CN117222407A - 用于再生器官修复的yap转录活性的小分子激活剂 - Google Patents
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Abstract
本公开内容提供了可以选择性地激活Yes相关蛋白1(YAP)的化合物或其互变异构体或其可药用盐,及其药物组合物。本公开内容的YAP激活剂可用于治疗例如伤口和器官修复,其包括例如治疗慢性溃疡。
Description
本申请要求于2021年2月12日提交的美国临时专利申请No.63/148,868的优先权权益,该申请以其整体并入,如同在本文中充分阐述一样。
背景技术
保守的Hippo-YAP途径在动物中控制器官尺寸。1,2当被激活时,该途径的转录效应子Yes相关蛋白1(Yes-associated protein,YAP)通过与TEAD转录因子的核相互作用来促进增殖和抗凋亡基因产物的表达。3YAP激活导致在器官水平的增殖和程序性细胞死亡的损失。4除器官尺寸控制之外,YAP还在哺乳动物中协调再生响应,该过程需要募集和增殖内源性干细胞和祖细胞。5
除器官尺寸控制之外,YAP还在哺乳动物中协调再生响应,该过程需要募集和增殖内源性干细胞和祖细胞。5aYAP转录活性对在多种干细胞群中维持干性是至关重要的,所述干细胞群包括多能干细胞、5b神经干细胞、5cLgr5+肠和结肠干细胞、5d,5e表皮角质形成细胞祖细胞、5f和另一些器官驻留祖细胞。YAP激活允许干细胞和前体细胞在器官受损时重新填充(repopulate)器官,因为增强和持续的YAP激活促进再生增殖。5a,5g此外,先前的工作已表明,YAP在终末分化细胞(如神经元、乳腺上皮和胰腺外分泌细胞)中强制表达,将这些细胞可逆地转化为更加干细胞样的转录状态,从而允许长期离体扩增并随后植入到小鼠中。5h最近,研究表明YAP的遗传激活可在非分裂细胞中促进修复性增殖。例如,Hippo失活在成年小鼠中促进心肌细胞增殖,导致在心力衰竭的啮齿动物模型中提高心脏功能。5i
迄今为止,药理学上激活YAP的尝试集中于靶向Hippo途径中的传统可成药靶标,特别是开发针对MST1/2和LATS1/2激酶的活性位点抑制剂。5j然而,除Hippo信号传导之外,MST1/2和LATS1/2还参与了许多细胞作用,包括细胞周期控制、应激信号传导以及转录,意味着即使是这些激酶的选择性抑制剂也可以具有不期望的靶向作用。5k-5p因此,迄今为止,尚不知完全激活YAP转录程序的药物。
发明概述
为了解决这些缺陷等,本公开内容提供了式(I)化合物、其互变异构体或可药用盐:
环是5至6元杂环或杂芳基,其中1至4个杂原子独立地选自N、O和S。在多个实施方案中,环/>选自:
R选自H和C1-C6烷基。
R1选自C6-C10芳基、5至10元杂芳基(其中1至4个杂芳基成员独立地选自N、O和S)。
R2在存在时选自H、C6-C10芳基、5至10元杂芳基(其中1至4个杂芳基成员独立地选自N、O和S)。
在一些实施方案中,R1和R2在与相邻原子结合时与它们所结合的原子一起形成稠合的C6-C10芳基或5至10元杂芳基(其中1至4个杂芳基成员独立地选自N、O和S)。
在一些实施方案中,L是C(O)、C(S)或CH2。V是NR3R4。
R3选自C1-C6烷基、-(C1-C6烷基)-S-(C1-C6烷基)、-C1-C6烷基-(C6-C10芳基)、-C1-C6烷基-(5至10元杂芳基(其中1至4个杂芳基成员独立地选自N、O和S))、C3-C14环烷基、3至14元杂环烷基(其中1至4个杂环烷基环成员独立地选自N、O和S)、-C1-C6烷基-(3至14元杂环烷基(其中1至4个杂环烷基环成员独立地选自N、O和S))。
R4选自H、C1-C6烷基、-C1-C6烷基-(C6-C10芳基)、5至10元杂芳基(其中1至4个杂芳基成员独立地选自N、O和S)。
在一些实施方案中,R3和R4与它们所结合的N原子一起形成5至7元杂环烷基,其任选地与3至14元杂环烷基(其中1至4个杂环烷基环成员独立地选自N、O和S)稠合或螺稠合。
在式(I)中,任意烷基、芳基、环烷基、杂芳基和杂环烷基任选地被一至四个独立地选自以下的取代基取代:
,CN,-OH,卤代,氧代,-ORA,-SRA,-S(O)RA,-S(O)2RA,NRARB,-C(O)RA,-C(O)2RA,-NRAC(O))2RB,-C(O)NRARB,-S(O)NRARB,-S(O)2NRARB,-NRAS(O))RB,-NRAS(O)2RB,
5至10元杂芳基(其中1至4个杂芳基成员独立地选自N、O和S)。
RA和RB独立地选自H、C1-C6烷基、C1-C6卤代烷基、-C1-C6烷基-C6-C10芳基、C(O)C1-C6烷基、C(O)C1-C6烷基-C6-C10芳基、C(O)OC1-C6烷基、C6-C10芳基、3至14元杂环烷基(其中1至4个杂环烷基环成员独立地选自N、O和S)、-C(O)(5至10元杂芳基(其中1至4个杂芳基成员独立地选自N、O和S))。
在RA和RB中,每个芳基和杂环烷基任选地被一至三个独立地选自C1-C6烷基、卤代、C1-C6卤代烷基和3至14元杂环烷基(其中1至4个环成员独立地选自N、O和S)的取代基取代;并且每个烷基任选地被一至三个独立地选自卤代、NRCRD(其中RC和RD独立地选自H、C1-C6烷基、C(O)C1-C6烷基和C(O)C6-C10芳基)的取代基取代。
在另一个实施方案中,本公开内容提供了用于在有此需要的对象中激活Yes相关蛋白1(YAP)的方法。所述方法包括向所述对象施用式(I)化合物、其互变异构体或可药用盐。
在一个另外的实施方案中,本公开内容提供了治疗疾病或病症的方法,所述疾病或病症的病因由于患有所述疾病或病症的对象中增殖修复不足而加剧,或者定义为患有所述疾病或病症的对象中增殖修复不足,或者所述疾病或病症通过诱导细胞的增殖而得以改善。所述方法包括向所述对象施用式(I)化合物、其互变异构体或可药用盐。
附图简述
图1A至图1E.图1A:化合物13的结构和细胞活性的总结。图1B:来自用化合物13处理24小时的293A-TEAD-LUC细胞的相对亮度值和细胞计数(n=3个生物学重复;平均值和s.e.m.)。图1C:来自在含血清培养基或血清耗尽培养基中用化合物13处理的293A细胞的YAP依赖性基因(ANKRD1、CTGF、CYR61)和YAP自身(YAP1)的相对转录物水平(n=3个生物学重复;平均值和s.d.)。图1D:来自用化合物13处理24小时的293A细胞的YAP依赖性基因集(精选和MSigDB:M2871)的基因集富集分析(gene set enrichment analysis,GSEA)图(10μM;P<0.0001,标称P值,GSEA)。数据来自生物学独立样品。图1E:通过24小时化合物13(10μM)处理的上调的GO类别的富集P值。
图2A至图2I.化合物13在离体和体内促进表皮角质形成细胞的扩增。在化合物13处理之后经罗丹明B染色的小鼠表皮角质形成细胞前体的代表性图像(图2A)和定量(图2B)(10μM;10天;n=3个生物学独立实验,平均值和s.d.;比例尺=7mm)。图2C:YAP靶转录物CYR61响应于化合物13处理的相对表达(10μM;n=3个生物学独立实验,平均值和s.d.)。图2D:在用化合物13处理十天之后小鼠表皮的经代表性H&E和抗角蛋白14(Keratin 14,K14)染色的组织学切片(10mg/mL;比例尺=50μm)。在研究结束时来自经化合物13处理的野生型或YAP敲除小鼠的表皮厚度(图2E)和角质形成细胞数目(图2F)(n=3只动物;平均值和s.d.)。在研究结束时小鼠表皮的抗KI67组织学染色的代表性图像(图2G)和定量(图2H)(n=3只动物;平均值和s.d.;比例尺=50μm)。图2I:在研究结束时YAP靶转录物CTGF、CYR61和ANKRD1的相对转录物水平(n=3;平均值和s.d.;NS=无统计学显著性)。统计学分析通过单变量双侧t检验进行(图B、C、E、F、H和I)。
图3A和图3B.化合物13的基于凝胶的制剂在表面施加药物后在小鼠中促进上表皮增生。用指定的化合物13制剂处理十天的小鼠的定量(图3A)和代表性组织学图像(图3B)。
图4A至图4D.化合物13的表面施用在尤卡坦小型猪(Yucatan mini pig)中促进表皮生长。图4A:在研究结束时(第10天)的表皮厚度、角质形成细胞数目和经代表性H&E染色的组织学切片。来自用指定浓度的化合物13处理的猪的真皮层的代表性图像(图4B)和核数目的定量(图4C)。图4D:在研究结束时得到的YAP控制的基因Cyr61和Ctgf的相对转录物水平。
图5A至图5E.化合物13在人皮肤等同物模型中促进伤口闭合加速。在用Mattek人皮肤等同物进行的6天体外伤口愈合研究结束时,经KI-67染色的切片的代表性图像(图5A),以及伤口厚度(图5B)、伤口直径(图5C)、每个伤口的角质形成细胞(图5D)和部分KI-67呈阳性的核(图5E)的定量。
