CN101142174B - Novel compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist, and pharmaceutical compositions containing the same - Google Patents

Novel compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist, and pharmaceutical compositions containing the same Download PDF

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CN101142174B
CN101142174B CN 200680008762 CN200680008762A CN101142174B CN 101142174 B CN101142174 B CN 101142174B CN 200680008762 CN200680008762 CN 200680008762 CN 200680008762 A CN200680008762 A CN 200680008762A CN 101142174 B CN101142174 B CN 101142174B
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c1
c5
tert
1h
phenyl
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CN101142174A (en
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吴禹泽
崔镇圭
张美贞
徐永钜
朴亨根
朴永镐
朴雪邻
李玘和
林庆珉
牟周炫
申松锡
禹柄英
郑然守
金善映
金星日
金熙斗
金珠贤
金镇官
高现珠
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株式会社Amorepacific
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Abstract

This present invention relates to novel compounds, isomer thereof or pharmaceutically acceptable salts thereof as vanilloid receptor (Vanilloid Receotor 1; VR1; TRPV1) antagonist; and a pharmaceutical composition containing the same. The present invention provides a pharmaceutical composition for preventing or treating a disease such as pain, migraine, arthralgia, neuralgia, neuropathies, nerve injury, skin disorder, urinary bladder hypersensitiveness, irritable bowel syndrome, fecal urgency, a respiratory disorder, irritation of skin, eye or mucous membrane, stomach-duodenal ulcer, inflammatory diseases, ear disease and heart disease.

Description

作为香草素受体拮抗剂的新化合物,其异构体或其药用盐; 和包含其的药物组合物 The new compounds as vanilloid receptor antagonist, an isomer thereof or a pharmaceutically acceptable salt thereof; and pharmaceutical compositions thereof

技术领域 FIELD

[0001] 本发明涉及作为香草素受体(香草素受体1 ;VRl ;TRPV1)拮抗剂的新化合物,其异构体或其药用盐;和包含其的药物组合物。 [0001] The present invention relates to a vanilloid receptor (vanilloid receptor 1; VRl; TRPV1) antagonist novel compounds, isomer thereof or a pharmaceutically acceptable salt thereof; and pharmaceutical compositions thereof.

背景技术 Background technique

[0002] 作为与香草素受体的活性相关的疾病(Nagy等,2004,Eur. J. Pharmacol. 500, 351-369),可以列举疼痛如急性痛,慢性痛,神经性疼痛,术后痛,风湿性关节痛,骨关节痛,带状疱疹后神经痛,神经痛,头痛和偏头痛(Petersen等,2000,Pain, 88, ppl25_133 ; Walker 等,2003,J. Pharmacol. Exp. Ther.,304,pp56_62);神经相关的疾病如神经病, HIV相关的神经病,神经损伤,神经变性和中风(Park等,1999,Arch. Pharm. Res. 22, pp432-434 ;Kim 等,2005,J. Neurosci. 25(3), pp662_671);糖尿病性神经病(Kamei 等, 2001,Eur. J. Pharmacol. 422, pp83_86);便急;肠易激综合征(Chan 等,2003,Lancet, 361,pp385-391);炎性肠病(Yiangou 等,2001,Lancet, 357, ppl338_1339);消化器官疾病如胃-十二指肠溃疡和局限性回肠炎(Holzer P,2004,Eur. J. Pharm. 500,pp231_241 ; Geppetti 等,2004,Br. J. Pharmacol.,141,ppl313_1320);呼吸器官 [0002] As the activity of the vanilloid receptor-related diseases (Nagy et, 2004, Eur. J. Pharmacol. 500, 351-369), can include pain such as acute pain, chronic pain, neuropathic pain, post operative pain , rheumatic joint pain, bone and joint pain, postherpetic neuralgia, neuralgia, headache and migraine (Petersen et, 2000, pain, 88, ppl25_133;... Walker et, 2003, J Pharmacol Exp Ther,. 304, pp56_62); nerve related diseases such as neuropathies, HIV-related neuropathy, nerve injury, neurodegeneration and stroke (Park et, 1999, Arch Pharm Res 22, pp432-434;... Kim et, 2005, J Neurosci. . 25 (3), pp662_671);.. diabetic neuropathy (Kamei et, 2001, Eur J. Pharmacol 422, pp83_86); fecal urgency; irritable bowel syndrome (Chan et, 2003, Lancet, 361, pp385-391 ); inflammatory bowel disease (Yiangou, etc., 2001, Lancet, 357, ppl338_1339);.. digestive diseases such as stomach - duodenal ulcers and Crohn's disease (Holzer P, 2004, Eur J. Pharm 500, pp231_241 ;. Geppetti et, 2004, Br J. Pharmacol, 141, ppl313_1320);. respiratory 病如哮喘,慢性阻塞性肺病(Hwang 等,2002,Curr Opin Pharm pp235_242 ;Spina 等,2002,Curr Opin Pharm pp264_272);尿失禁(Birder 等,2002,Nat. Neuroscience, 5, pp856_860);膀胱过敏(Birder 等,2001,Proc. Natl. Acad. Sci. 98, ppl3396_13401);神经性/ 变应性/ 炎性皮肤病如银屑病,瘙痒症和痒疹(Southall等,2003,J. Pharmacol. Exp. Ther.,304, PP217-222);皮肤,眼睛或粘膜的刺激(Tominaga 等,1998,Neuron 21 pp531_543);听觉过敏;耳鸣;前庭过敏(Balaban等,2003,Hear Res. 175,ppl65_70);心脏病如变力性缺血等(Scotland 等,2004,Circ. Res. 95, ppl027-1034 ;Pan 等,2004,Circulation, 110, ppl826-1831)。 Disorders such as asthma, chronic obstructive pulmonary disease (Hwang et, 2002, Curr Opin Pharm pp235_242; Spina et, 2002, Curr Opin Pharm pp264_272); urinary incontinence (. Birder et, 2002, Nat Neuroscience, 5, pp856_860); irritable bladder ( Birder et, 2001, Proc Natl Acad Sci 98, ppl3396_13401);.... neurotic / allergic / inflammatory skin diseases such as psoriasis, pruritus and prurigo (Southall et, 2003, J Pharmacol Exp... . Ther, 304, PP217-222); skin, eye or mucous membrane irritation (Tominaga et, 1998, Neuron 21 pp531_543); hyperacusis; tinnitus; vestibular allergies (Balaban et, 2003, Hear Res 175, ppl65_70);. heart diseases such as inotropic ischemia (Scotland et, 2004, Circ Res 95, ppl027-1034;.. Pan et, 2004, Circulation, 110, ppl826-1831).

[0003] 香草素受体(VRl)是辣椒素(8-甲基-N-香草基-6-壬烯酰胺),一种尖辣椒(hot pepper)中的刺激性成分的受体。 [0003] The vanilloid receptor (VRl) are capsaicin (8-methyl -N- vanillyl-6-nonene amide), a receptor irritating ingredients jalapeno (hot pepper) in. 还在1997年报道了其分子克隆(Caterina等,1997, Nature 389,pp816_824)。 Also in 1997, we reported the molecular cloning (Caterina et, 1997, Nature 389, pp816_824). 该受体是非选择性阳离子通道,其由6个跨膜结构域组成并属于TRP通道家族。 This receptor is a non-selective cation channel, which consists of six transmembrane domains and belong to the TRP channel family. 最近,其被命名为TRPVl。 Recently, it was named TRPVl. 在另一方面,已知香草素受体由刺激物如辣椒素,仙人掌毒素,热,酸,花生四烯酸乙醇酰胺,脂质代谢物等激活;因此其作为在哺乳动物中的理化有害的刺激物的分子整合物(integrator)起着关键作用(Tominaga等,1998, Neuron 21 pp531_543 ;Hwang 等,2000,PNAS,97,pp6155_6160)。 On the other hand, it is known by the vanilloid receptor stimuli such as capsaicin, resiniferatoxin, heat, acid, arachidonic acid diethanolamide, lipid metabolites activated; therefore harmful as in a mammal in physicochemical molecular integrant stimuli (Integrator) plays a key role (Tominaga et, 1998, Neuron 21 pp531_543; Hwang et, 2000, PNAS, 97, pp6155_6160). 由内源/ 外源刺激物对香草素受体的激活不仅导致有害刺激物的传递,还导致神经肽如物质P,CGRP (降钙素基因相关肽)等的释放,因此导致了神经原性的炎症。 The endogenous / exogenous stimuli vanilloid receptor activation not only results in delivery of noxious stimuli, also results as substance P, released (calcitonin gene-related peptide) and the like neuropeptide CGRP, thus resulting in neurogenic inflammation. 香草素受体在主要的传入感觉神经元中高度表达。 Vanilloid receptor in the primary afferent sensory neurons are highly expressed. 其还在各种器官和组织如膀胱,肾,肺,肠和皮肤和在包括脑和非神经元组织的中枢神经系统(CNS)中报道性地表达(Mezey 等,2000,PNAS,97,pp3655_3660 ;Stander 等, 2004,Exp. Dermatol. 13,ppl29_139 ;Cortright 等,2001,BBRC,281,ppll83_1189)。 It also various organs and tissues such as the bladder, kidney, lung, intestinal and skin and reporting of expression (Mezey et, 2000, PNAS in the central nervous system including the brain and non-neuronal tissues (CNS) in, 97, pp3655_3660 ;.. Stander, etc., 2004, Exp Dermatol 13, ppl29_139; Cortright, etc., 2001, BBRC, 281, ppll83_1189). 具体而言,TRPVl受体敲除小鼠显示对有害身体刺激物的正常反应,但是显示对香草素的热刺激物的疼痛应答和感官敏感性的减少,并甚至在炎症状态下几乎不显示对热刺激物的痛觉过敏(Caterina 等,2000,Science 288,pp306_313 ;Davis 等,2000,Nature 405,ppl83_187 ; Karai等,2004,J. Clin. Invest.,113,ppl344_1352)。 Specifically, TRPVl receptor knockout mice show normal response to stimuli was harmful to the body but showing vanilloid heat pain stimulus response and reduced sensory sensitivity, and to even almost no inflammation in thermal hyperalgesia stimuli (Caterina et, 2000, Science 288, pp306_313; Davis et, 2000, Nature 405, ppl83_187; Karai et, 2004, J Clin Invest, 113, ppl344_1352...). 最近,还通过展示香草素受体可能以具有TRPV3的异源多体,另一种TRP通道的形式存在的可能性来预期香草素受体的另外的作用(Smith 等,2002,Nature, 418, ppl86_190)。 Recently, by showing vanilloid receptor also is possible to have multiple heterologous TRPV3 the body, there is a possibility of another form of TRP channels to the expected effect of further vanilloid receptors (Smith et al, 2002, Nature, 418, ppl86_190).

[0004] 如上提及,香草素受体敲除小鼠显示对热或有害刺激物的减少的反应,因此增加了香草素受体拮抗剂可以用于预防或治疗各种疼痛病症的可能性。 [0004] As mentioned above, vanilloid receptor knockout mice show reduced responses to thermal or noxious stimuli, thus increasing the likelihood of vanilloid receptor antagonist can be used for the prevention or treatment of various pain conditions. 最近,这种可能性由众所周知的香草素受体拮抗剂,抗辣椒碱也减少由在炎症和神经性疼痛模型中的身体刺激物所导致的痛觉过敏的报道支持。 Recently, the possibility receptor antagonists known herbs, capsazepine be reduced by the body in inflammatory and neuropathic pain model supports reporter stimulus resulting hyperalgesia. (Walker 等,2003,JPET,304,pp56_62 ;Garcia-Martinez 等,2002,Proc. Natl. Acad. Sci. 99,2374-2379)。 (Walker et al, 2003, JPET, 304, pp56_62; Garcia-Martinez, etc., 2002, Proc Natl Acad Sci 99,2374-2379....). 此外,用香草素受体激动剂辣椒素等处理传入神经细胞的原代培养物导致对神经功能的损伤和神经细胞的进一步的死亡。 Further, by vanilloid receptor agonists such as capsaicin primary cultures treated afferent nerve cells death leads to further damage to nerve function and nerve cells. 香草素受体拮抗剂发挥对神经功能的这样的损伤和神经细胞死亡的防御作用(Holzer P,1991, Pharmacological Reviews, 43, ppl43-201 ;Mezey 等,2000,PNAS,97,3655—3660)。 Vanilloid receptor antagonist of defense against such neurological damage and neuronal cell death (Holzer P, 1991, Pharmacological Reviews, 43, ppl43-201; Mezey et, 2000, PNAS, 97,3655-3660). 香草素受体在胃肠道的所有区域,例如张肌神经节,肌层,粘膜和上皮细胞中表达。 Vanilloid receptor in all regions of the gastrointestinal tract, e.g. tensor expressing ganglia, muscularis, and mucosal epithelial cells. 具体而言,香草素受体在结肠和回肠的炎性疾病中高度表达。 Specifically, the vanilloid receptor is highly expressed in the colon and ileum inflammatory diseases.

[0005] 此外,香草素受体的激活刺激感觉神经,其又导致神经肽的释放,所述神经肽已知在肠疾病的发病机理中起关键作用。 [0005] Further, the activation of vanilloid receptor stimulation of sensory nerves, which in turn leads to the release of neuropeptides, neuropeptide known to play a critical role in the pathogenesis bowel disease. 香草素受体在胃肠疾病的发展中的作用在最近的科学文献和杂志,例如Holzer P,2004,Eur. J. Pharm. 500,pp231_241 ;G印petti 等,2004, Br. J. Pharmacol.,141,ppl313_1320中进行充分阐述和记载。 Vanilloid receptor in the development of gastrointestinal diseases role in the recent scientific literature, and magazines, for example Holzer P, 2004, Eur J. Pharm 500, pp231_241;.. G petti like India, 2004, Br J. Pharmacol.. , 141, ppl313_1320 performed fully set forth and described. 按照这些参考文献,似乎香草素受体拮抗剂对于预防或治疗胃肠疾病如胃-食管逆流病(GERD)和胃十二指肠溃疡(DU)是有效的。 According to these references, it seems to vanilloid receptor antagonists for the prevention or treatment of gastrointestinal disorders such as gastric - esophageal reflux disease (GERD) and stomach duodenal ulcer (DU) is effective. 已经报道表达香草素受体的感觉神经的数量在遭受过敏性大肠综合征的患者中增加并且已知香草素受体的这样增加的表达涉及所述疾病的发展(Chan等,2003, Lancet, 361, pp385_391)。 The number of sensory nerve has been reported that expression of the vanilloid receptor is known to increase and increased expression of vanilloid receptors involved in the development of the disease (Chan et in patients suffering from irritable bowel syndrome, 2003, Lancet, 361 , pp385_391). 其它的研究显示香草素受体的表达在遭受炎性肠病的患者中显著增加。 Other studies have shown that expression of vanilloid receptor significantly increased in patients suffering from inflammatory bowel disease. 总而言之,似乎香草素受体拮抗剂也可以有效治疗这样的肠病(Yiangou等,2001, Lancet,357,ppl338-1339)。 In summary, it seems that vanilloid receptor antagonists may also be effective in the treatment of such bowel disease (Yiangou et, 2001, Lancet, 357, ppl338-1339). 表达香草素受体的传入神经在呼吸道粘膜中大量分布。 Vanilloid receptor expressing afferent nerves distributed in a large number of respiratory mucosa. 支气管的过敏症与支气管的痛觉过敏非常类似,并且已知作为香草素受体的内源配体的质子和脂肪氧合酶产物是负责哮喘和慢性阻塞性肺病发展的众所周知的关键因子(Hwang等, 2002, Curr. Opin. Pharm. pp235_242 ;Spina 等,2002,Curr. Opin. Pharm. pp264_272)。 Bronchial allergies and bronchial hyperalgesia very similar, and it is known as a proton and lipoxygenase products endogenous vanilloid receptor ligands are known to be responsible for asthma and chronic obstructive pulmonary disease, a key factor in development (Hwang et , 2002, Curr Opin Pharm pp235_242;.... Spina, etc., 2002, Curr Opin Pharm pp264_272)... 此夕卜,已经报道作为一种导致哮喘的物质的空气污染物质,即颗粒物质特异性作用在香草素受体上并且这样的作用被抗辣椒碱所抑制,因此提示香草素受体拮抗剂对于呼吸性疾病的可能的应用性(Veronesi 等,2001,NeuroToxicology, 22, pp795_810)。 Bu this evening, has been reported as a cause of asthma air pollutant substances, i.e., particulate matter specifically acts on the vanilloid receptor, and this action is inhibited by capsazepine, therefore suggesting to vanilloid receptor antagonists possible applications respiratory diseases (Veronesi et, 2001, NeuroToxicology, 22, pp795_810). 膀胱过敏和尿失禁由各种中枢/外周神经疾病或损伤所导致,辣椒素_反应性感觉神经在膀胱功能控制和炎症中起重要作用。 Irritable bladder and urinary incontinence are caused by various central / peripheral nerve disorders or injury, reactive capsaicin _ sensory nerve plays an important role in bladder function control and inflammation. 此外,在大鼠的膀胱上皮(尿道上皮)中报道了香草素受体的免疫反应性,并且发现由辣椒素诱导的膀胱的过度活性由在神经纤维中存在的香草素受体或由香草素受体释放的各种递质刺激所导致(Birder等,2001,Proc. Natl. Acad. Sci. 98, PP13396-13401)。 Further, it is reported vanilloid receptor immunoreactivity in the bladder epithelium (urothelium) in rats, and found that by the excessive activity of capsaicin-induced bladder by a receptor present in the nerve fibers of vanilla or vanilloid the release of neurotransmitter receptors various stimuli leads (Birder et, 2001, Proc. Natl. Acad. Sci. 98, PP13396-13401). 此外,VRl (TRPVl)-/-小鼠在解剖上是正常的,但是与正常小鼠相比,显示非分泌性的由低收缩力导致的膀胱收缩,因此显示香草素受体影响膀胱的功能(Birder 等,2002,Nat. Neuroscience, 5, pp856_860)。 Further, VRl (TRPVl) - / - mice are anatomically normal but in comparison with normal mice, non-secreting display bladder contraction results in a low shrinkage, thus indicating bladder vanilloid receptor function (Birder et, 2002, Nat. Neuroscience, 5, pp856_860). 一些最近正在开发的香草素激动剂作为用于治疗膀胱疾病的治疗剂。 Some recent vanilloid agonist is being developed as a therapeutic agent for the treatment of bladder diseases. 香草素受体分布在人的表皮角化细胞以及一级传入感觉神经中(Denda 等,2001,Biochem. Biophys. Res. Commun.,285,ppl250_1252 ;Inoue 等,2002, Biochem. Biophys. Res. Commun.,291,ppl24_129),并且接着涉及各种有害刺激和疼痛如皮肤刺激和瘙痒的传递,由此与神经原性/非神经原性因子所导致的皮肤病和病症如皮肤炎症的病因密切相关。 Vanilloid receptors in human epidermal keratinocytes and one afferent sensory nerves (Denda et, 2001, Biochem Biophys Res Commun, 285, ppl250_1252;...... Inoue et, 2002, Biochem Biophys Res. commun., 291, ppl24_129), and then directed to various noxious stimuli and pain, irritation and itching of the skin, such as transmission, whereby the skin diseases and disorders neurogenic / non-neurogenic factors such as skin inflammation caused by the close cause related. 这由香草素受体拮抗剂,抗辣椒碱抑制人皮肤细胞中的炎性因子的报道所支持(Sout hall 等,2003,J. Pharmacol. Exp. Ther.,304,pp217_222)。 This is a vanilloid receptor antagonist, capsazepine inhibition of human skin cells supported by reports of inflammatory cytokines (Sout hall, etc., 2003, J. Pharmacol. Exp. Ther., 304, pp217_222).

[0006] 基于上述信息,各种香草素受体拮抗剂的开发在进行中,并且最近公开了涉及正在开发的香草素受体拮抗剂的一些专利和专利申请,其中充分描述了上述提及的信息(Rami 等,2004,Drug Discovery Today :Therapeutic Strategies,1,pp97_104)。 [0006] Based on the above information, a variety of vanilloid receptor antagonist during development, and relates to a number of recently published patents and patent applications are being developed vanilloid receptor antagonists, which are fully described in the above-mentioned information (Rami et, 2004, Drug Discovery Today: Therapeutic Strategies, 1, pp97_104).

[0007] 作为基于上述讨论的理论背景的广泛和集中研究的结果,本发明人已经合成了通过选择性作用在香草素受体上而具有拮抗活性的新化合物并因此完成了本发明。 [0007] As a result of extensive research and focus on the theoretical background discussed above, the present inventors have synthesized by selectively acting on the vanilloid receptor antagonist and novel compounds having activity and thus completed the present invention. 令人惊奇的是,已经确定了这样的化合物是香草素受体的特别具有活性的调节剂,其在其一个苯环上具有C2-C5链烯基或C2-C5炔基以及包含胺的取代基的二苄基脲,二苄基酰胺或二苄基肉桂酰结构。 Surprisingly, it has been determined that such a compound is particularly vanilloid receptor activity modulators, having a C2-C5 alkenyl or C2-C5 alkynyl group on its benzene ring a substituent containing an amine and dibenzyl urea groups, amide or dibenzyl dibenzyl cinnamoyl structure.

[0008] 因此,本发明的一个目的是提供用作香草素受体的有效拮抗剂的新化合物,其异构体和其药用盐;和包含其的药物组合物。 [0008] It is therefore an object of the present invention to provide novel compounds effective as vanilloid receptor antagonist, an isomer thereof and a pharmaceutically acceptable salt thereof; and pharmaceutical compositions thereof.

发明内容 SUMMARY

[0009] 本发明提供下列式(I)的新化合物,其异构体或其药用盐;和包含其的药物组合物。 [0009] The following novel compounds of formula (I) of the present invention provides, an isomer thereof or a pharmaceutically acceptable salt thereof; and pharmaceutical compositions thereof.

[0010]【式I】 [0010] [Formula I]

[0011] [0011]

Figure CN101142174BD00111

[0012] 其中 [0012] in which

[0013] X 是NHCH2, CR11 = CR12, NH, CHR11CHR12,或C 三C,其中R11 和R12 独立地是氢,卤素, C1-C5烷基,C1-C5烷氧基,卤代(C1-C5)烷基,或苯基; [0013] X is NHCH2, CR11 = CR12, NH, CHR11CHR12, or C and C, where R11 and R12 are independently hydrogen, halogen, C1-C5 alkyl, C1-C5 alkoxy, halo (C1-C5 ) alkyl, or phenyl;

[0014] R1是C2-C5链烯基,或C2-C5炔基; [0014] R1 is C2-C5 alkenyl, or C2-C5 alkynyl;

[0015] R2是氢,卤素,硝基,氰基,C1-C5烷基,C1-C5烷氧基,卤代(C1-C5)烷基,C2-C5链烯基,C2-C5炔基,羧基,C1-C5烷氧基羰基,C1-C5烷硫基,苯基,或苯基(C1-C3)烷基,其中每个苯基可以是未取代的或由选自下列各项的一个或多个取代基取代:羧基,C1-C5烷基, 卤素,硝基,C2-C5链烯基,C1-C5烷氧基,卤代(C1-C5)烷基,C1-C5烷基羰基,C1-C5烷硫基,C1-C5烷基磺酰基,和C1-C5烷氧基羰基; [0015] R2 is hydrogen, halo, nitro, cyano, C1-C5 alkyl, C1-C5 alkoxy, halo (C1-C5) alkyl, C2-C5 alkenyl, C2-C5 alkynyl group , carboxy, C1-C5 alkoxycarbonyl, C1-C5 alkylthio, phenyl, or phenyl (C1-C3) alkyl, wherein each phenyl group may be unsubstituted or substituted selected from the following one or more substituents: carboxy, C1-C5 alkyl, halogen, nitro, C2-C5 alkenyl, C1-C5 alkoxy, halo (C1-C5) alkyl, C1-C5 alkyl carbonyl, C1-C5 alkylthio groups, C1-C5 alkylsulfonyl group, and C1-C5 alkoxycarbonyl group;

[0016] R3是氢,C1-C5烷基,C1-C5烷氧基,或卤代(C1-C5)烷基;[0017] R4, R5, R6, R7,和R8独立地是氢,羧基,C1_C5烷基,硝基,C2_C5链烯基,C1-C5烷氧基,C2-C5炔基,卤代(C1-C5)烷基,C1-C5烷硫基,C1-C5烷基磺酰基,C1-C5烷基羰基, C1-C5烷氧基羰基,羟基,C2-C5链烯氧基,C1-C5烷氧基(C1-C5)烷氧基,C1-C5烷氧基(C1-C5)烷氧基(C1-C5)烷基,C1-C3烷基哌嗪基,哌嗪基(C1-C5)烷氧基,哌啶基(C1-C5) 烷氧基,C1-C5烷氧基(C1-C5)烷基氨基,C1-C7烷基氨基,吗啉基,吗啉基(C1-C5)烷基氧基,四氢吡喃基氧基,苯基,或卤素,其中苯基可以是未取代的或被选自下列各项的一个或多个取代基取代:羧基,C1-C5烷基,商素,硝基,C2-C5链烯基,C1-C5烷氧基,商代(C1-C5) 烷基,C1-C5烷基羰基,C1-C5烷硫基,C1-C5烷基磺酰基,C1-C5烷氧基羰基,或哌啶基氧基, 其不被取代或由C1-C5烷氧基羰基取代 [0016] R3 is hydrogen, C1-C5 alkyl, C1-C5 alkoxy, or halo (C1-C5) alkyl; [0017] R4, R5, R6, R7, and R8 are independently hydrogen, a carboxyl group , C1_C5 alkyl, nitro, C2_C5 alkenyl, C1-C5 alkoxy, C2-C5 alkynyl, halo (C1-C5) alkyl, C1-C5 alkylthio groups, C1-C5 alkylsulfonyl group , C1-C5 alkylcarbonyl, C1-C5 alkoxycarbonyl group, a hydroxyl group, C2-C5 alkenyloxy, C1-C5 alkoxy (C1-C5) alkoxy, C1-C5 alkoxy (C1 C5) alkoxy (C1-C5) alkyl, C1-C3-alkyl-piperazinyl, piperazinyl (C1-C5) alkoxy, piperidinyl (C1-C5) alkoxy, C1-C5 alkoxy alkoxy (C1-C5) alkylamino, C1-C7 alkylamino, morpholinyl, morpholinyl (C1-C5) alkyl group, tetrahydropyranyl, phenyl, or halo, wherein unsubstituted phenyl group may be selected from the following or one or more substituents: carboxy, C1-C5 alkyl, supplier, nitro, C2-C5 alkenyl, C1-C5 alkoxy Shang (C1-C5) alkyl, C1-C5 alkylcarbonyl, C1-C5 alkylthio groups, C1-C5 alkylsulfonyl group, C1-C5 alkoxycarbonyl group, or piperidinyl group, which does not substituted or substituted by a C1-C5 alkoxycarbonyl ;和 ;with

[0018] R9 和Rltl 独立地是氢,-SO2R13, -SOR13, C1-C5 烷基,C1-C5 烷氧基,卤代(C1-C5)烷基,C2-C5链烯基,C1-C5烷氧基羰基,C1-C5烷硫基,苯基,或苯基(C1-C3)烷基,其中每个苯基可以是未取代的或由选自下列各项的一个或多个取代基取代:羧基,C1-C5烷基,卤素,硝基,C2-C5链烯基,C1-C5烷氧基,卤代(C1-C5)烷基,C1-C5烷基羰基,C1-C5烷硫基, C1-C5烷基磺酰基,和C1-C5烷氧基羰基,和R13是氢,氨基,C1-C5烷基,C2-C5链烯基,C1-C5 烷氧基,卤代(C1-C5)烷基,三氟甲基,苯基,或苯基(C1-C3)烷基。 [0018] R9 and Rltl are independently hydrogen, -SO2R13, -SOR13, C1-C5 alkyl, C1-C5 alkoxy, halo (C1-C5) alkyl, C2-C5 alkenyl, C1-C5 alkoxycarbonyl, C1-C5 alkylthio, phenyl, or phenyl (C1-C3) alkyl, wherein each phenyl group may be unsubstituted or substituted selected from the one or more of the following groups substituent: carboxy, C1-C5 alkyl, halogen, nitro, C2-C5 alkenyl, C1-C5 alkoxy, halo (C1-C5) alkyl, C1-C5 alkylcarbonyl, C1-C5 alkoxy thio, C1-C5 alkylsulfonyl group, and C1-C5 alkoxycarbonyl, and R13 is hydrogen, amino, C1-C5 alkyl, C2-C5 alkenyl, C1-C5 alkoxy, halo ( C1-C5) alkyl, trifluoromethyl, phenyl, or phenyl (C1-C3) alkyl.

[0019] 本发明的一个优选的方面是式(I)的化合物,其异构体或其药用盐; [0019] A preferred compound aspect of the invention is of formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof;

[0020] 其中 [0020] in which

[0021] X是NHCH2, CR11 = CR12,或C = C,其中R11和R12独立地是氢,卤素,C1-C5烷基,或 [0021] X is NHCH2, CR11 = CR12, or C = C, wherein R11 and R12 are independently hydrogen, halogen, C1-C5 alkyl, or

苯基; Phenyl;

[0022] R1是C2-C5链烯基或C2-C5炔基; [0022] R1 is C2-C5 alkenyl or C2-C5 alkynyl;

[0023] R2是氢,卤素,硝基,氰基,C1-C5烷基,C1-C5烷氧基,卤代(C1-C5)烷基,C2-C5链烯基,C2-C5炔基,羧基,C1-C5烷氧基羰基,C1-C5烷硫基,苯基,或苯基(C1-C3)烷基,其中每个苯基可以是未取代的或由选自下列各项的一个或多个取代基取代:羧基,C1-C5烷基, 卤素,硝基,C2-C5链烯基,C1-C5烷氧基,卤代(C1-C5)烷基,C1-C5烷基羰基,C1-C5烷硫基,C1-C5烷基磺酰基,和C1-C5烷氧基羰基; [0023] R2 is hydrogen, halo, nitro, cyano, C1-C5 alkyl, C1-C5 alkoxy, halo (C1-C5) alkyl, C2-C5 alkenyl, C2-C5 alkynyl group , carboxy, C1-C5 alkoxycarbonyl, C1-C5 alkylthio, phenyl, or phenyl (C1-C3) alkyl, wherein each phenyl group may be unsubstituted or substituted selected from the following one or more substituents: carboxy, C1-C5 alkyl, halogen, nitro, C2-C5 alkenyl, C1-C5 alkoxy, halo (C1-C5) alkyl, C1-C5 alkyl carbonyl, C1-C5 alkylthio groups, C1-C5 alkylsulfonyl group, and C1-C5 alkoxycarbonyl group;

[0024] R3是氢,C1-C5烷基,C1-C5烷氧基,或卤代(C1-C5)烷基; [0024] R3 is hydrogen, C1-C5 alkyl, C1-C5 alkoxy, or halo (C1-C5) alkyl;

[0025] R4, R5, R6, R7,和R8独立地是氢,羧基,C1-C5烷基,硝基,C2-C5链烯基,C1-C5烷氧基,C2-C5炔基,卤代(C1-C5)烷基,C1-C5烷硫基,C1-C5烷基磺酰基,C1-C5烷基羰基, C1-C5烷氧基羰基,苯基,或卤素,其中苯基可以不被取代或由选自下列各项的一个或多个取代基取代:羧基,C1-C5烷基,卤素,硝基,C2-C5链烯基,C1-C5烷氧基,卤代(C1-C5)烷基,C1-C5烷基羰基,C1-C5烷硫基,C1-C5烷基磺酰基,和C1-C5烷氧基羰基;且 [0025] R4, R5, R6, R7, and R8 are independently hydrogen, carboxy, C1-C5 alkyl, nitro, C2-C5 alkenyl, C1-C5 alkoxy, C2-C5 alkynyl group, a halogen Generation (C1-C5) alkyl, C1-C5 alkylthio groups, C1-C5 alkylsulfonyl group, C1-C5 alkylcarbonyl, C1-C5 alkoxycarbonyl, phenyl, or halogen, phenyl which may not be selected from substituted or the one or more substituents of the following: carboxy, C1-C5 alkyl, halogen, nitro, C2-C5 alkenyl, C1-C5 alkoxy, halo (C1 C5) alkyl, C1-C5 alkylcarbonyl, C1-C5 alkylthio groups, C1-C5 alkylsulfonyl group, and C1-C5 alkoxycarbonyl group;

[0026] R9 和Rltl 独立地是氢,-SO2R13, -SOR13, C1-C5 烷基,C1-C5 烷氧基,卤代(C1-C5)烷基,C2-C5链烯基,C1-C5烷氧基羰基,C1-C5烷硫基,苯基,或苯基(C1-C3)烷基,其中每个苯基可以是未取代的或由选自下列各项的一个或多个取代基取代:羧基,C1-C5烷基,卤素,硝基,C2-C5链烯基,C1-C5烷氧基,卤代(C1-C5)烷基,C1-C5烷基羰基,C1-C5烷硫基, C1-C5烷基磺酰基,和C1-C5烷氧基羰基,和R13是氢,氨基,C1-C5烷基,C2-C5链烯基,C1-C5 烷氧基,卤代(C1-C5)烷基,三氟甲基,苯基,或苯基(C1-C3)烷基。 [0026] R9 and Rltl are independently hydrogen, -SO2R13, -SOR13, C1-C5 alkyl, C1-C5 alkoxy, halo (C1-C5) alkyl, C2-C5 alkenyl, C1-C5 alkoxycarbonyl, C1-C5 alkylthio, phenyl, or phenyl (C1-C3) alkyl, wherein each phenyl group may be unsubstituted or substituted selected from the one or more of the following groups substituent: carboxy, C1-C5 alkyl, halogen, nitro, C2-C5 alkenyl, C1-C5 alkoxy, halo (C1-C5) alkyl, C1-C5 alkylcarbonyl, C1-C5 alkoxy thio, C1-C5 alkylsulfonyl group, and C1-C5 alkoxycarbonyl, and R13 is hydrogen, amino, C1-C5 alkyl, C2-C5 alkenyl, C1-C5 alkoxy, halo ( C1-C5) alkyl, trifluoromethyl, phenyl, or phenyl (C1-C3) alkyl.

[0027] 本发明的另一个方面是按照上述式(I)的化合物;或其异构体或其药用盐; [0027] Another aspect of the present invention is the compound of formula (I); or a pharmaceutically acceptable salt thereof, or isomers thereof;

[0028] 其中[0029] X是NHCH2, CR11 = CR12,或C三C,其中R11和R12独立地是氢,卤素,C1-C5烷基,或 [0028] wherein [0029] X is NHCH2, CR11 = CR12, or C and C, where R11 and R12 are independently hydrogen, halogen, C1-C5 alkyl, or

苯基; Phenyl;

[0030] R1是乙烯基,乙炔基,丙烯基,或丙炔基 [0030] R1 is vinyl, ethynyl, propenyl, propynyl or

[0031] R2是氢,氟,氯,溴,碘,硝基,氰基,甲基,乙基,丙基,异丙基,丁基,异丁基,甲氧基,乙氧基,三氟甲基,羧基,甲氧基羰基,或苯基; [0031] R2 is hydrogen, fluoro, chloro, bromo, iodo, nitro, cyano, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, tris fluoro, carboxy, methoxycarbonyl, or phenyl;

[0032] R3是氢,甲基,或乙基; [0032] R3 is hydrogen, methyl, or ethyl;

[0033] R4, R5, R6, R7,和R8独立地是氢,羧基,甲基,乙基,丙基,异丙基,叔丁基,硝基,乙烯基,乙炔基,甲硫基,三氟甲基,甲氧基羰基,或卤素;且 [0033] R4, R5, R6, R7, and R8 are independently hydrogen, carboxy, methyl, ethyl, propyl, isopropyl, t-butyl, nitro, ethenyl, ethynyl, methylthio, trifluoromethyl, methoxycarbonyl, or halogen; and

[0034] R9 和Rltl 独立地是氢,-SO2R13, -SOR13, C1-C5 烷基,C1-C5 烷氧基,卤代(C1-C5)烷基,C2-C5链烯基,苯基,苯基(C1-C3)烷基,或C1-C3烷氧基苯基,其中R13是氢,氨基,C1-C5 烷基,C2-C5链烯基,三氟甲基,苯基,或苄基。 [0034] R9 and Rltl are independently hydrogen, -SO2R13, -SOR13, C1-C5 alkyl, C1-C5 alkoxy, halo (C1-C5) alkyl, C2-C5 alkenyl group, a phenyl group, phenyl (C1-C3) alkyl, C1-C3 alkoxy group or a phenyl group, wherein R13 is hydrogen, amino, C1-C5 alkyl, C2-C5 alkenyl, trifluoromethyl, phenyl, benzyl, or base.

[0035] 本发明的一个优选实施方案涉及上述式(I)的化合物,其具有下列一个或多个特征: [0035] In a preferred embodiment of the invention relates to compounds of formula (I) having one or more of the following features:

[0036] 其中R9是-SO2R13且Rltl是氢的化合物,其中R9更优选地是甲烷磺酰基,乙烷磺酰基,三氟甲烷磺酰基,或乙烯磺酰基,并且最优选地是甲烷磺酰基; [0036] wherein R9 is hydrogen and Rltl is -SO2R13, wherein R9 is more preferably a methanesulfonyl group, ethanesulfonyl group, trifluoromethanesulfonyl group, a sulfonyl group or ethylene, and most preferably a methanesulfonyl group;

[0037] 其中R6是C1-C5烷基,卤代(C1-C5)烷基,C1-C5烷硫基,或卤素的化合物;其中R6是卤代(C1-C3)烷基,异丙基或叔丁基的那些化合物是更优选的,且其中R6是异丙基或叔丁基的化合物是最优选的; [0037] wherein R6 is C1-C5 alkyl, halo (C1-C5) alkyl, C1-C5 alkylthio, halogen or a compound; wherein R6 is halo (C1-C3) alkyl, isopropyl t-butyl, or those compounds are more preferred, and a compound wherein R6 is isopropyl or tert-butyl group is most preferred;

[0038] 其中R3是氢或C1-C5烷基的化合物;其中R3是氢或甲基的化合物的是最优选的; [0038] wherein R3 is hydrogen or C1-C5 alkyl group; a compound wherein R3 is hydrogen or methyl are most preferred;

[0039] 其中R4, R5, R7,和R8优选地独立地是氢,C1-C5烷基,卤代(C1-C5)烷基,C1-C5烷硫基,或氢的化合物;其中R5, R7,和R8是氢的那些化合物是最优选的; [0039] wherein R4, R5, R7, and R8 are preferably independently hydrogen, C1-C5 alkyl, halo (C1-C5) alkyl, C1-C5 alkylthio group, or a hydrogen compound; wherein R5, R7, and R8 are hydrogen, those compounds are most preferred;

[0040] 其中R1是乙烯基,乙炔基,丙烯基,或丙炔基,最优选地是乙烯基或乙炔基的化合物;或 [0040] wherein R1 is vinyl, ethynyl, propenyl or propynyl group, most preferably a vinyl or ethynyl group of the compound; or

[0041] 其中R2是氢,氟,氯,溴,碘,硝基,氰基,甲基,乙基,丙基,异丙基,丁基,异丁基,甲氧基,乙氧基,三氟甲基,羧基,甲氧基羰基,或苯基的化合物;最优选地R2是氢,氟,氯,溴, 碘,或甲基。 [0041] wherein R2 is hydrogen, fluoro, chloro, bromo, iodo, nitro, cyano, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, trifluoromethyl, carboxy, methoxycarbonyl, or phenyl; most preferably R2 is hydrogen, fluoro, chloro, bromo, iodo, or methyl.

[0042] 本发明的另一个优选实施方案是上述式(I)的化合物,其中 [0042] Another preferred embodiment of the present invention is a compound of formula (I), wherein

[0043] X 是NHCH2, CH2 = CH2,或C 三C ; [0043] X is NHCH2, CH2 = CH2, and C or C;

[0044] R1是乙烯基或乙炔基; [0044] R1 is a vinyl or ethynyl;

[0045] R2是氢,氟,氯,溴,碘,硝基,氰基,甲基,乙基,丙基,异丙基,丁基,异丁基,甲氧基,乙氧基,三氟甲基,羧基,甲氧基羰基,或苯基; [0045] R2 is hydrogen, fluoro, chloro, bromo, iodo, nitro, cyano, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, tris fluoro, carboxy, methoxycarbonyl, or phenyl;

[0046] R3是氢,甲基,或乙基; [0046] R3 is hydrogen, methyl, or ethyl;

[0047] R4, R5, R7, R8,禾口R10 是氧; [0047] R4, R5, R7, R8, R10 Wo port is oxygen;

[0048] R6是氯,异丙基或叔丁基且特别优选地是异丙基或叔丁基;和 [0048] R6 is chloro, isopropyl or tert-butyl group, and particularly preferably isopropyl or tert-butyl; and

[0049] R9是甲烷磺酰基,乙烷磺酰基,三氟甲烷磺酰基,或乙烯磺酰基。 [0049] R9 is methanesulfonyl group, ethanesulfonyl group, trifluoromethanesulfonyl group, a sulfonyl group, or ethylene.

[0050] 本发明的一个特别优选的实施方案是式(Ia)的化合物 A particularly preferred compound of the [0050] embodiment of the present invention is of formula (Ia) is

[0051] [0051]

Figure CN101142174BD00141

[0052] 其中 [0052] in which

[0053] X 是NHCH2 或CH2 = CH2 ; [0053] X is NHCH2 or CH2 = CH2;

[0054] R1是乙烯基或乙炔基; [0054] R1 is a vinyl or ethynyl;

[0055] R2是氢,氟,氯,溴,碘,硝基,氰基,甲基,乙基,丙基,异丙基,丁基,异丁基,甲氧基,乙氧基,三氟甲基,羧基,甲氧基羰基,或苯基; [0055] R2 is hydrogen, fluoro, chloro, bromo, iodo, nitro, cyano, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, tris fluoro, carboxy, methoxycarbonyl, or phenyl;

[0056] R3是氢,甲基,或乙基; [0056] R3 is hydrogen, methyl, or ethyl;

[0057] R4, R5, R7,和R8 是氢;且 [0057] R4, R5, R7, and R8 are hydrogen;

[0058] R6是异丙基或叔丁基。 [0058] R6 is isopropyl or tert-butyl.

[0059] 本发明的另一个优选的实施方案涉及式I的化合物,其异构体,或其药用盐 [0059] The compounds of formula I according to another preferred embodiment of the present invention, an isomer thereof, or a pharmaceutically acceptable salt thereof

[0060] 其中 [0060] in which

[0061] X 是NHCH2, CR11 = CR12, NH, CHR11CHR12 或C 三C,其中R11 和R12 独立地是氢,氟,或 [0061] X is NHCH2, CR11 = CR12, NH, CHR11CHR12, or C and C, where R11 and R12 are independently hydrogen, fluoro, or

甲基; methyl;

[0062] R1是乙烯基,乙炔基,丙烯基,或丙炔基; [0062] R1 is vinyl, ethynyl, propenyl, or propynyl;

[0063] R2是氢,氟,氯,溴,碘,硝基,氰基,甲基,乙基,丙基,异丙基,丁基,异丁基,甲氧基,乙氧基,乙炔基,乙烯基,羧基,或甲氧基羰基; [0063] R2 is hydrogen, fluoro, chloro, bromo, iodo, nitro, cyano, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, acetylene group, a vinyl group, a carboxyl group, a carbonyl group or a methoxy group;

[0064] R3是氢,甲基,或乙基; [0064] R3 is hydrogen, methyl, or ethyl;

[0065] R4, R5, R7,和R8独立地是氢,氟,羧基,甲基,乙基,丙基,异丙基,叔丁基,硝基,乙烯基,乙炔基,三氟甲基,甲氧基羰基,卤素,甲氧基乙氧基,甲氧基乙氧基甲基,甲基哌嗪基, 甲氧基乙基氨基,羟基,甲氧基,烯丙基氧基,异己基氨基,异丁基氨基(ammino),异丙基氨基,吗啉基,吗啉基乙氧基,或四氢吡喃基氧基; [0065] R4, R5, R7, and R8 are independently hydrogen, fluoro, carboxy, methyl, ethyl, propyl, isopropyl, t-butyl, nitro, ethenyl, ethynyl, trifluoromethyl, , methoxycarbonyl, halogen, methoxyethoxy, methoxyethoxymethyl, methyl piperazinyl group, methoxyethyl group, a hydroxyl group, a methoxy group, an allyl group, isohexyl group, isobutylamino (ammino), an isopropyl group, a morpholino group, an ethoxy group morpholinyl, or tetrahydropyranyl group;

[0066] R6是C3-C5烷基或卤代(C1_C3)烷基且特别优选地是异丙基或叔丁基;且 [0066] R6 is C3-C5 alkyl group or a halo (C1_C3) alkyl and particularly preferably isopropyl or tert-butyl; and

[0067] R9和Rltl独立地是氢或甲烷磺酰基。 [0067] R9 and Rltl are independently hydrogen or a methanesulfonyl group.

[0068] 本发明的另一个优选实施方案是上述式I的化合物,其中 [0068] Another preferred embodiment of the present invention is a compound of the formula I, wherein

[0069] X 是NHCH2, CR11 = CR12, CHR11CHR12 或C 三C,其中R11 是氢或甲基且R12 是氢; [0069] X is NHCH2, CR11 = CR12, CHR11CHR12, or C three C, where R11 is hydrogen or methyl and R12 is hydrogen;

[0070] R1是乙烯基或乙炔基; [0070] R1 is a vinyl or ethynyl;

[0071] R2是氢,氟,甲基,或氯; [0071] R2 is hydrogen, fluoro, methyl, or chloro;

[0072] R3是氢或甲基; [0072] R3 is hydrogen or methyl;

[0073] R4,是氢,氟,甲氧基甲氧基,甲氧基乙氧基,甲氧基丙氧基,甲氧基,甲氧基乙基氨基,烯丙基氧基,或四氢吡喃基氧基; [0073] R4, is hydrogen, fluorine, methoxymethoxy, methoxyethoxy, methoxypropoxy, methoxy, methoxyethyl group, an allyl group, or tetra tetrahydropyranyl group;

[0074] R5,R7和R8是氢或氟; [0074] R5, R7 and R8 are hydrogen or fluorine;

[0075] R6是C3-C5烷基或卤代(C1-C3)烷基,[0076] 且特别优选地是异丙基或叔丁基;和 [0075] R6 is C3-C5 alkyl group or a halo (C1-C3) alkyl, [0076] and particularly preferably isopropyl or tert-butyl; and

[0077] R9是氢和Rltl表示甲烷磺酰基。 [0077] R9 is hydrogen and Rltl represents methanesulfonyl group.

[0078] 本发明的另一个优选的实施方案是上述式I的化合物,其中 [0078] Another preferred embodiment of the present invention is a compound of the formula I, wherein

[0079] X是CR11 = CR12,其中R11是氢或甲基且R12是氢; [0079] X is CR11 = CR12, wherein R11 is hydrogen or methyl and R12 is hydrogen;

[0080] R1是乙烯基或乙炔基; [0080] R1 is a vinyl or ethynyl;

[0081] R2是氢,氟,甲基,或氯; [0081] R2 is hydrogen, fluoro, methyl, or chloro;

[0082] R3是氢或甲基; [0082] R3 is hydrogen or methyl;

[0083] R4是氢,氟,甲氧基甲氧基,甲氧基乙氧基,甲氧基丙氧基,甲氧基,甲氧基乙基氨基,烯丙基氧基,或四氢吡喃基氧基; [0083] R4 is hydrogen, fluorine, methoxymethoxy, methoxyethoxy, methoxypropoxy, methoxy, methoxyethyl group, an allyl group, or tetrahydropyran pyranyl group;

[0084] R5,R7和R8是氢或氟; [0084] R5, R7 and R8 are hydrogen or fluorine;

[0085] R6是C3-C5烷基或卤代(C1-C3)烷基且特别优选地是异丙基或叔丁基;和 [0085] R6 is C3-C5 alkyl group or a halo (C1-C3) alkyl and particularly preferably isopropyl or tert-butyl; and

[0086] R9是氢和Rltl表示甲烷磺酰基。 [0086] R9 is hydrogen and Rltl represents methanesulfonyl group.

[0087] 本发明的另一个优选的实施方案是上述式I的化合物,其中 [0087] Another preferred embodiment of the present invention is a compound of the formula I, wherein

[0088] X 是C 三C ; [0088] X is C and C;

[0089] R1是乙烯基或乙炔基; [0089] R1 is a vinyl or ethynyl;

[0090] R2是氢,氟,甲基,或氯; [0090] R2 is hydrogen, fluoro, methyl, or chloro;

[0091] R3是氢或甲基; [0091] R3 is hydrogen or methyl;

[0092] R4是氢,氟,甲氧基甲氧基,甲氧基乙氧基,甲氧基丙氧基,甲氧基,甲氧基乙基氨基,烯丙基氧基,或四氢吡喃基氧基; [0092] R4 is hydrogen, fluorine, methoxymethoxy, methoxyethoxy, methoxypropoxy, methoxy, methoxyethyl group, an allyl group, or tetrahydropyran pyranyl group;

[0093] R5,R7和R8是氢或氟; [0093] R5, R7 and R8 are hydrogen or fluorine;

[0094] R6是C3-C5烷基或卤代(C1_C3)烷基且特别优选地是异丙基或叔丁基;和 [0094] R6 is C3-C5 alkyl group or a halo (C1_C3) alkyl and particularly preferably isopropyl or tert-butyl; and

[0095] R9是氢和Rltl表示甲烷磺酰基。 [0095] R9 is hydrogen and Rltl represents methanesulfonyl group.

[0096] 本发明的另一个优选的实施方案是上述式I的化合物,其中 [0096] Another preferred embodiment of the present invention is a compound of the formula I, wherein

[0097] X 是NHCH2, [0097] X is NHCH2,

[0098] R1是乙烯基或乙炔基; [0098] R1 is a vinyl or ethynyl;

[0099] R2是氢,氟,甲基,或氯; [0099] R2 is hydrogen, fluoro, methyl, or chloro;

[0100] R3是氢或甲基; [0100] R3 is hydrogen or methyl;

[0101] R4是氢,氟,甲氧基甲氧基,甲氧基乙氧基,甲氧基丙氧基,甲氧基, [0101] R4 is hydrogen, fluorine, methoxymethoxy, methoxyethoxy, methoxypropoxy group, a methoxy group,

[0102] 甲氧基乙基氨基, [0102] methoxyethyl group,

[0103] 烯丙基氧基,或四氢吡喃基氧基且特别优选地是氢或氟; [0103] an allyl group, or a tetrahydropyranyloxy group, and particularly preferably a hydrogen or fluorine;

[0104] R5,R7和R8是氢或氟; [0104] R5, R7 and R8 are hydrogen or fluorine;

[0105] R6是C3-C5烷基或卤代(C1-C3)烷基且特别优选地是异丙基或叔丁基;和 [0105] R6 is C3-C5 alkyl group or a halo (C1-C3) alkyl and particularly preferably isopropyl or tert-butyl; and

[0106] R9是氢且Rltl表示甲烷磺酰基。 [0106] R9 is hydrogen and Rltl represents methanesulfonyl group.

[0107] 本发明的另一个优选的实施方案是上述式I的化合物,其中 [0107] Another preferred embodiment of the present invention is a compound of the formula I, wherein

[0108] X是CHR11CHR12,其中R11是氢或甲基和R12是氢; [0108] X is CHR11CHR12, wherein R11 is hydrogen and R12 is hydrogen or methyl;

[0109] R1是乙烯基或乙炔基; [0109] R1 is a vinyl or ethynyl;

[0110] R2是氢,氟,甲基,或氯; [0110] R2 is hydrogen, fluoro, methyl, or chloro;

[0111] R3是氢或甲基; [0111] R3 is hydrogen or methyl;

[0112] R4是氢,氟,甲氧基甲氧基,甲氧基乙氧基,甲氧基丙氧基,甲氧基,甲氧基乙基氨基,烯丙基氧基,或四氢吡喃基氧基且特别优选地是氢,氟或四氢吡喃基氧基; [0112] R4 is hydrogen, fluorine, methoxymethoxy, methoxyethoxy, methoxypropoxy, methoxy, methoxyethyl group, an allyl group, or tetrahydropyran pyranyl group and particularly preferably hydrogen, fluoro or tetrahydropyranyloxy;

[0113] R5,R7和R8是氢或氟; [0113] R5, R7 and R8 are hydrogen or fluorine;

[0114] R6是C3-C5烷基或卤代(C1-C3)烷基且特别优选地是异丙基或叔丁基; [0114] R6 is C3-C5 alkyl group or a halo (C1-C3) alkyl and particularly preferably isopropyl or tert-butyl;

[0115]且 [0115] and

[0116] R9是氢和Rltl表示甲烷磺酰基。 [0116] R9 is hydrogen and Rltl represents methanesulfonyl group.

[0117] 本发明的另一个优选的实施方案是上述式I的化合物,其中 [0117] Another preferred embodiment of the present invention is a compound of the formula I, wherein

[0118] X 是NH, [0118] X is NH,

[0119] R1是乙烯基或乙炔基; [0120] R2是氢,氟,甲基,或氯; [0119] R1 is a vinyl or ethynyl; [0120] R2 is hydrogen, fluoro, methyl, or chloro;

[0121] R3是甲基; [0121] R3 is methyl;

[0122] R4是氢,氟,甲氧基甲氧基,甲氧基乙氧基,甲氧基丙氧基,甲氧基,甲氧基乙基氨基, [0122] R4 is hydrogen, fluorine, methoxymethoxy, methoxyethoxy, methoxypropoxy, methoxy, methoxyethyl group,

[0123] 烯丙基氧基,或四氢吡喃基氧基且特别优选地是氢或氟; [0123] an allyl group, or a tetrahydropyranyloxy group, and particularly preferably a hydrogen or fluorine;

[0124] R5,R7和R8是氢或氟; [0124] R5, R7 and R8 are hydrogen or fluorine;

[0125] R6是C3-C5烷基或卤代(C1-C3)烷基且特别优选地是异丙基或叔丁基; [0125] R6 is C3-C5 alkyl group or a halo (C1-C3) alkyl and particularly preferably isopropyl or tert-butyl;

[0126]且 [0126] and

[0127] R9是氢和Rltl表示甲烷磺酰基。 [0127] R9 is hydrogen and Rltl represents methanesulfonyl group.

[0128] 本发明的一个实施方案涉及如上进一步定义的式I的化合物,其中X是CHR11-CHR12。 [0128] In one embodiment of the present invention is directed to a compound of formula I as defined further above, wherein X is CHR11-CHR12. 这些化合物具有通式(lb)。 These compounds have the general formula (lb).

[0129] [0129]

Figure CN101142174BD00161

[0130] 其中 [0130] in which

[0131] R11和R12独立地是氢,卤素,C1-C5烷基,C1_C5烷氧基,卤代(C1-C5)烷基,或苯基; [0131] R11 and R12 are independently hydrogen, halogen, C1-C5 alkyl, C1_C5 alkoxy, halo (C1-C5) alkyl, or phenyl;

[0132] R1是C2-C5链烯基或C2-C5炔基; [0132] R1 is C2-C5 alkenyl or C2-C5 alkynyl;

[0133] R2是氢,卤素,硝基,氰基,C1-C5烷基,C1-C5烷氧基,卤代(C1-C5)烷基,C2-C5链烯基,C2-C5炔基,羧基,C1-C5烷氧基羰基,C1-C5烷硫基,苯基,或苯基(C1-C3)烷基,其中每个苯基可以是未取代的或由选自下列各项的一个或多个取代基取代:羧基,C1-C5烷基, 卤素,硝基,C2-C5链烯基,C1-C5烷氧基,卤代(C1-C5)烷基,C1-C5烷基羰基,C1-C5烷硫基,C1-C5烷基磺酰基,和C1-C5烷氧基羰基; [0133] R2 is hydrogen, halo, nitro, cyano, C1-C5 alkyl, C1-C5 alkoxy, halo (C1-C5) alkyl, C2-C5 alkenyl, C2-C5 alkynyl group , carboxy, C1-C5 alkoxycarbonyl, C1-C5 alkylthio, phenyl, or phenyl (C1-C3) alkyl, wherein each phenyl group may be unsubstituted or substituted selected from the following one or more substituents: carboxy, C1-C5 alkyl, halogen, nitro, C2-C5 alkenyl, C1-C5 alkoxy, halo (C1-C5) alkyl, C1-C5 alkyl carbonyl, C1-C5 alkylthio groups, C1-C5 alkylsulfonyl group, and C1-C5 alkoxycarbonyl group;

[0134] R3是氢,C1-C5烷基,C1-C5烷氧基,或卤代(C1-C5)烷基; [0134] R3 is hydrogen, C1-C5 alkyl, C1-C5 alkoxy, or halo (C1-C5) alkyl;

[0135] R4, R5, R6, R7,和R8独立地是氢,羧基,C1-C5烷基,硝基,C2-C5链烯基,C1-C5烷氧基,C2-C5炔基,卤代(C1-C5)烷基,C1-C5烷硫基,C1-C5烷基磺酰基,C1-C5烷基羰基, C1-C5烷氧基羰基,羟基,C2-C5链烯氧基,C1-C5烷氧基(C1-C5)烷氧基,C1-C5烷氧基(C1-C5)烷氧基(C1-C5)烷基,C1-C3烷基哌嗪基,哌嗪基(C1-C5)烷氧基,哌啶基(C1-C5) 烷氧基,C1-C5烷氧基(C1-C5)烷基氨基,C1-C7烷基氨基,吗啉基,吗啉基(C1-C5)烷基氧基,四氢吡喃基氧基,苯基,或商素,其中苯基可以是未取代的或由选自下列各项的一个或多个取代基取代:羧基,C1-C5烷基,商素,硝基,C2-C5链烯基,C1-C5烷氧基,商代(C1-C5) 烷基,C1-C5烷基羰基,C1-C5烷硫基,C1-C5烷基磺酰基,C1-C5烷氧基羰基,或是未取代的或由C1-C5烷氧基羰基取代的哌啶基氧基;其中R6优选地是C3-C5烷基或卤代(C1-C3)烷基,且特别优选 [0135] R4, R5, R6, R7, and R8 are independently hydrogen, carboxy, C1-C5 alkyl, nitro, C2-C5 alkenyl, C1-C5 alkoxy, C2-C5 alkynyl group, a halogen Generation (C1-C5) alkyl, C1-C5 alkylthio groups, C1-C5 alkylsulfonyl group, C1-C5 alkylcarbonyl, C1-C5 alkoxycarbonyl group, a hydroxyl group, C2-C5 alkenyloxy groups, C1 -C5 alkoxy (C1-C5) alkoxy, C1-C5 alkoxy (C1-C5) alkoxy (C1-C5) alkyl, C1-C3-alkyl-piperazinyl, piperazinyl (C1 -C5) alkoxy, piperidinyl (C1-C5) alkoxy, C1-C5 alkoxy (C1-C5) alkylamino, C1-C7 alkylamino, morpholinyl, morpholinyl (C1 -C5) alkyl group, a tetrahydropyranyl group, a phenyl group, or commercial pigment, wherein phenyl may be unsubstituted or substituted selected from the group of one or more of the following substituents: carboxyl group, a C1 -C5 alkyl, supplier, nitro, C2-C5 alkenyl, C1-C5 alkoxy, Shang (C1-C5) alkyl, C1-C5 alkylcarbonyl, C1-C5 alkylthio, C1 -C5 alkylsulfonyl group, C1-C5 alkoxycarbonyl group, or an unsubstituted or a C1-C5 alkoxycarbonyl-substituted piperidinyl group; wherein R6 is preferably a C3-C5 alkyl or halo (C1-C3) alkyl group, and particularly preferably 是异丙基或叔丁基;且 It is isopropyl or t-butyl; and

[0136] R9 和R10 独立地是氢,-SO2R13, -SOR13, C1-C5 烷基,C1-C5 烷氧基,(C1-C5)烷基, C2-C5链烯基,C1-C5烷氧基羰基,C1-C5烷硫基,苯基,或苯基(C1-C3)烷基,其中每个苯基可以是未取代的或由选自下列各项的一个或多个取代基取代:羧基,C1-C5烷基,卤素,硝基,C2-C5链烯基,C1-C5烷氧基,卤代(C1-C5)烷基,C1-C5烷基羰基,C1-C5烷硫基,C1-C5 烷基磺酰基,和C1-C5烷氧基羰基,且R13是氢,氨基,C1-C5烷基,C2-C5链烯基,C1-C5烷氧基,卤代(C1-C5)烷基,三氟甲基,苯基,或苯基(C1-C3)烷基。 [0136] R9 and R10 are independently hydrogen, -SO2R13, -SOR13, C1-C5 alkyl, C1-C5 alkoxy, (C1-C5) alkyl, C2-C5 alkenyl, C1-C5 alkoxy carbonyl group, C1-C5 alkylthio, phenyl, or phenyl (C1-C3) alkyl, wherein each phenyl group may be unsubstituted or selected from one or more of the following substituents: carboxy, C1-C5 alkyl, halogen, nitro, C2-C5 alkenyl, C1-C5 alkoxy, halo (C1-C5) alkyl, C1-C5 alkylcarbonyl, C1-C5 alkylthio , C1-C5 alkylsulfonyl group, and C1-C5 alkoxycarbonyl, and R13 is hydrogen, amino, C1-C5 alkyl, C2-C5 alkenyl, C1-C5 alkoxy, halo (C1 C5) alkyl, trifluoromethyl, phenyl, or phenyl (C1-C3) alkyl.

[0137] 优选地,在上述图(Ib)中, [0137] Preferably, in the FIG (Ib), the

[0138] R11禾口R12是甲基或氢; [0138] R11 R12 Wo port is methyl or hydrogen;

[0139] R1是乙烯基或乙炔基; [0139] R1 is a vinyl or ethynyl;

[0140] R2是氢,氟,氯,溴,碘,硝基,氰基,甲基,乙基,丙基,异丙基,丁基,异丁基,甲氧基,乙氧基,三氟甲基,羧基,或甲氧基羰基; [0140] R2 is hydrogen, fluoro, chloro, bromo, iodo, nitro, cyano, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, tris fluoromethyl, carboxyl, or methoxycarbonyl group;

[0141] R3是氢,甲基,或乙基; [0141] R3 is hydrogen, methyl, or ethyl;

[0142] R4, R5, R7,和R8独立地是氢,氟,羧基,甲基,乙基,丙基,异丙基,叔丁基,硝基,乙烯基,乙炔基,三氟甲基,甲氧基羰基,卤素,甲氧基乙氧基,甲氧基乙氧基甲基,甲基哌嗪基, 甲氧基乙基氨基,羟基,甲氧基,烯丙基氧基,异己基氨基,异丁基氨基(ammino),异丙基氨基,吗啉基,吗啉基乙氧基,或四氢吡喃基氧基;且 [0142] R4, R5, R7, and R8 are independently hydrogen, fluoro, carboxy, methyl, ethyl, propyl, isopropyl, t-butyl, nitro, ethenyl, ethynyl, trifluoromethyl, , methoxycarbonyl, halogen, methoxyethoxy, methoxyethoxymethyl, methyl piperazinyl group, methoxyethyl group, a hydroxyl group, a methoxy group, an allyl group, isohexyl group, isobutylamino (ammino), an isopropyl group, a morpholino group, an ethoxy group morpholinyl, or tetrahydropyranyl group; and

[0143] R6是异丙基,叔丁基,或卤代(C1-C3)烷基且特别优选地是异丙基或叔丁基。 [0143] R6 is isopropyl, t-butyl, or halo (C1-C3) alkyl and particularly preferably isopropyl or tert-butyl.

[0144] 甚至更优选地,在上述图(Ib)中, [0144] Even more preferably, in the FIG (Ib), the

[0145] R11是氢或甲基,且R12是氢; [0145] R11 is hydrogen or methyl, and R12 is hydrogen;

[0146] R1是乙烯基或乙炔基; [0146] R1 is a vinyl or ethynyl;

[0147] R2是氢,氟,氯,或甲基; [0147] R2 is hydrogen, fluoro, chloro, or methyl;

[0148] R4是氢,氟,甲氧基甲氧基,甲氧基乙氧基,甲氧基丙氧基,甲氧基,甲氧基乙基氨基,烯丙基氧基,或四氢吡喃基氧基; [0148] R4 is hydrogen, fluorine, methoxymethoxy, methoxyethoxy, methoxypropoxy, methoxy, methoxyethyl group, an allyl group, or tetrahydropyran pyranyl group;

[0149] R5, R7和R8是氢或氟; [0149] R5, R7 and R8 are hydrogen or fluorine;

[0150] R6 是叔丁基; [0150] R6 is tert-butyl;

[0151] R9是氢;且 [0151] R9 is hydrogen;

[0152] Rltl表示甲烷磺酰基。 [0152] Rltl represents a methanesulfonyl group.

[0153] 按照本发明的一个重要方面,在上述式⑴和(Ib)的化合物中,R9是氧,R10是甲烷磺酰基且R1以相对于甲烷磺酰基氨基的邻位结合于苯环。 [0153] According to an important aspect of the present invention, in the compound of formula ⑴ and (Ib) in, R9 is oxygen, R10 is methanesulfonyl group and an ortho position with respect to R1 methanesulfonyl group bound to a benzene ring. 那些优选的化合物具有通式(Ic)。 Preferred of those compounds of general formula (Ic).

[0154] [0154]

Figure CN101142174BD00181

[0155] 其中R1, R2, R3, R4, R5, R6, R7, R8和X具有按照上述定义的各种实施方案的含义,其中关于式I和(Ib)的化合物的各种优选的实施方案和特征也适用于式(Ic)的化合物。 [0155] wherein R1, R2, R3, R4, R5, R6, R7, R8 and X have the meanings defined above according to the various embodiments, wherein on various preferred compounds of formula I and (Ib) embodiment and wherein the compound also apply to formula (Ic) is.

[0156] 按照本发明的一个方面,在上述式(I)和(Ib)的化合物中,R9是氢,R10是甲烷磺酰基且R1和R2都以相对于甲烷磺酰基氨基的邻位结合于苯环。 [0156] According to an aspect of the present invention, in the compounds of formula (I) and (Ib) in, R9 is hydrogen, R10 is methanesulfonyl group and R1 and R2 are in ortho position relative to methane sulfonylamino binds to benzene ring. 那些优选的化合物具有通式(Id)。 Preferred of those compounds of general formula (Id).

[0157] [0157]

Figure CN101142174BD00182

[0158] 其中R1, R2, R3, R4, R5, R6, R7, R8和X具有按照上述定义的各种实施方案的含义,其中关于式I和(Ib)的化合物的各种优选的实施方案和特征也适用于式(Id)的化合物。 [0158] wherein R1, R2, R3, R4, R5, R6, R7, R8 and X have the meanings defined above according to the various embodiments, wherein on various preferred compounds of formula I and (Ib) embodiment and wherein the compound of formula also applies to (Id) of.

[0159] 在式(Ic)或(Id)的化合物中,最优选地 [0159] In the compounds of formula (Ic) or (Id), the most preferred

[0160] X 是CHR11CHR12 或X 选自NHCH2, CR11 = CR12 禾口C 三C ; [0160] X is selected from X is CHR11CHR12 or NHCH2, CR11 = CR12 Wo port C and C;

[0161] R1是乙烯基或乙炔基; [0161] R1 is a vinyl or ethynyl;

[0162] R2是氢,氟,氯,或甲基; [0162] R2 is hydrogen, fluoro, chloro, or methyl;

[0163] R3是氢或甲基; [0163] R3 is hydrogen or methyl;

[0164] R4是氢,氟,甲氧基甲氧基,甲氧基乙氧基,甲氧基丙氧基,甲氧基,甲氧基乙基氨基,烯丙基氧基,或四氢吡喃基氧基; [0164] R4 is hydrogen, fluorine, methoxymethoxy, methoxyethoxy, methoxypropoxy, methoxy, methoxyethyl group, an allyl group, or tetrahydropyran pyranyl group;

[0165] R5, R7和R8是氢或氟;且 [0165] R5, R7 and R8 are hydrogen or fluoro; and

[0166] R6是卤代(C1-C3)烷基,异丙基或,优选地,叔丁基。 [0166] R6 is halo (C1-C3) alkyl group, or an isopropyl group, preferably tert-butyl.

[0167] 按照本发明的化合物的优选实例选自由下列各项组成的组: [0167] selected from the group consisting of Preferred examples of compounds according to the present invention:

[0168] N-{4-[3-(4-叔丁基苄基)脲基甲基]-2-乙烯基苯基}甲烷磺酰胺, [0168] N- {4- [3- (4- tert-butylbenzyl) ureidomethyl] -2-vinyl-phenyl} methanesulfonamide,

[0169] N-{4-[3-(4-叔丁基苄基)脲基甲基]_2_氟_6_乙烯基苯基}甲烷磺酰胺, [0169] N- {4- [3- (4- tert-butylbenzyl) ureidomethyl] _2_ fluoro _6_ vinylphenyl} methanesulfonamide,

[0170] N-{4-[3-(4-叔丁基苄基)脲基甲基]-2-乙炔基_6_氟苯基}甲烷磺酰胺, [0170] N- {4- [3- (4- tert-butylbenzyl) ureidomethyl] -2-fluorophenyl} ethynyl _6_ methanesulfonamide,

[0171] N-{4-[3-(4-叔丁基苄基)脲基甲基]-5-氯-2-乙烯基苯基}甲烷磺酰胺, [0171] N- {4- [3- (4- tert-butylbenzyl) ureidomethyl] -5-chloro-2-vinyl-phenyl} methanesulfonamide,

[0172] N-{4-[3-(4-叔丁基苄基)脲基甲基]-5-氯-2-乙炔基苯基}甲烷磺酰胺, [0172] N- {4- [3- (4- tert-butylbenzyl) ureidomethyl] -5-chloro-2-ethynyl-phenyl} methanesulfonamide,

[0173] N-(4-{l-(R)-[3_(4-叔丁基苄基)脲基]乙基}_2_乙烯基苯基)甲烷磺酰胺, [0173] N- (4- {l- (R) - [3_ (4- tert-butyl-benzyl) ureido] ethyl} _2_ vinylphenyl) methanesulfonamide,

[0174] (R) -N- (4- {1- [3- (4_叔丁基-苄基)_脲基]-乙基} _2_氟_6_乙烯基-苯基)_甲烷磺酰胺,[0175] N- {4- [3- (4-叔丁基-苄基)_脲基甲基]_2_甲基_6_乙烯基-苯基}-甲烷磺酰胺, [0174] (R) -N- (4- {1- [3- (4_-tert-butyl-benzyl) - _ ureido] - ethyl} _2_ _6_ vinyl-fluoro-phenyl) - methane _ sulfonamide, [0175] N- {4- [3- (4- tert-butyl-benzyl) - _ ureidomethyl] _2_ _6_ vinyl methyl - phenyl} - methanesulfonamide,

[0176] N-{4-[3-(4-叔丁基-苄基)_脲基甲基]-2-氯-6-乙烯基-苯基}-甲烷磺酰胺, [0176] N- {4- [3- (4- tert-butyl-benzyl) - _ ureido methyl] -2-chloro-6-vinyl - phenyl} - methanesulfonamide,

[0177] 3-(4-叔丁基苯基)丙炔酸3-氟-4-甲烷磺酰基氨基_5_乙烯基苄基酰胺, [0177] 3- (4-tert-butyl-phenyl) propiolic acid 3-fluoro-4-methanesulfonyl-ylamino _5_ vinyl benzyl amide,

[0178] 3-(4-叔丁基苯基)丙炔酸[1-(3_氟-4-甲烷磺酰基氨基_5_乙烯基苯基)乙基]酰胺, [0178] 3- (4-tert-butyl-phenyl) propiolic acid [1- (3_ Fluoro-4-yl-amino _5_ vinylphenyl) ethyl] amide,

[0179] 3-(4_叔丁基苯基)-N-[l-(R)_(4-甲烷磺酰基氨基_3_乙烯基苯基)乙基]丙烯酰胺, [0179] 3- (4_-tert-butylphenyl) -N- [l- (R) _ (4- methanesulfonylamino-_3_ vinylphenyl) ethyl] acrylamide,

[0180] 3-(4-叔丁基苯基)-N-(3-氟-4-甲烷磺酰基氨基_5_乙烯基苄基)丙烯酰胺, [0181 ] 3- (4-叔丁基苯基)-N- (3-氟-5-乙炔基_4_甲烷磺酰基氨基-苄基)丙烯酰胺, [0180] 3- (4-tert-butylphenyl) -N- (3- Fluoro-4-ylamino _5_ vinyl benzyl) acrylamide, [0181] 3- (4-tert-butyl phenyl) -N- (3- fluoro-5-ethynyl-_4_ methane-sulfonylamino-benzyl) - acrylamide,

[0182] 3-(4-叔丁基苯基)-N-(4-甲烷磺酰基氨基_3_乙烯基苄基)丙烯酰胺, [0182] 3- (4-tert-butylphenyl) -N- (4- methanesulfonylamino-_3_ vinylbenzyl) acrylamide,

[0183] 3-(4-三氟甲基苯基)-N-(4-甲烷磺酰基氨基_3_乙烯基苄基)丙烯酰胺, [0183] 3- (4-trifluoromethylphenyl) -N- (4- methanesulfonylamino-_3_ vinylbenzyl) acrylamide,

[0184] 3-(4-叔丁基苯基)-N-(3-氯-4-甲烷磺酰基氨基_5_乙烯基苄基)丙烯酰胺, [0184] 3- (4-tert-butylphenyl) -N- (3- chloro-4-methanesulfonyl-ylamino _5_ vinylbenzyl) acrylamide,

[0185] 3- (4-叔丁基-2-吗啉-4-基-苯基)-N- (3_氟_4_甲烷磺酰基氨基_5_乙烯基苄基)丙烯酰胺, [0185] 3- (4-tert-butyl-2-morpholin-4-yl - phenyl) -N- (3_ fluoro _4_ _5_ methanesulfonylamino-vinylbenzyl) acrylamide,

[0186] 3-(4-叔丁基-2-甲氧基乙氧基-苯基)-N_(3-氟_4_甲烷磺酰基氨基_5_乙烯基苄基)丙烯酰胺, [0186] 3- (4-tert-butyl-2-methoxy-ethoxy - phenyl) -N_ (3- methanesulfonylamino-fluoro _4_ _5_ vinylbenzyl) acrylamide,

[0187] 3-[4_叔丁基-2-(2_甲氧基乙基氨基)苯基]-N-(3_氟_4_甲烷磺酰基氨基-5-乙烯基苄基)丙烯酰胺, [0187] 3- [4 _ t-butyl-2- (2_ methoxyethyl) phenyl] -N- (3_ _4_ methanesulfonyl-fluoro-5-vinylbenzyl-yl) acrylamide amide,

[0188] 3- (4-叔丁基-2-甲氧基苯基)-N- (3_氟_4_甲烷磺酰基氨基_5_乙烯基-苄基) 丙烯酰胺, [0188] 3- (4-tert-butyl-2-methoxyphenyl) -N- (3_ fluoro _4_ _5_ methanesulfonylamino-vinyl-benzyl) - acrylamide,

[0189] 3- (2-烯丙基氧基-4-叔丁基苯基)-N- (3_氟_4_甲烷磺酰基氨基_5_乙烯基苄基)丙烯酰胺, [0189] 3- (2-allyl-4-tert-butylphenyl) -N- (3_ fluoro _4_ _5_ methanesulfonylamino-vinylbenzyl) acrylamide,

[0190] 3- [4-叔丁基-2- (3-甲基丁基氨基)苯基]-N- (3_氟_4_甲烷磺酰基氨基_5_乙烯基苄基)丙烯酰胺, [0190] 3- [4-tert-Butyl-2- (3-methylbutyl) phenyl] -N- (3_ fluoro _4_ _5_ methanesulfonylamino-vinylbenzyl) acrylamide ,

[0191] 3-(4-叔丁基-2-异丙基氨基苯基)-N-(3-氟_4_甲烷磺酰基氨基_5_乙烯基苄基)丙烯酰胺, [0191] 3- (4-tert-butyl-2-isopropylamino-phenyl) -N- (3- methanesulfonylamino-fluoro _4_ _5_ vinylbenzyl) acrylamide,

[0192] 3-(4-叔丁基苯基)-N-[1-(3-氟-4-甲烷磺酰基氨基-5-乙烯基苯基)乙基]丙酰胺, [0192] 3- (4-tert-butylphenyl) -N- [1- (3- fluoro-4-methanesulfonyl-5-vinylphenyl) ethyl] propionamide,

[0193] 3-(4-叔丁基苯基)-N-[1-(3-氟-4-甲烷磺酰基氨基-5-乙烯基苯基)乙基]丙烯酰胺, [0193] 3- (4-tert-butylphenyl) -N- [1- (3- fluoro-4-methanesulfonyl-5-vinylphenyl) ethyl] acrylamide,

[0194] 3-(4-叔丁基苯基)-N-(3-氟-4-甲烷磺酰基氨基_5_乙烯基苄基)_2_甲基丙烯酰胺, [0194] 3- (4-tert-butylphenyl) -N- (3- Fluoro-4-ylamino _5_ vinylbenzyl) _2_ methacrylamide,

[0195] 3-(4-叔丁基苯基)-2-氟-N-(3-氟_4_甲烷磺酰基氨基_5_乙烯基苄基)丙烯酰胺, [0195] 3- (4-tert-butylphenyl) -2-fluoro -N- (3- methanesulfonylamino-fluoro _4_ _5_ vinylbenzyl) acrylamide,

[0196] 3-[4_叔丁基_2-(四氢吡喃-4-基氧基)苯基]_N_(3_氟_4_甲烷磺酰基氨基-5-乙烯基苄基)丙烯酰胺,[0197] 3-[4_叔丁基-2_(四氢吡喃-4-基氧基)苯基]_N_(3_氟_4_甲烷磺酰基氨基-5-乙烯基苄基)丙酰胺, [0196] 3- [tert-butyl _2- 4_ (tetrahydropyran-4-yloxy) phenyl] _N_ (3_ _4_ methanesulfonyl-fluoro-5-vinylbenzyl-yl) acrylamide amide, [0197] 3- [tert-butyl -2_ 4_ (tetrahydropyran-4-yloxy) phenyl] _N_ (3_ _4_ methanesulfonyl-fluoro-5-vinylbenzyl) propanamide,

[0198] 3-(4_叔丁基苯基)-N-[l_(4-甲烷磺酰基氨基_3_乙烯基苯基)乙基]_2_甲基丙烯酰胺, [0198] 3- (4_-tert-butylphenyl) -N- [l_ (4- methanesulfonylamino-_3_ vinylphenyl) ethyl] _2_ methacrylamide,

[0199] 3- (4-叔丁基苯基)-N- (3-氟_4_甲烷磺酰基氨基_5_乙烯基苄基)_2_甲基丙酰胺, [0199] 3- (4-tert-butylphenyl) -N- (3- methanesulfonylamino-fluoro _4_ _5_ vinylbenzyl) _2_ methylpropanamide

[0200] 3-[4_(叔丁基)苯基]-[N-4_(甲烷磺酰基氨基)-3_乙烯基苄基]丙酰胺, [0200] 3- [4_ (tert-butyl) phenyl] - [N-4_ (methane-sulfonylamino) -3_ vinyl benzyl] propanamide,

[0201] 3-[4_(叔丁基)苯基]-[N-3-氟_4-(甲烷磺酰基氨基)_5_乙烯基苄基]丙酰胺, [0201] 3- [4_ (tert-butyl) phenyl] - [N-3- fluoro _4- (methane-sulfonylamino) _5_ vinyl benzyl] propanamide,

[0202] 3-(4-叔丁基-苯基)-N_(3-乙炔基_5_氟_4_甲烷磺酰基氨基-苄基)_丙酰胺, [0202] 3- (4-tert-butyl - phenyl) -N_ (3- ethynyl _5_ _4_ methanesulfonylamino-fluoro-benzyl) - _ propanamide,

[0203] Ν-(4-{1-[3-(4-叔丁基苯基)脲基]乙基}_2_乙烯基苯基)甲烷磺酰胺, [0203] Ν- (4- {1- [3- (4- tert-butylphenyl) ureido] ethyl} _2_ vinylphenyl) methanesulfonamide,

[0204] Ν-(4-{1-[3-(4-叔丁基苯基)脲基]乙基}_2_乙炔基苯基)甲烷磺酰胺, [0204] Ν- (4- {1- [3- (4- tert-butylphenyl) ureido] ethyl} _2_ ethynylphenyl) methanesulfonamide,

[0205] N-{4-[3-(4-叔丁基苯基)脲基甲基]_2_氟_6_乙烯基苯基}甲烷磺酰胺,和 [0205] N- {4- [3- (4- tert-butylphenyl) ureidomethyl] _2_ fluoro _6_ vinylphenyl} methanesulfonamide, and

[0206] 乙烯磺酸(4-{1-[3-(4_叔丁基苯基)脲基]乙基}-2_乙烯基苯基)酰胺。 [0206] Ethylene acid (4- {1- [3- (4 _ t-butylphenyl) ureido] ethyl} -2_ vinylphenyl) amide.

