CN101076333A - 可用于治疗TNF-α和IL-1介导的疾病的吡唑并杂芳基化合物 - Google Patents
可用于治疗TNF-α和IL-1介导的疾病的吡唑并杂芳基化合物 Download PDFInfo
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- CN101076333A CN101076333A CNA2005800426060A CN200580042606A CN101076333A CN 101076333 A CN101076333 A CN 101076333A CN A2005800426060 A CNA2005800426060 A CN A2005800426060A CN 200580042606 A CN200580042606 A CN 200580042606A CN 101076333 A CN101076333 A CN 101076333A
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- Prior art keywords
- phenyl
- pyrazolo
- fluoro
- methoxyl group
- pyridine
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Abstract
式I化合物,其中基团R1-R4、X和Y如说明书中定义,可用于治疗TNF-A和IL-1介导的疾病。
Description
本发明涉及吡唑并杂芳基化合物,具体而言,涉及吡唑并[3,4-b]吡啶、吡唑并[3,4-d]嘧啶和吡唑并[3,4-b]吡嗪衍生物以及它们用于治疗TNFα和IL-1介导的疾病如类风湿性关节炎和骨代谢疾病、例如骨质疏松症的用途。
因此,本发明提供了式I化合物或其在药学上可接受的和可裂解的酯或酸加成盐,
其中:
X和Y独立地是碳或氮,
R1是H、卤素、羟基、低级烷氧基、低级烷基或卤代-低级烷基;
R2是H或任选被取代的“杂环基、低级烷基、低级链烯基、低级炔基或低级烷氧基”;
R3是H或任选被取代的“杂环基、低级烷基、低级链烯基、低级炔基或低级烷氧基”;或者
R2和R3连接在一起形成4-至6-元杂环,所述杂环含有一个或多个选自O、S、N或NR的杂原子,其中R为H或低级烷基;
R4表示一个、两个或三个卤素取代基,其可以相同或不同。
优选式I中的-X=Y-为-CH=N-或-N=CH-,且式I化合物为式I’、I”和I”’的吡唑并[3,4-b]吡啶、吡唑并[3,4-d]嘧啶和吡唑并[3,4-b]吡嗪衍生物,
其中取代基R1、R2、R3和R4如上定义。
在本说明书的上文以及其它部分,下述术语具有下述含义。
卤代或卤素指I、Br、Cl或F,优选Cl或F。
上文及下文中有机基团或化合物分别所涉及的术语“低级”定义为例如具有至多且包括7个、优选至多且包括4个、有利地为1或2个碳原子的支链或直链。
低级烷基为支链或直链基团,含有1至7个碳原子,优选1至4个碳原子。低级烷基表示例如甲基、乙基、丙基、丁基、异丙基或异丁基。
卤代-低级烷基为被至多6个卤素原子取代的C1-C7低级烷基。
低级烷氧基为支链或直链基团,含有1至7个碳原子,优选1至4个碳原子。低级烷氧基表示例如甲氧基、乙氧基、丙氧基、丁氧基、异丙氧基、异丁氧基或叔丁氧基。
低级烯烃或链烯基为支链或直链基团,含有2至7个碳原子,优选1至4个碳原子,并且含有至少一条碳-碳双键。低级烯烃或低级链烯基表示例如乙烯基、丙烯基、丁烯基、异丙烯基或异丁烯基。
低级炔烃或炔基为支链或直链基团,含有2至7个碳原子,优选1至4个碳原子,并且含有至少一条碳-碳三键。低级炔烃或炔基表示例如乙炔基、丙炔基、丁炔基、异丙炔基或异丁炔基。
杂环基可以是芳香性的,即,作为C3-18杂芳基,为部分不饱和的,含有3至18个环成员,或者是饱和的,即,作为C3-18杂环烷基,含有至少3个环原子,其中至少一个为杂原子,例如O、S、N或NR,其中R为H或低级烷基。
R1、R2和R3可以进一步被一个或多个、例如至多6个取代基取代,所述取代基独立地选自卤素、OH、CN、低级烷基、低级烷氧基、杂环基或NR5R6,其中R5和R6独立地是H或低级烷基。R1、R2和R3上的取代基低级烷基、低级烷氧基、杂环基或NR5R6可以进一步被一个或多个、各自至多被6个、更通常被至多3个、例如1或2个取代基取代,所述取代基独立地选自卤素、OH、CN、低级烷基、低级烷氧基、杂环基或NR5R6,其中R5和R6如上定义。
R1是优选卤素、C1-C4低级烷基、C1-C4低级烷氧基或卤代-C1-C4低级烷基。最优选R1是Cl、F、甲氧基或CF3。
优选R2和R3相互独立地是H或任选被取代的“C1-C4低级烷基、C1-C4低级烷氧基、C1-C7链烯基、C1-C7炔基、C5-C7N-杂环基、C5-C7杂环基C1-C4低级烷氧基、C5-C7杂环基C1-C4低级烷基、C5-C7杂环基C1-C4低级链烯基、C5-C7杂环基C1-C4低级炔基”,其中C5-C7杂环基任选地含有第二个杂原子,例如O、S、N、NR(其中R为H或低级烷基),并且任选的取代情况包括1或2个取代基,所述取代基单独地选自C1-C4烷基、卤素、羟基、C1-C4烷氧基或任选被单-或二-N-C1-4烷基取代的氨基。
具体而言,R2是H、C1-C4低级烷氧基或C5-C7杂环基C1-C4低级烷氧基。例如,在具体的实施方案中,R2是H、甲氧基和N-吗啉基乙氧基。
更优选R3是H或任选被取代的“C1-C4低级烷基、C1-C4低级链烯基、C1-C4低级炔基、C1-C4低级烷氧基、吗啉代基、吡啶基、吗啉代基-C1-C4低级烷氧基、咪唑基、哌啶基、C1-C4低级烷基氨基-C1-C4低级烷基、哌嗪基C1-C4低级烷基、吗啉代基C1-C4低级烷基、四氢吡喃基氨基C1-C4低级烷基、吡啶基氨基羰基、吗啉代基C1-C4低级链烯基、哌啶基C1-C4低级链烯基、哌嗪基C1-C4低级链烯基、吗啉代基C1-C4低级炔基、哌啶基C1-C4低级炔基、哌嗪基C1-C4低级炔基”。
作为R3的取代基的具体实例包括:H、甲氧基、N-吗啉代基、吡啶-4-基、吡啶-2-基氨基羰基2-(N-吗啉代基)乙氧基、1,5-二甲基咪唑-3-基、1-甲基-4-羟基哌啶-4-基、甲基氨基甲基、1-甲基哌嗪-4-基甲基、哌嗪-1-基甲基、丙基氨基甲基、四氢吡喃-4-基氨基甲基、N-吗啉基甲基、甲基氨基甲基、甲氧基、3-氨基-3-甲基-丁-1-炔基、3-氨基-3-甲基-丁基、3-羟基-3-甲基-丁-1-炔基、3-羟基-3-甲基-丁基、3-二甲基氨基丙-1-炔基、3-吗啉-4-基-丙-1-炔基、3-(4-甲基-哌嗪-1-基)-丙-1-炔基、1-甲基-4-羟基-哌啶-4-基乙炔基、(E)-3-二甲基氨基-丙烯基、(E)-3-吗啉-4-基丙烯基、(E)-3-(4-甲基-哌嗪-1-基)-丙烯基,其中任选的取代基如上定义。
当R2和R3连接形成杂环时,它们优选通过亚甲二氧基连接基连接,或者杂环优选是任选被1或2个取代基取代的咪唑环,所述取代基单独地选自C1-4烷基、卤素、羟基、C1-4烷氧基或者任选被单-或二-N-C1-4烷基取代的氨基。最优选当R2和R3连接形成杂环时,它们优选通过亚甲二氧基连接基连接。
R4优选的含义是二卤素,更优选是二氟,尤其是2,4-二氟。
因此,在优选的实施方案中,本发明提供了式II化合物或其在药学上可接受的和可裂解的酯或酸加成盐,
其中
X和Y独立地是碳或氮,
R1’是卤素、C1-C4低级烷基、C1-C4低级烷氧基或卤代-C1-C4低级烷基;
R2’和R3’相互独立地是H或任选被取代的“C1-C4低级烷基、C1-C4低级烷氧基、C1-C7链烯基、C1-C7炔基、C5-C7N-杂环基、C5-C7杂环基C1-C4低级烷氧基、C5-C7杂环基C1-C4低级烷基、C5-C7杂环基C1-C4低级链烯基、C5-C7杂环基C1-C4低级炔基”,其中C5-C7杂环基任选地含有第二个杂原子,并且任选的取代情况包括1或2个取代基,所述取代基单独地选自C1-C4烷基、卤素、羟基、C1-C4烷氧基或者或者任选被单-或二-N-C1-4烷基取代的氨基,或者
R2’和R3’通过亚甲二氧基连接基连接,或者在任选被1或2个取代基取代的咪唑环中连接,所述取代基单独地选自C1-4烷基、卤素、羟基、C1-4烷氧基或者任选被单-或二-N-C1-4烷基取代的氨基。
具体而言,本发明包括下述化合物:
实施例1:(2,4-二氟-苯基)-[3-(2-甲氧基-苯基)-1H-吡唑并[3,4-b]吡啶-6-基]-胺
实施例2:[3-(6-氯-苯并[1,3]二氧杂环戊烯-5-基)-1H-吡唑并[3,4-b]吡啶-6-基]-(2,4-二氟-苯基)-胺
实施例3:[3-(2-氯-苯基)-1H-吡唑并[3,4-b]吡啶-6-基]-(2,4-二氟-苯基)-胺
实施例4:(2,4-二氟-苯基)-[3-(2-三氟甲基-苯基)-1H-吡唑并[3,4-b]吡啶-6-基]-胺
实施例5:(2,4-二氟-苯基)-[3-(2,4-二甲氧基-苯基)-1H-吡唑并[3,4-b]吡啶-6-基]-胺
实施例6:[3-(2-氯-4,5-二甲氧基-苯基)-1H-吡唑并[3,4-b]吡啶-6-基]-(2,4-二氟-苯基)-胺
实施例7:(2,4二氟-苯基)-[3-(2-甲氧基-5-吗啉-4-基-苯基)-1H-吡唑并[3,4-b]吡啶-6-基]-胺
实施例22:(2,4-二氟-苯基)-{3-[2-甲氧基-5-(4-甲基-哌嗪-1-基)-苯基]-1H-吡唑并[3,4-b]吡啶-6-基}-胺
实施例8:(2,4-二氟-苯基)-[3-(2-甲氧基-5-吡啶-4-基-苯基)-1H-吡唑并[3,4-b]吡啶-6-基]-胺
实施例13:(2,4-二氟-苯基)-[3-(2-甲氧基-5-甲基氨基甲基-苯基)-1H-吡唑并[3,4-b]吡啶-6-基]-胺
实施例14:(2,4-二氟-苯基)-{3-[2-甲氧基-5-(4-甲基-哌嗪-1-基甲基)-苯基]-1H-吡唑并[3,4-b]吡啶-6-基}-胺
实施例12:4-{3-[6-(2,4-二氟-苯基氨基)-1H-吡唑并[3,4-b]吡啶-3-基]-4-甲氧基-苯基}-1-甲基-哌啶-4-醇
实施例15:(2,4-二氟-苯基)-[3-(2-甲氧基-5-吗啉-4-基甲基-苯基)-1H-吡唑并[3,4-b]吡啶-6-基]-胺
实施例16:(2,4-二氟-苯基)-[3-(2-甲氧基-5-哌嗪-1-基甲基-苯基)-1H-吡唑并[3,4-b]吡啶-6-基]-胺
实施例20:{3-[5-(3-氨基-3-甲基-丁-1-炔基)-2-甲氧基-苯基]-1H-吡唑并[3,4-b]吡啶-6-基}-(2,4-二氟-苯基)-胺
实施例21:{3-[5-(3-氨基-3-甲基-丁基)-2-甲氧基-苯基]-1H-吡唑并[3,4-b]吡啶-6-基}-(2,4-二氟-苯基)-胺
实施例9:{3-[2-氯-5-甲氧基-4-(2-吗啉-4-基-乙氧基)-苯基]-1H-吡唑并[3,4-b]吡啶-6-基}-(2,4-二氟-苯基)-胺
实施例10:{3-[2-氯-4-甲氧基-5-(2-吗啉-4-基-乙氧基)-苯基]-1H-吡唑并[3,4-b]吡啶-6-基}-(2,4-二氟-苯基)-胺
实施例17:(2,4-二氟-苯基)-[3-(2-甲氧基-5-丙基氨基甲基-苯基)-1H-吡唑并[3,4-b]吡啶-6-基]-胺
实施例18:(2,4-二氟-苯基)-(3-{2-甲氧基-5-[(四氢-吡喃-4-基氨基)-甲基]-苯基}-1H-吡唑并[3,4-b]吡啶-6-基)-胺
实施例11和19:(2,4-二氟-苯基)-{3-[5-(1,2-二甲基-1H-咪唑-4-基)-2-甲氧基-苯基]-1H-吡唑并[3,4-b]吡啶-6-基}-胺
实施例23:3-[6-(2,4-二氟-苯基氨基)-1H-吡唑并[3,4-b]吡啶-3-基]-4-甲氧基-N-吡啶-2-基-苯甲酰胺
实施例24:{3-[5-(3-氨基-3-甲基-丁-1-炔基)-2-甲氧基-苯基]-1H-吡唑并[3,4-d]嘧啶-6-基}-(2,4-二氟-苯基)-胺
实施例25:4-{3-[6-(2,4-二氟-苯基氨基)-1H-吡唑并[3,4-d]嘧啶-3-基]-4-甲氧基-苯基}-2-甲基-丁-3-炔-2-醇
实施例26:4-{3-[6-(2,4-二氟-苯基氨基)-1H-吡唑并[3,4-d]嘧啶-3-基]-4-甲氧基-苯基}-2-甲基-丁烷-2-醇