发明详述
本公开内容部分涉及一系列YAP激活小分子的鉴定,并且在多个实施方案中表明了它们在促进角质形成细胞的离体和体内扩增中的效用。本公开内容的化合物是选择性YAP激活剂,并因此可用于增强患有烧伤或慢性溃疡的患者的伤口修复;这些是通过当前标准护理治疗无法充分解决的疾病状态。39,40
基于无偏报道物的筛选鉴定了在离体和体内均稳健地扩增细胞的YAP驱动转录的小分子激活剂。更具体地说,我们使用了涵盖稳定整合盒的293A细胞系,所述整合盒包含萤光素酶上游的TEAD结合元件的8个拷贝(8xGTII-LUC)。这些细胞保留了对接触抑制诱导的YAP转录输出减少的响应性。6TEAD响应性报道物测定(通篇称为293A-TEAD-LUC)适合于1536孔形式,并随后用于筛选针对YAP诱导活性的约738k化合物的文库。鉴定出98种化合物,其剂量依赖性地激活TEAD-LUC信号、不诱导细胞毒性(<20μM)、不改变细胞中萤光素酶的酶活性(<20μM;293A-CMV-LUC)并且在历史筛选中没有注释活性。这些分子中的21种在其结构中带有5-苯基-异唑,并且是所鉴定的最高级的激活剂,如本文和整个实例中所举例说明的。
定义
“烷基”是指包含1至约20个碳原子的直链或支链烃基。例如,烷基可以具有1至10个碳原子或1至6个碳原子。示例性的烷基包括直链烷基,例如甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、壬基、癸基、十一烷基、十二烷基等,并且还包括直链烷基的支链异构体,例如但不限于
-CH(CH3)2,-CH(CH3)(CH2CH3),-CH(CH2CH3)2,-C(CH3)3,-C(CH2CH3)3,-CH2CH(CH3)2,-CH2CH(CH3)(CH2CH3),-CH2CH(CH2CH3)2,-CH2C(CH3)3,-CH2C(CH2CH3)3,-CH(CH3)CH(CH3)(CH2CH3),-CH2CH2CH(CH3)2,-CH2CH2CH(CH3)(CH2CH3),-CH2CH2CH(CH2CH3)2,-CH2CH2C(CH3)3,-CH2CH2C(CH2CH3)3,-CH(CH3)CH2CH(CH3)2,-CH(CH3)CH(CH3)CH(CH3)2,等。
因此,烷基包括伯烷基、仲烷基和叔烷基。烷基可以是未经取代的或任选地经一个或更多个如本文中所述的取代基取代的。
术语“卤素”、“卤化物”和“卤代”中的每一者是指-F或氟、-C1或氯、-Br或溴、或者-I或碘。
“卤代烷基”包括单卤代烷基;多卤代烷基,其中所有卤原子可以是相同的或不同的;以及全卤代烷基,其中所有氢原子被相同或不同的卤素原子(例如氟和/或氯原子)取代。卤代烷基的实例包括三氟甲基、1,1-二氯乙基、1,2-二氯乙基、1,3-二溴-3,3-二氟丙基、全氟丁基等。
术语“烷氧基”是指具有指定碳原子数的-O-烷基。例如,(C1-C6)-烷氧基包括-O-甲基、-O-乙基、-O-丙基、-O-异丙基、-O-丁基、-O-仲丁基、-O-叔丁基、-O-戊基、-O-异戊基、-O-新戊基、O-己基、-O-异己基和-O-新己基。
术语“环烷基”是指饱和的单环、二环、三环或多环的3至14元环体系,例如C3-C8环烷基。环烷基可以通过任何原子连接。环烷基的代表性实例包括但不限于环丙基、环丁基、环戊基和环己基。环烷基可以是未经取代的或任选地经一个或更多个如本文中所述的取代基取代的。
“芳基”在单独使用或作为另一术语的一部分使用时意指无论是否稠合的碳环芳族基团,其具有指定的碳原子数或者如果未指定数目则具有最多14个碳原子,例如C6-C10芳基或C6-C14芳基。芳基的实例包括苯基、萘基、联苯基、菲基、并四苯基等(参见例如Lang’sHandbook of Chemistry (Dean,J.A.,ed)13thed.表7-2[1985])。一个示例性芳基是苯基。芳基可以是未经取代的或任选地经一个或更多个如本文中所述的取代基取代的。
术语“杂原子”是指N、O和S。本公开内容的含N或S原子的化合物可以任选地被氧化成相应的N-氧化物、亚砜或砜化合物。
单独的“杂芳基”或与本文中所述的任何其他部分组合的“杂芳基”是含有5至10个(例如5或6个)环原子的单环芳族环结构或者具有8至10个原子的双环芳族基团,其含有一个或更多个(例如1至4个、1至3个或1至2个)独立地选自O、S和N的杂原子。杂芳基还旨在包含氧化的S或N,例如亚磺酰基、磺酰基和叔环氮的N-氧化物。碳或杂原子是杂芳基环结构的连接点,从而产生稳定的化合物。杂芳基的实例包括但不限于吡啶基、哒嗪基、吡嗪基、喹喔啉基、吲哚嗪基、苯并[b]噻吩基、喹唑啉基、嘌呤基、吲哚基、喹啉基、嘧啶基、吡咯基、吡唑基、唑基、噻唑基、噻吩基、异/>唑基、/>噻二唑基(oxathiadiazolyl)、异噻唑基、四唑基、咪唑基、三唑基、呋喃基、苯并呋喃基和吲哚基。杂芳基可以是未经取代的或任选地经一个或更多个如本文中所述的取代基取代的。
“杂环烷基”是饱和或部分不饱和的非芳族单环、二环、三环或多环环体系,其具有3至14个(例如3至5个、3至6个,或3至7个)原子,其中环中的1至3个碳原子被O、S或N杂原子替代。杂环烷基任选地与5至6个环成员的芳基或杂芳基稠合,并且包含氧化的S或N,例如亚磺酰基、磺酰基和叔环氮的N-氧化物。杂环烷基环的连接点在碳或杂原子处,使得稳定的环得以保持。杂环烷基的实例包括但不限于吗啉代、四氢呋喃基、二氢吡啶基、哌啶基、吡咯烷基、哌嗪基、二氢苯并呋喃基和二氢吲哚基。杂环烷基可以是未经取代的或任选地经一个或更多个如本文中所述的取代基取代的。
术语“腈”或“氰基”可互换使用,并且是指-CN基团。
术语“氧代”是指与作为饱和或不饱和部分的一部分的原子结合的=O原子。因此,=O原子可以与作为环状或非环状部分的一部分的碳、硫或氮原子结合。
“羟基(hydroxyl)”或“羟基(hydroxy)”是指-OH基团。
本文中所述的任何基团中的一个或更多个任选的取代基独立地选自
-CN,-OH,卤代,氧代,-ORA,-SRA,-S(O)RA,-S(O)2RA,NRARB,-C(O)RA,-C(O)2RA,-NRAC(O))2RB,-C(O)NRARB,-S(O)NRARB,-S(O)2NRARB,-NRAS(O)RB,-NRAS(O)2RB,
5至10元杂芳基(其中1至4个杂芳基成员独立地选自N、O和S)。
RA和RB独立地选自H、C1-C6烷基、C1-C6卤代烷基、-C1-C6烷基-C6-C10芳基、C(O)C1-C6烷基、C(O)C1-C6烷基-C6-C10芳基、C(O)OC1-C6烷基、C6-C10芳基、3至14元杂环烷基(其中1至4个杂环烷基环成员独立地选自N、O和S)、-C(O)(5至10元杂芳基(其中1至4个杂芳基成员独立地选自N、O和S))。
本文中所述的化合物可以以多种异构形式(包括构型异构体、几何异构体和构象异构体,包括例如顺式构象或反式构象)存在。所述化合物还可以以一种或更多种互变异构形式(包括单一互变异构体和互变异构体的混合物二者)存在。术语“异构体”旨在涵盖本公开内容的化合物的所有异构形式,包括化合物的互变异构形式。本公开内容的化合物还可以以开链或环化形式存在。在一些情况下,一种或更多种的环化形式可由失水产生。开链和环化形式的具体组成可取决于如何分离、储存或施用化合物。例如,化合物在酸性条件下可能主要以开链形式存在,但在中性条件下可能环化。所有形式都包含在本公开内容中。
本文中所述的一些化合物可具有不对称中心,并因此以不同的对映体和非对映体形式存在。如本文中所述的化合物可以呈光学异构体或非对映体的形式。因此,本公开内容涵盖了如本文中所述的呈其光学异构体、非对映体及其混合物(包括外消旋混合物)形式的化合物及其用途。本公开的化合物的光学异构体可通过已知技术(例如不对称合成、手性色谱、模拟移动床技术)获得,或者经由通过使用光学活性拆分剂对立体异构体进行化学分离获得。
除非另有指示,否则术语“立体异构体”意指化合物的一种立体异构体,其基本上不含该化合物的其他立体异构体。因此,具有一个手性中心的立体异构纯的化合物将基本上不含该化合物的相反对映体。具有两个手性中心的立体异构纯的化合物将基本上不含该化合物的其他非对映体。典型的立体异构纯的化合物包含按重量计大于约80%的该化合物的一种立体异构体和按重量计小于约20%的该化合物的其他立体异构体,例如按重量计大于约90%的该化合物的一种立体异构体和按重量计小于约10%的该化合物的其他立体异构体,或按重量计大于约95%的该化合物的一种立体异构体和按重量计小于约5%的该化合物的其他立体异构体,或按重量计大于约97%的该化合物的一种立体异构体和按重量计小于约3%的该化合物的其他立体异构体,或按重量计大于约99%的该化合物的一种立体异构体和按重量计小于约1%的该化合物的其他立体异构体。如上所述的立体异构体可被视为包含以本文中所述的其各自的重量百分比存在的两种立体异构体的组合物。
