CN104513239A - 吡唑并[3,4-c]吡啶-7-酮类化合物及其应用 - Google Patents
吡唑并[3,4-c]吡啶-7-酮类化合物及其应用 Download PDFInfo
- Publication number
- CN104513239A CN104513239A CN201410758114.2A CN201410758114A CN104513239A CN 104513239 A CN104513239 A CN 104513239A CN 201410758114 A CN201410758114 A CN 201410758114A CN 104513239 A CN104513239 A CN 104513239A
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- CN
- China
- Prior art keywords
- pyrazolo
- phenyl
- methoxyphenyl
- pyridin
- oxopiperidin
- 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
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 214
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 213
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- 125000001305 1,2,4-triazol-3-yl group Chemical group [H]N1N=C([*])N=C1[H] 0.000 claims description 27
- 229910052757 nitrogen Inorganic materials 0.000 claims description 25
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 23
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于医药技术领域,涉及通式I所示的含4,5-二氢-1 H -吡唑并[3,4-c]吡啶-7-酮衍生物及其药学上可接受的盐、水合物或前药,其中取代基A、R1和R2具有在说明书中给出的含义。本发明还涉及通式I的化合物及其药学上可接受的盐或前药的制备方法、含上述化合物的药用组合物以及上述化合物用作Xa因子抑制剂的用途,尤其在制备治疗和/或预防血栓栓塞性疾病的药物中的用途。
Description
技术领域
本发明涉及新的吡唑并[3,4-c]吡啶-7-酮类化合物及其药学上可接受的盐、水合物或其前药,它们的制备方法以及含有所述化合物的药物组合物。本发明还涉及吡唑并[3,4-c]吡啶-7-酮类化合物用作Xa因子抑制剂的用途,尤其在制备治疗和/或预防血栓栓塞性疾病的药物中的用途。
背景技术
血栓形成,即局部血液凝块形成,是引起心肌梗死和卒中等动脉疾病以及静脉血栓栓塞性疾病的主要原因。传统的抗凝血药物主要有华法林、肝素和低分子肝素。口服抗凝血药物华法林可抑制转录后成熟的凝血因子VII、IX、X和凝血酶原,对静脉和动脉血栓栓塞均有效,但治疗指数窄且起效慢,并与许多食物和药物存在相互作用,需要进行药物监测和剂量调整,限制了其应用。低分子量肝素和磺达肝癸钠为注射给药,存在安全性和给药不方便等问题,因而,研发一类安全有效的口服抗凝血药尤为必要。
人体内的凝血途径分为内源性与外源性两条途径。位于这两条途径接合处的Xa因子与V因子通过钙离子连接在磷脂表面,形成凝血酶原复合物,并使凝血酶原转化为凝血酶,继而促使血栓的形成。可见,Xa因子是凝血级联反应中的关键调节因子,位于凝血酶的上端,而凝血级联反应是逐级放大的程,Xa因子抑制剂发挥作用后,阻止了凝血的进一步放大效应,可获得更好的抗凝效果。
Xa因子抑制剂与凝血酶直接抑制剂(direct thrombin inhibitor,DTI)是近年来具有前景和代表性的新型抗凝血药。达比加群酯是一个有效的DTI,口服后迅速转变为具有抗凝活性的达比加群,对游离或与血栓结合的凝血酶都有拮抗作用。利伐沙班是口服有效的直接Xa因子抑制剂,起效迅速,临床试验结果表明,其有效性和安全性与传统抗凝剂相当,有望成为替代肝素和华法林的抗凝新药。
阿哌沙班(apixaban)是百时美施贵宝和辉瑞公司共同研发的抗凝血剂,直接作用于凝血因子Xa,用于治疗包括深静脉血栓(deep venous thrombosis,DVT)和肺栓塞(pulmonary embolism,PE)在内的静脉血栓疾病。2011年5月,欧盟批准口服Xa因子直接抑制剂阿哌沙班(商品名Eliquis)上市,用于择期髋关节或膝关节置换手术的成年患者,以预防静脉血栓形成(venousthrombembolic events,VTE)
阿哌沙班继达比加群酯和利伐沙班之后,成为第三个上市的口服有效抗凝剂,可直接抑制Xa因子。阿哌沙班对游离或与细胞结合Xa因子和凝血酶原都能发挥有效、可逆的抑制作用。阿哌沙班对人Xa因子的抑制常数大约是80pM(25℃),比其他丝氨酸蛋白酶选择性大30000倍。根据X射线结构显示,阿哌沙班与Xa因子活性位点之间以高度互补的方式结合。阿哌沙班不依赖于凝血酶的存在,因而不影响凝血酶的活性,保留凝血酶的止血作用。此外,阿哌沙班还能间接地通过诱导凝血酶来抑制血小板聚集。因而阿哌沙班是一个直接、可逆、高选择性的Xa因子抑制剂。
本发明人在参考文献的基础上,设计并合成了一系列新的吡唑并[3,4-c]吡啶-7-酮类衍生物。经过体外活性筛选,表明该类化合物具有Xa因子抑制剂的活性。
发明内容:
本发明涉及通式Ⅰ的化合物及其药学上可接受的盐、水合物或前药,其中,
其中:
R1为H,C1-C4直链或支链烷基,C1-C4烷氧基,卤素,羟基,氰基,游离的、成盐的、酯化的或酰胺化的羧基,任选被羟基、氨基或卤素取代的C1-C6烷基或C1-C6烷氧基;
R2选自CONHR3、NHCONHSO2Ar、5-10元杂环基、5-10元杂芳基,其中所述杂环基和杂芳基含有1-3个选自N、O或S的杂原子,并且所述杂环基或杂芳基任选1-3个相同或不同的R3取代;
R3为H、C1-C4直链或支链烷基、C1-C4烷氧基、C1-C4烷硫基、C1-C4烷氧基C1-C4烷基、C3-C7环烷基、任选被羟基、氨基或卤素取代的C1-C6烷基、C1-C4直链或支链烷基酰氧C1-C2烷基、卤代、羟基、氰基、羧基、C1-C10直链或支链烷氧甲酰基、(CH2)nNR4R5、5-10元杂环基,其中所述杂环基含有1-3个选自N、O或S的杂原子;
条件为当R2为CONH2时,A不为哌啶酮或吗啉酮;
n为0-6的整数,优选0-4的整数,更优选1-3的整数;
R4和R5相同或不同,分别独立地选自氢、C1-C10直链或支链烷基、C3-C7环烷基、C1-C4烷氧基、C2-C10烯基或C2-C10炔基,它们可以被0-3个相同或不同的R6任选取代;
或R4和R5与和它们所连接的氮原子一起形成5-10元杂环基或5-10元杂芳基,所述杂环基和杂芳基除了与R4和R5连接的氮原子外,任选含有0-4个选自N、O和S的杂原子,除了R4和R5所连接的氮原子外,所述杂环基任选包括0或2个碳碳双键或叁键,所述杂环基和杂芳基任选被0-3个相同或不同的R7取代;
A为5-10元杂环基、5-10元杂芳基,其中所述杂环基和杂芳基含有1-3个选自N、O或S的杂原子,并且所述杂环基或杂芳基任选0-3个相同或不同的R8取代;
Ar为C6-C10芳基、5-10元杂芳基,其中,所述杂芳基含有1-3个选自N、O或S的杂原子,并且Ar任选1-3个相同或不同的R7取代;
R6为C1-C4烷基、C1-C4烷氧基、卤素、羟基、氰基;
R7为C1-C4烷基、C1-C4烷氧基、卤素、羟基、氰基、羧基、酯基;
R8为氢、羰基、卤素、C1-C4烷基。
本发明优选涉及通式Ⅰ的化合物及其药学上可接受的盐、水合物或前药,
其中,
R1为H,C1-C4烷氧基,卤代,羟基,氰基,任选被羟基、氨基或卤代的C1-C6烷基或C1-C6烷氧基;优选R1为C1-C4烷氧基、卤代、被1-2个卤素取代的C1-C4烷基或C1-C4烷氧基。
进一步地,
R2为CONHR3、NHCONHSO2Ar、任选1-3个相同或不同的R3取代的三唑基,四唑基,二氢噻唑基、四氢吡啶基、1,3-二氮环庚基、异噁二唑酮基;优选如下结构:
其中,R3优选为H、甲基、乙基、异丙基、叔丁基、环丙基、甲氧基、甲硫基、甲氧基甲基、甲硫基甲基、被1-2个羟基取代的C1-C3烷基、特戊酰氧甲基、正己氧甲酰基、叔丁氧甲酰基、(CH2)nNR4R5;更优选:R3为H、甲基、乙基、异丙基、叔丁基、环丙基、特戊酰氧甲基、正己氧甲酰基、叔丁氧甲酰基、(CH2)nNR4R5;
优选地,R4和R5相同或不同,分别独立地选自氢、C1-C4烷基;
或R4和R5与和它们所连接的氮原子一起形成5-6元杂环基,所述杂环基除了与R4和R5连接的氮原子外,任选含有0-4个选自N、O和S的杂原子,所述杂环基和杂芳基任选被0-3个相同或不同的R7取代;
更优选地,R4和R5相同或不同,分别独立地选自氢、甲基、乙基;
或R4和R5与和它们所连接的氮原子一起形成
再进一步地,Ar为苯基、噻吩基,其中Ar任选1-3个相同或不同的R7取代;
如上化合物中,
A优选为5-10元杂环基,其中所述杂环基含有1-3个选自N、O或S的杂原子,并且所述杂环基任选0-3个相同或不同的R8取代;
可以为
本发明优选涉及通式Ⅰ的化合物及其药学上可接受的盐、水合物或前药,
其中,
R1为H,C1-C4烷氧基,卤代,羟基,氰基,任选被羟基、氨基或卤代的C1-C6烷基或C1-C6烷氧基;
R2选自CONHR3、NHCONHSO2Ar、5-7元杂环基、5-6元杂芳基,其中所述杂环基和杂芳基含有1-3个选自N、O或S的杂原子,并且所述杂环基或杂芳基任选1-3个相同或不同的R3取代;
R3为H、C1-C4直链或支链烷基、C1-C4烷氧基、C1-C4烷硫基、C1-C4烷氧基C1-C4烷基、C3-C7环烷基、任选被羟基、氨基或卤代的C1-C6烷基、C1-C4直链或支链烷基酰氧C1-C2烷基、卤代、羟基、氰基、羧基、C1-C10直链或支链烷氧甲酰基、(CH2)nNR4R5、5-10元杂环基,其中所述杂环基含有1-3个选自N、O或S的杂原子;
条件为当R2为CONH2时,A不为哌啶酮或吗啉酮;
n为0-6的整数;
R4和R5相同或不同,分别独立地选自氢、C1-C10直链或支链烷基、C3-C7环烷基、C1-C4烷氧基,它们可以被0-3个相同或不同的R6任选取代;
或R4和R5与和它们所连接的氮原子一起形成5-10元杂环基,所述杂环基除了与R4和R5连接的氮原子外,任选含有0-4个选自N、O和S的杂原子,除了R4和R5所连接的氮原子外,所述杂环基任选包括0或2个碳碳双键,所述杂环基和杂芳基任选被0-3个相同或不同的R7取代;
A为5-10元杂环基、5-10元杂芳基,其中所述杂环基和杂芳基含有1-3个选自N、O或S的杂原子,并且所述杂环基或杂芳基任选0-3个相同或不同的R8取代;
或者A为
Ar为C6-C10芳基、5-10元杂芳基,其中,所述杂芳基含有1-3个选自N、O或S的杂原子,并且Ar任选1-3个相同或不同的R7取代;
R6为C1-C4烷基、C1-C4烷氧基、卤代、羟基、氰基;
R7为C1-C4烷基、C1-C4烷氧基、卤代、羟基、氰基、羧基、酯基;
R8为氢、氧代、卤代、C1-C4烷基。
本发明还优选涉及通式Ⅰ的化合物及其药学上可接受的盐、水合物或前药,其中,
R1为C1-C4烷氧基、卤代、被1-2个卤素取代的C1-C4烷基或C1-C4烷氧基;
R2为CONHR3、NHCONHSO2Ar、任选1-3个相同或不同的R3取代的三唑基,四唑基,二氢噻唑基、四氢吡啶基、1,3-二氮环庚基、异噁二唑酮基;
R3为H、甲基、乙基、异丙基、叔丁基、环丙基、甲氧基、甲硫基、甲氧基甲基、甲硫基甲基、被1-2个羟基取代的C1-C3烷基、特戊酰氧甲基、正己氧甲酰基、叔丁氧甲酰基、(CH2)nNR4R5;
条件为当R2为CONH2时,A不为哌啶酮或吗啉酮;
n为0-4的整数;
R4和R5相同或不同,分别独立地选自氢、C1-C4烷基;
或R4和R5与和它们所连接的氮原子一起形成5-6元杂环基,所述杂环基除了与R4和R5连接的氮原子外,任选含有0-4个选自N、O和S的杂原子,所述杂环基和杂芳基任选被0-3个相同或不同的R7取代;
A为5-10元杂环基,其中所述杂环基含有1-3个选自N、O或S的杂原子,并且所述杂环基或杂芳基任选0-3个相同或不同的R8取代;
Ar为苯基、噻吩基,其中Ar任选1-3个相同或不同的R7取代;
R6为C1-C4烷基、C1-C4烷氧基、卤代;
R7为C1-C4烷基、C1-C4烷氧基、卤代;
R8为氢、氧代、卤代、甲基。
本发明还优选涉及通式Ⅰ的化合物及其药学上可接受的盐、水合物或前药,其中,
R1为C1-C4烷氧基、卤代、被1-2个卤素取代的C1-C4烷基或C1-C4烷氧基;
R2为选自CONHR3以及如下结构:
R3为H、甲基、乙基、异丙基、叔丁基、环丙基、甲氧基、甲硫基、甲氧基甲基、甲硫基甲基、被1-2个羟基取代的C1-C3烷基、特戊酰氧甲基、正己氧甲酰基、叔丁氧甲酰基、(CH2)nNR4R5;
条件为当R2为CONH2时,A不为哌啶酮或吗啉酮;
n为0-4的整数;
R4和R5相同或不同,分别独立地选自氢、C1-C4烷基;
或R4和R5与和它们所连接的氮原子一起形成5-6元杂环基,所述杂环基除了与R4和R5连接的氮原子外,任选含有0-4个选自N、O和S的杂原子,所述杂环基和杂芳基任选被0-3个相同或不同的R7取代;
A为5-10元杂环基,其中所述杂环基含有1-3个选自N、O或S的杂原子,并且所述杂环基任选0-3个相同或不同的R8取代;
Ar为苯基、噻吩基,其中Ar任选1-3个相同或不同的R7取代;
R6为C1-C4烷基、C1-C4烷氧基、卤代;
R7为C1-C4烷基、C1-C4烷氧基、卤代;
R8为氢、氧代、卤代、甲基。
