性或非水性液體懸浮液或溶液的形式。〆The pharmaceutical formulations of the present invention can be prepared by methods known in the art. For example, a 't tablet can be made by mixing the active ingredient with a common adjuvant and / or diluent, and then compressing the mixture in a conventional tablet press. Examples of "adjuvant or dilution" include: indica starch, potato starch, talc, stearic acid, gelatin, lactose, gum, and the like. Any other adjuvants or additives commonly used for such purposes, & colorants, fragrances, preservatives, etc. can be used, provided they are compatible with the active ingredient. Where appropriate, solid dosage forms can be prepared with a coating, such as an enteric coating, according to methods well known in the art, or they can be formulated to provide controlled release of the active ingredient, such as sustained or extended release. If a liquid carrier is used, the preparation may be in the form of a syrup, an emulsion, a soft gelatin capsule, or a sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution. 〆

例如張度劑、防腐劑、抗氧化劑等等 —就非經腸投藥而言，可使用本發明新穎化合物溶於無囷水溶液、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：，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鹽 53 200413280 水或《萄糖使之具有等張性。水溶液Μ μ + 又特別適合靜脈内、肌肉内、皮下及腹膜内投藥。所用之盔_ “、、圏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：糖锻、花生油、橄欖油、磷脂、脂肪酸、脂肪酸胺、聚氧乙烯及水。同樣地，載劑或稀釋劑可包含此技藝中已知的任何持續釋放物質，例如單硬脂酸甘油酯或二硬脂酸甘油酯，單獨或與鐵混合。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： 5. 0毫克 60毫克 30毫克 2. 4毫克 19. 2毫克式I化合物乳糖玉米澱粉經丙基纖維素微晶纖維素交聯羧甲基纖維素鈉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〇 · 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 200413280 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化合物山梨糖醇經丙基纖維素甘油甲基-對羥基苯曱酸酯丙基-對經基苯甲酸酉旨乙醇香料糖精鈉水 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For example, tonicity agents, preservatives, antioxidants, etc.-For parenteral administration, a solution of the novel compound of the present invention in an aqueous solution of rhenium-free, aqueous propylene glycol, aqueous vitamin E, or sesame oil or peanut oil can be used. Solutions for injection can be prepared by dissolving the active ingredients and possible additives in a portion of the solvent for injection, preferably sterile water, adjusting the solution to the desired volume, disinfecting the solution, and filling it into an appropriate ampoule or vial in. Any appropriate additions used in this technique can be added: Therefore, such solutions should be properly buffered if necessary, and the liquid diluent should be adequately salted first. 20042004280 Water or Glucose to make it isotonic. The aqueous solution M μ + is also particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The helmets used "", "圏, water-based media are all readily available through techniques known to those skilled in the art. Appropriate pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. Liquid carrier Examples are: sugar forged, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene, and water. Similarly, carriers or diluents can include any sustained release substance known in the art, such as monostearic acid Glyceryl ester or glyceryl distearate, alone or mixed with iron. Typical examples of the formulations of the invention are as follows: 1) Tablets containing 5.0 mg of the compound of the invention as free base: 5.0 mg 60 mg 30 mg 2.4 mg 19.2 mg of compound of formula I lactose corn starch via propylcellulose microcrystalline cellulose croscarmellose sodium type A 2.4 mg magnesium stearate 0.84 mg 2) tablets containing 0.5 mg of the compound of the present invention calculated as a free base. 0.5 mg of lactose 46.9 mg of corn starch 23.5 mg of polyvinylpyrrolidone 1.8 mg 54 200413280 microcrystalline Vitamins 14.4 mg croscarmellose sodium type A 1.8 mg magnesium stearate 0.63 mg 3) Syrup, containing per milliliter: Sorbitol of the formula I via propyl cellulose glycerol methyl-p Hydroxybenzoate propyl-p-menthylbenzoate ethanol alcohol flavor saccharin sodium water 25 mg 500 mg 15 mg 50 mg 1 mg 0.1 mg 0.005 ml 0.5 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鈉水 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 200413280 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) A solution for injection, containing, per milliliter, a compound of the formula I, sorbitol sodium saccharin sodium water, 0.5 mg, 5.1 mg, 0.05 mg, 0.5 mg, and 1 mg of the compound of the present invention. Compound I, 55 200413280 wherein R1, R2, R2 ', R3, X, Y, Z and q are as defined above, prepared by the method represented in the scheme and as described below:

56 200413280 (R5)m56 200413280 (R5) m

IlaIla

(R5)P(R5) P

Ilia 在下文中，R1、R2、R2’、r3、、R5 、R8、R9、R9’、R10、R1。’、X、γ、Z、W、m、n、p 和 q 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.❹⑽“打☆"助貧 1979,Ilia In the following, R1, R2, R2 ', r3 ,, R5, R8, R9, R9', R10, R1. Any one of ', X, γ, Z, W, m, n, p, and q is as defined above. Compounds of the general formula VII are based on methods well known to chemists familiar with the art (V. Bebenburg et al. ❹⑽ "打 ☆ " Poverty Alleviation 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：冑基氣、醯基溪、醯基碘、磺醯基氯、異氰酸鹽、碳酸肝、活性醋及烧基齒甲酸鹽反應，此係於有或無添加鹼，例如三烷基胺、碳酸鉀或鋰、納或鉀的醇鹽，錢當溶劑如醋酸乙醋、二聘烧、四氫呋喃、乙或 *-乙中，rir f 田/皿度如至溫或經由傳統加熱或微波 4下達到之回流溫度下進行，接著用適當還原劑如連二硫酸鈉、於氫氯酸水溶、、存合液或虱氣中之鐵粉或鋅粉將硝基還原，此係於適當_ /μ拙、田虱化催化劑如活性炭上當溶劑如甲醇或乙醇中，在適當溫度下進行存在了在適伴護二係經由通式1v化合物與在苯胺基上形成如鄰苯二甲酸軒在適當溶適當溫度下反應而製得。 9文γ ^ 57 200413280 通式VI化合物係經由熟諳此技藝之化學家所熟知的硝 …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中於適當溫度下反應。、者通式ΠΙ化合物係經由在適當溶劑如丨，2—二聘烷中於適田度下，用水合肼將苯胺官能去保護而自通式VI化合物製得。Sonderdruck 103 '3-15) and is prepared as outlined below: Compounds of general formula IV are prepared as follows: 4-nitroaniline and appropriate electrophilic reagents' such as, but not limited to, hydrazone, hydrazone, hydrazone Reaction of iodine, sulfonyl chloride, isocyanate, liver carbonate, active vinegar, and pyrogallium formate, with or without the addition of a base such as trialkylamine, potassium carbonate or lithium, sodium or potassium Alcohols, chalcone solvents such as ethyl acetate, dioxan, tetrahydrofuran, ethyl or * -ethyl, and the temperature of the rir f field / dish to the temperature or the reflux temperature reached by conventional heating or microwave 4, followed by using Appropriate reducing agents such as sodium dithionite, water soluble in hydrochloric acid, iron powder or zinc powder in storage solution or lice gas will reduce the nitro group. This is based on appropriate // μ, lice catalysts such as activated carbon. A solvent such as methanol or ethanol is prepared at a suitable temperature in a suitable companion system via a compound of the general formula 1v and reacted with an aniline group to form a phthalate compound at a suitable temperature and a suitable temperature. 9 γ ^ 57 200413280 Compounds of general formula VI are prepared from compounds of general formula V through nitrate, which is well known to chemists familiar with this technology, for example, reacting with fuming nitric acid in a suitable solvent such as glacial acetic acid at a suitable temperature. The compound of general formula II is prepared from the compound of general formula VI by deprotecting the aniline function with hydrazine hydrate in a suitable solvent such as 2-dioxane at a suitable degree.

或者，通式vn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]，[二胺基苯。在第一個步驟中，用適當保護基PG 物心Alternatively, compounds of general formula vn can be prepared from 2-nitro], [diaminobenzene in three steps as shown in the scheme and described below. In the first step, use the appropriate protective group PG

Synthesis, 3rd Edition T. w. Greene, P. G. M. Wuts hley lnterscience丨999]如第三丁氧幾基（b〇c基）將較不受阻且較枝應㈣苯胺氮料起來，此係經由在適當溶劑如乙腈中且於供給…“匕合物之適當溫度下，與形成保護基之適當試劑如二碳酸二第三丁醋反應來進行 3通式XII化合物係自通式XI化合物獲得如下··與形成 R -⑺q-Χ ^團之適當親電子言式齊J，例如炫基、芳基或潑芳基氯甲酸鹽或胺基甲醯氣、醢基氣、醯基漠、醯基/、磁醯基氯、異氰酸鹽、碳酸gf、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、1>2_二氯乙烷或二氯甲烧中適當溫度如室溫或經由傳統加熱或在微波昭射下所達到的回流溫度下’有或無添加驗，例如氧化鎮、碳酸鉀、三烧基胺、W咬或碳酸氫納，如以上對通式IV化 58 合物所敘述者。保護基係經由熟諳此技蓺之化士、议筑 < 化學豕所熟知的方法除去。尤其，可經由用適當酸如三氟 m 1日α夂在無或有溶劑如二氯Synthesis, 3rd Edition T. w. Greene, PGM Wuts hley lnterscience 丨 999] For example, the third butoxoyl group (boc group) will be more unobstructed and more responsive to aniline nitrogen. This is done by using a suitable solvent. For example, in acetonitrile and at a suitable temperature for the supply of the compound ", the reaction with a suitable reagent for forming a protective group such as di-tert-butyl dicarbonate is carried out to carry out the compound of general formula XII. Appropriate electrophilic formulas for forming R-⑺q-χ ^ groups, such as xyl, aryl, or aryl chloroformate or aminoformamidine, amidine, amido, amido, Magnetic fluorenyl chloride, isocyanate, carbonic acid gf, carbonic acid activated with an activating agent such as carbodiimide, or others well known to chemists skilled in the art, are reacted in a suitable solvent such as acetonitrile, tetrahydrofuran, 1 > 2_ Dichloroethane or dichloromethane in a suitable temperature such as room temperature or the reflux temperature reached by conventional heating or under microwave exposure, with or without addition test, such as oxidation ball, potassium carbonate, three Alkylamine, W-bit or sodium bicarbonate, as described above for compounds of general formula IV Narrator based protective group technology via skilled in the handiness of the persons, proposed building <. Hog known chemical method for removing particular, via a suitable acid such as trifluoroacetic α m 1 Day Fan in the absence or solvent such as methylene.

甲燒或甲苯存在下於供給通式VI 口遇式Vil化合物之溫度下處理而將Boc基裂解。通式VIII化合物之製備：使通式VII化合物進行與通式IIa< nia之盤（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j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、纟、二聘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IIIa之酸反應，此係在適當溶劑如曱醇、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、四氫呋喃、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ri是氫。或者’就R1之變化而言，可使所得通式νπ I化合物進行額外的還原性焼基化步驟，此係使用適當醛和還原劑 59 200413280 甲醇、乙醇、有或無添加催以上所敘述者次還原性烷基如硼氫化鈉或氰基硼氫化鈉，在適當溶劑如四氣咲喃、水、二聘烷或它們的混合物中，化量的酸，如醋酸，在適當溫度下進行，如。此步驟亦可在與通式Ila或Ilia醛之第— 化之後當場進行。進^，就'1之變化而言，可使所得通式VUI化合物 :仃：：反應，此係使用適當親電子試劑如醯基氯、醯基 “碘、磺醯基氯和烷基鹵基-甲酸鹽，有添加鹼，歹1 °二烷基胺、碳酸鉀或鋰、鈉或鉀的醇鹽，在適當溶劑如醋酸乙酯、二膛俨、& „十+ 士 _ ^ a ^ 70 虱呋喃或一乙醚中，在適當溫度下進仃，如以上所敘述者。化σ物，係經由通式VI11化合物與適當還原在有機溶劑如四氳呋喃或乙醇不存在或存在下之 < u i或§日^水Α液中之連二硫酸納、鐵粉或辞粉反 t或在適當氫化催化劑如活性炭上财子在下之氫氣，在、，劑如甲醇或乙醇或水/四氫呋鳴混合物中，在適當 /皿度下反應。所得化合物和本發明通式J化合物相同，其 H2和R2’是氫，且其"、^，、卜…係如以上所定義者。、/、中R不疋氫，且其中R2和視需要之R2,不是氫之通式I化合物，係經由盆φ丨一 T R不疋氲之通式IX化合物的反應獲得，利用下列方法：、=入R此係經由一個使用適當醛和還原劑如硼氫化納或亂基氣化納，4τ , ^ 在適當溶劑如甲醇、乙醇、四氫呋喃 200413280 、水、二腭烧或它們的混合物中，有或無添加催化量的酸如醋酸，在適當溫度下的還原性烷基化步驟進行，如以上所敘述者。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，在適當溶劑如曱醇、乙醇、四氫呋喃、水、二聘烷或它們的混合物中，有或無添加催化量的酸如醋酸，在適當溫度下的額外還原性烷基化步驟進行，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一甲酸鹽，有添加鹼，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酯、二腭烷、四氫呋喃或二乙鱗中’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Ri。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Ila和IIIa之化合物係經由熟諳此技藝之化學家所熟知的標準方法製備，如以下所概述者：魏酸S旨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、二曱亞硼/草醯氯的氧化反應。或者通式na和nia之化合物可經由與二氯甲基甲 200413280 基醚和四氣化鈦的曱醯化反應製備（Gross et a 1 〇rg Synth. Coll, 1973 Vol V, 365 ； Fanghaenel et al J /VMi· 6V?⑽· 1997，277 )。或者通式 IIa 和 nia 之化合物可經由熟諳此技藝之化學家所熟知的方法製備，例如經函素取代之雜芳族化合物如溴化物或碘化物的_素金屬交換反應，經由與金屬化試劑如烷基鋰或_化烷基鎂或二烷基鎂的反應。或者通式113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，例如噻吩與苯并噻吩與磷醯氯在趴甲基苯基甲醯胺存在下的反應（ King et al. /. α咖 1949，以，638)或在 u二甲基甲醯胺存在下的反應、（Vi— for—，Methanol or toluene is treated at a temperature to supply the compound of formula VI to the compound of formula Vil to cleave the Boc group. Preparation of compound of general formula VIII: The compound of general formula VII is subjected to a reductive alkylation reaction with a disk of general formula IIa < nia (where R5, W, m, n and p are as described above). Well known to chemists), using reducing agents such as sodium borohydride or sodium cyanoborohydride in a suitable solvent such as methanol, ethanol, tetrahydrofuran, amidine, dioxane or a mixture thereof, with or without a catalytic amount The acid 'such as acetic acid' is carried out at an appropriate temperature to form a compound of the general formula ¥ 111, where R1 is hydrogen. Alternatively, the compound of general formula VII can be reacted with an acid of general formula IIa or IIIa in a suitable solvent such as methanol, ethanol, tetrahydrofuran, dioxane, xylene or a mixture thereof, with or without a catalytic amount of acid added. For example, acetic acid or 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 imine can then be reduced to a compound of the general formula V111 in a suitable solvent such as methanol, ethanol, tetrahydrofuran, water, dioxane or a mixture thereof using a reducing agent such as sodium borohydride or sodium cyanoborohydride, where ri It's hydrogen. Or 'in terms of the change in R1, the resulting compound of the general formula νπI may be subjected to an additional reductive sulfonation step, using the appropriate aldehyde and reducing agent 59 200413280 methanol, ethanol, with or without the addition of those described above Sub-reducing alkyl groups such as sodium borohydride or sodium cyanoborohydride are carried out in a suitable solvent such as tetragas sulfan, water, dioxane, or a mixture thereof, with an acid such as acetic acid, at an appropriate temperature, Such as. This step can also be performed on the spot after the first reaction with the aldehyde of the general formula Ila or Ilia. Further, as far as the change of '1, the obtained compound of general formula VUI can be obtained: 仃 :: reaction, which uses appropriate electrophilic reagents such as fluorenyl chloride, fluorenyl "iodine, sulfonyl chloride and alkyl halide -Formate, with added base, 歹 1 ° dialkylamine, potassium carbonate or lithium, sodium or potassium alkoxide, in a suitable solvent such as ethyl acetate, diluent, & „十 + 士 _ ^ a ^ 70 Lice furan or diethyl ether, at the appropriate temperature, as described above. Chemical compounds are obtained through the compound of general formula VI11 and appropriate reduction in the absence or presence of organic solvents such as tetramethylenefuran or ethanol < ui or § sodium disulfate, iron powder or powder in water A solution Reverse t or hydrogen on a suitable hydrogenation catalyst such as activated carbon in a suitable solvent such as methanol or ethanol or a water / tetrahydrofuran mixture at a suitable temperature. The obtained compound is the same as the compound of the general formula J of the present invention, wherein H2 and R2 'are hydrogen, and ", ^ ,, ..., are as defined above. , /, R is not hydrogen, and R2 and optionally R2, not a compound of general formula I, which is not hydrogen, are obtained by the reaction of a compound of general formula IX, where TR is not TR, using the following methods: = R This is via a suitable aldehyde and reducing agent such as sodium borohydride or sodium radical gasification, 4τ, ^ In a suitable solvent such as methanol, ethanol, tetrahydrofuran 200413280, water, dioxan or their mixture, there are Alternatively or in the absence of a catalytic amount of an acid such as acetic acid, a reductive alkylation step at a suitable temperature is performed, as described above. If necessary, R2 'is introduced via an appropriate aldehyde and reducing agent such as sodium borohydride or sodium cyanoborohydride in an appropriate solvent such as methanol, ethanol, tetrahydrofuran, water, dioxane, 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 a suitable temperature is performed, as described above. Alternatively, R2 'or R2 is via the use of appropriate electrophilic reagents such as fluorenyl, fluorenyl bromide, fluorenyl iodide, sulfonyl sulfonyl, and alkyl halide monoformate, as described above, with added bases, such as Trialkylamines, potassium carbonate or alkoxides of lithium, sodium or potassium, are reacted in a suitable solvent such as ethyl acetate, dioxane, tetrahydrofuran or diethyl scale at a suitable temperature. In order to obtain compounds of the general formula I in which R1 is hydrogen, and R2 and optionally R2, not hydrogen, are preceded by a reduction reaction of a nitro group, the protecting group is as follows by methods well known to chemists familiar with this technology. Tributoxycarbonyl was introduced as Ri. This protecting group was introduced into R2 and optionally r2, and then cleaved by a known method. Compounds of the general formulae Ila and IIIa are prepared via standard methods well known to chemists familiar with the art, as outlined below: Weir acid S is reduced with an appropriate reducing agent such as diisobutylaluminum hydride, followed by the resulting Oxidation of benzyl alcohol with a suitable oxidant such as tetrapropylaluminum perruthenate / N-methylmorpholine oxide, pyridinium chlorochromate, boron dichloride / oxalochloride. Alternatively, compounds of the general formulas na and nia can be prepared via a halogenation reaction with dichloromethyl methyl 200413280 based ether and tetragas titanium (Gross et a 1 Og Synth. Coll, 1973 Vol V, 365; Fanghaenel et al J / VMi · 6V? ⑽ · 1997, 277). Alternatively, compounds of general formulae IIa and nia can be prepared by methods well known to chemists familiar with the art, such as the replacement of heteroaromatic compounds such as bromide or iodide by a metalloid metal exchange reaction with a metallizing agent Such as the reaction of alkyl lithium or alkyl magnesium or dialkyl magnesium. Alternatively, compounds of the general formulae 113 and IIIa can be prepared by methods well known to chemists familiar with the art, such as the reaction of thiophene with benzothiophene and phosphinochlor in the presence of methylphenylformamide (King et al. α coffee 1949, with, 638) or the reaction in the presence of u dimethylformamide, (Vi—for—,

