CN117098753A - 整合应激反应途径的调节剂 - Google Patents
整合应激反应途径的调节剂 Download PDFInfo
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- CN117098753A CN117098753A CN202180086788.0A CN202180086788A CN117098753A CN 117098753 A CN117098753 A CN 117098753A CN 202180086788 A CN202180086788 A CN 202180086788A CN 117098753 A CN117098753 A CN 117098753A
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- chloro
- fluorophenoxy
- piperidine
- acetamido
- carboxamide
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Neurology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Electrochromic Elements, Electrophoresis, Or Variable Reflection Or Absorption Elements (AREA)
- Amplifiers (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中R1、R2、R2a、R3、R4、R4a、R4b、R4c、R4d、R4e、R4f、R5、R6具有如说明书和权利要求中所指明的含义。本发明还涉及包含所述化合物的药物组合物、它们作为药物的用途以及在治疗或预防一种或多种与整合应激反应有关的疾病或障碍的方法中的用途
Description
本发明涉及式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体
其中R1,R2,R2a,R3,R4,R4a,R4b,R4c,R4d,R4e,R4f,R5和R6具有如在说明书和权利要求书中指出的含义。本发明进一步涉及包含所述化合物的药物组合物、它们作为药物以及在用于治疗或预防一种或多种与整合应激反应有关的疾病或障碍的方法中的用途。
整合应激反应(ISR)是所有真核生物共有的细胞应激反应(1)。ISR信号传递的调节异常具有重要的病理学后果,尤其是与炎症、病毒感染、糖尿病、癌症和神经变性疾病有关的后果。
ISR是不同类型的细胞应激的共同特征,导致在丝氨酸51上的真核翻译起始因子2(eIF2α)的α亚基的磷酸化,从而抑制正常蛋白合成和应激反应基因的表达(2)。在哺乳动物细胞中,所述磷酸化由四个eIF2α激酶的家族进行,即:PKR-样ER激酶(PERK)、双链RNA依赖性蛋白激酶(PKR)、亚铁血红素调节的eIF2α激酶(HRI)和一般性调控阻遏蛋白激酶2(GCN2),各自响应于不同的环境和生理应激(3)。
eIF2α与eIF2β和eIF2γ一起形成eIF2复合物,这是正常mRNA翻译起始的关键参与者(4)。eIF2复合物结合GTP和Met-tRNAi,从而形成三元复合物(eIF2-GTP-Met-tRNAi),其被核糖体募集用于翻译起始(5,6)。
eIF2B是由5种亚基(α、β、γ、δ、ε)组成的异十聚体复合物,所述亚基一式两份地形成GEF活性十聚体(7)。
响应于ISR活化,磷酸化的eIF2α抑制eIF2B介导的GDP与GTP的交换,导致三元复合物形成减少,并因此抑制以核糖体与5'AUG起始密码子结合为特征的正常mRNA的翻译(8)。在三元复合物丰度降低的这些条件下,包括编码转录因子ATF4的mRNA在内的几种特定mRNA的翻译通过涉及上游ORF(uORF)的翻译改变的机制被活化(7,9,10)。这些mRNA通常包含一个或多个uORF,所述uORF通常在未受应激的细胞中起作用以限制核糖体向主要编码ORF的流动。例如,在正常条件下,在ATF的5'UTR中的uORF占据核糖体并阻止ATF4的编码序列的翻译。但是,在应激条件下,即在三元复合物形成减少的条件下,核糖体扫描经过这些上游ORF并在ATF4编码ORF处开始翻译的可能性增加。ATF4和其它以这种方式表达的应激反应因子随后控制着一系列其它应激反应基因的表达。急性期在于旨在恢复稳态的蛋白的表达,而慢性期导致促凋亡因子的表达(1,11,12,13)。
ISR信号传递的标志物的上调已在多种病症中得到证实,其中包括癌症和神经变性疾病。在癌症中,ER应激调节的翻译增加对低氧条件的耐受性并促进肿瘤生长(14,15,16),并且已经证明通过基因靶向对PERK的删除可以减慢从转化的PERK-/-小鼠胚胎成纤维细胞衍生出的肿瘤的生长(14,17)。此外,最近的一份报告已经提供了如下的概念证据:使用在小鼠中的源自患者的异种移植模型,eIF2B的活化剂有效治疗一种侵袭性转移性前列腺癌(28)。总之,细胞保护性ISR信号传递的预防可能代表一种有效的抗增殖策略,其用于治疗至少某些形式的癌症。
此外,ISR信号传递的调节可以证明在保持突触功能和减少神经元衰退中是有效的,在特征在于错误折叠的蛋白和未折叠蛋白反应(UPR)的激活的神经变性疾病(诸如肌萎缩性侧索硬化(ALS)、额颞叶痴呆(FTD)、阿尔茨海默氏病(AD)、帕金森病(PD)和JakobCreutzfeld(朊病毒)疾病)中也是如此(18,19,20)。对于朊病毒病(存在的神经变性疾病的一个例子),其中已经表明,ISR信号传递的药理学以及遗传抑制可以使蛋白翻译水平正常化、挽救突触功能并预防神经元损失(21)。具体地,通过控制磷酸化eIF2α水平的磷酸酶的过表达来降低磷酸化eIF2α的水平会增加感染了朊病毒的小鼠的存活率,而持续的eIF2α磷酸化降低存活率(22)。
此外,控制蛋白表达水平对于适当脑功能的重要性的直接证据以影响eIF2和eIF2B的功能的罕见遗传性疾病的形式存在。破坏eIF2的复杂完整性且因此导致降低的正常蛋白表达水平的eIF2γ中的突变与智力障碍综合征(ID)相关(23)。在eIF2B的亚基中的部分功能丧失突变已被证实是罕见的脑白质营养不良白质消融性疾病(VWMD)的原因(24,25)。具体地,与ISRIB相关的小分子在VWMD小鼠模型中对eIF2B部分功能丧失的稳定化已被证实会减少ISR标记物并改善功能以及病理学终点(26,27)。
eIF2α途径的调节剂描述于WO 2014/144952 A2中。WO 2017/193030 A1、WO 2017/193034 A1、WO 2017/193041 A1和WO 2017/193063 A1描述了整合应激途径的调节剂。WO2017/212423 A1、WO 2017/212425 A1、WO 2018/225093 A1、WO 2019/008506 A1和WO2019/008507 A1描述了ATF4途径的抑制剂。WO 2019/032743A1、WO 2019/046779 A1、WO2020/167994 A1、WO 2020/168011 A1和WO 2020/181247 A1涉及真核起始因子2B调节剂。在WO 2020/77217 A1中,描述了可用于调节整合应激反应(ISR)和用于治疗相关的疾病、障碍和病症的化合物、组合物和方法。
描述整合应激途径的调节剂的其它文献是WO 2019/090069 A1、WO 2019/090074A1、WO 2019/090076 A1、WO 2019/090078A1、WO 2019/090081 A1、WO 2019/090082 A1、WO2019/090085 A1、WO 2019/090088 A1、WO 2019/090090 A1、WO 2020/223536 A1、WO 2020/223538 A1、WO 2020/252207 A1、WO 2020/252205 A1、WO 2021/180774 A1、WO 2021/151865 A1、WO 2020/216764 A1,WO 2020/216766 A1和欧洲专利申请20203311.4、21192154.9和20203309.8。
真核起始因子的调节剂描述于WO 2019/183589 A1中。WO 2019/118785 A2、WO2019/236710 A1和WO 2020/176428 A1描述了整合应激反应途径的抑制剂。作为ATF4抑制剂的杂芳基衍生物描述于WO 2019/193540 A1中。作为ATF4抑制剂的双环芳族环衍生物描述于WO 2019/193541 A1中。WO 2020/031107 A1和WO 2020/012339 A1描述了ATF4途径的抑制剂。
但是,仍然需要可用作整合应激反应途径的调节剂的具有良好药代动力学性能的新化合物。
因而,本发明的一个目的是提供一类新的作为整合应激反应途径的调节剂的化合物,其可以有效治疗整合应激反应途径相关的疾病并且其可以显示出改善的药学相关性能,包括活性、溶解度、选择性、ADMET性能和/或减少的副作用。
因此,本发明提供式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体
其中
R1为H或C1-4烷基,优选为H,其中C1-4烷基任选被一个或多个相同或不同的卤素取代;
R2为H、F或C1-4烷基,其中C1-4烷基任选被一个或多个相同或不同的卤素取代;
R2a为H或F,优选为H;
R3为苯基或6元芳族杂环基,其中R3任选被一个或多个相同或不同的R7取代;
R7为卤素、CN、C(O)OR8、OR8、C(O)R8、C(O)N(R8R8a)、S(O)2N(R8R8a)、S(O)N(R8R8a)、S(O)2R8、S(O)R8、N(R8)S(O)2N(R8aR8b)、SR8、N(R8R8a)、NO2、OC(O)R8、N(R8)C(O)R8a、N(R8)S(O)2R8a、N(R8)S(O)R8a、N(R8)C(O)OR8a、N(R8)C(O)N(R8aR8b)、OC(O)N(R8R8a)、C1-6烷基、C2-6烯基或C2-6炔基,其中C1-6烷基、C2-6烯基和C2-6炔基任选被一个或多个相同或不同的R9取代;
R8、R8a、R8b独立地选自H、C1-6烷基、C2-6烯基和C2-6炔基,其中C1-6烷基、C2-6烯基和C2-6炔基任选被一个或多个相同或不同的卤素取代;
R9是卤素、CN、C(O)OR10、OR10、C(O)R10、C(O)N(R10R10a)、S(O)2N(R10R10a)、S(O)N(R10R10a)、S(O)2R10、S(O)R10、N(R10)S(O)2N(R10aR10b)、SR10、N(R10R10a)、NO2、OC(O)R10、N(R10)C(O)R10a、N(R10)SO2R10a、N(R10)S(O)R10a、N(R10)C(O)N(R10aR10b)、N(R10)C(O)OR10a或OC(O)N(R10R10a);
R10、R10a、R10b独立地选自H、C1-6烷基、C2-6烯基和C2-6炔基,其中C1-6烷基、C2-6烯基和C2-6炔基任选被一个或多个相同或不同的卤素取代。
R4是H、C(O)OC1-4烷基或C1-4烷基,其中C(O)OC1-4烷基和C1-4烷基任选被一个或多个选自以下的取代基取代:卤素、OH和OC1-3烷基,其中取代基相同或不同;
R4a、R4b、R4c、R4f独立地选自H、卤素和C1-4烷基;和
R4d、R4e独立地选自H、OH、OC1-4烷基、卤素和C1-4烷基;
或者R4d和R4e之一与R4形成亚甲基或亚乙基;
或者R4与R4c形成亚乙基;
或者R4b与R4d形成共价单键;
R5为H或C1-6烷基,其中C1-6烷基任选被一个或多个相同或不同的卤素取代;和
R6是R11;或者
R5和R6连接,与它们所连接的氮原子一起形成环A1;
R11为OR12、SR12a、N(R12R12a)、A2、C1-6烷基、C2-6烯基或C2-6炔基,其中C1-6烷基、C2-6烯基和C2-6炔基任选被一个或多个相同或不同的R13取代;
R12、R12a独立地选自H、C1-6烷基、C2-6烯基、C2-6炔基和A2,其中C1-6烷基、C2-6烯基和C2-6炔基任选被一个或多个相同或不同的R15取代;
R13为卤素、OR14、CN或A2;
R14为H或C1-4烷基,其中C1-4烷基任选被一个或多个相同或不同的卤素取代;
R15为卤素、CN、OR14、OA2或A2;
A1为3至7元杂环基或7至12元杂双环基,其中A1任选被一个或多个相同或不同的R16取代;
A2为苯基、萘基、C3-7环烷基、C4-12双环烷基、3至7元杂环基或7至12元杂双环基,其中A2任选被一个或多个相同或不同的R16a取代;
R16、R16a独立地选自R17、OH、OR17、卤素和CN;
R17为环丙基、C1-6烷基、C2-6烯基或C2-6炔基,其中R17任选被一个或多个相同或不同的R18取代;
R18为卤素、CN或OR19;
R19为H或C1-4烷基,其中C1-4烷基任选被一个或多个相同或不同的卤素取代。
优选排除以下化合物:
这些化合物在WO2020/216766A1第71和72页上被称为中间体27、28和26,并且就本发明的化合物本身而言优选排除在本发明的范围之外。
令人惊讶的是,根据本发明所公开的实施例化合物具有有利的物理化学性质和/或选择性,它们结合起来有助于实现有益的治疗功效,同时限制意外的后果。
在变量或取代基可以选自一组不同变体并且这样的变量或取代基出现超过一次的情况下,各个变体可以相同或不同。
在本发明的含义内,如下使用术语:
术语“任选地被取代的”是指未被取代的或被取代的。通常,但不限于,“一个或多个取代基”是指一个、两个或三个取代基,优选一个或两个取代基,且更优选一个取代基。通常,这些取代基可以相同或不同。术语“一个或多个取代基”还表示例如一个、两个、三个、四个或五个,优选例如一个、两个、三个或四个。
“烷基”是指直链或支链烃链。烷基碳的每个氢可以被进一步指定的取代基替代。
“烯基”是指含有至少一个碳-碳双键的直链或支链烃链。烯基碳的每个氢可以被进一步指定的取代基替代。
“炔基”是指含有至少一个碳-碳三键的直链或支链烃链。炔基碳的每个氢可以被进一步指定的取代基替代。
“C1-4烷基”是指具有1-4个碳原子的烷基链,如果存在于分子的末端,例如:甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基,或者,当分子的两个部分通过烷基基团连接时,例如-CH2-、-CH2-CH2-、-CH(CH3)-、-CH2-CH2-CH2-、-CH(C2H5)-、-C(CH3)2-。C1-4烷基碳的每个氢可以被进一步指定的取代基替代。相应地定义术语“C1-3烷基”。
“C1-6烷基”是指具有1-6个碳原子的烷基链,如果存在于分子的末端,例如:C1-4烷基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、正己基,或者,当分子的两个部分通过烷基基团连接时,例如-CH2-、-CH2-CH2-、-CH(CH3)-、-CH2-CH2-CH2-、-CH(C2H5)-、-C(CH3)2-。C1-6烷基碳的每个氢可以被进一步指定的取代基替代。
“C2-6烯基”是指具有2-6个碳原子的烯基链,如果存在于分子的末端,例如:-CH=CH2、-CH=CH-CH3、-CH2-CH=CH2、-CH=CH-CH2-CH3、-CH=CH-CH=CH2,或者,当分子的两个部分通过烯基基团连接时,例如-CH=CH-。C2-6烯基碳的每个氢可以被进一步指定的取代基替代。
“C2-6炔基”是指具有2-6个碳原子的炔基链,如果存在于分子的末端,例如:-C≡CH、-CH2-C≡CH、CH2-CH2-C≡CH、CH2-C≡C-CH3,或者,当分子的两个部分通过炔基基团连接时,例如-C≡C-。C2-6炔基碳的每个氢可以被进一步指定的取代基替代。
“C3-7环烷基”或“C3-7环烷基环”是指具有3-7个碳原子的环烷基链,例如环丙基、环丁基、环戊基、环己基、环己烯基、环庚基。优选地,环烷基是指环丙基、环丁基、环戊基、环己基或环庚基。环烷基碳的每个氢可以被本文进一步指定的取代基替代。相应地定义术语“C3-5环烷基”或“C3-5环烷基环”。
“C5亚环烷基”是指具有5个碳原子的二价环烷基,即二价环戊基环。
“C5亚环烯基”是指二价亚环烯基,即二价环戊烯或环戊二烯。
“C4-12双环烷基”或“C4-12双环烷基环”是指具有4-12个碳原子的双环稠合的、桥连的或螺烷基链,例如六氢茚满、八氢并环戊二烯、双环[2.2.1]庚烷或螺(3.2)己烷。双环烷基碳的每个氢可以被本文进一步指定的取代基替代。
“卤素”是指氟、氯、溴或碘。通常优选地卤素是氟或氯。
“3-7元杂环基”或“3-7元杂环”是指具有3、4、5、6或7个环原子的环,其可以含有至多最大数目的双键(芳族环或完全饱和、部分饱和或不饱和的非芳族环),其中至少一个环原子直至4个环原子被选自硫(包括-S(O)-、-S(O)2-)、氧和氮(包括=N(O)-)的杂原子替代,且其中所述环经由碳或氮原子连接至分子的其余部分。3-7元杂环的例子是氮杂环丙烷、氮杂环丁烷、氧杂环丁烷、硫杂环丁烷、呋喃、噻吩、吡咯、吡咯啉、咪唑、咪唑啉、吡唑、吡唑啉、噁唑、噁唑啉、异噁唑、异噁唑啉、噻唑、噻唑啉、异噻唑、异噻唑啉、噻二唑、噻二唑啉、四氢呋喃、四氢噻吩、吡咯烷、咪唑烷、吡唑烷、噁唑烷、异噁唑烷、噻唑烷、异噻唑烷、噻二唑烷、环丁砜、吡喃、二氢吡喃、四氢吡喃、咪唑烷、吡啶、哒嗪、吡嗪、嘧啶、哌嗪、哌啶、吗啉、四唑、三唑、三唑烷、四唑烷、二氮杂环庚烷、氮杂环庚三烯或高哌嗪。术语“5-6元杂环基”或“5-6元杂环”相应地定义且包括5-6元芳族杂环基或杂环。术语“5元杂环基”或“5元杂环”相应地定义且包括5元芳族杂环基或杂环。
术语“含有氮环原子的5元亚杂环基”是指二价5元杂环,其中五个环原子中的至少一个是氮原子并且其中所述环经由碳或氮原子连接至分子的其余部分。
“饱和的4-7元杂环基”或“饱和的4-7元杂环”是指完全饱和的“4-7元杂环基”或“4-7元杂环”。
“4-7元至少部分饱和的杂环基”或“4-7元至少部分饱和的杂环”是指至少部分饱和的“4-7元杂环基”或“4-7元杂环”。
“5-6元芳族杂环基”或“5-6元芳族杂环”是指衍生自环戊二烯基或苯的杂环,其中至少一个碳原子被选自硫(包括-S(O)-、-S(O)2-)、氧和氮(包括=N(O)-)的杂原子替代。这样的杂环的例子是呋喃、噻吩、吡咯、咪唑、吡唑、噁唑、异噁唑、噻唑、异噻唑、噻二唑、三唑、四唑、吡啶、嘧啶、哒嗪、吡嗪、三嗪。
“5元芳族杂环基”或“5元芳族杂环”是指衍生自环戊二烯基的杂环,其中至少一个碳原子被选自硫(包括-S(O)-、-S(O)2-)、氧和氮(包括=N(O)-)的杂原子替代。这样的杂环的例子是呋喃、噻吩、吡咯、咪唑、吡唑、噁唑、异噁唑、噻唑、异噻唑、噻二唑、三唑、四唑。
