CN1439010A - 吡咯并[2,3-d]嘧啶化合物作为免疫抑制剂 - Google Patents
吡咯并[2,3-d]嘧啶化合物作为免疫抑制剂 Download PDFInfo
- Publication number
- CN1439010A CN1439010A CN01811792A CN01811792A CN1439010A CN 1439010 A CN1439010 A CN 1439010A CN 01811792 A CN01811792 A CN 01811792A CN 01811792 A CN01811792 A CN 01811792A CN 1439010 A CN1439010 A CN 1439010A
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- Prior art keywords
- base
- amino
- methyl
- wan
- pyrrolo
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- 229940125721 immunosuppressive agent Drugs 0.000 title 1
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- 150000003839 salts Chemical class 0.000 claims description 28
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Abstract
本发明涉及式(I)的化合物,其中R1,R2和R3如说明书中所定义。该化合物可用作蛋白激酶如酶Janus Kinase3的抑制剂。
Description
发明背景
本发明涉及吡咯并[2,3-d]嘧啶化合物,它们是蛋白激酶如酶JanusKinase 3(以下称为JAK3)的抑制剂,因而可作为免疫抑制剂用于治疗器官移植、移植排异、狼疮、多发性硬化、类风湿关节炎、牛皮癣、I型糖尿病和糖尿病并发症、癌症、哮喘、特应性皮肤病、自体免疫性甲状腺病、溃疡性结炎、Crohn病、阿尔茨海默病、白血病和其它免疫抑制的适应症。
本发明也涉及用这类化合物治疗哺乳动物特别是人的上述病症用的方法。
JAK3是蛋白激酶族Janus家族中的成员。虽然基本上所有组织均表达该家族的其它成员,但JAK3的表达限于造血细胞。这与通过IL-2、IL-4、IL-7、IL-9和IL-15的受体由JAK3与这些多链受体所共有的γ链进行非共价结合而进行的信号传递中的基本作用是一致的。现已检验出患XSCID群体的JAK3蛋白水平严重降低或其共有的γ链的基因缺损,显示免疫抑制作用是由于阻断了通过JAK3路径的信号传递。动物研究表明JAK3不仅对B和T淋巴细胞的成熟起着关键作用,而且从构成上讲也需要JAK3以维持T细胞的功能。由这种新的机理对免疫活性进行调节证实可将其用于治疗如移植排斥和自体免疫性疾病等的T细胞增殖性疾病。
发明概述
R1是下式的基团
其中y是0、1或2;
R4选自氢,(C1-C6)烷基,(C1-C6)烷基磺酰基,(C2-C6)链烯基,(C2-C6)炔基,其中烷基,链烯基和炔基任选地被下列基团取代:氘,羟基,氨基,三氟甲基,(C1-C4)烷氧基,(C1-C6)酰氧基,(C1-C6)烷氨基,((C1-C6)烷基)2氨基,氰基,硝基,(C2-C6)链烯基,(C2-C6)炔基或(C1-C6)酰氨基;或R4是(C3-C10)环烷基,其中该环烷基任选地被下列基团取代:氘,羟基,氨基,三氟甲基,(C1-C6)酰氧基,(C1-C6)酰氨基,(C1-C6)烷基氨基,((C1-C6)烷基)2氨基,氰基,氰基(C1-C6)烷基,三氟甲基(C1-C6)烷基,硝基,硝基(C1-C6)烷基或(C1-C6)酰基氨基;
R5是(C2-C9)杂环烷基,其中该杂环烷基必须被1至5个下列的基团取代:羧基,氰基,氨基,氘,羟基,(C1-C6)烷基,(C1-C6)烷氧基,卤素,(C1-C6)酰基,(C1-C6)烷基氨基,氨基(C1-C6)烷基,(C1-C6)烷氧基-CO-NH,(C1-C6)烷基氨基-CO-,(C2-C6)链烯基,(C2-C6)炔基,(C1-C6)烷基氨基,氨基(C1-C6)烷基,羟基(C1-C6)烷基,(C1-C6)烷氧基(C1-C6)烷基,(C1-C6)酰基氧(C1-C6)烷基,硝基,氰基(C1-C6)烷基,卤代(C1-C6)烷基,硝基(C1-C6)烷基,三氟甲基,三氟甲基(C1-C6)烷基,(C1-C6)酰基氨基,(C1-C6)酰基氨基(C1-C6)烷基,(C1-C6)烷氧基(C1-C6)酰基氨基,氨基(C1-C6)酰基,氨基(C1-C6)酰基(C1-C6)烷基,(C1-C6)烷基氨基(C1-C6)酰基,((C1-C6)烷基)2氨基(C1-C6)酰基,R15R16N-CO-O-,R15R16N-CO-(C1-C6)烷基,(C1-C6)烷基-S(O)m,R15R16NS(O)m,R15R16NS(O)m(C1-C6)烷基,R15S(O)mR16N,R15S(O)mR16N(C1-C6)烷基,其中m是0、1或2且R15和R16各自独立地选自氢或(C1-C6)烷基;以及下式基团:其中a是0、1、2、3或4;b、c、e、f和g各自独立地是0或1;d是0、1、2或3;X是S(O)n其中n是0、1或2;氧,羰基或-C(=N-氰基)-;Y是S(O)n其中n是0、1或2;或羰基;和Z是羰基,C(O)O-,C(O)NR-,其中R是氢或(C1-C6)烷基;或Z是S(O)n其中n是0、1或2;
R6、R7、R8、R9、R10和R11各自独立地选自下列的基团:氢或(C1-C6)烷基,其任选地被下列基团取代:氘,羟基,氨基,三氟甲基,(C1-C6)酰基氧,(C1-C6)酰基氨基,(C1-C6)烷基氨基,((C1-C6)烷基)2氨基,氰基,氰基(C1-C6)烷基,三氟甲基(C1-C6)烷基,硝基,硝基(C1-C6)烷基或(C1-C6)酰基氨基;
R12是(C6-C10)芳基,(C2-C9)杂芳基,(C3-C10)环烷基或(C2-C9)杂环烷基,其中芳基,杂芳基,环烷基和杂环烷基可任选地被1至4个下列基团取代:氢,氘,氨基,卤代,氧代,羟基,硝基,羧基,(C2-C6)链烯基,(C2-C6)炔基,三氟甲基,三氟甲氧基,(C1-C6)烷基,(C1-C6)烷氧基,(C3-C10)环烷基,(C1-C6)烷基-CO-NH-,(C1-C6)烷氧基-CO-NH-,(C1-C6)烷基-CO-NH-(C1-C6)烷基,(C1-C6)烷氧基-CO-NH-(C1-C6)烷基,(C1-C6)烷氧基-CO-NH-(C1-C6)烷氧基,羧基,羧基(C1-C6)烷基,羧基(C1-C6)烷氧基,苄氧基羰基(C1-C6)烷氧基,(C1-C6)烷氧基羰基(C1-C6)烷氧基,(C6-C10)芳基,氨基,氨基(C1-C6)烷基,(C1-C6)烷氧基羰基氨基,(C6-C10)芳基(C1-C6)烷氧基羰基氨基,(C1-C6)烷基氨基,((C1-C6)烷基)2氨基,(C1-C6)烷基氨基(C1-C6)烷基,((C1-C6)烷基)2氨基(C1-C6)烷基,羟基,(C1-C6)烷氧基,羧基,羧基(C1-C6)烷基,(C1-C6)烷氧基羰基,(C1-C6)烷氧基羰基(C1-C6)烷基,(C1-C6)烷氧基-CO-NH-,(C1-C6)烷基-CO-NH-,氰基,(C5-C9)杂环烷基,氨基-CO-NH-,(C1-C6)烷基氨基-CO-NH-,((C1-C6)烷基)2氨基-CO-NH-,(C6-C10)芳基氨基-CO-NH-,(C5-C9)杂芳基氨基-CO-NH-,(C1-C6)烷基氨基-CO-NH-(C1-C6)烷基,((C1-C6)烷基)2氨基-CO-NH-(C1-C6)烷基,(C6-C10)芳基氨基-CO-NH-(C1-C6)烷基,(C5-C9)杂芳基氨基-CO-NH-(C1-C6)烷基,(C1-C6)烷基氰基,(C1-C6)烷基羧基(C1-C6)烷氧基,(C1-C6)烷基羧基,磺酰氨基,氨基磺酰基,磺酰氨基(C1-C6)烷基,磺酰氨基羧基(C1-C6)烷基,(C1-C6)烷基磺酰基,(C1-C6)烷基磺酰氨基,(C1-C6)烷基磺酰氨基(C1-C6)烷基,(C6-C10)芳基磺酰基,(C6-C10)芳基磺酰氨基,(C6-C10)芳基磺酰氨基(C1-C6)烷基,(C1-C6)烷基磺酰氨基,(C1-C6)烷基磺酰氨基(C1-C6)烷基,(C3-C10)环烷基,(C3-C10)环烷氧基,(C1-C6)烷基氨基,((C1-C6)烷基)2氨基,(C6-C10)芳基氨基,(C1-C6)烷硫基,(C6-C10)芳硫基,(C1-C6)烷基亚磺酰基,(C6-C10)芳基亚磺酰基,(C1-C6)烷基磺酰基,(C6-C10)芳基磺酰基,(C1-C6)酰基,(C1-C6)烷氧基-CO-NH-,(C1-C6)烷基氨基-CO-,(C5-C9)杂芳基,(C2-C9)杂环烷基或(C6-C10)芳基,其中任选取代在R12的杂芳基,杂环烷基和芳基还可被1至3个下列的取代基取代:卤素,(C1-C6)烷基,(C1-C6)烷基-CO-NH-,(C1-C6)烷氧基-CO-NH-,(C1-C6)烷基-CO-NH-(C1-C6)烷基,(C1-C6)烷氧基-CO-NH-(C1-C6)烷基,(C1-C6)烷氧基-CO-NH-(C1-C6)烷氧基,羧基,羧基(C1-C6)烷基,羧基(C1-C6)烷氧基,苄氧基羰基(C1-C6)烷氧基,(C1-C6)烷氧基羰基(C1-C6)烷氧基,(C6-C10)芳基,氨基,氨基(C1-C6)烷基,(C1-C6)烷氧基羰基氨基,(C6-C10)芳基(C1-C6)烷氧基羰基氨基,(C1-C6)烷基氨基,((C1-C6)烷基)2氨基,(C1-C6)烷基氨基(C1-C6)烷基,((C1-C6)烷基)2氨基(C1-C6)烷基,羟基,(C1-C6)烷氧基,羧基,羧基(C1-C6)烷基,(C1-C6)烷氧基羰基,(C1-C6)烷氧基羰基(C1-C6)烷基,(C1-C6)烷氧基-CO-NH-,(C1-C6)烷基-CO-NH-,氰基,(C5-C9)杂环烷基,氨基-CO-NH-,(C1-C6)烷基氨基-CO-NH-,((C1-C6)烷基)2氨基-CO-NH-,(C6-C10)芳基氨基-CO-NH-,(C5-C9)杂芳基氨基-CO-NH-,(C1-C6)烷基氨基-CO-NH-(C1-C6)烷基,((C1-C6)烷基)2氨基-CO-NH-(C1-C6)烷基,(C6-C10)芳基氨基-CO-NH-(C1-C6)烷基,(C5-C9)杂芳基氨基-CO-NH-(C1-C6)烷基,(C1-C6)烷基磺酰基,(C1-C6)烷基磺酰基氨基,(C1-C6)烷基磺酰基氨基(C1-C6)烷基,(C6-C10)芳基磺酰基,(C6-C10)芳基磺酰基氨基,(C6-C10)芳基磺酰基氨基(C1-C6)烷基,(C1-C6)烷基磺酰基氨基,(C1-C6)烷基磺酰基氨基(C1-C6)烷基,(C5-C9)杂芳基和(C2-C9)杂环烷基;
R2和R3各自独立地选自下列这组基团:氢,氘,氨基,卤素,羟基,硝基,羧基,(C2-C6)链烯基,(C2-C6)炔基,三氟甲基,三氟甲氧基,(C1-C6)烷基,(C1-C6)烷氧基,(C3-C10)环烷基,其中烷基,烷氧基或环烷基可任选地被1至3个选自下列的基团取代:卤素,羟基,羧基,氨基(C1-C6)烷硫基,(C1-C6)烷基氨基,((C1-C6)烷基)2氨基,(C5-C9)杂芳基,(C2-C9)杂环烷基,(C3-C9)环烷基或(C6-C10)芳基;或者R2和R3各自独立地是(C3-C10)环烷基,(C3-C10)环烷氧基,(C1-C6)烷基氨基,((C1-C6)烷基)2氨基,(C6-C10)芳基氨基,(C1-C6)烷硫基,(C6-C10)芳硫基,(C1-C6)烷基亚磺酰基,(C6-C10)芳基亚磺酰基,(C1-C6)烷基磺酰基,(C6-C10)芳基磺酰基,(C1-C6)酰基,(C1-C6)烷氧基-CO-NH-,(C1-C6)烷基氨基-CO-,(C5-C9)杂芳基,(C2-C9)杂环烷基或(C6-C10)芳基,其中杂芳基、杂环烷基和芳基可任选地被下列1至3个基团取代:卤素,(C1-C6)烷基,(C1-C6)烷基-CO-NH-,(C1-C6)烷氧基-CO-NH-,(C1-C6)烷基-CO-NH-(C1-C6)烷基,(C1-C6)烷氧基-CO-NH-(C1-C6)烷基,(C1-C6)烷氧基-CO-NH-(C1-C6)烷氧基,羧基,羧基(C1-C6)烷基,羧基(C1-C6)烷氧基,苄氧基羰基(C1-C6)烷氧基,(C1-C6)烷氧基羰基(C1-C6)烷氧基,(C6-C10)芳基,氨基,氨基(C1-C6)烷基,(C1-C6)烷氧基羰基氨基,(C6-C10)芳基(C1-C6)烷氧基羰基氨基,(C1-C6)烷基氨基,((C1-C6)烷基)2氨基,(C1-C6)烷基氨基(C1-C6)烷基,((C1-C6)烷基)2氨基(C1-C6)烷基,羟基,(C1-C6)烷氧基,羧基,羧基(C1-C6)烷基,(C1-C6)烷氧基羰基,(C1-C6)烷氧基羰基(C1-C6)烷基,(C1-C6)烷氧基-CO-NH-,(C1-C6)烷基-CO-NH-,氰基,(C5-C9)杂环烷基,氨基-CO-NH-,(C1-C6)烷基氨基-CO-NH-,((C1-C6)烷基)2氨基-CO-NH-,(C6-C10)芳基氨基-CO-NH-,(C5-C9)杂芳基氨基-CO-NH-,(C1-C6)烷基氨基-CO-NH-(C1-C6)烷基,((C1-C6)烷基)2氨基-CO-NH-(C1-C6)烷基,(C6-C10)芳基氨基-CO-NH-(C1-C6)烷基,(C5-C9)杂芳基氨基-CO-NH-(C1-C6)烷基,(C1-C6)烷基磺酰基,(C1-C6)烷基磺酰基氨基,(C1-C6)烷基磺酰基氨基(C1-C6)烷基,(C6-C10)芳基磺酰基,(C6-C10)芳基磺酰基氨基,(C6-C10)芳基磺酰基氨基(C1-C6)烷基,(C1-C6)烷基磺酰基氨基,(C1-C6)烷基磺酰基氨基(C1-C6)烷基,(C5-C9)杂芳基或(C2-C9)杂环烷基;
