CN116670119A - 作为btk抑制剂的桥联双环化合物 - Google Patents
作为btk抑制剂的桥联双环化合物 Download PDFInfo
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- CN116670119A CN116670119A CN202180050894.3A CN202180050894A CN116670119A CN 116670119 A CN116670119 A CN 116670119A CN 202180050894 A CN202180050894 A CN 202180050894A CN 116670119 A CN116670119 A CN 116670119A
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- lymphoma
- btk
- compound
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- pharmaceutically acceptable
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Abstract
本发明涉及作为Bruton酪氨酸激酶(BTK)及其C481突变体抑制剂的桥联双环化合物A和B或其药学上可接受的盐。本发明还涉及制备化合物A和B或其药学上可接受的盐的方法。化合物A和B可用于治疗和/或预防由BTK或其C481突变体介导的相关疾病，尤其是癌症和自身免疫性疾病。
Description
技术领域
本发明涉及适用于调节或抑制Bruton酪氨酸激酶(BTK)及其C481突变体活性的桥联双环化合物或其药学上可接受的盐。本发明还涉及这些化合物或其药学上可接受的盐的制备方法。本发明进一步涉及所述化合物或其药学上可接受的盐在治疗和/或预防癌症和自身免疫性疾病中的用途和使用方法。
背景技术
BTK是一种重要的介导细胞信号转导的非受体酪氨酸激酶，存在于浆细胞，包括B细胞中。B细胞是通过B细胞受体(BCR)被活化的，而BTK在BCR介导的信号通路中起了重要的作用。B细胞上的BCR被活化后，引起BTK的激活，导致下游的磷脂酶C(PLC)浓度增加，并激活IP3和DAG信号通路。这一信号通路可以促进细胞的增殖、粘附和存活，在B细胞淋巴瘤的发展过程中起重要的作用。
BTK抑制剂通过抑制BTK的活性而抑制B淋巴瘤细胞的增殖，破坏瘤细胞的粘附，促进瘤细胞的凋亡，使BTK在B细胞相关的癌症中成为令人注目的药物靶点，比如针对治疗对非霍奇金淋巴瘤(NHL)、慢性淋巴细胞白血病(CLL)/小淋巴细胞淋巴瘤(SLL)、套细胞淋巴瘤(MCL)、华氏巨球蛋白血症(WM)、边缘区淋巴瘤(MZL)和中枢神经***白血病(CNSL)等等。目前已有几个BTK抑制剂上市，包括Abbvie/JNJ的ibrutinib、AZ的acalabrutinib、Beigene的zanubrutinib和Gilead/Ono的tirabrutinib，还有多种BTK抑制剂处于临床研究阶段。
除了治疗B细胞相关淋巴瘤外，BTK抑制剂还可以抑制B细胞自身抗体和细胞因子的产生。在自身免疫性疾病中，B细胞呈递自身抗原，促进T细胞活化，分泌引起组织损伤的炎症因子，同时激活B细胞产生大量抗体，引发自身免疫反应。T细胞和B细胞相互作用形成正反馈调节链，导致自身免疫反应失控，加重组织病理损伤。研究表明，体内存在调节性B细胞，通过分泌白细胞介素10(IL-10)或转化生长因子β1(TGF-B1)等机制，负向调节免疫反应，抑制免疫介导的炎症反应。因此，BTK可作为自身免疫性疾病的药物靶点，如类风湿性关节炎(RA)、多发性硬化症(MS)、***性红斑狼疮(SLE)、天疱疮等。对于自身免疫适应症，BTK抑制剂尚处于临床研究阶段。其中，赛诺菲的rilzabrutinib和默克雪兰诺的evobrutinib分别在治疗天疱疮和多发性硬化症方面取得了有效的效果。
