CN108473435A - 自噬潮和磷脂酶d的活化剂以及包括tau的蛋白聚集体的清除和蛋白质病的治疗 - Google Patents
自噬潮和磷脂酶d的活化剂以及包括tau的蛋白聚集体的清除和蛋白质病的治疗 Download PDFInfo
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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Abstract
本申请公开了作为自噬潮活化剂的化合物和包含所述活化剂的药物组合物。其进一步公开了所述化合物和所述药物组合物在治疗神经变性疾病、特别是蛋白质病和例如阿兹海默氏病的tau病中的用途。其进一步公开了增强自噬潮的方法。
Description
相关申请案
本申请要求2015年10月5日提交的美国临时申请序列号62/237,342的优先权。上述申请的全部内容通过引用并入本文,如同在本文中全部陈述一样。
技术领域
本公开涉及作为自噬潮活化剂的化合物和包含所述化合物的药物组合物。其进一步涉及所述化合物在治疗神经变性疾病、特别是阿兹海默氏病(Alzheimer’s disease)中的用途。
发明背景
阿兹海默氏病(AD)影响约五百万美国人,并且截至2050年,预计这个数字将增加三倍。目前,没有治疗阿尔茨海默氏病或其他相关tau病的疗法。尽管使用靶向淀粉样蛋白β(Aβ)的免疫疗法的临床试验已经取得了有限的成功,但是这仅仅是患有AD或其他神经变性疾病的那些患者的亚组。此外,没有靶向其他蛋白质病(包括tau,即AD的另一主要神经病理性组分)的疗法。AD占折磨65岁以上的个体的痴呆的大部分,并且估计每年为AD和其他痴呆患者提供医疗保健、长期护理和临终关怀花费2260亿美元。这种广泛的经济和社会负担并未虑及许多家庭主要照顾者(包括配偶和其他家庭成员)的收入损失。
已显示增强自噬在治疗阿兹海默氏病中具有治疗潜能。自噬潮(包括自噬体与溶酶体的融合)是自噬的新型调节因子,这是因为其导致蛋白聚集体的清除和病理生理学衰退的逆转。因此,对自噬潮启动子和带有蛋白质病的自噬体的清除存在持续需求。
发明内容
在一些实施方案中,提供了本文公开的化合物(包括其药学上可接受的盐)。
在一些实施方案中,提供了包含本文公开的化合物或其药学上可接受的盐的药物组合物。在其他实施方案中,(例如)下文提供的实施例中还提供了制备所述化合物和药物组合物的方法。
在一些实施方案中,提供了治疗神经变性疾病的方法,其包括向有需要的个体施用有效量的本文公开的化合物或药物组合物。
在一些实施方案中,提供了增强自噬潮的方法。这种方法包括为细胞或蛋白聚集体提供有效量的本文公开的化合物或药物组合物。
在下面的详细描述和实施例中进一步公开了本发明的这些和其他方面。
图示简单说明
以下图示构成本说明书的一部分,并且包括以进一步说明本发明的某些方面。通过参考这些附图中的一个或多个结合本文提出的具体实施方案的详细描述,可以更好地理解本发明。
图1是显示小鼠脑中的WHYKD8的光电二极管阵列(PDA)光谱的图。
图2显示用WHYKD1(±BafA1)或WHYKD5处理6小时后原代皮质神经元中LC3-II水平的蛋白质印迹。
图3显示用WHYKD1(上图)或WHYKD3、WHYKD5、WHYKD8、WHYKD9或WHYKD12(下图)处理6小时后器官特征切片培养物中LC3-II、tau和p62水平的蛋白质印迹。
图4是显示WHYKD系列化合物(10μM)对磷脂酶D(PLD)的活化以及其在乙醇存在下将磷脂转化成磷脂酰乙醇的能力的条形图。C=对照,12=WHYKD12,15=WHYKD15,19=WHYKD19,5=WHYKD5,8=WHYKD8,Fipi=PLD活性的非竞争性抑制剂。
