CN103097353A - 新型免疫调节剂和抗炎化合物 - Google Patents
新型免疫调节剂和抗炎化合物 Download PDFInfo
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- CN103097353A CN103097353A CN2011800287307A CN201180028730A CN103097353A CN 103097353 A CN103097353 A CN 103097353A CN 2011800287307 A CN2011800287307 A CN 2011800287307A CN 201180028730 A CN201180028730 A CN 201180028730A CN 103097353 A CN103097353 A CN 103097353A
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- phenylformic acid
- base carbamyl
- biphenyl
- unsubstituted
- substituted
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Classifications
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Abstract
本发明提供了二氢乳清酸脱氢酶抑制剂(I)、其制备方法、含有其的药物组合物和治疗、预防和/或改善其中已知所述二氢乳清酸脱氢酶的抑制显示出有益效果的疾病或病症的方法。
Description
本申请要求2010年5月6日提交的印度临时专利申请No.1265/CHE/2009的权益,该临时申请据此通过引用并入。
发明领域
本发明提供了二氢乳清酸脱氢酶抑制剂、其制备方法、含有其的药物组合物和治疗、预防和/或改善其中已知所述二氢乳清酸脱氢酶的抑制显示出有益效果的疾病或病症的方法。
发明背景
最近,过去的大量研已经致力于发现和理解与各种疾病相关的酶和生物分子的结构和功能。已经成为大量研究的对象的这样一个重要酶类为二氢乳清酸脱氢酶(DHODH)。
DHODH是催化嘧啶从头生物合成的第四个步骤的酶。DHODH将二氢乳清酸(DHO)转化为乳清酸(ORO)。人DHODH是普遍存在的黄素单核苷酸(FMN)部分黄素蛋白。在细菌(基因pyrD)中,DHODH位于胞质膜内部。在一些酵母中,例如在酿酒酵母(Saccharomycescerevisiae)(基因URA1)中,DHODH为胞质蛋白,而在其它真核生物中,其存在于线粒体中(见Proc.Natl.Acad.Sci.U.S.A.,89(19),8966-8970)。
已经在辅因子的基础上将DHODH分为I类或II类蛋白家族。人DHODH属于2类家族,与使用延胡索酸盐或NAD+代替的细菌家族1类蛋白不同,2类家族利用黄素作为氧化还原辅因子。在细胞中哺乳动物蛋白锚定在内部线粒体小叶上。在那里,DHODH催化DHO转化为ORO,这表示嘧啶从头生物合成的限速步骤。(见McLean等,Biochemistry 2001,40,2194-2200)。动力学研究表明了DHO转化为ORO的顺序乒乓机制(见Knecht等Chem.Biol.Interact.2000,124,61-76)。第一个半反应包括DHO还原为ORO。电子转移至FMN,FMN开始氧化为二氢黄素单核苷酸(FMNH2)。ORO从酶上解离后,由从线粒体内膜募得的泛醌分子再生FMNH2。动力学和结构研究分别显示了DHO/ORO和泛醌的两个不同结合位点。
人DHODH由通过扩张环连接的两个结构域构成,一个大C端结构域(Met78-Arg396)和一个较小N端结构域(Met30-Len68)。大C端结构域可被充分描述为具有被8个α螺旋围绕的8个平行β链的中心桶的α/β桶状折叠。由底物结合袋和结合辅因子FMN的位点形成的氧化还原位点位于该大C端结构域上。另一方面,小N端结构域由两个均通过短环连接的α螺旋(标记为α1和α2)组成。该小N端结构域容纳辅因子泛醌的结合位点。在所谓的疏水补丁中螺旋α1和α2跨过约的槽,而短α1-α2环在所述槽的窄端。槽形成在α1-α2环附近的FMN腔处结束的隧道的入口。该隧道向近端氧化还原位点缩小并且以若干带电或极生侧链(Gln47、Tyr356、Thr360和Arg136)结束。如以上所讨论,连同动力学研究的结构线索表明,可容易地扩散至线粒体内膜中的泛醌使用该隧道靠近FMN辅因子进行氧化还原反应(见Baumgartner等,J.Med.Chem.2006,49,1239-1247)。
The Journal of Biological Chemistry 2005,280(23),21847-21853中公开的研究正式证明了鉴定不抑制人体酶的恶性疟原虫(P.falciparum)DHODH的有效抑制剂的可能性。比较人DHODH晶体结构和疟疾DHODH氨基酸序列进一步表明,有机会结合物种特异性抑制剂。
在体内,DHODH催化合成细胞生长所必需的嘧啶。抑制DHODH抑制了快速增殖细胞的生长(病理学上),然而以正常速度生长的细胞可从正常代谢循环中获得其需要的嘧啶碱基。免疫反应最重要的细胞类型淋巴细胞专门利用嘧啶的合成以便其生长并且特别敏感地对DHODH抑制起反应。
DHODH抑制导致核糖核苷酸单磷酸尿苷(rUMP)的细胞水平下降,从而将增殖细胞阻滞于细胞周期的G1期。鉴于观察到当该途径阻断时淋巴细胞似乎不能进行克隆扩张,抑制嘧啶核苷酸从头合成引起人们很大的兴趣。抑制淋巴细胞生长的物质是治疗自身免疫性疾病的重要药物。
稳态增殖期间,不依赖于DHODH的补救途径似乎足以对细胞供给嘧啶碱基。只不过,周转率高的细胞,尤其是T和B淋巴细胞需要从头途径以增殖。在这些细胞中,DHODH抑制终止了细胞周期进展,抑制了DNA合成并因此抑制了细胞增殖(见Breedveld等,AnnRheum Dis 2000)。
因此,在特征为细胞增殖异常且不可控,引起慢性炎症和组织破坏的人类疾病中,DHODH的抑制剂显示出有益的免疫抑制剂和抗增殖效应。人体酶二氢乳清酸脱氢酶(DHODH)表示表征清楚的小分子量解疾病的抗风湿性药物(DMARD)的靶标。
一系列的已知DHODH抑制剂包括来氟米特、特立氟胺、布喹那(NSC 368390)(Cancer Research 1992,52,3521-3527)、二氯烯丙基散沫花素(The Journal of Biological Chemistry 1986,261(32),14891-14895)、长刺酸模(Maritimus)(FK 778)(Drugs of the Future 2002,27(8),733-739)和Redoxal(The Journal of Biological Chemistry 2002,277(44),41827-41834),
来氟米特 特立氟胺 布喹那
二氯烯丙基散沫花素 长刺酸模 Redoxal
主要研究了来氟米特、特立氟胺和布喹那。
一般而言,DHODH的抑制剂显示出有益的免疫抑制和抗增殖活性,对T细胞最显著(见Fairbanks等,J.Biol.Chem.1995,270,29682-29689)。布喹那和来氟米特是已经在临床上研究的DHODH小分子量抑制剂的两个实例。后者用于治疗难以用甲氨蝶呤治疗的类风湿性关节炎(见Rozman J.Rheumatol Suppl.1998,53,27-31;Pally等,Toxicology 1998,127,207-222)。两种分子的临床应用经受了各种副作用。在动物模型中疗效非常好的基础上,最初研发布喹那用于治疗器官移植排斥,但是转为癌症,作为继发性适应症。由于其治疗窗窄,化合物在临床上失败。当与环孢霉素组合给药时,口服施用布喹那及其一些类似物引起毒性作用,包括白细胞减少和血小板减少。来氟米特大约2周的长半衰期可能使得应用来氟米特有缺陷,这表示对已经出现副作用的患者的严重妨碍(见Fox等J.Rheumatol Suppl.1998,53,20-26;Alldred等,Expert Opin.Pharmacother.2001,2,125-137)。
除了消除淋巴细胞增殖外,DHODH抑制剂(例如,特立氟胺、长刺酸模(FK778)和布喹那)通过抑制细胞因子生成和核因子(NF)-κB-信号、单核细胞迁移和转化生长因子β-1的生成增多具有抗炎作用并且诱导1型辅助T细胞(TM)转化为2型(Th2)亚群分化(Manna等,J.Immunol 2000;Dimitrova等,J.Immunol 2002)。此外,通过DHODH抑制减少了核因子κB配体(RANKL)的受体激活剂介导的破骨细胞分化(Urushibara等,Arthrititis Rheum 2004)。在用两种DHODH抑制剂进行的达到临床试验的共结晶实验中,发现布喹那(Dexter等,CancerRes.1985)和特立氟胺(A77-1726)均在共同位点结合,即也认为是辅因子泛醌的结合位点(Liu等,Struc.Fold.Des.2000)。
以商品名称Arava(EP 0 780 128,WO 97/34600)出售的来氟米特是进入市场的第一种DHODH抑制剂。来氟米特是特立氟胺的前药,特立氟胺是以中等效能抑制人DHODH的活性代谢产物(Fox等,J.Rheumatol.Suppl.1998)。
来氟米特是来自Aventis的DMARD,其于1998年经FDA批准用于治疗类风湿性关节炎并且于2004年经EMEA批准用于治疗牛皮癣性关节炎。目前,来氟米特正处于积极开发中,以用于治疗全身性红斑狼疮、韦格纳氏肉芽肿病(Metzler等,Rheumatology 2004,43(3),315-320)和HIV感染。而且,来氟米特的活性代谢产物特立氟胺对多发性硬化有效并且目前正处于III期临床试验中(O′Connor等,Neurology 2006)。
在其它密切相关的疾病,例如强直性脊柱炎(Haibel等,Ann.Rheum.Dis.2005)、多关节型幼年特发性关节炎(Silverman等,ArthritisRheum.2005)和结节病(Baughman等,Sarcoidosis Vase.Diffuse LungDis.2004)中不断出现其它数据。此外,来氟米特和FK778已经显示出对巨细胞病毒的抗病毒活性。目前将来氟米特表示为器官移植后巨细胞病毒疾病的二线疗法(John等,Transplantation 2004)。另外,在可用常规剂量获得的浓度下,来氟米特减少HIV复制约75%(Schlapfer等,AIDS 2003)。
处于临床试验不同阶段的调查研究中的DHODH抑制剂为来自4SC AG的4SC-101(II期);来自Almirall Laboratories SA的LAS-186323(I期)和来自Active Biotech AB的ABR-224050、ABR-222417&ABR-214658(临床前)。所有这些分子的确切结构尚未揭示。
已经公开了各种DHODH抑制剂用于治疗或预防自身免疫性疾病、免疫和炎症性疾病、破坏性骨病、恶性肿瘤疾病、血管生成相关疾病、病毒性疾病和感染性疾病。见例如,WO2009137081、WO2009133379、WO2009021696、WO2009082691、WO2009029473、WO2009153043、US2009209557、US2009062318、US2009082374、WO2008097180、WO2008077639、US2008027079、US2007299114、US2007027193、US2007224672、WO2007149211、JP2007015952、WO2006044741、WO2006001961、WO2006051937、WO2006038606、WO2006022442、US2006 199856、WO2005075410、US7074831、WO2004056797、US7247736、WO2004056747、WO2004056746、JP2004099586、WO2003097574、WO2003030905、WO2003006425、WO2003 006424、US2003203951、WO2002080897、US7176241、US7423057、WO2001024785、US 6841561、WO9945926、WO9938846、WO9941239、EP767167和US5976848。
关于DHODH抑制剂另外的评论和文献,见Bio & Med.Chem.Letters,20(6),2010,第1981-1984页;J.Med.Chem.2009,52,2683-2693;J.Med.Chem.2008,51(12),3649-3653。所有这些出版物、专利申请和文献公开内容均整体并入本文中作为参考以用于所有目的。
尽管在人类疾病的DHODH抑制领域取得进展,但是在副作用和来自小分子抑制剂的预期临床受益方面仍存在挑战。因此,对用于治疗和/或改善已知与DHODH相关的疾病和病症的小分子DHODH抑制剂的需要仍未得到满足并且迫切需要。
发明概述
本发明涉及式(I)的化合物、其制备方法、包含其的药物组合物及其使用方法。式(I)的化合物具有结构:
或其互变异构体、立体异构体(例如对映异构体或非对映异构体)、药学上可接受的盐、药学上可接受的酯、前药或N-氧化物,其中
环A独立地选自经取代或未经取代的单环芳基和经取代或未经取代的单环杂芳基,其中每次出现的X独立地为CR4或N;
环B独立地选自经取代或未经取代的单环芳基和经取代或未经取代的单环杂芳基,其中每次出现的X1独立地为CR4或N;
R为氢、经取代或未经取代的(C1-6)烷基或-ORa;
R1选自-OH、-NRaOH、-COOH、-COORa、-CRaRbOH、-CRaRbCOOH、-SO2Ra、-CRaRbSO2Ra、-SO3Ra、-CRaRb-SO3Ra、-C(=Y)-NRaRb和-S(=O)q-NRaRb或-COOH基的电子等排体,例如SO3H、CONHOH、B(OH)2、PO3RaRb、SO2NRaRb、四唑、酰胺、酯或酸酐或任选地表示卤素、经取代或未经取代的(C1-6)烷基或Cy1;
X2为N或CR2并且X3为N或CR3,其中R2和R3可相同或不同并且独立地选自氢、卤素、经取代或未经取代的(C1-6)烷基或经取代或未经取代的(C1-6)烷氧基;
L1和L2独立地不存在或选自-(CRaRb)n-、-O-、-S(=O)q-、-NRa-、-C(=Y)-、-C(=Y)-CRaRb、-CRaRb-C(=Y)-、-C(=Y)-C(=Y)-、-CRaRb-Y-、-C(=Y)-NRaRb-、-S(=O)q-NRaRb-、-NRaRb--C(=Y)-、-NRaRb-S(=O)q-、经取代或未经取代的(C1-2)烷基、经取代或未经取代的(C2)烯基和经取代或未经取代的(C2)炔基;任选地,经取代或未经取代的(C1-2)烷基、经取代或未经取代的(C2)烯基和经取代或未经取代的(C2)炔基的每一个可被-O-、-C(=Y)-、-S(=O)q-和-NRa-间隔;
Cy选自经取代或未经取代的环烷基、经取代或未经取代的杂环基团、经取代或未经取代的芳基和经取代或未经取代的杂芳基;
Cy1选自经取代或未经取代的单环烷基、经取代或未经取代的单环杂环基团、经取代或未经取代的单环芳基和经取代或未经取代的单环杂芳基;
R4独立地选自氢、羟基、卤素、氰基、-ORa、-S(=O)q-Ra、-NRaRb、-C(=Y)-Ra、-C(=Y)-ORa、-C(=Y)-NRaRb、-S(=O)q-NRaRb、经取代或未经取代的烷基、经取代或未经取代的烯基、经取代或未经取代的炔基、经取代或未经取代的环烷基、经取代或未经取代的环烷基烷基、经取代或未经取代的环烯基,或当存在两个R4取代基时,它们可连接形成经取代或未经取代的饱和或不饱和3-10元环,所述环可任选地包括可相同或不同并且选自O、NRa或S的杂原子,或可选地,当芳环上两个R4取代基相互处于邻位时,它们可连接形成经取代或未经取代的饱和或不饱和4-10元环,所述环可任选地包括可相同或不同并且选自O、NRa或S的一个或多个杂原子;
每次出现的Ra和Rb可相同或不同并且独立地选自氢、卤素、羟基、氰基、经取代或未经取代的(C1-6)烷基、-ORc(其中Rc为经取代或未经取代的(C1-6)烷基)或当Ra和Rb与共同原子直接结合时,它们可连接形成氧代基(=O)或形成经取代或未经取代的饱和或不饱和3-10元环,所述环可任选地包括可相同或不同并且选自O、NRa或S的杂原子;
每次出现的Y独立地选自O、S和NRa;
每次出现的n独立地表示整数0、1、2、3或4;并且
每次出现的q独立地表示整数0、1或2。
本发明的一些化合物以不同互变异构体形式出现。例如,环A可包括互相转化为-C(O)-NH-并再次转化回-C(OH)=N-的-C(OH)=N-基团。
又一实施方案为具有式(I)的化合物,其中环A选自
,其任选地经一个或多个R4取代。
又一实施方案为具有式(I)的化合物,其中R1为-COOH,
又一实施方案为具有式(I)的化合物,其中每次出现的Y为O。
又一实施方案为具有式(I)的化合物,其中环A和基团-N(R)-之间的变量Y为O。
又一实施方案为具有式(I)的化合物,其中R为H。
又一实施方案为具有式(I)的化合物,其中每次出现的X为CH、C-Cl或C-F。
又一实施方案为具有式(I)的化合物,其中每次出现的X1为CH、N或CF。
又一实施方案为具有式(I)的化合物,其中每次出现的X2为CH、N、CCl或CF。
又一实施方案为具有式(I)的化合物,其中每次出现的X3为CH、N、CCl或CF。
又一实施方案为具有式(I)的化合物,其中环B选自
,其任选地经一个或多个R4取代。
又一实施方案为具有式(I)的化合物,其中L1和L2不存在。
又一实施方案为具有式(I)的化合物,其中L1不存在而L2为-O-CRaRb。
又一实施方案为具有式(I)的化合物,其中Cy选自
,其各自任选地经一个或多个R4取代。
在一个优选实施方案中,环A为苯基,环B为苯基,Cy为苯基或3-乙基-1H-吲哚-5-基,R1为-COOH,Y为O,L1不存在且L2不存在。在一个更优选的实施方案中,Cy为经一个或多个C1-C4烷氧基、-S-(C1-C4烷基)和/或卤素取代的苯基。在一个更优选的实施方案中,环B为经一个或多个氟基取代的苯基。
又一实施方案为式(IA)的化合物
或其互变异构体、立体异构体(例如对映异构体或非对映异构体)、药学上可接受的盐、药学上可接受的酯、前药或N-氧化物,其中
环A选自
,其任选地经一个或多个R4取代,并且R1独立地选自-OH、-NRaOH、-COOH、-COORa或-COOH基的电子等排体,例如SO3H、CONHOH,B(OH)2、PO3RaRb、SO2NHRa、四唑、酰胺、酯或酸酐;
环B选自
,其任选地经一个或多个R4取代,
并且所有其它变量与以上关于式(I)所述相同。
又一实施方案为式(IA)的化合物
或其互变异构体、立体异构体(例如对映异构体或非对映异构体)、药学上可接受的盐、药学上可接受的酯、前药或N-氧化物,其中
环A选自
环B选自
,其任选地经一个或多个R4取代;
L2不存在或为O-CRaRb-;
Cy为经取代的苯基、经取代的吲哚或经取代的吲唑,例如
并且所有其它变量与以上关于式(I)所述相同。
本发明的代表性化合物包括以下指定的化合物及其药学上可接受的盐(表1)。不得将本发明视为限于这些化合物。
1.2-(3,5-二氟-3′-甲氧基联苯-4-基氨甲酰基)苯甲酸
2.2-(3,5-二氟-3′-甲氧基联苯-4-基氨甲酰基)苯磺酸
3.2-(6-(3-甲氧基苯基)吡啶-3-基氨甲酰基)苯甲酸
4.2-(3′-乙氧基-3-氟联苯-4-基氨甲酰基)苯甲酸
5.2-(3′-乙氧基-3,5-二氟联苯-4-基氨甲酰基)苯甲酸
6.3-(3,5-二氟-3′-甲氧基联苯-4-基氨甲酰基)吡嗪-2-羧酸
7.3-(3,5-二氟-3′-乙氧基联苯-4-基氨甲酰基)吡嗪-2-羧酸
8.2-(2′-氯-3,5-二氟联苯-4-基氨甲酰基)苯甲酸
9.3-[3′-(苄氧基)-3,5-二氟联苯-4-基氨甲酰基]吡嗪-2-羧酸
10.2-(3,5-二氟联苯-4-基氨甲酰基)苯甲酸
11.3-(3-氯-3′-乙氧基-5-氟联苯-4-基氨甲酰基)吡嗪-2-羧酸
12.2-[3,5-二氟-3′-(三氟甲氧基)联苯-4-基氨甲酰基]苯甲酸
13.2-[3′-(苄氧基)-3,5-二氟联苯-4-基氨甲酰基]苯甲酸
14.4,5-二氯-2-(3-氯-3′-乙氧基-5-氟联苯-4-基氨甲酰基)苯甲酸
15.2-(3-氯-3′-乙氧基-5-氟联苯-4-基氨甲酰基)苯甲酸
16.4,5-二氯-2-(3,5-二氟-3′-甲氧基联苯-4-基氨甲酰基)苯甲酸
17.4,5-二氯-2-(3′-乙氧基-3,5-二氟联苯-4-基氨甲酰基)苯甲酸
18.2-(3,5-二氯-3′-甲氧基联苯-4-基氨甲酰基)苯甲酸
19.2-(3-氯-5-氟-3′-丙氧基联苯-4-基氨甲酰基)苯甲酸
20.2-(3-氯-2′,5-二氟联苯-4-基氨甲酰基)苯甲酸
21.2-(3,5-二氯-3′-乙氧基联苯-4-基氨甲酰基)苯甲酸
22.2-[3-氟-3′-(三氟甲氧基)联苯-4-基氨甲酰基]苯甲酸
23.2-[2′-氟-3-(三氟甲氧基)联苯-4-基氨甲酰基]苯甲酸
24.2-(3,5-二氯-2′-氟联苯-4-基氨甲酰基)苯甲酸
25.2-(3,5-二氟-3′-异丙氧基联苯-4-基氨甲酰基)苯甲酸
26.2-(3,5-二氟-3′-丙氧基联苯-4-基氨甲酰基)苯甲酸
27.4,5-二氯-2-(2′,3-二氯-5-氟联苯-4-基氨甲酰基)苯甲酸
28.4,5-二氯-2-(2′,3-二氯-5-氟联苯4-基氨甲酰基)苯甲酸
29.4,5-二氯-2-(2′,3-二氯-5-氟联苯-4-基氨甲酰基)苯甲酸
30.4,5-二氯-2-(2′-氯-3,5-二氟联苯-4-基氨甲酰基)苯甲酸
31.2-(3-氯-5-氟-3′-异丁氧基联苯-4-基氨甲酰基)苯甲酸
32.2-(2′,3,5-三氟联苯-4-基氨甲酰基)苯甲酸
33.2-(2′,3,5-三氯联苯-4-基氨甲酰基)苯甲酸
34.2-(3,5-二氟-3′-异丁氧基联苯-4-基氨甲酰基)苯甲酸
35.2-(3-丁氧基-3,5-二氟联苯-4-基氨甲酰基)苯甲酸
36.N-(3-氯-3′-乙氧基-5-氟联苯-4-基)-2-(羟甲基)苯甲酰胺
37.N-(3′-乙氧基-3,5-二氟联苯-4-基)-2-(羟甲基)苯甲酰胺
38.2-(3-氯-3′-乙氧基-5-氟联苯-4-基氨甲酰基)-6-氟苯甲酸
39.2-[3-氯-5-氟-3′-(三氟甲氧基)联苯-4-基氨甲酰基]苯甲酸
40.2-[4-(苄氧基)-2,6-二氟苯基氨甲酰基]苯甲酸
41.2-[3′-(环戊氧基)-3,5-二氟联苯-4-基氨甲酰基]苯甲酸
42.2-(3-氯-3′-(环戊氧基)-5-氟联苯-4-基氨甲酰基)苯甲酸
43.2-[3′-(二氟甲氧基)-3,5-二氟联苯-4-基氨甲酰基]苯甲酸
44.2-[3-氯-3′-(二氟甲氧基)-5-氟联苯-4-基氨甲酰基]苯甲酸
45.2-(2′-氯-3,5-二氟-5′-甲氧基联苯-4-基氨甲酰基)苯甲酸
46.2-(3,3′,5-三氟-5′-甲氧基联苯-4-基氨甲酰基)苯甲酸
47.2-[4-(苯并[d][1,3]间二氧杂环戊烯-5-基)-2,6-二氟苯基氨甲酰基]苯甲酸
48.2-[4-(苯并[d][1,3]间二氧杂环戊烯-5-基)-2-氯-6-氟苯基氨甲酰基]苯甲酸
49.2-(3,5-二氟-3′,4′-二甲基基联苯-4-基氨甲酰基)苯甲酸
50.2-(3,3′,5-三氟-5′-甲氧基联苯-4-基氨甲酰基)苯甲酸
51.2-(3,3′-二氯-5-氟-5′-甲氧基联苯-4-基氨甲酰基)苯甲酸
52.2-[4-(2,3-二氢苯并呋喃-5-基)-2,6-二氟苯基氨甲酰基]苯甲酸
53.2-[2-氯-4-(2,3-二氢苯并呋喃-5-基)-6-氟苯基氨甲酰基]苯甲酸
54.2-[4-(1,3-二甲基-1H-吲唑-5-基)-2,6-二氟苯基氨甲酰基]苯甲酸
55.2-(3′-氯-3,5-二氟-5′-甲氧基联苯-4-基氨甲酰基)苯甲酸
56.2-(3-氯-5-氟-3′,4′-二甲基基联苯-4-基氨甲酰基)苯甲酸
57.2-(2′,3-二氯-5-氟-5′-甲氧基联苯-4-基氨甲酰基)苯甲酸
58.2-(2′,3,5-三氟-5′-甲氧基联苯-4-基氨甲酰基)苯甲酸
59.2-(4′-氯-3,5-二氟-3′-甲氧基联苯-4-基氨甲酰基)苯甲酸
