CN111961035B - 一类含有羟基异喹啉类结构的化合物、药物组合物以及其应用 - Google Patents
一类含有羟基异喹啉类结构的化合物、药物组合物以及其应用 Download PDFInfo
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- CN111961035B CN111961035B CN201910419225.3A CN201910419225A CN111961035B CN 111961035 B CN111961035 B CN 111961035B CN 201910419225 A CN201910419225 A CN 201910419225A CN 111961035 B CN111961035 B CN 111961035B
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Abstract
本发明涉及一类含有羟基异喹啉类结构的化合物、药物组合物以及其应用，其具有式(I)结构。本发明的结构如式(I)所示的化合物对布鲁顿激酶活性具有很好的抑制作用，其半数抑制浓度普遍在10‑7mol.L‑1以下。同时，本发明实施例中制备的具有式(I)结构的化合物在不同的动物模型上均表现出明确的抗炎活性。
Description
技术领域
本发明涉及药物化学领域，具体涉及一类含有羟基异喹啉类结构的化合物、药物组合物以及其应用。
背景技术
蛋白质激酶组成人类酶的最大家族之一并且通过添加磷酸基团到蛋白质上来调节许多不同的信号传导过程(T.Hunter,Ce11 1987 50:823-829)。特别地，酪氨酸激酶磷酸化蛋白质在酪氨酸残基的酚部分。酪氨酸激酶家族包括控制细胞生长、迁移和分化的成员。异常的激酶活性己经涉及许多人类疾病，包括癌症，自身免疫疾病和炎性疾病。由于蛋白质激酶属于细胞信号传导的关键调节剂，它们提供用小分子激酶抑制剂来调节细胞功能的目标，并且因此成为了良好的药物设计靶标。除了激酶介导的疾病过程的治疗，激酶活性的选择性和有效抑制剂还可用于研究细胞信号传导过程和鉴定其它具有治疗意义的细胞靶标。
关于B细胞在自身免疫和/或炎性疾病的发病机制中的关键作用存在良好的证据。消耗B细胞的基于蛋白质的治疗剂如Rituxan针对自身抗体导致的炎性疾病如类风湿性关节炎是有效的(Rastetter等，Annu Rev Med 2004 55:477)。因此，在B细胞活化中发挥作用的蛋白质激酶的抑制剂应该是对于B细胞介导的疾病病理如自身抗体生成有用的治疗剂。
通过B细胞受体(BCR)的信号传导控制一系列B细胞应答，包括增殖和分化到成熟的抗体生成细胞。BCR是B细胞活性的关键调节点并且异常的信号传导可以导致失调的B细胞增殖和病原性自身抗体的形成，其导致多种自身免疫疾病和 /或炎性疾病。布鲁顿(Bruton's)酪氨酸酸蛋白激酶(Btk)是在BCR的膜近端和紧接下游的非BCR相关的激酶。Btk的缺乏己经显示阻断BCR信号传导，并且因此 Btk的抑制可以是阻断B细胞介导的疾病过程的有效治疗方法。
Btk是酪氨酸激酶Tec家族的成员，并且显示是早期B细胞形成以及成熟B 细胞活化和存活的关键调节剂(Khan等，Immunity 1995 3:283；E11meier等， J.Exp.Med.2000192:1611)。人的Btk突变导致病症X连锁丙球蛋白缺乏血症(XLA)(在Rosen等NewEng.J.Med.1995 333:431和Lindvall等Immunol. Rev.2005 203:200中综述)。这些患者是免疫受损的，并且显示受损的B细胞成熟，降低的免疫球蛋白和外用B细胞水平，减少的不依赖T细胞的免疫应答以及在BCR剌激后的减弱的钙动用。
关于Btk在自身免疫疾病和炎性疾病中的作用的证据己经由Btk缺陷型小鼠模型提供。在系统性红斑狼疮(SLE)的临床前鼠模型中，Btk缺陷型小鼠显示疾病进展的显著改善。此外，Btk-缺陷型小鼠对胶原诱导的关节炎具有抗性 (Jansson和HolmdahlClin.Exp.Immunol.1993 94:459)。己经证明选择性Btk 抑制剂在小鼠关节炎模型中的剂量依赖性功效(z.Pan等，Chem.Med Chem.2007 2:58-61)。
Btk还由除了B细胞之外可能涉及疾病过程的细胞表达。例如，Btk由肥大细胞表达并且Btk缺陷型骨髓来源的肥大细胞显示受损的抗原诱导的脱粒 (Iwaki等J.Biol.Chem.2005 280:40261)。这显示Btk可以用于治疗病理性肥大细胞反应如变态反应和哮喘。此外，其中缺乏Btk活性的来自XLA患者的单核细胞显示在剌激后减少的TNFα生成(Horwood等J Exp Med 197:1603,2003)。因此，TNFα介导的炎症可以由小分子Btk抑制剂调节。此外，己经报道Btk在细胞凋亡中发挥作用Oslam和Smith Immunol.Rev.2000178:49)，并且因此Btk抑制剂对于治疗某些B细胞淋巳瘤和白血病将是有效的(Feldhahn等JExp.Med.2005 201:183 7)。
尽管目前已公开了一系列的布鲁顿激酶抑制剂，但仍需要开发结构类型更丰富，新的可能具有活性跟高、成药性质更好的化合物。
发明内容