本发明特别优选涉及通式Ⅰ的化合物及其药学上可接受的盐、水合物或前药,其中,
R1为甲氧基、卤代、二氟甲氧基、三氟甲氧基;
R2为选自CONHR3以及如下结构:
条件为当R2为CONH2时,A不为哌啶酮或吗啉酮;
R3为H、甲基、乙基、异丙基、叔丁基、环丙基、特戊酰氧甲基、正己氧甲酰基、叔丁氧甲酰基、(CH2)nNR4R5;
n为1-3的整数
R4和R5相同或不同,分别独立地选自氢、甲基、乙基;
或R4和R5与和它们所连接的氮原子一起形成
A为
Ar为噻吩基,并且Ar任选1-3个R7取代
R6为C1-C4烷基、C1-C4烷氧基、卤代;
R7为氯、溴;
R8为氢、氧代、卤代、甲基。
本发明通式Ⅰ化合物及其药学上可接受的盐、水合物或前药优选以下化合物,但这些化合物并不意味着对本发明的任何限制:
此外,本发明还包括本发明衍生物的前药。本发明衍生物的前药是通式Ⅰ的衍生物,它们自身可能具有较弱的活性甚至没有活性,但是在给药后,在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。
本发明中“卤素是指氟、氯、溴或碘代;“烷基”是指直链或支链的烷基;“环烷基”是指取代或未取代的环烷基;“芳基”是指无取代基或连有取代基的苯基;“杂芳基”是指含有一个或多个选自N、O、S杂原子的单环或多环的环状体系,环状体系是芳香性的,如咪唑基、吡啶基、吡唑基、(1,2,3)-和(1,2,4)-三唑基、呋喃基、噻吩基、吡咯基、噻唑基、苯并噻唑基、噁唑基、异噁唑基、萘基、喹啉基、异喹啉基、苯并咪唑基和苯并噁唑基等;“饱和或部分饱和的杂环基”是指含有一个或多个选自N、O、S的杂原子的单环或多环的环状体系,如吡咯烷基、吗啉基、哌嗪基、哌啶基、吡唑烷基、咪唑烷基和噻唑啉基等。本发明优选的化合物为:
1-(4-甲氧基苯基)-6-[4-(3-氧代-4-吗啉基)苯基]-3-(1H-1,2,4-三氮唑-3-基)-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(3-氧代-4-吗啉基)苯基]-3-(1-甲基-1H-1,2,4-三氮唑-3-基)-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(3-氧代-4-吗啉基)苯基]-3-[4-甲基氨基-乙基-4H-1,2,4-三氮唑-3-基]-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(3-氧代-4-吗啉基)苯基]-3-[4-(3-二乙基氨基-丙基)-4H-1,2,4-三氮唑-3-基]-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(3-氧代-4-吗啉基)苯基]-3-[4-(3-二甲基氨基-丙基)-4H-1,2,4-三氮唑-3-基]-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(3-氧代-4-吗啉基)苯基]-3-(4-甲基-4H-1,2,4-三氮唑-3-基)-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(5-氯噻吩-2-磺酰脲基)苯基]-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-羧酰胺
1-(4-甲氧基苯基)-3-(1H-1,2,4-三氮唑-3-基)-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-6-苯基-4-(5-氯噻吩-2-磺酰基)脲
1-(4-甲氧基苯基)-6-[4-(5-溴噻吩-2-磺酰脲基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-羧酰胺
1-(4-甲氧基苯基)-3-(2-甲基-2H-1,2,4-三氮唑-3-基)-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-6-苯基-4-(5-氯噻吩-2-磺酰基)脲
1-(4-甲氧基苯基)-3-(1H-1,2,4-三氮唑-3-基)-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-6-苯基-4-(5-溴噻吩-2-磺酰基)脲
1-(4-甲氧基苯基)-6-[4-(噻吩-2-磺酰脲基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-羧酰胺
1-(4-甲氧基苯基)-6-[4-(4-甲基-苯磺酰脲基)-苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-羧酰胺
1-(4-甲氧基苯基)-3-(1H-1,2,4-三氮唑-3-基)-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-6-苯基-4-(4-氟苯磺酰基)脲
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(5-甲基-1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(5-环丙基-1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(5-四氢呋喃-2-基)-1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(5-乙基-1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(5-甲氧基甲基-1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(5-异丙基-1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(5-叔丁基-1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(5-二甲氨基甲基-1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(5-二乙氨基甲基-1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-[5-(四氢吡咯-1-基)甲基-1H-1,2,4-三氮唑-3-基)]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-[5-(哌啶基-1-基)甲基-1H-1,2,4-三氮唑-3-基)]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(5-吗啉基-甲基-1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(1H-咪唑-2-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(4-甲基-4,5-二氢-1H-咪唑-2-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(1,4,5,6-四氢嘧啶-2-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(4,5,6,7-四氢1H-1,3-二氮杂环庚基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(4,5-二氢噻唑-2-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(4,5-二氢-1H-咪唑-2-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-酰胺
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-[N-(四氢吡咯-1-基)甲基]酰胺
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-[N-(4甲基哌嗪-1-基)甲基]酰胺
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-[N-(哌啶-1-基)甲基]酰胺
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-(N-二乙氨基甲基)酰胺
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-(N-二甲氨基甲基)酰胺
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-(N-甲氧基甲基)酰胺
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-(N-二甲胺基亚甲基)酰胺
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(2-甲基-2H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(1-甲基-1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(1-二甲基氨基乙基-1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(4-甲基4H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(4-环丙基-4H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(4-二甲氨基乙基-4H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(4-二甲氨基-4H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(4-二甲氨基丙基-4H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(4-二乙氨基乙基-4H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(4-二乙氨基丙基-4H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-[4-(吗啉-1-基)-乙基-4H-1,2,4-三氮唑-3-基]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-[4-(吗啉-1-基)-丙基-4H-1,2,4-三氮唑-3-基]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-[4-(哌啶-1-基)-乙基-4H-1,2,4-三氮唑-3-基]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-[4-(四氢吡咯-1基)-乙基-4H-1,2,4-三氮唑-3-基]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-[4-(2,3-二羟基丙基)-4H-1,2,4-三氮唑-3-基]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3(1,2,4-噁二唑-4H-5-酮-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3(3-乙基-4H-1,2,4-三氮唑-4-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3(3-异丙基-4H-1,2,4-三氮唑-4-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3(3-叔丁基-4H-1,2,4-三氮唑-4-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3(3-环丙基-4H-1,2,4-三氮唑-4-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3(3-甲氧甲基-4H-1,2,4-三氮唑-4-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3[3-(四氢呋喃-2-基)-4H-1,2,4-三氮唑-4-基]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
N-(1-(4-甲氧基苯基-7-氧代-6-(4-(2-氧代哌啶基)苯基)-5,6-二氢)1H-吡唑并[3,4-c]吡啶-3-氨甲酰基)噻吩-2-磺酰胺
N-(1-(4-甲氧基苯基-7-氧代-6-(4-(2-氧代哌啶基)苯基)-5,6-二氢)1H-吡唑并[3,4-c]吡啶-3-氨甲酰基)-5-氯-噻吩-2-磺酰胺
N-(1-(4-甲氧基苯基-7-氧代-6-(4-(2-氧代哌啶基)苯基)-5,6-二氢)1H-吡唑并[3,4-c]吡啶-3-氨甲酰基)-5-溴-噻吩-2-磺酰胺