60.2-(3,4′-二氯-5-氟-3′-甲氧基联苯-4-基氨甲酰基)苯甲酸
61.2-(3-氯-2′,5-二氟-5′-甲氧基联苯-4-基氨甲酰基)苯甲酸
62.2-(3,4′,5-三氟-3′-甲氧基联苯-4-基氨甲酰基)苯甲酸
63.2-[2,6-二氟-4-(3-甲基-1H-吲哚-5-基)苯基氨甲酰基]苯甲酸
64.2-[2,6-二氟-4-(3-甲基-1H-吲唑-5-基)苯基氨甲酰基]苯甲酸
65.2-(3-氯-3′-乙基-5-氟联苯-4-基氨甲酰基)苯甲酸
66.2-(3-氯-3′-乙氧基-2′,5-二氟联苯-4-基氨甲酰基)苯甲酸
67.2-[2-氯-4-(2,3-二氢苯并[b][1,4]二噁英-6-基)-6-氟苯基氨甲酰基]苯甲酸
68.2-[3-氯-5-氟-3′-(2,2,2-三氟乙氧基)联苯-4-基氨甲酰基]苯甲酸
69.2-(3-氟-3′-甲氧基联苯-4-基氨甲酰基)苯甲酸
70.2-(3′-乙氧基联苯-4-基氨甲酰基)苯甲酸
71.2-[3′-(乙硫基)-3,5-二氟联苯-4-基氨甲酰基]苯甲酸
72.2-[3′-(乙基亚磺酰基)-3,5-二氟联苯-4-基氨甲酰基]苯甲酸
73.2-(3′-环丙氧基-3,5-二氟联苯-4-基氨甲酰基)苯甲酸
74.2-(3′-乙氧基-3,5-二氟联苯-4-基氨甲酰基)-6(5)-甲基苯甲酸
75.2-[4-(3-乙基-1H-吲哚-5-基)-2,6-二氟苯基氨甲酰基]苯甲酸
76.2-(3′-乙氧基-3,5-二氟联苯-4-基氨甲酰基)烟酸
77.4-(3′-乙氧基-3,5-二氟联苯-4-基氨甲酰基)烟酸
78.2-[3′-(乙硫基)-2,3,5,6-四氟联苯-4-基氨甲酰基]苯甲酸
79.2-(2′-氯-2-氟-5′-甲氧基联苯-4-基氨甲酰基)苯甲酸
80.2-(3-氟-3′-丙氧基联苯-4-基氨甲酰基)苯甲酸
81.2-(3′-丙氧基联苯-4-基氨甲酰基)苯甲酸
82.2-[3′-(乙硫基)-2-氟联苯-4-基氨甲酰基]苯甲酸
83.2-[3,5-二氟-3′-(2,2,2-三氟乙氧基)联苯-4-基氨甲酰基]苯甲酸
84.2-(3′-乙基-3,5-二氟联苯-4-基氨甲酰基)苯甲酸
85.2-(联苯-4-基氨甲酰基)苯甲酸
86.2-(2′-氯联苯-4-基氨甲酰基)苯甲酸
87.2-(3′-甲氧基联苯-4-基氨甲酰基)苯甲酸
88.2-[3′-(三氟甲氧基)联苯-4-基氨甲酰基]苯甲酸
89.2-[3′-(乙硫基)-2,6-二氟联苯-4-基氨甲酰基]苯甲酸
90.2-(3′-乙基联苯-4-基氨甲酰基)苯甲酸
91.2-(3′-丁氧基-2,3,5,6-四氟联苯-4-基氨甲酰基)苯甲酸
92.2-(3′-丁氧基-3-氟联苯-4-基氨甲酰基)苯甲酸
93.2-[3,5-二氟-3′-(三氟甲氧基)联苯-4-基氨甲酰基]苯甲酸
94.2-(3′-环丙氧基-3-氟联苯-4-基氨甲酰基)苯甲酸
95.2-(3′-环丙氧基联苯-4-基氨甲酰基)苯甲酸
96.2-(3′-丁氧基联苯-4-基氨甲酰基)苯甲酸
97.2-(3′-丁氧基-2-氟联苯-4-基氨甲酰基)苯甲酸
98.2-(3′-丁氧基-2,6-二氟联苯-4-基氨甲酰基)苯甲酸
99.2-[2,6-二氟-4-(3-丙基-1H-吲哚-5-基)苯基氨甲酰基]苯甲酸
100.2-[2-氯-4-(3-乙基-1H-吲哚-5-基)-6-氟苯基氨甲酰基]苯甲酸
又一实施方案为通过向患者施用有效量的式(I)或/和(IA)的化合物抑制有需要的患者体内的DHODH的方法。
又一实施方案为通过向患者施用有效量的式(I)或/和(IA)的化合物抑制有需要的患者体内的IL-17的方法。
具体而言,式(I)或/和(IA)的化合物或其药学上可接受的盐是治疗、预防和/或改善其中已知DHODH的抑制显示出有益效果的疾病或病症有用的DHODH抑制剂。
本发明的另一实施方案为通过向需要此类治疗的患者施用有效量的如以上定义的式(I)或/和(IA)的至少一种化合物以抑制DHODH,从而治疗免疫性病症、炎症性病症、癌症或其它增生性疾病的方法。
本发明的另一实施方案为通过向需要此类治疗的患者施用有效量的如以上定义的式(I)或/和(IA)的至少一种化合物以直接抑制IL-17或抑制DHODH,从而治疗免疫性病症、炎症性病症、癌症或其它增生性疾病的方法。
本发明的另一实施方案为通过向需要此类治疗的患者施用有效量的如以上定义的式(I)或/和(IA)的至少一种化合物以抑制IL-17以及DHODH,从而治疗免疫性病症、炎症性病症、癌症或其它增生性疾病的方法。
本发明的另一实施方案为通过向需要此类治疗的患者施用有效量的如以上定义的式(I)或/和(IA)的至少一种化合物与至少一种其它抗炎剂、免疫调节剂或抗癌剂的组合(同时或依次)以抑制DHODH,从而治疗免疫性病症、炎症性病症、癌症或其它增生性疾病的方法。
式(I)或/和(IA)的化合物用于治疗多种病症,包括但不限于自身免疫性疾病、免疫和炎症性疾病、破坏性骨病、癌症和恶性肿瘤疾病、血管生成相关疾病、病毒性疾病和感染性疾病。此类病症包括但不限于:
可预防(预防性)或治疗的自身免疫性疾病包括但不限于类风湿性关节炎、牛皮癣性关节炎、全身性红斑狼疮、多发性硬化、牛皮癣、强直性脊柱炎、韦格纳氏肉芽肿病(Wegener′sgranulomatosis)、多关节型幼年特发性关节炎、炎症性肠病(例
如溃疡性结肠炎和克罗恩氏病(Crohn′s disease))、莱特尔氏综合征(Reiter′s syndrome)、纤维肌痛和1型糖尿病。可预防(预防性)或治疗的免疫和炎症性疾病包括但不限于哮喘、COPD、呼吸窘迫综合征、急性或慢性胰腺炎、移植物抗宿主病、慢性结节病、移植排斥、接触性皮炎、特应性皮炎、变应性鼻炎、变应性结膜炎、贝赛特氏综合征(syndrome)、炎症性眼病(例如结膜炎和葡萄膜炎)。
可预防(预防性)或治疗的癌症和恶性肿瘤疾病包括但不限于前列腺癌、卵巢癌和脑癌。癌,包括膀胱癌、乳腺癌、结肠癌、肾癌、肝癌、肺癌(包括小细胞肺癌)、食道癌、胆囊癌、卵巢癌、胰腺癌、胃癌、宫颈癌、甲状腺癌和皮肤癌(包括鳞状细胞癌);淋巴细胞系的造血肿瘤,包括白血病、急性淋巴细胞白血病、急性成淋巴细胞性白血病、B细胞淋巴瘤、T细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、毛细胞淋巴瘤和伯奇氏淋巴瘤;骨髓细胞系的造血肿瘤,包括急慢性骨髓性白血病、骨髓增生异常综合征和前髓细胞性白血病;间叶细胞来源的肿瘤,包括纤维肉瘤和横纹肌肉瘤;中枢和外周神经系统的肿瘤,包括星细胞瘤、神经母细胞瘤、神经胶质瘤和神经鞘瘤;和其它肿瘤,包括黑素瘤、精原细胞瘤、畸胎癌、骨肉瘤、着色性干皮病、角化棘皮瘤滤、泡性甲状腺癌和卡波西肉瘤。
作为细胞凋亡调节剂的本发明化合物用于治疗癌症(包括但不限于上文提到的那些类型)、病毒性感染(包括但不限于疱疹病毒、痘病毒、爱波斯坦-巴尔病毒(Epstein-Barr virus)、辛德华斯病毒和腺病毒(Sindbis virus and adenovirus)),预防HIV感染个体的AIDS发展、自身免疫性疾病(包括但不限于全身性红斑狼疮、自身免疫介导的肾小球性肾炎、类风湿性关节炎、牛皮癣、炎症性肠病和自身免疫性糖尿病)、神经退行性疾病(包括但不限于阿耳茨海默氏病(Alzheimer′sdisease)、AIDS相关痴呆、帕金森氏症(Parkinson′s disease)、肌萎缩性侧索硬化、色素性视网膜炎、脊髓性肌萎缩和小脑变性)、骨髓增生异常综合征、再生障碍性贫血、与心肌梗塞、中风和再灌注损伤相关的缺血性损伤、心律不齐、动脉粥样硬化、毒素诱导或酒精相关的肝病、血液病(包括但不限于慢性贫血和再生障碍性贫血)、肌肉骨骼系统的退行性疾病(包括但不限于骨质疏松症和关节炎)、阿司匹林敏感性鼻窦炎、囊肿性纤维化、多发性硬化、肾病和癌性疼痛。
本发明的化合物可调节细胞RNA和DNA合成的水平。因此这些试剂用于治疗病毒性感染(包括但不限于HIV、人乳头瘤病毒、疱疹病毒、痘病毒、爱波斯坦-巴尔病毒、辛德华斯病毒和腺病毒)。
本发明的化合物用于癌症的化学预防。化学预防定义为通过阻断发起诱变事件或通过阻断已经经受损伤的癌前细胞进展来抑制浸润性癌发展或抑制肿瘤复发。化合物还用于抑制肿瘤血管生成和转移。
在治疗其中已知DHODH的抑制显示出有益效果的疾病时本发明的化合物也可与其它活性化合物组合。
在其它实施方案中,受益于DHODH的抑制的疾病、病状或病症包括但不限于免疫系统相关疾病(例如,自身免疫性疾病)、牵涉炎症的疾病或病症(例如,哮喘、慢性阻塞性肺疾病、类风湿性关节炎、炎症性肠病、神经炎症性疾病、多发性硬化、葡萄膜炎和免疫系统病症)、癌症或其它增生性疾病、肝脏疾病或病症、肾脏疾病或病症。
在一个实施方案中,本文所述化合物用作免疫抑制剂以预防移植排斥、同种异体或异种移植排斥(器官、骨髓、干细胞、其它细胞和组织)和移植物抗宿主病。在其它实施方案中,移植排斥由组织或器官移植产生。在更多实施方案中,移植物抗宿主病由骨髓或干细胞移植产生。
更特别的是,式(I)或/和(IA)的化合物用于治疗多种炎症性疾病,包括但不限于炎症、肾小球性肾炎、葡萄膜炎、肝脏疾病或病症、肾脏疾病或病症、慢性阻塞性肺疾病、类风湿性关节炎、炎症性肠病、脉管炎、皮炎、骨关节炎、炎症性肌肉疾病、变应性鼻炎、阴道炎、间质性膀胱炎、硬皮病、骨质疏松症、湿疹、同种异体或异种移植排斥、移植物抗宿主病、角膜移植排斥、红斑狼疮、全身性红斑狼疮、增生性狼疮性肾炎、I型糖尿病、肺纤维化、皮肌炎、甲状腺炎、重症肌无力、自身免疫性溶血性贫血、囊肿性纤维化、慢性复发性肝炎、原发性胆汁性肝硬变、变应性结膜炎、肝炎和特应性皮炎、哮喘和干燥综合征。
在一个实施方案中,本文所述化合物用于治疗多种疾病,包括但不限于费尔蒂综合征(Felty’s syndrome)、韦格纳氏肉芽肿病、克罗恩氏病、结节病、斯蒂尔病(Still’s disease)、类天疱疮、大动脉炎、全身性硬化症、复发性多软骨炎、顽固性IgA肾病、SAPHO2综合征(SAS)、巨细胞病毒感染(包括鼻炎或囊肿)、牛皮癣和多发性骨髓瘤。
本发明进一步提供了包含具有式(I)或/和(IA)的化合物和药学上可接受的载体的药物组合物。
发明详述
除非另有定义,本文所用的所有技术和科学术语具有与所要求保护的主题所属领域中通常所理解的相同含义。在本文术语有多种定义的情况下,以本节的定义为准。参考URL或其它如标识符或地址时,应了解此类标识符通常会发生变化并且网上的特定信息并不恒定,但是通过网络搜索找到了等效信息。对等效信息的参考证明了此类信息的可用性和公开传播。
应了解,前面的一般性描述和以下的详细描述仅为示例性和说明性并不限制所要求保护的任何主题。在本申请中,除非另有特别说明,单数的使用包括复数。必须注意的是,除非上下文另外明确指出,和用于说明书和所附权利要求中一样,单数形式“一个”、“一种”和“所述”包括复数个指示物。在本申请中,除非另有说明,“或”的使用指“和/或”。此外,术语“包括(including)”以及其它形式例如“包括(include)”“包括(includes)”和“包括(includes)”的使用并非限制性的。
在参考文献中找到了标准化学和分子生物学术语的定义,包括但不限于Carey和Sundberg″ADVANCED ORGANIC CHEMISTRY第4版″,第A(2000)和B(2001)卷,Plenum Press,New York and″MOLECULAR BIOLOGY OF THE CELL第5版″(2007),GarlandScience,New York。除非另外指出,质谱分析、NMR、HPLC、蛋白质化学、生物化学、重组DNA技术和药理学常规方法涵盖在本文公开的实施方案范围之内。
除非提供了特定定义,通常使用连同本文所述分析化学和医药化学采用的命名法及其实验室程序和技术。在一些实施方案中,标准技术用于化学分析、药物制备、配制和递送和患者的治疗。在其它实施方案中,标准技术用于重组DNA、寡核苷酸合成和组织培养和转化(例如,电穿孔、脂质转染)。在某些实施方案中,例如,使用厂商规格或如本文所述的试剂盒进行反应和纯化。前述技术和程序通常通过常规方法进行并且如遍及本说明书引用和讨论的各种一般性和更特定的参考文献中所述。
如本文所使用,除非另外指出,以下定义应适用。进一步地,本文定义的许多基团可被任选地取代。定义中列出的取代基为示例性的,不得视为限制说明书其它地方定义的取代基。
术语‘烷基’指仅由碳和氢原子组成,不含不饱和度,具有1-8个碳原子并且通过单键与分子的其余部分连接的直链或支链烃基,例如甲基、乙基、正丙基、1-甲基乙基(异丙基)、正丁基、正戊基和1,1-二甲基乙基(叔丁基)。
术语经取代或未经取代的(C1-2)烷基指如以上所定义的具有多达2个碳原子的烷基,而术语经取代或未经取代的(C1-6)烷基指如以上所定义的具有多达6个碳原子的烷基。
术语“烯基”指含有碳-碳双键,可为具有约2至约10个碳原子的直链或支链的脂肪族烃基,例如乙烯基、1-丙烯基、2-丙烯基(烯丙基)、异丙烯基、2-甲基-1-丙烯基、1-丁烯基和2-丁烯基。
术语经取代或未经取代的(C2)烯基指如以上所定义的具有2个碳原子的烯基。
术语“炔基”指具有至少一个碳-碳三键并且具有2至12个碳原子的直链或支链烃基(目前优选具有约2至10个碳原子的基团),例如乙炔基、丙炔基和丁炔基。
术语经取代或未经取代的(C2)炔基指如以上所定义的具有2个碳原子的炔基。
术语“烷氧基”指如以上所定义的通过氧键与分子的其余部分连接的烷基。这些基团的代表性实例为-OCH3和-OC2H5。
术语“环烷基”指约3-12个碳原子的非芳香族单环或多环环系,例如环丙基、环丁基、环戊基和环己基。多环环烷基的实例包括全氢奈基、金刚烷基和降莰基、桥环基团和螺双环基团,例如螺(4,4)壬-2-基。
术语“环烷基烷基”指含有3-8个直接与烷基连接的碳原子,然后与来自烷基的引起产生稳定结构的任何碳处的主体结构连接的含环基团,例如环丙基甲基、环丁基乙基和环戊基乙基。
术语“环烯基”指含有3-8个碳原子,具有至少一个碳-碳双键的含环基团,例如环丙烯基、环丁烯基和环戊烯基。术语“环烯基烷基”指直接与烷基连接,然后与来自烷基的引起产生稳定结构的任何碳处的主体结构连接的环烯基。
术语“芳基”指具有6至20个碳原子的芳香族基团,例如苯基、奈基、四氢奈基、茚满基和联苯。
术语“芳基烷基”指如以上所定义的直接与以上所定义的烷基键合的芳基,例如-CH2C6H5和-C2H5C6H5。
术语“杂环”指由碳原子和至少一个选自氮、磷、氧和硫的杂原子组成的非芳香族3-15元环基团。为了本发明的目的,杂环基团可为单环、双环、三环或四环环系,所述环系可包括稠环、桥环或螺环环系,并且杂环基团中的氮、磷、碳、氧或硫原子可任选地氧化为各种氧化态。另外,氮原子可任选地季铵化。杂环基团可与引起产生稳定结构的任何杂原子或碳原子处的主体结构连接。
术语“杂芳基”指具有一个或多个选自N、O和S的杂原子作为环原子的任选取代的5-14元芳环。杂芳基可为单环、双环或三环环系。此类杂芳基环基团的实例包括但不限于噁唑基、噻唑基、咪唑基、吡咯基、呋喃基、吡啶基、嘧啶基、吡嗪基、苯并呋喃基、吲哚基、苯并噻唑基、苯并噁唑基、咔唑基、喹啉基和异喹啉基。杂芳基环基团可与引起产生稳定结构的任何杂原子或碳原子处的主体结构连接。
此类“杂环”或“杂芳基”基团的实例包括但不限于氮杂环丁烷基、吖啶基、苯并二氧杂环戊烯基、苯并二噁烷基、苯并呋喃基、咔唑基、噌啉基、二氧戊环基、吲哚嗪基、萘啶基、全氢化氮杂卓基(perhydroazepinyl)、吩嗪基、吩噻嗪基、吩噁嗪基、酞嗪基、吡啶基、蝶啶基、嘌呤基、喹唑啉基、喹喔啉基、喹啉基、异喹啉基、四唑基、咪唑基、四氢异喹啉基、哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、2-氧代氮杂卓基、氮杂卓基、吡咯基、4-哌啶酮基、吡咯烷基、吡嗪基、嘧啶基、哒嗪基、噁唑基、噁唑啉基、噁唑烷基、三唑基、茚满基、异噁唑基、异噁唑烷基、吗啉基、噻唑基、噻唑啉基、四氢噻唑基、异噻唑基、奎宁环基、异四氢噻唑基、吲哚基、异吲哚基、吲哚啉基、异吲哚啉基、八氢吲哚基、八氢异吲哚基、喹啉基、异喹啉基、十氢异喹啉基、苯并咪唑基、噻二唑基、苯并吡喃基、苯并噻唑基、苯并噁唑基、呋喃基、四氢呋喃基、四氢吡喃基、噻吩基、苯并噻吩基、硫杂吗啉基、硫杂吗啉基亚砜、硫杂吗啉基砜、二氧磷杂环戊烷基、噁二唑基、苯并二氢吡喃基和异苯并二氢吡喃基。
术语“杂芳基烷基”指如以上所定义的直接与烷基键合的杂芳基环基团。杂芳基烷基可与来自烷基的引起产生稳定结构的任何碳原子处的主体结构连接。
术语“杂环基”指如以上所定义的杂环基团。杂环基环基团可与引起产生稳定结构的任何杂原子或碳原子处的主体结构连接。
术语“杂环基烷基”指如以上所定义的直接与烷基键合的杂环基团。杂环基烷基可与烷基中引起产生稳定结构的碳原子处的主体结构连接。
术语“环”指含有3-10个碳原子的环,任选地环碳原子中的一个或多个可被杂原子,例如N、O或S原子替换。
术语“单环”指含有3-10个碳原子的单个环,任选地环碳原子中的一个或多个可被杂原子,例如N、O或S原子替换。
使用的前缀“单环”,例如单环芳基,指其中芳基如以上多定义的单个芳基环。类似地,术语单环杂芳基指其中杂芳基如以上多定义的单个杂芳基环。同样也适用于术语单环环烷基和单环杂环的每一个。
除非另有说明,术语“经取代”指用以下任一取代基或任何组合取代并且可相同或不同,所述一个或多个取代基选自氢、羟基、卤素、羧基、氰基、硝基、氧代(=O)、硫代(=S)、经取代或未经取代的烷基、经取代或未经取代的烷氧基、经取代或未经取代的烯基、经取代或未经取代的炔基、经取代或未经取代的环烷基、经取代或未经取代的环烯基、经取代或未经取代的环烷基烷基、经取代或未经取代的环烯基烷基、经取代或未经取代的杂环、经取代或未经取代的杂环基烷基、经取代或未经取代的芳基、经取代或未经取代的芳基烷基、经取代或未经取代的杂芳基、经取代或未经取代的杂芳基烷基、经取代或未经取代的胍、-COORx、-C(O)Rx、-C(S)Rx、-C(O)NRxRy、-C(O)ONRxRy、-NRyRz、-NRxCONRyRz、-N(Rx)SORy、-N(Rx)SO2Ry、-(=N-N(Rx)Ry)、-NRxC(O)ORy、-NRxRy、-NRxC(O)Ry-、-NRxC(S)Ry-NRxC(S)NRyRz、-SONRxRy-、-SO2NRxRy-、-ORx、-ORxC(O)NRyRz、-ORxC(O)ORy-、-OC(O)Rx、-OC(O)NRxRy、-RxNRyC(O)Rz、-RxORy、-RxC(O)ORy、-RxC(O)NRyRz、-RxC(O)Rx、-RxOC(O)Ry、-SRx、-SORx、-SO2Rx、-ONO2,其中以上每个基团中的Rx、Ry和Rz可为氢、经取代或未经取代的烷基、经取代或未经取代的烷氧基、经取代或未经取代的烯基、经取代或未经取代的炔基、经取代或未经取代的环烷基、经取代或未经取代的环烯基、经取代或未经取代的环烷基烷基、经取代或未经取代的环烯基烷基、经取代或未经取代的杂环、经取代或未经取代的杂环基烷基、经取代或未经取代的芳基、经取代或未经取代的芳基烷基、经取代或未经取代的杂芳基、经取代或未经取代的杂芳基烷基,或Rx、Ry和Rz的任两个可连接形成经取代或未经取代的饱和或不饱和3-10元环,所述环可任选地包括可相同或不同并且选自O、NRX或S的杂原子。本发明预想到的取代基或取代基组合优选为引起形成稳定或化学可行的化合物的取代基或取代基组合。如本文所使用的术语稳定指当化合物或结构经受允许其生成、检测和优选其恢复、纯化和并入药物组合物的条件时,大体上不变。
术语“卤素”或“卤代”指氟、氯、溴和碘基团。
术语“保护基”或“PG”指用于防碍或保护特定官能团的取代基。化合物上的其它官能团可保持反应性。例如,“氨基保护基”是化合物中与氨基连接,防碍或保护氨基官能团的取代基。适合的氨基保护基包括但不限于乙酰基、三氟乙酰基、叔丁氧基羰基(BOC)、苄氧基羰基(CBz)和9-芴基亚甲氧基羰基(Fmoc)。类似地,“羟基保护基”指妨碍或保护羟基官能团的羟基取代基。适合的羟基保护基包括但不限于乙酰基和甲硅烷基。“羧基保护基”指妨碍或保护羧基官能团的羧基取代基。适合的羧基保护基包括但不限于-CH2CH2SO2Ph、氰基乙基、2-(三甲基甲硅烷基)乙基、2-(三甲基甲硅烷基)乙氧基甲基、-2-(对甲苯磺酰基)乙基、2-(对硝基苯亚磺酰)乙基、2-(二苯基膦基)-乙基和硝基乙基。保护基及其用途的一般性描述,见T.W.Greene,Protective Groupsin Organic Synthesis,John Wiley & Sons,New York,1991。
术语“立体异构体”指具有相同化学组成,但是在原子和基团在空间上的排列方面不同的化合物。这些立体异构体包括对映异构体、非对映异构体、几何异构体、阻转异构体或构象异构体。
本文所述化合物的所有立体异构体均在本发明范围之内。外消旋混合物也涵盖在本发明范围之内。因此,本化合物的单立体化学异构体以及对映异构体、非对映异构体和几何(或构象)异构体混合物属于本发明的范围。
术语“互变异构体”指特征在于异构体形式相对易于平衡地相互转化的化合物。这些异构体旨在通过本发明转化。
术语“前药”指为化合物的非活性前体,在体内通过正常代谢过程转化为其活性形式的化合物。
术语“酯”指通过酸和醇之间反应,除去水形成的化合物。酯可用式RCOOR′表示。
另外,本发明还包括仅在一个或多个同位素富集原子的存在方面不同,例如用氘等取代氢的化合物。
形成本发明的一部分的药学上可接受的盐包括由无机碱衍生的盐,例如Li、Na、K、Ca、Mg、Fe、Cu、Zn和Mn;有机碱的盐,例如N,N′-二乙酰基乙二胺、葡糖胺、三乙胺、胆碱、氢氧化物、二环己基胺、二甲双胍、苄胺、三烷基胺、硫胺等;手性碱,如烷基苯胺、甘氨醇和苯甘氨醇,天然氨基酸的盐例如甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、正亮氨酸、酪氨酸、胱氨酸、半胱氨酸、蛋氨酸、脯氨酸、羟基脯氨酸、组氨酸、鸟氨酸、赖氨酸、精氨酸和丝氨酸;具有烷基卤化物和烷基硫酸盐(例如MeI和(Me)2SO4)的本发明化合物的季铵盐,非天然氨基酸,例如D-异构体或经取代的氨基酸;胍、经取代的胍,其中取代基选自硝基、氨基、烷基、烯基、炔基、铵或经取代的铵盐和铝盐。盐可能包括酸加成盐,其中适当的为硫酸盐、硝酸盐、磷酸盐、高氯酸盐、硼酸盐、氢卤化物、醋酸盐、酒石酸盐、马来酸盐、柠檬酸盐、延胡索酸盐、琥珀酸盐、巴莫酸盐、甲烷磺酸盐、苯甲酸盐、水杨酸盐、苯磺酸盐、抗坏血酸盐、甘油磷酸盐和酮戊二酸盐。药学上可接受的溶剂可为水合物或包含其它结晶溶剂,例如醇。
另外,本发明还包括仅在一个或多个同位素富集原子的存在方面不同,例如用氘替换氢的化合物。
术语“受试者”或“患者”涵盖哺乳动物和非哺乳动物。哺乳动物的实例包括但不限于哺乳动物纲的任何成员:人、非人灵长类例如黑猩猩和其它猿和猴物种;饲养动物,例如牛、马、绵羊、山羊和猪;家畜,例如兔子、狗和猫;和实验室动物,包括啮齿动物,例如大鼠、小鼠和豚鼠。非哺乳动物的实例包括但不限于鸟、鱼等。在本文提供的方法和组合物的一个实施方案中,哺乳动物为人。
如本文所使用,术语“治疗”包括减轻、缓和或改善疾病、病症或病状症状,预防另外的症状,改善或预防症状的潜在病因,抑制疾病、病症或病状,例如阻止疾病、病症或病状的发展,缓解疾病、病症或病状,引起疾病、病症或病状消退,缓解疾病、病症或病状引起的状况,或预防性和/或治疗性终止疾病、病症或病状的症状。
如本文所使用,“改善”指改善疾病或病状或至少部分缓解疾病或病状相关的症状并且如本文所使用,通过施用特殊化合物或药物组合物改善特殊疾病、病症或病状的症状指归因于或与化合物或组合物的施用有关的任何减轻严重程度、延迟发作、减缓进展或缩短持续时间(永久性或暂时性、持久性或瞬时性)。
如本文所使用,术语“抑制”或DHODH的“抑制剂”指酶DHODH的抑制。
如本文所使用,用“药学上可接受的”指物质,例如载体或稀释剂,并未取消化合物的生物学活性或性质,并且相对无毒,即,向个体施用所述物质,不会引起不良生物学作用或以有害方式与含有所述物质的组合物的任何组分相互作用。
术语“药物组合物”指如本文所述能够抑制DHODH的化合物与其它化学组分,例如载体、稳定剂、稀释剂、分散剂、悬浮剂、增稠剂和/或赋形剂的混合物。药物组合物利于向微生物施用所述化合物。可通过各种施用途径施用本发明的化合物和药物组合物,包括但不限于静脉内、口服、气溶胶、肠胃外、眼部、肺部和局部施用。