“6元芳族杂环基”或“6元芳族杂环”是指衍生自苯的杂环,其中至少一个碳原子被选自硫(包括-S(O)-、-S(O)2-)、氧和氮(包括=N(O)-)的杂原子替代。这样的杂环的例子是吡啶、嘧啶、哒嗪、吡嗪、三嗪。
“7-12元杂双环基”或“7-12元杂双环”是指具有7-12个环原子的两个环的杂环系统,其中两个环共享至少一个环原子,并且其可以含有至多最大数目的双键(芳族环或完全饱和、部分饱和或不饱和的非芳族环),其中至少一个环原子直到6个环原子被选自硫(包括-S(O)-、-S(O)2-)、氧和氮(包括=N(O)-)的杂原子替代,且其中所述环经由碳或氮原子连接至分子的其余部分。7-12元杂双环的例子是吲哚、异吲哚、吲哚啉、苯并呋喃、苯并噻吩、苯并噁唑、苯并异噁唑、苯并噻唑、苯并二氧杂环戊烯、苯并异噻唑、苯并咪唑、苯并咪唑啉、喹啉、喹唑啉、二氢喹唑啉、喹啉、二氢喹啉、四氢喹啉、十氢喹啉、异喹啉、十氢异喹啉、四氢异喹啉、二氢异喹啉、苯并氮杂环庚三烯、嘌呤或蝶啶。术语7-12元杂双环还包括两个环的螺结构如6-氧杂-2-氮杂螺[3,4]辛烷、2-氧杂-6-氮杂螺[3.3]庚烷-6-基或2,6-二氮杂螺[3.3]庚烷-6-基,或桥连杂环如8-氮杂-双环[3.2.1]辛烷或2,5-二氮杂双环[2.2.2]辛烷-2-基或3,8-二氮杂双环[3.2.1]辛烷。
“饱和的7-12元杂双环基”或“饱和的7-12元杂双环”是指完全饱和的“7-12元杂双环基”或“7-12元杂双环”。
“7-12元至少部分饱和的杂双环基”或“7-12元至少部分饱和的杂双环”是指至少部分饱和的“7-12元杂双环基”或“7-12元杂双环”。
“9-11元芳族杂双环基”或“9-11元芳族杂双环”是指两个环的杂环系统,其中至少一个环是芳族的,并且其中所述杂环系统具有9-11个环原子,其中两个环共享两个环原子,并且其可以含有至多最大数目的双键(完全或部分芳族的),其中至少一个环原子直到6个环原子被选自硫(包括-S(O)-、-S(O)2-)、氧和氮(包括=N(O)-)的杂原子替代,且其中所述环经由碳或氮原子连接至分子的其余部分。9-11元芳族杂双环的例子是吲哚、吲哚啉、苯并呋喃、苯并噻吩、苯并噁唑、苯并异噁唑、苯并噻唑、苯并异噻唑、苯并咪唑、苯并咪唑啉、喹啉、喹唑啉、二氢喹唑啉、二氢喹啉、四氢喹啉、异喹啉、四氢异喹啉、二氢异喹啉、苯并氮杂环庚三烯、嘌呤或蝶啶。术语“9-10元芳族杂双环基”或“9-10元芳族杂双环”相应地定义。
优选的式(I)的化合物是其中所含的一个或多个残基具有上面或下面给出的含义的那些化合物,其中优选的取代基定义的所有组合都是本发明的主题。关于所有优选的式(I)的化合物,本发明还包括所有互变异构和立体异构形式及其所有比率的混合物,以及它们的药学上可接受的盐。
在本发明的优选实施方案中,下面提到的取代基独立地具有下列含义。因此,这些取代基中的一个或多个可以具有下面给出的优选的或更优选的含义。
优选地,R4为H、CH3、CH2CH3或CH2CH2OCH3;更优选H或CH3;甚至更优选H。
优选地,R4a、R4b、R4c、R4f独立地选自H、卤素和C1-4烷基并且R4d、R4e独立地选自H、OH、OC1-4烷基、卤素和C1-4烷基;更优选R4a、R4b、R4c、R4f、R4d、R4e独立地选自H、F和CH3;甚至更优选地,R4a、R4b、R4c、R4f、R4d、R4e是H。
优选地,R1是H或CH3;更优选H。
优选地,R2是H、F或CH3,更优选H。
优选地,式(I)中的R1、R2、R2a、R4、R4a、R4b、R4c、R4f、R4d、R4e是H,得到式(Ia)
优选地,R3是苯基或吡啶基,更优选苯基,其中R3任选地被一个或多个相同或不同的R7取代。
优选地,R3被一个、两个或三个、更优选一个或两个、甚至更优选两个相同或不同的R7取代。
优选地,R7为F、Cl、Br、CN、CHF2、CF3、OCH3、OCF3、CH=O、CH2OH或CH3;更优选R7是CF3、F或Cl;甚至更优选F或Cl。
优选地,选择式(I)中的R1、R2、R2a、R4、R4a、R4b、R4c、R4f、R4d、R4e、R3得到式(Ib)
其中每个R7独立地选自卤素和CF3。
优选地,选择式(Ib)中的R7基团以得到式(Ib1)
优选地,R5是H或CH3,更优选H。
优选地,R6为R11且R11为C1-6烷基或C1-6烯基,其中C1-6烷基和C1-6烯基被一个或多个相同或不同的R13取代。
优选地,R6是R11并且R11是C1-6烷基,更优选乙基或正丙基,其中C1-6烷基被一个R13取代。
优选地,R6是R11并且R11是乙基或正丙基,各自被一个R13取代,其中R13是OR14,优选OCF3。
优选地,R6为R11且R11为C1-6烷基,更优选正丙基或正戊基,其中C1-6烷基被三个F取代;更优选R11是3,3,3-三氟丙基或5,5,5-三氟戊基。
优选地,R6为R11且R11为C1-6烷基,优选甲基,其中C1-6烷基被一个R13取代,其中R13为A2,优选苯基、吡啶基、吡唑基、噁唑基、环丁基、环己基、呋喃基、双环[3.1.0]己-3-基或6-氧杂螺[3.4]辛-7-基。优选地,R6为R11且R11为C1-6烷基,优选甲基,其中C1-6烷基被一个R13取代,其中R13为A2,优选苯基、吡啶基、环丁基、环己基、呋喃基、双环[3.1.0]己-3-基或6-氧杂螺[3.4]辛-7-基。
优选地,R6为R11且R11为A2,优选苯基、吡啶基、吡嗪基、嘧啶基、哒嗪基、苯并二氧杂环戊烯基、环己基、环戊基、环丁基、吡唑基、噁唑基或氧杂环戊烷基。优选地,R6为R11且R11为A2,优选苯基、吡啶基、吡嗪基、嘧啶基、哒嗪基、环己基、环丁基、吡唑基、噁唑基或氧杂环戊烷基。
优选地,A2未被取代或被一个或两个R16a取代。
优选地,R16a是CH3、CHF2、CF3、CH2CF3、OCHF2、OCH2CF3、OCF3、OCH3、F或Cl。
优选地,R5和R6连接以与它们所连接的氮原子一起形成环A1。
优选地,A1为氮杂环丁烷、哌啶、氧氮杂环庚烷、二氢吲哚、异二氢吲哚、四氢异喹啉氮杂双环[3.1.0]己烷或氮杂螺[3.3]庚烷,其中A1任选被一个或多个相同或不同的R16取代。
优选地,A1未被取代或被一个R16取代。
优选地,R16是CF3、OCF3或OCH2CH2OCF3。
其中一些或所有上述基团具有优选或更优选含义的式(I)化合物也是本发明的目的。
对于本发明优选的具体化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,选择式(I)中的R1,R2,R2a,R3,R4,R4a,R4b,R4c,R4d,R4e,R4f,R5,R6得到
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[3-(三氟甲氧基)丙基]氨基甲酰基}哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[3-(三氟甲氧基)丙基]哌啶-2-甲酰胺盐酸盐;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-({[4-(三氟甲基)苯基]甲基}氨基甲酰基)哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-{[4-(三氟甲基)苯基]甲基}哌啶-2-甲酰胺;
2-(4-氯-3-氟苯氧基)-N-[(3S,6R)-6-{3-[2-(三氟甲氧基)乙氧基]氮杂环丁烷-1-羰基}哌啶-3-基]乙酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[2-(三氟甲氧基)乙氧基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-[(4-氯苯基)氨基甲酰基]哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-(4-氯苯基)哌啶-2-甲酰胺;
(2S,5R)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-(4-氯苯基)哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-苯基哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-(3-氯苯基)哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[3-(三氟甲基)苯基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[3-(三氟甲氧基)苯基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[(5-氯吡啶-2-基)甲基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[(1s,4s)-4-(三氟甲氧基)环己基]哌啶-2-甲酰胺;
(2R,5S)-N-(4-氯-2-甲氧基苯基)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-{[5-(三氟甲基)呋喃-2-基]甲基}哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-{[4-(三氟甲基)呋喃-2-基]甲基}哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-{[(1s,4s)-4-(三氟甲基)环己基]甲基}哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-(3-甲氧基苯基)哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[4-氟-3-(三氟甲基)苯基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[5-(三氟甲基)吡啶-3-基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-(3-氟苯基)哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[3-(二氟甲基)苯基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-(5-氯吡啶-2-基)哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[5-甲基-1-(2,2,2-三氟乙基)-1H-吡唑-4-基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[(1s,3s)-3-(三氟甲氧基)环丁基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-(3,5-二甲基苯基)哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-(5,5,5-三氟戊基)哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[3-(二氟甲氧基)苯基]哌啶-2-甲酰胺;
(2S,5R)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[3-(三氟甲基)苯基]哌啶-2-甲酰胺;
(2R,5S)-2-[[3,5-双(三氟甲基)苯基]氨基甲酰基]-5-[[2-(4-氯-3-氟-苯氧基)乙酰基]氨基]哌啶-1-甲酸叔丁酯;
(2R,5S)-N-[3,5-双(三氟甲基)苯基]-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[1-(三氟甲基)-1H-吡唑-3-基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[2-氟-5-(三氟甲基)苯基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[2-氟-3-(三氟甲基)苯基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[6-(三氟甲氧基)吡啶-2-基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[4-(三氟甲基)吡啶-2-基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{3-[2-(三氟甲氧基)乙氧基]氮杂环丁烷-1-羰基}哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[2-(三氟甲氧基)乙氧基]氨基甲酰基}哌啶-1-甲酸叔丁酯;
(2S,5R)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-[(4-氯苯基)氨基甲酰基]哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-(苯基氨基甲酰基)哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-[(3-氯苯基)氨基甲酰基]哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[3-(三氟甲基)苯基]氨基甲酰基}哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[3-(三氟甲氧基)苯基]氨基甲酰基}哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[(5-氯吡啶-2-基)甲基]氨基甲酰基}哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[(1s,4s)-4-(三氟甲氧基)环己基]氨基甲酰基}哌啶-1-甲酸叔丁酯;
(2R,5S)-2-[(4-氯-2-甲氧基苯基)氨基甲酰基]-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-({[5-(三氟甲基)呋喃-2-基]甲基}氨基甲酰基)哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-({[4-(三氟甲基)呋喃-2-基]甲基}氨基甲酰基)哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-({[(1s,4s)-4-(三氟甲基)环己基]甲基}氨基甲酰基)哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-[(3-甲氧基苯基)氨基甲酰基]哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[4-氟-3-(三氟甲基)苯基]氨基甲酰基}哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[5-(三氟甲基)吡啶-3-基]氨基甲酰基}哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-[(3-氟苯基)氨基甲酰基]哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[3-(二氟甲基)苯基]氨基甲酰基}哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-[(5-氯吡啶-2-基)氨基甲酰基]哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[5-甲基-1-(2,2,2-三氟乙基)-1H-吡唑-4-基]氨基甲酰基}哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[(1s,3s)-3-(三氟甲氧基)环丁基]氨基甲酰基}哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-[(3,5-二甲基苯基)氨基甲酰基]哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-[(5,5,5-三氟戊基)氨基甲酰基]哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[3-(二氟甲氧基)苯基]氨基甲酰基}哌啶-1-甲酸叔丁酯;
(2S,5R)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[3-(三氟甲基)苯基]氨基甲酰基}哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[1-(三氟甲基)-1H-吡唑-3-基]氨基甲酰基}哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[2-氟-5-(三氟甲基)苯基]氨基甲酰基}哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[2-氟-3-(三氟甲基)苯基]氨基甲酰基}哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[6-(三氟甲氧基)吡啶-2-基]氨基甲酰基}哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[4-(三氟甲基)吡啶-2-基]氨基甲酰基}哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-(2,2-二氟-2H-1,3-苯并二氧杂环戊烯-5-基)哌啶-2-甲酰胺;
2-(4-氯-3-氟苯氧基)-N-[(3S,6R)-6-[5-(三氟甲基)-2,3-二氢-1H-异吲哚-2-羰基]哌啶-3-基]乙酰胺;
2-(4-氯-3-氟苯氧基)-N-[(3S,6R)-6-[5-(三氟甲氧基)-2,3-二氢-1H-异吲哚-2-羰基]哌啶-3-基]乙酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-{[1-甲基-5-(三氟甲基)-1H-吡唑-3-基]甲基}哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-{[5-(三氟甲基)-1,2-噁唑-3-基]甲基}哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-{[4-(三氟甲基)吡啶-2-基]甲基}哌啶-2-甲酰胺;
