CN106220618A - 作为趋化因子受体调节剂的硫衍生物 - Google Patents
作为趋化因子受体调节剂的硫衍生物 Download PDFInfo
- Publication number
- CN106220618A CN106220618A CN201610576401.0A CN201610576401A CN106220618A CN 106220618 A CN106220618 A CN 106220618A CN 201610576401 A CN201610576401 A CN 201610576401A CN 106220618 A CN106220618 A CN 106220618A
- Authority
- CN
- China
- Prior art keywords
- chloro
- phenyl
- benzofuran
- compound
- sulfonamide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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- 108050000299 Chemokine receptor Proteins 0.000 title claims abstract description 28
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 240
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 155
- -1 3-nitrobenzyl Chemical group 0.000 claims description 147
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 147
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical class [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 15
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- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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Abstract
本发明涉及新的硫衍生物、它们的制备方法、含有它们的药物组合物和它们作为趋化因子受体的调节剂的药物的用途。
Description
本申请是2011年12月9日提交的申请号为PCT/US2011/064233、发明名称为“作为趋化因子受体调节剂的硫衍生物”的国际申请的分案申请,所述国际申请于2013年8月14日进入中国国家阶段,其申请号为201180067536.X。
相关申请
本申请要求于2011年12月16日提交的美国临时专利申请序列号61/423,940的权益,其公开内容在此通过引用整体并入本文。
发明领域
本发明涉及新的硫衍生物、它们的制备方法、含有它们的药物组合物和它们作为趋化因子受体的调节剂的药物的用途。本发明具体涉及这些化合物及其药物组合物治疗与趋化因子受体(CCR)调节相关的病症的用途。
发明背景
趋化因子是一组在炎症期间组织白细胞募集和迁移中起重要作用的7-至14-kd的肽,并因此表示抗炎症治疗的重要靶点(Wells等人,2006)。它们可以通过结合7次跨膜的G蛋白偶联受体,即趋化因子受体而起作用。趋化因子系统是复杂的,具有在人中鉴定的约50个趋化因子和20个趋化因子受体,通常以丰余方式起作用,使得很难选择特异性拮抗剂(Gerard和Rollins,2001)。基因敲除策略已证明趋化因子作为免疫功能调节剂的重要性,而特异性趋化因子的缺失仅仅在炎症反应中导致特异的和相对轻微的缺陷,进一步强调了系统的复杂丰余性。选择性对于趋化因子受体拮抗剂在牵涉趋化因子受体系统的全身性疾病例如动脉粥样硬化(atheroscelorsis)中的使用是至关重要的,在动脉粥样硬化中巨噬细胞/单核细胞系统是主要参与者以使得能够精细且特异性地控制免疫功能(Weisberg等人,2006;Feria和Diaz Gonzalez等人,2006)。
许多眼部病症的特征在于将细胞如白细胞和内皮细胞不适当地迁移和浸润到眼睛中并且对眼部结构具有有害影响(Wallace等人,2004)。趋化因子在此类疾病中已被鉴定并且趋化因子系统的错误调节在角膜移植排斥、糖尿病性视网膜病变、年龄相关性黄斑变性(ARMD)、慢性炎性疾病例如葡萄膜炎、干眼病等中是明显的。缺乏CCR2或MCP-1的小鼠随着年龄增加产生ARMD的特征,包括玻璃疣沉积、脉络膜新生血管形成和光感受器萎缩,表明这种趋化因子及其受体信号传导的关键作用(Amabati等人,2003)。因此,CCR2受体特异性抑制剂可能在眼部疾病例如ARMD中具有潜在治疗益处。相反,多种人和动物研究已经鉴定了几种趋化因子,葡萄膜炎,产生两种不同形式的定居和渗透单元,这强烈提示这些分子主要作用的用于在其发病机理。葡萄膜炎的大鼠和小鼠模型中的研究已经表明上调单核细胞化学引诱物蛋白-1(MCP-1)、巨噬细胞炎症性蛋白-1(MIP-1)、RANTES、基质细胞衍生因子-1(SDF-1),它们为单核细胞和T细胞的有效化学引诱物(Fang等人,2004;Keino等人,2003)。已经在患有急性前葡萄膜炎(AAU)即最常见的人葡萄膜炎形式的患者的外周血单核细胞中报道了相似的发现(Klitgaard等人,2004)。MCP-1敲除的小鼠和CCR5敲除的小鼠显示出降低的内毒素诱导的葡萄膜炎,这为AAU的动物模型(Takeuchi等人,2005;Tuallion等人,2002)。还已经证明通过使用NF-κ B阻滞剂来阻断趋化因子系统上游对显著削弱大鼠中的实验AAU(Yang等人,2005)。阻断NF-κ B导致多种趋化因子的转录抑制。由于葡萄膜炎发病机理的复杂性,单一疗法中选择性抑制趋化因子受体将不可能提供治疗益处。多个趋化因子的类似作用已显示与糖尿病性视网膜病和干眼病中的疾病临床分期相关(Meleth等人,2005;Yamagami等人,2005)。在这些眼科疾病中,抑制多种趋化因子功能的广谱性趋化因子受体抑制剂可能是有益的。
待报道的第一广谱性趋化因子抑制剂(BSCI)被称为Peptide 3,它衍生自人趋化因子MCP-1的序列,并且显示响应于MCP-1、MIP-1、RANTES和SDF-1而阻断单核细胞的迁移(Reckles和Grainger.1999)。观察到称为NR58-3.14.3的由反向序列中的D-氨基酸构建的环状逆向反转类似物Peptide 3是更有效的趋化因子抑制剂(Beech等人,2001)。NR58-3.14.3已经被用于测试动脉粥样硬化、肺部炎症、过敏性肠易激综合征等动物模型中的抗炎活性(Beech等人,2001;Grainger和Reckless.2003;Tokuyama等人,2005)。然而,使用这些BSCI作为长期治疗策略存在多个缺点。已知的BSCI肽具有相对较低的效力、较差的药物动力学,并且在体内是不稳定的。此外,广谱性趋化因子受体抑制剂的全身性使用由于其全身性抗炎症活性而可能导致有害的副作用。然而,在眼部疾病中,局部或表面施用可防止广谱性抑制剂被全身吸收。数种趋化因子受体的小分子抑制剂的鉴定可以对于治疗炎症性眼部疾病是非常有用的。由于在数种眼部疾病和这些结果中的多种趋化因子的作用的证据,我们认为使用小分子和大分子的广谱性趋化因子受体抑制剂将可用于眼部炎症性疾病的局部治疗,所述眼部炎症性疾病包括但不限于葡萄膜炎、干眼病、糖尿病视网膜病变、眼色素层炎、变应性眼病和增殖性视网膜病变。因此,操作多个趋化因子代表一种新的治疗眼部疾病的治疗方法。
WO2008008374公开了CCR2抑制剂及其使用方法。
WO03/099773公开了CCR9抑制剂及其使用方法。
US7622583公开了作为CCR2受体拮抗剂的杂芳基磺酰胺。
US 2008/0293720公开了吡啶基磺酰胺趋化因子受体调节剂。
US7393873公开了芳基磺酰胺衍生物。
发明概述
目前,我们已经发现了作为有效的和选择性的趋化因子受体调节剂的一组新的硫衍生物。因此,本文中所述的化合物可用于治疗许多种与趋化因子受体的调节相关的病症。本文中所用的术语“调节剂”包括但不限于:受体激动剂、拮抗剂、反向激动剂、逆向激动剂、部分激动剂、部分拮抗剂。
本发明描述了具有趋化因子受体生物活性的式I化合物。因此,根据本发明的化合物可用于医学,例如用于治疗患有可通过CCR调节得以缓解的疾病和疾患的人。
一方面,本发明提供具有式I的化合物或其药学上可接受的盐或其立体异构形式、或其单独的几何异构体、对映异构体、非对映异构体、互变异构体、两性离子及药学上可接受的盐:
其中:
R1是H
R2是取代或未取代的C1-6烷基、取代或未取代的C3-8环烷基或是取代或未取代的C3-8环烯基;
R5是-S-、-S(O)-或-S(O)2-;
R6是取代或未取代的杂环、取代或未取代的C3-8环烷基、取代或未取代的C3-8环烯基或是取代或未取代的C6-10芳基;
R17是H、取代或未取代的C1-6烷基、卤素、取代或未取代的-OC1-6烷基、CN、C(O)R19、NR20R21或羟基;
R18是H、取代或未取代的C1-6烷基、卤素、取代或未取代的-OC1-6烷基、CN、C(O)R22、NR23R24或羟基;
R7是H、卤素、CN、取代或未取代的-OC1-6烷基、取代或未取代的C1-6烷基或是取代或未取代的C3-8环烷基;
R8是H、取代或未取代的C1-6烷基、卤素、取代或未取代的-OC1-6烷基或羟基;
R19是H、OH或取代或未取代的C1-6烷基
R20是H或取代或未取代的C1-6烷基;
R21是H或取代或未取代的C1-6烷基;
R22是H、OH或取代或未取代的C1-6烷基
R23是H或取代或未取代的C1-6烷基;
R24是H或取代或未取代的C1-6烷基;且包括以下化合物:
N-{2-[(3-氨基苄基)硫基]苯基}-1-苯并呋喃-2-磺酰胺;
N-{2-[(3-硝基苄基)亚磺酰基]苯基}-1-苯并呋喃-2-磺酰胺;
N-{2-[(3-氨基苄基)亚磺酰基]苯基}-1-苯并呋喃-2-磺酰胺;
N-{2-[(3-硝基苄基)磺酰基]苯基}-1-苯并呋喃-2-磺酰胺;和
N-{2-[(3-氨基苄基)磺酰基]苯基}-1-苯并呋喃-2-磺酰胺;以及
附带条件是
a).R7、R8、R17和R18不能同时均为H;
b).当R8是取代或未取代的C1-6烷基时,该烷基不含有直接与苯基环连接的羰基;
c).该化合物不具有下列结构:
在另一方面,本发明提供具有式I的化合物,其中
R1是H;
R2是取代或未取代的C1-6烷基、取代或未取代的C3-8环烷基或取代或未取代的C3-8环烯基;
R5是S;
R6是取代或未取代的杂环、取代或未取代的C3-8环烷基、取代或未取代的C3-8环烯基或取代或未取代的C6-10芳基;
R17是H、取代或未取代的C1-6烷基、卤素、取代或未取代的-OC1-6烷基、CN、C(O)R19、NR20R21或羟基;
R18是H、C1-6烷基、卤素、取代或未取代的-OC1-6烷基、CN、C(O)R22、NR23R24或羟基;
R7是H、卤素、CN、取代或未取代的-OC1-6烷基、取代或未取代的C1-6烷基或取代或未取代的C3-8环烷基;
R8是H、取代或未取代的C1-6烷基、卤素、取代或未取代的-OC1-6烷基或羟基;
R19是H、OH或取代或未取代的C1-6烷基;
R20是H或取代或未取代的C1-6烷基;
R21是H或取代或未取代的C1-6烷基;
R22是H、OH或取代或未取代的C1-6烷基;
R23是H或取代或未取代的C1-6烷基;和
R24是H或取代或未取代的C1-6烷基;以及
附带条件是
a).R7、R8、R17和R18不能同时均为H;
b).当R8是取代或未取代的C1-6烷基时,该烷基不含有直接与苯基环连接的羰基;
c).该化合物不具有下列结构:
在另一方面,本发明提供具有式I的化合物,其中:
R1是H;
R2是取代或未取代的C1-6烷基、取代或未取代的C3-8环烷基或取代或未取代的C3-8环烯基;
R5是-S(O)-;
R6是取代或未取代的杂环、取代或未取代的C3-8环烷基、取代或未取代的C3-8环烯基或取代或未取代的C6-10芳基;
R17是H、取代或未取代的C1-6烷基、卤素、取代或未取代的-OC1-6烷基、CN、C(O)R19、NR20R21或羟基;
R18是H、取代或未取代的C1-6烷基、卤素、取代或未取代的-OC1-6烷基、CN、C(O)R22、NR23R24或羟基;
R7是H、卤素、CN、取代或未取代的-OC1-6烷基、取代或未取代的C1-6烷基或取代或未取代的C3-8环烷基;
R8是H、取代或未取代的C1-6烷基、卤素、取代或未取代的-OC1-6烷基或羟基;
R19是H、OH或取代或未取代的C1-6烷基;
R20是H或取代或未取代的C1-6烷基;
R21是H或取代或未取代的C1-6烷基;
R22是H、OH或取代或未取代的C1-6烷基;
R23是H或取代或未取代的C1-6烷基;和
R24是H或取代或未取代的C1-6烷基;以及
附带条件是
a).R7、R8、R17和R18不能同时均为H;
b).当R8是取代或未取代的C1-6烷基时,该烷基不含有直接与苯基环连接的羰基;
c).该化合物不具有下列结构:
在另一方面,本发明提供具有式I的化合物,其中:
R1是H;
R2是取代或未取代的C1-6烷基、取代或未取代的C3-8环烷基或取代或未取代的C3-8环烯基;
R5是-S(O)2-;
R6是杂环、取代或未取代的C3-8环烷基、取代或未取代的C3-8环烯基或取代或未取代的C6-10芳基;
R17是H、取代或未取代的C1-6烷基、卤素、-OC1-6烷基、CN、C(O)R19、NR20R21或羟基;
R18是H、取代或未取代的C1-6烷基、卤素、取代或未取代的-OC1-6烷基、CN、C(O)R22、NR23R24或羟基;
R7是H、卤素、CN、取代或未取代的-OC1-6烷基、取代或未取代的C1-6烷基或取代或未取代的C3-8环烷基;
R8是H、取代或未取代的C1-6烷基、卤素、-OC1-6烷基或羟基;
R19是H、OH或取代或未取代的C1-6烷基;
R20是H或取代或未取代的C1-6烷基;
R21是H或取代或未取代的C1-6烷基;
R22是H、OH或取代或未取代的C1-6烷基;
R23是H或取代或未取代的C1-6烷基;和
R24是H或取代或未取代的C1-6烷基;以及
附带条件是
a).R7、R8、R17和R18不能同时均为H;
b).当R8是取代或未取代的C1-6烷基时,该烷基不含有直接与苯基环连接的羰基;
c).该化合物不具有下列结构:
在另一方面,本发明提供具有式I的化合物,其中:
R1是H;
R2是取代或未取代的C1-6烷基、取代或未取代的C3-8环烷基或取代或未取代的C3-8环烯基;
R5是-S-、-S(O)-或-S(O)2-;
R6是取代或未取代的杂环或取代或未取代的C6-10芳基;
R17是H、取代或未取代的C1-6烷基或卤素;
R18是H、取代或未取代的C1-6烷基或卤素;
R7是卤素、CN、-OC1-6烷基、取代或未取代的C1-6烷基或取代或未取代的C3-8环烷基;
R8是H、取代或未取代的C1-6烷基或卤素;以及
附带条件是
b).当R8是取代或未取代的C1-6烷基时,该烷基不含有直接与苯基环连接的羰基;
c).该化合物不具有下列结构:
在另一方面,本发明提供具有式I的化合物,其中:
R1是H
R2是取代或未取代的C1-6烷基、取代或未取代的C3-8环烷基或取代或未取代的C3-8环烯基;
R5是-S-;
R6是取代或未取代的杂环或取代或未取代的C6-10芳基;
R17是H、取代或未取代的C1-6烷基或卤素;
R18是H、取代或未取代的C1-6烷基或卤素;
R7是卤素、CN、取代或未取代的-OC1-6烷基、取代或未取代的C1-6烷基或取代或未取代的C3-8环烷基;
R8是H、取代或未取代的C1-6烷基或卤素;以及
附带条件是
b).当R8是取代或未取代的C1-6烷基时,该烷基不含有直接与苯基环连接的羰基;
c).该化合物不具有下列结构:
在另一方面,本发明提供具有式I的化合物,其中:
R1是H;
R2是取代或未取代的C1-6烷基、取代或未取代的C3-8环烷基或取代或未取代的C3-8环烯基;
R5是-S(O)-;
R6是取代或未取代的杂环或取代或未取代的C6-10芳基;
R17是H、取代或未取代的C1-6烷基或卤素;
R18是H、取代或未取代的C1-6烷基或卤素;
R7是卤素、CN、-OC1-6烷基、取代或未取代的C1-6烷基或取代或未取代的C3-8环烷基;
R8是H、取代或未取代的C1-6烷基或卤素;以及
附带条件是
b).当R8是取代或未取代的C1-6烷基时,该烷基不含有直接与苯基环连接的羰基。
在另一方面,本发明提供具有式I的化合物,其中:
R1是H;
R2是取代或未取代的C1-6烷基、取代或未取代的C3-8环烷基或取代或未取代的C3-8环烯基;
R5是-S(O)2-;
R6是取代或未取代的杂环或取代或未取代的C6-10芳基;
R17是H、取代或未取代的C1-6烷基或卤素;
R18是H、取代或未取代的C1-6烷基或卤素;
R7是卤素、CN、取代或未取代的-OC1-6烷基、取代或未取代的C1-6烷基或取代或未取代的C3-8环烷基;
R8是H、取代或未取代的C1-6烷基或卤素;以及附件条件是
b).当R8是取代或未取代的C1-6烷基时,该烷基不含有直接与苯基环连接的羰基。
在另一方面,本发明提供具有式I的化合物,其中:
R1是H;
R2是取代或未取代的C1-6烷基;
R5是-S-、-S(O)-或-S(O)2-;
R6是取代或未取代的杂环或取代或未取代的苯基;
R17是H;
R18是H;
R7是卤素、CN、取代或未取代的-OC1-6烷基;
R8是H;以及
附带条件是
c).该化合物不具有下列结构:
在另一方面,本发明提供具有式I的化合物,其中:
R1是H;
R2是C1-6烷基;
R5是-S;
R6是取代或未取代的杂环或取代或未取代的苯基;
R17是H;
R18是H;
R7是卤素、CN、或取代或未取代的-OC1-6烷基;
R8是H;以及
附带条件是
c).该化合物不具有下列结构:
在另一方面,本发明提供具有式I的化合物,其中:
R1是H;
R2是取代或未取代的C1-6烷基;
R5是-S(O);
R6是取代或未取代的杂环或取代或未取代的苯基;
R17是H;
R18是H;
R7是卤素、CN或-OC1-6烷基;
R8是H。
在另一方面,本发明提供具有式I的化合物,其中:
R1是H;
R2是取代或未取代的C1-6烷基;
R5是-S(O)2-;
R6是取代或未取代的杂环或取代或未取代的苯基;
R17是H;
R18是H;
R7是卤素、CN或-OC1-6烷基;
R8是H。
在另一方面,本发明提供具有式I的化合物,其中:
R1是H;
R2是甲基、异丙基、2-羟基乙基、甲基丙酸酯、2-甲基吡啶、乙酸乙酯、N,N-二甲基丙酰胺、N-异丙基丙酰胺、丙酰胺、羟基环戊基、乙基、N,N-二甲基乙酰胺、N-甲基乙酰胺、2-氨基乙基、H-咪唑-2-基甲基、1H-咪唑-4-基甲基、2-[(氨基羰基)氨基]乙基、吡啶-2-基-氨基甲酸叔丁酯、6-氨基吡啶-2-基、2-氧代-1,3-噁唑烷-5-基-甲基、2,6-二氧代-1,2,3,6-四氢嘧啶-4-基)甲基、3-氨基丙基、N,N-二甲基丁酰胺、1H-吡唑-3-基甲基、甲基-1,3-噻唑-2-基-乙酰胺、1,3-噻唑-2-基-氨基甲酸叔丁酯、2-氨基-1,3-噻唑-4-基)甲基、3-甲基吡啶、3-硝基苄基、3-甲氧基苄基、5-硝基-1H-吡唑-3-基-甲基、5-氨基-1H-吡唑-3-基-甲基、1-丙基-1H-咪唑-4-基)甲基、1-氧代吡啶-2-基-氨基甲酸叔丁酯、3-羟基苄基、5-氨基-4H-1,2,4-三唑-3-基)甲基、2-吡啶-2-基乙基、2-(1H-吡唑-4-基)乙基、2-(3,5-二甲基-1H-吡唑-4-基)乙基、(2-氟吡啶-3-基)甲基、三氟甲基、苄基、3-硝基苄基、4-硝基苄基、2-氨基苄基、3-氨基苄基或嘧啶-2-基甲基;
R5是-S(O)2-、-S-或-S(O)-;
R6是4-氯-3-三氟甲基-苯基、3,4-二氯苯基、3-甲氧基苯基、4-甲基-3-硝基苯基、4-氯苯基、4-氯-3-甲基苯基、4-硝基-3-三氟甲基苯基、2,4-二氟苯基、4-氯-2-氟苯基、3-氯-2-氟苯基、4-异丙基苯基、4-溴苯基、4-碘苯基、3-氯苯基、2-苯并呋喃、5-甲基-2-呋喃、2-呋喃或苯基;
R7是氯、氰基、甲氧基或氟;
R17是H;
R18是H;且
R8是H。
本文中所述的“烷基”是指具有直链或直链部分或其组合并且含有1至6个碳原子的饱和、单价或二价烃部分。烷基的一个亚甲基(-CH2-)基团可被氧、硫、羰基、亚砜、氮、磺酰基、或被二价C3-6环烷基取代。烷基基团上的氢原子可被以下基团取代,所述基团包括但不限于:卤素、-OH、C3-8环烷基、非芳族杂环、芳族杂环、C6-10芳基、-O(C1-6烷基、胺基团、氨基、NO2、酰胺基团、磺酰胺基团、酯基团、醛基团、羧酸、酮基团。
本文中所用的术语“环烷基”是指由饱和环状烃衍生的3至8个碳原子的单价或二价基团。环烷基可以是单环或多环的。环烷基可以被以下基团取代,所述基团包括但不限于:卤素、-OH、C3-8环烷基、非芳族杂环、芳族杂环、C6-10芳基、-O(C1-6烷基)、胺基团、氨基、NO2、酰胺基团、羧酸、磺酰胺基团、酯基团、醛基团、酮基团。
本文中所用的术语“环烯基”是指由具有一个或多个双键的饱和环烷基衍生的3至8个碳原子的单价或或二价基团。环烯基可以是单环或多环的。环烯基可以被以下基团取代,所述基团包括但不限于:卤素、-OH、C3-8环烷基、非芳族杂环、芳族杂环、C6-10芳基、-O(C1-6烷基)、胺基团、氨基、NO2、酰胺基团、磺酰胺基团、羧酸、酯基团、醛基团、酮基团。
本文中所用的术语“卤素”是指氯、溴、氟、碘的原子。
本文中所用的术语“烯基”是指由具有至少一个双键的饱和烷基衍生的具有2至6个碳原子的单价或二价烃基团。C2-6烯基可以呈E或Z构型。烯基基团可以被C1-3烷基取代。
本文中所用的术语“炔基”是指由具有至少一个三键的饱和烷基衍生的具有2至6个碳原子的单价或二价烃基。
本文中所用的术语“杂环”是指3至10元环,其可以是芳族或非芳族的、饱和或非饱和的,含有中断碳环结构的至少一个选自O或N或S的杂原子或其至少两个的组合。杂环可以被C=O中断;S杂原子可以被氧化。杂环可以是单环或多环的。杂环部分可以被以下基团取代,所述基团包括但不限于:卤素、-OH、C3-8环烷基、非芳族杂环、芳族杂环、-OC1-6烷基、-NH2、-NO2、酰胺、醚、酯、酮、羧酸、醛、磺酰胺基团。
优选的取代的杂环基团包括但不限于:吡啶、呋喃、氮杂环丁烷、噻唑、噻吩、噁唑、吡唑、异噁唑、2-氧代二氢吲哚、2-氧代-2,3-二氢-1,3-苯并噁唑、2-氧代-2H-色烯、咪唑[2,1-b]噻唑、1-H-吡唑、吲哚、咪唑、喹啉、2-噻吩、2-苯并呋喃、5-甲基-2-呋喃、5-噁唑烷-2-酮、嘧啶-2,4(1H、3H)-二酮、嘧啶。
本文中所用的术语“芳基”是指由由含有6至10个碳原子的环组成的芳族烃通过去除一个氢而衍生的有机部分。芳基可以被以下基团取代,所述基团包括但不限于:卤素、-OH、C3-8环烷基、非芳族杂环、芳族杂环、-OC1-6烷基、-NH2、-NO2、酰胺、醚、酯、羧酸、醛、酮、磺酰胺基团。芳基可以是单环或双环。优选的取代的苯环基团包括但不限于:4-氯-3-三氟甲基-苯基、3,4-二氯苯基、3-甲氧基苯基、4-甲基-3-硝基苯基、4-氯苯基、4-氯-3-甲基苯基、4-硝基-3-三氟甲基苯基、2,4-二氟苯基、4-氯-2-氟苯基、3-氯-2-氟苯基、4-异丙基苯基、4-溴苯基、4-碘苯基、3-氯苯基。
本文中所用的术语“胺”表示式“-NRxRy“,其中Rx和Ry可以是相同或独立地是H、如上所定义的烷基、芳基、环烷基、环烯基、杂环。
本文中所用的术语“酰胺”表示式“-C(O)NRxRy,”或“-C(O)N(Rx)(Ry)”或“NRxC(O)Ry”的基团,其中Rx和Ry可以是相同或独立地是H、如上所定义的烷基、芳基、环烷基、环烯基、杂环。
本文中所用的术语“磺酰胺”表示式“-S(O)2NRxRy”或NRxRyS(O)2”或“-NRxS(O)2Ry”的基团,其中Rx和Ry可以是相同或独立地是H、如上所定义的烷基、芳基、环烷基、环烯基、杂环。
本文中所用的术语“酯”表示式“-C(O)O(Rx)”的基团,其中Rx是如上所定义的烷基、芳基、环烷基、环烯基、杂环。
本文中所用的术语“醛”表示式“-C(O)H”的基团。
本文中所用的术语“酮”表示式“-C(O)Rx”的基团,其中Rx是C1-6烷基。
本文中所用的术语“羟基”表示式“-OH”的基团。
本文中所用的术语“氨基”表示式“-NH2”的基团。
本文中所用的术语“羰基”表示式“-C(O)”的基团。
本文中所用的术语“羧基”表示式“-C(O)O-”的基团。
本文中所用的术语“磺酰基”表示式“-SO2”的基团。
本文中所用的术语“硫酸酯”表示式“-O-S(O)2-O-”的基团。
本文中所用的术语“羧酸”表示式“-C(O)OH”的基团。
本文中所用的术语“亚砜”表示式“-S=O”的基团。
本文中所用的术语“膦酸”表示式“-P(O)(OH)2”的基团。
本文中所用的术语“磷酸”表示式“-O-P(O)(OH)2”的基团。
本文中所用的术语“磺酸”表示式“-S(O)2OH”的基团。
本文中所用的式“H”表示氢原子。
本文中所用的式“O”表示氧原子。
本文中所用的式“N”表示氮原子。
本文中所用的式“S”表示硫原子。
一些本发明化合物是:
4-氯-N-[5-氯-2-(甲基亚磺酰基)苯基]-3-(三氟甲基)苯磺酰胺;
4-氯-N-[5-氯-2-(甲基磺酰基)苯基]-3-(三氟甲基)苯磺酰胺;
4-氯-N-[5-氯-2-(甲基硫基)苯基]-3-(三氟甲基)苯磺酰胺;
4-氯-N-[5-氯-2-(异丙基硫基)苯基]-3-(三氟甲基)苯磺酰胺;
4-氯-N-{5-氯-2-[(2-羟基乙基)硫基]苯基}-3-(三氟甲基)苯磺酰胺;
4-氯-N-[5-氯-2-(异丙基亚磺酰基)苯基]-3-(三氟甲基)苯磺酰胺;
4-氯-N-{5-氯-2-[(2-羟基乙基)亚磺酰基]苯基}-3-(三氟甲基)苯磺酰胺;
4-氯-N-{5-氯-2-[(2-羟基乙基)磺酰基]苯基}-3-(三氟甲基)苯磺酰胺;
3-{[4-氯-2-({[4-氯-3-(三氟甲基)苯基]磺酰基}氨基)苯基]亚磺酰基}丙酸甲酯;
4-氯-N-{5-氯-2-[(吡啶-2-基甲基)硫基]苯基}-3-(三氟甲基)苯磺酰胺;
4-氯-N-{5-氯-2-[(吡啶-3-基甲基)硫基]苯基}-3-(三氟甲基)苯磺酰胺;
4-氯-N-{5-氯-2-[(吡啶-2-基甲基)亚磺酰基]苯基}-3-(三氟甲基)苯磺酰胺;
4-氯-N-{5-氯-2-[(吡啶-3-基甲基)亚磺酰基]苯基}-3-(三氟甲基)苯磺酰胺;
{[4-氯-2-({[4-氯-3-(三氟甲基)苯基]磺酰基}氨基)苯基]亚磺酰基}乙酸乙酯;
3-{[4-氯-2-({[4-氯-3-(三氟甲基)苯基]磺酰基}氨基)苯基]硫基}-N-异丙基丙酰胺;
3-{[4-氯-2-({[4-氯-3-(三氟甲基)苯基]磺酰基}氨基)苯基]硫基}-N,N-二甲基丙酰胺;
3-{[4-氯-2-({[4-氯-3-(三氟甲基)苯基]磺酰基}氨基)苯基]亚磺酰基}-N-异丙基丙酰胺;
3-{[4-氯-2-({[4-氯-3-(三氟甲基)苯基]磺酰基}氨基)苯基]亚磺酰基}-N,N-二甲基丙酰胺;
3-{[4-氯-2-({[4-氯-3-(三氟甲基)苯基]磺酰基}氨基)苯基]亚磺酰基}丙酰胺;
N-[5-氯-2-(甲基亚磺酰基)苯基]苯磺酰胺;
3,4-二氯-N-[5-氯-2-(甲基亚磺酰基)苯基]苯磺酰胺;
N-[5-氯-2-(甲基硫基)苯基]硫基苯-2-磺酰胺;
N-[5-氯-2-(甲基亚磺酰基)苯基]硫基苯-2-磺酰胺;
4-氯-N-{5-氯-2-[(3-羟基环戊基)亚磺酰基]苯基}-3-(三氟甲基)苯磺酰胺;
4-氯-N-{5-氯-2-[(3-羟基环戊基)磺酰基]苯基}-3-(三氟甲基)苯磺酰胺;
4-氯-N-[5-氯-2-(乙基硫基)苯基]-3-(三氟甲基)苯磺酰胺;
4-氯-N-[5-氯-2-(乙基亚磺酰基)苯基]-3-(三氟甲基)苯磺酰胺;
4-氯-N-[5-氯-2-(乙基磺酰基)苯基]-3-(三氟甲基)苯磺酰胺;
N-[5-氯-2-(甲基硫基)苯基]-1-苯并呋喃-2-磺酰胺;
N-[5-氯-2-(甲基亚磺酰基)苯基]-1-苯并呋喃-2-磺酰胺;
N-[5-氯-2-(甲基磺酰基)苯基]-1-苯并呋喃-2-磺酰胺;
N-[5-氯-2-(甲基硫基)苯基]-4-甲基-3-硝基苯磺酰胺;
4-氯-N-[5-氯-2-(甲基硫基)苯基]苯磺酰胺;
4-氯-N-[5-氯-2-(甲基硫基)苯基]-3-甲基苯磺酰胺;
N-[5-氯-2-(甲基亚磺酰基)苯基]-4-甲基-3-硝基苯磺酰胺;
N-[5-氯-2-(甲基磺酰基)苯基]-4-甲基-3-硝基苯磺酰胺;
4-氯-N-[5-氯-2-(甲基亚磺酰基)苯基]苯磺酰胺;
4-氯-N-[5-氯-2-(甲基磺酰基)苯基]苯磺酰胺;
4-氯-N-[5-氯-2-(甲基亚磺酰基)苯基]-3-甲基苯磺酰胺;
4-氯-N-[5-氯-2-(甲基磺酰基)苯基]-3-甲基苯磺酰胺;
2-{[4-氯-2-({[4-氯-3-(三氟甲基)苯基]磺酰基}氨基)苯基]硫基}-N,N-二甲基乙酰胺;
2-{[4-氯-2-({[4-氯-3-(三氟甲基)苯基]磺酰基}氨基)苯基]硫基}-N-甲基乙酰胺;
2-{[4-氯-2-({[4-氯-3-(三氟甲基)苯基]磺酰基}氨基)苯基]亚磺酰基}-N,N-二甲基乙酰胺;
2-{[4-氯-2-({[4-氯-3-(三氟甲基)苯基]磺酰基}氨基)苯基]磺酰基}-N,N-二甲基乙酰胺;
2-{[4-氯-2-({[4-氯-3-(三氟甲基)苯基]磺酰基}氨基)苯基]亚磺酰基}-N-甲基乙酰胺;
2-{[4-氯-2-({[4-氯-3-(三氟甲基)苯基]磺酰基}氨基)苯基]磺酰基}-N-甲基乙酰胺;
N-{2-[(2-氨基乙基)硫基]-5-氯苯基}-4-氯-3-(三氟甲基)苯磺酰胺;
N-[5-氯-2-(甲基硫基)苯基]-3-硝基-4-(三氟甲基)苯磺酰胺;
N-[5-氯-2-(甲基磺酰基)苯基]-3-硝基-4-(三氟甲基)苯磺酰胺;
N-[5-氯-2-(甲基硫基)苯基]-2,4-二氟苯磺酰胺;
N-[5-氯-2-(甲基磺酰基)苯基]-2,4-二氟苯磺酰胺;
N-[5-氯-2-(甲基亚磺酰基)苯基]-2,4-二氟苯磺酰胺;
N-[5-氯-2-(甲基亚磺酰基)苯基]-3-硝基-4-(三氟甲基)苯磺酰胺;
N-[5-氯-2-(甲基硫基)苯基]-5-甲基呋喃-2-磺酰胺;
N-[5-氯-2-(甲基亚磺酰基)苯基]-5-甲基呋喃-2-磺酰胺;
N-[5-氯-2-(甲基磺酰基)苯基]-5-甲基呋喃-2-磺酰胺;
N-[5-氯-2-(甲基硫基)苯基]呋喃-2-磺酰胺;
N-[5-氯-2-(甲基亚磺酰基)苯基]呋喃-2-磺酰胺;
N-[5-氯-2-(甲基磺酰基)苯基]呋喃-2-磺酰胺;
N-{2-[(2-氨基乙基)磺酰基]-5-氯苯基}-4-氯-3-(三氟甲基)苯磺酰胺;
4-氯-N-[5-氯-2-(甲基硫基)苯基]-2-氟苯磺酰胺;
3-氯-N-[5-氯-2-(甲基硫基)苯基]-2-氟苯磺酰胺;
3-氯-N-[5-氯-2-(甲基磺酰基)苯基]-2-氟苯磺酰胺;
3-氯-N-[5-氯-2-(甲基亚磺酰基)苯基]-2-氟苯磺酰胺;
4-氯-N-[5-氯-2-(甲基磺酰基)苯基]-2-氟苯磺酰胺;
4-氯-N-[5-氯-2-(甲基亚磺酰基)苯基]-2-氟苯磺酰胺;
N-{2-[(2-氨基乙基)亚磺酰基]-5-氯苯基}-4-氯-3-(三氟甲基)苯磺酰胺;
4-氯-N-{5-氯-2-[(1H-咪唑-2-基甲基)硫基]苯基}-3-(三氟甲基)苯磺酰胺;
4-氯-N-{5-氯-2-[(1H-咪唑-2-基甲基)亚磺酰基]苯基}-3-(三氟甲基)苯磺酰胺;
4-氯-N-{5-氯-2-[(1H-咪唑-2-基甲基)磺酰基]苯基}-3-(三氟甲基)苯磺酰胺;
4-氯-N-{5-氯-2-[(1H-咪唑-4-基甲基)硫基]苯基}-3-(三氟甲基)苯磺酰胺;
4-氯-N-{5-氯-2-[(1H-咪唑-4-基甲基)亚磺酰基]苯基}-3-(三氟甲基)苯磺酰胺;
4-氯-N-{5-氯-2-[(1H-咪唑-4-基甲基)磺酰基]苯基}-3-(三氟甲基)苯磺酰胺;
N-{5-氯-2-[(1H-咪唑-2-基甲基)硫基]苯基}-1-苯并呋喃-2-磺酰胺;
N-{5-氯-2-[(1H-咪唑-2-基甲基)亚磺酰基]苯基}-1-苯并呋喃-2-磺酰胺;
N-{5-氯-2-[(1H-咪唑-2-基甲基)磺酰基]苯基}-1-苯并呋喃-2-磺酰胺;
N-{5-氯-2-[(1H-咪唑-4-基甲基)硫基]苯基}-1-苯并呋喃-2-磺酰胺;
N-{5-氯-2-[(1H-咪唑-4-基甲基)亚磺酰基]苯基}-1-苯并呋喃-2-磺酰胺;
N-{5-氯-2-[(1H-咪唑-4-基甲基)磺酰基]苯基}-1-苯并呋喃-2-磺酰胺;
3-({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}硫基)-N,N-二甲基丙酰胺;
3-({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}亚磺酰基)-N,N-二甲基丙酰胺;
3-({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}磺酰基)-N,N-二甲基丙酰胺;
N-[2-({2-[(氨基羰基)氨基]乙基}硫基)-5-氯苯基]-1-苯并呋喃-2-磺酰胺;
N-[2-({2-[(氨基羰基)氨基]乙基}亚磺酰基)-5-氯苯基]-1-苯并呋喃-2-磺酰胺;
N-[2-({2-[(氨基羰基)氨基]乙基}磺酰基)-5-氯苯基]-1-苯并呋喃-2-磺酰胺;
{6-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}亚磺酰基)甲基]吡啶-2-基}氨基甲酸叔丁酯;
N-(2-{[(6-氨基吡啶-2-基)甲基]硫基}-5-氯苯基)-1-苯并呋喃-2-磺酰胺;
N-(2-{[(6-氨基吡啶-2-基)甲基]亚磺酰基}-5-氯苯基)-1-苯并呋喃-2-磺酰胺;
N-(2-{[(6-氨基吡啶-2-基)甲基]磺酰基}-5-氯苯基)-1-苯并呋喃-2-磺酰胺;
N-(2-{[(6-氨基-1-氧代吡啶-2-基)甲基]磺酰基}-5-氯苯基)-1-苯并呋喃-2-磺酰胺;
N-(5-氯-2-{[3-(二甲基氨基)丙基]硫基}苯基)-1-苯并呋喃-2-磺酰胺;
N-(5-氯-2-{[3-(二甲基氨基)丙基]亚磺酰基}苯基)-1-苯并呋喃-2-磺酰胺;
