CN108473477A - 用于在流感病毒感染中使用的芳基取代的嘧啶 - Google Patents
用于在流感病毒感染中使用的芳基取代的嘧啶 Download PDFInfo
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- CN108473477A CN108473477A CN201780007200.1A CN201780007200A CN108473477A CN 108473477 A CN108473477 A CN 108473477A CN 201780007200 A CN201780007200 A CN 201780007200A CN 108473477 A CN108473477 A CN 108473477A
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Classifications
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- C07D513/04—Ortho-condensed systems
Abstract
本发明涉及具有式(I)的结构的化合物,这些化合物可用于治疗或抵抗流感感染。
Description
流感是一项严重的公共健康问题,人群体中发病率高,从而导致定期的大规模发病率和死亡率。流感是一种引发急性发热性疾病的高度传染性的空气传播疾病。就严重性而言,全身性症状从轻度疲劳到呼吸衰竭和死亡变化。根据WHO,每年流行病的平均全球负担可达约10亿病例,严重疾病300万至500万病例,并且每年死亡300,000–500,000病例。每年,流感病毒在人类中流行,通常影响所有年龄组的5%-20%的人口,在严重流行病期间这个数字上升到30%。严重疾病率和死亡率在以下人群中是最高的:年龄>65岁的人,年龄<2岁的儿童,以及任何年龄的患有使他们面临流感并发症的风险增加的医学症状(例如慢性心脏病、肺病、肾病、肝病、血液病或代谢疾病、或弱化的免疫系统)的人。虽然儿童死亡并不频发,但对于<5岁的儿童来说,住院率在每10万人中大约100人至500人的范围内(这取决于合并病症的存在或不存在)。年龄<24个月的儿童的住院率与年龄>65岁的人中报告的住院率是可比较的。
在美国,每年流感流行病导致大约3000万门诊患者就诊,由此导致每年医疗费用为100亿美元。由于疾病和生命损失而损失的收入表示为每年超过150亿美元的成本,并且美国每年流感流行病的总经济负担合计超过850亿美元。
引起流感的病原体是反义、单链RNA病毒,其属于正粘病毒科。存在三种类型的流感病毒:甲型、乙型和丙型。甲型流感病毒是最常见的形式,其可以在哺乳动物和鸟类中传播。甲型流感的亚型是由表面蛋白血球凝集素(H)和神经氨酸酶(N)的类型命名的。存在18种不同的血球凝集素和11种已知的神经氨酸酶。在人类中发现的当前季节性流感病毒主要是H1N1和H3N2亚型。通常只有在人类中发现乙型流感病毒。乙型流感病毒不分亚型,但可以进一步细分为不同的毒株。流感病毒的流行每年高度可变,并且甲型和乙型流感均在世界范围内引起季节性流行病。丙型流感病毒的症状要轻得多,其不引起流行病。
所有三种类型的病毒具有相似的基因组结构。该基因组包含8个区段,这些区段编码9–11种蛋白质,这取决于其类型。甲型流感编码11种蛋白质,其包括表面蛋白(血球凝集素(HA)和神经氨酸酶(NA))、聚合酶复合物(PA、PB1和PB2)、核蛋白(NP)、膜蛋白(M1和M2)、以及其他蛋白质(NS1、NS2、NEP)。在这三种流感病毒类型中,甲型流感具有最高的突变率。乙型流感进展比甲型慢但比丙型快。分段基因组允许在不同病毒株之间进行基因交换,这种基因交换产生流感病毒的新变体。
流感病毒可以通过与感染的个体或病毒污染的材料直接接触而在人类之间传播。也可以通过吸入空气中悬浮的病毒液滴来感染人。那些液滴通过感染的个体的咳嗽、打喷嚏或讲话而产生。季节性流感通过以下各项来表征:突然发作的高热、咳嗽(通常干咳)、头痛、肌肉疼痛和关节疼痛、严重不适(感觉不好)、咽喉痛以及流鼻涕。咳嗽可以是严重的并且可持续两周或更多周。大多数人不需要医疗救助能在一周内从发烧和其他症状中恢复。但是流感可以引起严重的疾病或死亡,特别是在如上提到的高危人群中。从感染到疾病的时间,称为潜伏期,约为两天。
预防该疾病和/或来自该疾病的严重后果的最有效方式是疫苗接种。安全且有效的疫苗是可获得的,并已使用了60多年。在健康成人中,流感疫苗可以提供合理的保护。然而,接种疫苗伴随若干限制。首先,流感疫苗在预防老年人疾病方面可能不太有效,并且可能仅降低疾病的严重性以及并发症和死亡的发生率。此外,当流行病毒与疫苗病毒良好匹配时,流感疫苗接种是最有效的,并且疫苗接种的成功在很大程度上取决于对该季节的最流行的病毒类型的良好预测。通过抗原性漂移,加上疫苗诱导的对目前流感疫苗的免疫应答的短期性质,使流感病毒株快速并持续进化,这意味着每年需要按季节接种适当的毒株以用于预防。
目前对流感的治疗使用直接抗病毒药物或减轻流感诱发的症状的药物。市场上有两类可用的流感抗病毒药物:神经氨酸酶抑制剂和M2通道抑制剂。神经氨酸酶抑制剂(奥司他韦或扎那米韦)是推荐用于预防和治疗流感的主要抗病毒剂。这些针对甲型和乙型流感病毒两者都有效。在治疗季节性流感和散发性奥司他韦耐受性2009H1N1病毒期间,已经鉴定了对这些抗病毒药物的耐受性的发展,但是迄今为止公共卫生影响受到限制。M2通道抑制剂(例如金刚烷胺和金刚乙胺(amantadane))对甲型流感毒株有活性,而对乙型流感毒株没有活性。流行的甲型流感病毒中的amantadane耐受性在2003-2004年间全球开始迅速增加。因此,金刚烷胺和金刚乙胺不被推荐用于目前流行的甲型流感病毒株的抗病毒治疗或化学预防。
2009年,由于来自人类、猪和鸟的H1N1病毒的基因重配,新颖的猪H1N1毒株导致意外的流感大流行。这种过去的大流行、以及高致病性禽类H5N1毒株的持续流行以及最近H7N9病毒(在中国分离的禽类来源的新重配体,并且与具有40%死亡率的严重呼吸道疾病相关,其可以潜在地适应为人与人之间的传播)的出现突出了世界人口面对新颖流感毒株时的脆弱性。虽然疫苗接种仍然是用于控制流感感染的主要预防策略,但为了在新疫苗变得可用之前渡过一段时间并为了治疗严重流感病例以及为了应对病毒耐受性的问题,需要更广泛地选择抗流感药物。因此,开发新流感抗病毒药再次成为高度优先且未满足的医疗需求。
本发明涉及具有式(I)的化合物,该化合物可用于治疗或抵抗病毒性流感感染:
其立体异构形式、药学上可接受的盐、溶剂化物或多晶型物,其中
X选自-CF或N;
Y选自N、-CF、-C-Cl、-C-CN或-C-CH3;
R1选自-H、-CH3、-COOH、-CF3、-环丙基、-CONH2、-CONH(C1-3烷基)、或-CON(C1-3烷基)2;
Q选自N或O,并且
R2是任选地被卤素、氰基、C1-3烷基、羟基、氨基、甲氧基、-COOH、-CF3或环烷基取代的杂环。
根据本发明的优选化合物之一具有以下结构:
本发明的一部分还是药物组合物,该药物组合物包含具有式(I)的化合物或其立体异构形式、药学上可接受的盐、溶剂化物或多晶型物,连同一种或多种药学上可接受的赋形剂、稀释剂或载体。
