CN116574093B - 一种苯并咪唑类化合物及其制备方法和应用 - Google Patents
一种苯并咪唑类化合物及其制备方法和应用 Download PDFInfo
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- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
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- C07D235/14—Radicals substituted by nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
本发明公开了一种苯并咪唑类化合物及其制备方法和应用，其通式如式（I）所示的化合物或其药学上可接受的盐，上述化合物能够选择性地抑制YTHDF2进而扩增造血干细胞，具有毒性低、安全性好、治疗效果好等优点，可用于制备扩增造血干细胞药物。
Description
技术领域
本发明涉及一种苯并咪唑类化合物及其制备方法和应用，属于药物化学领域。
背景技术
造血干细胞移植（HSCT）在临床上被广泛用于治疗多种恶性血液肿瘤、遗传代谢性疾病、自身免疫性疾病、镰刀状细胞贫血、严重的联合免疫缺陷（SCID）等严重疾病。到目前为止，尽管有很多有效的药物改善一些血液***疾病，但对于一些恶性血液***肿瘤，造血干细胞移植是最有效的和唯一可以根除疾病的疗法。造血干细胞的来源主要有四种：骨髓、外周动员血、脐带血和胎盘血。骨髓血和外周动员血是传统的和最常见的造血干细胞移植来源。不幸的是，由于缺乏人类白细胞抗原（HLA）匹配的供体，约30%的患者将没有HLA匹配的供体。此外，对于接受了不匹配的非血缘骨髓供体的患者，移植排异反应（GVHD）仍然移植相关死亡的首要因素。
近年来，脐带血由于HSC含量比例高、容易获得、病毒传播风险低、耐受部分HLA错配等诸多显著的优点，其应用发展迅速，成为越来越有吸引力的造血干细胞移植来源。更重要的是，脐带血移植的慢性GVHD发生率低，而慢性GVHD会威胁患者的长期生存率。然而，单份脐带血中造血干细胞的绝对数量较少，不能满足成人患者的用量需求，导致脐带血只能应用于儿童。单份脐带血中造血干细胞的数量少直接导致移植缓慢，具体表现为较长时间的中性粒细胞和血小板恢复，增加感染、移植失败和复发的风险。近年来，采用两份脐带血提高了干细胞输注量，但移植效果与单份脐带血相似，而伴随着更高的GVHD发生风险。为了获得足够的HSC数量，造血干细胞的体外扩增是一种很有前景的治疗手段，目前已有多种小分子扩增的脐带血正在临床实验中。
N6-甲基腺苷（m6A）是真核生物中信使RNA（mRNA）上最丰富的一种表观遗传修饰。作为一种转录后修饰方式，m6A修饰与胚胎时期造血干细胞的形成、分化以及白血病发生等生物进程密切相关。m6A修饰通过RNA甲基化酶（Writer）METTL3/METTL14，去甲基化酶（Eraser）FTO和ALKBH5，以及识别蛋白（Reader）YTH结构域蛋白家族（YTHDF1/2/3和YTHDC1/2蛋白）调控mRNA的剪接、翻译、转运和稳定性。YTHDF2是最早发现的一种m6A识别蛋白，它通过蛋白结构上的保守芳香疏水口袋识别m6A标记的mRNA，并随后通过招募CCR4-NOT脱腺苷酶复合体调控RNA的降解。最近的研究揭示小鼠条件性敲除YTHDF2后，体内造血干细胞的数量会增加，并且它们的功能是正常的，无异常谱系分化和白血病倾向。更重要的是，在人脐带血造血干细胞中敲除YTDHF2后，HSC的数量升高了10倍，功能性造血干细胞的数量升高了8倍。移植YTDHF2敲低的HSC可以重建免疫缺陷小鼠的造血***，并且二次移植仍可以稳定地在免疫缺陷小鼠中发挥正常造血功能，不会导致恶性血液肿瘤发生。机制研究显示YTHDF2缺失后增加了m6A修饰的mRNA的稳定性，而这些mRNA可以编码对造血干细胞自我更新具有关键调控作用的转录因子如Tal1，最终扩增造血干细胞。此外，来自爱丁堡大学的研究人员的证实YTHDF2对正常造血干细胞功能是非必需的，但对于白血病干细胞的生存是必需的。这些研究表明YTHDF2对体外扩增造血干细胞是一个有效、安全的靶点，而目前尚未有小分子抑制剂报道。
