CN106029659A - 谷氨酰胺酶抑制剂 - Google Patents
谷氨酰胺酶抑制剂 Download PDFInfo
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- CN106029659A CN106029659A CN201580009614.9A CN201580009614A CN106029659A CN 106029659 A CN106029659 A CN 106029659A CN 201580009614 A CN201580009614 A CN 201580009614A CN 106029659 A CN106029659 A CN 106029659A
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Abstract
本公开提供了作为谷氨酰胺酶抑制剂的式(I)至(III)的化合物、其制备方法、含有这些化合物的药物组合物,及治疗、预防和/或改善涉及谷氨酰胺的疾病或病症的方法。
Description
本申请要求以下印度专利申请号的权益:2014年1月6日提交的36/CHE/2014、2014年1月6日提交的39/CHE/2014、2014年5月29日提交的2639/CHE/2014、2014年5月29日提交的2647/CHE/2014、2014年6月6日提交的2783/CHE/2014、2014年7月18日提交的3525/CHE/2014、2014年7月24日提交的3612/CHE/2014、2014年7月24日提交的3613/CHE/2014及2014年10月31日提交的5438/CHE/2014,各案通过引用整体并入本文中。
发明领域
本发明提供了作为谷氨酰胺酶抑制剂的式(I)至(III)的化合物、其制备方法、含有这些化合物的药物组合物,及治疗、预防和/或改善涉及谷氨酰胺的疾病或病症的方法。
发明背景
谷氨酰胺酶(谷氨酰胺酶I、L-谷氨酰胺酶、谷氨酰胺氨基水解酶)是由谷氨酰胺产生谷氨酸的一种酰胺水解酶。据报导,谷氨酰胺酶具有组织特异性同工酶。谷氨酰胺酶在胶质细胞中具有重要作用。谷氨酰胺是人体中含量最丰富的游离氨基酸;它对于正常细胞和肿瘤细胞生长以及许多细胞类型的培养至关重要。谷氨酰胺是肿瘤组织的重要能量来源,并且其代谢产物特别包括谷氨酸(Glu)和谷胱甘肽(GSH),这两个分子在肿瘤增殖、侵袭及对疗法的抗性方面起到关键作用。正常和转化哺乳动物组织中的谷氨酰胺水解同样是由谷氨酰胺酶的不同同工型进行,其中的两个主要类型是肝型谷氨酰胺酶(LGA)和肾型谷氨酰胺酶(KGA)(参见Neurochem Int.,2009年7月-8月;55(1-3):71-5.doi:10.1016/j.neuint.2009.01.008.Epub 2009年2月)。
癌细胞需要稳定地供应还原的氮来产生核苷酸、非必需氢基酸及较高的细胞氧化还原活性。谷氨酰胺为呼吸作用提供主要底物并且为蛋白质、己糖胺和大分子的制造提供氮。因此,谷氨酰胺是癌症代谢中细胞增殖期间的关键分子之一。靶向癌症中的谷氨酰胺代谢的观点最初是通过由这一养分供养的路径的数量得到合理说明,近期的研究证实其代谢受致癌基因调控则强化了该观点。谷氨酰胺酶(GA)是三羧酸循环中将谷氨酰胺转化成谷氨酸的第一个酶,谷氨酸又被转化成α-酮戊二酸用于进一步代谢。哺乳动物体内的不同GA同工型是由两个基因Gls和Gls2编码。由于GA的每种酶形式都具有不同的动力学和分子特征,故据推测,GA同工型的差异调控可能反映不同组织或细胞状态的不同功能或需求。已显示,由Gls基因(GLS)编码的GA受致癌基因调控并且支持肿瘤细胞生长。由Gls2基因(GLS2)编码的GA可能通过谷胱甘肽依赖性抗氧化防御作用来降低细胞对活性氧物质相关性细胞凋亡的敏感性,并因此更类似于肿瘤抑制因子。因此,调节GA功能将是癌症治疗的新的治疗靶(参见Matés等人,Curr.Mol.Med.,2013年5月;13(4),514-534)。
癌细胞的一个特点是其适应于依靠改变的代谢流程,包括糖分解路径的改变(称为瓦伯格效应(Warburg effect)),及谷氨酰胺代谢增加。谷氨酰胺酶是一种线粒体酶,它在癌细胞中谷氨酰胺代谢方面起到关键作用,并且其抑制会显著影响恶性转化(参见Katt等人,Mol.Cancer Ther.,11(6);1269-78,2012)。依靠谷氨酰胺分解的供养,癌细胞能够生长并且分裂成肿瘤。因此,谷氨酰胺酶成为防止肿瘤发展的颇具前景的治疗目标。对于这一酶的抑制可以有效地使癌细胞缺乏能源。参见Medina等人,J.Nutr.,2001年9月1日,第131卷,第9号,2539S-2542S。
谷氨酰胺酶在癌症机制,如细胞存活、增殖及生长方面起到至关紧要的作用。报导有两种谷氨酰胺酶抑制剂,即,6-重氮-5-氧代-L-正亮氨酸(DON),最初从秘鲁土壤样品中的链霉菌(Streptomyces)分离并在1956年由Henry W Dion表征(参见Dion等人,Antibiotics and Chemotherapy,1954,78,3075-3077),而且被提出作为癌症疗法;及由Elan Pharmaceuticals公开的双-2-(5-苯基乙酰胺基-1,3,4-噻二唑-2-基)乙基硫醚(BPTES)。在Cornell University和Calithera Biosciencesis工作的其它团体正在进行研究,试图发现并鉴别出小分子谷氨酰胺酶抑制剂。另外,据报导,New Medical Enzymes AG评价了DON与PEG-PGA的组合。除BPTES和DON外,报导的其它谷氨酰胺酶抑制剂都概述于下表中。
有关癌症和其它疾病中的谷氨酰胺和谷氨酰胺酶的评述和研究提供于Medina等人,J.Nutr.,2001年9月1日,第131卷,笫9号,2539S-2542S;Ajit G.Thmas等人,Biochemical and Biophysical Research Communications,443,2014,32-36;MonicaSzeliga等人,Neurochemistrt Intermationa,55,2009,71-77;及Curthoys等人,Annu.Rev.Nutr.,1995,15,133-159中。所有这些文献的公开内容都通过引用整体并入本文中用于所有目的。
与谷氨酰胺酶抑制剂有关的专利文献包括国际公布号WO 99/09825、WO 00/59533、WO 03/022261、WO 04/108153、WO 07/128588、WO 10/033871、WO 10/111504、WO 11/076967、WO 11/143160、WO 12/006506、WO 12/034123、WO 13/044596、WO 13/078123、WO14/078645、WO 14/089048、WO 14/043633、WO 14/079011、WO 14/079136、WO 14/079150及WO 14/081925;美国公布号2002/0115698、2006/0276438、2013/0157998、2014/0050699、2014/0194421、2014/0369961、2015/0004134、20140142081及20140142146;美国专利号5,552,427、6,451,828、8,465,736、8,604,016及8,865,718;以及欧洲公布号656210,各案通过引用整体并入本文中用于所有目的。
对用于治疗与细胞增殖有关的疾病和病症,如癌症及其它免疫病症和神经病症的新颖谷氨酰胺酶抑制剂的需求仍有待满足。
发明概述
本发明涉及式(I)至(III)的化合物、其制备方法、含有这些化合物的药物组合物及利用这些化合物的治疗方法。确切地说,式(I)至(III)的化合物及其药学上可接受的盐可用于治疗、预防和/或改善涉及谷氨酰胺的疾病或病症。
在一个方面,本发明涉及一种式(I)的化合物:
或其互变异构体、其前药、其N-氧化物、其立体异构体、其药学上可接受的酯或其药学上可接受的盐,其中
L是-L1-L2-L3-;其中
L1不存在或独立地选自取代或未取代的C1-6烷基、取代或未取代的C2-6烯基、取代或未取代的C2-6炔基、O、S、-S(=O)q-、-C(=O)-及-NRx-;
L2是取代或未取代的3至14元杂环基;
L3不存在或独立地选自取代或未取代的C1-6烷基、取代或未取代的C2-6烯基、取代或未取代的C2-6炔基、O、S、-S(=O)q-、-C(=O)-及-NRx-;
A和B独立地选自
A和B各自任选地经一个或多个R3取代;
R3在每次出现时独立地是氢、卤素、取代或未取代的C1-3烷基、硝基、氨基、取代或未取代的C1-6烷氧基,或取代或未取代的C1-6烷基氨基;
P和Q独立地选自取代或未取代的烷基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、-NRx-C(=O)-(CRxRy)r-、-NH-C(=O)-C(RxRy)-、-(CRxRy)r-C(=O)-NRx-、-(CRxRy)-C(=O)-NH-、-C(=O)NRx-(CRxRy)r-、-C(=O)NH-C(RxRy)-、-(CRxRy)r-NRx-C(=O)-、-(CRxRy)-NH-C(=O)-、-NRx-、-NRxC(=O)-、-NRxC(=S)-、-NRxS(=O)q-、-C(=O)NRx-、-C(=S)NRx-、-S(=O)qNRx-、-NRxC(=O)NRx-、-NRxC(=S)NRx-、-C(=O)-、-C(=S)-、-C(=O)ONRx-、=N-N(Rx)-、-N(Rx)-N=或-NRxC(=O)O-;
R1和R2独立地选自氢、羟基、卤素、取代或未取代的烷基、取代或未取代的烷氧基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的环烷基、取代或未取代的环烯基、取代或未取代的环烷基烷基、取代或未取代的环烯基烷基、取代或未取代的杂环基、取代或未取代的杂环基烷基、取代或未取代的芳基、取代或未取代的芳基烷基、取代或未取代的杂芳基、取代或未取代的杂芳基烷基、-C(=O)ORz、-C(=O)Rz、-C(=S)Rz、-C(=O)NRzRz、-C(=O)ONRzRz、-NRzRz、-NRzC(=O)NRzRz、-NRzS(=O)Rz、-NRzS(=O)2Rz、=N-N-RzRz、-NRzC(=O)ORz、-NRzC(=O)Rz、-NRxC(=S)Ry-NRzC(=S)NRzRz、-SONRzRz、-SO2NRzRz、-ORz、-ORzC(=O)NRzRz、-ORzC(=O)ORz、-OC(=O)Rz、-OC(=O)NRzRz、-RzNRzC(=O)Rz、-RzORz、-RzC(=O)ORz、-RzC(=O)NRzRz、-RzC(=O)Rz、-RzOC(=O)Rz、-SRz、-SORz、-SO2Rz、-CRxRyC(=O)Rz或-CRxRyC(=S)Rz;
Rx、Ry及Rz在每次出现时独立地选自氢、取代或未取代的烷基、取代或未取代的烷氧基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的芳基、取代或未取代的芳基烷基、取代或未取代的杂芳基、取代或未取代的杂芳基烷基、取代或未取代的环烷基、取代或未取代的环烷基烷基、取代或未取代的环烯基、取代或未取代的杂环、取代的杂环基烷基环,或者取代或未取代的氨基,或Rx和Ry中的任何两个当结合到共用原子时可以连接形成(i)取代或未取代的饱和或不饱和的3至14元环,其可以任选地包括一个或多个相同或不同的杂原子并且杂原子选自O、NRz和S;或(ii)氧代(=O)、硫代(=S)或亚氨基(=NRz);
q在每次出现时独立地是0、1或2;并且
r在每次出现时独立地是0、1或2。
为避免疑问并且除非另外指明,否则式是以其所显示的方向阅读。例如,(a)如果在式(I)(即,R1-P-A-L-B-Q-R2)中,P是-CH2-C(=O)-NH-,则化合物将具有式R1-CH2-C(O)-NH-A-L-B-Q-R2;或(b)如果在式(I)(即,R1-P-A-L-B-Q-R2)中,P是-CH2-C(=O)-NH-并且Q是-NH-C(=O)-CH2-,则化合物将具有式R1-CH2-C(O)-NH-A-L-B-NH-C(=O)-CH2-R2。
另外优选具有式(I)的化合物,其中A和B独立地选自
及
其中R3是氢、卤素或取代或未取代的C1-3烷基(例如,甲基)。
另外优选具有式(I)的化合物,其中A和B独立地选自
及
另外优选具有式(I)的化合物,其中A和B独立地选自
及
另外优选具有式(I)的化合物,其中A和B独立地选自
另外优选具有式(I)的化合物,其中A和B独立地选自
另外优选具有式(I)的化合物,其中
A是并且B是
另外优选具有式(I)的化合物,其中
A是并且B是
另外优选具有式(I)的化合物,其中P和Q各自独立地选自-NRxC(=O)-(CRxRy)r-、-(CRxRy)r-C(=O)-NRx-、-C(=O)NRx-(CRxRy)r-、-(CRxRy)r-NRx-C(=O)-、-NH-C(=O)-C(RxRy)-、-(CRxRy)-C(=O)-NH-、-NRxC(=O)-、-NRxC(=S)-、-NRxS(=O)q-、-C(=O)NRz-、-C(=S)NRz-或-NRx-。
另外优选具有式(I)的化合物,其中P和Q各自独立地选自-NRxC(=O)-(CRxRy)-、-(CRxRy)-C(=O)-NRx-、-NRxC(=O)-或-NRx-,其中Rx和Ry独立地选自氢、取代或未取代的C1-3烷基、卤素、羟基及取代或未取代的C1-3烷氧基。
另外优选具有式(I)的化合物,其中P和Q各自独立地是-NH-C(=O)-(CRxRy)-、-(CRxRy)-C(=O)-NH-、-NH-C(=O)-或-NH-,其中Rx和Ry是氢。
另外优选具有式(I)的化合物,其中P和Q各自独立地是-NH-C(=O)-(CH2)-、-(CH2)-C(=O)-NH-、-NH-C(=O)-或-NH-。
另外优选具有式(I)的化合物,其中P是-(CH2)-C(=O)-NH-并且Q是-NH-C(=O)-CH2-、-NH-C(=O)-或-NH-。
另外优选具有式(I)的化合物,其中P是-(CH2)-C(=O)-NH-、-NH-C(=O)-或-NH-并且Q是-NH-C(=O)-CH2-。
另外优选具有式(I)的化合物,其中P是-(CH2)-C(=O)-NH-并且Q是-NH-C(=O)-CH2-。
又另一实施方案是具有式(II)或(III)的化合物:
或其互变异构体、其前药、其N-氧化物、其立体异构体、其药学上可接受的酯或其药学上可接受的盐,其中变量L、R1、R2、R3、Rx及Ry各自如以上关于式(I)所定义。
另外优选具有式(I)、(II)或(III)的化合物,其中
L1是不存在、取代或未取代的C1-6烷基或-NRx-,其中Rx是氢或C1-3烷基;
L2是取代或未取代的3至10元杂环基;并且
L3是不存在、取代或未取代的C1-6烷基或-NRx-,其中Rx是氢或C1-3烷基。
另外优选具有式(I)、(II)或(III)的化合物,其中
L1不存在或是取代或未取代的C1-6烷基;
L2是取代或未取代的3至10元杂环基;并且
L3不存在或是取代或未取代的C1-6烷基。
另外优选具有式(I)、(II)或(III)的化合物,其中
L1是取代或未取代的C1-6烷基;
L2是取代或未取代的3至10元杂环基;并且
L3是取代或未取代的C1-6烷基。
另外优选具有式(I)、(II)或(III)的化合物,其中
L1是取代或未取代的C1-6烷基;
L2是取代或未取代的3至10元杂环基;并且
L3不存在。
另外优选具有式(I)、(II)或(III)的化合物,其中
L1不存在;
L2是取代或未取代的3至10元杂环基;并且
L3是取代或未取代的C1-6烷基。
另外优选具有式(I)、(II)或(III)的化合物,其中
L1不存在。
L2是取代或未取代的3至10元杂环基;并且
L3不存在。
另外优选具有式(I)、(II)或(III)的化合物,其中L2选自
其中
D和E独立地选自CR”或N,其中R”在每次出现时独立地是氢、羟基、卤素或者取代或未取代的C1-3烷基;
Ra、Rb、Rc、Rd、Re、Rf、Rg及Rh在每次出现时独立地选自氢、硝基、羟基、氰基、卤素、取代或未取代的C1-6烷基、取代或未取代的C2-6烯基、取代或未取代的C2-6炔基、取代或未取代的C3-6环烷基、取代或未取代的C3-6环烷基烷基及取代或未取代的C3-6环烯基;或Ra、Rb、Rc、Rd、Re、Rf、Rg及Rh中的任意两个(如结合到共用原子或相邻原子的两个基团或当连接时形成化学稳定结构的任意两个基团)可连接形成(i)取代或未取代的、饱和或不饱和的3至14元环,其可以任选地包括一个或多个相同或不同的杂原子并且杂原子选自O、NR’(其中R’是H或C1-3烷基)及S;或(ii)氧代(=O)、硫代(=S)或亚氨基(=NR’);并且s、t、u及v各自是0、1或2,条件是s、t、u及v的总和不是0(即,s+t+u+v≥1)。
另外优选具有式(I)、(II)或(III)的化合物,其中Ra、Rb、Rc、Rd、Re、Rf、Rg及Rh在每次出现时独立地选自氢、羟基及取代或未取代的C1-3烷基,或Ra、Rb、Rc、Rd、Re、Rf、Rg及Rh中的任意两个当结合至共用原子时可以形成氧代(=O),或Ra、Rb、Rc、Rd、Re、Rf、Rg及Rh中的任意两个形成取代或未取代的环烷基。
另外优选具有式(I)、(II)或(III)的化合物,其中Ra、Rb、Rc、Rd、Re、Rf、Rg及Rh各自是氢并且s、t、u及v的总和是1至4,如1、2、3或4。
另外优选具有式(I)、(II)或(III)的化合物,其中Ra、Rb、Rc、Rd、Re、Rf、Rg及Rh是氢,s是0,t是1并且u和v的总和是3。
另外优选具有式(I)、(II)或(III)的化合物,其中
(i)Ra、Rb、Rc、Rd、Re、Rf、Rg及Rh是氢,并且s、t、u及v各自是1;
(ii)Ra、Rb、Rc、Rd、Re、Rf、Rg及Rh是氢,s是0,并且t、u及v各自是1;
(iii)Ra、Rb、Rc、Rd、Re、Rf、Rg及Rh是氢,s是0,t和v各自是1并且u是2;或
(iv)Ra、Rb、Rc、Rd、Re、Rf、Rg及Rh是氢,s是0,t是1并且u和v的总和是1、2或3。
另外优选具有式(I)、(II)或(III)的化合物,其中
(i)Ra、Rb、Rc、Rd、Re、Rf、Rg及Rh各自是氢,s是0,t是1并且u+v=3;
(ii)Ra、Rb、Rc、Rd、Re、Rf、Rg及Rh各自是氢并且s、t、u及v各自是1;
(iii)Ra、Rb、Rc、Rd、Re、Rf、Rg及Rh各自是氢,s是0并且t、u及v各自是1;
(iv)Ra、Rb、Rc、Rd、Re、Rf、Rg及Rh各自是氢并且s、t、u及v的总和是2;或
(v)Ra、Rb、Rc、Rd、Re、Rf、Rg及Rh各自是氢并且s、t、u及v的总和是1。
另外优选具有式(I)、(II)或(III)的化合物,其中D和E独立地选自CH和N。
另外优选具有式(I)、(II)或(III)的化合物,其中D是CH并且E是N。另外优选具有式(I)、(II)或(III)的化合物,其中D是N并且E是CH。另外优选具有式(I)、(II)或(III)的化合物,其中L(即,L1-L2-L3)选自
及
另外优选具有式(I)、(II)或(III)的化合物,其中L(即,L1-L2-L3)选自及
另外优选具有式(I)、(II)或(III)的化合物,其中L(即,L1-L2-L3)选自
另外优选具有式(I)、(II)或(III)的化合物,其中L2选自
及
另外优选具有式(I)、(II)或(III)的化合物,其中L2选自
另外优选具有式(I)、(II)或(III)的化合物,其中L1和L3独立地不存在或是-CH2-。
另外优选具有式(I)、(II)或(III)的化合物,其中
(i)L1和L3不存在;
(ii)L1和L3是-CH2-;
(iii)L1不存在并且L3是-CH2-;或
(iv)L1是-CH2-并且L3不存在。
另外优选具有式(I)、(II)或(III)的化合物,其中R3在每次出现时独立地是氢、卤素或者取代或未取代的C1-3烷基。
另外优选具有式(I)、(II)或(III)的化合物,其中R3在每次出现时独立地是氢、氟或甲基。
另外优选具有式(I)、(II)或(III)的化合物,其中R1或R2中的至少一个是氢。
另外优选具有式(I)、(II)或(III)的化合物,其中R1和R2各自独立地选自卤素、取代或未取代的烷基、-NRzRz、取代或未取代的杂环基、取代或未取代的杂环基烷基、取代或未取代的芳基、取代或未取代的芳基烷基、取代或未取代的杂芳基及取代或未取代的杂芳基烷基。
另外优选具有式(I)、(II)或(III)的化合物,其中R1和R2各自独立地选自-NRzRz、取代或未取代的芳基及取代或未取代的杂芳基。
另外优选具有式(I)、(II)或(III)的化合物,其中R1和R2各自独立地是取代或未取代的芳基。
另外优选具有式(I)、(II)或(III)的化合物,其中R1和R2各自独立地是取代或未取代的杂芳基。
另外优选具有式(I)、(II)或(III)的化合物,其中
(i)R1是取代或未取代的芳基并且R2是取代或未取代的杂芳基;
(ii)R1是取代或未取代的杂芳基并且R2是取代或未取代的芳基;
(iii)R1和R2独立地是取代或未取代的芳基;或
(iv)R1和R2独立地是取代或未取代的杂芳基。
另外优选具有式(I)、(II)或(III)的化合物,其中R1和R2各自独立地选自
及
另外优选具有式(I)、(II)或(III)的化合物,其中Rx和Ry各自独立地选自氢、羟基或-CH2OH。
另外优选具有式(I)、(II)或(III)的化合物,其中Rx和Ry各自是氢。
本发明的代表性化合物包括以下所列化合物(另参见表1)及其药学上可接受的盐。本发明不应解释为局限于这些化合物。
1. 2-(吡啶-2-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)吡啶-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺;
2. 2-(吡啶-2-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)吡啶-3-基)哌啶-3-基)-1,3,4-噻二唑-2-基)乙酰胺;
2A.(R)或(S)2-(吡啶-2-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)吡啶-3-基)哌啶-3-基)-1,3,4-噻二唑-2-基)乙酰胺;
2B.(S)或(R)2-(吡啶-2-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)吡啶-3-基)哌啶-3-基)-1,3,4-噻二唑-2-基)乙酰胺;
3. 2-(吡啶-3-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)吡啶-3-基)哌啶-3-基)-1,3,4-噻二唑-2-基)乙酰胺;
3A.(R)或(S)2-(吡啶-3-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)吡啶-3-基)哌啶-3-基)-1,3,4-噻二唑-2-基)乙酰胺;
3B.(S)或(R)2-(吡啶-3-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)吡啶-3-基)哌啶-3-基)-1,3,4-噻二唑-2-基)乙酰胺;
4. 2-(吡啶-3-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)吡啶-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺;
5. 2-(3-氰基苯基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)吡啶-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺;
6. 2-(吡啶-2-基)-N-(5-(4-(5-(2-(3-(三氟甲氧基)苯基)乙酰胺基)-1,3,4-噻二唑-2-基)哌啶-1-基)吡啶-2-基)乙酰胺;
7. 2-(吡啶-2-基)-N-(5-(3-(5-(2-(3-(三氟甲氧基)苯基)乙酰胺基)-1,3,4-噻二唑-2-基)哌啶-1-基)吡啶-2-基)乙酰胺;
8. 2-(吡啶-2-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺;
9. 2-(吡啶-2-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-3-基)-1,3,4-噻二唑-2-基)乙酰胺;
10. 2-(吡啶-3-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺;
