CN109790158B - 作为jak抑制剂杂环化合物，该化合物的盐类及其治疗用途 - Google Patents
作为jak抑制剂杂环化合物，该化合物的盐类及其治疗用途 Download PDFInfo
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- CN109790158B CN109790158B CN201780044794.3A CN201780044794A CN109790158B CN 109790158 B CN109790158 B CN 109790158B CN 201780044794 A CN201780044794 A CN 201780044794A CN 109790158 B CN109790158 B CN 109790158B
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- Prior art keywords
- pyrrolo
- pyridin
- pyrazol
- pyrimidin
- trifluoroethyl
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
公开了一类作为JAK抑制剂杂环衍生物，及该化合物的盐类，(II)、(III)、R的定义详见说明书。此外，还公开了以该化合物、及其盐类为活性成分的药物，及其在制备治疗免疫系统疾病、类风湿关节炎、肿瘤等与JAK相关靶点疾病的药物中的用途。
Description
技术领域
本发明涉及一类作为JAK抑制剂杂环化合物，该化合物的盐类和以该化合物或其盐类为活性成分的药物，及其在制备治疗免疫系统疾病、类风湿关节炎、肿瘤等JAK相关靶点疾病的药物中的用途。
背景技术
JAK-STAT信号通路是近年来发现的一条由细胞因子刺激的信号转导通路，JAK在细胞因子信号传导中起着重要的作用，激酶JAK家族的下游底物包括转录蛋白的信号转导剂和激活剂(STAT)。JAK蛋白是该通路中重要成员，而其活性的异常提高往往导致疾病的发生，很多疾病都与JAK-STAT信号通路异常细胞反应有关，这些疾病包括自身免疫病、炎性病、骨病、代谢病、神经和神经变性病、癌症、心血管病、变态反应和哮喘、阿尔兹海默氏病。
类风湿性关节炎(rheumatoid arthritis，RA)是一种临床常见的慢性自身免疫性疾病，主要表现为关节肿胀、疼痛、僵硬、畸形和功能严重受损等，人群发病率为0.5％-1.0％。由于RA的发病机制尚未明确，因此其病理过程难以控制，致残率高，严重损害患者身心健康，降低患者生存质量。目前用于治疗RA的药物主要有非甾体抗炎药(NSAID)、改善病情抗风湿药(DMARD)、以及抗体类药物。长期以来，治疗RA的一线药物为DMARDs，1988年，第1个DMARD药物甲氨蝶呤(MTX)获FDA批准治疗RA，MTX是RA治疗史上的一个重要里程碑。该药物因其有效性、耐受性、安全性等优势而被广泛应用，但其具有包括恶心、呕吐、胃部不适、肝毒性等不良反应。相比之下，新近发展的抗体类药物对于中重度RA具有较好的疗效性和安全性指标，但是因其靶向特定的细胞因子，获益人群受到明显限制，同时治疗费用和注射方式给药也限制了这类药物的推广。
在过去20年的发展历程中，RA治疗已经取得长足进步，患者病情经现有治疗方法已经可以有效控制。尽管如此，RA患者仍经受疾病复发、治疗有效性不理想、长期耐受性差及一些不良反应等问题。更为重要的是，RA患者的生活质量包括关节等器官功能在现有治疗手段并没有得到真正的改善，因此，着眼于恢复患者的正常机能在这一领域仍存在巨大的未满足的临床需求。
研究表明，在RA中起核心治病作用的是RA滑膜组织及细胞中浸润的单核/巨噬细胞、淋巴细胞等通过自分泌的方式产生大量细胞因子，这些细胞因子相互作用，通过不同途径激活JAK/STAT信号通路(Janus kinase/Signal transducer and activators oftranscription signaling pathway)，通过特异性抑制JAK/STAT信号通路，可阻断上述细胞因子的级联放大作用，从而改善RA患者受损关节症状，因此，JAK/STAT信号通路成为治疗RA的潜在靶点。2012年11月，口服JAK抑制剂Tofacitinib首获FDA批准用于治疗类风湿性关节炎(rheumatoid arthritis，RA)，成为该领域第1个成功的激酶抑制剂药物。
JAK-STAT信号通路是近年来发现的一条由细胞因子刺激的信号转导通路，JAK在细胞因子信号传导中起着重要的作用，JAK激酶(Janus kinase，简称JAKs，包括四个已知成员JAK1、JAK2、JAK3、TYK2)是胞浆内非受体酪氨酸蛋白激酶超家族中的一个小家族。JAK3分布于骨髓和淋巴系统中，JAK1、TYK2、JAK2则广泛分布于多种组织细胞中。当JAKs结合到细胞表面的细胞因子受体后，激活受体偶联的JAKs，进而使受体磷酸化，这为胞浆信号传导和转录激活因子STAT蛋白(Signal Transducers and ActivatorsOf Transcription，STAT1-4、STAT5a、STAT5b、STAT6)提供了募集反应位点，JAKs磷酸化STAT蛋白，后者二聚化后转移到细胞核内调控基因表达，这条途径即JAK/STAT信号通路(O’Shea J.J.,et al.,N.Engl.J.Med.,2013,368:161-170)。
JAK/STAT信号通路是一条由多种细胞因子和生长因子受体刺激的信号传导通路，这些因子包括白介素类、干扰素类(IFN-а、IFN-β、IFN-γ)、促红细胞生成素(EPO)、粒细胞和巨细胞集落刺激因子(GM-CSF)、促生长素(GH)、催乳素(PRL)、促血小板生成素(TPO)等，其在参与免疫细胞和造血干细胞的增殖、免疫调节的生物学过程中起关键作用(GhoreschiK.,et al.Immunol.Rev.,2009,228:273-287)。
JAK1可与IL-10、IL-19、IL-20、IL-22、IL-26、IL-28、IFN-а、IFN-γ、gp130家族中的IL-6以及含γc的其它受体等结合(Rodig S.J.,et al.Cell,1998,93:373-383)。小鼠模型上的JAK1基因敲除实验表明该酶在调节上述多种细胞因子受体的生物学效应中起着关键作用(Kisseleva T.,et al.,Gene,2002,285:1-24)。JAK1是免疫相关疾病、炎症和癌症等疾病领域的新型靶点。JAK1抑制剂可用于治疗/预防自身免疫性疾病炎症和(HornakovaT.,etal.,Blood,2010,115:3287-3295)，如白血病、淋巴瘤、黑色素瘤、关节炎、银屑病、克罗恩病、红斑狼疮、获得性免疫缺陷综合症(Hou S.,et al.,Hum.Genet.,2013,132:1049-1058)等。
JAK2在包括IL-3、IFN-γ、EPO、GH等多种受体信号的调节过程中发挥重要作用(Levy D.E.,et al.,Nat.Rev.Mol.Cell Biol.,2002,3:651-662；)。在小鼠模型中敲除JAK2可导致贫血动物死亡(Schindler C.,et al.,J.Biol.Chem.,2007,282:20059-20063)；人体中的JAK2基因上的一个碱基突变JAK2V617F，其与骨髓增生性疾病中的真性红细胞增多症(PV)、特发性血小板增多症(ET)等的发生密切相关(Ghoreschi K.,et al.,Immunol.Rev.,2009,228:273-287)。
JAK3通过与IL-2、IL-4、IL-7、IL-9、IL-15、IL-21等细胞因子受体复合物中的γ共链(γc)相结合，调节细胞信号传导。JAK3或γc突变都可导致重症联合免疫缺陷(SCID)(Villa A.,et al.,Blood,1996,88:817-823)。JAK3活性异常表现为T细胞和NK细胞大量减少，B细胞功能丧失，严重影响免疫系统等的正常生物学功能。基于其功能特点和特殊的组织分布，JAK3成为针对免疫系统相关疾病极具吸引力的药物靶点，其抑制剂在类风湿性关节炎(RA)、克罗恩病、系统性红斑狼疮、多发性硬化症、I型糖尿病、银屑病、过敏性疾病、哮喘、慢性阻塞性肺病、白血病、淋巴瘤、器官移植和其它等疾病的治疗/预防方面具有重要的临床应用价值(Papageorgiou A.C.,etal.,2004,Trends Pharm.Sci.,2004,25:558-562)。