条件是,R5必须被式II基团取代。
本发明还涉及式I化合物的药学上可接受的酸加成盐。用于制备本发明前述这些碱化合物的药学上可接受的酸加成盐的酸是那些形成无毒酸加成盐即含有药用阴离子的盐的酸,例如盐酸盐,氢溴酸盐,氢碘酸盐,硝酸盐,硫酸盐,硫酸氢盐,磷酸盐,酸式磷酸盐,乙酸盐,乳酸盐,柠檬酸盐,酸式檬酸盐,酒石酸盐,酒石酸氢盐,琥珀酸盐,马来酸盐,富马酸盐,葡糖酸盐,糖酸盐(saccharate),苯甲酸盐,甲磺酸盐,乙磺酸盐,苯磺酸盐,对甲苯磺酸盐和pamoate盐[即1,1′-亚甲基-双-(2-羟基-3-萘酸盐)]。
本发明还涉及式I的碱加成盐。可用作制备式I的那些性质上为酸性的化合物的药用碱式盐的反应试剂的化学碱,是那些与这些化合物形成无毒碱式盐的化学碱。这样的无毒碱式盐包括但不限于那些从药理学上可接受的阳离子如碱金属阳离子(例如钾和钠)和碱土金属阳离子(例如钙和镁)衍生的碱式盐,铵或水溶性胺加成盐如N-甲基葡糖胺-(麦格鲁明),以及低级烷醇铵和其它药学上可接受的有机胺的碱式盐。
术语“Oxone”是用于本发明中的单过硫酸盐化合物的名称,其化学式是2KHSO5·KHSO4·K2SO4,售自Aldrich Chemical Company,P.O.Box 2060,Milwaukee,WI 53201,USA。
本文中的“烷基”,除非另有说明,包括具有直链或支链或其组合部分的饱和的一价烃基。
本文中的“烷氧基”包括O-烷基,其中“烷基”的定义如上。
本文中的“卤代”,除非另有说明,包括氟代,氯代,溴代或碘代。
本发明化合物可含有双键。当存在这样的键时,本发明化合物以顺式和反式异构体及它们的混合物形式存在。
除非另有说明,本文中所用的烷基和链烯基,以及本文中所用的其它基团(如烷氧基)中的烷基部分,可以是直链或支链的,并且它们还可以是环状的(如,环丙基,环丁基,环戊基,环己基或环庚基)或者是直链或支链的并且含有环部分。除非另有说明,卤素包括氟,氯,溴和碘。
本文中所用的(C2-C9)杂环烷基,是指吡咯烷基,四氢呋喃基,二氢呋喃基,四氢吡喃基,吡喃基,硫代吡喃基,吖丙啶基(aziridinyl),环氧乙烷基(oxiranyl),环亚甲基二氧基(methylenedioxyl),苯并吡喃基(chromenyl),异噁唑烷基,1,3-噁唑烷-3基,异噻唑烷基,1,3-噻唑烷-3-基,1,2-吡唑烷-2-基,1,3-吡唑烷-1-基,哌啶基,硫代吗啉基,1,2-四氢噻嗪-2-基,1,3-四氢噻嗪-3-基,四氢噻二嗪基,吗啉基,1,2-四氢二嗪-2-基,1,3-四氢二嗪-1-基,四氢氮杂卓基(azepinyl),哌嗪基,苯并二氢吡喃基,等等。所述的(C2-C9)杂环烷基环是通过碳原子或sp3杂化的氮杂原子连接,这是本领域普通技术人员都能理解的。
本文中所用的(C2-C9)杂芳基是指呋喃基,噻吩基,噻唑基,吡唑基,异噻唑基,唑基,异噁唑基,吡咯基,三唑基,四唑基,咪唑基,1,3,5-二唑基,1,2,4-噁二唑基,1,2,3-噁二唑基,1,3,5-噻二唑基,1,2,3-噻二唑基,1,2,4-噻二唑基,吡啶基,嘧啶基,吡嗪基,哒嗪基,1,2,4-三嗪基,1,2,3-三嗪基,1,3,5-三嗪基,吡唑并[3,4-b]吡啶基,噌啉基,喋啶基,嘌吟基,6,7-二氢-5H-[1]吡啶基,苯并[b]硫代苯基,5,6,7,8-四氢-喹啉-3-基,苯并噁唑基,苯并噻唑基,苯并异噻唑基,苯并异噁唑基,苯并咪唑基,硫茚基,异硫茚基,苯并呋喃基,异苯并呋喃基,异吲哚基,吲哚基,中氮茚基,引唑基,异喹啉基,喹啉基,2,3-二氮杂萘基,喹喔啉基,喹唑啉基,苯并噁嗪基,等等。所述的(C2-C9)杂芳基是通过碳原子或sp3杂化的氮杂原子连接,这是本领域普通技术人员都能理解的。
本文中所用的(C6-C10)芳基是指苯基或萘基。
式(I)化合物可以按药用可接受的形式单独或与另外的一种或多种调节哺乳动物免疫系统的药剂或与抗炎剂联合给药。这些药剂包括但不限于环孢菌素A(如Sandimmune或Neoral),雷怕霉素(rapamycin),FK-506(tacrolimus),来氟米物(leflunomide),脱氧精胍菌素(deoxyspergualin),麦考酚酸酯(mycophenolate)(如Cellcept),硫唑嘌呤(azathioprine)(如Imuran),daclizumab(如Zenapax),OKT3(如Orthoclone),AtGam,阿斯匹林,乙酰氨基苯酚,布洛芬(ibuprofen),萘普生(naproxen),吡罗昔康(piroxicam),以及抗炎类固醇(如泼尼松龙(prednisolone)或地塞米松(dexamethasone))。这些药剂可以根据标准的用药方式、以相同剂型的一部分或不同的剂型形式、通过相同或不同的给药途径、按照相同或不同的时间安排给药。
本发明化合物包括所有的构型异构体(如顺式和反式异构体)。本发明化合物具有非对称中心,因而存在不同的对映体和非对映体。本发明涉及所有这些本发明化合物的光学异构体和立体异构体及它们的混合物的用途,以及涉及所有使用它们或包含它们的药物组合物和方法。从这方面而言,本发明包括E和Z两种构型。式I化合物也可以以互变异构体的形式存在。本发明还涉及所有这些互变异构体及它们的混合物的用途。
本发明还包括含有式I化合物的前药(prodrug)的药物组合物。本发明也包括治疗或预防那些能用蛋白激酶抑制剂治疗或预防的疾病的方法,该蛋白激酶抑制剂就如酶Janus Kinase 3,该方法包括服用式I化合物的药物前体。具有游离的氨基、酰氨基、羟基或羧基的式I化合物可以转化成药物前体。药物前体包括这样一些化合物即其中氨基酸残基或二种或多种(如二、三、或四种)氨基酸残基的多肽链通过肽键共价结合到式I化合物的游离氨基、羟基或羧酸基团上的一些化合物。该氨基酸残基包括通常用三个字符表示的20种天然存在的氨基酸,也包括4-羟基脯氨酸,羟基赖氨酸,demosine,isodemosine,3-甲基组氨酸,缬氨酸(norvlin),β-丙氨酸,γ-氨基丁酸,氨基甲酰鸟氨酸(citrulline),高半胱氨酸,高丝氨酸,鸟氨酸(omithine)和蛋氨酸砜。药物前体也包括这样的一些化合物即其中碳酸酯、氨基甲酸酯、酰胺和烷基酯都是通过药物前体侧链的羰基碳共价结合到式I化合物中上述取代基的一些化合物。
式I优选的化合物包括其中R5是任选地被一个至三个选自氘,羟基,(C1-C6)烷基,卤素,(C1-C6)烷氧基和式II的基团取代的(C2-C9)杂环烷基的那些化合物。
式I的其它优选的化合物包括那些其中a是0;b是1;X是羰基;c是0;d是0;e是0;f是0;g是0的化合物。
式I的其它优选的化合物包括那些其中a是0;b是1;X是羰基;c是0;d是1;e是0;f是0;g是0的化合物。
式I的其它优选的化合物包括那些其中a是0;b是1;X是羰基;c是1;d是0;e是0;f是0;g是0的化合物。
式I的其它优选的化合物包括那些其中a是0;b是1;X是-C(=N=氰基)-;c是1;d是0;e是0;f是0;g是0的化合物。
式I的其它优选的化合物包括那些其中a是0;b是0;c是0;d是0;e是0;f是0;g是1;Z是-C(O)-O-的化合物。
式I的其它优选的化合物包括那些其中a是0;b是1;X是S(O)n;n是2;c是0;d是0;e是0;f是0;g是0的化合物。
式I的其它优选的化合物包括那些其中a是0;b是1;X是S(O)n;n是2;c是0;d是2;e是0;f是1;g是1;Z是羰基的化合物。
式I的其它优选的化合物包括那些其中a是0;b是1;X是S(O)n;n是2;c是0;d是2;e是0;f是1;g是0的化合物。
式I的其它优选的化合物包括那些其中a是0;b是1;X是羰基;c是1;d是0;e是1;Y是S(O)n;n是2;f是0;g是0的化合物。
式I的其它优选的化合物包括那些其中a是0;b是1;X是S(O)n;n是2;c是1;d是0;e是0;f是0;g是0的化合物。
式I的其它优选的化合物包括那些其中a是1;b是1;X是羰基;c是1;d是0;e是0;f是0;g是0的化合物。
式I的其它优选的化合物包括那些其中a是0;b是1;X是S(O)n;c是0;d是1;e是1;Y是S(O)n;n是2;f是0;g是0的化合物。
式I的其它优选的化合物包括那些其中a是0;b是1;X是S(O)n;c是0;d是1;e是1;Y是S(O)n;n是2;f是1;g是0化合物。
式I的其它优选的化合物包括那些其中a是0;b是1;X是氧;c是0;d是1;e是1;Y是S(O)n;n是2;f是1;g是0的化合物。
式I的其它优选的化合物包括那些其中a是0;b是1;X是氧;c是0;d是1;e是1;Y是S(O)n;n是2;f是0;g是0的化合物。
式I的其它优选的化合物包括那些其中a是0;b是1;X是羰基;c是1;d是1;e是1;Y是S(O)n;n是2;f是0;g是0的化合物。
式I的其它优选的化合物包括那些其中a是0;b是1;X是羰基;c是1;d是1;e是1;Y是S(O)n;n是2;f是1;g是0的化合物。
式I的其它优选的化合物包括那些其中R12是(C6-C10)芳基或(C2-C9)杂芳基的化合物,其中该芳基或杂芳基任选地被一个至四个选自以下的基团取代:氢,卤素,羟基,羧基,三氟甲基,(C1-C6)烷基,(C1-C6)烷氧基,(C1-C6)烷基-CO-NH-,氨基,氨基(C1-C6)烷基,(C1-C6)烷基氨基,((C1-C6)烷基)2氨基,氰基,氨基-CO-NH-,(C1-C6)烷基氨基-CO-NH-,((C1-C6)烷基)2氨基-CO-NH-,(C5-C9)杂芳基氨基-CO-NH-,(C1-C6)烷基磺酰基,(C1-C6)烷基磺酰基氨基,(C6-C10)芳基磺酰基氨基,(C1-C6)烷基磺酰基氨基和(C1-C6)烷氧基-CO-NH-。
式I的具体优选的化合物包括那些选自下列这组的化合物:
4-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基甲基}-苯磺酰胺;
4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(4-氨磺酰基-苯基)-酰胺;
4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(4-硝基-苯基)-酰胺;
-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-2-四唑-1-基-乙酮(ethanone);
4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(4-甲基氨磺酰基-苯基)-酰胺;
(3-羟基-吡咯烷-1-基)-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-甲酮(methanone);
[2-({4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羰基}-氨基)-噻唑-4-基]-乙酸;
甲基-(4-甲基-5′-硝基-3,4,5,6-四氢-2H-[1,2′]联吡啶-3-基)-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺;
5-(2-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-2-氧-乙基)-噻唑烷-2,4-二酮;
{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-噻唑烷-3-基-甲酮;
甲基-[4-甲基-1-(5-硝基-噻唑-2-基)-哌啶-3-基]-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺;
[2-({4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羰基}-氨基)-噻唑-4-基]-乙酸乙基酯;
4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(4-甲磺酰基-苯基)-酰胺;
4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸噻唑-2-基酰胺;
4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(4-氰基-苯基)-酰胺;
{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-吡咯烷-1-基-甲酮;
呋喃-2-羧酸(2-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-磺酰基}-乙基)-酰胺;
{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}(四氢-呋喃-3-基)-甲酮;
4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸异噁唑-3-基酰胺;
4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(6-氰基-吡啶-3-基)-酰胺;
4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-3,4,5,6-四氢-2H-[1,2′]联吡啶基-5′-腈
4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(4-甲基-噻唑-2-基)-酰胺;