如本文所使用,术语“有效量”或“治疗有效量”指施用的会使治疗的疾病或病状的一种或多种症状缓解至一定程度的试剂或化合物的足够量。结果是疾病的病征、症状或病因减少和/或减轻,或生物系统的任何其它预期改变。例如,作治疗用的“有效量”是在疾病症状方面提供临床显著减少所需的包括能够如本文所述抑制DHODH的化合物的组合物的量。在一些实施方案中,任何个案中适当的“有效”量使用例如剂量递增研究的技术确定。
术语“载体”,如本文所使用,指促进化合物并入细胞或组织中的相对无毒的化合物或试剂。
术语“稀释剂”指递送之前用于稀释目标化合物的化学化合物。在一些实施方案中,因为稀释剂提供更稳定的环境,所以将稀释剂用于稳定化合物。利用溶于缓冲溶液(也提供pH控制或维持)中的盐作为稀释剂,包括但不限于磷酸盐缓冲盐水溶液。
如本文所使用,术语“免疫”包括免疫系统的细胞和在免疫反应中产生功能或活性的细胞,例如但不限于T细胞、B细胞、淋巴细胞、巨噬细胞、树突细胞、嗜中性粒细胞、嗜酸性细胞、嗜碱细胞、肥大细胞、浆细胞、白血细胞、抗原呈递细胞和自然杀伤细胞。
如本文所使用,“细胞因子”指由细胞分泌的在一些实施方案中改变分泌细胞或另一种细胞的行为或性质的可溶性小蛋白。细胞因子与细胞因子受体结合并且触发细胞内的行为或性质,例如细胞增殖、死亡或分化。示例性细胞因子包括但不限于白细胞介素(例如,IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-11、IL-12、IL-13、IL-15、IL-16、IL-17、IL-18、IL-1α、IL-1β和IL-1RA)、粒细胞集落刺激因子(G-CSF)、粒细胞-巨噬细胞集落刺激因子(GM-CSF)、制瘤素M、红细胞生成素、白血病抑制因子(LIF)、干扰素、B7.1(也称为CD80)、B7.2(也称为B70、CD86)、TNF家族成员(TNF-α、TNF-β、LT-β、CD40配体、Fas配体、CD27配体、CD30配体、4-1BBL、Trail)和MIF。
本发明的化合物还用于和已知的免疫调节剂和/或抗炎剂组合(一起或依次施用)用于治疗自身免疫性疾病、免疫和炎症性疾病、破坏性骨病、恶性肿瘤疾病、血管生成相关疾病、病毒性疾病和感染性疾病,例如
■抗TNF-α单克隆抗体,例如英夫利昔(Infliximab)、赛妥珠单抗(Certolizumab pegol)、戈利木单抗(Golimumab)、阿达木单抗(Adalimumab)和来自Applied Molecular Evolution的AME-527,
■抗代谢物化合物,例如咪唑立宾(Mizoribine)、环磷酰胺和硫唑嘌呤,
■钙调磷酸酶(PP-2B)抑制剂/INS表达抑制剂,例如环孢霉素A、他克莫司(Tacrolimus)和来自Isotechnika的ISA-247,
■环氧合酶抑制剂,例如醋氯芬酸、双氯芬酸、塞来昔布(Celecoxib)、罗非昔布(Rofecoxib)、依托考昔(Etoricoxib)、伐地昔布(Valdecoxib)、罗美昔布(Lumiracoxib)、西米考昔(Lumiracoxib)和来自Laboratorios Almirall,S.A.的LAS-34475,
■TNF-α拮抗剂,例如依那西普(Etanercept)、来那西普(Lenercept)、奥那西普(Onercept)和培那西普(Pegsunercept),
■NF-κB(NFKB)活化抑制剂,例如柳氮磺胺吡啶和艾拉莫德(Iguratimod),
■IL-1受体拮抗剂,例如阿那白滞素和来自Amgen的AMG-719,
■二氢叶酸还原酶(DHFR)抑制剂,例如甲氨蝶呤、氨喋呤和来自Chelsea的CH-1504,
■次黄嘌呤核苷5′-单磷酸脱氢酶(IMPDH)的抑制剂,例如咪唑立宾、利巴韦林(Ribavirin)、噻唑呋林(Tiazofurin)、阿米替韦(Amitivir)、麦考酚酸吗乙酯、利巴咪定(Ribamidine)和美泊地布(Merimepodib),
■糖皮质激素,例如强的松龙、甲基强的松龙、地塞米松、皮质醇、氢化可的松、丙酮缩去炎松、氟轻松、醋酸肤轻松、氯可托龙、醋丙氢可的松、磺庚甲泼尼龙,
■倍他米松丁酸丙酸酯、泼尼松、δ脱氢可的松、强的松、地塞米松磷酸钠、去炎松、戊酸倍他米松、倍他米松、氢化可的松琥珀酸钠、强的松龙磷酸钠、丙丁氢化可的松和二氟泼尼酯,
■抗CD20单克隆抗体,例如利妥昔单抗、奥法木单抗(Ofatumumab)、奥瑞珠单抗(Ocrelizumab)、维妥珠单抗(Veltuzumab)和来自Trubion Pharmaceuticals的TRU-015,
■靶向B细胞的疗法,例如BLYSS、BAFF和TACI-Ig,
■p38抑制剂,例如AMG-548(来自Amgen)、ARRY-797(来自Array Biopharma)、氯甲噻唑乙二磺酸盐、多马莫德(Doramapimod)、PS-540446、BMS-582949(来自BMS)、SB-203580、SB-242235、SB-235699、SB-281832、SB-681323、SB-856553(全部来自GlaxoSmithKline)、KC-706(来自Kemia)、LEO-1606、LEO-15520(全部来自Leo)、SC-80036、SD-06、PH-797804(全部来自Pfizer)、RWJ-67657(来自R.W.Johnson)、RO-3201195,、RO-4402257(全部来自Roche)、AVE-9940(来自Aventis)、SCIO-323、SCIO-469(全部来自Scios)、TA-5493(来自Tanabe Seiyaku)和VX-745、VX-702(全部来自Vertex)。
■Jak3抑制剂,例如来自Pfizer的CP690550、R-348
■Syk抑制剂,例如全部来自Rigel的R-112、R-406和福他替尼(Fostamatinib)(R-788),
■MEK抑制剂,例如ARRY-142886、ARRY-438162(全部来自Array Biopharma)、AZD-6244(来自AstraZeneca)、PD-098059、PD-0325901(全部来自Pfizer)、AR-119、AS703026
■P2X7受体拮抗剂,例如来自AstraZeneca的AZD-9056,
■S1 P1激动剂,例如芬戈莫德(Fingolimod)、来自Sankyo的CS-0777和来自Actelion的R-3477、来自Novartis的ONO-4641和KRP-203,
■抗CD49单克隆抗体,例如那他珠单抗(Natalizumab),
■整联蛋白抑制剂,例如西仑吉肽(Cilengitide)、非拉司特(Firategrast)、盐酸伐拉格特(Valategrast hydrochloride)、SB-273005、SB-683698(全部来自Glaxo)、来自Sanofi-Aventis的HMR-1031、来自Roche的R-1295、来自BMS的BMS-587101和来自UCB Celltech的CDP-323,
■抗CD88单克隆抗体,例如依库丽单抗(Eculizumab)和培克珠单抗(Pexelizumab),
■IL-6受体拮抗剂,例如来自InKine的CBP-1011和来自Amgen的C-326,
■(w)抗IL-6单克隆抗体,例如艾西莫单抗(Elsilimomab)、来自Centocor的CNTO-328和来自Vaccinex的VX-30,
■抗CD152单克隆抗体,例如伊匹单抗(lpilimumab)和曲美木单抗(Ticilimumab),
■包含与人免疫球蛋白G1的一部分连接的人细胞毒素T-淋巴细胞相关抗原4(CTLA-4)的细胞外结构域的融合蛋白,例如阿巴西普(Abatacept),
■用于治疗骨病的试剂,例如双膦酸盐(例如替鲁膦酸二钠、氯屈膦酸二钠、帕米膦酸二钠、依替膦酸二钠、Xydiphone(K1Na盐))、阿仑膦酸钠、奈立膦酸、二甲基-APD、奥帕膦酸钠盐、米诺膦酸、阿坡胺(Apomine)、伊班膦酸氢氧化钠和利塞膦酸钠,
■VEGF Try激酶抑制剂,例如哌加他尼钠(Pegaptaniboctasodium)、琥珀酸瓦他拉尼(Vatalanib succinate),
■索拉非尼(Sorafenib)、凡德他尼(Vandetanib)、苹果酸舒尼替尼(Sunitinib malate)、西地尼布(Cediranib)、盐酸帕唑帕尼(Pazopanib hydrochloride)和来自AEterna Zentaris的AE-941,
■对自身免疫性疾病有效的其它化合物,例如金盐、羟基氯奎宁、青霉胺、K-832、SMP114和AD452,
■嘌呤核苷磷酸化酶抑制剂,例如盐酸氟达拉滨(Forodesinehydrochloride)、来自Albert Einstein College of Medicine的R-3421、均来自Pfizer的CI-972和CI-1000,
■抗RANKL单克隆抗体,例如地诺单抗(Denosumab),
■抗CD25单克隆抗体,例如伊诺莫单抗(Inolimomab)、达昔单抗(Dacliximab)、巴利昔单抗(Basiliximab)和来自美国国家癌症研究所的LMB-2,
■组蛋白脱乙酰酶(HDAC)抑制剂,例如双丙戊酸钠、乙酰地那林、缩酯环肽、丁酸钠、苯丁酸钠、伏立诺他(Vorinostat)、来自Mitsui的MS-27-275、丙戊酸、吡啶基辛二酰胺、三丁酸甘油酯、来自Topo Target的PX-105684、来自MethylGene的MG-0103、来自TopoTarget的G2M-777和来自Celera的CG-781,和
■抗集落刺激因子(GM-CSF)单克隆抗体,例如来自KaloBios的KB-002。
本发明的化合物用于治疗类风湿性关节炎、牛皮癣性关节炎、强直性脊柱炎、多发性硬化、韦格纳氏肉芽肿病、全身性红斑狼疮、牛皮癣和结节病,可有利的是将本发明的化合物与已知对治疗此类疾病,例如类风湿性关节炎、牛皮癣性关节炎、强直性脊柱炎、多发性硬化、韦格纳氏肉芽肿病、全身性红斑狼疮、牛皮癣和结节病有用的其它活性化合物组合使用。
本发明的组合可用于治疗疾病和/或病症,其中已知DHODH的抑制显示出有益效果。因此,本申请涵盖了治疗这些病症的方法以及本发明组合在用于治疗这些病症的药物的制备中的用途。
本发明的化合物还用于和已知的抗癌治疗(例如放射疗法)或与细胞抑制剂或细胞毒素剂或抗癌剂组合(一起或依次施用),例如但不限于DNA交互剂,例如顺铂或阿霉素;拓扑异构酶II抑制剂,例如依托泊苷;拓扑异构酶I抑制剂,例如CPT-11或拓扑替康;自然存在或合成的微管蛋白交互剂,例如紫杉醇、多西他赛埃坡霉素(例如伊沙匹隆);激素剂,例如它莫西芬;胸苷酸合成酶抑制剂,例如5-氟尿嘧啶;和抗代谢物,例如甲氨蝶呤,其它酪氨酸激酶抑制剂,例如易瑞沙和OSI-774;血管生成抑制剂;EGF抑制剂;VEGF抑制剂;CDK抑制剂;SRC抑制剂;c-Kit抑制剂;Her1/2抑制剂和针对生长因子受体的单克隆抗体,例如爱必妥(EGF)和赫塞汀(Her2)以及其它蛋白激酶调节剂。
在一些实施方案中,使用本文公开的能够抑制DHODH的化合物、其组合物和本文提供用于鉴定能够抑制DHODH的化合物的方法治疗或预防的疾病、病症或病状包括牵涉炎症和/或与免疫系统相关的疾病、病状或病症。这些疾病包括但不限于哮喘、慢性阻塞性肺疾病、类风湿性关节炎、炎症性肠病、肾小球性肾炎、神经炎症性疾病(例如多发性硬化)和免疫系统紊乱。
因此,在一些实施方案中,DHODH的抑制产生一种治疗免疫和免疫相关病症的方法,包括例如,慢性免疫疾病/病症、急性免疫疾病/病症、自身免疫和免疫缺陷疾病/病症、牵涉炎症的疾病/病症、器官移植排斥和移植物抗宿主病和免疫反应改变(例如,极度活跃)。
免疫性病症的实例包括牛皮癣、类风湿性关节炎、脉管炎、炎症性肠病、皮炎、骨关节炎、哮喘、炎症性肌肉疾病、变应性鼻炎、阴道炎、间质性膀胱炎、硬皮病、骨质疏松症、湿疹、同种异体或异种移植(器官、骨髓、干细胞、其它细胞和组织)排斥、移植物抗宿主病、红斑狼疮、炎症性疾病、I型糖尿病、肺纤维化、皮肌炎、干燥综合征、甲状腺炎(例如,桥本氏甲状腺炎和自身免疫性甲状腺炎)、重症肌无力、自身免疫性溶血性贫血、多发性硬化、囊肿性纤维化、慢性复发性肝炎、原发性胆汁性肝硬变、变应性结膜炎和特应性皮炎。
在其它实施方案中,本文公开的能够抑制DHODH的化合物、其组合物和本文提供用于鉴定能够调节DHODH抑制剂的化合物的方法连同恶性肿瘤的治疗一起使用,包括但不限于淋巴网状内皮细胞来源的恶性肿瘤、膀胱癌、乳腺癌、结肠癌、子宫内膜癌、头颈癌、肺癌、黑素瘤、卵巢癌、前列腺癌和直肠癌。DHODH被认为在癌细胞的细胞增殖中起重要作用。
本文描述的以下一般方法提供了制备和使用本发明化合物的方式和过程并且为说明性而非限制性。也可设计提供的方法论的进一步修改和另外的新方法以便实现和服务于本发明的目的。因此,应了解,可能有其它实施方案属于说明书对此定义的本发明精神和范围之内。
本发明化合物制备的一般方法
可通过以下方法制备本发明的化合物。除非另外指出,当变量(例如A、B、Cy、R1、R、Y、L1、X、X1、X2、X3和L2)用于下列公式时,应理解为呈现以上关于式(I)-(IA)所述的基团。
方案1:该方案提供了一种制备式(I)化合物的方法,其中A为经取代或未经取代的单环芳基和经取代或未经取代的单环杂芳基并且其它变量,例如B、Cy、R1、R、Y、L1、X、X1、X2、X3和L2与以上关于式(I)所述的相同。
方案1
可使用酰胺偶联剂(例如DCC)或任选地在适合碱的存在下使其中Lg为离去基团(例如羟基或卤素)的式(1)化合物与适合溶剂中的式(2)化合物偶联,以产生中间产物(例如R1为COOEt),然后可一步或分多步将中间产物转化为式(I)的所需化合物,例如转化为R1为COOH,其中A为经取代或未经取代的单环芳基或经取代或未经取代的单环杂芳基并且其它变量,例如L、B、Cy、R2、R3、R4、m和n与以上关于式(I)所述的相同。
方案2:该方案提供了一种制备式(I)化合物的方法,其中R1为COOH,L2不存在,并且其它变量例如A、B、Cy、R1、R、Y、L1、X、X1、X2和X3与以上关于式(I)所述的相同。
方案2
在Pd(PPh3)4和金属碳酸盐(例如K2CO3)的存在下可使其中Hal表示卤素的式(3)化合物与式(4)化合物偶联(铃木偶联)以产生式(2a)化合物。可在适合溶剂的存在下使式(2a)化合物与式(1a)的适合化合物反应,以产生式(I)的所需化合物,其中R1为COOH,L2不存在,并且其它变量例如A、B、Cy、R、Y、L1、X、X1、X2和X3与以上关于式(I)所述的相同。
方案3:该方案提供了一种制备式(I)化合物的方法,其中R1为COOH,L2为-O-,并且其它变量例如A、B、Cy、R1、R、Y、L1、X、X1、X2、X3和n与以上关于式(I)所述的相同。
方案3
在适合溶剂的存在下可使式(1a)的化合物与其中Hal表示卤素的式(2a)的适合化合物反应,以产生式(5)的所需化合物。在适合碱(例如K2CO3)的存在下可使式(5)的化合物与式(6)的化合物偶联,以产生式(I)的所需化合物,其中R1为COOH,L2为-O-,并且其它变量例如A、B、Cy、R、Y、L1、X、X1、X2和X3与以上关于式(I)所述的相同。
如本领域技术人员所知,具有某些修改的相似方法论可用于使用适合中间产物和试剂合成式(I)或/和(IA)的化合物,其中将变量理解为呈现以上关于式(I)或/和(IA)所述的基团。
实验:
除非另外提及,后处理(work-up)意味着使反应混合物分布于括号内所示的水相和有机相之间,在Na2SO4上分离并干燥有机层并蒸发溶剂以产生残留物。除非另作说明,使用硅胶作为固定相和具有适合极性的石油醚(沸点为60-80℃)和乙酸乙酯或二氯甲烷和甲醇的混合物作为流动相通过柱色谱法纯化。RT指环境温度(25-28℃)。
铃木偶联的一般程序:
向芳基溴(1个当量)于二噁烷和水(5∶1)中的溶液添加芳基硼酸或芳基硼酸频哪醇酯(1.3个当量)、四(三苯基膦)钯(0)-(0.08个当量)和碳酸钾(3.3个当量)。用N2为混合物脱气30min并回流至通过TLC监测两种原材料均消失为止。后处理(H2O/AcOEt)并纯化产生所需产物。
使用一般程序-1制备中间产物1、4-27、32-54、56-63、65-84和86-89。
中间产物1:3,5-二氟-3′-甲氧基联苯-4-胺:由2,6-二氟-4-溴苯胺(1.1g,5.3mmol)和3-甲氧基苯基硼酸(1.04g,6.8mmol)制备呈浅黄色液体的标题化合物(992mg)。1H-NMR(δppm,CDCl3+DMSO-d6,400MHz):7.21-7.20(m,1H),6.99-6.89(m,3H),6.87-6.83(m,1H),6.74-6.68(m,1H),3.97(bs,2H),3.69(s,3H)。
中间产物2:2-(3-甲氧基苯基)-5-硝基吡啶:由2-氯-5-硝基吡啶(500mg,3.15mmol)和3-甲氧基苯基硼酸(623mg,4.1mmol)制备呈浅黄色固体的标题化合物(612mg)。1H-NMR(δppm,CDCl3,400MHz):9.50(d,J2.6,1H),8.53(dd,J2.6,8.8,1H),7.91(d,J8.8,1H),7.69-7.68(m,1H),7.63(d,J7.8,1H),7.44(t,J7.9,1H),7.08-7.05(m,1H),3.91(s,3H)。
中间产物3:6-(3-甲氧基苯基)吡啶-3-胺:向中间产物2(610mg,2.65mmol)于EtOH/H2O(2∶1,15mL)中的溶液添加铁粉(739mg,13.24mmol)和氯化铵(100mg,3.18mmol)并且使混合物回流1h。通过硅藻土过滤混合物并用乙醇洗涤硅藻土。后处理(H2O/AcOEt)并浓缩合并的层获得呈蜡状固体的中间产物3(330mg)。1H-NMR(δppm,DMSO-d6,400MHz):8.00(d,J2.7,1H),7.61(d,J8.5,1H),7.47-7.45(m,2H),7.27(t,J8,1H),6.97(dd,J2.8,8.5,1H),6.83-6.81(m,1H),5.46(s,2H),3.78(s,3H)。
中间产物4:3′-乙氧基-3-氟联苯-4-胺:由2-氟-4-溴苯胺(2.5g,13.1mmol)和3-乙氧基苯基硼酸(2.8g,17.0Tmmol)制备呈浅黄色液体的标题化合物(1.34g)。1H-NMR(δppm,DMSO-d6,400MHz):7.38-7.20(m,3H),7.10(d,J7.9,1H),7.07-7.05(m,1H),6.83-6.76(m,2H),5.24(s,2H),4.06(q,J7,2H),1.32(t,J7,3H)。
中间产物5:3′-乙氧基-3,5-二氟联苯-4-胺:由2,6-二氟-4-溴苯胺(0.5g,2.4mmol)和3-乙氧基苯基硼酸(0.517g,3.12mmol)制备呈浅黄色液体的标题化合物(0.219g)。1H-NMR(δppm,DMSO-d6,400MHz):7.30-7.24(m,3H),7.14(d,J7.9,1H),7.11(s,1H),6.82(dd,J2.1,8.1,1H),5.31(s,2H),4.07(q,J7,2H),1.32(t,J7,3H)。
中间产物6:2′-氯-3,5-二氟联苯-4-胺:由2,6-二氟-4-溴苯胺(0.22g,1.06mmol)和2-氯苯基硼酸(0.21g,1.38mmol)制备呈白色固体的标题化合物(0.140g)。1H-NMR(δppm,DMSO-d6,400MHz):7.52-7.50(m,1H),7.40-7.35(m,3H),7.00(d,J2.1,7.6,2H),539(s,2H)。
中间产物7:3,5-二氟联苯-4-胺:由2,6-二氟-4-溴苯胺(0.5g,2.4mmol)和苯基硼酸(0.38g,3.12mmol)制备呈白色固体的标题化合物(0.401g)。1H-NMR(δppm,DMSO-d6,400MHz):7.60(d,J7.4,2H),7.38(t,J7.5,2H),7.30-7.25(m,3H),5.33(s,2H)。
中间产物8:3,5-二氟-3′-(三氟甲氧基)联苯-4-胺:由2,6-二氟-4-溴苯胺(1g,4.8mmol)和3-(三氟甲氧基)苯基硼酸(1.28g,6.24mmol)制备呈无色液体的标题化合物(0.812g)。
中间产物9:3′-(苄氧基)-3,5-二氟联苯-4-胺:由2,6-二氟-4-溴苯胺(0.3g,1.4mmol)和3-(苄氧基)苯基硼酸(0.426g,1.8mmol)制备呈无色液体的标题化合物(0.143g)。1H-NMR(δppm,DMSO-d6,400MHz):7.49-7.44(m,2H),7.39(t,J7.2,2H),7.35-7.26(m,4H),7.24(s,1H),7.18(d,J7.8,1H),6.91(dd,J1.9,8.0,1H),5.33(s,2H),5.16(s,2H)。
中间产物10:3-氯-3′-乙氧基-5-氟联苯-4-胺:由4-溴-2-氯-6-氟苯胺(0.5g,2.0mmol)和3-乙氧基苯基硼酸(0.441g,2.65mmol)制备呈黄色液体的标题化合物(0.360g)。1H-NMR(δppm,DMSO-d6,400MHz):7.43-7.38(m,2H),7.27(t,J7.9,1H),7.14(d,J7.9,1H),7.10(s,1H),6.82(dd,J2.1,8.1,1H),5.51(s,2H),4.07(q,J7,2H),1.32(t,J7,3H)。
中间产物11:3,5-二氯-3′-甲氧基联苯-4-胺:由2,6-二氯-4-溴苯胺(0.5g,2.0mmol)和3-甲氧基苯基硼酸(0.409g,2.69mmol)制备呈白色固体的标题化合物(0.550g)。1H-NMR(δppm,DMSO-d6,400MHz):7.58(s,2H),7.29(t,J7.8,1H),7.18-7.10(m,2H),6.85(dd,J2,8.1,1H),5.63(s,2H),3.81(s,3H)。
中间产物12:3-氯-5-氟-3′-丙氧基联苯-4-胺:由4-溴-2-氯-6-氟苯胺(0.5g,2.2mmol)和3-丙氧基苯基硼酸(0.521g,2.9mmol)制备呈黄色液体的标题化合物(0.273g)。1H-NMR(δppm,DMSO-d6,400MHz):7.44-7.39(m,3H),7.27(t,J7.9,1H),7.16-7.10(m,2H),5.51(s,2H),3.97(t,J6.5,2H),1.75-1.70(m,2H),0.98(t,J7.9,3H)。
中间产物13:3-氯-2′,5-二氟联苯-4-胺:由4-溴-2-氯-6-氟苯胺(0.5g,2.2mmol)和2-氟苯基硼酸(0.363g,2.6mmol)制备呈浅黄色液体的标题化合物(0.392g)。1H-NMR(δppm,DMSO-d6,400MHz):7.51(td,J1.7,7.8,1H),7.38-7.32(m,1H),7.28(s,2H),7.27-7.22(m,2H),5.62(s,2H)。
中间产物14:3,5-二氯-3′-乙氧基联苯-4-胺:由4-溴-2,6-二氯苯胺(0.5g,2.2mmol)和3-乙氧基苯基硼酸(0.447g,2.7mmol)制备呈黄色液体的标题化合物(0.550g),通过用1H-NMR数据判断标题化合物纯度为约70%。1H-NMR(δppm,DMSO-d6,400MHz):7.56(s,2H),7.28(s,1H),7.16-7.08(m,2H),6.83(dd,J2,8.1,1H),5.62(s,2H),4.10(q,J7,2H),1.32(t,J7,3H)。
中间产物15:3-氟-3′-(三氟甲氧基)联苯-4-胺:由4-溴-2-氟苯胺(1g,5.3mmol)和3-(三氟甲氧基)苯基硼酸(1.4g,6.8mmol)制备呈黄色液体的标题化合物(0.5g)。1H-NMR(δppm,DMSO-d6,400MHz):7.62(d,J8,1H),7.53(s,1H),7.48(t,J8,1H),7.42(dd,J2,9.1,1H),7.28(dd,J2,8.3,1H),7.23(d,J11,1H),6.82(t,J8.5,1H),5.40(s,2H)。
中间产物16:2′-氟-3-(三氟甲氧基)联苯-4-胺:由2-三氟甲氧基-4-溴苯胺(0.5g,1.9mmol)和2-氟苯基硼酸(0.345g,2.5mmol)制备呈黄色液体的标题化合物(0.294g)。1H-NMR(δppm,DMSO-d6,400MHz):7.47(td,J1.2,4.7,1H),7.33-7.20(m,5H),6.89(d,J8.8,1H),5.62(s,2H)。
