CN112996790B - 用于调节cdk9活性的化合物、组合物和方法 - Google Patents
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- CN112996790B CN112996790B CN201980072853.7A CN201980072853A CN112996790B CN 112996790 B CN112996790 B CN 112996790B CN 201980072853 A CN201980072853 A CN 201980072853A CN 112996790 B CN112996790 B CN 112996790B
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
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Abstract
CDK9抑制剂,其是吡唑并[1,5‑a]嘧啶衍生物及其盐,对应于式(I):
Description
相关申请的交叉参考
本申请要求分别于2018年10月30日,2019年8月9日和2019年10月3日提交的美国临时专利申请号62/752,635、62/884,993和62/910,058的权益,将其全部内容并入本文作为参考。
领域
本公开提供了调节细胞周期蛋白依赖性激酶9(CDK9)活性的化合物,包含此类化合物的药物组合物,以及使用化合物和/或药物组合物治疗、改善和/或预防由CDK9活性引起的疾病,例如过度增殖性疾病、病毒诱导的感染性疾病和心血管疾病的方法。
背景
细胞周期蛋白依赖性激酶(CDK)家族的蛋白质是细胞周期和基因转录的关键调节因子。细胞周期是细胞生长和分裂时机的调节性细胞机制。细胞周期是一个多方面的过程,它通过一系列检查点指导细胞增殖,这些检查点可以纠正DNA损伤、遗传紊乱和其它错误。Nonhuman Primates in Biomedical Research(第二版,2012)。每个阶段都由细胞周期蛋白和CDK的组合控制,其中CDK使一组特定的细胞周期蛋白磷酸化,从而触发进入细胞周期下一阶段。Cell Cycle Merri Lynn Casern BA,PhD,in Case Studies in Cell Biology,2016。通过调节细胞周期蛋白mRNA转录,细胞周期蛋白的积累起着“生物开关”的作用,可以打开和关闭CDK,并且使细胞从一个阶段转移到下一个阶段。
CDK 1、2、3、4和6调节细胞分裂周期的时间,而CDK 7和CDK 9通过其羧基末端结构域的磷酸化调节RNA聚合酶II来调节转录活性。Lucking等人,ChemMedChem 2017,12,1776-1793。
CDK9控制关键致癌蛋白,例如AR、MYC、MCL-1和BCL-2的转录活性,并且刺激促炎转录因子,例如NFkB和STAT3。Gregory等人,Leukemia.2015年6月;29(6):1437-1441;等人,Curr Pharm Des.2012年7月;18(20):2883-2890。CDK9与四个细胞周期蛋白伴侣(细胞周期蛋白T1、细胞周期蛋白K、细胞周期蛋白T2a或细胞周期蛋白T2b)之一形成杂二聚体,称为正转录延伸因子(PTEFb)。由于负延伸因子的相互作用,RNA聚合酶II沿着DNA模板在20-40个核苷酸后暂停了mRNA转录,所述负延伸因子用作快速诱导基因转录的主要调控机制。PTEFb通过RNA聚合酶II的羧基末端结构域的磷酸化和负伸长因子的失活克服了RNA聚合酶II的暂停。靶向CDK9和PTEFb的化合物目前正在临床研究中。CDK9的酶活性对于刺激大多数蛋白质编码基因的转录延伸很重要。等人,Curr Pharm Des.2012年7月;18(20):2883-2890。
已经开发了许多具有杂环核心结构的CDK抑制剂。例如,嘌呤骨架已经是开发用于治疗癌症的CDK抑制剂的来源,包括塞利西利(seliciclib)(Cyclacel Pharmaceuticals,Inc)和其它嘌呤衍生物。S.C.Wilson等人,Bioorg&Med Chem 2011年11月;19(22):6949-6965。除了CDK9以外,这些嘌呤衍生物还靶向CDK7和CDK2,而抑制CDK2引起安全性和毒性问题。还已经开发了基于三嗪核心的CDK9抑制剂,例如阿维西利(Atuveciclib)Lucking等人,ChemMedChem 2017,12,1776-1793。不幸的是,用CDK9抑制剂治疗仍然相对不成功,并且涉及许多副作用。Morales等人,Cell Cycle 2016,vol.15,no.4,519-527。因此,需要用于治疗由CDK9介导的疾病的新的CDK9抑制剂。
概述
在一个实施方案中,本公开提供了作为CDK9抑制剂的吡唑并[1,5-a]嘧啶及其衍生物。
在一个实施方案中,本公开提供了式(I)化合物:
或其药学上可接受的盐,其中:
R1是C1-C6烷基、C3-C6环烷基、四氢呋喃基或四氢吡喃基,任选在任何位置被一个或多个D、卤素、R7CO2R8、CO2R8、CO2H、R7CO2H、NH2、NHR8、OH、OR8、SH、SR8、NHCOR8、NHSO2R8,SO2NH2、SO2NHR8取代,
或者R1是NH2、NHR8、OH、OR8、NHCOR8、NHSO2R8、SO2NH2、SO2NHR8,
或者R1和R2一起形成稠合的C5-C6环芳基,任选在任何位置被一个或多个D、卤素、NH2、NHR8、NR7R8、OH、OR8、SH、SR8、NHCOR8、NHSO2R8、SO2NH2或SO2NHR8取代;
R2、R3、R4和R5独立地是H、D、卤素或C1-C5烷基或C3-C6环烷基,任选在任何位置被一个或多个D、卤素、NH2、NHR8、NR7R8、OH、OR8、SH、SR8、NHCOR8、NHSO2R8、SO2NH2或SO2NHR8取代,
或者R3和R4一起形成稠合的C5-C6环芳基,任选在任何位置被一个或多个D、卤素、NH2、NHR8、NR7R8、OH、OR8、SH、SR8、NHCOR8、NHSO2R8、SO2NH2或SO2NHR8取代,
或者R2和R5一起形成稠合的C5-C6环芳基,任选在任何位置被一个或多个D、卤素、NH2、NHR8、NR7R8、OH、OR8、SH、SR8、NHCOR8、NHSO2R8、SO2NH2或SO2NHR8取代;
R6是H或D;
R7是(CH2)n,其中n是1至6的整数;并且
R8是C1-C6烷基或C3-C6环烷基,任选在任何位置被一个或多个D、卤素、OH、SH或NH2取代。
在另一个实施方案中,在式(I)化合物或其盐中,R1是C1-C6烷基或C3-C6环烷基,任选在任何位置被NH2取代,或者R1是NHCOR8;R2、R3、R4和R6是H;R5是环丁基、环戊基或环己基,任选在任何位置被D、NH2、OH、NHR8、OR8或其组合取代;并且R8是C1-C4烷基。
在另一个实施方案中,在式(I)化合物或其盐中,R1是甲基、乙基、异丙基、仲丁基、3-戊基、环丙基、环戊基或NHCOCH3;R2、R3、R4和R6是H;并且R5是环丁基、环戊基或环己基,任选在任何位置被NH2取代。
化合物可以是包含药学上可接受的载体的组合物的形式。