2-(4-氯-3-氟苯氧基)-N-[(3S,6R)-6-[4-(三氟甲基)-2,3-二氢-1H-吲哚-1-羰基]哌啶-3-基]乙酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[1-(2,2-二氟环丙基)-1H-吡唑-3-基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[3-(三氟甲氧基)环戊基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[2-(三氟甲基)嘧啶-4-基]氨基甲酰基}哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[2-(三氟甲基)嘧啶-4-基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[6-(三氟甲基)吡嗪-2-基]氨基甲酰基}哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[6-(三氟甲基)吡嗪-2-基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-1-甲基-N-[6-(三氟甲基)吡嗪-2-基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[(1S,3S)-3-(三氟甲氧基)环戊基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[(1R,3R)-3-(三氟甲氧基)环戊基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-[(2,2-二氟-2H-1,3-苯并二氧杂环戊烯-5-基)氨基甲酰基]哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-[5-(三氟甲基)-2,3-二氢-1H-异吲哚-2-羰基]哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-[5-(三氟甲氧基)-2,3-二氢-1H-异吲哚-2-羰基]哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-({[1-甲基-5-(三氟甲基)-1H-吡唑-3-基]甲基}氨基甲酰基)哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-({[5-(三氟甲基)-1,2-噁唑-3-基]甲基}氨基甲酰基)哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-({[4-(三氟甲基)吡啶-2-基]甲基}氨基甲酰基)哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-[4-(三氟甲基)-2,3-二氢-1H-吲哚-1-羰基]哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[1-(2,2-二氟环丙基)-1H-吡唑-3-基]氨基甲酰基}哌啶-1-甲酸叔丁酯;或
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[3-(三氟甲氧基)环戊基]氨基甲酰基}哌啶-1-甲酸叔丁酯。
在可以发生式(I)的化合物的互变异构(如例如,酮-烯醇互变异构)的情况下,分别包括以及作为任何比率的混合物包括各种形式,如例如酮和烯醇形式。这同样适用于立体异构体,如例如对映异构体、顺/反异构体、构象异构体等。
尤其是,当在根据式(I)的化合物中给出对映异构或非对映异构形式时,单独每种纯形式和至少两种纯形式的任何比率的任何混合物都被式(I)包含并且是本发明的主题。
一种优选的化合物是具有如在式(Ic)中所示的相对构型的式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体
同位素标记的式(I)的化合物也在本发明范围内。用于同位素标记的方法是本领域已知的。优选的同位素是元素H、C、N、O和S的同位素。式(I)的化合物的溶剂化物和水合物也在本发明的范围内。
如果需要的话,可以通过本领域众所周知的方法分离异构体,例如,通过液相色谱法。通过使用例如手性固定相,这同样适用于对映异构体。另外,可以如下分离对映异构体:将它们转化为非对映异构体,即,与对映异构纯的辅助化合物偶联,随后分离所得的非对映异构体,并裂解辅助残基。可替换地,使用光学纯的起始材料、试剂和/或催化剂,可以由立体选择性合成获得式(I)的化合物的任何对映异构体。
在根据式(I)的化合物含有一个或多个酸性或碱性基团的情况下,本发明也包含它们的相应的药学上或毒理学上可接受的盐,尤其是它们的药学上可利用的盐。因此,根据本发明,可以例如作为碱金属盐、碱土金属盐或作为铵盐使用含有酸性基团的式(I)的化合物。这样的盐的更确切的例子包括钠盐、钾盐、钙盐、镁盐或与氨或有机胺例如乙胺、乙醇胺、三乙醇胺或氨基酸的盐。可以存在含有一个或多个碱性基团(即,可以被质子化的基团)的式(I)的化合物,并且其根据本发明可以以它们与无机或有机酸形成的加成盐的形式使用。合适的酸的例子包括:盐酸、氢溴酸、磷酸、硫酸、硝酸、甲磺酸、对甲苯磺酸、萘二磺酸、草酸、乙酸、酒石酸、乳酸、水杨酸、苯甲酸、甲酸、丙酸、新戊酸、二乙基乙酸、丙二酸、琥珀酸、庚二酸、富马酸、马来酸、苹果酸、氨基磺酸、苯基丙酸、葡糖酸、抗坏血酸、异烟酸、柠檬酸、己二酸,以及本领域技术人员已知的其它酸。如果式(I)的化合物在分子中同时含有酸性和碱性基团,则除了提到的盐形式之外,本发明还包括内盐或内铵盐(两性离子)。通过本领域技术人员已知的常规方法,如例如,通过在溶剂或分散剂中使这些与有机或无机酸或碱接触,或通过与其它盐的阴离子交换或阳离子交换,可以获得根据式(I)的各种盐。本发明还包括式(I)的化合物的所有盐,所述盐由于低生理学相容性,不直接适用于药物,但其可用作例如化学反应的中间体或用于制备药学上可接受的盐。
如下所示,本发明的化合物据信适用于调节整合应激反应途径。
整合应激反应(ISR)是所有真核生物共有的细胞应激反应(1)。ISR信号传递的调节异常具有重要的病理学后果,尤其是与炎症、病毒感染、糖尿病、癌症和神经变性疾病有关的后果。
ISR是不同类型的细胞应激的共同特征,导致在丝氨酸51上的真核翻译起始因子2(eIF2α)的α亚基的磷酸化,从而抑制正常蛋白合成和应激反应基因的表达(2)。在哺乳动物细胞中,所述磷酸化由四个eIF2α激酶的家族进行,即:PKR-样ER激酶(PERK)、双链RNA依赖性蛋白激酶(PKR)、亚铁血红素调节的eIF2α激酶(HRI)和一般性调控阻遏蛋白激酶2(GCN2),各自响应于不同的环境和生理应激(3)。
eIF2α与eIF2β和eIF2γ一起形成eIF2复合物,这是正常mRNA翻译起始的关键参与者(4)。eIF2复合物结合GTP和Met-tRNAi,从而形成三元复合物(eIF2-GTP-Met-tRNAi),其被核糖体募集用于翻译起始(5,6)。
eIF2B是由5种亚基(α、β、γ、δ、ε)组成的异十聚体复合物,所述亚基一式两份地形成GEF活性十聚体(7)。
响应于ISR活化,磷酸化的eIF2α抑制eIF2B介导的GDP与GTP的交换,导致三元复合物形成减少,并因此抑制以核糖体与5'AUG起始密码子结合为特征的正常mRNA的翻译(8)。在三元复合物丰度降低的这些条件下,包括编码转录因子ATF4的mRNA在内的几种特定mRNA的翻译通过涉及上游ORF(uORF)的翻译改变的机制被活化(7,9,10)。这些mRNA通常包含一个或多个uORF,所述uORF通常在未受应激的细胞中起作用以限制核糖体向主要编码ORF的流动。例如,在正常条件下,在ATF的5'UTR中的uORF占据核糖体并阻止ATF4的编码序列的翻译。但是,在应激条件下,即在三元复合物形成减少的条件下,核糖体扫描经过这些上游ORF并在ATF4编码ORF处开始翻译的可能性增加。ATF4和其它以这种方式表达的应激反应因子随后控制着一系列其它应激反应基因的表达。急性期在于旨在恢复稳态的蛋白的表达,而慢性期导致促凋亡因子的表达(1,11,12,13)。
ISR信号传递的标志物的上调已在多种病症中得到证实,其中包括癌症和神经变性疾病。在癌症中,ER应激调节的翻译增加对低氧条件的耐受性并促进肿瘤生长(14,15,16),并且已经证明通过基因靶向对PERK的删除可以减慢从转化的PERK-/-小鼠胚胎成纤维细胞衍生出的肿瘤的生长(14,17)。此外,最近的一份报告已经提供了如下的概念证据:使用在小鼠中的源自患者的异种移植模型,eIF2B的活化剂有效治疗一种侵袭性转移性前列腺癌(28)。总之,细胞保护性ISR信号传递的预防可能代表一种有效的抗增殖策略,其用于治疗至少某些形式的癌症。
此外,ISR信号传递的调节可以证明在保持突触功能和减少神经元衰退中是有效的,在特征在于错误折叠的蛋白和未折叠蛋白反应(UPR)的激活的神经变性疾病(诸如肌萎缩性侧索硬化(ALS)、额颞叶痴呆(FTD)、阿尔茨海默氏病(AD)、帕金森病(PD)和JakobCreutzfeld(朊病毒)疾病)中也是如此(18,19,20)。对于朊病毒病(存在的神经变性疾病的一个例子),其中已经表明,ISR信号传递的药理学以及遗传抑制可以使蛋白翻译水平正常化、挽救突触功能并预防神经元损失(21)。具体地,通过控制磷酸化eIF2α水平的磷酸酶的过表达来降低磷酸化eIF2α的水平会增加感染了朊病毒的小鼠的存活率,而持续的eIF2α磷酸化降低存活率(22)。
此外,控制蛋白表达水平对于适当脑功能的重要性的直接证据以影响eIF2和eIF2B的功能的罕见遗传性疾病的形式存在。破坏eIF2的复杂完整性且因此导致降低的正常蛋白表达水平的eIF2γ中的突变与智力障碍综合征(ID)相关(23)。在eIF2B的亚基中的部分功能丧失突变已被证实是罕见的脑白质营养不良白质消融性疾病(VWMD)的原因(24,25)。具体地,与ISRIB相关的小分子在VWMD小鼠模型中对eIF2B部分功能丧失的稳定化已被证实会减少ISR标记物并改善功能以及病理学终点(26,27)。
本发明提供了要用于治疗本文提及的疾病或障碍的呈游离或药学上可接受的盐形式或呈溶剂化物、水合物、互变异构体或立体异构体形式的本发明的化合物。这同样适用于本发明的药物组合物。
因此,本发明的一个方面是用作药物的本发明的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体。这同样适用于本发明的药物组合物。
描述的治疗方法可以应用于哺乳动物诸如狗、猫、牛、马、兔、猴和人类。优选地,所述哺乳动物患者是人类患者。
因此,本发明提供了要用于治疗或预防一种或多种与整合应激反应有关的疾病或障碍的本发明的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体或药物组合物。
本发明的另一个方面是用于治疗或预防一种或多种与整合应激反应有关的障碍或疾病的方法的本发明的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体或药物组合物。
本发明的另一个方面是本发明的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体或药物组合物用于制备药物的用途,所述药物用于治疗或预防一种或多种与整合应激反应有关的障碍或疾病。
本发明的再另一个方面是一种用于治疗、控制、延迟或预防需要治疗的哺乳动物患者中的一种或多种与整合应激反应有关的疾病或障碍的方法,其中所述方法包括给所述患者施用治疗有效量的本发明的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体或药物组合物。
本发明提供要用于治疗或预防一种或多种下述疾病或障碍的本发明的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体或药物组合物。
本发明的另一个方面是用于治疗或预防一种或多种下述障碍或疾病的方法的本发明的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体或药物组合物。
本发明的另一个方面是本发明的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体或药物组合物用于制备药物的用途,所述药物用于治疗或预防一种或多种下述障碍或疾病。
本发明的再另一个方面是一种用于治疗、控制、延迟或预防需要治疗的哺乳动物患者中的一种或多种下述疾病或障碍的方法,其中所述方法包括给所述患者施用治疗有效量的本发明的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体或药物组合物。
疾病或障碍包括、但不限于脑白质营养不良,智力障碍综合征,神经变性疾病和障碍,肿瘤性疾病,感染性疾病,炎性疾病,肌肉骨骼疾病,代谢疾病,眼疾病以及选自器官纤维化、慢性和急性肝病、慢性和急性肺病、慢性和急性肾病、心肌梗塞、心血管疾病、心律失常、动脉粥样硬化、脊髓损伤、缺血性中风和神经性疼痛的疾病。
脑白质营养不良
脑白质营养不良的例子包括、但不限于白质消融性疾病(VWMD)和伴有CNS髓鞘形成不足的儿童共济失调(例如与eIF2或包括eIF2的信号转导或信号传递途径中的组分的功能受损相关)。
智力障碍综合征
智力障碍尤其是指这样的病症:其中人在智力功能如交流、照顾自己方面具有某些限制,和/或具有受损的社交技能。智力障碍综合征包括、但不限于与eIF2或包括eIF2的信号转导或信号传递途径中的组分的功能受损相关的智力障碍病症。
神经变性疾病/障碍
神经变性疾病和障碍的例子包括、但不限于亚历山大氏病、阿耳珀病、阿尔茨海默氏病、肌萎缩性侧索硬化、共济失调毛细血管扩张症、巴藤病(也被称作Spielmeyer-Vogt-Sjogren-Batten病)、牛海绵状脑病(BSE)、卡纳万病、科凯恩综合征、皮质基底变性、克雅病、额颞叶痴呆、Gerstmann-Straussler-Scheinker综合征、亨廷顿病、HIV相关的痴呆、肯尼迪病、克拉伯病、库鲁病、路易体痴呆、Machado-Joseph病(3型脊髓小脑性共济失调)、多发性硬化、多系统萎缩、发作性睡病、神经疏螺旋体病、帕金森病、佩梅病、皮克病、原发性侧索硬化、朊病毒疾病、进行性核上性麻痹、雷弗素姆氏病、山德霍夫氏病、谢耳德氏病、恶性贫血继发的亚急性脊髓混合变性、精神分裂症、脊髓小脑性共济失调(具有不同特征的多种类型)、脊髓性肌萎缩、Steele-Richardson-Olszewski病、脊髓痨和Tau病变。
神经变性疾病或障碍尤其选自阿尔茨海默氏病、帕金森病和肌萎缩性侧索硬化。
肿瘤性疾病
可以将肿瘤性疾病最广义地理解为起因于失控细胞生长的任何组织。在许多情况下,肿瘤至少导致庞大的组织块,其任选通过血管受到神经支配。它可以包含或不包含一个或多个转移/转移灶的形成。本发明的肿瘤性疾病可以是通过疾病和有关健康问题的国际统计分类第10次修订(International Statistical Classification of Diseases andRelated Health Problems 10th Revision)(ICD-10)类别C00-D48分类的任何肿瘤。
示例性地,根据本发明的肿瘤性疾病可以是一种或多种恶性肿瘤(肿瘤)(ICD-10类别C00-C97)的存在,可以是一种或多种原位肿瘤(ICD-10类别D00-D09)的存在,可以是一种或多种良性肿瘤(ICD-10类别D10-D36)的存在,或可以是一种或多种不确定或未知行为的肿瘤(ICD-10类别D37-D48)的存在。优选地,根据本发明的肿瘤性疾病是指一种或多种恶性肿瘤的存在,即,是恶性肿瘤形成(ICD-10类别C00-C97)。
在一个更优选的实施方案中,所述肿瘤性疾病是癌症。
可以将癌症最广义地理解为任何恶性肿瘤性疾病,即,一种或多种恶性肿瘤在患者中的存在。癌症可以是实体或血液学恶性肿瘤。本文涵盖但不限于白血病、淋巴瘤、癌和肉瘤。
在本文中尤其包括特征在于上调的ISR标志物的肿瘤性疾病,诸如癌症。
示例性的癌症包括、但不限于甲状腺癌、内分泌系统癌、胰腺癌、脑癌(例如多形性胶质母细胞瘤、神经胶质瘤)、乳腺癌(例如ER阳性的、ER阴性的、化学疗法抗性的、赫赛汀抗性的、HER2阳性的、多柔比星抗性的、他莫昔芬抗性的、导管癌、小叶癌、原发性的、转移性的)、子宫颈癌、卵巢癌、子宫癌、结肠癌、头颈癌、肝癌(例如肝细胞癌)、肾癌、肺癌(例如非小细胞肺癌、鳞状细胞肺癌、腺癌、大细胞肺癌、小细胞肺癌、类癌、肉瘤)、结肠癌、食管癌、胃癌、膀胱癌、骨癌、胃癌、前列腺癌和皮肤癌(例如黑素瘤)。
其它例子包括、但不限于骨髓瘤、白血病、间皮瘤和肉瘤。
另外的例子包括、但不限于髓母细胞瘤、霍奇金病、非霍奇金淋巴瘤、多发性骨髓瘤、神经母细胞瘤、神经胶质瘤、多形性胶质母细胞瘤、横纹肌肉瘤、原发性血小板增多、原发性巨球蛋白血症、原发性脑肿瘤、恶性胰腺胰岛瘤、恶性类癌、膀胱癌、恶化前的皮肤病变、睾丸癌、淋巴瘤、生殖尿道癌、恶性高钙血症、子宫内膜癌、肾上腺皮质癌、内分泌或外分泌胰腺肿瘤、髓样甲状腺癌、甲状腺髓样癌、黑素瘤、结肠直肠癌、乳头状甲状腺癌、肝细胞癌、佩吉特乳头病、叶状瘤、小叶癌、导管癌、胰腺星形细胞癌和肝星形细胞癌。
示例性的白血病包括、但不限于急性非淋巴细胞性白血病、慢性淋巴细胞性白血病、急性粒细胞性白血病、慢性粒细胞性白血病、急性早幼粒细胞性白血病、成年T-细胞白血病、白细胞不增多性白血病、白细胞增多性白血病、嗜碱细胞性白血病、胚细胞白血病、牛白血病、慢性粒细胞性白血病、皮肤白血病、胚细胞性白血病、嗜酸性粒细胞性白血病、Gross氏白血病、毛细胞白血病、成血细胞性白血病(hemoblastic leukemia)、成血细胞性白血病(hemocytoblastic leukemia)、组织细胞性白血病、干细胞白血病、急性单核细胞性白血病、白细胞减少性白血病、淋巴性白血病、成淋巴细胞性白血病、淋巴细胞性白血病、淋巴原性白血病、淋巴样白血病、淋巴肉瘤细胞白血病、肥大细胞白血病、巨核细胞白血病、微型成髓细胞白血病(micromyeloblastic leukemia)、单核细胞性白血病、成髓细胞性白血病、髓细胞性白血病、骨髓粒细胞性白血病、髓单核细胞性白血病、Naegeli白血病、浆细胞白血病、多发性骨髓瘤、浆细胞性白血病、早幼粒细胞性白血病、Rieder细胞白血病、希林氏白血病、干细胞白血病、亚白血性白血病和未分化细胞性白血病。
示例性的肉瘤包括、但不限于软骨肉瘤、纤维肉瘤、淋巴肉瘤、黑素肉瘤、粘液肉瘤、骨肉瘤、艾伯内西氏肉瘤、脂肪肉瘤、脂肉瘤、软组织腺泡状肉瘤、成釉细胞肉瘤、葡萄状肉瘤、绿色瘤肉瘤、绒毛膜癌、胚胎性肉瘤、肾母细胞瘤肉瘤、子宫内膜肉瘤、间质肉瘤、尤因氏肉瘤、筋膜肉瘤、成纤维细胞性肉瘤、巨细胞肉瘤、粒细胞肉瘤、霍奇金肉瘤、特发性多发性色素性出血性肉瘤、B细胞免疫母细胞肉瘤、淋巴瘤、T细胞免疫母细胞肉瘤、詹森肉瘤、卡波西氏肉瘤、库普弗细胞肉瘤、血管肉瘤、白血病性肉瘤、恶性间叶瘤肉瘤、骨膜外肉瘤、网状细胞肉瘤、劳斯肉瘤、浆液囊性肉瘤、滑膜肉瘤和毛细血管扩张性肉瘤。