实施例27:(2,4-二氟-苯基)-{3-[5-(3-二甲基氨基-丙-1-炔基)-2-甲氧基-苯基]-1H-吡唑并[3,4-d]嘧啶-6-基}-胺
实施例28:(2,4-二氟-苯基)-{3-[2-甲氧基-5-(3-吗啉-4-基-丙-1-炔基)-苯基]-1H-吡唑并[3,4-d]嘧啶-6-基}-胺
实施例29:(2,4-二氟-苯基)-(3-{2-甲氧基-5-[3-(4-甲基-哌嗪-1-基)-丙-1-炔基]-苯基}-1H-吡唑并[3,4-d]嘧啶-6-基)-胺
实施例30:4-{3-[6-(2,4-二氟-苯基氨基)-1H-吡唑并[3,4-d]嘧啶-3-基]-4-甲氧基-苯基乙炔基}-1-甲基-哌啶-4-醇
实施例31:(2,4-二氟-苯基)-{3-[5-((E)-3-二甲基氨基-丙烯基)-2-甲氧基-苯基]-1H-吡唑并[3,4-d]嘧啶-6-基}-胺
实施例32:(2,4-二氟-苯基)-{3-[2-甲氧基-5-((E)-3-吗啉-4-基-丙烯基)-苯基]-1H-吡唑并[3,4-d]嘧啶-6-基}-胺
实施例33:(2,4-二氟-苯基)-(3-{2-甲氧基-5-[(E)-3-(4-甲基-哌嗪-1-基)-丙烯基]-苯基}-1H-吡唑并[3,4-d]嘧啶-6-基)-胺
实施例34:4-{3-[6-(2,4-二氟-苯基氨基)-1H-吡唑并[3,4-b]吡嗪-3-基]-4-甲氧基-苯基}-2-甲基-丁-3-炔-2-醇
实施例35:(2,4-二氟-苯基)-{3-[5-(3-二甲基氨基-丙-1-炔基)-2-甲氧基-苯基]-1H-吡唑并[3,4-b]吡嗪-6-基}-胺或其在药学上可接受的和可裂解的酯或酸加成盐。
本发明的新的吡唑并吡啶、吡唑并嘧啶和吡唑并吡嗪化合物,特别是式I和II化合物以及上文列出的具体化合物,在下文中称为“本发明的物质”。
包含游离羟基的本发明的物质也可以以药学上可接受的、生理学上可裂解的酯存在,它们均包括在本发明的范围内。这类药学上可接受的酯优选是前药酯衍生物,其可通过溶剂解或在生理条件下裂解而转化为相应的包含游离羟基的本发明的物质。适宜的药学上可接受的前药酯是由羧酸、碳酸单酯或氨基甲酸衍生的那些,有利地是由任选被取代的低级链烷酸或芳基羧酸衍生的酯。
本发明的物质还可以以药学上可接受的盐存在,它们均包括在本发明的范围内。药学上可接受的盐包括与常规酸、例如无机酸或有机酸形成的酸加成盐,所述的无机酸例如有盐酸、硫酸或磷酸,所述的有机酸例如有脂肪族或芳香族羧酸或磺酸,例如乙酸、丙酸、琥珀酸、乙醇酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、马来酸、富马酸、羟基马来酸、丙酮酸、双羟萘酸、甲磺酸、甲苯磺酸、萘磺酸、对氨基苯磺酸或环己基氨磺酸;还有氨基酸,例如精氨酸和赖氨酸。对于具有酸性基团如游离羧基的本发明的化合物而言,药学上可接受的盐还表示金属盐和铵盐,例如碱金属或碱土金属盐,例如钠盐、钾盐、镁盐或钙盐,以及与氨或适宜有机胺所形成的铵盐。
其中R1’、R2’和R3’如上定义的式II’的本发明的物质可如下制备:
使其中R1’、R2’和R3’如上定义的式III的6-氯-3-苯基-1H-吡唑并[3,4-b]吡啶与2,4-二氟苯胺偶联。
优选偶联反应如Buchwald缩合反应进行;例如,在溶液如热二烷中、在例如R-(+)-BINAP、Pd(OAc)2和NaOtBu的存在下回流例如3小时进行。
式III化合物可如下获得:使相应的式IV的(2,6-二氯-吡啶-3-基)-苯基-甲酮与肼(H2NNH2)环化;例如在有机溶剂如EtOH/1-BuOH中在回流下进行,
其中R1’、R2’和R3’如上定义。
或者,其中R2’为H的式III化合物可如下获得:使其中R1’如上定义的式V的溴衍生物与相应的R3’前体偶联,
例如,当R3’是1-羟基-4-N-甲基哌啶-1-基时,R3’前体为N-甲基-4-哌啶酮,当R3’是4-N-甲基哌嗪-1-基时,R3’前体为N-甲基哌嗪,或者当R3’是3-氨基-3-甲基丁炔-1-基时,R3’前体为或3-氨基-3-甲基丁炔-1-基。用于这些偶联反应的条件如下文实施例所述。
式II化合物,其中R3’是烷基取代基,例如氨基取代的烷基,如3-氨基-3-甲基丁炔-1-基取代基,可通过使相应的炔烃取代的、例如被3-氨基-3-甲基丁炔-1-基取代的式II化合物还原来制备;例如如下文实施例所述。
式III化合物,其中R2’是H且R3’是-CH2-NR5R6,其中R5是H且R6是低级烷基或R5和R6在N-杂环基中连接,所述N-杂环基包含至少3个环原子和任选的其它杂原子,所述杂原子选自O、S、N或NR,其中R为H或低级烷基,可通过使式VI的3-(6-氯-1H-吡唑并[3,4-b]吡啶-3-基)-4-甲氧基-苯甲醛化合物与低级烷基胺或N-杂环前体反应来制备,
其中R1’如上定义;例如如下文实施例所述。式III化合物,其中R2’是H且R3’是-CH2-NR5R6,其中R5是H且R6是低级烷基或R5和R6在N-杂环基中连接,所述N-杂环基包含至少3个环原子和任选的其它杂原子,所述杂原子选自O、S、N或NR,其中R为H或低级烷基,可如上所述转化为式II化合物。
式VI化合物可通过使式V溴衍生物与DMF反应来制备;例如在用烷基锂试剂如nBuLi处理后,所述处理优选在冷却下进行。
如上定义的式IV化合物可通过使相应的式VII醇氧化来制备,
其中R1’、R2’和R3’如上定义。氧化可采用Jones试剂进行;例如如下文实施例所述。
式VII醇可通过使2,6-二氯吡啶与适当的式VIII苯甲醛前体偶联来获得,
其中R1’、R2’和R3’如上定义。例如,偶联反应可以在溶液(如THF)、优选含有二异丙胺的溶液中进行,所述溶液已经用nBuLi进行过预处理,所述预处理优选在冷却下进行。
如上所述的新的合成步骤、特别是式III化合物与2,6-二氟苯胺的偶联反应包括在本发明的范围内。
因此,本发明还提供了制备式II的本发明的物质的操作,
其中R1’、R2’和R3’如上定义,
该方法包括使式III的6-氯-3-苯基-1H-吡唑并[3,4-b]吡啶与2,6-二氟苯胺偶联,
其中R1’、R2’和R3’如上定义。
本发明进一步在下述实施例中通过仅仅是解释说明的方式来描述,这些实施例涉及式II的本发明的物质的制备。
实施例
具体描述了本发明物质的制备方法。本发明的物质可由醛I按照流程1来制备:
流程1(实施例1-11)
(2,4-二氟-苯基)-[3-(2-甲氧基-苯基)-1H-吡唑并[3,4-b]吡啶-6-基]-胺(实施例1)的制备举例说明了由可自商业途径获得的2-甲氧基苯甲醛进行的流程1的4-步合成法。
实施例1:(2,4-二氟-苯基)-[3-(2-甲氧基-苯基)-1H-吡唑并[3,4-b]吡啶-6-基]-胺
1a)(2,6-二氯-吡啶-3-基)-(2-甲氧基-苯基)-甲醇
将二异丙胺(10.3ml;74mmol)在THF(200ml)中冷却至-78℃,用nBuLi(42ml;67.6mmol,1.6M己烷溶液)处理。于-78℃5分钟后,滴加2,6-二氯吡啶(10g;67.6mmol)在THF(20ml)中的溶液,于-78℃搅拌50分钟。滴加2-甲氧基苯甲醛(8.75g;64.3mmol)在THF(15ml)中的溶液。于-75℃搅拌10分钟后,将反应混合物温热至-30℃,倒入20%NaCl水溶液(500ml)中,用TBME萃取三次。所合并的有机相经Na2SO4干燥,蒸发至干,残余物经色谱法纯化(SiO2;丙酮/己烷5/95>3/7),得到标题化合物(16.0g;87%),为略有色的粘稠油。
1H-NMR(400MHz;DMSO):3.73(s,3H):6.07(d,1H);6.15(d,1H);6.97(m,2H);7.29(m,2H);7.55(d,1H);7.83(d,1H).
MS(m/z)ES-:284(MH-;30);282(35);146(100).
1b)(2,6-二氯-吡啶-3-基)-(2-甲氧基-苯基)-甲酮
将(2,6-二氯-吡啶-3-基)-(2-甲氧基-苯基)-甲醇(16g;56.3mol)溶于丙酮(250ml)中,用Jones试剂(24ml;56mmol)处理5分钟。将反应混合物用己烷(1000ml)稀释,经SiO2短垫过滤,蒸发溶剂后,得到标题化合物(14.3g;90%),为褐色晶体。
1H-NMR(400MHz;DMSO):3.60(s,3H);7.13(t,1H);7.18(d,1H);7.62-7.75(m,3H);7.98(d,1H);
MS(m/z)EI:283(M+1,50);281(M-1,70);246(100);135(70);77(50).
1c)6-氯-3-(2-甲氧基-苯基)-1H-吡唑并[3,4-b]吡啶
将溶于EtOH/1-BuOH(66ml 10/1)中的(2,6-二氯-吡啶-3-基)-(2-甲氧基-苯基)-甲酮(4g;14.2mmol)用H2NNH2.H2O(24%,在水中)(5ml;37.5mmol)在回流下处理30分钟。加入第二批H2NNH2.H2O(24%,在水中)(4ml;30mmol)并另外回流30分钟。蒸发1-BuOH,将残余的水相用TBME萃取三次。所合并的有机相经Na2SO4干燥,蒸发至干,残余物经色谱法纯化(SiO2;丙酮/己烷2/8),用少量体积的丙酮研制后,得到纯形式的标题化合物(800mg;22%),为黄色晶体。
1H-NMR(400MHz;DMSO):3.82(s,3H);7.09(t,1H);7.22(d,1H);7.27(d,1H);7.47(t,1H);7.64(dd,1H);8.21(d,1H).
MS(m/z)EI:259(M+,100);230(40);194(30);152(25);77(25).
1d):(2,4-二氟-苯基)-[3-(2-甲氧基-苯基)-1H-吡唑并[3,4-b]吡啶-6-基]-胺
将6-氯-3-(2-甲氧基-苯基)-1H-吡唑并[3,4-b]吡啶(710mg;2.74mmol)溶于热二烷(10ml)中,依次加入R-(+)-BINAP(40mg;0.06mmol)、Pd(OAc)2(40mg;0.17mmol)、2,4-二氟苯胺(1.1ml;10.9mmol)和NaOtBu(1.05g;10.9mmol),将反应混合物回流3小时。然后将其直接倒在硅胶柱上,经色谱法纯化(TBME/己烷4/6>8/2,然后丙酮/己烷1/1),从丙酮/己烷中重结晶后,得到标题化合物,为灰白色晶体(675mg;69%)。
1H-NMR(400MHz;DMSO):3.85(s,3H);6.81(d,1H);7.07(t,1H);7.12(t,1H);7.20(1H);7.35(t,1H);7.43(t,1H);7.60(d,1H);7.88(d,1H);8.20(m,1H);8.98(s,1H);13.1(s,1H).MS(m/z)ES:351(MH-,100);331(20).
实施例2、3、4和5的化合物类似于实施例1、由可自商业途径获得的醛来制备。
实施例2:[3-(6-氯-苯并[1,3]二氧杂环戊烯-5-基)-1H-吡唑并[3,4-b]吡啶-6-基]-(2,4-二氟-苯基)-胺
1H-NMR(400MHz;DMSO):6.15(s,2H);6.82(d,1H);7.08(s,1H);7.12(dt,1H);7.23(s,1H);7.32(dt,1H);7.78(d,1H);8.13(m,1H);9.04(s,1H),13.2(s,1H).
MS(m/z)Cm:401(MH+,100);259(35);213(40);179(60);169(70);141(80);131(100).
实施例3:[3-(2-氯-苯基)-1H-吡唑并[3,4-b]吡啶-6-基]-(2,4-二氟-苯基)-胺
1H-NMR(400MHz;DMSO):6.84(d,1H);7.13(bt,1H);7.33(bt,1H);7.48(m,2H);7.62(m,2H);7.81(d,1H);8.14(m,1H);9.05(s,1H),13.2(s,1H).
MS(m/z)ES:355(MH-,100);335(15).
实施例4:(2,4-二氟-苯基)-[3-(2-三氟甲基-苯基)-1H-吡唑并[3,4-b]吡啶-6-基]-胺
1H-NMR(400MHz;DMSO):6.82(d,1H);7.11(bt,1H);7.33(bt,1H);7.63(d,1H);7.71t,2H);7.80(t,1H);7.92(d,1H);8.12(m,1H);9.05(s,1H),13.2(s,1H).
MS(m/z)ES:389(MH-,100);369(30).
