CN101801965B - 作为细胞坏死抑制剂的吲哚化合物 - Google Patents
作为细胞坏死抑制剂的吲哚化合物 Download PDFInfo
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- CN101801965B CN101801965B CN200880103002.6A CN200880103002A CN101801965B CN 101801965 B CN101801965 B CN 101801965B CN 200880103002 A CN200880103002 A CN 200880103002A CN 101801965 B CN101801965 B CN 101801965B
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- Prior art keywords
- indoles
- dihydro
- thiazole
- cyclopentyl
- ethyl
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
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Abstract
本发明涉及新型的用于预防或治疗细胞坏死和与坏死相关的疾病的吲哚化合物、其药学可接受的盐或异构体。本发明还涉及预防或治疗细胞坏死和与坏死相关的疾病的方法和组合物,包括所述吲哚化合物作为活性成分。
Description
技术领域
本发明涉及式(1)的吲哚化合物,其药学可接受的盐或异构体,以及包含它们作为活性成分的预防或治疗细胞坏死和与坏死相关的疾病的方法和组合物。
背景技术
与细胞死亡相关的大多数研究都关注的是细胞凋亡,也称作程序性细胞死亡(PCD)。在过去的10年间,随着半胱天冬酶的发现,很多制药公司都在加紧将半胱天冬酶抑制剂发展成为药物。但是,现在的情况是,这些药物几乎都没有被FDA所批准。这是因为细胞凋亡是在生理学情况下发生的细胞死亡,这种细胞死亡很可能是由于维持体内动态平衡的防御机制导致的。相反,坏死是主要发生在病态情况下的细胞死亡,在大多数情况下,其特征在于伴随炎性应答。人们已知,坏死是长期的不受控制的细胞死亡,但是近来的研究(ProskurykakovSY等人,2002,Biochemistry)报道了坏死是一种活性的/可控的细胞死亡。坏死导致的典型疾病包括缺血性疾病(例如心肌梗塞、中风、肾梗塞)、神经变性疾病和炎性疾病。由于人们相信坏死是一种在病态情况下不受控制的偶发的细胞死亡,因此很少对其进行功能性机制、分子靶、信号转导系统等等的研究。因此,出现了对发现和研发出用于治疗由坏死导致的缺血性疾病、神经变性疾病和炎性疾病的抑制坏死物质,并解释坏死的生物学、病理学原因的强烈需要。
从医学观点来看,本发明的吲哚衍生物具有极为有用的结构并且许多公开文献已经报道了关于这些结构的研究结果。在这些研究结果中,下面是所有结果中最有代表性的:专利WO2006/112549报告了对葡糖激酶具有活性的某些吲哚衍生物,专利WO95/07276报告了用作抗 肿瘤药和用作抗心血管系统疾病的抑制剂的那些化合物,且专利WO2004/018428报告了用作抗生素的那些化合物。
发明内容
要解决的技术主题
因此,本发明在上述技术背景下进行了广泛研究以研发新的化合物,该新的化合物表现出预防或治疗和改善细胞坏死和与坏死相关的疾病的效果,特别是可以用于预防或治疗肝病。由此,证实了如下所述的式(1)的吲哚衍生物表现出在预防和治疗细胞坏死和与坏死相关的疾病方面的优良效果,由此完成了本发明。
因此,本发明的目的在于提供了式(1)的新的吲哚衍生物。
本发明的另一个目的在于提供用于预防或治疗细胞坏死和与坏死相关的疾病、特别是用于保肝、肝功能改善、和预防或治疗急性/慢性肝病的组合物,其包含式(1)的化合物、其药学可接受的盐或异构体作为活性成分与药学可接受的载体或稀释剂,且本发明还提供了制备所述组合物的方法。
本发明的另一个目的在于提供使用所述组合物预防或治疗细胞坏死和与坏死相关的疾病、特别是用于保肝、肝功能改善和预防或治疗急性/慢性肝病的方法。
解决技术主题的手段
为了实现上述目的,本发明提供了下式(1)的吲哚化合物及其药学可接受的盐或异构体:
其中
n表示0-3的数,
A表示5元杂芳基或杂环,它们各自具有1-3个选自N、O和S的 杂原子,
R1表示R5-X-B-X′-,
B表示直接键,或者表示3~10元杂环或杂芳基,它们各自具有1-4个选自N、O和S的杂原子,
X和X′彼此独立地表示直接键,或选自-NR6-,-CO-,-CONR6-,-CO2-,-OC(O)-,-S(O)m-,-O-(CH2)m-,-(CH2)m-O-,-(CH2)m-,-NR6CO-,-(R6O)2P(O)-和-NHCO2-,其中m表示0-3的数,且R6表示氢,烷基或环烷基,
R5表示氢,腈,羟基,烷基,烷氧基,环烷基或芳基,或者表示3~10元单环或稠环杂环或杂芳基,它们各自具有1-3个选自N、O和S的杂原子并且任选被氧代或烷基取代,或
R5和R6可一起形成4~8元环,
R2表示-(CR8R9)p-Y-R7,
p表示0-2的数,
R8和R9彼此独立地表示氢或烷基或可一起形成4~8元环,
Y表示直接键或选自-O-,-S-,-NR6-,-NR6C(O)-,-CO2-,-C(O)-,-C(O)NR6-,-S(O)q-和-S(O)qNR6-,其中q表示0-2的数,
R7表示氢,卤素,氰基,羟基,硝基,烷基,环烷基或芳基,或者表示3~10元杂环或杂芳基,它们各自具有1-3个选自N、S和O的杂原子并且任选包含氧代,
R3表示氢,烷基,-(CH2)q-环烷基或-(CH2)q-杂环,
R4表示-(CH2)p-D-R10,
D表示直接键,表示任选包含氧代的环烷基,表示芳基,或者表示3~10元杂环或杂芳基,它们各自具有1-3个选自N、S和O的杂原子,
R10表示氢,卤素,氨基,氰基,硝基,羟基,烷基,烷基羰基,烷基磺酰基或-(CH2)p-NR8R9,
其中烷基,烷氧基,芳基,环烷基,杂环和杂芳基可以任选被取代,取代基是选自羟基,卤素,腈,氨基,烷基氨基,二烷基氨基, 烷基,卤代烷基,烷基磺酰基,羧基烷基,烷基羰基氧基,烷硫基,烷氧羰基,烷基氨基羰基,芳基烷氧基和氧代中的一个或多个。
在上述式(1)化合物的定义中,术语“烷基”意旨脂族烃基。烷基可以是不含烯基或炔基部分的饱和烷基或含至少一个烯基或炔基部分的不饱和烷基。“烯基”意旨含至少一个碳-碳双键的基团,且“炔基”意旨含至少一个碳-碳三键的基团。烷基在单独使用或以复合形式例如烷氧基形式使用时可以是支链或直链的。
除非另有定义,否则烷基可以具有1-20个碳原子。烷基可以是具有1-10个碳原子的中等大小的烷基。否则,烷基可以是具有1-6个碳原子的低级烷基。其典型实例包括、但不限于甲基,乙基,丙基,异丙基,正-丁基,异丁基,叔丁基,戊基,己基,乙烯基,丙烯基,丁烯基等。例如,C1-C4-烷基在烷基链上具有1-4个碳原子,其选自甲基,乙基,丙基,异丙基,正-丁基,异丁基,仲丁基和叔丁基。
除非另有定义,否则术语“烷氧基”意旨具有1-10个碳原子的烷氧基。
除非另有定义,否则术语“环烷基”意旨饱和脂族3~10元环。其典型实例包括、但不限于环丙基,环丁基,环戊基,环己基等。
除非另有定义,否则术语“芳基”包括至少一个具有共价π电子系统的环,例如单环或稠合多环(即共有相邻碳原子对的环)基团。在本说明书中,除非另有定义,否则芳基意旨芳族4~10元,优选6~10元单环或多环,包括苯基,萘基等。
除非另有定义,否则术语“杂芳基”意旨芳族3~10元,优选4~8元,更优选5~6元环,其具有1-4个选自N,O和S的杂原子且可以与苯并或C3-C8环烷基稠合。单环杂芳基包括、但不限于噻唑,噁唑,噻吩,呋喃,吡咯,咪唑,异噁唑,异噻唑,吡唑,三唑,三嗪,噻二唑,四唑,噁二唑,吡啶,哒嗪,嘧啶,吡嗪等。双环杂芳基包括,但不限于吲哚,二氢吲哚,苯并噻吩,苯并呋喃,苯并咪唑,苯并噁唑,苯并异噁唑,苯并噻唑,苯并噻二唑,苯并三唑,喹啉,异喹啉,嘌呤,嘌呤并吡啶等。
除非另有定义,否则术语“杂环”意旨3~10元,优选4~8元,更优选5~6元环,其具有1-4个选自N,O和S的杂原子,可以与苯并或C3-C8环烷基稠合,并且是饱和的或含有1或2个双键。所述杂环包括,但不限于吡咯啉,吡咯烷,咪唑啉,咪唑烷,吡唑啉,吡唑烷,吡喃,哌啶,吗啉,硫代吗啉,哌嗪,氢化呋喃等。
除非另有定义,否则本说明书中的其它术语和缩写可以理解为具有本领域技术人员在本领域中使用的常用含义。
上述式(1)化合物中优选的化合物是下述化合物,
其中
n表示0-3的数,
A表示5元杂芳基或杂环,它们各自具有1-3个选自N、O和S的杂原子,
R1表示R5-X-B-X′-,
B表示直接键,或者表示3~10元杂环或杂芳基,它们各自具有1-4个选自N、O和S的杂原子,
X和X′彼此独立地表示直接键,或选自-NR6-,-CO-,-CONR6-,-CO2-,-OC(O)-,-S(O)2-,-O-(CH2)m-,-(CH2)m-O-,-(CH2)m-,-NR6CO-,-(R6O)2P(O)-和-NHCO2-,其中m表示0-3的数,且R6表示氢,C1-C6-烷基或C3-C6-环烷基,
R5表示氢,腈,羟基,C1-C6-烷基,卤代-C1-C6-烷基,羟基-C1-C6-烷基,C4-C6-环烷基,苯基或卤代苯基,或者表示5~10元单环或稠环杂环或杂芳基,它们各自具有1-3个选自N、O和S的杂原子并且任选被氧代或卤代-C1-C6-烷基取代,或者
R5和R6可一起形成4~8元环,
R2表示-(CR8R9)p-Y-R7,
p表示0-2的数,
R8和R9彼此独立地表示氢或C1-C6-烷基或可一起形成5~6元环,
Y表示直接键或选自-O-,-NR6-,-NR6C(O)-,-C(O)-,-CO2-,-C(O)NR6-和-S(O)q-,其中q表示0-2的数,
R7表示氢,卤素,氰基,羟基,C1-C6-烷基,羟基-C1-C6-烷基或卤代-C1-C6-烷基,表示任选被C1-C6-烷基磺酰基取代的苯基,或者表示5~6元杂环或杂芳基,它们各自具有1-3个选自N和O的杂原子,
R3表示氢,C1-C6-烷基,-(CH2)-C3-C6-环烷基或-(CH2)-杂环,其中所述杂环是具有1-2个选自N,O和S的杂原子的5~6元环,
R4表示-(CH2)p-D-R10,
D表示直接键,表示任选含氧代的C3-C6-环烷基,或者表示5~6元杂环或杂芳基,它们各自具有1-2个选自N,O和S的杂原子,
R10表示氢,卤素,氨基,C1-C6-烷基,C1-C6-烷基羰基,卤代-C1-C6-烷基羰基,C1-C6-烷基磺酰基或-(CH2)p-NR8R9。
在本发明式(1)的化合物中,A更优选表示由下式(i)至(viii)表示的环,其中R表示氢,或者表示任选被羟基或氨基取代的C1-C4-烷基。
A最优选选自4,5-二氢-噻唑,噻唑,噁唑啉,噁二唑和异噁二唑。
在R1的式R5-X-B-X′-中,B更优选表示直接键,表示咪唑或噁二唑,或者表示具有1-2个选自N和O的杂原子的5~6元杂环,最优选表示可以由下式(ix)至(xii)之一表示的结构。
X更优选表示直接键或选自-CO-,-CONR6-,-CO2-,-SO2-,-(CH2)m-和-O-(CH2)m-,其中m表示0-2的数,R6表示氢,C1-C6-烷基或C3-C6-环烷基。最优选X选自-CO-,-CONH-,-CO2-,-SO2-,-(CH2)2-,-O-和-O-CH2-。
X′更优选表示直接键或选自-(CH2)2-,-NH-,-CO-,-CO2-,-CONH-,-S(O)2-,-(R6O)2P(O)-,-NHC(O)-和-NHCO2-。
R5更优选表示氢,腈,羟基,C1-C6-烷基,卤代-C1-C6-烷基,羟基-C1-C6-烷基,C4-C6-环烷基,苯基或卤代苯基,或者表示单环或稠环5~9元杂环或5~6元杂芳基,它们各自具有1-3个选自N、O和S的杂原子并且任选被氧代或三氟甲基取代。最优选R5选自氢,腈,羟基,甲基,乙基,异丙基,异丁基,羟基甲基,三氟甲基,环丁基,环戊基,环己基,吡咯烷,哌啶,2-氧代哌嗪,2-氧代吡咯烷,四氢呋喃,四氢吡喃,四氢噻喃,吗啉,呋喃,吡啶,1,3-吡嗪,1,1-二氧代-硫代吗啉,四唑,咪唑,吡唑和3-三氟甲基-5,6,7,8-四氢-2H-[1,2,4]三唑并[4,3-a]吡嗪。
在R2的式-(CR8R9)p-Y-R7中,R8和R9各自更优选表示氢。
Y更优选自-O-,-NR6-,-NR6C(O)-,-C(O)-,-C(O)NR6-和-S(O)2-,其中R6如上述优选范围所定义。最优选Y选自-O-,-NH-,-NHC(O)-,-SO2-和-C(O)-。
R7更优选表示氢,卤素,羟基,C1-C6-烷基,羟基甲基或卤代-C1-C6-烷基,表示任选被C1-C6-烷基磺酰基取代的苯基,或者表示5~6元杂环或杂芳基,它们各自具有1-2个选自N和O的杂原子。最优选R7选自氢,溴,氟,氯,甲基,乙基,丙基,羟基甲基,三氟甲基,苯基,4-甲基磺酰基-苯基,哌啶,吡咯烷,呋喃,吡咯,吡唑和吡啶。
R3更优选表示氢,甲基或异丁基。
R4更优选表示-R10,-D-R10或-CH2-D-R10,其中D表示任选含氧代的C3-C6-环烷基,表示具有1-2个选自N,O和S的杂原子的5~6元杂环,或者表示具有1-2个选自N和S的杂原子的5~6元杂芳基,且R10表示氢,卤素,氨基,C1-C6-烷基,C1-C3-烷基羰基,卤代-C1-C3-烷基羰基,C1-C3-烷基磺酰基或-(CH2)p-NR8R9,其中p,R8和R9如上述优选范围所定义。最优选R4选自氢,异丙基,异丁基,环丙基甲基,环戊基甲基,环丁基,环戊基,环己基,4-甲基-环己基,4,4-二氟环己基,4-氧代-环己基,四氢吡喃-4-基,(四氢吡喃-4-基)甲基,(四氢吡喃-2-基)甲基,四氢呋喃-3-基,哌啶-4-基,甲磺酰基,1-乙酰基-哌啶-4-基,1-甲磺酰基-哌啶-4-基,1-三氟乙酰基-哌啶-4-基,1-乙酰基-吡咯烷-3-基,四氢噻喃-4-基,噻吩-3-基和5-氨基-吡啶-2-基。
本发明式(1)的化合物还可以形成药学可接受的盐。这种“药学可接受的盐”包括含有药学可接受的阴离子的无毒性酸加成盐,例如与无机酸,例如硫酸、盐酸、硝酸、磷酸、氢溴酸、氢碘酸等形成的盐;与有机羧酸,例如酒石酸、甲酸、柠檬酸、乙酸、三氯乙酸、三氟乙酸、葡糖酸、苯甲酸、乳酸、富马酸、马来酸、水杨酸等形成的盐;或与磺酸,例如甲磺酸、乙磺酸、苯磺酸、对-甲苯磺酸、萘磺酸等形成的盐。式(I)的化合物还可以形成药学可接受的碱加成盐,例如与碱金属或碱土金属,例如锂、钠、钾、钙、镁等形成的盐;与氨基酸,例如赖氨酸、精氨酸、胍等形成的盐;与二环己胺、N-甲基-D-葡糖胺、三(羟甲基)甲胺、二乙醇胺、胆碱、三乙胺等形成的有机盐。可以根据任意常规方法将本发明式(I)的化合物转化成其盐,且本领域技术人员基于式(1)的结构而无需额外说明即可易于对其进行成盐。
本说明书中的术语“异构体”意旨具有与式(1)的化合物或其盐相同化学式或分子式,但光学或立体化学不同的那些化合物。本发明式(1)的化合物可以在结构上具有不对称中心,由此可以以光学异构体(R或S异构体)、外消旋物、非对映体的混合物或各自的对映异构体等的形式存在。当所述化合物具有双键时,它们可以以几何异构体(反式或 顺式异构体)的形式存在。本发明也涵盖所有这些异构体及其混合物。
在下文中,除非另有说明,否则式(1)的化合物包括其药学可接受的盐及其异构体。这些盐和异构体应被视为被本发明涵盖。为方便起见,本说明书将它们简单表示为式(1)的化合物。
式(1)化合物中的典型化合物选自如下化合物:
环戊基-[2-(4,5-二氢-1,3-噻唑-2-基)-1H-吲哚-7-基]-胺;
[(R)-2-(7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-1,3-噻唑-4-基]-甲醇;
[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸甲酯;
[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙醇;
(R)-2-[7-环戊基氨基-5-(羟基甲基)-1H-吲哚-2-基]-4,5-二氢-噻唑-4-基-甲醇;
[2-(4,5-二氢-噻唑-2-基)-1H-吲哚-7-基]-哌啶-4-基-胺;
[(R)-2-(5-甲基-7-(四氢吡喃-4-基)甲氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(S)-2-(5-甲基-7-(1-三氟乙酰基哌啶-4-基)氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
2-[(S)-2-(7-(四氢吡喃-2-基)甲氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(S)-2-(7-(四氢吡喃-4-基)氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(S)-2-(7-(四氢吡喃-4-基)甲氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(S)-2-(5-甲基-7-(1-乙酰基-吡咯烷-3-基)氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(S)-2-(7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(R)-2-(5-苯氧基-7-(四氢吡喃-4-基)甲氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(S)-2-(5-苯氧基-7-(四氢吡喃-4-基)氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(S)-2-(5-甲基-7-(4,4-二氟环己烷-4-基)氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(S)-2-(5-氯-7-(四氢吡喃-4-基)甲氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(S)-2-(5-甲基-7-环丁基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(S)-2-(5-甲基-7-(四氢呋喃-3-基)氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(S)-2-(5-甲基-7-环丙基甲氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(S)-2-(5-甲基-7-(四氢吡喃-4-基)甲氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(S)-2-(5-甲基-7-环戊基甲氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(S)-2-(5-甲基-7-(四氢吡喃-4-基)氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙醇;
[(S)-2-(5-甲基-7-(四氢吡喃-4-基)氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(S)-2-(5-甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
(噻吩-3-基)甲基-[2-(4,5-二氢-1,3-噻唑-2-基)-1H-吲哚-7-基]-胺;
(3-四氢呋喃)-[2-(4,5-二氢-1,3-噻唑-2-基)-1H-吲哚-7-基]- 胺;
[(R)-2-(7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-1,3-噻唑-4-基]-甲醇;
3-[(R)-2-(7-(四氢吡喃-4-基)氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-丙酸;
[(R)-2-(5-氯-7-异丙基氨基-1H-吲哚-2-基)-4,5-二氢-1,3-噻唑-4-基]-甲醇;
(四氢吡喃-4-基)-[2-(4,5-二氢-4-甲基-噻唑-2-基)-1H-吲哚-7-基]-胺;
[(R)-2-(5-(吗啉-4-基)甲基-7-(四氢吡喃-4-基)氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-甲醇;
[(R)-2-(5-(二甲氨基)甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-甲醇;
[(R)-2-(5-(吡咯-3-基)甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-甲醇;
[(R)-2-(5-(1,3-咪唑-1-基)甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-甲醇;
[(R)-2-(5-(吡唑-1-基)甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-甲醇;
[(R)-2-(5-乙酰基氨基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-甲醇;
[(R)-2-(5-苯氧基甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(R)-2-(5-(吡咯烷-1-基)甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸甲酯;
环戊基-[5-氯-2-((R)-4-异丁基-4,5-二氢-噻唑-2-基)-1H-吲哚-7-基)-胺;
[(R)-2-(7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-丙酸乙酯;
{(R)-2-[7-((3R)-1-乙酰基-吡咯烷-3-基)氨基-1H-吲哚-2-基]-4,5-二氢-1,3-噻唑-4-基}-甲醇;
环戊基-[5-氟-2-((R)-4-乙基-4,5-二氢-噻唑-2-基)-1H-吲哚-7-基]-胺;
{(R)-2-[7-(甲基-环戊基)氨基-5-氟-1H-吲哚-2-基]-4,5-二氢-1,3-噻唑-4-基}-甲醇;
[(S)-2-(5-乙氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸甲酯;
[(S)-2-(5-乙氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(S)-2-(5-乙氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙醇;
[(R)-2-(5-甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-甲酸乙酯;
[(S)-2-(5-苯氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(R)-2-(7-(四氢吡喃-4-基)氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-甲醇;
[(R)-2-(7-(四氢呋喃-3-基)氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-甲醇;
[(R)-2-(7-(1-(甲磺酰基)吡咯烷-3-基)氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-甲醇;
[(R)-2-(5-氟-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-甲醇;
[(R)-2-(5-氟-7-(四氢吡喃-4-基)氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-甲醇;
[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙醇;
[(R)-2-(5-氯-7-(四氢噻喃-4-基)氨基-1H-吲哚-2-基)-4,5-二 氢-噻唑-4-基]-甲醇;
[(R)-2-(5-溴-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-甲醇;
[(R)-2-(5-溴-7-(四氢吡喃-4-基)-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-甲醇;
[(R)-2-(5-甲氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-甲醇;
[(R)-2-(5-(吡啶-3-基)氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-甲醇;
[(R)-2-(5-(吡啶-3-基)氧基-7-(四氢吡喃-4-基)氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-甲醇;
[(R)-2-(5-甲磺酰基甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-甲醇;
[(R)-2-(5-(异吲哚-1,3-二酮-2-基)甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-甲醇;
[(R)-2-(5-氯-7-(四氢吡喃-4-基)氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸甲酯;
[(R)-2-(5-氯-7-(四氢吡喃-4-基)氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(R)-2-(5-氯-7-(四氢吡喃-4-基)氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙醇;
[(R)-2-(5-溴-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(R)-2-(5-溴-7-(四氢吡喃-4-基)氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙醇;
[(R)-2-(5-溴-7-(四氢吡喃-4-基)氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(R)-2-(5-氟-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(R)-2-(5-氟-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸乙酯;
[(R)-2-(5-氟-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙醇;
[(R)-2-(5-氟-7-(四氢吡喃-4-基)氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(R)-2-(7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(R)-2-(7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸乙酯;
[(R)-2-(7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙醇;
[(R)-2-(7-(四氢吡喃-4-基)氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-甲酸;
[(R)-2-(7-(四氢吡喃-4-基)氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙醇;
[(R)-2-(5-甲氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸甲酯;
[(R)-2-(5-甲氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(R)-2-(5-甲氧基-7-(四氢吡喃-4-基)氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(R)-2-(5-乙氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(R)-2-(5-丙氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(R)-2-(5-苯氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(R)-2-(5-苯氧基-7-(四氢吡喃-4-基)氨基-1H-吲哚-2- 基)-4,5-二氢-噻唑-4-基]-乙酸;
[(R)-2-(5-(吡啶-3-基)氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸甲酯;
[(R)-2-(5-(吡啶-3-基)氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(R)-2-(5-(吡啶-3-基)氧基-7-(四氢吡喃-4-基)氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸甲酯;
[(R)-2-(5-(吡啶-3-基)氧基-7-(四氢吡喃-4-基)氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(R)-2-(5-甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸甲酯;
[(R)-2-(5-甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(R)-2-(5-甲基-7-(四氢吡喃-4-基)氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(R)-2-(5-(4-(甲磺酰基)苯氧基)-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(R)-2-(5-苯氧基甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸甲酯;
[(R)-2-(5-苯基氨基甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸甲酯;
[(R)-2-(5-甲磺酰基甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸甲酯;
[(R)-2-(5-甲磺酰基甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(R)-2-(5-甲磺酰基甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙醇;
[(R)-2-(7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基乙酰胺;
3-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-丙酸;
[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-丙醇;
3-[(R)-2-(5-氯-7-(四氢吡喃-4-基)氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-丙酸;