该药物组合物还可以包括另外的治疗剂,像另一种抗病毒剂或流感疫苗或两者。
也属于本发明的是具有式(I)的化合物或其立体异构形式、药学上可接受的盐、溶剂化物或多晶型物或者药物组合物,用于用作药剂。
另外,本发明涉及式具有式(I)的化合物或其立体异构形式、药学上可接受的盐、溶剂化物或多晶型物或药物组合物,用于在治疗流感中使用。
所述用途还可以包括另外的治疗剂的共给予,其中所述另外的治疗剂选自抗病毒剂或流感疫苗或两者。
本发明的一部分是由以下结构式(I)表示的化合物
其立体异构形式、药学上可接受的盐、溶剂化物或多晶型物用于抑制生物样品或患者中的一种或多种流感病毒的复制的用途,其中
X选自-CF或N;
Y选自N、-CF、-C-Cl、-C-CN或-C-CH3;
R1选自-H、-CH3、-COOH、-CF3、-环丙基、-CONH2、-CONH(C1-3烷基)、或-CON(C1-3烷基)2;
Q选自N或O,并且
R2是任选地被卤素、氰基、C1-3烷基、羟基、氨基、甲氧基、-COOH、-CF3或环烷基取代的杂环。
术语“烷基”是指包含指定数目碳原子的直链或支链饱和脂肪族烃。
术语“环烷基”是指包含指定数目碳原子的碳环。
术语“杂环”是指包含一个或多个选自N、O或S,特别是选自N和O的杂原子的饱和或不饱和的分子。所述杂环可以具有4、5、6或7个环原子,并可任选地与另一个环系稠合。
具有式(I)的化合物的药学上可接受的盐包括其酸加成盐以及碱盐。合适的酸加成盐是从形成无毒盐的酸形成的。合适的碱盐是从形成无毒盐的碱形成的。
本发明的化合物还可以按非溶剂化的形式和溶剂化的形式存在。术语“溶剂化物”在此用以描述包含本发明的化合物以及一种或多种药学上可接受的溶剂分子(例如,乙醇)的分子复合物。
术语“多晶型物”是指本发明的化合物能够以多于一种的形式或晶体结构存在。
可以将本发明的化合物以晶态的或非晶态的产物给予。它们可以通过如沉淀、结晶、冷冻干燥、喷雾干燥或蒸发干燥等方法以例如固体填料、粉末或膜形式获得。它们可以单独给予或与一种或多种本发明的其他化合物组合给予或与一种或多种其他药物组合给予。通常,它们将作为与一种或多种药学上可接受的赋形剂相结合的配制品给予。术语“赋形剂”在此用以描述除本发明的一种或多种化合物之外的任何成分。赋形剂的选择大体上取决于如具体给予模式、赋形剂对溶解性和稳定性的影响以及剂型的性质等因素。
出于给予目的,本发明化合物或其任一亚组可配制成多种药物形式。作为适当的组合物,可能引用了所有经常用于全身性给药的组合物。为了制备本发明的药物组合物,将作为活性成分的有效量的具体化合物(任选地呈加成盐形式)与药学上可接受的载体组合在紧密混合物中,该载体取决于用于给予所希望的制剂的形式可以采用多种形式。令人希望地,这些药物组合物处于适合于例如口服、经直肠或经皮给予的单位剂型。例如,在制备处于口服剂型的组合物中,可以使用任何常见药物介质,在口服液体制剂(如悬浮液、糖浆剂、酏剂、乳液以及溶液)的情况下,例如像水、二醇类、油类、醇类等;或者在粉剂、丸剂、胶囊剂和片剂的情况下,固体载体诸如淀粉、糖、高岭土、稀释剂、润滑剂、粘合剂、崩解剂等。片剂和胶囊剂由于其给予简易性而代表了最有利的口服单位剂型,在该情况下显然采用固体药物载体。还包括在使用之前不久可以被转变为液体形式的固体形式制剂。在适合于经皮给予的组合物中,该载体任选地包括渗透增强剂和/或适合的润湿剂,任选地与小比例的具有任何性质的适合添加剂组合,这些添加剂并不在皮肤上引入显著的有害作用。所述添加剂可以促进对皮肤的给予和/或可以有助于制备所希望的组合物。能以不同方式给予这些组合物,例如,作为透皮贴剂、作为滴剂(spot-on)、作为软膏剂。还可以经由吸入或吹入借助于在本域中采用的用于经由此方式给予的方法和配制品来给予本发明的化合物。因此,通常,本发明的化合物能以溶液、悬浮液或干燥粉剂的形式而给予至肺部。
为了便于给药和剂量的均一性,将上述药物组合物配制成单位剂型是特别有利的。如在此所用的单位剂型是指适合作为单位剂量的物理离散单位,各单位含有预定量的活性成分,该预定量的活性成分经计算与所需药物载体相结合而产生所希望的治疗效果。此类单位剂型的实例是片剂(包括刻痕或包衣的片剂)、胶囊剂、丸剂、粉末包(powderpacket)、糯米纸囊剂(wafer)、栓剂、可注射溶液或悬浮液等,及其分离的多个。
在感染性疾病治疗领域中的普通技术人员将能够从下文所呈现的测试结果来确定有效量。通常,预期每日有效量将为从0.01mg/kg至50mg/kg体重,更优选从0.1mg/kg至10mg/kg体重。可适当地在全天以适宜间隔以两个、三个、四个或更多个子剂量给予所需剂量。所述子剂量可配制成单位剂型,例如每单位剂型含有1mg至1000mg,且具体来说5mg至200mg的活性成分。
如本领域的普通技术人员所熟知的,给予的精确剂量和频率取决于所使用的具有式(I)的具体化合物、正在被治疗的具体病状、正在被治疗的病状的严重性、具体患者的年龄、体重和总体身体状况以及个体可能服用的其他药物。此外,显然有效量可以降低或提高,这取决于所治疗的受试者的响应和/或取决于给出本发明化合物处方的医生的评估。因此,上文所述的有效量范围仅为指导且并不打算在任何程度上限制本发明的范围或使用。
本披露还旨在包括存在于本发明的化合物中的原子的任何同位素。例如,氢的同位素包括氚和氘,并且碳的同位素包括C-13和C-14。
用于本发明中的这些化合物还能以其立体化学异构形式存在,从而定义由相同键序列键合的相同原子组成但具有不可互换的不同三维结构的所有可能的化合物。除非另外提及或指明,化合物的化学命名涵盖所述化合物可以具有的所有可能的立体化学异构形式的混合物。
所述混合物可以包含所述化合物的基本分子结构的所有非对映异构体和/或对映异构体。用于本发明中的处于纯形式的或彼此混合的化合物的所有立体化学异构形式旨在被涵盖于本发明的范围内,包括任何外消旋混合物或外消旋体。
在此提到的化合物和中间体的纯的立体异构形式被定义为基本上不具有所述化合物或中间体的相同基本分子结构的其他对映异构或非对映异构形式的异构体。具体地说,术语“立体异构纯”涉及具有至少80%立体异构过量(即,最少90%的一种异构体和最大10%的其他可能的异构体)至100%立体异构过量(即,100%的一种异构体并且没有其他异构体)的化合物或中间体,更具体地具有90%至100%立体异构过量,甚至更具体地具有94%至100%立体异构过量并且最具体地具有97%至100%立体异构过量的化合物或中间体。应当以类似的方式理解术语“对映异构纯”和“非对映异构纯”,但是讨论中的分别是关于混合物中的对映异构过量以及非对映异构过量。
可以通过领域已知的程序的应用来获得用于本发明中的化合物和中间体的纯的立体异构形式。例如,对映异构体可以通过用光学活性酸或碱使它们的非对映异构盐进行选择性结晶而得以彼此分离。它们的实例是酒石酸、二苯甲酰基酒石酸、二甲苯甲酰基酒石酸以及樟脑磺酸。可替代地,可以通过使用手性固定相的层析技术分离对映异构体。所述纯的立体化学异构形式还可以衍生自适当起始材料的相对应的纯的立体化学异构形式,条件是反应立体特异性地发生。优选地,如果一种具体的立体异构体是所希望的,那么所述化合物将通过立体专一的制备方法得以合成。这些方法将有利地使用对映异构纯的起始材料。
实例
方案1.
