CN117813300A - 作为cdk2抑制剂的取代的嘧啶基-吡唑 - Google Patents
作为cdk2抑制剂的取代的嘧啶基-吡唑 Download PDFInfo
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- CN117813300A CN117813300A CN202280055901.3A CN202280055901A CN117813300A CN 117813300 A CN117813300 A CN 117813300A CN 202280055901 A CN202280055901 A CN 202280055901A CN 117813300 A CN117813300 A CN 117813300A
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Abstract
本公开提供由结构式(I)表示的化合物或其药学上可接受的盐,其可用于治疗癌症。
Description
相关申请的交叉引用
本申请要求2021年6月16日提交的美国临时专利申请第63/211,426号和2022年4月5日提交的美国临时专利申请第63/327,474号的权益和优先权,上述申请中的每一者的公开内容出于所有目的特此以引用的方式全文并入。
背景技术
细胞周期蛋白依赖性激酶(CDK)是在细胞周期进展中具有核心作用的丝氨酸/苏氨酸蛋白激酶。CDK水平在整个细胞周期中保持相对恒定,并且是特异性CDK的选择性激活使得细胞周期进展中的步骤顺序正确。CDK的激活需要与被称为细胞周期蛋白的调控亚基进行异二聚化。细胞周期失调是人类癌症的共同特征。
细胞周期蛋白依赖性激酶2(Cdk2)参与一系列生物活性。CDK2是关键的细胞周期调控因子,从G1期晚期一直活跃到整个S期。CDK2通过同源重组(HR)途径参与DNA损伤反应(DDR)。CDK2还调控细胞凋亡途径的若干方面。细胞周期蛋白E1(CCNE1)、细胞周期蛋白E2(CCNE2)、细胞周期蛋白A1(CCNA1)和细胞周期蛋白A2(CCNA2)连同p21Cip1/Waf1、p27Kip1和p57Kip2(细胞周期蛋白–CDK2复合物的细胞周期蛋白依赖性激酶抑制剂)是CDK2活性的主要调控因子。在癌症中,可能会发生细胞周期蛋白E1、E2、A1或A2对CDK2的结合失调或细胞周期蛋白依赖性激酶抑制剂蛋白的活性失调。(参见S.Tadesse等人,Drug DiscoveryToday,第25卷,第2期,2020年2月)
CDK2的失调可能通过若干机制发生。已经确认CCNE1的扩增或过表达在卵巢癌和乳腺癌中发生(参见Scaltriti,M.等人,Proc.Natl Acad.Sci.USA 108,3761–3766(2011);和Etemadmoghadam,D.等人,Proc.Natl Acad.Sci.USA 110,19489–19494(2013)。胃癌、子宫内膜癌及其它癌症的结果不良与CCNE1的过表达或扩增相关(参见Ooi等人,Hum Pathol.(2017)61:58-67;和Noske等人,Oncotarget(2017)8:14794-14805)。
虽然这些发现表明CDK2是CDK2活性失调的癌症的潜在靶标,但迄今尚未批准靶向CDK2的药剂。因此,需要开发新的CDK2抑制剂。
发明内容
申请人已经发现了作为CDK2的有效抑制剂的新型化合物(参见合成实施例1-46)。特别地,已经证明本公开的化合物有效抑制CDK2。本公开的化合物(本文中也被称为“所公开的化合物”)或其药学上可接受的盐有效抑制CDK2。(参见生物学实施例1),并且可用于治疗各种癌症。重要的是,所公开的化合物是选择性CDK2抑制剂,即所公开的化合物针对CDK1没有活性或活性低。与这种选择性相关的优点可包括促进有效的给药和降低CDK1介导的中靶毒性。一些所公开的化合物还具有微粒体稳定性高的优点。本公开的化合物还可具有与其它非激酶靶标有关的有利的毒性特征。
一方面,本公开提供由以下结构式(I)表示的化合物:
或其药学上可接受的盐,每个变量的定义在下文提供。
另一方面,本公开提供包含药学上可接受的载体或稀释剂和一种或多种本文公开的化合物或其药学上可接受的盐的药物组合物(“本公开的药物组合物”)。
本公开提供治疗患有癌症的受试者的方法,所述方法包括对受试者施用有效量的本公开的化合物(例如,式(I)的化合物)或其药学上可接受的盐或本公开的药物组合物。在一个实施方案中,所述癌症是子宫癌(包括子宫癌肉瘤、子宫体子宫内膜癌)、子宫内膜癌、乳腺癌(包括浸润性乳腺癌、TNBC(三阴性乳腺癌)、ER(***受体)+HER2(人表皮生长因子2)-乳腺癌和HER2+乳腺癌)、卵巢癌(例如卵巢浆液性囊腺癌)、胃部癌症(包括胃腺癌)、胃癌(包括胃肠道间质瘤)、结直肠癌、胰腺癌、肾癌、头颈癌、肝癌、***癌、皮肤癌、白血病(包括AML(急性髓性白血病))、淋巴瘤(包括B细胞淋巴瘤)、肉瘤、食道癌(包括食道上皮癌(esophageal carcinoma))、膀胱癌(包括膀胱尿路上皮癌)、肺癌(包括肺鳞状细胞癌和非小细胞肺癌,例如EGFRm(表皮生长因子受体突变体)+非小细胞肺癌)、胆管癌、肾上腺皮质癌或间皮瘤。
在一个实施方案中,要治疗的癌症具有CCNE1扩增或过表达。
本文公开的治疗方法进一步包括对受试者施用有效量的帕博西尼(例如,)、瑞博西尼、阿贝西利、他莫昔芬、来曲唑、奥拉帕尼(例如,/>)、尼拉帕尼、卡铂、顺铂、紫杉醇、吉西他滨、醋酸甲地孕酮、醋酸甲羟孕酮、卡培他滨(例如,/>)、瑞戈非尼(例如,/>)、阿法替尼(例如,/>)、奥希替尼(例如,/>)、吉非替尼(例如,/>)、埃罗替尼(例如,/>)、雷莫芦单抗(例如,/>)、EGFR抑制剂、普拉替尼、ABT-263(那维妥拉,navitoclax)、MK-1775(阿达色替,adavosertib)、BAY-1895344、柏佐舍替(berzosertib)、ceralasertib、SRA-737、LY2603618(拉布塞蒂,rabusertib)或曲妥珠单抗(例如,/>)或其组合。EGFR抑制剂可选自阿法替尼、奥希替尼、拉帕替尼、埃罗替尼、达克替尼、波齐替尼、来那替尼、吉非替尼、JBJ-04-125-02、艾氟替尼(AST 2818)、aumolertinib(以前的阿美替尼)(HS10296)、BBT-176、BI-4020、BPI-361175、BPI-D0316、CH7233163、吉瑞替尼(gilitertinib)、埃克替尼、JND-3229、拉泽替尼(lazertinib)、那扎替尼(nazartinib,EGF 816)、艾维替尼(avitinib)、PCC-0208027、瑞齐替尼(rezivertinib,BPI-7711)、TQB3804、佐利替尼(zorifertinib,AZ-3759)或DZD9008;EGFR抗体,如西妥昔单抗、帕尼单抗、耐昔妥珠单抗、HLX07、JMT101;或双特异性EGFR和MET抗体(例如,埃万妥单抗((JNJ-61186372,JNJ-372))。
本公开还提供在有需要的受试者中抑制CDK2的方法,所述方法包括对受试者施用有效量的本公开的化合物(例如,式(I)的化合物)或其药学上可接受的盐或本公开的药物组合物。
本公开还提供有效量的本公开的化合物(例如,式(I)的化合物)或其药学上可接受的盐或本公开的药物组合物用于制备治疗癌症的药物的用途。
另一方面,本文提供式(I)的化合物或其药学上可接受的盐或本公开的药物组合物,其用于治疗癌症。
一方面,本公开提供治疗患有与CDK2相关的疾病或病症或有患与CDK2相关的疾病或病症的风险的受试者的方法,所述方法包括对受试者施用治疗有效量的本文公开的化合物或其药学上可接受的盐或本文公开的药物组合物,其中受试者具有CCNE1基因的扩增和/或具有高于CCNE1的对照表达水平的CCNE1的表达水平。在一些实施方案中,与CDK2相关的疾病或病症是癌症。
本文还提供治疗具有扩增的CCNE1表达水平并罹患实体肿瘤癌症或有患实体肿瘤癌症的风险的患者的方法,所述方法包括对患者施用治疗有效量的本文公开的化合物或其药学上可接受的盐或本文公开的药物组合物。
预期的实体肿瘤癌症可以是以下中的至少一种:子宫癌(包括子宫癌肉瘤、子宫体子宫内膜癌)、子宫内膜癌、乳腺癌(包括浸润性乳腺癌、TNBC(三阴性乳腺癌)、ER(***受体)+HER2(人表皮生长因子2)-乳腺癌和HER2+乳腺癌)、卵巢癌(例如卵巢浆液性囊腺癌)、胃部癌症(包括胃腺癌)、胃癌(包括胃肠道间质瘤)、结直肠癌、胰腺癌、肾癌、头颈癌、肝癌、***癌、皮肤癌、淋巴瘤(包括B细胞淋巴瘤)、肉瘤、食道癌(包括食道上皮癌)、膀胱癌(包括膀胱尿路上皮癌)、肺癌(包括肺鳞状细胞癌和非小细胞肺癌,例如EGFRm(表皮生长因子受体突变体)+非小细胞肺癌)、胆管癌、肾上腺皮质癌或间皮瘤。
具体实施方式
定义
如本文所用的术语“卤代”意指卤素,并且包括氯代、氟代、溴代和碘代。
单独或作为更大部分如“烷氧基”或“卤代烷基”等的一部分使用的术语“烷基”意指饱和的脂族直链或支链单价烃基。除另有说明外,烷基通常具有1-4个碳原子,即(C1-C4)烷基。如本文所用,“(C1-C4)烷基”意指具有以直链或支链排列的1至4个碳原子的基团。实例包括甲基、乙基、正丙基、异丙基等。
术语“烷氧基”意指通过氧连接原子连接的烷基,由–O-烷基表示。例如,“(C1-C4)烷氧基”包括甲氧基、乙氧基、丙氧基和丁氧基。
术语“环烷基”是指单环饱和烃环体系。除另有说明外,环烷基具有3-6个碳原子。例如,C3-C6环烷基包括环丙基、环丁基、环戊基和环己基。除另有描述外,“环烷基”具有三至六个碳原子。
术语“杂环基”或“杂环”是指具有环碳原子和1至2个环杂原子的3至6元非芳族环体系的基团,其中每个杂原子独立地选自氮、季氮、氧化的氮(例如,NO)、氧和硫,包括亚砜和砜(“4-12元杂环基。在含有一个或多个氮原子的杂环基中,在化合价允许的情况下,连接点可以是碳或氮原子。示例性杂环基包括氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、四氢呋喃基、吡咯烷基、哌啶基、四氢吡喃基、哌嗪基、吗啉基、氮杂环庚烷基、氧杂环庚烷基、硫杂环庚烷基、四氢吡啶基等。
本公开的化合物
本文公开了具有式(I)的一般结构的化合物的实施方案。本发明提供了用于治疗癌症的本发明的化合物或其药学上可接受的盐。这些化合物是CDK2的选择性抑制剂。
在第一实施方案中,本公开提供由以下结构式(I)表示的化合物:
或其药学上可接受的盐,其中
每个R1独立地选自由以下组成的组:卤代、OH、CN、C1-C4烷基和C1-C4烷氧基,其中所述C1-C4烷基和C1-C4烷氧基各自任选被1至3个卤代取代;
每个R2独立地选自由以下组成的组:卤代、OH、CN、C1-C4烷基和C1-C4烷氧基,其中所述C1-C4烷基和C1-C4烷氧基各自任选被1至3个卤代取代;
R3是任选被1或2个各自独立地选自由卤代、OH、C3-C6环烷基和3至6元杂环基组成的组的基团取代的C1-C6烷基,其中所述C3-C6环烷基任选被OH取代,其中所述3至6元杂环基具有1至4个各自独立地选自由O、S和NRa组成的组的环杂原子,然后任选在环碳上被OH取代;或者
R3是C3-C6环烷基或3至6元杂环基,其中所述C3-C6环烷基任选被OH或-CH2OH取代,其中所述3至6元杂环基具有1至4个各自独立地选自由O、S和NRa组成的组的环杂原子,然后任选在环碳上被OH或-CH2OH取代;
每个Ra独立地为H或C1-C6烷基;
m选自由0、1、2、3和4组成的组,且
n选自由0、1和2组成的组。
在一些实施方案中,所述化合物具有式IIA、式IIB、式IIC或式IID
或其药学上可接受的盐。
在一些实施方案中,每个R1独立地选自由卤代、甲基和甲氧基组成的组。例如,R1是卤代,例如F、Cl、Br。
在某些实施方案中,每个R2独立地选自由卤代、CN、甲基和乙基组成的组,其中所述甲基和乙基各自任选被1至3个卤代取代。例如,R2是任选被1至3个卤代取代的甲基,例如甲基、CF3、CF2。例如,R2可以是CN。在一些实施方案中,R2可以是卤代,例如F、Cl、Br。
在其它实施方案中,R3是任选被1或2个各自独立地选自由卤代、OH、环丙基和氧杂环丁烷基组成的组的基团取代的C1-C5烷基,其中所述环丙基和氧杂环丁烷基各自任选被OH取代。
在一些实施方案中,R3是被OH取代的C1-C5烷基。
在某些实施方案中,R3是环丙基或氧杂环丁烷基,其中所述环丙基和氧杂环丁烷基各自任选被OH或CH2OH取代(如果R3是氧杂环丁烷基,则在环碳上)。
在某些实施方案中,R3是四氢吡喃。
在其它实施方案中,每个R1是甲基,每个R2独立地选自由卤代、甲基和CF3组成的组,且R3是被OH取代的C1-C6烷基。
在一些实施方案中,每个R1是卤代,每个R2独立地选自由卤代、CN、甲基、乙基和CF3组成的组,且R3是被OH取代的C1-C6烷基,或者R3是氧杂环丁烷基或环丙基,其中所述氧杂环丁烷基和环丙基各自任选被CH2OH取代(如果R3是氧杂环丁烷基,则在环碳上)。
在其它实施方案中,每个R1是甲氧基,每个R2独立地选自由卤代、甲基和CF3组成的组,且R3是被OH取代的C1-C6烷基。
在某些实施方案中,m可以是0。在一些实施方案中,m可以是1。在其它实施方案中,m可以是2。在某些实施方案中,n可以是0。在一些实施方案中,n可以是1。在其它实施方案中,n可以是2。
在一个实施方案中,本公开的化合物是实施例和表1中公开的任一种化合物或其药学上可接受的盐。
术语“药学上可接受的盐”是指在合理的医学判断范围内适合与人和低等动物的组织接触使用而没有不适当的毒性、刺激性和过敏反应并且与合理的益处/风险比相称的药用盐。药学上可接受的盐是本领域中熟知的。例如,S.M.Berge等人在J.Pharm.Sci.,1977,66,1-19中描述了药理学上可接受的盐。
本发明教导中包括本文公开的化合物的药学上可接受的盐。具有碱性基团的化合物可以与药学上可接受的酸形成药学上可接受的盐。本文所述的化合物的合适的药学上可接受的酸加成盐包括无机酸(如盐酸、氢溴酸、磷酸、偏磷酸、硝酸和硫酸)和有机酸(如乙酸、苯磺酸、苯甲酸、乙磺酸、甲磺酸和琥珀酸)的盐。具有酸性基团如羧酸的本发明教导的化合物可以与药学上可接受的碱形成药学上可接受的盐。合适的药学上可接受的碱性盐包括铵盐、碱金属盐(如钠盐和钾盐)和碱土金属盐(如镁盐和钙盐)。
具有一个或多个手性中心的化合物可以以各种立体异构形式存在,即每个手性中心可具有R或S构型,或者可以是两者的混合物。立体异构体是仅空间排列不同的化合物。立体异构体包括化合物的所有非对映体和对映体形式。对映体是彼此互为镜像的立体异构体。非对映体是具有两个或更多个彼此不相同且不互为镜像的手性中心的立体异构体。
当具有一个或多个手性中心的化合物中的手性中心处的立体化学构型由其化学名称(例如,在化学名称中由“R”或“S”指示构型的情况下)或结构(例如,由“楔形”键指示构型)描述时,所指示的构型相对于相反构型的富集度大于50%、60%、70%、80%、90%、99%或99.9%(当标示“外消旋(rac)”或“外消旋体”伴随结构或名称时除外,如以下两段中所解释)。“所指示的构型相对于相反构型的富集度”是摩尔百分比,并且通过在手性中心处具有所指示的立体化学构型的化合物的数量除以混合物中具有相同或相反立体化学构型的所有化合物的总数来确定。
当在化合物中的手性中心处的立体化学构型由化学名称(例如,在名称中由“R”或“S”指示构型的情况下)或结构(例如,由“楔形”键指示构型)描述,并且标示“外消旋”或“外消旋体”伴随结构或在化学名称中指定时,意指的是外消旋混合物。
当两种立体异构体由它们的化学名称或结构描述,并且化学名称或结构由“和”连接时,意指的是两种立体异构体的混合物。
当两种立体异构体由它们的化学名称或结构描述,并且名称或结构由“或”连接时,意指的是两种立体异构体中的一种或另一种,而不是两种。
当所公开的具有手性中心的化合物由结构描述而没有显示在该手性中心处的构型时,所述结构旨在涵盖在该手性中心处具有S构型的化合物、在该手性中心处具有R构型的化合物或在该手性中心处具有R和S混合构型的化合物。当所公开的具有手性中心的化合物由其化学名称描述而没有用“S”或“R”指示在该手性中心处的构型时,所述名称旨在涵盖在该手性中心处具有S构型的化合物、在该手性中心处具有R构型的化合物或在该手性中心处具有R和S混合构型的化合物。
外消旋混合物意指50%的一种对映体和50%的其相应的对映体的混合物。本发明教导涵盖本文公开的化合物的所有对映体纯的、对映体富集的、非对映体纯的、非对映体富集的和外消旋的混合物以及非对映体的混合物。
可以通过熟知的方法将对映体和非对映体混合物拆分成它们的组分对映体或立体异构体,如通过手性相气相色谱法、手性相高效液相色谱法、将化合物结晶为手性盐络合物或将化合物在手性溶剂中结晶。也可以通过熟知的不对称合成方法由非对映体或对映体纯的中间体、试剂和催化剂获得对映体和非对映体。
实验部分中的“峰1”是指获自色谱分离/纯化的预期反应产物化合物,其比来自同一先前反应的第二预期反应产物化合物更早洗脱。第二预期产物化合物被称为“峰2”。
当所公开的化合物由指示单一对映体的名称或结构定名时,除另指出外,所述化合物是至少60%、70%、80%、90%、99%或99.9%光学纯的(也称为“对映体纯”)。光学纯度是混合物中指定或描述的对映体的重量除以混合物中两种对映体的总重量。
当通过结构指定或描述所公开的化合物的立体化学,并且所指定或描述的结构涵盖多于一种立体异构体(例如,如在非对映体对中)时,要理解的是,除另指出外,所涵盖的立体异构体之一或所涵盖的立体异构体的任何混合物包括在内。要进一步理解的是,所指定或描述的立体异构体的立体异构体纯度为至少60重量%、70重量%、80重量%、90重量%、99重量%或99.9重量%。通过混合物中名称或结构所涵盖的立体异构体的总重量除以混合物中所有立体异构体的总重量来确定这种情况下的立体异构体纯度。
在本公开的化合物中,具体指定为“D”或“氘”的任何位置被理解为具有50%、80%、90%、95%、98%或99%的氘富集度。“氘富集度”是摩尔百分比,并且通过在指示位置处具有氘的化合物的数量除以所有化合物的总数来确定。当一个位置被指定为“H”或“氢”时,该位置具有天然丰度的氢。当没有说明一个位置是存在氢还是氘时,该位置具有天然丰度的氢。一个具体的替代实施方案涉及本公开的化合物,其在未具体指定为“D”或“氘”的一个或多个位置处具有至少5%、10%、25%、50%、80%、90%、95%、98%或99%的氘富集度。
如本文所用,许多部分(例如,烷基、烷氧基、环烷基或杂环基)被称为“取代的”或“任选取代的”。当部分被这些术语之一修饰时,除另有说明外,其表示本领域技术人员已知该部分中可用于取代的任何部分都可以被取代,其包括一个或多个取代基。在如果存在多于一个取代基的情况下,则可以独立地选择每个取代基。这类取代的方法是本领域中熟知的,和/或在本公开中有教导。任选的取代基可以是适合与所述部分连接的任何取代基。
本公开的化合物是CDK2抑制剂。如本文所用,术语“选择性CDK2抑制剂”意指相较于其它CDK和激酶组选择性抑制CDK2的化合物。换言之,选择性CDK2抑制剂针对其它CDK和激酶组没有活性或活性低。与针对其它CDK和许多其它激酶的抑制活性相比时,就IC50值来说,选择性CDK2抑制剂针对CDK2的抑制活性更强(即,IC50值是亚纳摩尔的)。可采用已知的生化测定法来测量效力。
在一些实施方案中,本公开的化合物相比于CDK1是针对CDK2为选择性的。在一些这类实施方案中,化合物对CDK2显示出相比于CDK1至少10倍的选择性。在其它实施方案中,化合物对CDK2显示出相比于CDK1至少20倍的选择性。在具体实施方案中,化合物对CDK2显示出相比于CDK1至少30倍的选择性。在某些实施方案中,化合物对CDK2显示出相比于CDK1至少40倍的选择性。在其它实施方案中,化合物对CDK2显示出相比于CDK1至少50倍的选择性。例如,化合物对CDK2显示出相比于CDK1至少100倍的选择性。在一些实施方案中,本发明的化合物相比于CDK4和/或CDK6是针对CDK2为选择性的。在一些这类实施方案中,化合物对CDK2显示出相比于CDK4和/或CDK6至少10倍的选择性。在其它实施方案中,化合物对CDK2显示出相比于CDK4和/或CDK6至少20倍的选择性。在具体实施方案中,化合物对CDK2显示出相比于CDK4和/或CDK6至少30倍的选择性。
本公开的一些化合物具有代谢稳定性良好的优点。良好的代谢稳定性的一个指标是高微粒体稳定性。肝脏代谢是小分子药物消除的主要途径。可以使用人肝微粒体(HLM)或人肝细胞在体外评估肝脏代谢对化合物的清除。将化合物与HLM加上适当的辅因子或人肝细胞一起温育,并测量化合物消耗以确定体外固有清除率(Clint)。将Clint换算成总全身清除率(CL),并通过CL除以标准人肝脏血流量来确定肝脏提取率(ER)。肝脏提取率低的化合物被认为具有良好的代谢稳定性。在一些实施方案中,本公开的化合物计算的ER<0.3、<0.4、<0.5、<0.6。
药物组合物
本公开的药物组合物(本文中也称为“所公开的药物组合物”)包含一种或多种药学上可接受的载体或稀释剂和本公开的化合物(例如,式(I)的化合物)或其药学上可接受的盐。