在另一个实施方案中,本公开提供了通过给需要的个体施用有效量的本文所述的吡唑并[1,5-a]嘧啶治疗、预防或改善CDK9介导的疾病,例如过度增殖性疾病(例如癌症)、病毒诱导的感染性疾病和心血管疾病的方法。
详细描述
在一个实施方案中,能够在本文所述的组合物或方法中使用的本文所述的化合物包含式(I)化合物或其盐、由其组成或基本上由其组成。一方面,将组合物配制成药物组合物或形式。
通过式(I)描述或显示为特定化合物的任何化合物可以是单一立体异构体或可能的立体异构体的混合物。例如,如果存在单一手性碳,则化合物相对于手性碳可以是(S)或(R)立体异构体,或者化合物可以是(S)和(R)异构体的非外消旋混合物,或者化合物可以是单独的(S)异构体或单独的(R)异构体。如果化合物包含一个以上的手性碳,则化合物可以是单一非对映异构体或非对映异构体的混合物。
“盐”是指药学上可接受的盐,例如盐酸盐。“药学上可接受的盐”是保留化合物活性而没有明显副作用的盐。药学上可接受的盐的实例包括有机或无机酸的盐,例如盐酸、硫酸、甲磺酸、富马酸、马来酸、琥珀酸、乙酸、苯甲酸、草酸、柠檬酸、酒石酸、碳酸、磷酸、三氟乙酸和甲酸。该盐可以每个化合物包含一个或多个当量的酸,即该化合物可以是二盐酸盐的形式。
公开的活性化合物也可以是其水合物的形式。术语“水合物”包括例如半水合物、一水合物、二水合物、三水合物和四水合物。
本公开的化合物可以表现出其天然同位素丰度,或者一个或多个原子可以被人工富集具有相同原子数,但是原子质量或质量数不同于自然界中主要发现的原子质量或质量数的特定同位素。本公开包括本文所述化合物的所有适合的同位素变体。
“烷基”是指支链和直链饱和脂族烃,并且如“C1-C6烷基”中所指定的碳原子数是指其具有1、2、3、4、5或6个碳的直链或支链排列的碳原子的所有异构体。因此,“C1-C6烷基”包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基等。
“环烷基”是指具有指定数目的碳的环状饱和脂族烃。
“D”是氘。
“卤素”是指卤素取代基,例如F、Cl或Br。式(I)化合物的实例包括:
“有效量”或“治疗有效量”是当施用于个体时足以实现如本文所述的有益或期望结果的化合物或组合物的量。有效的剂型、施用方式和剂量可以凭经验确定,并且这种确定在本领域技术范围内。本领域技术人员应理解,剂量将随施用途径、排泄速率、治疗持续时间、所施用的任何其它药物的性质,哺乳动物例如人患者的年龄,大小和种类等医学和兽医学领域众所周知的因素而不同。通常,适合的剂量将是有效产生所需效果而无副作用或有最小副作用的最低剂量的化合物的量。
根据本公开的化合物的剂量的适合的非限制性实例是约1ng/kg至约1000mg/kg,例如约1mg/kg至约100mg/kg,包括约5mg/kg至约50mg/kg。PI3K抑制剂的其它代表性剂量包括约1mg/kg、5mg/kg、10mg/kg、15mg/kg、20mg/kg、25mg/kg、30mg/kg、35mg/kg、40mg/kg、45mg/kg、50mg/kg、60mg/kg、70mg/kg、80mg/kg、90mg/kg、100mg/kg、125mg/kg、150mg/kg、175mg/kg、200mg/kg、250mg/kg、300mg/kg、400mg/kg、500mg/kg、600mg/kg、700mg/kg、800mg/kg、900mg/kg或1000mg/kg。
本公开的另一个实施方案是用于治疗CDK9介导的疾病的药物组合物。CDK9介导的疾病可能是过度增殖性疾病(例如癌症)、病毒诱导的感染性疾病或心血管疾病。实例包括急性骨髓性白血病、原发性腹膜癌、慢性淋巴细胞性白血病、复发性多发性骨髓瘤、非霍奇金淋巴瘤、急性淋巴母细胞性白血病、急性双表型性白血病、晚期乳癌、非小细胞肺癌、肝癌例如肝细胞癌和实体晚期肿瘤。特别地,化合物可以用于治疗由MYC-1或MCL-1的异常表达引起的癌症、血液恶性肿瘤或实体瘤。
药物组合物包含药学上可接受的载体和有效量的本文所述的化合物。
本公开的药物组合物可以以任何期望和有效的方式施用:用于口服摄取,或作为软膏剂或滴剂用于对眼的局部施用,或用于非肠道或其它施用的任何适当方式,例如腹膜内、皮下、局部、真皮内、吸入、肺内、直肠、阴道、舌下、肌内、静脉内、动脉内、鞘内或淋巴内。此外,本公开的药物组合物可以与其它治疗联合施用。如果需要的话,本公开的药物组合物可以被包封或以其它方式保护其免受胃或其它分泌物的影响。
本公开的药物组合物是药学上可接受的,并且包含一种或多种活性成分与一种或多种药学上可接受的载体和任选的一种或多种其它化合物、药物、成分和/或材料混合。不管选择的施用途径如何,通过本领域技术人员已知的常规方法,使用本领域众所周知的药学上可接受的载体将本公开的活性剂/化合物配制成药学上可接受的剂型(参见例如Remington,The Science and Practice of Pharmacy(2lst Edition,LippincottWilliams and Wilkins,Philadelphia,Pa.)和The National Formulary(AmericanPharmaceutical Association,Washington,D C.)),并且包含糖(例如乳糖、蔗糖、甘露醇和山梨醇)、淀粉、纤维素制备物、磷酸钙(例如磷酸二钙、磷酸三钙和磷酸氢钙)、柠檬酸钠、水、水溶液(例如盐水、氯化钠注射液、林格氏注射液、右旋糖注射液、右旋糖和氯化钠注射液、乳酸林格氏注射液)、醇(例如乙醇、丙醇和苯甲醇)、多元醇(例如甘油、丙二醇和聚乙二醇)、有机酯(例如油酸乙酯和甘油三酯)、可生物降解的聚合物(例如聚乳酸-聚乙醇酸、聚(原酸酯)和聚(酸酐))、弹性体基质、脂质体、微球、油(例如玉米油、胚芽油、橄榄油、蓖麻油、芝麻油、棉籽油和花生油)、可可脂、蜡(例如栓剂蜡)、石蜡、硅酮、滑石粉、硅酸盐等。在与制剂的其它成分相容并且对个体无害的意义上,本公开的药物组合物中使用的每种药学上可接受的载体是“可接受的”。适用于所选剂型和预期施用途径的载体是本领域众所周知的,并且对于所选剂型和施用方法的可接受载体可以使用本领域普通技术来确定。
本公开的药物组合物可以任选包含通常用于此类药物组合物中的其它成分和/或材料。这些成分和材料是本领域众所周知的,并且包括(1)填充剂或增量剂,例如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(2)粘合剂,例如羧甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、羟丙基甲基纤维素、蔗糖和阿拉伯胶;(3)保湿剂,例如甘油;(4)崩解剂,例如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐、淀粉羟乙酸钠、交联羧甲基纤维素钠和碳酸钠;(5)溶液阻滞剂,例如石蜡;(6)吸收加速剂,例如季铵化合物;(7)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(8)吸收剂,例如高岭土和膨润土;(9)润滑剂,例如滑石粉、硬脂酸钙、硬脂酸镁、固体聚乙二醇和月桂基硫酸钠;(10)助悬剂,例如乙氧基化异硬脂醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂和黄蓍胶;(11)缓冲剂;(12)赋形