CN115894500A - 一种作为btk激酶抑制剂的化合物及其制备方法与用途 - Google Patents
一种作为btk激酶抑制剂的化合物及其制备方法与用途 Download PDFInfo
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Abstract
本发明属于医药化学领域,具体涉及一类式I所示的各种不同类型取代的(7H‑吡咯并[2,3‑d]嘧啶‑5‑基)[4‑(苯基氧基)苯基]甲酮类衍生物作为非共价BTK激酶抑制剂的化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、同位素衍生物、药学上可接受的盐或前药,制备方法,以及含有这些化合物的药物组合物和这些化合物或组合物在药物制备中的应用。本发明的化合物对BTK激酶具有明显的抑制作用,为以BTK为治疗靶点的疾病如恶性肿瘤疾病或自身免疫性疾病等的治疗提供新的方案,可用于制备治疗相关疾病的药物,具有临床应用价值。
Description
技术领域
本发明属于医药技术领域,涉及一类吡咯并嘧啶类化合物及其制备方法、药物组合物和其在制备治疗BTK激酶过度表达所致疾病的药物中的用途。
背景技术
BTK(Bruton's tyrosine kinase,布鲁顿酪氨酸激酶)存在于细胞质中,作为Tec激酶家族的一员,是一种非受体酪氨酸激酶(NRTK)。人类BTK激酶发生功能性缺失突变可导致遗传性疾病——X连锁的无球蛋白血症(XLA),造成体内成熟外周B细胞缺失和血清免疫球蛋白水平降低,在儿童身上表现为早期反复发作的细菌感染和败血症。BTK在B细胞受体(B cell receptor,BCR)信号通路中发挥重要的信号转导作用,在B细胞激活、增殖、分化和存活过程中有着重要的作用,与多种B细胞肿瘤及自身免疫性疾病密切相关。
BTK激酶由五个区域组成:pleckstrin同源(PH)结构域、Tec同源(TH)结构域、Src同源3(SH3)结构域、Src同源2(SH2)结构域和具有酪氨酸激酶活性的C末端区或Src同源1结构域(TK/SH1)。其中PH结构域包括转录因子BAP-135/TFII-I的结合位点,同时可介导第二信使与PIP3的相互作用;TK/SH1结构域除了具有实现BTK初始激活的活化环外,还包含有ATP结合位点和变构抑制片段;SH2、SH3结构域则包含BTK激酶的自磷酸化位点,在完成BTK的完全激活方面发挥了重要作用。
现今已经批准上市的BTK抑制剂分子,如Ibrutinib、Acalabrutinib、Orelabrutinib等均为通过选择性地与关键半胱氨酸残基Cys481形成共价键发挥抑制作用的共价抑制剂分子,然而这类抑制剂无法规避BTK突变引起的活性下降,即Ibrutinib耐药性,这一临床需求使得靶向抑制BTK-C481S突变型的可逆抑制剂有望克服Ibrutinib耐药性,为该类患者提供新的治疗方案。
发明内容
本发明主要解决的技术问题是提供一类结构新颖、能够有效抑制突变型BTK激酶的化合物,可用于B细胞衍生的恶性肿瘤和自身免疫性疾病的治疗。
为解决上述技术问题,本发明采用的以下技术方案:
本发明的第一方面中,提供了式(Ⅰ)所示的化合物,
或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、同位素衍生物、药学上可接受的盐或前药,其中:
X1为N或CH;
Ra、Rb分别独立地选自:氢、卤素,可以为单、双或多取代;
Rc、Rd独立地选自:氢,取代或未取代的C1-8的直链或支链烷基,取代或未取代的环烷基,取代或未取代的杂环基,取代或未取代的杂烷基,芳基,Rc、Rd也可以成环但Rc、Rd不同时为氢;Rc、Rd也可以为-(CH2)mReRf,其中Re、Rf可选自氢,取代或未取代的C1-8的直链或支链烷基,取代或未取代的环烷基,取代或未取代的杂环基,取代或未取代的杂烷基,芳基,Re、Rf也可以成环或螺环但Re、Rf不同时为氢;
m独立地为0,1,2。
在某些优选的实施方案中,公开了式(Ⅰ)所示的化合物,或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、同位素衍生物、药学上可接受的盐或前药,其中:
Ra、Rb可分别独立地选自:氢、卤素,可以为单、双或多取代;
其中,X1为N或CH;
X2,X3为O,S,NH或CH2;
Rc、Rd独立地选自:氢,取代或未取代的C1-8的直链或支链烷基,取代或未取代的环烷基,取代或未取代的杂环基,取代或未取代的杂烷基,芳基,Rc、Rd也可以成环但Rc、Rd不同时为氢;Rc、Rd也可以为-(CH2)mReRf,其中Re、Rf可选自氢,取代或未取代的C1-8的直链或支链烷基,取代或未取代的环烷基,取代或未取代的杂环基,取代或未取代的杂烷基,芳基,Re、Rf也可以成环或螺环但Re、Rf不同时为氢;
Rg、Rh独立地选自:氢,取代或未取代的C1-4的直链或支链烷基,羟基取代的直链或支链烷基,卤素;Rg、Rh也可以为-NRiRj,其中Ri、Rj可选自氢,取代或未取代的C1-4的直链或支链烷基;
a,b,c独立地为0,1或2。
在某些更优选的实施方案中,本发明的化合物是如下表1中的任一化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、同位素衍生物、药学上可接受的盐或前药:
表1为本发明的部分化合物:
在又一方面,本发明提供了药物组合物,包含本发明的化合物,或它们的立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、同位素衍生物、药学上可接受的盐或前药,或任选的药学上可接受的载体、赋形剂、稀释剂、辅剂、媒介物或它们的组合。其中一些实施例为,这些化合物是蛋白质激酶抑制剂,另外一些实施例为,这些化合物是BTK激酶抑制剂。
在又一方面,本发明提供了如式C所示的化合物的制备方法,所述制备方法的反应式如下:
其中,X1,Ra,Rb,Rc,Rd如权利要求1所述;
所述制备方法具体包括以下步骤:
首先,以化合物A为原料,通过与正丁基锂发生卤素-金属交换反应形成有机锂化合物,再与4-苯氧基苯甲酸酯发生亲核加成反应,得到化合物B;然后以各种弱碱作为缚酸剂,化合物B与取代的杂环发生亲核取代反应,得到目标化合物C。
本发明另一方面提供了本发明的化合物,或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、同位素衍生物、药学上可接受的盐或前药在制备蛋白质激酶抑制剂中的用途;进一步地,所述激酶抑制剂为BTK抑制剂
本发明另一方面提供了本发明的化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、同位素衍生物、药学上可接受的盐或前药及包含本发明的化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、同位素衍生物、药学上可接受的盐或前药的药物组合物在制备用于治疗自身免疫性疾病、炎性疾病、血栓栓塞疾病、过敏症、感染性疾病、增生性疾病和癌症中的任意一种或多种疾病在药物中的用途。
在具体实施方案中,所述疾病选自:关节炎、类风湿性关节炎、荨麻疹、白癜风、器官移植排斥、溃疡性结肠炎、克罗恩病、皮炎、哮喘、干燥综合征、系统性红斑狼疮、多发性硬化、特发性血小板减少性紫癜、皮疹、抗嗜中性白细胞胞质抗体血管炎、天胞疮、寻常性天胞疮、慢性阻塞性肺疾病、银屑病;乳腺癌、套细胞淋巴瘤、卵巢癌、食道癌、喉癌、成胶质细胞瘤、成神经细胞瘤、胃癌、肝细胞癌、胶质瘤、子宫内膜癌、黑色素瘤、肾癌、膀胱癌、胆道癌、胰腺癌、淋巴瘤、毛细胞癌、鼻咽癌、大肠癌、直肠癌、脑和中枢神经系统癌症、宫颈癌、前列腺癌、睾丸癌、泌尿生殖道癌、肺癌、肺小细胞癌、小细胞癌、肺腺癌、骨癌、结肠癌、腺瘤、胰腺癌、甲状腺癌、滤泡性癌、霍奇金白血病、支气管癌、子宫体癌、子宫颈癌、多发性骨髓瘤、急性髓细胞源性白血病、慢性髓细胞源性白血病、淋巴细胞白血病、慢性淋巴样白血病、骨髓性白血病、非霍奇金淋巴瘤、原发性巨球蛋白血症。
本发明另一方面提供了本发明的化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、同位素衍生物、药学上可接受的盐或前药及包含本发明的化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、同位素衍生物、药学上可接受的盐或前药的药物组合物在制备用于治疗致使BTK激酶过度表达的疾病的药物中的用途。
本发明另一方面提供了本发明的化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、同位素衍生物、药学上可接受的盐或前药及包含本发明的化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、同位素衍生物、药学上可接受的盐或前药的药物组合物在制备用于治疗BTK激酶过度表达所致疾病的药物中的用途。
定义
下面更详细地描述具体官能团和化学术语的定义。
像本发明所描述的,本发明中的化合物可以任选地被一个或多个取代基所取代,如本发明的通式化合物,或者像实施例理特殊的例子、子类,和本发明所包含的一类化合物。应了解“任选取代的”这个术语与“取代与非取代的”这个术语可以交换使用。一般而言,术语“任选地”不论是否位于术语“取代的”之前,表示所给结构中的一个或多个氢原子被具体取代基所取代。除非其他方面表明,一个任选的取代基团可以有一个取代基在基团各个可取代的位置进行取代。当所给出的结构式中不止一个位置能被选自具体基团的一个或多个取代基所取代,那么取代基可以相同或不同地在各个位置取代。其中所述的取代基可以是,但并不限于,羟基,羟基烷基,氨基,卤素,氰基,氧代(=O),芳基,杂芳基,烷氧基,烷基,卤代烷基,氨基烷基,烷基氨基,烯基,炔基,杂环基,巯基,硝基,芳基氧基或芳基烷基等等。
本发明使用的术语“烷基”包括1-20个碳原子饱和直链或支链的单价烃基,其中烷基可以独立任选地被一个或多个本发明所描述的取代基所取代。其中一些实施例为,烷基含有1-10个碳原子,另外一些实施例为,烷基含有1-8个碳原子,另外一些实施例为,烷基含有1-6个碳原子,另外一些实施例为,烷基含有1-4个碳原子。烷基基团更进一步的实例包括,但并不限于,甲基(Me,-CH3),乙基(Et,-CH2CH3),正丙基(n-Pr,-CH2CH2CH3),异丙基(i-Pr,-CH(CH3)2),正丁基(n-Bu,-CH2CH2CH2CH3),异丁基(i-Bu,-CH2CH(CH3)2),仲丁基(s-Bu,-CH(CH3)CH2CH3),叔丁基(t-Bu,-C(CH3)3),正戊基(-CH2CH2CH2CH2CH3),2-戊基(-CH(CH3)CH2CH2CH3),3-戊基(-CH(CH2CH3)2),2-甲基-2-丁基(-C(CH3)2CH2CH3),3-甲基2-丁基(-CH(CH3)CH(CH3)2),3-甲基-1-丁基(-CH2CH2CH(CH3)2),2-甲基-1丁基(-CH2CH(CH3)CH2CH3),正己基,正庚基,等等。术语“烷基”和其前缀“烷”在此处使用,都包含直链和支链的饱和碳链。