“药学上可接受的载体”和“药学上可接受的稀释剂”是指有助于活性剂的配制和/或对受试者的施用和/或被受试者吸收的物质,并且可以包括在本公开的药物组合物中,而不会对受试者造成显著不利的毒理学效应。药学上可接受的载体和/或稀释剂的非限制性实例包括水、NaCl、生理盐水溶液、乳酸林格液、标准蔗糖、标准葡萄糖、粘结剂、填充剂、崩解剂、润滑剂、包衣、甜味剂、调味剂、盐溶液(如林格液)、醇、油、明胶、碳水化合物如乳糖、直链淀粉或淀粉、羟甲基纤维素、脂肪酸酯、聚乙烯吡咯烷酮和色素等。可以将这类制剂灭菌,并且如果需要的话,与助剂混合,所述助剂如润滑剂、防腐剂、稳定剂、润湿剂、乳化剂、影响渗透压的盐、缓冲剂、着色剂和/或芳香物质等,这些物质不会不利地与本文提供的化合物反应或干扰本文提供的化合物的活性。本领域普通技术人员将会认识到,其它药物赋形剂适合与所公开的化合物或其药学上可接受的盐一起使用。
本公开的药物组合物任选包括一种或多种用于其的药学上可接受的载体和/或稀释剂,如乳糖、淀粉、纤维素和右旋糖。还可以包括其它赋形剂,如调味剂、甜味剂和防腐剂,如对羟基苯甲酸甲酯、乙酯、丙酯和丁酯。合适赋形剂更完整的列表可见于Handbook ofPharmaceutical Excipients(第5版,Pharmaceutical Press(2005))。本领域技术人员将知晓如何制备适用于各种类型的施用途径的制剂。用于选择和制备合适制剂的常规程序和成分描述于例如Remington's Pharmaceutical Sciences(2003年-第20版)和1999年公布的美国药典:国家处方集(USP 24 NF19)中。载体、稀释剂和/或赋形剂在与药物组合物的其它成分相容并且对其接受者无害的意义上是“可接受的”。
治疗的方法
本文公开的化合物抑制CDK2,因此可用于治疗CDK2失调的疾病,如癌症。本公开提供在有需要的受试者中抑制CDK2的方法,所述方法包括对受试者施用有效量的本文公开的化合物、其药学上可接受的盐或本文公开的药物组合物。
在一些实施方案中,本公开提供治疗患者中与CDK2相关的疾病或病症的方法,所述方法包括对患者施用治疗有效量的如本文所述的式(I)或任何式的化合物或其药学上可接受的盐。在一些实施方案中,与CDK2相关的疾病或病症与细胞周期蛋白E1(CCNE1)基因的扩增和/或CCNE1的过表达相关。在一些实施方案中,所述疾病或病症是癌症。
“需要抑制CDK2”的受试者是患有可通过抑制CDK2实现有益治疗效果的疾病的那些受试者,所述有益治疗效果就疾病而言例如为减缓疾病进展、减轻与疾病相关的一种或多种症状或延长受试者的寿命。
在一些实施方案中,本公开提供治疗与CDK2相关或受CDK2调节的疾病/病状/或癌症的方法,其中CDK2的抑制具有治疗益处,包括但不限于治疗有需要的受试者的癌症。所述方法包括对受试者施用有效量的本文公开的化合物、其药学上可接受的盐或本文公开的药物组合物。
在另一实施方案中,本公开提供治疗患有癌症的受试者的方法,所述方法包括对受试者施用有效量的本文公开的化合物、其药学上可接受的盐或本文公开的药物组合物。在另一实施方案中,所述癌症的特征在于CCNE1或CCNE2的扩增或过表达。
因此,在所述方法的一些实施方案中,先前已经确定受试者或患者的细胞周期蛋白E1(CCNE1)基因扩增,和/或在获自受试者或患者的生物样品中的CCNE1的表达水平高于CCNE1的对照表达水平。
在另一实施方案中,本公开提供在体外抑制肿瘤(例如,癌症)细胞生长的方法。所述方法包括使肿瘤(例如癌症)细胞在体外与式(I)的化合物或其药学上可接受的盐接触。在另一实施方案中,本公开提供在受试者或患者中抑制具有CCNE1扩增和过表达的肿瘤(例如,癌症)细胞生长的方法。所述方法包括对有需要的受试者或患者施用治疗有效量的式(I)的化合物或其药学上可接受的盐。
在另一实施方案中,本公开提供治疗患有癌症的受试者的方法,所述方法包括与如下所述的其它药剂或标准癌症治疗结合对受试者施用有效量的本文公开的化合物、其药学上可接受的盐或本文公开的药物组合物。
如本文所用,“癌症”是指由异常细胞生长引起的任何恶性和/或侵袭性生长或肿瘤。癌症包括以形成它们的细胞的类型命名的实体肿瘤、血液癌、骨髓癌或淋巴***癌。实体肿瘤的实例包括肉瘤和癌瘤。血液癌包括但不限于白血病、淋巴瘤和骨髓瘤。癌症还包括起源于体内特定部位的原发性癌症、已经从其开始的位置扩散到身体的其它部位的转移性癌症、初始原发性癌症缓解后的复发以及第二原发性癌症,第二原发性癌症是在有与后一种癌症不同类型的既往癌症史的人中的新的原发性癌症。在一些这类实施方案中,所述癌症的特征在于CCNE1和/或CCNE2的扩增或过表达。
要根据所公开的方法治疗的癌症包括乳腺癌、卵巢癌、膀胱癌、子宫癌(例如,子宫癌肉瘤)、***癌、肺癌(包括NSCLC、SCLC、鳞状细胞癌或腺癌)、食道癌、头颈癌、结直肠癌(例如,结肠癌)、肾癌(包括RCC)、肝癌(包括HCC)、胰腺癌、胃部(即,胃)癌、尿路上皮癌、脑癌、间皮瘤、皮肤癌(例如,黑色素瘤)、肉瘤或甲状腺癌,包括所列的所有癌症的转移(特别是脑转移)。在一些实施方案中,所述癌症的特征在于本文所述的CCNE1和/或CCNE2的过表达或扩增。在本文提供的方法的一些实施方案中,受试者被确认为患有特征在于CCNE1和/或CCNE2的扩增或过表达的癌症。
在本文提供的方法的进一步实施方案中,所述癌症是乳腺癌、卵巢癌、膀胱癌、子宫癌、***癌、肺癌、食道癌、肝癌、胰腺癌或胃部癌症。在一些这类实施方案中,所述癌症的特征在于CCNE1和/或CCNE2的扩增或过表达。
在一些实施方案中,与CDK2相关的疾病或病症是腺癌、癌瘤或囊腺癌。
在其它实施方案中,所述癌症是乳腺癌,包括例如ER阳性/HR阳性、HER2阴性乳腺癌;ER阳性/HR阳性、HER2阳性乳腺癌;三阴性乳腺癌(TNBC);或炎性乳腺癌。在一些实施方案中,乳腺癌是化疗或放疗抗性乳腺癌、内分泌抗性乳腺癌、曲妥珠单抗抗性乳腺癌或对CDK4/CDK6抑制表现出原发性或获得性抗性的乳腺癌。在一些实施方案中,乳腺癌是晚期或转移性乳腺癌。在前述每一者的一些实施方案中,乳腺癌的特征在于CCNE1和/或CCNE2的扩增或过表达。
在一些实施方案中,所述癌症是卵巢癌。在一些这类实施方案中,所述癌症是特征在于CCNE1和/或CCNE2的扩增或过表达的卵巢癌。在一些这类实施方案中,所述癌症是(a)卵巢癌;(b)特征在于细胞周期蛋白E1(CCNE1)或细胞周期蛋白E2(CCNE2)的扩增或过表达;或(c)(a)和(b)两者。在一些实施方案中,所述癌症是卵巢癌。
在一些实施方案中,施用本公开的化合物作为一线疗法。在其它实施方案中,施用本公开的化合物作为二(或晚)线疗法。在一些实施方案中,在用内分泌治疗剂和/或CDK4/CDK6抑制剂治疗之后施用本公开的化合物作为二(或晚)线疗法。在一些实施方案中,在用内分泌治疗剂例如芳香酶抑制剂、SERM或SERD治疗之后施用本公开的化合物作为二(或晚)线疗法。在一些实施方案中,在用CDK4/CDK6抑制剂治疗之后施用本公开的化合物作为二(或晚)线疗法。在一些实施方案中,在用例如包括紫杉烷或铂剂在内的一种或多种化疗方案治疗之后施用本公开的化合物作为二(或晚)线疗法。在一些实施方案中,在用HER2靶向的药剂(例如,曲妥珠单抗)治疗之后施用本公开的化合物作为二(或晚)线疗法。
在一些实施方案中,与CDK2相关的疾病或病症是N-myc扩增的成神经细胞瘤细胞(参见Molenaar等人,Proc Natl Acad Sci USA 106(31):12968-12973)、K-Ras突变型肺癌(参见Hu,S.等人,Mol Cancer Ther,2015.14(11):2576-85)以及具有FBW7突变和CCNE1过表达的癌症(参见Takada等人,Cancer Res,2017.77(18):4881-4893)。
在一些实施方案中,本公开的化合物可用于治疗镰状细胞病和镰状细胞贫血。
可使用本公开的化合物治疗的癌症的实例包括但不限于骨癌、胰腺癌、皮肤癌、头颈癌、皮肤或眼内恶性黑色素瘤、子宫癌、卵巢癌、直肠癌、***区癌、胃部癌症、睾丸癌、子宫癌、输卵管癌、子宫内膜癌瘤、子宫内膜癌、***、***癌、外阴癌、霍奇金病、非霍奇金淋巴瘤、食道癌、小肠癌、内分泌***癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、***癌、慢性或急性白血病(包括急性髓性白血病、慢性髓性白血病、急性成淋巴细胞性白血病、慢性淋巴细胞性白血病)、儿童实体肿瘤、淋巴细胞性淋巴瘤、膀胱癌、肾或尿道癌、肾盂癌、中枢神经***(CNS)肿瘤、原发性CNS淋巴瘤、肿瘤血管生成、脊柱轴肿瘤、脑干神经胶质瘤、垂体腺瘤、卡波西肉瘤、表皮样癌、鳞状细胞癌、T细胞淋巴瘤、环境诱发的癌症(包括由石棉诱发的癌症)以及所述癌症的组合。本公开的化合物也可用于治疗转移性癌症。
在一些实施方案中,可用本公开的化合物治疗的癌症包括黑色素瘤(例如,转移性恶性黑色素瘤、BRAF和HSP90抑制抗性黑色素瘤)、肾癌(例如,透明细胞癌)、***癌(例如,激素难治性***腺癌)、乳腺癌、结肠癌、肺癌(例如,非小细胞肺癌和小细胞肺癌)、鳞状细胞头颈癌、尿路上皮癌(例如,膀胱)和具有高微卫星不稳定性的癌症(MSIhigh)。另外,本公开包括可使用本公开的化合物抑制其生长的难治性或复发性恶性肿瘤。
在一些实施方案中,可使用本公开的化合物治疗的癌症包括但不限于实体肿瘤(例如,***癌、结肠癌、食道癌、子宫内膜癌、卵巢癌、子宫癌、肾癌、肝癌、胰腺癌、胃癌、乳腺癌、肺癌、头颈癌、甲状腺癌、成胶质细胞瘤、肉瘤、膀胱癌等)、血液癌症(例如,淋巴瘤、白血病,如急性成淋巴细胞性白血病(ALL)、急性骨髓性白血病(AML)、慢性淋巴细胞性白血病(CLL)、慢性骨髓性白血病(CML)、DLBCL、套细胞淋巴瘤、非霍奇金淋巴瘤(包括滤泡性淋巴瘤,包括复发或难治性NHL和复发性滤泡性淋巴瘤)、霍奇金淋巴瘤或多发性骨髓瘤)以及所述癌症的组合。
在一些实施方案中,可使用本公开的化合物治疗的癌症包括但不限于胆管癌、胆道癌、三阴性乳腺癌、横纹肌肉瘤、小细胞肺癌、平滑肌肉瘤、肝细胞癌、尤文氏肉瘤、脑癌、脑肿瘤、星形细胞瘤、成神经细胞瘤、神经纤维瘤、基底细胞癌、软骨肉瘤、上皮样肉瘤、眼癌、输卵管癌、胃肠道癌、胃肠道间质瘤、毛细胞白血病、肠癌、胰岛细胞癌、口腔癌、口癌、咽喉癌、喉癌、唇癌、间皮瘤、颈癌、鼻腔癌、眼部癌症、眼部黑色素瘤、盆腔癌、直肠癌、肾细胞癌、唾液腺癌、鼻窦癌、脊柱癌、舌癌、管癌、尿道癌和输尿管癌。
在一些实施方案中,可使用本公开的化合物治疗的疾病和适应症包括但不限于血液癌症、肉瘤、肺癌、胃肠道癌、泌尿生殖道癌、肝癌、骨癌、神经***癌、妇科癌症和皮肤癌。
示例性血液癌症包括淋巴瘤和白血病,如急性成淋巴细胞性白血病(ALL)、急性骨髓性白血病(AML)、急性早幼粒细胞白血病(APL)、慢性淋巴细胞性白血病(CLL)、慢性骨髓性白血病(CML)、弥漫性大B细胞淋巴瘤(DLBCL)、套细胞淋巴瘤、非霍奇金淋巴瘤(包括复发或难治性NHL和复发性滤泡性淋巴瘤)、霍奇金淋巴瘤、骨髓增生性疾病(例如,原发性骨髓纤维化(PMF)、真性红细胞增多症(PV)和原发性血小板增多症(ET))、骨髓增生异常综合征(MDS)、T细胞急性成淋巴细胞性淋巴瘤(T-ALL)和多发性骨髓瘤(MM)。
示例性肉瘤包括软骨肉瘤、尤文氏肉瘤、骨肉瘤、横纹肌肉瘤、血管肉瘤、纤维肉瘤、脂肪肉瘤、粘液瘤、横纹肌瘤、横纹肉瘤、纤维瘤、脂肪瘤、错构瘤和畸胎瘤。
示例性肺癌包括非小细胞肺癌(NSCLC)、小细胞肺癌(SCLC)、支气管癌、鳞状细胞癌、未分化小细胞癌、未分化大细胞癌、腺癌、肺泡(细支气管)癌、支气管腺瘤、软骨瘤性错构瘤和间皮瘤。示例性胃肠道癌包括食道癌(鳞状细胞癌、腺癌、平滑肌肉瘤、淋巴瘤)、胃癌(癌瘤、淋巴瘤、平滑肌肉瘤)、胰腺癌(导管腺癌、胰岛素瘤、胰高血糖素瘤、胃泌素瘤、类癌瘤、舒血管肠肽瘤)、小肠癌(腺癌、淋巴瘤、类癌瘤、卡波西肉瘤、平滑肌瘤、血管瘤、脂肪瘤、神经纤维瘤、纤维瘤)、大肠癌(腺癌、管状腺瘤、绒毛状腺瘤、错构瘤、平滑肌瘤)和结直肠癌。
示例性泌尿生殖道癌包括肾癌(腺癌、维尔姆瘤[肾母细胞瘤])、膀胱癌和尿道癌(鳞状细胞癌、移行细胞癌、腺癌)、***癌(腺癌、肉瘤)和睾丸癌(***瘤、畸胎瘤、胚胎癌、畸胎癌瘤、绒毛膜癌、肉瘤、***癌、纤维瘤、纤维腺瘤、腺瘤样肿瘤、脂肪瘤)。
示例性肝癌包括肝细胞瘤(肝细胞癌)、胆管癌、肝母细胞瘤、血管肉瘤、肝细胞腺瘤和血管瘤。
示例性骨癌包括例如成骨肉瘤(骨肉瘤)、纤维肉瘤、恶性纤维组织细胞瘤、软骨肉瘤、尤文氏肉瘤、恶性淋巴瘤(网状细胞肉瘤)、多发性骨髓瘤、恶性巨细胞瘤脊索瘤、骨软骨瘤(骨软骨外生骨疣)、良性软骨瘤、成软骨细胞瘤、软骨粘液纤维瘤、骨样骨瘤和巨细胞瘤。
示例性神经***癌症包括颅骨癌(骨瘤、血管瘤、肉芽肿瘤、黄瘤、变形性骨炎)、脑膜癌(脑膜瘤、脑膜肉瘤、神经胶质瘤病)、脑癌(星形细胞瘤、成神经管细胞瘤、神经胶质瘤、室管膜瘤、生殖细胞瘤(松果体瘤)、成胶质细胞瘤、多形性成胶质细胞瘤、少突神经胶质瘤、神经鞘瘤、视网膜母细胞瘤、先天性肿瘤)和脊髓癌(神经纤维瘤、脑膜瘤、神经胶质瘤、肉瘤)以及成神经细胞瘤和Lhermitte-Duclos病。
示例性妇科癌症包括子宫癌(子宫内膜癌)、***(***瘤、瘤前宫颈发育不良)、卵巢癌(卵巢癌瘤(浆液性囊腺癌、粘液性囊腺癌、未分类癌)、粒层细胞-泡膜细胞瘤、Sertoli-Leydig细胞瘤、无性细胞瘤、恶性畸胎瘤)、外阴癌(鳞状细胞癌、上皮内癌、腺癌、纤维肉瘤、黑色素瘤)、***癌(透明细胞癌、鳞状细胞癌、葡萄样肉瘤(胚胎横纹肌肉瘤)和输卵管(癌)。
示例性皮肤癌包括黑色素瘤、基底细胞癌、默克尔细胞癌、鳞状细胞癌、卡波西肉瘤、畸形痣(moles dysplastic nevi)、脂肪瘤、血管瘤、皮肤纤维瘤和瘢痕疙瘩。在一些实施方案中,可使用本公开的化合物治疗的疾病和适应症包括但不限于镰状细胞病(例如,镰状细胞贫血)、三阴性乳腺癌(TNBC)、骨髓增生异常综合征、睾丸癌、胆道癌、食道癌和尿路上皮癌。
组合
本公开的化合物可作为单一药剂施用,或者可以与其它抗癌治疗剂、特别是适合于特定癌症的标准护理剂组合施用。
如本文所用的术语“另外的抗癌治疗剂”意指除本公开的化合物之外的任何一种或多种治疗剂,其用于或可用于治疗癌症。在一些实施方案中,这类另外的抗癌治疗剂包括来源于以下类别的化合物:有丝***抑制剂、烷化剂、抗代谢物、抗肿瘤抗生素、抗血管生成剂、拓扑异构酶I和II抑制剂、植物生物碱、激素剂和拮抗剂、生长因子抑制剂、辐射、信号转导抑制剂如蛋白酪氨酸激酶和/或丝氨酸/苏氨酸激酶的抑制剂、细胞周期抑制剂、生物反应调节剂、酶抑制剂、反义寡核苷酸或寡核苷酸衍生物、细胞毒素、免疫肿瘤剂等。
在一些实施方案中,另外的抗癌剂是内分泌剂,如芳香酶抑制剂、SERD或SERM。
在其它实施方案中,本公开的化合物可以与标准护理剂组合施用。在一些实施方案中,本公开的化合物可以与内分泌疗法组合施用,所述内分泌疗法例如为诸如来曲唑、氟维司群、他莫昔芬、依西美坦或阿那曲唑的药剂。在一些实施方案中,本公开的化合物可以与化疗剂例如多西他赛、紫杉醇、顺铂、卡铂、卡培他滨、吉西他滨或长春瑞滨组合施用。在其它实施方案中,本发明的化合物可以与抗HER2剂例如曲妥珠单抗或帕妥珠单抗组合施用。
在一些实施方案中,另外的抗癌剂是抗血管生成剂,包括例如VEGF抑制剂、VEGFR抑制剂、TIE-2抑制剂、PDGFR抑制剂、血管生成素抑制剂、PKCb抑制剂、COX-2(环氧合酶II)抑制剂、整联蛋白(α-v/β-3)、MMP-2(基质金属蛋白酶2)抑制剂和MMP-9(基质金属蛋白酶9)抑制剂。优选的抗血管生成剂包括舒尼替尼(SutentTM)、贝伐珠单抗(AvastinTM)、阿西替尼(AG 13736)、SU 14813(Pfizer)和AG 13958(Pfizer)。另外的抗血管生成剂包括瓦他拉尼(CGP 79787)、索拉非尼(NexavarTM)、哌加他尼八钠(MacugenTM)、凡德他尼(ZactimaTM)、PF-0337210(Pfizer)、SU 14843(Pfizer)、AZD 2171(AstraZeneca)、雷珠单抗(LucentisTM)、NeovastatTM(AE 941)、四硫代钼酸盐(CoprexaTM)、AMG 706(Amgen)、VEGF Trap(AVE0005)、CEP 7055(Sanofi-Aventis)、XL 880(Exelixis)、替拉替尼(BAY 57-9352)和CP-868,596(Pfizer)。其它抗血管生成剂包括恩扎妥林(LY 317615)、米哚妥林(CGP 41251)、哌立福辛(KRX 0401)、替普瑞酮(SelbexTM)和UCN 01(Kyowa Hakko)。抗血管生成剂的其它实例包括塞来昔布(CelebrexTM)、帕瑞昔布(DynastatTM)、德拉昔布(SC 59046)、罗美昔布(PreigeTM)、伐地昔布(BextraTM)、罗非昔布(VioxxTM)、艾拉莫德(CareramTM)、IP 751(Invedus)、SC-58125(Pharmacia)和依托昔布(ArcoxiaTM)。更进一步的抗血管生成剂包括依昔舒林(AptosynTM)、双水杨酯(AmigesicTM)、二氟尼柳(DolobidTM)、布洛芬(MotrinTM)、酮洛芬(OrudisTM)、萘丁美酮(RelafenTM)、吡罗昔康(FeldeneTM)、萘普生(AleveTM、NaprosynTM)、双氯芬酸(VoltarenTM)、吲哚美辛(IndocinTM)、舒林酸(ClinorilTM)、托美丁(TolectinTM)、依托度酸(LodineTM)、酮咯酸(ToradolTM)和奥沙普秦(DayproTM)。更进一步的抗血管生成剂包括ABT 510(Abbott)、阿雷司他(TMI 005)、AZD 8955(AstraZeneca)、茵克林(MetastatTM)和PCK 3145(Procyon)。
更进一步的抗血管生成剂包括阿曲汀(NeotigasonTM)、普利地新(aplidineTM)、西仑吉肽(EMD 121974)、康普瑞汀A4(CA4P)、芬维A胺(4HPR)、卤夫酮(TempostatinTM)、PanzemTM(2-甲氧基***)、PF-03446962(Pfizer)、瑞马司他(BMS275291)、卡妥索单抗(RemovabTM)、来那度胺(RevlimidTM)、角鲨胺(EVIZONTM)、沙利度胺(ThalomidTM)、UkrainTM(NSC 631570)、VitaxinTM(MEDI 522)和唑来膦酸(ZometaTM)。
在其它实施方案中,另外的抗癌剂是所谓的信号转导抑制剂(例如,抑制控制细胞生长、分化和存活的基本过程的调控分子如何在细胞内通讯)。信号转导抑制剂包括小分子、抗体和反义分子。信号转导抑制剂包括例如激酶抑制剂(例如,酪氨酸激酶抑制剂或丝氨酸/苏氨酸激酶抑制剂)和细胞周期抑制剂。更具体地,信号转导抑制剂包括例如法尼基蛋白转移酶抑制剂、EGF抑制剂、ErbB-1(EGFR)、ErbB-2、pan erb、IGF1R抑制剂、MEK、c-Kit抑制剂、FLT-3抑制剂、K-Ras抑制剂、PI3激酶抑制剂、JAK抑制剂、STAT抑制剂、Raf激酶抑制剂、Akt抑制剂、mTOR抑制剂、P70S6激酶抑制剂、WNT途径的抑制剂和所谓的多靶向激酶抑制剂。可与本发明的化合物和本文所述的药物组合物结合使用的信号转导抑制剂的另外的实例包括BMS 214662(Bristol-Myers Squibb)、洛那法尼(SarasarTM)、培利曲索(AG 2037)、马妥珠单抗(EMD 7200)、尼妥珠单抗(TheraCIM h-R3TM)、帕尼单抗(VectibixTM)、凡德他尼(ZactimaTM)、帕唑帕尼(SB 786034)、ALT 110(Alteris Therapeutics)、BIBW 2992(Boehringer Ingelheim)和CerveneTM(TP 38)。信号转导抑制剂的其它实例包括吉非替尼(IressaTM)、西妥昔单抗(ErbituxTM)、埃罗替尼(TarcevaTM)、曲妥珠单抗(HerceptinTM)、舒尼替尼(SutentTM)、伊马替尼(GleevecTM)、克唑替尼(Pfizer)、劳拉替尼(Pfizer)、达克替尼(Pfizer)、博舒替尼(Pfizer)、吉达利塞(Pfizer)、卡奈替尼(CI 1033)、帕妥珠单抗(OmnitargTM)、拉帕替尼(TycerbTM)、培利替尼(EKB 569)、米替福新(MiltefosinTM)、BMS599626(Bristol-Myers Squibb)、Lapuleucel-T(NeuvengeTM)、NeuVaxTM(E75癌症疫苗)、OsidemTM(IDM 1)、木利替尼(TAK-165)、CP-724,714(Pfizer)、帕尼单抗(VectibixTM)、ARRY142886(Array Biopharm)、依维莫司(CerticanTM)、唑他莫司(EndeavorTM)、替西罗莫司(ToriselTM)、AP 23573(ARIAD)和VX 680(Vertex)、XL 647(Exelixis)、索拉非尼(NexavarTM)、LE-AON(Georgetown University)和GI-4000(Globelmmune)。其它信号转导抑制剂包括ABT 751(Abbott)、阿伏西地(夫拉平度)、BMS 387032(Bristol Myers)、EM 1421(Erimos)、吲地磺胺(E 7070)、瑟利西利(CYC 200)、BIO 112(Onc Bio)、BMS 387032(Bristol-Myers Squibb)、帕博西尼(Pfizer)和AG 024322(Pfizer)。