示例性的黑素瘤包括、但不限于肢端雀斑痣样黑素瘤、无黑色素性黑素瘤、良性幼年型黑素瘤、克劳德曼氏黑素瘤(Cloudman'smelanoma)、S91黑素瘤、哈-帕二氏黑素瘤、幼年型黑素瘤、恶性雀斑样黑素瘤、恶性黑素瘤、结节性黑色素瘤、甲下黑素瘤和浅表扩散性黑素瘤。
示例性的癌包括、但不限于甲状腺髓样癌、家族性甲状腺髓样癌、腺泡癌、腺泡状癌、囊性腺样癌、腺样囊性癌、腺癌、肾上腺皮质癌、肺泡癌、肺泡细胞癌、基底细胞癌、基底上皮细胞癌、基底细胞样癌、基底鳞状细胞癌、细支气管肺泡癌、细支气管癌、支气管癌、脑样癌、胆管细胞癌、绒毛膜癌、胶体癌、粉刺状癌、子宫体癌、筛状癌、铠甲状癌、皮肤癌、柱状癌、柱状细胞癌、管癌、导管癌、硬癌、胚胎性癌、脑样癌、表皮样癌、腺样上皮癌、外生性癌、溃疡性癌、纤维癌、胶样癌、胶状癌、巨细胞癌(giant cell carcinoma)、巨细胞癌(carcinoma gigantocellulare)、腺癌、粒层细胞癌、毛基质癌、血样癌、肝细胞癌、Hurthle细胞癌、胶样癌(hyaline carcinoma)、肾上腺样癌、婴儿胚胎癌、原位癌、表皮内癌、上皮内癌、Krompecher癌、Kulchitzky细胞癌、大细胞癌、豆状癌(lenticular carcinoma)、豆状癌(carcinoma lenticulare)、脂肪瘤样癌、小叶癌、淋巴上皮癌、髓样癌(carcinomamedullare)、髓样癌(medullary carcinoma)、黑色素癌、软癌、粘液癌(mucinouscarcinoma)、粘液癌(carcinoma muciparum)、粘液细胞癌、粘液表皮样癌、粘液癌(carcinoma mucosum)、粘液癌(mucous carcinoma)、粘液瘤样癌(carcinomamyxomatodes)、鼻咽癌、燕麦细胞癌、骨化癌、骨样癌、乳头状癌、门脉周癌、浸润前癌、刺细胞癌、脑样癌(pultaceous carcinoma)、肾细胞癌、储备细胞癌、肉瘤样癌、施奈德癌、硬癌、阴囊癌、印戒细胞癌、单纯癌、小细胞癌、马铃薯状癌、球状细胞癌、梭形细胞癌、髓样癌、鳞状癌、鳞状细胞癌、绳捆癌、血管扩张性癌(carcinoma telangiectaticum)、血管扩张性癌(carcinoma telangiectodes)、移行细胞癌、结节性皮癌(carcinoma tuberosum)、管状癌、结节性皮癌(tuberous carcinoma)、疣状癌和绒毛状癌。
感染性疾病
例子包括、但不限于由病毒引起的感染(诸如由以下病毒引起的感染:HIV-1:人免疫缺陷病毒1型;IAV:甲型流感病毒;HCV:丙型肝炎病毒;DENV:登革热病毒;ASFV:非洲猪瘟病毒;EBV:爱泼斯坦-巴尔病毒;HSV1:单纯疱疹病毒1;CHIKV:基孔肯亚病毒;HCMV:人巨细胞病毒;SARS-CoV:重度急性呼吸综合征冠状病毒;SARS-CoV-2:重度急性呼吸综合征冠状病毒2)和由细菌引起的感染(诸如由军团菌属、布鲁杆菌属、西门坎氏菌属(Simkania)、衣原体属、螺杆菌属和弯曲杆菌属引起的感染)。
炎性疾病
炎性疾病的例子包括、但不限于手术后认知功能障碍(外科手术后认知功能下降)、创伤性脑损伤、关节炎、类风湿性关节炎、银屑病关节炎、青少年特发性关节炎、多发性硬化、系统性红斑狼疮(SLE)、重症肌无力、青少年型糖尿病、1型糖尿病、格-巴二氏综合征、桥本脑炎、桥本甲状腺炎、强直性脊柱炎、银屑病、舍格伦综合征、血管炎、肾小球肾炎、自身免疫甲状腺炎、贝切特氏病、克罗恩氏病、溃疡性结肠炎、大疱性类天疱疮、结节病、鱼鳞病、格雷夫斯眼病、炎性肠病、阿狄森氏病、白癫风、哮喘、变应性哮喘、寻常痤疮、乳糜泻、慢性前列腺炎、炎性肠病、盆腔炎性疾病、再灌注损伤、结节病、移植排斥、间质性膀胱炎、动脉粥样硬化和特应性皮炎。
肌肉骨骼疾病
肌肉骨骼疾病的例子包括、但不限于肌营养不良、多发性硬化、Freidrich氏共济失调、肌萎缩障碍(例如,肌肉萎缩、少肌症、恶病质)、包涵体肌病、进行性肌萎缩、运动神经元病、腕管综合征、上髁炎、腱炎、背痛、肌肉痛、肌肉酸痛、重复性劳损障碍和麻痹。
代谢疾病
代谢疾病的例子包括、但不限于糖尿病(尤其是II型糖尿病)、非酒精性脂肪性肝炎(NASH)、非酒精性脂肪肝病(NAFLD)、Niemann-Pick病、肝纤维化、肥胖、心脏病、动脉粥样硬化、关节炎、胱氨酸病、苯丙酮尿症、增殖性视网膜病变和Kearns-Sayre病。
眼疾病
眼疾病的例子包括、但不限于任何闭塞性或炎症性视网膜血管疾病的水肿或新生血管形成,诸如虹膜红变、新生血管性青光眼、翼状胬肉、血管化青光眼滤泡、结膜乳头状瘤;脉络膜新生血管形成,诸如新生血管年龄相关性黄斑变性(AMD)、近视、前葡萄膜炎(prior uveitis)、创伤或特发性;黄斑水肿,诸如手术后黄斑水肿、继发于葡萄膜炎(包括视网膜和/或脉络膜炎症)的黄斑水肿、继发于糖尿病的黄斑水肿、和继发于视网膜血管闭塞性疾病(即视网膜分支和中央静脉闭塞)的黄斑水肿;由糖尿病引起的视网膜新生血管形成,诸如视网膜静脉闭塞、葡萄膜炎、颈动脉疾病引起的眼缺血综合征、眼或视网膜动脉阻塞、镰状红细胞性视网膜病变、其它缺血性或闭塞性新生血管视网膜病变、早产儿视网膜病变或伊耳斯氏病;和遗传性障碍,诸如VonHippel-Lindau综合征。
其它疾病
其它疾病包括、但不限于器官纤维化(诸如肝纤维化、肺纤维化或肾纤维化)、慢性和急性肝病(诸如脂肪肝病或肝皮脂腺病)、慢性和急性肺病、慢性和急性肾病、心肌梗塞、心血管疾病、心律失常、动脉粥样硬化、脊髓损伤、缺血性中风和神经性疼痛。
本发明的再另一个方面是一种药物组合物,其包含至少一种本发明的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体以及药学上可接受的载体,任选地与一种或多种其它生物活性化合物或药物组合物组合。
优选地,所述一种或多种生物活性化合物是除式(I)的化合物之外的整合应激反应途径的调节剂。
“药物组合物”是指一种或多种活性成分和构成载体的一种或多种惰性成分,以及由任何两种或更多种成分组合、络合或聚集而直接或间接形成的任何产品,或者由一种或多种成分分解而直接或间接形成的任何产品,或者由一种或多种成分的其它类型的反应或相互作用而直接或间接形成的任何产品。因此,本发明的药物组合物包括通过混合本发明的化合物和药学上可接受的载体而制成的任何组合物。
本发明的药物组合物可以包含一种或多种另外的化合物作为活性成分,如在组合物中的式(I)的化合物的混合物或整合应激反应途径的其它调节剂。
所述活性成分可以包含在一种或多种不同的药物组合物(药物组合物的组合)中。
术语“药学上可接受的盐”是指由药学上可接受的无毒的碱或酸(包括无机碱或酸和有机碱或酸)制备的盐。
所述组合物包括适用于口服、直肠、局部、胃肠外(包括皮下、肌肉内和静脉内)、眼(眼部)、肺(鼻或含服吸入)或鼻施用的组合物,尽管在任何给定情况下最合适的途径取决于所治疗的病症的性质和严重程度以及活性成分的性质。它们可以方便地存在于单位剂型中,并且可以通过药学领域众所周知的任何方法制备。
在实际应用中,式(I)的化合物可以作为活性成分与药物载体根据常规药物混配技术合并为紧密混合物。载体可以采用多种形式,取决于预期施用的制剂的形式,例如,口服或胃肠外(包括静脉内)。在制备口服剂型组合物时,在口服液体制剂(例如,混悬液、酏剂和溶液)的情况下,可以使用任何常用的药物介质,诸如水、二醇类、油类、醇类、调味剂、防腐剂、着色剂等;或在口服固体制剂(诸如粉剂、硬和软胶囊剂和片剂)的情况下,可以使用载体诸如淀粉、糖、微晶纤维素、稀释剂、造粒剂、润滑剂、粘合剂、崩解剂等,其中固体口服制剂比液体制剂优选。
由于片剂和胶囊剂容易施用,片剂和胶囊剂代表最有利的口服剂量单位形式,在这样的情况下,显而易见地使用固体药用载体。如果需要的话,可以通过标准的水性或非水性技术包衣片剂。这样的组合物和制剂应该含有至少0.1%的活性化合物。活性化合物在这些组合物中的百分比当然可以改变,并且可以方便地为所述单位的重量的大约2%至大约60%。活性化合物在这种治疗上有用的组合物中的量是可获得有效剂量的量。也可以鼻内施用活性化合物,例如作为液体滴剂或喷雾剂。
片剂、丸剂、胶囊剂等还可以含有:粘合剂诸如黄蓍胶、阿拉伯胶、玉米淀粉或明胶;赋形剂诸如磷酸二钙;崩解剂诸如玉米淀粉、马铃薯淀粉、海藻酸;润滑剂诸如硬脂酸镁;和甜味剂诸如蔗糖、乳糖或糖精。当剂量单位形式是胶囊时,除了上述类型的物质之外,它还可以含有液体载体诸如脂肪油。
各种其它物质可以作为包衣存在,或用于改变剂量单位的物理形式。例如,可以用虫胶、糖或两者包衣片剂。除了活性成分之外,糖浆剂或酏剂还可以含有:作为甜味剂的蔗糖,作为防腐剂的对羟苯甲酸甲酯和对羟苯甲酸丙酯,染料和调味剂例如樱桃或橙调味剂。
也可以胃肠外地施用式(I)的化合物。可以在与表面活性剂诸如羟丙基纤维素适当混合的水中制备这些活性化合物的溶液或混悬液。还可以在甘油、液体聚乙二醇和其在油中的混合物中制备分散体。在贮存和使用的一般条件下,这些制品含有防腐剂以阻止微生物的生长。
适合于注射使用的药物形式包括无菌水溶液或分散体,和用于即时制备无菌注射溶液或分散体的无菌粉末。在所有情况下,该形式应该是无菌的,并且应该以易于注射的程度流动。它应当在制造和储存条件下是稳定的,并且应当针对微生物诸如细菌和真菌的污染作用进行保存。所述载体可以是溶剂或分散介质,其含有例如水、乙醇、多元醇(例如,甘油、丙二醇和液体聚乙二醇)、其合适混合物和植物油。
可以采用任何合适的施用途径以给哺乳动物、特别是人提供有效剂量的本发明的化合物。可以使用例如口服、直肠、局部、胃肠外、眼、肺、鼻途径等。剂型包括片剂、糖锭、分散体、混悬液、溶液、胶囊剂、乳膏剂、软膏剂、气雾剂等。优选地口服施用式(I)的化合物。
采用的活性成分的有效剂量可以随采用的特定化合物、施用模式、要治疗的病症和要治疗的病症的严重程度而变化。这样的剂量可以由本领域技术人员容易地确定。
用于合成本发明的优选实施方案的起始材料可以从商业可得来源诸如Array、Sigma Aldrich、Acros、Fisher、Fluka、ABCR购买,或者可以由本领域技术人员使用已知方法合成。
一般而言,几种方法可用于制备本发明的化合物。在某些情况下,可以组合各种策略。可以使用依序或会聚途径。下面描述了示例性合成途径。
实施例
I化学合成
实验程序:
使用下述缩写和缩略语:
aq 水性的
ACN 乙腈
AgSO3CF3 三氟甲磺酸银
盐水 NaCl在水中的饱和溶液
Bn 苄基
BnONH2·HCl O-苄基羟基胺盐酸盐
Boc 叔丁氧基羰基
Boc2O 二碳酸二叔丁酯
tBuOK 叔丁醇钾
CDCl3 氘代氯仿
DCM 二氯甲烷
DMSO 二甲基亚砜
DMSO-d6氘代二甲基亚砜
DIAD 偶氮二甲酸二异丙酯
DIPEA 二异丙基乙胺
DMF 二甲基甲酰胺
DMAP N,N-二甲基吡啶-4-胺
ESI+ 正电离模式
ESI- 负电离模式
EtOAc 乙酸乙酯
EtOH 乙醇
Et2O 乙醚
H2SO4 硫酸
HATU 1-[双(二甲基氨基)亚甲基]-1H-[1,2,3]三唑并[4,5-b]吡啶-1-鎓3-氧化物六氟磷酸盐
HCl 盐酸
HPLC 高效液相色谱法
h 小时
IPA 异丙醇
Josiphos SL-J009-1{(R)-1-[(Sp)-2-(二环己基膦基)二茂铁基]乙基二叔丁基膦}[2-(2′-氨基-1,1′-联苯基)]钯(II)甲磺酸盐
KHCO3 碳酸氢钾
KF 氟化钾
LiOH 氢氧化锂
m 多重峰
MeI 碘甲烷
MeNHNH2甲基肼
MeOH 甲醇
MgSO4 硫酸镁
min 分钟
MsCl 甲磺酰氯
MsOH 甲磺酸
mL 毫升
N2 氮气氛
Na2SO4 硫酸钠
NaHCO3碳酸氢钠
NH4Cl 氯化铵
NMM 4-甲基吗啉
NMR 核磁共振
Pd2(dba)3三(二亚苄基丙酮根合)二钯(0)
prep.制备型
POCl3三氯氧磷
PPh3 三苯基膦
r.t. 室温
RT 保留时间
satd 饱和的
Selectfluor 1-(氯甲基)-4-氟-1,4-二氮杂双环[2.2.2]辛烷-1,4-二鎓二四氟硼酸盐
T3P 丙烷膦酸酐
THF 四氢呋喃
TFA 2,2,2-三氟乙酸
TMSOI 三甲基氧化锍碘化物
XPhos 二环己基[2′,4′,6′-三(丙-2-基)[1,1′-联苯基]-2-基]磷化氢
ZnBr2二溴化锌
分析型LCMS条件如下:
系统1(S1):酸性IPC方法(MS18和MS19)
使用Kinetex Core shell C18柱(2.1mm×50mm,5μm;温度:40℃)和5-100%B的梯度(A=0.1%甲酸/H2O;B=0.1%甲酸/ACN)历时1.2min、然后在100%B保持0.1min,在Shimadzu LCMS系统上进行分析型(MET/CR/1410)HPLC-MS。然后历时0.01min施加100-5%B的第二梯度,注射体积为3μL,流速为1.2mL/min。使用SPD-M20A光电二极管阵列检测器(波谱范围:200-400nm),在215nm记录UV波谱。使用2010EV检测器得到质谱图。使用ShimadzuLCMS-Solutions和PsiPort软件整合和报告数据。
系统2(S2):酸性IPC方法(MSQ1、MSQ2和MSQ4)
使用WatersBEHTM C18柱(2.1mm×50mm,1.7μm;温度40℃)和5-100%B的梯度(A=0.1%甲酸/H2O:B=0.1%甲酸/ACN)历时1.1min、然后在100%B保持0.25min,在Waters Acquity uPLC系统上进行分析型(MET/uPLC/1704)uHPLC-MS。然后历时0.05min施加100-5%B的第二梯度并保持0.1min,注射体积为1μL,流速为0.9mL/min。在具有200-400nm的波谱范围的Waters Acquity PDA上在215nm记录UV波谱。使用Waters QDa得到质谱图。使用Waters MassLynx和OpenLynx软件整合和报告数据。
系统3(S3):碱性IPC方法(MS16)
使用WatersBEHTM C18柱(2.1mm×30mm,1.7μm;温度40℃)和5-100%B的梯度(A:2mM碳酸氢铵,缓冲至pH 10,B:ACN)历时0.75min、然后在100%B保持0.1min,在Waters Acquity uPLC系统上进行分析型(MET/CR/1602)uHPLC-MS。然后历时0.05min施加100-5%B的第二梯度并保持0.1min,注射体积为1μL,流速为1mL/min。在具有200-400nm的波谱范围的Waters Acquity PDA上在215nm记录UV波谱。使用Waters Quattro Premier XE得到质谱图。使用Waters MassLynx和OpenLynx软件整合和报告数据。
系统4(S4):酸性最终方法(MSQ1和MSQ2)
使用Phenomenex Kinetex-XB C18柱(2.1mm×100mm,1.7μM;温度:40℃)和5-100%B的梯度(A=0.1%甲酸/H2O;B=0.1%甲酸/ACN)历时5.3min、然后在100%B保持0.5min,在Waters Acquity uPLC系统上进行分析型(MET/uPLC/AB101)uHPLC-MS。然后历时0.02min施加100-5%B的第二梯度并保持1.18min,注射体积为1μL,流速为0.6mL/min。使用Waters Acquity PDA检测器(波谱范围:200-400nm)在215nm记录UV波谱。使用Waters SQD(MSQ1)或Waters Acquity QDA(MSQ2)得到质谱图。使用Waters MassLynx和OpenLynx软件整合和报告数据。
系统5(S5):酸性最终方法(MS18,MS19)
使用Waters Atlantis dC18柱(2.1mm×100mm,3μm;温度:40℃)和5-100%B的梯度(A=0.1%甲酸/H2O;B=0.1%甲酸/ACN)历时5min、然后在100%B保持0.4min,在Shimadzu LCMS系统上进行分析型(MET/CR/1416)HPLC-MS。然后历时0.02min施加100-5%B的第二梯度并保持1.58min,注射体积为3μL,流速为0.6mL/min。使用SPD-M20A光电二极管阵列检测器(波谱范围:200-400nm)在215nm记录UV波谱。使用2010EV检测器得到质谱图。使用Shimadzu LCMS-Solutions和PsiPort软件整合和报告数据。
系统6(S6):碱性最终方法(MS16)
使用WatersBEHTM C18柱(2.1mm×100mm,1.7μm柱;温度:40℃)和5-100%的梯度(A=2mM碳酸氢铵,缓冲至pH 10;B=ACN)历时5.3min、然后在100%B保持0.5min,在Waters Acquity uPLC系统上进行分析型(MET/uHPLC/AB105)uPLC-MS。然后历时0.02min施加100-5%B的第二梯度并保持1.18min,注射体积为1μL且流速为0.6mL/min。使用WatersAcquity光电二极管阵列检测器(波谱范围:200-400nm)在215nm记录UV波谱。使用WatersQuattro Premier XE质量检测器得到质谱图。使用Waters MassLynx和OpenLynx软件整合和报告数据。
纯化方法如下:
方法1:酸性早期方法
使用Waters Sunfire C18柱(30mm×100mm,10μM;温度:室温)和10-95%B的梯度(A=0.1%甲酸/H2O;B=0.1%甲酸/ACN)历时14.44min、然后在95%B保持2.11min,在Gilson LC系统上进行纯化(P1)LC。然后历时0.2min施加95-10%B的第二梯度,注射体积为1500μL,流速为40mL/min。使用Gilson检测器在215nm记录UV波谱。
方法2:酸性标准方法
使用Waters Sunfire C18柱(30mm×10mm,10μM;温度:室温)和30-95%B的梯度(A=0.1%甲酸/水;B=0.1%甲酸/ACN)历时11.00min、然后在95%B保持2.10min,在GilsonLC系统上进行纯化(P2)LC。然后历时0.2min施加95-30%B的第二梯度,注射体积为1500μL,流速为40mL/min。使用Gilson检测器在215nm记录UV波谱。
方法3:碱性早期方法