图5是显示WHYKD系列化合物(1μM)对磷脂酶D(PLD)的活化以及其在乙醇存在下将磷脂转化成磷脂酰乙醇的能力的条形图。
本发明的实施方式
尽管已知大自噬是一种必需的降解过程(其中自噬体介导细胞质组分被吞入和递送到溶酶体中),但不确定自噬体膜动力学下的脂质变化。发明人先前已经显示,主要与内体系统相关的PLD1在营养饥饿时部分地重新定位到自噬体样结构的外膜(达尔·阿米(Dall'Armi),2010)。PLD1的定位以及饥饿诱导的PLD活性的增加被渥曼青霉素(wortmannin,一种磷脂酰肌醇3-激酶抑制剂)改变,表明PLD1可能作用于Vps34的下游。小鼠细胞中PLD的药理学抑制和PLD1的遗传消融减少了饥饿诱导的LC3阳性区室的扩张,这与PLD1在调控自噬中的作用一致。此外,抑制PLD导致器官特征脑切片中更高水平的tau和p62聚集体。这些体外和体内发现确立PLD1在自噬中起作用。
在一些实施方案中,提供具有式(II)的化合物:
其中Y1和Y2独立地选自由以下各项组成的组:CH和N;
其中X是选自由以下各项组成的组:H、卤基和芳基;
其中R1是选自由以下各项组成的组:任选取代的硫代杂芳基、羟基取代的(2-氨基乙基)芳基、卤基、任选取代的硫代环烷基,其中所述环烷基的1到3个碳原子任选地由选自由O、S和N组成的组的杂原子置换;和硫代芳基,
或其盐、对映异构体、外消旋物、混合物或其组合。
在一些实施方案中,所述化合物是选自由以下各项组成的组:
或其盐、对映异构体、外消旋物、混合物或其组合。在一个实施方案中,所述化合物是:
或其盐、对映异构体、外消旋物、混合物或其组合。在另一实施方案中,所述化合物是:
或其盐、对映异构体、外消旋物、混合物或其组合。在一些实施方案中,提供具有式(III)的化合物:
其中Y1是CH;
其中Y2是N;
其中X是卤基;
其中R1是选自由以下各项组成的组:任选取代的硫代杂芳基、任选取代的(2-氨基乙基)芳基、卤基、任选取代的硫代环烷基,其中所述环烷基的1到3个碳原子任选地由选自由O、S和N组成的组的杂原子置换;和硫代芳基,
或其盐、对映异构体、外消旋物、混合物或其组合。
在一些实施方案中,所述化合物是选自由以下各项组成的组:
或其盐、对映异构体、外消旋物、混合物或其组合。
在一些实施方案中,提供具有式(IV)的化合物:
其中X是卤基;
其中R1是选自由以下各项组成的组:任选取代的硫代杂芳基、任选取代的(2-氨基乙基)芳基、卤基、任选取代的硫代环烷基,其中所述环烷基的1到3个碳原子任选地由选自由O、S和N组成的组的杂原子置换;和硫代芳基,
或其盐、对映异构体、外消旋物、混合物或其组合。
在一些实施方案中,所述化合物是选自由以下各项组成的组:
或其盐、对映异构体、外消旋物、混合物或其组合。
在一些实施方案中,提供具有式(V)的化合物:
其中X是H;
其中R1是选自由以下各项组成的组:任选取代的硫代杂芳基、任选取代的(2-氨基乙基)芳基、卤基、任选取代的硫代环烷基,其中所述环烷基的1到3个碳原子任选地由选自由O、S和N组成的组的杂原子置换;和硫代芳基,
或其盐、对映异构体、外消旋物、混合物或其组合。
在一些实施方案中,所述化合物是选自由以下各项组成的组:
或其盐、对映异构体、外消旋物、混合物或其组合。
在一些实施方案中,提供具有式(VI)的化合物:
其中X是H;
其中R1是选自由以下各项组成的组:任选取代的硫代杂芳基、任选取代的(2-氨基乙基)芳基、卤基、任选取代的硫代环烷基,其中所述环烷基的1到3个碳原子任选地由选自由O、S和N组成的组的杂原子置换;和硫代芳基,
或其盐、对映异构体、外消旋物、混合物或其组合。
在一些实施方案中,所述化合物是选自由以下各项组成的组:
或其盐、对映异构体、外消旋物、混合物或其组合。
在一些实施方案中,提供具有式(VII)的化合物:
其中R1是选自由以下各项组成的组:任选取代的硫代杂芳基、任选取代的(2-氨基乙基)芳基、卤基、任选取代的硫代环烷基,其中所述环烷基的1到3个碳原子任选地由选自由O、S和N组成的组的杂原子置换;和硫代芳基,
或其盐、对映异构体、外消旋物、混合物或其组合。
在一些实施方案中,所述化合物是选自由以下各项组成的组:
或其盐、对映异构体、外消旋物、混合物或其组合。
在一些实施方案中,提供具有式(VIII)的化合物:
其中R1是选自由以下各项组成的组:任选取代的硫代杂芳基、任选取代的(2-氨基乙基)芳基、卤基、任选取代的硫代环烷基,其中所述环烷基的1到3个碳原子任选地由选自由O、S和N组成的组的杂原子置换;和硫代芳基,
或其盐、对映异构体、外消旋物、混合物或其组合。
在一些实施方案中,所述化合物是选自由以下各项组成的组:
或其盐、对映异构体、外消旋物、混合物或其组合。
在一些实施方案中,提供具有式(IX)的化合物:
其中Y3是CH或N;
其中R2是任选取代的(2-氨基乙基)芳基,
或其盐、对映异构体、外消旋物、混合物或其组合。
在一些实施方案中,所述化合物是选自由以下各项组成的组:
或其盐、对映异构体、外消旋物、混合物或其组合。
在一些实施方案中,提供具有式(X)的化合物:
其中Y3是CH;
其中R2是选自由以下各项组成的组:任选取代的硫代杂芳基、任选取代的(2-氨基乙基)芳基、卤基、任选取代的硫代环烷基,其中所述环烷基的1到3个碳原子任选地由选自由O、S和N组成的组的杂原子置换;和硫代芳基,
或其盐、对映异构体、外消旋物、混合物或其组合。
在一些实施方案中,所述化合物是选自由以下各项组成的组:
或其盐、对映异构体、外消旋物、混合物或其组合。
在一些实施方案中,提供具有式(XI)的化合物:
其中R2是选自由以下各项组成的组:任选取代的硫代杂芳基、任选取代的(2-氨基乙基)芳基、卤基、任选取代的硫代环烷基,其中所述环烷基的1到3个碳原子任选地由选自由O、S和N组成的组的杂原子置换;和硫代芳基,
或其盐、对映异构体、外消旋物、混合物或其组合。
在一些实施方案中,所述化合物是选自由以下各项组成的组:
或其盐、对映异构体、外消旋物、混合物或其组合。
在一些实施方案中,提供具有式(XII)的化合物:
其中Y4是CH或N;
其中R3是选自由以下各项组成的组:任选取代的硫代杂芳基、任选取代的(2-氨基乙基)芳基、卤基、任选取代的硫代环烷基,其中所述环烷基的1到3个碳原子任选地由选自由O、S和N组成的组的杂原子置换;和硫代芳基,
或其盐、对映异构体、外消旋物、混合物或其组合。
在一些实施方案中,所述化合物是选自由以下各项组成的组:
或其盐、对映异构体、外消旋物、混合物或其组合。
在一些实施方案中,提供具有式(XIII)的化合物:
其中R2是选自由以下各项组成的组:任选取代的硫代杂芳基、任选取代的(2-氨基乙基)芳基、卤基、任选取代的硫代环烷基,其中所述环烷基的1到3个碳原子任选地由选自由O、S和N组成的组的杂原子置换;和硫代芳基,
或其盐、对映异构体、外消旋物、混合物或其组合。
在一些实施方案中,所述化合物是选自由以下各项组成的组:
或其盐、对映异构体、外消旋物、混合物或其组合。
在一些实施方案中,提供具有式(XIV)的化合物:
其中R2是选自由以下各项组成的组:任选取代的硫代杂芳基、任选取代的(2-氨基乙基)芳基、卤基、任选取代的硫代环烷基,其中所述环烷基的1到3个碳原子任选地由选自由O、S和N组成的组的杂原子置换;和硫代芳基,
或其盐、对映异构体、外消旋物、混合物或其组合。
在一些实施方案中,所述化合物是选自由以下各项组成的组:
或其盐、对映异构体、外消旋物、混合物或其组合。
在一些实施方案中,提供具有式(XV)的化合物:
其中X是H或卤基;
其中Z1是O;
其中R4是选自由以下各项组成的组:H、任选取代的烷基、Et、CF3、任选取代的环烷基、任选取代的芳基、任选取代的杂芳基和
在一些实施方案中,所述化合物是选自由以下各项组成的组:
环烷基、芳基、杂芳基,
或其盐、对映异构体、外消旋物、混合物或其组合。
在一个实施方案中,所述化合物是
或其盐、对映异构体、外消旋物、混合物或其组合。
在一些实施方案中,提供了包含本文公开的化合物或其药学上可接受的盐的药物组合物。
在一些实施方案中,提供了治疗神经变性疾病的方法,其包括向有需要的个体施用有效量的本文公开的化合物或药物组合物。在一些实施方案中,神经变性疾病是蛋白质病。蛋白质病包括但不限于帕金森氏病(Parkinson’s disease)、阿兹海默氏病、肌萎缩侧索硬化(ALS)、亨廷顿氏病(Huntington’s disease)、慢性创伤性脑病(CTE)、额颞叶痴呆(FTD)、包涵体肌病(IBM)、佩吉特骨病(Paget's disease of bone,PDB)、大脑β-淀粉样蛋白血管病、朊病毒病、家族性痴呆、CADASIL、淀粉样变性、亚历山大病(Alexanderdisease)、腓骨肌萎缩症、II型糖尿病、肺泡蛋白沉积症、白内障、囊性纤维化和镰刀形细胞病。在这个实施方案的一些方面,蛋白质病是tau病。tau病包括但不限于阿兹海默氏病、帕金森氏病、亨廷顿氏病、进行性核上麻痹、慢性创伤性脑病(CTE)、额颞叶痴呆(FTD)、利替可-波帝格病(Lytico-Bodig disease)、亚急性硬化性全脑炎、神经节神经胶质瘤、神经节细胞瘤和嗜银颗粒疾病。在优选的实施方案中,神经变性疾病是阿兹海默氏病。
在一些实施方案中,提供了增强自噬潮的方法。这种方法包括为细胞或蛋白聚集体提供有效量的本文公开的化合物或药物组合物。
本公开中描述的实施方案可以以各种方式组合。针对一个实施方案描述的任何方面或特征可以并入本公开中提及的任何其他实施方案中。尽管已经显示、描述和指出了本发明原理的各种新颖特征应用于其特定实施方案,但应该理解,本领域技术人员可以做出各种省略和替代和改变而不脱离本公开的精神。本领域技术人员将认识到,本发明的原理可以在除了所描述的实施方案以外的其他实施方案中实施,所描述的实施方案是出于说明的目的而不是限制的目的而提供。
实施例
提供以下实施例以进一步说明本发明的某些方面。这些实施例只是说明性的,并不打算以任何方式限制本发明的范围。
实施例1
实例性合成方案
方案1显示下式化合物的合成:
例如,式(II)和式(III)化合物。
方案1
X=H,F,Cl,Br,l,CH3,CF3
Y=S,NH,N
Y1=CH,N
Y2=CH,N
Y3=CH,N
R1=H,烷基、环烷基、芳基、杂芳基
n=0,1
方案2显示1-氯-7-氟异喹啉的制备。
方案2
试剂和条件:a)氨基乙醛二甲基缩醛,苯,回流;
b)1.)ClCO2Et,-10℃,THF,2.)P(OCH3)3,3.)TiCl4,CH2Cl2,回流;c)H2O2,AcOH,60℃;d)1.)Ac2O,2.)NaOH;e)POCl3,回流
方案3显示下式化合物的合成:
例如,式(IV)、式(V)、式(VI)、式(VII)和式(VIII)化合物。
方案3
Y=CH,N
Y1=CH,N
Y2=CH,N
Y3=CH,N
Y4=CH,N
Y5=CH,N
Z=S,N,NH
R1=H,烷基、环烷基、芳基、杂芳基
n=0,1
方案4显示下式化合物的合成:
例如,式(XII)和式(XIII)化合物。
方案4
Y=CH,N
Y1=CH,N
Z=S,N,NH