在其它实施方案中,另外的抗癌剂是所谓的经典抗肿瘤剂。经典抗肿瘤剂包括但不限于激素调节剂如激素、抗激素、雄激素激动剂、雄激素拮抗剂和抗***治疗剂、组蛋白脱乙酰酶(HDAC)抑制剂、DNA甲基转移酶抑制剂、沉默剂或基因激活剂、核糖核酸酶、蛋白体、拓扑异构酶I抑制剂、喜树碱衍生物、拓扑异构酶II抑制剂、烷化剂、抗代谢物、聚(ADP-核糖)聚合酶-1(PARP-1)抑制剂(比如他拉唑帕利、奥拉帕利、卢卡帕尼、尼拉帕尼、伊尼帕尼、维利帕尼)、微管蛋白抑制剂、抗生素、植物来源的纺锤体抑制剂、铂配位化合物、基因治疗剂、反义寡核苷酸、血管靶向剂(VTA)和他汀类药物。在与本发明的化合物、任选与一种或多种其它药剂的组合疗法中使用的经典抗肿瘤剂的实例包括但不限于糖皮质激素,如***、***、***龙、甲基***龙、氢化可的松,和孕激素,如甲羟孕酮、醋酸甲地孕酮(Megace)、米非司酮(RU-486)、选择性***受体调节剂(SERM;如他莫昔芬、雷洛昔芬、拉索昔芬、阿非昔芬、阿佐昔芬、巴多昔芬、非培米芬、奥美昔芬、奥培米芬、替米利芬、托瑞米芬、曲洛斯坦和CHF 4227(Cheisi),选择性***受体下调剂(SERD;如氟维司群)、依西美坦(Aromasin)、阿那曲唑(Arimidex)、阿他美坦、法屈唑、来曲唑(Femara)、福美司坦;促性腺素释放激素(GnRH;也通常称为***释放激素[LHRH])激动剂,如布舍瑞林(Suprefact)、戈舍瑞林(Zoladex)、亮丙瑞林(Lupron)和曲普瑞林(Trelstar)、阿巴瑞克(Plenaxis)、环丙孕酮、氟他胺(Eulexin)、甲地孕酮、尼鲁米特(Nilandron)和奥沙特隆、度他雄胺、爱普列特、非那雄胺、锯棕榈、PHL 00801、阿巴瑞克、戈舍瑞林、亮丙瑞林、曲普瑞林、比卡鲁胺;抗雄激素剂,如恩杂鲁胺、醋酸阿比特龙、比卡鲁胺(Casodex);及其组合。与本发明的化合物组合使用的经典抗肿瘤剂的其它实例包括但不限于辛二酰苯胺异羟肟酸(SAHA,Merck Inc./Aton Pharmaceuticals)、缩酚肽(FR901228或FK228)、G2M-777、MS-275、丁酸新戊酰氧基甲酯和PXD-101;豹蛙酶(Onconase/ranpirnase)、PS-341(MLN-341)、万珂(硼替佐米)、9-氨基喜树碱、贝洛替康、BN-80915(Roche)、喜树碱、二氟莫替康、依多卡林、依喜替康(Daiichi)、吉马替康、10-羟基喜树碱、伊立替康HCl(Camptosar)、勒托替康、Orathecin(鲁比替康,Supergen)、SN-38、拓扑替康、喜树碱、10-羟基喜树碱、9-氨基喜树碱、伊立替康、SN-38、依多卡林、拓扑替康、阿柔比星、阿霉素、氨萘非特、氨柔比星、安那霉素、道诺霉素、多柔比星、依沙芦星、表柔比星、依托泊苷、伊达比星、加柔比星、羟基脲素、奈莫柔比星、能灭瘤(米托蒽醌)、吡柔比星、匹克生琼、丙卡巴肼、蝴蝶霉素、索布佐生、他氟泊苷、戊柔比星、Zinecard(右雷佐生)、氮芥N-氧化物、环磷酰胺、AMD-473、六甲蜜胺、AP-5280、阿帕齐醌、brostallicin、苯达莫司汀、白消安、卡波醌、卡莫司汀、苯丁酸氮芥、达卡巴嗪、雌莫司汀、福莫司汀、葡磷酰胺、异环磷酰胺、KW-2170、洛莫司汀、马磷酰胺、二氯甲基二乙胺(mechlorethamine)、美法仑、二溴甘露醇、二溴卫矛醇、丝裂霉素C、米托蒽醌、尼莫司汀、雷莫司汀、替莫唑胺、噻替派和铂配位烷基化化合物,如顺铂、伯尔定(卡铂)、依铂、洛铂、奈达铂、乐沙啶(奥沙利铂,Sanofi)、链佐星、赛特铂及其组合。
还在其它实施方案中,另外的抗癌剂是所谓的二氢叶酸还原酶抑制剂(如甲氨蝶呤和NeuTrexin(葡糖醛酸三甲曲沙))、嘌呤拮抗剂(如6-巯嘌呤核苷、巯嘌呤、6-硫鸟嘌呤、克拉屈滨、氯法拉滨(Clolar)、氟达拉滨、奈拉滨和雷替曲塞)、嘧啶拮抗剂(如5-氟尿嘧啶(5-FU)、Alimta(培美曲塞二钠,LY231514,MTA)、卡培他滨(XelodaTM)、阿糖胞苷、GemzarTM(吉西他滨,Eli Lilly)、替加氟(UFT Orzel或Uforal,并且包括替加氟、吉美司他和奥特斯特(otostat)的TS-1组合)、多西氟尿啶、卡莫氟、阿糖胞苷(包括阿糖胞苷烷磷酯、磷酸硬脂酸酯,持续释放和脂质体形式)、依诺他滨、5-阿扎胞苷(Vidaza)、地西他滨和乙炔基胞苷)及其它抗代谢物,如依氟鸟氨酸、羟基脲、亚叶酸、诺拉曲塞(Thymitaq)、triapine、三甲曲沙、N-(5-[N-(3,4-二氢-2-甲基-4-氧代喹唑啉-6-基甲基)-N-甲基氨基]-2-噻吩甲酰基)-L-谷氨酸、AG-014699(Pfizer Inc.)、ABT-472(Abbott Laboratories)、INO-1001(InotekPharmaceuticals)、KU-0687(KuDOS Pharmaceuticals)和GPI 18180(Guilford PharmInc)及其组合。
经典抗肿瘤细胞毒性剂的其它实例包括但不限于白蛋白结合型紫杉醇(AbraxisBioScience,Inc.)、巴他布林(Amgen)、EPO 906(Novartis)、长春氟宁(Bristol-MyersSquibb Company)、放线菌素D、博来霉素、丝裂霉素C、新制癌菌素(Zinostatin)、长春碱、长春新碱、长春地辛、长春瑞滨(Navelbine)、多西他赛(泰索帝)、奥他赛、紫杉醇(包括DHA/紫杉醇缀合物Taxoprexin)、顺铂、卡铂、奈达铂、奥沙利铂(乐沙定)、赛特铂、卡博柔、卡培他滨(Xeloda)、奥沙利铂(乐沙定)、泰索帝阿利维甲酸、卡福磷酰胺(TelcytaTM)、DMXAA(Antisoma)、伊班膦酸、L-天冬酰胺酶、培门冬酶(OncasparTM)、乙丙昔罗(EfaproxynTM-放射疗法)、贝沙罗汀(TargretinTM)、替米利芬(DPPE–增强细胞毒素的功效)、TheratopeTM(Biomira)、维甲酸(VesanoidTM)、替拉扎明(TrizaoneTM)、莫特沙芬钆(XcytrinTM)、CotaraTM(mAb)和NBI-3001(Protox Therapeutics)、聚谷氨酸-紫杉醇(XyotaxTM)及其组合。经典抗肿瘤剂的进一步的实例包括但不限于Advexin(ING 201)、TNFerade(GeneVec,一种响应放射疗法而表达TNFα的化合物)、RB94(Baylor College of Medicine)、Genasense(奥利默森,Genta)、康普瑞汀A4P(CA4P)、Oxi-4503、AVE-8062、ZD-6126、TZT-1027、阿托伐他汀(立普妥,Pfizer Inc.)、普伐他汀(普拉瓦科尔,Bristol-Myers Squibb)、洛伐他汀(美降之,Merck Inc.)、辛伐他汀(舒降之,Merck Inc.)、氟伐他汀(来适可,Novartis)、西立伐他汀(拜可,Bayer)、罗素伐他汀(冠脂妥,AstraZeneca)、洛伐他汀、尼克酸(Advicor,KosPharmaceuticals)、脂脉优、立普妥、托彻普及其组合。
在其它实施方案中,另外的抗癌剂是表观遗传调节剂,例如抑制剂或EZH2、SMARCA4、PBRM1、ARID1A、ARID2、ARID1B、DNMT3A、TET2、MLL1/2/3、NSD1/2、SETD2、BRD4、DOT1L、HKMTsanti、PRMT1-9、LSD1、UTX、IDH1/2或BCL6。
在进一步的实施方案中,另外的抗癌剂是免疫调节剂,如CTLA-4、PD-1或PD-L1的抑制剂(例如,帕博利珠单抗、纳武利尤单抗或阿维鲁单抗)、LAG-3、TIM-3、TIGIT、4-1BB、OX40、GITR、CD40的抑制剂或CAR-T细胞疗法。
在一些实施方案中,另外的抗癌剂是EGFR抑制剂,如阿法替尼、奥希替尼、拉帕替尼、埃罗替尼、达克替尼、波齐替尼、来那替尼或吉非替尼,或EGFR抗体,如西妥昔单抗、帕尼单抗或耐昔妥珠单抗。
或者,本公开的化合物、其药学上可接受的盐或本文公开的药物组合物可以与不是EGFR抑制剂的其它抗癌剂组合施用,例如与以下组合施用:MEK,包括突变型MEK抑制剂(曲美替尼、考比替尼、贝美替尼、司美替尼、瑞法替尼);c-MET,包括突变型c-Met抑制剂(赛沃替尼、卡博替尼、福瑞替尼)和MET抗体(依玛妥珠单抗);有丝***激酶抑制剂(CDK4/6抑制剂,如帕博西尼、瑞博西尼、阿贝西尼);抗血管生成剂,例如贝伐单抗、尼达尼布;凋亡诱导剂,如Bcl-2抑制剂,例如维奈托克、奥巴克拉、那维妥拉,和Mcl-1抑制剂,例如AZD-5991、AMG-176、S-64315;以及mTOR抑制剂,例如雷帕霉素、替西罗莫司、依维莫司、地磷莫司(ridoforolimus)。
本公开的化合物、其药学上可接受的盐或本文公开的药物组合物还可以与有效量的选自由以下组成的组的第二药剂组合施用:帕博西尼(例如,)、瑞博西尼、阿贝西利、他莫昔芬、来曲唑、奥拉帕尼(例如,/>)、尼拉帕尼、卡铂、顺铂、紫杉醇、吉西他滨、醋酸甲地孕酮、醋酸甲羟孕酮、卡培他滨(例如,/>)、瑞戈非尼(例如,)、阿法替尼(例如,/>)、奥希替尼(例如,/>)、吉非替尼(例如,)、埃罗替尼(例如,/>)、雷莫芦单抗(例如,/>)、EGFR抑制剂、普拉替尼、ABT-263(那维妥拉)、MK-1775(阿达色替)、BAY-1895344、柏佐舍替、西拉塞替、SRA-737、LY2603618(拉布塞蒂)和曲妥珠单抗(例如,/>)或其组合。EGFR抑制剂可选自阿法替尼、奥希替尼、拉帕替尼、埃罗替尼、达克替尼、波齐替尼、来那替尼、吉非替尼、JBJ-04-125-02、艾氟替尼(AST 2818)、aumolertinib(以前的阿美替尼)(HS10296)、BBT-176、BI-4020、BPI-361175、BPI-D0316、CH7233163、吉瑞替尼、埃克替尼、JND-3229、拉泽替尼、那扎替尼(EGF 816)、艾维替尼、PCC-0208027、瑞齐替尼(BPI-7711)、TQB3804、佐利替尼(AZ-3759)或DZD9008;EGFR抗体,如西妥昔单抗、帕尼单抗、耐昔妥珠单抗、HLX07、JMT101;或双特异性EGFR和MET抗体(例如,埃万妥单抗((JNJ-61186372,JNJ-372))。
生物标志物和药效动力学标志物
本公开进一步提供预测标志物(例如,生物标志物和药效动力学标志物,例如基因拷贝数、基因序列、表达水平或磷酸化水平),以确认患有、疑似患有与CDK2相关的疾病或病症或有患与CDK2相关的疾病或病症的风险的人受试者,给这些受试者施用CDK2抑制剂(如本文所用的“CDK2抑制剂”是指本公开的化合物或其药学上可接受的盐)可能是有效的。
CCNE1
在一个实施方案中,生物标志物是CCNE1。特别地,生物样品中的细胞周期蛋白E1(CCNE1)基因的扩增和/或CCNE1的表达水平将表明患者或受试者可受益于施用式(I)的化合物或其药学上可接受的盐。
CCNE1是在G1/S转变时控制细胞周期所必需的细胞周期因子(Ohtsubo等人,1995,Mol.Cell.Biol.15:2612-2624)。CCNE1作为CDK2的调控亚基,与CDK2相互作用以形成丝氨酸/苏氨酸激酶全酶复合物。此全酶复合物的CCNE1亚基提供了复合物的底物特异性(Honda等人,2005,EMBO 24:452-463)。CCNE1由细胞周期蛋白E1(“CCNE1”)基因(GenBank登录号NM_001238)编码。人CCNE1的氨基酸序列见于GenBank登录号NP_001229/UniProtKB登录号P24864。
一方面,本公开提供治疗患有与CDK2相关的疾病或病症或有患与CDK2相关的疾病或病症的风险的受试者的方法,所述方法包括对受试者施用治疗有效量的本文公开的化合物或其药学上可接受的盐或本文公开的药物组合物,其中受试者具有CCNE1基因的扩增和/或具有高于CCNE1的对照表达水平的CCNE1的表达水平。在一些实施方案中,与CDK2相关的疾病或病症是癌症。
本文还提供治疗具有扩增的CCNE1表达水平并罹患实体肿瘤癌症或有患实体肿瘤癌症的风险的患者的方法,所述方法包括对患者施用治疗有效量的本文公开的化合物或其药学上可接受的盐或本文公开的药物组合物。
CCNE1基因的扩增和/或高于CCNE1的对照表达水平的CCNE1的表达水平指示/预测患有与CDK2相关的疾病或病症或有患与CDK2相关的疾病或病症的风险的人受试者将对CDK2抑制剂产生反应。在一些实施方案中,CCNE1的表达水平可以是CCNE1 mRNA的水平。在其它实施方案中,CCNE1的表达水平可以是CCNE1蛋白的水平。
其它生物标志物
在一些实施方案中,预期的生物标志物可以是p16(也称为细胞周期蛋白依赖性激酶抑制剂2A、细胞周期蛋白依赖性激酶4抑制剂A、多重肿瘤抑制因子1和p16-INK4a),其通过与CDK4和CDK6相互作用而充当正常细胞增殖的负调节因子。在其它实施方案中,预期的生物标志物可以是Rb在对应于氨基酸位置780的丝氨酸处的磷酸化。Rb是细胞周期的调节因子,并且充当肿瘤抑制剂。Rb在磷酸化时在Ser780和Ser795处被细胞周期蛋白D-CDK4/6以及在Ser807和Ser811处被细胞周期蛋白E/CDK2激活。
预期的生物标志物也可以选自由以下组成的组:RB1、RBL1、RBL2、CDKN2A、CDKN1A、CDKN1B、FBXW7、CCNE1、CCNE2、CCNA1、CCNA2、CCND1、CCND2、CCND3、CDK2、CDK3、CDK4、CDK6、CDKN2A、CDNK1A、CDKN1B E2F1、E2F2、E2F3、MYC、MYCL、MYCN、EZH2、ER、HER2、HER3、HPV+和EGFR。
生物样品
用于本文所述的方法的合适的生物样品包括含有获自或得自需要治疗的人受试者的血液或肿瘤细胞的任何样品。例如,生物样品可含有来自罹患实体肿瘤的患者的活检的肿瘤细胞。可通过本领域中已知的多种方式获得肿瘤活检。或者,血液样品可获自罹患血液癌症的患者。
生物样品可获自患有、疑似患有与CDK2相关的疾病或病症或有患与CDK2相关的疾病或病症的风险的人受试者。在一些实施方案中,与CDK2相关的疾病或病症是癌症(如上文所述的那些)。
保持样品中的分子(例如,核酸或蛋白质)的活性或完整性的获得和/或储存样品的方法是本领域技术人员熟知的。例如,可以使生物样品与一种或多种另外的试剂如缓冲剂和/或抑制剂进一步接触,包括保持样品中的分子或使样品中的分子变化最小的核酸酶、蛋白酶和磷酸酶抑制剂中的一者或多者。
施用方法和剂型
为对受试者提供“有效量”而施用的化合物的精确量将取决于施用模式、癌症的类型和严重程度以及受试者的特点,如一般健康状况、年龄、性别、体重和对药物的耐受性。技术人员将能够根据这些及其它因素确定适当的剂量。当与其它治疗剂组合施用时,例如当与抗癌剂组合施用时,任何另外的治疗剂的“有效量”将取决于所用药物的类型。经批准的治疗剂的合适剂量是已知的,并且可由技术人员根据受试者的状况、所治疗的病状的类型和所使用的式(I)的化合物的量按照例如文献中报道和Physician’s Desk Reference(第57版,2003)中推荐的剂量进行调整。
“治疗(treating/treatment)”是指获得所需的药理学和/或生理学效果。所述效果可以是治疗性的,其包括部分地或基本上实现以下结果中的一者或多者:部分地或基本上减少疾病、病状或癌症的程度;缓解或改善与疾病、病状或癌症相关的临床症状或指标;延迟、抑制疾病、病状或癌症的进展或降低疾病、病状或癌症进展的可能性;或降低疾病、病状或癌症复发的可能性。
术语“有效量”意指当对受试者施用时产生有益或所需结果的量,所述结果包括临床结果,例如与对照相比,抑制、阻止或减少受试者中所治疗的病状的症状。例如,可以以单位剂型给予治疗有效量(例如,每天0.1mg至约50g,或者每天1mg至约5g;并且在另一替代方案中每天10mg至1g)。
如本文所用的术语“施用(administer/administering/administration)”是指可用于实现将组合物递送到所需生物作用部位的方法。这些方法包括但不限于关节内(在关节中)、静脉内、肌内、肿瘤内、皮内、腹膜内、皮下、口服、局部、鞘内、吸入、透皮、经直肠等。本文所述的药剂和方法可采用的施用技术可见于例如Goodman和Gilman,ThePharmacological Basis of Therapeutics,现行版;Pergamon;和Remington的Pharmaceutical Sciences(现行版),Mack Publishing Co.,Easton,Pa中。
此外,本公开的化合物、其药学上可接受的盐或本公开的药物组合物可以与其它治疗剂共同施用。如本文所用,术语“共同施用”、“与...组合施用”及其语法等同表述意在涵盖对单一受试者施用两种或更多种治疗剂,并且旨在包括其中通过相同或不同的施用途径或在相同或不同的时间施用药剂的治疗方案。在一些实施方案中,本公开的一种或多种化合物、其药学上可接受的盐或本公开的药物组合物将与其它药剂共同施用。这些术语涵盖对受试者施用两种或更多种药剂,使得在受试者体内同时存在两种药剂和/或它们的代谢物。它们包括以分开的组合物同时施用、以分开的组合物在不同的时间施用和/或以其中存在两种药剂的组合物施用。因此,在一些实施方案中,以单一组合物施用本文所述的化合物和其它药剂。在一些实施方案中,将本文所述的化合物和其它药剂混合在组合物中。
特定的施用模式和给药方案将由主治临床医生考虑病例的具体情况(例如受试者、疾病、涉及的疾病状态、特定的治疗)来选择。治疗可涉及历时数天到数月或甚至数年的时间段每天给药、每天多次给药或不足每天给药(如每周或每月给药等)。然而,本领域普通技术人员查看使用公开的CDK2抑制剂作为指导治疗疾病所批准的组合物的剂量,将会立即意识到适当的和/或等效的剂量。
如本领域技术人员将理解的那样,可以以多种形式对患者施用本公开的化合物或其药学上可接受的盐,这取决于所选择的施用途径。可例如通过口服、肠胃外、经颊、舌下、经鼻、经直肠、贴剂、泵或透皮施用来施用本发明教导的化合物,并相应地配制药物组合物。肠胃外施用包括静脉内、腹膜内、皮下、肌内、经上皮、经鼻、肺内、鞘内、经直肠和局部施用模式。肠胃外施用可通过历时选定的时间段连续输注来进行。
本公开的药物组合物被配制为与其预期的施用途径相容。在实施方案中,根据常规程序将组合物配制为适合于对人静脉内、皮下、肌内、口服、鼻内或局部施用的药物组合物。在优选的实施方案中,配制用于静脉内施用的药物组合物。
通常,对于口服治疗施用,可以将本公开的化合物或其药学上可接受的盐与赋形剂掺混,并以可摄取的片剂、***片、锭剂、胶囊、酏剂、混悬剂、糖浆、威化片等形式使用。
通常对于肠胃外施用来说,本公开的化合物或其药学上可接受的盐的溶液通常可以在水中制备,水合适地与表面活性剂如羟丙基纤维素混合。也可以在甘油、液体聚乙二醇、DMSO及其含或不含醇的混合物中以及在油中制备分散体。在普通的储存和使用条件下,这些制剂含有防腐剂以阻止微生物的生长。
通常,对于注射用途,用于临时制备无菌可注射溶液或分散体的本公开的化合物的无菌水溶液或分散体和无菌粉末是适当的。
以下实施例旨在说明,并不旨在以任何方式限制本公开的范围。
范例
实施例
示例性化合物的制备
定义
TsOH 4-甲基苯磺酸
TEA 三乙胺
THF 四氢呋喃
MsCl 甲磺酰氯
DCM 二氯甲烷
NH4Cl 氯化铵
MgSO4 硫酸镁
NaN3 叠氮化钠
DMF 二甲基甲酰胺
EA 乙酸乙酯
Na2SO4 硫酸钠
MeOH 甲醇
N2 氮气
H2 氢气
LiAlH4 氢化铝锂
NaHCO3 碳酸氢钠
CbzCl 氯甲酸苄酯
PE 石油醚
DAST N-乙基-N-(三氟-硫烷基)乙胺
HCl 盐酸盐
ACN 乙腈
DIPEA 二异丙基乙胺
DMSO 二甲基亚砜
DMA 二甲基乙酰胺
h 小时
HPLC 高效液相色谱法
min 分钟
C 摄氏度
IC50 50%抑制浓度
IPA 异丙醇
MTBE 甲基叔丁基醚
rt 室温
TFA 三氟乙酸
IPA 异丙醇
可在有机合成领域的技术人员可以很容易地选择的合适溶剂中进行制备本发明的化合物的方法。在进行反应的温度下,例如可在溶剂的冷冻温度至溶剂的沸腾温度范围内的温度下,合适的溶剂可基本上不与原料(反应物)、中间体或产物反应。给定的反应可以在一种溶剂或多于一种溶剂的混合物中进行。根据特定的反应步骤,技术人员可以选择用于特定反应步骤的合适溶剂。
制备本发明的化合物可涉及各种化学基团的保护和脱保护。本领域技术人员可以很容易地确定保护和脱保护的需要以及适当保护基团的选择。保护基团的化学性质可见于例如Wuts和Greene,Protective Groups in Organic Synthesis,第5版,John Wiley&Sons:New Jersey,(2014)中,该文献以全文引用的方式并入本文。