3-[(R)-2-(5-氯-7-(四氢吡喃-4-基)氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-丙醇;
3-[(R)-2-(5-甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-丙酸乙酯;
3-[(R)-2-(5-甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-丙酸;
3-[(R)-2-(5-苯氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-丙酸;
3-[(R)-2-(5-氟-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-丙酸乙酯;
3-[(R)-2-(5-氟-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-丙酸;
3-[(R)-2-(5-溴-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-丙酸乙酯;
3-[(R)-2-(5-溴-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-丙酸;
3-[(R)-2-(7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-丙酸;
3-[(R)-2-(5-甲氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-丙酸;
3-[(R)-2-(5-乙氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-丙酸乙酯;
3-[(R)-2-(5-乙氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢- 噻唑-4-基]-丙酸;
3-[(R)-2-(5-三氟甲氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-丙酸乙酯;
3-[(R)-2-(5-三氟甲氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-丙酸;
[(R)-2-(5-甲基-7-(四氢吡喃-4-基)氨基-1H-吲哚-2-基)-4,5-二氢-噁唑-4-基]-乙醇;
[(S)-2-(5-甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噁唑-4-基]-乙酸;
[(S)-2-(5-甲基-7-(四氢吡喃-4-基)氨基-1H-吲哚-2-基)-4,5-二氢-噁唑-4-基]-乙酸;
[(S)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噁唑-4-基]-乙酸;
[(S)-2-(5-氯-7-(四氢吡喃-4-基)甲氨基-1H-吲哚-2-基)-4,5-二氢-噁唑-4-基]-乙酸;
[2-((4S,5R)-5-氨基甲基-4-苄基-二氢-噁唑-2-基)-5-氯-1H-吲哚-7-基]-环戊基-胺;
{2-[(R)-5-((S)-1-氨基-2-苯基-乙基)-4,5-二氢-噁唑-2-基]-5-氯-1H-吲哚-7-基}-环戊基-胺;
(四氢吡喃-4-基)-[2-(4,5-二氢-噁唑-2-基)-1H-吲哚-7-基]-胺;
[2-(7-(四氢吡喃-4-基)甲氨基-1H-吲哚-2-基)-4,5-二氢-异噁二唑-4-基]-乙酸;
[2-(7-(四氢吡喃-4-基)甲氨基-1H-吲哚-2-基)-4,5-二氢-异噁二唑-4-基]-乙醇;
环戊基-[2-(4,5-二氢-噁二唑-2-基)-1H-吲哚-7-基]-胺;
[2-(5-甲基-7-环戊基氨基-1H-吲哚-2-基)-噻唑-4-基]-甲醇;
[2-(5-甲基-7-环戊基氨基-1H-吲哚-2-基)-噻唑-5-基]-甲醇;
[2-(5-甲基-7-环戊基氨基-1H-吲哚-2-基)-噻唑-4-基]-甲酸乙 酯;
[2-(5-甲基-7-环戊基氨基-1H-吲哚-2-基)-噻唑-4-基]-甲酸;
[2-(7-环戊基氨基-1H-吲哚-2-基)-噻唑-4-基]-甲醇;
[2-(7-环戊基氨基-1H-吲哚-2-基)-噻唑-4-基]-甲酸甲酯;
{(R)-2-[5-甲基-7-(4-氧代-环己基氨基)-1H-吲哚-2-基]-4,5-二氢-噻唑-4-基}乙酸;
2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-1-吗啉-4-基-乙酮;
2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-1-(吗啉-4-基)乙氨基-乙酮;
2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-1-(吗啉-4-基)丙基氨基-乙酮;
2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-1-甲氨基-乙酮;
2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-1-二甲氨基-乙酮;
2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-1-[4-(甲基)哌嗪-1-基]-乙酮;
2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-1-(3-二甲氨基吡咯烷-1-基)-乙酮;
2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-1-(哌啶-4-基)-乙酮;
2-[(R)-2-(5-氯-7-(四氢吡喃-4-基)甲氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-1-甲氨基-乙酮;
2-[(R)-2-(5-氯-7-(四氢吡喃-4-基)甲氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-1-(吗啉-4-基)-乙酮;
2-[(R)-2-(5-氟-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-1-(4-(甲基)哌嗪-1-基)-乙酮;
2-[(R)-2-(5-氟-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑 -4-基]-1-(吗啉-4-基)乙氨基-乙酮;
2-[(R)-2-(5-甲氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-1-(甲氨基)-4-基-乙酮;
2-[(R)-2-(5-甲氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-1-(吗啉-4-基)-乙酮;
2-[(R)-2-(7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-1-甲氨基-乙酮;
2-[(R)-2-(7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-1-(吗啉-4-基)-乙酮;
2-[(R)-2-(7-(四氢吡喃-4-基)甲氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-1-甲氨基-乙酮;
2-[(R)-2-(7-(四氢吡喃-4-基)甲氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-1-(吗啉-4-基)-乙酮;
2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-1-(吗啉-4-基)乙氨基-乙酮;
2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-1-(4-(甲基)哌嗪-1-基)-乙酮;
环戊基-{5-甲磺酰基甲基-2-[(R)-4-(2-吗啉-4-基-乙基)-4,5-二氢-噻唑-2-基]-1H-吲哚-7-基}-胺;
1-(4-{2-[(R)-2-(7-环戊基氨基-5-甲磺酰基甲基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-哌嗪-]-基)-乙酮;
环戊基-[2-((R)-4-吡咯烷-1-基甲基-4,5-二氢-噻唑-2-基)-1H-吲哚-7-基]-胺;
{5-氯-2-[(R)-4-(2-二甲氨基-乙基)-4,5-二氢-噻唑-2-基]-1H-吲哚-7-基}-环戊基-胺;
{5-氯-2-[(R)-4-(2-哌嗪-1-基-乙基)-4,5-二氢-噻唑-2-基]-1H-吲哚-7-基}-环戊基-胺;
(5-氯-2-{(R)-4-[2-(4-乙磺酰基-哌嗪-1-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
1-(4-{2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-哌嗪-1-基)-2-羟基-乙酮;
{5-氯-2-[(R)-4-(2-吡唑-1-基-乙基)-4,5-二氢-噻唑-2-基]-1H-吲哚-7-基}-环戊基-胺;
(S)-1-{2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-吡咯烷-2-甲酸;
{5-氯-2-[(R)-4-(2-甲磺酰基-乙基)-4,5-二氢-噻唑-2-基]-1H-吲哚-7-基}-环戊基-胺;
3-{2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-5-甲基-3H-咪唑-4-甲酸乙酯;
3-{2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-5-甲基-3H-咪唑-4-甲酸;
1-(2-{(R)-2-[5-氯-7-(四氢-吡喃-4-基氨基)-1H-吲哚-2-基]-4,5-二氢-噻唑-4-基}-乙基)-哌啶-3-甲酸;
[(S)-1-(2-{(R)-2-[5-氯-7-(四氢-吡喃-4-基氨基)-1H-吲哚-2-基]-4,5-二氢-噻唑-4-基}-乙基)-吡咯烷-3-基]-氨基甲酸叔丁酯;
(2-{(R)-4-[2-((S)-3-氨基-吡咯烷-1-基)-乙基]-4,5-二氢-噻唑-2-基}-5-氯-1H-吲哚-7-基)-(四氢-吡喃-4-基)-胺;
N-[(S)-1-(2-{(R)-2-[5-氯-7-(四氢-吡喃-4-基氨基)-1H-吲哚-2-基]-4,5-二氢-噻唑-4-基}-乙基)-吡咯烷-3-基]-乙酰胺;
环戊基-{2-[(R)-4-(2-甲氧基-乙基)-4,5-二氢-噻唑-2-基]-1H-吲哚-7-基}-胺;
[2-((R)-4-氨基甲基-4,5-二氢-噻唑-2-基)-1H-吲哚-7-基]-环戊基-胺;
{2-[(R)-4-((R)-3-氨基-吡咯烷-1-基乙基)-4,5-二氢-噻唑-2-基]-5-氯-1H-吲哚-7-基}-环戊基-胺;
4-[(R)-2-(7-环戊基氨基-5-乙氧基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基乙基]-哌嗪-2-酮;
{2-[(R)-4-((S)-3-氨基-吡咯烷-1-基乙基)-4,5-二氢-噻唑-2-基]-5-氯-1H-吲哚-7-基}-环戊基-胺;
(5-氯-2-{(S)-4-[2-(3-二甲氨基-苯基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
1-(4-{2-[(S)-2-(7-环戊基氨基-5-氯-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-哌嗪-1-基)-乙酮;
1-(4-{2-[(S)-2-(7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-哌嗪-1-基)-乙酮;
(5-甲氧基-2-{(R)-4-[2-(吡咯烷-1-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(2-{(R)-4-[(吡咯烷-1-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-(四氢-吡喃-4-基)-胺;
(2-{(S)-4-[(2-氧代哌嗪-4-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-(四氢-吡喃-4-基)-胺;
(5-甲磺酰基甲基-2-{(S)-4-[(2-氧代哌嗪-4-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(5-甲基-2-{(S)-4-[(吗啉-4-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-(四氢-吡喃-4-基)-胺;
1-(4-{2-[(R)-2-(7-环戊基氨基-5-氯-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-哌嗪-1-基)-乙酮;
(5-氯-2-{(R)-4-[4-甲基-哌嗪-1-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(5-氯-2-{(R)-4-[4-(羟基)哌啶-1-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(5-氯-2-{(R)-4-[2-氧代哌嗪-4-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(5-氯-2-{(R)-4-[(哌啶-1-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(5-氯-2-{(R)-4-[(1,1-二氧代-硫代吗啉-4-基)-乙基]-4,5-二 氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(5-氯-2-{(R)-4-[(2-氧代吡咯烷-1-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(5-氯-2-{(R)-4-[((3S)-3-(二甲氨基羧基)哌啶-1-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-(四氢-吡喃-4-基)-胺;
(5-氯-2-{(R)-4-[(哌嗪-1-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-(四氢-吡喃-4-基)-胺;
1-(4-{2-[(R)-2-(5-氯-7-(四氢-吡喃-4-基氨基)-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-哌嗪-1-基)-2-羟基-乙酮;
(5-氯-2-{(R)-4-[(1-(三氟乙酰基)哌嗪-4-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-(四氢-吡喃-4-基)-胺;
(5-氯-2-{(R)-4-[(1-[(呋喃-2-基)羰基]哌嗪-4-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-(四氢-吡喃-4-基)-胺;
(5-氯-2-{(R)-4-[(1,4-吡嗪-2-基)哌嗪-4-基-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-(四氢-吡喃-4-基)-胺;
(5-氯-2-{(R)-4-[(1,3-吡嗪-2-基)哌嗪-4-基-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-(四氢-吡喃-4-基)-胺;
(5-氟-2-{(R)-4-(2-氨基乙基)-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
1-(4-{2-[(R)-2-(5-氟-7-环戊基氨基)-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-哌嗪-1-基)-2-羟基-乙酮;
(5-氟-2-{(R)-4-[(吗啉-4-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(5-氟-2-{(R)-4-(2-二甲氨基-乙基)-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(5-氟-2-{(R)-4-[(吡咯烷-1-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(5-氟-2-{(R)-4-[(1,1-二氧代-硫代吗啉-4-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(5-氟-2-{(R)-4-[(2-氧代吡咯烷-1-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
1-(4-{2-[(5-氟-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]乙基}-哌嗪-1-基)-2-羟基-乙酮;
(5-氟-2-{(R)-4-[甲磺酰基-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(5-氟-2-{(R)-4-(2-二甲氨基-乙基)-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-(四氢-吡喃-4-基)-胺;
(5-氟-2-{(R)-4-[(吡咯烷-1-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-(四氢-吡喃-4-基)-胺;
(5-氟-2-{(R)-4-[(吗啉-4-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-(四氢-吡喃-4-基)-胺;
1-(4-{2-[(R)-2-(7-(四氢-吡喃-4-基氨基)-5-氟-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-哌嗪-1-基)-乙酮;
(5-氟-2-{(R)-4-[(1,1-二氧代-硫代吗啉-4-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-(四氢-吡喃-4-基)-胺;
(5-氟-2-{(R)-4-[2-甲磺酰基-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-(四氢-吡喃-4-基)-胺;
(5-氟-2-{(R)-4-[2-氧代哌嗪-4-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-(四氢-吡喃-4-基)-胺;
1-(4-{2-[(R)-2-(5-氟-7-(四氢-吡喃-4-基氨基)-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-哌嗪-1-基)-2-羟基-乙酮;
(2-{(R)-4-[2-二甲氨基-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(2-{(R)-4-[(哌啶-1-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
2-{(R)-4-[2-甲磺酰基-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-(四氢-吡喃-4-基)-胺;
1-(4-{2-[(R)-2-(5-甲氧基-7-环戊基氨基-1H-吲哚-2- 基)-4,5-二氢-噻唑-4-基]-乙基}-哌嗪-1-基)-2-羟基-乙酮;
1-(4-{2-[(R)-2-(7-环戊基氨基)-5-氯-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-丙基}-哌嗪-1-基)-乙酮;
2-{(R)-4-[(吗啉-4-基)-甲基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(5-氯-2-{(R)-4-[(吗啉-4-基)-丙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(2-{(R)-4-[2-二甲氨基-甲基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(5-氯-2-{(S)-4-[(吗啉-4-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
{5-甲基-2-[(R)-4-(2-吗啉-4-基-乙基)-4,5-二氢-噁唑-2-基]-1H-吲哚-7-基}-(四氢吡喃-4-基)-胺;
{5-甲基-2-[(S)-4-(2-吗啉-4-基-乙基)-4,5-二氢-噻唑-2-基]-1H-吲哚-7-基}-(四氢-吡喃-4-基甲基)-胺;
1-(4-{2-[(S)-2-(5-苯氧基-7,7-二异丁基氨基)-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-哌嗪-1-基)-乙酮;
(5-苯氧基-2-{(S)-4-[(吡咯烷-1-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-二异丁基-胺;
1-(4-{2-[(S)-2-(5-苯氧基-7-环戊基氨基)-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-哌嗪-1-基)-2-羟基-乙酮;
(5-苯氧基-2-{(S)-4-[(哌嗪-1-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
叔丁基-(4-{2-[(S)-2-(5-苯氧基-7-环戊基氨基)-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-哌嗪-1-甲酸酯;
环戊基-(5-苯氧基-2-{(S)-4-[2-(3-氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-胺;
(5-苯氧基-2-{(S)-4-[2-氧代哌嗪-4-基)-乙基]-4,5-二氢-噻 唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(4-{2-[(S)-2-(5-苯氧基-7-环戊基氨基)-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-哌嗪-1-基)-环氧乙烷-2-基-甲酮;
(5-苯氧基-2-{(S)-4-[(吡啶-2-基)哌嗪-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(5-苯氧基-2-{(S)-4-[(2-氟苯基)哌嗪-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(5-氯-2-{(S)-4-[2-氧代哌嗪-4-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(5-苯氧基-2-{(S)-4-[(3S)-3-(氨基)吡咯烷-1-基-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
1-(4-{2-[(S)-2-(5-苯氧基-7-环戊基氨基)-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-哌嗪-1-基)-乙酮;
(5-甲基-2-{(S)-4-[2-(氨基羰基)吡咯烷-1-基-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-(四氢吡喃-4-基)甲基-胺;
(5-甲基-[(S)-2-(7-(四氢吡喃-4-基)甲氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基])-吡咯烷-2-基-甲醇;
(5-氯-[(S)-2-(7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基])-吡咯烷-3-基-乙酰胺;
(5-苯氧基-2-{(S)-4-[4-(苄基)哌嗪-1-基-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(5-甲基-2-{(S)-4-[2-二乙氧基磷酰基-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-(四氢吡喃-4-基)甲基-胺;
(5-甲基-2-{(S)-4-[吗啉-4-基-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-(四氢吡喃-4-基)甲基-胺;
(5-苯氧基-2-{(R)-4-[吡咯烷-1-基-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(5-苯氧基-2-{(S)-4-[吗啉-4-基-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-(四氢吡喃-4-基)甲基-胺;
(5-苯氧基-2-{(S)-4-[2-氧代哌嗪-4-基-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-(四氢吡喃-4-基)甲基-胺;
(5-苯氧基-2-{(S)-4-[吡咯烷-1-基-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(5-甲基-2-{(S)-4-[2-氧代哌嗪-4-基-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-4,4-二氟环己基-胺;
(5-甲基-2-{(S)-4-[吗啉-4-基-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-4,4-二氟环己基-胺;
(四氢吡喃-4-基)-(5-甲基-2-{(S)-4-[2-(3-氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-胺;
(5-甲基-2-{(S)-4-[2-氧代哌嗪-4-基-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-(四氢吡喃-4-基)甲基-胺;
(5-氯-2-{(S)-4-[1-(吡啶-2-基)哌嗪-4-基-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-(四氢吡喃-4-基)-胺;
(4-{2-[(S)-2-(5-氯-7-(四氢吡喃-4-基)-氨基)-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-哌嗪-1-基)-环氧乙烷-2-基-甲酮;
(5-甲氧基-2-{(R)-4-[2-氧代哌嗪-4-基-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-(四氢吡喃-4-基)-胺;
1-(4-{2-[(R)-2-(5-甲氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-哌嗪-1-基)-2-羟基-乙酮;
[(R)-2-(5-氨基甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-甲醇;
呋喃-2-甲酸[7-环戊基氨基-2-((R)-4-羟基甲基-4,5-二氢-噻唑-2-基)-1H-吲哚-5-基甲基]-酰胺;
[(R)-2-(7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基甲氧基]-乙酸甲酯;
[(R)-2-(7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基甲氧基]-乙酸;
环戊基-{2-[(R)-4-(3-环戊基-[1,2,4]噁二唑-5-基甲基)-4,5-二氢-噻唑-2-基]-1H-吲哚-7-基}-胺;和
环戊基-{2-[(R)-4-(3-哌啶-1-基-[1,2,4]噁二唑-5-基甲基)-4,5-二氢-噻唑-2-基]-1H-吲哚-7-基}-胺。
本发明还提供了制备式(1)化合物的方法。在下文中,制备式(1)化合物的方法被示例为典型反应方案,目的在于更好地理解。然而,本发明所属技术领域普通技术人员可以根据其结构,通过各种途径制备式(1)的化合物,且这样的方法应被视为属于本发明的范围。换句话说,可以通过任选地合并本说明书中所述的或现有技术中披露的各种合成方法制备式(1)的化合物。制备式(1)化合物的方法甚至涵盖这样的方法,不限于如下说明的那些。
首先,可以根据下述反应方案(1)、通过酰胺偶联反应或烷基化反应,由化合物(2)和(3)制备式(1)的化合物。
反应方案1
在上述反应方案(1)中,
A,R1,R2,R3,R4和n如上述所定义,且
W表示用于酰胺偶联反应的羧酸或用于偶联反应的卤素,烷基磺酸酯等。
特别地,在上述反应方案(1)中的R1优选表示含胺或碳亲核体的基团。
可以使用偶联剂,例如二环己基碳二亚胺(DCC),EDC,N-[二甲氨基-1H-1,2,3-三唑[4,5-b]-吡啶-1-基亚甲基]-N-甲基甲铵(HATU)等,与HOBT进行酰胺化反应。该反应在Et3N,DIPEA等的碱存在下、 在DMF或DCM中且在室温下进行4至12h。就含氮原子的亲核体而言,可以使用各种碱,例如Et3N,K2CO3,NMPA,DBU等在溶剂,例如乙腈,THF或DMF中,在25至80℃下进行4至24h。大部分化合物(3)是商购的。
在如下反应方案(2)中,化合物(2-1)和(2-2),其A是4,5-二氢-噻唑,可以通过水解化合物(4)的(4,5-二氢-噻唑-4-基)-酯类来制备,或通过首先经还原而合成醇类化合物,再通过引入卤化物或磺酰基作为离去基来制备。
反应方案2
在上述反应方案(2)中,
n,R2,R3和R4如上述所定义,
Q表示离去基,优选卤素或烷基磺酸酯,且
R′表示烷基,优选甲基,乙基,异丙基等。
特别地,可以通过水解酯化合物(4)获得羧酸化合物(2-1),其中2至10eq.的NaOH,LiOH,KOH等用作碱,且使用一种或多种选自水,甲醇,THF和二噁烷的溶剂。该水解反应在室温至100℃下进行30min至12h。
还可以通过还原酯化合物(4)获得醇化合物(5),其中NaBH4,LiBH4,LAH等用作还原剂,且醇,例如甲醇,THF,二噁烷等用作溶剂。该还原反应在室温至100℃下进行30min至24h。还原剂的用量通常是3-5eq.,但如果需要,可以使用超过约10eq.的量。
可以使用选自碘、溴、N-碘琥珀酰亚胺(NIS),N-溴琥珀酰亚胺(NBS)、四氯化碳(CCl4),四溴化碳(CBr4)等的试剂,在碱,例如咪唑,二甲氨基吡啶(DMAP)等和膦,例如三苯膦(Ph3P),三丁膦(Bu3P)等存在下进行醇化合物(5)的卤化反应。卤化试剂、碱和膦各自的常用量相对于化合物(5)为1-10eq.。该反应可以在选自醚类例如四氢呋喃、乙醚等,二氯甲烷,氯仿等的溶剂中、在0-50℃下进行10min至12h。
醇化合物(5)的磺酰化反应可以使用1-10eq.用量的选自甲磺酰氯,对-甲苯磺酰氯等的试剂,在有机碱,例如吡啶,三乙胺等存在下进行。该反应可以在选自二氯甲烷,二氯乙烷等的溶剂中、在0-50℃下进行10min至12h。