3的制备。
方案1:i)TBAHS、NaOH、甲苯ii)NBS、DMF iii)4,4,4',4',5,5,5',5'-八甲基-2,2'-双-1,3,2-二氧杂硼杂环戊烷、Pd(dppf)Cl2、KOAc、1,4-二噁烷,90℃
方案2.朝向具有式(I)的产物的一般方案。
10的制备。
方案2:i)PhCH2OH、DPPA、Et3N、甲苯,100℃,12h ii)HCl、CH2Cl2、CH3OH,室温,48hiii)DIPEA、CH3OH、THF,室温,12h iv)Na2CO3、Pd(PPh3)4、H2O、1,4-二噁烷,80℃,12h v)Pd/C、H2、THF vi)DIPEA、CH3OH、THF,80-90℃,2d vii)LiOH、1,4-二噁烷、H2O,回流
1的制备
在氮气下,搅拌5,7-二氟-1H-吲哚(30g,195.91mmol)于甲苯(500mL)中的溶液。添加TBAHS(5g,14.7mmol),随后添加NaOH(50%在H2O中)(105mL),并将混合物剧烈搅拌。添加对甲苯磺酰氯(63.5g,333.mmol)并将混合物在室温下搅拌12小时。将所得溶液用250mL甲苯稀释并且用水洗涤两次。将有机层经MgSO4干燥,通过过滤去除固体,并且将滤液中的溶剂在减压下去除。将粗产物在甲醇中研磨并在室温下搅拌12小时。将沉淀物通过过滤收集并在真空中干燥,从而产生5,7-二氟-1-甲苯磺酰基-1H-吲哚1。
2的制备
向5,7-二氟-1-甲苯磺酰基-1H-吲哚1(50.85g,165.46mmol)于DMF(330mL)中的溶液中分批添加NBS(35.34g,198.56mmol)。在50℃继续搅拌一小时。将混合物逐滴添加至NaOH(1N,200mL)于冰水(1L)中的搅拌溶液中并搅拌过夜。将沉淀物通过过滤收集并在真空中干燥,从而产生3-溴-5,7-二氟-1-甲苯磺酰基-1H-吲哚2。
3的制备
在N2下,将3-溴-5,7-二氟-1-甲苯磺酰基-1H-吲哚2(60g,155.35mmol)、4,4,4',4',5,5,5',5'-八甲基-2,2'-二-1,3,2-二氧杂环戊硼烷(118.35g,466.06mmol)、Pd(dppf)Cl2(22.74g,31.07mmol)和KOAc(45.74g,466.06mmol)于1,4-二噁烷(1.5L)中的混合物加热至90℃过夜。过滤并浓缩后,将粗品使用CH2Cl2至庚烷的梯度通过硅胶层析进行纯化。合并含有纯产物的级分,并在减压下去除溶剂,从而产生5,7-二氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1-甲苯磺酰基-1H-吲哚3。
4的制备
将三乙胺(35mL,251.6mmol)和二苯基磷酰基叠氮化物(39mL,181mmol)添加到顺式-3-[(叔丁氧基羰基)氨基]环己烷甲酸(39g,160.25mmol)在甲苯(600mL)中的搅拌溶液中,并将所得混合物在室温下搅拌3小时。添加苯甲醇(33.167mL,320.51mmol),并将混合物加热至100℃。12小时后,将该反应混合物冷却至室温,用EtOAc稀释,用盐水洗涤,干燥(Na2SO4),通过过滤去除固体并且将滤液在真空中浓缩。经正相手性分离(固定相:DaicelChiralpak AD 2kg,流动相:梯度从80%庚烷、20%乙醇至80%庚烷、20%乙醇)进行纯化,以提供(+)苄基叔丁基((顺式)-环己烷-1,3-二基)二氨基甲酸酯,[α]D 20+10.9(c 0.52,DMF)4b和(-)-苄基叔丁基((顺式)-环己烷-1,3-二基)二氨基甲酸酯,[α]D 20-10.9(c 0.47,DMF)4a。
5的制备
向配备有磁力搅拌棒的500mL圆底烧瓶中添加4a(10g,28.7mmol)、CH2Cl2(100mL)和甲醇(100mL)。缓慢添加于异丙醇中的6M HCL,同时在室温下搅拌48小时。将溶剂在减压下去除并将粗品在含有异丙醇的二异丙基醚中搅拌。将白色沉淀物通过过滤分离并在真空中干燥,从而产生(-)5。1H NMR(360MHz,DMSO-d6)δppm 1.01-1.13(m,1H)1.16-1.36(m,3H)1.66-1.80(m,2H)1.86-1.99(m,1H)2.14(m,1H)2.95-3.17(m,1H)3.28-3.51(m,1H)4.95-5.08(m,2H)7.27-7.45(m,5H)8.21(s,3H)。LC-MS ES+m/z=249.3;Rt:1.48min,方法C
6的制备
将5(40g,140.46mmol)和N,N-二异丙基乙胺(DIPEA,72.61mL,421.37mmol)的溶液在室温下在CH3OH(100mL)和THF(400mL)中搅拌。将2,4-二氯-5-氟嘧啶(23.5g,141mmol)分批加入到反应混合物中。允许将反应混合物在室温下搅拌18小时。将溶剂蒸发,溶解在乙酸乙酯中,并用水和盐水洗涤。将有机层经MgSO4干燥,通过过滤去除固体,并且将滤液中的溶剂在减压下去除。将残余物在含有约5%乙腈的二异丙基醚中在搅拌过周末时结晶。通过过滤收集晶体并在真空中干燥,从而产生6。1H NMR(DMSO-d6)δ:7.99-8.14(m,2H),7.24-7.45(m,6H),5.01(s,2H),3.82-3.99(m,1H),1.99(m,1H),1.67-1.85(m,3H),1.17-1.44(m,3H),1.00-1.15(m,1H)。LC-MS ES+m/z=379.2;Rt:1.94min,方法C。
7的制备
在装有磁力搅拌棒的250mL圆底烧瓶中放入3(5g,11.54mmol)、6(3.64g,9.62mmol)和Na2CO3(1.70g,16.03mmol)在水(10mL)中的混合物中,并用N2气流将1,4-二噁烷(80mL)脱气10分钟。添加Pd(PPh3)4(463mg,0.40mmol),并将混合物在80℃加热12小时。将该混合物在减压下浓缩,并溶解于CH2Cl2中。过滤除去沉淀物并将滤液使用CH2Cl2至CH2Cl2/CH3OH梯度通过硅胶柱层析进行纯化。将最好的级分的溶剂在减压下去除以提供7。LC-MSES+m/z=650.2;Rt:2.55min,方法C。
8的制备
在N2下,将Pd/C(10%)(2.90mg,2.71mmol)添加至CH3OH(240mL)和THF(240mL)的混合物中。之后,添加(-)-7(11.75mg,18.09mmol),并将反应混合物在H2下在室温下搅拌直至1当量氢气被消耗。将该催化剂通过硅藻土过滤除去。将滤液在减压下浓缩。将粗品溶解于CH2Cl2中并用在异丙醇中的6N HCl处理。将沉淀物在真空中干燥以提供8。LC-MS ES+m/z=516.1;Rt:2.10min,方法C。
9的制备
将8(250mg,0.49mmol)和DIPEA(0.25mL,1.46mmol)于甲醇(1mL)中的溶液在室温下搅拌。将4-氯-2-甲基嘧啶(62mg,0.49mmol)分批添加至反应混合物中并在80℃下搅拌18小时。添加额外当量的4-氯-2-甲基嘧啶(62mg,0.49mmol),并将整个混合物在90℃加热24小时。将混合物蒸发,并将粗品9不经进一步纯化而用于下一步骤。LC-MS ES+m/z=607.7;Rt:2.38min,方法D。
10的制备
在60℃下,在100mL烧瓶中,将9(300mg,0.26mmol)在1,4-二噁烷(9mL)中搅拌,同时添加LiOH(62mg,2.61mmol)在水(1mL)中的溶液。将混合物回流1小时,并允许在环境温度下搅拌过夜。蒸发溶剂,并将残余物吸收于CH3OH(30mL)中,搅拌并用浓盐酸中和。通过制备型HPLC纯化溶液(固定相:RP XBridge制备型C18 OBD-5μm,30x250mm,流动相:在水中的0.25%NH4HCO3溶液,CH3OH)。收集所希望的级分并蒸发至干燥。在添加CH3OH后,将溶液进行第二次浓缩以提供10。1H NMR(400MHz,DMSO-d6)δppm 1.14-1.42(m,3H)1.48-1.59(m,1H)1.80-1.92(m,1H)1.94-2.09(m,2H)2.24(s,3H)2.26-2.31(m,1H)4.05-4.30(m,2H)6.22-6.30(m,1H)7.02-7.08(m,1H)7.20(m,1H)7.50(m,1H)7.88(m,1H)8.04(m,1H)8.12-8.17(m,2H)12.17(s,1H)。LC-MS ES+m/z=453.8;Rt:1.86min,方法D