经过不断努力，本发明设计具有通式(I)所示的结构的化合物，并发现具有此类结构的化合物表现出优异的效果和作用。
本申请提供结构如式(I)所示的Btk抑制剂化合物，它的使用方法，如本文下面所述:
结构如式(I)所示的化合物或其药学上可接受的盐：
其中，
X、Y、Z、W独立选自CH或N；
环A为C6-C10芳基、C6-C10杂芳基；
环B为C3-C6环烷基、C3-C6杂环烷基；
R1、R2选自H、卤素、氰基、C1-C4烷基、C1-C3烷氧基、C3-C6环烷基、C3-C6杂环烷基，所述烷基、烷氧基、环烷基、杂环烷基任选被一个或多个卤素、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、C3-C6环烷基、C3-C6杂环烷基取代；
R3选自
进一步的，Z选自CH，W选自N或CH；或Z选自N，W选自CH。
进一步的，环A为苯环、吡啶环。
进一步的，环B为环己烷、环戊烷、哌啶、吗啉、吡咯烷。
进一步的，如式(I)所示的化合物或其药学上可接受的盐，至少一种如式 (II)的，
Z选自CH，W选自N或CH；或Z选自N，W选自CH；
环A为苯环、吡啶环；
环B为环己烷、环戊烷、哌啶、吗啉、吡咯烷；
R1、R2选自H、卤素、氰基、C1-C4烷基、C1-C3烷氧基、C3-C6环烷基、C3-C6杂环烷基，所述烷基、烷氧基、环烷基、杂环烷基任选被一个或多个卤素、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、C3-C6环烷基、C3-C6杂环烷基取代；
R3选自
进一步的，所述化合物选自：
上述化合物或其药学上可接受的盐在制备用于BTK抑制剂中的应用。
该类BTK抑制剂可用于治疗炎性和/或自身免疫病症的药物中的应用，特别是类风湿性关节炎。
为了检验本发明提供的化合物对于蛋白激酶的作用水平，采用生化水平酶活性测试和细胞水平酶活性测试来确定本发明的各种化合物对一种或多种PK的活性和作用水平。使用工艺中熟知的方法，对于任何激酶均可按照同样的方式设计类似的实验。
在生化水平酶活性测试中，利用HTRF技术检测酪氨酸激酶的活性，HTRF 是一种时间分辨荧光共振能力转移技术，可以按照已知的说明书或文献方法进行，参看Kolb等，“Tyrosine kinase assays adapted to homogenous time-resolved fluorescence”.Drug Discovery Today杂志.3卷:pp 333-342。HTRF(均相时间分辨荧光)是用来检测均相体系中待测物的一种最常用的方法，这种技术结合了荧光共振能量转移(FRET)和时间分辨技术(TR)，已经被广泛应用于基于细胞实验和生化实验的药物研发的不同阶段。根据HTRF法的测定原理，将纯酶与生物素化的底物以及ATP一起孵育反应后，加入亲和素标记的XL-665和识别底物磷酸化的 Eu标记的抗体，当底物被Btk磷酸化后，Eu标记的抗体即可以识别该磷酸化产物，与亲和素标记的XL665形成时间分辨的荧光共振能量转移(FRET)，而未被磷酸化的底物由于不能倍抗体识别而无法形成FRET信号，通过测定665nm 和620nm的荧光信号差值测定待测物在不同浓度下对Btk酪氨酸激酶的抑制活性。因而，采用此法可测定本发明化合物对Btk酪氨酸激酶的生化水平的活性作用，同时利用本领域熟知的方法，可以对其它蛋白激酶使用相似的测定方法。
在细胞水平酶活的测定是通过测定钙流实现的。该实验使用Fluo-4DirectTMCalcium Assay Kits试剂盒。其试剂盒中主要使用的染料为Fluo 4-AM。Fluo 4-AM 是Fluo4的一种乙酰甲酯衍生物，通过培养，能够轻易进入细胞中。AM进入细胞后会被胞内酯酶所水解，产生的Fluo 4随后会和钙离子结合并发出荧光，可以使用激光共聚焦显微镜或流式细胞仪等仪器检测细胞内钙离子浓度的变化。
采取通用的大鼠体内药代实验的测试方法，还可考察化合物在大鼠体内的药效性质。
采取通用的小鼠的Arthus Reaction模型或大鼠胶原诱导的关节炎(rCIA)模型，可考察化合物在小鼠或大鼠上的体内药效。
本发明制备的结构如式(I)所示的化合物对布鲁顿激酶活性具有很好的抑制作用，其半数抑制浓度(IC50)普遍在10-7mol/L以下。同时，本发明实施例中制备的具有式I结构的化合物具有良好的口服药代性质，并在Arthus Reaction 模型或大鼠胶原诱导的关节炎(rCIA)模型上显示出明确的体内药效。有此推知，本发明具有式(I)结构的化合物可应用于制备治疗有机体中布鲁顿激酶相关的疾炎性和/或自身免疫病症的药物。
除非有相反陈述，下列用在说明书和权利要求中的术语具有下述含义。
“烷基”指饱和的脂族烃基团。包括1至20个碳原子的直链或支链基团。优选含有1至6个碳原子的中等大小烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔丁基、戊基等。更优选的是含有1至4个碳原子的低级烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基或叔丁基等。烷基可以是取代的或未取代的，当被取代时，优选的基团为：卤素、C2-C6烯基、C6-C10芳基、C5-C10杂芳基、卤代C1-C6烷基、4至8元杂脂环基、羟基、C1-C6烷氧基、C6-C10芳氧基。