可以如如下反应方案(3)中所述,即通过将4,5-二氢-噻唑引入7-硝基-吲哚酯的起始化合物、还原硝基、进行还原氨基化反应以引入R3和R4,获得吲哚-4,5-二氢-噻唑化合物(4′)。
反应方案3
在上述反应方案(3)中,
R2如上述所定义,
R″表示对-甲氧基苄基(p-MeOBn)或三苯基甲基(Ph3C),且
R″′表示R1或被保护的R1,典型地表示烷氧羰基(烷基-OC(O)-)或烷基甲酸酯(烷基-CO2-)。
反应方案(3)中的水解反应按照与反应方案(2)中所说明的相同的方式进行,且酰胺偶联反应如在反应方案(1)中所说明的那样进行。环化反应可以使用五氯化磷(PCl5)在溶剂二氯甲烷中进行,此时R″是对-甲氧基苄基,或使用三氟甲磺酸酐(Tf2O)和三苯基氧化膦(Ph3PO)在溶剂二氯甲烷中进行,此时R″是三苯基甲基。
7-硝基吲哚化合物(10)上的硝基的还原可以使用酸催化剂和金属或使用金属催化剂在氢气环境中进行。在酸催化剂反应中,铁、锌、锂、钠或锡(典型地是氯化锡)可以用作金属;无机酸,例如盐酸、硫酸、硝酸、磷酸等;有机羧酸,例如乙酸,三氟乙酸等;胺酸盐,例如氯化铵等;优选盐酸、乙酸或氯化铵可以用作酸催化剂。此外,在氢气气氛下使用金属催化剂的还原中,可举出钯、镍、铂、钌、铑等,优选钯或镍作为可以使用的金属催化剂。
还原氨基化反应使用含羰基的化合物(酮或醛)进行。作为可以使用的还原剂,可举出硼氢化钠、氰基硼氢化钠、三乙酰氧基硼氢化钠等。该反应可以使用酸作为催化剂得到促进。作为可以使用的酸催化剂,可举出无机酸,例如盐酸、硫酸、硝酸、磷酸等;有机羧酸,例如乙酸、三氟乙酸等;胺酸盐,例如氯化铵等,更优选盐酸或乙酸。
在如下反应方案(4)中,化合物(11)和吲哚化合物(7)偶联得到化合物(9-1),然后在酸性条件下环化并水解成化合物(2-3),其中R″′是醇。此外,通过用离去基取代化合物(2-3)的醇基得到的化合物(2-4)可以与胺化合物(14)反应而得到胺化合物(2-5)。
反应方案4
在上述反应方案(4)中,
Q,R2,R5,R6和R″如上述所定义。
酰胺偶联和环化反应可以在与反应方案(1)和(3)所说明的相同的条件下进行。
获得化合物(2-3)的水解反应在水与有机溶剂的溶剂混合物中和碱存在下进行,其中THF,甲醇,二噁烷等可以用作有机溶剂、且LiOH,KOH,NaOH等可以用作碱。
引入离去基Q的反应可以在与对反应方案(2)说明的相同的条件下进行。引入胺基的化合物(2-5)的合成,通过使胺化合物(14)与化合物(2-4)在碱存在下,在25至80℃下反应20min至24h来进行。作为所述碱,可举出Et3N,DIPEA,DMAP等,但如果需要,该反应也可以在没有碱存在下进行。
7-硝基吲哚化合物(6)是商购的或可以根据如下反应方案(5)制备。
反应方案5
在上述反应方案(5)中,R2如上述所定义。
硝基-苯胺化合物(15)是商购的或可以根据Heterocycles,68(11),2285~99,2006或Bioorganic & MedicinalChemistry Letters,14(19),4903~4906,2004中已知的方法制备。
肼化合物(16)也是商购的或可以根据Journal of the AmericaChemical Society,198(48),15374~75,2006中已知的方法通过将化合物(15)的胺基修饰成肼基来制备。
腙化合物(18)可以通过合并酮化合物(17)与肼化合物(16)得到。当肼化合物(16)是中性形式时,不使用碱,而在化合物是酸式盐形式时应使用碱以使其成为中性形式。作为碱,可举出金属氢氧化物,例如氢氧化钠、氢氧化锂等;金属碳酸盐,例如碳酸氢钠、碳酸钾等;金属乙酸盐,例如乙酸钠等;有机碱,例如三乙胺,吡啶等,优选乙酸钠、碳酸氢钠等。
可以根据Organic Process Research & Development,2,1988,214~220中已知的Japp-Klingemann重排方法,通过在碱存在下使重氮盐与酮化合物(19)反应来制备腙化合物(18)。
化合物(18)的环化反应可以根据Journal of organic Chemistry, 68(24),2003,9506~9509,Tetrahedron,55(34),1999,10271~10282等中已知的方法进行。可以在该反应中使用的酸是多磷酸、盐酸、对-甲苯磺酸、硫酸、乙酸等。就多磷酸而言,可以单独使用或与选自苯、甲苯等的芳族烃一起使用。
在吲哚环的5-位上修饰的化合物可以如下列反应方案(6)中所示,获自化合物(6′)。
反应方案6
在上述反应方案(6)中,
R″,R″′和R7如上述所定义。
可以通过在碱存在下使用Boc2O保护(5-甲基-7-硝基-1H-吲哚-2-基)甲酸甲酯化合物(6′)的胺基,再通过使用溴化试剂将5-位上的甲基转化成溴甲基,由此获得化合物(20)。
然后使用乙酸钠对化合物(20)进行乙酰化,使BOC基团脱保护并进行水解反应可以得到醇化合物(22)。
可以使用五氯化磷对化合物(9-2)进行环化反应(所述化合物(9-2)获自如在反应方案(3)中说明的化合物(22)和(8)之间的酰胺偶联反应),得到化合物(2-6),其中醇被氯替代,且化合物(2-6)可以通过 引入基团R7被转化成化合物(2-7)。
可以如下述反应方案(7)所示,通过由邻苯二甲酰亚胺化合物(23)制化合物(24),再通过使获自化合物(24)的化合物(1-1)的胺基酰化,获得在吲哚环的5-位上具有胺基的化合物(1-2)。
反应方案7
在上述反应方案(7)中,
R4,R″,R″′和R10如上述所定义。
为引入邻苯二甲酰亚胺基而在烷基化反应中使用的邻苯二甲酰亚胺钾是商购的,且该反应可以在四氢呋喃,N,N-二甲基甲酰胺,N-甲基吡咯烷酮等存在下进行。该水解反应可以按照与制备反应方案(4)中的化合物(2-3)的方法相同的方式进行。化合物(23)的酰胺偶联、环化和还原以及化合物(24)的还原氨基化还可以按照与上述说明的相同的方式进行。可以使用肼进行除去化合物(24)的邻苯二甲酰亚胺基的反应。可以通过使用酰基氯化合物(25)来酰化胺化合物(1-1)而得到化合物(1-2),其中选自Et3N、DIPEA、DMAP、吡啶等的碱的典型使用量相对于胺化合物为2eq.以上。
在如下反应方案(8)中,通过保护氨基酸,例如半胱氨酸的巯基或通过将巯基引入来自谷氨酸、天冬氨酸等的氨基酸衍生物,来制备化 合物(8-1)和(8-2)。
反应方案8
在上述反应方案(8)中,
R″如上述所定义,且
R″″表示烷基,优选甲基,乙基,异丙基或环己基。
可以通过使胺-被保护的氨基酸化合物(28)与重氮甲烷反应得到偶氮化物,使用银离子例如苯甲酸银延长一个碳数,酯化酸基并除去胺保护基,由此制备化合物(8-1)。特别地,一个碳延长的反应可以如下进行:根据Helvetica Chimica Acta,87,2004,3131~3159中已知的方法,通过在室温下使化合物(28)与氯甲酸乙酯(EtOCOCl)或氯甲酸异丁酯(iBuOCOCl)在碱[例如N-甲基吗啉(NMM),三乙胺等]存在下、在四氢呋喃溶剂中反应,使得到的酸酐与重氮甲烷氢氧化钾水溶液在乙醚溶剂中在0℃下反应,然后与Ag离子[例如三氟乙酸银(CF3CO2Ag),苯甲酸银等]和烷基醇(例如甲醇,乙醇等)在暗处条件下反应,得到烷基酯化合物。
在上述反应中,可以通过使Diazald,N-甲基-N-亚硝基胍或N-甲基-N-亚硝基脲在KOH碱的存在下,根据本领域公知的常规方法反应,得到重氮甲烷。具有一个以上碳原子的酯化合物可以通过使重氮化合物与苯甲酸银在醇溶剂中反应来获得,其中适当的反应温度约为-15℃。为了完成反应,在加入苯甲酸银后将该反应混合物温至室温。作为溶剂,可以使用甲醇或乙醇。可以使用三氟乙酸或4N盐酸/ 乙醚或者盐酸/二噁烷溶液来除去BOC基团。
氨基酸化合物(28)(其胺基被BOC保护)可以通过在碱性条件下保护半胱氨酸的巯基,再用BOC保护胺基来获得。特别地,可以使用对-甲氧基苄基氯(PMBCl)或三苯基甲基氯(TrCl)在选自NaOH,NaH等的碱存在下保护巯基。可以使用(BOC)2O在碱性条件下进行胺基的BOC保护,其中所述碱可以包括NaOH,Et3N,NaHCO3等且可以使用选自DCM,二噁烷,水等的溶剂。
可以通过将巯基引入化合物(31)并通过除去其中的BOC基团来获得化合物(8-2)。特别地,可以使用PMB-SH(对-甲氧基苄硫醇)在选自NaH,CeCO3,K2CO3等的碱存在下进行巯基加成。另一方面,可以通过使用甲磺酰氯在碱Et3N或DIPEA存在下保护醇化合物(29)而得到化合物(31)。
化合物(29)可以从起始化合物谷氨酸或天冬氨酸,根据Synlett,15,2005,2397~2399或Journal of Organic Chemistry,66(5),2001,1919~1923等中已知的方法合成。
在如下反应方案(9)中,修饰半胱氨酸衍生物(28)的羧酸部分,得到化合物(11)。
反应方案9
在上述反应方案(9)中,R″如上述所定义。
可以使用(BOC)2O保护化合物(28)的胺基,可以使用异丁酰氯,叔-丁酰氯等在碱存在下进行酰化,可以使用NaBH4进行还原。
使用新戊酰氯在碱存在下对化合物(32)进行酰化并且如上所述除去BOC。
其制备方法在本说明书中并未具体说明的化合物本身是已知的或是可以由已知化合物根据已知方法或与其类似的方法制备的那些。
在本发明的方法中,混合物通过柱色谱法以常规方式分离。就终产物而言,可以在反应完成后通过重结晶或者正相或反相HPLC(Waters,Delta Pack,300x50mmI.D.,C185μm,100A)分离。当通过重结晶或HPLC纯化产物时,可以获得与三氟乙酸所成的盐的形式的化合物。当需要与盐酸所成的盐时,可以使用离子交换树脂。
正如上文说明的,本发明的化合物、制备它们的原料物质、中间体等可以通过各种方法获得,并且这种制备式(1)化合物的方法应被视为属于本发明的范围。
效果
本发明可以治疗和/或预防的坏死及相关疾病包括急性/慢性肝病(例如肝炎、肝纤维化、肝硬化)、神经变性疾病(例如痴呆、帕金森病、亨廷顿舞蹈病)、缺血性心脏病、再灌注损伤、缺血性发作或缺血性损伤、胰腺炎、细菌性/病毒性败血症、糖尿病或糖尿病并发症、糖尿病性血管疾病[特别是由胰脏细胞破坏物质导致的,以及由病毒、高血糖、脂肪酸、膳食、毒素、链脲霉素等介导的那些糖尿病]、坏死性直肠结肠炎、囊性纤维化、类风湿性关节炎、退行性关节炎、肾病、细菌感染、病毒感染(例如HIV)、多发性硬化症、白血病、淋巴瘤、新生儿呼吸窘迫综合征、窒息、肺结核、子宫内膜异位症、血管无力、牛皮癣、冻疮、类固醇治疗的并发症、坏疽、褥疮、血红蛋白尿、烧伤、过热、克罗恩病、乳糜泻、间隔综合征、脊髓损伤、肾小球性肾炎、肌营养不良症、遗传性代谢病、支原体病、炭疽、安德森氏病、先天性线粒体疾病、苯丙酮尿症、胎盘梗死、梅毒、无菌性坏死等。此外,由药物和毒性物质导致的坏死及相关疾病选自与酒精中毒相关的坏死,接触、和/或施用和/或自我施用可卡因、药物(例如,对乙酰氨基酚)、抗生素、抗癌药、多柔比星、嘌罗霉素、博来霉素、NSAID、环孢菌素、化学毒素(例如,四氯化碳、氰化物、甲醇、乙二醇)、毒气、 农业化学品、重金属(例如,铅、汞、镉)或者由于接触放射性/UV而导致的损伤及其相关的坏死。
特别地,根据本发明的组合物不仅显示保肝和肝功能改善的效果,而且也对慢性肝病例如脂肪肝、肝纤维化、肝硬化等、和由病毒或药物导致的急性/慢性肝病例如肝炎等显示预防和治疗效果。同时,也可以预防或治疗肝病的并发症包括但不限于肝门高压。更特别地,本发明的药物组合物对于治疗或预防选自肝移植、酒精或非酒精性脂肪肝、肝纤维化、肝硬化和由病毒或药物导致的肝炎,而且对于酒精性急性/慢性肝病也是有效的。
此外,本发明的组合物可以有效治疗或预防脂肪酸诱导的脂肪肝或由脂肪肝产生的急性/慢性肝病。
本文使用的“治疗”是指当用于显示疾病症状发生的个体时阻断或延缓疾病的进程,“预防”是指当用于不显示,但是有疾病症状发生的危险的个体时阻断或延缓疾病发生的征兆。
上述“药物组合物”可以包含本发明的化合物与药学可接受的载体、稀释剂、赋形剂,或者(如果需要)它们的组合。药物组合物利于将该化合物施用于活体中。存在很多的技术来施用该化合物,包括但不限于口服、注射、气雾剂、胃肠外和局部施用。
本文使用的“载体”是指促进化合物进入细胞或组织的物质。例如二甲亚砜(DMSO)是一种典型的载体,用于促进将各种有机化合物引入到活体的细胞或组织中。
本文使用的“稀释剂”定义为在溶解了化合物的水中稀释,以及稳定目标化合物的生物学活性形式的物质。在本领域中,将溶解于缓冲溶液的盐用作稀释剂。典型地使用的缓冲溶液是模拟盐形式的人体溶液的磷酸盐缓冲盐水。缓冲稀释剂几乎不会改变化合物的生物活性,因为低浓度的缓冲盐就可以控制溶液的pH。
本文使用的“药学可接受的”是指不会损害化合物的生物活性和物理特性的性质。
本发明的化合物可以根据所期望的目的配制成各种药物剂型。制 备本发明的药物组合物时,将活性成分,特别是式(1)的化合物、其药学可接受的盐或异构体与根据要制备的制剂选择的各种药学可接受的载体混合在一起。例如,本发明的药物组合物可以根据所期望的目的配制成注射制剂,口服制剂等等。
本发明的化合物可以通过本领域已知的方法,使用本领域已知的药物载体和赋形剂来配制,并放入到单位剂型或多剂型的容器中。制剂的形式可以是在油或水介质中的溶液、混悬液或乳液,包含典型的分散剂、助悬剂或稳定剂。此外,例如,它可以是干粉末的形式,在使用前通过溶于无菌、无热原的水重新溶解。本发明的化合物也可以使用典型的栓剂基质例如可可脂或其他甘油酯类配制成栓剂形式。作为用于口服的固体剂型,可以制备胶囊、片剂、丸剂、粉末剂和颗粒剂,胶囊和片剂是特别有用的。优选地,片剂和丸剂制备成肠溶包衣的形式。固体剂型可以通过将本发明的化合物与载体例如一种或多种惰性稀释剂例如蔗糖、乳糖、淀粉等,润滑剂例如硬脂酸镁,崩解剂,粘合剂等混合在一起来制备。
如果需要,本发明的化合物或包含其的药物组合物也可以与其他活性剂联合施用,包括具有不同类型的各种作用机制的细胞保护剂,特别是用于保肝、肝功能改进、以及预防或治疗肝病的现有药物——肝细胞再生促进剂、肝功能佐剂、抗病毒药、免疫抑制剂、纤维化抑制剂等。
本发明的化合物或包含其的药物组合物可以与任何用于药物产生的坏死及相关疾病的预防或治疗剂联合给药。这些药物包括任何疾病组的药物,例如抗生素、抗癌药、抗病毒药、抗感染药、消炎药、抗凝血药、血脂改善药、细胞死亡抑制剂、抗高血压药、抗糖尿病药/抗肥胖药、心血管疾病的治疗药、神经变性疾病的治疗药、抗衰老药和代谢性疾病的治疗药等。
本发明的化合物或包含其的药物组合物可以用于预防由各种原因例如毒素导致的细胞损伤和后续的坏死及相关疾病,这些原因包括活性氧(ROS)、重金属、酒精、食物、补充剂、辐射、膳食等。
式(1)的化合物的剂量取决于医生的处方,该处方要考虑以下因素,例如患者的体重、性别、年龄、健康状况和膳食、疾病的具体形式、药物的给药时间、给药方法、药物的混合比例以及疾病的严重程度等。但是,根据给药的强度和频率,治疗成年人所需的剂量典型地为约1.0mg-2,000mg/天。当通过肌内或静脉内途径施用于成年人时,典型地约1.0mg-300mg/天的总剂量在以单剂量单独施用时就足够了,但是一些患者则需要更高的每日剂量。
本发明还提供一种制备预防或治疗坏死及相关疾病的组合物的方法,包括将作为活性成分的式(1)的化合物、其药学可接受的盐或异构体与药学可接受的载体或稀释剂混合的步骤。
具体实施方式
本发明更具体地通过下列制备例和实施例来说明。然而,应理解它们用以示例本发明,而不以任何方式限定本发明的范围。在下列制备例和实施例中,M意旨摩尔浓度,N意旨标准浓度。
下列制备例更具体地说明了合成实施例化合物所需中间体的制备。用于下列制备例和实施例的缩写如下。
Ac:乙酰基
AIBN:2,2′-偶氮双(2-甲基丙腈)
BOC:叔-丁氧羰基
Bu:丁基
Bn:苄基
c-Pen:环戊基
c-Hex:环己基
CBZ(Cbz):苄氧羰基
DME:二甲氧基乙烷
DCM:二氯甲烷
DIPEA:二异丙基乙胺
DMAP:4-二甲氨基吡啶
DMF:N,N-二甲基甲酰胺
EDC:1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐
Et:乙基
EtOAC:乙酸乙酯
Hex:正-己烷
HOBT:羟基苯并三唑
HBTU:2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲六氟磷酸盐
i-Pr:异丙基
i-Pen:异戊基
Me:甲基
Ph:苯基
Pid:哌啶
Piz:哌嗪
Pyd:吡咯烷
PMB:对甲氧基苄基
TEA:三乙胺
TFA:三氟乙酸
THF:四氢呋喃
THP:四氢吡喃
t-Bu:叔丁基
制备例1:4-(吡啶-3-基氧基)苯胺
步骤A:4-(吡啶-3-基)氧基-1-硝基苯
将1-氯-4-硝基苯(40g,0.25mol)和3-羟基吡啶(36g,0.38mol)溶于N,N-二甲基甲酰胺(100mL)。向其中加入碳酸钾(52.6g,0.38mol),将该混合物在100℃下搅拌20h。在反应完成后,加入水。用乙酸乙酯萃取该反应混合物,用饱和氯化钠溶液洗涤,用无水硫酸镁干燥,得到标题化合物。
步骤B:4-(吡啶-3-基氧基)苯胺
将步骤A中制备的4-(吡啶-3-基)氧基-1-硝基苯溶于水(100mL)、四氢呋喃(100mL)和甲醇(100mL)的混合物。向其中加入铁粉(103g,1.84mol)和氯化铵(99g,1.84mol),将该混合物在80℃下使用机械搅拌器搅拌3h。在反应完成后,将该反应混合物通过硅藻土过滤,用甲醇洗涤,减压浓缩。过滤由此得到的固体,用乙醚洗涤并且干燥,得到标题化合物(17g,收率36%)。
质谱[M+H]:186(M+1)
制备例2:4-(4-甲磺酰基-苯氧基)苯胺
步骤A:1-(4-甲基硫烷基苯氧基)-4-硝基苯
将1-氯-4-硝基苯(15g,95mmol)和4-(甲基巯基)苯酚(13.3g,95mmol)溶于二甲亚砜(100mL)。向其中加入碳酸钾(15.8g,134mmol),将该混合物在100℃下搅拌12h。在反应完成后,加入过量水以沉淀固体,然后过滤并且干燥,得到标题化合物。
步骤B:4-(4-甲磺酰基-苯氧基)硝基苯
将步骤A中制备的1-(4-甲基硫烷基苯氧基)-4-硝基苯(86g,330mmol)溶于二氯甲烷(500mL)。向其中加入mCPBA(3-氯过苯甲酸)(83g,330mmol),将该混合物在0℃至室温下搅拌2h。在反应完成后,加入过量6N氢氧化钠水溶液。用乙酸乙酯和二氯甲烷萃取该反应混合物,用饱和氯化钠溶液洗涤,用无水硫酸镁干燥,得到标题化合物(28g,收率100%)。
步骤C:4-(4-甲磺酰基-苯氧基)苯胺
将步骤B中制备的4-(4-甲磺酰基-苯氧基)硝基苯(28g,95mmol)溶于甲醇(500mL)和乙酸乙酯(500mL)。向其中加入10%Pd/C(1.0g),将该混合物在氢气压力环境中搅拌3h。在反应完成后,将该反应混合物通过硅藻土过滤,用甲醇洗涤,减压浓缩,用无水硫酸镁干 燥,得到标题化合物(25g,收率100%)。
质谱[M+H]:263(M+1)
制备例3:4-乙氧基-2-硝基-苯胺
步骤A:4-乙氧基-1-乙酰基氨基苯
将4-乙氧基苯胺(40g,0.29mol)和三乙胺(61mL,0.44mol)溶于二氯甲烷(200mL)。向其中加入几滴乙酐(30mL,0.32mol),将该混合物在0℃至室温下搅拌1h。加入1N盐酸溶液,用乙酸乙酯萃取该反应混合物,用氯化钠溶液洗涤,用无水硫酸镁干燥,得到标题化合物。
步骤B:4-乙氧基-2-硝基-1-苯胺
将步骤A中制备的4-乙氧基-1-乙酰基氨基苯(51g,0.29mol)溶于二氯甲烷(200mL)。在0℃下向其中加入几滴发烟硝酸(13mL,0.29mol),将该混合物在0℃至室温下搅拌1h。向该反应混合物中加入饱和碳酸氢钠水溶液,然后用乙酸乙酯萃取,用饱和氯化钠溶液洗涤,用无水硫酸镁干燥。将得到的硝基化合物溶于甲醇(100mL)和四氢呋喃(100mL)。向其中加入几滴6N氢化钠,将该混合物在室温下搅拌6h。在反应完成后,使用6N盐酸溶液将该反应混合物中和至约pH 7,用乙酸乙酯萃取,用饱和氯化钠溶液洗涤,用无水硫酸镁干燥,得到标题化合物(44g,收率83%)。
质谱[M+H]:182(M+1)
制备例4至13:
根据与制备例3相同的方法使制备例1和2中制备的苯胺化合物与商购的苯胺反应,以合成下表中的制备例化合物。
制备例 | R2 | 质谱[M+H] |
4 | -O-(吡啶-3-基) | 231 |
5 | -O-(4-甲磺酰基苯基) | 308 |
6 | 甲氧基 | 168 |
7 | 苯氧基 | 231 |
8 | 氟 | 156 |
9 | 溴 | 217 |
10 | NAc | 195 |
11 | -O-(n-Pr) | 196 |
12 | -O-CF3 | 222 |
13 | 氯 | 172 |
制备例14:5-氯-7-硝基-1H-吲哚-2-甲酸甲酯
<方法A>
步骤A:(4-氯-2-硝基-苯基)肼盐酸盐
将制备例13中制备的4-氯-2-硝基苯胺(40g,0.23mol)溶于12N盐酸(100mL)。在0℃下向其中缓慢加入几滴溶于水(50mL)的亚硝酸钠(16g,0.23mol),将该混合物在0℃至室温下搅拌30分钟。将该反应混合物冷却至0℃,向其中缓慢加入几滴溶于12N盐酸(100mL)的氯化锡(II)(132g,0.70mol),将该混合物在0℃至室温下搅拌3h。过滤得到的黄色固体,用少量6N HCl洗涤并且干燥,得到标题化合物(30g,收率63%)。
1H-NMR(400HMz,DMSO-d6);δ9.21(s,1H),7.98(d,J=2.4Hz,1H),7.66(d,J=9.6Hz,1H),7.55(dd,J=2.4,9.6Hz,1H),4.74(brs,2H)
步骤B:2-[(4-氯-2-硝基-苯基)亚肼基]丙酸甲酯
将步骤A中制备的(4-氯-2-硝基-苯基)肼盐酸盐(30g,0.14mol)和丙酮酸甲酯(14.4mL,0.16mol)溶于甲醇(300mL),向其中加入 乙酸钠(14.2g,0.17mol)。将该反应溶液在室温下搅拌8h。过滤得到的黄色固体,用水和甲醇洗涤并且干燥,得到标题化合物(30g,收率82%)。
1H-NMR(400HMz,CDCl3);δ10.88(s,1H),8.21(d,J=2.4Hz,1H),8.01(d,J=9.2Hz,1H),7.56(dd,J=2.4,9.2Hz,1H),3.90(s,3H),2.23(s,3H)。
步骤C:5-氯-7-硝基-1H-吲哚-2-甲酸甲酯
向步骤B中制备的2-[(4-氯-2-硝基-苯基)亚肼基]丙酸甲酯(13g,46mmol)中加入多磷酸(100mL),将该混合物在100℃下加热4h。在反应完成后,在0℃下向该反应混合物中加入水。将得到的混合物搅拌2h,过滤以收集固体。用水洗涤该固体并且干燥,得到标题化合物(6.0g,收率49%)。
1H-NMR(400HMz,CDCl3);δ10.32(br s,1H),8.29(d,1H),8.03(d,J=2.4Hz,1H),7.31(d,J=2.0Hz,1H),4.01(s,3H)
<方法B>
步骤A:2-[(4-氯-2-硝基-苯基)-亚肼基]-丙酸甲酯
在烧瓶A中将制备例13中制备的4-氯-2-硝基-苯胺(11.0g,64.05mmol)溶于浓盐酸(32mL)并且冷却至-10℃。加入冰(90g),缓慢加入溶于水(50mL)的亚硝酸钠(4.42g,64.05mmol),将该混合物搅拌至变透明。
在烧瓶B中将2-甲基-3-氧代-丁酸甲酯(8.32g,64.05mmol)溶于乙醇(76mL)并且冷却至-10℃。向其中加入溶于水(19mL)的氢氧化钾(19.05mL),在-10℃下向其中加入烧瓶A中制备的溶液。将该混合物搅拌1h。过滤得到的红色固体,得到标题化合物(7.54g,收率46%)。
步骤B:5-氯-7-硝基-1H-吲哚-2-甲酸甲酯
根据与制备例14的<方法A>的步骤C相同的方法使步骤A中制备的2-[(4-氯-2-硝基-苯基)-亚肼基]-丙酸甲酯反应,得到标题化合物。
1H-NMR(400HMz,CDCl3);δ10.32(br s,1H),8.29(d,1H),8.03(d,J=2.4Hz,1H),7.31(d,J=2.0Hz,1H),4.01(s,3H)
制备例15至26:
使制备例的化合物与丙酮酸甲酯、丙酮酸乙酯、2-甲基-3-氧代-丁酸甲酯或2-甲基-3-氧代-丁酸乙酯根据制备例14的方法A或B反应,以合成下表中的制备例化合物。
制备例 | R | R2 | 1H-NMR |
15 | 甲基 | 甲基 | (500HMz,DMSO-d6);δ11.25(br s, 1H),8.08(3,1H),7.96(s,1H),7.32(s, 1H),3.87(s,3H),2.44(s,3H) |
16 | 甲基 | 甲氧基 | (400HMz,DMSO-d6);δ11.26(br s, 1H),7.84(s,1H),7.80(s,1H),7.35(s, 1H),3.91(s,3H),3.89(s,3H) |
17 | 甲基 | 氢 | 1H-NMR(500HMz,DMSO-d6);δ 11.36(br s,1H),8.23(d,1H),8.17(d, 1H),7.42(s,1H),7.32(t,1H),3.88(s, 3H) |
18 | 乙基 | 氟 | (400HMz,DMSO-d6);δ11.55(br s, 1H),8.16(m,1H),8.10(m,1H),7.42(s, 1H),4.40(q,2H),1.36(t,3H) |
19 | 乙基 | 乙氧基 | (400HMz,DMSO-d6);δ10.20(br s, 1H),7.86(s,1H),7.51(s,1H),7.26(s, |
1H),4.13(m,2H),3.98(s,3H),1.47(m, 3H) | |||
20 | 甲基 | 溴 | (400HMz,CDCl3);δ10.33(br s,1H), 8.41(s,1H),8.18(s,1H),7.30(d, J=4.0Hz,1H),4.01(s,3H) |
21 | 甲基 | 苯氧基 | (400HMz,CDCl3);δ10.26(br s,1H), 8.05(s,1H),7.69(s,1H),7.39(m, 2H),7.26(s,1H),7.15(m,1H),7.01(m, 2H),4.00(s,3H) |
22 | 乙基 | -O-(4-甲 -磺酰基) | (400HMz,DMSO-d6);δ8.099s,1H), 10.20(br s,1H),7.86(s,1H),7.51(s, 1H),7.26(s,1H),4.13(m,2H),3.98(s, 3H),1.47(m,3H) |
23 | 乙基 | -O-(吡啶-3-基) | 1H-NMR(400HMz,CDCl3);δ10.32(br s,1H),8.51~8.47(m,2H),8.05(d, J=2.4Hz,1H),7.73(d,J=2.0Hz,1H), 7.42~7.35(m,2H),7.31(d,J=2.4Hz, 1H),4.48(q,2H),1.47(t,3H) |
24 | 乙基 | -O-(n-Pr) | (400HMz,DMSO-d6);δ10.12(br s, 1H),7.92(s,1H),7.51(s,1H),7.24(s, 1H),4.44(m,2H),4.01(m,2H),1.91(m, 2H),1.44(m,3H),1.08(m,3H) |
25 | 乙基 | -O-CF3 | (400HMz,DMSO-d6);δ10.34(br s, 1H),7.91(s,1H),7.80(s,1H),7.45(s, 1H),4.34(m,2H),1.45(m,3H) |
26 | 乙基 | NAc | (400HMz,DMSO-d6);δ11.26(s,1H), 10.31(s,1H),8.55(s,1H),8.44(s, 1H),7.45(s,1H),4.40(q,2H),2.11(s, 3H),1.36(t,3H) |
制备例27:(R)-3-氨基-4-(4-甲氧基-苄基硫烷基)-丁酸甲酯盐酸盐
步骤A:(R)-2-氨基-3-(4-甲氧基-苄基硫烷基)-丙酸
在2h内将几滴溶于乙醚(400mL)的4-甲氧基苄醇(280g,1780mmol)加入到乙醚(400mL)和浓盐酸(400mL)的混合物中,将该混合物搅拌1h。分离有机层并且加入到通过将L-半胱氨酸(197g,1625mmol)和2N氢氧化钠水溶液(980mL)溶于乙醇(1890mL)而制备的溶液中。将该混合物在室温下搅拌2h。在反应完成后,将该反应混合物冷却至0℃并且使用3N盐酸水溶液中和至pH 7。过滤得到的固体并且干燥,得到标题化合物(250g,收率64%)。
步骤B:(R)-2-BOC-氨基-3-(4-甲氧基-苄基硫烷基)-丙酸
将步骤A中制备的(R)-2-氨基-3-(4-甲氧基-苄基硫烷基)-丙酸(30.7g,127.3mmol)溶于四氢呋喃(150mL)和水(150mL)。向其中加入碳酸钾(26.4g,190mmol)和(BOC)2O(27.7g,127.3mmol),将该混合物在室温下搅拌2h。在反应完成后,在减压下蒸馏该反应混合物以除去四氢呋喃。将残余物冷却至0℃并且使用3N盐酸水溶液酸化至pH 3。用水洗涤得到的固体并且干燥,得到标题化合物(43g,收率99%)。
步骤C:[(R)-3-重氮-1-(4-甲氧基-苄基硫烷基甲基)-2-氧代-丙基]-氨基甲酸叔丁酯
将步骤B中制备的(R)-2-BOC-氨基-3-(4-甲氧基-苄基硫烷基)-丙酸(43g,132mmol)、1-甲基吗啉(14.5mL,132mmol)和氯甲酸乙酯(14.1mL,132mmol)溶于四氢呋喃(500mL),将该混合物在-25℃下搅拌1h。同时,将氢氧化钾(75g,1336mmol)溶于水(75mL)和乙醚(750mL),在0℃下和2h内向其中加入几滴N-甲基-亚硝基脲(26g,252mmol),将该混合物搅拌30分钟。混合由此得到的两种 溶液,在-25℃至室温下搅拌3h。在反应完成后,向该反应混合物中加入水,然后用饱和碳酸氢钠水溶液和饱和氯化铵水溶液依次洗涤。浓缩有机层,得到标题化合物(46.0g,收率95%)。
1H-NMR(400HMz,CDCl3);δ7.25(d,J=8.8Hzm 2H),6.86(d,J=8.8Hz,2H),5.48(br s 1H),5.29(m,1H),4.31(m,1H),3.79(s,3H),3.69(s,2H),2.76(d,J-6.0Hz,2H),1.45(s,9H)
步骤D:(R)-3-叔-丁氧羰基氨基-4-(4-甲氧基-苄基硫烷基)-丁酸甲酯
将步骤C中制备的[(R)-3-重氮-1-(4-甲氧基-苄基硫烷基甲基)-2-氧代-丙基]-氨基甲酸叔丁酯(40g,109mmol)溶于甲醇(600mL),将该混合物冷却至-25℃。向其中加入三氟乙酸银并且缓慢温热该混合物。在反应完成后,通过硅藻土过滤除去固体部分。加入饱和NH4Cl水溶液,用EtOAc萃取该混合物,用MgSO4干燥。减压除去溶剂,通过柱色谱法纯化残余物(洗脱剂:EtOAc/n-Hex=1/3),得到标题化合物(30.6g,收率76%)。
1H-NMR(500HMz,CDCl3);δ7.24(d,J=8.6Hz,2H),6.83(d,J=8.6Hz,2H),5.09(m,1H),4.08(m,1H),3.79(s,3H),3.68(s,2H),3.66(s,3H),2.70~2.52(m,4H),1.44(s,9H)
步骤E:(R)-3-氨基-4-(4-甲氧基-苄基硫烷基)-丁酸甲酯
将步骤D中制备的(R)-3-叔-丁氧羰基氨基-4-(4-甲氧基-苄基硫烷基)-丁酸甲酯(30g,81.3mmol)溶于二氯甲烷(70mL)。向其中加入4N盐酸/1,4-二噁烷溶液(71mL),将该混合物在室温下搅拌2h。在反应完成后,减压浓缩该反应溶液。向残余物中加入二氯甲烷(30mL)和乙醚(150mL)。过滤并且干燥得到的固体,得到标题化合物(19.2g,收率87%)。
1H NMR(400MHz,DMSO-d6);δ8.21(br s,3H),7.25(d,2H),6.83(d,2H),3.78(s,3H),3.68(s,2H),3.65(s,3H),3.29(m, 1H),2.51-2.48(m,2H),2.35-2.31(m,2H)