N-(5-氯-2-{[3-(二甲基氨基)丙基]磺酰基}苯基)-1-苯并呋喃-2-磺酰胺;
N-(5-氯-2-{[3-(二甲基亚硝叉基)丙基]磺酰基}苯基)-1-苯并呋喃-2-磺酰胺;
N-(2-{[4-氯-2-({[4-氯-3-(三氟甲基)苯基]磺酰基}氨基)苯基]磺酰基}乙基)乙酰胺;
N-(2-{[4-氯-2-({[4-氯-3-(三氟甲基)苯基]磺酰基}氨基)苯基]亚磺酰基}乙基)乙酰胺;
N-(5-氯-2-{[(2-氧代-1,3-噁唑烷-5-基)甲基]亚磺酰基}苯基)-1-苯并呋喃-2-磺酰胺;
N-(5-氯-2-{[(2-氧代-1,3-噁唑烷-5-基)甲基]磺酰基}苯基)-1-苯并呋喃-2-磺酰胺;
N-(5-氯-2-{[(2,6-二氧代-1,2,3,6-四氢嘧啶-4-基)甲基]硫基}苯基)-1-苯并呋喃-2-磺酰胺;
N-(5-氯-2-{[(2,6-二氧代-1,2,3,6-四氢嘧啶-4-基)甲基]亚磺酰基}苯基)-1-苯并呋喃-2-磺酰胺;
N-(5-氯-2-{[(2,6-二氧代-1,2,3,6-四氢嘧啶-4-基)甲基]磺酰基}苯基)-1-苯并呋喃-2-磺酰胺;
N-{2-[(3-氨基丙基)硫基]-5-氯苯基}-1-苯并呋喃-2-磺酰胺;
N-{2-[(3-氨基丙基)亚磺酰基]-5-氯苯基}-1-苯并呋喃-2-磺酰胺;
N-{2-[(3-氨基丙基)磺酰基]-5-氯苯基}-1-苯并呋喃-2-磺酰胺;
4-({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}亚磺酰基)-N,N-二甲基丁酰胺;
4-({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}磺酰基)-N,N-二甲基丁酰胺;
5-氯-N-[5-氯-2-(甲基亚磺酰基)苯基]-1-苯并呋喃-2-磺酰胺;
5-氯-N-[5-氯-2-(甲基磺酰基)苯基]-1-苯并呋喃-2-磺酰胺;
N-{5-氯-2-[(1H-吡唑-3-基甲基)硫基]苯基}-1-苯并呋喃-2-磺酰胺;
N-{5-氯-2-[(1H-吡唑-3-基甲基)亚磺酰基]苯基}-1-苯并呋喃-2-磺酰胺;
N-{5-氯-2-[(1H-吡唑-3-基甲基)磺酰基]苯基}-1-苯并呋喃-2-磺酰胺;
N-(5-氯-2-{[(2,4-二氧代-1,2,3,4-四氢嘧啶-5-基)甲基]亚磺酰基}苯基)-1-苯并呋喃-2-磺酰胺;
N-(5-氯-2-{[(2,4-二氧代-1,2,3,4-四氢嘧啶-5-基)甲基]磺酰基}苯基)-1-苯并呋喃-2-磺酰胺;
N-{4-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}硫基)甲基]-1,3-噻唑-2-基}乙酰胺;
N-{4-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}亚磺酰基)甲基]-1,3-噻唑-2-基}乙酰胺;
N-{4-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}磺酰基)甲基]-1,3-噻唑-2-基}乙酰胺;
N-[5-氯-2-(甲基亚磺酰基)苯基]-4-异丙基苯磺酰胺;
4-溴-N-[5-氯-2-(甲基硫基)苯基]苯磺酰胺;
N-[5-氯-2-(甲基硫基)苯基]-4-碘苯磺酰胺;
N-[5-氯-2-(甲基磺酰基)苯基]-4-异丙基苯磺酰胺;
4-溴-N-[5-氯-2-(甲基亚磺酰基)苯基]苯磺酰胺;
N-[5-氯-2-(甲基亚磺酰基)苯基]-4-碘苯磺酰胺;
4-溴-N-[5-氯-2-(甲基磺酰基)苯基]苯磺酰胺;
N-[5-氯-2-(甲基磺酰基)苯基]-4-碘苯磺酰胺;
{4-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}硫基)甲基]-1,3-噻唑-2-基}氨基甲酸叔丁酯;
N-(2-{[(2-氨基-1,3-噻唑-4-基)甲基]硫基}-5-氯苯基)-1-苯并呋喃-2-磺酰胺;
{4-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}亚磺酰基)甲基]-1,3-噻唑-2-基}氨基甲酸叔丁酯;
N-(2-{[(2-氨基-1,3-噻唑-4-基)甲基]亚磺酰基}-5-氯苯基)-1-苯并呋喃-2-磺酰胺;
{4-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}磺酰基)甲基]-1,3-噻唑-2-基}氨基甲酸叔丁酯;
N-(2-{[(2-氨基-1,3-噻唑-4-基)甲基]磺酰基}-5-氯苯基)-1-苯并呋喃-2-磺酰胺;
N-{5-氯-2-[(吡啶-2-基甲基)硫基]苯基}-1-苯并呋喃-2-磺酰胺;
N-{5-氯-2-[(吡啶-3-基甲基)硫基]苯基}-1-苯并呋喃-2-磺酰胺;
N-{5-氯-2-[(吡啶-3-基甲基)亚磺酰基]苯基}-1-苯并呋喃-2-磺酰胺;
N-(5-氯-2-{[(1-氧代吡啶-3-基)甲基]亚磺酰基}苯基)-1-苯并呋喃-2-磺酰胺;
N-{5-氯-2-[(吡啶-3-基甲基)磺酰基]苯基}-1-苯并呋喃-2-磺酰胺;
N-(5-氯-2-{[(1-氧代吡啶-3-基)甲基]磺酰基}苯基)-1-苯并呋喃-2-磺酰胺;
N-{5-氯-2-[(3-硝基苄基)硫基]苯基}-1-苯并呋喃-2-磺酰胺;
N-{5-氯-2-[(3-甲氧基苄基)硫基]苯基}-1-苯并呋喃-2-磺酰胺;
N-(5-氯-2-{[(5-硝基-1H-吡唑-3-基)甲基]硫基}苯基)-1-苯并呋喃-2-磺酰胺;
N-(5-氯-2-{[(5-硝基-1H-吡唑-3-基)甲基]亚磺酰基}苯基)-1-苯并呋喃-2-磺酰胺;
N-(2-{[(5-氨基-1H-吡唑-3-基)甲基]硫基}-5-氯苯基)-1-苯并呋喃-2-磺酰胺;
N-(2-{[(5-氨基-1H-吡唑-3-基)甲基]亚磺酰基}-5-氯苯基)-1-苯并呋喃-2-磺酰胺;
N-(2-{[(5-氨基-1H-吡唑-3-基)甲基]磺酰基}-5-氯苯基)-1-苯并呋喃-2-磺酰胺;
N-(5-氯-2-{[(1-丙基-1H-咪唑-4-基)甲基]硫基}苯基)-1-苯并呋喃-2-磺酰胺;
N-(5-氯-2-{[(1-丙基-1H-咪唑-4-基)甲基]亚磺酰基}苯基)-1-苯并呋喃-2-磺酰胺;
N-(5-氯-2-{[(1-丙基-1H-咪唑-4-基)甲基]磺酰基}苯基)-1-苯并呋喃-2-磺酰胺;
N-{5-氯-2-[(吡啶-2-基甲基)亚磺酰基]苯基}-1-苯并呋喃-2-磺酰胺;
N-{5-氯-2-[(吡啶-2-基甲基)磺酰基]苯基}-1-苯并呋喃-2-磺酰胺;
N-(5-氯-2-{[(1-氧代吡啶-2-基)甲基]磺酰基}苯基)-1-苯并呋喃-2-磺酰胺;
N-(5-氯-2-{[(1-氧代吡啶-2-基)甲基]亚磺酰基}苯基)-1-苯并呋喃-2-磺酰胺;
{4-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}硫基)甲基]吡啶-2-基}氨基甲酸叔丁酯;
N-(2-{[(2-氨基吡啶-4-基)甲基]硫基}-5-氯苯基)-1-苯并呋喃-2-磺酰胺;
{4-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}磺酰基)甲基]吡啶-2-基}氨基甲酸叔丁酯;
{4-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}磺酰基)甲基]-1-氧代吡啶-2-基}氨基甲酸叔丁酯;
N-(2-{[(2-氨基吡啶-4-基)甲基]亚磺酰基}-5-氯苯基)-1-苯并呋喃-2-磺酰胺;
N-(2-{[(2-氨基吡啶-4-基)甲基]磺酰基}-5-氯苯基)-1-苯并呋喃-2-磺酰胺;
N-(2-{[(2-氨基-1-氧代吡啶-4-基)甲基]磺酰基}-5-氯苯基)-1-苯并呋喃-2-磺酰胺;
N-{2-[(3-氨基苄基)硫基]-5-氯苯基}-1-苯并呋喃-2-磺酰胺
N-{2-[(3-氨基苄基)亚磺酰基]-5-氯苯基}-1-苯并呋喃-2-磺酰胺;
N-{2-[(3-氨基苄基)磺酰基]-5-氯苯基}-1-苯并呋喃-2-磺酰胺;
N-{5-氯-2-[(3-羟基苄基)硫基]苯基}-1-苯并呋喃-2-磺酰胺;
N-{5-氯-2-[(3-羟基苄基)亚磺酰基]苯基}-1-苯并呋喃-2-磺酰胺;
N-{5-氯-2-[(3-羟基苄基)磺酰基]苯基}-1-苯并呋喃-2-磺酰胺;
3-{[4-氯-2-({[4-氯-3-(三氟甲基)苯基]磺酰基}氨基)苯基]磺酰基}-N,N-二甲基丙酰胺;
3-[(4-氯-2-{[(2,4-二氟苯基)磺酰基]氨基}苯基)硫基]-N,N-二甲基丙酰胺;
N-(2-{[(5-氨基-4H-1,2,4-三唑-3-基)甲基]硫基}-5-氯苯基)-1-苯并呋喃-2-磺酰胺;
N-(2-{[(5-氨基-4H-1,2,4-三唑-3-基)甲基]亚磺酰基}-5-氯苯基)-1-苯并呋喃-2-磺酰胺;
3-[(4-氯-2-{[(2,4-二氟苯基)磺酰基]氨基}苯基)亚磺酰基]-N,N-二甲基丙酰胺;
3-[(4-氯-2-{[(2,4-二氟苯基)磺酰基]氨基}苯基)磺酰基]-N,N-二甲基丙酰胺;
3-[(4-氯-2-{[(4-氯-2-氟苯基)磺酰基]氨基}苯基)硫基]-N,N-二甲基丙酰胺;
3-[(4-氯-2-{[(4-氯-2-氟苯基)磺酰基]氨基}苯基)亚磺酰基]-N,N-二甲基丙酰胺;
3-[(4-氯-2-{[(4-氯-2-氟苯基)磺酰基]氨基}苯基)磺酰基]-N,N-二甲基丙酰胺;
N-{5-氯-2-[(2-吡啶-2-基乙基)硫基]苯基}-1-苯并呋喃-2-磺酰胺;
N-(5-氯-2-{[2-(1H-吡唑-4-基)乙基]亚磺酰基}苯基)-1-苯并呋喃-2-磺酰胺;
N-{5-氯-2-[(2-吡啶-2-基乙基)亚磺酰基]苯基}-1-苯并呋喃-2-磺酰胺;
N-{5-氯-2-[(2-吡啶-2-基乙基)磺酰基]苯基}-1-苯并呋喃-2-磺酰胺;
N-(5-氯-2-{[2-(1H-吡唑-4-基)乙基]硫基}苯基)-1-苯并呋喃-2-磺酰胺;
N-(5-氯-2-{[2-(1H-吡唑-4-基)乙基]磺酰基}苯基)-1-苯并呋喃-2-磺酰胺;
N-(5-氯-2-{[2-(3,5-二甲基-1H-吡唑-4-基)乙基]硫基}苯基)-1-苯并呋喃-2-磺酰胺;
N-(5-氯-2-{[2-(3,5-二甲基-1H-吡唑-4-基)乙基]亚磺酰基}苯基)-1-苯并呋喃-2-磺酰胺;
N-(5-氯-2-{[2-(3,5-二甲基-1H-吡唑-4-基)乙基]磺酰基}苯基)-1-苯并呋喃-2-磺酰胺;
N-(5-氯-2-{[(2-氟吡啶-3-基)甲基]硫基}苯基)-1-苯并呋喃-2-磺酰胺;
N-(5-氯-2-{[(2-氟吡啶-3-基)甲基]亚磺酰基}苯基)-1-苯并呋喃-2-磺酰胺;
N-(5-氯-2-{[(2-氟吡啶-3-基)甲基]磺酰基}苯基)-1-苯并呋喃-2-磺酰胺;
N-{5-氯-2-[(三氟甲基)硫基]苯基}-1-苯并呋喃-2-磺酰胺;
N-{5-氯-2-[(三氟甲基)磺酰基]苯基}-1-苯并呋喃-2-磺酰胺;
N-{5-氯-2-[(三氟甲基)亚磺酰基]苯基}-1-苯并呋喃-2-磺酰胺;
N-[2-(苄基硫基)-5-氯苯基]-1-苯并呋喃-2-磺酰胺;
N-[2-(苄基亚磺酰基)-5-氯苯基]-1-苯并呋喃-2-磺酰胺;
N-[2-(苄基磺酰基)-5-氯苯基]-1-苯并呋喃-2-磺酰胺;
N-{2-[(3-氨基苄基)硫基]-5-氟苯基}-1-苯并呋喃-2-磺酰胺;
N-{5-氟-2-[(3-硝基苄基)亚磺酰基]苯基}-1-苯并呋喃-2-磺酰胺;
N-{2-[(3-氨基苄基)亚磺酰基]-5-氟苯基}-1-苯并呋喃-2-磺酰胺;
N-{5-氟-2-[(3-硝基苄基)磺酰基]苯基}-1-苯并呋喃-2-磺酰胺;
N-{2-[(3-氨基苄基)磺酰基]-5-氟苯基}-1-苯并呋喃-2-磺酰胺;
N-{2-[(3-氨基苄基)硫基]-5-甲氧基苯基}-1-苯并呋喃-2-磺酰胺;
N-{2-[(3-氨基苄基)磺酰基]-5-甲氧基苯基}-1-苯并呋喃-2-磺酰胺;
N-{2-[(3-氨基苄基)硫基]苯基}-1-苯并呋喃-2-磺酰胺;
N-{2-[(3-硝基苄基)亚磺酰基]苯基}-1-苯并呋喃-2-磺酰胺;
N-{2-[(3-氨基苄基)亚磺酰基]苯基}-1-苯并呋喃-2-磺酰胺;
N-{5-甲氧基-2-[(3-硝基苄基)亚磺酰基]苯基}-1-苯并呋喃-2-磺酰胺;
N-{2-[(3-氨基苄基)亚磺酰基]-5-甲氧基苯基}-1-苯并呋喃-2-磺酰胺;
N-{2-[(3-硝基苄基)磺酰基]苯基}-1-苯并呋喃-2-磺酰胺;
N-{2-[(3-氨基苄基)磺酰基]苯基}-1-苯并呋喃-2-磺酰胺;
N-{5-氯-2-[(4-硝基苄基)硫基]苯基}-1-苯并呋喃-2-磺酰胺;
N-{2-[(2-氨基苄基)硫基]-5-氯苯基}-1-苯并呋喃-2-磺酰胺;
N-{5-氯-2-[(4-硝基苄基)磺酰基]苯基}-1-苯并呋喃-2-磺酰胺;
N-{2-[(4-氨基苄基)磺酰基]-5-氯苯基}-1-苯并呋喃-2-磺酰胺;
N-{5-氯-2-[(2-硝基苄基)亚磺酰基]苯基}-1-苯并呋喃-2-磺酰胺;
N-{2-[(2-氨基苄基)亚磺酰基]-5-氯苯基}-1-苯并呋喃-2-磺酰胺;
N-{2-[(2-氨基苄基)磺酰基]-5-氯苯基}-1-苯并呋喃-2-磺酰胺;
N-{2-[(3-氨基苄基)硫基]-5-氯苯基}-2,4-二氟苯磺酰胺;
N-{2-[(3-氨基苄基)硫基]-5-氯苯基}-4-氯-2-氟苯磺酰胺;
N-{2-[(3-氨基苄基)磺酰基]-5-氯苯基}-2,4-二氟苯磺酰胺;
N-{2-[(3-氨基苄基)亚磺酰基]-5-氯苯基}-2,4-二氟苯磺酰胺;
N-{2-[(3-氨基苄基)磺酰基]-5-氯苯基}-4-氯-2-氟苯磺酰胺;
N-{2-[(3-氨基苄基)亚磺酰基]-5-氯苯基}-4-氯-2-氟苯磺酰胺;
N-{5-氯-2-[(嘧啶-2-基甲基)硫基]苯基}-1-苯并呋喃-2-磺酰胺;
N-{5-氯-2-[(嘧啶-2-基甲基)亚磺酰基]苯基}-1-苯并呋喃-2-磺酰胺;
N-{5-氯-2-[(嘧啶-2-基甲基)磺酰基]苯基}-1-苯并呋喃-2-磺酰胺;
N-{2-[(3-氨基苄基)硫基]-5-氯苯基}苯磺酰胺;
N-{2-[(3-氨基苄基)硫基]-5-氯苯基}-4-氯苯磺酰胺;
N-{2-[(3-氨基苄基)硫基]-5-氯苯基}-3-氯苯磺酰胺;
N-{2-[(3-氨基苄基)磺酰基]-5-氯苯基}苯磺酰胺;
N-{2-[(3-氨基苄基)亚磺酰基]-5-氯苯基}苯磺酰胺;
N-{2-[(3-氨基苄基)磺酰基]-5-氯苯基}-4-氯苯磺酰胺;
N-{2-[(3-氨基苄基)亚磺酰基]-5-氯苯基}-4-氯苯磺酰胺;
N-{2-[(3-氨基苄基)磺酰基]-5-氯苯基}-3-氯苯磺酰胺;
N-{2-[(3-氨基苄基)亚磺酰基]-5-氯苯基}-3-氯苯磺酰胺;
N-[2-(苄基硫基)-5-氰基苯基]-1-苯并呋喃-2-磺酰胺;
N-[2-(苄基亚磺酰基)-5-氰基苯基]-1-苯并呋喃-2-磺酰胺;
N-[2-(苄基磺酰基)-5-氰基苯基]-1-苯并呋喃-2-磺酰胺。
一些式I化合物及一些它们的中间体在它们的结构中具有至少一个手性中心。此手性中心可以R或S构型存在,所述R和S标记的使用与Pure Appli.Chem.(1976),45,11-13中所述的规则一致。
术语“药学上可接受的盐”是指指保持上文确定的化合物的所需生物活性并表现出最小的或不表现出非期望的毒理效应的盐或复合物。根据本发明的“药学上可接受的盐”包括式I化合物能够形成的具有治疗活性的无毒碱式或酸式盐形式。
作为碱以其游离形式存在的式I化合物的酸加成盐形式可通过用合适的酸处理游离碱而获得,诸如无机酸,例如氢卤酸,诸如盐酸、氢溴酸、硫酸、磷酸、硝酸等;或有机酸,例如乙酸、羟基乙酸、丙酸、乳酸、丙酮酸、丙二酸、延胡索酸、马来酸、草酸、酒石酸、琥珀酸、苹果酸、抗坏血酸、苯甲酸、鞣酸、扑酸、柠檬酸、甲磺酸、乙磺酸、苯磺酸、甲酸等(Handbook ofPharmaceutical Salts,P.Heinrich Stahal&Camille G.Wermuth(编辑),VerlagHelvetica Chemica Acta-Zürich,2002,329-345)。
以其酸形式存在的式I化合物的碱加成盐形式可以通过用合适的碱处理酸而获得,诸如无机碱,例如氢氧化钠、氢氧化镁、氢氧化钾、氢氧化钙、氨等;或有机碱例如L-精氨酸、乙醇胺、甜菜碱、苄星(benzathine)、吗啉等(Handbook of Pharmaceutical Salts,P.Heinrich Stahal&Camille G.Wermuth(编辑),Verlag Helvetica Chemica Acta-Zürich,2002,329-345)。
式I化合物及其盐可以呈溶剂化物形式,溶剂化物包括在本发明的范围内。这种溶剂化物包括例如水合物、醇化物等。
至于本发明提及一种化合物或多种化合物,旨在涵盖该化合物的每一种可能的同分异构形式及其混合物,除非具体提及的是特定的同分异构形式。
根据本发明的化合物可以不同的多晶型物存在。虽然未在上式中明确指明,但是此类形式旨在包括在本发明的范围内。
本发明化合物适用于治疗或预防其中可能存在涉及趋化因子受体的组分的疾患。
在另一个实施方案中,提供了在药学上可接受的载体中包含至少一种本发明化合物的药物组合物。
在本发明的进一步实施方案中,提供了用于治疗与趋化因子受体的调节相关的病症的方法。这种方法可以例如通过向有此需要的受试者施用含有治疗有效量的至少一种本发明化合物的药物组合物来实施。
这些化合物可用于治疗患有一系列可通过CCR调节得以缓解的疾患和疾病的哺乳动物,包括人。CCR调节剂的治疗效用是皮肤炎症性疾病和疾患,包括但不限于:酒渣鼻(正好在皮肤的血管扩张)、晒伤、慢性目光损伤、离散红斑、银屑病、特应性皮炎、绝经相关的热潮红、由睾丸切除术皮炎引起的热潮红、光老化、脂溢性皮炎、痤疮、过敏性皮炎、刺激性皮炎、面部毛细血管扩张(先前存在的小血管的膨胀扩张)、鼻赘(伴有滤泡扩张的鼻肥大)、红色球状鼻、痤疮样皮疹(可以渗出或结痂)、面部的燃烧或刺痛感、受刺激的和充血的和湿润的眼睛、伴有皮肤血管扩张的皮肤活动过度、Lyell氏综合征、史蒂文斯-约翰逊综合征、轻度多形性红斑、重度多形性红斑和其他炎症性皮肤疾病、光化性角化病、砷角化病、炎症性和非炎症性痤疮、鳞癣和皮肤的其它角质化和过度增生性病症、湿疹、伤口愈合。
CCR调节剂的治疗效用是眼部炎症性疾病,包括但不限于葡萄膜炎、视网膜退行性疾患、血管生成、干眼病、角膜炎、变应性眼病和影响眼睛后部的疾患,诸如黄斑病变和视网膜变性(包括非渗出性年龄相关黄斑变性、渗出性年龄相关黄斑变性、脉络膜新生血管形成、糖尿病性视网膜病变、急性黄斑视神经视网膜病变、中心性浆液性脉络膜视网膜病变、囊样黄斑水肿和糖尿病性黄斑水肿;葡萄膜炎、视网膜炎和脉络膜炎,诸如急性多灶性鳞状色素上皮病变、贝切特氏病、鸟枪弹样视网膜脉络膜病变、感染性(梅毒、莱姆病、结核病、弓形体病)、中间葡萄膜炎(睫状体平坦部炎(pars planitis))、多灶性脉络膜炎、多发性消散白点综合征(mewds)、眼部结节病、后巩膜炎、匐行状脉络膜炎、视网膜下纤维化和葡萄膜炎综合征、Vogt-Koyanagi-Harada综合征和血管疾病/渗出性疾病诸如视网膜动脉阻塞性疾病、视网膜中央静脉阻塞、弥散性血管内凝血病变、视网膜分支静脉阻塞、高血压性眼底改变、眼部缺血综合征、视网膜动脉血管瘤、柯氏症(Coat′s disease)、旁中心凹毛细管扩张、半侧视网膜静脉阻塞、视乳头静脉炎、视网膜中央动脉阻塞、视网膜分支动脉阻塞、颈动脉疾病(CAD)、磨砂分支血管炎、镰状红细胞性视网膜病变和其它血红蛋白病、血管样条纹症、家族性渗出性玻璃体视网膜病变和视网膜静脉周围炎;创伤性/外科疾患诸如交感性眼炎、葡萄膜炎视网膜疾病、视网膜脱离、创伤、激光引起的疾患、由光动力学疗法、光凝固、手术中的灌注不足引起的疾患、放射性视网膜病变和骨髓移植视网膜病变;增生性病症诸如增生性玻璃体视网膜病变和视网膜前膜、和增生性糖尿病性视网膜病变;感染性病症,例如眼组织胞浆菌病、眼弓蛔虫病、推测的假组织胞浆菌病综合征(POHS)、眼内炎、弓形体病、与HIV感染有关的视网膜疾病、与HIV感染相关的脉络膜病、与HIV感染相关的葡萄膜炎性病变、病毒性视网膜炎、急性视网膜坏死、进行性外部视网膜坏死、真菌视网膜疾病、眼梅毒、眼结核、弥漫性单侧亚急性视神经视网膜炎和蝇蛆病;遗传病症诸如色素性视网膜炎、与视网膜营养不良相关的全身性疾病、先天性静止性夜盲症、锥营养不良、斯特格氏病(Stargardt′s disease)和眼底黄色斑点症、贝斯特氏病、视网膜色素上皮的图形营养不良、X-连锁视网膜劈裂、Sorsby眼底营养不良、良性同心性黄斑病变、Bietti结晶样营养不良,和弹性假黄色瘤;视网膜撕裂/裂孔如视网膜脱离、黄斑裂孔和巨大视网膜撕裂;肿瘤诸如与肿瘤有关的视网膜疾病、视网膜色素上皮细胞先天性肥大、后部葡萄膜黑色素瘤、脉络膜血管瘤、脉络膜骨瘤、脉络膜转移、视网膜和视网膜色素上皮细胞的联合错构瘤、视网膜母细胞瘤、眼底血管增生性肿瘤、视网膜星形细胞瘤、和眼内淋巴肿瘤;以及影响眼睛后部的各种其它疾病,诸如点状内层脉络膜病变、急性多灶性鳞状色素上皮病变、近视视网膜变性和急性视网膜色素上皮炎。
在本发明的又一个实施方案中,提供了用于治疗与趋化因子受体的调节相关的病症的方法。这种方法可以例如通过向有此需要的受试者施用治疗有效量的至少一种本发明化合物或其任意组合、或其药学上可接受的盐、水合物、溶剂化物、晶型和单独的同分异构体、对映异构体和非对映异构体来实施。
本发明涉及式I化合物或其药学上可接受的盐在制备用于治疗眼部炎症性疾病的药物中的用途,所述眼部炎症性疾病包括但不限于葡萄膜炎、干眼病、角膜炎、变应性眼病和影响眼睛后部的疾患,诸如黄斑病变和视网膜变性(包括非渗出性年龄相关黄斑变性、渗出性年龄相关黄斑变性、脉络膜新生血管形成、糖尿病性视网膜病变、急性黄斑视神经视网膜病变、中心性浆液性脉络膜视网膜病变、囊样黄斑水肿和糖尿病性黄斑水肿;葡萄膜炎、视网膜炎和脉络膜炎,诸如急性多灶性鳞状色素上皮病变、贝切特氏病、鸟枪弹样视网膜脉络膜病变、感染性(梅毒、莱姆病、结核病、弓形体病)、中间葡萄膜炎(睫状体平坦部炎(parsplanitis))、多灶性脉络膜炎、多发性消散白点综合征(mewds)、眼部结节病、后巩膜炎、匐行状脉络膜炎、视网膜下纤维化和葡萄膜炎综合征、Vogt-Koyanagi-Harada综合征和血管疾病/渗出性疾病诸如视网膜动脉阻塞性疾病、视网膜中央静脉阻塞、弥散性血管内凝血病变、视网膜分支静脉阻塞、高血压性眼底改变、眼部缺血综合征、视网膜动脉血管瘤、柯氏症(Coat’s disease)、旁中心凹毛细管扩张、半侧视网膜静脉阻塞、视乳头静脉炎、视网膜中央动脉阻塞、视网膜分支动脉阻塞、颈动脉疾病(CAD)、磨砂分支血管炎、镰状红细胞性视网膜病变和其它血红蛋白病、血管样条纹症、家族性渗出性玻璃体视网膜病变和视网膜静脉周围炎;创伤性/外科疾患诸如交感性眼炎、葡萄膜炎视网膜疾病、视网膜脱离、创伤、激光引起的疾患、光动力学疗法、光凝固、手术中的灌注不足引起的疾患、放射性视网膜病变和骨髓移植视网膜病变;增生性病症诸如增生性玻璃体视网膜病变和视网膜前膜、和增生性糖尿病性视网膜病变;感染性病症,例如眼组织胞浆菌病、眼弓蛔虫病、推测的假组织胞浆菌病综合征(POHS)、眼内炎、弓形体病、与HIV感染有关的视网膜疾病、与HIV感染相关的脉络膜病、与HIV感染相关的葡萄膜炎性病变、病毒性视网膜炎、急性视网膜坏死、进行性外部视网膜坏死、真菌视网膜疾病、眼梅毒、眼结核、弥漫性单侧亚急性视神经视网膜炎和蝇蛆病;遗传病症诸如色素性视网膜炎、与视网膜营养不良相关的全身性疾病、先天性静止性夜盲症、锥营养不良、斯特格氏病(Stargardt’s disease)和眼底黄色斑点症、贝斯特氏病、视网膜色素上皮的图形营养不良、X-连锁视网膜劈裂、Sorsby眼底营养不良、良性同心性黄斑病变、Bietti结晶样营养不良,和弹性假黄色瘤;视网膜撕裂/裂孔如视网膜脱离、黄斑裂孔和巨大视网膜撕裂;肿瘤诸如与肿瘤有关的视网膜疾病、视网膜色素上皮细胞先天性肥大、后部葡萄膜黑色素瘤、脉络膜血管瘤、脉络膜骨瘤、脉络膜转移、视网膜和视网膜色素上皮细胞的联合错构瘤、视网膜母细胞瘤、眼底血管增生性肿瘤、视网膜星形细胞瘤、和眼内淋巴肿瘤;以及影响眼睛后部的各种其它疾病,诸如点状内层脉络膜病变、急性多灶性鳞状色素上皮病变、近视视网膜变性和急性视网膜色素上皮炎。
在任何给定情况下将施用的化合物的实际量将由医生考虑相关情况而确定,诸如疾患的严重性、患者的年龄和体重、患者的一般身体状况、疾患的原因和施用途径。
将以任何可接受的形式向患者口服施用所述化合物,诸如片剂、液体、胶囊、粉末等,或者其它途径可能是可取的或必要的,特别是如果患者出现恶心的情况。此类其它途径可以毫无例外地包括透皮、肠胃外、皮下、鼻内、通过植入支架、鞘内、玻璃体内、眼局部、眼后部、肌内、静脉内和直肠内递送模式。另外,可对制剂进行设计以在给定时间段内延迟活性化合物的释放,或仔细地控制在治疗过程期间于给定时间释放的药物量。
在本发明的另一个实施方案中,提供了在药学上可接受的载体中包括至少一种本发明化合物的药物组合物。短语“药学上可接受的”意指载体、稀释剂或赋形剂必须与制剂中的其他成分相容并且对其受者无害。
本发明的药物组合物可以固体、溶液、乳液、分散体、贴剂、胶束、脂质体等形式使用,其中所得到的组合物包含作为活性成分与适用于肠内或肠胃外应用的有机或无机载体或赋形剂配混的一种或多种本发明化合物。本发明化合物可例如与通常无毒、药学上可接受的用于片剂、丸剂、胶囊剂、栓剂、溶液、乳剂、混悬剂和任何其他适用形式的载体组合。可用的载体包括葡萄糖、乳糖、阿拉伯胶、明胶、甘露醇、淀粉糊、三硅酸镁、滑石、玉米淀粉、角蛋白、胶体二氧化硅、马铃薯淀粉、脲、中等链长甘油三酯、葡聚糖和其它适合于以固体、半固体或液体形式在制造制剂中使用的载体。此外,可以使用助剂、稳定剂、增稠剂和着色剂以及芳香剂。本发明化合物以足以对进程或病情产生所需效果的量包括在药物组合物中。
含有本发明化合物的药物组合物可以呈适合口服使用的形式,例如作为片剂、锭剂、糖锭剂、水性或油性混悬液、分散性粉末或颗粒、乳液、硬或软胶囊、或糖浆剂或酏剂。意图用于口服使用的组合物可根据本领域已知的用于制造药物组合物的任何方法制备,并且此类组合物可含有选自由以下组成的组的一种或多种试剂:甜味剂,诸如蔗糖、乳糖或糖精;调味剂,诸如薄荷油、冬青油或桂樱油;着色剂和防腐剂,以便提供药学上美观和可口的制剂。含有与无毒药学上可接受的赋形剂配混的本发明化合物的片剂也通过已知的方法制造。所用的赋形剂可以例如为:(1)惰性稀释剂,诸如碳酸钙、乳糖、磷酸钙或磷酸钠;(2)制粒剂和崩解剂,诸如玉米淀粉、马铃薯淀粉或藻酸;(3)粘合剂,诸如黄蓍胶、玉米淀粉、明胶或阿拉伯树胶;以及(4)润滑剂,诸如硬脂酸镁、硬脂酸或滑石。片剂可以无包衣或者它们可通过已知的技术包衣以延迟在胃肠道中的崩解和吸收并因此在较长的时间内提供持续作用。例如,可以采用诸如单硬脂酸甘油酯或二硬脂酸甘油酯的延时材料。
在一些情况下,口服使用的制剂可以为硬明胶胶囊形式,其中将本发明化合物与惰性固体稀释剂例如碳酸钙、磷酸钙或高岭土混合。它们也可以呈软明胶胶囊形式,其中将本发明化合物与水或油性介质例如花生油、液体石蜡或橄榄油混合。
药物组合物可以呈无菌注射用混悬剂形式。该混悬剂可根据已知的方法使用合适的分散剂或润湿剂和助悬剂配制。无菌注射用制剂也可以为无毒、肠胃外可接受的稀释剂或溶剂中的无菌注射用溶液或混悬剂,例如作为1,3-丁二醇中的溶液。通常将无菌、固定油用作溶剂或助悬介质。为此,可以采用任何温和的固定油,包括合成的单或二甘油酯、脂肪酸(包括油酸)、天然存在的植物油(如芝麻油、椰子油、花生油、棉籽油等)或合成的脂肪媒介物(如油酸乙酯)等等。可根据需要掺入缓冲剂、防腐剂、抗氧化剂等。
本发明化合物及其药学上可接受的盐可以通过不同的途径施用,包括但不限于局部用滴眼液、直接注射、在眼睛后部的应用或可进一步增加更长作用持续时间的制剂例如缓慢释放丸粒、混悬液、凝胶,或持续递送装置例如本领域已知的任何合适的药物递送系统(DDS)。尽管优选局部施用,但是该化合物也可用于眼内植入物,如美国美国专利7,931,909中所述。
本发明化合物可以用于药物直肠施用的栓剂形式施用。这些组合物可通过将本发明化合物与合适的非刺激性赋形剂混合来制备,所述赋形剂诸如可可油、合成的聚乙二醇甘油酯,它们在常温下为固体,但在直肠腔内则液化和/或溶解以释放药物。
由于个体受试者在症状严重性方面可表现出较大的变化并且每种药物具有其独特的治疗特性,因此每名受试者所采用的精确施用模式和剂量将由从业者决定。
本文所述的化合物和药物组合物可在哺乳动物(包括人)中用作药物,以用于对趋化因子受体的激动剂或功能性拮抗剂治疗有反应的疾病治疗和/或其病状缓解。因此,在本发明的进一步实施方案中,提供了用于治疗与趋化因子受体的调节相关的病症的方法。这种方法可以例如通过向有此需要的受试者施用含有治疗有效量的至少一种本发明化合物的药物组合物来实施。如本文所用,术语“治疗有效量”意指研究人员、兽医、医生或其他临床医生所寻求的将引起有此需要的受试者出现生物学或医学反应的药物组合物的量。在一些实施方案中,有此需要的受试者是哺乳动物。在一些实施方案中,所述哺乳动物是人。
本发明还涉及用于制备式I化合物的工艺。可采用与合成有机化学领域技术人员所理解的常规方法相似地制备根据本发明的式I化合物。下面给出的合成方案例示可如何制备根据本发明的化合物。本领域技术人员将能够常规地修改和/或变更流程1以合成式I所涵盖的任何本发明化合物。
所述的硫衍生物通过一般途径来制备,如流程1所示。在一个途径中,使适当取代的2-氨基-苯硫酚例如反应中间体A,可与亲电试剂诸如卤化物、甲苯磺酸酯、甲磺酸酯、烯酮、2-烯酸酯等在酸或碱存在下制备硫醚中间体B。可选地,硫醚中间体B可通过将在Mitsunobu条件下用醇处理中间体A来制备。中间体B与磺酰氯反应,提供式I的磺酰胺,其中R5是S。进一步,经用氧化剂例如间氯过氧苯甲酸处理,其中R5是S的式I化合物提供其中R5是S(O)或R5是S(O)2的化合物。
在另一途径中,二硫醚中间体E型可通过中间体A型的氧化来获得。中间体E与磺酰氯反应,得到磺酰胺中间体F。分别使用聚合物结合的三苯基膦或硼氢化钠来原位或逐步还原中间体F,随后所得苯硫醇与亲电试剂反应,提供式I的磺酰胺,其中R5是S。
流程1
发明详述
要理解的是,前文一般性描述和下文详细描述均仅仅为示例性和阐释性的,而不限制受权利要求书保护的本发明。如本文所用,除非另外具体指明,否则单数的使用包括复数。
对本领域技术人员将显而易见的是,一些本发明化合物可含有一个或多个不对称中心,使得所述化合物可以对映异构体形式以及以非对映异构体形式存在。除非另外具体指明,否则本发明的范围包括所有对映异构体、非对映体和外消旋混合物。一些本发明化合物可与药学上可接受的酸或碱形成盐,并且本文所述的化合物的此类药学上可接受的盐也在本发明的范围内。
本发明包括所有药学上可接受的同位素富集的化合物。任何本发明化合物可含有富集的或不同于天然比例的一种或多种同位素原子,如氘2H(或D)代替氚1H(或H),或者使用富含13C的材料代替12C等。类似的取代可用于N、O和S。同位素的使用可有助于本发明的分析以及治疗方面。例如,氘的使用可通过改变本发明化合物的代谢(率)来增加体内半衰期。这些化合物可根据通过使用富含同位素的试剂所述的制备方法来制备。
对本领域技术人员显而易见的是,可以通过按常规方式分离其混合物来获得单独的同分异构形式。例如,在非对映异构体的情况下可以采用色谱分离。
化合物名称由ACD版本8生成,以及在实施例中所使用的一些中间体和试剂名称由诸如来自MDL ISIS Draw 2.5 SP1的Chem Bio Draw Ultra版本12.0或Auto Nom 2000的软件生成。一般而言,根据以下方法进行化合物的表征:
在环境温度和指定溶剂下,将NMR光谱记录在Varian 600或Varian 300上;化学位移以[ppm]计,耦合常数以[Hz]计。
所有未描述其合成的试剂、溶剂、催化剂均购自化学品供应商,诸如SigmaAldrich、Fluka、Bio-Blocks、Combi-blocks、TCI、VWR、Lancaster、Oakwood、Trans WorldChemical、Alfa、Fisher、Maybridge、Frontier、Matrix、Ukrorgsynth、Toronto、RyanScientific、SiliCycle、Anaspec、Syn Chem、Chem-Impex、MIC-scientific,Ltd;然而一些已知的中间体则根据已公布的程序来制备。具有合适质量的溶剂购自商业来源,且原样使用。空气和/或水分敏感的反应在Ar或N2气氛下进行。
通常本发明化合物通过色谱法:CombiFlash Companion和RediSep Rf硅胶60(0.04-0.063毫米);制备型薄层色谱法(PTLC):Analtech(硅胶60F254、500或1000μm)来纯化。
在实施例中使用以下缩写:
NH3 氨
CH3CN 乙腈
CH2Cl2 二氯甲烷
DMF N,N-二甲基甲酰胺
NaOH 氢氧化钠
MeOH 甲醇
CD3OD 氘化甲醇
HCl 盐酸
Na2SO4 硫酸钠
HBTU 2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲六氟磷酸盐)
DIPEA N,N-二异丙基乙胺
CuI 碘化亚铜
Cs2CO3 碳酸铯
DMEDA N,N’-二甲基乙二胺
MgSO4 硫酸镁
EtOAc 乙酸乙酯
CDCl3 氘化氯仿
DMSO-d6 氘化二甲亚砜
TFA 三氟乙酸
THF 四氢呋喃
K2CO3 碳酸钾
mCPBA 间氯过氧苯甲酸
NaBH4 硼氢化钠
CaCl2 氯化钙
下列实施例仅用于示例的目的,并不旨在也不应将其解释为以任何方式限制本发明。本领域技术人员应理解,可在不超出本发明的精神或范围的情况下对下列实施例进行变更和修改。
具体实施例
一般程序A
中间体1
5-氯-2-[(1H-咪唑-4-基甲基)硫基]苯胺
将2-氨基-4-氯苯硫醇(CAS 1004-00-8)(1.1g,7.1mmol)、4-(氯甲基)-1H-咪唑盐酸盐(721mg,4.71mmol)和K2CO3(3.2g,23.6mmol)在DMF(10ml)中的混合物在室温搅拌过夜。将反应混合物倒入水(50ml)中并用乙酸乙酯萃取(2×50ml)。将有机层用盐水洗涤,经Na2SO4干燥,真空浓缩。粗产物通过硅胶柱色谱(0→100%乙酸乙酯的己烷溶液)纯化,得到中间体1,为固体(1.0g,60%)。
1H NMR(300MHz,CD3OD)δ7.58(s,1H),7.06(d,J=8.20Hz,1H),6.73(d,J=2.34Hz,1H),6.65(s,1H),6.48(dd,J=2.34,8.20Hz,1H),3.86(s,2H).