Raimund0 et al. /.办仏2002，67，205 )。實施例刀析的LC MS數據係以裝備有IonSpray源與Raimund0 et al. /. Office 2002, 67, 205). Example Analytical LC MS data is equipped with an IonSpray source and

Shimadzu LC-8A/SLC_1〇A LC 系統之 PE Sciex ΑΡΙ ι5〇Εχ 儀器獲得。管柱：3 〇 X 4 R吝半w 卜 4·6 ¢:未 Waters Symmetry C18 管柱，具有3· 5微米叔不j , w，4 寸子大小，浴劑糸統：A =水/三氟醋酸 (〇〇〇·05)和B =水/乙腈/三版醋酸（5: 95: 〇〇3); 方法：線性梯度沖提，4分鐘内從9〇心至1〇_，流速 2笔升/刀純度係由UV ( 254 nm)和ELSD描圖的承來測定°滯留時間⑷或tR)係以分鐘表示。製備LC-MS純化係用相同儀器進行。管柱：5" 毫米皿’具有5微米粒子大小：方法：線性相 62 200413280 沖提’ 7分鐘内從80%A至1〇〇%B，流速為22 7毫升/分。沖提分收集係藉由分流MS偵測來進行。 H NMR光谱係以Bruker Avance肫奵〇〇儀器於 500.1 3 MHz 記錄，或以 Bruker Ac 25〇儀器於 25〇 i3 記錄。使用氛化氯仿（99.8%D)或二甲亞碾（ 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= 七重峰，dd =雙雙重峰，ddd =雙雙二重峰，dt =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，有列出偶合常數溶點（ Μ.Ρ.)係以Btichi Β-540儀器記錄且未經校正。中間物之製備 (4-胺基-苯基）一胺基曱酸乙酯。將4-硝基-苯胺（100克，〇·72莫耳）溶於醋酸乙酯 (800毫升）並添加二異丙基乙基胺（㈣· 6毫升，〇· 9% 莫耳）。添加溶於醋酸乙酯（2〇〇毫升）中之氯甲酸乙酯 (252毫升，1· 45莫耳）並使溶液在周圍溫度下攪拌18小時。將混合物用2Μ HC1 ( 300毫升）和食鹽水（3〇〇毫升 )洗滌，乾燥（MgS〇4 )及在真空下濃縮至原始體積的一半。在所彳寸溶液中加入載於活性炭上之鈀（丨〇克，， so% h2o)並在帕爾（Parr)裝置（ph2 = 3巴）中於周圍 /JHL度下將混合物氫化12小時。使混合物經過塞里塑料（ 63 200413280Obtained from a PE Sciex AP 5050E × instrument of the Shimadzu LC-8A / SLC_1OA LC system. Column: 3 〇X 4 R 吝 ½ w 4 4.6 ¢: non-Waters Symmetry C18 column, with 3.5 μm tertiary j, w, 4 inch size, bath system: A = water / three Fluoroacetic acid (〇00.05) and B = water / acetonitrile / triacetic acid (5:95: 〇03); Method: Linear gradient elution, from 90 to 100% in 4 minutes, flow rate 2 Pen-liter / knife purity is measured by UV (254 nm) and ELSD tracing. ° Retention time (or tR) is expressed in minutes. Preparative LC-MS purification was performed using the same equipment. Column: 5 " Millimeter dish ' with 5 micron particle size: Method: Linear phase 62 200413280 Stripping ' From 80% A to 100% B in 7 minutes, with a flow rate of 22 7 ml / min. Extraction fraction collection is performed by shunt MS detection. H NMR spectra were recorded on a Bruker Avance 2000 instrument at 500.1 3 MHz, or on a Bruker Ac 250 instrument on 250 i 3. Aerated chloroform (99.8% D) or dimethyl arylene (99 8% d) was used as the solvent. Use TMS as an internal reference. Chemical shift values are expressed in ppm. The following abbreviations are used for the number of peak splits of the NMR signal: s = singlet 'd = doublet, t = triplet, q = quadruple, called 丨 = fivefold, d = sevenfold, dd = doubled Peaks, ddd = double doublet, dt = double triplet, dq = double quartet, tt = triplet of triplet, m = multiplet, and b = broad singlet. In some examples, the coupling constant melting point (M.P.) is listed on a Btichi B-540 instrument and is uncorrected. Preparation of intermediates (4-Amino-phenyl) monoaminoethylacetate. 4-Nitro-aniline (100 g, 0.72 mole) was dissolved in ethyl acetate (800 ml) and diisopropylethylamine (2.6 ml, 0.9% mole) was added. Ethyl chloroformate (252 ml, 1.45 mol) dissolved in ethyl acetate (200 ml) was added and the solution was stirred at ambient temperature for 18 hours. The mixture was washed with 2M HC1 (300 mL) and brine (300 mL), dried (MgS04) and concentrated under vacuum to half the original volume. To the solution was added palladium (100 g, so% h2o) on activated carbon and the mixture was hydrogenated in a Parr apparatus (ph2 = 3 bar) at ambient / JHL degree for 12 hours. Pass the mixture through Serry plastic (63 200413280

Celite)過濾並在真空中蒸發溶劑，得到ι18克（9〇% ) 標題化合物，為結晶產物。LC/MS 180· 9 (MH+) ; tR =〇·60 分。4 NMR (CDC13): 1·27 (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-苯基）一胺基曱酸丙酯。產率：98%。4 (CDC13): 0· 96 (t，3H) ; 1. 68 (m，2H) ; 3· 51 (b，2H) ; 4· 09 (t，2H) ; 6· 46 (b，1H); 6· 63 (d，2H) ; 7· 14 (m，2H)· (4-笨二甲醯亞胺基一苯基）—胺基甲酸乙酯。在氮氣下將（4-胺基-苯基）-胺基曱酸乙酯（118克，〇. 65莫耳）溶於冰醋酸（2· 〇升）中，並將混合物加熱到 9〇°〇將鄰笨二甲酸酐（1〇2· 〇克，〇· 69莫耳）分成幾部分於30分鐘期間加入。並使反應保持在90 °C下2小時。讓’混合物冷卻到周圍溫度，並將沈澱固體過濾出來。使固體在過遽器上經水（2升），接著經二乙醚（3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 (历々）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). 200413280 下列化合物係以類似方式製備： (4-苯二曱醯亞胺基—苯基）—胺基甲酸丙酯。產率：81%。 (2-硝基-4-苯二甲醯亞胺基—苯基）一胺基曱酸乙酯。將（4-苯二甲醯亞胺基-笨基）一胺基甲酸乙酯（99·〇克，〇·32莫耳）懸浮於冰醋酸（1·5升）中並加熱到9〇 % 。在90-95°C下將發煙硝酸（17·2毫升，〇·41莫耳）分成成邛分於30分鐘期間加入。然後使反應混合物在丨〇〇〇c 下攪拌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（5〇〇毫升）、水（1升）和一乙醚（1升）洗滌，然後在真空中乾燥，得到丨〇丨克（ 90 % )標題化合物，為黃色固體。LC/MS 355· 〇 (MH+) ; tR = 3·34 分。1H NMR (DMSO-4): 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-本一甲酿亞胺基-苯基）一胺基甲酸丙醋。產率：70%。 (4-胺基-2-硝基-苯基）-胺基甲酸乙酯。將1，2-二曱氧基乙烷（1· 0升）加到（2-硝基-4-笨二曱醯亞胺基_苯基）-胺基曱酸乙酯（101克，0.28莫耳）中，並在回流下加熱混合物。於10分鐘期間逐滴添加單水合肼（19· 6克，〇· 39莫耳），並使混合物於回流下攪拌 65 200413280 1.5小時。當冷卻到周圍溫度時，將混合物過濾，而固體係在過濾器上用二甲氧基乙烷（25〇毫升）洗滌。利用蒸發濃縮濾液，並使紅色結晶產物從甲苯（35〇毫升）再結晶，將沈澱的產物過濾出來並在真空中乾燥。將母液是濃縮到原始體積的-半，並讓其靜£ 16小時。將沈殿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% )深紅色的標題化合物。lC/ms (历々） 225.1 (MH+) ; tR = 2.08 分。iH 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）一胺基曱酸丙酯。產率· 91 %。iH NMR (CDCl3): 〇· 98 (乜 3JJ) ; l 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）-胺基甲酸第三丁酯。在2 —瑣基〜1，4 —二胺基苯（10.135克，66.18毫莫耳 )於四氫呋"南（1GG毫升）中的回流溶液内，纟2小時期間將BocW (二碳酸二第三丁酯，32· 6克，149毫莫耳）非成成4刀加入。將所得溶液倒入庚烷（2升）中，聲波振盈15分知’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：80 %。LC/MS 295· 4Celite) and the solvent was evaporated in vacuo to give 18 g (90%) of the title compound as a crystalline product. LC / MS 180 · 9 (MH +); tR = 0.60 minutes. 4 NMR (CDC13): 1.27 (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) monoaminopropylacetate. Yield: 98%. 4 (CDC13): 0.96 (t, 3H); 1. 68 (m, 2H); 3. 51 (b, 2H); 4.09 (t, 2H); 6.46 (b, 1H); 6. · 63 (d, 2H); 7. · 14 (m, 2H) · (4-benzyldimethylimino-phenyl) -urethane. (4-Amino-phenyl) -aminoacetic acid ethyl ester (118 g, 0.65 mol) was dissolved in glacial acetic acid (2.0 liters) under nitrogen, and the mixture was heated to 90 ° O O-dibenzoic anhydride (102.0 g, 0.69 mol) was added in portions over a period of 30 minutes. The reaction was kept at 90 ° C for 2 hours. The mixture was allowed to cool to ambient temperature and the precipitated solid was filtered out. The solid was washed on a decanter with water (2 liters), then with diethyl ether (3 liters) and then dried in vacuo. Yield: 127 g (62%) of the title compound 'as a white crystalline compound. LC / MS (calendar) 311.3 (MH +); tR = 2.57 minutes. 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). 200413280 The following compounds were prepared in a similar manner: (4-Benzodiamidoimino-phenyl) -propylcarbamate. Yield: 81%. Ethyl (2-nitro-4-benzylideneimino-phenyl) monoaminoacetate. (4-Benzenedimidino-benzyl) monocarbamate (99.0 g, 0.32 mol) was suspended in glacial acetic acid (1.5 liters) and heated to 90% . The fuming nitric acid (17.2 ml, 0.41 mol) was divided into halves at 90-95 ° C and added over a period of 30 minutes. The reaction mixture was then stirred at 1000 ° C. for 1 hour and then cooled to ambient temperature. The crystalline solid was filtered off and washed on the filter with glacial acetic acid (500 ml), water (1 liter) and monoethyl ether (1 liter), and then dried in vacuo to give 丨 g (90% ) The title compound as a yellow solid. LC / MS 355.0 (MH +); tR = 3.34 minutes. 1H NMR (DMSO-4): 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) · The following compounds were prepared in a similar manner: (2-nitro_4-benzylmethylimino-phenyl) monocarbamic acid propyl acetate. Yield: 70%. (4-Amino-2-nitro-phenyl) -urethane. 1,2-Dioxoethane (1.0 liter) was added to (2-nitro-4-benzimidinoimino_phenyl) -aminophosphonate ethyl ester (101 g, 0.28 Mol), and the mixture was heated under reflux. Hydrazine monohydrate (19.6 g, 0.39 mol) was added dropwise over a period of 10 minutes, and the mixture was stirred at reflux for 65 200413280 for 1.5 hours. When cooled to ambient temperature, the mixture was filtered and the solid was washed on the filter with dimethoxyethane (250 ml). The filtrate was concentrated by evaporation and the red crystalline product was recrystallized from toluene (350 ml). The precipitated product was filtered off and dried in vacuo. Concentrate the mother liquor to half its original volume and let it stand for 16 hours. The Shen Dian material was filtered out and recrystallized as before. The recrystallized solids were combined to give a total of 57.6 g (90%) of the title compound as a dark red. lC / ms (calendar) 225.1 (MH +); tR = 2.08 points. iH 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) monoaminophosphonate propyl. Yield: 91%. iH NMR (CDCl3): 0.98 (乜 3JJ); 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) -aminocarboxylic acid third butyl ester. In a refluxing solution of 2-Zoyl ~ 1,4-diaminobenzene (10.135 g, 66.18 mmol) in tetrahydrofuran (1GG ml), BocW (dicarbonate dicarbonate Tertiary butyl ester, 32.6 g, 149 millimoles) Non-cheng into 4 knives. The resulting solution was poured into heptane (2 liters), sonicated for 15 minutes, and 'filtered and dried under vacuum to obtain 13.40 g of the title compound' as a red solid. Yield: 80%. LC / MS 295 · 4

([M + H+MeCN] + ) ; tR = 2·54 (ϋν，ELSD)㈣，。lH 66 200413280 NMR (DMS0-d6): 1.47 (s， 9H) ; 6·96 ( -^ ^ -)；8,〇 (s, 1h；；：；2；；4 ^ NH). ，H， [4-(4-氣-苯磺醯基）—3—甲基一噻吩〜基]一甲醇。在Ή 4-（4_氯一苯石黃醯基）一3_甲基一瞎吩一 2一艘酸甲酉旨（992¾克，3 00臺宜I、& ρ 笔兄uo笔莫耳）於無水四氫呋喃（2〇毫升）和無水CH2C1? (1〇奎弁、、六人以笔升）中之浴液冷卻到q 〇c， DIBAL-Η (9·〇毫升，90 吝苗 1([M + H + MeCN] +); tR = 2.54 (ϋν, ELSD) ㈣. lH 66 200413280 NMR (DMS0-d6): 1.47 (s, 9H); 6.96 (-^^-); 8, 〇 (s, 1h ;;:; 2 ;; 4 ^ NH)., H, [ 4- (4-Gas-benzenesulfonyl) -3-methyl-thiophene ~ yl] -methanol. In the 4- (4_chloro-benzoxanthinyl)-3_methyl-benzophenone 2 2 acid methyl ester (992¾ g, 300 Taiwan Yi I, & 笔 uouo 笔莫耳) in The bath in anhydrous tetrahydrofuran (20 ml) and anhydrous CH2C1? (10 quinone, six people in pen liters) was cooled to qoc, DIBAL-Η (9.0 ml, 9090 seedlings 1