“亚烷基”表示1至10个碳原子的二价饱和直连烃基(例如(CH2)n)或2 至10个碳原子的支链饱和二价烃基(例如-CHMe)，除非另有。除了在亚甲基的情况下之外，亚烷基的开放态不连接到相同的原子上。亚烷基的实施例包含但不限于：亚甲基、亚乙基、亚丙基、2-甲基-亚丙基、1,1-二甲基-亚乙基、亚丁基、 2-乙基亚丁基。
“环烷基”指3至8元全碳单环、全碳5元/6元或6元/6元稠和环或多环稠和环(“稠和”环意味着系统中的每个环与系统中的其它环共享毗邻的一对碳原子) 基团，其中一个或多个环具有完全连接的π电子系统，环烷基的实例(不局限于) 为环丙烷、环丁烷、环戊烷、环戊烯、环己烷、金刚烷、环己二烯、环庚烷和环庚三烯。环烷基为可取代的和为取代的。当被取代时，取代基优选为一个或多个各自选自以下的基团，包括：氢、羟基、巯基、氧代、低级烷基、低级烷氧基、低级环烷基、低级杂环烷基、低级卤代烷氧基、烷硫基、卤素、低级卤代烷基、低级羟烷基、低级环烷基亚烷基、低级杂环烷基亚烷、芳基、杂芳基、烷氧基羰基、氨基、烷基氨基、烷基磺酰基、芳基磺酰基、烷基氨基磺酰基、芳基氨基磺酰基、烷基磺酰基氨基、芳基磺酰基氨基、烷基氨基羰基、芳基氨基羰基、烷基羰基氨基、芳基羰基氨基。
“芳基”表示6至14个碳原子的全碳单环或稠合多环基团，具有完全共轭的π电子系统。“芳基”包括：
六元的碳芳香环，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，芳基包括含六元的碳芳香环并一个六元杂环，这个杂环包含一个或多个选自氮、氧和硫的杂原子，条件是连接点在碳芳香环上。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环，由此产生的环系统是杂芳基，而不是芳基。芳基的非限制性实例有苯基、萘基。芳基可以是取代的或未取代的。当被取代时，优选的基团为：氢、羟基、硝基、氰基、氧代、低级烷基、低级烷氧基、低级环烷基、低级杂环烷基、低级卤代烷氧基、烷硫基、卤素、低级卤代烷基、低级羟烷基、低级环烷基亚烷基、低级杂环烷基亚烷、芳基、杂芳基、烷氧基羰基、氨基、烷基氨基、烷基磺酰基、芳基磺酰基、烷基氨基磺酰基、芳基氨基磺酰基、烷基磺酰基氨基、芳基磺酰基氨基、烷基氨基羰基、芳基氨基羰基、烷基羰基氨基、芳基羰基氨基。
“杂芳基”表示5至14个环原子的单环或稠合环基团，含有一个、两个、三个或四个选自N、O或S的环杂原子，其余环原子是C，另外具有完全共轭的π电子系统。杂芳基指的是：
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，1-3个杂原子，环上其他原子是碳原子；
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，1-3个杂原子，环上其他原子是碳原子；其中至少有一个环是芳香环；以及
11-14元的三环芳烃，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，1-3个杂原子，环上其他原子是碳原子；其中至少有一个环是芳香环。
例如，杂芳基包括一个5-6元的杂芳香环并一个5-6元的环烷基。对于这样的双环并起来的杂芳基，其中只有一个环含有一个或多个杂原子，连接位点在杂芳香环上。
当杂芳基上的硫原子和氧原子总数超过1时，这些杂原子不会一一相邻。在一些实施方案中，硫原子和氧原子在杂芳基中的总数不超过2。在一些实施方案中，硫原子和氧原子在杂芳基中的总数不超过1。
杂芳基的例子，包括但不限于，吡咯、呋喃、噻吩、咪唑、噁唑、噻唑、吡唑、三氮唑、嘧啶、吡啶、吡啶酮、咪啶、吡嗪、哒嗪、吲哚、氮杂吲哚、苯并咪唑、苯并三氮唑、吲哚啉、吲哚酮、喹啉、异喹啉、喹唑啉、噻吩并吡啶、噻吩并嘧啶等。此类基团的优选实施例为吡咯基、吡唑基、咪唑基、三氮唑基、呋喃基、噁唑基、噻吩基、噻唑基、苯并咪唑基、苯并三氮唑。杂芳基中的一个或全部氢原子可被下列基团取代：氢、羟基、硝基、氰基、氧代、低级烷基、低级烷氧基、低级环烷基、低级杂环烷基、低级卤代烷氧基、烷硫基、卤素、低级卤代烷基、低级羟烷基、低级环烷基亚烷基、低级杂环烷基亚烷、芳基、杂芳基、烷氧基羰基、氨基、烷基氨基、烷基磺酰基、芳基磺酰基、烷基氨基磺酰基、芳基氨基磺酰基、烷基磺酰基氨基、芳基磺酰基氨基、烷基氨基羰基、芳基氨基羰基、烷基羰基氨基、芳基羰基氨基。“杂环烷基”表示由一个或多个环，优选1至 2个环(包括螺环系统)组成的一价饱和环状基团，每个环3至8个原子，其结合有一个或多个环杂原子(选自N，O或S(O)0-2)，并且其可以任选独立地被一个或多个，优选1个或2个取代基取代，所述的取代基选自:氢、羟基、巯基、氧代、低级烷基、低级烷氧基、低级环烷基、低级杂环烷基、低级卤代烷氧基、烷硫基、卤素、低级卤代烷基、低级羟烷基、低级环烷基亚烷基、低级杂环烷基亚烷、芳基、杂芳基、烷氧基羰基、氨基、烷基氨基、烷基磺酰基、芳基磺酰基、烷基氨基磺酰基、芳基氨基磺酰基、烷基磺酰基氨基、芳基磺酰基氨基、烷基氨基羰基、芳基氨基羰基、烷基羰基氨基、芳基羰基氨基。除非另外指出。杂环烷基的实例包括但不限于，吗啉基，哌嗪基，哌啶基，氮杂环丁烷基，吡咯烷基，六氢氮杂草基，氧杂环丁烷基，四氢呋喃基，四氢噻吩基，噁唑烷基，噻唑烷基，异噁唑烷基，四氢吡喃基，硫代吗琳基，奎宁环基和眯咪唑啉基，优选