中间产物17:3,5-二氯-2′-氟联苯-4-胺:由4-溴-2,6-二氯苯胺(0.5g,1.9mmol)和2-氟苯基硼酸(0.363g,2.6mmol)制备呈白色固体的标题化合物(0.367g)。1H-NMR(δppm,DMSO-d6,400MHz):7.50(t,J6.3,1H),7.43(s,2H),7.39-7.31(m,1H),7.29-7.21(m,2H),5.73(s,2H)。
中间产物18:3,5-二氟-3′-异丙氧基联苯-4-胺:由4-溴-2,6-二氟苯胺(0.5g,24mmol)和3-异丙氧基苯基硼酸(0.337g,3.1mmol)制备呈红色液体的标题化合物(0.34g)。1H-NMR(δppm,DMSO-d6,400MHz):7.30-7.22(m,3H),7.16-7.07(m,2H),6.89(dd,J2.3,8.1,1H),5.32(s,2H),4.68(七重峰,J6,1H),1.26(d,J6,6H)。
中间产物19:3,5-二氟-3′-丙氧基联苯-4-胺:由4-溴-2,6-二氟苯胺(0.5g,2.4mmol)和3-丙氧基苯基硼酸(0.337g,3.1mmol)制备呈红色液体的标题化合物(0.3g)。1H-NMR(δppm,DMSO-d6,400MHz):7.30-7.24(m,3H),7.18-7.10(m,2H),6.86-6.80(m,1H),5.31(s,2H),3.97(t,J6.5,2H),1.75-1.65(m,2H),0.98(t,J7.4,3H)。
中间产物20:2′,3-二氯-5-氟联苯-4-胺:由4-溴-2-氯-6-氟苯胺(0.5g,2.4mmol)和2-氯苯基硼酸(0.453g,2.9mmol)制备呈白色固体的标题化合物(0.260g)。1H-NMR(δppm,DMSO-d6,400MHz):7.60(d,J7.3,1H),7.42-7.31(m,3H),7.18-7.11(m,2H),5.6(s,2H)。
中间产物21:3′-丁氧基-3-氯-5-氟联苯-4-胺:由4-溴-2-氯-6-氟苯胺(0.2g,0.89mmol)和3-丁氧基苯基硼酸(0.224g,1.16mmol)制备呈黄色固体的标题化合物(0.190g)。1H-NMR(δppm,DMSO-d6,400MHz):7.44-7.41(m,2H),7.27(t,J7.9,1H),7.17-7.10(m,2H),6.81-6.84(m,1H),5.50(s,2H),4.01(t,J5.3,2H),1.72-1.65(m,2H),1.50-1.41(m,2H),0.93(t,J7.4,3H)。
中间产物22:3-氯-5-氟-3′-异丁氧基联苯-4-胺:由4-溴-2-氯-6-氟苯胺(0.2g,0.89mmol)和3-异丁氧基苯基硼酸(0.224g,1.16mmol)制备呈黄色固体的标题化合物(0.180g)。1H-NMR(δppm,DMSO-d6,400MHz):7.44-7.41(m,2H),7.27(t,J7.9,1H),7.17-7.10(m,2H),6.84-6.81(m,1H),5.50(s,2H),3.83(d,J6.5,2H),2.07-1.97(m,1H),1.00(d,J6.7,6H)。
中间产物23:2′,3,5-三氟联苯-4-胺:由4-溴-2,6-二氟苯胺(0.5g,2.4mmo1)和2-氟苯基硼酸(0.436g,3.12mmol)制备呈黄色液体的标题化合物(0.492g)。1H-NMR(δppm,DMSO-d6,400MHz):7.51(td,J1.5,7.9,1H),7.38-7.31(m,1H),7.29-721(m,2H),7.14(d,J8.6,2H),5.44(s,2H)。
中间产物24:2′,3,5-三氯联苯-4-胺:由4-溴-2,6-二氯苯胺(0.5g,2.1mmol)和2-氯苯基硼酸(0.421g,2.7mmol)制备呈白色固体的标题化合物(0.4g)。1H-NMR(δppm,DMSO-d6,400MHz):7.55-7.50(m,1H),7.40-7.32(m,3H),7.29(s,2H),5.72(s,2H)。
中间产物25:3,5-二氟-3′-异丁氧基联苯-4-胺:由4-溴-2,6-二氟苯胺(0.2g,0.96mmol)和3-异丁氧基苯基硼酸(0.242g,1.2mmol)制备呈黄色液体的标题化合物(0.16g)。
中间产物26:3,5-二氟-3′-丁氧基联苯-4-胺:由4-溴-2,6-二氟苯胺(0.2g,0.96mmol)和3-丁氧基苯基硼酸(0.242g,1.2mmol)制备呈无色液体的标题化合物(0.104g)。
中间产物27:3-氯-5-氟-3′-(三氟甲氧基)联苯-4-胺:由4-溴-2-氯-6-二氟苯胺(0.5g,2.27mmol)和3-(三氟甲氧基)苯基硼酸(0.6g,2.89mmol)制备呈浅黄色液体的标题化合物(0.280g)。1H-NMR(δppm,DMSO-d6,400MHz):7.68-7.64(m,1H),7.62(s,1H),7.53-7.46(m,3H)7.29-7.22(m,1H),5.64(s,2H)。
中间产物28:5-(苄氧基)-1,3-二氟-2-硝基苯:向2,4,6-三氟硝基苯(500mg,2.8mmol)于DMF(5ml)中的溶液添加碳酸钾(544mg,3.94mmol)和苯甲醇(0.3ml,2.8mmol)。在环境温度下搅拌该混合物过夜。后处理(EtOAc/H2O)获得呈黄色液体的标题化合物(521mg),标题化合物用于下一步骤中,无需进一步纯化。
中间产物29:4-(苄氧基)-2,6-二氟苯胺:向中间产物28(500mg,1.8mmol)于EtOH/H2O(2∶1,15mL)中的溶液添加铁粉(502mg,9mmol)和氯化铵(192mg,3.6mmol)并且使混合物回流2h。通过硅藻土过滤混合物并用乙醇洗涤硅藻土。从合并的滤液中后处理(H2O/AcOEt)并纯化获得呈无色液体的标题化合物(24mg)。1H-NMR(δppm,DMSO-d6,400MHz):7.42-7.36(m,3H),7.35-7.28(m,2H),6.68(dd,J1.6,8.8,2H),4.97(s,2H),4.64(s,2H)。
中间产物30:1-溴-3-(环戊氧基)苯:向溶于乙腈中的3-溴苯酚(500mg,2.8mmol)添加碳酸钾(400mg,2.8mmol)并且使混合物回流1h并冷却至环境温度。添加溴代环戊烷(430mg,2.8mmol)并再次使混合物回流过夜。后处理(H2O/EtOAc)并纯化获得呈浅黄色液体的标题化合物。1H-NMR(δppm,CDCl3,400MHz):7.11(t,J8.3,1H),7.05-7.00(m,2H),6.82-6.76(m,1H),4.76-4.68(m,1H),1.94-1.73(m,6H),1.65-1.54(m,2H)。
中间产物31:2-(3-(环戊氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷:用N2为中间产物30(335mg,1.4mmol)、双(频哪醇合)二硼(351mg,1.4mmol)和醋酸钾(450mg,4.6mmol)于二噁烷中的混合物脱气30min。添加四(三苯基膦)钯(0)(128mg,0.11mmol)并且再继续脱气15min。使该混合物回流过夜。反应完全后,后处理(H2O/EtOAc)和柱纯化获得呈黄色液体的标题化合物(165mg)。
中间产物32:3′-(环戊氧基)-3,5-二氟联苯-4-胺:由4-溴-2,6-二氟苯胺(165mg,0.6mmol)和中间产物31(120mg,0.6mmol)制备呈浅黄色液体的标题化合物(22mg)。1H-NMR(δppm,DMSO-d6,400MHz):7.29-7.22(m,3H),7.12(d,J8,1H),7.06(s,1H),6.82-6.76(m,1H),5.30(s,2H),4.96-4.88(m,1H),1.96-1.82(m,2H),1.75-1.65(m,4H),1.60-1.51(m,2H)。
中间产物33:3-氯-3′-(环戊氧基)-5-氟联苯-4-胺:由4-溴-2-氯-6-氟苯胺(600mg,2.7mmo1)和中间产物31(1g,3.4mmol)制备呈黄色液体的标题化合物(450mg)。1H-NMR(δppm,DMSO-d6,400MHz):7.42-7.36(m,2H),7.26(t,J8,1H),7.11(d,J7.8,1H),7.08-7.05(m,1H),6.80(dd,J2.3,8.1,1H),5.49(s,2H),4.92-4.84(m,1H),1.97-1.87(m,2H),1.77-1.62(m,4H),1.60-1.50(m,2H)。
中间产物34:3′-(二氟甲氧基)-3,5-二氟联苯-4-胺:由4-溴-2,6-二氟苯胺(200mg,0.96mmol)和3-(二氟甲氧基)苯基硼酸(234mg,1.25mmol)制备呈白色固体的标题化合物(144mg)。1H-NMR(δppm,DMSO-d6,400MHz):7.49(d,J7.9,1H),7.43-7.39(m,2H),7.38-7.30(m,2H),7.32(t,J74,1H),7.06(dd,J1.8,7.9,1H),5.42(s,2H)。
中间产物35:2-[3′-(二氟甲氧基)-3,5-二氟联苯-4-基氨甲酰基]苯甲酸:由4-溴-2-氯-6-氟苯胺(89mg,1.16mmol)和3-(二氟甲氧基)苯基硼酸(217mg,1.16mmol)制备呈白色固体的标题化合物(155mg)。1H-NMR(δppm,DMSO-d6,400MHz):7.52-7.47(m,3H),7.46-7.44(m,1H),7.43-7.40(m,2H),7.32(t,J74.2,1H),5.60(s,2H)。
中间产物36:2′-氯-3,5-二氟-5′-甲氧基联苯-4-胺:由4-溴-2,6-二氟苯胺(100mg,0.48mmol)和2-氯-5-甲氧基苯基硼酸(116mg,0.62mmol)制备呈黄色固体的标题化合物(97mg)。1H-NMR(δppm,DMSO-d6,400MHz):7.40(d,J9.6,1H),7.02(d,J7.7,2H),6.92(s,2H),5.39(s,2H),3.77(s,3H)。
中间产物37:3,3′,5-三氟-5′-甲氧基联苯-4-胺:由4-溴-2,6-二氟苯胺(100mg,0.48mmol)和3-氟-5-甲氧基苯基硼酸(106mg,0.62mmol)制备呈黄色固体的标题化合物(51mg)。1H-NMR(δppm,DMSO-d6,400MHz):7.35(dd,J2.1,8.1,2H),7.06(d,J10.2,1H),7.01(s,1H),6.71(dd,J2,8.8,1H),5.42(s,2H),3.81(s,3H)。
中间产物38:4-(苯并[d][1,3]间二氧杂环戊烯-5-基)-2,6-二氟苯胺:由4-溴-2,6-二氟苯胺(200mg,0.96mmol)和苯并[d][1,3]间二氧杂环戊烯-5-基硼酸(207mg,1.25mmol)制备呈白色固体的标题化合物(143mg)。1H-NMR(δppm,DMSO-d6,400MHz):7.23-7.18(m,3H),7.08(dd,J1.8,8.2,1H),6.91(d,J8.1,1H),6.01(s,2H),5.24(s,2H)。
中间产物39:4-(苯并[d][1,3]间二氧杂环戊烯-5-基)-2-氯-6-氟苯胺:由4-溴-2-氯-6-氟苯胺(200mg,0.89mmol)和苯并[d][1,3]间二氧杂环戊烯-5-基硼酸(192mg,1.16mmol)制备呈白色固体的标题化合物(143mg)。1H-NMR(δppm,DMSO-d6,400MHz):7.36-7.30(m,2H),7.20(d,J1.7,1H),7.06(dd,J1.4,8.1,1H),6.91(d,J8.1,1H),6.01(s,2H),5.42(s,2H)。
中间产物40:3,5-二氟-3′,4′-二甲基基联苯-4-胺:由4-溴-2,6-二氟苯胺(100mg,0.48mmol)和3,4-二甲基基苯基硼酸(113mg,0.62mmol)制备呈浅黄色固体的标题化合物(39mg)。1H-NMR(δppm,DMSO-d6,400MHz):7.25(dd,J2,8.3,2H),7.18-7.10(m,2H),6.94(d,J8.4,1H),5.21(s,2H),3.81(s,3H),3.75(s,3H)。
中间产物41:3-氯-3′,5-二氟-5′-甲氧基联苯-4-胺:由4-溴-2-氯-6-氟苯胺(100mg,0.44mmol)和3-氟-5-甲氧基苯基硼酸(97mg,0.57mmol)制备呈浅黄色固体的标题化合物(71mg)。1H-NMR(δppm,DMSO-d6,400MHz):7.51-7.45(m,2H),7.05(d,J10.3,1H),7.00(s,1H),6.73(dd,J2.1,4.2,1H),5.60(s,2H),3.81(s,3H)。
中间产物42:3,3′-二氯-5-氟-5′-甲氧基联苯-4-胺:由4-溴-2-氯-6-氟苯胺(100mg,0.44mmol)和3-氯-5-甲氧基苯基硼酸(107mg,0.57mmol)制备呈浅黄色固体的标题化合物(41mg)。
中间产物43:4-(2,3-二氢苯并呋喃-5-基)-2,6-二氟苯胺:由4-溴-2,6-二氟苯胺(200mg,0.96mmol)和2,3-二氢苯并呋喃-5-基硼酸(204mg,1.25mmol)制备呈白色固体的标题化合物(182mg)。1H-NMR(δppm,DMSO-d6,400MHz):7.46(s,1H),7.30(dd,J1.8,8.3,1H),7.16(dd,J2.1,8.2,2H),6.75(d,J8.3,1H),5.18(s,2H),4.52(t,J8.7,2H),3.18(t,J8.5,2H)。
中间产物44:2-氯-4-(2,3-二氢苯并呋喃-5-基)-6-氟苯胺:由4-溴-2-氯-6-氟苯胺(200mg,0.89mmol)和2,3-二氢苯并呋喃-5-基硼酸(189mg,1.16mmol)制备呈浅黄色固体的标题化合物(86mg)。1H-NMR(δppm,DMSO-d6,400MHz):7.46(s,1H),7.33-7.25(m,3H),6.75(d,J8.3,1H),5.36(s,2H),4.52(t,J8.7,2H),3.18(t,J8.6,2H)。
中间产物45:4-(1,3-二甲基-1H-吲唑-5-基)-2,6-二氟苯胺:向5-溴-1,3-二甲基-1H-吲唑(240mg,1.06mmol)于二噁烷(10ml)中的溶液添加醋酸钾(0.344g,3.51mmol)和双(频哪醇合)二硼(351mg,1.4mmol)并且用氮气为混合物脱气30min。添加四(三苯基膦)钯(0)并再脱气30min。使反应混合物回流2h。反应完全后,后处理(AcOEt/H2O),接着进行柱色谱法获得呈白色固体的1,3-二甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-引唑(85mg)。由4-溴-2,6-二氟苯胺(50mg,0.24mmol)和1,3-二甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲唑(85mg,0.31mmol)制备呈白色固体的标题化合物(26mg)。1H-NMR(δppm,DMSO-d6,400MHz):7.93(s,1H),7.66(dd,J1.5,8.8,1H),7.55(d,J8.8,1H),7.33(dd,J2,8.2,2H),5.22(s,2H),3.94(s,3H),2.49(s,3H)。
中间产物46:3′-氯-3,5-二氟-5′-甲氧基联苯-4-胺:由4-溴-2,6-二氟苯胺(100mg,0.48mmol)和3-氯-5-甲氧基苯基硼酸(116mg,0.62mmol)制备呈浅黄色固体的标题化合物(39mg)。1H-NMR(δppm,DMSO-d6,400MHz):7.36(dd,J2.2,8.1,2H),7.25(s,1H),7.12(s,1H),6.91(t,J1.9,1H),5.43(s,2H),3.81(s,3H)。
中间产物47:3-氯-5-氟-3′,4′-二甲基基联苯-4-胺:由4-溴-2-氯-6-氟苯胺(100mg,0.442mmol)和3,4-二甲基基苯基硼酸(80mg,0.62mmol)制备呈浅黄色固体的标题化合物(39mg)。
中间产物48:2′,3-二氯-5-氟-5′-甲氧基联苯-4-胺:由4-溴-2-氯-6-氟苯胺(100mg,0.44mmol)和2-氯-5-甲氧基苯基硼酸(106mg,0.62mmol)制备呈浅黄色固体的标题化合物(39mg)。
中间产物49:2′,3,5-三氟-5′-甲氧基联苯-4-胺:由4-溴-2,6-二氟苯胺(100mg,0.48mmol)和2-氟-5-甲氧基苯基硼酸(106mg,0.62mmol)制备呈浅黄色固体的标题化合物(31mg)。
中间产物50:4′-氯-3,5-二氟-3′-甲氧基联苯-4-胺:由4-溴-2,6-二氟苯胺(100mg,0.48mmol)和4-氯-5-甲氧基苯基硼酸(116mg,0.62mmol)制备呈白色固体的标题化合物(81mg)。
中间产物51:3,4′-二氯-5-氟-3′-甲氧基联苯-4-胺:由4-溴-2-氯-6-氟苯胺(100mg,0.44mmol)和4-氯-5-甲氧基苯基硼酸(107mg,0.62mmol)制备呈浅黄色固体的标题化合物(82mg)。
中间产物52:3-氯-2′,5-二氟-5′-甲氧基联苯-4-胺:由4-溴-2-氯-6-氟苯胺(100mg,0.44mmol)和2-氟-5-甲氧基苯基硼酸(98mg,0.58mmol)制备呈白色固体的标题化合物(70mg)。1H-NMR(δppm,DMSO-d6,400MHz):7.30-7.24(m,2H),7.17(t,J9.1,1H),7.02-6.97(m,1H),6.90-6.84(m,1H),5.61(s,2H),3.77(s,3H)。
中间产物53:3,4′,5-三氟-3′-甲氧基联苯-4-胺:由4-溴-2,6-二氟苯胺(200mg,0.96mmol)和4-氟-5-甲氧基苯基硼酸(210mg,1.24mmol)制备呈白色固体的标题化合物(480mg)。1H-NMR(δppm,DMSO-d6,400MHz):7.39-7.29(m,3H),7.21-7.12(m,2H),5.33(s,2H),3.90(s,3H)。
中间产物54:2,6-二氟-4-(3-甲基-1H-吲哚-5-基)苯胺:由4-溴-2,6-二氟苯胺(100mg,0.48mmol)和3-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲哚(160mg,0.62mmol)制备呈白色固体的标题化合物(68mg)。1H-NMR(δppm,DMSO-d6,400MHz):10.71(s,1H),7.67(s,1H),7.33-7.29(m,2H),7.28-7.21(m,2H),7.09(s,1H),5.12(s,2H),2.27(s,3H)。
中间产物55:2,6-二氟-4-(3-甲基-1H-吲唑-5-基)苯胺:按照一般程序-1,由4-溴-2,6-二氟苯胺(250mg,1.2mmol)和3-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲唑-1-羧酸叔丁酯(559mg,1.56mmol)制备呈白色固体的5-(4-氨基-3,5-二氟苯基)-3-甲基-1H-吲唑-1-羧酸叔丁酯(106mg)。将5-(4-氨基-3,5-二氟苯基)-3-甲基-1H-吲唑-1-羧酸叔丁酯(205mg)溶于二氯甲烷(4ml)中,添加三氟乙酸(0.8ml)并且在环境温度下搅拌4h。去除溶剂并且用二氯甲烷共蒸发残留物4次。在高真空下干燥获得的固体以获得呈白色固体的标题化合物(243mg)。1H-NMR(δppm,DMSO-d6,400MHz):9.01(bs,1H),7.92(s,1H),7.58(dd,J1.4,8.7,1H),7.44(d,J8.7,1H),7.32(dd,J2,8.2,2H),5.22(s,2H),2.50(s,3H)。
中间产物56:3-氯-3′-乙基-5-氟联苯-4-胺:由4-溴-2,6-二氟苯胺(100mg,0.48mmol)和3-乙基苯基硼酸(86mg,0.57mmol)制备呈黄色液体的标题化合物(83mg)。
中间产物57:3-氯-3′-乙氧基-2′,5-二氟联苯-4-胺:由4-溴-2-氯-6-氟苯胺(120mg,0.53mmol)和3-乙氧基-2-氟苯基硼酸(120mg,0.69mmol)制备呈无色液体的标题化合物(65mg)。
中间产物58:2-氯-4-(2,3-二氢苯并[b][1,4]二噁英-6-基)-6-氟苯胺:由4-溴-2,6-二氟苯胺(100mg,0.48mmol)和2,3-二氢苯并[b][1,4]二噁英-6-基硼酸(160mg,0.62mmol)制备呈白色固体的标题化合物(68mg)。
中间产物59:3-氯-5-氟-3′-(2,2,2-三氟乙氧基)联苯-4-胺:由4-溴-2-氯-6-氟苯胺(100mg,0.44mmol)和3-(2,2,2-三氟乙氧基)苯基硼酸(127mg,0.57mmol)制备呈白色固体的标题化合物(85mg)。1H-NMR(δppm,DMSO-d6,400MHz):7.53-7.44(m,2H),7.38-7.26(m,3H),6.94(d,J7,1H),5.55(s,2H),4.83(q,J8.9,2H)。
中间产物60:3-氟-3′-甲氧基联苯-4-胺:由4-溴-6-氟苯胺(500mg,2.63mmol)和3-甲氧基苯基硼酸(519mg,3.42mmol)制备呈红色液体的标题化合物(430mg)。1H-NMR(δppm,DMSO-d6,400MHz):7.34(dd,J2,13.1,1H),7.27(t,J7.9,1H),7.22(dd,J2,8.3,1H),7.12(d,J7.9,1H),7.09-7.07(m,1H),6.84-6.78(m,2H),5.29(s,2H),3.78(s,3H)。
中间产物61:3′-乙氧基联苯-4-胺:由4-溴苯胺(300mg,1.74mmol)和3-乙氧基苯基硼酸(380mg,2.29mmol)制备呈无色液体的标题化合物(200mg)。1H-NMR(δppm,DMSO-d6,400MHz):7.33(d,J8.5,2H),7.26-7.22(m,1H),7.06(d,J7.9,1H),7.01(s,1H),6.75(dd,J5.8,8.1,1H),6.60(d,J8.5,2H),5.20(s,2H),4.04(q,J7,2H),1.16(t,J7,3H)。
中间产物62:3′-(乙硫基)-3,5-二氟联苯-4-胺:由4-溴-2,6-二氟苯胺(1g,4.8mmol)和3-(乙硫基)苯基硼酸(1.13g,6.24mmol)制备呈无色液体的标题化合物(900mg)。
中间产物63:3′-环丙氧基-3,5-二氟联苯-4-胺:由4-溴2,6-二氟苯胺(1.2g,5.76mmol)和2-(3-环丙氧基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(1.5g,5.76mmol)制备呈黄色液体的标题化合物(170mg)。
中间产物64:3-乙基-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲哚:向于Et2O(50ml)中由碘乙烷(14ml,176.96mmol)和镁(8.6g,176.96mmol)形成的乙基碘化镁滴加5-溴靛红(5g,22.12mmol)并且在环境温度下搅拌过夜。添加10%NH4Cl水溶液后进行后处理(EtOAc/H2O)并纯化产生5-溴-3-乙基-3-羟基吲哚啉-2-酮(1g)。向该中间产物(1g,3.93mmol)于THF(40ml)中的溶液添加硼烷二甲基硫醚于THF(10ml,19.65mmol)中的2M溶液并在环境温度下搅拌3h。后处理(EtOAc/H2O)和纯化获得5-溴-3-乙基吲哚(800mg)。向5-溴-3-乙基吲哚(800mg,3.57mmol)于二噁烷(10ml)中的溶液添加双(频哪醇合)二硼(1.078g,4.64mmol)、醋酸钾(1.15g,11.78mmol)和[1,1’-双(二苯基膦)二茂铁]二氯钯(II).CH2Cl2,脱气30min并回流过夜。后处理,接着纯化获得呈灰白色固体的标题化合物(800mg)。
