CN117396470A - 作为pi3k的可逆和不可逆共价抑制剂的三嗪衍生物 - Google Patents
作为pi3k的可逆和不可逆共价抑制剂的三嗪衍生物 Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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Abstract
本发明涉及新的三嗪化合物,其含有化学反应性基团(弹头)并且作为可逆和不可逆共价抑制剂。已经引入接头以靶向于距离核心可逆抑制剂
Description
技术领域
本发明涉及含有化学反应基团(弹头)的新的三嗪化合物,其作为治疗剂和化学探针用于调节细胞活性,例如信号转导、增殖、分化和细胞死亡。本发明的化合物调节激酶活性,特别是磷酸肌醇3-激酶(PI3K)的激酶活性。
背景技术
蛋白激酶参与信号事件,并控制响应细胞外介质或刺激物(包括生长因子、细胞因子或趋化因子)的细胞活化、生长、分化、存活和迁移。
增加的蛋白激酶活性涉及许多疾病,包括癌症、炎性病症、代谢和免疫疾病。这些可直接或间接地由因突变、过表达或酶活性的不适当控制而导致的控制机制失败引起。
磷酸肌醇3-激酶(PI3K)信号传导通路在许多细胞过程中起关键作用,包括细胞生长、增殖和存活。PI3K家族根据它们的氨基酸序列、同源性和底物特异性分为三类。I类PI3K在细胞表面受体的下游被激活,所述受体包括受体蛋白酪氨酸激酶(RTK)、G蛋白偶联受体(GPCR)和免疫球蛋白受体。IA类PI3K是专性异二聚体,由催化亚单位(p110α、p110β、或p110δ)和相关的调节亚单位(p85α、p85β、p50α、p55α、或p55γ)组成。IB类PI3K在GPCR的下游操作,并且由催化亚单位(p110γ)和衔接亚单位(p84或p101)组成。细胞表面受体激活PI3K产生PtdIns(3,4,5)P3,作为蛋白激酶B(PKB/Akt)和3-磷酸肌醇依赖性蛋白激酶1(PDK1)的停靠位点。这导致激酶结构域在两个调节位点处磷酸化,Thr308被PDK1磷酸化而Ser473被mTOR复合物2(mTORC2)磷酸化。PI3K/mTOR通路的超活化可在该信号级联的多个水平发生,最终促进癌症生长和进展。肿瘤抑制因子磷酸酶和张力蛋白同源物(PTEN)的缺失或失活、细胞表面受体的突变或扩增以及PIK3CA中激活热点突变的存在,在人类致癌作用中起关键作用。此外,PI3K/mTOR轴的过度活化与对多种癌症治疗的抗性有关。因此,PI3K抑制剂被认为是癌症治疗中有价值的资产。
已经进行了相当大的努力来开发靶向PI3K信号传导的药物,并且它们中的许多目前正在临床试验中评价。选择性PI3Kα抑制剂可有益于PIK3CA突变肿瘤和PIK3CA相关的过度生长综合征(PROS),使泛PI3K抑制剂的非靶代谢副作用最小化。来自Novartis的BYL719/Alpelisib/PIKRAY和来自Genentech的GDC-0032/Taselisib作为可逆修饰剂,并被称为PI3Kα选择性抑制剂。然而,在体内实验所需的浓度下,它们不能区分PI3K同工型。目前仅有一种高α位PI3Kα共价抑制剂可用,称为CNX-1351,但其显示有限的体外和细胞效力、低水溶性和代谢不稳定性。本专利申请描述了具有PI3K抑制活性并作为不可逆共价和可逆共价改性剂的某些三嗪衍生物,及其作为药物的用途。与CNX-1351相比,本文涵盖的化合物在效力、代谢稳定性和药物相似性性质方面具有显著的优点。此外,本专利申请描述了用于开发共价激酶抑制剂的接头。
发明内容
本发明涉及作为不可逆调节剂的新的基于三嗪的化合物及其作为治疗剂和化学探针的用途。
本发明的第一方面涉及式(IV)化合物,特别是式(IVa)化合物,或其前药、代谢物、互变异构体、溶剂化物或药学上可接受的盐,
其中
·X为CH或N,
·Y为H或F,
·R1和R2各自独立地选自H、CH3、环丙基、–F、-CH2–F、-CH2-CH2–F、CN、 其中R5为F或CH3,R6为C1-6烷基且z为0、1或2,
·R3为C1-3烷基或两个残基R3形成桥–(CH2)r–,其中r为1、2或3,
·v为0、1、2、3或4,
·R4为H、F或–CN,
·L2为选自 的部分,其中R5为C1-3烷基、F、-CH2CN或–CN且t为0、1或2,
·W1为CO或CH2,
·W2选自O、CH2和CO,
·U选自O、CH2、CO、NH、和N(CH3),
·n为1或2。
本发明的第二方面涉及用于治疗疾病的根据本发明第一方面的化合物。
本发明的第三方面涉及用于***疾病、过度生长综合征、神经疾病病症、免疫疾病病症的根据本发明第一方面的化合物。
本发明的第四方面涉及式(VI)中间体,
其中R1、R2、R4、L2、W2、U、n和W1如上所述定义,
Z为–OH、Br、COOH、–C(OH)NH2。
本发明的具体实施方式
现在将详细参考本发明的某些实施方式,其实例在所附结构和式中说明。虽然将结合列举的实施方式描述本发明,但是应当理解,它们不是要将本发明限制于这些实施例。相反,本发明旨在覆盖可包括在由权利要求限定的本发明的范围内的所有替代、修改和等同形式。本领域技术人员将认识到许多与本文所述的那些类似或等同的方法和材料,它们可用于本发明的实践中。本发明决不限于本文所述的方法和材料。
定义
如本文所用的术语“烷基”是指一至五个碳原子的饱和直链一价烃基(C1–C5)。烷基的实例包括但不限于甲基、乙基、1-丙基(正丙基)、1-丁基(正丁基)。
术语“杂环”、“杂环基”和“杂环”在本文中可互换使用,是指4至6个环原子的饱和或不饱和碳环基团,其中至少一个环原子是杂原子,特别是氮,其余环原子是碳原子,其中一个或多个环原子任选独立地被一个或多个取代基取代,所述取代基特别选自–CH3和–F。
术语“手性”是指具有镜像配偶体的不可重叠性的性质的分子,而术语“非手性的”是指可重叠在其镜像配偶体上的分子。
术语“立体异构体”是指具有相同化学组成但在原子或基团的空间排列方面不同的化合物。
“非对映异构体”是指具有两个或多个手性中心的立体异构体,其中化合物彼此不是镜像。非对映体具有不同的物理性质,例如熔点、沸点、光谱性质以及化学和生物反应性。非对映体的混合物可以在高分辨率分析操作如电泳和色谱下分离。
“对映体”是指化合物的两种立体异构体,它们彼此不能重叠成镜像。