剂,例如乳糖、牛乳糖、聚乙二醇、动植物脂肪、油、蜡、石蜡、可可脂、淀粉、黄蓍胶、纤维素衍生物、聚乙二醇、硅酮、膨润土、硅酸、滑石粉、水杨酸盐、氧化锌、氢氧化铝、硅酸钙和聚酰胺粉末;(13)惰性稀释剂,例如水或其它溶剂;(十四)防腐剂;(15)表面活性剂;(16)分散剂;(17)控释或吸收延迟剂,例如羟丙基甲基纤维素、其它聚合物基质、可生物降解的聚合物、脂质体、微球、单硬脂酸铝、明胶和蜡;(十八)遮光剂;(19)佐剂;(二十)润湿剂;(21)乳化和助悬剂;(22)增溶剂和乳化剂,例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、油(特别是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢呋喃醇、聚乙二醇和脱水山梨醇的脂肪酸酯;(23)抛射剂,例如氯氟烃和挥发性未取代的烃,例如丁烷和丙烷;(24)抗氧化剂,(25)使制剂与预期接受者的血液等渗的试剂,例如糖和氯化钠;(26)增稠剂;(27)包衣材料,例如卵磷脂;和(28)甜味剂、矫味剂、着色剂、芳香剂和防腐剂。每种此类成分或材料在与制剂的其它成分相容并且对个体无害的意义上必须是“可接受的”。适用于所选剂型和预期施用途径的成分和材料是本领域众所周知的,并且可以使用本领域普通技术确定用于所选剂型和施用方法的可接受的成分和材料。
适用于口服施用的药物组合物可以是胶囊剂、扁囊剂、丸剂、片剂、散剂、颗粒剂、在水性或非水性液体中的溶液剂或混悬剂、水包油或油包水液体乳剂、酏剂或糖浆剂、软锭剂、大丸剂、煎膏剂或糊剂。这些制剂可以通过本领域已知的方法制备,例如通过常规的锅包衣、混合、制粒或冻干方法。
可以例如通过混合活性成分和一种或多种药学上可接受的载体以及任选的一种或多种填充剂、增量剂、粘合剂、保湿剂、崩解剂、溶液阻滞剂、吸收加速剂、润湿剂、吸收剂、润滑剂和/或着色剂来制备用于口服施用的固体剂型(胶囊剂、片剂、丸剂、锭剂、散剂、颗粒剂等)。相似类型的固体组合物可以用作软和硬填充的明胶胶囊剂,使用适合的赋形剂。片剂可以通过压制或模制制备,任选与一种或多种辅助成分一起制备。可以使用适合的粘合剂、润滑剂、惰性稀释剂、防腐剂、崩解剂、表面活性剂或分散剂来制备压制片剂。模制片剂可以通过在适合的机器中模制来制备。片剂和其它固体剂型,例如锭剂、胶囊剂、丸剂和颗粒剂,可以任选刻痕或用包衣和壳,例如肠溶衣和药物配制领域众所周知的其它包衣进行制备。它们也可以被配制为提供其中的活性成分的缓慢或受控释放。它们可以通过例如通过阻留细菌的过滤器过滤来灭菌。这些组合物还可以任选包含遮光剂,并且可以是这样的组合物,使得它们仅或优选在胃肠道的某个部分中任选以延迟的方式释放活性成分。活性成分也可以是微囊形式。
口服施用的液体剂型包括药学上可接受的乳剂、微乳剂、溶液剂、混悬剂、糖浆剂和酏剂。液体剂型可以包含本领域通常使用的适合的惰性稀释剂。除惰性稀释剂外,口服组合物还可以包含佐剂,例如润湿剂、乳化和助悬剂、甜味剂、矫味剂、着色剂、芳香剂和防腐剂。混悬剂可以包含助悬剂。
用于直肠或阴道施用的药物组合物可以作为栓剂存在,可以通过将一种或多种活性成分与一种或多种适合的无刺激性载体混合来制备,所述载体在室温下为固体,但在体温下为液体,因此会在直肠或阴道腔中融化并且释放出活性化合物。适用于阴道施用的药物组合物还包括阴道栓、棉塞、乳膏剂、凝胶剂、糊剂、泡沫剂或喷雾剂,其包含本领域已知适合的药学上可接受的载体。
用于局部或透皮施用的剂型包括散剂、喷雾剂、软膏剂、糊剂、乳膏剂、洗剂、凝胶剂、溶液剂、贴剂、滴剂和吸入剂。活性剂/化合物可以在无菌条件下与适合的药学上可接受的载体混合。软膏剂、糊剂、乳膏剂和凝胶剂可以包含赋形剂。散剂和喷雾剂可以包含赋形剂和抛射剂。
适合于非肠道施用的药物组合物包含一种或多种活性剂/化合物组合一种或多种药学上可接受的无菌等渗水性或非水性溶液、分散液、混悬液或乳液,或无菌粉末,其可以在使用前重构为无菌注射溶液或分散液,其可以包含适合的抗氧化剂、缓冲剂、使制剂与预期接受者的血液等渗的溶质或助悬剂或增稠剂。可以例如通过使用包衣材料,在分散液的情况下通过维持所需的粒径以及通过使用表面活性剂来维持适当的流动性。这些组合物还可以包含适合的佐剂,例如润湿剂、乳化剂和分散剂。也可能需要包含等渗剂。另外,可以通过包含延迟吸收的试剂来延长可注射药物形式的吸收。
在某些情况下,为了延长药物(例如药物制剂)的作用,需要减慢其从皮下或肌内注射的吸收。这可以通过使用水溶性差的结晶或无定形材料的液体混悬液来实现。
然后,活性剂/药物的吸收速率取决于其溶出速率,而溶出速率又取决于晶体尺寸和晶型。可选择的是,可以通过将活性剂/药物溶解或悬浮在油性载体中来实现非肠道施用的活性剂/药物的延迟吸收。可以通过在可生物降解的聚合物中形成活性成分的微胶囊基质来制备可注射的贮库形式。取决于活性成分与聚合物的比例以及所使用的特定聚合物的性质,可以控制活性成分的释放速率。还可以通过将药物包埋在与身体组织相容的脂质体或微乳中来制备贮库可注射制剂。可注射材料可以例如通过阻留细菌的过滤器过滤而灭菌。
制剂可以以单位剂量或多剂量密封容器,例如安瓿和小瓶存在,并且可以在冻干条件下储存,在使用前立即仅加入无菌液体载体,例如注射用水。临时注射溶液和混悬液可以由上述类型的无菌粉末、颗粒和片剂制备。
如本文所用,“个体”是哺乳动物,优选人。除人外,在本公开范围内的哺乳动物的类别包括例如农用动物、家畜、实验动物等。农用动物的一些实例包括牛、猪、马、山羊等。家畜动物的一些实例包括狗、猫等。实验动物的一些实例包括大鼠、小鼠、兔、豚鼠等。
如本文所用,术语“治疗”及其语法变化是指使个体经受计划、方案、过程或补救,其中在该个体例如患者中期望获得生理响应或结果。特别地,本公开的方法和组合物可用于减缓疾病症状的发展或延迟疾病或病症的发作,或中止疾病发展的进程。然而,因为每个被治疗的个体可能不会对特定的治疗计划、方案、过程或补救有响应,所以治疗不需要在每个或所有个体或个体例如患者群中实现所需的生理响应或结果。因此,给定的个体或个体例如患者群可能不能对治疗做出响应或响应不足。
如本文所用,术语“改善”及其语法变化是指降低个体的疾病症状的严重程度。
如本文所用,术语“预防”及其语法变化是指将本公开的化合物或组合物施用于在施用时未被诊断出患有疾病或病症,但是可能会发展成疾病或病症,或处于疾病或病症的风险增加中的个体。预防还包括将至少一种本公开的化合物或组合物施用于那些由于年龄、家族史、遗传或染色体异常,由于存在疾病或病症的一种或多种生物标志物和/或由于环境因素而易患疾病或病症的个体。
以下实施例用于说明本公开的某些方面,而不旨在限制本公开。
实施例
下列实施例描述了代表性化合物的制备和测试。
实施例1:N-环戊基-5-甲基-吡唑并[1,5-a]嘧啶-7-胺(1)
将搅拌的7-氯-5-甲基-吡唑并[1,5-a]嘧啶(50.0mg,0.3000mmol)、环戊胺(30.48mg,0.3600mmol)和K2CO3(82.34mg,0.6000mmol)的MeCN(4mL)溶液加热至回流达4小时。将反应混合物过滤,减压浓缩并且通过柱色谱纯化,洗脱剂为在己烷中的30%乙酸乙酯,得到N-环戊基-5-甲基-吡唑并[1,5-a]嘧啶-7-胺(51.58mg,0.2358mmol,79.046%产率)(1),为淡黄色无定形固体。通过TLC(在己烷中的40%乙酸乙酯;产物Rf=0.4,SM Rf=0.6)监测反应混合物。