如果所示结构与该结构的给定名称之间存在差异,则以所示结构为准。另外,如果结构或结构的一部分的立体化学未用例如粗体或虚线表示,则该结构或该结构的一部分应解释为涵盖其所有立体异构体。然而,在一些情况下,在存在多于一个手性中心的情况下,结构和名称可以表示为单一对映体,以帮助描述相对立体化学。有机合成领域的技术人员将知道化合物是否由制备其的方法制备为单一对映体。
如本文所使用的,并且除非另有相反说明,否则术语“化合物”是包含性的,即其涵盖化合物或者其可药用盐、立体异构体和/或互变异构体。因此,例如,式IA或式IB化合物包括该化合物的互变异构体的可药用盐。
在本公开内容中,“可药用盐”是本文中所述化合物的可药用的有机或无机酸或碱盐。代表性的可药用盐包括,例如,碱金属盐、碱土盐、铵盐、水溶性和水不溶性盐,例如乙酸盐、氨茋磺酸盐(amsonate)(4,4-二氨基二苯乙烯-2,2-二磺酸盐)、苯磺酸盐、苯甲酸盐、碳酸氢盐、硫酸氢盐、酒石酸氢盐、硼酸盐、溴化物、丁酸盐、钙、依地酸钙、樟磺酸盐、碳酸盐、氯化物、柠檬酸盐、克拉维酸盐(clavulariate)、二盐酸盐、依地酸盐、乙二磺酸盐、依托酸盐(estolate)、乙磺酸盐(esylate)、延胡索酸盐(fiunarate)、葡庚糖酸盐、葡糖酸盐(gluconate)、谷氨酸盐、对羟乙酰氨基苯胂酸盐(glycollylarsanilate)、六氟磷酸盐、己基间苯二酚盐、海巴明(hydrabamine)、氢溴酸盐、盐酸盐、羟基萘甲酸盐、碘化物、异硫氰酸盐(isothionate)、乳酸盐、乳糖酸盐、月桂酸盐、苹果酸盐、马来酸盐、扁桃酸盐、甲磺酸盐、甲基溴化物、甲基硝酸盐、甲基硫酸盐、黏液酸盐(mucate)、萘磺酸盐、硝酸盐、N-甲基葡糖胺铵盐、3-羟基-2-萘甲酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐(1,1-亚甲基-双-2-羟基-3-萘甲酸盐、恩贝酸盐(einbonate))、泛酸盐、磷酸盐/二磷酸盐、苦味酸盐、多聚半乳糖醛酸盐、丙酸盐、对甲苯磺酸盐、水杨酸盐、硬脂酸盐、次醋酸盐、琥珀酸盐、硫酸盐、磺基水杨酸盐(sulfosaliculate)、苏拉酸盐(suramate)、单宁酸盐、酒石酸盐、茶氯酸盐(teoclate)、甲苯磺酸盐、三乙碘化物(triethiodide)和戊酸盐。可药用盐在其结构中可以具有多于一个的带电荷原子。在这种情况下,可药用盐可以具有多个反离子。因此,可药用盐可以具有一个或更多个带电荷原子和/或一个或更多个反离子。
术语“治疗”及其变化形式是指改善或根除疾病或与疾病相关的症状。在多个实施方案中,该术语是指因将一种或更多种本文中所述的预防性或治疗性化合物施用于患有疾病的患者而使得这样的疾病的传播或恶化最小化。
术语“预防”及其变化形式是指因施用本文中所述的化合物而实现对患者中疾病的发作、复发或扩散的预防。
术语“有效量”是指如本文中所述的化合物或其他活性成分的这样的量,所述量足以在疾病的治疗或预防中提供治疗性或预防性益处或使与疾病相关的症状延迟或最小化。此外,关于如本文中所述的化合物的治疗有效量意指单独的治疗剂或与其他治疗组合的治疗剂在疾病的治疗或预防中提供治疗性益处的量。与如本文中所述的化合物结合使用时,该术语可涵盖改善疾病的整体治疗、减少或避免疾病症状或原因,或者增强另一治疗剂的治疗效力或与另一治疗剂协同作用的量。
“患者”或“对象”包括动物,例如人、牛、马、绵羊、羔羊、猪、鸡、火鸡、鹌鹑、猫、狗、小鼠、大鼠、兔或豚鼠。根据一些实施方案,动物是哺乳动物,例如非灵长类和灵长类(例如,猴和人)。在一个实施例中,患者是人,例如人婴儿、儿童、青少年或成人。在本公开内容中,术语“患者”和“对象”可互换使用。
化合物
在多个实施方案中,本公开内容提供了式(I)化合物、其互变异构体或可药用盐:
环是5至6元杂环或杂芳基,其中1至4个杂原子独立地选自N、O和S。在多个实施方案中,环/>选自:
R选自H和C1-C6烷基。
R1选自C6-C10芳基、5至10元杂芳基(其中1至4个杂芳基成员独立地选自N、O和S)。
R2在存在时选自H、C6-C10芳基、5至10元杂芳基(其中1至4个杂芳基成员独立地选自N、O和S)。
在一些实施方案中,R1和R2在与相邻原子结合时与它们所结合的原子一起形成稠合的C6-C10芳基或5至10元杂芳基(其中1至4个杂芳基成员独立地选自N、O和S)。
在一些实施方案中,L是C(O)、C(S)或CH2。V是NR3R4。
R3选自C1-C6烷基、-(C1-C6烷基)-S-(C1-C6烷基)、-C1-C6烷基-(C6-C10芳基)、-C1-C6烷基-(5至10元杂芳基(其中1至4个杂芳基成员独立地选自N、O和S))、C3-C14环烷基、3至14元杂环烷基(其中1至4个杂环烷基环成员独立地选自N、O和S)、-C1-C6烷基-(3至14元杂环烷基(其中1至4个杂环烷基环成员独立地选自N、O和S))。
R4选自H、C1-C6烷基、-C1-C6烷基-(C6-C10芳基)、5至10元杂芳基(其中1至4个杂芳基成员独立地选自N、O和S)。
在一些实施方案中,R3和R4与它们所结合的N原子一起形成5至7元杂环烷基,其任选地与3至14元杂环烷基(其中1至4个杂环烷基环成员独立地选自N、O和S)稠合或螺稠合。
RA和RB独立地选自H、C1-C6烷基、C1-C6卤代烷基、-C1-C6烷基-C6-C10芳基、C(O)C1-C6烷基、C(O)C1-C6烷基-C6-C10芳基、C(O)OC1-C6烷基、C6-C10芳基、3至14元杂环烷基(其中1至4个杂环烷基环成员独立地选自N、O和S)、-C(O)(5至10元杂芳基(其中1至4个杂芳基成员独立地选自N、O和S))。
在RA和RB中,每个芳基和杂环烷基任选地被一至三个独立地选自C1-C6烷基、卤代、C1-C6卤代烷基和3至14元杂环烷基(其中1至4个环成员独立地选自N、O和S)的取代基取代;并且每个烷基任选地被一至三个独立地选自卤代、NRCRD(其中RC和RD独立地选自H、C1-C6烷基、C(O)C1-C6烷基和C(O)C6-C10芳基)的取代基取代。
在多个实施方案中,任选地与本文中所述的任何其他实施方案组合,L是C(O)。
在一些实施方案中,任选地与本文中所述的任何其他实施方案组合,R3是任选经取代的C1-C6烷基或-C1-C6烷基-(5至10元杂芳基(其中1至4个杂芳基成员独立地选自N、O和S))。在一个实施方案中,R3是任选经取代的-C1-C6烷基-(5至10元杂芳基(其中1至4个杂芳基成员独立地选自N、O和S))。
在另一些实施方案中,任选地与本文中所述的任何其他实施方案组合,R4是H。
在多个实施方案中,任选地与本文中所述的任何其他实施方案组合,R1是任选经取代的C6-C10芳基。在一些实施方案中,R1是任选经取代的苯基。在另一些实施方案中,R1是苯基。
在多个实施方案中,任选地与本文中所述的任何其他实施方案组合,R2是H。
在一些实施方案中,任选地与本文中所述的任何其他实施方案组合,本公开内容提供了式(I)化合物、其互变异构体或可药用盐,其中环是:
在另一些实施方案中,环选自:
在另一些实施方案中,环选自:
在一些另外的实施方案中,环选自:
在多个实施方案中,任选地与本文中所述的任何其他实施方案组合,本公开内容提供了式(I)化合物、其互变异构体或可药用盐,其中:
环是/>
R1是苯基或5至6元杂芳基(其中1至3个杂芳基成员独立地选自N、O和S),各自任选地被一至三个独立地选自以下的取代基取代:Br、Cl、F、-CN、C1-C6烷基、C1-C6卤代烷基、-OC1-C6烷基、-OC1-C6卤代烷基、任选经取代的苯基、-C(O)RA;
R2是H;
L是C(O);
R3是-C1-C6烷基-(5至7元杂芳基(其中1至3个杂芳基成员独立地选自N、O和S))或-C1-C6烷基(苯基),其中杂芳基或苯基任选地被一至三个独立地选自Br、Cl、F、C1-C6烷基、-OC1-C6烷基、C(O)RA和-C(O)NRARB的取代基取代;并且
R4是H。
在一个另外的实施方案中,任选地与本文中所述的任何其他实施方案组合,R1是苯基;并且R3是任选经取代的-C1-C6烷基-(5元杂芳基(其中1至2个杂芳基成员独立地选自N、O和S))或任选经取代的C1-C6烷基(苯基)。
在多个实施方案中,本公开内容还提供了如表1中所示的化合物或者其互变异构体或可药用盐:
表1:示例性化合物
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在一些另外的实施方案中,本公开内容提供了如表2中所示的化合物或者其互变异构体或可药用盐:
表2:示例性化合物
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药物组合物