TYK2是JAK家族中的第一个成员，其可被干扰素(IFNs)、IL-10、IL-12、IL-23、IL-27等多种受体激活。在小鼠中，TYK2功能缺失会引起多种细胞因子受体的信号
通路发生缺陷，进而导致病毒感染、抗菌免疫功能下降并增加了肺部感染的可能性等(Kisseleva T.,et al.，2002,Gene,285:1-24)。另外，LarnerA.C小组的研究表明TYK2可有助于抑制乳腺癌的生长和转移(Zhang Q.,etal.,2011,J.Interferon CytokineRes.,31:671-677)。
由于JAK激酶参与体内各种重要的生理过程，对不同亚型的广泛抑制有可能产生不良反应，Tofacitinib用于MTX反应不足或不耐受的中重度RA患者，临床试验观察其伴随一定的不良反应，包括感染、结核、肿瘤、贫血、肝损伤及胆固醇增加等。Tofacitinib对JAK1，JAK2，JAK3亚型均有显著的抑制活性，由于JAK2活性与红细胞分化以及脂代谢过程相关，上述部分不良反应被认为与该药物的非选择性抑制特点相关。因此，寻找选择性JAK1和/或JAK3抑制剂将成为RA药物研究的新方向。
目前JAK抑制剂已经被证实可以用于血液系统疾病、肿瘤、类风湿性关节炎及银屑病等治疗药物。由于JAK抑制剂有显著的医疗用途可以用于各种相关疾病药物，所以对该类化合物的研究及发现是极其有益的。
发明内容
本发明的第一个目的是提供一类JAK抑制剂杂环衍生物。
具体地说，本发明提供了一类JAK抑制剂杂环衍生物，其具有式(I)结构：
及其异构体、溶剂合物、或其药学上可接受的盐。
当
选自:
R选自：
当X为-CONH-R4时，R4为氢、C1-C6烷基、或C3-C6环烷基，并可被卤原子任意取代；
R1，R2独立地选自氢、C1-C6烷基，并可被C1-C6烷氧基、C1-C6烷基磺酰基取代，R1，R2还可与其相连的碳原子形成4-10杂环，该环碳原子可被N、O、S、-SO2-替代，该环可被C1-C6烷基磺酰基、C1-C6烷基、C1-C6烷基酰基取代；
R3为氢、C1-C7烷基酰基、或C3-C7环烷基酰基；
n选自0、1、2、3、4、5；
X1为N、-CR5；
R5为H、-CN、或卤原子；
当X为-CN时，
其中：
R1、R2为氢、C1-C6烷基，并可被C1-C6烷氧基、C1-C6烷基磺酰基取代，当R1、R2与其相连的碳原子形成4-10元环，该环可被C1-C6烷基、C1-C6烷基磺酰基、C1-C6烷基酰基取代，该C1-C6烷基、C1-C6烷基磺酰基、或C1-C6烷基酰基可被卤原子任意取代；
这时R1、R2选自与其相连的碳原子形成5-8元环，该环碳原子可被N、O、S、或-SO2-替代，该环可被C1-C6烷基、C1-C6烷基磺酰基取代；
当
选自：
X2为N、CR6；
X3为N、CR7；
R6、R7独立地选自氢、-CN、卤原子；
X1为N、或-CR5；
R5为H、-CN、或卤原子；
R选自：
当X选自-CONH-R4时，R4为氢、C1-C6烷基、C3-C6环烷基，并可被卤原子任意取代；
R1、R2选自与其相连的碳原子形成4-10元环，该环碳原子可被N、O、S、或-SO2-替代，该环可被C1-C6烷基、C1-C6烷基磺酰基、或C1-C6烷基酰基取代；
当X为-CN时，
R1，R2独立地选自氢、C1-C6烷基，并可使C1-C6烷氧基、C1-C6烷基磺酰基、芳基、杂芳基取代，R1，R2还可与其相连的碳原子形成4-10元环，该环碳原子可被N、O、S、或-SO2-替代，该环可被烷基磺酰基、C1-C6烷基、C1-C6烷基酰基取代；R1，R2之一还可以与R8连接成4-6元环；
R8为氢、或C1-C6烷基；
m选自0、1、2、3、4、5。
具体地，本发明所述的化合物具有式(II)结构：
及其异构体、溶剂合物、或其药学上可接受的盐；
其中：
当X为-CONH-R4时，R4为氢、C1-C6烷基、或C3-C6环烷基，并可被卤原子任意取代；
R1，R2独立地选自氢、C1-C6烷基，并可被C1-C6烷氧基、C1-C6烷基磺酰基取代，R1，R2还可与其相连的碳原子形成4-10杂环，该环碳原子可被N、O、S、或-SO2-替代，该环可被C1-C6烷基磺酰基、C1-C6烷基、或C1-C6烷基酰基取代；
R3为氢、C1-C7烷基酰基、或C3-C7环烷基酰基；
n选自0、1、2、3、4、5；
X1为N、或-CR5；
R5为H、-CN、或卤原子；
当X为-CN时，
其中：
R1、R2为氢、C1-C6烷基，并可被C1-C6烷氧基、或C1-C6烷基磺酰基取代，当R1、R2与其相连的碳原子形成4-10元环，该环可被C1-C6烷基、C1-C6烷基磺酰基、C1-C6烷基酰基取代，该C1-C6烷基、C1-C6烷基磺酰基、C1-C6烷基酰基可被卤原子任意取代；
当
选自:
这时R1、R2选自与其相连的碳原子形成5-8元环，该环碳原子可被N、O、S、或-SO2-替代，该环可被C1-C6烷基、或C1-C6烷基磺酰基取代。
优选地，本发明所述的式(Ⅱ)化合物选自但不限于以下结构：
2-(3-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)乙腈；
2-(4-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)乙腈
2-(4-(4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)乙腈
2-(4-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)乙腈；
2-(4-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1-(甲磺酰基)哌啶-4-基)-N-(2,2,2-三氟乙基)乙腈；
2-(3-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)乙酰胺；
2-(3-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)-N-(2,2,2-三氟乙基)乙酰胺；
2-(3-(4-(1H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)-N-(2,2,2-三氟乙基)乙酰胺；
2-(3-(4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)-N-(2,2,2-三氟乙基)乙酰胺；
2-(3-(4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)-N-甲基乙酰胺；
2-(3-(4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)乙酰胺；
2-(3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-1-(甲磺酰基)氮杂环丁-3-基)-N-(2,2,2-三氟乙基)乙酰胺；
2-(3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-1-(甲磺酰基)氮杂环丁-3-基)-N-甲基乙酰胺；
2-(3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-1-(甲磺酰基)氮杂环丁-3-基)乙酰胺；
2-(3-(4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1-(甲磺酰基)氮杂环丁-3-基)-N-(2,2,2-三氟乙基)乙酰胺；
2-(3-(4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1-(甲磺酰基)氮杂环丁-3-基)-N-甲基乙酰胺；
2-(3-(4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1-(甲磺酰基)氮杂环丁-3-基)乙酰胺；
2-(4-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)乙酰胺
2-(4-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)-N-(2,2,2-三氟乙基)乙酰胺；
2-(4-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)-N-(2,2,2-三氟乙基)乙酰胺；
