CN103298460A - 酪蛋白激酶1δ(CK1δ)抑制剂 - Google Patents
酪蛋白激酶1δ(CK1δ)抑制剂 Download PDFInfo
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- CN103298460A CN103298460A CN2011800601328A CN201180060132A CN103298460A CN 103298460 A CN103298460 A CN 103298460A CN 2011800601328 A CN2011800601328 A CN 2011800601328A CN 201180060132 A CN201180060132 A CN 201180060132A CN 103298460 A CN103298460 A CN 103298460A
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Abstract
本发明涉及包含酪蛋白激酶1δ(CK1δ)抑制剂的药物组合物以及所述抑制剂在治疗神经退行性疾病诸如阿尔茨海默氏病中的用途。
Description
本发明涉及包含酪蛋白激酶1δ(CK1δ)抑制剂的药物组合物以及所述抑制剂在治疗神经退行性疾病诸如阿尔茨海默氏病中的用途。
阿尔茨海默氏病(AD;也被称作阿尔茨海默型老年痴呆症(SDAT)、阿尔茨海默型原发性退行性痴呆(PDDAT)或阿尔茨海默症)是痴呆的最常见形式。通常，阿尔茨海默氏病的诊断是针对65岁以上的人，但有些少见的早发性阿尔茨海默氏病可能出现的要早得多。在2006年，全世界有2660万患者。预计到2050年，全球每85人中就将有1名阿尔茨海默氏病患者。
阿尔茨海默氏病是神经退行性疾病，其特征在于在脑中存在老年斑和神经原纤维缠结。死亡时的痴呆程度与神经原纤维缠结数的相关性高于老年斑计数。在神经元中存在神经原纤维缠结导致这些神经元的死亡，这意味着防止缠结的形成是一个重要的治疗目标。形成神经原纤维缠结的主要蛋白质是微管相关蛋白tau，其组装成具有以成对方式相互缠绕的外观的细丝，这些细丝被称作配对螺旋丝(PHF)。PHF存在于阿尔茨海默氏病患者脑中的退化神经元的不同位置，当有许多在神经元细胞体中聚集时，它们产生神经原纤维缠结(Lee等人,2001)。
Tau蛋白以AD患者典型的神经原纤维缠结的形式、或在多种其它神经退行性疾病中以其它形态学上不同的tau聚集体的形式在神经元内沉积是将这些病症分组为Tau病变的基础。因此，除AD外，Tau病变的主要例子是17号染色体相关的额颞痴呆兼帕金森综合征(FTDP-17)、进行性核上性麻痹(PSP)、匹克氏病、皮质基底节变性和多系统萎缩(MSA)。细胞内的tau沉积(通常是神经元细胞，但也可以是胶质细胞)都是丝状的，并且与对照人脑的tau的磷酸化水平相比大多数处于过度磷酸化状态。在AD的情况下，该过度磷酸化的tau通常被称作PHF-tau，因为其衍生自PHF。
Tau是一种磷酸化蛋白，磷酸化的功能还没有明确确定。但是，在多个丝氨酸和苏氨酸残基上增加的tau的磷酸化减弱了tau促进微管组装以及稳定组装好的微管的能力，在体外和细胞内均证实了这些效果。许多研究表明，AD脑的PHF-tau在丝氨酸和苏氨酸上的磷酸化比对照脑的tau更严重。这一点已部分通过蛋白测序证实，并部分通过证实某些单克隆抗体仅标记PHF-tau或仅标记非磷酸化的tau而不标记PHF-tau来证明;许多这些抗体的抗原表位被图示到存在于PHF-tau而在对照脑tau中缺乏的特定磷酸化残基上。大部分其它Tau病变的其它病例的病理性tau似乎对PHF-tau具有类似的过度磷酸化。
这些发现强烈暗示在包括AD在内的所有Tau病变中均存在类似的调节tau磷酸化的异常。
有许多脯氨酸定向的和非脯氨酸定向的蛋白激酶被认为在阿尔茨海默氏病患者脑中的PHF-tau的产生中起作用，包括酪蛋白激酶1。哺乳动物的酪蛋白激酶-1存在多种亚型，CK1α、CK1β、CK1у1、CK1у2、CK1у3、CK1δ和CK1ε。CK1δ作为潜在的tau激酶的作用是特别令人感兴趣的，因为已有报道表明，与同等对照物相比，CK1δ蛋白在阿尔茨海默氏病患者脑的海马中增加了30倍以上(Ghoshal,N.等人(1999)Am.J.Pathol155,1163-1172)，而其mRNA含量增加了24倍(Yasojima,K.等人(2000)BrainRes865,116-120)，并且CK1还表现出与PHF密切相关(Kuret,J.等人(1997)J.Neurochem69,2506-2515)。利用tau的磷酸特异性单克隆抗体进行检测，发现CK1δ在两个抗原表位上磷酸化tau，并且CK1δ在非神经元细胞中的外源性表达减弱了tau与微管的结合(Li,G.等人(2004)J.Biol.Chem.279,15938-15945)。关于阿尔茨海默氏病，值得关注的一篇报道是CK1活性受β-淀粉样肽(Aβ)的刺激，Aβ是老年神经炎斑块的组成部分，其与缠结一起构成了阿尔茨海默氏型脑的特征(Chauhan,A.等人(1993)Brain Res.629,47-52)。在阿尔茨海默氏病中CK1可能参与的其它证据来自所报道的在神经元中CK1对Aβ产生的调节的影响(Flajolet,M.等人(2007)PNASUSA104,4159-4164)。进一步的工作已证实，可以通过CK1δ在PHF-tau中产生至少6个新发现的磷酸化位点(都在丝氨酸或苏氨酸残基上)。在PHF-tau中，CK1是许多磷酸化位点的强的候选激酶，对于其中三个位点，CK1是唯一已知的激酶，这一发现意味着CK1对阿尔茨海默氏病的发病具有重要的贡献(Hanger等人(2007)J.Biol.Chem.282,23645-23654)。
因此，需要可在神经退行性疾病诸如Tau病变、包括阿尔茨海默氏病、17号染色体相关的额颞痴呆兼帕金森综合征(FTDP-17)、进行性核上性麻痹(PSP)、匹克氏病、皮质基底节变性和多系统萎缩(MSA)的治疗中产生潜在的治疗益处的CK1δ抑制剂。
本发明的第一方面提供了包含式(IB)化合物或其可药用盐或溶剂化物的药物组合物:
其中
“Het B”代表包含1至3个选自O、N或S的杂原子的5元杂环环系，其中所述的环系稠合到一个或多个(例如1-3个)另外的环上以形成包含最多4个环的多环环系;
Z代表键、–C(R7b)(R8b)-、(CH2)2、-O-、-S-、-CH2-O-、-(CH2)2-O-、NR6b、-N(R6b)-C(R7b)(R8b)-、-N(R6b)-(CH2)2-、-N(R6b)-(CH2)3-、-CH2-N(R6b)-(CH2)2-、-N(R6b)-CO-、-CH2-NH-CO-(CH2)2-、-N(R6b)-CO-CH2-、=N-、-N(R7b)-CH=、-C(H)(CN)-、-C(=N-NH-COC1-6烷基)-、-CH=C(R6b)-CO-、=CH-、-N=CH-、-N=C(Me)-、-C(R6b)=CH-、-NH-CO-C(=CH-杂芳基)-、-C(=C(R7b)(R8b))-、-CH=CH-CO-N(R6b)-、-CH=C(R6b)-CO-NH-CH2-、-CH=C(R6b)-NH-CO-、-CH=C(R6b)-CO-O-CH2-、-CS-S-CH2-、-NH-CS-NH-、-NH-CS-NH-CH2-、-NH-CS-NH-(CH2)2-、-CH2-N(CSNH2)-CH2-、-S-C(R5b)(R6b)-、-S-(CH2)2-O-、SO2、-NH-SO2-、-CH2-NH-SO2-、CO、-CH2-CO-、-(CH2)2-CO-、-O-CH2-CO-、-(CH2)2-CO-、COO、-COO-C(R7b)CO-、-CH=C(R5b)-CONH-CH2-、-CO-CH2-N(R6b)-CO-、-CO-CH2-C(R6b)-CH2-CO-、-CO-CH2-N(R6b)-CH2-、-CO-NH-N=C(R7b)-、-S-CH2-CO-、-S-CH2-CO-N(R6b)-、-S-CH2-CO-N(R6b)-CH2-、-SO2-N(R6b)-C(R7b)(R8b)-CONH-、-SO2-N(R6b)-CH(-CH2-芳基)-CONH-CH2-、-CH(-S-C1-6烷基)-C(Me)(OH)-、-CH2-C(R6b)(OH)-、-C(OH)(CH(Me)(C3-8环烷基))-CH2-、-C(OH)(R6b)-CH2-、-CH(Me)-NH-CO-CH2-、-CO-N(R6b)-CH2-、-C(H)(R6b)-CO-N(R5b)-CH2-、-CO-N(R6b)-CH2-CH2-、-CO-N(R6b)-CH2-CH2-CO-NH-CH2-、-CO-NH-C(-CONH2)=CH-、-CO-NH-CH(-CONH2)-CH2-、-CH2-C(H)(Me)-CH2-S-、-O-CH2-CO-NH-、-CH2-N(R6b)-CO-CH2-O-、-N(R6b)-CO-CH2-O-、-C(H)(-CH2-芳基)-、-C(H)(-CH2-杂芳基)-、-C(NH-芳基)=N-N=CH-、-C(NH-芳基)=N-N=CH-、-NH-CO-CH2-N(R6b)-、-NH-N=C(-芳基)-、-NH-N=C(-芳基)-CO-、-NH-C(=N-CO-C1-6烷基)-NH-(CH2)2-、-C(-NH-芳基)=N-N=CH-、-NH-C(-NH-芳基)=N-CONH-、-C(=CH-芳基)-CONH-CH2-、-CH=C(R6b)-CONH-、-CH(-CH2-芳基)-NH-CO-或-CH(OH)-，其中所述的Z的芳基或杂芳基基团可任选地被一个或多个卤素、C1-6烷基、C1-6烷氧基、NO2或羟基基团取代;
R5b代表氢、C1-6烷基或氰基;
R6b代表氢、C1-6烷基、C1-6烷氧基、氰基、COOH、-COOC1-6烷基、C3-8环烷基、-CH2-C3-8环烷基、芳基、杂芳基、-C1-6亚烷基-芳基、-CO-芳基、-O-CO-杂芳基、-CO-杂芳基或–C(R7b)(R8b)-杂芳基，其中所述的R6b的芳基基团可任选地被一个或多个卤素或C1-6烷氧基基团取代;
R7b和R8b独立地代表氢或C1-6烷基;
R1b代表芳基、C3-8环烷基、单环或二环杂环基或单环或二环杂芳基环系，其中R1b可被一个或多个(例如1、2或3个)R4b基团取代;