制备例28:(R)-3-氨基-4-(4-甲氧基-苄基硫烷基)-丁酰酸乙酯盐酸盐
使制备例27步骤C中制备的[(R)-3-重氮-1-(4-甲氧基-苄基硫烷基甲基)-2-氧代-丙基]-氨基甲酸叔丁酯和乙醇依次根据与制备例27的步骤D和E相同的方法反应,得到标题化合物。
1H NMR(400MHz,CDCl3);δ8.37(br s,3H),7.28(d,J=8.0Hz,2H),6.87(d,J=8.0Hz,2H),4.11(m,2H),3.73(s,3H),3.70(s,2H),2.81~2.67(m,4H),1.18(t,3H)
制备例29:(R)-4-氨基-5-(4-甲氧基-苄基硫烷基)-戊酸乙酯盐酸盐
步骤A: (R)-4-BOC-氨基-5-羟基-戊酸乙酯
将商购(R)-2-BOC-氨基-戊酸-5-乙酯-1-甲酯(57.8g,200mmol)溶于甲醇(200mL)。向其中加入LiBH4(1N THF溶液,400mL),将该混合物搅拌2h,同时将温度维持在10℃或10℃以下。在反应完成后,将该反应混合物冷却至0℃并且向其中缓慢加入水以使反应停止。减压除去甲醇,用饱和NaHCO3水溶液稀释残余物。用EtOAc萃取该混合物,用MgSO4干燥。减压除去溶剂,通过柱色谱法纯化残余物,得到标题化合物(39g,收率75%)。
步骤B:(R)-4-BOC-氨基-5-甲磺酰氧基-戊酸乙酯
将步骤A中制备的(R)-4-BOC-氨基-5-羟基-戊酸乙酯(36g,137.8mmol)和三乙胺(38.4mL,275.5mmol)溶于二氯甲烷(200mL)。向其中加入几滴甲磺酰氯(11.7mL,151.5mmol),将该混合物在0℃至室温下搅拌1h。在反应完成后,加入1N盐酸溶液,然后用乙酸乙酯萃取,用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥,得到标题化合物。
步骤C:(R)-4-BOC-氨基-5-(4-甲氧基-苄基硫烷基)-戊酸乙酯
将氢化钠(5.5g,137.8mmol)和4-甲氧基苄硫醇(15.4mL,110.2mmol)溶于N,N-二甲基甲酰胺(150mL),将该混合物在0℃下搅拌10分钟。向得到的溶液中加入几滴步骤B中制备的(R)-4-BOC-氨基-5-甲磺酰氧基-戊酸乙酯(46.7g,137.8mmol),将该混合物在0℃下搅拌4h。向其中加入水以使反应停,用乙酸乙酯萃取该反应混合物,用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥。减压除去溶剂,通过柱色谱法纯化残余物,得到标题化合物。
1H-NMR(400HMz,CDCl3);δ7.25(d,J=8.8Hz,2H),6.85(d,J=8.8Hz,2H),4.56(m,1H),4.12(m,2H),3.79(s,3H),3.69(s,2H),2.53(m,2H),2.33(t,2H),1.93(m,1H),1.70(m,1H),1.44(s,9H),1.25(t,3H)
步骤D:(R)-4-氨基-5-(4-甲氧基-苄基硫烷基)-戊酸乙酯盐酸盐
将步骤C中制备的(R)-4-BOC-氨基-5-(4-甲氧基-苄基硫烷基)-戊酸乙酯(11g,62.7mmol)溶于二氯甲烷(200mL)。向其中加入4N盐酸/乙酸乙酯溶液(20mL),将该混合物在室温下搅拌2h。在反应完成后,在减压下充分除去溶剂。使残余物从乙醚(150mL)中重结晶并且干燥,得到标题化合物(20g,收率96%)。
1H NMR(400MHz,DMSO-d6);δ8.69(br s,3H),7.29(d,J=8.0Hz,2H),6.89(d,J=8.0Hz,2H),4.08(m,2H),3.74(m,5H),3.26(m,1H),2.76~2.63(m,2H),2.49~2.40(m,2H),1.89(m,2H),1.20(t,3H)
制备例30:(S)-3-氨基-4-(甲氧基-苄基硫烷基)-丁酸异丙酯
步骤A:(S)-2-BOC-氨基-琥珀酸4-异丙酯1-甲酯
将商购(S)-2-BOC-氨基-琥珀酸1-甲酯(2.4g,10mmol)溶于DCM(30mL)并且向其中加入三乙胺(2.8mL,20mmol)。向该混合物中 加入异丙醇(660mg,11mmol),EDC(2.5g,26mmol)和HOBt(2.3g,30mmol),将该混合物在室温下搅拌4h。用饱和NaHCO3水溶液使反应停止。用EtOAc萃取该反应混合物,用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥。减压除去溶剂,通过柱色谱法纯化残余物,得到标题化合物(2.5g,收率87%)。
步骤B:(S)-3-氨基-4-(甲氧基-苄基硫烷基)-丁酸异丙酯
根据与制备例29相同的方法使步骤A中制备的(S)-2-BOC-氨基-琥珀酸4-异丙酯1-甲酯反应,得到标题化合物。
质谱[M+H]=397
制备例31:2,2-二甲基-丙酸(R)-2-氨基-3-(4-甲氧基-苄基硫烷基)-丙酯
步骤A:(R)-2-氨基-3-(4-甲氧基-苄基硫烷基)-丙酸甲酯
根据与制备例30相同的方法使制备例27的步骤B中制备的(R)-2-BOC-氨基-3-(4-甲氧基-苄基硫烷基)-丙酸和甲醇反应,得到标题化合物。
1H NMR(400MHz,DMSO-d6,HCl盐);δ8.81(br s,3H),7.29(d,J=8.4Hz,2H),6.91(d,J=8.4Hz,2H),4.28(m,1H),3.18(br s,8H),2.95(m,2H)
步骤B:(R)-2-BOC-氨基-3-(4-甲氧基-苄基硫烷基)-丙酸甲酯
将步骤A中制备的(R)-2-氨基-3-(4-甲氧基-苄基硫烷基)-丙酸甲酯(30.7g,127.3mmol)溶于DCM。向其中加入Et3N(26.4g,190mmol)和(BOC)2O(27.7g,127.3mmol),将该混合物在室温下搅拌2h。在反应完成后,在减压下蒸馏该反应混合物以除去DCM,不经进一步纯化而用于下一步反应。
步骤C:[(R)-2-羟基-1-(4-甲氧基-苄基硫烷基甲基)-乙基]-氨基甲酸叔丁酯
根据与制备例29步骤A相同的方法使步骤B中制备的(R)-2-BOC-氨基-3-(4-甲氧基-苄基硫烷基)-丙酸甲酯反应,得到标题化合物。
1H NMR(500MHz,DMSO-d6);δ7.24(d,J=8.6Hz,2H),6.84(d,J=8.6Hz,2H),4.96(br s,1H),3.78(s,3H),3.76(br s,1H),3.70(s,2H),3.7~3.66(m,3H),2.58(m,2H),1.44(s,9H)
步骤D:2,2-二甲基丙酸(R)-2-叔-丁氧羰基氨基-3-(4-甲氧基-苄基硫烷基)-丙酯
将步骤C中制备的[(R)-2-羟基-1-(4-甲氧基-苄基硫烷基甲基)-乙基]-氨基甲酸叔丁酯(71.3g,227.9mmol)溶于二氯甲烷(300mL)。向其中加入三乙胺(58mL,414.4mmol)和三甲基乙酰氯(28mL,227.9mmol),将该混合物在0℃下搅拌6h。加入水以使反应停止。用乙酸乙酯萃取该反应混合物,用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥。减压除去溶剂,通过柱色谱法纯化残余物,得到标题化合物(81.0g,收率95%)。
1H NMR(400MHz,CDCl3);δ7.25(d,J=8.8Hz,2H),6.85(d,J=8.8Hz,2H),4.71(m,1H),4.11(m,2H),3.79(s,3H),3.70(s,2H),2.55(d,J=6.4Hz,2H),1.52(s,(H,1.27(s,9H)
步骤E:2,2-二甲基-丙酸(R)-2-氨基-3-(4-甲氧基-苄基硫烷基)-丙酯
将步骤D中制备的2,2-二甲基-丙酸(R)-2-叔-丁氧羰基氨基-3-(4-甲氧基-苄基硫烷基)-丙酯(81g,196mmol)溶于二氯甲烷(300mL)。向其中加入4N盐酸/1,4-二噁烷溶液(100mL),将该混合物在室温下搅拌8h。在反应完成后,在减压下充分除去溶剂。使残余物从乙醚中重结晶并且干燥,得到标题化合物(68g,收率95%)。
1H NMR(400MHz,DMSO-d6,游离形式);δ7.24(d,J=12.0Hz,2H),6.85(dd,J=4.0,8.0Hz,2H),4.04(m,1H),3.95(m,1H), 3.80(s,3H),3.68(s,2H),3.10(m,1H),2.60(m,1H),2.36(m,1H),1.18(s,9H)
制备例32:2,2-二甲基-丙酸(S)-2-氨基-3-(4-甲氧基-苄基硫烷基)-丙酯
步骤A:(S)-2-BOC-氨基-3-甲基磺酰氧基-丙酸甲酯
根据与制备例29步骤B相同的方法使商购(S)-2-BOC-氨基-3-羟基-丙酸甲酯和甲磺酰氯反应,得到标题化合物。
步骤B:(S)-2-BOC-氨基-3-(4-甲氧基-苄基硫烷基)丙酸甲酯
根据与制备例29步骤C相同的方法使步骤A中制备的(S)-2-BOC-氨基-3-甲基磺酰氧基-丙酸甲酯和4-甲氧基-苄基-硫醇反应,得到标题化合物。
步骤C:(S)-2-叔-丁氧羰基氨基-3-(4-甲氧基-苄基硫烷基)-丙醇
根据与制备例29步骤A相同的方法使步骤B中制备的(S)-2-BOC-氨基-3-(4-甲氧基-苄基硫烷基)丙酸甲酯和LiBH4反应,得到标题化合物。
步骤D:2,2-二甲基-丙酸(R)-2-氨基-3-(4-甲氧基-苄基硫烷基)-丙酯
根据与制备例31的步骤D和E相同的方法使步骤C中制备的(S)-2-叔-丁氧羰基氨基-3-(4-甲氧基-苄基硫烷基)-丙醇、三甲基乙酰氯和HCl(4N二噁烷溶液)连续反应,得到标题化合物。
质谱[M+H]=397
制备例33:2-氨基-3-(4-甲氧基-苄基硫烷基)-丙酸甲酯
根据与制备例29步骤B,C和D相同的方法使商购BOC-Ser-OMe 依次反应,得到标题化合物。
质谱[M+H]=255(M+1)
制备例34:2-[(4-甲氧基-苄基硫烷基)乙胺
根据与制备例29步骤B和C和制备例31步骤E相同的方法使商购BOC-氨基-乙醇依次反应,得到标题化合物。
质谱[M+H]=197(M+1)
制备例35:(R)-1-[(4-甲氧基-苄基硫烷基)甲基]丙胺
根据与制备例29步骤B和C和制备例31步骤E相同的方法使商购(R)-2-BOC-氨基-1-丁醇依次反应,得到标题化合物。
质谱[M+H]=225(M+1)
制备例36:(R)-1-[(4-甲氧基-苄基硫烷基)甲基]-2-甲基-1-丙胺
根据与制备例29步骤A,B和C和制备例31步骤E相同的方法使商购2-BOC-氨基-3-甲基-丁酸甲酯依次反应,得到标题化合物。
质谱[M+H]=239(M+1)
制备例37:5-溴甲基-7-硝基-吲哚-2-甲酸甲酯
步骤A:1-BOC-5-甲基-7-硝基-吲哚-2-甲酸甲酯
将制备例15中制备的5-甲基-7-硝基-1H-吲哚-2-甲酸甲酯(24.0g,100mmol)溶于二氯甲烷(500mL),向其中加入三乙胺(84mL,601mmol)和4-(二甲氨基)吡啶(600mg,5mmol)。向其中加入几滴溶于二氯甲烷(100mL)的(BOC)2O(43.7g,200mmol),将该混合物在室温下搅拌8h。在反应完成后,加入水。用乙酸乙酯萃取该反应混合物,用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥,减压浓缩,得到标题化合物(34.0g,收率100%)。
1H-NMR(500HMz,CDCl3);δ7.80(s,1H),7.67(s,1H),7.15(s, 1H),3.93(s,3H),2.51(s,3H),1.62(s,9H)
步骤B:1-BOC-5-溴甲基-7-硝基-吲哚-2-甲酸甲酯
将步骤A中制备的1-BOC-5-甲基-7-硝基-吲哚-2-甲酸甲酯(34g,101.7mmol)溶于四氯化碳(100mL)。向其中加入N-溴琥珀酰亚胺(27.2g,152.6mmol)并且向其中加入AIBN(1.7g,10.2mmol),将该混合物在80℃下搅拌5h。在反应完成后,在减压下蒸馏该反应混合物,通过柱色谱法纯化,得到标题化合物(48.0g,收率100%)。
1H-NMR(500HMz,CDCl3);δ8.01(s,1H),7.90(s,1H),7.21(s,1H),4.60(s,2H),3.93(s,3H),1.62(s,9H)
步骤C:5-溴甲基-7-硝基-吲哚-2-甲酸甲酯
根据与制备例31步骤E相同的方法使步骤B中制备的1-BOC-5-溴甲基-7-硝基-吲哚-2-甲酸甲酯反应,得到标题化合物。
质谱[M+H]=313(M+1)
制备例38:5-羟基甲基-7-硝基-1H-吲哚-2-甲酸
步骤A:1-BOC-5-乙酰氧基甲基-7-硝基-吲哚-2-甲酸甲酯
将制备例37步骤B中制备的1-BOC-5-溴甲基-7-硝基-吲哚-2-甲酸甲酯(10.0g,24.2mmol)溶于N,N-二甲基甲酰胺(50mL)。向其中加入乙酸钠(2.4g,29.0mmol),将该混合物在室温下搅拌4h。在反应完成后,通过在减压下蒸馏除去溶剂。用乙酸乙酯萃取残余物,用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥。通过柱色谱法纯化残余物,得到标题化合物(4.7g,收率50%)。
1H-NMR(500HMz,CDCl3);δ7.99(s,1H),7.90(s,1H),7.21(s,1H),5.22(s,2H),3.94(s,3H),2.12(s,3H),1.63(s,9H)
步骤B:5-乙酰氧基甲基-7-硝基-1H-吲哚-2-甲酸甲酯
将步骤A中制备的1-BOC-5-乙酰氧基甲基-7-硝基-吲哚-2-甲酸 甲酯(4.7g,12.0mmol)溶于二氯甲烷(50mL)。向其中加入2N盐酸溶液(30mL,60mmol),将该混合物在室温下搅拌12h。在减压下蒸馏该反应混合物而得到固体标题化合物(3.5g,收率100%)。
1H-NMR(500HMz,CDCl3);δ10.33(br s,1H),8.32(s,1H),8.06(s,1H),7.34(s,1H),5.24(s,2H),3.99(s,3H),2.12(s,3H)
步骤C:5-羟基甲基-7-硝基-1H-吲哚-2-甲酸
将步骤B中制备的5-乙酰氧基甲基-7-硝基-1H-吲哚-2-甲酸甲酯(3.5g,12.0mmol)溶于四氢呋喃、甲醇和水(1∶1∶1,100mL)的溶剂混合物。向其中加入氢氧化锂水合物(1.5g,35.9mmol),将该混合物在室温下搅拌3h。在反应完成后,通过在减压下蒸馏除去甲醇和四氢呋喃。向残余物中加入1N盐酸。用乙酸乙酯萃取该反应混合物,用无水硫酸镁干燥,在减压下蒸馏以除去溶剂。通过柱色谱法纯化残余物,得到标题化合物(2.3g,收率81%)。
1H-NMR(500HMz,DMSO-d6);δ11.02(br s,1H),8.21(s,1H),8.10(s,1H),7.34(s,1H),5.43(br s,1H),4.64(s,2H)
制备例39:5-(1,3-二氧代-1,3-二氢-异吲哚-2-基甲基)-7-硝基-1H-吲哚-2-甲酸甲酯
步骤A:1-BOC-5-(1,3-二氧代-1,3-二氢-异吲哚-2-基甲基)-7-硝基-1H-吲哚-2-甲酸甲酯
将制备例37步骤B中制备的1-BOC-5-溴甲基-7-硝基-吲哚-2-甲酸甲酯(4.9g,11.4mmol)溶于N,N-二甲基甲酰胺(50mL)。向其中加入邻苯二甲酰亚胺钾(2.7g,14.8mmol),将该混合物在室温下搅拌4h。加入水以使反应停止。用乙酸乙酯萃取该反应混合物,用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥。通过在减压下蒸馏除去溶剂,通过柱色谱法纯化残余物,得到标题化合物(3.6g,收率66%)。
1H-NMR(500HMz,CDCl3);δ8.04(s,1H),7.98(s,1H),7.85(m, 2H),7.71(m,2H),7.17(s,1H),4.96(s,2H),4.37(q,2H),1.59(s,9H),1.39(t,3H)
步骤B:5-(1,3-二氧代-1,3-二氢-异吲哚-2-基甲基)-7-硝基-1H-吲哚-2-甲酸甲酯
根据与制备例38步骤B相同的方法使步骤A中制备的1-BOC-5-(1,3-二氧代-1,3-二氢-异吲哚-2-基甲基)-7-硝基-1H-吲哚-2-甲酸甲酯反应,得到标题化合物。
质谱[M+H]=379(M+1)
制备例40:2,2-二甲基-丙酸(R)-2-(7-硝基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基甲酯
步骤A:7-硝基-1H-吲哚-2-甲酸
将制备例17中制备的7-硝基-1H-吲哚-2-甲酸甲酯(13g,59mmol)溶于四氢呋喃和水(1∶1,300mL)的溶剂混合物,向其中加入1N氢氧化钠水溶液(180mL,177mmol)。将该混合物在室温下搅拌3h并且向其中加入过量6N盐酸溶液。用乙酸乙酯萃取该反应混合物。用饱和氯化钠水溶液洗涤萃取物,用无水硫酸镁干燥并且过滤。通过在减压下蒸馏除去溶剂并且干燥残余物,得到标题化合物(12g,收率99%)。
步骤B:2,2-二甲基-丙酸(R)-3-(4-甲氧基-苄基硫烷基)-2-[(7-硝基-1H-吲哚-2-羰基)-氨基]-丙酯
将步骤A中制备的7-硝基-1H-吲哚-2-甲酸(8.2g,22.7mmol)和制备例31中制备的2,2-二甲基-丙酸(R)-2-氨基-3-(4-甲氧基-苄基硫烷基)-丙酯(13.2g,27.2mmol)溶于N,N-二甲基甲酰胺(100mL)。向其中加入EDC(6.6g,25.0mmol)和HOBT(4.6g,25.0mmol),将该混合物在室温下搅拌8h。向该混合物中加入饱和碳酸氢钠水溶液以使反应停止。用乙酸乙酯萃取该反应混合物,用无水硫酸镁干燥,过滤,在减压下蒸馏。通过柱色谱法纯化残余物,得到标题化合物 (8.1g,收率71%)。
1H-NMR(400HMz,CDCl3);δ10.47(br s,1H),8.27(d,J=8.0Hz,1H),8.01(d,J=8.0Hz,1H),7.26(m,2H),6.93(d,J=4.0Hz,1H),6.83(m,2H),6.74(d,J=8.0Hz,1H),4.56(m,1H),4.44(m,1H),4.24(m,1H),3.74(m,5H),2.77(m,1H),2.62(m,1H),1.18(s,9H)
步骤C:2,2-二甲基-丙酸[(R)-2-(7-硝基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-甲酯
将步骤B中制备的2,2-二甲基-丙酸(R)-3-(4-甲氧基-苄基硫烷基)-2-[(7-硝基-1H-吲哚-2-羰基)-氨基]-丙酯(1.6g,3.2mmol)溶于二氯甲烷(50mL)。向其中加入五氯化磷(1.3g,6.4mmol),将该混合物在室温下搅拌5h。向该混合物中加入饱和碳酸氢钠水溶液以使反应停止。用乙酸乙酯萃取该反应混合物,用无水硫酸镁干燥,过滤,在减压下蒸馏。通过柱色谱法纯化残余物而得到标题化合物(0.8g,收率69%)。
1H-NMR(400HMz,CDCl3);δ10.53(br s,1H),8.26(d,J=8.0Hz,1H),7.99(d,J=8.0Hz,1H),7.04(d,J=2.0Hz,1H),6.90(d,J=7.6Hz,1H),4.78(m,1H),4.46(m,1H),4.30(m,1H),3.59(m,1H),3.36(m,1H),1.20(s,9H)
制备例41:2,2-二甲基-丙酸(R)-2-[(5-氯甲基-7-硝基-1H-吲哚-2-基)-(4,5-二氢-噻唑-4-基)甲酯
步骤A:2,2-二甲基-丙酸(R)-2-[(5-羟基甲基-7-硝基-1H-吲哚-2-羰基)-氨基]-3-(4-甲氧基-苄基硫烷基)-丙酯
根据与制备例40步骤B相同的方法使制备例38中制备的5-羟基甲基-7-硝基-1H-吲哚-2-甲酸和制备例31中制备的2,2-二甲基-丙酸(R)-2-氨基-3-(4-甲氧基-苄基硫烷基)-丙酯反应,得到标题化合物。
步骤B:2,2-二甲基-丙酸(R)-2-[(5-氯甲基-7-硝基-1H-吲哚-2-基)-(4,5-二氢-噻唑-4-基)甲酯
根据与制备例40步骤C相同的方法使步骤A中制备的2,2-二甲基-丙酸(R)-2-[(5-羟基甲基-7-硝基-1H-吲哚-2-羰基)-氨基]-3-(4-甲氧基-苄基硫烷基)-丙酯反应,得到标题化合物。
质谱[M+H]=395(M+1)
制备例42:(R)-2-[(5-氯甲基-7-硝基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]乙酸甲酯
根据与制备例40步骤B和C相同的方法使制备例38中制备的5-羟基甲基-7-硝基-1H-吲哚-2-甲酸和制备例27中制备的(R)-3-氨基-4-(4-甲氧基-苄基硫烷基)-丁酸甲酯盐酸盐反应,得到标题化合物。
质谱[M+H]=353(M+1)
制备例43:2,2-二甲基-丙酸(R)-2-[5-(2,2-二甲基-丙酰氧基甲基)-7-硝基-1H-吲哚-2-基]-4,5-二氢-噻唑-4-基-甲酯
步骤A:2,2-二甲基-丙酸(R)-2-{[5-(2,2-二甲基-丙酰氧基甲基)-7-硝基-1H-吲哚-2-羰基]-氨基}-3-(4-甲氧基-苄基硫烷基)-丙酯
将制备例41步骤A中制备的2,2-二甲基-丙酸(R)-2-[(5-羟基甲基-7-硝基-1H-吲哚-2-羰基)-氨基]-3-(4-甲氧基-苄基硫烷基)-丙酯(3.1g,6.01mmol)溶于DCM,向其中加入Et3N(1.68mL,12.02mmol)。向其中加入新戊酰氯(0.92mL,6.61mmol),将该混合物在室温下搅拌12h。在反应完成后,减压除去溶剂,通过柱色谱法纯化残余物(洗脱剂:EtOAc/n-Hex=1/1),得到标题化合物。
步骤B:2,2-二甲基-丙酸(R)-2-{[5-(2,2-二甲基-丙酰氧基甲基)-7-硝基-1H-吲哚-2-基]-4,5-二氢-噻唑-4-基-甲酯
根据与制备例40步骤C相同的方法使步骤A中制备的2,2-二甲 基-丙酸(R)-2-{[5-(2,2-二甲基-丙酰氧基甲基)-7-硝基-1H-吲哚-2-羰基]-氨基}-3-(4-甲氧基-苄基硫烷基)-丙酯反应,得到标题化合物。
质谱[M+H]=475(M+1)
制备例44:2,2-二甲基-丙酸(R)-2-{[5-甲磺酰基甲基-7-硝基-1H-吲哚-2-基]-4,5-二氢-噻唑-4-基-甲酯
步骤A:(5-甲磺酰基甲基-7-硝基-1H-吲哚-2-基)-甲酸甲酯
将制备例37中制备的5-溴甲基-7-硝基-吲哚-2-甲酸甲酯(251mg,0.805mmol)加入到DMF(8mL)中。向其中加入NaSO2Me(290mg,2.415mmol),将该混合物在室温下搅拌2h。用饱和NaHCO3水溶液使反应停止。用EtOAc萃取该反应混合物,用无水硫酸镁干燥。减压除去溶剂,将该残余物不经进一步纯化而用于下一步反应。
步骤B:2,2-二甲基-丙酸(R)-2-{[5-甲磺酰基甲基-7-硝基-1H-吲哚-2-基]-4,5-二氢-噻唑-4-基-甲酯
根据与制备例40相同的方法使步骤A中制备的(5-甲磺酰基甲基-7-硝基-1H-吲哚-2-基)-甲酸甲酯和制备例31中制备的2,2-二甲基-丙酸(R)-2-氨基-3-(4-甲氧基-苄基硫烷基)-丙酯反应,得到标题化合物。
质谱[M+H]=453(M+1)
制备例45:(R)-2-[5-甲磺酰基甲基-7-硝基-1H-吲哚-2-基]-4,5-二氢-噻唑-4-基-乙酸甲酯
根据与制备例40相同的方法使制备例44步骤A中制备的(5-甲磺酰基甲基-7-硝基-1H-吲哚-2-基)-甲酸甲酯和制备例27中制备的(R)-3-氨基-4-(4-甲氧基-苄基硫烷基)-丁酸甲酯盐酸盐反应,得到标题化合物。
质谱[M+H]=411(M+1)
制备例46至91
根据选自制备例40-45的方法,选择性地将制备例14-26、38和39的化合物和制备例27-36的化合物用于合成下表中的制备例化合物。
制备例 | R1 | * | n | R2 | 质谱[M+H] |
46 | MeO2C- | R | 1 | (吡啶-3-基)氧基 | 412 |
47 | (t-Bu)C(O)O | R | 1 | (吡啶-3-基)氧基 | 454 |
48 | MeO2C- | R | 1 | 4-(甲磺酰基)苯氧基 | 489 |
49 | MeO2C- | R | 1 | 甲氧基 | 347 |
50 | MeO2C- | R | 2 | 甲氧基 | 361 |
51 | MeO2C- | R | 1 | 甲氧基 | 347 |
52 | (i-Pr)O2C- | S | 1 | 甲基 | 361 |
53 | (t-Bu)C(O)O | R | 1 | 甲基 | 375 |
54 | EtO2C- | R | 1 | 甲基 | 347 |
55 | EtO2C- | S | 2 | 甲基 | 361 |
56 | EtO2C- | R | 2 | 甲基 | 361 |
57 | EtO2C- | R | 2 | 溴 | 412 |
58 | MeO2C- | R | 1 | 溴 | 386 |
59 | (t-Bu)C(O)O | R | 1 | 溴 | 440 |
60 | (t-Bu)C(O)O | R | 1 | 乙酰基氨基 | 418 |
61 | MeO2C- | S | 1 | 乙氧基 | 363 |
62 | EtO2C- | R | 2 | 乙氧基 | 391 |
63 | MeO2C- | R | 1 | 乙氧基 | 363 |
64 | EtO2C- | R | 1 | 氯 | 367 |
65 | (t-Bu)C(O)O | R | 1 | 氯 | 395 |
66 | (i-Pr)O2C- | S | 1 | 氯 | 381 |
67 | MeO2C- | R | 1 | 氯 | 353 |
68 | MeO2C- | R | 2 | 氯 | 367 |
69 | 异丁基 | R | 0 | 氯 | 323 |
70 | MeO2C- | R | 1 | 苯氧基 | 411 |
71 | (i-Pr)O2C- | S | 1 | 苯氧基 | 439 |
72 | MeO2C- | R | 2 | 苯氧基 | 425 |
73 | MeO2C- | R | 1 | 苯基氨基甲基 | 424 |
74 | 乙基 | R | 0 | 氟 | 293 |
75 | EtO2C- | R | 1 | 氟 | 351 |
76 | EtO2C- | R | 2 | 氟 | 365 |
77 | (t-Bu)C(O)O | R | 1 | 氟 | 379 |
78 | (t-Bu)C(O)O | R | 1 | CH2-(异吲哚-1,3-二酮 -1-基) | 520 |
79 | MeO2C- | R | 1 | CH2-(异吲哚-1,3-二酮 -1-基) | 478 |
80 | (t-Bu)C(O)OCH2 | R | 1 | H | 361 |
81 | MeO2C- | R | 1 | H | 319 |
82 | (i-Pr)O2C- | S | 1 | H | 347 |
83 | EtO2C- | R | 2 | H | 347 |
84 | (t-Bu)C(O)OCH2 | S | 1 | H | 361 |
85 | 甲基 | R | 0 | H | 261 |
86 | 乙基 | R | 0 | H | 275 |
87 | MeO2C- | R | 0 | H | 305 |
88 | (t-Bu)C(O)O | R | 2 | H | 375 |
89 | MeO2C- | R | 1 | O(n-Pr) | 363 |
90 | EtO2C- | R | 2 | OCF3 | 417 |
91 | t-BuC(O)O | R | 2 | OCH3 | 391 |
制备例92:2,2-二甲基-丙酸[(R)-2-(5-二甲氨基甲基-7-硝基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]甲酯
将制备例41中制备的2,2-二甲基-丙酸[(R)-2-(5-氯甲基-7-硝基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]甲酯(1.0g,2.4mmol)溶于二甲亚砜(15mL)。向其中加入二异丙基乙胺(0.6g,4.9mmol)和二甲胺(0.2g,4.9mmol),将该混合物在室温下搅拌6h。在反应完成后,加入水。用乙酸乙酯萃取该反应混合物,用无水硫酸镁干燥并且过滤。在减压下蒸馏滤液,通过柱色谱法纯化,得到标题化合物(0.7g,收率71%)。
质谱[M+H]=418(M+1)
制备例93:2,2-二甲基-丙酸{(R)-2-[5-(吗啉-4-基)甲基-7-硝基-1H-吲哚-2-基]-4,5-二氢-噻唑-4-基}甲酯
根据与制备例92相同的方法使制备例41中制备的2,2-二甲基-丙酸[(R)-2-(5-氯甲基-7-硝基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]甲酯和吗啉反应,除了将DMF代替DMSO用作溶剂,得到标题化合物。
质谱[M+H]=460(M+1)
制备例94:2,2-二甲基-丙酸{(R)-2-[5-(吡唑-1-基)甲基-7-硝基-1H-吲哚-2-基]-4,5-二氢-噻唑-4-基}甲酯
根据与制备例92相同的方法使制备例41中制备的2,2-二甲基-丙酸[(R)-2-(5-氯甲基-7-硝基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]甲酯和吡唑反应,除了将DMF代替DMSO用作溶剂,得到标题化合物。
质谱[M+H]=441(M+1)
制备例95:2,2-二甲基-丙酸{(R)-2-[5-(1,3-咪唑-1-基)甲基-7-硝基-1H-吲哚-2-基]-4,5-二氢-噻唑-4-基}甲酯
根据与制备例92相同的方法使制备例41中制备的2,2-二甲基-丙酸[(R)-2-(5-氯甲基-7-硝基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]甲酯和1,3-咪唑反应,除了将DMF代替DMSO用作溶剂,得到标题化合物。
质谱[M+H]=441(M+1)
制备例96:2,2-二甲基-丙酸{(R)-2-[5-(1,2,4-三唑-1-基)甲基-7-硝基-1H-吲哚-2-基]-4,5-二氢-噻唑-4-基}甲酯
根据与制备例92相同的方法使制备例41中制备的2,2-二甲基-丙酸[(R)-2-(5-氯甲基-7-硝基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]甲酯和1,2,4-三唑反应,除了将DMF代替DMSO用作溶剂,得到标题化合物。
质谱[M+H]=442(M+1)
制备例97:2,2-二甲基-丙酸{(R)-2-[5-(吡咯-1-基)甲基-7-硝基-1H-吲哚-2-基]-4,5-二氢-噻唑-4-基}甲酯
根据与制备例92相同的方法使制备例41中制备的2,2-二甲基-丙酸[(R)-2-(5-氯甲基-7-硝基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]甲酯和吡咯反应,除了将DMF代替DMSO用作溶剂,得到标题化合物。
质谱[M+H]=440(M+1)
制备例98:[(R)-2-(7-硝基-5-苯氧基甲基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸甲酯
将苯酚(192mg,2.04mmol)溶于DMF。加入NaH(60%矿物油,82mg,2.04mmol),将该反应溶液冷却至0℃。向其中缓慢加入在制备例42中制备的溶于DMF的(R)-2-(5-氯甲基-7-硝基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基-乙酸甲酯(500mg,1.36mmol)。将该反应 溶液温至室温并且搅拌4h。在加入饱和NH4Cl水溶液以使反应停止后,用EtOAc萃取该反应混合物,用MgSO4干燥并且过滤。减压除去溶剂,通过柱色谱法纯化残余物(洗脱剂:EtOAc/n-Hex=1/2),得到标题化合物。
质谱[M+H]=425(M+1)