本公开内容还提供了药物组合物,其包含与可药用载体混合的治疗有效量的一种或更多种如本文中所述的化合物或者其可药用盐、立体异构体和/或互变异构体。在一些实施方案中,根据药物复配(pharmaceutical compounding)的认可惯例(acceptedpractice),组合物还包含一种或更多种另外的治疗剂、可药用的赋形剂、稀释剂、辅料、稳定剂、乳化剂、防腐剂、着色剂、缓冲剂、风味赋予剂。
在一个实施方案中,药物组合物包含选自表1和表2中所示的那些的化合物或者其可药用盐、立体异构体和/或互变异构体,以及可药用载体。
本公开内容的药物组合物以符合良好医学实践的方式配制、给药和施用。在本上下文中考虑的因素包括所治疗的具体病症、所治疗的具体对象、对象的临床病症、病症的原因、药剂的递送部位、施用的方法、施用的时间安排以及医疗从业者已知的其他因素。
施用的化合物或者其可药用盐、立体异构体和/或互变异构体的“治疗有效量”由这样的考虑因素支配,并且是激活YAP转录活性、促进增殖性组织修复及其组合所需的最小量。这样的量可低于对正常细胞或作为整体的对象有毒的量。一般而言,施用本公开内容的化合物(或其可药用盐、立体异构体或互变异构体)的初始治疗有效量在约0.01mg/kg至约200mg/kg或约0.1mg/kg至约20mg/kg患者体重/天的范围内,其中典型的初始范围为约0.3mg/kg/天至约15mg/kg/天。经口单位剂型(例如片剂和胶囊剂)可包含约0.1mg至约1000mg的本公开内容的化合物(或其可药用盐、立体异构体或互变异构体)。在另一个实施方案中,这样的剂型包含约50mg至约500mg的本公开内容的化合物(或其可药用盐、立体异构体或互变异构体)。在另一个实施方案中,这样的剂型包含约25mg至约200mg的本公开内容的化合物(或其可药用盐、立体异构体或互变异构体)。在另一个实施方案中,这样的剂型包含约10mg至约100mg的本公开内容的化合物(或其可药用盐、立体异构体或互变异构体)。在另一个实施方案中,这样的剂型包含约5mg至约50mg的本公开内容的化合物(或其可药用盐、立体异构体或互变异构体)。在任意前述实施方案中,剂型可每天一次或每天两次施用。
本公开内容的组合物可以以剂量单位制剂经口、表面、肠胃外、通过吸入或喷雾或者经直肠施用。如本文所使用的术语肠胃外包括皮下注射、静脉内、肌内、胸骨内注射或输注技术。
如本文中所述的合适的经口组合物包括但不限于片剂、糖锭剂(troche)、锭剂(lozenge)、水性或油性混悬剂、可分散的散剂或颗粒剂、乳剂、硬胶囊剂或软胶囊剂、糖浆剂或酏剂。
在另一个方面中,还涵盖了适合于单一单位剂量的药物组合物,所述药物组合物包含本公开内容的化合物或其可药用立体异构体、盐或互变异构体以及可药用载体。
适合于经口使用的本公开内容的组合物可以根据本领域已知的用于制备药物组合物的任何方法来制备。例如,本公开内容的化合物的液体制剂包含一种或更多种选自甜味剂、矫味剂、着色剂和防腐剂的试剂,以提供本公开内容化合物的药学上适口的制剂。
对于片剂组合物,本公开内容化合物与无毒的可药用赋形剂混合用于制备片剂。这样的赋形剂的实例包括但不限于惰性稀释剂,例如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠;制粒剂和崩解剂,例如玉米淀粉或藻酸;黏合剂,例如淀粉、明胶或阿拉伯胶,以及润滑剂,例如硬脂酸镁、硬脂酸或滑石。片剂可以是未包衣的,或者可以通过已知的包衣技术对其进行包衣以延迟在胃肠道中的崩解和吸收,并从而在期望的时间段内提供持续的治疗作用。例如,可以使用时间延迟物质,例如单硬脂酸甘油酯或二硬脂酸甘油酯。
用于经口使用的制剂还可以制成硬明胶胶囊剂,其中活性成分与惰性固体稀释剂(例如,碳酸钙、磷酸钙或高岭土)混合,或制成软明胶胶囊剂,其中活性成分与水或油介质(例如,花生油、液体石蜡或橄榄油)混合。
对于水性混悬剂,将本公开内容的化合物与适合于维持稳定混悬剂的赋形剂混合。这样的赋形剂的实例包括但不限于羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯吡咯烷酮、黄蓍胶和阿拉伯胶。
经口混悬剂还可包含分散剂或润湿剂,例如天然存在的磷脂,例如卵磷脂,或环氧烷与脂肪酸的缩合产物,例如聚氧乙烯硬脂酸酯,或环氧乙烷与长链脂肪醇的缩合产物,例如十七碳乙烯氧基十六烷醇,或环氧乙烷与来源于脂肪酸和己糖醇的偏酯的缩合产物,例如聚氧乙烯山梨糖醇一油酸酯,或环氧乙烷与来源于脂肪酸和己糖醇酸酐的偏酯的缩合产物,例如聚氧乙烯脱水山梨糖醇一油酸酯。水性混悬剂还可以包含一种或更多种防腐剂,例如对羟基苯甲酸乙酯或对羟基苯甲酸正丙酯,一种或更多种着色剂,一种或更多种矫味剂,以及一种或更多种甜味剂,例如蔗糖或糖精。
可通过将本公开内容的化合物混悬在植物油(例如花生油、橄榄油、芝麻油或椰子油)中或在矿物油(例如液体石蜡)中来配制油性混悬剂。所述油性混悬剂可包含增稠剂,例如蜂蜡、硬石蜡或鲸蜡醇。
可以添加甜味剂(例如如上所示的那些)和矫味剂以提供适口的经口制剂。这些组合物可通过添加抗氧化剂(例如抗坏血酸)来保存。
适合于通过添加水来制备水性混悬剂的可分散的散剂和颗粒剂提供了与分散剂或润湿剂、助悬剂以及一种或更多种防腐剂混合的本公开内容化合物。合适的分散剂或润湿剂以及助悬剂通过上面已经提及的那些来例示。还可以存在另外的赋形剂,例如甜味剂、矫味剂和着色剂。
本公开内容的药物组合物还可以是水包油乳剂的形式。油相可以是植物油,例如橄榄油或花生油,或者矿物油,例如液体石蜡,或者这些的混合物。合适的乳化剂可以是天然存在的树胶(例如阿拉伯胶或黄芪胶)、天然存在的磷脂(例如大豆、卵磷脂),以及来源于脂肪酸和己糖醇酐的酯或偏酯(例如脱水山梨糖醇一油酸酯和所述偏酯与环氧乙烷的缩合反应产物(例如聚氧乙烯脱水山梨糖醇一油酸酯))。乳剂还可以包含甜味剂和矫味剂。
糖浆剂和酏剂可用甜味剂(例如甘油、丙二醇、山梨糖醇或蔗糖)配制。这样的制剂还可以包含缓和剂(demulcent)、防腐剂以及矫味剂和着色剂。
药物组合物可以是无菌可注射剂、水性混悬剂或油性混悬剂的形式。该混悬剂可以根据已知技术使用上面提及的那些合适的分散剂或润湿剂和助悬剂来配制。无菌注射制剂还可以是无毒的、肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液剂或混悬剂,例如作为在1,3-丁二醇中的溶液剂。在可接受载剂和溶剂中,可使用水、林格溶液(Ringer’ssolution)和等张氯化钠溶液。另外,无菌的不挥发油通常用作溶剂或助悬介质。出于该目的,可以使用任何温和的不挥发油,包括合成的甘油单酯或甘油二酯。另外,脂肪酸(例如油酸)可用于制备可注射剂。
如本文中所述的化合物还可以以用于经直肠施用药物的栓剂的形式施用。这些组合物可通过将药物与合适的非刺激性赋形剂混合来制备,所述赋形剂在常温下为固体,但在直肠温度下为液体,并因此将在直肠中融化以释放药物。这样的物质包括可可脂和聚乙二醇。
用于肠胃外施用的组合物在无菌介质中施用。取决于所使用载剂和浓度(制剂中药物的浓度),肠胃外制剂可以是混悬剂或含有溶解的药物的溶液剂。还可以将辅料(例如局部麻醉剂、防腐剂和缓冲剂)添加至肠胃外组合物。
使用方法
在一些另外的实施方案中,如通过本文的数据和实例所示的,本公开内容提供了用于在此需要的对象中激活Yes相关蛋白1(YAP)的方法。所述方法包括向所述对象施用如本文中所述的化合物(例如式(I)化合物)或者其互变异构体或可药用盐。
本文中所述化合物的优点在于其对激活YAP的选择性,并从而减少不想要的增殖。所述化合物因此特别可用于治疗,例如用于治疗疾病或病症的方法,所述疾病或病症的病因由于患有所述疾病或病症的对象中增殖修复不足而加剧,或者定义为患有所述疾病或病症的对象中增殖修复不足。在一些实施方案中,所述疾病或病症是通过诱导细胞的增殖而得以改善的疾病或病症。所述方法包括向所述对象施用如本文中所述的化合物(例如式(I)化合物)或者其互变异构体或可药用盐。
在一些实施方案中,所述方法可用于修复伤口或修复器官,其中所述疾病或病症是对伤口修复的需求或对器官修复的需求。示例性器官包括肺、心脏、肝、胰腺、肝和肠。
在另一些实施方案中,所述疾病或病症选自烧伤、溃疡、心力衰竭和炎性肠病。溃疡的实例包括慢性溃疡、糖尿病足溃疡和静脉腿溃疡。