可以根据本领域中已知的任意合适的方法监测反应。例如,可以通过谱学方法监测产物形成,如核磁共振(NMR)波谱法(例如,1H或13C)、红外(IR)光谱法、分光光度法(例如,UV-可见光)、质谱法(MS)或通过色谱方法如高效液相色谱法(HPLC)或薄层色谱法(TLC)。用于化合物表征的分析仪器和方法:
LC-MS:在22.4摄氏度下用配备Agilent Poroshel 120(EC-C18,2.7um粒度,3.0×50mm尺寸)反相柱、利用ES-API电离、使用Agilent型号6120质谱仪的Agilent型号-1260LC***获得液相色谱-质谱(LC-MS)数据(分析样品的纯度和属性)。流动相由溶剂0.1%甲酸在水中和0.1%甲酸在乙腈中的混合物组成。利用在4分钟的过程内从95%水性流动相/5%有机流动相至5%水性流动相/95%有机流动相的恒定梯度。流速恒定在1mL/min。
或者,在22.4摄氏度下用配备Agilent(Poroshel HPH-C18 2.7um粒度,3.0×50mm尺寸)反相柱、利用ESI电离、使用Shimadzu LCMS质谱仪的Shimadzu LCMS***获得液相色谱-质谱(LC-MS)数据(分析样品的纯度和属性)。流动相由溶剂5mM NH4HCO3(或0.05%TFA)在水和乙腈中的混合物组成。利用在2分钟的过程内从90%水性流动相/10%有机流动相至5%水性流动相/95%有机流动相的恒定梯度。流速恒定在1.5mL/min。
制备型LC-MS:制备型HPLC在配备Xtimate 10um 150A 21.2×250mm柱的ShimadzuDiscovery制备型***上在22.4摄氏度下进行。在碱性条件下,流动相由水(0.1%NH4HCO3)和ACN的混合物组成。利用在18分钟的过程内从85%水相/15%有机相至5%水相/95%有机相的恒定梯度。流速恒定在20mL/min。在酸性条件下,流动相由水(0.1%FA)和ACN的混合物组成。利用在8分钟的过程内从65%水相/35%有机相至55%水相/45%有机相的恒定梯度。
或者,制备型HPLC在配备柱:XBridge Shield RP18 OBD柱,30*150mm,5um的Waters制备型***上进行;流动相由溶剂水(10mmol/L NH4HCO3+0.05%NH3.H2O)和乙腈的混合物组成。利用在11分钟的过程内从95%水性流动相/5%有机流动相至5%水性流动相/95%有机流动相的恒定梯度。流速恒定在60mL/min。在微波中进行的反应是在BiotageInitiator微波装置中完成的。
硅胶色谱法:在Teledyne IscoRf装置、/>Isolera Four装置或/>Isolera Prime装置上进行硅胶色谱法。
质子NMR:用Varian 400MHz Unity Inova 400MHz NMR仪器(采集时间=3.5秒,延迟1秒;16至64次扫描)或Avance 400MHz Unity Inova 400MHz NMR仪器(采集时间=3.99秒,延迟1秒;4至64次扫描)或Avance 300MHz Unity Inova 300MHz NMR仪器(采集时间=5.45秒,延迟1秒;4至64次扫描)获得1H NMR谱。除另指出外,所有质子以在DMSO-d6溶剂中相对于残留DMSO(2.50ppm)的百万分率(ppm)报告。
实施例1.3-氟-4-((4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺
步骤1.合成1-(4-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)-2-甲基丙-2-醇(中间体1)
将2-甲基-1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)丙-2-醇(1.0g,3.75mmol)、2,4-二氯-5-(三氟甲基)嘧啶(2.4g,11.2mmol)、Na2CO3(1.18g,11.2mmol)和Pd(dppf)Cl2(306mg,375μmol)在二噁烷(20mL)和H2O(5mL)中的混合物在80℃和N2下搅拌2h。LCMS指示反应完成。将反应混合物浓缩,并通过硅胶快速色谱法纯化残留物,用EA/PE(1/4)洗脱,得到标题化合物(400mg,33%收率),为黄色固体。MS(ES+)C12H12ClF3N4O理论值:320,实测值:321[M+H]+。
步骤2.合成3-氟-4-((4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺(化合物1)
向中间体1(40mg,124μmol)和4-氨基-3-氟苯磺酰胺(23.5mg,124μmol)在IPA(2mL)中的混合物中添加TsOH(21.3mg,124μmol),然后在90℃下搅拌16h。LCMS指示反应完成。通过制备型HPLC纯化反应混合物(流动相:A=水(0.1% NH4HCO3),B=乙腈;梯度:18min内B=15%-95%;柱:Xtimate 10um 150A 21.2×250mm),得到标题化合物(32.2mg,54%收率),为白色固体。MS(ES+)C18H18F4N6O3S理论值:474,实测值:475[M+H]+。1H-NMR(400MHz,DMSO-d6)δppm 8.77(s,1H),8.25(s,1H),8.02(t,J=8.4Hz,1H),7.95(s,1H),7.70-7.67(m,2H),7.45(br.s.,1H),4.80(s,1H),4.12(s,2H),1.08(s,6H)。
实施例2.4-((4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲基苯磺酰胺
向中间体1(140mg,436μmol)和4-氨基-3-甲基苯磺酰胺(81.1mg,436μmol)在IPA(10mL)中的混合物中添加TsOH(75.0mg,436μmol),然后在90℃下搅拌16h。LCMS指示反应完成。通过制备型HPLC纯化反应混合物(流动相:A=水(0.1%NH4HCO3),B=乙腈;梯度:18min内B=15%-95%;柱:Xtimate 10um 150A 21.2×250mm),得到标题化合物(46.3mg,22%收率),为白色固体。MS(ES+)C19H21F3N6O3S理论值:470,实测值:471[M+H]+。1H-NMR(400MHz,DMSO-d6)δppm 9.68(s,1H),8.70(s,1H),8.22(s,1H),7.91(s,1H),7.75-7.68(m,3H),7.28(s,2H),4.77(s,1H),4.11(s,2H),2.34(s,3H),1.08(s,6H)。
实施例3.4-((5-氯-4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-2-基)氨基)苯磺酰胺
步骤1.合成1-(4-(2,5-二氯嘧啶-4-基)-1H-吡唑-1-基)-2-甲基丙-2-醇(中间体2)
将2-甲基-1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)丙-2-醇(200mg,751μmol)、2,4,5-三氯嘧啶(137mg,751μmol)、Na2CO3(279mg,2.25mmol)和Pd(dppf)Cl2(61.3mg,75.1μmol)在二噁烷(10mL)和H2O(2.5mL)中的混合物在80℃和N2下搅拌2h。LCMS指示反应完成。将反应混合物浓缩,并通过硅胶快速色谱法纯化残留物,用EA/PE(2/1)洗脱,得到标题化合物(200mg,93%收率),为白色固体。MS(ES+)C11H12Cl2N4O理论值:286,实测值:287[M+H]+。
步骤2.合成4-((5-氯-4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-2-基)氨基)苯磺酰胺(实施例3)
向中间体2(140mg,436μmol)和4-氨基苯磺酰胺(100mg,584μmol)在IPA(5mL)中的混合物中添加TsOH(167mg,974μmol),然后在90℃下搅拌反应16h。LCMS指示反应完成。通过制备型HPLC纯化反应混合物(碱性条件),得到标题化合物(25.9mg,12%收率),为白色固体。MS(ES+)C19H21F3N6O3S理论值:422,实测值:423[M+H]+。1H-NMR(400MHz,DMSO-d6)δppm10.16(s,1H),8.59(s,1H),8.58(s,1H),8.27(s,1H),7.93(d,J=8.8Hz,2H),7.78(d,J=8.8Hz,2H),7.19(s,2H),4.81(s,1H),4.16(s,2H),1.11(s,6H)。
实施例4.4-((5-(二氟甲基)-4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-2-基)氨基)苯磺酰胺
步骤1:合成2,4-二氯-5-(二氟甲基)嘧啶(中间体3)
向2,4-二氯嘧啶-5-甲醛(500mg,2.84mmol)在DCM(10mL)中的溶液中添加DAST(914mg,5.68mmol),并在室温下搅拌反应14h。LCMS指示反应完成。将反应混合物浓缩,并通过硅胶快速色谱法纯化残留物,用PE/EA(20/1)洗脱,得到标题化合物(450mg,80%收率),为无色油状物。1H-NMR(400MHz,CDCl3)δppm 8.82(s,1H),6.90(t,J=53.6Hz,1H)。
步骤2:合成1-(4-(2-氯-5-(二氟甲基)嘧啶-4-基)-1H-吡唑-1-基)-2-甲基丙-2-醇(中间体4)
按照与实施例3步骤1中所述类似的程序,由2-甲基-1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)丙-2-醇和中间体3得到标题化合物,为浅黄色固体,200mg,65%收率。MS(ES+)C12H13ClF2N4O理论值:302,实测值:303[M+H]+。
步骤3.合成4-((5-(二氟甲基)-4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-2-基)氨基)苯磺酰胺(实施例4)
向中间体4(200mg,0.66mmol)和4-氨基苯磺酰胺(114mg,0.66mmol)在IPA(3mL)中的混合物中添加TsOH(114mg,0.66mmol),然后在90℃下搅拌反应16h。LCMS指示反应完成。通过制备型HPLC纯化反应混合物(碱性条件),得到标题化合物(83.6mg,28%收率),为白色固体。MS(ES+)C18H20F2N6O3S理论值:438,实测值:439[M+H]+。1H-NMR(400MHz,DMSO-d6)δppm10.38(br.s,1H),8.72(s,1H),8.31(s,1H),8.05(s,1H),7.98(d,J=8.8Hz,2H),7.79(d,J=8.8Hz,2H),7.24(t,J=54.4Hz,1H),4.84(s,1H),4.14(s,2H),1.11(s,6H)。
实施例5.4-((4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺
按照与实施例4步骤3中所述类似的程序,由中间体1和4-氨基苯磺酰胺得到标题化合物,为白色固体,19.2mg,45%收率。MS(ES+)C18H19F3N6O3S理论值:456,实测值:457[M+H]+。1H-NMR(400MHz,DMSO-d6)δppm 10.55(br.s,1H),8.82(s,1H),8.32(s,1H),8.03(s,1H),7.96(d,J=8.8Hz,2H),7.80(d,J=8.8Hz,2H),7.21(br.s,2H),4.83(s,1H),4.15(s,2H),1.10(s,6H)。
实施例6.(S)-3-氟-4-((4-(1-(3-羟基-3-甲基丁-2-基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺或(R)-3-氟-4-((4-(1-(3-羟基-3-甲基丁-2-基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺。
步骤1.合成3-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)丁-2-酮(中间体5)
将4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑(4.00g,20.6mmol)和NaH(60%,880mg,22.7mmol)在无水DMF(200mL)中的混合物在0℃至室温下搅拌20分钟。在0℃下添加3-溴丁-2-酮(3.76g,24.90mmol),并将所得混合物在120℃下搅拌6h。将混合物冷却到室温,并添加水和EA。将水层用EA萃取,将合并的EA层用水洗涤并真空浓缩。将残留物通过硅胶快速色谱法纯化,用EA/PE=1/3洗脱,得到标题产物,为油状物(4.80g,88%收率)。MS(ES+)C13H21BN2O3理论值:264,实测值:265[M+H]+。
步骤2.合成3-(4-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)丁-2-酮(中间体6)
在N2下将2,4-二氯-5-(三氟甲基)嘧啶(2.05g,9.45mmol)、中间体5(1.25g,4.72mmol)、Pd(dppf)Cl2(192mg,0.24mmol)和Na2CO3(751mg,7.09mmol)在二噁烷(30mL)和水(7.5mL)中的混合物在90℃下加热16h。将其真空浓缩,并用EA萃取水性残留物。将合并的EA层真空浓缩。将残留物通过硅胶快速色谱法纯化,用EA/PE=1/1洗脱,得到标题产物,为油状物(200mg,13%收率)。MS(ES+)C12H10ClF3N4O理论值:318,实测值:319[M+H]+。
步骤3.合成(R)-3-(4-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)-2-甲基丁-2-醇和(S)-3-(4-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)-2-甲基丁-2-醇(中间体7和中间体8)
在0℃下向中间体6(800mg,2.51mmol)在THF(5mL)中的混合物中添加MeMgBr(3M,2mL,6mmol),并在0℃至室温下搅拌反应2h。在0℃下添加饱和NH4Cl水溶液,并用EA萃取所得混合物。将合并的EA层真空浓缩。通过硅胶快速色谱法纯化所得残留物,用EA/PE=2/1洗脱,得到3-(4-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)-2-甲基丁-2-醇。MS(ES+)C13H14ClF3N4O理论值:334,实测值:335[M+H]+。通过手性SFC分离此外消旋产物,柱:AD 20*250mm,10um(Daicel),柱温:35℃,流动相:CO2/MeOH(0.2%甲醇氨)=60/40,流速:80g/min,得到峰1,中间体7,214mg,(R)-3-(4-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)-2-甲基丁-2-醇或(S)-3-(4-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)-2-甲基丁-2-醇。
进一步洗脱得到峰2,中间体8,200mg,为白色固体,(S)-3-(4-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)-2-甲基丁-2-醇或(R)-3-(4-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)-2-甲基丁-2-醇。
步骤4.合成(S)-3-氟-4-((4-(1-(3-羟基-3-甲基丁-2-基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺或(R)-3-氟-4-((4-(1-(3-羟基-3-甲基丁-2-基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺(实施例6)
按照与实施例4步骤3中所述类似的程序,由中间体8和4-氨基-3-氟苯-1-磺酰胺得到标题化合物,为白色固体,80.2mg,27%收率。MS(ES+)C19H20F4N6O3S理论值:488,实测值:489[M+H]+。1H NMR(400MHz,DMSO)δ10.08(s,1H),8.76(s,1H),8.26(s,1H),8.02(t,J=8.0Hz,1H),7.94(s,1H),7.69(s,1H),7.67(s,1H),7.45(s,2H),4.76(s,1H),4.34(q,J=7.0Hz,1H),1.46(d,J=7.0Hz,3H),1.07(s,3H),1.02(s,3H)。
实施例7.(R)-3-氟-4-((4-(1-(3-羟基-3-甲基丁-2-基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺或(S)-3-氟-4-((4-(1-(3-羟基-3-甲基丁-2-基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺
按照与实施例4步骤3中所述类似的程序,由中间体7和4-氨基-3-氟苯-1-磺酰胺得到标题化合物,为白色固体,68.2mg,22%收率。MS(ES+)C19H20F4N6O3S理论值:488,实测值:489[M+H]+。1H NMR(400MHz,DMSO)δ10.08(s,1H),8.76(s,1H),8.26(s,1H),8.02(t,J=8.0Hz,1H),7.94(s,1H),7.69(s,1H),7.67(s,1H),7.45(s,2H),4.76(s,1H),4.34(q,J=7.0Hz,1H),1.46(d,J=7.0Hz,3H),1.07(s,3H),1.02(s,3H)。
实施例8.4-((5-氰基-4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-2-基)氨基)苯磺酰胺
步骤1.合成4-((4-氯-5-氰基嘧啶-2-基)氨基)苯磺酰胺
在25℃下向2,4-二氯嘧啶-5-甲腈(10.0g,57.5mmol)和4-氨基苯磺酰胺(9.90g,57.5mmol)在IPA(100mL)中的混合物中一次性添加DIPEA(11.1g,86.2mmol)。将混合物在50℃下搅拌1h。将反应混合物过滤,并在减压下浓缩,得到残留物。将合并的粗产物通过制备型HPLC纯化(酸性条件),得到标题化合物(3.0g),为黄色固体。
步骤2.合成4-((5-氰基-4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-2-基)氨基)苯磺酰胺(实施例8)
在N2气氛下向中间体9(74.3mg,0.240mmol)在DMF(3.0mL)中的混合物中添加2-甲基-1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)丙-2-醇(95.7mg,0.360mmol)、Cs2CO3(312mg,0.960mmol)、H2O(0.5mL)和Pd(dppf)Cl2(12.0μmol)。将反应混合物在100℃下搅拌16h。LCMS指示反应完成。将混合物过滤,并真空移除溶剂。通过制备型HPLC纯化残留物(酸性条件),得到标题化合物(36.8mg,37%)。MS(ES+)C18H19N7O3S理论值:413.5,实测值:414.1[M+H]+。1H NMR(500MHz,DMSO)δ10.59(s,1H),8.85(d,J=1.7Hz,1H),8.53(s,1H),8.22(s,1H),7.92–7.84(m,2H),7.80–7.71(m,2H),7.18(s,2H),4.77(d,J=1.7Hz,1H),4.11(s,2H),1.05(s,6H)。
实施例9.合成3-氟-4-((4-(1-((2S,3S)-3-羟基丁-2-基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺或3-氟-4-((4-(1-((2R,3R)-3-羟基丁-2-基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺或3-氟-4-((4-(1-((2R,3S)-3-羟基丁-2-基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺或3-氟-4-((4-(1-((2S,3R)-3-羟基丁-2-基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺
步骤1.合成3-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)丁-2-醇(中间体10)