开9.0笔莫耳，於甲笨中之1 M溶液）。3小時之後，加入另一份應L—H(4 5毫升，（5毫莫耳）’並繼續攪拌3 2小時。藉由添加飽和羅謝爾（Open 9.0 moles, 1 M solution in Jiaben). After 3 hours, add another portion of L-H (45 ml, (5 mmol) 'and continue stirring for 3 2 hours. By adding saturated Rochelle (

R〇Chelle)鹽溶液⑶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）卒取水相，並將收集的有機層經以#〇4乾燥及在真空中蒸 %、。產物係經由在FlashMaster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 Cl2H1GCl〇2S2 計算值·· 284.9805， =2·45 分。iH NMR (CDCl3)·· ι·84 (t，y = 5·7 hz， 1 H)，2·20 (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 Cs, 1 H). 67 200413280 下列化合物係以類似方式製備： (3-氯-睡吩-2-基）-甲醇。產率：73%。β NMR (CDC13): 1.92 (b，1 H)，4.81 (s，2 H)，6.91 (d，/ = 5.2 Hz，1 Η), 7.25 (d，/ = 5. 2 Hz, 1 H). (5-二甲基胺基-苯并[b]噻吩—3 一基）一曱醇。產率：63%。iH NMR (CDC13): 1·62 (b，1 Η)，3·01 (s， 6 Η)， 4·89 (s， 2 Η)， 6·96 (dd， 1 Η)， 7.11 (d， 1 Η), 7.34 (s, 1 Η), 7.68, (d, / = 9. 0 Hz, 1 Η). (5-二甲基胺基-3-甲基-苯并[b]噻吩—2 一基）一甲醇。產率：56%。4 NMR (CDC13): 1·69 (t，J = 5·9 Ηζ， 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-溪-3-甲氧基-瞳吩—2-基）一甲醇。將4-漠-3-經基-噻吩-2一羧酸甲酯（948毫克，4. 〇〇宅莫耳）、硫酸二甲酯（〇· 57毫升，6· 〇毫莫耳）和 2 3 (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（託毫升 )用Et0Ac ( 2 X 25毫升）萃取混合物，並將萃取物收集，經NaJO4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&下將溶液冷卻到〇 %，然後添加DIBAL-IU12毫升’ 12毫莫耳，於甲苯中之lM溶液 )2小牯之後，加入另一份DIBAL-H (6毫升，6毫莫耳 )，並繼續授拌另2小時。藉由添加飽和羅謝爾鹽溶液（ 68 200413280 30毫升）使反應淬滅，並使混合物在室溫下授拌丄小時。將相分離’用EtGAe (2 X 5G毫升）$取水相，並將收集的有機層㉟Na2SG4乾燥及在真空巾蒸發。產物係經由在 FlashMaster系統中使用庚烷/醋酸乙醋作為沖提液（從i :0至2: i之線性梯度沖提）在石夕凝膠上層析而純化。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%)。1H NMR (CDCl3): i 86 (b，1 η)，(RoChelle) salt solution (3 ml) quenched the reaction, and the mixture was stirred at room temperature for 1 hour. The phases were separated, the aqueous phase was extracted with EtOAc (2 X 50 mL), and the collected organic layers were dried over # 〇4 and evaporated in vacuo. The product was purified by chromatography on a silica gel in a FlashMaster system using heptane / ethyl acetate as the eluent (linear gradient elution from 1 ·· 0 to 6: 4). The product-containing fractions were collected and evaporated in vacuo to obtain the desired compound (788 mg, 87%). LC-MS ·· U / y = 285.2 (M-Η20 + Η +), calculated for Cl2H1GCl2S2 · 284.9805, = 2.45 points. iH NMR (CDCl3) ···· 84 (t, y = 5.7 hz, 1 H), 2.20 (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 Cs, 1 H). 67 200413280 The following compounds were prepared in a similar manner: (3-chloro -Sphenphen-2-yl) -methanol. Yield: 73%. β NMR (CDC13): 1.92 (b, 1 H), 4.81 (s, 2 H), 6.91 (d, / = 5.2 Hz, 1 Η), 7.25 (d, / = 5. 2 Hz, 1 H). (5-dimethylamino-benzo [b] thiophene-3 mono) monomethyl alcohol. Yield: 63%. iH NMR (CDC13): 1.62 (b, 1 Η), 3.01 (s, 6 Η), 4.89 (s, 2 Η), 6.96 (dd, 1 Η), 7.11 (d, 1 Η), 7.34 (s, 1 Η), 7.68, (d, / = 9. 0 Hz, 1 Η). (5-dimethylamino-3-methyl-benzo [b] thiophene-2 One base) one methanol. Yield: 56%. 4 NMR (CDC13): 1.69 (t, J = 5.9 Ηζ, 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-brook-3-methoxy-pidophen-2-yl) -methanol . Methyl 4-benz-3-yl-thiophene-2 monocarboxylate (948 mg, 4.0 μmol), dimethyl sulfate (0.57 mL, 6.0 mmol) and 2 A suspension of 3 (1.11 g, 8.0 mmol) in acetone (10 ml) was heated at reflux for 4 hours. After cooling to room temperature, water (Torr) was added to extract the mixture with EtAc (2 x 25 mL), and the extract was collected, dried over NaJO4 and evaporated in vacuo. The residue was dissolved in anhydrous tetrahydrofuran (20 ml), the solution was cooled to 0% under &, and then DIBAL-IU 12 ml '12 mmol, 1M solution in toluene) was added for 2 hrs. One portion of DIBAL-H (6 ml, 6 mmol) and continue to infuse for another 2 hours. The reaction was quenched by adding a saturated Rochelle salt solution (68 200413280 30 ml) and the mixture was allowed to stir at room temperature for hr. The phases were separated 'and the aqueous phase was taken with EtGAe (2 X 5G ml), and the collected organic layer ㉟Na2SG4 was dried and evaporated on a vacuum towel. The product was purified by flash chromatography on a Shixi gel using heptane / ethyl acetate as the eluent (a linear gradient from i: 0 to 2: i). The product-containing fractions were collected and evaporated in vacuo to give the desired compound (482 mg, 54%). 1H NMR (CDCl3): i 86 (b, 1 η),

3.90 (s，3 Η)，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]瞳吩—2 一基）—甲醇。 .9 Hz, 2 H), =8. 5 產率：75%。I NMR (CDC13): 1 92 Γ ^ H), 3,9 (s, 3 Η), ,9〇 (d, ；2=(；；/；ζ 7-33 (dd, / = 1.9, 8.5 Hz, 1 Η), 7. 64 (d Ηζ，1 Η), 7.73 (d, / = 1.9 Hz, 1 H). ，3.90 (s, 3 Η), 4.77 (s, 2 H), 7.15 (s, i H) The following compounds were prepared in a similar manner: (6-chloro-3-methoxy-benzo [b] pupil Phen-2 mono)-methanol. .9 Hz, 2 H), = 8.5 Yield: 75%. I NMR (CDC13): 1 92 Γ ^ H), 3,9 (s, 3 Η),, 9〇 (d,; 2 = (;; /; ζ 7-33 (dd, / = 1.9, 8.5 Hz , 1 Η), 7. 64 (d Ηζ, 1 Η), 7.73 (d, / = 1.9 Hz, 1 H).,

通式Ila和Ilia之雜芳基醛類的製锴 4 -（4-氣-苯磺醯基）一3—甲基一噻吩〜甲醛。在[4-U-氣-苯磺醯基）一3一甲基一噻吩_2_基]一甲醇 786毫克，2.6。毫莫耳）、"基嗎咐i氧化物（〇 ί二9毫莫耳）與粉末狀4A分子筛克，藉由 ”工中紐暫加熱使之活化）於CH C1 Γ 你Μ 2 2、『耄升）中的懸液内加入過釕酸四丙基銨（46毫克，〇 β π人k Η · 宅莫耳）。將, 侍此合物攪拌1小時，之後使其經 1固用EtOAc沖提ί 69 200413280 二氧化石夕（大約25克）塞子過濾。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/醋酸乙酯作為沖提液（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% ) 。4 NMR (CDCl3): 2·60 (s, 3 Η), 7.53 (d, / = 9.0 Hz, 2 H), 7.87 (d, 8.5 Hz，2 H)，8.53 (s，1 H)，10.01 (s，i h)· 下列醛類係以類似方式製備： 3- 氣-瞳吩-2〜甲酿。產率：94%。iH NMR (CDCl3): 7 〇7 (d，j = 5 2 Hz， 1 H)’ 7. 72 (d, J = 〇. 5，4. 7 Hz， 1 H)， 10. 07 (d， / = 〇· 9 Hz, 1 H)· 4- 溴-3-曱氧基〜噻吩一2-曱醛。產率：45%。匪R (CDC13): 4.18 (s，3 Η)，7·60 (d^ ^ - 1.4 Hz, 1 Η), 10.08 (d, / - 1.4 Hz, 1 Η). 6-氯-3-甲氧基〜苯并[b]噻吩-2-甲駿。產率：86%。4 NMR (CDC13): 4.34 (s，3 H)，7.36 (dd^ 8.7 Hz, 1 Η), 7.75 (d, / = 1.4 Hz, 1 H)，7·82 (d，/ = 8·5 Hz，1 H)，10.36 (s，i Η)· 5- 二甲基胺基〜苯并[b]噻吩-3-甲醛。產率·· 72%。沱 NMR (CDC13): 3·05 (s，6 H)，7.00 (dd, / = 2.4，9.0 Hz, 1 Η), 7·68 (d，/ = 9.0 Ηζ，1 7.99 (d, J- 2.8 Hz, 1 Η), 8.24 (s, 1 Η), 10.11 200413280 (s, 1 Η). 5-二曱基胺基-3-曱基-苯并[b]噻吩-2-甲醛。產率：73%。4 NMR (CDC13): 2.74 (s，3 H)，3.03 (s，6 H)，7.00 (d，/ = 2·4 Hz, 1 Η)，7·12 ⑷，/ = 2·4，9·〇 Hz，1 Η), 7·69 (d，9·0 Hz，1 Η), 10.30 (s，1 Η)· 5-氟-苯并呋喃-3-曱醛。在-60 °C的固定溫度下，將二曱爻楓（3· 27克， 41. 8毫莫耳）於二氯甲烷（10毫升）中之溶液加到草醯氯 (2· 65克，20 ·9毫莫耳）於二氣甲烷（3〇毫升）之溶液中，並將溶液擾拌15分鐘。於—60 cC下逐滴加入溶於二氯甲烷（60毫升）之1-（5-氟苯并呋喃-3-基）甲醇（3.16 克，19 · 〇毫莫耳）。將混合物攪拌2 0分鐘’接著添加三乙胺（9.61克，0.095毫莫耳）。在授拌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、飽和碳酸氫鈉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 fiMR (CDC13): 7· 13 (dt，1H) ; 7· 50 (dd，1H) ;7· 86 (dd，1H) ; 8. 30 (s，1H) ; ι〇· 15 (s，1H)· 5-氟-瞳吩-2-甲酸：。於0。(：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刀-BuLi ( 70毫升， 66毫莫耳，〇·95 Μ於己烷中），並於一5-0 0C下將溶液 71 200413280Preparation of Heteroarylaldehydes of General Formulas Ila and Ilia 4- (4-Gas-benzenesulfonyl) -3-methyl-thiophene ~ formaldehyde. In [4-U-Gas-benzenesulfenyl) -3-methyl-thiophene-2-yl] -methanol 786 mg, 2.6. Mol), " kimonium oxide (〇ί 二 9mmol) and powdered 4A molecular sieves, activated by "temporary heating in the process" in CH C1 Γ you M 2 2, To the suspension in [耄 liter] was added tetrapropylammonium perruthenate (46 mg, 〇β π person k Η · zemol). The mixture was stirred for 1 hour, and then allowed to solidify. EtOAc extraction 69 200413280 The plug of stone dioxide (approximately 25 grams) was filtered. The eluate was evaporated in vacuo and the product was passed through the use of heptane / ethyl acetate in the FlashMaster system (from 1 · · 〇～丨 · 丨 linear gradient elution) was purified by chromatography on a silica gel. The fractions containing the product were collected and evaporated in vacuo to give the title compound (644 mg, 82%). 4 NMR ( CDCl3): 2.60 (s, 3 Η), 7.53 (d, / = 9.0 Hz, 2 H), 7.87 (d, 8.5 Hz, 2 H), 8.53 (s, 1 H), 10.01 (s, ih ) · The following aldehydes were prepared in a similar manner: 3-Air-Titrin-2 ~ Carbon. Yield: 94%. IH NMR (CDCl3): 7 〇7 (d, j = 52 Hz, 1 H) '7. 72 (d, J = 0.5, 4. 7 Hz, 1 H), 10. 07 (d / = 0.9 Hz, 1 H) · 4-bromo-3-fluorenyloxy ~ thiophene 2-fluorenal. Yield: 45%. Bandit R (CDC13): 4.18 (s, 3 Η), 7 · 60 (d ^ ^-1.4 Hz, 1 Η), 10.08 (d, /-1.4 Hz, 1 Η). 6-Chloro-3-methoxy ~ benzo [b] thiophene-2-methyljun. Yield : 86%. 4 NMR (CDC13): 4.34 (s, 3 H), 7.36 (dd ^ 8.7 Hz, 1 Η), 7.75 (d, / = 1.4 Hz, 1 H), 7.82 (d, / = 8 · 5 Hz, 1 H), 10.36 (s, i Η) · 5-dimethylamino ~ benzo [b] thiophene-3-carbaldehyde. Yield · 72%. 沱 NMR (CDC13): 3 · 05 (s, 6 H), 7.00 (dd, / = 2.4, 9.0 Hz, 1 Η), 7.68 (d, / = 9.0 Ηζ, 1 7.99 (d, J- 2.8 Hz, 1 Η), 8.24 (s, 1 fluorene), 10.11 200413280 (s, 1 fluorene). 5-Difluorenylamino-3-fluorenyl-benzo [b] thiophene-2-carboxaldehyde. Yield: 73%. 4 NMR (CDC13): 2.74 (s, 3 H), 3.03 (s, 6 H), 7.00 (d, / = 2.4 Hz, 1 Η), 7 · 12 ⑷, / = 2.4, 9 · 〇Hz, 1 Η), 7.69 (d, 90.0 Hz, 1 Η), 10.30 (s, 1 Η), 5-fluoro-benzofuran-3-carbaldehyde. At a fixed temperature of -60 ° C, a solution of diosmium maple (3.27 g, 41.8 mmol) in dichloromethane (10 ml) was added to chloramphenicol (2.65 g, 20.9 mmol) in a solution of methane (30 ml) and the solution was stirred for 15 minutes. At -60 cC, 1- (5-fluorobenzofuran-3-yl) methanol (3.16 g, 19.0 mmol) dissolved in dichloromethane (60 ml) was added dropwise. The mixture was stirred for 20 minutes' followed by the addition of triethylamine (9.61 g, 0.095 mmol). After 10 minutes of incubation, the reaction mixture was heated to ambient temperature and stirred for an additional 20 minutes. The organic portion was successively washed with 50 ml portions of water, in HC1 aqueous solution, saturated sodium bicarbonate aqueous solution and brine, and then dried (MgS04) and concentrated under vacuum to obtain the crude title compound in mass yield. , As a beige crystalline solid. 1H fiMR (CDC13): 7.13 (dt, 1H); 7.50 (dd, 1H); 7.86 (dd, 1H); 8. 30 (s, 1H); 15 (s, 1H) ) · 5-Fluoro-Titphen-2-carboxylic acid :. At 0. (Next, knife-BuLi (70 ml, 66 mmol, 0.95 M in hexane was added dropwise to a solution of thiophene (4.8 ml, 60 mmol) in anhydrous Et20 (200 ml). Middle), and the solution 71 200413280 at a 5-0 0C

㈣1小時。然後將溫度調整到_70 〇c，並加入(phs〇2)2NF (28.4克，90毫莫耳）於無水四氫肤喃（ 200毫升）中之 =液’㈣使溫度維持在下。錢過夜將所得混 “勿緩慢地過夜溫熱到室溫，添加2ν_η(3〇〇毫升） ’過渡混合物’將有機層用2 Ν Ν_(2 χ 3〇〇毫升）和飽和NH4C1 ( 300毫升）洗滌，妙 4 可」〆无“然後經Na2S04乾燥。使用 40公分Vigreux管柱蒸餾除丰士加八k η 、、口F刀的Et20，最後與庚烧 (50毫升）共蒸德，得到20.7毫莫耳2_氣噻吩與u毫㈣ 1 hour. The temperature was then adjusted to -70 ° C, and (phs〇2) 2NF (28.4 g, 90 mmol) was added to anhydrous tetrahydrofuran (200 ml) = solution 'to maintain the temperature. The mixture was mixed overnight. "Do not slowly warm to room temperature overnight, add 2v_η (300ml) 'transition mixture' and the organic layer with 2N__ (2 x 300ml) and saturated NH4C1 (300ml) Washed, wonderful 4 "None" and then dried over Na2S04. Distilled Fonsga 8 k η, E F20 knife with F knife using a 40 cm Vigreux column distillation, and finally co-evaporated with heptane (50 ml) to get 20.7 Mormol 2_Gathiophene and u-milli