已上市及多数在研的BTK抑制剂都为不可逆抑制剂，通过共价结合位于BTK蛋白481的半胱氨酸残基而抑制BTK的活性。部分B细胞淋巴瘤患者接受ibrutinib治疗一段时间后，BTK的C481出现了突变，比如C481S，使ibrutinib失去了与蛋白共价结合的位点，导致ibrutinib的活性降低，从而使患者对ibrutinib产生了耐药性(Quinquenel，et.al Blood2019，134，641-644)。
需要一种有效抑制BTK及其C481突变体活性的BTK抑制剂，从而克服与不可逆BTK抑制剂相关的C481突变引起的耐药性。
发明内容
定义
除非另有说明，本申请中使用的下列术语具有以下含义。
“CSF/血浆比率(Kp，CSF)”是指脑脊液(CSF)中化合物浓度与血浆中化合物浓度的比率。化合物穿过血脑屏障(BBB)的能力是通过测量其在啮齿动物的CSF和血浆中的浓度，并确定比率(Kp，CSF)来评估的。
“异构体”是指分子式相同，但原子键合位置或空间排列不同的化合物。原子在空间排列不同的异构体称为“立体异构体”。立体异构体包括旋光异构体、几何异构体和构象异构体。
本发明的化合物可以以旋光异构体形式存在。旋光异构体包括对映异构体和非对映异构体。对映异构体是指两个立体异构体彼此镜像但相互不可重叠。外消旋混合物或外消旋体是指手性分子的左右手对映异构体数量相等的混合物。非对映异构体是指两个立体异构体不是彼此的镜像且不可重叠。当旋光异构体为单一异构体且其绝对构型确定，根据手性碳原子上取代基的构型，其为“R”或“S”的绝对构型；当旋光异构体的绝对构型未确定，依据所测的旋光值，其为(+)或(-)。制备和分离光学异构体的方法是本领域中已知的。
本发明的化合物还可以具有几何异构体，这是由于取代基围绕碳-碳双键、碳-氮双键、环烷基或杂环基分布而产生的。碳-碳双键或碳-氮键周围的取代基指定为Z或E构型，环烷基或杂环周围的取代基指定为顺式或反式构型。
本发明的化合物还可能显示互变异构现象，例如酮-烯醇互变异构。
本发明包括任何互变异构或立体异构形式及其混合物，并且不限于化合物命名法或化学结构式中使用的任何互变异构或立体异构形式。
“同位素”是指在本发明化合物中出现的原子的所有稳定同位素。同位素包括具有相同原子序数但不同质量数的那些原子。适合并入本发明化合物中的同位素的实例是氢、碳、氮、氧、磷、氟和氯，分别例如但不限于2H(D)、3H、13C、14C、15N、18O、17O、31P、32P、35S、18F和36Cl。本发明的同位素标记化合物通常可通过本领域技术人员已知的传统技术或通过与所附实施例中描述的那些类似的方法使用适当的同位素标记的试剂代替非同位素标记的试剂来制备。这样的化合物具有各种潜在用途，例如作为测定生物活性中的标样和试剂。在稳定同位素的情况下，这样的化合物具有有利地改变生物、药理学或药代动力学性质的潜力。氘2H(D)为本发明的优选同位素。例如甲基、亚甲基或次甲基中的氢可被氘取代。
本发明的化合物可以前药的形式给药。“前药”是指在体内的生理条件下，例如通过氧化、还原和水解(每一种过程都有或没有酶的参与)转化为具有生物活性化合物的衍生物。前药的实例有本发明的化合物中的氨基被酰化、烷基化或磷酸化，例如二十烷酰氨基、丙氨酰氨基和新戊酰氧基甲基氨基；羟基被酰化、烷基化或磷酸化或转化为硼酸酯，例如乙酰氧基、棕榈酰氧基、新戊酰氧基、琥珀酰氧基、富马酰氧基和丙氨酰氧基：羰基被酯化或酰胺化：硫醇与载体分子形成二硫键，选择性地将药物递送至靶标和/或细胞的胞质溶胶，例如肽。前药可根据众所周知的方法由本发明的化合物制备。