[0207] 按照本发明的特别优选的化合物是 [0207] According to a particularly preferred compounds of the invention are

[0208] (R) -N- (4- {1- [3- (4_叔丁基-苄基)_脲基]-乙基} _2_氟_6_乙烯基-苯基)_甲烷磺酰胺, [0208] (R) -N- (4- {1- [3- (4_-tert-butyl-benzyl) - _ ureido] - ethyl} _2_ _6_ vinyl-fluoro-phenyl) - methane _ sulfonamide,

[0209] 3-(4_叔丁基苯基)-N-[l-(R)_(4-甲烷磺酰基氨基_3_乙烯基苯基)乙基]丙烯酰胺, [0209] 3- (4_-tert-butylphenyl) -N- [l- (R) _ (4- methanesulfonylamino-_3_ vinylphenyl) ethyl] acrylamide,

[0210] 3-(4-叔丁基苯基)-N-(3-氟-4-甲烷磺酰基氨基_5_乙烯基苄基)丙烯酰胺, [0211 ] 3- (4-叔丁基苯基)-N- (3-氟-5-乙炔基_4_甲烷磺酰基氨基-苄基)丙烯酰胺, [0210] 3- (4-tert-butylphenyl) -N- (3- Fluoro-4-ylamino _5_ vinyl benzyl) acrylamide, [0211] 3- (4-tert-butyl phenyl) -N- (3- fluoro-5-ethynyl-_4_ methane-sulfonylamino-benzyl) - acrylamide,

[0212] (R)-3-(4-叔丁基苯基)-N-[1-(3-氟-4-甲烷磺酰基氨基-5-乙烯基苯基)乙基]丙酰胺, [0212] (R) -3- (4- tert-butylphenyl) -N- [1- (3- fluoro-4-methanesulfonyl-5-vinylphenyl) ethyl] propionamide,

[0213] 3-(4-叔丁基苯基)-N-(3-氟-4-甲烷磺酰基氨基_5_乙烯基苄基)_2_甲基丙烯酰胺, [0213] 3- (4-tert-butylphenyl) -N- (3- Fluoro-4-ylamino _5_ vinylbenzyl) _2_ methacrylamide,

[0214] 3-[4_叔丁基_2-(四氢吡喃-4-基氧基)苯基]_N_(3_氟_4_甲烷磺酰基氨基-5-乙烯基苄基)丙酰胺, [0214] 3- [tert-butyl _2- 4_ (tetrahydropyran-4-yloxy) phenyl] _N_ (3_ _4_ methanesulfonyl-fluoro-5-vinylbenzyl-yl) propan- amide,

[0215] (R)-3_(4-叔丁基苯基)-N-[l_(4-甲烷磺酰基氨基-3-乙烯基苯基)乙基]_2_甲基丙烯酰胺, [0215] (R) -3_ (4- tert-butylphenyl) -N- [l_ (4- methanesulfonyl-3-vinylphenyl) ethyl] _2_ methacrylamide,

[0216] N-{4-[3-(4-叔丁基苄基)脲基甲基]_2_氟_6_乙烯基苯基}甲烷磺酰胺, [0216] N- {4- [3- (4- tert-butylbenzyl) ureidomethyl] _2_ fluoro _6_ vinylphenyl} methanesulfonamide,

[0217] N-{4-[3-(4-叔丁基苄基)脲基甲基]-2-乙炔基_6_氟苯基}甲烷磺酰胺, [0217] N- {4- [3- (4- tert-butylbenzyl) ureidomethyl] -2-fluorophenyl} ethynyl _6_ methanesulfonamide,

[0218] 3-(4-叔丁基苯基)丙炔酸3-氟-4-甲烷磺酰基氨基_5_乙烯基苄基酰胺, [0218] 3- (4-tert-butyl-phenyl) propiolic acid 3-fluoro-4-methanesulfonyl-ylamino _5_ vinyl benzyl amide,

[0219] 3-(4-叔丁基苯基)-N-(4-甲烷磺酰基氨基_3_乙烯基苄基)丙烯酰胺, [0219] 3- (4-tert-butylphenyl) -N- (4- methanesulfonylamino-_3_ vinylbenzyl) acrylamide,

[0220] 3-[4_叔丁基-2-(2_甲氧基-乙氧基)_苯基]_N_(3_氟_4_甲烷磺酰基氨基-5-乙烯基-苄基)-丙烯酰胺, [0220] 3- [4 _ t-butyl-2- (2_ methoxy - ethoxy) phenyl _] _N_ (3_ fluoro _4_ methanesulfonylamino-5-vinyl-benzyl) - -Acrylamide,

[0221] 3-[4_叔丁基-2-(2_甲氧基乙基氨基)苯基]-N-(3_氟_4_甲烷磺酰基氨基-5-乙烯基苄基)丙烯酰胺, [0221] 3- [4 _ t-butyl-2- (2_ methoxyethyl) phenyl] -N- (3_ _4_ methanesulfonyl-fluoro-5-vinylbenzyl-yl) acrylamide amide,

[0222] 3- (4-叔丁基-2-甲氧基苯基)-N- (3_氟_4_甲烷磺酰基氨基_5_乙烯基-苄基)丙烯酰胺, [0222] 3- (4-tert-butyl-2-methoxyphenyl) -N- (3_ fluoro _4_ _5_ methanesulfonylamino-vinyl-benzyl) - acrylamide,

[0223] 3- (2-烯丙基氧基-4-叔丁基苯基)-N- (3_氟_4_甲烷磺酰基氨基_5_乙烯基苄基)丙烯酰胺, [0223] 3- (2-allyl-4-tert-butylphenyl) -N- (3_ fluoro _4_ _5_ methanesulfonylamino-vinylbenzyl) acrylamide,

[0224] (R)-3-(4-叔丁基苯基)-N-[1-(3-氟_4_甲烷磺酰基氨基_5_乙烯基苯基)乙基]丙烯酰胺, [0224] (R) -3- (4- tert-butylphenyl) -N- [1- (3- fluoro _4_ _5_ methanesulfonylamino-vinylphenyl) ethyl] acrylamide,

[0225] 3- (4-叔丁基苯基)-N- (3-氟_4_甲烷磺酰基氨基_5_乙烯基苄基)_2_甲基丙酰胺, [0225] 3- (4-tert-butylphenyl) -N- (3- methanesulfonylamino-fluoro _4_ _5_ vinylbenzyl) _2_ methylpropanamide

[0226] 3-[4_(叔丁基)苯基]-[N-4_(甲烷磺酰基氨基)]]_3_乙烯基苄基]丙酰胺, [0226] 3- [4_ (tert-butyl) phenyl] - [N-4_ (methane-sulfonylamino)]] _ 3_ vinyl benzyl] propanamide,

[0227] N-(4-{l-(R)-[3_(4-叔丁基苄基)脲基]乙基}_2_乙烯基苯基)甲烷磺酰胺, [0227] N- (4- {l- (R) - [3_ (4- tert-butyl-benzyl) ureido] ethyl} _2_ vinylphenyl) methanesulfonamide,

[0228] 3-[4_(叔丁基)苯基]-N-[3-氟-4-(甲烷磺酰基氨基)_5_乙烯基苄基]丙酰胺,和 [0228] 3- [4_ (tert-butyl) phenyl] -N- [3- fluoro-4- (methane-sulfonylamino) _5_ vinyl benzyl] propanamide, and

[0229] (R)-N-(4-{l-[3_(4-叔丁基苯基)脲基]乙基}_2_乙烯基苯基)甲烷磺酰胺。 [0229] (R) -N- (4- {l- [3_ (4- tert-butylphenyl) ureido] ethyl} _2_ vinylphenyl) methanesulfonamide.

[0230] 本发明的实施例化合物的结构显示在表1中。 [0230] Example Compound of the structure of the present invention is shown in Table 1.

[0231]【表1】 [0231] [Table 1]

Figure CN101142174BD00221
Figure CN101142174BD00231
Figure CN101142174BD00241
Figure CN101142174BD00251
Figure CN101142174BD00261
Figure CN101142174BD00271

[0238] 按照本发明的式(I)的化合物可以通过下列反应路线以化学方式进行合成。 [0238] can be synthesized chemically according to the present invention, compounds of formula (I) by the following reaction scheme. 然而,这些仅是出于举例说明本发明的目的给出,并不意欲限制它们。 However, these are merely for illustrative purposes of the present invention are given, they are not intended to limit.

[0239]【路线1】 [0239] [Route 1]

[0240] [0240]

Figure CN101142174BD00272

[0241] 上述路线1显示合成具有乙烯基或乙炔基的二苄基脲的方法。 [0241] The display method of Scheme 1 Synthesis of dibenzyl urea having a vinyl or ethynyl group. 首先,使取代的苄胺与二碳酸二叔丁酯反应以原位产生苄基氨基甲酸酯并向该反应混合物立即加入具有乙烯基或乙炔基的取代的苄胺(2)以产生具有乙烯基或乙炔基的二苄基脲(3)。 First, benzylamine with di-tert-butyl-substituted reaction in situ generated carbamate was added to the reaction mixture of a substituted benzylamine (2) having a vinyl or ethynyl immediately with ethylene to produce dibenzyl urea or acetylene group (3).

[0242]【路线2】 [0242] [Scheme 2]

[0243] [0243]

Figure CN101142174BD00281

[0244] 上述路线2显示合成脲衍生物的各种方法。 [0244] The method of Scheme 2 displays various urea derivatives. 首先,将4-硝基苄胺的Boc衍生物(4)还原产生苯胺化合物(5)。 First, the Boc derivatives of 4-nitrobenzyl amine (4) is reduced to produce aniline compound (5). 将碘基引入化合物(5)的氨基的相邻位置来产生化合物(6)。 The iodo group is introduced adjacent positions of Compound (5) to produce an amino compound (6). 化合物(5)的碘化作用还可以通过使用碘和硫酸银在0°C在氨基的邻位获得(Synth. Commun. 1992,22,3215-3219)。 Iodination of compound (5) may also be obtained (Synth. Commun. 1992,22,3215-3219) at 0 ° C and vicinal amino groups by using iodine and silver sulfate. 将乙烯基锡烷化合物偶联于化合物(6)以产生具有乙烯基的化合物(7)。 The stannane coupling a compound of the compound (6) to give compound (7) having a vinyl group. 将甲烷磺酰基引入化合物(7)的氨基以产生化合物(8)。 Introducing methane sulfonyl amino compound (7) to produce compound (8). 使用TFA(三氟乙酸)去除保护基(Boc)以产生苄胺化合物(9)。 Using TFA (trifluoroacetic acid) removal of the protecting group (Boc) benzylamine to produce the compound (9). 按照与路线1所述相似的方法合成二苄基脲衍生物(10)。 Dibenzyl urea derivative according to (10) the method of synthesizing a similar route.

[0245]【路线3】 [0245] [Route 3]

[0246] [0246]

Figure CN101142174BD00291

[0247] 在合成脲衍生物的各种反应中,上述路线3显示合成具有光学活性的脲衍生物的建议的方法。 [0247] In various urea derivatives were synthesized in the synthesis route 3 shows a method recommended urea derivative optically active. 按照上述路线3合成具有光学活性的脲化合物(17),其中将在R3位置具有甲基或乙基的反应体用作原材料。 According to the above Scheme 3 Synthesis of optically active compound having a urea (17), wherein the reaction body having methyl or ethyl as a starting material in the R3 position.

[0248]【路线4】 [0248] [Scheme 4]

[0249] [0249]

Figure CN101142174BD00292

[0250] 上述路线4显示合成丙烯酰胺化合物(19)的提议的方法。 [0250] The proposed synthesis routes 4 shows acrylamide compound (19) method. 将不饱和的芳基丙烯酸(18)和二乙基氰基膦酸酯溶解在DMF中并搅拌。 Unsaturated aryl acrylate (18) and diethyl cyano phosphonate was dissolved in DMF and stirred. 向该反应溶液中加入苄胺化合物(2) 并将得到的溶液搅拌过夜以产生丙烯酰胺化合物(19)。 To the reaction solution was added benzylamine compound (2) and the resulting solution was stirred overnight to produce acrylamide compound (19).

[0251]【路线5】 [0251] [5] route

[0252] [0252]

Figure CN101142174BD00293

[0253] 上述路线5显示合成丙烯酰胺化合物的另一种方法。 [0253] Scheme 5 above shows another method for the synthesis of acrylamide compound. 使用DMTMM{4-(4,6- 二甲氧基-1,3,5-三嗪-2-基)-4-甲基吗啉氯化物} (Tetrahedron Lett.,1999,40,5327)取代二乙基氰基膦酸酯来合成化合物(20)。 Using DMTMM {4- (4,6- dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride} (Tetrahedron Lett., 1999,40,5327) substituted diethyl cyano-phosphonate was synthesized compound (20).

[0254]【路线6】 [0254] [6] route

[0255] [0255]

Figure CN101142174BD00301

[0256] 上述路线6显示合成丙炔酰胺化合物(23)的推荐的方法。 [0256] Scheme 6 above show the recommended method for the synthesis propynyl amide compound (23). 使具有三键的酸化合物(22)与苄胺化合物(2)反应以产生目的化合物(23)。 The acid compound (22) with benzylamine compound (2) having a triple bond in the reaction to produce the object compound (23).

[0257]【路线7】 [0257] [7] route

[0258] [0258]

Figure CN101142174BD00302

[0259] 上述路线7显示合成丙烯酰胺衍生物(26)的推荐的方法。 [0259] Scheme 7 above show the recommended method for the synthesis of acrylamide derivative (26). 将在不饱和脂肪酸的烯位点具有各种取代基的脂肪酸酯化合物(24)水解以产生脂肪酸(25)。 Having various substituents at the site of an ethylenically unsaturated fatty fatty acid ester compound (24) is hydrolyzed to generate a fatty acid (25). 按照与路线4所述相同的方法,使用具有取代基的不饱和脂肪酸(25)来合成化合物(26)。 Having a substituent group according to the same manner as the route 4, the use of an unsaturated fatty acid (25) Synthesis of Compound (26).

[0260]【路线8】 [0260] [8] route

[0261] [0261]

Figure CN101142174BD00303

[0262] 上述路线8显示合成具有乙炔基取代基的丙烯酰胺化合物(34)的推荐的方法。 [0262] Scheme 8 shows the synthesis of the above-described preferred method of having a substituent ethynyl acrylamide compound (34). 首先,将碘引入苯胺化合物(28)的胺基的相邻位置以产生化合物(29)。 First adjacent positions, the iodine is introduced aniline compound (28) to produce amine compound (29). 还原碘化合物并且另外对苄胺进行Boc-保护以产生化合物(30)。 Further reduction of the iodine compound and benzyl amine Boc- protected to give compound (30). 还可以通过顺序进行还原和碘化作用来合成化合物(30)。 It may also be synthesized compound (30) by sequential reduction and iodination. 在用乙炔基取代化合物(30)的碘基后,将邻近苯的胺基用甲烷磺酰基处理以产生化合物(32)。 After a substituted ethynyl compound (30) is iodo, the group treated with the adjacent benzene methanesulfonyl group to yield compound (32). 将化合物(32)的Boc-保护基去除以制备苄胺化合物(33)。 Compound (32) of the Boc- protecting group removed to prepare the benzylamine compound (33). 将具有乙炔基取代基的苄胺化合物(33)与不饱和脂肪酸反应以产生丙烯酰胺化合物(34)。 The compound having a benzylamine substituent ethynyl (33) and unsaturated fatty acids reacted to produce acrylamide compound (34). [0263]【路线9】 [0263] [Route 9]

[0264] [0264]

Figure CN101142174BD00311

[0265] 上述路线9显示用乙炔基取代基合成脲化合物(35)的推荐的方法。 [0265] The method of Scheme 9 displays the recommended urea group compound (35) with a substituted ethynyl group.

[0266]【路线10】 [0266] [Scheme 10]

[0267] [0267]

Figure CN101142174BD00312

[0268] 上述路线10显示使用苄基异氰酸酯化合物合成脲化合物的新方法。 [0268] Scheme 10 above shows the new method of synthesis of urea compound benzyl isocyanate compound.

[0269]【路线11】 [0269] [Route 11]

[0270] [0270]

Figure CN101142174BD00313

[0271] 上述路线11显示合成各种脲衍生物的另外的反应。 [0271] The line 11 shows the synthesis of various further reaction of the urea derivative. 使具有各种取代基的苄胺化合物与(4-叔丁基-苄基)-氨基甲酸苯基酯反应以产生具有乙烯基的脲化合物(10)。 Benzylamine compound having various substituents and (4-tert - butylbenzyl) - carbamic acid phenyl ester The reaction to produce vinyl urea compound (10).

[0272]【路线12】 [0272] [Route 12]

[0273] [0273]

Figure CN101142174BD00314

[0274] 路线12显示合成具有乙烯基取代基的脲化合物(39)的推荐的方法。 [0274] Scheme 12 shows the synthesis method recommended having a vinyl group substituted urea compound (39).

[0275]【路线13】 [0275] [13] Route

[0276] [0276]

Figure CN101142174BD00321

[0277] 路线13显示合成具有乙烷磺酰基氨基的脲化合物的推荐的方法。 [0277] Scheme 13 shows the synthesis of a urea compound having the recommended method of ethanesulfonyl amino. 使苯胺化合物与2-氯乙烷磺酰氯反应以产生具有乙烯基磺酰基氨基的化合物(40)。 Aniline compound is reacted with 2-chloroethyl sulfonyl chloride to give compound (40) having the vinylsulfonyl group. 使化合物(40)与三丁基锡反应产生化合物(41)。 Compound (40) to produce the compound (41) is reacted with tributyltin. 去除化合物(41)的保护基以制备苄胺化合物(42)。 Removing the compound (41) protecting group to prepare a benzylamine compound (42). 使具有乙烯磺酰基氨基的苄胺化合物(42)与4-叔丁基苯基异氰酸酯反应以产生酰胺化合物(43)。 Benzylamine compound (42) having a vinylsulfonyl group is reacted with 4-tert-butylphenyl isocyanate to produce an amide compound (43).

[0278]【路线14】 [0278] [Route 14]

[0279] [0279]

Figure CN101142174BD00322

[0280] 路线14显示合成具有苯基乙炔基的脲化合物的推荐的方法。 [0280] Scheme 14 shows the synthesis of a urea compound having the recommended phenylethynyl group. 使碘苯胺化合物与苯基乙炔基通过sonogashira反应与苯基乙炔反应以产生化合物(44)。 Iodine and phenylethynyl aniline compound by reaction sonogashira reacted with phenylacetylene to give compound (44). 使化合物(44)与甲烷磺酰酐反应以产生化合物(45)。 Compound (44) is reacted with methanesulfonyl anhydride to give compound (45). 用TFA处理化合物(45)以产生苄胺化合物(46)。 Treating the compound with TFA (45) to produce a benzylamine compound (46). 将苯胺化合物(46)与苯基异氰酸酯反应以产生脲化合物(47)。 The aniline compound (46) and phenyl isocyanate were reacted to produce urea compound (47). 用Iindlar催化剂还原化合物(47)以制备具有苯基乙烷部分的脲化合物(48)。 Iindlar reduction catalyst with the compound (47) to prepare a urea compound (48) ethane phenyl moiety.

[0281]【路线I5】 [0281] I5 [Directions]

[0282] [0282]

Figure CN101142174BD00331

[0283] 路线15显示合成具有各种取代基的丙烯酰胺化合物。 [0283] Scheme 15 shows the synthesis of acrylamide compound having various substituents. 使3-叔丁基苯酚与NIS反应以产生化合物(50)。 3-tert-butylphenol with NIS reaction to give compound (50). 使化合物(50)与丙烯酸甲酯反应以产生化合物(51)。 Compound (50) Reaction with methyl acrylate to produce the compound (51). 使化合物(51)与烷基卤或烷氧基卤反应以产生化合物(52)。 Compound (51) is reacted with an alkyl halide or alkoxy halide to give compound (52). 在碱性条件下,水解化合物(52)。 Under alkaline conditions, hydrolysis of the compound (52). 化合物(53)与苄胺化合物反应以产生化合物(55)。 Compound (53) with benzylamine compound to produce compound (55).

[0284]【路线I6】 [0284] [path] I6

[0285] [0285]

Figure CN101142174BD00332

[0286] 路线16也显示合成具有各种取代基的丙烯酰胺化合物的推荐的方法。 [0286] Scheme 16 also shows the recommended method of synthesizing acrylamide compound with various substituents.

[0287]【路线17】 [0287] [Route 17]

[0288] [0288]

Figure CN101142174BD00333

[0289] 上述路线17显示合成丙酰胺化合物(61)的两种方法。 [0289] Scheme 17 above shows two propanamide Compound (61) method. 通过使用DEPC(二乙基氰基膦酸酯)或DMTMM来获得Amid化合物(61)。 Amid obtained compound (61) by using a DEPC-(diethyl cyanophosphonate) or DMTMM. [0290]【路线18】 [0290] [18] Route

[0291] [0291]

Figure CN101142174BD00341

[0292] 路线17显示合成(R)-N-[4-(1-氨基乙基)-2-氟-6-乙烯基苯基]甲烷磺酰胺(71)的方法。 [0292] Scheme 17 displays [2-fluoro-6-vinyl-phenyl-4- (1-aminoethyl)] methanesulfonamide (71) is synthesized (R) -N-. 将丁基乙烯基醚偶联于碘苯胺(62)以产生化合物(63)。 Butyl vinyl ether in the conjugated iodoaniline (62) to produce a compound (63). 化合物(62)的碘化作用通过使用NIS可以获得。 Iodination of compound (62) can be obtained by using NIS. 化合物(64)与(R)-(+)_2-甲基-2-丙烷-2-亚磺酰胺反应以产生2-甲基丙烷-2-亚磺酸[1-(4_氨基-3-氟-5-碘苯基)乙基]酰胺(65)。 Compound (64) and (R) - (+) _ 2- methyl-propane-2-sulfinamide reacted to produce 2-methylpropane-2-sulfinic acid [1- (4 _-amino-3- fluoro-5-iodo-phenyl) -ethyl] -amide (65). 用IN HCl溶液还原化合物(65)以产生化合物(67)。 Reducing the compound with a IN HCl solution (65) to produce a compound (67). 按照与路线3相似的方法合成化合物(71)。 Following a similar route method of synthesis of compound 3 (71).

[0293]【路线19】 [0293] [Route 19]

[0294] [0294]

Figure CN101142174BD00342

[0295] 路线17显示合成具体的不饱和的酰胺化合物(72),酰胺化合物(73)和脲化合物(74)的方法。 [0295] Scheme 17 displays a method amide compound (73) and the urea compound (74) (72) Synthesis of specific unsaturated amide compound.

[0296] 本发明还提供包含式⑴,(Ia),(Ib),(Ic)或(Id)的化合物,其异构体或其药用盐作为活性成分以及药用载体的药物组合物。 [0296] The present invention further provides a formula ⑴, (Ia), (Ib), (Ic) or (Id) is a compound, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier.

[0297] 在所述药物组合物中,作为活性成分的式(I), (Ia),(Ib),(Ic)或(Id)的化合物,其异构体,或其药用盐以及药用载体以有效量存在从而预防或治疗疼痛,急性痛,神经性疼痛,术后痛,偏头痛,关节痛,神经病,神经损伤,糖尿病性神经病,神经变性,中风,神经性/变应性/炎性皮肤病,银屑病,瘙痒症,痒疹,膀胱过敏,肠易激综合征,便急,局限性回肠炎,呼吸疾病如哮喘或慢性阻塞性肺病,皮肤、眼睛或粘膜的刺激,胃_十二指肠溃疡,炎性肠病或炎性疾病。 [0297] In the pharmaceutical composition, the formula (I) of the active ingredient, (Ia), (Ib), (Ic) or (Id) is a compound, an isomer thereof, or a pharmaceutically acceptable salt thereof and a drug The carrier is present in an amount effective to prevent or treat pain, acute pain, neuropathic pain, postoperative pain, migraine, arthralgia, neuropathies, nerve injury, diabetic neuropathy, neurodegeneration, stroke, neurotic / allergic / inflammatory skin disorders, psoriasis, pruritus, prurigo, irritable bladder, irritable bowel syndrome, fecal urgency, Crohn's disease, respiratory disease such as asthma or chronic obstructive pulmonary disease stimulation, skin, eyes or mucous membranes, stomach _ duodenal ulcer, inflammatory bowel disease or inflammatory disease. [0298] 本发明还提供药物组合物用于预防和治疗与病理性刺激和/或香草素受体的异常表达相关的疾病,其中所述组合物包含式(I),(la), (Ib),(Ic)或(Id)的化合物,其异构体或其药用盐;和药用载体。 [0298] The present invention further provides a pharmaceutical composition for preventing and treating the pathological stimulation and / or Ib aberrant expression of vanilloid receptor-related diseases, wherein said composition comprises the formula (I), (la), ( ), (Ic) or a compound (Id), an isomer thereof or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[0299] 本发明还提供药物组合物用于预防和治疗与香草素受体相关的病症,其中所述组合物包含式(I),(Ia),(Ib),(Ic)或(Id)的化合物,其异构体或其药用盐和药用载体。 [0299] The present invention further provides a pharmaceutical composition for the prevention and treatment of vanilloid receptor-associated disorder, wherein said composition comprises the formula (I), (Ia), (Ib), (Ic) or (Id) compound, an isomer thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0300] 在上述中,与香草素受体相关的所述病症是疼痛,偏头痛,关节痛,神经痛,神经病,神经损伤,皮肤疾病,膀胱过敏,肠易激综合征,便急,呼吸疾病,皮肤,眼睛或粘膜刺激, 胃_十二指肠溃疡,炎性疾病,耳病,或心脏病。 [0300] In the above, the condition associated with vanilloid receptor is pain, migraine, arthralgia, neuralgia, neuropathies, nerve injury, skin diseases, irritable bladder, irritable bowel syndrome, fecal urgency, respiratory disease, skin, eyes or mucous membrane irritation, stomach _ duodenal ulcers, inflammatory diseases, ear disease, or heart disease.

[0301 ] 更具体地,与香草素受体相关的所述病症是急性痛,慢性痛,神经性疼痛,术后痛, 风湿性关节痛,骨关节痛,带状疱疹后神经痛,糖尿病性神经病,HIV-相关的神经病,神经变性,中风,神经性/变应性/炎性皮肤病,银屑病,瘙痒症,痒疹,哮喘,慢性阻塞性肺病,尿失禁,炎性肠病,听觉过敏,耳鸣,前庭过敏,或变力性缺血。 [0301] More specifically, the condition related to vanilloid receptor is acute pain, chronic pain, nerve pain, post operative pain, rheumatic joint pain, bone and joint pain, postherpetic neuralgia, diabetic neuropathy, HIV-related neuropathy, neurodegeneration, stroke, neurotic / allergic / inflammatory skin disease, psoriasis, pruritus, prurigo, asthma, chronic obstructive pulmonary disease, urinary incontinence, inflammatory bowel disease, hearing allergy, tinnitus, vestibular allergies, or inotropic ischemia.

[0302] 在一个优选的方面,本发明提供药物组合物用于治疗选自下列各项的病症:疼痛, 关节的炎性疾病,包括关节的炎性自身免疫病,膀胱过敏,包括尿失禁,胃十二指肠溃疡,肠易激综合征(IBS)和炎性肠病(IBD),神经性/变应性/炎性皮肤病,银屑病,哮喘,慢性阻塞性肺病(COPD),瘙痒症,或痒疹,所述药物组合物包含按照式(I),(la), (Ib),(Ic)或(Id)任一项的化合物,其异构体或其药用盐,如上面进一步定义。 [0302] In a preferred aspect, the present invention provides a pharmaceutical composition for treating a condition selected from the following: pain, inflammatory joint diseases, inflammatory joint including autoimmune diseases, irritable bladder, including urinary incontinence, gastric ulcer, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), neurotic / allergic / inflammatory skin disease, psoriasis, asthma, chronic obstructive pulmonary disease (COPD), pruritus, or prurigo, the pharmaceutical composition comprising a compound according to formula (I), (la), (Ib), (Ic) or (Id) compound of any one, an isomer thereof or a pharmaceutically acceptable salt thereof, such as further defined above.

[0303] 更具体地,本发明的化合物可以用在药物组合物中,所述药物组合物用于治疗疼痛,其中所述疼痛是选自下列各项的病症:骨关节炎(“OA”),类风湿性关节炎(“RA”),强直性脊柱炎(“AS”),糖尿病性神经痛,术后痛,非炎性肌骨骼痛(包括纤维肌痛,肌筋膜痛综合征和背痛),偏头痛和其它类型的头痛或与其有关的疼痛。 [0303] More particularly, the compounds of the present invention can be used in a pharmaceutical composition, the pharmaceutical composition for treating pain, wherein said pain disorder is selected from the following: osteoarthritis ( "OA") , rheumatoid arthritis ( "RA"), ankylosing spondylitis ( "AS"), diabetic neuropathic pain, postoperative pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), migraine and other types of headaches, or pain associated therewith.

[0304] 如果认为本发明的化合物有效用于治疗与骨关节炎相关的疼痛,也不排除其还包括对骨关节炎的其它体征和症状的治疗。 [0304] If the compounds of the invention are considered useful in the treatment of pain associated with osteoarthritis, which does not rule out further comprising the treatment of other signs and symptoms of osteoarthritis. 除了减少与骨关节炎相关的疼痛之外,对骨关节炎的药学干预的目标可以是维持关节的运动性和使其的无能最小化。 In addition to reducing pain associated with osteoarthritis addition, certain pharmaceutical intervention of osteoarthritis can be maintained so that the joint motion and inability minimized.

[0305] 术语“关节的炎性疾病”包括涉及关节中或多或少程度的炎性过程的疾病,所述关节例如在膝盖,指,髋等中。 [0305] The term "inflammatory joint disease" includes diseases involving joints more or less degree of inflammatory processes, for example the knee joint, finger, hip, and the like. 这样的疾病的实例是骨关节炎。 Examples of such diseases are osteoarthritis. 术语“关节的炎性疾病”还包括可能涉及自身免疫过程的疾病或病症,诸如例如类风湿性关节炎或强直性脊柱炎。 The term "inflammatory joint disease" includes a disease or disorder may further involve autoimmune processes, such as for example rheumatoid arthritis or ankylosing spondylitis. 本发明对“关节的炎性疾病”的治疗的主要目标是治疗与这些病症相关的疼痛,但是目标也可以是直接或间接改善这些受影响的关节的功能,例如通过减少与所述关节的运动相关的疼痛。 The main objective of the present invention is the treatment of "inflammatory joint disease" is the treatment of pain associated with these conditions, but the target can be directly or indirectly affected by the function of improving these joints, for example by reducing the movement of the joint related pain.

[0306] 因此,向遭受所述关节的炎性疾病的患者施用本发明的化合物的一个结果是相对于在施用本发明的化合物或组合物之前受试者所遭受的疼痛,立即减少了遭受所述疾病的受试者经历的疼痛。 [0306] Accordingly, the present invention is administered to a patient suffering from an inflammatory disease of the joint of a compound that results in pain prior to administration with respect to the present invention, the subject compounds or compositions suffered, immediately reducing the suffering pain experienced by the subject of said disease. 所述治疗的另一个结果可以是预防疼痛的再发生,所述疼痛在以前已经因为药效或其它的治疗而得以减少。 Another outcome of treatment may be preventing recurrence of pain, a pain because of the efficacy or have other therapeutic and is reduced in the past. 治疗的另外的结果可以是减少涉及关节的炎性疾病的临床症状的发生和/或严重性,所述关节的炎性疾病特别包括骨关节炎,类风湿性关节炎强直性脊柱炎。 Further outcome of treatment may be to reduce the clinical symptoms of the inflammatory disease involving joint occurrence and / or severity of the diseases, particularly inflammatory joint including osteoarthritis, rheumatoid arthritis, ankylosing spondylitis. 所述治疗可以适当地导致关节功能的改善,诸如减少强直性,提高运动性。 The treatment may suitably result in improved joint function, such as reducing tonic to improve mobility.

[0307] 用于本文时,术语“骨关节炎(OA) ”典型地包括具有动关节性(可移动的,具有滑液的)关节的障碍的疾病。 [0307] As used herein, the term "osteoarthritis (OA)" typically include a (movable with the synovial fluid) movable joint disease of the joint disorder. 在原发性(原发)0A中,所述疾病的最常见的形式中,无素因性因素是显而易见的。 In primary (primary) 0A, the most common form of the disease, no predisposing factor is apparent. 继发性OA可归因于潜在的原因。 Secondary OA is attributable to the underlying cause. 疼痛和关节功能障碍是OA的主要症状。 Pain and joint dysfunction is the main symptom of OA. OA的关节疼痛经常被描述为深度疼痛并且定位于涉及的关节。 Joint pain of OA is often described as a deep ache and is positioned in the joints involved. 典型地,OA的疼痛因为关节的使用而恶化,通过休息减轻,但是,当疾病进展时,其可能会持续。 Typically, the pain of OA joint deteriorates because of the use by the break to reduce, but when disease progression, it is likely to continue. 干扰睡眠的夜间疼痛特别在髋的晚期OA中观察到,并可以减弱。 Interfere with sleep at night the pain is particularly observed in advanced OA of the hip in, and can be weakened. 在早上出现的或在休止状态时期后出现的涉及关节的强直性可能是显著的但是通常持续少于20分钟。 In the event of the morning or ankylosing involved in the joint after resting state during the appearance may be significant but usually lasts less than 20 minutes.

[0308] 术语“RA”指类风湿性关节炎。 [0308] The term "RA" refers to rheumatoid arthritis. RA是导致免疫系统攻击关节特别是关节中的滑膜的慢性炎性自身免疫病。 RA is an immune system to attack the joints leading to joint synovial particularly a chronic inflammatory autoimmune disease. 滑膜发炎并导致肿胀和疼痛。 Synovial inflammation and cause swelling and pain. RA的主要症状是关节疼痛和强直但是另外的症状包括肌肉疼痛,贫血和发烧。 The main symptoms of RA are joint pain and stiffness, but additional symptoms include muscle pain, anemia, and fever. RA的诊断可以通过检测血液中被称为“风湿性(“风湿样”)因子”的抗体和/或通过血沉测试得到证实。 RA diagnostic antibody may be called "rheumatic (" rheumatoid ") by detecting a blood factor" and / or erythrocyte sedimentation rate was confirmed by the test. 其它的有用的和常见的测试是检测“抗核抗体”或“C-反应性蛋白”。 Other common and useful test is the detection of "anti-nuclear antibody" or "the C-reactive protein."

[0309] “AS”代表强直性脊柱炎,其是慢性,进展性的自身免疫病,其特征在于关节炎,炎症和关节特别是脊椎关节的最终的不能移动。 [0309] "AS" representative of ankylosing spondylitis, autoimmune disease which is a chronic, progressive, characterized in that the end can not move arthritis, inflammation of joints and in particular of the vertebral joint. 作为脊椎关节(椎骨)的进行中的肿胀和刺激的结果,其导致背部的疼痛和强直(通常在早晨的时候)。 As a result of the spinal joints (vertebrae) in the swelling and irritation, which results in pain and stiffness of the back (usually in the morning time). 连接并给椎骨提供支持的腱和韧带的炎症可导致肋骨,肩胛骨,髋,大腿,胫骨,足跟以及沿脊柱的骨点的疼痛和触痛。 And connecting the vertebrae to provide support for the tendons and ligaments inflammation can lead to pain and tenderness bone points ribs, shoulder blades, hips, thighs, tibia, as well as along the spine of the heel.

[0310] 如果认为按照本发明的化合物用在治疗与关节的炎性自身免疫病相关的疼痛中, 这是指施用本发明的化合物或本发明的化合物的组合以减少由遭受关节的炎性自身免疫病的受试者所经历的至少一种疼痛症状,其包括与RA或AS相关的背痛,关节疼痛和肌肉疼痛。 [0310] If the compounds according to the invention that is used in the treatment of pain associated with inflammatory autoimmune diseases of joints, which refers to a combination of administration of compounds of the invention or the present invention to reduce the suffering from inflammatory joint itself at least one autoimmune disease pain experienced by the subject, including back pain, muscle pain and pain associated with RA or aS. 除了减轻疼痛之外,关节的炎性自身免疫病的治疗还可以包括特别是在遭受RA或AS 的患者中减少滑膜的炎症和/或肿胀并有助于改善关节的功能性(即维持运动性,并使无能最小化)。 In addition to reducing pain than treatment of an inflammatory autoimmune disease of joints may also include, in particular to reduce the synovium in patients suffering from RA or AS of inflammation and / or swelling and help improve the functionality of the joint (i.e., maintaining the movement sex, impotence and minimized).

[0311] “非炎性肌骨骼疼痛的治疗”指施用本发明的化合物或本发明的化合物的组合以减轻由遭受非炎性肌骨骼疼痛的受试者经历的疼痛,所述非炎性肌骨骼疼痛包括背痛,纤维肌痛,和肌筋膜疼痛综合征。 [0311] "non-inflammatory musculoskeletal pain treatment" refers to administering a combination of compounds of the invention or the present invention to alleviate the pain suffered by the subject non-inflammatory musculoskeletal pain experienced by the non-inflammatory muscle bone pain including back pain, fibromyalgia, and myofascial pain syndrome. 治疗的一个结果可以是相对于施用本发明的化合物或组合物之前,立即减轻由受试者所经历的疼痛。 One outcome of treatment may be administered prior to the present invention with respect to a compound or composition, immediately alleviate the pain experienced by the subject. 治疗的另一个的结果可以是预防疼痛的再发生, 所述疼痛在以前因为药效而被减轻。 Another outcome of treatment may be preventing recurrence of pain, the pain is alleviated because the efficacy is previously. 治疗的另一个的结果可以是减少涉及非炎性肌骨骼疼痛包括背痛,纤维肌痛,和肌筋膜疼痛综合征的临床症状的发生和/或严重性。 Another outcome of treatment may reduce the incidence and / or severity relates to non-inflammatory musculoskeletal pain including back pain, fibromyalgia, myofascial pain syndrome and symptoms of. 所述治疗可以适当地导致增加的肌肉敏感性的减少,所述增加的肌肉敏感性的特征在于由在正常情况下非伤害性刺激所引发的疼痛(异常性疼痛)或由伤害性刺激所引发的增加的疼痛的强度(痛觉过敏)。 The treatment may suitably result in a reduction of muscle increases sensitivity, the increased muscle sensitivity is characterized by pain caused by non-noxious stimuli normally caused (allodynia) or caused by a noxious stimuli the increased intensity of pain (hyperalgesia). 最终,非炎性肌骨骼疼痛的治疗还可以改善与背痛,纤维肌痛,和肌筋膜疼痛综合征有关的相关症状。 Finally, non-inflammatory musculoskeletal pain therapy can also improve the symptoms associated with back pain, fibromyalgia and myofascial pain syndrome.

[0312] 术语“纤维肌痛”或“FMS”涉及这样的综合征,其导致遍布支持和移动骨和关节的组织中的泛发的疼痛和强直。 [0312] The term "fibromyalgia" or "the FMS" relates to a syndrome, which results in moving across the support bones and joints and tissues generalized pain and stiffness. 纤维肌痛可以通过向18个特异性肌肉-腱位点中的至少11 个施加压力后过度触痛的存在而诊断。 Tendon site at least 11 after an excessive pressure is applied to the diagnosis of the presence of tender - fibromyalgia may be specific to muscle through 18.

[0313] “肌筋膜疼痛综合征”是慢性,非变性非炎性肌骨骼疼痛病症。 [0313] "myofascial pain syndrome" is a chronic, non-degenerative non-inflammatory musculoskeletal pain condition. 在肌肉中的独特的区域或它们的细软的结缔组织覆盖物(筋膜)变得异常增厚或紧绷。 Covering the muscle or unique region thereof was soft connective tissue (fascia) become abnormally thickened or tight. 当所述肌筋膜组织拉紧并失去它们的弹性时,能在脑和身体之间发送和接收信息的神经递质受到损伤。 When the myofascial tissues tighten and lose their elasticity, it can be transmitted and received between the body and the brain neurotransmitter nerve damage information. 症状包括在远离触发点的区域中的肌肉强直和疼痛和急剧的刺激痛或麻刺感和麻木感。 Symptoms include muscle rigidity and pain and sharp pain or irritation tingling and numbness in areas away from the trigger point of. 最常见的触发点在颈,背部或臀部中。 The most common trigger points in the neck, back or buttocks.

[0314] “背痛”是常见的非炎性肌骨骼疼痛病症,其可以是急性或慢性的。 [0314] "back pain" is a common non-inflammatory musculoskeletal pain conditions, which can be acute or chronic. 其可以由影响腰椎的多种疾病和病患所导致。 It may be caused by the influence of a variety of diseases and disorders of the lumbar spine. 下背痛通常伴随坐骨神经痛,这是涉及坐骨神经的疼痛并在下背,臀部和大腿背部感觉到。 Lower back pain is often accompanied by sciatica, which is pain involves the sciatic nerve and the lower back, hips and thighs back feel.

[0315] 本发明的化合物还用于治疗活动过度的膀胱的体征和症状如尿失禁,更具体的是紧迫性尿失禁,压力性尿失禁,尿急,夜尿症和/或尿频。 Compound [0315] of the present invention are also useful in the treatment of over active bladder signs and symptoms such as urinary incontinence, and more specifically urge incontinence, stress incontinence, urgency, nocturia, and / or frequent urination.

[0316] 按照本发明的药物组合物优选地用于口服施用。 [0316] The pharmaceutical compositions of the present invention are preferably for oral administration. 备选地,如果要治疗皮肤病,包含本发明化合物的药物组合物还可以被配制用于局部或经皮使用。 Alternatively, if you want to treat skin diseases, comprising a compound of the present invention the pharmaceutical composition may also be formulated for topical or transdermal use.

[0317] 在另一个方面中,本发明涉及在患者中抑制香草素配体结合香草素受体的方法, 所述方法包括使在患者中表达香草素受体的细胞与式(I),(Ia),(Ib),(Ic)或(Id)的化合物,其异构体,或其药用盐接触。 [0317] In another aspect, the present invention is a method of vanilloid ligand binding relates to inhibiting vanilloid receptor in a patient, said method comprising contacting cells expressing the formula (I) vanilloid receptor in a patient, ( Ia), (Ib), (Ic) or a compound (Id), an isomer thereof, or a pharmaceutically acceptable salt thereof.

[0318] 在另一个方面中,本发明涉及预防或治疗选自下列各项的疾病的方法:疼痛,偏头痛,关节痛,神经病,神经损伤,皮肤疾病,膀胱过敏,肠易激综合征,便急,呼吸疾病,皮肤、 眼睛或粘膜刺激,胃-十二指肠溃疡,炎性疾病,所述方法包括向需要其的包括人的哺乳动物施用治疗有效量的式(I),(Ia),(Ib),(Ic)或(Id)的化合物,其异构体,或其药用盐。 [0318] In another aspect, the present invention relates to a method for preventing or treating a disease selected from the following: pain, migraine, arthralgia, neuropathies, nerve injury, skin diseases, irritable bladder, irritable bowel syndrome, fecal urgency, a respiratory disease, skin, eye or mucous membrane irritation, stomach - duodenal ulcer, inflammatory diseases, said method comprising administering to a mammal in need thereof, including a human a therapeutically effective amount of a formula (I), (Ia ), (Ib), (Ic) or (Id) is a compound, an isomer thereof, or a pharmaceutically acceptable salt thereof.

[0319] 在上述方法中,所述疾病还选自急性痛,慢性痛,神经性疼痛,术后痛,糖尿病性神经病,神经变性,中风,神经性/变应性/炎性皮肤病,银屑病,瘙痒症,痒疫,哮喘,慢性阻塞性肺病,尿失禁或炎性肠病。 [0319] In the above method, the disease is further selected from acute pain, chronic pain, neuropathic pain, post-operative pain, diabetic neuropathy, neurodegeneration, stroke, neurotic / allergic / inflammatory skin disease, silver psoriasis, pruritis, itchy Phytophthora, asthma, chronic obstructive pulmonary disease, inflammatory bowel disease or urinary incontinence.

[0320] 在本发明的一个优选方面中,上述方法是治疗这样的疼痛,所述疼痛是选自下列各项的病症或是与其有关的疼痛:骨关节炎(“OA”),类风湿性关节炎(“RA”),强直性脊柱炎(“AS”),糖尿病性神经性疼痛,非炎性肌骨骼痛(包括纤维肌痛,肌筋膜痛综合征和背痛),术后痛,偏头痛和其它类型的头痛。 [0320] In a preferred aspect of the present invention, the above method is the treatment of such pain, the pain is selected from the disorder or pain associated therewith: osteoarthritis ( "OA"), rheumatoid arthritis ( "RA"), ankylosing spondylitis ( "AS"), diabetic neuropathic pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), post-operative pain , migraine and other types of headaches.

[0321] 在另一个方面中,本发明涉及式(I), (Ia),(Ib),(Ic)或(Id)的化合物,其异构体,或其药用盐作为香草素受体的拮抗剂的应用。 [0321] In another aspect, the present invention relates to formula (I), (Ia), (Ib), (Ic) or (Id) is a compound, an isomer thereof, or a pharmaceutically acceptable salt thereof as vanilloid receptor application antagonists.

[0322] 在另一个方面中,本发明涉及式(I), (Ia),(Ib),(Ic)或(Id)的化合物,其异构体,或其药用盐用于预防或治疗涉及香草素受体的病症的应用,所述病症更具体地与香草素受体的异常表达和/或异常激活相关。 [0322] In another aspect, the present invention relates to formula (I), (Ia), (Ib), (Ic) or (Id) is a compound, an isomer thereof, or a pharmaceutically acceptable salt thereof for preventing or treating application of a disorder relates to vanilloid receptor, more particularly the condition with abnormal expression of vanilloid receptors and / or associated with abnormal activation.

[0323] 在另一个方面中,本发明涉及式(I), (Ia),(Ib),(Ic)或(Id)的化合物,其异构体,或其药用盐在制备药物中的应用,所述药物用于预防或治疗涉及香草素受体的病症。 [0323] In another aspect, the present invention relates to formula (I), (Ia), (Ib), (Ic) or (Id) is a compound, an isomer thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament application of a medicament for the prevention or treatment of a disorder involving the vanilloid receptor.

[0324] 在优选的方面中,本发明涉及式(I),(la), (Ib),(Ic)或(Id)的化合物,其异构体,或其药用盐在制备用于预防或治疗选自下列各项的病症的药物中的应用,所述病症选自疼痛,关节的炎性自身免疫病,膀胱过敏包括尿失禁,胃十二指肠溃疡,肠易激综合征(IBS)和炎性肠病(IBD),神经性/变应性/炎性皮肤病,银屑病,哮喘,慢性阻塞性肺病(COPD),瘙痒症,或痒疹。 [0324] In a preferred aspect, the present invention relates to formula (I), (la), (Ib), (Ic) or a compound (Id), an isomer thereof, or a pharmaceutically acceptable salt thereof in preparation for the prevention or application of a condition selected from the medicament treatment of a disorder selected from pain, inflammatory autoimmune diseases of the joints, irritable bladder including urinary incontinence, stomach duodenal ulcer, irritable bowel syndrome (IBS ) and inflammatory bowel disease (IBD), neurotic / allergic / inflammatory skin disease, psoriasis, asthma, chronic obstructive pulmonary disease (COPD), pruritus or prurigo.

[0325] 在特别优选的方面中,本发明涉及使用化合物用于治疗上述疼痛,其中所述疼痛是选自下列各项的病症:骨关节炎(“0A”),类风湿性关节炎(“RA”),强直性脊柱炎(“AS”),糖尿病性神经性疼痛,术后痛,非炎性肌骨骼痛(包括纤维肌痛,肌筋膜痛综合征和背痛),偏头痛和其它类型的头痛,或是与其有关的疼痛。 [0325] In a particularly preferred aspect, the present invention relates to the above compounds for treating pain, wherein said pain disorder is selected from the following: osteoarthritis ( "0A"), rheumatoid arthritis ( " RA "), ankylosing spondylitis (" AS "), diabetic neuropathic pain, postoperative pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), migraine and other types of headaches, or pain associated therewith.

[0326] 在下文,将描述配制方法和各种赋形剂,但是本发明并不受限于它们。 [0326] Hereinafter, various excipients and formulation methods will be described, but the present invention is not limited to them.

[0327] 可以将按照本发明的式(I),(Ia),(Ib),(Ic)或(Id)的化合物,其异构体或其药用盐制备为包含药用载体,辅剂,稀释剂等的药物组合物。 [0327] may be in accordance with formula (I) of the present invention, (Ia), (Ib), (Ic) or (Id) of the compound prepared isomer thereof, or a pharmaceutically acceptable salt comprising a pharmaceutically acceptable carrier, adjuvant , diluents and other pharmaceutical compositions. 例如,可以将本发明的化合物溶解在油,丙二醇,或其它的通常用于产生注射剂的溶剂中。 For example, the compounds of the present invention may be dissolved in oils, propylene glycol or other solvents commonly used to produce injectables. 载体的适合的实例包括生理盐水,聚乙二醇,乙醇,植物油,十四烷基异丙酯等,但是并不受限于它们。 Examples of suitable carriers include physiological saline, polyethylene glycol, ethanol, vegetable oils, isopropyl tetradecyl, but is not limited to them. 对于局部施用,可以将本发明的化合物以软膏剂或乳膏剂的形式进行配制。 For topical administration, the compounds of the present invention may be formulated as ointments or creams.

[0328] 还可以将按照本发明的化合物以其药用盐的形式进行使用,并可以单独或组合或混合其它的药用活性化合物使用。 [0328] may be further compounds according to the invention in the form of pharmaceutically acceptable salts, and may be used alone or in combination, or mixed with other pharmaceutically active compounds.

[0329] 本发明的化合物可以通过在水溶性溶剂如盐水和5%右旋糖中或在不溶于水的溶剂如植物油,合成的甘油脂肪酸酯,更高级的脂肪酸酯和丙二醇中溶解,悬浮或乳化而配制成注射剂。 Compounds of the invention [0329] can be prepared by a water-soluble solvent such as saline and 5% dextrose or dissolved in a water-insoluble solvent such as vegetable oil, synthetic glycerol fatty acid esters, higher fatty acid esters and propylene glycol, formulated into a suspended or emulsified injections. 本发明的制剂可以包括任一种常用的添加剂,如溶解剂,等渗剂,悬浮剂,乳化齐U,稳定剂和防腐剂。 Formulations of the invention may comprise any of the conventional additives such as dissolving agents, isotonic agents, suspending agents, emulsifying homogeneous U, stabilizers and preservatives.

[0330] 按照本发明的化合物的优选的剂量水平取决于各种因素包括,患者的状况和体重,具体疾病的严重性,剂型,和给药途径和时期,但是可以由本领域技术人员适当地选择。 [0330] According to a preferred dose level depends on the compounds of the present invention comprises a variety of factors, body weight and condition of the patient, the severity of the particular disease, dosage form, and route and period, but may be suitably selected by those skilled in the art . 本发明的化合物优选地以在0. OOl-lOOmg/kg体重/天,更优选地0. 01-30mg/kg体重/天范围内的量进行给药。 The compounds of this invention are preferably in the 0. OOl-lOOmg / kg body weight / day, more preferably 0. 01-30mg / amount / day kg of body weight is administered. 给药可以是一天一次或用每个分剂量一天数次。 Administration may be once a day or several times in divided doses with each day. 本发明的化合物以基于组合物的总量的0. 0001〜10重量%,优选地0. 001〜1重量%的量用在药物组合物中。 Compounds of the present invention in 0. 0001~10 by weight based on the total composition%, preferably 0.5% by weight 001~1 used in pharmaceutical compositions.

[0331] 本发明的药物组合物可以通过各种途径施用于哺乳动物受试者,如大鼠,小鼠,家畜,人等。 The pharmaceutical composition of [0331] the present invention may be administered to a mammalian subject such as rat, mouse, domestic animals, human and the like through various routes. 可以容易地预期的施用方法包括口服和直肠施用;静脉内,肌内,皮下,子宫内,硬脑膜和脑室内注射。 It can be readily contemplated methods of administration include oral and rectal administration; intravenous, intramuscular, subcutaneous, intrauterine, and intraventricular injection dura.

[0332] 本发明定义的详述 [0332] The present invention is defined in the Detailed Description

[0333] 当描述化合物,包含所述化合物的药物组合物,使用这些化合物和组合物的方法, 和这些化合物和组合物的应用时,用在本申请中的所有的术语都具有本领域相关技术人员,例如医学化学师,药剂师或医师通常所用的含义。 [0333] When describing the compounds, pharmaceutical compositions comprising said compounds, methods of using these compounds and compositions, and the use of these compounds and compositions, all terms used in this application have the related art of the present art personnel, such as the meaning of medical chemists, pharmacists or physicians commonly used. 作为实例,在下面给出具体基团的一些定义: As an example, in the following some definitions of specific groups:

[0334]“烷基"包括单价饱和的脂族烃基。 [0334] "Alkyl" includes monovalent saturated aliphatic hydrocarbon group. 烃基链可以是直链或支链的。 Hydrocarbon chain may be straight or branched. 该术语由基团如甲基,乙基,正丙基,异丙基,正丁基,异丁基,叔丁基所例示。 This term was coined by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl illustrated.

[0335]“烷氧基"包括基团-0R,其中R是烷基。 [0335] "Alkoxy" includes the group -0R, wherein R is alkyl. 具体的烷氧基包括,作为实例,甲氧基, 乙氧基,正丙氧基,异丙氧基,正丁氧基,叔丁氧基,仲丁氧基,正戊氧基,1,2- 二甲基丁氧基寸。 Particular alkoxy groups include, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentyloxy, 1, 2- dimethylbutoxy inch.

[0336]“链烯基"包括单价烯属的不饱和的烃基,其是直链或支链的并具有至少一个双键。 [0336] "alkenyl" includes monovalent unsaturated olefinic hydrocarbon group, which is linear or branched and having at least one double bond. 具体的链烯基包括乙烯基(-CH = CH2),正丙烯基(-CH2CH = CH2),异丙烯基(C(CH3)= CH2),等。 Specific alkenyl groups include ethenyl (-CH = CH2), n-propenyl (-CH2CH = CH2), isopropenyl (C (CH3) = CH2), and the like. 优选的“链烯基”是乙烯基(乙烯基)。 Preferred "alkenyl" are vinyl (ethenyl).

[0337]“炔基"包括炔属的不饱和的烃基,其是直链或支链的,并具有至少一个三键。 [0337] "Alkynyl" includes acetylenically unsaturated hydrocarbon group which is straight or branched and having at least one triple bond. 优选的炔基是乙炔基(乙炔)。 Preferred alkynyl group is ethynyl (acetylene).

[0338] “烷基氨基”包括基团-NR' R",其中-R'是烷基而R"选自氢或烷基。 [0338] "Alkylamino" includes the group -NR 'R ", wherein -R' is an alkyl group and R" is selected from hydrogen or alkyl.

[0339]“烷基磺酰基"包括原子团-S (O)2R,其中R是如本文定义的烷基。 [0339] "Alkylsulfonyl" includes a radical -S (O) 2R, wherein R is an alkyl group as defined herein. 代表性的实例包括,但不限于,甲烷磺酰基,乙基磺酰基,丙基磺酰基,丁基磺酰基等。 Representative examples include, but are not limited to, methanesulfonyl group, ethylsulfonyl group, propylsulfonyl group, butylsulfonyl group and the like.

[0340]''烷硫基〃包括原子团-SR,其中R是如本文定义的烷基,可以任选地如本文定义被取代。 [0340] '' alkylthio radicals include 〃 -SR, wherein R is alkyl as defined herein, may be optionally substituted as defined herein. 代表性实例包括,但不限于甲硫基,乙硫基,丙硫基,丁硫基等。 Representative examples include, but are not limited, methylthio, ethylthio, propylthio, butylthio and the like.

[0341]“氨基〃指原子团-NH2. [0341] "Amino 〃 atomic group -NH2.

[0342]“羧基〃指原子团-C( = 0)0H。[0343]“乙烯基〃指-CH = CHs,其在本申请中也被称为“乙烯基”。 [0342] "Carboxy refers to the radical 〃 -C (= 0) 0H. [0343]" refers to vinyl 〃 -CH = CHs, which is also referred to herein as the "vinyl."

[0344] 〃乙炔基〃指-Ce CH。 [0344] ethynyl 〃 〃 means -Ce CH.

[0345]“卤代"或"卤素"指氟,氯,溴和碘。 [0345] "Halo" or "halogen" refers to fluoro, chloro, bromo and iodo. 优选的卤素基团是氟或氯。 Preferred halo groups are fluoro or chloro.

[0346] “卤烷基”包括如上文进一步定义的“烷基”,其被一个或多个卤素取代,所述卤素可以是相同的,例如在三氟甲基或五氟乙基中,或其可以是不同的。 [0346] "haloalkyl" includes "alkyl" as defined further above, which is substituted with one or more halogens, the halogens may be the same, for example, trifluoromethyl or pentafluoroethyl, or in it can be different.

[0347]“羟基〃指原子团-0H. [0347] "refers to a hydroxyl radical 〃 -0H.

[0348] 〃硝基〃指原子团-NO2. [0348] Nitro 〃 〃 atomic group -NO2.

[0349] “哌啶基(C1-C5)氧基”指结合于如上文进一步定义的“烷氧基”的哌啶基残基,其中所述哌啶基优选地通过氮原子或通过哌啶环的对位-C-原子连接于“烷氧基”的C原子。 [0349] "piperidinyl (C1-C5) group" means a piperidinyl residue as defined further above in conjunction with the "alkoxy", wherein the piperidinyl or preferably via a nitrogen atom by piperidine -C- atom attached to the para position "alkoxy" C-atoms of the ring.

[0350] “吗啉基(C1-C5)烷氧基”指结合于“烷氧基”的吗啉残基,其中所述吗啉环优选地通过吗啉环的氮原子结合于“烷氧基”的C原子。 [0350] "morpholino (C1-C5) alkoxy" refers to a binding morpholinyl residue "alkoxy", wherein said morpholine ring is preferably morpholino ring nitrogen atom by binding to a "alkoxy group "C atoms.

[0351] “四氢吡喃基氧基”指结合于氧代(-0-)基的四氢吡喃基,其中所述氧代基团优选地结合于四氢吡喃基的对位C原子。 [0351] "tetrahydropyranyloxy" refers to a binding oxo (-0-) group, tetrahydropyranyl group, wherein the oxo group is preferably bonded to the para position tetrahydropyranyl C atom.

[0352] “烷基哌嗪基”指携带“烷基”作为取代基的哌嗪环。 [0352] "piperazinyl" refers to carry "alkyl" as a substituent of the piperazine ring. 优选地所述哌嗪环结合于“烷基”并且通过其氮原子连接于第二连接位点。 Preferably the piperazine ring bound to "alkyl" and by the nitrogen atom attached to the second attachment sites.

[0353] “哌啶基氧基”指结合于氧代(-0-)基的哌啶基,其中所述氧代基团优选地结合于所述哌啶基的对位C原子。 [0353] "piperidinyl group" refers to a binding oxo (-0-) piperidinyl group, wherein the oxo group is preferably bonded to the para position of the piperidinyl C atoms.

[0354] “药用”意味着由联邦或政府的调控机构批准或在美国药典或其它通用药典中列出的用于动物和更具体地用于人。 [0354] "pharmaceutically acceptable" means approved by the federal government or regulatory agency or listed in the US Pharmacopeia or other common pharmacopoeia for use in animals and more particularly in humans.

[0355]“药用盐"指本发明的化合物的盐,其是药用的并具有母体化合物的理想的药理活性。 [0355] "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention, which are pharmaceutically acceptable and have the desired pharmacological activity of the parent compound. 这些盐包括:(1)与无机酸,如盐酸,氢溴酸,硫酸,硝酸,磷酸等形成的酸加成盐;或与有机酸,如乙酸,丙酸,己酸,环戊烷丙酸,羟基乙酸,丙酮酸,乳酸,丙二酸,琥珀酸,苹果酸,马来酸,富马酸,酒石酸,柠檬酸,苯甲酸,3- (4-羟基苯甲酰)苯甲酸,肉桂酸,扁桃酸, 甲烷磺酸,乙烷磺酸,1,2-乙烷-二磺酸,2-羟基乙烷磺酸,苯磺酸,4-氯苯磺酸,2萘磺酸, 4-甲苯磺酸,樟脑磺酸,4甲基二环[2. 2. 2]-辛-2-烯-1-羧酸,葡庚糖酸,3-苯基丙酸,三甲基乙酸,叔丁基乙酸,十二烷基硫酸,葡糖酸,谷氨酸,羟基萘甲酸,水杨酸,硬脂酸,粘康酸等形成的酸加成盐;或(2)当在母体化合物中存在的酸性质子被取代时形成的盐。 Such salts include: (1) with an inorganic acid, an acid addition salt such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric and the like; or with organic acids, such as acetic acid, propionic acid, hexanoic acid, cyclopentane propionic acid , glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid , mandelic acid, methanesulfonic acid, ethanesulfonic acid, ethane-1,2 - disulfonic acid, 2-hydroxy ethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2 naphthalenesulfonic acid, 4 toluenesulfonic acid, camphorsulfonic acid, 4-methyl-bicyclo [2.2.2] - oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary acid addition salts formed butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like; or (2) when the parent compound salts formed when an acidic proton present in substituted.

[0356]“药用载体"指借助其施用本发明化合物的稀释剂,辅剂,赋形剂或载体。 [0356] "pharmaceutically acceptable carrier" refers to administering a compound of the present invention by means of which a diluent, adjuvant, excipient or carrier.

[0357]“预防"指减少获得疾病或病患的风险(即导致疾病的至少一种临床症状在受试者中不发展,所述受试者可以暴露于或易感于所述疾病,但是尚未体验该疾病或显示该疾病的症状)。 [0357] "Preventing" refers to reducing the risk of acquiring a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject, the subject may be exposed to or predisposed to the disease but have not yet experienced the disease or show symptoms of the disease).

[0358]“受试者"包括人。 [0358] "Subject" includes humans. 术语"人,“患者"和"受试者"在本文互换使用。 The term "human" patient "and" subject "are used interchangeably herein.

[0359]“治疗有效量"指当施用于受试者治疗疾病时,足以对该疾病发挥治疗作用的化合物的量。 [0359] "therapeutically effective amount" means that when administered to a subject for treating a disease, is sufficient to play amount of a compound of the disease therapeutic effect. “治疗有效量"可以取决于化合物,疾病和其严重性,和待治疗的受试者的年龄,体重等而发生变化。 "Therapeutically effective amount" may be dependent on the compound, the age of the disease and its severity, and the subject to be treated, weight, etc., vary.

[0360] “治疗”任何疾病或病患指在一个实施方案中改善所述疾病或病患(S卩,阻滞或减少疾病的发展或其至少一种临床症状)。 [0360] "treatment" of any disease or disorder refers to ameliorating the disease or disorder (S Jie, arresting or reducing the development of the disease or at least one of the clinical symptoms) in one embodiment. 在另一个实施方案中,“治疗”指改善至少一种身体参数,其可能不由受试者识别。 In yet another embodiment, "treatment" refers to ameliorating at least one physical parameter, which may help to identify the subject. 在另一个实施方案中,“治疗”指调控疾病或病患,身体地(例如,可辨别症状的稳定),生理地(例如身体参数的稳定)或两者。 In yet another embodiment, "treatment" refers regulatory disease or disorder, the body (e.g., stabilization of a discernible symptom), physiologically (e.g., stabilization of a physical parameter), or both. 在另一个实施方案中,“治疗”指减缓疾病或病患的发作。 In yet another embodiment, "treating" refers to slowing the onset of a disease or disorder.

[0361] 实施本发明的方式 [0361] embodiment of the present invention.

[0362] 本发明通过下列实施例和经验例更具体地阐述。 [0362] The invention is explained more specifically by the following Examples and Examples experience. 然而,应该理解的是本发明的范围不受限于下列的实施例和经验例。 However, it should be understood that the scope of the present invention is not limited to the following embodiment examples and experience.

[0363] 实施例1 :N-{4-[3-(4-叔丁基苄基)脲基甲基]_2_乙烯基苯基}甲烷磺酰胺 [0363] Example 1: N- {4- [3- (4- tert-butylbenzyl) ureidomethyl] _2_ vinylphenyl} methanesulfonamide

[0364] [0364]

[0365] 步骤1 : (4-硝基苄基)氨基甲酸叔丁酯 [0365] Step 1: (4-nitrobenzyl) carbamate

[0366] 将4-硝基苄胺HCl(lg,5. 302mmOl,leq.)置于IOOml圆底烧瓶中并溶解于饱和溶液(NaHCO3 : CH2Cl2 = 1 : 1)。 [0366] 4-Nitro-benzylamine HCl (.. Lg, 5 302mmOl, leq) was placed IOOml round bottom flask and dissolved in a saturated solution (NaHCO3: CH2Cl2 = 1: 1). 向该溶液加入二碳酸二叔丁酯(3. 66ml,15. 906mmol,3eq.) 并搅拌3小时。 To this solution was added di-tert-butyl dicarbonate (3. 66ml, 15. 906mmol, 3eq.) And stirred for 3 hours. 在用TLC证实反应结束后,将反应溶液用二氯甲烷提取,用水(2次)和盐水洗涤,通过硫酸钠干燥,过滤并在减压下浓缩。 In the completion of the reaction was confirmed by TLC, the reaction solution was extracted with dichloromethane, washed with water (2x) and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. 将获得的液体进行柱色谱法(正己烷/乙酸乙酯=10/1)以产生浅绿色固体(1.3171g). The liquid obtained was subjected to column chromatography (hexane / ethyl acetate = 10/1) to give a pale green solid (1.3171g).

[0367] IR(KBr 片状沉淀物,cnT1) :3330,3080,301,2984,2916,1687,1513 ; [0367] IR (KBr pellet, cnT1): 3330,3080,301,2984,2916,1687,1513;

[0368] 1H NMR(400MHz, CDCl3) :8· 11 (d,2H,J = 8. 4Hz),7. 37 (d,2H,J = 8. 4Hz),4. 99 (bs, 1H),4. 37 (d, 2H, J = 5. 6Hz),1. 39 (s,9H) · [0368] 1H NMR (400MHz, CDCl3):.. 8 · 11 (d, 2H, J = 8. 4Hz), 7 37 (d, 2H, J = 8. 4Hz), 4 99 (bs, 1H), 4. 37 (d, 2H, J = 5. 6Hz), 1. 39 (s, 9H) ·

[0369] 步骤2 : (4-氨基苄基)氨基甲酸叔丁酯 [0369] Step 2: (4-aminobenzyl) carbamate

[0370] 将(4-硝基苄基)氨基甲酸叔丁酯(1. 3071g,5. 880mmol, leq.)置于IOOml圆底烧瓶中并溶解在甲醇中。 [0370] The (4-nitrobenzyl) carbamate (1. 3071g, 5. 880mmol, leq.) Was placed IOOml round bottom flask and dissolved in methanol. 将Pd/c (约底物的10wt% )加入反应混合物中。 The Pd / c (10wt% to about substrate) was added to the reaction mixture. 将烧瓶中的空气用氢气替换大约15次。 The air in the flask was replaced with hydrogen of about 15 times.

[0371] 将得到的溶液在室温搅拌2小时。 [0371] The resulting solution was stirred at room temperature for 2 hours. 在用TLC证实反应进程后,将反应溶液通过C 盐过滤并蒸发以产生浅黄色固体(1. 1451g)。 After confirming progress of the reaction by TLC, the reaction solution was filtered through C the salt and evaporated to give a pale yellow solid (1. 1451g).

[0372] IR(KBr 片状沉淀物,cnT1) :3426,3346,3021,2995,2976,1687 ; [0372] IR (KBr pellet, cnT1): 3426,3346,3021,2995,2976,1687;

[0373] 1H NMR(400MHz, CDCl3) :7· 09 (d,2H,J = 8. OHz),6. 70 (d,2H,J = 8. OHz),4. 74 (bs, 1H),4. 20 (d, 2H, J = 5. OHz),3. 34 (bs, 2H),1. 46 (s,9H) · [0373] 1H NMR (400MHz, CDCl3): 7 · 09 (d, 2H, J = 8. OHz), 6 70 (d, 2H, J = 8. OHz), 4 74 (bs, 1H),.. 4. 20 (d, 2H, J = 5. OHz), 3. 34 (bs, 2H), 1. 46 (s, 9H) ·

[0374] 步骤3 : (4-氨基-3-碘苄基)氨基甲酸叔丁酯 [0374] Step 3: (4-amino-3-iodobenzyl) carbamate

[0375] 用氩气充满IOOml的双颈圆底烧瓶并将(4_氨基苄基)氨基甲酸叔丁酯(986. 2mg,3. 909mmol, leq.)在二氯甲烷中的溶液置于烧瓶中。 [0375] IOOml filled with argon and-neck round bottom flask (4_ aminobenzyl) carbamate (986. 2mg, 3. 909mmol, leq.) Was placed in a flask in dichloromethane in. 向该溶液加入一氯化碘(698. 2mg,4. 300mmol, 1. leq.)并搅拌1小时。 To this was added a solution of iodine monochloride (698. 2mg, 4. 300mmol, 1. leq.) And stirred for 1 hour. 在用TLC证实反应结束后,向该溶液加入饱和的硫代硫酸钠溶液并搅拌。 In the end of the reaction was confirmed by TLC, this solution was added a saturated solution of sodium thiosulfate and stirred. 将反应溶液用二氯甲烷提取,用水(2次)和盐水洗涤,通过硫酸钠干燥,过滤并在减压下浓缩。 The reaction solution was extracted with dichloromethane, washed with water (2x) and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. 将获得的液体进行柱色谱法(正己烷/乙酸乙酯= 3/1)以产生褐色液体(640mg)。 The liquid obtained was subjected to column chromatography (hexane / ethyl acetate = 3/1) to give a brown liquid (640mg).

[0376] IR(NaCl 纯的,cnT1) :3421,3349,2976,2929,1695 ; [0376] IR (NaCl neat, cnT1): 3421,3349,2976,2929,1695;

[0377] 1H NMR(400MHz, CDCl3) :7· 49 (d,1H,J = 2. OHz),6. 98 (dd,1H,J = 8. 0,2. OHz), 6. 61 (d, 1H, J = 8. 0Hz),4. 87 (bs, 1H),4. 07 (d, 2H, J = 4. OHz),3. 98 (bs, 2H),1. 40 (s,9H) [0377] 1H NMR (400MHz, CDCl3): 7 · 49 (d, 1H, J = 2. OHz), 6 98 (dd, 1H, J = 8. 0,2 OHz.), 6. 61 (d. , 1H, J = 8. 0Hz), 4. 87 (bs, 1H), 4. 07 (d, 2H, J = 4. OHz), 3. 98 (bs, 2H), 1. 40 (s, 9H )

[0378] 步骤4 : (4-氨基-3-乙烯基苄基)氨基甲酸叔丁酯[0379] 用氩气充满50ml的双颈圆底烧瓶并将四(三苯基膦)钯(0) (123. 7mg, [0378] Step 4: (4-amino-3-vinyl benzyl) carbamate [0379] bis neck round bottom flask filled with argon and 50ml of tetrakis (triphenylphosphine) palladium (0) (123. 7mg,

0. 107mmol,0. 06eq.)和氯化锂(211. 9mg,4. 998mmol,2. 8eq.)在DMF 中的溶液置于烧瓶中。 0. 107mmol, 0. 06eq.) And lithium chloride (211. 9mg, 4. 998mmol, 2. 8eq.) In DMF was placed in a flask. 向该溶液加入(4-氨基-3-碘苄基)氨基甲酸叔丁酯(621.4mg,1.875mmol,leq.)和三丁基乙烯基锡(782. 5mg, 2. 678mmol, 1. 5eq.).将该混合物溶液加热到90°C以回流一夜。 To this solution was added tert-butyl (4-amino-3-iodobenzyl) (621.4mg, 1.875mmol, leq.) And tributylvinyltin (782. 5mg, 2. 678mmol, 1. 5eq. ). the mixture was heated to 90 ° C to reflux overnight. 在用TLC证实反应结束后,将反应溶液用二氯甲烷提取,用水和盐水洗涤,通过硫酸钠干燥,过滤并蒸发。 In the completion of the reaction was confirmed by TLC, the reaction solution was extracted with dichloromethane, washed with water and brine, dried over sodium sulfate, filtered and evaporated. 将获得的液体进行柱色谱法(正己烷/乙酸乙酯=3/1)以产生褐色液体。 The liquid obtained was subjected to column chromatography (hexane / ethyl acetate = 3/1) to give a brown liquid.

[0380] 步骤5 : (4-甲烷磺酰基氨基-3-乙烯基苄基)氨基甲酸叔丁酯 [0380] Step 5: (4-methanesulfonyl-3-vinylbenzyl) carbamate

[0381] 用氩气充满50ml的双颈圆底烧瓶,并将(4_氨基苄基)氨基甲酸叔丁酯(343. 0mg,1.381mmol,leq.)在二氯甲烷中的溶液置于烧瓶中。 [0381] bis neck round bottom flask filled with argon, 50ml, and (4_ aminobenzyl) carbamate (343. 0mg, 1.381mmol, leq.) In dichloromethane was placed in a flask in. 在0°C,向该溶液加入甲烷磺酰酐(264. 7mg,1.519mmol,l· leq·),随后加入吡啶(332. 0 μ 1,4. 413mmol,2eq.)并搅拌1小时。 At 0 ° C, this solution was added methanesulfonyl anhydride (264. 7mg, 1.519mmol, l · leq ·), followed by addition of pyridine (332. 0 μ 1,4. 413mmol, 2eq.) And stirred for 1 hour. 在用TLC证实反应结束后,向该溶液加入饱和的碳酸氢钠溶液并搅拌5分钟。 In the end of the reaction was confirmed by TLC, this solution was added saturated sodium bicarbonate solution and stirred for 5 minutes. 将反应溶液用二氯甲烷提取并用5% HC1,饱和的碳酸氢钠溶液,水和盐水洗涤。 The reaction solution was extracted with dichloromethane and saturated sodium bicarbonate solution washed with 5% HC1,, water and brine. 将得到的溶液通过硫酸钠干燥,过滤并蒸发。 The resulting solution was dried over sodium sulfate, filtered and evaporated. 将获得的固体进行柱色谱法(正己烷/乙酸乙酯=2/1)以产生浅黄色固体(161. 6mg)。 The obtained solid was subjected to column chromatography (hexane / ethyl acetate = 2/1) to give a pale yellow solid (161. 6mg).

[0382] IR(KBr 片状沉淀物,cnT1) :3414,3359,3269,3254,3083,2982,2927,1685 ; [0382] IR (KBr pellet, cnT1): 3414,3359,3269,3254,3083,2982,2927,1685;

[0383] 1H NMR(400MHz, CDCl3) :7. 35 (d,1H,J = 8. OHz),7. 33 (d,1H,J = 2. OHz),7. 14 (dd, 1H, J = 8. 0,2. 0Hz),6. 84 (dd, 1H, J = 17. 2,10. 8Hz),6. 44 (bs, 1H),5. 65 (d, 1H, J = 17. 2Hz) ,5. 40 (d, 1H, J = 10. 8Hz),4. 84 (bs,1H),4. 23 (d,2H,J = 5. 6Hz),2,91 (s,3H), [0383] 1H NMR (400MHz, CDCl3):.. 7 35 (d, 1H, J = 8. OHz), 7 33 (d, 1H, J = 2. OHz), 7 14 (dd, 1H, J. = 8. 0,2. 0Hz), 6. 84 (dd, 1H, J = 17. 2,10. 8Hz), 6. 44 (bs, 1H), 5. 65 (d, 1H, J = 17. 2Hz), 5. 40 (d, 1H, J = 10. 8Hz), 4. 84 (bs, 1H), 4. 23 (d, 2H, J = 5. 6Hz), 2,91 (s, 3H) ,

1. 39(s,9H) 1. 39 (s, 9H)

[0384] 步骤6 :N-(4-氨基甲基-2-乙烯基苯基)甲烷磺酰胺 [0384] Step 6: N- (4- aminomethyl-2-vinylphenyl) methanesulfonamide

[0385] 将(4-甲烷磺酰基氨基-3-乙烯基苄基)氨基甲酸叔丁酯(161. 6mg)置于1 OOml 圆底烧瓶并溶解于二氯甲烷。 [0385] (4-methanesulfonyl-3-vinylbenzyl) carbamate (161. 6mg) was placed 1 OOml round bottomed flask and dissolved in dichloromethane. 向该溶液加入三氟乙酸并搅拌一夜。 To this was added trifluoroacetic acid and stirred overnight. 在用TLC证实反应结束后,在减压下浓缩反应溶液以产生褐色液体(198. 6mg)。 In the completion of the reaction was confirmed by TLC, the reaction solution was concentrated under reduced pressure to give a brown liquid (198. 6mg).

[0386] 步骤7 :N-4-[3-(4-叔丁基苄基)脲基甲基]_2_乙烯基苯基甲烷磺酰胺 [0386] Step 7: N-4- [3- (4- tert-butylbenzyl) ureidomethyl] methanesulfonamide _2_ vinylphenyl

[0387] 用氩气充满25ml的双颈圆底烧瓶并将4_叔丁基苄胺(27. 7μ 1,0. 158mmol, leq.) 在二氯甲烷中的溶液置于烧瓶。 [0387] filled with a double necked round bottom flask and 25ml 4_ tert-butyl benzylamine with argon (27. 7μ 1,0. 158mmol, leq.) In dichloromethane was placed in a flask. 向该溶液加入4-二甲基氨基吡啶(3.9mg,0.032mmol, 0. 2eq.)和二碳酸二叔丁酯(43. 6 μ 1,0. 190mmol, 1. 2eq.)并在室温搅拌1小时30分钟。 To this was added 4-dimethylaminopyridine (3.9mg, 0.032mmol, 0. 2eq.) And di-tert-butyl dicarbonate (43. 6 μ 1,0. 190mmol, 1. 2eq.) And stirred at room temperature 1 hour 30 minutes. 将得到的溶液冷却到0°c并加入N- (4-氨基甲基-2-乙烯基-苯基)-甲烷磺酰胺(35. 7mg, 0. 158mmol,leq.)和三乙胺(44. 0 μ 1,0. 316mmol,2eq.)在二氯甲烷中的溶液。 The resulting solution was cooled to 0 ° c was added N- (4- aminomethyl-2-vinyl - phenyl) - methanesulfonamide (35. 7mg, 0. 158mmol, leq.) And triethylamine (44 . 0 μ 1,0. 316mmol, 2eq.) in dichloromethane in the. 将混合物溶液在室温搅拌过夜。 The mixture was stirred at room temperature overnight. 在用TLC证实反应结束后,在减压下去除二氯甲烷。 In the end of the reaction was confirmed by TLC, dichloromethane was removed under reduced pressure. 将残余物进行柱色谱法(正己烷/乙酸乙酯=1/2)以产生浅黄色固体(35. 6mg, 54. 2% )。 The residue was subjected to column chromatography (hexane / ethyl acetate = 1/2) to give a pale yellow solid (35. 6mg, 54. 2%).

[0388] mp :108-109°C ; [0388] mp: 108-109 ° C;

[0389] IR(KBr 片状沉淀物,cnT1) :3413,3023,2961,2927,1735 ; [0389] IR (KBr pellet, cnT1): 3413,3023,2961,2927,1735;

[0390] 1H NMR(400MHz, CDCl3) :7· 26 (d,1H,J = 1. 6Hz), 7. 24 (d, 2H, J = 8. 4Hz), 7. 17 (d, 1H, J = 8. 0Hz),7. 10 (d, 2H, J = 8. 4Hz),6. 99 (dd, 1H,J = 8· 0,1. 6Hz),6. 80 (dd, 1H, J = 17. 2,10. 8Hz),6. 70 (s, 1H),5. 58 (dd, 1H, J = 17. 2,0. 8Hz),5. 31 (dd, 1H, J = 10. 8,0. 8Hz), 4. 10 (bs, 2H),4. 20 (s, 2H),2. 83 (s, 3H),1. 21 (s,9H) [0390] 1H NMR (400MHz, CDCl3): 7 · 26 (d, 1H, J = 1. 6Hz), 7. 24 (d, 2H, J = 8. 4Hz), 7. 17 (d, 1H, J = 8. 0Hz), 7. 10 (d, 2H, J = 8. 4Hz), 6. 99 (dd, 1H, J = 8 · 0,1. 6Hz), 6. 80 (dd, 1H, J = 17. 2,10. 8Hz), 6. 70 (s, 1H), 5. 58 (dd, 1H, J = 17. 2,0. 8Hz), 5. 31 (dd, 1H, J = 10. 8 , 0. 8Hz), 4. 10 (bs, 2H), 4. 20 (s, 2H), 2. 83 (s, 3H), 1. 21 (s, 9H)

[0391] 实施例2 :N-{4-[3-(4-叔丁基苄基)脲基甲基]_2_氟_6_乙烯基苯基}甲烷磺酰胺[0392] [0391] Example 2: N- {4- [3- (4- tert-butylbenzyl) ureidomethyl] _2_ fluoro _6_ vinylphenyl} methanesulfonamide [0392]

Figure CN101142174BD00421

[0393] 步骤1 :4-氨基甲基-2-氟-6-碘苯胺 [0393] Step 1: 4-amino-2-fluoro-6-iodoaniline

[0394] 用氩气充满50ml的双颈圆底烧瓶并将4_氨基_3_氟_5_碘-苄腈(84. 4mg, 0. 322mmol, leq.)在四氢呋喃中的溶液置于烧瓶,接着冷却到0°C。 [0394] filled with argon, 50ml of a double necked round bottom flask and amino _3_ 4_ fluoro _5_ iodo - benzonitrile (. 84. 4mg, 0. 322mmol, leq) in tetrahydrofuran was placed in a flask , followed by cooling to 0 ° C. 向该溶液加入硼烷_THF 复合物溶液(1. OM在THF中的溶液,0. 64ml, 0. 644mmol,2eq.)。 To this solution was added a solution of borane _THF complex (1. OM solution in THF, 0. 64ml, 0. 644mmol, 2eq.). 将反应混合物的温度升高到室温。 The temperature of the reaction mixture was raised to room temperature. 将反应混合物加热并回流。 The reaction mixture was heated and refluxed. 在用TLC证实反应结束后,向该溶液加入5% HCl并搅拌20分钟。 In the end of the reaction was confirmed by TLC, this solution was added 5% HCl and stirred for 20 min. 使用IN KOH来碱化得到的溶液,用醚提取,用盐水洗涤,通过Na2SO4干燥。 Using IN KOH solution obtained was basified, extracted with ether, washed with brine, dried over Na2SO4. 将得到的液体在减压下浓缩以产生浅黄色固体(78. 4mg,80. 5% )。 The resulting liquid was concentrated under reduced pressure to give a pale yellow solid (78. 4mg, 80. 5%).