13的制备
将8(65mg,0.40mmol)分配在10mL DMF中,添加DBU(0.12mL,0.81mmol)和PYBOP(252mg,0.49mmol)。将混合物在室温下搅拌直至获得均匀溶液。添加2-氨基喹唑啉-4-醇(250mg,0.49mmol)并且将该反应混合物在室温下搅拌16小时。添加额外当量的DBU、PYBOP和2-氨基喹唑啉-4-醇,并将整个混合物在环境温度下搅拌过周末。蒸发溶剂,通过制备型HPLC纯化粗品(固定相:RP XBridge制备型C18 OBD-5μm,30x250mm,流动相:在水中的0.25%NH4HCO3溶液,CH3OH)。收集所希望的级分并蒸发至干燥。在添加CH3OH后,将溶液进行第二次浓缩以提供13。LC-MS ES+m/z=505.5;Rt:1.80min,方法D
17的制备
根据制备9的方法制备17。LC-MS ES+m/z=627.9;Rt:1.82min,方法C。
18的制备
在N2下,将Pd/C(10%)(0.02g,0.18mmol)添加至CH3OH(5mL)的混合物中。之后,添加17(183mg,0.29mmol),并将反应混合物在H2下在室温下搅拌直至1当量的H2被消耗。将该催化剂通过硅藻土过滤除去。将滤液在减压下浓缩。将溶剂蒸发并且通过制备型HPLC纯化粗品,该HPLC为从50%[25mM NH4HCO3]-50%[MeCN:CH3OH 1:1]至25%[25mM NH4HCO3]-75%[MeCN:CH3OH 1:1]。收集所希望的级分并蒸发至干燥。在添加CH3OH后,将溶液进行第二次浓缩以提供18。1H NMR(300MHz,甲醇-d4)δppm 1.23-1.55(m,3H)1.59-1.82(m,1H)1.89-2.64(m,4H)3.96-4.19(m,1H)4.26-4.39(m,1H)6.47(br d,J=6.0Hz,1H)6.76-6.86(m,1H)7.89-8.00(m,2H)8.04-8.11(m,2H)8.31(s,1H)。LC-MS ES+m/z=440.1;Rt:1.98min,方法C
20的制备
将在ACN(2mL)中的8(76mg,0.21mmol)、6-氯嘧啶-4-羧酸(0.05g,0.31mmol)和TEA(0.06mL,0.421mmol)的混合物在100℃下搅拌12小时。在3天的时间内重复添加6-氯嘧啶-4-羧酸(0.05g,0.315mmol)三次,并在100℃下加热。蒸发溶剂,并通过反相制备型HPLC纯化粗品。将所希望的级分收集并蒸发至干燥,以提供20。1H NMR(300MHz,甲醇-d4)δppm 1.24-1.73(m,4H)1.90-2.52(m,4H)3.97-4.21(m,1H)4.23-4.45(m,1H)6.66-6.93(m,1H)7.04(s,1H)7.99(d,J=4.1Hz,1H)8.04(br d,J=12.1Hz,1H)8.08(s,1H)8.21(s,1H)。LC-MS ES+m/z=483.9;Rt:2.10min,方法C
21的制备
将5-溴-7-氟-1H-吲哚(4g,18.68mmol)、氰化锌(1.31g,11.21mmol)、Pd2(dba)3(0.86g,0.93mmol)、Zn(0.31g,4.67mmol)和dppf(1.04g,1.87mmol)的混合物溶解在DMA(60mL)中并在N2下回流12小时。将混合物冷却到室温,过滤并且将滤液在真空中浓缩。将粗品用EtOAc萃取,并将合并的有机层用盐水进行洗涤,经MgSO4干燥,将固体通过过滤去除,并将滤液中的溶剂在减压下去除。将粗品使用正-庚烷至乙酸乙酯的梯度通过二氧化硅柱层析进行纯化。收集所希望的级分并在减压下浓缩,从而得到21。LC-MS ES+m/z=161.0;Rt:0.579min,方法C。
22的制备
将21(1.9g,11.86mmol)添加至甲苯(30mL)中,同时在氮气流下搅拌。然后,添加TBAHS(402mg,1.19mmol),随后添加NaOH(10%在H2O中)(10mL),并将混合物剧烈搅拌。添加对甲苯磺酰氯(3.39g,17.80mmol)在甲苯(30mL)中的溶液,并将全部混合物在室温下搅拌12小时。在减压下去除溶剂并添加乙酸乙酯。将有机层用水洗涤,经MgSO4干燥,将固体通过过滤去除,并将滤液中的溶剂在减压下去除。将得到的粗品使用正庚烷至EtOAc的梯度通过硅胶层析进行纯化。将包含纯产物的级分进行合并,并且将溶剂在减压下去除以产生22。LC-MS ES+m/z=315.0;Rt:1.01min,方法C。
23的制备
在0℃下,向在CH2Cl2(15mL)中的22(1.7mg,5.41mmol)的溶液中逐滴添加溴(0.33mL,6.49mmol)。将混合物在0℃下搅拌30分钟,并且然后在室温下再搅拌一小时。将反应混合物用饱和NaHCO3水溶液处理。将有机层进行分离,并用水性Na2S2O3、水和盐水洗涤,经MgSO4进行干燥,通过过滤除去固体,并且在减压下除去滤液中的溶剂,得到23,将其不经进一步纯化而用于下一步骤。LC-MS ES+m/z=394.0;Rt:1.15min,方法C。
24的制备
将溶剂1,4-二噁烷(10mL)脱气十分钟。在室温下在惰性气氛下添加23(1.10g,2.80mmol)、双(频哪醇并)二硼(2.13g,8.39mmol)、Pd(dppf)Cl2(204mg,0.28mmol)和KOAc(1.24g,12.59mmol)。将混合物在80℃加热并搅拌16小时。将得到的混合物冷却至室温,通过硅藻土垫过滤并用EtOAc洗涤。过滤并浓缩后,将粗品使用正庚烷至EtOAc的梯度通过硅胶层析进行纯化。将包含纯产物的级分进行合并,并且将溶剂在减压下去除以产生24。
25的制备
在氮气下,将Pd/C(10%)(3.05g,2.87mmol)添加至CH3OH(350mL)中。添加4(10g;28.70mmol)。该反应混合物在室温下在H2下搅拌直到吸收1当量的H2。在N2流下将该催化剂通过硅藻土过滤去除。将滤液在减压下浓缩以提供25,将其无需纯化即可进一步使用。
26的制备
将25(6.15g,28.70mmol)、2,4-二氯-5-氟-嘧啶(4.79g,28.70mmol)、DIPEA(29.7mL,172.2mmol)在EtOH(130mL)和THF(130mL)中的混合物在70℃下搅拌并加热17小时。将该反应混合物的溶剂在减压下进行蒸发。将所得残余物吸收于水中,用EtOAc萃取两次。将合并的有机层用水洗涤,经MgSO4干燥,通过过滤去除固体,并且将滤液中的溶剂在减压下去除。将所得粗品使用CH2Cl2至CH2Cl2/CH3OH梯度通过硅胶层析进行纯化。将包含纯产物的级分进行合并,并且将溶剂在减压下去除以产生26。LC-MS ES+m/z=345.0;Rt:1.97min,方法C。
27的制备
将24(1.10mg,2.50mmol)、26(0.86mg,2.50mmol)、Pd(dppf)Cl2(162mg,0.25mmol)和KOAc(1.59g,7.50mmol)在1,4-二噁烷(3mL)和H2O(0.3mL)中的混合物在微波辐射下加热至100℃持续30分钟。将该反应混合物经硅藻土过滤并且浓缩。然后,将混合物溶解在CH2Cl2中并用水洗涤。将有机层经MgSO4干燥,通过过滤去除固体,并且将滤液中的溶剂在减压下去除。将粗品使用正庚烷至EtOAc梯度通过硅胶层析进行纯化。将包含纯产物的级分进行合并,并且将溶剂在减压下去除以产生27。LC-MS ES+m/z=623;Rt:1.34min,方法C。
28的制备
将27(400mg,0.64mmol)溶解于1,4-二噁烷(2.5mL),并且然后缓慢添加在1,4-二噁烷(2.41mL,9.64mmol)中的4M HCl。将所得混合物在60℃下搅拌过夜。然后,将该反应混合物蒸发至干,通过添加饱和的NaHCO3水溶液进行淬灭,并用CH2Cl2进行萃取。将有机层用MgSO4干燥,通过过滤除去固体,并且在减压下去除滤液中的溶剂,以提供28,将其不经纯化而用于下一步骤。LC-MS ES+m/z=523;Rt:0.89min,方法C。