“药学上可接受的盐”是指本发明的化合物与药学上可接受的碱或酸，包括无机碱或酸和有机碱或酸，在化合物含有一个或多个酸性或碱性基团的条件下形成的盐。含有酸性基团的本发明化合物可以盐的形式存在，例如碱金属盐、碱土金属盐或铵盐。例如，此类盐包括钠盐、钾盐、钙盐、镁盐或氨或有机胺盐，例如乙胺、乙醇胺、三乙醇胺或氨基酸的盐。含有碱性基团的本发明化合物可以盐的形式存在，如无机酸盐或有机酸盐。合适的酸的实例包括盐酸、氢溴酸、磷酸、硫酸、硝酸、甲磺酸、对甲苯磺酸、萘二磺酸、草酸、乙酸、酒石酸、乳酸、水杨酸、苯甲酸、甲酸、丙酸、新戊酸、丙二酸、琥珀酸、庚二酸、富马酸、马来酸、苹果酸、氨基磺酸、苯丙酸、葡萄糖酸、抗坏血酸、异烟酸、柠檬酸、己二酸和其他本领域技术人员所熟知的酸。如果本发明的化合物在分子中同时含有酸性基团和碱性基团，则本发明除上述盐形式外还包括内盐。各盐可通过本领域技术人员已知的常规方法获得，例如通过将本发明的化合物与有机或无机酸或碱在溶剂或分散剂中混合，或通过与另一种盐的阴离子交换或阳离子交换获得。
“药物组合物”是指含有一种或多种本发明化合物或其药学上可接受的盐、稳定同位素衍生物、异构体、前药及其混合物，以及药学上可接受的载体和赋形剂等其他组分的组合物。
“癌症或淋巴瘤或白血病”包括但不限于B细胞恶性肿瘤、B细胞淋巴瘤、弥漫性大B细胞淋巴瘤、慢性淋巴细胞白血病、小淋巴细胞淋巴瘤、非霍奇金淋巴瘤(例如ABC-DLBCL)、套细胞淋巴瘤、滤泡性淋巴瘤、华氏巨球蛋白血症、边缘区淋巴瘤、中枢神经***淋巴瘤、慢性淋巴细胞淋巴瘤、B细胞前淋巴细胞白血病、浆细胞淋巴瘤、多发性骨髓瘤、各种实体瘤(例如黑素瘤、骨癌、脑癌、结肠癌、肝癌、皮肤癌、肾癌、肺癌、肌肉癌、膀胱癌、消化道/胃肠道癌、乳腺癌、卵巢癌、头颈癌、***癌)等。
“自身免疫或炎症性疾病”包括但不限于关节炎、多发性硬化症、骨质疏松症、炎症性肠疾病、结肠炎、克罗恩病、狼疮、类风湿性关节炎、银屑病关节炎、狼疮性肾炎、干燥综合症、IgG4相关疾病、特发性血小板减少性紫癜、免疫性血小板减少症、赖特综合症、银屑病、白塞病、哮喘、天疱疮、糖尿病、重症肌无力症、吉兰-巴雷综合症、格雷夫斯病、桥本甲状腺炎、脉管炎、自身免疫性血管炎、肉芽肿伴多发性血管炎、自身免疫性肝炎等。
“治疗有效量”是指本发明化合物能够有效抑制BTK及其C481突变体活性，和/或治疗或预防BTK及其C481突变体介导的疾病的量。
“患者”是指哺乳动物，尤其是人类。
本发明涉及两个桥联双环化合物A和B(结构如下)的可逆BTK抑制剂，能有效抑制BTK及其C481突变体的活性，从而克服与不可逆BTK抑制剂相关的C481突变引起的耐药性。
本发明涉及化合物A或B，或其药学上可接受的盐、前药、稳定同位素衍生物、异构体和混合物。
化合物A和B有效地抑制BTK及其C481突变体的活性，IC50小于10nM。化合物A和B为非脑渗透剂，Kp，CSF小于0.1。
本发明还涉及包含化合物A或B或其药学上可接受的盐、稳定同位素衍生物、异构体和前药以及一种或多种药学上可接受的载体或赋形剂的药物组合物。
本发明还涉及药物组合物，其包含通式(I)所示的化合物或其药学上可接受的盐、稳定同位素衍生物、异构体、前药及其混合物，以及至少一种另外的治疗剂，其中所述药剂可以是小分子化疗药物(如抗炎类固醇药物、激酶靶向药物、凋亡抑制剂、炎症调节剂、细胞毒性药物、DNA损伤相关药物)或大分子免疫和/或炎症调节剂(如CD-20抗体、CD19抗体、PD-1抗体)。
化合物A或B和另一种治疗剂可以存在于相同的药物组合物或不同的药物组合物中。式(I)的化合物和另一种药剂可以以相同或不同的形式同时或依次给药。