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-[3-(吗啉-1-基)甲基-4H-1,2,4-三氮唑-4-基]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-[3-(四氢吡咯-1-基)甲基-4H-1,2,4-三氮唑-4-基]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3[3-(2-氧代哌啶-1-基)甲基-4H-1,2,4-三氮唑-4-基]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-[3-(2-氧代吗啉-1-基)甲基-4H-1,2,4-三氮唑-4-基]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-[3-(2-氧代-4,5-二氢噁唑-3H-3-基)甲基-4H-1,2,4-三氮唑-4-基]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(3-甲基-4H-1,2,4-三氮唑-4-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(1H-1,2,3,4-四氮唑-1-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(4H-1,2,4-三氮唑-4-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(3-氨基-4H-1,2,4-三氮唑-4-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-[3-(四氢吡咯-1-基)甲基-4H-1,2,4-三氮唑-4-基]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(3-二乙氨基甲基-4H-1,2,4-三氮唑-4-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-三氟甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-氟苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-氯苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-二氟甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-溴苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(5-甲硫基-1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-(1,2,3,4-四氢苯并[4,5]咪唑[1,2-a]吡啶-7-基)-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-甲酰胺
1-(4-甲氧基苯基)-6-[4-(4,5-二氢-1H-咪唑-2-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-甲酰胺
1-(4-甲氧基苯基)-6-[4-(1,4,5,6-四氢吡啶-2-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-甲酰胺
1-(4-二氟甲氧基苯基)-6-[4-(4,5-二氢-1H-咪唑-2-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-甲酰胺
1-(4-二氟甲氧基苯基)-6-[4-(1,4,5,6-四氢吡啶-2-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-甲酰胺
1-(4-二氟甲氧基苯基)-6-[4-(4,5,6,7-1H-1,3-二氮杂卓-2-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-甲酰胺
1-(4-氟苯基)-6-[4-(4,5-二氢-1H-咪唑-2-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-甲酰胺
1-(4-氟苯基)-6-[4-(1,4,5,6-四氢吡啶-2-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-甲酰胺
1-(4-氟苯基)-6-[4-(4,5,6,7-1H-1,3-二氮杂卓-2-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-甲酰胺
1-(4-甲氧基苯基)-6-[4-(4,5,6,7-1H-1,3-二氮杂卓-2-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-甲酰胺
下文中提供的实施例和制备例进一步阐明和举例说明本发明化合物及其制备方法。应当理解,下述实例和制备例的范围并不以任何方式限制本发明的范围。
下面的合成路线描述了本发明的式Ⅰ衍生物的制备,所有的原料都是通过这些合成路线中描述的方式、通过有机化学领域普通技术人员熟知的方法制备的或者可商购。本发明的全部最终衍生物都是通过这些合成路线中描述的方法或通过与其类似的方法制备的,这些方法是有机化学领域普通技术人员熟知的。这些合成路线中应用的全部可变因数如下文的定义或如权利要求中的定义。
当A为R2为时,R1以甲氧基为例,I的制备方法见路线1
当A为R2为时,R1以甲氧基为例,I的制备方法见路线2:
当A为R2为时,R1以甲氧基为例,I的制备方法见路线3
当A为R2为时,R1以甲氧基为例,I的制备方法见路线4
当A为R2为时,R1以甲氧基为例,I的制备方法见路线5
当A为R2为时,R1以甲氧基为例,I的制备方法见路线6
当A为R2为时,R1以甲氧基为例,I的制备方法见路线7
当A为R2为时,R1以甲氧基为例,I的制备方法见路线8
当A为R2为时,R1以甲氧基为例,I的制备方法见路线9
当A为R2为NHCONHSO2Ar时,R1以甲氧基为例,I的制备方法见路线10
当A为R2为时,R1以甲氧基为例,I的制备方法见路线11
当A为NHCONHSO2Ar,R2为时,R1以甲氧基为例,I的制备方法见路线12
当A为R2为时,R1以甲氧基为例,I的制备方法见路线13
当为R2为时,R1以甲氧基为例,I的制备方法见路线14
以上14条路线A,R1,R2,R3,R4,R5,Ar如权利要求中所定义
具体实施方式:
实施例旨在阐述而不是限制本发明的范围。化合物的核磁共振氢谱用Bruker ARX-300测定,质谱用Agilent 1100LC/MSD测定;所用试剂均为分析纯或化学纯。
实施实例1:
步骤1 3,3-二氯-哌啶-2-酮(2)
室温下,将100g(1.01mol)原料(1)溶于500ml氯仿中,配置成溶液A。将632g(3.03mol)五氯化磷溶于500ml氯仿中,配置成溶液B。将溶液A缓慢滴入溶液B,滴入过程温度控制在0~-15℃,滴毕,升温至25℃,加入277ml(3.03mol)三氯氧磷,加毕,70℃反应4h。减压蒸去溶剂,得深棕色液体。搅拌下将该液体缓慢倒入800g碎冰中,使用K2CO3调节pH至8,室温搅拌1h,抽滤,得浅灰色固体155.2g(理论产量为168.7g),用1400ml无水乙醇进行重结晶,得136.6g白色针状晶体,总收率为81%。
步骤2 3-吗啉-4-基-5,6-二氢-1H-吡啶-2-酮(3)
室温下将100g(0.60mol)中间体(2)溶于400ml 1,4-二氧六环中,加入60ml(0.66mol)吗啡啉和210ml(1.50mol)三乙胺。升温至110℃。TLC检测4.5h反应完毕,冷却至室温,静止析出固体。抽滤,对滤液进行减压蒸馏,蒸干得黄色固体,用乙醚洗涤(2×400ml),用水洗涤(2×200ml),干燥得白色固体粉末100.5g(理论产量为108.5g),收率为92%。
步骤3 2-氯-2-(2-(4-甲氧基苯基)-腙)乙酸乙酯(5)
室温下,将100g(0.81mol)原料(3)加入到400ml水中,向反应液中滴入270ml(3.24mol)浓盐酸。滴毕,向反应液中滴入115g(1.62mol)亚硝酸钠与460ml水的混合溶液,滴加过程中控温控制在-5~-10℃。滴毕,控制温度在-5~-10℃反应30min。然后向反应液中滴入135ml(0.97mol)二氯乙酰乙酸乙酯与135ml甲醇的混合溶液,滴加过程中温度控温在-5~-10℃。滴毕,向反应液中滴加207g(2.43mol)无水乙酸钠与514ml水的混合溶液,滴加过程中温度保持在-5~-10℃。滴毕,控温在-10℃,反应2h。然后转移至室温下,静置过夜,有棕色固体析出,抽滤,滤饼用无水甲醇洗涤(2×300ml)。得黄色固体186.9g(理论产量为208.1g),收率为89%
步骤4 1-(4-甲氧基苯基)-7a-吗啉-4-基-7-氧代-3a,4,5,6,7,7a-六氢-1H-吡唑[3,4-c]吡啶-3-甲酸乙酯(6)
室温下将100g(0.55mol)中间体(3)和170g(0.132mol)中间体(5)溶于500ml乙酸乙酯中,加入310ml(2.20mol)三乙胺,升温至80℃,TLC检测5h后反应完毕。冷却至室温,静止析出固体。抽滤,得黄色固体,用乙醚洗涤(2×300ml),用水洗涤(2×400ml),干燥得黄色固体176.7g(理论产量220.9g)。收率80%。
步骤5 1-(4-甲氧基苯基)-4-基-7-氧代-3a,4,5,6,7,7a-六氢-1H-吡唑[3,4-c]吡啶-3-甲酸乙酯(7)
室温下将100g(0.25mol)中间体(6)溶于250ml四氢呋喃中。滴入100ml浓盐酸,滴毕,室温下反应5h,TLC监测反应完毕,减压蒸馏蒸干溶剂,得到的固体,用水洗涤(3×300ml),得白色固体66.6g(理论产量78.4g)。收率85%。
步骤6 3-吗啉酮(8)
氮气保护下,将Na(45.26g,1.97mol)分批加入到二氧六环和异丙醇的混合溶液中,升温至50℃促进Na的溶解(Na溶解很慢,一般需要4~5小时)。待Na全部溶解后,滴加氨基乙醇(98ml,1.67mo)l,滴毕,50℃下搅拌30~40min。移至冷井中,控温-10℃,滴加氯乙酸乙酯(182ml,1.75mol)。滴毕,-10℃搅拌30~40min。逐渐升温至80℃,反应约10h,完毕,趁热抽滤,滤液蒸干得到黄色油状液体,用乙酸乙酯溶解,静置,将上面清澈的乙酸乙酯层倒出冷却析晶,待析出白色针状晶体后抽滤,得到吗啉酮粗品。剩余的黄色油状物按上述方法再次重结晶,收率36%。
步骤7 4-(4-氨基苯基)3-吗啉酮(9)
氮气保护下,将8(21.3g,0.21mol),K3CO349.2g,催化量CuI,对碘苯胺(35.5g,0.16mol),加入到DMF中,升温至120℃,可见反应液颜色由黄色逐渐变为深棕色。反应时间30~40h。反应完毕,加入无水甲醇142ml,回流1h,趁热抽滤,蒸干滤液,加入355ml水,搅拌1h,抽滤,蒸干滤液,加入142ml无水乙醇,活性碳脱色,回流1h,趁热抽滤,滤液冷却析晶,得淡黄色固体15.5g,收率50%。
步骤8 4-(4-碘代苯基)3-吗啉酮(10)
将8(9g,0.047mol)溶于225ml水中,加入浓HCl,0℃以下滴加NaNO2(3.23g)水溶液(45ml水)。滴毕反应1h后,控温在0℃以下,用滴管滴加含有KI(8.56g,0.052mol)的45ml水溶液,滴毕反应2~3h。抽滤,滤饼用少量水洗,滤液用二氯甲烷萃取3次,合并有机层,用饱和食盐水洗有机层,干燥后蒸干溶剂,然后和滤饼合并后进行柱层析得产品7g,收率50%。
步骤9 1-(4-甲氧基苯基-7-氧代-6-(4-(3-吗啉酮基)苯基)-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-羧酸(11)
将7(2g,0.0063mol)、10(2.5g,0.0083mol)、K2CO3(1.75g)加入干燥的DMF中,通入N2气室温反应半小时后,加入CuI(0.25g)、8-OH喹啉(0.18g),升温到130℃反应30~40h。趁热将反应液过滤,用16.6ml甲醇洗滤饼,合并滤液后再加入3.4ml水于滤液中,加入3倍量的NaOH到滤液后60℃水解2~3h。将反应液蒸干,加入100ml水,搅拌半小时后,垫硅胶抽滤,滤液用乙酸乙酯洗3~4次,加入碎冰到水层中,用3N HCl液调PH到4,析出的固体抽滤,水洗到中性,干燥得产品1.98g,收率68%。
步骤10 1-(4-甲氧基苯基-7-氧代-6-(4-(3-吗啉酮基)苯基)-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-酰胺(12)
冰浴下,将11(2.7g,5.8mmol)溶于干燥THF中,加入TEA(1ml,7.54mmol),然后滴加ClCO2Et(0.72ml,7.54mmol),0℃反应1~1.5h后,将氨水滴入,继续反应2~3h。反应完毕,蒸出THF,加入水搅拌半小时后,抽滤,滤饼洗到中性,干燥得产品2g,收率74%。
步骤11N-((二甲氨基)亚甲基)1-(4-甲氧基苯基-7-氧代-6-(4-(3-吗啉酮基)苯基)-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-酰胺(13)
将12(2g,4.3mmol)加入二氯甲烷中,加入6倍量的DMF-DMA,回流反应2h。蒸干溶液,过夜挥干残余的DMF-DMA,直接投下一步。
步骤12 1-(4-甲氧基苯基)-6-[4-(3-氧代-4-吗啉基)苯基]-3-(1H-1,2,4-三氮唑-3-基)-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-7-酮(实施实例1)
将12溶于HAc中,加入6倍量水合肼,30℃反应1~2h。蒸出HAc,加水析出固体,抽滤后,柱层析得到产品1.5g,收率71%。
ESI-MS m/z:486.5[M+H]+;
步骤13 1-(4-甲氧基苯基)-6-[4-(3-氧代-4-吗啉基)苯基]-3-(1-甲基-1H-1,2,4-三氮唑-3-基)-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-7-酮(实施实例2)