莫耳瞳吩（經由㈣200微升膽作為内標準品mMR 測定）於大約100毫升四氫呋喃與庚烷（bp. 6〇 — 1〇〇。0中之溶液。將此溶液冷卻到Q並逐滴加人^^ (44毫升’ 41毫莫耳，〇.95 M於己烧中）。】小時之後，逐滴加人腳（4.8毫升，62毫莫耳）於EMU5毫升 )中之溶液’並於〇。(：下繼續授拌另i小時。缺後用飽和叫U2GG毫升）使反應淬滅。並用ΕΜ(2χ2〇{^ 升）萃取之’然後使萃取液經⑻叫乾燥。經由在大氣壓力下蒸饀（40公分Vigreux管柱）除去大部分的溶劑，然後真空蒸餾深色殘餘物，而得到大約5_氟—噻吩_2_甲醛與噻吩-2-甲酸（bp. 78-79吒，25咖11&)的ι〇:ι混合物 ’為金黃色油U.32克，44%)。無進—步純化即使用此混合物。1H NMR (CDC13): 6.65 (d，/ = 4.2，i H) ? 5〇 (d, / = 3.8 Hz, 1 H), 9.76 (d, / = 4. 2 Hz, 1 H). 通式VII中間物之製備 72 200413280 通式νπ "1物係經由以下所敘述之製備{4一[(5一氧— 苯并肤嚼-3-基甲基）-胺幻-2-石肖基—苯基卜胺基f酸乙醋的一般方法製備，或經由以下所敘述之製備N_(4_胺基_2_ 确基苯基）-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）一胺基]一2一硝基-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-硝基-苯基）一胺基甲酸乙酯（4·48克，ΐ9·9毫莫耳）_ 混合於鄰二甲苯（8〇毫升）中，並加人催化量的酸性離子交換樹脂（Amberlite齡84，⑽毫克）。將混合物加熱到回/瓜維持5小時’趁溫熱過濾及在真空中濃縮。將此粗產物溶於二聘烷：甲醇“ ·· η混合物（90毫升）中， ^將石朋氮化納（1· 50克，39· 8毫莫耳）分成幾份於30分鉍期間加入。使反應混合物於周圍溫度下攪拌過夜，然後將其倒入水（2 0 Π i1 / 卜、笔升）中，並用醋酸乙酯（3 X 75毫升鲁 )卒取°將合併的有機沖提分用食鹽水洗務’乾燥（MgS04 )及蒸發而得到粗製固體，經由在矽凝膠上層析（沖提劑。:醋酸乙酯：庚烷1 ·· 2)將其純化。此提供4.50克（61 % "^題化合物，為紅色結晶物質。Μ丽R (CDC13): 1.33 (t, 3H) ; 4.07 (t, 1H) ； 4. 23 (q, 2H) ； 4.42 (d, 2H)，6·99 (dd，1H) ; 7·〇5 (dt，1H) ; 7·25 (dd，1H); 7.42 (t, 1H) ; 7.44 (d, 1H) ; 7.65 (s, 1H) ； 8.31 (d, 1H) ; 9· 39 (s，1H)· 73 200413280 下列中間物係以類似方式製備： (4-[(5-甲基-噻吩-2-基甲基）一胺基]-2-硝基_苯基卜胺基甲酸乙酯產率：73%。LC/MS U/Z) 336 (MH+) ; tR = 3.41 分〇 U-[(3-甲基-噻吩-2-基甲基）一胺基]一2-硝基-苯基卜胺基甲酸乙酯產率：89%。LC/MS U/z) (4-[(噻吩-2-基甲基）-胺基]一2-硝基-苯基}-胺基甲酸乙_旨產率：71%。LC/MS U/z) 321 (MH+) ; tR = 3· 24 分〇 {4-[(噻吩-3-基甲基胺基]一2-硝基-苯基}-胺基甲酸乙西旨產率：69%。LC/MS U/z) 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· 15卜 152 °C. LC-MS U/z) 371.0 (MH+)，tR = 3· 59 分。 Ν-(4-胺基-2-硝基苯基）-2_(4-氟苯基）乙酿胺。在{4-[2-(4 -氟苯基）-乙醢基胺基]-3 -硝基-苯基}-胺基甲酸第三丁酯（2· 40克，6. 16毫莫耳）於二氣甲烷（5 毫升）中之經攪拌懸浮液内加入三氟醋酸（5毫升）。1 5 74 200413280 分鐘之後，將二氯曱烷蒸餾除去，然後隨著聲波振盪將殘餘的溶液轉移到飽和NaHC03水溶液（200毫升）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%，100%。ιΗ 匪r (dms〇-d6): 3.59 (s, 2H) ； 5.65 (b, 2H, NH2) ； 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-硝基苯基）一3, 3-二甲基丁醯胺。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)： l.〇〇 (s> 9H) ； 2.\2 (s, 2H) ； 3.45 (b, H2〇 + NH2) ； 6.84 (dd, 1H) ; 7.06 (d, 1H) ； 7.14 (d, 1H) ； 9. 64 (s, ih, NH). 通式VIII中間物之製備 N-丨4-[(5-氯噻吩基甲基）胺基]一2一硝基苯基丨一2一 (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（ 3 06毫克，1· 〇6毫莫耳）與5-氯噻吩甲醛（186毫克， 1 · 2當里）於無水乙醇（40毫升）中之溶液於7〇 0C加熱 30分鐘。將所得溶液濃縮到小量體積（大約3毫升），然 75 200413280 後用庚烧（15毫升）、、&、，製得毫克中：Γ藉由過滤將棕色結晶產物分離 > 月女4-[(5-氣噻吩-2-基亞甲基）胺基]-2 -石肖基苯基卜2 — 氣— ^ 氟本基）乙醯胺。產率：792% 。NMR (DMSO-d6)· 3 71 r μ 1U、. ·71 (s> 2H) ； 7.17 (t, 2H) ； 7.29 (d, 1H) ? 7. 36 (dd · n )，7·62 (d，1H) ; 7.63 (dd，1H) ,7· 71 (d，1H) ; 8. 83 (s 1u、 (，1H) ; 10· 44 (s，1H)·將此固體懸洋於甲醇（5毫升）中 A— 开J中，加入NaBH3CN ( 200毫克），接者加入醋酸（2臺弁） _ y 斤件溶液變成懸浮液。15分鐘之後，用水（50毫井1考本田士丄；處理之，經由過濾將產物分離，在真空中乾燥之後製得3加 dU笔克紅色固體。產率：93·8%。 LC/MS U/z) 420 ([Μ+Η1 +、· + HJ )h = 3· 34 (UV，ELSD) 97%， 100%。4 NMR (DMSO-d V q μ , α6>>. 3. 60 (s, 2H) ； 4. 45 (d, 2H) ;6· 87 (t，1H，NH) ; 6 的〜；b· 93 (dd， 1H) ; 6· 94 (d， 1H); 6.97 (d, 1H) ； 7 11 γη iW、 • Cd，1H) ; 7. 14 (t，2H) ; 7· 28 (d， 1H) ; 7· 32 (dd，2H) ; 9. 98 (s，1H) 下列化合物係以類似方式從對應苯胺製備： N-{4-[(5-氣噻吩+基甲基）胺基]u基苯基}_3,3_ 二甲基丁醯胺。如以上所述將粗製中間亞胺藉蒸發分離及還原。然後 ’將反m物蒸發到小量體積’用飽和腿⑶3水溶液和酉“夂乙酉曰處理’並瘵發有機層。將殘餘物溶於熱的二異丙醚中，用庚烧沈殺及過遽。產率：880毫克，87.6%。 LC/MS (,/,) 382.48 ; tfi = 3. 46 (UV, ELSD) 88 76 200413280 (s，9H) ; 2· 12 (s， NH) ； 6.92 (dd, 1H) 7· 07 (d，1H) ; 7· 19 %，91 %。％ NMR (DMSO-d6): 〇· 99 2H) ; 4. 45 (d，2H) ; 6· 84 (t，ih， ;6· 94 (d, 1H) ; 6· 97 (d，1H); (d，1H) ; 9. 69 (s，1H)· 通式XII中間物之製備 [2-(4-氟苯基）乙醯基胺基硝基苯基丨胺基甲酸第三丁酯。在（4-胺基-3-确基苯基）-胺基甲酸第三丁酯（1992 克’ 7. 87毫莫耳）與NaHC〇3 ( 5. 4克）於乙腈⑺毫升）中之懸浮液内加入（4-氟苯基）乙醯氯（18毫升，13當量 )。將所得懸浮液聲波振盪5分鐘，然後於周圍溫度擾拌 16小時。將它倒入水（200毫升）中，聲波振盪5分鐘，過遽’以及用水和庚m將所得殘餘物溶於熱的醋酸乙醋（3〇毫升）中’加入飽和NaHC〇3水溶液（5〇毫升） ’然後用庚炫（2(H)毫升）淬滅所得混合物。將所得懸浮液聲波« 5分鐘及過遽。將殘餘物用水和庚烧洗蘇及在真空中乾燥，製得2· 48克棕黃色固體。產率：8〇. 9%。 LC/MS (^) 412.54 ([M+Na] + ), 453.58 ([MiMeCNiNaJO ;tR = 3.33 (UV，ELSD) 97%，ι〇0%。丨"MR ⑽s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). 77 200413280 下列化合物係使用對應的醯氯以類似方式製備： [4-(3, 3-二甲基丁醯基胺基）-3-硝基苯基]胺基曱酸第三丁酯。使反應混合物與過量的第三丁基乙醯氯（3當量）一起於45 °C攪拌30分鐘。在醋酸乙酯-飽和NaHC03水溶液增濃之後分離出粗產物及經由在Si02 ( 50克）上使用ιοί 5 % 醋酸乙酯- 庚烧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 (τζζ/ζ) 415· 58 ([M + MeCN + Na] + ) ； tR = 3.31 (UV, ELSD) 99.5%, 99.9% 。H NMR (DMSO-d6): 1·〇1 (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· 01 (s，1H，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。Mortalol (determined via ㈣200 microliters of gallbladder as an internal standard mMR) in approximately 100 ml of a solution of tetrahydrofuran and heptane (bp 0.60-100.0). This solution was cooled to Q and added dropwise. Human ^^ (44 ml '41 mmol, 0.95 M in hexane).] After one hour, add a solution of human feet (4.8 ml, 62 mmol) in 5 ml of EMU) dropwise and add 〇. (: Continue mixing for another hour. After the absence, use a saturated solution called U2GG ml) to quench the reaction. Then, it was extracted with EM (2 × 2 0 {^ liter), and then the extract was dried by chirping. Most of the solvent was removed by distilling tritium (40 cm Vigreux column) at atmospheric pressure, and then the dark residue was distilled under vacuum to obtain about 5_fluoro-thiophene_2_formaldehyde and thiophene-2-carboxylic acid (bp. 78 -79 吒, 25 coffee 11 &) ιο: ι mixture 'is golden yellow oil U.32 g, 44%). This mixture was used without further purification. 1H NMR (CDC13): 6.65 (d, / = 4.2, i H)? 50 (d, / = 3.8 Hz, 1 H), 9.76 (d, / = 4.2 Hz, 1 H). Formula VII Preparation of intermediates 72 200413280 Formula νπ " 1 The system is prepared by the following process {4- 一 [(5 一 OX—benzophenone-3-ylmethyl) -amine phenanthrene-2 shithoyl-phenyl It is prepared by the general method of acetaminoacetic acid, or by the general method of preparing N_ (4-amino-2-acylphenyl) -2- (4-fluorophenyl) acetamidin described below. (4-[(5-Fluoro-benzofuran-3-ylmethyl) monoamino] -2 2-nitro-phenyl} -urethane. Three necks equipped with a Dean-Stark device In a round-bottomed flask, 5-fluoro-benzofuran-3-carboxaldehyde (3.59 g, 21.9 mmol) and (4-amino-nitro-phenyl) monocarbamate (4 · 48 g, ΐ9 · 9 mmol) _ mixed in o-xylene (80 ml) and added a catalytic amount of acidic ion exchange resin (Amberlite age 84, ⑽mg). The mixture is heated to the back / melon to maintain Filter for 5 hours while warming and concentrating in vacuo. This crude product is dissolved in a mixture of dioxane: methanol "·· η mixture (90 ml), and sodium pentaprate (1 · 50 g, 39 · 8 millimolar) was added in several portions over a period of 30 minutes bismuth. The reaction mixture was stirred at ambient temperature overnight, then poured into water (20 Π i 1 / bu, pen liters), and ethyl acetate (3 X 75 ml). The combined organic extracts were washed with brine, dried (MgS04) and evaporated to obtain a crude solid, which was chromatographed on a silica gel (eluent .: ethyl acetate: heptane 1 ·· 2) Purify it. This provides 4.50 g (61%) of the title compound as a red crystalline substance. M R (CDC13): 1.33 (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); 7.42 (t, 1H); 7.44 (d, 1H); 7.65 (s, 1H); 8.31 (d, 1H); 9.39 (s, 1H); 73 200413280 The following intermediates were prepared in a similar manner: (4-[(5-methyl- Thien-2-ylmethyl) monoamino] -2-nitro-phenylphenylaminocarboxylate Yield: 73%. LC / MS U / Z) 336 (MH +); tR = 3.41 min. Yield: [(3-methyl-thien-2-ylmethyl) -amino] -nitro-2-phenyl-p-phenylaminocarboxylic acid: 89%. LC / MS U / z) (4- [(Thien-2-ylmethyl) -amino]-2-nitro-phenyl} -carbamic acid ethyl ester Yield: 71%. LC / MS U / z) 321 (MH +); tR = 3.24 minutes {4-[(thien-3-ylmethylamino]-2-nitro-phenyl} -carbamic acid ethyl ester yield: 69%. LC / MS U / z) 320 (MH +); tR = 3.08 min. {4--(Benzo [b] pupilphen-3-ylmethyl) -amino group]-2-Schottyl-phenyl} -urethane yield: 87% . M · ρ · 15 and 152 ° C. LC-MS U / z) 371.0 (MH +), tR = 3.59 minutes. N- (4-amino-2-nitrophenyl) -2- (4-fluorophenyl) ethylamine. Tert-butyl {4- [2- (4-fluorophenyl) -ethenylamino] -3 -nitro-phenyl} -aminoformate (2.40 g, 6.16 mmol) ) Trifluoroacetic acid (5 ml) was added to the stirred suspension in methane (5 ml). 1 5 74 2004 13 280 minutes, dichloromethane is distilled off, and the remaining solution is transferred to a saturated aqueous solution of NaHC03 (200 ml) with sonication. The precipitate was filtered, washed with water and dried in vacuo to give 1-70 g of the title compound as a red-brown solid. Yield: 96.3%. LC / MS; tR = 2.25 (UV, ELSD) 89%, 100%. ιΗ Bandit (dms〇-d6): 3.59 (s, 2H); 5.65 (b, 2H, NH2); 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 following compounds were prepared in a similar manner: N- (4-amino-nitrophenyl) -3, 3-dimethylbutanamide. 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): 1.0. (S >9H); 2. \ 2 (s, 2H); 3.45 (b, H2〇 + NH2); 6.84 (dd, 1H); 7.06 (d, 1H); 7.14 (d, 1H); 9. 64 (s, ih, NH). Preparation of intermediates of general formula VIII N- 丨 4-[(5-chlorothienylmethyl) amino]-2 nitrate Phenyl phenyl-2-(4-fluorophenyl) acetamide. N- (4-amino-2-nitrophenyl 2- (4-fluorophenyl) acetamidamine (306 mg, 1.06 mmol) and 5-chlorothiophene formaldehyde (186 mg, 1 · 2 hours) The solution in absolute ethanol (40 ml) was heated at 700 C for 30 minutes. The resulting solution was concentrated to a small volume (approximately 3 ml). &, in milligrams produced: Γ separated the brown crystalline product by filtration > yue female 4-[(5-Gathiophene-2-ylmethylene) amino] -2 -stone stilbene phenyl 2- Gas — ^ fluorobenzyl) acetamide. Yield: 792%. NMR (DMSO-d6) · 3 71 r μ 1U, · · 71 (s >2H); 7.17 (t, 2H); 7.29 (d, 1H)? 7. 36 (dd · n), 7.62 (d , 1H); 7.63 (dd, 1H), 7.71 (d, 1H); 8.83 (s 1u, (, 1H); 10.44 (s, 1H). This solid was suspended in methanol (5 Ml) in A—K, add NaBH3CN (200 mg), and then add acetic acid (2 units of) _ y pieces of solution to become a suspension. After 15 minutes, use water (50 milliwell 1 test Honda Shiji; treatment In other words, the product was separated by filtration and dried in vacuo to obtain 3 dU pen grams of a red solid. Yield: 93.8%. LC / MS U / z) 420 ([M + Η1 +, · + HJ) h = 3.34 (UV, ELSD) 97%, 100%. 4 NMR (DMSO-d V q μ, α6 > >. 3. 60 (s, 2H); 4. 45 (d, 2H); 6 · 87 (t, 1H, NH); ~ of 6; b · 93 (dd, 1H); 6. 94 (d, 1H); 6.97 (d, 1H); 7 11 γη iW, • Cd, 1H); 7. 14 (t, 2H); 7.28 (d, 1H); 7.32 (dd, 2H); 9. 98 (s, 1H) The following compounds were prepared in a similar manner from the corresponding aniline: N- {4 -[(5-Gathiophene + ylmethyl) amino] u-based phenyl} _3,3_dimethylbutyramine The crude intermediate imine is separated and reduced by evaporation as described above. Then 'evaporate the anti-methane to a small volume' with a saturated aqueous solution of leg ⑶3 and "酉", and the organic layer is exploded. In hot diisopropyl ether, sacrifice and simmer with heptane. Yield: 880 mg, 87.6%. LC / MS (, /,) 382.48; tfi = 3. 46 (UV, ELSD) 88 76 200413280 (s, 9H); 2.12 (s, NH); 6.92 (dd, 1H) 7.07 (d, 1H); 7.19%, 91%.% NMR (DMSO-d6): 0.92 2H ); 4. 45 (d, 2H); 6. 84 (t, ih,; 6. 94 (d, 1H); 6. 97 (d, 1H); (d, 1H); 9. 69 (s, 1H) · Preparation of intermediates of general formula XII [2- (4-fluorophenyl) ethenylaminonitrophenyl 丨 aminocarbamic acid third butyl ester. In (4-Amino-3-acylphenyl) -carbamic acid third butyl ester (1992 g '7.87 mmol) with NaHC03 (5.4 g) in acetonitrile (1 ml) To the suspension was added (4-fluorophenyl) acetamidine chloride (18 ml, 13 eq). The resulting suspension was sonicated for 5 minutes and then stirred at ambient temperature for 16 hours. Pour it into water (200 ml), sonicate for 5 minutes, and dissolve the resulting residue in hot ethyl acetate (30 ml) with water and heptane. 'Add a saturated NaHC03 aqueous solution (5 (0 ml) 'The resulting mixture was then quenched with Hengxuan (2 (H) ml). The resulting suspension was sonicated for «5 minutes and simmered. The residue was washed with water and heptane and dried in vacuo to give 2.48 g of a brownish yellow solid. Yield: 80.9%. LC / MS (^) 412.54 ([M + Na] +), 453.58 ([MiMeCNiNaJO; tR = 3.33 (UV, ELSD) 97%, ι〇0%. 丨 & MR ⑽s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). 77 200413280 The following compounds were prepared in a similar manner using the corresponding fluorenyl chloride: [4- (3, 3-dimethylbutanylamino) -3-nitrate Phenyl] aminobutyl tertiary butyl ester. The reaction mixture was stirred with an excess of tert-butylacetamidine chloride (3 equivalents) at 45 ° C for 30 minutes. After concentrating ethyl acetate-saturated aqueous NaHC03 solution, the crude product was isolated and purified by flash chromatography on Si02 (50 g) using 5% ethyl acetate-heptane as the eluent. Yield • 2.20 g (78.6%), yellow solid. LC / MS (τζζ / ζ) 415 · 58 ([M + MeCN + Na] +); tR = 3.31 (UV, ELSD) 99.5%, 99.9%. H NMR (DMSO-d6): 1.01 (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 · 01 (s, 1H, NH). The compound of the present invention The acid addition salt of the compound of the present invention can be familiarized with this Methods known to the skilled person are easily formed.