本发明提供了一种治疗或预防由BTK或其C481突变体介导的疾病的方法。该方法包括向有需要的患者施用治疗有效量的化合物A或B或其药学上可接受的盐、稳定同位素衍生物、异构体、前药及其混合物。所述疾病包括但不限于癌症、淋巴瘤、白血病、自身免疫性疾病或炎性疾病，例如B细胞恶性肿瘤、B细胞淋巴瘤、弥漫性大B细胞淋巴瘤、慢性淋巴细胞白血病、小淋巴细胞淋巴瘤、非霍奇金淋巴瘤(例如ABC-DLBCL)、套细胞淋巴瘤、滤泡性淋巴瘤、华氏巨球蛋白血症、边缘区淋巴瘤、中枢神经***淋巴瘤、慢性淋巴细胞淋巴瘤、B细胞前淋巴细胞白血病、浆细胞淋巴瘤、多发性骨髓瘤、各种实体瘤(例如肺癌、***癌、头颈癌、乳腺癌、卵巢癌、子宫癌、胰脏癌、结肠癌、直肠癌、胃癌、食道癌、脑癌、肝癌、肾癌、皮肤癌、肌肉癌、上皮癌、膀胱癌、成神经细胞瘤、黑色素瘤、骨癌、黑素瘤)、关节炎、多发性硬化症、骨质疏松症、炎症性肠疾病、结肠炎、克罗恩病、狼疮、类风湿性关节炎、银屑病关节炎、狼疮性肾炎、干燥综合症、IgG4相关疾病、特发性血小板减少性紫癜、免疫性血小板减少症、赖特综合症、银屑病、白塞病、哮喘、天疱疮、糖尿病、重症肌无力症、吉兰-巴雷综合症、格雷夫斯病、桥本甲状腺炎、脉管炎、自身免疫性血管炎、肉芽肿伴多发性血管炎、自身免疫性肝炎，尤其是B细胞淋巴瘤、弥漫性大B细胞淋巴瘤、慢性淋巴细胞白血病、小淋巴细胞淋巴瘤、非霍奇金淋巴瘤(例如ABC-DLBCL)、套细胞淋巴瘤、滤泡性淋巴瘤、华氏巨球蛋白血症、边缘区淋巴瘤、中枢神经***淋巴瘤、慢性淋巴细胞淋巴瘤、类风湿性关节炎、***性红斑狼疮、多发性硬化症、狼疮性肾炎、干燥综合症、IgG4相关疾病、特发性血小板减少性紫癜、免疫性血小板减少症、天疱疮、荨麻疹等。
根据本发明，药物组合物可以是任何剂型，包括但不限于片剂、胶囊剂、溶液剂、冻干制剂和注射剂。
本发明的药物制剂可以以含有预定量活性成分的剂量单位的形式给药。这样的单位可以含有1mg至1g，优选5mg至700mg，更优选10mg至500mg的本发明化合物，这取决于所治疗的疾病、给药方法以及年龄，患者的体重和身体状况。可以使用制药领域众所周知的方法制备药物制剂，例如，通过将活性成分与一种或多种赋形剂或一种或多种佐剂一起配制。
本发明的药物制剂适合通过任何合适的方法给药，例如通过口服(包括口服或舌下)或肠胃外(包括皮下、肌内、静脉内或皮内)。
本发明还提供了化合物A和B的制备方法，本发明化合物的制备可以通过以下示例性方法和实施例来完成，但这些方法和实施例不应以任何方式被认为是对本发明范围的限制。也可通过本领域技术人员所知的合成技术合成本发明所述的化合物，或者综合使用本领域已知方法和本发明所述方法。每步反应所得的产物用本领域已知的分离技术得到，包括但不限于萃取、过滤、蒸馏、结晶、色谱分离等。合成所需的起始物料和化学试剂可以根据文献(可从SciFinder上查询)常规合成或购买。
实施例
本发明的起始原料可以按照本领域已知的方法来合成，或可购自ABCR GmbH&Co.KG、Acros Organics、Aldrich Chemical Company、韶远化学科技(Accela ChemBioInc.)、北京偶合等化学品公司。
本发明化合物的结构是通过核磁共振(NMR)和/或质谱(MS)来确定的。NMR的测定使用BrukerASCEND-400核磁仪，所用溶剂为氘代二甲基亚砜(DMSO-d6)、氘代氯仿(CDCl3)或氘代甲醇(CD3OD)等，内标为四甲基甲硅烷(TMS)，化学位移是以10-6(ppm)作为单位给出。MS的测定使用Agilent SQD(ESI)质谱仪(安捷伦6120)。
HPLC使用安捷伦1260DAD高压液相色谱仪(Poroshell 120 EC-C18，50×3.0mm，2.7μm色谱柱)或WatersArc高压液相色谱仪(Sunfirc C18，150×4.6mm，5μm色谱柱)。
薄层层析(TLC)采用青岛海阳化工有限公司GF254硅胶板，厚度0.15-0.2mm，薄层层析分离/纯化产品采用厚度0.4-0.5mm硅胶板。
柱层析一般使用青岛海阳化工有限公司的200-300目硅胶。
实施例中如无特殊说明，反应均在室温(20℃-30℃)、氩气气氛或氮气气氛下进行。氩气气氛或氮气气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢化反应在氢气气氛下进行。氢气气氛是指反应瓶在抽真空再充入氢气(反复3次)后，连接一个约1L容积的氢气气球。