1-(4-甲氧基苯基)-6-[4-(3-氧代-4-吗啉基)苯基]-3-[4-甲基氨基-乙基-4H-1,2,4-三氮唑-3-基]-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-7-酮(实施实例3)
将化合物14(0.1g,0.2mmol)溶于1mlDMF中,加入2eq碳酸钾,室温反应0.5h,加入CH3I(0.06g,0.4mmol),加毕,室温反应2h。反应完毕,将反应液倒入水中,析出固体,抽滤,住层析得到产物15(实施实例2)50mg,收率48%,16(实施实例3)(30mg)28%。
实施实例2
1-(4-甲氧基苯基)-6-[4-(3-氧代-4-吗啉基)苯基]-3-(1-甲基-1H-1,2,4-三氮唑-3-基)-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:500.5[M+H]+;
实施实例3
1-(4-甲氧基苯基)-6-[4-(3-氧代-4-吗啉基)苯基]-3-[4-甲基氨基-乙基-4H-1,2,4-三氮唑-3-基]-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:500.5[M+H]+;
步骤14N-((二甲氨基)亚甲基)1-(4-甲氧基苯基-7-氧代-6-(4-(3-吗啉酮基)苯基)-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-酰胺(18)
将羧酸(5g,0.01mol)悬浮溶于50mL乙酸乙酯中,滴入2mL三乙胺,搅拌20min后,滴加(1.85mL,0.013mol)氯甲酸叔丁酯,滴毕30℃反应2h;蒸干反应液,得到棕黄色固体;将上述棕黄色固体溶于最少量甲醇中(若有不溶物,可滴加少量二氯甲烷至溶解),将溶解后的甲醇溶液,冰浴下缓慢滴加到50mL水合肼里中,随滴加,逐渐析出大量白色固体。反应完毕加入适量水,抽滤,滤饼用水洗,乙醚洗,得到灰白色固体4.1g,收率79.6%。
步骤15N-((二甲氨基)亚甲基)1-(4-甲氧基苯基-7-氧代-6-(4-(3-吗啉酮基)苯基)-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-酰肼(19)
将中间体18(5g,0.01mol)溶于100mL二氯甲烷中,加入1.85mLDMF-DMA,升温回流反应4h。蒸干反应液,加入二氯甲烷和水萃取有机层,活性炭脱色,蒸干得土黄色固体5g,收率89.6%。
步骤16 1-(4-甲氧基苯基)-6-[4-(3-氧代-4-吗啉基)苯基]-3-(4-氨基-4H-1,2,4-三氮唑-3-基)-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-7-酮(实施实例4)
中间体19(0.1g,0.0002mol)溶于10mL冰醋酸中,缓慢滴加1mL水合肼,滴毕,升温至90℃反应2h。蒸干反应液,柱层析分离提纯得产品77mg,收率75%。
ESI-MS m/z:523.5[M+Na]+;
按照实施实例4的方法,将中间体19与不同的氨基反应制备得到实施实例5-9的化合物
实施实例5 1-(4-甲氧基苯基)-6-[4-(3-氧代-4-吗啉基)苯基]-3-[4-(3-二甲基氨基-乙基)-4H-1,2,4-三氮唑-3-基]-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:557.6[M+H]+;
实施实例6 1-(4-甲氧基苯基)-6-[4-(3-氧代-4-吗啉基)苯基]-3-[4-甲基氨基-乙基-4H-1,2,4-三氮唑-3-基]-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:515.5[M+H]+;
实施实例7 1-(4-甲氧基苯基)-6-[4-(3-氧代-4-吗啉基)苯基]-3-[4-(3-二乙基氨基-丙基)-4H-1,2,4-三氮唑-3-基]-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:621.7[M+Na]+;
实施实例8 1-(4-甲氧基苯基)-6-[4-(3-氧代-4-吗啉基)苯基]-3-[4-(3-二甲基氨基-丙基)-4H-1,2,4-三氮唑-3-基]-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:571.6[M+H]+;
实施实例9 1-(4-甲氧基苯基)-6-[4-(3-氧代-4-吗啉基)苯基]-3-(4-甲基-4H-1,2,4-三氮唑-3-基)-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:522.5[M+Na]+;
步骤17 5-氯-N-(4-碘代苯基)戊酰胺(21)
将对碘苯胺(18.6g,0.085mol)溶于140ml二氯甲烷中,加入15.3mlTEA,冰浴控温在零度以下滴加30ml二氯甲烷稀释的5-氯戊酰氯(14.2ml,0.11mol),滴毕,室温反应1h。待反应完毕后,水洗有机层,干燥蒸干,得到固体24g,收率85%。
步骤18 1-(4-碘代苯基)2-哌啶酮(22)
将21(4.28g,0.013mol)、K2CO32.3g加入到15mlDMSO中,80度反应4~5h。反应液冷却后,将入到大量冰水中,析出大量类白色固体,搅拌半小时后抽滤,将滤饼干燥得类白色固体3.81g,收率84%。
按照类似实施例1的方法,得到化合物实施例10
实施实例10 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:484.5[M+H]+;1H NMR(400MHz,CDCl3)δ8.14(s,1H),7.50(d,J=8.9Hz,2H),7.34(d,J=8.6Hz,2H),7.28–7.20(m,3H),6.92(d,J=8.9Hz,2H),5.30(s,1H),4.13(t,J=6.6Hz,2H),3.81(s,3H),3.59(d,J=5.3Hz,2H),3.39(t,J=6.5Hz,2H),2.58(d,J=5.7Hz,2H),1.99–1.87(m,4H).
参照类似实施实例2,3的方法分别得到实施实例11,12。
实施实例11 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(1-甲基-1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:498.6[M+H]+;
实施实例12 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(2-甲基-2H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:498.6[M+H]+;
参照实施实例4-9的合成方法得到实施实例13-25
实施实例13 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(1-二甲基氨基乙基-1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:555.6[M+H]+;
实施实例14 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(4-甲基4H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:498.6[M+H]+;
实施实例15 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(4-环丙基-4H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:524.6[M+H]+;
实施实例16 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(4-二甲氨基乙基-4H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:555.6[M+H]+;
实施实例17 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(4-二甲氨基-4H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:527.6[M+H]+;
实施实例18 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(4-二甲氨基丙基-4H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:569.7[M+H]+;
实施实例19 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(4-二乙氨基乙基-4H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:583.7[M+H]+;
实施实例20 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(4-二乙氨基丙基-4H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:597.7[M+H]+;
实施实例21 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-[4-(吗啉-1-基)-乙基-4H-1,2,4-三氮唑-3-基]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:597.7[M+H]+;
实施实例22 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-[4-(吗啉-1-基)-丙基-4H-1,2,4-三氮唑-3-基]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:611.7[M+H]+;
实施实例23 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-[4-(哌啶-1-基)-乙基-4H-1,2,4-三氮唑-3-基]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:595.7[M+H]+;
实施实例24 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-[4-(四氢吡咯-1基)-乙基-4H-1,2,4-三氮唑-3-基]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:581.7[M+H]+;
实施实例25 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-[4-(2,3-二羟基丙基)-4H-1,2,4-三氮唑-3-基]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:558.6[M+H]+;
参照实施实例1的合成方法得到实施实例26-30
实施实例26 1-(4-三氟甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:538.5[M+H]+;1H NMR(400MHz,CDCl3)δ8.14(s,1H),7.50(d,J=8.9Hz,2H),7.34(d,J=8.6Hz,2H),7.25(d,3H),6.92(d,J=8.9Hz,2H),5.30(s,1H),4.13(t,J=6.6Hz,2H),3.81(s,3H),3.59(t,J=5.3Hz,2H),3.39(t,J=6.5Hz,2H),2.58(t,J=5.7Hz,2H),2.00–1.87(m,4H)。
实施实例27 1-(4-氟苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:472.5[M+H]+;1H NMR(400MHz,CDCl3)δ8.14(s,1H),7.50(d,J=8.9Hz,1H),7.34(d,J=8.6Hz,1H),7.25(d,J=8.7Hz,1H),6.92(d,J=8.9Hz,1H),5.30(s,1H),4.13(t,J=6.6Hz,1H),3.81(s,3H),3.59(t,J=5.3Hz,1H),3.39(t,J=6.5Hz,1H),2.61–2.53(m,J=5.7Hz,1H),1.99–1.88(m,1H).
实施实例28 1-(4-氯苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:488.9[M+H]+;1H NMR(400MHz,CDCl3)δ8.14(s,1H),7.57(d,J=8.7Hz,1H),7.38–7.31(m,2H),7.26(d,J=4.3Hz,1H),4.13(t,J=6.6Hz,2H),3.61(t,J=5.3Hz,2H),3.36(t,J=6.6Hz,2H),2.59(d,J=5.8Hz,2H),1.99–1.91(m,4H).
实施实例29 1-(4-二氟甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:520.5[M+H]+;1H NMR(400MHz,CDCl3)δ7.60(d,J=8.6Hz,2H),7.33(d,J=8.7Hz,2H),7.26(d,J=8.2Hz,2H),7.11(d,J=8.6Hz,2H),6.51(t,J=73.6Hz,1H),4.11(t,J=6.5Hz,2H),3.61(s,2H),3.39–3.30(m,J=6.4Hz,4H),2.58(s,1H),2.01–1.89(m,4H).