2-(4-(4-(7H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)-N-(2,2,2-三氟乙基)乙酰胺；
2-(4-(4-(7H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1-(甲磺酰基)哌啶-4-基)-N-(2,2,2-三氟乙基)乙酰胺；
2-(4-(4-(7H-吡咯并[2,3-b]嘧啶-4-基)-1H-吡唑-1-基)-1-(甲磺酰基)哌啶-4-基)-N-(2,2,2-三氟乙基)乙酰胺；
2-(4-(4-(7H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1-(甲磺酰基)哌啶-4-基)-N-(2,2,2-三氟乙基)乙酰胺；
2-(1-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)环戊基)-N-(2,2,2-三氟乙基)乙酰胺；
2-(1-(4-(1H-吡咯并[2,3-b]嘧啶-4-基)-1H-吡唑-1-基)环戊基)-N-(2,2,2-三氟乙基)乙酰胺；
2-(1-(4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)环戊基)-N-(2,2,2-三氟乙基)乙酰胺；
3-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-3-甲基-N-(2,2,2-三氟乙基)丁酰胺；
3-(4-(7H-吡咯并[2,3-b]嘧啶-4-基)-1H-吡唑-1-基)-3-甲基-N-(2,2,2-三氟乙基)丁酰胺；
3-(4-(7H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-3-甲基-N-(2,2,2-三氟乙基)丁酰胺；
及其异构体、溶剂合物、或其药学上可接受的盐。
具体地、本发明所述的化合物具有式(Ⅲ)结构:
其中:
X2为N、或CR6；
X3为N、或CR7；
R6、R7独立地选自H、-CN、卤原子；
X1为N、-CR5；
R5为H、-CN、卤原子；
当X选自-CONH-R4时，
R1、R2选自与共相连的碳原子形成4-10元环，该环碳原子可被N、O、S、-SO2-替代，该环可被C1-C6烷基、C1-C6烷基磺酰基、C1-C6烷基酰基取代；
R4为氢、C1-C6烷基、C3-C6环烷基，并可被卤原子任意取代；
当X为-CN时，
R1，R2独立地选自氢、C1-C6烷基，并可使C1-C6烷氧基、C1-C6烷基磺酰基、芳基、或杂芳基取代，R1，R2还可与其相连的碳原子形成4-10元环，该环碳原子可被N、O、S、或-SO2-替代，该环可被烷基磺酰基、C1-C6烷基、C1-C6烷基酰基取代；R1，R2之一还可以与R8连接成4-6元环；
R8为氢、或C1-C6烷基；
m选自0、1、2、3、4、5。
优选地，本发明所述的式(Ⅲ)化合物选自但不限于以下结构：
3-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(甲磺酰基)-N-(2,2,2-三氟乙基)氮杂环丁烷-3-甲酰胺；
3-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(乙磺酰基)-N-(2,2,2-三氟乙基)氮杂环丁烷-3-甲酰胺；
3-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(环丙磺酰基)-N-(2,2,2-三氟乙基)氮杂环丁烷-3-甲酰胺；
3-(5-氟-2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(甲磺酰基)-N-(2,2,2-三氟乙基)氮杂环丁烷-3-甲酰胺；
3-(5-氟-2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(乙磺酰基)-N-(2,2,2-三氟乙基)氮杂环丁烷-3-甲酰胺；
3-(5-氟-2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(环丙磺酰基)-N-(2,2,2-三氟乙基)氮杂环丁烷-3-甲酰胺；
4-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(甲磺酰基)-N-(2,2,2-三氟乙基)哌啶-4-甲酰胺；
4-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(乙磺酰基)-N-(2,2,2-三氟乙基)哌啶-4-甲酰胺；
4-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(环丙磺酰基)-N-(2,2,2-三氟乙基)哌啶-4-甲酰胺；
4-((5-氟-2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(甲磺酰基)-N-(2,2,2-三氟乙基)哌啶-4-甲酰胺；
4-((5-氟-2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(乙磺酰基)-N-(2,2,2-三氟乙基)哌啶-4-甲酰胺；
4-((5-氟-2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(环丙磺酰基)-N-(2,2,2-三氟乙基)哌啶-4-甲酰胺；
4-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-N-(2,2,2-三氟乙基)四氢-2H-硫代吡喃-4-甲酰胺1,1-二氧化物；
4-((5-氟-2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-N-(2,2,2-三氟乙基)四氢-2H-硫代吡喃-4-甲酰胺1,1-二氧化物；
3-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(乙磺酰基)氮杂环丁烷-3-腈；
3-((2-(7H-吡咯并[2,3-d]嘧啶-4-基)嘧啶-4-基)氨基)-1-(乙磺酰基)氮杂环丁烷-3-腈；
3-((2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)氨基)-1-(乙磺酰基)氮杂环丁烷-3-腈；
3-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(甲磺酰基)氮杂环丁烷-3-腈；
3-((2-(7H-吡咯并[2,3-d]嘧啶-4-基)嘧啶-4-基)氨基)-1-(甲磺酰基)氮杂环丁烷-3-腈；
3-((2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)氨基)-1-(甲磺酰基)氮杂环丁烷-3-腈；
4-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)四氢-2H-硫代吡喃-4-腈1,1-二氧化物；
4-((2-(7H-吡咯并[2,3-d]嘧啶-4-基)嘧啶-4-基)氨基)四氢-2H-硫代吡喃-4-腈1,1-二氧化物；
4-((2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)氨基)四氢-2H-硫代吡喃-4-腈1,1-二氧化物；
1-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)环丁烷-3-腈；
1-((2-(7H-吡咯并[2,3-d]嘧啶-4-基)嘧啶-4-基)氨基)环丁烷-3-腈；
1-((2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)氨基)环丁烷腈；
1-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)环戊腈；
1-((2-(7H-吡咯并[2,3-d]嘧啶-4-基)嘧啶-4-基)氨基)环戊烷腈；
1-((2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)氨基)环戊烷腈；
(R)-2-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基-2-甲基丁腈；
(R)-2-((2-(7H-吡咯并[2,3-d]嘧啶-4-基)嘧啶-4-基)氨基-2-甲基丁腈；