11. 2-(3-(甲基磺酰胺基)苯基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺;
12. 2-(2-氯苯基)-N-(6-(4-(5-(2-(吡啶-2-基)乙酰胺基)-1,3,4-噻二唑-2-基)哌啶-1-基)哒嗪-3-基)乙酰胺;
13. 2-(2-氯苯基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-3-基)-1,3,4-噻二唑-2-基)乙酰胺;
14. 2-(2-氟苯基)-N-(6-(4-(5-(2-(吡啶-2-基)乙酰胺基)-1,3,4-噻二唑-2-基)哌啶-1-基)哒嗪-3-基)乙酰胺;
15. 2-(吡嗪-2-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺;
16. 2-(吡啶-2-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺二盐酸盐;
17. 2-(吡啶-2-基)-N-(6-(4-(5-(2-(3-(三氟甲氧基)苯基)乙酰胺基)-1,3,4-噻二唑-2-基)哌啶-1-基)哒嗪-3-基)乙酰胺;
18. 2-(吡啶-3-基)-N-(6-(4-(5-(2-(3-(三氟甲氧基)苯基)乙酰胺基)-1,3,4-噻二唑-2-基)哌啶-1-基)哒嗪-3-基)乙酰胺;
19. 2-(吡啶-3-基)-N-(6-(4-(5-(2-(2,3,6-三氟苯基)乙酰胺基)-1,3,4-噻二唑-2-基)哌啶-1-基)哒嗪-3-基)乙酰胺;
20. 2-(吡啶-2-基)-N-(6-(4-(5-(2-(2,3,6-三氟苯基)乙酰胺基)-1,3,4-噻二唑-2-基)哌啶-1-基)哒嗪-3-基)乙酰胺;
21. 2-(2,3-二氟苯基)-N-(5-(1-(6-(2-(吡啶-2-基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺;
22. 2-(3,4-二氟苯基)-N-(5-(1-(6-(2-(吡啶-2-基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺;
23. 2-(2-氟苯基)-N-(5-(1-(6-(2-(吡啶-2-基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺;
24. 2-(3-氟苯基)-N-(5-(1-(6-(2-(吡啶-2-基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺;
25. 2-(4-氟苯基)-N-(5-(1-(6-(2-(吡啶-2-基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺;
26. 2-(2-甲氧基苯基)-N-(5-(1-(6-(2-(吡啶-2-基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺;
27. 2-(2-氯苯基)-N-(5-(1-(6-(2-(吡啶-2-基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺;
28. 2-(5-氯-2-(三氟甲基)苯基)-N-(5-(1-(6-(2-(吡啶-2-基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺;
29. 2-(4-氯苯基)-N-(5-(1-(6-(2-(吡啶-2-基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺;
30. 2-(喹啉-6-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺;
31. 2-邻甲苯基-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺;
32.N-(6-(4-(5-(2-(1H-吲哚-3-基)乙酰胺基)-1,3,4-噻二唑-2-基)哌啶-1-基)哒嗪-3-基)-2-(3-(三氟甲氧基)苯基)乙酰胺;
33. 2-(2-氟苯基)-N-(6-(4-(5-(2-(吡嗪-2-基)乙酰胺基)-1,3,4-噻二唑-2-基)哌啶-1-基)哒嗪-3-基)乙酰胺;
34. 2-(3-(氮杂环丁烷-1-基)苯基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺;
35. 2-(3-氯苯基)-N-(5-(1-(6-(2-(吡啶-2-基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺;
36. 3-羟基-2-苯基-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)丙酰胺;
37.(R)-2-羟基-2-苯基-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺;
38. 2-(3-(3-氟氮杂环丁烷-1-基)苯基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺;
39. 2-(吡啶-2-基)-N-(5-((1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-4-基)甲基)-1,3,4-噻二唑-2-基)乙酰胺;
或其药学上可接受的盐。
表1
本发明的又另一实施方案是一种用于抑制患者体内的谷氨酰胺酶的方法,该方法是通过向患者施用有效量的至少一种本发明的化合物(例如,如以上所定义的式(I)、(II)或(III)的化合物)实现。
本发明的又另一实施方案是一种用于治疗炎症性疾病、自身免疫性疾病或增生性疾病(例如,经由抑制谷氨酰胺酶)的方法,该方法是通过向需要此治疗的患者施用有效量的至少一种本发明的化合物实现。在一个实施方案中,本发明的化合物抑制谷氨酰胺酶(即,施用有效量的化合物来抑制谷氨酰胺酶)。
本发明的又另一实施方案是一种治疗炎症性疾病、自身免疫性疾病或增生性疾病(例如,经由抑制谷氨酰胺酶)的方法,该方法是通过向需要此治疗的患者施用有效量的至少一种本发明的化合物,以及(同时或依序)至少另一种抗炎剂、免疫调节剂或抗癌剂来实现。在一个实施方案中,本发明的化合物抑制谷氨酰胺酶。
更确切地说,可以施用式(I)至(III)的化合物及其药学上可接受的酯或盐以治疗、预防和/或改善与谷氨酰胺相关的疾病或病症,特别是改善由谷氨酰胺介导的疾病或病症,包括但不限于,炎症性疾病或病症、自身免疫性疾病或病症,以及癌症和其它增生性疾病或病症。
本发明的化合物可用于治疗多种癌症,包括但不限于:
·癌症,包括膀胱癌、乳癌、结肠癌、肾癌、肝癌、肺癌(包括小细胞肺癌)、食道癌、胆囊癌、卵巢癌、胰脏癌、胃癌、子宫颈癌、甲状腺癌、前列腺癌,及皮肤癌,包括鳞状细胞癌;
·淋巴系血液系统肿瘤,包括白血病、急性淋巴细胞性白血病、急性淋巴母细胞性白血病、B细胞淋巴瘤、T细胞淋巴瘤、霍奇金氏淋巴瘤(Hodgkin′s lymphoma)、非霍奇金氏淋巴瘤、毛细胞淋巴瘤及伯基特氏淋巴瘤(Burkett′s lymphoma);
·髓系血液系统肿瘤,包括急性和慢性髓性白血病、骨髓增生异常综合症及早幼粒细胞白血病;
·间叶细胞起源的肿瘤,包括纤维肉瘤和横纹肌肉瘤;
·中枢神经系统和外周神经系统的肿瘤,包括星形细胞瘤、成神经细胞瘤、神经胶质瘤及许旺氏细胞瘤(schwannoma);及
·其它肿瘤,包括黑色素瘤、精原细胞瘤、畸胎瘤、骨肉瘤、着色性干皮病、角化棘皮瘤、甲状腺滤泡癌及卡波西氏肉瘤(Kaposi′s sarcoma)。
由于谷氨酰胺酶和谷氨酰胺在调控细胞增殖方面的关键作用,本发明的谷氨酰胺酶抑制剂可以用作可逆细胞抑制剂,并因此可用于治疗以异常细胞增殖为特征的任何疾病过程,例如良性前列腺肥大、家族性腺瘤性息肉病、神经纤维瘤病、动脉粥样硬化、肺纤维化、关节病(例如关节炎)、银屑病、肾小球肾炎、血管成形术或血管手术之后再狭窄、增生性瘢痕形成、炎症性肠病、移植排斥反应、内毒素休克及真菌感染。
本发明的化合物作为细胞凋亡调节剂可用于治疗癌症(包括但不限于,上文提到的那些类型)、病毒感染(包括但不限于,疱疹病毒、痘病毒、爱泼斯坦-巴尔病毒(Epstein-Barr virus)、辛德毕斯病毒(Sindbis virus)及腺病毒)、防止感染HIV的个体发展AIDS、自身免疫性疾病(包括但不限于,全身性红斑狼疮、自身免疫介导的肾小球肾炎、类风湿性关节炎、银屑病、炎症性肠病及自身免疫性糖尿病)、神经退化性病症(包括但不限于,阿尔茨海默氏病(Alzheimer′s disease)、AIDS相关痴呆、帕金森氏病(Parkinson′s disease)、肌萎缩侧索硬化、色素性视网膜炎、脊髓性肌萎缩及小脑退化)、骨髓增生异常综合症、再生障碍性贫血、与心肌梗塞相关的缺血性损伤、中风及再灌注损伤、心律不齐、动脉粥样硬化、毒素诱发或酒精相关性肝病、血液病(包括但不限于,慢性贫血和再生障碍性贫血)、肌肉骨骼系统退化性疾病(包括但不限于,骨质疏松症和关节炎)、阿司匹林敏感性鼻窦炎、囊肿性纤维化、多发性硬化、肾病及癌症疼痛。
本发明的化合物可以调节细胞RNA和DNA合成水平。因此,这些药剂可用于治疗病毒感染(包括但不限于,HIV、人乳头瘤病毒、疱疹病毒、痘病毒、爱泼斯坦-巴尔病毒、辛德毕斯病毒及腺病毒)。
本发明的化合物可用于癌症的化学预防。化学预防定义为通过阻止正在起始的突变事件或通过阻止已经受到损害的癌前期细胞的进展来抑制侵袭性癌症的发展,或抑制肿瘤复发。本文所描述的化合物还可用于抑制肿瘤血管生成和转移。本发明的一个实施方案是一种抑制有需要患者的肿瘤血管生成或转移的方法,该方法是通过施用有效量的一种或多种本发明的化合物实现。
本发明的另一实施方案是一种治疗免疫系统相关性疾病(例如,自身免疫性疾病)、涉及炎症的疾病或病症(例如,哮喘、慢性阻塞性肺病、类风湿性关节炎、炎症性肠病、肾小球肾炎、神经炎症性疾病、多发性硬化、葡萄膜炎及免疫系统病症)、癌症或其它增生性疾病、肝脏疾病或病症,或肾脏疾病或病症的方法。该方法包括施用有效量的一种或多种本发明的化合物。
免疫病症的实例包括但不限于,银屑病、类风湿性关节炎、血管炎、炎症性肠病、皮炎、骨关节炎、哮喘、炎症性肌病、过敏性疾病(例如过敏性鼻炎)、阴道炎、间质性膀胱炎、硬皮病、骨质疏松症、湿疹、同种异体或异种移植(器官、骨髓、干细胞及其它细胞和组织)移植物排斥反应、移植物抗宿主疾病、红斑狼疮、炎症性疾病、I型糖尿病、肺纤维化、皮肌炎、斯耶格伦综合症(Sjogren′s syndrome)、甲状腺炎(例如,桥本氏(Hashimoto′s)甲状腺炎和自身免疫性甲状腺炎)、重症肌无力、自身免疫性溶血性贫血、多发性硬化、囊肿性纤维化、慢性复发性肝炎、原发性胆汁性肝硬化、过敏性结膜炎及特应性皮炎。
在一个实施方案中,本文所描述的化合物被用作免疫抑制剂,用以预防移植物排斥反应、同种异体或异种移植排斥反应(器官、骨髓、干细胞、其它细胞及组织)及移植物抗宿主疾病。在其它实施方案中,移植物排斥反应是由组织或器官移植引起。在其它实施方案中,移植物抗宿主疾病由骨髓或干细胞移植引起。一个实施方案是一种预防或降低移植物排斥反应、同种异体或异种移植排斥反应(器官、骨髓、干细胞、其它细胞及组织)或移植物抗宿主疾病的风险的方法,该方法是通过施用有效量的一种或多种本发明的化合物实现。
本发明的化合物还可以与以下组合使用(一起或依序施用):已知的抗癌治疗,如放射疗法;或细胞抑制剂、细胞毒性剂或抗癌剂,如但不限于,DNA相互作用剂,如顺铂(cisplatin)或多柔比星(doxorubicin);拓扑异构酶II抑制剂;如依托泊苷(etoposide);拓扑异构酶I抑制剂,如CPT-11或拓扑替康(topotecan);微管蛋白相互作用剂,如紫杉醇(paclitaxel)、多西他赛(docetaxel),或天然存在或合成的埃博霉素(例如伊沙匹隆(ixabepilone));激素剂、如他莫昔芬(tamoxifen);胸苷酸合成酶抑制剂,如5-氟尿嘧啶;及抗代谢物,如甲氨蝶呤(methotrexate)、其它酪氨酸激酶抑制剂,如Iressa和OSI-774;血管生成抑制剂;EGF抑制剂;VEGF抑制剂;CDK抑制剂;SRC抑制剂;c-Kit抑制剂;Her1/2抑制剂,及针对生长因子受体的单克隆抗体,如爱必妥(erbitux)(EGF)和赫赛汀(herceptin)(Her2),及其它蛋白激酶调节剂。
本发明的化合物还可以与一种或多种类固醇抗炎药、非类固醇抗炎药(NSAID)或免疫选择性抗炎衍生物(ImSAID)组合使用(一起或依序施用)。
本发明另外提供一种药物组合物,该药物组合物包含一种或多种本发明的化合物(如式(I)、(II)或(III)的化合物)与药学上可接受的载剂。该药物组合物可以另外包含一种或多种以上标识的活性成分,如其它类固醇抗炎药、非类固醇抗炎药(NSAID)、免疫选择性抗炎衍生物(ImSAID)或抗癌剂。
在一个实施方案中,所述药物组合物包括治疗有效量的一种或多种式(I)、(II)或(III)的化合物。
又另一实施方案是一种治疗有需要患者的自身免疫性病症的方法,该方法是通过施用治疗有效量的本发明化合物实现。例如,本发明的化合物有效治疗哮喘、慢性阻塞性肺病(COPD)、类风湿性关节炎、银屑病、狼疮及实验性自身免疫性脑脊髓炎(EAE)。
又另一实施方案是一种治疗有需要患者的过敏性鼻炎的方法,该方法是通过施用治疗有效量的本发明化合物实现。
又另一实施方案是一种治疗有需要患者的癌症的方法,该方法是通过施用治疗有效量的本发明化合物实现。例如,本发明的化合物有效治疗淋巴系血液系统肿瘤,白血病、急性淋巴细胞性白血病、急性淋巴母细胞性白血病、B细胞淋巴瘤、T细胞淋巴瘤、霍奇金氏淋巴瘤、非霍奇金氏淋巴瘤、毛细胞淋巴瘤及伯基特氏淋巴瘤;髓系血液系统肿瘤,急性髓性白血病、慢性髓性白血病、骨髓增生异常综合症及早幼粒细胞白血病。本发明的化合物还有效治疗膀胱癌、乳癌、结肠癌、肾癌、肝癌、肺癌、小细胞肺癌、食道癌、胆囊癌、卵巢癌、胰脏癌、胃癌、子宫颈癌、甲状腺癌、前列腺癌、皮肤癌、鳞状细胞癌;间叶细胞起源的肿瘤,纤维肉瘤、横纹肌肉瘤;中枢神经系统和外周神经系统的肿瘤,星形细胞瘤、成神经细胞瘤、神经胶质瘤、许旺氏细胞瘤;黑色素瘤、精原细胞瘤、畸胎瘤、骨肉瘤、着色性干皮病、角化棘皮瘤、甲状腺滤泡癌及卡波西氏肉瘤。
又另一实施方案是一种治疗有需要患者的白血病的方法,该方法是通过施用治疗有效量的本发明化合物实现。例如,本发明的化合物有效治疗慢性淋巴细胞性白血病(CLL)、非霍奇金氏淋巴瘤(NHL)、急性髓性白血病(AML)、急性淋巴母细胞性白血病(ALL)、多发性骨髓瘤(MM)、小淋巴细胞性淋巴瘤(SLL)及惰性非霍奇金氏淋巴瘤(I-NHL)。
发明详述
除非另外指明,否则如本文所使用,以下定义应适用。另外,本文所定义的许多基团可以任选被取代。定义中的取代基列举是示例性的并且不应解释为限制在本说明书别处所定义的取代基。
除非另外说明,否则术语“烷基”是指不合不饱和度并且具有一至八个碳原子的仅由碳原子和氢原子组成的直链或分支链烃链基团,该基团经由单键附接到分子其余部分,例如甲基、乙基、正丙基、1-甲基乙基(异丙基)、正丁基、正戊基及1,1-二甲基乙基(叔丁基)。术语“C1-6烷基”是指具有最多6个碳原子的如以上所定义的烷基。术语”G1-3烷基”是指具有最多3个碳原子的如以上所定义的烷基。在适当情况下,术语“烷基”是指呈二价的如以上所提到的烃链基团。
除非另外说明,否则术语“烯基”是指含有一个或多个碳-碳双键并且具有约2至约10个碳原子的直链或分支链脂肪族烃基,例如乙烯基、1-丙烯基、2-丙烯基(烯丙基)、异丙烯基、2-甲基-1-丙烯基、1-丁烯基及2-丁烯基。术语“C2-6烯基”是指具有最多6个碳原子的如以上所定义的烯基。在适当情况下,术语“烯基”是指呈二价的如以上所提到的烃基。
除非另外说明,否则术语“炔基”是指具有至少一个碳-碳三键,并且碳原子数在2到12个范围内的直链或分支链烃基(目前优选碳原子数在2到10个范围内的基团),例如乙炔基、丙炔基及丁炔基。术语“C2-6炔基”是指具有最多6个碳原子的如以上所定义的炔基。在适当情况下,术语“炔基”是指呈二价的如以上所提到的烃基。
除非另作说明,否则术语“烷氧基”表示经由氧键附接到分子其余部分的如以上所定义的烷基、环烷基或环烷基烷基。术语“取代的烷氧基”是指烷基成分被取代的烷氧基(即,-O-(取代的烷基))。例如,“烷氧基”是指基团-O-烷基,包括通过氧原子附接到母体结构的具有1至8个碳原子的直链、分支链、环状结构及其组合。实例包括甲氧基、乙氧基、丙氧基、异丙氧基、环丙基氧基及环己基氧基。在适当情况下,术语“烷氧基”是指呈二价的如以上所提到的基团。
除非另作说明,否则术语“环烷基”表示具有约3至12个碳原子的非芳香族单环或多环系统,如环丙基、环丁基、环戊基及环己基。多环的环烷基的实例包括全氢萘基、金刚烷基和降冰片基、桥连环状基团及螺双环基团,如螺(4,4)壬-2-基。术语“C3-6环烷基”是指具有最多6个碳原子的如以上所定义的环烷基。
除非另作说明,否则术语“环烷基烷基”是指直接附接到烷基,接着在该烷基的任一碳处附接到主结构的碳原子数在约3至8个范围内的环状含环基团,如环丙基甲基、环丁基乙基及环戊基乙基。
除非另作说明,否则术语“环烯基”是指碳原子数在约3至8个范围内并且具有至少一个碳-碳双键的环状含环基团,如环丙烯基、环丁烯基及环戊烯基。术语“环烯基烷基”是指直接附接到烷基,接着在该烷基的任一碳处附接到主结构的环烯基。
除非另作说明,否则术语“芳基”是指碳原子数在6到20个范围内的芳香族基团,如苯基、萘基、四氢萘基、茚满基及联苯。
除非另作说明,否则术语“芳基烷基”是指直接键接到如以上所定义的烷基的如以上所定义的芳基,例如-CH2C6H5和-C2H5C6H5。
除非另作说明,否则术语“杂环”是指由碳原子和至少一个选自氮、磷、氧及硫的杂原子组成的非芳香族3至15元环基。出于本发明的目的,杂环基团可以是单环、双环、三环或四环系统,包括稠环系统、桥连环系统或螺环系统,并且杂环基团中的氮、磷、碳、氧或硫原子可任选被氧化成各种氧化态。此外,氮原子可任选被季铵化。杂环基团可以在任一杂原子或碳原子处附接到主结构。
除非另作说明,否则术语“杂环基”是指如以上所定义的杂环基团。杂环基环基团可以在任一杂原子或碳原子处附接到主结构。在适当情况下,术语“杂环基”是指呈二价的如以上所提到的烃链基团。
除非另作说明,否则术语“杂环基烷基”是指直接键接到烷基的如以上所定义的杂环基团。杂环基烷基可以在烷基中的任一碳原子处附接到主结构。此类杂环基烷基的实例包括但不限于,二氧戊环基、噻吩基[1,3]二噻烷基、十氢异喹啉基、咪唑啉基、咪唑烷基、异噻唑烷基、异噁唑烷基、吗啉基、八氢吲哚基、八氢异吲哚基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、噁唑烷基、哌啶基、哌嗪基、4-哌啶酮基、吡咯烷基、吡唑烷基、奎宁环基、噻唑烷基、四氢呋喃基、三噻烷基、四氢吡喃基、硫代吗啉基、噻吗啉基、1-氧代-硫代吗啉基及1,1-二氧代-硫代吗啉基。
除非另作说明,否则术语“杂芳基”是指具有一个或多个选自N、O及S的杂原子作为环原子的任选取代的5至14元芳香族环。杂芳基可以是单环、双环或三环系统。此类“杂环”或“杂芳基”的实例包括但不限于,噁唑基、噻唑基、咪唑基、吡咯基、呋喃基、吡啶基、嘧啶基、吡嗪基、苯并呋喃基、吲哚基、苯并噻唑基、苯并噁唑基、咔唑基、喹啉基、异喹啉基、氮杂环丁烷基、吖啶基、苯并间二氧杂环戊烯基、苯并二噁烷基、苯并呋喃基、咔唑基、噌啉基、二氧戊环基、吲嗪基、萘啶基、全氢氮杂基、吩嗪基、吩噻嗪基、吩噁嗪基、酞嗪基、蝶啶基、嘌呤基、喹唑啉基、喹喔啉基、四唑基、四氢异喹啉基、哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、2-氧代氮杂基、氮杂基、4-哌啶酮基、吡咯烷基、哒嗪基、噁唑啉基、噁唑烷基、三唑基、茚满基、异噁唑基、异噁唑烷基、吗啉基、噻唑啉基、噻唑烷基、异噻唑基、奎宁环基、异噻唑烷基、异吲哚基、吲哚啉基、异吲哚啉基、八氢吲哚基、八氢异吲哚基、十氢异喹啉基、苯并咪唑基、噻二唑基、苯并吡喃基、四氢呋喃基、四氢吡喃基、噻吩基、苯并噻吩基、硫代吗啉基、硫代吗啉基亚砜、硫代吗啉基砜、二氧磷杂环戊烷、噁二唑基、色满基及异色满基。杂芳基环基团可以在任一杂原子或碳原子处附接到主结构。术语“取代的杂芳基”还包括被一个或多个氧(-O-)取代基取代的环系统,如吡啶基N-氧化物。
除非另作说明,否则术语“杂芳基烷基”是指直接键接到烷基的如以上所定义的杂芳基环基团。杂芳基烷基可以在烷基的任一碳原子处附接到主结构。
术语“环状环”是指含有3至10个碳原子的环状环。
除非另作说明,否则术语“取代的”是指被以下取代基中的任一个或任何组合取代,这些取代基可以相同或不同并且独立地选自氢、羟基、卤素、羧基、氰基、硝基、氧代(=O)、硫代(=S)、取代或未取代的烷基、取代或未取代的烷氧基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的芳基、取代或未取代的芳基烷基、取代或未取代的环烷基、取代或未取代的环烷基烷基、取代或未取代的环烯基、取代或未取代的环烯基烷基、取代或未取代的杂芳基、取代或未取代的杂芳基烷基、取代或未取代的杂环、取代的杂环基烷基环、取代或未取代的胍、-COORx、-C(O)Rx、-C(S)Rx、-C(O)NRxRy、-C(O)ONRxRy、-NRyRz、-NRxCONRyRz、-N(Rx)SORy、-N(Rx)SO2Ry、=N-N(Rx)Ry)、-NRxC(O)ORy、-NRxRy、-NRxC(O)Ry-、-NRxC(S)Ry-NRxC(S)NRyRz、-SONRxRy-、-SO2NRxRy-、-ORx、-ORxC(O)NRyRz、-ORxC(O)ORy-、-OC(O)Rx、-OC(O)NRxRy、-RxNRyC(O)Rz、-RxORy、-RxC(O)ORy、-RxC(O)NRyRz、-RxC(O)Rx、-RxOC(O)Ry、-SRx、-SORx、-SO2Rx及-ONO2,其中以上每一基团中的Rx、Ry及Rz可以是氢、取代或未取代的烷基、取代或未取代的烷氧基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的芳基、取代或未取代的芳基烷基、取代或未取代的环烷基、取代或未取代的环烷基烷基、取代或未取代的环烯基、取代或未取代的氨基、取代或未取代的杂芳基、取代或未取代的杂芳基烷基、取代或未取代的杂环,或取代的杂环基烷基环,或Rx、Ry及Rz中的任意两个可以连接形成取代或未取代的饱和或不饱和的3至10元环,该环可以任选包括相同或不同的杂原子并且杂原子选自O、NRx(例如Rx可以是氢或C1-6烷基)或S。本发明所预想的取代或取代基组合优选是使得形成稳定或化学上可行的化合物的那些。如本文所使用,术语稳定是指化合物或结构在经历允许其产生、检测以及优选其回收、纯化并且掺入药物组合物中的条件时基本上不改变。以上提到的“取代的”基团中的取代基不能进一步被取代。例如,当“取代的烷基”上的取代基是“取代的芳基”时,“取代的芳基”上的取代基不能是“取代的烯基”。
术语“卤代”、“卤化物”或替代地,“卤素”意思指氟、氯、溴或碘。术语“卤代烷基”、“卤代烯基”、“卤代炔基”及“卤代烷氧基”包括被一个或多个卤代基或其组合取代的烷基、烯基、炔基及烷氧基结构。例如,术语“氟烷基”和“氟烷氧基”分别包括卤代基是氟的卤代烷基和卤代烷氧基。
术语“保护基”或“PG”是指用于阻止或保护特定官能团的取代基。化合物上的其它官能团可以保持反应性。例如,“氨基保护基”是附接到氨基以阻止或保护化合物中的氨基官能团的取代基。适合氨基保护基包括但不限于,乙酰基、三氟乙酰基、叔丁氧基羰基(BOC)、苯甲氧基羰基(CBz)及9-芴基甲氧羰基(Fmoc)。类似地,“羟基保护基”是指阻止或保护羟基官能团的羟基取代基。适合羟基保护基包括但不限于,乙酰基和硅烷基。“羧基保护基”是指阻止或保护羧基官能团的羧基取代基。适合羧基保护基包括但不限于,-CH2CH2SO2Ph、氰基乙基、2-(三甲基硅烷基)乙基、2-(三甲基硅烷基)乙氧基甲基、2-(对甲苯磺酰基)乙基、2-(对硝基苯基亚磺酰基)乙基、2-(二苯基膦基)-乙基及硝基乙基。有关保护基及其用途的大体说明,参见T.W.Greene,Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991。
本文所描述的某些化合物含有一个或多个不对称中心,并因此可以产生对映异构体、非对映异构体,及可以关于绝对立体化学定义的其它立体异构形式,如(R)-或(S)-。本发明的化学实体、药物组合物及方法意指包括所有这些可能的异构体,包括外消旋混合物、光学纯形式及中间体混合物。中间体混合物的非限制性实例包括10∶90、13∶87、17∶83、20∶80或22∶78比率的异构体混合物。光学活性(R)-异构体和(S)-异构体可以使用手性合成子或手性试剂制备,或使用常规技术拆分。当本文所描述的化合物含有烯系双键或其它几何不对称中心时,并且除非另作说明,否则预期这些化合物包括E和Z几何异构体。