一般程序B
化合物1
N-{5-氯-2-[(1H-咪唑-4-基甲基)硫基]苯基}-1-苯并呋喃-2-磺酰胺
将中间体1(300mg,1.26mmol)和1-苯并呋喃-2-磺酰氯(273mg,1.26mmol)在吡啶(4ml)中的混合物加热至100℃过夜。在减压下除去吡啶,残余物通过硅胶柱色谱(10%MeOH的CH2Cl2溶液)纯化,得到化合物1(157mg,30%)。
1H NMR(600MHz,丙酮-d6)δ7.94(s,1H),7.73(d,J=7.92Hz,1H),7.64(d,J=2.35Hz,1H),7.56(d,J=8.51Hz,1H),7.52(d,J=8.22Hz,1H),7.44-7.49(m,1H),7.42(s,1H),7.28-7.37(m,1H),7.11(dd,J=2.35,8.22Hz,1H),6.97(s,1H),3.91(s,2H).
化合物2
N-[5-氯-2-(甲基硫基)苯基]-1-苯并呋喃-2-磺酰胺
按照一般程序B,由5-氯-2-(甲基硫基)苯胺(CAS 16423-54-4)(200mg,1.15mmol)和1-苯并呋喃-2-磺酰氯(249mg,1.152mmol)制备标题化合物(243mg,60%)。
1H NMR(600MHz,丙酮-d6)δ7.75(d,J=7.92Hz,1H),7.60(d,J=8.51Hz,1H),7.48-7.54(m,2H),7.47(d,J=2.35Hz,1H),7.29-7.38(m,2H),7.22(dd,J=2.35,8.51Hz,1H),2.22(s,3H).
一般程序C
化合物3
N-[5-氯-2-(甲基亚磺酰基)苯基]-1-苯并呋喃-2-磺酰胺
在0℃向化合物2(194mg,0.554mmol)在CH2Cl2(6ml)中的溶液加入mCPBA(111mg,~0.554mmol)。在0℃将其搅拌30min后,将混合物分成两份。将一份(2ml)真空浓缩,且通过硅胶柱色谱(0→100%乙酸乙酯的己烷溶液,然后0→10%MeOH的CH2Cl2溶液)纯化,得到标题化合物,为固体(35mg,52%)。
可选地,标题化合物可通过在0℃至室温下用1当量的NaIO4在MeOH/CH3CN和H2O中的溶液处理化合物2来制备。
在另一个替代程序中,标题化合物可通过在室温下用1-1.4当量的在MeOH/CH3CN和H2O中的溶液处理化合物2来制备。
1H NMR(600MHz,CDCl3)δ7.74(d,J=1.76Hz,1H),7.71(d,J=8.22Hz,1H),7.52-7.59(m,2H),7.49(td,J=1.17,7.78Hz,1H),7.32-7.39(m,1H),7.25(d,J=8.22Hz,1H),7.15(dd,J=1.91,8.36Hz,1H),2.88(s,3H).
一般程序D
化合物4
N-[5-氯-2-(甲基磺酰基)苯基]-1-苯并呋喃-2-磺酰胺
向另一部分(4ml)的来自化合物3的溶液加入mCPBA(111mg,0.554mmol),将反应在室温搅拌1h。将混合物真空浓缩,残余物通过硅胶柱色谱(0→100%乙酸乙酯的己烷溶液)纯化,得到标题化合物,为固体(75mg,53%)。
可选地,标题化合物可通在室温用2-3当量的mCPBA处理化合物2来制备。
在另一个替代程序中,标题化合物可通过在室温下用3当量的在MeOH/CH3CN和H2O中的溶液处理化合物2来制备。
1H NMR(600MHz,CDCl3)δ9.43(s,1H),7.88(d,J=1.76Hz,1H),7.81(d,J=8.51Hz,1H),7.72(d,J=7.92Hz,1H),7.61(s,1H),7.47-7.57(m,2H),7.34-7.40(m,1H),7.26(s,1H),7.23(dd,J=2.05,8.51Hz,1H),3.05(s,3H).
中间体2
5-氯-2-(甲基亚磺酰基)苯胺
按照一般程序C,由5-氯-2-(甲基硫基)苯胺(1g,5.758mmol)制备标题化合物(914mg,84%)。
1H NMR(300MHz,CD3OD)δ7.32(d,J=8.20Hz,1H),6.81(d,J=2.05Hz,1H),6.72(dd,J=1.76,8.20Hz,1H),2.86(s,3H).
化合物5
3,4-二氯-N-[5-氯-2-(甲基硫基)苯基]苯磺酰胺
按照一般程序B,由5-氯-2-(甲基亚磺酰基)苯胺(中间体2)(120mg,0.635mmol)和3,4-二氯苯-1-磺酰氯(156mg,0.635mmol)制备标题化合物(52mg,21%)。
1H NMR(300MHz,CD3OD)δ7.87(d,J=1.76Hz,1H),7.55-7.70(m,2H),7.38(s,1H),7.17-7.27(m,2H),2.22(s,3H).
化合物6
3,4-二氯-N-[5-氯-2-(甲基亚磺酰基)苯基]苯磺酰胺
按照一般程序C,由3,4-二氯-N-[5-氯-2-(甲基硫基)苯基]苯磺酰胺(52mg,0.136mmol)制备标题化合物(28mg,52%)。
1H NMR(300MHz,丙酮-d6)δ10.70(br.s.,1H),8.06(s,1H),7.86(s,2H),7.44-7.59(m,2H),7.34(dd,J=1.90,8.35Hz,1H),2.84(s,3H).
化合物7
4-氯-N-[5-氯-2-(甲基亚磺酰基)苯基]-3-甲基苯磺酰胺
按照一般程序B和C,由5-氯-2-(甲基硫基)苯胺和4-氯-3-甲基苯-1-磺酰氯制备标题化合物(90mg)。
1H NMR(600MHz,CDCl3)δ10.62(s,1H),7.82(d,J=2.05Hz,1H),7.71(dd,J=1.91,8.36Hz,1H),7.63(d,J=2.05Hz,1H),7.48(d,J=8.51Hz,1H),7.02-7.15(m,2H),2.81(s,3H),2.43(s,3H).
化合物8
N-[5-氯-2-(甲基亚磺酰基)苯基]-3-硝基-4-(三氟甲基)苯磺酰胺
按照一般程序B和C,由5-氯-2-(甲基硫基)苯胺和4-硝基-3-(三氟甲基)苯-1-磺酰氯制备标题化合物(43mg)。
1H NMR(600MHz,丙酮-d6)δ8.25-8.35(m,2H),8.11(d,J=8.22Hz,1H),7.39-7.48(m,2H),6.75(dd,J=2.05,8.22Hz,1H),2.70(s,3H).
化合物9
4-氯-N-[5-氯-2-(甲基硫基)苯基]-2-氟苯磺酰胺
按照一般程序B,由5-氯-2-(甲基硫基)苯胺(273mg,1.57mmol)和4-氯-2-氟苯-1-磺酰氯(360mg,1.57mmol)制备标题化合物(380mg,66%)。
1H NMR(300MHz,丙酮-d6)δ8.77(br.s.,1H),7.84(t,J=8.06Hz,1H),7.53(dd,J=1.90,9.82Hz,1H),7.35-7.48(m,3H),7.25(dd,J=2.20,8.35Hz,1H),2.34(s,3H).
化合物10
4-氯-N-{5-氯-2-[(1H-咪唑-4-基甲基)磺酰基]苯基}-3-(三氟甲基)苯磺酰胺
按照一般程序B和D,由5-氯-2-[(1H-咪唑-4-基甲基)硫基]苯胺(301mg,1.26mmol)和4-氯-3-(三氟甲基)苯-1-磺酰氯(351mg,1.26mmol)制备标题化合物(95mg,36%)。
1H NMR(600MHz,丙酮-d6)δ8.27(s,1H),8.15(d,J=8.22Hz,1H),7.81(br.s.,1H),7.73(d,J=8.51Hz,1H),7.68(d,J=8.51Hz,1H),7.30(s,1H),6.91(dd,J=1.47,8.51Hz,1H),4.56(br.s.,2H).
中间体3
[4-(氯甲基)-1,3-噻唑-2-基氨基甲酸叔丁酯
将4-(氯甲基)-1,3-噻唑-2-胺盐酸盐(530mg,2.86mmol)、二碳酸二叔丁酯(750mg,3.44mmol)、三乙胺(0.6ml,4.30mmol)和DMAP(催化量)在THF(10ml)中的溶液在室温下搅拌过夜。将混合物用乙酸乙酯稀释,用水和盐水洗涤,经Na2SO4干燥,真空浓缩。将残余物通过柱色谱(30%乙酸乙酯的己烷溶液)纯化,得到标题化合物,为固体(391mg,45%)。
1H NMR(600MHz,CD3OD)δ7.02(s,1H),4.56(s,2H),1.54(s,9H).
中间体4
(4-{[(2-氨基-4-氯苯基)硫基]甲基}-1,3-噻唑-2-基)基甲酸叔丁酯
按照一般程序A,由含2-氨基-4-氯苯硫醇(376mg,2.36mmol)、[4-(氯甲基)-1,3-噻唑-2-基]氨基甲酸叔丁酯(391mg,1.57mmol)和K2CO3(1.08g,3.45mmol)的DMF(10ml)制备标题化合物(588mg,67%)。
1H NMR(300MHz,丙酮-d6)δ10.18(br.s.,1H),7.17(d,J=8.21Hz,1H),6.79(d,J=2.34Hz,1H),6.62(s,1H),6.51(dd,J=2.05,8.20Hz,1H),5.30(br.s.,1H),3.88(s,2H),1.53(s,9H).
化合物11
{4-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}硫基)甲基]-1,3-噻唑-2-基}氨基甲酸叔丁酯
按照一般程序B,由(4-{[(2-氨基-4-氯苯基)硫基]甲基}-1,3-噻唑-2-基)氨基甲酸叔丁酯(640mg,1.72mmol)和1-苯并呋喃-2-磺酰氯(372mg,1.72mmol)在吡啶(5ml)中制备标题化合物(380mg,54%)。
1H NMR(300MHz,丙酮-d6)δ11.20(br.s.,1H),9.82(br.s.,1H),7.78(d,J=7.91Hz,2H),7.67(d,J=2.34Hz,1H),7.62(s,1H),7.45-7.60(m,3H),7.31-7.43(m,1H),7.07-7.22(m,1H),6.77(s,1H),3.93(s,2H),1.55(s,9H).
一般程序E
化合物12
N-(2-{[(2-氨基-1,3-噻唑-4-基)甲基]硫基}-5-氯苯基)-1-苯并呋喃-2-磺酰胺
将化合物11{4-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}硫基)甲基]-1,3-噻唑-2-基}氨基甲酸叔丁酯(62mg,0.11mmol)、TFA(0.2ml)在CH2Cl2(1ml)中的溶液搅拌过夜。真空除去溶剂,粗产物通过硅胶柱色谱(50%乙酸乙酯的己烷溶液)纯化,得到标题化合物(45mg,88%)。
1H NMR(600MHz,丙酮-d6)δ8.78(br.s.,1H),7.77(d,J=7.92Hz,0H),7.55-7.66(m,3H),7.45-7.55(m,2H),7.29-7.41(m,1H),7.17(dd,J=2.20,8.36Hz,1H),6.33(s,1H),3.90(s,2H).
化合物13
4-氯-N-[5-氯-2-(甲基亚磺酰基)苯基]-3-(三氟甲基)苯磺酰胺
按照一般程序B和C,由5-氯-2-(甲基硫基)苯胺和4-硝基-3-(三氟甲基)苯-1-磺酰氯制备标题化合物。
1H NMR(300MHz,CD3OD)δ8.07(s,1H),7.96(d,J=8.50Hz,1H),7.82(d,J=8.21Hz,1H),7.76(d,J=8.50Hz,1H),7.41(d,J=7.91Hz,1H),7.07(s,1H),2.83(s,3H).
一般程序F
中间体5
N,N’-[二硫代双(5-氯-2,1-亚苯基)]双[4-氯-3-(三氟甲基)苯磺酰胺]
向2,2’-硫代双(5-氯苯胺)(CAS 29124-55-8)(1.59g,5.0mmol)在吡啶(20ml)中的溶液加入4-氯-3-(三氟甲基)苯-1-磺酰氯(2.76g,10.0mmol),将反应在室温下搅拌16h。另外的4-氯-3-(三氟甲基)苯-1-磺酰氯(2.76g,10.0mmol)和吡啶(20ml),将反应搅拌20h。将混合物真空浓缩,加入H2O。形成胶状半固体。倒出H2O后,将半固体用H2O漂洗(×2),溶解于EtOAc中,用1M HCl萃取(×2),用H2O、盐水洗涤,经Na2SO4干燥,真空浓缩,得到褐色粘稠糖浆(6.5g)。向该粗糖浆在甲醇(100ml)中的溶液加入4M NaOH(12ml),将混合物加热至100℃达15min,冷却至室温,在搅拌下用1M HCl(~50ml)缓慢地淬灭,冷却至pH 4-5。真空蒸发所得悬浮液的体积,然后用EtOAc萃取。将合并的有机层用盐水洗涤,经Na2SO4干燥,且真空浓缩。将含有磺酸的粗固体在饱和NaHCO3中粉碎,过滤,用最小量的乙醚漂洗,得到标题化合物,为灰白色固体(3.11g)。
1H NMR(600MHz,CD3OD)δ8.08(d,J=2.05Hz,2H),7.93(dd,J=2.20,8.36Hz,2H),7.81(d,J=8.51Hz,2H),7.22(d,J=2.05Hz,2H),7.18-7.20(m,2H),7.10(d,J=8.51Hz,2H).
化合物14
4-氯-N-[5-氯-2-(乙基硫基)苯基]-3-(三氟甲基)苯磺酰胺
向中间体5 N,N’-二硫代双[(5-氯-2,1-亚苯基)]双[4-氯-3-(三氟甲基)苯磺酰胺](0.32g,0.40mmol)在CH2Cl2(10ml)中的溶液加入饱和NaHCO3水溶液(1.0ml)、聚合物结合的三苯基膦(~3mmol/g三苯基膦负载,0.27g,0.80mmol)和乙基碘(64μl,0.80mmol)。将反应在室温搅拌2h,用EtOAc稀释,过滤,用盐水洗涤,经Na2SO4干燥,浓缩。残余物通过硅胶柱色谱(0→25%乙酸乙酯的己烷溶液)纯化,得到标题化合物,为黄色糖浆(204mg,59%)。
1H NMR(600MHz,CDCl3)δ8.12(d,J=2.35Hz,1H),7.88(dd,J=2.35,8.22Hz,1H),7.82(br.s.,1H),7.64(d,J=2.35Hz,1H),7.59(d,J=8.51Hz,1H),7.32(d,J=8.22Hz,1H),7.06(dd,J=2.20,8.36Hz,1H),2.60(q,J=7.34Hz,2H),1.10(t,J=7.34Hz,3H).
化合物15
4-氯-N-[5-氯-2-(乙基亚磺酰基)苯基]-3-(三氟甲基)苯磺酰胺
按照一般程序C,由4-氯-N-[5-氯-2-(乙基硫基)苯基]-3-(三氟甲基)苯磺酰胺制备标题化合物。
1H NMR(600MHz,CD3OD)δ8.15(d,J=2.35Hz,1H),8.00(dd,J=2.20,8.36Hz,1H),7.72(d,J=8.51Hz,1H),7.44(d,J=8.51Hz,1H),7.27(d,J=2.05Hz,1H),7.01(dd,J=2.05,8.51Hz,1H),3.10-3.18(m,1H),2.89-2.97(m,1H),1.11(t,J=7.34Hz,3H).
中间体6
6-[(叔丁氧基羰基)氨基]吡啶-2-羧酸乙酯
将6-氨基吡啶-2-羧酸乙酯(1.57g,9.43mmol)、DMAP(1.12g,9.18mmol)和二碳酸二叔丁酯(2.46g,11.3mmol)在THF(45ml)的混合物于60℃搅拌16h。除去溶剂,残余物通过硅胶色谱(10→15%乙酸乙酯的己烷溶液)纯化,得到标题化合物,为白色固体(2.50g,100%)。
中间体7
[6-(氯甲基)吡啶-2-基]氨基甲酸叔丁酯
向6-[(叔丁氧基羰基)氨基]吡啶-2-羧酸乙酯(456mg,1.71mmol)在无水乙醇(20ml)中的溶液加入粉末状CaCl2(395mg,3.42mmol)。将悬浮液搅拌,冷却至0℃,缓慢加入NaBH4(325mg,8.55mmol)。将反应在0℃搅拌2h,用水淬灭,用CHCl3萃取(×3)。将合并的有机层经Na2SO4干燥,蒸发。残余物通过硅胶柱色谱(30→50%乙酸乙酯的己烷溶液)纯化,得到无色糖浆(308mg),为含有[6-(羟基甲基)吡啶-2-基]氨基甲酸叔丁酯作为主要组分的混合物(~4∶1比率)。将上述混合物在CH2Cl2(10ml)中的溶液加入吡啶(144μl,1.79mmol)和SOCl2(120μl,1.65mmol)。将反应在室温搅拌4h,用水和Na2CO3淬灭,用CHCl3萃取。将合并的有机层经Na2SO4干燥,蒸发。残余物通过硅胶柱色谱(10%乙酸乙酯的己烷溶液)纯化,得到标题化合物,为无色糖浆(208mg,2步收率为50%)。
中间体8
N,N’-二硫代双[(5-氯-2,1-亚苯基)]双(1-苯并呋喃-2-磺酰胺)
按照一般程序F,由2,2’-硫代双(5-氯苯胺)和1-苯并呋喃-2-磺酰氯制备标题化合物。
1H NMR(600MHz,CD3OD)δ7.72(d,J=7.92Hz,2H),7.55(dd,J=0.59,8.51Hz,2H),7.48(s,2H),7.32-7.37(m,4H),7.22(d,J=2.05Hz,2H),6.99-7.02(m,2H),6.96-6.99(m,2H).
一般程序G
化合物16
{6-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}硫基)甲基]吡啶-2-基}氨基甲酸叔丁酯
向N,N’-二硫代双[(5-氯-2,1-亚苯基)]双(1-苯并呋喃-2-磺酰胺)(271mg,0.40mmol)在CH2Cl2(4ml)和二噁烷(4ml)中的溶液加入饱和NaHCO3水溶液(4ml)、聚合物结合的三苯基膦(~3mmol/g三苯基膦负载,0.40g,1.20mmol)、[6-(氯甲基)吡啶-2-基]氨基甲酸叔丁酯(195mg,0.80mmol)和四丁基碘化铵(30mg,0.08mmol)。将反应在室温搅拌4h,用EtOAc稀释,过滤,用盐水洗涤,经Na2SO4干燥,浓缩。残余物通过硅胶柱色谱(10→15%乙酸乙酯的己烷溶液)纯化,得到标题化合物,为黄色固体(260mg,59%)。
1H NMR(600MHz,CD3OD)δ7.74(d,J=8.22Hz,1H),7.70(d,J=7.63Hz,1H),7.50-7.57(m,2H),7.44-7.50(m,2H),7.41(s,1H),7.31-7.36(m,2H),7.09(d,J=8.22Hz,1H),6.65(d,J=7.34Hz,1H),3.88(s,2H),1.54(s,9H).
化合物17
N-(2-{[(6-氨基吡啶-2-基)甲基]硫基}-5-氯苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序E,由{6-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}硫基)甲基]吡啶-2-基}氨基甲酸叔丁酯制备标题化合物(33mg,78%)。
1H NMR(600MHz,CD3OD)δ7.63(d,J=7.92Hz,1H),7.58(d,J=2.35Hz,1H),7.40-7.44(m,1H),7.35-7.40(m,2H),7.31-7.35(m,2H),7.26(ddd,J=0.88,7.04,7.92Hz,1H),6.95(dd,J=2.35,8.22Hz,1H),6.55(d,J=8.51Hz,1H),6.31(d,J=7.04Hz,1H),3.78(s,2H).
化合物18
{6-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}亚磺酰基)甲基]吡啶-2-基}氨基甲酸叔丁酯
按照一般程序C,由{6-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}硫基)甲基]吡啶-2-基}氨基甲酸叔丁酯制备标题化合物(98mg,91%)。
1H NMR(600MHz,CD3OD)δ7.67(d,J=8.22Hz,1H),7.64(d,J=7.04Hz,1H),7.47(d,J=2.05Hz,1H),7.42-7.46(m,1H),7.36-7.39(m,1H),7.29-7.33(m,1H),7.22-7.26(m,2H),7.09(d,J=8.22Hz,1H),6.77(dd,J=1.91,8.36Hz,1H),6.68(d,J=7.34Hz,1H),4.59(d,J=12.62Hz,1H),4.16(d,J=12.62Hz,1H),1.52(s,9H).
化合物19
N-(2-{[(6-氨基吡啶-2-基)甲基]亚磺酰基}-5-氯苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序E,由{6-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}亚磺酰基)甲基]吡啶-2-基}氨基甲酸叔丁酯制备标题化合物(71mg,91%)。
1H NMR(300MHz,CD3OD)δ7.65(d,J=7.91Hz,1H),7.52-7.62(m,1H),7.50(d,J=1.47Hz,1H),7.39-7.46(m,1H),7.29-7.38(m,2H),7.20-7.29(m,2H),6.89(dd,J=1.47,8.50Hz,1H),6.79(d,J=8.79Hz,1H),6.44(d,J=7.03Hz,1H),4.60(d,J=13.48Hz,1H),4.25(d,J=13.19Hz,1H).
化合物20
{6-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}磺酰基)甲基]吡啶-2-基}氨基甲酸叔丁酯
按照一般程序E,由{6-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}硫基)甲基]吡啶-2-基}氨基甲酸叔丁酯制备标题化合物(60mg,56%)。
1H NMR(300MHz,CD3OD)δ7.79(d,J=1.76Hz,1H),7.65(d,J=7.62Hz,1H),7.55(d,J=8.50Hz,1H),7.44(s,1H),7.18-7.40(m,5H),6.72(dd,J=1.76,8.50Hz,1H),6.60(d,J=7.33Hz,1H),4.97(s,2H),1.51(s,9H).
化合物21
N-(2-{[(6-氨基吡啶-2-基)甲基]磺酰基}-5-氯苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序E,由{6-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}磺酰基)甲基]吡啶-2-基}氨基甲酸叔丁酯制备标题化合物(47mg,94%)。
1H NMR(300MHz,CD3OD)δ7.73(d,J=2.05Hz,1H),7.66(d,J=7.62Hz,1H),7.52(d,J=8.79Hz,1H),7.20-7.44(m,4H),7.14(t,J=7.77Hz,1H),6.73(dd,J=1.76,8.50Hz,1H),6.48(d,J=8.20Hz,1H),6.28(d,J=7.33Hz,1H),4.91(s,2H).
化合物22
3-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}硫基)甲基]-1H-吡唑-1-羧酸叔丁酯
按照一般程序G,由N,N’-二硫代双[(5-氯-2,1-亚苯基)]双(1-苯并呋喃-2-磺酰胺)和3-(溴甲基)-1H-吡唑-1-羧酸叔丁酯制备标题化合物(206mg,36%)。
1H NMR(600MHz,CDCl3)δ8.30(br.s.,1H),7.93(d,J=2.64Hz,1H),7.62-7.67(m,2H),7.47-7.52(m,1H),7.42-7.45(m,1H),7.41(s,1H),7.34(d,J=8.22Hz,1H),7.28-7.32(m,1H),7.00(dd,J=2.20,8.36Hz,1H),6.03(d,J=2.64Hz,1H),3.88(s,2H),1.64(s,9H).
化合物23
N-{5-氯-2-[(1H-吡唑-3-基甲基)硫基]苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序E,由3-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}硫基)甲基]-1H-吡唑-1-羧酸叔丁酯制备标题化合物(15mg,66%)。
1H NMR(600MHz,CD3OD)δ7.70(d,J=7.92Hz,1H),7.51-7.55(m,1H),7.45-7.50(m,2H),7.37-7.44(m,2H),7.34(t,J=7.19Hz,1H),7.25-7.31(m,1H),7.11(dd,J=1.76,8.22Hz,1H),5.88(br.s.,1H),3.89(s,2H).
一般程序H
中间体9
3-[(2-氨基-4-氯苯基)硫基]-N,N-二甲基丙酰胺
将2-氨基-4-氯苯硫醇(327mg,2.05mmol)、N,N-二甲基丙烯酰胺(203mg,2.05mmol)和HOAc(0.5ml)在CH2Cl2(5ml)中的混合物在室温搅拌3天。将反应用NaHCO3(水溶液)淬灭,然后用CH2Cl2萃取(2×10ml)。将有机层用水和盐水洗涤,在真空浓缩。粗产物通过硅胶色谱(50%乙酸乙酯的己烷溶液)纯化,得到标题化合物(284mg,54%)。
1H NMR(300MHz,CD3OD)δ7.26(d,J=8.21Hz,1H),6.76(d,J=2.05Hz,1H),6.56(dd,J=2.34,8.20Hz,1H),2.85-3.02(m,8H),2.57(t,J=7.03Hz,2H).
化合物24
3-{[4-氯-2-({[4-氯-3-(三氟甲基)苯基]磺酰基}氨基)苯基]亚磺酰基}-N,N-二甲基丙酰胺
按照一般程序B和C,由3-[(2-氨基-4-氯苯基)硫基]-N,N-二甲基丙酰胺(284mg,1.11mmol)制备标题化合物(280mg)。
1H NMR(600MHz,CD3OD)δ8.16(d,J=1.76Hz,1H),8.00(dd,J=2.05,8.22Hz,1H),7.75(d,J=8.51Hz,1H),7.57(d,J=8.51Hz,1H),7.32(s,1H),7.21(d,J=7.92Hz,1H),3.26(br.s.,1H),3.18(br.s.,1H),3.02(s,3H),2.95(s,3H),2.83-2.91(m,1H),2.62-2.76(m,1H).
化合物25
{4-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}亚磺酰基)甲基]-1,3-噻唑-2-基}氨基甲酸叔丁酯
按照一般程序C,将(4-(((2-(苯并呋喃-2-磺酰胺基)-4-氯苯基)硫基)甲基)噻唑-2-基)氨基甲酸叔丁酯(138mg,0.25mmol)氧化,得到标题化合物(97mg,68%)。
1H NMR(600MHz,丙酮-d6)δ10.43(br.s.,1H),7.75-7.84(m,2H),7.66(d,J=2.05Hz,1H),7.62(dd,J=0.88,8.51Hz,1H),7.50(ddd,J=1.32,7.26,8.44Hz,1H),7.32-7.41(m,1H),7.11-7.24(m,2H),6.74(s,1H),4.47(d,J=12.91Hz,1H),4.37(d,J=12.91Hz,1H),1.50(s,9H).
化合物26
N-(2-{[(2-氨基-1,3-噻唑-4-基)甲基]亚磺酰基}-5-氯苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序E,对{4-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}亚磺酰基)甲基]-1,3-噻唑-2-基}氨基甲酸叔丁酯(87mg,0.153mmol)进行脱-Boc,得到标题化合物(58mg,82%)。
1H NMR(600MHz,丙酮-d6)δ10.43(br.s.,1H),7.75-7.84(m,2H),7.66(d,J=2.05Hz,1H),7.62(dd,J=0.88,8.51Hz,1H),7.50(ddd,J=1.32,7.26,8.44Hz,1H),7.32-7.41(m,1H),7.11-7.24(m,2H),6.74(s,1H),4.47(d,J=12.91Hz,1H),4.37(d,J=12.91Hz,1H),1.50(s,9H).
化合物27
{4-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}磺酰基)甲基]-1,3-噻唑-2-基}氨基甲酸叔丁酯
按照一般程序D,由(4-(((2-(苯并呋喃-2-磺酰胺基)-4-氯苯基)硫基)甲基)噻唑-2-基)氨基甲酸叔丁酯(117mg,0.212mmol)制备标题化合物(112mg,90%)。
1H NMR(600MHz,丙酮-d6)δ7.80(d,J=7.92Hz,2H),7.78(d,J=1.76Hz,1H),7.67(d,J=8.51Hz,1H),7.59(d,J=7.92Hz,1H),7.50(t,J=7.63Hz,1H),7.37(t,J=7.48Hz,1H),6.99(s.,1H),4.70(s.,2H),1.53(s,9H)
1H NMR(600MHz,丙酮-d6)δ7.80(d,J=7.92Hz,2H),7.67(d,J=8.51Hz,1H),7.60(br.s.,1H),7.50(t,J=7.63Hz,1H),7.33-7.41(m,1H),6.99(br.s.,1H),4.70(br.s.,2H),1.53(s,9H).