术语“环烷基”是指一价或多价,非芳香族,饱和或部分不饱和环,包括3-12个碳原子的单环或7-12个碳原子的二环。具有7-12个院子的双碳环可以是二环[4,5],[5,5],[5,6]或[6,6]体系,同时具有9或10个原子的双碳环可以是二环[5,6]或[6,6]体系。合适的碳环基包括,但并不限于,环烷基,环烯基和环炔基。碳环基的实例进一步包括,但绝不限于,环丙基,环丁基,1-环戊基-1-烯基,1-环戊基-2-烯基,1-环戊基-3-烯基,环己基,1-环己基-1-烯基,1-环己基-2-烯基,1-环己基-3-烯基,环己二烯基,环庚基,环辛基,等等。并且,所述“碳环基”或“环烷基”可以是取代或费取代的,其中取代基可以是,但并不限于,羟基,氨基,卤素,氰基,芳基,杂芳基,烷氧基,烷基,烯基,炔基,杂环基,巯基,硝基,芳基氧基,芳基烷基等等。
术语“杂烷基”表示为烷基上一个或多个原子可以独立地任选地被杂原子所取代,烷基如本发明所定义的,并且由碳原子与其余分子相连,其中一些实施例为,“杂烷基”是1-10个原子的支链或直链(1-9个碳原子和选自N,O,S,P的1-3个杂原子,在此S或P任选地被一个或多个氧原子所取代得到像SO2,SO,PO,PO2的基团),这样的实例包括,但并不限于氨基甲基,甲氧基乙基等。
术语“杂原子”表示一个或多个O,S,N,P和Si,包括N,S和P任何氧化态的形式;伯、仲、叔胺和季铵盐的形式;或者杂环中氮原子上的氢被取代的形式,例如,N(像3,4-二氢-2H-吡咯基中的N),NH(像吡咯烷基中的NH)或NR(像N-取代的吡咯烷基中的NR)。
术语“卤素”或前缀“卤”,是指F,Cl,Br或I。
本发明所使用的术语“不饱和的”表示部分含有一个或多个不饱和度。
术语“芳基”可以单独使用或作为“芳烷基”“芳烷氧基””或“芳氧基烷基”的一大部分,表示共含有6-14元环的单环,双环和三环的碳环体系,其中,至少一个环体系是芳香族的,其中每一个环体系包含3-7元环,且只有一个附着点与分子的其他部分相连。术语“芳基”可以和术语“芳香环”交换使用,如方向华可以包括苯基,萘基和蔥。并且所述芳基可以是取代或非取代的,其中取代基可以是,但并不限于,羟基,氨基,卤素,氰基,芳基,杂芳基,烷氧基,烷基,烯基,炔基,杂环基,巯基,硝基,芳基氧基,芳基烷基等等。
像本发明所描述的,取代基画一个键连接到中心的环上形成的环体系(如a所示)代表Rg可以在环上任何可取代的位置都可以取代。例如a代表环上任何可能被取代的位置均可被Rg取代。
除非其他方面表明,本发明所描述的结构式包括所有的同分异构形式(如对映异构、非对映异构,和几何异构(或构象异构));例如含有不对称中心的R、S构型,双键的(Z)、(E)异构体,和(Z)、(E)的构象异构体。因此,本发明的化合物的单个立体化学异构体或其对映异构体,非对映异构体,或几何异构体(或构象异构体)的混合物都属于本发明的范围。
本发明中所述的“药学上可接受的”是指包括任意不干扰活性成分的生物活性的有效性且对它被给予的宿主无毒性的物质。
本发明中的药学上可接受的辅料,是药物中除主药以外的一切附加材料的总称,辅料应当具备如下性质:(1)对人体无毒害作用,几无副作用;(2)化学性质稳定,不易手温度、pH、保存时间等的影响;(3)与主药无配伍禁忌,不影响主药的疗效和质量检查;(4)不与包装材料相互发生作用。本发明中辅料包括但不限于填充剂(稀释剂)、润滑剂(助流剂或抗粘着剂)、分散剂、润湿剂、粘合剂、调节剂、增溶剂、抗氧剂、抑菌剂、乳化剂、崩解剂等。粘合剂包括糖浆、阿拉伯胶、明胶、山梨醇、黄芪胶、纤维素及其衍生物(如微晶纤维素、羧甲基纤维素钠、乙基纤维素或羟丙基纤维素等)、明胶浆、糖浆淀粉浆或聚乙烯吡咯烷酮等;填充剂包含乳糖、糖粉、糊精、淀粉及其衍生物、纤维素及其衍生物、无机钙盐(如硫酸钙、磷酸钙、磷酸氢钙、沉降碳酸钙等)、山梨醇或甘氨酸等;润滑剂包含微粉硅胶、硬脂酸镁、滑石粉、氢氧化铝、硼酸、氢化植物油、聚乙二醇等;崩解剂包含淀粉及其衍生物(如羧甲基淀粉钠、淀粉乙醇酸钠、预胶化淀粉、改良淀粉、羟丙基淀粉、玉米淀粉等)、聚乙烯吡咯烷酮或微晶纤维素等,润湿剂包含十二烷基硫酸钠、水或醇等;抗氧剂白喊亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠、二丁基苯酸等;抑菌剂包含0.5%苯酚、0.3%甲酚、0.5%三氯叔丁醇等;调节剂包含盐枸橼酸、氢氧化钾(钠)、枸橼酸钠及缓冲剂(包括磷酸氢二钠和磷酸二氢钠)等;乳化剂包含聚山梨酯-80、没酸山梨坦、普流罗尼克F-68、卵磷脂、豆磷脂等;增溶剂包含吐温-80、胆汁、甘油等。术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。上述酸碱为广义的路易斯酸碱。适合形成盐的酸包括但不限于:盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸,甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸、苯磺酸等有机酸;以及天冬氨酸、谷氨酸等酸性氨基酸。