实施例中的反应进程的监测使用安捷伦LCMS(1260/6120)或薄层色谱法。用于柱层析和TLC的溶剂洗脱***包括a)二氯甲烷和甲醇体系，b)石油醚和乙酸乙酯体系，或如实施例中所示。根据化合物的极性调整溶剂的比例，并根据需要加入少量三乙胺、或酸性或碱性试剂进一步调整。或者使用Waters带有MS检测器(SQD2)的MS引导自动制备***(缩写为prep-HPLC)进行化合物纯化，以20mL/min的流速在适当的乙腈/水(含0.1％TFA或甲酸)或乙腈/水(含0.05％的25-28％氢氧化铵)梯度(XBridge-C18，19×150mm，5μm)下洗脱。一些化合物用prep-HPLC纯化后，可通过向收集的馏分中加入1NHCl，然后减压干燥，制备为HCl盐。
缩写DMF是指N，N-二甲基甲酰胺。
缩写DIPEA是指N，N-二异丙基乙胺。
缩写DBU是指1，8-二氮杂二环十一碳-7-烯。
缩写NIS是指N-碘代琥珀酰亚胺。
Pd(dppf)Cl2是指[1，1′-双(二苯基膦基)二茂铁]二氯化钯。
缩写HATU是指2-(7-氮杂苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸盐。
实施例1
4-(4-氨基-5-(4-((5-氟-2-甲氧基苯甲酰胺基)甲基)苯基)咪唑并[5，1-f][1，2，4]三嗪-7-基)双环[2.2.2]辛烷-1-羧酸(化合物A)
第一步
(4-((5-氟-2-甲氧基苯甲酰胺基)甲基)苯基)硼酸(1b)
0℃下向5-氟-2-甲氧基苯甲酸1a(340mg，2mmol)和DMF(0.05mL)的二氯甲烷(10mL)溶液中加入草酰氯(279mg，2.2mmol)。将混合物逐渐升温到室温并搅拌1小时后，再次冷却到0℃，然后加入(4-(氨基甲基)苯基)硼酸盐酸盐(374mg，2mmol)和DIPEA(516mg，4mmol)的四氢呋喃(20mL)悬浮液。室温搅拌15小时后，减压除去溶剂，将残余物溶于乙酸乙酯(100mL)，然后用饱和氯化铵(50mL)和盐水(50mL)洗涤。将有机相用无水硫酸钠干燥，过滤后，滤液在减压条件下除去溶剂，得到目标化合物1b(460mg，76％)。
MS m/z(ESI)：304[M+H]
第二步
1-(2，5-二氧代吡咯烷-1-基)4-甲基二环[2.2.2]辛烷-1，4-二羧酸酯(1d)
0℃下向(甲氧基羰基)双环[2.2.2]辛烷-1-羧酸1c(850mg，4mmol)和1-羟基-吡咯烷-2，5-二酮(552mg，4.8mmol)的THF(50mL)溶液中加入DCC(1.07g，5.2mmol)。将混合物升温至室温并搅拌15小时，然后将混合物冷却至0℃并过滤。将滤液浓缩至干，得到目标化合物1d(1.4g，粗品)。
MS m/z(ESI)：310[M+H]
第三步
4-(((5-氧代-4，5-二氢-1，2，4-三嗪-6-基)甲基)氨基甲酰基)双环[2.2.2]辛烷-1-羧酸甲酯(1e)
向6-氨基甲基-4H-[1，2，4]三嗪-5-酮(252mg，2mmol)和DIPEA(1.03g，8mmol)的DMF(5mL)溶液中逐滴加入1d(1.4g，粗品)的THF(5mL)溶液。将混合物搅拌3小时，然后浓缩至干。残余物通过硅胶柱层析(二氯甲烷/甲醇＝50/1至10/1)纯化，得到目标化合物1e(150mg，两步23％)。
MS m/z(ESI)：321[M+H]
第四步
4-(4-氧代-3，4-二氢咪唑并[5，1-f][1，2，4]三嗪-7-基)双环[2.2.2]辛烷-1-羧酸甲酯(1f)
向1e(150mg，0.47mmol)的MeCN(10mL)溶液中加入POCl3(2mL)。将混合物加热至80℃并搅拌5小时。然后将混合物浓缩至干，得到目标化合物1f(150mg，100％)。
MS m/z(ESI)：303[M+H]
第五步
4-(5-碘-4-氧代-3，4-二氢咪唑并[5，1-f][1，2，4]三嗪-7-基)双环[2.2.2]辛烷-1-羧酸甲酯(1g)