29的制备
将在ACN(5mL)中的28(0.2g,0.38mmol)、2,4-二氯嘧啶(0.10g,0.70mmol)和DIPEA(0.2mL,1.15mmol)的混合物在120℃下搅拌12小时。将反应混合物的溶剂在减压下去除,并将粗产物用CH2Cl2萃取并用H2O洗涤。将有机层用MgSO4干燥,通过过滤除去固体,并且在减压下去除滤液中的溶剂,以提供29,将其不经进一步纯化而用于下一步骤。LC-MS ES+m/z=634.9;Rt:1.78min,方法C。
30的制备
根据制备19的方法制备30。1H NMR(300MHz,甲醇-d4)δppm 1.29-1.49(m,3H)1.66-1.84(m,1H)1.93-2.16(m,2H)2.19-2.30(m,1H)2.49-2.61(m,1H)3.96-4.18(m,1H)4.19-4.37(m,1H)6.42-6.53(m,1H)7.24-7.32(m,1H)7.87-7.95(m,1H)7.97-8.03(m,1H)8.15-8.24(m,2H)8.82(s,1H)。LC-MS ES+m/z=446.7;Rt:2.05min,方法C。
31的制备
根据制备6的方法制备31。LC-MS ES+m/z=393.2;Rt:2.02min,方法C。
32的制备
根据制备7的方法制备32。LC-MS ES+m/z=664.3;Rt:1.05min,方法A。
33的制备
根据制备8的方法制备33。LC-MS ES+m/z=496.2;Rt:0.89min,方法A。
34的制备
向配备有磁力搅拌棒并用氮气鼓泡的20mL试管中放置33(350mg,0.66mmol)、ACN(7mL)、DIPEA(0.29mL,1.65mmol)和2,4-二氯-6-(三氟甲基)嘧啶(150.6mg,0.70mmol)。将该烧瓶密封,并且将混合物在75℃下搅拌18小时。将含有34的粗品溶液不经进一步纯化用于下一步骤中。LC-MS ES+m/z=710.3;Rt:2.65min,方法C。
35的制备
向含有34的粗反应混合物中添加1,4-二噁烷(8mL),水(1mL)和LiOH(10当量)。将混合物加热至60℃并搅拌2天。在减压下去除溶剂之前,将该溶液用浓HCl中和。将该粗品经制备型HPLC纯化(固定相:RPXBridge制备型C18 OBD 5μm,30x250mm,流动相:在水中的0.25%NH4HCO3溶液,CH3OH)。收集所希望的级分并蒸发至干燥。在添加CH3OH后,将溶液进行第二次浓缩以提供35。LC-MS ES+m/z=556.2;Rt:2.31min,方法C。
43的制备
向配备有磁力搅拌棒并用氮气鼓泡的20mL试管中放置(-)33(0.3g,0.465mmol)、ACN(5mL)、DIPEA(0.24mL,1.39mmol)和2,4-二氯-5-氰基嘧啶(162mg,0.93mmol)。将该烧瓶密封,并且将混合物在70℃下搅拌18小时。将溶剂在减压下去除,并通过硅胶层析法(流动相梯度为从庚烷/AcOEt 75/25到50/50)纯化粗品,得到240mg白色固体,2-氯-4-(((顺)-3-((2-(5,7-二氟-1-对甲苯磺酰基-1H-吲哚-3-基)-5-氟-6-甲基嘧啶-4-基)氨基)环己基)氨基)嘧啶-5-甲腈。向该白色固体中添加水(0.54mL),LiOH(0.72g,3.0mmol)和THF(1.6mL)。在60℃下将混合物搅拌72h。添加乙酸乙酯,并将混合物用盐水洗涤,经MgSO4干燥,将固体通过过滤去除,并将滤液中的溶剂在减压下去除。通过硅胶层析法(流动相梯度为从CH2Cl2/CH3OH 98/2至94/6)纯化粗产物。将纯级分合并,并将溶剂在减压下去除。将得到的白色固体在醚中研磨,然后通过过滤分离,以得到白色固体,43。[α]D 20-219.2(c 0.25,DMF)。
48的制备
将DBU(2.58mL,17.2mmol)添加至5-氟乳清酸(3g,17.2mmol)于DMF(10mL)中的溶液中。搅拌30分钟后,向溶液中添加碘乙烷(2.69mg,17.2mmol),并将混合物加热至60℃保持2小时。将水(100ml)添加至混合物中,并将所得沉淀物通过过滤收集,用水洗涤,并干燥以给出485-氟乳清酸乙酯。LC-MS ES-m/z=200.9;Rt:0.91min,方法D。
49的制备
在90℃下,将5-氟乳清酸乙酯48(2.13g,10.54mmol)添加至N,N-二乙基苯胺(1.09mL,7.16mmol)和POCl3(2.64mL,28.45mmol)的混合物中并将混合物回流持续4小时。将溶液倾倒于冰水中,并且然后添加碳酸氢钠到pH 8。将反应混合物用乙酸乙酯萃取并用5%水性硫酸氢钾和盐水洗涤。将有机层经硫酸钠干燥并在真空中浓缩。将粗品使用正-庚烷至正庚烷/EtOAc(8/2)梯度通过硅胶柱层析进行纯化。合并所希望的级分并蒸发至干燥以提供492,6-二氯-5-氟嘧啶-4-甲酸乙酯。
50的制备
根据制备34的方法制备50。LC-MS ES+m/z=451.2;Rt:1.09min,方法A
51的制备
根据制备32的方法制备51。LC-MS ES+m/z=722.4;Rt:2.56min,方法B
52的制备
在室温下,在250mL烧瓶中,将51(1g,1.56mmol)在1,4-二噁烷(45mL)中搅拌,同时添加LiOH(374mg,15.63mmol)在水(5mL)中的溶液。将混合物在80℃和90℃之间加热约4小时。将反应混合物用37%HCl中和并将溶剂在减压下去除。将水层用EtOAc萃取,经MgSO4干燥,将固体通过过滤去除,并将滤液中的溶剂在减压下去除以提供52。LC-MS ES+m/z=540.2;Rt:0.83min,方法A
53的制备
在N2下,将Pd/C(10%)(172mg,0.16mmol)添加至CH3OH(15mL)和THF(15mL)的混合物中。之后,添加52(580mg,1.08mmol),并将反应混合物在H2气氛下在室温下搅拌直至1个当量H2被消耗。将催化剂通过经由硅藻土的过滤去除。将滤液在减压下浓缩以提供53。LC-MS ES+m/z=406.3;Rt:1.03min,方法B。
54的制备
根据制备34的方法制备54。1H NMR(400MHz,DMSO-d6)δppm 1.07-1.63(m,4H)1.93(m,3H)2.14(s,3H)2.17-2.26(m,1H)3.86-4.04(m,1H)4.12-4.30(m,1H)6.22(br s,1H)6.96-7.14(m,1H)7.54-7.69(m,1H)7.75(br s,1H)8.06(br d,J=11.9Hz,1H)8.18(s,1H)12.18(br s,1H)LC-MS ES+m/z=532.1;Rt:1.41min,方法B。
55的制备
在0℃下,向7H-吡咯并[2,3-d]嘧啶(11.5g,73.92mmol)于DMF(350mL)的搅拌溶液中添加溴(11.8g,73.84mmol)于DMF(50mL)中的溶液。除去冷却浴,并且将反应在20℃下搅拌8小时,然后将反应混合物倾倒于冰水中并用Na2CO3进行碱化。将混合物用乙酸乙酯萃取。将合并的有机层用10%Na2S2O3水溶液、盐水洗涤,经MgSO4干燥,通过过滤去除固体,并将滤液在减压下浓缩,以提供呈黄色固体的555-溴-7H-吡咯并[2,3-d]嘧啶,将其不经进一步纯化而用于下一步骤。1H NMR(400MHz,DMSO-d6)δppm 7.84(s,1H),8.84(s,1H),8.92(s,1H),12.57(br,1H)。
56的制备
