CN112679523B - 高活性sting蛋白偶联剂偶联化合物及其应用 - Google Patents
高活性sting蛋白偶联剂偶联化合物及其应用 Download PDFInfo
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Abstract
本公开提供式(I)化合物及其药物组合物,以及使用式(I)化合物预防和/或治疗免疫相关病症的方法。
Description
本申请为分案申请,其母案的中国专利申请申请号为201980005220.4,母案申请日为2019年08月22日。
本申请要求以下专利申请的优先权:(1)发明名称为“一种高活性STING蛋白激动剂”于2018年8月29日提交到中国专利局的中国专利申请201810996231.0的优先权,和(2)发明名称为“一种高活性STING蛋白激动剂”于2018年11月23日提交到中国专利局的中国专利申请201811407028.1的优先权,其内容均通过引用以整体并入本文。
技术领域
本发明涉及一种杂环化合物,具体地涉及一种高活性的STING蛋白激动剂及其用途。
背景技术
免疫治疗的阳性反应通常依赖于肿瘤细胞与肿瘤微环境(TME)内免疫调节的相互作用。在这些相互作用下,肿瘤微环境在抑制或增强免疫应答中发挥着重要的作用。认识免疫治疗与TME间的相互作用不仅是剖析作用机制的关键,也为改善目前免疫治疗的疗效提供了新的方法。细胞因子是可以调节免疫应答的一大类蛋白质,可以直接激活免疫效应细胞或刺激肿瘤基质细胞,以致为淋巴细胞的募集产生的趋化因子和粘附分子。这些功能表明根据不同的肿瘤微环境,针对细胞因子也可以是肿瘤免疫治疗的一种有效途径。
STING(干扰素基因刺激蛋白)是目前肿瘤免疫治疗领域药物研发中最新最热的免疫治疗靶点。干扰素基因刺激蛋白是一种跨膜蛋白,通常在152-173位区域交接形成二聚体并处于自我抑制状态。当受到部分配体的刺激后分子构型发生变化并被激活,招募细胞质中的TANK结合激酶1,介导TBK1对IRF3的磷酸化,导致干扰素-β和其它多种细胞素的形成。IFNβ的产生是STING活化的标志。肿瘤微环境天然免疫的信号传导是肿瘤特异性T细胞的激活和肿瘤浸润性淋巴细胞浸润的关键步骤。其中I型IFN对肿瘤激活的T细胞活化起着关键作用。这样,STING不仅诱导I型干扰素基因的表达,在天然免疫信号通路中起着重要作用;STING激动剂能激活包括树突状细胞等免疫刺激细胞,改变肿瘤微环境并诱导了肿瘤特异性T细胞的产生。在鼠科动物实验中,一种黄酮类血管破坏剂DMXAA通过激活鼠源STING蛋白,诱导IFN-β和其它天然细胞素的产生,并有效地抑制多种实体肿瘤的生长。但是该药在一个人体非小细胞临床实验中和标准化疗联合使用未能观察到明显疗效。后来实验证实,尽管人源和鼠源STING蛋白的相似度高达81%,前者基因编码379个氨基酸,后者基因编码378个氨基酸,但DMXAA却无法激活人源STING蛋白。环二核苷酸是到目前为止发现的唯一一类既能直接激活鼠源又能激活人源STING蛋白的STING激动剂。直接把CDN注射到B16黑色素瘤、CT26直肠癌、和4T1乳腺癌肿块,不仅导致明显的抑制作用直至肿瘤消失,同时也诱导系统的持久性抗原特异性T细胞免疫,造成动物其它部位未注射药物的肿瘤生长也受到抑制。MLRR-S2CDA引起多种实体肿瘤微环境的改变,激活有效的肿瘤引发的CD8+T细胞和持久的疗效。近年来大量的研究报道表明STING通路能有效地启动机体的天然免疫系统,是至今为数不多的、经多方验证能诱导产生细胞因子干扰素的信号传导通路,该通路在天然免疫中至关重要。淋巴细胞充分浸润到肿瘤组织是免疫治疗成功的关键。该作用靶点通路的激活也促进肿瘤微环境中效应T细胞的浸染及应答,因此该靶点逐渐成为是抗肿瘤治疗尤其是免疫治疗研究的重要靶标。在多个小鼠接种模型中对多种难治症、转移性实体肿瘤有效,不仅直接注射的肿瘤消失,其它部位生长的肿瘤生长也受到明显抑制,甚至还可以预防肿瘤的发生。
发明内容
本发明提供了一种化合物,其具有如下结构:
其中,W1表示(CRaRa’)s,其中任意一个CRaRa’任选地被0、1或2个O、S或NRb所替代,或者任意一个CRaRa’任选地共同形成-C=O;
s选自1、2和3的整数;