本发明所使用的术语“前药”,代表一个化合物在体内转化为式Ⅰ所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯,在现有的发明中酯可以作为前体药物的有苯酯类,脂肪族(C1-24)酯类,酰氧基甲基酯类,碳酸酯,氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基,即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯,如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。
除非其他方面表明,本发明的化合物的所有互变异构形式都包含在本发明的范围之内。另外,除非其他方面表明,本发明所描述的化合物的结构式包括一个或多个不同的原子的富集同位素。
“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定。这样的产物可以是通过给药化合物经过氧化,还原,水解,酰胺化,脱酰胺作用,酯化,脱脂作用,酶裂解等等方法得到。相应地,本发明包括化合物的代谢产物,包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。
本发明的化合物可以包含不对称中心或手性中心,因此存在不同的立体异构体。本发明的化合物所有的立体异构形式,包括但绝不限于,非对映体,对映异构体,阻转异构体,和它们的混合物,如外消旋混合物,组成了本发明的一部分。很多有机化合物都以光学活性形式存在,即它们有能力旋转平面偏振光的平面。在描述光学活性化合物时,前缀D、L或R、S用来表示分子手性中心的绝对构型。前缀d、l或(+)、(-)用来命名化合物平面偏振光旋转的符号,前缀(-)或l是指化合物是左旋的,前缀(+)或d是指化合物是右旋的。这些立体异构体的化学结构是相同的,但是它们的立体结构不一样。特定的立体异构体可以是对映体,异构体的混合物通常称为对映异构体混合物。50:50的对映体混合物被称为外消旋混合物或外消旋体,这可能导致化学反应过程中没有立体选择性或立体定向性。术语“外消旋混合物”和“外消旋体”是指等摩尔的两个对映异构体的混合物,缺乏光学活性。
术语“互变异构体”或“互变异构的形式”是指不同能量的结构的同分异构体可以通过低能垒互相转化。这样的实例包括,但并不限于,质子互变异构体((即质子移变的互变异构体)包括通过质子迁移的互变,如酮式-烯醇式和亚胺-烯胺的同分异构化作用。原子价(化合价)互变异构体包括一些成键电子的重组互变。
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的的缔合物。形成溶剂化物的溶剂包括,但并不限于,水,异丙醇,乙醇,甲醇,二甲亚砜,乙酸乙酯,乙酸,氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。
本发明的“同位素衍生物”是指在本专利中化合物被同位素标记的分子。通常用作同位素标记的同位素是:氢同位素:2H和3H;碳同位素:11C,13C和14C;氯同位素:35Cl和37Cl;氟同位素:18F;碘同位素:123I和125I;氮同位素:13N和15N;氧同位素:15O,17O和18O和硫同位素35S。这些同位素标记化合物可以用来研究药用分子在组织中的分布情况。尤其是氘2H和碳13C,由于它们容易标记且方便检测,运用更为广泛。某些重同位素,比如重氢(2H)的取代能增强代谢的稳定性,延长半衰期从而达到减少剂量的目而提供疗效优势。同位素标记的化合物一般从已被标记的起始物开始,用己知的合成技术像合成非同位素标记的化合物一样来完成其合成。
术语“保护基团”或“Pg”是指一个取代基与别的官能团起反应的时候,通常用来阻断或保护特殊的功能性。例如,“氨基的保护基团”是指一个取代基与氨基基团相连来阻断或保护化合物中氨基的功能性,合适的氨基保护基团包括乙酰基,三氟乙酰基,叔丁氧羰基(Boc),苄氧羰基(CBZ)和9-芴亚甲氧羰基(Fmoc)。相似地,“羟基保护基团”是指羟基的取代基用来阻断或保护羟基的功能性,合适的保护基团包括乙酰基和甲硅烷基。“羧基保护基团”是指羧基的取代基用来阻断或保护羧基的功能性,一般的羧基保护基包括-CH2CH2SO2Ph,氰基乙基,2-(三甲基硅烷基)乙基,2-(三甲基硅烷基)乙氧基甲基,2-(对甲苯磺酰基)乙基,2-(对硝基苯磺酰基)乙基,2-(二苯基膦基)乙基,硝基乙基,等等。
给药
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增溶剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐和碳酸钠;(e)缓溶剂,例如,石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如,鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其他本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域常规采用的惰性稀释剂,如水或其他溶剂,增溶剂和乳化剂,例如,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。