實施例1 h {2-胺基-4-[(5一氟-苯并呋喃-3一基曱基）一胺基]一苯基卜胺基曱酸乙酯。基卜醇（及鐵將U-[(5-氟-苯并呋喃_3一基曱基）_胺基]_2_硝基一苯胺基曱酸乙酯（4.50克’ 12.1亳莫耳）溶於無水乙 “〇毫升）中，在其中加入6N HC1 (38毫升）水溶液粉（5.70克’ 〇.1〇莫耳）。使此紅色混合物於6〇 % 78 200413280 加熱。直到強烈顏色消失（20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 1 〇〇毫升）萃取之。將合併的有機沖提分用食鹽水洗滌，乾燥（MgS04)及在真空中濃縮。經由在矽凝膠上層析（沖提劑：醋酸乙酯：庚元1 : 1)來純化粗產物，製得2.70克（66% )標題化合物’為固體。Μ· ρ· 150-151。(：·對 C18H18FN303 之計算值：c 62· 96 ; Η 5· 28 ; N 12. 24。實測值：C 63. 00 ; Η 5. 38 ; N 12·13· LC/MS U/z) 344 (ΜΗ+) ; tR = 2·00 分。1H NMR (DMS0—A): 1.19 (t，3Η) ; 4·03 (q，2Η) ; 4·26 (d，2Η) ·’ 4.55 (s，2H，NH2) ; 5.79 (t，1H) ; 5·91 (dd，1H); 6·〇2 (d，1H，NH) ; 6.72 (d，1H) ; 7.13 (dt，1H) ; 7.56 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氬氣酸加成鹽離析出來： lb {2-胺基一4-[(5-甲基-噻吩-2-基甲基）-胺基]-笨基 }〜胺基甲酸乙酯二鹽酸鹽。經由添加醚氫氣酸自醋酸乙酯製備粗產物，得到標題化合物。 Μ·ρ· 190。(：（dec·)·對 C15H19N302S，2HC1 之計算值：c 47. 00 ; Η 5· 67 ; N 10· 97。實測值·· C 46· 84 ; Η 5. 86 ; N Π·10· LC/MS U/z) 306 (ΜΗ+) ; tR = 1.77 分。1H NMR (DMSO-ί/6): 1·22 (t，3H); 2.37 (s，3H); 4·08 (q，2Η) 200413280 ;4.37 (s，2H) ; 6.64 (m，1H) ; 6·67 (dd，1H) ; 6 72 (d，1H) ; 6.86 (d，1H) ; 7.13 (d，1H) ; 8.93 (b，ih NH). ，， lc {2-胺基-4-[(3-甲基-瞳吩—2-基甲基）—胺基]一苯基 }-胺基曱酸乙酯二鹽酸鹽。經由添加驗氫氣酸自醋酸乙酯製備粗產物，得到標題化合物。 LC/MS (历々）306 (MH+) ; % = 168 分。1h n肫 (CDCl3)(自由驗）：U5 (t，3H) ; 2.23 (s，3H) ; 3·78 (b，3Η) ; 4.13 (q，2Η) ; 4.32 (s，2Η) ; 6.05-6.10 (m， 2H + NH) , 6. 82 (d, 1H) ； 6. 93 (d, 1H) ； 7.11 (d ih)Example 1 h {2-Amino-4-[(5-fluoro-benzofuran-3-ylfluorenyl) -amino] -phenylphenyliminoacetic acid ethyl ester. Glycol (and iron dissolves U-[(5-fluoro-benzofuran_3-ylfluorenyl) _amino] _2_nitro-aniline aminoacetic acid ethyl ester (4.50 g '12.1 mol) To anhydrous ethyl "0 ml" was added 6N HC1 (38 ml) aqueous powder (5.70 g '0.10 mole). The red mixture was heated at 60% 78 200413280. The intense color disappeared (20 Minutes). The solid was filtered off and the ethanol was removed from the filtrate by evaporation in vacuo. Aqueous ammonia (saturated) was added to the residue and then extracted with ethyl acetate (3 × 100 ml). The combined The organic extract was washed with brine, dried (MgS04) and concentrated in vacuo. The crude product was purified by chromatography on a silica gel (eluent: ethyl acetate: heptane 1: 1) to obtain 2.70 g (66%) of the title compound 'is a solid. M · ρ · 150-151. (: Calculated value for C18H18FN303: c 62 · 96; Η 5 · 28; N 12. 24. found: C 63. 00; Η 5. 38; N 12 · 13 · LC / MS U / z) 344 (ΜΗ +); tR = 2.00 minutes. 1H NMR (DMS0-A): 1.19 (t, 3Η); 4 · 03 (q, 2Η); 4.26 (d, 2 Η) · '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 2H); 7.95 (s, 1H); 8.16 (b, 1H, NH). The following compounds were prepared in a similar manner and isolated with their argon acid addition salts: lb {2-amine 4-[(5-methyl-thien-2-ylmethyl) -amino] -benzyl} ~ urethane dihydrochloride. The crude product was prepared from ethyl acetate by adding ether hydrogen acid, The title compound was obtained. M.ρ. 190. (: (dec.). Calculated for C15H19N302S, 2HC1: c 47. 00; Η 5.67; N 10.97. Found: C 46. 84; Η 5. 86; N Π · 10 · LC / MS U / z) 306 (ΜΗ +); tR = 1.77 minutes. 1H NMR (DMSO-ί / 6): 1.22 (t, 3H); 2.37 (s, 3H); 4.08 (q, 2Η) 200413280; 4.37 (s, 2H); 6.64 (m, 1H); 6.67 (dd, 1H); 6 72 (d, 1H); 6.86 (d, 1H) ; 7.13 (d, 1H); 8.93 (b, ih NH).,, Lc {2-amino-4-[(3-methyl-quinone-2-ylmethyl) -amino] -phenyl } -Ethyl aminophosphonate dihydrochloride. The crude product was prepared from ethyl acetate via the addition of hydrotest acid to give the title compound. LC / MS (calendar) 306 (MH +);% = 168 points. 1h n 肫 (CDCl3) (free test): U5 (t, 3H); 2.23 (s, 3H); 3.78 (b, 3Η); 4.13 (q, 2Η); 4.32 (s, 2Η); 6.05- 6.10 (m, 2H + NH), 6. 82 (d, 1H); 6. 93 (d, 1H); 7.11 (d ih)

Id {2-胺基-4一[(噻吩—2—基甲基）_胺基]-苯基卜胺基甲酸乙酯二鹽酸鹽。經由添力，氫氯酸自乙醇製備粗產物，得到標題化合物。 M.P. m對 Ci4h17N3〇2S 2hci 之計算值：c 46 16 ;η 5.26; Ν η·54。實测值：c 46·34; H 5 43; N 11.28. LC/MS 292 ⑽+);、= 158 *。iH 賺 (DMS0-.6): 1.22 (t, 3H)； 4.08 (q> 2H); 4>48 (s> 2H) ’ 6.71 (dd, ih)，6.79 (d，iH) ; 6·97 (dd，1H) ; 71〇 (d，1H) ’ 7.16 (d，1H)，7·4〇 (d，1H) ; 8.97 (b，1H， NH). le {2-胺基一4一[(噻吩—3〜基甲基）一胺基]一苯基卜胺基曱酸乙酯二鹽酸鹽。 80 200413280 經由添加鍵氮氯自醋酸乙醋酸製備粗產物，得到標題化合物。Id {2-amino-4 [[thiophene-2-ylmethyl] -amino] -phenylblylamidoethyl formate dihydrochloride. The crude product was prepared from ethanol via hydrochloric acid with hydrochloric acid to give the title compound. Calculated values of M.P.m. for Ci4h17N3O2S 2hci: c 46 16; η 5.26; η η · 54. Found: c 46 · 34; H 5 43; N 11.28. LC / MS 292 ⑽ +) ;, = 158 *. iH earns (DMS0-.6): 1.22 (t, 3H); 4.08 (q >2H); 4 > 48 (s > 2H) '6.71 (dd, ih), 6.79 (d, iH); 6.97 ( dd, 1H); 71〇 (d, 1H) '7.16 (d, 1H), 7.40 (d, 1H); 8.97 (b, 1H, NH). le {2-amine-4-a [( Thiophene-3 ~ ylmethyl) monoamino] -phenylphenylaminophosphonate ethyl dihydrochloride. 80 200413280 The crude product was prepared from acetic acid acetate via the addition of nitrogen nitrogen chloride to give the title compound.

M.p. 196-1 97 °C.對 C14H17N3〇2s，2HCl 之計算值：C 46.16； Η 5.26； N ：C46 23;H5>47;N 11.30. LC/MS U/z) 292 (ΜΙΠ ; tR = 154 分。1H NMR (DMSO-A): 1.21 (t，3H) ; 4.08 (q，2H) ; 4·29 (s，2H)Mp 196-1 97 ° C. Calculated for C14H17N3〇2s, 2HCl: C 46.16; Η 5.26; N: C46 23; H5> 47; N 11.30. LC / MS U / z) 292 (ΜΙΠ; tR = 154 1H NMR (DMSO-A): 1.21 (t, 3H); 4.08 (q, 2H); 4.29 (s, 2H)

;6.66 ⑽，1H); 6·73 (d，1H); 7.14 (dd，1H); 716 (d，1H); 7.51 (dd，1H); 8 86 (b，1H NH). ’; 6.66 ⑽, 1H); 6.73 (d, 1H); 7.14 (dd, 1H); 716 (d, 1H); 7.51 (dd, 1H); 8 86 (b, 1H NH). ’

If {2-胺基-4-[(苯并[bm吩基甲基）_胺基]—苯基 }-胺基曱酸乙酯二鹽酸鹽經由添加鍵氯氯酸自醋酸乙酿製備粗產物，得到標題化合物。 M.P. 213-214。(：.對 Cl8H2lN3Cl2〇2s 之計算值.cIf {2-Amino-4-[(benzo [bmphenylmethyl) _amino] -phenyl} -aminoacetic acid ethyl ester dihydrochloride is prepared from ethyl acetate by addition of chlorochloric acid The crude product gave the title compound. M.P. 213-214. (: Calculated value for Cl8H2lN3Cl2〇2s.c

51.68；H4.95；N10.05〇t，，Hi：c5l.88；H5>35；N51.68; H4.95; N10.05〇t ,, Hi: c5l.88; H5> 35; N