实施例2:N-环戊基-5-异丙基-吡唑并[1,5-a]嘧啶-7-胺(2)
将7-氯-5-异丙基-吡唑并[1,5-a]嘧啶(65.0mg,0.3300mmol)、环戊胺(0.04mL,0.4000mmol)和K2CO3(91.69mg,0.6600mmol)的MeCN(4mL)溶液加热至回流达4小时。将反应混合物过滤,减压浓缩,并且通过柱色谱纯化,洗脱剂在己烷中的15%乙酸乙酯,得到N-环戊基-5-异丙基-吡唑并[1,5-a]嘧啶-7-胺(48.02mg,0.1953mmol,58.789%产率)(2),为淡黄色无定形固体。通过TLC(在己烷中的20%乙酸乙酯;产物Rf=0.3,SM Rf=0.6)监测反应混合物。
实施例3:N-环戊基-5-仲丁基-吡唑并[1,5-a]嘧啶-7-胺(3)
将搅拌的7-氯-5-仲丁基-吡唑并[1,5-a]嘧啶(50.mg,0.2400mmol)、环戊胺(24.37mg,0.2900mmol)和K2CO3(82.28mg,0.6000mmol)的MeCN(5mL)溶液加热至回流达4小时。将反应混合物过滤,减压浓缩,并且通过柱色谱纯化,得到N-环戊基-5-仲丁基-吡唑并[1,5-a]嘧啶-7-胺(21.27mg,0.0823mmol,34.519%产率)(3),为淡黄色无定形固体。通过TLC(在己烷中的30%乙酸乙酯;产物Rf=0.4,SM Rf=0.5)监测反应混合物。
实施例4:[4-[(5-甲基吡唑并[1,5-a]嘧啶-4-
-7-基]氨基]环己基]铵二盐酸盐
(4)
在N-[4-[(5-甲基吡唑并[1,5-a]嘧啶-7-基)氨基]环己基]氨基甲酸叔丁酯(60.0mg,0.1700mmol)中加入在二烷中的HCl(2mL,0.1700mmol)并且在室温搅拌2小时。将反应混合物真空蒸发,得到[4-[(5-甲基吡唑并[1,5-a]嘧啶-4--7-基]氨基]环己基]铵二盐酸盐(39.89mg,0.1247mmol,71.803%产率)(4),为白色固体。通过TLC(100%乙酸乙酯;产物Rf=0.1,SM Rf=0.8)监测反应混合物。
实施例5:N,5-二环戊基吡唑并[1,5-a]嘧啶-7-胺(5)
将搅拌的7-氯-5-环戊基-吡唑并[1,5-a]嘧啶(50.0mg,0.2300mmol)、环戊胺(23.05mg,0.2700mmol)和K2CO3(77.81mg,0.5600mmol)的MeCN(5mL)溶液加热至回流达4小时。将反应混合物过滤,减压浓缩,并且通过柱色谱纯化,得到N,5-二环戊基吡唑并[1,5-a]嘧啶-7-胺(33.17mg,0.1227mmol,54.396%产率)(5),为淡黄色固体。通过TLC(在己烷中的30%乙酸乙酯;产物Rf=0.4,SM Rf=0.5)监测反应混合物。
实施例6:[4-[(5-异丙基吡唑并[1,5-a]嘧啶-4-
-7-基)氨基]环己基]铵二盐酸
盐(6)
在N-[4-[(5-异丙基吡唑并[1,5-a]嘧啶-7-基)氨基]环己基]氨基甲酸叔丁酯(80.0mg,0.2100mmol)中加入在二烷中的HCl(2.mL,0.2100mmol),并且在室温搅拌2小时。将反应混合物真空蒸发,得到[4-[(5-异丙基吡唑并[1,5-a]嘧啶-4--7-基)氨基]环己基]铵二盐酸盐(64.82mg,0.1796mmol,83.865%产率)(6),为灰白色固体。通过TLC(100%乙酸乙酯;产物Rf=0.1,SM Rf=0.8)监测反应混合物。
实施例7:[4-[(5-仲丁基吡唑并[1,5-a]嘧啶-4-
-7-基)氨基]环己基]二氯化铵
(7)
在N-[4-[(5-仲丁基吡唑并[1,5-a]嘧啶-7-基)氨基]环己基]氨基甲酸叔丁酯(65.0mg,0.1700mmol)中加入在二烷中的HCl(2.mL,0.1700mmol)并且在室温搅拌2小时。将反应混合物真空蒸发,得到[4-[(5-仲丁基吡唑并[1,5-a]嘧啶-4--7-基)氨基]环己基]铵二盐酸盐(46.75mg,0.1297mmol,77.35%产率)(7),为灰白色固体。通过TLC(100%乙酸乙酯;产物Rf=0.1,SM Rf=0.78)监测反应混合物。
实施例8:[4-[(5-环戊基吡唑并[1,5-a]嘧啶-4-
-7-基)氨基]环己基]铵二盐酸
盐(8)
在N-[4-[(5-环戊基吡唑并[1,5-a]嘧啶-7-基)氨基]环己基]氨基甲酸叔丁酯(72.17mg,0.1800mmol)中加入在二烷中的HCl(2.mL,0.1800mmol),并且在室温搅拌2小时。将反应混合物真空蒸发,得到[4-[(5-环戊基吡唑并[1,5-a]嘧啶-4--7-基)氨基]环己基]铵二盐酸盐(59.36mg,0.1594mmol,88.257%产率)(8),为灰白色固体。通过TLC(100%乙酸乙酯;产物Rf=0.1,SM Rf=0.8)监测反应混合物。
实施例9:[(1S,3S)-3-[(5-环戊基吡唑并[1,5-a]嘧啶-4-
-7-基)氨基]环戊基]
铵二盐酸盐(9)
在N-[(1S,3S)-3-[(5-环戊基吡唑并[1,5-a]嘧啶-7-基)氨基]环戊基]氨基甲酸叔丁酯(105.mg,0.2700mmol)中加入在二烷中的HCl(2.0mL,0.2700mmol)并且在室温搅拌2小时。将反应混合物真空蒸发,得到[(1S,3S)-3-[(5-环戊基吡唑并[1,5-a]嘧啶-4--7-基)氨基]环戊基]铵二盐酸盐(51.28mg,0.1431mmol,52.544%产率)(9),为淡黄色固体。通过TLC(100%乙酸乙酯;产物Rf=0.1,SM Rf=0.8)监测反应混合物。
实施例10:[(1S,3R)-3-[(5-甲基吡唑并[1,5-a]嘧啶-4-
-7-基)氨基]环戊基]
铵二盐酸盐(10)
在N-[(1S,3R)-3-[(5-甲基吡唑并[1,5-a]嘧啶-7-基)氨基]环戊基]氨基甲酸叔丁酯(100.0mg,0.3000mmol)中加入在二烷中的HCl(2mL,0.3000mmol)并且在室温搅拌2小时。将反应混合物真空蒸发,得到[(1S,3R)-3-[(5-甲基吡唑并[1,5-a]嘧啶-4--7-基)氨基]环戊基]铵二盐酸盐(84.11mg,0.2685mmol,88.979%产率)(10),为灰白色固体。通过TLC(100%乙酸乙酯;产物Rf=0.1,SM Rf=0.8)监测反应混合物。
实施例11:[3-[(5-甲基吡唑并[1,5-a]嘧啶-4-
-7-基)氨基]环丁基]铵二盐酸
盐(11)
在N-[3-[(5-甲基吡唑并[1,5-a]嘧啶-7-基)氨基]环丁基]氨基甲酸叔丁酯(90.mg,0.2800mmol)中加入在二烷中的HCl(2.0mL,0.2800mmol)并且在室温搅拌2小时。将反应混合物真空蒸发,得到[3-[(5-甲基吡唑并[1,5-a]嘧啶-4--7-基)氨基]环丁基]铵二盐酸盐(65.42mg,0.2240mmol,79.009%产率)(11),为淡棕色固体。通过TLC(100%乙酸乙酯;产物Rf=0.1,SM Rf=0.8)监测反应混合物。
实施例12:[(1R,3S)-3-[(5-甲基吡唑并[1,5-a]嘧啶-4-
-7-基)氨基]环戊基]
铵二盐酸盐(12)