本文所用的立体化学定义和惯例通常遵循S.P.Parker,Ed.,McRaw-HiffDictionary of Chemical Terms(1984),McGraw-Hill Book Company,New York;和Eliel,E.and Wilen,S.,“Stereochemistry of Organic Compounds”,John Wiley&Sons,Inc.,New York,1994。本发明的化合物可以含有不对称中心或手性中心,因此以不同的立体异构形式存在。本发明化合物的所有立体异构形式,包括但不限于非对映异构体、对映异构体和阻转异构体,以及它们的混合物如外消旋混合物,构成本发明的一部分。许多有机化合物以光学活性形式存在,即它们具有旋转平面偏振光平面的能力。在描述光学活性化合物时,前缀R和S用于表示分子围绕其手性中心的绝对构型。对于给定的化学结构,这些立体异构体是相同的,除了它们是彼此的镜像。特定的立体异构体也可称为对映异构体,并且此类异构体的混合物通常称为对映异构体混合物。对映体的50∶50混合物被称为外消旋混合物或外消旋体。术语“互变异构体”或“互变异构形式”是指不同能量的结构异构体,其可通过低能障相互转化。例如,质子互变异构体包括通过质子迁移的相互转化,例如酮-烯醇和亚胺-烯胺异构化。
术语“烯酮”是指α,β-不饱和羰基,其是由与酮共轭的烯烃组成的一类有机化合物。最简单的烯酮是甲基乙烯基酮(丁烯酮)或CH2=CHCOCH3。它们在羰基碳以及β-碳都是亲电子的。视情况而定,任一位点都受到亲核试剂的攻击。烯烃的加成被称为迈克尔加成,并且在本发明中用于共价修饰PI3Kα中的半胱氨酸862。
术语“丙烯酰胺”是指衍生自丙烯酸并且具有化学通式CH2=CHC(O)NH2的酰胺。丙烯酰胺用于本发明的化合物中,并且在PI3Kα中与半胱氨酸862进行迈克尔加成。
术语“PI3K”指磷酸肌醇3-激酶。
术语“PI3Kalpha”、“PI3Kα”或“p110a蛋白”涉及PI3KCA基因编码的PI3K的亚单位。
术语“不可逆的”或“不可逆抑制剂”是指能够以基本上不可逆的方式共价结合PI3激酶的抑制剂,而可逆的抑制剂能够结合激酶(但通常不能与激酶形成共价键),因此可从PI3激酶解离。一旦形成共价键,不可逆抑制剂将保持基本上与激酶结合。用于鉴定化合物是否充当不可逆抑制剂的方法是本领域普通技术人员已知的。这些方法包括但不限于,用激酶对化合物的抑制谱进行酶动力学分析、使用在抑制剂化合物存在下修饰的蛋白质药物靶标的质谱分析、使用X射线晶体学来解出蛋白质药物靶标和抑制剂化合物之间的复合物、不连续暴露(也称为“洗出”实验),以及本领域技术人员已知的其它方法。
术语“可逆共价”是指共价修饰靶向半胱氨酸的抑制剂,然而将非共价键合的反应物与键合产物分开的自由能差接***衡,并且活化屏障相对低,使得容易发生裂解化学键的逆反应(实例包括基于腈的可逆共价抑制剂)。
术语“弹头”或“弹头基团”是指存在于本发明化合物上的官能团,其中该官能团能够共价结合存在于靶蛋白的结合袋中的氨基酸残基(例如半胱氨酸、赖氨酸、组氨酸或能够被共价修饰的其它残基),从而不可逆地抑制蛋白。弹头基团对于共价地和不可逆地抑制蛋白质是必需的。
术语“抑制剂”定义为以可测量的亲和力结合并抑制PI3激酶的化合物。在某些实施方式中,抑制剂的特征在于IC50和/或不可逆失活的速率常数(kinact)。
术语“CNX-1351”是指1-[4-[[2-(1H-吲唑-4-基)-4-(4-吗啉基)噻吩并[3,2-d]嘧啶-6-基]甲基]-1-哌嗪基]-6-甲基-5-庚烯-1,4-二酮(CAS1276105-89-5)。
本文所用的短语“药学上可接受的盐”是指本发明化合物的药学上可接受的有机或无机盐。如果本发明的化合物是碱,则所需的药学上可接受的盐可以通过本领域可获得的任何合适的方法制备,例如,用无机酸如盐酸、氢溴酸、硫酸、硝酸、甲磺酸、磷酸等,或用有机酸如乙酸、三氟乙酸、马来酸、琥珀酸、扁桃酸、富马酸、丙二酸、丙酮酸、草酸、乙醇酸、水杨酸、吡喃糖苷酸如葡糖醛酸或半乳糖醛酸,α-羟基酸如柠檬酸或酒石酸,氨基酸如天冬氨酸或谷氨酸,芳香酸如苯甲酸或肉桂酸,磺酸如对甲苯磺酸或乙磺酸等,处理游离碱。
术语“保护基”是指在化合物上的其它官能团的反应期间通常用来阻断或保护特定官能团的取代基。例如,“氨基保护基”是与氨基连接的阻断或保护化合物中氨基官能团的取代基。合适的氨基保护基包括乙酰基、三氟乙酰基、叔丁氧基羰基(BOC)、苄氧基羰基和9-芴基亚甲氧基羰基(Fmoc)。关于保护基及其用途的一般描述,参见T.W.Greene,Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991。
术语“本发明的化合物”和“式(I)、(II)、(III)化合物”包括其立体异构体、几何异构体、互变异构体、溶剂化物、药学上可接受的盐及其盐的溶剂化物。
具体实施方式
本发明涉及作为PI3激酶、特别是PI3Kα的可逆或不可逆调节剂的新的基于三嗪的化合物,以及它们作为治疗剂和化学探针的用途。
与已知抑制剂CNX-1351相比,本发明化合物具有更高的水溶性(>30倍)、更高的体外和细胞内效力(>7倍)、和更高的代谢稳定性。
本发明的一个重要方面涉及优选分子(特别是特征在于形成丙烯酰胺部分的弹头的抑制剂)中的优良反应参数,其导致高度选择性的靶接合和降低的或可忽略的脱靶反应性:
i)共价抑制剂的非靶向反应由抑制剂解离常数Ki定义,其描述了酶(E)和抑制剂(I)复合物形成的可逆平衡
E+I←→E~I
和kinact,其定义了抑制剂和酶之间形成共价抑制剂-酶复合物(EI)的共价键的反应速率:
E~I→EI
ii)与生理环境如细胞和体液中存在的普遍存在的巯基(S)和其它亲核试剂的脱靶反应由弹头的固有反应性驱动,其由驱动S和I转化形成巯基加合物(SI)的kchem定义
S+I→SI
高固有弹头反应性(高kchem值)导致形成不需要的巯基加合物,导致化合物损失、细胞组分的共价修饰、毒性和抗化合物免疫反应:
如表1所示,优选的分子显示低的kchem、低的Ki、高的kinact、高的kinact/Ki比值,以保证更好的开对关靶结合。
本发明的第一方面涉及式(IV)化合物,特别是式(IVa)化合物,或其前药、代谢物、互变异构体、溶剂合物或药学上可接受的盐,特别是其互变异构体、溶剂合物或药学上可接受的盐,
其中
·X为CH或N,特别是N,
·Y为H或F,特别是H,
·R1和R2各自独立地选自H、CH3、环丙基、–F、-CH2–F、-CH2-CH2–F、–CN、 其中R5为F或CH3,R6为C1-6烷基且z为0、1或2,
·R3为C1-3烷基或两个残基R3形成桥–(CH2)r–,其中r为1、2或3,特别是r为1或2,
·v为0、1、2、3或4,
·R4为H、F或–CN,
·L2为选自 的部分,其中R5为C1-3烷基、F、-CH2CN或–CN且t为0、1或2,