本发明化合物同样可以用于注射制剂。其中,所述注射剂选自液体注射剂(水针)、注射用无菌粉末(粉针)或注射用片剂(系指药物用无菌操作法制成的模印片或机压片,临用是用注射用水溶解,供皮下或肌肉注射之用)。
其中,所述注射用粉剂的中除含有上述化合物外,还至少含有赋形剂。本发明中所述赋形剂,为有意加到药物中的成分,其在所用的量上不应具有药理学特性,但是,赋形剂可以有助于药物的加工、溶解或溶出、通过靶向给药途径或有助于稳定性。
本发明的有益效果是:本发明提供了一系列具有抑制BTK活性的化合物,试验表明其对BTK具有明显的抑制作用,为以BTK为治疗靶点的疾病如恶性肿瘤疾病或自身免疫性疾病等的治疗提供新的方案,可用于制备治疗相关疾病的药物,具有开阔的应用前景。
具体实施方式
提供以下实施例以便为领域技术人员提供如何实施、制备和评估本文请求保护的方法和化合物的完整公开和说明,旨在仅仅示例本发明而非限制本发明的范围。
本发明中,化合物的结构是通过质谱设备来确定的。化学缩写简称具有以下意义:
DMF:N,N-二甲基甲酰胺
TLC:薄层层析色谱
n-BuLi:正丁基锂
THF:四氢呋喃
DIPEA:N,N-二异丙基乙胺
EA:乙酸乙酯
DCM:二氯甲烷
HBTU:苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐
LiAlH4:氢化铝锂
合成方法
本发明化合物可按照本领域常规方法,并使用合适的试剂、原料和本领域技术人员已知的纯化方法制备。
下面更具体地描述本发明化合物的制备方法,但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得,这样的组合可由本发明所属领域的技术人员容易地进行。
实施例1制备[2-氯-4-(苯基氧基)苯基](4-{[(3R,6S)-6-{[(3,4,5,6-四氢-2H- 吡喃-4-基甲基)氨基]甲基}-3,4,5,6-四氢-2H-吡喃-3-基]氨基}-7H-吡咯并[2,3-d]嘧 啶-5-基)甲酮(化合物1)
步骤1:化合物1-3的合成
向反应瓶中加入化合物1-1(10.00g,53.03mmol),1-2(5.99g,63.63mmol),DMF(80mL),搅拌下加入碳酸钾(14.66g,106.05mmol),90℃搅拌反应3小时,TLC显示反应完全。反应体系倒入水中,乙酸乙酯萃取两次,合并有机层,水洗两次,饱和氯化钠溶液洗涤,无水Na2SO4干燥,抽滤,滤液减压浓缩,粗品经硅胶柱层析纯化得无色透明油状液体12g,为产物1-3,收率:86.15%。
步骤2:化合物1-5的合成
向三口反应瓶中加入化合物1-4(5.00g,21.51mmol),氮气置换,加入无水四氢呋喃(20mL),反应液冷却至-78℃,向反应瓶内滴加n-BuLi的四氢呋喃溶液(17.90mL,2.4M),搅拌反应1小时后,加入1-3(6.22g,23.66mmol)的四氢呋喃溶液,保温反应2小时,TLC显示反应完全。将反应液升至室温,加入饱和氯化铵溶液淬灭反应,乙酸乙酯萃取两次,合并有机层,水洗两次,饱和食盐水洗涤,无水Na2SO4干燥,抽滤,滤液减压浓缩,粗品经硅胶柱层析纯化得到5.00g白色固体,为产物1-5,收率:60.50%。
步骤3:化合物1-8的合成
在反应瓶中加入化合物1-6(500mg,3.44mmol),1-7(516mg,4.48mmol),N,N-二异丙基乙胺(579mg,4.48mmol),HBTU(2.60g,6.88mmol),二氯甲烷(40mL),35℃反应过夜,TLC显示反应完全。减压浓缩,粗品经硅胶柱层析纯化并冻干得到83.87mg无色透明油状液体,为1-8,收率:25.12%。
步骤4:化合物1-9的合成
向反应瓶中加入化合物1-8(150mg,0.62mmol)和四氢呋喃(8mL),室温搅拌下缓慢加入LiAlH4至无气泡产生,TLC显示反应完全。在-20℃条件下缓慢加入15%NaOH溶液和水淬灭,抽滤,洗涤,减压浓缩,得到126mg黄色固体,为产物1-9,收率:89.20%。
LC/MS:m/z=243.17[M+H]+。
步骤5:化合物1的合成
向反应瓶中加入化合物1-5(100.00mg,0.26mmol),1-9(89.14mg,0.39mmol),三乙胺(52.68mg,0.52mmol)和二氯甲烷(3mL),室温搅拌反应过夜,TLC显示反应完全。减压浓缩,粗品经硅胶柱层析纯化再冻干得到59mg白色固体,为产物1,收率:39.52%。
LC/MS:m/z=576.09[M+H]+。
实施例2制备[2-氯-4-(苯基氧基)苯基](4-{[(3R,6S)-6-[(3,4,5,6-四氢-2H-吡
喃-4-基氨基)甲基]-3,4,5,6-四氢-2H-吡喃-3-基]氨基}-7H-吡咯并[2,3-d]嘧啶-5-基)
甲酮(化合物2)
参照实施例1的方法,以1-6,2-7为原料,制得化合物2-9:LC/MS:m/z=215.19[M+H]+。
参照实施例1的方法,以中间体1-5为原料,制得化合物2:LC/MS:m/z=562.07[M+H]+。