术语“互变异构体”是指以处于平衡的异构体形式相对易于相互转化为特征的化合物。这些异构体意图涵盖在本发明中。“互变异构体”是通过互变异构而相互转化的结构不同的异构体。“互变异构”是一种异构化形式并且包括质子转移或质子移位互变异构,此被视为酸-碱化学的子集。“质子转移互变异构”或“质子移位互变异构”涉及伴随键次序改变的质子迁移,通常是单键与相邻双键的互变。在可能发生互变异构的情况下(例如,在溶液中),可以达到互变异构体的化学平衡。互变异构的一个实例是酮-烯醇互变异构。酮-烯醇互变异构的一个具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮互变异构体的相互转化。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-酚与吡啶-4(1H)-酮互变异构体的相互转化。
“离去基团或原子”是在反应条件下会从起始物质裂解,由此促进在指定位点处的反应的任何基团或原子。除非另作说明,否则此类基团的适合实例是卤素原子和甲磺酰氧基、对硝基苯磺酰氧基及甲苯磺酰氧基。
术语“前药”是指这样一种化合物,该化合物是一种化合物的无活性前驱物,在体内通过正常代谢过程而转化成其活性形式。前药设计大体上论述于Hardma等人(编),Goodman and Gilman′s The Pharmacological Basis of Therapeutics,第9版,第11-16页(1996)中。完整论述提供于Higuchi,T.等人,Pro-drugs as Novel Delivery Systems,第14卷,ASCD Symposium Series;及Roche(编),Bioreversible Carriers in DrugDesign,AmericanPharmaceutical Association and Pergamon Press(1987)中。例如,前药可以通过例如酯或酰胺键的水解,由此在所得产物上引入官能团或使所得产物上的官能团暴露而转化成药理学活性形式。前药可以被设计成与内源化合物反应以形成水溶性缀合物,该缀合物进一步增大化合物的药理学特性,例如增加循环半衰期。或者,前药可以被设计成在官能团上用例如葡糖醛酸、硫酸酯、谷胱甘肽、氨基酸或乙酸酯进行共价修饰。所得缀合物可以失活并且排泄于尿液中,或具有比母体化合物更强的效力。高分子量缀合物还可以排泄于胆汁中,经历酶促裂解,并释放回循环中,由此有效地增加最初施用的化合物的生物半衰期。
术语“酯”是指通过酸与醇反应并消除水而形成的化合物。酯可以由通式RCOOR′表示。
这些前药和酯意图在本发明的范围内。
另外,本发明还包括仅在一个或多个富含同位素的原子存在下而不同的化合物,例如氢被氘或氚置换,或碳被富含13C或14C的碳置换。
本发明的化合物还可以在构成这些化合物的一个或多个原子处含有非天然比例的原子同位素。例如,这些化合物可以用放射性同位素放射性标记,如氚(3H)、碘-125(125I)或碳-14(14C)。本发明化合物的所有同位素变化(无论是否是放射性的)都涵盖在本发明的范围内。
形成本发明的一部分的药学上可接受的盐包括衍生自以下各物的盐:无机碱,如Li、Na、K、Ca、Mg、Fe、Cu、Zn及Mn;有机碱,如N,N′-二乙酰基乙-二胺、葡糖胺、三乙胺、胆碱、氢氧化物、二环己胺、二甲双胍、苯甲胺、三烷基胺及硫胺;手性碱,如烷基苯胺、甘氨醇及苯基甘氨醇;天然氨基酸,如甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、正亮氨酸、酪氨酸、胱氨酸、半胱氨酸、甲硫氨酸、脯氨酸、羟基脯氨酸、组氨酸、鸟氨酸、赖氨酸、精氨酸及丝氨酸;本发明化合物与烷基卤化物、烷基硫酸酯(如MeI和(Me)2SO4)形成的季铵盐;非天然氨基酸,如D-异构体或取代的氨基酸;胍;及取代的胍,其中取代基选自硝基、氨基、烷基、烯基、炔基、铵或取代的铵盐,及铝盐。适当时,盐可以包括酸加成盐,这些盐是硫酸盐、硝酸盐、磷酸盐、高氯酸盐、硼酸盐、氢卤化物(例如盐酸盐)、乙酸盐、酒石酸盐、顺丁烯二酸盐、柠檬酸盐、反丁烯二酸盐、琥珀酸盐、双羟萘酸盐、甲烷磺酸盐、苯甲酸盐、水杨酸盐、苯磺酸盐、抗坏血酸盐、甘油磷酸盐及酮戊二酸盐。
当本文中使用物理特性(如分子量)或化学特性(如化学式)的范围时,意图包括其中的范围和具体实施方案的所有组合和子组合。当提到一个数字或数字范围时,术语“约”意思指,所提到数字或数字范围是在实验变化范围内(或在统计学实验误差范围内)的近似值,并因此该数字或数字范围可以在例如所述数字或数字范围的1%与15%间变化。术语“包含”(及相关术语,如“包含”、“具有”或“包括”)包括例如本文所描述的任何物质组成、组合物、方法或工艺的实施方案“由所述特征组成”或“基本上由所述特征组成”的那些实施方案。
以下缩写和术语具有通篇所指示的含义:AIDS=获得性免疫缺陷综合症;HIV=人免疫缺陷病毒;本文所使用的缩写具有其在化学和生物领域内的常规含义。
术语“细胞增殖”是指细胞数量因分裂而改变的现象。该术语也涵盖细胞形态符合增殖信号而改变(例如,大小增加)的细胞生长。
如本文所使用,术语“共施用”、“与...组合施用”及其语法等效表示都涵盖向动物施用两种或更多种药剂,以使药剂和/或其代谢物同时存在于动物体内。共施用包括同时施用独立组合物、在不同时间施用独立组合物或施用存在两种药剂的组合物。
术语“有效量”或“治疗有效量”是指足以实现预定应用,包括但不限于,如以下所定义的疾病治疗的本文所描述的化合物的量。治疗有效量可以取决于预定应用(体外或体内),或所治疗的受试者和疾病状况,例如受试者的体重和年龄、疾病状况的严重程度、施用方式等而变化,这可以由本领域普通技术人员容易地确定。该术语也适用于在靶细胞中诱导特定反应,例如减少血小板粘附和/或细胞迁移的剂量。具体剂量将取决于所选特定化合物、打算遵循的给药方案、是否与其它化合物组合施用、施用时程、待施用的组织及载运的物理递送系统而变化。在一个实施方案中,施用的化合物的量的范围是约0.1mg到5g、约1mg到2.0g、约100mg到1.5g、约200mg到1.5g、约400mg到1.5g及约400mg到1.0g。
如本文所使用,“治疗”或“改善”可互换使用。这些术语是指用于获得有益或所期望的结果,包括但不限于,治疗益处和/或预防益处的方法。治疗益处意思指所治疗的潜在病症的根除或改善。另外,治疗益处是通过根除或改善与潜在病症相关的一种或多种生理学症状,由此在患者中观察到改良来实现,不过该患者可能仍患有该潜在病症。对于预防益处,可以将组合物施用给有发生特定疾病的风险的患者,或报告一种疾病之一种或多种生理学症状的患者,即使该疾病可能尚未得到诊断。
如本文所使用的术语“治疗作用”涵盖如以上所描述的治疗益处和/或预防益处。预防作用包括延迟或消除疾病或病状的出现;延迟或消除疾病或病状的症状的发作;减慢、停止或逆转疾病或病状的进展;或其任何组合。
术语“受试者”或“患者”是指动物,如哺乳动物,例如人类。本文所描述的方法可用于人类治疗和兽医应用(例如,狗、猫、牛、绵羊、猪、马、山羊、鸡、火鸡、鸭及鹅)。
在一些实施方案中,患者是哺乳动物,而在一些实施方案中,患者是人类。
“放射疗法”意思指使用从业人员已知的常规方法和组合物使患者曝露于放射发射器,如发射α-粒子的放射性核素(例如锕和钍放射性核素)、低线性能量传递(LET)放射发射器(即,β发射器)、变换电子发射器(例如锶-89和钐-153-EDTMP)或高能放射,包括但不限于,x射线、γ射线及中子。
术语“药学上可接受的赋形剂”包括但不限于,任何和所有溶剂、分散介质、包衣、抗细菌剂和抗真菌剂、等渗剂和吸收延迟剂、一种或多种适合的稀释剂、填充剂、盐、崩解剂、粘合剂、润滑剂、助流剂、润湿剂、控制释放基质、着色剂/调味剂、载剂、缓冲剂、稳定剂、增溶剂及其组合。除非任何常规介质或试剂与活性成分不相容,否则涵盖其在本发明的治疗性组合物中的应用。还可以在这些组合物中并入补充性活性成分。
如本文所使用,“炎性反应”是以发红、发热、肿胀及疼痛(即,炎症)为特征并且典型地涉及组织损伤或损害。炎性反应通常是由组织损伤或损害引起的局部保护性反应,用于破坏、减弱有害因素或隔开(隔离)有害因素与受损组织。炎性反应与白细胞流入和/或白细胞(例如嗜中性粒细胞)趋化性明显相关。炎性反应可以由感染致病生物体和病毒、如外伤或者在心肌梗塞或中风后的再灌注等非感染性途径、针对外来抗原的免疫反应及自身免疫性疾病引起。适于用根据本发明的方法和化合物治疗的炎性反应涵盖与特异性防御系统的反应有关的情形以及与非特异性防御系统的反应有关的情形。
本发明的治疗方法包括用于改善与炎性细胞活化有关的病状的方法。“炎性细胞活化”是指增殖性细胞反应的刺激物(包括但不限于,细胞因子、抗原或自体抗体)的诱导、可溶性介体(包括但不限于,细胞因子、氧自由基、酶、前列腺素类或血管活性胺)的产生,或者炎性细胞(包括但不限于,单核细胞、巨噬细胞、T淋巴细胞、B淋巴细胞、粒细胞(多形核白细胞,包括嗜中性粒细胞、嗜碱性粒细胞及嗜酸性粒细胞)、肥大细胞、树突状细胞、郎格罕细胞(Langerhans cell)及内皮细胞)中的新介体或增加数量的介体(包括但不限于,主要组织相容性抗原或细胞粘附分子)的细胞表面表达。本领域技术人员应理解,在这些细胞中这些表型中的一种或组合的活化可以促进炎性病状的起始、持续或加剧。
如本文所使用,“自身免疫性疾病”是指组织损伤与针对身体自身成分的体液反应或细胞介导的反应有关的任何一组病症。如本文所使用,“移植物排斥反应”(或“移植排斥反应”)是指针对移植的组织(包括器官或细胞(例如骨髓))的任何免疫反应(以移植的组织和周围组织的功能丧失、疼痛、肿胀、白细胞增多及血小板减少为特征)。如本文所使用,“过敏性疾病”是指由过敏引起的任何症状、组织损害或组织功能丧失。如本文所使用,“关节炎疾病”是指以多种病原引起的关节炎性病变为特征的任何疾病。如本文所使用,“皮炎”是指以多种病原引起的皮肤炎症为特征的一大类皮肤疾病中的任一种。
本发明的方法可以在体内或离体用于细胞群。“体内”意思指在活个体内,以及动物或人类体内,或在受试者体内。在此情形下,本发明的方法可以治疗性或预防性用于个体。“离体”或“体外”意思指在活个体外。离体细胞群的实例包括体外细胞培养物及生物样品,包括但不限于,从个体获得的流体或组织样品。此类样品可以通过本领域中已知的方法获得。示例性生物流体样品包括血液、脑脊髓液、尿液及唾液。示例性组织样品包括肿瘤及其活检样品。在此情形下,本发明可以用于多种目的,包括治疗和实验目的。例如,本发明可以离体或体外使用以确定施用谷氨酰胺酶抑制剂用于指定适应症、细胞类型、个体的最佳时程和/或剂量,及其它参数。从此类应用收集的信息可以用于实验或诊断目的,或用于诊所中以设置体内治疗方案。适于本发明的其它离体应用在下面描述或将为本领域技术人员显而易见。
药物组合物
本发明提供了包含一种或多种本发明化合物的药物组合物。该药物组合物可以包括一种或多种如本文所描述的另外的活性成分。可以施用该药物组合物用于本文所描述的任何病症。
主题药物组合物典型地被配制用于提供治疗有效量的本发明化合物作为活性成分。必要时,药物组合物含有作为活性成分的本发明化合物,及一种或多种药学上可接受的载剂或赋形剂,如惰性固体稀释剂和填充剂;稀释剂,包括无菌水溶液和各种有机溶剂;渗透增强剂;增溶剂;及佐剂。
药物组合物可以单独施用或与一种或多种其它药剂组合施用,这些其它药剂也典型地以药物组合物形式施用。必要时,主题化合物和其它药剂可以混合于一种制剂中,或两种组分可以被配制成独立制剂以分开地或同时组合使用。
方法包括施用单独或呈如本文所描述的组合形式的本发明化合物,并且在每一情形中,任选包括一种或多种适合稀释剂、填充剂、盐、崩解剂、粘合剂、润滑剂、助流剂、润湿剂、控制释放基质、着色剂/调味剂、载剂、赋形剂、缓冲剂、稳定剂、增溶剂及其组合。
各种药物组合物的制备是本领域中已知的。参见例如,Anderson,Philip O.;Knoben,James E.;Troutman,William G编辑,Handbook of Clinical Drug Data,第十版,McGraw-Hill,2002;Pratt和Taylor编,Principles of Drug Action,第三版,ChurchillLivingston,New York,1990;Katzung编,Basic and Clinical Pharmacology,第九版,McGraw Hill,2003;Goodman和Gilman编,The Pharmacological Basis of Therapeutics,第十版,McGraw Hill,2001;Remingtons Pharmaceutical Sciences,第20版,LippincottWilliams&Wilkins.,2000;Martindale,The ExtraPharmacopoeia,第三十二版(ThePharmaceutical Press,London,1999),所有这些参考文献都通过引用整体并入本文中。
本发明的化合物或药物组合物可以通过能够将化合物递送到作用部位的任何途径施用,如口服途径、十二指肠内途径、胃肠外注射(包括静脉内、动脉内、皮下、肌肉内、血管内、腹膜内或输注)、外敷施用(例如透皮应用)、直肠施用、经由导管或支架或通过吸入的局部递送。这些化合物还可以通过脂肪内或鞘内施用。
施用的组合物可以是固体、半固体、液体或气体形式,或者可以是干燥的粉末,如冻干形式。药物组合物可以包装成适宜递送的形式,包括例如固体剂型,如胶囊、囊剂、扁囊剂、明胶、纸、片剂、胶囊、栓剂、药丸、丸剂、片剂及锭剂。包装类型一般取决于所期望的施用途径。也涵盖植入式持续释放配制物,以及透皮配制物。
治疗方法
本发明还提供了使用本发明的化合物或药物组合物治疗疾病的方法,所述疾病包括但不限于,与谷氨酰胺酶过表达相关的和/或由谷氨酰胺过量引起的疾病。
本文提供的治疗方法包括向受试者施用治疗有效量的本发明化合物。在一个实施方案中,本发明提供了一种治疗哺乳动物的炎症(包括自身免疫性疾病)的方法。该方法包括向哺乳动物施用治疗有效量的本发明化合物。
应理解,本发明的治疗方法可用于人类医学和兽医学领域。因此,待治疗的个体可以是哺乳动物,优选是人类,或其它动物。出于兽医目的,个体包括但不限于,农场动物,包括奶牛、绵羊、猪、马及山羊;伴侣动物,如狗和猫;外来和/或动物园动物;实验动物,包括小鼠、大鼠、兔、豚鼠及仓鼠;及家禽,如鸡、火鸡、鸭及鹅。
在一些实施方案中,治疗炎性疾病或自身免疫性疾病的方法包括向受试者(例如哺乳动物)施用治疗有效量的一种或多种抑制谷氨酰胺酶的本发明化合物。谷氨酰胺酶的此种抑制可以有利地治疗本文所描述的任何疾病或病状。例如,抑制谷氨酰胺酶可以抑制与炎症性疾病、自身免疫性疾病,或与不期望的免疫反应有关的疾病,包括但不限于,哮喘、气肿、过敏、皮炎、类风湿性关节炎、银屑病、红斑狼疮或移植物抗宿主疾病有关的炎性反应。抑制谷氨酰胺酶可以进一步减少炎性反应或不期望的免疫反应,但减少细菌、病毒和/或真菌感染的能力不会伴随降低。
在其它实施方案中,本发明提供了使用所述化合物或药物组合物治疗呼吸系统疾病的方法,所述疾病包括但不限于,影响肺叶、胸腔、支气管、气管、上呼吸道,或者用于呼吸的神经和肌肉的疾病。例如,提供了治疗阻塞性肺病的方法。慢性阻塞性肺病(COPD)是有关以气道阻塞或限制为特征的一组呼吸道疾病的概括性术语。这一概括性术语中包括的病状包括慢性支气管炎、肺气肿及支气管扩张。
在另一实施方案中,本文所描述的化合物被用于治疗哮喘。另外,本文所描述的化合物或药物组合物可以用于治疗内毒素性血症和败血症。在一个实施方案中,本文所描述的化合物或药物组合物被用于治疗类风湿性关节炎(RA)。在又另一实施方案中,本文所描述的化合物或药物组合物被用于治疗接触性或特应性皮炎。接触性皮炎包括刺激性皮炎、光毒性皮炎、过敏性皮炎、光过敏性皮炎、接触性荨麻疹、全身性接触型皮炎等。刺激性皮炎是在皮肤上使用过多物质时或在皮肤对某些物质敏感时发生。特应性皮炎,有时称为湿疹,是皮炎的一个种类,即,特应性皮肤疾病。
本发明还涉及一种治疗哺乳动物的过度增生性疾病的方法,该方法包括向所述哺乳动物施用治疗有效量的本发明化合物,或其药学上可接受的盐、酯、前药、溶剂合物、水合物或衍生物。在一些实施方案中,所述方法涉及治疗癌症,如急性髓性白血病、胸腺癌、脑癌、肺癌、鳞状细胞癌、皮肤癌、眼癌、成视网膜细胞瘤、眼内黑素瘤、口腔癌和口咽癌、膀胱癌、胃(gastric)癌、胃(stomach)癌、胰脏癌、膀胱癌、乳癌、子宫颈癌、头癌、颈癌、肾(renal)癌、肾(kidney)癌、肝癌、卵巢癌、前列腺癌、结肠直肠癌、食道癌、睾丸癌、妇科癌症、甲状腺癌、CNS癌症、PNS癌症、AIDS相关癌症(例如淋巴瘤和卡波西氏肉瘤)或病毒诱发的癌症。在一些实施方案中,所述方法涉及治疗非癌症过度增生性病症,如良性皮肤增生(例如银屑病)、再狭窄或良性前列腺增生(例如,良性前列腺肥大(BPH))。
本发明还涉及一种治疗哺乳动物的与血管发生或血管生成有关的疾病的方法,该方法包括向所述哺乳动物施用治疗有效量的本发明化合物。在一些实施方案中,所述方法是用于治疗选自由以下各疾病组成的组的疾病:肿瘤血管生成、慢性炎性疾病如类风湿性关节炎、动脉粥样硬化、炎症性肠病,皮肤病如银屑病、湿疹及硬皮病,糖尿病、糖尿病性视网膜病变、早产儿视网膜病变、年龄相关性黄斑变性、血管瘤、神经胶质瘤、黑素瘤、卡波西氏肉瘤,以及卵巢癌、乳癌、肺癌、胰脏癌、前列腺癌、结肠癌及表皮样癌。
可以根据本发明的方法用本发明化合物治疗的患者包括例如,已被诊断患有以下疾病的患者:银屑病;再狭窄;动脉粥样硬化;BPH;乳癌,如乳腺导管组织中的导管癌、髓质癌、胶样癌、小管癌及炎症性乳癌;卵巢癌,包括上皮性卵巢肿瘤,如卵巢腺癌以及从卵巢迁移到腹腔中的腺癌;子宫癌;子宫颈癌,如子宫颈上皮腺癌,包括鳞状细胞癌和腺癌;前列腺癌,如选自以下的前列腺癌:腺癌或迁移到骨骼的腺癌;胰脏癌,如胰腺管组织的上皮样癌和胰腺管中的腺癌;膀胱癌,如膀胱的移行细胞癌、尿路上皮癌(移行细胞癌)、衬于膀胱的尿路上皮细胞肿瘤、鳞状细胞癌、腺癌及小细胞癌;白血病,如急性髓细胞样白血病(AML)、急性淋巴细胞性白血病、慢性淋巴细胞性白血病、慢性髓细胞样白血病、毛细胞白血病、骨髓增生异常、骨髓增生性病症、急性髓性白血病(AML)、慢性髓性白血病(CML)、肥大细胞增多症、慢性淋巴细胞性白血病(CLL)、多发性骨髓瘤(MM)及骨髓增生异常综合症(MDS);骨癌;肺癌,如非小细胞肺癌(NSCLC),其分成鳞状细胞癌、腺癌和大细胞未分化型癌,以及小细胞肺癌;皮肤癌,如基底细胞癌、黑素瘤、鳞状细胞癌,及光化性角化病,此为有时会发展成鳞状细胞癌的皮肤病状;眼部成视网膜细胞瘤;皮肤或眼内(眼部)黑素瘤;原发性肝癌(在肝脏中开始的癌症);肾癌;甲状腺癌,如乳头状甲状腺癌、滤泡性甲状腺癌、甲状腺髓样癌及甲状腺未分化癌;AIDS相关淋巴瘤,如弥漫型大B细胞淋巴瘤、B细胞免疫母细胞性淋巴瘤及小非核裂细胞性淋巴瘤;卡波西氏肉瘤;病毒诱发的癌症,包括乙型肝炎病毒(HBV)、丙型肝炎病毒(HCV)及肝细胞癌;1型人类嗜淋巴细胞病毒(HTLV-I)及成人T细胞白血病/淋巴瘤;及人乳头瘤病毒(HPV)和子宫颈癌;中枢神经系统(CNS)癌症,如原发性脑肿瘤,包括神经胶质瘤(星形细胞瘤、间变性星形细胞瘤或多形性胶质母细胞瘤)、寡树突神经胶质细胞瘤、室管膜瘤、脑膜瘤、淋巴瘤、许旺氏瘤及髓母细胞瘤;外周神经系统(PNS)癌症,如听神经瘤及恶性周围神经鞘膜瘤(MPNST),包括神经纤维瘤和许旺氏瘤、恶性纤维细胞瘤、恶性纤维组织细胞瘤、恶性脑膜瘤、恶性间皮瘤及恶性混合型缪勒管肿瘤;口腔癌和口咽癌,如下咽癌、喉癌、鼻咽癌及口咽癌;胃癌,如淋巴瘤、胃间质瘤及类癌瘤;睾丸癌,如生殖细胞肿瘤(GCT),包括精原细胞瘤和非精原细胞瘤,及性腺间质瘤,包括莱迪希氏细胞瘤(Leydigcell tumor)和塞尔托利氏细胞瘤(Sertoli cell tumor);胸腺癌,如胸腺瘤、胸腺癌、霍奇金氏病、非霍奇金氏淋巴瘤类癌或类癌瘤;肾癌;及结肠癌。
在另一方面,本发明提供了破坏白细胞功能或破坏破骨细胞功能的方法。该方法包括使白细胞或破骨细胞与功能破坏量的本发明化合物接触。
在本发明另一方面,提供了用于治疗眼科疾病的方法,这些方法是通过向受试者的眼部施用一种或多种本文所描述的化合物或药物组合物实现。
本发明另外提供了抑制谷氨酰胺酶的方法,这些方法是通过使谷氨酰胺酶与足以抑制谷氨酰胺酶活性的量的本发明化合物接触来实现。在一些实施方案中,本发明提供了抑制谷氨酰胺酶活性的方法,这些方法是通过使谷氨酰胺酶与足以抑制谷氨酰胺酶活性的量的本发明化合物接触来实现。在一些实施方案中,本发明提供了抑制谷氨酰胺酶活性的方法。这种抑制可以在溶液中、在表达一种或多种谷氨酰胺酶的细胞中、在包含了表达谷氨酰胺酶的细胞的组织中或在表达谷氨酰胺酶的有机体中进行。在一些实施方案中,本发明提供了抑制动物(包括哺乳动物,如人类)体内谷氨酰胺酶活性的方法,这些方法是通过使所述动物与足以抑制所述动物体内谷氨酰胺酶活性的量的本发明化合物接触来实现。
下文描述的通用方法提供了制备和使用本发明化合物的方式和方法并且是说明性而非限制性的。也可以对所提供的方法进一步修改并且另外设计新方法以实现并用于本发明的目的。因此,应了解,其它实施方案可以在说明书所界定的本发明的精神和范围内。
说明性本发明化合物包括上表1中所说明的那些及其药学上可接受的盐。本发明不应解释为仅仅局限于这些化合物。
通用制备方法
本发明的化合物可以通过以下方法制备。除非另外指明,否则各变量(例如R1、R2、P、Q、A、B及L)当用于以下各式中时,应理解为表示上文关于式(I)所描述的那些基团。这些方法可以在进行或不进行修改情况下类似地应用于如上文所提供的其它式(I)的化合物。
方案1:本方案提供了一种用于制备式(I)化合物的方法,其中R1和R2独立地是取代或未取代的芳基,或者取代或未取代的杂芳基,P和Q独立地是-NRxC(O)-(CRxRy)r-或-C(RxRy)r-C(O)-NRx-,L是-L1-L2-L3-,其中L2是取代或未取代的3至14元杂环基,L1和L3不存在或是取代或未取代的C1-6烷基(如甲基),A是 B是r是0或1,并且所有其它变量(包括Rx和Ry)如上文关于式(I)所描述。
方案1
式(1)的化合物(其中s和v是0或1并且R是烷基)可以与式(2)的化合物偶合,形成式(3)的化合物。式(3)的化合物可以使用如Fe/NH4Cl、EtOH及水等适合还原剂还原,形成式(4)的化合物。式(4)的化合物接着可以与式(5)的化合物例如在HATU、DMF及DIPEA存在下偶合,形成式(6)的化合物。式(6)的化合物接着可以水解,得到式(7)的化合物,该化合物接着可以与式(8)的化合物在POCl3存在下反应,形成式(9)的化合物,式(9)的化合物接着可以与式(10)的化合物例如在HATU、DMF及DIPEA存在下偶合,形成式(I)的化合物。本方案通过以下说明1和说明2进行说明。
说明1
说明2
方案2:本方案提供了一种用于制备式(I)化合物的方法,其中R1和R2独立地是取代或未取代的芳基,或者取代或未取代的杂芳基,P和Q独立地是-NRxC(O)-(CRxRy)r-或-C(RxRy)r-C(O)-NRx-,L是-L1-L2-L3-,其中L2是取代或未取代的3至14元杂环基,L1和L3不存在或是取代或未取代的C1-6烷基(如甲基),A是 B是r是0或1,并且所有其它变量(包括Rx和Ry)如以上关于式(I)所描述。
方案2
式(11)的化合物可以与式(12)的化合物(其中X是离去基团)偶合,形成式(13)的化合物。式(13)的化合物可以与式(14)的化合物反应,形成式(15)的化合物,该化合物接着可以与式(8)的化合物例如在POCl3存在下反应,形成式(16)的化合物。式(16)的化合物可以与式R2-CH2-COOH的化合物偶合,得到式(I)的化合物,其中各变量如以上所定义。
方案2a
式(12)的化合物可以与式(14a)的化合物偶合,形成式(17)的化合物。式(17)的化合物可以与式R1-CH2-COOH的化合物反应,随后酯水解,形成式(15)的化合物。式(15)的化合物接着可以与式(8)的化合物例如在POCl3存在下反应,形成式(16)的化合物,该化合物可以与式R2-CH2-COOH的化合物偶合,得到式(I)的化合物,其中各变量如以上所定义。本方案通过以下说明1和说明2进行说明。
说明1
说明2
方案3:本方案提供一种制备式(I)化合物的方法,其中R1和R2独立地是取代或未取代的芳基,或者取代或未取代的杂芳基,P和Q独立地是-NRxC(O)-(CRxRy)r-或-C(RxRy)r-C(O)-NRx-,L是-L1-L2-L3-,其中L2是取代或未取代的3至14元杂环基,L1和L3不存在或是取代或未取代的C1-6烷基(如甲基),A是 B是r是0或1,s是0或1,v是0或1,并且所有其它变量(包括Rx和Ry)如上文关于式(I)所描述。
步骤1
步骤2