通过本文公开的方法治疗的疾病和病症的实例包括以下:糖尿病足溃疡(diabetic foot ulcer,DFU)、静脉性溃疡(淤积性溃疡)、压力溃疡、全层或局部厚度烧伤、湿疹、银屑病、蜂窝织炎、脓疱病、特应性皮炎、大疱性表皮松解症、苔藓硬化、鱼鳞病、白癜风、肢端剥脱性皮肤综合征、Blau综合征(Blau syndrome)、原发性皮肤淀粉样变、皮肤脓肿、睑缘炎、疖病、毛细血管炎、蜂窝织炎、角膜擦伤、角膜糜烂、干燥病、扁平苔藓、慢性单纯性苔藓、特发性肺纤维化(idiopathic pulmonary fibrosis,IPF)、急性呼吸窘迫综合征(acute respiratory distress syndrome,ARDS)、慢性阻塞性肺疾病(chronicobstructive pulmonary disease,COPD)、肺气肿、硅沉着病、石棉沉着病、肺尘埃沉着病、肺矾土沉着病、铁钒土纤维化、铍中毒、肺铁末沉着病、锡尘肺、滑石肺、拉布拉多尔肺(Labrador lung)(混合性粉尘肺尘埃沉着病)、结节病、过敏性肺炎(hypersensitivitypneumonitis,HP)/外源性变应性肺泡炎(extrinsic allergic alveolitis,EAA)、脱屑性间质性肺炎(desquamative interstitial pneumonia,DIP)、呼吸性细支气管炎间质性肺疾病(respiratory bronchiolitis interstitial lung disease,RBILD)、急性间质性肺炎(acute interstitial pneumonia,AIP)、非特异性间质性肺炎(nonspecificinterstitial pneumonia,NSIP)、隐源性机化性肺炎(cryptogenic organizingpneumonia,COP=特发性BOOP)、继发性机化性肺炎(BOOP)、淋巴样间质性肺炎(lymphoidinterstitial pneumonia,LIP)、特发性间质性肺炎:未明、嗜酸性粒细胞增多性肺疾病(hypereosinophilic lung disease)、结核病(tuberculosis,TB)、肺水肿、间质性肺疾病、隐源性机化性肺炎(Cryptogenic Organizing Pneumonia,COP)、电子烟或雾化产品使用相关肺损伤(e-cigarette or vaping use-associated lung injury,EVALI)、汉坦病毒肺综合征(Hantavirus Pulmonary Syndrome,HPS)、组织胞浆菌病、军团病、MAC肺疾病、α1-抗胰蛋白酶缺乏症、曲霉病、淋巴管平滑肌瘤病(lymphangioleiomyomatosis,LAM)、中东呼吸综合征(Middle Eastern Respiratory Syndrome,MERS)、非结核分枝杆菌肺疾病(Nontuberculous Mycobacterial Lung Disease,NTM)、肺栓塞、古德帕斯丘综合征(goodpasture syndrome)、特发性肺含铁血黄素沉着症、肺泡蛋白沉积症、肺淀粉样变、原发性肺淋巴瘤、原发性纤毛运动障碍(不伴或伴内脏反位)、罕见原因的过敏性肺炎(除农民肺疾病和鸽饲养者肺疾病之外的所有原因)、遗传性出血性毛细血管扩张症(hereditaryhemorrhagic telangiectasia,HHT)中的肺动静脉畸形、系统性硬化症中的间质性肺疾病、类风湿性关节炎中的间质性肺疾病、特发性炎性肌病中的间质性肺疾病(多肌炎、皮肌炎、抗合成酶综合征)、舍格伦综合征( syndrome)中的间质性肺疾病、混合性结缔组织病(mixed connective tissue disease,MCTD)中的间质性肺疾病、重叠综合征中的间质性肺疾病、未分化结缔组织病中的间质性肺疾病、闭塞性细支气管炎(在非移植患者中)、感染性结肠炎、溃疡性结肠炎、克罗恩病(Crohn’s disease)、缺血性结肠炎、放射性结肠炎、消化性溃疡、肠癌、肠梗阻、类风湿性关节炎、银屑病关节炎、桥本甲状腺炎、系统性红斑狼疮、多发性硬化、格雷夫斯病(Graves’Disease)、1型糖尿病、银屑病、强直性脊柱炎、硬皮病、肌炎、痛风、抗磷脂抗体综合征(Antiphospholipid Antibody Syndrome,APS)、血管炎、扩张型心肌病、肥厚型心肌病、限制型心肌病、收缩性心力衰竭、舒张性心力衰竭(射血分数保留的心力衰竭)、房间隔缺损、房室隔缺损、主动脉缩窄、双出口右心室、d型大动脉转位(d-Transposition of the Great Artery)、埃布斯坦异常(Ebstein Anomaly)、左心发育不良综合征、主动脉弓中断、肺动脉瓣闭锁、单心室、法洛四联症(Tetralogy of Fallot)、全肺静脉异位回流、三尖瓣闭锁、动脉干、室间隔缺损、多囊肾病、尿崩症、古德帕斯丘病(Goodpasture’s Disease)、IgA血管炎、IgA肾病、狼疮性肾炎、成人肾病综合征、儿童肾病综合征、溶血尿毒症综合征、髓质海绵肾、肾发育不良、肾动脉狭窄、肾血管性高血压、肾小管性酸中毒、奥尔波特综合征(Alport syndrome)、韦氏肉芽肿病(Wenger’sgranulomatosis)、阿拉日耶综合征(Alagille syndrome)、胱氨酸病、法布里病(Fabrydisease)、局灶性节段性肾小球硬化(focal segmental glomerulosclerosis,FSGS)、肾小球肾炎、aHUS(非典型溶血尿毒症综合征)、溶血尿毒症综合征(hemolytic uremicsyndrome,HUS)、肯诺克-肖林紫癜(Henoch-/> purpura)、IgA肾病(伯杰氏病,Berger’s disease)、间质性肾炎、微小变化疾病(Minimal change disease)、肾病综合征、血栓性血小板减少性紫癜(thrombotic thrombocytopenic purpura,TTP)、肉芽肿性多血管炎(granulomatosis with polyangiitis,GPA)、成人斯蒂尔病(adult Still’sdisease)、无丙种球蛋白血症、斑秃、自身免疫性血管性水肿、自身免疫性自主神经功能障碍、自身免疫性脑脊髓炎、自身免疫性肝炎、自身免疫性心肌炎、自身免疫性卵巢炎、自身免疫性睾丸炎、自身免疫性胰腺炎、自身免疫性视网膜病变、自身免疫性荨麻疹、轴突和神经元神经病(AMAN)、巴洛病(Balódisease)、大疱性类天疱疮、乳糜泻、慢性复发性多灶性骨髓炎(chronic recurrent multifocal osteomyelitis,CRMO)、许尔许斯特劳斯综合征(Churg-Strauss Syndrome,CSS)或嗜酸性肉芽肿(Eosinophilic Granulomatosis,EGPA)、瘢痕性类天疱疮、Cogan综合征(Cogan’s syndrome)、冷凝集素病、柯萨奇病毒性心肌炎(Coxsackie myocarditis)、CREST综合征、疱疹样皮炎、皮肌炎、德维克病(Devic’sdisease)(视神经脊髓炎)、盘状狼疮、嗜酸性食管炎(eosinophilic esophagitis,EoE)、嗜酸性筋膜炎、结节性红斑、原发性混合性冷球蛋白血症、巨细胞动脉炎(颞动脉炎)、巨细胞心肌炎、肉芽肿性多血管炎、吉兰-巴雷综合征(Guillain-Barre syndrome)、桥本甲状腺炎、肯诺克-肖林紫癜(Henoch-Schonlein purpura,HSP)、妊娠疱疹或妊娠类天疱疮(pemphigoid gestationis,PG)、低丙球蛋白血症、IgG4相关硬化性疾病、免疫性血小板减少性紫癜(immune thrombocytopenic purpura,ITP)、包涵体肌炎(inclusion bodymyositis,IBM)、兰伯特-伊顿综合征(Lambert-Eaton syndrome)、白细胞碎裂性血管炎、线状IgA病(linear IgAdisease,LAD)、显微镜下多血管炎(microscopic polyangiitis,MPA)、混合性结缔组织病(mixed connective tissue disease,MCTD)、蚕蚀性角膜溃疡(Mooren’s ulcer)、Mucha-Habermann病(Mucha-Habermann disease)、多灶性运动神经病(Multifocal Motor Neuropathy,MMN)或MMNCB、多发性硬化、重症肌无力、肌炎、发作性睡病、新生儿狼疮、视神经脊髓炎、中性粒细胞减少、眼瘢痕性类天疱疮、视神经炎、复发性风湿病(palindromic rheumatism,PR)、PANDAS、副肿瘤性小脑变性(paraneoplasticcerebellar degeneration,PCD)、阵发性夜间血红蛋白尿(paroxysmal nocturnalhemoglobinuria,PNH)、帕里龙贝格综合征(Parry Romberg syndrome)、睫状体扁平部炎(周围葡萄膜炎)、Parsonage-Turner综合征、天疱疮、周围神经病、静脉周围脑脊髓炎、恶性贫血(pernicious anemia,PA)、POEMS综合征、结节性多动脉炎、I、II、III型多腺综合征、风湿性多肌痛、多肌炎、原发性胆汁性肝硬化、原发性硬化性胆管炎、孕酮皮炎、纯红细胞再生障碍(pure red cell aplasia,PRCA)、坏疽性脓皮病、雷诺现象(Raynaud’s phenomenon)、反应性关节炎、反射性交感神经营养不良、复发性多软骨炎、下肢不宁综合征(restlesslegs syndrome,RLS)、腹膜后纤维化、风湿热、类风湿性关节炎、结节病、施密特综合征、巩膜炎、硬皮病、舍格伦综合征、精子和睾丸自身免疫、僵人综合征(stiff person syndrome,SPS)、亚急性细菌性心内膜炎(subacute bacterial endocarditis,SBE)、Susac综合征(Susac’s syndrome)、交感性眼炎(sympathetic ophthalmia,SO)、大动脉炎、颞动脉炎/巨细胞动脉炎、血小板减少性紫癜(thrombocytopenic purpura,TTP)、甲状腺眼病(thyroideye disease,TED)、阿拉日耶综合征、酒精相关肝病、自身免疫性肝炎、胆道闭锁、肝硬化、溶酶体酸性脂肪酶缺乏症(Lysosomal Acid Lipase Deficiency,LAL-D)、新生儿黄疸、非酒精性脂肪性肝病、非酒精性脂肪性肝炎、原发性胆汁性胆管炎(Primary BiliaryCholangitis,PBC)和进行性家族性肝内胆汁淤积(Progressive Familial IntrahepaticCholestasis,PFIC)。