实施例5:(2,4-二氟-苯基)-[3-(2,4-二甲氧基-苯基)-1H-吡唑并[3,4-b]吡啶-6-基]-胺
1H-NMR(400MHz;DMSO):3.82(s,3H);3.84(s,3H);6.64(dd,1H);6.72(d,1H);6.78(d,1H);7.10(bt,1H);7.32(bt,1H);7.50(d,1H);7.83(d,1H);8.18(m,1H);8.94(s,1H);13.2(s,1H).
MS(m/z)ES:381(MH-,100);361(50).
通过类似于实施例1所述的试验方法,在按照流程1转化为实施例6-10的产物之前,如下制备醛1-5和8(流程2):
流程2
醛1的制备:按照L.L.Miller等人,J.Org.Chem 1978,43(8),1580-6。
2-氯-4-甲氧基-5-(2-吗啉-4-基-乙氧基)-苯甲醛(2)的制备
a)2-氯-4-甲氧基-5-羟基苯甲醛
将2-氯-4,5-二羟基苯甲醛(Kaiser,C.等人,J.Org.Chem.1974,17(10),1071-5)(5.7g;33.1mmol)、MeI(2.0ml;33.1mmol)和K2CO3(4.6g;33.1mmol)在丙酮(250ml)中回流1.5小时。蒸发丙酮,将残余物溶于TBME中,用TBME萃取三次。所合并的有机相经Na2SO4干燥,蒸发至干。经色谱法纯化(丙酮/己烷15/85),在第一份级分中得到2-氯-4,5-二甲氧基苯甲醛(1.4g;23%),随后是标题化合物2-氯-4-甲氧基-5-羟基苯甲醛(2.45g;40%;无色晶体)、2-氯-4-羟基-5-甲氧基苯甲醛(0.23g;3.8%)和2-氯-4,5-二羟基苯甲醛(2.11g;37%未反应的原料)。
1H-NMR(400MHz;CHCl3):3.90(s,3H);5.52(s,1H);6.81(s,1H);7.37(s,1H);10.22(s,1H).
MS(m/z)ES-:187(30);185(MH-,100).
b)2-氯-4-甲氧基-5-(2-吗啉-4-基-乙氧基)-苯甲醛(2)
将2-氯-4-甲氧基-5-羟基苯甲醛(500mg;2.7mmol)、N-(2-氯乙基)吗啉.HCl(510mg;2.7mmol)和K2CO3(830mg;6mmol)在乙腈(3ml)中回流3小时。蒸发溶剂,将残余物溶于丙酮(100ml)中,过滤,浓缩至分离出标题化合物,为略黄色晶体(487mg;60%)。
1H-NMR(400MHz;DMSO):2.50(bt,4H);2.72(t,2H);3.58(bt,4H);3.92(s,3H);4.15(t,2H);7.20(s,1H);7.40(s,1H);10.21(s,1H).通过ROESY证明区域化学。
MS(m/z)EI:299(M+,60);100(100).
2-氯-5-甲氧基-4-(2-N-吗啉基乙氧基)苯甲醛(3)的制备
a)2-氯-5-羟基-4-(2-N-吗啉基乙氧基)苯甲醛
将2-氯-4,5-二羟基苯甲醛(Kaiser,C.等人,J.Org.Chem.1974,17(10),1071-5)(500mg;2.9mmol)、N-(2-氯乙基)吗啉.HCl(540mg;2.9mmol)、K2CO3(880mg;6.4mmol)在乙腈(3ml)中回流3小时,倒入1N HCl中,用乙酸乙酯萃取两次。加入饱和NaHCO3溶液调节水相为碱性,用乙酸乙酯萃取三次。所合并的有机相经Na2SO4干燥,蒸发至干,得到标题化合物,为略有色的晶体(208mg;25%)。
1H-NMR(400MHz;DMSO):2.50(bt,4H);2.73(bt,2H);3.59(bt,4H);4.25(t,2H);7.22(s,1H);7.27(s,1H);10.17(s,1H).
MS(m/z)Cm:286(MH+,100).
b)2-氯-5-甲氧基-4-(2-N-吗啉基乙氧基)苯甲醛(3)
将2-氯-5-羟基-4-(2-N-吗啉基乙氧基)苯甲醛(2.54g:8.9mmol)在丙酮(60ml)中与MeI(0.56ml;8.9mml)和K2CO3(1.2g;8.9mmol)一起回流1小时。将反应混合物用水(100ml)和2N NaOH(20ml)稀释,用乙酸乙酯萃取三次。所合并的有机相经Na2SO4干燥,蒸发至干,经色谱法纯化(SiO2;丙酮/己烷4/6>1/1),得到标题化合物,为黄色晶体(850mg;32%)
1H-NMR(400MHz;DMSO):2.50(m,4H);2.73(t,2H);3.58(t,4H);3.83(s,3H);4.23(t,2H);7.26(s,1H);7.35(s,1H);10.20(s,1H).
MS(m/z)Cm:286(MH+,100).
2-甲氧基-5-N-吗啉基苯甲醛(4)的制备
a)2-(1,3-二氧环戊烷-2-基)-4-N-吗啉基茴香醚
将2-(1,3-二氧环戊烷-2-基)-4-溴茴香醚(Hall C.等人:J.Organomet.Chem.1998,561(1-2),209-219)(2.6g;10mmol)、吗啉(2.1g;24mmol)、NaOtBu(2.7g;28mmol)、Pd2(dba)3(46mg;0.05mmol)和三邻甲苯基膦(61mg;0.2mmol)在二烷(40ml)中回流1小时,倒入水中,用乙酸乙酯萃取三次。所合并的有机相用水洗涤,经Na2SO4干燥,蒸发至干,经色谱法纯化(SiO2;环己烷/丙酮85/15),得到标题化合物,为黄色晶体(500mg;19%)。
1H-NMR(400MHz;DMSO):3.00(bt,4H);3.77(s,3H);3.78(bt,4H);3.92(m,2H);4.06(m,2H);5.95(s,1H);6.96(s,2H);7.03(s,1H).
MS(m/z)EI:265(M+,100);250(5);207(25);135(50).
b)2-甲氧基-5-N-吗啉基苯甲醛(4)
将2-(1,3-二氧环戊烷-2-基)-4-N-吗啉基茴香醚(265mg;1mmol)用丙酮/H2SO4(10ml/215mg)于室温处理10分钟。将反应混合物倒入2N Na2CO3中,用乙酸乙酯萃取两次。所合并的有机相用水洗涤,经Na2SO4干燥,蒸发至干,经色谱法纯化(SiO2;环己烷/丙酮85/15),得到标题化合物,为黄色油(200mg;90%)。
1H-NMR(400MHz;DMSO):3.08(bt,4H);3.76(bt,4H);3.88(s,3H);7.19(d,1H);7.20(s,1H);7.47(dd,1H);10.35(s,1H).
MS(m/z)EI:221(M+;100);206(25);163(80);148(20);134(20);117(15).
2-甲氧基-5-(4-吡啶基)苯甲醛(5)的制备
a)2-(1,3-二氧环戊烷-2-基)-4-(4-吡啶基)茴香醚
将溶于二甲苯(10ml)中的2-(1,3-二氧环戊烷-2-基)-4-溴茴香醚(Hall C.等人:J.Organomet.Chem.1998,561(1-2),209-219)(500mg;0.19mmol)与4-三甲基甲锡烷基吡啶(560mg;0.23mmol)和PdCl2(PPh3)2(140mg;0.019mmol)合并,回流15分钟。将反应混合物用甲苯稀释,滗析,经色谱法纯化(SiO2;丙酮/己烷2/8>4/6),得到标题化合物(346mg;70%),为粘稠油。
1H-NMR(400MHz;DMSO):3.87(s,3H);3.95(m,2H);4.10(m,2H);6.03(s,1H);7.20(d,1H);7.67(d,2H);7.82(d,1H);7.85(d,1H);8.58(d,2H).
MS(m/z)EI:257(M+,100).
b)2-甲氧基-5-(4-吡啶基)苯甲醛(5)
将2-(1,3-二氧环戊烷-2-基)-4-(4-吡啶基)茴香醚(100mg;0.39mmol)和丙酮/浓H2SO4(6ml/90mg;0.8mmol)一起回流10分钟。将反应混合物倒入2N Na2CO3中,用乙酸乙酯萃取三次。所合并的有机相用水洗涤,经Na2SO4干燥,蒸发至干,得到标题化合物,为黄色油(79mg;95%)。
1H-NMR(400MHz;DMSO):4.02(s,3H);7.43(d,1H);7.75(d,2H);8.10(d,1H);8.17(dd,1H);8.63(d,2H);10.42(s,1H).
MS(m/z)EI:213(M+,100);196(30);167(25);115(15).
5-(1,2-二甲基-1H-咪唑-4-基)-2-甲氧基-苯甲醛(8)
a)4-(3-[1,3]二氧环戊烷-2-基-4-甲氧基-苯基)-1,2-二甲基-1H-咪唑
将1,2-二甲基-1H-咪唑(4.8g,50mmol)、2-(5-溴-2-甲氧基-苯基)-[1,3]二氧环戊烷(6.5g,25mmol)、Pd(OAc)2(140mg,0.625mmol)、PPh3(327mg,1.25mmol)和Cs2CO3(8.15g;25mmol)溶于DMF(50ml)中,在氩气中于145℃加热5小时。将反应混合物倒入饱和NaCl溶液中,用EtOAc萃取三次。有机相经Na2SO4干燥,蒸发至干,经色谱法纯化(SiO2,丙酮/EtOH9/1),得到标题化合物,为澄清油(4.0g;58%)。
1H-NMR(400MHz;DMSO-d6):2.33(s,3H);3.46(s,3H);3.82(s,3H);3.92(m,2H);4.05(m,2H);6.02(s,1H);6.78(s,1H);7.12(d,1H);7.40(m,2H).
MS(m/z)ES+:275(MH+,100).
b)5-(1,2-二甲基-1H-咪唑-4-基)-2-甲氧基-苯甲醛
将4-(3-[1,3]二氧环戊烷-2-基-4-甲氧基-苯基)-1,2-二甲基-1H-咪唑(4.0g,14.5mmol)溶于丙酮/浓H2SO4(264ml/3.2g)中,于室温搅拌3小时。部分蒸发丙酮,将残余物溶于EtOAc中,用2N Na2CO3和水洗涤,经Na2SO4干燥,蒸发至干。将粗品从TBME/己烷中重结晶,得到标题化合物,为无色晶体(2.8g,83%)。
1H-NMR(400MHz;DMSO-d6):2.34(s,3H);3.49(s,3H);3.96(s,3H);6.85(s,1H);7.34(d,1H);7.66(d,1H);7.73(dd,1H);10.38(s,1H).
MS(m/z)EI:230(M+,100),215(10(;187(40).
按照流程1,采用实施例1所述的通用方法,将醛1-6转化为实施例6-11的化合物。
实施例6:[3-(2-氯-4,5-二甲氧基-苯基)-1H-吡唑并[3,4-b]吡啶-6-基]-(2,4-二氟-苯基)-胺
1H-NMR(400MHz;DMSO):3.80(s,3H);3.87(s,3H);6.83(d,1H);7.11(m,2H);7.19(s,1H);7.35(bt,1H);7.84(d,1H);8.17(m,1H);9.03(s,1H);13.20(s,1H).
MS(m/z)Cm:415(MH-,100);367(50);322(40);255(15);209(80).
实施例7:(2,4-二氟-苯基)-[3-(2-甲氧基-5-吗啉-4-基-苯基)-1H-吡唑并[3,4-b]吡啶-6-基]-胺
1H-NMR(400MHz;DMSO):3.03(m,4H);3.78(m,7H);6.80(d,1H);7.03(dd,1H);7.10(m,2H);7.18(d,1H);7.33(m,1H);7.87(d,1H);8.18(m,1H);8.97(s,1H);13.2(s,1H).
MS(m/z)ES:438(M+,100);330(20).
实施例8:(2,4-二氟-苯基)-[3-(2-甲氧基-5-吡啶-4-基-苯基)-1H-吡唑并[3,4-b]吡啶-6-基]-胺
1H-NMR(400MHz;DMSO):3.93(s,3H);6.82(d,1H);7.12(m,1H);7.33(m,2H);7.75(d,2H);7.91(m,2H);8.00(d 1H);8.20(m,1H);8.62(d,2H);9.01(s,1H);13.2(s,1H).
MS(m/z)ES:430(MH+,100);317(10).
实施例9:{3-[2-氯-5-甲氧基-4-(2-吗啉-4-基-乙氧基)-苯基]-1H-吡唑并[3,4-b]吡啶-6-基}-(2,4-二氟-苯基)-胺
1H-NMR(400MHz;DMSO):2.53(bs,4H);2.75(t,2H);3.62(t,4H);3.82(s,3H);4.20(t,2H);6.84(d,1H);7.10(s,1H);7.13(bd,1H);7.24(s,1H);7.35(dt,1H);7.84(d,1H);8.17(m,1H);9.05(s,1H);13.10(s,1H).
MS(m/z)ES+:516(MH+,100).
实施例10:{3-[2-氯-4-甲氧基-5-(2-吗啉-4-基-乙氧基)-苯基]-1H-吡唑并[3,4-b]吡啶-6-基}-(2,4-二氟-苯基)-胺
1H-NMR(400MHz;DMSO):2.47(t,4H);2.70(t,2H);3.58(t,4H);3.88(s,3H);4.13(t,2H);6.83(d,1H);7.12(bd,1H);7.16(s,1H);7.19(s,1H);7.33(m,1H);7.84(d,1H);8.18(m,1H);9.05(s,1H);13.20(2,1H).
MS(m/z)ES+:516(MH+,100).
实施例11:(2,4-二氟-苯基)-{3-[5-(1,2-二甲基-1H-咪唑-4-基)-2-甲氧基-苯基]-1H-吡唑并[3,4-b]吡啶-6-基}-胺
1H-NMR(400MHz;DMSO):2.33(s,3H);3.52(s,3H);3.87(s,3H);6.78(d,1H);6.82(s,1H);7.09(bt,1H);7.26(d,1H);7.34(dt,1H);7.43(dd,1H);7.57(d,1H);7.87(d,1H);8.18(m,1H);8.98(s,1H,NH);13.12(s,1H,NH).