2-环丙基-1-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-乙酮;
环戊基-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-甲酮;
4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(3-甲基-异噁唑-4-基)-酰胺;
[4-({4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羰基}-氨基)-苯基]-乙酸;
[1-(5-氨基-噻唑-2-基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺;
4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(3-甲基-异噻唑-5-基)-酰胺;
3-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羰基}-环戊酮;
4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸苄基-甲基-酰胺;和
4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸二甲基酰胺。
本发明还涉及一种药物组合物,用于(a)治疗或预防哺乳动物包括人的下列疾病或症状:该病症选自器官移植排斥、移植排异、狼疮、多发性硬化、类风湿关节炎、牛皮癣、I型糖尿病和糖尿病并发症、癌症、哮喘、特应性皮肤病、自体免疫性甲状腺病、溃疡性结肠炎、Crohn病、阿尔茨海默病、白血病和其它自体免疫性疾病,或(b)抑制哺乳动物包括人的蛋白激酶或Janus Kinase 3(JAK3),该药物组合物含有对所述疾病或症状有效的一定量的式I化合物或其药学上可接受的盐和药学上可接受的载体。
本发明还涉及一种抑制哺乳动物包括人的蛋白酪氨酸激酶或JanusKinase 3(JAK3)的方法,包括给所述的哺乳动物服用有效量的式I化合物或其药学上可接受的盐。
本发明还涉及一种治疗或预防哺乳动物包括人的下列疾病或症状的方法,该疾病或症状选自器官移植排斥、移植排异、狼疮、多发性硬化、类风湿关节炎、牛皮癣、I型糖尿病和糖尿病并发症、癌症、哮喘、特应性皮肤病、自体免疫性甲状腺病、溃疡性结肠炎、Crohn病、阿尔茨海默病、白血病和其它自体免疫性疾病,该方法包括给所述哺乳动物服用对治疗这些疾病有效的一定量的式I化合物或其药学上可接受的盐。
发明详述
下列反应方案解释了本发明化合物的制备过程。在该反应方案和随后讨论中的R2、R3、R4和R5定义如上,除非另有说明。
在制备A的反应1中,R为氢或如苯磺酰基或甲苯基保护基的式XXI 4-氯吡咯并[2,3-d]嘧啶化合物,通过将式XXI化合物与N-氯代琥珀酸亚胺、N-溴代琥珀酸亚胺或N-碘代琥珀酸亚胺反应,转化为其中Y是氯、溴、或碘的式XX的4-氯-5-卤代吡咯并[2,3-d]嘧啶化合物。该反应混合物在氯仿中加热回流约1小时至约3小时,优选约1小时。或者,在制备A的反应1中,R为氢的式XXI的4-氯吡咯并[2,3-d]嘧啶化合物,通过将XXI化合物与硝酸反应,转化为相应的其中Y是硝基的XX的4-氯-5-硝基吡咯并[2,3-d]嘧啶,该反应在约-10℃至约10℃的温度,优选约0℃下在硫酸中进行,反应时间为约5分钟至约15分钟,优选约10分钟。Y是硝基的式XXI化合物转化为相应的Y为氨基的式XX的4-氯-5-氨基吡咯并[2,3-d]嘧啶化合物,XXI转化成XX的反应是在本领域技术人员已知的多种条件下进行,例如钯氢解或用氯化锡(IV)和盐酸。
在制备A的反应2中,其中R是氢的式XX的4-氯-5-卤代吡咯并[2,3-d]嘧啶化合物,通过将XX用N-丁基锂处理,转化为相应的其中R2是(C1-C6)烷基或苄基的XIX化合物,该反应在约-78℃下进行,并且将由此形成的二阴离子中间体在温度约-78℃至室温下,优选在室温下,与烷基卤化物或苄基卤化物反应。或者,由此形成的二阴离子化合物与分子氧反应,生成相应的R2为羟基的式XIX的4-氯-5-羟基吡咯并[2,3-d]嘧啶化合物。Y是溴或碘且R是苯磺酸根的式XX化合物,在约-78℃下通过用N-丁基锂对其进行处理,接着在约-78℃下加氯化锌,转化为式XIX化合物,其中R2是(C6-C12)的芳基或乙烯基。然后使由此形成的该相应的有机锌中间体在催化量的钯存在下与芳基碘或乙烯基碘反应。将该反应混合物在约50℃至约80℃,优选约70℃下,搅拌约1至约3小时,优选约1小时。
在制备A的反应3中,式XIX化合物在极性非质子溶剂如四氢呋喃的存在下,在约-78℃的温度下,用N-丁基锂、二异丙基胺锂或氢化钠处理,转化为相应的式XVI化合物。由此形成的阴离子中间体再经以下的(a)、(b)、和(c)反应:(a)当R3是烷基或苄基时,在约-78℃至室温,优选-78℃下,与烷基卤化物或苄基卤化物反应;(b)当R3是烷氧基时,在约-78℃至室温,优选-78℃下,与醛或酮反应;和(c)在约-78℃至室温,优选-78℃下,与氯化锌反应,以及然后将由上述反应形成的相应的有机锌中间体在催化量的钯存在下与芳基碘或乙烯基碘反应。将生成的该反应混合物在约50℃至约80℃,优选约70℃下,搅拌约1至约3小时,优选约1小时。或者,使由此形成的阴离子与分子氧反应生成相应的R3是羟基的式XVI4-氯-6-羟基吡咯并[2,3-d]嘧啶化合物。
在制备B的反应1中,式XXI的4-氯吡咯并[2,3-d]嘧啶化合物,按照与上述制备A的反应3相类似的方法,转化为相应的式XXII化合物。
在制备B的反应2中,式XXII的化合物,按照与上述制备A的反应1和2相类似的方法,转化为相应的式XVI化合物。
在制备C的反应1中,式XXXI的4-甲基吡啶化合物在极性非质子溶剂如丙酮的存在下通过与苄基氯化物首先进行烷基化反应而转化为相应的式XXX化合物。将此反应混合物在约40℃至约80℃下搅拌约4至约24小时。然后使由此形成的吡啶鎓中间体在极性质子溶剂如甲醇、乙醇、水或它们的混合物存在下被还原剂如硼氢化钠还原。将该反应在约0℃至约室温下搅拌约18至24小时。
在制备C的反应2中,式XXX化合物在还原剂和非质子溶剂如四氢呋喃的存在下通过用三氟化硼醚合物处理XXX而转化为相应的式XXIX化合物。将此反应混合物在约0℃至室温下搅拌约1至约3小时。然后将由此形成的中间体复合物在约0℃至室温下用含水氢氧化钠碱化并再用氧化剂如过氧化氢或Oxone处理约12至24小时。
在制备C的反应3中,式XXIX化合物在环境温度下用氧化剂处理约1至3小时,该氧化剂是例如氧化铬或二甲基砜、草酰氯或SO3-吡啶络合物。然后将由此形成的酮中间体在酸如乙酸存在下,在约室温下,在有机溶剂如甲醇、乙醇或四氢呋喃中,用胺(R4-NH2)处理约2至约24小时。然后将由此形成的相应的亚胺中间体在环境温度下用还原剂如硼氢化钠或氰基硼氢化钠或三乙酰氧基硼氢化钠处理约2至约24小时。
在反应方案1的反应1中,式XVII的4-氯吡咯并[2,3-d]嘧啶化合物在碱如氢化钠或碳酸钾和极性非质子溶剂如二甲基甲酰胺或四氢呋喃存在下,用苯磺酰氯、苄基氯或苄基溴处理XVII,从而使其转化为相应的式XVI化合物,式中的R是苯磺酰基或苄基。将该反应混合物在约0℃至约70℃,优选约30℃下搅拌约1至约3小时,优选约2小时。
在反应方案1的反应2中,式XVI的4-氯代吡咯并[2,3-d]嘧啶化合物与式HNR4R5的胺偶联,转化为相应的式XV的4-氨基吡咯并[2,3-d]嘧啶化合物。该反应是在醇溶剂或其它高沸点的有机溶剂中进行,醇溶剂如叔丁醇、甲醇或乙醇,其它高沸点的有机溶剂如二甲基甲酰胺、三乙胺、1,4-二噁烷或1,2-二氯乙烷,反应温度为约60℃至约120℃,优选约80℃,通常的反应时间为约2小时至约48小时,优选约16小时。当R5是含氮的杂环烷基时,每个氮必须被保护基如苄基保护。R5保护基的除去要在适合于特定保护基的条件下进行,该条件使所用的R保护基不会对吡咯并[2,3-d]嘧啶环产生影响。用苄基时该R5保护基的除去是在氢和催化剂如氢氧化钯/碳存在下在溶剂如乙醇中进行。由此生成的R5含氮的杂环烷基可进一步与式II各种不同的亲电子试剂反应。对于生成尿素来说,将式II的亲电子试剂如异氰酸酯、氨基甲酸酯和氨基甲酰基氯在溶剂中,如在乙腈或二甲基甲酰胺中,在碱如碳酸钠或钾的存在下,在约20℃至约100℃的温度下,与该R5杂环烷基的氮反应,反应时间约24小时至约72小时。对于生成酰胺和磺酰胺来说,将式II的亲电子试剂如酰氯和磺酰氯在如二氯甲烷那样的溶剂中,在碱如吡啶存在下,在环境温度下,与该R5杂环烷基的氮反应,反应时间约12小时至约24小时。酰胺的生成也可以通过将羧酸在碳二酰亚胺如1-(3-二甲基氨基丙基)-3-乙基碳二酰亚胺在溶剂如二氯甲烷中,在环境温度下,与该杂烷基进行反应,反应时间为12-24小时。对于烷基的形成方法,是将诸如α,β-不饱和的酰胺、酸、氰、酯和α-卤代酰胺这样的式II亲电子试剂在一种溶剂如甲醇中,在环境温度下,与R5杂烷基的氮反应,反应时间为约12小时至约18小时。烷基的形成也可以是通过使醛在一种还原剂如氰基硼氢化钠存在下,在一种溶剂如甲醇中,在环境温度下,与该杂烷基反应,反应时间约12小时至约18小时。
在反应方案1的反应3中,从R为苯磺酰基的式XV化合物中除去保护基以得到相应的式I化合物的反应是这样进行的,即用一种强碱(alkalibase)如氢氧化钠或氢氧化钾,在一种醇溶剂如甲醇或乙醇或混合溶剂如乙醇/四氢呋喃或乙醇/水中,处理该式XV化合物。该反应在室温下进行约15分钟至约1小时,优选为30分钟。从R为苄基的式XV化合物中除去保护基,是在氨水中用钠在约-78℃的温度下,对该式XV进行处理,该反应的时间为约15分钟至约1小时。
在反应方案2的反应1中,是按照类似于上述反应方案1的反应2的方法使该式XX的4-氯代吡咯并[2,3-d]嘧啶化合物转化为相应的式XXIV的4-氨基吡咯并[2,3-d]嘧啶化合物。
在反应方案2的反应2中,R为苯磺酰基且Z为溴或碘的式XXIV的4-氨基-5-氯代吡咯并[2,3-d]嘧啶化合物通过使XXIV进行以下(a)、(b)和(c)反应转化为相应的式XXIII化合物:(a)当R2是芳基时,则在一种非极性溶剂如四氢呋喃或二烷中,在催化量的钯(O)存在下,在约50℃至约100℃,优选约70℃的温度下,与芳基硼酸反应约2小时至约48小时,优选约12小时;(b)当R2是炔基时,则在催化量的碘化铜(I)和钯(O)以及一种极性溶剂如二甲基甲酰胺存在下,在室温下,与炔烃反应约1小时至约5小时,优选约3小时;和(c)当R2是乙烯基或苯乙烯基时,则在催化量的在二甲基甲酰胺、二噁烷或四氢呋喃中的钯存在下,在约80℃至约100℃,优选约100℃的温度下,与烯烃或苯乙烯反应约2小时至约48小时,优选约48小时。
在反应方案2的反应3中,按照与上述制备A的反应3中相类似的方法将式XXIII化合物转化为相应的式XV化合物。
在反应方案3的反应1中,按照与上述反应方案1的反应2中相类似的方法将式XXII化合物转化为相应的式I化合物。
本发明的化合物本质上是碱性,能与多种无机和有机酸形成很多种类不同的盐。这些盐对于给动物服用虽然必须是药学上可以接受的,但在实践中总是将起初从该反应混合物中分离的本发明化合物作为药学上不可接受的盐,然后用碱性试剂处理使该盐简单地转变回到游离碱化合物状态,接着将该游离碱转化为药学上可接受的酸加成盐。本发明的这种碱性化合物的酸加成盐是容易制备的,它是用一种基本上等当量的所选定的无机或有机酸在一种含水溶剂培养基中或在一种合适的有机溶剂如甲醇或乙醇中处理该碱式化合物,在小心地蒸发掉溶剂后,就容易地得到了所需的这种固体盐。该酸加成盐也可以在一种有机溶剂中加一种相应的无机酸或有机酸而将它从该溶液中沉淀出来。
本发明的那些本质上为酸性的化合物能与多种药学上可接受的阳离子形成碱式盐。这种盐的例子包括碱金属或碱土金属的盐,特别是钠和钾盐。这些盐均可用常规的方法制备。用于制备本发明药学上可接受的碱式盐的反应试剂的化学碱是与本发明的酸性化合物形成无毒碱式盐的那些。这种无毒碱式盐包括从这样的药学上可接受的阳离子衍生的那些,该阳离子如钠、钾、钙和镁等。将相应的酸性化合物用含所需的药学上可接受阳离子的水溶液处理,然后将所得溶液蒸干,优选在减压下蒸干就可容易地制得这些盐。或者,它们也可以用另一种方法制备,即:将该酸性化合物的低级链烷醇的溶液与所需的碱金属醇盐一起混合,然后将所得的溶液用前述相同方法蒸干。在每种情况下均优选采用化学计量量的反应试剂以保证完全反应和获得所需最终产物的最大收率。
本发明的组合物可以按传统方式使用一种或多种药学上可接受的载体来配制。因此可将本发明的活性化全物配制成口服、颊、鼻内、肠胃外(如静脉内、肌内或皮下)或直肠给药形式或者配制成适合于吸入或吹入方法给药的剂型。本发明的活性化合物也可配成缓释形式。
口服给药的药物组合物可以采用的剂型有如片剂或胶囊,它们是通过常规的方法用药学上可接受的赋型剂如粘结剂(如,预凝胶的玉米沉粉、聚乙烯吡咯烷酮或羟丙基甲基纤维素);填料(如,乳糖、微晶纤维素或磷酸钙);润滑剂(如硬酯酸镁、滑石或二氧化硅);崩解剂(如土豆沉粉或羟基乙酸淀粉钠);或湿润剂(如十二烷基硫酸钠)。片剂可以用现有技术中众所周知的方法将其包衣。口服液体制剂采用的剂型可以是溶液、糖浆或混悬剂,或者它们可以以一种干品的形式存在,使用前再与水或其它合适的载体兑勾。这样的液体制剂可以通过常规的方法用药学上可接受的添加剂来制备,如用悬浮剂(如山梨醇糖浆、甲基纤维素或氢化食用脂);乳化剂(如卵磷脂或阿拉伯胶(acacia));非水载体(如杏仁油、油性酯或乙醇);以及防腐剂(如,对羟基苯甲酸甲酯或丙酯或山梨酸)。
颊给药用的组合物,可采用的剂型是用常规方法配制的片剂或糖锭。