实施例
本公开内容的一些另外的实施方案存在于本文更详细描述的具体实施例和数据中。
实施例1A:5-苯基-N-(3-(噻唑-2-基)丙基)异唑-3-甲酰胺(化合物13)的合成:/>
在室温下,向5-苯基-1,2-唑-3-羧酸(5.50g,29.1mmol,1.0当量)和3-(噻唑-2-基)丙烷-1-胺二盐酸盐(4.13g,29.1mmol,1.0当量)在二氯甲烷(60.0mL)中的搅拌溶液添加三乙胺(12.6mL,90.1mmol,3.1当量),并搅拌5分钟。将该溶液冷却至0℃并添加丙基膦酸酐(T3P,在乙酸乙酯中的50%溶液,59.2mL,93.0mmol,3.2当量)。将所得溶液在室温下搅拌3小时,在其之后将反应混合物用水(200mL)稀释,并用二氯甲烷(3×75mL)萃取。将合并的有机层经无水硫酸钠干燥、过滤并浓缩。将粗制物质通过柱色谱使用为正己烷中的0%至50%乙酸乙酯的流动相梯度进行纯化以获得作为白色固体的5-苯基-N-(3-(噻唑-2-基)丙基)异/>唑-3-甲酰胺(化合物13,5.20g,16.3mmol,56%)。
实施例1B:5-苯基-N-(3-(噻唑-2-基)丙基)异唑-3-甲酰胺(化合物13)的替代合成:将5-苯基异/>唑-3-羧酸(1.0g,5.3mmol,1.0当量)溶解于15mL无水DMF中,并将溶液用冰浴冷却;将HATU(2.0g,5.3mmol,1.0当量)添加至溶液,随后分批添加Hunig碱(1.9mL,10.6mmol,2.0当量),并将混合物搅拌15分钟。添加3-(噻唑-2-基)丙烷-1-胺(827mg,5.8mmol,1.1当量),并且将混合物在室温下搅拌过夜。TLC和LC-MS分析指示,起始物质已被消耗并转化为期望的产物。然后将混合物通过棉塞过滤,将挥发物在真空下除去,并且将产物通过柱色谱在硅胶上通过干加载粗制反应物(己烷中的30%至70%乙酸乙酯)进行纯化。在色谱后,将化合物重悬于10mL的5:1丙酮/甲苯混合物中,并在回流后溶解。将溶液冷却至室温并在-20℃下静置过夜后,将结晶固体在烧结漏斗(fritted funnel)上过滤,用冰冷的丙酮洗涤并通过抽吸干燥。
实施例2:N-[3-(4-甲基哌嗪-1-基)丙基]-5-苯基-1,2-唑-3-甲酰胺(化合物127)的合成:
在室温下,向5-苯基-1,2-唑-3-羧酸(150mg,793μmol,1.0当量)和3-(4-甲基哌嗪-1-基)丙烷-1-胺(125mg,793μmol,1.0当量)在二氯甲烷(5.0mL)中的搅拌溶液添加三乙胺(343μL,2.46mmol,3.1当量),并搅拌5分钟。将该溶液冷却至0℃并添加丙基膦酸酐(T3P,在乙酸乙酯中的50%溶液,1.61mL,2.54mmol,3.2当量)。将所得溶液在室温下搅拌16小时,在其之后将挥发物在真空下除去。首先将粗制物质通过柱色谱使用二氯甲烷中的10%甲醇氨的流动相进行纯化。将所得化合物通过反相制备型HPLC再次纯化,并将期望的级分冻干以获得作为灰白色固体的N-[3-(4-甲基哌嗪-1-基)丙基]-5-苯基-1,2-/>唑-3-甲酰胺(化合物127,63.0mg,188μmol,24%)。
实施例3:N-(2-(1H-吡咯-1-基)乙基)-5-苯基异唑-3-硫代酰胺(化合物106)的合成
在室温下,向5-苯基-N-[2-(1H-吡咯-1-基)乙基]-1,2-唑-3-甲酰胺(200mg,711μmol)在四氢呋喃(8.00mL)中的搅拌溶液添加双(4-甲氧基苯基)-1,3,2λ5,4λ5-二硫杂二膦烷-2,4-二硫酮(劳森试剂(Laweson’sreagent),863mg,3当量,2.13mmol),并在65℃下搅拌18小时。在反应完成之后,将反应混合物用水稀释,并用乙酸乙酯萃取。将合并的有机层经无水硫酸钠干燥、过滤并浓缩以获得粗制物。将粗制物在Combi快速色谱中使用12.0gRedi Sep柱并用庚烷中的15%至20%乙酸乙酯洗脱进行纯化。将期望的级分浓缩,并且将所获得的固体用乙醚洗涤,并真空干燥以得到作为淡黄色固体的N-(2-(1H-吡咯-1-基)乙基)-5-苯基异/>唑-3-硫代酰胺。
实施例4:一些另外的化合物的合成
化合物1至105的合成以及某些已知化合物(107至157)的再合成是根据针对化合物13和127概述的示例性操作进行的。在室温下,向代表性羧酸(i,1.0当量)和代表性胺(ii,1.0当量)在二氯甲烷中的搅拌溶液添加三乙胺(3.1当量),并搅拌5分钟。将该溶液冷却至0℃并添加丙基膦酸酐(T3P,在乙酸乙酯中的50%溶液,3.2当量)。将所得溶液在室温下搅拌3小时,在其之后将挥发物在真空下除去。将粗制物质通过柱色谱进行纯化以获得作为粉末的期望化合物,或使用反相制备型HPLC再次纯化。通过LC/MS和/或1H NMR确定所有合成的化合物均为>95%纯度。
实施例5:YAP激活测定
为了举例说明式(I)化合物以及存在于表1和表2中的化合物,在化合物13(噻唑取代的衍生物)中鉴定并例示了5-苯基-3-甲酰胺取代的异唑支架,当细胞以高细胞密度平板接种时,在存在或不存在血清的情况下,化合物13在293A-TEAD-LUC细胞中剂量依赖性地诱导萤光素酶活性(分别EC50=1.5和1.6μM;图1A和图1B)。结果表明化合物1不模拟血清的弱YAP激活特性。7
该转录响应的程度与在报道物测定中观察到的关键Hippo信号传导蛋白NF2(Merlin)敲低的程度类似。8化合物13处理还剂量依赖性地促进了细胞中YAP与TEAD蛋白的缔合,并诱导了YAP响应于细胞密度提高的核定位,表明化合物13处理可以克服Hippo途径激活的YAP抑制作用。
另外,化合物13处理稳健地提高了293A细胞和另一些人细胞系(即,MCF-10A、HEK293T、H69、HaCaT)中的经YAP控制的转录物(即,ANRKD1、CYR61、CTGF)的水平,但没有增加YAP自身(YAP1)的水平,表明化合物1广泛地激活了YAP但不是通过YAP转录物的正调节(图1C)。基于RNA-seq的293A细胞表达谱显示通过基因集富集分析(GSEA)提高了注释的YAP结合位点的转录物以及先前的YAP转录靶标。9-11类似地,化合物13处理上调了与细胞生长、分化和伤口愈合相关的转录物,如通过DAVID分析确定的(图1D和图1E)。此外,化合物13激活TEAD-LUC报道物信号和上调经YAP控制的转录物的能力取决于YAP蛋白的存在,表明化合物13是充当YAP上游的YAP转录活性的稳健且特定的激活剂。
将对本公开内容的一些另外的化合物进行上述测定。结果和所选择的特征数据在下表3和表4中示出。
表3:TEAD-LUC激活测定中的化合物的YAP激活
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表4:TEAD-LUC激活测定中的化合物的YAP激活
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实施例6:表皮重塑
我们评价了原代细胞和组织对化合物13处理的增殖响应。在本上下文中,周期性的YAP激活维持小鼠中角蛋白14(K14)呈阳性的角质形成细胞祖细胞的生长,从而向表皮屏障贡献新的角质形成细胞。12,13此外,YAP的持续遗传激活在离体和小鼠中促进了角质形成细胞及其前体的增生,表明YAP对于基底表皮更新至关重要,但可以被增强以提高生长。13当原代小鼠表皮角质形成细胞在真皮饲养层上培养超过10天生长期时,化合物13处理提高了原代小鼠表皮角质形成细胞的集落形成潜力(约10倍)(图2A和图2B)。另外,化合物13处理允许经罗丹明B染色的角质形成细胞的二次重新平板接种扩增以及YAP驱动的转录物Cyr61的时间依赖性表达(图2A至C)。