W选自O、S或NR12，各基团如前所述，实例还可以是双环的，诸如，例如，3，8-二氮杂-双环[3.2.1] 辛烷、2，5-二氮杂双环[2.2.2]辛烷或八氢-吡嗪并[2，1-c][1,4]噁嗪。其杂环烷基 (和衍生物)包括其离子形式。
“烷氧基”表示-O-(未取代的烷基)和-O(未取代的环烷基)。代表性的实例包括但不限于甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基等。
“芳氧基”表示-O-芳基和-O-杂芳基。代表性实例包括但不限于苯氧基、吡啶氧基、呋喃氧基、噻吩氧基、嘧啶氧基、吡嗪氧基等及其衍生物。
“芳基亚烷基”表示烷基，优选如上所定义的低级烷基，它被如上所述的芳基取代，例如-CH2苯基、-(CH2)2苯基、-(CH2)3苯基、CH3CH(CH3)CH2苯基及其衍生物。
“杂芳基亚烷基”表示烷基，优选如上所定义的低级烷基，它被如上所述的杂芳基取代，例如-CH2吡啶基、-(CH2)2嘧啶基、-(CH2)3咪唑基等及其衍生物。
“羟基”表示-OH基团。
“巯基”表示-SH基团。
“卤素”表示氟、氯、溴或碘，优选为氟或氯。
“卤代烷基”表示烷基，优选如上所定义的低级烷基，它被一个或多个相同或不同的卤原子取代，例如-CH2Cl、-CF3、-CCl3、-CH2CF3、-CH2CCl3等。
“氰基”表示-CN基团。
“氨基”表示-NH2基团。
“硝基”表示-NO2基团。所谓“任选地”的意思是指后续描述的事件或情形可能会也可能不会发生，并且该描述包括事物或情形可能会也可能不会发生，并且该描述包括事物或情形发生和不发生两种情况。
在一些实施方案中，“被一个或多个基团取代”是指在指定的原子或基团中的一个、两个、三个或四个氢原子分别被指定范围的基团中选出的相同或不同的基团替换。
波浪线表示连接位点；
“药学上可接受的盐”表示保留母体化合物的生物有效性和性质的那些盐。这类盐包括：
(1)与酸成盐，通过母体化合物的游离碱与无机酸或有机酸的反应而得，无机酸包括盐酸、氢溴酸、硝酸、磷酸、偏磷酸、硫酸、亚硫酸和高氯酸等，有机酸包括乙酸、丙酸、丙烯酸、草酸、(D)或(L)苹果酸、富马酸、马来酸、羟基苯甲酸、γ-羟基丁酸、甲氧基苯甲酸、邻苯二甲酸、甲磺酸、乙磺酸、萘-1- 磺酸、萘-2-磺酸、对甲苯磺酸、水杨酸、酒石酸、柠檬酸、乳酸、扁桃酸、琥珀酸或丙二酸等。
(2)存在于母体化合物中的酸性质子被金属离子代替或者与有机碱配位化合所生成的盐，金属例子例如碱金属离子、碱土金属离子或铝离子，有机碱例如乙醇胺、二乙醇胺、三乙醇胺、氨丁三醇、N-甲基葡糖胺等。
“药物组合物”指将本发明中的化合物中的一个或多个或其药学上可接受的盐、溶剂化物、水合物或前药与别的化学成分，例如药学上可接受的载体，混合。药物组合物的目的是促进给药给动物的过程。
“药用载体”指的是对有机体不引起明显的刺激性和不干扰所给予化合物的生物活性和性质的药物组合物中的非活性成分，例如但不限于：碳酸钙、磷酸钙、各种糖(例如乳糖、甘露醇等)、淀粉、环糊精、硬脂酸镁、纤维素、碳酸镁、丙烯酸聚合物或甲基丙烯酸聚合物、凝胶、水、聚乙二醇、丙二醇、乙二醇、蓖麻油或氢化蓖麻油或多乙氧基氢化蓖麻油、芝麻油、玉米油、花生油等。
前述的药物组合物中，除了包括药学上可接受的载体外，还可以包括在药(剂) 学上常用的辅剂，例如：抗细菌剂、抗真菌剂、抗微生物剂、保质剂、调色剂、增溶剂、增稠剂、表面活性剂、络合剂、蛋白质、氨基酸、脂肪、糖类、维生素、矿物质、微量元素、甜味剂、色素、香精或它们的结合等。
具体实施方式
以下结合实施例用于进一步描述本发明，但这些实施例并非限制着本发明的范围。
实施例1：N-(1-(8-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)-1-氧代-1,2-二氢异喹啉-6-基)哌啶-3-基)丙烯酰胺(EXP1)的制备
1)6-氯-8-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)异喹啉-1(2H)-酮(化合物C)的制备
将8-溴-6-氯异喹啉-1(2H)-酮(2590mg，10mmol)、5-(4-甲基哌嗪-1-基)吡啶-2-胺(1923mg，10mmol)、Pd(dppf)2Cl2·CH2Cl2(2340mg，2.3mmol)置于100mL的三颈烧瓶中，用氩气置换三次后加入1,4-二氧六环(50mL)后搅拌 5分钟，加入2M的Na2CO3(2700mg，25.5mmol)后用氩气置换三次后升温至 100℃反应2小时，停止反应冷至室温下，垫硅藻土抽滤，滤液加水、乙酸乙酯 (100mL*3)萃取，再用饱和NaCl(25mL)洗一次，最后酯层用无水Na2SO4干燥后柱层析分离后得化合物C(925mg,2.5mmol)，收率25％。 MS(ESI)m/z:[M+H]+＝370.5。1H-NMR(DMSO-d6，400MHz)：δ11.84(s,1H),10.05(s,1H),7.71(m,1H),7.46(s,1H),7.13-7.18(m,2H),6.79(d,1H),6.61(d, 1H),6.21(d,1H),3.10-3.17(m,4H),2.30-2.37(m,4H),2.21(s,3H)ppm。
2)1-(8–((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)-1-氧代-1,2-二氢异喹啉-6-基) 哌啶-3-基叔丁基)氨基甲酸酯(化合物D)的制备