R1=H,烷基、环烷基、芳基、杂芳基
n=0,1
方案5显示下式化合物的合成:
例如,式(IX)、式(X)和式(XI)化合物。
方案5
X=O,S
Y=CH,N
Y1=CH,N
Z=S,N,NH
R1=H,烷基、环烷基、芳基、杂芳基
n=0,1
方案6显示下式化合物的合成:
例如,式(XIV)化合物。
方案6
Y=CH,N
Y1=CH,N
Z=S,N,NH
R1=H,烷基、环烷基、芳基、杂芳基
n=0,1
实施例2
自噬潮和磷脂酶D的活化剂
基于分子量(MW)和分配系数(log P),根据李平斯基的CNS渗透率原则(Lipinski’s Rule for CNS penetrance):MW≤400,log P≤5,合成WHYKD系列化合物以获得最佳脑渗透率。
根据下式的活化剂:
是根据上述方案合成。计算分子量和log P。结果显示于下表1中。
表1
根据下式的活化剂:
是根据上述方案合成。计算分子量和log P。结果显示于下表2中。
表2
根据下式的活化剂:
是根据上述方案合成。计算分子量和log P。结果显示于下表3中。
表3
根据下式的活化剂:
是根据上述方案合成。计算分子量和log P。结果显示于下表4中。
表4
实施例3
衍生物的设计
多个系列的衍生物是基于以下先导化合物来合成:
除了log P之外,还计算了拓扑极性表面积(tPSA)、CLogP(通过基团贡献法计算的log P)和LogS(溶解度)。结果显示于下表中。
表5:对核和侧链做出的修改(系列1)
表6:对核和侧链做出的修改(系列2)
表7:对核和侧链做出的修改(系列3)
表8:对核和侧链做出的修改(系列4)
表9:对核和侧链做出的修改(系列5)
表10:对核和侧链做出的修改(系列6)
表11:对核和侧链做出的修改(系列7)
表12:对核和侧链做出的修改(系列8)
表13:对核和侧链做出的修改(系列9)
表14:对核和侧链做出的修改(系列10)
表15:喹唑啉酮(系列11)
实施例4
WHYKD化合物的检测和结果
使用光电二极管阵列(PDA)检测小鼠脑中的WHYKD8(图1)。利用基于时间的离散峰(左)以及利用可测量的曲线下面积(AUC)(插图)容易地检测到样品。
在用WHYKD1、WHYKD5或WHYKD1+BafA1处理6小时后,测量原代皮质神经元中的LC3-II水平(图2)。LC3-II的存在指示自噬。
在用WHYKD1处理6小时后,然后测量器官特征切片培养物中的LC3-II水平(图3,顶部小图)。WHYKD系列中的其他化合物产生了类似的结果(图3,底部小图)。RFP是tau蛋白上的标签,并且也可以被探测。
这些实验显示,WHYKD系列化合物可以诱导自噬并减少聚集形式的τ以及其聚集体替代物p62。
PLD活化在乙醇存在下将磷脂转化成磷脂酰乙醇。测量所述转化以显示WHYKD系列化合物以10μM浓度(图4)和1μM(图5)活化PLD。FIPI是PLD活性的非竞争性抑制剂,并用作阴性对照。
上文引用的所有专利、专利申请和出版物通过引用整体并入本文,如同在本文中全部引用一样。
由此描述了本发明,显而易见的是其可以以多种方式变化。不认为这些变化背离本发明的精神和范围,并且所有所述修改均打算包括在下面的权利要求的范围内。
Claims (37)
1.一种具有式(II)的化合物,
其中Y1和Y2独立地选自由以下各项组成的组:CH和N;
其中X是选自由以下各项组成的组:H、卤基和芳基;
其中R1是选自由以下各项组成的组:任选取代的硫代杂芳基、羟基取代的(2-氨基乙基)芳基、卤基、任选取代的硫代环烷基,其中所述环烷基的1到3个碳原子任选地由选自由O、S和N组成的组的杂原子置换;和硫代芳基,
或其盐、对映异构体、外消旋物、混合物或其组合。