步骤1:式(18)的化合物(其中FG是硝基或氨基并且X是离去基团,如溴)可以与式(19)的化合物(其中Pg是保护基)任选在叔丁基碘化铵(TBAI)和如K2CO3等适合碱存在下偶合,形成式(20)的化合物。式(20)的化合物(其中FG1是硝基(-NO2))可以被还原,形成式(21)的化合物,该化合物可以与式(22)的化合物偶合,形成式(23)的化合物。或者,式(20)的化合物(其中FG2是氨基(-NH2))可以与式(22)的化合物偶合,形成式(23)的化合物。
步骤2:式(23)的化合物可以脱除保护基,形成式(23a)的化合物。式(23a)的化合物可以与式(8)的化合物例如在POCl3存在下反应,形成式(24)的化合物,该化合物可以与式(25)的化合物在如HATU和DIPEA等适合试剂存在下偶合,形成式(I)的化合物。本方案通过以下说明1和说明2进行说明。
说明1
步骤1:
步骤2:
说明2
步骤1:
步骤2:
方案4:本方案提供一种制备式(I)化合物的方法,其中R1和R2独立地是取代或未取代的芳基,或者取代或未取代的杂芳基,P和Q独立地是-NRxC(O)-(CRxRy)r-或-C(RxRy)r-C(O)-NRx-,L是-L1-L2-L3-,其中L2是取代或未取代的3至14元杂环基,L1和L3不存在或是取代或未取代的C1-6烷基(如甲基),A是 B是r是0或1,s是0或1,v是0或1,并且所有其它变量(包括Rx和Ry)如上文关于式(I)所描述。
步骤1:
步骤2:
步骤1:式(18)的化合物(其中FG是硝基或氨基,并且X是离去基团,如溴)可以与式(19)的化合物(其中Pg是保护基)例如在叔丁基碘化铵(TBAI)和如K2CO3等适合碱存在下偶合,形成式(20)的化合物。式(20)的化合物可以使用氨水溶液转化,形成式(26)的化合物,该化合物可以使用例如甲磺酰氯转化,形成式(27)的化合物。式(27)的化合物(其中FG1是硝基(-NO2))可以被还原,形成化合物(28),该化合物可以与式(22)的化合物在如HATU和DIPEA等适合试剂存在下偶合,形成式(29)的化合物。或者,式(27)的化合物(其中FG2是氨基(-NH2))可以与式(22)的化合物在如HATU和DIPEA等适合试剂存在下偶合,形成式(29)的化合物。
步骤2:式(29)的化合物可以与式(8)的化合物反应,形成式(24)的化合物。式(24)的化合物可以与式(25)的化合物在如HATU和DIPEA等适合试剂存在下偶合,形成式(I)的化合物。本方案通过以下说明1和说明2进行说明。
说明
步骤1:
步骤2:
方案5:本方案提供一种制备式(I)化合物的方法,其中R1和R2独立地是取代或未取代的芳基,或者取代或未取代的杂芳基,P和Q独立地是-NRxC(O)-(CRxRy)r-或-C(RxRy)r-C(O)-NRx-,L是-L1-L2-L3-,其中L2是取代或未取代的3至14元杂环基,L1和L3不存在或是取代或未取代的C1-6烷基(如甲基),A是 B是r是0或1,s是0或1,v是0或1,并且所有其它变量(包括Rx和Ry)如上文关于式(I)所描述。
步骤1
步骤2
步骤1:式(18)的化合物(其中FG是硝基或氨基并且X是离去基团,如溴)可以与式(30)的化合物偶合,形成式(27)的化合物。式(27)的化合物(其中FG1是硝基(-NO2))可以被还原,形成化合物(28),该化合物可以与式(22)的化合物在如HATU和DIPEA等适合试剂存在下偶合,形成式(29)的化合物。或者,式(27)的化合物(其中FG2是氨基(-NH2))可以与式(22)的化合物在如HATU和DIPEA等适合试剂存在下偶合,形成式(29)的化合物。
步骤2:式(29)的化合物可以与式(8)的化合物反应,形成式(24)的化合物,该化合物可以与式(25)的化合物在如HATU和DIPEA等适合试剂存在下偶合,形成式(I)的化合物。本方案通过以下说明1和说明2进行说明。
说明
步骤1
步骤2:
可以使用类似方法,加上本领域技术人员已知的修改,使用适合的中间体和试剂合成式(I)、(II)及(III)的化合物,其中所有变量都应理解为表示以上所描述的基团。
实验
以下提供的实施例和制备方法进一步说明并例证本发明的化合物和制备这些化合物的方法。应了解,以下实施例和制备方法的范围不以任何方式限制本发明的范围。在以下实施例中,除非另外说明,否则具有单一手性中心的分子是以外消旋混合物形式存在。除非另外说明,否则具有两个或更多个手性中心的分子是以非对映异构体的外消旋混合物形式存在。单一对映异构体/非对映异构体可以通过本领域技术人员已知的方法获得。
中间体表:
中间体1:1-(6-硝基吡啶-3-基)哌啶-4-甲酸乙酯:将3-溴-6-硝基吡啶(2g,9.85mmol)、异哌啶甲酸乙酯(1.7g,10.8mmol)、K2CO3(1.36g,9.84mmol)及叔丁基碘化铵溶解于DMSO(10ml)中。在惰性气氛下,在100℃搅拌此混合物16小时。反应完成后,将反应物冷却至室温并用水稀释。用EtOAc萃取水层。在无水Na2SO4上干燥有机层。在旋转蒸发器上去除EtOAc,得到粗品。粗品在combi-flash上使用EtOAc和石油醚(1∶2)作为洗脱剂进行纯化,得到呈黄色固体状的标题化合物(2.2g)。1H-NMR(δppm,DMSO-d6,400MHz):8.16-8.10(m,2H),7.20(dd,J 9.1,2.8,1H),4.18(q,J7.1,2H),3.92-3.82(m,2H),3.20-3.10(m,2H),2.65-2.55(m,1H),2.15-2.03(m,2H),1.95-1.85(m,2H),1.27(t,J 7.1,3H)。
中间体2:1-(6-氨基吡啶-3-基)哌啶-4-甲酸乙酯:将中间体1(2.2g,7.9mmol)溶解于EtOH(25ml)和H2O(5ml)的混合物中。向此混合物中添加铁粉(2.2g,39.4mmol)和NH4Cl(850mg,15.9mmol)。在90℃下搅拌此混合物16小时。反应完成后,反应混合物经硅藻土垫过滤。用DCM洗涤硅藻土垫。滤液用NaHCO3水溶液碱化。用DCM萃取水层。在无水Na2SO4上干燥合并的DCM层。在旋转蒸发器上去除DCM,得到粗品。粗品通过在60-120目硅胶上的柱,使用MeOH和DCM(3∶97)作为洗脱剂进行纯化,得到呈褐色固体状的标题化合物(1.7g)。1H-NMR(δppm,DMSO-d6,400MHz):7.59(d,J 2.8,1H),7.13(dd,J 8.8,2.8,1H),6.38(d,J8.8,1H),5.32(bs,2H),4.07(q,J 7.1,2H),3.31-3.25(m,2H),2.63-2.55(m,2H),2.45-2.33(m,1H),1.87(d,J 12.6,2H),1.73-1.62(m,2H),1.18(t,J 7.1,3H)。
中间体3:1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)吡啶-3-基)哌啶-4-甲酸乙酯:将中间体2(1.0g,3.8mmol)、3-(三氟甲氧基)苯基乙酸(1.03g,4.7mmol)、HATU(1.82g,4.7mmol)、DIPEA(1.1ml,8.5mmol)溶解于DMF(6ml)中。在惰性气氛下,在室温下搅拌此混合物12小时。用水稀释反应物,得到固体。过滤固体并干燥,得到呈灰色固体状的标题化合物。1H-NMR(δppm,DMSO-d6,400MHz):10.43(s,1H),7.99(d,J 2.7,1H),7.86(d,J 9,1H),7.47-7.41(m,1H),7.39-7.31(m,3H),7.22(d,J 8,1H),4.07(q,J 7.1,2H),3.73(s,2H),3.56(d,J 12.2,2H),2.75(t,J 11.4,2H),2.50-2.41(m,1H),1.90(d,J 11.1,2H),1.72-1.60(m,2H),1.18(t,J 7,3H)。
中间体4:1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)吡啶-3-基)哌啶-4-甲酸:将中间体3(1.59g,3.5mmol)溶解于MeOH和水中。向此混合物中添加NaOH(590mg,14.7mmol)。在室温下搅拌此混合物1小时。在旋转蒸发器上去除MeOH并将残余物用2N HCl酸化到约pH5。用MeOH和DCM(1∶9)的混合物萃取上部水层。在无水Na2SO4上干燥有机层并在旋转蒸发器上蒸发,得到粗品。用Et2O研磨粗品,得到呈褐色固体状的标题化合物(1.19g)。1H-NMR(δppm,DMSO-d6,400MHz):12.14(bs,1H),10.43(s,1H),7.99(s,1H),7.86(d,J 7.9,1H),7.49-7.41(m,1H),7.29-7.30(m,3H),7.22(d,J 8.2,1H),3.73(s,2H),3.56(d,J 11.8,2H),2.74(t,J 11.1,2H),2.41-2.33(m,1H),1.93-1.85(m,2H),1.70-1.58(m,2H)。
中间体5:N-(5-(4-(5-氨基-1,3,4-噻二唑-2-基)哌啶-1-基)吡啶-2-基)-2-(3-(三氟甲氧基)苯基)乙酰胺:将中间体4(290mg,0.45mmol)、硫代氨基脲(230mg)及POCl3(12ml)混合并加热至90℃,保持16小时。反应完成后,将反应物冷却至室温并在碎冰(150g)中骤冷。所得混合物用NaOH饱和水溶液碱化至pH 14。用DCM和MeOH(9:1)的混合物萃取水层。在无水Na2SO4上干燥有机层并在旋转蒸发器上蒸发,得到粗品(110mg)。粗品不经进一步纯化即用于下一步骤中。1H-NMR(δppm,DMSO-d6,400MHz):10.44(s,1H),8.03(s,1H),7.88(d,J 9,1H),7.48-7.30(m,4H),7.22(d,J 7.8,1H),6.97(s,2H),3.73(s,2H),3.63(d,12.4,2H),3.19-3.09(m,1H),2.88(t,J 10.9,2H),2.8(d,13.3,2H),1.90-1.78(m,2H)。
中间体6:1-(6-硝基吡啶-3-基)哌啶-3-甲酸乙酯:将3-溴-6-硝基吡啶(2g,9.85mmol)、哌啶甲酸乙酯(1.7g,10.8mmol)、K2CO3(1.36g,9.84mmol)及叔丁基碘化铵(360mg,0.98mmol)溶解于DMSO(10ml)中。在惰性气氛下,在100℃下搅拌此混合物16小时。反应完成后,将反应物冷却至室温并用水稀释。用EtOAc萃取水层。在无水Na2SO4上干燥有机层。在旋转蒸发器上去除EtOAc,得到粗品。粗品在combi-flash上,使用EtOAc和石油醚(1∶2)作为洗脱剂进行纯化,得到呈黄色固体状的标题化合物(2.3g)。
中间体7:1-(6-氨基吡啶-3-基)哌啶-3-甲酸乙酯:将中间体6(2.2g,7.9mmol)溶解于EtOH(25ml)和H2O(5ml)的混合物中。向此混合物中添加铁粉(2.2g,39.4mmol)和NH4Cl(850mg,15.9mmol)。在90℃下搅拌此混合物16小时。反应完成后,反应混合物经硅藻土垫过滤。用DCM洗涤硅藻土垫。用NaHCO3水溶液碱化滤液。用DCM萃取水层。在无水Na2SO4上干燥合并的DCM层。在旋转蒸发器上去除DCM,得到粗品。粗品通过combi-flash,使用MeOH和DCM(4∶96)作为洗脱剂进行纯化,得到呈褐色液体状的标题化合物(1.8g)。1H-NMR(δppm,DMSO-d6,400MHz):7.60(d,J 2.8,1H),7.13(dd,J 8.8,2.9,1H),6.38(dd,J 8.8,3,1H),5.35(bs,2H),4.10(q,J 6.8,2H),3.30-3.20(m,1H),3.11-3.04(m,1H),2.84-2.76(m,1H),2.69-2.58(m,2H),1.88-1.81(m,1H),1.75-1.68(m,1H),1.60-1.50(m,2H),1.18(t,J 7.1,3H)。
中间体8:1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)吡啶-3-基)哌啶-3-甲酸乙酯:将中间体7(1.8g,7.2mmol)、3-(三氟甲氧基)苯基乙酸(1.9g,8.63mmol)、HATU(3.3g,8.7mmol)、DIPEA(3.8ml,21.6mmol)溶解于DMF(5ml)中。在惰性气氛下,在室温下搅拌此混合物12小时。用水稀释反应物并用DCM萃取。在无水Na2SO4上干燥DCM层。在旋转蒸发器上去除DCM,得到标题化合物(3.2g),不经进一步纯化即用于下一步骤中。1H-NMR(δppm,DMSO-d6,400MHz):10.45(s,1H),7.99(d,J 2.6,1H),7.87(d,J 9,1H),7.48-7.41(m,1H),7.39-7.30(m,3H),7.22(d,J 8,1H),4.08(q,J 7.1,2H),3.73(s,2H),3.60-3.53(m,1H),3.41-3.33(m,1H),3.05-2.96(m,1H),2.86-2.78(m,1H),2.70-2.50(m,1H),1.95-1.85(m,1H),1.78-1.68(m,1H),1.63-1.54(m,2H),1.18(t,J 7.1,3H)。MS(m/z):452.6[M+H]+。
中间体9:1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)吡啶-3-基)哌啶-3-甲酸:将中间体8(1.6g,3.5mmol)溶解于MeOH和水中。向此混合物中添加NaOH(430mg,10.5mmol)。在室温下搅拌此混合物30分钟。在旋转蒸发器上去除MeOH并将残余物用2N HCl酸化至约pH5。此后,用MeOH和DCM(2:8)的混合物萃取上部水层。在无水Na2SO4上干燥有机层并在旋转蒸发器上蒸发,得到粗品。用Et2O研磨粗品,得到呈褐色固体状的标题化合物(950mg)。1H-NMR(δppm,DMSO-d6,400MHz):12.25(s,1H),10.44(s,1H),7.99(d,J 2.7,1H),7.87(d,J 8.8,1H),7.47-7.41(m,1H),7.38-7.31(m,3H),7.22(d,J 7.2,1H),3.73(s,2H),3.58(d,J12.4,1H),3.40(d,J 11.4,1H),3.07-2.90(m,1H),2.82-2.73(m,1H),2.60-2.50(m,1H),1.95-1.83(m,1H),1.75-1.68(m,1H),1.60-1.50(m,2H)。
中间体10:N-(5-(3-(5-氨基-1,3,4-噻二唑-2-基)哌啶-1-基)吡啶-2-基)-2-(3-(三氟甲氧基)苯基)乙酰胺:将中间体9(950mg,2.24mmol)、硫代氨基脲(610mg,6.7mmol)及POCl3(10ml)混合并加热至90℃,保持16小时。反应完成后,将反应物冷却至室温并在碎冰(150g)中骤冷。所得混合物用NaOH饱和水溶液碱化至pH 14。用DCM和MeOH(9∶1)的混合物萃取水层。在无水Na2SO4上干燥有机层并在旋转蒸发器上蒸发,得到粗品。用EtOAc和石油醚(1∶1)的混合物研磨粗品,得到呈褐色固体状的标题化合物(1g)。MS(m/z):479.4[M+H]+。
中间体11:1-(6-硝基吡啶-3-基)哌啶-4-甲酰胺:将中间体1(7.8g,27.9mmol)溶解于MeOH(39ml)中并添加氨水溶液(46.8ml)。将此混合物加热至50℃,保持12小时。过滤反应混合物中形成的固体并真空干燥,得到呈黄色固体状的标题化合物(1.7g)。1H-NMR(δppm,DMSO-d6,400MHz):8.23(d,J 2.9,1H),8.11(d,J 9.2,1H),7.45(dd,J 3,9.2,1H),7.25(bs,1H),6.74(bs,1H),4.06(d,J 12.3,2H),3.10-3.00(m,2H),2.45-2.35(m,1H),1.81(d,J 10.8,2H),1.65-1.51(m,2H)。MS(m/z):250.9[M+H]+。
中间体12:1-(6-硝基吡啶-3-基)哌啶-4-甲腈:将中间体11(1.7g 6.79mmol)溶解于氯仿(25ml)中并添加TEA(4.8ml,34mmol)。将此混合物冷却至-5℃并逐滴添加三氟乙酸酐(2.23ml,17mmol)。在N2气氛下,在室温下搅拌以上混合物1小时。用水稀释反应物并分离有机层。在无水Na2SO4上干燥有机层。在旋转蒸发器上蒸馏有机层,得到呈黄色固体状的标题化合物(1.36g)。其不经进一步纯化即用于下一步骤中。1H-NMR(δppm,DMSO-d6,400MHz):8.25(d,J 3,1H),8.13(d,J 9.2,1H),7.48(dd,J3,9.2,1H),3.80-3.70(m,2H),3.42-3.33(m,2H),3.20-3.11(m,1H),2.05-1.96(m,2H),1.85-1.75(m,2H)。
中间体13:1-(6-氨基吡啶-3-基)哌啶-4-甲腈:将中间体12(1.36g,5.85mmol)溶解于EtOH(40ml)和H2O(8ml)的混合物中。向此混合物中添加铁粉(1.63g,29.3mmol)和NH4Cl(624mg,11.7mmol)。在90℃下搅拌此混合物16小时。反应完成后,反应混合物经硅藻土垫过滤。用DCM洗涤硅藻土垫。用NaHCO3水溶液碱化滤液。用DCM萃取水层。在无水Na2SO4上干燥合并的DCM层。在旋转蒸发器上去除DCM,得到粗品。用Et2O研磨粗品,得到呈褐色固体状的标题化合物(1g)。1H-NMR(δppm,DMSO-d6,400MHz):7.61(d,J 2.6,1H),7.15(dd,J 3,8.8,1H),6.39(d,J8.8,1H),5.38(bs,2H),3.10-3.03(m,2H),2.99-2.91(m,1H),2.86-2.78(m,2H),2.00-1.93(m,2H),1.85-1.75(m,2H)。
中间体14:N-(5-(4-氰基哌啶-1-基)吡啶-2-基)-2-(吡啶-2-基)乙酰胺:将中间体13(440mg,2.29mmol)、2-吡啶基乙酸盐酸盐(453mg,2.6mmol)、HATU(992mg,2.6mmol)、DIPEA(1.1ml,6.5mmol)溶解于DMF(3ml)中。在惰性气氛下,在室温下搅拌此混合物12小时。用水稀释反应物并过滤所形成的固体。用水洗涤固体并在高真空下干燥,得到呈灰白色固体状的标题化合物(320mg)。1H-NMR(δppm,DMSO-d6,400MHz):10.42(s,1H),8.49(d,J 4.3,1H),8.01(d,J 1.8,1H),7.89(d,J 9,1H),7.73((t,J 7.5,1H),7.41-7.35(m,2H),7.27-7.21(m,1H),3.87(s,2H),3.35-3.28(m,2H),3.07-2.98(m,3H),2.03-1.94(m,2H),1.86-1.77(m,2H)。
中间体15:N-(5-(4-(5-氨基-1,3,4-噻二唑-2-基)哌啶-1-基)吡啶-2-基)-2-(吡啶-2-基)乙酰胺:将中间体14(320mg,0.894mmol)、硫代氨基脲(162mg,1.79mmol)及三氟乙酸(2ml)混合并加热至90℃,保持2小时。2小时后,将反应混合物冷却至室温并碱化至pH14,得到固体。用Et2O研磨固体,得到呈褐色固体状的标题化合物(300mg)。1H-NMR(δppm,DMSO-d6,400MHz):10.39(s,1H),8.49(d,J 3.2,1H),8.02(d,J 2.2,1H),7.89(d,J 8.7,1H),7.73(t,J 7.8,1H),7.41-7.35(m,2H),7.28-7.22(m,1H),6.96(bs,2H),3.87(s,2H),3.67(d,J 12.1,2H),3.07-2.98(m,1H),2.80(t,J11.9,2H),2.03(d,J 11.3,2H),1.82-1.70(m,2H)。
中间体16:1-(6-硝基吡啶-3-基)哌啶-3-甲酰胺:将中间体6(5g,17.9mmol)溶解于MeOH(25ml)中并添加氨水溶液(30ml)。将此混合物加热至50℃,保持12小时。过滤反应混合物中形成的固体并真空干燥,得到呈黄色固体状的标题化合物(1.4g)。1H-NMR(δppm,DMSO-d6,400MHz):8.24(d,J 2.7,1H),8.10(d,J 9.2,1H),7.46(dd,J 2.9,9.2,1H),7.35(bs,1H),6.85(bs,1H),4.09-3.95(m,2H),3.13(t,J 11,1H),3.03(t,J 10,1H),2.45-2.35(m,1H),1.93-1.85(m,1H),1.79-1.61(m,2H),1.55-1.42(m,1H)。MS(m/z):251.0[M+H]+。
中间体17:1-(6-硝基吡啶-3-基)哌啶-3-甲腈:将中间体16(1.4g 5.6mmol)溶解于氯仿(20ml)中并添加TEA(3.9ml,28mmol)。将此混合物冷却至-5℃并逐滴添加三氟乙酸酐(1.95ml,14mmol)。在N2气氛下,在室温下搅拌以上混合物1小时。用水稀释反应物并分离有机层。在无水Na2SO4上干燥有机层。在旋转蒸发器上蒸馏有机层,得到呈黄色固体状的标题化合物(1g)。其不经进一步纯化即用于下一步骤中。1H-NMR(δppm,DMSO-d6,400MHz):8.30(d,J 2.9,1H),8.13(d,J 9.2,1H),7.54(dd,J 3,9.2,1H),3.88-3.75(m,2H),3.62-3.45(m,2H),3.17-3.09(m,1H),2.01-1.75(m,2H),1.70-1.58(m,2H)。MS(m/z):232.9[M+H]+。
中间体18:1-(6-氨基吡啶-3-基)哌啶-3-甲腈:将中间体17(1g,4.3mmol)溶解于EtOH(30ml)和H2O(6ml)的混合物中。向此混合物中添加铁粉(1.20g,21.5mmol)和NH4Cl(460mg,8.7mmol)。在90℃下搅拌此混合物16小时。反应完成后,反应混合物经硅藻土垫过滤。用DCM洗涤硅藻土垫。用NaHCO3水溶液碱化滤液。用DCM萃取水层。合并的DCM层在无水Na2SO4上干燥。在旋转蒸发器上去除DCM,得到粗品。粗品通过combi-flash,使用MeOH和DCM(3:97)作为洗脱剂进行纯化,得到呈黑色凝胶状的标题化合物(880mg)。
中间体19:N-(5-(3-氰基哌啶-1-基)吡啶-2-基)-2-(吡啶-2-基)乙酰胺:将中间体18(440mg,2.2mmol)、2-吡啶基乙酸盐酸盐(453mg,2.6mmol)、HATU(992mg,2.6mmol)、DIPEA(1.1ml,6.5mmol)溶解于DMF(3ml)中。在惰性气氛下,在室温下搅拌此混合物12小时。用水稀释反应物并用DCM萃取。在无水Na2SO4上干燥DCM并在旋转蒸发器上去除DCM,得到粗品。粗品通过combi-flash,使用MeOH和DCM(3∶97)作为洗脱剂进行纯化,得到呈褐色固体状的标题化合物(450mg)。1H-NMR(δppm,DMSO-d6,400MHz):10.45(s,1H),8.49(d,J 4,1H),8.03(d,J 2.5,1H),7.90(d,J 8.4,1H),7.73(t,J 6.3,1H),7.44-7.33(m,2H),7.27-7.21(m,1H),3.87(s,2H),3.40-3.31(m,2H),3.20-3.04(m,3H),1.90-1.71(m,3H),1.70-1.59(m,1H)。MS(m/z):322.0[M+H]+。
中间体20:N-(5-(3-(5-氨基-1,3,4-噻二唑-2-基)哌啶-1-基)吡啶-2-基)-2-(吡啶-2-基)乙酰胺:将中间体19(425mg,1.87mmol)、硫代氨基脲(216mg,2.37mmol)及三氟乙酸(2ml)混合并加热至90℃,保持2小时。2小时后,将反应混合物冷却至室温并碱化至pH14。用MeOH和DCM(1:9)的混合物萃取水层。在无水Na2SO4上干燥有机层并在旋转蒸发器上去除MeOH和DCM,得到粗品。粗品通过combi-flash,使用MeOH和DCM(7∶93)作为洗脱剂进行纯化,得到呈粉色固体状的标题化合物(164mg)。MS(m/z):396.1[M+H]+。
中间体21:1-(6-氨基哒嗪-3基)哌啶-4-甲酸乙酯:3-氨基-6-氯哒嗪(1g,7.72mmol)和异哌啶甲酸乙酯(2.4g,15.39mmol)混合并加热至180℃,保持6小时。6小时后,将反应物冷却至室温并添加NaHCO3饱和水溶液(50ml)。用DCM萃取此混合物。在旋转蒸发器上去除DCM,得到粗品。粗品通过combi-flash,使用MeOH和DCM(3∶97)作为洗脱剂进行纯化,得到呈褐色固体状的标题化合物(1.5g).