将6-氯-8-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)异喹啉-1(2H)-酮(738mg，2mmol)、哌啶-3-基氨基甲酸叔丁酯(1001mg，5mmol)、Pd(OAc)2(100mg， 0.44mmol)、醋酸钾(980mg，100mmol)溶于100mL无水1,4-二氧六环中，氮气保护，升温至回流，反应12小时。停止反应冷至室温下，垫硅藻土抽滤，滤液加水、乙酸乙酯(150mL*3)萃取，再用饱和NaCl(25mL)洗一次，最后酯层用无水Na2SO4干燥后柱层析分离后得化合物D(960mg,1.8mmol)。
3)N-(1-(8-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)-1-氧代-1,2-二氢异喹啉-6-基)哌啶-3-基)丙烯酰胺(EXP1)的制备
将1-(8–((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)-1-氧代-1,2-二氢异喹啉-6-基)哌啶-3-基叔丁基)氨基甲酸酯(化合物D)(534mg，1mmol)，盐酸0.1mL，二氯甲烷50mL加到100mL茄形瓶中，氮气保护，室温反应12小时。反应结束后水相用二氯甲烷(50mL*3)萃取。有机相合并后纯水洗涤3次。有机相经无水硫酸钠干燥，过滤，浓缩后直接用于下步反应。
上述浓缩液中加入无水二氯甲烷50mL，三乙胺(303mg,3mmol)，丙烯酰氯(180mg,2mmol)，氮气保护，45℃反应4小时。反应结束后，反应液浓缩至干，柱层析后得N-(1-(8-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)-1-氧代-1,2-二氢异喹啉-6-基)哌啶-3-基)丙烯酰胺(146mg，0.3mmol)，收率：30％。
MS(ESI)m/z:[M+H]+＝488.4。1H-NMR(DMSO-d6，400MHz)：δ12.01(s,1H),10.04(s,1H),8.45(m,1H),7.69-7.72(m,1H),7.13-7.18(m,1H),6.65-6.79(m ,2H),6.42-6.51(m,2H),6.04-6.17(m,2H),5.74(m,1H),3.54(m,1H),3.42(m,1H),3.08-3.1 9(m,3H),2.32-2.37(m,4H),2.18(s,3H),1.42-1.57(m,4H),ppm。
实施例2：N-(1-(8-氧代-1-((4-(2-(吡咯烷-1-基)乙基)苯基)氨基)-7,8-二氢-2,7- 萘啶-3-基)吡咯烷-3-基)丙烯酰胺(EXP2)的制备
参照实施例1的方法，N-(1-(8-氧代-1-((4-(2-(吡咯烷-1-基)乙基)苯基)氨基)-7,8-二氢-2,7-萘啶-3-基)吡咯烷-3-基)丙烯酰胺(EXP2)35mg，收率：25％。 MS(ESI)m/z:[M+H]+＝473.50.1H-NMR(DMSO-d6，400MHz)：δ11.78(s,1H),10.52(s,1H),8.34(s,1H),7.82(d,1H),7.45(d,2H),7.05(d,2H),6.54(t,1H),6.2 8(s,1H),6.12(m,1H),5.85(m,1H),5.72(m,1H),3.65(m,1H),3.13-3.52(m,4H),2.65-2.69( m,2H),2.45-2.51(m,4H),1.65-1.94(m,4H)ppm。
实施例3：N-(1-(5-氧代-4-((4-(2-(吡咯烷-1-基)乙基)苯基)氨基)-5,6-二氢-1,6- 二氮杂萘-2-基)吡咯烷-3-基)丙烯酰胺(EXP3)的制备
参照实施例1的方法，制备得到N-(1-(5-氧代-4-((4-(2-(吡咯烷-1-基)乙基)苯基)氨基)-5,6-二氢-1,6-二氮杂萘-2-基)吡咯烷-3-基)丙烯酰胺(EXP3)65mg，收率：35％。MS(ESI)m/z:[M+H]+＝473.2.1H-NMR(DMSO-d6，400MHz)：δ11.82(s,1H),11.55(s,1H),8.35(s,1H),7.84(d,1H),7.47(d,2H),7.08(d,2H),6.47(m,1H),6. 08-6.15(s,2H),5.76(m,1H),3.67(m,1H),3.08-3.45(m,4H),2.65(m,2H),2.52-2.55(m,6H), 1.67-1.69(m,6H)ppm。
实施例4：N-(1-(5-氧代-4-((4-(2-(吡咯烷-1-基)乙基)苯基)氨基)-5,6-二氢吡啶并[4,3-d]嘧啶-2-基基)吡咯烷-3-基)丙烯酰胺(EXP4)的制备
参照实施例1的方法，制备得到N-(1-(5-氧代-4-((4-(2-(吡咯烷-1-基)乙基)苯基)氨基)-5,6-二氢吡啶并[4,3-d]嘧啶-2-基基)吡咯烷-3-基)丙烯酰胺(EXP4)28mg，收率：29％。MS(ESI)m/z:[M+H]+＝474.3.1H-NMR(DMSO-d6，400MHz)：δ11.78(s,1H),8.83(s,1H),8.34(s,1H),7.54(d,1H),7.38(d,2H),7.05(d,2H),6.45(m,1H),6.0 8(m,1H),5.93(d,1H),5.75(m,1H),3.69(m,1H),3.45(m,1H),3.14-3.19(m,2H),3.05(m,1H ),2.68(m,2H),2.53(m,4H),1.64-1.69(m,6H)ppm。