向1f(150mg，粗品，0.47mmol)的DMF(5mL)溶液中添加NIS(529mg，2.35mmol)。将混合物加热至55℃并搅拌5小时。冷却至室温后，将混合物通过prep-HPLC纯化，得到目标化合物1g(80mg，40％)。
MS m/z(ESI)：429[M+H]
第六步
4-(4-氨基-5-碘咪唑并[5，1-f][1，2，4]三嗪-7-基)双环[2.2.2]辛烷-1-羧酸甲酯(1h)
向1H-[1，2，4]***(131mg，1.9mmol)的吡啶(2mL)溶液中加入POCl3(86mg，0.56mmol)。将混合物搅拌10分钟后加入1g(80mg，0.19mmol)的吡啶(2mL)溶液。再次搅拌1小时后，向混合物中加入NH3溶液(2M的异丙醇溶液，10mL)并搅拌0.5小时。然后将混合物浓缩至干，残余物通过prep-HPLC纯化，得到目标化合物1h(60mg，74％)。
MS m/z(ESI)：428[M+H]
第七步
4-(4-氨基-5-(4-((5-氟-2-甲氧基苯甲酰氨基)甲基)苯基)咪唑并[5，1-f][1，2，4]三嗪-7-基)双环[2.2.2]辛烷-1-羧酸甲酯(li)
混合物1h(60mg，0.14mmol)、1b(64mg，0.21mmol)、K2CO3(39mg，0.28mmol)、Pd(dppf)Cl2(11mg，0.014mmol)、1，4-二氧六环(4mL)和水(1mL)在氮气氛下加热至100℃并搅拌2小时。冷却至室温后，将混合物浓缩至干，残余物通过硅胶柱层析(石油醚/EtOAc＝20∶1至1∶2)纯化，得到目标化合物1i(60mg，77％)。
MS m/z(ESI)：559[M+H]
第八步
4-(4-氨基-5-(4-((5-氟-2-甲氧基苯甲酰胺基)甲基)苯基)咪唑并[5，1-f][1，2，4]三嗪-7-基)双环[2.2.2]辛烷-1-羧酸(A)
向1i(55mg，0.098mmol)的THF(10mL)溶液中加入氢氧化锂溶液(1N，4mL)。将混合物加热至40℃并搅拌48小时。冷却至室温后，向反应混合物中加入冰醋酸(1mL)并用乙酸乙酯(2×50mL)萃取。合并的有机相经无水硫酸钠干燥，过滤并减压浓缩。残余物通过prep-HPLC纯化，得到目标化合物A(40mg，固体，75％)。
MS m/z(ESI)：545[M+1]
1H NMR(400MHz，CD3OD)δ7.80(s，1H)，7.64-7.56(m，3H)，7.53(d，J＝8.1Hz，2H)，7.28-7.22(m，1H)，7.17(dd，J＝9.1，4.2Hz，1H)，4.69(s，2H)，3.96(d，J＝7.6Hz，3H)，2.30-2.22(m，6H)，1.98-1.90(m，6H).
实施例2
N-(4-(4-氨基-7-(4-(吗啉-4-羰基)双环[2.2.2]辛-1-基)咪唑[5，1-f][1，2，4]三嗪-5-基)苄基)-5-氟-2-甲氧基苯甲酰胺(化合物B)
向A(75mg，0.137mmol)、吗啉(12mg，0.137mmol)、DIPEA(53mg，0.409mmol)的DMF(5mL)溶液中加入HATU(58mg，0.151mmol)。将所得混合物在室温下搅拌5分钟，然后通过prep-HPLC纯化，得到目标化合物B(40mg，固体，48％)。
MS m/z(ESI)：614.2[M+1]
1H NMR(400MHz，DMSO-d6)δ8.84(t，J＝6.0Hz，1H)，7.88(s，1H)，7.58(d，J＝8.2Hz，2H)，7.52(dd，J＝9.2，3.3Hz，1H)，7.46(d，J＝8.2Hz，2H)，7.39-7.29(m，1H)，7.19(dd，J＝9.1，4.3Hz，1H)，4.57(d，J＝6.1Hz，2H)，3.90(s，3H)，3.57(d，J＝9.6Hz，8H)，2.21-2.09(m，6H)，1.97-1.84(m，6H).