在N-[(1R,3S)-3-[(5-甲基吡唑并[1,5-a]嘧啶-7-基)氨基]环戊基]氨基甲酸叔丁酯(80.0mg,0.2400mmol)中加入在二烷中的HCl(2.0mL,0.2400mmol)并且在室温搅拌2小时。将反应混合物真空蒸发,得到[(1R,3S)-3-[(5-甲基吡唑并[1,5-a]嘧啶-4--7-基)氨基]环戊基]铵二盐酸盐(61.39mg,0.1993mmol,82.568%产率)(12),为灰白色固体。通过TLC(100%乙酸乙酯;产物Rf=0.1,SM Rf=0.8)监测反应混合物。
实施例13:(1S,3R)-N3-(5-异丙基吡唑并[1,5-a]嘧啶-7-基)环戊烷-1,3-二胺
(13)
在N-[(1S,3R)-3-[(5-异丙基吡唑并[1,5-a]嘧啶-7-基)氨基]环戊基]氨基甲酸叔丁酯(80.0mg,0.2200mmol)中加入在二烷中的HCl(2.0mL,0.2200mmol)并且在室温搅拌2小时。将反应混合物真空蒸发,并且用PL-HCO3 MP SPE 200MG/6ML柱中和,得到(1S,3R)-N3-(5-异丙基吡唑并[1,5-a]嘧啶-7-基)环戊烷-1,3-二胺(26.03mg,0.0978mmol,43.966%产率)(13),为淡黄色无定形固体。通过TLC(100%乙酸乙酯;产物Rf=0.1,SM Rf=0.8)监测反应混合物。
实施例14:(1S,3R)-N3-(5-仲丁基吡唑并[1,5-a]嘧啶-7-基)环戊烷-1,3-二胺
(14)
在N-[(1S,3R)-3-[(5-仲丁基吡唑并[1,5-a]嘧啶-7-基)氨基]环戊基]氨基甲酸叔丁酯(100.mg,0.2700mmol)中加入在二烷中的HCl(2.0mL,0.2700mmol)并且在室温搅拌2小时。将反应混合物真空蒸发,并且用PL-HCO3 MP SPE 200MG/6ML柱中和,得到(1S,3R)-N3-(5-仲丁基吡唑并[1,5-a]嘧啶-7-基)环戊烷-1,3-二胺(34.04mg,0.1245mmol,46.505%产率)(14),为淡绿色无定形固体。通过TLC(100%乙酸乙酯;产物Rf=0.1,SM Rf=0.8)监测反应混合物。
实施例15:N-[(1S,3R)-3-[(5-环戊基吡唑并[1,5-a]嘧啶-7-基)氨基]环戊基]氨 基甲酸叔丁酯(15)
在N-[(1S,3R)-3-[(5-环戊基吡唑并[1,5-a]嘧啶-7-基)氨基]环戊基]氨基甲酸叔丁酯(100.mg,0.2600mmol)中加入在二烷中的HCl(2.0mL,0.2600mmol)并且在室温搅拌2小时。将反应混合物真空蒸发,并且用PL-HCO3 MP SPE 200MG/6ML柱中和,得到(1S,3R)-N3-(5-环戊基吡唑并[1,5-a]嘧啶-7-基)环戊烷-1,3-二胺(31.91mg,0.1118mmol,43.103%产率)(15),为淡黄色无定形固体。通过TLC(100%乙酸乙酯,产物Rf=0.1,SM Rf=0.8)监测反应混合物。
实施例16:(1R,3S)-N3-(5-异丙基吡唑并[1,5-a]嘧啶-7-基)环戊烷-1,3-二胺
(16)
在N-[(1R,3S)-3-[(5-异丙基吡唑并[1,5-a]嘧啶-7-基)氨基]环戊基]氨基甲酸叔丁酯(75.mg,0.2100mmol)中加入在二烷中的HCl(2.0mL,0.2100mmol)并且在室温搅拌2小时。将反应混合物真空蒸发,并且用PL-HCO3 MP SPE 200MG/6ML柱中和,得到(1R,3S)-N3-(5-异丙基吡唑并[1,5-a]嘧啶-7-基)环戊烷-1,3-二胺(30.78mg,0.1158mmol,55.49%产率)(16),为黄色无定形固体。通过TLC(100%乙酸乙酯;产物Rf=0.1,SM Rf=0.8)监测反应混合物。
实施例17:(1S,3S)-N3-(5-异丙基吡唑并[1,5-a]嘧啶-7-基)环戊烷-1,3-二胺
(17)
在N-[(1S,3S)-3-[(5-异丙基吡唑并[1,5-a]嘧啶-7-基)氨基]环戊基]氨基甲酸叔丁酯(80.0mg,0.2200mmol)中加入在二烷中的HCl(2.0mL,0.2200mmol)并且在室温搅拌2小时。将反应混合物真空蒸发,并且用PL-HCO3 MP SPE 200MG/6ML柱中和,得到(1S,3S)-N3-(5-异丙基吡唑并[1,5-a]嘧啶-7-基)环戊烷-1,3-二胺(31.02mg,0.1160mmol,52.142%产率)(17),为淡黄色胶状物。通过TLC(100%乙酸乙酯;产物Rf=0.1,SM Rf=0.8)监测反应混合物。
实施例18:(1S,3S)-N3-(5-仲丁基吡唑并[1,5-a]嘧啶-7-基)环戊烷-1,3-二胺
(18)
在N-[(1S,3S)-3-[(5-仲丁基吡唑并[1,5-a]嘧啶-7-基)氨基]环戊基]氨基甲酸叔丁酯(105.0mg,0.2800mmol)中加入在二烷中的HCl(2.0mL,0.2800mmol)并且在室温搅拌2小时。将反应混合物真空蒸发,并且用PL-HCO3 MP SPE 200MG/6ML柱中和,得到(1S,3S)-N3-(5-仲丁基吡唑并[1,5-a]嘧啶-7-基)环戊烷-1,3-二胺(20.55mg,0.0752mmol,26.738%产率)(18),为淡黄色无定形固体。通过TLC(100%乙酸乙酯;产物Rf=0.1,SM Rf=0.8)监测反应混合物。
实施例19:N1-(5-仲丁基吡唑并[1,5-a]嘧啶-7-基)环丁烷-1,3-二胺(19)
在N-[3-[(5-仲丁基吡唑并[1,5-a]嘧啶-7-基)氨基]环丁基]氨基甲酸叔丁酯(85.0mg,0.2400mmol)中加入在二烷中的HCl(2.0mL,0.2400mmol)并且在室温搅拌2小时。将反应混合物真空蒸发,并且用PL-HCO3 MP SPE 200MG/6ML柱中和,得到N1-(5-仲丁基吡唑并[1,5-a]嘧啶-7-基)环丁烷-1,3-二胺(30.61mg,0.1180mmol,49.914%产率)(19),为淡黄色无定形固体。通过TLC(100%乙酸乙酯;产物Rf=0.1,SM Rf=0.8)监测反应混合物。
实施例20:N1-(5-环戊基吡唑并[1,5-a]嘧啶-7-基)环丁烷-1,3-二胺(20)
在N-[3-[(5-环戊基吡唑并[1,5-a]嘧啶-7-基)氨基]环丁基]氨基甲酸叔丁酯(80.0mg,0.2200mmol)中加入在二烷中的HCl(2.0mL,0.2200mmol)并且在室温搅拌2小时。将反应混合物真空蒸发,并且用PL-HCO3 MP SPE 200MG/6ML柱中和,得到N1-(5-环戊基吡唑并[1,5-a]嘧啶-7-基)环丁烷-1,3-二胺(29.52mg,0.1088mmol,50.514%产率)(20),为淡黄色胶状物。通过TLC(100%乙酸乙酯;产物Rf=0.1,SM Rf=0.8)监测反应混合物。
实施例21:N1-(5-异丙基吡唑并[1,5-a]嘧啶-7-基)环丁烷-1,3-二胺(21)
在N-[3-[(5-异丙基吡唑并[1,5-a]嘧啶-7-基)氨基]环丁基]氨基甲酸叔丁酯(75.0mg,0.2200mmol)中加入在二烷中的HCl(2.0mL,0.2200mmol)并且在室温搅拌2小时。将反应混合物真空蒸发,并且用PL-HCO3 MP SPE 200MG/6ML柱中和,得到N1-(5-异丙基吡唑并[1,5-a]嘧啶-7-基)环丁烷-1,3-二胺(32.01mg,0.1251mmol,57.616%产率)(21),为淡黄色无定形固体。通过TLC(100%乙酸乙酯;产物Rf=0.1,SM Rf=0.8)监测反应混合物。