在0℃下在氮气下,向5-溴-7H-吡咯并[2,3-d]嘧啶(12.8g,55.11mmol)在THF中的搅拌溶液中分批添加NaH(4.48g,112.01mmol)。将混合物在5℃下搅拌1小时,然后分批添加对甲苯磺酰氯(11.6g,60.85mmol)。允许将反应混合物加温至20℃并搅拌3小时。在搅拌的同时,将反应混合物倒入冰和1M水性HCl的混合物中。将混合物用乙酸乙酯萃取。将合并的有机层用盐水洗涤,经MgSO4干燥,通过过滤去除固体并将滤液在减压下浓缩。通过从乙酸乙酯中结晶来纯化粗品,以提供呈白色固体的565-溴-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶。1H NMR(400MHz,DMSO-d6)δppm 2.36(s,3H),7.47(d,J=8.0Hz,2H),8.06(d,J=8.0Hz,2H),8.31(s,1H),9.03(s,1H),9.06(s,1H)。LC-MS ES+m/z=351.8;Rt:2.02min,方法D。
57的制备
在氮气下在80℃下,将5-溴-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶(10g,28.39mmol)、双(频哪醇并)二硼(14.42g,56.79mmol)、乙酸钾(8.36g,85.18mmol)、Pd(dppf)Cl2(1g,1.37mmol)于1,4-二噁烷(170mL,用氮气脱气)中的混合物在配备有回流冷凝器的500mL圆底烧瓶中加热16小时。将反应混合物冷却至室温,通过填充硅藻土过滤,并将固体用乙酸乙酯漂洗。将滤液在减压下浓缩,并将粗品使用正-庚烷至乙酸乙酯的梯度通过二氧化硅柱层析进行纯化。收集所需的级分,并在减压下进行浓缩,以提供57,5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶。1H NMR(400MHz,DMSO-d6)δppm 1.33(s,12H)2.37(s,3H)7.47(d,J=8.36Hz,2H)8.11(d,J=8.58Hz,2H)8.14(s,1H)9.00(s,1H)9.10(s,1H)。LC-MS ES+m/z=318.1;Rt:0.74min,方法A。
58的制备
在密封管中,将57(1.525g,3.82mmol)、31(1.6g,4.07mmol)、和K2CO3(5.73mL,2M,11.46mmol)于DME(24mL)中的溶液用N2吹扫5分钟并且然后添加Pd(dppf)Cl2.CH2Cl2(313mg,0.38mmol)。将混合物搅拌并在高压釜中在110℃加热60分钟,然后经硅藻土过滤,并将滤液在减压下浓缩。将粗品使用正庚烷至25%EtOAc于正-庚烷中的梯度通过二氧化硅柱层析进行纯化。将最好的级分的溶剂在减压下去除以提供58。LC-MS ES+m/z=630.2;Rt:1.28min,方法A
59的制备
在N2下,将Pd/C(10%)(173mg,0.16mmol)添加至CH3OH(15mL)和THF(15mL)的混合物中。之后,添加58(410mg,0.65mmol)并将反应混合物在H2下在室温下搅拌直至1当量H2被消耗。将该催化剂通过硅藻土过滤除去。将滤液在减压下浓缩。将粗品溶解于CH2Cl2中,并用在IPA中的6N HCl的混合物处理。通过过滤分离形成的沉淀物,然后在真空中干燥,以提供59。LC-MS ES+m/z=496.2;Rt:0.89min,方法A。
60和61的制备
将2,4-二氯-6-甲基嘧啶(303mg,1.86mmol)和DIPEA(0.53mL,3.10mmol)于DMF(15mL)中的溶液在室温下在氮气下搅拌。然后添加59(330mg,0.62mmol)并在60℃下继续搅拌四小时。将混合物倾倒进冰水中并且搅拌过夜。通过过滤收集沉淀物,并在真空中干燥,以提供60和61的混合物。
62和63的制备
在N2气氛下,将Pd/C(10%)(102mg,0.10mmol)添加至CH3OH(30mL)和THF(15mL)的混合物中。之后,添加60和61(240mg,0.39mmol)的混合物,并将反应混合物在H2下在室温下搅拌直至1当量氢气被消耗。将该催化剂通过硅藻土过滤除去。将滤液在减压下浓缩,得到62和63的混合物。
64和65的制备
在85℃下,在100mL烧瓶中,将62和63的混合物(110mg,0.19mmol)在1,4-二噁烷(18mL)中搅拌,同时添加LiOH(90mg,3.74mmol)在水(2mL)中的溶液。将混合物回流1小时,并允许在环境温度下搅拌过夜。蒸发1,4-二噁烷并将粗品在乙酸乙酯(20mL)中重构,搅拌并用浓HCl中和。将溶剂在减压下去除。将该粗品经制备型HPLC纯化(固定相:RPXBridge制备型C18 OBD 5μm,30x250mm,流动相:0.25%NH4HCO3水溶液,CH3CN)进行纯化。收集希望的级分并蒸发至干燥以提供64。1H NMR(400MHz,DMSO-d6)δppm 1.10-1.45(m,3H)1.50-1.59(m,1H)1.81-1.92(m,1H)1.93-2.07(m,2H)2.16(s,3H)2.29-2.37(m,1H)2.33(d,J=3.2Hz,3H)3.84-4.03(m,1H)4.07-4.31(m,1H)6.33(s,1H)7.00(br d,J=7.3Hz,1H)7.12-7.33(m,1H)8.09(s,1H)8.29(s,1H)8.78(s,1H)9.66(s,1H)12.19(br s,1H)。LC-MS ES+m/z=434.3;Rt:0.72分钟,方法A。以及651H NMR(400MHz,DMSO-d6)δppm 1.15-1.43(m,3H)1.43-1.57(m,1H)1.81-1.88(m,1H)1.90-2.01(m,2H)2.17(s,3H)2.27(m,1H)2.33(d,J=2.9Hz,3H)3.84-4.00(m,1H)4.08-4.22(m,1H)6.39(d,J=5.0Hz,1H)7.00(br d,J=7.7Hz,1H)7.36(m,1H)8.08(d,J=5.0Hz,1H)8.14(s,1H)8.80(s,1H)9.66(s,1H)。LC-MS ES+m/z=434.3;Rt:1.64min,方法B。
66的制备
在适当干燥和惰性的条件下,在氮气气氛下,向(3-羟基环己基)氨基甲酸叔丁酯(3.0g,16.5mmol)在无水THF(20mL)中的混合物中滴加2,4-二氯-6-甲基嘧啶(2.781g,16.72mmol)。将反应混合物在室温下搅拌15-20分钟,然后在0℃下滴加叔丁醇钾。1小时后,用0℃的冷水淬灭反应,并且用EtOAc萃取水层并用盐水洗涤。将有机相干燥并浓缩,得到粗物质。将粗品使用正-庚烷至EtOAc的梯度通过二氧化硅柱层析进行纯化。将最好的级分的溶剂在减压下去除以提供66。LC-MS ES+m/z=342.2;Rt:2.14min,方法C
67的制备
在N2下,将Pd/C(10%)(934mg,0.88mmol)添加至THF(80mL)的混合物中。之后,添加66(3g,8.78mmol),并将反应混合物在H2下在常温下搅拌直至1当量氢气被消耗。将该催化剂通过硅藻土过滤除去。将滤液在减压下浓缩,得到67的混合物。LC-MS ES+m/z=308.2;Rt:0.96min,方法A
68的制备
向配备有磁力搅拌棒的100mL圆底烧瓶中添加在1,4-二噁烷(25mL)中的67(3g,9.76mmol)。缓慢添加在1,4-二噁烷(12mL)中的4M HCL,同时在室温下搅拌18小时。在减压下去除溶剂并将粗品68用于下一步骤。
69的制备
将2,4-二氯-5-氟-6-甲基嘧啶(0.78g,4.31mmol)和DIPEA(1.77mL,10.26mmol)于CH3CN(20mL)中的溶液在室温下在N2下搅拌。然后添加68(1g,4.10mmol),并在室温下继续搅拌16小时。将反应混合物在减压下浓缩,并将粗品使用正庚烷至乙酸乙酯的梯度通过二氧化硅柱层析进行纯化。收集所希望的级分并在减压下浓缩,从而得到69。
70的制备
根据制备7的方法制备70。LC-MS ES+m/z=623.2;Rt:2.73min,方法D。
71的制备