发明内容
发明目的：为了解决脐带血中造血干细胞含量不足的问题，本发明利用YTHDF2缺失可以扩增造血干细胞的生物学功能，提供了一种苯并咪唑类化合物或其药学上可接受的盐抑制造血干细胞中的YTHDF2，从而扩增造血干细胞。本发明还提供了该化合物的具体制备方法和应用于扩增造血干细胞的药物，有望为临床治疗提供候选化合物。
技术方案：为解决上述问题，本发明提供了一种苯并咪唑类化合物，如通式(I)所示的化合物或其药学上可接受的盐：
；
其中，R1选自以下基团：
。
其中，本申请所述的化合物I-1至I-5的结构式如下所示：
。
进一步地，上述药学上可接受的盐为通式（I）化合物的酸加成盐，其中用于成盐的酸包括无机酸或有机酸，所述无机酸包括盐酸、硫酸或磷酸，有机酸包括乙酸、三氯乙酸、丙酸、丁酸、马来酸、对甲苯磺酸、苹果酸、丙二酸、肉桂酸、柠檬酸、富马酸、樟脑酸、二葡糖酸、天冬氨酸、酒石酸或甲磺酸。
进一步地，本发明中所述的药学上可接受的盐为盐酸盐。
本发明还提供了通式（I）化合物的制备方法。
本发明还提供了一种药用组合物，包含上述通式（I）化合物或其药学上可接受的盐或其异构体以及药学上可接受的载体。
药学上可接受的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赋形剂或稀释剂。
本发明所述的化合物或其药学上可接受的盐在制备YTHDF2靶点抑制剂药物中的应用。
本发明所述的化合物或其药学上可接受的盐在制备用于扩增造血干细胞的药物中的应用。
本发明所述的通式（I）化合物或其药学上可接受的盐，具有YTHDF2靶点抑制活性，对扩增造血干细胞具有治疗效果。
有益效果：本发明和现有技术相比，具有如下显著性特点：本发明首次提供了一种新的通式（I）所示的化合物，能够选择性地抑制YTHDF2进而扩增造血干细胞，具有毒性低、安全性好、治疗效果好等优点，可用于制备扩增造血干细胞药物。
附图说明
图1为本发明化合物在体外对造血干细胞的扩增效果：图1中A为本发明化合物体外处理小鼠骨髓单个核细胞14天后，流式细胞术检测小鼠LSK造血干细胞频率；图1中B为本发明化合物体外处理小鼠骨髓单个核细胞14天后，流式细胞术检测小鼠LSK造血干细胞绝对数量；图1中C为本发明化合物体外处理小鼠骨髓单个核细胞14天后，流式细胞术检测小鼠CD48–CD150+造血干细胞频率；图1中D为本发明化合物体外处理小鼠骨髓单个核细胞14天后，流式细胞术检测小鼠CD48–CD150+造血干细胞绝对数量；
图2为化合物I-5处理造血干细胞后，小鼠细胞、髓系细胞或B细胞在体内移植效果：图2中A为DMSO和化合物I-5体外处理CD45.2小鼠造血干细胞后，移植入受到致死辐射的CD45.1受体小鼠体内，流式细胞术检测CD45.2小鼠细胞在CD45.1受体小鼠体内的比例；图2中B为DMSO和化合物I-5体外处理CD45.2小鼠造血干细胞后，移植入受到致死辐射的CD45.1受体小鼠体内，流式细胞术检测CD45.2小鼠髓系细胞在CD45.1受体小鼠体内的比例；图2中C为DMSO和化合物I-5体外处理CD45.2小鼠造血干细胞后，移植入受到致死辐射的CD45.1受体小鼠体内，流式细胞术检测CD45.2小鼠B细胞在CD45.1受体小鼠体内的比例；
图3为化合物I-5处理造血干细胞14天后，Lin–细胞和LSK细胞占总单个核细胞的比例及绝对数量：图3中A为DMSO和化合物I-5体外处理CD45.2小鼠造血干细胞后，移植入受到致死辐射的CD45.1受体小鼠体内，流式细胞术检测CD45.1受体小鼠体内Lin–细胞占总单个核细胞的比例及绝对数量；图3中B为DMSO和化合物I-5体外处理CD45.2小鼠造血干细胞后，移植入受到致死辐射的CD45.1受体小鼠体内，流式细胞术检测CD45.1受体小鼠体内LSK细胞占总单个核细胞的比例及绝对数量；