R4b代表卤素、C1-6烷基、C1-6烯基、C1-6炔基、C3-8环烷基、卤代C1-6烷基、羟基、C1-6烷氧基、-O-C1-6烯基、卤代C1-6烷氧基、-COOH、-CO-C1-6烷基、-COO-C1-6烷基、-CONH2、-CH2-CONH2、-NH-C1-6烷基、-NH-C2-6烯基、-NH-CO-C1-6烷基、-CO-NH-C1-6烷基、-O-CH2-CO-NH-C1-6烷基、-CH2-CH2-CO-NH-C1-6烷基、-S-C1-6烷基、-SO-C1-6烷基、-SO2-C1-6烷基、-SO2-NH2、-SO2-NH-C1-6烷基、-S-CH2-CO-C2-6烯基、-SO2-OH、氨基、氰基、NO2、=O、-CO-NH-(CH2)2)-OMe、-NH-C3-8环烷基、-CH2-CO-NH-C3-8环烷基、-CO-杂环基、-CO-杂芳基、-COO-(CH2)2-杂环基、-CH2-芳基、-OCH2-芳基、-OCH2-杂芳基、-CH2-O-CO-芳基、-O-芳基、-NH-CO-芳基、-NH-CO-杂芳基、-NH-CO-CH2-芳基、-NH-芳基、芳基或杂芳基基团，其中所述的R4b的芳基、杂环基或杂芳基基团可任选地被一个或多个卤素、C1-6烷基、C1-6烷氧基、=S或羟基基团取代，并且其中所述的R4b的C1-6烷基或C2-6烯基基团可任选地被一个或多个羟基、氨基、氰基、C1-6烷氧基、CONH2或-COO-C1-6烷基基团取代;
m代表0至3的整数;
R2b代表卤素、卤代C1-6烷基、C1-6烷基、C3-8环烷基、羟基、C1-6烷氧基、-S-C1-6烷基、-CH2-S-C1-6烷基、-S-C2-6炔基、氨基、氰基、NO2、=O、=S、-SO2-C1-6烷基、-CONH2、-CO-C1-6烷基、-COO-C1-6烷基、-NH-C1-6烷基、-NH-CO-C1-6烷基、-NH-CO-CH=CH-CH2-N(Me)2、C1-6烷基、-CO-NH-C1-6烷基、-CO-NH-CH(Me)-COOH、-S-CH2-CO-N(Et)2、-NH-(CH2)2-OH、-NH-(CH2)3-OH、-NH-CH(Et)-CH2-OH、-CO-NH-(CH2)3-OH、-CH(CH2OH)2或-S-CH2-CO-NH-CO-NH-C1-6烷基，其中所述的R2b的C1-6烷基基团可任选地被一个或多个氰基或羟基基团取代;
条件是化合物不是序号为54、373、458、496、585、590、594、596-597、601-602、649、703、778、877、891、910、912、926和962-963的化合物。
根据本文所述的本发明的一个特定方面，提供了作为酪蛋白激酶1δ(CK1δ)抑制剂用于治疗神经退行性疾病诸如Tau病变的式(IB)化合物或其可药用盐或溶剂化物:
其中
“Het B”代表包含1至3个选自O、N或S的杂原子的5元杂环环系，其中所述的环系稠合到一个或多个(例如1-3个)另外的环上以形成包含最多4个环的多环环系;
Z代表键、–C(R7b)(R8b)-、(CH2)2、-O-、-S-、-CH2-O-、-(CH2)2-O-、NR6b、-N(R6b)-C(R7b)(R8b)-、-N(R6b)-(CH2)2-、-N(R6b)-(CH2)3-、-CH2-N(R6b)-(CH2)2-、-N(R6b)-CO-、-CH2-NH-CO-(CH2)2-、-N(R6b)-CO-CH2-、=N-、-C(H)(CN)-、-C(=N-NH-COC1-6烷基)-、-CH=C(R6b)-CO-、=CH-、-N=CH-、-N=C(Me)-、-C(R6b)=CH-、-NH-CO-C(=CH-杂芳基)-、-C=C(Me)2-、-CH=CH-CO-N(R6b)-、-CH=C(R6b)-CO-NH-CH2-、-CH=C(R6b)-NH-CO-、-CH=C(R6b)-CO-O-CH2-、-CS-S-CH2-、-NH-CS-NH-、-NH-CS-NH-CH2-、-NH-CS-NH-(CH2)2-、-CH2-N(CSNH2)-CH2-、-S-C(R5b)(R6b)-、-S-(CH2)2-O-、SO2、-NH-SO2-、-CH2-NH-SO2-、CO、-CH2-CO-、-(CH2)2-CO-、-O-CH2-CO-、-(CH2)2-CO-、COO、-COO-C(R7b)CO-、-CH=C(R5b)-CONH-CH2-、-CO-CH2-N(R6b)-CO-、-CO-CH2-C(R6b)-CH2-CO-、-CO-CH2-N(R6b)-CH2-、-CO-NH-N=C(R7b)-、-S-CH2-CO-、-S-CH2-CO-N(R6b)-、-S-CH2-CO-N(R6b)-CH2-、-SO2-N(R6b)-C(R7b)(R8b)-CONH-、-SO2-N(R6b)-CH(-CH2-芳基)-CONH-CH2-、-CH(-S-C1-6烷基)-C(Me)(OH)-、-CH2-C(R6b)(OH)-、-C(OH)(CH(Me)(C3-8环烷基))-CH2-、-C(OH)(R6b)-CH2-、-CH(Me)-NH-CO-CH2-、-CO-N(R6b)-CH2-、-C(H)(R6b)-CO-N(R5b)-CH2-、-CO-N(R6b)-CH2-CH2-、-CO-N(R6b)-CH2-CH2-CO-NH-CH2-、-CO-NH-C(-CONH2)=CH-、-CO-NH-CH(-CONH2)-CH2-、-CH2-C(H)(Me)-CH2-S-、-O-CH2-CO-NH-、-CH2-N(R6b)-CO-CH2-O-、-N(R6b)-CO-CH2-O-、-C(H)(-CH2-芳基)-、-C(H)(-CH2-杂芳基)-、-C(NH-芳基)=N-N=CH-、-C(NH-芳基)=N-N=CH-、-NH-CO-CH2-N(R6b)-、-NH-N=C(-芳基)-、-NH-N=C(-芳基)-CO-、-NH-C(=N-CO-C1-6烷基)-NH-(CH2)2-、-C(-NH-芳基)=N-N=CH-、-NH-C(-NH-芳基)=N-CONH-、-C(=CH-芳基)-CONH-CH2-、-CH=C(R6b)-CONH-、-CH(-CH2-芳基)-NH-CO-或-CH(OH)-，其中所述的Z的芳基或杂芳基基团可任选地被一个或多个卤素、C1-6烷基、C1-6烷氧基、NO2或羟基基团取代;
R5b代表氢、C1-6烷基或氰基;
R6b代表氢、C1-6烷基、C1-6烷氧基、氰基、COOH、-COOC1-6烷基、C3-8环烷基、-CH2-C3-8环烷基、芳基、杂芳基、-C1-6亚烷基-芳基、-CO-芳基、-O-CO-杂芳基、-CO-杂芳基或–C(R7b)(R8b)-杂芳基，其中所述的R6b的芳基基团可任选地被一个或多个卤素或C1-6烷氧基基团取代;
R7b和R8b独立地代表氢或C1-6烷基;
R1b代表芳基、C3-8环烷基、单环或二环杂环基或单环或二环杂芳基环系，其中R1b可被一个或多个(例如1、2或3个)R4b基团取代;
R4b代表卤素、C1-6烷基、C1-6烯基、C1-6炔基、C3-8环烷基、卤代C1-6烷基、羟基、C1-6烷氧基、-O-C1-6烯基、卤代C1-6烷氧基、-COOH、-CO-C1-6烷基、-COO-C1-6烷基、-CONH2、-CH2-CONH2、-NH-C1-6烷基、-NH-C2-6烯基、-NH-CO-C1-6烷基、-CO-NH-C1-6烷基、-O-CH2-CO-NH-C1-6烷基、-CH2-CH2-CO-NH-C1-6烷基、-S-C1-6烷基、-SO-C1-6烷基、-SO2-C1-6烷基、-SO2-NH-C1-6烷基、-S-CH2-CO-C2-6烯基、-SO2-OH、氨基、氰基、NO2、=O、-CO-NH-(CH2)2)-OMe、-NH-C3-8环烷基、-CH2-CO-NH-C3-8环烷基、-CO-杂环基、-CO-杂芳基、-COO-(CH2)2-杂环基、-OCH2-芳基、-OCH2-杂芳基、-CH2-O-CO-芳基、-O-芳基、-NH-CO-芳基、-NH-CO-杂芳基、-NH-CO-CH2-芳基、-NH-芳基、芳基或杂芳基基团，其中所述的R4b的芳基、杂环基或杂芳基基团可任选地被一个或多个卤素、C1-6烷基、C1-6烷氧基、=S或羟基基团取代，并且其中所述的R4b的C1-6烷基或C2-6烯基基团可任选地被一个或多个羟基、氨基、氰基、C1-6烷氧基、CONH2或-COO-C1-6烷基基团取代;
m代表0至3的整数;
R2b代表卤素、卤代C1-6烷基、C1-6烷基、羟基、C1-6烷氧基、-S-C1-6烷基、-CH2-S-C1-6烷基、-S-C2-6炔基、氨基、氰基、NO2、=O、=S、-SO2-C1-6烷基、-CONH2、-CO-C1-6烷基、-COO-C1-6烷基、-NH-C1-6烷基、-NH-CO-C1-6烷基、-NH-CO-CH=CH-CH2-N(Me)2、C1-6烷基、-CO-NH-C1-6烷基、-CO-NH-CH(Me)-COOH、-S-CH2-CO-N(Et)2、-NH-(CH2)2-OH、-NH-(CH2)3-OH、-NH-CH(Et)-CH2-OH、-CO-NH-(CH2)3-OH、-CH(CH2OH)2或-S-CH2-CO-NH-CO-NH-C1-6烷基，其中所述的R2b的C1-6烷基基团可任选地被一个或多个羟基基团取代;
条件是化合物不是序号为54、373、496和585的化合物。
根据本文所述的本发明的另一个特定方面，提供了作为酪蛋白激酶1δ(CK1δ)抑制剂用于治疗神经退行性疾病诸如Tau病变的式(IB)化合物或其可药用盐或溶剂化物:
其中
“Het B”代表包含1至3个选自O、N或S的杂原子的5元杂环环系，其中所述的环系稠合到一个或多个(例如1-3个)另外的环上以形成包含最多4个环的多环环系;