可将本发明的活性化合物配制成注射用的肠胃外给药的型式,例如用通常的导管插入术或输液方法进行注射给药。注射用的剂型可以是单位剂量的形式,如在安瓿中或多剂量的容器中,加有防腐剂。该药物组合物可采用的剂型有在油性或水性载体中的混悬剂、溶液剂或乳液剂等,并且可包含配制剂如悬浮剂、稳定剂和/或分散剂。或者,该活性组合物可以是在使用之前用合适的载体如高温灭菌水重新再配制的粉剂。
本发明的活性化合物也可配制成直肠用的药物组合物,例如栓剂或停留灌肠剂,如含有可可脂或其它甘油酯的常用栓剂基料。
用于鼻内给药或通过吸入给药,一般是将本发明活性化合物的溶液或混悬液剂型从泵喷雾的容器中由患者挤压或者以气溶胶喷雾形式从压力容器或喷雾器中泵送出,其中可适当用一种推进剂如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其它合适的气体。在加压气溶胶的情况下,剂量单位可以由输送一定计量的活塞来确定。加压容器或喷雾器可含有本发明活性化合物的溶液或混悬液。含本发明化合物和合适的粉状基料如乳糖或淀粉等的粉末混合物可配制成在吸入器或吹入器中用的胶囊或药筒(cartridge)(例如,由凝胶制成的)。
本发明活性化合物用于治疗平均的成年人上述疾病(如类风湿关节炎)的口服、非肠胃或颊给药的推荐剂量是例如每单位剂量的活性组分为0.1-1000mg,可按每天1-4次服用。
用于治疗平均的成年人上述疾病(如哮喘)的气溶胶制剂的剂量范围优选是每计量剂量或每“吹”一次气溶胶其中含20μg-1000μg的本发明化合物。用气溶胶的每天总剂量在0.1mg-1000mg范围内。可以是每天分几次用,例如2、3、4或8次,每次1、2或3个剂量。
式(I)化合物可以药学上可接受的形式单独服用或与一种或多种其它调节哺乳动物免疫系统的药剂或与抗炎药剂联合服用。其中所述的药剂包括但不限于环孢菌素A(如Sandimmune或Neoral,雷怕霉素,FK-506(藤霉素),Leflunomide,deoxyspergualin,霉酚酸盐(mycophnolate)(如Cellcept),硫唑嘌呤(如Imuran),daclizumab(如Zenapax),OKT3(如Orthocolone),AtGam,阿司匹林,acctamincphen,布洛芬,naproxen,吡罗昔康和抗炎性类固醇(如泼尼松龙或地塞米松);并且这些药剂可以按照标准的用药实践经相同或不同的服药途径以及以相同或不同的用药方案作为相同剂型的一部分或不同剂型来服用。
FK506(藤霉素)的口服是在手术后的头48小时内每12小时服用0.10-0.15mg/Kg体重。这必须用血清中藤霉素含量来监控。
环孢霉素A(Sandimmune的口服或静脉内制剂,或者Neoral,口服溶液或胶囊)的口服是在手术后的48小时内每12小时服用5mg/Kg体重。这必须用血清中Cyclosporin A含量来监控。
这些活性药剂可以按本领域技术人员已知的方法将它们配制成缓释制剂。这些制剂的例子可在US 3538214、4060598、4173626、3119742和3492397中找到。
式(I)化合物或它们药学上可接受的盐抑制Janus Kinase 3的能力以及由此证明它们治疗以Janus Kinase 3为特征的疾病的有效性,通过以下体外分析试验表示。
生物学测定
JAK3(JH1:GST)酶的测定
JAK3激酶测定是利用一种表达在经谷胱甘肽—琼脂糖凝胶亲和层析而纯化的杆状病毒感染的SF9细胞(一种GST和人JAK3的催化功能域的融合蛋白质)的蛋白质中。该反应的底物是聚-谷氨酸-酪氨酸(PGT(4∶1),Sigmacatalog#P0275),用100μg/ml的浓度将其涂在Nunc Maxi Sorp板上,在37℃下过夜。涂层后的早上将板清洗三次并将JAK3加到含100μl激酶缓冲液(50mM HEPES,pH7.3,125mM NaCl,24mM MgCl2+0.2μM ATP+1mM原钒酸钠)的每个孔中。该反应在室温下进行30分钟并清洗该板三次以上。用抗磷酸酪氨酸抗体(ICN PY20,Cat.#69-151-1)经标准的ELISA分析来定量在指定孔中的磷酸化酪氨酸的含量。
人IL-2依赖性T细胞胚增殖的抑制
这种筛选测定了化合物对体外IL-2依赖性T细胞胚增殖的抑制作用。由于通过IL-2受体传送信号需要JAK-3,所以JAK-3的细胞活性抑制剂应抑制IL-2依赖性T细胞胚增殖。
用于本测试的细胞是从新鲜的人血中分离出来的。在用AccuspinSystem-Histopaque-1077(Sigma#A7054)分离单核细胞之后,用Lympho-Kwik T(One Lambda,Inc.,Cat#LK-50T)经负选分离出初生的人T-细胞。T-细胞以1-2×106/ml的浓度在培养基(RPMI+10%热灭活的胎牛血清(Hyclone Cat#A-1111-L)+1%青霉素/链霉素(Gibco))中培养,并通过加10μg/ml PHA(Murex Diagnostics,Cat#HA 16)诱导增殖。在5%CO2中37℃下三天之后,细胞在培养基中清洗三次,再混悬至密度1-2X106细胞/ml的培养基和100单位/ml的人重组IL-2(R&D体系,Cat#202-IL)。一星期后,该细胞成为IL-2依赖性的并通过每周加两次等体积的培养基+100单位/mlIL-2,使该细胞保持3周。
为检测受试化合物抑制IL-2依赖性T细胞增殖的能力,将IL-2依赖性细胞清洗3次,再混悬在培养基中,然后置于平底96孔微量滴定板中(Falcon#353075)。将在DMSO中的原试验化合物从10 mM连续稀释2倍,将其加在10μM开始的三个孔中。一小时之后,将10单位/ml的IL-2加到每个试验孔中。然后将这些板在37℃、5%CO2中保温72小时。然后用3H-胸苷(0.5μCi/孔)(NEN Cat#NET-027A)对板加脉冲,再保温18小时。然后用96孔板的采集器采集该培养板,并在Packard Top Count闪烁计数器上计数测定加入到增殖细胞中3H-胸苷的量。将增殖抑制的百分数%对试验化合物浓度作图。从该图确定IC50值(μM)。
以下实施例说明本发明化合物的制备,但本发明并不限于实施例的细节。所用的工业纯试剂未加进一步纯化。THF是四氢呋喃。DMF是N,N-二甲基甲酰胺。采用化学电离(铵)的Hewlett Packard 5989,或者用50/50的乙腈/水混合物与0.1%甲酸作为电离剂的电离场Fisons(或MicroMass)Atmospheric Pressure Chemical Ionization(APCI),记录低分辨率质谱。室温或环境温度为20-25℃。
实施例1
呋喃-2-基-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-
哌啶-1-基}-甲酮方法A1-苄基-4-甲基-吡啶鎓氯化物
向4-甲基吡啶(26ml/0.268mol)在70ml丙酮中的搅拌溶液中加31ml(0.286mol)苯甲基氯。将所得混合物在50℃下搅拌18小时。冷却至室温后,过滤,用丙酮清洗并在减压下干燥得到38g标题化合物。滤液在减压下浓缩生成另外的5.6克标题化合物(74%合并的产率)。
LRMS:184。方法B1-苄基-4-甲基-1,2,3,6-四氢-吡啶
向溶解在0℃下140mL 10∶1的乙醇/水中的方法A产物(38克/0.171mol)的搅拌溶液中在25分钟内分批加16克(0.427mol)硼氢化钠。将所得混合物在室温下搅拌18小时,在此期间加100mL水猝灭反应。将反应混合物过滤,滤饼用水和乙酸乙酯清洗,并将合并的滤液在减压下浓缩除去有机物。残余物用水(100mL)稀释,用150mL乙酸乙酯萃取。萃取物经Na2SO4干燥并在真空下浓缩至干,得到32克(100%)标题化合物为黄色的油。
LRMS:188(M+1)。方法C1-苄基-4-甲基-吡啶-3-醇
向溶解在240mL THF中的方法B产物(72.45g/0.387mol)的溶液中加21.4g NaBH4,将该混合物冷却到0℃,然后在1.5小时内滴加三氟化硼醚合物溶液(109.4mL溶解在200mLTHF中)。添加时该反应混合物就达到室温,搅拌2小时。再将反应冷却到0℃并在15分钟内滴加29.3mL水,接着在20分钟内滴加2N氢氧化钠(97.5mL)。将所得混合物在0℃下搅拌40分钟,然后使其达到室温。将过氧化氢(30%)(97.5mL)以不使反应混合物超过50℃的速度滴加(大约30分钟)。加完时搅拌该反应混合物10分钟后冷却至0℃。用5分钟时间加浓盐酸(97.5mL),在真空下使反应混合物的体积减少到它原来的三分之一,并用6N的氢氧化钠将pH调节到9-10。所得混合物用醚萃取三次,合并的醚层经MgSO4干燥,真空蒸干,得到65.32g(79%)标题化合物为黄色的油。
LRMS:206.1(M+1)
另一种方法:向室温和N2下THF(150mL)中的方法B产物(18.7g/0.1mol)的溶液中加NaBH4(6.5g/0.170mol)。将此浆状物冷却到0℃,并通过加液漏斗缓慢加入BF3-OEt2(15mL,16.8g/0.118mol)的THF(25mL)溶液。该加入速度要足够缓慢使得反应混合物的温度一直保持在0℃以下。加完之后,将该反应混合物在0℃下搅拌1小时以及在室温下1.5小时。使反应再冷却到0℃并缓慢加水(50mL)以破坏过量的硼烷。将该反应在室温下搅拌2小时,接着在0℃下加入Oxone(110g/0.343mol)的水(500mL)溶液。使反应混合物温热到室温并搅拌过夜。加固体的NaHSO3直到所有过量的氧化剂被破坏(KI/淀粉试纸)时猝灭反应。该反应混合物的pH为1-2。然后用50mL乙酸乙酯萃取该反应混合物三次,用6N氢氧化钠将水层的pH调节到12并用乙酸乙酯萃取(4次,100mL)。有机层用盐水清洗,经MgSO4干燥,真空浓缩,得到19.0g(92%)标题化合物为油状物。
LRMS:206.1(M+1)。方法D1-苄基-4-甲基-哌啶-3-醇-甲苯-4-磺酸盐
向溶解在175mL丙酮中并冷却到0℃的方法C产物(65.32g/0.318mol)的搅拌溶液中,用2小时时间加对甲苯磺酸一水合物在350mL丙酮中的溶液(滴加),再将所得混合物在0℃搅拌1.5小时。过滤沉淀物并用90mL二异丙基醚清洗滤饼。然后将固体在真空中干燥,得到标题化合物58.55g(100%),为白色固体。
LRMS:378.5(M+1)。方法E1-苄基-4-甲基-哌啶-3-酮
向溶解在250mL二氯甲烷并冷却到0℃的方法D产物(9.8g/0.026mol)和31.7mL二异丙基乙胺的溶液中用40分钟时间滴加溶解在153mL二甲基砜中的12.4gSO3-吡啶复合物。一旦加入,将该反应混合物在室温下搅拌1.5小时,然后加200 mL饱和NaHCO3(含水)猝灭反应。真空除去二氯甲烷并将剩余的含水残余物用二异丙基醚(150mL)提取四次。合并的醚层用水(100ml)清洗四次,经Na2SO4干燥,真空浓缩至干,得到3.81g(72.97%)标题化合物,为黄色的油。
LRMS:204(M+1)。方法F(1-苄基-4-甲基-哌啶-3-基)-甲基-胺
向方法E产物(3.81g/0.019mol)和38mL2.0M甲胺的THF搅拌溶液中加2.2mL乙酸,将所得混合物在室温下搅拌1.5小时。
加三氢化乙酰氧基硼钠(NaB(OAc)3H)(7.94g/0.038mol)固体,将该新的混合物在室温下搅拌18小时。用2N盐酸猝灭反应并将pH调节到1。将该反应混合物用醚清洗两次,然后用6N氢氧化钠(含水)调节水层的pH到12并用二氯甲烷萃取三次。合并的二氯甲烷层经Na2SO4干燥,过滤并真空蒸发至干,得到3.51g(87.75%)标题化合物,暗黄色的油。
LRMS:219.1(M+1)。方法G(1-苄基-4-甲基-哌啶-3-基)-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺
将Davoll(J.Am.Chem.Soc.,(1960),82,131)的方法制得的4-氯代吡咯并[2,3-d]嘧啶(2.4g,15.9mmol)、方法F的产物(1.7g,7.95mmol)和10mL三乙胺的混合物在一个密封管中在100℃下加热4天。冷却到室温并减压浓缩之后,将残余物经快速色谱(硅胶,3%甲醇/二氯甲烷)纯化,得到1.0g(38%)的标题化合物,无色的油。
LRMS:336.1(M+1)。方法H甲基-(4-甲基-哌啶-3-基)-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺
向溶解在15mL乙醇中的方法G产物(0.7g,2.19mmol)的溶液中加0.5g的20%氢氧化钯/碳(50%水)(Aldrich),并将所得的混合物在氢气压下(50psi)在室温下搅拌二天(Parr-Shaker)。将Celite过滤的反应混合物真空浓缩至干,残余物经快速色谱(硅胶;5%甲醇/二氯甲烷)纯化,得到0.48g(90%)标题化合物。
LRMS:246.1(M+1)。方法I[1-(4-甲氧基-苯磺酰基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺
向1mL吡啶和9mL二氯甲烷的搅拌溶液中加40mg(0.163mmol)的方法H产物和20L的4-甲氧基-苯磺酰氯,将所得的混合物在室温下搅拌18小时。然后加200mL饱和NaHCO3(含水)猝灭反应。除去有机层并将水层用二氯甲烷萃取。该二氯甲烷层经Na2SO4干燥,在真空中浓缩至干。残余物用PTLC(硅胶;10∶1二氯甲烷/甲醇)纯化,得到22mg(32%)标题化合物,淡黄色固体。
LRMS:416.5(M+1)。
实施例2-297的化合物是用实施例1所述的方法制备的。
实施例2
[1-(4-甲氧基-苯磺酰基)-4-甲基-哌啶-3-基]-甲基-(7H-
吡咯并[2,3-d]嘧啶-4-基)-胺
LRMS:416.