q选自0和1;
r选自0和1;
并且q和r不同时为0;
其中,R1、R2、R3、R4各自独立地表示氢、卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、-ORc、-O-(C1-C6亚烷基)-NRcRc’、-NRcRc’、-OC(O)Rc、-C(O)Rc、-CO2Rc、-CON(Rc)(Rc’)、-C(=NH)N(Rc)(Rc’)、-NRcC(O)Rc’、-SO2Rc、-SO2NRcRc’、-N(Rc)-SO2-(C1-C6烷基)-NRcRc’、-N(Rc)-C(O)-(C1-C6烷基)-NRcRc’、-NRcS(O)Rc’、-NRcSO2Rc’、-O-P(O)(ORc)(ORc’)、6-12元芳基或5-12元杂芳基;
R5选自氢或C1-C6烷基;
其中,当q=0时,QA1分别独立地选自氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、-(C0-C6烷基)-(C3-C6环烷基)、-(C0-C6烷基)-(4-6元杂环基)、-(C0-C6烷基)-(6-12元芳基)、和-(C0-C6烷基)-(5-12元杂芳基);或者QA1、R5以及与之相邻的原子一起形成3-6元环,并且该环中任选地含有0、1或2个选自O、N和S的杂原子;QA2分别独立地选自氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、-(C0-C6烷基)-(C3-C6环烷基)、-(C0-C6烷基)-(4-6元杂环基)、-(C0-C6烷基)-(6-12元芳基)、和-(C0-C6烷基)-(5-12元杂芳基);
当q=1时,-QA1-A-QA2-一起形成选自以下的连接基团:-C1-C6亚烷基-、-C2-C6亚烯基-、-C2-C6亚炔基-、-(C0-C6亚烷基)-O-(C0-C6亚烷基)-、-(C0-C6亚烷基)-C(O)-(C0-C6亚烷基)-、-C(O)-(C0-C6亚烷基)-O-(C0-C6亚烷基)-、-(C0-C6亚烷基)-OC(O)-(C0-C6亚烷基)-、-(C0-C6亚烷基)-NRc-C(O)-(C0-C6亚烷基)-、-(C0-C6亚烷基)-C(O)-NRc-(C0-C6亚烷基)-、-(C0-C6亚烷基)-NRc-(C0-C6亚烷基)-、-(C0-C6亚烷基)-C(O)O-(C0-C6亚烷基)-、-(C0-C6亚烷基)-(C3-C6碳环)-(C0-C6亚烷基)-、-(C0-C6亚烷基)-(4-6元杂环基)-(C0-C6亚烷基)-、-(C0-C6亚烷基)-(6-12元芳基)-(C0-C6亚烷基)-、和-(C0-C6亚烷基)-(5-12元杂芳基)-(C0-C6亚烷基)-;
其中,当r=0时,QB1和QB2分别独立地选自氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、-(C0-C6烷基)-(C3-C6环烷基)、-(C0-C6烷基)-(4-6元杂环基)、-(C0-C6烷基)-(6-12元芳基)、和-(C0-C6烷基)-(5-12元杂芳基);
当r=1时,-QB1-B-QB2-一起形成选自以下的连接基团:-C1-C6亚烷基-、-C2-C6亚烯基-、-C2-C6亚炔基-、-(C0-C6亚烷基)-O-(C0-C6亚烷基)-、-(C0-C6亚烷基)-C(O)-(C0-C6亚烷基)-、-C(O)-(C0-C6亚烷基)-O-(C0-C6亚烷基)-、-(C0-C6亚烷基)-OC(O)-(C0-C6亚烷基)-、-(C0-C6亚烷基)-NRc-C(O)-(C0-C6亚烷基)-、-(C0-C6亚烷基)-C(O)-NRc-(C0-C6亚烷基)-、-(C0-C6亚烷基)-NRc-(C0-C6亚烷基)-、-(C0-C6亚烷基)-C(O)O-(C0-C6亚烷基)-、-(C0-C6亚烷基)-(C3-C6碳环)-(C0-C6亚烷基)-、-(C0-C6亚烷基)-(4-6元杂环基)-(C0-C6亚烷基)-、-(C0-C6亚烷基)-(6-12元芳基)-(C0-C6亚烷基)-、和-(C0-C6亚烷基)-(5-12元杂芳基)-(C0-C6亚烷基)-;
RI和RII各自独立地表示氢或C1-C6烷基;