Z代表键、–C(R7b)(R8b)-、(CH2)2、-O-、-S-、-CH2-O-、-(CH2)2-O-、NR6b、-N(R6b)-C(R7b)(R8b)-、-N(R6b)-(CH2)2-、-N(R6b)-(CH2)3-、-CH2-N(R6b)-(CH2)2-、-N(R6b)-CO-、-CH2-NH-CO-(CH2)2-、-N(R6b)-CO-CH2-、=N-、-C(H)(CN)-、-C(=N-NH-COC1-6烷基)-、-CH=C(R6b)-CO-、=CH-、-N=CH-、-N=C(Me)-、-C(R6b)=CH-、-NH-CO-C(=CH-杂芳基)-、-C=C(Me)2-、-CH=CH-CO-N(R6b)-、-CH=C(R6b)-NH-CO-、-CH=C(R6b)-CO-O-CH2-、-CS-S-CH2-、-NH-CS-NH-、-NH-CS-NH-CH2-、-NH-CS-NH-(CH2)2-、-CH2-N(CSNH2)-CH2-、-S-CH2-、-S-(CH2)2-O-、SO2、-NH-SO2-、-CH2-NH-SO2-、CO、-CH2-CO-、-(CH2)2-CO-、-O-CH2-CO-、-(CH2)2-CO-、COO、-COO-C(R7b)CO-、-CH=C(R5b)-CONH-CH2-、-CO-CH2-N(R6b)-CO-、-CO-CH2-C(R6b)-CH2-CO-、-CO-CH2-N(R6b)-CH2-、-CO-NH-N=C(R7b)-、-S-CH2-CO-、-S-CH2-CO-N(R6b)-、-S-CH2-CO-N(R6b)-CH2-、-SO2-N(R6b)-C(R7b)(R8b)-CONH-、-SO2-N(R6b)-CH(-CH2-芳基)-CONH-CH2-、-CH(-S-C1-6烷基)-C(Me)(OH)-、-CH2-C(R6b)(OH)-、-C(OH)(CH(Me)(C3-8环烷基))-CH2-、-C(OH)(R6b)-CH2-、-CH(Me)-NH-CO-CH2-、-CO-N(R6b)-CH2-、-CO-N(R6b)-CH2-CH2-、-CO-N(R6b)-CH2-CH2-CO-NH-CH2-、-CO-NH-C(-CONH2)=CH-、-CO-NH-CH(-CONH2)-CH2-、-CH2-C(H)(Me)-CH2-S-、-O-CH2-CO-NH-、-CH2-N(R6b)-CO-CH2-O-、-N(R6b)-CO-CH2-O-、-C(H)(-CH2-芳基)-、-C(H)(-CH2-杂芳基)-、-C(NH-芳基)=N-N=CH-、-C(NH-芳基)=N-N=CH-、-NH-N=C(-芳基)-、-NH-N=C(-芳基)-CO-、-NH-C(=N-CO-C1-6烷基)-NH-(CH2)2-、-C(-NH-芳基)=N-N=CH-、-NH-C(-NH-芳基)=N-CONH-、-C(=CH-芳基)-CONH-CH2-、-CH=C(R6b)-CONH-、-CH(-CH2-芳基)-NH-CO-或-CH(OH)-，其中所述的Z的芳基或杂芳基基团可任选地被一个或多个卤素、C1-6烷基、C1-6烷氧基、NO2或羟基基团取代;
R5b代表氢、C1-6烷基或氰基;
R6b代表氢、C1-6烷基、C1-6烷氧基、氰基、C3-8环烷基、-CH2-C3-8环烷基、芳基、杂芳基、-C1-6亚烷基-芳基、-CO-芳基、-CO-杂芳基或–C(R7b)(R8b)-杂芳基，其中所述的R6b的芳基基团可任选地被一个或多个卤素或C1-6烷氧基基团取代;
R7b和R8b独立地代表氢或C1-6烷基;
R1b代表芳基、C3-8环烷基、单环或二环杂环基或单环或二环杂芳基环系，其中R1b可被一个或多个(例如1、2或3个)R4b基团取代;
R4b代表卤素、C1-6烷基、C1-6烯基、C1-6炔基、C3-8环烷基、卤代C1-6烷基、羟基、C1-6烷氧基、-O-C1-6烯基、卤代C1-6烷氧基、-COOH、-CO-C1-6烷基、-COO-C1-6烷基、-CONH2、-CH2-CONH2、-NH-C1-6烷基、-NH-C2-6烯基、-NH-CO-C1-6烷基、-CO-NH-C1-6烷基、-O-CH2-CO-NH-C1-6烷基、-CH2-CH2-CO-NH-C1-6烷基、-S-C1-6烷基、-SO-C1-6烷基、-SO2-C1-6烷基、-SO2-NH-C1-6烷基、-S-CH2-CO-C2-6烯基、-SO2-OH、氨基、氰基、NO2、=O、-CO-NH-(CH2)2)-OMe、-NH-C3-8环烷基、-CO-杂环基、-CO-杂芳基、-COO-(CH2)2-杂环基、-OCH2-芳基、-OCH2-杂芳基、-CH2-O-CO-芳基、-O-芳基、-NH-CO-杂芳基、-NH-CO-CH2-芳基、芳基或杂芳基基团，其中所述的R4b的芳基、杂环基或杂芳基基团可任选地被一个或多个卤素、C1-6烷基、C1-6烷氧基、=S或羟基基团取代，并且其中所述的R4b的C1-6烷基或C2-6烯基基团可任选地被一个或多个羟基、氨基、氰基、C1-6烷氧基、CONH2或-COO-C1-6烷基基团取代;
m代表0至3的整数;
R2b代表卤素、卤代C1-6烷基、C1-6烷基、羟基、C1-6烷氧基、-S-C1-6烷基、-CH2-S-C1-6烷基、-S-C2-6炔基、氨基、氰基、NO2、=O、=S、-SO2-C1-6烷基、-CONH2、-CO-C1-6烷基、-COO-C1-6烷基、-NH-C1-6烷基、-NH-CO-C1-6烷基、-NH-CO-CH=CH-CH2-N(Me)2、C1-6烷基、-CO-NH-C1-6烷基、-CO-NH-CH(Me)-COOH、-S-CH2-CO-N(Et)2、-NH-(CH2)2-OH、-NH-(CH2)3-OH、-NH-CH(Et)-CH2-OH、-CO-NH-(CH2)3-OH、-CH(CH2OH)2或-S-CH2-CO-NH-CO-NH-C1-6烷基，其中所述的R2b的C1-6烷基基团可任选地被一个或多个羟基基团取代。
在式(IB)化合物的一种实施方案中，
“Het B”代表包含1至3个选自O、N或S的杂原子的5元杂环环系，其中所述的环系稠合到6元环上形成二环杂环环系;
Z代表键、–C(R7b)(R8b)-、-O-、-S-、-CH2-O-、-N(R6b)-C(R7b)(R8b)-、-N(R6b)-(CH2)2-、-N(R6b)-(CH2)3-、-N(R6b)-CO-、-N(R6b)-CO-CH2-、-N(R7b)-CH=、=CH-、-N=CH-、-C(R6b)=CH-、-C(=C(R7b)(R8b))-、SO2、-CH2-NH-SO2-、CO、-O-CH2-CO-、-SO2-N(R6b)-C(R7b)(R8b)-CONH-、-SO2-N(R6b)-CH(-CH2-芳基)-CONH-CH2-、-CH(-S-C1-6烷基)-C(Me)(OH)-、-C(H)(R6b)-CO-N(R5b)-CH2-、-O-CH2-CO-NH-、-N(R6b)-CO-CH2-O-、-C(H)(-CH2-芳基)-、-C(NH-芳基)=N-N=CH-、-NH-CO-CH2-N(R6b)-、-NH-N=C(-芳基)-、-NH-C(=N-CO-C1-6烷基)-NH-(CH2)2-、-C(=CH-芳基)-CONH-CH2-或-CH(-CH2-芳基)-NH-CO-，其中所述的Z的芳基或杂芳基基团可任选地被一个或多个卤素、C1-6烷基、C1-6烷氧基、NO2或羟基基团取代;
R5b代表氢;
R6b代表氢、甲基、C1-6烷氧基、-COOH、-CO-芳基、-O-CO-杂芳基或-CO-杂芳基，其中所述的R6b的芳基基团可任选地被一个或多个卤素或C1-6烷氧基基团取代;
R7b和R8b独立地代表氢或C1-6烷基;
R1b代表单环芳基或杂芳基环系，其中R1b可被一个或多个(例如1、2或3个)R4b基团取代;
R4b代表卤素、羟基、-O-C1-6烯基、-COO-C1-6烷基、-NH-C1-6烷基、-SO2-NH2、氨基、氰基、=O、-CH2-CO-NH-C3-8环烷基、-CH2-芳基、-OCH2-杂芳基、-O-芳基、-NH-CO-芳基、-NH-芳基或杂芳基基团，其中所述的R4b的芳基、杂环基或杂芳基基团可任选地被一个或多个卤素、C1-6烷基、C1-6烷氧基、=S或羟基基团取代，并且其中所述的R4b的C1-6烷基或C2-6烯基基团可任选地被一个或多个羟基、氨基、氰基、C1-6烷氧基、CONH2或-COO-C1-6烷基基团取代;
m代表0至2的整数;并且
R2b代表卤素、卤代C1-6烷基、C1-6烷基、C3-8环烷基、羟基、C1-6烷氧基、-S-C1-6烷基、氨基、氰基、NO2、=O、-CONH2、-CO-C1-6烷基、-COO-C1-6烷基、C1-6烷基、-CO-NH-C1-6烷基或-CO-NH-CH(Me)-COOH，其中所述的R2b的C1-6烷基基团可任选地被一个或多个氰基或羟基基团取代。
在一个实施方案中，Het B代表包含1至3个选自O、N或S的杂原子的5元杂环环系，其中所述的环系稠合到6元环上形成二环杂环环系。在另一个实施方案中，Het B代表苯并唑基、吲哚基或中氮茚基。
在一个实施方案中，R5b代表氢。
在一个实施方案中，R6b代表氢、C1-6烷基、C1-6烷氧基、-COOH、-CO-芳基、-O-CO-杂芳基、-CO-杂芳基或–C(R7b)(R8b)-杂芳基，其中所述的R6b的芳基基团可任选地被一个或多个卤素或C1-6烷氧基基团取代。
在一个实施方案中，R1b代表单环芳基或杂芳基环系，其中R1b可被一个或多个(例如1、2或3个)R4b基团取代。在另一个实施方案中，R1b代表单环芳基，例如任选地被一个或多个(例如1个)R4b基团取代的苯基。在另一个实施方案中，R1b代表单环杂芳基，例如任选地被一个或多个(例如1或2个)R4b基团取代的噻吩基、嘧啶基或吡唑啉基。
在一个实施方案中，R4b代表卤素、羟基、-O-C1-6烯基、-COO-C1-6烷基、-NH-C1-6烷基、-SO2-NH2、氨基、氰基、=O、-CH2-CO-NH-C3-8环烷基、-CH2-芳基、-OCH2-杂芳基、-O-芳基、-NH-CO-芳基、-NH-芳基或杂芳基基团，其中所述的R4b的芳基、杂环基或杂芳基基团可任选地被一个或多个卤素、C1-6烷基、C1-6烷氧基、=S或羟基基团取代，并且其中所述的R4b的C1-6烷基或C2-6烯基基团可任选地被一个或多个羟基、氨基、氰基、C1-6烷氧基、CONH2或-COO-C1-6烷基基团取代。
在另一个实施方案中，R4b代表卤素(例如氟)、氨基或杂芳基(例如吡啶基)。
在一个实施方案中，Z代表键、–C(R7b)(R8b)-、-O-、-S-、-CH2-O-、-N(R6b)-C(R7b)(R8b)-、-N(R6b)-(CH2)2-、-N(R6b)-(CH2)3-、-N(R6b)-CO-、-N(R6b)-CO-CH2-、-N(R7b)-CH=、=CH-、-N=CH-、-C(R6b)=CH-、-C(=C(R7b)(R8b))-、SO2、-CH2-NH-SO2-、CO、-O-CH2-CO-、-SO2-N(R6b)-C(R7b)(R8b)-CONH-、-SO2-N(R6b)-CH(-CH2-芳基)-CONH-CH2-、-CH(-S-C1-6烷基)-C(Me)(OH)-、-C(H)(R6b)-CO-N(R5b)-CH2-、-O-CH2-CO-NH-、-N(R6b)-CO-CH2-O-、-C(H)(-CH2-芳基)-、-C(NH-芳基)=N-N=CH-、-NH-CO-CH2-N(R6b)-、-NH-N=C(-芳基)-、-NH-C(=N-CO-C1-6烷基)-NH-(CH2)2-、-C(=CH-芳基)-CONH-CH2-或-CH(-CH2-芳基)-NH-CO-，其中所述的Z的芳基或杂芳基基团可任选地被一个或多个卤素、C1-6烷基、C1-6烷氧基、NO2或羟基基团取代。
在另一个实施方案中，Z代表键或CO。
在一个实施方案中，m代表0至2的整数。在一个实施方案中，m代表0。在另一个实施方案中，m代表2。