·W1为CO或CH2,
·W2选自O、CH2和CO,
·U选自O、CH2、CO、NH、和N(CH3),特别是O、CH2、NH、和N(CH3),
·n为1或2。
本发明的抑制剂包含多环骨架和通过接头与骨架连接的所谓弹头。所述支架包含被三个杂环取代的三嗪部分,即吗啉基、哌嗪基和吡啶基或嘧啶基部分。吡啶基或嘧啶基部分被氟化甲基和胺部分取代。吗啉基部分为任选取代的。哌嗪基与由L2、W2、U、C1-2烷基和W1组成的接头结合。
这些分子具有某些活性官能团,被称为“弹头”。本文所用的术语“弹头”或“弹头基团”是指存在于本发明化合物上的官能团,其中该官能团能够与存在于靶蛋白的结合袋中的氨基酸残基(例如半胱氨酸、赖氨酸、组氨酸或能够被共价修饰的其它残基)共价结合,从而不可逆地抑制该蛋白。
本发明的抑制剂可以共价结合PI3Kα的Cys862。这种抑制剂的特征在于弹头中的碳-碳双键。键的稳定性可以通过取代基R1、R2和R4调节,以获得形成稳定共价键或可逆共价键的抑制剂。
本文公开的化合物显示良好的PI3激酶抑制,特别是良好的PI3Kα抑制,以及良好的稳定性。
在某些实施方式中,R1为H、CH3或-CH2F。
在某些实施方式中,R2为H或环丙基。
在某些实施方式中,R2为环丙基且R4为–CN。
在某些实施方式中,R3为C1-3烷基,特别是CH3。
在某些实施方式中,v为0、1或2,更特别是0或1。
在某些实施方式中,所述化合物为式(V)化合物,特别是式(Va)化合物,
其中X、Y、R1、R2、R3、R4、W1、n、U、W2、L2如上所述定义,
v为0或1。
在某些实施方式中,根据本发明第一方面的化合物是式(I)或(II)化合物,
其中
R为H或CH3,
R1为H或CH3,
L2为选自 的部分,其中R5为C1-3烷基、F、-CH2CN或–CN且t为0、1或2,
其中
R3为H或CH3
L2为选自 的部分,其中R5为C1-3烷基、F、-CH2CN或–CN且t为0、1或2
当U为CH2时W2为O,或当U为O时为W2为CH2;
当W2为CH2时U为O,或当W2为O时U为CH2;
R1为H或-CH2–F,
R2为H或环丙基,
R4为H或F,
和其可逆的类似物、前药、代谢物、互变异构体、溶剂化物和药学上可接受的盐(I)、(II)。
在某些实施方式中,本发明第一方面的化合物是式(Ia)化合物,
其中
R为H或CH3;
W1为CO和CH2;
L2为选自 的部分,其中R5为C1-3烷基、F、-CH2CN或–CN且t为0、1或2。
此外,本发明涉及如上文所定义的式(I)、(II)化合物的合成,包括所述化合物的互变异构体、溶剂化物、中间体、前药和盐。
本发明的第二方面涉及用于治疗疾病的根据本发明第一方面的化合物。
本发明的另一方面涉及用于治疗疾病的根据本发明第一方面的化合物,其中所述疾病由PI3KCA基因的激活突变或I类PI3K、特别是PI3Kα的激活引起。I类PI3K,特别是PI3Kα的活化可以通过细胞表面受体、上游过表达或突变的上游激活子或PI3KCA基因或PI3K相互作用和调节蛋白的活化突变,包括PIK3R1、PIK3R1、PIK3R1的基因产物,而发生。
本发明的第三方面涉及用于***疾病、过度生长综合征、神经疾病、免疫疾病的根据本发明第一方面的化合物。
在某些实施方式中,所述肿瘤是实体瘤且/或所述肿瘤疾病选自淋巴瘤和白血病。
在某些实施方式中,根据本发明第一方面的化合物用于治疗增殖性疾病;任何良性或恶性肿瘤;从肉瘤出现的肿瘤;肺;支气管;***;***;胰腺;胃肠癌;结肠;直肠;结肠癌;结直肠腺瘤;甲状腺;肝脏;肝内胆管;肝细胞;肾上腺;胃;胃;胶质瘤;成胶质细胞瘤;子宫内膜;黑素瘤;肾;肾盂;膀胱;子宫体;子宫颈;***;卵巢;多发性骨髓瘤;食道;
治疗白血病;急性髓细胞性白血病;慢性髓细胞性白血病;淋巴细胞白血病;骨髓性白血病;脑;脑癌;口腔和咽;喉;小肠;非霍奇金淋巴瘤;黑素瘤;绒毛状结肠腺瘤;瘤形成;上皮特征的瘤形成;淋巴瘤;乳腺癌的治疗;基底细胞癌;鳞状细胞癌;光化性角化病;肿瘤疾病,包括实体瘤;颈部或头部的肿瘤;真性红细胞增多症;特发性血小板增多症;骨髓纤维化伴骨髓化生;和华氏巨球蛋白血症;考登氏病和多发性错构瘤综合征,包括散发性癌症,例如乳腺癌、甲状腺癌、子宫癌、和在患有这些综合征的患者中出现的其它癌症;PIK3CA相关过度生长谱(PROS)相关病症,包括纤维脂肪增生(也称为纤维脂肪过度生长)、CLOVES综合征、大脑-毛细血管畸形综合征(MCAP综合征)、半增生-多发性脂肪瘤综合征(HHML综合征)、半脑性血小板增多症、和其它器官中的面部和浸润脂肪瘤;一般性血管和淋巴畸形、和肿瘤新生血管形成;眼部新生血管和黄斑变性(AMD)、增殖性糖尿病性视网膜病(PDR)、和早产儿视网膜病(ROP)。
本发明还涉及作为具有抗癌活性的化疗剂的这类靶向PI3K的化合物、其药物制剂,它们潜在地可用于治疗由增强的细胞***、生长、迁移、粘附和转移调节的疾病、病况和/或病症。该化合物可抑制哺乳动物中的肿瘤生长,并可用于治疗人类癌症患者。
本发明还涉及通过调节弹头的出口载体(6元、5元环上的间位、邻位或4元环上)来调节抑制剂的固有反应性的能力。
此外,对于癌症治疗,本发明还涉及使用这类化合物治疗由细胞过度活化引起的病原性细胞状态。靶向PI3K的分子可用于治疗多种过度增殖性疾病,用于治疗或预防由PI3K调节的疾病或病况。
本发明还涉及作为化学探针的靶向PI3K的化合物,以剖析PI3K同工型在癌症和代谢中的作用。
此外,本发明涉及使用这些化合物进行体外、原位、和体内诊断操作或治疗哺乳动物细胞、生物体或相关病理状况或生产过程的方法。
在另外的方面,本发明涉及包含如上文所定义的式(I)、(II)化合物的药物组合物,以及预防或治疗由PI3K调节的疾病或病症,特别是治疗过度增殖性病症的方法。
本发明的另外的方面涉及有效量的如上文所定义的式(I)、(II)化合物单独或与标准治疗如化疗、放疗、靶向疗法或免疫疗法联合用于治疗由PI3K调节的疾病或病症,特别是过度增殖性病症,的用途。
在另外的方面,本发明涉及式(III)化合物在靶向蛋白激酶的共价化合物的设计和合成中作为接头的用途。
其中
U等于NH、NCH3、O或CH2;
Y等于CO、O或CH2;
L2为氮杂环丁烷或吡咯烷或哌啶,其中箭头表示式(III)中的键:
本发明的另一方面包括如上文所定义的式(I)、(II)、(III)化合物,包括所述化合物的中间体、前药和盐,的制备方法、分离方法和纯化方法。
本发明的另一方面包括用于制备如上文所定义的式(I)、(II)、(III)化合物的新颖中间体。