其中,Ra、Ra’分别独立地表示氢、卤素、羟基、C1-C6烷基、C1-C6烷基硫基、-(C0-C6亚烷基)-(C3-C6环烷基)、-(C0-C6亚烷基)-(4-6元杂环基)、-(C0-C6亚烷基)-(6-12元芳基)、-(C0-C6亚烷基)-(5-12元杂芳基)、-NRdRd’、-NRdCORd’、-NRdS(O)Rd’、-NRdSO2Rd’、-ORd、或-OCORd;
Rb各自独立地表示氢、C1-C6烷基、C3-C6环烷基、-(C0-C6亚烷基)-(6-12元芳基)、-C(O)Re、-SORe、-SO2Re、-C(O)ORe、或-C(O)NReRe’;
Rc、Rc’分别独立地表示氢、C1-C6烷基、-(C0-C6亚烷基)-(C3-C6环烷基)或-(C0-C6亚烷基)-(4-6元杂环基);
或者对于Ra、Ra’而言,其任选地和与之相连的原子相互环合成3-6元环,并且该环中任选地含有0、1或2个选自O、N和S的杂原子;
或者对于Rc、Rc’而言,其任选地和与之相连的原子相互环合成3-6元环,并且该环中任选地含有0、1或2个选自O、N和S的杂原子;
其中,m=1、2、3或4;
n=1、2或3;
o=1或2;
p=1或2;
或者当m=2时,相邻的两个R1和与之连接的原子任选地相互环合成5-8元环,并且该环中任选地含有0、1或2个选自O、N和S的杂原子;
或者当n=2时,相邻的两个R2和与之连接的原子任选地相互环合成5-8元环,并且该环中任选地含有0、1或2个选自O、N和S的杂原子;
或者当p=2时,相邻的两个R4和与之连接的原子任选地相互环合成5-8元环,并且该环中任选地含有0、1或2个选自O、N和S的杂原子;
对于上述所定义的任意的烷基、烷氧基、烯基、炔基、亚烷基、芳基、杂芳基、碳环、杂环基而言,其任选地被选自以下的0、1、2、3或4个取代基所取代:
C1-C6烷基、C2-C6烯基、C2-C6炔基、卤素、磺酸基、氰基、3-8元碳环、3-8元杂环基、6-12元芳基、5-12元杂芳基、硝基、氧代、C1-C6巯基、C1-C6烷氧基、-ORf、-C(O)-ORf、-OC(O)Rf、-S(O)Rf、-S(O)2Rf、-S(O)2NRfRf’、-OCONRfRf’、-NRfCORf’、-NRfS(O)Rf’、-NRfS(O)2Rf’、-NRfC(O)ORf’、-CONRfRf’、-NRfRf’、-NHC=NHNRfRf’、C1-C6卤代烷基、C1-C6卤代烷氧基、和-O-P(O)(ORf)(ORf’);
其中Rd、Rd’、Re、Re’、Rf、Rf’彼此互相独立的表示氢或者C1-C6烷基,其中所述的C1-C6烷基还任选地被C1-C6烷基、C2-C6烯基、C2-C6炔基、卤素、磺酸基、氰基、3-8元碳环、3-8元杂环基、6-12元芳基、5-12元杂芳基、硝基、氧代、C1-C6巯基、C1-C6烷氧基、-ORg、-C(O)-ORg、-OC(O)Rg、-S(O)Rg、-S(O)2Rg、-S(O)2NRgRg’、-OCONRgRg’、-NRgCORg’、-NRgS(O)Rg’、-NRgS(O)2Rg’、-NRgC(O)ORg’、-CONRgRg’、-NRgRg’、C1-C6卤代烷基、C1-C6卤代烷氧基、或-O-P(O)(ORg)(ORg’)所取代;
或者Rd、Rd’、Re、Re’、Rf、Rf’彼此一起和与之相连的氮原子形成5-8元碳环或者5-8元杂环;
其中Rg、Rg’各自独立地选自氢或C1-C6烷基。
在本发明的化合物中,其中,R1和R2分别各自独立地选自氢、卤素、氰基、C1-C6烷基、-CON(Rc)(Rc’)。
在本发明的化合物中,其中,Rc、Rc’分别独立地表示氢、C1-C6烷基。
在本发明的化合物中,其中,R3、R4各自独立地选自氢、C1-C6烷基或C1-C6卤代烷基;其中,R5、R6为氢或者C1-C6烷基。
在本发明的化合物中,其中,m、n为1。
在本发明的化合物中,其中,W1为-O-(CRaRa’)-,其中,Ra、Ra’自独立地表示氢、C1-C6烷基、或C3-C6环烷基。
在本发明的化合物中,其中,W2为-O-(CRhRh’)-,其中Rh、Rh’各自独立地表示氢、C1-C6烷基、或C3-C6环烷基。
在本发明的化合物中,其中,-QA1-A-QA2-一起形成-CH2CH2CH2-。