在一个实施方案中，R2b代表卤素、卤代C1-6烷基、C1-6烷基、C3-8环烷基、羟基、C1-6烷氧基、-S-C1-6烷基、氨基、氰基、NO2、=O、-CONH2、-CO-C1-6烷基、-COO-C1-6烷基、C1-6烷基、-CO-NH-C1-6烷基或-CO-NH-CH(Me)-COOH，其中所述的R2b的C1-6烷基基团可任选地被一个或多个氰基或羟基基团取代。
在另一个实施方案中，R2b代表氨基或-CONH2。
在一个实施方案中，式(IB)化合物选自本文所述的化合物2-3、26-28、30-33、35、47-48、51、57-60、63-64、78、84、113、123、127-129、145、155-157、171-173、204、206-207、210、225、227、233、235-236、241-242、244、249、269、285、288、303、307-312、314-316、320、324-325、333、336、351、357-360、374-375、384-391、396、399-402、404-405、407-411、414、424-425、427-428、437、448、456-457、482、484-485、489-491、495、497-498、505、507、516、519、524、526、553、559-560、568、570、575、609、615-616、618、626-627、638、653、669、692-694、705、709、712、716、719、725、734、738、740、746、749、753-754、756、758-759、767、770、777、784-785、790、792、796、800-801、804-805、808、819、821、827-828、831、833、838、844、847、857-858、869、872、875、933、952、955、969、987、990或999中的任何一种或其可药用盐或溶剂化物。
在另一个实施方案中，式(IB)化合物选自本文所述化合物2-3、26-28、30、32-33、47-48、51、59-60、84、113、123、127、129、145、155、157、172-173、204、206-207、210、225、233、235-236、241、244、269、285、288、307-311、315-316、320、324-325、333、336、351、357-360、374-375、385-386、388-391、396、399-402、404-405、407-410、414、424、427-428、437、457、482、490、495、497-498、505、516、519、553、559-560或568中的任何一种或其可药用盐或溶剂化物。
在另一个实施方案中，式(IB)化合物选自本文所述化合物30、314、324-325、391、405、626、705、753-754、759、770、784、808、833或847中的任何一种或其可药用盐或溶剂化物。
在另一个实施方案中，式(IB)化合物选自本文所述化合物324-325、405、754或847中的任何一种或其可药用盐或溶剂化物。
在一个实施方案中，式(IB)化合物选自本文所述化合物30、288、314、324-325、336、374、391、405、615-616、626、705、740、753-754、756、759、770、784、808、819、833、844、847、869、872、875、933、952、955、969、987、990和999中的任何一种或其可药用盐或溶剂化物。该实施方案的化合物在本文所述的CK1δ抑制试验中进行了测试并且表现出抑制活性大于5%。
在另一个实施方案中，式(IB)化合物选自本文所述化合物324-325、405、754、847、952、987、990和999中的任何一种或其可药用盐或溶剂化物。该实施方案的化合物在本文所述的CK1δ抑制试验中进行了测试并且表现出抑制活性大于50%。
在另一个实施方案中，式(IB)化合物选自以下化合物或其可药用盐或溶剂化物中的任一种:
5-(1,3-苯并
唑-2-基)-4-(吡啶-4-基)嘧啶-2-胺(化合物324);
2-氨基-3-[(噻吩-2-基)羰基]中氮茚-1-甲酰胺(化合物847);
2-[3-(吡啶-4-基)-1H-吡唑-4-基]-1,3-苯并唑(化合物952);
2-氨基-3-[(4-氟苯基)羰基]中氮茚-1-甲酰胺(化合物987);
2-氨基-3-苯甲酰基中氮茚-1-甲酰胺(化合物990);和
2-氨基-1-[(4-氟苯基)羰基]-1H-吲哚-3-甲酰胺(化合物999)。
在另一个实施方案中，式(IB)化合物选自本文所述化合物324、952、987、990和999中的任何一种或其可药用盐或溶剂化物。该实施方案的化合物在本文所述的CK1δ抑制试验中进行了测试并且表现出抑制活性大于90%。
在另一个实施方案中，式(IB)化合物选自本文所述化合物324、952、987和999中的任何一种或其可药用盐或溶剂化物。该实施方案的化合物在一系列激酶抑制试验中进行了测试，其不仅在本文所述的CK1δ抑制试验中表现出抑制活性大于90%，而且与其它激酶相比，对于CK1δ表现出显著的和选择性抑制。
例如，化合物编号324(5-(1,3-苯并
唑-2-基)-4-(吡啶-4-基)嘧啶-2-胺)表现出对CK1δ的选择性超过ABL2/ARG、ALK4/ACVR1B、ALK5/TGFBR1、CDK5/p25、CK1a1、CK1g1、CK1g3、CLK2、c-SRC、EGFR、EPHA2、FGFR1、GSK3b、HGK/MAP4K4、JNK2、KDR/VEGFR2、LCK、MSK1/RPS6KA5、PDK1/PDPK1、PIM3、PKA、PKCa、PKCb2、RIPK2、ROCK1、TNIK和YES/YES1，对它们的抑制活性均小于40%。
例如，化合物编号952(2-[3-(吡啶-4-基)-1H-吡唑-4-基]-1,3-苯并
唑)表现出对CK1δ的选择性超过ABL2/ARG、ALK4/ACVR1B、ALK5/TGFBR1、CDK5/p25、CK1g1、CK1g2、CK1g3、c-SRC、EGFR、EPHA2、FGFR1、KDR/VEGFR2、LCK、MSK1/RPS6KA5、PDK1/PDPK1、PIM3、PKA、PKCa、PKCb2、ROCK1和YES/YES1，对它们的抑制活性均小于40%。
例如，化合物编号987(2-氨基-3-[(4-氟苯基)羰基]中氮茚-1-甲酰胺)表现出对CK1δ的选择性超过ABL2/ARG、CDK5/p25、CK1g1、CK1g2、CK1g3、CLK2、c-SRC、FGFR1、GSK3b、HGK/MAP4K4、JNK2、KDR/VEGFR2、LCK、MSK1/RPS6KA5、PDK1/PDPK1、PIM3、PKCa、PKCb2、ROCK1和TNIK，对它们的抑制活性均小于40%。
例如，化合物编号999(2-氨基-1-[(4-氟苯基)羰基]-1H-吲哚-3-甲酰胺)表现出对CK1δ的选择性超过ABL2/ARG、CDK5/p25、CK1g1、CK1g2、CLK2、c-SRC、FGFR1、GSK3b、HGK/MAP4K4、KDR/VEGFR2、LCK、MSK1/RPS6KA5、PDK1/PDPK1、PIM3、PKCa、PKCb2和ROCK1，对它们的抑制活性均小于40%。
在另一个实施方案中，式(IB)化合物选自本文所述化合物324和987中的任何一种或其可药用盐或溶剂化物。该实施方案的化合物已被证实对细胞存活具有保护作用，这一点可从本文提供的数据、尤其是从图1和2中看出。该实施方案的化合物还被证实可抑制Tau蛋白内的两个不同氨基酸残基(即Ser396和Thr391)的磷酸化，如图4和5所示。
在另一个实施方案中，式(IB)化合物是本文所述的化合物324或其可药用盐或溶剂化物。该实施方案的化合物已被证实以剂量依赖的方式对细胞存活产生保护作用，这一点可从本文提供的数据、尤其是从图1中看出。该实施方案的化合物还被证实可抑制Tau蛋白内的两个不同氨基酸残基(即Ser396和Thr391)的磷酸化，如图4A和5所示。
在本文中，术语“可药用盐”是指对患者无害的盐。所述的盐包括可药用酸加成盐、可药用金属盐和可药用碱加成盐。酸加成盐包括无机酸以及有机酸的盐。
适当的无机酸的代表性的例子包括盐酸、氢溴酸、氢碘酸、磷酸、硫酸、硝酸等。适当的有机酸的代表性的例子包括甲酸、乙酸、三氯乙酸、三氟乙酸、丙酸、苯甲酸、肉桂酸、柠檬酸、富马酸、乙醇酸、乳酸、马来酸、苹果酸、丙二酸、扁桃酸、草酸、苦味酸、丙酮酸、水杨酸、琥珀酸、甲磺酸、乙磺酸、酒石酸、抗坏血酸、双羟萘酸、二亚甲基水杨酸、乙二磺酸、葡糖酸、柠康酸、天冬氨酸、硬脂酸、棕榈酸、EDTA、乙醇酸、对-氨基苯甲酸、谷氨酸、苯磺酸、对-甲苯磺酸等。其它的可药用无机或有机酸加成盐的例子包括J.Pharm.Sci.1977,66,2中列出的可药用盐，在此将其引入作为参考。金属盐的例子包括锂、钠、钾、镁盐等。铵和烷基化铵盐的例子包括铵、甲基铵、二甲基铵、三甲基铵、乙基铵、羟基乙基铵、二乙基铵、丁基铵、四甲基铵盐等。
碱金属盐的代表性的例子包括例如钠、钾、锂、钙、镁或铵或有机碱诸如甲基胺、乙基胺、丙基胺、三甲基胺、二乙基胺、三乙基胺、N,N-二甲基乙醇胺、三(羟基甲基)氨基甲烷、乙醇胺、吡啶、哌啶、哌嗪、甲基吡啶、二环己基胺、吗啉、苄基胺、普鲁卡因、赖氨酸、精氨酸、组氨酸、N-甲基葡糖胺。
根据本发明，式(IB)化合物可以是外消旋形式以及纯对映体形式或对映体的非外消旋混合物，包括当式(IB)化合物具有一个以上的手性中心的情况。在式(IB)化合物具有不饱和碳碳双键的情况下，顺式(Z)和反式(E)异构体及其混合物都属于本发明。
本文所提及的“卤素”是指氟、氯、溴或碘原子。
本文所提及的“C1-6烷基”是指任何具有1至6个碳原子的直链、支链烃基团或具有3至6个碳原子的环烃基团。该烷基基团的代表性的例子包括甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基、正-戊基、异戊基、新戊基、环丙基、环丁基、环戊基和环己基。所提及的“卤代C1-6烷基”是指被本文所定义的一个或多个卤素原子取代的C1-6烷基。
本文所提及的“C1-6亚烷基”是指具有指定数目的成员原子的饱和二价烃链。例如，C1-6亚烷基是指键或具有1至6个成员原子的亚烷基。亚烷基基团可以是直链或支链。代表性的支链亚烷基基团具有一个或两个分支。亚烷基包括亚甲基、亚乙基、亚丙基(正亚丙基和异亚丙基)和亚丁基(正亚丁基、异亚丁基和叔亚丁基)。