使用Waters X-Bridge C18柱(30mm×100mm,10μM;温度:室温)和10-95%B的梯度(A=0.2%NH4OH/H2O;B=0.2%NH4OH/ACN)历时14.44min、然后在95%B保持2.11min,在Gilson LC系统上进行纯化(P3)LC。然后历时0.2min施加95-10%B的第二梯度,注射体积为1500μL,流速为40mL/min。使用Gilson检测器在215nm记录UV波谱。
方法4:碱性标准方法
使用Waters X-Bridge C18柱(30mm×10mm,10μM;温度:室温)和30-95%B的梯度(A=0.2%NH4OH/水;B=0.2%NH4OH/ACN)历时11.00min、然后在95%B保持2.10min,在Gilson LC系统上进行纯化(P4)LC。然后历时0.21min施加95-30%B的第二梯度,注射体积为1500μL,流速为40mL/min。使用Gilson检测器在215nm记录UV波谱。
手性分离方法:
NMR条件
除非另有说明,否则分别在Bruker Avance III HD 500MHz波谱仪、BrukerAvance III HD 400MHz波谱仪或Bruker Avance III HD 250MHz波谱仪上在500MHz、400MHz或250MHz记录1H NMR谱。化学位移δ以百万份数(ppm)为单位引用,并参考残余溶剂峰。使用以下缩写表示多重性和一般指定:s(单峰)、d(双峰)、t(三重峰)、q(四重峰)、dd(双二重峰)、ddd(双二重峰的二重峰)、dt(双三重峰)、dq(双四重峰)、hep(七重峰)、m(多重峰)、pent(五重峰)、td(三二重峰)、qd(四二重峰)、app.(明显)和br.(宽峰)。将耦合常数J引用到最接近的0.1Hz。
一般合成:
已经以>95%的纯度合成了所有化合物,除非另外指出。
路线1的方案
中间体1:2-(4-氯-3-氟苯氧基)乙酰氯
在0℃向2-(4-氯-3-氟苯氧基)乙酸(5.16g,22.7mmol)在DCM(45mL)中的溶液中加入草酰氯(10mL,0.115mol),随后加入DMF(81μL,1.11mmol),并将混合物在室温搅拌17h。将反应混合物在真空中浓缩以提供为橙色油的标题化合物(90%纯度,5.30g,21.4mmol,94%产率);1H NMR(400MHz,CDCl3)δ7.31(t,J=8.6Hz,1H),6.75(dt,J=10.2,2.9Hz,1H),6.66(ddd,J=8.9,2.9,1.2Hz,1H),4.96(s,2H)。
路线2的方案
步骤2.a:(2R)-5-[(苄基氧基)亚氨基]-2-{[(叔丁氧基)羰基]氨基}-6-氯己酸乙酯
将DMSO(75mL)添加到TMSOI(12.89g,58.3mmol)和tBuOK(6.27g,55.9mmol)在无水THF(60mL)中的溶液中并将混合物在室温下搅拌1h。将反应混合物冷却至-12℃并加入Boc-D-焦谷氨酸乙酯(12.5g,48.6mmol)在无水THF(38mL)中的溶液并在室温下搅拌16h。反应混合物用饱和的NH4Cl水溶液(80mL)、H2O(15mL)和EtOAc(200mL)稀释,分离有机层,用盐水洗涤,真空浓缩至约100mL。添加BnONH2·HCl(8.14g,51.0mmol)在EtOAc(62mL)中的溶液并将混合物在回流下搅拌2小时。将反应混合物冷却至室温,用H2O和盐水洗涤,真空浓缩有机层,得到标题化合物(85%纯度,19.5g,40.1mmol,83%产率),为无色油;1H NMR(400MHz,CDCl3)δ7.16–7.33(m,5H),5.01–5.06(m,2H),3.95–4.30(m,5H),2.32–2.50(m,2H),1.98–2.13(m,1H),1.75–1.92(m,1H),1.30–1.40(m,9H),1.12–1.24(m,3H)。
步骤2.b:(2R)-5-[(苄基氧基)亚氨基]哌啶-2-甲酸乙酯
向(2R)-5-[(苄基氧基)亚氨基]-2-{[(叔丁氧基)羰基]氨基}-6-氯己酸乙酯(85%纯度,19.5g,40.1mmol)在EtOAc(157mL)中的溶液添加MsOH(7.8mL,0.12mol),并将混合物在42℃下搅拌2h。将所得混合物添加到KHCO3(20.1g,0.201mol)在H2O(100mL)中的溶液中并在52℃下搅拌2小时。将反应混合物冷却至室温,分离有机层,用盐水洗涤,经Na2SO4干燥,真空浓缩得到定量产率的标题化合物(85%纯度,13.0g,40.0mmol),为深橙色油;1HNMR(400MHz,CDCl3)δ7.20–7.34(m,5H),4.99(d,J=4.8Hz,2H),4.13(q,J=7.1Hz,2H),3.45–3.56(m,1H),3.25(dd,J=14.9,9.8Hz,1H),3.08(dt,J=14.5,4.3Hz,1H),2.01–2.32(m,3H),1.55–1.80(m,1H),1.21(t,J=7.1Hz,3H)。
步骤2.c:(2R,5S)-5-[(苄基氧基)氨基]哌啶-2-甲酸乙酯草酸
将丙酸(23mL,0.240mol)加入到NaBH4(3.03g,80.0mmol)在EtOAc(95mL)中的悬浮液中并将混合物在室温下搅拌1小时。将所得混合物在-20℃下加入到(2R)-5-[(苄基氧基)亚氨基]哌啶-2-甲酸乙酯(85%纯度,13.0g,40.0mmol)在EtOAc(95mL)和H2SO4(11mL,0.20mol)中的溶液中,在室温下搅拌60小时。将反应混合物用H2O(75mL)稀释并用NH4OH水溶液中和。分离有机层,用盐水洗涤,经Na2SO4干燥,并在真空中浓缩至~75mL体积。将溶液加热至45℃,加入MeOH(30mL),然后加入草酸(3.60g,40.0mmol)的MeOH(15mL)溶液。将混合物冷却至0℃,通过真空过滤分离所得沉淀物,用MeOH:EtOH(1:4)和EtOAc洗涤,得到标题化合物(7.17g,19.1mmol,48%产率);1H NMR(500MHz,DMSO-d6)δ7.25–7.42(m,5H),4.59(s,2H),4.17–4.24(m,2H),3.92(dd,J=12.3,3.2Hz,1H),3.34–3.40(m,1H),3.10(ddd,J=15.1,7.6,3.9Hz,1H),2.64(t,J=11.5Hz,1H),2.13(dt,J=10.2,3.4Hz,1H),1.87(dd,J=9.0,3.8Hz,1H),1.65(qd,J=13.2,3.6Hz,1H),1.40(qd,J=12.8,3.9Hz,1H),1.23(t,J=7.1Hz,3H);M/Z:279,[M+H]+,ESI+,RT=0.81(S1)。
中间体2(步骤2.d):(2R,5S)-5-[(苄基氧基)氨基]哌啶-1,2-二甲酸1-叔丁酯2-乙酯
在0℃下向(2R,5S)-5-[(苄基氧基)氨基]哌啶-2-甲酸乙酯草酸(2.22g,6.03mmol)在无水DCM(30mL)中的溶液中加入Et3N(3.6mL,25.8mmol)、DMAP(76mg,0.622mmol)和Boc2O(4.2mL,18.3mmol)并将混合物在室温下搅拌17小时。反应混合物用饱和NH4Cl水溶液和DCM稀释,分离有机层,用H2O和盐水洗涤,用Na2SO4干燥,并在真空中浓缩。通过硅胶色谱法(0-20%EtOAc/庚烷)纯化残余物,得到标题化合物(86%纯度,1.40g,3.18mmol,53%产率),为无色油;1H NMR(500MHz,CDCl3)δ7.40–7.26(m,5H),5.51–5.41(m,1H),4.92–4.80(m,1H),4.79–4.62(m,2H),4.19(q,J=7.0Hz,3H),3.11(d,J=45.4Hz,2H),1.96(s,2H),1.73–1.60(m,1H),1.55–1.49(m,1H),1.46(s,9H),1.27(t,J=7.1Hz,3H);M/Z:379,[M+H]+,ESI+,RT=1.09(S2)。
路线3的方案
步骤3.a:(2R,5S)-5-氨基哌啶-1,2-二甲酸1-叔丁酯2-乙酯
在N2下向(2R,5S)-5-[(苄基氧基)氨基]哌啶-1,2-二甲酸1-叔丁酯2-乙酯(93%纯度,8.7g,21.3mmol,中间体2)在无水EtOH(200mL)中的溶液中加入Pd/C(10%,2.28g,2.14mmol)并将混合物在H2下在室温下搅拌17小时。将反应混合物通过硅藻土垫过滤并将滤液真空浓缩。使用SCX-2柱纯化残余物,首先用MeOH冲洗,然后用3MNH3/MeOH洗脱,得到标题化合物(4.88g,17.0mmol,80%产率),为淡黄色油;1H NMR(400MHz,CDCl3)δ4.98–4.57(m,1H),4.18(q,J=7.1Hz,2H),3.87–3.64(m,1H),3.35–2.99(m,2H),2.14–1.92(m,2H),1.64–1.52(m,2H),1.45(s,11H),1.26(t,J=7.1Hz,3H)。
步骤3.b:(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]哌啶-1,2-二甲酸1-叔丁酯2-乙酯
在0℃向DCM(170mL)中的(2R,5S)-5-氨基哌啶-1,2-二甲酸1-叔丁酯2-乙酯(4.88g,17.0mmol)和Et3N(14mL,0.103mol)的混合物滴加2-(4-氯-3-氟-苯氧基)乙酰氯(4.19g,18.8mmol,中间体1)在DCM(10mL)中的溶液并在室温下搅拌48h。将反应混合物用DCM(250mL)稀释并用饱和NaHCO3水溶液(2×100mL)和盐水(100mL)洗涤,经Na2SO4干燥并在真空中浓缩。通过硅胶色谱法(0-50%EtOAc/庚烷)纯化残余物,得到标题化合物(7.14g,15.6mmol,91%产率),为无色油;1H NMR(400MHz,CDCl3)δ7.32(t,J=8.6Hz,1H),6.86–6.72(m,2H),6.69–6.63(m,1H),4.98–4.66(m,1H),4.45(s,2H),4.29–4.13(m,3H),4.09–3.87(m,1H),3.33–3.10(m,1H),2.23–2.02(m,1H),2.00–1.71(m,2H),1.56(s,1H),1.44(s,9H),1.28(t,J=7.2Hz,3H);M/Z:459,461[M+H]+,ESI+,RT=3.83(S4)。
中间体3(步骤3.c):(2R,5S)-1-[(叔丁氧基)羰基]-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]哌啶-2-甲酸
将LiOH(0.78g,31.1mmol)添加到(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]哌啶-1,2-二甲酸1-叔丁酯2-乙酯(7.1g,15.6mmol)在EtOH(80mL)和H2O(20mL)中的溶液中,并将混合物在室温搅拌3h。将反应混合物真空浓缩,溶解于H2O(50mL)中,并用DCM(2×100mL)萃取。然后使用2M盐酸水溶液将水层酸化至pH 2,并用EtOAc(3×100mL)萃取。将合并的有机萃取物用盐水(100mL)洗涤,经无水Na2SO4干燥,并在真空中浓缩以提供标题化合物(87%纯度,5.60g,11.3mmol,73%产率),为白色固体;1H NMR(400MHz,DMSO-d6)δ8.02(d,J=7.3Hz,1H),7.47(t,J=8.9Hz,1H),7.03(dd,J=11.4,2.8Hz,1H),6.83–6.75(m,1H),4.59–4.54(m,2H),3.93(s,1H),3.73(d,J=54.2Hz,1H),3.13–2.94(m,1H),2.06–1.87(m,2H),1.61(d,J=12.2Hz,1H),1.56–1.43(m,1H),1.37(s,10H);M/Z:429,431
[M+H]+,ESI+,RT=0.91min(S1)。
表1中的中间体是根据如中间体3所示例的通用路线3使用相应的起始原料合成的。
表1
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路线4的方案
步骤4.a:(1-二苯甲基氮杂环丁烷-3-基)甲磺酸酯
向1-(二苯基甲基)氮杂环丁烷-3-醇(500mg,2.09mmol)在无水DCM(5mL)中的溶液中加入MsCl(0.19mL,2.51mmol),然后加入DIPEA(0.55mL,3.13mmol),将混合物在室温搅拌30分钟。将反应混合物用H2O(20mL)稀释,分离水相并用DCM(2×20mL)萃取。合并有机相,用盐水洗涤,使用分相柱干燥并真空浓缩得到标题化合物(738mg,2.05mmol,98%产率),为黄色固体;1H NMR(400MHz,CDCl3)δ7.44–7.39(m,4H),7.33–7.27(m,4H),7.24–7.19(m,2H),5.18–5.09(m,1H),4.52–4.44(m,1H),3.80–3.68(m,2H),3.35–3.20(m,2H),2.99(s,3H).M/Z:318[M+H]+,ESI+,RT=0.66(S2)。
步骤4.b:1-二苯甲基-3-[2-(三氟甲氧基)乙氧基]氮杂环丁烷
将(1-二苯甲基氮杂环丁烷-3-基)甲磺酸酯(590mg,1.64mmol)和2-(三氟甲氧基)乙醇(0.80mL,8.18mmol)在无水甲苯(0.6mL)中的溶液在110℃在微波小瓶中照射30分钟。反应混合物用EtOAc(10mL)稀释,有机层用H2O(10mL)和饱和NaHCO3水溶液(10mL)洗涤。有机层经MgSO4干燥,真空浓缩,并通过硅胶色谱法纯化(5-100%EtOAc/庚烷),得到标题化合物(140mg,0.319mmol,19%产率),为粘稠的橙色油;M/Z:352[M+H]+,ESI+,RT=0.70(S2)。
中间体5(步骤4.c):3-[2-(三氟甲氧基)乙氧基]氮杂环丁烷;盐酸盐
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在0℃下,将氯甲酸1-氯乙酯(0.038mL,0.351mmol)添加到1-二苯甲基-3-[2-(三氟甲氧基)乙氧基]氮杂环丁烷(140mg,0.319mmol)的无水DCM(2.5mL)溶液中并将混合物在室温下搅拌1小时。加入无水EtOH(2.5mL),并将所得混合物在45℃下搅拌1小时。然后将混合物冷却至室温并搅拌过夜。加入第二份氯甲酸1-氯乙酯(0.017mL,0.159mmol),并将反应混合物在室温下搅拌6小时。真空除去溶剂并将所得残余物溶解于无水DCM(2.5mL)中并加入TFA(0.24mL,3.19mmol)。将反应在室温下搅拌3小时,然后真空浓缩,得到标题化合物(270mg,0.183mmol,57%产率),为橙色油;M/Z:186[M+H]+,ESI+,RT=0.33(S2)。
路线5的方案
步骤5.a:2-[2-(三氟甲氧基)乙氧基]-2,3-二氢-1H-异吲哚-1,3-二酮
在0℃向2-(三氟甲氧基)乙醇(350mg,2.69mmol)、2-羟基-2,3-二氢-1H-异吲哚-1,3-二酮(461mg,2.83mmol)和PPh3(776mg,2.96mmol)在无水THF(17.5mL)中的溶液中加入DIAD(556μL,2.83mmol)并将混合物在室温下搅拌3h。将反应混合物真空浓缩,残余物通过硅胶色谱法纯化(10-100%EtOAc/庚烷),得到标题化合物(770mg,2.66mmol,99%产率),为白色固体;1H NMR(500MHz,CDCl3)δ7.88–7.84(m,2H),7.79–7.75(m,2H),4.48–4.44(m,2H),4.36–4.31(m,2H);M/Z:276[M+H]+,ESI+,RT=3.00(S4)。
中间体6(步骤5.b):O-[2-(三氟甲氧基)乙基]羟胺
向2-[2-(三氟甲氧基)乙氧基]-2,3-二氢-1H-异吲哚-1,3-二酮(770mg,2.66mmol)在DCM(15mL)中的溶液中加入MeNHNH2(122mg,2.66mmol)并将混合物在室温下搅拌1小时。通过真空过滤除去所得沉淀物并将滤液真空浓缩(35℃,700毫巴),得到标题化合物(41%纯度,905mg,2.56mmol,96%产率),为淡黄色油;1H NMR(400MHz,DMSO-d6)δ6.12(s,2H),4.22–4.17(m,2H),3.76–3.69(m,2H)。
路线6的方案
步骤6.a:N-[3-(三氟甲氧基)环戊基]氨基甲酸苄酯
在室温,在氮气下,在盖上箔的烧瓶中,将2-氟吡啶(0.73mL,8.50mmol)和TMS-CF3(1.3mL,8.50mmol)添加到外消旋-N-[(1S*,3S*)-3-羟基环戊基]氨基甲酸苄基酯(1.00g,4.25mmol)、AgSO3CF3(2.19g,8.50mmol)、Selectfluor(2.26g,6.38mmol)和KF(0.74g,12.8mmol)在EtOAc(20mL)中的溶液中,并将混合物在室温下搅拌6天。将反应混合物通过硅藻土垫过滤并用EtOAc(100mL)洗涤,然后真空浓缩得到橙棕色油。
在室温,在氮气下,在盖上箔的烧瓶中,将2-氟吡啶(0.73mL,8.50mmol)和TMS-CF3(1.3mL,8.50mmol)添加到外消旋-N-[(1S*,3R*)-3-羟基环戊基]氨基甲酸苄基酯(1.00g,4.25mmol)、AgSO3CF3(2.19g,8.50mmol)、Selectfluor(2.26g,6.38mmol)和KF(0.74g,12.8mmol)在EtOAc(20mL)中的溶液中,并将混合物在室温下搅拌6天。将反应混合物通过硅藻土垫过滤并用EtOAc(100mL)洗涤,然后真空浓缩得到橙棕色油。
将来自两个反应的粗物质合并并通过硅胶FCC纯化(0–100%EtOAc/庚烷),得到标题化合物,为四种异构体的混合物(90%纯度,1.60g,4.75mmol,56%产率)为无色油;1HNMR(500MHz,DMSO-d6)δ7.43(dd,J=18.2,7.1Hz,1H),7.39–7.29(m,6H),5.01(s,2H),4.91(tt,J=6.4,3.4Hz,1H),4.83–4.76(m,1H),4.05–3.96(m,1H),3.83(h,J=7.5Hz,1H),2.35(dt,J=14.4,7.4Hz,1H),2.16–1.79(m,7H),1.78–1.53(m,3H),1.47(ddt,J=13.0,8.9,6.5Hz,1H);M/Z:304[M+H]+,ESI+,RT=0.97(S2)。
中间体7(步骤6.b):3-(三氟甲氧基)环戊烷-1-胺盐酸盐