2.如权利要求1所述的化合物,其中所述化合物是选自由以下各项组成的组:
或其盐、对映异构体、外消旋物、混合物或其组合。
3.如权利要求1所述的化合物,其中所述化合物是:
或其盐、对映异构体、外消旋物、混合物或其组合。
4.如权利要求1所述的化合物,其中所述化合物是:
或其盐、对映异构体、外消旋物、混合物或其组合。
5.一种具有式(III)的化合物,
其中Y1是CH;
其中Y2是N;
其中X是卤基;
其中R1是选自由以下各项组成的组:任选取代的硫代杂芳基、任选取代的(2-氨基乙基)芳基、卤基、任选取代的硫代环烷基,其中所述环烷基的1到3个碳原子任选地由选自由O、S和N组成的组的杂原子置换;和硫代芳基,
或其盐、对映异构体、外消旋物、混合物或其组合。
6.如权利要求5所述的化合物,其中所述化合物是选自由以下各项组成的组:
或其盐、对映异构体、外消旋物、混合物或其组合。
7.一种具有式(IV)的化合物,
其中X是卤基;
其中R1是选自由以下各项组成的组:任选取代的硫代杂芳基、任选取代的(2-氨基乙基)芳基、卤基、任选取代的硫代环烷基,其中所述环烷基的1到3个碳原子任选地由选自由O、S和N组成的组的杂原子置换;和硫代芳基,
或其盐、对映异构体、外消旋物、混合物或其组合。
8.如权利要求7所述的化合物,其中所述化合物是选自由以下各项组成的组:
或其盐、对映异构体、外消旋物、混合物或其组合。
9.一种具有式(V)的化合物,
其中X是H;
其中R1是选自由以下各项组成的组:任选取代的硫代杂芳基、任选取代的(2-氨基乙基)芳基、卤基、任选取代的硫代环烷基,其中所述环烷基的1到3个碳原子任选地由选自由O、S和N组成的组的杂原子置换;和硫代芳基,
或其盐、对映异构体、外消旋物、混合物或其组合。
10.如权利要求9所述的化合物,其中所述化合物是选自由以下各项组成的组:
或其盐、对映异构体、外消旋物、混合物或其组合。
11.一种具有式(VI)的化合物,
其中X是H;
其中R1是选自由以下各项组成的组:任选取代的硫代杂芳基、任选取代的(2-氨基乙基)芳基、卤基、任选取代的硫代环烷基,其中所述环烷基的1到3个碳原子任选地由选自由O、S和N组成的组的杂原子置换;和硫代芳基,
或其盐、对映异构体、外消旋物、混合物或其组合。
12.如权利要求11所述的化合物,其中所述化合物是选自由以下各项组成的组:
或其盐、对映异构体、外消旋物、混合物或其组合。
13.一种具有式(VII)的化合物,
其中R1是选自由以下各项组成的组:任选取代的硫代杂芳基、任选取代的(2-氨基乙基)芳基、卤基、任选取代的硫代环烷基,其中所述环烷基的1到3个碳原子任选地由选自由O、S和N组成的组的杂原子置换;和硫代芳基,
或其盐、对映异构体、外消旋物、混合物或其组合。
14.如权利要求13所述的化合物,其中所述化合物是选自由以下各项组成的组:
或其盐、对映异构体、外消旋物、混合物或其组合。
15.一种具有式(VIII)的化合物,
其中R1是选自由以下各项组成的组:任选取代的硫代杂芳基、任选取代的(2-氨基乙基)芳基、卤基、任选取代的硫代环烷基,其中所述环烷基的1到3个碳原子任选地由选自由O、S和N组成的组的杂原子置换;和硫代芳基,
或其盐、对映异构体、外消旋物、混合物或其组合。
16.如权利要求15所述的化合物,其中所述化合物是选自由以下各项组成的组:
或其盐、对映异构体、外消旋物、混合物或其组合。
17.一种具有式(IX)的化合物,
其中Y3是CH或N;
其中R2是任选取代的(2-氨基乙基)芳基,
或其盐、对映异构体、外消旋物、混合物或其组合。
18.如权利要求17所述的化合物,其中所述化合物是选自由以下各项组成的组:
或其盐、对映异构体、外消旋物、混合物或其组合。
19.一种具有式(X)的化合物,