(R)-2-((2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)氨基-2-甲基丁腈；
及其异构体、溶剂合物、或其药学上可接受的盐。
专业术语
术语“烷基”是指链中具有1至12个碳原子的直链或支链的烷基，烷基的实例包括甲基(Me)、乙基(Et)、正丙基、异丙基、丁基、异丁基、仲丁基、叔丁基(t-Bu)、戊基，异戊基、叔戊基、己基，异己基、以及根据本领域普通技术人员和文本所提供的教导认为是相当于上述实例中的任何一种基团。
术语“烷氧基”是指键接氧原子的如上定义的烷基。烷氧基经由氧原子连接到母体结构。
术语“氨基”是指-NH2基团或单或二烷基氨基。
术语环烷基是指饱和和部分饱和的，单环的、稠合多环的、桥连多环的、或螺多环的碳环，每个碳环具有3至12个环原子数。环烷基的说明性实例包括以下部分的适当键合形式：
术语“芳基”是指5-6元的碳芳香环，如，苯；
双环，其中至少有一个环是碳芳香环，如，萘，茚和1，2，3，4-四氢喹啉；以及三环，其中至少有一个环是碳芳香环，如，芴。
例如，芳基包括含5-6元的碳芳香环并一个5-7元杂环，这个杂环包括一个或多个选自氮﹑氧和硫的杂原子，条件是连接点在碳芳香环上.通过取代的苯的衍生物且环上原子有自由价态的形成二价自由基，其命名为取代的亚苯基自由基。由命名以“基”结尾的单价多环烃自由基通过减少一个自由价态的氢原子衍生而来的二价自由基，其命名就是在相应的单价自由基的后面加上“亚基”，例如，有两个连接点的萘基被称为亚萘基。但是，芳基不包含﹑也不通过任何方式与下面分别定义的杂环芳基重叠。因此，在此定义，如果一个或多个碳芳香环与一个杂芳香环并列，由此产生的环系统是芳杂环基，而不是芳基。
术语“芳杂基”指的是：
5-8元的单环芳烃，含一个或多个选自N，O和S的杂原子，如1-4个杂原子，在一些实施方案中，为1-3个杂原子，环上其它原子是碳原子；
8-12元的双环芳烃，含一个或多个选自N，O和S的杂原子，如1-4个杂原子，在一些实施方案中，为1-3个杂原子，环上其它原子是碳原子；其中至少有一个环是芳香环；以及
术语“杂环烷基”是指饱和或部分不饱和单环或多环环状烃取代基，其包括3至20个环原子，其中一个或多个环原子选自氮、氧或S(O)m(其中m是0-2的整数)的杂原子，其余环原子为碳。优选包括3至12个环原子，其中1～4个杂原子，更优选的杂环烷基环包含3至10个环原子，更优选的杂环烷基环包含5至6个环原子。单环杂环烷基的非限制性实例包含吡咯烷基、哌啶基、吗啉基四氢呋喃基等。多环杂环烷基包括螺环、稠环和桥环的杂环烷基。杂环可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、卤代烷基、烷氧基、烷基氨基、卤素、羟基、氨基、氧代基、烷氨基、环烷基、杂环烷基、杂环烷氧基、羟烷基、羧基或羧酸酯基。
术语”卤素”表示氯、氟、溴或碘。术语“卤代”代表氯代，氟代，溴代或碘代。术语“卤代烷基”是指如上所定义的烷基，其被一个或多个卤原子取代。
术语“卤代烷氧基”是指如上所定义的烷氧基，其被一个或多个卤原子取代。
术语“酰基”是指1至10个碳原子的直链、支链、或环状构型或其组合的基团R-C(O)-，其通过羰基官能团连接到母体结构，这样的基团可以是饱和的或不饱和的，和酯族或芳族的。
在本发明所提供的实施方案中，本发明的化合物如含有碱性基团，则可与酸成盐，采用本领域技术人员所熟知的方法可以制备嘧啶类衍生物的盐。
常见酸盐有有机酸盐、无机酸盐等。通常，比较常用的有机酸盐有枸橼酸盐、富马酸盐、草酸盐、苹果酸盐、乳酸盐、磺酸盐(例如樟脑磺酸盐、对甲苯磺酸盐、甲磺酸盐等)等；无机酸盐有氢卤酸盐、硫酸盐、磷酸盐、硝酸盐等。
例如，与低级烷基磺酸，如甲磺酸，三氟甲磺酸等可形成甲磺酸盐、三氟甲磺酸盐；与芳基磺酸，如苯磺酸或对甲苯磺酸等可形成对甲苯磺酸盐、苯磺酸盐；与有机羧酸，如乙酸，富马酸，酒石酸，草酸，马来酸，苹果酸，琥珀酸或柠檬酸等可形成相应的盐；与氨基酸，如谷氨酸或天冬氨酸可形成谷氨酸盐或天冬氨酸盐。与无机酸，如氢卤酸(如氢氟酸、氢溴酸、氢碘酸、氢氯酸)，硝酸，碳酸，硫酸或磷酸等也可形成相应的盐。
在本发明所提供的实施方案中，本发明的化合物如含有酸性基团，则可与碱成盐，采用本领域技术人员所熟知的方法可以制备本发明化合物的盐，例如，与碱金属，如钠、钾或锂形成的盐；与碱土金属如钙或钡形成的盐；与其它金属如镁、铝形成的盐；也可与有机碱形成盐，如二环己基胺、胍或三乙胺形成盐。
第二方面，本发明提供利用本发明式(I)JAK抑制剂化合物、异构体或其药学上可接受的盐或溶剂化合物为活性成分的药物。在上述药物中还可以含有一种或多种药学上可接受的载体，所述载体包括药学领域的常规稀释剂，赋形剂，填充剂，粘合剂，湿润剂，崩解剂，吸收促进剂，表面活性剂，吸附载体，润滑剂等，必要时还可以加入香味剂，甜味剂等。本发明药物可以制成片剂，粉剂，粒剂，胶囊，口服液及注射用药等多种形式，上述各剂型的药物均可以按照药学领域的常规方法制备。
第三方面，本发明提供式(I)JAK抑制剂杂环化合物、异构体及其药学上可接受的盐可应用治疗人或动物自身免疫疾病、类风湿性关节炎、皮肤病症、多发性硬化，银屑性关节炎、炎性肠病、重症肌无力、牛皮藓中的药物中，特别是JAK激酶相关疾病的药物中的应用。
本发明发明人通过实验证实，本发明所公开的一些化合物对JAK激酶特别是JAK1具有较好的抑制作用，对JAK2、JAK3抑制活性较低，提示本品为选择性JAK抑制剂，对采用式(I)化合物、或其药学上可接的盐治疗自身免疫疾病、类风湿性关节炎、皮肤病症、多发性硬化，类风湿关节炎、银屑性关节炎、炎性肠病、重症肌无力、牛皮藓的药物中，具有更低的毒性。
具体实施方式
下面通过实施例来说明本发明的可实施性，本领域的技术人员应当理解，根据现有技术的教导，对相应的技术特征进行修改或替换，仍然属于本发明要求保护的范围
实施例1、2-(3-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)乙腈
步骤1、3-(1-(1-乙氧乙基)-1H-吡唑-4-基)-1-((2-三甲硅基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶
将2.7g 3-溴-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶，3.2g1-(1-乙氧乙基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1H-吡唑，3g碳酸钾，90mgPd(dppf)Cl2溶于21ml正丁醇和7ml水，加热到100℃反应20小时，反应完全，将反应液浓缩至干，乙酸乙酯萃取，有机层用无水硫酸钠干燥，过滤，浓缩，硅胶柱层析，得1.2g油状物。
步骤2、3-(1H-吡唑-4-基)-1-((2-三甲硅基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶
将步骤1产物1.2g加入四氢呋喃9ml，H2O 22.5ml，然后加入10％稀盐酸3ml，室温搅拌反应，1小时后反应完全，然后加入30％氢氧化钠调PH至7，二氯甲烷萃取，干燥(Na2SO4)，浓缩得1.0g油状物。
步骤3、2-(1-(乙磺酰基)-3-(4-(1-((2-三甲硅基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-氮杂环丁-3-基)乙腈
将步骤2产物0.5g，2-(1-(乙磺酰基)氮杂环丁-3-亚基)乙腈0.2g加入20ml乙腈中，在室温下加入DBU 10mg，反应5小时，待反应完全，加乙酸乙酯萃取，水洗，有机层干燥，过滤，浓缩，柱层析得目标物0.6g。
步骤4、2-(3-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)乙腈
取步骤3产物0.5g，加入5ml三氟乙酸，室温反应3h，薄层层析(乙酸乙酯/石油醚1：2)，待反应完全，浓缩至干，加入1ml乙二胺反应2h，浓缩至干，过滤，浓缩，柱层析得目标物0.3g。
1HNMR(400MHz,DMSO-D6)δ11.74(s,1H),8.51(s,1H),8.33(d,J＝7.9Hz,1H),8.26(d,J＝4.6Hz,1H),8.09(s,1H),7.80(d,J＝1.8Hz,1H),7.15(dd,J＝7.9,4.7Hz,1H),4.55(d,J＝8.8Hz,2H),4.22(d,J＝8.8Hz,2H),3.64(s,2H),3.25(q,J＝7.3Hz,2H),1.25(t,J＝7.3Hz,3H).