图4为DMSO和化合物I-5体外处理CD45.2小鼠造血干细胞14天后，移植入受到致死辐射的CD45.1受体小鼠体内，流式细胞术检测CD45.1受体小鼠体内造血干细胞占总单个核细胞的比例及绝对数量；
图5为DMSO和化合物I-5体外处理CD45.2小鼠造血干细胞14天后，移植入受到致死辐射的CD45.1受体小鼠体内，流式细胞术检测CD45.1受体小鼠体内各类造血祖细胞细胞占总单个核细胞的比例；
图6为DMSO和化合物I-5体外处理CD45.2小鼠造血干细胞14天后，移植入受到致死辐射的CD45.1受体小鼠体内，流式细胞术检测CD45.1受体小鼠体内B细胞、髓系细胞、红细胞、T细胞占总单个核细胞的比例。
具体实施方式
下面结合具体实施例对本申请作出详细说明。
实施例1：甲基(3-(5-硝基-1H-苯并咪唑-2-基)丙基)对苯二甲酸酯（I-1）
合成路线：
。
合成方法：
步骤一，取4-硝基邻苯二胺（3.0 g，19.59 mmol）和4-氯丁酸（3.02 g，24.68mmol）至圆底烧瓶中，加入4 N HCl（50 mL），升温至100℃，反应回流24 h。反应结束后，水相用浓NaOH溶液调至碱性pH = 8，减压浓缩，硅胶柱色谱纯化（DCM : MeOH = 20 : 1），得到化合物A1（3.0 g，产率69%）。1H NMR (400 MHz, DMSO-d 6)δ12.94 (s, 1H), 8.38 (s, 1H),8.07 (dd,J= 8.8, 2.3 Hz, 1H), 7.64 (d,J= 8.9 Hz, 1H), 4.63 (s, 1H), 3.49 (t,J= 6.3 Hz, 2H), 2.93 (t,J= 7.5 Hz, 1H), 2.02–1.86 (m, 2H). HPLC,t R= 7.580 min,purity 97.7%。
步骤二，取A1（3.0 g，13.56 mmol）和4-(氯甲酰基)苯甲酸甲酯（4.04 g，20.34mmol）至原底烧瓶中，加入二氯甲烷80 mL，随后缓慢滴加三乙胺3 mL，有大量固体析出，反应搅拌3 h后，TLC监测反应完全，抽滤除去三乙胺盐酸盐固体，有机相用水洗涤两次，无水硫酸钠干燥，减压浓缩，硅胶柱色谱纯化（PE : EA = 1 : 1）得到白色固体I-1（3.5 g，产率67%）。1H NMR (400 MHz, DMSO-d 6)δ 12.97 (s, 1H), 8.39–8.20 (m, 1H), 8.03 (d,J=8.9 Hz, 1H), 7.97–7.87 (m, 4H), 7.68–7.50 (m, 1H), 4.43 (t,J= 6.0 Hz, 2H),3.88 (s, 3H), 3.08 (t,J= 7.2 Hz, 2H), 2.35–2.24 (m, 2H).13C NMR (101 MHz,DMSO-d 6) δ 165.85, 165.30, 133.84, 133.74, 129.72, 129.66, 65.18,52.94,26.60, 26.17. HPLC,t R= 9.407 min, purity 99.7%。
实施例2：N-(2-(1H-苯并咪唑-2-基)乙基)-2,3-二氢苯并二噁烷-6-甲酰胺（I-2）
合成路线：
。
合成方法：
步骤一，取化合物B1（0.5 g，2.78 mmol）溶于10 mL氯化亚砜中，升温至80℃，回流搅拌反应2 h，反应液减压浓缩，得到500 mg白色固体产物B2。