中间产物65:4-(3-乙基-1H-吲哚-5-基)-2,6-二氟苯胺:由4-溴-2,6-二氟苯胺(662mg,2.57mmol)和中间产物64(440mg,1.78mmol)制备呈黄色液体的标题化合物(220mg)。1H-NMR(δppm,DMSO-d6,400MHz):10.74(s,1H),7.69(s,1H),7.33-7.29(m,2H),7.23(dd,J1.8,8.3,2H),7.09(s,1H),5.12(s,2H),2.73(q,J7.5,2H),1.27(q,J7.5,3H)。
中间产物66:3′-(乙硫基)-2,3,5,6-四氟联苯-4-胺:由4-溴-2,3,5,6-四氟苯胺(300mg,1.22mmol)和3-(乙硫基)苯基硼酸(291mg,1.6mmol)制备呈无色液体的标题化合物(280mg)。
中间产物67:2′-氯-2-氟-5′-甲氧基联苯-4-胺:由4-溴-3-氟苯胺(227mg,1.2mmol)和2-氯-5-甲氧基苯基硼酸(290mg,1.6mmol)制备呈浅黄色液体的标题化合物(280mg)。
中间产物68:3-氟-3′-丙氧基联苯-4-胺:由4-溴-2-氟苯胺(390mg,1.6mmol)和3-丙氧基苯基硼酸(369mg,2mmol)制备呈无色液体的标题化合物(280mg)。
中间产物69:3′-丙氧基联苯-4-胺:由4-溴苯胺(300mg,1.7mmol)和3-丙氧基苯基硼酸(408mg,2.3mmol)制备呈无色液体的标题化合物(280mg)。
中间产物70:3′-(乙硫基)-2-氟联苯-4-胺:由4-溴-3-氟苯胺(300mg,1.6mmol)和3-(乙硫基)苯基硼酸(370mg,2.0mmol)制备呈黄色液体的标题化合物(430mg)。
中间产物71:3,5-二氟-3′-(2,2,2-三氟乙氧基)联苯-4-胺:由4-溴-2,6-二氟苯胺(80mg,0.38mmol)和3-(2,2,2-三氟乙氧基)苯基硼酸(108mg,0.5mmol)制备呈无色液体的标题化合物(89mg)。
中间产物72:3′-乙基-3,5-二氟联苯-4-胺:由4-溴-2,6-二氟苯胺(100mg,0.48mmol)和3-乙基苯基硼酸(99mg,0.6mmol)制备呈无色液体的标题化合物(89mg)。。
中间产物73:2′-氯联苯-4-胺:由4-溴苯胺(300mg,1.74mmol)和2-氯苯基硼酸(354mg,2.26mmol)制备呈黄色固体的标题化合物(176mg)。
中间产物74:3′-甲氧基联苯-4-胺:由4-溴苯胺(300mg,1.74mmol)和3-甲氧基苯基硼酸(344mg,2.26mmol)制备呈黄色液体的标题化合物(58mg)。
中间产物75:3′-(三氟甲氧基)联苯-4-胺:由4-溴苯胺(300mg,1.74mmol)和3-(三氟甲氧基)苯基硼酸(466mg,2.26mmol)制备呈浅黄色液体的标题化合物(280mg)。
中间产物76:3′-(乙硫基)-2,6-二氟联苯-4-胺:由4-溴-3,5-二氟苯胺(300mg,1.74mmol)和3-(乙硫基)苯基硼酸(340mg,1.86mmol)制备呈黄色液体的标题化合物(500mg)。
中间产物77:3′-乙基联苯-4-胺:由4-溴苯胺(270mg,1.56mmol)和3-乙基苯基硼酸(300mg,2.04mmol)制备呈无色液体的标题化合物(300mg)。
中间产物78:3′-丁氧基-2,3,5,6-四氟联苯-4-胺:由4-溴-2,3,5,6-四氟苯胺(300mg,1.23mmol)和3-丁氧基苯基硼酸(310mg,1.59mmol)制备呈黄色液体的标题化合物(250mg)。
中间产物79:3′-丁氧基-3-氟联苯-4-胺:由4-溴-2-氟苯胺(240mg,1.26mmol)和3-丁氧基苯基硼酸(310mg,1.59mmol)制备呈黄色液体的标题化合物(170mg)。
中间产物80:3′-环丙氧基-3-氟联苯-4-胺:由4-溴-2-氟苯胺(1g,5.26mmol)和3-异丙氧基苯基硼酸(1.8g,6.84mmol)制备呈黄色液体的标题化合物(230mg)。
中间产物81:3′-环丙氧基联苯-4-胺:由4-溴苯胺(1g,5.81mmol)和3-异丙氧基苯基硼酸(1.96g,7.55mmol)制备呈黄色液体的标题化合物(98mg)。
中间产物82:3′-丁氧基-3-氟联苯-4-胺:由4-溴苯胺(200mg,1.16mmol)和3-丁氧基苯基硼酸(293mg,1.5mmol)制备呈黄色液体的标题化合物(84mg)。
中间产物83:3′-丁氧基-2-氟联苯-4-胺:由4-溴-3-氟苯胺(200mg,1.05mmol)和3-丁氧基苯基硼酸(265mg,1.4mmol)制备呈无色液体的标题化合物(241mg)。
中间产物84:3′-丁氧基-2,6-二氟联苯-4-胺:由4-溴-3,5-二氟苯胺(200mg,1mmol)和3-丁氧基苯基硼酸(242mg,1.2mmol)制备呈无色液体的标题化合物(172mg)。
中间产物85:3-丙基-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲哚:通过使用按照中间产物64的程序,由乙醚(50ml)中的丙基溴(16.2ml,176.96mmol)和镁(4.3g,176.96mmol)生成的丙基溴化镁、5-溴靛红(5g,22.12mmol)、THF(20ml)、THF中的2M硼烷二甲基硫醚(10ml,19.65mmol)、双(频哪醇合)二硼(600mg,2.3mmol)、醋酸钾(600mg,2.3mmol)和[1,1’-双(二苯基膦)二茂铁]二氯钯(II).CH2Cl2(44mg,0.03mmol)和二噁烷(10ml)制备呈无色粘稠液体的标题化合物(500mg)。
中间产物86:2,6-二氟-4-(3-丙基-1H-吲哚-5-基)苯胺:由4-溴-2,6-二氟苯胺(400mg,1.55mmol)和中间产物85(500mg,2.11mmol)制备呈无色胶状液体的标题化合物(240mg)。
中间产物87:2-氯-4-(3-乙基-1H-吲哚-5-基)-6-氟苯胺:由4-溴-2-氯-6-氟苯胺(300mg,1.1mmol)和中间产物64(316mg,1.42mmol)制备呈褐色粘稠液体的标题化合物(60mg)。
中间产物88:2′-氯-3-氟-5′-甲氧基联苯-4-胺:由4-溴-2-氟苯胺(150mg,0.79mmol)和2-氯-5-甲氧基苯基硼酸(191mg,1.02mmol)制备呈无色液体的标题化合物(134mg)。
中间产物89:2′-氯-5′-甲氧基联苯-4-胺:由4-溴苯胺(150mg,0.87mmol)和2-氯-5-甲氧基苯基硼酸(211mg,1.13mmol)制备呈无色粘稠液体的标题化合物(154mg)。
酰胺形成的一般程序:
程序-1
将酸酐(1.3个当量)和胺(1个当量)的溶液溶于二噁烷中并回流过夜。蒸发二噁烷并将所得的残留物溶于AcOEt中并萃取至2NNaHCO3水溶液中。用2N HCl水溶液酸化水层以获得固体,过滤并干燥固体以产生所需酰胺。
使用一般程序-1合成实施例1-11、14、16-17和20。
程序-2
将胺(1个当量)溶于甲苯中并分批添加酸酐(1个当量)并且加热混合物至60℃并保持4h。过滤固化产物并用2N HCl水溶液洗涤并且在真空下干燥以获得所需产物。
使用一般程序-2合成实施例12和13。
程序-3
将胺(1个当量)溶于醋酸中并添加酸酐(2个当量)并且在环境温度下搅拌混合物过夜。过滤分离出的固体并用石油醚洗涤并且在真空下干燥以获得所需产物。
使用一般程序-3制备实施例15、18、19、21-35、38-71和73-100。
实施例1
2-(3,5-二氟-3′-甲氧基联苯-4-基氨甲酰基)苯甲酸:
由中间产物1(150mg,0.64mmol)和邻苯二甲酸酐(189mg)获得呈白色固体的标题化合物(52mg)。熔点:168-173℃。1H-NMR(δppm,DMSO-d6,400MHz):13.05(s,1H),10.19(s,1H),7.83(d,J7.4,1H),7.69-7.63(m,1H),7.62-7.52(m,4H),7.39(t,J7.9,1H),7.34-7.27(m,2H),6.98(d,J6.8,1H),3.83(s,3H).MS(m/z):381.55([M-H]-)。
实施例2
2-(3,5-二氟-3′-甲氧基联苯-4-基氨甲酰基)苯磺酸:
由中间产物1(150mg,0.64mmol)和2-磺基苯甲环酸酐(235mg)获得呈褐色固体的标题化合物(64mg)。熔点:97-102℃。1H-NMR(δppm,DMSO-d6,400MHz):11.48(s,1H),7.92(d,J7.1,1H),7.80(d,J7,1H),7.57-7.49(m,4H),7.38(t,J7.8,1H),7.34-7.28(m,2H),6.97(d,J8.1,1H),3.83(s,3H).MS(m/z):417.6([M-H]-)。
实施例3
2-(6-(3-甲氧基苯基)吡啶-3-基氨甲酰基)苯甲酸:
由中间产物3(100mg,0.5mmol)和邻苯二甲酸酐(147mg,1mmol)获得呈白色固体的标题化合物(48mg)。熔点:194-199℃。1H-NMR(δppm,DMSO-d6,400MHz):13.17(bs,1H),10.64(s,1H),8.88(d,J2,1H),8.22(dd,J2.2,8.7,1H),7.97(d,J8.7,1H),7.90(d,J7,1H),7.70-7.66(m,1H),7.63-7.56(m,4H),7.38(t,J8,1H),6.98-6.95(m,1H),3.82(s,3H).MS(m/z):347.30([M-H]-)。
实施例4
2-(3′-乙氧基-3-氟联苯-4-基氨甲酰基)苯甲酸:
由中间产物4(100mg,0.5mmol)和邻苯二甲酸酐(128mg,1mmol)获得呈白色固体的标题化合物(26mg)。熔点:151-157℃。1H-NMR(δppm,DMSO-d6,400MHz):13.06(s,1H),10.22(s,1H),7.95(t,J8.5,1H),7.89(d,J7.7,1H),7.68-7.52(m,5H),7.35(t,J7.9,1H),7.25(d,J8.2,1H),7.21(s,1H),6.92(d,J8.4,1H),4.10(q,J7,2H),1.34(t,J7,3H).MS(m/z):379.24([M]-)。
实施例5
2-(3′-乙氧基-3,5-二氟联苯-4-基氨甲酰基)苯甲酸:
由中间产物5(100mg,0.43mmol)和邻苯二甲酸酐(118mg,0.86mmol)获得呈白色固体的标题化合物(15mg)。熔点:136-141℃。1H-NMR(δppm,DMSO-d6,400MHz):13.04(s,1H),10.19(s,1H),7.83(d,J7.4,1H),7.69-7.64(m,1H),7.62-7.51(m,4H),7.37(t,J7.9,1H),7.32-7.25(m,2H),6.96(dd,J1.7,8.3,1H),4.11(q,J7,2H),1.34(t,J7,3H).MS(m/z):395.81([M-H]-)。
实施例6
3-(3,5-二氟-3′-甲氧基联苯-4-基氨甲酰基)吡嗪-2-羧酸:
由中间产物1(150mg,0.64mmol)和2,3-吡嗪二羧酸酐(190mg,1.26mmol)获得呈白色固体的标题化合物(270mg)。熔点:180.1-183.4℃。1H-NMR(δppm,DMSO-d6,400MHz):13.82(bs,1H),10.7(s,1H),8.92(d,J5.7,2H),7.59(d,J9.1,2H),7.42-7.38(m,1H),7.36-7.28(m,2H),7.00(d,J8,1H),3.83(s,3H).MS(m/z):384.05([M-H]-)。
实施例7
3-(3,5-二氟-3′-乙氧基联苯-4-基氨甲酰基)吡嗪-2-羧酸:
由中间产物5(100mg,0.4mmol)和2,3-吡嗪二羧酸酐(120mg,0.8mmol)获得呈白色固体的标题化合物(84mg)。熔点:133.4-137.3℃。1H-NMR(δppm,DMSO-d6,400MHz):13.76(s,1H),10.68(s,1H),8.92(dd,J2.3,7.7,2H),7.58(d,J9.2,2H),7.41-7.36(m,1H),7.34-7.26(m,2H),6.98(d,J8,1H),4.11(q,J6.9,2H),1.35(t,J6.9,3H).MS(m/z):398.19([M-H]-)。
实施例8
2-(2′-氯-3,5-二氟联苯-4-基氨甲酰基)苯甲酸:
由中间产物6(140mg,0.59mmol)和邻苯二甲酸酐(170mg,1.17mmol)获得呈白色固体的标题化合物(110mg)。熔点:143.5-145.1℃。1H-NMR(δppm,DMSO-d6,400MHz):13.06(s,1H),10.2(s,1H),7.85(d,J7.6,1H),7.67(t,J7.3,1H),7.63-7.56(m,3H),7.52-7.43(m,3H),7.28(d,J8.4,2H).MS(m/z):386.15([M-H]-)。
实施例9
3-[3′-(苄氧基)-3,5-二氟联苯-4-基氨甲酰基]吡嗪-2-羧酸:
由中间产物9(65mg,0.21mmol)和2,3-吡嗪二羧酸酐(62mg,0.42mmol)获得呈白色固体的标题化合物(42mg)。熔点:142-144.5℃。1H-NMR(δppm,DMSO-d6,400MHz):13.77(bs,1H),10.69(s,1H),8.92(dd,J2.4,7.7,2H),7.60(d,J9.2,2H),7.48(d,J7.3,2H),7.44-7.32(m,6H),7.07(d,J6.5,1H),5.20(s,2H).MS(m/z):460.28([M-H]-)。
实施例10
2-(3,5-二氟联苯-4-基氨甲酰基)苯甲酸:
由中间产物7(100mg,0.48mmol)和邻苯二甲酸酐(144mg,0.86mmol)获得呈白色固体的标题化合物(85mg)。熔点:161.2-165.7℃。1H-NMR(δppm,DMSO-d6,400MHz):13.04(s,1H),10.19(s,1H),7.83(d,J7.6,1H),7.76(d,J7.4,2H),7.65(d,J8.2,1H),7.62-7.48(m,6H),7.43(d,J7.2,1H).MS(m/z):352.06([M-H]-)。
实施例11
3-(3-氯-3′-乙氧基-5-氟联苯-4-基氨甲酰基)吡嗪-2-羧酸:
由中间产物10(100mg,0.38mmol)和2,3-吡嗪二羧酸酐(112mg,0.75mmol)获得呈白色固体的标题化合物(30mg)。熔点:148-153℃。1H-NMR(δppm,DMSO-d6,400MHz):13.74(bs,1H),10.72(s,1H),8.93(dd,J2.3,6.4,2H),7.76(s,1H),7.70(d,J10.7,1H),7.42-7.36(m,1H),7.34-7.26(m,2H),6.98(dd,J1.8,8.1,1H),4.12(q,J6.9,2H),1.34(t,J6.9,3H).MS(m/z):414.01([M-H]-)。
实施例12
2-[3,5-二氟-3′-(三氟甲氧基)联苯-4-基氨甲酰基]苯甲酸:
由中间产物8(100mg,0.34mmol)和邻苯二甲酸酐(50mg,0.34mmol)获得呈白色固体的标题化合物(15mg)。熔点:148.2-151.4℃。1H-NMR(δppm,DMSO-d6,400MHz):13.07(s,1H),10.24(s,1H),7.83(t,J6.2,2H),7.79(s,1H),7.54-7.50(m,6H),7.42(d,J8.8,1H).MS(m/z):436.13([M-H]-)。
实施例13
2-[3′-(苄氧基)-3,5-二氟联苯-4-基氨甲酰基]苯甲酸:
由中间产物9(100mg,0.32mmol)和邻苯二甲酸酐(47mg,0.32mmol)获得呈白色固体的标题化合物(12mg)。熔点:140.3-143.4℃。1H-NMR(δppm,DMSO-d6,400MHz):13.04(s,1H),10.19(s,1H),7.83(d,J7.6,1H),7.68-7.64(m,1H),7.62-7.53(m,4H),7.48(d,J7.2,2H),7.42-7.37(m,4H),7.36-7.32(m,2H),7.05(dd,J2,7.7,1H),5.20(s,2H).MS(m/z):457.83([M-H]-)。
实施例14
4,5-二氯-2-(3-氯-3′-乙氧基-5-氟联苯-4-基氨甲酰基)苯甲酸:
由中间产物10(100mg,0.38mmol)和邻苯二甲酸酐(160mg,0.75mmol)获得呈灰白色固体的标题化合物(42mg)。熔点:260-265℃。1H-NMR(δppm,DMSO-d6,400MHz):15.33(s,1H),8.16(s,1H),7.96(s,1H),7.71(s,1H),7.64(d,J11,1H),7.36(t,J7.8,1H),7.27-7.22(m,2H),6.95(dd,J1.8,8.1,1H),4.12(d,J7,2H),1.34(t,J7,3H).MS(m/z):481.02([M-H]-)。
实施例15
2-(3-氯-3′-乙氧基-5-氟联苯-4-基氨甲酰基)苯甲酸:
由中间产物10(145mg,0.55mmol)和邻苯二甲酸酐(160mg,1.1mmol)获得呈白色固体的标题化合物(86mg)。熔点:135-140℃。1H-NMR(δppm,DMSO-d6,400MHz):13.02(s,1H),10.23(s,1H),7.82(d,J7.6,1H),7.72(s,1H),7.70-7.58(m,4H),7.38(t,J7.8,1H),7.33-7.26(m,2H),6.97(dd,J2,8.1,1H),4.12(q,J6.9,2H),1.35(t,J6.9,3H).MS(m/z):412.05([M-H]-)。
实施例16
4,5-二氯-2-(3,5-二氟-3′-甲氧基联苯-4-基氨甲酰基)苯甲酸:
由中间产物1(100mg,0.42mmol)和5,6-二氯异苯并呋喃-1,3-二酮(182mg,0.84mmol)获得呈白色固体的标题化合物(95mg)。熔点:158.6-162.2℃。1H-NMR(δppm,DMSO-d6,400MHz):13.58(s,1H),10.40(s,1H),7.57(d,J9.1,2H),8.03(s,1H),7.83(s,1H),7.39(t,J7.9,1H),7.34-7.28(m,2H),6.98(dd,J1.9,6.9,1H),3.83(s,3H).MS(m/z):451.24([M-H]-)。
实施例17
4,5-二氯-2-(3′-乙氧基-3,5-二氟联苯-4-基氨甲酰基)苯甲酸:
由中间产物5(100mg,0.42mmol)和5,6-二氯异苯并呋喃-1,3-二酮(173mg,0.8mmol)获得呈白色固体的标题化合物(87mg)。熔点:190.1-192.4℃。1H-NMR(δppm,DMSO-d6,400MHz):13.58(s,1H),10.39(s,1H),8.03(s,1H),7.82(s,1H),7.56(d,J9.2,2H),7.37(t,J7.9,1H),7.33-7.26(m,2H),6.97(dd,J1.8,8.1,1H),4.11(q,J7,2H),1.34(t,J7,3H).MS(m/z):464.92([M-H]-)。
实施例18
2-(3,5-二氯-3′-甲氧基联苯-4-基氨甲酰基)苯甲酸:
由中间产物11(150mg,0.56mmol)和邻苯二甲酸酐(165mg,1.12mmol)获得呈白色固体的标题化合物(20mg)。熔点:163-168℃。1H-NMR(δppm,DMSO-d6,400MHz):13.0(s,1H),10.37(s,1H),7.86(s,2H),7.80(d,J7.5,1H),7.74-7.65(m,2H),7.60(t,J7.5,1H),7.40(t,J7.9,1H),7.34-7.27(m,2H),6.99(d,J7.5,1H),3.84(s,3H).MS(m/z):415.15([M-H]-)。
实施例19
2-(3-氯-5-氟-3′-丙氧基联苯-4-基氨甲酰基)苯甲酸:
由中间产物12(100mg,0.36mmol)和邻苯二甲酸酐(105mg,0.72mmol)获得呈白色固体的标题化合物(38mg)。熔点:144-148℃。1H-NMR(δppm,DMSO-d6,400MHz):13.03(s,1H),10.24(s,1H),7.82(d,J7.5,1H),7.73(s,1H),7.70-7.57(m,4H),7.38(t,J7.7,1H),7.32-7.26(m,2H),6.98(d,J8.1,1H),4.02(t,J6.5,2H),1.77-1.72(m,2H),0.99(t,J7.4,3H).MS(m/z):426.05([M-H]-)。
实施例20
2-(3-氯-2′,5-二氟联苯-4-基氨甲酰基)苯甲酸:
由中间产物13(100mg,0.34mmol)和邻苯二甲酸酐(100mg,0.68mmol)获得呈白色固体的标题化合物(15mg)。熔点:163-167℃。1H-NMR(δppm,DMSO-d6,400MHz):13.05(s,1H),10.3(s,1H),7.83(d,J7.6,1H),7.70-7.58(m,5H),7.57-7.46(m,2H),7.40-7.31(m,2H).MS(m/z):386.15([M-H]-)。
实施例21
2-(3,5-二氯-3′-乙氧基联苯-4-基氨甲酰基)苯甲酸:
由中间产物14(150mg,0.53mmol)和邻苯二甲酸酐(157mg,1.06mmol)获得呈白色固体的标题化合物(30mg)。熔点:135.9-138.2℃。1H-NMR(δppm,DMSO-d6,400MHz):13.0(s,1H),10.37(s,1H),7.86(s,2H),7.80(d,J7.3,1H),7.74-7.64(m,2H),7.62-7.55(m,1H),7.38(t,J7.9,1H),7.32-7.26(m,2H),7.00-6.96(m,1H),4.12(q,J7,2H),1.34(t,J7,3H).MS(m/z):429.30([M-H]-)。
实施例22
2-[3-氟-3′-(三氟甲氧基)联苯-4-基氨甲酰基]苯甲酸
由中间产物15(100mg,0.44mmol)和邻苯二甲酸酐(130mg,0.9mmol)获得呈白色固体的标题化合物(124mg)。熔点:128.3-132.1℃。1H-NMR(δppm,DMSO-d6,400MHz):13.07(s,1H),10.28(s,1H),7.99(t,J8.3,1H),7.88(d,J7.4,1H),7.77(d,J8,1H),7.67(s,1H),7.69-7.52(m,6H),7.37(d,J8.2,1H).MS(m/z):417.86([M-H]-)。
实施例23
2-[2′-氟-3-(三氟甲氧基)联苯-4-基氨甲酰基]苯甲酸:
由中间产物16(100mg,0.36mmol)和邻苯二甲酸酐(109mg,0.72mmol)获得呈白色固体的标题化合物(82mg)。熔点:142.2-148.1℃。1H-NMR(δppm,DMSO-d6,400MHz):13.08(s,1H),10.36(s,1H),8.03(d,J8.2,1H),7.90(d,J7.8,1H),7.68(t,J7.5,1H),7.65-7.54(m,4H),7.49-7.41(m,2H),7.38-7.30(m,2H).MS(m/z):418.00([M-H]-)。
实施例24
2-(3,5-二氯-2′-氟联苯-4-基氨甲酰基)苯甲酸:
由中间产物17(100mg,0.39mmol)和邻苯二甲酸酐(115mg,0.78mmol)获得呈白色固体的标题化合物(78mg)。熔点:185.4-193.6℃。1H-NMR(δppm,DMSO-d6,400MHz):13.02(s,1H),10.42(s,1H),7.81(d,J7.4,1H),7.74(s,2H),7.72-7.58(m,4H),7.53-7.47(m,1H),7.40-7.31(m,2H).MS(m/z):402.11([M-H]-)。