将Pd/C(10%,253mg,0.237mmol)添加到圆底烧瓶中,将烧瓶抽真空并用氮气吹扫五次。添加N-[3-(三氟甲氧基)环戊基]氨基甲酸苄基酯(90%纯度,1.60g,4.75mmol)/EtOH(15mL),然后添加12MHCl(0.40mL,4.75mmol)。将烧瓶抽真空并用氮气吹扫五次,然后用H2吹扫和抽真空五次。将反应置于H2下并在室温下搅拌20小时。反应混合物通过硅藻土过滤,滤液在真空中浓缩,得到标题化合物(75%纯度,0.42g,1.51mmol,32%产率),为黄色油;1HNMR(500MHz,DMSO-d6)δ4.97(tt,J=6.4,3.6Hz,1H),4.81(p,J=6.1,5.5Hz,1H),3.55(dt,J=13.4,7.1Hz,1H),3.34(p,J=7.2Hz,1H),2.38(dt,J=14.2,7.3Hz,1H),2.18(dq,J=14.6,6.7Hz,1H),2.11–1.82(m,2H),1.82–1.71(m,1H),1.69–1.45(m,1H);M/Z:170[M+H]+,ESI+(S4)。
路线7的方案
实施例1(步骤7.a):(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[3-(三氟甲氧基)丙基]氨基甲酰基}哌啶-1-甲酸叔丁酯
向(2R,5S)-1-[(叔丁氧基)羰基]-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]哌啶-2-甲酸(100mg,0.220mmol,中间体3)在DMSO(1.5mL)中的溶液中加入DIPEA(120μL,0.661mmol)和HATU(101mg,0.265mmol),并将混合物在室温下搅拌10分钟。然后加入3-(三氟甲氧基)丙-1-胺盐酸盐(48mg,0.265mmol)并将混合物在室温下搅拌1h。将反应混合物用ACN/H2O(3:2,1.5mL)稀释并通过制备HPLC(方法4)纯化,得到标题化合物(97mg,0.174mmol,79%产率),为无色玻璃状;M/Z:456.2,458.3[M-BOC+H]+,ESI+,RT=1.01(S2)。
实施例2(步骤7.b):(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[3-(三氟甲氧基)丙基]哌啶-2-甲酰胺盐酸盐
向(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[3-(三氟甲氧基)丙基]氨基甲酰基}哌啶-1-甲酸叔丁酯(97mg,0.174mmol,实施例1)在无水1,4-二噁烷(3mL)中的溶液加入在1,4-二噁烷(1.0mL,4.00mmol)中的4M HCl,并将混合物在室温下搅拌16h。将反应混合物真空浓缩得到标题化合物(89mg,0.174mmol,99%产率),为白色粉末;1HNMR(500MHz,DMSO-d6)δ9.42–8.89(m,2H),8.58(s,1H),8.24(s,1H),7.51(t,J=8.9Hz,1H),7.09(dd,J=11.3,2.8Hz,1H),6.92–6.82(m,1H),4.55(s,2H),4.15–4.09(m,2H),4.08–4.01(m,1H),3.77–3.68(m,1H),3.27–3.18(m,3H),2.89–2.76(m,1H),2.22–2.13(m,1H),1.97–1.88(m,1H),1.88–1.80(m,2H),1.70–1.50(m,2H);M/Z:456.2,458.2[M+H]+,ESI+,RT=2.03(S4)。
路线8的方案
实施例3(步骤8.a):(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-({[4-(三氟甲基)苯基]甲基}氨基甲酰基)哌啶-1-甲酸叔丁酯
向(2R,5S)-1-[(叔丁氧基)羰基]-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]哌啶-2-甲酸(200mg,0.464mmol,中间体3)在无水DMF(2.5mL)中的溶液中加入DIPEA(163μL,0.933mmol)和HATU(194mg,0.510mmol)并将混合物在室温下搅拌10分钟。加入1-[4-(三氟甲基)苯基]甲胺(73μL,0.512mmol),并将混合物在室温下搅拌4小时。反应混合物用EtOAc(20mL)和H2O(10mL)稀释。分离有机层,用盐水(2×10mL)洗涤,用MgSO4干燥,真空浓缩得到标题化合物(341mg,99%产率,80%纯度),为橙色固体;M/Z:488,490[M+H]+,ESI+,RT=1.13(S2)。该化合物无需进一步纯化即继续使用。
实施例4(步骤8.b):(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-{[4-(三氟甲基)苯基]甲基}哌啶-2-甲酰胺
在0℃下向(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-({[4-(三氟甲基)苯基]甲基}氨基甲酰基)哌啶-1-甲酸叔丁酯(80%纯度,341mg,0.464mmol,实施例3)在DCM(3mL)中的溶液中添加TFA(350μL,4.71mmol),并将混合物在室温下搅拌4小时。将反应混合物用DCM(10mL)稀释并用饱和NaHCO3水溶液(3×10mL)洗涤。使用相分离柱干燥有机层并真空浓缩。残余物通过制备HPLC(方法4)纯化,得到标题化合物(119mg,0.244mmol,53%产率),为白色粉末;1H NMR(500MHz,DMSO-d6)δ8.35(t,J=6.2Hz,1H),7.92(d,J=8.1Hz,1H),7.67(d,J=8.1Hz,2H),7.52–7.42(m,3H),7.06(dd,J=11.4,2.8Hz,1H),6.85(ddd,J=9.0,2.8,1.1Hz,1H),4.53–4.47(m,2H),4.34(d,J=6.1Hz,2H),3.70–3.60(m,1H),3.08–3.00(m,1H),3.00–2.91(m,1H),2.47–2.41(m,1H),2.38–2.30(m,1H),1.93–1.79(m,2H),1.48–1.32(m,2H);M/Z:488,490[M+H]+,ESI+,RT=2.18(S4)。
表2中的实施例化合物是根据如实施例4所示例的通用路线8使用相应的中间体合成的。编号实施例的相应的boc保护的中间体也是本发明的实施例。
表2
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路线9的方案
实施例7(步骤9.a):(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-[(4-氯苯基)氨基甲酰基]哌啶-1-甲酸叔丁酯
向(2R,5S)-1-[(叔丁氧基)羰基]-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]哌啶-2-甲酸(90%纯度,200mg,0.418mmol,中间体3)、T3P(50%/EtOAc,0.30mL,0.501mmol)和DIPEA(150μL,0.836mmol)在EtOAc(5mL)中的溶液中加入4-氯苯胺(53mg,0.418mmol)并在80℃下搅拌1小时。添加更多部分的T3P(50%/EtOAc,99μL,0.167mmol)和DIPEA(58μL,0.334mmol),并将混合物在80℃下搅拌1.5小时。将反应混合物冷却至室温,用H2O(20mL)稀释,并用EtOAc(3×20mL)萃取。合并的有机萃取物用盐水洗涤,经MgSO4干燥,并在真空中浓缩以提供标题化合物(70%纯度,245mg,0.317mmol,76%产率),为无色油;M/Z:440,442,444[M-Boc+H]+,ESI+,RT=1.06(S2)。产物未经进一步纯化即以粗品使用。
实施例8(步骤9.b):(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-(4-氯苯基)哌啶-2-甲酰胺
向(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-[(4-氯苯基)氨基甲酰基]哌啶-1-甲酸叔丁酯(70%纯度,245mg,0.317mmol,实施例7)在无水1,4-二噁烷(1mL)中的溶液中加入4M HCl/1,4-二噁烷(0.79mL,3.17mmol),并将混合物在室温下搅拌2h。将反应混合物真空浓缩并将残余物通过制备HPLC(方法1),然后通过制备HPLC(方法3)纯化,得到标题化合物(21mg,0.0471mmol,15%产率),为白色固体;1H NMR(400MHz,DMSO-d6)δ9.70(s,1H),7.82(d,J=8.0Hz,1H),7.71–7.63(m,2H),7.48(t,J=8.9Hz,1H),7.36–7.28(m,2H),7.06(dd,J=11.4,2.8Hz,1H),6.86(ddd,J=9.0,2.8,1.1Hz,1H),4.51(s,2H),3.73–3.63(m,1H),3.08–3.00(m,1H),2.46–2.36(m,2H),1.99–1.85(m,2H),1.55–1.41(m,2H);M/Z:440,442,444[M+H]+,ESI+,RT=2.24(S4)。
表3中的实施例化合物是根据如实施例8所示例的通用路线9使用相应的中间体合成的。编号实施例的相应的boc保护的中间体也是本发明的实施例。
表3
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路线10的方案
实施例10:(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-苯基哌啶-2-甲酰胺
向(2R,5S)-1-[(叔丁氧基)羰基]-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]哌啶-2-甲酸(100mg,0.232mmol,中间体3)在无水1,4-二噁烷(2.5mL)中的溶液中加入HATU(88mg,0.232mmol)和DIPEA(81μL,0.464mmol),并在室温下搅拌45分钟。加入苯胺(163μL,0.232mmol),并将混合物在室温下搅拌4小时。将反应混合物冷却至0℃并在N2吹扫下逐滴加入4M HCl/1,4-二噁烷(1.0mL,4.00mmol)。将混合物在室温下搅拌2小时,用EtOAc(10mL)稀释并用H2O(5mL)洗涤。将有机萃取物用饱和NaHCO3水溶液洗涤,用MgSO4干燥,并在真空中浓缩。残余物通过制备HPLC(方法4)纯化,得到标题化合物(12mg,0.030mmol,13%产率),为白色固体;1H NMR(500MHz,DMSO-d6)δ9.66(s,1H),7.94(d,J=8.2Hz,1H),7.64(d,J=7.6Hz,2H),7.51(t,J=8.9Hz,1H),7.36–7.24(m,2H),7.14–6.97(m,2H),6.90–6.79(m,1H),4.52(s,2H),3.78–3.60(m,1H),3.23–3.14(m,1H),3.12–2.94(m,1H),2.45–2.38(m,2H),2.00–1.86(m,2H),1.47(t,J=10.0Hz,2H);M/Z:406,408[M+H]+,ESI+,RT=3.10(S6)。
表4中的实施例化合物是根据如实施例10所示例的通用路线10使用相应的中间体合成的。编号实施例的相应的boc保护的中间体也是本发明的实施例。
表4
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路线11的方案
实施例32(步骤11.a):(2R,5S)-2-[[3,5-双(三氟甲基)苯基]氨基甲酰基]-5-[[2-(4-氯-3-氟-苯氧基)乙酰基]氨基]哌啶-1-甲酸叔丁酯
在0℃下向(2R,5S)-1-[(叔丁氧基)羰基]-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]哌啶-2-甲酸(200mg,0.441mmol,中间体3)在无水DCM(4mL)中的溶液中加入3,5-双(三氟甲基)苯胺(101mg,0.441mmol)、吡啶(178μL,2.20mmol),然后加入POCl3(101mg,0.661mmol),并将混合物在室温下搅拌18小时。将反应混合物用DCM(6mL)稀释,冷却至0℃,然后在0℃小心滴加到饱和NaHCO3水溶液(12mL)中。将所得溶液升温至室温,同时搅拌1小时。使用分相柱分离有机层,然后真空浓缩,得到标题化合物(70%纯度,312mg,0.340mmol,77%产率),为橙色固体;M/Z:488,490[M+H]+,RT=1.13(S2)。产物不经进一步纯化而继续使用。
实施例33(步骤11.b):(2R,5S)-N-[3,5-双(三氟甲基)苯基]-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]哌啶-2-甲酰胺
向(2R,5S)-2-[[3,5-双(三氟甲基)苯基]氨基甲酰基]-5-[[2-(4-氯-3-氟-苯氧基)乙酰基]氨基]哌啶-1-甲酸叔丁酯(70%纯度,312mg,0.340mmol,实施例32)在无水1,4-二噁烷(2mL)中的溶液中加入4MHCl/1,4-二噁烷(3.0mL,3.00mmol),并将混合物在室温下搅拌2小时。将反应混合物真空浓缩,残余物通过制备HPLC(方法3)纯化,得到标题化合物(106mg,0.196mmol,58%产率),为白色粉末;1H NMR(400MHz,DMSO-d6)δ10.67–10.11(m,1H),8.42(s,2H),7.96(d,J=8.1Hz,1H),7.75(s,1H),7.51(t,J=8.9Hz,1H),7.08(dd,J=11.4,2.8Hz,1H),6.87(ddd,J=9.0,2.8,1.1Hz,1H),4.53(s,2H),3.82–3.64(m,1H),3.25–3.19(m,1H),3.09–3.00(m,1H),2.45–2.38(m,1H),2.03–1.85(m,2H),1.57–1.41(m,2H);M/Z:542,544[M+H]+,ESI+,RT=2.61(S4)。
表5中的实施例化合物是根据如实施例33所示例的通用路线11使用相应的中间体合成的。编号实施例的相应的boc保护的中间体也是本发明的实施例。
表5
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路线12的方案
中间体8(步骤12.a):(2R,5S)-2-氨基甲酰基-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]哌啶-1-甲酸叔丁酯
将NMM(0.61mL,5.57mmol)和氯甲酸异丁酯(0.72mL,5.57mmol)添加到(2R,5S)-1-[(叔丁氧基)羰基]-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]哌啶-2-甲酸(中间体3,2.00g,4.64mmol)在无水THF(32mL)中的溶液中。20分钟后,加入NH4OH(35%,0.51mL,9.28mmol),并将混合物在室温下搅拌2小时。将反应混合物真空浓缩并将所得残余物溶解于EtOAc(100mL)中并用H2O(50mL)洗涤。有机萃取物用MgSO4干燥并真空浓缩得到标题化合物(1.82g,4.02mmol,87%产率),为白色无定形固体;1H NMR(500MHz,CDCl3)δ7.32(t,J=8.6Hz,1H),6.89–6.64(m,3H),6.04(s,1H),5.51(s,1H),4.79(s,1H),4.50–4.40(m,2H),4.12(s,2H),3.12(d,J=13.6Hz,1H),2.21–2.15(m,1H),1.95–1.88(m,1H),1.71–1.63(m,2H),1.44(s,9H);M/Z:452,454[M+Na]+,ESI+,RT=0.82(S2)。
实施例48(步骤12.b):(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[2-(三氟甲基)嘧啶-4-基]氨基甲酰基}哌啶-1-甲酸叔丁酯
向(2R,5S)-2-氨基甲酰基-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]哌啶-1-甲酸叔丁酯(中间体8,129mg,0.300mmol)在无水1,4-二噁烷(2mL)中的溶液中加入4-溴-2-(三氟甲基)嘧啶(68mg,0.300mmol)、Pd2(dba)3(14mg,0.0150mmol)、tBuOK(47mg,0.420mmol)和XPhos(14mg,0.0300mmol)。将反应小瓶在N2下脱气,然后在微波辐射下于120℃加热2小时。将反应混合物用EtOAc(10mL)稀释并用H2O(2×10mL)洗涤。真空浓缩有机萃取物并通过硅胶FCC纯化(10-100%EtOAc/庚烷),得到标题化合物(50%纯度,68mg,0.0590mmol,20%产率),为黄色胶;M/Z:476,478[M-Boc+H]+,ESI+,RT=3.98(S4)。
实施例49(步骤12.c):(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[2-(三氟甲基)嘧啶-4-基]哌啶-2-甲酰胺
向(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[2-(三氟甲基)嘧啶-4-基]氨基甲酰基}哌啶-1-甲酸叔丁酯(实施例48,50%纯度,68mg,0.0590mmol)在无水1,4-二噁烷(0.6mL)中的溶液中加入4M HCl/1,4-二噁烷(1.2mL,5.00mmol)并在室温下搅拌过夜。将反应混合物用NaHCO3(15mL)猝灭并用EtOAc(2×15mL)洗涤。合并有机萃取物,经MgSO4干燥,并真空浓缩。残余物通过制备HPLC(方法3)纯化,得到标题化合物(9.0mg,0.0189mmol,32%产率),为白色粉末;1H NMR(400MHz,DMSO-d6)δ8.88(d,J=5.8Hz,1H),8.29(d,J=5.8Hz,1H),7.93(d,J=8.1Hz,1H),7.50(t,J=8.9Hz,1H),7.07(dd,J=11.4,2.9Hz,1H),6.85(ddd,J=8.9,1.8Hz,1H),4.51(s,2H),3.73–3.62(m,1H),3.43–3.37(m,2H),3.03–2.97(m,1H),2.40–2.35(m,1H),1.97–1.85(m,2H),1.49–1.43(m,2H),1.28–1.21(m,1H););M/Z:476,478[M+H]+,ESI+,RT=1.98(S4)。
路线13的方案