MS(m/z)ES+:447(MH+,100).
实施例12-22中的化合物(流程3)的常见前体是溴化物6,其按照流程1由可自商业途径获得的5-溴-2-甲氧基苯甲醛和2,6-二氯吡啶按照实施例1c所述的通用方法以三步法来制备。化合物6按照流程3转化为醛7,醛7用作实施例13-18中的胺的前体。化合物6在实施例22中进一步转化为哌嗪类似物,在实施例20和21中进一步转化为伯胺。
流程3(实施例12-22)
化合物6:3-(5-溴-2-甲氧基-苯基)-6-氯-1H-吡唑并[3,4-b]吡啶
根据流程1,按照6-氯-3-(2-甲氧基-苯基)-1H-吡唑并[3,4-b]吡啶(1c)所述的通用方法,由可自商业途径获得的5-溴-2-甲氧基苯甲醛以三步法制备。
1H-NMR(400MHz;DMSO):3.87(s,3H);7.21(d,1H);7.29(d,1H);7.63(dd,1H);7.78(d,1H);8.25(d,1H).
MS(m/z)Cm:338(MH-,100);255(20);173(25);155(50).
实施例12:4-{3-[6-(2,4-二氟-苯基氨基)-1H-吡唑并[3,4-b]吡啶-3-基]-4-甲氧基-苯基}-1-甲基-哌啶-4-醇
a)4-[3-(6-氯-1H-吡唑并[3,4-b]吡啶-3-基)-4-甲氧基-苯基]-1-甲基-哌啶-4-醇
将nBuLi(1.46ml;2.33mmol,1.6M己烷溶液)于-78℃缓慢加入3-(5-溴-2-甲氧基-苯基)-6-氯-1H-吡唑并[3,4-b]吡啶(化合物6)(400mg;1.2mmol)在THF(10ml)中的溶液中。将黄色溶液于-78℃搅拌10分钟,然后快速加入N-甲基-4-哌啶酮(0.272ml;2.4mmol)在THF(0.5ml)中的溶液。于-78℃另外搅拌10分钟后,将反应混合物倒入NaCl水溶液中,用乙酸乙酯萃取三次。所合并的有机相用水洗涤,经Na2SO4干燥,蒸发至干,得到标题化合物,为黄色泡沫,加入乙醚中进行结晶(280mg;62%)。
1H-NMR(400MHz;DMSO):1.63(bd,2H);1.97(dt,2H);2.22(s,3H);2.37(bt,2H);2.53(bt,2H);3.83(s,3H);4.77(s,1H,OH);7.15(d,1H);7.20(bd,1H);7.51(dd,1H);7.78(d,1H);8.19(d,1H).
MS(m/z)ES+:373(MH+;100).
b)4-{3-[6-(2,4-二氟-苯基氨基)-1H-吡唑并[3,4-b]吡啶-3-基]-4-甲氧基-苯基}-1-甲基-哌啶-4-醇
将4-[3-(6-氯-1H-吡唑并[3,4-b]吡啶-3-基)-4-甲氧基-苯基]-1-甲基-哌啶-4-醇(280mg;0.75mmol)和2,4-二氟苯胺(3ml;29mmol)溶于热二烷中,与NaOtBu(280mg;2.9mmol)、Pd(OAc)2(25mg;0.11mol)和R-(+)-BINAP(25mg;0.04mmol)合并,回流30分钟。将反应混合物倒入水/NaCl中,用乙酸乙酯萃取三次。所合并的有机相用水洗涤,经Na2SO4干燥,蒸发至干,经色谱法纯化(SiO2;TBME/MeOH/浓NH380/20/2),得到标题化合物,为褐色晶体(180mg;52%)
1H-NMR(400MHz;DMSO):1.64(bd,2H);1.96(dt,2H);2.22(s,3H);2.37(bt,2H);2.53(bt,2H);3.83(s,3H);4.73(s,1H);6.80(d,1H);7.11(m,2H);7.33(dt,1H);7.48(dd,1H);7.72(d,1H);7.87(d,1H);8.20(m,1H);8.97(s,1H);13.10(s,1H).
MS(m/z)ES+:466(MH+,100).
实施例13:(2,4-二氟-苯基)-[3-(2-甲氧基-5-甲基氨基甲基-苯基)-1H-吡唑并[3,4-b]吡啶-6-基]-胺
a)3-(6-氯-1H-吡唑并[3,4-b]吡啶-3-基)-4-甲氧基-苯甲醛
将3-(5-溴-2-甲氧基-苯基)-6-氯-1H-吡唑并[3,4-b]吡啶(化合物6)(1g;2.9mmol)在THF(50ml)中冷却至-78℃,用nBuLi(3.7ml;5.9mml,1.6M己烷溶液)处理。于-78℃10分钟后,加入DMF(0.455ml;6.6mmol)并继续搅拌10分钟。将反应混合物温热至-30℃,倒入水/NaCl中,用TBME萃取三次。所合并的有机相用水洗涤,经Na2SO4干燥,蒸发至干,经色谱法纯化(SiO2;丙酮/己烷1/9>2/8),得到所需的醛(270mg;31%,为无色晶体)和脱溴化的原料(330mg)
1H-NMR(400MHz;DMSO):4.00(s,3H);7.31(d,1H);7.46(d,1H);8.06(dd,1H);8.21(s,1H);8.27(d,1H);10.00(s,1H);14.10(s,1H,NH).
MS(m/z)EI:287(M+,100);271(15);258(25).
b)[3-(6-氯-1H-吡唑并[3,4-b]吡啶-3-基)-4-甲氧基-苄基]-甲基-胺
将3-(6-氯-1H-吡唑并[3,4-b]吡啶-3-基)-4-甲氧基-苯甲醛(270mg;0.94mmol)溶于EtOH(75ml)中,温热至40℃,与MeNH2在EtOH(4.5ml)中的10%溶液合并。于40℃搅拌2分钟后,加入NaBH4(54mg;1.4mmol)在EtOH(2ml)中的溶液,继续搅拌5分钟。将反应混合物倒入水/NaCl中,用TBME萃取三次。所合并的有机相用水洗涤,经Na2SO4干燥,蒸发至干,经色谱法纯化(SiO2;TBME/MeOH/浓NH380(18/2),得到标题化合物,为无色泡沫(140mg;49%)。
1H-NMR(400MHz;DMSO):2.31(s,3H);3.68(s,2H);3.85(s,3H);7.18(bt,1H);7.25(s,1H);7.43(bs,1H);7.60(s,1H);8.22(s,1H).
MS(m/z)EI:302(M+,40);272(50);139(40).
c)(2,4-二氟-苯基)-[3-(2-甲氧基-5-甲基氨基甲基-苯基)-1H-吡唑并[3,4-b]吡啶-6-基]-胺
类似于实施例12b)进行Buchwald反应,得到所需化合物,为无色泡沫,产率为10%。
1H-NMR(400MHz;DMSO):2.28(s,3H);3.63(s,2H);3.82(s,3H);6.80(d,1H);7.11(m,2H);7.32(m,2H);7.54(d,1H);7.88(d,1H);8.20(m,1H);8.98(s,1H);13.05(s,1H).
MS(m/z)ES+:396(MH+,20);365(100).
通过还原胺化、随后类似于实施例13进行Buchwald反应,由3-(6-氯-1H-吡唑并[3,4-b]吡啶-3-基)-4-甲氧基-苯甲醛(实施例13a)制备实施例14-18的化合物。
实施例14:(2,4-二氟-苯基)-{3-[2-甲氧基-5-(4-甲基-哌嗪-1-基甲基)-苯基]-1H-吡唑并[3,4-b]吡啶-6-基}-胺
1H-NMR(400MHz;DMSO):2.17(s,3H);2.24-2.48(m,8H);3.43(s,2H);3.82(s,3H);6.80(d,1H);7.11(m,2H);7.29-7.38(m,2H);7.53(s,1H);7.88(d,1H);8.18(m,1H);8.98(s,1H);13.2(s,1H).
MS(m/z)ES+:465(MH+,100);365(20).
实施例15:(2,4-二氟-苯基)-[3-(2-甲氧基-5-吗啉-4-基甲基-苯基)-1H-吡唑并[3,4-b]吡啶-6-基]-胺
1H-NMR(400MHz;DMSO):2.38(bs,4H);3.47(s,2H);3.59(bs,4H);3.84(s,3H);6.80(d,1H);7.12(m,2H);7.33(m,2H);7.56(d,1H);7.88(d,1H);8.19(m,1H);8.97(s,1H);13.2(s,1H).
MS(m/z)ES+:452(MH+,100);365(50);330(10);289(10).
实施例16:(2,4-二氟-苯基)-[3-(2-甲氧基-5-哌嗪-1-基甲基-苯基)-1H-吡唑并[3,4-b]吡啶-6-基]-胺
1H-NMR(400MHz;DMSO):2.31(m,4H);2.67(m,4H);3.41(s,2H);3.83(s,3H);6.80(d,1H);7.11(m,2H);7.28-7.37(m,2H);7.52(d,1H);7.88(d,1H);8.18(m,1H);8.97(s,1H);13.10(s,1H).
MS(m/z)ES+:451(MH+,100);365(20).
实施例17:(2,4-二氟-苯基)-[3-(2-甲氧基-5-丙基氨基甲基-苯基)-1H-吡唑并[3,4-b]吡啶-6-基]-胺
1H-NMR(400MHz;DMSO):0.88(t,3H);1.44(q,2H);2.47(t,2H);3.69(s,2H);3.83(s,3H);6.82(d,1H);7.12(m,2H);7.35(m,2H);7.56(d,1H);7.88(d,1H);8.21(m,1H);8.98(s,1H,NH);13.09(s,1H,NH).
MS(m/z)ES+:422(MH+,100).
实施例18:(2,4-二氟-苯基)-(3-{2-甲氧基-5-[(四氢-吡喃-4-基氨基)-甲基]-苯基}-1H-吡唑并[3,4-b]吡啶-6-基)-胺
1H-NMR(400MHz;DMSO):1.22-1.47(m,2H);1.82(bd,2H);2.63(m,1H);3.30(m,2H);3.75(bs,2H);3.87(m,2H);3.83(s,3H);6.81(d,1H);7.12(m,2H);7.31-7.40(m,2H);7.58(d,1H);7.88(d,1H);8.13-8.23(m,1H);8.98(s,1H,NH);13.09(s,1H,NH).
MS(m/z)ES+:466(MH+,100).
实施例19:(2,4-二氟-苯基)-{3-[5-(1,2-二甲基-1H-咪唑-4-基)-2-甲氧基-苯基]-1H-吡唑并[3,4-b]吡啶-6-基}-胺
如实施例1a)-1d)所述,由5-(1,2-二甲基-1H-咪唑-4-基)-2-甲氧基-苯甲醛(化合物8)和2,6-二氯吡啶通过四步制得(2,4-二氟-苯基)-{3-[5-(1,2-二甲基-1H-咪唑-4-基)-2-甲氧基-苯基]-1H-吡唑并[3,4-b]吡啶-6-基}-胺。
1H-NMR(400MHz;DMSO):2.33(s,3H);3.52(s,3H);3.87(s,3H);6.78(d,1H);6.82(s,1H);7.08(bt,1H);7.26(d,1H);7.33(dt,1H);7.43(dd,1H);7.57(5,1H);7.87(d,1H);8.13(m,1H);8.98(s,1H,NH);13.12(s,1H,NH).
MS(m/z)ES+:447(MH+,100).
通过与3-氨基-3-甲基-1-丁炔进行Sonogashira偶联、随后进行Buchwald反应,由3-(5-溴-2-甲氧基-苯基)-6-氯-1H-吡唑并[3,4-b]吡啶(化合物6)通过两步制备实施例20(流程3)。将三键氢化得到实施例21的化合物。
实施例20:{3-[5-(3-氨基-3-甲基-丁-1-炔基)-2-甲氧基-苯基]-1H-吡唑并[3,4-b]吡啶-6-基}-(2,4-二氟-苯基)-胺
a)3-[3-(6-氯-1H-吡唑并[3,4-b]吡啶-3-基)-4-甲氧基-苯基]-1,1-二甲基-丙-2-炔基胺
将3-(5-溴-2-甲氧基-苯基)-6-氯-1H-吡唑并[3,4-b]吡啶(化合物6)(1g;2.94mmol)、3-氨基-3-甲基-1-丁炔(0.35ml;3.3mmol)、PdCl2(PPh3)2(210mg;0.29mmol)和CuI(172mg;0.29mmol)在三乙胺(140ml)和二烷(30ml)中回流3小时。将反应混合物过滤,蒸发,经色谱法纯化(SiO2;TBME/MeOH/浓NH390/9/1),得到标题化合物,为黄色泡沫(218mg;20%)。
1H-NMR(400MHz;DMSO):1.40(s,6H);3.88(s,3H);7.20(d,1H);7.28(d,1H);7.47(dd,1H);7.63(d,1H);8.23(d,1H);
MS(m/z)EI:340(M+,10);325(100),277(20).
b){3-[5-(3-氨基-3-甲基-丁-1-炔基)-2-甲氧基-苯基]-1H-吡唑并[3,4-b]吡啶-6-基}-(2,4-二氟-苯基)-胺
将3-[3-(6-氯-1H-吡唑并[3,4-b]吡啶-3-基)-4-甲氧基-苯基]-1,1-二甲基-丙-2-炔基胺(350mg;1.02mmol)在二烷(7ml)中与2,4-二氟苯胺(3ml;19.3mmol)、NaOtBu(350mg;3.6mmol)、Pd(OAc)2(70mg;0.308mol)和R-(+)-BINAP(70mg;0.112mmol)合并,回流1小时。将反应混合物倒入2NHCl中,用乙酸乙酯萃取三次。用2N NaOH调节所合并的有机相为碱性,用乙酸乙酯萃取三次。所合并的有机相经Na2SO4干燥,蒸发至干。将残余物溶于热甲苯中并在冷却后滤除所形成的暗色沉淀,从而纯化残余物。蒸发甲苯,将残余物从乙酸乙酯中重结晶,得到标题化合物,为灰白色晶体(20mg;6%)。
1H-NMR(400MHz;DMSO):1.39(s,6H);2.06(bs,2H);3.80(s,3H);6.81(d,1H);7.11(bd,1H);7.15(d,1H);7.34(dt,1H);7.40(d,1H);7.59(d,1H);7.88(d,1H);8.18(m,1H);9.00(s,1H);13.17(s,1H).