在本发明的化合物中,其中,-QB1-B-QB2-一起形成选自以下的连接基团:-C1-C6亚烷基-、-C2-C6亚烯基-、-(C0-C6亚烷基)-NRc-(C0-C6亚烷基)-。
除此之外,本发明还提供了一种化合物,其具有以下结构:
实施例58和59
化合物58和59由以下步骤制备:
第一步:将化合物58a(10g,79.29mmol)溶于DMSO(100mL)中,加入碳酸氢钠(10g,118.94mmol),室温搅拌30分钟后加入溴化苄(8.95mL,75.33mmol),室温搅拌过夜,LCMS监测原料反应完全。将反应液倒入水(300mL)中,乙酸乙酯(100mL*3)萃取,有机相合并,饱和食盐水洗,硫酸钠干燥,过滤浓缩,残余物硅胶柱层析纯化得化合物58b(4.5g),白色固体,收率26%。ESI-MS(m/z):217.2[M+H]+。
第二歩:将化合物58b(4.5g,20.81mmol)和1-氯-5-三甲基硅基-4-戊炔58c(3.82g,21.85mmol)溶于DMF(50mL)中,加入碳酸钾(5.75g,41.62mmol),60℃反应过夜,LCMS监测原料反应完全。反应液冷却到室温,倒入水(200mL)中,乙酸乙酯(50mL*3)萃取,有机相合并,饱和食盐水洗,无水硫酸钠干燥,过滤浓缩得化合物58d(粗品,7.0g),黄色油,化合物直接用于下一步反应。ESI-MS(m/z):355.3[M+H]+。
第三歩:将化合物58d(粗品,7.0g,从第二步反应得到)溶于乙醇(100mL)中,加入碳酸钾(4.09g,29.62mmol),室温反应过夜,LCMS监测反应完全。过滤除去固体,滤液浓缩,残余物硅胶柱层析纯化得化合物58e(1.2g),黄色固体,两步反应收率27%,ESI-MS(m/z):221.2[M+H]+。
第四步:将化合物58e(1.2g,5.45mmol)和58f(2.0g,6.54mmol)溶于1,4-二氧六环(20mL)中,加入CuI(103mg,0.54mmol),Pd(PPh3)2Cl2(382mg,0.54mmol),三乙胺(2.27mL,16.34mmol),氮气保护下50℃反应过夜,LCMS监测反应完全。反应液浓缩,残余物硅胶柱层析纯化得化合物58g(1.8g),白色固体,收率82%。ESI-MS(m/z):401.1[M+H]+。
第五步:将化合物58g(1.8g,4.49mmol)溶于乙醇(20mL)中,加入氯化钯(80mg,0.45mmol),室温氢化反应过夜,LCMS监测原料反应完全。过滤除去固体,滤液浓缩得化合物58h(1.2g),淡黄色固体,收率66%。ESI-MS(m/z):405.3[M+H]+。
第六步:将化合物58h(1.2g,2.97mmol)溶于甲醇(20mL),加入NaOH(154mg,3.86mmol)的水(5mL)溶液,室温反应过夜,LCMS监测原料反应完全。反应液浓缩,残留固体用水(30mL)溶解分散,二氯甲烷(20mL*2)洗,然后水相用浓盐酸调到pH 3~4,乙酸乙酯(30mL*3)萃取,有机相合并,饱和食盐水洗,无水硫酸钠干燥,过滤浓缩,得化合物58i(650mg),黄色固体,收率62%。ESI-MS(m/z):349.4[M+H]+。
第七歩:将化合物10h(100mg,0.19mmol)和化合物58i(69mg,0.19mmol)溶于NMP(6mL)中,加入HATU(165mg,0.43mmol),三乙胺(60mg,0.59mmol),微波140℃反应1小时,LCMS监测原料反应完全。反应液直接反向制备HPLC纯化得得化合物58j-P1(20mg,极性大,先出峰)和58j-P2(20mg),棕色固体,收率24%。ESI-MS(m/z):817.3[M+H]+。化合物58j-P1和58j-P2是位置异构体,目前暂定58j-P1和58j-P2各自对应反应式中具体的结构。