实施例5：N-(1-(8-((4-(2-甲氧基乙氧基)苯基)氨基)-1-氧代-1,2-二氢异喹啉-6- 基)吡咯烷-3-基)丙烯酰胺(EXP5)的制备
参照实施例1的方法，制备得到N-(1-(8-((4-(2-甲氧基乙氧基)苯基)氨基)-1-氧代-1,2-二氢异喹啉-6-基)吡咯烷-3-基)丙烯酰胺(EXP5)65mg，收率：12％。 MS(ESI)m/z:[M+H]+＝448.6.1H-NMR(DMSO-d6，400MHz)：δ12.36(s,1H),11.85(s,1H),8.33(s,1H),7.68(d,1H),7.42(d,2H),6.95(d,2H),6.43-6.45(m, 3H),6.08-6.18(m,2H),5.75(d,1H),4.32(m,2H),3.78(m,2H),3.40-3.44(m,4H),3.05-3.19( m,3H),1.64-1.69(m,2H)ppm。
实施例6：N-(1-(8-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)-1-氧代-1,2-二氢异喹啉-6-基)吡咯烷-3-基)丙烯酰胺(EXP6)的制备
参照实施例1的方法，制备得到N-(1-(8-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)-1-氧代-1,2-二氢异喹啉-6-基)吡咯烷-3-基)丙烯酰胺(EXP6)74mg，收率：12％。MS(ESI)m/z:[M+H]+＝474.3。1H-NMR(DMSO-d6，400MHz)：δ12.03(s,1H),10.07(s,1H),8.37(m,1H),7.74(m,1H),7.19(m,1H),6.79(m,1H),6.67(m,1H ),6.45(m,3H),6.07-6.16(m,2H),5.78(m,1H),3.68(m,1H),3.05-3.44(m,4H),2.38(m,4H), 2.18(m,3H),1.67-1.92(m,2H)ppm。
实施例7：N-(1-(8-((5-((S)-3-甲基-4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基) 氨基)-1-氧代-1,2-二氢异喹啉-6-基)吡咯烷-3-基)丁-2-炔酰胺(EXP7)的制备
参照实施例1的方法，制备得到N-(1-(8-((5-((S)-3-甲基-4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-2-基)氨基)-1-氧代-1,2-二氢异喹啉-6-基)吡咯烷-3-基)丁-2-炔酰胺(EXP7)82mg，收率：35％。MS(ESI)m/z:[M+H]+＝542.5。1H-NMR(DMSO-d6， 400MHz)：δ11.91(s,1H),10.01(s,1H),8.09(s,1H),7.68(d,1H),7.18(s,1H),6.79(d,1H),6.68(d,1H),6.44(m,2H),6.18(m,1H),4.68-4.82(m,4H),3.67-3.85(m,2H),2.80-3.41(m,11H),1.69-1.80 (m,5H),1.08(d,3H)ppm。
实施例8：(N-1-(8-((4-(吗啉-4-羰基)苯基)氨基)-1-氧代-1,2-二氢异喹啉-6-基) 吡咯烷-3-基)丙烯酰胺(EXP8)的制备
参照实施例1的方法，制备得到N-1-(8-((4-(吗啉-4-羰基)苯基)氨基)-1-氧代 -1,2-二氢异喹啉-6-基)吡咯烷-3-基)丙烯酰胺(EXP8)71mg，收率：25％。
1H-NMR(DMSO-d6，400MHz)：δ12.23(br,1H),11.87(br,1H),8.32(br,1H),7.68-7.70(m,5H),6.45-6.90(m,2H),6.10-6.19( m,2H),5.74(d,1H),3.50-3.61(m,4H),3.08-3.16(m,4H),1.68-1.90(m,2H)ppm。
实施例9：N-(1-(1-氧代-8-((4-(2-(吡咯烷-1-基)乙基)苯基)氨基)-1,2-二氢异喹啉-6-基)吡咯烷-3-基)丙烯酰胺(EXP9)的制备
参照实施例1的方法，制备得到N-(1-(1-氧代-8-((4-(2-(吡咯烷-1-基)乙基)苯基)氨基)-1,2-二氢异喹啉-6-基)吡咯烷-3-基)丙烯酰胺(EXP9)34mg，收率：32％。 MS(ESI)m/z:[M+H]+＝472.2。1H-NMR(DMSO-d6，400MHz)：δ12.31(br,1H),11.91(br,1H),8.34(br,1H),8.71(m,1H),7.38(d,2H),7.05(d,2H),6.41-6.47( m,3H),6.10-6.19(m,2H),5.74(d,1H),3.71(m,1H),3.05-3.44(m,4H),2.74(t,2H),2.52-2.5 5(m,6H),1.67-1.91(m,6H)ppm。