化合物28
N-(2-{[(2-氨基-1,3-噻唑-4-基)甲基]磺酰基}-5-氯苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序E,由{4-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}亚磺酰基)甲基]-1,3-噻唑-2-基}氨基甲酸叔丁酯(77mg,0.153mmol)制备标题化合物(54mg,86%)。
1H NMR(600MHz,丙酮-d6)δ7.74-7.85(m,2H),7.68(d,J=2.35Hz,1H),7.64(dd,J=0.88,8.51Hz,1H),7.53(ddd,J=1.32,7.19,8.51Hz,1H),7.39(ddd,J=0.88,7.26,8.00Hz,1H),7.16-7.24(m,2H),6.74(s,1H),4.32-4.46(m,2H),1.47-1.55(m,9H).
中间体10
5-氯-2-(((5-硝基-1H-吡唑-3-基)甲基)硫基)苯胺
将(5-硝基-1H-吡唑-3-基)甲醇(524mg,3.66mmol)首先用SOCl2(3ml)在CH2Cl2(5ml)中于35℃处理2小时。除去溶剂,得到粗的3-(氯甲基)-5-硝基-1H-吡唑。然后按照一般程序A,由2-氨基-4-氯苯硫醇(161mg,1.01mmol)、粗的3-(氯甲基)-5-硝基-1H-吡唑、K2CO3(468mg,3.39mmol)在DMF(3ml)中制备标题化合物(515mg,49%)。
1H NMR(600MHz,CD3OD)δ7.05(d,J=8.22Hz,1H),6.77(d,J=2.35Hz,1H),6.60(s,1H),6.49(dd,J=2.05,8.22Hz,1H),3.95(s,2H).
化合物29
N-(5-氯-2-{[(5-硝基-1H-吡唑-3-基)甲基]硫基}苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序B,由5-氯-2-(((5-硝基-1H-吡唑-3-基)甲基)硫基)苯胺(503mg,1.77mmol)和苯并呋喃-2-磺酰氯(384mg,1.77mmol)在吡啶(5ml)中制备标题化合物(580mg,71%)。
1H NMR(600MHz,CD3OD)δ7.70-7.73(m,1H),7.53-7.56(m,1H),7.49(d,J=1.47Hz,1H),7.47-7.49(m,1H),7.47(d,J=1.17Hz,1H),7.45(d,J=2.35Hz,1H),7.44(d,J=0.88Hz,1H),7.35(ddd,J=0.88,7.26,8.00Hz,1H),7.15(dd,J=2.35,8.22Hz,1H),6.42(s,1H),3.97(s,2H).
化合物30
N-(5-氯-2-{[(5-硝基-1H-吡唑-3-基)甲基]亚磺酰基}苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序C,由N-(5-氯-2-{[(5-硝基-1H-吡唑-3-基)甲基]硫基}苯基)-1-苯并呋喃-2-磺酰胺(245mg,0.528mmol)制备标题化合物(155mg,61%)。
1H NMR(600MHz,CD3OD)δ7.67(dt,J=0.77,7.56Hz,1H),7.42-7.45(m,2H),7.35(td,J=1.32,7.85Hz,1H),7.24-7.29(m,2H),7.09(d,J=8.22Hz,1H),6.85(d,J=8.22Hz,1H),6.33(s,1H),4.61(d,J=14.09Hz,1H),4.48(d,J=14.09Hz,1H).
一般程序I
化合物31
N-(2-{[(5-氨基-1H-吡唑-3-基)甲基]硫基}-5-氯苯基)-1-苯并呋喃-2-磺酰胺
在H2气球下将N-(5-氯-2-{[(5-硝基-1H-吡唑-3-基)甲基]硫基}苯基)-1-苯并呋喃-2-磺酰胺(77mg,0.166mmol)在存在Pd/C(10%wt,18mg)下在MeOH(3ml)中还原成标题化合物。
1H NMR(600MHz,CD3OD)δ7.70(d,J=7.92Hz,1H),7.52-7.56(m,2H),7.48(ddd,J=1.17,7.12,8.44Hz,1H),7.44(s,1H),7.40(s,1H),7.34(t,J=7.48Hz,1H),7.28(d,J=8.51Hz,1H),7.11(dd,J=2.20,8.36Hz,1H),3.74(s,2H).
化合物32
N-(2-{[(5-氨基-1H-吡唑-3-基)甲基]亚磺酰基}-5-氯苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序I,由N-(5-氯-2-{[(5-硝基-1H-吡唑-3-基)甲基]亚磺酰基}苯基)-1-苯并呋喃-2-磺酰胺(46mg,0.096mmol)还原标题化合物(39mg,91%)。
1H NMR(600MHz,CD3OD)δ7.91-7.99(m,1H),7.67-7.72(m,1H),7.56-7.62(m,1H),7.50-7.55(m,1H),7.41-7.48(m,2H),7.29-7.40(m,2H),7.13(dd,J=1.91,8.36Hz,1H),4.55(d,J=13.79Hz,1H),4.05(d,J=13.79Hz,1H)
化合物33
N-(2-{[(5-氨基-1H-吡唑-3-基)甲基]磺酰基}-5-氯苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序D和H,由N-(5-氯-2-{[(5-硝基-1H-吡唑-3-基)甲基]硫基}苯基)-1-苯并呋喃-2-磺酰胺制备标题化合物(27mg)。
1H NMR(600MHz,CD3OD)δ7.69-7.74(m,2H),7.62-7.58(m,3H),7.51(dd,J=0.59,8.51Hz,1H),7.44(ddd,J=1.17,7.12,8.44Hz,1H),7.26-7.35(m,1H),7.09(dd,J=1.91,8.66Hz,1H),4.59(s,2H).
中间体11
1-丙基-1H-咪唑-4-甲醛
在冰冷却下向NaH(95%,231mg,9.18mmol)在THF(20ml)中的悬浮液加入4-咪唑甲醛(588mg,6.12mmol)。在氮气气氛下将混合物回流2小时。将混合物冷却至室温,将1-碘丙烷(5ml)加至混合物中,然后再回流2小时。将混合物冷却至室温,用水淬灭。将溶液用EtOAc萃取(2x50ml),用盐水洗涤,经Na2SO4干燥,真空浓缩。粗产物通过硅胶柱色谱(0-10%MeOH在CH2Cl2中的溶液)纯化,得到标题化合物(487mg,58%)。
1H NMR(600MHz,CD3OD)δ9.73(s,1H),7.97(s,1H),7.84(s,1H),4.07(t,J=7.04Hz,2H),1.73-1.92(m,2H),0.93(t,J=7.34Hz,3H).
中间体12
(1-丙基-1H-咪唑-4-基)甲醇
在0℃、向LAH(2.0M的THF溶液,1.9ml,3.882mmol)在THF(10ml)中的溶液滴加1-丙基-1H-咪唑-4-甲醛(487mg,3.529mmol)在THF(4ml)中的溶液。在0℃搅拌5min后,在0℃下将水(0.2ml)、15%NaOH(0.2ml)滴加至反应混合物。将反应混合物在室温再搅拌2小时。将MgSO4加至混合物中,滤掉固体,将滤液真空浓缩,得到黄色油状物,其不经进一步纯化即可使用。
1H NMR(600MHz,CD3Cl3)δ7.42(s,1H),6.86(s,1H),4.59(s,2H),3.87(t,J=7.04Hz,2H),1.73-1.82(m,2H),0.93(t,J=7.34Hz,3H).
中间体13
5-氯-2-(((1-丙基-1H-咪唑-4-基)甲基)硫基)苯胺
将(1-丙基-1H-咪唑-4-基)甲醇(535mg,3.11mmol)首先用SOCl2(3ml)在CH2Cl2(5ml)中于35℃处理2小时。除去溶剂,得到粗的4-(氯甲基)-1-丙基-1H-咪唑。然后按照一般程序A,由2-氨基-4-氯苯硫醇(744mg,4.66mmol)、粗的4-(氯甲基)-1-丙基-1H-咪唑、K2CO3(2.1g,15.54mmol)在DMF(10ml)中制备标题化合物(587mg,67%)。
1H NMR(600MHz,CDCL3)δ7.38(s,1H),7.17(d,J=8.22Hz,1H),6.67(d,J=2.05Hz,1H),6.57(dd,J=2.20,8.07Hz,1H),6.51(s,1H),3.85(s,2H),3.79(t,J=7.04Hz,2H),1.67-1.76(m,2H),0.88(t,J=7.34Hz,3H).
化合物34
N-(5-氯-2-{[(1-丙基-1H-咪唑-4-基)甲基]硫基}苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序B,由5-氯-2-(((1-丙基-1H-咪唑-4-基)甲基)硫基)苯胺(587mg,2.082mmol)和苯并呋喃-2-磺酰氯(451mg,2.082mmol)在吡啶(10ml)中制备标题化合物(463mg,48%)。
1H NMR(600MHz,CD3OD)δ7.71(dt,J=1.03,7.92Hz,1H),7.57(d,J=1.17Hz,1H),7.52-7.55(m,1H),7.44-7.51(m,2H),7.42(d,J=0.88Hz,1H),7.34(td,J=1.03,7.56Hz,1H),7.27(d,J=8.22Hz,1H),7.07(dd,J=2.35,8.51Hz,1H),6.44-6.51(m,1H),3.75-3.81(m,4H),1.63(dquin,J=7.19,7.34Hz,2H),0.74-0.82(m,3H).
化合物35
N-(5-氯-2-{[(1-丙基-1H-咪唑-4-基)甲基]亚磺酰基}苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序C,由N-(5-氯-2-{[(1-丙基-1H-咪唑-4-基)甲基]硫基}苯基)-1-苯并呋喃-2-磺酰胺制备标题化合物(148mg,75%)。
1H NMR(600MHz,CD3OD)δ8.46(s,1H),7.70(dd,J=1.47,8.22Hz,1H),7.49(dd,J=0.88,8.51Hz,1H),7.38-7.43(m,2H),7.35(d,J=0.88Hz,1H),7.30(ddd,J=1.03,7.19,7.92Hz,1H),7.12(d,J=8.51Hz,1H),6.91(dd,J=1.91,8.36Hz,1H),6.80(s,1H),4.57(d,J=14.38Hz,1H),4.43(d,J=14.09Hz,1H),3.84-3.99(m,2H),1.57-1.71(m,2H),0.81(t,J=7.34Hz,3H).
化合物36
N-(5-氯-2-{[(1-丙基-1H-咪唑-4-基)甲基]磺酰基}苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序D,由N-(5-氯-2-{[(1-丙基-1H-咪唑-4-基)甲基]硫基}苯基)-1-苯并呋喃-2-磺酰胺制备标题化合物(115mg,60%)。
1H NMR(300MHz,CD3OD)δ7.82(s,1H),7.71(dd,J=1.32,7.77Hz,1H),7.67(d,J=2.05Hz,1H),7.55(d,J=8.50Hz,1H),7.44-7.50(m,2H),7.41(td,J=1.32,7.69Hz,1H),7.25-7.35(m,1H),6.85(dd,J=2.05,8.79Hz,1H),6.76(s,1H),4.57(s,2H),3.74(t,J=7.03Hz,2H),1.54(quind,J=6.89,7.07Hz,2H),0.69(t,J=7.47Hz,3H).
中间体14
将(4-(羟基甲基)吡啶-2-基)氨基甲酸叔丁酯
将(2-氨基吡啶-4-基)甲醇(547mg,4.408mmol)、二碳酸二叔丁酯(1.25g,5.730mmol)在t-BuOH(20ml)中的溶液在室温下搅拌过夜。除去溶剂,加入乙酸乙酯,滤掉固体,将滤液真空浓缩。残余物通过柱色谱(10%MeOH的CH2Cl2溶液)纯化,得到标题化合物,为白色固体(703mg,71%)。
1H NMR(600MHz,CDCl3)δ8.18(d,J=5.28Hz,1H),8.00(s,1H),6.92-7.10(m,1H),4.75(s,2H),1.32-1.66(m,9H).
中间体15
(4-(((2-氨基-4-氯苯基)硫基)甲基)吡啶-2-基)氨基甲酸叔丁酯
将(4-(羟基甲基)吡啶-2-基)氨基甲酸叔丁酯(600mg,2.679mmol)首先用SOCl2(3ml)在CH2Cl2(5ml)中于室温处理2小时。除去溶剂,得到粗的(4-(氯甲基)吡啶-2-基)氨基甲酸叔丁酯。然后按照一般程序A,由2-氨基-4-氯苯硫醇(641mg,4.019mmol)、K2CO3(1.8g,13.39mmol)在DMF(20ml)中制备标题化合物(667mg,68%)。
1H NMR(600MHz,CDCl3)δ9.83(br.s.,1H),8.20(d,J=4.70Hz,1H),7.85(s,1H),6.92-7.18(m,1H),6.60-6.75(m,2H),6.55(dd,J=2.05,8.22Hz,1H),4.42(br.s.,2H),3.78(s,2H),1.54(s,9H).
化合物37
{4-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}硫基)甲基]吡啶-2-基}氨基甲酸叔丁酯
按照一般程序B,由(4-(((2-氨基-4-氯苯基)硫基)甲基)吡啶-2-基)氨基甲酸叔丁酯(667mg,1.827mmol)和苯并呋喃-2-磺酰氯(396mg,1.827mmol)在吡啶(10ml)中制备标题化合物(555mg,56%)。
1H NMR(600MHz,CD3OD)δ7.99(d,J=4.99Hz,1H),7.64-7.73(m,2H),7.59(d,J=1.17Hz,1H),7.50-7.55(m,1H),7.42-7.50(m,2H),7.30-7.39(m,1H),7.15(dd,J=1.03,8.36Hz,1H),6.96-7.05(m,1H),6.56(d,J=5.28Hz,1H),3.77(s,2H),1.48-1.61(m,9H).
化合物38
N-(2-{[(2-氨基吡啶-4-基)甲基]硫基}-5-氯苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序E,由{4-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}硫基)甲基]吡啶-2-基}氨基甲酸叔丁酯(96mg,0.176mmol)制备标题化合物(76mg,100%)。
1H NMR(600MHz,CD3OD)δ7.72-7.76(m,2H),7.65(d,J=6.46Hz,2H),7.58(dd,J=0.73,8.36Hz,1H),7.46-7.53(m,2H),7.42(d,J=2.05Hz,1H),7.37(td,J=1.03,7.56Hz,1H),7.31(d,J=8.51Hz,1H),7.16(dd,J=2.35,8.51Hz,1H),6.64(dd,J=1.61,6.60Hz,1H),6.50(s,1H),3.90(s,2H).
化合物39
{4-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}磺酰基)甲基]吡啶-2-基}氨基甲酸叔丁酯
按照一般程序D,由{4-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}硫基)甲基]吡啶-2-基}氨基甲酸叔丁酯制备标题化合物(49mg)。
1H NMR(600MHz,CD3OD)δ7.93(d,J=6.75Hz,1H),7.78(s,1H),7.73(d,J=2.05Hz,1H),7.63(d,J=7.63Hz,1H),7.41(d,J=8.80Hz,1H),7.33(s,1H),7.29(d,J=3.81Hz,1H),7.23(dt,J=3.96,7.92Hz,2H),6.85(dd,J=2.20,6.60Hz,1H),6.68(d,J=7.92Hz,1H),4.56(br.s.,2H),1.47(s,9H).
化合物40
{4-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}磺酰基)甲基]-1-氧代吡啶-2-基}氨基甲酸叔丁酯
按照一般程序D,由{4-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}硫基)甲基]吡啶-2-基}氨基甲酸叔丁酯制备标题化合物(82mg)。
1H NMR(600MHz,CD3OD)δ8.22(d,J=6.46Hz,1H),7.96(s,1H),7.76(d,J=16.73Hz,1H),7.60-7.68(m,1H),7.43(d,J=8.51Hz,1H),7.37(s,1H),7.31(br.s.,1H),7.21-7.27(m,1H),7.09(d,J=6.46Hz,1H),6.85(d,J=6.75Hz,1H),6.72(d,J=7.63Hz,1H),4.60(br.s.,2H),1.55(s,9H).
化合物41
N-(2-{[(2-氨基吡啶-4-基)甲基]磺酰基}-5-氯苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序E,由{4-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}磺酰基)甲基]吡啶-2-基}氨基甲酸叔丁酯制备标题化合物(32mg,100%)。
1H NMR(600MHz,丙酮-d6)δ7.74-7.85(m,3H),7.61-7.70(m,2H),7.52-7.58(m,1H),7.45(td,J=1.17,7.92Hz,1H),7.28-7.38(m,1H),7.09(dd,J=2.05,8.51Hz,1H),6.88(s,1H),6.57-6.66(m,1H),4.89(s,2H).
化合物42
N-(2-{[(2-氨基-1-氧代吡啶-4-基)甲基]磺酰基}-5-氯苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序E,由{4-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}磺酰基)甲基]-1-氧代吡啶-2-基}氨基甲酸叔丁酯(77mg,0.130mmol)制备标题化合物(43mg,67%)。
1H NMR(600MHz,丙酮-d6)δ8.07(d,J=4.70Hz,3H),7.76-7.81(m,2H),7.74(s,1H),7.64(d,J=8.51Hz,1H),7.58(d,J=8.51Hz,1H),7.46-7.49(m,1H),7.32-7.37(m,1H),7.15(dd,J=1.32,8.36Hz,1H),6.94(br.s.,1H),6.52(d,J=4.99Hz,1H),4.76(s,2H).
化合物43
N-(2-{[(2-氨基吡啶-4-基)甲基]亚磺酰基}-5-氯苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序C和一般程序E,由{4-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}硫基)甲基]吡啶-2-基}氨基甲酸叔丁酯制备标题化合物(103mg)。
1H NMR(600MHz,丙酮-d6)δ8.29(br.s.,1H),7.74(dd,J=7.04,18.19Hz,2H),7.40-7.61(m,4H),7.25-7.37(m,2H),7.05(d,J=7.04Hz,1H),6.84(s,1H),6.49(d,J=6.16Hz,1H),4.50(d,J=12.62Hz,2H),4.40(d,J=12.62Hz,1H).
中间体16
3-((2-氨基-4-氯苯基)硫基)-N,N-二甲基丙酰胺
将2-氨基-4-氯苯硫醇(824mg,5.126mmol)、N,N-二甲基丙烯酰胺(512mg,5.162mmol)和HOAc(1ml)在CH2Cl2(10ml)中的溶液在室温搅拌4天。除去溶剂,将残余物负载到硅胶柱上并纯化,得到白色固体(1.08g,83%)。
1H NMR(600MHz,CD3OD)δ7.26(d,J=8.22Hz,1H),6.76(d,J=2.05Hz,1H),6.56(dd,J=2.05,8.22Hz,1H),2.93-2.97(m,5H),2.90(s,3H),2.58(t,J=7.04Hz,2H).
化合物44
3-{[4-氯-2-({[4-氯-3-(三氟甲基)苯基]磺酰基}氨基)苯基]磺酰基}-N,N-二甲基丙酰胺
按照一般程序B和D,由3-((2-氨基-4-氯苯基)硫基)-N,N-二甲基丙酰胺(104mg,0.405mmol)和4-氯-3-(三氟甲基)苯-1-磺酰氯(113mg,0.405mmol)制备标题化合物(73mg)。
1H NMR(600MHz,CD3OD)δ8.31(d,J=1.47Hz,1H),8.12(dd,J=1.76,8.51Hz,1H),7.70(dd,J=8.51,18.49Hz,2H),7.58(s,1H),6.90(s.,1H),3.73(br.s.,2H),3.01(s,3H),2.95(s,3H),2.78(t,J=6.75Hz,2H).
化合物45
3-[(4-氯-2-{[(2,4-二氟苯基)磺酰基]氨基}苯基)硫基]-N,N-二甲基丙酰胺
按照一般程序B,由3-((2-氨基-4-氯苯基)硫基)-N,N-二甲基丙酰胺(300mg,1.167mmol)和2,4-二氟苯-1--磺酰氯(248mg,1.167mmol)在吡啶(5ml)中制备标题化合物(364mg,72%)。
1H NMR(600MHz,CD3OD)δ7.86(td,J=6.02,8.44Hz,1H),7.38-7.45(m,2H),7.13-7.21(m,2H),7.09(tdd,J=0.88,2.49,8.44Hz,1H),2.95-3.01(m,5H),2.93(s,3H),2.56(t,J=7.04Hz,2H).
化合物46
3-[(4-氯-2-{[(2,4-二氟苯基)磺酰基]氨基}苯基)亚磺酰基]-N,N-二甲基丙酰胺
按照一般程序C,由3-[(4-氯-2-{[(2,4-二氟苯基)磺酰基]氨基}苯基)硫基]-N,N-二甲基丙酰胺制备标题化合物(130mg,88%)。
1H NMR(600MHz,CD3OD)δ7.90(td,J=5.87,8.51Hz,1H),7.69(d,J=8.51Hz,1H),7.43(dd,J=2.05,8.51Hz,1H),7.31(d,J=2.05Hz,1H),7.20-7.27(m,1H),7.11-7.17(m,1H),3.24-3.29(m,1H),3.12-3.20(m,1H),3.05(s,3H),2.93(s,3H),2.85-2.92(m,J=4.40Hz,1H),2.72-2.80(m,J=6.46,6.46,17.02Hz,1H).
化合物47
3-[(4-氯-2-{[(2,4-二氟苯基)磺酰基]氨基}苯基)磺酰基]-N,N-二甲基丙酰胺
按照一般程序D,由3-[(4-氯-2-{[(2,4-二氟苯基)磺酰基]氨基}苯基)硫基]-N,N-二甲基丙酰胺制备标题化合物(70mg,71%)。
1H NMR(600MHz,CD3OD)δ8.01-8.12(m,1H),7.76(d,J=8.51Hz,2H),7.49-7.60(m,2H),6.95-7.24(m,3H),3.72(br.s.,2H),3.01(s,3H),2.90(s,3H),2.78(t,J=7.04Hz,2H).
化合物48
3-[(4-氯-2-{[(4-氯-2-氟苯基)磺酰基]氨基}苯基)硫基]-N,N-二甲基丙酰胺
按照一般程序B,由3-((2-氨基-4-氯苯基)硫基)-N,N-二甲基丙酰胺(364mg,1.42mmol)和4-氯-2-氟苯-1--磺酰氯(325mg,1.42mmol)在吡啶(5ml)中制备标题化合物(476mg,75%)。
1H NMR(600MHz,丙酮-d6)δ9.57(br.s.,1H),7.86(t,J=8.07Hz,1H),7.50-7.56(m,2H),7.45(dd,J=1.91,9.83Hz,1H),7.40(dd,J=1.91,8.36Hz,1H),7.17(dd,J=2.35,8.22Hz,1H),2.94-3.01(m,5H),2.91(s,3H),2.54(t,J=6.46Hz,3H).
化合物49
3-[(4-氯-2-{[(4-氯-2-氟苯基)磺酰基]氨基}苯基)亚磺酰基]-N,N-二甲基丙酰胺
按照一般程序C,由3-[(4-氯-2-{[(4-氯-2-氟苯基)磺酰基]氨基}苯基)硫基]-N,N-二甲基丙酰胺制备标题化合物(90mg,55%)。
1H NMR(600MHz,CD3OD)δ7.78-7.90(m,1H),7.48(d,J=8.51Hz,1H),7.27-7.34(m,2H),7.26(d,J=2.05Hz,1H),7.03(d,J=7.92Hz,1H),3.43(ddd,J=6.31,9.02,13.43Hz,1H),3.16(ddd,J=5.58,9.10,13.50Hz,1H),2.99(s,3H),2.92(s,3H),2.79-2.88(m,J=6.46,9.17,16.07Hz,1H),2.52-2.64(m,1H).
化合物50
3-[(4-氯-2-{[(4-氯-2-氟苯基)磺酰基]氨基}苯基)磺酰基]-N,N-二甲基丙酰胺
按照一般程序D,由3-[(4-氯-2-{[(4-氯-2-氟苯基)磺酰基]氨基}苯基)硫基]-N,N-二甲基丙酰胺制备标题化合物(81mg,48%)。
1H NMR(600MHz,CD3OD)δ7.89-7.98(m,1H),7.69(d,J=8.51Hz,1H),7.46(d,J=2.05Hz,1H),7.20-7.30(m,2H),6.76(d,J=7.63Hz,1H),3.86(t,J=7.19Hz,2H),2.97(s,3H),2.93(s,3H),2.70(t,J=7.34Hz,2H).
中间体17
(5-(羟基甲基)-4H-1,2,4-三唑-3-基)氨基甲酸叔丁酯
将(5-氨基-4H-1,2,4-三唑-3-基)甲醇(467mg,4.093mmol)、二碳酸二叔丁酯(1.16g,5.32mmol)在t-BuOH(20ml)中在室温下搅拌过夜。除去溶剂,加入乙酸乙酯,滤掉固体,将滤液真空浓缩。残余物通过柱色谱(10%MeOH的CH2Cl2溶液)纯化,得到标题化合物,为黄色固体(190mg,22%)。
1H NMR(300MHz,CD3OD)δ4.44(s,2H),1.63(s,9H).
一般程序J
中间体18
(5-(((2-氨基-4-氯苯基)硫基)甲基)-4H-1,2,4-三唑-3-基)氨基甲酸叔丁酯
将(5-(羟基甲基)-4H-1,2,4-三唑-3-基)氨基甲酸叔丁基酯(190mg,0.888mmol)、2-氨基-4-氯苯硫酚(213mg,1.332mmol)、PPh3(466mg,1.776mmol)和偶氮二羧酸二叔丁酯(409mg,1.776mmol)在CH2Cl2(10ml)中的溶液在室温下搅拌2天。然后除去溶剂,将粗残余物负载在硅胶柱上,得到标题化合物。
1H NMR(600MHz,CD3OD)δ7.18(s,1H),6.73(d,J=2.35Hz,1H),6.49(dd,J=2.35,8.22Hz,2H),3.68(s,2H),1.60(s,9H).
中间体19
(5-(((2-(苯并呋喃-2-磺酰胺基)-4-氯苯基)硫基)甲基)-4H-1,2,4-三唑-3-基)氨基甲酸叔丁酯
按照一般程序B,由(5-(((2-氨基-4-氯苯基)硫基)甲基)-4H-1,2,4-三唑-3-基)氨基甲酸叔丁酯(330mg,0.925mmol)和苯并呋喃-2-磺酰氯(200mg,0.925mmol)在吡啶(2ml)中制备标题化合物。
1H NMR(600MHz,CD3OD)δ7.69(dd,J=0.88,7.92Hz,1H),7.45-7.57(m,4H),7.40(s,1H),7.29-7.35(m,1H),7.16(dd,J=2.35,8.22Hz,1H),3.70(s,2H),1.61(s,9H).
化合物51
N-(2-{[(5-氨基-4H-1,2,4-三唑-3-基)甲基]硫基}-5-氯苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序E,由(5-(((2-(苯并呋喃-2-磺酰胺基)-4-氯苯基)硫基)甲基)-4H-1,2,4-三唑-3-基)氨基甲酸叔丁酯制备标题化合物(13mg)。
1H NMR(600MHz,CD3OD)δ7.71(d,J=7.92Hz,1H),7.55(d,J=8.51Hz,1H),7.39-7.51(m,5H),7.31-7.37(m,1H),7.16(d,J=7.04Hz,1H),3.82(s,2H).
化合物52
N-(2-{[(5-氨基-4H-1,2,4-三唑-3-基)甲基]亚磺酰基}-5-氯苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序C和E,由(5-(((2-(苯并呋喃-2-磺酰胺基)-4-氯苯基)硫基)甲基)-4H-1,2,4-三唑-3-基)氨基甲酸叔丁酯制备标题化合物(15mg)。
1H NMR(600MHz,CD3OD)δ7.75(dd,J=1.17,7.92Hz,1H),7.57-7.64(m,2H),7.51-7.55(m,1H),7.50(d,J=0.88Hz,1H),7.44(dd,J=1.91,8.36Hz,1H),7.35-7.41(m,1H),7.20(d,J=2.05Hz,1H),4.45(d,J=14.09Hz,1H),4.24(d,J=14.09Hz,1H).
中间体20
5-氯-2-((2-(吡啶-2-基)乙基)硫基)苯胺
将2-(吡啶-2-基)乙醇(1g,8.12mmol)首先用SOCl2(3ml)在CH2Cl2(10ml)中于室温处理3小时。除去溶剂,得到粗的2-(2-氯乙基)吡啶。然后按照一般程序A,由2-氨基-4-氯苯硫醇(1.6g,9.74mmol)、K2CO3(3.36g,24.36mmol)在DMF(20ml)中制备标题化合物(1.69g,79%)。
1H NMR(600MHz,CD3OD)δ8.39-8.42(m,1H),7.73(td,J=1.76,7.63Hz,1H),7.28(d,J=7.63Hz,1H),7.23(d,J=8.22Hz,2H),6.75(d,J=2.35Hz,1H),6.55(dd,J=2.35,8.22Hz,1H),3.06-3.10(m,2H),2.96-3.01(m,2H).
化合物53
N-{5-氯-2-[(2-吡啶-2-基乙基)硫基]苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序B,由5-氯-2-((2-(吡啶-2-基)乙基)硫基)苯胺(439mg,1.663mmol)和苯并呋喃-2-磺酰氯(2x359mg,2x1.663mmol)在吡啶(5ml)中制备标题化合物。
1H NMR(600MHz,CD3OD)δ8.54-8.62(m,1H),7.85(s,1H),7.71-7.78(m,1H),7.67(dt,J=1.03,7.92Hz,1H),7.56(d,J=2.35Hz,1H),7.39-7.48(m,2H),7.36(s,1H),7.27-7.32(m,2H),7.15-7.22(m,2H),2.98(t,J=7.04Hz,2H),2.74(t,J=6.90Hz,2H).
化合物54
N-{5-氯-2-[(2-吡啶-2-基乙基)亚磺酰基]苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序C,由N-{5-氯-2-[(2-吡啶-2-基乙基)硫基]苯基}-1-苯并呋喃-2-磺酰胺制备标题化合物(45mg,79%)。
1H NMR(600MHz,CD3OD)δ8.52-8.60(m,1H),7.81(td,J=1.76,7.63Hz,1H),7.64-7.71(m,2H),7.26-7.47(m,8H),3.40-3.50(m,1H),3.29-3.37(m,1H),3.16-3.26(m,0H),2.83-2.95(m,J=7.48,7.48,14.97Hz,1H).
化合物55
N-{5-氯-2-[(2-吡啶-2-基乙基)磺酰基]苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序D,由N-{5-氯-2-[(2-吡啶-2-基乙基)硫基]苯基}-1-苯并呋喃-2-磺酰胺制备标题化合物(20mg)。
1H NMR(600MHz,CD3OD)δ8.30(ddd,J=1.47,1.61,4.55Hz,1H),7.71-7.76(m,2H),7.61-7.68(m,2H),7.52(d,J=0.88Hz,1H),7.31-7.36(m,1H),7.24-7.31(m,2H),7.18-7.23(m,2H),7.05(dd,J=2.05,8.51Hz,1H),3.84-3.89(m,2H),3.00-3.14(m,2H).
中间体21
2-((2-(1H-吡唑-4-基)乙基)硫基)-5-氯苯胺
按照一般程序J,由2-(1H-吡唑-4-基)乙醇(472mg,4.218mmol)、2-氨基-4-氯苯硫醇(1.01g,6.327mmol)、PPh3(2.21g,8.436mmol)和偶氮二羧酸二叔丁酯(1.9g,8.436mmol)在CH2Cl2(20ml)中制备标题中间体。
1H NMR(600MHz,CD3OD)δ7.98(d,J=0.88Hz,1H),7.64(s,1H),7.23(d,J=8.22Hz,1H),6.76(d,J=2.35Hz,1H),6.55(dd,J=2.05,8.22Hz,1H),2.89-3.00(m,2H),2.65-2.77(m,2H).
化合物56
N-(5-氯-2-{[2-(1H-吡唑-4-基)乙基]硫基}苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序B,2-((2-(1H-吡唑-4-基)乙基)硫基)-5-氯苯胺(157mg,0.618mmol)和苯并呋喃-2-磺酰氯(133mg,0.618mmol)在吡啶(3ml)中制备标题化合物(123mg)。
1H NMR(600MHz,CD3OD)δ7.70(d,J=7.92Hz,1H),7.43-7.53(m,3H),7.39(s,1H),7.28-7.36(m,4H),7.17(dd,J=1.76,8.51Hz,1H),2.82(t,J=7.63Hz,2H),2.45(t,J=7.63Hz,2H).
化合物57
N-(5-氯-2-{[2-(1H-吡唑-4-基)乙基]亚磺酰基}苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序C,由N-{5-氯-2-[(2-吡啶-2-基乙基)硫基]苯基}-1-苯并呋喃-2-磺酰胺制备标题化合物(52mg,40%)。
1H NMR(600MHz,CD3OD)δ7.75-7.81(m,1H),7.72(td,J=1.76,7.63Hz,1H),7.67(d,J=0.88Hz,1H),7.48-7.59(m,3H),7.40-7.45(m,2H),7.19-7.34(m,3H),7.17(d,J=2.35Hz,1H),3.19-3.26(m,3H),2.87(t,J=7.63Hz,2H).
化合物58
N-(5-氯-2-{[2-(1H-吡唑-4-基)乙基]磺酰基}苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序D,由N-{5-氯-2-[(2-吡啶-2-基乙基)硫基]苯基}-1-苯并呋喃-2-磺酰胺制备标题化合物(75mg,73%)。
1H NMR(600MHz,CD3OD)δ7.67-7.74(m,2H),7.62(d,J=7.63Hz,1H),7.39(s,2H),7.31(t,J=7.19Hz,2H),7.22-7.26(m,1H),7.17(d,J=8.22Hz,1H),6.80-6.90(m,1H),3.89(br.s.,2H),2.71-2.81(m,2H).
中间体22
5-氯-2-[2-(3,5-二甲基-1H-吡唑-4-基)乙基硫烷基]-苯基胺
按照一般程序A,由2-氨基-4-氯-苯硫醇(590mg,3.693mmol)和4-(2-溴-乙基)-3,5-二甲基-1H-吡唑(500mg,2.462mmol)、K2CO3(1.7g,12.31mmol)在DMF(20ml)中制备标题化合物(517mg,74%)。
1H NMR(600MHz,CD3OD)δ7.24(d,J=8.22Hz,1H),6.77(d,J=2.05Hz,1H),6.56(dd,J=2.35,8.22Hz,1H),2.75-2.80(m,2H),2.53-2.61(m,2H),2.08(s,6H).
化合物59
N-(5-氯-2-{[2-(3,5-二甲基-1H-吡唑-4-基)乙基]硫基}苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序B,2-((2-(1H-吡唑-4-基)乙基)硫基)-5-氯苯胺(157mg,0.618mmol)和苯并呋喃-2-磺酰氯(133mg,0.618mmol)在吡啶(3ml)中制备标题化合物(235mg)。
1H NMR(600MHz,CD3OD)δ7.68(dd,J=0.88,7.92Hz,1H),7.52(d,J=2.35Hz,1H),7.39-7.47(m,3H),7.27-7.35(m,2H),7.18(dd,J=2.35,8.51Hz,1H),2.65-2.72(m,J=7.63Hz,2H),2.28-2.35(m,2H),1.97(s,6H).
中间体23
5-氯-2-(((2-氟吡啶-3-基)甲基)硫基)苯胺
将(2-氟吡啶-3-基)甲醇(508mg,3.998mmol)首先用SOCl2(1.5ml)在CH2Cl2(5ml)中于室温处理3小时。除去溶剂,得到粗的3-(氯甲基)-2-氟吡啶。然后按照一般程序A,由2-氨基-4-氯苯硫醇(957mg,5.995mmol)、K2CO3(2.7g,19.98mmol)在DMF(20ml)中制备标题化合物(910mg,85%)。
1H NMR(600MHz,CD3OD)δ8.01(dt,J=0.88,4.99Hz,1H),7.42(ddd,J=1.91,7.48,9.68Hz,1H),7.10(ddd,J=1.76,5.14,7.19Hz,1H),6.91(d,J=8.22Hz,1H),6.73(d,J=2.05Hz,1H),6.42(dd,J=2.35,8.22Hz,1H),3.90(s,2H).