MS(ESI):367.14(M+1)
实施例2、2-(4-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)乙腈
参考实施例1方法合成。
1HNMR(400MHz,DMSO-D6)δ11.72(s,1H),8.50(s,1H),8.36-8.31
(m,1H),8.26(dd,1H),8.06(s,1H),7.79(d,1H),7.14(dd,1H),3.29(d,4H),3.13-2.96(m,4H),2.55(d,2H).
MS(ESI):356.11(M+1)
实施例3、2-(4-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)乙腈
参考实施例1方法合成；
或按下列步骤合成：
步骤1、2-(1,1-二氧代-4-(4-(7-((2-(三甲硅基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-四氢-2H-硫代吡喃-4-基)乙腈
在250ml圆底烧瓶中，室温加入15g 4-(1H-吡唑-4-基)-7-((2-(三甲硅基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶、100ml乙腈，氮气保护，冰浴冷却至0℃，然后加入0.72gDBU，9.0g 2-(1,1-二氧代二氢-2H-硫代吡喃-4(3H)-亚基)乙腈，继续在0℃反应5小时，然后室温20℃反应一晚上，至原料基本反应完毕，薄层层析监测反应，过滤固体，乙酸乙酯洗涤，滤液浓缩至干，加乙酸乙酯析出固体，乙酸乙酯/正己烷洗涤，得固体，合并固体，干燥后得产物8g。
步骤2、2-(4-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)乙腈
取5g步骤1产物，加入30ml三氟乙酸，室温反应3h，薄层层析(乙酸乙酯/石油醚1：2)，待反应完全，浓缩至干，加入1ml乙二胺反应2h，
浓缩至干，过滤，浓缩，柱层析得目标物2.6g。
1HNMR(400MHz,DMSO-D6)δ12.15(s,1H),8.91(s,1H),8.71(s,1H),8.47(s,1H),7.62(m,1H),7.10(m,1H),3.41(s,2H),3.29(m,2H),3.00-3.17(m,4H),2.54-2.60(m,2H).
MS(ESI):356.11(M+1)
实施例4、2-(4-(4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)乙腈
参考实施例1方法合成。
1HNMR(400MHz,DMSO-D6)δ11.72(s,1H),8.78(s,1H),8.33(s,1H),8.20(d,1H),7.53(d,1H),7.36(d,1H),6.90(d,1H),3.38(s,2H),3.28-3.33(m,2H),3.12(m,2H),3.02(m,2H),2.56(m,2H).
MS(ESI):356.11(M+1)
施例5、2-(4-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1-(甲磺酰基)哌啶-4-基)-N-(2,2,2-三氟乙基)乙腈
参考实施例1方法合成。
MS(ESI):385.14(M+1)
实施例6、2-(3-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)乙酰胺
取实施例(1)产物0.3g，甲醇10ml，加1M氢氧化钠2ml，50℃反应2小时，盐酸调PH至7，除甲醇，过滤得目的物。
1HNMR(400MHz,DMSO-D6)δ11.70(s,1H),8.33–8.23(m,3H),7.99(s,1H),7.74(d,J＝2.5Hz,1H),7.47(s,1H),7.12(dd,J＝7.9,4.7Hz,1H),6.97(s,1H),4.46(d,J＝8.9Hz,2H),4.35(d,J＝8.9Hz,2H),3.20(q,J＝7.1Hz,2H),3.08(s,2H),1.24(t,J＝7.3Hz,3H).
MS(ESI):389.14(M+1)
实施例7、2-(3-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)-N-(2,2,2-三氟乙基)乙酰胺
步骤1、2-(3-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)乙酸
取0.6g实施例(1)产物，加1M氢氧化钠4ml，20ml甲醇，回流反应10小时，盐酸调PH至6，除甲醇，二氯甲烷萃取，干燥，浓缩，过滤得目的物0.4g。
步骤2、2-(3-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)-N-(2,2,2-三氟乙基)乙酰胺
取0.4g步骤1产物溶于5ml干燥DMF中，加入0.18g N-(3-二甲氨基丙基)-N'-乙基碳二亚胺盐酸盐(EDC.HCl)，搅拌1小时后，加入0.1g三氟乙胺，2小时反应完毕后，加水稀释，二氯甲烷萃取，干燥，浓缩，柱层析得目的物0.3g。
1H NMR(400MHz,DMSO-D6)δ11.68(s,1H),8.76(m,1H),8.24-8.28(m,3H),7.98(s,1H),7.12(m,1H),4.47(d,2H),4.35(d,2H),3.83(m,2H),3.20(m,4H),1.24(t,3H).
MS(ESI):471.14(M+1)
实施例8、2-(3-(4-(1H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)-N-(2,2,2-三氟乙基)乙酰胺
参考实施例7步骤2方法制备。
1H NMR(400MHz,DMSO-D6)δ11.12(s,1H),8.73(m,1H),8.71(m,1H),8.68(m,1H),8.39(s,1H),7.59(d,1H),7.02(d,1H),4.53(d,2H),4.36(d,2H),3.81(m,2H),3.27(s,2H),3.18-3.23(m,2H),1.23(t,3H).
MS(ESI):472.13(M+1)
实施例9、2-(3-(4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)-N-(2,2,2-三氟乙基)乙酰胺
参考实施例7步骤2方法制备。
MS(ESI):471.14(M+1)
实施例10、2-(3-(4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)-N-甲基乙酰胺
参考实施例7步骤2方法制备。
MS(ESI):403.15(M+1)
实施例11、2-(3-(4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)乙酰胺
参考实施例6方法制备。
1HNMR(400MHz,DMSO-D6)δ11.72(s,1H),8.52(s,1H),8.21(s,1H),8.14(d,J＝5.0Hz,1H),7.46(dd,J＝8.5,5.4Hz,2H),7.27(d,J＝5.0Hz,1H),6.94(s,1H),7.79(dd,J＝3.5,1.8Hz,1H),3.64(s,2H),4.47(d,J＝9.0Hz,2H),4.32(d,J＝9.0Hz,2H),3.17(q,J＝7.3Hz,2H),3.08(s,2H),1.20(t,J＝7.3Hz,3H).