[0395] IR (KBr 片状沉淀物,cnT1) :3429,2923,2853,1626 ; [0395] IR (KBr pellet, cnT1): 3429,2923,2853,1626;

[0396] 1H NMR(400MHz, CD3OD) :7. 33 (s, 1H) ,6. 93 (dd, 1H, J = 11. 6,2. OHz),3. 58(s,2H), [0396] 1H NMR (400MHz, CD3OD):.. 7 33 (s, 1H), 6 93 (dd, 1H, J = 11. 6,2 OHz.), 3 58 (s, 2H),.

[0397] 步骤2 : (4-氨基-3-氟-5-碘苄基)氨基甲酸叔丁酯 [0397] Step 2: (4-Amino-3-fluoro-5-iodobenzyl) carbamate

[0398] 用氩气充满25ml的双颈圆底烧瓶并将4_氨基甲基_2_氟_6_碘苯胺(31. 9mg, 0. 120mmol,leq.)和三乙胺(18.4μ 1,0. 132mmol,l. leq.)在二氯甲烷中的溶液置于烧瓶并接着冷却到0°c。 [0398] filled with a double necked round bottom flask and 25ml 4_ fluoro-aminomethyl _2_ _6_ iodoaniline (31. 9mg, 0. 120mmol, leq.) With argon and triethylamine (18.4μ 1 , 0. 132mmol, l. leq.) in dichloromethane was placed in a flask and then cooled to 0 ° c. 向该溶液加入4-二甲基氨基吡啶(1.47mg,0.012mmOl,0. leq.)和二碳酸二叔丁酯(27.6μ 1,0. 120mmOl,leq.)并搅拌5小时。 To this was added 4-dimethylaminopyridine (1.47mg, 0.012mmOl, 0. Leq.) And di-tert-butyl dicarbonate (27.6μ 1,0. 120mmOl, leq.) And stirred for 5 hours. 在用TLC证实反应结束后,反应溶液用二氯甲烷提取,用水和盐水洗涤,通过硫酸钠干燥,并在减压下浓缩。 In the end of the reaction was confirmed by TLC, the reaction solution was extracted with dichloromethane, washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. 将获得的液体进行柱色谱法(正己烷/乙酸乙酯=5/1)以产生黄色液体(9. 8mg,22. 3% )。 The liquid obtained was subjected to column chromatography (hexane / ethyl acetate = 5/1) to give a yellow liquid (9. 8mg, 22. 3%).

[0399] IR(NaCl 纯的,cnT1) :3451,3351,2975,2928,1698 ; [0399] IR (NaCl neat, cnT1): 3451,3351,2975,2928,1698;

[0400] 1H NMR (400MHz, CDCl3) :7· 87 (s,0· 2H),7. 44 (d,0· 2H,J= 11. 2Hz),7· 26 (s,1H), 6. 87 (d, 1H, J=Il. 2Hz),4· 72(bs,2H),4· 08(d,2H,J = 4. 4Ηζ),1. 39(s,9H) [0400] 1H NMR (400MHz, CDCl3):. 7 · 87 (s, 0 · 2H), 7 44 (d, 0 · 2H, J = 11. 2Hz), 7 · 26 (s, 1H), 6. 87 (d, 1H, J = Il. 2Hz), 4 · 72 (bs, 2H), 4 · 08 (d, 2H, J = 4. 4Ηζ), 1. 39 (s, 9H)

[0401] 步骤3 : (4-氨基-3-氟-5-乙烯基苄基)氨基甲酸叔丁酯 [0401] Step 3: (4-Amino-3-fluoro-5-vinylbenzyl) carbamate

[0402] 用氩气充满25ml的双颈圆底烧瓶并将四(三苯基膦钯(0) (18. 9mg,0. 016mmol, 0. 06eq.)和氯化锂(32. 4mg,0. 765mmol,2. 8eq.)在DMF中的溶液置于烧瓶。向该溶液加入(4-氨基-3-氟-5-碘-苄基)-氨基甲酸叔丁酯(100mg,0. 273mmol, leq.)和三丁基乙烯基锡(119. 7μ l,0.410mmol,1.5eq.)并加热到回流5小时。在用TLC证实反应结束后,将得到的溶液用乙酸乙酯提取,用水和盐水洗涤,通过硫酸钠干燥并在减压下浓缩。将获得的液体进行柱色谱法(正己烷/乙酸乙酯=5/1)以产生褐色液体(52.5mg,72.2%)。 [0402] filled with argon, 25ml of double-neck round bottom flask and tetrakis (triphenylphosphine palladium (0) (18. 9mg, 0. 016mmol, 0. 06eq.) And lithium chloride (32. 4mg, 0 .. 765mmol, 2 8eq) in DMF was placed in a flask and this solution was added (4-amino-3-fluoro-5-iodo -. benzyl) - carbamate (100mg, 0 273mmol, Leq.) and tributylvinyltin (119. 7μ l, 0.410mmol, 1.5eq.) and heated to reflux for 5 hours at the end of the reaction was confirmed by TLC, the resulting solution was extracted with ethyl acetate, washed with water, and washed with brine, and concentrated under reduced pressure over sodium sulfate. the liquid obtained was subjected to column chromatography (hexane / ethyl acetate = 5/1) to give a brown liquid (52.5mg, 72.2%).

[0403] IR(NaCl 纯的,cnT1) :3412,3088,2958,2925,1689 ; [0403] IR (NaCl neat, cnT1): 3412,3088,2958,2925,1689;

[0404] 1H NMR(400MHz, CDCl3) :7. 53 (d, 1H, J = 2. OHz),7. 39 (dd, 1H, J = 10. 8,2. OHz), 6. 64 (dd, 1H, J = 17. 6,11. 2Hz),5. 69 (d,1H,J = 17. 6Hz),5. 42 (d,1H,J = 11. 2Hz), 4. 36(s,2H),1. 49(s,9H) [0404] 1H NMR (400MHz, CDCl3):.. 7 53 (d, 1H, J = 2. OHz), 7 39 (. Dd, 1H, J = 10. 8,2 OHz), 6. 64 (dd , 1H, J = 17. 6,11. 2Hz), 5. 69 (d, 1H, J = 17. 6Hz), 5. 42 (d, 1H, J = 11. 2Hz), 4. 36 (s, 2H), 1. 49 (s, 9H)

[0405] 步骤4 : (3-氟-4-甲烷磺酰基氨基-5-乙烯基苄基)氨基甲酸叔丁酯 [0405] Step 4: (3-Fluoro-4-methanesulfonyl-5-vinylbenzyl) carbamate

[0406] 用氩气充满25ml的双颈圆底烧瓶,并将(4_氨基_3_氟_5_乙烯基-苄基)-氨基甲酸叔丁酯(27. 3mg,0. 103mmol, leq.)在吡啶中的溶液置于烧瓶并接着冷却到0°C。 [0406] bis neck round bottom flask filled with argon, 25ml, and (4_ fluoro _5_ amino _3_ vinyl - benzyl) - carbamate (27. 3mg, 0 103mmol, leq .) in pyridine was placed in a flask and then cooled to 0 ° C. 向该溶液加入甲烷磺酰氯(11.9μ 1,0. 154mm0l,1.5eq.)并加热回流一夜。 To this solution was added methanesulfonyl chloride (11.9μ 1,0. 154mm0l, 1.5eq.) And heated to reflux overnight. 在用TLC证实反应结束后,向该溶液加入溶液(THF : H2O = 2 : 1)禾PNa0H(20.6mg,0.515mmol,5eq.)并在室温搅拌1小时。 In the end of the reaction was confirmed by TLC, this solution was added a solution (THF: H2O = 2: 1) (. 20.6mg, 0.515mmol, 5eq) and stirred at Wo PNa0H room temperature for 1 hour. 用10% HCl酸化反应溶液,用乙酸乙酯提取,用水和盐水洗涤,通过硫酸钠干燥并蒸发。 The reaction was acidified with 10% HCl solution, extracted with ethyl acetate, washed with water and brine, dried over sodium sulphate and evaporated.

[0407] 将获得的固体进行柱色谱法(正己烷/乙酸乙酯=2/1)以产生黄色液体。 [0407] The obtained solid was subjected to column chromatography (hexane / ethyl acetate = 2/1) to give a yellow liquid.

[0408] IR(NaCl 纯的,cnT1) :3349,3236,2956,2921,2850,1689 ; [0408] IR (NaCl neat, cnT1): 3349,3236,2956,2921,2850,1689;

[0409] 1H NMR(400MHz, CDCl3) :7. 27 (s, 1H),7. 10 (dd, 1H, J = 17. 6,10. 8Hz) ,6. 97 (d, 1H, J = 10. 0Hz),5. 88 (bs, 1H),5. 73 (d, 1H, J = 17. 6Hz),5. 39 (d, 1H, J = 10. 8Hz),4. 87 (bs, 1H),4. 25 (d, 2H, J = 6. OHz),3. 00 (s, 3H),1. 40 (s,9H) [0409] 1H NMR (400MHz, CDCl3):... 7 27 (s, 1H), 7 10 (. Dd, 1H, J = 17. 6,10 8Hz), 6 97 (d, 1H, J = 10 . 0Hz), 5. 88 (bs, 1H), 5. 73 (d, 1H, J = 17. 6Hz), 5. 39 (d, 1H, J = 10. 8Hz), 4. 87 (bs, 1H ), 4. 25 (d, 2H, J = 6. OHz), 3. 00 (s, 3H), 1. 40 (s, 9H)

[0410] 步骤5 :N-(4-氨基甲基-2-氟-6-乙烯基苯基)甲烷磺酰胺 [0410] Step 5: N- (4- amino-2-fluoro-6-vinylphenyl) methanesulfonamide

[0411] 将(3-氟-4-甲烷磺酰基氨基-5-乙烯基-苄基)_氨基甲酸叔丁酯(Iml)置于25ml圆底烧瓶并溶解于二氯甲烷。 [0411] (3-fluoro-4-methanesulfonyl-5-vinyl-benzyl) - _ carbamate (of Iml) placed in 25ml round bottomed flask and dissolved in dichloromethane. 向该溶液加入三氟乙酸(Iml)并搅拌一夜。 To this solution was added trifluoroacetic acid (of Iml) was added and stirred overnight. 在用TLC证实反应结束后,在减压下浓缩反应溶液以产生褐色粗制液体(236. 7mg). In the completion of the reaction was confirmed by TLC, the reaction solution was concentrated under reduced pressure to give a brown crude liquid (236. 7mg).

[0412] 步骤6 :N-4-[3-(4-叔丁基苄基)脲基甲基]_2_氟_6_乙烯基苯基甲烷磺酰胺 [0412] Step 6: N-4- [3- (4- tert-butylbenzyl) ureidomethyl] _2_ fluoro _6_ vinylphenyl methanesulfonamide

[0413] 用氩气充满25ml的双颈圆底烧瓶并将4_叔丁基苄胺 [0413] filled with a double necked round bottom flask and 25ml 4_ tert-butyl benzylamine with argon

[0414] (59. 3μ 1,0. 338mm0l,leq.)在二氯甲烷中的溶液置于烧瓶。 [0414] (59. 3μ 1,0. 338mm0l, leq.) In dichloromethane was placed in a flask. 向该溶液加入4_ 二甲基氨基吡啶(8. 3mg,0. 068mmol,0. 2eq.)和二叔丁基二碳酸酯(93. 3 μ 1,0. 406mmol, 1.2eq.)并在室温搅拌3小时。 To the solution was added dimethylaminopyridine 4_ (8. 3mg, 0. 068mmol, 0. 2eq.) And di-tert-butyl dicarbonate (93. 3 μ 1,0. 406mmol, 1.2eq.) At room for 3 hours. 将得到的溶液冷却到0°C。 The resulting solution was cooled to 0 ° C. 加入3_氟_4_甲烷磺酰基氨基-5-乙烯基苄基-铵,三氟乙酸盐(121. Img,0. 338mmol,leq.)和三乙胺(94. 2μ 1, 0. 676mmol,2eq.)在二氯甲烷中的溶液并将该混合物溶液在室温搅拌一夜。 _4_ added 3_ fluoro-5-methanesulfonyl-vinyl benzyl - ammonium trifluoroacetate (.. 121. Img, 0 338mmol, leq) and triethylamine (94. 2μ 1, 0. 676mmol, 2eq.) in dichloromethane solution was added and the mixture was stirred overnight at rt. 在用TLC证实反应结束后,二氯甲烷在减压下进行去除。 With TLC confirmed completion of the reaction, the methylene chloride was removed under reduced pressure. 将剩余的液体进行柱色谱法(正己烷/乙酸乙酯=1/1(仅乙酸乙酯))以产生白色固体(35mg,23.9% )0 The remaining liquid was subjected to column chromatography (hexane / ethyl acetate = 1/1 (ethyl acetate only)) as a white solid (35mg, 23.9%) 0

[0415] mp :163-164°C ; [0415] mp: 163-164 ° C;

[0416] IR(KBr 片状沉淀物,cnT1) :3376,3250,3057,2961,1636,1580,1319,1151 ; [0416] IR (KBr pellet, cnT1): 3376,3250,3057,2961,1636,1580,1319,1151;

[0417] 1H NMR (400MHz, CD3OD) :7. 42 (d, 1H, J = 1. 6Hz),7. 33(d,2H,J = 8. 4Hz),7. 19 (d, 2H, J = 8. 4Hz),7. 15 (dd, 1H, J = 17. 6,11. 2Hz),7. 05 (dd, 1H, J = 10. 8,1. 6Hz),5. 79 (d, 1H, J = 17. 6Hz) ,5. 36 (d, 1H, J = 11. 2Hz),4. 33(s,2H),4. 29(s,2H),3. 00(s,3H),1. 28 (s, 9H) [0417] 1H NMR (400MHz, CD3OD):.. (D, 1H, J = 1. 6Hz) 7 42, 7 33 (d, 2H, J = 8. 4Hz), 7 19 (d, 2H, J. = 8. 4Hz), 7. 15 (dd, 1H, J = 17. 6,11. 2Hz), 7. 05 (dd, 1H, J = 10. 8,1. 6Hz), 5. 79 (d, 1H, J = 17. 6Hz), 5. 36 (d, 1H, J = 11. 2Hz), 4. 33 (s, 2H), 4. 29 (s, 2H), 3. 00 (s, 3H) , 1. 28 (s, 9H)

[0418] 实施例3 :N-{4-[3-(4-叔丁基苄基)脲基甲基]_2_乙炔基_6_氟苯基}甲烷磺酰胺 [0418] Example 3: N- {4- [3- (4- tert-butylbenzyl) ureidomethyl] _2_ ethynyl _6_ fluorophenyl} methanesulfonamide

[0419] [0419]

Figure CN101142174BD00431

[0420] 步骤1 : (4-氨基-3-氟-5-三甲基硅烷基乙炔基苄基)氨基甲酸叔丁酯 [0420] Step 1: (4-Amino-3-fluoro-5-trimethylsilyl-ethynyl-benzyl) carbamate

[0421] 将(4-氨基-3-氟-5-碘苄基)氨基甲酸叔丁酯(100mg,0. 273mmol, leq. ),二氯(二-三苯基膦),钯(9. 8mg,0. 014mmol,0. 05eq.)和碘化铜(2. 6mg,0. 014mmol,0. 05eq.) 在THF中的溶液置于25ml双颈圆底烧瓶中,并在室温搅拌30分钟。 [0421] (4-Amino-3-fluoro-5-iodobenzyl) carbamate (100mg, 0 273mmol, leq..), Dichloro (two - triphenylphosphine) palladium (9. 8mg, 0. 014mmol, 0. 05eq.) and copper iodide (2. 6mg, 0. 014mmol, 0. 05eq.) in THF was placed in a 25ml two-necked round bottom flask, and stirred at room temperature for 30 minutes . 向该溶液加入三乙胺(114. 2μ 1,0. 819mmol,3eq.)禾口(三甲基甲硅烷基)乙炔基(50. 2 μ 1,0. 355mmol, 1. 3eq.)并加热以回流一夜。 To this solution was added triethylamine (114. 2μ 1,0. 819mmol, 3eq.) Wo port (trimethylsilyl) ethynyl (50. 2 μ 1,0. 355mmol, 1. 3eq.) And heated reflux overnight. 反应溶液在减压下浓缩并进行柱色谱法(正己烷/乙酸乙酯=5/1) 以产生褐色液体(84. 0mg,91.4% ). The reaction solution was concentrated and subjected to column chromatography (hexane / ethyl acetate = 5/1) under reduced pressure to give a brown liquid (84. 0mg, 91.4%).

[0422] IR(NaCl,纯的,cnT1) :3459,3360,2965,2148,1698 ; [0422] IR (NaCl, neat, cnT1): 3459,3360,2965,2148,1698;

[0423] 1H NMR(400MHz, CDCl3) :7.00(d,lH,J = 0. 8Hz),6· 91 (dd,1H,J = 11. 6,0. 8Hz), 4. 77 (bs, 1H),4. 36-3. 91 (m, 2H),4. 15 (s, 2H),1. 46 (s,9H),0. 27 (s,9H). [0423] 1H NMR (400MHz, CDCl3): 7.00 (d, lH, J = 0. 8Hz), 6 · 91 (dd, 1H, J = 11. 6,0 8Hz.), 4. 77 (bs, 1H ), 4. 36-3. 91 (m, 2H), 4. 15 (s, 2H), 1. 46 (s, 9H), 0. 27 (s, 9H).

[0424] 步骤2 : (3-乙炔基-5-氟-4-甲烷磺酰基氨基苄基)氨基甲酸叔丁酯 [0424] Step 2: (3-ethynyl-5-fluoro-4-methanesulfonyl aminobenzyl) carbamate

[0425] 用氩气充满25ml的双颈圆底烧瓶,将(4_氨基_3_氟_5_三甲基硅烷基乙炔基苄基)氨基甲酸叔丁酯(80mg,0. 238mmol,leq.)在二氯甲烷的溶液置于烧瓶并接着冷却到0°C。 [0425] bis neck round bottom flask filled with argon, 25ml, the (amino _3_ 4_ fluoro _5_ trimethylsilyl ethynyl benzyl) carbamate (80mg, 0. 238mmol, leq .) in dichloromethane were placed in a flask and then cooled to 0 ° C. 向该溶液加入甲烷磺酰氯(92. 0 μ 1,1. 189mmol,5eq.)和三乙胺(99. 5μ 1, 0. 714mmol,3eq.),并在室温搅拌一夜。 To this solution was added methanesulfonyl chloride (92. 0 μ 1,1. 189mmol, 5eq.) And triethylamine (99. 5μ 1, 0. 714mmol, 3eq.), And stirred overnight at rt. 在用TLC证实反应结束后,用饱和的碳酸氢钠溶液猝灭反应。 In the completion of the reaction was confirmed by TLC, the reaction was quenched with saturated sodium bicarbonate solution. 用二氯甲烷提取得到的溶液,用饱和的CuSO4溶液,水和盐水洗涤,通过硫酸钠干燥,过滤并在减压下浓缩。 The resulting solution was extracted with dichloromethane, washed with saturated CuSO4 solution, water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. 将获得的固体溶解于溶液(THF : H2O = 2 : 1)。 The solid obtained was dissolved in a solution (THF: H2O = 2: 1). 向该溶液加入恥0!1(47.611^,1.190_01,569.),在室温搅拌3小时并用10% HCl酸化。 To this solution was added shame 0! 1 (47.611 ^, 1.190_01,569.), Stirred for 3 hours at room temperature and acidified with 10% HCl. 将溶液用乙酸乙酯提取,用水和盐水洗涤,通过硫酸钠干燥,过滤并在减压下浓缩。 The solution was extracted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. 将获得的固体进行柱色谱法(正己烷/乙酸乙酯=5/1)以产生褐色固体(51.4mg,63.0% )。 The obtained solid was subjected to column chromatography (hexane / ethyl acetate = 5/1) to give a brown solid (51.4mg, 63.0%).

[0426] mp : 146-147 °C ; [0426] mp: 146-147 ° C;

[0427] IR(KBr 片状沉淀物,cnT1) :3420,3288,2979,2933,2112,1691 ; [0427] IR (KBr pellet, cnT1): 3420,3288,2979,2933,2112,1691;

[0428] 1H NMR(400MHz, CDCl3) :7. 17 (d, 1H, J = O. 8Hz),7. 05 (dd, 1H, J = 10. 8,0. 8Hz), 6. 38 (bs, 1H),4. 89 (bs, 1H),4. 20 (d, 2H, J = 6. OHz),3. 40 (s, 1H),3. 18 (s,3H),1. 39 (s, 9H). [0428] 1H NMR (400MHz, CDCl3):.. 7 17 (d, 1H, J = O. 8Hz), 7 05 (. Dd, 1H, J = 10. 8,0 8Hz), 6. 38 (bs , 1H), 4. 89 (bs, 1H), 4. 20 (d, 2H, J = 6. OHz), 3. 40 (s, 1H), 3. 18 (s, 3H), 1. 39 ( s, 9H).

[0429] 步骤3 :3-乙炔基-5-氟-4-甲烷磺酰基氨基苄基铵;三氟乙酸盐 [0429] Step 3: 3-ethynyl-5-fluoro-4-methanesulfonyl aminobenzyl ammonium; trifluoroacetate

[0430] 将(3-乙炔基-5-氟-4-甲烷磺酰基氨基苄基)_氨基甲酸叔丁酯(301.6mg, 0. 881mmol,leq.)置于50ml圆底烧瓶中并溶解于二氯甲烷。 [0430] (3-ethynyl-5-fluoro-4-methanesulfonyl aminobenzyl) _ carbamate (301.6mg, 0. 881mmol, leq.) Was placed in a 50ml round bottom flask and dissolved in methylene chloride. 向该溶液加入10滴三氟乙酸并搅拌一夜。 To this solution was added 10 drops of trifluoroacetic acid and stirred overnight. 在用TLC证实反应结束后,在减压下浓缩反应溶液以产生褐色粗制液体(564mg)。 In the completion of the reaction was confirmed by TLC, the reaction solution was concentrated under reduced pressure to produce a crude brown liquid (564mg).

[0431] 步骤4 :N-{4-[3-(4-叔丁基苄基)脲基甲基]_2_乙炔基_6_氟苯基}甲烷磺酰胺 [0431] Step 4: N- {4- [3- (4- tert-butylbenzyl) ureidomethyl] _2_ ethynyl _6_ fluorophenyl} methanesulfonamide

[0432] 用氩气充满25ml的双颈圆底烧瓶,并将4-叔丁基苄胺(83. 0 μ 1,0. 473mmol, leq.)在二氯甲烷中的溶液置于烧瓶。 [0432] 25ml filled with argon-neck round bottom flask, and 4-tert-butyl-benzylamine (83. 0 μ 1,0. 473mmol, leq.) In dichloromethane was placed in a flask. 向该溶液加入4-二甲基氨基吡啶(11.6mg, 0. 095mmol,0. 2eq.)和二碳酸二叔丁酯(130. 5 μ 1,0. 568mmol, 1. 2eq.)并在室温搅拌3 小时。 To this was added 4-dimethylaminopyridine (11.6mg, 0. 095mmol, 0. 2eq.) And di-tert-butyl dicarbonate (130. 5 μ 1,0. 568mmol, 1. 2eq.) At room for 3 hours. 将得到的溶液冷却到0°c并加入3-乙炔基-5-氟-4-甲烷磺酰基氨基苄基铵,三氟乙酸盐(168. 5mg,0. 473mmol,leq.),和三乙胺(131. 9μ 1,0. 946mmol,2eq.)在二氯甲烷中的溶液。 The resulting solution was cooled to 0 ° c and 3-ethynyl-5-fluoro-4-methanesulfonyl-amino benzyl ammonium trifluoroacetate (168. 5mg, 0. 473mmol, leq.), And tris triethylamine (131. 9μ 1,0. 946mmol, 2eq.) in dichloromethane in the. 将混合物溶液在室温搅拌一夜。 The mixture was stirred overnight at rt. 在用TLC证实反应结束后,二氯甲烷在减压下进行去除。 With TLC confirmed completion of the reaction, the methylene chloride was removed under reduced pressure. 将剩余的液体进行柱色谱法(正己烷/乙酸乙酯=1/1)以产生白色固体(48.4mg, 23. 7% )。 The remaining liquid was subjected to column chromatography (hexane / ethyl acetate = 1/1) to give a white solid (48.4mg, 23. 7%).

[0433] mp : 117-118°C ; [0433] mp: 117-118 ° C;

[0434] IR(KBr 片状沉淀物,cnT1) :3418,3051,2962,2112,1634,1582,1318,1152 ; [0434] IR (KBr pellet, cnT1): 3418,3051,2962,2112,1634,1582,1318,1152;

[0435] 1H NMR(400MHz, CD3OD) :7. 30(d,2H,J = 8. 4Hz),7. 25 (d, 1H, J = 2. OHz),7. 15 (d, 2H, J = 8. 4Hz) ,7. 10 (dd, 1H, J = 10. 8,2. OHz),4. 26 (s,2H),4. 25 (s,2H),3. 44 (s,1H),3. 06(s,3H),1. 25(s,9H) [0435] 1H NMR (400MHz, CD3OD):.. 7 30 (d, 2H, J = 8. 4Hz), 7 25 (d, 1H, J = 2. OHz), 7 15 (d, 2H, J. = 8. 4Hz), 7. 10 (dd, 1H, J = 10. 8,2. OHz), 4. 26 (s, 2H), 4. 25 (s, 2H), 3. 44 (s, 1H ), 3. 06 (s, 3H), 1. 25 (s, 9H)

[0436] 实施例4 :N-{4-[3-(4-叔丁基苄基)脲基甲基]_5_氯_2_乙烯基苯基}甲烷磺酰胺 [0436] Example 4: N- {4- [3- (4- tert-butylbenzyl) ureidomethyl] _5_ chloro _2_ vinylphenyl} methanesulfonamide

[0437] [0437]

Figure CN101142174BD00451

[0438] 步骤1 : (4-氨基-2-氯-5-乙烯基苄基)氨基甲酸叔丁酯 [0438] Step 1: (4-amino-2-chloro-5-vinylbenzyl) carbamate

[0439] 用氩气充满干燥的25ml的双颈圆底烧瓶,将Pd(PPh3)4(0. 06eq,0. Olmmol, 11.09mg)和LiCl(2. 8eq,0. 45mmol,18. 99mg)在DMF中的溶液加入烧瓶。 [0439] filled with argon and dried two-necked round bottom flask of 25ml, the Pd (PPh3) 4 (0. 06eq, 0. Olmmol, 11.09mg) and LiCl (2. 8eq, 0. 45mmol, 18. 99mg) in DMF was added to the flask. 向该溶液加入(4-氨基-2-氯-5-碘-苄基)-氨基甲酸叔丁酯(60mg,0. 16mmol)和三丁基乙烯基锡(1.5eq,0. 24mmol, 74. 71 μ 1)并加热以回流12小时。 To this solution was added (4-amino-2-chloro-5-iodo-benzyl) - - carbamate (. 60mg, 0 16mmol) and tributylvinyltin (1.5eq, 0 24mmol, 74.. 71 μ 1) and heated to reflux for 12 hours. 在用TLC证实反应结束后,在减压下去除DMF,用乙酸乙酯提取残余物。 With TLC confirmed completion of the reaction, the DMF was removed under reduced pressure, the residue was extracted with ethyl acetate. 用水和盐水洗涤乙酸乙酯层,通过硫酸钠干燥,过滤并在减压下浓缩。 The ethyl acetate layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. 将获得的液体进行柱色谱法(正己烷/乙酸乙酯=5/1)以产生深黄色糖浆(17. lmg,底物回收-35. 7mg,38. 59% )。 The liquid obtained was subjected to column chromatography (hexane / ethyl acetate = 5/1) to give a dark yellow syrup (17. lmg, the substrate was recovered -35. 7mg, 38. 59%).

[0440] IR(NaCl 纯的,cnT1) :3359,3085,2976,1698,760 ; [0440] IR (NaCl neat, cnT1): 3359,3085,2976,1698,760;

[0441] 1H NMR (400MHz, CDCl3) :7· 19 (s,1H),6. 65 (s,1H),6. 60 (dd,1H,J = 17. 2, [0441] 1H NMR (400MHz, CDCl3):.. 7 · 19 (s, 1H), 6 65 (s, 1H), 6 60 (dd, 1H, J = 17. 2,

10. 8Hz) ,5. 55 (dd, 1H, J = 17. 2,0. 8Hz),5. 27 (dd,1H,J = 10. 8,1. 2Hz),4. 83 (bs,1H), 4. 22 (d, 2H, J = 6. 0Hz),1. 37 (s,9H) 10. 8Hz), 5. 55 (dd, 1H, J = 17. 2,0. 8Hz), 5. 27 (dd, 1H, J = 10. 8,1. 2Hz), 4. 83 (bs, 1H ), 4. 22 (d, 2H, J = 6. 0Hz), 1. 37 (s, 9H)

[0442] 步骤2 : (2-氯-4-甲烷磺酰基氨基-5-乙烯基苄基)氨基甲酸叔丁酯 [0442] Step 2: (2-Chloro-4-methanesulfonyl-5-vinylbenzyl) carbamate

[0443] 用氩气充满干燥的25ml的双颈圆底烧瓶,将(4_氨基_2_氯_5_乙烯基-苄基)_氨基甲酸叔丁酯(103. Omg,0. 37mmol)在二氯甲烷中的溶液加入烧瓶中并接着冷却到O0C0向该溶液缓慢加入甲烷磺酰氯(5eq,1. 83mmol, 141. 29 μ 1)和三乙胺(3eq,1. 1 lmmol, 154. 71 μ 1),并在室温搅拌12小时。 [0443] filled with argon and dried two-necked round bottom flask of 25ml, the (4_ amino _2_ _5_ vinyl chloride - benzyl) carbamate _ (. 103. Omg, 0 37mmol) in dichloromethane was added to the flask and then cooled to O0C0 to this solution was slowly added methanesulfonyl chloride (5eq, 1. 83mmol, 141. 29 μ 1) and triethylamine (3eq, 1. 1 lmmol, 154. 71 μ 1), and stirred at room temperature for 12 hours. 用TLC证实反应结束后,用NaHCO3溶液猝灭反应。 After completion of the reaction was confirmed by TLC, the reaction was quenched with NaHCO3 solution. 反应溶液用二氯甲烷提取,用CuSO4,水和盐水洗涤,通过硫酸钠干燥,过滤并在减压下浓缩。 The reaction solution was extracted with dichloromethane, washed with CuSO4 as, water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. 将获得的液体用溶液(THF : Η20 = 2 : 1)稀释,并加入NaOH(5eq,1.85mm0l,74mg)。 The obtained liquid solution (THF: 1: Η20 = 2) was diluted and added NaOH (5eq, 1.85mm0l, 74mg). 将溶液搅拌1小时,接着用TLC证实反应结束。 The solution was stirred for 1 hour, then the reaction was confirmed by TLC. 用10% HCl酸化反应溶液,用乙酸乙酯提取,用水和盐水洗涤,并通过硫酸钠干燥,过滤并在减压下浓缩。 The reaction solution was acidified with 10% HCl, extracted with ethyl acetate, washed with water and brine, and dried over sodium sulfate, filtered and concentrated under reduced pressure. 将获得的液体进行柱色谱法(正己烷/乙酸乙酯=3/1)以产生白色固体(103.9mg,79.03% )。 The liquid obtained was subjected to column chromatography (hexane / ethyl acetate = 3/1) to give a white solid (103.9mg, 79.03%).

[0444] mp :136 〜138°C ; [0444] mp: 136 ~138 ° C;

[0445] IR(KBr 片状沉淀物,cnT1) :3353,3025,2983,1683,1322,757 ; [0445] IR (KBr pellet, cnT1): 3353,3025,2983,1683,1322,757;

[0446] 1H NMR(400MHz, CDCl3) : δ 7. 42 (s, 1H), 7. 39 (s, 1H), 6. 76 (dd, 1H, J = 17. 2, [0446] 1H NMR (400MHz, CDCl3): δ 7. 42 (s, 1H), 7. 39 (s, 1H), 6. 76 (dd, 1H, J = 17. 2,

11. 2Hz) ,6. 69 (bs, 1H) 11. 2Hz), 6. 69 (bs, 1H)

[0447] 步骤3 :N-(4-氨基甲基-5-氯_2_乙烯基苯基)甲烷磺酰胺 [0447] Step 3: N- (4- aminomethyl-5-chloro _2_ vinylphenyl) methanesulfonamide

[0448] 向干燥的25ml圆底烧瓶中加入(2_氯_4_甲烷磺酰基氨基_5_乙烯基-苄基)-氨基甲酸叔丁酯(103.9mg,0. 29mmol)并用二氯甲烷稀释。 [0448] added (2_ methanesulfonyl chloride _4_ vinyl group _5_ - benzyl) - To a dried 25ml round-bottomed flask carbamate (. 103.9mg, 0 29mmol) and dichloromethane dilution. 向该溶液加入5_6滴的CF3COOH并搅拌12小时。 To this solution was added dropwise 5_6 of CF3COOH and stirred for 12 hours. 在用TLC证实反应结束后,将得到的溶液使用甲苯在减压下浓缩以产生褐色糖浆(98. Img, 130. 74% ) „ In the end of the reaction was confirmed by TLC, the resulting toluene solution was concentrated under reduced pressure to give a brown syrup (98. Img, 130. 74%) "

[0449] 1H NMR (400MHz,CD3OD) : δ 7. 81 (s, 1H), 7. 55 (s, 1H) , 7. 04 (dd, 1Η, J = 17. 2, [0449] 1H NMR (400MHz, CD3OD): δ 7. 81 (s, 1H), 7. 55 (s, 1H), 7. 04 (dd, 1Η, J = 17. 2,

4510. 8Hz),5. 88 (d, 1H, J = 17. 2Hz),5. 47 (d, 1H, J = 10. 8Hz),4. 27 (s, 2H),2. 98 (s, 3H) · 4510. 8Hz), 5. 88 (d, 1H, J = 17. 2Hz), 5. 47 (d, 1H, J = 10. 8Hz), 4. 27 (s, 2H), 2. 98 (s, 3H) ·

[0450] 步骤4 :N-{4-[3-(4-叔丁基苄基)脲基甲基]_5_氯_2_乙烯基苯基}甲烷磺酰胺 [0450] Step 4: N- {4- [3- (4- tert-butylbenzyl) ureidomethyl] _5_ chloro _2_ vinylphenyl} methanesulfonamide

[0451] 用氩气充满干燥的25ml的双颈圆底烧瓶,并将4-叔丁基苄胺(29.38μ1, 0. 18mmol)在二氯甲烷中的溶液加入烧瓶。 [0451] 25ml of dried filled with argon-neck round bottom flask, and 4-tert-butyl-benzylamine (29.38μ1, 0. 18mmol) was added in dichloromethane solution in the flask. 向该溶液缓慢加入Boc20(l. 5eq,0. 27mmol, 151. 78 μ 1)和DMAP(0. 2eq,0. 09mmol,10. 15mg)并搅拌5 小时。 To this solution was slowly added Boc20 (l. 5eq, 0. 27mmol, 151. 78 μ 1) and DMAP (0. 2eq, 0. 09mmol, 10. 15mg) and stirred for 5 hours. 在用TLC 证实产生1-叔丁基-4-异氰酰甲基-苯后,向该溶液加入N-(4-氨基甲基-5-氯-2-乙烯基-苯基)-甲烷磺酰胺(leq,0. 18mmol,46. 3mg)和TEA (2eq,0. 36mmol,50. 17 μ 1)并搅拌12 小时。 Produced was confirmed by TLC in 1 -tert-butyl 4-isocyanato-methyl - of benzene, to this solution was added N- (4- amino-5-chloro-2-vinyl - phenyl) - methanesulfonamide amide (leq, 0. 18mmol, 46. 3mg) and TEA (2eq, 0. 36mmol, 50. 17 μ 1) and stirred for 12 hours. 在证实反应进程后,将反应溶液用二氯甲烷提取,用水和盐水洗涤,通过硫酸钠干燥,过滤并在减压下浓缩。 After confirming progress of the reaction, the reaction solution was extracted with dichloromethane, washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. 将获得的液体进行柱色谱法(正己烷/乙酸乙酯=1/1)以产生白色固体(15. 5mg, 19. 18% )。 The liquid obtained was subjected to column chromatography (hexane / ethyl acetate = 1/1) to give a white solid (15. 5mg, 19. 18%).

[0452] mp :140 〜142°C ; [0452] mp: 140 ~142 ° C;

[0453] IR(KBr 片状沉淀物,cnT1) :3366,2961,1635,1313,757 ; [0453] IR (KBr pellet, cnT1): 3366,2961,1635,1313,757;

[0454] 1H NMR (400MHz, CDCl3) : δ 7. 42 (s, 1H), 7. 40 (s, 1H), 7. 28 (d, 2H, J = 8. 4Hz), 7. 16(d,2H,J = 8. 4Ηζ),6· 68 (dd, 1Η, J = 17. 2,11. 2Ηζ),6· 45 (bs, 1Η),5. 60 (d, 1Η, J = 17. 2Ηζ),5. 41 (d, 1Η, J=Il. 2Ηζ),4. 36 (s, 2Η),4. 27 (s, 2Η),2. 93 (s, 3Η),1. 23 (s,9H) · [0454] 1H NMR (400MHz, CDCl3): δ 7. 42 (s, 1H), 7. 40 (s, 1H), 7. 28 (d, 2H, J = 8. 4Hz), 7. 16 (d , 2H, J = 8. 4Ηζ), 6 · 68 (dd, 1Η, J = 17. 2,11. 2Ηζ), 6 · 45 (bs, 1Η), 5. 60 (d, 1Η, J = 17. 2Ηζ), 5. 41 (d, 1Η, J = Il. 2Ηζ), 4. 36 (s, 2Η), 4. 27 (s, 2Η), 2. 93 (s, 3Η), 1. 23 (s , 9H) ·

[0455] 实施例5 :N-{4-[3-(4-叔丁基苄基)脲基甲基]_5_氯_2_乙炔基苯基}甲烷磺酰胺 [0455] Example 5: N- {4- [3- (4- tert-butylbenzyl) ureidomethyl] _5_ chloro _2_ ethynyl phenyl} methanesulfonamide

Figure CN101142174BD00461

[0457] 步骤1 : (4-氨基-2-氯-5-三甲基硅烷基乙炔基苄基)氨基甲酸叔丁酯 [0457] Step 1: (4-amino-2-chloro-5-trimethylsilanyl-ethynyl-benzyl) carbamate

[0458] 用氩气充满干燥的25ml的双颈圆底烧瓶,并将(4_氨基_2_氯_5_碘-苄基)-氨基甲酸叔丁酯(60mg,0. 16mmol), CuI (0. 05eq, 0. 008mmol, 1. 52mg)禾Π PdCl2 (PPh3)2 在DMF 中的溶液置于烧瓶。 [0458] filled with dry two-necked round bottom flask with argon, 25ml, and (4_ amino _2_ _5_ iodo-chloro - benzyl) - carbamate (. 60mg, 0 16mmol), CuI (0. 05eq, 0. 008mmol, 1. 52mg) Wo Π PdCl2 (PPh3) 2 in DMF was placed in a flask. 将溶液在室温搅拌30分钟。 The solution was stirred at room temperature for 30 minutes. 向该溶液加入(TMS)乙炔基(1.3叫, To this was added a solution of (TMS) acetylene (1.3 call,

0. 21mmol,29. 39mg)和三乙胺(3eq,0. 48mmol,66. 90 μ 1)并加热以回流12 小时。 0. 21mmol, 29. 39mg) and triethylamine (3eq, 0. 48mmol, 66. 90 μ 1) and heated to reflux for 12 hours. 在用TLC 证实反应结束后,将得到的溶液用乙酸乙酯提取,用水和盐水洗涤,通过硫酸钠干燥,过滤并在减压下浓缩。 In the end of the reaction was confirmed by TLC, the resulting solution was extracted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. 将获得的液体进行柱色谱法(正己烷/乙酸乙酯=6/1)以产生橙色固体(44. 9mg,81. 17% ) „ The liquid obtained was subjected to column chromatography (hexane / ethyl acetate = 6/1) to give an orange solid (44. 9mg, 81. 17%) "

[0459] mp :104 〜106°C ; [0459] mp: 104 ~106 ° C;

[0460] IR(KBr 片状沉淀物,cnT1) :3356,2962,2143,1698,843 ; [0460] IR (KBr pellet, cnT1): 3356,2962,2143,1698,843;

[0461] 1H NMR(400MHz, CDCl3) :7· 17 (s,1H),6. 61 (s,1H),4. 77 (bs,1H),4. 14 (d,2H,J = 6. 0Hz),1. 35(s,9H),0· 15(s,9H). [0461] 1H NMR (400MHz, CDCl3):... 7 · 17 (s, 1H), 6 61 (s, 1H), 4 77 (bs, 1H), 4 14 (d, 2H, J = 6. 0Hz), 1. 35 (s, 9H), 0 · 15 (s, 9H).

[0462] 步骤2 : (2-氯-5-乙炔基-4-甲烷磺酰基氨基苄基)氨基甲酸叔丁酯 [0462] Step 2: (2-Chloro-5-ethynyl-4-methanesulfonyl-aminobenzyl) carbamate

[0463] 用氩气充满干燥的25ml的双颈圆底烧瓶。 [0463] 25ml of dried filled with argon, two-necked round bottom flask. 将(4_氨基_2_氯_5_三甲基硅烷基乙炔基-苄基)-氨基甲酸叔丁酯(225. 3mg,0. 64mmol)在二氯甲烷中的溶液置于烧瓶并接着冷却到0°C。 The (4_ amino _2_ chloro _5_ trimethylsilanyl ethynyl - benzyl) - carbamate (. 225. 3mg, 0 64mmol) in dichloromethane was placed in a flask and then It was cooled to 0 ° C. 向该溶液缓慢加入甲烷磺酰氯(5eq,3. 20mmol,247. 60 μ 1)和三乙胺(3eq, To this solution was slowly added methanesulfonyl chloride (5eq, 3. 20mmol, 247. 60 μ 1) and triethylamine (3eq,

1. 92mmol,267. 61 μ 1)并在室温搅拌12小时。 1. 92mmol, 267. 61 μ 1) and stirred at room temperature for 12 hours. 在用TLC证实反应结束后,用NaHCO3溶液猝灭反应。 In the end of the reaction was confirmed by TLC, the reaction was quenched with NaHCO3 solution. 将反应溶液用二氯甲烷提取,用CuSO4,水和盐水洗涤,通过硫酸钠干燥,过滤并在减压下浓缩。 The reaction solution was extracted with dichloromethane, washed with CuSO4 as, water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. 将获得的液体用溶液(THF : H20 = 2 : 1)稀释并向该溶液加入NaOH(5eq, The obtained liquid was diluted and the solution was added NaOH (5eq the solution, (THF: 1: H20 = 2)

3. 20mmol, 128mg)。 3. 20mmol, 128mg). 将混合物搅拌1小时。 The mixture was stirred for 1 hour. 在用TLC证实反应结束后,用10% HCl将反应溶液酸化,用乙酸乙酯提取,用水和盐水洗涤,通过硫酸钠干燥,过滤,并在减压下浓缩。 In the end of the reaction was confirmed by TLC, the reaction with 10% HCl solution was acidified, extracted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. 将获得的液体进行柱色谱法(正己烷/乙酸乙酯=3/1)以产生白色固体(182. 6mg,79. 70% )。 The liquid obtained was subjected to column chromatography (hexane / ethyl acetate = 3/1) to give a white solid (182. 6mg, 79. 70%).

[0464] mp :138 〜140°C ; [0464] mp: 138 ~140 ° C;

[0465] IR(KBr 片状沉淀物,cnT1) :3371,3025,2987,1694,1327,701 ; [0465] IR (KBr pellet, cnT1): 3371,3025,2987,1694,1327,701;

[0466] 1H NMR (400MHz, CDCl3) : δ 7. 53 (s,1H),7. 40 (s,1H),6. 99 (bs,1H),5. 06 (s,1H), [0466] 1H NMR (400MHz, CDCl3):... Δ 7. 53 (s, 1H), 7 40 (s, 1H), 6 99 (bs, 1H), 5 06 (s, 1H),

4. 23 (d, 2H, J = 6. OHz),2. 95 (s, 3H),1. 35 (s,9H) · 4. 23 (d, 2H, J = 6. OHz), 2. 95 (s, 3H), 1. 35 (s, 9H) ·

[0467] 步骤3 :N-(4-氨基甲基-5-氯_2_乙炔基苯基)甲烷磺酰胺 [0467] Step 3: N- (4- aminomethyl-5-chloro _2_ ethynylphenyl) methanesulfonamide

[0468] 用氩气充满干燥的25ml的双颈圆底烧瓶,并将(2_氯_5_乙炔基_4_甲烷磺酰基氨基-苄基)-氨基甲酸叔丁酯(182.6mg,0.51mmOl)在二氯甲烷中的溶液置于烧瓶中。 [0468] 25ml of dried filled with argon-neck round bottom flask, and (2_ chloro _5_ ethynyl _4_ methane sulfonylamino - benzyl) - carbamic acid tert-butyl ester (182.6mg, 0.51 mmol) in dichloromethane was placed in a flask. 向该溶液加入5〜6滴的CF3COOH并搅拌12小时。 To this solution was added 5 ~ 6 drops of CF3COOH and stirred for 12 hours. 在用TLC证实反应结束后,将得到的溶液使用甲苯在减压下浓缩以产生褐色糖浆(98. Img, 114. 23% )0 In the end of the reaction was confirmed by TLC, the resulting toluene solution was concentrated under reduced pressure to give a brown syrup (98. Img, 114. 23%) 0

[0469] 1H NMR (400MHz,CD3OD) : δ 7· 69 (s,1H),7· 66 (s,1H),4· 22 (s,2H),4· 04 (s,1H), 3. 03(s,3H). [0469] 1H NMR (400MHz, CD3OD): δ 7 · 69 (s, 1H), 7 · 66 (s, 1H), 4 · 22 (s, 2H), 4 · 04 (s, 1H), 3. 03 (s, 3H).

[0470] 步骤4 :N-{4-[3-(4-叔丁基苄基)脲基甲基]_5_氯_2_乙炔基苯基}甲烷磺酰胺 [0470] Step 4: N- {4- [3- (4- tert-butylbenzyl) ureidomethyl] _5_ chloro _2_ ethynyl phenyl} methanesulfonamide

[0471] 用氩气充满干燥的25ml的双颈圆底烧瓶,并将4_叔丁基-苄胺(44. 08 μ 1, 0. 27mmol)在二氯甲烷中的溶液置于烧瓶中。 [0471] 25ml of dried filled with argon-neck round bottom flask, and t-butyl 4 _ - benzylamine (44. 08 μ 1, 0. 27mmol) in dichloromethane was placed in a flask. 向该溶液缓慢加入BOc20(l. 5eq,0. 41mmol, 93. 14 μ 1)和DMAP(0. 2eq,0. 05讓ol,6. 59mg)并搅拌5小时。 To this solution was slowly added BOc20 (l. 5eq, 0. 41mmol, 93. 14 μ 1) and DMAP (0. 2eq, 0. 05 let ol, 6. 59mg) and stirred for 5 hours. 在用TLC证实产生1-叔丁基-4-异氰酰甲基-苯后,向该溶液加入N-(4-氨基甲基-5-氯-2-乙炔基-苯基)-甲烷磺酰胺(leq,0. 27mmol,70mg)和TEA(2eq,0. 54mmol,75. 27 μ 1)并搅拌12 小时。 Produced was confirmed by TLC in 1 -tert-butyl 4-isocyanato-methyl - of benzene, to this solution was added N- (4- aminomethyl-5-chloro-2-ethynyl - phenyl) - methanesulfonamide amide (leq, 0. 27mmol, 70mg) and TEA (2eq, 0. 54mmol, 75. 27 μ 1) and stirred for 12 hours. 在用TLC 证实反应进程后,将反应溶液用二氯甲烷提取,用水和盐水洗涤,通过硫酸钠干燥,过滤并在减压下浓缩。 After confirming progress of the reaction by TLC, the reaction solution was extracted with dichloromethane, washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. 将获得的液体进行柱色谱法(正己烷/乙酸乙酯=1/1)以产生白色固体(20. 20mg, 16. 73% )。 The liquid obtained was subjected to column chromatography (hexane / ethyl acetate = 1/1) to give a white solid (20. 20mg, 16. 73%).

[0472] mp :116 〜118°C ; [0472] mp: 116 ~118 ° C;

[0473] IR(KBr 片状沉淀物,cnT1) :3282,3025,2961,2202,1636,1329,762 ; [0473] IR (KBr pellet, cnT1): 3282,3025,2961,2202,1636,1329,762;

[0474] 1H NMR (400MHz, CDCl3) : δ 7. 53 (s, 1H) , 7. 46 (s , 1H) , 7. 27 (d, 2H, J = 8. 4Hz) 7. 14 (d, 2H, J = 8. OHz) ,6. 91 (bs, 1H),4. 30 (s, 2H),4. 25 (s,2H) 3. 44 (s, 3H), 3. 02 (s,1H),2. 95 (s, 3H),1. 22 (s,9H) · [0474] 1H NMR (400MHz, CDCl3): δ 7. 53 (s, 1H), 7. 46 (s, 1H), 7. 27 (d, 2H, J = 8. 4Hz) 7. 14 (d, 2H, J = 8. OHz), 6. 91 (bs, 1H), 4. 30 (s, 2H), 4. 25 (s, 2H) 3. 44 (s, 3H), 3. 02 (s, 1H), 2. 95 (s, 3H), 1. 22 (s, 9H) ·

[0475] 实施例6 :N-(4-{l-(R)-[3-(4-叔丁基苄基)脲基]乙基}_2_乙烯基苯基)甲烷磺酰胺 [0475] Example 6: N- (4- {l- (R) - [3- (4- tert-butyl-benzyl) ureido] ethyl} _2_ vinylphenyl) methanesulfonamide

[0476] [0476]

Figure CN101142174BD00471

[0477] 步骤1 :(R)-[1_(4-硝基苯基)乙基]氨基甲酸叔丁酯[0478] 将(R)-甲基-4-硝基苄胺HCl (50mg,0. 25mmol)置于25ml圆底烧瓶中并溶解于饱和溶液(NaHCO3 : CH2Cl2 = 1 : 1)。 [0477] Step 1: (R) - [1_ (4- nitrophenyl) ethyl] carbamate [0478] The (R) - methyl-4-nitro-benzylamine HCl (50mg, 0 . 25mmol) placed in 25ml round bottom flask and dissolved in a saturated solution (NaHCO3: CH2Cl2 = 1: 1). 向该溶液加入二叔丁基二碳酸酯(135mg,0. 60mmol, 2. 5eq)并搅拌3小时。 To this solution was added di-tert-butyl dicarbonate (135mg, 0. 60mmol, 2. 5eq) and stirred for 3 hours. 用二氯甲烷稀释反应混合物,用水和盐水洗涤,通过硫酸钠干燥并在减压下浓缩。 The reaction was diluted mixture was washed with water and with dichloromethane and brine, dried over sodium sulfate and concentrated under reduced pressure. 将获得的液体进行柱色谱法(正己烷/乙酸乙酯=10/1)以产生浅黄色固体(62. Omg,94. 38% ) „ The liquid obtained was subjected to column chromatography (hexane / ethyl acetate = 10/1) to give a pale yellow solid (62. Omg, 94. 38%) "

[0479] [ α ]2L6d :-43. 66°C (c 1. 33,CHCl3); . [0479] [α] 2L6d: -43 66 ° C (c 1. 33, CHCl3);

[0480] IR(NaCl 纯的,cnT1) :3403,3332,2977,2932,1697,1522,1347 ; [0480] IR (NaCl neat, cnT1): 3403,3332,2977,2932,1697,1522,1347;

[0481] 1H NMR(400MHz, CDCl3) :8.20(d,2H,J = 8. 8Hz),7· 47 (d,2H,J = 8· 8Hz),4· 91 (s, 1Η),4. 85 (s,1Η),1. 46 (d, 3H, J = 6. 8Hz),1. 42 (s,9H) · [0481] 1H NMR (400MHz, CDCl3): 8.20 (d, 2H, J = 8. 8Hz), 7 · 47 (d, 2H, J = 8 · 8Hz), 4 · 91 (s, 1Η), 4. 85 (s, 1Η), 1. 46 (d, 3H, J = 6. 8Hz), 1. 42 (s, 9H) ·

[0482] 步骤2 :(R)-[1_(4-氨基苯基)乙基]氨基甲酸叔丁酯 [0482] Step 2: (R) - [1_ (4- aminophenyl) ethyl] carbamate

[0483] 将(R)-[1-(4-硝基苯基)乙基]氨基甲酸叔丁酯(25mg,0. 09mmol)置于25ml圆底烧瓶中并溶解在甲醇中。 [0483] The (R) - [1- (4- nitrophenyl) ethyl] carbamate (. 25mg, 0 09mmol) was placed in a 25ml round bottomed flask and dissolved in methanol. 向该溶液加入Pd(7mg,底物的30%。用氢气替换烧瓶中的空气,并搅拌2小时。在用TLC证实反应结束后,滤去Pd/C,在减压下去除甲醇以产生透明黄色液体(21. 7mg,91. 93% ) „ To this solution was added Pd (7mg, 30% of the substrate. Alternatively the air in the flask with hydrogen, and stirred for 2 hours at the end of the reaction was confirmed by TLC, was filtered off Pd / C, methanol was removed under reduced pressure to yield a clear a yellow liquid (21. 7mg, 91. 93%) "

[0484] [ α ]22-°d :-69. 75°C (c 1. 02,CHCl3); . [0484] [α] 22- ° d: -69 75 ° C (c 1. 02, CHCl3);

[0485] IR(NaCl 纯的,cnT1) :3353,3035,2974,2937,1695,1623,1366 ; [0485] IR (NaCl neat, cnT1): 3353,3035,2974,2937,1695,1623,1366;

[0486] 1H NMR(400MHz, CDCl3) :7· 10(d,2H,J = 8. 0Hz),6· 40(d,2H,J = 8. 0Hz) ,4. 70 (s, 2H), 3. 60(s,2H),1. 42 (s, 12H). [0486] 1H NMR (400MHz, CDCl3): 7 · 10 (d, 2H, J = 8. 0Hz), 6 · 40 (d, 2H, J = 8. 0Hz), 4 70 (s, 2H),. 3. 60 (s, 2H), 1. 42 (s, 12H).

[0487] 步骤3:(R)-[1_(4-氨基-3-碘苯基)乙基]氨基甲酸叔丁酯 [0487] Step 3: (R) - [1_ (4- amino-3-iodo-phenyl) ethyl] carbamate

[0488] 将[1-(4_氨基-苯基)_乙基]-氨基甲酸叔丁酯(141. lmg,0. 60mmol,Ieq.)在二氯甲烷中的溶液置于50ml双颈圆底烧瓶中。 [0488] [1- (4_ amino - phenyl) _ ethyl] - carbamate (.. 141. lmg, 0 60mmol, Ieq) in dichloromethane was placed in a 50ml two-necked round bottom flask. 向该溶液加入一氯化碘(106. 6mg,0. 66mmol, 1. leq.)并在室温搅拌1小时。 To this was added a solution of iodine monochloride (106. 6mg, 0. 66mmol, 1. leq.) And stirred at room temperature for 1 hour. 在用TLC证实反应结束后,将得到的溶液用饱和的Na2S2O3 溶液,水和盐水洗涤,通过硫酸钠干燥,过滤,并蒸发。 In the end of the reaction was confirmed by TLC, the resulting solution was washed with saturated Na2S2O3 solution, water and brine, dried over sodium sulfate, filtered, and evaporated. 将获得的液体进行柱色谱法(正己烷/乙酸乙酯=5/1)以产生褐色液体(102. 7mg)。 The liquid obtained was subjected to column chromatography (hexane / ethyl acetate = 5/1) to give a brown liquid (102. 7mg).

[0489] [α ]23d :+55. 03°C (c 0. 60,CHCl3); . [0489] [α] 23d: +55 03 ° C (c 0. 60, CHCl3);

[0490] IR(NaCl 纯的,cnT1) :3423,3343,2973,296,1692,1498,1167 ; [0490] IR (NaCl neat, cnT1): 3423,3343,2973,296,1692,1498,1167;

[0491] 1H NMR(400MHz, CDCl3) :7.48(d,lH,J = 1. 6Hz), 7. 01 (d, 1H, J = 8. 4Hz) ,6. 62 (d, 1H, J = 8. 4Hz),4. 63-4. 57 (m, 2H),1. 35 (s,9H),1. 32 (d, 3H, J = 6. 8Hz) · [0491] 1H NMR (400MHz, CDCl3): 7.48 (d, lH, J = 1. 6Hz), 7. 01 (d, 1H, J = 8. 4Hz), 6 62 (d, 1H, J = 8. . 4Hz), 4. 63-4. 57 (m, 2H), 1. 35 (s, 9H), 1. 32 (d, 3H, J = 6. 8Hz) ·

[0492] 步骤4:(R)-[1_(4-氨基-3-乙烯基苯基)乙基]氨基甲酸叔丁酯 [0492] Step 4: (R) - [1_ (4- amino-3-vinylphenyl) ethyl] carbamate

[0493] 用氩气充满干燥的25ml的双颈圆底烧瓶,并将四(三苯基膦)钯(0) (27. 9mg, 0. 02mmol,0. 06eq.)和氯化锂(47. 7mg, 1. 13mmol,2. 8eq.)在DMF中的溶液置于烧瓶。 [0493] 25ml of dried filled with argon-neck round bottom flask, and tetrakis (triphenylphosphine) palladium (0) (27. 9mg, 0. 02mmol, 0. 06eq.) And lithium chloride (47 . 7mg, 1. 13mmol, 2. 8eq.) in DMF was placed in a flask. 向该溶液加入[1-(4-氨基-3-碘苯基)乙基]氨基甲酸叔丁酯(145. 5mg,0. 40mmol,leq.)和三丁基乙烯基锡(176. 2μ l,0.60mmOl,1.5eq.)并加热到90°C以回流一夜。 To this solution was added [1- (4-amino-3-iodophenyl) ethyl] carbamate (145. 5mg, 0. 40mmol, leq.) And tributylvinyltin (176. 2μ l , 0.60mmOl, 1.5eq.) and heated to 90 ° C to reflux overnight. 在用TLC证实反应结束后,在减压下去除DMF并用二氯甲烷提取。 With TLC confirmed completion of the reaction, the DMF was removed under reduced pressure and extracted with dichloromethane. 用水和饱和的盐水洗涤二氯甲烷层,通过硫酸钠干燥,过滤并在减压下浓缩。 Water and saturated brine dichloromethane layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. 将获得的液体进行柱色谱法(正己烷/乙酸乙酯= 5/1)以产生褐色液体(76. 3mg,72. 3%). The liquid obtained was subjected to column chromatography (hexane / ethyl acetate = 5/1) to give a brown liquid (76. 3mg, 72. 3%).

[0494] [α ]23d :+59. 07°C (c 0. 43,CHCl3); . [0494] [α] 23d: +59 07 ° C (c 0. 43, CHCl3);

[0495] IR(NaCl 纯的,cnT1) :3369,2972,2922,2852,1687 ; [0495] IR (NaCl neat, cnT1): 3369,2972,2922,2852,1687;

[0496] 1H NMR(400MHz, CDCl3) :7. 14 (d, 1H, J=L 6Ηζ),6· 96 (dd, 1H, J = 8· 4,1. 6Ηζ), [0496] 1H NMR (400MHz, CDCl3):. 7 14 (d, 1H, J = L 6Ηζ), 6 · 96 (dd, 1H, J = 8 · 4,1 6Ηζ.),

486. 69 (dd, 1H, J = 17. 6,11. 2Hz) ,6. 58 (d, 1H, J = 8. 4Hz),5. 56 (dd, 1H, J = 17. 6,1. 6Hz), 5. 25 (dd, 1H, J = 11. 2,1. 6Hz) ,4. 64(bs,2H),1. 37-1. 35 (m, 12H). 486. 69 (dd, 1H, J = 17. 6,11. 2Hz), 6. 58 (d, 1H, J = 8. 4Hz), 5. 56 (dd, 1H, J = 17. 6,1. 6Hz), 5. 25 (dd, 1H, J = 11. 2,1. 6Hz), 4. 64 (bs, 2H), 1. 37-1. 35 (m, 12H).

[0497] 步骤5 : (R)-[l-(4-甲烷磺酰基氨基_3_乙烯基苯基)乙基]氨基甲酸叔丁酯 [0497] Step 5: (R) - [l- (4- methanesulfonylamino-_3_ vinylphenyl) ethyl] carbamate

[0498] 用氩气充满IOOml的双颈圆底烧瓶,并将(R)-[l_(4_氨基_3_乙烯基苯基)乙基]氨基甲酸叔丁酯(358. 5mg,1.366mmol,leq.)在二氯甲烷中的溶液置于所述烧瓶并接着冷却到0°C。 [0498] IOOml filled with argon-neck round bottom flask, and (R) - [l_ (4_ amino _3_ vinylphenyl) ethyl] carbamate (358. 5mg, 1.366mmol , leq.) in dichloromethane was placed in the flask and then cooled to 0 ° C. 向该溶液加入甲烷磺酰酐(285. 7mg,1.640mmol,1.2eq.)随后加入吡啶(328. 4 μ 1,4. 098mmol,2eq.)并搅拌1小时。 To this solution was added methanesulfonyl anhydride (285. 7mg, 1.640mmol, 1.2eq.) Was added followed by pyridine (328. 4 μ 1,4. 098mmol, 2eq.) And stirred for 1 hour. 在用TLC证实反应结束后,向该溶液加入饱和的碳酸氢钠溶液并搅拌5分钟。 In the end of the reaction was confirmed by TLC, this solution was added saturated sodium bicarbonate solution and stirred for 5 minutes. 得到的溶液用二氯甲烷提取,用5% HC1,饱和的NaHCO3 溶液,水和盐水洗涤,通过硫酸钠干燥,过滤并蒸发。 The resulting solution was extracted with dichloromethane, washed with 5% HC1, saturated NaHCO3 solution, water and brine, dried over sodium sulfate, filtered and evaporated. 将获得的固体进行柱色谱法(正己烷/乙酸乙酯=2/1)以产生浅黄色固体(169. Omg,47. 2% )。 The obtained solid was subjected to column chromatography (hexane / ethyl acetate = 2/1) to give a pale yellow solid (169. Omg, 47. 2%).

[0499] [a J20d :+34. 74°C (c 0. 43,CHCl3); . [0499] [a J20d: +34 74 ° C (c 0. 43, CHCl3);

[0500] IR (KBr 片状沉淀物,cnT1) :3361,3265,3080,2978,2929,2851,1682 ; [0500] IR (KBr pellet, cnT1): 3361,3265,3080,2978,2929,2851,1682;

[0501] 1H NMR(400MHz, CDCl3) :7. 36 (d,1H,J = 8. 4Hz),7. 34 (d. 1H,J = 2. OHz),7. 17 (dd, 1H, J = 8· 4,2. OHz),6. 83 (dd, 1Η, J = 17. 2,10. 8Ηζ),6. 35 (bs, 1Η),5. 66 (d, 1Η, J = 17. 2Ηζ),5. 40 (d, 1Η, J = 10. 8Ηζ),4. 82-4. 63 (m, 2Η),2. 92 (s, 3H),1. 38-1. 36 (m, 12H) · [0501] 1H NMR (400MHz, CDCl3):. 7 36 (d, 1H, J = 8. 4Hz), 7 34, 7 17 (dd, 1H, J. (D 1H, J = 2. OHz.). = 8 · 4,2. OHz), 6. 83 (dd, 1Η, J = 17. 2,10. 8Ηζ), 6. 35 (bs, 1Η), 5. 66 (d, 1Η, J = 17. 2Ηζ), 5. 40 (d, 1Η, J = 10. 8Ηζ), 4. 82-4. 63 (m, 2Η), 2. 92 (s, 3H), 1. 38-1. 36 (m, 12H) ·

[0502] 步骤6 : (R)-[1-(4-甲烷磺酰基氨基-3-乙烯基苯基)乙基]铵三氟-乙酸盐 [0502] Step 6: (R) - [1- (4- methanesulfonyl-3-vinylphenyl) ethyl] ammonium trifluoro - acetate

[0503] 将[1-(4_甲烷磺酰基氨基-3-乙烯基苯基)乙基]氨基甲酸叔丁酯(158. 4mg, 0.465 mm0l,leq.)置于IOOml圆底烧瓶中并溶解于二氯甲烷。 [0503] [1- (4_ methanesulfonyl-3-vinylphenyl) ethyl] carbamate (158. 4mg, 0.465 mm0l, leq.) Was placed in a round bottom flask and dissolved IOOml in dichloromethane. 向该溶液加入三氟乙酸(179. 2μ 1,2. 326mmol,5eq.)并搅拌一夜。 To this solution was added trifluoroacetic acid (179. 2μ 1,2. 326mmol, 5eq.) And stirred overnight. 在用TLC证实反应结束后,在减压下浓缩反应溶液以产生褐色粗制液体(236. 7mg)。 In the completion of the reaction was confirmed by TLC, the reaction solution was concentrated under reduced pressure to give a brown crude liquid (236. 7mg).

[0504]步骤 7 : [0504] Step 7:

[0505] N-(4-{l-(R)-[3_(4-叔丁基苄基)脲基]乙基}_2_乙烯基苯基)甲烷磺酰胺 [0505] N- (4- {l- (R) - [3_ (4- tert-butyl-benzyl) ureido] ethyl} _2_ vinylphenyl) methanesulfonamide

[0506] 用氩气充满25ml的双颈圆底烧瓶,并将4-叔丁基苄胺(14. 8 μ 1,0. 084mmol, leq.)在二氯甲烷中的溶液置于所述烧瓶。 [0506] bis neck round bottom flask filled with argon, 25ml, and 4-tert-butyl-benzylamine (14. 8 μ 1,0. 084mmol, leq.) In dichloromethane was placed in the flask . 向该溶液加入4-二甲基氨基吡啶(2. lmg, 0. 017mmol,0. 2eq.)和二碳酸二叔丁酯(23. 2μ 1,0. IOlmmol,1. 2eq.)并在室温搅拌3 小时。 To this was added 4-dimethylaminopyridine (2. lmg, 0. 017mmol, 0. 2eq.) And di-tert-butyl dicarbonate (23. 2μ 1,0. IOlmmol, 1. 2eq.) At room for 3 hours. 将得到的溶液冷却到0°c并加入[1-(4_甲烷磺酰基氨基-3-乙烯基苯基)乙基]铵三氟-乙酸盐(30mg,0.084mmol,leq.)和三乙胺(23. 4μ 1,0. 168mmol,2eq.)在二氯甲烷中的溶液。 The resulting solution was cooled to 0 ° c was added [1- (4_ methanesulfonyl-3-vinylphenyl) ethyl] ammonium trifluoromethyl - (. 30mg, 0.084mmol, leq) acetate and tris of triethylamine in dichloromethane (23. 4μ 1,0. 168mmol, 2eq.). 将混合物溶液在室温搅拌一夜。 The mixture was stirred overnight at rt. 在用TLC证实反应结束后,在减压下去除二氯甲烷。 In the end of the reaction was confirmed by TLC, dichloromethane was removed under reduced pressure. 将剩余的液体进行柱色谱法(正己烷/乙酸乙酯=1/1)以产生浅黄色固体(21.8mg, 60. 4% )。 The remaining liquid was subjected to column chromatography (hexane / ethyl acetate = 1/1) to give a pale yellow solid (21.8mg, 60. 4%).

[0507] mp : 105. 1-105. 8°C ; . [0507] mp: 105. 1-105 8 ° C;

[0508] [a J23d :-5. 00°C (c 0. 46,CHCl3); . [0508] [a J23d: -5 00 ° C (c 0. 46, CHCl3);

[0509] IR(KBr 片状沉淀物,cnT1) :3418,3029,2963,2926,2869,1634 ; [0509] IR (KBr pellet, cnT1): 3418,3029,2963,2926,2869,1634;

[0510] 1H NMR(400MHz, CDCl3) :7. 33 (d, 1H, J = 1. 6Hz),7. 30 (d, 1H, J = 8. 4Hz),7. 26 (d, 2H, J = 8. OHz) ,7. 11-7. 08 (m, 3H), 6. 81 (dd, 1H, J = 17. 2,10. 8Hz) ,6. 49 (bs, 1H),5. 62 (d, 1H, J = 17. 2Hz),5. 37 (d, 1H, J = 10. 8Hz),4. 77 (q, 1H, J = 6. 8Hz),4. 64 (bs, 2H),4. 24 (s, 2H),2. 89 (s,3H),1. 34 (d, 3H, J = 6. 8Hz),1. 23 (s,9H) · [0510] 1H NMR (400MHz, CDCl3):. (D, 1H, J = 1. 6Hz) 7 33, 7 30 (d, 1H, J = 8. 4Hz), 7 26 (d, 2H, J.. = 8. OHz), 7. 11-7. 08 (m, 3H), 6. 81 (dd, 1H, J = 17. 2,10. 8Hz), 6. 49 (bs, 1H), 5. 62 (d, 1H, J = 17. 2Hz), 5. 37 (d, 1H, J = 10. 8Hz), 4. 77 (q, 1H, J = 6. 8Hz), 4. 64 (bs, 2H) , 4. 24 (s, 2H), 2. 89 (s, 3H), 1. 34 (d, 3H, J = 6. 8Hz), 1. 23 (s, 9H) ·

[0511] 实施例7: [0511] Example 7:

[0512] (R) -N- (4- {1- [3- (4_叔丁基-苄基)_脲基]-乙基} _2_氟_6_乙烯基-苯基)_甲烷磺酰胺 [0512] (R) -N- (4- {1- [3- (4_-tert-butyl-benzyl) - _ ureido] - ethyl} _2_ _6_ vinyl-fluoro-phenyl) - methane _ sulfonamide

[0513] [0513]

[0514] 步骤1 : 1- (4-氨基-3-氟苯基)乙烷酮 [0514] Step 1: 1- (4-amino-3-fluorophenyl) ethanone

[0515] 用氩气充满25ml的双颈圆底烧瓶并将2_氟_4_碘苯胺(1500mg,6. 33mmol)在DMF 中的溶液,乙酸钯(II) (0. 19mmol,42. 62mg),1,3-双苯基膦基丙烷(0. 06eq,0. 38mmol, 156. 65mg),乙酸铊(I) (6. 96mmol, 1834. 19mg),丁基乙烯基醚(2eq, 12. 66mmol, 1. 64ml)置于所述烧瓶。 [0515] bis neck round bottom flask filled with argon and 25ml 2_ fluoro _4_ iodoaniline (1500mg, 6. 33mmol) in DMF, and palladium (II) acetate (0. 19mmol, 42. 62mg ), 1,3-bis diphenylphosphino propane (0. 06eq, 0. 38mmol, 156. 65mg), thallium (I) acetate (6. 96mmol, 1834. 19mg), butyl vinyl ether (2eq, 12 . 66mmol, 1. 64ml) was placed on the flask. 将反应混合物加热并搅拌15小时。 The reaction mixture was heated and stirred for 15 hours. 将反应混合物倾入THF溶液中,并接着缓慢加入10%HC1。 The reaction mixture was poured in THF, and then slowly added to 10% HC1. 用乙酸乙酯提取反应混合物(300X3),用H2O和盐水洗涤。 The reaction mixture was extracted with ethyl acetate (300X3), washed with H2O and brine. 将合并的有机溶液用硫酸钠干燥并接着用柱色谱法(n-Hx : EA = 3 : 1)进行纯化以产生浅黄色固体(343. Omg, 35. 40% ) „ The combined organic solution was then dried over sodium sulfate and purified by column chromatography (n-Hx: 1: EA = 3) to give a pale yellow solid (343. Omg, 35. 40%) "

[0516] mp:77〜79°C; [0516] mp: 77~79 ° C;

[0517] IR(KBr 片状沉淀物,cnT1) :3373,3326,1663,1296 ;1H NMR(400MHz, CDCl3): δ 7. 53 (m, 2H),6. 69 (m, 1H),3. 41 (s, 2H),2. 43 (s, 3H). [0517] IR (KBr pellet, cnT1): 3373,3326,1663,1296; 1H NMR (400MHz, CDCl3):. Δ 7. 53 (m, 2H), 6 69 (m, 1H), 3 . 41 (s, 2H), 2. 43 (s, 3H).

[0518] 步骤2 : 1-(4-氨基-3-氟-5-碘苯基)乙烷酮 [0518] Step 2: Preparation of 1- (4-amino-3-fluoro-5-iodophenyl) ethanone

[0519] 将1-(4_氨基-3-氟苯基)乙烷酮(0. 30mmol,45.6mg)加入乙腈,并接着加入NIS(0.33mol,73.73mg)。 [0519] 1- (4_-amino-3-fluorophenyl) ethanone (0. 30mmol, 45.6mg) was added acetonitrile, and then added NIS (0.33mol, 73.73mg). 将反应混合物搅拌12小时。 The reaction mixture was stirred for 12 hours. 用硫代硫酸钠猝灭反应混合物。 The reaction mixture was quenched with sodium thiosulfate. 用EtOAC和H2O提取反应混合物,用盐水洗涤合并的有机层并用Na2SO4干燥,接着在真空中浓缩。 The reaction mixture was extracted with EtOAC and H2O, organic layer was washed with brine and dried over Na2SO4, then concentrated in vacuo. 将剩余的层用柱色谱法(n-Hx : EtOAc = 7 : 1)进行纯化以产生褐色固体(53. 92mg, 64. 43% )。 The remaining layer was purified by column chromatography (n-Hx: EtOAc = 7: 1) was purified to yield a brown solid (53. 92mg, 64. 43%).

[0520] mp :124 〜126°C ; [0520] mp: 124 ~126 ° C;

[0521] IR(KBr 片状沉淀物):3455, 3331, 3073, 2921,1659,1259cm-1 ; [0521] IR (KBr pellet): 3455, 3331, 3073, 2921,1659,1259cm-1;

[0522] 1H NMR(400MHz, CDCl3) : 5 8. 01(dd, 1H, J = 1. 6,1. 2Hz),7. 65 (dd,1H,J = 11. 6, 2. 0Hz) ,4. 61 (bs, 2H),2. 46 (s, 3H) · [0522] 1H NMR (400MHz, CDCl3):. 5 8. 01 (. Dd, 1H, J = 1. 6,1 2Hz), 7 65 (dd, 1H, J = 11. 6, 2. 0Hz), 4. 61 (bs, 2H), 2. 46 (s, 3H) ·

[0523] 步骤3 :2-甲基丙烷-2-亚磺酸[1-(4_氨基_3_氟_5_碘苯基)乙基]酰胺 [0523] Step 3: 2-Methyl-2-sulfinic acid [l- (amino _3_ 4_ fluoro _5_ iodophenyl) ethyl] amide

[0524]将 1-(4-氨基-3-氟-5-碘苯基)乙烷酮(0. 36mmol, IOOmg),Ti (OEt) 4 (0. 59mmol, 122. 68μ 1), (R)_(+)-2-甲基-2-丙烷亚磺酰胺(0. 32mmol,39. 27mg)加入THF 溶液。 [0524] 1- (4-amino-3-fluoro-5-iodophenyl) ethanone (0. 36mmol, IOOmg), Ti (OEt) 4 (0. 59mmol, 122. 68μ 1), (R ) _ (+) - 2- methyl-2-propanesulfinamide (0. 32mmol, 39 27mg) in THF was added. 将反应混合物加热并搅拌12小时。 The reaction mixture was heated and stirred for 12 hours. 在用TLC证实反应结束后,将反应混合物冷却到-40°C。 In the completion of the reaction was confirmed by TLC, the reaction mixture was cooled to -40 ° C. 将妝8扎(1.1911111101,45.081^)加入反应混合物中。 The makeup 8 bar (1.1911111101,45.081 ^) was added to the reaction mixture. 将反应混合物在_40°C搅拌12小时。 The reaction mixture was stirred at _40 ° C 12 h. 将MeOH加入反应混合物中。 MeOH was added to the reaction mixture. 将反应混合物加热到室温。 The reaction mixture was warmed to room temperature. 将反应混合物用C盐过滤。 The reaction mixture was filtered salt C. 滤液用EtOAC提取,用H2O和盐水洗涤,用Na2SO4干燥并接着在真空中浓缩。 The filtrate was extracted with EtOAC, washed with H2O and brine, dried and then concentrated in vacuo with Na2SO4. 将剩余的层用柱色谱法(正己烷:EtOAc = 3:1)进行纯化以产生褐色糖浆(29. Img, 20. 30% )0 The remaining layer was purified by column chromatography (hexane: EtOAc = 3: 1) was purified to give a brown syrup (29. Img, 20. 30%) 0

[0525] [α ]D20 :-6. 0 (CHCl3, c 0. 24); . [0525] [α] D20: -6 0 (CHCl3, c 0. 24);

[0526] IR(KBr 片状沉淀物):3322,3211,2974,1491,1051,717cm—1 ; [0526] IR (KBr pellet): 3322,3211,2974,1491,1051,717cm-1;

[0527] 1H NMR(400MHz, CDCl3) : δ 7. 34 (s, 1H) ,6. 96 (dd, 1H, J = 11. 2,2. OHz) ,4. 34 (qd, 1H, J = 6· 4,2. 8Hz),3. 33 (d, 1H, J = 2. OHz),1. 41 (d, 3H, J = 6. 4Hz),1. 18 (s,9H) · [0527] 1H NMR (400MHz, CDCl3): δ 7. 34 (s, 1H), 6 96 (dd, 1H, J = 11. 2,2 OHz.), 4 34 (qd, 1H, J =.. 6 · 4,2. 8Hz), 3. 33 (d, 1H, J = 2. OHz), 1. 41 (d, 3H, J = 6. 4Hz), 1. 18 (s, 9H) ·

50[0528] 步骤4 :4-(1_氨基乙基)-2_氟-6-碘苯胺 50 [0528] Step 4: 4- (1_ aminoethyl) -2_ fluoro-6-iodoaniline

[0529] 将2-甲基丙烷-2-亚磺酸[1-(4-氨基-3-氟-5-碘苯基)乙基]酰胺(0. 07mmol, 29. Img)加入MeOH lml。 [0529] 2-methyl-2-sulfinic acid [1- (4-amino-3-fluoro-5-iodo-phenyl) -ethyl] -amide (0. 07mmol, 29. Img) was added MeOH lml. 加入在0. 25ml的1,4_ 二噁烷中的4NHC1。 1,4_ added 4NHC1 in dioxane in 0. 25ml. 将反应混合物搅拌12 小时。 The reaction mixture was stirred for 12 hours. 在真空中浓缩反应混合物。 The reaction mixture was concentrated in vacuo. 用玻璃滤器过滤残余物。 The residue was filtered with a glass filter. 将滤液在真空中浓缩以产生褐色固体(31. 2mg)。 The filtrate was concentrated in vacuo to yield a brown solid (31. 2mg).