实施例22:(1R,3S)-N3-(5-仲丁基吡唑并[1,5-a]嘧啶-7-基)环戊烷-1,3-二胺
(22)
在N-[(1R,3S)-3-[(5-仲丁基吡唑并[1,5-a]嘧啶-7-基)氨基]环戊基]氨基甲酸叔丁酯(100.0mg,0.2700mmol)中加入在二烷中的HCl(2.0mL,0.2700mmol)并且在室温搅拌2小时。将反应混合物真空蒸发,并且用PL-HCO3 MP SPE 200MG/6ML柱中和,得到(1R,3S)-N3-(5-仲丁基吡唑并[1,5-a]嘧啶-7-基)环戊烷-1,3-二胺(28.39mg,0.1038mmol,38.786%产率)(22),为淡黄色无定形固体。通过TLC(100%乙酸乙酯;产物Rf=0.1,SM Rf=0.8)监测反应混合物。
实施例23:(1R,3S)-N3-(5-环戊基吡唑并[1,5-a]嘧啶-7-基)环戊烷-1,3-二胺
(23)
在N-[(1R,3S)-3-[(5-环戊基吡唑并[1,5-a]嘧啶-7-基)氨基]环戊基]氨基甲酸叔丁酯(100.0mg,0.2600mmol)中加入在二烷中的HCl(2.0mL,0.2600mmol)并且在室温搅拌2小时。将反应混合物真空蒸发,并且用PL-HCO3 MP SPE 200MG/6ML柱中和,得到(1R,3S)-N3-(5-环戊基吡唑并[1,5-a]嘧啶-7-基)环戊烷-1,3-二胺(33.05mg,0.1158mmol,44.643%产率)(23),为淡黄色无定形固体。通过TLC(100%乙酸乙酯;产物Rf=0.1,SM Rf=0.8)监测反应混合物。
实施例24:(1S,3S)-N3-(5-甲基吡唑并[1,5-a]嘧啶-7-基)环戊烷-1,3-二胺(24)
在N-[(1S,3S)-3-[(5-甲基吡唑并[1,5-a]嘧啶-7-基)氨基]环戊基]氨基甲酸叔丁酯(80.0mg,0.2400mmol)中加入在二烷中的HCl(2.0mL,0.2400mmol)并且在室温搅拌2小时。将反应混合物真空蒸发,并且用PL-HCO3 MP SPE 200MG/6ML柱中和,并且通过制备型HPLC纯化,得到(1S,3S)-N3-(5-甲基吡唑并[1,5-a]嘧啶-7-基)-环戊烷-1,3-二胺(21.15mg,0.0899mmol,37.263%产率)(24),为灰白色固体。通过TLC(100%乙酸乙酯;产物Rf=0.1,SM Rf=0.8)监测反应混合物。
实施例25:(1R,3R)-N3-(5-乙基吡唑并[1,5-a]嘧啶-7-基)环戊烷-1,3-二胺(25)
在0℃,在搅拌的N-[(1R,3R)-3-[(5-乙基吡唑并[1,5-a]嘧啶-7-基)氨基]环戊基]氨基甲酸叔丁酯(62.0mg,0.1800mmol)的DCM(3.5896mL)溶液中加入三氟乙酸(0.34mL,4.49mmol)。使反应温至室温,并且历经2小时持续搅拌,随后LC-MS显示反应完成。将反应直接浓缩,用戊烷洗涤并且干燥,得到(1R,3R)-N3-(5-乙基吡唑并[1,5-a]嘧啶-7-基)环戊烷-1,3-二胺(35mg,0.1427mmol,79.491%产率)(25)。通过TLC(100%乙酸乙酯;产物Rf=0.1,SM Rf=0.8)监测反应混合物。
实施例26:(1R,3R)-N3-(5-丙基吡唑并[1,5-a]嘧啶-7-基)环戊烷-1,3-二胺(26)
在0℃,在搅拌的N-[(1R,3R)-3-[(5-丙基吡唑并[1,5-a]嘧啶-7-基)氨基]环戊基]氨基甲酸叔丁酯(41.0mg,0.1100mmol)的DCM(2.2811mL)溶液中加入三氟乙酸(0.22mL,2.85mmol)。使反应温至室温,并且历经2小时持续搅拌,随后LC-MS显示反应完成。将反应直接浓缩,用戊烷洗涤并且干燥,得到(1R,3R)-N3-(5-丙基吡唑并[1,5-a]嘧啶-7-基)环戊烷-1,3-二胺(16mg,0.0617mmol,54.089%产率)(26)。通过TLC(100%乙酸乙酯;产物Rf=0.1,SM Rf=0.8)监测反应混合物。
实施例27:(1S,3S)-N3-(5-丙基吡唑并[1,5-a]嘧啶-7-基)环戊烷-1,3-二胺(27)
在0℃,在搅拌的N-[(1S,3S)-3-[(5-丙基吡唑并[1,5-a]嘧啶-7-基)氨基]环戊基]氨基甲酸叔丁酯(47.0mg,0.1300mmol)的DCM(2.615mL)溶液中加入三氟乙酸(0.25mL,3.27mmol)。使反应温至室温,并且历经2小时持续搅拌,随后LC-MS显示反应完成。将反应直接浓缩,用戊烷洗涤并且干燥,得到(1S,3S)-N3-(5-丙基吡唑并[1,5-a]嘧啶-7-基)环戊烷-1,3-二胺(33mg,0.1272mmol,97.318%产率)(27)。通过TLC(100%乙酸乙酯;产物Rf=0.1,SM Rf=0.8)监测反应混合物。
实施例28:(1S,3S)-N3-(5-乙基吡唑并[1,5-a]嘧啶-7-基)环戊烷-1,3-二胺(28)
在0℃,向搅拌的N-[(1S,3S)-3-[(5-乙基吡唑并[1,5-a]嘧啶-7-基)氨基]环戊基]氨基甲酸叔丁酯(64.0mg,0.1900mmol)的DCM(3.7054mL)溶液中加入三氟乙酸(0.35mL,4.63mmol)。使反应温至室温,并且历经2小时持续搅拌,随后LC-MS显示反应完成。将反应直接浓缩,用戊烷洗涤并且干燥,得到(1S,3S)-N3-(5-乙基吡唑并[1,5-a]嘧啶-7-基)环戊烷-1,3-二胺(17mg,0.0693mmol,37.403%产率)(28)。通过TLC(100%乙酸乙酯;产物Rf=0.1,SM Rf=0.8)监测反应混合物。
实施例29:N-环己基-5-异丙基-吡唑并[15-a]嘧啶-7-胺(29)
将搅拌的7-氯-5-异丙基-吡唑并[1,5-a]嘧啶(100.0mg,0.4800mmol),环己胺(56.76mg,0.5700mmol)和K2CO3(197.44mg,1.43mmol)的MeCN(10mL)溶液加热至回流达16小时。通过TLC(在己烷中的20%乙酸乙酯;产物Rf=0.3,SM Rf=0.6)监测反应混合物。完成后,将反应混合物减压浓缩。然后加入水(50mL)并且用乙酸乙酯(20mL×2)萃取。将合并的有机层合并,应用无水Na2SO4干燥,过滤,浓缩并且通过柱色谱(在己烷中的20%乙酸乙酯)纯化,得到N-环己基-5-异丙基-吡唑并[1,5-a]嘧啶-7-胺(110mg,0.4216mmol,88.399%产率)(29),为灰白色固体。
实施例30:5-异丙基-N-[(3R)-四氢呋喃-3-基]吡唑并[1,5-a]嘧啶-7-胺(30)
将搅拌的7-氯-5-异丙基-吡唑并[1,5-a]嘧啶(100.0mg,0.4800mmol)、(3R)-四氢呋喃-3-胺(49.86mg,0.5700mmol)和K2CO3(197.44mg,1.43mmol)的MeCN(10mL)溶液加热至回流达16小时。将反应混合物减压浓缩,然后加入水(50mL),并且用乙酸乙酯(20mL×2)萃取。合并的有机层用无水Na2SO4干燥并且浓缩。粗产物通过柱色谱(在己烷中的20%乙酸乙酯)纯化,得到5-异丙基-N-[(3R)-四氢呋喃-3-基]吡唑并[1,5-a]嘧啶-7-胺(50mg,0.2016mmol,42.275%产率)(30),为无色稠液体。