中间体22:1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-4-甲酸乙酯:将中间体21(1.5g,5.99mmol)、3-(三氟甲氧基)苯基乙酸(1.58g,7.17mmol)、HATU(5g,13.14mmol)、DIPEA(3.1ml,17.78mmol)溶解于DMF(4ml)中。在惰性气氛下,在室温下搅拌此混合物12小时。用水稀释反应物并用DCM萃取。在无水Na2SO4上干燥DCM层并在旋转蒸发器上去除DCM,得到粗品。粗品通过combi-flash,使用MeOH和DCM(1∶99)作为洗脱剂进行纯化,得到呈褐色粘性固体状的标题化合物(1.1g)。1H-NMR(δppm,DMSO-d6,400MHz):10.93(s,1H),7.98(d,J 9.8,1H),7.48-7.42(m,1H),7.38-7.30(m,3H),7.24(d,J 8,1H),4.15(d,J13.3,2H),4.06(q,J 7.1,2H),3.78(s,2H),2.98(t,J 11.4,2H),2.63-2.55(m,1H),1.89(d,J 10.6,2H),1.62-1.50(m,2H),1.17(t,J 7.1,3H)。
中间体23:1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-4-甲酸:将中间体22(1.1g,2.43mmol)溶解于MeOH和水中。向此混合物中添加NaOH(290mg,7.25mmol)。在室温下搅拌此混合物16小时。反应物用稀HCl酸化至约pH 5,得到固体。过滤固体并干燥,得到呈黄色固体状的标题化合物(450mg)。1H-NMR(δppm,DMSO-d6,400MHz):12.27(bs,1H),10.92(s,1H),7.97(d,J 9.8,1H),7.47-7.42(m,1H),7.37-7.29(m,3H),7.28-7.20(m,1H),4.14(d,J 13.2,2H),3.78(s,2H),3.40-3.30(m,1H),3.01-2.93(m,2H),1.87(d,J 10.6,2H),1.60-1.49(m,2H)。MS(m/z):425.0[M+H]+。
中间体24:N-(6-(4-(5-氨基-1,3,4-噻二唑-2-基)哌啶-1-基)哒嗪-3-基)-2-(3-(三氟甲氧基)苯基)乙酰胺:将中间体23(510mg,1.20mmol)、硫代氨基脲(330mg,3.6mmol)及POCl3(5ml)混合并加热至90℃,保持3小时。反应完成后,将反应物冷却至室温并在碎冰(150g)中骤冷。用NaOH饱和水溶液将所得混合物碱化至pH 10。用DCM和MeOH(9∶1)的混合物萃取水层。在无水Na2SO4上干燥有机层并在旋转蒸发器上蒸发,得到粗品。粗品通过combi-flash,使用MeOH和DCM(6∶94)作为洗脱剂进行纯化,得到呈浅黄色固体状的标题化合物(100mg)。1H-NMR(δppm,DMSO-d6,400MHz):10.93(s,1H),7.98(d,J 9.8,1H),7.48-7.42(m,1H),7.37-7.32(m,3H),7.24(d,J 8,1H),7.00(s,2H),4.27(d,J 13.3,2H),3.78(s,2H),3.20-3.10(m,1H),3.01(t,J 11.6,2H),2.02(d,J 10.8,2H),1.70-1.58(m,2H)。MS(m/z):479.8[M+H]+。
中间体25:1-(6-氨基哒嗪-3-基)哌啶-3-甲酸乙酯:将3-氨基-6-氯哒嗪(3g,23.2mmol)和哌啶甲酸乙酯(7.3g,46.4mmol)混合并加热至180℃,保持6小时。6小时后,将反应物冷却至室温并添加NaHCO3饱和水溶液(50ml)。用DCM萃取此混合物。在旋转蒸发器上去除DCM,得到粗品。粗品通过柱色谱法,在60-120目硅胶上使用MeOH和DCM(3∶97)作为洗脱剂进行纯化,得到呈褐色粘性固体状的标题化合物(2.9g)。MS(m/z):250.8[M+H]+。
中间体26:1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-3-甲酸乙酯:将中间体25(2.9g,11.6mmol)、3-(三氟甲氧基)苯基乙酸(3.06g,13.9mmol)、HATU(9.7g,25.5mmol)、DIPEA(2ml,34.75mmol)溶解于DMF(6ml)中。在惰性气氛下,在室温下搅拌此混合物12小时。用水稀释反应物并用DCM萃取。在无水Na2SO4上干燥DCM层并在旋转蒸发器上去除DCM,得到粗品。粗品通过柱色谱法,在60-120目硅胶上使用MeOH和DCM(1∶99)作为洗脱剂进行纯化,得到呈褐色固体状的标题化合物(3.1g)。1H-NMR(δppm,DMSO-d6,400MHz):10.91(s,1H),7.97(d,J 9.8,1H),7.47-7.43(m,1H),7.37-7.31(m,3H),7.24(d,J 8,1H),4.25(d,J13,1H),4.06(q,J 7,2H),3.90(d,J 12.9,1H),3.78(s,2H),3.21-3.05(m,2H),2.60-2.51(m,1H),2.00-1.91(m,1H),1.72-1.53(m,2H),1.52-1.41(m,1H),1.17(t,J 7.1,3H)。
中间体27:1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-3-甲酸:将中间体26(3.1g,6.85mmol)溶解于MeOH和水中。向此混合物中添加NaOH(1.64g,41.1mmol)。在室温下搅拌此混合物3小时。反应物用稀HCl酸化至约pH 5,得到固体。过滤固体并干燥,得到呈黄色固体状的标题化合物(1.4g)。1H-NMR(δppm,DMSO-d6,400MHz):MS(m/z):425.0[M+H]+。12.33(bs,1H),10.92(s,1H),7.97(d,J 9.7,1H),7.48-7.42(m,1H),7.38-7.31(m,3H),7.24(d,J 7.6,1H),4.25(d,J 11.3,1H),3.95(d,J 13.3,1H),3.78(s,2H),3.15-3.00(m,2H),2.00-1.90(m,1H),1.75-1.60(m,2H),1.55-1.40(m,1H)。MS(m/z):425.0[M+H]+。
中间体28:N-(6-(3-(5-氨基-1,3,4-噻二唑-2-基)哌啶-1-基)哒嗪-3-基)-2-(3-(三氟甲氧基)苯基)乙酰胺:将中间体27(1.4g,3.3mmol)、硫代氨基脲(900mg,9.9mmol)及POCl3(14ml)混合并加热至90℃,保持3小时。反应完成后,将反应物冷却至室温并在碎冰中骤冷。所得混合物用NaOH饱和水溶液碱化至pH 10。用DCM和MeOH(9∶1)的混合物萃取水层。在无水Na2SO4上干燥有机层并在旋转蒸发器上蒸发,得到粗品。粗品通过combi-flash,使用MeOH和DCM(6∶94)作为洗脱剂进行纯化,得到呈白色固体状的标题化合物(180mg)。1H-NMR(δppm,DMSO-d6,400MHz):10-94(s,1H),7.98(d,J 9.5,1H),7.48-7.42(m,1H),7.41-7.32(m,3H),7.24(d,J 7.7,1H),7.04(s,2H),4.38(d,J 12.2,1H),4.02(d,J 12.4,1H),3.78(s,2H),3.23-3.05(m,3H),2.11-2.03(m,1H),1.80-1.70(m,2H),1.65-1.53(m,1H)。MS(m/z):480.4[M+H]+。
中间体29:1-(6-(2-(2-氯苯基)乙酰胺基)哒嗪-3-基)哌啶-4-甲酸乙酯:将中间体21(1.35g,5.4mmol)、2-氯苯基乙酸(1.11g,6.5mmol)、HATU(4.5g,11.85mmol)、DIPEA(2.8ml,16.2mmol)溶解于DMF(4ml)中。在惰性气氛下,在室温下搅拌此混合物12小时。用水稀释反应物并用DCM萃取。在无水Na2SO4上干燥DCM层并在旋转蒸发器上去除DCM,得到粗品。粗品通过在60-120目硅胶上的柱色谱法,使用MeOH和DCM(1∶99)作为洗脱剂进行纯化,得到呈褐色粘性固体状的标题化合物(510mg)。1H-NMR(δppm,DMSO-d6,400MHz):10.91(s,1H),7.97(d,J 9.7,1H),7.45-7.38(m,2H),7.36-7.25(m,3H),4.20-4.13(m,2H),4.06(q,J7.1,2H),3.90(s,2H),2.99(t,J 11.1,2H),2.64-2.56(m,1H),1.93-1.85(m,2H),1.62-1.51(m,2H),1.17(t,J 7.1,3H)。
中间体30:1-(6-(2-(2-氯苯基)乙酰胺基)哒嗪-3-基)哌啶-4-甲酸:将中间体29(510mg,1.26mmol)溶解于MeOH和水中。向此混合物中添加NaOH(302mg,7.6mmol)。在室温下搅拌此混合物6小时。反应物用稀HCl酸化至约pH 5,得到固体。过滤固体并干燥,得到呈黄色固体状的标题化合物(350mg)。1H-NMR(δppm,DMSO-d6,400MHz):12.22(s,1H),10.90(s,1H),7.96(d,J 9.5,1H),7.45-7.38(m,2H),7.36-7.25(m,3H),4.14(d,J 13.2,2H),3.90(s,2H),2.98(t,J 11.4,2H),2.55-2.50(m,1H),1.87(d,J11.2,2H),1.61-1.50(m,2H)。
中间体31:N-(6-(4-(5-氨基-1,3,4-噻二唑-2-基)哌啶-1-基)哒嗪-3-基)-2-(2-氯苯基)乙酰胺:将中间体30(350mg,0.93mmol)、硫代氨基脲(255mg,2.3mmol)及POCl3(3.5ml)混合并加热至90℃,保持3小时。反应完成后,将反应物冷却至室温并在碎冰(150g)中骤冷。用NaOH饱和水溶液将所得混合物碱化至pH 10。用DCM和MeOH(9∶1)的混合物萃取水层。在无水Na2SO4上干燥有机层并在旋转蒸发器上蒸发,得到粗品。粗品通过combi-flash,使用MeOH和DCM(6∶94)作为洗脱剂进行纯化,得到呈褐色固体状的标题化合物(40mg)。1H-NMR(δppm,DMSO-d6,400MHz):10.91(s,1H),7.98(d,J 9.4,IH),7.46-7.35(m,3H),7.31-7.25(m,2H),7.01(s,2H),4.28(d,J 12.9,2H),3.90(s,2H),3.20-3.11(m,1H),3.10(t,J11.4,2H),2.02(d,J 11.6,2H),1.70-1.59(m,2H)。
中间体32:1-(6-氨基哒嗪-3-基)哌啶-4-甲腈:将3-氨基-6-氯哒嗪(3g,23.2mmol)和4-氰基哌啶(3.8g,34.7mmol)混合并加热至180℃,保持4小时。4小时后,将反应物冷却至室温并将硬反应物溶解于MeOH和DCM(1∶9)的混合物中。在旋转蒸发器上去除MeOH和DCM,得到粗品。粗品通过在60-120目硅胶上的柱色谱法纯化,得到呈深红色固体状的标题化合物(4.6g)。
中间体33:N-(6-(4-氰基哌啶-1-基)哒嗪-3-基)-2-(2-氟苯基)乙酰胺:将中间体32(365mg,1.8mmol)、2-氟苯基乙酸(388mg,2.5mmol)、HATU(1.5g,3.95mmol)、DIPEA(0.9ml,5.4mmol)溶解于DMF(3ml)中。在惰性气氛下,在室温下搅拌此混合物1小时。用水稀释反应物,得到固体。在高真空下干燥固体,得到呈褐色固体状的标题化合物(80mg)。1H-NMR(δppm,DMSO-d6,400MHz):10.93(s,1H),7.99(d,J 9.8,1H),7.40-7.25(m,3H),7.19-7.11(m,2H),3.85-3.75(m,4H),3.41-3.35(m,2H),3.16-3.05(m,1H),1.98-1.90(m,2H),1.80-1.70(m,2H)。
中间体34:N-(6-(4-(5-氨基-1,3,4-噻二唑-2-基)哌啶-1-基)哒嗪-3-基)-2-(2-氟苯基)乙酰胺:将中间体33(80mg,0.24mmol)、硫代氨基脲(43mg,0.47mmol)及三氟乙酸(1ml)混合并加热至90℃,保持3小时。反应完成后,将反应物冷却至室温并用NaOH饱和水溶液碱化至pH 14,得到固体。过滤固体并在高真空下干燥,得到呈浅褐色固体状的标题化合物(60mg)。1H-NMR(δppm,DMSO-d6,400MHz):10.91(s,1H),7.98(d,J 10,1H),7.40-7.26(m,3H),7.19-7.12(m,2H),7.01(s,2H),4.28(d,J 12.6,2H),3.80(s,2H),3.20-3.10(m,1H),3.01(t,J 12.2,2H),2.03(d,J 11.6,2H),1.70-1.58(m,2H)。
中间体35:N-(6-(4-氰基哌啶-1-基)哒嗪-3-基)-2-(吡啶-2-基)乙酰胺:将中间体32(500mg,2.5mmol)、2-吡啶乙酸盐酸盐(500mg,2.95mmol)、HATU(2.05g,5.41mmol)、DIPEA(1.27ml,7.38mmol)溶解于DMF(3ml)中。在惰性气氛下,在室温下搅拌此混合物1小时。用水稀释反应物,得到固体。在高真空下干燥固体,得到呈褐色固体状的标题化合物(370mg)。MS(m/z):322.26[M+H]+。
中间体36:N-(6-(4-(5-氨基-1,3,4-噻二唑-2-基)哌啶-1-基)哒嗪-3-基)-2-(吡啶-2-基)乙酰胺:将中间体35(360mg,1.1mmol)、硫代氨基脲(203mg,2.22mmol)及三氟乙酸(4ml)混合并加热至90℃,保持3小时。反应完成后,将反应物冷却至室温并用NaOH饱和水溶液碱化至pH 14,得到固体。过滤固体并在高真空下干燥,得到呈浅褐色固体状的标题化合物(180mg)。
中间体37:N-(6-(4-氰基哌啶-1-基)哒嗪-3-基)-2-(吡啶-3-基)乙酰胺:将中间体32(500mg,2.5mmol)、3-吡啶乙酸盐酸盐(500mg,2.95mmol)、HATU(2.05g,5.41mmol)、DIPEA(1.27ml,7.38mmol)溶解于DMF(3ml)中。在惰性气氛下,在室温下搅拌此混合物1小时。用水稀释反应物,得到固体。固体通过combi-flash,使用MeOH和DCM(5∶95)作为洗脱剂进行纯化,得到呈褐色固体状的标题化合物(180mg)。MS(m/z):322.8[M+H]+。
中间体38:N-(6-(4-(5-氨基-1,3,4-噻二唑-2-基)哌啶-1-基)哒嗪-3-基)-2-(吡啶-3-基)乙酰胺:将中间体37(180mg,0.55mmol)、硫代氨基脲(101mg,1.1mmol)及三氟乙酸(3ml)混合并加热至90℃,保持3小时。反应完成后,将反应物冷却至室温并用NaOH饱和水溶液碱化至pH 14,得到固体。过滤固体并在高真空下干燥,得到呈浅褐色固体状的标题化合物(60mg)。
中间体39:2-(1-(6-氨基哒嗪-3-基)哌啶-4-基)乙腈:将3-氨基-6-氯哒嗪(350mg,2.70mmol)和2-(哌啶-4-基)乙腈(670mg,5.4mmol)混合并加热至180℃,保持4小时。4小时后,将反应物冷却至室温并将硬反应物溶解于MeOH和DCM(1∶9)的混合物中。在旋转蒸发器上去除MeOH和DCM,得到粗品。粗品通过在60-120目硅胶上的柱色谱法纯化,得到呈褐色粘性固体状的标题化合物(300mg)。
中间体40:N-(6-(4-(氰基甲基)哌啶-1-基)哒嗪-3-基)-2-(3-(三氟甲氧基)苯基)乙酰胺:将中间体39(300mg,1.38mmol)、3-(三氟甲氧基)苯基乙酸(360mg,1.63mmol)、HATU(1.2g,3.16mmol)、DIPEA(0.73ml’4.2mmol)溶解于DMF(3ml)中。在惰性气氛下,在室温下搅拌此混合物1小时。用水稀释反应物,得到固体。固体通过柱色谱法,使用MeOH和DCM(2∶98)作为洗脱剂进行纯化,得到呈褐色固体状的标题化合物(50mg)。1H-NMR(δppm,DMSO-d6,400MHz):10.91(s,1H),7.96(d,J 9.7,1H),7.48-7.42(m,1H),7.38-7.30(m,3H),7.23(d,J8.1,1H),4.27(d,J 13.2,2H),2.86(t,J 11.7,2H),2.55-2.50(m,2H),1.95-1.85(m,1H),1.77(d,J 12.9,2H),1.73-1.58(m,2H)。
中间体41:N-(6-(4-((5-氨基-1,3,4-噻二唑-2-基)甲基)哌啶-1-基)哒嗪-3-基)-2-(3-(三氟甲氧基)苯基)乙酰胺:将中间体40(50mg,0.12mmol)、硫代氨基脲(22mg,0.24mmol)及三氟乙酸(2ml)混合并加热至90℃,保持12小时。反应完成后,将反应物冷却至室温并用NaOH饱和水溶液碱化至pH 14,得到固体。过滤固体并在高真空下干燥,得到呈褐色固体状的标题化合物(34mg)。MS(m/z):494.1[M+H]+。
实施例1
2-(吡啶-2-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)吡啶-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺:
将中间体5(100mg,0.21mmol)、2-吡啶基乙酸盐酸盐(44mg,0.25mmol)、HATU(96mg,0.25mmol)、N-乙基二异丙胺(0.1ml,0.62mmol)溶解于DMF(2ml)中。在室温下搅拌此混合物30分钟。用水稀释反应物并用EtOAc萃取。用水洗涤有机层。在无水Na2SO4上干燥有机层。在旋转蒸发器上去除EtOAc,得到粗品。粗品通过在60-120目硅胶上的柱色谱法,使用甲醇和DCM(3∶97)作为洗脱剂进行纯化,得到呈褐色固体状的标题化合物(15mg)。M.P.:195-197℃。1H-NMR(δppm,DMSO-d6,400MHz):12.64(s,1H),10.44(s,1H),8.47(d,J 4.2,1H),8.03(d,J 2.7,1H),7.87(d,J 9,1H),7.75(t,J 7.7,1H),7.48-7.32(m,5H),7.30-7.20(m,2H),4.00(s,2H),3.73(s,2H),3.72-3.65(m,2H),3.30-3.20(m,1H),2.84(t,J 11.7,2H),2.11(d,J 11.5,2H),1.90-1.78(m,2H)。
实施例2
(RS)-2-(吡啶-2-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)吡啶-3-基)哌啶-3-基)-1,3,4-噻二唑-2-基)乙酰胺:
将中间体10(500mg,1.04mmol)、2-吡啶基乙酸盐酸盐(220mg,1.27mmol)、HATU(480mg,1.27mmol)、N-乙基二异丙胺(0.5ml,3.09mmol)溶解于DMF(3ml)中。在室温下搅拌此混合物30分钟。用水稀释反应物并用DCM萃取。用水洗涤有机层。在无水Na2SO4上干燥有机层。在旋转蒸发器上去除DCM,得到粗品。粗品通过利用combi-flash的柱色谱法,使用甲醇和DCM(4∶96)作为洗脱剂进行纯化,得到呈褐色固体状的标题化合物(10mg)。M.P.:187-190℃。1H-NMR(δppm,DMSO-d6,400MHz):12.63(s,1H),10.46(s,1H),8.48(d,J 4,1H),8.04(d,J2.6,1H),7.88(d,J 9,1H),7.75(d,J 7.6,1H),7.46-7.30(m,5H),7.29-7.20(m,2H),3.99(s,2H),3.79-3.69(m,3H),3.48-3.40(m,1H),3.15-3.08(m,1H),3.00-2.90(m,1H),2.30-2.20(m,1H),2.15-2.05(m,1H),1.82-1.70(m,3H)。
实施例2A
(R)或(S)2-(吡啶-2-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)吡啶-3-基)哌啶-3-基)-1,3,4-噻二唑-2-基)乙酰胺:
对映异构纯异构体是通过制备型SFC条件,在CHIRALPAK IC4.6*250,5um(Daicel)上使用正己烷(0.1%DEA)/乙醇(0.1%DEA)=40/60作为流动相,以流速1.0ml/min自2-(吡啶-2-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)吡啶-3-基)哌啶-3-基)-1,3,4-噻二唑-2-基)乙酰胺(实施例:2)(0.300g)分离,得到呈褐色固体状的标题化合物(55mg),e.e.100%。Rt:12.34min。M.P.:122-124℃。1H-NMR(δppm,DMSO-d6,400MHz):12.63(s,1H),10.46(s,1H),8.48(d,J 4,1H),8.04(d,J 2.6,1H),7.88(d,J 9,1H),7.75(d,J 7.6,1H),7.46-7.30(m,5H),7.29-7.20(m,2H),3.99(s,2H),3.79-3.69(m,3H),3.48-3.40(m,1H),3.15-3.08(m,1H),3.00-2.90(m,1H),2.30-2.20(m,1H),2.15-2.05(m,1H),1.82-1.70(m,3H)。
实施例2B
(S)或(R)2-(吡啶-2-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)吡啶-3-基)哌啶-3-基)-1,3,4-噻二唑-2-基)乙酰胺:
对映异构纯异构体是通过制备型SFC条件,在CHIRALPAK IC4.6*250,5um(Daicel)上使用正己烷(0.1%DEA)/乙醇(0.1%DEA)=40/60作为流动相,以流速1.0ml/min自2-(吡啶-2-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)吡啶-3-基)哌啶-3-基)-1,3,4-噻二唑-2-基)乙酰胺(实施例:2)(0.300g)分离,得到呈褐色固体状的标题化合物(45mg),e.e.100%。Rt:14.47min。M.P.:129-131℃。1H-NMR(δppm,DMSO-d6,400MHz):12.63(s,1H),10.46(s,1H),8.48(d,J 4,1H),8.04(d,J 2.6,1H),7.88(d,J 9,1H),7.75(d,J 7.6,1H),7.46-7.30(m,5H),7.29-7.20(m,2H),3.99(s,2H),3.79-3.69(m,3H),3.48-3.40(m,1H),3.15-3.08(m,1H),3.00-2.90(m,1H),2.30-2.20(m,1H),2.15-2.05(m,1H),1.82-1.70(m,3H)。
实施例3
(RS)-2-(吡啶-3-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)吡啶-3-基)哌啶-3-基)-1,3,4-噻二唑-2-基)乙酰胺:
将中间体10(500mg,1.04mmol)、3-吡啶基乙酸盐酸盐(220mg,1.26mmol)、HATU(480mg,1.25mmol)、N-乙基二异丙胺(0.5ml,3.1mmol)溶解于DMF(3ml)中。在室温下搅拌此混合物30分钟。用水稀释反应物并用DCM萃取。用水洗涤有机层。在无水Na2SO4上干燥有机层。在旋转蒸发器上去除DCM,得到粗品。粗品通过combi-flash,使用甲醇和DCM(5∶95)作为洗脱剂进行纯化,得到呈浅黄色固体状的标题化合物(6mg)。M.P.:145-147℃。1H-NMR(δppm,DMSO-d6,400MHz):12.69(s,1H),10.47(s,1H),8.55-8.51(m,2H),8.03(s,1H),7.90-7.80(m,2H),7.49-7.40(m,3H),7.30-7.27(m,2H),7.22(d,J 8,1H),3.89(s,2H),3.75-3.70(m,3H),3.20-3.10(m,2H),3.05-2.92(m,2H),2.13-2.04(m,1H),1.80-1.60(m,3H)。
实施例3A
(R)或(S)2-(吡啶-3-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)吡啶-3-基)哌啶-3-基)-1,3,4-噻二唑-2-基)乙酰胺:
对映异构纯异构体是通过制备型SFC条件,在CHIRALPAK IC4.6*250,5um(Daicel)上使用正己烷(0.1%DEA)/乙醇(0.1%DEA)=50/50作为流动相,以流速1.0ml/min自2-(吡啶-3-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)吡啶-3-基)哌啶-3-基)-1,3,4-噻二唑-2-基)乙酰胺(实施例:3)(460mg)分离,得到呈褐色固体状的标题化合物(100mg),e.e.100%。Rt:12.11min。M.P.:170-172℃。1H-NMR(δppm,DMSO-d6,400MHz):12.69(s,1H),10.47(s,1H),8.55-8.51(m,2H),8.03(s,1H),7.90-7.80(m,2H),7.49-7.40(m,3H),7.30-7.27(m,2H),7.22(d,J 8,1H),3.89(s,2H),3.75-3.70(m,3H),3.20-3.10(m,2H),3.05-2.92(m,2H),2.13-2.04(m,1H),1.80-1.60(m,3H)。
实施例3B
(S)或(R)2-(吡啶-3-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)吡啶-3-基)哌啶-3-基)-1,3,4-噻二唑-2-基)乙酰胺:
对映异构纯异构体是通过制备型SFC条件,在CHIRALPAK IC4.6*250,5um(Daicel)上使用正己烷(0.1%DEA)/乙醇(0.1%DEA)=50/50作为流动相,以流速1.0ml/min自2-(吡啶-3-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)吡啶-3-基)哌啶-3-基)-1,3,4-噻二唑-2-基)乙酰胺(实施例:3)(460mg)分离,得到呈褐色固体状的标题化合物(100mg),e.e.100%。Rt:14.12min。M.P.:141-143℃。1H-NMR(δppm,DMSO-d6,400MHz):12.69(s,1H),10.47(s,1H),8.55-8.51(m,2H),8.03(s,1H),7.90-7.80(m,2H),7.49-7.40(m,3H),7.30-7.27(m,2H),7.22(d,J 8,1H),3.89(s,2H),3.75-3.70(m,3H),3.20-3.10(m,2H),3.05-2.92(m,2H),2.13-2.04(m,1H),1.80-1.60(m,3H)。
实施例4
2-(吡啶-3-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)吡啶-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺:
将中间体5(70mg,0.15mmol)、3-吡啶基乙酸盐酸盐(31mg,0.18mmol)、HATU(67mg,0.18mmol)、N-乙基二异丙胺(0.1ml,0.45mmol)溶解于DMF(2ml)中。在室温下搅拌此混合物16小时。用水稀释反应物并用DCM萃取。用水洗涤有机层。在无水Na2SO4上干燥有机层。在旋转蒸发器上去除DCM,得到粗品。粗品通过在60-120目硅胶上的柱色谱法,使用甲醇和DCM(5∶95)作为洗脱剂进行纯化,得到呈浅褐色固体状的标题化合物(15mg)。M.P.:208-210℃。1H-NMR(δppm,DMSO-d6,400MHz):12.70(s,1H),10.47(s,1H),8.58(s,1H),8.54(d,J 4.8,1H),8.03(d,J 2.7,1H),7.91-7.85(m,2H),7.51-7.39(m,3H),7.38-7.32(m,2H),7.22(d,J7.6,1H),3.92(s,2H),3.73(s,2H),3.72-3.65(m,2H),3.31-3.20(m,1H),2.85(t,J 10.8,2H),2.10(d,J 11.9,2H),1.90-1.76(m,2H)。
实施例5
2-(3-氰基苯基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)吡啶-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺:
将中间体5(100mg,0.15mmol)、3-氰基苯基乙酸(58mg,0.36mmol)、HATU(96mg,0.25mmol)、N-乙基二异丙胺(0.11ml,0.63mmol)溶解于DMF(2ml)中。在室温下搅拌此混合物16小时。用水稀释反应物并用DCM萃取。用水洗涤有机层。在无水Na2SO4上干燥有机层。在旋转蒸发器上去除DCM,得到粗品。粗品通过combi-flash,使用甲醇和DCM(5∶95)作为洗脱剂进行纯化,得到呈浅黄色固体状的标题化合物(50mg)。M.P.:211-213℃。1H-NMR(δppm,DMSO-d6,400MHz):12.71(s,1H),10.5(s,1H),8.03(d,J 2.4,1H),7.88(d,J 9,1H),7.79-7.73(m,2H),7.65(d,J 7.9,1H),7.57-7.51(m,1H),7.48-7.37(m,2H),7.36-7.31(m,2H),7.23(d,J 7.9,1H),3.90(s,2H),3.75-3.65(m,4H),3.30-3.20(m,1H),2.83(t,J 11.6,2H),2.10(d,J 12.6,2H),1.88-1.78(m,2H)。
实施例6
2-(吡啶-2-基)-N-(5-(4-(5-(2-(3-(三氟甲氧基)苯基)乙酰胺基)-1,3,4-噻二唑-2-基)哌啶-1-基)吡啶-2-基)乙酰胺:
将中间体15(100mg,0.25mmol)、3-(三氟甲氧基)苯基乙酸(66mg,0.3mmol)、HATU(114mg,0.3mmol)、N-乙基二异丙胺(0.13ml,0.76mmol)溶解于DMF(1.5ml)中。在室温下搅拌此混合物16小时。用水稀释反应物并用DCM萃取。用水洗涤有机层。在无水Na2SO4上干燥有机层。在旋转蒸发器上去除DCM,得到粗品。粗品通过combi-flash,使用甲醇和DCM(8:92)作为洗脱剂进行纯化,得到呈浅黄色固体状的标题化合物(60mg)。M.P.:188-191℃。1H-NMR(δppm,DMSO-d6,400MHz):12.65(s,1H),10.40(s,1H),8.49(d,J 4.8,1H),8.03(d,J 2.8,1H),7.89(d,J 9,1H),7.73(dt,J 1.8,7.7,1H),7.49-7.43(m,1H),7.42-7.31(m,4H),7.28-7.22(m,2H),3.88(s,2H),3.87(s,2H),3.70(d,J 12.6,2H),3.25-3.20(m,1H),2.84(t,J11.6,2H),2.11(d,J 11.5,2H),1.90-1.77(m,2H)。
实施例7
2-(吡啶-2-基)-N-(5-(3-(5-(2-(3-(三氟甲氧基)苯基)乙酰胺基)-1,3,4-噻二唑-2-基)哌啶-1-基)吡啶-2-基)乙酰胺:
将中间体20(100mg,0.25mmol)、3-(三氟甲氧基)苯基乙酸(66mg,0.3mmol)、HATU(114mg,0.3mmol)、N-乙基二异丙胺(0.13ml,0.76mmol)溶解于DMF(1.5ml)中。在室温下搅拌此混合物16小时。用水稀释反应物并用DCM萃取。用水洗涤有机层。在无水Na2SO4上干燥有机层。在旋转蒸发器上去除DCM,得到粗品。粗品通过combi-flash,使用甲醇和DCM(5∶95)作为洗脱剂进行纯化,得到呈浅黄色固体状的标题化合物(40mg)。M.P.:151-153℃。1H-NMR(δppm,DMSO-d6,400MHz):12.69(s,1H),10.47(s,1H),8.48(d,J 4.0,1H),8.04(d,J 2.8,1H),7.90(d,J 9,1H),7.73(dt,J 1.7,7.7,1H),7.49-7.40(m,2H),7.39-7.32(m,3H),7.28-7.23(m,2H),3.87(s,4H),3.70(d,J 12.4,1H),3.49-3.39(m,2H),3.14-3.06(m,1H),2.99-2.90(m,1H),2.10-2.04(m,1H),1.80-1.65(m,3H)。MS(m/z):597.8[M+H]+。
实施例8
2-(吡啶-2-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺:
将中间体24(100mg,0.2mmol)、2-吡啶基乙酸盐酸盐(44mg,0.25mmol)、HATU(170mg,0.44mmol)、N-乙基二异丙胺(0.1ml,0.57mmol)溶解于DMF(2ml)中。在室温下搅拌此混合物1小时。用水稀释反应物并用DCM萃取。用水洗涤有机层。在无水Na2SO4上干燥有机层。在旋转蒸发器上去除DCM,得到粗品。粗品在Combi-flash上,使用DCM和MeOH(95∶5)作为洗脱剂进行纯化,得到呈黄色固体状的标题化合物(60mg)。M.P.:202-205℃。1H-NMR(δppm,DMSO-d6,400MHz):12.68(bs,1H),10.93(s,1H),8.48(d,J 4.2,1H),7.99(d,J 9.8,1H),7.75(dt,J 1.7,7.7,1H),7.47-7.43(m,1H),7.39-7.32(m,4H),7.29-7.21(m,2H),4.30(d,J 13.2,2H),3.99(s,2H),3.78(s,2H),3.40-3.30(m,1H),3.05(t,J 11.7,2H),2.09(d,J10.6,2H),1.80-1.65(m,2H)。MS(m/z):599.6[M+H]+。
实施例9
2-(吡啶-2-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-3-基)-1,3,4-噻二唑-2-基)乙酰胺:
将中间体28(80mg,0.17mmol)、2-吡啶基乙酸盐酸盐(34mg,0.2mmol)、HATU(138mg,0.37mmol)、N-乙基二异丙胺(0.08ml,0.5mmol)溶解于DMF(1ml)中。在室温下搅拌此混合物1小时。用水稀释反应物并用DCM∶MeOH(9∶1)萃取。用水洗涤有机层。在无水Na2SO4上干燥有机层。在旋转蒸发器上去除DCM和MeOH,得到粗品。粗品在Combi-flash上,使用DCM和MeOH(95∶5)作为洗脱剂进行纯化,得到呈浅黄色固体状的标题化合物(20mg)。M.P.:202-205℃。M.P.:243-246℃。1H-NMR(δppm,DMSO-d6,400MHz):12.71(s,1H),10.95(s,1H),8.47(d,J 4.4,1H),7.99(d,J 9.5,1H),7.75(t,J 7.4,1H),7.48-7.32(m,5H),7.30-7.21(m,2H),4.42(d,J 10,1H),4.05-3.97(m,3H),3.78(s,2H),3.45-3.35(m,2H),3.15(t,J 11.1,1H),2.19-2.10(m,1H),1.90-1.74(m,2H),1.67-1.58(m,1H)。MS(m/z):599.5[M+H]+。
实施例10
2-(吡啶-3-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺:
将中间体24(80mg,0.17mmol)、3-吡啶基乙酸盐酸盐(35mg,0.2mmol)、HATU(140mg,0.37mmol)、N-乙基二异丙胺(0.08ml,0.5mmol)溶解于DMF(2ml)中。在室温下搅拌此混合物1小时。用水稀释反应物,得到固体。过滤固体并在Combi-flash上,使用DCM和MeOH(94∶6)作为洗脱剂进行纯化,得到呈浅黄色固体状的标题化合物(25mg)。M.P.:222-223℃。1H-NMR(δppm,DMSO-d6,400MHz):12.72(s,1H),10.93(s,1H),8.50(bs,1H),8.46(bs,1H),7.99(d,J 9.7,1H),7.72(d,J 7.8,1H),7.48-7.42(m,1H),7.39-7.32(m,4H),7.24(d,J8.1,1H),4.30(d,J 13.3,2H),3.85(s,2H),3.78(s,2H),3.40-3.35(m,1H),3.05(t,J11.7,2H),2.09(d,J11.2,2H),1.80-1.67(m,2H)。
实施例11
2-(3-(甲基磺酰胺基)苯基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺:
将中间体24(80mg,0.17mmol)、2-(3-(甲基磺酰胺基)苯基)乙酸(46mg,0.2mmol)、HATU(140mg,0.37mmol)、N-乙基二异丙胺(0.08ml,0.5mmol)溶解于DMF(2ml)中。在室温下搅拌此混合物1小时。用水稀释反应物。用DCM和MeOH(9∶1)的混合物萃取水层。用水和NaHCO3水溶液洗涤有机层。在无水Na2SO4上干燥有机层并在旋转蒸发器上蒸馏有机层,得到粗品。粗品在Combi-flash上,使用DCM和MeOH(95∶5)作为洗脱剂进行纯化,得到呈浅褐色固体状的标题化合物(20mg)。M.P.:228-231℃。1H-NMR(δppm,DMSO-d6,400MHz):12.69(s,1H),10.93(s,1H),9.72(s,1H),7.99(d,J 9.8,1H),7.49-7.42(m,1H),7.39-7.32(m,3H),7.30-7.22(m,2H),7.16(s,1H),7.10(d,J 7.9,1H),7.04(d,J 7.5,1H),4.30(d,J 13,2H),3.78(s,2H),3.76(s,2H),3.40-3.30(m,1H),3.05(t,J 11.6,2H),2.97(s,3H),2.13-2.05(m,2H),1.80-1.65(m,2H)。
实施例12
2-(2-氯苯基)-N-(6-(4-(5-(2-(吡啶-2-基)乙酰胺基)-1,3,4-噻二唑-2-基)哌啶-1-基)哒嗪-3-基)乙酰胺
将中间体31(38mg,0.09mmol)、2-吡啶基乙酸盐酸盐(18mg,0.1mmol)、HATU(73mg,0.19mmol)、N-乙基二异丙胺(0.05ml,0.26mmol)溶解于DMF(1ml)中。在室温下搅拌此混合物1小时。用水稀释反应物并用DCM∶MeOH(9∶1)萃取。用水洗涤有机层。在无水Na2SO4上干燥有机层。在旋转蒸发器上去除DCM和MeOH,得到粗品。粗品在Combi-flash上,使用DCM和MeOH(95∶5)作为洗脱剂进行纯化,得到呈浅褐色固体状的标题化合物(8mg)。M.P.:225-227℃。1H-NMR(δppm,DMSO-d6,400MHz):12.68(s,1H),10.92(s,1H),8.48(d,J 4.1,1H),7.98(d,J9.8,1H),7.75(dt,J 1.8,7.7,1H),7.44-7.36(m,4H),7.33-7.25(m,3H),4.31(d,J 13,2H),3.99(s,2H),3.90(s,2H),3.40-3.35(m,1H),3.05(t,J 11.8,2H),2.10(d,J 11.8,2H),1.81-1.69(m,2H)。
实施例13
2-(2-氯苯基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-3-基)-1,3,4-噻二唑-2-基)乙酰胺:
将中间体28(100mg,0.2mmol)、2-氯苯基乙酸(42mg,0.25mmol)、HATU(173mg,0.46mmol)、N-乙基二异丙胺(0.1ml,0.6mmol)溶解于DMF(1ml)中。在室温下搅拌此混合物1小时。用水稀释反应物并用DCM∶MeOH(9∶1)萃取。用水洗涤有机层。在无水Na2SO4上干燥有机层。在旋转蒸发器上去除DCM和MeOH,得到粗品。粗品在Combi-flash上,使用DCM和MeOH(97∶3)作为洗脱剂进行纯化,得到呈浅褐色固体状的标题化合物(40mg)。M.P.:202-205℃。M.P.:127-130℃。1H-NMR(δppm,DMSO-d6,400MHz):12.75(s,1H),10.94(s,1H),7.98(d,J9.7,1H),7.48-7.29(m,8H),7.24(d,J 7.5,1H),4.41(d,J 10.1,1H),4.05-3.95(m,3H),3.78(s,2H),3.40-3.35(m,2H),3.20-3.10(m,1H),2.19-2.10(m,1H),1.88-1.71(m,2H),1.68-1.57(m,1H)。
实施例14
2-(2-氟苯基)-N-(6-(4-(5-(2-(吡啶-2-基)乙酰胺基)-1,3,4-噻二唑-2-基)哌啶-1-基)哒嗪-3-基)乙酰胺:
将中间体34(60mg,0.15mmol)、2-吡啶基乙酸盐酸盐(30mg,0.17mmol)、HATU(121mg,0.32mmol)、N-乙基二异丙胺(0.08ml,0.5mmol)溶解于DMF(1ml)中。在室温下搅拌此混合物1小时。用水稀释反应物。用DCM和MeOH(9∶1)的混合物萃取水层。用水和NaHCO3水溶液洗涤有机层。在无水Na2SO4上干燥有机层并在旋转蒸发器上蒸馏有机层,得到粗品。粗品在Combi-flash上,使用DCM和MeOH(96∶4)作为洗脱剂进行纯化,得到呈褐色固体状的标题化合物(13mg)。M.P.:229-231℃。1H-NMR(δppm,DMSO-d6,400MHz):12.69(s,1H),10.92(s,1H),8.48(d,J,1H),7.98(d,J 9.9,1H),7.75(dt,J 1.8,7.7,1H),7.40-7.25(m,5H),7.19-7.11(m,2H),4.31(d,J 13.3,2H),3.99(s,2H),3.80(s,2H),3.41-3.35(m,1H),3.05(t,J 11.4,2H),2.10(d,J 11,2H),1.80-1.69(m,2H)。
实施例15
2-(吡嗪-2-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺:
将中间体24(80mg,0.17mmol)、2-(吡嗪-2-基)乙酸(27mg,0.2mmol)、HATU(140mg,0.37mmol)、N-乙基二异丙胺(0.08ml,0.5mmol)溶解于DMF(1ml)中。在室温下搅拌此混合物1小时。用水稀释反应物。用DCM和MeOH(9∶1)的混合物萃取水层。用水和NaHCO3水溶液洗涤有机层。在无水Na2SO4上干燥有机层并在旋转蒸发器上蒸馏有机层,得到粗品。粗品在Combi-flash上,使用DCM和MeOH(94∶6)作为洗脱剂进行纯化,得到呈浅黄色固体状的标题化合物(10mg)。M.P.:216-218℃。1H-NMR(δppm,DMSO-d6,400MHz):12.76(s,1H),10.94(s,1H),8.66(s,1H),8.58-8.53(m,2H),7.99(d,J 9.6,1H),7.48-7.42(m,1H),7.39-7.32(m,3H),7.24(d,J 8.3,1H),4.30(d,J 12.8,2H),4.08(s,2H),3.78(s,2H),3.40-3.35(m,1H),3.05(t,J 11.9,2H),2.10(d,J 13.4,2H),1.80-1.65(m,2H)。
实施例16
2-(吡啶-2-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺二盐酸盐:
将实施例8(50mg,0.08mmol)溶解于THF(15ml)中并添加Et2O.HCl(5ml)。在氮气氛下搅拌此混合物30分钟。30分钟后,在旋转蒸发器上去除THF和乙醚,得到残余物。用乙醚研磨残余物,得到呈褐色固体状的标题化合物(40mg)。M.P.:240-243℃。1H-NMR(δppm,DMSO-d6,400MHz):12.95(bs,1H),11.45(s,1H),8.76(d,J 5,1H),8.30(t,J 6.6,1H),8.24(d,J10.1,1H),7.94(d,J 10,1H),7.83(d,J 7.7,1H),7.76(t,J 6.4,1H),7.48-7.42(m,1H),7.38-7.34(m,2H),7.25(d,J 8,1H),4.35-4.27(m,4H),3.84(s,2H),3.51-3.44(m,1H),3.39-3.29(m,2H),2.20-2.10(m,2H),1.91-1.79(m,2H)。
实施例17
2-(吡啶-2-基)-N-(6-(4-(5-(2-(3-(三氟甲氧基)苯基)乙酰胺基)-1,3,4-噻二唑-2-基)哌啶-1-基)哒嗪-3-基)乙酰胺:
将中间体36(150mg,0.38mmol)、3-(三氟甲氧基)苯基乙酸(100mg,0.45mmol)、HATU(316mg,0.37mmol)、N-乙基二异丙胺(0.2ml,1.134mmol)溶解于DMF(1ml)中。在室温下搅拌此混合物1小时。将反应物倒入水中,得到固体。过滤固体并且固体通过在60-120硅胶上的柱色谱法,使用MeOH和DCM(8∶92)作为洗脱剂进行纯化,得到呈浅褐色固体状的标题化合物(30mg)。M.P.:220-222℃。1H-NMR(δppm,DMSO-d6,400MHz):12.70(s,1H),10.92(s,1H),8.49(s,1H),8.01(d,J 8.7,1H),7.80-7.70(m,1H),7.50-7.20(m,7H),4.30(d,J 12.2,2H),3.92(s,2H),3.87(s,2H),3.50-3.40(m,1H),3.05(t,J 12.2,2H),2.10(d,J 11.1,2H),1.80-1.65(m,2H)。
实施例18
2-(吡啶-3-基)-N-(6-(4-(5-(2-(3-(三氟甲氧基)苯基)乙酰胺基)-1,3,4-噻二唑-2-基)哌啶-1-基)哒嗪-3-基)乙酰胺:
将中间体38(75mg,0.19mmol)、3-(三氟甲氧基)苯基乙酸(50mg,0.22mmol)、HATU(158mg,0.42mmol)、N-乙基二异丙胺(0.1ml,0.5mmol)溶解于DMF(1ml)中。在室温下搅拌此混合物1小时。将反应物倒入水中,得到固体。过滤固体并通过在60-120目硅胶上的柱色谱法,使用MeOH和DCM(7:93)作为洗脱剂进行纯化,得到呈浅褐色固体状的标题化合物(15mg)。M.P.:125-127℃。1H-NMR(δppm,DMSO-d6,400MHz):12.70(s,1H),10.97(s,1H),8.51(s,1H),8.45(s,1H),7.99(d,J 9.5,1H),7.73(d,J 6.9,1H),7.50-7.42(m,1H),7.40-7.30(m,4H),7.26(d,J 7.4,1H),4.30(d,J 12.2,2H),3.87(s,2H),3.76(s,2H),3.40-3.35(m,1H),3.04(t,J 12,2H),2.09(d,J 12,2H),1.80-1.68(m,2H)。
实施例19
2-(吡啶-3-基)-N-(6-(4-(5-(2-(2,3,6-三氟苯基)乙酰胺基)-1,3,4-噻二唑-2-基)哌啶-1-基)哒嗪-3-基)乙酰胺:
将中间体38(75mg,0.19mmol)、2,3,6-三氟苯基乙酸(120mg,0.30mmol)、HATU(255mg,0.67mmol)、N-乙基二异丙胺(0.15ml,0.92mmol)溶解于DMF(1ml)中。在室温下搅拌此混合物1小时。将反应物倒入水中,得到固体。过滤固体并在高真空下干燥。用Et2O研磨此固体,得到呈褐色固体状的标题化合物(70mg)。M.P.:252-254℃。1H-NMR(δppm,DMSO-d6,400MHz):12.84(s,1H),10.96(s,1H),8.51(s,1H),8.44(s,1H),7.98(d,J 8.1,1H),7.76-7.70(m,1H),7.51-7.29(m,3H),7.20-7.10(m,1H),4.30(d,J 10.6,2H),3.96(s,2H),3.76(s,2H),3.41-3.35(m,1H),3.10-3.00(m,2H),2.10(d,J 10,2H),1.81-1.69(m,2H)。
实施例20
2-(吡啶-2-基)-N-(6-(4-(5-(2-(2,3,6-三氟苯基)乙酰胺基)-1,3,4-噻二唑-2-基)哌啶-1-基)哒嗪-3-基)乙酰胺:
将中间体36(100mg,0.25mmol)、2,3,6-三氟苯基乙酸(58mg,0.30mmol)、HATU(211mg,0.55mmol)、N-乙基二异丙胺(0.13ml,0.76mmol)溶解于DMF(1ml)中。在室温下搅拌此混合物1小时。将反应物倒入水中,得到固体。过滤固体并且固体通过在60-120硅胶上的柱色谱法,使用MeOH和DCM(4∶96)作为洗脱剂进行纯化,得到呈褐色固体状的标题化合物(40mg)。M.P.:214-218℃。1H-NMR(δppm,DMSO-d6,400MHz):12.84(s,1H),10.92(s,1H),8.49(d,J 3.7,1H),8.01(d,J 9.8,1H),7.74(dt,J 1.6,7.7,1H),7.50-7.43(m,1H),7.40-7.35(m,2H),7.28-7.23(m,1H),7.20-7.13(m,1H),4.31(d,J 13.3,2H),3.97(s,2H),3.91(s,2H),3.40-3.30(m,1H),3.05(t,J 11.8,2H),2.10(d,J 11.2,2H),1.80-1.70(m,2H)。
实施例21
2-(2,3-二氟苯基)-N-(5-(1-(6-(2-(吡啶-2-基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺:
将中间体36(100mg,0.25mmol)、2,3-二氟苯基乙酸(52mg,0.30mmol)、HATU(211mg,0.55mmol)、N-乙基二异丙胺(0.13ml,0.76mmol)溶解于DMF(1ml)中。在室温下搅拌此混合物1小时。将反应物倒入水中,得到固体。过滤固体并且固体通过在60-120硅胶上的柱色谱法,使用MeOH和DCM(4∶96)作为洗脱剂进行纯化,得到呈褐色固体状的标题化合物(18mg)。M.P.:203-206℃。1H-NMR(δppm,DMSO-d6,400MHz):12.76(s,1H),10.92(s,1H),8.49(d,J 3.7,1H),8.01(d,J 10.1,1H),7.75(t,J 6.4,1H),7.40-7.33(m,3H),7.27-7.23(m,1H),7.20-7.15(m,2H),4.30(d,J 13.2,2H),3.95(s,2H),3.91(s,2H),3.40-3.35(m,1H),3.05(t,J 12.4,2H),2.10(d,J 11.4,2H),1.80-1.70(m,2H)。
实施例22
2-(3,4-二氟苯基)-N-(5-(1-(6-(2-(吡啶-2-基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺:
将中间体36(100mg,0.25mmol)、3,4-二氟苯基乙酸(52mg,0.30mmol)、HATU(211mg,0.55mmol)、N-乙基二异丙胺(0.13ml,0.76mmol)溶解于DMF(1ml)中。在室温下搅拌此混合物1小时。将反应物倒入水中,得到固体。过滤固体并且固体通过在60-120硅胶上的柱色谱法,使用MeOH和DCM(4∶96)作为洗脱剂进行纯化,得到呈浅褐色固体状的标题化合物(37mg)。M.P.:211-214℃。1H-NMR(δppm,DMSO-d6,400MHz):12.67(s,1H),10.92(s,1H),8.49(d,J 4,1H),8.01(d,J 9.8,1H),7.74(dt,J1.7,7.7,1H),7.41-7.33(m,4H),7.29-7.23(m,1H),7.16-7.10(m,1H),4.30(d,J 13.1,2H),3.91(s,2H),3.81(s,2H),3.40-3.35(m,1H),3.05(t,J 11.4,2H),2.09(d,J 11.2,2H),1.80-1.58(m,2H)。