其中Y3是CH;
其中R2是选自由以下各项组成的组:任选取代的硫代杂芳基、任选取代的(2-氨基乙基)芳基、卤基、任选取代的硫代环烷基,其中所述环烷基的1到3个碳原子任选地由选自由O、S和N组成的组的杂原子置换;和硫代芳基,
或其盐、对映异构体、外消旋物、混合物或其组合。
20.如权利要求19所述的化合物,其中所述化合物是选自由以下各项组成的组:
或其盐、对映异构体、外消旋物、混合物或其组合。
21.一种具有式(XI)的化合物,
其中R2是选自由以下各项组成的组:任选取代的硫代杂芳基、任选取代的(2-氨基乙基)芳基、卤基、任选取代的硫代环烷基,其中所述环烷基的1到3个碳原子任选地由选自由O、S和N组成的组的杂原子置换;和硫代芳基,
或其盐、对映异构体、外消旋物、混合物或其组合。
22.如权利要求21所述的化合物,其中所述化合物是选自由以下各项组成的组:
或其盐、对映异构体、外消旋物、混合物或其组合。
23.一种具有式(XII)的化合物,
其中Y4是CH或N;
其中R3是选自由以下各项组成的组:任选取代的硫代杂芳基、任选取代的(2-氨基乙基)芳基、卤基、任选取代的硫代环烷基,其中所述环烷基的1到3个碳原子任选地由选自由O、S和N组成的组的杂原子置换;和硫代芳基,
或其盐、对映异构体、外消旋物、混合物或其组合。
24.如权利要求23所述的化合物,其中所述化合物是选自由以下各项组成的组:
或其盐、对映异构体、外消旋物、混合物或其组合。
25.一种具有式(XIII)的化合物,
其中R2是选自由以下各项组成的组:任选取代的硫代杂芳基、任选取代的(2-氨基乙基)芳基、卤基、任选取代的硫代环烷基,其中所述环烷基的1到3个碳原子任选地由选自由O、S和N组成的组的杂原子置换;和硫代芳基,
或其盐、对映异构体、外消旋物、混合物或其组合。
26.如权利要求25所述的化合物,其中所述化合物是选自由以下各项组成的组:
或其盐、对映异构体、外消旋物、混合物或其组合。
27.一种具有式(XIV)的化合物,
其中R2是选自由以下各项组成的组:任选取代的硫代杂芳基、任选取代的(2-氨基乙基)芳基、卤基、任选取代的硫代环烷基,其中所述环烷基的1到3个碳原子任选地由选自由O、S和N组成的组的杂原子置换;和硫代芳基,
或其盐、对映异构体、外消旋物、混合物或其组合。
28.如权利要求27所述的化合物,其中所述化合物是选自由以下各项组成的组:
或其盐、对映异构体、外消旋物、混合物或其组合。
29.一种具有式(XV)的化合物,
其中X是H或卤基;
其中Z1是O;
其中R4是选自由以下各项组成的组:H、任选取代的烷基、Et、CF3、任选取代的环烷基、任选取代的芳基、任选取代的杂芳基和
30.如权利要求29所述的化合物,其中所述化合物是选自由以下各项组成的组:
或其盐、对映异构体、外消旋物、混合物或其组合。
31.如权利要求29所述的化合物,其中所述化合物是:
或其盐、对映异构体、外消旋物、混合物或其组合。
32.一种药物组合物,其包含如权利要求1至31中任一项所述的化合物或其药学上可接受的盐。
33.一种治疗神经变性疾病的方法,其包括向有需要的个体施用有效量的如权利要求1至31中任一项所述的化合物或如权利要求32所述的药物组合物。
34.如权利要求33所述的方法,其中所述神经变性疾病是蛋白质病。
35.如权利要求34所述的方法,其中所述蛋白质病是tau病。
36.如权利要求33所述的方法,其中所述神经变性疾病是阿兹海默氏病。
37.一种增强自噬潮的方法,其包括为细胞或蛋白聚集体提供有效量的如权利要求1至31中任一项所述的化合物或如权利要求32所述的药物组合物。
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