实施实例30 1-(4-溴苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:533.4[M+H]+;
步骤19 3-(1-(4-甲氧基苯基)-7-氧代-6-[4-(3-氧代-4-吗啉基)苯基]-7-氧代-
4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-基)-1H-1,2,4三氮唑基-1-羧酸己酯(实施实例31)
将实施例1(0.1g,0.2mmol),2eq的三乙胺溶于1mlDMF中,加入氯甲酸己酯(0.05g,0.3mmol),加毕,室温反应2h,反应完毕倒入水中,抽滤得固体,柱层析纯化得产物80mg,收率65%
ESI-MS m/z:614.7[M+H]+;
步骤20 3-(1-(4-甲氧基苯基)-7-氧代-6-[4-(3-氧代-4-吗啉基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-基)-1H-1,2,4三氮唑基-1-甲基特戊酸酯(实施实例32)
将实施例1(0.1g,0.2mmol)溶于1mlDMF中,加入2eq碳酸钾,室温反应0.5h,完毕加入特戊酸氯甲酯(0.047g,0.3mmol)室温反应2h,反应完毕倒入水中,抽滤得固体,柱层析纯化得产物75mg,收率63%
ESI-MS m/z:6000.6[M+H]+;
参照实施实例31,32的方法得到实施实例33-35
实施实例33 3-(1-(4-甲氧基苯基)-7-氧代-6-[4-(2-氧代哌啶-1-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-基)-1H-1,2,4三氮唑基-1-羧酸己酯
ESI-MS m/z:612.7[M+H]+;
实施实例34 3-(1-(4-甲氧基苯基)-7-氧代-6-[4-(2-氧代哌啶-1-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-基)-1H-1,2,4三氮唑基-1-甲基特戊酸酯
ESI-MS m/z:598.7[M+H]+;1H NMR(400MHz,DMSO)δ8.84(s,1H),7.51(d,J=9.0Hz,2H),7.42(s,2H),7.01(d,J=9.0Hz,2H),6.21(s,2H),4.21(s,2H),4.12(t,J=6.6Hz,2H),4.01–3.95(m,2H),3.81(s,3H),3.76–3.72(m,2H),3.28(t,J=6.5Hz,2H),1.14(s,9H)。
实施实例35 3-(1-(4-甲氧基苯基)-7-氧代-6-[4-(2-氧代哌啶-1-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-基)-1H-1,2,4三氮唑基-1-羧酸叔丁酯
ESI-MS m/z:584.6[M+H]+;
步骤21 1-(4-甲氧基苯基-7-氧代-6-(4-(2-氧代哌啶基)苯基)-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-甲腈(33)
将A(5g,0.01mol)悬浮于50ml二氯甲烷中,加入TEA6.1ml,搅拌30min后,30度下缓慢滴加(CF3CO)2O,滴毕,30度下反应1~2h。水洗至中性,蒸干溶剂得到淡黄色固体,乙醚打浆,用乙酸乙酯或甲醇进行重结晶后得到类白色固体3.5g,79%。
步骤22 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(5-环丙基-1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮(实施实例36)
将中间体33(0.2g,0.45mmol),环丙基甲酰肼(0.09g,0.9mmol),碳酸钾(0.063g,0.46mmol)加入10ml正丁醇中,回流反应20~30小时。反应完毕,蒸干溶剂,加入二氯甲烷将固体溶解,用水将残余的碳酸钾洗净,饱和食盐水洗后,蒸干溶剂,得到淡黄色固体,柱层析纯化得产品0.1g,收率42%。
ESI-MS m/z:524.6[M+H]+;
参照实施实例36的合成方法得到实施实例37-48
实施实例37 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(5-甲硫基-1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:530.6[M+H]+;
实施实例38 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(5-四氢呋喃-2-基)-1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:554.6[M+H]+;
实施实例39 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(5-乙基-1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:512.6[M+H]+;
实施实例40 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(5-甲氧基甲基-1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:528.6[M+H]+;
实施实例41 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(5-异丙基-1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:526.6[M+H]+;
实施实例42 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(5-叔丁基-1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:540.6[M+H]+;1H NMR(400MHz,CDCl3)δ7.49(d,J=8.7Hz,2H),7.35(d,J=8.4Hz,1H),7.25(d,J=10.6Hz,2H),6.90(d,J=8.7Hz,1H),4.13(t,J=6.5Hz,2H),3.80(s,3H),3.60(s,2H),3.39(t,J=6.4Hz,2H),2.56(s,2H),1.99–1.87(m,4H),1.44(s,9H)。
实施实例43 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(5-二甲氨基甲基-1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:541.6[M+H]+;
实施实例44 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(5-二乙氨基甲基-1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:569.7[M+H]+;
实施实例45 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-[5-(四氢吡咯-1-基)甲基-1H-1,2,4-三氮唑-3-基)]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:567.7[M+H]+;
实施实例46 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-[5-(哌啶基-1-基)甲基-1H-1,2,4-三氮唑-3-基)]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:581.7[M+H]+;
实施实例47 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(5-吗啉基-甲基-1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:583.7[M+H]+;
实施实例48 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(5-甲基-1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:498.6[M+H]+;1H NMR(400MHz,CDCl3)δ7.51(d,J=8.9Hz,2H),7.33(d,J=8.6Hz,2H),7.23(d,J=8.6Hz,2H),6.89(d,J=8.9Hz,2H),4.09(t,J=6.5Hz,2H),3.80(s,3H),3.60(t,2H),3.31(t,J=6.5Hz,2H),2.57(t,2H),2.41(s,3H),1.99–1.89(m,4H).
步骤23 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(1,4,5,6-四氢嘧啶-2-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮(实施实例49)
将33(0.2g,0.45mmol)、丙二胺1ml和升华硫0.0036g加入25ml茄形瓶中,116度回流反应3h。反应液冷至室温,加入水,析出白色固体,搅拌半小时后,抽滤,水洗至中性,干燥后得到白色固体0.14g,收率57%。
ESI-MS m/z:499.6[M+H]+;1H NMR(400MHz,CDCl3)δ7.47(d,J=8.9Hz,2H),7.34(d,J=8.7Hz,2H),7.27(d,J=8.7Hz,2H),6.98(d,J=8.9Hz,1H),4.01(t,J=6.4Hz,2H),3.79(s,3H),3.59(t,J=5.4Hz,2H),3.32(t,J=6.6Hz,2H),3.19(t,J=6.4Hz,2H),2.55(t,J=5.6Hz,2H),2.38(t,J=6.1Hz,2H),1.85(m,10.3Hz,4H),1.76–1.67(m,2H)。
参照实施实例49的合成方法得到实施实例50-53
实施实例50 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(4-甲基-4,5-二氢-1H-咪唑-2-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:499.6[M+H]+;
实施实例51 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(4,5-二氢噻唑-2-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:502.6[M+H]+;1H NMR(400MHz,DMSO)δ7.48(d,J=8.9Hz,2H),7.35(d,J=8.7Hz,2H),7.28(d,J=8.8Hz,2H),7.01(d,J=8.8Hz,2H),4.42(t,J=8.4Hz,2H),4.07(t,J=6.7Hz,2H),3.81(s,3H),3.59(t,J=5.4Hz,2H),3.37(t,J=8.3Hz,2H),3.19(t,J=6.7Hz,2H),2.38(t,J=6.3Hz,2H),1.85(m,4H).
实施实例52 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(4,5,6,7-四氢1H-1,3-二氮杂环庚基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:513.6[M+H]+;1H NMR(400MHz,DMSO)δ7.48(d,J=8.8Hz,2H),7.34(d,J=8.6Hz,2H),7.27(d,J=8.8Hz,2H),6.98(d,J=8.9Hz,2H),4.01(t,J=6.6Hz,2H),3.80(s,3H),3.59(t,J=5.3Hz,2H),3.32(t,J=6.6Hz,2H),3.18(t,J=6.6Hz,2H),2.55(t,J=5.6Hz,2H),2.38(t,J=6.0Hz,2H),1.85(m,4H),1.71(m,4H)。
实施实例53 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(4-甲基-4,5-二氢-1H-咪唑-2-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:499.6[M+H]+;1H NMR(400MHz,CDCl3)δ7.50(d,J=8.9Hz,2H),7.35(d,J=8.7Hz,2H),7.28(d,J=8.7Hz,2H),7.00(d,J=8.9Hz,2H),4.04(t,J=6.5Hz,2H),3.80(s,3H),3.75(t,J=9.8Hz,2H),3.59(t,J=5.5Hz,2H),3.37(d,J=9.8Hz,2H),3.16(t,J=6.5Hz,2H),3.12(s,3H),2.39(t,J=6.2Hz,2H),
1.91–1.78(m,4H)。
步骤24 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(1H-咪唑-2-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮(实施实例54)
将33(0.2g,0.45mmol)、乙二胺1ml和升华硫0.0036g加入25ml茄形瓶中,116度回流反应3h。反应液冷至室温,加入水,析出白色固体,搅拌半小时后,抽滤,水洗至中性,干燥后得到白色固体0.14g,收率59%。
将上述产品溶于5ml乙腈中,分批加入KMnO4(0.18g,1.14mmol)和SiO20.23g,室温反应24h。反应完毕,将SiO2过滤,蒸干,用二氯甲烷萃取,水洗,二氯甲烷层干燥后,浓缩柱层析得到产品80mg,收率57%
ESI-MS m/z:483.5[M+H]+;1H NMR(400MHz,DMSO)δ12.66(s,1H),7.54–7.49(d,2H),7.39–7.35(d,2H),7.31–7.26(d,2H),7.18(s,1H),7.07(s,1H),7.02–6.98(d,1H),4.10(t,J=6.7Hz,2H),3.81(s,3H),3.60(t,J=5.5Hz,1H),3.29(t,J=6.8Hz,2H),2.39(t,J=6.3Hz,2H),1.85(m,4H).