9.95. LC/MS (m/z) 342.2 (M+H+) ; + f ^ 2.08 分。NMR (DMSO-A): 1. 22 (t，3H) ; 4. 08 (q ;6. 81 (dd，1H) ; 6. 93 (d，1H); 2H) , 4. 53 (s5 2H) 19 (d, 1H) ； 7.41 (m, 2H) , 7.70 (s, 1H) ; 7.98 (m 9u、。， 2H) ; 8. 97 (b，ih NH). n，基實施例2 2a (2-胺基-4-{[4-(4-氣-苯磺驗甲基]-胺基}-苯基）-胺基甲酸乙酉旨 &)-3-甲基-噻吩 —2— 81 200413280 在I下，使4-（4-氯—苯石黃醯基）一3一甲基—噻吩一2-曱醛 (301毫克，loo毫莫耳）與（4 —胺基—硝基—苯基）-胺基甲酉文乙g曰（293¾克，ι·3〇毫莫耳）於無水乙醇（1〇毫升 )中之懸浮液在回流下加熱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耄克’ 61% )，將其懸浮於甲醇··醋酸i〇 : 1 ( 耄升）中。添加NaBH3CN (〇·19克，3.0毫莫耳），並於室 /皿下將此合物攪拌i小時，然後添加另一份( 19克’ 3· 0毫莫耳），在另1小時之後，添加飽和碳酸氫鈉水，合液（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 ¾克，94%)，將其 a浮於無水乙醇（10毫升）中。對此加入β N HC1 ( 1. 1 笔升，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至“〇。。，直到紅色褪色成黃色，力10 20分鐘。將混合物倒入飽和碳酸氫鈉水溶液（笔升）和EtOAc ( 50毫升）中，將所得混合物過濾，使相分離’並將水相進—步用Εΐ· (2 χ 5()毫升）萃取。等：併的有機相乾€ ( Na2S〇4 )並在真空中蒸發溶劑。產系、、、二由在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⑻8 ·· 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中蒸發而得到才示題化合物，為淺黃色固體（213毫克，78% ) 。LOMS: = 48(M (M+H+)，對 C21H23C1N304S2 計算值·· h - 2.35 分，UV 純度=72 4%， ELS 純度= 82 200413280 86·5%。1H _ (DMS〇—认 1.19 (b，3 Η)，2·16 (s，3 H), 4.02 (q, /= 6.9 Hz, 2 H), 4.23 (d, / = 6. 1 Hz, 2 H)，4.57 (s，2 H), 5·81 ⑷，…·4, 8·5 Hz，i H), 5.91-5.95 (m, 2 H), 6. 72 ( ^ d, / = 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，i H)· 下列化合物係以類似方式製備： 2b {2-胺基-4-[(3-氯-噻吩一基甲基）一胺基]—苯基卜胺基曱酸乙酉旨產率：76%。LC-MS:(历/y = 326 〇 (M+H+)，對 C14H17C1N302S 計算值：326· 0725，tR = 1· 95 分，UV 純度= 85.8%，ELS 純度=98.1%。4 NMR (DMSO-A): 1.19 (b， 3 Η), 4.03 (q, / = 7. 1 Hz, 2 Η), 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}-胺基曱酸乙醋。產率：66%。LC-MS: U/W = 402.0 (M+H+)，對 C15H19BrN303S 計算值：400· 0325 (1 00 % ) ， 402.0310 (97·3% )，tR = 1.97 分，UV 純度=87.9%，ELS 純度= 98.2%。卬丽R (DMSO-ί/6): 1.20 (b，3 H)，3.83 (s，3 83 200413280 Η), 4.03 (q, / = 6.9 Hz, 2 Η), 4.32 (d, / = 6. 1 Hz,9.95. LC / MS (m / z) 342.2 (M + H +); + f ^ 2.08 points. NMR (DMSO-A): 1. 22 (t, 3H); 4. 08 (q; 6. 81 (dd, 1H); 6. 93 (d, 1H); 2H), 4. 53 (s5 2H) 19 (d, 1H); 7.41 (m, 2H), 7.70 (s, 1H); 7.98 (m 9u,., 2H); 8. 97 (b, ih NH). N, base embodiment 2 2a (2 -Amino-4-{[4- (4-Gas-benzenesulfonylmethyl) -amino} -phenyl) -aminoformic acid ethyl ester &)-3-methyl-thiophene-2 81 81 13280 Under I, make 4- (4-chloro-benzoxanthinyl) -3-methyl-thiophene-2-oxanal (301 mg, loo mmol) and (4-amino-nitro-phenyl) -A suspension of amidoformine B (293¾ g, 30 mmol) in absolute ethanol (10 ml) was heated under reflux for 20 hours. After cooling, the formed plate-colored to red solid imine was collected by filtration and dried under vacuum to obtain a crude product (312 g of '61%), which was suspended in methanol · acetic acid i0: 1 (耄 liter). NaBH3CN (0.19 g, 3.0 mmol) was added, and the mixture was stirred under a chamber / dish for one hour, then another portion (19 g '3.0 mmol) was added, after another 1 hour Saturated sodium bicarbonate water was added to the mixture (20 ml). The red solid imine formed was collected by filtration and dried under vacuum to obtain a crude product (293 ¾ g, 94%), which was floated in absolute ethanol ( 10 ml). To this was added β N HC1 (1.1 pen liters, 6.6 mmol) and iron powder (193 mg, 3.46 mmol), and the red mixture was heated to "0 ..." until the red color faded to yellow For 10 to 20 minutes, pour the mixture into a saturated aqueous sodium bicarbonate solution (pencil) and EtOAc (50 ml), filter the resulting mixture, separate the phases, and add the aqueous phase—step with Εΐ · (2 x 5 () Ml) extraction. Etc .: Coherent organic coherence (Na2SO4) and evaporation of the solvent in vacuum. Production lines ,,, and bismuth use heptane / ethyl acetate as the eluent (linear Gradient elution, usually ⑻8 ·· 2 to 1: 1) and purified by chromatography on silica gel. The fractions containing the product are collected and evaporated in vacuo to obtain the title compound, which is a pale yellow solid (213 mg , 78%). LOMS: = 48 (M (M + H +), calculated for C21H23C1N304S2 ·· h-2.35 points, UV purity = 72 4%, ELS purity = 82 200413280 86 · 5%. 1H _ (DMS〇 — Identify 1.19 (b, 3 Η), 2.16 (s, 3 H), 4.02 (q, / = 6.9 Hz, 2 H), 4.23 (d, / = 6. 1 Hz, 2 H), 4.57 ( s, 2 H), 5.81 ⑷ … · 4, 8 · 5 Hz, i H), 5.91-5.95 (m, 2 H), 6. 72 (^ d, / = 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, i H) · The following compounds were prepared in a similar manner: 2b {2-amino -4-[(3-Chloro-thienylmethyl) monoamino] -phenylphenylaminoacetic acid ethyl acetate Yield: 76%. LC-MS: (Ca / y = 326 〇 (M + H + ), Calculated for C14H17C1N302S: 326 0725, tR = 1.95 minutes, UV purity = 85.8%, ELS purity = 98.1%. 4 NMR (DMSO-A): 1.19 (b, 3 Η), 4.03 (q, / = 7. 1 Hz, 2 Η), 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 (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-fluorenyloxy-thiophen-2-ylmethyl) -amino] -benzene Ethyl} -aminoacetic acid ethyl acetate. Yield: 66%. LC-MS: U / W = 402.0 (M + H +), calculated for C15H19BrN303S: 400 · 3252 (100%), 402.0310 (97 · 3%), tR = 1.97 points, UV purity = 87.9%, ELS purity = 98.2%. Lili R (DMSO-ί / 6): 1.20 (b, 3 H), 3.83 (s, 3 83 200413280 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-甲氧基-苯并[b]瞳吩-2-基曱基）-胺基]-苯基卜胺基甲酸乙酯。產率：60%。LC-MS: = 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 (DMSO-ί/6): 1.19 (b， 3 Η), 3.95 (s, 3 Η), 4.02 (q, / = 7. 1 Hz, 2 Η), 4.43 (d, /= 6.1 Hz, 2 H), 4.56 (s, 2 H), 5.90 (dd, / = 2. 4, 8. 5 Hz, 1 H), 5. 96 (t, /=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, / = 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-[(5-二甲基-胺基-苯并[b]噻吩-3-基甲基）-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%。卬 fiMR (DMSO-心）：1.19 (b， 3 Η)，2·94 (s，6 Η), 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), 200413280 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, l H), 7.38 (s, 1 H)，7.71 (d, 8.5 Hz, 1 H), 8.15 (b， 1 H). 2f {2-胺基[ (5-二甲基-胺基-3-甲基-苯并[b]噻吩 -2-基甲基胺基]一苯基卜胺基甲酸乙酯。產率：36%。LC-MS: = 399·2 (M+H+)，對 C21H27N402S 計算值：399.1849，tR = 1.31 分，UV 純度= 98·4%，ELS 純度=99.4%。4 NMR (DMSO-Α): ΐ·ι9 (b， 3 Η), 2.33 (s, 3 Η), 2.93 (s, 6 Η), 4.02 (q, j = 6.9 Hz, 2 H), 4.37 (d, / = 5. 7 Hz, 2 H), 4.54 (s, 2 H), 5.86 (dd, / = 2.4, 8.5 Hz, 1 H), 5.89 (t, J = 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-胺基一 4一[(5一甲基一噻吩一 2 一基甲基）一（甲基）一胺基]-苯基}-胺基甲酸乙酯。 ^在訏下，使5一甲基一2 一噻吩甲醛（108微升，1· 〇〇毫 '耳）（4月女基-2 一硝基-苯基）-胺基甲酸乙酯（225毫身甲笨（4古、耳）和Amberlite IRC-84 (10毫克）於鄰二真：中中之混合物於回流下加熱5小時。藉由在 —。發除去揮發物，然後將殘餘物溶於乙腈（5毫升 85 2004132802 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-methoxy-benzo [b] pupilphen-2-ylfluorenyl) -amino] -benzene Ethyl urethane. Yield: 60%. LC-MS: = 405.3 (M + H +), calculated for C19H21C1N303S: 406.0987, tR = 2.39 points, UV purity = 95.0%, ELS purity = 99.6%. 4 NMR (DMSO-ί / 6): 1.19 (b, 3 Η), 3.95 (s, 3 Η), 4.02 (q, / = 7. 1 Hz, 2 Η), 4.43 (d, / = 6.1 Hz, 2 H), 4.56 (s, 2 H), 5.90 (dd, / = 2. 4, 8. 5 Hz, 1 H), 5. 96 (t, /=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, / = 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-dimethyl-amino-benzo [b] Thien-3-ylmethyl) -amino] -phenyl} -carbamic acid ethyl ester. Yield: 13%. LC-MS: U / W = 385.0 (M + H +), calculated for C20H25N4O2S: 385.1693, tR = 1.29 points, UV purity = 87.8%, ELS purity = 93.5%.卬 fiMR (DMSO-heart): 1.19 (b, 3 Η), 2.94 (s, 6 Η), 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), 200413280 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, l H), 7.38 (s, 1 H), 7.71 (d, 8.5 Hz, 1 H), 8.15 (b, 1 H). 2f {2-amino [(5-dimethyl-amino-3-methyl-benzo [b] thiophene-2- Methylmethylamino] ethyl phenylphenylaminoformate. Yield: 36%. LC-MS: = 399.2 (M + H +), calculated for C21H27N402S: 399.1849, tR = 1.31 points, UV purity = 98 · 4%, ELS purity = 99.4%. 4 NMR (DMSO-Α): ΐ · ι9 (b, 3 Η), 2.33 (s, 3 Η), 2.93 (s, 6 Η), 4.02 (q, j = 6.9 Hz, 2 H), 4.37 (d, / = 5. 7 Hz, 2 H), 4.54 (s, 2 H), 5.86 (dd, / = 2.4, 8.5 Hz, 1 H), 5.89 (t , J = 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). 'Example 3 _ 3a {2-Amino-4 — [(5-methyl-thiophene-2 2-ylmethyl) — ( Methyl) monoamino] -phenyl} -urethane. ^ Under 訏, make 5-methyl-2 2-thiophene formaldehyde (108 microliters, 1. 00 milli'ear) (April Female -2 mononitro-phenyl) -urethane (225 milligrams of carbamidine (4 mg, urethane) and Amberlite IRC-84 (10 mg) in o-dizhen: the mixture in the middle is heated under reflux 5 hours. Remove the volatiles by spraying the residue and dissolve the residue in acetonitrile (5 ml 85 200413280

)中。在所得溶液中加入NaB ,i# ^ . 3 、u· d 克，4· 0 毫莫耳）接者加入liOAc (5滴）。在攪拌今’ :加甲…之水溶液，〇.89毫升，12毫莫: I績㈣3〇分鐘，並偶爾添加黯反應混合物蒸發至乾燥，狹 U將鈉水、、” 作-後將殘餘物分配於飽和碳酸氫鈉水洛液（50毫升）和Et〇Ac(5〇 (5〇毫升）萃取水相，秋後之間。用_ w ^ ^ …、後將口併的有機層乾燥（Na2S04)in. To the resulting solution was added NaB, i # ^. 3, u · d g, 4.0 mmol. Then liOAc (5 drops) was added. After stirring this time: add an aqueous solution of 0,89 ml, 12 mmol: 30 minutes, and occasionally add the dark reaction mixture to evaporate to dryness, and then make the sodium water, and " Partition between saturated sodium bicarbonate water solution (50 ml) and EtOAc (50 (50 ml)), extract the aqueous phase, and after the fall. Dry the organic layer with _ w ^ ^, ( Na2S04

''在真空中蒸發溶劑。然後將殘餘物溶於乙醇（ι〇毫升加人6NHC1水溶液（2·0毫升，12毫莫耳）和鐵々0.34克’ 6.0毫莫耳）’並將此紅色混合物於。。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納水溶液（50毫升）和遍c(5〇毫升）中 ’將所得混合物過遽、’使相分離，並將水相進一步用'' The solvent was evaporated in vacuo. The residue was then dissolved in ethanol (10 ml of 6NHC1 aqueous solution (2.0 ml, 12 mmol) and iron (0.34 g '6.0 mmol)) and the red mixture was dried. . Heat until red fades to yellow, about 15 minutes. Pour the mixture into a saturated aqueous solution of sodium bicarbonate (50 ml) and pass through c (50 ml). ‘Pass the resulting mixture through 遽,’ to separate the phases, and use the aqueous phase further

EtOAc (2 X 50¾升）萃取。將合併的有機層乾燥（n〜s〇4EtOAc (2 X 50 ¾ liters). The combined organic layers were dried (n ~ s〇4