实施例3制备[2-氯-4-(苯基氧基)苯基](4-{[(3R,6S)-6-[(四氢呋喃-3-基氨基)
甲基]-3,4,5,6-四氢-2H-吡喃-3-基]氨基}-7H-吡咯并[2,3-d]嘧啶-5-基)甲酮(化合物3)
参照实施例1的方法,以1-6,3-7为原料,制得化合物3-9:LC/MS:m/z=201.14[M+H]+。
参照实施例1的方法,以中间体1-5为原料,制得化合物3:LC/MS:m/z=548.04[M+H]+。
实施例4制备[2-氯-4-(苯基氧基)苯基](4-{[(3R,6S)-6-{[(四氢呋喃-3-基甲
基)氨基]甲基}-3,4,5,6-四氢-2H-吡喃-3-基]氨基}-7H-吡咯并[2,3-d]嘧啶-5-基)甲酮
(化合物4)
参照实施例1的方法,以1-6,4-7为原料,制得化合物4-9:LC/MS:m/z=215.18[M+H]+。
参照实施例1的方法,以中间体1-5为原料,制得化合物4:LC/MS:m/z=562.07[M+H]+。
实施例5制备[2-氯-4-(苯基氧基)苯基](4-{[(3R,6S)-6-[(氧杂环丁-3-基氨基)
甲基]-3,4,5,6-四氢-2H-吡喃-3-基]氨基}-7H-吡咯并[2,3-d]嘧啶-5-基)甲酮(化合物5)
参照实施例1的方法,以1-6,5-7为原料,制得化合物5-9:LC/MS:m/z=187.17[M+H]+。
参照实施例1的方法,以中间体1-5为原料,制得化合物5:LC/MS:m/z=534.01[M+H]+。
实施例6制备[2-氯-4-(苯基氧基)苯基](4-{[(3R,6S)-6-{[(氧杂环丁-3-基甲
基)氨基]甲基}-3,4,5,6-四氢-2H-吡喃-3-基]氨基}-7H-吡咯并[2,3-d]嘧啶-5-基)甲酮
(化合物6)
参照实施例1的方法,以1-6,6-7为原料,制得化合物6-9:LC/MS:m/z=201.16[M+H]+。
参照实施例1的方法,以中间体1-5为原料,制得化合物6:LC/MS:m/z=548.04[M+H]+。
实施例7制备[2-氯-4-(苯基氧基)苯基](4-{[(3R,6S)-6-(2-氮杂-7-氧杂螺
[3.5]壬-2-基甲基)-3,4,5,6-四氢-2H-吡喃-3-基]氨基}-7H-吡咯并[2,3-d]嘧啶-5-基)
甲酮(化合物7)
参照实施例1的方法,以1-6,7-7为原料,制得化合物7-9:LC/MS:m/z=241.18[M+H]+。
参照实施例1的方法,以中间体1-5为原料,制得化合物7:LC/MS:m/z=588.11[M+H]+。
实施例8制备[2-氯-4-(苯基氧基)苯基](4-{[(3R,6S)-6-({[(3,3-二氟环丁基)
甲基]氨基}甲基)-3,4,5,6-四氢-2H-吡喃-3-基]氨基}-7H-吡咯并[2,3-d]嘧啶-5-基)甲
酮(化合物8)
参照实施例1的方法,以1-6,8-7为原料,制得化合物8-9:LC/MS:m/z=235.15[M+H]+。
参照实施例1的方法,以中间体1-5为原料,制得化合物8:LC/MS:m/z=582.05[M+H]+。
实施例9制备[2-氯-4-(苯基氧基)苯基](4-{[(3R,6S)-6-{[4-(二甲基氨基)六氢
吡啶-1-基]甲基}-3,4,5,6-四氢-2H-吡喃-3-基]氨基}-7H-吡咯并[2,3-d]嘧啶-5-基)甲
酮(化合物9)
参照实施例1的方法,以1-6,9-7为原料,制得化合物9-9:LC/MS:m/z=242.23[M+H]+。
参照实施例1的方法,以中间体1-5为原料,制得化合物9:LC/MS:m/z=589.14[M+H]+。
实施例10制备[2-氯-4-(苯基氧基)苯基](4-{[(3R,6S)-6-({[4-(二甲基氨基)环
己基]氨基}甲基)-3,4,5,6-四氢-2H-吡喃-3-基]氨基}-7H-吡咯并[2,3-d]嘧啶-5-基)甲
酮(化合物10)
参照实施例1的方法,以1-6,10-7为原料,制得化合物10-9:LC/MS:m/z=255.25[M+H]+。
参照实施例1的方法,以中间体1-5为原料,制得化合物10:LC/MS:m/z=603.16[M+H]+。
实施例11制备[2-氯-4-(苯基氧基)苯基](4-{[(3R,6S)-6-[(4-甲基哌嗪-1-基)
甲基]-3,4,5,6-四氢-2H-吡喃-3-基]氨基}-7H-吡咯并[2,3-d]嘧啶-5-基)甲酮(化合物
11)
参照实施例1的方法,以1-6,11-7为原料,制得化合物11-9:LC/MS:m/z=214.18[M+H]+。
参照实施例1的方法,以中间体1-5为原料,制得化合物11:LC/MS:m/z=561.08[M+H]+。
实施例12制备[[2-氯-4-(苯基氧基)苯基](4-{[(3R,6S)-6-{[(1-甲基六氢吡啶-
4-基)氨基]甲基}-3,4,5,6-四氢-2H-吡喃-3-基]氨基}-7H-吡咯并[2,3-d]嘧啶-5-基)甲
酮(化合物12)
参照实施例1的方法,以1-6,12-7为原料,制得化合物12-9:LC/MS:m/z=228.22[M+H]+。
参照实施例1的方法,以中间体1-5为原料,制得化合物12:LC/MS:m/z=575.11[M+H]+。
实施例13制备[2-氯-4-(苯基氧基)苯基](4-{[(3R,6S)-6-({[(1-甲基六氢吡啶-