步骤二，取化合物B3（0.49 g，2.09 mmol）溶于10 mL二氯甲烷中，加入三乙胺2mL，向其中缓慢滴加溶有500 mg白色固体产物B2的二氯甲烷溶液（10 mL），反应液用水洗涤两次，减压浓缩，硅胶色谱柱纯化，得到白色固体产物I-2（0.5 g，产率74%）。1H NMR (400MHz, DMSO-d 6)δ12.26 (s, 1H), 8.51 (t,J= 5.6 Hz, 1H), 7.58–7.47 (m, 1H), 7.45–7.30 (m, 3H), 7.16–7.05 (m, 2H), 6.90 (d,J= 8.2 Hz, 1H), 4.32–4.18 (m, 4H),3.67 (q,J= 6.0 Hz, 2H), 3.06 (t,J= 7.3 Hz, 2H).13C NMR (101 MHz, DMSO-d 6)δ165.89, 153.35, 146.40, 143.32, 127.90, 121.09, 117.19, 116.68, 64.76, 64.44,38.48, 29.37. HPLC,t R= 6.632 min, purity 99.3%。
实施例3：N-(2-(1-(2,3-二氢苯并二噁烷-6-羰基)-1H-苯并咪唑-2-基)乙基)-2,3-二氢苯并二噁烷-6-甲酰胺（I-3）
合成路线：
。
合成方法：
取实施例2制备的化合物B2（1.27 g）和化合物B3（0.5 g，2.14 mmol）溶于20 mL二氯甲烷中，向其中缓慢滴加5 mL三乙胺，随后室温搅拌6 h，反应液用水洗涤两次，减压浓缩，硅胶色谱柱纯化，得到白色固体产物I-3（0.79 g，产率76%）。1H NMR (400 MHz, CDCl3)δ7.75 (dt,J= 8.1, 0.9 Hz, 1H), 7.53–7.43 (m, 1H), 7.36 (d,J= 2.1 Hz, 2H),7.32–7.27 (m, 2H), 7.26–7.23 (m, 1H), 7.19–7.13 (m, 1H), 6.99–6.82 (m, 3H),4.42–4.21 (m, 8H), 4.00 (q,J= 5.8 Hz, 2H), 3.28 (t,J= 5.3 Hz, 2H). HPLC,t R=9.536 min, purity 95.9%.
实施例4：N-(2-(1H-苯并咪唑-2-基)乙基)-4-溴苯甲酰胺（I-4）
将原料B1更换为对溴苯甲酸，参照实施例2的合成方法，得到化合物I-4。收率80%。1HNMR (400 MHz, DMSO-d 6)δ12.40 (s, 1H), 8.78 (t,J= 5.6 Hz, 1H), 7.85–7.73 (m,2H), 7.72–7.61 (m, 2H), 7.55–7.41 (m, 2H), 7.18–7.08 (m, 2H), 3.74–3.65 (m,2H), 3.09 (t,J= 7.3 Hz, 2H).13C NMR (101 MHz, DMSO-d 6)δ165.83, 153.26, 133.97,131.76, 129.80, 125.38, 38.58, 29.22. HPLC,t R= 7.337 min, purity 98.7%.
实施例5：4-溴-N-(2-(1-(4-溴苯基)-1H-苯并咪唑-2-基)乙基)苯甲酰胺（I-5）
将原料B2更换为对溴苯甲酰氯，参照实施例3的合成方法，得到化合物I-5。收率74%。1H NMR (400 MHz, DMSO-d 6)δ8.70 (t,J= 5.5 Hz, 1H), 7.83–7.55 (m, 9H), 7.31–7.23 (m,1H), 7.19–7.09 (m,1H), 6.70–6.63 (d,J= 8.2 Hz, 1H), 3.74 (q,J= 6.5Hz, 2H), 3.30 (t,J= 6.9 Hz, 2H).13C NMR (101 MHz, DMSO-d 6)δ 168.03, 165.88,154.78, 142.58, 133.87, 133.84, 132.54, 132.52, 132.36, 131.66, 129.67,128.64, 125.32, 124.20, 124.09, 119.77, 113.81, 38.28, 29.96. HPLC,t R= 10.874min, purity 95.5%.