MS(m/z)ES+:434(MH+,70);417(100).
实施例21:{3-[5-(3-氨基-3-甲基-丁基)-2-甲氧基-苯基]-1H-吡唑并[3,4-b]吡啶-6-基}-(2,4-二氟-苯基)-胺
将{3-[5-(3-氨基-3-甲基-丁-1-炔基)-2-甲氧基-苯基]-1H-吡唑并[3,4-b]吡啶-6-基}-(2,4-二氟-苯基)-胺(50mg;0.11mmol)溶于EtOH(100ml)中,经10%Pd/C(100mg)氢化1小时。将反应混合物过滤,蒸发,从乙醚/己烷中重结晶,得到标题化合物,为无色晶体(30mg;60%)。
1H-NMR(400MHz;DMSO):1.08(s,6H);1.53-1.60(m,4H);2.58-2.63(m,2H);3.81(s,3H);6.80(d,1H);7.03-7.14(m,2H);7.22(d,1H);7.32(bt,1H);7.43(s,1H);7.87(d,1H);8.19(m,1H);8.90(s,1H);13.10(s,1H).
MS(m/z)ES+:438(MH+,100);421(20);192(10);180(50).
实施例22:(2,4-二氟-苯基)-{3-[2-甲氧基-5-(4-甲基-哌嗪-1-基)-苯基]-1H-吡唑并[3,4-b]吡啶-6-基}-胺
a)6-氯-3-[2-甲氧基-5-(4-甲基-哌嗪-1-基)-苯基]-1H-吡唑并[3,4-b]吡啶
将3-(5-溴-2-甲氧基-苯基)-6-氯-1H-吡唑并[3,4-b]吡啶(化合物6)(200mg;0.588mmol)、NaOtBu(224mg;2.3mmol)、Pd(OAc)2(20mg;0.08mol)和R-(+)-BINAP(20mg;0.03mmol)和N-甲基哌嗪(0.1ml;1mmol)在二烷(4ml)中回流3小时。向反应混合物中加入TBME(20ml),滤出沉淀,经色谱法纯化(SiO2;TBME/MeOH/浓NH390/10/1),从乙醚/己烷中重结晶,得到标题化合物(40mg;19%)。
1H-NMR(400MHz;DMSO):2.24(s,3H);2.48(bt,4H);3.10(bt,4H);3.78(s,3H);7.05-7.11(m,2H);7.20(d,1H);7.28(d,1H);8.20(d,1H);13.90(bs,1H).
MS(m/z)Cm:358(MH+,100);324(10).
b)(2,4-二氟-苯基)-{3-[2-甲氧基-5-(4-甲基-哌嗪-1-基)-苯基]-1H-吡唑并[3,4-b]吡啶-6-基}-胺(实施例8)
将6-氯-3-[2-甲氧基-5-(4-甲基-哌嗪-1-基)-苯基]-1H-吡唑并[3,4-b]吡啶(186mg;0.52mmol)在二烷(4ml)中与2,4-二氟苯胺(3ml;19.3mmol)、NaOtBu(186mg;1.9mmol)、Pd(OAc)2(40mg;0.175mol)和R-(+)-BINAP(40mg;0.063mmol)合并,回流1小时。将反应混合物溶于2N HCl中,用乙酸乙酯洗涤两次。用2N NaOH调节水层为碱性,用乙酸乙酯萃取三次。所合并的有机相经Na2SO4干燥,过滤,蒸发至干,得到暗色残余物,从热甲苯中结晶两次,得到标题化合物,为略有色晶体(45mg;20%)。
1H-NMR(400MHz;DMSO):2.23(s,3H);2.45(m,4H);3.07(m,4H);3.77(s,3H);6.79(d,1H);7.01(dd,1H);7.05-7.14(m,2H);7.18(d,1H);7.33(m,1H);7.85(d,1H);8.19(m,1H);8.96(s,1H);13.2(s,1H).
MS(m/z)Cm:451(MH+,100).
实施例23:3-[6-(2,4-二氟-苯基氨基)-1H-吡唑并[3,4-b]吡啶-3-基]-4-甲氧基-N-吡啶-2-基-苯甲酰胺
a)3-(5-溴-2-甲氧基-苯基)-6-氯-1-(2-三甲基甲硅烷基-乙氧基甲基)-1H-吡唑并[3,4-b]吡啶
将3-(5-溴-2-甲氧基-苯基)-6-氯-1H-吡唑并[3,4-b]吡啶(6.8g;20mmol)溶于THF(240ml)中,于-78℃用KN(TMS)2(5.25g;25mmol)处理。于-78℃搅拌15分钟后,加入(2-氯甲氧基-乙基)-三甲基-甲硅烷(4.47ml;25mmol),于-78℃继续搅拌15分钟。将反应混合物温热至0℃,倒入水/NaCl中,用TBME萃取三次。所合并的有机相经Na2SO4干燥,蒸发至干。经色谱法纯化(SiO2;TBME/环己烷10/90),得到标题化合物,为无色泡沫(6.0g;64%),其在其异构体3-(5-溴-2-甲氧基-苯基)-6-氯-2-(2-三甲基甲硅烷基-乙氧基甲基)-2H-吡唑并[3,4-b]吡啶(3.2g;34%)之前被洗脱出。
1H-NMR(400MHz;DMSO):-0.08(s,9H);0.88(t,2H);3.68(t,2H);3.88(s,3H);5.81(s,2H);7.23(d,1H);7.40(d,1H);7.68(dd,1H);7.76(d,1H);8.28(d,1H).
MS(m/z)ES+:470(MH+;100).
b)3-[6-氯-1-(2-三甲基甲硅烷基-乙氧基甲基)-1H-吡唑并[3,4-b]吡啶-3-基]-4-甲氧基-苯甲酸
将3-(5-溴-2-甲氧基-苯基)-6-氯-1-(2-三甲基甲硅烷基-乙氧基甲基)-1H-吡唑并[3,4-b]吡啶(3g;6.38mmol)在THF(90ml)中冷却至-78C,用nBuLi(4.4ml;7.02mmol,1.6M己烷溶液)处理。继续搅拌10分钟,然后通入CO2气体达5分钟。将反应混合物于-78℃搅拌10分钟,然后倒入0.1M HCl溶液中,用EtOAc萃取三次。有机相用盐水洗涤,经Na2SO4干燥,蒸发至干。经色谱法纯化(SiO2,丙酮/己烷/HOAc 20/80/1),得到标题化合物(3.2g;58%),为无色晶体。
1H-NMR(400MHz;DMSO):-0.08(s,9H);0.88(t,2H);3.68(t,2H);3.95(s,3H);5.82(s,2H);7.33(d,1H);7.38(d,1H);8.09(dd,1H);8.22(d,1H);8.30(d,1H).
MS(m/z)ES-:432(MH-;100).
c)3-[6-(2,4-二氟-苯基氨基)-1-(2-三甲基甲硅烷基-乙氧基甲基)-1H-吡唑并[3,4-b]吡啶-3-基]-4-甲氧基-苯甲酸
将3-[6-氯-1-(2-三甲基甲硅烷基-乙氧基甲基)-1H-吡唑并[3,4-b]吡啶-3-基]-4-甲氧基-苯甲酸(3.2g;7.39mmol)、R-(+)-BINAP(229mg;0.369mmol)、Pd(OAc)2(248mg;1.1mmol)、PPh3(503mg;1.9mmol)、2,4-二氟苯胺(18.7ml;184mmol)和NaOtBu(1.77g;18.47mmol)溶于二烷(50ml)中,于130℃加热15分钟。将反应混合物倒入盐水中,用EtOAc萃取两次。将所合并的有机相用0.1N HCl和水洗涤,经Na2SO4干燥,蒸发至干。粗品经色谱法纯化(SiO2,丙酮/环己烷/HOAc 20/80/1),得到标题化合物,为呈黄色晶体(3.4g;87%)。
1H-NMR(400MHz;DMSO):-0.08(s,9H);0.85(t,2H);3.62(t,2H);3.93(s,3H);5.68(s,2H);6.90(d,1H);7.11(dt,1H);7.28-7.38(m,2H);7.92(d,1H);8.03(dd,1H);8.23(d,1H);8.35-8.45(m,1H);9.20(s,1H).
MS(m/z)ES-:525(MH-;100).
d)3-[6-(2,4-二氟-苯基氨基)-1-(2-三甲基甲硅烷基-乙氧基甲基)-1H-吡唑并[3,4-b]吡啶-3-基]-4-甲氧基-N-吡啶-2-基-苯甲酰胺
将3-[6-(2,4-二氟-苯基氨基)-1-(2-三甲基甲硅烷基-乙氧基甲基)-1H-吡唑并[3,4-b]吡啶-3-基]-4-甲氧基-苯甲酸(1.1g;2.08mmol)和1,1’-羰二咪唑(674mg;4.16mmol)溶于THF(7ml)中,回流5分钟直至停止气体放出。将反应混合物冷却至35℃,加入2-氨基吡啶(1.17g;12.48mmol)。于80℃加热5分钟后,将反应混合物蒸发,于130℃放置30分钟。经色谱法纯化(SiO2,丙酮/己烷25/75),得到标题化合物粗品,为无色晶体(1.0g),用于下一步骤。
e)3-[6-(2,4-二氟-苯基氨基)-1H-吡唑并[3,4-b]吡啶-3-基]-4-甲氧基-N-吡啶-2-基-苯甲酰胺
将3-[6-(2,4-二氟-苯基氨基)-1-(2-三甲基甲硅烷基-乙氧基甲基)-1H-吡唑并[3,4-b]吡啶-3-基]-4-甲氧基-N-吡啶-2-基-苯甲酰胺(1.0g;1.66mol)在EtOH/浓HCl(100ml;1∶1)中于室温放置15分钟,倒入饱和Na2CO3溶液(300ml)中,用EtOAc/THF(10∶1)萃取。将所合并的有机相用Na2CO3饱和溶液和盐水洗涤,蒸发至干,经色谱法纯化(SiO2,丙酮/己烷30/70>100/0),得到标题化合物,为白色晶体(680mg;86%)。
1H-NMR(400MHz;DMSO):3.95(s,3H);6.82(d,1H);7.08-7.18(m,2H);7.29(d,1H);7.35(dt,1H);7.84(dt,1H);7.91(d,1H);8.13-8.23(m,3H);8.30(d,1H);8.40(d,1H);9.01(s,1H,NH);10.75(s,1H,NH);13.20(s,1H,NH).
MS(m/z)ES+:473(MH+,100).
流程4
II”类型的3-苯基-1H-吡唑并[3,4-d]嘧啶如下制备:
II”类型的化合物的合成如实施例24所示例:
实施例24:{3-[5-(3-氨基-3-甲基-丁-1-炔基)-2-甲氧基-苯基]-1H-吡唑并[3,4-d]嘧啶-6-基}-(2,4-二氟-苯基)-胺
a)(5-溴-2-甲氧基-苯基)-(2,4-二氯-嘧啶-5-基)-甲醇
将nBuLi(31.25ml;50mmol,1.6M己烷溶液;50mmol)于-50℃加入二异丙胺(7.7ml;50mmol)在THF/异戊烷(75ml/20ml)中的溶液中,于-50℃搅拌10分钟,然后冷却至-100℃。加入2,4-二氯嘧啶(3.72g;25mmol)在THF(45ml)中的溶液,于-100℃搅拌15分钟。于-100℃向黑色反应混合物中加入5-溴-o-茴香醛(3.22g;15mmol)在THF(15ml)中的溶液,于-78℃搅拌10分钟,倒入盐水中,用TBME萃取三次。所合并的有机相经Na2SO4干燥,蒸发,经色谱法纯化(SiO2,环己烷/TBME 7/3),得到标题化合物,为黄色油(2.2g;40%),用于下一步骤。
b)(5-溴-2-甲氧基-苯基)-(2,4-二氯-嘧啶-5-基)-甲酮
将(5-溴-2-甲氧基-苯基)-(2,4-二氯-嘧啶-5-基)-甲醇(2.2g;6mmol)溶于丙酮(190ml)中,以15分钟间隔加入3批MnO2(3×2.1g)进行处理。过滤混合物,蒸发,从TBME/己烷中重结晶,得到标题化合物,为黄色晶体(1.5g;68%)。
1H-NMR(400MHz;DMSO):3.70(s,3H);7.23(d,1H);7.90(m,2H);8.93(s,1H).MS(m/z)EI:362(M+,100);327(25);215(75);213(80).
c)3-(5-溴-2-甲氧基-苯基)-6-氯-1H-吡唑并[3,4-d]嘧啶
将(5-溴-2-甲氧基-苯基)-(2,4-二氯-嘧啶-5-基)-甲酮(3.0g;8.2mmol)溶于温热EtOH(240ml)中,冷却至30℃。于30℃、在搅拌下加入H2NNH2.H2O(3.26ml;18.2mmol,24%水溶液)在2N HCl(10.8ml;21.75mmol)中的溶液。加入NaHCO3(49.4ml;57.2mmol;饱和溶液),将所得沉淀搅拌15分钟,将反应混合物倒入水中,用TBME萃取两次。所合并的有机相用盐水洗涤,经Na2SO4干燥,蒸发至干,得到标题化合物,为固体,将其从TBME中重结晶进行纯化(2.2g;75%)
1H-NMR(400MHz;DMSO):3.92(s,3H);7.25(d,1H);7.68(dd,1H);7.88(d,1H);9.28(s,1H);14.50(s,1H,NH).