4-基)甲基]氨基}甲基)-3,4,5,6-四氢-2H-吡喃-3-基]氨基}-7H-吡咯并[2,3-d]嘧啶-5-
基)甲酮(化合物13)
参照实施例1的方法,以1-6,13-7为原料,制得化合物13-9:LC/MS:m/z=242.23[M+H]+。
参照实施例1的方法,以中间体1-5为原料,制得化合物13:LC/MS:m/z=589.14[M+H]+。
实施例14制备[2-氯-4-(苯基氧基)苯基](4-{[(3R,6S)-6-{[4-(2-羟基乙基)哌
嗪-1-基]甲基}-3,4,5,6-四氢-2H-吡喃-3-基]氨基}-7H-吡咯并[2,3-d]嘧啶-5-基)甲酮
(化合物14)
参照实施例1的方法,以1-6,14-7为原料,制得化合物14-9:LC/MS:m/z=244.19[M+H]+。
参照实施例1的方法,以中间体1-5为原料,制得化合物14:LC/MS:m/z=591.11[M+H]+。
实施例15制备[2-氯-4-(苯基氧基)苯基](4-{[(3R,6S)-6-(1,4-氧杂氮杂环己-
4-基甲基)-3,4,5,6-四氢-2H-吡喃-3-基]氨基}-7H-吡咯并[2,3-d]嘧啶-5-基)甲酮(化合
物15)
参照实施例1的方法,以1-6,15-7为原料,制得化合物15-9:LC/MS:m/z=201.15[M+H]+。
参照实施例1的方法,以中间体1-5为原料,制得化合物15:LC/MS:m/z=548.04[M+H]+。
实施例16制备[2-氯-4-(苯基氧基)苯基](4-{[(3R,6S)-6-[(苯基氨基)甲基]-3,
4,5,6-四氢-2H-吡喃-3-基]氨基}-7H-吡咯并[2,3-d]嘧啶-5-基)甲酮(化合物16)
参照实施例1的方法,以1-6,16-7为原料,制得化合物16-9:LC/MS:m/z=207.15[M+H]+。
参照实施例1的方法,以中间体1-5为原料,制得化合物16:LC/MS:m/z=554.05[M+H]+。
实施例17制备[2-氯-4-(苯基氧基)苯基](4-{[(3R,6S)-6-[(环丙基氨基)甲基]-
3,4,5,6-四氢-2H-吡喃-3-基]氨基}-7H-吡咯并[2,3-d]嘧啶-5-基)甲酮(化合物17)
参照实施例1的方法,以1-6,17-7为原料,制得化合物17-9:LC/MS:m/z=171.14[M+H]+。
参照实施例1的方法,以中间体1-5为原料,制得化合物17:LC/MS:m/z=518.01[M+H]+。
生物活性测试(一)化合物进行体外细胞增殖(SU-DHL-4)抑制活性的测定
1:SU-DHL-4弥漫性大B淋巴瘤细胞系从广州吉妮欧生物科技有限公司购买获得,以RPMI-1640加10%胎牛血清(Gibcol公司),置于37℃、5%CO2、95%湿度条件下培养。
2:以下为一般实验步骤
(1)收获处于对数生长期的细胞用台盼蓝染色检测细胞活力,并以细胞计数仪(thermo countness II)进行细胞计数取合适的细胞量,调整细胞浓度,分别添加50μL细胞悬液至96孔板中,每孔5000个细胞,培养过夜;
(2)配制待测化合物溶液,向每孔细胞中加入50μL待测化合物的溶液,每种待测化合物两个终浓度,分别为5μM和0.5μM,每个化合物浓度设置三个复孔,于培养箱中继续培养72小时;
(3)给药后培养72小时后,每孔加入10μL CCK-8溶液,后将96孔板放置于培养箱中,继续培养2小时后在450nm处读取吸光值,并计算其相对抑制率,结果如下表2。
表3.本发明部分化合物对SU-DHL-4细胞增殖抑制活性
(二)体外BTK激酶活性抑制试验
1:化合物配制
将化合物粉末溶解在100%DMSO中,配制成10mM储存液,-20℃避光冻存。
2:激酶反应过程
(1)配制4X kinase buffer和1X kinase buffer;
(2)化合物的配制:受测试的化合物浓度为50μM,率先稀释成100倍终浓度的100%DMSO溶液,利用4X kinase buffer稀释成5倍终浓度的5%DMSO溶液,8个浓度。分液器转移1μL到384孔板,每个化合物两复孔;
(3)利用4X kinase buffer配制2.5倍终浓度的激酶溶液;
(4)在化合物和阳性对照孔加入2μL的2.5倍终浓度的激酶溶液,阴性对照孔加入3μL的1X kinase buffer;
(5)反应板震荡混匀后室温孵育10分钟;
(6)利用4X kinase buffer配制2.5倍终浓度的ATP和Kinase substrate的混合溶液;
(7)加入2μL的ATP和Kinase substrate的混合溶液,起始反应;
(8)震荡混匀后室温孵育60分钟;
(9)加入5μL ADP-Glo试剂,震荡混匀,终止反应,并室温孵育60min消耗残余的ATP;
(10)加入10μL kinase detection reagent,震荡混匀,室温孵育40min;
(11)用酶标仪读取数据,计算抑制率。
3:数据分析
计算公式:
其中:Conversion%_sample是样品的转化率读数;Conversion%_min:阴性对照孔均值,代表没有酶活孔的转化率读数;Conversion%_max:阴性对照孔比值均值,代表没有化合物抑制孔的转化率读数。结果如下表3。
表3.本发明部分化合物对BTK激酶抑制活性
化合物 | IC50(nM) |