当在十天时间内表面施加于野生型成年C57BL/6小鼠的背侧皮肤时,化合物13(10μM)促进角质形成细胞和K14呈阳性的前体的显著扩增,如在研究结束时通过H&E和抗K14组织学染色评估的(图2D)。化合物处理导致表皮厚度近似加倍,该结果来源于每单位长度皮肤的角质形成细胞的数目增加(图2E和图2F)。角质形成细胞数目的增加取决于YAP的存在,因为在不存在YAP的情况下条件性YAP敲除动物对药物处理表现出不敏感性(图2E和图2F)。14该观察结果与先前的工作以及从GEO获得的来自原代小鼠和人表皮组织的公开可获得的RNA-seq数据一致,其指示YAP而不是其旁系同源物TAZ(含WW结构域的转录调节物;WWTR)的活性在表皮中占优势。13此外,KI-67呈阳性的角质形成细胞在药物处理后显著增加,表明角质形成细胞扩增是由药物诱导的增殖引起的(图2G和图2H)。另外,在实验的终点,化合物处理导致YAP依赖性转录物Ctgf、Cyr61和Ankrd1的稳健上调(图2I)。综上所述,这些结果表明,化合物13(作为本文所公开的化合物的示例)在成年动物中激活促增殖的YAP依赖性转录程序,能够通过增殖来重塑表皮。
实施例7:伤口愈合
在一个示例性实施方案中,化合物13处理在人细胞中促进伤口愈合,并在人皮肤替代物种尤卡坦小型猪中诱导对角质形成细胞的促增殖作用。因此,开发了化合物13的基于凝胶的制剂,其允许稳定的室温储存和以高浓度(高至约1.5重量百分比)表面递送。发现与在丙酮或DMSO中的药物递送相比,化合物13的表面递送以更显著的程度在小鼠中促进表皮增厚(图3)。此外,化合物13的表面递送在尤卡坦小型猪中促进了表皮增生、真皮增生和YAP依赖性基因表达(图4)。另外,化合物13对受3mm全层厚度伤口创伤的人皮肤等同物的处理促进了角质形成细胞的增生并促进了伤口收缩(图5)。
通过广泛询问大型化学文库关于通过不涉及直接抑制Hippo激酶的机制选择性地激活YAP驱动的转录的化合物,我们鉴定了经噻唑取代的3-羧酰胺-5-苯基-异唑PY-60。与仅部分激活YAP驱动的转录的MST1/2抑制相反,我们发现PY-60显著增强YAP的转录输出,导致细胞中YAP激活水平与NF2敲低水平类似。PY-60处理很大程度上拟表型了YAP转基因强制表达的增殖响应,导致MCF10A细胞在琼脂中的无血清扩增,并允许MDCK细胞绕过细胞增殖的接触抑制。这些数据表明,PY-60将是有价值的体外工具化合物,允许人们用小分子药物的时间控制和剂量依赖性控制来探询完全YAP转录激活的细胞作用。
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Claims (30)
1.用于在有此需要的对象中激活Yes相关蛋白1(YAP)的方法,其包括向所述对象施用式(I)化合物或者其互变异构体或可药用盐:
其中环选自:
R选自H和C1-C6烷基;
R1选自C6-C10芳基、5至10元杂芳基(其中1至4个杂芳基成员独立地选自N、O和S),
R2在存在时选自H、C6-C10芳基、5至10元杂芳基(其中1至4个杂芳基成员独立地选自N、O和S),
或R1和R2在与相邻原子结合时与它们所结合的原子一起形成稠合的C6-C10芳基或5至10元杂芳基(其中1至4个杂芳基成员独立地选自N、O和S);
L是C(O)、C(S)或CH2;
V是NR3R4,其中
R3选自C1-C6烷基、-(C1-C6烷基)-S-(C1-C6烷基)、-C1-C6烷基-(C6-C10芳基)、-C1-C6烷基-(5至10元杂芳基(其中1至4个杂芳基成员独立地选自N、O和S))、C3-C14环烷基、3至14元杂环烷基(其中1至4个杂环烷基环成员独立地选自N、O和S)、-C1-C6烷基-(3至14元杂环烷基(其中1至4个杂环烷基环成员独立地选自N、O和S)),
R4选自H、C1-C6烷基、-C1-C6烷基-(C6-C10芳基)、5至10元杂芳基(其中1至4个杂芳基成员独立地选自N、O和S);
或R3和R4与它们所结合的N原子一起形成5至7元杂环烷基,其任选地与3至14元杂环烷基(其中1至4个杂环烷基环成员独立地选自N、O和S)稠合或螺稠合;
并且其中任意烷基、芳基、环烷基、杂芳基和杂环烷基任选地被一至四个独立地选自以下的取代基取代:
-CN,-OH,卤代,氧代,-ORA,-SRA,-S(O)RA,-S(O)2RA,NRARB,-C(O)RA,-C(O)2RA,-NRAC(O)2RB,-C(O)NRARB,-S(O)NRARB,-S(O)2NRARB,-NRAS(O)RB,-NRAS(O)2RB,
5至10元杂芳基(其中1至4个杂芳基成员独立地选自N、O和S);
RA和RB独立地选自H、C1-C6烷基、C1-C6卤代烷基、-C1-C6烷基-C6-C10芳基、C(O)C1-C6烷基、C(O)C1-C6烷基-C6-C10芳基、C(O)OC1-C6烷基、C6-C10芳基、3至14元杂环烷基(其中1至4个杂环烷基环成员独立地选自N、O和S)、-C(O)(5至10元杂芳基(其中1至4个杂芳基成员独立地选自N、O和S)),其中
每个芳基和杂环烷基任选地被一至三个独立地选自C1-C6烷基、卤代、C1-C6卤代烷基和3至14元杂环烷基(其中1至4个环成员独立地选自N、O和S)的取代基取代;并且
每个烷基任选地被一至三个独立地选自卤代、NRCRD(其中RC和RD独立地选自H、C1-C6烷基、C(O)C1-C6烷基和C(O)C6-C10芳基)的取代基取代。
2.治疗疾病或病症的方法,所述疾病或病症的病因由于患有所述疾病或病症的对象中增殖修复不足而加剧,或者定义为患有所述疾病或病症的对象中增殖修复不足,或者所述疾病或病症通过诱导细胞的增殖而得以改善,所述方法包括向所述对象施用式(I)化合物或者其互变异构体或可药用盐:
其中
环选自:
R选自H和C1-C6烷基;
R1选自C6-C10芳基、5至10元杂芳基(其中1至4个杂芳基成员独立地选自N、O和S),
R2在存在时选自H、C6-C10芳基、5至10元杂芳基(其中1至4个杂芳基成员独立地选自N、O和S),
或R1和R2在与相邻原子结合时与它们所结合的原子一起形成稠合的C6-C10芳基或5至10元杂芳基(其中1至4个杂芳基成员独立地选自N、O和S);
L是C(O)、C(S)或CH2;
V是NR3R4,其中
R3选自C1-C6烷基、-(C1-C6烷基)-S-(C1-C6烷基)、-C1-C6烷基-(C6-C10芳基)、-C1-C6烷基-(5至10元杂芳基(其中1至4个杂芳基成员独立地选自N、O和S))、C3-C14环烷基、3至14元杂环烷基(其中1至4个杂环烷基环成员独立地选自N、O和S)、-C1-C6烷基-(3至14元杂环烷基(其中1至4个杂环烷基环成员独立地选自N、O和S)),
R4选自H、C1-C6烷基、-C1-C6烷基-(C6-C10芳基)、5至10元杂芳基(其中1至4个杂芳基成员独立地选自N、O和S);
或R3和R4与它们所结合的N原子一起形成5至7元杂环烷基,其任选地与3至14元杂环烷基(其中1至4个杂环烷基环成员独立地选自N、O和S)稠合或螺稠合;
并且其中任意烷基、芳基、环烷基、杂芳基和杂环烷基任选地被一至四个独立地选自以下的取代基取代:
-CN,-OH,卤代,氧代,-ORA,-SRA,-S(O)RA,-S(O)2RA,NRARB,-C(O)RA,-C(O)2RA,-NRAC(O)2RB,-C(O)NRARB,-S(O)NRARB,-S(O)2NRARB,-NRAS(O)RB,-NRAS(O)2RB,
5至10元杂芳基(其中1至4个杂芳基成员独立地选自N、O和S),
RA和RB独立地选自H、C1-C6烷基、C1-C6卤代烷基、-C1-C6烷基-C6-C10芳基、C(O)C1-C6烷基、C(O)C1-C6烷基-C6-C10芳基、C(O)OC1-C6烷基、C6-C10芳基、3至14元杂环烷基(其中1至4个杂环烷基环成员独立地选自N、O和S)、-C(O)(5至10元杂芳基(其中1至4个杂芳基成员独立地选自N、O和S)),其中
每个芳基和杂环烷基任选地被一至三个独立地选自C1-C6烷基、卤代、C1-C6卤代烷基和3至14元杂环烷基(其中1至4个环成员独立地选自N、O和S)的取代基取代;并且
每个烷基任选地被一至三个独立地选自卤代、NRCRD(其中RC和RD独立地选自H、C1-C6烷基、C(O)C1-C6烷基和C(O)C6-C10芳基)的取代基取代。
3.根据权利要求1或2所述的方法,其中L是C(O)。
4.根据权利要求1至3中任一项所述的方法,其中R3是任选经取代的C1-C6烷基或-C1-C6烷基-(5至10元杂芳基(其中1至4个杂芳基成员独立地选自N、O和S))。
5.根据权利要求1至4中任一项所述的方法,其中R3是任选经取代的-C1-C6烷基-(5至10元杂芳基(其中1至4个杂芳基成员独立地选自N、O和S))。
6.根据权利要求1至5中任一项所述的方法,其中R4是H。