本文所提及的“C2-6烯基”是指具有至少一个双键的任何具有2至6个碳原子的直链、支链烃基团或具有3至6个碳原子环烃基。烯基基团的代表性的例子包括乙烯基、丙烯基、丁烯基和环己烯基。
本文所提及的“C2-6炔基”是指具有至少一个三键的任何具有2至6个碳原子的直链或支链烃基团。该炔基基团的代表性的例子包括乙炔基、丙炔基和丁炔基。
本文所提及的“C1-6烷氧基”是指-O-C1-6烷基，其中C1-6烷基如本文所定义。该基团的例子包括甲氧基、乙氧基、丙氧基、丁氧基、戊氧基或己氧基等。
本文所提及的“C3-8环烷基”是指3至8个碳原子的饱和单环烃环。该基团的例子包括环丙基、环丁基、环戊基、环己基、环庚基或环辛基等。
本文所提及的“芳基”是指C6-12单环或二环烃环，其中至少一个环是芳香族的。该基团的例子包括苯基、茚基或萘基等。
本文所提及的“杂原子”是指氮、硫或氧原子。
本文所提及的“杂环基”是指包含1至4个杂原子作为环中成员原子的饱和或不饱和的非芳香族环。包含1个以上杂原子的杂环基基团可含有不同的杂原子。杂环基基团可任选地被一个或多个本文所定义的取代基取代。杂环基基团是单环环系或稠合的二环或多环环系，或是被称作杂环“螺”环系的二环结构。在某些实施方案中，杂环基是饱和的。在其它实施方案中，杂环基是不饱和的并且是非芳香族的。单环杂环基环系的非限制性的例子包括吡咯烷基、四氢呋喃基、二氢呋喃基、吡喃基、四氢吡喃基、二氢吡喃基、四氢噻吩、吡唑烷基、唑烷基、噻唑烷基、哌啶基、高哌啶基、哌嗪基、吗啉基、硫代吗啉基、1,3-二氧戊环基、1,3-二氧杂环己基、1,4-二氧杂环己基、1,3-氧硫杂环戊基、1,3-氧硫杂环己基、1,3-二硫杂环己基和氮杂环丁基。
本文所提及的“杂芳基”是指含有1至4个杂原子作为环中的成员原子的芳环。包含1个以上的杂原子的杂芳基基团可含有不同的杂原子。杂芳基基团可任选地被一个或多个本文所定义的取代基取代。杂芳基基团是单环环系或是稠合的二环或多环环系。单环杂芳基环具有5或6个成员原子。二环杂芳基环具有7至11个成员原子。二环杂芳基环包括其中苯基和单环杂环基环相连形成稠合的二环环系的那些环，以及其中的单环杂芳基环和单环环烷基、环烯基、杂环基或杂芳基环相连形成稠合的二环环系的那些环。杂芳基的非限制性的例子包括吡咯基、吡唑基、咪唑基、
唑基、异
唑基、噻唑基、异噻唑基、呋喃基、呋咱基、噻吩、三唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、三嗪基、四嗪基、吲哚基、异吲哚基、中氮茚基、吲唑基、嘌呤基、喹啉基、异喹啉基、喹喔啉基、喹唑啉基、蝶啶基、噌啉基、苯并咪唑基、苯并吡喃基、苯并
唑基、苯并呋喃基、异苯并呋喃基、苯并噻唑基、苯并噻吩基、呋喃并吡啶基和萘啶基。
本文所提及的“杂环环系”是指上文所定义的杂环基环系或杂芳基环系。
代表性的式(IB)化合物包括以下所列出的化合物:
本发明的另一个方面提供了作为酪蛋白激酶1δ(CK1δ)抑制剂用于治疗神经退行性疾病诸如Tau病变的式(IB)化合物。
式2-3、26-28、30-33、35、47-48、51、57-60、63-64、78、84、113、123、127-129、145、155-157、171-173、204、206-207、210、225、227、233、235-236、241-242、244、249、269、285、288、303、307-312、314-316、320、324-325、333、336、351、357-360、374-375、384-391、396、399-402、404-405、407-411、414、424-425、427-428、437、448、456-457、482、484-485、489-491、495、497-498、505、507、516、519、524、526、553、559-560、568、570、575、609、615-616、618、626-627、638、653、669、692-694、705、709、712、716、719、725、734、738、740、746、749、753-754、756、758-759、767、770、777、784-785、790、792、796、800-801、804-805、808、819、821、827-828、831、833、838、844、847、857-858、869、872、875、933、952、955、969、987、990或999的化合物要么是可购买的，要么可按照已知的合成方法制备。
本方面的另一方面提供了用于治疗神经退行性疾病诸如Tau病变的包含式(IB)化合物的药物组合物。
除了上述物质之一外，本发明的药物组合物还可包含可药用赋形剂、载体、缓冲剂、稳定剂或其它本领域技术人员已知的物质。所述的物质应该是无毒的，并且不应该干扰活性成分的效能。载体或其它物质的确切性质取决于给药途径，例如口服、静脉注射、皮肤或皮下、鼻内、肌内、腹膜内途径。
用于口服给药的药物组合物可以是片剂、胶囊、粉剂或液体形式。片剂可包括固体载体诸如明胶或辅助剂。
液体药物组合物通常包括液体载体诸如水、石蜡油、动物或植物油、矿物油或合成油。
生理盐水溶液、葡萄糖或其它糖类溶液或二醇类诸如乙二醇、丙二醇或聚乙二醇也可包括在内。
对于静脉、皮肤或皮下注射或在患病部位注射，活性成分可以是胃肠外可接受的水溶液形式，该溶液是无热原的并且具有适当的pH、等渗性和稳定性。本领域的有关技术人员能够利用例如等渗溶媒诸如氯化钠注射液、林格注射液、乳酸钠林格注射液制备适当的溶液。在需要时还包括防腐剂、稳定剂、缓冲剂、抗氧化剂和/或其它添加剂。
确信式(IB)化合物是酪蛋白激酶1δ(CK1δ)抑制剂。某些式(IB)化合物的抑制活性大于5%，特别是大于10%、更特别是大于25%、更特别是大于50%，尤其是大于75%，诸如大于90%。该化合物可用于治疗神经退行性疾病诸如Tau病变。Tau病变是特在于神经原纤维缠结或tau蛋白聚集的状况。Tau病变是本领域技术人员已知一类病症，包括阿尔茨海默氏病、17号染色体相关的额颞痴呆兼帕金森综合征(FTDP-17)、进行性核上性麻痹(PSP)、匹克氏病、皮质基底节变性、多系统萎缩(MSA)、伴有铁聚集的神经基底节变性、I型(Hallervorden-Spatz)、嗜银颗粒性痴呆、唐氏综合症、伴有钙化的弥散性神经原纤维缠结、拳击员痴呆症、Gerstmann-Straussler-Scheinker病、强直性肌营养不良症、Niemann-Pick病C型、渐进型皮层下神经胶质增生、朊蛋白脑淀粉样血管病、仅缠结性老年痴呆、脑炎后帕金森综合征、亚急性硬化性全脑炎、克雅氏病、肌萎缩性侧索硬化症/帕金森痴呆复合征、伴有神经原纤维缠结/痴呆的非-Guamanian运动神经元疾病以及帕金森氏病。细胞内的tau沉积通常是神经元或神经胶质性的，并且是细丝状的，与对照人脑中的tau的磷酸化水平相比，通常是过度磷酸化的状态。在AD的情况下，该过度磷酸化的tau通常被称作配对螺旋丝tau(PHF)tau，因为其衍生自PHF。在一种实施方案中，tau病变包括阿尔茨海默氏病。
本发明的另一个方面提供了治疗神经退行性疾病诸如Tau病变的方法，该方法包括施用治疗有效量的式(IB)化合物。
生物学数据
1.CK1δ抑制试验
可将本发明化合物根据US2010/0152157、EP1,636,375或Hanger等人(2007)J.Biol.Chem.282,23645-23654所述的试验方案测试对酪蛋白激酶1δ(CK1δ)的抑制。具体的讲，该试验按照以下方案进行：
反应缓冲液:
基础反应缓冲液;20mM Hepes(pH7.5),10mM MgCl2,1mM EGTA,0.02%Brij35,0.02mg/ml BSA,0.1mM Na3VO4,2mM DTT,1%DMSO。
应注意，将所需的辅助因子单独加入到每个激酶反应液中。
反应方法:
1.在新制备的上述基础反应缓冲液中制备所示的底物
2.将任何所需的辅助因子加入到底物溶液中
3.将所示的激酶加入到底物溶液中并轻轻混合
4.将化合物的DMSO溶液加入到激酶反应混合物中
5.将33P-ATP(最终的比活性0.01μCi/μl)加入到反应混合物中以引发反应
6.将激酶反应液在室温下保温120min
7.将反应液点到P81离子交换纸(Whatman#3698-915)上
8.用0.75%磷酸充分洗涤过滤器
激酶信息:
CK1d–Genbank登录号NP_620693
重组人全长构建体。GST-标记，在昆虫细胞中表达。
试验中的终浓度=4nM
底物:CK1tide
底物序列:[KRRRAL[pS]VASLPGL]
试验中最终的底物浓度=20μM
应注意，不向反应混合物中添加额外的辅助因子。
化合物30、288、314、324-325、336、374、391、405、615-616、626、705、740、753-754、756、759、770、784、808、819、833、844、847、869、872、875、933、952、955、969、987、990和999在CK1δ抑制试验中进行了测试并且表现出大于5%的抑制活性。
尤其是化合物324-325、405、754、847、952、987、990和999表现出大于50%的抑制活性。
化合物324、952、987、990和999表现出大于90%的抑制活性。
2.测定化合物对Ck1d-介导的Tau磷酸化的影响
Tau蛋白的体内磷酸化非常复杂，涉及多种推定的蛋白激酶。普遍认为，激酶GSK3b和CDK5在PHF Tau(在阿尔茨海默氏病的神经原纤维缠结中发现的致病形式)的生成中起重要作用。最近，已经有越来越多的证据支持其它激酶尤其是CK1δ在体内Tau过度磷酸化中的作用。Hanger等人2007(J.Biol.Chem.282,23645-23654)在人的PHF Tau中确定了37个磷酸化位点，并且能够利用重组的tau和各种纯化的激酶制剂在体外重述这些。这些研究证实，某些位点只被CK1δ磷酸化，并且某些其它位点需要CK1δ和其它激酶，其中CK1δ提供上游磷酸化以使目标位点可被第二种激酶利用。因此，为了评价候选化合物是否能够直接地或通过阻断其启动其它激酶来选择性地抑制CK1δ活性，已经进行了多种不同的筛选。在WO2005/001114中提供了这些筛选的一般概念。
为了测定推定CK1δ抑制剂对CK1δ-介导的磷酸化水平的影响，进行选择的反应监测试验，该试验提供在Tau的转基因人和内源性鼠形式的特定位点上磷酸根占据的定量相关测定。