本发明的另一方面包括式(I)、(II)、(III)化合物关于CNX-1351的新的、改进的性质。这些性质包括但不限于体外和细胞效力、代谢稳定性、溶解性和药物相似性性质。
本发明的另一方面包括通过修饰出口载体(6元、5元环上的间位、邻位或4元环上)来调节抑制剂的固有反应性。
本发明的不可逆抑制剂共价修饰所针对的PI3Kα的半胱氨酸残基为非保守Cys862。
医学治疗、剂型和盐
类似地,在本发明的范围内的是一种在有需要的患者中***疾病、过度生长综合征、神经疾病病症和/或免疫性疾病病症的方法,其包括向所述患者施用根据以上描述的化合物。
类似地,提供了用于预防或***疾病、过度生长综合征、神经疾病病症和/或免疫性疾病病症的剂型,其包含根据本发明的任何上述方面或实施方式的化合物。
技术人员知道本文提及的任何具体提及的药物化合物可以作为药物的药学上可接受的盐存在。药学上可接受的盐包括离子化的药物和带相反电荷的抗衡离子。药学上可接受的阴离子盐形式的非限制性实例包含乙酸盐、苯甲酸盐、苯磺酸盐、酒石酸氢盐、溴盐、碳酸盐、氯盐、柠檬酸盐、乙二胺四乙酸盐、乙二磺酸盐、恩波酸盐、十二烷基磺酸盐、富马酸盐、葡庚糖酸盐、葡糖酸盐、氢溴酸盐、盐酸盐、碘盐、乳酸盐、乳糖酸盐、苹果酸盐、马来酸盐、扁桃酸盐、甲磺酸盐、溴化甲基盐、硫酸甲基盐、黏酸盐、萘磺酸盐、硝酸盐、帕莫酸盐、磷酸盐、焦磷酸盐、水杨酸盐、水杨酸氢盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、甲苯磺酸盐、碘化三乙基盐和戊酸盐。药学上可接受的阳离子盐形式的非限制性实例包含铝盐、苄星盐、钙盐、乙二胺盐、赖氨酸盐、镁盐、葡甲胺盐、钾盐、普鲁卡因盐、钠盐、氨丁三醇盐和锌盐。
剂型可以是用于肠内施用,例如鼻、颊、直肠、经皮或口服施用,或作为吸入形式或栓剂。或者,可以使用肠胃外给药,例如皮下、静脉内、肝内或肌内注射形式。任选地,可以存在药学上可接受的载体和/或赋形剂。
局部给药也在本发明的有利用途的范围内。本领域技术人员知道用于提供局部制剂的宽范围的可能配方,例如Benson and Watkinson(Eds.),Topical and TransdermalDrug Delivery:Principles and Practice(1st Edition,Wiley 2011,ISBN-13:978-0470450291);和Guy and Handcraft:Transdermal Drug Delivery Systems:Revised andExpanded(2nd Ed.,CRC Press 2002,ISBN-13:978-0824708610);Osborne and Amann(Eds.):Topical Drug Delivery Formulations(1st Ed.CRC Press 1989;ISBN-13:978-0824781835)。
药物组合物和施用
本发明的另一方面涉及包括本发明化合物、或其药学上可接受的盐、和药学上可接受的载体,的药物组合物。在进一步的实施方式中,组合物包括至少二个药学上可接受的载体,例如本文所述的那些。
在本发明的某些实施方式中,本发明的化合物通常被配制成药物剂型以提供药物的容易控制的剂量并给予患者简洁的且容易操作的产品。
在涉及本发明化合物的局部用途的本发明实施方式中,以适于局部给药的方式配制药物组合物,例如水溶液、悬浮液、软膏、乳膏、凝胶或可喷雾制剂,例如用于通过气雾剂等递送,包括活性成分以及本领域技术人员已知的增溶剂、稳定剂、张力增强剂、缓冲剂和防腐剂中的一或更多个一起。
所述药物组合物可以配制成用于肠内给药,特别是口服给药或直肠给药。此外,本发明的药物组合物可以制成固体形式(包含但不限于胶囊、片剂、丸剂、颗粒剂、粉剂或栓剂),或液体形式(包含但不限于溶液、悬浮液或乳液)。
所述药物组合物可以配制成用于肠胃外施用,例如通过静脉内输注、皮内、皮下或肌内施用。
本发明化合物的剂量方案将根据已知因素而变化,例如特定药剂的药效学特征及其施用模式和途径;接受者的人种、年龄、性别、健康、医学状况、和体重;症状的性质和程度;并行治疗的种类;治疗频率;给药途径、患者的肾和肝功能、以及所需的效果。在某些实施方式中,本发明的化合物可以以单次日剂量施用,或者总日剂量可以以每日二次、三次、或四次的分剂量施用。
在某些实施方式中,本发明的药物组合物可以是约1–1000mg活性成分的单位剂量,用于约50–70kg的受试者。化合物、药物组合物、或其组合的治疗有效剂量取决于所治疗的受试者的物种、体重、年龄和个体状况、病症或疾病或其严重性。普通的内科医生、临床医生或兽医可以容易地确定预防、治疗或抑制病症或疾病进展所需的每个活性成分的有效量。
本发明的药物组合物可以进行常规的制药操作,例如灭菌和/或可以含有常规的惰性稀释剂、润滑剂、或缓冲剂,以及佐剂,例如防腐剂、稳定剂、润湿剂、乳化剂和缓冲剂等。它们可以通过标准方法生产,例如通过常规的混合、制粒、溶解或冻干方法。许多制备药物组合物的流程和方法是本领域已知的,参见例如L.Lachman et al.The Theory andPractice of Industrial Pharmacy,4th Ed,2013(ISBN 8123922892)。
根据本发明的制造方法和治疗方法
作为另外的方面,本发明还包括如本文鉴定的根据本发明第一方面的化合物或如上文详细说明的其药学上可接受的盐在制备用于治疗或预防选自肿瘤疾病、过度生长综合征、神经疾病病症和/或免疫疾病病症的病况的药物的方法中的用途。
类似地,本发明包括治疗已被诊断患有与肿瘤疾病、过度生长综合征、神经疾病病症和/或免疫疾病病症相关的疾病的患者的方法。该方法需要向患者施用有效量的如本文详细说明的如本文鉴定出的化合物(具体的)、或其药学上可接受的盐。
凡是单一可分离特征的替代方案,例如,同种型蛋白或编码序列、配体类型或医学适应症,在此作为“实施方式”列出,应理解为这些替代方案可自由组合,形成本文所公开的本发明的离散实施方式。因此,可检测标记的任何替代实施方式可以与配体的任何替代实施方式组合,并且这些组合可以与本文提及的任何医学适应症或诊断方法组合。
通过以下实施例和附图进一步说明本发明,从这些实施例和附图中可以得到进一步的实施方式和优点。这些实施例旨在说明本发明而不是限制其范围。
在某些实施方式中,根据本发明第一方面的化合物选自下表中所示的化合物1至50。
在某些实施方式中,根据本发明第一方面的化合物选自下表中所示的化合物1至52。最优选的是下式所示的化合物:
(相应结构的名称是使用ChemBioDraw Ultra,16.0版产生的)。