实施例25
2-(3,5-二氟-3′-异丙氧基联苯-4-基氨甲酰基)苯甲酸:
由中间产物18(100mg,0.38mmol)和邻苯二甲酸酐(112mg,0.76mmol)获得呈白色固体的标题化合物(64mg)。熔点:122-125℃。1H-NMR(δppm,DMSO-d6,400MHz):13.05(s,1H),10.20(s,1H),7.83(d,J7.5,1H),7.66(t,J7.3,1H),7.60-7.52(m,4H),7.37(t,J7.8,1H),7.30-7.24(m,2H),6.96(dd,J2.1,8.2,1H),4.76(七重峰,J6.0,1H),1.28(d,J6,6H).MS(m/z):410.02([M-H]-)。
实施例26
2-(3,5-二氟-3′-丙氧基联苯-4-基氨甲酰基)苯甲酸:
由中间产物19(100mg,0.38mmol)和邻苯二甲酸酐(112mg,0.76mmol)获得呈白色固体的标题化合物(68mg)。熔点:128.6-132.1℃。1H-NMR(δppm,DMSO-d6,400MHz):13.05(s,1H),10.19(s,1H),7.83(d,J7.7,1H),7.66(t,J7.4,1H),7.62-7.52(m,4H),7.37(t,J7.8,1H),7.32-7.26(m,2H),6.97(dd,J2,8.1,1H),4.01(t,J6.5,2H),1.77-1.67(m,2H),0.99(t,J7.4,3H).MS(m/z):410.16([M-H]-)。
实施例27
4,5-二氯-2-(2′,3-二氯-5-氟联苯-4-基氨甲酰基)苯甲酸:
由中间产物20(100mg,0.39mmol)和5,6-二氯异苯并呋喃-1,3-二酮(169mg,0.78mmol)获得呈白色固体的标题化合物(110mg)。熔点:202.3-206.5℃。1H-NMR(δppm,DMSO-d6,400MHz):13.60(s,1H),10.50(s,1H),8.04(s,1H),7.82(s,1H),7.63-7.58(m,1H),7.52-7.43(m,5H).MS(m/z):471.69([M-H]-)。
实施例28
4,5-二氯-2-(2′,3-二氯-5-氟联苯-4-基氨甲酰基)苯甲酸:
由中间产物5(100mg,0.4mmol)和4,7-二氯异苯并呋喃-1,3-二酮(173mg,0.8mmol)获得呈白色固体的标题化合物(51mg)。熔点:126.9-131.4℃。1H-NMR(δppm,DMSO-d6,400MHz):13.96(s,1H),10.56(s,1H),7.68(s,2H),7.55(d,J9.1,2H),7.38(t,J7.9,1H),7.32-7.26(m,2H),6.97(dd,J1.7,12.2,1H),4.12(q,J7,2H),1.34(t,J7,3H)。
实施例29
4,5-二氯-2-(2′,3-二氯-5-氟联苯-4-基氨甲酰基)苯甲酸:
由中间产物21(90mg,0.31mmol)和邻苯二甲酸酐(90mg,0.6mmol)获得呈白色固体的标题化合物(39mg)。熔点:128-130℃。1H-NMR(δppm,DMSO-d6,400MHz):13.02(s,1H),10.23(s,1H),7.82(d,J7.9,1H),7.73(s,1H),7.60-7.57(m,4H),7.37(t,J7.9,1H),7.32-7.25(m,2H),6.99-6.96(m,1H),4.06(t,J6.4,2H),1.73-1.68(m,2H),1.45(h,J7.5,2H),0.94(t,J7.4,3H).MS(m/z):440.19([M-H]-)。
实施例30
4,5-二氯-2-(2′-氯-3,5-二氟联苯-4-基氨甲酰基)苯甲酸:
由中间产物6(100mg,4.18mmol)和5,6-二氯异苯并呋喃-1,3-二酮(181mg,8.4mmol)获得呈白色固体的标题化合物(150mg)。熔点:202-205.5℃。1H-NMR(δppm,DMSO-d6,400MHz):13.61(s,1H),10.45(s,1H),8.04(s,1H),7.83(s,1H),7.62-7.58(m,1H),7.52-7.49(m,1H),7.48-7.43(m,2H),7.30(d,J8.5,2H).MS(m/z):455.94([N-H]-)。
实施例31
2-(3-氯-5-氟-3′-异丁氧基联苯-4-基氨甲酰基)苯甲酸:
由中间产物22(100mg,4.18mmol)和5,6-二氯异苯并呋喃-1,3-二酮(181mg,8.4mmol)获得呈白色固体的标题化合物(150mg)。熔点:202-205.5℃。1H-NMR(δppm,DMSO-d6,400MHz):13.03(s,1H),10.23(s,1H),7.82(d,J7.4,1H),7.73(s,1H),7.70-7.57(m,4H),7.38(t,J7.8,1H),7.32-7.26(m,2H),6.99(dd,J1.7,8.2,1H),3.83(d,J6.5,2H),2.10-1.99(m,1H),1.00(d,J6.7,6H).MS(m/z):439.84([M-H]-)。
实施例32
2-(2′,3,5-三氟联苯-4-基氨甲酰基)苯甲酸:
由中间产物23(100mg,0.44mmol)和邻苯二甲酸酐(130mg,0.88mmol)获得呈白色固体的标题化合物(72mg)。熔点:152.2-156.3℃。1H-NMR(δppm,DMSO-d6,400MHz):13.06(s,1H),10.25(s,1H),7.84(d,J7.6,1H),7.70-7.56(m,4H),7.52-7.45(m,1H),7.43-7.38(m,2H),7.36-7.31(m,2H).MS(m/z):369.91([M-H]-)。
实施例33
2-(2′,3,5-三氯联苯-4-基氨甲酰基)苯甲酸:
由中间产物24(100mg,0.37mmol)和邻苯二甲酸酐(130mg,0.88mmol)获得呈白色固体的标题化合物(20mg)。熔点:182-185℃。1H-NMR(δppm,DMSO-d6,400MHz):13.01(s,1H),10.40(s,1H),7.82(d,J7.2,1H),7.72-7.67(m,2H),7.64-7.59(m,4H),7.53-7.50(m,1H),7.49-7.45(m,2H).MS(m/z):419.61([M-H]-)。
实施例34
2-(3,5-二氟-3′-异丁氧基联苯-4-基氨甲酰基)苯甲酸:
由中间产物25(100mg,0.36mmol)和邻苯二甲酸酐(106mg,0.72mmol)获得呈白色固体的标题化合物(34mg)。熔点:112.6-116.4℃。1H-NMR(δppm,DMSO-d6,400MHz):13.04(s,1H),10.18(s,1H),7.83(d,J7.5,1H),7.68-7.64(m,1H),7.62-7.52(m,4H),7.37(t,J7.8,1H),7.33-7.25(m,2H),6.98(d,J8.2,1H),3.84(d,J6.5,2H),2.10-1.99(m,1H),1.00(d,J6.7,6H).MS(m/z):423.95([M-H]-)。
实施例35
2-(3′-丁氧基-3,5-二氟联苯-4-基氨甲酰基)苯甲酸:
由中间产物26(100mg,0.36mmol)和邻苯二甲酸酐(106mg,0.72mmol)获得呈白色固体的标题化合物(32mg)。熔点:119.3-123.3℃。1H-NMR(δppm,DMSO-d6,400MHz):13.04(s,1H),10.19(s,1H),7.83(d,J7.4,1H),7.69-7.63(m,1H),7.62-7.52(m,4H),7.37(t,J7.9,1H),7.32-7.26(m,2H),6.97(dd,J1.6,8,1H),4.05(t,J6.4,2H),1.72(q,J6.4,2H),1.47(h,J7.5,2H),0.94(t,J7.3,3H).MS(m/z):423.88([M-H]-)。
实施例36
N-(3-氯-3′-乙氧基-5-氟联苯-4-基)-2-(羟甲基)苯甲酰胺:
向2-(甲氧基羰基)苯甲酸(590mg,3.27mmol)于二氯甲烷(10ml)中的溶液添加草酰氯(0.86ml,9.8mml)和2滴DMF并冷却至0℃并且在环境温度下搅拌30min。30min后,去除溶剂以获得2-(氯甲酰基)苯甲酸甲酯(定量)。在0℃下将该中间产物(401mg,2.03mmol)于二氯甲烷中的溶液加入中间产物10(540mg,2.03mmol)和吡啶(0.19ml,2.43mmol)于二氯甲烷(5ml)中的溶液并且在环境温度下搅拌30min。后处理(CH2Cl2/H2O)并纯化产生呈灰白色固体的2-(3-氯-3′-乙氧基-5-氟联苯-4-基氨甲酰基)苯甲酸甲酯(250mg)。在0℃下,向该产物(200mg,0.47mmol)于THF(5ml)中的溶液添加硼氢化锂(20mg,0.94mmol)并且在环境温度下搅拌混合物2h。后处理(EtOAc/10%NH4Cl水溶液,然后为H2O)并纯化获得呈白色固体的标题化合物(30mg)。熔点:139.2-141.5℃。1H-NMR(δppm,DMSO-d6,400MHz):10.22(s,1H),7.76(s,1H),7.73-7.60(m,3H),7.54(t,J6.7,1H),7.43-7.36(m,2H),7.33-7.26(m,2H),6.97(dd,J1.8,8.1,1H),5.32(t,J5.6,1H),4.72(d,J5.6,2H),4.12(q,J7,2H),1.35(t,J7,3H).。
实施例37
N-(3′-乙氧基-3,5-二氟联苯-4-基)-2-(羟甲基)苯甲酰胺:
将2-(氯甲酰基)苯甲酸甲酯(如实施例37所述制备,361mg,2.0mmol)于二氯甲烷中的溶液缓慢加入中间产物5(500mg,2.0mmol)和吡啶(0.19ml,2.43mmol)于二氯甲烷(5ml)中的溶液并且在0℃下搅拌和在环境温度下搅拌30min。后处理(CH2Cl2/H2O)并纯化产生呈浅黄色固体的2-(3′-乙氧基-3,5-二氟联苯-4-基氨甲酰基)苯甲酸甲酯(212mg)。在0℃下,向该中间产物(200mg,0.48mmol)于THF(3ml)中的溶液中添加硼氢化锂(21mg,0.96mmol)并且在环境温度下搅拌混合物2h。后处理(EtOAc/10%NH4Cl水溶液,然后为H2O)并纯化产生呈白色固体的标题化合物(21mg)。熔点:94.8-99.1℃。1H-NMR(δppm,DMSO-d6,400MHz):10.16(s,1H),7.64(d,J7.8,1H),7.61-7.51(m,4H),7.42-7.35(m,2H),7.32-7.26(m,2H),6.97(dd,J2,7.6,1H),5.31(t,J5.6,1H),4.70(d,J5.6,2H),4.11(q,J7,2H),1.35(t,J7,3H)。
实施例38
2-(3-氯-3′-乙氧基-5-氟联苯-4-基氨甲酰基)-6-氟苯甲酸:
由中间产物10(100mg,0.38mmol)和4-氟异苯并呋喃-1,3-二酮(125mg,0.75mmol)获得呈白色固体的标题化合物(20mg)。熔点:156.3-158.2℃。1H-NMR(δppm,DMSO-d6,400MHz):13.42(s,1H),10.44(s,1H),7.79-7.69(m,2H),7.59-7.50(m,3H),7.42-7.34(m,1H),7.32-7.24(m,2H),6.97(d,J7.6,1H),4.12(t,J7,2H),1.33(q,J7,3H)。
实施例39
2-[3-氯-5-氟-3′-(三氟甲氧基)联苯-4-基氨甲酰基]苯甲酸:
由中间产物27(150mg,0.6mmol)和邻苯二甲酸酐(176mg,1.2mmol)获得呈白色固体的标题化合物(38mg)。熔点:153-156.5℃。1H-NMR(δppm,DMSO-d6,400MHz):13.04(s,1H),10.28(s,1H),7.87-7.73(m,5H),7.69-7.55(m,4H),7.43(d,J7.6,1H).MS(m/z):451.95([M-H]-)。
实施例40
2-[4-(苄氧基)-2,6-二氟苯基氨甲酰基]苯甲酸:
由中间产物29(160mg,0.65mmol)和邻苯二甲酸酐(193mg,1.3mmol)获得呈白色固体的标题化合物(134mg)。熔点:176.2-180.6℃。1H-NMR(δppm,DMSO-d6,400MHz):12.98(bs,1H),9.88(s,1H),7.79(d,J7.6,1H),7.67-7.61(m,1H),7.60-7.52(m,2H),7.45(d,J7,2H),7.40(t,J7,2H),7.37-7.32(m,1H),6.90(d,J9.4,2H),5.14(s,2H)。
实施例41
2-[3′-(环戊氧基)-3,5-二氟联苯-4-基氨甲酰基]苯甲酸:
由中间产物32(150mg,0.6mmol)和邻苯二甲酸酐(176mg,1.2mmol)获得呈白色固体的标题化合物(38mg)。熔点:153-156.5℃。1H-NMR(δppm,DMSO-d6,400MHz):13.05(s,1H),10.18(s,1H),7.83(d,J7.6,1H),7.69-7.64(m,1H),7.62-7.49(m,4H),7.36(t,J8,1H),7.30-7.25(m,1H),7.23(m,1H),6.95(dd,J 2,8.1,1H),5.00-4.92(m,1H),2.00-1.90(m,2H),1.76-1.68(m,4H),1.64-1.54(m,2H).MS(m/z):436.13([M-H]-)。
实施例42
2-(3-氯-3′-(环戊氧基)-5-氟联苯-4-基氨甲酰基)苯甲酸:
由中间产物33(100mg,0.33mmol)和邻苯二甲酸酐(96mg,0.65mmol)获得呈白色固体的标题化合物(38mg)。熔点:122-126℃。1H-NMR(δppm,DMSO-d6,400MHz):13.02(s,1H),10.23(s,1H),7.82(d,J7.4,1H),7.71(s,1H),7.68-7.58(m,4H),7.37(t,J7.6,1H),7.30-7.21(m,2H),6.95(dd,J2.2,8.1,1H),5.00-4.93(s,1H),2.00-1.88(m,2H),1.80-1.68(m,4H),1.63-1.54(m,2H).MS(m/z):452.16([M-H]-)。
实施例43
2-[3′-(二氟甲氧基)-3,5-二氟联苯-4-基氨甲酰基]苯甲酸:
由中间产物34(40mg,0.15mmol)和邻苯二甲酸酐(43mg,0.29mmol)获得呈白色固体的标题化合物(36mg)。熔点:148.2-150.5℃。1H-NMR(δppm,DMSO-d6,400MHz):13.05(s,1H),10.22(s,1H),7.84(d,J7.7,1H),7.69-7.51(m,8H),7.36(t,J74,1H),7.22(dd,J1.8,9.7,1H)。
实施例44
2-[3-氯-3′-(二氟甲氧基)-5-氟联苯-4-基氨甲酰基]苯甲酸:
由中间产物35(40mg,0.14mmol)和邻苯二甲酸酐(41mg,0.28mmol)获得呈白色固体的标题化合物(41mg)。熔点:156.5-159.5℃。1H-NMR(δppm,DMSO-d6,400MHz):13.03(s,1H),10.26(s,1H),7.83(d,J7.6,1H),7.79(s,1H),7.75-7.70(m,1H),7.69-7.58(m,5H),7.54(t,J6.1,1H),7.37(t,J74,1H),7.22(dd,J1.8,7.8,1H)。
实施例45
2-(2′-氯-3,5-二氟-5′-甲氧基联苯-4-基氨甲酰基)苯甲酸:
由中间产物36(40mg,0.15mmol)和邻苯二甲酸酐(44mg,0.3mmol)获得呈白色固体的标题化合物(41mg)。熔点:167-172℃。1H-NMR(δppm,DMSO-d6,400MHz):13.06(s,1H),10.23(s,1H),7.85(d,J7.6,1H),7.69-7.65(m,1H),7.62-7.55(m,2H),7.48(d,J8.6,1H),7.29(d,J8.3,2H),7.08-7.00(m,2H),2.49(s,3H)。
实施例46
2-(3,3′,5-三氟-5′-甲氧基联苯-4-基氨甲酰基)苯甲酸:
由中间产物37(40mg,0.15mmol)和邻苯二甲酸酐(46mg,0.31mmol)获得呈白色固体的标题化合物(37mg)。熔点:166.2-167.8℃。1H-NMR(δppm,DMSO-d6,400MHz):13.04(s,1H),10.22(s,1H),7.84(d,J7.6,1H),7.70-7.52(m,5H),7.23(d,J9.8,1H),7.18(s,1H),6.88(d,J10.8,1H),3.85(s,3H)。
实施例47
2-[4-(苯并[d][1,3]间二氧杂环戊烯-5-基)-2,6-二氟苯基氨甲酰基]苯甲酸:
由中间产物38(40mg,0.15mmol)和邻苯二甲酸酐(46mg,0.31mmol)获得呈白色固体的标题化合物(37mg)。熔点:166.2-167.8℃。1H-NMR(δppm,DMSO-d6,400MHz):13.02(s,1H),10.14(s,1H),7.83(d,J5.9,1H),7.67-7.64(m,1H),7.60-7.56(m,2H),7.47(d,J9.2,2H),7.38(s,1H),7.26(dd,J1.5,8.2,1H),7.01(d,J8.1,1H),6.07(s,2H)。
实施例48
2-[4-(苯并[d][1,3]间二氧杂环戊烯-5-基)-2-氯-6-氟苯基氨甲酰基]苯甲酸:
由中间产物39(50mg,0.19mmol)和邻苯二甲酸酐(55mg,0.38mmol)获得呈白色固体的标题化合物(23mg)。熔点:182-184.5℃。1H-NMR(δppm,DMSO-d6,400MHz):13.00(s,1H),10.21(s,1H),7.81(d,J7.5,1H),7.68-7.56(m,5H),7.39(s,1H),7.26(dd,J1.4,9.4,1H),7.01(d,J8.1,1H),6.08(s,2H)。
实施例49
2-(3,5-二氟-3′,4′-二甲基基联苯-4-基氨甲酰基)苯甲酸:
由中间产物40(50mg,0.19mmol)和邻苯二甲酸酐(55mg,0.38mmol)获得呈白色固体的标题化合物(23mg)。熔点:182-184.5℃。1H-NMR(δppm,DMSO-d6,400MHz):13.03(s,1H),10.14(s,1H),7.83(d,J7.6,1H),7.67-7.64(m,1H),7.58(t,J7.1,2H),7.52(d,J9.3,2H),7.33-7.28(m,2H),7.04(d,J9,1H),3.86(s,3H),3.79(s,3H)。
实施例50
2-(3,3′,5-三氟-5′-甲氧基联苯-4-基氨甲酰基)苯甲酸:
由中间产物41(40mg,0.14mmol)和邻苯二甲酸酐(44mg,0.28mmol)获得呈白色固体的标题化合物(35mg)。熔点:164-166℃。1H-NMR(δppm,DMSO-d6,400MHz):13.02(s,1H),10.25(s,1H),7.85-7.78(m,2H),7.73(d,J11.2,1H),7.69-7.56(m,3H),7.24(d,J9.9,1H),7.18(s,1H),6.88(d,J10.8,1H),3.85(s,3H)。
实施例51
2-(3,3′-二氯-5-氟-5′-甲氧基联苯-4-基氨甲酰基)苯甲酸:
由中间产物42(40mg,0.14mmol)和邻苯二甲酸酐(44mg,0.28mmol)获得呈白色固体的标题化合物(41mg)。熔点:159.6-161.2℃。1H-NMR(δppm,DMSO-d6,400MHz):13.01(s,1H),10.25(s,1H),7.82(d,J7.9,1H),7.79(s,1H),7.74(d,J10.7,1H),7.69-7.57(m,3H),7.43(s,1H),7.28(s,1H),7.08(s,1H),3.86(s,3H)。
实施例52
2-[4-(2,3-二氢苯并呋喃-5-基)-2,6-二氟苯基氨甲酰基]苯甲酸:
由中间产物43(50mg,0.2mmol)和邻苯二甲酸酐(59mg,0.40mmol)获得呈白色固体的标题化合物(46mg)。熔点:176-177.5℃。1H-NMR(δppm,DMSO-d6,400MHz):13.02(s,1H),10.12(s,1H),7.83(d,J7.6,1H),7.67(s,2H),7.61-7.53(m,2H),7.49(d,J7.6,1H),7.43(d,J9.2,2H),6.84(d,J8.3,1H),4.57(t,J8.7,2H),3.23(t,J8.6,2H)。
实施例53
2-[2-氯-4-(2,3-二氢苯并呋喃-5-基)-6-氟苯基氨甲酰基]苯甲酸:
由中间产物44(40mg,0.15mmol)和邻苯二甲酸酐(44mg,0.30mmol)获得呈白色固体的标题化合物(44mg)。熔点:177-179℃。1H-NMR(δppm,DMSO-d6,400MHz):13.01(s,1H),10.18(s,1H),7.82(d,J7.6,1H),7.69-7.55(m,6H),7.50(d,J8.2,1H),6.85(d,J8.4,1H),4.58(t,J8.8,2H),3.23(t,J8.8,2H)。
实施例54
2-[4-(1,3-二甲基-1H-吲唑-5-基)-2,6-二氟苯基氨甲酰基]苯甲酸:
由中间产物45(25mg,0.09mmol)和邻苯二甲酸酐(27mg,0.18mmol)获得呈白色固体的标题化合物(16mg)。熔点:276.4-277.5℃。1H-NMR(δppm,DMSO-d6,400MHz):13.02(s,1H),10.14(s,1H),8.14(s,1H),7.83(d,J7.2,1H),7.79(d,J9,1H),7.68-7.57(m,6H),3.98(s,1H),2.53(s,3H)。
实施例55
2-(3′-氯-3,5-二氟-5′-甲氧基联苯-4-基氨甲酰基)苯甲酸:
由中间产物46(35mg,0.13mmol)和邻苯二甲酸酐(39mg,0.25mmol)获得呈白色固体的标题化合物(37mg)。熔点:171-175℃。1H-NMR(δppm,DMSO-d6,400MHz):13.04(s,1H),10.22(s,1H),7.83(d,J7.7,1H),7.70-7.55(m,5H),7.42(s,1H),7.28(s,1H),7.07(s,1H),3.85(s,3H)。
实施例56
2-(3-氯-5-氟-3′,4′-二甲基基联苯-4-基氨甲酰基)苯甲酸:
由中间产物47(30mg,0.1mmol)和邻苯二甲酸酐(31mg,0.2mmol)得如白色固体的标题化合物(24mg)。熔点:179.6-182.1℃。1H-NMR(δppm,DMSO-d6,400MHz):13.0(s,1H),10.18(s,1H),7.82(d,J7.7,1H),7.72(s,1H),7.68-7.57(m,4H),7.33-7.28(m,2H),7.04(d,J8.8,1H),3.86(s,3H),3.79(s,3H)。
实施例57
2-(2′,3-二氯-5-氟-5′-甲氧基联苯-4-基氨甲酰基)苯甲酸:
由中间产物48(30mg,0.1mmol)和邻苯二甲酸酐(30mg,0.2mmol)获得呈白色固体的标题化合物(54mg)。熔点:165-167℃。1H-NMR(δppm,DMSO-d6,400MHz):13.03(s,1H),10.27(s,1H),7.83(d,J7.4,1H),7.70-7.57(m,3H),7.51-7.47(m,2H),7.43(d,J10,1H),7.08-7.01(m,2H),3.80(s,3H)。
实施例58
2-(2′,3,5-三氟-5′-甲氧基联苯-4-基氨甲酰基)苯甲酸:
由中间产物49(30mg,0.1mmol)和邻苯二甲酸酐(38mg,0.22mmol)获得呈白色固体的标题化合物(23mg)。熔点:173.4-176.5℃。1H-NMR(δppm,DMSO-d6,400MHz):13.04(s,1H),10.24(s,1H),7.84(d,J7.7,1H),7.67(t,J7.1,1H),7.60(t,J8,2H),7.41(d,J8.6,2H),7.27(t,J9.5,1H),7.15-7.12(m,1H),7.03-6.96(m,1H),3.80(s,3H)。
实施例59
2-(4′-氯-3,5-二氟-3′-甲氧基联苯-4-基氨甲酰基)苯甲酸:
由中间产物50(80mg,0.3mmol)和邻苯二甲酸酐(85mg,0.6mmol)获得呈白色固体的标题化合物(42mg)。熔点:156.1-158.3℃。1H-NMR(δppm,DMSO-d6,400MHz):13.04(s,1H),10.21(s,1H),7.84(d,J12.6,2H),7.70-7.57(m,4H),7.55-7.49(m,1H),7.46(s,1H),7.34(d,J8.1,1H),3.97(s,3H)。
实施例60
2-(3,4′-二氯-5-氟-3′-甲氧基联苯-4-基氨甲酰基)苯甲酸:
由中间产物51(80mg,0.27mmol)和邻苯二甲酸酐(83mg,0.55mmol)获得呈白色固体的标题化合物(63mg)。熔点:147.6-150.4℃。1H-NMR(δppm,DMSO-d6,400MHz):13.02(s,1H),10.24(s,1H),7.85-7.79(m,2H),7.73(d,J7.8,1H),7.70-7.58(m,3H),7.51(d,J8.1,1H),7.46(s,1H),7.34(d,J6.5,1H),3.97(s,3H)。
实施例61
2-(3-氯-2′,5-二氟-5′-甲氧基联苯-4-基氨甲酰基)苯甲酸:
由中间产物52(70mg,0.26mmol)和邻苯二甲酸酐(76mg,0.52mmol)获得呈灰白色固体的标题化合物(40mg)。熔点:160.1-163.5℃。1H-NMR(δppm,DMSO-d6,400MHz):13.05(s,1H),10.28(s,1H),7.83(d,J7.3,1H),7.70-7.51(m,5H),7.28(d,J9.5,1H),7.17-7.11(m,1H),7.05-6.97(m,1H),3.81(s,3H)。
实施例62
2-(3,4′,5-三氟-3′-甲氧基联苯-4-基氨甲酰基)苯甲酸:
由中间产物53(200mg,0.79mmol)和邻苯二甲酸酐(230mg,1.58mmol)获得呈灰白色固体的标题化合物(60mg)。熔点:125.6-128.8℃。1H-NMR(δppm,DMSO-d6,400MHz):13.04(s,1H),10.18(s,1H),7.83(d,J7.6,1H),7.68-7.64(m,1H),7.63-7.54(m,4H),7.50(d,J8,1H),7.35-7.28(m,2H),3.94(s,3H)。
实施例63
2-[2,6-二氟-4-(3-甲基-1H-吲哚-5-基)苯基氨甲酰基]苯甲酸:
由中间产物54(66mg,0.25mmol)和邻苯二甲酸酐(75mg,0.51mmol)获得呈白色固体的标题化合物(84mg)。熔点:182-186.5℃。1H-NMR(δppm,DMSO-d6,400MHz):13.03(s,1H),10.86(s,1H),10.11(s,1H),7.87(s,1H),7.83(d,J7.3,1H),7.69-7.63(m,1H)7.62-7.57(m,2H),7.52(d,J9.3,2H),7.45(d,J8.5,1H),7.40(d,J8.4,1H),7.15(s,1H),2.31(s,3H)。
实施例64
2-[2,6-二氟-4-(3-甲基-1H-吲唑-5-基)苯基氨甲酰基]苯甲酸:
由中间产物55(50mg,0.19mmol)和邻苯二甲酸酐(57mg,0.39mmol)获得呈白色固体的标题化合物(38mg)。熔点:179-184℃。1H-NMR(δppm,DMSO-d6,400MHz):12.79(bs,1H),10.15(s,1H),8.14(s,1H),7.84(d,J7.3,1H),7.73(d,J7.3,1H),7.69-7.65(m,1H),7.62-7.55(m,4H),7.53(d,J8.7,1H),6.02(bs,1H),2.54(s,3H)。
实施例65
2-(3-氯-3′-乙基-5-氟联苯-4-基氨甲酰基)苯甲酸:
由中间产物56(50mg,0.19mmol)和邻苯二甲酸酐(57mg,0.39mmol)获得呈白色固体的标题化合物(38mg)。熔点:179-184℃。1H-NMR(δppm,DMSO-d6,400MHz):13.02(bs,1H),10.22(s,1H),7.82(d,J7.7,1H),7.74-7.54(m,7H),7.39(t,J7.6,1H),7.27(d,J7.6,1H).2.68(q,J7.6,2H),1.23(t,J7.6,3H)。
实施例66
2-(3-氯-3′-乙氧基-2′,5-二氟联苯-4-基氨甲酰基)苯甲酸:
由中间产物57(60mg,0.21mmol)和邻苯二甲酸酐(63mg,0.42mmol)获得呈白色固体的标题化合物(54mg)。熔点:160-163℃。1H-NMR(δppm,DMSO-d6,400MHz):13.04(s,1H),10.29(s,1H),7.83(d,J7.6,1H),7.70-7.55(m,4H),7.51(d,J10,1H),7.26-7.21(m,2H),7.16-7.10(m,1H),4.14(q,J6.8,2H),1.37(t,J6.8,3H)。
实施例67
2-[2-氯-4-(2,3-二氢苯并[b][1,4]二噁英-6-基)-6-氟苯基氨甲酰基]苯甲酸:
由中间产物58(60mg,0.21mmol)和邻苯二甲酸酐(63mg,0.42mmol)获得呈白色固体的标题化合物(54mg)。熔点:147-151℃。1H-NMR(δppm,DMSO-d6,400MHz):13.02(s,1H),10.19(s,1H),7.82(d,J7.5,1H),7.68-7.53(m,5H),7.29(d,J2.1,1H),7.24(dd,J2.1,8.4,1H),6.94(d,J8.4,1H),4.28(s,4H)。
实施例68
2-[3-氯-5-氟-3′-(2,2,2-三氟乙氧基)联苯-4-基氨甲酰基]苯甲酸:
由中间产物59(80mg,0.25mmol)和邻苯二甲酸酐(74mg,0.5mmol)获得呈白色固体的标题化合物(21mg)。熔点:133-137℃。1H-NMR(δppm,DMSO-d6,400MHz):13.02(s,1H),10.25(s,1H),7.86-7.79(m,2H),7.72(d,J10.5,1H),7.70-7.55(m,3H),7.48-7.42(m,3H),7.15-7.06(m,1H),4.88(q,J9.3,2H)。
实施例69
2-(3-氟-3′-甲氧基联苯-4-基氨甲酰基)苯甲酸:
由中间产物60(150mg,0.69mmol)和邻苯二甲酸酐(200mg,1.4mmol)获得呈白色固体的标题化合物(82mg)。熔点:141-143℃。1H-NMR(δppm,DMSO-d6,400MHz):13.04(s,1H),10.23(s,1H),7.97-7.93(m,1H),7.87(d,J7.5,1H),7.70-7.50(m,5H),7.37(t,J7.9,1H),7.29-7.20(m,2H),6.94(d,J6.1,1H),3.82(s,3H)。
实施例70
2-(3′-乙氧基联苯-4-基氨甲酰基)苯甲酸:
由中间产物61(150mg,0.69mmol)和邻苯二甲酸酐(200mg,1.4mmol)获得呈白色固体的标题化合物(82mg)。熔点:141-143℃。1H-NMR(δppm,DMSO-d6,400MHz):13.03(s,1H),10.41(s,1H),7.87(d,J7.6,1H),7.76(d,J8.6,2H),7.69-7.61(m,3H),7.60-7.52(m,2H),7.33(t,J7.9,1H),7.20(d,J7.8,1H),7.14(s,1H),6.87(dd,J2.1,8.0,1H),4.07(q,J7,2H),1.34(t,J7,2H)。
实施例71
2-[3′-(乙硫基)-3,5-二氟联苯-4-基氨甲酰基]苯甲酸:
由中间产物62(150mg,0.69mmol)和邻苯二甲酸酐(200mg,1.4mmol)获得呈白色固体的标题化合物(65mg)。熔点:137.8-142.1℃。1H-NMR(δppm,DMSO-d6,400MHz):13.03(s,1H),10.2(s,1H),7.84(d,J7.6,1H),7.70-7.52(m,7H),7.42(t,J7.7,1H),7.34(d,J7.6,1H),3.08(q,J7.3,2H),1.26(t,J7.3,3H).MS(m/z):413.80([M+H]+)。
实施例72
2-[3′-(乙基亚磺酰基)-3,5-二氟联苯-4-基氨甲酰基]苯甲酸:
向实施例71(210mg,0.43mmol)于水-丙酮(1∶1,4.2ml)中的溶液添加过硫酸氢钾制剂(241mg,0.39mmol)并且在环境温度下搅拌2h。过滤反应混合物中形成的固体并干燥以获得呈白色固体的标题化合物(95mg)。1H-NMR(δppm,DMSO-d6,400MHz):13.04(s,1H),10.26(s,1H),8.19(s,1H),8.14(d,J7.8,1H),7.91(d,J7.8,1H),7.84(d,J7.3,1H),7.77(t,J7.8,1H),7.72-7.64(m,3H),7.62-7.56(m,2H),3.41(q,J7.3,2H),1.13(t,J7.3,3H).MS(m/z):430.07([M+H]+)。
实施例73
2-(3′-环丙氧基-3,5-二氟联苯-4-基氨甲酰基)苯甲酸:
由中间产物63(160mg,0.61mmol)和邻苯二甲酸酐(181mg,1.2mmol)获得呈白色固体的标题化合物(96mg)。熔点:125-127℃。MS(m/z):410.2([M+H]+)。
实施例74
2-(3′-乙氧基-3,5-二氟联苯-4-基氨甲酰基)-6(5)-甲基苯甲酸:
由中间产物5(200mg,0.8mmol)和4-甲基异苯并呋喃-1,3-二酮(260mg,1.6mmol)获得呈白色固体的标题化合物(75mg)。熔点:138-140℃。1H-NMR(δppm,DMSO-d6,400MHz):13.02(s,1H),10.09(s,1H),7.77(d,J7.8,1H),7.52(d,J9.3,3H),7.47-7.41(m,1H),7.38(t,J7.9,1H),7.32-7.24(m,2H),6.98-6.95(m,1H),4.11(q,J6.9,2H),2.41(s,3H),1.35(t,J6.9,3H).MS(m/z):410.07([M-H]-)。
实施例75
2-[4-(3-乙基-1H-吲哚-5-基)-2,6-二氟苯基氨甲酰基]苯甲酸:
由中间产物65(250mg,0.992mmol)和邻苯二甲酸酐(271mg,1.84mmol)获得呈白色固体的标题化合物(75mg)。熔点:157.9-160.9℃。1H-NMR(δppm,DMSO-d6,400MHz):13.03(s,1H),10.88(s,1H),10.11(s,1H),7.89(s,1H),7.83(d,J7.3,1H),7.69-7.63(m,1H),7.62-7.56(m,2H),7.51(d,J9.3,2H),7.47-7.39(m,2H),7.16(s,1H),2.75(q,J7.4,2H),1.28(t,J7.4,3H).MS(m/z):418.75([M-H]-)。
实施例76
2-(3′-乙氧基-3,5-二氟联苯-4-基氨甲酰基)烟酸:
由中间产物5(150mg,0.6mmol)和氟[3,4-b]吡啶-5,7-二酮(180mg,1.2mmol)获得呈灰色固体的标题化合物(15mg)。熔点:207-210℃。MS(m/z):399.08([M+H]+)。
实施例77
4-(3′-乙氧基-3,5-二氟联苯-4-基氨甲酰基)烟酸:
由中间产物5(100mg,0.4mmol)和氟[3,4-c]吡啶-1,3-二酮(119mg,0.8mmol)获得呈白色固体的标题化合物(10mg)。熔点:219-221℃。MS(m/z):399.01([M+H]+)。区域化学排布基于早期报道,例如Nailton等Bioorganic & Medicinal Chemistry Letters 2010,20(1),74-77。
实施例78
2-[3′-(乙硫基)-2,3,5,6-四氟联苯-4-基氨甲酰基]苯甲酸:
由中间产物66(280mg,0.93mmol)和邻苯二甲酸酐(206mg,1.4mmol)获得呈白色固体的标题化合物(82mg)。熔点:158-160℃。MS(m/z):448.29([M-H]-)。
实施例79
2-(2′-氯-2-氟-5′-甲氧基联苯-4-基氨甲酰基)苯甲酸:
由中间产物67(210mg,0.83mmol)和邻苯二甲酸酐(185mg,1.2mmol)获得呈灰色固体的标题化合物(50mg)。熔点:185-187℃。MS(m/z):398.24([M-H]-)。
实施例80
2-(3-氟-3′-丙氧基联苯-4-基氨甲酰基)苯甲酸:
由中间产物68(170mg,0.7mmol)和邻苯二甲酸酐(153mg,1.03mmol)获得呈白色固体的标题化合物(14mg)。熔点:116-119℃。MS(m/z):394.2([M+H]+)。
实施例81
2-(3′-丙氧基联苯-4-基氨甲酰基)苯甲酸:
由中间产物69(60mg,0.26mmol)和邻苯二甲酸酐(58mg,0.4mmol)获得呈白色固体的标题化合物(60mg)。熔点:152-154℃。MS(m/z):376.2([M+H]+)。
实施例82
2-[3′-(乙硫基)-2-氟联苯-4-基氨甲酰基]苯甲酸:
由中间产物70(430mg,1.74mmol)和邻苯二甲酸酐(380mg,2.6mmol)获得呈白色固体的标题化合物(200mg)。熔点:74-76℃。MS(m/z):395.72([M+H]+)。
实施例83
2-[3,5-二氟-3′-(2,2,2-三氟乙氧基)联苯-4-基氨甲酰基]苯甲酸:
由中间产物71(88mg,0.29mmol)和邻苯二甲酸酐(86mg,0.58mmol)获得呈白色固体的标题化合物(80mg)。熔点:152-156℃。1H-NMR(δppm,DMSO-d6,400MHz):13.04(s,1H),10.19(s,1H),7.84(d,J7.2,1H),7.68-7.53(m,6H),7.46-7.41(m,2H),7.13-7.06(m,1H),4.87(q,J9,2H)。
实施例84
2-(3′-乙基-3,5-二氟联苯-4-基氨甲酰基)苯甲酸:
由中间产物72(170mg,0.73mmol)和邻苯二甲酸酐(210mg,1.45mmol)获得呈白色固体的标题化合物(15mg)。熔点:132-136℃。1H-NMR(δppm,DMSO-d6,400MHz):13.04(s,1H),10.18(s,1H),7.83(d,J7.3,1H),7.69-7.48(m,7H),7.39(t,J7.6,1H),7.26(d,J7.3,1H),2.67(q,J7.6,2H),1.23(t,J7.6,3H)。
实施例85
2-(联苯-4-基氨甲酰基)苯甲酸:
由联苯-4-胺(65mg,0.38mmol)和邻苯二甲酸酐(85mg,0.58mmol)获得呈白色固体的标题化合物(46mg)。熔点:276-278℃。MS(m/z):318.1([M+H]+)。
实施例86
2-(2′-氯联苯-4-基氨甲酰基)苯甲酸:
由中间产物73(170mg,0.83mmol)和邻苯二甲酸酐(185mg,1.25mmol)获得呈白色固体的标题化合物(223mg)。熔点:243-247℃。MS(m/z):352.1([M+H]+)。
实施例87
2-(3′-甲氧基联苯-4-基氨甲酰基)苯甲酸:
由中间产物74(170mg,0.83mmol)和邻苯二甲酸酐(185mg,1.25mmol)获得呈白色固体的标题化合物(223mg)。熔点:243-247℃。MS(m/z):348.2([M+H]+)。
实施例88
2-[3′-(三氟甲氧基)联苯-4-基氨甲酰基]苯甲酸:
由中间产物75(280mg,1.1mmol)和邻苯二甲酸酐(245mg,1.66mmol)获得呈白色固体的标题化合物(110mg)。熔点:154.4-158.5℃。MS(m/z):402.2([M+H]+)。
实施例89
2-[3′-(乙硫基)-2,6-二氟联苯-4-基氨甲酰基]苯甲酸:
由中间产物76(240mg,0.9mmol)和邻苯二甲酸酐(200mg,1.35mmol)获得呈白色固体的标题化合物(50mg)。熔点:162-167℃。MS(m/z):414.2([M+H]+)。
实施例90
2-(3′-乙基联苯-4-基氨甲酰基)苯甲酸:
由中间产物77(100mg,0.5mmol)和邻苯二甲酸酐(110mg,0.76mmol)获得呈灰白色固体的标题化合物(96mg)。熔点:178-182℃。MS(m/z):346.2([M+H]+)。
实施例91
2-(3′-丁氧基-2,3,5,6-四氟联苯-4-基氨甲酰基)苯甲酸:
由中间产物78(180mg,0.57mmol)和邻苯二甲酸酐(127mg,0.86mmol)获得呈白色固体的标题化合物(130mg)。熔点:215.5-218.5℃。MS(m/z):460.18([M-H]-)。
实施例92
2-(3′-丁氧基-3-氟联苯-4-基氨甲酰基)苯甲酸:
由中间产物79(170mg,0.65mmol)和邻苯二甲酸酐(145mg,0.98mmol)获得呈白色固体的标题化合物(130mg)。熔点:102-105℃。MS(m/z):406.17([M-H]-)。
实施例93
2-[3,5-二氟-3′-(三氟甲氧基)联苯-4-基氨甲酰基]苯甲酸:
由中间产物8(200mg,0.69mmol)和邻苯二甲酸酐(150mg,1.03mmol)获得呈白色固体的标题化合物(50mg)。熔点:158-160℃。MS(m/z):435.93([M-H]-)。
实施例94
2-(3′-环丙氧基-3-氟联苯-4-基氨甲酰基)苯甲酸:
由中间产物80(100mg,0.41mmol)和邻苯二甲酸酐(91mg,0.62mmol)获得呈白色固体的标题化合物(120mg)。熔点:134.5-137.5℃。MS(m/z):390.27([M-H]-)。
实施例95
2-(3′-环丙氧基联苯-4-基氨甲酰基)苯甲酸:
由中间产物81(98mg,0.43mmol)和邻苯二甲酸酐(96mg,0.65mmol)获得呈白色固体的标题化合物(90mg)。熔点:150.2-154.3℃。MS(m/z):372.14([M-H]-)。
实施例96
2-(3′-丁氧基联苯-4-基氨甲酰基)苯甲酸:
由中间产物82(80mg,0.33mmol)和邻苯二甲酸酐(73mg,0.5mmol)获得呈白色固体的标题化合物(37mg)。熔点:155-157℃。MS(m/z):388.38([M-H]-)。
实施例97
2-(3′-丁氧基-2-氟联苯-4-基氨甲酰基)苯甲酸:
由中间产物83(240mg,0.92mmol)和邻苯二甲酸酐(205mg,1.3mmol)获得呈白色固体的标题化合物(171mg)。熔点:164-167℃。MS(m/z):406.31([M-H]-)。
实施例98
2-(3′-丁氧基-2,6-二氟联苯-4-基氨甲酰基)苯甲酸:
由中间产物84(170mg,0.6mmol)和邻苯二甲酸酐(136mg,0.9mmol)获得呈灰白色固体的标题化合物(91mg)。熔点:181.1-184.2℃。MS(m/z):423.95([M-H]-)。
实施例99
2-[2,6-二氟-4-(3-丙基-1H-吲哚-5-基)苯基氨甲酰基]苯甲酸:
由中间产物86(240mg,0.84mmol)和邻苯二甲酸酐(186mg,1.25mmol)获得呈白色固体的标题化合物(150mg)。熔点:76-80℃。1H-NMR(δppm,DMSO-d6,400MHz):10.88(s,1H),7.88(s,1H),7.81(d,J6.6,1H),7.75-7.71(m,1H),7.53-7.47(m,5H),7.44-7.38(m,2H),7.14(s,1H),2.72(t,J7.4,2H),1.69(h,J7.5,2H),0.96(t,J7.3,3H).MS(m/z):433.13([M-H]-)。
实施例100
2-[2-氯-4-(3-乙基-1H-吲哚-5-基)-6-氟苯基氨甲酰基]苯甲酸:
由中间产物87(60mg,0.21mmol)和邻苯二甲酸酐(46mg,0.31mmol)获得呈白色固体的标题化合物(25mg)。熔点:98-102℃。MS(m/z):435.23([M-H]-)。
生物学测定
可通过许多生物学和药理学测定确认本发明化合物的性质。以下例示出可用根据本发明所述的化合物和/或其药学上可接受的盐进行的生物学和药理学测定。类似地,也可使用其它测定,例如对人全血和PBMC的细胞因子(IL-17和干扰素γ)评估来测试本发明的化合物。
也可在各种动物模型中测试本发明的化合物以确定本发明化合物的各种治疗潜力。
1.体外DHODH抑制测定
可通过许多生物学和药理学测定确认本发明化合物的性质。以下例示出可用根据本发明所述的化合物和/或其药学上可接受的盐进行的生物学和药理学测定。类似地,也可使用其它测定,例如对人全血和PBMC的细胞因子(IL-17、干扰素γ等)评估来测试本发明的化合物。
二氢-乳清酸脱氢酶抑制测定
在嘧啶的从头生物合成期间,二氢-乳清酸脱氢酶(DHODH)催化二氢乳清酸还原为乳清酸。通过二氢乳清酸推动2,6-二氯酚靛酚(DCIP)还原测定U937膜制备中对DHODH活性的抑制。
在含有1mM EDTA的20mM Tris/HCl(pH 7.2)中匀化U937细胞。通过在2000×g下离心10min去除细胞碎片。通过在4℃下,在160000×g下离心上清液1h粒化膜部分并且用含有125mM蔗糖和150mM NaCl的缓冲液洗涤。洗涤之后,将小颗粒溶于含有150mMNaCl、1mM EDTA和1%辛基糖苷的20mM Tris/HCl中,置于冰上1h。通过在4℃下,在100000×g下离心1h去除微粒物质。将提取物(~50μg蛋白质)加入96孔板中含有所需浓度的抑制剂的测定混合物(200μMCoQD、500μM二氢-乳清酸、100mM HEPES pH 8.0中的75μM DCIP、150mM NaCl、10%丙三醇、0.05%Triton X-100)中。在37℃下培育混合物4h,然后用酶标仪(BMG Labtech.,Germany)在600nm下测量吸光度的变化。使用GraphPad Prism分析数据。基于二氢乳清酸还原的抑制百分比测定每种化合物的IC50。
结果:
表-2
2.抑制IL-17从小鼠脾细胞释放:按1×106个细胞/ml的浓度将从Balb/c小鼠分离的脾细胞重悬于RPMI培养基中并接种于6孔板上。在用10ng/ml PMA+1μM离子霉素诱导之前,用所需浓度的抑制剂培育细胞15min。培育3h后,收集上清液并使用ELISA试剂盒分析IL-17浓度。使用GraphPad Prism分析数据。基于和对照相比,由试验化合物引起的抑制百分比测定每种化合物的IC50值。
结果:
表-3
3.用流式细胞术测定IL-17生成细胞:在用Cytostim(MiltenyBiotech,Germany)刺激之前,用所需浓度的试验化合物刺激和处理从人血中分离的PBMC。4h后,按照生产商说明,使用IL-17分泌测定试剂盒为IL-17分泌细胞染色并且归一化为PBMC种群中的总CD4+细胞。使用Graph pad prism分析数据。例如,实施例29显示在1μM下试验时抑制为43.6%。结果表明本发明化合物抑制IL17释放的潜力不依赖于DHODH抑制。
4.体外抑制外周血单核细胞(PBMC)中的增殖和细胞因子释放
a.抑制PHA诱导的PBMC增殖:使用Histopaque通过密度梯度从新收集的HWB分离PBMC并接种于96孔板中。用所需浓度的抑制剂培育孔15min。通过在37℃下于含有95%CO2的氛围中添加2μM植物血球凝集素来诱导增殖。48h后使用3-(4,5-二甲基噻唑-2-基)-2,5-二苯基溴化四氮唑(MTT)测定法测定存活率。使用GraphPadPrism分析数据。基于和对照相比由试验化合物引起的抑制百分比来测定每种化合物的抑制百分比和/或GI50值。例如,实施例29、42和75显示当在10μM下试验时抑制大于70%。