参照实施实例31的合成方法得到实施实例55
实施实例55 2-(1-(4-甲氧基苯基)-7-氧代-6-[4-(2-氧代哌啶-1-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-基)-4,5-二氢1H-咪唑基-1-羧酸己酯
ESI-MS m/z:613.7[M+H]+;
步骤25 1-(4-甲氧基苯基-7-氧代-6-(4-(2-氧代哌啶-1-基)苯基)-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-氨基甲酸甲酯(40)
将KOH(1.55g,0.028mol)加入到150ml甲醇中,20℃搅拌10min,溶解后加入(5g,0.011mol)A和3.5g醋酸碘苯,20℃搅拌2h后,反应液由浑浊变成淡红色透明液体。蒸干溶剂得到5g红色固体,所得的固体直接投下一步。
步骤26 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-氨基-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮(41)
将上一步得到的5g中间体1、2g NaOH、20mL水、150ml二氧六环加入至500ml的茄形瓶中,100℃反应6-10小时。蒸掉部分溶剂,加水抽滤,水洗两次得到淡黄色固体2.5g,这一步和上一步的总产率约为50%。
步骤27N’-(1-(4-甲氧基苯基-7-氧代-6-(4-(2-氧代哌啶-1-基)苯基)-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3基)-N,N-二甲基甲脒(42)
将中间体41(2g,4.6mmol)和DMF-DMA20ml加入茄形瓶中,104摄氏度回流12h趁热抽滤,无水乙醚洗涤2次,得到淡黄色固体2.1g,收率90%。
步骤28 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(4H-1,2,4-三氮唑-4-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮(实施实例56)
将(0.15g,0.3mmol)42、(0.022g,0.36mmol)甲酰肼和1ml冰醋酸80摄氏度反应2h。反应完毕,倒入水中。洗出固体。抽滤,柱层析得到产物0.1g。收率67%
ESI-MS m/z:484.5[M+H]+;
参照实施实例56的合成方法得到实施实例57-71
实施实例57 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(3-氨基-4H-1,2,4-三氮唑-4-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:499.5[M+H]+;
实施实例58 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-[3-(四氢吡咯-1-基)甲基-4H-1,2,4-三氮唑-4-基]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:567.7[M+H]+;
实施实例59 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(3-二乙氨基甲基-4H-1,2,4-三氮唑-4-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:569.7[M+H]+;1H NMR(400MHz,DMSO)δ8.90(s,1H),7.49(d,J=9.0Hz,2H),7.38(d,J=8.8Hz,2H),7.29(d,J=8.8Hz,2H),7.02(d,J=9.0Hz,2H),4.09(t,J=6.5Hz,2H),3.80(s,3H),3.79(s,2H),3.60(t,J=5.6Hz,2H),2.92(t,J=6.5Hz,2H),2.38(q,J=7.1Hz,4H),1.85(d,J=4.5Hz,4H),0.79(t,J=7.1Hz,6H)。
实施实例60 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(3-甲基-4H-1,2,4-三氮唑-4-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:498.6[M+H]+;
实施实例61 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-[3-(2-氧代-4,5-二氢噁唑-3H-3-基)甲基-4H-1,2,4-三氮唑-4-基]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:583.6[M+H]+;
实施实例62 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-[3-(2-氧代吗啉-1-基)甲基-4H-1,2,4-三氮唑-4-基]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:597.6[M+H]+;
实施实例63 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3[3-(2-氧代吡啶-1-基)甲基-4H-1,2,4-三氮唑-4-基]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:591.6[M+H]+;
实施实例64 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-[3-(四氢吡咯-1-基)甲基-4H-1,2,4-三氮唑-4-基]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:567.7[M+H]+;
实施实例65 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-[3-(吗啉-1-基)甲基-4H-1,2,4-三氮唑-4-基]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:583.7[M+H]+;
实施实例66 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3[3-(四氢呋喃-2-基)-4H-1,2,4-三氮唑-4-基]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:554.6[M+H]+;
实施实例67 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3(3-甲氧甲基-4H-1,2,4-三氮唑-4-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:528.6[M+H]+;
实施实例68 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3(3-环丙基-4H-1,2,4-三氮唑-4-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:524.6[M+H]+;
实施实例69 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3(3-叔丁基-4H-1,2,4-三氮唑-4-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:540.6[M+H]+;
实施实例70 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3(3-异丙基-4H-1,2,4-三氮唑-4-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:526.6[M+H]+;
实施实例71 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3(3-乙基-4H-1,2,4-三氮唑-4-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:512.6[M+H]+;
步骤29 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(1H-1,2,3,4-四氮唑-1-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮(实施实例72)
在50ml茄形瓶中,一次加入0.12ml原甲酸三乙酯,(0.2g 0.46mmol)41,20ml冰醋酸,45摄氏度反应2h,然后加入0.045g NaN3,100摄氏度反应5小时。待反应完毕后,蒸干溶剂,二氯甲烷溶解后水洗2次,无水硫酸钠干燥,蒸干得到黄色固体1.4g。收率65%。
ESI-MS m/z:485.5[M+H]+;
步骤30 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3(1,2,4-噁二唑-4H-5-酮-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮(实施实例73)
将中间体33(0.44g,0.001mol)溶于5ml乙醇中,加入(0.69g,0.01mol)盐酸羟胺,回流反应5h,冷却析出固体0.38g,收率80%
将上述所得产品溶于5mlTHF中,加入CDI(0.2g,1.2mmol),室温反应过夜,反应完毕,蒸干溶剂,加入二氯甲烷溶解,水洗,干燥蒸干,柱层析得到产品0.31g,收率71%。
ESI-MS m/z:501.5[M+H]+;
步骤31 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(5-氯噻吩-2-磺酰脲基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮(实施实例74)
将41(0.2g,0.43mmol),,5-氯-2-噻吩磺酰胺(0.185g,0.56mmol)加入12ml甲苯中,回流反应5~6小时。反应完毕后,趁热抽滤,滤饼用甲苯洗后干燥即得淡紫色产品0.19g,收率67%。
ESI-MS m/z:656.1[M+H]+;
参照实施实例74的合成方法得到实施实例75-76
实施实例75 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(噻吩-2-磺酰脲基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
ESI-MS m/z:621.7[M+H]+;
实施实例76 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(5-溴噻吩-2-磺酰脲基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
参照中间体13的合成方法得到实施实例77
实施实例77 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-(N-二甲胺基亚甲基)酰胺
ESI-MS m/z:515.6[M+H]+;
步骤32 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-[N-(哌啶-1-基)甲基]酰胺(实施实例78)
于250ml茄形瓶中加入(3.8g,8.3mmol)阿哌沙班,(0.82g,9.1mmol)哌啶,(0.73g,9mmol)37%的甲醛溶液,室温反应0.5h,然后升温回流反应0.5h,冷却,析出固体,抽滤,得产品3.7g,收率80%。
ESI-MS m/z:557.7[M+H]+;
参照实施实例78的合成方法得到实施实例79-83
实施实例79 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-(N-二甲氨基甲基)酰胺
ESI-MS m/z:517.6[M+H]+;
实施实例80 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-(N-二乙氨基甲基)酰胺
ESI-MS m/z:545.6[M+H]+;
实施实例81 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-(N-甲氧基甲基)酰胺
ESI-MS m/z:504.6[M+H]+;
实施实例82 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-[N-(4甲基哌嗪-1-基)甲基]酰胺
ESI-MS m/z:572.7[M+H]+;
实施实例83 1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-[N-(四氢吡咯-1-基)甲基]酰胺
ESI-MS m/z:543.6[M+H]+;
步骤33 1-(4-甲氧基苯基)-6-(4-氨基苯基)-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3羧酸(50)
参照中间体11的合成方法得到中间体50,收率74%。
步骤34 1-(4-甲氧基苯基)-6-[4-(5-氯噻吩-2-磺酰脲基)苯基]-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-羧酸(51)
将中间体50(0.2g,0.53mmol),(5-氯-2-噻吩)磺酰基氨基甲酸乙酯(0.19g,0.69mmol)加入到12ml甲苯中,回流反应6h。反应完毕,趁热抽滤,得产品510.18g,收率57%。
步骤35 1-(4-甲氧基苯基)-6-[4-(5-氯噻吩-2-磺酰脲基)苯基]-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-羧酰胺(实施实例84)
参照中间体12的合成方法得到实施实例84,收率85%。
ESI-MS m/z:602.1[M+H]+;
参照实施实例84的合成方法得到实施实例85-87
实施实例85 1-(4-甲氧基苯基)-6-[4-(5-溴噻吩-2-磺酰脲基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-羧酰胺
ESI-MS m/z:646.5[M+H]+;
实施实例86 1-(4-甲氧基苯基)-6-[4-(噻吩-2-磺酰脲基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-羧酰胺
ESI-MS m/z:567.6[M+H]+;
实施实例87 1-(4-甲氧基苯基)-6-[4-(4-甲基-苯磺酰脲基)-苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-羧酰胺
ESI-MS m/z:575.6[M+H]+;
参照实施实例1,3的合成方法得到实施实例88-91
实施实例88 1-(4-甲氧基苯基)-3-(1H-1,2,4-三氮唑-3-基)-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-6-苯基-4-(5-溴噻吩-2-磺酰基)脲
ESI-MS m/z:670.5[M+H]+;
实施实例89 1-(4-甲氧基苯基)-3-(1H-1,2,4-三氮唑-3-基)-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-6-苯基-4-(5-氯噻吩-2-磺酰基)脲
ESI-MS m/z:626.1[M+H]+;
实施实例90 1-(4-甲氧基苯基)-3-(2-甲基-2H-1,2,4-三氮唑-3-基)-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-6-苯基-4-(5-氯噻吩-2-磺酰基)脲
ESI-MS m/z:640.1[M+H]+;
实施实例91 1-(4-甲氧基苯基)-3-(1H-1,2,4-三氮唑-3-基)-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-6-苯基-4-(4-氟苯磺酰基)脲
ESI-MS m/z:603.6[M+H]+;
步骤36 4-(2-氧代哌啶基)苯甲腈(57)
参照中间体9的合成方法得到中间体57,收率80%。
步骤37 4-(3,3-二氯-2-氧代哌啶-1-基)苯甲腈(58)
将中间体57(11g,0.055mol)加入到66ml二氯甲烷中,搅拌下室温分批缓慢加入PCl5,加毕,升温回流反应3h。将反应液冷却后倒入冰水中,分出有机层,水层用二氯甲烷萃取3次,合并有机层,饱和Na2CO3溶液洗2次,饱和食盐水洗3次,干燥后,减压蒸出溶剂,得到黄色固体8g,收率54%。
步骤38 4-(3-吗啉-2-氧代-5,6-二氢-1(2H)-基)苯甲腈(59)
将中间体58(1g,3.7mmol)溶于3.6ml吗啉中,80度反应5h。冷却到室温,减压蒸去吗啉得到深棕色固体,加水,搅拌抽滤,滤饼水洗,干燥得棕色固体0.76g,收率72%。
步骤39 1-(4-甲氧基苯基)-6-(4-氰基苯基)-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-羧酸乙酯(61)
在25ml茄形瓶中加入18ml乙酸乙酯、中间体59(1.8g,6.4mmol)、中间体5(1.8g,7mmol)、TEA1.26ml,升温至70度反应,有三乙胺盐酸盐析出。反应完毕后,将反应液冷却到0度,滴加3N盐酸10ml,滴加过程中,盐先溶解,然后有黄色粘状物析出,滴毕,25度反应,黄色粘状物慢慢溶解,然后有粉末状黄色固体析出。抽滤,滤饼水洗,正己烷洗,干燥后得到黄色固体2.1g,收率79%。