MS(m/z)ES-:339(MH-,100);249(50).
d)[3-(5-溴-2-甲氧基-苯基)-1H-吡唑并[3,4-d]嘧啶-6-基]-(2,4-二氟-苯基)-胺
将3-(5-溴-2-甲氧基-苯基)-6-氯-1H-吡唑并[3,4-d]嘧啶(8.6g;25mmol)和2,4-二氟苯胺(25ml)加热至150℃。5分钟后,形成沉淀;继续加热另外10分钟。将反应混合物冷却,用己烷(800ml)稀释,过滤,将固体用水洗涤和研制。将绿色产物溶于1.5升热EtOAc/THF/EtOH(1∶1∶1)中,浓缩至~100ml体积。将所得沉淀用TBME/己烷(100ml/200ml)稀释,过滤,得到标题化合物,为绿色晶体(9.7g;89%)。
1H-NMR(400MHz;DMSO):3.91(s,3H);7.12(bt,1H);7.20(d,1H);7.35(bt,1H);7.63(dd,1H);7.73(m,1H);7.81(d,1H);8.97(s,1H);9.38(s,1H,NH);13.50(s,1H,NH).
MS(m/z)ES-:432,430(MH-;100).
e){3-[5-(3-氨基-3-甲基-丁-1-炔基)-2-甲氧基-苯基]-1H-吡唑并[3,4-d]嘧啶-6-基}-(2,4-二氟-苯基)-胺
将[3-(5-溴-2-甲氧基-苯基)-1H-吡唑并[3,4-d]嘧啶-6-基]-(2,4-二氟-苯基)-胺(648mg;1.5mmol)和1,1-二甲基-丙-2-炔基胺(1.5ml;15mmol)、PdCl2(PPh3)2(105mg;0.15mmol)、CuI(114mg;0.6mmol)、Cs2CO3(487mg;1.5mmol)溶于Huenigs碱(150ml)中,于130℃加热1小时。将反应混合物蒸发,溶于TBME/EtOH中,过滤,滤液经色谱法纯化(SiO2,TBME/MeOH95/5>TBME/MeOH/浓NH390/9/1),得到标题化合物,为黄棕色晶体(100mg;15%)。
1H-NMR(400MHz;DMSO):1.40(s,6H);2.14(bs,2H,NH2);3.90(s,3H);7.11(bt,1H);7.19(d,1H);7.33(bt,1H);7.42(d,1H);7.66(s,1H);7.72(m,1H);8.94(s,1H);9.23(s,1H);13.45(s,1H,NH).
MS(m/z)ES-:433(M-H;100).
实施例25:4-{3-[6-(2,4-二氟-苯基氨基)-1H-吡唑并[3,4-d]嘧啶-3-基]-4-甲氧基-苯基}-2-甲基-丁-3-炔-2-醇
将[3-(5-溴-2-甲氧基-苯基)-1H-吡唑并[3,4-d]嘧啶-6-基]-(2,4-二氟-苯基)-胺(3-04g;7mmol)、2-甲基-丁-3-炔-2-醇(2.83ml;28mmol)、Et3N(16ml)、DMF(28ml)、PdCl2(PPh3)2(981mg;40mmol)和CuI(266mg;1.4mmol)于100℃加热1小时。将反应混合物蒸发,溶于甲苯(100ml)中,过滤,滤液经色谱法纯化(SiO2,甲苯/TBME 70/30>甲苯/TBME 50/50),从甲苯/己烷/TBME中重结晶,得到标题化合物,为黄色固体(1.6g;52%)。
1H-NMR(400MHz;DMSO):1.49(s,6H);3.93(s,3H);5.43(s,1H,OH);7.12(dt,1H);7.21(d,1H);7.35(dt,1H);7.49(dd,1H);7.71(d,1H);7.72-7.78(m,1H);8.97(s,1H);9.23(s,1H,NH);13.35(s,1H,NH).
MS(m/z)ES+:436(MH+;100).
实施例26:4-{3-[6-(2,4-二氟-苯基氨基)-1H-吡唑并[3,4-d]嘧啶-3-基]-4-甲氧基-苯基}-2-甲基-丁烷-2-醇
将4-{3-[6-(2,4-二氟-苯基氨基)-1H-吡唑并[3,4-d]嘧啶-3-基]-4-甲氧基-苯基}-2-甲基-丁-3-炔-2-醇(1.0g;2.3mmol)溶于EtOH(150ml)中,在正常压力下经Pd/C(10%;400mg)氢化4小时。将反应物过滤,蒸发,经色谱法纯化(SiO2,丙酮/己烷2/8),从丙酮/TBME中结晶,得到标题化合物,为白色固体(700mg;70%)。
1H-NMR(400MHz;DMSO):1.17(s,6H);1.62-1.70(m,2H);2.61-2.68(m,2H);3.86(s,3H);4.25(s,1H,OH),7.10-7.15(m,2H);7.28(dd,1H);7.33(dt,1H);7.52(d,1H);7.71-7.78(m,1H);8.93(s,1H);9.20(s,1H,NH);13.30(s,1H,NH).
MS(m/z)ES+:440(MH+;100).
实施例27:(2,4-二氟-苯基)-{3-[5-(3-二甲基氨基-丙-1-炔基)-2-甲氧基-苯基]-1H-吡唑并[3,4-d]嘧啶-6-基}-胺
将[3-(5-溴-2-甲氧基-苯基)-1H-吡唑并[3,4-d]嘧啶-6-基]-(2,4-二氟-苯基)-胺(1g;2.3mmol)、R-BINAP(100mg;1.6mmol)、CuI(75mg;0.39mmol)、Pd(OAc)2(100mg;0.44mmol)、PPh3(175mg;0.66mmol)、NaOtBu(444mg;4.6mmol)和二甲基-丙-2-炔基-胺(5.3ml;46mmol)溶于二甘醇二甲醚(100ml)中,在高压釜中于135℃加热1小时。将反应混合物蒸发,溶于2N HCl中,用EtOAc洗涤,将水相用浓Na2CO3调为碱性,过滤,用EtOAc萃取三次。所合并的有机相经Na2SO4干燥,蒸发至干,经色谱法纯化(SiO2,丙酮/己烷4/6>100/0>TBME/MeOH/浓NH390/10/1),从二氯甲烷中重结晶后,得到纯的标题化合物(447mg;45%)。
1H-NMR(400MHz;DMSO):2.24(s,6H);3.44(s,2H);3.90(s,3H);7.10(dt,1H);7.21(d,1H);7.32(dt,1H);7.70(d,1H);7.50(dd,1H);7.74(m,1H);8.92(s,1H);9.21(s,1H,NH);13.45(bs,1H,NH).
MS (m/z)ES+:435(MH+,100).
实施例28:(2,4-二氟-苯基)-{3-[2-甲氧基-5-(3-吗啉-4-基-丙-1-炔基)-苯基]-1H-吡唑并[3,4-d]嘧啶-6-基}-胺
类似于实施例27,由[3-(5-溴-2-甲氧基-苯基)-1H-吡唑并[3,4-d]嘧啶-6-基]-(2,4-二氟-苯基)-胺和4-丙-2-炔基-吗啉获得标题化合物,产率为70%,无色晶体。
1H-NMR(400MHz;DMSO):2.53(bt,4H);3.50(s,2H);3.61(bt,4H);3.91(s,3H);7.11(dt,1H);7.22(d,1H);7.32(dt,1H);7.51(dd,1H);7.71(dd,2H);8.93(s,1H);9.23(s,1H,NH);13.45(s,1H,NH).
MS(m/z)ES+:477(MH+,40),390(100).
实施例29:(2,4-二氟-苯基)-(3-{2-甲氧基-5-[3-(4-甲基-哌嗪-1-基)-丙-1-炔基]-苯基}-1H-吡唑并[3,4-d]嘧啶-6-基)-胺
类似于实施例27,由[3-(5-溴-2-甲氧基-苯基)-1H-吡唑并[3,4-d]嘧啶-6-基]-(2,4-二氟-苯基)-胺和1-甲基-4-丙-2-炔基-哌嗪获得标题化合物,产率为75%,无色晶体。
1H-NMR(400MHz;DMSO):2.15(s,3H);2.34(bs,4H);2.53(bs,4H);3.51(s,2H);3.90(s,3H);7.10(dt,1H);7.21(d,1H);7.32(dt,1H);7.49(dd,1H);7.70(d,1H);7.72(m,1H);8.93(s,1H,NH);9.22(s,1H,NH);13.45(bs,1H,NH).
MS(m/z)ES+:490(MH+,100).
实施例30:4-{3-[6-(2,4-二氟-苯基氨基)-1H-吡唑并[3,4-d]嘧啶-3-基]-4-甲氧基-苯基乙炔基}-1-甲基-哌啶-4-醇
将[3-(5-溴-2-甲氧基-苯基)-1H-吡唑并[3,4-d]嘧啶-6-基]-(2,4-二氟-苯基)-胺(1.38g;3.2mmol)、4-乙炔基-1-甲基-哌啶-4-醇(0.9g;6.5mmol)、PdCl2(PPh3)2(0.43g;0.6mmol)、Cs2CO3(2.7g;8.3mmol)和CuI(133mg;0.7mmol)溶于二甘醇二甲醚(32ml)和N,N-二异丙基乙基胺(16ml)中,于140℃加热15分钟。将反应混合物过滤,蒸发,经色谱法纯化(SiO2,EtOAc/MeOH/浓NH395/4.5/0.5>90/9/1),从EtOH/TBME中结晶,得到标题化合物(900mg;54%)。
1H-NMR(400MHz;DMSO):1.72(m,2H);1.83(m,2H);2.16(s,3H);2.26(m,2H);2.54(m,2H);3.91(s,3H);5.50(s,1H,OH);7.11(dt,1H);7.22(d,1H);7.32(dt,1H);7.48(dd,1H);7.69(d,1H);7.72(m,1H);8.93(s,1H);9.24(s,1H,NH);13.44(bs,1H,NH)
MS(m/z)ES+:491(MH+,100).
实施例31:(2,4-二氟-苯基)-{3-[5-((E)-3-二甲基氨基-丙烯基)-2-甲氧基-苯基]-1H-吡唑并[3,4-d]嘧啶-6-基}-胺
将二甲基-((E)-3-三丁基甲锡烷基-烯丙基)-胺(312mg,0.83mmol)和[3-(5-溴-2-甲氧基-苯基)-1H-吡唑并[3,4-d]嘧啶-6-基]-(2,4-二氟-苯基)-胺(200mg,0.69mmol)加入Pd(OAc)2(15mg,0.07mmol)和PPh3(75mg,0.2mmol)在二甘醇二甲醚(16ml)中的溶液中,于130℃在氩气下加热40分钟。将反应混合物蒸发至干,经第一次色谱法(SiO2,丙酮/己烷6/4>9/1>丙酮/MeOH 9/1)、然后经第二次色谱法(SiO2,TBME/MeOH/浓NH395/5/0.5>90/10/1)进行纯化,得到标题化合物,为浅黄色晶体(60mg;20%)。
1H-NMR(400MHz;DMSO):2.16(s,6H);3.01(bd,2H);3.88(s,3H);6.19(dt,1H);6.52(d,1H);7.10(bt,1H);7.17(d,1H);7.32(bt,1H);7.52(bd,1H);7.71-7.80(m,2H);8.91(s,1H);9.20(bs,1H,NH);13.40(s,1H,NH).
MS(m/z)ES+:424(MH+,100).
实施例32:(2,4-二氟-苯基)-{3-[2-甲氧基-5-((E)-3-吗啉-4-基-丙烯基)-苯基]-1H-吡唑并[3,4-d]嘧啶-6-基}-胺
类似于实施例30,由4-((E)-3-三丁基甲锡烷基-烯丙基)-吗啉和[3-(5-溴-2-甲氧基-苯基)-1H-吡唑并[3,4-d]嘧啶-6-基]-(2,4-二氟-苯基)-胺获得标题化合物,产率为47%,无色晶体。
1H-NMR(400MHz;DMSO):2.39(bs,4H);3.07(bd,2H);3.58(bt,4H);3.88(s,3H);6.21(dt,1H);6.54(d,1H);7.11(dt,1H);7.17(d,1H);7.33(dt,1H);7.55(dd,1H);7.71(m,2H);8.91(s,1H);9.21(s,1H,NH);13.40(s,1H,NH).
MS(m/z)ES+:479(MH+,100).
实施例33:(2,4-二氟-苯基)-(3-{2-甲氧基-5-[(E)-3-(4-甲基-哌嗪-1-基)-丙烯基]-苯基}-1H-吡唑并[3,4-d]嘧啶-6-基)-胺
类似于实施例31,由1-甲基-4-((E)-3-三丁基甲锡烷基-烯丙基)-哌嗪和[3-(5-溴-2-甲氧基-苯基)-1H-吡唑并[3,4-d]嘧啶-6-基]-(2,4-二氟-苯基)-胺获得标题化合物,产率为10%,元色晶体。
1H-NMR(400MHz;DMSO:2.14(s,3H);2.25-2.50(m,8H);3.07(d,2H);3.87(s,3H);6.18(dt,1H);6.52(d,1H);7.11(dt,1H);7.17(d,1H);7.32(dt,1H);7.52(dd,1H);7.70-7.78(m,2H);8.91(s,1H);9.22(s,1H,NH);13.40(s,1H,NH).
MS(m/z)ES+:492(MH+,100).