PhosphoTau SRM V2试验在5个最常用的Tau研究位点上测定总的tau和相对磷酸化水平，并且从Proteome Sciences plc(Cobham,England)得到。在V2试验中没有一个位点是仅能被CK1δ磷酸化的，并且一种可能性是，通过该方法测定的化合物诱导的对磷酸化的抑制可能是通过其它激酶诸如GSK3b和/或CDK5的混杂抑制来实现的。为了解决该限制，Proteome Sciences开发了V3试验，该试验除了测定四个其它已被证实在体外被至少一个除了CK1δ之外的其它Tau激酶磷酸化的位点之外，还测定总的tau和两个仅能被CK1δ磷酸化的位点。表1列出了各个被覆盖的位点以及在Hanger等人(2007)中所报道的候选的Tau激酶。
表1:Tau磷酸化SRM V2和V3试验覆盖的Tau磷酸化位点
基于人2N4R tau的编号。
*-CK1d的专属位点
SH-SY5Y-TMHT细胞系
SH-SY5Y-TMHT细胞系(JSW Life Sciences,Graz,Austria)代表tau病变的体外模型。细胞系通过用含有全长人2N4R Tau亚型(其带有两个常见病相关性突变(V337M/R406W))的载体稳定转染人神经母细胞瘤衍生的SH-SY5Y细胞系来产生。在最近的研究(Flunkert等人2011提交,Loeffler等人2011提交)中，SH-SY5Y-TMHT细胞系和带有相同的人类转基因的转基因小鼠细胞系均显示出表达高水平的人Tau，其在多个抗原表位被过度磷酸化，而这些抗原表位之前已被证实在包括阿尔茨海默氏病在内的各种人类Tau病变中被磷酸化。此外，在接触不同激酶抑制剂、包括JNK-抑制剂SP600125和CK1抑制剂IC261的SH-SY5Y-TMHT细胞中，Tau在关键致病位点的磷酸化水平以与靶向激酶的已知的位点特异性相一致的方式减少。因此，SH-SY5Y-TMHT细胞系非常适于新的Tau激酶抑制剂的筛选。
在SH-SY5Y-TMHT细胞中筛选化合物
将SH-SY5Y-TMHT细胞在培养基(DMEM培养基,10%FCS,1%NEAA,1%L-谷氨酰胺,100μg/ml庆大霉素,300μg/ml遗传霉素G-418)中培养2天直至80-90%融合。然后将细胞在补充有10μM维甲酸(RA)的培养基中分化7天，每2至3天更换培养基。将分化的细胞分别以每孔1.25x106和8x105个细胞的密度接种到6孔板和96孔板上。在分化后的第8天，将待测化合物、参照化合物和溶媒对照物加入到培养基中。与化合物接触6小时后，将一个板的细胞进行MTT试验以评价待测化合物和参照化合物对细胞存活率的影响。将剩余的孔用冷的PBS洗涤一次并在300μl RIPA-缓冲液[50mM Tris pH7.4,1%Nonident P40,0.25%脱氧胆酸钠,150mM NaCl,1mM EDTA,1μM NaF,1μM原矾酸钠,80mM磷酸甘油,补充有新鲜加入的蛋白酶(Calbiochem)和磷酸酶(Sigma)抑制剂合剂]中收获。将细胞悬浮液转移到1.5ml试管中并在冰上超声溶解。取出20μl等分试样以确定蛋白浓度(BCA试验)。随后将溶解液快速冷冻并储存在-80°C下直至使用。
如表2所示以一式三(四)份进行两个独立的实验。
表2
细胞存活率测试
为了测定化合物的活性，需要控制所有分子的潜在的细胞毒性。培养物的存活率通过MTT试验确定。该试验能够测定可将黄色的MTT还原成深蓝色甲结晶的线粒体脱氢酶活性。由于该反应仅在活细胞内催化，所以该试验可用于确定细胞存活率。将MTT溶液以终浓度0.5mg/ml加入到每个孔中。2小时后吸出包含MTT的培养基。将细胞溶解于3%SDS并将甲
结晶溶于异丙醇/HCl。用板式读数器在波长570nm处测定光密度。将细胞存活率用光密度(OD)表达。以对照值的百分比的形式计算该数值。
总蛋白含量的定量测定
在评价具体的Tau磷酸化状态之前，将各细胞溶解液中的总蛋白浓度利用标准的BCA试验(Pierce Biotechnology,Rockford,USA)测定。简单地讲，在试验中根据制造商的说明使用20μl细胞溶解液。
总Tau和磷酸化的Tau的定量测定
质谱试验
将来自分别用化合物324、化合物987、PF670462和相关的溶媒对照物处理的TMHT细胞系的全细胞溶解液首先进行一维的SDS-PAGE以纯化蛋白质级分。基于BCA试验结果，在堆积凝胶上负载约100μg总蛋白。跑胶直至总蛋白含量在堆积凝胶中形成单一离散带。然后将各蛋白带从凝胶中切下并用胰蛋白酶或Asp-N消化，然后分别用PhosphoTau SRM试验V2或V3分析。所有试验方法均利用三重四级杆质谱仪(TSQ Vantage,ThermoScientific,Hemel Hempstead,UK)定量临床前材料中的磷酸化。在SRM分析之前，将磷酸肽和临床前样品通过RP-色谱(XBridge柱,Waters,Manchester,UK)拆分，9分钟内的梯度为0-30%ACN(缓冲液A;0.1%FA,缓冲液B;ACN,0.1%FA)。通过多次SRM转换，利用优化的S镜头值和碰撞能量设置监测每种肽和磷酸肽的轻质和重质形式。采用SRM LC峰下的面积定量各细胞溶解液中存在的分析物的量，结果表示为参照重肽添加物信号的单一点。还绘制了轻质磷酸肽的11点校正曲线以确定试验特性(LOD,LOQ,精度和准确度)，在曲线中的每一个点添加100fmol重质磷酸肽。对于各个特定的tau群体，将各tau磷酸肽的内源性水平用其校准曲线(在柱上0.25-1000fmol)进行定量。在进行LC-SRM分析之前，向各个tau群体中添加100fmol重质磷酸肽标准物。将所有数据用Pinpoint软件(ThermoScientific)处理并将结果以pg磷酸肽/μg总蛋白的形式报告。
蛋白质印记法
在Laemmli缓冲液中制备处理过的细胞的溶解液并将10μg上样到10%Nu-PAGE凝胶(Invitrogen,UK)的每个泳道内。展开样品，直至考马斯亮蓝染料前沿在凝胶底部的1cm内。将分离的蛋白质转移到硝基纤维素上并分别用总tau特异性抗体(多克隆兔抗人tau,Dako,UK(cat#A0024))和磷酸化-苏氨酸231特异性抗体(Tau(Phospho-Thr231)抗体,SignalwayAntibody,USA(cat#11110))展开印记。在所有情况下，将结合的抗体用ECL Rabbit IgG,HRP-Linked(来自驴)(GE Healthcare,UK(cat#NA934))进行检测。
结果
待测和参比化合物对SH-SY5Y-TMHT细胞的细胞存活率的影响
通过MTT试验在分化的SH-SY5Y-TMHT细胞中测定细胞存活率。待测和参比化合物的使用浓度分别为0.05μM至10μM和0.1μM至1μM。处理6小时后评价细胞存活率。图1显示了化合物324对SH-SY5Y-TMHT细胞的细胞存活率的影响，其中该图以溶媒对照(VC,白色条棒)的%的形式表示化合物324对SH-SY5Y-TMHT细胞的细胞存活率的影响。统计学意义用*<0.05,**<0.01,***<0.001表示并且通过One-Way ANOVA测定。将来自两个独立实验的数据表示为组平均+/-SEM(n=8)。从图1可以看出，化合物324以剂量依赖的方式对SH-SY5Y-TMHT细胞的细胞存活率表现出保护作用，尽管该作用仅在10μM的浓度下具有统计学意义。图2显示了化合物987对SH-SY5Y-TMHT细胞的细胞存活率的影响，其中该图以溶媒对照(VC,白色条棒)的%的形式表示化合物987对SH-SY5Y-TMHT细胞的细胞存活率的影响。统计学意义用*<0.05,**<0.01,***<0.001表示并且通过One-WayANOVA测定。将来自两个独立实验的数据表示为组平均+/-SEM(n=8)。从图2可以看出，化合物987在较低和较高的浓度范围内降低了细胞存活率。在1和0.5μM浓度下未观察到细胞毒性作用。图3显示了PF670462对SH-SY5Y-TMHT细胞的细胞存活率的影响，其中该图以溶媒对照(VC,白色条棒)的%的形式表示PF670462对SH-SY5Y-TMHT细胞的细胞存活率的影响。统计学意义用*<0.05,**<0.01,***<0.001表示并通过One-WayANOVA测定。将来自两个独立实验的数据表示为组平均+/-SEM(n=8)。从图3可以看出，参比化合物PF670462仅在浓度0.5μM下对SH-SY5Y-TMHT细胞的细胞存活率显示出显著的保护作用。
处理后的SH-SY5Y-TMHT细胞的蛋白测定
利用标准BCA试验测定处理的SH-SY5Y-TMHT细胞的细胞溶解液的蛋白质浓度。一式两份地测定所有样品的蛋白质量。样品的蛋白浓度在预期的范围内(根据每个12-孔板的细胞接种量，预期的蛋白浓度范围为150–350μg/ml)。
测定化合物处理对特定磷酸化位点的影响
质谱试验
SH-SY5Y-TMHT细胞溶解液的测定利用PhosphoTau SRM试验V2和V3进行。当将各位点上磷酸化的相对水平与溶媒处理的对照的比值相比较时，用化合物324(给出了10μM时的数据)和化合物987(给出了10μM时的数据)处理的细胞中磷酸肽的水平明显减少。显示在丝氨酸396上的磷酸化减少的例子如图4所示。该图显示了CK1d-选择性化合物对SH-SY5Y-TMHT细胞中的丝氨酸396磷酸化的质谱测定。A组表示用溶媒对照(VC)或化合物324(T.I.1_10μM)处理的细胞，B组表示用溶媒对照(VC)或化合物987(T.I.2_10μM)处理的细胞。
在与溶媒对照接触的细胞中，约83%的Tau在S396磷酸化。用10μM化合物324处理可将其降至38%，而用10μM化合物987处理可将pS396水平降低至24%。这些结果证实了CK1d选择性试剂对pS396的抑制作用。
蛋白质印记试验
通过蛋白质印记法定量用溶媒对照、化合物394(10μM)、化合物987(10μM)和PF670462(5μM)处理的SH-SY5Y-TMHT细胞溶解液中在苏氨酸231上的总Tau和磷酸化Tau的量。图5显示了在用选择性CK1d抑制剂处理的SH-SY5Y-TMHT细胞中pT231(A组)和总Tau(B组)水平的蛋白质印记测定结果。如图5所示，所有三种化合物均减少了Tau蛋白中pT231的可检测水平，而该抗原表位强烈地存在于溶媒处理的细胞中。除了用PF670462-处理的溶解液(其似乎含有比其它物质处理的溶解液略少的总Tau)之外，在制剂之间的可检测的总Tau水平没有明显差别。这些结果证实了CK1d选择性试剂对pT231的抑制作用。
权利要求书(按照条约第19条的修改)
1.包含式(IB)化合物或其可药用盐或溶剂化物的药物组合物:
其中
“Het B”代表吲哚基或中氮茚基;
Z代表CO;
R1b代表芳基、C3-8环烷基、单环或二环杂环基或单环或二环杂芳基环系，其中R1b可被一个或多个(例如1、2或3个)R4b基团取代;