实施例3.BTK的活性抑制测试
使用体外激酶检测实验评估本发明的化合物对BTK活性的影响(表1)。
实验方法概述如下：
使用均相时间分辨荧光(HTRF)激酶检测试剂盒(Cisbio，货号62TK0PEC)，通过检测激酶反应中底物的磷酸化水平来测定BTK的酶活性。反应缓冲液包含试剂盒自带酶反应缓冲液(1×)、5mM MgCl2、1mM DTT、10nM SEB和0.01％Tween-20；人源重组BTK蛋白(CarnaBiosciences，货号08-180)用反应缓冲液稀释成0.2ng/μL的激酶反应溶液；底物反应溶液包含用反应缓冲液稀释成0.5μM的生物素标记的酪氨酸激酶底物和40μM ATP；检测缓冲液包含用反应缓冲液稀释成0.05ng/μL的Eu3+标记的笼状抗体和31.25nM的链霉亲和素标记的XL665抗体；化合物用DMSO溶解稀释至100μM，然后用DMSO进行4倍的系列稀释至最低浓度为6.1nM，每个浓度点再使用反应缓冲液稀释40倍。如果化合物IC50值非常低，可以降低化合物的起始浓度。
向384孔检测板(Corning，货号3674)中添加4μL系列浓度的化合物溶液和2μL激酶反应溶液，混合均匀后室温孵育15分钟：随后加入4μL底物反应溶液，将反应混合物在室温反应50分钟；随后加入10μL检测缓冲液，混合均匀并室温静置60分钟后，用Envision读板机(Perkin Elmer)在620nm和665nm波长下读取信号数值。信号值(吸光度665nm/吸光度620nm)与底物的磷酸化程度呈正相关性，从而检测出BTK的激酶活性。该实验中，未加BTK组为阴性对照(100％抑制)，加BTK但未加化合物组为阳性对照(0％抑制)。使用XLfit软件(IDBusiness Solutions Ltd.，UK)绘制化合物抑制曲线并计算其IC50值。
实施例4.BTK C481S的活性抑制测试
使用体外激酶检测实验评估本发明的化合物对BTK C481S活性的影响(表1)。
实验方法概述如下：
使用均相时间分辨荧光(HTRF)激酶检测试剂盒(Cisbio，货号62TKOPEC)，通过检测激酶反应中底物的磷酸化水平来测定BTK C481S的酶活性。反应缓冲液包含试剂盒自带酶反应缓冲液(1×)、5mM MgCl2、1mM DTT、10nM SEB和0.01％Tween-20；人源重组BTKC481S蛋白(公司内部提纯)用反应缓冲液稀释成1.5ng/μL的激酶反应溶液；底物反应溶液包含用反应缓冲液稀释成0.4μM的生物素标记的酪氨酸激酶底物和35μM ATP；检测缓冲液包含用反应缓冲液稀释成0.05ng/μL的Eu3+标记的笼状抗体和31.25nM的链霉亲和素标记的XL665抗体；化合物用DMSO溶解稀释至100μM，然后用DMSO进行4倍的系列稀释至最低浓度为6.1nM，每个浓度点再使用反应缓冲液稀释40倍。如果化合物IC50值非常低，可以降低化合物的起始浓度。
向384孔检测板(Corning，货号3674)中添加4μL系列浓度的化合物溶液和2μL激酶反应溶液，混合均匀后室温孵育15分钟；随后加入4μL底物反应溶液，将反应混合物在室温反应50分钟；随后加入10μL检测缓冲液，混合均匀并室温静置60分钟后，用Envision读板机(Perkin Elmer)在620nm和665nm波长下读取信号数值。信号值(吸光度665nm/吸光度620nm)与底物的磷酸化程度呈正相关性，从而检测出BTK C481S的激酶活性。该实验中，未加BTKC481S组为阴性对照(100％抑制)，加BTK C481S但未加化合物组为阳性对照(0％抑制)，使用XLfit软件(ID Business Solutions Ltd.，UK)绘制化合物抑制曲线并计算其IC50值。
表1显示化合物A和B的BTK IC50和BTK C481S IC50的结果。
表1
| 化合物编号 | BTK IC50(nM) | BTK C481S IC50(nM) |
| A | 0.7 | 1.3 |
| B | 1.0 | 1.2 |
实施例5.脑渗透性测试
化合物A或B在含有5％N，N-二甲基乙酰胺+10％solutol+85％生理盐水的0.5mg/mL溶液中以5mg/kg的剂量口服给予12只雄性Sprague Dawley大鼠。在给药后1、2、4和8小时(每个时间点从三只动物取样)收集血浆、脑组织匀浆(用于测量Kp，brain)和脑脊液(用于测量Kp，CSF)样品。
使用API-4500质谱仪通过LC-MS/MS分别量化血浆、脑组织匀浆和CSF中化合物的浓度。分析的定量限(LOQ)为1ng/mL。使用WinNonlin通过非房室法计算药代动力学(PK)参数。Kp，brain和Kp，CSF分别通过AUCbrain/AUCplasma和AUCCSF/AUCplasma计算。结果如表2所示，化合物A和B均为非脑渗透剂。
表2
| 化合物编号 | Kp，brain | Kp，CSF |
| A | 0.0355 | 0.0054 |
| B | 0.0315 | 0.0043 |
本发明以及制造和使用它的方式和过程现在以完整、清晰、简明和准确的术语进行描述，以使所属领域的任何技术人员能够制造和使用它们。应当理解，前面描述了本发明的优选实施例，并且可以在不脱离如权利要求所规定的本发明的范围的情况下对其进行修改。为了特别指出和明确要求被视为发明的主题，以下权利要求总结了说明书。