MS(ESI):389.14(M+1)
实施例12、2-(3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-1-(甲磺酰基)氮杂环丁-3-基)-N-(2,2,2-三氟乙基)乙酰胺
参考实施例7步骤2方法制备。
MS(ESI):458.12(M+1)
实施例13、2-(3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-1-(甲磺酰基)氮杂环丁-3-基)-N-甲基乙酰胺
参考实施例7步骤2方法制备。
MS(ESI):390.13(M+1)
实施例14、2-(3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-1-(甲磺酰基)氮杂环丁-3-基)乙酰胺
参考实施例6方法制备。
MS(ESI):376.11(M+1)
实施例15、2-(3-(4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1-(甲磺酰基)氮杂环丁-3-基)-N-(2,2,2-三氟乙基)乙酰胺
参考实施例7步骤2方法制备。
MS(ESI):457.12(M+1)
实施例16、2-(3-(4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1-(甲磺酰基)氮杂环丁-3-基)-N-甲基乙酰胺
参考实施例7步骤2方法制备。
MS(ESI):389.14(M+1)
实施例17、2-(3-(4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1-(甲磺酰基)氮杂环丁-3-基)乙酰胺
参考实施例6方法制备。
MS(ESI):375.12(M+1)
实施例18、2-(4-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)乙酰胺
参考实施例6方法制备。
1HNMR(400MHz,DMSO-D6)δ11.67(s,1H),8.37-8.27(m,2H),8.25(dd,J＝4.6Hz,1.4Hz,1H),7.98(s,1H),7.75(d,J＝2.5Hz,1H),7.31(s,1H),7.12(dd,J＝7.9,4.7Hz,1H),6.91(s,1H),3.21(d,J＝13.2Hz,2H),2.55(d,J＝11.9Hz,2H),3.08(d,J＝14.7Hz,2H),3.08(t,J＝13.4Hz,2H),2.95(t,J＝13.4Hz,2H),2.69(t,J＝12.5Hz,2H),2.61(s,2H).
MS(ESI):374.12(M+1)
实施例19、2-(4-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)-N-(2,2,2-三氟乙基)乙酰胺
参考实施例7步骤2方法制备。
1HNMR(400MHz,DMSO-D6)δ11.68(s,1H),8.61(m,1H),8.28-8.32(m,2H),8.24-8.25(m,1H),7.98(s,1H),7.74(d,1H),7.12(m,1H),3.82(m,2H),2.65-3.34(m,8H),2.50(m,2H).
MS(ESI):456.13(M+1)
实施例20、2-(4-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)-N-(2,2,2-三氟乙基)乙酰胺
参考实施例7步骤2方法制备。
1HNMR(400MHz,DMSO-D6)δ12.11(s,1H),8.72(s,1H),8.67(s,1H),8.59(m,1H),8.39(s,1H),7.59(d,1H),7.05(d,1H),3.81(m,2H),3.24(m,2H),3.12(m,2H),2.97(m,2H),2.83(s,2H),2.67(m,2H).
MS(ESI):457.12(M+1)
实施例21、2-(4-(4-(7H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)-N-(2,2,2-三氟乙基)乙酰胺
参考实施例7步骤2方法制备。
MS(ESI):456.12(M+1)
实施例22、2-(4-(4-(7H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1-(甲磺酰基)哌啶-4-基)-N-(2,2,2-三氟乙基)乙酰胺
参考实施例7步骤2方法制备。
MS(ESI):485.15(M+1)
实施例23、2-(4-(4-(7H-吡咯并[2,3-b]嘧啶-4-基)-1H-吡唑-1-基)-1-(甲磺酰基)哌啶-4-基)-N-(2,2,2-三氟乙基)乙酰胺
参考实施例7步骤2方法制备。
MS(ESI):486.15(M+1)
实施例24、2-(4-(4-(7H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1-(甲磺酰基)哌啶-4-基)-N-(2,2,2-三氟乙基)乙酰胺
参考实施例7步骤2方法制备。
MS(ESI):485.15(M+1)
实施例25、2-(1-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)环戊基)-N-(2,2,2-三氟乙基)乙酰胺
参考实施例7步骤2方法制备。
1HNMR(400MHz,DMSO-D6)δ11.60(s,1H),8.42(m,1H),8.22(m,2H),8.10(s,1H),7.84(s,1H),7.66(d,1H),7.10(m,1H),3.79(m,2H),2.86(s,2H),2.50(m,2H),2.07(m,2H),1.71(m,2H),1.58(m,2H).
MS(ESI):485.15(M+1)
实施例26、2-(1-(4-(1H-吡咯并[2,3-b]嘧啶-4-基)-1H-吡唑-1-基)环戊基)-N-(2,2,2-三氟乙基)乙酰胺
参考实施例7步骤2方法制备。
MS(ESI):485.15(M+1)
实施例27、2-(1-(4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)环戊基)-N-(2,2,2-三氟乙基)乙酰胺
参考实施例7步骤2方法制备。
MS(ESI):392.17(M+1)
实施例28、3-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-3-甲基-N-(2,2,2-三氟乙基)丁酰胺
参考实施例7步骤2方法制备。
MS(ESI):366.15(M+1)
实施例29、3-(4-(7H-吡咯并[2,3-b]嘧啶-4-基)-1H-吡唑-1-基)-3-甲基-N-(2,2,2-三氟乙基)丁酰胺
参考实施例7步骤2方法制备。
MS(ESI):367.14(M+1)
实施例30、3-(4-(7H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-3-甲基-N-(2,2,2-三氟乙基)丁酰胺
参考实施例7步骤2方法制备。
MS(ESI):367.14(M+1)
实施例31、3-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(甲磺酰基)-N-(2,2,2-三氟乙基)氮杂环丁烷-3-甲酰胺
步骤1、3-((2-氯嘧啶-4-基)氨基)-1-(甲磺酰基)氮杂环丁烷-3-甲酸甲酯
3.3g 2,4-二氯嘧啶、5g 3-氨基-1-(甲磺酰基)氮杂环丁烷-3-甲酸甲酯溶于50ml四氢呋喃中，加入5ml DIPEA，40℃反应3小时，加水稀释，二氯甲烷萃取，干燥，过滤，浓缩，柱层析得目标物6g。
步骤2、3-((2-氯嘧啶-4-基)氨基)-1-(甲磺酰基)氮杂环丁烷-3-甲酸
取步骤1产物2g溶于10ml，加2M氢氧化钾4ml，室温搅拌反应2小时，除溶剂，加盐酸调PH值至6，过滤，晾干的目的物1.6g。
步骤3、1-(甲磺酰基)-3-((2-(1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)氮杂环丁烷-3-甲酸
在二氧六环/水(5:1)24ml中，加入2g步骤2产物，1.26g 3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊烷-2-基)-1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶，1.0g碳酸钾，0.1g Pd(dppf)Cl2，加热至90℃反应3h，加盐酸调PH值至6，过滤，滤液，减压除二氧六环加水稀释，乙酸乙酯萃取，干燥，浓缩，柱层析析得目标物1.8g。
步骤4、3-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(甲磺酰基)氮杂环丁烷-3-甲酸
取0.8g步骤3产物加2M氢氧化钾3ml，10ml甲醇，回流2小时，除溶剂，加盐酸调PH值至6，过滤，得目标物0.5g。
步骤5、3-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(甲磺酰基)-N-(2,2,2-三氟乙基)氮杂环丁烷-3-甲酰胺