第八歩:将化合物58j(20mg,0.024mmol)溶于DMSO(3mL)中,加入NaOH(3mg,0.073mmol),升温至60℃,缓慢滴加双氧水(30%wt,0.5mL),60℃反应5分钟,LCMS监测反应完全。反应液直接通过反相制备HPLC纯化得化合物58(4mg),白色固体,收率19%。ESI-MS(m/z):835.8[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.40(s,2H),7.96(s,1H),7.87(s,1H),7.74(s,1H),7.67(s,1H),7.35-7.25(m,3H),7.21(s,1H),4.88-4.78(m,1H),4.60-4.50(m,1H),4.47-4.38(m,2H),4.23-4.15(m,2H),4.11-4.02(m,2H),4.00-3.90(m,3H),3.05(s,3H),3.02-2.92(m,2H),2.15(s,3H),2.07(s,3H),1.93-1.64(m,8H),1.40-1.31(m,4H),1.24(t,J=7.1Hz,3H)。
采用相同的方法水解58j-P2得化合物59(5mg),白色固体,收率24%。ESI-MS(m/z):836.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ12.71(s,2H),8.40(s,2H),7.96(s,1H),7.88(s,1H),7.59(s,1H),7.40-7.20(m,5H),6.40(s,1H),4.55-4.40(m,4H),4.21-4.10(m,6H),4.05-3.88(m,3H),3.15(s,3H),3.13-3.08(m,2H),2.22(s,3H),2.05(s,3H),2.00-1.70(m,8H),1.40-1.20(m,7H)。
实施例60和61
化合物60和61由以下步骤制备:
第一步:将化合物10e(2.0g,5.83mmol)和1-溴-3-氟-2-硝基苯60e(1.54g,6.99mmol)溶于DMF(20mL)中,加入碳酸钾(3.22g,23.31mmol),70℃反应4小时,LCMS监测原料反应完全。反应液倒入水(100mL)中,乙酸乙酯(30mL*3)萃取,有机相合并,饱和食盐水洗,无水硫酸钠干燥,过滤浓缩,残余物硅胶柱层析纯化得化合物60b(1.8g),黄色固体,收率66%。
第二歩:将化合物60b(1.8g,3.89mmol)溶于AcOH(20mL)中,加入锌粉(1.27g,19.47mmol),室温反应2小时,LCMS监测原料反应完全。过滤除去锌粉,滤液浓缩,残余物硅胶柱层析纯化得化合物60c(1.4g),红棕色色固体,收率89%。ESI-MS(m/z):403.3[M+H]+。
第三歩:将化合物60c(1.4g,3.48mmol)溶于甲醇(40mL)中,加入溴氰(1.84g,17.4mmol),室温反应过夜,LCMS监测反应完全。反应液浓缩,残留固体用乙酸乙酯打浆,过滤得化合物60d(1.0g),棕色固体,收率63%。ESI-MS(m/z):452.1[M+H]+。
第四歩:将化合物60d(500mg,1.11mmol)和化合物58i(348mg,1.11mmol)溶于NMP(10mL)中,加入HATU(924mg,2.43mmol),三乙胺(335mg,3.32mmol)微波140℃反应1小时,LCMS监测原料反应完全。反应液直接通过反向制备HPLC纯化得化合物60e-P1(70mg,极性大,先出峰),和化合物60e-P2(80mg),棕色固体,总收率17.74%,ESI-MS(m/z):764.1[M+H]+。化合物60e-P1和60e-P2是位置异构体,目前暂定60e-P1和60e-P2各自对应反应式中具体的结构。
第五歩:将化合物60e-P1(70mg,0.091mmol)溶于DMSO(3mL)中,加入NaOH(11mg,0.27mmol),升温至60℃,缓慢滴加双氧水(30%wt,0.5mL),60℃反应5min,LCMS监测反应完全。反应液直接通过反应制备HPLC纯化得化合物60(30mg),白色固体,收率41%,ESI-MS(m/z):782.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.27(s,1H),7.90(s,1H),7.70(s,1H),7.47(d,J=8.0Hz,1H),7.38(d,J=8.0Hz,1H),7.28(s,1H),7.24(s,1H),7.15(t,J=8.0Hz,1H),6.20(s,1H),4.81(br s,1H),4.53-4.35(m,4H),4.21(dd,J=12.0,3.0Hz,2H),4.06-4.00(m,2H),2.90-2.80(m,1H),2.72-2.60(m,1H),2.22(s,3H),2.09(s,3H),2.05-1.70(m,6H),1.48-1.30(m,2H),1.24(d,J=6.5Hz,3H),1.20-1.08(m,2H)。