化合物60
N-(5-氯-2-{[(2-氟吡啶-3-基)甲基]硫基}苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序B,由5-氯-2-(((2-氟吡啶-3-基)甲基)硫基)苯胺(522mg,1.948mmol)和苯并呋喃-2-磺酰氯(421mg,1.948mmol)在吡啶(5ml)中制备标题化合物(235mg)。
1H NMR(600MHz,丙酮-d6)δ9.00(br.s.,1H),8.05(dt,J=1.47,4.70Hz,1H),7.79(d,J=6.75Hz,1H),7.55-7.63(m,3H),7.43-7.54(m,2H),7.33-7.40(m,1H),7.26(d,J=8.22Hz,1H),7.07-7.17(m,2H),4.01(s,2H).
化合物61
N-(5-氯-2-{[(2-氟吡啶-3-基)甲基]亚磺酰基}苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序C,由N-(5-氯-2-{[(2-氟吡啶-3-基)甲基]硫基}苯基)-1-苯并呋喃-2-磺酰胺制备标题化合物(100mg,59%)。
1H NMR(600MHz,CD3OD)δ7.99(dd,J=1.91,4.84Hz,1H),7.65(d,J=7.34Hz,1H),7.49(d,J=2.05Hz,1H),7.38(d,J=8.51Hz,1H),7.28-7.33(m,1H),7.19-7.26(m,3H),7.00(ddd,J=1.47,5.21,7.12Hz,1H),6.81(d,J=8.22Hz,1H),6.70(dd,J=2.05,8.22Hz,1H),4.43-4.59(m,2H).
化合物62
N-(5-氯-2-{[(2-氟吡啶-3-基)甲基]磺酰基}苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序D,由N-(5-氯-2-{[(2-氟吡啶-3-基)甲基]硫基}苯基)-1-苯并呋喃-2-磺酰胺制备标题化合物(176mg,67%)。
1H NMR(600MHz,丙酮-d6)δ8.04(d,J=4.70Hz,1H),7.91(d,J=2.05Hz,1H),7.70(d,J=7.63Hz,1H),7.18-7.44(m,6H),6.90(t,J=5.43Hz,1H),6.67(d,J=7.63Hz,1H),4.96(s,2H).
中间体24
2-(苄基硫基)-5-氯苯胺
按照一般程序A,由2-氨基-4-氯苯硫醇(700mg,4.39mmol)、(溴甲基)苯(560mg,2.92mmol)、K2CO3(2.0g,14.62mmol)在DMF(20ml)中制备标题化合物(819mg,100%)。
1H NMR(600MHz,CD3OD)δ7.15-7.24(m,3H),7.07-7.13(m,2H),6.97(d,J=8.22Hz,1H),6.73(d,J=2.05Hz,1H),6.43(dd,J=2.05,8.22Hz,1H),3.86(s,2H).
化合物63
N-[2-(苄基硫基)-5-氯苯基]-1-苯并呋喃-2-磺酰胺
按照一般程序B,由2-(苄基硫基)-5-氯苯胺(509mg,2.052mmol)和苯并呋喃-2-磺酰氯(443mg,2.052mmol)在吡啶(5ml)中制备标题化合物(235mg)。
1H NMR(600MHz,CD3OD)δ7.73(d,J=7.92Hz,3H),7.45-7.56(m,3H),7.42(s,1H),7.32-7.38(m,1H),7.10-7.18(m,4H),7.04-7.08(m,1H),6.85-6.94(m,2H),3.81(s,2H).
化合物64
N-[2-(苄基亚磺酰基)-5-氯苯基]-1-苯并呋喃-2-磺酰胺
按照一般程序C,由N-[2-(苄基硫基)-5-氯苯基]-1-苯并呋喃-2-磺酰胺制备标题化合物(139mg,84%)。
1H NMR(600MHz,CD3OD)δ7.65(d,J=7.92Hz,1H),7.49(d,J=2.05Hz,1H),7.37(dd,J=0.73,8.36Hz,1H),7.28-7.33(m,1H),7.16-7.27(m,3H),7.08-7.14(m,2H),7.01(d,J=6.75Hz,2H),6.97(d,J=8.51Hz,1H),6.73(dd,J=1.91,8.36Hz,1H),4.50(d,J=12.91Hz,1H),4.14(d,J=12.91Hz,1H).
化合物65
N-[2-(苄基磺酰基)-5-氯苯基]-1-苯并呋喃-2-磺酰胺
按照一般程序D,由N-[2-(苄基硫基)-5-氯苯基]-1-苯并呋喃-2-磺酰胺制备标题化合物(212mg,95%)。
1H NMR(600MHz,CD3OD)δ7.63-7.73(m,2H),7.40(dd,J=0.73,8.36Hz,1H),7.30-7.37(m,3H),7.23-7.29(m,1H),7.08-7.16(m,3H),6.98-7.05(m,2H),6.60(dd,J=2.05,8.51Hz,1H),4.99(s,2H).
一般程序K
中间体25
2-氨基-4-氟苯硫醇
将5-氟-2-甲基苯并[d]噻唑(1.2g,7.18mmol)在乙二醇和NaOH(5N,2ml)中的溶液在N2下脱气10min,然后在129℃回流3小时。将溶液冷却至0℃,然后使用浓HCl酸化至pH 3~4。将混合物用EtOAc萃取(2x50ml)。将有机层用盐水洗涤,经Na2SO4干燥,且真空浓缩。粗残余物(1.01g,98%)直接用于下一步骤而无需纯化。
1H NMR(600MHz,CD3OD)δ7.24(dd,J=6.16,8.51Hz,1H),6.97(dd,J=6.46,8.51Hz,1H),6.20(td,J=2.79,8.58Hz,1H).
中间体26
5-氟-2-((3-硝基苄基)硫基)苯胺
按照一般程序A,由2-氨基-4-氟苯硫醇(562g,3.93mmol)、1-(溴甲基)-3-硝基苯(566mg,2.62mmol)、K2CO3(1.8g,13.10mmol)在DMF(10ml)中制备标题化合物(460mg,97%)。
1H NMR(600MHz,CD3OD)δ8.04(dt,J=2.09,7.26Hz,1H),7.89(s,1H),7.34-7.54(m,2H),6.93(dd,J=6.46,8.51Hz,1H),6.35-6.53(m,1H),6.15(td,J=2.64,8.51Hz,1H),3.95(s,2H).
化合物66
N-(5-氟-2-((3-硝基苄基)硫基)苯基)苯并呋喃-2-磺酰胺
按照一般程序B,由2-((3-氨基苄基)硫基)-5-氟苯胺(460mg,1.655mmol)和苯并呋喃-2-磺酰氯(357mg,1.655mmol)在吡啶(5ml)中制备标题化合物(474mg,63%)。
1H NMR(600MHz,CD3OD)δ7.98(ddd,J=0.88,2.35,8.22Hz,1H),7.68-7.79(m,2H),7.49-7.54(m,2H),7.42-7.48(m,1H),7.25-7.39(m,4H),7.16(dd,J=6.16,8.80Hz,1H),6.78(td,J=2.93,8.36Hz,1H),3.91(s,2H).
一般程序L
化合物67
N-{2-[(3-氨基苄基)硫基]-5-氟苯基}-1-苯并呋喃-2-磺酰胺
将N-(5-氟-2-((3-硝基苄基)硫基)苯基)苯并呋喃-2-磺酰胺(91mg,0.199mmol)溶于MeOH(2ml)中。将Zn(322mg,4.967mmol)和NH4Cl(1ml)加至溶液中。将混合物在室温搅拌30min后,过滤固体,将滤液真空浓缩,然后将粗残余物通过柱色谱法(0~30%EtOAc的己烷溶液)纯化,得到标题产物(50mg,59%)。
1H NMR(600MHz,CD3OD)δ7.71(d,J=7.92Hz,1H),7.50-7.54(m,1H),7.48(d,J=0.88Hz,1H),7.46(ddd,J=1.32,7.26,8.44Hz,1H),7.28-7.38(m,2H),7.19(dd,J=6.16,8.80Hz,1H),6.83-6.89(m,1H),6.77(td,J=2.79,8.44Hz,1H),6.46-6.54(m,1H),6.36(t,J=1.76Hz,1H),6.22(d,J=7.63Hz,1H),3.63(s,2H).
化合物68
N-{2-[(3-氨基苄基)亚磺酰基]-5-氟苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序L,由N-(5-氟-2-[(3-硝基苯基)亚磺酰基]苯基}-1-苯并呋喃-2-磺酰胺制备标题化合物(130mg,84%)。
1H NMR(600MHz,CD3OD)δ7.75(dd,J=0.88,7.92Hz,1H),7.53-7.60(m,2H),7.48(ddd,J=1.32,7.26,8.44Hz,1H),7.33-7.38(m,1H),7.28(dd,J=6.16,8.80Hz,1H),7.14(dd,J=2.64,10.27Hz,1H),6.88-7.02(m,2H),6.71(dt,J=1.06,8.14Hz,1H),6.57(s,1H),6.41(d,J=7.63Hz,1H),4.24(d,J=12.62Hz,1H),4.06(d,J=12.91Hz,1H).
化合物69
N-{5-氟-2-[(3-硝基苄基)磺酰基]苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序D,由N-(5-氟-2-((3-硝基苯基)硫基)苯基)苯并呋喃-2-磺酰胺制备标题化合物(136mg,74%)。
1H NMR(600MHz,CD3OD)δ8.10(ddd,J=1.17,2.13,8.14Hz,1H),7.72-7.81(m,3H),7.65(dd,J=6.02,8.95Hz,1H),7.55(d,J=8.51Hz,1H),7.45-7.51(m,3H),7.41-7.45(m,1H),7.33-7.39(m,1H),6.80-7.09(m,1H),4.70(s,2H).
化合物70
N-{2-[(3-氨基苄基)磺酰基]-5-氟苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序L,由N-(5-氟-2-[(3-硝基苯基)磺酰基]苯基}-1-苯并呋喃-2-磺酰胺制备标题化合物(91mg,81%)。
1H NMR(600MHz,丙酮-d6)δ7.87(br.s.,1H),7.84(d,J=7.92Hz,2H),7.57-7.65(m,2H),7.50-7.56(m,2H),7.39(t,J=7.48Hz,1H),6.94-7.02(m,1H),6.83(t,J=7.78Hz,1H),6.53(d,J=8.80Hz,1H),6.38(s,1H),6.13(d,J=7.34Hz,1H),4.38(s,2H).
中间体27
5-甲氧基-2-((3-硝基苄基)硫基)苯胺
按照一般程序K和A,由5-甲氧基-2-甲基苯并[d]噻唑制备标题化合物(474mg)。
1H NMR(600MHz,CD3OD)δ8.03(dt,J=2.05,7.34Hz,1H),7.84(d,J=1.76Hz,1H),7.34-7.48(m,2H),6.83(d,J=8.51Hz,1H),6.32(s,1H),6.06(dd,J=2.79,8.36Hz,1H),3.90(s,2H),3.69(s,3H).
化合物71
N-{2-[(3-氨基苄基)硫基]-5-甲氧基苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序L,由N-(5-甲氧基-2-((3-硝基苄基)硫基)苯基)苯并呋喃-2-磺酰胺制备标题化合物(82mg,70%)。
1H NMR(600MHz,CD3OD)δ7.69(d,J=7.92Hz,1H),7.50(dd,J=0.88,8.51Hz,1H),7.40-7.47(m,2H),7.31(ddd,J=1.03,7.19,7.92Hz,1H),7.07-7.13(m,2H),6.84-6.90(m,1H),6.57(dd,J=2.79,8.66Hz,1H),6.50-6.54(m,1H),6.37(t,J=1.91Hz,1H),6.25(d,J=7.63Hz,1H),3.72(s,3H),3.57(s,2H).
化合物72
N-{5-甲氧基-2-[(3-硝基苄基)亚磺酰基]苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序C,由N-(5-甲氧基-2-((3-硝基苄基)硫基)苯基)苯并呋喃-2-磺酰胺制备标题化合物(95mg,46%)。
1H NMR(600MHz,丙酮-d6)δ10.74(br.s.,1H),8.16(ddd,J=0.88,2.35,8.22Hz,1H),7.78-7.86(m,2H),7.75(s,1H),7.61(dd,J=0.88,8.51Hz,1H),7.56(t,J=7.92Hz,1H),7.44-7.52(m,2H),7.35-7.40(m,1H),7.09(d,J=2.35Hz,1H),7.06(d,J=8.80Hz,1H),6.69(dd,J=2.49,8.66Hz,1H),4.45-4.53(m,2H),3.77(s,3H).
化合物73
N-{2-[(3-氨基苄基)亚磺酰基]-5-甲氧基苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序L,由N-{5-甲氧基-2-[(3-硝基苄基)亚磺酰基]苯基}-1-苯并呋喃-2-磺酰胺制备标题化合物(55mg,65%)。
1H NMR(600MHz,丙酮-d6)δ7.75-7.85(m,2H),7.59(dd,J=0.59,8.51Hz,1H),7.44-7.53(m,1H),7.32-7.40(m,1H),7.25(s,1H),6.93(d,J=8.51Hz,1H),6.85-6.90(m,1H),6.61(dd,J=2.49,8.66Hz,1H),6.53-6.58(m,1H),6.40(t,J=1.76Hz,1H),6.21(d,J=7.92Hz,1H),4.25(d,J=12.32Hz,1H),4.08(d,J=11.74Hz,2H),3.78(s,3H).
化合物74
N-(5-甲氧基-2-((3-硝基苄基)磺酰基)苯基)苯并呋喃-2-磺酰胺
按照一般程序D,由N-(5-甲氧基-2-((3-硝基苄基)硫基)苯基)苯并呋喃-2-磺酰胺制备标题化合物(165mg,83%)。
1H NMR(600MHz,CDCl3)δ9.28(s,1H),8.14-8.19(m,1H),7.70(d,J=7.63Hz,1H),7.64(s,1H),7.58(s,1H),7.41-7.50(m,3H),7.37(d,J=9.10Hz,1H),7.33(td,J=1.03,7.41Hz,1H),7.29(d,J=2.35Hz,1H),7.26(s,1H),6.57(dd,J=2.35,8.80Hz,1H),4.38(s,2H),3.86(s,3H).
化合物75
N-{2-[(3-氨基苄基)磺酰基]-5-甲氧基苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序L,由N-(5-甲氧基-2-((3-硝基苄基)磺酰基)苯基)苯并呋喃-2-磺酰胺制备标题化合物(67mg,45%)。
1H NMR(600MHz,CD3OD)δ7.70(d,J=7.63Hz,1H),7.42-7.50(m,2H),7.35-7.41(m,1H),7.33(d,J=8.80Hz,1H),7.27-7.31(m,1H),7.22(d,J=2.35Hz,1H),6.76(t,J=7.78Hz,1H),6.53(dd,J=1.32,8.07Hz,1H),6.45(s,1H),6.39(d,J=8.51Hz,1H),6.27(d,J=7.63Hz,1H),4.61(br.s.,2H),3.76(s,3H).
化合物76
苯并呋喃-2-磺酸[2-(3-硝基-苄基硫烷基)-苯基]-酰胺
按照一般程序B,由2-((3-硝基苄基)硫基)苯胺(741mg,2.85mmol)、苯并呋喃-2-磺酰氯(616mg,2.85mmol)在吡啶(10ml)中制备标题化合物(520mg,41%)。
1H NMR(600MHz,CD3OD)δ7.97-8.04(m,1H),7.79-7.89(m,1H),7.70(d,J=0.88Hz,1H),7.50(d,J=0.88Hz,1H),7.29-7.47(m,6H),7.15-7.25(m,2H),7.02-7.11(m,1H),3.99(s,2H).
化合物77
N-{2-[(3-氨基苄基)硫基]苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序L,由苯并呋喃-2-磺酸[2-(3-硝基-苄基硫烷基)-苯基]-酰胺制备标题化合物(67mg,45%)。
1H NMR(600MHz,CD3OD)δ7.66(d,J=7.92Hz,1H),7.47-7.52(m,1H),7.38-7.46(m,2H),7.26-7.35(m,2H),7.12-7.22(m,2H),7.04(td,J=1.47,7.63Hz,1H),6.88(t,J=7.78Hz,1H),6.54(dd,J=1.47,7.92Hz,1H),6.43(t,J=1.76Hz,1H),6.28(d,J=7.63Hz,1H),3.69(s,2H).
化合物78
N-{2-[(3-硝基苄基)亚磺酰基]苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序C,由苯并呋喃-2-磺酸[2-(3-硝基-苄基硫烷基)-苯基]-酰胺制备标题化合物(172mg,73%)。
1H NMR(600MHz,丙酮-d6)δ10.45(br.s.,1H),8.15(d,J=8.22Hz,1H),7.85(s,1H),7.80(d,J=7.92Hz,1H),7.66(d,J=0.88Hz,1H),7.59-7.63(m,1H),7.42-7.57(m,5H),7.34-7.40(m,1H),7.13-7.24(m,2H),4.54-4.60(m,1H),4.45-4.51(m,1H).
化合物79
N-{2-[(3-氨基苄基)亚磺酰基]苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序L,由N-{2-[(3-硝基苄基)亚磺酰基]苯基}-1-苯并呋喃-2-磺酰胺制备标题化合物(122mg,90%)。
1H NMR(600MHz,CD3OD)δ7.73(d,J=7.63Hz,1H),7.59(d,J=8.22Hz,1H),7.43-7.53(m,3H),7.29-7.42(m,3H),7.20(d,J=7.63Hz,1H),6.97(t,J=7.63Hz,1H),6.66(d,J=7.34Hz,1H),6.57(br.s.,1H),6.43(d,J=7.34Hz,1H),4.27(d,J=12.91Hz,1H),3.99(d,J=12.91Hz,1H).
化合物80
N-{2-[(3-氨基苄基)磺酰基]苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序L,由N-{2-[(3-硝基苄基)磺酰基]苯基}-1-苯并呋喃-2-磺酰胺制备标题化合物(75mg,82%)。
1H NMR(600MHz,丙酮-d6))δ7.75-7.85(m,3H),7.62-7.70(m,1H),7.59(d,J=8.51Hz,1H),7.56(dd,J=1.76,7.92Hz,1H),7.49(td,J=1.17,7.92Hz,1H),7.36(t,J=7.48Hz,1H),7.16-7.22(m,1H),6.83(t,J=7.78Hz,1H),6.57(dd,J=1.47,7.92Hz,1H),6.43(t,J=1.91Hz,1H),6.15(d,J=7.34Hz,1H),4.37(s,2H).
中间体28
5-氯-2-((4-硝基苄基)硫基)苯胺
按照一般程序A,由2-氨基-4-氯苯硫醇(555mg,3.10mmol)、1-(溴甲基)-4-硝基苯(490mg,2.268mmol)和K2CO3(1.3g,9.50mmol)在DMF(20ml)中制备标题化合物(624mg,92%)。
1H NMR(600MHz,CD3OD)δ8.07(d,J=8.80Hz,2H),7.30(d,J=8.80Hz,2H),6.93(d,J=8.22Hz,1H),6.73(d,J=2.35Hz,1H),6.43(dd,J=2.35,8.22Hz,1H),3.97(s,2H).
化合物81
N-{5-氯-2-[(4-硝基苄基)硫基]苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序B,由5-氯-2-((4-硝基苄基)硫基)苯胺(411mg,1.40mmol)和苯并呋喃-2-磺酰氯(303mg,1.40mmol)在吡啶(5ml)中制备标题化合物(475mg,72%)。
1H NMR(600MHz,CD3OD)δ7.94-8.00(m,2H),7.72(d,J=7.92Hz,1H),7.50-7.55(m,1H),7.45-7.49(m,2H),7.43(s,1H),7.31-7.38(m,1H),7.11-7.19(m,3H),7.07(dd,J=2.35,8.51Hz,1H),3.96(s,2H).
化合物82
N-{5-氯-2-[(4-硝基苄基)磺酰基]苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序D,由N-{5-氯-2-[(4-硝基苄基)硫基]苯基}-1-苯并呋喃-2-磺酰胺制备标题化合物(120mg,85%)。
1H NMR(600MHz,丙酮-d6)δ9.59(br.s.,1H),8.01(d,J=7.34Hz,2H),7.86(s,1H),7.76(d,J=7.92Hz,1H),7.72(s,1H),7.52(d,J=8.51Hz,1H),7.39-7.49(m,2H),7.25-7.36(m,3H),7.00(s,1H),4.96(s,2H).
化合物83
N-{2-[(4-氨基苄基)磺酰基]-5-氯苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序L,由N-{5-氯-2-[(4-硝基苄基)磺酰基]苯基}-1-苯并呋喃-2-磺酰胺制备标题化合物(68mg,81%)。
1H NMR(600MHz,丙酮-d6)δ7.75-7.88(m,3H),7.61(d,J=8.51Hz,1H),7.44-7.54(m,2H),7.34-7.41(m,1H),7.22(dd,J=1.76,8.51Hz,1H),6.69(d,J=8.51Hz,2H),6.49(d,J=8.51Hz,2H),4.38(s,2H).
中间体29
5-氯-2-((2-硝基苄基)硫基)苯胺
按照一般程序A,由2-氨基-4-氯苯硫醇(441mg,2.76mmol)、1-(溴甲基)-2-硝基苯(398mg,1.84mmol)和K2CO3(1.27g,9.21mmol)在DMF(20ml)中制备标题化合物(548mg,95%)。
1H NMR(600MHz,CD3OD)δ7.89-7.98(m,1H),7.37-7.46(m,2H),6.99-7.04(m,1H),6.81(d,J=8.22Hz,1H),6.71(d,J=2.05Hz,1H),6.37(dd,J=2.05,8.22Hz,1H),4.22(s,2H).
化合物84
N-(5-氯-2-((2-硝基苄基)硫基)苯基)苯并呋喃-2-磺酰胺
按照一般程序B,由5-氯-2-((2-硝基苄基)硫基)苯胺(435mg,1.48mmol)和苯并呋喃-2-磺酰氯(320mg,1.48mmol)在吡啶(5ml)中制备标题化合物(485mg,69%)。
1H NMR(600MHz,CDCl3)δ8.03(dd,J=1.47,7.92Hz,1H),7.65-7.71(m,2H),7.48-7.53(m,2H),7.43-7.48(m,1H),7.31-7.42(m,3H),7.03(d,J=8.22Hz,1H),6.90(dd,J=2.05,8.22Hz,1H),6.76(dd,J=1.32,7.48Hz,1H),4.16(s,2H).
化合物85
N-{2-[(2-氨基苄基)硫基]-5-氯苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序L,由N-(5-氯-2-((2-硝基苄基)硫基)苯基)苯并呋喃-2-磺酰胺制备标题化合物(44mg,40%)。
1H NMR(600MHz,丙酮-d6)δ7.77(d,J=7.92Hz,1H),7.59(dd,J=0.88,8.51Hz,1H),7.47-7.55(m,3H),7.31-7.41(m,2H),7.10(dd,J=2.35,8.51Hz,1H),6.86-6.95(m,1H),6.72(dd,J=0.88,7.92Hz,1H),6.57(dd,J=1.32,7.48Hz,1H),6.38(td,J=1.03,7.41Hz,1H),3.97(s,2H).
化合物86
N-{5-氯-2-[(2-硝基苄基)亚磺酰基]苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序C,由N-(5-氯-2-((2-硝基苄基)硫基)苯基)苯并呋喃-2-磺酰胺制备标题化合物(160mg,79%)。
1H NMR(600MHz,丙酮-d6)δ7.92(d,J=8.22Hz,1H),7.71(dd,J=0.73,7.78Hz,1H),7.59(d,J=2.05Hz,1H),7.47(d,J=8.51Hz,1H),7.39-7.44(m,1H),7.33-7.38(m,2H),7.19-7.30(m,2H),6.71-6.80(m,2H),6.67(d,J=8.22Hz,1H),5.13(d,J=12.91Hz,2H),4.73(d,J=12.62Hz,2H).
化合物87
N-{2-[(2-氨基苄基)亚磺酰基]-5-氯苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序L,由N-{5-氯-2-[(2-硝基苄基)亚磺酰基]苯基}-1-苯并呋喃-2-磺酰胺制备标题化合物(67mg,50%)。
1H NMR(600MHz,CD3OD)δ7.72(d,J=7.92Hz,1H),7.56(d,J=7.63Hz,1H),7.44-7.52(m,2H),7.41(d,J=8.51Hz,2H),7.31-7.37(m,1H),7.28(d,J=1.47Hz,1H),7.21(dd,J=1.76,8.22Hz,1H),7.06-7.13(m,1H),6.88(d,J=7.92Hz,1H),6.75(d,J=7.04Hz,1H),6.60-6.67(m,1H),4.50(d,J=13.50Hz,2H),4.23(d,J=12.91Hz,2H).
化合物88
N-{2-[(2-氨基苄基)磺酰基]-5-氯苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序D和K,由N-(5-氯-2-((2-硝基苄基)硫基)苯基)苯并呋喃-2-磺酰胺制备标题化合物(52mg)。
1H NMR(300MHz,CD3OD)δ7.69-7.78(m,2H),7.56-7.65(m,2H),7.50-7.55(m,1H),7.45(td,J=1.17,7.77Hz,1H),7.28-7.38(m,1H),6.99-7.15(m,2H),6.88(d,J=7.03Hz,1H),6.67-6.75(m,1H),6.58-6.66(m,1H),4.68(s,2H).
中间体30
5-氯-2-((嘧啶-2-基甲基)硫基)苯胺
按照一般程序A,由2-氨基-4-氯苯硫醇(529mg,3.33mmol)、2-(氯甲基)嘧啶(366mg,2.22mmol)和K2CO3(1.53g,11.09mmol)在DMF(10ml)中制备标题化合物(284mg,39%)。
1H NMR(600MHz,CD3OD)δ8.65(d,J=4.99Hz,2H),7.31(t,J=4.99Hz,1H),7.03(d,J=8.22Hz,1H),6.70(s,1H),6.43(dd,J=2.05,8.22Hz,1H),4.07(s,2H).
化合物89
N-{5-氯-2-[(嘧啶-2-基甲基)硫基]苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序B,由5-氯-2-((嘧啶-2-基甲基)硫基)苯胺(280mg,1.11mmol)和苯并呋喃-2-磺酰氯(240mg,1.11mmol)在吡啶(3ml)中制备标题化合物(243mg,51%)。
1H NMR(600MHz,丙酮-d6)δ11.69(br.s.,1H),8.87(d,J=4.99Hz,2H),7.74(dd,J=0.88,7.92Hz,1H),7.66(s,1H),7.62(d,J=8.22Hz,1H),7.59(d,J=0.59Hz,1H),7.45-7.52(m,3H),7.33(ddd,J=1.76,6.38,8.00Hz,1H),7.14(dd,J=2.20,8.36Hz,1H),4.24(s,2H).
化合物90
N-{5-氯-2-[(嘧啶-2-基甲基)亚磺酰基]苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序C,由N-{5-氯-2-[(嘧啶-2-基甲基)硫基]苯基}-1-苯并呋喃-2-磺酰胺制备标题化合物(82mg)。
1H NMR(600MHz,CD3OD)δ8.68(dd,J=1.47,4.99Hz,2H),7.73(d,J=7.92Hz,1H),7.53-7.60(m,2H),7.45-7.52(m,2H),7.30-7.41(m,4H),4.63(d,J=13.50Hz,1H),4.46(d,J=13.50Hz,1H).
化合物91
N-{5-氯-2-[(嘧啶-2-基甲基)磺酰基]苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序D,由N-{5-氯-2-[(嘧啶-2-基甲基)硫基]苯基}-1-苯并呋喃-2-磺酰胺制备标题化合物(60mg)。
1H NMR(600MHz,DMSO-d6)δ8.68(dd,J=1.47,4.99Hz,2H),7.76(s,1H),7.68(br.s.,1H),7.61(d,J=8.22Hz,1H),7.54-7.58(m,2H),7.46(t,J=7.34Hz,1H),7.41(t,J=4.84Hz,1H),7.30-7.37(m,1H),7.19(d,J=7.92Hz,1H),5.11-5.19(m,2H).
一般程序M
中间体31
4-巯基-3-硝基苯甲腈
向4-氯-3-硝基苯甲腈(530mg,2.88mmol)在二噁烷(5ml)/水(1ml)中的溶液加入Na2S·9H2O9692mg,2.88mmol)。将其在室温搅拌2小时后,将反应用HCl(1N)淬灭。将混合物用EtOAc萃取(2x50ml)。将有机层用水、盐水洗涤,经Na2SO4干燥,真空浓缩。标题化合物通过硅胶柱色谱(0-30%EtOAc的己烷溶液)纯化。
1H NMR(600MHz,丙酮-d6)δ8.67(d,J=1.76Hz,1H),8.01(s,1H),7.93(dd,J=1.76,8.51Hz,1H),5.30(s,1H).
中间体32
4-(苄基硫基)-3-硝基苯甲腈
按照一般程序A,由4-巯基-3-硝基苯甲腈(473mg,2.63mmol)、(溴甲基)苯(449mg,2.63mmol)、K2CO3(1.81g,13.14mmol)在DMF(10ml)中制备标题化合物(580mg,82%)。
1H NMR(600MHz,DMSO-d6)δ8.68(d,J=1.76Hz,1H),8.10(dd,J=1.47,8.51Hz,1H),7.88(d,J=8.51Hz,1H),7.43(d,J=7.34Hz,2H),7.34(t,J=7.63Hz,2H),7.25-7.30(m,1H),4.44(s,2H).
中间体33
3-氨基-4-(苄基硫基)苯甲腈
按照一般程序L,由4-(苄基硫基)-3-硝基苯甲腈(518mg,1.92mmol)制备标题化合物(372mg,81%)。
1H NMR(600MHz,CD3OD)δ7.11-7.25(m,6H),6.96(d,J=1.76Hz,1H),6.71-6.78(m,1H),4.00(s,2H).
化合物92
N-[2-(苄基硫基)-5-氰基苯基]-1-苯并呋喃-2-磺酰胺
按照一般程序B,由3-氨基-4-(苄基硫基)苯甲腈(370mg,1.54mmol)和苯并呋喃-2-磺酰氯(333mg,1.54mmol)在吡啶(3ml)中制备标题化合物(419mg,65%)。
1H NMR(600MHz,CD3OD)δ7.73(d,J=8.51Hz,1H),7.65(d,J=1.17Hz,1H),7.50-7.56(m,2H),7.48(dd,J=1.47,8.22Hz,1H),7.39(ddd,J=2.05,6.16,7.92Hz,1H),7.31-7.36(m,2H),7.09-7.20(m,3H),6.92(d,J=7.04Hz,2H),3.97(s,2H).
化合物93
N-[2-(苄基亚磺酰基)-5-氰基苯基]-1-苯并呋喃-2-磺酰胺
按照一般程序C,由N-[2-(苄基硫基)-5-氰基苯基]-1-苯并呋喃-2-磺酰胺制备标题化合物(109mg)。
1H NMR(600MHz,CD3OD)δ7.74(d,J=7.63Hz,1H),7.66(s,1H),7.53(d,J=8.51Hz,1H),7.50(s,1H),7.45(t,J=7.48Hz,1H),7.30-7.39(m,2H),7.28(d,J=7.92Hz,1H),7.20-7.25(m,1H),7.16(t,J=7.48Hz,2H),6.96(d,J=7.34Hz,2H),4.47(d,J=13.21Hz,1H),4.21(d,J=12.91Hz,1H).
化合物94
N-[2-(苄基磺酰基)-5-氰基苯基]-1-苯并呋喃-2-磺酰胺
按照一般程序D,由N-[2-(苄基硫基)-5-氰基苯基]-1-苯并呋喃-2-磺酰胺制备标题化合物(230mg)。
1H NMR(600MHz,CD3OD)δ7.97(d,J=1.47Hz,1H),7.68(d,J=7.63Hz,1H),7.52(d,J=8.22Hz,1H),7.43(s,1H),7.32-7.38(m,2H),7.24-7.30(m,1H),7.09-7.18(m,3H),6.98-7.06(m,2H),6.87(dd,J=1.47,8.22Hz,1H),5.05(s,2H).
化合物95
4-氯-N-[5-氯-2-(甲基磺酰基)苯基]-3-(三氟甲基)苯磺酰胺
按照一般程序B和D,由5-氯-2-(甲基硫基)苯胺和4-氯-3-(三氟甲基)苯-1-磺酰氯制备标题化合物。
1H NMR(300MHz,CD3OD)δ8.26(s,1H),8.11(d,J=8.50Hz,1H),7.74-7.87(m,2H),7.58(d,J=1.47Hz,1H),7.16(d,J=8.50Hz,1H),3.19(s,3H).
化合物96
4-氯-N-[5-氯-2-(甲基硫基)苯基]-3-(三氟甲基)苯磺酰胺
按照一般程序B,由5-氯-2-(甲基硫基)苯胺和4-氯-3-(三氟甲基)苯-1-磺酰氯制备标题化合物。
1H NMR(300MHz,CDCl3)δ8.13(d,J=1.47Hz,1H),7.88(dd,J=1.90,8.35Hz,1H),7.60(dd,J=2.64,12.60Hz,2H),7.28(d,J=8.50Hz,1H),7.10(dd,J=2.05,8.50Hz,1H),2.21(s,3H).
化合物97
4-氯-N-[5-氯-2-(异丙基硫基)苯基]-3-(三氟甲基)苯磺酰胺
按照一般程序A和B,由2-氨基-4-氯-苯硫醇、2-碘-丙烷和4-氯-3-(三氟甲基)苯-1-磺酰氯制备标题化合物。
1H NMR(300MHz,CD3OD)δ8.13(d,J=1.47Hz,1H),7.92(dd,J=2.05,8.50Hz,1H),7.76(d,J=8.50Hz,1H),7.53(d,J=2.05Hz,1H),7.33(d,J=8.50Hz,1H),7.15-7.23(m,1H),3.03-3.21(m,1H),1.06(d,J=6.45Hz,6H).
化合物98
4-氯-N-{5-氯-2-[(2-羟基乙基)硫基]苯基}-3-(三氟甲基)苯磺酰胺
按照一般程序A和B,由2-氨基-4-氯-苯硫醇、2-碘-乙醇和4-氯-3-(三氟甲基)苯-1-磺酰氯制备标题化合物。
1H NMR(300MHz,CD3OD)δ8.09(d,J=1.47Hz,1H),7.92(dd,J=1.90,8.35Hz,1H),7.76(d,J=8.50Hz,1H),7.51(d,J=2.34Hz,1H),7.41(d,J=8.50Hz,1H),7.20(dd,J=2.20,8.35Hz,1H),3.49(t,J=6.15Hz,2H),2.80(t,J=6.15Hz,2H).
化合物99
4-氯-N-[5-氯-2-(异丙基亚磺酰基)苯基]-3-(三氟甲基)苯磺酰胺
按照一般程序C,由4-氯-N-[5-氯-2-(异丙基硫基)苯基]-3-(三氟甲基)苯磺酰胺制备标题化合物(55mg)。
化合物100
4-氯-N-{5-氯-2-[(2-羟基乙基)亚磺酰基]苯基}-3-(三氟甲基)苯磺酰胺
按照一般程序C,由4-氯-N-{5-氯-2-[(2-羟基乙基)硫基]苯基}-3-(三氟甲基)苯磺酰胺制备标题化合物(109mg)。
1H NMR(300MHz,CD3OD)δ8.09(d,J=1.17Hz,1H),7.96-8.03(m,1H),7.84(d,J=8.20Hz,1H),7.71(d,J=8.50Hz,1H),7.44(dd,J=1.76,8.50Hz,1H),7.21(d,J=1.76Hz,1H),3.98(td,J=4.10,8.06Hz,1H),3.77-3.88(m,1H),3.19(ddd,J=5.27,8.42,13.26Hz,1H),2.95-3.06(m,1H).
化合物101
4-氯-N-{5-氯-2-[(2-羟基乙基)磺酰基]苯基}-3-(三氟甲基)苯磺酰胺
按照一般程序D,由4-氯-N-{5-氯-2-[(2-羟基乙基)硫基]苯基}-3-(三氟甲基)苯磺酰胺制备标题化合物。
1H NMR(600MHz,CD3OD)δ8.27(d,J=1.47Hz,1H),8.11(dd,J=2.05,8.51Hz,1H),7.74(dd,J=8.51,14.97Hz,2H),7.54-7.59(m,1H),6.96-7.08(m,1H),3.82(t,J=6.02Hz,2H),3.57-3.68(m,2H).