实施例31:N-环丁基-5-异丙基-吡唑并[1,5-a]嘧啶-7-胺(31)
将搅拌的7-氯-5-异丙基-吡唑并[1,5-a]嘧啶(100.0mg,0.4800mmol)、环丁胺(40.7mg,0.5700mmol)和K2CO3(197.44mg,1.43mmol)的MeCN(10mL)溶液加热至回流达16小时。将反应混合物减压浓缩,然后加入水(50mL),并且用乙酸乙酯(20mL×2)萃取。合并的有机层用无水Na2SO4干燥。将粗产物通过柱色谱(在己烷中的20%乙酸乙酯)纯化,得到N-环丁基-5-异丙基-吡唑并[1,5-a]嘧啶-7-胺(50mg,0.2135mmol,44.77%产率)(31),为灰白色固体。
实施例32:[(1R,3R)-3-[(5-环丙基吡唑并[1,5-a]嘧啶-7-基)氨基]环戊基]铵; 2,2,2-三氟乙酸盐(32)
在搅拌的N-[(1R,3R)-3-[(5-环丙基吡唑并[1,5-a]嘧啶-7-基]氨基]环戊基]氨基甲酸叔丁酯(110.0mg,0.3100mmol)的HFIP(51.71mg,0.3100mmol)溶液中加入N-[(1R,3R)-3-[(5-环丙基吡唑并[1,5-a]嘧啶-7-基)氨基]环戊基]氨基甲酸叔丁酯(110.0mg,0.3100mmol)和三氟乙酸(0.12mL,1.54mmol)并且在室温搅拌2小时。将反应混合物浓缩并且将所得固体与醚一起研磨,得到[(1R,3R)-3-[(5-环丙基吡唑并[1,5-a]嘧啶-7-基)氨基]环戊基]铵;2,2,2-三氟乙酸盐(58.37mg,0.1572mmol,51.076%产率);为淡棕色无定形固体。通过TLC(100%乙酸乙酯;产物Rf=0.1,SM Rf=0.8)监测反应混合物。
化合物33和34的代表性合成方案:
实施例33a
在0℃,在5,7-二氯吡唑并[1,5-a]嘧啶(200.0mg,1.06mmol)的MeCN(5mL)溶液中加入N-氯琥珀酰亚胺(149.15mg,1.12mmol)。将所得混合物在室温搅拌2小时。将反应混合物减压浓缩,通过柱色谱纯化,得到3,5,7-三氯吡唑并[1,5-a]嘧啶(175mg,0.7867mmol,73.95%产率),为淡黄色固体。通过TLC(在己烷中的20%乙酸乙酯;产物Rf=0.6,SM Rf=0.5)监测反应混合物。
实施例33b
将搅拌的3,5,7-三氯吡唑并[1,5-a]嘧啶(0.4g,1.8mmol)、N-[(1R,3R)-3-氨基环戊基]氨基甲酸叔丁酯(0.4g,1.98mmol)和K2CO3(0.74g,5.39mmol)的MeCN(20mL)溶液加热至回流达16小时。将反应混合物过滤,浓缩并且通过柱色谱(在己烷中的30%乙酸乙酯)纯化,得到N-[(1R,3R)-3-[(3,5-二氯吡唑并[1,5-a]嘧啶-7-基)氨基]环戊基]氨基甲酸叔丁酯(0.5500g,1.4238mmol,79.187%产率),为灰白色固体。通过TLC(在己烷中的40%乙酸乙酯;产物Rf=0.5,SM Rf=0.8)监测反应混合物。
实施例33c
将搅拌的N-[(1R,3R)-3-[(3,5-二氯吡唑并[1,5-a]嘧啶-7-基)氨基]环戊基]氨基甲酸叔丁酯(100.0mg,0.2600mmol)、乙酰胺(22.94mg,0.3900mmol)、Cs2CO3(252.41mg,0.7800mmol)、Pd2(dba)3(23.71mg,0.0300mmol)和Xantphos(43.83mg,0.0500mmol)的二烷(5mL)溶液在密封管中在100℃加热10小时。将反应混合物通过硅藻土垫过滤,减压浓缩并且通过柱色谱纯化,得到N-[(1R,3R)-3-[(5-乙酰氨基-3-氯-吡唑并[1,5-a]嘧啶-7-基]氨基]环戊基]氨基甲酸叔丁酯(70mg,0.1712mmol,66.131%产率),为棕色液体。通过TLC(在己烷中的30%乙酸乙酯;产物Rf=0.4,SM Rf=0.6)监测反应混合物。
实施例33:[(1R,3R)-3-[(5-乙酰氨基-3-氯-吡唑并[1,5-a]嘧啶-7-基)氨基]环
戊基]铵;2,2,2-三氟乙酸盐(33)
在搅拌的N-[(1R,3R)-3-[(5-乙酰氨基-3-氯-吡唑并[1,5-a]嘧啶-7-基)氨基]环戊基]氨基甲酸叔丁酯(65.0mg,0.1600mmol)的HFIP(1.1mL,0.1600mmol)溶液中加入三氟乙酸(0.06mL,0.7900mmol)并且在室温搅拌2小时。将反应混合物浓缩,并且将所得固体用醚研磨,得到[(1R,3R)-3-[(5-乙酰氨基-3-氯-吡唑并[1,5-a]嘧啶-7-基)氨基]环戊基]铵;2,2,2-三氟乙酸盐(47.21mg,0.1117mmol,70.241%产率)(33);为灰白色无定形固体。通过TLC(100%乙酸乙酯;产物Rf=0.1,SM Rf=0.8)监测反应混合物。
实施例34:[(1R,3R)-3-[(5-乙酰氨基吡唑并[1,5-a]嘧啶-7-基)氨基]环戊基]
铵;2,2,2-三氟乙酸盐(34)
在搅拌的N-[(1R,3R)-3-[(5-乙酰氨基吡唑并[1,5-a]嘧啶-7-基)氨基]环戊基]氨基甲酸叔丁酯(65.0mg,0.1700mmol)的HFIP(29.17mg,0.1700mmol)溶液中加入三氟乙酸(0.07mL,0.8700mmol)并且在室温搅拌2小时。将反应混合物浓缩,并且将所得固体与醚一起研磨,得到[(1R,3R)-3-[(5-乙酰氨基吡唑并[1,5-a]嘧啶-7-基)氨基]环戊基]铵;2,2,2-三氟乙酸盐(19.5mg,0.0502mmol,28.925%产率),为棕色固体。通过TLC(100%乙酸乙酯;产物Rf=0.1,SM Rf=0.8)监测反应混合物。
实施例35:(1S,3S)-N3-[5-(1-乙基丙基)吡唑并[1,5-a]嘧啶-7-基]环戊烷-1,3-
二胺(35)
步骤1
将2-乙基丁酸(7.5g,64.57mmol)溶于THF(150mL)中,并且冷却至0℃。在20分钟内,分批加入CDI(16.23g,100.08mmol)。将反应温至室温(rt),并且将混合物在室温搅拌过夜(溶液A)。在另一个烧瓶中,将MgCl2(6.14g,64.57mmol)和3-乙氧基-3-氧代丙酸钾(17g,100.1mmol)与THF(150mL)混合,并且在氩气下在50℃搅拌过夜。将所得白色悬浮液冷却至室温,并且历经10分钟滴加溶液A,并且将反应混合物(RM)在室温搅拌16小时。几分钟后,出现粘稠的无定形固体,数小时后,反应混合物在外观上变得均匀。RM浓缩至约三分之一,溶于半饱和的硫酸氢钾溶液,并且用乙酸乙酯萃取两次。随后将有机层用饱和碳酸氢钠溶液洗涤,合并,经无水硫酸钠干燥,过滤并且蒸发。通过柱色谱纯化,得到4-乙基-3-氧代己酸乙酯(4.3g,23.087mmol,35.8%产率),为透明液体。通过TLC(在己烷中的10%乙酸乙酯,产物Rf=0.6,SM Rf=0.1)监测RM。
步骤2