)並在真空中蒸發溶劑。產物係經以⑴她咖系統中使用庚烷/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。收集含產物之冲提分並在真空中療發而得到標題化合物，為淺黃色固體 (145 毫克，45% 總率）。Lc—MS:(仍/y = 319· g (M+H+) ，對 c16h22n3o2s 計算值：32〇 1427，tR = 18〇分，υν 純度=98.4%，ELS 純度=97·2%。lH (CDCl3): 129 (t， / = 7·1， 3 H)， 2.41 (s, 3 H)， 2.91 (s， 3 H)， 3.76 (b，2 H)，4·19 (q，/= 71 Hz，2 H)，4·52 (s, 2 H)，6· 02 (b，1 H)，6· 17 (d，/ = 2· 8 Hz, 1 H)， 86 200413280 6.25 (dd, /-2.8, 8.5 Hz, 1 H), 6.53-6.58 (m, 1 H), 6.66 (d, /- 3.3 Hz, 1 H), 6.98 (d, / = 8. 5 Hz, 1 H). 下化合物係以類似方式製備·· 3b {2-胺基-4-[(5-氯-噻吩-2-基甲基甲基）-胺基 ]-苯基}-胺基曱酸乙酯。產率：34%。LC-MS: U/z) = 340·0 (M+H+)，對 C15H19C1N302S 計算值：340.0881，tR = 2.14 分，UV 純度二 82.3%，ELS 純度=90.2%。4 匪R (CDC13): 1.29 (t，/ =6.8, 3 Η), 2.91 (s, 3 Η), 3.78 (b, 2 Η), 4.20 (q, / = 7.2 Hz, 2 H), 4.49 (s, 2 H), 6.05 (b, 1 H), 6.16 (d, J - 2.4 Hz, 1 H), 6.24 (dd, J = 2.4, 8.5 Hz，1 H), 6.73 (d，/ = 3.8 Hz，1 H), 6.99 (d，/ = 8. 5 Hz, 1 H). 下列化合物係以類似方式製備，但將甲醛換成乙醛： 3c {2-胺基-4 -[(5 -氯-瞳吩-2-基甲基）-(乙基）-胺基 ]-苯基}-胺基甲酸乙酯。產率：12%。LC-MS·· (7Z//Z) = 353.9 (M + H+)，對 C16H21C1N302S 計算值：354.1 038，tR = 2.02 分，UV 純度二 97.5%，ELS 純度=99.0%。卬 NMR (CDC13): 1.16 (t，/ =7.1，3 H)，1.29 (t，/ = 6.8，3 Η), 3·36 (q，J = 7·1 Hz，2 H)，3.76 (b，2 H)，4.19 (q，/= 7·2 Hz, 2 87 200413280 Η), Hz, “7 (s，2 Η)，6·〇5 (b, 1 Η), 6· 19 ⑷，/ = 2· 4, 3· 8 Ηζ，1 Η)，6·9β (d，/ 1 Η), 6. 13 (d，/ = 2· 4 9. 0 Hz, 1 Η), 6. 73 (d, =8. 0 Hz, 1 Η). 下列化合广系以類似方式製備，但省略甲搭添加： &龙3(1 {2胺基4'[(5~敗—_吩~2-基甲基）-胺基]-苯基卜月女基甲酸乙酯 310. 2 (M + H+)，對 1· 76分，UV純度率的乂（在製備LC-MS純化以除去未氟化副產物之後為 25% )。LC_MS:U/幻 c14h17fN3〇2S 計算值：31〇1〇2()，、 H ’ ELS 純度=83.4%。lH _ (CDC13): 1.29 (b，3 .5 3*82 (b，2 H)，4*19 ((1> ^ = 7.2 Hz, 2 H), 4.31 ,/= 2-° HZ> 2 H)> 6.05 (b, ! H), 6.09 (d, / = •〇Hz，1H)，6.29(dd，/ =15, 38Hz，ih)，658 3.5 Hz, 1 H), 6.94 (d, / = 8. 0 Hz, 1 H). 實施例4 參 4a {2-胺基-4-[(5-氯__吩_2_基甲基）_胺基卜苯基卜胺基甲酸乙酯。將5-氯噻吩-2-曱醛溶液（24〇微升，1U微莫耳， 463 mM於ι，2-二氣乙烷中）加到4 —胺基—2 —硝基苯基胺基 :酸乙酯溶液（ 240微升，lu微莫耳，463 於丨，2一二氯乙燒）中。添加三乙醯氧基爛氫化納（118毫克，咖微莫耳），然後於4〇 C將所得混合物攪拌3· 5小時。使混 88 合物冷卻到周圍溫度，夕 ^ …、後加水（100微升）。使混厶物經矽凝膠（500毫克） ^ 使此口 )沖洗q “ 用U-二氯乙烧（3毫升 T洗g柱。在真空中將合供籽口併的有機相4發至乾燥。將所付固體溶於乙醇（3毫升） $ ?將鐵（19毫克）加到三分 :的所仔溶液（1毫升）+，接著添加氫氯酸水溶液（以升，6Μ)ι所得混合物置於超聲波浴中10分鐘。 ;、;f:添加飽和碳酸氫納水溶液（2毫升）。用醋酸乙醋毛升）卒取混合物。將有機相用水（3毫升）和食鹽 7 (3毫升）洗膝’經硫酸鎂乾燥，過濾及在真^中蒸發至乾燥。將所得產物溶力19〇冑升二曱亞楓中，並進行製備LC-MS」屯化。使所得溶液在真空中蒸發至乾燥。產率 (6.8 笔克，56% ) 。LC-MS 以/之）（Μ+Η)+ 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-噻吩基甲基）一胺基]—苯基}一胺基曱酸乙酉旨。 LC-MS (m/z) (M+H)+ 371.9 RT=1.94 (UV, ELSD) 89% ，98% 〇 4c丨2-胺基-4-[(4-溴-噻吩基曱基）-胺基]-苯基}- 胺基曱酸乙酯。 LC-MS (m/z) (M+H)+ 372.0 RT=1.96 (UV, ELSD) 76% ，100% 〇 4d {2-胺基-4-[(5-乙基-噻吩—2一基曱基）一胺基]一苯基 89 200413280 }-胺基甲酸乙酯。 LC-MS (m/z) (M+H)+ 320.1 RT=1.90 (UV, ELSD) 72% ，96% 〇 4e {2-胺基-4-[(苯并[b]噻吩—2-基甲基）—胺基]一苯基 }-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-基甲基）-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% 〇實施例5 5a {2-胺基-4-[(苯并[b]噻吩_2-基曱基）一胺基]一苯基 } -胺基甲酸丙酯將苯并[办]噻吩-2-曱醛（1· 36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，8·36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丨6〇維持2分鐘。冷卻時，添加NaBH3CN ( 1.06克，16·7毫莫耳）和Ac〇H (48微升， 0· 84毫莫耳），然後於25 °C將混合物授拌3〇分鐘。添加水/食鹽水（1:1， 1〇〇毫升），然後用醋酸乙酯（3χ 100宅升）卒取、混合物。將有機相經硫酸鎭乾燥，過渡及在真空中浪細。使粗製中間物經由在矽凝膠上之急驟層析 200413280 (沖提劑··醋酸乙酯：庚烷！： 9 )純化， … 及蒸發至乾燥。然後將此中間物溶於四氫呋喃（2〇毫、 ’、 jtK u r r ^ Τ’並添加溶於水（50毫升）之( 3· 67克，21 名π笔莫耳）。在氬氣下使所得混合㈣㈣下㈣5小時。將所得混合物用醋酸乙醋（3x 10。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i : υ純化，製得〇·3克（1〇% )標題化合物，為固體。LC/MS U々）356 ([M+H] + ) ; RT = 2·45 分 ° 4 NMR (CDC13): 〇·95 (t，3Η) ; 1·67 (m，2Η) ; 4·08 (t> 2Η) ; 4.55 (s, 2Η) ； 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-[(笨并[b]噻吩-3-基甲基）-胺基]-苯基 } -胺基曱酸丙醋。產率：16%。LC/MS (/z//z) 356 ([M+H] + ) ; RT = 2· 24 分。1H NMR (CDC13): 〇· 96 (t，3H) ; l 68 (m，2iQ ; 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-{2-胺基-4-[(5一氯噬吩-2一基甲基）胺基]苯基}一 200413280 2-(4 -氟苯基）-乙醯胺。在N-{ 4-[(5-氯_吩-2-基甲基）胺基]- 2-硝基苯基}-2-(4-氟苯基）乙醯胺（320毫克，0· 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中，將鋅粉（粒子大小<1 〇微米，丨〇克）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Si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_/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280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%。iH NMR (DMS〇—dj: 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—氯噻吩_2_基甲基）胺基]苯基}_ 3，3 -二甲基丁酿胺。) And the solvent was evaporated in vacuo. The product was purified by chromatography on a silica gel using a heptane / ethyl acetate extraction system (linear gradient elution, usually from 8: 2 to 1: 1) in a Sunta coffee system. The product-containing fractions were collected and treated in vacuo to give the title compound as a pale yellow solid (145 mg, 45% overall rate). Lc—MS: (still / y = 319 · g (M + H +), calculated for c16h22n3o2s: 32〇1427, tR = 18〇minutes, νν purity = 98.4%, ELS purity = 97 · 2%. LH (CDCl3 ): 129 (t, / = 7.1, 3 H), 2.41 (s, 3 H), 2.91 (s, 3 H), 3.76 (b, 2 H), 4.19 (q, / = 71 Hz , 2 H), 4.52 (s, 2 H), 6.02 (b, 1 H), 6.17 (d, / = 2.8 Hz, 1 H), 86 200413280 6.25 (dd, /- 2.8, 8.5 Hz, 1 H), 6.53-6.58 (m, 1 H), 6.66 (d, /-3.3 Hz, 1 H), 6.98 (d, / = 8. 5 Hz, 1 H). The following compounds are 3b {2-Amino-4-[(5-chloro-thien-2-ylmethylmethyl) -amino] -phenyl} -aminophosphonic acid ethyl ester was prepared in a similar manner. 34%. LC-MS: U / z) = 340.0 (M + H +), calculated for C15H19C1N302S: 340.0881, tR = 2.14 points, UV purity 22.3%, ELS purity = 90.2%. 4 Bandit R (CDC13): 1.29 (t, / = 6.8, 3 Η), 2.91 (s, 3 Η), 3.78 (b, 2 Η), 4.20 (q, / = 7.2 Hz, 2 H), 4.49 ( s, 2 H), 6.05 (b, 1 H), 6.16 (d, J-2.4 Hz, 1 H), 6.24 (dd, J = 2.4, 8.5 Hz, 1 H), 6.73 (d, / = 3.8 Hz , 1 H), 6.99 (d, / = 8. 5 Hz, 1 H). The following compounds were prepared in a similar manner, but the formaldehyde was replaced by acetaldehyde: 3c {2-amino-4-[(5-chloro -Pidophen-2-ylmethyl)-(ethyl) -amino] -phenyl} -urethane. Yield: 12%. LC-MS ... (7Z // Z) = 353.9 (M + H +), calculated for C16H21C1N302S: 354.1 038, tR = 2.02 points, UV purity 2 97.5%, ELS purity = 99.0%.卬 NMR (CDC13): 1.16 (t, / = 7.1, 3 H), 1.29 (t, / = 6.8, 3 Η), 3.36 (q, J = 7.1 Hz, 2 H), 3.76 (b , 2 H), 4.19 (q, / = 7.2 Hz, 2 87 200413280 Η), Hz, "7 (s, 2 Η), 6.05 (b, 1 Η), 6.19 ⑷, / = 2 · 4, 3 · 8 Ηζ, 1 Η), 6. · 9β (d, / 1 Η), 6. 13 (d, / = 2 · 4 9. 0 Hz, 1 Η), 6. 73 (d , = 8. 0 Hz, 1 Η). The following chemical compounds are prepared in a similar manner, but the addition of chloroform is omitted: & 龙 3 (1 {2amino group 4 '[(5 ~ defe — phen ~ 2-base (Methyl) -amino] -phenyl-triazine ethyl ester 30.2 (M + H +), 1.76 minutes, UV purity of 乂 (purified in preparative LC-MS to remove unfluorinated by-products After the product is 25%). LC_MS: U / magic c14h17fN302S Calculated: 31〇1〇2 (), H 'ELS purity = 83.4%. LH_ (CDC13): 1.29 (b, 3.5 3 * 82 (b, 2 H), 4 * 19 ((1 > ^ = 7.2 Hz, 2 H), 4.31, / = 2- ° HZ > 2 H) > 6.05 (b,! H), 6.09 (d, / = • 0 Hz, 1H), 6.29 (dd, / = 15, 38Hz, ih), 658 3.5 Hz, 1 H), 6.94 (d, / = 8. 0 Hz, 1 H). Example 4 Reference 4a {2-Amino-4-[(5-chloro__phen_2_ylmethyl) _aminophenylphenylphenyl Ethyl carbamate. A solution of 5-chlorothiophene-2-carboxaldehyde (24.0 microliters, 1U micromolar, 463 mM in 2,2-digasethane) was added to 4-amino- 2- Nitrophenylamine: Ethyl acetate solution (240 μl, 1 μmol, 463 in 1,2, dichloroethane). Add triethyloxolan sodium hydride (118 mg, Cevimo) Ear), and the resulting mixture was stirred at 40 ° C for 3.5 hours. The mixed mixture was cooled to ambient temperature, and then water (100 microliters) was added. The mixture was passed through a silica gel (500 mg ) ^ Make this mouth) Rinse q "with U-dichloroethane (3 ml T wash g column. The organic phase of the seed supply is dried in a vacuum to dryness. The paid solid is dissolved in ethanol (3 Ml) Add iron (19 mg) to three points: the soy solution (1 ml) +, then add hydrochloric acid aqueous solution (in liters, 6M), and place the resulting mixture in an ultrasonic bath for 10 minutes. ;,; F: Add saturated aqueous sodium bicarbonate solution (2 ml). The mixture was extracted with ethyl acetate (e.g. ethyl acetate). The organic phase was washed with water (3 ml) and common salt 7 (3 ml), dried over magnesium sulfate, filtered, and evaporated to dryness. The obtained product was dissolved in 190 liters of Acer sylvestris, and subjected to preparative LC-MS. The resulting solution was evaporated to dryness in vacuo. Yield (6.8 pen grams, 56%). LC-MS: (M + Η) + 326.1 RT = 1.90 (UV, ELSD) 92%, 99%. The following compounds were prepared in a similar manner: 4b {2-Amino-4-[(5-bromo-thienylmethyl) monoamino] -phenyl} monoaminoacetic acid ethyl ester. LC-MS (m / z) (M + H) + 371.9 RT = 1.94 (UV, ELSD) 89%, 98% 〇4c 丨 2-amino-4-[(4-bromo-thienylfluorenyl)- Amino] -phenyl} -aminoacetic acid ethyl ester. LC-MS (m / z) (M + H) + 372.0 RT = 1.96 (UV, ELSD) 76%, 100% 〇4d {2-amino-4-[(5-ethyl-thiophene-2-one) Fluorenyl) monoamino] monophenyl 89 200413280} -urethane. LC-MS (m / z) (M + H) + 320.1 RT = 1.90 (UV, ELSD) 72%, 96% 〇4e {2-amino-4-[(benzo [b] thiophen-2-yl Methyl) -amino] -phenyl} -urethane. LC-MS (m / z) (M + H) + 342.1 RT = 2.06 (UV, ELSD) 75%, 100%. 4f {2-Amino-4-[(5-phenyl-thien-2-ylmethyl) -amino] -phenyl} -urethane. LC-MS (m / z) (M + H) + 368.2 RT = 2.21 (UV, ELSD) 90%, 99% 〇 Example 5 5a {2-amino-4-[(benzo [b] thiophene_ 2-ylfluorenyl) monoamino] monophenyl} -carbamic acid propyl [benzo] thiophene-2-fluorenal (1.36 g, 8.38 mmol) was added to (4- Amino-2-nitro-phenyl) -propylaminoacetate (200 g, 8.36 mmol) in acetonitrile (10 ml). The mixture was heated to 60 in a 20 ml sealed microwave processing vial for 2 minutes. While cooling, NaBH3CN (1.06 g, 16.7 mmol) and AcOH (48 μl, 0.84 mmol) were added, and the mixture was then stirred at 25 ° C for 30 minutes. Water / saline (1: 1, 100 ml) was added, and the mixture was taken with ethyl acetate (3 x 100 liters). The organic phase was dried over osmium sulfate, transitioned and finely waved in vacuo. The crude intermediate was purified by flash chromatography on a silica gel 200413280 (eluent ·· ethyl acetate: heptane !: 9), and evaporated to dryness. This intermediate was then dissolved in tetrahydrofuran (20 mmol, ', jtKurr ^ T') and added to water (50 ml) (3.67 g, 21 π pen moles). The resulting was made under argon The mixture was mixed for 5 hours. The resulting mixture was extracted with ethyl acetate (3 x 10. ml), the combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (eluent: ethyl acetate : Heptane i: υ purification to obtain 0.3 g (10%) of the title compound as a solid. LC / MS U々) 356 ([M + H] +); RT = 2.45 minutes ° 4 NMR (CDC13): 0.95 (t, 3Η); 1.67 (m, 2Η); 4.08 (t >2Η); 4.55 (s, 2Η); 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 are based on Prepared in a similar manner: 5b {2-amino-4-[(benzy [b] thiophen-3-ylmethyl) -amino] -phenyl} -propylaminoacetate. Yield: 16%. LC / MS (/ z // z) 356 ([M + H] +); RT = 2.24 minutes. 1H NMR (CDC13): 0.96 (t, 3H); 68 (m, 2iQ; 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- {2-Amino-4-[(5-chlorochlorophen-2-ylmethyl) amino] phenyl} -200413280 2 -(4-fluorophenyl) -acetamidamine. In N- {4-[(5-chloro_phen-2-ylmethyl) amino] -2-nitrophenyl} -2- (4- Fluorophenyl) acetamide (320 mg, 0.762 mmol) in a stirred red solution of tetrahydrofuran (25 ml) and acetic acid (8 ml). Zinc powder (particle size < 10 μm, (0 g) was added periodically in portions over a period of 30 minutes. The solution became colorless after 5 minutes. The resulting colorless suspension was filtered through a plug of SiO 2 (10 g) and ethyl acetate was used as the eluent. The resulting solution was then evaporated in vacuo. The resulting solid was dissolved in a mixture of ethyl acetate / propion / trifluoroacetic acid (3 ml / 3 ml / 0.2 ml), and a saturated NaHC03 aqueous solution (50 ml) and Treatment with heptane (30 ml) and isolation of the product by filtration yielded 280 mg of a light gray solid. Yield: 94.2%. LC / MS (m / z) 390.4 ([M + H] +); RT = 2.26 (UV, ELSD) 99%, 100%. iH NMR (DMS〇-dj: 3 56 (s, 2H); 4.28 (d, 2H); 4.57 (s, 2H, NH2); 5.87 (dd, 1H); 5.98 (m, 2H, NH and aromatic Family 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 were prepared in a similar manner from the corresponding nitro compounds: 6b N- {2-amino-4-[(5-chlorothiophen-2-ylmethyl) amino] phenyl} _3,3 -Dimethyl butanolamine.