b.抑制PHA诱导的细胞因子(IL17)释放:使用Histopaque通过密度梯度从新收集的HWB分离PBMC并接种于96孔板中。用所需浓度的抑制剂培育孔15min。通过在37℃下于含有95%CO2的氛围中添加2μM植物血球凝集素来诱导增殖。48h后收集上清液以便通过ELISA评估细胞因子。使用GraphPad Prism分析数据。基于和对照相比由试验化合物引起的抑制百分比来测定每种化合物的抑制百分比和IC50值。例如,实施例5显示当在10μM下试验时抑制大于50%。
c.抑制人全血中PHA诱导的CD4+细胞增殖:用所需浓度的抑制剂处理HWB并用5μM PHA诱导。48h后用流式细胞术测定CD4+细胞存活率%。使用GraphPad Prism分析数据。基于和对照相比由试验化合物引起的抑制百分比来测定每种化合物的抑制百分比和IC50值。例如,实施例29和75显示当在1μM下试验时抑制大于65%。
d.抑制PBMC中PHA诱导的CD4+细胞增殖:用所需浓度的抑制剂处理PBMC并用5μM PHA诱导。48h后用流式细胞术测定CD4+细胞存活率%。使用GraphPad Prism分析数据。基于和对照相比由试验化合物引起的抑制百分比来测定每种化合物的IC50值。例如,实施例29和75显示当在1μM下试验时抑制大于90%。
5.单剂量口服肝毒性测定:
使用8-10周龄,体重范围为18-25g的BALB/cJ(n=4或5/性别)。将它们饲养在控制温度和湿度和12h光/暗循环的条件下。使它们连续饮用瓶装泉水并任意进食标准食物。使用前使小鼠适应环境1周。在实验当天,使小鼠禁食12h过夜并通过口服途径施用试验项制剂(100mg/kg体重/口服)或媒介物(10ml/从)并且在试验项施用4h后喂食。施用24h后,从所有动物的眼窝窦收集血样并分离血清以评价肝毒性。通过使用可从Sigma(St.Louis,MO)购买获得的试剂盒测量丙氨酸转氨酶(ALT)和天冬氨酸转氨酶(AST)的血清酶活性测定肝功能的生物化学评估。
结果:发现本发明的化合物无肝毒性并且数据如本文下表-4所揭示。
6.已经或可使用以下给出的方法确定使用体内动物模型评估DHODH调节剂在各种抗炎性和自身免疫性病症中的效用。
i.抑制Wistar大鼠体内伴刀豆球蛋白诱导的淋巴细胞增殖:ConA常用于准备具有高水平的细胞毒性T-淋巴细胞的实验动物,因为这些细胞涉及人体内病毒感染的发展。为评估抑制剂对大鼠体内淋巴细胞增殖的影响,在静脉内施用5mg/kg伴刀豆球蛋白A之前,用10mg/kg(口服)的本发明化合物处理动物。48h后用Medonic血液分析仪测定淋巴细胞数。数据表明用试验化合物处理后外周血淋巴细胞减少~75%,这暗示了在免疫介导的病症(例如类风湿性关节炎)中化合物的治疗潜力。
ii.抑制Balb/c小鼠体内伴刀豆球蛋白诱导的IL-17释放:在静脉内施用20mg/kg伴刀豆球蛋白A之前,用10mg/kg(口服)的本发明化合物处理动物。2h后获得血浆并通过ELISA评估对IL-17释放的抑制。试验化合物使从Th17细胞的IL-17分泌以剂量依赖方式减少。
iii.抑制Balb/c小鼠体内TNBS诱导的结肠炎:雌性BALB/c小鼠禁食过夜并在异氟烷麻醉下施用PBS、50%乙醇/PBS或50%乙醇/20mg/kg TNBS(40μL灌肠剂)(研究第1天)。动物口服媒介物、地塞米松(5mg/kg)或试验化合物(例如25mg/kg)。在研究第1天(TNBS灌肠剂后5h)开始给药。第7天处死小鼠。基本上根据先前公开的研究测量结肠炎的各种参数(见Fitzpatrick等,Inflammatory BowelDiseases,2010)。
其中可测试在各种抗炎性和自身免疫性病症中DHODH的作用的其它体内模型包括雄性DBA/a Ola HSD小鼠中胶原诱导的关节炎和C57/B16J小鼠中的慢性实验性自身免疫性脑脊髓炎:啮齿动物模型中胶原诱导的关节炎除用作由人类风湿性关节炎确认治疗剂的替代外,还已经广发用于说明和理解疾病的发展。用异氟烷麻醉小鼠并且在弗氏完全佐剂注射中给予150μl牛II型胶原(第0天和第21天)。在研究第O天开始处理并继续每天1次(口服,一天一次)。从第18天开始,对每只爪(右前、左前、右后、左后)进行临床评分并持续至处死当天(第34天)。
实验性自身免疫性脑脊髓炎(EAE)是一种中枢神经系统的炎症性疾病并且广泛用作多发性硬化的动物模型。在第0天经静脉内为动物施用百日咳毒素并且经皮下施用少突胶质细胞糖蛋白(MOG)。在第O天开始处理并持续至处死。在第9天和第42天之间观察到EAE发展。在处理期结束时,处死动物以对血浆进行组织病理学分析以及细胞因子评估。
尽管已参照特定实施方案描述了本发明,但是应了解,这些实施方案仅仅是为了说明本发明的原理和应用。因此应了解,在不背离上文和所附权利要求所述的本发明精神和范围的前提下,可对示例性实施方案做许多修改并且可设计出其它排列方式。
本申请中引用的所有出版物和专利和/或专利申请均如同特别单独地指出将每个单独的公布或专利申请通过引用并入的相同程度以引用并入本文。
Claims (30)
1.一种式(I)的化合物
或其互变异构体、立体异构体(例如对映异构体或非对映异构体)、药学上可接受的盐、药学上可接受的酯、前药或N-氧化物,其中
环A独立地选自经取代或未经取代的单环芳基和经取代或未经取代的单环杂芳基,其中每次出现的X独立地为CR4或N;
环B独立地选自经取代或未经取代的单环芳基和经取代或未经取代的单环杂芳基,其中X1为CR4或N;任选地,两个相互处于邻位的R4取代基可连接形成经取代或未经取代的饱和或不饱和4-10元环,所述环可任选地包括可相同或不同并且选自O、NRa或S的杂原子;
R为氢、经取代或未经取代的(C1-6)烷基或-ORa;
R1选自-OH、-NRaOH、-COOH、-COORa、-CRaRbOH、-CRaRbCOOH、-SO2Ra、-CRaRbSO2Ra、-SO3Ra、-CRaRb-SO3Ra、-C(=Y)-NRaRb和-S(=O)q-NRaRb或-COOH基的电子等排体或任选地表示卤素、经取代或未经取代的(C1-6)烷基或Cy1;
X2为N或CR2并且X3为N或CR3,其中R2和R3可相同或不同并且独立地选自氢、卤素或经取代或未经取代的(C1-6)烷基或经取代或未经取代的(C1-6)烷氧基;
L1和L2独立地不存在或选自-(CRaRb)n-、-O-、-S(=O)q-、-NRa-、-C(=Y)-、-C(=Y)-CRaRb、-CRaRb-C(=Y)-、-C(=Y)-C(=Y)-、-CRaRb-Y-、-C(=Y)-NRaRb-、-S(=O)q-NRaRb-、-NRaRb--C(=Y)-、-NRaRb-S(=O)q-、经取代或未经取代的(C1-2)烷基、经取代或未经取代的(C2)烯基和经取代或未经取代的(C2)炔基;任选地,经取代或未经取代的(C1-2)烷基、经取代或未经取代的(C1-2)烯基和经取代或未经取代的(C1-2)炔基的每一个可被-O-、-C(=Y)-、-S(=O)q-和-NRa-间隔;
Cy选自经取代或未经取代的环烷基、经取代或未经取代的杂环基团、经取代或未经取代的芳基和经取代或未经取代的杂芳基;
Cy1选自经取代或未经取代的单环烷基、经取代或未经取代的单环杂环基团、经取代或未经取代的单环芳基和经取代或未经取代的单环杂芳基;
R4独立地选自氢、羟基、卤素、氰基、-ORa、-S(=O)q-Ra、-NRaRb、-C(=Y)-Ra、-C(=Y)-ORa、-C(=Y)-NRaRb、-S(=O)q-NRaRb、经取代或未经取代的烷基、经取代或未经取代的烯基、经取代或未经取代的炔基、经取代或未经取代的环烷基、经取代或未经取代的环烷基烷基、经取代或未经取代的环烯基,或当存在两个R4取代基时,它们可连接形成经取代或未经取代的饱和或不饱和3-10元环,所述环可任选地包括可相同或不同并且选自O、NRa或S的杂原子,或可选地,当芳环上两个R4取代基相互处于邻位时它们可连接形成经取代或未经取代的饱和或不饱和4-10元环,所述环可任选地包括可相同或不同并且选自O、NRa或S的一个或多个杂原子;
每次出现的Ra和Rb可相同或不同并且独立地选自氢、卤素、羟基、氰基、经取代或未经取代的(C1-6)烷基、-ORc(其中Rc为经取代或未经取代的(C1-6)烷基)或当Ra和Rb与共同原子直接结合时,它们可连接形成氧代基(=O)或形成经取代或未经取代的饱和或不饱和3-10元环,所述环可任选地包括可相同或不同并且选自O、NRa或S的杂原子;
每次出现的Y独立地选自O、S和NRa;
每次出现的n独立地表示整数0、1、2、3或4;并且
每次出现的q独立地表示整数0、1或2。
3.根据权利要求1或2所述的化合物,其中R1为-COOH。
4.根据前述权利要求中任一项所述的化合物,其中Y为O。
5.根据前述权利要求中任一项所述的化合物,其中R为H。
6.根据前述权利要求中任一项所述的化合物,其中每次出现的X为CH、C-Cl、C-F或N。
7.根据前述权利要求中任一项所述的化合物,其中每次出现的X1为CH、N或CF。
8.根据前述权利要求中任一项所述的化合物,其中X2为CH、C-Cl、C-F或N。
9.根据前述权利要求中任一项所述的化合物,其中X3为CH、C-Cl、C-F或N。
11.根据前述权利要求中任一项所述的化合物,其中L1和L2不存在。
12.根据前述权利要求中任一项所述的化合物,其中L1存在而L2为-O-CRaRb。
13.根据前述权利要求中任一项所述的化合物,其中Cy为
,其任选地经一个或多个R4取代。
14.一种下式化合物
或其互变异构体、立体异构体(例如对映异构体或非对映异构体)、药学上可接受的盐、药学上可接受的酯、前药或N-氧化物,其中
包括X的环A选自
,其任选地经一个或多个R4取代;
R1独立地选自-OH、-NRaOH、-COOH、-COORa或-COOH基的电子等体,例如SO3H、CONHOH、B(OH)2、PO3RaRb、SO2NHRa、四唑、酰胺、酯或酸酐;
包括X1、X2和X3的环B选自
,其任选地经一个或多个R4取代;
L2不存在或可独立地选自-(CRaRb)n-、-O-、-S(=O)q-、-NRa-、-C(=Y)-、-C(=Y)-CRaRb、-CRaRb-C(=Y)-、-C(=Y)-C(=Y)-、-CRaRb-Y-、-C(=Y)-NRaRb-、-S(=O)q-NRaRb-、-NRaRb--C(=Y)-、-NRaRb-S(=O)q-、经取代或未经取代的(C1-2)烷基、经取代或未经取代的(C2)烯基和经取代或未经取代的(C2)炔基;任选地,经取代或未经取代的(C1-2)烷基、经取代或未经取代的(C2)烯基和经取代或未经取代的(C2)炔基的每一个可被-O-、-C(=Y)-、-S(=O)q-和-NRa-间隔;
Cy独立地选自经取代或未经取代的环烷基、经取代或未经取代的杂环基团,经取代或未经取代的芳基和经取代或未经取代的杂芳基;
R4独立地选自氢、羟基、卤素、氰基、-ORa、-S(=O)q-Ra、-NRaRb、-C(=Y)-Ra、-C(=Y)-ORa、-C(=Y)-NRaRb、-S(=O)q-NRaRb、经取代或未经取代的烷基、经取代或未经取代的烯基、经取代或未经取代的炔基、经取代或未经取代的环烷基、经取代或未经取代的环烷基烷基或经取代或未经取代的环烯基,或当存在两个R4取代基时,它们可连接形成经取代或未经取代的饱和或不饱和3-10元环,所述环可任选地包括可相同或不同并且选自O、NRa或S的杂原子,或可选地,当芳环上两个R4取代基相互处于邻位时它们可连接形成经取代或未经取代的饱和或不饱和4-10元环,所述环可任选地包括可相同或不同并且选自O、NRa或S的一个或多个杂原子;
每次出现的Ra和Rb可相同或不同并且独立地选自氢、卤素、羟基、氰基、经取代或未经取代的(C1-6)烷基、-ORc(其中Rc为经取代或未经取代的(C1-6)烷基)或当Ra和Rb与共同原子直接结合时,它们可连接形成氧代基(=O)或形成经取代或未经取代的饱和或不饱和3-10元环,所述环可任选地包括可相同或不同并且选自O、NRa或S的杂原子;
每次出现的Y独立地选自O、S和NRa;
每次出现的n独立地表示整数0、1、2、3或4;并且
每次出现的q独立地表示整数0、1或2。
17.一种化合物,其选自:
2-(3,5-二氟-3′-甲氧基联苯-4-基氨甲酰基)苯甲酸
2-(3,5-二氟-3′-甲氧基联苯-4-基氨甲酰基)苯磺酸
2-(6-(3-甲氧基苯基)吡啶-3-基氨甲酰基)苯甲酸
2-(3′-乙氧基-3-氟联苯-4-基氨甲酰基)苯甲酸
2-(3′-乙氧基-3,5-二氟联苯-4-基氨甲酰基)苯甲酸
2-(2′-氯-3,5-二氟联苯-4-基氨甲酰基)苯甲酸
2-(3,5-二氟联苯-4-基氨甲酰基)苯甲酸
2-[3,5-二氟-3′-(三氟甲氧基)联苯-4-基氨甲酰基]苯甲酸
2-[3′-(苄氧基)-3,5-二氟联苯-4-基氨甲酰基]苯甲酸
4,5-二氯-2-(3-氯-3′-乙氧基-5-氟联苯-4-基氨甲酰基)苯甲酸
2-(3-氯-3′-乙氧基-5-氟联苯-4-基氨甲酰基)苯甲酸
4,5-二氯-2-(3,5-二氟-3′-甲氧基联苯-4-基氨甲酰基)苯甲酸
4,5-二氯-2-(3′-乙氧基-3,5-二氟联苯-4-基氨甲酰基)苯甲酸
2-(3,5-二氯-3′-甲氧基联苯-4-基氨甲酰基)苯甲酸
2-(3-氯-5-氟-3′-丙氧基联苯-4-基氨甲酰基)苯甲酸
2-(3-氯-2′,5-二氟联苯-4-基氨甲酰基)苯甲酸
2-(3,5-二氯-3′-乙氧基联苯-4-基氨甲酰基)苯甲酸
2-[3-氟-3′-(三氟甲氧基)联苯-4-基氨甲酰基]苯甲酸
2-[2′-氟-3-(三氟甲氧基)联苯-4-基氨甲酰基]苯甲酸
2-(3,5-二氯-2′-氟联苯-4-基氨甲酰基)苯甲酸
2-(3,5-二氟-3′-异丙氧基联苯-4-基氨甲酰基)苯甲酸
2-(3,5-二氟-3′-丙氧基联苯-4-基氨甲酰基)苯甲酸
4,5-二氯-2-(2′,3-二氯-5-氟联苯-4-基氨甲酰基)苯甲酸
4,5-二氯-2-(2′,3-二氯-5-氟联苯-4-基氨甲酰基)苯甲酸
4,5-二氯-2-(2′,3-二氯-5-氟联苯-4-基氨甲酰基)苯甲酸
4,5-二氯-2-(2′-氯-3,5-二氟联苯-4-基氨甲酰基)苯甲酸
2-(3-氯-5-氟-3′-异丁氧基联苯-4-基氨甲酰基)苯甲酸
2-(2′,3,5-三氟联苯-4-基氨甲酰基)苯甲酸
2-(2′,3,5-三氯联苯-4-基氨甲酰基)苯甲酸
2-(3,5-二氟-3′-异丁氧基联苯-4-基氨甲酰基)苯甲酸
2-(3′-丁氧基-3,5-二氟联苯-4-基氨甲酰基)苯甲酸
2-(3-氯-3′-乙氧基-5-氟联苯-4-基氨甲酰基)-6-氟苯甲酸
2-[3-氯-5-氟-3′-(三氟甲氧基)联苯-4-基氨甲酰基]苯甲酸
2-[4-(苄氧基)-2,6-二氟苯基氨甲酰基]苯甲酸
2-[3′-(环戊氧基)-3,5-二氟联苯-4-基氨甲酰基]苯甲酸
2-(3-氯-3′-(环戊氧基)-5-氟联苯-4-基氨甲酰基)苯甲酸
2-[3′-(二氟甲氧基)-3,5-二氟联苯-4-基氨甲酰基]苯甲酸
2-[3-氯-3′-(二氟甲氧基)-5-氟联苯-4-基氨甲酰基]苯甲酸
2-(2′-氯-3,5-二氟-5′-甲氧基联苯-4-基氨甲酰基)苯甲酸
2-(3,3′,5-三氟-5′-甲氧基联苯-4-基氨甲酰基)苯甲酸
2-[4-(苯并[d][1,3]间二氧杂环戊烯-5-基)-2,6-二氟苯基氨甲酰基]苯甲酸
2-[4-(苯并[d][1,3]间二氧杂环戊烯-5-基)-2-氯-6-氟苯基氨甲酰基]苯甲酸
2-(3,5-二氟-3′,4′-二甲基基联苯-4-基氨甲酰基)苯甲酸
2-(3,3′,5-三氟-5′-甲氧基联苯-4-基氨甲酰基)苯甲酸
2-(3,3′-二氯-5-氟-5′-甲氧基联苯-4-基氨甲酰基)苯甲酸
2-[4-(2,3-二氢苯并呋喃-5-基)-2,6-二氟苯基氨甲酰基]苯甲酸
2-[2-氯-4-(2,3-二氢苯并呋喃-5-基)-6-氟苯基氨甲酰基]苯甲酸
2-[4-(1,3-二甲基-1H-吲唑-5-基)-2,6-二氟苯基氨甲酰基]苯甲酸
2-(3′-氯-3,5-二氟-5′-甲氧基联苯-4-基氨甲酰基)苯甲酸
2-(3-氯-5-氟-3′,4′-二甲基基联苯-4-基氨甲酰基)苯甲酸
2-(2′,3-二氯-5-氟-5′-甲氧基联苯-4-基氨甲酰基)苯甲酸
2-(2′,3,5-三氟-5′-甲氧基联苯-4-基氨甲酰基)苯甲酸
2-(4′-氯-3,5-二氟-3′-甲氧基联苯-4-基氨甲酰基)苯甲酸
2-(3,4′-二氯-5-氟-3′-甲氧基联苯-4-基氨甲酰基)苯甲酸
2-(3-氯-2′,5-二氟-5′-甲氧基联苯-4-基氨甲酰基)苯甲酸
2-(3,4′,5-三氟-3′-甲氧基联苯-4-基氨甲酰基)苯甲酸
2-[2,6-二氟-4-(3-甲基-1H-吲哚-5-基)苯基氨甲酰基]苯甲酸
2-[2,6-二氟-4-(3-甲基-1H-吲唑-5-基)苯基氨甲酰基]苯甲酸
2-(3-氯-3′-乙基-5-氟联苯-4-基氨甲酰基)苯甲酸
2-(3-氯-3′-乙氧基-2′,5-二氟联苯-4-基氨甲酰基)苯甲酸
2-[2-氯-4-(2,3-二氢苯并[b][1,4]二噁英-6-基)-6-氟苯基氨甲酰基]苯甲酸
2-[3-氯-5-氟-3′-(2,2,2-三氟乙氧基)联苯-4-基氨甲酰基]苯甲酸
2-(3-氟-3′-甲氧基联苯-4-基氨甲酰基)苯甲酸
2-(3′-乙氧基联苯-4-基氨甲酰基)苯甲酸
2-[3′-(乙硫基)-3,5-二氟联苯-4-基氨甲酰基]苯甲酸
2-[3′-(乙基亚磺酰基)-3,5-二氟联苯-4-基氨甲酰基]苯甲酸
2-(3′-环丙氧基-3,5-二氟联苯-4-基氨甲酰基)苯甲酸
2-(3′-乙氧基-3,5-二氟联苯-4-基氨甲酰基)-6(5)-甲基苯甲酸
2-[4-(3-乙基-1H-吲哚-5-基)-2,6-二氟苯基氨甲酰基]苯甲酸
2-[3′-(乙硫基)-2,3,5,6-四氟联苯-4-基氨甲酰基]苯甲酸
2-(2′-氯-2-氟-5′-甲氧基联苯-4-基氨甲酰基)苯甲酸
2-(3-氟-3′-丙氧基联苯-4-基氨甲酰基)苯甲酸
2-(3′-丙氧基联苯-4-基氨甲酰基)苯甲酸
2-[3′-(乙硫基)-2-氟联苯-4-基氨甲酰基]苯甲酸
2-[3,5-二氟-3′-(2,2,2-三氟乙氧基)联苯-4-基氨甲酰基]苯甲酸
2-(3′-乙基-3,5-二氟联苯-4-基氨甲酰基)苯甲酸
2-(联苯-4-基氨甲酰基)苯甲酸
2-(2′-氯联苯-4-基氨甲酰基)苯甲酸
2-(3′-甲氧基联苯-4-基氨甲酰基)苯甲酸
2-[3′-(三氟甲氧基)联苯-4-基氨甲酰基]苯甲酸
2-[3′-(乙硫基)-2,6-二氟联苯-4-基氨甲酰基]苯甲酸
2-(3′-乙基联苯-4-基氨甲酰基)苯甲酸
2-(3′-丁氧基-2,3,5,6-四氟联苯-4-基氨甲酰基)苯甲酸
2-(3′-丁氧基-3-氟联苯-4-基氨甲酰基)苯甲酸
2-[3,5-二氟-3′-(三氟甲氧基)联苯-4-基氨甲酰基]苯甲酸
2-(3′-环丙氧基-3-氟联苯-4-基氨甲酰基)苯甲酸
2-(3′-环丙氧基联苯-4-基氨甲酰基)苯甲酸
2-(3′-丁氧基联苯-4-基氨甲酰基)苯甲酸
2-(3′-丁氧基-2-氟联苯-4-基氨甲酰基)苯甲酸
2-(3′-丁氧基-2,6-二氟联苯-4-基氨甲酰基)苯甲酸
2-[2,6-二氟-4-(3-丙基-1H-吲哚-5-基)苯基氨甲酰基]苯甲酸
2-[2-氯-4-(3-乙基-1H-吲哚-5-基)-6-氟苯基氨甲酰基]苯甲酸。
18.一种化合物,其选自:
3-(3,5-二氟-3′-甲氧基联苯-4-基氨甲酰基)吡嗪-2-羧酸
3-(3,5-二氟-3′-乙氧基联苯-4-基氨甲酰基)吡嗪-2-羧酸
3-[3′-(苄氧基)-3,5-二氟联苯-4-基氨甲酰基]吡嗪-2-羧酸
3-(3-氯-3′-乙氧基-5-氟联苯-4-基氨甲酰基)吡嗪-2-羧酸
N-(3-氯-3′-乙氧基-5-氟联苯-4-基)-2-(羟甲基)苯甲酰胺
N-(3′-乙氧基-3,5-二氟联苯4-基)-2-(羟甲基)苯甲酰胺
2-(3′-乙氧基-3,5-二氟联苯-4-基氨甲酰基)烟酸
4-(3′-乙氧基-3,5-二氟联苯-4-基氨甲酰基)烟酸。
19.一种药物组合物,其包含根据权利要求1-18中任一项所述的化合物和药学上可接受的载体。
20.根据权利要求19所述的药物组合物,进一步包含一种或多种选自抗炎剂、免疫抑制剂和/或免疫调节剂、类固醇、非类固醇抗炎剂、抗组胺剂、止痛剂及其合适混合物的附加治疗剂。
21.一种抑制哺乳动物体内的DHODH活性的方法,其包括向所述哺乳动物施用根据权利要求1-18中任一项所述的化合物,其中根据权利要求1-18中任一项所述的化合物抑制所述哺乳动物体内的DHODH活性。
22.一种通过抑制哺乳动物体内的所述DHODH来抑制细胞因子释放的方法,其包括向所述哺乳动物施用根据权利要求1-18中任一项所述的化合物,其中根据权利要求1-18中任一项所述的化合物抑制所述哺乳动物体内的细胞因子释放。
23.一种抑制细胞中细胞因子生成的方法,其包括向所述细胞施用根据权利要求1-18中任一项所述的化合物。
24.根据权利要求22或23所述的方法,其中所述细胞因子选自IL-17或IFN-γ及其组合。
25.一种抑制哺乳动物体内IL 17细胞因子释放的方法,其包括向所述哺乳动物施用根据权利要求1-18中任一项所述的化合物,其中根据权利要求1-19中任一项所述的化合物不依赖于DHODH抑制来抑制细胞因子释放。
26.根据权利要求1-18中任一项所述的化合物在用于治疗将受益于抑制二氢乳清酸脱氢酶的疾病、病症或病状的药物的制备中的用途。
27.一种通过抑制DHODH或IL17及其组合治疗自身免疫性疾病、免疫和炎症性疾病、破坏性骨病、各种癌症和恶性肿瘤疾病、血管生成相关疾病、病毒性疾病或感染性疾病的方法,其包括向有需要的受试者施用有效量的根据权利要求1-18中任一项所述的化合物的步骤。
28.根据权利要求27所述的方法,其中所述疾病选自类风湿性关节炎、牛皮癣性关节炎、全身性红斑狼疮、多发性硬化、牛皮癣、强直性脊柱炎、韦格纳氏肉芽肿病、多关节型幼年特发性关节炎、炎症性肠病如溃疡性结肠炎、克罗恩氏病、莱特尔氏综合征、纤维肌痛、慢性胰腺炎、移植物抗宿主病、慢性结节病、移植排斥、接触性皮炎、特应性皮炎、变应性鼻炎、变应性结膜炎、贝赛特氏综合征、炎症性眼病如结膜炎、葡萄膜炎、骨质疏松症、骨关节炎、血管瘤、眼部新生血管、黄斑变性、HIV感染、肝炎和巨细胞病毒感染、脓毒症、败血症性休克、内毒素性休克、革兰氏阴性脓毒症、中毒性休克综合征、志贺菌病和其它原生动物感染如疟疾。
29.根据权利要求27所述的方法,其中所述疾病选自慢性阻塞性肺疾病、类风湿性关节炎、炎症性肠病、变应性鼻炎、哮喘、多发性硬化、牛皮癣、克罗恩氏病、结肠炎、溃疡性结肠炎、关节炎与骨吸收增多相关的骨病或慢性阻塞性气道疾病、费尔蒂综合征、韦格纳氏肉芽肿病、克罗恩氏病、结节病、斯蒂尔病、类天疱疮、大动脉炎、全身性硬化症、复发性多软骨炎、顽固性IgA肾病、SAPHO2综合征(SAS)、巨细胞病毒感染包括鼻炎或囊肿、牛皮癣和多发性骨髓瘤。
30.根据权利要求27所述的方法,其中所述疾病选自类风湿性关节炎、多发性硬化或炎症性肠病。
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US10968216B2 (en) | 2016-10-27 | 2021-04-06 | Bayer Aktiengesellschaft | 4,5-annulated 1,2,4-triazolones |
US11787797B2 (en) | 2016-10-27 | 2023-10-17 | Bayer Aktiengesellschaft | 4,5-annulated 1,2,4-triazolones |
CN111757756A (zh) * | 2018-02-22 | 2020-10-09 | 学校法人东海大学 | Il-17a活性抑制剂及其用途 |
CN114828842A (zh) * | 2019-10-21 | 2022-07-29 | 理森制药股份公司 | 用于治疗急性髓系白血病的包含dhodh抑制剂的组合物 |
CN111559977A (zh) * | 2020-06-04 | 2020-08-21 | 广州市朝利良生物科技有限公司 | 一类小分子化合物及其在制备抗肿瘤转移药物中应用 |
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