实施例3(1-苯磺酰基-4-甲基-哌啶-3-基)-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺
LRMS:386.
实施例42-(2-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-磺酰基}-乙
基)-异吲哚-1,3-二酮
LRMS:483.
实施例5环己烷羧酸(2-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-
磺酰基}-乙基)-酰胺
RMS:463.
实施例62-氯-N-(2-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基氨基]-哌啶-1-磺酰
基}-乙基)-苯甲酰胺
LRMS:492.
实施例74-氯-N-(2-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-磺酰
基}-乙基)-苯甲酰胺
LRMS:492.
实施例8呋喃-2-羧酸(2-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-
磺酰基}-乙基)-酰胺
LRMS:447.
实施例93-甲氧基-N-(2-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-
磺酰基}-乙基)-苯甲酰胺
LRMS:487.
实施例10异噁唑-5-羧酸(2-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶
-1-磺酰基}-乙基)-酰胺
LRMS:448.
实施例112,4-二氟-N-(2-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-
磺酰基}-乙基)-苯甲酰胺
LRMS:493.
实施例123-氯-N-(2-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-磺酰
基}-乙基)-苯甲酰胺
LRMS:492.
实施例133-氟-N-(2-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-磺酰
基}-乙基)-苯甲酰胺
LRMS:475.
实施例142-氟-N-(2-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-磺酰
基}-乙基)-苯甲酰胺
LRMS:475.
实施例154-氟-N-(2-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-磺酰
基}-乙基)-苯甲酰胺
LRMS:475.
实施例16N-(2-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-磺酰基}-
乙基)-苯甲酰胺
LRMS:457.
实施例17环丙烷甲酸(2-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-
磺酰基}-乙基)-酰胺
LRMS:421.
实施例18环戊烷甲酸(2-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-
磺酰基}-乙基)-酰胺
LRMS:449.
实施例19环戊基-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-甲
酮
LRMS:342.
实施例20四氢-呋喃-2-羧酸(2-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌
啶-1-磺酰基}-乙基)-酰胺
LRMS:451.
实施例21四氢-呋喃-3-羧酸(2-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌
啶-1-磺酰基}-乙基)-酰胺
LRMS:451.
实施例22{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-(四氢-呋喃
-2-基)-甲酮
LRMS:344.
实施例23{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-(四氢-呋喃
-3-基)-甲酮
LRMS:344.
实施例24环己烷甲酸(3-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-
基}-3-氧-丙基)-酰胺
LRMS:427.
实施例252-环丙基-1-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-
乙酮
LRMS:328.
实施例262-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羰基}-吡咯烷
-1-羧酸叔丁酯
LRMS:443.
实施例27{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-吡咯烷-2-
基-甲酮
LRMS:343.
实施例281-(2-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羰基}-吡咯
烷-1-基)-乙酮盐酸盐
LRMS:385.
实施例29呋喃-3-基-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-
甲酮
LRMS:340.
实施例30{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-吡啶-2-基-
甲酮
LRMS:351.
实施例31{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-苯基-甲酮
LRMS:350.
实施例321-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-2-苯基-乙
酮
LRMS:364.
实施例332-环丙基-1-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-
乙酮盐酸盐
LRMS:364.
实施例342-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羰基}-吡咯烷
-1-羧酸叔丁酯
LRMS:443.
实施例354-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸苯甲酰胺
LRMS:379.
实施例364-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸苯酰胺
LRMS:365.
实施例374-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸四氢-呋喃
-3-基酯
LRMS:360.
实施例381-(4-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羰基}-哌啶
-1-基)-乙酮
LRMS:399.
实施例392-环戊基-1-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-
乙酮
LRMS:356.
实施例404-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸环己酰胺
LRMS:371.
实施例41氮杂环丁(azetidin)-3-基-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨
基]-哌啶-1-基}-甲酮三氟乙酸酯
LRMS:443.
实施例42{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-吡咯烷-1-
基-甲酮
LRMS:343.
实施例434-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸甲基-苯基-
酰胺
LRMS:379.
实施例44{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-吗啉-4-基-
甲酮
LRMS:359.
实施例45甲基-(4-甲基-3,4,5,6-四氢-2H-[1,2′]联吡啶基-3-基)-(7H-吡咯并[2,3-d]嘧
啶-4-基)-胺
LRMS:323.
实施例46甲基-(4-甲基-1-噻唑-2-基-哌啶-3-基)-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺
LRMS:329.
实施例474-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸吡啶-3-基
酰胺
LRMS:366.
实施例484-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(4-氟-苯
基)-酰胺
LRMS:383.
实施例494-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(4-硝基-苯
基)-酰胺
LRMS:410.
实施例504-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(4-甲氧基-
苯基)-酰胺
LRMS:395.
实施例514-({4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羰基}-氨基)-
苯甲酸乙基酯
LRMS:437.
实施例52{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-哌啶-1-基-
甲酮
LRMS:357.
实施例53甲基-(4-甲基-5′-硝基-3,4,5,6-四氢-2H-[1,2′]联吡啶基-3-基)-(7H-吡咯并
[2,3-d]嘧啶-4-基)-胺
LRMS:368.
实施例544-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(3-氟-苯
基)-酰胺
LRMS:383.
实施例554-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(2,4-二氟-
苯基)-酰胺
LRMS:401.
实施例56甲基-[4-甲基-1-(吡咯烷-1-磺酰基)-哌啶-3-基]-(7H-吡咯并[2,3-d]嘧啶-4-
基)-胺
LRMS:379.
实施例574-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(3-甲氧基-
苯基)-酰胺
LRMS:395.
实施例584-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(3-硝基-苯
基)-酰胺
LRMS:410.
实施例591-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羰基}-吡咯烷
-2-羧酸甲基酯
LRMS:401.
实施例60甲基-[4-甲基-1-(5-硝基-噻唑-2-基)-哌啶-3-基]-(7H-吡咯并[2,3-d]嘧啶-4-
基)-胺
LRMS:374.
实施例614-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-3,4,5,6-四氢-2H-[1,2′]
联吡啶基-5′-羧酸甲基酯
LRMS:381.
实施例62{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-3,4,5,6-四氢-2H-[1,2′]
联吡啶基-5′-基}-甲醇
LRMS:353.
实施例63甲基-[4-甲基-1-(哌啶-1-磺酰基)-哌啶-3-基]-(7H-吡咯并[2,3-d]嘧啶-4-基)-
胺(amino)
LRMS:393.
实施例644-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(3-氰基-苯
基)-酰胺
LRMS:390.
实施例654-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(3,4-二氟-
苯基)-酰胺
LRMS:401.
实施例66甲基-[4-甲基-1-(吗啉-4-磺酰基)-哌啶-3-基]-(7H-吡咯并[2,3-d]嘧啶-4-基)-
胺
LRMS:395.
实施例674-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(4-氯-苯
基)-酰胺
LRMS:399.
实施例68甲基-[4-甲基-1-(6-甲基-哒嗪-3-基)-哌啶-3-基]-(7H-吡咯并[2,3-d]嘧啶-4-
基)-胺
LRMS:338.
实施例694-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(4-氰基-苯
基)-酰胺
LRMS:390.
实施例704-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸联苯基-4-
基酰胺
LRMS:441.
实施例714-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(4-三氟甲
基-苯基)-酰胺
LRMS:433.
实施例72甲基-(2-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-磺酰
基}-乙基)-氨基甲酸苯甲基酯
LRMS:501.
实施例73环丙基-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-甲
酮
LRMS:314.
实施例74环丁基-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-甲
酮
LRMS:328.
实施例75四氢-呋喃-3-羧酸甲基-(2-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨
基]-哌啶-1-磺酰基}-乙基)-酰胺
LRMS:465.
实施例76环己烷甲酸甲基-(2-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌
啶-1-磺酰基}-乙基)-酰胺
LRMS:477.
实施例77(5,7-二氯-1H-吲哚-2-基)-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨
基]-哌啶-1-基}-甲酮
LRMS:458.
实施例784-({4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羰基}-氨基)-
苯甲酸
LRMS:409.
实施例79(1-苯并噁唑-2-基-4-甲基-哌啶-3-基)-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺
LRMS:363.
实施例80(1H-吲哚-2-基)-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶
-1-基}-甲酮
LRMS:389.
实施例81(5-氟-1H-吲哚-2-基)-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-
哌啶-1-基}-甲酮
LRMS:407.
实施例82(5-甲氧基-3-甲基-苯并呋喃-2-基)-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶
-4-基)-氨基]-哌啶-1-基}-甲酮
LRMS:434.
实施例83(5-氯-苯并呋喃-2-基)-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-
哌啶-1-基}-甲酮
LRMS:424.
实施例84{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-(5-硝基-苯
并呋喃-2-基)-甲酮
LRMS:435.
实施例85(5-氯-2,3-二氢-苯并呋喃-2-基)-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-
基)-氨基]-哌啶-1-基}-甲酮
LRMS:426.
实施例86(4-羟基-哌啶-1-基)-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌
啶-1-基}-甲酮
LRMS:373.
实施例871-(2-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羰基}-苯并
呋喃-5-基)-乙酮
LRMS:432.
实施例881-(3-甲基-2-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羰
基}-1H-吲哚-5-基)-乙酮
LRMS:445.
实施例89[1-(5-氯-苯并噻唑-2-基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶-4-
基)-胺
LRMS:413.
实施例90(3-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羰基}-3-氮杂
-二环[3.1.0]己-6-基)-氨基甲酸叔丁基酯
LRMS:470.
实施例913-(4-氯-苯氧基)-1-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶
-1-基}-丙烷-1-酮
LRMS:428.
实施例924-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸吡啶-2-基
酰胺
LRMS:366.
实施例931-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羰基}-哌啶-4-
羧酸酰胺盐酸盐
LRMS:436.
实施例944-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(5-氯-吡啶
-2-基)-酰胺
LRMS:400.
实施例953-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羰基}-环戊酮
LRMS:356.
实施例96(3-羟基-环戊基)-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶
-1-基}-甲酮
LRMS:358.
实施例974-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羰基}-环己酮
LRMS:370.
实施例983-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羰基}-环己酮
LRMS:370.
实施例994-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(5-硝基-吡
啶-2-基)-酰胺
LRMS:413.
实施例100[4-({4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羰基}-氨
基)-苯基]-乙酸
LRMS:423.
实施例101(4-氨基-哌啶-1-基)-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌
啶-1-基}-甲酮盐酸盐
LRMS:408.
实施例1024-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(6-甲基-吡
啶-2-基)-酰胺
LRMS:380.
实施例1031-甲基-4-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羰基}-
吡咯烷-2-酮
LRMS:371.
实施例1041-苄基-3-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羰基}-
吡咯烷-2-酮
LRMS:447.
实施例1054-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(5-三氟甲
基-吡啶-2-基)-酰胺
LRMS:434.
实施例1064-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-环己烷羧酸(4-氰基-苯
基)-酰胺
LRMS:389.
实施例1074-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(4-氨基甲
酰基-苯基)-酰胺
LRMS:408.
实施例1084-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(4-氨基磺
酰基-苯基)-酰胺
LRMS:444.
实施例1094-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(5-甲基-噻
唑-2-基)-酰胺
LRMS:386.
实施例1104-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(5,6-二氯-
苯并噻唑-2-基)-酰胺
LRMS:491.
实施例1114-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(4-甲基-噻
唑-2-基)-酰胺
LRMS:386.
实施例112氮杂环丁-1-基-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-
基}-甲酮盐酸盐
LRMS:365.
实施例113[2-({4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羰基}-氨
基)-噻唑-4-基]-乙酸乙基酯
LRMS:458.
实施例1144-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(4,5-二甲
基-噻唑-2-基)-酰胺
LRMS:400.
实施例115[2-({4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羰基}-氨
基)-噻唑-4-基]-乙酸
LRMS:430.
实施例1164-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸苯并噻唑
-2-基酰胺
LRMS:422.
实施例1174-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸噻唑-2-基
酰胺
LRMS:372.
实施例1184-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸[6-(2-二甲
基氨基-乙基氨基)-吡啶-3-基]-酰胺
LRMS:452.
实施例119N-(4-氯-苯基)-2-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶
-1-基}-乙酰胺
LRMS:413.
实施例120N,N-二甲基-2-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-
基}-乙酰胺
LRMS:331.
实施例1214-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸[6-(2-吡咯
烷-1-基-乙基氨基)-吡啶-3-基]-酰胺
LRMS:478.
实施例122{2-[5-({4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羰基}-氨
基)-吡啶-2-基氧]-乙基}-氨基甲酸叔丁基酯
LRMS:525.
实施例1234-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸[6-(2-氨基-
乙氧基)-吡啶-3-基]-酰胺
LRMS:425.
实施例1244-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(4-甲基氨
基磺酰基-苯基)-酰胺
LRMS:458.
实施例1254-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(4-甲磺酰
基-苯基)-酰胺
LRMS:443.
实施例1264-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(5-甲基-[1,3,
4]噻二唑-2-基)-酰胺
LRMS:387.
实施例1274-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(4-甲基氨
基磺酰基-苯基)-酰胺盐酸盐
LRMS:495.
实施例128甲基-[4-甲基-1-(1-苯基-乙基)-哌啶-3-基]-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺
LRMS:350.
实施例129(3-羟基-吡咯烷-1-基)-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-
哌啶-1-基}-甲酮
LRMS:359.
实施例1304-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸叔-丁基酯
LRMS:346.
实施例1314-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸[4-(2-二甲
基氨基-乙基)-噻唑-2-基]-酰胺
LRMS:443.
实施例1324-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸4-甲磺酰基
-苯甲酰胺
LRMS:457.
实施例1334-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羟酸(4-乙酰基
氨基磺酰基-苯基)-酰胺
LRMS:486.
实施例1341-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-2-苯基-乙
-1,2-二酮
LRMS:378.
实施例135甲基-[4-甲基-1-(6-甲基氨基-嘧啶-4-基)-哌啶-3-基]-(7H-吡咯并[2,3-d]嘧啶
-4-基)-胺
LRMS:353.
实施例136甲基-[4-甲基-1-(6-吡咯烷-1-基-嘧啶-4-基)-哌啶-3-基]-(7H-吡咯并[2,3-d]嘧
啶-4-基)-胺
LRMS:393.