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最优选的接头是下式所示的下列化合物(及其相应的对映体):
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附图说明
本发明的一些化合物与CNX-1351相比的总结数据:固有反应性和体外数据(表1);本发明的一些化合物和CNX-1351的细胞效力(表2)。
图1:使用用I期代谢辅因子NADPH强化的大鼠肝微粒体,对18、25和33以及CNX-1351的代谢稳定性。
实施例
本发明化合物的制备
本发明的化合物可以通过合成路线合成,所述合成路线包括与化学领域中众所周知的那些方法类似的方法,特别是根据本文包含的描述。原料通常可从商业来源获得或使用本领域技术人员熟知的方法容易地制备。
为了说明的目的,方案1–4显示了制备本发明化合物以及关键中间体的一般方法。对于各个反应步骤的更详细描述,参见下文实施例。本领域技术人员将理解,其它合成途径可用于合成本发明的化合物。尽管在方案中描述了具体的起始原料和试剂,并在下面讨论,但其它起始原料和试剂可以容易地被取代以提供各种衍生物和/或反应条件。此外,根据本公开内容,使用本领域技术人员公知的常规化学,可以进一步修饰通过下述方法制备的许多化合物。
在制备本发明的化合物时,可能需要对中间体的远端官能团(例如伯胺或仲胺)进行保护和脱保护。对这种保护的需要将根据远端官能团的性质和制备方法的条件而变化。合适的氨基保护基包括叔丁氧羰基(BOC)或N,N-二甲基甲脒基。本领域技术人员容易确定对这种保护的需要。关于保护基及其用途的一般描述,参见T.W.Greene,ProtectiveGroups in Organic Synthesis,John Wiley&Sons,New York,1991。
方案1
方案1显示了使用亲核芳族取代和铃木偶联制备抑制剂结构单元的一般方法。试剂和条件:(i)Et3N,DCM,-50℃,3h;(ii)1-boc-哌嗪,DIPEA,EtOH,0℃→室温,5小时;(iii)N-[5-溴-4-(二氟甲基)嘧啶-2-基]-N-[(叔丁氧基)羰基]氨甲酸叔丁酯,联硼酸频哪醇酯,AcOK,Pd(dppf)Cl2,二烷,95℃,1.5h,(2)一氯三嗪,XPhosPdG2(催化剂),K3PO4,H2O,100℃,过夜,(3)HCl,二/>烷/H2O,80℃,过夜。
方案2
方案2显示了制备具有酰胺间隔基的式(I)的共价抑制剂的一般方法。R1为H或CH3。试剂和条件:(i)结构单元或HCl盐,HCTU,DIPEA,DMF,0℃→室温,4–16h;(ii)HCl的二烷溶液(4M),THF,室温,3–16h。
方案3
方案3显示了制备式(II)化合物的方法。首先,通过亲核取代,接着使用在水/THF中的强碱使酯水解,合成在接头中携带醚的酸。试剂和条件:(i)NaH(60%分散液于矿物油中),DMF,0℃,15分钟;(ii)LiOH(5M于H2O中),THF;(iii)结构单元或HCl盐,HCTU,DIPEA,DMF,0℃→室温,2小时;(iv)HCl的二烷溶液(4M),THF,室温,过夜。
方案4
方案4显示了制备式(II)化合物的方法。首先,通过亲核取代,接着使用在水/THF中的强碱使酯水解,合成在接头中携带醚的酸。试剂和条件:(i)NaH(60%分散液于矿物油中),DMF,0℃,15分钟;(ii)LiOH(5M于H2O中),THF;(iii)结构单元或HCl盐,HCTU,DIPEA,DMF,0℃→室温,2小时;(iv)HCl的二烷溶液(4M),THF,室温,过夜。
分离方法
在制备本发明化合物的方法中,将反应产物彼此分离和/或与原料分离可能是有利的。通过本领域常用的技术将每个步骤或系列步骤的所需产物分离和/或纯化至所需的同质程度。通常,这种分离包括萃取、从溶剂或溶剂混合物中结晶、或色谱。色谱可涉及任何数量的方法,包括例如:反相和正相;高压、中压和低压液相色谱方法和装置;小规模分析;制备型薄层或厚层色谱,以及小规模薄层和快速色谱的技术。
合适的分离方法的选择取决于所涉及的材料的性质,例如,色谱中极性官能团的存在或不存在,多相提取中在酸性和碱性介质中材料的稳定性。本领域技术人员将应用最可能实现所需分离的技术。
实施例
实施例旨在说明本发明而不是限制本发明。
实施例中描述的化学反应可以容易地适用于制备本发明的许多其它抑制剂,并且用于制备本发明化合物的替代方法被认为在本发明的范围内。例如,本发明的非示例性化合物的合成可以通过本领域技术人员显而易见的修改成功地进行,例如通过适当地保护干扰基团,通过利用除了所述那些之外的本领域已知的其它合适的试剂,和/或通过对反应条件进行常规修改。或者,本文公开的或本领域已知的其它反应将被认为可应用于制备本发明的其它化合物。
试剂以最高商业质量购自Acros Organics、Sigma-Aldrich、Apollo Scientific或Fluorochem,并且不经进一步纯化而使用。溶剂购自Acros Organics,带分子筛的瓶包装。格利雅反应、交叉偶联反应和肽偶联反应在氮气气氛下在无水溶剂中进行,并且玻璃器皿在使用前经烘箱干燥。薄层色谱(TLC)板购自Merck KGaA(Polygram SIL/UV254,0.2mm带有荧光指示剂的二氧化硅),UV光(254nm)用于使化合物显色。使用预装的硅胶柱(40–60μm粒度RediSep),用Isco CombiFlash Company Systems进行快速色谱。1H、19F和13C NMR光谱在Bruker Avance400分光计上记录。NMR谱在氘代溶剂,即CDCl3或(CD3)2SO中获得。化学位移(δ值)以ppm报告,并校正至氘化溶剂的信号(对于CDCl3为7.26ppm(1H NMR)和77.16ppm(13C NMR);并对于(CD3)2SO为2.50ppm(1H NMR)和39.52ppm(13C NMR)。19F NMR光谱相对于作为外部标准的CFCl3(δ=0ppm)进行了校准。当报告峰多重性时,使用下列缩写:s(单峰)、d(双重峰)、dd(双重双重峰)、t(三重峰)、td(三重双重峰)、q(四重峰)、dq(双重四重峰)、m(多重峰)、br(宽峰)。当给出时,偶合常数以赫兹(Hz)表示。在Thermo FisherScientific LTQ Orbitrap XL(nanoESI-MS)光谱仪上记录高分辨率质谱(HRMS)。MALDI-ToF质谱在Voyager-DeTM Pro上以m/z测定。通过在来自ThermoFisher的具有LPG-3400SD泵***、ACC-3000自动进样器和柱温箱以及DAD-3000二极管阵列检测器的极限3000SD***上的高效液相色谱(HPLC)分析,测定最终化合物的色谱纯度。使用得自ThermoFisher的Acclaim-120 C18反相柱作为固定相。使用由CH3CN/MeOH∶H2O(10∶90)组成的流动相,在40℃下,流速0.5mL/min进行梯度洗脱(5∶95进行0.2分钟,5∶95→100∶0进行超过10分钟,100∶0进行3分钟)。所有最终化合物的纯度都高于95%。