实施例23
2-(2-氟苯基)-N-(5-(1-(6-(2-(吡啶-2-基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺:
将中间体36(100mg,0.25mmol)、2-氟苯基乙酸(47mg,0.30mmol)、HATU(211mg,0.55mmol)、N-乙基二异丙胺(0.13ml,0.76mmol)溶解于DMF(1ml)中。在室温下搅拌此混合物1小时。将反应物倒入水中,得到固体。过滤固体并且固体通过在60-120硅胶上的柱色谱法,使用MeOH和DCM(4∶96)作为洗脱剂进行纯化,得到呈浅褐色固体状的标题化合物(40mg)。M.P.:220-223℃。1H-NMR(δppm,DMSO-d6,400MHz):12.71(bs,1H),10.92(s,1H),8.49(d,J 4.1,1H),8.01(d,J 9.5,1H),7.74(t,J 7.8,1H),7.41-7.30(m,4H),7.29-7.23(m,1H),7.20-7.13(m,2H),4.30(d,J 13,2H),3.91(s,2H),3.87(s,2H),3.41-3.35(m,1H),3.05(t,J 11.6,2H),2.10(d,J11.1,2H),1.81-1.67(m,2H)。
实施例24
2-(3-氟苯基)-N-(5-(1-(6-(2-(吡啶-2-基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺:
将中间体36(100mg,0.25mmol)、3-氟苯基乙酸(47mg,0.30mmol)、HATU(211mg,0.55mmol)、N-乙基二异丙胺(0.13ml,0.76mmol)溶解于DMF(1ml)中。在室温下搅拌此混合物1小时。将反应物倒入水中,得到固体。过滤固体并且固体通过在60-120硅胶上的柱色谱法,使用MeOH和DCM(7∶93)作为洗脱剂进行纯化,得到呈褐色固体状的标题化合物(40mg)。M.P.:210-213℃。1H-NMR(δppm,DMSO-d6,400MHz):12.69(bs,1H),10.92(s,1H),8.49(d,J4,1H),8.01(d,J 9.8,1H),7.74(dt,J 1.7,7.4,1H),7.40-7.33(m,3H),7.27-7.23(m,1H),7.18-7.05(m,3H),4.30(d,J 13.1,2H),3.91(s,2H),3.82(s,2H),3.40-3.35(m,1H),3.05(t,J 11.8,2H),2.09(d,J 11.4,2H),1.80-1.67(m,2H)。
实施例25
2-(4-氟苯基)-N-(5-(1-(6-(2-(吡啶-2-基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺:
将中间体36(100mg,0.25mmol)、4-氟苯:基乙酸(47mg,0.30mmol)、HATU(211mg,0.55mmol)、N-乙基二异丙胺(0.13ml,0.76mmol)溶解于DMF(1ml)中。在室温下搅拌此混合物1小时。将反应物倒入水中,得到固体。过滤固体并且固体通过在60-120硅胶上的柱色谱法,使用MeOH和DCM(4∶96)作为洗脱剂进行纯化,得到呈褐色固体状的标题化合物(25mg)。M.P.:194-197℃。1H-NMR(δppm,DMSO-d6,400MHz):12.67(s,1H),10.92(s,1H),8.49(d,J4.6,1H),8.01(d,J 9.8,1H),7.74(dt,J 1.7,7.7,1H),7.40-7.31(m,4H),7.28-7.22(m,1H),7.17-7.11(m,2H),4.30(d,J 13.1,2H),3.91(s,2H),3.78(s,2H),3.40-3.35(m,1H),3.05(t,J 11.8,2H),2.09(d,J11.6,2H),1.80-1.65(m,2H)。
实施例26
2-(2-甲氧基苯基)-N-(5-(1-(6-(2-(吡啶-2-基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺:
将中间体36(100mg,0.25mmol)、2-甲氧基苯基乙酸(50mg,0.30mmol)、HATU(211mg,0.55mmol)、N-乙基二异丙胺(0.13ml,0.76mmol)溶解于DMF(1ml)中。在室温下搅拌此混合物1小时。将反应物倒入水中,得到固体。过滤固体并且固体通过在60-120硅胶上的柱色谱法,使用MeOH和DCM(4∶96)作为洗脱剂进行纯化,得到呈黄色固体状的标题化合物(37mg)。M.P.:160-163℃。1H-NMR(δppm,DMSO-d6,400MHz):12.55(s,1H),10.92(s,1H),8.49(d,J 4.1,1H),8.01(d,J 9.8,1H),7.75(dt,J 1.8,7.7,1H),7.40-7.36(m,2H),7.29-7.23(m,2H),7.21-7.18(m,1H),6.96(d,J8.2,1H),6.91-6.86(m,1H),4.31(d,J 13.2,2H),3.91(s,2H),3.76(s,2H),3.71(s,3H),3.40-3.33(m,1H),3.05(t,J 11.6,2H),2.10(d,J 11.2,2H),1.80-1.69(m,2H)。
实施例27
2-(2-氯苯基)-N-(5-(1-(6-(2-(吡啶-2-基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺:
将中间体36(100mg,0.25mmol)、2-氯苯基乙酸(52mg,0.30mmol)、HATU(211mg,0.55mmol)、N-乙基二异丙胺(0.13ml,0.76mmol)溶解于DMF(1ml)中。在室温下搅拌此混合物1小时。将反应物倒入水中,得到固体。过滤固体并且固体通过在60-120硅胶上的柱色谱法,使用MeOH和DCM(4:96)作为洗脱剂进行纯化,得到呈褐色固体状的标题化合物(35mg)。M.P.:194-196℃。1H-NMR(δppm,DMSO-d6,400MHz):12.73(s,1H),10.91(s,1H),8.49(d,J3.9,1H),8.01(d,J 8.6,1H),7.77-7.71(m,1H),7.47-7.35(m,4H),7.34-7.28(m,2H),7.27-7.22(m,1H),4.30(d,J 13.1,2H),3.98(s,2H),3.91(s,2H),3.41-3.36(m,1H),3.05(t,J 11.8,2H),2.10(d,J11.5,2H),1.80-1.66(m,2H)。
实施例28
2-(5-氯-2-(三氟甲基)苯基)-N-(5-(1-(6-(2-(吡啶-2-基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺:
将中间体36(100mg,0.25mmol)、5-氯-2-三氟甲基苯基乙酸(72mg,0.30mmol)、HATU(211mg,0.55mmol)、N-乙基二异丙胺(0.13ml,0.76mmol)溶解于DMF(1ml)中。在室温下搅拌此混合物1小时。将反应物倒入水中,得到固体。过滤固体并且固体通过在60-120硅胶上的柱色谱法,使用MeOH和DCM(4∶96)作为洗脱剂进行纯化,得到呈黄色固体状的标题化合物(17mg)。M.P.:232-234℃。1H-NMR(δppm,DMSO-d6,400MHz):12.74(s,1H),10.91(s,1H),8.49(d,J 4.5,1H),8.01(d,J 9.6,1H),7.77-7.72(m,2H),7.67(s,1H),7.60(d,J 8.8,1H),7.41-7.34(m,2H),7.27-7.23(m,1H),4.30(d,J 13,2H),4.09(s,2H),3.91(s,2H),3.41-3.30(m,1H),3.05(t,J12,2H),2.10(d,J 11.2,2H),1.80-1.67(m,2H)。
实施例29
2-(4-氯苯基)-N-(5-(1-(6-(2-(吡啶-2-基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺:
将中间体36(100mg,0.25mmol)、4-氯苯基乙酸(52mg,0.30mmol)、HATU(211mg,0.55mmol)、N-乙基二异丙胺(0.13ml,0.76mmol)溶解于DMF(1ml)中。在室温下搅拌此混合物1小时。将反应物倒入水中,得到固体。过滤固体并且固体通过在60-120硅胶上的柱色谱法,使用MeOH和DCM(4∶96)作为洗脱剂进行纯化,得到呈浅黄色固体状的标题化合物(40mg)。M.P.:220-222℃。1H-NMR(δppm,DMSO-d6,400MHz):12.68(s,1H),10.91(s,1H),8.49(d,J 3.5,1H),8.01(d,J 9.7,1H),7.75(dt,J 1.5,7.7,1H),7.41-7.32(m,6H),7.28-7.23(m,1H),4.30(d,J 13.3,2H),3.91(s,2H),3.79(s,2H),3.41-3.35(m,1H),3.05(t,J 11.8,2H),2.09(d,J 12.7,2H),1.80-1.65(m,2H)。
实施例30
2-(喹啉-6-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺:
将中间体24(100mg,0.25mmol)、喹啉-6-乙酸(47mg,0.25mmol)、HATU(173mg,0.46mmol)、N-乙基二异丙胺(0.11ml,0.62mmol)溶解于DMF(1ml)中。在室温下搅拌此混合物1小时。将反应物倒入水中,得到固体。过滤固体并且固体通过在60-120硅胶上的柱色谱法,使用MeOH和DCM(4∶96)作为洗脱剂进行纯化,得到呈灰白色固体状的标题化合物(35mg)。M.P.:219-221℃。1H-NMR(δppm,DMSO-d6,400MHz):12.77(s,1H),10.92(s,1H),8.87-8.85(m,1H),8.33(d,J 8.6,1H),8.01-7.95(m,2H),7.88(s,1H),7.70(dd,J 1.7,8.7,1H),7.54-7.49(m,1H),7.48-7.42(m,1H),7.37-7.32(m,3H),7.23(d,J 8,1H),4.29(d,J 13,2H),4.02(s,2H),3.78(s,2H),3.40-3.32(m,1H),3.04(t,J 11.7,2H),2.09(d,J12.2,2H),1.80-1.67(m,2H)。
实施例31
2-邻甲苯基-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺:
将中间体24(100mg,0.25mmol)、邻甲苯基乙酸(37mg,0.25mmol)、HATU(173mg,0.46mmol)、N-乙基二异丙胺(0.11ml,0.62mmol)溶解于DMF(1ml)中。在室温下搅拌此混合物1小时。将反应物倒入水中,得到固体。过滤固体并且固体通过在60-120硅胶上的柱色谱法,使用MeOH和DCM(5∶95)作为洗脱剂进行纯化,得到呈灰白色固体状的标题化合物(40mg)。M.P.:198-200℃。1H-NMR(δppm,DMSO-d6,400MHz):12.69(bs,1H),10.94(s,1H),7.98(d,J 9.8,1H),7.48-7.42(m,1H),7.38-7.32(m,3H),7.26-7.19(m,2H),7.17-7.09(m,3H),4.29(d,J 13.1,2H),3.79(s,2H),3.77(s,2H),3.40-3.32(m,1H),3.04(t,J 11.7,2H),2.24(s,3H),2.08(d,J 10.9,2H),1.80-1.67(m,2H)。
实施例32
N-(6-(4-(5-(2-(1H-吲哚-3-基)乙酰胺基)-1,3,4-噻二唑-2-基)哌啶-1-基)哒嗪-3-基)-2-(3-(三氟甲氧基)苯基)乙酰胺:
将中间体24(100mg,0.25mmol)、吲哚-3-乙酸(43mg,0.25mmol)、HATU(173mg,0.46mmol)、N-乙基二异丙胺(0.11ml,0.62mmol)溶解于DMF(1ml)中。在室温下搅拌此混合物1小时。将反应物倒入水中,得到固体。过滤固体并且固体通过在60-120硅胶上的柱色谱法,使用MeOH和DCM(5∶95)作为洗脱剂进行纯化,得到呈褐色固体状的标题化合物(35mg)。M.P.:220-223℃。1H-NMR(δppm,DMSO-d6,400MHz):12.60(s,1H),10.92(s,1H),7.98(d,J9.9,1H),7.55(d,J 7.8,1H),7.48-7.42(m,1H),7.38-7.32(m,4H),7.28-7.21(m,2H),7.08-7.03(m,1H),6.98-6.94(m,1H),4.29(d,J 13,2H),3.87(s,2H),3.78(s,2H),3.40-3.30(m,1H),3.04(t,J 11.8,2H),1.80-1.66(m,2H)。
实施例33
2-(2-氟苯基)-N-(6-(4-(5-(2-(吡嗪-2-基)乙酰胺基)-1,3,4-噻二唑-2-基)哌啶-1-基)哒嗪-3-基)乙酰胺:
将中间体34(300mg,0.75mmol)、2-(吡嗪-2-基)乙酸(120mg,0.87mmol)、HATU(600mg,1.59mmol)、N-乙基二异丙胺(0.3ml,2.17mmol)溶解于DMF(4ml)中。在室温下搅拌此混合物1小时。将反应物倒入水中,得到固体。过滤固体并且固体通过在60-120硅胶上的柱色谱法,使用MeOH和DCM(5∶95)作为洗脱剂进行纯化,得到呈浅褐色固体状的标题化合物(13mg)。M.P.:232-234℃。1H-NMR(δppm,DMSO-d6,400MHz):12.74(s,1H),10.90(s,1H),8.65(s,1H),8.57-8.52(m,2H),7.98(d,J 9.8,1H),7.40-7.36(m,2H),7.35-7.25(m,1H),7.18-7.12(m,2H),4.30(d,J 13.3,2H),4.06(s,2H),3.79(s,2H),3.40-3.31(m,1H),3.05(t,J12,2H),2.10(d,J10.7,2H),1.80-1.66(m,2H)。
实施例34
2-(3-(氮杂环丁烷-1-基)苯基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺:
将中间体24(100mg,0.25mmol)、2-(3-(氮杂环丁烷-1-基)苯基)乙酸(45mg,0.25mmol)、HATU(170mg,0.44mmol)、N-乙基二异丙胺(0.11ml,0.62mmol)溶解于DMF(2ml)中。在室温下搅拌此混合物1小时。将反应物倒入水中,得到固体。过滤固体并且固体通过在60-120硅胶上的柱色谱法,使用MeOH和DCM(4∶96)作为洗脱剂进行纯化,得到呈灰白色固体状的标题化合物(40mg)。M.P.:140-142℃。1H-NMR(δppm,DMSO-d6,400MHz):12.60(s,1H),10.93(s,1H),7.99(d,J 9.8,1H),7.48-7.42(m,1H),7.40-7.32(m,3H),7.24(d,J 7.6,1H),7.07(t,J 7.8,1H),6.59(d,J 7.3,1H),6.36(s,1H),6.28(d,J 7.8,1H),4.29(d,J12.9,2H),3.81-3.73(m,6H),3.66(s,2H),3.40-3.31(m,1H),3.04(t,J 11.8,2H),2.81-2.72(m,2H),2.08(d,J11,2H),1.80-1.66(m,2H)。
实施例35
2-(3-氯苯基)-N-(5-(1-(6-(2-(吡啶-2-基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺:
将中间体36(100mg,0.25mmol)、3-氯苯基乙酸(52mg,0.30mmol)、HATU(211mg,0.55mmol)、N-乙基二异丙胺(0.13ml,0.76mmol)溶解于DMF(1ml)中。在室温下搅拌此混合物1小时。将反应物倒入水中,得到固体。过滤固体并且固体通过在60-120硅胶上的柱色谱法,使用MeOH和DCM(4∶96)作为洗脱剂进行纯化,得到呈浅黄色固体状的标题化合物(35mg)。M.P.:198-201℃。1H-NMR(δppm,DMSO-d6,400MHz):12.68(s,1H),10.91(s,1H),8.49(d,J 4.2,1H),8.01(d,J 9.8,1H),7.76-7.72(m,1H),7.40-7.30(m,5H),7.28-7.22(m,2H),4.30(d,J 13.2,2H),3.91(s,2H),3.82(s,2H),3.40-3.29(m,1H),3.05(t,J 11.8,2H),2.10(d,J 11.7,2H),1.80-1.77(m,2H)。
实施例36
3-羟基-2-苯基-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)丙酰胺:
将中间体24(100mg,0.21mmol)、托品酸(42mg,0.25mmol)、HATU(173mg,0.46mmol)、N-乙基二异丙胺(0.11ml,0.62mmol)溶解于DMF(2ml)中。在室温下搅拌此混合物1小时。将反应物倒入水中,得到固体。过滤固体并且固体通过在60-120硅胶上的柱色谱法,使用MeOH和DCM(5∶95)作为洗脱剂进行纯化,得到呈灰白色固体状的标题化合物(12mg)。M.P.:212-214℃。1H-NMR(δppm,DMSO-d6,400MHz):12.66(s,1H),10.94(s,1H),7.99(d,J 9.9,1H),7.48-7.42(m,4H),7.39-7.22(m,9H),5.06-5.02(m,1H),4.30(d,J 13.8,2H),4.10-4.00(m,2H),3.78(s,2H),3.62-3.57(m,1H),3.40-3.30(m,2H),3.05(t,J 12.4,2H),2.09(d,J 10.8,2H),1.80-1.68(m,2H)。
实施例37
(R)-2-羟基-2-苯基-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺:
将中间体24(100mg,0.21mmol)、(R)-(-)-扁桃酸(35mg,0.25mmol)、HATU(173mg,0.46mmol)、N-乙基二异丙胺(0.11ml,0.62mmol)溶解于DMF(2ml)中。在室温下搅拌此混合物1小时。将反应物倒入水中,得到固体。过滤固体并且固体通过在60-120硅胶上的柱色谱法,使用MeOH和DCM(5:95)作为洗脱剂进行纯化,得到呈浅褐色固体状的标题化合物(15mg)。1H-NMR(δppm,DMSO-d6,400MHz):12.41(s,1H),10.93(s,1H),7.98(d,J 9.7,1H),7.50-7.30(m,10H),6.32(bs,1H),5.30(s,1H),4.29(d,J13,2H),3.78(s,2H),3.50-3.40(m,1H),3.04(t,J 11.7,2H),2.09(d,J 11,2H),1.80-1.65(m,2H)。
实施例38
2-(3-(3-氟氮杂环丁烷-1-基)苯基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺:
将中间体24(100mg,0.21mmol)、2-(3-(3-氟氮杂环丁烷-1-基)苯基)乙酸(53mg,0.25mmol)、HATU(173mg,0.46mmol)、N-乙基二异丙胺(0.11ml,0.62mmol)溶解于DMF(2ml)中。在室温下搅拌此混合物1小时。将反应物倒入水中,得到固体。过滤固体并且固体通过在60-120硅胶上的柱色谱法,使用MeOH和DCM(4∶96)作为洗脱剂进行纯化,得到呈灰白色固体状的标题化合物(40mg)。1H-NMR(δppm,DMSO-d6,400MHz):12.62(s,1H),10.93(s,1H),7.99(d,J 9.7,1H),7.48-7.42(m,1H),7.39-7.22(m,4H),7.11(t,J 5.8,1H),6.65(d,J 7.5,1H),6.43(s,1H),6.36(d,J 8,1H),4.29(d,J 13.2,2H),4.18-4.06(m,2H),3.90-3.76(m,5H),3.68(s,2H),3.40-3.30(m,1H),3.04(t,J 11.8,2H),2.07(d,J 12.2,2H),1.80-1.66(m,2H)。
实施例39
2-(吡啶-2-基)-N-(5-((1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-4-基)甲基)-1,3,4-噻二唑-2-基)乙酰胺:
将中间体41(34mg,0.07mmol)、2-吡啶基乙酸盐酸盐(15mg,0.086mmol)、HATU(58mg,0.15mmol)、N-乙基二异丙胺(0.04ml,0.15mmol)溶解于DMF(2ml)中。在室温下搅拌此混合物1小时。将反应物倒入水中,得到固体。过滤固体并且固体通过combi-flash,使用MeOH和DCM(4∶96)作为洗脱剂进行纯化,得到呈灰白色固体状的标题化合物(2mg)。1H-NMR(δppm,DMSO-d6,400MHz):12.67(s,1H),10.90(s,1H),8.48(d,J 4,1H),7.95(d,J 9.8,1H),7.76(dt,J 2,7.7,1H),7.48-7.22(m,7H),4.23(d,J 12.9,2H),3.99(s,2H),3.77(s,2H),2.93(d,J 7,2H),2.82(t,J 12,2H),2.00-1.90(m,1H),1.72(d,J 12,2H),1.30-1.18(m,2H)。
生物测定
本文所描述的化合物的药理学特性可以通过以下所描述的多种药理学测定确定。
测定1:测定谷氨酰胺酶活性
可以使用生物化学测定,以具有2个步骤的程序评估化合物抑制重组谷氨酰胺酶1(GAC)的酶活性的能力:1.利用GAC将L-谷氨酰胺转化成谷氨酸;及2.在谷氨酸脱氢酶(GDH)催化下,将谷氨酸转化成α-酮戊二酸。以分光光度法测定吸光度的改变,由此表明NAD+还原成NADH。制备底物溶液(50mM Tris-HCl pH8.0、0.2mM EDTA、150mM K2HPO4、0.1mg/ml BSA、1mM DTT、20mM L-谷氨酰胺、2mM NAD+及10ppm消泡剂)并将50μl底物溶液添加到96孔半量澄清板中。添加化合物的DMSO溶液。通过添加50μl酶溶液(50mM Tris-HCl pH 8.0、0.2mMEDTA、150mM K2HPO4、0.1mg/ml BSA、1mM DTT、10ppm消泡剂、4个单位/ml GDH、4mM二磷酸腺苷及4nM GAC)起始酶反应,并且在20℃下于Molecular Devices M5板读取器中读取。该板读取器被配置成以动力学模式读取吸光度(λ=340nm),持续15分钟。数据是以每分钟毫吸收单位记录并且将斜率与同一板上的对照化合物和仅DMSO对照物相比较。斜率低于DMSO对照物的化合物可以被视为抑制剂并且使用对照化合物评估板变化性。测试化合物的活性是以%抑制报告。对于IC50测定,数据是使用Graphpad Prism(Graphpad软件;San Diego CA)进行分析。
测定2:通过估算氨来测定酶活性
L-谷氨酰胺酶测定可以使用比色法,通过使用奈氏试剂(Nessler’s Reagent)在分光光度分析中定量氨形成来进行。该程序改编自British Microbiology ResearchJournal,4(1),97-115,2014,稍作修改。
对于常规测定,将0.1ml适当稀释的酶(与或不与测试化合物一起温育)添加到0.4ml含0.025M L-谷氨酰胺溶液的0.1M硼酸-硼酸盐缓冲液(pH8.0)中。在37℃下温育30分钟之后,通过添加0.5ml的1N H2SO4停止反应。通过离心去除沉淀的蛋白质并且将0.2ml上清液添加到3.8ml蒸馏水中。随后,添加0.5ml奈氏试剂,并在1至3分钟内在400nm下测量吸光度。在所有测定中都包括酶和底物空白组,并且标准曲线是以氯化铵制备。酶活性是以单位(U)/ml表示。一单位L-谷氨酰胺酶定义为在标准条件下每分钟释放一微摩尔(μmol)氨的酶量。比活性(sp.activity)定义为每毫克蛋白质的L-谷氨酰胺酶单位数。相应地,报导在存在和不存在测试化合物情况下谷氨酰胺酶比活性的变化。
测定3:使用谷氨酰胺酶测定来自小鼠脑/肾脏的谷氨酰胺酶活性
步骤1:组织匀浆的制备:向雄性Balb/c小鼠施用含0.28M氯化铵的饮用水,持续7天。处死动物并将脑/肾脏器官收集到干冰上。将这些器官悬浮于含有20mM磷酸盐缓冲液(pH 7.4)、0.5mM EDTA、5mM 2-巯基乙醇、25%甘油及0.02%BSA的均质化缓冲液中。使组织均质化并在-80℃下储存上清液,直到进行酶测定。
步骤2:酶测定
目标:评估化合物抑制小鼠脑/肾脏匀浆中存在的L-谷氨酰胺酶的酶活性的能力。
方案:该测定是使用比色法,用奈氏试剂,通过定量在L-谷氨酰胺酶促转化成谷氨酸期间作为副产物形成的氨的量进行。在常规测定中,将16μl组织匀浆添加到33μlTris-Hcl磷酸盐缓冲液(pH 8)和1μl含有所期望的最终浓度的DMSO/测试化合物中,并短暂涡旋。添加50μl的20mM L-谷氨酰胺Tris缓冲液以起始反应,并在37℃下温育15分钟。通过在96孔板中将20μl反应混合物添加到冷水中,随后添加20μl奈氏试剂来检测所形成的氨。在450nm下测量显现的颜色。数据分析:测试化合物的活性是以%抑制报导,并且对于IC50测定,数据是使用Graphpad Prism(Graphpad软件;San Diego CA)进行分析。