向中间体5(2g,7.57mmol)在MeOH(20mL)中的溶液中添加NaBH4(427mg,11.3mmol),并在室温下搅拌反应30分钟。LCMS指示反应完成。用水淬灭反应,并用DCM萃取。将合并的有机层用水和盐水洗涤,经硫酸钠干燥,过滤并浓缩。将残留物通过硅胶快速色谱法纯化,用PE/EA(1/1)洗脱,得到标题化合物(1.2g,59%收率),为无色油状物。MS(ES+)C13H23BN2O3理论值:266,实测值:267[M+H]+。
步骤2.合成(2R,3R)-3-(4-(2-氨基-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)丁-2-醇、(2S,3S)-3-(4-(2-氨基-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)丁-2-醇、(2R,3S)-3-(4-(2-氨基-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)丁-2-醇和(2S,3R)-3-(4-(2-氨基-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)丁-2-醇(中间体12-P1、12-P2、13-P1和13-P2)
将中间体10(1g,3.75mmol)、4-氯-5-(三氟甲基)嘧啶-2-胺(740mg,3.75mmol)、Na2CO3(1.09g,11.2mmol)和Pd(dppf)Cl2(275mg,375μmol)在二噁烷(15mL)和H2O(4mL)中的混合物在90℃和N2下搅拌过夜。LCMS指示反应完成。将残留物通过硅胶快速色谱法纯化,用EA/PE(1/1)洗脱,然后通过制备型HPLC纯化(碱性条件),得到3-(4-(2-氨基-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)丁-2-醇(800mg,71%收率)。将此产物(800mg)通过手性HPLC分离,得到峰1,中间体12,顺式-外消旋-(2R,3R)-3-(4-(2-氨基-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)丁-2-醇,或(280mg)反式-外消旋-(2R,3S)-3-(4-(2-氨基-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)丁-2-醇,和峰2,中间体13,反式-外消旋-(2R,3S)-3-(4-(2-氨基-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)丁-2-醇,或顺式-外消旋-(2R,3R)-3-(4-(2-氨基-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)丁-2-醇(350mg)。
通过手性SFC分离中间体12(280mg)(柱:IG 20*250mm,10um(Daicel);柱温:35℃;流动相:CO2/MeOH(0.2%甲醇氨)=80/20;流速:100g/min,得到中间体12-P1(110mg),(2R,3R)-3-(4-(2-氨基-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)丁-2-醇或(2S,3S)-3-(4-(2-氨基-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)丁-2-醇或(2R,3S)-3-(4-(2-氨基-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)丁-2-醇或(2S,3R)-3-(4-(2-氨基-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)丁-2-醇,和中间体12-P2(100mg),(2S,3S)-3-(4-(2-氨基-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)丁-2-醇或(2R,3R)-3-(4-(2-氨基-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)丁-2-醇或(2R,3S)-3-(4-(2-氨基-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)丁-2-醇或(2S,3R)-3-(4-(2-氨基-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)丁-2-醇,为白色固体。
通过手性SFC分离中间体13(350mg)(柱:IG 20*250mm,10um(Daicel);柱温:35℃;流动相:CO2/MeOH(0.2%甲醇氨)=80/20;流速:100g/min,得到中间体13-P1(140mg),(2R,3S)-3-(4-(2-氨基-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)丁-2-醇或(2S,3R)-3-(4-(2-氨基-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)丁-2-醇或(2R,3R)-3-(4-(2-氨基-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)丁-2-醇或(2S,3S)-3-(4-(2-氨基-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)丁-2-醇,和中间体13-P2(190mg),(2S,3R)-3-(4-(2-氨基-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)丁-2-醇或(2R,3S)-3-(4-(2-氨基-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)丁-2-醇或(2R,3R)-3-(4-(2-氨基-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)丁-2-醇或(2S,3S)-3-(4-(2-氨基-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)丁-2-醇,为白色固体。MS(ES+)C12H14F3N5O理论值:301,实测值:302[M+H]+。
步骤3.合成3-氟-4-((4-(1-((2S,3S)-3-羟基丁-2-基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺或3-氟-4-((4-(1-((2R,3R)-3-羟基丁-2-基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺或3-氟-4-((4-(1-((2R,3S)-3-羟基丁-2-基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺或3-氟-4-((4-(1-((2S,3R)-3-羟基丁-2-基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺(实施例9)
将中间体12-P2(100mg,331μmol)、4-溴-3-氟苯-1-磺酰胺(84.0mg,331μmol)、乙酸钾(97.4mg,993μmol)和BrettPhos Pd G4(50.8mg,33.1μmol)在二噁烷(5mL)中的混合物在90℃和N2下搅拌过夜。将反应混合物浓缩,并通过硅胶快速色谱法纯化残留物,用EA/PE(5/1)洗脱,然后通过制备型HPLC纯化(碱性条件),得到标题产物(29.6mg,18%收率),为白色固体。MS(ES+)C18H18F4N6O3S理论值:474,实测值:475[M+H]+。1H-NMR(400MHz,DMSO-d6)δppm 10.08(s,1H),8.76(s,1H),8.27(s,1H),8.03(t,J=8.4Hz,1H),7.96(s,1H),7.70-7.67(m,2H),7.43(s,2H),5.06-5.04(m,1H),4.32-4.28(m,1H),3.88-3.85(m,1H),1.46(d,J=6.8Hz,3H),0.90(d,J=6.0Hz,3H)。
实施例10.4-((5-氯-4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-2-基)氨基)-3-氟苯磺酰胺
按照实施例4步骤3中所述的程序,由中间体2和4-氨基-3-氟苯磺酰胺得到标题化合物,为白色固体,23.6mg,8%收率。MS(ES+)C17H18ClFN6O3S理论值:440,实测值:441[M+H]+。1H-NMR(400MHz,DMSO-d6)δppm 9.63(br.s,1H),8.55(s,2H),8.19(s,1H),7.98(t,J=8.4Hz,1H),7.69-7.63(m,2H),7.41(br.s,2H),4.82(s,1H),4.14(s,2H),1.10(s,6H)。
实施例11.4-((5-(二氟甲基)-4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-2-基)氨基)-3-氟苯磺酰胺
按照实施例4步骤3中所述的程序,由中间体4和4-氨基-3-氟苯磺酰胺得到标题化合物,为白色固体,156.8mg,19%收率。MS(ES+)C18H19F3N6O3S理论值:456,实测值:457[M+H]+。1H-NMR(400MHz,DMSO-d6)δppm 9.84(s,1H),8.67(s,1H),8.26(s,1H),8.10(t,1H,J=8.0Hz),7.98(s,1H),7.68-7.65(m,2H),7.42(s,2H),7.22(t,1H,J=53.6Hz),4.79(s,1H),4.12(s,2H),1.09(s,6H)。
实施例12.(R)-3-氟-4-((4-(1-(2-羟基-2-甲基丁基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺或(S)-3-氟-4-((4-(1-(2-羟基-2-甲基丁基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺
步骤1.合成2-甲基-1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)丁-2-醇(中间体14)
将4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑(400mg,2.05mmol)、2-乙基-2-甲基环氧乙烷(220mg,2.05mmol)和Cs2CO3(2.02g,6.16mmol)在NMP(10mL)中的混合物在微波照射下加热到120℃持续30分钟,LCMS显示有约75%的产物,将所得反应混合物直接用于下一步。MS(ES+)C14H25BN2O3理论值:280,实测值:281[M+H]+。
步骤2.合成1-(4-(2-氨基-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)-2-甲基丁-2-醇(中间体15)
向步骤1(中间体14)的反应混合物中添加4-氯-5-(三氟甲基)嘧啶-2-胺(404mg,2.05mmol)、Pd(dppf)Cl2(38mg,0.05mmol)、Cs2CO3、二噁烷(3mL)和H2O(1mL)。将所得混合物在90℃和N2下搅拌2h。将反应混合物浓缩,并将残留物通过硅胶快速色谱法纯化,用MeOH/DCM(1/20)洗脱,得到标题化合物(250mg,39%收率),为黄色固体。MS(ES+)C13H16F3N5O理论值:315,实测值:316[M+H]+。
步骤3.合成3-氟-4-((4-(1-(2-羟基-2-甲基丁基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺(中间体16)
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将中间体15(250mg,0.79mmol)、4-溴-3-氟苯-1-磺酰胺(201mg,792μmol)、乙酸钾(232mg,2.37mmol)和BrettPhos Pd G4在二噁烷(5mL)中的混合物在90℃和N2下搅拌2h。将反应混合物浓缩,并通过硅胶快速色谱法纯化残留物,用MeOH/DCM(1/10)洗脱,然后通过制备型HPLC纯化(碱性条件),得到标题产物(180mg)。
步骤4.合成(R)-3-氟-4-((4-(1-(2-羟基-2-甲基丁基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺或(S)-3-氟-4-((4-(1-(2-羟基-2-甲基丁基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺(实施例12)
通过手性SFC分离中间体16(180mg)(柱:AD-H 20*250mm,10um(Daicel);柱温:35℃;流动相:CO2/IPA(1%甲醇氨)=80/20;流速:80g/min,得到峰1,实施例12(73.2mg,19%收率)。MS(ES+)C19H20F4N6O3S理论值:488,实测值:489[M+H]+。1H-NMR(400MHz,DMSO-d6)δppm10.11(s,1H),8.77(s,1H),8.25(s,1H),8.04-8.00(m,1H),7.95(s,1H),7.70-7.67(m,2H),7.45(s,2H),4.67(s,1H),4.12(s,2H),1.34(q,2H,J=7.6Hz),1.00(s,3H),0.87(t,3H,J=7.6Hz)。
实施例13.3-氟-4-((4-(1-((2S,3R)-3-羟基丁-2-基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺或3-氟-4-((4-(1-((2R,3S)-3-羟基丁-2-基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺或3-氟-4-((4-(1-((2R,3R)-3-羟基丁-2-基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺或3-氟-4-((4-(1-((2S,3S)-3-羟基丁-2-基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺
按照实施例9步骤3中所述的程序,由中间体13-P1和4-溴-3-氟苯-1-磺酰胺得到标题化合物,为白色固体,72mg,32%收率。MS(ES+)C18H18F4N6O3S理论值:474,实测值:475[M+H]+。1H-NMR(400MHz,DMSO-d6)δppm 10.08(s,1H),8.76(s,1H),8.24(s,1H),8.02(t,J=8.4Hz,1H),7.95(s,1H),7.70-7.67(m,2H),7.45(s,2H),4.95(s,1H),4.32-4.28(m,1H),3.88-3.85(m,1H),1.42(d,J=7.2Hz,3H),0.90(d,J=6.4Hz,3H)。
实施例14.4-((5-氯-4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-2-基)氨基)-3-甲基苯磺酰胺
将4-氨基-3-甲基苯-1-磺酰胺(30mg,161μmol)和中间体2(50.8mg,177μmol)在IPA(6mL)和TsOH(55.4mg,322μmol)中的混合物在120℃下搅拌两天。通过制备型HPLC纯化反应混合物(碱性条件),得到标题化合物(2.1mg,2%收率),为白色固体。MS(ES+)C18H21ClN6O3S理论值:436,实测值:437[M+H]+。1H-NMR(400MHz,DMSO-d6)δppm 9.11(s,1H),8.51(s,1H),8.47(s,1H),8.13(s,1H),7.84(d,J=8.4Hz,1H),7.68-7.64(m,2H),7.23(br.s,2H),4.80(br.s,1H),4.12(s,2H),2.33(s,3H),1.09(s,6H)。
实施例15:3-氟-4-((4-(1-((2R,3S)-3-羟基丁-2-基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺或3-氟-4-((4-(1-((2S,3R)-3-羟基丁-2-基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺或3-氟-4-((4-(1-((2R,3R)-3-羟基丁-2-基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺或3-氟-4-((4-(1-((2S,3S)-3-羟基丁-2-基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺
按照实施例9步骤3中所述的程序,由中间体13-P2和4-溴-3-氟苯-1-磺酰胺得到标题化合物,96.2mg,47%收率,为白色固体。MS(ES+)C18H18F4N6O3S理论值:474,实测值:475[M+H]+。1H-NMR(400MHz,DMSO-d6)δppm 10.08(s,1H),8.76(s,1H),8.24(s,1H),8.02(t,J=8.0Hz,1H),7.95(s,1H),7.70-7.67(m,2H),7.45(s,2H),4.93(s,1H),4.33-4.29(m,1H),3.88-3.85(m,1H),1.42(d,J=6.8Hz,3H),1.02(d,J=6.0Hz,3H)。
实施例16:3-氟-4-((4-(1-(1-(羟甲基)环丙基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺
步骤1.合成1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)环丙烷-1-甲酸甲酯(中间体17)
在0℃下向4-溴-1H-吡唑(1g,6.80mmol)在无水DMF中的溶液中添加NaH(326mg,13.6mmol),接着添加2,4-二溴丁酸甲酯(1.94g,7.48mmol)。将混合物在室温下搅拌过夜。LCMS指示反应完成。将反应混合物通过硅胶快速色谱法纯化,用EA/PE(1/1)洗脱,得到1-(4-溴-1H-吡唑-1-基)环丙烷-1-甲酸甲酯(700mg,42%收率),为白色固体。
将4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,3,2-二氧杂环戊硼烷(1.08g,4.27mmol)、1-(4-溴-1H-吡唑-1-基)环丙烷-1-甲酸甲酯(700mg,2.85mmol)、Pd(dppf)Cl2(417mg,570μmol)和KOAc(559mg,5.7mmol)的混合物在100℃和N2下搅拌过夜。LCMS指示反应完成。将反应混合物浓缩,并通过硅胶快速色谱法纯化残留物,用EA/PE(1/1)洗脱,得到标题化合物(700mg,84%收率),为白色固体。MS(ES+)C14H21BN2O4理论值:292,实测值:293[M+H]+。
步骤2.合成1-(4-(2-氨基-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)环丙烷-1-甲酸甲酯(中间体18)
将4-氯-5-(三氟甲基)嘧啶-2-胺(403mg,2.04mmol)、中间体17(400mg,1.36mmol)、Na2CO3(288mg,2.7mmol)和Pd(dppf)Cl2(199mg,272μmol)在二噁烷(20mL)和H2O(5mL)中的混合物在80℃和N2下搅拌过夜。LCMS指示反应完成。将反应混合物浓缩,并通过硅胶快速色谱法纯化残留物,用MeOH/DCM(5%)洗脱,得到标题化合物(203mg,46%收率),为白色固体。MS(ES+)C13H12F3N5O2理论值:327,实测值:328[M+H]+。
步骤3.合成1-(4-(2-((2-氟-4-氨磺酰基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)环丙烷-1-甲酸甲酯(中间体19)
将中间体18(200mg,611μmol)、4-溴-3-氟苯-1-磺酰胺(232mg,916μmol)、BrettPhos Pd G4(100mg)和KOAc(119mg,1.22mmol)在二噁烷(5mL)中的混合物在100℃和N2下搅拌过夜。LCMS指示反应完成。将反应混合物通过硅胶快速色谱法纯化,用MeOH/DCM(5%)洗脱,得到标题化合物(71mg,23%收率),为白色固体。MS(ES+)C19H16F4N6O4S理论值:500,实测值:501[M+H]+。