制备例99:2,2-二甲基-丙酸{(R)-2-[7-硝基-5-(苯基氨基)甲基-1H-吲哚-2-基]-4,5-二氢-噻唑-4-基}甲酯
根据与制备例98相同的方法使制备例42中制备的(R)-2-(5-氯甲基-7-硝基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基-乙酸甲酯和苯胺反应,得到标题化合物。
质谱[M+H]=466(M+1)
制备例100:2,2-二甲基-丙酸{(R)-2-[7-硝基-5-(吡咯烷-1-基)甲基-1H-吲哚-2-基]-4,5-二氢-噻唑-4-基}甲酯
根据与制备例92相同的方法,使制备例41中制备的2,2-二甲基-丙酸(R)-2-[(5-氯甲基-7-硝基-1H-吲哚-2-基)-(4,5-二氢-噻唑-4-基)甲酯和吡咯烷反应,除了将DMF代替DMSO用作溶剂,得到标题化合物。
质谱[M+H]=444(M+1)
制备例101:2-(4,5-二氢-噻唑-2-基)-7-硝基-1H-吲哚
步骤A:7-硝基-1H-吲哚-2-甲酸
将商购7-硝基吲哚-2-甲酸乙酯(500mg,2.14mmol)溶于四氢呋喃和水(1∶1,20mL)的溶剂混合物。向其中加入氢氧化锂水合物(448mg,10.7mmol),将该混合物在室温下搅拌8h。加入1N-盐酸溶液,用乙酸乙酯萃取该反应混合物。用无水硫酸镁干燥并过滤萃取物。在减压下蒸馏滤液,得到标题化合物。
步骤B:7-硝基-1H-吲哚-2-甲酸(2-氯-乙基)-酰胺
将步骤A中制备的7-硝基-1H-吲哚-2-甲酸(371mg,3.2mmol)溶于N,N-二甲基甲酰胺(10mL)。加入三乙胺(0.6mL,4.3mmol)、EDC(614mg,3.2mmol)和HOBT(433mg,3.2mmol),加入2-氯乙胺(252.8mg,3.2mmol),将该混合物在室温下搅拌8h。加入1N-盐酸溶液,用乙酸乙酯萃取该反应混合物,用饱和碳酸氢钠水溶液洗涤,用无水硫酸镁干燥并且过滤。在减压下蒸馏滤液,得到标题化合物。
1H NMR(400MHz,CDCl3);δ10.51(br s,1H),8.28(d,J=6.4Hz,1H),8.02(d,J=6.4Hz,1H),7.27(t,1H),7.03(s,1H),6.62(brs,1H),3.86(m,2H),3.77(m,2H)
步骤C:2-(4,5-二氢-噻唑-2-基)-7-硝基-1H-吲哚
将步骤B中制备的7-硝基-1H-吲哚-2-甲酸(2-氯-乙基)-酰胺(267mg,1mmol)溶于二氯乙烷(10mL)并且向其中加入甲苯(10mL)和Lawessson试剂(1.29g,3.2mmol)。将该混合物回流4h,在减压下蒸馏。向其中加入水,用乙酸乙酯萃取该反应混合物,用无水硫酸镁干燥并且过滤。在减压下蒸馏滤液,通过柱色谱法纯化浓缩物而得到标题化合物,为环化反应产物(148mg,收率60%)。
1H-NMR(400HMz,CDCl3);δ10.49(br s,1H),8.24(d,J=8.0Hzm1H),7.98(d,J=7.6Hz,1H),7.23(t,1H),7.02(s,1H),4.47(t,2H),3.51(t,2H)
制备例102:[(S)-2-(5-氯-7-硝基-1H-吲哚-2-基)-4,5-二氢噁唑-4-基]-甲酸异丙酯
步骤A:(S)-3-氨基-4-羟基-丁酸异丙酯
根据与制备例29的步骤A至D相同的方法使制备例30步骤A中制备的(S)-2-BOC-氨基-琥珀酸4-异丙酯1-甲酯依次反应,得到标题化合物。
步骤B:[(S)-3-(5-氯-7-硝基-1H-吲哚-2-羰基)-氨基]-4-羟基-丁酸异丙酯
根据与制备例40步骤B相同的方法,使根据制备例40步骤A,通过水解制备例14中制备的5-氯-7-硝基-1H-吲哚-2-甲酸甲酯而获得的5-氯-7-硝基-1H-吲哚-2-甲酸和步骤A中制备的(S)-3-氨基-4-羟基-丁酸异丙酯反应,得到标题化合物。
步骤C:[(S)-3-(5-氯-7-硝基-1H-吲哚-2-羰基)-氨基]-4-甲磺酰氧基-丁酸异丙酯
根据与制备例29步骤B相同的方法使步骤B中制备的[(S)-3-(5-氯-7-硝基-1H-吲哚-2-羰基)-氨基]-4-羟基-丁酸异丙酯反应,得到标题化合物。
步骤D:[(S)-2-(5-氯-7-硝基-1H-吲哚-2-基)-4,5-二氢 噁唑-4-基]-甲酸异丙酯
将步骤C中制备的[(S)-3-(5-氯-7-硝基-1H-吲哚-2-羰基)-氨基]-4-甲磺酰氧基-丁酸异丙酯(930mg,2mmol)加入到THF(10mL)中。向其中加入K2CO3(330mg,10mmol),将该混合物在80℃下搅拌2h。加入水以使反应停止。用EtOAc萃取该反应混合物,用MgSO4干燥。减压除去溶剂,通过柱色谱法纯化残余物(洗脱剂:EtOAc/n-Hex/DMC=1/4/1),得到标题化合物(445mg,收率61%)。
质谱[M+H]=365(M+1)
制备例103:(1S,2R)-(3-氨基-1-苄基-2-羟基-丙基)-氨基甲酸叔丁酯
步骤A:(1S,2R)-(3-叠氮基-1-苄基-2-羟基-丙基)-氨基甲酸叔丁酯
将商购(1-环氧乙烷-2-苯基-乙基)-氨基甲酸叔丁酯(2.6g,10 mmol)溶于DMF(30mL)。向其中加入叠氮化钠(655mg,10mmol),将该混合物在80℃下搅拌12h。加入水以使反应停止。用EtOAc萃取该反应混合物,用MgSO4干燥。减压除去溶剂,通过柱色谱法纯化残余物,得到标题化合物(2.75g,收率90%)。
步骤B:(1S,2R)-(3-氨基-1-苄基-2-羟基-丙基)-氨基甲酸叔丁酯
将步骤A中制备的(1S,2R)-(3-叠氮基-1-苄基-2-羟基-丙基)-氨基甲酸叔丁酯(2.5g,8.17mmol)溶于甲醇(15mL),向其中加入Pd/C(100mg)。使该混合物在氢气反应器(50psi)中反应12h,通过硅藻土过滤。减压除去溶剂,不经进一步纯化将残余物用于下一步反应。
质谱[M+H]=280(M+1)
制备例104:[(1S,2R)-1-苄基-3-(1,3-二氧代-1,3-二氢-异吲哚-2-基)-2-羟基-丙基]氨基甲酸叔丁酯
将制备例103中制备的(1R,2S)-(3-氨基-1-苄基-2-羟基-丙基)-氨基甲酸叔丁酯(1.4g,5mmol)溶于DMF(20mL),向其中加入邻苯二甲酸酐(735mg,5mmol)。再向其中加入Et3N(1.4mL,10mmol),将该混合物在80℃下搅拌24h。用水使反应停止,用EtOAc萃取该反应混合物,用MgSO4干燥。减压除去溶剂,将残余物溶于DCM。向其中加入TFA,将该混合物在室温下搅拌2h。在反应完成后,减压除去溶剂。使残余物从DCM/Hex(DCM/己烷)中重结晶,得到标题化合物(1.18g,收率71%)。
质谱[M+H]=410(M+1)
制备例105至109:
根据与制备例101中相同的方法使制备例14,15和17中制备的吲哚-2-甲酸酯类和商购或在制备例103和104中制备的氨基乙醇衍生物反应,以合成下表中的制备例化合物。
制备例110:2-(噻唑-2-基)-7-硝基-1H-吲哚
步骤A:7-硝基-1H-吲哚-2-硫代羟酸酰胺
根据与制备例101步骤B和C相同的方法使制备例101步骤A中制备的7-硝基-1H-吲哚-2-甲酸和氯化铵反应,得到标题化合物。
步骤B:2-(噻唑-2-基)-7-硝基-1H-吲哚
将步骤A中制备的7-硝基-1H-吲哚-2-硫代羟酸酰胺(1.15g,5mmol)溶于DMF(15mL)。向其中加入2-溴-1,1-二氧基乙烷(985mg,5mmol),将该混合物在100℃下和回流中搅拌2h。用水使反应停止,用EtOAc萃取该反应混合物,用MgSO4干燥。减压除去溶剂,通过柱色谱法纯化残余物,得到标题化合物(612mg,收率65%)。
质谱[M+H]=245(M+1)
制备例111:2-(7-硝基-1H-吲哚-2-基)-噻唑-4-甲酸甲酯
根据与制备例110相同的方法使制备例110步骤A中制备的3-氯 -2-氧代-丙酸甲酯和7-硝基-1H-吲哚-2-硫代羟酸酰胺反应,得到标题化合物。
质谱[M+H]=303(M+1)
制备例112:[2-(7-硝基-1H-吲哚-2-基)-噻唑-4-基]-甲醇
根据与制备例29步骤A相同的方法使制备例111中制备的2-(7-硝基-1H-吲哚-2-基)-噻唑-4-甲酸甲酯反应,得到标题化合物。
质谱[M+H]=275(M+1)
制备例113:2-(5-甲基-7-硝基-1H-吲哚-2-基)-噻唑-4-甲酸乙酯
步骤A:(5-甲基-7-硝基-1H-吲哚-2-基)硫代羟酸酰胺
根据与制备例110步骤A相同的方法使(5-甲基-7-硝基-1H-吲哚-2-基)甲酸反应,得到标题化合物。
步骤B:2-(5-甲基-7-硝基-1H-吲哚-2-基)-噻唑-4-甲酸乙酯
根据与制备例110步骤B相同的方法使步骤A中制备的(5-甲基-7-硝基-1H-吲哚-2-基)硫代羟酸酰胺和3-氯-2-氧代-丙酸乙酯反应,得到标题化合物。
质谱[M+H]=331(M+1)
制备例114:[2-(5-甲基-7-硝基-1H-吲哚-2-基)-噻唑-4-基]-甲醇
根据与制备例29步骤A相同的方法使制备例113中制备的2-(5-甲基-7-硝基-1H-吲哚-2-基)-噻唑-4-甲酸甲酯反应,得到标题化合物。
质谱[M+H]=289(M+1)
制备例115:[5-(7-硝基-1H-吲哚-2-基)-[1,2,4]噁二唑-3-基]-乙酸甲酯
步骤A:2-(N-羟基脒基(carbamimidoyl))-乙酸甲酯
将2-氰基-乙酸甲酯(990mg,10mmol)溶于THF(30mL)。向其中加入羟基胺(690mg,HCl盐,10mmol),将该混合物在80℃下搅拌2h。在反应完成后,加入1N HCl。用EtOAc萃取该反应混合物,用MgSO4干燥。减压除去溶剂,将残余物不经进一步纯化而用于下一步反应。
步骤B:3-(羟基亚氨基)-3-[(7-硝基-1H-吲哚-2-羰基)-氨基]-丙酸甲酯
根据与制备例101步骤B相同的方法使步骤A中制备的2-(N-羟基脒基)-乙酸甲酯和制备例101步骤A中制备的7-硝基-1H-吲哚-2-甲酸反应,得到标题化合物。
步骤C:2-[5-(7-硝基-1H-吲哚-2-基)-[1,2,4]噁二唑-3-基]-乙酸甲酯
将步骤B中制备的3-(羟基氨基)-3-[(7-硝基-1H-吲哚-2-羰基)-氨基]-丙酸甲酯(960mg,1mmol)溶于DMF(10mL)。向其中加入吡啶(1mL),将该混合物在80℃下搅拌4h。用NH4Cl水溶液使反应停止。用EtOAc萃取该反应混合物,用MgSO4干燥。减压除去溶剂,通过柱色谱法纯化残余物,得到标题化合物(830mg,收率90%)。
质谱[M+H]=302(M+1)
制备例116:2-[5-(7-硝基-1H-吲哚-2-基)-[1,2,4]噁二唑-3-基]-乙醇
根据与制备例29步骤A相同的方法使制备例115中制备的2-[5-(7-硝基-1H-吲哚-2-基)-[1,2,4]噁二唑-3-基]-乙酸甲酯反应,得到标题化合物。
质谱[M+H]=274(M+1)
制备例117:5-甲基-7-硝基-2-[1,3,4]噁二唑-2-基-1H-吲哚
将制备例15中制备的5-甲基-7-硝基-1H-吲哚-2-甲酸甲酯(234mg,1mmol)溶于甲醇(10mL),向其中加入肼(3mL)。将该反应溶液回流3h,减压浓缩。向浓缩物中加入原甲酸三甲酯(10mL),将该混合物回流8h。在减压下蒸馏该反应混合物,用乙酸乙酯洗涤得到的固体,得到标题化合物(49mg,收率20%)。
实施例1:环戊基-[2-(4,5-二氢-1,3-噻唑-2-基)-1H-吲哚-7-基]-胺
步骤A:[2-(4,5-二氢-1,3-噻唑-2-基)-1H-吲哚-7-基]-胺
根据与制备例1步骤B相同的方法使制备例101中制备的2-(4,5-二氢-噻唑-2-基)-7-硝基-1H-吲哚反应,得到标题化合物。
步骤B:环戊基-[2-(4,5-二氢-1,3-噻唑-2-基)-1H-吲哚-7-基]-胺
将步骤A中制备的[2-(4,5-二氢-1,3-噻唑-2-基)-1H-吲哚-7-基]-胺(15mg,0.07mmol)溶于1,2-二氯乙烷(10mL)。向其中加入环戊酮(12mg,0.14mmol)和三乙酰氧基硼氢化钠(29mg,0.14mmol),将该混合物搅拌3h在室温下。用水使反应停止,用乙酸乙酯萃取该反应混合物,用无水硫酸镁干燥并且过滤。减压除去溶剂,通过柱色谱法纯化残余物,得到标题化合物(6.7mg,收率34%)。
1H-NMR(400HMz,CDCl3);δ10.27(s,1H),7.06(d,J=8.0Hz,1H),7.00(t,J=7.6Hz,1H),6.92(s,1H),6.52(d,J=7.2Hz,1H),4.42(m,2H),4.38(m,1H),4.35(m,2H),2.00(m,2H),1.64(m,4H),1.46(m,2H)
实施例2:[(R)-2-(7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-1,3-噻唑-4-基]-甲醇
步骤A:2,2-二甲基-丙酸[(R)-2-(7-环戊基氨基)-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]甲酯
根据与实施例1步骤B相同的方法使制备例40中制备的2,2-二甲基-丙酸(R)-2-(7-氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基甲酯反应,得到标题化合物。
步骤B:[(R)-2-(7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-1,3-噻唑-4-基]-甲醇
根据与制备例29步骤A相同的方法使步骤A中制备的2,2-二甲基-丙酸[(R)-2-(7-环戊基氨基)-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]甲酯反应,得到标题化合物。
1H-NMR(500HMz,CDCl3);δ11.17~11.08(m,1H),7.09(m,1H),6.99(t,1H),6.96(s,1H),6.52(m,1H),4.72(m,1H),4.04(m,1H),3.75(m,1H),3.65(m,1H),3.51(m,1H),3.40(m,1H),1.90(m,2H),1.60~1.49(m,4H),1.41~1.24(m,2H)
实施例3:[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸甲酯
根据与实施例1步骤A和B相同的方法使制备例67中制备的[(R)-2-(5-氯-7-硝基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸甲酯和环戊酮反应,得到标题化合物。
1H NMR(DMSO-d6,ppm);δ11.51(s,1H),6.79(s,1H),6.79(s,1H),6.16(s,1H),6.13(d,1H),4.85(m,1H),3.80(m,1H),3.62(m,1H),3.58(s,3H),3.19(m,1H),2.71(m,1H),2.63(m,1H),1.93(m,2H),1.69(m,2H),1.56(m,4H)
实施例4:[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸
根据与制备例29步骤A相同的方法使实施例3中制备的[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4- 基]-乙酸甲酯反应,得到标题化合物。
1H NMR(DMSO-d6,ppm);δ12.51(br s,1H),11.51(s,1H),6.79(s,1H),6.79(s,1H),6.16(s,1H),6.14(d,1H),4.87(m,1H),3.80(m,1H),3.61(m,1H),3.19(m,1H),2.72(m,1H),2.64(m,1H),1.93(m,2H),1.69(m,2H),1.56(m,4H)
实施例5:2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙醇
将实施例4中制备的[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸(391mg,1mmol)溶于DCM(10mL)。向其中加入三乙胺(280μl,2mmol)和异丁酰氯(106mg,1mmol),将该混合物在0℃下搅拌30分钟。在反应完成后,减压除去溶剂。用THF稀释残余物。向其中加入NaBH4(74mg,2mmol),将该混合物搅拌12h。用少量水使反应停止。向该反应混合物中加入过量水,然后搅拌30min,用EtOAc萃取,用MgSO4干燥并且过滤。减压除去溶剂,通过柱色谱法纯化残余物,得到标题化合物(272mg,收率72%)。
1H NMR(400MHz,DMSO-d6);δ11.47(s,1H),6.79(s,1H),6.67(s,1H),6.11(s,1H),6.09(m,1H),4.65(t,1H),4.54(m,1H),3.80(m,2H),3.61(m,2H),3.52(m,1H),3.15(m,1H),2.47(m,1H),1.97(m,2H),1.68(m,2H),1.54(m,4H)
实施例6:(R)-2-[7-环戊基氨基-5-(羟基甲基)-1H-吲哚-2-基]-4,5-二氢-噻唑-4-基-甲醇
步骤A:2,2-二甲基-丙酸(R)-2-[7-环戊基氨基-5-(2,2-二甲基-丙酰氧基甲基)-1H-吲哚-2-基]-4,5-二氢-噻唑-4-基-甲酯
根据与实施例1相同的方法使制备例43中制备的2,2-二甲基-丙酸(R)-2-[5-(2,2-二甲基-丙酰氧基甲基)-7-硝基-1H-吲哚-2-基]-4,5-二氢-噻唑-4-基-甲酯和环戊酮反应,得到标题化合物。
步骤B:(R)-2-[7-环戊基氨基-5-(羟基甲基)-1H-吲哚-2-基]-4,5-二氢-噻唑-4-基-甲醇
根据与制备例29步骤A相同的方法使步骤A中制备的2,2-二甲基-丙酸(R)-2-[7-环戊基氨基-5-(2,2-二甲基-丙酰氧基甲基)-1H-吲哚-2-基]-氨基}-4,5-二氢-噻唑-4-基-甲酯反应,得到标题化合物。
1H-NMR(400MHz,CDCl3);δ9.63(brs,1H),7.40(s,1H),7.18(s,1H),6.90(s,1H),4.80(m,1H),4.73(s,2H),4.06(m,1H),3.84(m,1H),3.66(m,2H),3.48(m,1H),3.31(m,1H),1.79(m,2H),1.43(m,4H),1.26(m,2H)
实施例7:[2-(4,5-二氢-噻唑-2-基)-1H-吲哚-7-基]-哌啶-4-基-胺
步骤A:[2-(4,5-二氢-噻唑-2-基)-1H-吲哚-7-基]-(1-BOC-哌啶-4-基)-胺
根据与实施例1相同的方法使制备例101中制备的2-(4,5-二氢-噻唑-2-基)-7-硝基-1H-吲哚和1-BOC-4-哌啶酮反应,得到标题化合物。
步骤B:[2-(4,5-二氢-噻唑-2-基)-1H-吲哚-7-基]-哌啶-4-基-胺
根据与制备例29步骤D相同的方法使步骤A中制备的[2-(4,5-二氢-噻唑-2-基)-1H-吲哚-7-基]-(1-BOC-哌啶-4-基)-胺反应,得到标题化合物。
1H-NMR(400HMz,CDCl3,MeOH-d4);δ7.39(s,1H),7.07(d,J=8.0Hz,1H),6.99(t,J=8.0Hz,1H),6.93(s,1H),6.47(d,J=7.6Hz,1H),4.41(m,2H),3.77(m,1H),3.48(m,4H),3.11(m,2H),2.29(m,2H),1.87(m,2H)
实施例8至117:
根据选自实施例1-7的方法使制备例40,48至100中制备的化合物反应,以合成下表中的实施例化合物。
实施例118至123:
根据选自实施例1-7的方法使制备例102和105至109中制备的化合物反应,以合成下表中的实施例化合物。
实施例124:[2-((4S,5R)-5-氨基甲基-4-苄基-二氢-噁唑-2-基)-5-氯-1H-吲哚-7-基]-环戊基-胺
步骤A:2-[(4S,5R)-苄基-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噁唑-5-基甲基]异吲哚-1,3-二酮
根据与实施例1相同的方法使制备例108中制备的2-[(4S,5R)- 苄基-2-(5-氯-7-硝基-1H-吲哚-2-基)-4,5-二氢-噁唑-5-基甲基]异吲哚-1,3-二酮和环戊酮反应,得到标题化合物。
步骤B:[2-((4S,5R)-5-氨基甲基-4-苄基-二氢-噁唑-2-基)-5-氯-1H-吲哚-7-基]-环戊基-胺
将步骤A中制备的2-[(4S,5R)-苄基-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噁唑-5-基甲基]异吲哚-1,3-二酮(50mg,1mmol)溶于乙醇(10mL)。向其中加入肼盐酸盐(1.8mL,0.33mmol),将该混合物在80℃下搅拌4h。在反应完成后,减压除去溶剂,通过柱色谱法纯化残余物,得到标题化合物(16mg,收率39%)。
1H-NMR(400MHz,MeOH-d4);δ7.36-7.18(6H,m),6.95(1H,s),6.75(1H,s),6.27(1H,d,J=1.2Hz),3.84(1H,brs),3.77(1H,brs),3.66-3.56(1H,m),3.34(1H,brs),2.77(2H,brs),1.93(2H,brs),1.54-1.48(6H,m)
实施例125:{2-[(R)-5-((S)-1-氨基-2-苯基-乙基)-4,5-二氢-噁唑-2-基]-5-氯-1H-吲哚-7-基}-环戊基-胺
根据与实施例1相同的方法使制备例107中制备的{(S)-1-[(R)-2-(5-氯-7-硝基-1H-吲哚-2-基)-4,5-二氢-噁唑-5-基]-2-苯基-乙基}-氨基甲酸叔丁酯反应,将由此得到的产物(50mg,1mmol)溶于DCM(2mL)。向其中加入TFA(2mL),将该混合物搅拌2h。减压除去溶剂,通过柱色谱法纯化残余物,得到标题化合物(38mg,收率92%)。
1H-NMR(400MHz,MeOH-d4);δ10.4(1H,brs),7.34-7.31(2H,m),7.27-7.20(3H,m),7.03(1H,d,J=1.6Hz),6.95(1H,s),6.46(1H,d,J=1.6Hz),4.65-4.59(1H,m),4.25-4.04(2H,m),3.92-3.83(2H,m),3.15-3.07(1H,m),2.90-2.85(1H,m),2.72-2.64(1H,m),2.05-2.00(2H,m),1.58(2H,brs),1.68-1.63(4H,m),1.49-1.47(2H,m)
实施例126至134:
根据选自实施例1-7的方法使制备例110-117中制备的化合物反应,以合成下表中的实施例化合物。
实施例135:{(R)-2-[5-甲基-7-(4-氧代-环己基氨基)-1H-吲哚-2-基]-4,5-二氢-噻唑-4-基}乙酸
步骤A:{(R)-2-[7-(1,4-二氧杂-螺[4,5]癸-8-基氨基)-5-甲基-1H-吲哚-2-基]-4,5-二氢-噻唑-4-基}-乙酸乙酯
根据与实施例1相同的方法使制备例54中制备的[(R)-2-(5-甲基-7-硝基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸乙酯和1,4-二氧杂-螺[4,5]癸烷-8-酮反应,得到标题化合物。
步骤B:{(R)-2-[5-甲基-7-(4-氧代-环己基氨基)-1H-吲哚-2-基]-4,5-二氢-噻唑-4-基}乙酸
将步骤A中制备的{(R)-2-[7-(1,4-二氧杂-螺[4,5]癸-8-基)氨基-5-甲基-1H-吲哚-2-基]-4,5-二氢-噻唑-4-基}-乙酸乙酯(177mg,4mmol)溶于甲醇(10mL)。向其中加入HCl(浓,2mL)并且使该混合物在60℃下反应6h。减压除去溶剂并且向残余物中加入水。用EtOAc萃取该反应混合物,干燥,浓缩,通过HPLC纯化,得到标题化合物(76mg,收率50%)。
1H-NMR(500MHz,CDCl3);δ11.99(br s,1H),7.00(s,1H),6.79(s,1H),6.30(s,1H),5.34(m,1H),3.89(m,1H),3.71(m,1H),3.21(m,1H),2.66(m,2H),2.59(m,2H),2.43-2.35(m,5H),2.26(m,2H),1.97(m,2H)
实施例136:2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-1-吗啉-4-基-乙酮
根据与制备例101步骤B相同的方法使实施例4中制备的[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸和吗啉反应,得到标题化合物。
1H-NMR(500MHz,DMSO-d6);δ11.52(br s,1H),6.80(s,1H),6.69(s,1H),6.16(s,1H),6.12(m,1H),4.95(m,1H),3.81(m,1H),3.63(m,1H),3.41(m,8H),3.12(m,1H),2.85(m,1H),2.69(m,1H),1.93(m,2H),1.68(m,2H),1.56(m,4H)
实施例137至155:
根据与制备例101步骤B相同的方法实施例4,11,66,71,75,81和101中制备的化合物和商购胺类化合物反应,以合成下表中的实施例化合物。
实施例156:环戊基-{5-甲磺酰基甲基-2-[(R)-4-(2-吗啉-4-基-乙基)-4,5-二氢-噻唑-2-基]-1H-吲哚-7-基}-胺
步骤A:环戊基-{2-[(R)-4-(2-碘-乙基)-4,5-二氢-噻唑-2-基]-5-甲磺酰基甲基-1H-吲哚-7-基}-胺
将实施例99中制备的2-[(R)-2-(7-环戊基氨基-5-甲磺酰基甲基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙醇(178mg,0.42mmol)溶于四氢呋喃(10mL)。向其中加入碘(161mg,0.63mmol),三苯膦(166mg,0.63mmol)和咪唑(86mg,1.23mmol),将该混合物在室温下搅拌8h。用水使反应停止,用乙酸乙酯萃取该反应混合物。用饱和氯化钠水溶液洗涤萃取物,用无水硫酸镁干燥并且过滤。减压除去溶剂,通过柱色谱法纯化残余物,得到标题化合物(120mg,收率54%)。
步骤B:环戊基-{5-甲磺酰基甲基-2-[(R)-4-(2-吗啉-4-基-乙基)-4,5-二氢-噻唑-2-基]-1H-吲哚-7-基}-胺
将步骤A中制备的环戊基-{2-[(R)-4-(2-碘-乙基)-4,5-二氢-噻唑-2-基]-5-甲磺酰基甲基-1H-吲哚-7-基}-胺(116mg,0.22mmol)溶于N,N-二甲基甲酰胺(4mL)。向其中加入吗啉(57mg,0.66mmol),将该混合物在室温下搅拌8h。用水使反应停止,用乙酸乙酯萃取该反应混合物。用无水硫酸镁干燥萃取物。减压除去溶剂,通过柱色谱法纯化残余物,得到标题化合物(68mg,收率64%)。
1H-NMR(500HMz,CDCl3);δ10.60(br s,1H),6.99(s,1H),6.89(s,1H),6.49(s,1H),4.79(m,1H),4.26(s,2H),3.86(m,1H),3.57(m,5H),3.19(m,1H),2.72(s,3H),2.45(m,2H),2.32(m,2H),2.26(m,2H),2.04(m,2H),1.80(m,2H),1.66(m,4H),1.41(m,2H)
实施例157:1-(4-{2-[(R)-2-(7-环戊基氨基-5-甲磺酰基甲基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-哌嗪-1-基)-乙酮
根据与实施例156步骤B相同的方法使实施例156步骤A中制备的环戊基-{2-[(R)-4-(2-碘-乙基)-4,5-二氢-噻唑-2-基]-5-甲磺酰基甲基-1H-吲哚-7-基}-胺和乙酰基哌嗪反应,得到标题化合物。
1H-NMR(500HMz,CDCl3);δ10.62(br s,1H),6.99(s,1H),6.89(s,1H),6.46(s,1H),4.77(m,1H),4.26(s,2H),3.87(m,1H),3.57(m,1H),3.30(m,2H),3.16(m,1H),2.72(s,3H),2.46(m,2H),2.31(m,2H),2.21(m,2H),2.04(s,3H),2.03(m,2H),1.79(m,2H),1.64(m,4H),1.45(m,2H)
实施例158:环戊基-[2-((R)-4-吡咯烷-1-基甲基-4,5-二氢-噻唑-2-基)-1H-吲哚-7-基]-胺
根据与实施例156相同的方法使实施例2中制备的[(R)-2-(7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-甲醇和吡咯烷反应, 得到标题化合物。
1H-NMR(400HMz,DMSO-d6);δ11.37(br s,1H),6.83(m,1H),6.75(d,J=2.0Hz,1H),6.29(d,J=8.0Hz,1H),5.86(d,J=8.0Hz,1H),4.80(m,1H),3.87(m,1H),3.52(m,1H),3.43(m,1H),3.33(m,2H),2.78(m,2H),2.61(m,2H),1.99(m,2H),1.72(m,6H),1.60(m,4H)
实施例159:{5-氯-2-[(R)-4-(2-二甲氨基-乙基)-4,5-二氢-噻唑-2-基]-1H-吲哚-7-基}-环戊基-胺
根据与实施例156相同的方法使实施例5中制备的2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙醇和二甲胺反应,得到标题化合物。
1H-NMR(500HMz,CDCl3);δ10.07(br s,1H),6.99(s,1H),6.80(s,1H),6.42(s,1H),4.67(m,1H),3.54(m,1H),3.16(m,1H),2.46(m,1H),2.37(m,1H),2.19(s,6H),2.02(m,3H),1.81(m,4H),1.69(m,4H)
实施例160:{5-氯-2-[(R)-4-(2-哌嗪-1-基-乙基)-4,5-二氢-噻唑-2-基]-1H-吲哚-7-基}-环戊基-胺
步骤A:{5-氯-2-[(R)-4-(2-1-BOC-哌嗪-4-基-乙基)-4,5-二氢-噻唑-2-基]-1H-吲哚-7-基}-环戊基-胺
根据与实施例156相同的方法使实施例5中制备的2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙醇和1-BOC-哌嗪反应,得到标题化合物。
步骤B:{5-氯-2-[(R)-4-(2-哌嗪-1-基-乙基)-4,5-二氢-噻唑-2-基]-1H-吲哚-7-基}-环戊基-胺
将步骤A中制备的{5-氯-2-[(R)-4-(2-1-BOC-哌嗪-4-基-乙基)-4,5-二氢-噻唑-2-基]-1H-吲哚-7-基}-环戊基-胺溶于二氯甲烷 (50mL)。向其中加入4N盐酸乙酸乙酯溶液(1.3mL,5.28mmol),将该混合物在室温下搅拌4h。在反应完成后,减压除去溶剂。使残余物从DCM和乙醚中重结晶,得到标题化合物(125mg,收率55%)。
1H NMR(DMSO-d6,ppm);δ11.48(1H,s),6.79(1H,s),6.67(1H,s),6.11(1H,s),6.10(1H,d),4.61(1H,m),3.80(1H,m),3.54(1H,m),3.15(1H,m),2.93(2H,m),2.50-2.41(2H,m),2.31(3H,m),1.95(4H,m),1.79(1H,m),1.68(3H,m),1.57-1.50(4H,m),1.20(1H,m)
FAB MS(m/e)=432
实施例161:(5-氯-2-{(R)-4-[2-(4-乙磺酰基-哌嗪-1-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺
根据与制备例29步骤B相同的方法使实施例160中制备的{5-氯-2-[(R)-4-(2-哌嗪-1-基-乙基)-4,5-二氢-噻唑-2-基]-1H-吲哚-7-基}-环戊基-胺和乙磺酰氯反应,得到标题化合物。
1H-NMR(500HMz,CDCl3);δ11.29(br s,1H),6.97(s,1H),6.86(s,1H),6.37(s,1H),4.93(m,1H),3.92(br s,1H),3.77(m,1H),3.57(m,1H),3.16(m,1H),2.95(m,2H),2.80(m,4H),2.42-2.28(m,4H),2.03(m,4H),1.74(m,3H),1.63(m,4H),1.43(m,1H),1.32(t,3H)
实施例162:1-(4-{2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-哌嗪-1-基)-2-羟基-乙酮
根据与制备例101步骤B相同的方法使实施例160中制备的{5-氯-2-[(R)-4-(2-哌嗪-1-基-乙基)-4,5-二氢-噻唑-2-基]-1H-吲哚-7-基}-环戊基-胺和乙醇酸反应,得到标题化合物。
1H-NMR(500HMz,DMSO-d6);δ11.47(br s,1H),6.79(s,1H),6.68(s,1H),6.16(s,1H),6.10(m,1H),4.63(m,1H),4.50(m,1H),4.04(m,2H),3.81(m,1H),3.55(m,1H),3.43(m,2H),3.16(m, 1H),2.52(m,2H),2.35(m,4H),1.95(m,3H),1.81(m,1H),1.68(m,2H),1.53(m,4H)
实施例163:{5-氯-2-[(R)-4-(2-吡唑-1-基-乙基)-4,5-二氢-噻唑-2-基]-1H-吲哚-7-基}-环戊基-胺
将实施例5中制备的2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙醇(81mg,0.11mmol)溶于四氢呋喃(4mL)。向其中加入碘(13.2mg,0.11mmol)和咪唑(9.7mg,0.14mmol),将该混合物在室温下搅拌2h。在反应完成后,过滤该反应混合物以除去固体部分。减压除去溶剂并且向残余物中加入四氢呋喃(4mL)。向其中加入吡唑(58mg,0.85mmol)和氢化钠(60%矿物油,21mg,0.85mmol),将该混合物在室温下搅拌8h。用水使反应停止,用乙酸乙酯萃取该反应混合物,用无水硫酸镁干燥并且过滤。减压除去溶剂,通过柱色谱法纯化残余物,得到标题化合物(24mg,收率34%)。
1H NMR(DMSO-d6,ppm);δ11.50(1H,s),7.76(1H,s),7.42(1H,s),6.80(1H,s),6.70(1H,s),6.22(1H,s),6.17(1H,s),6.11(1H,d),4.49(1H,quin),4.32(2H,m),3.80(1H,m),3.53(1H,t),3.12(1H,t),2.38(1H,m),2.14(1H,m),1.92(2H,m),1.68(2H,m),1.59-1.50(4H,m)
实施例164:(S)-1-{2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-吡咯烷-2-甲酸
步骤A:2-{2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-吡咯烷-2-甲酸甲酯
根据与实施例156相同的方法使实施例5中制备的2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙醇和(S)-吡咯烷-2-基-甲酸甲酯反应,得到标题化合物。
步骤B:(S)-1-{2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-吡咯烷-2-甲酸
根据与制备例101步骤A相同的方法使步骤A中制备的2-{2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-吡咯烷-2-甲酸甲酯水解,得到标题化合物。
1H NMR(CDCl3,ppm);δ12.04(1H,s),11.02(1H,s),6.85(1H,s),6.69(1H,s),6.31(1H,s),6.24(1H,m),4.37(1H,m),4.10(1H,m),3.86(1H,m),3.79(1H,m),3.59(1H,m),3.28(1H,m),3.17(1H,m),2.88(2H,m),2.59(1H,m),2.21(1H,m),2.06-1.59(11H,m),1.23(1H,m)
实施例165:{5-氯-2-[(R)-4-(2-甲磺酰基-乙基)-4,5-二氢-噻唑-2-基]-1H-吲哚-7-基}-环戊基-胺
将实施例5中制备的2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙醇(50mg,0.11mmol)溶于N,N-二甲基甲酰胺(2mL)。向其中加入甲磺酸钠(54mg,0.55mmol),将该混合物在室温下搅拌8h。用水使反应停止。用乙酸乙酯萃取该反应混合物,用无水硫酸钠干燥并且过滤。减压除去溶剂,通过柱色谱法纯化残余物,得到标题化合物(19mg,收率45%)。
1H-NMR(400HMz,CDCl3);δ10.39(br s,1H),7.03(s,1H),6.89(s,1H),6.48(s,1H),6.17(s,1H),4.77(m,1H),3.87(m,1H),3.59(m,1H),3.29(m,1H),3.17(m,2H),2.86(s,3H),2.26(m,2H),2.10(m,2H),1.70(m,4H),1.51(m,2H)
实施例166:3-{2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-5-甲基-3H-咪唑-4-甲酸乙酯
根据与实施例156相同的方法使实施例5中制备的2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙醇和5-甲基-3H-咪唑-4-甲酸乙酯反应,得到标题化合物。
1H-NMR(500HMz,DMSO-d6);δ11.49(br s,1H),7.71(s,1H),6.80(s,1H),6.72(s,1H),6.17(s,1H),6.08(m,1H),4.56(m,1H),4.16(m,4H),3.81(m,1H),3.58(m,1H),3.18(m,1H),2.46(s,3H),2.11(m,2H),1.95(m,2H),1.68(m,2H),1.53(m,4H),1.22(m,3H)
实施例167:3-{2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-5-甲基-3H-咪唑-4-甲酸
根据与制备例101步骤A相同的方法使实施例166中制备的3-{2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-5-甲基-3H-咪唑-4-甲酸乙酯反应,得到标题化合物。
1H NMR(DMSO-d6,ppm);δ11.50(1H,s),7.71(1H,s),6.80(1H,s),6.72(1H,s),6.17(1H,s),6.08(1H,m),4.55(1H,m),4.13(2H,m),3.80(1H,m),3.55(2H,m),2.19-2.15(2H,m),1.95(3H,m),1.68(3H,m),1.51(5H,m)
实施例168:1-(2-{(R)-2-[5-氯-7-(四氢-吡喃-4-基氨基)-1H-吲哚-2-基]-4,5-二氢-噻唑-4-基}-乙基)-哌啶-3-甲酸
步骤A:1-(2-{(R)-2-[5-氯-7-(四氢-吡喃-4-基氨基)-1H-吲哚-2-基]-4,5-二氢-噻唑-4-基}-乙基)-哌啶-3-甲酸乙酯
根据与实施例156相同的方法使实施例67中制备的2-{2-[(R)-5-氯-7-(四氢吡喃-4-基)氨基-1H-吲哚-2-基]-4,5-二氢-噻唑-4-基]}-乙醇和哌啶-3-甲酸乙酯反应,得到标题化合物。
1H NMR(DMSO-d6,ppm);δ11.48(1H,s),6.82(1H,s),6.67(1H,s),6.29(1H,s),6.04(1H,d),4.61(1H,quin),4.47(1H,m),3.87(2H,m),3.62(2H,q),3.56(2H,m),3.44-3.39(4H,m),3.14(2H,m),2.52(1H,m),2.37-2.30(6H,m),1.96-1.92(3H,m),1.81(1H,m),1.42(2H,m),1.28(3H,t)
步骤B:1-(2-{(R)-2-[5-氯-7-(四氢-吡喃-4-基氨基)-1H-吲哚-2-基]-4,5-二氢-噻唑-4-基}-乙基)-哌啶-3-甲酸
根据与制备例101步骤A相同的方法使步骤A中制备的1-(2-{(R)-2-[5-氯-7-(四氢-吡喃-4-基氨基)-1H-吲哚-2-基]-4,5-二氢-噻唑-4-基}-乙基)-哌啶-3-甲酸乙酯反应,得到标题化合物。
1H NMR(DMSO-d6,ppm);δ13.17(1H,s),11.94(1H,s),6.80(1H,s),6.68(1H,s),6.28(1H,s),6.04(1H,d),4.62(1H,quin),4.47(1H,m),3.87(2H,m),3.56(2H,m),3.44-3.39(4H,m),3.14(2H,m),2.52(1H,m),2.37-2.30(6H,m),1.96-1.92(3H,m),1.80(1H,m),1.40(2H,m)
实施例169:[(S)-1-(2-{(R)-2-[5-氯-7-(四氢-吡喃-4-基氨基)-1H-吲哚-2-基]-4,5-二氢-噻唑-4-基}-乙基)-吡咯烷-3-基]-氨基甲酸叔丁酯
根据与实施例156相同的方法使实施例67中制备的2-{2-[(R)-5-氯-7-(四氢吡喃-4-基)氨基-1H-吲哚-2-基]-4,5-二氢-噻唑-4-基]}-乙醇和(S)-3-BOC-氨基-吡咯烷反应,得到标题化合物。
1H-NMR(500HMz,DMSO-d6);δ11.48(br s,1H),6.92(m,1H),6.81(s,1H),6.68(s,1H),6.28(m,1H),6.05(m,1H),4.63(m,1H),3.86(m,3H),3.59(m,1H),3.54(m,1H),3.44(m,2H),3.14(m,1H),2.71-2.58(m,2H),2.25(m,1H),1.95(m,4H),1.75(m,1H),1.52(m,1H),1.39(m,2H),1.37-1.32(m,11H)
实施例170:(2-{(R)-4-[2-((S)-3-氨基-吡咯烷-1-基)-乙基]-4,5-二氢-噻唑-2-基}-5-氯-1H-吲哚-7-基)-(四氢-吡喃-4-基)-胺
将实施例169中制备的[(S)-1-(2-{(R)-2-[5-氯-7-(四氢-吡喃-4-基氨基)-1H-吲哚-2-基]-4,5-二氢-噻唑-4-基}-乙基)-吡咯烷-3-基]-氨基甲酸叔丁酯(150mg,0.27mmol)溶于二氯甲烷(30mL)。 向其中加入4N盐酸二噁烷溶液(0.34mL,1.35mmol),将该混合物在室温下搅拌4h。在反应完成后,减压除去溶剂。使残余物从DCM/乙醚中重结晶,得到标题化合物(92mg,收率75%)。
1H NMR(DMSO-d6,ppm);δ10.92(1H,s),8.63(2H,s,br),6.86(1H,s),6.83(1H,s),6.43(1H,s),6.11(1H,m),4.72(1H,m),3.65(5H,m),3.45(5H,m),3.22(3H,m),2.37(2H,m),2.19(3H,m),1.90(2H,m),1.49(2H,m)
实施例171:N-[(S)-1-(2-{(R)-2-[5-氯-7-(四氢-吡喃-4-基氨基)-1H-吲哚-2-基]-4,5-二氢-噻唑-4-基}-乙基)-吡咯烷-3-基]-乙酰胺
将实施例170中制备的(2-{(R)-4-[2-((S)-3-氨基-吡咯烷-1-基)-乙基]-4,5-二氢-噻唑-2-基}-5-氯-1H-吲哚-7-基)-(四氢-吡喃-4-基)-胺(85mg,0.19mmmol)溶于二氯甲烷(10mL)。向其中加入二异丙基乙胺(0.13mL,0.75mmol)和乙酰氯(0.013mL,0.19mmol),将该混合物在室温下搅拌30分钟。用水使反应停止,用乙酸乙酯萃取该反应混合物,用无水硫酸镁干燥并且过滤。减压除去溶剂,通过柱色谱法纯化残余物,得到标题化合物(39mg,收率42%)。
1H NMR(DMSO-d6,ppm);δ11.49(1H,s),7.97(1H,s),6.81(1H,s),6.69(1H,s),6.28(1H,s),6.05(1H,d),4.64(1H,quin),4.12(1H,m),3.85(2H,m),3.53(2H,m),3.44(2H,t),3.34(2H,m),3.15(1H,t),2.72-2.60(3H,m),2.39(1H,m),2.05-1.87(4H,m),1.80-1.72(4H,m),1.53(1H,m),1.37(2H,m)
实施例172:环戊基-{2-[(R)-4-(2-甲氧基-乙基)-4,5-二氢-噻唑-2-基]-1H-吲哚-7-基}-胺
根据与实施例165相同的方法,使实施例77中制备的2-[2-(7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙醇和甲醇钠反应,得到标题化合物。
1H-NMR(500HMz,DMSO-d6);δ10.62(br s,1H),7.03(d,J=7.95Hz,1H),6.99(t,1H),6.93(s,1H),6.48(d,J=7.35Hz,1H),4.83(m,1H),3.83(m,1H),3.56(m,1H),3.46(m,2H),3.20(m,4H),2.05~1.87(m,4H),1.70~1.38(m,6H)
实施例173至224:
根据选自实施例156至172的方法,使实施例2,5,24,56,67,73,77,79,99和102中制备的化合物和商购胺类化合物或甲磺酸钠反应,以合成下表中的实施例化合物。
实施例225:{5-甲基-2-[(R)-4-(2-吗啉-4-基-乙基)-4,5-二氢-噁唑-2-基]-1H-吲哚-7-基}-(四氢吡喃-4-基)-胺
根据与实施例1、制备例29步骤A和实施例156相同的方法依次使实施例104中制备的2-[(R)-2-(5-甲基-7-硝基-1H-吲哚-2-基)-4,5-二氢-噁唑-4-基]乙酸,四氢吡喃-4-酮和吗啉反应,得到标题化合物。
1H NMR(400MHz,CDCl3);δ10.11(brs,1H),6.91(s,1H),6.86(s,1H),6.34(s,1H),4.60(t,1H),4.48(m,1H),4.10~3.93(m,5H),3.63~3.52(m,3H),2.39(s,3H),2.07(d,2H),1.94(m,2H),1.58(m,2H)
实施例226:{5-甲基-2-[(S)-4-(2-吗啉-4-基-乙基)-4,5-二氢-噻唑-2-基]-1H-吲哚-7-基}-(四氢-吡喃-4-基甲基)-胺
步骤A:((S)-2-{5-甲基-7-[(四氢-吡喃-4-基甲基)-氨基]-1H-吲哚-2-基}-4,5-二氢-噻唑-4-基)-乙酸异丙酯
根据与实施例1相同的方法使制备例52中制备的[(5-甲基-7-硝基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸异丙酯和四氢吡喃-4-羧基醛反应,得到标题化合物。
步骤B:2-((R)-2-{5-甲基-7-[(四氢-吡喃-4-基甲基)-氨基]-1H-吲哚-2-基}-4,5-二氢-噻唑-4-基)-乙醇
根据与实施例5相同的方法使步骤A中制备的((S)-2-{5-甲基 -7-[(四氢-吡喃-4-基甲基)-氨基]-1H-吲哚-2-基}-4,5-二氢-噻唑-4-基)-乙酸异丙酯反应,得到标题化合物。
步骤C:{5-甲基-2-[(S)-4-(2-吗啉-4-基-乙基)-4,5-二氢-噻唑-2-基]-1H-吲哚-7-基}-(四氢-吡喃-4-基甲基)-胺
根据与实施例156相同的方法使步骤B中制备的2-((R)-2-{5-甲基-7-[(四氢-吡喃-4-基甲基)-氨基]-1H-吲哚-2-基}-4,5-二氢-噻唑-4-基)-乙醇和吗啉反应,得到标题化合物。
1H NMR(500MHz,CDCl3);δ11.13(s,1H),6.82(d,2H),6.24(s,1H),4.81-4.78(m,1H),3.88-3.81(m,2H),3.60-3.46(m,5H),3.35-3.30(m,2H),3.19-3.17(m,1H),3.01(br,2H),2.38-2.26(m,7H),2.14(s,2H),1.91-1.88(m,1H),1.75-1.71(m,2H),1.53~1.47(m,2H),1.28-1.16(m,2H)。
实施例227至257:
根据与实施例226相同的方法使实施例10,22,51,66和82的化合物反应,或根据与实施例226相同的方法选择性地使制备例52和71的化合物和商购醛类或酮类和胺类化合物反应,以合成下表中的实施例化合物。
实施例258:[(R)-2-(5-氨基甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-甲醇
将实施例64中制备的2-[7-环戊基氨基-2-((R)-4-羟基甲基-4,5-二氢-噻唑-2-基)-1H-吲哚-5-基甲基]-异吲哚-1,3-二酮(27mg,0.07mmol)溶于乙醇(3mL)。向其中加入水合肼(0.6mL,0.11mmol),将该混合物在80℃下搅拌3h。在反应完成后,减压蒸馏该反应混合物,通过柱色谱法纯化,得到标题化合物(7mg,收率37%)。
1H-NMR(500HMz,CDCl3);δ10.50(brs,1H),6.98(s,1H),6.88(s,1H),6.46(s,1H),4.72(m,1H),4.40(m,1H),3.86(s,2H),3.81(m,1H),3.70(m,1H),3.44(m,2H),1,97(m,2H),1.59(m,4H),1.41(m,2H)
实施例259:呋喃-2-甲酸[7-环戊基氨基-2-((R)-4-羟基甲基-4,5-二氢-噻唑-2-基)-1H-吲哚-5-基甲基]-酰胺
根据与制备例101步骤B相同的方法使实施例258中制备的[(R)-2-(5-氨基甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-甲醇和呋喃-2-甲酸反应,得到标题化合物。
1H-NMR(CDCl3);δ11.01(1H,br),7.38(1H,s),7.12(1H,d,J=3.7Hz),7.03(1H,s),6.90(1H,s),6.58(1H,br),6.49~6.45(2H,m),4.76~4.67(1H,m),4.60(2H,d,J=5.5Hz),4.06~4.01(1H,m),3.80~3.73(1H,m),3.70~3.64(1H,m),3.52~3.46(1H,m),3.45~3.38(1H,m),1.99~1.86(2H,m),1.62~1.46(4H,m),1.41~1.32(1H,m),1.32~1.24(1H,m)
实施例260:[(R)-2-(7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基甲氧基]-乙酸甲酯
根据与制备例29步骤B相同的方法使实施例2中制备的[(R)-2-(7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-1,3-噻唑-4-基]-甲醇和乙酸溴乙酯反应,得到标题化合物。
1H-NMR(400MHz,CDCl3);δ10.16(br s,1H),6.87(s,1H),6.66(dd,J=2.4,9.2Hz,1H),6.30(dd,J=2.4,11.8Hz,1H),4.94(m, 1H),4.25(q,2H),4.13(d,J=5.6Hz,2H),3.87(m,1H),3.76(d,J=6.4Hz,2H),3.56(m,1H),3.44(m,1H),2.07(m,2H),1.67(m,4H),1.51(m,2H),1.30(t,3H)
实施例261:[(R)-2-(7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基甲氧基]-乙酸
根据与制备例101步骤A相同的方法使实施例260中制备的[(R)-2-(7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基甲氧基]-乙酸甲酯反应,得到标题化合物。
1H-NMR(400MHz,DMSO-d6);δ12.70(br s,1H),7.07(s,1H),6.57(d,J=8.8Hz,1H),6.23(d,J=12Hz,1H),5.13(m,1H),4.34(m,1H),4.07(m,2H),3.89(m,1H),3.63(m,3H),2.03(m,2H),1.58(m,6H)
实施例262:环戊基-{2-[(R)-4-(3-环戊基-[1,2,4]噁二唑-5-基甲基)-4,5-二氢-噻唑-2-基]-1H-吲哚-7-基}-胺
将实施例75中制备的[(7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]乙酸(140mg,0.41mmol)溶于N,N-二甲基甲酰胺(5mL)。向其中加入1,1′-二羰基二咪唑(73mg,0.45mmol),将该混合物在室温下搅拌30分钟。向其中加入N-羟基-环戊烷甲脒(260mg,2.03mmol),将该混合物在80℃下搅拌5h。在反应完成后,加入水。用乙酸乙酯萃取该反应混合物,用无水硫酸镁干燥并且过滤。在减压下蒸馏滤液,通过柱色谱法纯化残余物,得到标题化合物(100mg,收率56%)。
1H-NMR(400HMz,CDCl3);δ10.62(br s,1H),7.04(d,1H),6.97(t,1H),6.92(d,1H),6.49(d,1H),5.20(m,1H),3.83(m,2H),3.64(m,1H),3.39(m,1H),3.31(m,1H),3.17(m,1H),3.01(m,1H),1.97(m,4H),1.73(m,4H),1.60(m,6H),1.46(m,2H),1.34(m,2H)
实施例263:环戊基-{2-[(R)-4-(3-哌啶-1-基-[1,2,4]噁二唑-5-基甲基)-4,5-二氢-噻唑-2-基]-1H-吲哚-7-基}-胺
根据与实施例262相同的方法使实施例75中制备的[(7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]乙酸和N-羟基哌啶甲脒反应,得到标题化合物。
1H-NMR(400HMz,CDCl3);δ10.56(br s,1H),7.01(d,1H),6.96(t,1H),6.90(d,1H),6.46(d,1H),5.23(m,1H),3.83(m,2H),3.64(m,1H),3.36(m,1H),3.31(m,1H),3.17(m,2H),3.01(m,1H),1.95(m,2H),1.68-1.43(m,11H),1.35(m,1H)
实验例1:实施例化合物抗导致肝细胞毒性的物质的肝细胞保护效果的测定和分析
对细胞的各种内源性/外源性攻击会触发细胞死亡机制,该机制广义上分为两类,即细胞凋亡或坏死。在本实验例中,利用这些细胞死亡机制,用在临床上证实导致肝细胞毒性的严重副作用的药物或导致细胞死亡的各种化学品来处理从大鼠中分离出来的原肝细胞,在24-48小时后评价实施例合成的化合物的肝细胞保护效果。用于导致肝细胞死亡的物质包括CCl4、ActD、H2O2、多柔比星、抗-Fas Ab/放线菌素D、扑热息痛、EtOH、CdCl2、棕榈酸盐、硬脂酸盐、环磷酰胺、特非那定、双氯芬酸、辛伐他汀和阿德福韦。使用Seglen PO的方法(Experimental Cell Research 74(1972)pp450-454)分离原肝细胞。简言之,根据两步胶原酶灌注法莱分离肝细胞,使用Percoll梯度,通过低速(500rpm)离心10分钟来除去死亡的细胞(Kreamer BL等,In Vitro Cellular & Developmental Biology 22(1986)pp201-211)。在该步骤中,细胞存活率维持在90%以上。将细胞悬浮在HepatoZYME培养基(Gibco BRL)中,计数细胞的数目。将100μl的1.5X104个细胞置入胶原蛋白覆盖的96孔培养板(BD biocoat)中,附着在底部3-4小时。
为评价肝细胞保护效果,用实施例化合物预处理上述附着细胞30分钟。此时,根据实验的不同,由30μM,10μM或1μM开始,以5步骤将实施例化合物的浓度系列稀释2倍或3倍,将DMSO的最终浓度调节至0.2%。在用化合物处理30分钟后,用浓度如表1所示的导致肝细胞死亡的物质或肝毒性药物处理细胞。24-48小时后,测定细胞的存活率以评价肝细胞保护效果。用WST-1(MK-400,Takeda)法,通过440nm处的吸光度测定细胞存活率。将实施例化合物的肝细胞保护效果表示为“EC50”,它是由测定值计算的。本文的“EC50”是指在实验中获得最大保护效果的50%时的化合物浓度。
优选实施例化合物的EC50是30μM以下,更优选10μM以下,特别优选1.0μM以下。
表1表示衍生肝毒性的各种物质的处理浓度和实施例4的化合物的肝细胞保护作用。表2表示实施例化合物对抗导致肝细胞毒性的物质多柔比星的肝细胞保护作用。
表1
实施例4的化合物对抗导致肝细胞毒性的物质的细胞保护作用
导致肝细胞毒性的 物质 | 处理浓度 | EC50(μM) | 对有关导致肝细胞毒性的 物质的注释 |
特非那定 | 10μM | 0.4 | 抗过敏药 |
辛伐他汀 | 16μM | <10μM | 降脂药 |
双氯芬酸 | 350μM | 在3-100 μM下的存 活率40% | 非甾体抗炎药 (NSAID) |
阿德福韦 | 100μM | 在3-30μM 下50%的存 活率 | 抗病毒药 |
表2在肝细胞中抗多柔比星的细胞保护作用
实施例 | EC50, μM | 实施例 | EC50, μM | 实施例 | EC50, μM | 实施例 | EC50, μM |
1 | >1 | 38 | 2.0 | 109 | 0.61 | 229 | 0.25 |
2 | 0.1 | 40 | 15.58 | 115 | <1 | 230 | >0.32 |
4 | 0.3 | 43 | 1~10 | 117 | <0.5 | 231 | 0.2 |
6 | 4.93 | 45 | 1.32 | 118 | 0.41 | 232 | 0.24 |
7 | 1.17 | 46 | 0.4 | 119 | 0.17 | 233 | 0.27 |
8 | 0.41 | 47 | 0.36 | 120 | 1.12 | 234 | 0.09 |
9 | >2 | 48 | 0.2 | 121 | 0.47 | 235 | >0.54 |
10 | 0.6 | 50 | 0.25 | 122 | 0.96 | 236 | 0.16 |
11 | 2.8 | 51 | 0.6 | 127 | 1.18 | 237 | 0.2 |
12 | 3.25 | 52 | 0.75 | 128 | 0.2 | 238 | 0.33 |
13 | 1.13 | 61 | 0.78 | 130 | 0.1 | 239 | 0.83 |
14 | 0.19 | 62 | 3.77 | 133 | 0.31 | 240 | 0.28 |
15 | 0.6 | 64 | 0.54 | 134 | 0.51 | 241 | 0.21 |
16 | 1.29 | 67 | >1 | 135 | 1.26 | 244 | 0.195 |
17 | 0.315 | 68 | 0.49 | 158 | 0.91 | 246 | 0.35 |
18 | 2.42 | 71 | 1.1 | 173 | 1.98 | 247 | 0.86 |
19 | 0.35 | 78 | 29.44 | 176 | >1 | 249 | 0.11 |
20 | 5.77 | 83 | 0.6 | 177 | >1 | 250 | 0.09 |
21 | 0.3 | 84 | 1.6 | 178 | 0.23 | 251 | 0.3 |
22 | 0.25 | 85 | 0.4 | 182 | 0.375 | 252 | 0.51 |
23 | 0.14 | 88 | 1.87 | 184 | 0.18 | 253 | 0.2 |
24 | 0.13 | 90 | 7.92 | 193 | 0.65 | 254 | 1.0 |
25 | 0.76 | 93 | 0.55 | 201 | 0.33 | 257 | <0.4 |
26 | 0.2 | 94 | 28.14 | 205 | 0.34 | ||
32 | 2.12 | 97 | 4.1 | 218 | 0.26 | ||
33 | 4.04 | 101 | 1~10 | 222 | 0.18 | ||
34 | 5.58 | 108 | <0.5 | 228 | 0.13 |
实验例2:当tBHP(叔丁基羟基过氧化物;t-BuOOH)处理肝细胞和来自不同组织的其他细胞时的保护效果
1)当tBHP处理原肝细胞时的保护效果
根据与实验例1相同的方法分离肝细胞,悬浮在DMEM(Gibco+10%FBS+1X抗生素)培养基中,分配到培养板上。在肝细胞分布24小时后,通过3倍系列稀释将化合物稀释成最终浓度为30,10,3,1,0.3,0.1μM,用它们预处理各孔30分钟。用最终浓度300μM的tBHP处理细胞,1小时后测定保护效果。如实验例1所述,在用WST-1(Takeda,10μL)处理1.5小时后,通过使用SpectraMax酶标仪(MolecularDevice)在440nm处测定吸光度来计算EC50值。
优选实施例化合物的EC50是30μM以下,更优选10μM以下,特别优选1.0μM以下。
2)当tBHP处理胰脏细胞(Linm5F)时的保护效果
为了评价对胰脏细胞的保护效果,将一种β细胞-Linm5F细胞以2X104个细胞/孔的量分配于96孔培养板中,培养24小时。通过3倍系列稀释将实施例化合物稀释成最终浓度为30,10,3,1,0.3,0.1μM,用它们预处理各孔1小时。用最终浓度400μM的tBHP处理细胞,再培养5小时。用SRB(磺酰罗丹明B蛋白)法测定保护效果,其中全部的细胞蛋白质被染色。简言之,将细胞培养5小时,向各孔加入50μL的4%甲醛溶液以固定细胞,在室温下储藏约30分钟。在弃去培养基后,用蒸馏水洗涤各孔2-3次,在50℃下在烘箱中干燥培养板。向各孔中加入50μL的SRB溶液,在室温下静置约30分钟。在除去SRB溶液后,用1%乙酸溶液洗涤该培养板2-3次。在50℃的烘箱中干燥该培养板后,加入100μL的10mM Tris以洗脱使细胞蛋白质染色的SRB。使用SpectrMax酶标仪在590nm和650nm处测定吸光度,用590nm处的吸光度减去650nm处的吸光度来计算EC50值。
优选实施例化合物的EC50是30μM以下,更优选10μM以下,特别优选1.0μM以下。有代表性的是,实施例14的化合物的EC50是0.15 μM,实施例22化合物的EC50是0.20μM。
3)当tBHP处理心肌细胞(H9C2,大白鼠心肌细胞)时的保护效果
为了评价对心肌细胞的保护效果,将H9C2细胞以1.5X104个细胞/孔的量分配,培养24小时。通过3倍系列稀释将实施例化合物稀释成最终浓度为30,10,3,1,0.3,0.1μM,用它们预处理各孔45分钟。用最终浓度400μM的tBHP处理细胞,培养2小时。使用与上述2)的对Linm5F处理相同的SRB法来测定各化合物的保护效果。
优选实施例化合物的EC50是30μM以下,更优选10μM以下,特别优选1.0μM以下。有代表性的实施例化合物的EC50值如下:实施例22:0.17μM和实施例85:0.7μM。