[0530] mp :180 〜182°C ; [0530] mp: 180 ~182 ° C;

[0531] [a ]D20 :+3. 27 (CHCl3, c 0. 41) ;IR(KBr 片状沉淀物):3354,3018,2966,1283, 756cm 1 ; . [0531] [a] D20: +3 27 (CHCl3, c 0. 41); IR (KBr pellet): 3354,3018,2966,1283, 756cm 1;

[0532] 1H NMR (400MHz, CDCl3) : δ 7. 72 (s, 1H), 7. 35 (dd, 1H, J = 11.2,2. OHz),4. 41 (q, 1H, J = 6. 8Hz),1. 58 (d, 3H, J = 6. 8Hz),1. 30 (s, 3H) · [0532] 1H NMR (400MHz, CDCl3): δ 7. 72 (s, 1H), 7. 35 (dd, 1H, J = 11.2,2 OHz.), 4 41 (q, 1H, J = 6.. 8Hz), 1. 58 (d, 3H, J = 6. 8Hz), 1. 30 (s, 3H) ·

[0533] 步骤5 : [1-(4-氨基-3-氟_5_碘苯基)乙基]氨基甲酸叔丁酯 [0533] Step 5: [1- (4-iodo-3-fluoro _5_ phenyl) ethyl] carbamate

[0534] 用氩气充满25ml的双颈烧瓶并将4_ (1_氨基乙基)_2_氟_6_碘苯胺(0. 18mmol, 50. Omg)溶解于THF。 [0534] filled with a two-neck flask and 25ml 4_ (1_ aminoethyl) with argon _2_ fluoro _6_ iodoaniline (0. 18mmol, 50. Omg) was dissolved in THF. 加Λ BOC2O(0. 20mol,45. 18mg), DMAP(0. 02mol,2. 20mg),和TEA(0. 23mol,32. 61mg)。 Plus Λ BOC2O (0. 20mol, 45. 18mg), DMAP (0. 02mol, 2. 20mg), and TEA (0. 23mol, 32. 61mg). 将反应混合物搅拌12小时。 The reaction mixture was stirred for 12 hours. 反应混合物用EtOAc提取,用H2O和盐水洗涤,用Na2SO4干燥,并在真空中浓缩。 The reaction mixture was extracted with EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. 将残余物用柱色谱法(正己烷:EtOAc = 7 : 1) 进行纯化以产生固体(65. 9mg,94. 44% )· The residue was purified by column chromatography (n-hexane: 1: EtOAc = 7) was purified to give a solid (65. 9mg, 94 44%.) ·

[0535] mp :88 〜90 °C ; [0535] mp: 88 ~90 ° C;

[0536] [a ]D20 :33. 35 (CHCl3, c 2. 98); . [0536] [a] D20: 33 35 (CHCl3, c 2. 98);

[0537] IR(KBr 片状沉淀物):3364,3026,2958,1696,1169cm-1 ; [0537] IR (KBr pellet): 3364,3026,2958,1696,1169cm-1;

[0538] 1H NMR(400MHz, CDCl3) : δ 7. 31 (s, 1H), 6. 90 (d, 1H, J = 11. 6Hz) ,4. 72 (s, 1H), [0538] 1H NMR (400MHz, CDCl3):. Δ 7. 31 (s, 1H), 6. 90 (d, 1H, J = 11. 6Hz), 4 72 (s, 1H),

4. 59 (s,1Η),3. 76 (bs, 2H),1. 38 (s,9H),1. 3 (d, 3H, J = 6. 8Hz) · 4. 59 (s, 1Η), 3. 76 (bs, 2H), 1. 38 (s, 9H), 1. 3 (d, 3H, J = 6. 8Hz) ·

[0539] 步骤6 : [1-(4-氨基-3-氟_5_乙烯基苯基)乙基]氨基甲酸叔丁酯 [0539] Step 6: [1- (4-Amino-3-fluoro _5_ vinylphenyl) ethyl] carbamate

[0540]在氩气气氛下将 Pd (PPh3) 4(0. Olmmol,11. 79mg)和LiCl (0. 48mmol,20. 58mg)加入DMF。 [0540] Under an argon atmosphere, Pd (PPh3) 4 (0. Olmmol, 11. 79mg) and LiCl (0. 48mmol, 20. 58mg) was added DMF. 加入[1-(4-氨基-3-氟-5-乙烯基苯基)乙基]氨基甲酸叔丁酯(0. 17mmol,65. 9mg) 和三丁基乙烯基锡(0. 25mmol,74. 52 μ 1)。 Was added [1- (4-amino-3-fluoro-5-vinylphenyl) ethyl] carbamate (0. 17mmol, 65. 9mg) and tributylvinyltin (0. 25mmol, 74 . 52 μ 1). 将反应混合物在回流中搅拌12小时。 The reaction mixture was stirred at reflux for 12 hours. 将反应溶剂在真空中去除。 The reaction solvent was removed in vacuo. 反应混合物用EtOAc提取,用H2O和盐水洗涤,用Na2SO4干燥,并在真空中浓缩。 The reaction mixture was extracted with EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. 将残余物用柱色谱法(正己烷:EtOAc = 7 : 1)进行纯化以产生黄色固体(23. 4mg, 47. 06% )。 The residue was purified by column chromatography (n-hexane: 1: EtOAc = 7) was purified to yield a yellow solid (23. 4mg, 47. 06%).

[0541] mp:59 〜61°C; [0541] mp: 59 ~61 ° C;

[0542] [α ]D20 :+47. 0 (CHCl3, c 0. 10); . [0542] [α] D20: +47 0 (CHCl3, c 0. 10);

[0543] IR(KBr 片状沉淀物):3357, 3088, 2975,1696,1640,1168cm-1 ;1HNMR(400MHz, CDCl3) : 5 6. 93(s,lH),6. 81(dd, 1H, J = 11. 6,2. OHz) ,6. 65 (dd, 1H, J = 17. 2,11. 2Hz), [0543] IR (KBr pellet): 3357, 3088, 2975,1696,1640,1168cm-1; 1HNMR (400MHz, CDCl3):. 5 6. 93 (s, lH), 6 81 (dd, 1H , J = 11. 6,2. OHz), 6. 65 (dd, 1H, J = 17. 2,11. 2Hz),

5. 29 (dd, 1H, J = 11. 2,1. 2Hz),4. 64 (s, 1H),4· 61 (s,1H),3. 66 (bs, 2H),1. 35 (s, 12H) · 5. 29 (dd, 1H, J = 11. 2,1. 2Hz), 4. 64 (s, 1H), 4 · 61 (s, 1H), 3. 66 (bs, 2H), 1. 35 ( s, 12H) ·

[0544] 步骤7 : [1-(3-氟-4-甲烷磺酰基氨基_5_乙烯基苯基)乙基]氨基甲酸叔丁酯 [0544] Step 7: [1- (3-Fluoro-4-yl-amino _5_ vinylphenyl) ethyl] carbamate

[0545] 用氩气充满25ml的双颈烧瓶并将[1_(4_氨基_3_氟_5_乙烯基苯基)乙基]氨基甲酸叔丁酯(0. OSmmo 1,23. 4mg)加入二氯甲烷中。 [0545] 25ml two-neck flask filled with argon and [1_ (4_ fluoro _5_ amino _3_ vinylphenyl) ethyl] carbamate (0. OSmmo 1,23. 4mg) dichloromethane was added. 将反应混合物冷却到0°C。 The reaction mixture was cooled to 0 ° C. 将甲烷磺酰氯(0. 40mmol,32. 32mmol)和TEA(0. 24mmol,33. 45mg)加入反应混合物中。 Methanesulfonyl chloride (0. 40mmol, 32. 32mmol) and TEA (0. 24mmol, 33. 45mg) was added to the reaction mixture. 将反应混合物加热到室温。 The reaction mixture was warmed to room temperature. 通过加入NaHCO3溶液猝灭反应混合物。 The reaction mixture was quenched by addition of NaHCO3 solution. 用CH2Cl2提取反应混合物。 The reaction mixture was extracted with CH2Cl2. 将合并的有机层用CuSO,H2O和盐水洗涤,用Na2SO4干燥,并在真空中浓缩。 The combined organic layers were washed with CuSO, H2O and brine, dried over Na2SO4, and concentrated in vacuo. 将残余物加入THF : H2O=2 : lsoln.加入Na0H(0. 40mmol,16mg)。 The residue was added to THF: H2O = 2: lsoln added Na0H (0 40mmol, 16mg.).. 将反应混合物搅拌12小时。 The reaction mixture was stirred for 12 hours. 在用TLC证实反应结束后,反应混合物用10% HCl soln酸化。 In the completion of the reaction was confirmed by TLC, the reaction mixture was acidified with 10% HCl soln. 将反应混合物搅拌12小时。 The reaction mixture was stirred for 12 hours. 将反应混合物用EtOAc提取,用H2O和盐水洗涤,用Na2SO4干燥,并在真空中浓缩。 The reaction mixture was extracted with EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. 将残余物用柱色谱法进行纯化(正己烷:EtOAc = 7:1)以产生褐色糖浆(20. 2mg,75. 0% )。 The residue was purified (hexane: EtOAc = 7: 1) column chromatography to give a brown syrup (20. 2mg, 75 0%.).

[0546] [α ]D20 :+llO. 0(CHC13, c 0. 05); [0546] [α] D20:. + LlO 0 (CHC13, c 0. 05);

[0547] IR(KBr 片状沉淀物):3235,2977,1685,1156cm-1 ; [0547] IR (KBr pellet): 3235,2977,1685,1156cm-1;

[0548] 1H NMR(400MHz, CDCl3) : δ 7. 28 (s, 1H),7· 10 (dd, 1H, J = 18. 0,11. 2Ηζ),6· 95 (d, 1Η, J = 10. 4Ηζ),6· 16 (s,1Η),5. 73 (d, 1Η, J = 17. 6Ηζ),5. 37 (d, 1Η, J = 11. 2Ηζ),4· 80 (s, 1Η),4. 69 (s,1Η),2. 99 (s, 3Η),1. 35 (s, 12Η). [0548] 1H NMR (400MHz, CDCl3): δ 7. 28 (s, 1H), 7 · 10 (dd, 1H, J = 18. 0,11 2Ηζ.), 6 · 95 (d, 1Η, J = 10. 4Ηζ), 6 · 16 (s, 1Η), 5. 73 (d, 1Η, J = 17. 6Ηζ), 5. 37 (d, 1Η, J = 11. 2Ηζ), 4 · 80 (s, 1Η), 4. 69 (s, 1Η), 2. 99 (s, 3Η), 1. 35 (s, 12Η).

[0549] 步骤8 :Ν-[4-(1-氨基乙基)_2_氟_6_乙烯基苯基]甲烷磺酰胺 [0549] Step 8: Ν- [4- (1- aminoethyl) _2_ fluoro _6_ vinylphenyl] methanesulfonamide

[0550] 将[1-(3_氟-4-甲烷磺酰基氨基-5-乙烯基苯基)乙基]氨基甲酸叔丁酯(0. 06mmol,20. 2mg)溶解于二氯甲烷,加入5〜6滴的CF3COOH0将反应混合物搅拌12小时。 [0550] [1- (3_-fluoro-4-methanesulfonyl-5-vinylphenyl) ethyl] carbamate (0. 06mmol, 20. 2mg) was dissolved in dichloromethane, was added 5 to 6 drops CF3COOH0 reaction mixture was stirred for 12 hours. 加入甲苯。 Toluene was added. 将所述反应混合物在真空中浓缩以产生褐色糖浆(20. 8mg,100.0%)。 The reaction mixture was concentrated in vacuo to give a brown syrup (20. 8mg, 100.0%).

[0551] 1H NMR(400MHz, CD3OD) : δ 7. 60 (s, 1H),7· 25 (dd, 1H, J = 10. 4,2. OHz),7· 16 (dd, 1Η, J = 18. 0,11. 2Ηζ),5· 89 (d, 1Η, J = 17. 6Ηζ),5· 43 (d, 1Η, J = 11. 2Ηζ),4· 48 (q, 1Η, J = 6. 8Ηζ),3. 02 (s,3Η),1. 61 (d, 3Η, J = 6. 8Hz) · [0551] 1H NMR (400MHz, CD3OD): δ 7. 60 (s, 1H), 7 · 25 (dd, 1H, J = 10. 4,2 OHz.), 7 · 16 (dd, 1Η, J = 18. 0,11. 2Ηζ), 5 · 89 (d, 1Η, J = 17. 6Ηζ), 5 · 43 (d, 1Η, J = 11. 2Ηζ), 4 · 48 (q, 1Η, J = 6 . 8Ηζ), 3. 02 (s, 3Η), 1. 61 (d, 3Η, J = 6. 8Hz) ·

[0552] 步骤9 :Ν-(4-{1-[3-(4-叔丁基苄基)脲基]乙基} _2_氟_6_乙烯基苯基)甲烷磺酰胺 [0552] Step 9: Ν- (4- {1- [3- (4- tert-butyl-benzyl) ureido] ethyl} _2_ fluoro _6_ vinylphenyl) methanesulfonamide

[0553] 用氩气充满25ml的双颈烧瓶并将4_叔丁基苄胺(2eq.,35. 10 μ 1,0. 22mmol) 在二氯甲烷中加入。 [0553] full two-neck flask and 25ml of tert-butyl-benzylamine 4_ with argon (2eq., 35. 10 μ 1,0. 22mmol) in dichloromethane were added. 将BOC2Od. 5eq.,0. 17mmol,37. 95 μ 1)和DMAP (0. 2eq.,0. 02mmol, 2. 69mg)缓慢加入。 The BOC2Od. 5eq., 0. 17mmol, 37. 95 μ 1) and DMAP (0. 2eq., 0. 02mmol, 2. 69mg) was slowly added. 将反应混合物搅拌5小时。 The reaction mixture was stirred for 5 hours. 在证实合成1-叔丁基-4-异氰酰甲基苯后, 加入N-[4-(1-氨基-乙基)-2-氟-6-乙烯基-苯基]-甲烷磺酰胺(0. Ilmmol,40. Omg) 和TEA(2eq.,0. 58mmol,80. 84μ 1)。 After confirming the synthesis of 1-tert-butyl-4-isocyanato-methyl benzene, was added N- [4- (1- amino - ethyl) -2-fluoro-6-vinyl - phenyl] - methanesulfonamide (0. Ilmmol, 40. Omg) and TEA (2eq., 0. 58mmol, 80. 84μ 1). 将反应混合物搅拌12小时。 The reaction mixture was stirred for 12 hours. 在用TLC证实反应结束后,用二氯甲烷提取反应混合物,用H2O和盐水洗涤,用Na2SO4干燥,并在真空中浓缩。 In the end of the reaction was confirmed by TLC, the reaction mixture was extracted with dichloromethane, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. 残余物用柱色谱法(正己烷:EtOAc = 1:1)进行纯化以产生白色固体(21. 7mg,27. 56% )。 The residue was purified by column chromatography (n-hexane: 1: EtOAc = 1) was purified as a white solid (21. 7mg, 27 56%.).

[0554] mp:89〜91°C; [0554] mp: 89~91 ° C;

[0555] [α ]D20 :-8. 34(CHCl3, c 0. 49); . [0555] [α] D20: -8 34 (CHCl3, c 0. 49);

[0556] IR(KBr 片状沉淀物):337,3092,2963,1636,1154cm-1 ; [0556] IR (KBr pellet): 337,3092,2963,1636,1154cm-1;

[0557] 1H NMR(400MHz, CDCl3) : δ 7. 29(d,2H,J = 8. OHz),7· 27 (s, 1Η),7· 13(d,2H,J = 8. OHz),7. 09 (dd, 1Η, J = 17. 6,11. 2Ηζ),6. 91 (d, 1Η, J = 10. OHz),6. 41 (s, 1Η),5. 71 (d, 1H, J = 17. 6Ηζ),5· 37 (d, 1Η, J=Il. 2Ηζ),4· 79 (q, 1Η, J = 6. OHz),4· 24(s,2H),2· 99(s,3H), 1. 33 (d, 3Η, J = 6. 8Ηζ),1. 26 (s,9H) · [0557] 1H NMR (400MHz, CDCl3): δ 7. 29 (d, 2H, J = 8. OHz), 7 · 27 (s, 1Η), 7 · 13 (d, 2H, J = 8. OHz) , 7. 09 (dd, 1Η, J = 17. 6,11. 2Ηζ), 6. 91 (d, 1Η, J = 10. OHz), 6. 41 (s, 1Η), 5. 71 (d, 1H, J = 17. 6Ηζ), 5 · 37 (d, 1Η, J = Il. 2Ηζ), 4 · 79 (q, 1Η, J = 6. OHz), 4 · 24 (s, 2H), 2 · 99 (s, 3H), 1. 33 (d, 3Η, J = 6. 8Ηζ), 1. 26 (s, 9H) ·

[0558] 实施例8 : [0558] Example 8:

[0559] N- {4- [3- (4-叔丁基-苄基)_脲基甲基]_2_甲基_6_乙烯基-苯基}-甲烷磺酰胺 [0559] N- {4- [3- (4- tert-butyl-benzyl) - _ ureidomethyl] _2_ _6_ vinyl methyl - phenyl} - methanesulfonamide

[0560]3s [0560] 3s

[0561] 步骤1 :4-氨基-3-甲基苄腈 [0561] Step 1: 4-amino-3-methylbenzonitrile

[0562]将 4-碘-2-甲基苯胺(2000mg,8. 58mmol)和氰化物(1. 15g, 12. 87mmol, 1. 5eq)加入吡啶。 [0562] A mixture of 4-iodo-2-methylaniline (2000mg, 8. 58mmol) and cyanide (1. 15g, 12. 87mmol, 1. 5eq) was added pyridine. 反应混合物加热到150〜160°C,搅拌12小时。 The reaction mixture was heated to 150~160 ° C, stirred for 12 hours. 用二氯甲烷稀释反应混合物。 The reaction mixture was diluted with dichloromethane. 用硫酸铜洗涤稀释的溶液数次。 Diluted solution was washed several times with copper sulfate. 用H2O (2次)和盐水洗涤混合物,接着用Na2SO4干燥。 H2O (2 times) and the mixture was washed with brine, then dried over Na2SO4. 将残余物用柱色谱法(正己烷:EtOAc = 2:1)进行纯化以产生固体(786. 5mg,69. 34% )。 The residue was purified by column chromatography (hexane: 1: EtOAc = 2) to give a solid (786. 5mg, 69 34%.).

[0563] mp :78 〜80 °C ; [0563] mp: 78 ~80 ° C;

[0564] IR(NaCl 纯的,cnT1) :3403, 3335, 3220, 2942, 2220 ; [0564] IR (NaCl neat, cnT1): 3403, 3335, 3220, 2942, 2220;

[0565] 1H NMR (400MHz, CDCl3) :7· 24 (m,2H),6. 57 (d,1H,J = 8. 4Hz),4· 03 (bs,2H), 2. 08(s,9H). [0565] 1H NMR (400MHz, CDCl3):. 7 · 24 (m, 2H), 6 57 (d, 1H, J = 8. 4Hz), 4 · 03 (bs, 2H), 2. 08 (s, 9H).

[0566] 步骤2 : 4-氨基-3-碘-5-甲基苄腈 [0566] Step 2: 4-amino-3-iodo-5-methyl-benzonitrile

[0567]将 4-氨基-3-甲基-苄腈(786. 5 μ 1,5. 95mmol)禾Π ICl (1. leq,6. 55mmol, 1. 06g) 加入二氯甲烷。 [0567] 4-Amino-3-methyl - benzonitrile (. 786. 5 μ 1,5 95mmol) Wo Π ICl (. 1. leq, 6 55mmol, 1. 06g) was added dichloromethane. 反应混合物搅拌12小时。 The reaction mixture was stirred for 12 hours. 通过加入硫代硫酸钠溶液猝灭反应混合物。 The reaction mixture was quenched by the addition of sodium thiosulfate solution. 用MC提取水溶液。 Aqueous solution was extracted with MC. 用H2O和盐水洗涤合并的有机溶液,用Na2SO4干燥,并在真空中浓缩。 With H2O and the organic solution was washed with brine, dried over Na2SO4, and concentrated in vacuo. 将残余物用柱色谱法(n-Hx : EA = 3 : 1)进行纯化以产生固体(600. 6mg,39. 11% )0 The residue was purified by column chromatography (n-Hx: 1: EA = 3) to give a solid (600. 6mg, 39 11%.) 0

[0568] mp :131 〜133°C ; [0568] mp: 131 ~133 ° C;

[0569] IR(KBr 片状沉淀物,cnT1) :3462,3366,2923,2214,1623 ; [0569] IR (KBr pellet, cnT1): 3462,3366,2923,2214,1623;

[0570] 1H NMR (400MHz, CDCl3) : δ 7. 22 (d, 1H, J = 2. OHz),7. 21 (m,1H),2. 16(s,3H) [0570] 1H NMR (400MHz, CDCl3):.. Δ 7. 22 (d, 1H, J = 2. OHz), 7 21 (m, 1H), 2 16 (s, 3H)

[0571] 步骤3 : (4-氨基-3-碘-5-甲基苄基)氨基甲酸叔丁酯 [0571] Step 3: (4-amino-3-iodo-5-methylbenzyl) carbamate

[0572] 将4-氨基-3-碘-5-甲基苄腈(200mg,0. 77mmol)在0°C溶解于THF。 [0572] 4-amino-3-iodo-5-methyl-benzonitrile (200mg, 0. 77mmol) from 0 ° C was dissolved in THF. 在将硼烷-THF复合物(4eq,3. 10mmol,3. 10ml)缓慢加入所述反应混合物中后,将反应温度加热到回流。 After the borane -THF complex (4eq, 3. 10mmol, 3. 10ml) was slowly added to the reaction mixture, the reaction temperature was heated to reflux. 在回流的情况下,将反应混合物搅拌12小时。 Under reflux, the reaction mixture was stirred for 12 hours. 在证实反应结束后,加入MeOH。 After the reaction was confirmed, adding MeOH. 将混合物搅拌4小时。 The mixture was stirred for 4 hours. 在真空中去除反应溶剂。 The reaction solvent was removed in vacuo. 残余物用乙酸乙酯提取,用H2O和盐水洗涤,用Na2SO4干燥,并在真空中浓缩以产生4-氨基甲基-2-碘-6-甲基-苯胺(194mg)。 The residue was extracted with ethyl acetate, washed with H2O and brine, dried over Na2SO4, and concentrated to give 4-amino-2-iodo-6-methyl in vacuo - phenylamine (194mg).

[0573] 将4-氨基甲基-2-碘-6-甲基-苯胺(195mg,0. 76mmol)溶解于THF,接着缓慢加入BOC2Od. Ieq,0. 21mmol,47. 48ml)。 [0573] 4-amino-2-iodo-6-methyl - aniline (. 195mg, 0 76mmol) was dissolved in THF, followed by slow addition BOC2Od Ieq, 0 21mmol, 47 48ml).... 搅拌反应混合物达12小时。 The reaction mixture was stirred for 12 hours. 反应混合物用乙酸乙酯提取,用H2O和盐水洗涤,用Na2SO4干燥,在真空中浓缩。 The reaction mixture was extracted with ethyl acetate, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. 将残余物用柱色谱法进行纯化(n-Hx : EA = 5 : 1)以获得固体(73. 2mg, 34. 77% ) „ The residue was purified (n-Hx: EA = 5: 1) column chromatography to obtain a solid (73. 2mg, 34. 77%) "

[0574] mp :135 〜137°C ; [0574] mp: 135 ~137 ° C;

[0575] IR(KBr 片状沉淀物,cnT1) :3354,2995,1675,1617,726 ; [0575] IR (KBr pellet, cnT1): 3354,2995,1675,1617,726;

[0576] 1H NMR(400MHz, CDCl3) : δ 7. 38 (s, 1H),6· 90 (s, 1H),4· 78 (s, 1H),4· 08(d,2H,J = 5. 2Hz) ,4. 01 (bs, 2Η),2. 16 (s, 3Η),1. 42 (s,9H) [0576] 1H NMR (400MHz, CDCl3): δ 7. 38 (s, 1H), 6 · 90 (s, 1H), 4 · 78 (s, 1H), 4 · 08 (d, 2H, J = 5 . 2Hz), 4. 01 (bs, 2Η), 2. 16 (s, 3Η), 1. 42 (s, 9H)

[0577] 步骤4 : (4-氨基-3-甲基-5-乙烯基苄基)氨基甲酸叔丁酯 [0577] Step 4: (4-amino-3-methyl-5-vinyl benzyl) carbamate

[0578]将Pd(PPh3)4(0. 06eq,0. 017mmol, 19. 41mg)和LiCl(2. 8eq,0. 74mmol,33. 23mg)溶解于DMF。 [0578] The Pd (PPh3) 4 (0. 06eq, 0. 017mmol, 19. 41mg) and LiCl (2. 8eq, 0. 74mmol, 33. 23mg) was dissolved in DMF. 将(4-氨基-3-碘-5-甲基苄基)氨基甲酸叔丁酯(100mg,0. 28mmol)和三丁基乙烯基锡(1.5eq,0.41mmOl,121.08y 1)加入所述反应混合物。 (4-amino-3-iodo-5-methylbenzyl) carbamate (100mg, 0. 28mmol) and tributylvinyltin (1.5eq, 0.41mmOl, 121.08y 1) was added to the The reaction mixture was. 将反应混合物在回流中搅拌12小时。 The reaction mixture was stirred at reflux for 12 hours. 按照与步骤3相似的方法纯化反应混合物以获得固体(61. 8mg,85. 34% )。 The reaction mixture according to a method similar to Step 3 to obtain a purified solid (61. 8mg, 85. 34%).

[0579] IR(NaCl 纯的,cnT1) :3373,2965,1697,1632 ; [0579] IR (NaCl neat, cnT1): 3373,2965,1697,1632;

[0580] 1H NMR (400MHz, CDCl3) : δ 6. 99 (s, 1H), 6. 85 (s, 1H), 6. 69 (dd, 1H, J = 17. 2, [0580] 1H NMR (400MHz, CDCl3): δ 6. 99 (s, 1H), 6. 85 (s, 1H), 6. 69 (dd, 1H, J = 17. 2,

10. 8Hz) ,5. 53 (dd, 1H, J = 17. 2,1. 6Hz),5. 24 (dd,1H,J = 10. 8,1. 6Hz),4. 68 (bs,1H), 4. 10 (d, 2H, J = 5. 2Hz),3. 70 (bs, 2H),2. 08 (s, 3H),1. 38 (s,9H) 10. 8Hz), 5. 53 (dd, 1H, J = 17. 2,1. 6Hz), 5. 24 (dd, 1H, J = 10. 8,1. 6Hz), 4. 68 (bs, 1H ), 4. 10 (d, 2H, J = 5. 2Hz), 3. 70 (bs, 2H), 2. 08 (s, 3H), 1. 38 (s, 9H)

[0581] 步骤5 : (4-甲烷磺酰基氨基-3-甲基-5-乙烯基苄基)氨基甲酸叔丁酯 [0581] Step 5: (4-methanesulfonyl-3-methyl-5-vinyl benzyl) carbamate

[0582] 将(4-氨基-3-甲基-5-乙烯基-苄基)_氨基甲酸叔丁酯(30. 9mg,0. 12mmol), 甲烷磺酰氯(10eq,l. 2 mmol,91y 1)和三乙胺(6eq,0. 36mmol,50. 17)加入二氯甲烷。 [0582] The (4-amino-3-methyl-5-vinyl-benzyl) - carbamate _ (. 30. 9mg, 0 12mmol), methanesulfonyl chloride (10eq, l 2 mmol, 91y 1) and triethylamine (6eq, 0. 36mmol, 50. 17) dichloromethane was added. 搅拌反应混合物12小时。 The reaction mixture was stirred for 12 hours. 用与实施例8步骤4相似的方法纯化反应混合物以获得糖浆(9. 5mg, 23. 70% )。 Example 8 is reacted with a method similar to Step 4 to obtain a mixture of purified syrup (9. 5mg, 23. 70%) a.

[0583] IR(NaCl 纯的,cnT1) :3371,2961,1697,1513,1316 ; [0583] IR (NaCl neat, cnT1): 3371,2961,1697,1513,1316;

[0584] 1H NMR(400MHz, CDCl3) : δ 7. 27 (s, 1H), 7. 06 (s, 1H), 7. 01 (dd, 1H, J = 17. 6, [0584] 1H NMR (400MHz, CDCl3): δ 7. 27 (s, 1H), 7. 06 (s, 1H), 7. 01 (dd, 1H, J = 17. 6,

11. 2Hz), 5. 80 (s, 1H), 5. 68 (dd, 1Η, J = 17. 7,0. 8Hz),5. 33 (dd,1Η,J = 11. 2,0. 8Hz), 4. 79 (s,1H),4. 22 (d, 2H, J = 6. OHz),2. 98 (s, 3H),2. 36 (s, 3H),1. 40 (s,9H) · 11. 2Hz), 5. 80 (s, 1H), 5. 68 (dd, 1Η, J = 17. 7,0. 8Hz), 5. 33 (dd, 1Η, J = 11. 2,0. 8Hz ), 4. 79 (s, 1H), 4. 22 (d, 2H, J = 6. OHz), 2. 98 (s, 3H), 2. 36 (s, 3H), 1. 40 (s, 9H) ·

[0585] 步骤6 :N-(4-氨基甲基-2-甲基_6_乙烯基-苯基)_甲烷磺酰胺 [0585] Step 6: N- (4- aminomethyl-2-methyl _6_ vinyl - phenyl) methanesulfonamide _

[0586] 将(4-甲烷磺酰基氨基-3-甲基-5-乙烯基苄基)氨基甲酸叔丁酯(85.9mg, 0. 09mmol)溶解于CH2C12。 [0586] (4-methanesulfonyl-3-methyl-5-vinyl benzyl) carbamate (85.9mg, 0. 09mmol) was dissolved in CH2C12. 加入5〜6滴的CF3C00H。 Adding 5 to 6 drops of CF3C00H. 将反应混合物搅拌12小时。 The reaction mixture was stirred for 12 hours. 浓缩反应混合物以产生褐色糖浆(100. 4mg)。 The reaction mixture was concentrated to give a brown syrup (100. 4mg).

[0587] 1H NMR (400MHz,CD3OD) : δ 7. 57 (d, 1H, J = 1. 6Hz),7. 28 (d,1H,J = 1. 6Hz), 7. 17 (dd, 1H, J = 17. 6,10. 8Hz),5. 03(d,1H,J = 17. 6Hz) ,5. 38 (d, 1H, J = 10. 8Hz), 4. 06 (s,2H),3. 00 (s, 3H),2. 41 (s, 3H) [0587] 1H NMR (400MHz, CD3OD):. Δ 7. 57 (d, 1H, J = 1. 6Hz), 7 28 (d, 1H, J = 1. 6Hz), 7. 17 (dd, 1H, J = 17. 6,10. 8Hz), 5. 03 (d, 1H, J = 17. 6Hz), 5. 38 (d, 1H, J = 10. 8Hz), 4. 06 (s, 2H), 3. 00 (s, 3H), 2. 41 (s, 3H)

[0588] 步骤7 :N-{4-[3-(4-叔丁基-苄基)脲基甲基]_2_甲基_6_乙烯基苯基}甲烷磺酰胺 [0588] Step 7: N- {4- [3- (4- tert-butyl-benzyl) - methyl ureido] methyl _6_ _2_ vinylphenyl} methanesulfonamide

[0589] 将4-叔丁基-苄胺(1.5eq,71.91y 1,0. 44mmol)加入CH2Cl2并接着缓慢加入BOC2Od. 5eq,0. 44mmol, 101. 19 μ 1)和DMAP (0. 2eq0. 06mmol,7. 08mg)。 [0589] 4-tert-butyl - benzylamine (. 1.5eq, 71.91y 1,0 44mmol) was added followed by the slow addition of CH2Cl2 and BOC2Od 5eq, 0 44mmol, 101. 19 μ 1) and DMAP (0. 2eq0.. . 06mmol, 7. 08mg). 在证实合成1-叔丁基-4-异氰酰甲基-苯后,将N- (4-氨基甲基-2-甲基-6-乙烯基-苯基)-甲烷磺酰胺(leq,0. 29mmol,70. 5mg)和TEA(2eq,0. 58mmol,80. 84 μ 1)加入到反应混合物。 Validating Synthesis of l-tert-butyl 4-isocyanato-methyl - of benzene, the N- (4- aminomethyl-2-methyl-6-vinyl - phenyl) - methanesulfonamide (Leq, 0. 29mmol, 70. 5mg) and TEA (2eq, 0. 58mmol, 80. 84 μ 1) was added to the reaction mixture. 将反应混合物搅拌12小时。 The reaction mixture was stirred for 12 hours. 按照与实施例7的步骤9纯化反应混合物以获得N-{4-[3-(4-叔丁基-苄基)脲基甲基]-2-甲基-6-乙烯基苯基}甲烷磺酰胺(29. 75mg,23. 9% )。 The reaction mixture was purified in accordance with step 9 of Example 7 to obtain N- {4- [3- (4- tert-butyl-benzyl) - ureido methyl] -2-methyl-6-vinyl-phenyl} methane sulfonamide (29. 75mg, 23. 9%).

[0590] mp :105 〜107°C ; [0590] mp: 105 ~107 ° C;

[0591] IR(KBr 片状沉淀物,cnT1) :3359, 3280, 2963,1636,1316 ;1H NMR(400MHz, CDCl3): δ 7. 32 (s,1Η),7. 27 (d, 2H, J = 8. OHz),7. 16 (d, 2H, J = 8. OHz),7. 09 (s, 1H),6. 72 (dd, 1H, J = 17. 2,10. 8Hz),5. 71 (d, 1H, J = 17. 6Hz),5. 37 (d, 2H, J = 10. 8Hz),4. 30 (d, 4H, J = 10. OHz),3. 42 (s,3H),2. 23 (s, 3H),1. 22 (s,9H) [0591] IR (KBr pellet, cnT1): 3359, 3280, 2963,1636,1316; 1H NMR (400MHz, CDCl3):. Δ 7. 32 (s, 1Η), 7 27 (d, 2H, J = 8. OHz), 7. 16 (d, 2H, J = 8. OHz), 7. 09 (s, 1H), 6. 72 (dd, 1H, J = 17. 2,10. 8Hz), 5. 71 (d, 1H, J = 17. 6Hz), 5. 37 (d, 2H, J = 10. 8Hz), 4. 30 (d, 4H, J = 10. OHz), 3. 42 (s , 3H), 2. 23 (s, 3H), 1. 22 (s, 9H)

[0592] 实施例9 : [0592] Example 9:

[0593] N- {4- [3- (4-叔丁基-苄基)_脲基甲基]_2_氯_6_乙烯基-苯基} _甲烷磺酰胺 [0593] N- {4- [3- (4- tert-butyl-benzyl) - _ ureidomethyl] _2_ _6_ vinyl chloride - phenyl} methanesulfonamide _

[0594] [0594]

Figure CN101142174BD00551

[0595] 步骤1 :4-氨基-3-氯-5-碘苄腈 [0595] Step 1: 4-amino-3-chloro-5-iodo-benzonitrile

[0596]将 4-氨基-3-氯-节腈(100mg,0. 66mmol)禾Π ICl (1. leq,0. 72mmol, 117. 05mg)加入二氯甲烷。 [0596] 4-Amino-3-chloro - Section carbonitrile (. 100mg, 0 66mmol) Wo Π ICl (. 1. leq, 0 72mmol, 117. 05mg) in dichloromethane was added. 搅拌反应混合物达12小时。 The reaction mixture was stirred for 12 hours. 将所述反应混合物按照与实施例8的步骤2相似的方法进行纯化以获得4-氨基-3-氯-5-碘苄腈(65. 2mg, 35. 80% )0 The reaction mixture was purified according to Example 8 Step 2 to obtain a similar manner to 4-amino-3-chloro-5-iodo-benzonitrile (65. 2mg, 35. 80%) 0

[0597] mp :121 〜123°C ; [0597] mp: 121 ~123 ° C;

[0598] IR(KBr 片状沉淀物,cnT1) :3365,2942,2221,1634,728 ; [0598] IR (KBr pellet, cnT1): 3365,2942,2221,1634,728;

[0599] 1H NMR (400MHz, CDCl3) : δ 7. 42 (d, 1H, J = 1. 6Hz) ,7. 43 (d, 1H, J = 1. 6Hz), [0599] 1H NMR (400MHz, CDCl3): δ 7. 42 (d, 1H, J = 1. 6Hz), 7 43 (d, 1H, J = 1. 6Hz),.

5. 01(bs,2H). 5. 01 (bs, 2H).

[0600] 步骤2 : (4-氨基-3-氯-5-碘苄基)氨基甲酸叔丁酯 [0600] Step 2: (4-Amino-3-chloro-5-iodobenzyl) carbamate

[0601] 将4-氨基-3-氯-5-碘苄腈(65. 2mg,0. 23mmol)在0°C溶解于THF。 [0601] 4-amino-3-chloro-5-iodo-benzonitrile (65. 2mg, 0. 23mmol) from 0 ° C was dissolved in THF. 在将硼烷-THF复合物Geq,0. 94mmol,0. 94ml)缓慢加入反应混合物后,将反应温度加热到回流。 After the borane -THF complex Geq, 0. 94mmol, 0. 94ml) was slowly added to the reaction mixture, the reaction was heated to reflux temperature. 在回流的情况下,将反应混合物搅拌12小时。 Under reflux, the reaction mixture was stirred for 12 hours. 在证实反应结束后,加入MeOH。 After the reaction was confirmed, adding MeOH. 将混合物搅拌4小时。 The mixture was stirred for 4 hours. 将反应溶剂在真空中去除。 The reaction solvent was removed in vacuo. 残余物用乙酸乙酯提取,用H2O和盐水洗涤,用Na2SO4 干燥,并在真空中浓缩以产生4-氨基甲基-2-碘-6-甲基-苯胺(19. 4mg)。 The residue was extracted with ethyl acetate, washed with H2O and brine, dried over Na2SO4, and concentrated to give 4-amino-2-iodo-6-methyl in vacuo - aniline (19. 4mg).

[0602] 将4-氨基甲基-2-氯-6-碘苯胺(52. 92mg,0. 19mmol)溶解于THF,接着缓慢加入BOC2Od. Ieq,0. 21mmol,47. 48ml)。 [0602] 4-Amino-2-chloro-6-iodo aniline (52. 92mg, 0. 19mmol) was dissolved in THF, followed by slow addition BOC2Od. Ieq, 0. 21mmol, 47. 48ml). 将反应混合物搅拌12小时。 The reaction mixture was stirred for 12 hours. 反应混合物用乙酸乙酯提取,用H2O和盐水洗涤,用Na2SO4干燥,并在真空中浓缩。 The reaction mixture was extracted with ethyl acetate, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. 将残余物用柱色谱法(n-Hx : EA =5:1)进行纯化以获得固体(34. 37mg,47. 94% )。 The residue was purified by column chromatography (n-Hx: 1: EA = 5) was purified to obtain a solid (34. 37mg, 47 94%.).

[0603] mp :113 〜115°C ; [0603] mp: 113 ~115 ° C;

[0604] IR(KBr 片状沉淀物,cnT1) :3343,1615,717 ; [0604] IR (KBr pellet, cnT1): 3343,1615,717;

[0605] 1H 匪lU400MHz,CDCl3) : δ 7. 39 (s, 1H), 7. 09 (s, 1H), 4. 76 (bs, 1H), 4. 05 (bs, 2H), 4. 05(s,2H),1. 38(s,9H) [0605] 1H bandit lU400MHz, CDCl3): δ 7. 39 (s, 1H), 7. 09 (s, 1H), 4. 76 (bs, 1H), 4. 05 (bs, 2H), 4. 05 (s, 2H), 1. 38 (s, 9H)

[0606] 步骤3 : (4-氨基-3-氯-5-乙烯基苄基)氨基甲酸叔丁酯 [0606] Step 3: (4-Amino-3-chloro-5-vinylbenzyl) carbamate

[0607]将 Pd (PPh3) 4(0· 06eq,0. Olmmol,18. 15mg)和LiCl (2. 8eq,0. 73mmol,30. 86mg)溶解于DMF。 [0607] The Pd (PPh3) 4 (0 · 06eq, 0. Olmmol, 18. 15mg) and LiCl (2. 8eq, 0. 73mmol, 30. 86mg) was dissolved in DMF. 将4-氨基-3-氯-5-碘苄基)氨基甲酸叔丁酯(100mg,0. ^nrnol)和三丁基乙烯基锡(1. 5eq,0. 39mmol, 114. 76 μ 1)加入。 4-amino-3-chloro-5-iodo benzyl) carbamate (100mg, 0. ^ Nrnol) and tributylvinyltin (1. 5eq, 0. 39mmol, 114. 76 μ 1) added. 将反应混合物在回流中搅拌12小时。 The reaction mixture was stirred at reflux for 12 hours. 将反应混合物按照与步骤3相似的方法进行纯化以获得固体(61. 8mg,85. 34% )。 The reaction mixture was purified in accordance with a method similar to Step 3 to give a solid (61. 8mg, 85. 34%).

[0608] mp :85 〜87 V ; [0608] mp: 85 ~87 V;

[0609] IR(KBr 片状沉淀物,cnT1) :3316,2977,1702,1635,725 ; [0609] IR (KBr pellet, cnT1): 3316,2977,1702,1635,725;

[0610] 1H NMR (400MHz, CDCl3) : δ 7. 06 (d, 1H, J = 2. OHz) ,7. 01 (d, 1H, J = 2. OHz), [0610] 1H NMR (400MHz, CDCl3): δ 7. 06 (d, 1H, J = 2. OHz), 7 01 (d, 1H, J = 2. OHz),.

6. 64 (dd, 1H, J = 17. 6,11. 2Hz),5. 56 (dd, 1H, J = 17. 2,1. 2Hz),5. 30 (dd, 1H, J = 11. 2, 1. 2Ηζ),4· 72 (bs, 1H) ,4. ll(d,2H,J = 5. 2Hz),1. 38(s,9H). 6. 64 (dd, 1H, J = 17. 6,11. 2Hz), 5. 56 (dd, 1H, J = 17. 2,1. 2Hz), 5. 30 (dd, 1H, J = 11. 2, 1. 2Ηζ), 4 · 72 (bs, 1H), 4. ll (d, 2H, J = 5. 2Hz), 1. 38 (s, 9H).

[0611] 步骤4 : (3-氯-4-甲烷磺酰基氨基-5-乙烯基苄基)氨基甲酸叔丁酯 [0611] Step 4: (3-Chloro-4-methanesulfonyl-5-vinylbenzyl) carbamate

[0612] 将氨基-3-氯-5-乙烯基苄基)氨基甲酸叔丁酯GO. 2mg,0. 14mmol),甲烷磺酰氯(5eq,0. 71mmol,55. 15 μ 1),和三乙胺(3eq,0. 42mmol,58. 34 μ 1)加入二氯甲烷中。 [0612] The amino-3-chloro-5-vinylbenzyl) carbamate GO. 2mg, 0. 14mmol), methanesulfonyl chloride (5eq, 0. 71mmol, 55. 15 μ 1), and tris amine (3eq, 0. 42mmol, 58. 34 μ 1) was added dichloromethane.

55将所述反应混合物搅拌5小时。 55 The reaction mixture was stirred for 5 hours. 用与实施例8的步骤5相似的方法纯化反应混合物以获得标题化合物(30. 7mg, 59. 83% ) „ The reaction mixture was purified as in Step 5 in a similar manner to Example 8 to obtain the title compound (30. 7mg, 59. 83%) "

[0613] mp :133 〜135°C ; [0613] mp: 133 ~135 ° C;

[0614] IR(KBr 片状沉淀物,cnT1) :3353,2981,1691,1524,1322,740 ; [0614] IR (KBr pellet, cnT1): 3353,2981,1691,1524,1322,740;

[0615] 1H NMR(400MHz, CDCl3) : δ 7. 40 (s, 1H) ,7. 25 (d, 1H, J=L 2Hz),7. 19 (d, 1H, J = 1. 2Ηζ),7· 14 (dd, 1H, J = 17. 6,11. 2Ηζ),6· 18 (s, 1H),5. 70 (d, 1H, J = 17. 2Hz),5. 34 (d, 1H, J = 11. 2Ηζ),4· 88 (s,1Η),4· 24(d,2H,J = 6. OHz),3· 00(s,3H),1. 40(s,9H). [0615] 1H NMR (400MHz, CDCl3):.. Δ 7. 40 (s, 1H), 7 25 (d, 1H, J = L 2Hz), 7 19 (d, 1H, J = 1. 2Ηζ), 7 · 14 (dd, 1H, J = 17. 6,11. 2Ηζ), 6 · 18 (s, 1H), 5. 70 (d, 1H, J = 17. 2Hz), 5. 34 (d, 1H , J = 11. 2Ηζ), 4 · 88 (s, 1Η), 4 · 24 (d, 2H, J = 6. OHz), 3 · 00 (s, 3H), 1. 40 (s, 9H).

[0616] 步骤5 :N-(4-氨基甲基-2-氯_6_乙烯基苯基)甲烷磺酰胺 [0616] Step 5: N- (4- aminomethyl-2-chloro _6_ vinylphenyl) methanesulfonamide

[0617] 将(3-氯-4-甲烷磺酰基氨基-5-乙烯基苄基)氨基甲酸叔丁酯(30.7mg, 0. 09mmol)和CF3COOH(5_6滴)加入二氯甲烷。 [0617] (3-chloro-4-methanesulfonyl-5-vinylbenzyl) carbamate (30.7mg, 0. 09mmol) and CF3COOH (5_6 drops) was added dichloromethane. 将反应混合物搅拌12小时。 The reaction mixture was stirred for 12 hours. 将反应混合物在真空中浓缩以获得标题化合物(33. 4mg, 100% )0 The reaction mixture was concentrated in vacuo to give the title compound (33. 4mg, 100%) 0

[0618] 1H NMR (400MHz, CD3OD) : δ 7. 75 (d, 1H, J = 1. 6Hz),7. 55 (d,1H,J = 2. 0Hz), 7. 22 (dd, 1H, J = 17. 6,10. 8Hz),5. 88 (d,1H,J = 17. 6Hz),5. 43 (d,1H,J = 11. 2Hz), 4. 13(s,2H),3. 10(s,3H) [0618] 1H NMR (400MHz, CD3OD):. Δ 7. 75 (d, 1H, J = 1. 6Hz), 7 55 (d, 1H, J = 2. 0Hz), 7. 22 (dd, 1H, J = 17. 6,10. 8Hz), 5. 88 (d, 1H, J = 17. 6Hz), 5. 43 (d, 1H, J = 11. 2Hz), 4. 13 (s, 2H), 3. 10 (s, 3H)

[0619] 步骤6 :N-{4-[3-(4-叔丁基苄基)脲基甲基]_2_氯_6_乙烯基苯基}甲烷磺酰胺 [0619] Step 6: N- {4- [3- (4- tert-butylbenzyl) ureidomethyl] _2_ chloro _6_ vinylphenyl} methanesulfonamide

[0620]将 4-叔丁基苄胺(1. kq,71. 10μ 1,0. 44mmol),BOC2Od. kq,0. 44mmol, 101. 19 μ 1),和DMAP (0. 2eq,0. 06mmol,7. 08mg)加入二氯甲烷。 [0620] 4-tert-butyl-benzylamine (1. kq, 71. 10μ 1,0. 44mmol), BOC2Od. Kq, 0. 44mmol, 101. 19 μ 1), and DMAP (0. 2eq, 0. 06mmol, 7. 08mg) was added dichloromethane. 将反应混合物搅拌5小时。 The reaction mixture was stirred for 5 hours. 在用TLC证实合成1-叔丁基-4-异氰酰甲基苯后,将N-(4-氨基甲基-2-氯-6-乙烯基苯基)甲烷磺酰胺(leq,0. 29mmol, 108. 6mg)和TEA(2eq,0. 58mmol,80. 84 μ 1)加入反应混合物。 After confirming Synthesis of 1-tert-butyl-isocyanato by TLC -4- methylbenzene, the N- (4- aminomethyl-2-chloro-6-vinylphenyl) methanesulfonamide (leq, 0. 29mmol, 108. 6mg) and TEA (2eq, 0. 58mmol, 80. 84 μ 1) was added the reaction mixture. 将反应混合物搅拌12小时并用与实施例8的步骤7相似的方法纯化以获得标题化合物(23. Omg, 17. 66% ) „ The reaction mixture was stirred for 12 hours and purified similar to the procedure of Example 8 Example 7 to obtain the title compound (23. Omg, 17. 66%) "

[0621] mp :165 〜167°C ; [0621] mp: 165 ~167 ° C;

[0622] IR(KBr 片状沉淀物,cnT1) :3333,2961,1625,1323,1155,765 ; [0622] IR (KBr pellet, cnT1): 3333,2961,1625,1323,1155,765;

[0623] 1H NMR (400MHz, CD3 0D) : δ 7. 52 (d, 1H, J = 1. 6Hz),7. 33 (d,1H,J = 1. 6Hz), 7. 31 (d, 2H, J = 8. 4Hz),7. 18 (dd, 1H, J = 17. 6,11. 2Hz),7. 17 (d, 2H, J = 8. 4Hz),5. 75 (d, 1H, J = 17. 6Hz),5. 32 (d, 1H, J = 11. 2Hz),4. 30(s,2H),4. 27(s,2H),3. 05(s,3H),1. 26 (s, 9H). [0623] 1H NMR (400MHz, CD3 0D): δ 7. 52 (d, 1H, J = 1. 6Hz), 7 33 (d, 1H, J = 1. 6Hz), 7. 31 (d, 2H. , J = 8. 4Hz), 7. 18 (dd, 1H, J = 17. 6,11. 2Hz), 7. 17 (d, 2H, J = 8. 4Hz), 5. 75 (d, 1H, J = 17. 6Hz), 5. 32 (d, 1H, J = 11. 2Hz), 4. 30 (s, 2H), 4. 27 (s, 2H), 3. 05 (s, 3H), 1 . 26 (s, 9H).

[0624] 实施例10 : [0624] Example 10:

[0625] N- {4- [3- (4-叔丁基-苄基)_脲基甲基]_2_三氟甲基_6_乙烯基-苯基}-甲烷磺酰胺 [0625] N- {4- [3- (4- tert-butyl-benzyl) - _ ureido methyl] _2_ _6_ vinyl trifluoromethyl - phenyl} - methanesulfonamide

Figure CN101142174BD00561

[0627] 步骤1 : 4-碘-2-三氟甲基苯胺 [0627] Step 1: 4-iodo-2-trifluoromethyl aniline

[0628]将 2-三氟甲基苯胺(30mg,0. 21mmol)和ICl (1. leq,0. 24mmol,38. 97mg)加入二氯甲烷。 [0628] A mixture of 2-trifluoromethyl aniline (30mg, 0. 21mmol) and ICl (1. leq, 0. 24mmol, 38. 97mg) was added dichloromethane. 将反应混合物搅拌12小时。 The reaction mixture was stirred for 12 hours. 所述反应混合物按照实施例8的步骤2纯化以获得标题化合物(25. 6mg,42. 48% )„ The reaction mixture was purified by the procedure of Example 2 according to the embodiment 8 to obtain the title compound (25. 6mg, 42. 48%) "

[0629] IR(NaCl 纯的,cnT1) :3411,3066,1109,701 ; [0629] IR (NaCl neat, cnT1): 3411,3066,1109,701;

[0630] 1H NMR(400MHz, CDCl3) : δ7. 61(d, 1H,J = 2· OHz),7· 46 (dd,1H,J = 8· 4,1. 2Hz), 6. 45 (d, 1H, J = 8. 4Hz),4. 05 (bs, 2H) · [0630] 1H NMR (400MHz, CDCl3):. Δ7 61 (d, 1H, J = 2 · OHz), 7 · 46 (. Dd, 1H, J = 8 · 4,1 2Hz), 6. 45 (d , 1H, J = 8. 4Hz), 4. 05 (bs, 2H) ·

[0631] 步骤2 :4-氨基-3-三氟甲基苄腈 [0631] Step 2: 4-amino-3-trifluoromethyl benzonitrile

[0632]将 4-碘-2-三氟甲基苯胺(50mg,0. 17mmol), Zn (CN) 2 (0. 88eq,0. 15mmol, 18. OOmg),和Pd(PPh3)4(0. leq,0. 02mmol,19. 64mg)力口入DMF。 [0632] A mixture of 4-iodo-2-trifluoromethyl-aniline (50mg, 0. 17mmol), Zn (CN) 2 (0. 88eq, 0. 15mmol, 18. OOmg), and Pd (PPh3) 4 (0 . leq, 0. 02mmol, 19. 64mg) force the mouth DMF. 将Zn (CN) 2 (0. 88eq, The Zn (CN) 2 (0. 88eq,

0. 15mmol, 18. OOmg)和Pd(PPti3)4(0. leq,0. 02mmol, 19. 64mg)加入所述反应混合物。 0. 15mmol, 18. OOmg) and Pd (PPti3) 4 (0. Leq, 0. 02mmol, 19. 64mg) was added to the reaction mixture. 将反应混合物搅拌12小时。 The reaction mixture was stirred for 12 hours. 按照实施例8的步骤1纯化反应混合物以获得作为黄色固体的标题产物(31. 4mg,99. 28% ) „ The reaction mixture was purified by a procedure of Example 8 to obtain the title product as a yellow solid (31. 4mg, 99. 28%) "

[0633] Mp:54〜56°C ;IR(KBr 片状沉淀物,cnT1) :3385,3263,2924,2220,1124,701 [0633] Mp: 54~56 ° C; IR (KBr pellet, cnT1): 3385,3263,2924,2220,1124,701

[0634] 1H NMR(400MHz, CDCl3) : δ 7. 65 (d, 1H, J = 2. OHz),7. 45 (dd, 1H, J = 8. 4,2. OHz), 6. 69 (d, 1H, J = 8. 4Hz),4. 65 (s, 2H) · [0634] 1H NMR (400MHz, CDCl3):. Δ 7. 65 (d, 1H, J = 2. OHz), 7 45 (. Dd, 1H, J = 8. 4,2 OHz), 6. 69 ( d, 1H, J = 8. 4Hz), 4. 65 (s, 2H) ·

[0635] 步骤3 : 4-氨基-3-碘-5-三氟甲基苄腈 [0635] Step 3: 4-amino-3-iodo-5-trifluoromethyl-benzonitrile

[0636]将 4-氨基-3-三氟甲基苄腈(100mg,0. 54mmol)禾Π ICl (1. leq,0. 58mmol, 96. OOmg)加入二氯甲烷。 [0636] 4-amino-3-trifluoromethyl benzonitrile (100mg, 0. 54mmol) Wo Π ICl (1. leq, 0. 58mmol, 96. OOmg) was added dichloromethane. 将混合物搅拌12小时。 The mixture was stirred for 12 hours. 按照实施例8的步骤2纯化反应混合物以得到标题化合物(30. 5mg,18. 10% ) „ mp :86〜88°C ; The reaction mixture was purified according to the procedure of Example 8 to afford the title compound embodiment (. 30. 5mg, 18 10%) "mp: 86~88 ° C;

[0637] IR(KBr 片状沉淀物,cnT1) :3371,3080,2924,2226,1125,701 ; [0637] IR (KBr pellet, cnT1): 3371,3080,2924,2226,1125,701;

[0638] 1H NMR (400MHz, CDCl3) : δ 8. 02 (d, 1H, J = 1. 6Hz) ,7. 35 (dd, 1H, J = 133.2, [0638] 1H NMR (400MHz, CDCl3): δ 8. 02 (d, 1H, J = 1. 6Hz), 7 35 (dd, 1H, J = 133.2,.

1. 6Hz),7. 65 (dd, 1H, J= 10. 0,1. 6Hz),5. 20 (d, 2H, J = 22. OHz) · 1. 6Hz), 7. 65 (dd, 1H, J = 10. 0,1. 6Hz), 5. 20 (d, 2H, J = 22. OHz) ·

[0639] 步骤4 : (4-氨基-3-碘-5-三氟甲基苄基)氨基甲酸叔丁酯 [0639] Step 4: (4-amino-3-iodo-5-trifluoromethyl-benzyl) carbamate

[0640] 将4-氨基-3-碘-5-三氟甲基苄腈(1805. ang,5. 19mmol)在0°C溶解于THF。 [0640] 4-amino-3-iodo-5-trifluoromethyl benzonitrile (1805. ang, 5. 19mmol) from 0 ° C was dissolved in THF. 在将硼烷-THF复合物C3eq,17. 36mmol, 17. 36ml)缓慢加入反应混合物后,将反应温度加热到回流。 After the borane -THF complex C3eq, 17. 36mmol, 17. 36ml) was slowly added to the reaction mixture, the reaction was heated to reflux temperature. 在回流的情况下,将反应混合物搅拌12小时。 Under reflux, the reaction mixture was stirred for 12 hours. 在证实反应结束后,加入MeOH。 After the reaction was confirmed, adding MeOH. 将所述混合物搅拌4小时。 The mixture was stirred for 4 hours. 在真空中去除反应溶剂。 The reaction solvent was removed in vacuo. 残余物用乙酸乙酯提取,用H2O和盐水洗涤,用Na2SO4干燥并在真空中浓缩以产生4-氨基甲基-2-碘-6-三氟甲基苯胺(55. Img)。 The residue was extracted with ethyl acetate, washed with H2O and brine, dried over Na2SO4 and concentrated in vacuo to yield 4-amino-2-iodo-6-trifluoromethyl aniline (55. Img).

[0641] 将4-氨基甲基-2-碘-6-三氟甲基-苯胺Q025. 7mg,6. 45mmol)溶解于THF,接着缓慢加入BOC2O (0. 8eq,5. 16mmol, 1187. 15 μ 1)。 [0641] 4-amino-2-iodo-6-trifluoromethyl - phenylamine Q025 7mg, 6 45mmol) was dissolved in THF, followed by slow addition of BOC2O (0. 8eq, 5 16mmol, 1187. 15. μ 1). 将反应混合物搅拌12小时。 The reaction mixture was stirred for 12 hours. 反应混合物用乙酸乙酯提取,用H2O和盐水洗涤,并用Na2SO4干燥,在真空中浓缩。 The reaction mixture was extracted with ethyl acetate, washed with H2O and brine, and dried over Na2SO4, and concentrated in vacuo. 残余物用柱色谱法进行纯化(η-Ηχ : EA = 5 : 1)以产生固体(1501. Img, 55. 94% )。 The residue was purified (η-Ηχ: EA = 5: 1) column chromatography to give a solid (1501. Img, 55. 94%).

[0642] mp :120 〜122°C ; [0642] mp: 120 ~122 ° C;

[0643] IR(KBr 片状沉淀物,cnT1) :3387,2984,1687,1107,701 ; [0643] IR (KBr pellet, cnT1): 3387,2984,1687,1107,701;

[0644] 1H NMR (400MHz, CDCl3) : δ 7. 43 (d, 1H, J = 160. 4Hz),7. 27 (d, 1H, J = 37. 2Hz), 4. 92 (s,1H),4. 54 (s, 2H),4. 13 (s, 2H),1. 41 (s,9H). [0644] 1H NMR (400MHz, CDCl3):. Δ 7. 43 (d, 1H, J = 160. 4Hz), 7 27 (d, 1H, J = 37. 2Hz), 4. 92 (s, 1H) , 4. 54 (s, 2H), 4. 13 (s, 2H), 1. 41 (s, 9H).

[0645] 步骤5 : (4-氨基-3-三氟甲基-5-乙烯基苄基)氨基甲酸叔丁酯 [0645] Step 5: (4-Amino-3-trifluoromethyl-5-vinyl benzyl) carbamate

[0646]将Pd(PPti3)4(0. 06eq,0. 014mmol, 16. 64mg)和LiCl O. 8eq,0. 67mmol,28. 49mg)加入DMF。 [0646] The Pd (PPti3) 4 (0. 06eq, 0. 014mmol, 16. 64mg) and LiCl O. 8eq, 0. 67mmol, 28. 49mg) was added DMF. 将(4-氨基-3-碘-5-三氟甲基苄基)氨基甲酸叔丁酯(100mg,0. 24mmol)和三丁基乙烯基锡(1. 5eq,0. 36mmol, 105. 37 μ 1)加入反应混合物。 (4-amino-3-iodo-5-trifluoromethyl-benzyl) carbamate (100mg, 0. 24mmol) and tributylvinyltin (1. 5eq, 0. 36mmol, 105. 37 μ 1) was added the reaction mixture. 将所述反应混合物在回流中搅拌12小时。 The reaction mixture was stirred at reflux for 12 hours. 按照实施例8的步骤4纯化反应混合物以得到标题产物,黄色糖浆(51.5mg,67. 87% )。 The reaction according to Step 8 Example 4 mixture was purified to give the title product as a yellow syrup (51.5mg, 67. 87%).

[0647] mp :90 〜92 °C ; [0647] mp: 90 ~92 ° C;

[0648] IR(NaCl 纯的,CnT1) :3357,2981,1702,1635,1116 ; [0648] IR (NaCl neat, CnT1): 3357,2981,1702,1635,1116;

[0649] 1H NMR (400MHz, CDCl3) : δ 7. 24 (s, 1H), 7. 22 (s, 1H), 6. 64 (dd, 1H, J = 17. 2, [0649] 1H NMR (400MHz, CDCl3): δ 7. 24 (s, 1H), 7. 22 (s, 1H), 6. 64 (dd, 1H, J = 17. 2,

6. 4Hz) ,5. 57 (dd, 1H, J = 17. 2,1. 2Hz),5. 36 (dd,1H,J = 10. 8,1. 2Hz),4. 71 (s,1H), 4. 15 (s,2H),4. 14 (d, 2H J = 5. 2Hz),1. 39 (s,9H) 6. 4Hz), 5. 57 (dd, 1H, J = 17. 2,1. 2Hz), 5. 36 (dd, 1H, J = 10. 8,1. 2Hz), 4. 71 (s, 1H ), 4. 15 (s, 2H), 4. 14 (d, 2H J = 5. 2Hz), 1. 39 (s, 9H)

[0650] 步骤6 : (4-甲烷磺酰基氨基-3-三氟甲基-5-乙烯基苄基)氨基甲酸叔丁酯[0651 ] 将氨基-3-三氟甲基-5-乙烯基苄基)氨基甲酸叔丁酯(235. 6mg,0. 75mmol), 甲烷磺酰氯(5eq,3. 73mmol,沘8. 40 μ 1),和三乙胺(3eq,2. 25mmol,313. 60 μ 1)加入到二氯甲烷。 [0650] Step 6: (4-methanesulfonyl-3-trifluoromethyl-5-vinyl benzyl) carbamate [0651] The amino-3-trifluoromethyl-5-vinyl benzyl) carbamate (235. 6mg, 0. 75mmol), methanesulfonyl chloride (5eq, 3. 73mmol, Bi 8. 40 μ 1), and triethylamine (3eq, 2. 25mmol, 313. 60 μ 1) was added to methylene chloride. 将反应混合物搅拌5小时。 The reaction mixture was stirred for 5 hours. 将反应混合物按照实施例8的步骤5纯化以得到标题产物,黄色糖浆(89. 3mg, 30. 21% )0 5 The reaction mixture was purified according to the procedure of Example 8 to give the title product, a yellow syrup (89. 3mg, 30. 21%) 0

[0652] IR(KBr 片状沉淀物,cnT1) :3361,2977,1692,1330,1152 ; [0652] IR (KBr pellet, cnT1): 3361,2977,1692,1330,1152;

[0653] 1H NMR(400MHz, CDCl3) :7. 65 (s, 1H) , 7. 46 (s, 1H) , 7. 13 (dd, 1H, J = 11. 2, 17. 6Hz), 6. 09 (s, 1H), 5. 73 (d, 1H, J = 17. 6Hz) ,5. 42 (d, 1H, J = 11. 2Hz),4. 90 (s,1H), 4. 29 (d, 2H, J = 5. 6Hz),3. 07 (s, 3H),1. 40 (s,9H) [0653] 1H NMR (400MHz, CDCl3):. 7 65 (s, 1H), 7. 46 (s, 1H), 7. 13 (dd, 1H, J = 11. 2, 17. 6Hz), 6. 09 (s, 1H), 5. 73 (d, 1H, J = 17. 6Hz), 5. 42 (d, 1H, J = 11. 2Hz), 4. 90 (s, 1H), 4. 29 ( d, 2H, J = 5. 6Hz), 3. 07 (s, 3H), 1. 40 (s, 9H)

[0654] 步骤7 :N-(4-氨基甲基-2-三氟甲基_6_乙烯基苯基)甲烷磺酰胺 [0654] Step 7: N- (4- aminomethyl-2-trifluoromethyl _6_ vinylphenyl) methanesulfonamide

[0655] 将(4-甲烷磺酰基氨基-3-三氟甲基-5-乙烯基苄基)氨基甲酸叔丁酯(89. 3mg, 0. 23mmol)和CF3COOH(5〜6滴)加入到二氯甲烷。 [0655] (4-methanesulfonyl-3-trifluoromethyl-5-vinyl-benzyl) carbamate (89. 3mg, 0. 23mmol) and CF3COOH (5~6 drops) was added to methylene chloride. 将所述混合物搅拌12小时。 The mixture was stirred for 12 hours. 将所述反应混合物按照实施例8的步骤6纯化以得到标题产物(101. 4mg, 100% )0 The reaction mixture was purified by the procedure of Example 8 to give the title product according to 6 (101. 4mg, 100%) 0

[0656] 1H NMR(400MHz,CD3OD) :8. 02 (s, 1H) , 7. 77 (s, 1H) , 7. 27 (dd, 1H, J = 17. 6, 11.2Hz),5. 92 (d, 1H, J = 17. 6Hz),5. 51 (d,1H,J = 11. 2Hz) ,4. 20(s,2H),3. ll(s,3H). [0656] 1H NMR (400MHz, CD3OD):. 8 02 (s, 1H), 7. 77 (s, 1H), 7. 27 (dd, 1H, J = 17. 6, 11.2Hz), 5 92. (d, 1H, J = 17. 6Hz), 5. 51 (d, 1H, J = 11. 2Hz), 4. 20 (s, 2H), 3. ll (s, 3H).

[0657] 步骤8 :N-{4-[3-(4-叔丁基苄基)脲基甲基]_2_三氟甲基_6_乙烯基苯基}甲烷磺酰胺 [0657] Step 8: N- {4- [3- (4- tert-butylbenzyl) ureidomethyl] _2_ trifluoromethylphenyl _6_ vinylphenyl} methanesulfonamide

[0658]将 4-叔丁基-节胺(1. 5eq, 15. 20 μ 1,0. 09mmol), B0C20(1. 5eq,0. 09mmol, 20. 70 μ 1),和DMAP (0. 2eq, 0. Olmmol, 1. 34mg)加入到二氯甲烷。 [0658] 4-tert-butyl - amine section (. 1. 5eq, 15. 20 μ 1,0 09mmol), B0C20 (.. 1 5eq, 0 09mmol, 20. 70 μ 1), and DMAP (0. 2eq, 0. Olmmol, 1. 34mg) was added to the methylene chloride. 将反应混合物搅拌5小时。 The reaction mixture was stirred for 5 hours. 在用TLC证实合成1-叔丁基-4-异氰酰甲基苯后,将N- (4-氨基甲基-2-三氟甲基-6-乙烯基苯基)甲烷磺酰胺(leq,0. 06mmol,20. 5mg)和TEA(2eq,0. 12讓ol,16. 72 μ 1)加入反应混合物。 After confirming the synthesis of 1-tert-butyl-4-isocyanato-methyl-benzene TLC, the N- (4- aminomethyl-6-vinyl-2-trifluoromethyl-phenyl) methanesulfonamide (Leq , 0. 06mmol, 20. 5mg) and TEA (2eq, 0. 12 let ol, 16. 72 μ 1) was added the reaction mixture. 将反应混合物搅拌12小时并用与实施例8的步骤7相似的方法纯化以得到标题化合物(10. 7mg 36. 88% ) „ The reaction mixture was stirred for 12 hours and purified similar to the procedure of Example 8, Method 7 to afford the title compound (10. 7mg 36. 88%) "

[0659] mp :134 〜136°C ; [0659] mp: 134 ~136 ° C;

[0660] IR(KBr 片状沉淀物,cnT1) :3361,2962,1642,1261,1151 ; [0660] IR (KBr pellet, cnT1): 3361,2962,1642,1261,1151;

[0661] 1H NMR (400MHz, CDCl3) : δ 7. 64 (s, 1H), 7. 44 (s, 1H), 7. 28 (d, 2H, J = 8. OHz), [0661] 1H NMR (400MHz, CDCl3): δ 7. 64 (s, 1H), 7. 44 (s, 1H), 7. 28 (d, 2H, J = 8. OHz),

7. 16(d,2H,J = 8. 0Hz),7. ll(dd,lH,J = 17. 2,11. 2Hz),6. 03 (s,1H),5. 71 (d,1H,J = 17. 2Hz),5. 41 (d, 1H, J = 11. 2Hz),4. 37 (s, 2H),4. 29 (s, 2H),3. 06 (s, 3H),1. 23 (s,9H) · 7. 16 (d, 2H, J = 8. 0Hz), 7. Ll (dd, lH, J = 17. 2,11. 2Hz), 6. 03 (s, 1H), 5. 71 (d, 1H , J = 17. 2Hz), 5. 41 (d, 1H, J = 11. 2Hz), 4. 37 (s, 2H), 4. 29 (s, 2H), 3. 06 (s, 3H), 1. 23 (s, 9H) ·

[0662] 实施例11 : [0662] Example 11:

[0663] 3-(4-叔丁基苯基)-N-[l-(R)_(4-甲烷磺酰基氨基_3_乙烯基苯基)乙基]丙炔酰胺 [0663] 3- (4-tert-butylphenyl) -N- [l- (R) _ (4- methanesulfonylamino-_3_ vinylphenyl) ethyl] propiolamide

[0664] [0664]

58 58

Figure CN101142174BD00591

[0665] 步骤1 :(4-叔丁基-苯基)-丙炔酸甲基酯 [0665] Step 1: (4-tert-butyl - phenyl) - propiolic acid methyl ester

[0666] 用氩气充满IOOml的双颈圆底烧瓶,并将4_叔丁基-苯甲酰氯(500mg,2. 34mmol) 在甲苯中的溶液置于所述烧瓶中。 [0666] IOOml filled with argon-neck round bottom flask, and t-butyl 4 _ - benzoyl chloride (. 500mg, 2 34mmol) in toluene was placed in the flask. 向该溶液加入(三苯基亚正膦基)乙酸甲基酯(l.kq, 3. 52mmol,1178. 39mg)并在90〜100°C回流12小时.在用TLC证实反应结束后,在减压下去除甲苯并进行柱色谱法(正己烷/乙酸乙酯=4/1)以产生黄色固体(产物1)。 To this solution was added (triphenylphosphoranylidene) acetic acid methyl ester (l.kq, 3. 52mmol, 1178. 39mg) and refluxed for 12 hours at 90~100 ° C. At the end of the reaction was confirmed by TLC, the toluene was removed under reduced pressure and subjected to column chromatography (hexane / ethyl acetate = 4/1) to give a yellow solid (product 1).

[0667] 用氩气充满50ml的双颈圆底烧瓶并将所述产物(1)置于所述烧瓶,加热,并在250°C搅拌90分钟。 [0667] filled with argon, 50ml of a double necked round bottom flask and the product (1) was placed in the flask was heated and stirred at 250 ° C 90 min. 用二氯甲烷提取反应化合物并进行柱色谱法(正己烷/乙酸乙酯= 25/1)以产生黄色液体(产物(2),81. 7mg, 19. 69% )0 The reaction was extracted with dichloromethane and the compound was subjected to column chromatography (hexane / ethyl acetate = 25/1) to give a yellow liquid (product (2), 81. 7mg, 19. 69%) 0

[0668] IR(KBr 片状沉淀物,cnT1) :2963,2224,1715,1506,1460 ; [0668] IR (KBr pellet, cnT1): 2963,2224,1715,1506,1460;

[0669] 1H NMR(400MHz, CDCl3) product (1) 7. 70 〜7. 65 (m,6H),7. 59 (d,2H,J = 8. 4Hz), 7. 47 〜7. 35 (m, 9H),7. 29 (d, 2H, J = 8. 8Hz) ;product (2) 7. 50 (d, 2H, J = 8. OHz),7. 36 (d, 2H, J = 8. OHz),3. 80 (s, 3H),1. 28 (s,9H) · [0669] 1H NMR (400MHz, CDCl3) product (1) 7. 70 ~7. 65 (m, 6H), 7. 59 (d, 2H, J = 8. 4Hz), 7. 47 ~7. 35 ( m, 9H), 7 29 (d, 2H, J = 8. 8Hz);.. product (2) 7. 50 (d, 2H, J = 8. OHz), 7 36 (d, 2H, J = 8 . OHz), 3. 80 (s, 3H), 1. 28 (s, 9H) ·

[0670] 步骤2 : (4-叔丁基苯基)-丙炔酸 [0670] Step 2: (4-tert-butylphenyl) - propiolic acid

[0671] 将(4-叔丁基-苯基)-丙酸甲基酯(21.7mg,0. llmmol)置于25ml的圆底烧瓶中并溶解于少量甲醇。 [0671] (4-tert-butyl - phenyl) - propionic acid methyl ester (. 21.7mg, 0 llmmol) was placed in 25ml round bottom flask and dissolved in a small amount of methanol. 向该溶液缓慢加入K2CO3溶液,并搅拌1小时。 To this solution was slowly added a solution of K2CO3 and stirred for 1 hour. 在用TLC证实反应结束后,在减压下去除甲醇并用乙酸乙酯提取残余物。 In the end of the reaction was confirmed by TLC, methanol was removed under reduced pressure and the residue was extracted with ethyl acetate. 将所述乙酸乙酯层用水和盐水洗涤,通过硫酸钠干燥,过滤并在减压下浓缩。 The ethyl acetate layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. 将获得的液体进行柱色谱法(甲醇:乙酸乙酯=1 : 1) 以产生白色液体(20. 8mg,95. 37% )0 The liquid obtained was subjected to column chromatography (methanol: ethyl acetate = 1: 1) to yield a white liquid (20. 8mg, 95 37%.) 0

[0672] IR(KBr 片状沉淀物,cnT1) :3419,2963,2214,1576,1460 ; [0672] IR (KBr pellet, cnT1): 3419,2963,2214,1576,1460;

[0673] 1H NMR(400MHz, CDCl3) :7. 44(d,2H,J = 8. 8Hz),7. 40(d,2H,J = 8. 4Hz),1. 30 (s, 9H). [0673] 1H NMR (400MHz, CDCl3):.. 7 44 (d, 2H, J = 8. 8Hz), 7 40 (d, 2H, J = 8. 4Hz), 1 30 (s, 9H)..

[0674] 步骤3 :3-(4-叔丁基苯基)-N-[I-(R)-(4-甲烷磺酰基氨基_3_乙烯基苯基)乙基]丙炔酰胺 [0674] Step 3: 3- (4-tert-butylphenyl) -N- [I- (R) - (4- methanesulfonylamino-_3_ vinylphenyl) ethyl] propiolamide

[0675] 用氩气充满干燥的25ml的双颈圆底烧瓶,并将N_ (R) - [4-(1-氨基-乙基)_2_乙烯基-苯基]-甲烷磺酰胺(110. 55mg,0.46mmol)和(4-叔丁基-苯基)-丙酸(1. &q, 0. 56mmol, 110. 4mg)在DMF中的溶液置于所述烧瓶。 [0675] 25ml of dried filled with argon-neck round bottom flask, and N_ (R) - [4- (1- amino - ethyl) _2_ vinyl - phenyl] - methanesulfonamide (110. 55mg, 0.46mmol) and (4-tert-butyl - phenyl) - propionic acid (1. & q, 0. 56mmol, 110. 4mg) in DMF was placed in the flask. 向该溶液加入三乙胺Qeq,0. 92mmol, 128. 23mg)和二乙基氰基膦酸酯(1. 2eq,0. 56mmol,83. 76 μ 1)并搅拌12小时。 To this solution was added triethylamine Qeq, 0. 92mmol, 128. 23mg) and diethyl cyano phosphonate (1. 2eq, 0. 56mmol, 83. 76 μ 1) and stirred for 12 hours. 在用TLC证实反应结束后,在减压下去除DMF,用乙酸乙酯提取残余物。 With TLC confirmed completion of the reaction, the DMF was removed under reduced pressure, the residue was extracted with ethyl acetate. 乙酸乙酯层用水和盐水洗涤,通过硫酸钠干燥,过滤并在减压下浓缩。 The ethyl acetate layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. 将获得的液体进行柱色谱法(正己烷/乙酸乙酯= 2/1)以产生黄色固体(54mg, 28. 62% )0 The liquid obtained was subjected to column chromatography (hexane / ethyl acetate = 2/1) to give a yellow solid (54mg, 28. 62%) 0

[0676] mp:89 〜91°C; [0676] mp: 89 ~91 ° C;

[0677] [α ]20d :-30. 72°C (CHCl3, cl. 51); . [0677] [α] 20d: -30 72 ° C (. CHCl3, cl 51);

[0678] IR(KBr 片状沉淀物,cnT1) :3259,3023,2965,2212,1628,1323 ; [0678] IR (KBr pellet, cnT1): 3259,3023,2965,2212,1628,1323;

[0679] 1H NMR(400MHz, CDCl3) :7. 45 (d, 1H, J = 2. OHz),7. 44(d,2H,J = 8. 4Hz),7. 39 (d,1H, J = 8. 4Hz),7. 32 (d, 2H, J = 8. 8Hz),7. 24 (dd, 1H, J = 8. 0,2. 4Hz),6. 91 (dd, 1H, J =17. 2,11. 2Hz) ,6. 76 (s, 1H),6· 35 (d, 1H, J = 8. OHz),5· 70 (dd, 1H, J = 17. 6,0. 8Hz), [0679] 1H NMR (400MHz, CDCl3):.. 7 45 (d, 1H, J = 2. OHz), 7 44 (d, 2H, J = 8. 4Hz), 7 39 (d, 1H, J. = 8. 4Hz), 7. 32 (d, 2H, J = 8. 8Hz), 7. 24 (dd, 1H, J = 8. 0,2. 4Hz), 6. 91 (dd, 1H, J = 17. 2,11. 2Hz), 6. 76 (s, 1H), 6 · 35 (d, 1H, J = 8. OHz), 5 · 70 (dd, 1H, J = 17. 6,0. 8Hz ),

5. 42 (dd, 1H, J = 10. 8,0. 8Hz) ,5. 15(五重峰,1H, J = 6. 8Hz),2. 93 (s, 3H),1. 50 (d, 3H, J = 5. 42 (dd, 1H, J = 10. 8,0. 8Hz), 5. 15 (quintet, 1H, J = 6. 8Hz), 2. 93 (s, 3H), 1. 50 (d , 3H, J =

6. 8Hz),1. 26(s,9H) 6. 8Hz), 1. 26 (s, 9H)

[0680] 实施例12 :3-(4-叔丁基苯基)丙炔酸3-氟-4-甲烷磺酰基氨基_5_乙烯基苄基酰胺 [0680] Example 12: 3- (4-tert-butyl-phenyl) propiolic acid 3-fluoro-4-methanesulfonyl-ylamino _5_ vinyl benzyl amide

[0681] [0681]

Figure CN101142174BD00601

[0682] 将(4-叔丁基苯基)丙炔酸(实施例11的步骤2,0. 16mmol,33. Omg)和N_(4_氨基甲基-2-氟-6-乙烯基苯基)甲烷磺酰胺(实施例2的步骤6,0. 19mmol,39. 20mg), DEPC(1. 2eq,0. 19mmol,29. 13μ 1),TEA(2eq,0. 32mmol,44. 60 μ 1)在DMF 中的混合物在氩气气氛下在室温搅拌12小时。 [0682] (4-tert-butyl-phenyl) propiolic acid (Example 11, Step 2,0. 16mmol, 33. Omg) and N_ (4_ amino-2-fluoro-6-vinyl benzene yl) methanesulfonamide (Example 2 step 6,0. 19mmol, 39. 20mg), DEPC (1. 2eq, 0. 19mmol, 29. 13μ 1), TEA (2eq, 0. 32mmol, 44. 60 μ 1) in DMF was stirred for 12 hours at room temperature under argon atmosphere. 在结束后,如通过TLC所测定,通过KOAc (150ml X幻提取反应溶液,有机相用H2O洗涤,干燥(Na2SO4),过滤和浓缩。在进行硅胶柱色谱法(正己烷/ EtOAc = 2 : 1)后,分离3-(4-叔丁基苯基)丙炔酸3-氟-4-甲烷磺酰基氨基_5_乙烯基苄基酰胺5mg,0. 1 Immol,72. 25% ) „ At the end, as determined by TLC, the reaction solution was extracted by KOAc (150ml X magic, the organic phase was washed with H2O, dried (Na2SO4), filtered and concentrated performing silica gel column chromatography (hexane / EtOAc = 2:. 1 after) separation of 3- (4-tert-butyl-phenyl) propiolic acid 3-fluoro-4-methanesulfonyl-ylamino _5_ vinyl benzyl amide 5mg, 0. 1 Immol, 72. 25%) "

[0683] mp :155 〜157°C ; [0683] mp: 155 ~157 ° C;

[0684] IR(KBr 片状沉淀物,cnT1) :3238,3026,2964,2223,1634,1321,1154 ; [0684] IR (KBr pellet, cnT1): 3238,3026,2964,2223,1634,1321,1154;

[0685] 1H NMR (400MHz,CDCl3) : δ 7. 51 (d, 1H, J = 8. 8Hz) ,7. 45 (d,2H, J = 8. 4Hz), 7. 35 (s,1H), 7. 14 (dd, 1H, J = 17. 6,11. 2Hz),7. 07 (dd, 1H, J = 10. 0,1. 6Hz),6. 28 (t, 1H, J = 5. 6Hz),6. 03 (s,1H),5. 80 (d, 1H, J = 17. 6Hz),5. 45 (d, 1H, J = 11. 2Hz),4. 51 (d, 2H, J =6. 0Hz),3. 06 (s,3H),1. 28 (s,9H) [0685] 1H NMR (400MHz, CDCl3):. Δ 7. 51 (d, 1H, J = 8. 8Hz), 7 45 (d, 2H, J = 8. 4Hz), 7. 35 (s, 1H) , 7. 14 (dd, 1H, J = 17. 6,11. 2Hz), 7. 07 (dd, 1H, J = 10. 0,1. 6Hz), 6. 28 (t, 1H, J = 5 . 6Hz), 6. 03 (s, 1H), 5. 80 (d, 1H, J = 17. 6Hz), 5. 45 (d, 1H, J = 11. 2Hz), 4. 51 (d, 2H , J = 6. 0Hz), 3. 06 (s, 3H), 1. 28 (s, 9H)

[0686] 实施例13 :3-(4-叔丁基苯基)丙炔酸N_[l_(3_氟_4_甲烷磺酰基氨基_5_乙烯基苯基)乙基]酰胺 [0686] Example 13: 3- (4-tert-butyl-phenyl) propiolic acid N_ [l_ (3_ fluoro _4_ _5_ methanesulfonylamino-vinylphenyl) ethyl] amide

[0687] [0687]

Figure CN101142174BD00602

[0688] 将N44-(l-氨基-乙基)-2-氟-6-乙烯基苯基]甲烷磺酰胺(0. 03mmol, 10. Omg),(4-叔丁基苯基)丙炔酸(实施例11的步骤2,0. 03mmol,6. 52mg), DEPC(0. 03mmol,5. 46 μ 1),和TEA(0. 06mmol,8. 36 μ 1)加入DMF。 [0688] The N44- (l- amino - ethyl) -2-fluoro-6-vinylphenyl] methanesulfonamide (0. 03mmol, 10. Omg), (4- tert-butylphenyl) propynyl acid (Example 11, step 2,0. 03mmol, 6. 52mg), DEPC (0. 03mmol, 5. 46 μ 1), and TEA (0. 06mmol, 8. 36 μ 1) was added DMF. 将混合物搅拌12 小时。 The mixture was stirred for 12 hours. 按照实施例12纯化反应混合物以得到标题产物(11. 3mg,95. 09% )0 According to Example 12 Purification of the reaction mixture to give the title product (11. 3mg, 95. 09%) 0

[0689] mp :108 〜110°C ; [0689] mp: 108 ~110 ° C;

[0690] [α ]D20 :-14. 54(CHCl3, c 0. 81); . [0690] [α] D20: -14 54 (CHCl3, c 0. 81);

[0691] IR(KBr 片状沉淀物,cnf1) :3248,3025,2965,2211,1629,1323,1152 ;1HnmrgoomHz5CDCI3) : δ I. 44(d,2H, J = 8. 4Hz),7· 38(s,1H),7· 34(d,2H,J = 8. 4Hz), 7. 14 (dd, 1H, J = 17. 6,10. 8Hz),7. 06 (dd, 1H, J = 10. 4,2. OHz),6. 17 (d, 1H, J = 7. 6Hz), 5. 80 (d, 1H, J = 17. 6Hz),5. 43 (d, 1H, J = 10. 8Hz) ,5. 15(五重峰,1H, J = 7. 2Hz),3. 05 (s, 3H),1. 52 (d, 3H, J = 6. 8Hz),1. 28 (s, 9H) [0691] IR (KBr pellet, cnf1): 3248,3025,2965,2211,1629,1323,1152; 1HnmrgoomHz5CDCI3): δ I. 44 (d, 2H, J = 8. 4Hz), 7 · 38 (s, 1H), 7 · 34 (d, 2H, J = 8. 4Hz), 7. 14 (dd, 1H, J = 17. 6,10. 8Hz), 7. 06 (dd, 1H, J = 10. 4,2. OHz), 6. 17 (d, 1H, J = 7. 6Hz), 5. 80 (d, 1H, J = 17. 6Hz), 5. 43 (d, 1H, J = 10 . 8Hz), 5. 15 (quintet, 1H, J = 7. 2Hz), 3. 05 (s, 3H), 1. 52 (d, 3H, J = 6. 8Hz), 1. 28 (s , 9H)

[0692] 实施例14 : [0692] Example 14:

[0693] 3-(4-叔丁基苯基)-N-[l-(R)_(4-甲烷磺酰基氨基_3_乙烯基苯基)乙基]丙烯酰胺 [0693] 3- (4-tert-butylphenyl) -N- [l- (R) _ (4- methanesulfonylamino-_3_ vinylphenyl) ethyl] acrylamide

[0694] [0694]

Figure CN101142174BD00611

[0695] 用氩气充满25ml的双颈圆底烧瓶,将3_(4_叔丁基-苯基)-丙烯酸Ql. lmg, [0695] bis neck round bottom flask 25ml filled with argon, the 3_ (4_ t-butyl - phenyl) - acrylic acid Ql lmg,

0. 103mmol,leq.)和二乙基氰基瞵酸酯(17. 2μ 1,0. 113mmol,l. leq.)在DMF 中的溶液置于所述烧瓶。 0. 103mmol, leq.) And diethyl phosphine cyano acetate (17. 2μ 1,0. 113mmol, l. Leq.) In DMF was placed in the flask. 向该溶液加入I-(R)-(4-甲烷磺酰基氨基-3-乙烯基-苯基)-乙基-铵,三氟-乙酸酯(36. 7mg,0. 103mmol, leq.)和三乙胺1 μ 1,0. 309mmol,3eq.)在DMF 中的溶液。 To this was added a solution of I- (R) - (4- methanesulfonyl-3-vinyl - phenyl) - ethyl - ammonium, trifluoromethyl - (.. 36. 7mg, 0 103mmol, leq) acetate and triethylamine 1 μ 1,0. 309mmol, 3eq.) in DMF solution. 将混合物溶液搅拌一夜。 The mixture was stirred overnight. 在用TLC证实反应结束后,在减压下去除DMF并将所述残余物用乙酸乙酯提取。 With TLC confirmed completion of the reaction, the DMF was removed and the residue was extracted with ethyl acetate under reduced pressure. 用水和盐水洗涤乙酸乙酯层,通过硫酸钠干燥并在减压下去除乙酸乙酯。 The ethyl acetate layer was washed with water and brine, dried over sodium sulfate, and ethyl acetate was removed under reduced pressure. 将获得的液体进行柱色谱法(正己烷/乙酸乙酯=1/1)以产生浅黄色固体(33.%ig, 76. 0% )。 The liquid obtained was subjected to column chromatography (hexane / ethyl acetate = 1/1) to give a pale yellow solid (33.% ig, 76. 0%).