化合物102
3-{[4-氯-2-({[4-氯-3-(三氟甲基)苯基]磺酰基}氨基)苯基]亚磺酰基}丙酸甲酯
按照一般程序H、B和C,由2-氨基-4-氯苯硫醇制备标题化合物。
1H NMR(300MHz,CD3OD)δ8.09(s,1H),7.99(dd,J=1.76,8.50Hz,1H),7.85(d,J=8.20Hz,1H),7.71(d,J=8.50Hz,1H),7.47(dd,J=1.61,8.35Hz,1H),7.11(d,J=1.76Hz,1H),3.63(s,3H),3.24-3.39(m,1H),3.08-3.22(m,1H),2.54-2.82(m,2H).
化合物103
4-氯-N-{5-氯-2-[(吡啶-2-基甲基)硫基]苯基}-3-(三氟甲基)苯磺酰胺
按照一般程序A和B,由2-氨基-4-氯苯硫醇制备标题化合物。
1H NMR(600MHz,CD3OD)δ8.63(d,J=3.81Hz,1H),8.03(d,J=2.35Hz,1H),7.87(dd,J=2.20,8.36Hz,1H),7.75(td,J=1.76,7.63Hz,1H),7.70(d,J=8.51Hz,1H),7.54(d,J=2.35Hz,1H),7.37(d,J=8.51Hz,1H),7.32-7.35(m,1H),7.21(d,J=7.63Hz,1H),7.13(dd,J=2.35,8.22Hz,1H),4.00(s,2H).
化合物104
4-氯-N-{5-氯-2-[(吡啶-3-基甲基)硫基]苯基}-3-(三氟甲基)苯磺酰胺
按照一般程序A和B,由2-氨基-4-氯苯硫醇制备标题化合物。
1H NMR(600MHz,CD3OD)δ8.38(d,J=3.82Hz,1H),8.25(br.s.,1H),8.11(d,J=2.35Hz,1H),7.93(dd,J=2.05,8.51Hz,1H),7.78(d,J=8.51Hz,1H),7.60(dt,J=1.91,7.92Hz,1H),7.39(d,J=2.35Hz,1H),7.33(dd,J=4.84,7.78Hz,1H),7.20(d,J=8.51Hz,1H),7.14(s,J=2.35,2.35,8.51,8.51Hz,1H),3.95(s,2H).
化合物105
4-氯-N-{5-氯-2-[(吡啶-2-基甲基)亚磺酰基]苯基}-3-(三氟甲基)苯磺酰胺
按照一般程序C,由4-氯-N-{5-氯-2-[(吡啶-2-基甲基)硫基]苯基}-3-(三氟甲基)苯磺酰胺制备标题化合物。
1H NMR(600MHz,DMSO-d6)d8.44(d,J=4.40Hz,1H),8.03(d,J=2.05Hz,1H),7.98(dd,J=2.05,8.22Hz,1H),7.88(d,J=8.22Hz,1H),7.74(t,1H),7.25-7.33(m,2H),7.20(d,J=7.63Hz,1H),7.14(br.s.,1H),7.03(d,J=1.47Hz,1H),4.49(d,J=12.62Hz,1H),4.06(d,J=12.91Hz,1H).
化合物106
4-氯-N-{5-氯-2-[(吡啶-3-基甲基)亚磺酰基]苯基}-3-(三氟甲基)苯磺酰胺
按照一般程序C,由4-氯-N-{5-氯-2-[(吡啶-3-基甲基)硫基]苯基}-3-(三氟甲基)苯磺酰胺制备标题化合物。
1H NMR(600MHz,CD3OD)d 8.35(dd,J=1.61,4.84Hz,1H),8.24(d,J=2.35Hz,1H),8.07(d,J=2.05Hz,1H),8.03(d,J=1.76Hz,1H),7.71(d,J=8.51Hz,1H),7.38(s,1H),7.27(d,J=2.05Hz,1H),7.23-7.26(m,1H),6.75(d,J=8.22Hz,1H),6.65(dd,J=1.91,8.36Hz,1H),4.45(d,J=13.50Hz,1H),4.37(d,J=13.21Hz,1H).
一般程序N
中间体34
4-氯-N-(5-氯-2-巯基-苯基)-3-三氟甲基-苯磺酰胺
向中间体5 N,N′-[二硫代双(5-氯-2,1-亚苯基)]双[4-氯-3-(三氟甲基)苯磺酰胺](106mg,0.13mmol)在THF(3ml)中的溶液于0℃加入NaBH4(20mg,0.53mmol),将混合物在室温搅拌1h,用H2O稀释,小心用6M HCl酸化,用EtOAc萃取。将有机层用盐水洗涤,经Na2SO4干燥,真空浓缩,得到109mg灰白色固体,为表位化合物。
1H NMR(600MHz,甲醇-d4)δ8.05(s,1H),7.91(d,J=8.51Hz,1H),7.78(d,J=8.51Hz,1H),7.30(dd,J=1.47,8.22Hz,1H),7.23-7.25(m,1H),7.14(dd,J=2.20,8.36Hz,1H).
化合物107
{[4-氯-2-({[4-氯-3-(三氟甲基)苯基]磺酰基}氨基)苯基]亚磺酰基}乙酸乙酯
按照一般程序A和C,制备标题化合物由中间体34 4-氯-N-(5-氯-2-巯基-苯基)-3-三氟甲基-苯磺酰胺和2-溴乙酸乙酯。
1H NMR(300MHz,CD3OD)d 8.06(s,1H),7.96(d,J=8.50Hz,1H),7.84(dd,J=8.50,10.84Hz,2H),7.52(dd,J=1.61,8.64Hz,1H),7.06(d,J=1.47Hz,1H),4.17(q,J=7.23Hz,2H),4.06(d,J=14.65Hz,1H),3.88(d,J=14.36Hz,1H),1.22(t,J=7.18Hz,3H).
一般程序O
中间体35
4-氯-N-[5-氯-2-(3-氧代-环戊基硫烷基)-苯基]-3-三氟甲基-苯磺酰胺
向中间体5 N,N′-[二硫代双[(5-氯-2,1-亚苯基)]双[4-氯-3-(三氟甲基)苯磺酰胺](105mg,0.13mmol)在CH2Cl2(2ml)、MeOH(0.5ml)和H2O(0.25ml)中的溶液加入聚合物结合的三苯基膦(~3mmol/g三苯基膦负载,87mg,0.26mmol)、环戊-2-烯酮(33μl,0.39mmol)和PTSA(催化量)。将反应物在室温下搅拌4小时,然后直接通过硅胶柱色谱(0→100%乙酸乙酯的己烷溶液)纯化,得到标题化合物,为灰白色固体(133mg,100%)。
1H NMR(600MHz,氯仿-d)δ8.16(d,J=2.35Hz,1H),7.93(dd,J=2.35,8.51Hz,1H),7.89(s,1H),7.62-7.65(m,2H),7.35(d,J=8.22Hz,1H),7.07(dd,J=2.20,8.36Hz,1H),3.46(quin,J=6.53Hz,1H),2.44-2.49(m,1H),2.38-2.44(m,1H),2.21(s,2H),2.05-2.11(m,1H),1.84-1.90(m,1H).
化合物108
4-氯-N-{5-氯-2-[(3-羟基环戊基)亚磺酰基]苯基}-3-(三氟甲基)苯磺酰胺
按照一般程序D,接著用NaBH4的MeOH溶液处理粗产物,由4-氯-N-[5-氯-2-(3-氧代-环戊基硫烷基)-苯基]-3-三氟甲基-苯磺酰胺(中间体35)制备标题化合物。
1H NMR(600MHz,CD3OD)δ8.13(d,J=2.05Hz,1H),7.99(dd,J=2.20,8.36Hz,1H),7.73(d,J=8.51Hz,1H),7.46(d,J=8.51Hz,1H),7.34(d,J=2.05Hz,1H),7.06(dd,J=2.05,8.51Hz,1H),4.17-4.22(m,1H),3.70-3.77(m,1H),2.19-2.26(m,1H),1.90-2.00(m,1H),1.78-1.86(m,1H),1.62-1.76(m,2H),1.29-1.38(m,1H).
化合物109
4-氯-N-[5-氯-2-(乙基磺酰基)苯基]-3-(三氟甲基)苯磺酰胺
按照一般程序D,由4-氯-N-[5-氯-2-(乙基硫基)苯基]-3-(三氟甲基)苯磺酰胺制备标题化合物。
1H NMR(600MHz,CD3OD)δ8.30(d,J=1.76Hz,1H),8.14(dd,J=2.20,8.36Hz,1H),7.72-7.80(m,2H),7.64(d,J=2.05Hz,1H),7.10(br.s.,1H),3.30-3.38(m,2H),1.09(t,J=7.34Hz,3H)
化合物110
2-{[4-氯-2-({[4-氯-3-(三氟甲基)苯基]磺酰基}氨基)苯基]硫基}-N,N-二甲基乙酰胺
按照一般程序G,由中间体5 N,N′-二硫代双[(5-氯-2,1-亚苯基)]双[4-氯-3-(三氟甲基)苯磺酰胺]和2-氯-N,N-二甲基-乙酰胺制备标题化合物。
1H NMR(600MHz,CD3OD)δ8.09(d,J=2.35Hz,1H),7.94(dd,J=2.05,8.51Hz,1H),7.76(d,J=8.22Hz,1H),7.47-7.50(m,2H),7.18(dd,J=2.35,8.51Hz,1H),3.68(s,2H),2.97(s,3H),2.93(s,3H).
化合物111
2-{[4-氯-2-({[4-氯-3-(三氟甲基)苯基]磺酰基}氨基)苯基]硫基}-N-甲基乙酰胺
按照一般程序G,由中间体5 N,N′-二硫代双[(5-氯-2,1-亚苯基)]双[4-氯-3-(三氟甲基)苯磺酰胺]和2-氯-N-甲基-乙酰胺制备标题化合物。
1H NMR(600MHz,CD3OD)δ8.09(d,J=2.35Hz,1H),7.93(dd,J=2.35,8.51Hz,1H),7.76(d,J=8.51Hz,1H),7.48(d,J=2.35Hz,1H),7.44(d,J=8.22Hz,1H),7.20(dd,J=2.35,8.51Hz,1H),3.40(s,2H),2.69(s,3H).
化合物112
2-{[4-氯-2-({[4-氯-3-(三氟甲基)苯基]磺酰基}氨基)苯基]亚磺酰基}-N,N-二甲基乙酰胺
按照一般程序C,由2-{[4-氯-2-({[4-氯-3-(三氟甲基)苯基]磺酰基}氨基)苯基]硫基}-N,N-二甲基乙酰胺制备标题化合物。
1H NMR(600MHz,CD3OD)δ8.16(d,J=2.35Hz,1H),8.01(dd,J=2.05,8.22Hz,1H),7.68(d,J=8.51Hz,1H),7.45(d,J=8.51Hz,1H),7.28(d,J=1.76Hz,1H),6.90(dd,J=2.05,8.22Hz,1H),4.65-4.71(m,1H),3.51-3.57(m,1H),3.11(s,3H),2.98(s,3H).
化合物113
2-{[4-氯-2-({[4-氯-3-(三氟甲基)苯基]磺酰基}氨基)苯基]磺酰基}-N,N-二甲基乙酰胺
按照一般程序D,由2-{[4-氯-2-({[4-氯-3-(三氟甲基)苯基]磺酰基}氨基)苯基]硫基}-N,N-二甲基乙酰胺制备标题化合物。
1H NMR(600MHz,CD3OD)δ8.29(d,J=2.05Hz,1H),8.09-8.14(m,1H),7.72(d,J=8.51Hz,1H),7.68(d,J=8.51Hz,1H),7.48(d,J=1.76Hz,1H),6.81(d,J=8.22Hz,1H),3.16(s,3H),3.00(s,3H).
化合物114
2-{[4-氯-2-({[4-氯-3-(三氟甲基)苯基]磺酰基}氨基)苯基]亚磺酰基}-N-甲基乙酰胺
按照一般程序C,由2-{[4-氯-2-({[4-氯-3-(三氟甲基)苯基]磺酰基}氨基)苯基]硫基}-N-甲基乙酰胺制备标题化合物。
1H NMR(600MHz,CD3OD)δ8.15(d,J=2.05Hz,1H),8.01(dd,J=2.20,8.36Hz,1H),7.72(d,J=8.51Hz,1H),7.51(d,J=8.22Hz,1H),7.22(d,J=2.05Hz,1H),7.02(dd,J=1.91,8.36Hz,1H),4.21(d,J=13.50Hz,1H),3.49(d,J=13.21Hz,1H),2.76(s,3H)
化合物115
2-{[4-氯-2-({[4-氯-3-(三氟甲基)苯基]磺酰基}氨基)苯基]磺酰基}-N-甲基乙酰胺
按照一般程序D,由2-{[4-氯-2-({[4-氯-3-(三氟甲基)苯基]磺酰基}氨基)苯基]硫基}-N-甲基乙酰胺制备标题化合物。
1H NMR(600MHz,CD3OD)δ8.29(d,J=2.05Hz,1H),8.09-8.13(m,1H),7.69(d,J=8.51Hz,1H),7.66(d,J=8.22Hz,1H),7.44(d,J=2.05Hz,1H),6.75(dd,J=1.91,8.66Hz,1H),2.77(s,3H).
化合物116
N-{2-[(2-氨基乙基)硫基]-5-氯苯基}-4-氯-3-(三氟甲基)苯磺酰胺
按照一般程序G,由中间体5 N,N′-二硫代双[(5-氯-2,1-亚苯基)]双[4-氯-3-(三氟甲基)苯磺酰胺]和2-溴-乙胺氢溴酸盐制备标题化合物。
1H NMR(600MHz,CD3OD)δ8.18(d,J=2.05Hz,1H),7.99(dd,J=2.05,8.22Hz,1H),7.65(d,J=8.51Hz,1H),7.38(d,J=8.22Hz,1H),7.30(d,J=2.35Hz,1H),6.72(dd,J=2.35,8.22Hz,1H),2.96-3.05(m,4H).
化合物117
N-{2-[(2-氨基乙基)磺酰基]-5-氯苯基}-4-氯-3-(三氟甲基)苯磺酰胺
按照一般程序D,随后在室温用MeOH中的过量锌粉、NH4Cl水溶液和HOAc处理粗产物2h,由N-{2-[(2-氨基乙基)硫基]-5-氯苯基}-4-氯-3-(三氟甲基)苯磺酰胺制备标题化合物。
1H NMR(600MHz,CD3OD)δ8.27(d,J=2.05Hz,1H),8.10(dd,J=1.91,8.36Hz,1H),7.74(d,J=8.51Hz,1H),7.67(d,J=8.51Hz,1H),7.42(d,J=1.76Hz,1H),6.80(dd,J=2.05,8.51Hz,1H),3.88-3.92(m,2H),3.45-3.51(m,2H).
化合物118
N-{2-[(2-氨基乙基)亚磺酰基]-5-氯苯基}-4-氯-3-(三氟甲基)苯磺酰胺
按照一般程序C,由N-(2-[(2-氨基乙基)硫基]-5-氯苯基}-4-氯-3-(三氟甲基)苯磺酰胺制备标题化合物。
1H NMR(300MHz,CD3OD)δ8.15(d,J=1.76Hz,1H),8.00(dd,J=1.90,8.35Hz,1H),7.69(d,J=8.21Hz,1H),7.46(d,J=8.50Hz,1H),7.25(d,J=2.05Hz,1H),6.94(dd,J=1.90,8.35Hz,1H),3.53-3.67(m,1H),3.36-3.50(m,1H),3.17-3.31(m,2H).
化合物119
3-({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}硫基)-N,N-二甲基丙酰胺
按照一般程序O,由中间体8 N,N′-二硫代双[(5-氯-2,1-亚苯基)]双(1-苯并呋喃-2-磺酰胺)和N,N-二甲基-丙烯酰胺制备标题化合物。
1H NMR(600MHz,CD3OD)δ7.69(d,J=7.92Hz,1H),7.53-7.56(m,1H),7.45-7.49(m,2H),7.39(s,1H),7.37(d,J=8.51Hz,1H),7.31-7.35(m,1H),7.17-7.20(m,1H),2.90(t,J=7.19Hz,2H),2.87(s,3H),2.85(s,3H),2.33(t,J=7.19Hz,2H).
化合物120
3-({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}亚磺酰基)-N,N-二甲基丙酰胺
按照一般程序C,由3-({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}硫基)-N,N-二甲基丙酰胺制备标题化合物。
1H NMR(600MHz,CD3OD)δ7.72(d,J=7.34Hz,1H),7.64(d,J=8.22Hz,1H),7.58(d,J=8.51Hz,1H),7.46-7.51(m,1H),7.46(s,1H),7.39(d,J=1.76Hz,1H),7.32-7.37(m,2H),3.27-3.34(m,1H),3.16-3.24(m,1H),2.96(s,3H),2.90(s,3H),2.77-2.86(m,1H),2.59-2.66(m,1H).
化合物121
3-({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}磺酰基)-N,N-二甲基丙酰胺
按照一般程序D,由3-({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}硫基)-N,N-二甲基丙酰胺制备标题化合物。
1H NMR(300MHz,CD3OD)δ7.59-7.75(m,3H),7.40-7.49(m,1H),7.30-7.41(m,1H),7.20-7.30(m,2H),6.79(dd,J=1.76,8.50Hz,1H),3.94(t,J=7.47Hz,2H),2.87(s,3H),2.81(s,3H),2.59(t,J=7.47Hz,2H).
化合物122
N-(2-{[(6-氨基-1-氧代吡啶-2-基)甲基]磺酰基}-5-氯苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序D和E,由{6-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}硫基)甲基]吡啶-2-基}氨基甲酸叔丁酯制备标题化合物。
1H NMR(300MHz,CD3OD)δ7.77(d,J=1.76Hz,1H),7.59-7.71(m,2H),7.29-7.44(m,3H),7.20-7.29(m,1H),7.10(t,J=7.91Hz,1H),6.77-6.88(m,2H),6.57(d,J=7.33Hz,1H),5.41(br.s.,2H),4.57(br.s.,1H).
一般程序P
化合物123
N-(2-{[4-氯-2-({[4-氯-3-(三氟甲基)苯基]磺酰基}氨基)苯基]磺酰基}乙基)乙酰胺
向N-{2-[(2-氨基乙基)磺酰基]-5-氯苯基}-4-氯-3-(三氟甲基)苯磺酰胺(23mg,0.048mmol)在CH2Cl2(2ml)中的溶液加入Et3N(14μl,0.10mmol)、乙酸酐(5μl,0.053mmol)和催化量的DMAP。将反应混合物在室温搅拌1h,浓缩。粗产物通过硅胶柱色谱(0→10%的乙酸乙酯溶液)纯化,然后进行PTLC(10%甲醇的乙酸乙酯溶液),得到标题化合物。
1H NMR(600MHz,CD3OD)δ8.29(d,J=2.05Hz,1H),8.13(dd,J=2.05,8.51Hz,1H),7.65-7.75(m,2H),7.51(d,J=2.05Hz,1H),6.82(dd,J=2.05,8.51Hz,1H),3.75(t,J=6.60Hz,2H),3.51(t,J=6.60Hz,2H),1.86(s,3H).
化合物124
N-(2-{[4-氯-2-({[4-氯-3-(三氟甲基)苯基]磺酰基}氨基)苯基]亚磺酰基}乙基)乙酰胺
按照一般程序P和C,由N-{2-[(2-氨基乙基)硫基]-5-氯苯基}-4-氯-3-(三氟甲基)苯磺酰胺制备标题化合物。
1H NMR(600MHz,CD3OD)δ8.12(s,1H),8.01(dd,J=1.91,8.36Hz,1H),7.77(d,J=8.51Hz,1H),7.56(d,J=8.22Hz,1H),7.17(s,1H),7.13(d,J=7.63Hz,1H),3.60-3.71(m,1H),3.44-3.54(m,1H),3.33-3.42(m,1H),3.04-3.15(m,1H),1.98(s,3H).
中间体36
4-氯-N,N-二甲基丁酰胺
在5℃向4-氯-丁酰氯(1.12ml,10.0mmol)和二甲基-胺盐酸盐(4.1g,50.0mmol)在THF中的溶液加入2M NaOH(30ml,60.0mmol),历经30分钟,同时保持反应温度在5-10℃。将反应混合物再搅拌1.5h,浓缩,用EtOAc萃取(×2)。将合并的有机层用1M HCl(×2)、盐水洗涤,经Na2SO4干燥,真空浓缩,得到标题化合物,为无色油状物(1.5g,~100%)。粗品不经进一步纯化即可使用。
化合物125
4-({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}亚磺酰基)-N,N-二甲基丁酰胺
按照一般程序G和C,由中间体8 N,N′-[二硫代双(5-氯-2,1-亚苯基)]双(1-苯并呋喃-2-磺酰胺)和4-氯-N,N-二甲基-丁酰胺制备标题化合物。
1H NMR(300MHz,CD3OD)δ7.68(d,J=7.62Hz,1H),7.53(d,J=2.05Hz,1H),7.35-7.49(m,3H),7.32(d,J=0.88Hz,1H),7.25-7.32(m,1H),6.95(dd,J=2.05,8.20Hz,1H),3.33-3.49(m,1H),2.98(s,3H),2.91-3.08(m,1H),2.90(s,3H),2.38-2.57(m,2H),1.92-2.09(m,2H).
化合物126
4-({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}磺酰基)-N,N-二甲基丁酰胺
按照一般程序G和D,由中间体8 N,N′-[二硫代双(5-氯-2,1-亚苯基)]双(1-苯并呋喃-2-磺酰胺)和4-氯-N,N-二甲基-丁酰胺制备标题化合物。
1H NMR(600MHz,CD3OD)δ7.76(s,1H),7.74(d,J=8.51Hz,1H),7.70(d,J=7.92Hz,1H),7.38-7.48(m,3H),7.31(t,J=7.34Hz,1H),6.86-7.05(m,1H),3.46-3.69(m,2H),2.97(s,3H),2.91(s,3H),2.43-2.59(m,2H),1.93-2.09(m,2H).
化合物127
5-氯-N-[5-氯-2-(甲基亚磺酰基)苯基]-1-苯并呋喃-2-磺酰胺
按照一般程序B和C,由5-氯-2-(甲基硫基)苯胺和5-氯-苯并呋喃-2-磺酰氯(CAS#:128852-02-8)制备标题化合物(Bioorganic&Medicinal Chemistry 13(2005)3927-3954)。
1H NMR(300MHz,CDCl3)δ11.00(br.s.,1H),7.80(d,J=1.47Hz,1H),7.68(d,J=1.76Hz,1H),7.40-7.54(m,3H),7.05-7.16(m,2H),2.91(s,3H).
化合物128
5-氯-N-[5-氯-2-(甲基磺酰基)苯基]-1-苯并呋喃-2-磺酰胺
按照一般程序B和D,由5-氯-2-(甲基硫基)苯胺和5-氯-苯并呋喃-2-磺酰氯(CAS#:128852-02-8)制备标题化合物(Bioorganic&Medicinal Chemistry 13(2005)3927-3954)。
1H NMR(600MHz,CD3OD)δ7.74(s,1H),7.74(d,J=5.58Hz,1H),7.64(d,J=1.76Hz,1H),7.43(d,J=8.80Hz,1H),7.30-7.35(m,2H),6.88(dd,J=2.05,8.51Hz,1H),3.33(s,3H).
化合物129
N-{5-氯-2-[(1H-吡唑-3-基甲基)亚磺酰基]苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序C和E,由3-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}硫基)甲基]-1H-吡唑-1-羧酸叔丁酯(化合物22)制备标题化合物。
1H NMR(600MHz,CD3OD)δ7.67(d,J=7.63Hz,1H),7.42-7.47(m,2H),7.41(d,J=2.05Hz,1H),7.37(td,J=1.47,7.78Hz,1H),7.32(d,J=0.88Hz,1H),7.28(td,J=0.88,7.48Hz,1H),7.22(d,J=8.51Hz,1H),6.96(dd,J=1.76,8.51Hz,1H),5.92(s,1H),4.56(d,J=13.50Hz,1H),4.28(d,J=13.50Hz,1H).
化合物130
N-[5-氯-2-(甲基亚磺酰基)苯基]-4-异丙基苯磺酰胺
按照一般程序B和C,由5-氯-2-(甲基硫基)苯胺和4-异丙基-苯磺酰氯制备标题化合物。
1H NMR(600MHz,氯仿-d)δ10.42(br.s.,1H),7.80-7.86(m,2H),7.68(s,1H),7.35(s,2H),7.05-7.08(m,1H),7.01-7.03(m,1H),2.94(spt,J=6.90Hz,1H),2.69(s,3H),1.22(d,J=7.04Hz,6H).
化合物131
4-溴-N-[5-氯-2-(甲基硫基)苯基]苯磺酰胺
按照一般程序B,由5-氯-2-(甲基硫基)苯胺和4-溴-苯磺酰氯制备标题化合物。
1H NMR(600MHz,氯仿-d)δ7.65-7.68(m,2H),7.61-7.63(m,2H),7.58-7.60(m,2H),7.29(d,J=8.22Hz,1H),7.04(dd,J=2.20,8.36Hz,1H),2.17(s,3H).
化合物132
N-[5-氯-2-(甲基硫基)苯基]-4-碘苯磺酰胺
按照一般程序B,由5-氯-2-(甲基硫基)苯胺和4-碘-苯磺酰氯制备标题化合物。
1H NMR(600MHz,氯仿-d)δ7.80(d,J=8.80Hz,2H),7.62-7.64(m,1H),7.61(d,J=2.05Hz,1H),7.49-7.53(m,2H),7.30(d,J=8.22Hz,1H),7.04(dd,J=2.20,8.36Hz,1H),2.17(s,3H).
化合物133
4-溴-N-[5-氯-2-(甲基亚磺酰基)苯基]苯磺酰胺
按照一般程序C,由4-溴-N-[5-氯-2-(甲基硫基)苯基]苯磺酰胺制备标题化合物。
1H NMR(600MHz,氯仿-d)δ10.63-10.77(m,1H),7.79-7.82(m,2H),7.64-7.68(m,3H),7.05(dd,J=1.17,2.35Hz,2H),2.79(s,3H).
化合物134
N-[5-氯-2-(甲基亚磺酰基)苯基]-4-碘苯磺酰胺
按照一般程序C,由N-[5-氯-2-(甲基硫基)苯基]-4-碘苯磺酰胺制备标题化合物。
1H NMR(600MHz,氯仿-d)δ10.69(br.s.,1H),7.83-7.91(m,2H),7.61-7.69(m,3H),7.01-7.08(m,2H),2.79(s,3H).
化合物135
4-溴-N-[5-氯-2-(甲基磺酰基)苯基]苯磺酰胺
按照一般程序D,由4-溴-N-[5-氯-2-(甲基硫基)苯基]苯磺酰胺制备标题化合物。
1H NMR(600MHz,氯仿-d)δ9.20-9.27(m,1H),7.80(dd,J=1.32,8.36Hz,2H),7.76(d,J=8.51Hz,1H),7.68(dd,J=1.47,8.80Hz,2H),7.25(d,J=1.47Hz,1H),7.18-7.21(m,1H),2.93(d,J=1.47Hz,3H).
化合物136
N-[5-氯-2-(甲基磺酰基)苯基]-4-碘苯磺酰胺
按照一般程序D,由N-[5-氯-2-(甲基硫基)苯基]-4-碘苯磺酰胺制备标题化合物。
1H NMR(600MHz,氯仿-d)δ9.17-9.25(m,1H),7.90(d,J=8.51Hz,2H),7.76(d,J=8.51Hz,1H),7.67(d,J=1.76Hz,1H),7.64(d,J=8.51Hz,2H),7.19(dd,J=1.76,8.51Hz,1H),2.93(s,3H).
化合物137
N-{5-氯-2-[(吡啶-2-基甲基)硫基]苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序A和B,由2-氨基-4-氯-苯硫醇、2-溴甲基-吡啶氢溴酸盐和苯并呋喃-2-磺酰氯制备标题化合物。
1H NMR(600MHz,氯仿-d)δ12.32(br.s,1H),8.87(dt,J=0.77,4.92Hz,1H),7.76(d,J=2.05Hz,1H),7.58-7.65(m,2H),7.44(dd,J=0.88,8.22Hz,1H),7.34-7.42(m,3H),7.25-7.30(m,2H),7.06(d,J=7.63Hz,1H),6.96-7.01(m,1H),3.98(s,2H).
化合物138
N-{5-氯-2-[(吡啶-3-基甲基)硫基]苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序A和B,由2-氨基-4-氯-苯硫醇、3-溴甲基-吡啶氢溴酸盐和苯并呋喃-2-磺酰氯制备标题化合物。
1H NMR(600MHz,氯仿-d)δ8.42(dd,J=1.61,4.84Hz,1H),8.12(d,J=1.76Hz,2H),7.66-7.70(m,2H),7.50(d,J=1.17Hz,1H),7.46-7.49(m,1H),7.42-7.46(m,1H),7.33(ddd,J=1.17,6.97,8.00Hz,1H),7.26-7.29(m,1H),7.13(ddd,J=0.88,4.70,7.92Hz,1H),7.00(d,J=8.51Hz,1H),6.89(dd,J=2.20,8.36Hz,1H),3.75(s,2H).
化合物139
N-{5-氯-2-[(吡啶-3-基甲基)亚磺酰基]苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序C,由N-{5-氯-2-[(吡啶-3-基甲基)硫基]苯基}-1-苯并呋喃-2-磺酰胺制备标题化合物。
1H NMR(600MHz,甲醇-d4)δ8.28(d,J=4.11Hz,1H),7.86(br.s.,1H),7.68-7.71(m,J=0.73,1.32Hz,1H),7.54(d,J=1.76Hz,1H),7.36-7.41(m,2H),7.31-7.35(m,1H),7.25-7.29(m,J=1.03,7.78Hz,1H),7.24(d,J=7.92Hz,1H),7.12(dd,J=4.99,7.63Hz,1H),6.73(d,J=8.51Hz,1H),6.68(dd,J=2.05,8.51Hz,1H),4.55(s,2H).
化合物140
N-(5-氯-2-{[(1-氧代吡啶-3-基)甲基]亚磺酰基}苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序C,由N-{5-氯-2-[(吡啶-3-基甲基)硫基]苯基}-1-苯并呋喃-2-磺酰胺制备标题化合物。
1H NMR(600MHz,甲醇-d4)δ8.10-8.14(m,1H),8.01(t,J=1.47Hz,1H),7.66-7.68(m,1H),7.42-7.49(m,2H),7.34(ddd,J=1.17,7.12,8.44Hz,1H),7.23-7.29(m,2H),7.14(dd,J=6.60,7.78Hz,1H),6.87(d,J=7.92Hz,1H),6.83(d,J=8.22Hz,1H),6.71(dd,J=2.05,8.22Hz,1H),4.63(d,J=13.21Hz,1H),4.37(d,J=13.21Hz,1H).
化合物141
N-{5-氯-2-[(吡啶-3-基甲基)磺酰基]苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序D,由N-{5-氯-2-[(吡啶-3-基甲基)硫基]苯基}-1-苯并呋喃-2-磺酰胺制备标题化合物。
1H NMR(600MHz,甲醇-d4)δ8.27(d,J=4.11Hz,1H),8.04(br.s.,1H),7.78(t,J=1.76Hz,1H),7.65(d,J=7.92Hz,1H),7.46(d,J=0.88Hz,1H),7.31-7.37(m,2H),7.27-7.31(m,1H),7.21-7.26(m,2H),7.06(dd,J=5.14,7.48Hz,1H),6.67(dt,J=1.76,8.51Hz,1H),4.98(s,2H).
化合物142
N-(5-氯-2-{[(1-氧代吡啶-3-基)甲基]磺酰基}苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序D,由N-{5-氯-2-[(吡啶-3-基甲基)硫基]苯基}-1-苯并呋喃-2-磺酰胺制备标题化合物。
1H NMR(600MHz,DMSO-d6)δ8.01-8.08(m,2H),7.68(d,J=7.92Hz,1H),7.53(d,J=8.22Hz,1H),7.46-7.48(m,1H),7.31-7.37(m,2H),7.23-7.27(m,2H),7.11-7.15(m,1H),6.98(d,J=7.92Hz,1H),6.58-6.61(m,1H),5.09(s,2H).
化合物143
N-{5-氯-2-[(3-硝基苄基)硫基]苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序G,由中间体8 N,N′-二硫代双[(5-氯-2,1-亚苯基)]双(1-苯并呋喃-2-磺酰胺)和1-溴甲基-3-硝基-苯制备标题化合物。
1H NMR(600MHz,氯仿-d)δ8.08(s,1H),8.02(ddd,J=1.17,2.35,8.22Hz,1H),7.77(t,J=2.05Hz,1H),7.65-7.69(m,2H),7.50(d,J=0.88Hz,1H),7.45-7.48(m,1H),7.41-7.45(m,1H),7.30-7.36(m,2H),7.21(dq,J=0.88,7.63Hz,1H),7.03(d,J=8.22Hz,1H),6.89(dd,J=2.05,8.22Hz,1H),3.84(s,2H).
化合物144
N-{5-氯-2-[(3-甲氧基苄基)硫基]苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序G,由中间体8 N,N′-二硫代双[(5-氯-2,1-亚苯基)]双(1-苯并呋喃-2-磺酰胺)和1-溴甲基-3-甲氧基-苯制备标题化合物。
1H NMR(600MHz,氯仿-d)δ8.11(s,1H),7.64-7.68(m,2H),7.40-7.50(m,3H),7.31(ddd,J=0.88,7.04,7.92Hz,1H),7.07-7.13(m,2H),6.90(dd,J=2.05,8.22Hz,1H),6.73(ddd,J=1.17,2.49,8.36Hz,1H),6.53-6.56(m,1H),6.48(t,J=2.35Hz,1H),3.74(s,2H),3.66(s,3H).
化合物145
N-{5-氯-2-[(吡啶-2-基甲基)亚磺酰基]苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序C,由N-{5-氯-2-[(吡啶-2-基甲基)硫基]苯基}-1-苯并呋喃-2-磺酰胺制备标题化合物。
1H NMR(600MHz,甲醇-d4)δ8.46(d,J=4.70Hz,1H),7.64-7.73(m,2H),7.48(d,J=8.51Hz,1H),7.38-7.45(m,3H),7.25-7.34(m,3H),7.07-7.17(m,2H),4.58(d,J=12.91Hz,1H),4.35(d,J=12.91Hz,1H).
化合物146
N-{5-氯-2-[(吡啶-2-基甲基)磺酰基]苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序D,由N-{5-氯-2-[(吡啶-2-基甲基)硫基]苯基}-1-苯并呋喃-2-磺酰胺制备标题化合物。
1H NMR(600MHz,甲醇-d4)δ8.42(dt,J=0.84,4.77Hz,1H),7.75(d,J=2.05Hz,1H),7.67(d,J=7.63Hz,1H),7.41-7.49(m,3H),7.31-7.39(m,2H),7.22-7.29(m,2H),7.07(d,J=7.63Hz,1H),6.76(dd,J=1.91,8.66Hz,1H),5.07(s,2H).
化合物147
N-(5-氯-2-{[(1-氧代吡啶-2-基)甲基]磺酰基}苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序D,由N-{5-氯-2-[(吡啶-2-基甲基)硫基]苯基}-1-苯并呋喃-2-磺酰胺制备标题化合物。
1H NMR(600MHz,甲醇-d4)δ8.35(d,J=6.46Hz,1H),7.74(d,J=2.05Hz,1H),7.66(d,J=7.92Hz,1H),7.60(d,J=8.51Hz,1H),7.38(s,2H),7.34(d,J=10.56Hz,3H),7.25(s,2H),6.77(dd,J=1.32,8.36Hz,1H),5.54(br.s,2H).
化合物148
N-(5-氯-2-{[(1-氧代吡啶-2-基)甲基]亚磺酰基}苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序D,由N-{5-氯-2-[(吡啶-2-基甲基)硫基]苯基}-1-苯并呋喃-2-磺酰胺制备标题化合物。
1H NMR(600MHz,甲醇-d4)δ8.31(d,J=6.16Hz,1H),7.66(d,J=7.92Hz,1H),7.46-7.50(m,1H),7.38-7.42(m,1H),7.30-7.38(m,2H),7.28(s,3H),7.19(d,J=8.51Hz,1H),7.05(d,J=7.63Hz,1H),6.82(d,J=8.22Hz,1H),5.14(d,J=12.62Hz,1H),4.68(d,J=12.32Hz,1H).