4)当tBHP处理肾细胞(LLC-PK1)时的保护效果
为了评价对肾细胞的保护效果,每孔分配4X104个细胞,培养24小时。用最终浓度30,10,3,1,0.3,0.1μM的实施例化合物预处理细胞,培养30分钟。用400μM的tBHP处理细胞,再培养6小时。使用与上述2)的对Linm5F处理相同的SRB法来测定各化合物的保护效果。
优选实施例化合物的EC50是30μM以下,更优选10μM以下,特别优选1.0μM以下。
5)当tBHP处理软骨细胞时的保护效果
为了评价对软骨细胞的保护效果,从16周龄的SD大鼠(体重:450-460g)的2个后腿中分离软骨细胞。分离方法如下。将从大鼠后腿的膝盖区分离的软骨转移到包含PBS(+1X抗生素)的100pi培养板中。将PBS维持在4℃的冰浴中。用新鲜的PBS交换,以1000rpm离心。在除去PBS后,在37℃的温度下加入3mL的1X胰蛋白酶(Gibco),然后处理15分钟。离心后弃去上清液,再用PBS洗涤。离心后弃去上清液。在向其中加入0.2%的胶原酶(Worthington,II型) 后,通过在旋转的37℃孵育箱中过夜来分离细胞。将过滤后的细胞溶液离心,弃去上清液。再用PBS洗涤后,将细胞悬浮于10mL的DMEM/F-12(Gibco,10%FBS)中。每孔分配2X104个细胞,培养24小时。通过3倍系列稀释将实施例化合物稀释成最终浓度为30,10,3,1,0.3,0.1μM,用它们预处理各孔1小时。用最终浓度为500μM的tBHP处理细胞,再培养3小时。使用与上述2)的Linm5F中相同的SRB法来测定各化合物的保护效果。
优选实施例化合物的EC50是30μM以下,更优选10μM以下,特别优选1.0μM以下。
6)当tBHP处理脑细胞(SK-N-MC)时的保护效果
为了评价对脑细胞的保护效果,将2X104个脑细胞分配于使用DMEM培养基(Gibco,10%FBS)的96孔培养板中,培养24小时。通过3倍系列稀释将实施例化合物稀释成最终浓度为30,10,3,1,0.3,0.1μM,用它们处理各孔1小时。用最终浓度400μM的tBHP处理细胞,再培养6小时。从各孔中取出50μL的培养基进行LDH分析(Promega)。在LDH分析中,将50μL的培养基与50μL的分析用溶液混合。在室温下反应30分钟后,用SpectraMax酶标仪(MolecularDevice)在490nm处测定吸光度。
优选实施例化合物的EC50是30μM以下,更优选10μM以下,特别优选1.0μM以下。有代表性的例如实施例4的化合物在本实验中表现出极佳活性,其EC50值是0.1μM以下。
工业实用性
正如上述结果中证实的,本发明的新化合物不仅表现出肝保护作用和肝功能改善,而且可以用于预防和治疗慢性肝病,例如脂肪肝、肝纤维化、肝硬化等,以及急性/慢性肝病,例如由病毒或药物导致的肝炎等。本发明的化合物还在来自胰腺、肾、脑、软骨和心脏的细胞中表现出抑制坏死的功效。
因此,本发明的化合物可以用于预防和治疗坏死及其相关疾病。
在本领域技术人员能力范围内,可以在不脱离本发明范围的情况下进行各种应用和变型。
Claims (36)
1.下式(1)的吲哚化合物:
其中
n表示0-3的数,
A表示5元杂芳基或非芳族杂环,它们各自具有1-3个选自N、O和S的杂原子,
R1表示R5-X-B-X′-,
B表示直接键,或者表示3~10元非芳族杂环或杂芳基,它们各自具有1-4个选自N、O和S的杂原子,
X和X′彼此独立地选自-NR6-,-CO-,-CONR6-,-CO2-,-OC(O)-,-S(O)m-,-O-(CH2)m-,-(CH2)m-O-,-(CH2)m-,-NR6CO-,和-NHCO2-,其中m表示0-3的数,且R6表示氢或C1-C6-烷基,
R5表示氢,羟基,C1-C6-烷基,C1-C6-烷氧基,C4-C6-环烷基或苯基,或者表示3~10元单环或稠环的非芳族杂环或杂芳基,它们各自具有1-3个选自N、O和S的杂原子并且任选被氧代或C1-C6-烷基取代,
R2表示-(CR8R9)p-Y-R7,
p表示0-2的数,
R8和R9彼此独立地表示氢或C1-C6-烷基,
Y表示直接键或选自-O-,-NR6-,-NR6C(O)-,和-S(O)q-,其中q表示0-2的数,
R7表示氢,卤素,羟基,C1-C6-烷基,或苯基,或者表示3~10元非芳族杂环或杂芳基,它们各自具有1-3个选自N、S和O的杂原子并且任选包含氧代,
R3表示氢或C1-C6-烷基,
R4表示C3-C6-环烷基,
其中烷基,烷氧基,苯基,环烷基,非芳族杂环和杂芳基可以任选被取代,该取代基是选自羟基,卤素,氨基,C1-C6-烷基氨基,二-C1-C6-烷基氨基,C1-C6-烷基,卤代-C1-C6-烷基,C1-C6-烷基磺酰基,羧基-C1-C6-烷基,和氧代中的一个或多个;
及其药学可接受的盐、光学异构体或非对映体。
2.权利要求1的化合物,其中A表示由式(i)至(viii)之一表示的环:
其中
n和R1如权利要求1中所定义,且
R表示氢、或C1-C4-烷基。
3.权利要求2的化合物,其中A选自4,5-二氢-噻唑,噻唑,唑啉,二唑和异二唑。
4.权利要求1的化合物,其中B表示直接键,表示咪唑或二唑,或者表示具有1-2个选自N和O的杂原子的5~6元非芳族杂环。
5.权利要求4的化合物,其中B表示由下式(ix)至(xii)之一表示的结构:
其中R5如权利要求1中所定义。
6.权利要求1的化合物,其中X选自-CO-,-CONR6-,-CO2-,-SO2-,-(CH2)m-和-O-(CH2)m-,其中m表示0-2的数,且R6表示氢或C1-C6-烷基。
7.权利要求6的化合物,其中X选自-CO-,-CONH-,-CO2-,-SO2-,-(CH2)2-,-O-和-O-CH2-。
8.权利要求1的化合物,其中X′表示直接键或选自-(CH2)2-,-NH-,-CO-,-CO2-,-CONH-,-S(O)2-,-NHC(O)-和-NHCO2-。
9.权利要求1的化合物,其中R5表示氢,羟基,C1-C6-烷基,卤代-C1-C6-烷基,羟基-C1-C6-烷基,C4-C6-环烷基,苯基或卤代苯基,或者表示单环或稠环5~9元非芳族杂环或5~6元杂芳基,它们各自具有1-3个选自N、O和S的杂原子并且任选被氧代或三氟甲基取代。
10.权利要求9的化合物,其中R5选自氢,羟基,甲基,乙基,异丙基,异丁基,羟基甲基,三氟甲基,环丁基,环戊基,环己基,吡咯烷,哌啶,2-氧代哌嗪,2-氧代吡咯烷,四氢呋喃,四氢吡喃,四氢噻喃,吗啉,呋喃,吡啶,吡嗪,1,1-二氧代-硫代吗啉,咪唑和吡唑。
11.权利要求1的化合物,其中R8和R9各自表示氢。
12.权利要求1的化合物,其中Y选自-O-,-NR6-,-NR6C(O)-,和-S(O)2-,其中R6如权利要求1中所定义。
13.权利要求12的化合物,其中Y选自-O-,-NH-,-NHC(O)-,和-SO2-。
14.权利要求1的化合物,其中R7表示氢,卤素,羟基,C1-C6-烷基,羟基甲基或卤代-C1-C6-烷基,表示任选被C1-C6-烷基磺酰基取代的苯基,或者表示5~6元非芳族杂环或杂芳基,它们各自具有1-2个选自N和O的杂原子。
15.权利要求14的化合物,其中R7选自氢,溴,氟,氯,甲基,乙基,丙基,羟基甲基,三氟甲基,苯基,4-甲基磺酰基-苯基,哌啶,吡咯烷,呋喃,吡咯,吡唑和吡啶。
16.权利要求1的化合物,其中R3表示氢,甲基或异丁基。
17.权利要求1的化合物,其中R4选自环丁基、环戊基、环己基、4-甲基-环己基和4,4-二氟环己基。
18.化合物,选自:
环戊基-[2-(4,5-二氢-1,3-噻唑-2-基)-1H-吲哚-7-基]-胺;
[(R)-2-(7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-1,3-噻唑-4-基]-甲醇;
[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸甲酯;
[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙醇;
(R)-2-[7-环戊基氨基-5-(羟基甲基)-1H-吲哚-2-基]-4,5-二氢-噻唑-4-基-甲醇;
[(S)-2-(7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(S)-2-(5-甲基-7-(4,4-二氟环己烷-4-基)氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(S)-2-(5-甲基-7-环丁基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(S)-2-(5-甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(R)-2-(7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-1,3-噻唑-4-基]-甲醇;
[(R)-2-(5-(二甲氨基)甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-甲醇;
[(R)-2-(5-(吡咯-3-基)甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-甲醇;
[(R)-2-(5-(1,3-咪唑-1-基)甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-甲醇;
[(R)-2-(5-(吡唑-1-基)甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-甲醇;
[(R)-2-(5-乙酰基氨基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-甲醇;
[(R)-2-(5-苯氧基甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(R)-2-(5-(吡咯烷-1-基)甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸甲酯;
环戊基-[5-氯-2-((R)-4-异丁基-4,5-二氢-噻唑-2-基)-1H-吲哚-7-基)-胺;
[(R)-2-(7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-丙酸乙酯;
环戊基-[5-氟-2-((R)-4-乙基-4,5-二氢-噻唑-2-基)-1H-吲哚-7-基]-胺;
{(R)-2-[7-(甲基-环戊基)氨基-5-氟-1H-吲哚-2-基]-4,5-二氢-1,3-噻唑-4-基}-甲醇;
[(S)-2-(5-乙氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸甲酯;
[(S)-2-(5-乙氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(S)-2-(5-乙氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙醇;
[(R)-2-(5-甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-甲酸乙酯;
[(S)-2-(5-苯氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(R)-2-(5-氟-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-甲醇;
[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙醇;
[(R)-2-(5-溴-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-甲醇;
[(R)-2-(5-甲氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-甲醇;
[(R)-2-(5-(吡啶-3-基)氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-甲醇;
[(R)-2-(5-甲磺酰基甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-甲醇;
[(R)-2-(5-(异吲哚-1,3-二酮-2-基)甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-甲醇;
[(R)-2-(5-溴-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(R)-2-(5-氟-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(R)-2-(5-氟-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸乙酯;
[(R)-2-(5-氟-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙醇;
[(R)-2-(7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(R)-2-(7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸乙酯;
[(R)-2-(5-甲氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸甲酯;
[(R)-2-(5-甲氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(R)-2-(5-乙氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(R)-2-(5-丙氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(R)-2-(5-苯氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(R)-2-(5-(吡啶-3-基)氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸甲酯;
[(R)-2-(5-(吡啶-3-基)氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(R)-2-(5-甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸甲酯;
[(R)-2-(5-甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(R)-2-(5-(4-(甲磺酰基)苯氧基)-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(R)-2-(5-苯氧基甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸甲酯;
[(R)-2-(5-苯基氨基甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸甲酯;
[(R)-2-(5-甲磺酰基甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸甲酯;
[(R)-2-(5-甲磺酰基甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙酸;
[(R)-2-(5-甲磺酰基甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙醇;
[(R)-2-(7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基乙酰胺;
3-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-丙酸;
[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-丙醇;
3-[(R)-2-(5-甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-丙酸乙酯;
3-[(R)-2-(5-甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-丙酸;
3-[(R)-2-(5-苯氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-丙酸;
3-[(R)-2-(5-氟-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-丙酸乙酯;
3-[(R)-2-(5-氟-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-丙酸;
3-[(R)-2-(5-溴-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-丙酸乙酯;
3-[(R)-2-(5-溴-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-丙酸;
3-[(R)-2-(7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-丙酸;
3-[(R)-2-(5-甲氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-丙酸;
3-[(R)-2-(5-乙氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-丙酸乙酯;
3-[(R)-2-(5-乙氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-丙酸;
3-[(R)-2-(5-三氟甲氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-丙酸乙酯;
3-[(R)-2-(5-三氟甲氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-丙酸;
[(S)-2-(5-甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-唑-4-基]-乙酸;
[(S)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-唑-4-基]-乙酸;
[2-((4S,5R)-5-氨基甲基-4-苄基-二氢-唑-2-基)-5-氯-1H-吲哚-7-基]-环戊基-胺;
{2-[(R)-5-((S)-1-氨基-2-苯基-乙基)-4,5-二氢-唑-2-基]-5-氯-1H-吲哚-7-基}-环戊基-胺;
环戊基-[2-(4,5-二氢-二唑-2-基)-1H-吲哚-7-基]-胺;
[2-(5-甲基-7-环戊基氨基-1H-吲哚-2-基)-噻唑-4-基]-甲醇;
[2-(5-甲基-7-环戊基氨基-1H-吲哚-2-基)-噻唑-5-基]-甲醇;
[2-(5-甲基-7-环戊基氨基-1H-吲哚-2-基)-噻唑-4-基]-甲酸乙酯;
[2-(5-甲基-7-环戊基氨基-1H-吲哚-2-基)-噻唑-4-基]-甲酸;
[2-(7-环戊基氨基-1H-吲哚-2-基)-噻唑-4-基]-甲醇;
[2-(7-环戊基氨基-1H-吲哚-2-基)-噻唑-4-基]-甲酸甲酯;
2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-1-吗啉-4-基-乙酮;
2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-1-(吗啉-4-基)乙氨基-乙酮;
2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-1-(吗啉-4-基)丙基氨基-乙酮;
2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-1-甲氨基-乙酮;
2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-1-二甲氨基-乙酮;
2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-1-[4-(甲基)哌嗪-1-基]-乙酮;
2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-1-(3-二甲氨基吡咯烷-1-基)-乙酮;
2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-1-(哌啶-4-基)-乙酮;
2-[(R)-2-(5-氟-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-1-(4-(甲基)哌嗪-1-基)-乙酮;
2-[(R)-2-(5-氟-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-1-(吗啉-4-基)乙氨基-乙酮;
2-[(R)-2-(5-甲氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-1-(甲氨基)-4-基-乙酮;
2-[(R)-2-(5-甲氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-1-(吗啉-4-基)-乙酮;
2-[(R)-2-(7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-1-甲氨基-乙酮;
2-[(R)-2-(7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-1-(吗啉-4-基)-乙酮;
2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-1-(吗啉-4-基)乙氨基-乙酮;
2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-1-(4-(甲基)哌嗪-1-基)-乙酮;
环戊基-{5-甲磺酰基甲基-2-[(R)-4-(2-吗啉-4-基-乙基)-4,5-二氢-噻唑-2-基]-1H-吲哚-7-基}-胺;
1-(4-{2-[(R)-2-(7-环戊基氨基-5-甲磺酰基甲基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-哌嗪-1-基)-乙酮;
环戊基-[2-((R)-4-吡咯烷-1-基甲基-4,5-二氢-噻唑-2-基)-1H-吲哚-7-基]-胺;
{5-氯-2-[(R)-4-(2-二甲氨基-乙基)-4,5-二氢-噻唑-2-基]-1H-吲哚-7-基}-环戊基-胺;
{5-氯-2-[(R)-4-(2-哌嗪-1-基-乙基)-4,5-二氢-噻唑-2-基]-1H-吲哚-7-基}-环戊基-胺;
(5-氯-2-{(R)-4-[2-(4-乙磺酰基-哌嗪-1-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
1-(4-{2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-哌嗪-1-基)-2-羟基-乙酮;
{5-氯-2-[(R)-4-(2-吡唑-1-基-乙基)-4,5-二氢-噻唑-2-基]-1H-吲哚-7-基}-环戊基-胺;
(S)-1-{2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-吡咯烷-2-甲酸;
{5-氯-2-[(R)-4-(2-甲磺酰基-乙基)-4,5-二氢-噻唑-2-基]-1H-吲哚-7-基}-环戊基-胺;
3-{2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-5-甲基-3H-咪唑-4-甲酸乙酯;
3-{2-[(R)-2-(5-氯-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-5-甲基-3H-咪唑-4-甲酸;
环戊基-{2-[(R)-4-(2-甲氧基-乙基)-4,5-二氢-噻唑-2-基]-1H-吲哚-7-基}-胺;
[2-((R)-4-氨基甲基-4,5-二氢-噻唑-2-基)-1H-吲哚-7-基]-环戊基-胺;
{2-[(R)-4-((R)-3-氨基-吡咯烷-1-基乙基)-4,5-二氢-噻唑-2-基]-5-氯-1H-吲哚-7-基}-环戊基-胺;
4-[(R)-2-(7-环戊基氨基-5-甲氧基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基乙基]-哌嗪-2-酮;
{2-[(S)-4-((S)-3-氨基-吡咯烷-1-基乙基)-4,5-二氢-噻唑-2-基]-5-氯-1H-吲哚-7-基}-环戊基-胺;
(5-氯-2-{(S)-4-[2-(3-二甲氨基-苯基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
1-(4-{2-[(S)-2-(7-环戊基氨基-5-氯-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-哌嗪-1-基)-乙酮;
1-(4-{2-[(S)-2-(7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-哌嗪-1-基)-乙酮;
(5-甲氧基-2-{(R)-4-[2-(吡咯烷-1-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(5-甲磺酰基甲基-2-{(S)-4-[(2-氧代哌嗪-4-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
1-(4-{2-[(R)-2-(7-环戊基氨基-5-氯-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-哌嗪-1-基)-乙酮;
(5-氯-2-{(R)-4-[4-甲基-哌嗪-1-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(5-氯-2-{(R)-4-[4-(羟基)哌啶-1-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(5-氯-2-{(R)-4-[2-氧代哌嗪-4-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(5-氯-2-{(R)-4-[(哌啶-1-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(5-氯-2-{(R)-4-[(1,1-二氧代-硫代吗啉-4-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(5-氯-2-{(R)-4-[(2-氧代吡咯烷-1-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(5-氟-2-{(R)-4-(2-氨基乙基)-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
1-(4-{2-[(R)-2-(5-氟-7-环戊基氨基)-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-哌嗪-1-基)-2-羟基-乙酮;
(5-氟-2-{(R)-4-[(吗啉-4-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(5-氟-2-{(R)-4-(2-二甲氨基-乙基)-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(5-氟-2-{(R)-4-[(吡咯烷-1-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(5-氟-2-{(R)-4-[(1,1-二氧代-硫代吗啉-4-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(5-氟-2-{(R)-4-[(2-氧代吡咯烷-1-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
1-(4-{2-[(5-氟-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]乙基}-哌嗪-1-基)-2-羟基-乙酮;
(5-氟-2-{(R)-4-[甲磺酰基-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(2-{(R)-4-[2-二甲氨基-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(2-{(R)-4-[(哌啶-1-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
1-(4-{2-[(R)-2-(5-甲氧基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-哌嗪-1-基)-2-羟基-乙酮;
1-(4-{2-[(R)-2-(7-环戊基氨基)-5-氯-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-丙基}-哌嗪-1-基)-乙酮;
2-{(R)-4-[(吗啉-4-基)-甲基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(5-氯-2-{(R)-4-[(吗啉-4-基)-丙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(2-{(R)-4-[2-二甲氨基-甲基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(5-氯-2-{(S)-4-[(吗啉-4-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
1-(4-{2-[(S)-2-(5-苯氧基-7-环戊基氨基)-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-哌嗪-1-基)-2-羟基-乙酮;
(5-苯氧基-2-{(S)-4-[(哌嗪-1-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
叔丁基-(4-{2-[(S)-2-(5-苯氧基-7-环戊基氨基)-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-哌嗪-1-甲酸酯;
环戊基-(5-苯氧基-2-{(S)-4-[2-(3-氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪--基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-胺;
(5-苯氧基-2-{(S)-4-[2-氧代哌嗪-4-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(4-{2-[(S)-2-(5-苯氧基-7-环戊基氨基)-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-哌嗪-1-基)-环氧乙烷-2-基-甲酮;