实施例137[1-(6-苄基氨基-嘧啶-4-基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶
-4-基)-胺
LRMS:429.
实施例138N,N-二甲基-N′-(6-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌
啶-1-基}-嘧啶-4-基)-乙-1,2-二胺
LRMS:410.
实施例139[1-(6-氯-嘧啶-4-基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-
胺
LRMS:358.
实施例140[1-(2-氟-苄基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺
LRMS:354
实施例141[1-(2-氯-嘧啶-4-基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-
胺
LRMS:359.
实施例142[1-(4-氯-嘧啶-2-基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-
胺
LRMS:359.
实施例143甲基-[4-甲基-1-(2-甲基氨基-嘧啶-4-基)-哌啶-3-基]-(7H-吡咯并[2,3-d]嘧啶
-4-基)-胺
LRMS:353.
实施例144甲基-[4-甲基-1-(4-吡咯烷-1-基-嘧啶-2-基)-哌啶-3-基]-(7H-吡咯并[2,3-d]嘧
啶-4-基)-胺
LRMS:353.
实施例1454-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(3-甲基-异
噁唑-5-基)-酰胺
LRMS:370.
实施例1464-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(3-甲基-异
噁唑-4-基)-酰胺
LRMS:370.
实施例1474-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(5-甲基-异
噁唑-3-基)-酰胺
LRMS:370.
实施例1484-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(5-叔-丁基-
异噁唑-3-基)-酰胺
LRMS:412.
实施例1494-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸异噁唑-3-
基酰胺
LRMS:356.
实施例150N-甲基-3-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-
丙酰胺
LRMS:331.
实施例1511-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-丙-2-酮
LRMS:302.
实施例152{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基]-氧-乙酸甲
酯
LRMS:332.
实施例153(1-环己基甲基-4-甲基-哌啶-3-基)-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺
LRMS:342.
实施例154[1-(5-氨基-噻唑-2-基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶-4-
基)-胺
LRMS:344.
实施例155
甲基-(4-甲基-哌啶-3-基)-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺
LRMS:246.
实施例1563-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-3-氧-丙酸
甲酯
LRMS:346.
实施例157(1-苯磺酰基甲基-4-甲基-哌啶-3-基)-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺
LRMS:400.
实施例158(3-羟基-吡咯烷-1-基)-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-
哌啶-1-基}-甲酮
LRMS:359.
实施例1591-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-丙-1,2-二
酮
LRMS:316.
实施例1604-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(6-氨基磺
酰基-吡啶-3-基)-酰胺
LRMS:445.
实施例1614-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(6-乙酰氨
基-吡啶-3-基)-酰胺
LRMS:423.
实施例1624-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸[4-(2-di甲
基氨基-乙基氨基磺酰基)-苯基]-酰胺
LRMS:515.
实施例1634-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(6-氰基-吡
啶-3-基)-酰胺
LRMS:391.
实施例1644-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-3,4,5,6-四氢-2H-[1,2′]
联吡啶基-5′-磺酸吡啶-2-基酰胺
LRMS:479.
实施例1654-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸[6-(吡咯烷
-1-羰基)-吡啶-3-基]-酰胺
LRMS:463.
实施例1662-咪唑-1-基-1-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-
基}-乙酮
LRMS:354.
实施例1674-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-3,4,5,6-四氢-2H-[1,2′]
联吡啶基-5′-羧酸甲基酰胺
LRMS:380.
实施例168{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-3,4,5,6-四氢-2H-[1,2′]
联吡啶基-5′-基}-吗啉-4-基-甲酮
LRMS:436.
实施例1695-({4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羰基}-氨基)-
吡啶-2-羧酸丙基酰胺
LRMS:451.
实施例1704-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-3,4,5,6-四氢-2H-[1,2′]
联吡啶基-5′-羧酸酰胺
LRMS:366.
实施例1714-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-3,4,5,6-四氢-2H-[1,2′]
联吡啶基-5′-腈
LRMS:348.
实施例1724-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸[4-(吡咯烷
-1-磺酰基)-苯基]-酰胺
LRMS:498.
实施例1734-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸[4-(吗啉-4-
磺酰基)-苯基]-酰胺
LRMS:514.
实施例174(3-羟基-吡咯烷-1-基)-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-
哌啶-1-基}-甲酮
LRMS:359.
实施例1754-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸[6-(吗啉-4-
羰基)-吡啶-3-基]-酰胺
LRMS:479.
实施例1764-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸[6-(吗啉-4-
羰基)-吡啶-3-基]-酰胺
LRMS:479.
实施例1772-咪唑-1-基-1-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-
基}-乙酮
LRMS:354.
实施例1784-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸异噁唑-3-
基酰胺
LRMS:356.
实施例1794-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(2,5-甲基
-2H-吡唑-3-基)-酰胺
LRMS:383.
实施例1804-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(5-环丙基
-2-甲基-2H-吡唑-3-基)-酰胺
LRMS:409.
实施例1814-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(3-甲基-异
噻唑-5-基)-酰胺
LRMS:386.
实施例1824-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基甲基}-苯甲
酸
LRMS:380.
实施例183甲基-[4-甲基-5′-(吡咯烷-1-磺酰基)-3,4,5,6-四氢-2H-[1,2′]联吡啶基-3-
基]-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺
LRMS:456.
实施例1844-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基)-3,4,5,6-四氢-2H-[1,2′]
联吡啶基-5′-磺酸甲基酰胺
LRMS:416.
实施例1854-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基甲基}-苯磺
酰胺
LRMS:415.
实施例186N-叔-丁基-4-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基
甲基}-苯磺酰胺
LRMS:472.
实施例1871-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-2-吡唑-1-
基-乙酮
LRMS:354.
实施例188甲基-[4-甲基-1-(5-硝基-苯并噁唑-2-基)-哌啶-3-基]-(7H-吡咯并[2,3-d]嘧啶
-4-基)-胺
LRMS:408.
实施例1894-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-3,4,5,6-四氢-2H-[1,2′]
联吡啶基-5′-磺酸(2-羟基-乙基)-酰胺
LRMS:446.
实施例190N-叔-丁基-4-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基
甲基}-苯磺酰胺
LRMS:471.
实施例191N-甲基-2-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-
基}-2-氧-乙酰胺
LRMS:331.
实施例192[1-(5-乙磺酰基-苯并噁唑-2-基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]
嘧啶-4-基)-胺
LRMS:455.
实施例193甲基-[4-甲基-1-(5-甲基-苯并噁唑-2-基)-哌啶-3-基]-(7H-吡咯并[2,3-d]嘧啶
-4-基)-胺
LRMS:377.
实施例1944-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(6-氯-吡啶
-3-基)-酰胺
LRMS:400.
实施例195甲基-(4-甲基-1-奎啉-2-基-哌啶-3-基)-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺
LRMS:373.
实施例1964-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-3,4,5,6-四氢-2H-[1,2′]
联吡啶基-5′-磺酸酰胺
LRMS:402.
实施例1971-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-2-吡咯烷
-1-基-乙-1,2-二酮
LRMS:371.
实施例198甲基-[4-甲基-1-(4-甲基-苯并噁唑-2-基)-哌啶-3-基]-(7H-吡咯并[2,3-d]嘧啶
-4-基)-胺
LRMS:377.
实施例1991-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-2-吗啉-4-
基-乙-1,2-二酮
LRMS:387.
实施例2004-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(6-甲磺酰
基-吡啶-3-基)-酰胺
LRMS:444.
实施例2014-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(6-甲磺酰
基-吡啶-3-基)-酰胺
LRMS:444.
实施例202甲基-[4-甲基-1-(6-硝基-苯并噁唑-2-基)-哌啶-3-基]-(7H-吡咯并[2,3-d]嘧啶
-4-基)-胺
LRMS:408.
实施例2034-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(6-甲磺酰
基-吡啶-3-基)-酰胺
LRMS:444.
实施例2044-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(6-甲磺酰
基-吡啶-3-基)-酰胺
LRMS:444.
实施例205甲基-[4-甲基-1-(6-硝基-苯并噁唑-2-基)-哌啶-3-基]-(7H-吡咯并[2,3-d]嘧啶
-4-基)-胺
LRMS:408.
实施例206甲基-[4-甲基-1-(甲苯-3-磺酰基)-哌啶-3-基]-(7H-吡咯并[2,3-d]嘧啶-4-基)-
胺
LRMS:400.
实施例207甲基-[4-甲基-1-(4-三氟甲基-苯磺酰基)-哌啶-3-基]-(7H-吡咯并[2,3-d]嘧啶
-4-基)-胺
LRMS:454.
实施例208(1-苯并噻唑-2-基-4-甲基-哌啶-3-基)-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺
LRMS:379.
实施例209[1-(5,7-二甲基-苯并唑-2-基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]
嘧啶-4-基)-胺
LRMS:391.
实施例2102-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-苯并噁唑
-6-羧酸甲酯
LRMS:421.
实施例211甲基-[4-甲基-1-(6-甲基-苯并噁唑-2-基)-哌啶-3-基]-(7H-吡咯并[2,3-d]嘧啶
-4-基)-胺
LRMS:377.
实施例212[1-(6-甲氧基-苯并噁唑-2-基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧
啶-4-基)-胺
LRMS:393.
实施例213甲基-[4-甲基-1-(5-三氟甲基-苯并噻唑-2-基)-哌啶-3-基]-(7H-吡咯并[2,3-d]
嘧啶-4-基)-胺
LRMS:447.
实施例214[1-(5,7-二氯-苯并噁唑-2-基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧
啶-4-基)-胺
LRMS:432.
实施例215[1-(6-氯-吡啶-3-磺酰基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶-4-
基)-胺
LRMS:422.
实施例216[1-(4-氯-苯磺酰基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺
LRMS:421.
实施例217[1-(4-氟-苯磺酰基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-
胺
LRMS:404.
实施例2184-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-磺酰基}-苄腈
LRMS:411.
实施例2194-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-磺酰基}-苯磺
酰基氟化物
LRMS:468.
实施例2202-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-磺酰基}-苄腈
LRMS:411.
实施例2211-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-2-四唑-1-
基-乙酮
LRMS:356.
实施例222甲基-[4-甲基-1-(2,2,2-三氟-乙磺酰基)-哌啶-3-基]-(7H-吡咯并[2,3-d]嘧啶
-4-基)-胺
LRMS:392.
实施例223[1-(2,6-二氟-苯磺酰基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶-4-
基)-胺
LRMS:422.
实施例224[1-(4-叔-丁基-苯磺酰基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶-4-
基)-胺
LRMS:442.
实施例225[1-(2,4-二氟-苯磺酰基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶-4-
基)-胺
LRMS:422.
实施例226甲基-[4-甲基-1-(2-三氟甲基-苯磺酰基)-哌啶-3-基]-(7H-吡咯并[2,3-d]嘧啶
-4-基)-胺
LRMS:454.
实施例227[1-(3,5-双-三氟甲基-苯磺酰基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]
嘧啶-4-基)-胺
LRMS:522.
实施例228[1-(3,5-二氯-苯磺酰基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶-4-
基)-胺
LRMS:455.
实施例2294-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-磺酰基}-苯甲
酸
LRMS:431.
实施例230[1-(6-氯-吡啶-3-磺酰基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶-4-
基)-胺
LRMS:422.
实施例231[1-(4-氯-苯磺酰基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-
胺
LRMS:421.
实施例232[1-(4-氟-苯磺酰基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-
胺
LRMS:404.
实施例2334-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-磺酰基}-苄腈
LRMS:411.
实施例2344-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-磺酰基}-苯磺
酰基氟化物
LRMS:468.
实施例2352-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-磺酰基}-苄腈
LRMS:411.
实施例2361-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-2-四唑-1-
基-乙酮
LRMS:356.
实施例237甲基-[4-甲基-1-(2,2,2-三氟-乙磺酰基)-哌啶-3-基]-(7H-吡咯并[2,3-d]嘧啶
-4-基)-胺
LRMS:392.
实施例238[1-(2,6-二氟-苯磺酰基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶-4-
基)-胺
LRMS:422.
实施例239[1-(4-叔-丁基-苯磺酰基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶-4-
基)-胺
LRMS:442.
实施例240[1-(2,4-二氟-苯磺酰基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶-4-
基)-胺
LRMS:422.
实施例241甲基-[4-甲基-1-(2-三氟甲基-苯磺酰基)-哌啶-3-基]-(7H-吡咯并[2,3-d]嘧啶
-4-基)-胺
LRMS:454.
实施例242[1-(3,5-双-三氟甲基-苯磺酰基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]
嘧啶-4-基)-胺
LRMS:522.
实施例243[1-(3,5-二氯-苯磺酰基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶-4-
基)-胺
LRMS:455.
实施例2444-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-磺酰基}-苯甲
酸
LRMS:431
实施例245(3-氟-苯基)-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-
基}-甲酮LRMS:368.
实施例246异噻唑-4-基-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-
基}-甲酮
LRMS:357.
实施例247{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-噻吩-3-基-
甲酮
LRMS:356.
实施例248{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-(5-甲基
-1H-吡唑-3-基)-甲酮
LRMS:354.
实施例249(5-甲基-异噁唑-3-基)-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-
哌啶-1-基}-甲酮.
LRMS:355.
实施例250{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-(5-甲基-噻
吩-2-基)-甲酮
LRMS:371.
实施例251(4-氟-苯基)-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-
基}-甲酮
LRMS:368.
实施例252甲基-[4-甲基-1-(3-硝基-苯磺酰基)-哌啶-3-基]-(7H-吡咯并[2,3-d]嘧啶-4-
基)-胺
LRMS:431.
实施例253[1-(3-氟-苯磺酰基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-
胺
LRMS:404.
实施例254(2-氟-苯基)-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-
基}-甲酮
LRMS:368.
实施例255(1,5-二甲基-1H-吡唑-3-基)-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-
氨基]-哌啶-1-基}-甲酮
LRMS:368.
实施例256{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-(2-甲基-噻
唑-4-基)-甲酮
LRMS:371.
实施例257{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-噻唑-4-基-
甲酮
LRMS:357.
实施例258(4-甲基-异噻唑-5-基)-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-
哌啶-1-基}-甲酮
LRMS:371.
实施例2592,2-二甲基-5-(2-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶
-1-基}-2-氧-乙基)-[1,3]二氧戊环-4-酮
LRMS:403.
实施例2602-环丙基-N-(2-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-
磺酰基}-乙基)-乙酰胺
LRMS:436.