化合物149
N-{2-[(3-氨基苄基)硫基]-5-氯苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序L,由N-{5-氯-2-[(3-硝基苄基)硫基]苯基}-1-苯并呋喃-2-磺酰胺制备标题化合物。
1H NMR(600MHz,氯仿-d)δ7.64-7.68(m,2H),7.47-7.51(m,1H),7.40-7.46(m,2H),7.29-7.34(m,1H),7.14(d,J=8.22Hz,1H),6.97(t,J=7.78Hz,1H),6.92(dd,J=2.35,8.22Hz,1H),6.48-6.52(m,1H),6.35(dd,J=0.59,7.63Hz,1H),6.28(t,J=1.91Hz,1H),3.67(s,2H).
化合物150
N-{2-[(3-氨基苄基)亚磺酰基]-5-氯苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序C和K,由N-{5-氯-2-[(3-硝基苄基)硫基]苯基}-1-苯并呋喃-2-磺酰胺制备标题化合物。
1H NMR(600MHz,甲醇-d4)δ7.69(d,J=7.92Hz,1H),7.48(d,J=8.51Hz,1H),7.37-7.43(m,3H),7.30(td,J=0.88,7.48Hz,1H),7.20(d,J=8.51Hz,1H),7.01(dd,J=2.05,8.51Hz,1H),6.95(t,J=7.78Hz,1H),6.70-6.74(m,1H),6.64(t,J=1.76Hz,1H),6.45(d,J=7.63Hz,1H),4.40(d,J=12.62Hz,1H),4.00(d,J=12.62Hz,1H).
化合物151
N-{2-[(3-氨基苄基)磺酰基]-5-氯苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序D和K,由N-{5-氯-2-[(3-硝基苄基)硫基]苯基}-1-苯并呋喃-2-磺酰胺制备标题化合物。
1H NMR(600MHz,甲醇-d4)δ7.80(d,J=2.05Hz,1H),7.69(d,J=7.63Hz,1H),7.52(d,J=0.59Hz,1H),7.40(d,J=8.51Hz,1H),7.35(td,J=1.32,7.70Hz,1H),7.31(d,J=8.51Hz,1H),7.26-7.30(m,J=7.92Hz,1H),6.78(dd,J=2.05,8.51Hz,1H),6.65(t,J=7.78Hz,1H),6.49(dd,J=1.91,7.78Hz,1H),6.33(t,J=1.76Hz,1H),6.05(d,J=7.34Hz,1H),4.66(s,2H).
化合物152
N-{5-氯-2-[(3-羟基苄基)硫基]苯基}-1-苯并呋喃-2-磺酰胺
于室温向N-{5-氯-2-[(3-甲氧基苄基)硫基]苯基}-1-苯并呋喃-2-磺酰胺(315mg,0.69mmol)在CH2Cl2(5ml)中的溶液加入BBr3(1MCH2Cl2溶液,2.1ml,2.1mmol),将反应搅拌2h,用EtOAc稀释,用盐水洗涤,经Na2SO4干燥,真空浓缩。粗产物通过硅胶柱色谱(25%乙酸乙酯的己烷溶液)纯化,得到标题化合物(196mg,64%)。
1H NMR(600MHz,氯仿-d)δ8.10(br.s.,1H),7.63-7.69(m,2H),7.41-7.51(m,3H),7.32(td,J=0.88,7.48Hz,1H),7.12(d,J=8.22Hz,1H),7.05(t,J=7.92Hz,1H),6.91(dd,J=2.35,8.22Hz,1H),6.66(ddd,J=0.73,2.57,8.14Hz,1H),6.51(d,J=7.92Hz,1H),6.45-6.48(m,1H),5.07(br.s.,1H),3.71(s,2H).
化合物153
N-{5-氯-2-[(3-羟基苄基)亚磺酰基]苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序C,由N-{5-氯-2-[(3-羟基苄基)硫基]苯基}-1-苯并呋喃-2-磺酰胺制备标题化合物。
1H NMR(600MHz,氯仿-d)δ10.27-11.14(m,1H),7.73(d,J=2.05Hz,1H),7.67(d,J=7.92Hz,1H),7.53(s,1H),7.43-7.47(m,1H),7.38-7.42(m,1H),7.28-7.33(m,1H),7.04(t,J=7.92Hz,1H),6.92(dd,J=1.47,8.22Hz,1H),6.79(d,J=8.22Hz,1H),6.74(dd,J=2.05,8.22Hz,1H),6.59(s,1H),6.40(d,J=7.34Hz,1H),4.33(d,J=12.32Hz,1H),4.16(d,J=12.62Hz,1H).
化合物154
N-{5-氯-2-[(3-羟基苄基)磺酰基]苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序D,由N-{5-氯-2-[(3-羟基苄基)硫基]苯基}-1-苯并呋喃-2-磺酰胺制备标题化合物。
1H NMR(600MHz,氯仿-d)δ7.76(br.s.,1H),7.65-7.72(m,1H),7.56(br.s.,1H),7.44(br.s.,3H),7.33(s,1H),7.02(br.s.,2H),6.77(br.s.,1H),6.58(br.s.,1H),6.39-6.47(m,1H),4.28(br.s.,2H).
中间体37
苯并呋喃-2-磺酸(5-氯-2-巯基-苯基)酰胺
按照一般程序N,由中间体8 N,N′-[二硫代双(5-氯-2,1-亚苯基)]双(1-苯并呋喃-2-磺酰胺)制备标题化合物,其不经进一步纯化即可使用。
化合物155
N-{5-氯-2-[(三氟甲基)硫基]苯基}-1-苯并呋喃-2-磺酰胺
在-78℃向苯并呋喃-2-磺酸(5-氯-2-巯基-苯基)-酰胺(332mg,0.98mmol)在CH2Cl2(10ml)中的溶液加入3,3-二甲基-1-(三氟甲基)-1,2-苯并碘氧杂戊环(CAS#。887144-97-0,354mg,1.07mmol),将反应搅拌1小时,在真空中浓缩。粗产物通过硅胶柱色谱(CH2Cl2)纯化,得到标题化合物(375mg,94%)。
1H NMR(600MHz,氯仿-d)δ7.88(s,1H),7.82(d,J=2.05Hz,1H),7.67(dd,J=0.59,7.92Hz,1H),7.49-7.54(m,3H),7.44-7.49(m,1H),7.33(td,J=1.03,7.56Hz,1H),7.11(dd,J=2.20,8.36Hz,1H).
化合物156
N-{5-氯-2-[(三氟甲基)磺酰基]苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序D,使用在回流的CH2Cl2中的10当量的mCPBA,由N-{5-氯-2-[(三氟甲基)硫基]苯基}-1-苯并呋喃-2-磺酰胺制备标题化合物。
1H NMR(600MHz,丙酮-d6)δ7.90(d,J=2.05Hz,1H),7.78(d,J=8.80Hz,1H),7.71(d,J=7.92Hz,1H),7.51(d,J=8.22Hz,1H),7.36-7.43(m,2H),7.29(t,J=7.48Hz,1H),6.92(d,J=6.46Hz,1H).
化合物157
N-{5-氯-2-[(三氟甲基)亚磺酰基]苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序D,使用在回流的CH2Cl2中的10当量的mCPBA,由N-{5-氯-2-[(三氟甲基)硫基]苯基}-1-苯并呋喃-2-磺酰胺制备标题化合物。
1H NMR(600MHz,丙酮-d6)δ10.00(br.s.,1H),7.89(d,J=8.22Hz,1H),7.78-7.81(m,1H),7.63-7.66(m,1H),7.50-7.59(m,4H),7.39(ddd,J=0.88,7.26,8.00Hz,1H).
化合物158
N-{2-[(3-氨基苄基)硫基]-5-氯苯基}-2,4-二氟苯磺酰胺
按照一般程序A、B和K,由2-氨基-4-氯-苯硫醇、1-溴甲基-3-硝基-苯和2,4-二氟-苯磺酰氯制备标题化合物。
1H NMR(600MHz,氯仿-d)δ7.92(td,J=6.16,8.51Hz,1H),7.47(d,J=2.35Hz,1H),7.19(d,J=8.22Hz,1H),7.01-7.06(m,1H),6.95-7.01(m,1H),6.88-6.94(m,2H),6.57(dd,J=1.47,8.80Hz,1H),6.40-6.45(m,2H),3.72(s,2H).
化合物159
N-{2-[(3-氨基苄基)磺酰基]-5-氯苯基}-2,4-二氟苯磺酰胺
按照一般程序A、B、D和K,由2-氨基-4-氯-苯硫醇、1-溴甲基-3-硝基-苯和2,4-二氟-苯磺酰氯制备标题化合物。
1H NMR(600MHz,甲醇-d4)δ8.05(td,J=6.16,8.51Hz,1H),7.48-7.54(m,2H),7.14-7.25(m,2H),7.09(dd,J=2.05,8.51Hz,1H),6.96(t,J=7.78Hz,1H),6.66-6.71(m,1H),6.54(t,J=1.91Hz,1H),6.34(d,J=7.63Hz,1H),4.44(s,2H).
化合物160
N-{2-[(3-氨基苄基)磺酰基]-5-氯苯基}-4-氯-2-氟苯磺酰胺
按照一般程序A、B、D和K,由2-氨基-4-氯-苯硫醇、1-溴甲基-3-硝基-苯和4-氯-2-氟-苯磺酰氯制备标题化合物。
1H NMR(600MHz,甲醇-d4)δ7.97(t,J=8.51Hz,1H),7.54(d,J=8.51Hz,1H),7.43-7.52(m,3H),7.13-7.17(m,1H),6.98(t,J=7.78Hz,1H),6.67-6.72(m,1H),6.53(s,1H),6.33(d,J=7.63Hz,1H),4.42(s,2H).
化合物161
N-{2-[(3-氨基苄基)亚磺酰基]-5-氯苯基}-4-氯-2-氟苯磺酰胺
按照一般程序A、B、C和K,由2-氨基-4-氯-苯硫醇、1-溴甲基-3-硝基-苯和4-氯-2-氟-苯磺酰氯制备标题化合物。
1H NMR(600MHz,甲醇-d4)δ7.85(t,J=8.07Hz,1H),7.49(dd,J=1.76,9.98Hz,1H),7.40(dd,J=1.91,8.36Hz,1H),7.33(d,J=8.22Hz,1H),7.23(dd,J=1.91,8.36Hz,1H),7.16(d,J=2.05Hz,1H),7.04(t,J=7.78Hz,1H),6.72-6.75(m,1H),6.63(t,J=1.91Hz,1H),6.50(d,J=7.34Hz,1H),4.30(d,J=12.91Hz,1H),4.04(d,J=12.62Hz,1H).
化合物162
N-{2-[(3-氨基苄基)硫基]-5-氯苯基}苯磺酰胺
按照一般程序A、B和K,由2-氨基-4-氯-苯硫醇、1-溴甲基-3-硝基-苯和苯磺酰氯制备标题化合物。
1H NMR(600MHz,甲醇-d4)δ7.75-7.79(m,2H),7.57-7.62(m,1H),7.48-7.53(m,2H),7.44(d,J=2.05Hz,1H),7.14(d,J=8.22Hz,1H),6.99(dd,J=2.35,8.22Hz,1H),6.95(t,J=7.78Hz,1H),6.56-6.60(m,1H),6.45(t,J=1.91Hz,1H),6.35(d,J=7.34Hz,1H),3.58(s,2H).
化合物163
N-{2-[(3-氨基苄基)硫基]-5-氯苯基}-4-氯苯磺酰胺
按照一般程序A、B和K,由2-氨基-4-氯-苯硫醇、1-溴甲基-3-硝基-苯和4-氯-苯磺酰氯制备标题化合物。
1H NMR(600MHz,氯仿-d)δ7.69-7.72(m,2H),7.54(d,J=2.35Hz,1H),7.40-7.44(m,2H),7.17(d,J=8.22Hz,1H),7.03(t,J=7.78Hz,1H),6.95(dd,J=2.20,8.36Hz,1H),6.58(dd,J=1.76,7.92Hz,1H),6.34-6.39(m,2H),3.61(s,2H).
化合物164
N-{2-[(3-氨基苄基)硫基]-5-氯苯基}-3-氯苯磺酰胺
按照一般程序A、B和K,由2-氨基-4-氯-苯硫醇、1-溴甲基-3-硝基-苯和3-氯-苯磺酰氯制备标题化合物。
1H NMR(600MHz,氯仿-d)δ7.80(t,J=1.91Hz,1H),7.63-7.66(m,1H),7.56(d,J=2.35Hz,1H),7.52(ddd,J=0.88,1.98,8.00Hz,1H),7.39(t,J=7.92Hz,1H),7.16(d,J=8.51Hz,1H),7.02(t,J=7.78Hz,1H),6.96(dd,J=2.05,8.22Hz,1H),6.55-6.59(m,1H),6.35(d,J=7.63Hz,1H),6.32(t,J=1.91Hz,1H),3.56(s,2H).
化合物165
N-{2-[(3-氨基苄基)磺酰基]-5-氯苯基}苯磺酰胺
按照一般程序A、B、D和K,由2-氨基-4-氯-苯硫醇、1-溴甲基-3-硝基-苯和苯磺酰氯制备标题化合物。
1H NMR(600MHz,甲醇-d4)δ7.90-7.93(m,2H),7.63-7.68(m,1H),7.56-7.62(m,3H),7.42(d,J=8.51Hz,1H),7.11(dd,J=2.05,8.51Hz,1H),6.93(t,J=7.78Hz,1H),6.66(ddd,J=0.73,2.27,8.14Hz,1H),6.39(t,J=1.91Hz,1H),6.16(d,J=7.34Hz,1H),4.18(s,2H).
化合物166
N-{2-[(3-氨基苄基)亚磺酰基]-5-氯苯基}苯磺酰胺
按照一般程序A、B、C和K,由2-氨基-4-氯-苯硫醇、1-溴甲基-3-硝基-苯和苯磺酰氯制备标题化合物。
1H NMR(600MHz,甲醇-d4)δ7.82-7.86(m,2H),7.64-7.69(m,1H),7.56-7.62(m,2H),7.27-7.31(m,1H),7.22-7.27(m,1H),7.08(d,J=2.05Hz,1H),6.99(t,J=7.78Hz,1H),6.67(ddd,J=0.88,2.35,8.22Hz,1H),6.50(t,J=1.91Hz,1H),6.36(d,J=7.63Hz,1H),4.12(d,J=12.62Hz,1H),3.95(d,J=12.91Hz,1H).
化合物167
N-{2-[(3-氨基苄基)磺酰基]-5-氯苯基}-4-氯苯磺酰胺
按照一般程序A、B、D和K,由2-氨基-4-氯-苯硫醇、1-溴甲基-3-硝基-苯和4-氯-苯磺酰氯制备标题化合物。
1H NMR(600MHz,甲醇-d4)δ7.85-7.88(m,2H),7.58-7.62(m,2H),7.55(d,J=2.05Hz,1H),7.49(d,J=8.51Hz,1H),7.15(dd,J=1.91,8.66Hz,1H),6.95(t,J=7.78Hz,1H),6.68(ddd,J=0.88,2.20,8.07Hz,1H),6.45(t,J=1.91Hz,1H),6.21(d,J=7.63Hz,1H),4.28(s,2H).
化合物168
N-{2-[(3-氨基苄基)亚磺酰基]-5-氯苯基}-4-氯苯磺酰胺
按照一般程序A、B、C和K,由2-氨基-4-氯-苯硫醇、1-溴甲基-3-硝基-苯和4-氯-苯磺酰氯制备标题化合物。
1H NMR(600MHz,甲醇-d4)δ7.79(d,J=8.51Hz,2H),7.59(d,J=8.80Hz,2H),7.32(d,J=8.51Hz,1H),7.24-7.29(m,1H),7.06(d,J=1.76Hz,1H),6.99(t,J=7.78Hz,1H),6.65-6.69(m,1H),6.52(s,1H),6.38(d,J=7.34Hz,1H),4.16(d,J=12.91Hz,1H),3.97(d,J=12.91Hz,1H).
化合物169
N-{2-[(3-氨基苄基)磺酰基]-5-氯苯基}-3-氯苯磺酰胺
按照一般程序A、B、D和K,由2-氨基-4-氯-苯硫醇、1-溴甲基-3-硝基-苯和3-氯-苯磺酰氯制备标题化合物。
1H NMR(600MHz,甲醇-d4)δ8.00(t,J=1.91Hz,1H),7.89-7.93(m,1H),7.42-7.51(m,3H),7.38(d,J=8.51Hz,1H),6.89(t,J=7.78Hz,1H),6.66(dd,J=1.76,8.51Hz,1H),6.59(d,J=8.22Hz,1H),6.55(s,1H),6.37(d,J=7.63Hz,1H),4.69(s,2H).
化合物170
N-{2-[(3-氨基苄基)亚磺酰基]-5-氯苯基}-3-氯苯磺酰胺
按照一般程序A、B、C和K,由2-氨基-4-氯-苯硫醇、1-溴甲基-3-硝基-苯和3-氯-苯磺酰氯制备标题化合物。
1H NMR(600MHz,甲醇-d4)δ7.85(s,1H),7.77(d,J=7.63Hz,1H),7.51-7.55(m,1H),7.47(t,J=7.92Hz,1H),7.22(d,J=8.22Hz,1H),7.19(d,J=1.76Hz,1H),6.93-7.00(m,2H),6.65(dd,J=2.20,8.07Hz,1H),6.58(s,1H),6.43(d,J=7.63Hz,1H),4.35(d,J=12.91Hz,1H),3.82(d,J=12.91Hz,1H).
化合物171
3-{[4-氯-2-({[4-氯-3-(三氟甲基)苯基]磺酰基}氨基)苯基]硫基}-N-异丙基丙酰胺
按照一般程序H、B,由2-氨基-4-氯-苯硫醇、N-异丙基丙烯酰胺和4-氯-3-三氟甲基-苯磺酰氯制备标题化合物。
1H NMR(300MHz,CD3OD)δ8.19(d,J=1.47Hz,1H),7.98(d,J=8.20Hz,1H),7.60(d,J=8.20Hz,1H),7.23(d,J=2.05Hz,1H),7.06(d,J=8.20Hz,1H),6.75(dd,J=2.20,8.35Hz,1H),3.85-4.03(m,1H),3.00(t,J=7.33Hz,2H),2.39(t,J=7.47Hz,2H),1.12(d,6H).
化合物172
3-{[4-氯-2-({[4-氯-3-(三氟甲基)苯基]磺酰基}氨基)苯基]硫基}-N,N-二甲基丙酰胺
按照一般程序H、B,由2-氨基-4-氯-苯硫醇、N,N-二甲基-丙烯酰胺和4-氯-3-三氟甲基-苯磺酰氯制备标题化合物。
1H NMR(300MHz,CD3OD)δ8.11(s,1H),7.90(d,J=7.91Hz,1H),7.71-7.79(m,1H),7.49(d,J=2.34Hz,1H),7.39(d,J=8.50Hz,1H),7.21(无,J=2.34,8.50Hz,1H),2.96(d,J=7.62Hz,6H),2.90(t,J=7.03Hz,2H),2.51(t,J=7.03Hz,2H).
化合物173
3-{[4-氯-2-({[4-氯-3-(三氟甲基)苯基]磺酰基}氨基)苯基]亚磺酰基}-N-异丙基丙酰胺
按照一般程序C,由3-{[4-氯-2-({[4-氯-3-(三氟甲基)苯基]磺酰基}氨基)苯基]硫基}-N,N-二甲基丙酰胺制备标题化合物。
1H NMR(300MHz,CD3OD)δ8.17(d,J=1.76Hz,1H),8.01(d,J=8.20Hz,1H),7.67(d,J=8.50Hz,1H),7.39(d,J=8.20Hz,1H),7.24(d,J=1.76Hz,1H),6.88(dd,J=1.90,8.35Hz,1H),3.91(quin,J=6.59Hz,1H),3.37-3.52(m,1H),3.09-3.25(m,1H),2.58(ddd,J=5.71,9.89,15.16Hz,1H),2.26(ddd,J=5.86,9.74,15.16Hz,1H),1.10(dd,4H).
化合物174
3-{[4-氯-2-({[4-氯-3-(三氟甲基)苯基]磺酰基}氨基)苯基]亚磺酰基}丙酰胺
按照一般程序H、B,由2-氨基-4-氯-苯硫醇、丙烯酰胺和4-氯-3-三氟甲基-苯磺酰氯制备标题化合物。
1H NMR(600MHz,CD3OD)δ8.16(d,J=1.76Hz,1H),8.00(dd,J=2.05,8.22Hz,1H),7.75(d,J=8.51Hz,1H),7.57(d,J=8.51Hz,1H),7.32(s,1H),7.21(d,J=7.92Hz,1H),3.26(br.s.,1H),3.18(br.s.,1H),2.99-3.07(m,3H),2.95(s,3H),2.88(dt,J=7.37,16.95Hz,1H),2.62-2.77(m,1H).
化合物175
N-[5-氯-2-(甲基亚磺酰基)苯基]苯磺酰胺
按照一般程序B、C,由5-氯-2-(甲基亚磺酰基)苯胺和苯磺酰氯制备标题化合物。
1H NMR(300MHz,丙酮-d6)δ10.64(br.s.,1H),7.93(d,J=7.03Hz,2H),7.59-7.79(m,3H),7.55(d,J=1.76Hz,1H),7.45(d,J=8.50Hz,1H),7.26(dd,J=1.90,8.35Hz,1H),2.74(s,3H).
化合物176
N-[5-氯-2-(甲基硫基)苯基]硫基苯-2-磺酰胺
按照一般程序B,由5-氯-2-(甲基亚磺酰基)苯胺和噻吩-2-磺酰氯制备标题化合物。
1H NMR(300MHz,CD3OD)δ7.75(dd,J=1.17,4.98Hz,1H),7.50(dd,J=1.32,3.66Hz,1H),7.40(d,J=2.05Hz,1H),7.26-7.34(m,1H),7.15-7.24(m,1H),7.08(dd,J=3.81,4.98Hz,1H),2.23(s,3H).
化合物177
N-[5-氯-2-(甲基亚磺酰基)苯基]硫基苯-2-磺酰胺
按照一般程序C,由N-[5-氯-2-(甲基硫基)苯基]噻吩-2-磺酰胺制备标题化合物。
1H NMR(600MHz,CD3OD)δ7.81(d,J=4.40Hz,1H),7.75(d,J=8.51Hz,1H),7.51-7.57(m,1H),7.43(d,J=7.92Hz,1H),7.15(dd,J=4.84,8.66Hz,2H),2.79(s,3H).
化合物178
N-{2-[(3-硝基苄基)磺酰基]苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序D,由苯并呋喃-2-磺酸[2-(3-硝基-苄基硫烷基)-苯基]-酰胺制备标题化合物(136mg,82%)。
1H NMR(600MHz,丙酮-d6)δ9.57(br.s.,1H),8.17(dt,J=2.53,6.38Hz,1H),7.93(d,J=0.88Hz,1H),7.74-7.83(m,3H),7.69(td,J=1.47,7.92Hz,1H),7.63(dd,J=1.47,7.92Hz,1H),7.52-7.59(m,3H),7.47(ddd,J=1.17,7.41,8.44Hz,1H),7.30-7.38(m,1H),7.23(t,J=7.63Hz,1H),4.85(s,2H).
化合物179
N-(5-氯-2-{[2-(3,5-二甲基-1H-吡唑-4-基)乙基]亚磺酰基}苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序C,由N-(5-氯-2-{[(2-(3,5-二甲基-1H-吡唑-4基)乙基]硫基}苯基)-1-苯并呋喃-2-磺酰胺制备标题化合物(79mg,73%)。
1H NMR(600MHz,CD3OD)δ7.61(d,J=7.92Hz,1H),7.46(d,J=2.05Hz,1H),7.44(d,J=8.22Hz,1H),7.28-7.32(m,1H),7.21-7.26(m,1H),7.19(dd,J=0.73,8.36Hz,1H),7.15(d,J=0.88Hz,1H),6.92(dd,J=1.91,8.36Hz,1H),3.52-3.62(m,1H),2.80-2.91(m,2H),2.56-2.65(m,1H),2.11(s,6H).
化合物180
4-氯-N-{5-氯-2-[(3-羟基环戊基)磺酰基]苯基}-3-(三氟甲基)苯磺酰胺
按照一般程序D,接著用NaBH4的MeOH溶液处理粗产物,由4-氯-N-[5-氯-2-(3-氧代-环戊基硫烷基)-苯基]-3-三氟甲基-苯磺酰胺(中间体35)制备标题化合物。
1H NMR(600MHz,CD3OD)δ8.34(s,1H),8.18(dd,J=1.91,8.36Hz,1H),7.70-7.79(m,2H),7.65(s,1H),7.00(br.s.,1H),4.12-4.18(m,2H),1.98-2.10(m,2H),1.72-1.84(m,2H),1.63-1.71(m,2H).
化合物181
N-[5-氯-2-(甲基硫基)苯基]-4-甲基-3-硝基苯磺酰胺
按照一般程序B,制备5-氯-2-甲基硫烷基-苯基胺(150mg,0.87mmol)和4-甲基-3-硝基-苯磺酰氯(235mg,0.87mmol)制备标题化合物(197mg,61%)。
1H NMR(600MHz,CD3OD)δ8.29(d,J=1.76Hz,1H),7.85(dd,J=1.91,8.07Hz,1H),7.57(d,J=8.22Hz,1H),7.39(d,J=2.05Hz,1H),7.17-7.25(m,2H),2.60(s,3H),2.20(s,3H).
化合物182
氯-2-(甲基亚磺酰基)苯基]-4-甲基-3-硝基苯磺酰胺
按照一般程序C,由N-[5-氯-2-(甲基硫基)苯基]-4-甲基-3-硝基苯磺酰胺制备标题化合物。
1H NMR(600MHz,CDCL3)δ10.88(br.s.,1H),8.53(d,J=2.05Hz,1H),8.05(dd,J=1.91,8.07Hz,1H),7.64(d,J=1.76Hz,1H),7.54(d,J=8.22Hz,1H),7.04-7.16(m,2H),2.87(s,3H),2.67(s,3H).
化合物183
N-[5-氯-2-(甲基磺酰基)苯基]-4-甲基-3-硝基苯磺酰胺
按照一般程序D,由N-[5-氯-2-(甲基硫基)苯基]-4-甲基-3-硝基苯磺酰胺制备标题化合物。
1H NMR(600MHz,CDCL3)δ9.36(br.s.,1H),8.52(d,J=2.05Hz,1H),8.05(dd,J=2.05,8.22Hz,1H),7.79(d,J=8.51Hz,1H),7.67(d,J=2.05Hz,1H),7.58(d,J=7.92Hz,1H),7.23(dd,J=1.76,8.51Hz,1H),3.04(s,3H),2.68(s,3H).
化合物184
4-氯-N-[5-氯-2-(甲基硫基)苯基]苯磺酰胺
按照一般程序B,由5-氯-2-甲基硫烷基-苯基胺(110mg,0.64mmol)和4-氯-苯磺酰氯(134mg,0.64mmol)制备标题化合物(150mg,68%)。
1H NMR(600MHz,CD3OD)δ7.72(d,J=9.10Hz,2H),7.51(d,J=8.80Hz,2H),7.37(d,J=2.05Hz,1H),7.25(d,J=8.51Hz,1H),7.19(dd,J=2.05,8.22Hz,1H),2.20(s,3H).
化合物185
4-氯-N-[5-氯-2-(甲基亚磺酰基)苯基]苯磺酰胺
按照一般程序C,由4-氯-N-[5-氯-2-(甲基硫基)苯基]苯磺酰胺制备标题化合物。
1H NMR(600MHz,CDCL3)δ10.67(br.s.,1H),7.89(d,J=8.80Hz,2H),7.66(d,J=1.76Hz,1H),7.50(d,J=8.80Hz,2H),6.91-7.16(m,2H),2.80(无,3H).
化合物186
4-氯-N-[5-氯-2-(甲基磺酰基)苯基]苯磺酰胺
按照一般程序D,由4-氯-N-[5-氯-2-(甲基硫基)苯基]苯磺酰胺制备标题化合物。
1H NMR(600MHz,CDCL3)δ7.89(d,J=8.80Hz,2H),7.78(d,J=8.51Hz,1H),7.68(d,J=1.76Hz,1H),7.53(d,J=8.80Hz,2H),7.20(dd,J=2.05,8.51Hz,1H),2.96(s,3H).
化合物187
4-氯-N-[5-氯-2-(甲基硫基)苯基]-3-甲基苯磺酰胺
按照一般程序B,由5-氯-2-甲基硫烷基-苯基胺(165mg,0.95mmol)和4-氯-3-甲基-苯磺酰氯(215mg,0.95mmol)制备标题化合物(205mg,59%)。
1H NMR(600MHz,CDCL3)δ7.71(d,1H),7.65(s,1H),7.62(d,J=2.05Hz,1H),7.57(dd,J=2.05,8.22Hz,1H),7.41(d,J=8.22Hz,1H),7.32(d,J=8.51Hz,1H),7.04(dd,J=2.20,8.36Hz,1H),2.39(s,3H),2.19(s,3H).
化合物188
4-氯-N-[5-氯-2-(甲基亚磺酰基)苯基]-3-甲基苯磺酰胺
按照一般程序C,由4-氯-N-[5-氯-2-(甲基硫基)苯基]-3-甲基苯磺酰胺制备标题化合物。
1H NMR(600MHz,CDCL3)δ10.62(s,1H),7.82(d,J=2.05Hz,1H),7.71(dd,J=1.91,8.36Hz,1H),7.63(d,J=2.05Hz,1H),7.48(d,J=8.51Hz,1H),7.02-7.15(m,2H),2.81(s,3H),2.43(s,3H).
化合物189
4-氯-N-[5-氯-2-(甲基磺酰基)苯基]-3-甲基苯磺酰胺
按照一般程序D,由4-氯-N-[5-氯-2-(甲基硫基)苯基]-3-甲基苯磺酰胺制备标题化合物。
1H NMR(600MHz,CDCL3)δ9.24(br.s.,1H),7.83(d,J=2.05Hz,1H),7.78(d,J=8.51Hz,1H),7.71(dd,J=2.05,8.51Hz,1H),7.67(d,J=1.76Hz,1H),7.50(d,J=8.22Hz,1H),7.19(dd,J=1.76,8.51Hz,1H),2.97(s,3H),2.44(s,3H).
化合物190
N-[5-氯-2-(甲基硫基)苯基]-3-硝基-4-(三氟甲基)苯磺酰胺
按照一般程序B,由5-氯-2-甲基硫烷基-苯基胺(167mg,0.95mmol)和4-硝基-3-三氟甲基-苯磺酰氯(278mg,0.95mmol)制备标题化合物(176mg,43%)。
1H NMR(300MHz,CD3OD)δ8.04-8.22(m,3H),7.42(d,J=2.05Hz,1H),7.16-7.32(m,2H),2.20(s,3H).
化合物191
N-[5-氯-2-(甲基磺酰基)苯基]-3-硝基-4-(三氟甲基)苯磺酰胺
按照一般程序D,由制备标题化合物N-[5-氯-2-(甲基硫基)苯基]-3-硝基-4-(三氟甲基)苯磺酰胺制备标题化合物。1H NMR(600MHz,丙酮-d6)δ9.64(br.s.,1H),8.49-8.65(m,2H),8.33(d,J=8.51Hz,1H),7.89(d,J=8.51Hz,1H),7.70(d,J=1.76Hz,1H),7.39(d,J=8.22Hz,1H),3.24(s,3H).
化合物192
N-[5-氯-2-(甲基亚磺酰基)苯基]-3-硝基-4-(三氟甲基)苯磺酰胺
按照一般程序D,由N-[5-氯-2-(甲基硫基)苯基]-3-硝基-4-(三氟甲基)苯磺酰胺制备标题化合物。
1H NMR(600MHz,丙酮-d6)δ8.25-8.35(m,2H),8.11(d,J=8.22Hz,1H),7.39-7.48(m,2H),6.75(dd,J=2.05,8.22Hz,1H),2.70(s,3H).
化合物193
N-[5-氯-2-(甲基硫基)苯基]-2,4-二氟苯磺酰胺
按照一般程序B,由5-氯-2-甲基硫烷基-苯基胺(189mg,1.09mmol)和2,4-二氟-苯磺酰氯(231mg,1.09mmol)制备标题化合物(358mg,94%)。
1H NMR(300MHz,CD3OD)δ7.82(td,J=6.15,8.50Hz,1H),7.34(d,J=2.05Hz,1H),7.16-7.30(m,3H),7.00-7.16(m,1H),2.27(s,3H).
化合物194
N-[5-氯-2-(甲基磺酰基)苯基]-2,4-二氟苯磺酰胺
按照一般程序D,由N-[5-氯-2-(甲基硫基)苯基]-2,4-二氟苯磺酰胺制备标题化合物。
1H NMR(300MHz,丙酮-d6)δ9.81(br.s.,1H),8.15-8.32(m,1H),7.91(d,J=8.50Hz,1H),7.63(d,J=1.76Hz,1H),7.24-7.46(m,3H),3.27(s,3H).
化合物195
N-[5-氯-2-(甲基亚磺酰基)苯基]-2,4-二氟苯磺酰胺
按照一般程序D,由N-[5-氯-2-(甲基硫基)苯基]-2,4-二氟苯磺酰胺制备标题化合物。
1H NMR(600MHz,丙酮-d6)δ10.97(br.s.,1H),8.10(td,J=6.16,8.51Hz,1H),7.51(d,J=8.22Hz,1H),7.46(d,J=2.05Hz,1H),7.30-7.38(m,1H),7.24-7.31(m,2H),2.90(s,3H).
化合物196
N-[5-氯-2-(甲基硫基)苯基]-5-甲基呋喃-2-磺酰胺
按照一般程序B,由5-氯-2-甲基硫烷基-苯基胺(189mg,1.09mmol)和5-甲基-呋喃-2-硫烷基-磺酰氯(250mg,1.38mmol)制备标题化合物(212mg,48%)。
1H NMR(300MHz,丙酮-d6)δ8.53(br.s.,1H),7.37-7.49(m,2H),7.25(dd,J=2.34,8.50Hz,1H),6.96(d,J=3.22Hz,1H),6.24(d,J=2.64Hz,1H),2.38(s,3H),2.34(s,3H).
化合物197
N-[5-氯-2-(甲基亚磺酰基)苯基]-5-甲基呋喃-2-磺酰胺
按照一般程序C,由N-[5-氯-2-(甲基硫基)苯基]-5-甲基呋喃-2-磺酰胺制备标题化合物。
1H NMR(600MHz,丙酮-d6)δ10.74(br.s.,1H),7.55(d,J=2.05Hz,1H),7.51(d,J=8.22Hz,1H),7.30(dd,J=1.91,8.36Hz,1H),7.18(d,J=3.23Hz,1H),6.24-6.35(m,1H),2.90(s,3H),2.34(s,3H).
化合物198
N-[5-氯-2-(甲基磺酰基)苯基]-5-甲基呋喃-2-磺酰胺
按照一般程序D,由N-[5-氯-2-(甲基硫基)苯基]-5-甲基呋喃-2-磺酰胺制备标题化合物。
1H NMR(600MHz,丙酮-d6)δ9.54(br.s.,1H),7.90(d,J=8.51Hz,1H),7.73(d,J=2.05Hz,1H),7.39(dd,J=1.76,8.51Hz,1H),7.31(d,J=3.52Hz,1H),6.32(d,J=3.23Hz,1H),3.24(s,3H),2.33(s,3H).
化合物199
N-[5-氯-2-(甲基硫基)苯基]呋喃-2-磺酰胺
按照一般程序B,由5-氯-2-甲基硫烷基-苯基胺(260mg,1.50mmol)和呋喃-2-磺酰氯(250mg,1.50mmol)制备标题化合物(215mg,47%)。
1H NMR(300MHz,丙酮-d6)δ8.67(br.s.,1H),7.84(s,1H),7.32-7.46(m,2H),7.26(dd,J=2.20,8.35Hz,1H),7.07(d,J=3.52Hz,1H),6.63(dd,J=1.76,3.52Hz,1H),2.36(s,3H).