步骤40 1-(4-甲氧基苯基)-6-(4-氰基苯基)-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3羧酸(62)
将中间体61(1g,2.4mmol)、NaOH 0.29g加入到10ml甲醇与水的混合液中(甲醇:水=5:1),40度反应半小时。蒸出甲醇,加入适量水,水层用EtAc洗3次,然后在水层中加入碎冰,使用3N盐酸调节PH至4~5,析出白色固体,抽滤,水洗滤饼,干燥后得到白色固体0.8g,收率86%。
步骤41 1-(4-甲氧基苯基)-6-(4-氰基苯基)-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3羧酰胺(63)
参照中间体12的合成方法得到中间体63,收率71%
步骤42 1-(4-甲氧基苯基)-6-[4-(4,5-二氢-1H-咪唑-2-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-酰胺(实施实例92)
将中间体63(0.2g,0.52mmol)、乙二胺1ml、升华硫4.1mg加入25ml茄形瓶中,116度回流反应2~3h。反应液冷却至室温,加入水,搅拌半小时后,抽滤,得到白色产物0.17g,收率71%。
ESI-MS m/z:431.5[M+H]+;
参照实施实例92的合成方法得到实施实例93-100
实施实例93 1-(4-甲氧基苯基)-6-[4-(1,4,5,6-四氢吡啶-2-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-甲酰胺
ESI-MS m/z:445.2[M+H]+
实施实例94 1-(4-二氟甲氧基苯基)-6-[4-(4,5-二氢-1H-咪唑-2-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-甲酰胺
ESI-MS m/z:467.2[M+H]+
实施实例95 1-(4-二氟甲氧基苯基)-6-[4-(1,4,5,6-四氢吡啶-2-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-甲酰胺
ESI-MS m/z:481.2[M+H]+
实施实例96 1-(4-二氟甲氧基苯基)-6-[4-(4,5,6,7-1H-1,3-二氮杂卓-2-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-甲酰胺
ESI-MS m/z:495.2[M+H]+
实施实例97 1-(4-氟苯基)-6-[4-(4,5-二氢-1H-咪唑-2-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-甲酰胺
ESI-MS m/z:419.2[M+H]+
实施实例98 1-(4-氟苯基)-6-[4-(1,4,5,6-四氢吡啶-2-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-甲酰胺
ESI-MS m/z:433.2[M+H]+
实施实例99 1-(4-氟苯基)-6-[4-(4,5,6,7-1H-1,3-二氮杂卓-2-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-甲酰胺
ESI-MS m/z:447.2[M+H]+
实施实例100 1-(4-甲氧基苯基)-6-[4-(4,5,6,7-1H-1,3-二氮杂卓-2-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-甲酰胺
ESI-MS m/z:459.2[M+H]+
步骤43 1-(4-碘-2-硝基苯基哌啶)-2-酮(65)
冰浴下,将浓硫酸(42.5g,0.05mol)缓慢滴加至浓硝酸(42.5g,0.15mol)中,滴毕,摇匀,降温后备用。将中间体22(5g,0.0166mol)溶于DCM中,控温-20℃至-15℃,滴加混酸,滴毕,0℃反应。待反应完全后,将反应液倒入冰水中,用DCM萃取3次,合并有机层,饱和NaHCO3洗3次,脱溶剂得一深褐色油状物。过层析柱得纯品3.7g,收率64%。
步骤44 1-(4-甲氧基苯基)-6-(3-硝基-4-(2-氧代哌啶-1-基)苯基)-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-羧酸乙酯(66)
于三颈瓶中加中间体7(1.8g,5.7mmol)、DMF30ml、65(3g,8.7mmol)、K2CO31.6g,室温下搅拌,通氮气0.5h,加CuI 0.2g,8-羟基喹啉0.2g,升温至130℃反应。反应完成后用硅胶和硅藻土抽滤,加水,DCM萃取,蒸干得灰色固体2.1g,收率71%。
步骤45 1-(4-甲氧基苯基)-6-(1,2,3,4-四氢苯并[4,5]咪唑[1,2-a]吡啶-7-基)-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-羧酸乙酯(67)
于50ml茄型瓶中加60%HAc23ml和铁粉1.21g,升温至100℃活化10min。缓慢加入中间体66(2.3g,0.0043mol),继续反应4h。抽滤,脱去溶剂,得一褐色油状物,加DCM溶解,饱和NaHCO3、饱和NaCl洗,蒸干DCM得一褐色固体1.7g,收率81%。
步骤46 1-(4-甲氧基苯基)-6-(1,2,3,4-四氢苯并[4,5]咪唑[1,2-a]吡啶-7-基)-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-羧酸(68)
于50ml茄型瓶中加EtOH/H2O15ml,中间体67(1.1g,2.3mmol)NaOH0.27g,升温至65℃反应6h,反应完毕,蒸去乙醇,残余物加水溶解,用3NHCl调PH至3-4,析出黄色固体,抽滤,干燥得产物0.91g,收率87%。
步骤46 1-(4-甲氧基苯基)-6-(1,2,3,4-四氢苯并[4,5]咪唑[1,2-a]吡啶-7-基)-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-羧酰胺(实施实例101)
参照中间体12的合成方法得到实施实例101,
ESI-MS m/z:457.2[M+H]+
体外PT、APTT实验
Xa因子抑制剂(Apixaban类似物)与Xa因子结合,阻止凝血酶的产生。通过测定凝血酶时间(PT)及活化部分凝血酶时间(APTT)考察化合物活性。
步骤1:全血样品的采集
将家兔用用3%戊巴比妥钠麻醉后,颈总动脉采血,并立即将血与3.8%枸橼酸钠按照9:1比例混合均匀。
步骤2:贫血小板血浆(PPP)的制备
将混合均匀的抗凝血离心,转速是2000-2500转/分,时间控制在10分钟左右,取出上清即为PPP。
步骤3:待测药品的制备
称取待测药品2.5mg,加入100ul DMSO充分溶解,然后加入900ul生理盐水混匀,从中吸取100ul加到900ul生理盐水中即成最高浓度药液(药液终浓度250ug/ml),后用生理盐水依次稀释成中浓度50ug/ml,10ug/ml的药液备用。
步骤4:样品的测定
按照PT、APTT试剂盒要求操作。药物的终浓度分别为:25ug/ml,5ug/ml,1ug/ml。具体操作如下:
PT:
APTT:
受试物活性用将空白血浆APTT或PT时间增加一倍的受试物浓度(EC2x)表示,EC2x计算根据曲线拟合。实验结果如下表所示:
实施例 | APTT(s) | PT(s) | 实施例 | APTT(s) | PT(s) |
实施例1 | 1.5 | 1.4 | 实施例2 | 12 | 2.5 |
实施例3 | 12.5 | 10 | 实施例5 | 20 | 10 |
实施例6 | 5.1 | 0.5 | 实施例9 | 4.5 | 2.0 |
实施例10 | 4.5 | 2.8 | 实施例11 | 14 | 2.1 |
实施例12 | 4.2 | 5.1 | 实施例14 | 5.5 | 1.3 |
实施例16 | 7.5 | 1.1 | 实施例17 | 19 | 4.8 |
实施例18 | 10 | 7.8 | 实施例19 | 16.5 | 2.7 |
实施例20 | 18 | 4.1 | 实施例21 | 20 | 7.3 |
实施例22 | 17 | 2.5 | 实施例23 | 20 | 8 |
实施例24 | 13.5 | 3.5 | 实施例25 | 15.5 | 2.9 |
实施例26 | 3.5 | 10.5 | 实施例27 | 2.2 | 3.8 |
实施例28 | 3.1 | 4.2 | 实施例29 | 1.1 | 1.9 |
实施例30 | 10.6 | 8.2 | 实施例36 | 3 | 5.1 |
实施例38 | 3.2 | 5.4 | 实施例39 | 1.5 | 2.8 |
实施例40 | 5.1 | 3.9 | 实施例41 | 2.9 | 4.9 |
实施例42 | 3.5 | 0.5 | 实施例43 | 4.2 | 8.0 |
实施例45 | 12 | 0.3 | 实施例46 | 13 | 4.5 |
实施例47 | 15 | 2.5 | 实施例48 | 4.7 | 8.5 |
实施例49 | 8 | 6 | 实施例50 | 6 | 3.5 |
实施例51 | 16.2 | 13 | 实施例52 | 4 | 2.8 |
实施例53 | 7 | 1.6 | 实施例56 | 1.6 | 0.7 |
实施例57 | 3.0 | 1.3 | 实施例58 | 19 | 7 |
实施例60 | 2.0 | 1.3 | 实施例61 | 4.0 | 4.0 |
实施例62 | 3.0 | 7.0 | 实施例64 | 3.0 | 2.7 |
实施例65 | 0.5 | 0.5 | 实施例66 | 2.2 | 1.6 |
实施例67 | 2.3 | 2.7 | 实施例68 | 1.5 | 2.3 |
实施例69 | 0.3 | 0.5 | 实施例70 | 2.8 | 0.5 |
实施例71 | 1.5 | 1.5 | 实施例72 | 6.7 | 1.9 |
实施例73 | 13.5 | 5.5 | 实施例77 | 2.2 | - |
实施例78 | 10 | 8 | 实施例79 | 1.4 | 6 |
实施例80 | 2.5 | 2.9 | 实施例92 | 1.11 | 0.5 |
Claims (11)
1.通式Ⅰ的化合物及其药学上可接受的盐、水合物或前药,
其中:
R1为H,C1-C4直链或支链烷基,C1-C4烷氧基,卤素,羟基,氰基,游离的、成盐的、酯化的或酰胺化的羧基,任选被羟基、氨基或卤素取代的C1-C6烷基或C1-C6烷氧基;
R2选自CONHR3、NHCONHSO2Ar、5-10元杂环基、5-10元杂芳基,其中所述杂环基和杂芳基含有1-3个选自N、O或S的杂原子,并且所述杂环基或杂芳基任选1-3个相同或不同的R3取代;
R3为H、C1-C4直链或支链烷基、C1-C4烷氧基、C1-C4烷硫基、C1-C4烷氧基C1-C4烷基、C3-C7环烷基、任选被羟基、氨基或卤代的C1-C6烷基、C1-C4直链或支链烷基酰氧C1-C2烷基、卤代、羟基、氰基、羧基、C1-C10直链或支链烷氧甲酰基、(CH2)nNR4R5、5-10元杂环基,其中所述杂环基含有1-3个选自N、O或S的杂原子;
条件为当R2为CONH2时,A不为哌啶酮或吗啉酮;
n为0-6的整数;
R4和R5相同或不同,分别独立地选自氢、C1-C10直链或支链烷基、C3-C7环烷基、C1-C4烷氧基、C2-C10烯基和C2-C10炔基,它们可以被0-3个相同或不同的R6任选取代;
或R4和R5与和它们所连接的氮原子一起形成5-10元杂环基或5-10元杂芳基,所述杂环基和杂芳基除了与R4和R5连接的氮原子外,任选含有0-4个选自N、O和S的杂原子,除了R4和R5所连接的氮原子外,所述杂环基任选包括0或2个碳碳双键或叁键,所述杂环基和杂芳基任选被0-3个相同或不同的R7取代;
A为5-10元杂环基、5-10元杂芳基,其中所述杂环基和杂芳基含有1-3个选自N、O或S的杂原子,并且所述杂环基或杂芳基任选0-3个相同或不同的R8取代;
Ar为C6-C10芳基、5-10元杂芳基,其中,所述杂芳基含有1-3个选自N、O或S的杂原子,并且Ar任选1-3个相同或不同的R7取代;
R6为C1-C4烷基、C1-C4烷氧基、卤代、羟基、氰基;
R7为C1-C4烷基、C1-C4烷氧基、卤代、羟基、氰基、羧基、酯基;
R8为氢、羰基、卤代、C1-C4烷基。
2.权利要求1的通式Ⅰ的化合物及其药学上可接受的盐、水合物或前药,其中,
R1为H、C1-C4烷氧基、卤代、羟基、氰基、任选被羟基、氨基或卤素取代的C1-C6烷基或C1-C6烷氧基;
R2选自CONHR3、NHCONHSO2Ar、5-7元杂环基、5-6元杂芳基,其中所述杂环基和杂芳基含有1-3个选自N、O或S的杂原子,并且所述杂环基或杂芳基任选1-3个相同或不同的R3取代;
条件为当R2为CONH2时,A不为哌啶酮或吗啉酮;
R4和R5相同或不同,分别独立地选自氢、C1-C10直链或支链烷基、C3-C7环烷基、C1-C4烷氧基,它们可以被0-3个相同或不同的R6任选取代;
或R4和R5与和它们所连接的氮原子一起形成5-10元杂环基,所述杂环基除了与R4和R5连接的氮原子外,任选含有0-4个选自N、O和S的杂原子,除了R4和R5所连接的氮原子外,所述杂环基任选包括0或2个碳碳双键,所述杂环基和杂芳基任选被0-3个相同或不同的R7取代。
3.权利要求2的通式Ⅰ的化合物及其药学上可接受的盐、水合物或前药,其中,
R1为C1-C4烷氧基、卤代、被1-2个卤素取代的C1-C4烷基或C1-C4烷氧基;
R2为CONHR3、NHCONHSO2Ar、任选1-3个相同或不同的R3取代的三唑基,四唑基,二氢噻唑基、四氢吡啶基、1,3-二氮环庚基、异噁二唑酮基;
R3为H、甲基、乙基、异丙基、叔丁基、环丙基、甲氧基、甲硫基、甲氧基甲基、甲硫基甲基、被1-2个羟基取代的C1-C3烷基、特戊酰氧甲基、正己氧甲酰基、叔丁氧甲酰基、(CH2)nNR4R5;
条件为当R2为CONH2时,A不为哌啶酮或吗啉酮;
n为0-4的整数;
R4和R5相同或不同,分别独立地选自氢、C1-C4烷基;
或R4和R5与和它们所连接的氮原子一起形成5-6元杂环基,所述杂环基除了与R4和R5连接的氮原子外,任选含有0-4个选自N、O和S的杂原子,所述杂环基和杂芳基任选被0-3个相同或不同的R7取代;
A为5-10元杂环基,其中所述杂环基含有1-3个选自N、O 或S的杂原子,并且所述杂环基或杂芳基任选0-3个相同或不同的R8取代;
Ar为苯基、噻吩基,其中Ar任选1-3个相同或不同的R7取代;
R6为C1-C4烷基、C1-C4烷氧基、卤素;
R7为C1-C4烷基、C1-C4烷氧基、卤素;
R8为氢、羰基、卤代、甲基。
4.权利要求3的通式Ⅰ的化合物及其药学上可接受的盐、水合物或前药,其中,
R2为选自如下结构:
A为5-10元杂环基,其中所述杂环基含有1-3个选自N、O或S的杂原子,并且所述杂环基任选0-3个相同或不同的R8取代。
5.权利要求4的通式Ⅰ的化合物及其药学上可接受的盐、水合物或前药,其中,
R1为甲氧基、卤代、二氟甲氧基、三氟甲氧基;
R2为选自如下结构:
R3为H、甲基、乙基、异丙基、叔丁基、环丙基、特戊酰氧甲基、正己氧甲酰基、叔丁氧甲酰基、(CH2)nNR4R5;
n为1-3的整数
R4和R5相同或不同,分别独立地选自氢、甲基、乙基;
或R4和R5与和它们所连接的氮原子一起形成
6.权利要求5的通式Ⅰ的化合物及其药学上可接受的盐、水合物或前药,其中,
Ar为噻吩基,并且Ar任选1-3个R7取代
R7为氯、溴。
7.权利要求6的通式Ⅰ的化合物及其药学上可接受的盐、水合物或前药,其中,
A为
8.下列通式Ⅰ的化合物及其药学上可接受的盐、水合物或前药:
1-(4-甲氧基苯基)-6-[4-(3-氧代-4-吗啉基)苯基]-3-(1H-1,2,4-三氮唑-3-基)-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(3-氧代-4-吗啉基)苯基]-3-(1-甲基-1H-1,2,4-三氮唑-3-基)-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(3-氧代-4-吗啉基)苯基]-3-[4-甲基氨基-乙基-4H-1,2,4-三氮唑-3-基]-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(3-氧代-4-吗啉基)苯基]-3-[4-(3-二乙基氨基-丙基)-4H-1,2,4-三氮唑-3-基]-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(3-氧代-4-吗啉基)苯基]-3-[4-(3-二甲基氨基-丙基)-4H-1,2,4-三氮唑-3-基]-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(3-氧代-4-吗啉基)苯基]-3-(4-甲基-4H-1,2,4-三氮唑-3-基)-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(5-氯噻吩-2-磺酰脲基)苯基]-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-羧酰胺
1-(4-甲氧基苯基)-3-(1H-1,2,4-三氮唑-3-基)-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-6-苯基-4-(5-氯噻吩-2-磺酰基)脲
1-(4-甲氧基苯基)-6-[4-(5-溴噻吩-2-磺酰脲基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-羧酰胺
1-(4-甲氧基苯基)-3-(2-甲基-2H-1,2,4-三氮唑-3-基)-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-6-苯基-4-(5-氯噻吩-2-磺酰基)脲