[0696] mp :111. 2-112. 5°C ; .. [0696] mp: 111 2-112 5 ° C;

[0697] [a]23D :-19. 70°C (c 1. 12,CHCl3); . [0697] [a] 23D: -19 70 ° C (c 1. 12, CHCl3);

[0698] IR(KBr 片状沉淀物,cnT1) :3428,3377,3274,3087,2964,2868,1655,1618 ; [0698] IR (KBr pellet, cnT1): 3428,3377,3274,3087,2964,2868,1655,1618;

[0699] 1H NMR (400MHz, CDCl3) :7. 55 (d, 1H, J= 15. 6Hz),7. 39 (d, 1H, J= 1. 6Hz),7. 35 (d, 2H, J = 8. 0Hz),7. 29 (d, 3H, J = 8. OHz),6. 84 (dd, 1H, J = 17. 2,10. 8Hz) ,6. 68( bs, 1H), 6. 33 (d, 1H, J = 15. 6Hz),6. 07 (d, 1H, J = 8. OHz),5. 63 (dd, 1H, J = 17. 2,0. 8Hz),5. 34 (dd, 1H, J= 10. 8,0. 8Hz) ,5. 15(五重峰,1H, J = 6. 8Hz),2. 90 (s, 3H),1. 45 (d, 3H, J = 6. 8Hz), [0699] 1H NMR (400MHz, CDCl3):.. (D, 1H, J = 15. 6Hz) 7 55, 7 39 (d, 1H, J = 1. 6Hz), 7 35 (d, 2H, J. = 8. 0Hz), 7. 29 (d, 3H, J = 8. OHz), 6. 84 (dd, 1H, J = 17. 2,10. 8Hz), 6. 68 (bs, 1H), 6 . 33 (d, 1H, J = 15. 6Hz), 6. 07 (d, 1H, J = 8. OHz), 5. 63 (dd, 1H, J = 17. 2,0. 8Hz), 5. 34 (dd, 1H, J = 10. 8,0. 8Hz), 5. 15 (quintet, 1H, J = 6. 8Hz), 2. 90 (s, 3H), 1. 45 (d, 3H , J = 6. 8Hz),

1. 24(s,9H) 1. 24 (s, 9H)

[0700] 实施例15 : [0700] Example 15:

[0701] 3-(4-叔丁基苯基)-N-(3-氟-4-甲烷磺酰基氨基_5_乙烯基苄基)丙烯酰胺 [0701] 3- (4-tert-butylphenyl) -N- (3- Fluoro-4-ylamino _5_ vinylbenzyl) acrylamide

[0702] [0702]

Figure CN101142174BD00612

[0703] 用氩气充满25ml的双颈圆底烧瓶,将3_(4_叔丁基苯基)-丙烯酸^ig, 0. 227mmol,leq.)和二乙基氰基膦酸酯(37. 9μ 1,0. 250mmol,l. leq.)在DMF中的溶液置于所述烧瓶。 [0703] 25ml filled with argon-neck round bottom flask, 3_ (4_-tert-butylphenyl) - acrylic acid ^ ig, 0. 227mmol, leq) and diethyl cyanophosphonate (37. 9μ 1,0. 250mmol, l. leq.) in DMF was placed in the flask. 向该溶液加入在实施例2的步骤5中合成的3-氟-4-甲烷磺酰基氨基-5-乙烯基节基-铵,三氟乙酸盐(81.4mg,0. 227mmol, leq.)和三乙胺(94. 9 μ 1,0. 681mmol,3eq.) To this solution was added in step 5 of Example 2 Synthesis of 3-fluoro-4-methanesulfonyl-5-yl-vinyl section - (.. 81.4mg, 0 227mmol, leq) ammonium, trifluoroacetate and triethylamine (94. 9 μ 1,0. 681mmol, 3eq.)

在DMF中的溶液。 In DMF was. 将所述溶液搅拌一夜。 The solution was stirred overnight. 在用TLC证实反应结束后,在减压下去除DMF并将残余物用乙酸乙酯提取。 With TLC confirmed completion of the reaction, the DMF was removed under reduced pressure and the residue was extracted with ethyl acetate. 将乙酸乙酯层用水和盐水洗涤,通过硫酸钠干燥,并在减压下去除乙酸乙酯。 The ethyl acetate layer was washed with water and brine, dried over sodium sulfate, and ethyl acetate was removed under reduced pressure. 将获得的液体进行柱色谱法(正己烷/乙酸乙酯=1/1)以产生白色固体(80. 9mg,82. 8% )。 The liquid obtained was subjected to column chromatography (hexane / ethyl acetate = 1/1) to give a white solid (80. 9mg, 82. 8%).

[0704] mp :182-183 °C ; [0704] mp: 182-183 ° C;

[0705] IR(KBr 片状沉淀物,cnT1) :3418,3238,3073,2962,1654,1622,1321,1153 ; [0705] IR (KBr pellet, cnT1): 3418,3238,3073,2962,1654,1622,1321,1153;

[0706] 1H NMR(400MHz, CD3OD) :7. 53 (d,1H,J = 16. OHz),7. 47 (d,2H,J = 8. 4Hz),7. 45 (d, 1H, J = 2. 0Hz),7. 40 (d, 2H, J = 8. 4Hz),7. 15 (dd, 1H, J= 17. 6,10. 8Hz),7. 08 (dd, 1H, J = 10. 4,2. 0Hz),6. 58 (d, 1H, J = 16. OHz),5. 81 (d, 1H, J = 17. 6Hz),5. 35 (d, 1H, J = 10. 8Hz), 4. 47 (s,2H),2. 98 (s, 3H),1. 29 (s,9H) [0706] 1H NMR (400MHz, CD3OD):.. 7 53 (d, 1H, J = 16. OHz), 7 47 (d, 2H, J = 8. 4Hz), 7 45 (d, 1H, J. = 2. 0Hz), 7. 40 (d, 2H, J = 8. 4Hz), 7. 15 (dd, 1H, J = 17. 6,10. 8Hz), 7. 08 (dd, 1H, J = 10. 4,2. 0Hz), 6. 58 (d, 1H, J = 16. OHz), 5. 81 (d, 1H, J = 17. 6Hz), 5. 35 (d, 1H, J = 10 . 8Hz), 4. 47 (s, 2H), 2. 98 (s, 3H), 1. 29 (s, 9H)

[0707] 实施例16 : [0707] Example 16:

[0708] 3- (4-叔丁基苯基)-N- (3-氟_5_乙炔基_4_甲烷磺酰基氨基-苄基)丙烯酰胺 [0708] 3- (4-tert-butylphenyl) -N- (3- fluoro-ethynyl _4_ _5_ methane sulfonylamino-benzyl) - acrylamide

[0709] [0709]

Figure CN101142174BD00621

[0710] 用氩气充满25ml的双颈圆底烧瓶,并将3_(4_叔丁基苯基)-丙烯酸(66. 6mg, 0. 326mmol, leq.)和二乙基氰基膦酸酯(54. 4 μ 1,0. 359mmol, 1. leq.)在DMF中的溶液置于所述烧瓶。 [0710] bis neck round bottom flask filled with argon, 25ml, and 3_ (4_-tert-butylphenyl) - acrylic acid (. 66. 6mg, 0. 326mmol, leq) and diethyl cyanophosphonate (54. 4 μ 1,0. 359mmol, 1. leq.) in DMF was placed in the flask. 向该溶液加入在实施例3的步骤3中获得的3-氟-5-乙炔基-4-甲烷磺酰基氨基节基-铵,三氟乙酸盐(116. 3mg,0. 3^mmol,leq.)和三乙胺(136. 3μ 1 0. 978mmol, 3eq.)在DMF中的溶液。 To this solution was added 3-fluoro obtained in the procedure of Example 3, 5-ethynyl-3-yl-4-methanesulfonyl amino group Section - ammonium trifluoroacetate (116. 3mg, 0 3 ^ mmol, Leq.) and triethylamine (136. 3μ 1 0. 978mmol, 3eq.) in DMF solution. 将溶液搅拌一夜。 The solution was stirred overnight. 在用TLC证实反应结束后,在减压下去除DMF并用乙酸乙酯提取残余物。 With TLC confirmed completion of the reaction, the DMF was removed under reduced pressure and the residue was extracted with ethyl acetate. 乙酸乙酯层用水和盐水洗涤,通过硫酸钠干燥,在减压下去除乙酸乙酯。 The ethyl acetate layer was washed with water and brine, dried over sodium sulfate, ethyl acetate was removed under reduced pressure. 将获得的液体进行柱色谱法(正己烷/乙酸乙酯=1/1)以产生白色固体(109. 6mg, 77. 9% )。 The liquid obtained was subjected to column chromatography (hexane / ethyl acetate = 1/1) to give a white solid (109. 6mg, 77. 9%).

[0711] mp :149-150°C ; [0711] mp: 149-150 ° C;

[0712] IR(KBr 片状沉淀物,cnT1) :3413,3254,3069,2963,2107,1621,1325,1154 ; [0712] IR (KBr pellet, cnT1): 3413,3254,3069,2963,2107,1621,1325,1154;

[0713] 1H 匪IU400MHz,CD30D) :7. 54 (d,1H,J = 16. OHz),7. 48 (d,2H,J = 8. 4Hz),7. 41 (d, 2H, J = 8. 4Hz),7. 30 (d, 1H, J = 2. OHz),7. 19 (dd, 1H, J = 10. 4,2. OHz),6. 58 (d, 1H, J = 16. 0Hz),4. 44 (s,2H),3. 86 (s, 1H),3. 09 (s, 3H),1. 30 (s,9H) [0713] 1H bandit IU400MHz, CD30D):.. 7 54 (d, 1H, J = 16. OHz), 7 48 (d, 2H, J = 8. 4Hz), 7 41 (d, 2H, J =. 8. 4Hz), 7. 30 (d, 1H, J = 2. OHz), 7. 19 (dd, 1H, J = 10. 4,2. OHz), 6. 58 (d, 1H, J = 16 . 0Hz), 4. 44 (s, 2H), 3. 86 (s, 1H), 3. 09 (s, 3H), 1. 30 (s, 9H)

[0714] 实施例17 :3-(4-叔丁基苯基)-N44-甲烷磺酰基氨基_3_乙烯基苄基)丙烯酰胺 Acrylamide 3- (4-tert-butylphenyl) -N44- _3_ methanesulfonylamino-vinylbenzyl): [0714] Example 17

[0716] 用氩气充满干燥的25ml的双颈圆底烧瓶,并将N_(4_氨基甲基_2_乙烯基-苯基)_甲烷磺酰胺(51mg,0. 23mmol)和3-(4-叔丁基-苯基)-丙烯酸(lJeq,0. 27mmol, 55. 26mg)在DMF中的溶液置于所述烧瓶。 [0716] 25ml of dried filled with argon-neck round bottom flask, and N_ - (. 51mg, 0 23mmol) (4_ aminomethyl _2_ vinylphenyl) _ -methanesulfonamide and 3- ( 4-tert-butyl - phenyl) - acrylic acid (lJeq, 0 27mmol, 55. 26mg) in DMF was placed in the flask. 向该溶液加入三乙胺Qeq,0. 46mmol,64. 12mg) 和二乙基氰基膦酸酯(1.2eq,0. 27mmol, 41. 88 μ 1)并搅拌12小时。 To this solution was added triethylamine Qeq, 0. 46mmol, 64. 12mg) and diethyl cyanophosphonate (1.2eq, 0. 27mmol, 41. 88 μ 1) and stirred for 12 hours. 在用TLC证实反应结 The reaction was confirmed by TLC junction

[0715] [0715]

Figure CN101142174BD00622

束后,将反应溶液用二氯甲烷提取,用水和盐水洗涤通过硫酸钠干燥,过滤,并在减压下浓缩。 After beaming, the reaction solution was extracted with dichloromethane, washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. 将获得的液体进行柱色谱法(正己烷/乙酸乙酯=1/1)以产生白色固体GS.^ig, 43. 37% )。 The liquid obtained was subjected to column chromatography (hexane / ethyl acetate = 1/1) to give a white solid GS. ^ Ig, 43. 37%).

[0717] 1H NMR(400 MHz, CDCl3) :7.59(d,lH,J = 15. 6Hz) ,7. 37(d,2H, J = 8. 0Hz), 7. 34 (s,1H),7. 31 (d, 1H, J = 10. 4Hz),7. 18 (d, 2H, J = 8. 0Hz),6. 82 (dd, 1H, J = 17. 6, 11. 2Hz),6. 44(s,1H),6. 33(d,1H,J = 7. 6Hz),6. 01 (bs,1H),5. 65 (d,1H,J = 17. 6Hz), 5. 39 (d, 1H, J = 11. 2Hz),4. 47(d,2H,J = 5. 6Hz),2. 91(s,3H),1. 24(s,9H). [0717] 1H NMR (400 MHz, CDCl3): 7.59 (d, lH, J = 15. 6Hz), 7 37 (d, 2H, J = 8. 0Hz), 7. 34 (s, 1H), 7. . 31 (d, 1H, J = 10. 4Hz), 7. 18 (d, 2H, J = 8. 0Hz), 6. 82 (dd, 1H, J = 17. 6, 11. 2Hz), 6. 44 (s, 1H), 6. 33 (d, 1H, J = 7. 6Hz), 6. 01 (bs, 1H), 5. 65 (d, 1H, J = 17. 6Hz), 5. 39 ( d, 1H, J = 11. 2Hz), 4. 47 (d, 2H, J = 5. 6Hz), 2. 91 (s, 3H), 1. 24 (s, 9H).

[0718] 实施例18 : [0718] Example 18:

[0719] 3-(4-三氟甲基苯基)-N-甲烷磺酰基氨基-3-乙烯基苄基)丙烯酰胺 [0719] 3- (4-trifluoromethylphenyl) -N- methanesulfonyl-amino-3-vinyl benzyl) acrylamide

[0720] [0720]

Figure CN101142174BD00631

[0721] 按照与实施例17中相似的方法所述相同的方法合成丙烯酰胺(90mg)。 [0721] acrylamide (90 mg of) as in Example 17 in a similar manner by the same method.

[0722] 1H NMR (300MHz, CDCl3) :7.71(d,lH,J = 15. 9Hz),7· 62 (m,4H),7· 47 (m,2H), 6. 88(dd,lH,J = 17. 4,11. 1Hz),6. 53 (d,1H,J = 15. 6Hz),6. 27 (bs,1H),5. 93 (bs,1H), 5. 74 (d, 1H, J = 17. 4Hz),5. 51 (d, 1H, J = 11. 1Hz),4. 59(d,2H,J = 6Hz),3. 01(s,3H) [0722] 1H NMR (300MHz, CDCl3): 7.71 (d, lH, J = 15. 9Hz), 7 · 62 (m, 4H), 7 · 47 (m, 2H), 6. 88 (dd, lH, J = 17. 4,11. 1Hz), 6. 53 (d, 1H, J = 15. 6Hz), 6. 27 (bs, 1H), 5. 93 (bs, 1H), 5. 74 (d, 1H, J = 17. 4Hz), 5. 51 (d, 1H, J = 11. 1Hz), 4. 59 (d, 2H, J = 6Hz), 3. 01 (s, 3H)

[0723] 实施例19 : [0723] Example 19:

[0724] 3- (4-甲硫基苯基)-N- (4-甲烷磺酰基氨基_3_乙烯基苄基)丙烯酰胺 [0724] 3- (4-methylthiophenyl) -N- (4- methanesulfonylamino-_3_ vinylbenzyl) acrylamide

[0725] [0725]

Figure CN101142174BD00632

[0726] 将丙烯酰胺(120mg)按照与在实施例11中所述的相同的方法进行合成。 [0726] acrylamide (120 mg of) synthesized in accordance with the same procedure as described in Example 11.

[0727] 1H NMR(300MHz, CDC13) :7. 64(d,lH, J = 15. 6Hz),7. 43 (m,2H),7. 25 (m,4H), 6. 87 (dd, 1H, J = 17. 1,6. 6Hz) ,6. 36 (d, 1H, J = 15. 3Hz),6. 26 (bs,1H),5. 86 (bs,1H), 5. 74 (d, 1H, J = 17. 1Hz),5· 50 (d, 1H, J = 11. 1Hz),4· 58(d,2H,J = 6Hz),3. 00(s,3H), 2. 50(s,3H) [0727] 1H NMR (300MHz, CDC13):.. (D, lH, J = 15. 6Hz) 7 64, 7 43 (m, 2H), 7 25 (m, 4H), 6. 87 (dd,. 1H, J = 17. 1,6. 6Hz), 6. 36 (d, 1H, J = 15. 3Hz), 6. 26 (bs, 1H), 5. 86 (bs, 1H), 5. 74 ( d, 1H, J = 17. 1Hz), 5 · 50 (d, 1H, J = 11. 1Hz), 4 · 58 (d, 2H, J = 6Hz), 3. 00 (s, 3H), 2. 50 (s, 3H)

[0728] 实施例20 :3- (4-叔丁基-苯基)-N- (4-甲烷磺酰基氨基_3_甲基_5_乙烯基苄基)丙烯酰胺 [0728] Example 20: 3- (4-tert-butyl - phenyl) -N- (4- methanesulfonylamino-methyl _5_ _3_ vinyl benzyl) acrylamide

[0729] [0729]

Figure CN101142174BD00633

[0730] 将N- (4-氨基甲基-2-甲基-6-乙烯基苯基)甲烷磺酰胺(leq,33. 5mg, 0. 14mmol) ,3-(4-叔丁基苯基)丙烯酸(Ueq,0. 17mmol,34. 18mg),DEPC(1. 2eq, 0. 17mmol,25. 49 μ 1),和TEAQeq,0. 28mmol,39. 03 μ 1)加入DMF。 [0730] The N- (4- aminomethyl-2-methyl-6-vinylphenyl) methanesulfonamide (leq, 33. 5mg, 0. 14mmol), 3- (4- tert-butylphenyl ) acrylic acid (Ueq, 0. 17mmol, 34. 18mg), DEPC (1. 2eq, 0. 17mmol, 25. 49 μ 1), and TEAQeq, 0. 28mmol, 39. 03 μ 1) was added DMF. 将所述混合物搅拌12 小时。 The mixture was stirred for 12 hours. 反应混合物按照实施例17进行纯化以得到白色固体83mg,51. 3% )。 The reaction mixture was purified according to Example 17 to give a white solid 83mg, 51. 3%).

[0731] mp :182 〜184°C ;IR(KBr 片状沉淀物,cnT1) :3287,3069,2963,1655,1315 [0731] mp: 182 ~184 ° C; IR (KBr pellet, cnT1): 3287,3069,2963,1655,1315

[0732] 1H NMR (400MHz, CD3 0D) : δ 7. 52 (d, 1H, J = 15. 6Hz),7. 46(d,2H,J = 8. 4Hz), 7. 43(s,1H),7· 40(d,2H,J = 8. 4Hz),7· 16(s,! H),7. 15 (dd,1H,J = 17. 6,11. 2Hz), 6. 58 (d, 1H, J = 15. 6Hz),5. 75 (d, 1H, J = 17. 6Hz),5. 32 (d, 1H, J = 11. 2Hz),4· 43(s,2H), 2. 97 (s,3H),2. 38 (s, 3H),1. 29 (s,9H) [0732] 1H NMR (400MHz, CD3 0D): δ 7. 52 (d, 1H, J = 15. 6Hz), 7 46 (d, 2H, J = 8. 4Hz), 7. 43 (s, 1H. ), 7 · 40 (d, 2H, J = 8. 4Hz), 7 · 16 (s ,! H), 7. 15 (dd, 1H, J = 17. 6,11. 2Hz), 6. 58 ( d, 1H, J = 15. 6Hz), 5. 75 (d, 1H, J = 17. 6Hz), 5. 32 (d, 1H, J = 11. 2Hz), 4 · 43 (s, 2H), 2. 97 (s, 3H), 2. 38 (s, 3H), 1. 29 (s, 9H)

[0733] 实施例21. [0733] ​​Example 21.

[0734] 3- (4-叔丁基苯基)-N- (3-氯_4_甲烷磺酰基氨基_5_乙烯基苄基)丙烯酰胺 [0734] 3- (4-tert-butylphenyl) -N- (3- methanesulfonylamino-chloro _4_ _5_ vinylbenzyl) acrylamide

[0735] [0735]

Figure CN101142174BD00641

[0736] 将N-(4-氨基甲基-2-氯-6-乙烯基苯基)甲烷磺酰胺(实施例9的步骤5,leq, 33.4mg,0.09mmol),344-叔丁基苯基)丙烯酸(Ueq,0. 1 Immol,21. 87mg),DEPC (1. 2eq, 0. 1 Immol, 16. 63 μ 1),和TEAQeq,0. 18mmol,25. 09 μ 1)加入DMF。 [0736] The N- (4- aminomethyl-2-chloro-6-vinylphenyl) methanesulfonamide (step 9 of Example 5, leq, 33.4mg, 0.09mmol), 344- tert-butylbenzene yl) acrylic acid (Ueq, 0. 1 Immol, 21. 87mg), DEPC (1. 2eq, 0. 1 Immol, 16. 63 μ 1), and TEAQeq, 0. 18mmol, 25. 09 μ 1) was added DMF. 将混合物搅拌12 小时。 The mixture was stirred for 12 hours. 反应混合物按照实施例17纯化以得到白色固体OO. 8mg,51. 80% )。 The reaction mixture was purified according to Example 17 to give a white solid OO. 8mg, 51. 80%).

[0737] mp :157 〜159°C ; [0737] mp: 157 ~159 ° C;

[0738] IR(KBr 片状沉淀物,cnT1) :3248,3064,2962,1653,1321,701 ; [0738] IR (KBr pellet, cnT1): 3248,3064,2962,1653,1321,701;

[0739] 1H 匪lU400MHz,CD3OD) : δ 7. 58 (d, 1H, J = 1. 6Hz) ,7. 53 (d, 1H, J = 16. OHz), 7. 47 (d, 2H, J = 8. 4Hz),7. 40 (d, 2H, J = 8. 4Hz),7. 38 (d, 1H, J=L 6Hz),7. 19 (dd, 1H, J = 17. 6,11. 2Hz),6. 59 (d, 1H, J = 16. OHz),5. 79 (d, 1H, J = 17. 6Hz),5. 34 (d, 1H, J = 11. 2Hz),4· 46(s,2H),3· 05(s,3H),1. 29(s,9H). [0739] 1H bandit lU400MHz, CD3OD): δ 7. 58 (d, 1H, J = 1. 6Hz), 7 53 (d, 1H, J = 16. OHz), 7. 47 (d, 2H, J. = 8. 4Hz), 7. 40 (d, 2H, J = 8. 4Hz), 7. 38 (d, 1H, J = L 6Hz), 7. 19 (dd, 1H, J = 17. 6,11 . 2Hz), 6. 59 (d, 1H, J = 16. OHz), 5. 79 (d, 1H, J = 17. 6Hz), 5. 34 (d, 1H, J = 11. 2Hz), 4 · 46 (s, 2H), 3 · 05 (s, 3H), 1. 29 (s, 9H).

[0740] 实施例22. 3-(4-叔丁基_2_吗啉_4_基-苯基)-N_(3_氟_4_甲烷磺酰基氨基-5-乙烯基苄基)丙烯酰胺 [0740] Embodiment 22. 3- (4-tert-butyl-morpholin _4_ _2_ yl-phenyl) - Example -N_ (3_ _4_ methanesulfonyl-fluoro-5-vinylbenzyl-yl) acrylamide amide

Figure CN101142174BD00642

[0742] 步骤1 :3-(4-叔丁基-2-吗啉_4_基-苯基)丙烯酸乙酯将乙酸钯(II) (1. 4mg, 0. 006mmole,6mol% eq),rac_2,2,-双(二苯基膦基)-1,1' -联萘(7. 5mg,0. 012mmole, 12mol% eq),和碳酸铯(50. 3mg,0. 155mmole, 1. 5eq)加入无水甲苯。 [0742] Step 1: 3- (4-tert-butyl-2-yl-morpholin _4_ - phenyl) propenoate palladium (II) acetate (1. 4mg, 0. 006mmole, 6mol% eq), rac_2,2, - bis (diphenylphosphino) -1,1 '- binaphthyl (. 7. 5mg, 0 012mmole, 12mol% eq), and cesium carbonate (50. 3mg, 0 155mmole, 1. 5eq. ) was added anhydrous toluene. 将在甲苯溶剂中的3-(4-叔丁基-2-三氟甲烷磺酰基氧基苯基)丙烯酸乙酯(36. 2mg,0. 103mmol,leq)通过套管加入。 The toluene solvent 3- (4-tert-butyl-2-trifluoromethanesulfonyl-phenyl) acrylate (36. 2mg, 0. 103mmol, leq) was added via cannula. 加入吗啉(Morphloline) (13. 5 μ 1,0. 155mmol,1.5eq)。 Was added morpholine (Morphloline) (13. 5 μ 1,0. 155mmol, 1.5eq). 将混合物在回流中搅拌12小时。 The mixture was stirred at reflux for 12 hours. 在用TLC证实反应结束后,将反应混合物用C盐过滤。 In the completion of the reaction was confirmed by TLC, the reaction mixture was filtered over C salt. 将滤液在真空中浓缩, 接着,用柱色谱法(n-Hx : EA = 12 : 1)纯化残余物以得到标题产物(16. 7mg,51. 2% )。 The filtrate was concentrated in vacuo, then purified by column chromatography (n-Hx: EA = 12: 1) The residue was purified to give the title product (16. 7mg, 51 2%.).

[0743] 1H 匪RGOOMHz,CDCl3) : δ 7. 98 (d, J = 16. 0Hz,1H),7. 41 (d,J = 8. OHz, 1H),7. 05(dd, J = 8. 0,1. 6Hz, 1H),6· 99 (d, J = 1. 6Hz, 1H),6· 32 (d, J = 16. OHz, 1H),4· 19 (q, J =7. 2Ηζ,2Η),3. 82 (t, J = 4. 8Ηζ,4Η),2. 90 (t, J = 4. 8Ηζ,4Η),1. 29-1. 25(ml2H) [0743] 1H bandit RGOOMHz, CDCl3):.. Δ 7. 98 (d, J = 16. 0Hz, 1H), 7 41 (d, J = 8. OHz, 1H), 7 05 (dd, J = 8 . 0,1. 6Hz, 1H), 6 · 99 (d, J = 1. 6Hz, 1H), 6 · 32 (d, J = 16. OHz, 1H), 4 · 19 (q, J = 7. 2Ηζ, 2Η), 3. 82 (t, J = 4. 8Ηζ, 4Η), 2. 90 (t, J = 4. 8Ηζ, 4Η), 1. 29-1. 25 (ml2H)

[0744] 步骤2 :3-(4-叔丁基-2-吗啉-4-基-苯基)-N-(3-氟-4-甲烷磺酰基氨基-5-乙烯基苄基)丙烯酰胺 [0744] Step 2: 3- (4-tert-butyl-2-morpholin-4-yl - phenyl) -N- (3- fluoro-4-methanesulfonyl-5-vinylbenzyl-yl) acrylamide amide

[0745]将 3-(4-叔丁基-2-吗啉-4-基-苯基)丙烯酸乙酯(29. Img, 0. 092mmol, leq) 加入甲醇和H20。 [0745] 3- (4-tert-butyl-2-morpholin-4-yl-phenyl) - ethyl acrylate (29. Img, 0. 092mmol, leq) was added methanol and H20. 加入氢氧化钠(36. 7mg,0. 917mmole,10eq)。 Sodium hydroxide (36. 7mg, 0. 917mmole, 10eq). 搅拌混合物12小时。 The mixture was stirred for 12 hours. 在证实反应结束后,将反应混合物冷却到0°C。 After completion of the reaction was confirmed, the reaction mixture was cooled to 0 ° C. 用5% HCl酸化反应混合物。 The reaction mixture was acidified with 5% HCl. 反应溶剂在减压下去除以得到黄色固体(26. 6mg, 100% )。 The reaction solvent is divided down under reduced pressure to give a yellow solid (26. 6mg, 100%). TLC : & = 0. 15 (正己烧:EtOAc = 2 : 1/KMnO4)。 TLC: & = 0. 15 (n-burning: EtOAc = 2: 1 / KMnO4).

[0746]将 3-½-叔丁基-2-吗啉-4-基-苯基)丙烯酸25. 9mg(0. 092mmol, leq.)和二乙基氰基膦(16.8μ 1,0. IlOmmoia. 2eq)在氩气气氛下加入DMF。 [0746] The tert-butyl-3-½- morpholin-4-yl - phenyl) acrylic acid 25. 9mg (0 092mmol, leq) and diethyl cyanophosphonate (16.8μ 1,0.. IlOmmoia. 2eq) in DMF was added under an argon atmosphere. 将N_(4_氨基甲基-2-氟-6-乙烯基苯基)甲烷磺酰胺(49. 3mg,0. 138mmol, 1. 2eq.)和三乙胺(38. 5 μ 1, 0. 276mmol,3eq)加入反应混合物。 The N_ (4_ Aminomethyl-2-fluoro-6-vinylphenyl) methanesulfonamide (49. 3mg, 0. 138mmol, 1. 2eq.) And triethylamine (38. 5 μ 1, 0. 276mmol, 3eq) was added the reaction mixture. 在证实反应结束后,在真空中去除反应溶剂。 After completion of the reaction was confirmed, the reaction solvent was removed in vacuo. 残余物用KOAc提取,用盐水洗涤,用Na2SO4干燥并接着在真空中浓缩。 The residue was extracted with KOAc, washed with brine, dried and then concentrated in vacuo with Na2SO4. 用柱色谱法(正己烷:KOAc =1 : 1)纯化残余物以得到发白固体08.&^,62.4%)。 By column chromatography (n-hexane: KOAc = 1: 1) to give the residue was purified whitish solid & ^ 08, 62.4%).

[0747] mp ( 0C ) :171-173 °C ;IR(KBr 片状沉淀物,cnT1) :3422,2959,2857,1649,1617, 1322,1154 ;1H NMR(400MHz, CDCl3) :8. 01 (d, J = 15. 6Hz,1H),7. 53 (d,J = 8.8Ηζ,1Η), 7. 50 (s,1H),7. 19 (dd, J = 11. 2,17. 6Hz, 1H),7. 15-7. ll(m,3H),6. 61 (d, J = 15. 6Hz, 1H), 5. 84 (d, J = 17. 6Hz, 1H),5. 38 (d, J = 11. 2Hz, 1H), 4. 51(s,2H),3. 88 (t, J = 4. 4Hz,4H), 3. 02(s,2H),2· 94 (t, J = 4. 4Hz,4H),1. 32(s,9H) [0747] mp (0C): 171-173 ° C; IR (KBr pellet, cnT1):. 3422,2959,2857,1649,1617, 1322,1154; 1H NMR (400MHz, CDCl3): 8 01 (d, J = 15. 6Hz, 1H), 7. 53 (d, J = 8.8Ηζ, 1Η), 7. 50 (s, 1H), 7. 19 (dd, J = 11. 2,17. 6Hz , 1H), 7. 15-7. ll (m, 3H), 6. 61 (d, J = 15. 6Hz, 1H), 5. 84 (d, J = 17. 6Hz, 1H), 5. 38 (d, J = 11. 2Hz, 1H), 4. 51 (s, 2H), 3. 88 (t, J = 4. 4Hz, 4H), 3. 02 (s, 2H), 2 · 94 (t , J = 4. 4Hz, 4H), 1. 32 (s, 9H)

[0748] 实施例23. [0748] Example 23.

[0749] 3-[4-叔丁基-2-(2-甲氧基-乙氧基)_苯基]_N_(3_氟_4_甲烷磺酰基氨基-5-乙烯基-苄基)-丙烯酰胺 [0749] 3- [4-tert-butyl-2- (2-methoxy-ethoxy) - phenyl _] _N_ (3_ fluoro _4_ methanesulfonylamino-5-vinyl-benzyl) - -Acrylamide

[0750] [0750]

Figure CN101142174BD00651

[0751] 步骤1 :4-叔丁基-1-碘-2-(2-甲氧基乙氧基)苯 [0751] Step 1: 4-tert-butyl-1-iodo-2- (2-methoxyethoxy) benzene

[0752] NaH(21. Omg,0. 5250mmol,60% disp. oil,5eq)和叔丁基_2_碘-苯酚(29. Omg, 0. 105mmol,leq)加入DMF。 [0752] NaH (21 Omg, 0 5250mmol, 60% disp oil, 5eq...) And tert-butyl iodide _2_ - phenol (29. Omg, 0. 105mmol, leq) was added DMF. 将氯乙基甲基醚(23. 96 μ 1,0. 26mmol,2. 5eq)加入混合物。 The chloroethyl methyl ether (23. 96 μ 1,0. 26mmol, 2. 5eq) added to the mixture. 在90°C将反应混合物搅拌过夜。 At 90 ° C and the reaction mixture was stirred overnight. 通过加入H2O猝灭反应混合物。 The reaction mixture was quenched by addition of H2O. 在真空中去除DMF后,用KOAc 提取残余物。 After removal of DMF in vacuo, the residue was extracted with KOAc. 合并的有机层用H2O和盐水洗涤,用Na2SO4干燥,接着在真空中浓缩。 The combined organic layers were washed with H2O and brine, dried over Na2SO4, then concentrated in vacuo. 将残余物用柱色谱法(正己烷:KOAc = 20 : 1)纯化以得到液体(32. Omg,91. 2% )。 The residue was purified by column chromatography (n-hexane: KOAc = 20: 1) to give a liquid (32. Omg, 91 2%.).

[0753] 1H NMR (400MHz,CDCl3) : δ 7. 58 (d, J = 8. 4Hz, 1H) ,6. 82 (d, J = 2. OHz, 1H), 6. 69 (dd, J = 8. 4,2. 4Hz, 1H) ,4. 10 (t, J = 4. 8Hz,2H),3. 75 (dd,J = 4. 8,4. 4Hz,2H), 3. 43(s,3H),1. 22(s,9H) ;IR(NaCl 纯的,cnT1) :2960,2871,1713,1628,1607,1165. [0753] 1H NMR (400MHz, CDCl3):. Δ 7. 58 (d, J = 8. 4Hz, 1H), 6 82 (d, J = 2. OHz, 1H), 6. 69 (dd, J = 8. 4,2. 4Hz, 1H), 4. 10 (t, J = 4. 8Hz, 2H), 3. 75 (dd, J = 4. 8,4. 4Hz, 2H), 3. 43 (s ., 3H), 1 22 (s, 9H); IR (NaCl neat, cnT1): 2960,2871,1713,1628,1607,1165.

[0754] 步骤2 :3-[4-叔丁基-2-(2-甲氧基乙氧基)苯基]丙烯酸甲基酯 [0754] Step 2: 3- [4-tert-butyl-2- (2-methoxyethoxy) phenyl] acrylic acid methyl ester

[0755]将乙酸钯(63. 77mg,0. ^41mmol,6 % mo leq),和1· 1,-双(二苯基膦基)二茂铁(314.99mg,0.5682mmol,12% mol eq)加入DMF 溶液。 [0755] Palladium acetate (63. 77mg, 0 ^ 41mmol, 6% mo leq.), And 1-1, - bis (diphenylphosphino) ferrocene (314.99mg, 0.5682mmol, 12% mol eq ) in DMF was added. 将丙烯酸甲酯(469. 01 μ 1, Methyl acrylate (469. 01 μ 1,

5. 2082mmol, 1. leq),三乙胺(1. 3171ml, 9. 4694mmol,,和4-叔丁基-1-碘-2-甲氧基-乙氧基)-苯(1. 5823g,4. 7347mmol,leq)加入。 5. 2082mmol, 1. leq), triethylamine (1. 3171ml, 9. 4694mmol ,, and 4-tert-butyl-1-iodo-2-methoxy - ethoxy) - benzene (1. 5823g, 4. 7347mmol, leq) was added. 在60°C过夜搅拌反应混合物。 The reaction mixture was stirred at 60 ° C overnight. 将反应混合物按照步骤1纯化以得到红色液体(1. 1156g,83. 5% )。 The reaction mixture was purified according to Step 1 to give a red liquid (1. 1156g, 83. 5%).

[0756] 1H 匪RGOOMHz,CDCl3) : δ 7. 96 (d, J = 16. OHz, 1H) ,7. 43 (d, J = 8·4Ηζ,1Η), [0756] 1H bandit RGOOMHz, CDCl3):. Δ 7. 96 (d, J = 16. OHz, 1H), 7 43 (d, J = 8 · 4Ηζ, 1Η),

6. 99(dd, J = 8. 0,1. 6Hz, 1H),6· 96 (d, J = 1. 6Hz, 1H),6· 52 (d, J = 16. 4Hz, 1H),4· 23 (q, J =7. 2Ηζ,2Η),4· 19 (t,J = 4. 8Hz,2H),3. 81 (t,J = 4. 8Hz,2H),3. 47 (s,3H),1. 33-1. 30 (m, 12H) ;IR(NaCl 纯的,cnT1) :3408,2964,2869,1683,1624 6. 99 (dd, J = 8. 0,1. 6Hz, 1H), 6 · 96 (d, J = 1. 6Hz, 1H), 6 · 52 (d, J = 16. 4Hz, 1H), 4 · 23 (q, J = 7. 2Ηζ, 2Η), 4 · 19 (t, J = 4. 8Hz, 2H), 3. 81 (t, J = 4. 8Hz, 2H), 3. 47 (s, .. 3H), 1 33-1 30 (m, 12H); IR (NaCl neat, cnT1): 3408,2964,2869,1683,1624

[0757]步骤 3 :3-(4-叔丁基-2-吗啉(morpholie) _4_ 基-苯基)-N_(3_ 氟~4~ 甲烷磺酰基氨基-5-乙烯基苄基)丙烯酰胺 [0757] Step 3: 3- (4-tert-butyl-2-morpholino (morpholie) _4_ yl - phenyl) -N_ (3_ ~ 4 ~ methanesulfonyl-fluoro-5-vinylbenzyl-yl) acrylamide

[0758] 将3-[4-叔丁基-2-(2-甲氧基乙氧基)苯基]丙烯酸乙酯4mg,0. 132mmol, leq)和氢氧化钠(52.8mg,1.32mmOle,10eq)加入甲醇和H20。 [0758] 3- [4-tert-butyl-2- (2-methoxyethoxy) phenyl] acrylate 4mg, 0. 132mmol, leq) and sodium hydroxide (52.8mg, 1.32mmOle, 10 eq) were added methanol and H20. 将反应混合物按照实施例22 的步骤2纯化以得到3-[4-叔丁基-2-(2-甲氧基乙氧基)苯基]丙烯酸(36. 5mg,77. 3%). 将3- [4-叔丁基-2- (2-甲氧基乙氧基)-苯基]丙烯酸(26. 4mg, 0. 095mmol, leq.),二乙基氰基膦(17. 3μ 1,0. 1 Hmmol,Ueq),N-氨基甲基-2-氟-6-乙烯基苯基)甲烷磺酰胺(40. 8mg,0. 1114mol,1. 2eq.),和三乙胺(39. 7 μ 1,0. 285mmol,3eq)加入DMF。 The reaction mixture was purified according to the steps of Example 22 to give 3- [4-tert-butyl-2- (2-methoxyethoxy) phenyl] acrylic acid (36. 5mg, 77. 3%). The 3- [4-tert-butyl-2- (2-methoxyethoxy) - phenyl] acrylic acid (. 26. 4mg, 0. 095mmol, leq), diethyl cyanophosphonate (17. 3μ 1 , 0. 1 Hmmol, Ueq), N- amino-2-fluoro-6-vinylphenyl) methanesulfonamide (40. 8mg, 0. 1114mol, 1. 2eq.), and triethylamine (39 . 7 μ 1,0. 285mmol, 3eq) was added DMF. 将混合物在室温搅拌过夜。 The mixture was stirred at room temperature overnight. 按照实施例17纯化反应混合物以得到发白固体4mg,59. 2% )。 The reaction mixture was purified according to Example 17 to give a whitish solid 4mg, 59. 2%).

[0759] IR(KBr 片状沉淀物,cnT1) :3422,2959,2857,1649,1617,1322,1154 ; [0759] IR (KBr pellet, cnT1): 3422,2959,2857,1649,1617,1322,1154;

[0760] 1H NMR(400MHz, CDCl3) :7. 79 (d,J = 16. 0Hz,1H),7. 48 (s,1H),7. 38 (d,J = 8. 0Hz, 1H) ,7. 08 (dd, J = 11.2,17. 6Hz, 1H), 7. 01 (dd, J = 10. 4,1. 6Hz,1H),6. 95-6. 89 (m,2H), 6. 60 (d, J = 16. OHz, 1H),5. 74 (d, J = 17. 6Hz, 1H),5. 28 (d, J = 11. 2Hz, 1H), 4. 39(s,2H), 4. 10 (t, J = 4. 4Ηζ,2Η),3· 71(t,J = 4. 4Ηζ,2Η),3· 64-3. 60 (m,2H),3· 34 (s,2H),2· 91 (s, 3Η),1. 22(s,9H) [0760] 1H NMR (400MHz, CDCl3):... 7 79 (d, J = 16. 0Hz, 1H), 7 48 (s, 1H), 7 38 (d, J = 8. 0Hz, 1H), 7. 08 (dd, J = 11.2,17. 6Hz, 1H), 7. 01 (dd, J = 10. 4,1. 6Hz, 1H), 6. 95-6. 89 (m, 2H), 6 . 60 (d, J = 16. OHz, 1H), 5. 74 (d, J = 17. 6Hz, 1H), 5. 28 (d, J = 11. 2Hz, 1H), 4. 39 (s, 2H), 4. 10 (t, J = 4. 4Ηζ, 2Η), 3 · 71 (t, J = 4. 4Ηζ, 2Η), 3 · 64-3. 60 (m, 2H), 3 · 34 ( s, 2H), 2 · 91 (s, 3Η), 1. 22 (s, 9H)

[0761] 实施例Μ: [0761] Example Μ:

[0762] 3- (4-叔丁基苯基)-N- (4-甲烷磺酰基氨基_3_三氟甲基_5_乙烯基苄基)丙烯酰胺 [0762] 3- (4-tert-butylphenyl) -N- (4- methanesulfonylamino-trifluoromethyl _5_ _3_ vinyl benzyl) acrylamide

Figure CN101142174BD00661

[0764] 将N-(4-氨基甲基-2-三氟甲基-6-乙烯基苯基)甲烷磺酰胺(实施例10中的步M 7, leq, 44. lmg,0. 13mmol),3_叔丁基-苯基)-丙烯酸(1. Ieq, 0. 15mmol,29. 99mg), DEPC(1. 2eq,0. 16mmol,23. 67 μ 1)和TEA(2eq,0. 26mmol,36. 24 μ 1)加入DMF。 [0764] The N- (4- aminomethyl-6-vinyl-2-trifluoromethyl-phenyl) methanesulfonamide (Example 10, step M 7, leq, 44. lmg, 0. 13mmol) , 3_ t-butyl - phenyl) -..... acrylic acid (1. Ieq, 0. 15mmol, 29 99mg), DEPC (1 2eq, 0 16mmol, 23 67 μ 1) and TEA (2eq, 0 26mmol , 36. 24 μ 1) was added DMF. 将反应混合物搅拌12小时。 The reaction mixture was stirred for 12 hours. 按照实施例17纯化反应混合物以得到白色固体(55. 4mg,88. 75% )。 The reaction mixture was purified to give Example 17 as a white solid (55. 4mg, 88. 75%).

[0765] mp:174 〜176°C ;IR(KBr 片状沉淀物,cnT1) :3257,3078,2964,1653,1326 ; [0765] mp: 174 ~176 ° C; IR (KBr pellet, cnT1): 3257,3078,2964,1653,1326;

[0766] 1H 匪lU400MHz,CDCl3) : δ 7. 67 (d, 1H, J = 1. 6Hz) ,7. 60 (d, 1H, J = 15. 6Hz), 7. 47 (d, 1H, J=L 6Hz),7. 38 (d, 2H, J = 8. 4Hz),7. 32 (d, 2H, J = 8. 4Hz),7. 13 (dd, 1H, J = 17. 6,10. 8Hz),6. 65 (s, 1H),6. 62 (t, 1H, J = 6. OHz),6. 39 (d, 1H, J = 16. OHz),5. 71 (d, 1H, [0766] 1H bandit lU400MHz, CDCl3): δ 7. 67 (d, 1H, J = 1. 6Hz), 7 60 (d, 1H, J = 15. 6Hz), 7. 47 (d, 1H, J. = L 6Hz), 7. 38 (d, 2H, J = 8. 4Hz), 7. 32 (d, 2H, J = 8. 4Hz), 7. 13 (dd, 1H, J = 17. 6,10 . 8Hz), 6. 65 (s, 1H), 6. 62 (t, 1H, J = 6. OHz), 6. 39 (d, 1H, J = 16. OHz), 5. 71 (d, 1H ,

[0763]J = 17. 6Hz) ,5. 39 (d, 1H, J=Il. 2Hz) ,4. 49(d,2H,J = 5. 6Hz),3. 07(s,3H),1. 26(s,9H). [0763] J = 17. 6Hz), 5. 39 (d, 1H, J = Il. 2Hz), 4. 49 (d, 2H, J = 5. 6Hz), 3. 07 (s, 3H), 1 . 26 (s, 9H).

[0767] 实施例25 :3-[4-叔丁基-2-(4-甲基哌嗪基)苯基]-N-(3_氟_4_甲烷磺酰基氨基-5-乙烯基苄基)丙烯酰胺 [0767] Example 25: 3- [4-tert-Butyl-2- (4-methylpiperazin-l-yl) phenyl] -N- (3_ _4_ methanesulfonyl-fluoro-5- vinylbenzyl yl) acrylamide

[0768] [0768]

Figure CN101142174BD00671

[0769] 步骤1 :3-[4-叔丁基-2-(4-甲基哌嗪基)苯基]丙烯酸乙酯 [0769] Step 1: 3- [4-tert-Butyl-2- (4-methylpiperazin-l-yl) phenyl] acrylate

[0770]将乙酸钯 O. 8mg,0. 013mmol,6% mol eq),rac_2,2,-双(二苯基膦基)1,1,-联萘(16. 2mg,0. 026mmol, 12% mol eq),和碳酸铯(102. 6mg,0. 315mmol, 1. 5eq)在氩气气氛下加入无水甲苯。 . [0770] The palladium acetate O. 8mg, 0 013mmol, 6% mol eq), rac_2,2, - bis (diphenylphosphino) 1,1 - binaphthyl (16. 2mg, 0 026mmol, 12 % mol eq), and cesium carbonate (102. 6mg, 0. 315mmol, 1. 5eq) was added dry toluene under an argon atmosphere. 搅拌5分钟后,加入3-(4-叔丁基-2-三氟甲烷磺酰基-氧基苯基)丙烯酸乙酯(74. Omg, 0. 210mmol, leq)和N-甲基哌嗪(34. 9 μ 1,0. 315mmole, 1. 5eq)。 After stirring for 5 min, 3- (4-tert-butyl-2-trifluoromethanesulfonyloxy - methoxyphenyl) acrylate (74. Omg, 0. 210mmol, leq) and N- methylpiperazine ( 34. 9 μ 1,0. 315mmole, 1. 5eq). 将混合物在80°C搅拌M小时。 The mixture was stirred at 80 ° C M hr. 反应混合物按照实施例22的步骤1纯化以得到黄色液体(50. 8mg, 73. 2% )。 The reaction mixture was purified in the step 1 according to Example 22 to give a yellow liquid (50. 8mg, 73. 2%).

[0771]步骤 2: [0771] Step 2:

[0772] 3-[4_叔丁基-2-(4-甲基哌嗪-1-基)苯基]_N_(3_氟_4_甲烷磺酰基氨基_5_乙烯基苄基)丙烯酰胺 [0772] 3- [4_-tert-butyl-2- (4-methyl-piperazin-1-yl) phenyl] _N_ (3_ fluoro _4_ _5_ methanesulfonylamino-vinylbenzyl) acrylamide amide

[0773] 3-[4-叔丁基-2-(4-甲基哌嗪基)苯基]丙烯酸乙酯(29. Img, 0. 092mmol, leq)和氢氧化钠(36. 7mg,0. 917mmole加入甲醇和H2O0搅拌混合物12小时。用5% HCl 酸化反应混合物。反应混合物在真空中浓缩以得到黄色固体、2Ί. 8mg, 100% )。 [0773] 3- [4-tert-Butyl-2- (4-methylpiperazin-l-yl) phenyl] acrylate (29. Img, 0. 092mmol, leq) and sodium hydroxide (36. 7mg, 0 . 917mmole H2O0 was added methanol and the mixture was stirred for 12 hours. the reaction mixture was acidified with 5% HCl. the reaction mixture was concentrated in vacuo to give a yellow solid, 2Ί. 8mg, 100%).

[0774]将 3-[4-叔丁基-2-(4-甲基哌嗪基)苯基]丙烯酸6mg,0. 154mmol, leq.)和二乙基氰基膦0μ 1,0. 185mmol,l. 2eq)加入DMF。 [0774] 3- [4-tert-Butyl-2- (4-methylpiperazin-l-yl) phenyl] acrylic acid 6mg, 0. 154mmol, leq.) And diethyl cyanophosphonate 0μ 1,0. 185mmol , l. 2eq) was added DMF. 加入NQ-氨基甲基-2-氟-6-乙烯基苯基)甲烷磺酰胺(60. 7mg,0. 169mmol, 1. leq.)和三乙胺(64. 4 μ 1, 0.462mmOl,;3eq)。 Was added NQ- Aminomethyl-2-fluoro-6-vinylphenyl) methanesulfonamide (60. 7mg, 0. 169mmol, 1. leq.) And triethylamine (64. 4 μ 1, 0.462mmOl ,; 3eq). 将反应混合物在室温搅拌过夜。 The reaction mixture was stirred at room temperature overnight. 在真空中去除反应溶剂。 The reaction solvent was removed in vacuo. 用KOAc提取残余物。 Residue was extracted with KOAc. 将合并的有机层用盐水洗涤,通过硫酸钠干燥并接着在真空中浓缩。 The combined organic layers were washed with brine, and then concentrated in vacuo and dried over sodium sulfate. 将残余物用柱色谱法(MeOH : EtOAc = 1:1)进行纯化以得到固体(63. 9mg,71. 3% )。 The residue was purified by column chromatography (MeOH: 1: EtOAc = 1) was purified to give a solid (63. 9mg, 71 3%.).

[0775] IR(KBr 片状沉淀物,cnT1) :3422,2959,2857,1649,1617,1322,1154 ; [0775] IR (KBr pellet, cnT1): 3422,2959,2857,1649,1617,1322,1154;

[0776] 1H NMR(400MHz, CDCl3) :7. 96 (d,J = 15. 6Hz,1H),7. 54 (d,J = 8. 8Hz,1H),7. 49 (s, 1H),7. 26-7. 09 (m, 4H),6. 62 (d, J = 15. 6Hz, 1H),5. 84 (d, J = 17. 6Hz, 1H),5. 39 (d, J = 10. 8Hz, 1H),4· 51 (s,2H),3. 03 (s,4H),2. 87 (s,4H),2· 51 (s,4H),1. 32 (s,9H) [0776] 1H NMR (400MHz, CDCl3):... 7 96 (d, J = 15. 6Hz, 1H), 7 54 (d, J = 8. 8Hz, 1H), 7 49 (s, 1H), 7. 26-7. 09 (m, 4H), 6. 62 (d, J = 15. 6Hz, 1H), 5. 84 (d, J = 17. 6Hz, 1H), 5. 39 (d, J = 10. 8Hz, 1H), 4 · 51 (s, 2H), 3. 03 (s, 4H), 2. 87 (s, 4H), 2 · 51 (s, 4H), 1. 32 (s, 9H)

[0777] 实施例沈:3-[4-叔丁基-2-(2-哌啶-1-基-乙氧基)苯基]_N_ (3_氟_4_甲烷磺酰基氨基-5-乙烯基苄基)丙烯酰胺 [0777] Example Shen: 3- [4-tert-Butyl-2- (2-piperidin-yl-ethoxy) - phenyl] _N_ (3_-fluoro-5- methanesulfonyl _4_ vinyl benzyl) acrylamide

[0778] [0778]

Figure CN101142174BD00681

[0779] 步骤1 :3-[4-叔丁基-2-(2-哌啶基-乙氧基)苯基]丙烯酸乙酯 [0779] Step 1: 3- [4-tert-butyl-2- (2-piperidin-yl-ethoxy) - phenyl] acrylate

[0780]将 3-(4-叔丁基-2-羟基苯基)丙烯酸乙酯(59. Omg, 0. 238mmol)和Na!K47. 5mg, 60% disp.oil,5eq)加入无水DMF。 [0780] 3- (4-tert-butyl-2-hydroxyphenyl) acrylate (59. Omg, 0. 238mmol) and Na! K47. 5mg, 60% disp.oil, 5eq) was added anhydrous DMF . 将反应混合物冷却到0°C。 The reaction mixture was cooled to 0 ° C. 将1_(2_氯乙基)哌啶盐酸盐(87.6mg 0. 476mmol,2eq)加入。 1_ piperidine hydrochloride (2_ chloroethyl) (87.6mg 0. 476mmol, 2eq) was added. 将混合物加热到90°C。 The mixture was heated to 90 ° C. 在90°C搅拌反应12小时。 The reaction was stirred for 12 hours at 90 ° C. 通过加入H2O猝灭反应。 The reaction was quenched by addition of H2O. 用KOAc提取反应混合物,接着用H2O和盐水洗涤。 The reaction mixture was extracted with KOAc, and then washed with H2O and brine. 用柱色谱法(EtOAc)纯化残余物以得到黄色液体(14. Omg, 16. 4% ) 0 By column chromatography (EtOAc) to afford the residue was purified as a yellow liquid (14. Omg, 16. 4%) 0

[0781] 1H 匪RGOOMHz,CDCl3) : δ 7. 86 (d, J = 16. OHz, 1H) ,7. 39 (d, J = 8·8Ηζ,1Η), 6. 95-6. 93(m,2H),4· 15-4. 09(m,4H),2· 77 (t, J = 5. 6Ηζ,2Η),2· 52(s,4H),1. 54(五重峰,J =5. 6Hz,4H),1. 42-1. 36 (m, 2H),1. 23(s,9H) [0781] 1H bandit RGOOMHz, CDCl3):.. Δ 7. 86 (d, J = 16. OHz, 1H), 7 39 (d, J = 8 · 8Ηζ, 1Η), 6. 95-6 93 (m , 2H), 4 · 15-4. 09 (m, 4H), 2 · 77 (t, J = 5. 6Ηζ, 2Η), 2 · 52 (s, 4H), 1. 54 (quintet, J = 5. 6Hz, 4H), 1. 42-1. 36 (m, 2H), 1. 23 (s, 9H)

[0782]步骤 2 : [0782] Step 2:

[0783] 3-[4-叔丁基-2-(2-哌啶基-乙氧基)苯基]_N_(3_氟_4_甲烷磺酰基氨基-5-乙烯基苄基)丙烯酰胺 [0783] 3- [4-tert-butyl-2- (2-piperidin-yl-ethoxy) - phenyl] _N_ (3_ _4_ methanesulfonyl-fluoro-5-vinylbenzyl-yl) acrylamide

[0784] 3-[4-叔丁基-2-(2-哌啶-1-基-乙氧基)苯基]丙烯酸乙酯(14. Omg, 0. 039mmol,leq)和氢氧化钠(7. 8mg,0. 195mmole, 5eq)加入甲醇和H20。 [0784] 3- [4-tert-Butyl-2- (2-piperidin-yl-ethoxy) - phenyl] acrylate (14. Omg, 0. 039mmol, leq) and sodium hydroxide ( 7. 8mg, 0. 195mmole, 5eq) was added methanol and H20. 将反应混合物在室温搅拌12小时。 The reaction mixture was stirred at room temperature for 12 hours. 用5% HCl溶液酸化反应混合物。 The reaction mixture was acidified with 5% HCl solution. 将反应混合物在真空中浓缩以得到黄色固体(12. 9mg, 100% )。 The reaction mixture was concentrated in vacuo to give a yellow solid (12. 9mg, 100%).

[0785] 将3-[4-叔丁基-2-(2-哌啶-1-基-乙氧基)苯基丙烯酸(0. 039mmol,leq. ),二乙基氰基膦7. 1 μ 1 (0. 0. 047mmol, 1. 2eq),N- (4_氨基甲基_2_氟_6_乙烯基苯基)-甲烷磺酰胺16. 8mg(0. 047mmol, 1. 2eq.),和三乙胺16. 3 μ 1(0. 117mmol,3eq)加入DMF。 [0785] 3- [4-tert-Butyl-2- (2-piperidin-yl-ethoxy) - phenyl acrylate, (. 0. 039mmol, leq), diethyl cyanophosphonate 7.1 μ 1 (0. 0. 047mmol, 1. 2eq), N- (4_ fluoro-aminomethyl _2_ _6_ vinylphenyl) - methanesulfonamide 16. 8mg (0 047mmol, 1. 2eq. ), and triethylamine 16. 3 μ 1 (0. 117mmol, 3eq) was added DMF. 将所述混合物在室温搅拌过夜。 The mixture was stirred at room temperature overnight. 将反应混合物按照实施例25纯化以得到固体(32. 6mg, 100% )0 The reaction mixture was purified in Example 25 according to obtain a solid (32. 6mg, 100%) 0

[0786] 1H NMR(400MHz, CDCl3) :7. 83 (d,J = 16. 0Hz,1H),7. 44 (d,J = 8. 0Hz,1H),7. 38 (s, 1H), 7. 09 (dd, J = 11. 2,18. OHz, 1H),7. 03-6. 99 (m, 2H), 6. 96 (s, 1H) ,6. 55 (d, J = 16. OHz, 1H), 5. 73 (d, J = 17. 6Hz, 1H), 4. 04(s,2H),4. 25 (t, J = 10. 2Hz,2H),3. 17 (t,J = 10. 2Hz, 2H), 2. 97-2. 92(m,9H),1. 66(五重峰,J = 5. 6Hz,4H),1. 48-1. 47 (m, 2H),1. 23(s,9H) [0786] 1H NMR (400MHz, CDCl3):... 7 83 (d, J = 16. 0Hz, 1H), 7 44 (d, J = 8. 0Hz, 1H), 7 38 (s, 1H), 7. 09 (dd, J = 11. 2,18. OHz, 1H), 7. 03-6. 99 (m, 2H), 6. 96 (s, 1H), 6. 55 (d, J = 16 . OHz, 1H), 5. 73 (d, J = 17. 6Hz, 1H), 4. 04 (s, 2H), 4. 25 (t, J = 10. 2Hz, 2H), 3. 17 (t , J = 10. 2Hz, 2H), 2. 97-2. 92 (m, 9H), 1. 66 (quintet, J = 5. 6Hz, 4H), 1. 48-1. 47 (m, 2H), 1. 23 (s, 9H)

[0787] 实施例27 : [0787] Example 27:

[0788] 3-[4_叔丁基-2-(2-甲氧基乙基氨基)苯基]-N-(3_氟_4_甲烷磺酰基氨基-5-乙烯基苄基)丙烯酰胺 [0788] 3- [4 _ t-butyl-2- (2-methoxyethyl) phenyl] -N- (3_ _4_ methanesulfonyl-fluoro-5-vinylbenzyl-yl) acrylamide amide

[0789] [0789]

Figure CN101142174BD00682

[0790] 步骤1 :3-[4-叔丁基-2-(2-甲氧基乙基氨基)苯基]丙烯酸甲基酯 [0790] Step 1: 3- [4-tert-butyl-2- (2-methoxyethyl) phenyl] acrylic acid methyl ester

[0791] 将三(二亚苄基丙酮)_ 二钯(19. lmg,0.021mmol),l,l,-双(二苯基膦基)-二茂铁(34. 7mg,0. 063 mmol) ,2-甲氧基乙基胺(72. 5 μ 1,0. 834mmol),和3-½-叔丁基-2-三氟甲烷磺酰基氧基苯基)_丙烯酸甲基酯(152. 6mg,0.417mmol,leq)加入到无水甲苯中。 [0791] tris (Dibenzylideneacetone) dipalladium _ (19. lmg, 0.021mmol), l, l, - bis (diphenylphosphino) - ferrocene (34. 7mg, 0 063 mmol. ), 2-methoxyethyl amine (72. 5 μ 1,0. 834mmol), and 3-½- butyl-2-trifluoromethanesulfonyl-phenyl) acrylic acid methyl ester _ (152 . 6mg, 0.417mmol, leq) were added to dry toluene. 将碳酸铯O03.8mg,0.623mmol)加入混合物。 Cesium carbonate O03.8mg, 0.623mmol) added to the mixture. 将反应混合物在80°C搅拌12小时。 The reaction mixture was stirred at 80 ° C 12 h. 按照实施例27的步骤1纯化反应混合物以得到绿色液体(64. 3mg,52. 9% )0 The reaction mixture following the procedure of Example 27 to give a purified 1 green liquid (64. 3mg, 52. 9%) 0

[0792] 1H 匪RGOOMHz,CDCl3) : δ 7. 75 (d, J = 16. OHz, 1H) ,7. 25 (d, J = 8·0Ηζ,1Η), 6. 71 (dd, J = 8· 0,1. 6Hz, 1Η),6· 63 (d, J=L 6Hz, 1Η),6· 24 (d, J = 16. OHz, 1Η),3· 72 (s, 3Η),3· 57(t, J = 5. 2Ηζ,2Η),3· 33(s,3H),3· 29 (t, J = 5. 2Ηζ,2Η),1. 23(s,9H) ;IR(NaCl 纯的,cnT1) :3441,2960,2871,1713,1628,1607,1165. [0792] 1H bandit RGOOMHz, CDCl3):. Δ 7. 75 (d, J = 16. OHz, 1H), 7 25 (d, J = 8 · 0Ηζ, 1Η), 6. 71 (dd, J = 8 · 0,1. 6Hz, 1Η), 6 · 63 (d, J = L 6Hz, 1Η), 6 · 24 (d, J = 16. OHz, 1Η), 3 · 72 (s, 3Η), 3 · 57 (t, J = 5. 2Ηζ, 2Η), 3 · 33 (s, 3H), 3 · 29 (t, J = 5. 2Ηζ, 2Η), 1 23 (s, 9H);. IR (NaCl pure of, cnT1): 3441,2960,2871,1713,1628,1607,1165.

[0793]步骤 2 : [0793] Step 2:

[0794] 3-[4_叔丁基-2-(2-甲氧基乙基氨基)苯基]-N-(3_氟_4_甲烷磺酰基氨基-5-乙烯基苄基)丙烯酰胺 [0794] 3- [4 _ t-butyl-2- (2-methoxyethyl) phenyl] -N- (3_ _4_ methanesulfonyl-fluoro-5-vinylbenzyl-yl) acrylamide amide

[0795] 将3-[4-叔丁基-2-(2-甲氧基乙基氨基)苯基]丙烯酸甲基酯(64. ;3mg, 0. 221mmol, leq)和氢氧化钠Img, 1. 103mmole, 5eq)加入甲醇和H2O中。 [0795] 3- [4-tert-butyl-2- (2-methoxyethyl) phenyl] acrylic acid methyl ester (64.; 3mg, 0. 221mmol, leq) and sodium hydroxide Img, 1. 103mmole, 5eq) was added methanol and H2O. 在室温搅拌反应混合物12小时。 The reaction mixture was stirred at room temperature for 12 hours. 反应混合物用5% HCl溶液酸化。 The reaction mixture was acidified with 5% HCl solution. 将反应混合物在真空中浓缩以得到黄色固体(50. 2mg, 100% )。 The reaction mixture was concentrated in vacuo to give a yellow solid (50. 2mg, 100%).

[0796] 3- [4-叔丁基-2- (2-甲氧基乙基氨基)苯基]丙烯酸(0. 22lmmol),和二乙基氰基膦(40. 2 μ 1,0. 265mmol,l. 2eq)加入DMF。 [0796] 3- [4-tert-butyl-2- (2-methoxyethyl) phenyl] acrylate (0. 22lmmol), and diethyl cyanophosphonate (40. 2 μ 1,0. 265mmol, l. 2eq) was added DMF. 加入N-(4-氨基甲基-2-氟-6-乙烯基苯基) 甲烷磺酰胺(95. 5mg,0. 265mmol)和三乙胺(92. 4μ 1,0. 663mmol)。 Was added N- (4- amino-2-fluoro-6-vinylphenyl) methanesulfonamide (95. 5mg, 0. 265mmol) and triethylamine (92. 4μ 1,0. 663mmol). 在室温搅拌反应混合物过夜。 The reaction mixture was stirred at room temperature overnight. 按照实施例M的步骤2纯化反应混合物以得到绿色固体(77. 8mg,71. 3% )。 The reaction mixture was purified according to the procedure of Example M to give a green solid (77. 8mg, 71. 3%).

[0797] mp(°C ) :196-198 ;IR(KBr 片状沉淀物,cnT1) :3434,3254,2961,1648,1608,1321, 1153,974 ;1H 匪RQOOMHz,CDCl3) :7. 76 (d,J = 15. 2Hz, 1H), 7. 27 (s, 1Η) ,7. 23 (d, J = 8. 4Hz, 1Η),7· 07 (dd, J = 17. 6,10. 8Hz, 1Η),6· 97 (d, J = 8. OHz, 1Η),6· 69 (d, J = 8. OHz, 1Η),6· 34(s,lH),6. 23(t,8. 0Ηζ,1Η),5· 71(d,J = 17. 6Hz,1Η),5. 45 (d,J = 10. 4Hz, 1Η), 4. 46 (d, J = 6. ΟΗζ,2Η),3. 57 (t, J = 5. 2Ηζ,2Η),3. 32-3. 28 (m, 5Η),2. 99 (s, 3Η),2. 51 (s, 3Η),1. 23(s,9H) [0797] mp (° C): 196-198; IR (KBr pellet, cnT1):. 3434,3254,2961,1648,1608,1321, 1153,974; 1H bandit RQOOMHz, CDCl3): 7 76 (d, J = 15. 2Hz, 1H), 7. 27 (s, 1Η), 7. 23 (d, J = 8. 4Hz, 1Η), 7 · 07 (dd, J = 17. 6,10. 8Hz, 1Η), 6 · 97 (d, J = 8. OHz, 1Η), 6 · 69 (d, J = 8. OHz, 1Η), 6 · 34 (s, lH), 6. 23 (t, 8. 0Ηζ, 1Η), 5 · 71 (d, J = 17. 6Hz, 1Η), 5. 45 (d, J = 10. 4Hz, 1Η), 4. 46 (d, J = 6. ΟΗζ, 2Η ), 3. 57 (t, J = 5. 2Ηζ, 2Η), 3. 32-3. 28 (m, 5Η), 2. 99 (s, 3Η), 2. 51 (s, 3Η), 1. 23 (s, 9H)

[0798] 实施例28 : [0798] Example 28:

[0799] 3- (4-叔丁基-2-甲氧基苯基)-N- (3_氟_4_甲烷磺酰基氨基_5_乙烯基-苄基) 丙烯酰胺 [0799] 3- (4-tert-butyl-2-methoxyphenyl) -N- (3_ fluoro _4_ _5_ methanesulfonylamino-vinyl-benzyl) - acrylamide

Figure CN101142174BD00691

[0801] 步骤1 :3-(4-叔丁基-2-甲氧基苯基)丙烯酸甲基酯 [0801] Step 1: 3- (4-tert-butyl-2-methoxyphenyl) methyl acrylate

[0802]将碳酸钾(59. Omg,0. 427mmol)和碘乙烧(25. 6 μ 1,0. 320mmol)加入丙酮。 [0802] Potassium carbonate (59. Omg, 0. 427mmol) and iodine burning acetate (25. 6 μ 1,0. 320mmol) of acetone was added. 将3-(4-叔丁基-2-羟基苯基)丙烯酸甲基酯(50. 0mg,0. 213mmol)加入反应混合物。 3- (4-tert-butyl-2-hydroxyphenyl) acrylic acid methyl ester (50. 0mg, 0. 213mmol) was added the reaction mixture. 在回流的情况下,将反应混合物搅拌5小时。 Under reflux, the reaction mixture was stirred for 5 hours. 反应溶剂在真空中去除。 The reaction solvent was removed in vacuo. 用KOAc提取残余物。 Residue was extracted with KOAc. 将合并的有机层用盐水洗涤,通过硫酸钠干燥,在减压下浓缩。 The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. 用柱色谱法(正己烷:KOAc =10 : 1)纯化残余物以获得固体(56. 4mg,67. 2% )0 By column chromatography (n-hexane: KOAc = 10: 1) to obtain a solid residue was purified (56. 4mg, 67 2%.) 0

[0800][0803] IR(KBr 片状沉淀物,cnT1) :2952,1686,1625,1439 ; [0800] [0803] IR (KBr pellet, cnT1): 2952,1686,1625,1439;

[0804] 1H 匪lU400MHz,CDCl3) : δ 7. 99 (d, J = 16. 8Hz, 1H) ,7. 44 (d, J = 8. OHz, 1H), [0804] 1H bandit lU400MHz, CDCl3): δ 7. 99 (d, J = 16. 8Hz, 1H), 7 44 (d, J = 8. OHz, 1H),.

6. 96 (dd, J = 8. 0,19. 2Ηζ,2Η),4· 13 (dd, J = 6. 8,13. 6Ηζ,2Η),3· 80(s,3H),1. 33(bs,9H). 6. 96 (dd, J = 8. 0,19. 2Ηζ, 2Η), 4 · 13 (dd, J = 6. 8,13. 6Ηζ, 2Η), 3 · 80 (s, 3H), 1. 33 (bs, 9H).

[0805]步骤 2 : [0805] Step 2:

[0806] 3- (4-叔丁基-2-甲氧基苯基)-N- (3_氟_4_甲烷磺酰基氨基_5_乙烯基-苄基) 丙烯酰胺 [0806] 3- (4-tert-butyl-2-methoxyphenyl) -N- (3_ fluoro _4_ _5_ methanesulfonylamino-vinyl-benzyl) - acrylamide

[0807] 将3-(4-叔丁基-2-甲氧基苯基)丙烯酸甲基酯(125mg,leq),和Na0H(75mg, 1. 88mmol)加入H2O中。 [0807] 3- (4-tert-butyl-2-methoxyphenyl) acrylic acid methyl ester (125mg, leq), and Na0H (75mg, 1. 88mmol) in H2O was added. 将反应混合物搅拌12小时。 The reaction mixture was stirred for 12 hours. 反应混合物用5% HCl溶液酸化。 The reaction mixture was acidified with 5% HCl solution. 反应混合物在真空中浓缩以得到固体(121mg,100% )。 The reaction mixture was concentrated in vacuo to give a solid (121mg, 100%).

[0808] 将3-(4-叔丁基-2-甲氧基苯基)丙烯酸(12111^,0.519讓01,1叫),^(4-氨基甲基-2-氟-6-乙烯基-苯基)-甲烷磺酰胺(148. 8mg,0. 415mmol), DEPC (94. 5 μ 1,0. 62mmol, 1. 2eq)和ΤΕΑ(217μ 1,1. 56mmol)加入DMF。 [0808] 3- (4-tert-butyl-2-methoxyphenyl) acrylic acid (12111 ^, 0.519 so called 01,1), ^ (4-amino-2-fluoro-6-vinyl - phenyl) -... methanesulfonamide (148. 8mg, 0 415mmol), DEPC (94. 5 μ 1,0 62mmol, 1. 2eq) and ΤΕΑ (217μ 1,1 56mmol) of DMF was added. 将反应混合物搅拌5小时。 The reaction mixture was stirred for 5 hours. 在真空中去除反应溶剂。 The reaction solvent was removed in vacuo. 用KOAc提取残余物。 Residue was extracted with KOAc. 将合并的有机层用盐水洗涤,通过硫酸钠干燥,在真空中浓缩。 The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. 用柱色谱法(正己烷:KOAc =1:1)纯化残余物以获得固体(96. 2mg,50. 3% )。 By column chromatography (n-hexane: KOAc = 1: 1) to obtain a solid residue was purified (96. 2mg, 50 3%.).

[0809] mp. :150-152°C ;IR(KBr 片状沉淀物,cnT1) :3435,1651,1616,1448,1321 ; [0809] mp: 150-152 ° C; IR (KBr pellet, cnT1):. 3435,1651,1616,1448,1321;

[0810] 1H 匪lU400MHz,CDCl3) : δ 7. 77 (d, J = 15. 6Hz, 1H) ,7. 37 (d, J = 9·2Ηζ,1Η), [0810] 1H bandit lU400MHz, CDCl3):. Δ 7. 77 (d, J = 15. 6Hz, 1H), 7 37 (d, J = 9 · 2Ηζ, 1Η),

7. 12 (dd, J = 11. 2,18. OHz, 1H) ,7. 01 (dd, J = 10. 4,1. 6Hz, 1H),6. 95-6. 89 (m, 2H),6. 62 (d, J = 15. 6Hz, 1H) ,5. 74 (dd, J = 17. 6,0. 8Hz,1H),5. 28 (d,J = 11. 6Hz,1H),4. 39 (s,2H), 3. 79 (s,3H),2. 92 (d, J = O. 8Hz,3H),1. 23 (s, 3H) · 7. 12 (dd, J = 11. 2,18. OHz, 1H), 7. 01 (dd, J = 10. 4,1. 6Hz, 1H), 6. 95-6. 89 (m, 2H) , 6. 62 (d, J = 15. 6Hz, 1H), 5. 74 (dd, J = 17. 6,0. 8Hz, 1H), 5. 28 (J = 11. 6Hz d,, 1H), 4. 39 (s, 2H), 3. 79 (s, 3H), 2. 92 (d, J = O. 8Hz, 3H), 1. 23 (s, 3H) ·

[0811] 实施例四: [0811] Example IV:

[0812] 3-(4-叔丁基-2-羟基苯基)-N-(3-氟_4_甲烷磺酰基氨基_5_乙烯基苄基)丙烯酰胺 [0812] 3- (4-tert-butyl-2-hydroxyphenyl) -N- (3- methanesulfonylamino-fluoro _4_ _5_ vinylbenzyl) acrylamide

[0814] 步骤1 :5-叔丁基-2碘苯酚 [0814] Step 1: 5-tert-Butyl-2-iodophenol

[0815] 3-叔丁基苯酚(30mg,0. 199mmol, leq)和N-碘琥珀酰亚胺(44. 9mg,0. 199mmol) 在氩气气氛下加入无水乙腈。 [0815] 3-tert-butyl-phenol (30mg, 0. 199mmol, leq) and N- iodosuccinimide (44. 9mg, 0. 199mmol) in anhydrous acetonitrile was added under an argon atmosphere. 将混合物搅拌1小时。 The mixture was stirred for 1 hour. 在真空中去除反应溶剂。 The reaction solvent was removed in vacuo. 用CH2Cl2提取残余物。 Residue was extracted with CH2Cl2. 将合并的有机层用H2O和盐水洗涤,通过硫酸钠干燥,并在真空中浓缩。 The combined organic layers were washed with H2O and brine, dried over sodium sulfate, and concentrated in vacuo. 残余物用柱色谱法(正己烷:KOAc = 30 : 1)纯化以获得黄色糖浆9mg,85. 1% )0 The residue was purified by column chromatography (n-hexane: KOAc = 30: 1) to obtain a yellow syrup was purified 9mg, 85 1%) 0.