实施例10：N-(1-(8-((2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)氨基)-1-氧代-1,2-二氢异喹啉-6-基)吡咯烷-3-基)丙烯酰胺(EXP10)的制备
参照实施例1的方法，制备得到N-(1-(8-((2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)氨基)-1-氧代-1,2-二氢异喹啉-6-基)吡咯烷-3-基)丙烯酰胺(EXP10)23mg，收率： 19％。MS(ESI)m/z:[M+H]+＝503.5。1H-NMR(DMSO-d6，400MHz)：δ11.98(br,1H),9.98(br,1H),8.36(m,1H),7.75(d,1H),7.69(d,1H),6.44-6.48(m,3H),6.37(s ,1H),5.75(m,1H),3.88(s,3H),3.72(m,1H),3.05-3.44(m,4H),2.36(t,4H),2.18(s,3H),1.67- 1.90(m,2H)ppm。
实施例11：(E)-3-(二甲基氨基)-N-(1-(8-((2-氟-4-(4-甲基哌嗪-1-基)苯基)氨基)-1-氧代-1,2-二氢异喹啉-6-基)吡咯烷-3-基)丙烯酰胺(EXP11)的制备
参照实施例1的方法，制备得到(E)-3-(二甲基氨基)-N-(1-(8-((2-氟-4-(4-甲基哌嗪-1-基)苯基)氨基)-1-氧代-1,2-二氢异喹啉-6-基)吡咯烷-3-基)丙烯酰胺(EXP11)83mg，收率：47％。MS(ESI)m/z:[M+H]+＝534.5。1H-NMR(DMSO-d6，400MHz)：δ11.95(br,1H),10.02(br,1H),8.93(d,1H),8.33(s,1H),7.73(d,1H),6.98(d,1H),6.82(d,1H), 6.53(m,1H),6.44(m,2H),6.21(d,1H),5.25(m,1H),3.73(m,1H),3.15-3.44(m,7H),3.06(m, 1H),2.86(s,6H),2.38(t,6H),2.18(s,3H),1.65-1.90(m,2H)ppm。
实施例12：N-(1-(8-((6-((4-甲基哌嗪-1-基)甲基)吡啶-3-基)氨基)-1-氧代-1,2- 二氢异喹啉-6-基)吡咯烷-3-基)丙烯酰胺(EXP12)的制备
参照实施例1的方法，制备得到N-(1-(8-((6-((4-甲基哌嗪-1-基)甲基)吡啶-3-基)氨基)-1-氧代-1,2-二氢异喹啉-6-基)吡咯烷-3-基)丙烯酰胺(EXP12)78mg，收率：20％。MS(ESI)m/z:[M+H]+＝488.2。1H-NMR(DMSO-d6，400MHz)：δ11.98(br,1H),9.25(s,1H),8.33(s,1H),7.70(m,2H),7.45(d,1H),7.19(d,1H),6.45-6.52(m, 3H),6.10-6.22(m,2H),5.75(m,1H),3.98(s,2H),3.59(m,1H),3.05-3.45(m,4H),2.45(t,4H), 2.35(t,4H),2.13(s,3H),1.71-1.87(m,2H)ppm。
实施例13：体外生化水平抑制蛋白激酶活性实验
材料与方法：BTK激酶，来源于Invitrogen；HTRF KinEASE；TK kit(Cisbio 公司)；384孔板(Greiner公司)；ATP(sigma公司)，MgCl2(sigma)公司； PHERAstar FS多功能酶标仪(BMG公司)；低速离心机(StaiteXiangyi公司)；恒温箱(Binder公司)。选取的阳性药为Reference compound，结构如下：
化合物溶解及保存：视溶解性用DMSO将受试化合物配置成0.5-10mmol/L 的母液，分装后-20℃保存；
化合物工作液的配制：测试前将分装的化合物从冰箱取出，用纯DMSO稀释到50×所需浓度；然后用去离子水将化合物稀释至4×所需浓度；
1.33×Enzymatic buffer的配制：将5×Enzymatic buffer来源于HTRF kit)用去离子水稀释到1.33×，并且加入1.33×终浓度的相应成分：1.33mmol/L DTT和 1.33mmol/LMgCl2；
激酶工作液的配制：用1.33×Enzymatic buffer将Btk稀释到2×所需终浓度0.2ng/μL；
底物工作液的配制：用1.33×Enzymatic buffer将substrate-biotin(来源于HTRF kit)和ATP(10mM)稀释为4×所需终浓度的混合液；
检测工作液的配制：用HTRF detection buffer将16.67μmol/L的 Streptavidin-XL665稀释到4×所需终浓度，然后与等体积的Antibody-Cryptate混合(均来源于HTRFkit)。
酶反应步骤：向低体积384微孔板的每个孔中加入4μLμl的激酶工作液，同时加入4μL的1.33×Enzymatic buffer作为阴性对照(Negative)；向孔加入2μl 的化合物工作液，同时加入2μL的8％DMSO水溶液作为零化合物浓度对照(即阳性对照，Positive)；于25℃(或30℃)孵育5-10min；向孔中加入2μL底物工作液启动酶反应，于25℃(或30℃)振荡反应15-60min。