步骤4.合成3-氟-4-((4-(1-(1-(羟甲基)环丙基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺(实施例16)
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向中间体19(60mg,119μmol)在THF/EtOH(v/v=1:1,1mL)中的溶液中添加LiBH4(25.9mg,1.19mmol),并将混合物在0℃下搅拌1h。LCMS指示反应完成。通过制备型HPLC纯化反应混合物(碱性条件),得到标题化合物(5.6mg,10%收率),为白色固体。MS(ES+)C18H16F4N6O3S理论值:472,实测值:473[M+H]+。1H-NMR(400MHz,DMSO-d6)δppm 10.08(s,1H),8.77(s,1H),8.27(s,1H),8.02(t,J=8.0Hz,1H),7.94(s,1H),7.70-7.65(m,2H),7.44(s,2H),5.10(t,J=5.6Hz,1H),3.63(d,J=5.6Hz,2H),1.24-1.05(m,4H)。
实施例17.合成4-((4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-5-甲基嘧啶-2-基)氨基)苯磺酰胺
步骤1.合成1-(4-(2-氯-5-甲基嘧啶-4-基)-1H-吡唑-1-基)-2-甲基丙-2-醇(中间体20)
按照实施例3步骤1中所述的程序,由2-甲基-1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)丙-2-醇和2,4,5-三氯嘧啶得到标题化合物,为白色固体,170mg,85%收率。MS(ES+)C11H12Cl2N4O理论值:266,实测值:267[M+H]+。
步骤2.合成4-((4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-5-甲基嘧啶-2-基)氨基)苯磺酰胺(实施例17)
向中间体20(160mg,599μmol)和4-氨基苯磺酰胺(123mg,718μmol)在IPA(5mL)中的混合物中添加TsOH(204mg,1.19mmol)。将反应混合物在90℃下搅拌16h。LCMS指示反应完成。通过制备型HPLC纯化反应混合物(碱性条件),得到标题化合物(76.3mg,31%收率),为白色固体。MS(ES+)C18H22N6O3S理论值:402,实测值:403[M+H]+。1H-NMR(400MHz,DMSO-d6)δppm 9.85(s,1H),8.37(s,1H),8.34(s,1H),8.10(s,1H),7.96(d,J=8.8Hz,2H),7.54(d,J=8.8Hz,2H),7.16(s,2H),4.81(s,1H),4.14(s,2H),2.34(s,3H),11(s,6H)。
实施例18.4-((5-氟-4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-2-基)氨基)苯磺酰胺
步骤1.合成1-(4-(2-氯-5-氟嘧啶-4-基)-1H-吡唑-1-基)-2-甲基丙-2-醇(中间体21)
按照与实施例3步骤1中所述类似的程序,由2-甲基-1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)丙-2-醇和2,4-二氯-5-氟嘧啶得到标题化合物,200mg,62%收率。MS(ES+)C11H12ClFN4O理论值:270,实测值:271[M+H]+。
步骤2.4-((5-氟-4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-2-基)氨基)苯磺酰胺(实施例18)
按照实施例4步骤3中所述的程序,由中间体21和4-氨基苯磺酰胺得到标题化合物,为白色固体,15.1mg,10%收率。MS(ES+)C17H19FN6O3S理论值:406,实测值:407[M+H]+。1H-NMR(400MHz,DMSO-d6)δppm 10.08(s,1H),8.59(s,1H,J=2.8Hz),8.39(s,1H),8.13(s,1H),7.94(d,J=8.8Hz,2H),7.76(d,J=8.8Hz,2H),7.18(s,2H),4.82(s,1H),4.16(s,2H),1.10(s,6H)。
实施例19.4-((5-氰基-4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-2-基)氨基)-3-氟苯磺酰胺
步骤1.合成4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-2-(甲硫基)嘧啶-5-甲腈(中间体22)
按照与实施例3步骤1中所述类似的程序由2-甲基-1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)丙-2-醇和4-氯-2-(甲硫基)嘧啶-5-甲腈得到标题化合物,为黄色固体,400mg,85%收率。MS(ES+)C13H15N5OS理论值:289,实测值:290[M+H]+。
步骤2.合成4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-2-(甲基磺酰基)嘧啶-5-甲腈(中间体23)
向中间体22(400mg,1.38mmol)在DCM(20mL)中的混合物中添加m-CPBA(477mg,2.76mmol)。将反应混合物在25℃下搅拌16h。将混合物过滤,并通过硅胶快速色谱法纯化滤液,用EA/PE(5/1)洗脱,得到标题化合物(110mg,24%收率),为黄色固体。MS(ES+)C13H15N5O3S理论值:321,实测值:322[M+H]+。
步骤3.合成4-((5-氰基-4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-2-基)氨基)-3-氟苯磺酰胺(实施例19)
按照与实施例4步骤3中所述类似的程序,由中间体23和4-氨基-3-氟苯磺酰胺得到标题化合物,为白色固体,23.6mg,22%收率。MS(ES+)C18H18FN7O3S理论值:431,实测值:432[M+H]+。1H-NMR(400MHz,DMSO-d6)δppm 9.96(s,1H),8.87(s,1H),8.53(s,1H),8.16(s,1H),8.02-7.98(m,1H),7.71-7.67(m,2H),7.47(s,2H),4.84(s,1H),4.15(s,2H),1.09(s,6H)。
实施例20.(R)-3-氟-4-((4-(1-(2-羟丙基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺
步骤1.合成(R)-1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)丙-2-醇(中间体24)
将4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑(1.0g,5.15mmol)、(2R)-2-甲基环氧乙烷(448mg,7.72mmol)和Cs2CO3(5.01g,15.4mmol)在ACN(15mL)中的混合物在80℃和N2下搅拌过夜。LCMS指示反应完成。将反应混合物浓缩,并通过硅胶快速色谱法纯化残留物,用PE/EA (1/1)洗脱,得到标题化合物(800mg,62%收率),为黄色固体。MS(ES+)C12H21BN2O3理论值:252,实测值:253[M+H]+。
步骤2.合成(2R)-1-(4-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)丙-2-醇(中间体25)
将中间体24(500mg,1.98mmol)和2,4-二氯-5-(三氟甲基)嘧啶(642mg,2.96mmol)、Pd(dppf)Cl2(72.6mg,99.0μmol)和碳酸钾(409mg,2.96mmol)在二噁烷(6mL)和H2O(1.5mL)中的混合物在90℃和N2下搅拌过夜。LCMS指示反应完成。将反应混合物浓缩,并通过硅胶快速色谱法纯化残留物,用PE/EA(1/1)洗脱,得到标题化合物(300mg,49%收率),为黄色固体。MS(ES+)C11H10ClF3N4O理论值:306,实测值:307[M+H]+。
步骤3.合成(R)-3-氟-4-((4-(1-(2-羟丙基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺(实施例20)
向中间体25(150mg,489μmol)和4-氨基-3-氟苯-1-磺酰胺(111mg,586μmol)在IPA(8mL)中的混合物中添加TsOH(84.2mg,498μmol),并在90℃下搅拌反应16h。LCMS指示反应完成。通过制备型HPLC纯化反应混合物(酸性条件),得到标题化合物(21.8mg,9%收率),为白色固体。MS(ES+)C17H16F4N6O3S理论值:460,实测值:461[M+H]+。1H NMR(400MHz,DMSO)δ10.08(s,1H),8.77(s,1H),8.25(s,1H),8.02(t,J=8.0Hz,1H),7.96(s,1H),7.70-7.67(m,2H),7.44(s,2H),4.98(s,1H),4.14-4.09(m,2H),4.00(s,1H),1.05(d,J=6.0Hz,3H)。
实施例21.3-氟-4-((4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-甲基苯磺酰胺
步骤1.合成4-溴-3-氟-2-甲基苯磺酰胺(中间体26)
在0℃下向4-溴-3-氟-2-甲基苯胺(204mg,1.00mmol)在ACN(12mL)中的混合物中添加AcOH(0.6mL)和浓HCl(0.7mL)。缓慢添加在水(0.5mL)中的亚硝酸钠(82.1mg,1.19mmol)。在0℃下搅拌20分钟后,在0-5℃下将SO2泵入反应混合物中持续1.5h,然后添加CuCl2(159mg,1.19mmol),并将SO2泵入所得混合物中再持续1h。然后在0℃下搅拌反应1h,添加冷水,并用DCM萃取混合物。将有机层用盐水洗涤并浓缩。将残留物用DCM溶解,然后缓慢添加到冷的NH3/MeOH溶液中。搅拌10分钟后,将反应物用DCM稀释,用水洗涤并浓缩。然后添加EA/PE=1:5,并通过过滤收集所得固体,得到标题产物(120mg,45%收率),为黄色固体。MS(ES+)C7H7BrFNO2S理论值:267,实测值:268[M+H]+。
步骤2.合成1-(4-(2-氨基-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)-2-甲基丙-2-醇(中间体27)
按照实施例3步骤1中所述的程序,由4-氯-5-(三氟甲基)嘧啶-2-胺和2-甲基-1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)丙-2-醇得到标题化合物,为黄色固体,1.7g,74%收率。MS(ES+)C12H14F3N5O理论值:301,实测值:302[M+H]+。
步骤2.合成3-氟-4-((4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-甲基苯磺酰胺(实施例21)
按照实施例12步骤3中所述的程序,由4-溴-3-氟-2-甲基苯-1-磺酰胺和1-(4-(2-氨基-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)-2-甲基丙-2-醇得到标题化合物,为黄色固体,54.8mg,25%收率。MS(ES+)C19H20F4N6O3S理论值:488,实测值:489[M+H]+。1H-NMR(400MHz,DMSO-d6)δppm 9.97(s,1H),8.77(s,1H),8.25(s,1H),7.95(s,1H),7.90-7.84(m,1H),7.74-7.71(m,1H),7.49(s,2H),5.60(s,1H),4.12(s,2H),2.54(s,3H),1.08(s,6H)。
实施例22.3-氟-4-((4-(1-(1-羟基-2-甲基丙烷-2-基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺
步骤1.合成2-甲基-2-(4-(2-(甲硫基)-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)丙-1-醇(中间体28)
按照实施例3步骤1中所述的程序,由2-甲基-2-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)丙-1-醇和4-氯-2-(甲硫基)-5-(三氟甲基)嘧啶得到标题化合物,为黄色固体,150mg,48%收率。MS(ES+)C13H15F3N4OS理论值:332,实测值:333[M+H]+。
步骤2.合成2-甲基-2-(4-(2-(甲基磺酰基)-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)丙-1-醇(中间体29)
向中间体28(150mg,451μmol)在DCM(20.0mL)中的混合物中添加m-CPBA(155mg,902μmol)。将反应混合物在25℃下搅拌16h。将混合物过滤,并通过硅胶快速色谱法纯化滤液,用EA/PE(5/1)洗脱,得到标题化合物(135mg,79%收率),为黄色固体。MS(ES+)C13H15F3N4O3S理论值:364,实测值:365[M+H]+。
步骤3.合成3-氟-4-((4-(1-(1-羟基-2-甲基丙烷-2-基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺(实施例22)
向中间体29(90mg,247μmol)和4-氨基-3-氟苯磺酰胺(51mg,271μmol)在IPA(10.0mL)中的混合物中添加TsOH(4mg,24μmol),并在90℃下搅拌反应16h。LCMS指示反应完成。通过制备型HPLC纯化反应混合物(碱性条件),得到标题化合物(4.9mg,4%收率),为白色固体。MS(ES+)C18H18F4N6O3S理论值:474,实测值:475[M+H]+。1H-NMR(400MHz,DMSO-d6)δppm 10.08(s,1H),8.76(s,1H),8.27(s,1H),8.02(t,J=8.0Hz,1H),7.96(s,1H),7.70-7.67(m,2H),7.67(s,1H),7.45(s,2H),5.15(s,1H),3.61(m,2H),1.50(s,6H)。
实施例23.3-氯-4-((5-氯-4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-2-基)氨基)苯磺酰胺
向4-氨基-3-氯苯-1-磺酰胺(70mg,338μmol)和中间体2(97.0mg,338μmol)在IPA(6mL)中的混合物中添加TsOH(116mg,676μmol),然后将混合物在120℃下搅拌过夜。通过制备型HPLC纯化反应混合物(碱性条件),得到标题化合物(18.4mg,12%收率),为白色固体。MS(ES+)C17H18Cl2N6O3S理论值:456,实测值:457[M+H]+。1H-NMR(400MHz,DMSO-d6)δppm 9.16(s,1H),8.56(s,1H),8.54(s,1H),8.18(s,1H),8.16(d,J=8.8Hz,1H),7.90(d,J=2.4Hz,1H),7.80(dd,J=8.8Hz,2.4Hz,1H),7.43(s,2H),4.79(s,1H),4.13(s,2H),1.09(s,6H)。
实施例24.4-((5-乙基-4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-2-基)氨基)苯磺酰胺
步骤1.合成1-(4-(2-氯-5-乙基嘧啶-4-基)-1H-吡唑-1-基)-2-甲基丙-2-醇(中间体30)
按照实施例3步骤1中所述的程序,由2-甲基-1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)丙-2-醇和2,4-二氯-5-乙基嘧啶得到标题化合物,为白色固体,163mg,84%收率。MS(ES+)C13H17ClN4O理论值:280,实测值:281[M+H]+。
步骤2.4-((5-乙基-4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-2-基)氨基)苯磺酰胺(实施例24)
向中间体30(140mg,498μmol)和4-氨基苯磺酰胺(102mg,597μmol)在IPA(5mL)中的混合物中添加TsOH(171mg,996μmol),并在90℃下搅拌反应16h。LCMS指示反应完成。通过制备型HPLC纯化反应混合物(碱性条件),得到标题化合物(74.6mg,36%收率),为白色固体。MS(ES+)C19H24N6O3S理论值:416,实测值:417[M+H]+。1H-NMR(400MHz,DMSO-d6)δppm 9.87(s,1H),8.39(s,1H),8.31(s,1H),8.06(s,1H),7.96(d,J=8.8Hz,2H),7.74(d,J=8.8Hz,2H),7.12(s,2H),4.81(s,1H),4.14(s,2H),2.74(d,J=7.6Hz,2H),1.22(d,J=7.6Hz,3H),1.11(s,6H)。
实施例25.3-氟-4-((4-(1-((2R,3R)-3-羟基丁-2-基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺或3-氟-4-((4-(1-((2S,3S)-3-羟基丁-2-基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺或3-氟-4-((4-(1-((2R,3S)-3-羟基丁-2-基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺或3-氟-4-((4-(1-((2S,3R)-3-羟基丁-2-基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺
按照实施例9步骤3中所述的程序,由中间体12-P1和4-溴-3-氟苯-1-磺酰胺得到标题化合物,为白色固体,43.5mg,25%收率。MS(ES+)C18H18F4N6O3S理论值:474,实测值:475[M+H]+。1H-NMR(400MHz,DMSO-d6)δppm 10.09(s,1H),8.76(s,1H),8.27(s,1H),8.04(t,J=8.0Hz,1H),7.96(s,1H),7.70-7.67(m,2H),7.43(s,2H),5.06-5.04(m,1H),4.32-4.28(m,1H),3.88-3.85(m,1H),1.46(d,J=6.8Hz,3H),0.90(d,J=6.0Hz,3H)。
实施例26.(S)-3-氟-4-((4-(1-(2-羟基-2-甲基丁基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺或(R)-3-氟-4-((4-(1-(2-羟基-2-甲基丁基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺
通过手性SFC分离中间体16(180mg)(柱:AD-H 20*250mm,10um(Daicel);柱温:35℃;流动相:CO2/IPA(1%甲醇氨)=80/20;流速:80g/min,得到峰1,实施例12(73.2mg,19%收率),和峰2,实施例26(70.8mg,18%收率)。MS(ES+)C19H20F4N6O3S理论值:488,实测值:489[M+H]+。1H-NMR(400MHz,DMSO-d6)δppm 10.11(s,1H),8.77(s,1H),8.25(s,1H),8.04-8.00(m,1H),7.95(s,1H),7.70-7.67(m,2H),7.45(s,2H),4.67(s,1H),4.12(s,2H),1.34(q,2H,J=7.6Hz),1.00(s,3H),0.87(t,3H,J=7.6Hz)。
实施例27.4-((4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯磺酰胺
按照实施例4步骤3中所述的程序,由中间体1和4-氨基-3-甲氧基苯磺酰胺得到标题化合物,为白色固体,52.3mg,34%收率。MS(ES+)C19H21F3N6O4S理论值:486,实测值:487[M+H]+。1H-NMR(400MHz,DMSO-d6)δppm 9.00(s,1H),8.77(s,1H),8.30(s,1H),8.22(d,J=8.4Hz,1H),8.00(s,1H),7.51-7.47(m,2H),7.30(s,2H),4.80(s,1H),4.14(s,2H),3.93(s,3H),1.10(s,6H)。