[0816] 1H NMR(400MHz, CDCl3) : δ 7· 46 (d,J = 8. 0Hz,1H),6· 95 (s,1H),6· 64 (dd,J = 8· 0, 2. 4Hz,1Η),5. 20(bs,1Η),1. 20(s,9H) ;IR(NaCl 纯的,cnT1) :3489,2963,1561,1399,1304, 1190 [0816] 1H NMR (400MHz, CDCl3): δ 7 · 46 (d, J = 8. 0Hz, 1H), 6 · 95 (s, 1H), 6 · 64 (dd, J = 8 · 0, 2. .. 4Hz, 1Η), 5 20 (bs, 1Η), 1 20 (s, 9H); IR (NaCl neat, cnT1): 3489,2963,1561,1399,1304, 1190

[0817] 步骤2 : (4-叔丁基-2-羟基苯基)丙烯酸甲基酯 [0817] Step 2: (4-tert-butyl-2-hydroxyphenyl) acrylic acid methyl ester

[0818]将乙酸钯(16. 8mg,0. 075mmol),1· 1,-双(二苯基膦基)二茂铁9mg, 0. 090mmol),三乙胺(418. 1 μ 1,3. OOOmmol),和丙烯酸甲酯(148. 6 μ 1,1. 650mmol)加入到无水甲苯中。 [0818] Palladium acetate (16. 8mg, 0 075mmol.), 1 · 1, - bis (diphenylphosphino) ferrocene 9mg, 0. 090mmol), triethylamine (418. 1 μ 1,3 . OOOmmol), and methyl acrylate (148. 6 μ 1,1. 650mmol) were added to dry toluene. 加入5-叔丁基-2-碘苯酚(414. %ig,1. 500mmol)。 Was added 2-iodo-5-tert-butyl-phenol (414.% ig, 1. 500mmol). 将反应混合物在60°C过 The reaction mixture was passed at 60 ° C

[0813] [0813]

Figure CN101142174BD00701

夜搅拌。 Night stirring. 在真空中去除反应溶剂。 The reaction solvent was removed in vacuo. 将残余物按照以前类似的工作方法进行纯化以获得固体(322. 3mg,91. 7% )。 The residue was purified in accordance with the previous similar working process to obtain a solid (322. 3mg, 91. 7%).

[0819] 1H 匪RGOOMHz,CDCl3) : δ 7. 93 (d, J = 16. 0Hz,1H),7. 31 (d,J = 8. OHz, 1H), [0819] 1H bandit RGOOMHz, CDCl3): δ 7. 93 (d, J = 16. 0Hz, 1H), 7 31 (d, J = 8. OHz, 1H),.

6. 87 (dd, J = 8. 0,2. OHz, 1H),6· 80 (d, J=L 6Hz, 1H),6· 53 (dd, J = 16. 0,2. OHz, 1H), 3. 75(s,3H),1. 21(s,9H) ;IR(KBr 片状沉淀物,cnT1) :3362,2952,1686,1625,1439,1325 6. 87 (dd, J = 8. 0,2. OHz, 1H), 6 · 80 (d, J = L 6Hz, 1H), 6 · 53 (dd, J = 16. 0,2. OHz, 1H ), 3. 75 (s, 3H), 1 21 (s, 9H); IR (KBr pellet, cnT1):. 3362,2952,1686,1625,1439,1325

[0820] 步骤3 :3- (4-叔丁基-2-羟基苯基)-N- (3_氟_4_甲烷磺酰基氨基_5_乙烯基苄基)丙烯酰胺 [0820] Step 3: 3- (4-tert-butyl-2-hydroxyphenyl) -N- (3_ fluoro _4_ _5_ methanesulfonylamino-vinylbenzyl) acrylamide

[0821] 将3-(4-叔丁基-2-羟基-苯基)-N_(3-氟-4-甲烷磺酰基氨基_5_乙烯基苄基)丙烯酸9mg,0. 092mmol),二乙基氰基膦(19. 85 μ 1,0. 131mmol),N-(4-氨基甲基-2-氟-6-乙烯基苯基)-甲烷磺酰胺(46. 8mg,0. 131mmol),和三乙胺(45. 58 μ 1, 0. 327mmol)在氩气气氛下加入DMF。 [0821] 3- (4-tert-butyl-2-hydroxy - phenyl). -N_ (3- Fluoro-4-ylamino _5_ vinylbenzyl) acrylate 9mg, 0 092mmol), two ethyl cyanophosphonate (19. 85 μ 1,0 131mmol.), N- (4- amino-2-fluoro-6-vinyl-phenyl) - methanesulfonamide (. 46. 8mg, 0 131mmol) , and triethylamine (45. 58 μ 1, 0. 327mmol) was added under argon atmosphere DMF. 按照步骤2纯化反应混合物以获得固体(30. lmg, 51% )。 The reaction mixture was purified according to step 2 to obtain a solid (30. lmg, 51%).

[0822] mp(°C ) :171-173 ;IR(KBr 片状沉淀物,cnT1) :3422,2959,2857,1649,1617,1322, 1154 ;1H NMR(400MHz, CDCl3) :7. 74(d, J = 16Hz, 1H),7· 38 (S, 1Η),7· 29 (d, 1H, J = 804Hz), [0822] mp (° C): 171-173; IR (KBr pellet, cnT1):. 3422,2959,2857,1649,1617,1322, 1154; 1H NMR (400MHz, CDCl3): 7 74 ( d, J = 16Hz, 1H), 7 · 38 (S, 1Η), 7 · 29 (d, 1H, J = 804Hz),

7. 08 (dd, 1H, J = 15. 6,11. 2Hz),7. 01 (d,1H,J = 10. 4Hz),6. 81 (d,2H,J = 11. 2Hz), 6. 65 (d, J = 16Hz, 1H),5. 75 (d, J = 17. 6Hz, 1H),5. 28 (d, J = 10. 8Hz, 1H),4. 39(s,2H), 2. 92(s,3H),1. 19(s,9H) 7. 08 (dd, 1H, J = 15. 6,11. 2Hz), 7. 01 (d, 1H, J = 10. 4Hz), 6. 81 (d, 2H, J = 11. 2Hz), 6 . 65 (d, J = 16Hz, 1H), 5. 75 (d, J = 17. 6Hz, 1H), 5. 28 (d, J = 10. 8Hz, 1H), 4. 39 (s, 2H) , 2. 92 (s, 3H), 1. 19 (s, 9H)

[0823] 实施例30 : [0823] Example 30:

[0824] 3- (2-烯丙基氧基-4-叔丁基苯基)-N- (3_氟_4_甲烷磺酰基氨基_5_乙烯基苄基)丙烯酰胺 [0824] 3- (2-allyl-4-tert-butylphenyl) -N- (3_ fluoro _4_ _5_ methanesulfonylamino-vinylbenzyl) acrylamide

[0826] 步骤1 :3-(2-烯丙基氧基-4-叔丁基苯基)丙烯酸甲基酯 [0826] Step 1: 3- (2-allyl-4-tert-butylphenyl) methyl acrylate

Figure CN101142174BD00711

[0827] 将3-(4-叔丁基-2-羟基-苯基)_丙烯酸甲基酯(50mg,0. 21mmol),烯丙基-碘化物(29. 26 μ 1,0. 32mmol),和K2CO3 (58. 05mg,0. 42mmol)加入丙酮。 [0827] 3- (4-tert-butyl-2-hydroxy - phenyl) _ methyl acrylate (50mg, 0 21mmol.), Allyl - iodide (. 29. 26 μ 1,0 32mmol) and K2CO3 (58. 05mg, 0. 42mmol) of acetone was added. 将反应混合物搅拌过夜。 The reaction mixture was stirred overnight. 用柱色谱法(正己烷:KOAc = 10 : 1)进行纯化以得到固体(51. 4mg,89. 3% )。 Purification to give a solid (51. 4mg, 89 3%.) By column chromatography (n-hexane 1:: KOAc = 10).

[0828] mp. :170. 5 〜171. 2°C ;IR(KBr 片状沉淀物,cnT1) :3227,3076,1685,1651,1617, 1153 ; [0828] mp: 170 5 ~171 2 ° C; IR (KBr pellet, cnT1):... 3227,3076,1685,1651,1617, 1153;

[0829] 1H 匪lU400MHz,CDCl3) : δ 7. 93 (d, J = 16. OHz, 1H) ,7. 36 (d, J = 8·0Ηζ,1Η), 6. 91 (d, J = 8. 0Hz, 1H) ,6. 84 (s, 1H) ,6. 43 (d, J = 16. 0Hz,1H),5. 98 (m,1H),5. 36 (d, J = 17. 2Hz, 1H),5· 23 (d, J = 10. 4Hz, 1H),4· 56(s,2H),3· 70(s,3H),1. 23(s,9H) [0829] 1H bandit lU400MHz, CDCl3):. Δ 7. 93 (d, J = 16. OHz, 1H), 7 36 (d, J = 8 · 0Ηζ, 1Η), 6. 91 (d, J = 8 . 0Hz, 1H), 6. 84 (s, 1H), 6. 43 (d, J = 16. 0Hz, 1H), 5. 98 (m, 1H), 5. 36 (d, J = 17. 2Hz , 1H), 5 · 23 (d, J = 10. 4Hz, 1H), 4 · 56 (s, 2H), 3 · 70 (s, 3H), 1. 23 (s, 9H)

[0830]步骤 2 : [0830] Step 2:

[0831 ] 3- (2-烯丙基氧基-4-叔丁基苯基)-N- (3_氟_4_甲烷磺酰基氨基_5_乙烯基苄基)丙烯酰胺 [0831] 3- (2-allyl-4-tert-butylphenyl) -N- (3_ fluoro _4_ _5_ methanesulfonylamino-vinylbenzyl) acrylamide

[0832] 将3-(2-烯丙基氧基-4-叔丁基-苯基)丙烯酸甲基酯(51. 4mg,0. 18mmol, leq) 和Na0H(37. 5mg,0. 94mmolJeq)加入H2O中。 [0832] 3- (2-allyl-4-tert-butyl-phenyl) - acrylic acid methyl ester (. 51. 4mg, 0 18mmol, leq) and Na0H (.. 37 5mg, 0 94mmolJeq) H2O is added in. 将反应混合物搅拌12小时。 The reaction mixture was stirred for 12 hours. 反应混合物用 The reaction mixture was

[0825]5% HCl溶液酸化。 [0825] 5% HCl solution was acidified. 在真空中浓缩反应混合物以得到固体8mg, 100% )。 The reaction mixture was concentrated in vacuo to give a solid 8mg, 100%).

[0833] 将3- (2-烯丙基氧基-4-叔丁基-苯基)-丙烯酸(46. 8mg, 0. 18mmol),N- (4_氨基甲基-2-氟-6-乙烯基-苯基)-甲烷磺酰胺(78.8;3mg,0. 22mmol), DEPC(33. 38μ 1, 0. 22mmol, 1. ,和TEA(75. 27 μ 1,0. 54mmol)加入DMF。将反应混合物搅拌5小时。反应混合物按照实施例27的步骤2纯化以得到固体(78. 7mg,89. 9% )。 [0833] 3- (2-allyl-4-tert-butyl - phenyl) - acrylic acid (46. 8mg, 0. 18mmol), N- (4_ Aminomethyl-2-fluoro-6 - vinyl - phenyl) - methanesulfonamide (78.8; 3mg, 0 22mmol), DEPC (33 38μ 1, 0. 22mmol, 1., and TEA (75 27 μ 1,0 54mmol....) was added DMF the reaction mixture was stirred for 5 hours. the reaction mixture was purified according to the steps of Example 27 to give a solid (78. 7mg, 89. 9%).

[0834] mp. :176. 3 〜178. 2°C ;IR(KBr 片状沉淀物,cm—1) :3440,3076,1652,1617,1321 ; [0834] mp:... 176 3 ~178 2 ° C; IR (KBr pellet, cm-1): 3440,3076,1652,1617,1321;

[0835] 1H 匪lU400MHz,CDCl3) : δ 7. 85 (d, J = 15. 6Hz, 1H) ,7. 34 (d, J = 8. OHz, 1H), 7. 28 (s,1H),7· 08 (dd, J = 17. 6,11. 2Hz, 1H),7. 01 (d, J=L 2Hz, 1H),6· 98 (s, J=L 2Hz, 1H) ,6. 90 (dd, J = 8. 0,1. 6Hz,1H),6. 49(d,J = 16Hz,1H),5. 72 (d,J = 17. 6Hz,1H), 5. 40 (m, 1H) ,5. 34 (d, J = 6Hz, 1H) ,5. 26 (m, 1H) ,5. 23 (s, 1H) ,4. 56 (d, J = 1.2Hz,2H), 4. 80 (d, J = 5. 6Hz,2H),2. 99(s,3H),1. 24 (m, 9H) [0835] 1H bandit lU400MHz, CDCl3): δ 7. 85 (d, J = 15. 6Hz, 1H), 7 34 (d, J = 8. OHz, 1H), 7. 28 (s, 1H),. 7 · 08 (dd, J = 17. 6,11. 2Hz, 1H), 7. 01 (d, J = L 2Hz, 1H), 6 · 98 (s, J = L 2Hz, 1H), 6. 90 (dd, J = 8. 0,1. 6Hz, 1H), 6. 49 (d, J = 16Hz, 1H), 5. 72 (d, J = 17. 6Hz, 1H), 5. 40 (m, 1H), 5. 34 (d, J = 6Hz, 1H), 5. 26 (m, 1H), 5. 23 (s, 1H), 4. 56 (d, J = 1.2Hz, 2H), 4. 80 (d, J = 5. 6Hz, 2H), 2. 99 (s, 3H), 1. 24 (m, 9H)

[0836] 实施例31 :4-(5-叔丁基-2_[2_(3-氟_4_甲烷磺酰基氨基_5_乙烯基苄基氨基甲酰基)乙烯基]苯氧基)-哌啶-ι-羧酸叔丁酯 [0836] Example 31: 4- (5-tert-butyl -2_ [2_ (3-fluoro-methanesulfonylamino-_5_ _4_ vinyl benzyl carbamoyl) ethenyl] phenoxy) - piperidine piperidine carboxylate -ι-

Figure CN101142174BD00721

[0838] 步骤1 :4-[5_叔丁基-2-(2-甲氧基羰基乙烯基)苯氧基]哌啶羧酸叔丁酯 [0838] Step 1: 4- [5_-tert-butyl-2- (2-methoxycarbonyl) phenoxy] piperidine-carboxylate

[0839] 将3-(4-叔丁基-2-羟基苯基)丙烯酸甲基酯7mg,0. 105mmole),4-甲烷磺酰基氧基哌啶-1-羧酸叔丁酯(58. 7mg, 0. 210mmol),碳酸钾(43. 7mg, 0. 316mmol)加入DMF。 [0839] 3- (4-tert-butyl-2-hydroxyphenyl) acrylic acid methyl ester 7mg, 0. 105mmole), 4- methanesulfonyloxy group piperidine-1-carboxylate (58. 7mg, 0. 210mmol), potassium carbonate (43. 7mg, 0. 316mmol) was added DMF. 将反应混合物搅拌过夜。 The reaction mixture was stirred overnight. 反应混合物按照实施例30的步骤1纯化以得到固体6mg, 100% )。 The reaction mixture was a purification step according to Example 30 to give a solid 6mg, 100%).

[0840] 1H 匪RGOOMHz,CDCl3) : δ 7. 90 (d, J = 16. 4Hz, 1H) ,7. 39 (d, J = 8. OHz, 1H), 6. 93 (d, J = 8. OHz, 1H),6· 85 (s, 1H),6· 41 (dd, J = 8. 0,2. 8Hz, 1Η),4· 50(五重峰,J = 3. 2Hz, 1Η),3. 72 (s,3H),3. 61 (m, 2H),3. 35 (m, 2H),1. 87 (m, 2H),1. 76 (m, 2H),1. 41 (s, 9H), 1. 24(s,9H). [0840] 1H bandit RGOOMHz, CDCl3): δ 7. 90 (d, J = 16. 4Hz, 1H), 7 39 (d, J = 8. OHz, 1H), 6. 93 (d, J = 8. . OHz, 1H), 6 · 85 (s, 1H), 6 · 41 (dd, J = 8. 0,2. 8Hz, 1Η), 4 · 50 (quintet, J = 3. 2Hz, 1Η) , 3. 72 (s, 3H), 3. 61 (m, 2H), 3. 35 (m, 2H), 1. 87 (m, 2H), 1. 76 (m, 2H), 1. 41 ( s, 9H), 1. 24 (s, 9H).

[0841 ] 步骤2 :4- (5-叔丁基-2- [2_ (3_氟_4_甲烷磺酰基氨基_5_乙烯基苄基氨基甲酰基)乙烯基]苯氧基)-哌啶-ι-羧酸叔丁酯 [0841] Step 2: 4- (5-tert-butyl-2- [2_ (3_ fluoro _4_ _5_ methanesulfonylamino-vinyl benzyl carbamoyl) ethenyl] phenoxy) - piperidine piperidine carboxylate -ι-

[0842] 将4-[5_叔丁基-2-(2-甲氧基羰基乙烯基)苯氧基]哌啶羧酸叔丁酯(56. 3mg,0. 135mol, leq)和NaOH(26. 9mg,0. 674mmol)加入H2O0 将反应混合物搅拌12 小时。 [0842] 4- [5_-tert-butyl-2- (2-methoxycarbonyl) phenoxy] piperidine-carboxylate (56. 3mg, 0. 135mol, leq) and NaOH ( 26. 9mg, 0. 674mmol) was added H2O0 the reaction mixture was stirred for 12 hours. 用5% HCl溶液酸化反应混合物。 The reaction mixture was acidified with 5% HCl solution. 将反应混合物在真空中浓缩以得到固体(54. 5mg, 100% )。 The reaction mixture was concentrated in vacuo to give a solid (54. 5mg, 100%).

[0843] 3-[4-叔丁基-2-(2-甲氧基乙氧基)-苯基]丙烯酸(0. 135mmol),二乙基氰基膦1,0. 162mmol,1.2eq), N_(4_氨基甲基_2_氟_6_乙烯基苯基)甲烷磺酰胺(58. Omg, 0. 162mmol),和三乙胺(56. 4μ 1,0. 405mmol, 3eq)在氩气气氛下加入DMF。 [0843] 3- [4-tert-butyl-2- (2-methoxyethoxy) - phenyl] acrylic acid (0. 135mmol), diethyl cyanophosphonate 1,0 162mmol, 1.2eq) , N_ (4_ fluoro-aminomethyl _2_ _6_ vinylphenyl) methanesulfonamide (58. Omg, 0. 162mmol), and triethylamine (56. 4μ 1,0. 405mmol, 3eq) in DMF was added under an argon atmosphere. 将反应混合物搅拌过夜。 The reaction mixture was stirred overnight. 将反应混合物按照实施例27的步骤2纯化以得到固体(52. 6mg, 100% )0[0844] mp ( 0C ) :122-124 °C ;IR(KBr 片状沉淀物,cnT1) :3423,3086,2964,1655,1607, 1420,1329,1275,1156 ; The reaction mixture was purified according to the steps of Example 27 to give a solid (52. 6mg, 100%) 0 [0844] mp (0C): 122-124 ° C; IR (KBr pellet, cnT1): 3423, 3086,2964,1655,1607, 1420,1329,1275,1156;

[0845] 1H NMR(400MHz, CDCl3) :7. 87 (d,J = 16. 0Hz,1H),7. 35 (d,J = 8. 0Hz,1H),7. 20 (s, 1H),7. 04 (dd, J = 17. 6,10. 8Hz, 1H),6. 94 (d, J = 10. OHz, 1H),6. 88-6. 80 (m, 3H),6. 45 (d, J =15. 6Hz, 1H),5· 66(d, J = 17. 6Hz, 1H),5. 29(d,J= 11. 6Hz, 1H), 4. 42(d, J = 6. OHz, 1H), 4. 06-3. 98 (m. 1H),3. 61-3. 57 (m. 2H),3. 30-3. 24 (m. 2H),2. 94 (s,3H),1. 86-1. 82 (m. 2H), 1. 76-1. 70 (m. 2H),1. 37 (s,9H),1. 22 (s,9H) [0845] 1H NMR (400MHz, CDCl3):... 7 87 (d, J = 16. 0Hz, 1H), 7 35 (d, J = 8. 0Hz, 1H), 7 20 (s, 1H), 7. 04 (dd, J = 17. 6,10. 8Hz, 1H), 6. 94 (d, J = 10. OHz, 1H), 6. 88-6. 80 (m, 3H), 6. 45 (d, J = 15. 6Hz, 1H), 5 · 66 (d, J = 17. 6Hz, 1H), 5. 29 (d, J = 11. 6Hz, 1H), 4. 42 (d, J = 6. OHz, 1H), 4. 06-3. 98 (m. 1H), 3. 61-3. 57 (m. 2H), 3. 30-3. 24 (m. 2H), 2. 94 ( s, 3H), 1. 86-1. 82 (m. 2H), 1. 76-1. 70 (m. 2H), 1. 37 (s, 9H), 1. 22 (s, 9H)

[0846] 实施例32 :3-[4_叔丁基-2-(3-甲基丁基氨基)苯基]-N-(3_氟_4_甲烷磺酰基氨基-5-乙烯基苄基)丙烯酰胺 [0846] Example 32: 3- [4_ tert-Butyl-2- (3-methylbutyl) phenyl] -N- (3_ _4_ methanesulfonyl-fluoro-5- vinylbenzyl yl) acrylamide

[0848] 步骤1 :3-(4-叔丁基-2- 丁基氨基苯基)丙烯酸甲基酯 [0848] Step 1: 3- (4-tert-butyl-aminophenyl) acrylic acid methyl ester

[0849]三(二亚苄基丙酮)二钯(5%,0.04mmol,37.49mmol),l,l,-双(二苯基膦基)二茂铁(15%,0. 12mmol,68. 19mg),异戊基胺(1. 64mmol,190. 87 μ 1),禾Π 3-(4-叔丁基-2-三氟甲烷磺酰基氧基苯基)丙烯酸甲基酯(0.82mmol,300mg)加入甲苯。 [0849] tris (dibenzylideneacetone) dipalladium (5%, 0.04mmol, 37.49mmol), l, l, - bis (diphenylphosphino) ferrocene (15%, 0 12mmol, 68.. 19mg), iso-pentyl amine (1. 64mmol, 190. 87 μ 1), Wo Π 3- (4- tert-butyl-2-trifluoromethanesulfonyl-phenyl) acrylic acid methyl ester (0.82mmol, 300 mg of) toluene was added. 加入碳酸铯(1. 23mmol,400. 76mg)。 Cesium carbonate (1. 23mmol, 400. 76mg). 将反应混合物在80°C搅拌12小时。 The reaction mixture was stirred at 80 ° C 12 h. 按照实施例27的步骤1纯化反应混合物以得到黄色糖浆(100. 5mg,40. 42% )。 The reaction mixture was purified by 1 following the procedure of Example 27 to give a yellow syrup (100. 5mg, 40. 42%).

[0850] IR(NaCl 纯的,cnT1) :3353,3235,3028,2977,1685,1156 ; [0850] IR (NaCl neat, cnT1): 3353,3235,3028,2977,1685,1156;

[0851] 1H 匪lU400MHz,CDCl3) : δ 7. 80 (d, 1H, J = 15. 6Hz), 7. 33 (s, 1H), 7. 30 (d, 1H, J =8. 0Hz),6. 78 (d, 1H, J = 8. OHz),6. 77 (s, 1H),6. 28 (d, 1H, J = 15. 6Hz),3. 77 (s, 3H), 3. 17 (t, 2H, J = 7. 6Hz),1. 64 〜1. 53 (m, 1H),1. 28 (s,9H),1. 94 (d, 6H, J = 6. 8Hz) · [0851] 1H bandit lU400MHz, CDCl3): δ 7. 80 (d, 1H, J = 15. 6Hz), 7. 33 (s, 1H), 7. 30 (d, 1H, J = 8 0Hz),. 6. 78 (d, 1H, J = 8. OHz), 6. 77 (s, 1H), 6. 28 (d, 1H, J = 15. 6Hz), 3. 77 (s, 3H), 3. 17 (t, 2H, J = 7. 6Hz), 1. 64 ~1. 53 (m, 1H), 1. 28 (s, 9H), 1. 94 (d, 6H, J = 6. 8Hz) ·

[0852] 步骤2 :3-[4-叔丁基-2-(3-甲基丁基氨基)苯基]_N_(3_氟_4_甲烷磺酰基氨基-5-乙烯基苄基)丙烯酰胺 [0852] Step 2: 3- [4-tert-Butyl-2- (3-methylbutyl) phenyl] _N_ (3_ _4_ methanesulfonyl-fluoro-5-vinylbenzyl-yl) acrylamide amide

[0853] 将3-(4-叔丁基-2-丁基氨基苯基)丙烯酸甲基酯(0. 20mmOl,61. Img)和Na0H(5eq,l. OOmmol,40. 30mg)加入甲醇和水。 [0853] 3- (4-tert-butyl-aminophenyl) acrylic acid methyl ester (0. 20mmOl, 61. Img) and Na0H (5eq, l. OOmmol, 40. 30mg) was added and methanol water. 将反应混合物搅拌12小时。 The reaction mixture was stirred for 12 hours. 反应混合物用5% HCl溶液酸化。 The reaction mixture was acidified with 5% HCl solution. 将反应残余物在真空中浓缩以得到固体(39. 34mg, 100% ). The reaction residue is concentrated in vacuo to give a solid (39. 34mg, 100%).

[0854]将 3-[4_ 叔丁基-2-(3-甲基丁基氨基)苯基]丙烯酸(0. 13mmol,39. 3%ig), N-(4-氨基甲基-2-氟-6-乙烯基苯基)甲烷磺酰胺(0. 15讓ol,51.99mg),DEPC(1.2eq, 0. 16mmol,23. 67 μ 1),和TEAQeq,0. 26mmol,36. 24 μ 1)加入DMF。 [0854] 3- [4_ tert-butyl-2- (3-methylbutyl) phenyl] acrylate (0. 13mmol, 39. 3% ig), N- (4- aminomethyl-2 fluoro-6-vinylphenyl) methanesulfonamide (0.15 so ol, 51.99mg), DEPC (1.2eq, 0. 16mmol, 23. 67 μ 1), and TEAQeq, 0. 26mmol, 36. 24 μ 1) was added DMF. 将反应混合物搅拌过夜。 The reaction mixture was stirred overnight. 按照实施例27的步骤2纯化反应混合物以得到黄色固体3mg,61. 54% )。 The reaction mixture was purified according to the steps of Example 27 to give a yellow solid 3mg, 61. 54%).

[0855] mp :164 〜166°C ; [0855] mp: 164 ~166 ° C;

[0856] IR(KBr 片状沉淀物,cnT1) :3279,3239,3073,2957,1649,1611,1321,1153 ; [0856] IR (KBr pellet, cnT1): 3279,3239,3073,2957,1649,1611,1321,1153;

[0857] 1H NMR(400MHz, CDCl3) : δ 7. 76 (d, 1H, J = 15. 2Hz), 7. 24 (s, 1H), 7. 21 (d, 1H, J = 8. OHz),7· 05 (dd, 1Η, J = 17. 6,11. 2Ηζ),6· 94 (d, 1Η, J = 10. OHz),6· 65 (d, 1Η, J = 8. OHz), 6. 62 (s,1Η),6. 38 (s, 1Η),6. 21 (d, 1Η, J = 14. 8Ηζ),6. 12 (s, 1Η),5. 69 (d, 1H, J = 17. 6Hz), [0857] 1H NMR (400MHz, CDCl3): δ 7. 76 (d, 1H, J = 15. 2Hz), 7. 24 (s, 1H), 7. 21 (d, 1H, J = 8. OHz) , 7 · 05 (dd, 1Η, J = 17. 6,11. 2Ηζ), 6 · 94 (d, 1Η, J = 10. OHz), 6 · 65 (d, 1Η, J = 8. OHz), 6. 62 (s, 1Η), 6. 38 (s, 1Η), 6. 21 (d, 1Η, J = 14. 8Ηζ), 6. 12 (s, 1Η), 5. 69 (d, 1H, J = 17. 6Hz),

[0847] [0847]

Figure CN101142174BD00731

5.34 (d, 1H, J=Il. 2Hz) ,4. 44(d,2H,J = 6. 4Hz),3. 13(t,2H,J = 7. 2Hz),2. 98(s,3H), 1. 65 (dq, 1H, J = 13. 2,6. 4Hz),1. 48 (td,2H,J = 7. 2Hz),1. 23 (s,9H),0. 88 (d,6H,J = 5.34 (d, 1H, J = Il. 2Hz), 4. 44 (d, 2H, J = 6. 4Hz), 3. 13 (t, 2H, J = 7. 2Hz), 2. 98 (s, 3H ), 1. 65 (dq, 1H, J = 13. 2,6. 4Hz), 1. 48 (td, 2H, J = 7. 2Hz), 1. 23 (s, 9H), 0. 88 (d , 6H, J =

6.4Hz), 6.4Hz),

[0858] 实施例33 :3-(4-叔丁基-2-异丁基氨基苯基)-N_(3-氟-4-甲烷磺酰基氨基-5-乙烯基苄基)丙烯酰胺 [0858] Example 33: 3- (4-tert-butyl-2-isobutyl-aminophenyl) -N_ (3- fluoro-4-methanesulfonyl-5-vinylbenzyl-yl) acrylamide

[0859] [0859]

Figure CN101142174BD00741

[0860] 步骤1 :3-(4-叔丁基-2-异丁基氨基苯基)丙烯酸甲基酯 [0860] Step 1: 3- (4-tert-butyl-2-isobutyl-aminophenyl) acrylic acid methyl ester

[0861]三(二亚苄基丙酮)_ 二钯(5%,0.04mmol,37.24mmol),l,l,-双(二苯基膦基)_ 二茂铁(15%,0. 12mmol,67. 36mg),异丁基胺(1. 62mmol, 160. 98 μ 1),禾Π 3-(4-叔丁基-2-三氟甲烷磺酰基氧基-苯基)丙烯酸甲基酯(0.81mmOlJ98mg)加入甲苯。 [0861] tris (Dibenzylideneacetone) dipalladium _ (5%, 0.04mmol, 37.24mmol), l, l, - bis (diphenylphosphino) ferrocene _ (15%, 0 12mmol,. 67. 36mg), iso-butylamine (1. 62mmol, 160. 98 μ 1), Wo Π 3- (4- tert- butyl-2-yloxy trifluoromethanesulfonyloxy-phenyl) - acrylic acid methyl ester ( 0.81mmOlJ98mg) of toluene was added. 加入碳酸铯(1. 22mmol,395. 87mg)。 Cesium carbonate (1. 22mmol, 395. 87mg). 将反应混合物在80°C搅拌12小时。 The reaction mixture was stirred at 80 ° C 12 h. 按照实施例27的步骤1 纯化反应混合物以得到黄色糖浆8mg, 10% )0 The reaction mixture was purified by 1 following the procedure of Example 27 to give a yellow syrup 8mg, 10%) 0

[0862] IR(NaCl 纯的,cnT1) :3440,2961,1651,1597 ; [0862] IR (NaCl neat, cnT1): 3440,2961,1651,1597;

[0863] 1H 匪RGOOMHz,CDCl3) : δ 7. 80 (d, 1H, J = 15. 6Hz), 7. 30 (d, 1H, J = 8· OHz), [0863] 1H bandit RGOOMHz, CDCl3): δ 7. 80 (d, 1H, J = 15. 6Hz), 7. 30 (d, 1H, J = 8 · OHz),

6. 76 (d, 1H, J = 8. 0Hz),6. 75 (s, 1H),6. 28 (d, 1H, J = 15. 6Hz),3. 77 (s, 3H),2. 98 (d, 2H, J =6. 8Hz),1· 99 〜1. 89 (m, 1H),1. 28 (s, 9H),1. 00 (d, 6H, J = 6. 8Hz) · 6. 76 (d, 1H, J = 8. 0Hz), 6. 75 (s, 1H), 6. 28 (d, 1H, J = 15. 6Hz), 3. 77 (s, 3H), 2. 98 (d, 2H, J = 6. 8Hz), 1 · 99 ~1. 89 (m, 1H), 1. 28 (s, 9H), 1. 00 (d, 6H, J = 6. 8Hz) ·

[0864] 步骤2 :3-(4-叔丁基-2-异丁基氨基苯基)丙烯酸 [0864] Step 2: 3- (4-tert-butyl-2-isobutyl-aminophenyl) acrylic acid

[0865] 将3-(4-叔丁基-2-异丁基氨基苯基)丙烯酸甲基酯(0.08mmol,22.8mg)和NaOH(0. 39mmol, 15. 76mg)加入甲醇和水。 [0865] 3- (4-tert-butyl-2-isobutyl-aminophenyl) acrylic acid methyl ester (0.08mmol, 22.8mg) and NaOH (0. 39mmol, 15. 76mg) were added methanol and water. 将反应混合物搅拌12小时。 The reaction mixture was stirred for 12 hours. 将反应混合物用5% HCl溶液酸化。 The reaction mixture was acidified with 5% HCl solution. 将反应混合物在真空中浓缩以得到固体02 mg, 100% )。 The reaction mixture was concentrated in vacuo to give a solid 02 mg, 100%).

[0866] 1H 匪lU400MHz,CD3OD) : δ 7. 86 (d, 1H, J = 15. 2Hz),7. 82 (d,1H,J = 8.0Hz), [0866] 1H bandit lU400MHz, CD3OD):. Δ 7. 86 (d, 1H, J = 15. 2Hz), 7 82 (d, 1H, J = 8.0Hz),

7. 63 (s,1H),7. 58 (d, 1H, J = 8. OHz),6. 59 (d, 1H, J = 15. 6Hz),3. 18 (d, 2H, J = 7. 2Hz), 2· 21 〜2· 12 (m, 1H),1. 33 (s,9H),1. 10 (d, 6H, J = 6. 8Hz), 7. 63 (s, 1H), 7. 58 (d, 1H, J = 8. OHz), 6. 59 (d, 1H, J = 15. 6Hz), 3. 18 (d, 2H, J = 7 . 2Hz), 2 · 21 ~2 · 12 (m, 1H), 1. 33 (s, 9H), 1. 10 (d, 6H, J = 6. 8Hz),

[0867]步骤 3 : [0867] Step 3:

[0868] 3- (4-叔丁基-2-异丁基氨基苯基)-N- (3_氟_4_甲烷磺酰基氨基_5_乙烯基苄基)丙烯酰胺 [0868] 3- (4-tert-butyl-2-isobutyl-aminophenyl) -N- (3_ fluoro _4_ _5_ methanesulfonylamino-vinylbenzyl) acrylamide

[0869] 将3-(4-叔丁基-2-异丁基氨基苯基)丙烯酸(0.08mmol,22.02mg),N-(4-氨基甲基-2-氟-6-乙烯基苯基)甲烷磺酰胺(0. 08mmol,31. 54mg),DEPC(0. 09mmol, 14. 57 μ 1), 和TEA(2eq,0. 16mmol,22. 30 μ 1)加入DMF。 [0869] 3- (4-tert-butyl-2-isobutyl-aminophenyl) acrylic acid (0.08mmol, 22.02mg), N- (4- amino-2-fluoro-6-vinylphenyl ) methanesulfonamide (0. 08mmol, 31. 54mg), DEPC (0. 09mmol, 14. 57 μ 1), and TEA (2eq, 0. 16mmol, 22. 30 μ 1) was added DMF. 将反应混合物搅拌过夜。 The reaction mixture was stirred overnight. 按照实施例27的步骤2纯化反应混合物以获得黄色固体Img, 57. 60% )。 2 purification procedure of Example 27 the reaction mixture to obtain a yellow solid Img, 57. 60%).

[0870] mp:165 〜167°C ;IR(KBr 片状沉淀物,cnT1) :3238,2957,1649,1608,1321,1154 ; 1H NMR(400MHz, CD3OD) : δ 7. 76 (d, 1H, J = 15. 6Hz),7. 46 (s, 1H),7. 30 (d, 1H, J = 8. OHz), 7. 16 (dd, 1H, J = 17. 6,11. 2Hz),7. 09 (dd, 1H, J = 10. 4,1. 2Hz) ,6. 67 (d, 1H, J = 8. OHz), 6. 64 (s,1H) ,6. 42 (d, 1H, J = 15. 2Hz),5. 82 (d, 1H, J = 17. 6Hz),5. 36 (d, 1H, J = 11. 2Hz), 4. 47 (s, 2H), 2. 29 (s, 3H), 2. 96 (d, 2H, J = 6. 8Hz),1. 97 〜1. 87 (m,1H),1. 26 (s,9H), [0870] mp: 165 ~167 ° C; IR (KBr pellet, cnT1): 3238,2957,1649,1608,1321,1154; 1H NMR (400MHz, CD3OD): δ 7. 76 (d, 1H , J = 15. 6Hz), 7. 46 (s, 1H), 7. 30 (d, 1H, J = 8. OHz), 7. 16 (dd, 1H, J = 17. 6,11. 2Hz) , 7. 09 (dd, 1H, J = 10. 4,1. 2Hz), 6. 67 (d, 1H, J = 8. OHz), 6. 64 (s, 1H), 6. 42 (d, 1H, J = 15. 2Hz), 5. 82 (d, 1H, J = 17. 6Hz), 5. 36 (d, 1H, J = 11. 2Hz), 4. 47 (s, 2H), 2. 29 (s, 3H), 2. 96 (d, 2H, J = 6. 8Hz), 1. 97 ~1. 87 (m, 1H), 1. 26 (s, 9H),

[0859]0. 98(d,6H,J = 6. 8Hz), [0859] 0. 98 (d, 6H, J = 6. 8Hz),

[0871] 实施例34 :3-(4-叔丁基-2-异丙基氨基苯基)-N_(3-氟-4-甲烷磺酰基氨基-5-乙烯基苄基)丙烯酰胺 [0871] Example 34: 3- (4-tert-butyl-2-isopropyl-phenyl) -N_ (3- fluoro-4-methanesulfonyl-5-vinylbenzyl-yl) acrylamide

[0872] [0872]

Figure CN101142174BD00751

[0873] 步骤1 :3-(4-叔丁基-2-三氟甲烷磺酰基氧基苯基)丙烯酸乙酯 [0873] Step 1: 3- (4-tert-butyl-2-trifluoromethanesulfonyl-phenyl) acrylate

[0874] 在将3-(4-叔丁基-2-羟基苯基)丙烯酸乙酯(101.9mg,0.410mmOl)加入二氯甲烷后,将反应温度冷却到-78°C。 [0874] After 3- (4-tert-butyl-2-hydroxyphenyl) acrylate (101.9mg, 0.410mmOl) in dichloromethane was added, the reaction temperature was cooled to -78 ° C. 加入2,6_ 二甲基吡啶(119. 5μ l,1.026mmol)和triflic anhydride (137. 9 μ 1,0. 820mmol,2eq)。 2,6_ was added lutidine (119. 5μ l, 1.026mmol) and triflic anhydride (137. 9 μ 1,0. 820mmol, 2eq). 将反应混合物加温到室温。 The reaction mixture was warmed to room temperature. 通过加入饱和的NaHCO3 溶液来猝灭反应。 By the addition of saturated NaHCO3 solution to quench the reaction. 用CH2Cl2提取反应混合物。 The reaction mixture was extracted with CH2Cl2. 用H2O和盐水洗涤合并的有机层,通过硫酸钠干燥。 The organic layer was washed with H2O brine, dried over sodium sulfate. 用柱色谱法(正己烷:KOAc = 10 : 1)纯化残余物以得到糖浆(103. 9mg, 72. 4% )。 By column chromatography (n-hexane: KOAc = 10: 1) to afford the residue was purified syrup (103. 9mg, 72. 4%).

[0875] 1H 匪RGOOMHz,CDCl3) : δ 7. 77 (d, J = 16. OHz, 1H) ,7. 55 (d, J = 8·4Ηζ,1Η), 7. 34(dd, J = 8. 0,1. 6Hz, 1H),7· 25 (d, J = 1. 6Hz, 1Η),6· 39 (d, J = 16. OHz, 1Η),4· 20 (q, J =7. 2Ηζ,2Η),1. 31-1. 25 (m, 12Η) ;IR(NaCl 纯的,cnT1) :2960,2871,1713,1628,1607,1165 [0875] 1H bandit RGOOMHz, CDCl3):. Δ 7. 77 (d, J = 16. OHz, 1H), 7 55 (d, J = 8 · 4Ηζ, 1Η), 7. 34 (dd, J = 8 . 0,1. 6Hz, 1H), 7 · 25 (d, J = 1. 6Hz, 1Η), 6 · 39 (d, J = 16. OHz, 1Η), 4 · 20 (q, J = 7. .. 2Ηζ, 2Η), 1 31-1 25 (m, 12Η); IR (NaCl neat, cnT1): 2960,2871,1713,1628,1607,1165

[0876] 步骤2 :3-(4-叔丁基-2-异丙基氨基苯基)丙烯酸甲基酯 [0876] Step 2: 3- (4-tert-butyl-2-isopropylamino-phenyl) acrylic acid methyl ester

[0877]将三(二亚苄基丙酮)二钯(5%,0.04mmol,37.24mmol),l,l,-双(二苯基膦基)二茂铁(15%,0. 12mmol,67. 36mg),异丙基胺(1. 62mmol, 137. 98 μ 1)和3-(4-叔丁基-2-三氟甲烷磺酰基氧基苯基)-丙烯酸甲基酯(0.81mmOlJ98mg)在氩气气氛下加入甲苯。 [0877] tris (dibenzylideneacetone) dipalladium (5%, 0.04mmol, 37.24mmol), l, l, - bis (diphenylphosphino) ferrocene (15%, 0 12mmol, 67. . 36mg), isopropylamine (1. 62mmol, 137. 98 μ 1) and 3- (4-tert-butyl-2-trifluoromethanesulfonyl-phenyl) - acrylic acid methyl ester (0.81mmOlJ98mg) toluene was added under argon atmosphere. 将碳酸铯(1.22mm0l,395.87mg)加入反应混合物。 Cesium carbonate (1.22mm0l, 395.87mg) was added the reaction mixture. 将反应混合物在80°C搅拌12小时。 The reaction mixture was stirred at 80 ° C 12 h. 按照实施例22的步骤1纯化反应混合物以产生糖浆(37. 3mg, 17. 28% )0 A purification step according to Example 22 the reaction mixture to produce a syrup (37. 3mg, 17. 28%) 0

[0878] IR(NaCl 纯的片状沉淀物,cnT1) =3428,2965,1725,1638 ; [0878] IR (NaCl pellet was pure, cnT1) = 3428,2965,1725,1638;

[0879] 1H 匪lU400MHz,CDCl3) : δ 7. 76 (d, 1H, J = 15. 6Hz), 7. 29 (d, 1H, J = 8· OHz), 6. 71 (d, 1H, J = 8. 4Hz),6· 68(s, 1H),6· 27 (d, 1H, J = 15. 6Hz),3. 77(s,3H),3· 74 〜 3. 67 (m, 1Η),1. 28 (s,9H),1. 24 (d, 6H, J = 6. 4Hz), [0879] 1H bandit lU400MHz, CDCl3): δ 7. 76 (d, 1H, J = 15. 6Hz), 7. 29 (d, 1H, J = 8 · OHz), 6. 71 (d, 1H, J = 8. 4Hz), 6 · 68 (s, 1H), 6 · 27 (d, 1H, J = 15. 6Hz), 3. 77 (s, 3H), 3 · 74 ~ 3. 67 (m, 1Η ), 1. 28 (s, 9H), 1. 24 (d, 6H, J = 6. 4Hz),

[0880] 步骤3 :3-(4-叔丁基-2-异丙基氨基苯基)丙烯酸 [0880] Step 3: 3- (4-tert-butyl-2-isopropylamino-phenyl) acrylic acid

[0881] 将3-(4-叔丁基-2-异丙基氨基苯基)丙烯酸甲基酯(0. Hmmol,37. 7mg)和NaOH(0. 68mmol,27. 39mg)加入甲醇和水。 [0881] 3- (4-tert-butyl-2-isopropylamino-phenyl) acrylic acid methyl ester (0. Hmmol, 37. 7mg) and NaOH (0. 68mmol, 27. 39mg) was added methanol and water . 将反应混合物在室温搅拌12小时。 The reaction mixture was stirred at room temperature for 12 hours. 将反应混合物用5% HCl溶液酸化。 The reaction mixture was acidified with 5% HCl solution. 将混合物在真空中浓缩以产生黄色固体(36. 56mg, 100% )0 The mixture was concentrated to give a yellow solid (36. 56mg, 100%) 0 in vacuo

[0882] 1H 匪RGOOMHz,CD3OD) : δ 7. 84 (d, 1H, J = 15. 6Hz),7. 35 (d,1H,J = 8.0Hz), 6. 77 (s,1H),6. 76 (d, 1H, J = 8. OHz),6. 26 (d, 1H, J = 15. 6Hz),3. 67 〜3. 61 (m, 1H), 1. 26 (s,9H),1. 22 (d, 6H, J = 6. 4Hz), [0882] 1H bandit RGOOMHz, CD3OD): δ 7. 84 (d, 1H, J = 15. 6Hz), 7 35 (d, 1H, J = 8.0Hz), 6. 77 (s, 1H), 6. . 76 (d, 1H, J = 8. OHz), 6. 26 (d, 1H, J = 15. 6Hz), 3. 67 ~3. 61 (m, 1H), 1. 26 (s, 9H) , 1. 22 (d, 6H, J = 6. 4Hz),

[0883] 步骤4 :3- (4-叔丁基-2-异丙基氨基苯基)-N- (3_氟_4_甲烷磺酰基氨基_5_乙烯基苄基)丙烯酰胺 [0883] Step 4: 3- (4-tert-butyl-2-isopropylamino-phenyl) -N- (3_ fluoro _4_ _5_ methanesulfonylamino-vinylbenzyl) acrylamide

[0884] 将3- (4-叔丁基-2-异丙基氨基苯基)丙烯酸(0. Hmmol,36. 56mg),N- (4_氨基甲基-2-氟-6-乙烯基苯基)甲烷磺酰胺(0. 15mmol,55. 17mg), DEPC(1. 2eq,0. 17mmol,25. 49 μ 1)和TEA(2eq,0. 28mmol,39. 02 μ 1)加入DMF。 [0884] 3- (4-tert-butyl-2-isopropylamino-phenyl) acrylic acid (0. Hmmol, 36. 56mg), N- (4_-amino-2-fluoro-6-vinyl phenyl) methanesulfonamide (0. 15mmol, 55. 17mg), DEPC (1. 2eq, 0. 17mmol, 25. 49 μ 1) and TEA (2eq, 0. 28mmol, 39. 02 μ 1) was added DMF. 将反应混合物搅拌过夜。 The reaction mixture was stirred overnight. 按照实施例22的步骤2纯化反应混合物以产生黄色固体(38. 9mg,57. 03% )。 Following the procedure of Example 22 the reaction mixture was purified by 2 to give a yellow solid (38. 9mg, 57. 03%).

[0885] mp :168 〜170°C ;IR(KBr 片状沉淀物,cnT1) :3236,3022,2964,1609,1321,1154¾ NMR(400MHz, CD3OD) : δ 7. 74 (d, 1H, J = 15. 6Hz), 7. 46 (s, 1H), 7. 31 (d, 1H, J = 8· OHz), 7. 16 (dd, 1H, J= 17. 6,10. 8Hz),7. 09 (dd, 1H, J = 10. 4,1. 6Hz),6. 71 (s,1H),6. 69 (d, 1H, J = 8. 0Hz),6· 41 (d, 1H, J = 15. 6Hz),5. 82 (d, 1H, J = 17. 6Hz),5. 36 (d, 1H, J = 11. 2Hz), 4. 47 (s,2H),3· 74 〜3. 64 (m, 1H),2. 99 (s, 3H),1. 26 (s,9H),1. 21 (d, 6H, J = 6. 4Hz) · [0885] mp: 168 ~170 ° C; IR (KBr pellet, cnT1): 3236,3022,2964,1609,1321,1154¾ NMR (400MHz, CD3OD): δ 7. 74 (d, 1H, J = 15. 6Hz), 7. 46 (s, 1H), 7. 31 (d, 1H, J = 8 ·), 7. 16 (dd, 1H, J = 17. 6,10. 8Hz) OHz, 7 . 09 (dd, 1H, J = 10. 4,1. 6Hz), 6. 71 (s, 1H), 6. 69 (d, 1H, J = 8. 0Hz), 6 · 41 (d, 1H, J = 15. 6Hz), 5. 82 (d, 1H, J = 17. 6Hz), 5. 36 (d, 1H, J = 11. 2Hz), 4. 47 (s, 2H), 3 · 74 ~ 3. 64 (m, 1H), 2. 99 (s, 3H), 1. 26 (s, 9H), 1. 21 (d, 6H, J = 6. 4Hz) ·

[0886] 实施例35 : [0886] Example 35:

[0887] (R)-3-(4-叔丁基苯基)-N-[1-(3-氟-4-甲烷磺酰基氨基-5-乙烯基苯基)乙基]丙酰胺 [0887] (R) -3- (4- tert-butylphenyl) -N- [1- (3- fluoro-4-methanesulfonyl-5-vinylphenyl) ethyl] propionamide

[0889] 将N44-(l-氨基乙基)-2-氟-6-乙烯基苯基]甲烷亚磺酰胺(实施例7的步骤5,0. 08mmol,30. 611^),3-[4-叔丁基-2-(3-甲基丁基氨基)苯基]丙酸(0. 09mmol, 18. 65), DEPC(0. IOmmol,14. 57 μ 1)和ΤΕΑ(0· 16mmol,22. 49 μ 1)加入DMF。 [0889] The N44- (l- aminoethyl) -2-fluoro-6-vinyl phenyl] methane sulfinamide (Example 7 step 5,0. 08mmol, 30. 611 ^), 3- [ 4-tert-butyl-2- (3-methylbutyl) phenyl] propionic acid (0. 09mmol, 18. 65), DEPC (0. IOmmol, 14. 57 μ 1) and ΤΕΑ (0 · 16mmol , 22. 49 μ 1) was added DMF. 将反应混合物搅拌12 小时。 The reaction mixture was stirred for 12 hours. 按照实施例21纯化反应混合物以产生固体、2Ί. 2mg,67. 73% )。 The reaction mixture was purified according to Example 21 to give a solid, 2Ί. 2mg, 67. 73%).

[0890] mp :154 〜156°C ; [0890] mp: 154 ~156 ° C;

[0891] [α ]D20 :+8. 59 (CHCl3, c 0. 27); . [0891] [α] D20: +8 59 (CHCl3, c 0. 27);

[0892] IR(KBr 片状沉淀物):3223,2963,1645,1261,1097 CnT151H NMR(400MHz, CDCl3): δ 7. 25 (s,1Η),7. 24(d,2H,J = 17. 6,11. 2Hz),7. 06(d,2H,J = 8. OHz),6. 86 (dd, 1H, J = 10. 4,2. 0Hz),5. 84 (s, 1H),5. 71 (d, 1H, J = 17. 6Hz),5. 42 (d, 1H, J = 6. 8Hz),5. 39 (d, 1H, J =11. 2Hz),4· 96 (q, 1H, J = 6. 4Hz),3. 00(s,3H),2. 87(t,2H,J = 8. 0Hz),2. 43(t,2H,J = 8. 0Hz),1. 30 (d, 3H, J = 6. 8Hz),1. 23 (s,9H) · [0892] IR (KBr pellet): 3223,2963,1645,1261,1097 CnT151H NMR (400MHz, CDCl3):. Δ 7. 25 (s, 1Η), 7 24 (d, 2H, J = 17 . 6,11. 2Hz), 7. 06 (d, 2H, J = 8. OHz), 6. 86 (dd, 1H, J = 10. 4,2. 0Hz), 5. 84 (s, 1H) , 5. 71 (d, 1H, J = 17. 6Hz), 5. 42 (d, 1H, J = 6. 8Hz), 5. 39 (d, 1H, J = 11. 2Hz), 4 · 96 ( q, 1H, J = 6. 4Hz), 3. 00 (s, 3H), 2. 87 (t, 2H, J = 8. 0Hz), 2. 43 (t, 2H, J = 8. 0Hz), 1. 30 (d, 3H, J = 6. 8Hz), 1. 23 (s, 9H) ·

[0893] 实施例36 : (R)-3-(4-叔丁基苯基)-N-[1-(3-氟-4-甲烷磺酰基氨基_5_乙烯基苯基)乙基]丙烯酰胺 [0893] Example 36: (R) -3- (4- tert-butylphenyl) -N- [1- (3- Fluoro-4-yl-amino _5_ vinylphenyl) ethyl] Acrylamide

[0895] 将N44-(l-氨基乙基)-2-氟-6-乙烯基苯基]甲烷亚磺酰胺(0. 7mmol,25. 3mg), 3- [4-叔丁基-2- (3-甲基丁基氨基)苯基]丙烯酸(0. 7mmol, 15. 27mg),DEPC (0. 08mmol, 12. 75 μ 1),和ΤΕΑ(0· 14mmol, 19. 51 μ 1)加入DMF。 [0895] The N44- (l- aminoethyl) -2-fluoro-6-vinyl phenyl] methane sulfinamide (0. 7mmol, 25. 3mg), 3- [4- tert-butyl- (3-methylbutyl) phenyl] acrylate (0. 7mmol, 15. 27mg), DEPC (0. 08mmol, 12. 75 μ 1), and ΤΕΑ (0 · 14mmol, 19. 51 μ 1) was added DMF. 将反应混合物搅拌12小时。 The reaction mixture was stirred for 12 hours. 按照实施例21的相似的方法纯化反应混合物以产生标题产物(36. Img, 100. 0% )0 The reaction mixture in a similar manner as in Example 21 to yield purified title product (36. Img, 100. 0%) 0

[0896] mp :127 〜129°C ; [0896] mp: 127 ~129 ° C;

[0897] [a ]D20 :-20. 33 (CH3OH, c 1. 26); . [0897] [a] D20: -20 33 (CH3OH, c 1. 26);

[0898] IR(KBr 片状沉淀物):3236,3087,四63,1734,1325,ΙΙδΙαιΓ1 ; [0898] IR (KBr pellet): 3236,3087, four 63,1734,1325, ΙΙδΙαιΓ1;

[0888] [0888]

Figure CN101142174BD00761

[0894] [0894]

Figure CN101142174BD00762

[0899] 1H 匪lU400MHz,CDCl3) : δ 7. 55 (d, 1H, J = 15. 6Hz),7. 35 (d,2H,J = 8. 4Hz), 7. 29 (d, 2H, J = 8. 4Hz),7. 06 (dd, 1H, J= 17. 6,10. 8Hz),6. 97 (dd, 1H, J = 10. 4,1. 6Hz), 6. 33 (d, 1H, J = 17. 6Hz),6. 26 (s, 1H),6. 06 (d, 1H, J = 7. 6Hz),5. 69 (d, 1H, J = 17. 6Hz), 5. 33 (d, 1H, J = 11. 2Hz),5. 12 (q, 1H, J = 7. 2Hz),2. 98 (s, 3H),1. 43 (d, 3H, J = 7. 2Hz), 1. 24(s,9H). [0899] 1H bandit lU400MHz, CDCl3): δ 7. 55 (d, 1H, J = 15. 6Hz), 7 35 (d, 2H, J = 8. 4Hz), 7. 29 (d, 2H, J. = 8. 4Hz), 7. 06 (dd, 1H, J = 17. 6,10. 8Hz), 6. 97 (dd, 1H, J = 10. 4,1. 6Hz), 6. 33 (d, 1H, J = 17. 6Hz), 6. 26 (s, 1H), 6. 06 (d, 1H, J = 7. 6Hz), 5. 69 (d, 1H, J = 17. 6Hz), 5. 33 (d, 1H, J = 11. 2Hz), 5. 12 (q, 1H, J = 7. 2Hz), 2. 98 (s, 3H), 1. 43 (d, 3H, J = 7. 2Hz ), 1. 24 (s, 9H).

[0900] 实施例37 : [0900] Example 37:

[0901] 3-(4-叔丁基苯基)-N-(3-氟-4-甲烷磺酰基氨基_5_乙烯基苄基)_2_甲基丙烯酰胺 [0901] 3- (4-tert-butylphenyl) -N- (3- Fluoro-4-ylamino _5_ vinylbenzyl) methacrylamide _2_

[0902] [0902]

Figure CN101142174BD00771

[0903] N-(4-氨基甲基-2-氟-6-乙烯基苯基)甲烷磺酰胺(0. 15mmol,54. 21mg), 3-(4-叔丁基-苯基)-2-甲基丙烯酸(0. 14mmol,30mg),DEPC(1. 2eq,0. 17mmol, 25. 49μ 1),和TEA(2eq,0. 28mmol,39. 03 μ 1)加入DMF。 [0903] N- (4- amino-2-fluoro-6-vinylphenyl) methanesulfonamide (0. 15mmol, 54 21mg.), 3- (4- tert-butyl - phenyl) -2 - methacrylic acid (0. 14mmol, 30mg), DEPC (.. 1 2eq, 0 17mmol, 25. 49μ 1), and TEA (.. 2eq, 0 28mmol, 39 03 μ 1) was added DMF. 将反应混合物搅拌12小时。 The reaction mixture was stirred for 12 hours. 按照实施例21的相似的方法纯化反应混合物以产生标题产物(34. 8mg,55. 96% )。 The reaction mixture in a similar manner as in Example 21 to yield purified title product (34. 8mg, 55. 96%).

[0904] mp :136 〜138°C ; [0904] mp: 136 ~138 ° C;

[0905] IR(KBr 片状沉淀物,CnT1) :3235,2962,1645,1321,1153 ; [0905] IR (KBr pellet, CnT1): 3235,2962,1645,1321,1153;

[0906] 1H NMR (400MHz, CDCl3) : δ 7. 37 (d, 2Η, J = 8. 4Hz),7. 35 (s,1H),7. 31 (s,1H), 7. 26 (d, 2H, J = 8. 4Hz),7. 12 (dd, 1H, J = 17. 2,10. 8Hz),7. 01 (dd, 1H, J = 10. 0,1. 6Hz), 6. 48 (s,1H),5. 75 (d, 1H, J = 17. 2Hz),5. 39 (d, 1H, J = 10. 8Hz),4. 49 (d, 2H, J = 6. 4Hz), 3. 02 (s,3H),2. 11 (s,3H),1. 30 (s,9H). [0906] 1H NMR (400MHz, CDCl3): δ 7. 37 (d, 2Η, J = 8. 4Hz), 7 35 (s, 1H), 7 31 (s, 1H), 7. 26 (d.. , 2H, J = 8. 4Hz), 7. 12 (dd, 1H, J = 17. 2,10. 8Hz), 7. 01 (dd, 1H, J = 10. 0,1. 6Hz), 6. 48 (s, 1H), 5. 75 (d, 1H, J = 17. 2Hz), 5. 39 (d, 1H, J = 10. 8Hz), 4. 49 (d, 2H, J = 6. 4Hz ), 3. 02 (s, 3H), 2. 11 (s, 3H), 1. 30 (s, 9H).

[0907] 实施例38 : [0907] Example 38:

[0908] 3- (4-叔丁基苯基)-2-氟-N- (3_氟_4_甲烷磺酰基氨基_5_乙烯基苄基)丙烯酰胺 [0908] 3- (4-tert-butylphenyl) -2-fluoro -N- (3_ fluoro _4_ _5_ methanesulfonylamino-vinylbenzyl) acrylamide

[0909] [0909]

Figure CN101142174BD00772

[0910] 将N-(4_氨基甲基-2-氟-6-乙烯基苯基)甲烷磺酰胺(1. leq,0. 15mmol, 53. 24mg) ,3-½-叔丁基苯基)-2-氟丙烯酸(leq,0. 14mmol, 30mg) ,DEPC(1. 2eq,0. 17mmol, 25. 49μ 1),和TEAQeq,0. 28mmol,39. 09μ 1)在氩气气氛下加入DMF。 [0910] The N- (4_ Aminomethyl-2-fluoro-6-vinylphenyl) methanesulfonamide (1. leq, 0. 15mmol, 53. 24mg), 3-½--tert-butylphenyl ) -2-fluoro acrylate (leq, 0. 14mmol, 30mg), DEPC (1. 2eq, 0. 17mmol, 25. 49μ 1), and TEAQeq, 0. 28mmol, 39. 09μ 1) was added under an argon atmosphere DMF. 将反应混合物搅拌12小时。 The reaction mixture was stirred for 12 hours. 按照实施例21的相似的方法纯化反应混合物以产生标题产物(30. Omg,48% )。 The reaction mixture in a similar manner as in Example 21 to yield purified title product (30. Omg, 48%).

[0911] mp :165 〜167°C ; [0911] mp: 165 ~167 ° C;

[0912] IR(KBr 片状沉淀物,cnf1) :3246,2920,1644,1323,1155 ; [0912] IR (KBr pellet, cnf1): 3246,2920,1644,1323,1155;

[0913] 1H NMR(400MHz, CDCl3) : δ 7. 54(dd,2H,J = 8. 8,2. OHz),7. 40(dd,2H,J = 8. 0, 2. 0Hz), 7. 35 (s, 1H), 7. 24 (d, 1H, J = 2. 4Hz) ,7. 14(ddd, 1H, J = 17. 6,10. 8,2. 0Hz), 7. 06 (d, 1H, J = 10. 0Hz),6. 95 (dd, 1H, J = 39. 6,2. 0Hz),6. 73 (s, 1H),6. 06 (s, 1H), [0913] 1H NMR (400MHz, CDCl3): δ 7. 54 (dd, 2H, J = 8. 8,2 OHz.), 7 40 (dd, 2H, J = 8. 0, 2. 0Hz),. 7. 35 (s, 1H), 7. 24 (d, 1H, J = 2. 4Hz), 7. 14 (ddd, 1H, J = 17. 6,10. 8,2. 0Hz), 7. 06 (d, 1H, J = 10. 0Hz), 6. 95 (dd, 1H, J = 39. 6,2. 0Hz), 6. 73 (s, 1H), 6. 06 (s, 1H),

775. 79 (dd, 1H, J= 17. 2,1. 2Hz),5. 44 (dd, 1H, J = 10. 8,1. 2Hz),4. 56 (d, 2H, J = 4. 8Hz), 3. 05(s,3H),l. 31(s,9H) 775. 79 (dd, 1H, J = 17. 2,1. 2Hz), 5. 44 (dd, 1H, J = 10. 8,1. 2Hz), 4. 56 (d, 2H, J = 4. 8Hz), 3. 05 (s, 3H), l. 31 (s, 9H)

[0914] 实施例39 :3-[4-叔丁基-2-(2-吗啉-4-基-乙氧基)苯基]_N_ (3_氟_4_甲烷磺酰基氨基-5-乙烯基苄基)丙烯酰胺 [0914] Example 39: 3- [4-tert-Butyl-2- (2- morpholin-4-yl-ethoxy) - phenyl] _N_ (3_-fluoro-5- methanesulfonyl _4_ vinyl benzyl) acrylamide

[0915] [0915]

Figure CN101142174BD00781

[0916] 步骤1 :3-[4_叔丁基-2-(2-吗啉-4-基-乙氧基)_苯基]丙烯酸甲基酯 [0916] Step 1: 3- [4_-tert-butyl-2- (2-morpholin-4-yl-ethoxy) - _ phenyl] acrylic acid methyl ester

[0917] 将3-(4-叔丁基-2-羟基苯基)丙烯酸甲基酯(实施例四的步骤2,101.5mg, 0. 866mmole) ,4-½-氯乙基)吗啉HCl (161. Img, 0. 866mmol,2eq),和氢化钠(86. 6mg, 2. 166mmol,5eq)在氩气气氛下加入DMF。 [0917] 3- (4-tert-butyl-2-hydroxyphenyl) acrylic acid methyl ester (step according to a fourth embodiment 2,101.5mg, 0. 866mmole), 4-½- chloroethyl) morpholine HCl (161. Img, 0. 866mmol, 2eq), and sodium hydride (86. 6mg, 2. 166mmol, 5eq) in DMF was added under an argon atmosphere. 将反应混合物搅拌过夜。 The reaction mixture was stirred overnight. 在证实反应结束后,在减压下去除DMF。 After completion of the reaction was confirmed, the DMF was removed under reduced pressure. 残余物用KOAc提取。 The residue was extracted with KOAc. 合并的有机层用H2O和盐水洗涤,通过硫酸钠干燥, 在真空中浓缩。 The combined organic layers were washed with H2O and brine, dried over sodium sulfate, and concentrated in vacuo. 用柱色谱法^tOAc)纯化残余物以产生糖浆(33.0mg,21.9%)。 By column chromatography ^ tOAc) The residue was purified to yield a syrup (33.0mg, 21.9%).

[0918] 1H 匪RGOOMHz,CDCl3) : δ 7. 86 (d, J = 16. OHz, 1H) ,7. 35 (d, J = 8·0Ηζ,1Η), 6. 93 (dd, J = 8· 0,1. 6Hz, 1Η),6· 86 (s, 1Η),6· 51 (d, J = 16. OHz, 1Η),4· 13 (t,J = 6. OHz, 1Η),3· 72(s,3H),3· 68(t, J = 5. 2Ηζ,4Η),2· 81(t,J = 5. 2Ηζ,2Η),2· 55(s,4H),1. 25(s,9H) [0918] 1H bandit RGOOMHz, CDCl3):. Δ 7. 86 (d, J = 16. OHz, 1H), 7 35 (d, J = 8 · 0Ηζ, 1Η), 6. 93 (dd, J = 8 · 0,1. 6Hz, 1Η), 6 · 86 (s, 1Η), 6 · 51 (d, J = 16. OHz, 1Η), 4 · 13 (t, J = 6. OHz, 1Η), 3 · 72 (s, 3H), 3 · 68 (t, J = 5. 2Ηζ, 4Η), 2 · 81 (t, J = 5. 2Ηζ, 2Η), 2 · 55 (s, 4H), 1. 25 (s, 9H)

[0919]步骤 2: [0919] Step 2:

[0920] 3-[4-叔丁基-2-(2-吗啉_4_基-乙氧基)苯基]-N_(3_氟_4_甲烷磺酰基氨基-5-乙烯基苄基)丙烯酰胺 [0920] 3- [4-tert-Butyl-2- (2-morpholin _4_ yl-ethoxy) - phenyl] -N_ (3_ _4_ methanesulfonyl-fluoro-5- vinylbenzyl yl) acrylamide

[0921] 3-[4-叔丁基-2-(2-吗啉-4-基-乙氧基)苯基]丙酸甲基酯(15. 3mg, 0. 044mmol,leq)和氢氧化钠(8. 8mg,0. 220mmole,kq)加入甲醇和水。 [0921] 3- [4-tert-Butyl-2- (2- morpholin-4-yl-ethoxy) - phenyl] propionic acid methyl ester (15. 3mg, 0. 044mmol, leq) and ammonium hydroxide sodium (8. 8mg, 0. 220mmole, kq) was added methanol and water. 将反应混合物搅拌12小时。 The reaction mixture was stirred for 12 hours. 反应混合物用5% HCl溶液酸化。 The reaction mixture was acidified with 5% HCl solution. 将反应混合物在真空中浓缩以产生固体(14. 6mg, 100% )。 The reaction mixture was concentrated in vacuo to give a solid (14. 6mg, 100%).

[0922] 将3-[4-叔丁基-2-(2-吗啉-4-基-乙氧基)苯基]丙烯酸(0. 044mmol,leq.), 二乙基氰基膦(8. 0μ 1,0. 053mmol,lJeq),N-(4_氨基甲基_2_氟_6_乙烯基苯基)甲烷磺酰胺(18. 9mg,0. 053mmol,1.2eq·),和TEA(18. 4 μ 1,0. 132mmol,3eq)在氩气气氛下加入DMF。 [0922] 3- [4-tert-Butyl-2- (2- morpholin-4-yl-ethoxy) - phenyl] acrylic acid (. 0. 044mmol, leq), diethyl cyanophosphonate (8 . 0μ 1,0. 053mmol, lJeq), N- (4_ fluoro-aminomethyl _2_ _6_ vinylphenyl) methanesulfonamide (18. 9mg, 0. 053mmol, 1.2eq ·), and TEA (18. 4 μ 1,0. 132mmol, 3eq) in DMF was added under an argon atmosphere. 将反应混合物在室温搅拌过夜。 The reaction mixture was stirred at room temperature overnight. 在真空中去除01^,用KOAc提取残余物。 01 ^ removed in vacuo, the residue was extracted with KOAc. 用盐水洗涤合并的有机层,通过硫酸钠干燥,并在真空中浓缩。 The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. 用柱色谱法(正己烷:KOAc = 1:1) 纯化残余物以产生固体(13. Img, 53. 2. % )0 By column chromatography (n-hexane: KOAc = 1: 1) to give a solid residue was purified (13. Img, 53. 2.%) 0

[0923] IR(KBr 片状沉淀物,cnT1) :3434,3254,2961,1648,1608,1321,1153,974 ; [0923] IR (KBr pellet, cnT1): 3434,3254,2961,1648,1608,1321,1153,974;

[0924] 1H NMR(400MHz, CDCl3) :7. 82 (d,J = 16. 0Hz,1H),7. 35 (d,J = 8. 0Hz,1H),7. 29 (s, 1H) ,7. 08 (dd, J = 17.6,10. 8Hz, 1H), 7. 01 (d, J = 10. 4Hz,1H),6. 92 (d,J = 8. ΟΗζ,ΙΗ), 6. 85 (s,1H),6. 50 (d, J = 16. OHz, 1Η),6. 25 (bs. 1Η),5. 72 (d, J = 18. OHz, 1Η),5. 75 (d, J =11. 2Hz, 1H),4· 48 (d, J = 5. 6Ηζ,2Η),4· 14 (t,J = 5. 6Ηζ,2Η),3· 65 (t, J = 4. 4Ηζ,4Η), 2. 99 (s,3Η),2. 88-2. 81 (m. 2Η),2. 56 (s. 4Η),1. 23 (s,9H) [0924] 1H NMR (400MHz, CDCl3):... 7 82 (d, J = 16. 0Hz, 1H), 7 35 (d, J = 8. 0Hz, 1H), 7 29 (s, 1H), 7. 08 (dd, J = 17.6,10. 8Hz, 1H), 7. 01 (d, J = 10. 4Hz, 1H), 6. 92 (d, J = 8. ΟΗζ, ΙΗ), 6. 85 (s, 1H), 6. 50 (d, J = 16. OHz, 1Η), 6. 25 (bs. 1Η), 5. 72 (d, J = 18. OHz, 1Η), 5. 75 (d , J = 11. 2Hz, 1H), 4 · 48 (d, J = 5. 6Ηζ, 2Η), 4 · 14 (t, J = 5. 6Ηζ, 2Η), 3 · 65 (t, J = 4. 4Ηζ, 4Η), 2. 99 (s, 3Η), 2. 88-2. 81 (m. 2Η), 2. 56 (s. 4Η), 1. 23 (s, 9H)

[0925] 实施例40 :[0926] 3-[4_叔丁基-2-(四氢吡喃-4-基氧基)苯基]_N_(3_氟_4_甲烷磺酰基氨基-5-乙烯基苄基)丙烯酰胺 [0925] Example 40: [0926] 3- [4_ tert-butyl-2- (tetrahydropyran-4-yloxy) phenyl] _N_ (3_-fluoro-methanesulfonyl-amino-5 _4_ - vinylbenzyl) acrylamide

[0927] [0927]

Figure CN101142174BD00791

[0928] 步骤1 :3-[4_叔丁基-2-(四氢吡喃-4-基氧基)_苯基]丙烯酸甲基酯 [0928] Step 1: 3- [4_ tert-butyl-2- (tetrahydropyran-4-yloxy) _ phenyl] acrylic acid methyl ester

[0929] 将3-(4-叔丁基-2-羟基苯基)丙烯酸甲基酯(75. 9mg,0. 324mmole)和4_甲烷磺酸四氢吡喃-4-基酯(70. Img, 0. 389mmol, 1. 2eq),和碳酸钾(134. 3mg,0. 972mmol,5eq) 在氩气气氛下加入DMF。 [0929] 3- (4-tert-butyl-2-hydroxyphenyl) acrylic acid methyl ester (75. 9mg, 0. 324mmole) 4_ and methanesulfonic acid tetrahydropyran-4-yl ester (70. Img, 0. 389mmol, 1. 2eq), and potassium carbonate (134. 3mg, 0. 972mmol, 5eq) in DMF was added under an argon atmosphere. 在加热的情况下,将反应混合物搅拌过夜。 In the case of heating, the reaction mixture was stirred overnight. 在真空中去除DMF。 The DMF was removed in vacuo. 用KOAc提取残余物。 Residue was extracted with KOAc. 合并的有机层用H2O和盐水洗涤,通过硫酸钠干燥,并在真空中浓缩。 The combined organic layers were washed with H2O and brine, dried over sodium sulfate, and concentrated in vacuo. 用柱色谱法纯化残余物以产生糖浆3mg)。 The residue was purified by column chromatography to give a syrup 3mg).

[0930] 将糖浆和乙酸酐(174. 5 μ 1,1. 850mmole, IOeq)加入吡啶。 [0930] The syrups and acetic anhydride (174. 5 μ 1,1. 850mmole, IOeq) pyridine. 将反应混合物搅拌过夜。 The reaction mixture was stirred overnight. 通过加入H2O猝灭反应。 The reaction was quenched by addition of H2O. 用KOAc提取反应混合物。 The reaction mixture was extracted with KOAc. 用饱和的CuSO4, H2O和盐水洗涤合并的有机层,通过硫酸钠干燥,并在真空中浓缩。 The organic layer was saturated CuSO4, H2O, and brine, dried over sodium sulfate, and concentrated in vacuo. 将残余物用柱色谱法(正己烷:KOAc =10 : 1)纯化以产生糖浆(31. 5mg,43. 2% )。 The residue was purified by column chromatography (n-hexane: KOAc = 10: 1) to yield purified syrup (31. 5mg, 43 2%.).

[0931 ] 1H 匪R (400MHz,CDCl3) :Α_ δ 7. 93 (d, J= 16. 4Hz,1H) ,7. 39 (d, J = 8. OHz,1H), [0931] 1H bandit R (400MHz, CDCl3): Α_ δ 7. 93 (d, J = 16. 4Hz, 1H), 7 39 (d, J = 8. OHz, 1H),.

6. 94(d, J = 8. 0Hz, 1H),6· 85 (s, 1H),6· 43(d, J = 16. OHz, 1H),4· 50(setp, J = 3. 6Hz, 1H), 3. 92 (m, 2H),3. 73 (s, 3H),3. 55 (m, 2H),1. 97 (m, 2H),1. 81 (m, 2H),1. 24 (s,9H) 6. 94 (d, J = 8. 0Hz, 1H), 6 · 85 (s, 1H), 6 · 43 (d, J = 16. OHz, 1H), 4 · 50 (setp, J = 3. 6Hz , 1H), 3. 92 (m, 2H), 3. 73 (s, 3H), 3. 55 (m, 2H), 1. 97 (m, 2H), 1. 81 (m, 2H), 1 . 24 (s, 9H)

[0932] 步骤2 :3-[4-叔丁基-2-(四氢吡喃_4_基氧基)苯基]_N_(3_氟_4_甲烷磺酰基氨基-5-乙烯基苄基)丙烯酰胺 [0932] Step 2: 3- [4-tert-butyl-2- (tetrahydropyran-_4_-yloxy) phenyl] _N_ (3_ _4_ methanesulfonyl-fluoro-5- vinylbenzyl yl) acrylamide

[0933] 将3-[4_叔丁基-2-(四氢吡喃-4-基氧基)苯基]丙烯酸甲基酯(31. 5mg, [0933] 3- [4_ tert-butyl-2- (tetrahydropyran-4-yloxy) phenyl] acrylic acid methyl ester (31. 5mg,

0. 099mmol,leq)和氢氧化钠(19. 8mg,0. 4955mmole)加入甲醇和H20。 0. 099mmol, leq) and sodium hydroxide (19. 8mg, 0. 4955mmole) was added methanol and H20. 将反应混合物搅拌12小时。 The reaction mixture was stirred for 12 hours. 用5% HCl酸化反应混合物。 The reaction mixture was acidified with 5% HCl. 将混合物在真空中浓缩以产生3-[4-叔丁基-2-(四氢吡喃-4-基氧基)-苯基]丙烯酸(30. Img, 100% )0 The mixture was concentrated in vacuo to yield 3- [4-tert-butyl-2- (tetrahydropyran-4-yloxy) - phenyl] acrylic acid (30. Img, 100%) 0

[0934] 将3-[4-叔丁基-2-(四氢吡喃-4-基氧基)苯基]丙烯酸(0. 099mmol, leq),二乙基氰基膦(18. 1 μ 1,0. 1119mmol,1.2eq), N_(4_氨基甲基_2_氟-6-乙烯基苯基)甲烷磺酰胺(42. 5mg,0. 119mmol,1.2eq·),和TEA(41. 4 μ 1,0. 297mmol,3eq)在氩气气氛下加入DMF。 [0934] 3- [4-tert-butyl-2- (tetrahydropyran-4-yloxy) phenyl] acrylate (0. 099mmol, leq), diethyl cyanophosphonate (18. 1 μ 1,0. 1119mmol, 1.2eq), N_ (4_ aminomethyl _2_ fluoro-6-vinylphenyl) methanesulfonamide (42. 5mg, 0. 119mmol, 1.2eq ·), and TEA (41 . 4 μ 1,0. 297mmol, 3eq) in DMF was added under an argon atmosphere. 将反应混合物在室温搅拌过夜。 The reaction mixture was stirred at room temperature overnight. 按照实施例20的相似的方法纯化反应混合物以产生固体(35. 6mg,69. 6% )。 The reaction mixture in a similar manner as in Example 20 to produce purified solid (35. 6mg, 69. 6%).

[0935] IR(KBr 片状沉淀物,cnT1) :3423,3086,2964,1655,1607,1420,1329,1275,1156 ; 1H NMR(400MHz, CDCl3) :7. 87 (d,J = 16. 0Hz,1H),7. 35 (d,J = 8. 0Hz,1H),7. 23 (s,1H), [0935] IR (KBr pellet, cnT1):. 3423,3086,2964,1655,1607,1420,1329,1275,1156; 1H NMR (400MHz, CDCl3): 7 87 (d, J = 16. 0Hz, 1H), 7. 35 (d, J = 8. 0Hz, 1H), 7. 23 (s, 1H),

7. 03 (dd, J = 17. 2,10. 8Hz, 1H),6· 93 (d, J = 9. 6Hz, 1H),6· 87 (d, J = 8. OHz, 1H),6· 84 (s, 1Η) ,5. 66 (d, J = 17. 6Ηζ, 1Η), 5. 29 (d, J = 10. 8Hz,1Η),4. 47-4. 41 (m,3Η),3. 88 (t,J = 5. 6Ηζ,2Η),3· 49 (t, J = 8. 0Ηζ,2Η),2· 95(s,3H),1. 96-1. 93 (m. 2Η),1. 75-1. 74 (m. 2Η), 7. 03 (dd, J = 17. 2,10. 8Hz, 1H), 6 · 93 (d, J = 9. 6Hz, 1H), 6 · 87 (d, J = 8. OHz, 1H), 6 · 84 (s, 1Η), 5. 66 (d, J = 17. 6Ηζ, 1Η), 5. 29 (d, J = 10. 8Hz, 1Η), 4. 47-4. 41 (m, 3Η) , 3. 88 (t, J = 5. 6Ηζ, 2Η), 3 · 49 (t, J = 8. 0Ηζ, 2Η), 2 · 95 (s, 3H), 1. 96-1. 93 (m. 2Η), 1. 75-1. 74 (m. 2Η),

1. 22(s,9H) 1. 22 (s, 9H)

[0936] 实施例41 :3-[4-叔丁基-2-(四氢吡喃_4_基氧基)苯基]-N-(3_氟_4_甲烷磺酰基氨基-5-乙烯基苄基)丙酰胺 [0936] Example 41: 3- [4-tert-butyl-2- (tetrahydropyran-_4_-yloxy) phenyl] -N- (3_-fluoro-5- methanesulfonyl _4_ vinyl benzyl) propanamide

[0937] [0937]

Figure CN101142174BD00801

[0938] 步骤1 :3-[4_叔丁基-2-(四氢吡喃_4_基氧基)苯基]丙酸甲基酯 [0938] Step 1: 3- [4_-tert-butyl-2- (tetrahydropyran-_4_-yloxy) phenyl] propionic acid methyl ester

[0939] 将3-[4_叔丁基-2-(四氢吡喃-4-基氧基)苯基]丙烯酸甲基酯(14. ^ig, 0. 045mmole)和IOwt. %的钯加入MeOH。 [0939] 3- [4_ tert-butyl-2- (tetrahydropyran-4-yloxy) phenyl] acrylic acid methyl ester (14. ^ ig, 0. 045mmole) and IOwt.% Palladium adding MeOH. 将反应混合物在氢气气氛下搅拌过夜。 The reaction mixture was stirred under a hydrogen atmosphere overnight. 用C盐垫过滤反应混合物。 The reaction mixture was filtered with Celite pad C. 将滤液在真空中浓缩并用柱色谱法纯化以产生糖浆(14. Img,97. 3% )。 The filtrate was concentrated and purified by column chromatography to yield a syrup in vacuo (14. Img, 97. 3%).