在、·二過Si〇2過濾及蒸發之後，使產物從醋酸乙酯-飽和陳〇3水溶液（5毫升/2G毫升）與庚烧（5G毫升）之雙相溶液中沈澱出來。產率：580毫克，71.5%。LC/MS 92 200413280 Οπ/ζ) 352.48 _m 2·16 ⑽，_ 96%，⑽ % 。 4 NMR (DMSO-d6): 1·01 (s， 9H)， 211 (s， 2H); 4.29 (d, 2H)；4.54 (s, 2H, NH2)；5.88 (dd, 1H) ； 5. 97 (t，iH，NH) ·, 5.99 (d，1H) ; 6·72 (d，1H) ; 6·87 (d， 1H) ; 6. 93 (d，1H) ; 8. 82 (s，ih)· 活體外與活體内試驗本發明之化合物已經在下列模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（（CPM_er/CPMsuper+ CPMcell)Cmpd/ (CPMsut)er/CPMsuper+ CPMcenLsmM kci)*1〇〇 —1〇〇〇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 200413280 最大電休克本试驗係在幾組雄小鼠中進行，使用角膜電極並給予 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^厥（Wlaz et ai·办"印印力 1998，30, 219-229)。毛果芸香鹼誘發之癲癇發作毛果芸香驗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鹼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， 321-325) 〇電痛癇發作閾試驗使用一種上下法（up-and-down method )之改良（ Kimball et a·，心⑽…《的〜力1 957，卜12)來測疋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（ • 4 5 〇赫餘）並觀察癲癇發作活動性。如果觀察到癲癇發作，則對下一隻小氟將電流減少i mA，然而，如果沒有觀察到癲癇發作，則將電流增加1mA。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 200413280 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. /户力 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側杏仁核。手術之後，讓動物恢復，然後使這幾組大鼠接受不同劑量的試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。（Racim EIectroencephal〇graphy _After filtering through SiO 2 and evaporation, the product was precipitated from a biphasic solution of ethyl acetate-saturated aqueous EtOAc (5 ml / 2 G ml) and heptane (5 G ml). Yield: 580 mg, 71.5%. LC / MS 92 200413280 0π / ζ) 352.48 _m 2 · 16 ⑽, _ 96%, ⑽%. 4 NMR (DMSO-d6): 1.01 (s, 9H), 211 (s, 2H); 4.29 (d, 2H); 4.54 (s, 2H, NH2); 5.88 (dd, 1H); 5. 97 (t, iH, NH) ·, 5.99 (d, 1H); 6.72 (d, 1H); 6.87 (d, 1H); 6. 93 (d, 1H); 8. 82 (s, ih ) · In vitro and in vivo tests The compounds of the invention have been tested in one or more of the following modes and have shown effects: Relative outflow through the KCNQ2 channel. One day before the experiment, cells stably showing the voltage-gated KCNQ2 channel were inoculated and loaded with [86Rb]. On the day of the experiment, cells were washed with HBS-containing buffer. Cells were pre-cultured with the drug, and then stimulated with sub-limiting concentration of 15 mM KC1 in the presence of the drug [86Rb +]. After an appropriate incubation time, the supernatant was removed and counted in a liquid flash counter (Tricarb). Cells were lysed with 2 mM NaOH and the amount of 86Rb + was calculated. Calculate relative outflow ((CPM_er / CPMsuper + CPMcell) Cmpd / (CPMsut) er / CPMsuper + CPMcenLsmM kci) * 100-1000) The compound of the present invention has an EC5Q of less than 20000 nM, and in most cases it is less than 2000 nM, and In many cases it is less than 200 nM. Therefore, the compounds of the present invention are considered to be useful for the treatment of diseases related to the potassium channel of the KCNQ family. 93 200413280 Maximum electrical shock This test was performed in several groups of male mice, using a corneal electrode and given a square wave of 26 mA for 0.4 seconds in order to induce turbulence characterized by tonic hindlimb extension (Wlaz et ai · Office " Printronix 1998, 30, 219-229). Pilocarpine-induced seizures Pilocarpine test-induced seizures were induced by intraperitoneal injection of 250 mg / kg pilocarpine in several groups of male mice, and the seizure activity that caused postural loss (starr et al. Pharmacology Biochemistry and Behavior 1993, 45, 321-325) 〇 The electric pain epileptic threshold test uses an improvement of the up-and-down method (Kimball et al., Heart palpitations ... ~~ 1 957, Bu 12) to measure the mid-threshold threshold of tetanic hindlimb extension in response to corneal shock in several groups of male mice. The first mouse of each group was subjected to a 14 mA electrical shock (more than 450 Hz) and the seizure activity was observed. If a seizure is observed, the current is reduced by i mA for the next small fluorine, however, if no seizure is observed, the current is increased by 1 mA. Repeat this step for all 15 mice in the treatment group. Chemical Seizure Threshold Test 94 200413280 Threshold doses of pentyltetrazole required to induce clonic convulsions are obtained by extending pentamyltetrazole (5 mg / ml at 0.05 ml / min) into several groups of male mice The tail vein was measured by timed infusion (Nutt et al./Huri 1986, 38, 697-698). Amygdala activation Rats are operated to implant a tripolar electrode into the dorsal lateral amygdala. After surgery, the animals were allowed to recover, and these groups of rats were then exposed to different doses of the test compound or drug carrier. These animals were stimulated daily with their initial threshold + 25 μA after discharge for 3-5 weeks, and the severity of seizures, duration of seizures, and duration of electricity after each discharge were recorded. (Racim EIectroencephal〇graphy _

Neurophysiology 1972, 32, 281-294) 副作用小鼠維持在旋轉裝置 Drug and ChemicalNeurophysiology 1972, 32, 281-294) Side effects Mice maintained on a rotating device Drug and Chemical

中樞神經系統副作用係藉由測量上的日π間來測量（Capacio et al. 加―_ 1992, 15, 177_2G1);或藉由利用計算在試驗籠中交又的紅外光束數目測量它們的活動能力來測量（ Watson et al. Neuropharmacology i997> 36> 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人能夠測量溫度之無線電遙發送器來測量…啊 et al. Physiology and Behavi〇ur 177-184 ) 95 200413280 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。Central nervous system side effects are measured by measuring day-to-day intervals (Capacio et al. Plus __ 1992, 15, 177_2G1); or by using calculations to measure the number of infrared beams crossing in the test cage To measure (Watson et al. Neuropharmacology i997 > 36 > 1369_1375). The low-temperature effects of the compounds on the core body temperature of animals are measured by rectal probes or radiotelephone transmitters capable of measuring temperature by the implanted human ... ah et al. Physiology and Behaviour 177-184) 95 200413280 The kinetic properties were determined by intravenous and oral administration of Spraque Daw ley rats, after which blood samples were taken over a period of 20 hours. Plasma concentrations were determined by LC / MS / MS.

9696

Claims

200413280 Scope of patent application: 1. A formula of 1,2,4-triaminobenzene derivative

Among them, R1 is selected from the group consisting of fatigue, Γ. I-6-alkane (alkene / alkynyl) group, c3_8-cycloalkane (en) yl group (diluted) group_Ci_6, mono- (diluted / quick) group, and hydroxy-Cb6 -An alk (en / alkyn) group and a group formed by the group -Ch-cycloalk (en) group; R and R are independently selected from hydrogen and R. Bu 6-alk (en / alkynyl), cycloalk (en) yl, aryl, W-cycloalk (en) yl-Ch-alk (en / alkynyl), aryl-Cif (alkene / block) group , Gf group, a group R3 consisting of a Ci-6 alkyl (alkene / alkynyl) group and a hydroxy-CH-cycloalkene (alkene) group: selected from hydrogen. Alkyl 6-alkene, alkenyl, alkenyl, aryl, cycloalkenyl-ch-alk (en / alkynyl), square-ch-alk (en / alkynyl) , Hydroxy-Ch-alk (en / alkynyl), aryl-C3-8-cycloalk (en) yl, NRi0RH, -alk (en / alkynyl), NR R1 ()-C3_8-cycloalkyl ( A group consisting of alkenyl) and hydroxy-CH-naphthenic (en) yl groups; of which 97: and r. 'Are independently selected from the group consisting of gas, C1_L3-8-% hydrazone (bar,), and meridian c V (dilute) radical -Cl… dilute, bulk, meridian 1 1 dilute / alkyne), meridian—ring-fired (diluted) W heart suspect 3Γ " burned (diluted) radical-Cl · 6—burned ( Alkenyl, alkynyl, alkynyl, r-dialkynyl, alkynyl 3-8-cycloalkane (alkenyl), self-radical _C 8 monophosphazene (alkene, its —Γ oxen 3 ~ / alkyne ) Bu:! FW alkynyl) group, cyano H (dilute) A c louse r. 3-8 —cycloalkyl (alkenyl) and cyano-C3f cycloalkene (alkene — ^ 6-alkane (alkene / alkynyl) groups, or

f R, together with the nitrogen atom to which they are attached, form a 4- to 8-membered saturated or unsaturated ring with 1, 2 or 3 other heteroatoms as required; x is co or so2; z is 0 or NR4, where R It is selected from the group consisting of hydrogen, C6-6 (diluted / quick) group, C3_8-cycloalkane (diluted C3_8-% alk (en) yl-Ch-alk (ene / alkynyl) group, hydroxy-Ci_6 alkane ( A group consisting of alkenyl / alkynyl and hydroxy-CM-naphthenic (alkenyl) groups: or

R3 and R4 together with the nitrogen atom to which they are attached form a 4- to 8-membered saturated or unsaturated ring with 3, 1, 2 or 3 other heteroatoms as required, and the ring formed by R and R4 and the nitrogen atom It needs to be substituted by one or more substituents independently selected from the group consisting of c—6-alk (en / alkynyl), aryl and aryl-Ch-alk (en / alkynyl) groups; q is 0 or 1; And Y represents a heteroaryl group of formula II or III: 98 200413280

among them

W is 0 or s; m is 0, 1, 2, or 3; η is 0, 1, 2, 3, or 4; P is 0 or 1; and each R5 is independently selected from Ci "alkane (alkene, alkyne ) -Based cycloalkane (diluted), aryl, Ch_cycloalkyl (diluted) n (dilute-8 alkynyl), aryl-Cl_6-alkane (alkene / alkynyl), fluorenyl, halo-Cl-6 : Alkane (diluted / block), alkane (diluted / fast) oxy,. ", Alkyl, nitro, -Q p 8 〇 / -VQ ⑽ R, -SR, -S02R8, S〇2〇R8 Group

Where = and R6 are independently selected from the group consisting of hydrogen, c, "burned (diluted / block) group, C3-8 $ clothing burned (diluted) group," ίψ ^ ί \ -a- ^, its ... A group consisting of alk (en) yl-Ch-alk (en) yl and square groups; R7 and R7 'are independently selected from hydrogen, Ci "alk (ene, alkynyl), m (dilute), c " _Cyclo (en) yl_Ci "group consisting of alkenyl, aryl and fluorenyl; and R8 is selected from Cl_" alk (en), CH_cycloalkane (The group consisting of "ene" 99 200413280, C3_8-cycloalkyl (en) yl_Ci_6-alk (en / alkynyl), aryl and -Sin 9R9, where R9 and R9 'are independently selected from A group consisting of hydrogen, Cl_ "alkane (diluted / fast), c3_8-cycloalk (en) yl and C38_cycloalk (en) yl, meaning alkane (ene / alkyne); or a pharmaceutically acceptable group thereof 2. The compound is claimed as item No. 丨 in the patent scope, in which R1 is selected from the group consisting of hydrogen and Cn-alkene (alkene / alkynyl) groups. 3. According to Zhongqing patent scope No.} and 2 Any of the compounds of the item, wherein at least one of the substituents R2 and R2 'is a hydrogen atom 4. The compound according to any one of the claims ^, wherein both R and R2 are hydrogen atoms. 5. The compound according to any one of the claims 1-4, wherein X is C0. 6. The compound according to any one of the m items in the scope of the patent application, where q is 0. 7. According to the compound in any one of the 1-5 items of the patent scope, where q is 1 and Z is an oxygen atom 38. The compound according to any one of items 1 to 7 of the scope of the patent application, wherein R is remote from the Cl-6-alkyl (alkene / alkynyl) group and the aryl- (: ) Groups. 9. Compounds according to item 8 of the scope of patent application, where R3 is Ci6-alk (ene / alkynyl) group. 10. Compounds according to item 8 of the scope of patent application, where R3 is aromatic. 100 200413280 base-Cu-burnt (dilute / quick) group. 11. The compound according to any one of items 1 to 10 of the scope of the patent application, wherein W is an oxygen atom. 12. According to the scope of the patent application, items 1 to 11 A compound according to any one, wherein W is a sulfur atom. 13. A compound according to any one of claims 1-12, wherein Y has formula 1 1.

14. A compound according to any one of claims 1-12, wherein Y has formula III. 15. The compound according to any one of claims 1-14, wherein Y has the formula lib or Illb: (R5) mw

lib

Wherein W, m, η, p and R5 are as defined above.

16. Compounds according to the scope of patent application in which Y has the formula lie or IIIc: any of 1 to 14

w He

Wherein W, m, η, p and R5 are as defined above. 17. The compound according to any one of items 1 to 16 of the scope of the applied patent, 101 200413280, wherein each R5 is independently selected from Ci "alkyl (diluted / fast) group, aryl, halogen, Ch-alkane (ene / A group consisting of alkynyl) oxy, nr7r7 ', and -s〇2R8. 18. According to the compound of any one of claims 1-17, the distant compound is selected from the group consisting of the following: Group: {2-Amino-4-[(5-chloro-thiophene-2-ylmethyl) -methyl_amino] -phenyl} -aminoammonium ethyl ester; {2-Amino-4 -[(5-Chloro-thien-2-ylmethyl) -amino] -phenylphenylaminosulfonic acid ethyl ester; {2-amino-4-[(5-fluorenyl-thiophen-2-yl) Methyl) monomethyl-amino] monophenyl} -urethane; {2-amino_4-[(5-bromo-thien-2-ylmethyl) monoamino] -phenyl } Ethyl monoaminophosphonate; {2-amino-4-[(6-chloro-3-methoxy-benzo [b] _phen-2-ylmethyl) -amino] -phenyl丨 Ethylaminophosphonate; {2-amino-4-[(benzo [13] thiophen-2-ylmethyl) -amino] -phenyl} -aminophosphonate ethyl ester; {2 -Amino-4-[(5-methyl- pupill-2-ylmethyl) -amino] -phenylaminoethylacetate; { 2-amino-[(4-bromo-3-methoxy-thien-2-ylmethyl) -amino] -phenyl} -urethane; {2-amino [(5-benzene -Thienyl-2-ylmethyl) -amino] -phenylphenylaminosulfonic acid ethyl ester; {2-amino-4-4-[(3-mono-thiophen-2-ylmethyl) -amino] Monophenylethylamine 102 200413280 ethyl formate; (2-amino-4-{[4- (4-chloro-benzenesulfonyl) -3-methylphen-2-ylfluorenyl] -amino } -Phenyl) -urethane; {2-amino-4-[(3-methyl-thien-2-ylmethyl) -amino] -phenylurethane; {2 -Womenyl- 4-[(5-Mer-phenylsulfan-3 -ylfluorenyl) -amino] -phenyl} -aminophosphonic acid ethyl ester; {2-amino-4-[( Thien-2-ylfluorenylamino] -phenylphenylaminophosphonic acid ethyl ester; {2-amino-4-[(4-bromo-_phen-2-ylmethyl) -amino] -benzene Ethyl} -aminoammonium ethyl ester; {2-amino_4-[(5-ethyl-thien-2-ylmethyl) -amino] -phenyl} -aminoammonium ethyl ester; { 2-amino-4-[(thien-3-ylfluorenyl) -amino] -phenyl} -aminophosphonic acid ethyl ester; -2-Methyl) -ethyl-amino] -phenyl} -aminophosphonic acid ethyl ester; {2-amino-4-[(benzene [b] Thien-3-ylfluorenyl) -amino] -phenyl} -aminophosphonic acid ethyl ester; {2-amino-4-[(5-dimethyl-amino-benzo-benzo [b ] Thiophen-3-ylmethyl) -amino] -phenyl} -ethylaminoformate; {2-amino-4- [(5-dimethyl-amino-3-fluorenyl-benzo) [b] Thienyl-2-ylmethyl) -amino] -phenylphenylaminophosphonium ethyl ester; {2-amino-4-[(5-fluoro-thiophen-2-ylfluorenyl) -amine Phenyl] -phenylbutanyl 103 200413280 ethyl carbamic acid ethyl ester; η {2-amino_4 mono [(benzo [b] thiophene-2-ylmethyl) monoamino phenylphenyl amino aminopropyl Ester; {2-Amino-4 — [[benzo [b] thiophene_3-methylmethyl) _amino] _phenylphenylamino propyl ester; / {2- 月女基 -4- [ (5-Chloro-thien-2-ylmethyl) amino] phenyl group 2 1 (4 mouse to the base)-ethyl amine; and {2 amino-4- [(5-chloro-warm phen- 2-ylmethyl) amino] phenylphenyl 3,3-dimethyl-butanidine, amidine or a pharmaceutically acceptable salt thereof. 19. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of item 18 of the scope of patent application and one or more pharmaceutically acceptable carriers or diluents. 20. · A compound for use according to any one of items i to 19 of the scope of application for a patent, which is a pharmaceutical preparation for preventing, treating and / or inhibiting a central nervous system disorder. 21 · The use according to item 20 of the scope of the patent application, characterized in that the disorders of the mesenteric nervous system are selected from the group consisting of seizures such as convulsions, epilepsy and status epilepticus. 22. The use according to item 21 of the scope of patent application, characterized in that the disorders of the middle drag system are selected from neuropathy and migraine disorders, such as touch pain, hyperalgesia pain, phantom pain, and related to diabetic neuropathy A group of neuropathic pain 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 nervous system in 104 200413280 is selected from anxiety disorders, such as anxiety, generalized anxiety, panic anxiety, obsessive-compulsive disorder, social phobia, Composed of anxiety, post-traumatic stress disorder, acute stress response, adaptation disorder, suspected disorder, separation anxiety disorder, aphobia, specific phobia, anxiety caused by general medical conditions, and substance-induced anxiety Group.

24. The use of claim 21 in the scope of Roots Patent, characterized in that the central nervous system disorder is selected from neurodegenerative disorders such as Alzheimer's disease, Huntington's disease, multiple sclerosis, Amyotrophic spinal cord = sclerosis, AIDS-induced encephalopathy, and other encephalopathy related to infections caused by German germviruses, tetroviruses, Borrelia, and unknown pathogens, Kouja's disease, Parkinson's disease, trauma-induced neurodegeneration Group. 25. The use according to item 21 of the patent application, characterized in that the disorder of the central nervous system is selected from the group consisting of goods, from a state of excessive excitement of neurons such as drug withdrawal or poisoning . Pick up, 囷 style:

(None) 105 200413280 (1) Designated representative map: (1) The designated representative map in this case is: (none) map. (2) Brief description of the representative symbols of the components in this representative map:

捌 If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention

5