2 | 130.3 |
3 | 188.4 |
5 | 195.8 |
6 | 110.8 |
7 | 225.3 |
17 | 375.9 |
ARQ-531 | 197.1 |
由以上实施例可知,本发明作为BTK蛋白激酶抑制剂的部分化合物对BTK激酶有很强的抑制作用,细胞抗增殖活性和激酶抑制活性可观,可用于制备治疗BTK激酶过度表达所致疾病的药物。
尽管已经示出了和描述了本发明的实施例,对于本领域的普通技术人员而言,可以理解在不脱离本发明的原理和精神的情况下可以对这些实施例进行多种变化、修改、替换和变型,本发明的范围由所附权利要求及其等同物限定。
Claims (10)
1.一种作为BTK激酶抑制剂的化合物,其特征在于,具有式Ⅰ所示结构或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、同位素衍生物、药学上可接受的盐或前药:
其中:X1为N或CH;
Ra、Rb分别独立地选自:氢、卤素,可以为单、双或多取代;
Rc、Rd独立地选自:氢,取代或未取代的C1-8的直链或支链烷基,取代或未取代的环烷基,取代或未取代的杂环基,取代或未取代的杂烷基,芳基,Rc、Rd也可以成环但Rc、Rd不同时为氢;Rc、Rd也可以为-(CH2)mReRf,其中Re、Rf可选自氢,取代或未取代的C1-8的直链或支链烷基,取代或未取代的环烷基,取代或未取代的杂环基,取代或未取代的杂烷基,芳基,Re、Rf也可以成环或螺环但Re、Rf不同时为氢;
m独立地为0,1,2。
2.根据权利要求1所述的一种作为BTK激酶抑制剂的化合物,其特征在于,具有式Ⅰ所示结构或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、同位素衍生物、药学上可接受的盐或前药,其中:
Ra、Rb分别独立地选自:氢、卤素,可以为单、双或多取代;
其中,
X1为N或CH;
X2,X3为O,S,NH或CH2;
Rc、Rd独立地选自:氢,取代或未取代的C1-8的直链或支链烷基,取代或未取代的环烷基,取代或未取代的杂环基,取代或未取代的杂烷基,芳基,Rc、Rd也可以成环但Rc、Rd不同时为氢;Rc、Rd也可以为-(CH2)mReRf,其中Re、Rf可选自氢,取代或未取代的C1-8的直链或支链烷基,取代或未取代的环烷基,取代或未取代的杂环基,取代或未取代的杂烷基,芳基,Re、Rf也可以成环或螺环但Re、Rf不同时为氢;
Rg、Rh独立地选自:氢,取代或未取代的C1-4的直链或支链烷基,羟基取代的直链或支链烷基,卤素;Rg、Rh也可以为-NRiRj,其中Ri、Rj可选自氢,取代或未取代的C1-4的直链或支链烷基;
a,b,c独立地为0,1或2。
4.权利要求1-3任一项所述的作为BTK激酶抑制剂的化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、同位素衍生物、药学上可接受的盐或前药在制备蛋白质激酶抑制剂中的用途;进一步地,所述激酶抑制剂为BTK抑制剂。
5.一种药物组合物,其特征在于,该药物组合物活性成分选自权利要求1-3任一项所述的化合物,或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、同位素衍生物、药学上可接受的盐或前药。
7.权利要求1-3任一项所述的化合物,或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、同位素衍生物、药学上可接受的盐或前药或权利要求5所述的药物组合物,在制备用于治疗自身免疫性疾病、炎性疾病、血栓栓塞疾病、过敏症、感染性疾病、增生性疾病和癌症中的任意一种或多种疾病在药物中的用途。
8.根据权利要求7所述的用途,其特征在于,所述疾病选自:关节炎、类风湿性关节炎、荨麻疹、白癜风、器官移植排斥、溃疡性结肠炎、克罗恩病、皮炎、哮喘、干燥综合征、系统性红斑狼疮、多发性硬化、特发性血小板减少性紫癜、皮疹、抗嗜中性白细胞胞质抗体血管炎、天胞疮、寻常性天胞疮、慢性阻塞性肺疾病、银屑病;乳腺癌、套细胞淋巴瘤、卵巢癌、食道癌、喉癌、成胶质细胞瘤、成神经细胞瘤、胃癌、肝细胞癌、胶质瘤、子宫内膜癌、黑色素瘤、肾癌、膀胱癌、胆道癌、胰腺癌、淋巴瘤、毛细胞癌、鼻咽癌、大肠癌、直肠癌、脑和中枢神经系统癌症、宫颈癌、前列腺癌、睾丸癌、泌尿生殖道癌、肺癌、肺小细胞癌、小细胞癌、肺腺癌、骨癌、结肠癌、腺瘤、胰腺癌、甲状腺癌、滤泡性癌、霍奇金白血病、支气管癌、子宫体癌、子宫颈癌、多发性骨髓瘤、急性髓细胞源性白血病、慢性髓细胞源性白血病、淋巴细胞白血病、慢性淋巴样白血病、骨髓性白血病、非霍奇金淋巴瘤、原发性巨球蛋白血症。
9.权利要求1-3任一项所述化合物,或其立体异构体、几何异构体、互变异构体、氮氧化物、溶剂化物、水合物、代谢产物、同位素衍生物、药学上可接受的盐或前药或权利要求5所述的药物组合物在制备用于治疗致使BTK激酶过度表达的疾病的药物中的用途。
10.权利要求1-3任一项所述化合物,或其立体异构体、几何异构体、互变异构体、氮氧化物、溶剂化物、水合物、代谢产物、同位素衍生物、药学上可接受的盐或前药或权利要求5所述的药物组合物在制备用于治疗BTK激酶过度表达所致疾病的药物中的用途。
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