[0940] 1H 匪lU400MHz,CDCl3) : δ 7. 01 (d, J = 8. 4Hz, 1H) ,6. 83 (dd, J = 8·0,1·6Ηζ, 1H),6. 78(d,J = 1. 6Hz,1Η),4. 48(setp,J = 3. 6Hz,1Η),3. 90 (setp,J = 3. 6Ηζ,2Η), 3. 60 (s,3Η),3. 56 (setp, J = 3. 6Ηζ,2Η),2. 85 (t, J = 8. 0Hz,2Η),2. 56 (t, J = 8. 0Hz,2Η), [0940] 1H bandit lU400MHz, CDCl3): δ 7. 01 (d, J = 8. 4Hz, 1H), 6 83 (dd, J = 8 · 0,1 · 6Ηζ, 1H), 6 78 (d.. , J = 1. 6Hz, 1Η), 4. 48 (setp, J = 3. 6Hz, 1Η), 3. 90 (setp, J = 3. 6Ηζ, 2Η), 3. 60 (s, 3Η), 3 . 56 (setp, J = 3. 6Ηζ, 2Η), 2. 85 (t, J = 8. 0Hz, 2Η), 2. 56 (t, J = 8. 0Hz, 2Η),

2. 00-1. 93 (m, 2Η),1. 79-1. 71 (m, 2H),1. 23 (s,9H) 2. 00-1. 93 (m, 2Η), 1. 79-1. 71 (m, 2H), 1. 23 (s, 9H)

[0941]步骤 2: [0941] Step 2:

[0942] 3-[4_叔丁基-2-(四氢吡喃-4-基氧基)苯基]_N_(3_氟_4_甲烷磺酰基氨基-5-乙烯基苄基)丙酰胺 [0942] 3- [4_ tert-butyl-2- (tetrahydropyran-4-yloxy) phenyl] _N_ (3_ _4_ methanesulfonyl-fluoro-5-vinylbenzyl-yl) propan- amide

[0943] 将3-[4_叔丁基-2-(四氢吡喃-4-基氧基)苯基]丙酸甲基酯(14. Img, [0943] 3- [4_ tert-butyl-2- (tetrahydropyran-4-yloxy) phenyl] propionic acid methyl ester (14. Img,

0. 044mmol, leq)和氢氧化钠(8. 8mg,0. 220mmole, 5eq)加入甲醇和H20。 0. 044mmol, leq) and sodium hydroxide (8. 8mg, 0. 220mmole, 5eq) was added methanol and H20. 将反应混合物搅拌12小时。 The reaction mixture was stirred for 12 hours. 用5% HCl溶液酸化反应混合物。 The reaction mixture was acidified with 5% HCl solution. 将反应混合物在真空中浓缩以产生3-[4_叔丁基-2-(四氢吡喃-4-基氧基)苯基]丙酸(13. 5mg,100% )0 The reaction mixture was concentrated in vacuo to yield 3- [4 _ t-butyl-2- (tetrahydropyran-4-yloxy) phenyl] propionic acid (13. 5mg, 100%) 0

[0944] 将3-[4-叔丁基-2-(四氢吡喃-4-基氧基)苯基]丙酸(0. 044mmol,leq. ),二乙基氰基膦8. 0 μ 1 (0. 053mmol, 1. 2eq),N-(4-氨基甲基_2_氟_6_乙烯基苯基)甲烷磺酰胺19. Omg(0. 053mmol, 1. 2eq.),和TEA(18. 4 μ 1,0. 132mmol,3eq)在氩气气氛下加入DMF。 [0944] 3- [4-tert-butyl-2- (tetrahydropyran-4-yloxy) phenyl] propionic acid (0. 044mmol, leq.), Diethyl cyanophosphonate 8.0 μ 1 (0. 053mmol, 1. 2eq), N- (4- aminomethyl-fluoro _6_ _2_ vinylphenyl) methanesulfonamide 19. Omg (0. 053mmol, 1. 2eq.), and TEA (18. 4 μ 1,0. 132mmol, 3eq) in DMF was added under an argon atmosphere. 将反应混合物在室温搅拌过夜。 The reaction mixture was stirred at room temperature overnight. 在真空中去除DMF。 The DMF was removed in vacuo. 用KOAc提取残余物。 Residue was extracted with KOAc. 将残余物用盐水洗涤,通过硫酸钠干燥,并在真空中浓缩。 The residue was washed with brine, dried over sodium sulfate, and concentrated in vacuo. 用柱色谱法(己烷:KOAc =1:1)纯化残余物以产生固体(23. 4mg,99. 8% )„ By column chromatography (hexane: KOAc = 1: 1) to give a solid residue was purified (23. 4mg, 99 8%.) "

[0945] IR (KBr 片状沉淀物,cnT1) :3423,3086,2964,1655,1607,1420,1329,1275,1156 ;1H NMR(400MHz, CDCl3) :7. 21 (s,1H),7. 16-7. 01 (m,2H),6. 91 (s,1H),6. 85 (d,J = 8. OHz, 1H), 6. 32 (s,1H),5· 97 (s,1Η),5· 69 (d, J = 17. 6Hz, 1H),5· 36 (d, J = 11. 2Hz, 1Η),4· 44 (sept, J = 3. 6Hz, 1Η) ,4. 33 (d, J = 6. 0Ηζ,2Η) ,3. 87 (sept, J = 3. 6Hz, 1Η), 3. 51 (sept, J = [0945] IR (KBr pellet, cnT1): 3423,3086,2964,1655,1607,1420,1329,1275,1156; 1H NMR (400MHz, CDCl3): 7 21 (s, 1H), 7. . 16-7. 01 (m, 2H), 6. 91 (s, 1H), 6. 85 (d, J = 8. OHz, 1H), 6. 32 (s, 1H), 5 · 97 (s , 1Η), 5 · 69 (d, J = 17. 6Hz, 1H), 5 · 36 (d, J = 11. 2Hz, 1Η), 4 · 44 (sept, J = 3. 6Hz, 1Η), 4 . 33 (d, J = 6. 0Ηζ, 2Η), 3. 87 (sept, J = 3. 6Hz, 1Η), 3. 51 (sept, J =

3. 6Ηζ,2Η),2. 98 (s,3H),2. 91-2. 87 (m. 3Η),2. 50 (t, J = 7. 2Hz,2H),1. 96-1. 91 (m, 2H), 3. 6Ηζ, 2Η), 2. 98 (s, 3H), 2. 91-2. 87 (m. 3Η), 2. 50 (t, J = 7. 2Hz, 2H), 1. 96-1. 91 (m, 2H),

1. 73-1. 65(m,2H),1. 22(s,9H). 1. 73-1. 65 (m, 2H), 1. 22 (s, 9H).

[0946] 实施例42 : [0946] Example 42:

[0947] (R)-3_(4-叔丁基苯基)-N-[l_(4-甲烷磺酰基氨基-3-乙烯基苯基)乙基]_2_甲 [0947] (R) -3_ (4- tert-butylphenyl) -N- [l_ (4- methanesulfonyl-3-vinylphenyl) ethyl] _2_ A

基丙烯酰胺 Acrylamide

[0948] [0948]

Figure CN101142174BD00811

[0949] 将N- W- (1-氨基乙基)-2-乙烯基苯基]甲烷磺酰胺(0. 26mmol, 58. 6mg), 3-(4-叔丁基苯基)-2-甲基丙烯酸(0. 28mmol,62. 13mg),DEPC(1. 2eq,0. 31mmol, 47. !Μμ 1),和TEAQeq,0. 52mmol,72. 48μ 1)在氩气气氛下加入DMF。 [0949] The N- W- (1- aminoethyl) -2-vinylphenyl] methanesulfonamide (0. 26mmol, 58. 6mg), 3- (4- tert-butylphenyl) -2- methacrylic acid (0. 28mmol, 62. 13mg), DEPC (1. 2eq, 0. 31mmol, 47.! Μμ 1), and TEAQeq, 0. 52mmol, 72. 48μ 1) in DMF was added under an argon atmosphere. 将反应混合物搅拌12小时。 The reaction mixture was stirred for 12 hours. 按照实施例22的相似的方法纯化反应混合物以产生固体(60. 8mg, 54. 87% )。 The reaction mixture in a similar manner as in Example 22 to produce purified solid (60. 8mg, 54. 87%).

[0950] [ α ]d20-24. 96 (CHCl3, c 0. 125) ;Mp :97 〜99°C ; [0950] [α] d20-24 96 (CHCl3, c 0. 125); Mp:. 97 ~99 ° C;

[0951] IR(KBr 片状沉淀物,cnT1) :3272,2964,1646,1322 ; [0951] IR (KBr pellet, cnT1): 3272,2964,1646,1322;

[0952] 1H NMR(400MHz, CDCl3) : δ 7. 45 (d, 1H, J = 2. OHz),7. 39 (s, 1H),7. 36(d,2H,J = 8. 0Hz),7. 30 (s,1H),7. 25 (d, 2H, J = 8. OHz),6. 91 (dd, 1H, J = 17. 2,11. 2Hz),6. 72 (s, 1H), 6. 14 (d, 1H, J = 7. 6Hz) ,5. 69 (d, 1H, J = 17. 2Hz),5. 42 (d, 1H, J = 11. 2Hz),5. 18(五重峰, 1H, J = 6. 8Hz),2. 94 (s, 3H),2. 09 (s, 3H),1. 52 (d, 3H, J = 6. 8Hz),1. 30 (s,9H) · [0952] 1H NMR (400MHz, CDCl3):.. Δ 7. 45 (d, 1H, J = 2. OHz), 7 39 (s, 1H), 7 36 (d, 2H, J = 8. 0Hz) , 7. 30 (s, 1H), 7. 25 (d, 2H, J = 8. OHz), 6. 91 (dd, 1H, J = 17. 2,11. 2Hz), 6. 72 (s, 1H), 6. 14 (d, 1H, J = 7. 6Hz), 5. 69 (d, 1H, J = 17. 2Hz), 5. 42 (d, 1H, J = 11. 2Hz), 5. 18 (quintet, 1H, J = 6. 8Hz), 2. 94 (s, 3H), 2. 09 (s, 3H), 1. 52 (d, 3H, J = 6. 8Hz), 1. 30 (s, 9H) ·

[0953] 实施例43 : 3- (4-叔丁基苯基)-N- (3_氟_4_甲烷磺酰基氨基_5_乙烯基苄基)-2-甲基丙酰胺 [0953] Example 43: 3- (4-tert-butylphenyl) -N- (3_ fluoro _4_ _5_ methanesulfonylamino-vinylbenzyl) -2-methyl-propanamide

[0954] [0954]

Figure CN101142174BD00812

[0955] 步骤1 :3-(4-叔丁基苯基)-2-甲基丙酸 [0955] Step 1: 3- (4-tert-butylphenyl) -2-methylpropanoic acid

[0956] 将3-(4-叔丁基苯基)-2-甲基丙烯酸9mg,0. 19mmol)和IOwt. %钯碳加入甲醇。 [0956] 3- (4-tert-butylphenyl) -2-methyl-acrylic acid 9mg, 0. 19mmol) and IOwt.% Methanol was added palladium on carbon. 在H2气体下将反应混合物搅拌5小时。 The reaction mixture was stirred under H2 gas for 5 hours. 用C盐过滤反应混合物。 The reaction mixture was filtered with a salt C. 将滤液在真空中浓缩以获得标题化合物(39. Img,93. 47% ) „ 1H 匪RQOOMHz,CD3OD) : δ 7. 25(d,2H,J = 8. 4Hz), 7. 07 (d, 2H, J = 8. 4Hz),2. 92 (q, 1H, J = 6. 4Hz),2· 67 〜2. 54 (m, 2Η),1. 25 (s,9H),1. 08 (d, 3H, J = 6. 8Hz). The filtrate was concentrated in vacuo to give the title compound (39. Img, 93 47%.) "1H bandit RQOOMHz, CD3OD): δ 7. 25 (d, 2H, J = 8. 4Hz), 7. 07 (d, 2H, J = 8. 4Hz), 2. 92 (q, 1H, J = 6. 4Hz), 2 · 67 ~2. 54 (m, 2Η), 1. 25 (s, 9H), 1. 08 ( d, 3H, J = 6. 8Hz).

[0957] 步骤2 : 3-(4-叔丁基苯基)-N-(3-氟-4-甲烷磺酰基氨基_5_乙烯基苄基)_2_甲基丙酰胺 [0957] Step 2: 3- (4-tert-butylphenyl) -N- (3- Fluoro-4-ylamino _5_ vinylbenzyl) _2_ methylpropionamide

[0958] 将N-(4-氨基甲基-2-氟-6-乙烯基苯基)甲烷磺酰胺(0. lOmmol,;35. Omg), 3-(4-叔丁基苯基)-2-甲基丙酸(0. Ilmmol, 23. 65mg), DEPC(0. 12mmol, 18. 21 μ 1),和TEA(0. 20mmol,27. 8 μ 1)在氩气气氛下加入DMF。 [0958] The N- (4- amino-2-fluoro-6-vinylphenyl) methanesulfonamide (. 0. lOmmol,; 35 Omg), 3- (4- tert-butylphenyl) - 2-methylpropanoic acid (0. Ilmmol, 23. 65mg), DEPC (0. 12mmol, 18. 21 μ 1), and TEA (0. 20mmol, 27. 8 μ 1) in DMF was added under an argon atmosphere. 将反应混合物搅拌12小时。 The reaction mixture was stirred for 12 hours. 按照实施例21的相似的方法纯化反应混合物以产生固体(37. Img,83. 14% )。 The reaction mixture in a similar manner as in Example 21 to produce purified solid (37. Img, 83. 14%).

[0959] mp:156 〜158°C ;IR(KBr 片状沉淀物,cnT1) :3288,3229,2964,1647,1321,1155 [0959] mp: 156 ~158 ° C; IR (KBr pellet, cnT1): 3288,3229,2964,1647,1321,1155

[0960] 1H 匪lU400MHz,CDCl3) : δ 7. 26 (d,2H, J = 8. 4Hz),7· 20 (s,1H),7· 10 (dd,1H,J =17. 6,11. 2Hz),7· 06(d,2H,J = 8. 4Hz) ,6. 79 (dd, 1H, J = 10. 4,1. 6Hz) ,6. 20 (s, 1H), 5. 72 (d, 1H, J = 17. 2Hz),5. 67 (t, 1H, J = 6. 0Hz),5. 40 (d, 1H, J = 11. 2Hz),4. 30 (d, 2H, J = 6. 0Hz),3. 02 (s,3H),3. 00 〜2. 89 (m, 1H),2· 66 〜2. 60 (m, 1H),2· 51 〜2. 43 (m, 1H), 1. 26 (s,9H),1. 19 (d, 3H, J = 6. 8Hz) ·[0961] 实施例44 :N-{4-[3-(4-氯苄基)脲基甲基]_2_乙烯基苯基}甲烷磺酰胺 [0960] 1H bandit lU400MHz, CDCl3): δ 7. 26 (d, 2H, J = 8. 4Hz), 7 · 20 (s, 1H), 7 · 10 (dd, 1H, J = 17 6,11. . 2Hz), 7 · 06 (d, 2H, J = 8. 4Hz), 6. 79 (dd, 1H, J = 10. 4,1. 6Hz), 6. 20 (s, 1H), 5. 72 (d, 1H, J = 17. 2Hz), 5. 67 (t, 1H, J = 6. 0Hz), 5. 40 (d, 1H, J = 11. 2Hz), 4. 30 (d, 2H, J = 6. 0Hz), 3. 02 (s, 3H), 3. 00 ~2. 89 (m, 1H), 2 · 66 ~2. 60 (m, 1H), 2 · 51 ~2. 43 ( . m, 1H), 1. 26 (s, 9H), 1 19 (d, 3H, J = 6. 8Hz) · [0961] Example 44: N- {4- [3- (4- chlorobenzyl ) ureido methyl] _2_ vinylphenyl} methanesulfonamide

[0962] [0962]

Figure CN101142174BD00821

[0963] 如在路线12中所述,甲烷磺酰基氨基-3-乙烯基苄基)氨基甲酸叔丁酯(50mg,0. 153mmol)和三乙胺(0. Iml)和4-氯苄胺(26mg)在乙腈溶剂存在情况下搅拌一夜。 [0963] As described in Scheme 12, methanesulfonylamino-3-vinyl-benzyl) carbamate (50mg, 0. 153mmol) and triethylamine (0. Iml) and 4-chloro benzylamine (26mg) in acetonitrile was stirred overnight in the presence of a solvent. 从反应混合物中去除溶剂,并通过柱色谱法纯化以产生目的化合物(9mg)。 The solvent was removed from the reaction mixture and purified by column chromatography to yield the desired compound (9mg).

[0964] 1H NMR (300MHz, CDCl3) :7. 45 (s,1H),7· 41 (m,2H),7· 29 (m,4H),6· 90 (dd,1H,J =17. 7,11. 1Hz) ,6. 44 (bs, 1H) ,5. 73 (d, 1H, J = 17. 4Hz),5. 55 (s,1H),5. 48 (d,1H,J = 11. 1Hz),4. 90 (bs, 1H), 4. 34 (m, 4H), 2. 99(s,3H) [0964] 1H NMR (300MHz, CDCl3):. 7 45 (s, 1H), 7 · 41 (m, 2H), 7 · 29 (m, 4H), 6 · 90 (dd, 1H, J = 17. 7,11. 1Hz), 6. 44 (bs, 1H), 5. 73 (d, 1H, J = 17. 4Hz), 5. 55 (s, 1H), 5. 48 (d, 1H, J = 11. 1Hz), 4. 90 (bs, 1H), 4. 34 (m, 4H), 2. 99 (s, 3H)

[0965] 实施例45 :3-½-(叔丁基)苯基]-N44-(甲烷磺酰基氨基)_3_乙烯基苄基]丙酰胺 [0965] Example 45: 3-½- (t-butyl) phenyl] -N44- (methane-sulfonylamino) _3_ vinyl benzyl] propanamide

[0966] [0966]

Figure CN101142174BD00822

[0967] 步骤1 :叔丁基甲烷磺酰基氨基)-3-乙烯基苄基]氨基甲酸酯 [0967] Step 1: tert-butyl-methanesulfonyl-amino) -3-vinylbenzyl] carbamate

[0968] 将叔丁基甲烷磺酰基氨基)-3-碘苄基]氨基甲酸酯(1.0g,2.3mmOl)溶解于甲苯(20mL)。 [0968] The tert-butyl-methanesulfonyl-amino) -3-iodo-benzyl] carbamate (1.0g, 2.3mmOl) was dissolved in toluene (20mL). 三丁基乙烯基锡(0. 8mL,2. aiimol)和Pd (PPh3) 4 (140mg,0. 12mmol)逐滴加入。 Tributylvinyltin (0. 8mL, 2. Aiimol) and Pd (PPh3) 4 (140mg, 0. 12mmol) was added dropwise. 在回流中将反应混合物搅拌4小时。 In the reaction mixture was refluxed for 4 hours. 在真空中去除甲苯。 Toluene was removed in vacuo. 用KOAc提取残余物。 Residue was extracted with KOAc. 用H2O,盐水洗涤合并的有机层,通过MgSO4干燥,并在真空中浓缩。 The organic layer was H2O, washed with brine, dried over MgSO4, and concentrated in vacuo. 将残余物用柱色谱法(EtOAc :正己烷=1 : 2)纯化以产生标题化合物(740mg,97%)。 The residue was purified by column chromatography (EtOAc in: n-hexane = 1: 2) to give the title compound (740mg, 97%).

[0969] 1H-NMR(300MHz, CDCl3) : δ 1. 44(s,9H) ,2. 96(s,3H) ,4. 29 d,2H,J = 5. 9Hz), 4. 86 (bs, 1H) ,5. 46 (dd, 1H, J = 11. 0,0. 93Hz),5. 71 (dd,1H,J = 17. 0,0. 93Hz) ,6. 32 (bs, 1H) ,6. 87 (dd, 1H, J = 17. 0,11. 0Hz),7. 20 (dd, 1H, J = 8. 3,1. 8Hz),7. 38 (d, 1H, J = 2. 0Hz),7.41(d,lH,J = 8. 2Hz) [0969] 1H-NMR (300MHz, CDCl3):.. Δ 1. 44 (s, 9H), 2 96 (s, 3H), 4 29 d, 2H, J = 5. 9Hz), 4. 86 (bs , 1H), 5. 46 (dd, 1H, J = 11. 0,0. 93Hz), 5. 71 (dd, 1H, J = 17. 0,0. 93Hz), 6. 32 (bs, 1H) , 6. 87 (dd, 1H, J = 17. 0,11. 0Hz), 7. 20 (dd, 1H, J = 8. 3,1. 8Hz), 7. 38 (d, 1H, J = 2 . 0Hz), 7.41 (d, lH, J = 8. 2Hz)

[0970] 步骤2 :NW-(氨基甲基)-2-乙烯基苯基]甲烷磺酰胺 [0970] Step 2: NW- (aminomethyl) -2-vinylphenyl] methanesulfonamide

[0971] 将叔丁基甲烷磺酰基氨基)-3-乙烯基苄基]氨基甲酸酯(lOOmg, 0. 23mmol)和TFA(Ojml)加入二氯甲烷QmL)。 [0971] The tert-butyl-methanesulfonyl-amino) -3-vinylbenzyl] carbamate (lOOmg, 0. 23mmol) and TFA (Ojml) was added dichloromethane QmL). 将反应混合物在室温过夜搅拌。 The reaction mixture was stirred at room temperature overnight. 将反应混合物在真空中浓缩以产生标题化合物(100% )。 The reaction mixture was concentrated in vacuo to give the title compound (100%).

[0972] 步骤3 :344-(叔丁基)苯基]-N44-(甲烷磺酰基氨基)_3_乙烯基苄基]丙酰胺 [0972] Step 3: 344- (t-butyl) phenyl] -N44- (methane-sulfonylamino) _3_ vinyl benzyl] propanamide

[0973] 将NW-(氨基甲基)-2-乙烯基苯基]甲烷磺酰胺(0. 23mol)悬浮在二氯甲烷中并用三乙胺,随后用3-(4-叔丁基-苯基)-丙酸和DMTMMGOmg)处理。 [0973] The NW-(aminomethyl) -2-vinylphenyl] methanesulfonamide (0. 23mol) was suspended in dichloromethane and treated with triethylamine, followed by 3- (4-tert-butyl - benzene yl) - propionic acid and DMTMMGOmg) process. 将得到的混合物在环境温度下搅拌2天并在减压下浓缩。 The resulting mixture was stirred at ambient temperature for 2 days and concentrated under reduced pressure. 粗制的残余物进行柱色谱法(己烷/乙酸乙酯= 3/2)以产生白色固体(73%)。 The crude residue was subjected to column chromatography (hexane / ethyl acetate = 3/2) to give a white solid (73%). [0974] 1H-WrGOOMHz, CDCl3) : δ 1. 28(s,9H) ,2. 51 (t,2H, J = 7. 6Hz) ,2. 92-2. 97 (m, 5H),4. 38(d,2H,J = 5. 9Hz),5. 47 (d,1H,J = 11. 0Hz), 5. 62 (bs, 1H) ,5. 69 (d, 1H, J = 18. OHz), 6. 23 (bs, 1H), 6. 84 (dd, 1H, J = 17. 0,11. OHz),7. 09-7. 14 (m,3H),7. 25-7. 41 (m, 4H) [0974] 1H-WrGOOMHz, CDCl3):. Δ 1. 28 (s, 9H), 2 51 (t, 2H, J = 7. 6Hz), 2 92-2 97 (m, 5H), 4... 38 (d, 2H, J = 5. 9Hz), 5. 47 (d, 1H, J = 11. 0Hz), 5. 62 (bs, 1H), 5. 69 (d, 1H, J = 18. OHz ), 6. 23 (bs, 1H), 6. 84 (dd, 1H, J = 17. 0,11. OHz), 7. 09-7. 14 (m, 3H), 7. 25-7. 41 (m, 4H)

[0975] IR(纯的knT1 1 3295,2960,1648,1541,1324,1152 [0975] IR (neat knT1 1 3295,2960,1648,1541,1324,1152

[0976] Mass (FAB) :415 [M+H] + [0976] Mass (FAB): 415 [M + H] +

[0977] 实施例46 : [0977] Example 46:

[0978] 3-W-(叔丁基)苯基]-N-[3-氟-4-(甲烷磺酰基氨基)_5_乙烯基苄基]丙酰胺 [0978] 3-W- (tert-butyl) phenyl] -N- [3- fluoro-4- (methane-sulfonylamino) _5_ vinyl benzyl] propanamide

[0979] [0979]

Figure CN101142174BD00831

[0980] 将标题化合物(63% )按照类似于用于合成实施例45的方法的方法进行合成。 [0980] The title compound (63%) was synthesized according to the method of Example 45 for the synthesis of similar embodiments.

[0981] 1H-NMR(300MHz, CDCl3) : δ 1. 28(s,9H) ,2. 52(t,2H, J = 7. 6Hz),2· 96 (t,2H, J = 7. 7Hz),3· 05(s,3H),4· 39(d,2H,J = 6. OHz) ,5. 44 (d, 1H, J = 11. 0Hz) ,5. 69 (bs, 1H),5. 76 (d, 1H, J = 17. 0Hz),5. 92 (bs, 1H),6. 92 (d, 1H, J = 10. OHz),7. 08-7. 18 (m, 3H), 7. 22-7. 32(m,3H) [0981] 1H-NMR (300MHz, CDCl3):. Δ 1. 28 (s, 9H), 2 52 (t, 2H, J = 7. 6Hz), 2 · 96 (t, 2H, J = 7. 7Hz ), 3 · 05 (s, 3H), 4 · 39 (d, 2H, J = 6. OHz), 5. 44 (d, 1H, J = 11. 0Hz), 5. 69 (bs, 1H), 5. 76 (d, 1H, J = 17. 0Hz), 5. 92 (bs, 1H), 6. 92 (d, 1H, J = 10. OHz), 7. 08-7. 18 (m, 3H ), 7. 22-7. 32 (m, 3H)

[0982] IR(纯的)cmDl 3233,2922,1646,1540,1317,1151 [0982] IR (neat) cmDl 3233,2922,1646,1540,1317,1151

[0983] Mass (FAB) 433 [M+H] + [0983] Mass (FAB) 433 [M + H] +

[0984] 实施例47 : [0984] Example 47:

[0985] 3- (4-叔丁基-苯基)-N- (3-乙炔基_5_氟_4_甲烷磺酰基氨基-苄基)_丙酰胺 [0985] 3- (4-tert-butyl - phenyl) -N- (3- ethynyl _5_ _4_ methanesulfonylamino-fluoro-benzyl) - propanamide _

[0986] [0986]

Figure CN101142174BD00832

[0987] 将标题化合物(90% )按照类似于用于合成实施例45的方法的方法进行合成。 [0987] The title compound (90%) was synthesized according to the method of Example 45 for the synthesis of similar embodiments.

[0988] 1H-NMR (300MHz, CDCl3) : δ 1. 28(s,9H) ,2. 49 〜2. 54 (t,2H),2. 92 〜2. 97 (t, 2H) 3. 23 (s,3H),3. 46 (s, 1H),4. 32 (d, 2H, J = 6. IHz),5. 68 (bs, 1H),6. 39 (bs, 1H),6. 99 〜 7. 02 (d, 2H, J = 10. 6 Hz),7. 09 〜7. 18 (m, 3H),7. 28 〜7. 31 (m, 2H) [0988] 1H-NMR (300MHz, CDCl3):.. Δ 1. 28 (s, 9H), 2 49 ~2 54 (t, 2H), 2 92 ~2 97 (t, 2H) 3. 23.. (s, 3H), 3. 46 (s, 1H), 4. 32 (d, 2H, J = 6. IHz), 5. 68 (bs, 1H), 6. 39 (bs, 1H), 6. 99 ~ 7. 02 (d, 2H, J = 10. 6 Hz), 7. 09 ~7. 18 (m, 3H), 7. 28 ~7. 31 (m, 2H)

[0989] IR(纯的)cm-l 3269,2959,1581,1482,1332,1154 [0989] IR (neat) cm-l 3269,2959,1581,1482,1332,1154

[0990] Mass (FAB+) 431 [M+H] + [0990] Mass (FAB +) 431 [M + H] +

[0991] 实施例48: [0991] Example 48:

[0992] N- {4- [3- (4-叔丁基-苄基)_脲基甲基]_5_甲氧基_2_乙烯基-苯基}-甲烷磺酰胺 [0992] N- {4- [3- (4- tert-butyl-benzyl) - _ ureidomethyl] _5_ methoxy _2_ vinyl - phenyl} - methanesulfonamide

[0993] [0993]

Figure CN101142174BD00841

[0994] 步骤1 : 氨基-2-甲氧基-苄基)-氨基甲酸叔丁酯 [0994] Step 1: 2-methoxy - benzyl) - carbamic acid tert-butyl ester

[0995] 将2-甲氧基-4-硝基-苄腈(1. 78g,IOmmol)和Pd/C (4小勺)悬浮在包含c-HCl 的MeOH中,将所述混合物在40psi氢压下进行氢化4小时。 [0995] 2-methoxy-4-nitro - benzonitrile (1. 78g, IOmmol) and Pd / C (4 tsp) was suspended in MeOH in comprising c-HCl, the mixture was 40psi hydrogen pressure hydrogenation for 4 hours. 将反应混合物通过C盐过滤,将滤液在减压下浓缩以产生黄色固体(1.58g,70%)。 The reaction mixture was filtered through a C salt, and the filtrate was concentrated to give a yellow solid (1.58g, 70%) under reduced pressure. 将固体溶解于THF,将溶液冷却到0°C。 The solid was dissolved in THF, the solution was cooled to 0 ° C. 将三乙胺(1. 43g,14mmol)加入溶液,随后加入Boc2O,在环境温度将反应混合物搅拌过夜。 Triethylamine (1. 43g, 14mmol) was added, followed by addition of Boc2O, the reaction mixture was stirred at ambient temperature overnight. 通过加入水和KOAc来猝灭反应,分离有机相。 By adding water and the reaction was quenched with KOAc, the organic phase was separated. 用KOAc提取水相三次,并用盐水洗涤合并的有机层,通过无水MgS04干燥,过滤,在减压下浓缩。 KOAc aqueous phase was extracted with three times, and the organic layer was washed with brine, dried over anhydrous MgS04, filtered, and concentrated under reduced pressure. 将粗制残余物进行柱色谱法(己烷/乙酸乙酯=1/1到1/2)以产生白色固体(1.3g,73% )。 The crude residue was subjected to column chromatography (hexane / ethyl acetate = 1/1 to 1/2) to give a white solid (1.3g, 73%).

[0996] 1HNMR(300MHz, CDCl3) :7.03(d,lH,J = 8. 4Hz),6. 23 (m,2H),4. 91 (bs,1H), [0996] 1HNMR (300MHz, CDCl3):.. 7.03 (d, lH, J = 8. 4Hz), 6 23 (m, 2H), 4 91 (bs, 1H),

4. 18 (d, 2H, J = 5. 7Hz),3. 78 (s, 3H),3. 72 (bs, 2H),1. 44 (s,9H) · 4. 18 (d, 2H, J = 5. 7Hz), 3. 78 (s, 3H), 3. 72 (bs, 2H), 1. 44 (s, 9H) ·

[0997] 步骤2 : (4-氨基-5-碘-2-甲氧基-苄基)_氨基甲酸叔丁酯 [0997] Step 2: (4-amino-5-iodo-2-methoxy - benzyl) carbamate _

[0998] 在0°C,向碘和AgNO2在二氯甲烷中的混悬液加入(4-氨基-2-甲氧基-苄基)_氨基甲酸叔丁酯(1. 3g,5. 15mmol)在二氯甲烷中的溶液,并将混合物在0°C搅拌30分钟,在环境温度下再搅拌30分钟。 [0998] at 0 ° C, was added (4-amino-2-methoxy - benzyl) iodide and the suspension AgNO2 dichloromethane _ carbamate (1. 3g, 5 15mmol. ) in dichloromethane and the mixture was stirred at 0 ° C 30 minutes and was stirred at ambient temperature for 30 minutes. 用Na2S2O3猝灭反应。 The reaction was quenched with Na2S2O3. 将反应溶液用二氯甲烷提取,用水和盐水洗涤,通过无水MgS04干燥,过滤并在减压下浓缩。 The reaction solution was extracted with dichloromethane, washed with water and brine, dried over anhydrous MgS04, filtered and concentrated under reduced pressure. 将获得的液体进行柱色谱法(己烷/乙酸乙酯=2/1)以产生(4-氨基-5-碘-2-甲氧基-苄基)-氨基甲酸叔丁酯(925mg,47%)。 The liquid obtained was subjected to column chromatography (hexane / ethyl acetate = 2/1) to give (4-amino-5-iodo-2-methoxy - benzyl) - carbamate (925mg, 47 %).

[0999] 1HNMR (300MHz, CDC13) :7. 45 (s,1H),6. 28 (s,1H),4. 88 (bs,1H),4. 14 (d,2H,J = 6. 0Hz),4. 08 (bs, 2H),3. 77 (s, 3H),1. 45 (s,9H) · [0999] 1HNMR (300MHz, CDC13):.... 7 45 (s, 1H), 6 28 (s, 1H), 4 88 (bs, 1H), 4 14 (d, 2H, J = 6. 0Hz ), 4. 08 (bs, 2H), 3. 77 (s, 3H), 1. 45 (s, 9H) ·

[1000] 步骤3 : (4-氨基-2-甲氧基-5-乙烯基-苄基)-氨基甲酸叔丁酯 [1000] Step 3: (4-Amino-5-vinyl-2-methoxy - benzyl) - carbamic acid tert-butyl ester

[1001] 在氩气下,向(4-氨基-5-碘-2-甲氧基-苄基)_氨基甲酸叔丁酯(700mg, 1. 85mmol)和三丁基乙烯基锡(783mg,2. 68mmol)在甲苯中的溶液加入Pd(PPh3)4(2Hmg, 0. 19mmol)。 [1001] Under argon, a solution of (4-amino-5-iodo-2-methoxy-benzyl) - _ carbamate (700mg, 1. 85mmol) and tributylvinyltin (783 mg, 2. 68mmol) in toluene was added Pd (PPh3) 4 (2Hmg, 0. 19mmol). 在回流的情况下,将得到的混合物加热8小时,通过C盐过滤,接着在减压下浓缩。 The mixture was under reflux, was heated for 8 hours and filtered through a salt C, then concentrated under reduced pressure. 将粗制残余物进行柱色谱法(己烷/乙酸乙酯=2/1到1/1)以产生(4-氨基-2-甲氧基-5-乙烯基-苄基)-氨基甲酸叔丁酯(220mg,43% )0 The crude residue was subjected to column chromatography (hexane / ethyl acetate = 2/1 to 1/1) to give (4-amino-5-vinyl-2-methoxy - benzyl) - carbamic acid tert butyl ester (220mg, 43%) 0

[1002] 1HNMR(300MHz, CDC13) :7. 18 (s,1H),6. 67 (dd,1H,J = 11 禾口17Hz) ,6. 19 (s, 1H), [1002] 1HNMR (300MHz, CDC13):. 7 18 (s, 1H), 6 67 (dd, 1H, J = 11 Wo port 17Hz), 6 19 (s, 1H),..

5. 53 (dd, 1H, J = 0. 9 和17Hz),5· 20 (dd, 1H, J = 0. 9 和11Hz),4· 91 (bs, 1H),4· 20(d,2H,J =6. OHz),3. 79 (s,3Η),1. 44 (s,9H) · 5. 53 (dd, 1H, J = 0. 9 and 17Hz), 5 · 20 (dd, 1H, J = 0. 9 and 11Hz), 4 · 91 (bs, 1H), 4 · 20 (d, 2H , J = 6. OHz), 3. 79 (s, 3Η), 1. 44 (s, 9H) ·

[1003]步骤 4: [1003] Step 4:

[1004] (4-甲烷磺酰基氨基-2-甲氧基-5-乙烯基-苄基)_氨基甲酸叔丁酯 [1004] (4-methanesulfonylamino-2-methoxy-5-vinyl-benzyl) - carbamate _

[1005] 向氨基-2-甲氧基-5-乙烯基-苄基)_氨基甲酸叔丁酯Q20mg,0. 79mmol) 在二氯甲烷中的冰冷溶液中加入三乙胺(132L),随后加入甲烷磺酰氯(72L)。 [1005] To 2-methoxy-5-vinyl - benzyl) carbamate _ Q20mg, 0 79mmol) was added triethylamine (132L) in dichloromethane was ice-cooling, followed by was added methanesulfonyl chloride (72L). 将混合物加温到室温并搅拌4小时。 The mixture was warmed to room temperature and stirred for 4 hours. 用水猝灭反应,并将反应溶液用二氯甲烷提取,用水和盐水洗涤, 通过无水MgSO4干燥,过滤,并在减压下浓缩。 The reaction was quenched with water, and the reaction solution was extracted with dichloromethane, washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. 用IN Na0H/Me0H/THF(1/2/1)处理得到的残余物2小时,接着通过加入IN HCl进行中和。 (1/2/1) The resulting residue was treated IN Na0H / Me0H / THF 2 hours, followed by addition of IN HCl and. 在蒸发甲醇后,将水加入残余物。 After methanol was evaporated, water was added to the residue. 将得到的混合物用KOAc进行提取,将合并的有机层用盐水洗涤,通过无水MgS04干燥,过滤并在减压下浓缩。 The resulting mixture was subjected to extraction with KOAc, combined organic layers were washed with brine, dried over anhydrous MgS04, filtered and concentrated under reduced pressure. 将粗制的残余物进行柱色谱法(己烷/乙酸乙酯=1/1)以产生白色固体(260mg, 92% )。 The crude residue was subjected to column chromatography (hexane / ethyl acetate = 1/1) to give a white solid (260mg, 92%).

[1006] 1HNMR(300MHz, CDC13) :7. 38 (s,1H),7. 04 (s,1H),6. 77 (dd,1H,J = 11 禾口17Hz), 6. 52 (bs, 1H),5· 63 (d, 1Η, J = 17Ηζ),5· 37 (d, 1Η, J = IlHz),5. 02 (bs, 1Η),4· 28(d,2H,J = 6. OHz),3. 79 (s,3Η),2. 96 (s, 3Η),1. 45 (s,9H) · [1006] 1HNMR (300MHz, CDC13):. 7 38 (s, 1H), 7 04 (s, 1H), 6 77 (dd, 1H, J = 11 Wo port 17Hz), 6. 52 (bs,.. 1H), 5 · 63 (d, 1Η, J = 17Ηζ), 5 · 37 (d, 1Η, J = IlHz), 5. 02 (bs, 1Η), 4 · 28 (d, 2H, J = 6. OHz), 3. 79 (s, 3Η), 2. 96 (s, 3Η), 1. 45 (s, 9H) ·

[1007] 步骤5 :N-{4-[3-(4-叔丁基-苄基)-脲基甲基]-5-甲氧基_2_乙烯基-苯基}_甲烷磺酰胺 [1007] Step 5: N- {4- [3- (4- tert-butyl-benzyl) - - ureido methyl] -5-methoxy _2_ vinyl - phenyl} methanesulfonamide _

[1008] (4-甲烷磺酰基氨基-2-甲氧基-5-乙烯基-苄基)_氨基甲酸叔丁酯(220mg, 0. 73mmol)在二氯甲烷中的冰冷溶液用三氟乙酸(100mg,0. 88mmol)处理1小时,接着在减压下浓缩。 [1008] (4-methanesulfonylamino-2-methoxy-5-vinyl-benzyl) - _ carbamate (220mg, 0. 73mmol) in a solution of ice cold dichloromethane was treated with trifluoroacetic acid (100mg, 0. 88mmol) for 1 hour, then concentrated under reduced pressure. 将粗制残余物(100mg,0. 27mmol)的部分悬浮在二氯甲烷中并用三乙胺处理,随后用(4-叔丁基-苄基)_氨基甲酸苯酯(9aiig,0. 32mmol)处理。 The crude residue (. 100mg, 0 27mmol) was suspended in portions of dichloromethane and treated with triethylamine, followed by (4-tert-butyl-benzyl) - carbamate _ (. 9aiig, 0 32mmol) deal with. 将得到的混合物在回流的情况下加热3天,并在减压下浓缩。 The resulting mixture was heated under reflux for 3 days and concentrated under reduced pressure. 将粗制残余物进行柱色谱法(己烷/乙酸乙酯=1/2) 以产生白色固体(8.8mg,7.0% )。 The crude residue was subjected to column chromatography (hexane / ethyl acetate = 1/2) to give a white solid (8.8mg, 7.0%).

[1009] 1HNMR(300MHz, CDCl3) :7. 39 (s,1H),7· 34 (d,2H,J = 8. 1Hz),7· 24 (d,2H,J = 8. IHz),7· 00 (s,1H),6· 77 (dd, 1Η,J = 11 禾口17Ηζ),6· 59 (bs, 1Η),5. 63 (d, 1Η, J = 17Ηζ), [1009] 1HNMR (300MHz, CDCl3):. 7 39 (s, 1H), 7 · 34 (d, 2H, J = 8. 1Hz), 7 · 24 (d, 2H, J = 8. IHz), 7 · 00 (s, 1H), 6 · 77 (dd, 1Η, J = 11 Wo port 17Ηζ), 6 · 59 (bs, 1Η), 5. 63 (d, 1Η, J = 17Ηζ),

5. 37 (d, 1Η, J = 11Hz),4. 93 (bs, 1H),4. 77 (bs, 1H),4. 32(d,4H,J = 5. 1Hz),3. 76(s,3H), 2. 93(s,3H),1. 30(s,9H). 5. 37 (d, 1Η, J = 11Hz), 4. 93 (bs, 1H), 4. 77 (bs, 1H), 4. 32 (d, 4H, J = 5. 1Hz), 3. 76 ( s, 3H), 2. 93 (s, 3H), 1. 30 (s, 9H).

[1010] 实施例49: [1010] Example 49:

[1011] 3-(4-叔丁基-苯基)-N-甲烷磺酰基氨基-2-甲氧基-5-乙烯基-苄基)_丙 [1011] 3- (4-tert-butyl - phenyl) -N- methanesulfonylamino-2-methoxy-5-vinyl-benzyl) - propan _

烯酰胺 Enamide

[1012] [1012]

Figure CN101142174BD00851

[1013] 将4-甲烷磺酰基氨基-2-甲氧基-5-乙烯基-苄胺和在合成实施例48中制备的HCl盐(220mg,0. 73mmol)在二氯甲烷中的冰冷溶液用三氟乙酸(100mg,0. 88mmol))处理1 小时,接着在减压下浓缩。 [1013] 4- methanesulfonylamino-2-methoxy-5-vinyl - and benzylamine (. 220mg, 0 73mmol) in ice-cold solution of the HCl salt prepared in Synthesis Example 48 in dichloromethane 1 hour with trifluoroacetic acid (100mg, 0. 88mmol)), then concentrated under reduced pressure. 将粗制残余物的部分(50mg,0. 13mmol)悬浮在二氯甲烷中,并用三乙胺处理,随后用3-(4-叔丁基-苯基)_丙烯酸(30mg)和DMTMMGOmg)进行处理。 Part (. 50mg, 0 13mmol) crude residue was suspended in dichloromethane and treated with triethylamine followed by 3--- for (4-tert-butylphenyl) _ acrylic acid (30mg) and DMTMMGOmg) deal with. 将得到的混合物在环境温度下搅拌2天,并在减压下浓缩。 The resulting mixture was stirred at ambient temperature for 2 days and concentrated under reduced pressure. 将粗制残余物进行柱色谱法(己烷/乙酸乙酯=3/2)以产生白色固体(llmg,19% )0 The crude residue was subjected to column chromatography (hexane / ethyl acetate = 3/2) to give a white solid (llmg, 19%) 0

[1014] 1HNMR (300MHz, CDCl 3) :7.63(d,2H,J = 16Hz),7. 45 (s,1H),7. 43 (d,2H,J = 8. 1Hz),7· 38(d,2H,J = 8. 1Hz),7. 09 (s, 1H) ,6. 74 (dd, 1H,J = 11 禾口17Hz),6· 48 (s, 1H), [1014] 1HNMR (300MHz, CDCl 3):.. 7.63 (d, 2H, J = 16Hz), 7 45 (s, 1H), 7 43 (d, 2H, J = 8. 1Hz), 7 · 38 ( d, 2H, J = 8. 1Hz), 7. 09 (s, 1H), 6. 74 (dd, 1H, J = 11 Wo port 17Hz), 6 · 48 (s, 1H),

6. 36 (d, 1H, J = 16Hz),6· 12 (t,1H),5. 63 (d, 1H, J = 17Hz),5· 37 (d, 1H, J = 11Hz),4· 54 (d, 2H, J = 6. 0Hz),3. 90 (s, 3H),2. 96 (s, 3H),1. 32 (s,9H) · 6. 36 (d, 1H, J = 16Hz), 6 · 12 (t, 1H), 5. 63 (d, 1H, J = 17Hz), 5 · 37 (d, 1H, J = 11Hz), 4 · 54 (d, 2H, J = 6. 0Hz), 3. 90 (s, 3H), 2. 96 (s, 3H), 1. 32 (s, 9H) ·

[1015] 实施例50 : ι- (4-氨基-3-氟-5-乙烯基-苄基)~3~ (4~叔丁基-苄基)_脲 [1015] Example 50: ι- (4- amino-3-fluoro-5-vinyl-benzyl) - ~ 3 ~ (4 ~ tert-butyl-benzyl) - urea _

[1016] [1016]

Figure CN101142174BD00861

[1017] 步骤1 : 1- (4-氨基-3-氟-苄基)-3- (4-叔丁基-苄基)_脲 [1017] Step 1: Preparation of 1- (4-Amino-3-fluoro - benzyl) -3- (4-tert-butyl-benzyl) - urea _

[1018] 将4-氨基-3-氟苄胺盐酸盐(0.46g,3. ^mmol)和4_叔丁基苄基氨基甲酸苯酯(1. leq,1.02g)置于50ml的圆底烧瓶中。 [1018] 4-Amino-3-fluoro benzylamine hydrochloride (0.46g, 3. ^ Mmol) and tert-butyl 4_ benzyl carbamate (1. leq, 1.02g) was placed in 50ml round bottom flask. 向该混合物倾入20ml乙腈并加入三乙胺(过量, 0. 5ml),回流12小时。 To this mixture was poured into 20ml of acetonitrile was added triethylamine (excess, 0. 5ml), refluxed for 12 hours. 在用TLC证实反应结束后,将反应混合物用乙酸乙酯提取,用IN HCl 溶液洗涤,并将合并的有机层通过MgSO4干燥,过滤并在减压下浓缩。 In the completion of the reaction was confirmed by TLC, the reaction mixture was extracted with ethyl acetate, washed with IN HCl solution, and the combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. 将获得的液体进行柱色谱法(正己烷/乙酸乙酯=1/1)。 The liquid obtained was subjected to column chromatography (hexane / ethyl acetate = 1/1).

[1019]产率:0. 5g,46. 4% [1019] Yield:.. 0 5g, 46 4%

[1020] 步骤2 : 1- (4-氨基-3-氟-5-碘-苄基)_3_ (4_叔丁基-苄基)_脲 [1020] Step 2: Preparation of 1- (4-amino-3-fluoro-5-iodo-benzyl) - _3_ (4_-tert-butyl-benzyl) - urea _

[1021]将 1-(4-氨基-3-氟-苄基)-3-(4-叔丁基-苄基)-脲(0. 25g,0. 76mmol)和Ag2SO4 (1. leq,0. 26g)置于50ml的圆底烧瓶,接着冷却到0°C。 [1021] 1- (4-Amino-3-fluoro - benzyl) -3- (4-tert-butyl-benzyl) - - urea (. 0. 25g, 0 76mmol) and Ag2SO4 (1. leq, 0 . 26g) was placed in 50ml round bottom flask, followed by cooling to 0 ° C. 向该混合物中倾入20ml乙醇并逐份加入I2 (1. Oeq, 0. 193g),在室温搅拌3小时。 To this mixture was poured into 20ml of ethanol was added portionwise and I2 (1. Oeq, 0. 193g), stirred at room temperature for 3 hours. 在用TLC证实反应结束后,通过C盐过滤反应混合物,并在减压下浓缩。 In the end of the reaction was confirmed by TLC, the reaction mixture was filtered through C salt, and concentrated under reduced pressure.

[1022] 步骤3 : 1-(4-氨基-3-氟-5-乙烯基-苄基)_3_ (4_叔丁基-苄基)_脲 [1022] Step 3: Preparation of 1- (4-amino-3-fluoro-5-vinyl-benzyl) - _3_ (4_-tert-butyl-benzyl) - urea _

[1023]将 1-(4-氨基-3-氟-5-碘-苄基)-3-(4-叔丁基-苄基)_脲(0. 17g,0. 37mmol) 和Pd(PPh3)4(0. 05eq,21. 3mg)置于50ml的圆底烧瓶。 [1023] 1- (4-amino-3-fluoro-5-iodo-benzyl) - 3- (4-tert-butyl-benzyl) - urea _ (. 0. 17g, 0 37mmol) and Pd (PPh3 ) 4 (0. 05eq, 21. 3mg) was placed in 50ml round bottom flask. 并通过注射器向该反应混合物加入20ml甲苯和三丁基(乙烯基)锡(1. leq,0. 13g),回流2小时。 And added to the reaction mixture via syringe and 20ml of toluene tributyl (vinyl) tin (1. leq, 0. 13g), refluxed for 2 hours. 在用TLC证实反应结束后, 用乙酸乙酯提取反应混合物,用IM KF溶液洗涤。 In the end of the reaction was confirmed by TLC, the reaction mixture was extracted with ethyl acetate, washed with IM KF solution. 并将合并的有机层通过MgSO4干燥,过滤并在减压下浓缩。 And the combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. 将获得的液体进行柱色谱法(正己烷/乙酸乙酯=2/1)。 The liquid obtained was subjected to column chromatography (hexane / ethyl acetate = 2/1).

[1024]产率:88mg,66. 9% [1024] Yield:. 88mg, 66 9%

[1025] 实施例51 : [1025] Example 51:

[1026] 3- (4-叔丁基-苯基)-N- (4-甲烷磺酰基氨基_3_乙烯基-苄基)_2_苯基-丙烯酰胺 [1026] 3- (4-tert-butyl - phenyl) -N- (4- methanesulfonylamino-vinyl _3_ - benzyl) phenyl _2_ - acrylamide

[1027] [1027]

Figure CN101142174BD00862

[1028] 步骤1 :3-(4-叔丁基-苯基)-2-苯基-丙烯酸 [1028] Step 1: 3- (4-tert-butyl - phenyl) -2-phenyl - acrylic acid

[1029]将苯基乙酸 089mg,3. 59mmol)和4_叔丁基苯甲醛(573_g,3. 53mmol), TEA(5ml) 和乙酸酐(5ml)加入圆底烧瓶。 [1029] The phenylacetic acid 089mg, 3. 59mmol) and t-butyl benzaldehyde 4_ (573_g, 3. 53mmol), TEA (5ml) and acetic anhydride (5ml) was added a round bottom flask. 将反应混合物加热并搅拌过夜。 The reaction mixture was heated and stirred overnight. 将反应混合物倾入5% HCl 水溶液(30ml)。 The reaction mixture was poured into 5% aqueous HCl (30ml). 用MC (30ml X幻提取水溶液。将合并的有机层通过MgSO4干燥,并接着在真空中浓缩。将粗制残余物进行柱色谱法(己烷/乙酸乙酯=4/1)以产生白色固体(38aiig, 73% )。 With MC (30ml X Magic aqueous solution was extracted. The combined organic layers were dried over MgSO4, and then concentrated in vacuo. The crude residue was subjected to column chromatography (hexane / ethyl acetate = 4/1) to yield a white solid (38aiig, 73%).

[1030] 1HNMR (300MHz, CDCl3) :7. 88 (s,1H),7· 37 〜7. ;35 (m,4Η),7· 23 〜7.21(m,2H), 7. 14 (d, 2H, J = 8. 4Hz),7. 96 (d, 2H, J = 8. 4Hz) 1. 20 (s,9H)[1031]步骤 2: [1030] 1HNMR (300MHz, CDCl3): 7 88 (s, 1H), 7 · 37 ~7; 35 (m, 4Η), 7 · 23 ~7.21 (m, 2H), 7. 14 (d,.. 2H, J = 8. 4Hz), 7 96 (d, 2H, J = 8. 4Hz) 1. 20 (s, 9H) [1031] step 2:

[1032] 3- (4-叔丁基-苯基)-N- (4-甲烷磺酰基氨基_3_乙烯基-苄基)_2_苯基-丙烯酰胺 [1032] 3- (4-tert-butyl - phenyl) -N- (4- methanesulfonylamino-vinyl _3_ - benzyl) phenyl _2_ - acrylamide

[1033] 使4-甲烷磺酰基氨基-3-乙烯基-苄胺和HCl盐(153mg,0. 582mmol)与3-(4-叔丁基-苯基)-2-苯基-丙烯酸(160. ^ig)反应以得到3-(4-叔丁基-苯基)-N-(4-甲烷磺酰基氨基-3-乙烯基-苄基)-2-苯基-丙烯酰胺(130. 8mg,46% )0 [1033] 4-methanesulfonylamino-3-vinyl - and benzylamine HCl salt (153mg, 0 582mmol.) With 3- (4-tert-butyl - phenyl) -2-phenyl - acrylic acid (160 . ^ ig) reacted to give 3- (4-tert-butyl - phenyl) -N- (4- methanesulfonyl-3-vinyl-benzyl) - 2-phenyl - acrylamide (130. 8mg , 46%) 0

[1034] 1Hnmr(SoomHzJDCI3) :7. 84 (S,1H),7· 43 〜7· 38(m,3H),7· 32(d,2H,J = 8. IHz), 7. 26 〜7. 22(m,3H),7. 11 (m,2H),7· 01 (m,2H),6. 89(m,2H),6. 12 (br, 1Η), 5. 76 (t, 1Η, J = 5. 4Ηζ),4. 40 (d, 1Η, J = 6Ηζ),2. 95 (s, 3Η),1. 19 (s,9H) · [1034] 1Hnmr (SoomHzJDCI3):. 7 84 (S, 1H), 7 · 43 ~7 · 38 (m, 3H), 7 · 32 (d, 2H, J = 8. IHz), 7. 26 ~7 . 22 (m, 3H), 7. 11 (m, 2H), 7 · 01 (m, 2H), 6. 89 (m, 2H), 6. 12 (br, 1Η), 5. 76 (t, 1Η, J = 5. 4Ηζ), 4. 40 (d, 1Η, J = 6Ηζ), 2. 95 (s, 3Η), 1. 19 (s, 9H) ·

[1035] IR(cm-l) :2962,1654,1606,1513,1365,1154. [1035] IR (cm-l): 2962,1654,1606,1513,1365,1154.

[1036] 实施例52 :N- (4-甲烷磺酰基氨基_3_乙烯基-苄基)_2,3_ 二苯基-丙烯酰胺 [1036] Example 52: N- (4- methanesulfonylamino-vinyl _3_ - benzyl) diphenyl _2,3_ - acrylamide

[1037] [1037]

Figure CN101142174BD00871

[1038] 步骤1 :2,3_ 二苯基-丙烯酸 [1038] Step 1: 2,3_ diphenyl - acrylic acid

[1039] 按照相似的方法,使苯基乙酸(1. 94g,14. 24mmol)和苯甲醛(1. 491g, 14. 05mmol), TEA (5ml)和乙酸酐(5ml)反应以得到2,3-二苯基-丙烯酸。 [1039] In a similar manner, so that phenylacetic acid (1. 94g, 14. 24mmol) and benzaldehyde (1. 491g, 14. 05mmol), TEA (5ml) and acetic anhydride (5ml) were reacted to give 2,3 - diphenyl - acid. 1HNMR(300MHz, CDCl3) :8. 06 (s,1H),7. 49 (m, 3H),7. 37 〜7. 19 (m, 5H),7. 16 (m, 2H). 1HNMR (300MHz, CDCl3):..... 8 06 (s, 1H), 7 49 (m, 3H), 7 37 ~7 19 (m, 5H), 7 16 (m, 2H).

[1040] 步骤2 =N- (4-甲烷磺酰基氨基-3-乙烯基-苄基)-2,3- 二苯基-丙烯酰胺 [1040] Step 2 = N- (4- methanesulfonyl-amino-3-vinyl-benzyl) - 2,3-diphenyl - acrylamide

[1041] 使4-甲烷磺酰基氨基-3-乙烯基苄胺和HCl盐(131mg,0. 499mmol)与通过报道的方法制备的2,3-二苯基-丙烯酸(115mg,0.512mmOl)进行反应,以得到N-甲烷磺酰基氨基-3-乙烯基-苄基)_2,3-二苯基-丙酰胺(146mg,68% )。 [1041] 4-methanesulfonylamino-3-vinyl benzyl amine and HCl salt (131mg, 0 499mmol.) And 2,3-diphenyl prepared by the method reported by - acrylic acid (115mg, 0.512mmOl) for The reaction to give N- methanesulfonylamino-3-vinyl-benzyl) - _2,3- diphenyl - propionamide (146mg, 68%).

[1042] 1HNMR (300MHz, CDC13) :7. 85 (s, 1H) , 7. 37 (m, 3H) , 7. 29 (m, 3H) , 7. 07 (m, 4H), 6. 94 (m, 3H),6. 84 (s, 1H),5. 87 (t, 1H, J = 5. 7Hz),5. 63 (dd, 1H, J = 17. 4,1. 2Hz),3. 38 (s, 1H, J= 10. 8,0. 9), 4. 44 (d, 2H, J = 6. 3Hz),2. 90 (s, 3H) · [1042] 1HNMR (300MHz, CDC13):. 7 85 (s, 1H), 7. 37 (m, 3H), 7. 29 (m, 3H), 7. 07 (m, 4H), 6. 94 ( m, 3H), 6. 84 (s, 1H), 5. 87 (t, 1H, J = 5. 7Hz), 5. 63 (dd, 1H, J = 17. 4,1. 2Hz), 3. 38 (s, 1H, J = 10. 8,0. 9), 4. 44 (d, 2H, J = 6. 3Hz), 2. 90 (s, 3H) ·

[1043] IR(cm-l) :3176,1652,1595,1515,1311. [1043] IR (cm-l): 3176,1652,1595,1515,1311.

[1044] 实施例53 :(R)-N44-{l-[3-(4-叔丁基苯基)脲基]乙基}_2_乙烯基苯基)甲 [1044] Example 53: (R) -N44- {l- [3- (4- tert-butylphenyl) ureido] ethyl} _2_ vinylphenyl) methyl

烷磺酰胺 Alkyl sulfonamide

[1045] [1045]

Figure CN101142174BD00872

[1046] 将NW-(1-氨基乙基)-2-乙烯基苯基]甲烷磺酰胺(236. 7mg,0. 985mmol,leq.) 和三乙胺074. 6μ l,1.970mmoUeq.)加入二氯甲烷。 [1046] The NW- (1- aminoethyl) -2-vinylphenyl] methanesulfonamide (236. 7mg, 0. 985mmol, leq.) And triethylamine 074. 6μ l, 1.970mmoUeq.) Was added methylene chloride. 将反应混合物冷却到0°C。 The reaction mixture was cooled to 0 ° C. 加入4-叔丁基苯基异氰酸酯(192. 5 μ 1,1. 083mmol, 1. 3eq.)。 Was added 4-tert-butylphenyl isocyanate (192. 5 μ 1,1. 083mmol, 1. 3eq.). 将反应混合物搅拌40分钟。 The reaction mixture was stirred for 40 minutes. 在真空中去除二氯甲烷。 Methylene chloride was removed in vacuo. 用柱色谱法(n-Hx : EA = 2 : 1)纯化残余物以产生作为白色固体的标题化合物(155. 4mg,38% )。 By column chromatography (n-Hx: EA = 2: 1) to yield the residue was purified title compound as a white solid (155. 4mg, 38%).

[1047] IR(KBr 片状沉淀物,cnT1) :3350, 3025, 2962, 2863,1648 ; [1047] IR (KBr pellet, cnT1): 3350, 3025, 2962, 2863,1648;

[1048] 1H NMR(400MHz, CDCl3) :7. 30 (d, 1H, J = 1. 6Hz),7. 18(d,2H,J = 8. 4Hz),7. 15 (d, 1H, J = 8. 4Hz),7· 08(d,2H,J = 8. 4Hz),7. 03 (dd,1H,J = 8. 4,1. 6Hz),6. 96 (s,1H), 6. 80 (dd, 1H, J = 17. 2,11. 2Hz),5. 55 (d, 1H, J = 17. 2Hz),5. 26 (d, 1H, J = 11. 2H), 4. 81 (q, 1H, J = 6. 4Hz),2. 83 (s, 3H),1. 25 (d, 3H, J = 6. 4Hz),1. 18 (s,9H) [1048] 1H NMR (400MHz, CDCl3):. (D, 1H, J = 1. 6Hz) 7 30, 7 18 (d, 2H, J = 8. 4Hz), 7 15 (d, 1H, J.. = 8. 4Hz), 7 · 08 (d, 2H, J = 8. 4Hz), 7. 03 (dd, 1H, J = 8. 4,1. 6Hz), 6. 96 (s, 1H), 6 . 80 (dd, 1H, J = 17. 2,11. 2Hz), 5. 55 (d, 1H, J = 17. 2Hz), 5. 26 (d, 1H, J = 11. 2H), 4. 81 (q, 1H, J = 6. 4Hz), 2. 83 (s, 3H), 1. 25 (d, 3H, J = 6. 4Hz), 1. 18 (s, 9H)

[1049] 实施例M : (R)-N-[3-(4-叔丁基苯基)脲基]乙基} _2_三甲基硅烷基乙 [1049] Example M: ​​(R) -N- [3- (4- tert-butylphenyl) ureido] ethyl} _2_ trimethylsilyl acetate

炔基苯基)甲烷磺酰胺 Alkynyl phenyl) methanesulfonamide

[1050] [1050]

Figure CN101142174BD00881

[1051] 步骤1 :(R)-[1_(4-氨基-3-三甲基硅烷(sianyl)乙炔基苯基)乙基]氨基甲酸叔丁酯 [1051] Step 1: (R) - [1_ (4- amino-3-trimethylsilyl (sianyl) ethynyl phenyl) ethyl] carbamate

[1052] 将[1-(4-氨基-3-碘-苯基)-乙基]-氨基甲酸叔丁酯(100mg,0. 276mmol, leq·),二氯(双三苯基膦)钯(9. 8mg,0. 014mmol,0. (^eq.)和碘化铜(2. 6mg,0. 014mmol, [1052] [1- (4-amino-3-iodo - phenyl) - ethyl] - carbamate (. 100mg, 0 276mmol, leq ·), dichloro (bis triphenylphosphine) palladium (9. 8mg, 0. 014mmol, 0. (^ eq.) and copper iodide (2. 6mg, 0. 014mmol,

0. 05eq.)溶解于THF。 0. 05eq.) Was dissolved in THF. 在搅拌30分钟后,将三乙胺(115.4μ 1,0. 828mmol,3eq.),和(三甲基甲硅烷基)乙炔基6μ 1,0. 359mmol, 1. 3eq)加入反应混合物中。 After stirring for 30 minutes, triethylamine (115.4μ 1,0. 828mmol, 3eq.), And (trimethylsilyl) ethynyl 6μ 1,0. 359mmol, 1. 3eq) was added to the reaction mixture. 将反应混合物搅拌过夜。 The reaction mixture was stirred overnight. 在真空中蒸发反应混合物。 The reaction mixture was evaporated in vacuo. 用柱色谱法(n-Hx : EA = 5 : 1)纯化残余物以产生作为黄色液体的标题化合物(70. 8mg)。 By column chromatography (n-Hx: EA = 5: 1) The residue was purified to give the title compound (70. 8mg) as a yellow liquid.

[1053] [α ]23D :+40. 80 ° (c 0· 2,CHCl3) ;IR(NaCl 纯的,cnT1) :3374,2974,2928,2141, 1694 ;1H NMR (400MHz, CDCl3) :7.23(d,lH,J = 1. 6Hz), 7. 05 (dd, 1H, J = 8· 4,1. 6Hz), . [1053] [α] 23D: +40 80 ° (c 0 · 2, CHCl3); IR (NaCl neat, cnT1): 3374,2974,2928,2141, 1694; 1H NMR (400MHz, CDCl3): 7.23 (d, lH, J = 1. 6Hz), 7. 05 (dd, 1H, J = 8 · 4,1. 6Hz),

6. 64(d,lH,J = 8. 4Hz) ,4.73-4. 71 (m,lH) ,4.63 (bs,lH),4.09 (bs,2H),1.42 (s,9H), 6. 64 (d, lH, J = 8. 4Hz), 4.73-4. 71 (m, lH), 4.63 (bs, lH), 4.09 (bs, 2H), 1.42 (s, 9H),

1. 39 (d, 3H, J = 6. 8Hz),0. 26 (s,9H) 1. 39 (d, 3H, J = 6. 8Hz), 0. 26 (s, 9H)

[1054] 步骤2 : (R)-[1-甲烷磺酰基氨基-3-三甲基硅烷基乙炔基苯基)乙基]氨基甲酸叔丁酯 [1054] Step 2: (R) - [1- methanesulfonyl-amino-3-trimethylsilyl-ethynyl phenyl) ethyl] carbamate

[1055] 将(R)-[l_(4-氨基-3-三基硅烷基乙炔基苯基)乙基]氨基甲酸叔丁酯(67. 9mg, 0. 20mmol, leq.),甲烷磺酰酐(39. lmg,0. 23mmol, 1. leq.)禾P 吡啶(49. 0 μ 1,0. 61mmol, 3eq)加入二氯甲烷。 [1055] The (R) - [l_ (4- amino-silyl-3-yl-ethynylphenyl) ethyl] carbamate (67. 9mg, 0. 20mmol, leq.), Methanesulfonyl anhydride (39. lmg, 0. 23mmol, 1. leq.) Wo P pyridine (49. 0 μ 1,0. 61mmol, 3eq) was added dichloromethane. 在室温将混合物搅拌5小时。 The mixture was stirred at room temperature for 5 hours. 通过加入饱和NaHCO3溶液猝灭反应混合物。 The reaction mixture was quenched by addition of saturated NaHCO3 solution. 用二氯甲烷提取反应混合物。 The reaction mixture was extracted with dichloromethane. 合并的有机层用5% HCl,饱和NaHCO3溶液,和H2O洗涤,通过硫酸钠干燥,并在真空中浓缩。 The organic layers were washed with 5% HCl, saturated NaHCO3 solution, washed and H2O, dried over sodium sulfate, and concentrated in vacuo. 将残余物用柱色谱法纯化以产生作为固体的标题产物(50. 4mg, 79. 6% ) „ The residue was purified by column chromatography to give the title product as a solid (50. 4mg, 79. 6%) "

[1056] [α ]23 D :+42. 88 ° (c 0· 41,CHCl3) ;IR(KBr 片状沉淀物):3410,四72,2929, 2152,1678cm-1 . [1056] [α] 23 D: +42 88 ° (c 0 · 41, CHCl3); IR (KBr pellet): 3410, four 72,2929, 2152,1678cm-1

[1057] 1H NMR (400MHz,CDCl3) : δ 7. 53 (d, 1H, J = 8. 4Hz) ,7. 40 (d. 1H, J = 2· OHz), [1057] 1H NMR (400MHz, CDCl3): δ 7. 53 (d, 1H, J = 8. 4Hz), 7 40,. (D 1H, J = 2 · OHz.)

7. 28 (dd, 1H, J = 8. 4,2. OHz),6. 94 (bs, 1H),4. 83 (d, 2H, J = 7. 6Hz),4. 72 (bs, 1H),2. 99 (s, 3H),1. 42-1. 40 (m, 12H),0. 29 (s,9H).[1058] 步骤3 : (R)-NGU-[3-(4-叔丁基苯基)脲基]乙基} _2_三甲基硅烷基乙炔基苯基)甲烷磺酰胺 7. 28 (dd, 1H, J = 8. 4,2. OHz), 6. 94 (bs, 1H), 4. 83 (d, 2H, J = 7. 6Hz), 4. 72 (bs, 1H ...), 2 99 (s, 3H), 1 42-1 40 (m, 12H), 0 29 (s, 9H) [1058] step 3:.. (R) -NGU- [3- (4 - tert-butyl-phenyl) ureido] ethyl} _2_ trimethylsilyl ethynyl phenyl) methanesulfonamide

[1059] 将[1-(4-甲烷磺酰基氨基-3-三甲基硅烷基乙炔基-苯基)-乙基]-氨基甲酸叔丁酯(300mg,0. 724mmol,leq)加入二氯甲烷。 [1059] [1- (4-methanesulfonyloxy-3-trimethylsilanyl ethynyl - phenyl) - ethyl] - carbamic acid tert-butyl ester (. 300mg, 0 724mmol, leq) was added dichloro methane. 将三氟乙酸(279 μ 1, 3. 619mmol, 3eq.)加入混合物。 Trifluoroacetic acid (279 μ 1, 3. 619mmol, 3eq.) Added to the mixture. 将反应混合物搅拌M小时。 The reaction mixture was stirred for M hour. 将混合物在真空中浓缩以产生作为液体的标题化合物(440. Img)。 The mixture was concentrated in vacuo to yield the title compound as a liquid (440. Img).

[1060] 将(R)-N44_(l-氨基-乙基)-2-三甲基硅烷基乙炔基苯基]甲烷磺酰胺(75. Omg, 0. 242mmol,leq.)和三乙胺(67. 5 μ 1,0. 484mmol,2eq.)溶解于二氯甲烷。 [1060] The (R) -N44_ (l- amino - ethyl) -2-trimethylsilyl ethynyl phenyl] methanesulfonamide (75. Omg, 0. 242mmol, leq.) And triethylamine ( 67. 5 μ 1,0. 484mmol, 2eq.) was dissolved in dichloromethane. 将混合物冷却到0°C。 The mixture was cooled to 0 ° C. 将4-叔丁基苯基异氰酸酯2μ 1,0. 266mmol, 1. leq.)加入反应混合物中。 4-tert-butylphenyl isocyanate 2μ 1,0. 266mmol, 1. leq.) Was added to the reaction mixture. 将反应混合物搅拌40分钟。 The reaction mixture was stirred for 40 minutes. 在真空中去除反应溶剂。 The reaction solvent was removed in vacuo. 用柱色谱法(n-Hx : EA = 2 : 1)纯化残余物以产生作为固体的标题化合物05.^^,39% )。 By column chromatography (n-Hx: EA = 2: 1) to yield the residue was purified title compound as a solid 05 ^^, 39%).

[1061] mp :118. 5-119. 5 °C ;[a ]23D-24. 79 ° (c 0. 63,CHCl3),IR(KBr 片状沉淀物, cm—1) :3406, 2962, 2928, 2868, 2150,1649 ;1H NMR(400MHz, CDCl3) :7. 43 (d,1H,J = 8. 4Hz), 7. 35 (d, 1H, J = 2. 0Hz),7. 24 (d, 2H, J = 8. 8Hz),7. 21 (dd, 1H, J = 8. 4,2. OHz),7. 09 (d, 2H, J = 8. 8Hz),6. 86 (bs, 1H),6. 40 (bs, 1H),4. 86 (q, 1H, J = 6. 8Hz),2· 91 (s,9H),1. 34 (q, 1H, J = 6. 8Hz),1. 22 (s,9H),0· 21 (s,9H) .. [1061] mp: 118 5-119 5 ° C; [a] 23D-24 79 ° (c 0. 63, CHCl3), IR (KBr pellet, cm-1):. 3406, 2962, 2928, 2868, 2150,1649; 1H NMR (400MHz, CDCl3):.. 7 43 (d, 1H, J = 8. 4Hz), 7. 35 (d, 1H, J = 2. 0Hz), 7 24 ( d, 2H, J = 8. 8Hz), 7. 21 (dd, 1H, J = 8. 4,2. OHz), 7. 09 (d, 2H, J = 8. 8Hz), 6. 86 (bs , 1H), 6. 40 (bs, 1H), 4. 86 (q, 1H, J = 6. 8Hz), 2 · 91 (s, 9H), 1. 34 (q, 1H, J = 6. 8Hz ), 1. 22 (s, 9H), 0 · 21 (s, 9H)

[1062] 实施例55 :(R)-N44-{l-[3-(4-叔丁基苯基)脲基]乙基}_2_乙炔基苯基)甲烷磺酰胺 [1062] Example 55: (R) -N44- {l- [3- (4- tert-butylphenyl) ureido] ethyl} _2_ ethynylphenyl) methanesulfonamide

[1063] [1063]

Figure CN101142174BD00891

[1064] 将(R)-N44-{l-[3_(4-叔丁基-苯基)脲基]乙基}_2_三甲基硅烷基乙炔基-苯基)甲烷磺酰胺(llmg,0. 023mmol)溶解于THF。 [1064] The (R) -N44- {l- [3_ (4- tert-butyl-phenyl) - ureido] ethyl} _2_ trimethylsilanyl ethynyl - phenyl) methanesulfonamide (llmg, 0. 023mmol) was dissolved in THF. 将反应混合物冷却到0°C。 The reaction mixture was cooled to 0 ° C. 将1. OM的四丁基铵氟化物在THF (0. 068ml,0. 068mmol, 3eq.)中的溶液加入反应混合物中。 A 1. OM tetrabutylammonium fluoride in THF (0. 068ml, 0. 068mmol, 3eq.) Was added to the reaction mixture. 将反应混合物搅拌1. 5小时。 The reaction mixture was stirred for 1.5 hours. 将反应混合物在真空中进行浓缩并用柱色谱法(n-Hx : EA = 1 : 1)进行纯化以产生作为固体的标题化合物(7. Omg, 74% )。 The reaction mixture was concentrated in vacuo and purified by column chromatography (n-Hx: EA = 1: 1) was purified to give the title compound (7. Omg, 74%) as a solid.

[1065] mp :88. 4-89. 4°C ;[a ]23D_28. 19° (c 0. 31,CHCl3); .. [1065] mp: 88 4-89 4 ° C; [a] 23D_28 19 ° (c 0. 31, CHCl3);.

[1066] IR(KBr 片状沉淀物,cnT1) :3410,2961,2926,2855,2104,1645 ; [1066] IR (KBr pellet, cnT1): 3410,2961,2926,2855,2104,1645;

[1067] 1H NMR(400MHz, CDCl3) :7. 49 (d, 1H, J = 8. 4Hz),7. 39 (d, 1H, J = 1. 6Hz),7. 26 (d, 3H, J = 8. 8Hz),7. 10 (d, 2H, J = 8. 8Hz),6. 89 (bs, 1H),6. 22 (bs, 1H),4. 96 (bs, 1H),4. 89 (q, 1H, J = 6. 8Hz),3. 40 (s, 1H),2. 94 (s, 3H),1. 36 (d, 3H, J = 6. 8Hz),1. 23 (s,9H) · [1067] 1H NMR (400MHz, CDCl3):.. 7 49 (d, 1H, J = 8. 4Hz), 7 39 (d, 1H, J = 1. 6Hz), 7 26 (d, 3H, J. = 8. 8Hz), 7. 10 (d, 2H, J = 8. 8Hz), 6. 89 (bs, 1H), 6. 22 (bs, 1H), 4. 96 (bs, 1H), 4. 89 (q, 1H, J = 6. 8Hz), 3. 40 (s, 1H), 2. 94 (s, 3H), 1. 36 (d, 3H, J = 6. 8Hz), 1. 23 ( s, 9H) ·

[1068] 实施例56 :Ν44-{1-[3-(4-叔丁基苯基)脲基]甲基}_2_乙烯基苯基)甲烷磺酰胺 [1068] Embodiment 56 cases: Ν44- {1- [3- (4- tert-butylphenyl) ureido] methyl} _2_ vinylphenyl) methanesulfonamide

[1069] [1069]

Figure CN101142174BD00901

[1070] 将NW-(1-氨基-乙基)-2-乙烯基-苯基]-甲烷磺酰胺036. 7mg,0.985mmol) 和三乙胺(274. 6 μ 1,1. 970mmol,2eq)加入二氯甲烷。 [1070] The NW- (1- amino - ethyl) -2-vinyl - phenyl] - methanesulfonamide 036. 7mg, 0.985mmol) and triethylamine (274. 6 μ 1,1 970mmol, 2eq ) was added dichloromethane. 将反应混合物冷却到0°C。 The reaction mixture was cooled to 0 ° C. 将4_叔丁基苯基异氰酸酯(192. 5 μ 1,1. 083mmol, 1. 3eq.)加入混合物。 The 4_-tert-butylphenyl isocyanate (192. 5 μ 1,1. 083mmol, 1. 3eq.) Added to the mixture. 将反应混合物搅拌40分钟。 The reaction mixture was stirred for 40 minutes. 在真空中去除反应溶剂。 The reaction solvent was removed in vacuo. 将残余物用色谱法(n-Hx : EA = 2 : 1)纯化以产生作为白色固体的标题化合物(155. 4mg,47% )。 The residue was purified by chromatography (n-Hx: EA = 2: 1) was purified to yield the title compound as a white solid (155. 4mg, 47%).

[1071] 1H NMR(400MHz, CDCl3) :8. 02(d,2H,J = 8. 8Hz),7. 30(d,2H,J = 8. 8Hz),7· 03 (d, 2Η, J = 8. 4Ηζ),6. 99 (d, 2Η, J = 8. 4Hz) ,5. 51 (bs, 1Η),4. 90 (q, 1Η, J = 6. 8Ηζ),2. 44 (t, 2Η, J = 7. 2Ηζ),1. 50 (sextet, 2H, J = 7. 2Hz),1. 26 (d, 3H, J = 6. 8Hz),0. 84 (t, 3H, J = 7. 2Hz) [1071] 1H NMR (400MHz, CDCl3):.. 8 02 (d, 2H, J = 8. 8Hz), 7 30 (d, 2H, J = 8. 8Hz), 7 · 03 (d, 2Η, J = 8. 4Ηζ), 6. 99 (d, 2Η, J = 8. 4Hz), 5. 51 (bs, 1Η), 4. 90 (q, 1Η, J = 6. 8Ηζ), 2. 44 (t , 2Η, J = 7. 2Ηζ), 1. 50 (sextet, 2H, J = 7. 2Hz), 1. 26 (d, 3H, J = 6. 8Hz), 0. 84 (t, 3H, J = 7. 2Hz)

[1072] 实施例57 :N-{4-[3-(4-叔丁基苯基)脲基甲基]_2_氟_6_乙烯基苯基}甲烷磺酰胺 [1072] Example 57: N- {4- [3- (4- tert-butylphenyl) ureidomethyl] _2_ fluoro _6_ vinylphenyl} methanesulfonamide

[1073] [1073]

Figure CN101142174BD00902

[1074] 将N-(4-氨基甲基-2-氟-6-乙烯基苯基)甲烷磺酰胺(37. ftng,0. llmmol),1_叔丁基-4-异氰酰苯(1. 2eq, 0. 13mmol, 22. 49 μ 1),和TEA (3eq, 0. 33mmol, 45. 99 μ 1)加入二氯甲烷。 [1074] The N- (4- amino-2-fluoro-6-vinylphenyl) methanesulfonamide (37. ftng, 0. Llmmol), 1_ tert-butyl-4-isocyanato-benzene ( 1. 2eq, 0. 13mmol, 22. 49 μ 1), and TEA (3eq, 0. 33mmol, 45. 99 μ 1) was added dichloromethane. 将反应混合物搅拌12小时。 The reaction mixture was stirred for 12 hours. 用二氯甲烷提取反应混合物。 The reaction mixture was extracted with dichloromethane. 将合并的有机层用H2O 和盐水洗涤,通过硫酸钠干燥并在真空中浓缩。 The combined organic layers were washed with H2O and brine, dried over sodium sulfate and concentrated in vacuo. 用柱色谱法(n-Hx : EA = 1 : 1)纯化残余物以产生作为白色固体的标题化合物Img, 55% )。 By column chromatography (n-Hx: EA = 1: 1) The residue was purified to give the title compound as a white solid Img, 55%).

[1075] Mp :167 〜170°C ; [1075] Mp: 167 ~170 ° C;

[1076] IR(KBr 片状沉淀物,CnT1) :3328,3246,3072,2961,1320,1152 ; [1076] IR (KBr pellet, CnT1): 3328,3246,3072,2961,1320,1152;

[1077] 1H NMR (400MHz, CD3OD) : δ 7. 44 (s,1H),7. 26 (d,2H,J = 8. OHz),7. 23 (d,2H,J =8. OHz),7· 16 (dd, 1H, J = 17. 6,11. 2Hz),7. 09 (dd, 1H, J = 10. 4,1. 6Hz),6· 89 (s, 1H), 5. 82 (d, 1H, J = 17. 6Hz),5. 35 (d, 1H, J = 11. 2Hz),4. 35(s,2H),2. 99(s,3H),1. 37(s,9H). [1077] 1H NMR (400MHz, CD3OD):.. Δ 7. 44 (s, 1H), 7 26 (d, 2H, J = 8. OHz), 7 23 (d, 2H, J = 8 OHz.) , 7 · 16 (dd, 1H, J = 17. 6,11. 2Hz), 7. 09 (dd, 1H, J = 10. 4,1. 6Hz), 6 · 89 (s, 1H), 5. 82 (d, 1H, J = 17. 6Hz), 5. 35 (d, 1H, J = 11. 2Hz), 4. 35 (s, 2H), 2. 99 (s, 3H), 1. 37 ( s, 9H).