取0.3g步骤4产物溶于5ml干燥DMF中，加入0.16g N-(3-二甲氨基丙基)-N'-乙基碳二亚胺盐酸盐(EDC.HCl)，搅拌2小时后，加入0.098g2,2,2-三氟乙胺，1小时反应完毕后，加水稀释，二氯甲烷萃取，干燥，浓缩，柱层析得目的物0.2g。
MS(ESI):470.12(M+1)
实施例32、3-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(乙磺酰基)-N-(2,2,2-三氟乙基)氮杂环丁烷-3-甲酰胺
参考实施例31方法制备。
MS(ESI):484.13(M+1)
实施例33、3-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(环丙磺酰基)-N-(2,2,2-三氟乙基)氮杂环丁烷-3-甲酰胺
参考实施例31方法制备。
MS(ESI):496.13(M+1)
实施例34、3-(5-氟-2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(甲磺酰基)-N-(2,2,2-三氟乙基)氮杂环丁烷-3-甲酰胺
参考实施例31方法制备。
MS(ESI):488.10(M+1)
实施例35、3-(5-氟-2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(乙磺酰基)-N-(2,2,2-三氟乙基)氮杂环丁烷-3-甲酰胺
参考实施例31方法制备。
MS(ESI):502.12(M+1)
实施例36、3-(5-氟-2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(环丙磺酰基)-N-(2,2,2-三氟乙基)氮杂环丁烷-3-甲酰胺
参考实施例31方法制备。
MS(ESI):514.12(M+1)
实施例37、4-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(甲磺酰基)-N-(2,2,2-三氟乙基)哌啶-4-甲酰胺
参考实施例31方法制备。
MS(ESI):498.15(M+1)
实施例38、4-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(乙磺酰基)-N-(2,2,2-三氟乙基)哌啶-4-甲酰胺
参考实施例31方法制备。
MS(ESI):412.16(M+1)
实施例39、4-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(环丙磺酰基)-N-(2,2,2-三氟乙基)哌啶-4-甲酰胺
参考实施例31方法制备。
MS(ESI):524.16(M+1)
实施例40、4-((5-氟-2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(甲磺酰基)-N-(2,2,2-三氟乙基)哌啶-4-甲酰胺
参考实施例31方法制备。
MS(ESI):516.16(M+1)
实施例41、4-((5-氟-2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(乙磺酰基)-N-(2,2,2-三氟乙基)哌啶-4-甲酰胺
参考实施例31方法制备。
MS(ESI):530.16(M+1)
实施例42、4-((5-氟-2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(环丙磺酰基)-N-(2,2,2-三氟乙基)哌啶-4-甲酰胺
参考实施例31方法制备。
MS(ESI):542.16(M+1)
实施例43、4-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-N-(2,2,2-三氟乙基)四氢-2H-硫代吡喃-4-甲酰胺1,1-二氧化物
参考实施例31方法制备。
MS(ESI):469.12(M+1)
实施例44、4-((5-氟-2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-N-(2,2,2-三氟乙基)四氢-2H-硫代吡喃-4-甲酰胺1,1-二氧化物
参考实施例31方法制备。
MS(ESI):487.11(M+1)
实施例45、3-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(乙磺酰基)氮杂环丁烷-3-腈
参考实施例31方法制备。
MS(ESI):384.12(M+1)
实施例46、3-((2-(7H-吡咯并[2,3-d]嘧啶-4-基)嘧啶-4-基)氨基)-1-(乙磺酰基)氮杂环丁烷-3-腈
参考实施例31方法制备。
MS(ESI):385.12(M+1)
实施例47、3-((2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)氨基)-1-(乙磺酰基)氮杂环丁烷-3-腈
参考实施例31方法制备。
MS(ESI):385.12(M+1)
实施例48、3-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(甲磺酰基)氮杂环丁烷-3-腈
参考实施例31方法制备。
MS(ESI):370.1(M+1)
实施例49、3-((2-(7H-吡咯并[2,3-d]嘧啶-4-基)嘧啶-4-基)氨基)-1-(甲磺酰基)氮杂环丁烷-3-腈
参考实施例32方法制备。
MS(ESI):371.1(M+1)
实施例50、3-((2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)氨基)-1-(甲磺酰基)氮杂环丁烷-3-腈
参考实施例31方法制备。
MS(ESI):370.1(M+1)
实施例51、4-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)四氢-2H-硫代吡喃-4-腈1,1-二氧化物
参考实施例31方法制备。
MS(ESI):369.1(M+1)
实施例52、4-((2-(7H-吡咯并[2,3-d]嘧啶-4-基)嘧啶-4-基)氨基)四氢-2H-硫代吡喃-4-腈1,1-二氧化物
参考实施例31方法制备。
MS(ESI):370.1(M+1)
实施例53、4-((2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)氨基)四氢-2H-硫代吡喃-4-腈1,1-二氧化物
参考实施例31方法制备。
MS(ESI):369.1(M+1)
实施例54、1-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)环丁烷-3-腈
参考实施例31方法制备。
MS(ESI):291.13(M+1)
实施例55、1-((2-(7H-吡咯并[2,3-d]嘧啶-4-基)嘧啶-4-基)氨基)环丁烷-3-腈
参考实施例31方法制备。
MS(ESI):292.13(M+1)
实施例56、1-((2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)氨基)环丁烷腈
参考实施例31方法制备。
MS(ESI):291.13(M+1)
实施例57、1-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)环戊腈
参考实施例31方法制备。
MS(ESI):305.15(M+1)
实施例58、1-((2-(7H-吡咯并[2,3-d]嘧啶-4-基)嘧啶-4-基)氨基)环戊烷腈
参考实施例31方法制备。
MS(ESI):306.14(M+1)
实施例59、1-((2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)氨基)环戊烷腈
参考实施例31方法制备。
MS(ESI):305.14(M+1)
实施例60、(R)-2-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基-2-甲基丁腈
参考实施例31方法制备。
MS(ESI):293.14(M+1)
实施例61、(R)-2-((2-(7H-吡咯并[2,3-d]嘧啶-4-基)嘧啶-4-基)氨基-2-甲基丁腈
参考实施例31方法制备。
MS(ESI):294.15(M+1)
实施例62、(R)-2-((2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)氨基-2-甲基丁腈
参考实施例31方法制备。
MS(ESI):293.15(M+1)
实施例63、对JAK的抑制作用
研究化合物对纯化的重组JAK活性的影响,是从酶学水平研究化合物对JAK的抑制活性。其实验原理为采用一种发光法激酶检测方法，用于检测JAK与底物Poly(4:1Glu,Tyr)肽反应产生的ADP含量：ADP转化为ATP后，ATP即可作为Ultra-Glo荧光素酶催化反应的底物，产生光信号。发光信号与ADP的量和激酶活性正相关。因此，通过观察化合物对JAK与底物反应产生的发光信号来确定其对重组的JAK的抑制效果，用IC50表示。