流程5
I”’类型的苯基-(3-苯基-1H-吡唑并[3,4-b]吡嗪-6-基)-胺的合成在实施例33和35中示例。
实施例34:4-{3-[6-(2,4-二氟-苯基氨基)-1H-吡唑并[3,4-b]吡嗪-3-基]-4-甲氧基-苯基}-2-甲基-丁-3-炔-2-醇
a)(5-溴-2-甲氧基-苯基)-(3,5-二氯-吡嗪-2-基)-甲醇
将四甲基哌啶(5.25ml;30.75mmol)在THF(450ml)中冷却至-15℃,用nBuLi(18.7ml;30mmol,1.6M己烷溶液)处理10分钟,然后冷却至-90℃。历经1分钟加入2,6-二氯-吡嗪(3.34g;22.5mmol)在THF(45ml)中的溶液,将红棕色反应混合物于-90℃至-100℃搅拌30秒。于-90℃历经1分钟加入5-溴-2-甲氧基-苯甲醛(3.2g;15mmol)在THF(45ml)中的溶液,将反应物于-78℃搅拌10分钟。将黑色反应混合物倒入盐水中,用TBME萃取两次。所合并的有机相用水洗涤,经Na2SO4干燥,过滤,蒸发至干。经色谱法纯化(SiO2,甲苯),得到标题化合物,为无色晶体(3g;55%)。
1H-NMR(400MHz;DMSO:3.62(s,3H);6.25(s,1H);6.90(d,1H);7.45(dd,1H);7.70(d,1H);8.71(s,1H).
MS(m/z)EI:364(M+,90);333(65);215(100).
b)(5-溴-2-甲氧基-苯基)-(3,5-二氯-吡嗪-2-基)-甲酮
于室温,将(5-溴-2-甲氧基-苯基)-(3,5-二氯-吡嗪-2-基)-甲醇(9g;24.7mmol)在丙酮(800ml)中用Jones试剂(53ml;123mmol,2.33mol溶液)处理15分钟。馏出丙酮(~700ml),将残余物倒入饱和Na2CO3溶液中,用EtOAc萃取两次。所合并的有机相经Na2SO4干燥,过滤,蒸发至干,得到标题化合物,为白色晶体(7.9g;88%)。
1H-NMR(400MHz;DMSO):3.62(s,3H);6.71(d,1H);7.83-7.93(m,2H);8.90(s,1H).MS(m/z)EI:362(M+,30);331(30);213(100).
b)3-(5-溴-2-甲氧基-苯基)-6-氯-1H-吡唑并[3,4-b]吡嗪
将(5-溴-2-甲氧基-苯基)-(3,5-二氯-吡嗪-2-基)-甲酮(7.9g;21.8mmol)溶于温热(50℃)MeOH(790ml)中,用H2NNH2.H2O(2.37ml;48mmol,98%水溶液)处理。于50℃1小时后,加入第二批H2NNH2.H2O(1.2ml;24mmol,98%水溶液),继续搅拌30分钟。过滤黄色固体,得到标题化合物(2.66g;36%)。
1H-NMR(400MHz;DMSO):3.83(s,3H);6.70(d,1H);7.65(dd,1H);7.95(bs,1H);8.75(s,1H).
MS(m/z)ES-339(MH-;100).
d)[3-(5-溴-2-甲氧基-苯基)-1H-吡唑并[3,4-b]吡嗪-6-基]-(2,4-二氟-苯基)-胺
将3-(5-溴-2-甲氧基-苯基)-6-氯-1H-吡唑并[3,4-b]吡嗪(2.8g;8.27mmol)和2,4-二氟苯胺(16.5ml)于175℃加热1小时。反应混合物(起初为混悬液)形成溶液,然后再次沉淀。向冷却的反应物中加入己烷(500ml),滤出沉淀,溶于EtOAc/THF(500ml 4∶1)中,用水(400ml)洗涤。将水相用EtOAc萃取,所合并的有机相经Na2SO4干燥,蒸发至干,得到标题化合物,将其从EtOAc/TBME中结晶(3.3g;91%)。
1H-NMR(400MHz;DMSO):3.81(s,3H);7.13-7.22(m,2H);7.41(dt,1H);7.62(dd,1H);7.85(s,1H);8.08-8.18(m,1H);8.47(s,1H);9.61(bs,1H,NH);13.50(s,1H,NH).MS(m/z)ES-:432(M+,100);430(100).
c)4-{3-[6-(2,4-二氟-苯基氨基)-1H-吡唑并[3,4-b]吡嗪-3-基]-4-甲氧基-苯基}-2-甲基-丁-3-炔-2-醇
类似于实施例25,由[3-(5-溴-2-甲氧基-苯基)-1H-吡唑并[3,4-b]吡嗪-6-基]-(2,4-二氟-苯基)-胺和2-甲基-丁-3-炔-2-醇获得标题化合物,产率为42%。
1H-NMR(400MHz;DMSO):1.48(s,6H);3.84(bs,3H);5.43(s,1H,OH);7.11-7.19(m,2H);7.38(dt,1H);7.45(d,1H);7.70-7.85(bs,1H);8.17(bs,1H);8.37(s,1H);9.55(bs,1H,NH);13.30(s,1H,NH).
MS(m/z)ES-:434(MH-;100).
实施例35:(2,4-二氟-苯基)-{3-[5-(3-二甲基氨基-丙-1-炔基)-2-甲氧基-苯基]-1H-吡唑并[3,4-b]吡嗪-6-基}-胺
类似于实施例27,由[3-(5-溴-2-甲氧基-苯基)-1H-吡唑并[3,4-b]吡嗪-6-基]-(2,4-二氟-苯基)-胺和二甲基-丙-2-炔基-胺获得标题化合物,产率为20%。
1H-NMR(400MHz;DMSO):2.27(s,6H);3.47(s,2H);3.82(s,3H);7.19(bd,2H);7.41(t,1H);7.52(d,1H);7.74(bs,1H);7.78(bs,1H);8.18(bs,1H);9.60(s,1H,NH);13.40(s,1H,NH).
MS(m/z)ES-:433(MH-,100).
游离或可药用的酸加成盐形式的如上所定义的本发明的物质,例如式I、II和V的那些,尤其是所示例的那些,显示出药理学活性,可用作药物,例如用于治疗如下所示的疾病和病症。
具体而言,本发明的物质具有p38MAP激酶(促分裂原活化蛋白激酶)抑制活性。因此,本发明的物质抑制炎性细胞因子如TNF和IL-1的产生,还能够有效地阻断这些细胞因子对它们的靶细胞的作用。本发明的这些和其它药理活性可以在标准试验方法、例如下文所述的方法中证明。
p38MAP激酶分析
于4℃将底物(GST-ATF-2;包含ATF-2的氨基酸1-109和GST蛋白质的融合蛋白,通过在大肠杆菌(E.coli)中表达获得)涂敷在微量滴定板的孔上(50μl/孔;1μg/ml,在PBS/0.02%叠氮化钠中)过夜。第二天,将微量滴定板用PBS/0.5%吐温20/0.02%叠氮化钠洗涤四次,于37℃用PBS/2%BSA/0.02%叠氮化钠封闭1小时。将板再次用PBS/0.5%吐温20/0.02%叠氮化钠洗涤四次。然后加入10μl等分试样的下述反应物至终反应体积为50μl,从而引发激酶级联反应。
1.本发明的物质,由10递减至0.001μM,在10-倍稀释液或溶剂(DMSO)或H2O中。
2.激酶缓冲液(5×);pH7.4;125mM Hepes(1M储备液;Gibco #15630-056),125mM β-磷酸甘油(Sigma #G-6251);125mM MgCl2(Merck #5833);0.5mM原钒酸钠(Sigma #5-6508),10mM DTT(Boehringer Mannheim#708992)。(5×)激酶缓冲液必须在分析当天由于室温放置的5×储备液新鲜制备。DTT于-20℃放置,最后加入。
3.His-p38MAP激酶(10ng/孔;Novartis——包含全长鼠p38MAP激酶和His尾的融合蛋白,通过在大肠杆菌(E.coli)中表达获得)。
4.无放射性ATP(终浓度120μM;Sigma #A-9187)。
5.水。
于37℃达1小时后,如前所述洗涤板四次,从而终止激酶反应。然后通过加入如下物质检测被磷酸化的GST-ATF-2:
1.磷酸化Plus ATF-2(Thr71)抗体(50μl/孔;1/1000最终稀释度,在PBS/2%BSA/0.02%叠氮化钠中;New England Biolabs #9221L),90分钟,室温。
2.生物素标记的羊抗兔IgG(50μl/孔;1/3000最终稀释度,在PBS/2%BSA/0.02%叠氮化钠中;Sigma #B-9642),90分钟,室温。
3.链霉抗生物素-碱性磷酸酶(50μl/孔;1/5000最终稀释度,在PBS/2%BSA/0.02%叠氮化钠中;Jackson Immunoresearch #016-050-084),30分钟,室温。
4.底物(100μl/孔;Sigma 104磷酸酶底物片剂,5mg/片;#104-105;1mg/ml,在底物缓冲液二乙醇胺(97ml/l;Merck #803116)+MgCl2.6H2O(100mg/l;Merck #5833)+叠氮化钠(0.2g/l)+HCl 1M(pH 9.8)中,30分钟,室温。
在第1、2和3步后,将微量滴定板用PBS/0.5%吐温20/0.02%叠氮化钠洗涤四次。在第4步后,在Bio-Rad微量板读数器上以双波长模式(测量滤光器405nm,参比滤光器490nm)读板。减去背景值(无ATP),采用Origin计算机程序计算IC50值(4参数逻辑函数)。
当在上述分析中测试时,对p38 MAP激酶抑制而言,本发明的物质通常具有约100nM至约10nM或更低的IC50。
抑制TNF-α从hPBMC中释放的分析
根据Hansell等人,J.Imm.Methods(1991)145:105的方法,采用聚蔗糖-泛影葡胺(Ficoll-Hypaque)密度分离法,由健康志愿者的外周血制备人外周血单核细胞(hPBMC),以在含有10%FCS的RPMI 1640中105个细胞/孔的浓度使用。于37℃将细胞在测试化合物的系列稀释液中孵育30分钟,加入IFNg(100U/ml)和LPS(5mg/ml),然后进一步孵育3小时。通过于1400RPM离心10分钟终止孵育。采用市售ELISA(Innotest hTNFα,可自Innogenetics N.V.获得,Zwijnaarde,比利时)测定上清液中的TNF-α。以0至10mM浓度测试本发明的物质。当在本分析中测试时,所举例的本发明的物质通常以约10mM至约100nM或更低的IC50在本分析中抑制TNF释放。
在LPS刺激小鼠中抑制TNF-α生成的分析
注射脂多糖(LPS)诱导可溶性肿瘤坏死因子(TNF-α)向周围的快速释放。该模型用于分析预期的体内TNF释放阻滞剂。
将LPS(20mg/kg)静脉内注射入OF1小鼠(雌性,8周龄)。1小时后,从动物取血,通过ELISA法、采用TNF-α的抗体分析血浆中的TNF水平。采用20mg/kg LPS通常诱导至多15ng TNF-α/ml血浆的水平。在LPS注射前4小时,经口服和经皮下给予欲评价的化合物。以LPS-诱导的TNF-释放的抑制作为读数。
在上述分析中,当以10mg/kg经口施用时,本发明的物质通常以直至约50%至更高的程度抑制TNF生成,当以30mg/kg经口施用时,其抑制程度直至约98%或更高。
如上文分析中所指出的,本发明的物质是TNF-α释放的有效抑制剂。因此,该新化合物具有如下的药学功效:
本发明的物质可用于预防和治疗通过细胞因子如TNFα和IL-1介导的疾病或病理学病症,例如炎性病症、自身免疫性疾病、重度感染以及器官或组织移植排斥,例如用于治疗心脏、肺、联合心-肺、肝脏、肾脏、胰脏、皮肤或角膜移植物的接受者和用于预防移植物抗宿主疾病,例如在骨髓移植后。
本发明的物质可特别用于治疗、预防或改善自身免疫性疾病和炎性病症,特别是其病因学包括自身免疫组分的炎性病症,例如关节炎(例如类风湿性关节炎、arthritis chronica progrediente和变形性关节炎)和风湿性关节炎。适用本发明物质的具体自身免疫性疾病包括自身免疫性血液病学紊乱(包括例如溶血性贫血、再生障碍性贫血、纯红细胞贫血和特发性血小板减少)、系统性红斑狼疮、多发性软骨炎、系统性硬化病(sclerodoma)、韦格纳肉芽肿病、皮肌炎、慢性活动性肝炎、重症肌无力、银屑病、斯-约综合征、特发性口炎性腹泻、自身免疫性炎性肠病(包括例如溃疡性结肠炎和节段性回肠炎)、内分泌性眼病、格雷夫斯病、结节病、多发性硬化症、原发性胆汁性肝硬化、幼年型糖尿病(I型糖尿病)、眼色素层炎(前和后眼色素层炎)、干燥性角膜结膜炎和春季角膜结膜炎、肺间质纤维化、银屑病性关节炎和肾小球肾炎(有或无肾病综合征,例如包括特发性肾病综合征或微小病变肾病)。
本发明的物质还可用于治疗、预防或改善哮喘、支气管炎、尘肺病、肺气肿和其它阻塞性或炎性气道疾病。
本发明的物质可用于治疗不希望的通过TNF、尤其是TNFα介导的急性和超急性炎性反应,例如急性感染,例如败血症性休克(如内毒素性休克和成人呼吸窘迫综合征)、脑膜炎、肺炎以及严重灼伤;并且可用于治疗恶病质或衰竭综合征,与病态TNF释放有关,由感染、癌症或器官功能障碍引起,尤其是ASID相关性恶病质,例如与HIV感染有关或由其引起。
本发明的物质可用于治疗神经变性疾病,例如阿尔茨海默氏病、急性脑炎、脑损伤、多发性硬化症(包括多发性硬化症中的脱髓鞘作用和少突胶质细胞损失)以及炎性神经系统疾病如神经炎症和中风。
发明的物质可特别用于治疗骨代谢疾病,包括骨关节炎、骨质疏松症和其它炎性关节炎。
对于上述适应症,适当的剂量当然将随着例如所用的具体的本发明物质、所治疗的对象、施用模式以及所治疗病症的性质和严重程度而不同。然而,通常以约1至约10mg/kg/天的日剂量口服施用可以在动物中获得令人满意的结果。在较大型哺乳动物、例如人中,指示日剂量为约50至约750mg本发明的物质,每天一次或更适宜地以分开剂量两次至四次/天口服施用。