相同的方法水解60e-P2(80mg)得化合物61(25mg),白色固体,收率34%。ESI-MS(m/z):782.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ8.33(s,1H),7.87(s,1H),7.60(s,1H),7.57(d,J=8.0Hz,1H),7.44(d,J=8.0Hz,1H),7.26(s,2H),7.19(t,J=8.0Hz,1H),6.34(s,1H),4.60-4.50(m,2H),4.46-4.37(m,1H),4.30-4.20(m,1H),4.15-4.02(m,4H),2.90-2.65(m,2H),2.25(s,3H),2.10(s,3H),1.90-1.66(m,6H),1.40-1.00(m,7H)。
STING激动剂生物学筛选和结果
试验例3:化合物刺激THP1细胞释放IFNβ
本实验通过检测化合物刺激THP1细胞产生IFNβ的能力来评估其激活STING的能力。THP1细胞购买自中科院细胞所(Cat#TCHu 57)。根据化合物的溶解度设置起始浓度,并以3倍稀释设置8个浓度点,用培养基稀释成2×工作液,DMSO浓度0.2%。取对数生长期的THP1细胞用培养基稀释成2×106cells/ml,每孔加入50ul细胞悬液后再加50ul稀释好的化合物,使得DMSO浓度为0.1%。充分混匀后放入37℃,5%CO2的细胞培养箱中孵育24h收集上清。用human IFNβELISA KIT(R&D,DY814-05)检测上清中的IFNβ。最终的数据用GraphPadPrism或者XLfit进行曲线拟合并计算EC50。
化合物 | hIFNβELISA(EC50,μM) |
58 | >4.3 |
59 | >5.6 |
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- 2019-08-22 CN CN201980005220.4A patent/CN111655682A/zh active Pending
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CN112679523A (zh) | 2021-04-20 |
CA3110474A1 (en) | 2020-03-05 |
WO2020042995A1 (zh) | 2020-03-05 |
JP7166028B2 (ja) | 2022-11-07 |
TW202024063A (zh) | 2020-07-01 |
AU2019331993A1 (en) | 2021-03-25 |
EP3848366A1 (en) | 2021-07-14 |
EP3848366A4 (en) | 2022-03-16 |
CN112661773A (zh) | 2021-04-16 |
TWI723511B (zh) | 2021-04-01 |
AU2019331993B2 (en) | 2022-06-02 |
KR102653190B1 (ko) | 2024-03-29 |
CA3110474C (en) | 2024-04-23 |
CN112661773B (zh) | 2022-03-11 |
CN111655682A (zh) | 2020-09-11 |
KR20210049895A (ko) | 2021-05-06 |
CN112608331A (zh) | 2021-04-06 |
JP2021535909A (ja) | 2021-12-23 |
CN112608331B (zh) | 2022-03-11 |
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