实施例6 生物学评价实验
（1）小分子与YTHDF2蛋白相互作用活性测试—微量热泳动实验（MST）
本实验采用PerkinElmer公司的Lance Ultra方法进行检测。
首先取100μL、10μMYTHDF2蛋白（杭州华安生物技术有限公司，氨基酸序列如SEQID NO.1所示：SEPHPVLEKLRSINNYNPKDFDWNLKHGRVFIIKSYSE DDIHRSIKYNIWCSTEHGNKRLDAAYRSMNGKGPVYLLFSVNGSGHFCGV AEMKSAVDYNTCAGVWSQDKWKGRFDVRWIFVKDVPNSQLRHIRLENNENKPVTNSRDTQEVPLEKAKQVLKIIASYKHT TSI），采用30K超滤管浓缩换液成PBS缓冲液，根据蛋白标记试剂盒RED-NHS的试验方案对蛋白进行标记。用于MST实验的化合物用PBS缓冲液稀释至DMSO含量为5%。标记好的蛋白与稀释好的不同浓度的化合物（500μM，250 μM，125 μM，62.5 μM， 31.25 μM，15.63 μM，7.81 μM，3.91 μM，1.95 μM，0.98 μM，0.49 μM，0.24 μM，0.12 μM，0 μM）等体积（5μL:5μL）混合，37℃避光孵育30分钟。在20% LED灯源下通过检测热泳动来测量化合物和蛋白的结合，最后使用Mo.Affinity Analysis v2.2.4对所测数据进行分析处理，所有实验均重复至少三次。
根据不同浓度测试得到的数据，使用Mo.Affinity Analysis v2.2.4软件计算出的解离常数K D值如下表1，从实验结果可以看出，本发明化合物对YTHDF2蛋白具有结合活性。
表1 本发明化合物对YTHDF2蛋白的K D测量值
（2）小分子体外扩增造血干细胞活性测试
选取7周龄的C57BL/6J小鼠（上海斯莱克实验动物有限责任公司），在无菌的条件下从股骨和胫骨中分离出骨髓细胞，每孔2 × 105个骨髓细胞在100 μL的stemspan（Stemcell，02691）培养基（含有100 ng/mL小鼠干细胞因子（Sinobiological，50487-M08B）和100 ng/mL小鼠促血小板生成素（Sinobiological，50146-M08H））种入96孔U型板中，在37℃、5%CO2的条件下进行细胞培养。24h后，将实施例1~5制备的小分子抑制剂（终浓度20 μM）分别加入到100 μL的stemspan培养基（含有100 ng/mL小鼠干细胞因子和100 ng/mL小鼠促血小板生成素）中，每隔3天进行半数换液并分别添加对应的小分子抑制剂（终浓度20 μM）。培养14天后收集并计数，流式细胞术检测造血干细胞比例及数目。测得的结果如图1，从实验结果可以看出，本发明制备的化合物I-1、I-2、I-3、I-4、I-5对造血干细胞均具有显著的扩增活性。其中，统计分析使用非配对Student’s t双尾检验，P值小于0.05认为具有统计学差异，**，P<0.01; ***，P<0.001；
（3）小分子体内移植造血干细胞活性测试
骨髓移植前一天，将7周的CD45.1小鼠（上海斯莱克实验动物有限责任公司）进行致死剂量的全身辐照，4.5戈瑞两次，中间间隔3 h，总剂量9戈瑞。移植前一周及后一周在饮用水中添加1 mL拜有利（德国拜耳）。辐照小鼠后第二天将小分子抑制剂处理后的2×105个骨髓细胞（来自CD45.2小鼠，上海斯莱克实验动物有限责任公司），加上2 × 105个CD45.1保护细胞，按每只200 μL的液体体积尾静脉注射至致死辐照的CD45.1受体小鼠体内。对于二代移植，将一代移植的受体小鼠处死后的1×106个骨髓细胞尾静脉移植入致死剂量辐照的CD45.1受体小鼠中，分别在移植后4周、8周、12周、16周，采外周血进行流式细胞术分析实验检测CD45.2嵌合率及淋系和髓系分化情况。