根据制备64的方法制备71。通过制备型SFC进行纯化(固定相:Chiralpak DiacelAD-H 20mm x 250mm,流动相:CO2,异丙醇+0.4%异丙胺),得到71。1H NMR(600MHz,DMSO-d6)δppm 1.33-1.42(m,1H)1.34-1.42(m,1H)1.51–1.59(m,2H)1.89(m,1H)2.03(m,1H)2.15(m,1H)2.27(m,1H)2.32(d,J=2.8Hz,3H)2.46–2.53(m,1H)4.20(m,1H)5.20(m,1H)6.76(s,1H)7.04(m,1H)7.34(d,1H)8.06(m,1H)8.14(s,1H)8.59(s,1H)12.18(br s,1H)。LC-MS ES+m/z=469.2;Rt:2.30min,方法D。分析型SFC-MS Rt:3.79min,m/z=469.1。(分析型SFC条件:固定相:Chiralpak Diacel AD-H4.6mm x 250mm,流动相A:CO2,B:EtOH+0.2%异丙胺,梯度:25%B保持4min,然后在1min内到50%B,保持2min。流速为5mL/min,并且柱温为40℃)。
表1.具有式(I)的化合物及相应的分析数据。根据上述方法或其类似方法制备化合物。Rt=以分钟计的保留时间
使用LC泵、二极管阵列(DAD)或UV检测器以及如在对应的方法中所指定的柱进行高效液相层析(HPLC)测量。如果必要的话,包括其他检测器(参见下文的方法表)。
将来自柱的流带入配置有大气压离子源的质谱仪(MS)。设置调谐参数(例如扫描范围、停留时间等)以便获得允许鉴别化合物的标称单一同位素分子量(MW)的离子是在技术人员的知识内。使用适当的软件进行数据采集。
通过其实验保留时间(Rt)和离子描述化合物。如果未在数据表中不同地指定,那么所报告的分子离子对应于[M+H]+(质子化的分子)和/或[M-H]-(去质子的分子)。在化合物不是直接可电离的情况下,指定加合物的类型(即[M+NH4]+、[M+HCOO]-等)。对于具有多种同位素模式的分子(Br、Cl等)来说,所报告的值是针对最低同位素质量获得的值。获得的所有结果均具有通常与所使用的方法相关的实验不确定性。
“SQD”单四极检测器,“RT”是指室温,“BEH”是指桥连的乙基硅氧烷/二氧化硅杂合体,“HSS”是指高强度二氧化硅,“DAD”是指二极管阵列检测器。以mL/min表示流量;以℃表示柱温(T);以分钟表示运行时间。
具有式(I)的化合物的生物活性
使用基于细胞的抗病毒测定来确定这些化合物的体外抗病毒活性。在该测定中,在存在或不存在这些化合物的情况下监测被甲型流感病毒/台湾/1/86(H1N1)感染的Madin-Darby犬肾(MDCK)细胞中的细胞病变效应(CPE)。使用回波液处理器(Labcyte公司,森尼维尔市,加利福尼亚州)经声滴喷射来填充白色384孔微量滴定测定板(格瑞纳(Greiner))。将二百纳升的化合物母液(100%DMSO)转移到测定板上。将MDCK细胞以25,000或6,000个细胞/孔的最终密度分配到平板上。然后分别以0.001或0.01的感染复数添加甲型流感/台湾/1/86(H1N1)病毒。这些孔每体积包含0.5%DMSO。每个测试中包括病毒感染的和假感染的对照。在37℃下在5%CO2中孵育这些平板。病毒暴露三天后,通过根据制造商的说明书使用ATPliteTM试剂盒(铂金埃尔默公司(PerkinElmer),扎芬特姆(Zaventem),比利时)测量ATP水平的降低来定量细胞病变效应。将IC50定义为50%抑制浓度。平行地,将化合物在白色384孔微量滴定板中孵育三天,并且通过根据制造商的说明书使用ATPliteTM试剂盒(铂金埃尔默公司,扎芬特姆,比利时)来测量细胞的ATP含量来确定MDCK细胞中的化合物的体外细胞毒性。细胞毒性报告为CC50,这是造成细胞活力降低50%的浓度。
表2.具有式(I)的化合物的生物活性。
Claims (8)
1.一种具有式(I)的化合物
其立体异构形式、药学上可接受的盐、溶剂化物或多晶型物,其中
X选自-CF或N;
Y选自N、-CF、-C-Cl、-C-CN或-C-CH3;
R1选自-H、-CH3、-COOH、-CF3、-环丙基、-CONH2、-CONH(C1-3烷基)或-CON(C1-3烷基)2;
Q选自N或O,并且
R2是任选地被卤素、氰基、C1-3烷基、羟基、氨基、甲氧基、-COOH、-CF3或环烷基取代的杂环。
2.根据权利要求1所述的化合物,该化合物具有以下结构式
3.一种药物组合物,该药物组合物包含根据权利要求1或权利要求2所述的具有式(I)的化合物或其立体异构形式、药学上可接受的盐、溶剂化物或多晶型物,连同一种或多种药学上可接受的赋形剂、稀释剂或载体。
4.根据权利要求1所述的具有式(I)的化合物或其立体异构形式、药学上可接受的盐、溶剂化物或多晶型物或根据权利要求3所述的药物组合物,用于用作药剂。
5.根据权利要求1所述的具有式(I)的化合物或其立体异构形式、药学上可接受的盐、溶剂化物或多晶型物或者根据权利要求3所述的药物组合物,用于在治疗流感中使用。
6.由以下结构式(I)表示的化合物
其立体异构形式、药学上可接受的盐、溶剂化物或多晶型物用于抑制生物样品或患者中的一种或多种流感病毒的复制的用途,其中
X选自-CF或N;
Y选自N、-CF、-C-Cl、-C-CN或-C-CH3;
R1选自-H、-CH3、-COOH、-CF3、-环丙基、-CONH2、-CONH(C1-3烷基)或-CON(C1-3烷基)2;
Q选自N或O,并且
R2是任选地被卤素、氰基、C1-3烷基、羟基、氨基、甲氧基、-COOH、-CF3或环烷基取代的杂环。
7.如权利要求6所述的用途,该用途进一步包括共同给予另外的治疗剂。
8.如权利要求7所述的用途,其中该另外的治疗剂选自抗病毒剂或流感疫苗或两者。
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JP (1) | JP6989509B2 (zh) |
KR (1) | KR20180100375A (zh) |
CN (1) | CN108473477B (zh) |
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Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
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RS55341B1 (sr) | 2009-06-17 | 2017-03-31 | Vertex Pharma | Inhibitori replikacije virusa gripa |
UA118010C2 (uk) | 2011-08-01 | 2018-11-12 | Вертекс Фармасьютікалз Інкорпорейтед | Інгібітори реплікації вірусів грипу |
WO2016183120A1 (en) | 2015-05-13 | 2016-11-17 | Vertex Pharmaceuticals Incorporated | Inhibitors of influenza viruses replication |
KR20180087290A (ko) | 2015-11-27 | 2018-08-01 | 얀센 사이언시즈 아일랜드 유씨 | 인플루엔자 바이러스 감염에서 사용하기 위한 복소환식 인돌 |
CA3010327A1 (en) * | 2016-01-20 | 2017-07-27 | Janssen Sciences Ireland Uc | Aryl substituted pyrimidines for use in influenza virus infection |
CN107759571B (zh) * | 2016-08-16 | 2021-03-02 | 广东东阳光药业有限公司 | 流感病毒复制抑制剂及其使用方法和用途 |
US10647693B2 (en) | 2016-08-30 | 2020-05-12 | North & South Brother Pharmacy Investment Company Limited | Inhibitors of influenza virus replication, application methods and uses thereof |