本发明的物质可通过任意常规途径施用,例如经口服(例如以饮用溶液、片剂或胶囊形式)或经胃肠道外(例如以可注射溶液或混悬液形式)施用。对于全身施用而言,通常优选口服剂型,虽然对于一些适应症而言本发明的物质还可以局部或经皮施用,例如以皮用霜剂或凝胶剂等制剂施用,或者为了施用于眼,以眼用霜剂、凝胶剂或滴眼剂的形式施用;或者可以通过吸入施用,例如对于治疗哮喘而言。适于口服施用的单位剂型每单位剂量包含例如25至250mg的本发明的物质。
根据前文,本发明还提供了一系列其它实施方案:
A.在需要该治疗的受治疗者(即哺乳动物,尤其是人)中抑制可溶性TNF、尤其是TNFα的生成或者减少炎症的方法,该方法包括给所述受治疗者施用有效量的本发明的物质,或者治疗任意上述病症的方法,特别是治疗炎性或自身免疫性疾病或病症、例如类风湿性关节炎或者缓解任意上述病症的一种或多种症状的方法。
B.用作药物的本发明的物质,例如用作免疫抑制剂或抗炎剂或者用于预防、改善或治疗任意上述疾病或病症、例如自身免疫性或炎性疾病或病症的本发明的物质。
C.药物组合物,包含本发明的物质和可药用的稀释剂或载体,例如用作免疫抑制剂或抗炎剂或者用于预防、改善或治疗任意上述疾病或病症、例如自身免疫性或炎性疾病或病症。
D.本发明的物质在制备药物中的用途,所述药物用作免疫抑制剂或抗炎剂或者用于预防、改善或治疗任意上述疾病或病症、例如自身免疫性或炎性疾病或病症。
Claims (10)
3.式II化合物或其在药学上可接受的和可裂解的酯或酸加成盐,
其中
X和Y独立地是碳或氮,
R1’是卤素、C1-C4低级烷基、C1-C4低级烷氧基或卤代-C1-C4低级烷基;
R2’和R3’相互独立地是H或任选被取代的“C1-C4低级烷基、C1-C4低级烷氧基、C1-C7链烯基、C1-C7炔基、C5-C7N-杂环基、C5-C7杂环基C1-C4低级烷氧基、C5-C7杂环基C1-C4低级烷基、C5-C7杂环基C1-C4低级链烯基、C5-C7杂环基C1-C4低级炔基”,其中C5-C7杂环基任选地含有第二个杂原子,并且任选的取代情况包括1或2个取代基,所述取代基单独地选自C1-C4烷基、卤素、羟基、C1-C4烷氧基或者任选被单-或二-N-C1-4烷基取代的氨基,或者
R2’和R3’通过亚甲二氧基连接基连接,或者在任选被1或2个取代基取代的咪唑环中连接,所述取代基单独地选自C1-4烷基、卤素、羟基、C1-4烷氧基或者任选被单-或二-N-C1-4烷基取代的氨基。
4.化合物,选自:
实施例1:(2,4-二氟-苯基)-[3-(2-甲氧基-苯基)-1H-吡唑并[3,4-b]吡啶-6-基]-胺
实施例2:[3-(6-氯-苯并[1,3]二氧杂环戊烯-5-基)-1H-吡唑并[3,4-b]吡啶-6-基]-(2,4-二氟-苯基)-胺
实施例3:[3-(2-氯-苯基)-1H-吡唑并[3,4-b]吡啶-6-基]-(2,4-二氟-苯基)-胺
实施例4:(2,4-二氟-苯基)-[3-(2-三氟甲基-苯基)-1H-吡唑并[3,4-b]吡啶-6-基]-胺
实施例5:(2,4-二氟-苯基)-[3-(2,4-二甲氧基-苯基)-1H-吡唑并[3,4-b]吡啶-6-基]-胺
实施例6:[3-(2-氯-4,5-二甲氧基-苯基)-1H-吡唑并[3,4-b]吡啶-6-基]-(2,4-二氟-苯基)-胺
实施例7:(2,4-二氟-苯基)-[3-(2-甲氧基-5-吗啉-4-基-苯基)-1H-吡唑并[3,4-b]吡啶-6-基]-胺
实施例22:(2,4-二氟-苯基)-{3-[2-甲氧基-5-(4-甲基-哌嗪-1-基)-苯基]-1H-吡唑并[3,4-b]吡啶-6-基}-胺
实施例8:(2,4-二氟-苯基)-[3-(2-甲氧基-5-吡啶-4-基-苯基)-1H-吡唑并[3,4-b]吡啶-6-基]-胺
实施例13:(2,4-二氟-苯基)-[3-(2-甲氧基-5-甲基氨基甲基-苯基)-1H-吡唑并[3,4-b]吡啶-6-基]-胺
实施例14:(2,4-二氟-苯基)-{3-[2-甲氧基-5-(4-甲基-哌嗪-1-基甲基)-苯基]-1H-吡唑并[3,4-b]吡啶-6-基}-胺
实施例12:4-{3-[6-(2,4-二氟-苯基氨基)-1H-吡唑并[3,4-b]吡啶-3-基]-4-甲氧基-苯基}-1-甲基-哌啶-4-醇
实施例15:(2,4-二氟-苯基)-[3-(2-甲氧基-5-吗啉-4-基甲基-苯基)-1H-吡唑并[3,4-b]吡啶-6-基]-胺
实施例16:(2,4-二氟-苯基)-[3-(2-甲氧基-5-哌嗪-1-基甲基-苯基)-1H-吡唑并[3,4-b]吡啶-6-基]-胺
实施例20:{3-[5-(3-氨基-3-甲基-丁-1-炔基)-2-甲氧基-苯基]-1H-吡唑并[3,4-b]吡啶-6-基}-(2,4-二氟-苯基)-胺
实施例21:{3-[5-(3-氨基-3-甲基-丁基)-2-甲氧基-苯基]-1H-吡唑并[3,4-b]吡啶-6-基}-(2,4-二氟-苯基)-胺
实施例9:{3-[2-氯-5-甲氧基-4-(2-吗啉-4-基-乙氧基)-苯基]-1H-吡唑并[3,4-b]吡啶-6-基}-(2,4-二氟-苯基)-胺
实施例10:{3-[2-氯-4-甲氧基-5-(2-吗啉-4-基-乙氧基)-苯基]-1H-吡唑并[3,4-b]吡啶-6-基}-(2,4-二氟-苯基)-胺
实施例17:(2,4-二氟-苯基)-[3-(2-甲氧基-5-丙基氨基甲基-苯基)-1H-吡唑并[3,4-b]吡啶-6-基]-胺
实施例18:(2,4-二氟-苯基)-(3-{2-甲氧基-5-[(四氢-吡喃-4-基氨基)-甲基]-苯基}-1H-吡唑并[3,4-b]吡啶-6-基)-胺
实施例11和19:(2,4-二氟-苯基)-{3-[5-(1,2-二甲基-1H-咪唑-4-基)-2-甲氧基-苯基]-1H-吡唑并[3,4-b]吡啶-6-基}-胺
实施例23:3-[6-(2,4-二氟-苯基氨基)-1H-吡唑并[3,4-b]吡啶-3-基]-4-甲氧基-N-吡啶-2-基-苯甲酰胺
实施例24:{3-[5-(3-氨基-3-甲基-丁-1-炔基)-2-甲氧基-苯基]-1H-吡唑并[3,4-d]嘧啶-6-基}-(2,4-二氟-苯基)-胺
实施例25:4-{3-[6-(2,4-二氟-苯基氨基)-1H-吡唑并[3,4-d]嘧啶-3-基]-4-甲氧基-苯基}-2-甲基-丁-3-炔-2-醇
实施例26:4-{3-[6-(2,4-二氟-苯基氨基)-1H-吡唑并[3,4-d]嘧啶-3-基]-4-甲氧基-苯基}-2-甲基-丁烷-2-醇
实施例27:(2,4-二氟-苯基)-{3-[5-(3-二甲基氨基-丙-1-炔基)-2-甲氧基-苯基]-1H-吡唑并[3,4-d]嘧啶-6-基}-胺
实施例28:(2,4-二氟-苯基)-{3-[2-甲氧基-5-(3-吗啉-4-基-丙-1-炔基)-苯基]-1H-吡唑并[3,4-d]嘧啶-6-基}-胺
实施例29:(2,4-二氟-苯基)-(3-{2-甲氧基-5-[3-(4-甲基-哌嗪-1-基)-丙-1-炔基]-苯基}-1H-吡唑并[3,4-d]嘧啶-6-基)-胺
实施例30:4-{3-[6-(2,4-二氟-苯基氨基)-1H-吡唑并[3,4-d]嘧啶-3-基]-4-甲氧基-苯基乙炔基}-1-甲基-哌啶-4-醇
实施例31:(2,4-二氟-苯基)-{3-[5-((E)-3-二甲基氨基-丙烯基)-2-甲氧基-苯基]-1H-吡唑并[3,4-d]嘧啶-6-基}-胺
实施例32:(2,4-二氟-苯基)-{3-[2-甲氧基-5-((E)-3-吗啉-4-基-丙烯基)-苯基]-1H-吡唑并[3,4-d]嘧啶-6-基}-胺
实施例33:(2,4-二氟-苯基)-(3-{2-甲氧基-5-[(E)-3-(4-甲基-哌嗪-1-基)-丙烯基]-苯基}-1H-吡唑并[3,4-d]嘧啶-6-基)-胺
实施例34:4-{3-[6-(2,4-二氟-苯基氨基)-1H-吡唑并[3,4-b]吡嗪-3-基]-4-甲氧基-苯基}-2-甲基-丁-3-炔-2-醇
实施例35:(2,4-二氟-苯基)-{3-[5-(3-二甲基氨基-丙-1-炔基)-2-甲氧基-苯基]-1H-吡唑并[3,4-b]吡嗪-6-基}-胺
或其在药学上可接受的和可裂解的酯或酸加成盐。
5.在需要该治疗的受治疗者中抑制可溶性TNF、尤其是TNFα的生成或者减少炎症的方法,该方法包括给所述受治疗者施用有效量的本发明的物质。
6.用作药物、例如用作免疫抑制剂或抗炎剂的本发明的物质。
7.药物组合物,包含本发明的物质和可药用的稀释剂或载体,例如用作免疫抑制剂或抗炎剂。
8.本发明的物质在制备用作免疫抑制剂或抗炎剂的药物中的用途。
10.基本如上文所述并具体参考实施例的所有新的化合物、操作、方法和用途。
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BRPI0615442A2 (pt) | 2005-08-25 | 2011-05-17 | Hoffmann La Roche | inibidores de p38 map cinase e métodos para uso dos mesmos |
WO2011049988A2 (en) * | 2009-10-20 | 2011-04-28 | Eiger Biopharmaceuticals, Inc. | Indazoles to treat flaviviridae virus infection |
US8362023B2 (en) | 2011-01-19 | 2013-01-29 | Hoffmann-La Roche Inc. | Pyrazolo pyrimidines |
US11466017B2 (en) | 2011-03-10 | 2022-10-11 | Board Of Regents, The University Of Texas System | Heterocyclic inhibitors of PTPN11 |
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CN103874699A (zh) | 2011-09-20 | 2014-06-18 | 赛尔佐姆有限公司 | 吡唑并[4,3-c]吡啶衍生物作为激酶抑制剂 |
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- 2005-12-14 JP JP2007545941A patent/JP2008524141A/ja active Pending
- 2005-12-14 ES ES05822740T patent/ES2345207T3/es active Active
- 2005-12-14 KR KR1020077013508A patent/KR20070087607A/ko not_active Application Discontinuation
- 2005-12-14 PL PL05822740T patent/PL1833477T3/pl unknown
- 2005-12-14 RU RU2007126968/04A patent/RU2007126968A/ru not_active Application Discontinuation
- 2005-12-14 CN CNA2005800426060A patent/CN101076333A/zh active Pending
- 2005-12-14 MX MX2007007218A patent/MX2007007218A/es not_active Application Discontinuation
- 2005-12-14 AT AT05822740T patent/ATE469646T1/de not_active IP Right Cessation
- 2005-12-14 CA CA002586543A patent/CA2586543A1/en not_active Abandoned
- 2005-12-14 EP EP05822740A patent/EP1833477B1/en not_active Not-in-force
Also Published As
Publication number | Publication date |
---|---|
EP1833477B1 (en) | 2010-06-02 |
BRPI0519337A2 (pt) | 2009-01-20 |
US20090258874A1 (en) | 2009-10-15 |
AU2005315849A1 (en) | 2006-06-22 |
MX2007007218A (es) | 2007-08-14 |
GB0427604D0 (en) | 2005-01-19 |
AU2005315849B2 (en) | 2009-05-28 |
ES2345207T3 (es) | 2010-09-17 |
WO2006063820A1 (en) | 2006-06-22 |
PL1833477T3 (pl) | 2010-11-30 |
CA2586543A1 (en) | 2006-06-22 |
RU2007126968A (ru) | 2009-01-27 |
ATE469646T1 (de) | 2010-06-15 |
EP1833477A1 (en) | 2007-09-19 |
DE602005021697D1 (de) | 2010-07-15 |
JP2008524141A (ja) | 2008-07-10 |
PT1833477E (pt) | 2010-08-20 |
KR20070087607A (ko) | 2007-08-28 |
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