实施例50(步骤13.a):(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[6-(三氟甲基)吡嗪-2-基]氨基甲酰基}哌啶-1-甲酸叔丁酯
在小瓶A中装入Josiphos SL-J009-1(12mg,0.0221mmol)和Pd2(dba)3(10mg,0.0110mmol)。在小瓶B中装入(2R,5S)-2-氨基甲酰基-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]哌啶-1-甲酸叔丁酯(中间体8,95mg,0.220mmol)、tBuONa(42mg,0.441mmol)和2-溴-6-(三氟甲基)吡嗪(50mg,0.220mmol)。将两个小瓶密封并用N2吹扫。将脱气的DME(4mL)添加到小瓶A中,并将溶液搅拌5分钟以形成活性催化剂溶液。然后将此溶液添加到小瓶B中,并将混合物在100℃下搅拌18小时。将反应混合物冷却至室温,用H2O(10mL)稀释并用EtOAc(2×10mL)萃取。合并的有机萃取物用盐水(10mL)洗涤,经Na2SO4干燥并真空浓缩,得到标题化合物(34%纯度,160mg,0.0945mmol,43%产率),为棕色油;M/Z:476,478[M-Boc+H]+,ESI+,RT=1.05(S2)。
实施例51(步骤13.b):(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[6-(三氟甲基)吡嗪-2-基]哌啶-2-甲酰胺
向(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[6-(三氟甲基)吡嗪-2-基]氨基甲酰基}哌啶-1-甲酸叔丁酯(实施例50,34%纯度,160mg,0.0945mmol)在无水1,4-二噁烷(1mL)中的溶液中加入4M HCl/1,4-二噁烷(2.0mL,8.00mmol),混合物在室温下搅拌24小时。将反应混合物用NaHCO3(15mL)猝灭并用EtOAc(2×15mL)洗涤。合并的有机萃取物经MgSO4干燥,真空浓缩,并通过制备HPLC(方法3)纯化,得到标题化合物(26mg,0.0544mmol,58%产率),为黄色粉末;1H NMR(500MHz,DMSO-d6)δ9.62(s,1H),8.88(s,1H),7.94(d,J=8.2Hz,1H),7.50(t,J=8.9Hz,1H),7.07(dd,J=11.4,2.8Hz,1H),6.86(ddd,J=9.0,2.8,1.1Hz,1H),4.51(s,2H),3.73–3.65(m,1H),3.40(dd,J=10.2,2.9Hz,1H),3.01(dd,J=12.3,3.0Hz,1H),2.44–2.38(m,1H),2.00–1.86(m,2H),1.53–1.44(m,2H);M/Z:476,478[M+H]+,ESI+,RT=1.96(S4)。
路线14的方案
实施例52:(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-1-甲基-N-[6-(三氟甲基)吡嗪-2-基]哌啶-2-甲酰胺
向(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[6-(三氟甲基)吡嗪-2-基]哌啶-2-甲酰胺(实施例51,90%纯度,33mg,0.0624mmol)和K2CO3(17mg,0.125mmol)在DMF(1mL)中的溶液中添加MeI(3.5μL,0.0562mmol)并将混合物在室温下搅拌2h。将反应混合物用EtOAc(20mL)稀释并用H2O(10mL)洗涤。有机萃取物经MgSO4干燥,真空浓缩,并通过制备HPLC(方法3)纯化,得到标题化合物(18mg,0.0357mmol,57%产率),为白色无定形固体;1HNMR(500MHz,DMSO-d6)δ11.01(s,1H),9.63(s,1H),8.88(s,1H),8.03(d,J=8.2Hz,1H),7.50(t,J=8.9Hz,1H),7.08(dd,J=11.4,2.8Hz,1H),6.88–6.83(m,1H),4.52(s,2H),4.00–3.82(m,1H),2.94(dd,J=10.7,3.6Hz,1H),2.80(dd,J=10.8,2.8Hz,1H),2.17(s,3H),1.94–1.79(m,3H),1.76–1.64(m,1H),1.39–1.27(m,1H);M/Z:490,492[M+H]+,ESI+,RT=2.10(S4)。
路线15的方案
实施例53和54:(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰氨基]-N-[3-(三氟甲氧基)环戊基]哌啶-2-甲酰胺的手性分离(实施例47)
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰氨基]-N-[3-(三氟甲氧基)环戊基]哌啶-2-甲酰胺(148mg,实施例47)使用以下方法进行手性纯化:
纯化方法=90:10庚烷:EtOH+0.2%DEA;直链淀粉-2,21.2×250mm,5μm,18ml/min。样品稀释剂:MeOH,IPA。
接着是:
纯化方法=90:10庚烷:IPA;Chiralpak AD-H,20×250mm,5μm,18ml/min。样品稀释剂:MeOH、IPA。
这得到(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰氨基]-N-[(1S,3S)-3-(三氟甲氧基)环戊基]哌啶-2-甲酰胺(实施例53,4mg)和(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰氨基]-N-[(1R,3R)-3-(三氟甲氧基)环戊基]哌啶-2-甲酰胺(实施例54,18mg),以及两种异构体(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰氨基]-N-[(1R,3S)-3-(三氟甲氧基)环戊基]哌啶-2-甲酰胺和(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰氨基]-N-[(1S,3R)-3-(三氟甲氧基)环戊基]哌啶-2-甲酰胺,为白色粉末。任意归属每种化合物的戊基环中的立体化学。
表6中的实施例化合物是根据如实施例53和54所示例的通用路线15使用相应的中间体和方法手性纯化的。
表6
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II测定
HEK-ATF4高内涵成像测定
在HEK-ATF4高内涵成像测定中测试实施例化合物,以评估它们的阻止衣霉素诱导的ISR的药理学效力。将野生型HEK293细胞以每孔12,000个细胞的密度铺板于384-孔成像测定板中的生长培养基(含有DMEM/F12、10%FBS、2mM L-谷氨酰胺、100U/mL青霉素-100μg/mL链霉素)中并在37℃、5%CO2下温育。24小时后,将培养基更换为每孔50μL测定培养基(DMEM/F12、0.3%FBS、2mM L-谷氨酰胺、100U/mL青霉素-100μg/mL链霉素)。将实施例化合物在DMSO中连续稀释,点样至中间板中,并用含有3.3μM衣霉素的测定培养基预稀释,以产生最终测定浓度的11倍过量。除了实施例化合物测试区域之外,所述平板还含有多个用于测定归一化目的的对照孔、含有衣霉素但不含实施例化合物的孔(高对照)、以及既不含实施例化合物又不含衣霉素的孔(低对照)。通过将5μL从中间板转移进测定板中开始测定,随后在37℃、5%CO2下温育6小时。随后,将细胞固定(4%PFA/PBS,在室温20分钟)并进行间接ATF4免疫荧光染色(一级抗体兔抗ATF4,克隆D4B8,Cell Signaling Technologies;二级抗体Alexa Fluor 488山羊抗-兔IgG(H+L),Thermofisher Scientific)。使用Hoechst染料(Thermofisher Scientific)将细胞核染色,并在配备405nm和488nm激发的Opera PhenixHigh Content成像平台上对平板成像。最后,使用基于脚本的算法分析图像。主要读数HEK-ATF4监测细胞核和细胞质之间的ATF4信号比。衣霉素诱导总体ATF4比率信号的增加,这被调节ISR的实施例化合物所阻止。此外,将对应于健康细胞的染色细胞核的数目计数,衍生出HEK-CellCount读数。该读数充当内部毒性对照。本文的实施例化合物在CellCount中没有产生显著的减少。
测试的实施例化合物的HEK ATF4活性提供于如下表6中:
+++=IC50 1-500nM;++=IC50>500-2000nM;+=IC50>2000-15000nM。
表6
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Claims (29)
1.式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体
其中
R1为H或C1-4烷基,优选为H,其中C1-4烷基任选被一个或多个相同或不同的卤素取代;
R2为H、F或C1-4烷基,其中C1-4烷基任选被一个或多个相同或不同的卤素取代;
R2a为H或F,优选为H;
R3为苯基或6元芳族杂环基,其中R3任选被一个或多个相同或不同的R7取代;
R7为卤素、CN、C(O)OR8、OR8、C(O)R8、C(O)N(R8R8a)、S(O)2N(R8R8a)、S(O)N(R8R8a)、S(O)2R8、S(O)R8、N(R8)S(O)2N(R8aR8b)、SR8、N(R8R8a)、NO2、OC(O)R8、N(R8)C(O)R8a、N(R8)S(O)2R8a、N(R8)S(O)R8a、N(R8)C(O)OR8a、N(R8)C(O)N(R8aR8b)、OC(O)N(R8R8a)、C1-6烷基、C2-6烯基或C2-6炔基,其中C1-6烷基、C2-6烯基和C2-6炔基任选被一个或多个相同或不同的R9取代;
R8、R8a、R8b独立地选自H、C1-6烷基、C2-6烯基和C2-6炔基,其中C1-6烷基、C2-6烯基和C2-6炔基任选被一个或多个相同或不同的卤素取代;
R9是卤素、CN、C(O)OR10、OR10、C(O)R10、C(O)N(R10R10a)、S(O)2N(R10R10a)、S(O)N(R10R10a)、S(O)2R10、S(O)R10、N(R10)S(O)2N(R10aR10b)、SR10、N(R10R10a)、NO2、OC(O)R10、N(R10)C(O)R10a、N(R10)SO2R10a、N(R10)S(O)R10a、N(R10)C(O)N(R10aR10b)、N(R10)C(O)OR10a或OC(O)N(R10R10a);
R10、R10a、R10b独立地选自H、C1-6烷基、C2-6烯基和C2-6炔基,其中C1-6烷基、C2-6烯基和C2-6炔基任选被一个或多个相同或不同的卤素取代;
R4是H、C(O)OC1-4烷基或C1-4烷基,其中C(O)OC1-4烷基和C1-4烷基任选被一个或多个选自以下的取代基取代:卤素、OH和O-C1-3烷基,其中取代基相同或不同;
R4a、R4b、R4c、R4f独立地选自H、卤素和C1-4烷基;和
R4d、R4e独立地选自H、OH、OC1-4烷基、卤素和C1-4烷基;
或者R4d和R4e之一与R4形成亚甲基或亚乙基;
或者R4与R4c形成亚乙基;
或者R4b与R4d形成共价单键;
R5为H或C1-6烷基,其中C1-6烷基任选被一个或多个相同或不同的卤素取代;和
R6是R11;或者
R5和R6连接,与它们所连接的氮原子一起形成环A1;
R11为OR12、SR12a、N(R12R12a)、A2、C1-6烷基、C2-6烯基或C2-6炔基,其中C1-6烷基、C2-6烯基和C2-6炔基任选被一个或多个相同或不同的R13取代;
R12、R12a独立地选自H、C1-6烷基、C2-6烯基、C2-6炔基和A2,其中C1-6烷基、C2-6烯基和C2-6炔基任选被一个或多个相同或不同的R15取代;
R13为卤素、OR14、CN或A2;
R14为H或C1-4烷基,其中C1-4烷基任选被一个或多个相同或不同的卤素取代;
R15为卤素、CN、OR14、OA2或A2;
A1为3至7元杂环基或7至12元杂双环基,其中A1任选被一个或多个相同或不同的R16取代;
A2为苯基、萘基、C3-7环烷基、C4-12双环烷基、3至7元杂环基或7至12元杂双环基,其中A2任选被一个或多个相同或不同的R16a取代;
R16、R16a独立地选自R17、OH、OR17、卤素和CN;
R17为环丙基、C1-6烷基、C2-6烯基或C2-6炔基,其中R17任选被一个或多个相同或不同的R18取代;
R18为卤素、CN或OR19;
R19为H或C1-4烷基,其中C1-4烷基任选被一个或多个相同或不同的卤素取代;
前提是排除以下化合物:
2.根据权利要求1所述的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中R4为H、CH3、CH2CH3或CH2CH2OCH3;优选H或CH3;更优选H。
3.根据权利要求1或2所述的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中R4a、R4b、R4c、R4f独立地选自H、卤素和C1-4烷基并且R4d、R4e独立地选自H、OH、OC1-4烷基、卤素和C1-4烷基;优选R4a、R4b、R4c、R4f、R4d、R4e独立地选自H、F和CH3;更优选地,R4a、R4b、R4c、R4f、R4d、R4e是H。
4.根据权利要求1-3中任一项所述的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中R1是H或CH3;优选H。
5.根据权利要求1-4中任一项所述的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中R2是H、F或CH3,优选H。
6.根据权利要求1-5中任一项所述的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中式(I)中的R1、R2、R2a、R4、R4a、R4b、R4c、R4f、R4d、R4e是H,得到式(Ia)
7.根据权利要求1-6中任一项所述的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中R3是苯基或吡啶基,优选苯基,其中R3任选地被一个或多个相同或不同的R7取代。
8.根据权利要求1-7中任一项所述的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中R3被一个、两个或三个、优选一个或两个、更优选两个相同或不同的R7取代。
9.根据权利要求1-8中任一项所述的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中R7为F、Cl、Br、CN、CHF2、CF3、OCH3、OCF3、CH=O、CH2OH或CH3;优选R7是CF3、F或Cl;更优选F或Cl。
10.根据权利要求1-9中任一项所述的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中选择式(I)中的R1、R2、R2a、R4、R4a、R4b、R4c、R4f、R4d、R4e、R3得到式(Ib)
其中每个R7独立地选自卤素和CF3。
11.根据权利要求1-10中任一项所述的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中R5是H或CH3,优选H。
12.根据权利要求1-11中任一项所述的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中R6为R11且R11为C1-6烷基或C1-6烯基,其中C1-6烷基和C1-6烯基被一个或多个相同或不同的R13取代。
13.根据权利要求1-12中任一项所述的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中R6是R11并且R11是C1-6烷基,优选乙基或正丙基,其中C1-6烷基被一个R13取代。
14.根据权利要求1-13中任一项所述的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中R6是R11并且R11是乙基或正丙基,各自被一个R13取代,其中R13是OR14,优选OCF3。
15.根据权利要求1-12中任一项所述的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中R6为R11且R11为C1-6烷基,优选正丙基或正戊基,其中C1-6烷基被三个F取代;更优选R11是3,3,3-三氟丙基或5,5,5-三氟戊基。
16.根据权利要求1-12中任一项所述的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中R6为R11且R11为C1-6烷基,优选甲基,其中C1-6烷基被一个R13取代,其中R13为A2,优选苯基、吡啶基、吡唑基、噁唑基、环丁基、环己基、呋喃基、双环[3.1.0]己-3-基或6-氧杂螺[3.4]辛-7-基。
17.根据权利要求1-11中任一项所述的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中R6为R11且R11为A2,优选苯基、吡啶基、吡嗪基、嘧啶基、哒嗪基、苯并二氧杂环戊烯基、环己基、环戊基、环丁基、吡唑基、噁唑基或氧杂环戊烷基。
18.根据权利要求1-14、16和17中任一项所述的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中A2未被取代或被一个或两个R16a取代。
19.根据权利要求1-14和16-18中任一项所述的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中R16a是CH3、CHF2、CF3、CH2CF3、OCHF2、OCH2CF3、OCF3、OCH3、F或Cl。
20.根据权利要求1-10中任一项所述的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中R5和R6连接以与它们所连接的氮原子一起形成环A1。
21.根据权利要求20所述的化合物,其中A1为氮杂环丁烷、哌啶、氧氮杂环庚烷、二氢吲哚、异二氢吲哚、四氢异喹啉氮杂双环[3.1.0]己烷或氮杂螺[3.3]庚烷,以及其中A1任选被一个或多个相同或不同的R16取代。
22.根据权利要求20或21所述的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中A1未被取代或被一个R16取代。