7.根据权利要求1至6中任一项所述的方法,其中R1是任选经取代的C6-C10芳基。
8.根据权利要求1至7中任一项所述的方法,其中R1是任选经取代的苯基。
9.根据权利要求1至8中任一项所述的方法,其中R1是苯基。
10.根据权利要求1至9中任一项所述的方法,其中R2是H。
11.根据权利要求1至10中任一项所述的方法,其中环是:
12.根据权利要求1至10中任一项所述的方法,其中环选自:
13.根据权利要求1至10中任一项所述的方法,其中环选自:
14.根据权利要求1至10中任一项所述的方法,其中环选自:
15.根据权利要求1或2所述的方法,其中:
环是/>
R1是苯基或5至6元杂芳基(其中1至3个杂芳基成员独立地选自N、O和S),各自任选地被一至三个独立地选自以下的取代基取代:Br、Cl、F、-CN、C1-C6烷基、C1-C6卤代烷基、-OC1-C6烷基、-OC1-C6卤代烷基、任选经取代的苯基、-C(O)RA;
R2是H;
L是C(O);
R3是-C1-C6烷基-(5至7元杂芳基(其中1至3个杂芳基成员独立地选自N、O和S))或-C1-C6烷基(苯基),其中杂芳基或苯基任选地被一至三个独立地选自Br、Cl、F、C1-C6烷基、-OC1-C6烷基、C(O)RA和-C(O)NRARB的取代基取代;并且
R4是H。
16.根据权利要求15所述的方法,其中:
R1是苯基;并且
R3是任选经取代的-C1-C6烷基-(5元杂芳基(其中1至2个杂芳基成员独立地选自N、O和S))或任选经取代的C1-C6烷基(苯基)。
17.根据权利要求1或2所述的方法,其中所述化合物或者其互变异构体或可药用盐选自下表:
18.根据权利要求1或2所述的方法,其中所述化合物或者其互变异构体或可药用盐选自下表:
/>
/>
19.根据权利要求2至18中任一项所述的方法,其中所述疾病或病症是对伤口修复的需求或对器官修复的需求。
20.根据权利要求2至18中任一项所述的方法,其中所述疾病或病症选自烧伤、溃疡、心力衰竭和炎性肠病。
21.根据权利要求20所述的方法,其中所述疾病或病症是烧伤。
22.根据权利要求20所述的方法,其中所述疾病或病症是溃疡。
23.根据权利要求22所述的方法,其中所述溃疡是慢性溃疡。
24.根据权利要求22或23所述的方法,其中所述溃疡是糖尿病足溃疡和静脉腿溃疡。
25.根据权利要求2至19中任一项所述的方法,其中所述疾病或病症是对伤口修复的需求。
26.根据权利要求2至19中任一项所述的方法,其中所述疾病或病症是对器官修复的需求。
27.根据权利要求26所述的方法,其中所述器官选自肺、心脏、肝、胰腺、肝和肠。
28.根据权利要求2至18中任一项所述的方法,其中所述疾病或病症是选自以下的疾病或病症:糖尿病足溃疡(DFU)、静脉性溃疡(淤积性溃疡)、压力溃疡、全层或局部厚度烧伤、湿疹、银屑病、蜂窝织炎、脓疱病、特应性皮炎、大疱性表皮松解症、苔藓硬化、鱼鳞病、白癜风、肢端剥脱性皮肤综合征、Blau综合征、原发性皮肤淀粉样变、皮肤脓肿、睑缘炎、疖病、毛细血管炎、蜂窝织炎、角膜擦伤、角膜糜烂、干燥病、扁平苔藓、慢性单纯性苔藓、特发性肺纤维化(IPF)、急性呼吸窘迫综合征(ARDS)、慢性阻塞性肺疾病(COPD)、肺气肿、硅沉着病、石棉沉着病、肺尘埃沉着病、肺矾土沉着病、铁钒土纤维化、铍中毒、肺铁末沉着病、锡尘肺、滑石肺、拉布拉多尔肺(混合性粉尘肺尘埃沉着病)、结节病、过敏性肺炎(HP)/外源性变应性肺泡炎(EAA)、脱屑性间质性肺炎(DIP)、呼吸性细支气管炎间质性肺疾病(RBILD)、急性间质性肺炎(AIP)、非特异性间质性肺炎(NSIP)、隐源性机化性肺炎(COP=特发性BOOP)、继发性机化性肺炎(BOOP)、淋巴样间质性肺炎(LIP)、特发性间质性肺炎:未明、嗜酸性粒细胞增多性肺疾病、结核病(TB)、肺水肿、间质性肺疾病、隐源性机化性肺炎(COP)、电子烟或雾化产品使用相关肺损伤(EVALI)、汉坦病毒肺综合征(HPS)、组织胞浆菌病、军团病、MAC肺疾病、α1-抗胰蛋白酶缺乏症、曲霉病、淋巴管平滑肌瘤病(LAM)、中东呼吸综合征(MERS)、非结核分枝杆菌肺疾病(NTM)、肺栓塞、古德帕斯丘综合征、特发性肺含铁血黄素沉着症、肺泡蛋白沉积症、肺淀粉样变、原发性肺淋巴瘤、原发性纤毛运动障碍(不伴或伴内脏反位)、罕见原因的过敏性肺炎(除农民肺疾病和鸽饲养者肺疾病之外的所有原因)、遗传性出血性毛细血管扩张症(HHT)中的肺动静脉畸形、系统性硬化症中的间质性肺疾病、类风湿性关节炎中的间质性肺疾病、特发性炎性肌病中的间质性肺疾病(多肌炎、皮肌炎、抗合成酶综合征)、舍格伦综合征中的间质性肺疾病、混合性结缔组织病(MCTD)中的间质性肺疾病、重叠综合征中的间质性肺疾病、未分化结缔组织病中的间质性肺疾病、闭塞性细支气管炎(在非移植患者中)、感染性结肠炎、溃疡性结肠炎、克罗恩病、缺血性结肠炎、放射性结肠炎、消化性溃疡、肠癌、肠梗阻、类风湿性关节炎、银屑病关节炎、桥本甲状腺炎、系统性红斑狼疮、多发性硬化、格雷夫斯病、1型糖尿病、银屑病、强直性脊柱炎、硬皮病、肌炎、痛风、抗磷脂抗体综合征(APS)、血管炎、扩张型心肌病、肥厚型心肌病、限制型心肌病、收缩性心力衰竭、舒张性心力衰竭(射血分数保留的心力衰竭)、房间隔缺损、房室隔缺损、主动脉缩窄、双出口右心室、d型大动脉转位、埃布斯坦异常、左心发育不良综合征、主动脉弓中断、肺动脉瓣闭锁、单心室、法洛四联症、全肺静脉异位回流、三尖瓣闭锁、动脉干、室间隔缺损、多囊肾病、尿崩症、古德帕斯丘病、IgA血管炎、IgA肾病、狼疮性肾炎、成人肾病综合征、儿童肾病综合征、溶血尿毒症综合征、髓质海绵肾、肾发育不良、肾动脉狭窄、肾血管性高血压、肾小管性酸中毒、奥尔波特综合征、韦氏肉芽肿病、阿拉日耶综合征、胱氨酸病、法布里病、局灶性节段性肾小球硬化(FSGS)、肾小球肾炎、aHUS(非典型溶血尿毒症综合征)、溶血尿毒症综合征(HUS)、肯诺克-肖林紫癜、IgA肾病(伯杰氏病)、间质性肾炎、微小变化疾病、肾病综合征、血栓性血小板减少性紫癜(TTP)、肉芽肿性多血管炎(GPA)、成人斯蒂尔病、无丙种球蛋白血症、斑秃、自身免疫性血管性水肿、自身免疫性自主神经功能障碍、自身免疫性脑脊髓炎、自身免疫性肝炎、自身免疫性心肌炎、自身免疫性卵巢炎、自身免疫性睾丸炎、自身免疫性胰腺炎、自身免疫性视网膜病变、自身免疫性荨麻疹、轴突和神经元神经病(AMAN)、巴洛病、大疱性类天疱疮、乳糜泻、慢性复发性多灶性骨髓炎(CRMO)、许尔许斯特劳斯综合征(CSS)或嗜酸性肉芽肿(EGPA)、瘢痕性类天疱疮、Cogan综合征、冷凝集素病、柯萨奇病毒性心肌炎、CREST综合征、疱疹样皮炎、皮肌炎、德维克病(视神经脊髓炎)、盘状狼疮、嗜酸性食管炎(EoE)、嗜酸性筋膜炎、结节性红斑、原发性混合性冷球蛋白血症、巨细胞动脉炎(颞动脉炎)、巨细胞心肌炎、肉芽肿性多血管炎、吉兰-巴雷综合征、桥本甲状腺炎、肯诺克-肖林紫癜(HSP)、妊娠疱疹或妊娠类天疱疮(PG)、低丙球蛋白血症、IgG4相关硬化性疾病、免疫性血小板减少性紫癜(ITP)、包涵体肌炎(IBM)、兰伯特-伊顿综合征、白细胞碎裂性血管炎、线状IgA病(LAD)、显微镜下多血管炎(MPA)、混合性结缔组织病(MCTD)、蚕蚀性角膜溃疡、Mucha-Habermann病、多灶性运动神经病(MMN)或MMNCB、多发性硬化、重症肌无力、肌炎、发作性睡病、新生儿狼疮、视神经脊髓炎、中性粒细胞减少、眼瘢痕性类天疱疮、视神经炎、复发性风湿病(PR)、PANDAS、副肿瘤性小脑变性(PCD)、阵发性夜间血红蛋白尿(PNH)、帕里龙贝格综合征、睫状体扁平部炎(周围葡萄膜炎)、Parsonage-Turner综合征、天疱疮、周围神经病、静脉周围脑脊髓炎、恶性贫血(PA)、POEMS综合征、结节性多动脉炎、I、II、III型多腺综合征、风湿性多肌痛、多肌炎、原发性胆汁性肝硬化、原发性硬化性胆管炎、孕酮皮炎、纯红细胞再生障碍(PRCA)、坏疽性脓皮病、雷诺现象、反应性关节炎、反射性交感神经营养不良、复发性多软骨炎、下肢不宁综合征(RLS)、腹膜后纤维化、风湿热、类风湿性关节炎、结节病、施密特综合征、巩膜炎、硬皮病、舍格伦综合征、精子和睾丸自身免疫、僵人综合征(SPS)、亚急性细菌性心内膜炎(SBE)、Susac综合征、交感性眼炎(SO)、大动脉炎、颞动脉炎/巨细胞动脉炎、血小板减少性紫癜(TTP)、甲状腺眼病(TED)、阿拉日耶综合征、酒精相关肝病、自身免疫性肝炎、胆道闭锁、肝硬化、溶酶体酸性脂肪酶缺乏症(LAL-D)、新生儿黄疸、非酒精性脂肪性肝病、非酒精性脂肪性肝炎、原发性胆汁性胆管炎(PBC)和进行性家族性肝内胆汁淤积(PFIC)。
29.化合物或者其互变异构体或可药用盐,其选自下表:
/>
/>
/>
/>
30.药物组合物,其包含根据权利要求29所述的化合物或者其互变异构体或可药用盐,以及可药用载体。
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