以下缩写用于下文:DMSO(二甲亚砜)、HCl(盐酸)、M(摩尔)、MALDI(基质辅助激光解吸/电离)、HRMS(高分辨率质谱)、MS(质谱)、PBS(磷酸盐缓冲盐水)、TLC(薄层色谱)。
中间体化合物的制备:
使用下列方法制备用于制备式(I)、(II)化合物的中间体化合物。
方法1:4-(4-氯-6-(N-吗啉基)-1,3,5-三嗪-2-基)哌嗪-1-甲酸叔丁酯
在0℃下向2,4-二氯-6-(吗啉-4-基)-1,3,5-三嗪(20.7g,87.9mmol,0.9当量)的乙醇溶液中加入DIPEA(16.2g,21.4ml,125.6mmol,1.3当量)和1-Boc-哌嗪(18.0g,96.6mmol,1.0当量)。将反应混合物在室温下搅拌5小时。减压除去溶剂。加入二氯甲烷(300mL),用饱和NaHSO4水溶液(4×200mL)洗涤产生的有机层。有机层用无水Na2SO4干燥,过滤并减压浓缩。产物从二氯甲烷/庚烷中重结晶,得到4-(4-氯-6-(N-吗啉基)-1,3,5-三嗪-2-基)哌嗪-1-甲酸叔丁酯,为无色固体(22.7g,58.9mmol,80%)。MALDI-MS:m/z=385.643[M+H]+。HPLC:tR=6.53分钟(100.0%纯度)。
方法2:4-(二氟甲基)-5-(4-(N-吗啉基)-6-(哌嗪-1-基)-1,3,5-三嗪-2-基)嘧啶-2-胺
步骤1.在氮气气氛下,将N-[5-溴-4-(二氟甲基)嘧啶-2-基]-N-[(叔丁氧基)羰基]氨甲酸叔丁酯(7.00g,16.50mmol,1.0当量)、联硼酸频哪醇酯(6.29g,24.75mmol,1.5当量)、乙酸钾(5.02g,51.15mmol,3.1当量)、[1,1′-双(二苯基膦基)二茂铁]二氯化钯(II)(Pd(dppf)Cl2,1.21g,1.65mmol,0.1当量)装入烧瓶中。加入无水1,4-二烷(40mL),混合物在95℃搅拌1.5小时。反应完成后,使混合物冷却至室温。步骤2.加入4-(4-氯-6-(N-吗啉基)-1,3,5-三嗪-2-基)哌嗪-1-甲酸一氯三嗪酯(6.99g,18.15mmol,1.1当量)、氯(2-二环己基膦基-2′,4′,6′-三异丙基-1,1′-联苯)[2-(2′-氨基-1,1′-联苯)]钯(II)(XPhos PdG2,0.519g,0.66mmol,0.04当量)、磷酸三钾(10.51g,49.50mmol,3.0当量)和去离子H2O(10mL)。将所得混合物在100℃搅拌过夜。反应完成后,使混合物冷却至室温,并将粗产物在硅藻土上过滤。向该溶液中加入去离子水H2O(300mL)和乙酸乙酯(300mL)。分离各层,用去离子H2O和盐水(2×)洗涤有机层。水层用二氯甲烷(2×)萃取。将合并的有机层减压浓缩。步骤3.将上述残余物溶解在1,4-二/>烷(40mL)中,加入HCl水溶液(3M,40mL)。将反应混合物在80℃搅拌过夜。反应完成后,将混合物冷却至室温。加入乙酸乙酯(200mL)和去离子H2O(200mL),分离两层。水层用乙酸乙酯(3×)洗涤。将水层碱化至pH=10。过滤形成的固体,用乙腈洗涤,得到4-(二氟甲基)-5-(4-(N-吗啉基)-6-(哌嗪-1-基)-1,3,5-三嗪-2-基)嘧啶-2-胺,为米色固体(4.91g,12.48mmol,76%)。MALDI-MS:m/z=394.205[M+H]+。
方法3:3-((2-(4-(4-(2-氨基-4-(二氟甲基)嘧啶-5-基)-6-(N-吗啉基)-1,3,5-三嗪-2-基)哌嗪-1-基)-2-氧亚基乙基)(甲基)氨甲酰基)氮杂环丁烷-1-甲酸叔丁酯
在0℃和氮气氛下,向1-(叔丁氧羰基)氮杂环丁烷-3-甲酸(581mg,2.89mmol,1.2当量)的无水N,N-二甲基甲酰胺(DMF,约1mL/0.18mmol)溶液中加入六氟磷酸-O-(1H-6-氯苯并***-1-基)-1,1,3,3-四甲基脲(HCTU,1.2当量)和N,N-二异丙基乙胺(3.2当量)。将所得混合物在0℃下搅拌5分钟,然后加入氯化-2-(4-(4-(2-氨基-4-(二氟甲基)嘧啶-5-基)-6-(N-吗啉基)-1,3,5-三嗪-2-基)哌嗪-1-基)-N-甲基-2-氧亚基乙烷-1-铵(或相应的HCl盐),并将反应在室温下搅拌4–16小时。反应完成后,在高真空下除去DMF。将粗产物溶于DCM,用去离子H2O(2×)和饱和Na2CO3水溶液(3×)洗涤有机层。有机层用Na2SO4干燥,过滤并减压浓缩。通过硅胶柱色谱纯化(二氯甲烷/甲醇/氨:100∶0∶0→96∶4∶0.04),得到化合物3-((2-(4-(4-(2-氨基-4-(二氟甲基)嘧啶-5-基)-6-(N-吗啉基)-1,3,5-三嗪-2-基)哌嗪-1-基)-2-氧亚基乙基)(甲基)氨甲酰基)氮杂环丁烷-1-甲酸叔丁酯,为无色固体(1.237g,1.91mmol,79%)。MALDI-MS:m/z=648.7[M+H]+;m/z=548.4[(M–叔丁基)+H]+。
方法4:氯化-3-((2-(4-(4-(2-氨基-4-(二氟甲基)嘧啶-5-基)-6-(N-吗啉基)-1,3,5-三嗪-2-基)哌嗪-1-基)-2-氧亚基乙基)(甲基)氨甲酰基)氮杂环丁烷-1-
向各Boc保护的胺(1.0当量)的THF(约1mL/0.10mmol)溶液中滴加4M HCl的二烷(17当量)溶液。将混合物在室温下搅拌16小时。将混合物减压至干燥。产物从ACN中沉淀,过滤并用冷ACN洗涤。产物的盐酸盐不经进一步纯化用于下一步骤。获得氯化-3-((2-(4-(4-(2-氨基-4-(二氟甲基)嘧啶-5-基)-6-(N-吗啉基)-1,3,5-三嗪-2-基)哌嗪-1-基)-2-氧亚基乙基)(甲基)氨甲酰基)氮杂环丁烷-1-/>,为无色固体(987mg,1.69mmol,91%)。MALDI-MS:m/z=548.4[M+H]+。
本发明化合物的制备
通用流程1:
在0℃和氮气氛下,向各羧酸(1.0-1.5当量)的无水N,N-二甲基甲酰胺(DMF,约1mL/0.18mmol)溶液中加入六氟磷酸-O-(1H-6-氯苯并***-1-基)-1,1,3,3-四甲基脲(HCTU,1.1当量)和N,N-二异丙基乙胺(3.2当量)。将所得混合物在0℃下搅拌5分钟,然后加入各自的HCl盐(1.0当量),并将反应在室温下搅拌4–16小时。反应完成后,在高真空下除去DMF。将粗产物溶于DCM,用去离子H2O(2×)和饱和Na2CO3水溶液(3×)洗涤有机层。有机层用Na2SO4干燥,过滤并减压浓缩。粗产物通过硅胶柱色谱纯化,然后从二氯甲烷/戊烷中重结晶。
实施例1:
1-((R)-3-((2-(4-(4-(2-氨基-4-(二氟甲基)嘧啶-5-基)-6-((S)-3-甲基-N-吗啉基)-1,3,5-三嗪-2-基)哌嗪-1-基)-2-氧亚基乙氧基)甲基)哌啶-1-基)丙-2-烯-1-酮
根据通用流程1,由氯化-(R)-3-((2-(4-(4-(2-氨基-4-(二氟甲基)嘧啶-5-基)-6-((S)-3-甲基-N-吗啉基)-1,3,5-三嗪-2-基)哌嗪-1-基)-2-氧亚基乙氧基)甲基)哌啶-1-(193mg,0.32mmol,1.0当量)和丙烯酸(26mg,0.35mmol,1.1当量)制备1-((R)-3-((2-(4-(4-(2-氨基-4-(二氟甲基)嘧啶-5-基)-6-((S)-3-甲基-N-吗啉基)-1,3,5-三嗪-2-基)哌嗪-1-基)-2-氧亚基乙氧基)甲基)哌啶-1-基)丙-2-烯-1-酮。通过硅胶柱色谱纯化(二氯甲烷/甲醇/氨:100∶0∶0→96∶4∶0.04),得到所需化合物,为无色固体(65mg,0.11mmol,33%)。HRMS(m/z):针对C28H38F2N10NaO4的[M+Na]+计算值:639.2938;实测值:639.2948。HPLC(含0.1% TFA的乙腈):tR=7.20分钟(98.9%纯度)。
实施例2:
1-((R)-3-(3-(4-(4-(2-氨基-4-(二氟甲基)嘧啶-5-基)-6-((S)-3-甲基-N-吗啉基)-1,3,5-三嗪-2-基)哌嗪-1-基)-3-氧亚基丙氧基)哌啶-1-基)丙-2-烯-1-酮
根据通用流程1,由氯化-(R)-3-(3-(4-(4-(2-氨基-4-(二氟甲基)嘧啶-5-基)-6-((S)-3-甲基-N-吗啉基)-1,3,5-三嗪-2-基)-3-氧亚基丙氧基)哌啶-1-(150mg,0.25mmol,1.0当量)和丙烯酸(20mg,0.27mmol,1.1当量)制备1-((R)-3-(3-(4-(4-(2-氨基-4-(二氟甲基)嘧啶-5-基)-6-((S)-3-甲基-N-吗啉基)-1,3,5-三嗪-2-基)哌嗪-1-基)-3-氧亚基丙氧基)哌啶-1-基)丙-2-烯-1-酮。通过硅胶柱色谱纯化(二氯甲烷/甲醇/氨:100∶0∶0→97∶3∶0.03),得到所需化合物,为无色固体(32mg,0.052mmol,20%)。HRMS(m/z):针对C28H38F2N10NaO4的[M+Na]+计算值:639.2938;实测值:639.2947。HPLC:tR=7.08分钟(>99.9%纯度)。
实施例3:
(R,Z)-2-(3-((2-(4-(4-(2-氨基-4-(二氟甲基)嘧啶-5-基)-6-(N-吗啉基)-1,3,5-三嗪-2-基)哌嗪-1-基)-2-氧亚基乙氧基)甲基)哌啶-1-羰基)-3-环丙基丙烯腈
根据通用流程1,由氯化-(R)-3-((2-(4-(4-(2-氨基-4-(二氟甲基)嘧啶-5-基)-6-(N-吗啉基)-1,3,5-三嗪-2-基)哌嗪-1-基)-2-氧亚基乙氧基)甲基)哌啶-1-(226mg,0.39mmol,1.0当量)和(Z)-2-氰基-3-环丙基丙烯酸(118mg,0.85mmol,2.2当量)制备(R,Z)-2-(3-((2-(4-(4-(2-氨基-4-(二氟甲基)嘧啶-5-基)-6-(N-吗啉基)-1,3,5-三嗪-2-基)哌嗪-1-基)-2-氧亚基乙氧基)甲基)哌啶-1-羰基)-3-环丙基丙烯腈(118mg,0.39mmol,1.0当量)。通过硅胶柱色谱纯化(二氯甲烷/甲醇/氨:100∶0∶0→92∶8∶0.08),得到所需化合物,为无色固体(148mg,0.22mmol,57%)。HRMS(m/z):针对C31H39F2N10NaO4的[M+Na]+计算值:690.3047;实测值:690.3052。HPLC:tR=7.50分钟(96.7%纯度)。
实施例4:
(R)-1-丙烯酰基-N-(2-(4-(4-(2-氨基-4-(二氟甲基)嘧啶-5-基)-6-(N-吗啉基)-1,3,5-三嗪-2-基)哌嗪-1-基)-2-氧亚基乙基)-N-甲基哌啶-3-甲酰胺
/>
根据通用流程1,由氯化-(R)-3-((2-(4-(4-(2-氨基-4-(二氟甲基)嘧啶-5-基)-6-(N-吗啉基)-1,3,5-三嗪-2-基)哌嗪-1-基)-2-氧亚基乙基)(甲基)氨甲酰基)哌啶-1-(1.139g,1.86mmol,1.0当量)和丙烯酸(147mg,2.05mmol,1.1当量)制备(R)-1-丙烯酰基-N-(2-(4-(4-(2-氨基-4-(二氟甲基)嘧啶-5-基)-6-(N-吗啉基)-1,3,5-三嗪-2-基)哌嗪-1-基)-2-氧亚基乙基)-N-甲基哌啶-3-甲酰胺。通过硅胶柱色谱纯化(二氯甲烷/甲醇/氨:100∶0∶0→97∶3∶0.03),得到所需化合物,为无色固体(305mg,0.48mmol,26%)。HRMS(m/z):针对C28H37F2N11NaO4的[M+Na]+计算值:652.2890;实测值:652.2893。HPLC:tR=6.20分钟(98.3%纯度)。
实施例5:
(R)-1-丙烯酰基-N-(2-(4-(4-(2-氨基-4-(二氟甲基)嘧啶-5-基)-6-(N-吗啉基)-1,3,5-三嗪-2-基)哌嗪-1-基)-2-氧亚基乙基)吡咯烷-3-甲酰胺
根据通用流程1,由氯化-(R)-3-((2-(4-(4-(2-氨基-4-(二氟甲基)嘧啶-5-基)-6-(N-吗啉基)-1,3,5-三嗪-2-基)哌嗪-1-基)-2-氧亚基乙基)氨甲酰基)吡咯烷-1-(274mg,0.47mmol,1.0当量)和丙烯酸(37mg,0.52mmol,1.1当量)制备(R)-1-丙烯酰基-N-(2-(4-(4-(2-氨基-4-(二氟甲基)嘧啶-5-基)-6-(N-吗啉基)-1,3,5-三嗪-2-基)哌嗪-1-基)-2-氧亚基乙基)吡咯烷-3-甲酰胺。通过硅胶柱色谱纯化(二氯甲烷/甲醇/氨:100∶0∶0→96∶4∶0.04),得到所需化合物,为无色固体(134mg,0.22mmol,47%)。HRMS(m/z):针对C26H33F2N11NaO4的[M+Na]+计算值:624.2577;实测值:624.2581。HPLC:tR=5.84分钟(98.4%纯度)。