HTRF试剂检测步骤：向孔加入8μL的检测工作液终止反应；25℃反应1h；
HTRF信号的读取：采用PHERAstar FS读数检测信号，仪器相应设置如下：
Optic module 
Integration delay(lag time)50μs
Integration time 400μs
Number of flashes 200
对于每孔读出的原始数据，比值＝665nm/620nm；
抑制率的计算：
IC50值的计算：以化合物浓度的对数为横坐标，抑制率为纵坐标，在GraphPadPrism 5中，拟合非线性曲线：log(inhibitor)vs.response--Variable slope，求出酶活抑制率为50％时的待测化合物浓度即IC50。
实验结果：BTK激酶活性半数抑制浓度(IC50，nM)
本发明提供结构如式I所示化合物对BTK激酶活性的半数抑制浓度(IC50)
| Reference compound | EXP 1 | EXP2 | EXP3 | EXP4 | EXP5 | EXP6 |
| 25.6nM | 3.5nM | 8.8nM | 6.3nM | 3.2nM | 0.8nM | 0.9nM |
| EXP7 | EXP8 | EXP9 | EXP10 | EXP11 | EXP12 | |
| 2.4nM | 0.5nM | 8.2nM | 2.6nM | 1.5nM | 5.8nM |
实施例:14：体外细胞水平抑制蛋白激酶活性实验
材料与方法：Fluo-4DirectTM Calcium Assay Kits试剂盒，Invitrogen公司；RPMI1640培养基：GIBCO公司；96孔黑板：CORNING公司；PHERAstar FS 多功能酶标仪(BMG)；低速离心机(StaiteXiangyi)。选取的阳性药为RN486。
细胞处理：用无血清培养基清洗细胞，去除血清。
染料配制：然后用无血清的培养基将2χ的染料稀释成1×。
细胞重悬：用上述配制的1×染料，重悬清洗过的细胞。
细胞接种：20万/孔，40μl/孔，96孔板，需要黑壁板。
染料孵育：放入孵箱中，孵育40min。
加药：然后加入一系列配制好的化合物，10μl/孔，继续作用20min。
室温平衡：将测试板拿出，室温平衡5min。
测定基线：在没有加入激动剂前，先用PHERStar酶标仪检测基线。
加入激动剂：加入终浓度为10μg/ml的IgM，10μl/孔。
测定：加入激动剂后，立即用PHERStar酶标仪进行检测，每隔10s，共检测8min。
数据处理：OD(最高值)－OD(基线)，然后用GraphPad Prism 5软件计算IC50值。
实验结果：BTK细胞钙流半数抑制浓度(IC50，nM)
本发明提供结构如式I所示化合物对BTK细胞钙流的半数抑制浓度(IC50)
| RN486 | EXP1 | EXP2 | EXP3 | EXP4 | EXP5 | EXP6 |
| 45.7nM | 3.2nM | 3.5nM | 10.2nM | 8.9nM | 5.2nM | 6.5nM |
| EXP7 | EXP8 | EXP9 | EXP10 | EXP11 | EXP12 | Reference compound |
| 12.6nM | 1.2nM | 5.3nM | 11.5nM | 20.3nM | 13.9nM | 185nM |
实施例15：大鼠胶原诱导的关节炎(rCIA)模型上的药效研究
本发明化合物抑制类风湿性关节炎的作用，选择DBA/1J小鼠，将50ug牛Ⅱ型胶原与等体积完全弗氏佐剂(CFA)完全乳化后皮下注射。21天后以50ug相同抗原与不完全弗氏佐剂(IFA充分乳化后，加强免疫1次。从第45天开始观察记录。采用1-4计分法：1分，正常；2分，1个关节肿胀；3分，超过1个关节肿胀，但并未累积全部关节；4分，整个爪的严重肿胀或强直。每只爪的评分相加即得到小鼠关节炎症的总评分。关节总评分大于1的小鼠为模型建立成功。成功建立小鼠类风湿关节炎模型后采用本发明化合物给小鼠灌胃给药，给药2周后对小鼠的关节炎症进行评分，结果显示本品对小鼠类风湿性关节炎有明显的治疗作用。
| 化合物组别 | 关节炎评分 |
| Control | 1 |
| 生理盐水对照组 | 4 |
| 环孢菌素对照组 | 2.4 |
| EXP8 | 0.8 |
| Reference compound | 2.8 |
己经通过举例说明和实施例的方式比较详细地描述了上述发明，以用于阐述和理解的目的。对于本领域技术人员显而易见的是，可以在后附权利要求的范围内进行改变和改进。因此，应该理解上述说明意在是举例说明性的而不是限制性的。因此，本发明的范围不应该参考上述说明书而确定，而应该参考下列后附的权利要求以及由权利要求授权的等价物的全部范围而确定。
Claims (4)
1.一种化合物，结构如下所述：
2.一种药用组合物，其包含治疗有效量的权利要求1所述的化合物和药物可接受的赋形剂或稀释剂。
3.权利要求1所述的化合物在制备用于BTK抑制剂中的应用。
4.根据权利要求1所述的化合物在制备用于治疗炎性和/或自身免疫病症的药物中的应用，其特征在于，所述炎性病症为类风湿性关节炎。
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