23.根据权利要求20-22中任一项所述的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中R16是CF3、OCF3或OCH2CH2OCF3。
24.根据权利要求1-23中任一项所述的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中选择式(I)中的R1,R2,R2a,R3,R4,R4a,R4b,R4c,R4d,R4e,R4f,R5,R6得到
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[3-(三氟甲氧基)丙基]氨基甲酰基}哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[3-(三氟甲氧基)丙基]哌啶-2-甲酰胺盐酸盐;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-({[4-(三氟甲基)苯基]甲基}氨基甲酰基)哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-{[4-(三氟甲基)苯基]甲基}哌啶-2-甲酰胺;
2-(4-氯-3-氟苯氧基)-N-[(3S,6R)-6-{3-[2-(三氟甲氧基)乙氧基]氮杂环丁烷-1-羰基}哌啶-3-基]乙酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[2-(三氟甲氧基)乙氧基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-[(4-氯苯基)氨基甲酰基]哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-(4-氯苯基)哌啶-2-甲酰胺;
(2S,5R)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-(4-氯苯基)哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-苯基哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-(3-氯苯基)哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[3-(三氟甲基)苯基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[3-(三氟甲氧基)苯基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[(5-氯吡啶-2-基)甲基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[(1s,4s)-4-(三氟甲氧基)环己基]哌啶-2-甲酰胺;
(2R,5S)-N-(4-氯-2-甲氧基苯基)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-{[5-(三氟甲基)呋喃-2-基]甲基}哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-{[4-(三氟甲基)呋喃-2-基]甲基}哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-{[(1s,4s)-4-(三氟甲基)环己基]甲基}哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-(3-甲氧基苯基)哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[4-氟-3-(三氟甲基)苯基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[5-(三氟甲基)吡啶-3-基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-(3-氟苯基)哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[3-(二氟甲基)苯基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-(5-氯吡啶-2-基)哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[5-甲基-1-(2,2,2-三氟乙基)-1H-吡唑-4-基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[(1s,3s)-3-(三氟甲氧基)环丁基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-(3,5-二甲基苯基)哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-(5,5,5-三氟戊基)哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[3-(二氟甲氧基)苯基]哌啶-2-甲酰胺;
(2S,5R)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[3-(三氟甲基)苯基]哌啶-2-甲酰胺;
(2R,5S)-2-[[3,5-双(三氟甲基)苯基]氨基甲酰基]-5-[[2-(4-氯-3-氟-苯氧基)乙酰基]氨基]哌啶-1-甲酸叔丁酯;
(2R,5S)-N-[3,5-双(三氟甲基)苯基]-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[1-(三氟甲基)-1H-吡唑-3-基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[2-氟-5-(三氟甲基)苯基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[2-氟-3-(三氟甲基)苯基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[6-(三氟甲氧基)吡啶-2-基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[4-(三氟甲基)吡啶-2-基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{3-[2-(三氟甲氧基)乙氧基]氮杂环丁烷-1-羰基}哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[2-(三氟甲氧基)乙氧基]氨基甲酰基}哌啶-1-甲酸叔丁酯;
(2S,5R)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-[(4-氯苯基)氨基甲酰基]哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-(苯基氨基甲酰基)哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-[(3-氯苯基)氨基甲酰基]哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[3-(三氟甲基)苯基]氨基甲酰基}哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[3-(三氟甲氧基)苯基]氨基甲酰基}哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[(5-氯吡啶-2-基)甲基]氨基甲酰基}哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[(1s,4s)-4-(三氟甲氧基)环己基]氨基甲酰基}哌啶-1-甲酸叔丁酯;
(2R,5S)-2-[(4-氯-2-甲氧基苯基)氨基甲酰基]-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-({[5-(三氟甲基)呋喃-2-基]甲基}氨基甲酰基)哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-({[4-(三氟甲基)呋喃-2-基]甲基}氨基甲酰基)哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-({[(1s,4s)-4-(三氟甲基)环己基]甲基}氨基甲酰基)哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-[(3-甲氧基苯基)氨基甲酰基]哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[4-氟-3-(三氟甲基)苯基]氨基甲酰基}哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[5-(三氟甲基)吡啶-3-基]氨基甲酰基}哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-[(3-氟苯基)氨基甲酰基]哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[3-(二氟甲基)苯基]氨基甲酰基}哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-[(5-氯吡啶-2-基)氨基甲酰基]哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[5-甲基-1-(2,2,2-三氟乙基)-1H-吡唑-4-基]氨基甲酰基}哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[(1s,3s)-3-(三氟甲氧基)环丁基]氨基甲酰基}哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-[(3,5-二甲基苯基)氨基甲酰基]哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-[(5,5,5-三氟戊基)氨基甲酰基]哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[3-(二氟甲氧基)苯基]氨基甲酰基}哌啶-1-甲酸叔丁酯;
(2S,5R)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[3-(三氟甲基)苯基]氨基甲酰基}哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[1-(三氟甲基)-1H-吡唑-3-基]氨基甲酰基}哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[2-氟-5-(三氟甲基)苯基]氨基甲酰基}哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[2-氟-3-(三氟甲基)苯基]氨基甲酰基}哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[6-(三氟甲氧基)吡啶-2-基]氨基甲酰基}哌啶-1-甲酸叔丁酯;或
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[4-(三氟甲基)吡啶-2-基]氨基甲酰基}哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-(2,2-二氟-2H-1,3-苯并二氧杂环戊烯-5-基)哌啶-2-甲酰胺;
2-(4-氯-3-氟苯氧基)-N-[(3S,6R)-6-[5-(三氟甲基)-2,3-二氢-1H-异吲哚-2-羰基]哌啶-3-基]乙酰胺;
2-(4-氯-3-氟苯氧基)-N-[(3S,6R)-6-[5-(三氟甲氧基)-2,3-二氢-1H-异吲哚-2-羰基]哌啶-3-基]乙酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-{[1-甲基-5-(三氟甲基)-1H-吡唑-3-基]甲基}哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-{[5-(三氟甲基)-1,2-噁唑-3-基]甲基}哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-{[4-(三氟甲基)吡啶-2-基]甲基}哌啶-2-甲酰胺;
2-(4-氯-3-氟苯氧基)-N-[(3S,6R)-6-[4-(三氟甲基)-2,3-二氢-1H-吲哚-1-羰基]哌啶-3-基]乙酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[1-(2,2-二氟环丙基)-1H-吡唑-3-基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[3-(三氟甲氧基)环戊基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[2-(三氟甲基)嘧啶-4-基]氨基甲酰基}哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[2-(三氟甲基)嘧啶-4-基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[6-(三氟甲基)吡嗪-2-基]氨基甲酰基}哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[6-(三氟甲基)吡嗪-2-基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-1-甲基-N-[6-(三氟甲基)吡嗪-2-基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[(1S,3S)-3-(三氟甲氧基)环戊基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-N-[(1R,3R)-3-(三氟甲氧基)环戊基]哌啶-2-甲酰胺;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-[(2,2-二氟-2H-1,3-苯并二氧杂环戊烯-5-基)氨基甲酰基]哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-[5-(三氟甲基)-2,3-二氢-1H-异吲哚-2-羰基]哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-[5-(三氟甲氧基)-2,3-二氢-1H-异吲哚-2-羰基]哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-({[1-甲基-5-(三氟甲基)-1H-吡唑-3-基]甲基}氨基甲酰基)哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-({[5-(三氟甲基)-1,2-噁唑-3-基]甲基}氨基甲酰基)哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-({[4-(三氟甲基)吡啶-2-基]甲基}氨基甲酰基)哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-[4-(三氟甲基)-2,3-二氢-1H-吲哚-1-羰基]哌啶-1-甲酸叔丁酯;
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[1-(2,2-二氟环丙基)-1H-吡唑-3-基]氨基甲酰基}哌啶-1-甲酸叔丁酯;或
(2R,5S)-5-[2-(4-氯-3-氟苯氧基)乙酰胺基]-2-{[3-(三氟甲氧基)环戊基]氨基甲酰基}哌啶-1-甲酸叔丁酯。
25.根据权利要求1-24中任一项所述的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中式(I)具有在式(Ic)中所示的立体化学
26.一种药物组合物,包含至少一种权利要求1-25中任一项所述的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,以及药学上可接受的载体,任选地与一种或多种其它生物活性化合物或药物组合物组合。
27.根据权利要求1-25中任一项所述的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其用作药物。
28.根据权利要求1-25中任一项所述的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,或根据权利要求26的药物组合物,用于治疗或预防一种或多种与整合应激反应有关的疾病或障碍的方法中。
29.根据权利要求1-25中任一项所述的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,或根据权利要求26的药物组合物,用于治疗或预防一种或多种选自以下的疾病或障碍的方法中:脑白质营养不良,智力障碍综合征,神经变性疾病和障碍,肿瘤性疾病,感染性疾病,炎性疾病,肌肉骨骼疾病,代谢疾病,眼疾病以及选自器官纤维化、慢性和急性肝病、慢性和急性肺病、慢性和急性肾病、心肌梗塞、心血管疾病、心律失常、动脉粥样硬化、脊髓损伤、缺血性中风和神经性疼痛的疾病。
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MX (1) | MX2023004626A (zh) |
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2021
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WO2022084446A1 (en) | 2022-04-28 |
EP4232153A1 (en) | 2023-08-30 |
CA3195290A1 (en) | 2022-04-28 |
US20230391725A1 (en) | 2023-12-07 |
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