实施例28.4-((5-氯-4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-2-基)氨基)-3-甲氧基苯磺酰胺
将4-氨基-3-甲氧基苯-1-磺酰胺(100mg,494μmol)、中间体2(184mg,642μmol)和TsOH(170mg,988μmol)在二噁烷(6mL)中的混合物在120℃下搅拌4天。通过制备型HPLC纯化反应混合物(碱性条件),得到标题化合物(16.7mg,7%收率),为白色固体。MS(ES+)C18H21ClN6O4S理论值:452,实测值:453[M+H]+。1H-NMR(400MHz,DMSO-d6)δppm 8.59(s,1H),8.57(s,1H),8.43(s,1H),8.38(d,J=7.6Hz,1H),8.26(s,1H),7.51-7.47(m,2H),7.26(s,2H),4.82(s,1H),4.15(s,2H),3.94(s,3H),1.11(s,6H)。
实施例29.合成2,3-二氟-4-((4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺
步骤1.合成4-溴-2,3-二氟苯磺酰胺(中间体31)
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在0℃下向NH3在二噁烷中的溶液(0.5M,5mL)中添加4-溴-2,3-二氟苯-1-磺酰氯(300mg,1.02mmol),并将反应混合物在0℃下搅拌1h。将反应混合物用EA稀释,并用水和盐水洗涤。将有机层浓缩,并通过硅胶快速色谱法纯化残留物,用EA/PE(1/2)洗脱,得到标题化合物(270mg,97%收率),为黄色固体。
步骤2.合成2,3-二氟-4-((4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺
将中间体31(270mg,992μmol)、中间体27(298mg,992μmol)、BrettPhos Pd G4(91.3mg,99.2μmol)和KOAc(291mg,2.97mmol)在二噁烷(10mL)中的混合物在90℃和N2下搅拌14h。LCMS显示反应完成。通过制备型HPLC纯化反应混合物(碱性条件),得到标题化合物(100mg,20%收率),为白色固体。MS(ES+)C18H17F5N6O3S理论值:492,实测值:493[M+H]+。1H-NMR(400MHz,DMSO-d6)δppm8.80(s,1H),8.26(s,1H),7.96(s,1H),7.82(t,J=7.2Hz,1H),7.62(t,J=7.2Hz,1H),4.80(s,1H),4.12(s,2H),1.08(s,6H)。
实施例30.3-氟-4-((5-氟-4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-2-基)氨基)苯磺酰胺
按照实施例4步骤3中所述的程序,由中间体21和4-氨基-3-氟苯磺酰胺得到标题化合物,为白色固体,6mg,5%收率。MS(ES+)C17H18F2N6O3S理论值:424,实测值:425[M+H]+。1H-NMR(400MHz,DMSO-d6)δppm 9.46(s,1H),8.56(d,J=2.8Hz,1H),8.35(s,1H),8.24(t,J=8.0Hz,1H),8.07(s,1H),7.69-7.60(m,2H),7.38(s,2H),4.80(s,1H),4.15(s,2H),1.10(s,6H)。
实施例31.4-((5-氟-4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-2-基)氨基)-3-甲基苯磺酰胺
将中间体21(80mg,296μmol)、4-氨基-3-甲基苯磺酰胺(55mg,296μmol)、KOAc(87mg,888μmol)、tBuXPhos(12.5mg,29.6μmol)和Pd2(dba)3(27.1mg,29.6μmol)在二噁烷(2mL)中的混合物在90℃和N2下搅拌16h。LCMS指示反应完成。通过制备型HPLC纯化反应混合物(碱性条件),得到标题化合物(45.4mg,36%收率),为白色固体。MS(ES+)C18H21FN6O3S理论值:420,实测值:421[M+H]+。1H-NMR(400MHz,DMSO-d6)δppm 8.93(s,1H),8.49(d,J=3.2Hz,1H),8.31(s,1H),8.02(s,1H),7.90(d,J=8.4Hz,1H),7.66-7.63(m,2H),7.20(s,2H),4.79(s,1H),4.14(s,2H),2.34(s,2H),1.10(s,6H)。
实施例32.4-((4-(1-(2-环丙基-2-羟乙基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)-3-氟苯磺酰胺
步骤1.合成1-环丙基-2-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)乙-1-酮(中间体32)
向2-溴-1-环丙基乙-1-酮(402mg,2.47mmol)在MeCN(6mL)中的溶液中添加4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑(400mg,2.06mmol)和K2CO3(840mg,6.18mmol)。将混合物在60℃下搅拌过夜。LCMS指示反应完成。将反应混合物浓缩,并通过硅胶快速色谱法纯化残留物,用EA/PE(1/4)洗脱,得到标题化合物(362mg,64%收率),为黄色固体。MS(ES+)C14H21BN2O3理论值:276,实测值:277[M+H]+。
步骤2.合成1-环丙基-2-(4-(2-(甲硫基)-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)乙-1-酮(中间体33)
将中间体32(240mg,864μmol)、2,4-二氯-5-(三氟甲基)嘧啶(187.2mg,864μmol)、Na2CO3(183mg,1.7mmol)和Pd(tBu3P)2(88.2mg,173μmol)在二噁烷(4mL)和H2O(1mL)中的混合物在90℃和N2下搅拌过夜。LCMS指示反应完成。将反应混合物浓缩,并通过硅胶快速色谱法纯化残留物,用EA/PE(1/2)洗脱,得到标题化合物(200mg,70%收率),为黄色固体。MS(ES+)C14H13F3N4OS理论值:342,实测值:343[M+H]+。
步骤3.合成1-环丙基-2-(4-(2-(甲硫基)-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)乙-1-醇(中间体34)
向中间体33(200mg,584μmol)在MeOH(10mL)中的溶液中添加NaBH4(43.8mg,1.16mmol)。将反应混合物在室温下搅拌过夜。LCMS指示反应完成。将反应混合物通过硅胶快速色谱法纯化,用MeOH/DCM(5%)洗脱,得到标题化合物(113mg,56%收率),为黄色固体。MS(ES+)C14H15F3N4OS理论值:344,实测值:345。
步骤4.合成1-环丙基-2-(4-(2-(甲基磺酰基)-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)乙-1-醇(中间体35)
向中间体34(90mg,261μmol)在DCM(2mL)中的溶液中添加m-CPBA(90mg,522μmol),并在室温下过夜搅拌反应。LCMS指示反应完成。将反应混合物通过硅胶快速色谱法纯化,用EA/PE(1/1)洗脱,得到标题化合物(73mg,74%收率),为黄色固体。MS(ES+)C14H15F3N4O3S理论值:376,实测值:377。
步骤5.合成4-((4-(1-(2-环丙基-2-羟乙基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)-3-氟苯磺酰胺(实施例32)
向4-氨基-3-氟苯-1-磺酰胺(20.1mg,106μmol)和中间体35(40mg,106μmol)在二噁烷(2mL)中的混合物中添加TsOH(9.12mg,53μmol)。将混合物在90℃下搅拌16h。LCMS指示反应完成。通过制备型HPLC纯化反应混合物(碱性条件),得到标题化合物(2.2mg,4%收率),为黄色固体。MS(ES+)C19H18F4N6O3S理论值:486,实测值:487[M+H]+。1H-NMR(400MHz,DMSO-d6)δppm 8.75(s,1H),8.25(s,1H),8.00(t,J=8Hz,1H),7.85(s,1H),7.68(s,1H),7.66(s,1H),5.02(s,1H),4.29-4.17(m,2H),3.30-3.20(m,1H),0.85-0.76(m,1H),0.41-0.31(m,2H),0.31-0.26(m,1H),0.12-0.06(m,1H)。
实施例33.3-氟-4-((4-(1-(2-羟乙基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺或3-氟-4-((2-(1-(2-羟乙基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-4-基)氨基)苯磺酰胺
步骤1.合成2-(4-(4-氯-5-(三氟甲基)嘧啶-2-基)-1H-吡唑-1-基)乙-1-醇(中间体36)或2-(4-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)乙-1-醇
将2-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)乙-1-醇(328mg,1.38mmol)、2,4-二氯-5-(三氟甲基)嘧啶(300mg,1.38mmol)、Na2CO3(380mg,3.58mmol)和Pd(dppf)Cl2(32mg,35μmol)在二噁烷(6mL)和H2O(2mL)中的混合物在90℃和N2下搅拌过夜。LCMS指示反应完成。将反应混合物浓缩,并通过硅胶快速色谱法纯化残留物,用PE/EA(1/1)洗脱,得到峰1(15mg),中间体36,2-(4-(2-氯-5-(三氟甲基)嘧啶-2-基)-1H-吡唑-1-基)乙-1-醇或2-(4-(4-氯-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)乙-1-醇,和峰2(35mg),2-(4-(4-氯-5-(三氟甲基)嘧啶-2-基)-1H-吡唑-1-基)乙-1-醇或2-(4-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)乙-1-醇,为黄色固体。MS(ES+)C10H8ClF3N4O理论值:292,实测值:293[M+H]+。
步骤2.合成3-氟-4-((2-(1-(2-羟乙基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-4-基)氨基)苯磺酰胺(实施例33)
将中间体36(35mg,120μmol)、4-氨基-3-氟苯-1-磺酰胺(22.7mg,120μmol)和TsOH(22.7mg,120μmol)在IPA(2mL)中的溶液在90℃下搅拌15h。LCMS指示反应完成。通过制备型HPLC纯化反应混合物(碱性条件),得到标题化合物(24.7mg,46%收率),为白色固体。MS(ES+)C16H14F4N6O3S理论值:446,实测值:447[M+H]+。1H NMR(400MHz,DMSO)δ9.13(s,1H),8.66(s,1H),8.15(s,1H),7.77-7.70(m,4H),7.51(s,2H),4.92-4.90(m,1H),4.19-4.06(m,2H),3.74-3.72(m,2H)。
实施例34.4-((5-氰基-4-(1-(2-羟乙基)-1H-吡唑-4-基)嘧啶-2-基)氨基)苯磺酰胺
向中间体9(70mg,226μmol)和2-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)乙-1-醇(64.5mg,271μmol)在二噁烷(5mL)和水(0.5mL)中的混合物中添加Pd(t-Bu3P)2(46.1mg,90.4μmol)和Na2CO3(71.8mg,678μmol),并在100℃下搅拌反应2h。LCMS指示反应完成。通过制备型HPLC纯化反应混合物(碱性条件),得到标题化合物(9.7mg,11%收率),为白色固体。MS(ES+)C16H15N7O3S理论值:385,实测值:386[M+H]+。1H-NMR(400MHz,DMSO-d6)δppm 10.67(s,1H),8.91(s,1H),8.59(s,1H),8.30(s,1H),7.96(d,J=9.0Hz,2H),7.82(d,J=9.0Hz,2H),7.25(s,2H),5.00(t,J=5.2Hz,1H),4.31(t,J=5.2Hz,2H),3.78(q,J=5.2Hz,2H)。
实施例35.(S)-3-氟-4-((4-(1-(2-羟丙基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺
步骤1.合成(S)-1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)丙-2-醇(中间体37)
将4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑(1.0g,5.15mmol)、(S)-2-甲基环氧乙烷(1.49g,25.77mmol)和Cs2CO3(5.02g,15.45mmol)在ACN(25mL)中的混合物在80℃和N2下搅拌48h。LCMS指示反应完成。将反应混合物浓缩,并通过硅胶快速色谱法纯化残留物,用DCM/MeOH(20/1)洗脱,得到标题化合物(700mg,54%收率),为无色油状物。MS(ES+)C12H21BN2O3理论值:252,实测值:253[M+H]+。
步骤2.合成(S)-1-(4-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)丙-2-醇(中间体38)
将中间体37(250mg,0.99mmol)、2,4-二氯-5-(三氟甲基)嘧啶(214mg,0.99mmol)、NaHCO3(249mg,2.97mmol)和Pd(dppf)Cl2(145mg,0.19mmol)在THF(10mL)和H2O(3mL)中的混合物在60℃和N2下搅拌2h。LCMS指示反应完成。将反应混合物浓缩,并通过硅胶快速色谱法纯化残留物,用EA/PE(1/1)洗脱,得到标题化合物(140mg,46%收率),为黄色固体。MS(ES+)C11H10ClF3N4O理论值:306,实测值:307[M+H]+。
步骤3.合成(S)-3-氟-4-((4-(1-(2-羟丙基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺(实施例35)
按照实施例4步骤3中所述的程序,由中间体38和4-氨基-3-氟苯磺酰胺得到标题化合物,为白色固体,39.2mg,18%收率。MS(ES+)C17H16F4N6O3S理论值:460,实测值:461[M+H]+。1H-NMR(400MHz,DMSO-d6)δppm 10.08(s,1H),8.77(s,1H),8.24(s,1H),8.02(t,J=8.0Hz,1H),7.96(s,1H),7.69(s,1H),7.67(s,1H),7.44(s,2H),4.97(d,J=4.8Hz,1H),4.17-4.06(m,2H),4.02-3.96(m,1H),1.06(d,J=6.4Hz,3H)。
实施例36.3-氟-4-((4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-5-甲基嘧啶-2-基)氨基)苯磺酰胺
按照实施例4步骤3中所述的程序,由中间体20和4-氨基-3-氟苯-1-磺酰胺得到标题化合物,为白色固体,83.8mg,35%收率。MS(ES+)C18H21FN6O3S理论值:420,实测值:421[M+H]+。1H NMR(400MHz,DMSO)δ9.13(s,1H),8.35-8.32(m,3H),8.06(s,1H),7.66-7.60(m,2H),7.35(s,2H),4.78(s,1H),4.12(s,2H),2.34(s,3H),1.10(s,6H)。
实施例37.4-((4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)-2,6-二甲基苯磺酰胺
将4-溴-2,6-二甲基苯磺酰胺(130mg,0.492mmol)、中间体27(148mg,0.492mmol)、BrettPhos Pd G4(78mg,0.05mmol)和乙酸钾(74mg,0.76mmol)在二噁烷(5mL)中的混合物在100℃和N2下搅拌过夜。LCMS显示反应物完全转化,将反应混合物用制备型HPLC纯化(碱性条件),得到标题产物(58.2mg,36%收率),为白色固体。MS(ES+)C20H23F3N6O3S理论值:484,实测值:485[M+H]+。1H-NMR(400MHz,DMSO-d6)δppm 10.27(s,1H),8.80(s,1H),8.26(s,1H),8.04-7.99(m,1H),7.96(s,1H),7.85(d,J=8.8Hz,1H),7.72(s,2H),4.78(s,1H),4.12(s,2H),1.08(s,6H)。
实施例38.2-氯-3-氟-4-((4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺
步骤1.合成4-溴-2-氯-3-氟苯磺酰氯(中间体39)
在0℃下向4-溴-2-氯-3-氟苯胺(400mg,1.78mmol)在ACN(12mL)中的混合物中添加AcOH(0.6mL)和浓HCl(0.7mL)。缓慢添加在水(0.5mL)中的亚硝酸钠(142mg,2.14mmol)。在0℃下搅拌20分钟后,在0-5℃下将SO2泵入反应混合物中持续1.5h,然后添加CuCl2(287mg,2.14mmol),并将SO2泵入所得混合物中再持续1h。在0℃下搅拌反应1h,添加冷水,并用DCM萃取混合物。将有机层用盐水洗涤并浓缩,得到粗产物(200mg),为黄色油状物,将其不经任何进一步纯化用于下一步。
步骤2.合成4-溴-2-氯-3-氟苯磺酰胺(中间体40)
将在DCM(3mL)中的步骤1的粗物质(中间体39,200mg,0.66mmol)添加到冷的NH3/MeOH(10mL)中,并搅拌反应10分钟。将反应物用DCM稀释,用水洗涤并浓缩有机层,添加EA,并通过过滤收集所得固体,得到标题产物(120mg,64%收率),为白色固体。MS(ES+)C6H4BrClFNO2S理论值:287,实测值:288[M+H]+。
步骤3.合成2-氯-3-氟-4-((4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺(实施例38)
按照实施例9步骤3中所述的程序,由中间体27和中间体40得到标题化合物,为黄色固体,60mg,28%收率。MS(ES+)C18H17ClF4N6O3S理论值:508,实测值:509[M+H]+。1H-NMR(400MHz,DMSO-d6)δppm 10.33(s,1H),8.81(s,1H),8.30(s,1H),8.00(s,1H),7.64(s,2H),7.17(s,2H),4.80(br.s,1H),4.13(s,2H),2.59(s,6H),1.10(s,6H)。
实施例39.4-((5-氰基-4-(1-(氧杂环丁烷-3-基)-1H-吡唑-4-基)嘧啶-2-基)氨基)苯磺酰胺
向中间体9(100mg,322μmol)和1-(氧杂环丁烷-3-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑(96.5mg,386μmol)在二噁烷(10mL)和H2O(1mL)中的溶液中添加Pd(t-Bu3P)2(65.4mg,128μmol)和Na2CO3(102mg,965μmol)。在100℃下搅拌反应2h。通过制备型HPLC纯化反应混合物(碱性条件),得到标题化合物(17.2mg,13.5%收率),为白色固体。MS(ES+)C17H15N7O3S理论值:397,实测值:398[M+H]+。1H-NMR(400MHz,DMSO-d6)δppm 10.70(s,1H),8.93(s,1H),8.69(s,1H),8.43(s,1H),7.96(d,J=8.8Hz,2H),7.83(d,J=8.8Hz,2H),7.26(s,2H),5.86-5.82(m,1H),4.98-4.92(m,4H)。
实施例40.3-氟-4-((4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-甲氧基苯磺酰胺
步骤1.合成4-溴-3-氟-2-甲氧基苯磺酰氯(中间体41)