[1078] 实施例58:乙烯磺酸G-{l_[3-(4-叔丁基苯基)脲基]乙基}_2_乙烯基苯基) 酰胺 [1078] Example 58: Ethylene acid G- {l_ [3- (4- tert-butylphenyl) ureido] ethyl} _2_ vinylphenyl) amide

[1079] [1079]

Figure CN101142174BD00903

步骤1:乙烯磺酸G-{l-[l-(2,2-二甲基丙基)乙烯基氨基]乙基}-2_碘苯基)[1081] 将4-{1-[142,2-二甲基丙基)乙烯基氨基]乙基}-2_碘苯胺(218. lmg, 0. 65mmol)溶解于二氯甲烷。 Step 1: vinyl sulfonic G- {l- [l- (2,2- dimethylpropyl) ethenyl amino] ethyl} -2_ iodophenyl) [1081] 4- {1- [142 , 2-dimethylpropyl) ethenyl amino] ethyl} -2_ iodoaniline (218. lmg, 0. 65mmol) was dissolved in dichloromethane. 将反应混合物冷却到0°C。 The reaction mixture was cooled to 0 ° C. 将2-氯乙烷磺酰氯C3eq,1. 95mmol, 203. 64 μ 1)和吡啶(3eq, 1. 95mmol, 157. 71 μ 1)加入混合物。 A mixture of 2-chloroethane sulfonyl chloride C3eq, 1. 95mmol, 203. 64 μ 1) and pyridine (3eq, 1. 95mmol, 157. 71 μ 1) added to the mixture. 将反应混合物搅拌48小时。 The reaction mixture was stirred for 48 hours. 在证实合成结束后,在真空中去除反应溶剂。 After confirming the end of the synthesis, the reaction solvent was removed in vacuo. 用二氯甲烷提取残余物。 The residue was extracted with methylene chloride. 将合并的有机层用H2O和盐水洗涤,通过NaSO4干燥,并在真空中浓缩。 The combined organic layers were washed with H2O and brine, dried NaSO4, and concentrated in vacuo. 用柱色谱法(n-Hx : EA = 3 : 1)纯化残余物以产生作为褐色固体的标题化合物(104. 9mg,78% )。 By column chromatography (n-Hx: EA = 3: 1) to yield the residue was purified title compound as a brown solid (104. 9mg, 78%).

[1082] mp :112 〜114°C ; [1082] mp: 112 ~114 ° C;

[1083] [a ]d20+31. 69 (CHCl3, c 1. 74); . [1083] [a] d20 + 31 69 (CHCl3, c 1. 74);

[1084] IR(KBr 片状沉淀物,cnT1) :3323,2976,1693,736 ;1H NMR(400MHz, CDCl3): δ 7. 66 (s, 1H) ,7. 47 (dd, 1H, J = 8. 4,8. OHz),7. 22 (d,1H,J = 8. 4Hz),6. 59 (s,1H), 6. 54 (qd, 1H, J= 16. 8,10. 0,1. 2Hz),6. 20 (d, 1H, J = 16. 4Hz),5. 91 (d,H,J = 10. OHz), [1084] IR (KBr pellet, cnT1): 3323,2976,1693,736; 1H NMR (400MHz, CDCl3):. Δ 7. 66 (s, 1H), 7 47 (dd, 1H, J = 8. 4,8. OHz), 7. 22 (d, 1H, J = 8. 4Hz), 6. 59 (s, 1H), 6. 54 (qd, 1H, J = 16. 8,10. 0 , 1. 2Hz), 6. 20 (d, 1H, J = 16. 4Hz), 5. 91 (d, H, J = 10. OHz),

4. 77 (bs, 1H),4. 65 (bs, 1H),1. 36 (s, 12H) 4. 77 (bs, 1H), 4. 65 (bs, 1H), 1. 36 (s, 12H)

[1085] 步骤2 : [1-(4-乙烯磺酰基氨基-3-乙烯基苯基)乙基]氨基甲酸叔丁酯 [1085] Step 2: [1- (4-vinyl-3- vinylphenyl) ethyl] carbamate

[1086] 将[1-(4-乙烯磺酰基氨基-3-碘苯基)乙基]氨基甲酸叔丁酯(58.%ig, [1086] [1- (4-vinyl-3- iodophenyl) ethyl] carbamate (58.% ig,

0. 13mmol),Pd (PPh3) 4 (0. 06eq, 0. 0078mmol, 9. IOmg),LiCl (2. 8eq, 0. 19mmol, 15. 43mg),和TEA(1. 5eq,0. 19mmol,56. 99 μ 1)加入DMF。 0. 13mmol), Pd (PPh3) 4 (0. 06eq, 0. 0078mmol, 9. IOmg), LiCl (2. 8eq, 0. 19mmol, 15. 43mg), and TEA (1. 5eq, 0. 19mmol, 56. 99 μ 1) was added DMF. 在90°C将反应混合物搅拌12小时。 At 90 ° C and the reaction mixture stirred for 12 hours. 在真空中去除DMF。 The DMF was removed in vacuo. 用乙酸乙酯提取残余物。 The residue was extracted with ethyl acetate. 将合并的有机层用H2O和盐水洗涤,通过硫酸钠干燥, 并在真空中浓缩。 The combined organic layers were washed with H2O and brine, dried over sodium sulfate, and concentrated in vacuo. 用柱色谱法(N-Hx : EA = 3 : 1)纯化残余物以产生作为褐色液体的标题化合物(24. 8mg,18% )0 By column chromatography (N-Hx: EA = 3: 1) The residue was purified to give the title compound as a brown liquid (24. 8mg, 18%) 0

[1087] mp :80 〜82 °C ; [1087] mp: 80 ~82 ° C;

[1088] [ α ]D20 :+6. 21 (CHCl3, c 0. 47); [1088] [α] D20:. +6 21 (CHCl3, c 0. 47);

[1089] IR(NaCl 纯的,cnT1) :3347,2958,1686 ;1H NMR(400MHz, CDCl3) :7.30(t,lH,J = [1089] IR (NaCl neat, cnT1): 3347,2958,1686; 1H NMR (400MHz, CDCl3): 7.30 (t, lH, J =

1. 2Hz),7. 28 (s,1H),7. 12 (dd, 1H,J = 8. 0,1. 2Hz) 6. 80 (q, 1H, J = 6· 4,10. 8Ηζ),6. 50 (dq, 1Η, J = 10. 8,6. 4,0. 8Ηζ),6. 41 (s, 1Η),5. 86 (d, 1H, J = 10. OHz),5. 62 (d, 1H, J = 17. 6Hz), 1. 2Hz), 7. 28 (s, 1H), 7. 12 (dd, 1H, J = 8. 0,1. 2Hz) 6. 80 (q, 1H, J = 6 · 4,10. 8Ηζ) , 6. 50 (dq, 1Η, J = 10. 8,6. 4,0. 8Ηζ), 6. 41 (s, 1Η), 5. 86 (d, 1H, J = 10. OHz), 5. 62 (d, 1H, J = 17. 6Hz),

5. 37 (d, 1H, J = 11. 2Hz),4. 75 (s, 1H),4. 68 (s, 1H). 5. 37 (d, 1H, J = 11. 2Hz), 4. 75 (s, 1H), 4. 68 (s, 1H).

[1090] 步骤3:乙烯磺酸0-{l-[3-(4-叔丁基苯基)脲基]乙基}-2_乙烯基苯基)酰胺 [1090] Step 3: vinyl sulfonic acid 0- {l- [3- (4- tert-butylphenyl) ureido] ethyl} -2_ vinylphenyl) amide

[1091] 将[1- (4-乙烯磺酰基氨基-3-乙烯基-苯基)-乙基]-氨基甲酸叔丁酯Omg, 0. 04mmol)和CF3COOH(5eq,0. 22mmol,17. 04 μ 1)溶解于二氯甲烷。 [1091] [1- (4-vinyl-3- vinyl - phenyl) - ethyl] - carbamate Omg, 0. 04mmol) and CF3COOH (5eq, 0 22mmol, 17.. 04 μ 1) was dissolved in dichloromethane. 将反应混合物搅拌12小时。 The reaction mixture was stirred for 12 hours. 浓缩反应混合物以产生[1-(4-乙烯磺酰基氨基-3-乙烯基-苯基)-乙基胺(15. 6mg, 76% )。 The reaction mixture was concentrated to give [1- (4-vinyl-3- vinyl - phenyl) - ethylamine (15. 6mg, 76%).

[1092] 将乙烯磺酸W-(1-氨基-乙基)-2-乙烯基-苯基]-酰胺(15. 6mg,0. 04mmol), 4-叔丁基苯基异氰酸酯(1. 2eq,0. 053mmol,9. 45 μ 1),和ΤΕΑ(1· 2eq,0. 12mmol, 16. 73 μ 1) 加入MC。 [1092] Ethylene acid W- (1- amino - ethyl) -2-vinyl - phenyl] - amide (. 15. 6mg, 0 04mmol), 4- tert-butylphenyl isocyanate (1. 2eq , 0. 053mmol, 9. 45 μ 1), and ΤΕΑ (1 · 2eq, 0. 12mmol, 16. 73 μ 1) was added MC. 将反应混合物搅拌5小时。 The reaction mixture was stirred for 5 hours. 用二氯甲烷提取反应混合物。 The reaction mixture was extracted with dichloromethane. 将合并的有机层用H2O和盐水洗涤,通过硫酸钠干燥并在真空中浓缩。 The combined organic layers were washed with H2O and brine, dried over sodium sulfate and concentrated in vacuo. 将残余物用柱色谱法(n-Hx : EA = 3 : 1- > 2 : 1)纯化以产生标题化合物(34. aiig,40% )。 The residue was purified by column chromatography (n-Hx: EA = 3: 1-> 2: 1) was purified to give the title compound (34. aiig, 40%).

[1093] mp :60 〜62 °C ; [1093] mp: 60 ~62 ° C;

[1094] [ α ]d20-17. 57 (CHCl3, c 0. 28); . [1094] [α] d20-17 57 (CHCl3, c 0. 28);

[1095] IR(NaCl 纯的,cnT1) :3346,3189,2962,1649,1318 ;[1096] 1H NMR (400MHz,CD3 0D) :7.59(d,lH,J = 1. 6Hz) ,7. 27 (t, 1H, J = 2. 4Hz), 7. 26 (s,1H),7· 25(s,2H),7· 23(s,2H),7· 10 (q, 1H, J = 11. 2,6. 4Hz),6· 69 (q, 1H, J = 6. 8, 9. 6Hz),6. 02 (d, 1H, J = 16. 4Hz),5. 90 (d, 1H, J = 10. 0Hz),5. 77 (dd, 1H,J = 1. 2,17. 6Hz), 5. 33 (dd, 1H,J = 1. 2,10. 8Hz),1. 45 (d, 3H, J = 6. 8Hz),1. 27 (s,9H) · [1095] IR (NaCl neat, cnT1): 3346,3189,2962,1649,1318; [1096] 1H NMR (400MHz, CD3 0D): 7.59 (d, lH, J = 1. 6Hz), 7 27. (t, 1H, J = 2. 4Hz), 7. 26 (s, 1H), 7 · 25 (s, 2H), 7 · 23 (s, 2H), 7 · 10 (q, 1H, J = 11 . 2,6. 4Hz), 6 · 69 (q, 1H, J = 6. 8, 9. 6Hz), 6. 02 (d, 1H, J = 16. 4Hz), 5. 90 (d, 1H, J = 10. 0Hz), 5. 77 (dd, 1H, J = 1. 2,17. 6Hz), 5. 33 (dd, 1H, J = 1. 2,10. 8Hz), 1. 45 (d , 3H, J = 6. 8Hz), 1. 27 (s, 9H) ·

[1097] 实施例59 :N44-{l-[3-(4-叔丁基苯基)脲基]乙基}_2_苯基乙炔基苯基)甲烷磺酰胺 [1097] Example 59: N44- {l- [3- (4- tert-butylphenyl) ureido] ethyl} _2_ phenylethynyl-phenyl) methanesulfonamide

[1099] 步骤1 : [1-(4-氨基-3-苯基乙炔基苯基)乙基]氨基甲酸叔丁酯 [1099] Step 1: [1- (4-amino-3-phenylethynyl-phenyl) ethyl] carbamate

Figure CN101142174BD00921

[1100] 将[1-(4-氨基-3-碘苯基)乙基]氨基甲酸叔丁酯(500mg,1.380mmol,leq.), 二氯(双三苯基膦)钯(48. 4mg,0. 069mmol,0. 05eq.)和碘化铜13. Img (0. 069mmol, [1100] [1- (4-amino-3-iodophenyl) ethyl] carbamate (500mg, 1.380mmol, leq.), Dichloro (bis triphenylphosphine) palladium (48. 4mg , 0. 069mmol, 0. 05eq.) and copper iodide 13. Img (0. 069mmol,

0. 05eq.)加入THF。 0. 05eq.) Was added THF. 在室温搅拌30分钟后,将TEA(577. 0 μ 1,4. 140mmol,3eq)和苯基乙炔基(197. 0 μ 1,1. 794mmol, 1. 3eq)加入反应混合物。 After stirring at room temperature for 30 min, TEA (577. 0 μ 1,4. 140mmol, 3eq) phenylethynyl, and (197. 0 μ 1,1. 794mmol, 1. 3eq) was added the reaction mixture. 在回流的情况下,将反应混合物搅拌过夜。 In the case of reflux, the reaction mixture was stirred overnight. 在真空中去除反应溶剂。 The reaction solvent was removed in vacuo. 用柱色谱法(n-Hx : EA = 5 : 1)纯化残余物以产生作为黄色液体的标题化合物(452. 7mg)。 By column chromatography (n-Hx: EA = 5: 1) The residue was purified to give the title compound (452. 7mg) as a yellow liquid.

[1101] [a]23D-4.80° (c 0· 83,CHCl3); [1101] [a] 23D-4.80 ° (c 0 · 83, CHCl3);

[1102] IR(NaCl 纯的,cnT1) :3433,2968,2922,2852,2198,1684 ; [1102] IR (NaCl neat, cnT1): 3433,2968,2922,2852,2198,1684;

[1103] 1H NMR (400MHz, CDCl3) :7. 44—7. 40 (m,2H),7. 26 (—7. 16 (m,4H),6. 97 (dd,1H,J = 8. 0,1. 2Hz),6. 56 (d, 1H, J = 8. OHz),4. 76 (d, 1H, J = 7. 6Hz),4. 58 (bs, 1H),1. 33 (s,9H), [1103] 1H NMR (400MHz, CDCl3):..... 7 44-7 40 (m, 2H), 7 26 (-7 16 (m, 4H), 6 97 (dd, 1H, J = 8. 0,1. 2Hz), 6. 56 (d, 1H, J = 8. OHz), 4. 76 (d, 1H, J = 7. 6Hz), 4. 58 (bs, 1H), 1. 33 ( s, 9H),

1. 31(d,3H,J = 7. 2Hz). 1. 31 (d, 3H, J = 7. 2Hz).

[1104] 步骤2 : [1-(4-甲烷磺酰基氨基-3-苯基乙炔基苯基)乙基]氨基甲酸叔丁酯 [1104] Step 2: [1- (4-methanesulfonyloxy-3-phenyl-ethynylphenyl) ethyl] carbamate

[1105] 将[1-(4-氨基-3-苯基乙炔基苯基)乙基]氨基甲酸叔丁酯(487. lmg, 1. 448mmol, leq.)和甲烷磺酰酐(302. 7mg,0. 737mmol, 1. 2eq.)加入二氯甲烷。 [1105] [1- (4-amino-3-phenylethynyl-phenyl) ethyl] carbamate (487. lmg, 1. 448mmol, leq.) And methanesulfonyl anhydride (302. 7mg , 0. 737mmol, 1. 2eq.) was added dichloromethane. 将反应混合物冷却到O0C0将吡啶(348. 1 μ 1,4. 344mmol,3eq.)加入反应混合物中。 The reaction mixture was cooled to O0C0 pyridine (348. 1 μ 1,4. 344mmol, 3eq.) Was added to the reaction mixture. 将反应混合物搅拌1小时。 The reaction mixture was stirred for 1 hour. 通过加入饱和NaHCO3溶液猝灭反应。 The reaction was quenched by addition of saturated NaHCO3 solution. 用二氯甲烷提取反应混合物。 The reaction mixture was extracted with dichloromethane. 将合并的有机层用5% HCl,饱和的NaHCO3溶液,H2O接着盐水洗涤通过Na2SO4干燥,接着在真空中浓缩。 The combined organic layers were washed with 5% HCl, saturated NaHCO3 solution, H2O followed by brine and dried over Na2SO4, then concentrated in vacuo. 用柱色谱法(n-Hx : EA = 5 : 1)纯化残余物以产生标题化合物(300mg,83% )。 By column chromatography (n-Hx: EA = 5: 1) The residue was purified to give the title compound (300mg, 83%).

[1106] mp :157-158°C ; [1106] mp: 157-158 ° C;

[1107] [α ]23D+45. 52° (c 0· 31,CHCl3); . [1107] [α] 23D + 45 52 ° (c 0 · 31, CHCl3);

[1108] IR(KBr 片状沉淀物,cnT1) :3362,3253,3013,2974,2930,1684 ;1HNMR(400MHz, CDCl3) :7. 51 (d, 1H, J = 8. 4Hz),7. 48-7. 45 (m, 2H),7. 42 (d. 1H, J = 2. OHz),7. 35-7. 31 (m, 3H),7. 24 (dd, 1H, J = 8. 4,2. OHz),6. 91 (s,1H),4. 72 (bs, 2H),2. 97 (s, 3H),1. 39-1. 36 (m, 12H). [1108] IR (KBr pellet, cnT1):. 3362,3253,3013,2974,2930,1684; 1HNMR (400MHz, CDCl3): 7 51 (d, 1H, J = 8. 4Hz), 7. 48-7. 45 (m, 2H), 7. 42 (d. 1H, J = 2. OHz), 7. 35-7. 31 (m, 3H), 7. 24 (dd, 1H, J = 8 . 4,2. OHz), 6. 91 (s, 1H), 4. 72 (bs, 2H), 2. 97 (s, 3H), 1. 39-1. 36 (m, 12H).

[1109] 步骤3 :Ν44-{1-[3-(4-叔丁基苯基)脲基]乙基} _2_苯基乙炔基苯基)甲烷磺酰胺 [1109] Step 3: Ν44- {1- [3- (4- tert-butylphenyl) ureido] ethyl} _2_ phenylethynyl-phenyl) methanesulfonamide

[1098][1110] 将[1-(4-甲烷磺酰基氨基-3-苯基乙炔基苯基)乙基]氨基甲酸叔丁酯(300mg, [1098] [1110] [1- (4-methanesulfonyloxy-3-phenyl-ethynylphenyl) ethyl] carbamate (300mg,

0. 724mmol)和三氟乙酸Q79 μ 1,3. 619mmol,!3eq)加入二氯甲烷。 0. 724mmol) and trifluoroacetic acid Q79 μ 1,3. 619mmol,! 3eq) in dichloromethane was added. 将反应混合物搅拌M 小时。 The reaction mixture was stirred for M hour. 在真空中去除反应溶剂以产生144-甲烷磺酰基氨基-3-苯基乙炔基苯基)乙基胺G40. lmg,100% )。 The reaction solvent was removed in vacuo to yield 144- amino-3-methanesulfonyl-phenylethynyl-phenyl) ethylamine G40. Lmg, 100%). 将N44-(l-氨基乙基)-2-苯基乙炔基苯基]甲烷磺酰胺040. lmg, The N44- (l- aminoethyl) -2-phenyl ethynyl-phenyl] methanesulfonamide 040. lmg,

1. 40mmol)和TEA(390. 3 μ 1,2. 800mmol,2eq)加入二氯甲烷。 1. 40mmol) and TEA (390. 3 μ 1,2. 800mmol, 2eq) in dichloromethane was added. 将反应混合物冷却到0°C。 The reaction mixture was cooled to 0 ° C. 将4-叔丁基苯基异氰酸酯(M8. 8 μ 1,1. 540mmol, 1. 3eq.)加入所述混合物。 4-tert-butylphenyl isocyanate (M8. 8 μ 1,1. 540mmol, 1. 3eq.) Was added to the mixture. 将反应混合物搅拌1小时。 The reaction mixture was stirred for 1 hour. 在真空中去除二氯甲烷。 Methylene chloride was removed in vacuo. 用柱色谱法(n-Hx : EA = 2 : 1)纯化残余物以产生作为固体的标题化合物(Ml. 4mg,35% )。 By column chromatography (n-Hx: EA = 2: 1) The residue was purified to give the title compound (Ml 4mg, 35%.) As a solid.

[1111] 1H NMR(400MHz, CDCl3) :8. 02(d,2H,J = 8. 8Hz),7. 30(d,2H,J = 8. 8Hz),7· 03 (d, 2Η, J = 8. 4Ηζ),6. 99 (d, 2Η, J = 8. 4Hz) ,5. 51 (bs, 1Η),4. 90 (q, 1Η, J = 6. 8Ηζ),2. 44 (t, 2Η, J = 7. 2Ηζ),1. 50 (sextet, 2H, J = 7. 2Hz),1. 26 (d, 3H, J = 6. 8Hz),0. 84 (t, 3H, J = 7. 2Hz); [1111] 1H NMR (400MHz, CDCl3):.. 8 02 (d, 2H, J = 8. 8Hz), 7 30 (d, 2H, J = 8. 8Hz), 7 · 03 (d, 2Η, J = 8. 4Ηζ), 6. 99 (d, 2Η, J = 8. 4Hz), 5. 51 (bs, 1Η), 4. 90 (q, 1Η, J = 6. 8Ηζ), 2. 44 (t , 2Η, J = 7. 2Ηζ), 1. 50 (sextet, 2H, J = 7. 2Hz), 1. 26 (d, 3H, J = 6. 8Hz), 0. 84 (t, 3H, J = 7. 2Hz);

[1112] mp :103-104°C ; [1112] mp: 103-104 ° C;

[1113] [α ]23d :-38. 55° (c 0· 33,CHCl3); . [1113] [α] 23d: -38 55 ° (c 0 · 33, CHCl3);

[1114] IR(KBr 片状沉淀物):3375, 3056, 2962, 2903, 2260cm-1 [1114] IR (KBr pellet): 3375, 3056, 2962, 2903, 2260cm-1

[1115] 实施例60 :N-[3-(4-叔丁基苯基)脲基]乙基}-2-styryl苯基)甲烷磺 [1115] Example 60: N- [3- (4- tert-butylphenyl) ureido] ethyl} -2-styryl phenyl) methanesulfonamide

酰胺 Amide

[1116] [1116]

Figure CN101142174BD00931

[1117] 将N- (4-{1-[3- (4-叔丁基-苯基)-脲基]-乙基} _2_苯基乙炔基苯基)-甲烷磺酰胺(50mg,0. 102mmol,leq.)和用铅(Lindlar催化剂)抑制的钯碳酸钙加入甲醇。 [1117] The N- (4- {1- [3- (4- tert-butyl - phenyl) - ureido] - ethyl} _2_ phenylethynyl-phenyl) - methanesulfonamide (50mg, 0 . 102mmol, leq.) and palladium on calcium carbonate with lead (Lindlar catalyst) inhibition methanol was added. 将反应混合物在H2气氛下搅拌12小时。 The reaction mixture was stirred under H2 atmosphere for 12 hours. 将反应混合物用C盐垫过滤。 The reaction mixture was filtered through a pad of celite C. 在真空中浓缩滤液。 The filtrate was concentrated in vacuo. 用柱色谱法(n-Hx : EA = 2 : 1)纯化残余物以产生标题化合物(16mg,32% )。 By column chromatography (n-Hx: EA = 2: 1) The residue was purified to give the title compound (16mg, 32%).

[1118] [a]23D-8.80° (c 0· 5,CHCl3); [1118] [a] 23D-8.80 ° (c 0 · 5, CHCl3);

[1119] IR(KBr 片状沉淀物,cnT1) :3407,3025,2962,2927,1648,1543 ; [1119] IR (KBr pellet, cnT1): 3407,3025,2962,2927,1648,1543;

[1120] 1H NMR(400MHz, CDCl3) :7. 39 (d, 1H, J = 8. 4Hz),7. 25-7. 00 (m, 11H),6· 72 (d, 1H, J =12. 4Hz),6. 44 (d, 1H, J = 12. 4Hz),6. 38 (bs, 1H),4. 83 (q, 1H, J = 6. 8Hz),2. 60 (s, 3H), 1. 29 (d, 3H, J = 6. 8Hz),1. 22 (s,9H) · [1120] 1H NMR (400MHz, CDCl3):... 7 39 (d, 1H, J = 8. 4Hz), 7 25-7 00 (m, 11H), 6 · 72 (d, 1H, J = 12 . 4Hz), 6. 44 (d, 1H, J = 12. 4Hz), 6. 38 (bs, 1H), 4. 83 (q, 1H, J = 6. 8Hz), 2. 60 (s, 3H ), 1. 29 (d, 3H, J = 6. 8Hz), 1. 22 (s, 9H) ·

[1121] 实验实施例:生物效力测试 Biological efficacy tests: Example [1121] Experimental

[1122] L45Ca流入测试 [1122] L45Ca inflow Test

[1123] 1)新生大鼠的脊柱背根神经节(DRG)的分离及其原代培养物 Spine [1123] 1) isolated neonatal rat dorsal root ganglia (the DRG) and primary cultures

[1124] 将新生天龄或小于2-3天龄)的SD大鼠置于冰上5分钟以麻醉并用70%的乙醇消毒。 [1124] The day old neonatal or less than 2-3 day old) SD rats were put in ice for 5 minutes to anesthetized and sterilized with 70% ethanol. 解剖脊髓的所有部分的DRG(Wood等,1988,J. Neurosci. 8,pp3208_3220)并将其收集在DME/F12培养基中,向所述培养基中加入1. 2g/l碳酸氢钠,50mg/l的庆大霉素。 DRG of all part of the anatomy of the spinal cord (Wood et, 1988, J. Neurosci. 8, pp3208_3220) and collected in DME / F12 medium was added 1. 2g / l sodium bicarbonate to the medium, 50mg / l gentamicin. 将DRG继续在37°C分别在200U/ml的胶原酶和2. 5mg/ml的胰蛋白酶中温育30分钟。 The DRG were continued in pancreatic 200U / ml collagenase and 2. 5mg / ml of proteinase and incubated for 30 min at 37 ° C. 用补充以10%马血清的DME/F12培养基洗涤神经节2次,通过火琢的巴斯德吸管研磨,通过Nitex80膜过滤以获得单细胞混悬液并将所述混悬液再次洗涤。 Supplemented with 10% horse serum in DME / F12 medium ganglia were washed twice, by grinding a fire-polished Pasteur pipette by Nitex80 membrane filtration to obtain a single cell suspension and the suspension is washed again. 将其进行离心,接着以一定水平的细胞密度重悬浮在细胞培养基中。 Which was centrifuged followed by a certain level of cell density were resuspended in cell culture medium. 作为细胞培养基,将补充以10%马血清的DME/F12培养基用汇合成片的C6胶质瘤细胞调节2天的相同培养基稀释(1 : 1),并加入NGF (神经生长因子)以调节200ng/ml的最终浓度。 As the cell culture medium will be supplemented with 10% horse serum in DME / F12 medium was adjusted in the same medium for 2 days was diluted with C6 glioma cells confluent sheet (1: 1), was added and the NGF (nerve growth factor) to adjust the final concentration of 200ng / ml of. 将细胞培养在加入阿糖胞苷(Ara-C,100 μ M)以杀死正在分裂的非神经细胞的培养基中2天后,用无Ara-C的培养基替换所述培养基。 The cells were cultured in a medium added cytarabine (Ara-C, 100 μ M) to kill non-neuronal cells of dividing the 2 days, the medium was replaced with medium free of Ara-C. 将重悬浮的细胞以1500-2000神经元/孔的密度平板接种在预先用10 μ g/ml聚-D-鸟苷酸包被的Terasaki平板上。 The cells were resuspended at a density of 1500-2000 neurons plate / well in Terasaki plates in advance with the 10 μ g / ml poly -D- guanylate package.

[1125] 2) 45Ca流入实验 [1125] 2) 45Ca inflow experiment

[1126]通过用 HEPES (10mM,pH 7. 4)-缓冲的无Ca2+,Mg2+的HBSS (H-HBSS)洗涤4 次,来平衡来自2天的原代培养物的DRG神经细胞。 [1126] by treatment with HEPES (10mM, pH 7. 4) - free buffer DRG neurons Ca2 +, Mg2 + in HBSS (H-HBSS) washed 4 times, to balance the primary cultures from the two days. 从各个孔中去除每个孔中的溶液。 Each well was removed from each well. 将在H-HBSS 中包含测试化合物加辣椒素(终浓度0. 5 μ M)和45Ca (终浓度10 μ Ci/ml)的培养基加入每个孔中并在室温温育10分钟。 Containing the test compounds in H-HBSS plus capsaicin (final concentration of 0. 5 μ M), and 45Ca (final concentration of 10 μ Ci / ml) medium was added to each well and incubated at room temperature for 10 minutes. 用H-HBSS洗涤Terasaki板5次并在室温干燥。 Terasaki plates were washed with H-HBSS 5 times and dried at room temperature. 向每个孔中,加入0.3% SDS(IOyl)以洗脱45Ca。 To each well was added 0.3% SDS (IOyl) to elute 45Ca. 在将闪烁混合物添加到每个孔后,通过计算放射性来测量流到神经元中的45Ca的量。 After the scintillation mixture was added to each well, radioactivity was measured by calculating the amount of flow of neurons 45Ca. 将测试化合物针对香草素受体的拮抗活性计算为对在0. 5μ M的浓度的辣椒素的最大反应的抑制的百分比。 The test compound was calculated as a percentage of the maximum response at 0. 5μ M concentrations of capsaicin for the inhibition of the vanilloid receptor antagonistic activity. 总而言之,本发明的所有实施例显示良好到优越的介于20和500ηΜ之间的IC50值,其中大多数化合物具有低于200ηΜ的IC50 值。 In summary, all embodiments of the present invention exhibit good to superior IC50 values ​​ranging between 20 and 500ηΜ, wherein most of the compounds have an IC50 value of less than 200ηΜ.

[1127]【表2】 [1127] [Table 2]

[1128] 钙流入测试的结果 [1128] Test results of calcium influx

[1129] [1129]

Figure CN101142174BD00941
Figure CN101142174BD00951
Figure CN101142174BD00961

[1130] 3.止痛活性测试:通过用苯基-P-醌诱导进行的小鼠挣扎测试 [1130] 3. The analgesic activity of the test: the struggle for the test mice by inducing with phenyl quinone -P-

[1131] 将雄性ICR小鼠(平均体重25g)维持在受控制的光照环境(12小时开/12小时关)进行实验。 [1131] Male ICR mice (average body weight 25g) maintained (12 hours on / 12 hours off) in a controlled lighting environment experiment. 动物接受0. 3ml的化学刺激物苯基-ρ-醌(溶解在包含5%乙醇的盐水中, 至剂量为4. 5mg/kg)的腹膜内注射,6分钟后,在随后的6分钟时期中计算腹部收缩的数量。 Animals received 0. 3ml chemical irritant phenyl -ρ- quinone (dissolved in saline containing 5% ethanol, to the dose of 4. 5mg / kg) intraperitoneal injection, for 6 minutes, in the subsequent 6 minutes period the number of abdominal contractions in the calculation. 动物(10只动物/组)腹膜内接受在乙醇/吐温80/盐水(10/10/80)的载体中的0. 2ml 的测试化合物溶液,30分钟后注射苯基-ρ-醌。 The animals (10 animals / group) intraperitoneally acceptable carrier in ethanol / Tween 80 / saline (10/10/80) in 0. 2ml of test compound solution, 30 minutes after injection -ρ- phenyl quinone. 认为相对于在盐水对照组中反应的数量, 对测试药物化合物反应的挣扎的次数减少是止痛效果的指示。 That the reaction relative to the amount of saline in the control group, the number of test drug compound of struggling reduction is an indication of an analgesic effect. 通过%抑制等式(%抑制= (CT) /CX 100)计算止痛效果,其中C和T表示分别表示在对照和化合物-对照组中的挣扎的次数(表3)。 Analgesic effect is calculated by% inhibition equation (% inhibition = (CT) / CX 100), wherein C and T represent, respectively, and a compound represented in the control - the number of struggling in the control group (Table 3).

[1132]【表3】 [1132] TABLE 3

[1133] 对于由苯基-ρ-醌引起的挣扎的止痛活性的测试结果 [1133] caused by the struggle for the phenyl quinone -ρ- analgesic activity of test results

[1134] [1134]

Figure CN101142174BD00962
Figure CN101142174BD00971

[1135] 工业应用性 [1135] Industrial Applicability

[1136] 如上所阐述,将按照本发明的化合物用于预防和治疗疼痛,偏头痛,关节痛,神经痛,神经病,神经损伤,皮肤疾病,膀胱过敏,肠易激综合征,便急,呼吸疾病,皮肤、眼睛或粘膜刺激,胃-十二指肠溃疡,炎性疾病,耳病,和心脏病等。 [1136] As set forth above, for the prevention and treatment of pain according to the present invention compounds, migraine, arthralgia, neuralgia, neuropathies, nerve injury, skin diseases, irritable bladder, irritable bowel syndrome, fecal urgency, respiratory disease, skin, eyes or mucous membrane irritation, stomach - duodenal ulcers, inflammatory diseases, ear disease, and heart disease.

[1137] 更具体地,按照本发明的化合物用于预防和治疗急性痛,慢性痛,神经性疼痛,术后痛,风湿性关节痛,骨关节痛,带状疱疹后神经痛,糖尿病性神经病,HIV-相关的神经病, 神经变性中风,神经性/变应性/炎性皮肤病,银屑病,瘙痒症,痒疹,哮喘,慢性阻塞性肺病,尿失禁,炎性肠病,听觉过敏,耳鸣,前庭过敏,和变力性缺血。 [1137] More specifically, the compounds according to the present invention for the prevention and treatment of acute pain, chronic pain, neuropathic pain, post operative pain, rheumatic joint pain, bone and joint pain, postherpetic neuralgia, diabetic neuropathy , HIV-related neuropathy, neurodegeneration, stroke, neurotic / allergic / inflammatory skin disease, psoriasis, pruritus, prurigo, asthma, chronic obstructive pulmonary disease, urinary incontinence, inflammatory bowel disease, hyperacusis, tinnitus, vestibular allergies, and inotropic ischemia.

Claims (24)

1.式(I)的化合物,其异构体或其药用盐: 1. A compound of formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof:
Figure CN101142174BC00021
其中X 是NHCH2, CR11 = CR12, CHR11CHR12,或C 三C,其中R11 和R12 独立地是氢,卤素,C1-C5 烷基,C1-C5烷氧基,卤代(C1-C5)烷基,或苯基;礼是C2-C5链烯基或C2-C5炔基;R2是氢,卤素,硝基,氰基,C1-C5烷基,C1-C5烷氧基,卤代(C1-C5)烷基,C2-C5链烯基,C2-C5炔基,羧基,C1-C5烷氧基羰基,C1-C5烷硫基,苯基,或苯基(C1-C3)烷基,其中每个苯基可以是未取代的或由选自下列各项的一个或多个取代基取代:羧基,C1-C5烷基,卤素,硝基,C2-C5链烯基,C1-C5烷氧基,卤代(C1-C5)烷基,C1-C5烷基羰基,C1-C5烷硫基, C1-C5烷基磺酰基,和C1-C5烷氧基羰基;R3是氢,C1-C5烷基,C1-C5烷氧基,或卤代(C1-C5)烷基;R4, R5, R6, R7,和R8独立地是氢,羧基,C1-C5烷基,硝基,C2-C5链烯基,C1-C5烷氧基, C2-C5炔基,商代(C1-C5)烷基,C1-C5烷硫基,C1-C5烷基磺酰基,C1-C5烷基羰基,C1-C5烷氧基羰基,羟基 Wherein X is NHCH2, CR11 = CR12, CHR11CHR12, or C and C, where R11 and R12 are independently hydrogen, halogen, C1-C5 alkyl, C1-C5 alkoxy, halo (C1-C5) alkyl, or phenyl; Li is C2-C5 alkenyl or C2-C5 alkynyl group; R2 is hydrogen, halo, nitro, cyano, C1-C5 alkyl, C1-C5 alkoxy, halo (C1-C5 ) alkyl, C2-C5 alkenyl, C2-C5 alkynyl, carboxy, C1-C5 alkoxycarbonyl, C1-C5 alkylthio, phenyl, or phenyl (C1-C3) alkyl, wherein each of phenyl unsubstituted or may be selected from the one or more of the following substituents: carboxy, C1-C5 alkyl, halogen, nitro, C2-C5 alkenyl, C1-C5 alkoxy , halo (C1-C5) alkyl, C1-C5 alkylcarbonyl, C1-C5 alkylthio groups, C1-C5 alkylsulfonyl group, and C1-C5 alkoxycarbonyl group; R3 is hydrogen, C1-C5 alkoxy groups, C1-C5 alkoxy, or halo (C1-C5) alkyl; R4, R5, R6, R7, and R8 are independently hydrogen, carboxy, C1-C5 alkyl, nitro, C2-C5 chain alkenyl, C1-C5 alkoxy, C2-C5 alkynyl group, Shang (C1-C5) alkyl, C1-C5 alkylthio groups, C1-C5 alkylsulfonyl group, C1-C5 alkylcarbonyl, C1- C5 alkoxycarbonyl group, a hydroxyl group ,C2-C5链烯氧基,C1-C5烷氧基(C1-C5)烷氧基,C1-C5烷氧基(C1-C5)烷氧基(C1-C5)烷基,C1-C3烷基哌嗪基,哌嗪基(C1-C5)烷氧基,哌啶基(C1-C5)烷氧基,C1-C5 烷氧基(C1-C5)烷基氨基,C1-C7烷基氨基,吗啉基,吗啉基(C1-C5)烷基氧基,四氢吡喃基氧基,苯基,或卤素,其中苯基可以是未取代的或由选自下列各项的一个或多个取代基取代:羧基,C1-C5烷基,卤素,硝基,C2-C5链烯基,C1-C5烷氧基,卤代(C1-C5)烷基,C1-C5 烷基羰基,C1-C5烷硫基,C1-C5烷基磺酰基,C1-C5烷氧基羰基,或未取代的或由C1-C5烷氧基羰基取代的哌啶基氧基;且R9和R10独立地是氢,-SO2R13, -SOR13, C1-C5烷基,C1-C5烷氧基,卤代(C1-C5)烷基, C2-C5链烯基,C1-C5烷氧基羰基,C1-C5烷硫基,苯基,或苯基(C1-C3)烷基,其中每个苯基可以是未取代的或由选自下列各项的一个或多个取代基取代:羧基,C1-C5烷基, , C2-C5 alkenyloxy, C1-C5 alkoxy (C1-C5) alkoxy, C1-C5 alkoxy (C1-C5) alkoxy (C1-C5) alkyl, C1-C3 alkoxy piperazinyl, piperazinyl (C1-C5) alkoxy, piperidinyl (C1-C5) alkoxy, C1-C5 alkoxy (C1-C5) alkylamino, C1-C7 alkylamino , morpholinyl, morpholinyl (C1-C5) alkyl group, tetrahydropyranyl, phenyl, or halo, wherein phenyl may be unsubstituted or substituted by one of the following selected items or a plurality of substituents: carboxy, C1-C5 alkyl, halogen, nitro, C2-C5 alkenyl, C1-C5 alkoxy, halo (C1-C5) alkyl, C1-C5 alkylcarbonyl group, C1-C5 alkylthio groups, C1-C5 alkylsulfonyl group, C1-C5 alkoxycarbonyl, unsubstituted or substituted by C1-C5 alkoxycarbonyl-piperidinyloxy; and R9 and R10 are independently is hydrogen, -SO2R13, -SOR13, C1-C5 alkyl, C1-C5 alkoxy, halo (C1-C5) alkyl, C2-C5 alkenyl, C1-C5 alkoxycarbonyl, C1-C5 alkylthio, phenyl, or phenyl (C1-C3) alkyl, wherein each phenyl group may be unsubstituted or substituted selected from the group of one or more of the following substituents: carboxy, C1-C5 alkoxy base, 素,硝基,C2-C5链烯基,C1-C5烷氧基,卤代(C1-C5)烷基,C1-C5烷基羰基,C1-C5烷硫基,C1-C5 烷基磺酰基,和C1-C5烷氧基羰基,且R13是氢,氨基,C1-C5烷基,C2-C5链烯基,C1-C5烷氧基,卤代(C1-C5)烷基,三氟甲基,苯基,或苯基(C1-C3)烷基。 , Nitro, C2-C5 alkenyl, C1-C5 alkoxy, halo (C1-C5) alkyl, C1-C5 alkylcarbonyl, C1-C5 alkylthio groups, C1-C5 alkylsulfonyl group , and C1-C5 alkoxycarbonyl, and R13 is hydrogen, amino, C1-C5 alkyl, C2-C5 alkenyl, C1-C5 alkoxy, halo (C1-C5) alkyl, trifluoromethanesulfonic , phenyl, or phenyl (C1-C3) alkyl.
2.按照权利要求1的式(I)的化合物、其异构体或其药用盐, 其中X是NHCH2, CR11 = CR12,或C三C,其中R11和R12独立地是氢,卤素,C1-C5烷基,或苯基;R1是C2-C5链烯基或C2-C5炔基;R2是氢,卤素,硝基,氰基,C1-C5烷基,C1-C5烷氧基,卤代(C1-C5)烷基,C2-C5链烯基,C2-C5炔基,羧基,C1-C5烷氧基羰基,C1-C5烷硫基,苯基,或苯基(C1-C3)烷基,其中每个苯基可以是未取代的或由选自下列各项的一个或多个取代基取代:羧基,C1-C5烷基,卤素,硝基,C2-C5链烯基,C1-C5烷氧基,卤代(C1-C5)烷基,C1-C5烷基羰基,C1-C5烷硫基, C1-C5烷基磺酰基,和C1-C5烷氧基羰基;R3是氢,C1-C5烷基,C1-C5烷氧基,或卤代(C1-C5)烷基;R4, R5, R6, R7,和R8独立地是氢,羧基,C1-C5烷基,硝基,C2-C5链烯基,C1-C5烷氧基, C2-C5炔基,卤代(C1-C5)烷基,C1-C5烷硫基,C1-C5烷基磺酰基,C1-C5烷基羰基,C1-C5 烷 2. A compound of formula (I) according to claim 1, an isomer thereof or a pharmaceutically acceptable salt thereof, wherein X is NHCH2, CR11 = CR12, or C and C, where R11 and R12 are independently hydrogen, halogen, a C1 -C5 alkyl, or phenyl; Rl is C2-C5 alkenyl or C2-C5 alkynyl group; R2 is hydrogen, halo, nitro, cyano, C1-C5 alkyl, C1-C5 alkoxy, halo Generation (C1-C5) alkyl, C2-C5 alkenyl, C2-C5 alkynyl, carboxy, C1-C5 alkoxycarbonyl, C1-C5 alkylthio, phenyl, or phenyl (C1-C3) alkyl, wherein each phenyl group may be unsubstituted or substituted by the selected one or more substituents of the following: carboxyl, C1-C5 alkyl, halogen, nitro, C2-C5 alkenyl groups, C1 -C5 alkoxy, halo (C1-C5) alkyl, C1-C5 alkylcarbonyl, C1-C5 alkylthio groups, C1-C5 alkylsulfonyl group, and C1-C5 alkoxycarbonyl group; R3 is hydrogen , C1-C5 alkyl, C1-C5 alkoxy, or halo (C1-C5) alkyl; R4, R5, R6, R7, and R8 are independently hydrogen, carboxy, C1-C5 alkyl group, a nitro group , C2-C5 alkenyl, C1-C5 alkoxy, C2-C5 alkynyl, halo (C1-C5) alkyl, C1-C5 alkylthio groups, C1-C5 alkylsulfonyl group, C1-C5 alkoxy carbonyl group, C1-C5 alkoxy 基羰基,苯基,或卤素,其中苯基可以不被取代或由选自下列各项的一个或多个取代基取代:羧基,C1-C5烷基,卤素,硝基,C2-C5链烯基,C1-C5烷氧基,卤代(C1-C5)烷基,C1-C5 烷基羰基,C1-C5烷硫基,C1-C5烷基磺酰基,和C1-C5烷氧基羰基;且R9和R10独立地是氢,-SO2R13, -SOR13, C1-C5烷基,C1-C5烷氧基,卤代(C1-C5)烷基, C2-C5链烯基,C1-C5烷氧基羰基,C1-C5烷硫基,苯基,或苯基(C1-C3)烷基,其中每个苯基可以是未取代的或由选自下列各项的一个或多个取代基取代:羧基,C1-C5烷基,卤素,硝基,C2-C5链烯基,C1-C5烷氧基,卤代(C1-C5)烷基,C1-C5烷基羰基,C1-C5烷硫基,C1-C5 烷基磺酰基,和C1-C5烷氧基羰基,且R13是氢,氨基,C1-C5烷基,C2-C5链烯基,C1-C5烷氧基,卤代(C1-C5)烷基,三氟甲基,苯基,或苯基(C1-C3)烷基。 Carbonyl group, a phenyl group, or halo, wherein the substituted phenyl group or may not be selected from the following one or more substituents: carboxy, C1-C5 alkyl, halogen, nitro, C2-C5 alkenyl groups, C1-C5 alkoxy, halo (C1-C5) alkyl, C1-C5 alkylcarbonyl, C1-C5 alkylthio groups, C1-C5 alkylsulfonyl group, and C1-C5 alkoxycarbonyl group; and R9 and R10 are independently hydrogen, -SO2R13, -SOR13, C1-C5 alkyl, C1-C5 alkoxy, halo (C1-C5) alkyl, C2-C5 alkenyl, C1-C5 alkoxy carbonyl group, C1-C5 alkylthio, phenyl, or phenyl (C1-C3) alkyl, wherein each phenyl group may be unsubstituted or selected from one or more of the following substituents: carboxy, C1-C5 alkyl, halogen, nitro, C2-C5 alkenyl, C1-C5 alkoxy, halo (C1-C5) alkyl, C1-C5 alkylcarbonyl, C1-C5 alkylthio , C1-C5 alkylsulfonyl group, and C1-C5 alkoxycarbonyl, and R13 is hydrogen, amino, C1-C5 alkyl, C2-C5 alkenyl, C1-C5 alkoxy, halo (C1 C5) alkyl, trifluoromethyl, phenyl, or phenyl (C1-C3) alkyl.
3.按照前述权利要求任一项的化合物,其异构体或其药用盐; 其中X是NHCH2, CR11 = CR12,或C三C,其中R11和R12独立地是氢,卤素,C1-C5烷基,或苯基;R1是乙烯基,乙炔基,丙烯基,或丙炔基;R2是氢,氟,氯,溴,碘,硝基,氰基,甲基,乙基,丙基,异丙基,丁基,异丁基,甲氧基,乙氧基,三氟甲基,羧基,甲氧基羰基,或苯基; R3是氢,甲基,或乙基;R4, R5, R6, R7,和R8独立地是氢,羧基,甲基,乙基,丙基,异丙基,叔丁基,硝基,乙烯基, 乙炔基,甲硫基,三氟甲基,甲氧基羰基,或卤素;且R9和R10独立地是氢,-SO2R13, -SOR13, C1-C5烷基,C1-C5烷氧基,卤代(C1-C5)烷基, C2-C5链烯基,苯基,苯基(C1-C3)烷基,或C1-C3烷氧基苯基,其中R13是氢,氨基,C1-C5烷基,C2-C5链烯基,三氟甲基,苯基,或苄基。 3. A compound according to any one of the preceding claims, an isomer thereof or a pharmaceutically acceptable salt thereof; wherein X is NHCH2, CR11 = CR12, or C and C, where R11 and R12 are independently hydrogen, halogen, C1-C5 alkyl, or phenyl; Rl is vinyl, ethynyl, propenyl or propynyl group; R2 is hydrogen, fluoro, chloro, bromo, iodo, nitro, cyano, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, trifluoromethyl, carboxy, methoxycarbonyl, or phenyl; R3 is hydrogen, methyl, or ethyl; R4, R5, R6, R7, and R8 are independently hydrogen, carboxy, methyl, ethyl, propyl, isopropyl, t-butyl, nitro, ethenyl, ethynyl, methylthio, trifluoromethyl, methoxy carbonyl group, or a halogen; and R9 and R10 are independently hydrogen, -SO2R13, -SOR13, C1-C5 alkyl, C1-C5 alkoxy, halo (C1-C5) alkyl, C2-C5 alkenyl , phenyl, phenyl (C1-C3) alkyl, C1-C3 alkoxy group or a phenyl group, wherein R13 is hydrogen, amino, C1-C5 alkyl, C2-C5 alkenyl, trifluoromethyl, phenyl group, or a benzyl group.
4.按照权利要求1的化合物,其异构体或其药用盐; 其中X 是NHCH2, CH2 = CH2,或C 三C ; R1是乙烯基或乙炔基;R2是氢,氟,氯,溴,碘,硝基,氰基,甲基,乙基,丙基,异丙基,丁基,异丁基,甲氧基,乙氧基,三氟甲基,羧基,甲氧基羰基,或苯基; R3是氢,甲基,或乙基; R4,R5, R7J R8,禾口R10 是Mi ; R6是异丙基或叔丁基;且R9是甲烷磺酰基,乙烷磺酰基,三氟甲烷磺酰基,或乙烯磺酰基。 4. A compound according to claim 1, an isomer thereof or a pharmaceutically acceptable salt thereof; wherein X is NHCH2, CH2 = CH2, and C or C; Rl is vinyl or ethynyl; R2 is hydrogen, fluoro, chloro, bromo , iodo, nitro, cyano, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, trifluoromethyl, carboxy, methoxycarbonyl, or phenyl; R3 is hydrogen, methyl, or ethyl; R4, R5, R7J R8, R10 is a port Wo Mi; R6 is isopropyl or t-butyl; and R9 is methanesulfonyl group, ethanesulfonyl group, tris trifluoromethanesulfonyl, or vinylsulfonyl.
5.按照权利要求1具有式(Ia)的化合物,其异构体,或其药用盐; 其中X 是NHCH2 或CH2 = CH2 ; R1是乙烯基或乙炔基;R2是氢,氟,氯,溴,碘,硝基,氰基,甲基,乙基,丙基,异丙基,丁基,异丁基,甲氧基,乙氧基,三氟甲基,羧基,甲氧基羰基,或苯基; R3是氢,甲基,或乙基; R4, R5J R7J 禾口R8 是氧;且R6是异丙基或叔丁基。 5. A compound having the formula (Ia) according to claim, an isomer thereof, or a pharmaceutically acceptable salt thereof; wherein X is NHCH2 or CH2 = CH2; R1 is vinyl or ethynyl; R2 is hydrogen, fluoro, chloro, bromo, iodo, nitro, cyano, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, trifluoromethyl, carboxy, methoxycarbonyl, or phenyl; R3 is hydrogen, methyl, or ethyl; R4, R5J R7J Wo port R8 is oxygen; and R6 is isopropyl or t-butyl.
6.按照权利要求1的化合物,其异构体,或其药用盐; 其中X是NHCH2, CR11 = CR12, CHR11CHR12或C三C,其中R11和R12独立地是氢,氟或甲基; R1是乙烯基,乙炔基,丙烯基,或丙炔基;R2是氢,氟,氯,溴,碘,硝基,氰基,甲基,乙基,丙基,异丙基,丁基,异丁基,甲氧基,乙氧基,乙炔基,乙烯基,羧基,或甲氧基羰基; R3是氢,甲基,或乙基;R4, R5, R7,和R8独立地是氢,氟,羧基,甲基,乙基,丙基,异丙基,叔丁基,硝基,乙烯基, 乙炔基,三氟甲基,甲氧基羰基,卤素,甲氧基乙氧基,甲氧基乙氧基甲基,甲基哌嗪基,甲氧基乙基氨基,羟基,甲氧基,烯丙基氧基,异己基氨基,异丁基氨基(ammino),异丙基氨基,吗啉基,吗啉基乙氧基,或四氢吡喃基氧基; R6是C3-C5烷基或卤代(C1-C3)烷基;且R9和Rltl独立地是氢或甲烷磺酰基。 6. A compound according to claim 1, an isomer thereof, or a pharmaceutically acceptable salt thereof; wherein X is NHCH2, CR11 = CR12, CHR11CHR12, or C and C, where R11 and R12 are independently hydrogen, fluoro or methyl; Rl is vinyl, ethynyl, propenyl or propynyl group; R2 is hydrogen, fluoro, chloro, bromo, iodo, nitro, cyano, methyl, ethyl, propyl, isopropyl, butyl, isobutyl butyl, methoxy, ethoxy, ethynyl, vinyl, carboxyl, or methoxycarbonyl group; R3 is hydrogen, methyl, or ethyl; R4, R5, R7, and R8 are independently hydrogen, fluoro , carboxy, methyl, ethyl, propyl, isopropyl, t-butyl, nitro, ethenyl, ethynyl, trifluoromethyl, methoxycarbonyl, halogen, methoxy ethoxy, methoxy ethoxymethyl group, piperazinyl methyl, methoxyethyl group, a hydroxyl group, a methoxy group, an allyl group, isohexyl group, isobutylamino (ammino), isopropylamino, it quinolinyl, morpholinyl ethoxy group, or a tetrahydropyranyl group; R6 is C3-C5 alkyl group or a halo (C1-C3) alkyl; and R9 and Rltl are independently hydrogen or a methanesulfonyl group.
7.按照权利要求1或6的化合物,其异构体,或其药用盐; 其中X是NHCH2, CR11 = CR12, CHR11CHR12或C三C,其中R11是氢或甲基且R12 是S ;R1是乙烯基或乙炔基; R2是氢,氟,甲基,或氯; R3是氢或甲基;R4,是氢,氟,甲氧基甲氧基,甲氧基乙氧基,甲氧基丙氧基,甲氧基,甲氧基乙基氨基,烯丙基氧基,或四氢吡喃基氧基; R5, R7和R8是氢或氟; R6是异丙基或叔丁基;且R9是氢和Rltl表示甲烷磺酰基。 7. A compound according to claim 1 or claim 6, an isomer thereof, or a pharmaceutically acceptable salt thereof; wherein X is NHCH2, CR11 = CR12, CHR11CHR12, or C and C, where R11 is hydrogen or methyl and R12 is S; R1 is vinyl or ethynyl; R2 is hydrogen, fluoro, methyl, or chloro; R3 is hydrogen or methyl; R4, is hydrogen, fluoro, methoxymethoxy, methoxyethoxy, methoxy propoxy group, a methoxy group, methoxyethyl group, an allyl group, or a tetrahydropyranyl group; R5, R7 and R8 are hydrogen or fluoro; R6 is isopropyl or t-butyl; and R9 is hydrogen and Rltl represents methanesulfonyl group.
8.按照权利要求1的化合物,其中X是CHR11-CHR12。 8. A compound according to claim 1, wherein X is CHR11-CHR12.
9.按照权利要求8的化合物, 其中X 是CHR11-CHR12 ; R11和R12是甲基或氢; R1是乙烯基或乙炔基;R2是氢,氟,氯,溴,碘,硝基,氰基,甲基,乙基,丙基,异丙基,丁基,异丁基,甲氧基,乙氧基,三氟甲基,羧基,或甲氧基羰基; R3是氢,甲基,或乙基;R4, R5, R7,和R8独立地是氢,氟,羧基,甲基,乙基,丙基,异丙基,叔丁基,硝基,乙烯基, 乙炔基,三氟甲基,甲氧基羰基,卤素,甲氧基甲氧基,甲氧基乙氧基,甲氧基丙氧基,甲氧基乙氧基甲基,甲基哌嗪基,甲氧基乙基氨基,羟基,甲氧基,烯丙基氧基,异己基氨基,异丁基氨基(ammino),异丙基氨基,吗啉基,吗啉基乙氧基,或四氢吡喃基氧基;且R6是异丙基,叔丁基,或卤代(C1-C3)烷基。 9. The compound according to claim 8, wherein X is CHR11-CHR12; R11 and R12 are hydrogen or methyl; Rl is vinyl or ethynyl; R2 is hydrogen, fluoro, chloro, bromo, iodo, nitro, cyano , methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, trifluoromethyl, carboxyl or methoxycarbonyl group; R3 is hydrogen, methyl, or ethyl; R4, R5, R7, and R8 are independently hydrogen, fluoro, carboxy, methyl, ethyl, propyl, isopropyl, t-butyl, nitro, ethenyl, ethynyl, trifluoromethyl, , methoxycarbonyl, halogen, methoxymethoxy, methoxyethoxy, methoxypropoxy, methoxyethoxymethyl, methyl piperazinyl, methoxyethylamino , a hydroxyl group, a methoxy group, an allyl group, isohexyl group, isobutylamino (ammino), an isopropyl group, a morpholino group, an ethoxy group morpholinyl, or tetrahydropyranyl group; and R6 is isopropyl, t-butyl, or halo (C1-C3) alkyl.
10.按照权利要求8和9任一项的化合物,其中R11是氢或甲基,且R12是氢;R1是乙烯基或乙炔基; R2是氢,氟,氯,或甲基;R4是氢,氟,甲氧基甲氧基,甲氧基乙氧基,甲氧基丙氧基,甲氧基,甲氧基乙基氨基,烯丙基氧基,或四氢吡喃基氧基; R5, R7和R8是氢或氟;R6是叔丁基;R9是氢;且R10表示甲烷磺酰基。 8 and 10. The compound according to any one of claims 9, wherein R11 is hydrogen or methyl, and R12 is hydrogen; Rl is vinyl or ethynyl; R2 is hydrogen, fluoro, chloro, or methyl; R4 is hydrogen , fluoro, methoxymethoxy, methoxyethoxy, methoxypropoxy, methoxy, methoxyethyl group, an allyl group, or a tetrahydropyranyl group; R5, R7 and R8 are hydrogen or fluoro; R6 is tert-butyl; R9 is hydrogen; and R10 represents methanesulfonyl group.
11.按照权利要求1的式(Id)的化合物,或其药用盐; 11. A compound according to claim of formula (Id) is 1, or a pharmaceutically acceptable salt thereof;
Figure CN101142174BC00051
其中Rl, R2,R3,R4,R5,R6,R7,R8和X具有前述权利要求任一项的含义。 Wherein Rl, R2, R3, R4, R5, R6, R7, R8 and X have the meanings of any one of the preceding claims.
12. 一种化合物,其异构体,或其药用盐,其中所述化合物选自由下列各项组成的组: N-{4-[3-(4-叔丁基苄基)脲基甲基]-2-乙烯基苯基}甲烷磺酰胺,N-{4-[3-(4-叔丁基苄基)脲基甲基]-2-氟-6-乙烯基苯基}甲烷磺酰胺, N-{4-[3-(4-叔丁基苄基)脲基甲基]-2-乙炔基-6-氟苯基}甲烷磺酰胺,N-{4-[3-(4-叔丁基苄基)脲基甲基]-5-氯-2-乙烯基苯基}甲烷磺酰胺, N-{4-[3-(4-叔丁基苄基)脲基甲基]-5-氯-2-乙炔基苯基}甲烷磺酰胺, N-(4-{l-(R)-[3-(4-叔丁基苄基)脲基]乙基}-2_乙烯基苯基)甲烷磺酰胺, (R) -N- (4- {1-[3- (4-叔丁基-苄基)_脲基]-乙基} -2-氟-6-乙烯基-苯基)甲烷磺酰胺,N-{4-[3-(4-叔丁基-苄基)_脲基甲基]-2-甲基-6-乙烯基-苯基}甲烷磺酰胺, N-{4-[3-(4-叔丁基-苄基)_脲基甲基]-2-氯-6-乙烯基-苯基}甲烷磺酰胺, 3-(4-叔丁基苯基)丙炔酸3-氟-4-甲烷磺酰基氨基-5-乙烯基苄基酰胺, 3_ 12. A compound, an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of: N- {4- [3- (4- tert-butylbenzyl) allophanate yl] -2-vinyl-phenyl} methanesulfonamide, N- {4- [3- (4- tert-butylbenzyl) ureidomethyl] -2-fluoro-6-vinyl-phenyl} methanesulfonamide amide, N- {4- [3- (4- tert-butylbenzyl) ureidomethyl] -2-ethynyl-6-fluorophenyl} methanesulfonamide, N- {4- [3- (4 - tert-butylbenzyl) ureidomethyl] -5-chloro-2-vinyl-phenyl} methanesulfonamide, N- {4- [3- (4- tert-butylbenzyl) ureidomethyl] 5-chloro-2-ethynyl-phenyl} methanesulfonamide, N- (4- {l- (R) - [3- (4- tert-butyl-benzyl) ureido] ethyl} ethylene -2_ phenyl) methanesulfonamide, (R) -N- (4- {1- [3- (4- tert-butyl-benzyl) - _ ureido] - ethyl} -2-fluoro-6-vinyl - phenyl) methanesulfonamide, N- {4- [3- (4- tert-butyl-benzyl) - _ ureido methyl] -2-methyl-6-vinyl - phenyl} methanesulfonamide N- {4- [3- (4- tert-butyl-benzyl) - _ ureido methyl] -2-chloro-6-vinyl - phenyl} methanesulfonamide, 3- (4-tert-butylbenzene yl) propiolic acid 3-fluoro-4-methanesulfonyl-5-vinyl benzyl amide, 3_ (4-叔丁基苯基)丙炔酸[1-(3-氟-4-甲烷磺酰基氨基-5-乙烯基苯基)乙基]酰胺, 3-(4_叔丁基苯基)-N-[l-(R)-(4-甲烷磺酰基氨基-3-乙烯基苯基)乙基]丙烯酰胺,3- (4-叔丁基苯基)-N- (3-氟-4-甲烷磺酰基氨基-5-乙烯基苄基)丙烯酰胺, 3-(4-叔丁基苯基)-N-(3-氟-5-乙炔基-4-甲烷磺酰基氨基_苄基)丙烯酰胺, 3- (4-叔丁基苯基)-N- (4-甲烷磺酰基氨基-3-乙烯基苄基)丙烯酰胺, 3-(4-三氟甲基苯基)-N-(4-甲烷磺酰基氨基-3-乙烯基苄基)丙烯酰胺, 3- (4-叔丁基苯基)-N- (3-氯-4-甲烷磺酰基氨基-5-乙烯基苄基)丙烯酰胺, 3- (4-叔丁基-2-吗啉-4-基-苯基)-N- (3-氟-4-甲烷磺酰基氨基_5_乙烯基苄基) 丙烯酰胺,3-(4-叔丁基-2-甲氧基乙氧基-苯基)-N-(3-氟-4-甲烷磺酰基氨基-5-乙烯基苄基)丙烯酰胺,3- [4-叔丁基-2- (2-甲氧基乙基氨基)苯基]-N- (3-氟-4-甲烷磺酰基氨基_5_乙烯基苄基)丙 (4-tert-butyl-phenyl) propiolic acid [1- (3-fluoro-4-methanesulfonyl-5-vinylphenyl) ethyl] amide, 3- (4_-tert-butylphenyl) -N- [l- (R) - (4- methanesulfonyl-3-vinylphenyl) ethyl] acrylamide, 3- (4-tert-butylphenyl) -N- (3- fluoro - 4- methanesulfonylamino-5-vinyl-benzyl) acrylamide, 3- (4-tert-butylphenyl) -N- (3- fluoro-5-ethynyl-4-methanesulfonylamino-benzyl _ ) acrylamide, 3- (4-tert-butylphenyl) -N- (4- methanesulfonyl-3-vinyl benzyl) acrylamide, 3- (4-trifluoromethylphenyl) -N - (4-methanesulfonyl-3-vinyl benzyl) acrylamide, 3- (4-tert-butylphenyl) -N- (3- chloro-4-methanesulfonyl-5-vinylbenzyl yl) acrylamide, 3- (4-tert-butyl-2-morpholin-4-yl - phenyl) -N- (3- fluoro-4-ylamino _5_ vinylbenzyl) acrylamide 3- (4-tert-butyl-2-methoxy-ethoxy - phenyl) -N- (3- fluoro-4-methanesulfonyl-5-vinyl-benzyl) acrylamide, 3- [ 4-tert-butyl-2- (2-methoxyethyl) phenyl] -N- (3- fluoro-4-methanesulfonyl _5_ vinylbenzyl amino) propyl 烯酰胺,3- (4-叔丁基-2-甲氧基苯基)-N- (3-氟-4-甲烷磺酰基氨基-5-乙烯基_苄基)丙烯酰胺,3- (2-烯丙基氧基-4-叔丁基苯基)-N- (3-氟-4-甲烷磺酰基氨基-5-乙烯基苄基) 丙烯酰胺,3- [4-叔丁基-2- (3-甲基丁基氨基)苯基]-N- (3-氟-4-甲烷磺酰基氨基_5_乙烯基苄基)丙烯酰胺,3-(4-叔丁基-2-异丙基氨基苯基)-N-(3-氟-4-甲烷磺酰基氨基-5-乙烯基苄基) 丙烯酰胺,3-(4_叔丁基苯基)-Ν-[1-(3-氟-4-甲烷磺酰基氨基-5-乙烯基苯基)乙基]丙酰胺,3-(4_叔丁基苯基)-Ν-[1-(3-氟-4-甲烷磺酰基氨基-5-乙烯基苯基)乙基]丙烯酰胺,3_(4-叔丁基苯基)-N-(3-氟-4-甲烷磺酰基氨基-5-乙烯基苄基)-2_甲基丙烯酰胺,3- (4-叔丁基苯基)-2-氟-N- (3-氟-4-甲烷磺酰基氨基-5-乙烯基苄基)丙烯酰胺3- [4-叔丁基-2-(四氢吡喃-4-基氧基)苯基]-N- (3-氟-4-甲烷磺酰基氨基_5_乙烯基苄基)丙烯酰胺,3- [4-叔丁基 Enamide, 3- (4-tert-butyl-2-methoxyphenyl) -N- (3- fluoro-4-methanesulfonyl-5-vinyl-_ benzyl) acrylamide, 3- (2 - allyl-4-tert-butylphenyl) -N- (3- fluoro-4-methanesulfonyl-5-vinyl-benzyl) acrylamide, 3- [4-tert-butyl-2 - (3-methylbutyl) phenyl] -N- (3-fluoro-4-ylamino _5_ vinyl benzyl) acrylamide, 3- (4-tert-butyl-2-isobutyl propyl-aminophenyl) -N- (3- fluoro-4-methanesulfonyl-5-vinyl-benzyl) acrylamide, 3- (4_-tert-butylphenyl) -Ν- [1- (3 - fluoro-4-methanesulfonyl-5-vinylphenyl) ethyl] propionamide, 3- (4_-tert-butylphenyl) -Ν- [1- (3- fluoro-4-yl amino-5-vinylphenyl) ethyl] acrylamide, 3_ (4-tert-butylphenyl) -N- (3- fluoro-4-methanesulfonyl-5-vinylbenzyl) -2_ methacrylamide, 3- (4-tert-butylphenyl) -2-fluoro -N- (3- fluoro-4-methanesulfonyl-5-vinylbenzyl-yl) acrylamide 3- [4-tert butyl-2- (tetrahydropyran-4-yloxy) phenyl] -N- (3- fluoro-4-ylamino _5_ vinyl benzyl) acrylamide, 3- [4- tert-butyl -2-(四氢吡喃-4-基氧基)苯基]-N- (3-氟-4-甲烷磺酰基氨基_5_乙烯基苄基)丙酰胺,3-(4-叔丁基苯基)-N-[1-(4-甲烷磺酰基氨基-3-乙烯基苯基)乙基]-2-甲基丙烯酰胺,3- (4-叔丁基苯基)-N- (3-氟-4-甲烷磺酰基氨基-5-乙烯基苄基)-2-甲基丙酰胺, 3-[4-(叔丁基)苯基]-N-[4-(甲烷磺酰基氨基)-3_乙烯基苄基]丙酰胺, 3-[4-(叔丁基)苯基]-N-[3-氟-4-(甲烷磺酰基氨基)-5_乙烯基苄基]丙酰胺, 3-(4-叔丁基-苯基)-N-(3-乙炔基-5-氟-4-甲烷磺酰基氨基_苄基)_丙酰胺, Ν-(4-{1-[3-(4-叔丁基苯基)脲基]乙基}-2_乙烯基苯基)甲烷磺酰胺, Ν-(4-{1-[3-(4-叔丁基苯基)脲基]乙基}-2_乙炔基苯基)甲烷磺酰胺, N-{4-[3-(4-叔丁基苯基)脲基甲基]-2-氟-6-乙烯基苯基}甲烷磺酰胺,和乙烯磺酸(4-{1-[3-(4_叔丁基苯基)脲基]乙基}-2_乙烯基苯基)酰胺。 -2- (tetrahydropyran-4-yloxy) phenyl] -N- (3- Fluoro-4-ylamino _5_ vinylbenzyl) propanamide, 3- (4-tert-butyl phenyl) -N- [l- (4-methanesulfonyl-3-vinylphenyl) ethyl] -2-methyl-acrylamide, 3- (4-tert-butylphenyl) -N- (3-fluoro-4-methanesulfonyl-5-vinylbenzyl) -2-methyl-propanamide, 3- [4- (tert-butyl) phenyl] -N- [4- (methanesulfonyl amino) -3_ vinyl benzyl] propanamide, 3- [4- (tert-butyl) phenyl] -N- [3- fluoro-4- (methane-sulfonylamino) -5_ vinylbenzyl] propionamide, 3- (4-tert-butyl - phenyl) -N- (3- ethynyl-5-fluoro-4-methanesulfonyl benzyl group _) _ propanamide, Ν- (4- {1- [3- (4-tert-butylphenyl) ureido] ethyl} -2_ vinylphenyl) methanesulfonamide, Ν- (4- {1- [3- (4- tert-butylphenyl) ureido] ethyl} -2_ ethynylphenyl) methanesulfonamide, N- {4- [3- (4- tert-butylphenyl) ureidomethyl] -2-fluoro-6-vinyl benzene yl} methanesulfonamide, vinyl sulfonic acid and (4- {1- [3- (4 _ t-butylphenyl) ureido] ethyl} -2_ vinylphenyl) amide.
13.按照权利要求12的化合物,其异构体,或其药用盐,其中所述化合物选自由下列各项组成的组:(R) -N- (4- {1- [3- (4-叔丁基-苄基)_脲基]-乙基} -2-氟-6-乙烯基-苯基)-甲烷磺酰胺,3-(4_叔丁基苯基)-N-[l-(R)-(4-甲烷磺酰基氨基-3-乙烯基-苯基)乙基]丙烯酰胺,3- (4-叔丁基苯基)-N- (3-氟-4-甲烷磺酰基氨基-5-乙烯基-苄基)丙烯酰胺, 3_ (4-叔丁基苯基)-N-(3-氟-5-乙炔基-4-甲烷磺酰基氨基-苄基)丙烯酰胺, (R)-3-(4-叔丁基苯基)-Ν-[1-(3-氟-4-甲烷磺酰基氨基-5-乙烯基苯基)乙基]丙酰胺,3_(4-叔丁基苯基)-N-(3-氟-4-甲烷磺酰基氨基-5-乙烯基苄基)-2_甲基丙烯酰胺,3-[4-叔丁基-2-(四氢吡喃-4-基氧基)苯基]-N- (3-氟-4-甲烷磺酰基氨基_5_乙烯基苄基)丙酰胺,(R) -3- (4-叔丁基苯基)-N-[1- (4-甲烷磺酰基氨基-3-乙烯基苯基)乙基]-2-甲基丙烯酰胺,N-{4-[3-(4-叔丁基苄基)脲基甲 13. The compound according to claim 12, an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of: (R) -N- (4- {1- [3- (4 - tert-butyl-benzyl) - _ ureido] - ethyl} -2-fluoro-6-vinyl - phenyl) - methanesulfonamide, 3- (4_-tert-butylphenyl) -N- [l - (R & lt) - (4-methanesulfonyl-3-vinyl - phenyl) ethyl] acrylamide, 3- (4-tert-butylphenyl) -N- (3- fluoro-4-sulfo acylamino-5-vinyl-benzyl) - acrylamide, 3_ (4-tert-butylphenyl) -N- (3- ethynyl-4-fluoro-5-methane-sulfonylamino-benzyl) - acrylamide, (R) -3- (4- tert-butylphenyl) -Ν- [1- (3- fluoro-4-methanesulfonyl-5-vinylphenyl) ethyl] propionamide, 3_ (4- tert-butylphenyl) -N- (3- fluoro-4-methanesulfonyl-5-vinylbenzyl) -2_ methacrylamide, 3- [4-tert-butyl-2- (tetrahydro pyran-4-yloxy) phenyl] -N- (3- fluoro-4-ylamino _5_ vinylbenzyl) propanamide, (R) -3- (4- tert-butyl-benzene yl) -N- [1- (4- methanesulfonyl-3-vinylphenyl) ethyl] -2-methyl-acrylamide, N- {4- [3- (4- tert-butylbenzyl ) allophanate ]-2-氟-6-乙烯基苯基}甲烷磺酰胺, N-{4-[3-(4-叔丁基苄基)脲基甲基]-2-乙炔基-6-氟苯基}甲烷磺酰胺, 3-(4-叔丁基苯基)丙炔酸3-氟-4-甲烷磺酰基氨基-5-乙烯基苄基酰胺, 3- (4-叔丁基苯基)-N- (4-甲烷磺酰基氨基-3-乙烯基苄基)丙烯酰铵, 3-[4-叔丁基-2- (2-甲氧基-乙氧基)_苯基]-N- (3-氟-4-甲烷磺酰基氨基_5_乙烯基-苄基)-丙烯酰胺,3- [4-叔丁基-2- (2-甲氧基乙基氨基)苯基]-N- (3-氟-4-甲烷磺酰基氨基_5_乙烯基苄基)丙烯酰胺,3- (4-叔丁基-2-甲氧基苯基)-N- (3-氟-4-甲烷磺酰基氨基-5-乙烯基-苄基)丙烯酰胺,3-(2-烯丙基氧基-4-叔丁基苯基)-N-(3-氟-4-甲烷磺酰基氨基-5-乙烯基苄基) 丙烯酰胺,(R)-3-(4-叔丁基苯基)-Ν-[1-(3-氟-4-甲烷磺酰基氨基-5-乙烯基苯基)乙基]丙烯酰胺,3-(4-叔丁基苯基)-N-(3-氟-4-甲烷磺酰基氨基-5-乙烯基苄基)-2-甲基丙酰胺,3-[4-(叔丁基)苯 ] -2-fluoro-6-vinyl-phenyl} methanesulfonamide, N- {4- [3- (4- tert-butylbenzyl) ureidomethyl] -2-ethynyl-6-fluorophenyl } methanesulfonamide, 3- (4-tert-butyl-phenyl) propiolic acid 3-fluoro-4-methanesulfonyl-5-vinyl-benzylamide, 3- (4-tert-butylphenyl) - N- (4- methanesulfonyl-3-vinylbenzyl) ammonium acryloyl, 3- [4-tert-butyl-2- (2-methoxy-ethoxy) - _ phenyl] -N- (3-fluoro-4-methanesulfonyl amino _5_ vinyl - benzyl) - acrylamide, 3- [4-tert-butyl-2- (2-methoxyethyl) phenyl] -N - (3-fluoro-4-methanesulfonyl amino _5_ vinyl benzyl) acrylamide, 3- (4-tert-butyl-2-methoxyphenyl) -N- (3- fluoro-4- methanesulfonylamino-5-vinyl-benzyl) - acrylamide, 3- (2-allyl-4-tert-butylphenyl) -N- (3- fluoro-4-ylamino - 5-vinyl-benzyl) acrylamide, (R) -3- (4- tert-butylphenyl) -Ν- [1- (3- fluoro-4-methanesulfonyl-5-vinylphenyl) ethyl] acrylamide, 3- (4-tert-butylphenyl) -N- (3- fluoro-4-methanesulfonyl-5-vinylbenzyl) -2-methyl-propanamide, 3- [ 4- (tert-butyl) benzene 基]-N-[4-(甲烷磺酰基氨基)-3_乙烯基苄基]丙酰胺,N-(4-{l-(R)-[3-(4-叔丁基苄基)脲基]乙基}-2_乙烯基苯基)甲烷磺酰胺,3-[4-(叔丁基)苯基]-N-[3-氟-4-(甲烷磺酰基氨基)-5_乙烯基苄基]丙酰胺,和(R)-N-(4-{l-[3-(4-叔丁基苯基)脲基]乙基}-2_乙烯基苯基)甲烷磺酰胺。 Yl] -N- [4- (methane-sulfonylamino) -3_ vinyl benzyl] propanamide, N- (4- {l- (R) - [3- (4- tert-butylbenzyl) urea yl] ethyl} -2_ vinylphenyl) methanesulfonamide, 3- [4- (tert-butyl) phenyl] -N- [3- fluoro-4- (methane-sulfonylamino) ethylene -5_ benzyl] propanamide, and (R) -N- (4- {l- [3- (4- tert-butylphenyl) ureido] ethyl} -2_ vinylphenyl) methanesulfonamide.
14.按照权利要求1或12的化合物,其用作药物。 14. The compound according to claim 1 or claim 12, for use as a medicament.
15. 一种药物组合物,其包含作为活性成分的按照权利要求1-13任一项的化合物、其异构体、或其药用盐,以及药用载体。 15. A pharmaceutical composition comprising as active ingredient a compound according to any one of claims 1-13, an isomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
16. 一种用于预防和治疗与香草素受体的病理性刺激和/或异常表达相关的病症的药物组合物,其中所述组合物包含按照权利要求1-13中任一项的化合物、其异构体、或其药用盐;及其药用载体。 16. A method for stimulating pathologic prevention and treatment of vanilloid receptor and / or aberrant expression of a disorder related to a pharmaceutical composition, wherein said composition comprises a compound according to any one of 1-13 claims, an isomer thereof, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
17.按照权利要求15或16的药物组合物,其用于治疗选自下列各项的病症:疼痛,关节的炎性疾病,膀胱过敏,包括尿失禁,胃十二指肠溃疡,肠易激综合征(IBS)和炎性肠病(IBD,神经性/变应性/炎性皮肤病,银屑病,哮喘,慢性阻塞性肺病,瘙痒症,或痒疹。 17. The pharmaceutical composition as claimed in claim 15 or 16, for the treatment of a condition selected from the following: pain, inflammatory joint disease, irritable bladder, including urinary incontinence, stomach duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD, neurotic / allergic / inflammatory skin disease, psoriasis, asthma, chronic obstructive pulmonary disease, pruritus or prurigo.
18.按照权利要求17的药物组合物,其中所述疼痛是选自下列各项的病症或与其相关:骨关节炎,类风湿性关节炎,强直性脊柱炎,糖尿病性神经性疼痛,术后痛,非炎性肌骨骼疼痛,偏头痛和其它的类型的头痛。 18. The pharmaceutical composition as claimed in claim 17, wherein said pain is selected from the following or a condition associated therewith: osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, post pain, non-inflammatory musculoskeletal pain, migraine and other types of headaches.
19.按照权利要求18的药物组合物,其中所述非炎性肌骨骼疼痛包括纤维肌痛,肌筋膜疼痛综合征和背痛。 19. The pharmaceutical composition as claimed in claim 18, wherein the non-inflammatory musculoskeletal pain including fibromyalgia, myofascial pain syndrome and back pain.
20.按照权利要求15-19任一项的药物组合物,其特征在于其适合于口服施用。 20. The pharmaceutical composition as claimed in any one of claims 15-19, characterized in that it is suitable for oral administration.
21.按照权利要求1-13任一项的化合物、其异构体、或其药用盐用于预防或治疗与香草素受体的异常表达和/或异常激活相关的病症的应用。 21. The compound according to any one of claims 1-13, an isomer thereof, or a pharmaceutically acceptable salt thereof for the aberrant expression and / or treatment or prophylaxis of an abnormal activation of vanilloid receptor associated disorders.
22.按照权利要求1-13任一项的化合物、其异构体、或其药用盐用于制备药物的应用, 所述药物用于预防或治疗选自疼痛,关节的炎性疾病,膀胱过敏,包括尿失禁,胃十二指肠溃疡,肠易激综合征(IBS)和炎性肠病(IBD),神经性/变应性/炎性皮肤病,银屑病,哮喘, 慢性阻塞性肺病,瘙痒症,或痒疹的病症。 22. The compound according to any one of claims 1-13, an isomer thereof, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament, said medicament for preventing or treating pain selected, inflammatory diseases of the joints, urinary bladder allergies, including urinary incontinence, stomach duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), neurotic / allergic / inflammatory skin disease, psoriasis, asthma, chronic obstructive pulmonary disease, pruritus, prurigo or illness.
23.按照权利要求22的化合物的应用,其中所述病症是疼痛,或其是选自下列各项的病症或与其相关:骨关节炎,类风湿性关节炎,强直性脊柱炎,糖尿病性神经性疼痛,术后痛,非炎性肌骨骼疼痛,偏头痛,和其它的类型的头痛。 22 23. The use of a compound according to claim, wherein said pain disorder, or a disorder selected from the following or associated with: osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathy pain, postoperative pain, non-inflammatory musculoskeletal pain, migraine, and other types of headaches.
24.按照权利要求23的化合物的应用,其中所述非炎性肌骨骼疼痛包括纤维肌痛,肌筋膜疼痛综合征和背痛。 24. The use of a compound according to claim 23, wherein the non-inflammatory musculoskeletal pain including fibromyalgia, myofascial pain syndrome and back pain.
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CN106543046B (en) * 2016-09-28 2018-05-22 齐鲁工业大学 A kind of new 3- anisyls-benzamides adjusts the compound and its medical usage of estrogen-related receptor activity

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