测定3的结果:
对于抑制百分比(%):A是>75%到100%;B是>50%到≤75%;C是>25%到≤50%,并且D是≤25%。对于IC50:A是<50nM;B是≥50nM到<200nM;C是≥200nM到<500nM;D是≥500nM到≤1000nM;并且E是≥1000nM到≤2000nM。
测定4:在癌细胞系中进行的体外细胞增殖测定
使用补充10%FBS的培养基进行生长抑制测定。将细胞以5000-20,000个细胞/孔的浓度接种于96孔板中。24小时之后,添加浓度在0.01至10000nM范围内的测试化合物。在0小时(添加测试化合物之前)和添加测试化合物之后72小时,使用溴化3-[4,5-二甲基噻唑-2-基]-2,5-二苯基四唑盐(MTT)染料还原测试来评估生长情况。在Fluostar Optima(BMGLabtech,Germany)上,在450nm波长下读取吸光度。使用GraphPadPrism分析数据并相应地计算由测试化合物与对照物相比较得到的抑制百分比。结果如下显示。
对于GI50:A是<100nM;B是≥100nM到<250nM;C是≥250nM到<500nM;D是≥500nM到<1000nM并且E是≥1000nM到≤3000nM。
尽管在本文中已经参照特定实施方案描述本发明,但应了解,这些实施方案只是对本发明的原理和应用的说明。因此,应了解,在不背离如以上所描述的本发明的精神和范围的情况下,可以对说明性实施方案作出多种修改并且可以设计出其它布置。预期所附权利要求书界定本发明的范围,并且在这些权利要求和其等效物范围内的方法和结构都涵盖于其中。
本说明书中所提到的所有出版物及专利和/或专利申请都通过引用并入本文中,其引用的程度就如同明确地并且个别地指示每一个别出版物或专利申请是通过引用并入本文中一般。
Claims (48)
1.一种式(I)的化合物,
或其互变异构体、其前药、其N-氧化物、其立体异构体、其药学上可接受的酯或其药学上可接受的盐,其中
L是-L1-L2-L3-;
L1不存在或独立地选自取代或未取代的C1-6烷基、取代或未取代的C2-6烯基、取代或未取代的C2-6炔基、O、S、-S(=O)q-、-C(=O)-或-NRx-;
L2是取代或未取代的3至14元杂环基;
L3不存在或独立地选自取代或未取代的C1-6烷基、取代或未取代的C2-6烯基、取代或未取代的C2-6炔基、O、S、-S(=O)q-、-C(=O)-或-NRx-;
A和B独立地选自
其中A和B各自任选地经一个或多个R3取代;
R3在每次出现时独立地是氢、卤素、取代或未取代的C1-3烷基、硝基、氨基、取代或未取代的C1-6烷氧基,或者取代或未取代的C1-6烷基氨基;
P和Q独立地选自取代或未取代的烷基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、-NRx-C(=O)-(CRxRy)r-、-NH-C(=O)-C(RxRy)-、-(CRxRy)r-C(=O)-NRx-、-(CRxRy)-C(=O)-NH-、-C(=O)NRx-(CRxRy)r-、-C(=O)NH-C(RxRy)-、-(CRxRy)r-NRx-C(=O)-、-(CRxRy)-NH-C(=O)-、-NRx-、-NRxC(=O)-、-NRxC(=S)-、-NRxS(=O)q-、-C(=O)NRx-、-C(=S)NRx-、-S(=O)qNRx-、-NRxC(=O)NRx-、-NRxC(=S)NRx-、-C(=O)-、-C(=S)-、-C(=O)ONRx-、=N-N(Rx)-、-N(Rx)-N=或-NRxC(=O)O-;
R1和R2独立地选自氢、羟基、卤素、取代或未取代的烷基、取代或未取代的烷氧基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的环烷基、取代或未取代的环烯基、取代或未取代的环烷基烷基、取代或未取代的环烯基烷基、取代或未取代的杂环基、取代或未取代的杂环基烷基、取代或未取代的芳基、取代或未取代的芳基烷基、取代或未取代的杂芳基、取代或未取代的杂芳基烷基、-C(=O)ORz、-C(=O)Rz、-C(=S)Rz、-C(=O)NRzRz、-C(=O)ONRzRz、-NRzRz、-NRzC(=O)NRzRz、-NRzS(=O)Rz、-NRzS(=O)2Rz、-(=N-N(Rz)Rz)、-NRzC(=O)ORz、-NRzC(=O)Rz、-NRxC(=S)Ry-NRzC(=S)NRzRz、-SONRzRz、-SO2NRzRz、-ORz、-ORzC(=O)NRzRz、-ORzC(=O)ORz、-OC(=O)Rz、-OC(=O)NRzRz、-RzNRzC(=O)Rz、-RzORz、-RzC(=O)ORz、-RzC(=O)NRzRz、-RzC(=O)Rz、-RzOC(=O)Rz、-SRz、-SORz、-SO2Rz、-CRxRyC(=O)Rz或-CRxRyC(=S)Rz;
Rx、Ry及Rz在每次出现时独立地选自氢、取代或未取代的烷基、取代或未取代的烷氧基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的芳基、取代或未取代的芳基烷基、取代或未取代的杂芳基、取代或未取代的杂芳基烷基、取代或未取代的环烷基、取代或未取代的环烷基烷基、取代或未取代的环烯基、取代或未取代的杂环、取代的杂环基烷基环,或者取代或未取代的氨基,或Rx和Ry中的任何两个当结合到共用原子时可以连接形成(i)取代或未取代的、饱和或不饱和的3至14元环,其可以任选地包括一个或多个相同或不同的杂原子并且所述杂原子选自O、NRz和S;或(ii)氧代(=O)、硫代(=S)或亚氨基(=NRz),其中Rz是Rx;
q在每次出现时独立地是0、1或2;并且
r在每次出现时独立地是0、1或2。
2.如权利要求1所述的化合物,其中A和B独立地选自
其中R3是氢、卤素或取代或未取代的C1-3烷基。
3.如权利要求1和2中任一项所述的化合物,其中A和B独立地选自
4.如权利要求1至3中任一项所述的化合物,其中A和B独立地选自
5.如权利要求1至4中任一项所述的化合物,其中A和B独立地选自
6.如权利要求1至4中任一项所述的化合物,其中A和B独立地选自
7.如权利要求1至4中任一项所述的化合物,其中A是并且B是
8.如权利要求1至4中任一项所述的化合物,其中A是并且B是
9.如权利要求1至8中任一项所述的化合物,其中P和Q各自独立地选自-NRxC(=O)-(CRxRy)r-、-(CRxRy)r-C(=O)-NRx-、-C(=O)NRx-(CRxRy)r-、-(CRxRy)r-NRx-C(=O)-、-NH-C(=O)-C(RxRy)-、-(CRxRy)-C(=O)-NH-、-NRxC(=O)-、-NRxC(=S)-、-NRxS(=O)q-、-C(=O)NRx-、-C(=S)NRx-或-NRx-。
10.如权利要求1至9中任一项所述的化合物,其中P和Q各自独立地选自-NRxC(=O)-(CRxRy)-、-(CRxRy)-C(=O)-NRx-、-NRxC(=O)-或-NRx-,其中Rx和Ry独立地选自氢、取代或未取代的C1-3烷基、卤素、羟基及取代或未取代的C1-3烷氧基。
11.如权利要求1至10中任一项所述的化合物,其中P和Q各自独立地选自-NH-C(=O)-(CRxRy)-、-(CRxRy)-C(=O)-NH-、-NH-C(=O)-或-NH-,其中Rx和Ry是氢。
12.如权利要求1至11中任一项所述的化合物,其中
(i)P和Q各自独立地是-NH-C(=O)-(CH2)-、-(CH2)-C(=O)-NH-、-NH-C(=O)-或-NH-;
(ii)P是-(CH2)-C(=O)-NH-并且Q是-NH-C(=O)-CH2-、-NH-C(=O)-或-NH-;
(iii)P是-(CH2)-C(=O)-NH-、-NH-C(=O)-或-NH-并且Q是-NH-C(=O)-CH2-;或
(iv)P是-(CH2)-C(=O)-NH-并且Q是-NH-C(=O)-CH2-。
13.如权利要求1至12中任一项所述的化合物,其中P和Q独立地选自-NH-C(=O)-CH2-或-CH2-C(=O)-NH-。
14.一种式(II)或(III)的化合物,
或其互变异构体、其前药、其N-氧化物、其立体异构体、其药学上可接受的酯或其药学上可接受的盐,其中
L是-L1-L2-L3-;
L1不存在或独立地选自取代或未取代的C1-6烷基、取代或未取代的C2-6烯基、取代或未取代的C2-6炔基、O、S、-S(=O)q-、-C(=O)-及-NRx-;
L2是取代或未取代的3至14元杂环基;
L3不存在或独立地选自取代或未取代的C1-6烷基、取代或未取代的C2-6烯基、取代或未取代的C2-6炔基、O、S、-S(=O)q-、-C(=O)-及-NRx-;
R1和R2独立地选自氢、羟基、卤素、取代或未取代的烷基、取代或未取代的烷氧基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的环烷基、取代或未取代的环烯基、取代或未取代的环烷基烷基、取代或未取代的环烯基烷基、取代或未取代的杂环基、取代或未取代的杂环基烷基、取代或未取代的芳基、取代或未取代的芳基烷基、取代或未取代的杂芳基、取代或未取代的杂芳基烷基、-C(=O)ORz、-C(=O)Rz、-C(=S)Rz、-C(=O)NRzRz、-C(=O)ONRzRz、-NRzRz、-NRzC(=O)NRzRz、-NRzS(=O)Rz、-NRzS(=O)2Rz、=N-NRzRz、-NRzC(=O)ORz、-NRzC(=O)Rz、-NRxC(=S)Ry-NRzC(=S)NRzRz、-SONRzRz、-SO2NRzRz、-ORz、-ORzC(=O)NRzRz、-ORzC(=O)ORz、-OC(=O)Rz、-OC(=O)NRzRz、-RzNRzC(=O)Rz、-RzORz、-RzC(=O)ORz、-RzC(=O)NRzRz、-RzC(=O)Rz、-RzOC(=O)Rz、-SRz、-SORz、-SO2Rz、-CRxRyC(=O)Rz或-CRxRyC(=S)Rz;
Rx、Ry及Rz在每次出现时独立地选自氢、取代或未取代的烷基、取代或未取代的烷氧基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的芳基、取代或未取代的芳基烷基、取代或未取代的杂芳基、取代或未取代的杂芳基烷基、取代或未取代的环烷基、取代或未取代的环烷基烷基、取代或未取代的环烯基、取代或未取代的杂环、取代的杂环基烷基环,或者取代或未取代的氨基,或Rx和Ry中的任何两个当结合到共用原子时可以连接形成(i)取代或未取代的饱和或不饱和的3至14元环,其可以任选地包括一个或多个相同或不同的杂原子并且所述杂原子选自O、NRz或S;或(ii)氧代(=O)、硫代(=S)或亚氨基(=NRz);
R3是氢、卤素、取代或未取代的C1-3烷基、硝基、氨基、取代或未取代的C1-6烷氧基,或者取代或未取代的C1-6烷基氨基;并且
q在每次出现时独立地是0、1或2。
15.如权利要求1至14中任一项所述的化合物,其中
L1是不存在、取代或未取代的C1-6烷基或NRx,其中Rx是氢或C1-3烷基;
L2是取代或未取代的3至10元杂环基;并且
L3是不存在、取代或未取代的C1-6烷基或NRx,其中Rx是氢或C1-3烷基。
16.如权利要求1至15中任一项所述的化合物,其中
L1不存在或是取代或未取代的C1-6烷基;
L2是取代或未取代的3至10元杂环基;并且
L3不存在或是取代或未取代的C1-6烷基。
17.如权利要求1至16中任一项所述的化合物,其中L2是取代或未取代的3至10元杂环基,并且
(i)L1和L3不存在;
(ii)L1和L3是-CH2-;
(iii)L1是-CH2-并且L3不存在;或
(iv)L1不存在并且L3是-CH2-。
18.如权利要求1至17中任一项所述的化合物,其中L2选自
其中
D和E独立地选自CR”或N,其中R”是氢、羟基、卤素或取代或未取代的C1-3烷基;
Ra、Rb、Rc、Rd、Re、Rf、Rg及Rh在每次出现时独立地选自氢、硝基、羟基、氰基、卤素、取代或未取代的C1-6烷基、取代或未取代的C2-6烯基、取代或未取代的C2-6炔基、取代或未取代的C3-6环烷基、取代或未取代的C3-6环烷基烷基以及取代或未取代的C3-6环烯基;或Ra、Rb、Rc、Rd、Re、Rf、Rg及Rh中的任意两个可连接形成(i)取代或未取代的饱和或不饱和的3至14元环,其可以任选地包括一个或多个相同或不同的杂原子并且所述杂原子选自O、NR’(其中R’是H或C1-3烷基)及S;或(ii)氧代(=O)、硫代(=S)或亚氨基(=NR’);并且
s、t、u及v各自独立地是0、1或2,条件是s、t、u及v的总和不是0。
19.如权利要求18所述的化合物,其中Ra、Rb、Rc、Rd、Re、Rf、Rg及Rh在每次出现时独立地选自氢、羟基、取代或未取代的C1-3烷基,或Ra、Rb、Rc、Rd、Re、Rf、Rg及Rh中的任意两个当结合到共用原子时形成氧代(=O)或取代或未取代的环烷基。
20.如权利要求19所述的化合物,其中
Ra、Rb、Rc、Rd、Re、Rf、Rg及Rh各自是氢并且s、t、u及v的总和是1、2、3或4。
21.如权利要求20所述的化合物,其中
(i)Ra、Rb、Rc、Rd、Re、Rf、Rg及Rh各自是氢,s是0,t是1并且u+v=3;
(ii)Ra、Rb、Rc、Rd、Re、Rf、Rg及Rh各自是氢并且s、t、u及v各自是1;
(iii)Ra、Rb、Rc、Rd、Re、Rf、Rg及Rh各自是氢,s是0并且t、u及v各自是1;或
(iv)Ra、Rb、Rc、Rd、Re、Rf、Rg及Rh各自是氢并且s、t、u及v的总和是2;或
(v)Ra、Rb、Rc、Rd、Re、Rf、Rg及Rh各自是氢并且s、t、u及v的总和是1。
22.如权利要求18至21中任一项所述的化合物,其中D和E独立地选自CH和N。
23.如权利要求18至22中任一项所述的化合物,其中(i)D是CH并且E是N或(ii)D是N并且E是CH。
24.如权利要求1至23中任一项所述的化合物,其中L1和L3各自不存在或选自取代或未取代的C1-3烷基。
25.如权利要求1至24中任一项所述的化合物,其中L(L1-L2-L3)选自
26.如权利要求1至25中任一项所述的化合物,其中L2选自
27.如权利要求1至26中任一项所述的化合物,其中L2选自
28.如权利要求1至27中任一项所述的化合物,其中L1和L3各自独立地不存在或是-CH2-。
29.如权利要求1至28中任一项所述的化合物,其中R3是氢、卤素,或者取代或未取代的C1-3烷基。
30.如权利要求1至29中任一项所述的化合物,其中R3是氢、氟或甲基。
31.如权利要求1至30中任一项所述的化合物,其中R1和R2各自独立地选自氢、卤素、取代或未取代的烷基、-NRzRz、取代或未取代的杂环基、取代或未取代的杂环基烷基、取代或未取代的芳基、取代或未取代的芳基烷基、取代或未取代的杂芳基,及取代或未取代的杂芳基烷基。
32.如权利要求1至31中任一项所述的化合物,其中R1和R2各自独立地选自-NRzRz、取代或未取代的芳基及取代或未取代的杂芳基。
33.如权利要求1至32中任一项所述的化合物,其中R1和R2各自独立地选自取代或未取代的芳基及取代或未取代的杂芳基。
34.如权利要求1至33中任一项所述的化合物,其中
(i)R1是取代或未取代的芳基并且R2是取代或未取代的杂芳基;
(ii)R1是取代或未取代的杂芳基并且R2是取代或未取代的芳基;
(iii)R1和R2是取代或未取代的芳基,或
(iv)R1和R2是取代或未取代的杂芳基。
35.如权利要求1至34中任一项所述的化合物,其中R1和R2各自独立地选自
36.如权利要求1至35中任一项所述的化合物,其中Rx和Ry是氢、羟基或-CH2OH。
37.一种化合物,所述化合物选自:
2-(吡啶-2-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)吡啶-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺;
(RS)-2-(吡啶-2-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)吡啶-3-基)哌啶-3-基)-1,3,4-噻二唑-2-基)乙酰胺;
(R)-2-(吡啶-2-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)吡啶-3-基)哌啶-3-基)-1,3,4-噻二唑-2-基)乙酰胺;
(S)-2-(吡啶-2-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)吡啶-3-基)哌啶-3-基)-1,3,4-噻二唑-2-基)乙酰胺;
(RS)-2-(吡啶-3-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)吡啶-3-基)哌啶-3-基)-1,3,4-噻二唑-2-基)乙酰胺;
(R)-2-(吡啶-3-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)吡啶-3-基)哌啶-3-基)-1,3,4-噻二唑-2-基)乙酰胺;
(S)-2-(吡啶-3-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)吡啶-3-基)哌啶-3-基)-1,3,4-噻二唑-2-基)乙酰胺;
2-(吡啶-3-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)吡啶-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺;
2-(3-氰基苯基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)吡啶-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺;
2-(吡啶-2-基)-N-(5-(4-(5-(2-(3-(三氟甲氧基)苯基)乙酰胺基)-1,3,4-噻二唑-2-基)哌啶-1-基)吡啶-2-基)乙酰胺;
2-(吡啶-2-基)-N-(5-(3-(5-(2-(3-(三氟甲氧基)苯基)乙酰胺基)-1,3,4-噻二唑-2-基)哌啶-1-基)吡啶-2-基)乙酰胺;
2-(吡啶-2-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺;
2-(吡啶-2-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-3-基)-1,3,4-噻二唑-2-基)乙酰胺;
2-(吡啶-3-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺;
2-(3-(甲基磺酰胺基)苯基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺;
2-(2-氯苯基)-N-(6-(4-(5-(2-(吡啶-2-基)乙酰胺基)-1,3,4-噻二唑-2-基)哌啶-1-基)哒嗪-3-基)乙酰胺;
2-(2-氯苯基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-3-基)-1,3,4-噻二唑-2-基)乙酰胺;
2-(2-氟苯基)-N-(6-(4-(5-(2-(吡啶-2-基)乙酰胺基)-1,3,4-噻二唑-2-基)哌啶-1-基)哒嗪-3-基)乙酰胺;
2-(吡嗪-2-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺;
2-(吡啶-2-基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺二盐酸盐;
2-(吡啶-2-基)-N-(6-(4-(5-(2-(3-(三氟甲氧基)苯基)乙酰胺基)-1,3,4-噻二唑-2-基)哌啶-1-基)哒嗪-3-基)乙酰胺;
2-(吡啶-3-基)-N-(6-(4-(5-(2-(3-(三氟甲氧基)苯基)乙酰胺基)-1,3,4-噻二唑-2-基)哌啶-1-基)哒嗪-3-基)乙酰胺;
2-(吡啶-3-基)-N-(6-(4-(5-(2-(2,3,6-三氟苯基)乙酰胺基)-1,3,4-噻二唑-2-基)哌啶-1-基)哒嗪-3-基)乙酰胺;
2-(吡啶-2-基)-N-(6-(4-(5-(2-(2,3,6-三氟苯基)乙酰胺基)-1,3,4-噻二唑-2-基)哌啶-1-基)哒嗪-3-基)乙酰胺;
2-(2,3-二氟苯基)-N-(5-(1-(6-(2-(吡啶-2-基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺;
2-(3,4-二氟苯基)-N-(5-(1-(6-(2-(吡啶-2-基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺;
2-(2-氟苯基)-N-(5-(1-(6-(2-(吡啶-2-基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺;
2-(3-氟苯基)-N-(5-(1-(6-(2-(吡啶-2-基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺;
2-(4-氟苯基)-N-(5-(1-(6-(2-(吡啶-2-基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺;
2-(3-氯苯基)-N-(5-(1-(6-(2-(吡啶-2-基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺;
3-羟基-2-苯基-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)丙酰胺;
(R)-2-羟基-2-苯基-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺;
2-(3-(3-氟氮杂环丁烷-1-基)苯基)-N-(5-(1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-4-基)-1,3,4-噻二唑-2-基)乙酰胺;
2-(吡啶-2-基)-N-(5-((1-(6-(2-(3-(三氟甲氧基)苯基)乙酰胺基)哒嗪-3-基)哌啶-4-基)甲基)-1,3,4-噻二唑-2-基)乙酰胺;
及其药学上可接受的盐。
38.一种药物组合物,所述药物组合物包含如权利要求1至37中任一项所述的化合物及药学上可接受的载剂。
39.如权利要求38所述的药物组合物,所述药物组合物另外包含一种或多种选自以下的另外的治疗剂:抗癌剂、抗炎剂、免疫抑制剂、类固醇、非类固醇抗炎剂、抗组胺、止痛剂及其混合物。
40.一种抑制细胞中存在的谷氨酰胺酶的催化活性的方法,所述方法包括使所述细胞与有效量的如权利要求1至37中任一项所述的化合物接触。
41.如权利要求40所述的方法,其中所述抑制发生于罹患选自以下的疾病或病症的受试者:癌症、神经病症或免疫疾病、骨骼病症、炎症性疾病、免疫疾病、神经系统疾病、代谢疾病、呼吸系统疾病、血栓症或心脏病。
42.如权利要求1至37中任一项所述的化合物在制造用于治疗将得益于抑制谷氨酰胺酶催化活性的疾病、病症或病状的药物中的用途。
43.一种用于治疗谷氨酰胺酶相关性疾病或病症的方法,所述方法包括以下步骤:向有需要的受试者施用有效量的如权利要求1至37中任一项所述的化合物。
44.如权利要求43所述的方法,所述方法另外包括以下步骤:向有需要的受试者同时或依序施用至少另一种抗癌剂、抗炎剂、免疫抑制剂、类固醇、非类固醇抗炎剂、抗组胺、止痛剂或其混合物。
45.如权利要求43或44所述的方法,其中所述谷氨酰胺酶相关性疾病、病症或病状是免疫系统相关疾病、涉及炎症的疾病或病症、癌症或其它增生性疾病、肝脏疾病或病症,或者肾脏疾病或病症。
46.如权利要求43或44所述的方法,其中所述谷氨酰胺酶相关性疾病、病症或病状选自炎症、肾小球肾炎、葡萄膜炎、肝脏疾病或病症、肾脏疾病或病症、慢性阻塞性肺病、类风湿性关节炎、炎症性肠病、血管炎、皮炎、骨关节炎、炎症性肌病、过敏性鼻炎、阴道炎、间质性膀胱炎、硬皮病、骨质疏松症、湿疹、同种异体或异种移植、移植物排斥反应、移植物抗宿主疾病、红斑狼疮、肺纤维化、皮肌炎、甲状腺炎、重症肌无力、自身免疫性溶血性贫血、囊肿性纤维化、慢性复发性肝炎、原发性胆汁性肝硬化、过敏性结膜炎、肝炎、特应性皮炎、哮喘、斯耶格伦综合症、器官移植排斥反应、多发性硬化、格林-巴利二氏综合症、自身免疫性葡萄膜炎、自身免疫性溶血性贫血、恶性贫血、自身免疫性血小板减少症、颞动脉炎、抗磷脂综合症、血管炎病如韦格纳氏肉芽肿、白塞氏病、银屑病、疱疹样皮炎、寻常天疱疮、白癜风、克罗恩氏病、结肠炎、溃疡性结肠炎、原发性胆汁性肝硬化、自身免疫性肝炎、1型或免疫介导的糖尿病、格雷夫斯氏病、桥本氏甲状腺炎、自身免疫性卵巢炎和睾丸炎、自身免疫性肾上腺病症、全身性红斑狼疮、多肌炎、皮肌炎、强直性脊柱炎、移植排斥反应、皮肤移植物排斥反应、关节炎、骨吸收增加相关性骨病、回肠炎、巴瑞特氏综合症、成人呼吸窘迫综合症、慢性阻塞性气道疾病、角膜营养不良、沙眼、盘尾丝虫病、交感性眼炎、眼内炎、齿龈炎、牙周炎、结核病、麻疯病、尿毒症并发症、肾病、硬化性皮炎、银屑病、神经系统慢性脱髓鞘疾病、AIDS相关神经退化、阿尔茨海默氏病、感染性脑膜炎、脑脊髓炎、帕金森氏病、亨廷顿氏病、肌萎缩性侧索硬化、病毒性或自身免疫性脑炎、自身免疫性病症、免疫复合物血管炎、全身性狼疮和红斑、全身性红斑狼疮(SLE)、心肌症、缺血性心脏病、高胆固醇血症、动脉粥样硬化、先兆子痫、慢性肝衰竭、脑和脊髓外伤,及癌症。
47.如权利要求43或44所述的方法,其中所述谷氨酰胺相关性疾病、病症或病状选自淋巴系血液系统肿瘤,白血病、急性淋巴细胞性白血病、急性淋巴母细胞性白血病、B细胞淋巴瘤、T细胞淋巴瘤、霍奇金氏淋巴瘤、非霍奇金氏淋巴瘤、毛细胞淋巴瘤及伯基特氏淋巴瘤;髓系血液系统肿瘤,急性髓性白血病、慢性髓性白血病、骨髓增生异常综合症、早幼粒细胞白血病;膀胱癌、乳癌、结肠癌、肾癌、肝癌、肺癌、小细胞肺癌、食道癌、胆囊癌、卵巢癌、胰脏癌、胃癌、子宫颈癌、甲状腺癌、前列腺癌、皮肤癌、鳞状细胞癌;间叶细胞起源的肿瘤,纤维肉瘤、横纹肌肉瘤;中枢神经系统和外周神经系统的肿瘤,星形细胞瘤、成神经细胞瘤、神经胶质瘤、许旺氏细胞瘤;黑色素瘤、精原细胞瘤、畸胎瘤、骨肉瘤、着色性干皮病、角化棘皮瘤、甲状腺滤泡癌及卡波西氏肉瘤。
48.一种化合物,所述化合物选自
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