R4b代表卤素、C1-6烷基、C1-6烯基、C1-6炔基、C3-8环烷基、卤代C1-6烷基、羟基、C1-6烷氧基、-O-C1-6烯基、卤代C1-6烷氧基、-COOH、-CO-C1-6烷基、-COO-C1-6烷基、-CONH2、-CH2-CONH2、-NH-C1-6烷基、-NH-C2-6烯基、-NH-CO-C1-6烷基、-CO-NH-C1-6烷基、-O-CH2-CO-NH-C1-6烷基、-CH2-CH2-CO-NH-C1-6烷基、-S-C1-6烷基、-SO-C1-6烷基、-SO2-C1-6烷基、-SO2-NH2、-SO2-NH-C1-6烷基、-S-CH2-CO-C2-6烯基、-SO2-OH、氨基、氰基、NO2、=O、-CO-NH-(CH2)2)-OMe、-NH-C3-8环烷基、-CH2-CO-NH-C3-8环烷基、-CO-杂环基、-CO-杂芳基、-COO-(CH2)2-杂环基、-CH2-芳基、-OCH2-芳基、-OCH2-杂芳基、-CH2-O-CO-芳基、-O-芳基、-NH-CO-芳基、-NH-CO-杂芳基、-NH-CO-CH2-芳基、-NH-芳基、芳基或杂芳基基团，其中所述的R4b的芳基、杂环基或杂芳基基团可任选地被一个或多个卤素、C1-6烷基、C1-6烷氧基、=S或羟基基团取代，并且其中所述的R4b的C1-6烷基或C2-6烯基基团可任选地被一个或多个羟基、氨基、氰基、C1-6烷氧基、CONH2或-COO-C1-6烷基基团取代;
m代表2;
R2b代表氨基或-CONH2。
2.如权利要求1所定义的药物组合物，其中R1b代表单环芳基或杂芳基环系，其中R1b可被一个或多个(例如1、2或3个)R4b基团取代。
3.如权利要求2所定义的药物组合物，其中R1b代表单环芳基诸如任选地被一个或多个(例如1个)R4b基团取代的苯基，或单环杂芳基诸如任选地被1个或多个(例如1或2个)R4b基团取代的噻吩基、嘧啶基或吡唑啉基。
4.如权利要求3所定义的药物组合物，其中R1b代表任选地被一个或多个(例如1个)R4b基团取代的苯基。
5.如权利要求1至4中的任一项所定义的药物组合物，其中R4b代表卤素、羟基、-O-C1-6烯基、-COO-C1-6烷基、-NH-C1-6烷基、-SO2-NH2、氨基、氰基、=O、-CH2-CO-NH-C3-8环烷基、-CH2-芳基、-OCH2-杂芳基、-O-芳基、-NH-CO-芳基、-NH-芳基或杂芳基基团，其中所述的R4b的芳基、杂环基或杂芳基基团可任选地被一个或多个卤素、C1-6烷基、C1-6烷氧基、=S或羟基基团取代，并且其中所述的R4b的C1-6烷基或C2-6烯基基团可任选地被一个或多个羟基、氨基、氰基、C1-6烷氧基、CONH2或-COO-C1-6烷基基团取代。
6.如权利要求5所定义的药物组合物，其中R4b代表卤素(例如氟)、氨基或杂芳基(例如吡啶基)。
7.如权利要求6所定义的药物组合物，其中R4b代表卤素(例如氟)。
8.如权利要求1所定义的药物组合物，其中式(IB)化合物选自本文所述化合物847、987、990或999中的任何一种或其可药用盐或溶剂化物。
9.如权利要求8所定义的药物组合物，其中式(IB)化合物选自以下化合物中的任一种：
2-氨基-3-[(4-氟苯基)羰基]中氮茚-1-甲酰胺(化合物987);和
2-氨基-1-[(4-氟苯基)羰基]-1H-吲哚-3-甲酰胺(化合物999);
或其可药用盐或溶剂化物。
10.如权利要求8或权利要求9所定义的药物组合物，其中式(IB)化合物是2-氨基-3-[(4-氟苯基)羰基]中氮茚-1-甲酰胺(化合物987)或其可药用盐或溶剂化物。
11.用于治疗的权利要求1至10中的任一项所定义的式(IB)化合物。
12.在神经退行性疾病、诸如Tau病变的治疗中用作酪蛋白激酶δ(CK1δ)抑制剂的权利要求1至10中的任一项所定义的式(IB)化合物。
13.权利要求12所定义的化合物，其中的Tau病变选自阿尔茨海默氏病、17号染色体相关的额颞痴呆兼帕金森综合征(FTDP-17)、进行性核上性麻痹(PSP)、匹克氏病、皮质基底节变性、多系统萎缩(MSA)、伴有铁聚集的神经基底节变性、I型(Hallervorden-Spatz)、嗜银颗粒性痴呆、唐氏综合症、伴有钙化的弥散性神经原纤维缠结、拳击员痴呆症、Gerstmann-Straussler-Scheinker病、强直性肌营养不良症、Niemann-Pick病C型、渐进型皮层下神经胶质增生、朊蛋白脑淀粉样血管病、仅缠结性老年痴呆、脑炎后帕金森综合征、亚急性硬化性全脑炎、克雅氏病、肌萎缩性侧索硬化症/帕金森痴呆复合征、伴有神经原纤维缠结/痴呆的非-Guamanian运动神经元疾病以及帕金森氏病。
14.权利要求12或权利要求13所定义的化合物，其中的Tau病变包含阿尔茨海默氏病。
Claims (19)
1.包含式(IB)化合物或其可药用盐或溶剂化物的药物组合物:
其中
“Het B”代表包含1至3个选自O、N或S的杂原子的5元杂环环系，其中所述的环系稠合到一个或多个(例如1-3个)另外的环上以形成包含最多4个环的多环环系;
Z代表键、–C(R7b)(R8b)-、(CH2)2、-O-、-S-、-CH2-O-、-(CH2)2-O-、NR6b、-N(R6b)-C(R7b)(R8b)-、-N(R6b)-(CH2)2-、-N(R6b)-(CH2)3-、-CH2-N(R6b)-(CH2)2-、-N(R6b)-CO-、-CH2-NH-CO-(CH2)2-、-N(R6b)-CO-CH2-、=N-、-N(R7b)-CH=、-C(H)(CN)-、-C(=N-NH-COC1-6烷基)-、-CH=C(R6b)-CO-、=CH-、-N=CH-、-N=C(Me)-、-C(R6b)=CH-、-NH-CO-C(=CH-杂芳基)-、-C(=C(R7b)(R8b))-、-CH=CH-CO-N(R6b)-、-CH=C(R6b)-CO-NH-CH2-、-CH=C(R6b)-NH-CO-、-CH=C(R6b)-CO-O-CH2-、-CS-S-CH2-、-NH-CS-NH-、-NH-CS-NH-CH2-、-NH-CS-NH-(CH2)2-、-CH2-N(CSNH2)-CH2-、-S-C(R5b)(R6b)-、-S-(CH2)2-O-、SO2、-NH-SO2-、-CH2-NH-SO2-、CO、-CH2-CO-、-(CH2)2-CO-、-O-CH2-CO-、-(CH2)2-CO-、COO、-COO-C(R7b)CO-、-CH=C(R5b)-CONH-CH2-、-CO-CH2-N(R6b)-CO-、-CO-CH2-C(R6b)-CH2-CO-、-CO-CH2-N(R6b)-CH2-、-CO-NH-N=C(R7b)-、-S-CH2-CO-、-S-CH2-CO-N(R6b)-、-S-CH2-CO-N(R6b)-CH2-、-SO2-N(R6b)-C(R7b)(R8b)-CONH-、-SO2-N(R6b)-CH(-CH2-芳基)-CONH-CH2-、-CH(-S-C1-6烷基)-C(Me)(OH)-、-CH2-C(R6b)(OH)-、-C(OH)(CH(Me)(C3-8环烷基))-CH2-、-C(OH)(R6b)-CH2-、-CH(Me)-NH-CO-CH2-、-CO-N(R6b)-CH2-、-C(H)(R6b)-CO-N(R5b)-CH2-、-CO-N(R6b)-CH2-CH2-、-CO-N(R6b)-CH2-CH2-CO-NH-CH2-、-CO-NH-C(-CONH2)=CH-、-CO-NH-CH(-CONH2)-CH2-、-CH2-C(H)(Me)-CH2-S-、-O-CH2-CO-NH-、-CH2-N(R6b)-CO-CH2-O-、-N(R6b)-CO-CH2-O-、-C(H)(-CH2-芳基)-、-C(H)(-CH2-杂芳基)-、-C(NH-芳基)=N-N=CH-、-C(NH-芳基)=N-N=CH-、-NH-CO-CH2-N(R6b)-、-NH-N=C(-芳基)-、-NH-N=C(-芳基)-CO-、-NH-C(=N-CO-C1-6烷基)-NH-(CH2)2-、-C(-NH-芳基)=N-N=CH-、-NH-C(-NH-芳基)=N-CONH-、-C(=CH-芳基)-CONH-CH2-、-CH=C(R6b)-CONH-、-CH(-CH2-芳基)-NH-CO-或-CH(OH)-，其中所述的Z的芳基或杂芳基基团可任选地被一个或多个卤素、C1-6烷基、C1-6烷氧基、NO2或羟基基团取代;
R5b代表氢、C1-6烷基或氰基;
R6b代表氢、C1-6烷基、C1-6烷氧基、氰基、COOH、-COOC1-6烷基、C3-8环烷基、-CH2-C3-8环烷基、芳基、杂芳基、-C1-6亚烷基-芳基、-CO-芳基、-O-CO-杂芳基、-CO-杂芳基或–C(R7b)(R8b)-杂芳基，其中所述的R6b的芳基基团可任选地被一个或多个卤素或C1-6烷氧基基团取代;
R7b和R8b独立地代表氢或C1-6烷基;
R1b代表芳基、C3-8环烷基、单环或二环杂环基或单环或二环杂芳基环系，其中R1b可被一个或多个(例如1、2或3个)R4b基团取代;
R4b代表卤素、C1-6烷基、C1-6烯基、C1-6炔基、C3-8环烷基、卤代C1-6烷基、羟基、C1-6烷氧基、-O-C1-6烯基、卤代C1-6烷氧基、-COOH、-CO-C1-6烷基、-COO-C1-6烷基、-CONH2、-CH2-CONH2、-NH-C1-6烷基、-NH-C2-6烯基、-NH-CO-C1-6烷基、-CO-NH-C1-6烷基、-O-CH2-CO-NH-C1-6烷基、-CH2-CH2-CO-NH-C1-6烷基、-S-C1-6烷基、-SO-C1-6烷基、-SO2-C1-6烷基、-SO2-NH2、-SO2-NH-C1-6烷基、-S-CH2-CO-C2-6烯基、-SO2-OH、氨基、氰基、NO2、=O、-CO-NH-(CH2)2)-OMe、-NH-C3-8环烷基、-CH2-CO-NH-C3-8环烷基、-CO-杂环基、-CO-杂芳基、-COO-(CH2)2-杂环基、-CH2-芳基、-OCH2-芳基、-OCH2-杂芳基、-CH2-O-CO-芳基、-O-芳基、-NH-CO-芳基、-NH-CO-杂芳基、-NH-CO-CH2-芳基、-NH-芳基、芳基或杂芳基基团，其中所述的R4b的芳基、杂环基或杂芳基基团可任选地被一个或多个卤素、C1-6烷基、C1-6烷氧基、=S或羟基基团取代，并且其中所述的R4b的C1-6烷基或C2-6烯基基团可任选地被一个或多个羟基、氨基、氰基、C1-6烷氧基、CONH2或-COO-C1-6烷基基团取代;
m代表0至3的整数;