(5-苯氧基-2-{(S)-4-[(吡啶-2-基)哌嗪-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(5-苯氧基-2-{(S)-4-[(2-氟苯基)哌嗪-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(5-氯-2-{(S)-4-[2-氧代哌嗪-4-基)-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(5-苯氧基-2-{(S)-4-[(3S)-3-(氨基)吡咯烷-1-基-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
1-(4-{2-[(S)-2-(5-苯氧基-7-环戊基氨基)-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-乙基}-哌嗪-1-基)-乙酮;
(5-氯-[(S)-2-(7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基])-吡咯烷-3-基-乙酰胺;
(5-苯氧基-2-{(S)-4-[4-(苄基)哌嗪-1-基-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(5-苯氧基-2-{(R)-4-[吡咯烷-1-基-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(5-苯氧基-2-{(S)-4-[吡咯烷-1-基-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-环戊基-胺;
(5-甲基-2-{(S)-4-[2-氧代哌嗪-4-基-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-4,4-二氟环己基-胺;
(5-甲基-2-{(S)-4-[吗啉-4-基-乙基]-4,5-二氢-噻唑-2-基}-1H-吲哚-7-基)-4,4-二氟环己基-胺;
[(R)-2-(5-氨基甲基-7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基]-甲醇;
呋喃-2-甲酸[7-环戊基氨基-2-((R)-4-羟基甲基-4,5-二氢-噻唑-2-基)-1H-吲哚-5-基甲基]-酰胺;
[(R)-2-(7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基甲氧基]-乙酸甲酯;
[(R)-2-(7-环戊基氨基-1H-吲哚-2-基)-4,5-二氢-噻唑-4-基甲氧基]-乙酸;
环戊基-{2-[(R)-4-(3-环戊基-[1,2,4]二唑-5-基甲基)-4,5-二氢-噻唑-2-基]-1H-吲哚-7-基}-胺;和
环戊基-{2-[(R)-4-(3-哌啶-1-基-[1,2,4]二唑-5-基甲基)-4,5-二氢-噻唑-2-基]-1H-吲哚-7-基}-胺,
及其药学可接受的盐、光学异构体或非对映体。
19.用于预防或治疗坏死和与坏死相关的疾病的组合物,包含治疗有效量的权利要求1定义的式(1)的化合物、其药学可接受的盐、光学异构体或非对映体作为活性成分与药学可接受的载体或稀释剂。
20.权利要求19的组合物,其中坏死和与坏死相关的疾病选自急性/慢性肝病,神经变性疾病,缺血性疾病,糖尿病,胰腺炎,细菌/病毒性败血症,坏死性直肠结肠炎,囊性纤维化,类风湿性关节炎,退行性关节炎,肾病,细菌感染,病毒感染,多发性硬化,白血病,淋巴瘤,新生儿呼吸窘迫综合征,窒息,肺结核,子宫内膜异位症,血管无力,银屑病,冻疮,类固醇治疗并发症,坏疽,褥疮,血红蛋白尿,烧伤,过热,克罗恩病,乳糜泻,间隔综合征,脊髓损伤,肌营养不良症,遗传性代谢病,支原体病,炭疽,安德森病,先天性线粒体疾病,苯丙酮尿症,胎盘梗死,梅毒和无菌性坏死。
21.权利要求19的组合物,其中坏死和与坏死相关的疾病因药物和毒性物质导致并且选自与酒精中毒相关的坏死、接触或施用或自我施用药物、化学毒素、毒气、农业化学品、重金属或因接触放射性/UV导致的损伤及其相关的坏死。
22.权利要求21的组合物,其中所述药物选自可卡因、抗生素、抗癌药、NSAID和环孢菌素。
23.权利要求19的组合物,用于保肝、肝功能改善、和预防或治疗肝病。
24.权利要求23的组合物,其中所述的肝病选自肝移植、酒精或非酒精性脂肪肝、肝纤维化、肝硬化、和因病毒或药物导致的肝炎。
25.权利要求23的组合物,其中所述的肝病是酒精急性/慢性肝病。
26.权利要求23的组合物,其中所述的肝病是脂肪酸-诱导的脂肪肝或来源于脂肪肝的急性/慢性肝病。
27.权利要求23的组合物,其中所述的肝病由活性氧(ROS)介导。
28.权利要求23的组合物,其中所述的肝病由重金属介导。
29.权利要求19的组合物,其与用于药物-衍生的坏死和与坏死相关的疾病的预防或治疗剂共同给药。
30.权利要求29的组合物,其中所述用于药物-衍生的坏死和与坏死相关的疾病的预防或治疗剂选自抗生素、抗癌药、抗病毒药、抗感染药、抗炎药、抗凝血药、脂质改善剂、细胞死亡抑制剂、用于心血管疾病的治疗剂、用于神经变性疾病的治疗剂、抗衰老药和用于代谢疾病的治疗剂。
31.权利要求23的组合物,其与选自肝细胞再生促进剂、肝功能佐剂、抗病毒药、免疫抑制剂和纤维化抑制剂的药物共同给药。
32.权利要求20的组合物,其中所述神经变性疾病是痴呆,帕金森病或亨廷顿舞蹈病。
33.权利要求20的组合物,其中所述缺血性疾病是心脏病、再灌注损伤、缺血性中风或缺血性损伤。
34.权利要求20的组合物,其中所述糖尿病因破坏胰腺细胞的物质、糖尿病并发症或糖尿病血管疾病导致。
35.权利要求34的组合物,其中所述糖尿病由病毒、高血糖症、脂肪酸、膳食、毒素或链脲霉素介导。
36.制备用于预防或治疗坏死和与坏死相关的疾病的组合物的方法,包括混合作为活性成分的权利要求1定义的式(1)的化合物、其药学可接受的盐、光学异构体或非对映体与药学可接受的载体的步骤。
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Families Citing this family (44)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8222414B2 (en) | 2007-08-17 | 2012-07-17 | Lg Life Sciences Ltd. | Indole compounds as an inhibitor of cellular necrosis |
US20090142832A1 (en) * | 2007-11-29 | 2009-06-04 | James Dalton | Indoles, Derivatives, and Analogs Thereof and Uses Therefor |
US20100267708A1 (en) | 2007-12-20 | 2010-10-21 | Lg Life Sciences Ltd. | Glucokinase activators and pharmaceutical compositions containing the same as an active ingredient |
CN101952281B (zh) * | 2008-01-04 | 2014-04-02 | 株式会社Lg生命科学 | 具有细胞、组织及器官保存效果的吲哚及吲唑衍生物 |
MX2010011138A (es) * | 2008-04-10 | 2010-11-12 | Takeda Pharmaceutical | Compuestos de anillo fusionados y uso de los mismos. |
EP2371826A4 (en) * | 2008-12-29 | 2012-06-27 | Takeda Pharmaceutical | NEW CONNECTION WITH CONDENSED RINGS AND ITS USE |
TW201119651A (en) | 2009-10-26 | 2011-06-16 | Lg Life Sciences Ltd | Pharmaceutical composition comprising indole compound |
KR101304772B1 (ko) * | 2011-04-11 | 2013-09-05 | 인제대학교 산학협력단 | NecroX―5를 유효성분으로 포함하는 미토콘드리아 기능 조절용 조성물 |
CN102766083B (zh) * | 2011-05-03 | 2014-10-22 | 中国科学院上海有机化学研究所 | 2-氨基-3-全氟乙酰吲哚类化合物及其衍生物、制备方法和应用 |
US20150038500A1 (en) * | 2011-11-25 | 2015-02-05 | Catholic University Industry-Academic Cooperation Foundation | Pharmaceutical composition for preventing and treating ophthalmic disorders |
KR101941004B1 (ko) * | 2013-03-25 | 2019-01-23 | 주식회사 엘지화학 | 조절 t 세포로의 분화 유도 및 증식 촉진을 통한 면역 반응 억제용 약학 조성물 |
KR102139338B1 (ko) * | 2013-06-24 | 2020-07-29 | 주식회사 엘지생활건강 | 인돌 화합물을 포함하는 용해도가 개선된 화장료 조성물 |
KR102139339B1 (ko) * | 2013-06-24 | 2020-07-29 | 주식회사 엘지생활건강 | 인돌 화합물을 포함하는 용해도가 개선된 화장료 조성물 |
KR101985886B1 (ko) * | 2013-06-24 | 2019-06-04 | 주식회사 엘지생활건강 | 인돌 화합물 및 판테놀을 포함하는 자외선에 의한 피부손상 예방 및 개선용 조성물 |
CN105658625B (zh) * | 2013-08-22 | 2019-05-03 | 株式会社Lg化学 | 作为细胞坏死阻碍剂的吲哚酰胺化合物 |
EP3037418B1 (en) * | 2013-08-22 | 2019-10-02 | LG Chem, Ltd. | Indole compound as inhibitor of necrosis |
CN103601662B (zh) * | 2013-11-21 | 2016-04-06 | 深圳市药品检验所 | 一种褪黑素半抗原、褪黑素完全抗原及其制备方法和应用 |
WO2015111947A1 (en) * | 2014-01-24 | 2015-07-30 | Lg Life Sciences Ltd. | Composition for preventing or treating acute lung injury and acute respiratory distress syndrome |
CN113967215A (zh) * | 2014-04-18 | 2022-01-25 | Lg 化学株式会社 | 用于预防或治疗脂肪肝疾病的组合物 |
TW201707707A (zh) * | 2015-03-26 | 2017-03-01 | Lg生命科學股份有限公司 | 包含吲哚化合物之製劑及其製備方法 |
HUE057044T2 (hu) * | 2015-04-07 | 2022-04-28 | Ela Pharma Ltd | Sejt- vagy szövetnekrózis kezelésére és/vagy megelõzésére szolgáló, katepszin C-t és/vagy CELA1-et és/vagy CELA3A-t és/vagy szerkezetileg rokon enzimeket specifikusan targetáló készítmények |
CN110494136A (zh) * | 2017-01-10 | 2019-11-22 | 瑞士苏黎世联邦理工学院 | 细胞保护性化合物及其用途 |
AU2019405477A1 (en) | 2018-12-17 | 2021-06-24 | Vertex Pharmaceuticals Incorporated | Inhibitors of APOL1 and methods of using same |
CN109884212A (zh) * | 2019-03-27 | 2019-06-14 | 清华大学深圳研究生院 | 基于化学衍生化与hplc-ms的不饱和脂肪酸定量方法 |
WO2020256429A1 (ko) * | 2019-06-19 | 2020-12-24 | 주식회사 엘지화학 | 인돌 또는 인다졸 화합물의 제조방법 |
CN114080386B (zh) | 2019-06-19 | 2024-05-31 | 株式会社Lg化学 | 制备吲哚或吲唑化合物的方法 |
CN114096534B (zh) * | 2019-06-19 | 2024-01-02 | 株式会社Lg化学 | 制备吲哚或吲唑化合物的方法 |
JPWO2021075476A1 (zh) * | 2019-10-18 | 2021-04-22 | ||
AU2021214148A1 (en) * | 2020-01-30 | 2022-07-14 | Anima Biotech Inc. | Collagen 1 translation inhibitors and methods of use thereof |
TW202139996A (zh) | 2020-03-06 | 2021-11-01 | 美商維泰克斯製藥公司 | 治療apol-1依賴性局灶性節段性腎小球硬化之方法 |
JP2023522308A (ja) * | 2020-03-31 | 2023-05-30 | エルジー・ケム・リミテッド | 膵島移植保護用組成物 |
WO2021252849A1 (en) * | 2020-06-12 | 2021-12-16 | Vertex Pharmaceuticals Incorporated | Inhibitors of apol1 and use of the same |
WO2022039506A1 (ko) | 2020-08-19 | 2022-02-24 | 주식회사 미토이뮨테라퓨틱스 | Mabc-r 감염에 의한 병적 염증 치료제로서의 미토콘드리아 표적 항산화제 |
BR112023003423A2 (pt) | 2020-08-26 | 2023-03-21 | Vertex Pharma | Inibidores de apol1 e métodos de uso destes |
WO2022220517A1 (ko) | 2021-04-12 | 2022-10-20 | 주식회사 미토이뮨테라퓨틱스 | 줄기세포의 염증 또는 노화 억제용 조성물 및 이의 염증 또는 노화 억제 방법 |
BR112023021066A2 (pt) | 2021-04-12 | 2023-12-12 | Mitoimmune Therapeutics Inc | Forma cristalina a, método para preparar a forma cristalina a, composição farmacêutica, e, composição |
EP4324829A1 (en) | 2021-04-12 | 2024-02-21 | MitoImmune Therapeutics Inc. | Sulfate of 5-[(1,1-dioxido-4-thiomorpholinyl)methyl]-2-phenyl-n-(tetrahydro-2h-pyran-4-yl)-1h-indole-7-amine, and novel crystal form thereof |
EP4382524A1 (en) | 2021-08-02 | 2024-06-12 | MitoImmune Therapeutics Inc. | Indole derivative, method for preparing same, and use thereof |
WO2023013994A1 (ko) | 2021-08-02 | 2023-02-09 | 주식회사 미토이뮨테라퓨틱스 | 신규한 인돌 유도체, 이를 포함하는 약학적 조성물, 및 이의 용도 |
WO2023106973A1 (ru) * | 2021-12-10 | 2023-06-15 | Общество С Ограниченной Ответственностью "Валента-Интеллект" | Новые гепатопротекторные средства |
KR20230115934A (ko) | 2022-01-27 | 2023-08-03 | 주식회사 미토이뮨테라퓨틱스 | 난소의 항노화용 약학적 조성물 및 이의 용도 |
KR20230140401A (ko) | 2022-03-25 | 2023-10-06 | 주식회사 미토이뮨테라퓨틱스 | 항바이러스용 약학적 조성물 및 이의 용도 |
KR20240117495A (ko) | 2023-01-25 | 2024-08-01 | 주식회사 미토이뮨테라퓨틱스 | 치환기를 가지는 인돌 유도체, 및 약학적 용도 |
KR20240118677A (ko) | 2023-01-27 | 2024-08-05 | 주식회사 미토이뮨테라퓨틱스 | 페롭토시스 억제제로서 인돌 화합물의 용도 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0673937A1 (en) * | 1993-09-10 | 1995-09-27 | Eisai Co., Ltd. | Bicyclic heterocyclic sulfonamide and sulfonic ester derivatives |
Family Cites Families (43)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB599834A (en) * | 1943-04-08 | 1948-03-22 | Francolor Sa | Improvements in or relating to the manufacture of azodyestuffs |
US3755332A (en) * | 1971-07-01 | 1973-08-28 | Ciba Geigy Corp | Substituted 4 indazolaminoquinolines |
BE792078A (fr) * | 1971-12-01 | 1973-05-29 | Wander Ag Dr A | Nouveaux derives de l'indazole, leur preparation et leur application comme medicaments |
DE2653005A1 (de) * | 1975-12-03 | 1977-06-08 | Sandoz Ag | Neue organische verbindungen, ihre verwendung und herstellung |
JPS6160648A (ja) * | 1984-08-31 | 1986-03-28 | Teikoku Hormone Mfg Co Ltd | 2−(3,5−ジアルキル−4−ヒドロキシフエニル)インド−ル誘導体 |
US5254135A (en) * | 1989-10-20 | 1993-10-19 | L'oreal | Methods for dyeing keratinous fibres with aminoindoles, compositions and devices for use |
FR2659552B2 (fr) * | 1989-10-20 | 1994-11-04 | Oreal | Procede de teinture des fibres keratiniques avec des aminoindoles, composition et dispositif de mise en óoeuvre. |
WO1992002500A1 (en) * | 1990-07-31 | 1992-02-20 | Teikoku Hormone Mfg. Co., Ltd. | 2-phenylindole derivative |
AU675932B2 (en) * | 1992-04-03 | 1997-02-27 | Pharmacia & Upjohn Company | Pharmaceutically active bicyclic-heterocyclic amines |
EP0676967A4 (en) | 1992-12-30 | 1996-10-02 | Fmc Corp | RELEASED, EXTENDED, EASY TO PRODUCE EXCIPIENT, BASED ON KONJAC GLUCOMANNANE. |
JP3545461B2 (ja) * | 1993-09-10 | 2004-07-21 | エーザイ株式会社 | 二環式ヘテロ環含有スルホンアミド誘導体 |
ATE264318T1 (de) | 1996-11-19 | 2004-04-15 | Amgen Inc | Aryl und heteroaryl substituierte kondensierte pyrrole als entzündunghemmende mittel |
FR2767475A1 (fr) * | 1997-08-25 | 1999-02-26 | Oreal | Compositions de teinture des fibres keratiniques contenant des derives d'indazoles et procede |
US6858577B1 (en) * | 1999-06-29 | 2005-02-22 | Ortho-Mcneil Pharmaceutical, Inc. | Indole peptidomimetics as thrombin receptor antagonists |
EP1212327B8 (en) * | 1999-09-17 | 2004-02-25 | Abbott GmbH & Co. KG | Pyrazolopyrimidines as therapeutic agents |
US7217722B2 (en) * | 2000-02-01 | 2007-05-15 | Kirin Beer Kabushiki Kaisha | Nitrogen-containing compounds having kinase inhibitory activity and drugs containing the same |
NZ520299A (en) * | 2000-02-03 | 2004-05-28 | Eisai Co Ltd | Integrin expression inhibitors containing sulphonamide derivatives |
AU2001280187A1 (en) * | 2000-08-28 | 2002-03-13 | Toray Industries, Inc. | Cyclic amine derivatives |
EP1847263A3 (en) * | 2000-12-18 | 2009-08-26 | Institute of Medicinal Molecular Design, Inc. | Inhibitors against the production and release of inflammatory cytokines |
KR20040007497A (ko) | 2001-04-16 | 2004-01-24 | 에자이 가부시키가이샤 | 신규 1h-인다졸 화합물 |
WO2002100833A1 (fr) * | 2001-06-12 | 2002-12-19 | Sumitomo Pharmaceuticals Company, Limited | Inhibiteurs de rho kinase |
ITMI20012060A1 (it) * | 2001-10-05 | 2003-04-05 | Recordati Chem Pharm | Nuovi eterocilcli n-acilati |
TW200306819A (en) * | 2002-01-25 | 2003-12-01 | Vertex Pharma | Indazole compounds useful as protein kinase inhibitors |
DE10228103A1 (de) | 2002-06-24 | 2004-01-15 | Bayer Cropscience Ag | Fungizide Wirkstoffkombinationen |
CN101423497A (zh) | 2002-07-19 | 2009-05-06 | 记忆药物公司 | 作为磷酸二酯酶4抑制剂的6-氨基-1h-吲唑和4-氨基苯并呋喃化合物 |
AU2003265336B8 (en) * | 2002-07-29 | 2009-04-23 | Rigel Pharmaceuticals, Inc. | Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds |
US20040110802A1 (en) * | 2002-08-23 | 2004-06-10 | Atli Thorarensen | Antibacterial benzoic acid derivatives |
KR101129933B1 (ko) * | 2002-09-25 | 2012-03-23 | 메모리 파마슈티칼스 코포레이션 | 인다졸, 벤조티아졸 및 벤조이소티아졸 및 그의 제조 및용도 |
CA2511806A1 (en) * | 2003-01-22 | 2004-08-12 | Eli Lilly And Company | Indole-derivative modulators of steroid hormone nuclear receptors |
US7563748B2 (en) * | 2003-06-23 | 2009-07-21 | Cognis Ip Management Gmbh | Alcohol alkoxylate carriers for pesticide active ingredients |
KR101163800B1 (ko) * | 2003-10-15 | 2012-07-09 | 산텐 세이야꾸 가부시키가이샤 | 신규 인다졸 유도체 |
BRPI0507657A (pt) * | 2004-03-03 | 2007-07-10 | Lilly Co Eli | composto ou um sal farmaceuticamente aceitável do mesmo, composição farmacêutica, método para tratar um distúrbio, e, uso de um composto ou um sal farmaceuticamente aceitável do mesmo |
EP1769092A4 (en) | 2004-06-29 | 2008-08-06 | Europ Nickel Plc | IMPROVED LIXIVIATION OF BASE METALS |
EP1632491A1 (en) | 2004-08-30 | 2006-03-08 | Laboratorios Del Dr. Esteve, S.A. | Substituted indole compounds and their use as 5-HT6 receptor modulators |
WO2006058338A2 (en) * | 2004-11-29 | 2006-06-01 | Janssen Pharmaceutica N.V. | 4 - piperidinecarboxamide derivatives as modulators of vanilloid vr1 receptor |
WO2006062982A2 (en) * | 2004-12-07 | 2006-06-15 | Locus Pharmaceuticals, Inc. | Urea inhibitors of map kinases |
JP5094394B2 (ja) | 2005-04-20 | 2012-12-12 | 武田薬品工業株式会社 | 縮合複素環化合物 |
WO2007076161A2 (en) * | 2005-12-27 | 2007-07-05 | Myriad Genetics, Inc | Compounds with therapeutic activity |
TW200736232A (en) * | 2006-01-26 | 2007-10-01 | Astrazeneca Ab | Pyrimidine derivatives |
BRPI0717722A2 (pt) * | 2006-10-19 | 2013-10-29 | Takeda Pharmaceutical | Composto ou um sal do mesmo, pró-droga, ativador de glicoquinase, agente farmacêutico, métodos para ativar uma glicoquinase em um mamífero e para a profilaxia ou o tratamento de diabetes ou obesidade em um mamífero, e, uso do composto ou uma pró-droga do mesmo |
US8222414B2 (en) * | 2007-08-17 | 2012-07-17 | Lg Life Sciences Ltd. | Indole compounds as an inhibitor of cellular necrosis |
US20100267708A1 (en) * | 2007-12-20 | 2010-10-21 | Lg Life Sciences Ltd. | Glucokinase activators and pharmaceutical compositions containing the same as an active ingredient |
CN101952281B (zh) * | 2008-01-04 | 2014-04-02 | 株式会社Lg生命科学 | 具有细胞、组织及器官保存效果的吲哚及吲唑衍生物 |
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Patent Citations (1)
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EP0673937A1 (en) * | 1993-09-10 | 1995-09-27 | Eisai Co., Ltd. | Bicyclic heterocyclic sulfonamide and sulfonic ester derivatives |
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