CN108218873B (zh) | 2016-12-15 | 2020-07-07 | 广东东阳光药业有限公司 | 流感病毒复制抑制剂及其用途 |
WO2018127096A1 (en) | 2017-01-05 | 2018-07-12 | Sunshine Lake Pharma Co., Ltd. | Inhibitors of influenza virus replication and uses thereof |
US10927118B2 (en) | 2017-03-02 | 2021-02-23 | Sunshine Lake Pharma Co., Ltd. | Inhibitors of influenza virus replication and uses thereof |
MA54758A (fr) | 2019-01-18 | 2022-04-27 | Astrazeneca Ab | Inhibiteurs de pcsk9 et leurs procédés d'utilisation |
Citations (2)
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WO2010148197A1 (en) * | 2009-06-17 | 2010-12-23 | Vertex Pharmaceuticals Incorporated | Inhibitors of influenza viruses replication |
WO2013184985A1 (en) * | 2012-06-08 | 2013-12-12 | Vertex Pharmaceuticals Incorporated | Inhibitors of influenza viruses replication |
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EP2532667A1 (en) | 2005-09-30 | 2012-12-12 | Vertex Pharmaceuticals Incorporated | Deazapurines useful as inhibitors of janus kinases |
CN101641349A (zh) * | 2007-02-08 | 2010-02-03 | 泰博特克药品有限公司 | 嘧啶取代的大环抑制剂 |
WO2012032065A1 (en) | 2010-09-08 | 2012-03-15 | Glaxo Group Limited | Indazole derivatives for use in the treatment of influenza virus infection |
CN103562205A (zh) | 2010-12-16 | 2014-02-05 | 沃泰克斯药物股份有限公司 | 流感病毒复制的抑制剂 |
RU2013132681A (ru) | 2010-12-16 | 2015-01-27 | Вертекс Фармасьютикалз Инкорпорейтед | Ингибиторы репликации вирусов гриппа |
EP2694484B1 (en) * | 2011-04-08 | 2018-07-18 | Janssen Sciences Ireland UC | Pyrimidine derivatives for the treatment of viral infections |
UA118010C2 (uk) | 2011-08-01 | 2018-11-12 | Вертекс Фармасьютікалз Інкорпорейтед | Інгібітори реплікації вірусів грипу |
PT2909195T (pt) * | 2012-10-16 | 2017-09-13 | Janssen Sciences Ireland Uc | Compostos antivirais de vsr |
US9598378B2 (en) * | 2013-02-21 | 2017-03-21 | Janssen Sciences Ireland Uc | 2-aminopyrimidine derivatives for the treatment of viral infections |
KR20180087290A (ko) | 2015-11-27 | 2018-08-01 | 얀센 사이언시즈 아일랜드 유씨 | 인플루엔자 바이러스 감염에서 사용하기 위한 복소환식 인돌 |
CA3010327A1 (en) * | 2016-01-20 | 2017-07-27 | Janssen Sciences Ireland Uc | Aryl substituted pyrimidines for use in influenza virus infection |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2010148197A1 (en) * | 2009-06-17 | 2010-12-23 | Vertex Pharmaceuticals Incorporated | Inhibitors of influenza viruses replication |
WO2013184985A1 (en) * | 2012-06-08 | 2013-12-12 | Vertex Pharmaceuticals Incorporated | Inhibitors of influenza viruses replication |
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MX2018008803A (es) | 2018-11-09 |
JP2019507119A (ja) | 2019-03-14 |
CL2018001960A1 (es) | 2018-08-31 |
ECSP18061667A (es) | 2018-10-31 |
US20200231577A1 (en) | 2020-07-23 |
US20190047989A1 (en) | 2019-02-14 |
JP6989509B2 (ja) | 2022-01-05 |
CO2018007669A2 (es) | 2018-08-10 |
BR112018014794A2 (pt) | 2018-12-11 |
US10611755B2 (en) | 2020-04-07 |
US11117887B2 (en) | 2021-09-14 |
CA3010327A1 (en) | 2017-07-27 |
EP3405466A1 (en) | 2018-11-28 |
EP3405466B1 (en) | 2020-11-18 |
DK3405466T3 (da) | 2021-02-01 |
HUE053078T2 (hu) | 2021-06-28 |
EA201891666A1 (ru) | 2019-01-31 |
KR20180100375A (ko) | 2018-09-10 |
WO2017125506A1 (en) | 2017-07-27 |
CN108473477B (zh) | 2021-10-22 |
AU2017209925B2 (en) | 2021-04-08 |
ES2850575T3 (es) | 2021-08-30 |
AU2017209925A1 (en) | 2018-07-12 |
LT3405466T (lt) | 2021-01-25 |
HRP20202051T1 (hr) | 2021-02-19 |
SI3405466T1 (sl) | 2021-02-26 |
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