按照实施例38步骤1中所述的程序,由4-溴-3-氟-2-甲氧基苯胺得到标题化合物(200mg,粗)。
步骤2.合成4-溴-3-氟-2-甲氧基苯磺酰胺(中间体42)
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按照与实施例28步骤2中所述类似的程序,由中间体41得到标题化合物,为黄色固体,150mg,80%收率。MS(ES+)C7H7BrFNO3S理论值:283,实测值:284[M+H]+。
步骤3.合成3-氟-4-((4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-甲氧基苯磺酰胺(实施例40)
按照实施例9步骤3中所述的程序,由中间体27和中间体42得到标题化合物,为黄色固体,60mg,28%收率。MS(ES+)C19H20F4N6O4S理论值:504,实测值:505[M+H]+。1H-NMR(400MHz,DMSO-d6)δppm 10.09(s,1H),8.77(s,1H),8.24(s,1H),7.95(s,1H),7.67(dd,J=8.8Hz,6.4Hz,1H),7.58(d,J=8.8Hz,1H),7.33(s,2H),4.78(s,1H),4.11(s,2H),3.98(s,3H),1.07(s,6H)。
实施例41.3-氟-4-((4-(1-((3-羟基氧杂环丁烷-3-基)甲基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺
步骤1.合成3-((4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)甲基)氧杂环丁烷-3-醇(中间体43)
在80℃下向4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑(931mg,4.80mmol)、3-(羟甲基)氧杂环丁烷-3-醇(500mg,4.80mmol)和三苯基磷(1.51g,5.76mmol)在甲苯(20mL)中的混合物中滴加DIAD(1.16g,5.76mmol)。将反应混合物搅拌过夜。LCMS指示反应完成。用水淬灭反应,并用EA萃取。将合并的有机层用水和盐水洗涤,经硫酸钠干燥,过滤并浓缩。将残留物通过硅胶快速色谱法纯化,用PE/EA(4/1)洗脱,得到标题化合物(700mg,52%收率),为黄色固体。MS(ES+)C13H21BN2O4理论值:280,实测值:281[M+H]+。
步骤2.合成3-((4-(2-氨基-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)甲基)氧杂环丁烷-3-醇(中间体44)
将中间体43(250mg,892μmol)、4-氯-5-(三氟甲基)嘧啶-2-胺(176mg,892μmol)、Na2CO3(283mg,2.67mmol)和Pd(dppf)Cl2(65.2mg,89.2μmol)在二噁烷(10mL)和H2O(2.5mL)中的混合物在80℃和N2下搅拌4h。LCMS指示反应完成。将反应混合物浓缩,并通过硅胶快速色谱法纯化残留物,用DCM/MeOH(5/1)洗脱,得到标题化合物(170mg,60%收率),为白色固体。MS(ES+)C12H12F3N5O2理论值:315,实测值:316[M+H]+。
步骤3.合成3-氟-4-((4-(1-((3-羟基氧杂环丁烷-3-基)甲基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺(实施例41)
向中间体44(140mg,444μmol)和4-溴-3-氟苯磺酰胺(112mg,444μmol)在二噁烷(5mL)中的混合物中添加Pd2(dba)3(40.6mg,44.4μmol)、t-BuXPhos(18.8mg,44.4μmol)和KOAc(130mg,1.33mmol),然后在100℃和N2下搅拌4h。LCMS指示反应完成。通过制备型HPLC纯化反应混合物(碱性条件),得到标题化合物(30.1mg,13%收率),为白色固体。MS(ES+)C18H16F4N6O4S理论值:488,实测值:489[M+H]+。1H NMR(400MHz,DMSO)δ10.10(s,1H),8.78(s,1H),8.26(s,1H),8.02(t,J=8.0Hz,1H),7.98(s,1H),7.71(s,1H),7.68(s,1H),7.45(s,2H),6.22(s,1H),4.60-4.57(m,2H),4.53(s,2H),4.45-4.44(m,2H)。
实施例42.4-((5-乙基-4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-2-基)氨基)-3-氟苯磺酰胺
步骤1.合成1-(4-(2-氯-5-乙基嘧啶-4-基)-1H-吡唑-1-基)-2-甲基丙-2-醇(中间体45)
将2-甲基-1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)丙-2-醇(270mg,1.01mmol)、2,4-二氯-5-乙基嘧啶(357mg,2.02mmol)、Na2CO3(136mg,1.29mmol)、Pd(dppf)Cl2(37.0mg,50.5μmol)在二噁烷(12mL)和H2O(3mL)中的混合物在90℃和N2下搅拌过夜。LCMS指示反应完成。将反应混合物浓缩,并通过硅胶快速色谱法纯化残留物,用PE/EA(1/1)洗脱,得到标题化合物(150mg,53%收率),为黄色固体。MS(ES+)C13H17ClN4O理论值:280,实测值:281[M+H]+。
步骤2.合成4-((5-乙基-4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-2-基)氨基)-3-氟苯磺酰胺(实施例42)
将中间体45(120mg,427μmol)、4-氨基-3-氟苯-1-磺酰胺(97.3mg,512μmol)、TsOH(73.5mg,427μmol)在IPA(10mL)中的混合物在90℃下搅拌3d。LCMS指示反应完成。通过制备型HPLC纯化反应混合物(酸性条件),得到标题化合物(24.3mg,13%收率),为白色固体。MS(ES+)C19H23FN6O3S理论值:434,实测值:435[M+H]+。1H NMR(400MHz,DMSO)δ9.16(s,1H),8.37-8.28(m,3H),8.02(s,1H),7.65-7.60(m,2H),7.35(s,2H),4.78(s,1H),4.12(s,2H),2.75(q,J=7.2Hz,2H),1.23-1.16(m,4H),1.10(s,6H)。
实施例43.3-氟-4-((4-(1-(氧杂环丁烷-3-基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺
步骤1.合成4-(1-(氧杂环丁烷-3-基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-胺(中间体46)
按照与实施例3步骤1中所述类似的程序,由4-氯-5-(三氟甲基)嘧啶-2-胺和1-(氧杂环丁烷-3-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑得到标题化合物,为黄色固体,200mg,69%收率。MS(ES+)C11H10F3N5O理论值:285,实测值:286[M+H]+。
步骤2.合成3-氟-4-((4-(1-(氧杂环丁烷-3-基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺(实施例43)
将中间体46(150mg,525μmol)、4-溴-3-氟苯-1-磺酰胺(199mg,787μmol)、乙酸钾(154mg,1.57mmol)、BrettPhos Pd G4(80.6mg,52.5μmol)在二噁烷(3mL)中的溶液在90℃和N2下搅拌过夜。LCMS指示反应完成。通过制备型HPLC纯化反应混合物(碱性条件),得到标题化合物(110.4mg,45%收率),为白色固体。MS(ES+)C17H14F4N6O3S理论值:458,实测值:459[M+H]+。1H NMR(400MHz,DMSO)δ10.11(s,1H),8.79(s,1H),8.36(s,1H),8.11(s,1H),8.02(t,J=8.0Hz,1H),7.71-7.67(m,2H),7.45(s,2H),5.80-5.75(m,1H),4.96-4.89(m,4H)。
实施例44.3-氯-4-((5-氟-4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-2-基)氨基)苯磺酰胺
将中间体21(80mg,296μmol)、4-氨基-3-氯苯磺酰胺(61mg,296μmol)、KOAc(87mg,888μmol)、tBuXPhos(12.5mg,29.6μmol)和Pd2(dba)3(27.1mg,29.6μmol)在二噁烷(2mL)中的混合物在90℃和N2下搅拌16h。LCMS指示反应完成。通过制备型HPLC纯化反应混合物(碱性条件),得到标题化合物(11.8mg,9%收率),为白色固体。MS(ES+)C17H18ClFN6O3S理论值:440,实测值:441[M+H]+。1H-NMR(400MHz,DMSO-d6)δppm 8.90(s,1H),8.57(d,J=2.8Hz,1H),8.36(s,1H),8.28(d,J=8.8Hz,1H),8.08(s,1H),7.90(s,1H),7.80(dd,J=8.8Hz,2.4Hz,1H),7.39(s,2H),4.80(s,1H),4.15(s,2H),1.10(s,6H)。
实施例45.5-氟-4-((4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-甲基苯磺酰胺
将4-溴-5-氟-2-甲基苯磺酰胺(225mg,839μmol)、1-(4-(2-氨基-5-(三氟甲基)嘧啶-4-基)-1H-吡唑-1-基)-2-甲基丙-2-醇(中间体27,252mg,839μmol)、BrettPhos Pd G4(100mg,1.01mmol)和乙酸钾(245mg,2.51mmol)在二噁烷(5mL)中的混合物在100℃和N2下搅拌过夜。将反应混合物冷却到室温并浓缩,得到残留物,通过硅胶快速柱色谱法将其纯化,用PE/EA(1/4)洗脱,然后通过制备型HPLC纯化(碱性条件),得到标题产物(102mg,25%收率)。为白色固体。MS(ES+)C19H20F4N6O3S理论值:488,实测值:489[M+H]+。1H-NMR(400MHz,DMSO-d6)δppm 10.04(s,1H),8.77(s,1H),8.25(s,1H),7.94(s,1H),7.84(d,J=7.6Hz,1H),7.67(d,J=11.2Hz,1H),7.49(s,2H),4.79(s,1H),4.12(s,2H),2.58(s,3H),1.09(s,6H)。
实施例46.4-((5-氟-4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-2-基)氨基)-3-甲氧基苯磺酰胺
向中间体21(100mg,369μmol)和4-氨基-3-甲氧基苯磺酰胺(74.6mg,369μmol)在二噁烷(5mL)中的混合物中添加Pd2(dba)3(33.7mg,36.8μmol)、t-BuXPhos(15.6mg,36.7μmol)和KOAc(107mg,1.10mmol),然后在100℃和N2下搅拌4h。LCMS指示反应完成。通过制备型HPLC纯化反应混合物(碱性条件),得到标题化合物(2.0mg,1%收率),为白色固体。MS(ES+)C18H21FN6O4S理论值:436,实测值:437[M+H]+。1H-NMR(400MHz,DMSO-d6)δppm 8.59(d,J=2.8Hz,1H),8.48(d,J=8.4Hz,1H),8.41(s,1H),8.25(s,1H),8.14(s,1H),7.50(dd,J=8.4Hz,2.8Hz,1H),7.46(s,1H),7.23(s,2H),4.80(s,1H),4.16(s,2H),3.96(s,3H),1.10(s,6H)。
实施例47.3-氟-4-((4-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺
步骤1.合成4-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-胺(中间体47)
将1-(四氢-2H-吡喃-4-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑(400mg,1.43mmol)、4-氯-5-(三氟甲基)嘧啶-2-胺(422mg,2.14mmol)、Na2CO3(454mg,4.29mmol)和Pd(dppf)Cl2(104mg,143μmol)在二噁烷(10mL)和H2O(1mL)中的混合物在80℃和N2下搅拌2h。LCMS指示反应完成。将反应混合物浓缩,并通过硅胶快速色谱法纯化残留物,用EA/PE(1/4)洗脱,得到标题化合物(324mg,72%收率),为黄色固体。MS(ES+)C13H14F3N5O理论值:313,实测值:314[M+H]+。
步骤2.合成3-氟-4-((4-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-基)氨基)苯磺酰胺(实施例47)
向中间体47(324mg,1.03mmol)和4-溴-3-氟苯磺酰胺(312mg,1.23mmol)在二噁烷(10mL)中的混合物中添加KOAc(202mg,2.06mmol)和BrettPhos Pd G4(25mg),然后在90℃和N2下搅拌16h。LCMS指示反应完成。通过制备型HPLC纯化反应混合物(碱性条件),得到标题化合物(197.6mg,39%收率),为白色固体。MS(ES+)C19H18F4N6O3理论值:486,实测值:487[M+H]+。1H-NMR(400MHz,DMSO-d6)δppm 10.07(br.s.,1H),8.77(s,1H),8.29(s,1H),8.05-7.98(m,2H),7.70-7.66(m,2H),7.45(br.s.,2H),4.59-4.55(m,1H),3.99-3.96(m,2H),3.50-3.43(m,2H),2.01-1.95(m,4H)。
生物学实施例1.生化CDK抑制测定
在生化测定中测量本公开的化合物的抑制作用,所述生化测定在腺苷-5'-三磷酸(ATP)和在100mM 2-[4-(2-羟乙基)哌嗪-1-基]乙磺酸(HEPES),pH 7.5、10mM MgCl2、0.015% Brij-35、1mM二硫苏糖醇(DTT)、1.0%二甲基亚砜(DMSO)中的不同浓度的测试化合物存在下测量CDK酶与细胞周期蛋白的复合物磷酸化7.5微摩尔浓度的荧光标记的肽底物5-FAM-QSPKKG-CONH2,(FL-肽18,Perkin Elmer,760362)的酶磷酸化活性。测定在1.0mMATP或CDK酶与细胞周期蛋白的复合物的ATP Km下进行。反应持续进行,直到10%至20%之间的总肽在室温(25℃)下被磷酸化,并用35mM 2,2',2”,2”'-(乙烷-1,2-二基二次氮基)四乙酸(EDTA)终止。采用Caliper迁移率变化检测方法检测产物,其中将磷酸化的肽(产物)和底物电泳分离并进行测量。将活性百分比对化合物的浓度的对数和点进行绘图以生成表观IC50。这些测定中使用以下CDK酶与不同细胞周期蛋白的复合物:
CDK1/细胞周期蛋白B1,GST-标签(BPS,40454),测定中使用1.5nM
CDK2/细胞周期蛋白E(Eurofins,14-475),测定中使用1.25nM
下表1中提供测试化合物的生物测定数据。对于针对CDK2/细胞周期蛋白E突变体的抑制活性,采用以下指定:≤10nM=A;>10-20nM=B;>20-30nM=C;>30–100nM=D,和>100=E。对于抑制CDK1/细胞周期蛋白B1,GST-标签:≥500nM=A;<100-500nM=B;<100nM=C。
表1.列成表格的数据:
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Claims (17)
1.一种式I的化合物
或其药学上可接受的盐,其中
每个R1独立地选自由以下组成的组:卤代、OH、CN、C1-C4烷基和C1-C4烷氧基,其中所述C1-C4烷基和C1-C4烷氧基各自任选被1至3个卤代取代;
每个R2独立地选自由以下组成的组:卤代、OH、CN、C1-C4烷基和C1-C4烷氧基,其中所述C1-C4烷基和C1-C4烷氧基各自任选被1至3个卤代取代;
R3是任选被1或2个各自独立地选自由卤代、OH、C3-C6环烷基和3至6元杂环基组成的组的基团取代的C1-C6烷基,其中所述C3-C6环烷基任选被OH取代,其中所述3至6元杂环基具有1至4个各自独立地选自由O、S和NRa组成的组的环杂原子,然后任选在环碳上被OH取代;或者
R3是C3-C6环烷基或3至6元杂环基,其中所述C3-C6环烷基任选被OH或-CH2OH取代,其中所述3至6元杂环基具有1至4个各自独立地选自由O、S和NRa组成的组的环杂原子,然后任选在环碳上被OH或-CH2OH取代;
每个Ra独立地为H或C1-C6烷基;
m选自由0、1、2、3和4组成的组,且
n选自由0、1和2组成的组。
2.如权利要求1所述的化合物,其中所述化合物具有式IIA、式IIB、式IIC或式IID
或其药学上可接受的盐。
3.如权利要求1或2所述的化合物,其中每个R1独立地选自由卤代、甲基和甲氧基组成的组。
4.如权利要求1至3中任一项所述的化合物,其中每个R2独立地选自由卤代、CN、甲基和乙基组成的组,其中所述甲基和乙基各自任选被1至3个卤代取代。
5.如权利要求1至4中任一项所述的化合物,其中R3是任选被1或2个各自独立地选自由卤代、OH、环丙基和氧杂环丁烷基组成的组的基团取代的C1-C5烷基,其中所述环丙基和氧杂环丁烷基各自任选被OH取代。
6.如权利要求1至4中任一项所述的化合物,其中R3是被OH取代的C1-C5烷基。
7.如权利要求1至4中任一项所述的化合物,其中R3是环丙基或氧杂环丁烷基,其中所述环丙基和氧杂环丁烷基各自任选被OH或CH2OH取代(如果R3是氧杂环丁烷基,则在环碳上)。
8.如权利要求1或2所述的化合物,其中每个R1是甲基,每个R2独立地选自由卤代、甲基和CF3组成的组,且R3是被OH取代的C1-C6烷基。
9.如权利要求1或2所述的化合物,其中每个R1是卤代,每个R2独立地选自由卤代、CN、甲基、乙基和CF3组成的组,且R3是被OH取代的C1-C6烷基,或者R3是氧杂环丁烷基或环丙基,其中所述氧杂环丁烷基和环丙基各自任选被CH2OH取代(如果R3是氧杂环丁烷基,则在环碳上)。
10.如权利要求1或2所述的化合物,其中每个R1是甲氧基,每个R2独立地选自由卤代、甲基和CF3组成的组,且R3是被OH取代的C1-C6烷基。
11.一种药物组合物,所述药物组合物包含药学上可接受的载体和权利要求1-10中任一项所述的化合物或其药学上可接受的盐。
12.一种治疗有需要的受试者的癌症的方法,所述方法包括对所述受试者施用有效量的权利要求1-10中任一项所述的化合物或其药学上可接受的盐或权利要求11所述的药物组合物。
13.如权利要求12所述的方法,其中所述癌症是乳腺癌。
14.一种抑制CDK2的方法,所述方法包括对有需要的受试者施用有效量的权利要求1-10中任一项所述的化合物或其药学上可接受的盐或权利要求11所述的药物组合物。
15.一种治疗患有与CDK2相关的疾病或病症或有患与CDK2相关的疾病或病症的风险的受试者的方法,所述方法包括对所述受试者施用治疗有效量的权利要求1-10中任一项所述的化合物或其药学上可接受的盐或权利要求11所述的药物组合物,其中所述受试者具有CCNE1基因的扩增和/或具有高于CCNE1的对照表达水平的CCNE1的表达水平。
16.如权利要求15所述的方法,其中所述与CDK2相关的疾病或病症是癌症。
17.一种治疗具有扩增的CCNE1的表达水平并罹患实体肿瘤癌症或有患实体肿瘤癌症的风险的患者的方法,所述方法包括对所述患者施用治疗有效量的权利要求1-10中任一项所述的化合物或其药学上可接受的盐或权利要求11所述的药物组合物。18.如权利要求17所述的方法,其中所述实体肿瘤癌症是以下中的至少一种:子宫癌(包括子宫癌肉瘤、子宫体子宫内膜癌)、子宫内膜癌、乳腺癌(包括浸润性乳腺癌、TNBC(三阴性乳腺癌)、ER(***受体)+HER2(人表皮生长因子2)-乳腺癌和HER2+乳腺癌)、卵巢癌(例如卵巢浆液性囊腺癌)、胃部癌症(包括胃腺癌)、胃癌(包括胃肠道间质瘤)、结直肠癌、胰腺癌、肾癌、头颈癌、肝癌、***癌、皮肤癌、淋巴瘤(包括B细胞淋巴瘤)、肉瘤、食道癌(包括食道上皮癌)、膀胱癌(包括膀胱尿路上皮癌)、肺癌(包括肺鳞状细胞癌和非小细胞肺癌,例如EGFRm(表皮生长因子受体突变体)+非小细胞肺癌)、胆管癌、肾上腺皮质癌或间皮瘤。
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