Claims (4)
1.化合物A或B，或其药学上可接受的盐、稳定同位素衍生物或立体异构体：
2.一种药物组合物，包含化合物A或B或其药学上可接受的盐、稳定同位素衍生物或立体异构体，以及其药学上可接受的载体。
3.一种预防或治疗由BTK或其C481突变体介导的相关疾病的方法，该方法包括给予有需要的患者治疗有效量的化合物A或B或其药学上可接受的盐、稳定同位素衍生物或立体异构体，其中由BTK及其C481突变体介导的疾病选自癌症、淋巴瘤、白血病、自身免疫性疾病和炎性疾病。
4.根据权利要求3所述的方法，其中所述疾病为B细胞淋巴瘤、慢性淋巴细胞白血病、小淋巴细胞淋巴瘤、套细胞淋巴瘤、华氏巨球蛋白血症、边缘区淋巴瘤、滤泡性淋巴瘤、中枢神经***淋巴瘤、非霍奇金淋巴瘤、弥漫性大B细胞淋巴瘤、多发性骨髓瘤、类风湿性关节炎、***性红斑狼疮、多发性硬化症、狼疮性肾炎、干燥综合征、IgG4相关疾病、特发性血小板减少性紫癜、免疫性血小板减少症或天疱疮。
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| CN202180050894.3A Pending CN116670119A (zh) | 2020-08-20 | 2021-08-19 | 作为btk抑制剂的桥联双环化合物 |
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| WO2021180107A1 (en) * | 2020-03-12 | 2021-09-16 | Fochon Pharmaceuticals, Ltd. | Compounds useful as kinase inhibitors |
| CN114573586B (zh) * | 2020-11-28 | 2023-11-03 | 杭州和正医药有限公司 | 一种抑制布鲁顿酪氨酸激酶活性的多环化合物、药物组合物及其应用 |
| CN114634512B (zh) * | 2020-12-16 | 2023-11-14 | 江苏恒瑞医药股份有限公司 | 作为布鲁顿酪氨酸激酶抑制剂的化合物、其制备方法和医药应用 |
| WO2023165570A1 (zh) * | 2022-03-03 | 2023-09-07 | 深圳市塔吉瑞生物医药有限公司 | 环烷基或杂环基取代的杂芳基化合物及其组合物及用途 |
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| CA2934989C (en) * | 2014-02-03 | 2017-08-08 | Cadila Healthcare Limited | Novel heterocyclic compounds |
| GB201410430D0 (en) * | 2014-06-11 | 2014-07-23 | Redx Pharma Ltd | Compounds |
| WO2016106652A1 (en) * | 2014-12-31 | 2016-07-07 | Merck Sharp & Dohme Corp. | Biarylether imidazopyrazine btk inhibitors |
| WO2016106623A1 (en) * | 2014-12-31 | 2016-07-07 | Merck Sharp & Dohme Corp. | Benzamide imidazopyrazine btk inhibitors |
| WO2016106624A1 (en) * | 2014-12-31 | 2016-07-07 | Merck Sharp & Dohme Corp. | Tertiary alcohol imidazopyrazine btk inhibitors |
| CN114685516A (zh) * | 2015-09-16 | 2022-07-01 | 洛克索肿瘤学股份有限公司 | 用于治疗癌症的作为btk抑制剂的吡唑并嘧啶衍生物 |
| CN112424203B (zh) * | 2018-07-20 | 2022-07-26 | 正大天晴药业集团股份有限公司 | 布鲁顿酪氨酸激酶抑制剂 |
| CN110964016B (zh) * | 2018-09-29 | 2021-05-28 | 南京药捷安康生物科技有限公司 | 氨基降茨烷衍生物及其制备方法与应用 |
| CN113365631A (zh) * | 2019-01-18 | 2021-09-07 | 杭州邦顺制药有限公司 | 布鲁顿酪氨酸激酶抑制剂 |
| WO2021180107A1 (en) * | 2020-03-12 | 2021-09-16 | Fochon Pharmaceuticals, Ltd. | Compounds useful as kinase inhibitors |
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