实施例6:
1-丙烯酰基-N-(2-(4-(4-(2-氨基-4-(二氟甲基)嘧啶-5-基)-6-(N-吗啉基)-1,3,5-三嗪-2-基)哌嗪-1-基)-2-氧亚基乙基)-N-甲基氮杂环丁烷-3-甲酰胺
根据通用流程1,由氯化-3-((2-(4-(4-(2-氨基-4-(二氟甲基)嘧啶-5-基)-6-(N-吗啉基)-1,3,5-三嗪-2-基)哌嗪-1-基)-2-氧亚基乙基)(甲基)氨甲酰基)氮杂环丁烷-1-(946mg,1.62mmol,1.0当量)和丙烯酸(128mg,1.78mmol,1.1当量)制备1-丙烯酰基-N-(2-(4-(4-(2-氨基-4-(二氟甲基)嘧啶-5-基)-6-(N-吗啉基)-1,3,5-三嗪-2-基)哌嗪-1-基)-2-氧亚基乙基)-N-甲基氮杂环丁烷-3-甲酰胺。通过硅胶柱色谱纯化(二氯甲烷/甲醇/氨:100∶0∶0→96∶4∶0.04),得到所需化合物,为无色固体(358mg,0.60mmol,37%)。HRMS(m/z):针对C26H33F2N11NaO4的[M+Na]+计算值:624.2577;实测值:624.2579。HPLC:tR=5.81分钟(98.4%纯度)。
抑制剂表观解离常数的测定
通过LanthaScreen Technology(Life Technologies)测定化合物对p110α的表观解离常数[Ki(app)],如参考文献21中所述。
动力学常数的测定
通过LanthaScreen Technology(Life Technologies)测定化合物对p110α的第一可逆结合的最大可能形成速率(kinact)和解离常数(Ki)。动力学参数的计算通过使用KinTekGlobal Dynamic Explorer建模软件进行数值积分的全局拟合进行22-27。
在细胞中Western细胞PI3K信号传导和IC50测定
如下检测蛋白质磷酸化:通过细胞内Western试验,用来自Cell SignalingTechnology(CST)的兔多克隆抗体(#4058)处理PKB/Akt的pSer473,其中如参考文献21中所述,1.2×104SKOV3细胞/孔于96孔板中铺板(Cell Carrier,PerkinElmer)24小时(37℃,5% CO2)。
NanoBRET靶接合试验
N端NanoLuc融合的PI3K在pFN31K表达载体(Promega)中编码,其包括在NanoLuc和包括PI3Kα、PI3KαC862S、PI3Kβ、和PI3Kδ的每个全长的靶激酶之间的柔性Gly–Ser–Ser–Gly–Ala–Ile–Ala接头。使用JetPEI转染试剂(Polyplus转染,#101B-010N)以质量比1∶10用NanoLuc/PI3K和其调节亚单位p85共转染HEK293细胞。
表1本发明的一些化合物和CNX-1351的固有反应性和体外数据。
a Marvin/Jchem 20.9用于计算log P(分配系数)。b用HPLC测量抑制剂的本征反应性(1mM抑制剂+600mMβME;n=3)。$每个平均值和SD由2或3个独立的测量值计算。
表2本发明的一些化合物和CNX-1351的细胞数据。
$每个平均值和SD由2或3个独立的测量值计算。
参考文献:
21.Bohnacker,T.;Prota,A.E.;Beaufils,F.;Burke,J.E.;Melone,A.;Inglis,A.J.;Rageot,D.;Sele,A.M.;Cmiljanovic,V.;Cmiljanovic,N.;Bargsten,K.;Aher,A.;Akhmanova,A.;Diaz,J.F.;Fabbro,D.;Zvelebil,M.;Williams,R.L.;Steinmetz,M.O.;Wymann,M.P.,Deconvolution of Buparlisib's mechanism of action definesspecific PI3K and tubulin inhibitors for therapeutic intervention.Nat Commun2017,8,14683.
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Claims (14)
1.式(IV)化合物,特别是式(IVa)化合物,或其前药、代谢物、互变异构体、溶剂化物或药学上可接受的盐,
其中
·X为CH或N,特别是N,
·Y为H或F,特别是H,
·R1和R2各自独立地选自H、CH3、环丙基、–F、-CH2–F、-CH2-CH2–F、–CN、 其中R5为F或CH3,R6为C1-6烷基且z为0、1或2,
·R3为C1-3烷基或两个残基R3形成桥–(CH2)r–,其中r为1、2或3,
·v为0、1、2、3或4,
·R4为H、F或–CN,
·L2为选自 的部分,其中R5为C1-3烷基、F、-CH2CN或–CN且t为0、1或2,
·W1为CO或CH2,
·W2选自O、CH2和CO,
·U选自O、CH2、CO、NH、和N(CH3),
·n为1或2。
2.根据权利要求1所述的化合物,其中R1为H、CH3或-CH2F。
3.根据前述权利要求任一所述的化合物,其中R2为H或环丙基。
4.根据前述权利要求任一所述的化合物,其中R2为环丙基且R4为–CN。
5.根据前述权利要求任一所述的化合物,其中R3为C1-3烷基,特别是CH3。
6.根据前述权利要求任一所述的化合物,其中v为0、1或2,更特别是0或1。
7.根据前述权利要求任一所述的化合物,其中U选自O、CH2、NH和N(CH3)。
8.根据前述权利要求任一所述的化合物,其中所述化合物为式(V)化合物,特别是式(Va)化合物,
其中X、Y、R1、R2、R3、R4、W1、n、U、W2、L2如上所述定义,
v为0或1。
9.根据权利要求1至8任一所述的化合物,用于治疗疾病。
10.根据权利要求9所述的化合物,其中所述疾病为由PI3KCA基因的激活突变或I类PI3K、特别是PI3Kα的激活引起的疾病。
11.根据权利要求1至8任一所述的化合物,用于***疾病、过度生长综合征、神经疾病病症、免疫性疾病病症。
12.根据权利要求11所述的化合物,其中所述肿瘤为实体瘤。
13.根据权利要求11所述的化合物,其中所述肿瘤疾病选自淋巴瘤和白血病。
14.式(VI)中间体,
其中R1、R2、R4、L2、W2、U、n和W1如上所述定义,
Z为–OH、Br、COOH、–C(OH)NH2。
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