测得的结果如图2~图6，从实验结果可以看出，本发明中化合物I-5在体外处理造血干细胞后，能显著提高CD45.2供体小鼠造血干细胞重建受到致死辐射的CD45.1受体小鼠的造血***的能力，即提高CD45.2小鼠各类血液细胞在CD45.1小鼠体内的嵌合比例；同时，I-5只扩增造血干细胞，并不对各类造血祖细胞（淋巴系祖细胞CLP、髓系祖细胞CMP、粒细胞巨噬细胞祖GMP、巨核细胞–红细胞祖细胞MEP）和成熟的B细胞（Bcell）、髓系细胞（Myeioid）、红细胞（Erythro）和T细胞（T cells）有扩增效果，即不造成白血病倾向，显示了化合物I-5的安全性。其中，统计分析使用非配对Student’st双尾检验，P值小于0.05，具有统计学差异，*，P<0.05; **，P<0.01; ***，P<0.001；N.S, Notsignificant。
Claims (7)
1.一种通式（I）所示的化合物或其药学上可接受的盐：
，
其中，R1选自以下基团：
。
2.根据权利要求1所述的化合物或其药学上可接受的盐，其特征在于：所述化合物如下所示：
。
3.根据权利要求1所述的化合物或其药学上可接受的盐，其特征在于：所述药学上可接受的盐为通式（I）化合物的酸加成盐，其中用于成盐的酸为无机酸或有机酸，所述无机酸为盐酸、硫酸或磷酸，有机酸为乙酸、三氯乙酸、丙酸、丁酸、马来酸、对甲苯磺酸、苹果酸、丙二酸、肉桂酸、柠檬酸、富马酸、樟脑酸、二葡糖酸、天冬氨酸和酒石酸或甲磺酸。
4.一种权利要求2所述的化合物或其药学上可接受的盐的制备方法，其特征在于，当所述化合物选自I-3时，所述化合物的合成包括以下步骤：
；
化合物B2和化合物B3溶于二氯甲烷中，滴加三乙胺，得到化合物I-3；
当所述化合物选自I-5时，所述化合物的合成包括以下步骤：
；
取化合物C2和化合物B3溶于二氯甲烷中，滴加三乙胺，搅拌，得到化合物I-5。
5.一种药用组合物，其特征在于：包含权利要求1的通式（I）化合物或其药学上可接受的盐以及药学上可接受的载体。
6.根据权利要求1所述的化合物或其药学上可接受的盐或权利要求5所述的组合物在制备YTHDF2靶点抑制剂药物中的应用。
7.根据权利要求1所述的化合物或其药学上可接受的盐或权利要求5所述的组合物在制备用于扩增造血干细胞药物中的应用。
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Non-Patent Citations (4)
| Title |
|---|
| Barlin, Gordon B.，等.Imidazo[1,2-b]pyridazines. XVI. Synthesis and central nervous system activities of some 6-(chloro,alkylthio, phenylthio, benzylthio or benzoyl)imidazo[1,2-b]pyridazines.《Australian Journal of Chemistry》.1994,第47卷(第11期),第1989-1999页. * |
| Barlin, Gordon B..Imidazo[1,2-b]pyridazines: syntheses and interaction with central and peripheral-type (mitochondrial) benzodiazepine receptors.《Journal of Heterocyclic Chemistry》.1998,第35卷(第5期),第1205-1217页. * |
| Fragment Ligands of the m6A‑RNA Reader YTHDF2;Francesco Nai，等;《ACS Medicinal Chemistry Letters》;第13卷;1500−1509 * |
| Transient regulation of RNA methylation in human hematopoietic stem cells promotes their homing and engraftment;Xuepeng Wang，等;Leukemia;第37卷;453-464 * |
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