1-(4-甲氧基苯基)-3-(1H-1,2,4-三氮唑-3-基)-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-6-苯基-4-(5-溴噻吩-2-磺酰基)脲
1-(4-甲氧基苯基)-6-[4-(噻吩-2-磺酰脲基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-羧酰胺
1-(4-甲氧基苯基)-6-[4-(4-甲基-苯磺酰脲基)-苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-羧酰胺
1-(4-甲氧基苯基)-3-(1H-1,2,4-三氮唑-3-基)-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-6-苯基-4-(4-氟苯磺酰基)脲
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(5-甲基-1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(5-环丙基-1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(5-四氢呋喃-2-基)-1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(5-乙基-1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(5-甲氧基甲基-1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(5-异丙基-1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(5-叔丁基-1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(5-二甲氨基甲基-1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(5-二乙氨基甲基-1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-[5-(四氢吡咯-1-基)甲基-1H-1,2,4-三氮唑-3-基)]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-[5-(哌啶基-1-基)甲基-1H-1,2,4-三氮唑-3-基)]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(5-吗啉基-甲基-1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(1H-咪唑-2-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(4-甲基-4,5-二氢-1H-咪唑-2-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(1,4,5,6-四氢嘧啶-2-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(4,5,6,7-四氢1H-1,3-二氮杂环庚基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(4,5-二氢噻唑-2-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(4,5-二氢-1H-咪唑-2-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-酰胺
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-[N-(四氢吡咯-1-基)甲基]酰胺
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-[N-(4甲基哌嗪-1-基)甲基]酰胺
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-[N-(哌啶-1-基)甲基]酰胺
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-(N-二乙氨基甲基)酰胺
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-(N-二甲氨基甲基)酰胺
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-(N-甲氧基甲基)酰胺
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-(N-二甲胺基亚甲基)酰胺
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(2-甲基-2H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(1-甲基-1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(1-二甲基氨基乙基-1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(4-甲基4H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(4-环丙基-4H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(4-二甲氨基乙基-4H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(4-二甲氨基-4H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(4-二甲氨基丙基-4H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(4-二乙氨基乙基-4H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(4-二乙氨基丙基-4H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-[4-(吗啉-1-基)-乙基-4H-1,2,4-三氮唑-3-基]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-[4-(吗啉-1-基)-丙基-4H-1,2,4-三氮唑-3-基]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-[4-(哌啶-1-基)-乙基-4H-1,2,4-三氮唑-3-基]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-[4-(四氢吡咯-1基)-乙基-4H-1,2,4-三氮唑-3-基]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-[4-(2,3-二羟基丙基)-4H-1,2,4-三氮唑-3-基]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3(1,2,4-噁二唑-4H-5-酮-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3(3-乙基-4H-1,2,4-三氮唑-4-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3(3-异丙基-4H-1,2,4-三氮唑-4-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3(3-叔丁基-4H-1,2,4-三氮唑-4-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3(3-环丙基-4H-1,2,4-三氮唑-4-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3(3-甲氧甲基-4H-1,2,4-三氮唑-4-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3[3-(四氢呋喃-2-基)-4H-1,2,4-三氮唑-4-基]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
N-(1-(4-甲氧基苯基-7-氧代-6-(4-(2-氧代哌啶基)苯基)-5,6-二氢)1H-吡唑并[3,4-c]吡啶-3-氨甲酰基)噻吩-2-磺酰胺
N-(1-(4-甲氧基苯基-7-氧代-6-(4-(2-氧代哌啶基)苯基)-5,6-二氢)1H-吡唑并[3,4-c]吡啶-3-氨甲酰基)-5-氯-噻吩-2-磺酰胺
N-(1-(4-甲氧基苯基-7-氧代-6-(4-(2-氧代哌啶基)苯基)-5,6-二氢)1H-吡唑并[3,4-c]吡啶-3-氨甲酰基)-5-溴-噻吩-2-磺酰胺
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-[3-(吗啉-1-基)甲基-4H-1,2,4-三氮唑-4-基]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-[3-(四氢吡咯-1-基)甲基-4H-1,2,4-三氮唑-4-基]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3[3-(2-氧代哌啶-1-基)甲基-4H-1,2,4-三氮唑-4-基]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-[3-(2-氧代吗啉-1-基)甲基-4H-1,2,4-三氮唑-4-基]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-[3-(2-氧代-4,5-二氢噁唑-3H-3-基)甲基-4H-1,2,4-三氮唑-4-基]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(3-甲基-4H-1,2,4-三氮唑-4-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(1H-1,2,3,4-四氮唑-1-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(4H-1,2,4-三氮唑-4-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(3-氨基-4H-1,2,4-三氮唑-4-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-[3-(四氢吡咯-1-基)甲基-4H-1,2,4-三氮唑-4-基]-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(3-二乙氨基甲基-4H-1,2,4-三氮唑-4-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-三氟甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-氟苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-氯苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-二氟甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-溴苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-[4-(2-氧代哌啶-1-基)苯基]-3-(5-甲硫基-1H-1,2,4-三氮唑-3-基)-5,6-二氢-1H-吡唑并[3,4-c]吡啶-7-酮
1-(4-甲氧基苯基)-6-(1,2,3,4-四氢苯并[4,5]咪唑[1,2-a]吡啶-7-基)-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-甲酰胺
1-(4-甲氧基苯基)-6-[4-(4,5-二氢-1H-咪唑-2-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-甲酰胺
1-(4-甲氧基苯基)-6-[4-(1,4,5,6-四氢吡啶-2-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-甲酰胺
1-(4-二氟甲氧基苯基)-6-[4-(4,5-二氢-1H-咪唑-2-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-甲酰胺
1-(4-二氟甲氧基苯基)-6-[4-(1,4,5,6-四氢吡啶-2-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-甲酰胺
1-(4-二氟甲氧基苯基)-6-[4-(4,5,6,7-1H-1,3-二氮杂卓-2-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-甲酰胺
1-(4-氟苯基)-6-[4-(4,5-二氢-1H-咪唑-2-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-甲酰胺
1-(4-氟苯基)-6-[4-(1,4,5,6-四氢吡啶-2-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-甲酰胺
1-(4-氟苯基)-6-[4-(4,5,6,7-1H-1,3-二氮杂卓-2-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-甲酰胺
1-(4-甲氧基苯基)-6-[4-(4,5,6,7-1H-1,3-二氮杂卓-2-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-甲酰胺 。
9.下列通式Ⅰ的化合物及其药学上所指的前药为:
2-(1-(4-甲氧基苯基)-7-氧代-6-[4-(2-氧代哌啶-1-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-基)-4,5-二氢1H-咪唑基-1-羧酸己酯
3-(1-(4-甲氧基苯基)-7-氧代-6-[4-(2-氧代哌啶-1-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-基)-1H-1,2,4三氮唑基-1-羧酸己酯
3-(1-(4-甲氧基苯基)-7-氧代-6-[4-(3-氧代-4-吗啉基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-基)-1H-1,2,4三氮唑基-1-羧酸己酯
3-(1-(4-甲氧基苯基)-7-氧代-6-[4-(3-氧代-4-吗啉基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-基)-1H-1,2,4三氮唑基-1-甲基特戊酸酯
3-(1-(4-甲氧基苯基)-7-氧代-6-[4-(2-氧代哌啶-1-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-基)-1H-1,2,4三氮唑基-1-甲基特戊酸酯
3-(1-(4-甲氧基苯基)-7-氧代-6-[4-(2-氧代哌啶-1-基)苯基]-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-基)-1H-1,2,4三氮唑基-1-羧酸叔丁酯 。
10.一种药用组合物,包含权利要求1-9中任何一项的化合物及其药学上可接受的盐、水合物或前药作为活性成分以及药学上可接受的赋形剂。
11.权利要求1-9中任何一项的化合物及其药学上可接受的盐、水合物或前药或权利要求10所述的组合物在制备治疗/或预防血栓栓塞性疾病药物中的应用。
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US11613542B2 (en) | 2017-08-15 | 2023-03-28 | Inflazome Limited | Sulfonylureas and sulfonylthioureas as NLRP3 inhibitors |
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CN114805347A (zh) * | 2022-05-12 | 2022-07-29 | 贵州大学 | 一种有机催化合成手性吡唑并[3,4-b]吡啶酮类化合物及应用 |
CN114805347B (zh) * | 2022-05-12 | 2023-10-20 | 贵州大学 | 一种有机催化合成手性吡唑并[3,4-b]吡啶酮类化合物及应用 |
WO2024084217A1 (en) * | 2022-10-19 | 2024-04-25 | Kalvista Pharmaceuticals Limited | 3a,4,5,6-tetrahydro-1 h-pyrazolo[3,4-c]pyridin-7(7ah)-one derivatives as factor xiia inhibitors |
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