R2b代表卤素、卤代C1-6烷基、C1-6烷基、C3-8环烷基、羟基、C1-6烷氧基、-S-C1-6烷基、-CH2-S-C1-6烷基、-S-C2-6炔基、氨基、氰基、NO2、=O、=S、-SO2-C1-6烷基、-CONH2、-CO-C1-6烷基、-COO-C1-6烷基、-NH-C1-6烷基、-NH-CO-C1-6烷基、-NH-CO-CH=CH-CH2-N(Me)2、C1-6烷基、-CO-NH-C1-6烷基、-CO-NH-CH(Me)-COOH、-S-CH2-CO-N(Et)2、-NH-(CH2)2-OH、-NH-(CH2)3-OH、-NH-CH(Et)-CH2-OH、-CO-NH-(CH2)3-OH、-CH(CH2OH)2或-S-CH2-CO-NH-CO-NH-C1-6烷基，其中所述的R2b的C1-6烷基基团可任选地被一个或多个氰基或羟基基团取代;
条件是所述化合物不是序号为54、373、458、496、585、590、594、596-597、601-602、649、703、778、877、891、910、912、926和962-963的化合物。
2.如权利要求1所定义的药物组合物，其中:
“Het B”代表包含1至3个选自O、N或S的杂原子的5元杂环环系，其中所述的环系稠合到6元环上以形成二环杂环环系;
Z代表键、–C(R7b)(R8b)-、-O-、-S-、-CH2-O-、-N(R6b)-C(R7b)(R8b)-、-N(R6b)-(CH2)2-、-N(R6b)-(CH2)3-、-N(R6b)-CO-、-N(R6b)-CO-CH2-、-N(R7b)-CH=、=CH-、-N=CH-、-C(R6b)=CH-、-C(=C(R7b)(R8b))-、SO2、-CH2-NH-SO2-、CO、-O-CH2-CO-、-SO2-N(R6b)-C(R7b)(R8b)-CONH-、-SO2-N(R6b)-CH(-CH2-芳基)-CONH-CH2-、-CH(-S-C1-6烷基)-C(Me)(OH)-、-C(H)(R6b)-CO-N(R5b)-CH2-、-O-CH2-CO-NH-、-N(R6b)-CO-CH2-O-、-C(H)(-CH2-芳基)-、-C(NH-芳基)=N-N=CH-、-NH-CO-CH2-N(R6b)-、-NH-N=C(-芳基)-、-NH-C(=N-CO-C1-6烷基)-NH-(CH2)2-、-C(=CH-芳基)-CONH-CH2-或-CH(-CH2-芳基)-NH-CO-，其中所述的Z的芳基或杂芳基基团可任选地被一个或多个卤素、C1-6烷基、C1-6烷氧基、NO2或羟基基团取代;
R5b代表氢;
R6b代表氢、甲基、C1-6烷氧基、-COOH、-CO-芳基、-O-CO-杂芳基或-CO-杂芳基，其中所述的R6b的芳基基团可任选地被一个或多个卤素或C1-6烷氧基基团取代;
R7b和R8b独立地代表氢或C1-6烷基;
R1b代表单环芳基或杂芳基环系，其中R1b可被一个或多个(例如1、2或3个)R4b基团取代;
R4b代表卤素、羟基、-O-C1-6烯基、-COO-C1-6烷基、-NH-C1-6烷基、-SO2-NH2、氨基、氰基、=O、-CH2-CO-NH-C3-8环烷基、-CH2-芳基、-OCH2-杂芳基、-O-芳基、-NH-CO-芳基、-NH-芳基或杂芳基基团，其中所述的R4b的芳基、杂环基或杂芳基基团可任选地被一个或多个卤素、C1-6烷基、C1-6烷氧基、=S或羟基基团取代，并且其中所述的R4b的C1-6烷基或C2-6烯基基团可任选地被一个或多个羟基、氨基、氰基、C1-6烷氧基、CONH2或-COO-C1-6烷基基团取代;
m代表0至2的整数;并且
R2b代表卤素、卤代C1-6烷基、C1-6烷基、C3-8环烷基、羟基、C1-6烷氧基、-S-C1-6烷基、氨基、氰基、NO2、=O、-CONH2、-CO-C1-6烷基、-COO-C1-6烷基、C1-6烷基、-CO-NH-C1-6烷基或-CO-NH-CH(Me)-COOH，其中所述的R2b的C1-6烷基基团可任选地被一个或多个氰基或羟基基团取代。
3.如权利要求1或权利要求2所定义的药物组合物，其中Het B代表包含1至3个选自O、N或S的杂原子的5元杂环环系，其中所述的环系稠合到6元环上以形成二环杂环环系。
4.如权利要求3所定义的药物组合物，其中Het B代表苯并
唑基、吲哚基或中氮茚基。
5.如权利要求1至4中的任一项所定义的药物组合物，其中R1b代表单环芳基或杂芳基环系，其中R1b可被一个或多个(例如1、2或3个)R4b基团取代。
6.如权利要求5所定义的药物组合物，其中R1b代表单环芳基诸如任选地被一个或多个(例如1个)R4b基团取代的苯基，或单环杂芳基诸如任选地被1个或多个(例如1或2个)R4b基团取代的噻吩基、嘧啶基或吡唑啉基。
7.如权利要求1至6中的任一项所定义的药物组合物，其中R4b代表卤素、羟基、-O-C1-6烯基、-COO-C1-6烷基、-NH-C1-6烷基、-SO2-NH2、氨基、氰基、=O、-CH2-CO-NH-C3-8环烷基、-CH2-芳基、-OCH2-杂芳基、-O-芳基、-NH-CO-芳基、-NH-芳基或杂芳基基团，其中所述的R4b的芳基、杂环基或杂芳基基团可任选地被一个或多个卤素、C1-6烷基、C1-6烷氧基、=S或羟基基团取代，并且其中所述的R4b的C1-6烷基或C2-6烯基基团可任选地被一个或多个羟基、氨基、氰基、C1-6烷氧基、CONH2或-COO-C1-6烷基基团取代。
8.如权利要求7所定义的药物组合物，其中R4b代表卤素(例如氟)、氨基或杂芳基(例如吡啶基)。
9.如权利要求1至8中的任一项所定义的药物组合物，其中Z代表键、–C(R7b)(R8b)-、-O-、-S-、-CH2-O-、-N(R6b)-C(R7b)(R8b)-、-N(R6b)-(CH2)2-、-N(R6b)-(CH2)3-、-N(R6b)-CO-、-N(R6b)-CO-CH2-、-N(R7b)-CH=、=CH-、-N=CH-、-C(R6b)=CH-、-C(=C(R7b)(R8b))-、SO2、-CH2-NH-SO2-、CO、-O-CH2-CO-、-SO2-N(R6b)-C(R7b)(R8b)-CONH-、-SO2-N(R6b)-CH(-CH2-芳基)-CONH-CH2-、-CH(-S-C1-6烷基)-C(Me)(OH)-、-C(H)(R6b)-CO-N(R5b)-CH2-、-O-CH2-CO-NH-、-N(R6b)-CO-CH2-O-、-C(H)(-CH2-芳基)-、-C(NH-芳基)=N-N=CH-、-NH-CO-CH2-N(R6b)-、-NH-N=C(-芳基)-、-NH-C(=N-CO-C1-6烷基)-NH-(CH2)2-、-C(=CH-芳基)-CONH-CH2-或-CH(-CH2-芳基)-NH-CO-，其中所述的Z的芳基或杂芳基基团可任选地被一个或多个卤素、C1-6烷基、C1-6烷氧基、NO2或羟基基团取代。
10.如权利要求9所定义的药物组合物，其中Z代表键或CO。
11.如权利要求1至10中的任一项所定义的药物组合物，其中m代表0至2的整数、诸如0或2。
12.如权利要求1至11中的任一项所定义的药物组合物，其中R2b代表卤素、卤代C1-6烷基、C1-6烷基、C3-8环烷基、羟基、C1-6烷氧基、-S-C1-6烷基、氨基、氰基、NO2、=O、-CONH2、-CO-C1-6烷基、-COO-C1-6烷基、C1-6烷基、-CO-NH-C1-6烷基或-CO-NH-CH(Me)-COOH，其中所述的R2b的C1-6烷基基团可任选地被一个或多个氰基或羟基基团取代。
13.如权利要求12所定义的药物组合物，其中R2b代表氨基或-CONH2。
14.如权利要求1所定义的药物组合物，其中式(IB)化合物选自本文所述化合物2-3、26-28、30-33、35、47-48、51、57-60、63-64、78、84、113、123、127-129、145、155-157、171-173、204、206-207、210、225、227、233、235-236、241-242、244、249、269、285、288、303、307-312、314-316、320、324-325、333、336、351、357-360、374-375、384-391、396、399-402、404-405、407-411、414、424-425、427-428、437、448、456-457、482、484-485、489-491、495、497-498、505、507、516、519、524、526、553、559-560、568、570、575、609、615-616、618、626-627、638、653、669、692-694、705、709、712、716、719、725、734、738、740、746、749、753-754、756、758-759、767、770、777、784-785、790、792、796、800-801、804-805、808、819、821、827-828、831、833、838、844、847、857-858、869、872、875、933、952、955、969、987、990或999中的任何一种或其可药用盐或溶剂化物。
15.如权利要求14所定义的药物组合物，其中式(IB)化合物选自以下化合物中的任一种：
5-(1,3-苯并
唑-2-基)-4-(吡啶-4-基)嘧啶-2-胺(化合物324);
2-[3-(吡啶-4-基)-1H-吡唑-4-基]-1,3-苯并
唑(化合物952);
2-氨基-3-[(4-氟苯基)羰基]中氮茚-1-甲酰胺(化合物987);和
2-氨基-1-[(4-氟苯基)羰基]-1H-吲哚-3-甲酰胺(化合物999);
或其可药用盐或溶剂化物。
16.用于治疗的权利要求1至15中的任一项所定义的式(IB)化合物。
17.在神经退行性疾病、诸如Tau病变的治疗中用作酪蛋白激酶δ(CK1δ)抑制剂的权利要求1至15中的任一项所定义的式(IB)化合物。
18.权利要求17所定义的化合物，其中的Tau病变选自阿尔茨海默氏病、17号染色体相关的额颞痴呆兼帕金森综合征(FTDP-17)、进行性核上性麻痹(PSP)、匹克氏病、皮质基底节变性、多系统萎缩(MSA)、伴有铁聚集的神经基底节变性、I型(Hallervorden-Spatz)、嗜银颗粒性痴呆、唐氏综合症、伴有钙化的弥散性神经原纤维缠结、拳击员痴呆症、Gerstmann-Straussler-Scheinker病、强直性肌营养不良症、Niemann-Pick病C型、渐进型皮层下神经胶质增生、朊蛋白脑淀粉样血管病、仅缠结性老年痴呆、脑炎后帕金森综合征、亚急性硬化性全脑炎、克雅氏病、肌萎缩性侧索硬化症/帕金森痴呆复合征、伴有神经原纤维缠结/痴呆的非-Guamanian运动神经元疾病以及帕金森氏病。
19.权利要求17或权利要求18所定义的化合物，其中的Tau病变包含阿尔茨海默氏病。
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