实施例261N-(2-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-磺酰基}-
乙基)-甲磺酰胺
LRMS:432.
实施例262(3-羟基-吡咯烷-1-基)-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-
哌啶-1-基}-甲酮
LRMS:359.
实施例2634-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基甲基}-苄腈
LRMS:362.
实施例2643-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-磺酰基}-苯磺
酰基氟化物
LRMS:469.
实施例2652,2-二甲基-5-(2-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶
-1-基}-2-氧-乙基)-[1,3]二氧戊环-4-酮
LRMS:402.
实施例2664-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸苯甲酸酯
LRMS:381.
实施例2674-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基甲基}-苯磺
酰胺
LRMS:416.
实施例268[1-(1H-咪唑-2-基甲基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶-4-
基)-胺
LRMS:326.
实施例2694-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸2-氯-苄基
酯
LRMS:415.
实施例270甲基-[4-甲基-1-(1-甲基-1H-咪唑-2-基甲基)-哌啶-3-基]-(7H-吡咯并[2,3-d]嘧
啶-4-基)-胺
LRMS:340.
实施例2711-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-2-苯氧基-
乙酮
LRMS:380.
实施例2722-(4-氟-苯氧基)-1-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶
-1-基}-乙酮
LRMS:381.
实施例2734-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸2,2,2-三氯
-乙基酯
LRMS:420.
实施例2742-(2-氯-苯氧基)-1-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶
-1-基}-乙酮
LRMS:415.
实施例2752-(3-氯-苯氧基)-1-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶
-1-基}-乙酮
LRMS:415.
实施例2762-甲磺酰基-1-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-
基}-乙酮
LRMS:367.
实施例2772-(1,1-二氧-四氢-1$l%6&-噻吩-3-基)-1-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]
嘧啶-4-基)-氨基]-哌啶-1-基}-乙酮
LRMS:407.
实施例278甲基-[4-甲基-1-(1-苯基-乙基)-哌啶-3-基]-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺
LRMS:351.
实施例2791-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-2-(甲苯
-4-磺酰基)-乙酮
LRMS:443.
实施例2802-羟基-1-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-乙
酮
LRMS:304.
实施例2811-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-3-硝基-丙
-1-酮
LRMS:347.
实施例2825-(2-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-2-氧-
乙基)-噻唑烷-2,4-二酮
LRMS:404.
实施例2833-羟基-1-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-丙
-1-酮
LRMS:318.
实施例284N-(4-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-4-氧-
丁基)-甲磺酰胺
LRMS:410.
实施例2854-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸2,2-二甲基
-丙基酯
LRMS:360.
实施例2861-{4-甲基-3-[甲基-(7H-咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-2-(噻唑烷
-3-磺酰基)-乙酮
LRMS:440.
实施例287(3,4-二羟基-吡咯烷-1-基)-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨
基]-哌啶-1-基}-甲酮
LRMS:376.
实施例2884-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羰基}-噻唑烷
-2-酮
LRMS:376
实施例2894-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸丙-2-炔酯
LRMS:328.
实施例2904-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(2-氰基-乙
基)-酰胺
LRMS:342.
实施例2914-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(2-氰基-乙
基)-酰胺
LRMS:342.
实施例2921-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-环己基}-乙酮肟
LRMS:302.
实施例2934-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸氰基甲基-
甲基-酰胺
LRMS:342.
实施例2944-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸异丙基酯
LRMS:332.
实施例2954-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(2-氰基-乙
基)-甲基-酰胺
LRMS:356.
实施例2964-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基甲基}-吡啶
-1-醇
LRMS:355.
实施例297{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-乙腈
LRMS:285.
实施例298[1-(2-氟-苄基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺方法J
向方法H的产物(50mg,mmols?)溶解在5mL甲醇的溶液中加154ul(mmols?)的2-氟-苯甲醛。将所得混合物在室温下搅拌4小时,同时加xmg(ymmol)氰硼氢化钠并将该新的混合物在室温下搅拌18小时。加2滴1N的NaOH(含水)并减压除去甲醇。残余物溶于氯仿中并用水清洗。将含水层用氯仿回洗三次,合并的氯仿萃取液经MgSO4干燥并将其真空浓缩至干。然后经快速色谱(硅胶;2.5%甲醇/氯仿)纯化,得到36mg(47.5%)标题化合物,白色固体。
LRMS:372.4(M+1)。
实施例299-324的化合物是用实施例298所述的方法制备的。
实施例299
(1-苄基-4-甲基-哌啶-3-基)-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺
LRMS:336.
实施例300(1-呋喃-2-基甲基-4-甲基-哌啶-3-基)-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺
LRMS:326.
实施例301[1-(4-甲氧基-苄基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-
胺
LRMS:366.
实施例302[1-(4-氟-苄基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺
LRMS:354.
实施例303甲基-(4-甲基-1-吡啶-3-基甲基-哌啶-3-基)-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺
LRMS:337.
实施例304甲基-(4-甲基-1-噻唑-2-基甲基-哌啶-3-基)-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺
LRMS:343.
实施例305甲基-(4-甲基-1-吡啶-2-基甲基-哌啶-3-基)-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺
LRMS:337.
实施例306甲基-[4-甲基-1-(1-苯基-乙基)-哌啶-3-基]-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺
LRMS:350.
实施例307
(1-苄基-4-甲基-哌啶-3-基)-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺
LRMS:336.
实施例308
(1-苄基-4-甲基-哌啶-3-基)-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺
LRMS:336.
实施例3093-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基甲基}-苄腈
LRMS:361.
实施例310[1-(3-氟-苄基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺
LRMS:354.
实施例311[1-(3-甲氧基-苄基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-
胺
LRMS:366.
实施例3123-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基甲基}-苯甲
酸
LRMS:380.
实施例313[1-(2-氟-苄基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺
LRMS:354.
实施例314[1-(2,6-二氟-苄基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-
胺
LRMS:372.
实施例315
甲基-(4-甲基-1-苯乙基-哌啶-3-基)-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺
LRMS:350.
实施例316[1-(2,3-二氟-苄基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺
LRMS:372.
实施例317[1-(3,4-二氟-苄基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-
胺
LRMS:372.
实施例318[1-(4-甲磺酰基-苄基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶-4-
基)-胺
LRMS:414.
实施例319甲基-{4-甲基-1-[4-(哌啶-1-磺酰基)-苄基]-哌啶-3-基}-(7H-吡咯并[2,3-d]嘧
啶-4-基)-胺
LRMS:483.
实施例320[1-(3,5-二氟-苄基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-
胺
LRMS:372.
实施例321[1-(3-氯-苄基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺
LRMS:371.
实施例322[1-(3,5-二氟-苄基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-
胺
LRMS:372.
实施例323[1-(3-氯-苄基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺
LRMS:371.
实施例324[1-(3,5-二氯-苄基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-
胺
LRMS:405.
Claims (27)
1.式I的化合物或其药学上可接受的盐,其中
R1是下式的基团其中y是0、1或2;
R4选自氢,(C1-C6)烷基,(C1-C6)烷基磺酰基,(C2-C6)链烯基,(C2-C6)炔基,其中烷基、链烯基和炔基任选地被下列基团取代:氘,羟基,氨基,三氟甲基,(C1-C4)烷氧基,(C1-C6)酰氧基,(C1-C6)烷氨基,((C1-C6)烷基)2氨基,氰基,硝基,(C2-C6)链烯基,(C2-C6)炔基或(C1-C6)酰氨基;或R4是(C3-C10)环烷基,其中该环烷基任选地被下列基团取代:氘,羟基,氨基,三氟甲基,(C1-C6)酰氧基,(C1-C6)酰氨基,(C1-C6)烷基氨基,((C1-C6)烷基)2氨基,氰基,氰基(C1-C6)烷基,三氟甲基(C1-C6)烷基,硝基,硝基(C1-C6)烷基或(C1-C6)酰基氨基;
R5是(C2-C9)杂环烷基,其中该杂环烷基必须被1至5个下列的基团取代:羧基,氰基,氨基,氘,羟基,(C1-C6)烷基,(C1-C6)烷氧基,卤素,(C1-C6)酰基,(C1-C6)烷基氨基,氨基(C1-C6)烷基,(C1-C6)烷氧基-CO-NH,(C1-C6)烷基氨基-CO-,(C2-C6)链烯基,(C2-C6)炔基,(C1-C6)烷基氨基,氨基(C1-C6)烷基,羟基(C1-C6)烷基,(C1-C6)烷氧基(C1-C6)烷基,(C1-C6)酰基氧(C1-C6)烷基,硝基,氰基(C1-C6)烷基,卤代(C1-C6)烷基,硝基(C1-C6)烷基,三氟甲基,三氟甲基(C1-C6)烷基,(C1-C6)酰基氨基,(C1-C6)酰基氨基(C1-C6)烷基,(C1-C6)烷氧基(C1-C6)酰基氨基,氨基(C1-C6)酰基,氨基(C1-C6)酰基(C1-C6)烷基,(C1-C6)烷基氨基(C1-C6)酰基,((C1-C6)烷基)2氨基(C1-C6)酰基,R15R16N-CO-O-,R15R16N-CO-(C1-C6)烷基,(C1-C6)烷基-S(O)m,R15R16NS(O)m,R15R16NS(O)m(C1-C6)烷基,R15S(O)mR16N,R15S(O)mR16N(C1-C6)烷基,其中m是0、1或2且R15和R16各自选自氢或(C1-C6)烷基;以及下式基团:其中
a是0、1、2、3或4;
b、c、e、f和g各自是0或1;
d是0、1、2、或3;
X是S(O)n其中n是0、1或2;氧、羰基或-C(=N-氰基)-;
Y是S(O)n其中n是0、1或2;或羰基;和
Z是羰基,C(O)O-,C(O)NR-,其中R是氢或(C1-C6)烷基;或Z是S(O)n其中n是0、1或2;
R6、R7、R8、R9、R10和R11各自选自下列的基团:氢或(C1-C6)烷基,该烷基任选地被下列基团取代:氘,羟基,氨基,三氟甲基,(C1-C6)酰基氧,(C1-C6)酰基氨基,(C1-C6)烷基氨基,((C1-C6)烷基)2氨基,氰基,氰基(C1-C6)烷基,三氟甲基(C1-C6)烷基,硝基,硝基(C1-C6)烷基或(C1-C6)酰基氨基;