在70℃历经4小时在4-乙基-3-氧代-己酸乙酯(4.4g,23.62mmol)的乙酸(11mL)悬浮液中分两批(在搅拌第一部分2小时后加入第二部分)加入1H-吡唑-5-胺(4.71g,56.7mmol)。通过TLC指示耗尽SM后,将反应冷却至室温,并且在旋转蒸发仪中蒸发溶剂。将残留物用乙酸乙酯处理并且过滤,得到5-(1-乙基丙基)-4H-吡唑并[1,5-a]嘧啶-7-酮(3.7g,17.7mmol,74.9%产率),为灰白色固体。通过TLC(在二氯甲烷中的5%甲醇,产物Rf=0.3,SM Rf=0.8)监测反应混合物。
步骤3
将搅拌的5-(1-乙基丙基)-4H-吡唑并[1,5-a]嘧啶-7-酮(3.7g,18.03mmol)的POCl3(33.7mL,360.52mmol)溶液加热至回流达4小时。将反应混合物冷却至室温,将过量的试剂在旋转蒸发仪中蒸发,并且将残留物用冰水处理。通过DCM从含水混合物中萃取氯化产物。将有机层分离,经无水Na2SO4干燥,过滤并且通过柱色谱纯化,得到7-氯-5-(1-乙基丙基)吡唑并[1,5-a]嘧啶(3.1g,13.9mmol,76.9%产率),为淡黄色液体。通过TLC(在己烷中的20%乙酸乙酯,产物Rf=0.6,SM Rf=0.1)监测反应混合物。
步骤4
将搅拌的7-氯-5-(1-乙基丙基)吡唑并[1,5-a]嘧啶(2.3g,10.28mmol)、((1S,3S)-3-氨基环戊基)氨基甲酸叔丁酯(2.27g,11.31mmol)和K2CO3(4.26g,30.84mmol)的MeCN(20mL)溶液加热至回流达16小时。将反应混合物过滤,减压浓缩并且通过柱色谱纯化,洗脱剂在己烷中的30%乙酸乙酯,得到N-[(1S,3S)-3-[[5-(1-乙基丙基)吡唑并[1,5-a]嘧啶-7-基]氨基]环戊基]氨基甲酸叔丁酯(4.5g,11.6mmol,112.8%产率),为灰白色固体。通过TLC(在己烷中的40%乙酸乙酯,产物Rf=0.5,SM Rf=0.7)监测反应混合物。
步骤5
在N-[(1S,3S)-3-[[5-(1-乙基丙基)吡唑并[1,5-a]嘧啶-7-基]氨基]环戊基]氨基甲酸叔丁酯(1.0g,2.58mmol)的1,4-二烷(0.2mL)溶液中加入在二烷中的4M HCl(3.22mL,12.9mmol),并且在室温搅拌4小时。将反应混合物真空蒸发,用戊烷研磨,并且从MeCN:H2O冻干,得到[(1S,3S)-3-[[5-(1-乙基丙基)吡唑并[1,5-a]嘧啶-4--7-基]氨基]环戊基]铵二盐酸盐(0.9g,2.5mmol,96.8%产率),为淡黄色粘性固体。通过TLC(100%乙酸乙酯,产物Rf=0.1,SM Rf=0.8)监测反应混合物。1H NMR(400MHz,DMSO-d6)δ15.00(s,1H),9.93-9.86(m,1H),8.51(s,3H),8.30(s,1H),6.84(s,1H),6.58(s,1H),4.95(q,J=7.8Hz,1H),3.77-3.66(m,1H),2.84-2.71(m,1H),2.29-2.05(m,4H),1.94-1.63(m,6H),0.81(t,J=7.4Hz,6H)。LC-MS(m/z 287.21,实测值288.0[M+H+])。
步骤6
在[(1S,3S)-3-[[5-(1-乙基丙基)吡唑并[1,5-a]嘧啶-4--7-基]氨基]环戊基]铵二盐酸盐(0.2g,0.5600mmol)中加入NH3水溶液(4.0mL,0.56mmol)并且在室温搅拌4小时。将反应混合物真空蒸发,用戊烷研磨,并且从MeCN:H2O冻干,得到(1S,3S)-N3-[5-(1-乙基丙基)吡唑并[1,5-a]嘧啶-7-基]环戊烷-1,3-二胺(140mg,0.49mmol,87.8%产率),为淡黄色粘性固体。通过TLC(100%乙酸乙酯,产物Rf=0.1,SM Rf=0.8)监测反应混合物。1HNMR(400MHz,DMSO-d6)δ7.95(d,J=2.2Hz,1H),6.86(s,1H),6.29(d,J=2.2Hz,1H),5.95(s,1H),4.31-4.19(m,1H),3.57-3.44(m,1H),2.52-2.44(m,1H),2.36-2.22(m,1H),2.09-1.79(m,3H),1.80-1.59(m,5H),1.58-1.24(m,3H),0.83(t,J=7.4Hz,6H)。LC-MS(m/z287.21,实测值288.5[M+H+])。
表:化合物数据
实施例35:CDK9/细胞周期蛋白T1抑制
测试了本发明的示例性化合物(1-34)对CDK9/细胞周期蛋白T1的抑制。使用放射测定法(反应时间60分钟)以10-剂量IC50一式两份模式测试化合物,从10μM开始进行3倍系列稀释。对照化合物(星形孢菌素)以10-剂量IC50模式测试,从10μM开始进行3倍系列稀释。反应在10μM ATP下进行。下表列出了测试化合物的结果。将数据标准化为阳性和阴性对照,并且使用GraphPad软件进行曲线拟合,并且在最高化合物浓度下酶活度低于65%下进行曲线拟合。
测试了本发明的示例性化合物(35-126)对CDK/细胞周期蛋白T1激酶的抑制。使用LANCE测定法(反应时间60分钟),以10-剂量IC50一式两份模式测试化合物,从4.3μM开始进行3倍系列稀释。对照化合物(SNS-032)以10-剂量IC50模式测试,从10μM开始进行3倍系列稀释。反应在10μM ATP下进行。下表列出了测试化合物的结果。将数据标准化为阳性和阴性对照,并且使用XLFIT5分析曲线拟合,抑制%对log[化合物浓度],使用4参数对数模型205。fit=(A+((B-A)/(1+((C/x)^D))));Res=(y-fit)
表:细胞周期蛋白T1抑制的结果
功效等级:A=1-500nM;B=501-1000nM;C≥1001nM
测试数据显示本文公开的化合物作为CDK9抑制剂是有效的并且是用于涉及CDK9介导的障碍的治疗的适合候选物。
在本申请中引用的所有参考文献,在审专利申请和公开专利的内容在此明确并入本文作为参考。
前述实施方案仅以示例的方式给出。相关领域的普通技术人员将理解,可以在不脱离本发明的精神和范围的情况下进行多种修改。
Claims (10)
1.化合物:
或其药学上可接受的盐。
2.药物组合物,其包含药学上可接受的载体和根据权利要求1所述的化合物或其药学上可接受的盐。
3.化合物:
4.药物组合物,其包含药学上可接受的载体和根据权利要求3所述的化合物。
5.根据权利要求1所述的化合物在制备用于治疗CDK9介导的疾病的患者的药物中的用途。
6.根据权利要求5所述的用途,其中CDK9介导的疾病是由MYC-1或MCL-1的异常表达引起的癌症、血液恶性肿瘤或实体瘤。
7.根据权利要求6所述的用途,其中CDK9介导的疾病是急性骨髓性白血病、原发性腹膜癌、慢性淋巴细胞性白血病、复发性多发性骨髓瘤、非霍奇金淋巴瘤、急性淋巴母细胞性白血病、急性双表型性白血病、晚期乳癌、非小细胞肺癌或肝癌。
8.根据权利要求3所述的化合物在制备用于治疗CDK9介导的疾病的患者的药物中的用途。
9.根据权利要求8所述的用途,其中CDK9介导的疾病是由MYC-1或MCL-1的异常表达引起的癌症、血液恶性肿瘤或实体瘤。
10.根据权利要求9所述的用途,其中CDK9介导的疾病是急性骨髓性白血病、原发性腹膜癌、慢性淋巴细胞性白血病、复发性多发性骨髓瘤、非霍奇金淋巴瘤、急性淋巴母细胞性白血病、急性双表型性白血病、晚期乳癌、非小细胞肺癌或肝癌。
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