化合物200
N-[5-氯-2-(甲基亚磺酰基)苯基]呋喃-2-磺酰胺
按照一般程序C,由N-[5-氯-2-(甲基硫基)苯基]呋喃-2-磺酰胺制备标题化合物。
1H NMR(600MHz,丙酮-d6)δ10.85(br.s.,1H),7.89(s,1H),7.49-7.59(m,2H),7.28-7.36(m,2H),6.68(dd,J=1.76,3.52Hz,1H),2.88(s,3H).
化合物201
N-[5-氯-2-(甲基磺酰基)苯基]呋喃-2-磺酰胺
按照一般程序D,由N-[5-氯-2-(甲基硫基)苯基]呋喃-2-磺酰胺制备标题化合物。
1H NMR(600MHz,丙酮-d6)δ9.62(br.s.,1H),7.90(d,J=8.51Hz,2H),7.74(d,J=2.05Hz,1H),7.27-7.48(m,2H),6.70(dd,J=1.76,3.52Hz,1H),3.22(s,3H).
化合物202
4-氯-N-[5-氯-2-(甲基硫基)苯基]-2-氟苯磺酰胺
按照一般程序B,由5-氯-2-甲基硫烷基-苯基胺(273mg,1.57mmol)和4-氯-2-氟-苯磺酰氯(360mg,1.57mmol)制备标题化合物(380mg,66%)。
1H NMR(300MHz,丙酮-d6)δ8.77(br.s.,1H),7.84(t,J=8.06Hz,1H),7.53(dd,J=1.90,9.82Hz,1H),7.35-7.48(m,3H),7.25(dd,J=2.20,8.35Hz,1H),2.34(s,3H).
化合物203
4-氯-N-[5-氯-2-(甲基亚磺酰基)苯基]-2-氟苯磺酰胺
按照一般程序C,由4-氯-N-[5-氯-2-(甲基硫基)苯基]-2-氟苯磺酰胺制备标题化合物。
1H NMR(300MHz,丙酮-d6)δ10.95(br.s.,1H),8.03(t,J=8.20Hz,1H),7.39-7.61(m,4H),7.28(dd,J=1.90,8.35Hz,1H),2.93(s,3H).
化合物204
4-氯-N-[5-氯-2-(甲基磺酰基)苯基]-2-氟苯磺酰胺
按照一般程序D,由4-氯-N-[5-氯-2-(甲基硫基)苯基]-2-氟苯磺酰胺制备标题化合物。
1H NMR(300MHz,丙酮-d6)δ9.84(br.s.,1H),8.12(t,J=8.20Hz,1H),7.90(d,J=8.50Hz,1H),7.46-7.69(m,3H),7.33(dd,J=1.47,8.50Hz,1H),3.27(s,3H).
化合物205
3-氯-N-[5-氯-2-(甲基硫基)苯基]-2-氟苯磺酰胺
按照一般程序B,由5-氯-2-甲基硫烷基-苯基胺(297mg,1.71mmol)和3-氯-2-氟-苯磺酰氯(392mg,1.71mmol)制备标题化合物(386mg,62%)。
1H NMR(300MHz,丙酮-d6)δ8.87(br.s.,1H),7.70-7.93(m,2H),7.32-7.47(m,3H),7.20-7.31(m,1H),2.32(s,3H).
化合物206
3-氯-N-[5-氯-2-(甲基磺酰基)苯基]-2-氟苯磺酰胺
按照一般程序D,由3-氯-N-[5-氯-2-(甲基硫基)苯基]-2-氟苯磺酰胺制备标题化合物。
1H NMR(300MHz,丙酮-d6)δ7.89-8.04(m,1H),7.69(d,J=8.50Hz,1H),7.55-7.65(m,2H),7.23-7.37(m,1H),6.72(dd,J=1.90,8.64Hz,1H),3.22(s,3H).
化合物207
3-氯-N-[5-氯-2-(甲基亚磺酰基)苯基]-2-氟苯磺酰胺
按照一般程序C,由3-氯-N-[5-氯-2-(甲基硫基)苯基]-2-氟苯磺酰胺制备标题化合物。
1H NMR(300MHz,丙酮-d6)δ7.94-8.04(m,1H),7.83-7.93(m,1H),7.42-7.59(m,3H),7.29(dd,J=1.90,8.35Hz,1H),2.93(s,3H).
化合物208
4-氯-N-{5-氯-2-[(1H-咪唑-2-基甲基)硫基]苯基}-3-(三氟甲基)苯磺酰胺
按照一般程序A、B,由2-氨基-4-氯-苯硫醇、2-氯甲基-1H-咪唑和4-氯-3-三氟甲基-苯磺酰氯制备标题化合物。
1H NMR(300MHz,CD3OD)δ8.06(d,J=1.76Hz,1H),7.89(dd,J=2.05,8.50Hz,1H),7.63-7.78(m,2H),7.45(d,J=2.05Hz,1H),7.30(d,J=8.50Hz,1H),7.14(dd,J=2.34,8.50Hz,1H),6.73(s,1H),3.83(s,2H).
化合物209
4-氯-N-{5-氯-2-[(1H-咪唑-2-基甲基)亚磺酰基]苯基}-3-(三氟甲基)苯磺酰胺
按照一般程序C,由4-氯-N-{5-氯-2-[(1H-嘧啶-2-基甲基)硫基]苯基}-3-(三氟甲基)苯磺酰胺制备标题化合物。
1H NMR(600MHz,CD3OD)δ8.18(d,1H),8.03(dd,J=1.91,8.36Hz,1H),7.72(d,J=8.22Hz,1H),7.41(s,2H),7.20(d,J=1.76Hz,1H),7.06(d,J=8.51Hz,1H),6.84(dd,J=1.91,8.36Hz,1H),4.76(d,J=8.22Hz,2H).
化合物210
4-氯-N-{5-氯-2-[(1H-咪唑-2-基甲基)磺酰基]苯基}-3-(三氟甲基)苯磺酰胺
1H NMR(600MHz,丙酮-d6)δ8.33(d,J=1.76Hz,1H),8.18(dd,J=1.76,8.22Hz,1H),7.70(d,J=8.22Hz,1H),7.66(d,J=8.51Hz,1H),7.58(d,J=2.05Hz,1H),7.10(s,2H),6.72(dd,J=1.91,8.36Hz,1H),4.86(s,2H).
化合物211
4-氯-N-{5-氯-2-[(1H-咪唑-4-基甲基)硫基]苯基}-3-(三氟甲基)苯磺酰胺
按照一般程序A、B,由2-氨基-4-氯-苯硫醇、4-氯甲基-1H-咪唑盐酸盐和4-氯-3-三氟甲基-苯磺酰氯制备标题化合物。
1H NMR(600MHz,丙酮-d6)δ8.07(d,J=2.05Hz,1H),7.89-7.97(m,2H),7.77(d,J=8.51Hz,1H),7.61(d,J=2.35Hz,1H),7.56(d,J=8.22Hz,1H),7.16(dd,J=2.35,8.22Hz,1H),7.02(s,1H),3.87(s,2H).
化合物212
4-氯-N-{5-氯-2-[(1H-咪唑-4-基甲基)亚磺酰基]苯基}-3-(三氟甲基)苯磺酰胺
按照一般程序C,由4-氯-N-{5-氯-2-[(1H-嘧啶-4-基甲基)硫基]苯基}-3-(三氟甲基)苯磺酰胺制备标题化合物。
1H NMR(600MHz,丙酮-d6)δ8.26(br.s.,1H),8.17(s,1H),8.08(dd,J=1.76,8.51Hz,1H),7.82(d,J=8.51Hz,1H),7.47(br.s.,1H),7.38(d,J=8.51Hz,1H),7.30(s,1H),7.09(d,J=7.92Hz,1H),4.48(dd,J=2.35,13.79Hz,1H),4.20(d,J=14.09Hz,1H).
化合物213
N-{5-氯-2-[(1H-咪唑-2-基甲基)硫基]苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序A、B,由2-氨基-4-氯-苯硫醇、2-氯甲基-1H-咪唑和1-苯并呋喃-2-磺酰氯制备标题化合物。
1H NMR(600MHz,丙酮-d6)δ7.74(d,J=7.92Hz,1H),7.64(d,J=2.35Hz,1H),7.61(d,J=8.51Hz,1H),7.53(d,J=8.51Hz,1H),7.46(td,J=1.17,7.78Hz,1H),7.41(s,1H),7.33(t,J=7.48Hz,1H),7.17(s,2H),7.09(dd,J=2.35,8.22Hz,1H),4.10(s,2H).
化合物214
N-{5-氯-2-[(1H-咪唑-2-基甲基)亚磺酰基]苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序C,由N-{5-氯-2-[(1H-咪唑-2-基甲基)硫基]苯基}-1-苯并呋喃-2-磺酰胺制备标题化合物。
1H NMR(300MHz,DMSO-d6)δ7.68(d,J=7.62Hz,1H),7.51-7.61(m,3H),7.41(d,J=2.05Hz,1H),7.32-7.40(m,1H),7.21-7.32(m,1H),7.17(s,1H),6.92(d,J=8.50Hz,1H),6.74(dd,J=1.90,8.06Hz,1H),4.89(d,J=14.07Hz,1H),4.56(d,J=13.77Hz,1H).
化合物215
N-{5-氯-2-[(1H-咪唑-2-基甲基)磺酰基]苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序D,由N-{5-氯-2-[(1H-咪唑-2-基甲基)硫基]苯基}-1-苯并呋喃-2-磺酰胺制备标题化合物。
1H NMR(300MHz,丙酮-d6)δ7.69-7.79(m,3H),7.66(s,2H),7.46-7.54(m,1H),7.41(s,2H),7.24-7.34(m,1H),6.88(dd,J=1.90,8.64Hz,1H),5.62(s,2H).
化合物216
N-{5-氯-2-[(1H-咪唑-4-基甲基)亚磺酰基]苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序C,由N-{5-氯-2-[(1H-咪唑-4-基甲基)硫基]苯基}-1-苯并呋喃-2-磺酰胺制备标题化合物。
1H NMR(300MHz,丙酮-d6)δ8.34(s,1H),7.75(d,J=7.91Hz,1H),7.60(d,J=2.05Hz,1H),7.47-7.56(m,2H),7.43(t,J=7.33Hz,1H),7.24-7.38(m,3H),7.03(d,J=10.55Hz,1H),4.58(d,J=14.36Hz,1H),4.24(d,J=13.77Hz,1H)
化合物217
N-{5-氯-2-[(1H-咪唑-4-基甲基)磺酰基]苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序D,由N-{5-氯-2-[(1H-咪唑-4-基甲基)硫基]苯基}-1-苯并呋喃-2-磺酰胺制备标题化合物。
1H NMR(300MHz,丙酮-d6)8.20(br.s.,1H),7.66-7.81(m,3H),7.35-7.53(m,4H),7.23-7.35(m,1H),6.95(dd,J=2.05,8.50Hz,1H),4.87(s,2H)。
化合物218
N-[2-({2-[(氨基羰基)氨基]乙基}硫基)-5-氯苯基]-1-苯并呋喃-2-磺酰胺
按照一般程序A、B,由2-氨基-4-氯-苯硫醇、(2-氯乙基)-脲和1-苯并呋喃-2-磺酰氯制备标题化合物。
1H NMR(300MHz,丙酮-d6)δ7.77(d,J=7.91Hz,1H),7.45-7.66(m,5H),7.31-7.42(m,1H),7.22(dd,J=2.05,8.50Hz,1H),6.02(br.s.,1H),5.40(br.s.,2H),3.14(q,J=6.15Hz,2H),2.84(t,J=6.45Hz,2H).
化合物219
N-[2-({2-[(氨基羰基)氨基]乙基}亚磺酰基)-5-氯苯基]-1-苯并呋喃-2-磺酰胺
按照一般程序C,由N-[2-({2-[(氨基羰基)氨基]乙基}硫基)-5-氯苯基]-1-苯并呋喃-2-磺酰胺制备标题化合物。
1H NMR(600MHz,CD3OD)δ7.68(d,J=7.92Hz,1H),7.54(dd,J=5.28,8.22Hz,2H),7.42(t,J=7.92Hz,1H),7.37(s,1H),7.27-7.34(m,2H),7.10(d,J=6.75Hz,1H),3.58-3.67(m,1H),3.44-3.53(m,1H),3.36-3.43(m,1H),2.98-3.09(m,1H).
化合物220
N-[2-({2-[(氨基羰基)氨基]乙基}磺酰基)-5-氯苯基]-1-苯并呋喃-2-磺酰胺
按照一般程序D,由>N-[2-({2-[(氨基羰基)氨基]乙基}硫基)-5-氯苯基]-1-苯并呋喃-2-磺酰胺制备标题化合物。
1H NMR(600MHz,CD3OD)δ7.85(d,J=8.51Hz,1H),7.80(d,J=2.05Hz,1H),7.77(d,J=7.92Hz,1H),7.72(s,1H),7.61(d,J=8.51Hz,1H),7.52(t,J=7.34Hz,1H),7.31-7.40(m,2H),3.36-3.47(m,4H).
化合物221
N-(5-氯-2-{[3-(二甲基氨基)丙基]硫基}苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序A、B,由2-氨基-4-氯-苯硫醇、(3-氯-丙基)-二甲基-胺盐酸盐和1-苯并呋喃-2-磺酰氯制备标题化合物。
1H NMR(600MHz,丙酮-d6)δ7.62-7.72(m,2H),7.49(d,J=8.22Hz,1H),7.31-7.38(m,2H),7.25(t,J=7.48Hz,1H),7.18(s,1H),6.69(dd,J=2.05,8.22Hz,1H),3.44(t,J=5.58Hz,2H),3.30(s,3H),3.12(s,3H),2.97(t,J=6.31Hz,2H),1.96-2.10(m,2H)
化合物222
N-(5-氯-2-{[3-(二甲基氨基)丙基]亚磺酰基}苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序C,由N-(5-氯-2-{[3-(二甲基氨基)丙基]硫基}苯基)-1-苯并呋喃-2-磺酰胺制备标题化合物。
1H NMR(600MHz,丙酮-d6)δ7.67(d,J=7.92Hz,1H),7.60(d,J=1.76Hz,1H),7.50(d,J=8.22Hz,1H),7.41(d,J=8.22Hz,1H),7.33(t,J=7.92Hz,1H),7.20-7.28(m,2H),6.83(dd,J=1.76,8.22Hz,1H),3.69(ddd,J=4.99,8.58,13.43Hz,1H),3.61(ddd,J=4.11,10.71,14.23Hz,1H),3.48(ddd,J=5.58,5.72,13.35Hz,1H),3.07-3.21(m,7H),2.30-2.42(m,1H),2.16-2.30(m,1H).
化合物223
N-(5-氯-2-{[3-(二甲基氨基)丙基]磺酰基}苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序D,由N-(5-氯-2-{[3-(二甲基氨基)丙基]硫基}苯基)-1-苯并呋喃-2-磺酰胺制备标题化合物。
1H NMR(600MHz,丙酮-d6)δ7.63(d,J=7.63Hz,1H),7.53(d,J=1.76Hz,1H),7.48(d,J=8.22Hz,1H),7.43(d,J=8.22Hz,1H),7.30(t,J=7.34Hz,1H),7.21(t,J=7.21Hz,1H),7.17(s,1H),6.74(dd,J=2.05,8.22Hz,1H),3.60-3.69(m,2H),3.36-3.48(m,1H),3.20-3.33(m,6H),2.90-3.01(br.s.,1H),2.29-2.42(m,J=6.75Hz,1H),2.08-2.21(m,1H).
化合物224
N-(5-氯-2-{[3-(二甲基亚硝叉基)丙基]磺酰基}苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序D,由N-(5-氯-2-{[3-(二甲基氨基)丙基]硫基}苯基)-1-苯并呋喃-2-磺酰胺制备标题化合物。
1H NMR(600MHz,丙酮-d6)d 7.79(s,1H),7.70(d,J=8.51Hz,1H),7.64(d,J=7.63Hz,1H),7.52(d,J=8.51Hz,1H),7.29-7.38(m,2H),7.19-7.28(m,1H),6.74(d,J=8.51Hz,1H),3.74-3.84(m,2H),3.60-3.65(m.,2H),3.26(s,6H),2.27-2.39(m,2H).
化合物225
N-(5-氯-2-{[(2-氧代-1,3-噁唑烷-5-基)甲基]亚磺酰基}苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序A、B、C,由2-氨基-4-氯-苯硫醇、5-氯甲基-噁唑烷-2-酮和1-苯并呋喃-2-磺酰氯制备标题化合物。
1H NMR(600MHz,丙酮-d6)δ7.62(dd,J=7.92,11.15Hz,1H),7.44-7.54(m,2H),7.26-7.44(m,3H),7.20(ddd,J=7.48,7.63,11.30Hz,1H),6.87-7.05(m,1H),6.51(br.s.,1H),4.69-5.03(m,1H),3.60(q,J=8.31Hz,1H),3.45-3.55(m,1H),3.23-3.45(m,1H),3.06-3.17(m,1H).
化合物226
N-(5-氯-2-{[(2-氧代-1,3-噁唑烷-5-基)甲基]磺酰基}苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序D,由N-(5-氯-2-{[(2-氧代-1,3-噁唑烷-5-基)甲基]硫基)苯基)苯并呋喃-2-磺酰胺制备标题化合物。
1H NMR(600MHz,丙酮-d6)δ7.81(d,J=1.76Hz,1H),7.68(d,J=8.22Hz,2H),7.54(d,J=8.22Hz,1H),7.29-7.40(m,2H),7.22-7.29(m,1H),6.79(br.s.,1H),6.47(br.s.,1H),4.94(dt,J=6.93,14.01Hz,1H),4.17(dd,J=5.58,14.09Hz,1H),3.96(dd,J=6.90,14.23Hz,1H),3.65(t,J=8.66Hz,1H),3.32-3.47(m,1H).
化合物227
N-(5-氯-2-{[(2,6-二氧代-1,2,3,6-四氢嘧啶-4-基)甲基]硫基}苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序A和B,由2-氨基-4-氯-苯硫醇、6-氯甲基-1H-吡啶-2,4-二酮和1-苯并呋喃-2-磺酰氯制备标题化合物。
1H NMR(600MHz,CD3OD)δ7.72(d,J=7.92Hz,1H),7.57(d,J=8.22Hz,1H),7.45-7.51(m,1H),7.44(d,J=2.05Hz,1H),7.42(s,1H),7.27-7.37(m,2H),7.09(br.s.,1H),5.05(s,1H),3.64(s,2H).
化合物228
N-(5-氯-2-{[(2,6-二氧代-1,2,3,6-四氢嘧啶-4-基)甲基]亚磺酰基}苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序C,由N-(5-氯-2-{[(2,6-二氧代-1,2,3,6-四氢嘧啶-4-基)甲基]硫基}苯基)-1-苯并呋喃-2-磺酰胺制备标题化合物。
1H NMR(600MHz,CD3OD)δ7.68(d,J=7.92Hz,1H),7.52(d,J=8.51Hz,1H),7.49(d,J=8.51Hz,1H),7.41(t,J=7.92Hz,1H),7.32-7.37(m,2H),7.27-7.32(m,1H),7.09(d,J=8.22Hz,1H),5.32(s,1H),4.40(d,J=13.21Hz,1H),3.89(d,J=12.91Hz,1H).
化合物229
N-(5-氯-2-{[(2,6-二氧代-1,2,3,6-四氢嘧啶-4-基)甲基]磺酰基}苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序D,由N-(5-氯-2-{[(2,6-二氧代-1,2,3,6-四氢嘧啶-4-基)甲基]硫基}苯基)-1-苯并呋喃-2-磺酰胺制备标题化合物。
1H NMR(600MHz,丙酮-d6)δ10.36(br.s.,1H),10.15(br.s.,1H),7.78(br.s.,1H),7.70(d,J=8.51Hz,1H),7.65(d,J=7.92Hz,1H),7.42-7.51(m,2H),7.35(t,J=7.63Hz,1H),7.26(t,J=7.48Hz,1H),6.87(d,J=6.75Hz,1H),5.48(br.s.,1H),4.76(br.s.,2H).
化合物230
N-{2-[(3-氨基丙基)硫基]-5-氯苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序F,G,用2,2’-二硫代双(5-氯苯胺)、1-苯并呋喃-2-磺酰氯和3-溴-丙胺盐酸盐制备标题化合物。
1H NMR(600MHz,DMSO-d6)δ8.03(br.s.,2H),7.69(d,J=7.63Hz,1H),7.56(d,J=8.22Hz,1H),7.37(t,J=7.78Hz,1H),7.23-7.32(m,2H),7.05-7.20(m,2H),6.60(br.s.,1H),3.03(br.s.,2H),2.91(t,J=6.60Hz,2H),1.74-1.92(m,2H).
中间体38
(3-溴-丙基)氢基甲酸叔丁酯
将3-溴-丙胺盐酸盐(523mg,2.39mmol)、二碳酸二叔丁酯(573mg,2.63mmol)、NaOH(1N,1.5ml)的MeOH中的溶液在室温搅拌过夜。向混合物加入水,用EtOAc萃取。将有机层用盐水洗涤,经Na2SO4干燥,且真空浓缩。残余物通过硅胶柱色谱纯化。
1H NMR(600MHz,CDCl3)δ4.65(br.s.,1H),3.38-3.56(m,2H),3.28(d,J=5.28Hz,2H),1.95-2.14(m,2H),1.45(br.s.,9H).
化合物231
N-{2-[(3-氨基丙基)亚磺酰基]-5-氯苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序F、G、C、E,由2,2’-二硫代双(5-氯苯胺)、1-苯并呋喃-2-磺酰氯和(3-溴-丙基)-氨基甲酸叔丁酯制备标题化合物。
1H NMR(600MHz,丙酮-d6)δ7.78(d,J=7.92Hz,1H),7.63(d,J=8.51Hz,1H),7.54-7.59(m,2H),7.46-7.52(m,2H),7.32-7.40(m,1H),7.21(d,J=7.92Hz,1H),4.03-4.14(m,1H),3.88-4.00(m,1H),3.35(ddd,J=6.97,7.19,13.72Hz,1H),3.10(ddd,J=6.46,6.60,13.35Hz,1H),2.16-2.36(m,2H).
化合物232
N-{2-[(3-氨基丙基)磺酰基]-5-氯苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序F、G、D、E,由2,2’-二硫代双(5-氯苯胺)、1-苯并呋喃-2-磺酰氯和(3-溴-丙基)-氨基甲酸叔丁酯制备标题化合物。
1H NMR(600MHz,CD3OD)δ7.88(d,J=8.51Hz,1H),7.79(d,J=7.92Hz,1H),7.72(d,J=1.76Hz,1H),7.68(s,1H),7.61(d,J=8.51Hz,1H),7.53(t,J=7.78Hz,1H),7.40(t,J=7.63Hz,1H),7.34(d,J=8.51Hz,1H),3.47(t,J=7.04Hz,2H),3.02(t,J=7.63Hz,2H),2.06(quin,2H).
化合物233
N-(5-氯-2-{[(2,4-二氧代-1,2,3,4-四氢嘧啶-5-基)甲基]亚磺酰基}苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序A、B、C,由2-氨基-4-氯-苯硫醇、5-(氯甲基)尿嘧啶和1-苯并呋喃-2-磺酰氯制备标题化合物。
1H NMR(600MHz,DMSO-d6)δ10.99(s,1H),10.75(br.s.,1H),7.61(d,J=7.63Hz,1H),7.51(d,J=8.22Hz,1H),7.32(t,J=7.48Hz,1H),7.16-7.27(m,3H),7.01-7.10(m,1H),6.86(br.s.,1H),6.64-6.79(m,1H),4.02(d,J=13.21Hz,1H),3.85(d,J=13.21Hz,1H).
化合物234
N-(5-氯-2-{[(2,4-二氧代-1,2,3,4-四氢嘧啶-5-基)甲基]磺酰基}苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序A、B、D,由2-氨基-4-氯-苯硫醇、5-(氯甲基)尿嘧啶和1-苯并呋喃-2-磺酰氯制备标题化合物。
1H NMR(600MHz,CD3OD)δ7.69(d,J=2.05Hz,1H),7.63-7.67(m,2H),7.44(t,J=8.36Hz,1H),7.32-7.39(m,2H),7.27(t,J=7.04Hz,1H),7.18(s,1H),6.82(d,J=7.92Hz,1H),4.70(s,2H).
化合物235
N-{4-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}硫基)甲基]-1,3-噻唑-2-基}乙酰胺
按照一般程序A、B,由2-氨基-4-氯-苯硫醇、N-(4-氯甲基-噻唑-2-基)-乙酰胺和1-苯并呋喃-2-磺酰氯制备标题化合物。
1H NMR(600MHz,CD3OD)d 7.70(d,J=7.92Hz,1H),7.49-7.54(m,2H),7.45-7.50(m,1H),7.42(s,1H),7.29-7.36(m,2H),7.11(dd,J=2.20,8.36Hz,1H),6.45(s,1H),3.84(s,2H),2.21(s,3H).
化合物236
N-{4-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}亚磺酰基)甲基]-1,3-噻唑-2-基}乙酰胺
按照一般程序C,由N-{4-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}硫基)甲基]-1,3-噻唑-2-基}乙酰胺制备标题化合物。
1H NMR(600MHz,丙酮-d6)δ10.93(br.s.,1H),7.83(d,J=7.92Hz,1H),7.80(s,1H),7.62-7.67(m,2H),7.49-7.58(m,1H),7.39(t,J=7.48Hz,1H),7.08-7.22(m,2H),6.74(s,1H),4.29-4.46(m,2H),2.23(s,3H).
化合物237
N-{4-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}磺酰基)甲基]-1,3-噻唑-2-基}乙酰胺
按照一般程序D,由N-{4-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}硫基)甲基]-1,3-噻唑-2-基}乙酰胺制备标题化合物。
1H NMR(600MHz,丙酮-d6)δ10.90(br.s.,1H),9.65(br.s.,1H),7.81(d,J=7.34Hz,2H),7.75(d,J=2.05Hz,1H),7.65(d,J=8.51Hz,1H),7.60(s.,1H),7.51(s.,1H),7.38(t,J=7.19Hz,1H),7.27(s.,1H),6.95(s,1H),4.67(br.s.,2H),2.21(s,3H).
化合物238
N-(5-氯-2-{[2-(3,5-二甲基-1H-吡唑-4-基)乙基]磺酰基}苯基)-1-苯并呋喃-2-磺酰胺
按照一般程序D,由N-(5-氯-2-{[2-(3,5-二甲基-1H-吡唑-4-基)乙基]硫基}苯基)-1-苯并呋喃-2-磺酰胺制备标题化合物((53mg,38%)。
1H NMR(600MHz,CD3OD)δ7.79(d,J=1.76Hz,1H),7.76(d,J=8.51Hz,1H),7.67(d,J=7.92Hz,1H),7.57(d,J=0.59Hz,1H),7.37(ddd,J=1.17,7.19,8.36Hz,1H),7.26-7.31(m,1H),7.20-7.24(m,1H),7.15(dd,J=1.76,8.51Hz,1H),3.40-3.50(m,2H),2.60-2.72(m,2H),2.01(s,6H).
化合物239
N-{5-氟-2-[(3-硝基苄基)亚磺酰基]苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序C,由N-(5-氟-2-((3-硝基苄基)硫基)苯基)苯并呋喃-2-磺酰胺制备标题化合物(174mg,79%)。
1H NMR(600MHz,CD3OD)δ7.98(d,J=9.10Hz,1H),7.67(d,J=7.63Hz,1H),7.49(br.s.,1H),7.40(s,1H),7.35(d,J=8.51Hz,1H),7.26-7.32(m,2H),7.21-7.26(m,2H),7.12(d,J=7.63Hz,1H),6.74-6.80(m,1H),6.40(t,J=7.34Hz,1H),4.52-4.64(m,2H).
化合物240
N-{2-[(3-氨基苄基)亚磺酰基]-5-氯苯基}-2,4-二氟苯磺酰胺
按照一般程序A、B、C和K,由2-氨基-4-氯-苯硫醇、1-溴甲基-3-硝基-苯和2,4-二氟-苯磺酰氯制备标题化合物。
1H NMR(600MHz,甲醇-d4)δ7.95(d,J=6.16Hz,1H),7.19-7.30(m,3H),7.11-7.19(m,2H),7.00(t,J=7.78Hz,1H),6.72(dd,J=1.47,7.92Hz,1H),6.61(s,1H),6.44(d,J=7.04Hz,1H),4.34(d,J=12.91Hz,1H),4.07(d,J=12.90Hz,1H).
化合物241
N-[5-氯-2-(甲基磺酰基)苯基]-4-异丙基苯磺酰胺
按照一般程序B和D,由5-氯-2-(甲基硫基)苯胺和4-异丙基-苯磺酰氯制备标题化合物。
1H NMR(600MHz,氯仿-d)δ9.13(s,1H),7.80-7.85(m,2H),7.71-7.76(m,2H),7.34-7.39(m,2H),7.16(dd,J=2.05,8.51Hz,1H),2.95(spt,J=6.90Hz,1H),2.81(s,3H),1.22(d,J=7.04Hz,6H).
化合物242
N-(5-甲氧基-2-((3-硝基苄基)硫基)苯基)苯并呋喃-2-磺酰胺
按照一般程序B,由5-甲氧基-2-((3-硝基苄基)硫基)苯胺(450mg,1.552mmol)和苯并呋喃-2-磺酰氯(335mg,1.552mmol)在吡啶(5ml)中制备标题化合物(406mg,56%)。
1H NMR(600MHz,CD3OD)δ8.53(dd,J=1.76,5.87Hz,1H),7.96(ddd,J=1.03,2.27,8.14Hz,1H),7.70(d,J=7.92Hz,1H),7.63(t,J=1.91Hz,1H),7.51(s,1H),7.42(dd,J=1.17,8.22Hz,1H),7.24-7.37(m,3H),7.11(s,1H),7.00(s,1H),6.55(dd,J=2.79,8.66Hz,1H),3.83(s,2H),3.71(s,3H).
化合物243
N-{5-氯-2-[(1H-吡唑-3-基甲基)磺酰基]苯基}-1-苯并呋喃-2-磺酰胺
按照一般程序D和E,由3-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}硫基)甲基]-1H-吡唑-1-羧酸叔丁酯(化合物22)制备标题化合物。
1H NMR(600MHz,CD3OD)δ7.71(d,J=1.76Hz,1H),7.66(d,J=7.92Hz,1H),7.51(d,J=8.51Hz,1H),7.31-7.43(m,4H),7.24-7.29(m,1H),6.79(d,J=7.04Hz,1H),5.82(br.s.,1H),4.99(br.s.,2H).
化合物244
N-{2-[(3-氨基苄基)硫基]-5-氯苯基}-4-氯-2-氟苯磺酰胺
按照一般程序A、B和K,由2-氨基-4-氯-苯硫醇、1-溴甲基-3-硝基-苯和4-氯-2-氟-苯磺酰氯制备标题化合物。
1H NMR(600MHz,氯仿-d)δ7.84(t,J=8.22Hz,1H),7.47(d,J=2.05Hz,1H),7.25(dt,J=1.03,8.51Hz,1H),7.17-7.22(m,2H),7.04(t,J=7.63Hz,1H),6.93(dd,J=2.35,8.22Hz,1H),6.58(dt,J=1.17,7.92Hz,1H),6.40-6.45(m,2H),3.72(s,2H).
生物学数据
将稳定表达CCR2的HEK-Gqi5细胞培养在(DMEM高葡萄糖、10%FBS、1%PSA、400μg/ml遗传霉素和50μg/ml潮霉素中。合适的阳性对照趋化因子(MCP-1、MIP1A或RANTES)用作阳性对照激动剂,以用于筛选在FLIPRTetra上测定的化合物诱导的钙活性。在384-孔微板中使用EP3和MultiPROBE机器人液体处理系统制备药物板。合成化合物,并测试其的CCR2活性。
表1示出CCR2受体的活性:(IC50)nM
表1
Claims (9)
1.一种具有式I的化合物,其对映异构体、非对映异构体、水合物、溶剂化物、晶型及单独的同分异构体、互变异构体或其药学上可接受的盐:
其中:
R1是H;
R2是甲基、N,N-二甲基丙酰胺基团或3-硝基苄基;
R5是-S-、-S(O)-或-S(O)2-;
R6是4-氯-3-三氟甲基-苯基、3,4-二氯苯基、4-甲基-3-硝基苯基或2-苯并呋喃基;
R17是H;
R18是H;
R7是氯、甲氧基或氟;
R8是H;
且包括以下化合物:
{6-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}硫基)甲基]吡啶-2-基}氨基甲酸叔丁酯;
{6-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}磺酰基)甲基]吡啶-2-基}氨基甲酸叔丁酯;
3-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}硫基)甲基]-1H-吡唑-1-羧酸叔丁酯;和
苯并呋喃-2-磺酸[2-(3-硝基-苄基硫烷基)-苯基]-酰胺。
2.根据权利要求1所述的化合物,其中:
R5是S。
3.根据权利要求1所述的化合物,其中:
R5是-S(O)-。
4.根据权利要求1所述的化合物,其中:
R5是-S(O)2-。
5.根据权利要求1所述的化合物,选自:
3,4-二氯-N-[5-氯-2-(甲基硫基)苯基]苯磺酰胺;
{6-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}硫基)甲基]吡啶-2-基}氨基甲酸叔丁酯;
{6-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}磺酰基)甲基]吡啶-2-基}氨基甲酸叔丁酯;
3-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}硫基)甲基]-1H-吡唑-1-羧酸叔丁酯;
3-{[4-氯-2-({[4-氯-3-(三氟甲基)苯基]磺酰基}氨基)苯基]亚磺酰基}-N,N-二甲基丙酰胺;
N-(5-氟-2-((3-硝基苄基)硫基)苯基)苯并呋喃-2-磺酰胺;
N-(5-甲氧基-2-((3-硝基苄基)磺酰基)苯基)苯并呋喃-2-磺酰胺;
苯并呋喃-2-磺酸[2-(3-硝基-苄基硫烷基)-苯基]-酰胺;
N-(5-氯-2-((2-硝基苄基)硫基)苯基)苯并呋喃-2-磺酰胺;
N-[5-氯-2-(甲基亚磺酰基)苯基]-4-甲基-3-硝基苯磺酰胺;和
N-(5-甲氧基-2-((3-硝基苄基)硫基)苯基)苯并呋喃-2-磺酰胺。
6.一种药物组合物,包含作为活性成分的治疗有效量的根据权利要求1所述的化合物和药学上可接受的佐剂、稀释剂或载体。
7.根据权利要求6所述的药物组合物,其中所述化合物选自:
3,4-二氯-N-[5-氯-2-(甲基硫基)苯基]苯磺酰胺;
{6-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}硫基)甲基]吡啶-2-基}氨基甲酸叔丁酯;
{6-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}磺酰基)甲基]吡啶-2-基}氨基甲酸叔丁酯;
3-[({2-[(1-苯并呋喃-2-基磺酰基)氨基]-4-氯苯基}硫基)甲基]-1H-吡唑-1-羧酸叔丁酯;
3-{[4-氯-2-({[4-氯-3-(三氟甲基)苯基]磺酰基}氨基)苯基]亚磺酰基}-N,N-二甲基丙酰胺;
N-(5-氟-2-((3-硝基苄基)硫基)苯基)苯并呋喃-2-磺酰胺;
N-(5-甲氧基-2-((3-硝基苄基)磺酰基)苯基)苯并呋喃-2-磺酰胺;
苯并呋喃-2-磺酸[2-(3-硝基-苄基硫烷基)-苯基]-酰胺;
N-(5-氯-2-((2-硝基苄基)硫基)苯基)苯并呋喃-2-磺酰胺;
N-[5-氯-2-(甲基亚磺酰基)苯基]-4-甲基-3-硝基苯磺酰胺;和
N-(5-甲氧基-2-((3-硝基苄基)硫基)苯基)苯并呋喃-2-磺酰胺。
8.一种药物组合物用于制备治疗有此需要的哺乳动物中与趋化因子受体调节相关的病症的药剂的用途,其中所述药物组合物包含治疗有效量的至少一种权利要求1的式I化合物。
9.如权利要求8所述的用途,其中所述病症为眼部炎症性疾病或皮肤炎症性疾病。
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