R12是(C6-C10)芳基,(C2-C9)杂芳基,(C3-C10)环烷基或(C2-C9)杂环烷基,其中芳基,杂芳基,环烷基和杂环烷基任选地被1至4个下列基团取代:氢,氘,氨基,卤代,氧代,羟基,硝基,羧基,(C2-C6)链烯基,(C2-C6)炔基,三氟甲基,三氟甲氧基,(C1-C6)烷基,(C1-C6)烷氧基,(C3-C10)环烷基,(C1-C6)烷基-CO-NH-,(C1-C6)烷氧基-CO-NH-,(C1-C6)烷基-CO-NH-(C1-C6)烷基,(C1-C6)烷氧基-CO-NH-(C1-C6)烷基,(C1-C6)烷氧基-CO-NH-(C1-C6)烷氧基,羧基,羧基(C1-C6)烷基,羧基(C1-C6)烷氧基,苄氧基羰基(C1-C6)烷氧基,(C1-C6)烷氧基羰基(C1-C6)烷氧基,(C6-C10)芳基,氨基,氨基(C1-C6)烷基,(C1-C6)烷氧基羰基氨基,(C6-C10)芳基(C1-C6)烷氧基羰基氨基,(C1-C6)烷基氨基,((C1-C6)烷基)2氨基,(C1-C6)烷基氨基(C1-C6)烷基,((C1-C6)烷基)2氨基(C1-C6)烷基,羟基,(C1-C6)烷氧基,羧基,羧基(C1-C6)烷基,(C1-C6)烷氧基羰基,(C1-C6)烷氧基羰基(C1-C6)烷基,(C1-C6)烷氧基-CO-NH-,(C1-C6)烷基-CO-NH-,氰基,(C5-C9)杂环烷基,氨基-CO-NH-,(C1-C6)烷基氨基-CO-NH-,((C1-C6)烷基)2氨基-CO-NH-,(C6-C10)芳基氨基-CO-NH-,(C5-C9)杂芳基氨基-CO-NH-,(C1-C6)烷基氨基-CO-NH-(C1-C6)烷基,((C1-C6)烷基)2氨基-CO-NH-(C1-C6)烷基,(C6-C10)芳基氨基-CO-NH-(C1-C6)烷基,(C5-C9)杂芳基氨基-CO-NH-(C1-C6)烷基,(C1-C6)烷基氰基,(C1-C6)烷基羧基(C1-C6)烷氧基,(C1-C6)烷基羧基,磺酰氨基,氨基磺酰基,磺酰氨基(C1-C6)烷基,磺酰氨基羧基(C1-C6)烷基,(C1-C6)烷基磺酰基,(C1-C6)烷基磺酰氨基,(C1-C6)烷基磺酰氨基(C1-C6)烷基,(C6-C10)芳基磺酰基,(C6-C10)芳基磺酰氨基,(C6-C10)芳基磺酰氨基(C1-C6)烷基,(C1-C6)烷基磺酰氨基,(C1-C6)烷基磺酰氨基(C1-C6)烷基,(C3-C10)环烷基,(C3-C10)环烷氧基,(C1-C6)烷基氨基,((C1-C6)烷基)2氨基,(C6-C10)芳基氨基,(C1-C6)烷硫基,(C6-C10)芳硫基,(C1-C6)烷基亚磺酰基,(C6-C10)芳基亚磺酰基,(C1-C6)烷基磺酰基,(C6-C10)芳基磺酰基,(C1-C6)酰基,(C1-C6)烷氧基-CO-NH-,(C1-C6)烷基氨基-CO-,(C5-C9)杂芳基,(C2-C9)杂环烷基或(C6-C10)芳基,其中R12上任选被取代的杂芳基,杂环烷基和芳基还可被1至3个下列的取代基取代:卤素,(C1-C6)烷基,(C1-C6)烷基-CO-NH-,(C1-C6)烷氧基-CO-NH-,(C1-C6)烷基-CO-NH-(C1-C6)烷基,(C1-C6)烷氧基-CO-NH-(C1-C6)烷基,(C1-C6)烷氧基-CO-NH-(C1-C6)烷氧基,羧基,羧基(C1-C6)烷基,羧基(C1-C6)烷氧基,苄氧基羰基(C1-C6)烷氧基,(C1-C6)烷氧基羰基(C1-C6)烷氧基,(C6-C10)芳基,氨基,氨基(C1-C6)烷基,(C1-C6)烷氧基羰基氨基,(C6-C10)芳基(C1-C6)烷氧基羰基氨基,(C1-C6)烷基氨基,((C1-C6)烷基)2氨基,(C1-C6)烷基氨基(C1-C6)烷基,((C1-C6)烷基)2氨基(C1-C6)烷基,羟基,(C1-C6)烷氧基,羧基,羧基(C1-C6)烷基,(C1-C6)烷氧基羰基,(C1-C6)烷氧基羰基(C1-C6)烷基,(C1-C6)烷氧基-CO-NH-,(C1-C6)烷基-CO-NH-,氰基,(C5-C9)杂环烷基,氨基-CO-NH-,(C1-C6)烷基氨基-CO-NH-,((C1-C6)烷基)2氨基-CO-NH-,(C6-C10)芳基氨基-CO-NH-,(C5-C9)杂芳基氨基-CO-NH-,(C1-C6)烷基氨基-CO-NH-(C1-C6)烷基,((C1-C6)烷基)2氨基-CO-NH-(C1-C6)烷基,(C6-C10)芳基氨基-CO-NH-(C1-C6)烷基,(C5-C9)杂芳基氨基-CO-NH-(C1-C6)烷基,(C1-C6)烷基磺酰基,(C1-C6)烷基磺酰基氨基,(C1-C6)烷基磺酰基氨基(C1-C6)烷基,(C6-C10)芳基磺酰基,(C6-C10)芳基磺酰基氨基,(C6-C10)芳基磺酰基氨基(C1-C6)烷基,(C1-C6)烷基磺酰基氨基,(C1-C6)烷基磺酰基氨基(C1-C6)烷基,(C5-C9)杂芳基和(C2-C9)杂环烷基;
R2和R3各自独立地选自下列基团:氢,氘,氨基,卤素,羟基,硝基,羧基,(C2-C6)链烯基,(C2-C6)炔基,三氟甲基,三氟甲氧基,(C1-C6)烷基,(C1-C6)烷氧基,(C3-C10)环烷基,其中烷基,烷氧基或环烷基任选地被1至3个选自下列的基团取代:卤素,羟基,羧基,氨基(C1-C6)烷基硫代基,(C1-C6)烷基氨基,((C1-C6)烷基)2氨基,(C5-C9)杂芳基,(C2-C9)杂环烷基,(C3-C9)环烷基或(C6-C10)芳基;或者R2和R3各自独立地是(C3-C10)环烷基,(C3-C10)环烷氧基,(C1-C6)烷基氨基,((C1-C6)烷基)2氨基,(C6-C10)芳基氨基,(C1-C6)烷硫基,(C6-C10)芳硫基,(C1-C6)烷基亚磺酰基,(C6-C10)芳基亚磺酰基,(C1-C6)烷基磺酰基,(C6-C10)芳基磺酰基,(C1-C6)酰基,(C1-C6)烷氧基-CO-NH-,(C1-C6)烷基氨基-CO-,(C5-C9)杂芳基,(C2-C9)杂环烷基或(C6-C10)芳基,其中杂芳基,杂环烷基和芳基任选地被1至3个下列基团取代:卤素,(C1-C6)烷基,(C1-C6)烷基-CO-NH-,(C1-C6)烷氧基-CO-NH-,(C1-C6)烷基-CO-NH-(C1-C6)烷基,(C1-C6)烷氧基-CO-NH-(C1-C6)烷基,(C1-C6)烷氧基-CO-NH-(C1-C6)烷氧基,羧基,羧基(C1-C6)烷基,羧基(C1-C6)烷氧基,苄氧基羰基(C1-C6)烷氧基,(C1-C6)烷氧基羰基(C1-C6)烷氧基,(C6-C10)芳基,氨基,氨基(C1-C6)烷基,(C1-C6)烷氧基羰基氨基,(C6-C10)芳基(C1-C6)烷氧基羰基氨基,(C1-C6)烷基氨基,((C1-C6)烷基)2氨基,(C1-C6)烷基氨基(C1-C6)烷基,((C1-C6)烷基)2氨基(C1-C6)烷基,羟基,(C1-C6)烷氧基,羧基,羧基(C1-C6)烷基,(C1-C6)烷氧基羰基,(C1-C6)烷氧基羰基(C1-C6)烷基,(C1-C6)烷氧基-CO-NH-,(C1-C6)烷基-CO-NH-,氰基,(C5-C9)杂环烷基,氨基-CO-NH-,(C1-C6)烷基氨基-CO-NH-,((C1-C6)烷基)2氨基-CO-NH-,(C6-C10)芳基氨基-CO-NH-,(C5-C9)杂芳基氨基-CO-NH-,(C1-C6)烷基氨基-CO-NH-(C1-C6)烷基,((C1-C6)烷基)2氨基-CO-NH-(C1-C6)烷基,(C6-C10)芳基氨基-CO-NH-(C1-C6)烷基,(C5-C9)杂芳基氨基-CO-NH-(C1-C6)烷基,(C1-C6)烷基磺酰基,(C1-C6)烷基磺酰基氨基,(C1-C6)烷基磺酰基氨基(C1-C6)烷基,(C6-C10)芳基磺酰基,(C6-C10)芳基磺酰基氨基,(C6-C10)芳基磺酰基氨基(C1-C6)烷基,(C1-C6)烷基磺酰基氨基,(C1-C6)烷基磺酰基氨基(C1-C6)烷基,(C5-C9)杂芳基或(C2-C9)杂环烷基;
条件是,R5必须被式II的基团取代。
2.权利要求1的化合物,其中R5是任选地被一至三个选自氘,羟基,(C1-C6)烷基,卤素,(C1-C6)烷氧基和式II的基团取代的(C2-C9)杂环烷基。
3.权利要求1的化合物,其中a是0;b是1;X是羰基;c是0;d是0;e是0;f是0;g是0。
4.权利要求1的化合物,其中a是0;b是1;X是羰基;c是0;d是1;e是0;f是0,g是0。
5.权利要求1的化合物,其中a是0;b是1;X是羰基;c是1;d是0;e是0;f是0;g是0。
6.权利要求1的化合物,其中a是0;b是1;X是-C(=N=氰基)-;c是1;d是0;e是0;f是0;g是0。
7.权利要求1的化合物,其中a是0;b是0;c是0;d是0;e是0;f是0;g是1;Z是-C(O)-O-。
8.权利要求1的化合物,其中a是0;b是1;X是S(O)n;n是2;c是0;d是0;e是0;f是0;g是0。
9.权利要求1的化合物,其中a是0;b是1;X是S(O)n;n是2;c是0;d是2;e是0;f是1;g是1;Z是羰基。
10.权利要求1的化合物,其中a是0;b是1;X是S(O)n;n是2;c是0;d是2;e是0;f是1;g是0。
11.权利要求1的化合物,其中a是0;b是1;X是羰基;c是1;d是0;e是1;Y是S(O)n;n是2;f是0;g是0。
12.权利要求1的化合物,其中a是0;b是1;X是S(O)n;n是2;c是1;d是0;e是0;f是0;g是0。
13.权利要求1的化合物,其中a是1;b是1;X是羰基;c是1;d是0;e是0;f是0;g是0。
14.权利要求1的化合物,其中a是0;b是1;X是S(O)n;c是0;d是1;e是1;Y是S(O)n;n是2;f是0;g是0。
15.权利要求1的化合物,其中a是0;b是1;X是S(O)n;c是0;d是2、3或4;e是1;Y是S(O)n;n是2;f是1;g是0。
16.权利要求1的化合物,其中a是0;b是1;X是氧;c是0;d是2、3或4;e是1;Y是S(O)n;n是2;f是1;g是0。
17.权利要求1的化合物,其中a是0;b是1;X是氧;c是0;d是2、3或4;e是1;Y是S(O)n;n是2;f是0;g是0。
18.权利要求1的化合物,其中a是0;b是1;X是羰基;c是1;d是2、3或4;e是1;Y是S(O)n;n是2;f是0;g是0。
19.权利要求1的化合物,其中a是0;b是1;X是羰基;c是1;d是2、3或4;e是1;Y是S(O)n;n是2;f是1;g是0。
20.权利要求1的化合物,其中R12是(C6-C10)芳基或(C2-C9)杂芳基,其中该芳基或杂芳基任选地被一至四个选自以下的基团取代:氢,卤素,羟基,羧基,三氟甲基,(C1-C6)烷基,(C1-C6)烷氧基,(C1-C6)烷基-CO-NH-,氨基,氨基(C1-C6)烷基,(C1-C6)烷基氨基,((C1-C6)烷基)2氨基,氰基,氨基-CO-NH-,(C1-C6)烷基氨基-CO-NH-,((C1-C6)烷基)2氨基-CO-NH-,(C5-C9)杂芳基氨基-CO-NH-,(C1-C6)烷基磺酰基,(C1-C6)烷基磺酰基氨基,(C6-C10)芳基磺酰基氨基,(C1-C6)烷基磺酰基氨基和(C1-C6)烷氧基-CO-NH-。
21.权利要求1的化合物,其中所述的化合物是选自下列这组的化合物:
4-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基甲基}-苯磺酰胺;
4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(4-氨磺酰基-苯基)-酰胺;
4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(4-硝基-苯基)-酰胺;
1-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-2-四唑-1-基-乙酮;
4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(4-甲基氨磺酰基-苯基)-酰胺;
(3-羟基-吡咯烷-1-基)-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-甲酮;
[2-({4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羰基}-氨基)-噻唑-4-基]-乙酸;
甲基-(4-甲基-5′-硝基-3,4,5,6-四氢-2H-[1,2′]联吡啶-3-基)-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺;
5-(2-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-2-氧-乙基)-噻唑烷-2,4-二酮;
{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶4-基)-氨基]-哌啶-1-基}-噻唑烷-3-基-甲酮;
甲基-[4-甲基-1-(5-硝基-噻唑-2-基)-哌啶-3-基]-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺;
[2-({4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羰基}-氨基)-噻唑-4-基]-乙酸乙基酯;
4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(4-甲磺酰基-苯基)-酰胺;
4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸噻唑-2-基酰胺;
4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(4-氰基-苯基)-酰胺;
{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-吡咯烷-1-基-甲酮;
呋喃-2-羧酸(2-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-磺酰基}-乙基)-酰胺;
{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}(四氢-呋喃-3-基)-甲酮;
4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸异噁唑-3-基酰胺;
4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(6-氰基-吡啶-3-基)-酰胺;
4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-3,4,5,6-四氢-2H-[1,2′]联吡啶基-5′-腈;
4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(4-甲基-噻唑-2-基)-酰胺;
2-环丙基-1-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-乙酮;
环戊基-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-甲酮;
4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(3-甲基-异噁唑-4-基)-酰胺;
[4-({4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羰基}-氨基)-苯基]-乙酸;
[1-(5-氨基-噻唑-2-基)-4-甲基-哌啶-3-基]-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺;
4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸(3-甲基-异噻唑-5-基)-酰胺;
3-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羰基}-环戊酮;
4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸苄基-甲基-酰胺;和
4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-羧酸二甲基酰胺。
22.一种药物组合物,用于(a)治疗或预防哺乳动物包括人的下列疾病或症状:器官移植排斥、移植排异、狼疮、多发性硬化、类风湿关节炎、牛皮癣、I型糖尿病和糖尿病并发症、癌症、哮喘、特应性皮肤病、自体免疫性甲状腺病、溃疡性结肠炎、Crohn病、阿尔茨海默病、白血病和其它自体免疫性疾病,或(b)抑制哺乳动物包括人的蛋白激酶或Janus Kinase 3(JAK3),该药物组合物含有对所述疾病或症状有效的一定量的权利要求1化合物或其药学上可接受的盐和药学上可接受的载体。
23.一种药物组合物,用于(a)治疗或预防哺乳动物包括人的下列疾病或症状:器官移植排斥、移植排异、狼疮、多发性硬化、类风湿关节炎、牛皮癣、I型糖尿病和糖尿病并发症、癌症、哮喘、特应性皮肤病、自体免疫性甲状腺病、溃疡性结肠炎、Crohn病、阿尔茨海默病、白血病和其它自体免疫性疾病,或(b)抑制哺乳动物包括人的蛋白激酶或Janus Kinase 3(JAK3),该药物组合物含有对所述疾病或症状有效的一定量的权利要求1化合物或其药学上可接受的盐,单独或与一种或多种另外的调节哺乳动物免疫系统的药剂联合或与抗炎剂联合,并含有药学上可接受的载体。
24.一种抑制哺乳动物包括人的蛋白激酶或Janus Kinase 3(JAK3)的方法,包括给所述的哺乳动物服用有效量的权利要求1化合物或其药学上可接受的盐。
25.一种治疗或预防哺乳动物包括人的下列疾病或症状的方法,该疾病或症状选自器官移植排斥、移植排异、狼疮、多发性硬化、类风湿关节炎、牛皮癣、I型糖尿病和糖尿病并发症、癌症、哮喘、特应性皮肤病、自体免疫性甲状腺病、溃疡性结肠炎、Crohn病、阿尔茨海默病、白血病和其它自体免疫性疾病,该方法包括给所述哺乳动物服用对治疗所述疾病有效的一定量的权利要求1化合物或其药学上可接受的盐。
26.一种抑制哺乳动物包括人的蛋白激酶或Janus Kinase 3(JAK3)的方法,包括给所述的哺乳动物服用有效的一定量的权利要求1化合物或其药学上可接受的盐,单独服用或与一种或多种另外的调节哺乳动物免疫系统的药剂联合或与抗炎剂联合服用。
27.一种治疗或预防哺乳动物包括人的下列疾病或症状的方法,该疾病或症状选自器官移植排斥、移植排异、狼疮、多发性硬化、类风湿关节炎、牛皮癣、I型糖尿病和糖尿病并发症、癌症、哮喘、特应性皮肤病、自体免疫性甲状腺病、溃疡性结肠炎、Crohn病、阿尔茨海默病、白血病和其它自体免疫性疾病,该方法包括给所述哺乳动物服用对治疗所述疾病有效的一定量的权利要求1化合物或其药学上可接受的盐,单独服用或与一种或多种另外的调节哺乳动物免疫系统的药剂联合或与抗炎剂联合服用。
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WO2022117075A1 (zh) * | 2020-12-04 | 2022-06-09 | 广州费米子科技有限责任公司 | 氮杂并环化合物、其制备方法及其用途 |
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