实验方法：10个不同浓度的化合物分别在37℃与JAK1、JAK2和JAK3孵育60分钟，然后加入底物及ATP混合，37℃反应50分钟后加入25μlADP-GloTM混合2分钟，室温反应50分钟。再加入50μl检测试剂混合2分钟，室温孵育50分钟，用化学发光仪检测。结果见表1。
表1本发明化合物对JAK的抑制作用实验结果
注：1.(a)20nM以下；
2.(b)>20nM至50nM；
3.(c)>50nM
其中，以实施例3为例，与同等实验条件下的现有JAK抑制剂的实验结果进行比较，结果见表2。
表2本发明化合物与现有JAK抑制剂对JAK的抑制作用对比
注：Ruxolitinib*、Baricitinib*的试验结果来自FDA的新药申报资料。
结果表明：实施例3化合物对JAK1的抑制活性高，对JAK2的抑制活性低，提示化合物对JAK1的选择性较Baricitinib和Ruxolitinib(CN101448826A公开的化合物)更高，后两个阳性药对JAK1、JAK2没有选择性。
实施例64、本发明化合物重复给药对大鼠血液学指标的影响
取健康Wistar大鼠48只，♀♂各半。按体重随机分为对照组(Veh)，罐胃给药实施例3化合物，为剂量1.5mg·kg-1·d-1和4.5mg·kg-1·d-1，罐胃给药Ruxolitinib剂量4.5mg·kg-1·d-1，每组12只，♀♂各半。每天灌胃给药1次，连续给药4周，末次给药1d、2d后进行血液学指标检查。结果给药结束，罐胃给药实施例3化合物1.5mg·kg-1·d-1剂量组、4.5mg·kg-1·d-1剂量组，动物血液学指标WBC值与对照组(Veh)组比较无明显降低(P<0.05)；Ruxolitinib(CN101448826A公开的化合物)4.5mg·kg-1·d-1剂量组，动物血液学指标WBC值与对照组(Veh)组比较明显降低(P<0.05)，提示本发明化合物治疗类风湿关节炎时副作用较小。
结果表明：实施例3化合物对JAK1的抑制活性高，对JAK2的抑制活性低，提示化合物对JAK1的选择性较Baricitinib和Ruxolitinib(CN101448826A公开的化合物)更高，后两个阳性药对JAK1、JAK2没有选择性。
Claims (6)
1.式(Ⅱ)的化合物，
或其药学上可接受的盐；
其中：
X选自-CONH-R4或-CN，n选自1；
当X为-CONH-R4时，R4为氢或C1-C6烷基，并可被卤原子任意取代；
R1、R2与其相连的碳原子形成
X1为N或-CR5；
R5为H；
R1、R2与其相连的碳原子形成
X1为N或-CR5；
R5为H；
当X为-CN时，
这时R1、R2与其相连的碳原子形成
X1为N或-CR5；
R5为H。
2.化合物，所述化合物选自以下结构：
2-(4-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)乙腈；
2-(4-(4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)乙腈；
2-(4-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)乙腈；
2-(4-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)乙酰胺；
2-(4-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)-N-(2,2,2-三氟乙基)乙酰胺；
2-(4-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)-N-(2,2,2-三氟乙基)乙酰胺；
2-(4-(4-(7H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)-N-(2,2,2-三氟乙基)乙酰胺；
或其药学上可接受的盐。
3.一种药物组合物，其包括根据权利要求1-2中任一项所述的化合物或其药学上可接受的盐，以及药学上可接受的载体。
4.根据权利要求1-2中任一项所述的化合物在制备治疗JAK激酶相关疾病的药物中的应用。
5.根据权利要求4所述的应用，其特征在于是在制备治疗自身免疫疾病、类风湿性关节炎、皮肤病、多发性硬化、银屑性关节炎、炎性肠病或者重症肌无力的药物中的应用。
6.根据权利要求4所述的应用，其特征在于是在制备治疗牛皮藓的药物中的应用。
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| PCT/CN2017/094253 WO2018019222A1 (zh) | 2016-07-26 | 2017-07-25 | 作为jak抑制剂杂环化合物，该化合物的盐类及其治疗用途 |
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| CN109843883B (zh) | 2016-07-26 | 2022-01-14 | 苏州隆博泰药业有限公司 | 作为选择性jak抑制剂化合物，该化合物的盐类及其治疗用途 |
| WO2020038457A1 (zh) * | 2018-08-23 | 2020-02-27 | 珠海联邦制药股份有限公司 | 作为JAK抑制剂的[1，2，4]三唑并[1，5-a]吡啶类化合物及其应用 |
| CN111620873B (zh) * | 2019-02-28 | 2021-12-28 | 沈阳药科大学 | 一类含哌啶的吡咯并[2,3-d]嘧啶衍生物及其制备和用途 |
| CN110028509B (zh) * | 2019-05-27 | 2020-10-09 | 上海勋和医药科技有限公司 | 作为选择性jak2抑制剂的吡咯并嘧啶类化合物、其合成方法及用途 |
| KR20220127900A (ko) * | 2020-02-13 | 2022-09-20 | 주하이 유나이티드 라보라토리즈 컴퍼니 리미티드 | Jak 키나아제 관련 질병의 치료를 위한 약물의 제조에 있어서 jak 억제제의 용도 |
| US20230091250A1 (en) * | 2020-02-21 | 2023-03-23 | Zhuhai United Laboratories Co., Ltd. | Crystalline form of jak inhibitor and application thereof |
| WO2022161205A1 (zh) * | 2021-01-29 | 2022-08-04 | 珠海联邦制药股份有限公司 | 一种含有jak抑制剂或其盐或其晶型的口服制剂及其制备方法和应用 |
| WO2023239727A1 (en) * | 2022-06-06 | 2023-12-14 | The Usa, As Represented By The Secretary, Dept. Of Health And Human Services | Lats inhibitors and uses thereof |
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Also Published As
| Publication number | Publication date |
|---|---|
| JP6978097B2 (ja) | 2021-12-08 |
| EP3492469B1 (en) | 2021-12-01 |
| EP3492469A4 (en) | 2019-10-09 |
| CN109843883A (zh) | 2019-06-04 |
| US20190270740A1 (en) | 2019-09-05 |
| WO2018019223A1 (zh) | 2018-02-01 |
| EP3492468B1 (en) | 2022-02-23 |
| JP2019532913A (ja) | 2019-11-14 |
| KR102598246B1 (ko) | 2023-11-02 |
| KR20190034234A (ko) | 2019-04-01 |
| EP3492468A4 (en) | 2020-03-04 |
| KR102492378B1 (ko) | 2023-01-27 |
| JP2019532914A (ja) | 2019-11-14 |
| EP3492469A1 (en) | 2019-06-05 |
| WO2018019222A1 (zh) | 2018-02-01 |
| US11279699B2 (en) | 2022-03-22 |
| KR20190035755A (ko) | 2019-04-03 |
| US11414413B2 (en) | 2022-08-16 |
| EP3492468A1 (en) | 2019-06-05 |
| CN109790158A (zh) | 2019-05-21 |
| CN109843883B (zh) | 2022-01-14 |
| JP6978098B2 (ja) | 2021-12-08 |
| US20200190080A1 (en) | 2020-06-18 |
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